PMID- 25906529 TI - PUO--a rare (and forgotten) cause! AB - Splenic tuberculosis is an extremely rare clinical entity and a frequently forgotten cause of pyrexia of unknown origin (PUO). We present the case of a 42 year old man who presented with fever of unknown origin. Ultrasonography revealed multiple hypoechoic areas within the spleen. As the abscesses did not respond to broad spectrum antibiotics splenectomy was done. The excised organ showed multiple cysts filled with pultaceous material. Histopathological examination revealed areas of granular caseating necrosis surrounded by epitheloid cells and Langhan's type giant cells consistent with splenic tuberculosis.There was no evidence of a primary focus in the lungs or in any other organ.The presence of isolated tubercular foci in the spleen without any evidence of tuberculosis in lung or other extra-pulmonary site prompted us to report this case. PMID- 25906530 TI - Multiple giant coronary arterial aneurysms following sirolimus drug eluting stents implantation. AB - Coronary artery aneurysm after coronary interventions are rare but variable (0.2% 1.7%) clinicopathological entity depending on whether a incidental or a routine 6 monthly angiographic follow up finding and is seen more common with drug eluting stents (DES) rather than bare metal stents (BMS). It is of three types and depending on the type and patient clinical response further strategy (conservative, covered stents or coronary artery bypass surgery) is decided. We report a patient with large type 2 coronary artery aneurysms post percutaneous coronary intervention (PCI) to the right coronary artery (RCA) and the Left anterior descending (LAD) coronary artery and presenting four months later. PMID- 25906531 TI - Dioctophymatosis renalis in humans: first case report from India. AB - Dioctophymatosis is an infestation by Dioctophyma renalis (the giant kidney worm), a relatively uncommon parasitic roundworm that infects carnivorous mammals. Since the early 1900s, dioctophymatosis has been confirmed in < 20 humans worldwide. A 70-year-old man attended our Hospital, complaining of having expelled 2 large worms while urination along with haematuria 2 days post admission. On MR UROGRAM we confirmed it as dioctophyma renale.wet mount preparation of urine under microscopy showed eggs specific for the parasite. On review of literature we found that this was the first case reported in india. PMID- 25906532 TI - Stroke in young with primary protein--S deficiency. AB - Stroke in young is a major health problem in developing countries along with CAD, according to various Indian studies its prevalence is 25-34%. Thrombophilic disorders constitute aetiology in 60% cases of stroke of undetermined aetiology. A 20 yrs old young female presented with symptoms of left PCA thrombosis (P2 syndrome), on evaluation--Isolated Protein--S deficiency is noticed. In this case Protein-S deficiency seems to be the only risk factor responsible for stroke. PMID- 25906533 TI - Dr. Madhusudan Mohanlal Desai. PMID- 25906534 TI - Emil Theodor Kocher. PMID- 25906535 TI - Pierre E Roux--Pasteur's assistant and a true savant. PMID- 25906536 TI - Newer cardiac biomarkers in myocardial necrosis. PMID- 25906537 TI - Metronidazole encephalopathy. PMID- 25906538 TI - Reply from author. PMID- 25906539 TI - Cutaneous ciliated cyst of right popliteal fossa. PMID- 25906540 TI - An unusual cause of upper gastrointestinal bleed. PMID- 25906541 TI - [Croatian guidelines for screening, prevention and treatment of protein-energy wasting in chronic kidney disease patients]. AB - There is a high incidence of cardiovascular morbidity and mortality among patients with chronic kidney disease (CKD) and malnutrition is a powerful predictor of cardiovascular morbidity and mortality in this population of patients. A multitude of factors related to CKD and renal replacement therapy can affect the nutritional status of CKD patients and lead to the development of malnutrition. In patients with CKD, protein energy wasting (PEW) is a condition that is distinct from undernutrition and is associated with inflammation, increased resting energy expenditure, low serum levels of albumin and prealbumin, sarcopenia, weight loss and poor clinical outcomes. Nutritional and metabolic derangements are implicated for the development of PEW in CKD and leading to the development of chronic catabolic state with muscle and fat loss. Prevention is the best way in treating PEW. Appropriate management of CKD patients at risk for PEW requires a comprehensive combination of strategies to diminish protein and energy depletion, and to institute therapies that will avoid further losses. The mainstay of nutritional treatment in MHD patients is nutritional counselling and provision of an adequate amount of protein and energy, using oral supplementation as needed. Intradialytic parenteral nutrition and total enteral nutrition should be attempted in CKD patients who cannot use the gastrointestinal tract efficiently. Other strategies such as anemia correction, treatment of secondary hyperparathyroidism and acidosis, delivering adequate dialysis dose can be considered as complementary therapies in CKD patients. Multidisciplinary work of nephrologists, gastroenterologist and dietician is needed to achieve best therapeutic goals in treating CKD patients with PEW. PMID- 25906542 TI - [Coarctation of the aorta in children in the 10-year epidemiological study: diagnostic and therapeutic consideration]. AB - Our study is a clinical epidemiological retrospective analysis of coarctation of the aorta in a 10-year follow-up (2001-2011). The study includes 201 children, 72 (35.82%) girls and 129 (64.18%) boys (1:1,6), with an average age of 28.57-49.37 mo (0.1-204 mo). They are categorized in 4 age groups: <1 month, 1 month - 1 year, 1 year - 6 years, >6 years. Isolated coarctation of the aorta was found in 125 (62.19%) patients; 33 (16.42%) preductal and 92 (45.77%) postductal. Coarctation of the aorta with an additional heart defect was found in 76 (37.81%) patients; 32 (15.32%) with ventricular septal defect, 28 (13.93%) within a complex heart defect, 11 (5.47%) within the Shone syndrome, and 5 (2.49%) with a dilated cardiomyopathy. Tiredness, intense tachypneic and dyspneic difficulties are dominant features in lower age groups (newborns and infants), while claudications, headaches and epistaxis are typical in older children. In the case of as many as 61 (30.35%) patients diagnosis was missed on the previous cardiological examination. In 20 (9.95%) patients coarctation is found within the known syndromes (Turner, Noonan, Williams Beuren, Ellis van Creveld, Down, partial trisomy 18, fetal valproate syndrome). Echocardiography was performed in all patients, and in 45 (22.38%) it was the only diagnos tic procedure. Altogether, 123 heart catheterizations, 38 multislice computed tomography and 15 magnetic resonance imagings were performed. The gradient on the place of coarctation before surgery or emergency procedures measured by catheter in 132 (65.67%) patients was 57.99 +/- 18.68 mmHg (20-100 mmHg). In 82 (40.80%) patients a bicuspid aortic valve was found. Average age at the time of surgery was 27.92 +/- 47.98 months (0.1-204 mo.). In 169 (84.07%) patients a cardiosurgical intervention was performed; 109 (54.23%) T-T anastomoses, 30 (14.29%) therapeutic catheterisations (balloon dilatation or stent implantation). Fatal outcome occurred in 4 (1.99%) children, all newborns or infants. PMID- 25906543 TI - [First report of carbapenemases in Osijek-Baranja County in imported Enterobacter cloacae isolate in vitro susceptible to carbapenems]. AB - Carbapenems are often the only therapeutic option to treat infections caused by multidrug-resistant Gram-negative bacteria. Emergence of carbapenemases in the isolates of Enterobacteriaceae limits therapeutic options. Carbapenem-resistant Enterobacteriaceae have emerged since 2008 throughout Croatia. In Osijek-Baranja County carbapenem-resistant strains of Enterobacteriaceae were not reported until 2013. The first carbapenem-resistant strain (Enterobacter cloacae) was identified in August 2013 in a patient previously hospitalized at University Hospital Center Zagreb for the treatment of acute lymphoblastic leukemia. Molecular analysis revealed the production of VIM-1 metallo-beta-lactamase (MBL). In spite of the metallo-beta-lactamase production the strain was not resistant to imipenem and meropenem in disk-diffusion and microdilution test. This report shows that routine susceptibility testing carried out in most laboratories does not necessarily detect carbapenemase production in Enterobacteriaceae. Since these enzymes are encoded on mobile genetic elements there is a risk of horizontal spread to other enterobacterial isolates and the development of hospital outbreaks. PMID- 25906544 TI - [Combined pulmonary fibrosis and emphysema syndrome]. AB - CPFE-combined pulmonary fibrosis and emphysema is a new term for a syndrome whose main characteristic is fibrosis in lower pulmonary lobes with simultaneous emphysema in upper pulmonary lobes. CPFE patients have well preserved pulmonary test values for unexpectedly long period, but extremely lowered carbon monoxide diffusion capacity and significant arterial hypertension. All CPFE studies indicate that CPFE occurs predominately in older male population. Smoking is considered main cause in developing CPFE. Reduced survival rate is linked with arterial hypertension extent, and mortality rate is greater than that for patients with isolated pulmonary fibrosis or emphysema. This study is focused on characteristics of twelve CPFE patients. This paper describes cases of 12 patients with the syndrome of pulmonary fibrosis associated with emphysema. All patients were male, mean age of 68 years. At the certain period of life they all were smokers, but most of them were also exposed to air pollution due to their profession. Shortness of breath on exertion was present in all patients. All patients had neat pulmonary function tests with significantly reduced diffusing capacity for carbon mon- oxide (average 39%). Pulmonary arterial hypertension (PAH) averaged 56 mmHg (range 25-75 mmHg) was present in 75% of patients. Four patients died during the period of four months, of which three patients had PAH greater than 70 mmHg. The fourth patient died of lung cancer. PMID- 25906545 TI - [A patient with rheumatoid arthritis and primary biliary cirrhosis successfully treated with adalimumab]. AB - Rheumatoid arthritis and primary biliary cirrhosis coexist in up to 6% of cases. Tumor necrosis factor alpha seems to have an important role in the pathogenesis of both diseases. Tumor necrosis factor alpha inhibitors have become an established therapeutic regimen for patients with rheumatoid arthritis. The only approved drug for primary biliary cirrhosis is ursodeoxycholic acid. We describe the case of a female patient with both rheumatoid arthritis and primary biliary cirrhosis in a long term remission of both diseases induced with adalimumab. This case report is an important addendum to a few published similar reports. PMID- 25906546 TI - [Clinical characteristics of patients with a double pylori]. AB - Double pylorus (DP), is a form of gastroduodenal fistula, which consists of a short accessory canal from the gastic antrum to the duodenal bulb, and mostly occrus in the background of peptic ulcer disease. Prevalence, as well long-term follow-up of patients with DP is less elucidated in western countries. Aim of our study was to analyse demografic, clinical and endoscopic characteristics in our case-series. During 2008-2013. a total of 23836 upper endoscopies were performed in 16759 patients. DP was diagnosed in 6 patients (prevalence of 0.04%). The follow-up period was f 8 to 72 months. In 87% DP was a complication of the upper gastrointestinal bleeding. In 83% cases opening of the fistula was on lesser curvature of gastric antrumu. During follow-up period the fistula healing did not occur in any of our patients. DP is a very rare entity, with a benign course of the disease Associated comorbidity and use of ulceriform medications plays important role in persistence of DP, wheras possible eradication of Helicobacter infection in this background remains elusive. PMID- 25906547 TI - [Hormone replacement therapy and venous thromboembolism]. AB - Venous thromboembolism (VTE) is the most important side effect of using hormone replacement therapy (HRT). Biological and epidemiological studies have shown that oral administration of estrogen is associated with an increased risk of VTE compared to transdermal route of administration. Addition of progestogen to estrogen further increases the risk of VTE. Different pharmacological classes of progestogens differently contribute to the risk of VTE. Observational studies observed that the application of micronized progesterone and didrogesteron are safer regarding the risk of VTE compared to other progestins. These results should be further confirmed in the randomized studies. A personal or family history of VTE, existence of hereditary thrombophilia or/and multiple risk factors for VTE represent a strong contraindication to oral HRT use. In such persons the application of transdermal estrogen can be considered after careful individual evaluation of the benefits and risks. Transdermal estrogen should be also the first choice in overweight/obese women requiring HRT. PMID- 25906548 TI - [Attachment and sexual self-views in shaping sexual and relationship satisfaction -review]. AB - Gradual demystification of sexuality, in lay as well as in scientific research terms, has resulted in an increased number of papers which examined the relationship between behavioral-motivational systems of attachment and sexuality over the past decade. Attachment theory was widely used in the studies of human behavior as well as cognitive and emotional characteristics underlying these behaviors. Attachment styles, as relatively stable lifetime patterns, partially determine sexual self-image, and moderate the degree of sexual and relationship satisfaction. Final understanding of these relations, although the subject of considerable research interest, is still missing. In this article, the researches examining the link between attachment and sexuality systems were presented, as well as contribution of those systems to sexual and relationship satisfaction in order to encourage further research in this important area of human life. PMID- 25906549 TI - [Usutu virus: a novel flavivirus in Croatia]. AB - Usutu virus (USUV) belongs to the family Flaviviridae, genus Flavivirus, Japanese encephalitis serocomplex. The virus was discovered in 1959 in South Africa and has emerged since 1996 causing epizootics with high avian mortality in Europe. The importance of USUV in humans is not fully understood. However, several human clinical cases of USUV infection described so far indicate the role of this virus as an antropozoonotic agent. In Croatia, serologic evidence of USUV was first documented in 2011 in two horses from Zagreb and Sisak-Moslavina County. In 2012, USUV neutralizing antibodies were found in one human sample from a resident of a Vukovar-Srijem County. Human clinical cases of USUV infection were detected for the first time during the West Nile virus outbreak from July to September 2013. Three patients with USUV neuroinvasive disease were detected in the City of Zagreb and Zagreb County. Our results indicate USUV circulation in Croatia. Further human cases could be expected in the next transmission seasons. PMID- 25906551 TI - [Croatian nationale programme of publicly available early defibrillation "Start the heart--save a life"]. PMID- 25906550 TI - [Abortion (ICD 040), call of conscience or the right of choice]. PMID- 25906552 TI - [Guidelines for the management of hyperglycaemia in hospitalised adult patients]. PMID- 25906553 TI - [Not Available]. PMID- 25906554 TI - [Not Available]. PMID- 25906555 TI - [A different service style, an extensive service field, and a bigger role of acupuncture]. PMID- 25906556 TI - [Remodeling of cross electro-nape-acupuncture on cough reflex in patients with tracheotomy after cerebral hemorrhage: a randomized controlled trial]. AB - OBJECTIVE: To observe the effects of cross electro-nape-acupuncture on reflex remodeling of airway protective reflex cough in patients with tracheotomy after cerebral hemorrhage. METHODS: With the method of completely random design, according to treatment order, 60 patients who received tracheotomy after cerebral hemorrhage accompanied with cough reflex difficulty were randomly divided into a cross electro-nape-acupuncture group and an acupuncture group, 30 cases in each group. Both groups were treated with basic treatment, including anti inflammation, eliminating phlegm, improving cerebral metabolism and so on. The acupuncture group was treated with acupuncture at Yifeng (TE 17), Fengchi (GB 20), Lianquan (CV 23), Baihui (GV 20), Touwei (ST 8), Dicang (ST 4) through Jiache (ST 6), Hegu (LI 4), Quchi (LI 11), and motor area on the affected side, and the needles were retained for 30 min. Based on the treatment of acupuncture group, the cross electro-nape-acupuncture group was additionally treated with cross electro-nape-acupuncture (continuous wave) for 30 min per treatment. The treatment was both given twice a day from Monday to Friday and once a day on Saturday and Sun day for 4 weeks. Tracheostomy cough reflex grading score (TCRGS) and clinical pulmonary infection score (CPIS) were observed before and after treatment in the two groups, and the clinical efficacy of two groups was evaluated. RESULTS: Compared before the treatment, TCRGS and CPIS were both reduced in two groups (both P < 0.01); after treatment, there were significant differences of TCRGS and CPIS between two groups (both P < 0.01), indicating cross electro-nape-acupuncture group was superior to acupuncture group. Regarding the effects of cough reflex remodeling, the cured and markedly effective rate was 96.7% (29/30) in the cross electro-nape-acupuncture group, which was significantly different from 55.2% (16/29) in the acupuncture group (P < 0.01). CONCLUSION: Cross electro-nape-acupuncture could effectively improve the remodeling of cough reflex and promote the recovery of lung infection in patients with tracheotomy after cerebral hemorrhage, leading to an increased quality of life. PMID- 25906557 TI - [Clinical efficacy on peripheral facial paralysis at acute stage treated with opposing needling technique]. AB - OBJECTIVE: To compare the differences in clinical efficacy on peripheral facial paralysis at acute stage between the opposing needling technique and routine acupuncture at the affected side so as to provide the evidence on the acupuncture treatment for peripheral facial paralysis at acute stage. METHODS: Forty patients were rando- mized into an opposing needling technique group (19 cases) and an affected side needling technique group (21 cases). The basic medication was same in the two groups. The acupoints were Fengchi (GB 20), Yangbai (GB 14) to Yuyao (EX-HN 4) (penetrating needling method), Jingming (BL 1), Chengqi (ST 1), Xiaguan (ST 7), Jiache (ST 6) to Dicang (ST 4), Hegu (LI 4) and Zusanli (ST 36). In supplementation, in the opposing needling technique group, the acupoints were stimulated on the face of healthy side. In the affected side needling technique group, the acupoints were stimulated on the face of the affected side. The treatment was given three times a week, for 4 weeks. House-Brackmann (H-B) facial nerve function assessment was used to evaluate facial nerve function before and after treatment in the patients of the two groups. The efficacy was compared between the two groups. RESULTS: The facial nerve function was recovered in the two groups and the total effective rate was 100.0% in the two groups (P>0.05). The curative rate was 68.4% (13/19) in the opposing needling technique group and better than 47.6% (10/21) in the affected side needling technique group (P<0.05). On the 7th and 14th day, scores of H-B in the opposing needling technique group were better than those in the affected side needling technique group (both P<0.05). The curative time in the opposing needling technique group was apparently shorter than that in the affected side needling technique group ((23.95 +/- 4.30) days vs. (29.14 +/- 5.43) days, P<0.01). CONCLUSION: The opposing needling technique accelerates the recovery of facial nerve function in peripheral facial paralysis at acute stage and apparently shortens the curative time. The efficacy is better than that in acupuncture on the affect- ed side of the face. PMID- 25906558 TI - [Electroacupuncture combined with half sqat exercise for 32 cases of enthesiopathy of apex patellae]. PMID- 25906559 TI - [Clinical research of electroacupuncture combined with transperineal injection of BTX-A for neurogenic bladder after spinal cord injury]. AB - OBJECTIVE: To evaluate the clinical efficacy of electroacupuncture (EA) combined with transperineal injection of botulinum toxin-A (BTX-A) on neurogenic bladder caused by spinal cord injury. METHODS: One day af ter surgery, 35 cases of spinal cord injury accompanied with neurogenic bladder were randomly divided into a BTX A plus EA group (20 cases, group A) and a BTX-A group (15 cases, group B). The two groups were both treated with regular rehabilitation training of bladder function and injection of 200 IU (4 ml) BTX-A through perineum external urethral sphincter; the group A was additionally treated with EA at Zhongji (CV 3), Guanyuan (CV 4), Shenshu (3BL 23), Huiyang (BL 35) and Baliao (Shangliao (BL 31), Ciliao (BL 32), Zhongliao (BL 33), Xialiao (BL 34)), once a day, 40 min per treatment. The treatment was given 6 times per week for 4 weeks. The urination status in two groups before and after treatment was observed, and urodynamics examination and urethral pressure test were also made. RESULTS: After 4-week treatment, mean times of urinary incontinence, mean urethral catheter output, pressure of bladder and volume of urinary incontinence were all improved in two groups (all P<0.05), which were more significant in the group A (all P<0.05). The residual urine, maximum bladder capacity, maximum urethral closure pressure and maximum urine flow rate were all improved in two groups after treatment (all P<0.01); the improvement of residual urine, maximum bladder capacity, maximum urethral closure pressure in the group A was more significant than that in the group B (all P<0.05). CONCLUSION: Electroacupuncture com bined with transperineal injection of BTX-A could effectively improve the urination dysfunction in patients with neurogenic bladder after spinal cord injury. PMID- 25906560 TI - [Clinical observation of acupuncture at trigone of urinary bladder for urination dysfunction induced by spinal cord injury]. AB - OBJECTIVE: To observe the clinical efficacy differences between regular acupuncture combined with acupuncture at trigone of urinary bladder and simple regular acupuncture for treatment of urination dysfunction induced by spinal cord injury. METHODS: Sixty patients were randomized into an observation group and a control group, 30 cases in each one. The control group was treated with regular acupuncture at Sanyinjiao (SP 6), Zusanli (ST 36), Zhongwan (CV 12) and Tianshu (ST 25), etc. Based on the treatment of control group, the observation group was additionally treated with intensive needling at trigone of urinary bladder, once a day, 30 min per treatment. Ten treatments were considered as one course, and there was an interval of two days between courses, 4 courses of treatment were given in two groups. The improvement of urination function in two groups was evaluated, and the efficacy of urination function in two groups was compared. RESULTS: After treatment, the times of urine leakage, maximum urine output, bladder capacity and residual urine were all improved in two groups (all P<0.05). The improvement of times of urine leakage, bladder capacity and residual urine in the observation group was superior to that in the control group (all P<0.05). The total effective rate was 96.7% (29/30) in the observation group, which was superior to 83.3% (25/30) in the control group (P<0.05). CONCLUSION: The efficacy of regular acupuncture combined with intensive needling at trigone of urinary bladder on urination dysfunction induced by spinal cord injury is significantly superior to that of simple regular acupuncture. PMID- 25906561 TI - [Efficacy on somatoform pain disorder treated with resuscitation and tranquilization acupuncture technique]. AB - OBJECTIVE: To compare the efficacy differences in the treatment of somatoform pain disorder between resuscitation and tranquilization acupuncture technique and oral administration of deanxit. METHODS: Forty cases of somatoform pain disorder (complicated with mild and moderate depression) were randomized into an acupuncture group and a western medication group, 20 cases in each one. In the acupuncture group. acupuncture was applied to Shenting (GV 24). Shuigou (V 26). Sishencong (EX HN I) to Baihui ((V 20) (penetrating technique). Feng-chi (GB 20). etc. The treatment was given once every day. 6 times a week. In the western medication group. the anti depression drug. deanxit was prescribed for oral administration, 1 tablet in every morning and lunchtime each day. In 8 weeks of continuous treatment, the visual analogue scale (VAS) and Hamilton depression scale 17 items (HAMD) were used to evaluate the efficacy in the patients of the two groups, the adverse reactions were observed and the recurrence rate was followed up in 3 months. RESULTS: After treatment. VAS and HIIAMD scores were all apparently reduced as compared with those before treatment in the patients of the two groups (all P<0.05). The reducing amplitude of VAS score in the acupuncture group was greater than that in the western medication group (P<0.05) and that of HAM) score was not different significantly as compared with that in the western mnedica tion group (P > 0.05). There was no adverse reaction in the acupuncture group and were 3 cases as dizziness, trembling. dry mouth and constipation in the western medication group. The curative and remarkably effective rate was 50.0 (10(20)) in the acupuncture group, better than 15.0% (3/20) in the western medication group (P<0.05). The recurrence rate was 10.0 (2/20) in the acupuncture group. lower than 35.0% (7/20) in the western medication group (P<0.05). CONCLUSION: The resuscitation and tranquilization acupuncture technique achieves the definite efficacy on somatoform pain disorder, relieves depression symptoms of patients, especially pain and reduces adverse reactions and recurrence rate. The effects of this therapy are advanced as compared with deanxit. PMID- 25906562 TI - [Forty-four cases of cervical spondylosis with dissociated motor loss in upper extremity treated with needle scalpel combined with traction]. PMID- 25906563 TI - [Short-term and long-term efficacy analysis of acupoint catgut embedding at cervical Jiaji (EX-B 2) points combined with electroacupuncture at acupoints near ears for nervous tinnitus]. AB - OBJECTIVE: To observe the efficacy differences between acupoint catgut embedding at cervical Jiaji (EX-B 2) points combined with electroacupuncture (EA) at acupoints near ear and simple EA for the treatment of nervous tinnitus. METHODS: Sixty-three patients were randomly divided into an observation group (31 cases) and a control group (32 cases). The observation group was treated with acupoint catgut embedding at C4-C7 Jiaji (EXB 2) points on the affected side combined with EA at acupoints near ears, including Ermen (TE 21). Tinggong (SI 19), Tinghui (GB 2), etc.; the control group was treated with EA at regular acupoints near ears alone. The EA treatment was given five times per week, and the acupoint catgut embedding was given once every two weeks. All the treatment was given for 6 weeks. The Tinnitus severity score (TSS)was applied to assess the severity of tinnitus before the treatment, 2 weeks, 4 weeks and 6 weeks into treatment and one month after treat ment. Also the efficacy of two groups was compared. RESULTS: After the treatment, the severity of tinnitus was both improved in two groups at each time point (all P<0.05). which was more significant in the observation group (P<0.05, P<0.01). The cured and markedly effective rate was 77.4% (24/31) in the observation group, which was superior to 50.0% (16/32) in the control group (P<0.05). CONCLUSION: The short-term and long-term efficacy of acupoint catgut embedding at cervical Jiaji (EX-B 2) points combined with electroacupuncture are both superior to those of simple electroacupuncture for treatment of nervous tinnitus. PMID- 25906564 TI - [Acupuncture with function of improving the level of consciousness for 24 cases of coma patients after cardiac surgery]. PMID- 25906565 TI - [Triple-strong stimulation therapy at Dazhui (GV 14) in prevention and treatment of children allergic rhinitis: a randomized controlled trial]. AB - OBJECTIVE: To evaluate the short-term efficacy and long-term preventive effect on recurrence in prevention and treatment of children allergic rhinitis treated with the multiple therapy at Dazhui (GV 14) as the main acupoint and acupoint plaster therapy. METHODS: One hundred and twenty cases of children allergic rhinitis were randomized into a triple-strong stimulation therapy group and an acupoint plaster therapy group, 60 cases in each one. In the triple-strong stimulation therapy group, Dazhui (GV 14) was the main acupoint, combined with one of Feishu (BL 13), Zhiyang (GV 9) and Shenshu (BL 23) accordingly. The heavy needling technique was adopted with the three-edged needle, followed by heavy cupping and heavy moxibustion. The treatment was given once every 3 days, continuously for 10 times. In the acupoint plaster therapy group, the acupoints selected were same as the triple-strong stimulation therapy group. The self-prepared Chinese herbal plaster was used, 4 h to 8 h each one time, once every 3 days, continuously for 10 times. The changes in the symptom and physical sign scores were observed before treatment, after treatment and in 6 months follow-up visit after treatment in the two groups. The clinical efficacy was compared between the two groups. RESULTS: After treatment and in 6 months follow-up visit after treatment, the symptom scores, physical sign scores and symptom scores of each item were different signi ficantly as compared with those before treatment in the triple strong stimulation therapy group (P<0.01, P<0.05), and the results in the triple strong stimulation therapy group were better than those in the acupoint plaster therapy group (all P<0.01). In 6 months follow-up visit, the total effective rate was 94.6% (53/56) in the triple-strong stimulation therapy group and was 25.9% (15/58) in the acupoint plaster therapy group, indicating the significant difference (P<0.001). CONCLUSION: The triple-strong stimulation therapy at Dazhui (GV 14) achieves the superior effect on the prevention and treatment of children allergic rhinitis as compared with the acupoint plas ter therapy and has good long-term effect of the prevention from recurrence. PMID- 25906566 TI - [Blood-letting therapy combined with acupuncture for 50 cases of ankle joint sprain]. PMID- 25906567 TI - [Case of trigeminal neuralgia]. PMID- 25906568 TI - [Abdominal skin temperature changes in penetrating moxibustion]. AB - OBJECTIVE: To explore the technique of temperature control on the abdomen in penetrating moxibustion through observing moxibustion time on the abdomen, abdominal skin temperature and effect after moxibustion so as to provide the safe, effective and easily applicable method for penetrating moxibustion. METHODS: Thirty-two patients were selected in an observation group, 32 healthy persons in a control group. In the observation group, the penetrating moxibustion was applied to the corresponding acupoint locations according to different symptoms. In the control group, moxibustion was used on the abdomen around the umbilicus. The skin temperature was recorded once every minute. The skin temperature of known heat sensation, the time of known heat sensation, the known reduced temperature, the time of temperature reducing, the skin temperature difference, the duration of penetrating moxibustion and the reaction of moxibustion from participants were recorded. RESULTS: The differences in the skin temperature of known heat sensation, the time of known heat sensation and the duration of penetrating moxibustion were significant statistically in comparison between the observation group and the control group (all P<0.01). The differences in the known reduced temperature, the time of temperature reducing and the skin tem- perature difference were not significant (all P>0.05). The differences were significant statistically in skin rashes and moxibustion reaction (gastrointestinal peristalsis, chills, ant climbing feeling and hunger, etc.) between the two groups (P<0.01). The differences were not significant statistically in flushing, sweating and blisters (all P>0.05). CONCLUSION: (1) The level of temperature sensitivity in the observation group is lower than that in the control group. During penetrating moxibustion, the sensations such as gastrointestinal peristalsis, chills, ant climbing feeling and hunger appear easily, suggesting the positive self-adjustment in the body. (2) During penetrating moxibustion, the warm feeling is penetrated not just from the epidermis to the abdominal cavity and lumbar region, but also up to thehead and down to the knee. (3) The flushing, sweating and skin rashes are the important indices for the effectiveness of penetrating moxibustion. (4) The temperature control is the core technique of penetrating moxibustion. The penetrating moxibustion in 28 min to 32 min and the temperature controlled in 43 degrees C to 45 degrees C can solve the moxibustion smoky impact to the environment, but also relieve pains of the patients. PMID- 25906569 TI - [Reinforcing and reducing manipulation in the needle sticking]. AB - In order to have a better basic research of needle sticking, reports regarding basic research of needle sticking in recent years are arranged and summarized, including the concepts of needle sticking, the history origin, manipulation methods, precautions and selection requirements of needles. In the meanwhile, the reinforcing and reducing manipulation in sticking of the needle is preliminarily analyzed, and based on analysis of ancient records, three hypotheses are proposed: (1) needle sticking partly belongs to reinforcing method; (2) needle sticking partly belongs to reducing method; (3) needle sticking can perform reinforcing and reducing effects according to different manipulations. It is also believed that the needle sticking in modern clinical research is mostly used for reducing effects. However reinforcing and reducing manipulation in sticking of the needle still lacks of the support from ancient literature theory and modern clinical application, which needs to be improved. PMID- 25906570 TI - [Effects of acupuncture on PI3K/Akt/mTOR signaling pathway in rats with premature ovarian failure]. AB - OBJECTIVE: To explore the effects of acupuncture and medication on PI3K/Akt/mTOR signaling pathway in rats with premature ovarian failure. METHODS: Ten of fifty SPF-grade female SD rats were randomly selected into a normal group, and the remaining 40 rats were treated with intraperitoneal injection of cyclophospha mide (30 mg/kg) for consecutive 5 days to establish rat model of premature ovarian failure. Thirty five successful rat models were randomly divided into a model group (9 cases), a medication group (9 cases), an acupuncture group A (9 cases) and an acupuncture group B (8 cases). The rats in the model group and normal group did not receive any treatment. The rats in the medication group were treated with intragastric administration of diethylstil bestrol, once a day. The rats in the acupuncture group A and acupuncture group B were respectively treated with acupuncture at different acupoints, twice a day. All the treatment was given for 4 weeks. After the treatment, enzyme-linked immunosorbent assay (ELISA) was applied to test the levels of estradiol (E2), progesterone (P), follicle stimulating hormone (FSH) and luteotropic hormone (LH). The ovarian tissue sample was processed with hematoxylin eosin (HE) staining as well as RNA and protein extraction to test the mRNA expression of estrogen receptor alpha (ERalpha), estrogen receptor beta (ERP), phosphatidylinositol 3-kinase/serine/threonine kinase (PI3K), protein kinase B (Akt) and mammalian target of rapamycin (mTOR). RESULTS: High-dose short-term in- tervention of cyclophosphamide could establish rat model of premature ovarian failure with a successful rate of 87.5%. Compared with the normal group, the vaginal smear in the model group was featured with signs of estro gen deficiency, early-follicle reduction, structural damage to the follicle, and reducing number of mature follicles; the level of E2 was significantly reduced (P<0.05), levels of P, FSH and ILH were increased (all P<0.05), and mRNA expression of estrogen-related ERP3, PI3K, Akt and mTOR were all reduced (all P<0.05). Compared with the model group, the number of mature follicle was increased in the medication group and acupuncture groups, the levels of E2 was obviously increased (all P<0.05). level of FSH was reduced (all P<0.05), and mRNA expression of PI3K, Akt and mTOR all showed an increasing trend (all P<0.05). The differences of each index result between acupuncture groups and medication group were not significant (all P>0.05). CONCLUSION: Acupuncture has certain advantage for the treatment of premature ovarian failure, which achieves similar therapeu tic effect as estrogen; the possible mechanism may be related to up-regulation of gene and protein expression in PI3K/Akt/mTOR signaling pathway. PMID- 25906571 TI - [Effects of grain-sized moxibustion on expression of Abeta(1-42) in prefrontal cortex and hippocampus in double-transgenic AD mice]. AB - OBJECTIVE: To explore the therapeutic effect of grain-sized moxibustion at "Xinshu" (BL 15) and "Shenshu" (BL 23) on early-stage Alzheimer's disease (AD) in transgenosis AD mice. METHODS: The genotyping of amyloid precursor protein/presenilin 1(APP/PS1I) double-transgenic AD mice were detected by PCR method. Seventeen 1.5-month female transgenic (Tg 6799) mice were randomly divided into a model group (9 cases) and a treatment group (8 cases). Nine female C57BL/6J wild-type mice with identical age and background were selected into a normal group. The treatment group was treated with grain-sized moxibustion at bilateral "Xinshu" (BI. 15) and "Shenshu" (BL 23), once a day, ten treatments were considered as one course, and total 9 courses were given. The model group and normal group were treated with stimulus such as grabbing, immobilization and non-ignited moxa cone. Morris water maze (escape latency, crossing times and dwell time in the target quadrant) was applied to evaluate the learning and memory ability. Hematoxylin-Eosin (HE) staining was used to observe morphology changes in the brains of AD mice. beta-amyloid protein 1-42 (Abeta(1-42)) in the area of prefrontal cortex and hippocampus was detected by immunohistochemical method. RESULTS: After the treatment of grain-sized moxibustion, learning and memory ability in the treatment group was increased; compared with the model group, the escape latency was shorten, crossing times was increased, and dwell time in the target quadrant was prolonged (all P<0. 05). The crossing times and dwell time in the target quadrant in the treatment group were not significantly different from those in the normal group (both P>0.05). Compared with the normal group, the positive area and integral optical density of Abeta(1-42) in prefrontal cortex and hippocampus in the model group were increased (all P<0.01). Compared with the model group, the positive area and integral optical density of Abeta(1-42) in prefrontal cortex and hippocampus in the treatment group were reduced (P<0.01, P<0.05). CONCLUSION: The grain-sized moxibustion at "Xinshu" (BL 15) and "Shenshu" (BL 23) could significantly improve the learning and memory ability in APP/PS1 double- transgenic AD mice, and inhibit the over expression and accumulation of Abeta(1-42). PMID- 25906572 TI - [Plum-blossom needle therapy for 43 cases of tears sequela after facial paralysis]. PMID- 25906573 TI - [Two cases of ocular disease treated with three-dimension therapy]. PMID- 25906574 TI - [Primary discussion of qualitative and quantitative recognition on deqi after acupuncture: a study report of West China School of Medicine]. AB - OBJECTIVE: To determine the recognition of healthy medical students on deqi after acupuncture, reveal the qualitative and quantitative rules of deqi and understand whether these rules are the factors of the clinical application of acupuncture therapy. METHODS: The class questionnaires were used for the investigation study on the understanding of deqi after acupuncture at Hegu (LI 4) or Zusanli (ST 36) in 86 healthy students in the clinical medicine class. RESULTS: (1) Deqi was a kind of complicated compound feelings, with many sensation qualities such as distending pain, distension and pain. (2) Deqi was a kind of mild and moderate sensations. In 10-score credit sys tem of Massachusetts General Hospital acupuncture sensation scale (MASS), the scores of distending pain (4.69 +/- 2.83), distension (4.39 +/- 2.91) and soreness and distension (3.93 +/- 2.93) were around 5 (moderate degree), the scores of stabbing pain (1.89 +/- 2.02) were around 2 (mild degree). (3) The differences in the quantitative scores were significant for stabbing pain, distending pain, distention, soreness and distention and the others before and after treatment (all P<0.05). CONCLUSION: Deqi of acupuncture is the mild and moderate complicated sensations manifested as distension, soreness, pain and numbness. As the invasive therapy, the filiform needle puncture will bring a certain psychological impacts on the receptors. The subjective sensation is possibly the factor for the patients' selection of acupuncture treatment. PMID- 25906575 TI - [Acupuncture combined with excercise for 41 cases of stiff neck]. PMID- 25906576 TI - [Retrospective analysis on acupuncture in treatment of cerebral infarction evaluated with propensity score]. AB - The actual efficacy of acupuncture on cerebral infarction was explored in clinical practice. The retro spective cohort study was adopted to investigate 344 cases via inpatient's medical cases. According to whether acupuncture was received or not, an acupuncture group (207 cases) and a non-acupuncture group (137 cases) were divided. The matching method, regression method and weighting method of propensity score (PS) were adopted, and the efficacy on muscle strength was taken as effect index so that the specific impacts of acupuncture were ex plored on the muscle strength in the patients of cerebral infarction. Before matching, COX regression model and Logistic regression model were used. And PS hierarchical regression, PS inverse probability weighting method (IPTW) and PS standardized mortality weighting method (SMRW) were applied to the analysis on the relationship between the muscle strengthen changes and the total effective rate in the two groups. It was found that the efficacy in the acupuncture group was better than that in the non-acupuncture group, indicating the significant difference (P<0.05). Meanwhile, the rehabilitation therapy also brought the obvious impacts on the efficacy evaluation (OR=2.737, P=0.0055). After PS matching, the Logistic regression model was used to analyze whether acupuncture or rehabilitation therapy impacted the total effective rate of muscle strength. The results showed that the efficacy was impacted apparently with the rehabilitation therapy involved (OR=2.930, P=0.0247). Without the rehabilitation effect considered, the efficacy in the acupuncture group was better potentially than that in the non-acupuncture group, but without significant difference (OR=2. 235, P=0,058 7). All of these indicate that on the basis of routine treatment, without the effect of rehabilitation therapy considered, acupuncture improves in tenden cy of the muscle strength of the patients with cerebral infarction. However, it is expected to increase the study medical cases for further verification. PMID- 25906577 TI - [Theoretical study of corresponding points for pain]. AB - The theoretical basis of "corresponding points" originates from opposing needling, contralateral needling and distal needling in acupuncture. It is to select points in corresponding area that is distant from diseased re gion to balance yin and yang and to activate meridians. Acupuncture at corresponding points, through reflex regu- lation of nervous system. could activate protective inhibition of cerebral cortex and cutoff of local malignant stimu lation, leading to quick elimination of pain. In clinic, it is mostly used for pain-related diseases. PMID- 25906578 TI - [Case of pruritus vulvae]. PMID- 25906579 TI - [Thinking on acupuncture depth]. AB - With acupuncture depth as a perspective, some related issues are discussed in this paper. Firstly, the possible reasons of divergence on needling depth are explained. Secondly, by literature retrieval, the advantages and disadvantages of the clinical efficacy of deep needling and shallow needling are explored, and the essential value of shallow needling is emphasized in promoting acupuncture. Thirdly, due to the placebo acupuncture that led to the controversy of the curative effect of acupuncture, it is crucial to establish a method of modern system of scientific research which should be suitable for the development of acupuncture. Finally, the "cun" in acupuncture is inappropriate to transform into millimeter, and the standardization of acupuncture should focus on the improvement of curative efficacy. From the acupuncture depth, it is clear that there are plenty of problems in acupuncture, which could not only limit the development of acupuncture, but also affect the future of acupuncture. PMID- 25906580 TI - [Analysis on academic frame of A-B classic of acupuncture and moxibustion by Huang Fumi]. AB - The acupuncture-moxibustion academic frame system was firstly and systematically established in A-B Classic of Acupuncture and Moxibustion authored by HUANG Fu mi, which explained the knowledge and logical relationship among different parts of acupuncture-moxibustion. The academic frame consisted of acupuncture moxibustion basis and clinical application. In the basic theory, zang-fu, qi blood, meridians, acupoint, pulse diagnosis, acupuncture manipulation, etiology and pathogenesis, etc. were included; in the clinical application, various kinds of clinical diseases and their acupuncture treatment were included. The academic frame established by A-B Classic of Acupuncture and Moxibustion is broader than the modern academic frame of acupuncture-moxibustion, in which the attribution and location of four-seas theory has certain differences from modern acupuncture moxibustion theory. PMID- 25906581 TI - [Preliminary study on lacquer figure with meridian-points marked of the western Han dynasty unearthed in Laoguanshan, Chengdu]. AB - The lacquer figure with meridian-points marked of the western Han dynasty, unearthed in Tianhui town, Jinniu district, Chengdu in 2012, has been the earliest and the most complete human figure of meridian-acupoints in China so far. There were over ten courses of meridians, and over 100 visible acupoints as well as multiple intaglio inscriptions. All of them are valuable in academic study. The writers introduced the lacquer figure un- earthed in Laoguanshan in terms of the briefs and characteristics of meridian and acupoint distributions, which give the references to the future studies. PMID- 25906582 TI - [Zhu Lian's characteristics and experiences in clinical practice of acupuncture and moxibustion]. AB - This paper aims at discussing the clinical characteristics and experiences of ZHU Lian, the renowned contemporary acupuncture master from the following three aspects: "characteristics of clinical manipulations and techniques", "thoughts on diagnosis and treatment" and "examples of clinical cases". The study has shown that ZHU Lian invented the slow insertion technique by rotating needle and the embedding needle technique, improved moxibustion technique with moxa roll and proposed the three keys on the treatment with acupuncture and moxibustion, as well as discovered new acupoints for treatment. The pioneering and distinguished achievements she con tributed play the great demonstrating and driving role in the development of clinical study and practice of acupuncture and moxibustion. PMID- 25906583 TI - [Design and development of new sham-acupuncture device]. AB - The simple and effective controlled needle devices were provided for acupuncture clinical trial so that the double blind acupuncture trial could be conducted possibly. The basic structure of filiform needle was modified. The needle handle was designed as hollow, the upper 1/3 of needle body as hollow and the lower 2/3 part as solid. The upper and lower parts were linked with an elastic unit. At the same time, the needle pad was attached. With this method, the new sham acupuncture device was designed and developed. The new sham-acupuncture device could simulate needle insertion, manipulation and the techniques of reinforcing and reducing, without inserting into the human body. This innovation lays the foundation for perfecting the clinical randomized controlled blind trial of acupuncture. PMID- 25906584 TI - [Mechanism on atrial natriuretic peptide receptor in anti-anxiety with acupuncture based on its tranquilizing effect]. AB - Anxiety disorder is one of the most common mental disorders and seriously impairs the physical and mental health of patients. Due to the efficacy of acupuncture for tranquilization, acupuncture displays its unique advantage on the treatment of anxiety disorder, but the relevant biological mechanism has not been elaborated. The modern medicine study has proved that the heart and brain have their own independent natriuretic peptide (NP) system. The dysfunction of ANP and its receptor are closely related to the occurrence of anxiety disorder. The ANP acts on anti-anxiety. Hence, focusing on the three aspects, named the anti anxiety effect of acupuncture based on its tranquilizing effect, the anti-anxiety effect of ANP and the positive regulation of acupuncture on NP, the mechanism on ANP and its receptor was explored in anti-anxiety with acupuncture based on tranquilizing effect, and the idea was put forward on that the anti-anxiety effect of acupuncture was possibly based on its action of tranquilization through regulating the ANP and its receptor. As a result, it is expected to provide the theoretic support for the mechanism study on anti-anxiety with acupuncture based on its tranquilizing effect. PMID- 25906585 TI - Decision making software for effective selection of treatment train alternative for wastewater using analytical hierarchy process. AB - Proper selection of treatment process and synthesis of treatment train is complex engineering activity requires crucial decision making during planning and designing of any Wastewater Treatment Plant (WWTP). Earlier studies on process selection mainly considered cost as the most important selection criteria and number of studies focused on cost optimization models using dynamic programming, geometric programming and nonlinear programming. However, it has been noticed that traditional cost analysis alone cannot be applied to evaluate Treatment Train (TT) alternatives, as number of important non-tangible factors cannot be easily expressed in monetary units. Recently researches focus on use of multi criteria technique for selection of treatment process. AHP provides a powerful tool for multi-hierarchy and multi-variable system overcoming limitation of traditional techniques. The AHP model designed to facilitate proper decision making and reduce the margin of errors during optimization due to number of parameters in the hierarchy levels has been used in this study. About 14 important factors and 13 sub factors were identified for the selection of treatment alternatives for wastewater and sludge stream although cost is one of the most important selection criteria. The present paper provides details of developing a soft-tool called "ProSelArt" using an AHP model aiding for proper decision making. PMID- 25906586 TI - Discritization of the Gaussian plume model. AB - In general a plume is more known than a puff for stack emissions. A plume may be regarded as a number of puffs ejected out in quick succession. Conversely a continuous plume can be discritized (dissected) at intervals to form puffs. The main objective of the present study is to establish a relationship between a plume and a puff by dissecting the plume longitudinally and equating the contents of the segmented plume to a spheroidal shaped puff for different distances and stabilities to meet vagaries of weather. PMID- 25906587 TI - Variation in temperature during composting of food and vegetable waste. AB - Composting is one of the suitable method for disposal of organic waste and convert it in to organic fertilizer. For effective composting, role of temperature within the composting heap is important. Variation of temperature in the composting heap is the indicator of type of microbial biomass present during the composting. Present study was conducted to find out the minimum volume of waste for effective composting. The present study was conducted in two phases. The first phase of study was conducted to monitor the temperature variation in different volume of composting heap and second phase of study was conducted to study the leachate production in food and vegetable waste. The results of the present study revealed that minimum 80 and 100 kg of food and vegetable waste required maintaining the thermophilic and mesophilic stage. To attain the thermophilic stage the minimum volume should be around 0.5 m3 and minimum height 0.6m. Leachate was produced at initial stage of degradation and it was more in vegetable waste compared to food waste. PMID- 25906588 TI - Physico-chemical change in vertical soil horizon characteristics of distillery affected soil. AB - Effect of treated distillery effluent on the physico-chemical characteristics of vertical soil horizon was studied to observe the impact of effluent on soil of nearby area where distillery canal flows. The studies were also carried out with respect to the unaffected region to compare the soil characteristics. The results showed that in distillery affected soil pH, bulk density and alkalinity increased with depth whereas water holding capacity, chloride, organic carbon, available nitrogen, phosphorus and potassium decreased with depth compared to unaffected soil horizon. Preliminary study revealed that although most of the parameters were high in distillery affected soil horizon which might promote growth of plants but increase in pH and other toxic substances with depth could cause ground water pollution through constant and continuous leaching. PMID- 25906589 TI - Five year studies on suspended particulate matter and heavy metals trends in Brass City of India. AB - Moradabad is historically an important city of western Uttar Pradesh which is popularly known as Brass City of India, as about one thousand large and small scale brassware industries are located in and around the city. Suspended Particulate Matter (SPM) was collected two times in a week using High Volume Samplers (HVS) at six selected sites representing different areas of the city. The result indicates the annual and seasonal variations of SPM from 2005-2010. The highest value (869 MUg/m3) was recorded at industrial site, i.e. Mughalpura in June (2008-09) while lowest value (71 MUg/m3) at PTC in the month of July (2005-06). Five heavy metals, i.e. Cu, Zn, Fe, Cd and Pb were also observed at all the sites. Among the metals highest concentration of Zn were recorded at almost all the sites whereas Cu and Zn were found at industrial site, may be attributed to melting of Brass silly to prepare the different Brassware items. Pb and Cd were abundant at commercial site, located nearby Railway station as traffic density remains high during the day and night. PMID- 25906590 TI - Measurement and chemical speciation of PM10 in Mumbai City, India. AB - Mass concentrations of PM10 were high at all locations of Mumbai city in all seasons. From the enrichment analysis, it was observed that high enrichment of metals existed at all sites, the reason for which could be the effects of meteorology and trans-boundary movement of pollutants. Multivariate statistical analysis tools were used to identify common sources, viz. road dust, biomass burning, secondary aerosol, brake wear, residual oil combustion, smelting, natural soil, vehicles tyre wear, and marine aerosol. Findings indicate that most of the sites were dominated by local sources based on activities in the vicinity of the sampling locations. PMID- 25906591 TI - Assessment of water quality index of bore well water samples from some selected locations of South Gujarat, India. AB - The present study calculates the water quality index (WQI) of some selected sites from South Gujarat (India) and assesses the impact of industries, agriculture and human activities. Chemical parameters were monitored for the calculation of WQI of some selected bore well samples. The results revealed that the WQI of the some bore well samples exceeded acceptable levels due to the dumping of wastes from municipal, industrial and domestic sources and agricultural runoff as well. Inverse Distance Weighting (IDW) was implemented for interpolation of each water quality parameter (pH, EC, alkalinity, total hardness, chloride, nitrate and sulphate) for the entire sampled area. The bore water is unsuitable for drinking and if the present state of affairs continues for long, it may soon become an ecologically dead bore. PMID- 25906592 TI - Bioremediation of municipal solid waste by windrow composting. AB - Due to rapid urbanization and economic development the urban cities are facing the problem of solid waste management. It is one among the major challenges faced by governing bodies. Bioremediation of municipal solid waste can be effectively done by windrow composting. In this study, a consortium of effective microorganisms was used for the windrow composting process. About 500 kg of shredded waste was placed in two windrows and 1 litre effective microorganisms were sprayed on one of the windrows. The variation in physical and chemical parameters was monitored throughout the process. The results indicate that usage of effective microorganisms not only shortens the stabilization time but also improves product quality. The final product was more stable and homogenous and can be effectively used as soil conditioner. PMID- 25906593 TI - Experimental study on biodegradation of dairy wastewater using bacterial isolate. AB - The activated sludge process facilitates the removal of carbonaceous BOD, the coagulation of colloidal solids and the stabilization of organic matter by a variety of microorganisms (principally bacteria). Bacillus sporogenes is one of the predominant bacteria found in dairy waste water. The bacteria Bacillus .sp was isolated from the dairy wastewater and inoculated into the samples taken from the dairy industry. Laboratory tests were carried out by inoculating varied cell concentrations and incubating under aerobic conditions to determine the removal of COD and protein from the samples. During the incubation, microbial growth was monitored by the measurement of optical density. The biodegradation ability of the native bacteria was also compared with the commercial inoculum of the same isolate. It was observed that the sample inoculated with 5 x 10(6) CFU/mL cell concentration showed a maximum protein degradation of 92.8% after 14 days and COD removal of 91.3% in 18 days. The COD removal was higher for the commercial inoculum and the protein removal was higher in the selected native strain. PMID- 25906594 TI - Adequacy assessment studies of improved circular clarifier for type-II settling for storm water treatment. AB - The adequacy of an improved circular clarifier was assessed for solids-liquid separation of chemically treated storm water. The storm water was treated with alum and polyelectrolyte to enhance settling. The performance of the clarifier was studied under various operating conditions by varying suspended solids concentrations and turbidity, and the hydraulic retention time. It was observed that the clarifier worked at an optimum hydraulic retention time of 1.5 hours for initial suspended solids concentration of less than 500 mg/L. However, for treatment of storm water with suspended solids concentration more than 500 mg/L, the hydraulic retention time needs to be selected taking the required effluent turbidity and effluent usage into consideration, i.e. for high turbidity removal an optimum hydraulic retention time of 2 hours must be used against a hydraulic retention time of 1.5 hours for a relatively low turbidity removal. Thus, the clarifier can be effectively used on field scale for solids-liquid separation of flocculent suspensions. PMID- 25906595 TI - Treatment of textile dyehouse effluent using ceramic membrane based process in combination with chemical pretreatment. AB - Treatment of highly concentrated dyebath effluent and comparatively dilute composite effluent having mixture of various reactive dyes collected from a cotton fabric dyeing unit was undertaken in the present study. Ceramic microfiltration membrane prepared from a cost effective composition of alumina and clay was used. Prior to microfiltration, a chemical pretreatment was carried out with aluminium sulphate in combination with a polymeric retention aid. An optimum dose of 100 mg/L of aluminium sulphate and 1 ml/L of a commercial flocculant Afilan RAMF was found effective for dye removal (> 98%) from the synthetic solutions of reactive dyes with initial concentration of 150 mg/L in both the single component and two component systems. In the microfiltration study, effect of operating pressure in the permeate flux was observed for both the pretreated and untreated effluents and permeate samples were analyzed for dye concentration, COD, turbidity, TSS, etc. during constant pressure filtration. About 98-99% removal of dyes was obtained in the combined process with COD reduction of 54-64%. PMID- 25906596 TI - Ergonomic evaluation of the wood cutting task using chain saw. AB - Workers whose hands are regularly exposed to hand-arm vibration may suffer from damage to the tissues of the hands and arms, which cause the symptoms collectively known as hand-arm vibration syndrome. However, investigations have shown that vibration hazards can be controlled and risks might be reduced by good design of the task/tools. In the present study, an experiment was conducted for the evaluation of risk in operating chain saw. The evaluation of chain saw ergonomically performed based on four parameters--Discomfort level, EMG activity of seven different forearm muscles (ECRB, ECU, EPB, FCR, FDS, FCU and PT), angular deviation in hand-arm system and the vibration transfer to hand-arm system, while operating the chain saw on a wooden block. Ten male candidates participated for the discomfort level experiment, four participants volunteered for the EMG activity and angular deviation experiment and two participants were involved in vibration transfer recordings. The results showed that ECRB muscle was mostly affected muscle in this task of operating a chain saw. The findings also indicated that the problems were occurred due to the bad design of the rear handle of chain saw in association with the available vibration levels on hand arm system. PMID- 25906597 TI - Gaseous and bioaerosol emissions from municipal wastewater treatment plants. AB - Wastewater treatment plants (WWTPs) are identified as potential emission sources of greenhouse gases (GHGs) and bioaerosols. This paper reviews and analyse the potential sources of GHGs and bioaerosols from different unit operations and processes of WWTPs. Aeration tanks of activated sludge process (ASP) are found to be the most important sources of GHGs as well as bioaerosol emissions. Nitrification and denitrification processes are found to be important sources of nitrous oxide (N2O) emissions. To minimize the N2O emissions from WWTPs, dissolved oxygen (DO) concentration should be kept greater than 2 mg/L in nitrification process, whereas purely anoxic condition (0 mg/L DO) is required in denitrification process. Diffused aeration emits fewer microbes into the air than surface aerators. It is observed that fixed-film processes emit microbes by two orders of magnitude less than aeration tanks. The various WWTPs discussed in this study used different methods of treatment sample collection and species of microorganisms studied. It is realised that the standardisation of the microorganisms to be analysed and methods of sample collection needs to be done. It is also found that from the microbiological point of view, there is no clean air in the vicinity of a WWTP. PMID- 25906598 TI - Nitrate in ground water of Beed City of Maharashtra (India). AB - An attempt was made to investigate the water pollution caused by nitrate in the ground water of Beed City of Maharashtra inIndia. The samples were collected randomly at different time periods from different places of Beed City and analysed for nitrate contents. The level of nitrate was found high and above permissible limit in the groundwater of the city. PMID- 25906599 TI - Integrated teaching: a less trodden path. PMID- 25906600 TI - Role of dopamine--D2 receptor in spatial memory retention and retrieval determined using Hebb-Williams complex maze. AB - Effects of bromocriptine and sulpiride were observed on encoding and retrieval of spatial memory in Wistar rats using Hebb-Williams complex maze. Rat was placed in entry chamber and allowed to reach reward chamber. Ten trials were given each day per rat for 3 consecutive days. Within-day encoding score indicative of learning and between-day retrieval score indicative of memory were calculated. Effects of bromocriptine and sulpiride were observed on encoding and retrieval of spatial memory. General learning index was calculated to compare the effect on spatial memory between groups. Bromocriptine increased while sulpiride decreased within day encoding index but had no effect on retrieval index. In general learning index, sulpiride group showed more errors whereas bromocriptine group did not show any difference as compared to control. These results suggest that dopamine D2 receptors are involved in memory encoding but not retrieval. Also general learning is under positive modulation by D2 receptors. PMID- 25906601 TI - Assessment of maternal vascular stiffness indices in three trimesters of normal pregnancy. AB - Normal pregnancy is associated with intense alterations in the maternal cardiovascular system. The aim of the present study was, to assess the influence of normal pregnancy on maternal central aortic pressures, arterial stiffness, and arterial wave reflection using non-invasive PC based cardiovascular risk analysis system (Periscope). The current study was conducted on 137 women with, normotensive, healthy, singleton pregnancies at first trimester (n = 42), second trimester (n = 48), third trimester (n = 47) of pregnancy and 35 age matched non pregnant controls. There was no significant correlation between the estimated means for age and systolic and diastolic blood pressure. There was progressive and significant increase in BMI as pregnancy progresses (p = 0.0001). Heart rate rose significantly from Pre-pregnant to second and second to third trimesters (P < 0.003). There were no significant changes observed in central aortic diastolic pressure (AoDiaBP) as pregnancy progressed (p = 0.235) however Post Hoc comparisons showed a significant increase in central aortic systolic blood pressure (AoSysBP) and central aortic pulse pressure (AoPP) during first trimester when compared with non pregnant control group (p = 0.039 and 0.048 respectively). There was significant increase in central aortic augmentation pressure (AoAugP) in first trimester compared to non pregnant control group (p = 0.024). All the parameters of central aortic pressures were increased in the first trimester but decreased in the second trimester and again increased in the third trimester of pregnancy. There was a significant drop in Brachial-Ankle Pulse wave Velocity (baPWV) during first trimester of pregnancy compared to non pregnant control group (p = 0.0001) after that there is a progressive increase in baPWV in second and third trimester of pregnancy. In the third trimester baPWV is increased to more than non-pregnant control group but it was non significant (p = 0.562) however it was significantly higher than first trimester (p = 0.0001). Carotid-femoral Pulse wave velocity (cfPWV) also followed the same sequence as BaPWV but the drop in cfPWV during first trimester was not significant (P = 0.135). All of the variables of hemodynamic and arterial compliance differed between participants with various trimester of pregnancy and non-pregnant control group. A significant up and down changes in Augmentation index (Aix) was observed from control to first, second and third trimester of pregnancy (3.14 to 6.74 to 2.63 to 10.51 respectively, P < 0.0001). To summarize our report show that normal pregnancy is associated with a significant cardiovascular adaptation indicated by alteration in central aortic blood pressure, augmentation index and pulse wave velocity. PMID- 25906602 TI - Pulmonary functions in tannery workers--a cross sectional study. AB - Tannery workers are at potential exposure to detrimental agents rendering them vulnerable to respiratory and dermal problems. Thus by performing pulmonary functions among leather tannery workers, we can decipher the effect of chromium and leather dust on lung functions and also the decline of respiratory functions with increasing years of exposure to leather dust. Pulmonary functions were assessed for 130 tannery workers and compared with the 130 unexposed office workers. Pulmonary function measurements namely FVC, FEV1, FEF25-75% and PEFR were measured using portable data logging Spirometer (KOKO Spirometer). The observed pulmonary functions of Tannery-workers in this study showed a reduction in FEV1, FVC, FEV1/FVC ratio, FEF25-75 and PEFR in relation to their predicted values and also compared to the unexposed. Smokers showed a decline in pulmonary functions compared to the non smokers because smoking acts as an additional risk factor in the development of respiratory illnesses. It is worthy to mention that the pulmonary function values correlate negatively with the duration of exposure to leather dust. So this study could provide base line information based upon which legal implementation of preventive measures could be undertaken. PMID- 25906603 TI - Effect of controlled breathing exercises on the psychological status and the cardiac autonomic tone: Sudarshan Kriya and Prana-Yoga. AB - OBJECTIVE: The objective of the study was to observe the effect of controlled breathing exercises including Sudarshan Kriya (SK) and Prana-Yoga (PY) on the psycho-physiological status. METHODS: The study group included 60 healthy volunteers (M:30, F:30) in the age group of 18 to 30 years (21.3 +/- 3.2 yrs), randomly divided in to three groups of 20 subjects each--(1) The SK group (2) the PY group and the (3) Control group. The psycho-physiological data was collected at the following four time interventions: Baseline, 6th, 60th and the 150th day. Psychological assessment was done using questionnaires and for the autonomic tone quantification Heart Rate Variability (HRV) analysis was done using the standard lead II electrocardiogram recordings. In a post-hoc analysis each group was further sub divided in to the following two patterns, based on the baseline values of normalized Low Frequency (LF) power (cutoff 64 ms2): (i) Pattern A Subjects with low level LF power, and (ii) Pattern B- subjects with high level LF power. RESULTS: The stress management skills have shown significant increase in SK group but not in PY and Control group. Subjects of SK, PY, and control group showed significant increase in LF value and LF:HF ratio for pattern A and significant decrease for pattern B. Plotted LF value for pattern A & B in SK and PY practitioners showed convergence, coming to a mean value over the period of 150 days. The LF:HF ratio curve plotted over time for pattern A & B showed convergence in SK group only. No such convergence in LF value & LF/HF ratio for pattern A & B was seen in control group. CONCLUSION: In conclusion, Sudarshan Kriya positively modifies stress coping behavior and initiates appropriate balance in cardiac autonomic tone. PMID- 25906604 TI - A study on association of leptin receptor gene polymorphism with obstructive sleep apnea syndrome in overweight and obese north Indian subjects. AB - Obesity is an important risk factor of Obstructive Sleep Apnea Syndrome (OSAS). Previous studies suggested Leptin Receptor (LEPR) gene Polymorphisms is associated with obesity and OSAS. Study was conducted to asses association of LEPR gene polymorphism K109R, Q223R and K656N with OSAS in North Indian subjects. Genotyping and estimation of serum Leptin levels were done in 190 subjects. Polysomnography, anthropometrical measures and biochemical investigations were done in all the subjects who qualified for inclusion in the study. We observed significant association of Q223R gene polymorphism with blood pressure (BP) (P < 0.05) and nocturnal max pulse rate (P < 0.05). K656N gene polymorphism was associated with AHI (P < 0.05), average desaturation levels (P < 0.05) and HDL-C (P < 0.05). No association was observed in genotype distribution of these subjects according to obesity and disease severity. These findings suggest that LEPR Q223R and K656N gene Polymorphism may influence BP, Max Pulse rate, AHI, Average desaturation levels and HDL levels in these Subjects. PMID- 25906605 TI - Effect of different forms of acute stress in the generation of reactive oxygen species in albino Wistar rats. AB - Stress is common for all organisms either in the form of eustress (beneficial) or as distress (harmful). Stress is highly diverse in present world and its effects in organisms are well studied. This study is a comparative effect of stress in the generation of reactive oxygen species in albino Wistar rats, which are seldom reported. Here animals were grouped into four and the test animals of each group were administered with any one of the following stress, namely forced swimming induced stress (FS), and noise induced stress (NS), immobilization stress (IS) and overcrowding stress (OS). After stress administration, serum cortisol was estimated as a bio marker of stress in the albino rats, and the liver homogenate were used to estimate superoxide dismutase (SOD) by using rat Elisa kit in the spectrophotometer. The data were processed with unpaired 't' test. The cortisol levels were found to be increased in a highly significant level (P < 0.001) in all the groups as compared to the normal control. And the stress level was found to be maximum in the FS group in comparison with other groups. The mean cortisol level in different stress groups such as FS, NS, IS and OS were found to be 4.15, 3.7, 3.63, 3.62 MU gm/dl respectively. Among all the stressed groups, the SOD level in the FS group were found to be increased in a highly significant level (P < 0.001) in comparison with normal control group. The SOD level in FS group was (30.75 U/mgm. protein) followed by OS (28.96), noise (28.88) and IS (28.77). PMID- 25906606 TI - Efficacy of naturopathy and yoga in bronchial asthma. AB - The aim of the study was to test the efficacy of a one month in-patient naturopathy and yoga programme for patients with asthma. Retrospective data of 159 bronchial asthma patients, undergoing the naturopathy and yoga programme, was analyzed for Forced Vital Capacity, Forced Expiratory Volume at the end of 1 second, Maximum Voluntary Ventilation and Peak Expiratory Flow Rate on admission, 11th day, on discharge and once in three months for three years. The paired sample t test results showed significant increase in the Forced Vital Capacity and Forced Expiratory Volume from the date of admission up to 6th month (P < 0.0035) post Bonferroni correction. Maximum Voluntary Ventilation significantly increased from admission till the date of discharge (P < 0.0035) and Peak Expiratory Flow Rate significantly increased from admission till the 36th month of follow-up (P < 0.0035), post Bonferroni correction. This validated the beneficial effect of combining naturopathy and yoga for the management of bronchial asthma. PMID- 25906607 TI - Catha edulis deteriorates spatial working memory in rats, but spares reference memory. AB - The effects of Catha edulis, a CNS stimulant, on humans and animals have been studied on various aspects like anorectic effect, self-administration, stereotyped behavior, aggressive behavior, operant task, locomotor sensitization, psychosis etc., but how C. edulis influence spatial learning and memory in rats is not clear. C. edulis contains amphetamine like substances, which enhances spatial learning and memory. So, we hypothesize C. edulis will also influence spatial learning and memory. In the aim to assess this effect of C.edulis, a comparative study is conceded using another CNS stimulant, methylphenidate (MPD), which is currently used, for treatment of attention deficit hyperactive disorder (ADHD), instead of amphetamine. Spatial learning and memory was assessed using radial arm maze, by analyzing five dependent measures obtained on every trial: time to complete a trial, latency to first arm entry, number of reference memory errors, number of working memory correct and incorrect errors. Our results show that C. edulis and not MPD fed rats had impaired learning and memory, implicated by increased time to complete a trial. But both C. edulis and MPD increased attention in rats, as in both groups latency to first arm entry was less. Further analysis showed that C. edulis fed rats were more effected in the working memory component and reference memory was intact. These results highlight the importance of restricting the widespread use of C. edulis in humans. The use of MPD as a choice of drug in treatment of ADHD is also supported by this study as it did not deteriorate the learning and memory, in spite of increased attention and alertness. These results are further discussed on the basis of differential action of C. edulis and MPD on neurotransmitter systems of brain, and this reveals the need for detailed analysis in future studies for the effect of C. edulis on hippocampal network. PMID- 25906608 TI - Topical amiloride delays healing of deep thermal wounds in albino rabbits. AB - The present investigation was undertaken to explore the ulcer healing properties of three dosage schedules of different strengths of topically administered amiloride solution in thermally produced skin ulcers on the side of the midline on the back of the rabbits. Four circular thermal burns about 4.0 cm in diameter (two on either side of the midline) were made 4.0 cm apart on the pre shaved back of each anaesthetized (with thiopentone sod., 45 mg/kg, ip) rabbit with a heated template, applied for 30 sec. Three days later under anaesthesia, the burns were excised removing epidermis, dermis and subcutaneous tissue. The animals were randomly divided into various groups. Ulcers on one side of the midline were treated with normal saline and served as control, whereas those on the other side were treated with amiloride solutions. Each ulcer was observed for its size, slough formation and any sign of irritation on alternate days until healing was complete. Healing of ulcers were significantly delay in comparison to control group with all the strength of amiloride (0.02%, 0.5% and 1%) in all the dosage schedule (o.d., b.i.d. and q.i.d.) in terms of days required for complete healing (except with b.i.d. dosage schedule of 0.5% & q.i.d. dosage schedule of 1% amiloride solution), ulcer size and area under the size time curve (except with b.i.d. &q.i.d. dosage schedule of 1% amiloride solution). Thus, it is concluded that unlike mechanical ulcers topical amiloride delays wound repair in deep burn lesions. PMID- 25906609 TI - Effects of physical activity on pupil cycle time (PCT) in healthy Indian male. AB - Globally, physical inactivity is an important risk factor for the development of non-communicable disease consisting of coronary artery disease, as well as, other diseases including hypertension, diabetes, obesity, osteoporosis, and certain types of cancers. Parasympathetic nervous system (PNS) activity in the eye is determined by the pupil cycle time (PCT) can be comparable with cardiac parasympathetic response and thereby determine the morbidity and mortality among individuals. The PCT is measured by throwing white light on the edge of the pupil. Pupil cycling is a feature of pupillary reflex arc. The aim of this study is to establish the effect of physical activity on the PCT. The counting of PCT was done for 90 cycles and average one count is considered a single PCT. The physical activity level (PAL) was determined by administering a physical activity level questionnaire developed in the Division of Nutrition, St. John's Medical College, Bangalore. The PAL is classified as < 1.4 as sedentary, 1.55 to 1.75 moderately active, and > 1.75 heavily active. Thirty healthy male volunteers in the age group of 18-50 years and with BMI of 18.5 kg/m2-30 kg/m2 were studied. We obtained PCT of 962.00 +/- 105.72 msec in sedentary, 896.77 +/- 85.88 msec in moderately active and 889.45 +/- 68.71 msec in heavily active individuals. Linear regression analysis shows there is statistically significant difference between the three different groups of physical activity level with a b value of 0 and R2 being 0.19. Increase in physical activity led to decrease in the PCT i.e. increase in the parasympathetic tone in the eye. Pupil cycle time (PCT) is a simple noninvasive tool to assess and differentiate the PNS function in different activity level of individual. PMID- 25906610 TI - Arterial blood pressure is inversely associated with vascular sympathetic reactivity (isometric handgrip exercise) in Gujarati Indian adolescents. AB - Studies conducted earlier have found that vascular sympathetic reactivity to isometric handgrip exercise is either low or high in adolescents with higher blood pressure (Hypertensives) as compared to adolescents with relatively lower blood pressure (Normotensive). The current study was conducted to determine the correlation of vascular sympathetic reactivity to isometric handgrip exercise with blood pressure in Gujarati Indian adolescents so as to understand the pathogenesis and/consequences of Hypertension in this population. A cross sectional study was conducted on 651 Gujarati Indian adolescents (285 girls, 366 boys) of age group 13-19 years. Blood pressure was measured by oscillometry and vascular sympathetic reactivity (Percentage rise in Diastolic Blood Pressure, %RDBP) was assessed using isometric handgrip test. Pearson's correlation coefficient was determined to study the correlation between %RDBP and blood pressure. In both girls and boys, %RDBP showed significant negative correlation with resting SBP, DBP and MAP. The study thus indicates that an inverse association exist between arterial blood pressure and vascular sympathetic reactivity to isometric handgrip exercise in Gujarati Indian adolescents. PMID- 25906611 TI - Subjective and objective convergence of the eyes at simulated altitude of 18,000 feet preceded by short-term exposure to heat stress. AB - Armed forces personnel including military aviators are quite often exposed concurrently to various environmental stressors like high environmental temperature and hypoxia. Literatures have suggested that exposure to one environmental stressor may modify the physiological response on subsequent exposure to same or different stressor. The present study was undertaken to investigate the impact of cross tolerance between two environmental stressors of aviation (heat and hypoxia) in ten healthy adult males in a simulated altitude chamber in a within subject experimental study. They were assessed for their convergence ability of the eyes at ground and at simulated altitude of 18,000 ft with or without pre-exposure to heat stress. Subjective convergence at simulated altitude of 18,000 ft did not show any improvement following pre-exposure to heat stress. Objective convergence was improved following pre-exposure to heat stress and was found to be 10.76 cm and 9.10 cm without and with heat stress respectively at simulated altitude of 18,000 ft. Improved objective convergence at high altitude as a result of pre-exposure to heat stress is indicative of better ocular functions. This might benefit aviators while flying at hypoxic condition. PMID- 25906612 TI - Functional status of auditory pathways in children with borderline intellectual functioning: evoked potential study. AB - The present study was undertaken to determine whether impairment of sensory conduction in the auditory pathway is one of the contributory factors of performance in children with borderline intelligence. The study was conducted on children having borderline intelligence (IQ 71-84). The functional integrity of the central auditory pathway was assessed using Auditory Evoked Responses i.e. Auditory Brainstem response (ABR), Mid Latency Response (MLR) and Slow Vertex Response (SVR). The recordings were done using a computerized evoked potential recorder by 10-20 electrode placement system. There was no significant difference in the absolute peak latencies, the interpeak latencies and amplitude of ABR in the subjects as compared to controls. There was prolongation of the latency of MLR and SVR waves in subjects though not statistically significant indicating no conduction abnormality in the auditory pathway of the study subjects. Electrophysiological methods reveal underlying immaturity or abnormal brainstem timing and may serve as reliable tool in individuals with learning difficulties. PMID- 25906613 TI - Comparison of foetomaternal circulation in normal pregnancies and pregnancy induced hypertension using color Doppler studies. AB - The aim of present study was to assess fetomaternal blood flows in normal and abnormal pregnancies using color Doppler indices. Subjects were divided into two groups as: Group A of 25 subjects of normal pregnancy as controls and group B of 25 subjects of pregnancy induced hypertension. All the subjects were lying in the age-group of 25-35 years and having 28 to 34 weeks of gestation; the patients were evaluated by detailed history and were subjected to complete general examination. Blood pressure was taken on two occasions at least 6 hours apart. Systemic examination and obstetrical examination was done in all subjects. All cases were subjected to pathological tests- Haemogram, Test for proteins in urine. Ultrasound assessment of fetal growth was done by measuring BPD (Biparietal diameter), HC (Head circumference), FL (Femur length) and AC (Abdominal circumference): Average gestational age and effective fetal weight was then calculated by ultrasound machine. Color Doppler was used to assess the various Doppler indices indices: Pulsatility index (PI), Resistive index (RI) and Systolic diastolic ratio (S/D ratio) in bilateral uterine, umbilical and middle cerebral arteries and compared to the standard normograms. Percentage of subjects having abnormal Doppler indices were calculated. Assessment of percentage of SGA (small for gestational age) fetuses was done in all the three groups. Decline in mean values of all Doppler indices was found with advancing gestational age in normal pregnancy suggesting decreased vascular resistance and increased blood flow in fetomaternal circulation. In pregnancy induced hypertensives, the mean values of Doppler indices showed a decline as in normal pregnancy but showed an increase (more than 2 S.D. of the mean) for that gestational age in comparison to the control group suggesting increased impedance to blood flow in uteroplacental and fetomaternal circulation. Umbilical artery Doppler indices were found to be the most sensitive indicator of uteroplacental and fetoplacental insufficiency in pregnancy induced hypertensives (P = 0.001). Thus we concluded that color Doppler can detect changes in fetomaternal circulation which correlate strongly with the fetal growth and therefore associated with pregnancy outcome. PMID- 25906614 TI - Predicted equations for pulmonary function in normal adolescent south Indian population. AB - Pulmonary functions are affected by variables like age, sex, height, weight, and geographic location. Our study aims to establish predicted, equations for pulmonary functions in normal South Indian adolescent population. 400 subjects were grouped into pre & peripubertal (10-14 years) and pubertal (15 to 18 years) age categories. Anthropometric data collected, PFT assessed using portable data logging Spirometer MIR II. Mean FVC and FEV1 values were 2.80 L, 2.49 L in boys and 2.34 L, 2.12 L in girls respectively. Predicted equations for both adolescent age groups were generated by using linear regression analysis. PFT were significantly different in both age categories in boys and girls. PFT increased with increasing age and significantly correlated with the anthropometric parameters. Region specific and age specific predicted equations for PFT are generated from this study. PMID- 25906615 TI - Second digit and fourth digit ratio--an adjunct tool to predict obstructive sleep apnea. AB - Obstructive sleep apnea (OSA) is a sleep related breathing disorder associated with high morbidity and mortality. Digit ratio (2D:4D) a sexually dimorphic trait is a putative indicator of prenatal testosterone exposure and adult testosterone level. Present study aimed at investigating the correlation between 2D:4D ratio and OSA based on the study conducted on 290 volunteered participants of both the sexes in the age range of 20-45 years. A significant negative correlation was observed for 2D:4D with OSA related parameters specifically Berlin score, Epworth score and certain key anthropometric measurements, neck circumference (NC) and waist-hip ratio (WHR). The study thus showed that lower 2D:4D ratio, increases risk of developing OSA and hence it can be used as an adjunct tool in the prediction of OSA. PMID- 25906616 TI - Study of stress, self-esteem and depression in medical students and effect of music on perceived stress. AB - Medical students are exposed to many stressors and if stress is perceived negatively or becomes excessive can affect academic performance and health adversely. The objective of this study was to assess stress, predominant stressor and effect of music on perceived stress. 90 undergraduate students were selected randomly. A written questionnaire about personal information, stressful factors, ways to cope up stress, Rosenberg self-esteem scale (Rosenberg, 1965) and 'Quick Inventory of Depressive Symptomatology' self-rated 16 (QIDS-SR-16) was given.45.6% Students had mild stress, 7.7% students had moderate stress and 1.1% students had severe stress. Academic factors were the predominant cause of stress in most students, followed by physical, social and emotional. On Rosenberg self esteem scale (Rosenberg, 1965) 85.6% students had high self-esteem and on QIDS SR16 50% students had depression. Effect of music on perceived stress was statistically significant. Medical curriculum is associated with increased stress in students. Music can be used as simple, inexpensive and effective therapy for stress. PMID- 25906617 TI - Pulmonary function tests in stone crushers. AB - A cross-sectional type of observational study was conducted at 7 various stone crusher units on 120 male stone crushers and 120 healthy male controls. Values of FEF25-27% and PEFR were recorded on computerized spirometer and were compared between workers and age matched controls group. The value of FEF25-75% and PEFR was significantly reduced in stone crushers as compared to controls. Also as the duration of exposure increases the values of flow rates goes on decreasing among workers. Stone crushers of Marathwada region of Maharashtra exposed to silica dust were prone to develop lung disorders as indicated by reduced value of FEF25 75% and PEFR. PMID- 25906618 TI - Effect of yogic training on physiological variables in working women. AB - Depression and anxiety in women sharply rising. Working women have high level of stress than non working women. Increasing amount of work stress at home and work place and its impact on family and home environment can be seen, which affect their emotional, psychological and physical health. The concept of yoga is helpful for reducing anxiety and improving cardiorespiratory parameters has created a great interest in the medical research field. The present study was conducted to assessing the effect of yogic exercises and meditation in working women. Yogic session was carried out for 16 weeks. Cardiorespiratory parameters (pulse rate, respiratory rate, blood pressure and breath holding time) were measured before and after yoga training. Stress was measured by anxiety score as an indicator of stress, also Visual reaction time as an indicator of cognitive function and finger dexterity score as an indicator of motor skills were measured before and after yoga training. Statistical analysis was done by paired 't' test. It was found that statistically significant improvement in cardiorespiratory parameters, anxiety score, visual reaction time and finger dexterity score (P < 0.05) after yogic training. Thus, a combined practice of asana, breathing exercises, and meditation & relaxation technique in a sequence is the best available resource to meet the.present day needs of society. PMID- 25906619 TI - "Named Formulas" database available. PMID- 25906620 TI - Depyrogenation options for the compounding cleanroom. AB - Compounding pharmacies, especially those awarded 503B status under the U.S. Federal Food, Drug, and Cosmetic Act that resulted from the Drug Quality and Security Act, must meet increasingly strict standards for the preparation of sterile formulations. Depyrogenating the containers and tools used in such compounding is essential to meeting those standards and ensuring patient safety. Although pyrogens are relatively thermally stable, treating aseptic-compounding glassware and implements in a dry-heat oven or tunnel is the most common method of depyrogenation. Depyrogenation tunnels are used at larger facilities in which automation and a higher throughput can justify the cost of that equipment, but a small batch oven is an inexpensive and appropriate solution to meeting sterilization and depyrogenation requirements in a smaller compounding pharmacy. In this article, we discuss the appropriate use of depyrogenation ovens and tunnels, compare those types of equipment, and describe the selection and use of a cleanroom oven in a compounding pharmacy. PMID- 25906621 TI - Standards of practice, professional judgment, and scientific evidence to establish and extend a beyond-use date. AB - The establishment of both a beyond-use date and the extension of a beyond-use date need to be scientifically based. What is accepted as scientific evidence is at times misleading. The pharmacist may have the right to utilize some degree of professional judgment in both establishing and extending a beyond-use date, after a review of appropriate scientific literature. Notwithstanding this scientific review, it is the concept of professional judgment that seemingly needs to be better defined. A new-found appreciation for professional judgment will bring us to the understanding that a validated stability-indicating assay is the correct manner in which to extend a beyond-use date. This article addresses and discusses the recommendations and rigor required to establish and extend a beyond-use date. The perspectives of the pharmacist and physician are explored, as well as the impact of an extended beyond-use date, or lack thereof, are discussed. The application of a set of fundamental principles will be revealed, which will lead to finite conclusions as to the necessary methodology to establish as well as extend a beyond-use date. PMID- 25906622 TI - Evaluation of the most frequently prescribed extemporaneously compounded medications in a rural setting: a case study from the Delmarva Peninsula. AB - Extemporaneous drug formulation is essential to provide optimal pharmaceutical care to infants, children, and other special patient populations when medications are not available in a suitable dosage form. This study examined the prescription patterns of extemporaneously compounded preparations from representative sites on the Delmarva Peninsula. Professional pharmacy students assigned to community pharmacy and hospital clinical sites were asked to collect the following data at their respective rotation sites: a list of the most commonly prescribed extemporaneously compounded products to include: drug indication, generic name, dosage form, stability dating, dose regimen, route of administration, and age group. A database was constructed and each compounded prescription was allocated to a therapeutic category based on the American Hospital Formulary Service. Data was obtained from a total of 555 prescriptions, available from 113 entries. The most frequently prescribed therapeutic categories were gastrointestinal agents, skin and mucous membrane agents, and anti-infective agents, accounting for 41%, 26%, and 14% of all prescriptions, respectively. Community pharmacies accounted for 54%, 76%, and 27% of prescriptions in the gastrointestinal, skin care, and anti-infective agents' individual categories, respectively. Hospital pharmacies accounted for 46%, 24%, and 73%, of prescriptions in the gastrointestinal, skin care, and anti-infective agents' individual categories, respectively. Prescriptions containing lidocaine along with other active ingredients, mainly gastrointestinal cocktail and magic mouthwash, were the most commonly filled prescriptions in the gastrointestinal category. Overall, suspensions were the most dispensed extemporaneously compounded dosage form at both community and hospital sites. In an era of personalized medicine, extemporaneous compounding for specialized needs will continue to play an important role in patient therapy. PMID- 25906623 TI - Compounding legislation: focus shifts to states. PMID- 25906624 TI - Quality control: can compounding pharmacy learn from the automotive industry? AB - The healthcare system is vast in scope, with constant concerns of how the system's major changes will affect the quality of future patient care. This article concerns only one small corner of the healthcare system--pharmaceutical compounding. Despite our best efforts, we are not going to single-handedly change all of the grim statistics, no matter how many years we are given or how much assistance Americans obtain from their international colleagues. Yet, the "good" news is that although in my opinion the overall quality of America's healthcare system has declined, perhaps the modest niche of compounding pharmacy can become a role model of what actually works and can offer immense opportunities to improve the efficiency and effectiveness of health care. PMID- 25906625 TI - Basics of sterile compounding: unique and special characteristics of sterile dosage forms. AB - Sterile dosage forms are unique pharmaceutical dosage forms with characteristics and requirements unlike any other dosage form. This article features and focuses on the seven unique characteristics of sterile dosage forms. PMID- 25906627 TI - Using Facebook to market your compounding pharmacy. PMID- 25906626 TI - Basics of compounding: tips and hints, part 6: Prescription evaluation, calculations, ingredients, quality-assurance practices, patient counseling, shipping and distribution, miscellaneous. PMID- 25906628 TI - Skin permeation and antinociception of topical gabapentin formulations. AB - Chronic pain affects greater than 116 million Americans each year. Even with the best pain management approaches, many chronic pain patients still suffer from moderate to severe pain. An alternative therapy to treat chronic pain includes compounded topical formulations of common analgesics. Compounded dosage forms of gabapentin are commonly used for pain management, however, the penetration and efficacy of gabapentin in these compounded topical formulations has not been fully studied. In this study, the transdermal penetration of gabapentin was studied in Franz diffusion cells using porcine skin. Gabapentin was compounded in two commercially available bases; Lipobase, Lipoderm, and a standard poloxamer lecithin organogel. The penetration and retention of gabapentin in the skin was dependent upon the base. The most rapid and greatest penetration and retention of gabapentin in the skin occurred with a poloxamer lecithin organogel base. Lipobase and Lipoderm bases produced slow and smaller penetration and retention of gabapentin as compared to poloxamer lecithin organogel base. Gabapentin 1% and 5% compounded in Lipoderm were tested in the in vivo preclinical formalin pain model. Topical 5% gabapentin produced a similar reduction in nociception in both Phase 1 and Phase 2 of the formalin response as systemic subcutaneous gabapentin (100 mg/kg). Topical 1% gabapentin reduced Phase 2, but not Phase 1 formalin induced nociceptive behaviors. These findings suggest that topical administration of gabapentin may produce local antinociception. PMID- 25906629 TI - In vitro skin penetration and skin content of progesterone from various topical formulations. AB - Progesterone has been compounded by pharmacists over the last decade using a variety of different dosage forms including, suppositories, troches, solutions, capsules, nasal sprays, creams, ointments, and gels. In particular, the topical/transdermal route has become very popular among physicians, compounders, and patients. There are a few studies in the medical literature that address the transdermal permeation of progesterone from topically applied dosageforms. The results are typically controversial with some studies showing permeation and others showing little to no permeation. Coupled with the high saliva levels that are often seen in patients undergoing topical/transdermal treatment with progesterone and the accompanying lack of progesterone blood levels, the transdermal route of delivery for progesterone is controversial. In this study, we examined the transdermal penetration of progesterone from four different formulations and the skin retention of progesterone in porcine skin. Our results indicate that only minute quantities of progesterone transdermally penetrated through the porcine skin. However, there was significant partitioning of progesterone in the skin tissues. Consequently, these results suggest that the lymphatic circulation that exists in the skin may potentially account for the systemic delivery of topically applied progesterone that is often observed clinically. PMID- 25906630 TI - Effect of emulsifier pairs on physical stability of emulsions containing three different natural oils. AB - The purpose of this study was to formulate oil-in-water (o/w) emulsions containing 40% w/w natural oil (i.e., olive oil, rice bran oil, or sesame oil), 10% w/w emulsifier blend, and 50% w/w water. The hydrophile-lipophile balance system was used to calculate the amount of each non-ionic emulsifier in the formulations. All studied oils have an identical required hydrophile-lipophile balance of 7. In emulsifier blend, polyoxyethylene (20) sorbitan monooleate (hydrophile-lipophile balance = 15.0) was fixed as a high hydrophile-lipophile balance emulsifier, while sorbitan monostearate (hydrophile-lipophile balance = 4.7) or sorbitan monooleate (hydrophile-lipophile balance = 4.3) was used as a low hydrophile-lipophile balance emulsifier. The effect of emulsifier pairs on physical properties of the prepared samples was investigated. The physical stability of the emulsions was evaluated at ambient temperature (~ 30 degrees C) after storage for 30 and 60 days. It was found that emulsifier pairs influenced both characteristics and stability of the samples. Sorbitan monostearate could provide stable emulsions of all studied natural oils when blended with polyoxyethylene (20) sorbitan monooleate while sorbitan monooleate could not. From the obtained results, it could be concluded that not only suitable hydrophile-lipophile balance but also suitable emulsifier pair were important parameters in emulsion formulations. PMID- 25906631 TI - High-performance liquid chromatographic method optimization for ondansetron assay in extemporaneous topical gel and in marketed products. AB - The compounding and evaluation of ondansetron hydrochloride dihydrate topical gel, 2.5% w/w, were conducted in this study. The gelling agent was Carbopol 940. Ethanol 70% in purified water was used to dissolve the drug and disperse the gelling agent. A gel was formed by adding drops of 0.1 N sodium hydroxide solution. To assay this gel, we developed a simple and reproducible stability- indicating high-performance liquid chromatographic method. This method was validated for specificity, accuracy, and precision. The compounded gel was assayed in triplicate, and the average recovery was 98.3%. Ondansetron marketed products were analyzed for comparison with the compounded formulation. Assay, accuracy, and precision data of the compounded topical gel were comparable to the marketed products. PMID- 25906632 TI - Pharmacy Compounding Accreditation Board: past, present, and future. PMID- 25906633 TI - The efficacy of bevacizumab in diabetic macular oedema in a 12-month follow-up. AB - PURPOSE: To evaluate visual acuity and anatomic response of the macula following intravitreal bevacizumab injections in diabetic macular oedema. MATERIAL AND METHODS: In the retrospective, non-randomised study 35 eyes of 28 subjects (whose mean age was 59.6 years) with focal or diffuse diabetic macular oedema were included. Patients underwent best corrected visual acuity testing with Snellen charts converted to a number of letters, intraocular pressure measurement, slit lamp examination, macular biomicroscopy, central macular thickness measurement by optical coherence tomography as well as fluorescein angiography at baseline and all follow-up visits. Patients were treated with one or two intravitreal injections of 1.25 mg of bevacizumab. RESULTS: A total of 49 intravitreal injections were performed. All patients had a 6-12-month follow-up after the first injection. The mean baseline best-corrected visual acuity was 5.0 +/- 4.3 letters and the mean central macular thickness in the baseline optical coherence tomography was 482.0 +/- 109.7 MUm. An improvement in the mean best-corrected visual acuity (6.2 +/- 6.3, p = 0.020) and central macular thickness (426.8 +/- 131.7 MUm, p = 0.010) was statistically significant during the follow-up after first injection. There was no statistically significant difference in the best corrected visual acuity (6.2 +/- 6.5, p = 0.055) and central macular thickness (461.2 +/- 148.3 MUm, p 0.200) after the second injection. There was no correlation between the best corrected visual acuity and central macular thickness. No serious adverse events were observed. CONCLUSIONS: Intravitreal bevacizumab injections significantly improve visual acuity and decrease central macular thickness in patients with diabetic macular edema. This treatment is safe for patients but the therapeutic effect is temporary. PMID- 25906634 TI - Evaluation of macular thickness after uneventful phacoemulsification in selected patient populations using optical coherence tomography. AB - PURPOSE: To quantitatively evaluate the effect of uneventful phacoemulsification on central retinal thickness and foveal volume with regard to the following factors: age, gender, systemic diseases: diabetes mellitus, arterial hypertension, coronary heart disease, phacoemulsification parameters (power and time); and to identify patient population at high risk of postoperative changes in macular thickness. MATERIAL AND METHODS: 87 eyes of 87 patients were examined. Foveal volume and central retinal thickness were measured using optical coherence tomography on postoperative days 1, 7, 30, 90 and 180. 10 patients did not complete the study, because of independent factors, these were excluded from the analysis. The results were analyzed within the predefined patient groups. RESULTS: There was a significant increase of central retinal thickness and foveal volume values on postoperative days 7, 30, 90 and 180, as compared to baseline (1st day after surgery). These values were higher in males and in patients with coronary heart disease. The presence of diabetes and hypertension was associated with the increased central retinal thickness, especially when both considered factors were present. No significant relation was found between the patient age and central retinal thickness during the 6-month's follow up. However, a significant association was observed between the age and the risk of retinal thickening. Higher phaco power (over 40.0%) settings increased both central retinal thickness and the risk of retinal thickening during the follow-up period. CONCLUSION: There is a significant increase in macular parameters after uneventful phacoemulsification. Despite downward trend, they remain elevated throughout the 6-month observation period. Diabetes and hypertension increase the risk of post-operative changes in macular thickness, especially if they coexist. Higher phaco power increases the risk of retinal thickening after cataract surgery. Early macular evaluation using the optical coherence tomography identifies patients at high risk of complications, who might benefit from additional anti-inflammatory treatment. PMID- 25906635 TI - [Evaluation of quality of life of patients after phacoemulsification with accommodating lens implantation]. AB - INTRODUCTION: Intraocular lens implantation is an important part of cataract surgery, as it has a significant influence on the final result. Accommodative intraocular lenses (IOLs) are the latest solution for the lack of accommodation in pseudophakic eyes. PURPOSE: To evaluate the quality of life of patients who underwent cataract surgery with accommodating IOL implantation and to compare the data with results of patients after standard monofocal IOL implantation. MATERIAL AND METHODS: The study group consisted of 20 patients (40 eyes), aged from 48 to 73 years old, who underwent phacoemulsification through a 2.75 mm clear corneal incision followed by the implantation of an accommodating IOL Crystalens HD (Bausch & Lomb, USA). The control group consisted of 20 patients (40 eyes), aged from 63 to 83 years old, who underwent phacoemulsification through a 2.75 mm clear corneal incision followed by the implantation of a standard monofocal single-piece acrylic intraocular lens AcrySof (Alcon, USA). All enrolled patients had no coexisting ocular diseases which could influence the final visual acuity. All surgeries were uneventful. At one month postoperatively, the patients were requested to answer 36 questions included in the questionnaire in order to evaluate the quality of visual function. RESULTS: There was a significant improvement in the quality of life in both groups after cataract surgery. The study group tended to assess their own eyesight higher than the control group. Patients from the study group use spectacle correction for a lower number of activities, they find it easier to use fine motor skills when performing activities without spectacle correction in comparison with patients from the control group. Patients from the study group use spectacle correction for reading significantly less frequently, they also find it easier to read the normal size and small print without spectacle correction, in comparison with patients from the control group. CONCLUSIONS: Patients with accommodating IOLs self-evaluate their own eyesight highly, use spectacle correction for a lower number of activities and find it significantly easier to perform precise activities without spectacle correction, in comparison with patients after the standard monofocal intraocular lens implantation. PMID- 25906636 TI - [Anatomical and functional results of pars plana vitrectomy with the internal limiting membrane removal in patients with rhegmatogenous retinal detachment]. AB - AIM: To evaluate the benefits of the internal limiting membrane removal in patients with rhegmatogenous retinal detachment who underwent pars plana vitrectomy. MATERIAL AND METHODS: The first study group (B) consisted of 26 patients who underwent vitrectomy with the internal limiting membrane peeling. The second control group (K) consisted of 15 patients, in whom vitrectomy was performed without he internal limiting membrane peeling. Macular detachment was confirmed preoperatively in all patients. Ophthalmic examination was performed 6 months after surgery. This included the best corrected visual acuity for distance and near, M-Charts, fundus examination and spectral domain--optical coherent tomography. RESULTS: The results were statistically analyzed using the Shapiro Wilk test and the Ch2 test of homogeneity. In the study group (B), the mean postoperative best corrected visual acuity for distance was 0.46, while in the control group (K) it was 0.35 (p = 0.35). The best corrected visual acuity for near in group B was 0.83 and 1.01 (p = 0.63) in group K. Central retinal thickness in group B was 268.64 MUm, while in group K it was 335.07 MUm (p = 0.20). The statistical analysis revealed significant differences between the two groups regarding the prevalence of defects in the ellipsoidal layer (p = 0.004). They were found to occur more frequently in group K (64.29%) than in group B (20.00%). The prevalence of epiretinal membrane was higher in group K (28.57%) than in group B (3.85%) (p = 0.02). CONCLUSIONS: The internal limiting membrane peeling reduces the risk of secondary epiretinal membrane, restores the ellipsoidal layer integrity and does not affect the visual acuity for distance and near. PMID- 25906637 TI - [Bilateral choroidal osteoma--a case report]. AB - Choroidal osteoma is a an extremely rare (especially located bilaterally), benign, intraocular tumor, the type of choristoma. It occurs between 2-3 decades of life, women are particularly vulnerable. The main complication in 1/3 cases is a subretinal neovascularization which may cause bleeding. The gradually progressive decalcification develops within the tumour over time, which causes atrophy of the retinal pigment epithelium and Bruch's membrane deformity. The article presents a case of a 26-year-old woman with bilateral choroidal osteoma complicated by subretinal hemorrhage; the diagnosis was based on clinical examination (biomicroscopy and indirect ophthalmoscopy) as well as specialised tests including: ultrasonography, optical coherence tomography, and fluorescein angiography. PMID- 25906638 TI - [Plexiform neurofibroma of the upper eyelid and orbit in a patient with von Recklinghausen's disease--case report]. AB - Neurofibromatosis type 1 is an autosomal dominant genetic disease, which belongs to the neuro-oculo-cutaneous syndromes (phakomatoses). The authors present a case of a girl with familial neurofibromatosis. In addition to typical skin lesions and Lisch nodules on the iris, the plexiform neurofibroma of the upper eyelid and orbit as well as hamartoma of the central nervous system were observed. Due to the massive infiltration of the left upper eyelid causing its complete ptosis and, in turn, the amblyopia of the left eye, the tumour was partially rexcised. This lesion is not totally removable in most cases due to the early development of neurofibroma during the fetal period and its strong adhesion to the healthy tissues. A massive eyelid infiltration causing amblyopia and dissociation of binocular vision is an indication for early surgery. PMID- 25906639 TI - Asteroid hyalosis--current state of knowledge. AB - The search query into the Cochrane Library, Medline, Web of Science, Embase, Scopus and ScienceDirect enabled selection of research papers addressing the issue of asteroid hyalosis published in English between 1963 and January 2014. Asteroid hyalosis is a degenerative condition of the vitreous in which small, creamy or white, spherical particles (asteroid bodies) are randomly diffused within the vitreous. They consist mainly of calcium and phosphorus and have a structure of hydroxy lapatite. In 80.2-92.0% of cases the condition affects one eye only and it occurs in 0.36-1.96% of population, mostly in patients over 50 years of age and in males. Hypercholesterolemia and hypertension are systemic risk factors, but asteroid hyalosis is postulated to occur more often in retinitis pigmentosa and Leber amaurosis caused by mutations in lecithin retinol acyltransferase gene. Asteroid hyalosis also causes calcification of some intraocular lenses--mostly silicone ones. Vitreous of patients with asteroid hyalosis shows reduced gel liquefaction and anomalous vitreoretinal adhesion. PMID- 25906640 TI - [Current concepts in pathogenesis of age-related macular degeneration]. AB - Age-related macular degeneration is the leading cause of central blindness in elderly population of the western world. The pathogenesis of this disease, likely multifactorial, is not well known, although a number of theories have been put forward, including oxidative stress, genetic interactions, hemodynamic imbalance, immune and inflammatory processes. The understanding of age-related macular degeneration pathogenesis will give rise to new approaches in prevention and treatment of the early and late stages of both atrophic and neovascular age related macular degeneration. PMID- 25906641 TI - [Witold Jodko-Narkiewicz (1834-1898)--the first Head of the Ophthalmic Institute in Warsaw, Poland]. AB - Witold Jodko-Narkiewicz (1834-1898), a Polish ophthalmologist, the head of the Ophthalmic Institute in Warsaw. He studied medicine at the University of Dorpat. In 1860, he received the title of Doctor of Medicine and became the Associate Professor in 1862. His son Thomas (1864-1924)--a journalist and politician, was a friend of Jozef Pilsudski and Wladyslaw Sikorski. Witold Jodko-Narkiewicz was the author of more than 80 clinical and research works. They concerned surgical and diagnostic techniques, treatment of ocular injuries, neuro-ophthalmology, ophthalmic oncology and pharmacology. The translation of Wecker's Ophthalmology by Jodko-Narkiewicz and Gepner deserves particular attention. PMID- 25906643 TI - [Unresolved problems and the prospects for research in area of the multiple sclerosis: virologic, immunologic and therapeutic aspects]. AB - Multiple sclerosis--important and unsolved problem of modern neurology. Despite a great deal of publications, in the modern theory of multiple sclerosis there remain many unresolved problems, without solving of which no further advances in the diagnosis and treatment can be possible. The present work elucidates blind spots in pathogenesis of the disease to indicate the most perspective directions of research, the results of which would allow the optimization of existing diagnostic and therapeutic algorithms. Microbial triggers, immunopathological mechanisms, association with immunodeficiencies, efficacy of the immunotherapy and side effects of the immunosuppressants as well as additional antimicrobial treatment are discussed. PMID- 25906644 TI - [Influence of the technogenic environment on health new-borns infant children in Lugansk region]. AB - The aim of the work was to evaluate the health of new-borns born to mothers who lived constantly influenced of the technogenic environmentat on health infant children in Luhansk region. We exameded evaluation of the influence of the technogenic environmental factors on the health of 1119 children in Alchevsk city, Perevalsk town with mining towns and rural villages of Perevalsky area of Lugansk region and Zhovtnev district of Lugansk region. The children were measured in anthropometric studies conducted body length, body weight, chest circumference and the head. Evaluation of the physical development of the children carried tsentilnym method. Prior to discharge from the hospital new borns divided into three main groups--healthy, risk group, pathology. Also we have done the analysis of the statistical information on the health status of all newborns administrative units Lugansk region. Found that the percentage of new borns with normal anthropometric variables (from 3 to 97 centile), body length and head circumference was significantly higher in rural areas Perevalsky area with more favorable environmental conditions compared to the industrial city of Alchevsk. New-borns with abnormal significantly higher in women who are domiciled in the city of Alchevsk (19.01% +/- 1.44%) under the impact of emissions components ferrous metallurgy and coke-chemical, compared with Perevalskiy and mining towns (13.82% +/- 2.20%), as well as rural villages Perevalsky area (11.90% +/- 2.89%). Over the period 2004-2011, the incidence of congenital anomalies of new-borns weighing 1000 g or more (per 1000 live births and stillbirths) were significantly higher in the industrial cities of Luhansk region -19.70 +/- 0.61 compared with rural areas--15.51 +/- 0.73. The incidence of this pathology is one of the highest in Alchevsk--31.88 +/- 2.48, which was significantly higher than.in urban areas, as well as in the whole of Luhansk region--19.13 +/- 0.55. Therefore, the health of new-born babies is determined by man-made ecological environment of life. The preventive recommendations are developed. PMID- 25906645 TI - [Peroxysome proliferator-activated receptors at pathogenesis and treatment of atherosclerosis (achievements, paradoxes and perspectives)]. AB - All three types of peroxisome proliferation activating rexeptiors (PPAR): alpha, beta/delta and gamma, are sensors of fat acids and their derivatives and carry out the transcription adjusting of genes of exchange of lipids, including circulation of cholesterol and sensitiveness of tissues to insulin. They possess antiinflammatory properties, control activity of cells of the immune system, endothelia and smooth musculature of vessels. Such combination of functions does PPAR an ideal target for a prophylaxis and treatment of atherosclerosis. Nevertheless, 20-years-old experience of the use of tiazolidinodiones--agonists of PPARgamma, as antidiabetic facilities, did not bring to the decline of morbidity and death rate of patients with diabetes mellitus 2 types from cardiovascular complication. The only exception is pioglitazone, which significantly reduces the mortality rate of patients with T2DM remains effective in the prevention and treatment of atherosclerosis. Effective not enough in this plan and fibrates--agonists of PPARa. Possible reasons of it and nearest perspestives are examined in a review. PMID- 25906646 TI - [The up-to-date methods of management of NSAIDs-induced injuries of small intestine]. AB - In the article the incidence, pathogenesis, clinical featuries, diagnostic, prevention and treatment of NSAIDs-induced injuries of small intestine are presented. The different strategies of management of NSAID-induced enteropathy, such as use of PPI, COX-2-inhibitors, prostaglandins, antibiotics and probiotics, new combination of NSAIDs with phosphatidylcholine, NO or H2S, food supplements and other drugs are discussed. PMID- 25906647 TI - [Role of polymorphism NO-synthase gene in the pathogenesis of multifactorial diseases]. AB - The review of the literature about the results of the study of the role of 4a/b VNTR-polymorphism of eNOS in pathophysiology of various states of the body. It is shown that the data are ambiguous and sometimes contradictory. The study of the contribution of candidate genes to the implementation of multifactorial diseases can increase the accuracy of prediction of the set of risk factors, early diagnosis facilitate and sufficient therapy of multifactorial diseases. PMID- 25906648 TI - [New possibilities of correction of hypercholesterolemia in patients with diabetes mellitus]. AB - This article presents scientific data to prove effect of statins on carbohydrate metabolism and the need to optimize hypolipidemic therapy in patients with diabetes. Systematized the available scientific data on the mechanism of action, parameters of hypolipidemic activity and the possibility of using policosanol. Author is giving us his own clinical experience with herbal drug FitoStatin (policosanol) in patients with diabetes based on 6-month follow-up. PMID- 25906649 TI - [Influence of dopamine receptors agonists on clinical and hemodynamic and neurohumoral indicators in hypertensive patients with concomitant obesity]. AB - The article analyzes the results of studying the effects of antihypertensive treatment with the use of agonists dopamine receptors on clinical and hemodynamic and neurohumoral indicators in hypertensive patients with concomitant obesity. Special role is given to the patogenetice factor as dopamine and his relationship with the renin - angiotensin.- aldosterone system, endothelial function, which are aimed at the regulation of blood pressure and obesity formation and progression. PMID- 25906650 TI - [Changes of the hemodynamics, heart structure and functional state in patients with reactive arthritis]. AB - Our investigation showed for the patients with reactive arthritis typical is hyperkinetic type of haemodynamic, and also structural changes of the heart which manifestate by interventricular partition's thickness as a result of inflammatory edema and it's valve consolidation frequently whithout expressed blood regurgitation, and diastolic dysfunction's development of the left and right heart ventricles in hypertrophic type with disorders of their active relaxation and growth their chamber's rigidity. These changes, probably, evidence about development of the inflammatory cardiopathy in these patients and can be preconditions of the heart failure. PMID- 25906651 TI - [Metabolic consequences of preclinical glycemia in patients with pulmonary tuberculosis]. AB - Studied concentration of glycosylated hemoglobin in patiens with lung tuberculosis with disorders of tolerance to glucosis and glukemic disorders on an empty stomach and in patients, which had not such disorders. Medium of glycosylated hemoglobin concentration in patients with preclinical disorders glukemia takes middle position between of concentration HbA(1c) in healthy people and diabetes mellitus. This is indicative of stabilities of hyperglukemic episodes during previous 6-9 weeks. Got by us results persuasively about indicative of need of the goal-directed correction of preclinical disorders carbohydrate metabolism in patients with pulmonary tuberculosis. PMID- 25906652 TI - [State of intestinal microbiota in patients with type 2 diabetes mellitus and non alcoholic fatty liver disease]. AB - High prevalence of type 2 diabetes mellitus (DM) and nonalcoholic fatty liver disease (NAFLD) contributes to the intensification of scientific research the aim of which is to improve existing treatment. It is given the data about the state of intestinal microbiota in 64 patients with type 2 DM and NAFLD, 26 patients with type 2 DM and 28--with NAFLD. The research revealed significant changes in microbiota composition in patients with type 2 DM combined with NAFLD. Decompensated dysbiosis was registered in 71.9% of patients in this group which manifested in increased quantitative indicators of transient microflora crop with pathogenic characteristics and lack of microflora with protective characteristics. PMID- 25906653 TI - [The survivability of patients with cervical cancer of IIB stage]. AB - To the present tense finally mine-out not tactic of treatment of patients with the cervical cancer (CC) of IIB stage, but in the standards of diagnostics and treatment there are different variants of treatment of this pathology, and choice, most optimum, as a rule, depends on subjective opinion of doctor. Consequently, purpose of our work--to promote efficiency of treatment of patients on CC IIB the stage, by application of neoadjuvant chemotherapy in the combined treatment. The results of treatment are analysed 291 patients on CC IIB stages which got radical treatment in Ivano-Frankivsk OKOD from 1998 to 2013 years. At the use of neoadjuvant chemotherapy index of general 5-years-survival and nonrecurrence survivability made 74.4% and 70.8%, and to preoperative chemotherapy--70.8% and 68.3% accordingly. At application of independent chemoradial therapy, to the index of general 5-years-survival and nonrecurrence survivability was 51.1% and 49.3%, accordingly. It is not exposed reliable difference (P < 0.05) at comparison of indexes of 5-years-survivability of patients which have got the combined methods of treatment, but a reliable difference is exposed when compared to patients which have got independent chemoradial therapy (P > 0.05). Consequently, application of the combined methods of treatment of patients of CC IIB stages were improved by indexes general 5 years and to nonrecurrence survivability by comparison to independent cheradial therapy. . PMID- 25906654 TI - [Pulmonary atresia with ventricular septal defect and major aorto-pulmonary collateral arteries: diagnosis and treatment]. AB - The basic principles of diagnosis and management of pulmonary atresia with ventricular septal defect and major aorto-pulmonary collateral arteries are systematizes in this paper. The personal experience of surgical treatment of consecutive 66 patients with this disease is analyzed, including one-stage and multistage approaches. PMID- 25906655 TI - [Structural changes of the neuronal and stromal components of the n. tibialis in the case of diabetes mellitus]. AB - The author of the article has studied structural changes of the neuronal and stromal components of the n. tibialis in the case of diabetes mellitus. It has been established that axonopathy, myelinopathy and sclerosis of the endo-, peri-, edpineurium occur in the case of diabetes mellitus. PMID- 25906656 TI - [Autonomic regulation at emotional stress under hypoxic conditions in the elderly with physiological and accelerated aging: effect of hypoxic training]. AB - The effect of hypoxic training on autonomic regulation in psycho-emotional stress conditions in hypoxic conditions in older people with physiological (25 people) and accelerated (28 people) aging respiratory system. It is shown that hypoxic training leads to an increase in vagal activity indicators (HF) and reduced simpatovagal index (LF/HF), have a normalizing effect on the autonomic balance during stress loads in older people with different types of aging respiratory system. PMID- 25906657 TI - [The nature of postoperative complications in patients with peritonitis]. AB - We studied the postoperative period in patients with peritonitis. The structure of the most important factors that slow down the healing process and lead to mortality. Among the factors that affect the healing process is the most important character of fluid, and the prevalence of peritonitis (causative factor), which causes complications on the part of the internal organs and wounds. PMID- 25906658 TI - [The efficacy of immunoprevention of intrauterine infections in women with herpes virus]. AB - For the prevention of intrauterine infection in pregnant women in the identification of herpes virus infection in the acute stage or the presence of chronic infectionin combination with a complicated obstetric and gynecological history (miscarriage, still birth, intrauterine infection in a child) is recommended to treats pecific immunoglobulins. The studies demonstrated the efficacy of such a therapeutic and prophylactic complex, as.confirmed by the improvement of children's condition at birth, reduced frequency disadaptation syndromes, clinical signs of intrauterine infection (pneumonia, etc.), neonatal mortality, a decrease at 41.7% intrauterine infection frequency by laboratory test. PMID- 25906659 TI - [Optimization of long-term treatment with rosuvastatin of patients with myocardial infarction in combination with non-alcoholic steatohepatitis]. AB - Dynamics of indices of lipidograma, functional state of liver and level C reactive of protein (CRP) was investigated in 36 patients with heart attack of myocardium diseases in combination with non-alcoholic steatohepatitis, who received 9-months treatment by rosuvastatin of 20 mg dose and rosuvastatin of 10 mg dose in combination with ursodeoxycholic acid (UDCA), in a comparative aspect. The equivalence of hypolipidemia effect of both conditions reliable advantage in decline of triglycerides level and CRP normalization under the influence of combined therapy was discovered. The treatment by combination of rosuvastatin of 10 mg dose with UDCA has shown the advantages in comparison with the treatment by rosuvastatin of 20 mg dose in decline and normalization of transaminases and gamma-glutamiltranspeptidase activity. The data obtained resulted in optimization of standard treatment by statins of patients with heart attack of myocardium diseases in combination with non-alcoholic steatohepatitis by means of combination the initial rosuvastatin dose with UDCA. PMID- 25906660 TI - [Experience of Vasonat usage in treatment of patients with chronic toxic hepatitis]. AB - The authors performed the clinical study of efficiency of Vasonat usage in complex treatment of chronic toxic hepatitis. Under observation there were 122 patients with chronic toxic hepatitis (37--with chronic medicament hepatitis and 85--with chronic alcohol hepatitis). During treatment with Vasonat the severity of clinical signs decreased to 0-1 points, GGTP level decreased in 2,2 times that showed the better efficiency of Vasonat usage compare with basis treatment. Thus Vasonat in dosage 500 mg per day may be recommend to inclusion on complex treatment of patients with chronic toxic hepatitis. PMID- 25906661 TI - [Correlation of adiponectin in patients with type 2 diabetes with nonalcoholic fatty liver disease depending on transaminases level]. AB - We studied the changes of serum adiponectin and it correlations in patients with type 2 diabetes (T2D) and NAFLD related to transaminases levels. Serum adiponectin levels were significantly lower in the increased ALT group than in the normal ALT and control group. After adjusting for age, sex, and adiposity adiponectin was significantly correlated in control group with fasting insulin, and insulin resistance by homeostasis model of assessment (HOMA-IR); in the normal ALT group with HDL-cholesterol , triglycerides, fasting insulin and HOMA IR; in the elevated transaminases group with ALT, fasting insulin and HOMA-IR. Step-wise multiple linear regression analyses demonstrated that in NAFLD with normaltransaminases, independent predictors of adiponectin was HOMA-IR, triglycerides, BMI and duration of T2D. In NAFLD with elevated transaminases, adiponectin was associated with HOMA-IR, BMI, male genderand ALT. PMID- 25906662 TI - [Influence of iron nanoparticles on cardiac performance and hemodynamics in rabbits after intravenous administration in acute experiment]. AB - Iron nanoparticles are possessed by high potential in the creation of effective and safe antianemic drugs due to the enhanced biological activity of metal nanoparticles. As a step of intravenous dosage form development the study of short-term effects of iron nanoparticles on the cardiovascular system is important. Dose-dependent changes of systemic hemodynamics' parameters were established in acute experiment on rabbits after several intravenous injections of zero-valent iron nanoparticles solution. PMID- 25906663 TI - [Study of the effect of colloidal solution of silver nanoparticles on parameters of cardio- and hemo-dynamics in rabbits]. AB - Metal nanoparticles and silver nanoparticles in particular are extensively studied recently considering their prominent antimicrobial properties. Nevertheless, their toxicity aspects and probable side effects remain not well studied. In this article the results of study of the influence of silver nanoparticles onto a cardiovascular system in an in vivo experiment were provided, changes in parameters of cardio- and hemodynamics were defined, and the principles of such influence were identified. Dose-dependent effect of these nanoparticles was established when administered in dose of 4.3 mg/kg three times and 20 mg/kg once. PMID- 25906664 TI - [Research of the durability of connective tissue complexes formed in the implantation area of various types of allograft during the experiment]. AB - The aim of the study is to examine in the experiment on the animals the mechanical properties of connective tissue complexes formed in alloplasty area using the intraperitoneal on lay mesh and sublay methodologies with further comparison of them. The experiment has been conducted on 12 rabbits of Russian chinchilla breed. Animals were distributed in the following way: the first group- operated by intraperitoneal on lay mesh methodology (n = 6) through implantation of composite grid Proceed with one-side celullose coating produced by "Ethicon" company. The second group--performed modeling of preperitoneal plastic using two component composite grid with large-pores Ultrapro produced by "Ethicon" company (n = 6). For the tensometric evaluation of the strength of implant integration into the red wall was used entire area of anterior red wall together with the implanted transplant. According to the deflection diagrams and dynamometer rates defined the maximum burden rates which is equivalent of muscular tissue budge against polymeric matrix. Statistically significant distinctions during 14 days were not detected; however strength during 30 days in the first group was 3 times higher than in the second group. We consider that the methodology of intraperitoneal on lay mesh can be considered as operation of choice of surgery treatment of the umbilical hernias. PMID- 25906665 TI - [Change of well-being and of the emotional state of students upon learning of teaching material]. AB - This article presents the results of studying the dynamics of changes in indicators being recorded by students V-VIII classes of secondary schools in Kiev during the process of development of educational information. In addition, the article shows the results of the study the patterns of the indicators of the emotional state of the representatives of this category of students. It is established that there is a relationship between the values of indicators of health and emotional state school and degree that the level of complexity of the material being studied individual abilities of students about their ability to appreciate and understand the essence of a full training material. The more high performance, indicating a deterioration of health and emotional state, were among those students who strive to achieve excellent results in their studies, but for some reason failed to achieve them. In contrast, the most favorable figures were well-being and emotional state of the two categories of students: those students whose individual capacities for perception and Learning scales with difficulty, and those students who are not particularly sought to achieve good results in studies. PMID- 25906666 TI - [Health status of occupants in the prison system of Ukraine]. AB - It is set research, that for the last five years (2006 for 2011) the level of general morbidity among the contingent of establishments of implementation of punishments went down concerning all illnesses on 14%, and primary--on 25%. At the same time, prevalence of illnesses of blood among the contingent of establishments of implementation of punishments for the same period grew on 64%, psychical illnesses on 10%, and nervous--on 19%. Primary morbidity on illness of blood grew on 83%, and concerning psychical illnesses--on 94%. State of health of contingent, which is in SIZO, is considerably worse than health already convict. Found out the difference of indexes of health at the contingent of establishments of implementation of punishments in the separate areas of Ukraine, as on general so primary morbidity. Changes in the levels of general and primary morbidity contingent jail were the same as contingent convicted in some areas, but much more pronounced. PMID- 25906667 TI - Variance Distribution in Sibling Relationships: Advantages of Multilevel Modeling Using Full Sibling Groups. AB - The majority of research on sibling relationships has investigated only one or two siblings in a family, but there are many theoretical and methodological limitations to this single dyadic perspective. This study uses multiple siblings (541 adults) in 184 families, where 96 of these families had all siblings complete the study, to demonstrate the value in including full sibling groups when conducting research on sibling relationships. Two scales, positivity and willingness to sacrifice, are evaluated with a multilevel model to account for the nested nature of family relationships. The distribution of variance across three levels: relationship, individual, and family are computed, and results indicate that the relationship level explains the most variance in positivity, whereas the individual level explains the majority of variance in willingness to sacrifice. These distributions are affected by gender composition and family size. The results of this study highlight an important and often overlooked element of family research: The meaning of a scale changes based on its distribution of variance at these three levels. Researchers are encouraged to be cognizant of the variance distribution of their scales when studying sibling relationships and to incorporate more full sibling groups into their research methods and study design. PMID- 25906668 TI - Longitudinal Stability of Genetic and Environmental Influences on Irritability: From Childhood to Young Adulthood. AB - OBJECTIVE: Little is known about genetic influences on juvenile irritability and whether such influences are developmentally stable and/or dynamic. This study examined the temporal pattern of genetic and environmental effects on irritability using data from a prospective, four-wave longitudinal twin study. METHOD: Parents and their twin children (N=2,620 children) from the Swedish Twin Study of Child and Adolescent Development reported on the children's irritability, defined using a previously identified scale from the Child Behavior Checklist. RESULTS: Genetic effects differed across the sexes, with males exhibiting increasing heritability from early childhood through young adulthood and females exhibiting decreasing heritability. Genetic innovation was also more prominent in males than in females, with new genetic risk factors affecting irritability in early and late adolescence for males. Shared environment was not a primary influence on irritability for males or females. Unique, nonshared environmental factors suggested strong effects early for males followed by an attenuating influence, whereas unique environmental factors were relatively stable for females. CONCLUSIONS: Genetic effects on irritability are developmentally dynamic from middle childhood through young adulthood, with males and females displaying differing patterns. As males age, genetic influences on irritability increase while nonshared environmental influences weaken. Genetic contributions are quite strong in females early in life but decline in importance with age. In girls, nonshared environmental influences are fairly stable throughout development. PMID- 25906669 TI - The Intergenerational Transmission of Anxiety: A Children-of-Twins Study. AB - OBJECTIVE: The transmission of anxiety within families is well recognized, but the underlying processes are poorly understood. Twin studies of adolescent anxiety demonstrate both genetic and environmental influence, and multiple aspects of parenting are associated with offspring anxiety. To date, the children of-twins design has not been used to evaluate the relative contributions of genetic transmission compared with direct transmission of anxiety from parents to their offspring. METHOD: Anxiety and neuroticism measures were completed by 385 monozygotic and 486 dizygotic same-sex twin families (37% male twin pair families) from the Twin and Offspring Study in Sweden. Structural equation models tested for the presence of both genetic and environmental transmission from one generation to the next. RESULTS: For both anxiety and neuroticism, the models provide support for significant direct environmental transmission from parents to their adolescent offspring. In contrast, there was no evidence of significant genetic transmission. CONCLUSIONS: The association between parental and offspring anxiety largely arises because of a direct association between parents and their children independent of genetic confounds. The lack of genetic transmission may reflect there being different genetic effects on these traits in adolescence and adulthood. Direct environmental transmission is in line with developmental theories of anxiety suggesting that children and adolescents learn anxious behaviors from their parents through a number of pathways such as modeling. Future analyses should combine children-of-twins data with child twin data in order to examine whether this direct effect solely represents parental influences on the offspring or whether it also includes child/adolescent anxiety evoking parental anxiety. PMID- 25906671 TI - Simulation models in population breast cancer screening: A systematic review. AB - The aim of this review was to critically evaluate published simulation models for breast cancer screening of the general population and provide a direction for future modeling. A systematic literature search was performed to identify simulation models with more than one application. A framework for qualitative assessment which incorporated model type; input parameters; modeling approach, transparency of input data sources/assumptions, sensitivity analyses and risk of bias; validation, and outcomes was developed. Predicted mortality reduction (MR) and cost-effectiveness (CE) were compared to estimates from meta-analyses of randomized control trials (RCTs) and acceptability thresholds. Seven original simulation models were distinguished, all sharing common input parameters. The modeling approach was based on tumor progression (except one model) with internal and cross validation of the resulting models, but without any external validation. Differences in lead times for invasive or non-invasive tumors, and the option for cancers not to progress were not explicitly modeled. The models tended to overestimate the MR (11-24%) due to screening as compared to optimal RCTs 10% (95% CI - 2-21%) MR. Only recently, potential harms due to regular breast cancer screening were reported. Most scenarios resulted in acceptable cost effectiveness estimates given current thresholds. The selected models have been repeatedly applied in various settings to inform decision making and the critical analysis revealed high risk of bias in their outcomes. Given the importance of the models, there is a need for externally validated models which use systematical evidence for input data to allow for more critical evaluation of breast cancer screening. PMID- 25906672 TI - The impact of pain on health-related quality of life 3 months after stroke. AB - BACKGROUND: Pain is common in stroke; however, its impacts on health-related quality of life (HRQoL) are unclear due to the limitations of previous studies. OBJECTIVES: The current study aims to examine and compare the demographic and clinical characteristics of Chinese stroke patients with and without pain and explore the correlations between poststroke pain and HRQoL. METHOD: Four hundreds and forty-one participants recruited in an acute stroke unit in a regional hospital. They were assessed 3 months after the index stroke with the following instruments. HRQoL was measured using the Short Form-12 (SF-12). The Chinese version of the Faces Pain Rating Scale-Revised (FPS-R) was used to determine the presence and intensity of pain. The demographic and clinical characteristics of patients were obtained using Barthel Index (BI), Fatigue Severity Scale (FSS), Geriatric Depression Scale (GDS), Anxiety subscale of the Hospital Anxiety and Depression Scale (HADSA), Instrumental Activities of Daily Living (IADL), Mini Mental State Examination (MMSE), Modified Rankin Scale (MRS), and National Institutes of Health Stroke Scale (NIHSS). RESULTS: Of all participants screened, 167 reported pain and 69 had novel pain. The pain group had significantly lower physical component summary (PCS) scores after adjusting for sex, education, DSM IV depression and BI, GDS, HADSA, and FSS scores. The FPS score was negatively correlated with a lower PCS score in patients with pain and with novel pain. CONCLUSION: The presence and intensity of pain have significant negative effects on HRQoL in stroke survivors. Interventions for pain could make a valuable contribution to improving HRQoL in stroke survivors. PMID- 25906670 TI - Lack of weight gain after angiotensin AT1 receptor blockade in diet-induced obesity is partly mediated by an angiotensin-(1-7)/Mas-dependent pathway. AB - BACKGROUND AND PURPOSE: Angiotensin AT1 receptor antagonists induce weight loss; however, the mechanism underlying this phenomenon is unknown. The Mas receptor agonist angiotensin-(1-7) is a metabolite of angiotensin I and of angiotensin II . As an agonist of Mas receptors, angiotensin-(1-7) has beneficial cardiovascular and metabolic effects. EXPERIMENTAL APPROACH: We investigated the anti-obesity effects of transgenically overexpressed angiotensin-(1-7) in rats. We secondly examined whether weight loss due to telmisartan (8 mg.kg(-1) .d(-1) ) in diet induced obese Sprague Dawley (SD) rats can be blocked when the animals were co treated with the Mas receptor antagonist A779 (24 or 72 MUg.kg(-1) .d(-1) ). KEY RESULTS: In contrast to wild-type controls, transgenic rats overexpressing angiotensin-(1-7) had 1.) diminished body weight when they were regularly fed with chow; 2.) were protected from developing obesity although they were fed with cafeteria diet (CD); 3.) showed a reduced energy intake that was mainly related to a lower CD intake; 5.) remained responsive to leptin despite chronic CD feeding; 6.) had a higher, strain-dependent energy expenditure, and 7.) were protected from developing insulin resistance despite CD feeding. Telmisartan induced weight loss in SD rats was partially antagonized after a high, but not a low dose of A779. CONCLUSIONS AND IMPLICATIONS: Angiotensin-(1-7) regulated food intake and body weight and contributed to the weight loss after AT1 receptor blockade. Angiotensin-(1-7)-like agonists may be drug candidates for treating obesity. PMID- 25906673 TI - Noninvasive Imaging of Activated Complement in Ischemia-Reperfusion Injury Post Cardiac Transplant. AB - Ischemia-reperfusion injury (IRI) is inevitable in solid organ transplantation, due to the transplanted organ being ischemic for prolonged periods prior to transplantation followed by reperfusion. The complement molecule C3 is present in the circulation and is also synthesized by tissue parenchyma in early response to IRI and the final stable fragment of activated C3, C3d, can be detected on injured tissue for several days post-IRI. Complement activation post-IRI was monitored noninvasively by single photon emission computed tomography (SPECT) and CT using (99m) Tc-recombinant complement receptor 2 ((99m) Tc-rCR2) in murine models of cardiac transplantation following the induction of IRI and compared to (99m) Tc-rCR2 in C3(-/-) mice or with the irrelevant protein (99m) Tc-prostate specific membrane antigen antibody fragment (PSMA). Significant uptake with (99m) Tc-rCR2 was observed as compared to C3(-/-) or (99m) Tc-PSMA. In addition, the transplanted heart to muscle ratio of (99m) Tc-rCR2 was significantly higher than (99m) Tc-PSMA or C3(-/-) . The results were confirmed by histology and autoradiography. (99m) Tc-rCR2 can be used for noninvasive detection of activated complement and in future may be used to quantify the severity of transplant damage due to complement activation postreperfusion. PMID- 25906676 TI - Opinion paper: is there a role for breeding for welfare improvement? PMID- 25906674 TI - Differential kinetics of response and toxicity using stereotactic radiation and interventional radiological coiling for pulmonary arterio-venous shunting from metastatic leiomyosarcoma. AB - Case report demonstrating the differential kinetics of response and toxicity using stereotactic radiation and interventional radiological coiling for pulmonary arterio-venous shunting from leiomyosarcoma pulmonary metastases. PMID- 25906677 TI - Submammary Placement With Mastopexy for Implantable Pulse Generator Site Pain in Thin Women. AB - OBJECTIVE: Implantable pulse generators for neurostimulation and other indications are becoming more widespread. Pain at the generator site, erosion through the subcutaneous issues, and migration of the generator are frequent post operative complications that result in high rates of re-operation. We report a case where a submammary combined approach with plastic surgery for improved soft tissue coverage resulted in better esthetic and functional outcomes in a thin woman. MATERIALS AND METHODS: A 40-year-old thin woman presented for revision of spinal cord stimulator due to pain at the bilateral infraclavicular generator sites secondary to lack of soft tissue coverage. She underwent revision of the implantable generator site with placement of the generator in the submammary location and concurrent mastopexy with plastic surgery. RESULTS: At two-year follow-up she continues to be pain-free after surgery and is very satisfied by the cosmetic outcome. CONCLUSION: Submammary placement of implantable pulse generators in thin women combined with mastopexy may result in improved soft tissue coverage, decreased pain at the generator site, and a low rate of complications. PMID- 25906678 TI - Methods of cryopreservation of Tambaqui semen, Colossoma macropomum. AB - This study compared three different techniques for sperm cryopreservation of Tambaqui (Colossoma macropomum). Semen was diluted in Beltsville Thawing Solution with the addition of dimethyl sulfoxide (DMSO) at various concentrations (5%, 10%, 15% and 20%). Cryopreservation was performed using three methods: Box Conditioner Method with straws at a 5 cm distance from liquid nitrogen vapor (N2L); Dry Shipper Method placing the straws inside the machine; Vitrification Method placing the straws directly into N2L, amounting to 12 treatments (four DMSO concentrations*three freezing methods). The samples were evaluated for analysis of sperm quality in vivo and in vitro. Use of the Vitrification Method at different concentrations of DMSO provided the least values in the different evaluations. Fertilization, hatching rates and plasma membrane integrity using the Box Conditioner Method with 5% and 10% DMSO did not differ (P>0.05) but use of the concentration of 5% DMSO resulted in greater values than the other treatments (P<0.05) as well as for sperm motility and latency time (P<0.05), although sperm viability was superior using the Dry Shipper Method with 20% of the cryoprotectant. Mitochondrial functionality was impaired by use of the Vitrification Method with all DMSO concentration tested showing the most desirable values when the Box Conditioner Method was used with 5%, 10%, 15% DMSO and the Dry Shipper Method was used with 10% and 15% DMSO. Considering the variables evaluated, the use of the Box Conditioner Method is associated with enhanced Tambaqui semen quality with freeze concentrations of 5% and 10% DMSO. PMID- 25906679 TI - Climatic factors associated with abortion occurrences in Japanese commercial pig herds. AB - Objectives were to determine climatic and production factors associated with abortions in commercial swine herds and to compare the reproductive performances and culling patterns between aborting and non-aborting females that were re inseminated. There were 309,427 service records analyzed for 56,375 females entered into 100 herds. Climate data were obtained from 21 weather stations located close to the herds. Mean daily average temperatures (Tavg) for the 21-day pre-mating period for each female were combined with the female's reproductive data. Generalized linear model assessments were conducted for abortion risk per service. Abortion risk per service (+/-SE) was 0.7+/-0.06%, and mean value of Tavg (range) was 15.0 degrees C (-10.7 to 32.7 degrees C). Risk factors associated with an increased abortion risk per service were greater numbers of parities, delivering more stillbirth fetuses, greater mean Tavg for the 21-day pre-mating periods and re-servicing of females that did not get pregnant at the first servicing (P<0.05). Abortion risk per service for parities 1-5 increased by 0.1-0.3% when the Tavg increased from 20 to 30 degrees C (P<0.05), but there were no such associations for parities 0 and 6 or greater (P>=0.37). Aborting re serviced females had 0.4 fewer pigs born alive than non-aborting re-serviced females (P<0.05). Also, 64.6% of all aborting females were culled for reproductive failure, compared with only 23.4% of non-aborting females. In conclusion, producers should closely monitor females at greater risk of aborting and apply more advanced cooling systems. PMID- 25906680 TI - Overexpression and purification of HSV-2 glycoprotein D in suspension CHO cells with serum-free medium and immunogenicity analysis. AB - Glycoprotein D (gD2) is the most important candidate antigen for herpes simplex virus type 2 (HSV-2) vaccine development. Establishment of a stable eukaryotic cell line to overexpress gD2 and an efficient purification process to purify is essential for the development of subunit vaccine against HSV-2. The DNA sequence of the extracellular epitope-rich fragment of gD2 was optimized, chemically synthesized, and cloned into plasmid pMD902. The recombinant plasmid pMD902-gD was stably transfected into CHO-DG44 cells, and cell lines with high levels of expression of gD2 were established. The recombinant gD2 was purified efficiently using an anion exchange column and a Sephadex G-25 desalting column. The yield of the purified gD2 was 57 mg/L of serum-free culture medium, and its purity was determined to be about 95% by HPLC analysis. Finally, the immunogenicity of the purified gD2 was measured and it induced strong and specific humoral immunity and higher level of cellular immune response than gD2 expressed in prokaryotic cells. We established a stable, secretory, and high-yield gD2-expression cell line and an easy and efficient gD2-purification process, which lays the foundation for preparation of large amount of gD2 that is essential for HSV-2 subunit vaccine development. PMID- 25906681 TI - Fenofibrate insulates diacylglycerol in lipid droplet/ER and preserves insulin signaling transduction in the liver of high fat fed mice. AB - Hepatic steatosis is often associated with insulin resistance as a hallmark of the metabolic syndrome in the liver. The present study investigated the effects of PPARalpha activation induced by fenofibrate (FB) on the relationship of insulin resistance and hepatic steatosis in mice fed a high-fat (HF) diet, which increases lipid influx into the liver. Mice were fed HF diet to induce insulin resistance and hepatic steatosis with or without FB. FB activated PPARalpha and ameliorated HF diet-induced glucose intolerance and hepatic insulin resistance without altering either hepatic steatosis or inflammation signaling (JNK or IKK). Interestingly, FB treatment simultaneously increased fatty acid (FA) synthesis (50%) and oxidation (66%, both p<0.01) into intermediate lipid metabolites, suggesting a FA oxidation-synthesis cycling in operation. Associated with these effects, diacylglycerols (DAGs) were sequestered within the lipid droplet/ER compartment, thus reducing their deposition in the cellular membrane, which is known to impair insulin signal transduction. These findings suggest that the reduction in membrane DAGs (rather than total hepatic steatosis) may be critical for the protection by fenofibrate-induced PPARalpha activation against hepatic insulin resistance induced by dietary fat. PMID- 25906682 TI - A fresh look at saccadic trajectories and task irrelevant stimuli: Social relevance matters. AB - A distractor placed nearby a saccade target will cause interference during saccade planning and execution, and as a result will cause the saccade's trajectory to curve in a systematic way. It has been demonstrated that making a distractor more task-relevant, for example by increasing its similarity to the target, will increase the interference it imposes on the saccade and generate more deviant saccadic trajectories. Is the extent of a distractor's interference within the oculomotor system limited to its relevance to a particular current task, or can a distractor's general real-world meaning influence saccade trajectories even when it is made irrelevant within a task? Here, it is tested whether a task-irrelevant distractor can influence saccade trajectory if it depicts a stimulus that is normally socially relevant. Participants made saccades to a target object while also presented with a task-irrelevant (upright or inverted) face, or scrambled non-face equivalent. Results reveal that a distracting face creates greater deviation in saccade trajectory than does a non face distractor, most notably at longer saccadic reaction times. These results demonstrate the sensitivity of processing that distractors are afforded by the oculomotor system, and support the view that distractor relevance beyond the task itself can also influence saccade planning and execution. PMID- 25906683 TI - A new model of strabismic amblyopia: Loss of spatial acuity due to increased temporal dispersion of geniculate X-cell afferents on to cortical neurons. AB - Although the neural locus of strabismic amblyopia has been shown to lie at the first site of binocular integration, first in cat and then in primate, an adequate mechanism is still lacking. Here we hypothesise that increased temporal dispersion of LGN X-cell afferents driven by the deviating eye onto single cortical neurons may provide a neural mechanism for strabismic amblyopia. This idea was investigated via single cell extracellular recordings of 93 X and 50 Y type LGN neurons from strabismic and normal cats. Both X and Y neurons driven by the non-deviating eye showed shorter latencies than those driven by either the strabismic or normal eyes. Also the mean latency difference between X and Y neurons was much greater for the strabismic cells compared with the other two groups. The incidence of lagged X-cells driven by the deviating eye of the strabismic cats was higher than that of LGN X-cells from normal animals. Remarkably, none of the cells recorded from the laminae driven by the non deviating eye were of the lagged class. A simple computational model was constructed in which a mixture of lagged and non-lagged afferents converge on to single cortical neurons. Model cut-off spatial frequencies to a moving grating stimulus were sensitive to the temporal dispersion of the geniculate afferents. Thus strabismic amblyopia could be viewed as a lack of developmental tuning of geniculate lags for neurons driven by the amblyopic eye. Monocular control of fixation by the non-deviating eye is associated with reduced incidence of lagged neurons, suggesting that in normal vision, lagged neurons might play a role in maintaining binocular connections for cortical neurons. PMID- 25906684 TI - Oculomotor behavior of blind patients seeing with a subretinal visual implant. AB - Electronic implants are able to restore some visual function in blind patients with hereditary retinal degenerations. Subretinal visual implants, such as the CE approved Retina Implant Alpha IMS (Retina Implant AG, Reutlingen, Germany), sense light through the eye's optics and subsequently stimulate retinal bipolar cells via ~1500 independent pixels to project visual signals to the brain. Because these devices are directly implanted beneath the fovea, they potentially harness the full benefit of eye movements to scan scenes and fixate objects. However, so far, the oculomotor behavior of patients using subretinal implants has not been characterized. Here, we tracked eye movements in two blind patients seeing with a subretinal implant, and we compared them to those of three healthy controls. We presented bright geometric shapes on a dark background, and we asked the patients to report seeing them or not. We found that once the patients visually localized the shapes, they fixated well and exhibited classic oculomotor fixational patterns, including the generation of microsaccades and ocular drifts. Further, we found that a reduced frequency of saccades and microsaccades was correlated with loss of visibility. Last, but not least, gaze location corresponded to the location of the stimulus, and shape and size aspects of the viewed stimulus were reflected by the direction and size of saccades. Our results pave the way for future use of eye tracking in subretinal implant patients, not only to understand their oculomotor behavior, but also to design oculomotor training strategies that can help improve their quality of life. PMID- 25906685 TI - Amblyopia and the binocular approach to its therapy. AB - There is growing evidence that abnormal binocular interactions play a key role in amblyopia. In particular, stronger suppression of the amblyopic eye has been associated with poorer amblyopic eye visual acuity and a new therapy has been described that directly targets binocular function and has been found to improve both monocular and binocular vision in adults and children with amblyopia. Furthermore, non-invasive brain stimulation techniques that alter excitation and inhibition within the visual cortex have been shown to improve vision in the amblyopic eye. The aim of this review is to summarize this previous work and interpret the therapeutic effects of binocular therapy and non-invasive brain stimulation in the context of three potential neural mechanisms; active inhibition of signals from the amblyopic eye, attenuation of information from the amblyopic eye and metaplasticity of synaptic long term potentiation and long term depression. PMID- 25906687 TI - Stabilization of Phenylalanine Ammonia Lyase from Rhodotorula glutinis by Encapsulation in Polyethyleneimine-Mediated Biomimetic Silica. AB - Phenylalanine ammonia lyase (PAL) from Rhodotorula glutinis was encapsulated within polyethyleneimine-mediated biomimetic silica. The main factors in the preparation of biomimetic silica were optimized by response surface methodology (RSM). Compared to free PAL (about 2 U), the encapsulated PAL retained more than 43 % of their initial activity after 1 h of incubation time at 60 degrees C, whereas free PAL lost most of activity in the same conditions. It was clearly indicated that the thermal stability of PAL was improved by encapsulation. Moreover, the encapsulated PAL exhibited the excellent stability of the enzyme against denaturants and storage stability, and pH stability was improved by encapsulation. Operational stability of 7 reaction cycles showed that the encapsulated PAL was stable. Nevertheless, the K m value of encapsulated PAL in biomimetic silica was higher than that of the free PAL due to lower total surface area and increased mass transfer resistance. PMID- 25906686 TI - Spatiotemporal modelling of hormonal crosstalk explains the level and patterning of hormones and gene expression in Arabidopsis thaliana wild-type and mutant roots. AB - Patterning in Arabidopsis root development is coordinated via a localized auxin concentration maximum in the root tip, requiring the regulated expression of specific genes. However, little is known about how hormone and gene expression patterning is generated. Using a variety of experimental data, we develop a spatiotemporal hormonal crosstalk model that describes the integrated action of auxin, ethylene and cytokinin signalling, the POLARIS protein, and the functions of PIN and AUX1 auxin transporters. We also conduct novel experiments to confirm our modelling predictions. The model reproduces auxin patterning and trends in wild-type and mutants; reveals that coordinated PIN and AUX1 activities are required to generate correct auxin patterning; correctly predicts shoot to root auxin flux, auxin patterning in the aux1 mutant, the amounts of cytokinin, ethylene and PIN protein, and PIN protein patterning in wild-type and mutant roots. Modelling analysis further reveals how PIN protein patterning is related to the POLARIS protein through ethylene signalling. Modelling prediction of the patterning of POLARIS expression is confirmed experimentally. Our combined modelling and experimental analysis reveals that a hormonal crosstalk network regulates the emergence of patterns and levels of hormones and gene expression in wild-type and mutants. PMID- 25906688 TI - Expression and Characterization of the Extracellular Domain of Human HER2 from Escherichia Coli, and Production of Polyclonal Antibodies Against the Recombinant Proteins. AB - Human epidermal growth factor receptor 2 (HER2) is a member of the epidermal growth factor receptor (EGFR) family. In this study, the whole extracellular domain gene of HER2 was amplified by RT-PCR from human breast cancer cell line SK BR-3. The genes of membrane-distal region (A) and membrane proximal region (B) of HER2 extracellular domain were amplified from the cloned template, and then inserted into the expression vector pET-28a and pET-30a, respectively. The recombinant expression vectors were transformed into Escherichia coli BL21 (DE3) cells and induced by isopropyl-b-D-thiogalactopyranoside (IPTG) for expression of proteins His-A and His-B. The expressed proteins were detected by sodium dodecyl sulfate-polyacrylamide gel electrophoresis (SDS-PAGE) and western blot. The optimization of culture conditions led us to accomplish the recombinant protein induction with 1.0 mM IPTG at 37 degrees C for 8 h, and both proteins were expressed in the insoluble form. Both proteins were purified under the denaturing condition using Ni-NTA sepharose column. Balb/c mice were immunized with the purified proteins and then effectively produced polyclonal antibodies, which reached to a relatively high titer by ELISA testing and had good specificity by western blot detection. The HER2 ECD proteins His-A and His-B could be expressed in E. coli and were suitable for production of high titer antibodies against HER2 ECD. PMID- 25906689 TI - Attitudes toward stuttering of nonstuttering preschool and kindergarten children: A comparison using a standard instrument prototype. AB - PURPOSE: This study investigated attitudes of nonstuttering preschool and kindergarten children toward peers who stutter in order to identify differences by age groups and better understand the genesis of stuttering attitudes. The study also examined the use of a new stuttering attitudes instrument designed for use with young children. METHOD: The newly developed Public Opinion Survey on Human Attributes-Stuttering/Child was verbally administered to 27 preschool and 24 kindergarten children who do not stutter in the mid-Atlantic region of the USA. RESULTS: Overall, preschoolers held more negative stuttering attitudes than kindergarteners, but results were not uniformly in that direction. In both groups, the attribute of stuttering was viewed more negatively than individuals who stutter. Children viewed the potential of peers who stutter as quite positive, whereas their knowledge about and experience with stuttering were generally limited and some of their beliefs quite negative. CONCLUSIONS: Negative or uninformed stuttering attitudes among nonstuttering children begin as early as the preschool years. This study provides empirical evidence for the need to educate young children about the nature of stuttering and how to respond appropriately to peers who stutter. EDUCATIONAL OBJECTIVES: Readers should be able to: (a) describe attitudinal differences between kindergarteners and preschoolers toward peers who stutter; (b) describe the parameters of the POSHA S/Child; (c) describe the nature of stuttering attitudes in young children relative to their beliefs and self reactions; and (d) describe the implications and future direction of stuttering attitude research in young children. PMID- 25906690 TI - The learning curve for robotic distal pancreatectomy: an analysis of outcomes of the first 100 consecutive cases at a high-volume pancreatic centre. AB - BACKGROUND: Robotic distal pancreatectomy (RDP) is performed increasingly, but knowledge of the number of cases required to attain procedural proficiency is lacking. The aim of this study was to identify the learning curve associated with RDP at a high-volume pancreatic centre. METHODS: Metrics of perioperative safety and efficiency for all consecutive RDPs were evaluated. Outcomes were followed to 90 days. Cumulative sum (CUSUM) analysis was used to identify inflexion points corresponding to the learning curve. RESULTS: Between 2008 and 2013, 100 patients underwent RDP. There was no 90-day mortality. In two patients (2.0%), surgery was converted to laparotomy. Thirty procedures were performed for pancreatic adenocarcinoma. Precipitous operative time reductions from an initial operative time of 331 min were observed after the first 20 and 40 cases to 266 min and 210 min, respectively (P < 0.0001). The likelihood of readmission was significantly lower after the first 40 cases (P = 0.04), and non-significant reductions were observed in incidences of major (Clavien-Dindo Grade II or higher) morbidity and Grade B and C leaks, and length of stay. CONCLUSIONS: In this experience, RDP outcomes were optimized after 40 cases. Familiarity with the platform and dedicated training are likely to contribute to significantly shorter learning curves in future adopters. PMID- 25906691 TI - Risk factors for mesh erosion after female pelvic floor reconstructive surgery: a systematic review and meta-analysis. AB - OBJECTIVES: To explore the risk factors for mesh erosion after female pelvic floor reconstructive surgery based on published literature. MATERIALS AND METHODS: A systematic literature search of the PubMed, Embase, Cochrane Library, Chinese Biomedical Literature (CBM), China National Knowledge Infrastructure (CNKI) and Chinese Science and Technology Periodical (VIP) databases was performed to identify studies related to the risk factors for mesh erosion after female pelvic floor reconstruction published before December 2014. Summary unadjusted odds ratios (ORs) with 95% confidence intervals (CIs) were calculated to assess the strength of associations between the factors and mesh erosion. RESULTS: In all, 25 studies containing 7,084 patients were included in our systematic review and meta-analysis. Statistically significant differences in mesh erosion after female pelvic floor reconstruction were found in older vs younger patients (OR 0.96, 95% CI 0.94-0.98), more parities vs less parities (OR 1.27, 95% CI 1.07-1.51), the presence of premenopausal/oestrogen replacement therapy (ERT) (OR 1.36, 95% CI 1.03-1.79), diabetes mellitus (OR 1.87, 95% CI 1.35-2.57), smoking (OR 2.35, 95% CI 1.80-3.08), concomitant pelvic organ prolapse (POP) surgery (OR 0.37, 95% CI 0.16-0.84), concomitant hysterectomy (OR 1.46, 95% CI 1.03-2.07), preservation of the uterus at surgery (OR 0.22, 95% CI 0.08-0.63), and surgery performed by senior vs junior surgeons (OR 0.42, 95% CI 0.30-0.58). CONCLUSION: Our study indicates that younger age, more parities, premenopausal/ERT, diabetes mellitus, smoking, concomitant hysterectomy, and surgery performed by a junior surgeon were significant risk factors for mesh erosion after female pelvic floor reconstructive surgery. Moreover, concomitant POP surgery and preservation of the uterus may be the potential protective factors for mesh erosion. PMID- 25906692 TI - Electrophysiological characterization of the first Tityus serrulatus alpha-like toxin, Ts5: Evidence of a pro-inflammatory toxin on macrophages. AB - Tityus serrulatus (Ts) venom is composed of mainly neurotoxins specific for voltage-gated K(+) and Na(+) channels, which are expressed in many cells such as macrophages. Macrophages are the first line of defense invasion and they participate in the inflammatory response of Ts envenoming. However, little is known about the effect of Ts toxins on macrophage activation. This study investigated the effect of Ts5 toxin on different sodium channels as well as its role on the macrophage immunomodulation. The electrophysiological assays showed that Ts5 inhibits the rapid inactivation of the mammalian sodium channels Nav1.2, Nav1.3, Nav1.4, Nav1.5, Nav1.6 and Nav1.7. Interestingly, Ts5 also inhibits the inactivation of the insect Drosophila melanogaster sodium channel (DmNav1), and it is therefore classified as the first Ts alpha-like toxin. The immunological experiments on macrophages reveal that Ts5 is a pro-inflammatory toxin inducing the cytokine production of tumor necrosis factor (TNF)-alpha and interleukin (IL) 6. On the basis of recent literature, our study also stresses a possible mechanism responsible for venom-associated molecular patterns (VAMPs) internalization and macrophage activation and moreover we suggest two main pathways of VAMPs signaling: direct and indirect. This work provides useful insights for a better understanding of the involvement of VAMPs in macrophage modulation. PMID- 25906693 TI - MicroRNA-494 inhibition protects nucleus pulposus cells from TNF-alpha-induced apoptosis by targeting JunD. AB - BACKGROUND: Human nucleus pulposus cell (HNPC) apoptosis plays an important role in the development of intervertebral disc degeneration (IVDD). Our previous research revealed that among all of the dysregulated microRNAs in the degenerated nucleus pulposus tissues of patient with IVDD, miRNA-494 (miR-494) is the most significantly increased. However, the influence of miR-494 HNPC apoptosis has not been confirmed. OBJECTIVE: This study was designed to evaluate the effect of miR 494 on the HNPC apoptosis induced by TNF-alpha and to explore the possible mechanism of this process. METHODS: First, HNPCs were stimulated with TNF-alpha at different concentrations (0 ng/ml, 10 ng/ml, 50 ng/ml, or 100 ng/ml) for 0 h, 8 h, 16 h, or 24 h. Annexin V-PE/7-AAD assays and real-time quantitative PCR were used to detect the cell apoptosis rates and miR-494 expression. Second, we successfully knocked down endogenous miR-494 in HNPCs via lentiviral antigomiR 494 vector infection and then stimulated with TNF-alpha (100 ng/ml, 16 h). The rates of apoptosis and miR-494 expression were then detected again. Additionally, a dual-luciferase reporter assay and western blotting were used to determine whether JunD is a target of miR-494. Finally, western blotting was used to analyze the expression of cytochrome C. RESULTS: We found that the rate of apoptosis increased with concentration, time (p < 0.05) and miR-494 expression (p < 0.05). The rate of apoptosis in the 100 ng/ml, 16 h group appeared to be suitable. After transfection, the apoptosis rate and miR-494 expression were significantly decreased in the antigomiR-494+TNF-alpha group compared to the controls (p < 0.05). We also revealed that JunD is a target of miR-494. Western blotting analysis demonstrated that treatment with the lentiviral antigomiR-494 vector resulted in increased expression of JunD (p < 0.05) and decreased expression of cytochrome C (p < 0.05). CONCLUSION: These results indicated that miR-494 is a novel regulator of HNPC apoptosis induced by TNF-alpha. The knock out of miR-494 expression protected the HNPCs from apoptosis via the up regulation of JunD, which was possibly mediated via cytochrome C apoptotic signaling. These findings suggest that the miR-494/JunD signaling pathway might represent a novel therapeutic target for the prevention of IVDD. PMID- 25906694 TI - Abnormal quantity and function of regulatory T cells in peripheral blood of patients with severe aplastic anemia. AB - Severe aplastic anemia is a rare autoimmune disease characterized by severe pancytopenia and bone marrow failure, which is caused by activated T lymphocytes. Tregs are believed to control development and progression of autoimmunity by suppressing autoreactive T cells. This study aims at understanding the quantity and function of peripheral Tregs in SAA. The expression of related biomarkers on Treg cell surface were determined by flow cytometry. The frequency of Tregs and the expression of CTLA-4 in SAA was significantly decreased than that in normal controls. The expression of perforin in SAA was significantly increased than that in controls, while expression of CD39, CD73 and GITR in Tregs did not show any significant difference between the two groups. These data revealed that CTLA-4 could be responsible for Treg abnormalities in SAA, but suppression mediated by perforin, CD39, CD73 and GITR, and survival capability of single Treg cell may not be injured. PMID- 25906695 TI - A novel cyclic dipeptide from deep marine-derived fungus Aspergillus sp. SCSIOW2. AB - A novel cyclic dipeptide, 14-hydroxy-cyclopeptine (1), was purified from a deep sea derived fungal isolate identified as an Aspergillus sp. The structure was elucidated by detailed spectroscopic analyses using 1D and 2D NMR experiments and high resolution mass spectrometry. The absolute configuration of the amino acid was determined by Marfey's method. Two conformational isomers of 1 were established by ROE analyses. 1 inhibited nitric oxide production with IC50 values at 40.3 MUg/mL in a lipopolysaccharide and recombinant mouse interferon-gamma activated macrophage-like cell line, RAW 264.7 and showed no cytotoxic effect in the tested dose range up to 100 MUg/mL. PMID- 25906696 TI - Integrating the learner's perspective in the refinement of competency-based assessments. PMID- 25906697 TI - Enrollment, expenditures, and utilization after CHIP expansion: evidence from Alabama. AB - OBJECTIVE: In October 2009, Alabama expanded eligibility in its Children's Health Insurance Program (CHIP), known as ALL Kids, from 200% to 300% of the federal poverty level (FPL). We examined the expenditures, utilization, and enrollment behavior of expansion enrollees relative to traditional enrollees (100-200% FPL) and assessed the impact of expansion on total program expenditures. METHODS: We compared unadjusted mean person-month-level expenditures and utilization of expansion enrollees and various categories of existing enrollees and used a 2 part modeling strategy to examine differences after controlling for enrollee characteristics. We used probit models to examine adjusted differences in reenrollment behavior by eligibility category. RESULTS: Expansion enrollees had higher total monthly expenditures ($10.33, P < .05) than traditional ALL Kids enrollees, including higher outpatient ($5.35, P < .001) and dental ($0.85, P < .01) expenditures but lower emergency department (-$1.34, P < .001) expenditures. Expansion enrollees had marginally lower utilization of emergency department services for low-severity conditions and higher utilization of physician outpatient visits. Expansion enrollees were 4.47 percentage points (P < .001) more likely to reenroll before their contract expiration date than traditional ALL Kids enrollees. As of October 2012, expansion enrollees accounted for approximately 20% of ALL Kids enrollment and expenditures. CONCLUSIONS: The expansion population was characterized by moderately higher health expenditures and utilization, and more persistent enrollment relative to fee group enrollees who are subject to the same levels of cost sharing and annual premiums. Although states are prohibited from changing program eligibility until 2019, the costs associated with the expansion population will be important to future policy decisions. PMID- 25906698 TI - Associations between practice-reported medical homeness and health care utilization among publicly insured children. AB - BACKGROUND: The patient-centered medical home (PCMH) is widely promoted as a model to improve the quality of primary care and lead to more efficient use of health care services. Few studies have examined the relationship between PCMH implementation at the practice level and health care utilization by children. Existing studies show mixed results. METHODS: Using practice-reported PCMH assessments and Medicaid claims from child-serving practices in 3 states participating in the Children's Health Insurance Program Reauthorization Act of 2009 Quality Demonstration Grant Program, this study estimates the association between medical homeness (tertiles) and receipt of well-child care and nonurgent, preventable, or avoidable emergency department (ED) use. Multilevel logistic regression models are estimated on data from 32 practices in Illinois (IL) completing the National Committee for Quality Assurance's (NCQA) medical home self-assessment and 32 practices in North Carolina (NC) and South Carolina (SC) completing the Medical Home Index (MHI) or Medical Home Index-Revised Short Form (MHI-RSF). RESULTS: Medical homeness was not associated with receipt of age appropriate well-child visits in either sample. Associations between nonurgent, preventable, or avoidable ED visits and medical homeness varied. No association was seen among practices in NC and SC that completed the MHI/MHI-RSF. Children in practices in IL with the highest tertile NCQA self-assessment scores were less likely to have a nonurgent, preventable, or avoidable ED visit than children in practices with low (odds ratio 0.65; 95% confidence interval 0.47-0.92; P < .05) and marginally less likely to have such a visit compared with children in practices with medium tertile scores (odds ratio 0.72, 95% confidence interval 0.52-1.01; P = .06). CONCLUSIONS: Higher levels of medical homeness may be associated with lower nonurgent, preventable, or avoidable ED use by publicly insured children. Robust longitudinal studies using multiple measures of medical homeness are needed to confirm this observation. PMID- 25906699 TI - A planned care approach and patient registry to improve adherence to clinical guidelines for the diagnosis and management of attention-deficit/hyperactivity disorder. AB - BACKGROUND: Attention-deficit/hyperactivity disorder (ADHD) affects almost 2.4 million US children. Because American Academy of Pediatrics guidelines for ADHD recommend use of standardized diagnostic instruments, regular follow-up and the chronic care model, this pilot project sought to implement and assess an electronic registry of patients with ADHD combined with care coordination by a planned care team. METHODS: This quality improvement project was structured with 2 intervention and 2 control clinics to facilitate evaluation of the use of a planned care system for management of ADHD. Care teams included a pediatrician, nurse, medical assistant, and care coordinator and tracked patients using an electronic registry with data drawn from the EMR. Clinical work flows were pilot tested to facilitate use of the Vanderbilt scales and their incorporation into the EMR at intervention sites. Outcome measures included 2 recommended clinical follow-ups based on HEDIS measures as well as use of the Vanderbilt rating scales. Initiation phase measure was for follow-up after initiating medication, while the continuation phase measure was for subsequent follow-up during the first year of treatment. Measures were monitored during the project year and then also in the ensuing period of spread of the intervention to other sites. RESULTS: Although the modified HEDIS initiation phase measure for patients newly on medication remained static at approximately 50% throughout the project period, the continuation phase measure showed improvement from 35% at baseline to 45% at the end of the project assessment year, a 29% increase. Follow-up for patients stable on medications also remained unchanged during the project period, but during subsequent spreading of the intervention to nonproject sites, follow-up of these patients improved to over 90%. In adjusted analyses, patients with ADHD at intervention sites were over 2 times more likely than patients at control sites to have had a Vanderbilt score documented in their records. CONCLUSIONS: The project achieved modest improvements in the diagnostic and treatment process for patients with ADHD. The use of a planned care system and electronic patient registry shows promise for improving the diagnosis and treatment process for patients with ADHD. PMID- 25906701 TI - Are unmet breastfeeding expectations associated with maternal depressive symptoms? AB - OBJECTIVE: Most US women intend and initiate breastfeeding, yet many do not breastfeed as long as desired. Not meeting one's own prenatal expectations is a plausible mechanism for the previously observed association between lack of breastfeeding and postpartum depression (PPD). This study explored whether meeting prenatal expectations for exclusive breastfeeding was associated with PPD symptoms. METHODS: The 2005 Infant Feeding Practices Study II (IFPSII) followed US mothers, primarily white women with higher education and income, from midpregnancy to 1 year postpartum. Depressive symptoms were defined as Edinburgh Postnatal Depression Scale (EPDS) of 10 or higher, measured at 2 months postpartum. Logistic regression analysis evaluated the odds of maternal depressive symptoms as a function of meeting prenatal expectations for exclusive breastfeeding, accounting for breastfeeding behavior, demographics, and postnatal experiences. RESULTS: Among IFPSII participants, 1501 intended exclusive breastfeeding and completed the EPDS. At 2 months, 589 (39.2%) had met prenatal expectations for exclusive breastfeeding. EPDS was 10 or higher for 346 participants (23.1%). Adjusted odds of depressive symptoms were lower among women meeting prenatal exclusive breastfeeding expectations versus those who were not (odds ratio 0.71, 95% confidence interval 0.52-0.96). In subgroup analysis, there was no association between met expectations and depressive symptoms among women with lower incomes (<200% federal poverty level) or those intending mixed breast and formula feeding. CONCLUSIONS: Among middle- and higher-income women who intended exclusive breastfeeding, those meeting prenatal breastfeeding expectations reported fewer PPD symptoms at 2 months postpartum. Clinician understanding and support of maternal expectations may improve maternal mental health. PMID- 25906700 TI - Pediatric-based intervention to motivate mothers to seek follow-up for depression screens: The Motivating Our Mothers (MOM) trial. AB - OBJECTIVE: To determine the initial effectiveness of a novel, pediatric office based intervention in motivating mothers to seek further assessment of positive depression screens. METHODS: In this pilot randomized controlled trial, English speaking mothers (n = 104) with positive 2-question depression screens and presenting with children 0 to 12 years old for well-child care to a general pediatric training clinic received interventions from a trained research assistant. The Motivating Our Mothers (MOM) intervention included office-based written and verbal targeted depression education and motivational messages encouraging further depression assessment and a semistructured telephone booster delivered 2 days later. The control intervention included nontargeted written and verbal messages and 2 days later, an attention control telephone survey. Both groups received a list of depression care resources. The primary outcome was the proportion of mothers in each group who reported trying to contact any of 6 types of resources to discuss the positive screen at 2 weeks after intervention (ClinicalTrials.gov NCT01453790). RESULTS: Despite 6 contact attempts, 10 MOM and 9 control mothers were lost to follow-up. More mothers in the MOM intervention tried to contact a resource compared to control (73.8% vs 53.5%, difference 20.3%, 95% confidence interval for difference -0.1 to 38.5, P = .052). CONCLUSIONS: Mothers receiving the MOM intervention made more attempts to contact a resource for follow-up of positive depression screens. If found effective in larger studies, MOM may prove a promising approach for motivating depression screen-positive mothers identified in general pediatric settings within and beyond the postpartum period to seek further depression assessment and support. PMID- 25906702 TI - Management of newborns born to mothers with chorioamnionitis: is it time for a kinder, gentler approach? AB - OBJECTIVE: Current recommendations are that newborns of mothers with chorioamnionitis have a complete blood count, blood culture, and antibiotic therapy. We hypothesized that utilizing the early-onset sepsis (EOS) risk calculator and a clinical symptom assessment could safely reduce the number of newborns subjected to laboratory testing and antibiotics. METHODS: We reviewed 698 well-appearing newborns of estimated gestational age of >=34 weeks born to mothers with chorioamnionitis. RESULTS: Sixty-five percent of newborns were managed according to the guidelines; 1 (0.14%) had culture-positive EOS. A strategy based on the use of the EOS calculator and clinical appearance of the newborn would have reduced the proportion having laboratory tests and antibiotics to 12% and would not have missed any cases of EOS. CONCLUSIONS: The EOS risk in well-appearing newborns of mothers with chorioamnionitis is low. Applying a strategy based on readily obtainable measures rather than the obstetrical diagnosis of chorioamnionitis would result in a substantial reduction of newborns undergoing laboratory tests and being exposed to antibiotics. Further prospective trials evaluating the safety of this approach are warranted. PMID- 25906703 TI - Prompting discussions of youth violence using electronic previsit questionnaires in primary care: a cluster randomized trial. AB - OBJECTIVE: Youth violence (YV) screening during primary care visits is not routinely performed. Electronic previsit questionnaires (PVQs) are viewed favorably by adolescents and can prompt disclosure and discussion of sensitive health topics. This study aimed to determine the efficacy of an electronic PVQ in prompting YV discussions. METHODS: A 4-month cluster-randomized controlled trial was conducted in a large urban academic primary care clinic. The clinic's 4 practice groups were randomized to intervention or control assignment. A consecutive sample of adolescents aged 13 to 19 years presenting for annual visits were recruited. Participants completed an electronic PVQ (TickiT) either with (intervention) or without (control) YV questions. PVQ results were delivered to physicians before the visit. The frequency of YV discussions was measured using exit surveys of adolescents. Patients who reported YV discussion rated the helpfulness of the discussion. Multilevel mixed effect logistic regression was conducted to compare likelihood of YV discussion between intervention and control groups. RESULTS: A total of 183 adolescents (90% of eligible) participated. Overall, 30% of adolescents reported some YV involvement. Sixty-five percent of the intervention group and 42% of the control group reported discussing YV during their visit. Thirty-one percent of adolescents in the intervention group who disclosed YV involvement reported not having a YV discussion. The intervention group had 2.6 (95% confidence interval 1.2-5.6) times the odds of discussing YV. Sixty-six percent of adolescents who discussed YV with their doctor rated the discussion as very helpful. CONCLUSIONS: An electronic PVQ with items related to YV is acceptable and feasible, and it significantly improves frequency of patient provider YV discussion. PMID- 25906704 TI - Body Composition Affects Urea Distribution Volume Estimated by Watson's Formula. AB - OBJECTIVE: Dialysis machines use the Watson formula (Vwatson) to estimate the urea distribution volume (UDV) to calculate the online Kt/V for each dialysis session. However, the equation could give rise to inaccuracies. The present study analyzes whether body composition affects UDV estimated by Vwatson in comparison to bioimpedance spectroscopy (Vbis) as the reference method. DESIGN: This is a transversal study performed in the setting of a hemodialysis unit. SUBJECTS: Prevalent hemodialysis patients. INTERVENTION: The same day, UDV was measured using Vwatson and Vbis. We compared their results. MAIN OUTCOME MEASURE: Differences between UDV using Watson equation and Vbis. RESULTS: We included 144 prevalent patients. Vwatson overestimated the volume with regard to Vbis (Vwatson - Vbis) by 2.5 L (1.8 L; P = .001). We found an excellent correlation between the 2 methods. A higher mean Vwatson - Vbis value was correlated to older age (P = .03), body mass index (P = .01), fat tissue index (P = .001), lower lean tissue index (P = .001), lower extracellular water (P = .01), and intracellular water (P = .001). CONCLUSION: Body composition affects UDV estimated by Vwatson, thus modifying the result of Kt/V. In young patients who present more lean tissue and less fat tissue, Kt/V is underestimated with Vwatson. PMID- 25906705 TI - The role of joint mobility in evaluating and monitoring the risk of diabetic foot ulcer. AB - AIMS: Evaluation of how ankle joint mobility (AJM) can be useful in the identification of patients with diabetes at risk of foot ulcer (FU). METHODS: Plantar and dorsal flexion of foot were evaluated using an inclinometer in 87 patients (54 type 2 and 33 type 1), and 35 healthy sex- and age-matched control subjects. Patients with diabetes were followed up for diagnosis of FU over the next 8 years and subsequently, patients were subdivided into: those without a history of FU (18 type 1 and 33 type 2), those who had a history of FU detected before baseline evaluation (14 type 2) and those who had history of first ulceration detected by the 8th year of the evaluation period (7 type 2). RESULTS: Aging and diabetes caused a significant reduction in mobility of each of the movements investigated (p<0.001), whereas after adjusting for the confounding effect of age, diabetes specifically reduced plantar flexion (p<0.0001). AJM was significantly lower in those with history of previous FU compared to all the other groups (p<0.001). The first ulceration was detected in the same foot presenting lower AJM in 17 of the 22 subjects with diabetes with history of ulcer (77.27%). CONCLUSIONS: Diabetes and aging reduce AJM although diabetes seems to reduce plantar flexion to a more specific extent. Reduced AJM is mostly associated with a previous history of FU. The evaluation of AJM is a valid and reliable ulcer risk scale that indicates which foot is at higher ulcer risk. PMID- 25906706 TI - A Randomized Controlled Trial on the Efficacy and Safety of a New Crosslinked Hyaluronan Gel in Reducing Adhesions after Gynecologic Laparoscopic Surgeries. AB - STUDY OBJECTIVE: To evaluate the safety and efficacy of a new crosslinked hyaluronan (NCH) gel in reducing postoperative adhesions. DESIGN: Randomized controlled trial (Canadian Task Force classification I). SETTINGS: Seven departments of obstetrics and gynecology in China. PATIENTS: A total of 216 women scheduled for gynecologic laparoscopic surgery for primary removal of adhesions, myomas, ovarian cysts, or endometriotic cysts. INTERVENTIONS: Patients were randomized to receive either NCH gel or saline with 1:1 allocation. MEASUREMENTS AND MAIN RESULTS: All patients were evaluated using a modified American Fertility Society (mAFS) scoring system for the incidence, extent, and severity of pre existing and postoperative adhesions at the 10 anatomic sites of ovaries/tubes and at the expanded 23 or 24 anatomic sites throughout the abdominopelvic cavity by laparoscopy. A total of 215 randomized patients were treated with either saline solution (108 of 108) or NCH gel (107 of 108), composing the full analysis set (FAS), and 196 patients (94 of 108 in the saline control group and 102 of 108 in the NCH gel group) completed the entire study, composing the per protocol set (PPS). The postoperative incidence of moderate or severe adhesions evaluated at the 10 sites (the primary endpoint for efficacy) was 27.7% in the control group and 9.8% in the NCH gel group, a difference of 14.4% (95% confidence interval [CI], 2.6%-20.6%) in the PPS, and 37.0% in the control group and 14.0% in the NCH gel group, a difference of 20.0% (95% CI, 8.9%-26.8%) in the FAS. The postoperative incidence of moderate or severe adhesions evaluated at the 24 sites was also significantly lower in the NCH gel group compared with the control group (5.9% vs 14.9%; p = .036) in the PPS. Also in the PPS, the NCH gel group had significantly lower postoperative adhesion scores of severity, extent, and mAFS: 60.0%, 50.8%, and 76.9%, respectively (median scores of the 10 sites; p = .002) and 48.5%, 50.0%, and 72.2% (median scores of the 24 sites; p = .001) lower than those recorded in the control group. No serious adverse events were observed, and the safety profile of NCH gel was comparable to that of saline control. CONCLUSION: This study demonstrates that NCH gel is safe and significantly reduces adnexal adhesion formation and global adhesion formation throughout the abdominopelvic cavity after gynecologic laparoscopic surgery. PMID- 25906707 TI - Crohn's Disease With Ovarian Granuloma: A Case Report and Review of the Literature. AB - We present an interesting case of a 35-year-old nulligravida with Crohn's disease with ovarian involvement. This is a rare manifestation of Crohn's disease, felt to arise from fistulization between the ovary and the intestine, most commonly the ileum. Our review of the literature revealed 11 additional case reports published in English with a total of 15 cases. The mean age at time of presentation was 33.7 years, with a predominance of right-sided involvement. This series included 10 patients with affected right ovaries, 3 with affected left ovaries, and 2 with bilateral involvement. We conclude that ovarian involvement in Crohn's disease, although rare, can exist, and that the gynecologic surgeon should be aware of this relevant disease manifestation. PMID- 25906709 TI - Trace elements distributions at Datoko-Shega artisanal mining site, northern Ghana. AB - Environmental geochemistry classifies elements into essential, non-essential and toxic elements in relationship to human health. To assess the environmental impact of mining at Datoko-Shega area, the distributions and concentrations of trace elements in stream sediments and soil samples were carried out. X-ray fluorescence analytical technique was used to measure the major and trace element concentrations in sediments and modified fire assay absorption spectrometry in soils. The results showed general depletion of major elements except titanium oxide (TiO2) compared to the average crustal concentrations. The retention of TiO2 at the near surface environment probably was due to the intense tropical weathering accompanied by the removal of fine sediments and soil fractions during the harmattan season by the dry north-east trade winds and sheet wash deposits formed after flash floods. The results also showed extreme contamination of selenium (Se), cadmium (Cd) and mercury (Hg), plus strong contaminations of arsenic (As) and chromium (Cr) in addition to moderate contamination of lead (Pb) in the trace element samples relative to crustal averages in the upper continental crust. However Hg, Pb and Cd concentrations tend to be high around the artisanal workings. It was recognised from the analysis of the results that the artisanal mining activity harnessed and introduces some potentially toxic elements such as Hg, Cd and Pb mostly in the artisan mine sites. But the interpretation of the trace element data thus invalidates the elevation of As concentrations to be from the mine operations. It consequently noticed As values in the mine-impacted areas to be similar or sometimes lower than As values in areas outside the mine sites from the stream sediment results. PMID- 25906708 TI - [(64) Cu]-labelled trastuzumab: optimisation of labelling by DOTA and NODAGA conjugation and initial evaluation in mice. AB - The human epidermal growth factor receptor-2 (HER2) is overexpressed in 20-30% of all breast cancer cases, leading to increased cell proliferation, growth and migration. The monoclonal antibody, trastuzumab, binds to HER2 and is used for treatment of HER2-positive breast cancer. Trastuzumab has previously been labelled with copper-64 by conjugation of a 1,4,7,10-tetraazacyclododecane 1,4,7,10-tetraacetic acid (DOTA) chelator. The aim of this study was to optimise the (64) Cu-labelling of DOTA-trastuzumab and as the first to produce and compare with its 1,4,7-triazacyclononane, 1-glutaric acid-5,7 acetic acid (NODAGA) analogue in a preliminary HER2 tumour mouse model. The chelators were conjugated to trastuzumab using the activated esters DOTA mono-N-hydroxysuccinimide (NHS) and NODAGA-NHS. (64) Cu-labelling of DOTA-trastuzumab was studied by varying the amount of DOTA-trastuzumab used, reaction temperature and time. Full (64) Cu incorporation could be achieved using a minimum of 10-ug DOTA-trastuzumab, but the fastest labelling was obtained after 15 min at room temperature using 25 ug of DOTA-trastuzumab. In comparison, 80% incorporation was achieved for (64) Cu labelling of NODAGA-trastuzumab. Both [(64) Cu]DOTA-trastuzumab and [(64) Cu]NODAGA-trastuzumab were produced after purification with radiochemical purities of >97%. The tracers were injected into mice with HER2 expressing tumours. The mice were imaged by positron emission tomography and showed high tumour uptake of 3-9% ID/g for both tracers. PMID- 25906710 TI - Historical perspectives of The American Association for Thoracic Surgery: Dr Wilfred G. Bigelow. PMID- 25906711 TI - Beware of the "Medusa". PMID- 25906712 TI - Managing conflicts of interest. AB - The more extensive conflict of interest information will permit reviewers and editors to ensure the accuracy, balance,and lack of bias of papers accepted for publication.Therefore, a brief conflict statement will be published on the cover page and a more extensive description will be published at the end of the paper to allow concerned readers to make their own judgments about the quality of the information reported. PMID- 25906713 TI - Recognizing immense potential and iterating toward greatness. PMID- 25906714 TI - Diffusion-weighted magnetic resonance imaging may identify candidates for alternatives to lobectomy for early stage lung cancer. PMID- 25906715 TI - The physiologic and histologic properties of the distal internal thoracic artery and its subdivisions. AB - OBJECTIVE: We compared the flow rates, reactivity, and morphology of the distal internal thoracic artery and its branches, the superior epigastric and musculophrenic arteries, to test their applicability as possible conduits in coronary artery bypass grafting surgeries. METHODS: Skeletonized internal thoracic artery and subdivisions of patients undergoing coronary artery bypass grafting were studied intraoperatively (n = 100) for flow and length measurements and in vitro in organ baths (n = 58) for active response to norepinephrine. Quantitative microscopic analysis of the muscle density and degree of intimal hyperplasia was performed. Results were analyzed according to age, gender, risk factors, and medications. RESULTS: Internal thoracic artery subdivisions contributed an average extra length of 2 cm. Free flow rates were 129 +/- 45 mL/min, 114 +/- 41 mL/min, and 93 +/- 36 mL/min in the internal thoracic artery, superior epigastric artery, and musculophrenic artery, respectively. Sternum and internal thoracic artery length and free flow rates were significantly lower in women. The subdivisions were significantly more reactive to norepinephrine than the distal internal thoracic artery (P ~ .005), although sensitivity to norepinephrine was similar. Patients treated with beta-blockers had significantly decreased reactivity (P = .009). Microscopic analysis suggests similar muscle content in the internal thoracic artery and subdivisions. Eccentric (28%) and concentric (62%) intimal hyperplasia were observed in 90% of specimens, with no evidence for atherosclerotic plaques. There was no significant difference in the degree of intimal hyperplasia between the distal internal thoracic artery and its subdivisions, and there was no correlation to risk factors. CONCLUSIONS: Our results confirm the previous studies on the higher contractility in internal thoracic artery subdivisions, suggesting caution in the use of the bifurcation for revascularization. However, the extra length, sufficient flow, and favorable histologic properties suggest that the bifurcation may be appropriate for coronary revascularization in selected cases. PMID- 25906716 TI - Do the "eyes" have it? Lobbying for magnetic resonance imaging to guide transcatheter aortic valve deployment. PMID- 25906717 TI - First-in-man endovascular preconditioning of the paraspinal collateral network by segmental artery coil embolization to prevent ischemic spinal cord injury. AB - OBJECTIVE: Spinal cord injury remains an invincible complication affecting up to 1 of 5 patients after thoracoabdominal aortic aneurysm repair. A staged surgical approach has been suggested to eliminate paraplegia by induction of arteriogenesis within the paraspinal collateral network; however, its clinical implementation was deferred because it required 2 major procedures. METHODS: First-in-man experience with minimally invasive, selective segmental artery endovascular coil embolization before Crawford type II and III thoracoabdominal aortic aneurysm repair for arteriogenic preconditioning of the collateral network is reported. A 45-year-old man received bilateral elective minimally invasive, selective segmental artery endovascular coil embolization of 2 unilateral lumbar segmental arteries 4 weeks before open surgical repair. A 67-year-old woman who was planned for total endovascular treatment received minimally invasive, selective segmental artery endovascular coil embolization at the fourth lumbar level and coil embolization of the inferior mesenteric artery 8 weeks before endovascular repair. RESULTS: Minimally invasive, selective segmental artery endovascular coil embolization was technically successful and did not result in any neurologic impairment. Both patients were discharged after 72 hours of clinical surveillance. Patient 1 returned for definite open single-stage thoracoabdominal aortic aneurysm repair after 4 weeks and left the hospital without any neurologic impairment on day 35 postoperatively. Patient 2 returned for total endovascular repair 8 weeks after she underwent minimally invasive, selective segmental artery endovascular coil embolization; she recovered well and was discharged without spinal cord injury 8 days after extensive single-stage endovascular thoracoabdominal aortic aneurysm repair. Both patients are alive with no neurologic injury at 1-year follow-up. CONCLUSIONS: Minimally invasive, selective segmental artery endovascular coil embolization for arteriogenic preconditioning of the paraspinal arterial collateral network is clinically feasible and may eventually eliminate ischemic spinal cord injury to enable safe open or endovascular repair of extensive thoracoabdominal aortic aneurysms and prevent paraplegia altogether in the near future. PMID- 25906718 TI - Keeping the fundamentals in mind. PMID- 25906721 TI - The continued evolution of a transformational operation: New options for wrapping the Ross autograft? PMID- 25906722 TI - The state of off-pump coronary artery bypass in 2015. PMID- 25906723 TI - Benefits of OPCAB are not for everybody. Costs are. PMID- 25906724 TI - Focusing on the second arterial conduit. PMID- 25906725 TI - Can we discuss bilateral internal thoracic artery grafts without embracing skeletonization? PMID- 25906726 TI - Resuscitation in cardiac surgical patients: Symptoms versus cause. PMID- 25906727 TI - Do emergent aortic dissection operations increase postoperative neurologic complications? PMID- 25906728 TI - The importance lies on the process and care delivery of resuscitation in perioperative cardiac surgical care. PMID- 25906729 TI - Repair or replace the aortic valve? More questions, no answers. PMID- 25906730 TI - Repair or replace the aortic valve: the weight of evidence. PMID- 25906731 TI - Arrhythmia prevalence after extra cardiac conduit Fontan: A viewpoint. PMID- 25906732 TI - A recommendation for modification of the hourglass-shaped resection technique for repair of tall mitral valve posterior prolapse. PMID- 25906733 TI - Lack of influence of heterotaxy on arrhythmia prevalence after intracardiac versus extracardiac Fontan operations. PMID- 25906734 TI - About lemons and lemonade. PMID- 25906735 TI - Outcomes for LVRS: finding the correct lemonade recipe. PMID- 25906736 TI - Combined transcatheter aortic valve replacement and endovascular ascending aortic repair: Fiction or reality? PMID- 25906737 TI - Design and Stereoselective Synthesis of ProM-2: A Spirocyclic Diproline Mimetic with Polyproline Type II (PPII) Helix Conformation. AB - With the aim of developing polyproline type II helix (PPII) secondary-structure mimetics for the modulation of prolin-rich-mediated protein-protein interactions, the novel diproline mimetic ProM-2 was designed by bridging the two pyrrolidine rings of a diproline (Pro-Pro) unit through a Z-vinylidene moiety. This scaffold, which closely resembles a section of a PPII helix, was then stereoselectively synthesized by exploiting a ruthenium-catalyzed ring-closing metathesis (RCM) as a late key step. The required vinylproline building blocks, that is, (R)-N-Boc-2 vinylproline (Boc=tert-butyloxycarbonyl) and (S,S)-5-vinylproline-tert-butyl ester, were prepared on a gram scale as pure stereoisomers. The difficult peptide coupling of the sterically demanding building blocks was achieved in good yield and without epimerization by using 2-(1H-7-azabenzotriazol-1-yl)-1,1,3,3 tetramethyluronium hexafluorophosphate (HATU)/N,N-diisopropylethylamine (DIPEA). The RCM proceeded smoothly in the presence of the Grubbs II catalyst. Stereostructural assignments for several intermediates were secured by X-ray crystallography. As a proof of concept, it was shown that certain peptides containing ProM-2 exhibited improved (canonical) binding towards the Ena/VASP homology 1 (EVH1) domain as a relevant protein interaction target. PMID- 25906738 TI - Sub-nanometre resolution imaging of polymer-fullerene photovoltaic blends using energy-filtered scanning electron microscopy. AB - The resolution capability of the scanning electron microscope has increased immensely in recent years, and is now within the sub-nanometre range, at least for inorganic materials. An equivalent advance has not yet been achieved for imaging the morphologies of nanostructured organic materials, such as organic photovoltaic blends. Here we show that energy-selective secondary electron detection can be used to obtain high-contrast, material-specific images of an organic photovoltaic blend. We also find that we can differentiate mixed phases from pure material phases in our data. The lateral resolution demonstrated is twice that previously reported from secondary electron imaging. Our results suggest that our energy-filtered scanning electron microscopy approach will be able to make major inroads into the understanding of complex, nano-structured organic materials. PMID- 25906739 TI - Micromotor-based energy generation. AB - A micromotor-based strategy for energy generation, utilizing the conversion of liquid-phase hydrogen to usable hydrogen gas (H2), is described. The new motion based H2-generation concept relies on the movement of Pt-black/Ti Janus microparticle motors in a solution of sodium borohydride (NaBH4) fuel. This is the first report of using NaBH4 for powering micromotors. The autonomous motion of these catalytic micromotors, as well as their bubble generation, leads to enhanced mixing and transport of NaBH4 towards the Pt-black catalytic surface (compared to static microparticles or films), and hence to a substantially faster rate of H2 production. The practical utility of these micromotors is illustrated by powering a hydrogen-oxygen fuel cell car by an on-board motion-based hydrogen and oxygen generation. The new micromotor approach paves the way for the development of efficient on-site energy generation for powering external devices or meeting growing demands on the energy grid. PMID- 25906741 TI - MR lymphangiography: How i do it. AB - Lymphedema is a chronic progressive edematous disease that in the United States is most commonly related to malignancy and its treatment. Lymphaticovenular anastomosis is a recently introduced microsurgical treatment option for lymphedema that requires the identification and mapping of individual lymphatic channels. While nuclear medicine lymphoscintigraphy has been the primary imaging modality performed to evaluate suspected lymphedema, lymphoscintigraphy does not provide the spatial information necessary for presurgical planning. High resolution dynamic 3D magnetic resonance imaging (MRI) can noninvasively image abnormal lymphatic channels to both diagnose lymphedema and depict the location and number of individual lymphatic channels for surgical planning. MR lymphangiography can be performed at 1.5T or 3.0T using multichannel phased array surface coils. The main components of the exam are a heavily T2 -weighted 3D sequence to define the severity and extent of edema, a high-resolution dynamic 3D gradient echo imaging after intracutaneous contrast injection to visualize lymphatic channels, and a delayed 3D gradient echo sequence after intravenous contrast to define veins. This article reviews the pathophysiology and microsurgical treatment of lymphedema, presents the imaging protocol used at our institution, and describes exam interpretation and the image postprocessing performed for surgical planning. PMID- 25906742 TI - HoLaMa: A Klenow sub-fragment lacking the 3'-5' exonuclease domain. AB - The design, construction, overexpression, and purification of a Klenow sub fragment lacking the 3'-5' exonuclease domain is presented here. In particular, a synthetic gene coding for the residues 515-928 of Escherichia coli DNA polymerase I was constructed. To improve the solubility and stability of the corresponding protein, the synthetic gene was designed to contain 11 site-specific substitutions. The gene was inserted into the pBADHis expression vector, generating 2 identical Klenow sub-fragments, bearing or not a hexahistidine tag. Both these Klenow sub-fragments, denominated HoLaMa and HoLaMaHis, were purified, and their catalytic properties were compared to those of Klenow enzyme. When DNA polymerase activity was assayed under processive conditions, the Klenow enzyme performed much better than HoLaMa and HoLaMaHis. However, when DNA polymerase activity was assayed under distributive conditions, the initial velocity of the reaction catalyzed by HoLaMa was comparable to that observed in the presence of Klenow enzyme. In particular, under distributive conditions HoLaMa was found to strongly prefer dsDNAs bearing a short template overhang, to the length of which the Klenow enzyme was relatively insensitive. Overall, our observations indicate that the exonuclease domain of the Klenow enzyme, besides its proofreading activity, does significantly contribute to the catalytic efficiency of DNA elongation. PMID- 25906743 TI - Oxidized low-density lipoprotein accelerates the destabilization of extracellular superoxide dismutase mRNA during foam cell formation. AB - Extracellular-superoxide dismutase (EC-SOD) is one of the main anti-oxidative enzymes that protect cells against the damaging effects of superoxide. In the present study, we investigated the regulation of EC-SOD expression during the oxidized low density lipoprotein (oxLDL)-induced foam cell formation of THP-1 derived macrophages. The uptake of oxLDL into THP-1-derived macrophages was increased and EC-SOD expression was decreased in a time-dependent manner by oxLDL. Furthermore, EC-SOD suppression by oxLDL was mediated by the binding to scavenger receptors, especially CD36, from the results with siRNA experience. EC SOD expression is known to be regulated by histone acetylation and binding of the transcription factor Sp1/3 to the EC-SOD promoter region in human cell lines. However, oxLDL did not affect these processes. On the other hand, the stability of EC-SOD mRNA was decreased by oxLDL. Moreover, oxLDL promoted destabilization of ectopically expressed mRNA from EC-SOD or chimeric Cu,Zn-SOD gene with the sequence corresponding to 3'UTR of EC-SOD mRNA, whereas oxLDL had no effect on ectopic mRNA produced from EC-SOD gene lacking the sequence. These results suggested that oxLDL decreased the expression of EC-SOD, which, in turn, accelerated the destabilization of EC-SOD mRNA, leading to weaker protection against oxidative stress and atherosclerosis. PMID- 25906744 TI - Characterization and physiological role of two types of chloroplastic fructose 1,6-bisphosphatases in Euglena gracilis. AB - The chloroplastic fructose-1,6-bisphosphatase (FBPase) is a late-limiting enzyme in the Calvin cycle. In the present study, we isolated and characterized the cDNAs encoding two types of chloroplastic FBPase isoforms (EgFBPaseI and II) from Euglena gracilis. The Km values of recombinant EgFBPaseI and EgFBPaseII for fructose 1,6-bisphosphate (Fru 1,6-P2) were 165 +/- 17 and 2200 +/- 200 MUM, respectively. The activity of EgFBPaseI was inhibited by 1mM H2O2 and recovered when incubated with DTT. The activity of EgFBPaseII was resistant to concentrations of H2O2 up to 1mM, which was distinct from those of EgFBPaseI and spinach chloroplastic FBPase. The suppression of EgFBPaseI gene expression by gene silencing markedly decreased photosynthetic activity and inhibited cell growth. The results of the present study clearly demonstrated that EgFBPaseI played a critical role in photosynthesis in Euglena chloroplasts. PMID- 25906745 TI - ERG deregulation induces IGF-1R expression in prostate cancer cells and affects sensitivity to anti-IGF-1R agents. AB - Identifying patients who may benefit from targeted therapy is an urgent clinical issue in prostate cancer (PCa). We investigated the molecular relationship between TMPRSS2-ERG (T2E) fusion gene and insulin-like growth factor receptor (IGF-1R) to optimize the use of IGF-1R inhibitors.IGF-1R was analyzed in cell lines and in radical prostatectomy specimens in relation to T2E status. ERG binding to IGF-1R promoter was evaluated by chromatin immunoprecipitation (ChIP). Sensitivity to anti-IGF-1R agents was evaluated alone or in combination with anti androgen abiraterone acetate in vitro at basal levels or upon ERG modulation.IGF 1R analysis performed in PCa cells or clinical samples showed that T2E expression correlated with higher IGF-1R expression at mRNA and protein levels. Genetic modulation of ERG directly affected IGF-1R protein levels in vitro. ChIP analysis showed that ERG binds IGF-1R promoter and that promoter occupancy is higher in T2E-positive cells. IGF-1R inhibition was more effective in cell lines expressing the fusion gene and combination of IGF-1R inhibitors with abiraterone acetate produced synergistic effects in T2E-expressing cells.Here, we provide the rationale for use of T2E fusion gene to select PCa patients for anti-IGF-1R treatments. The combination of anti-IGF-1R-HAbs with an anti-androgen therapy is strongly advocated for patients expressing T2E. PMID- 25906746 TI - MicroRNA-146a modulates B-cell oncogenesis by regulating Egr1. AB - miR-146a is a NF-kappaB induced microRNA that serves as a feedback regulator of this critical pathway. In mice, deficiency of miR-146a results in hematolymphoid cancer at advanced ages as a consequence of constitutive NF-kappaB activity. In this study, we queried whether the deficiency of miR-146a contributes to B-cell oncogenesis. Combining miR-146a deficiency with transgenic expression of c-Myc led to the development of highly aggressive B-cell malignancies. Mice transgenic for c-Myc and deficient for miR-146a were characterized by significantly shortened survival, increased lymph node involvement, differential involvement of the spleen and a mature B-cell phenotype. High-throughput sequencing of the tumors revealed significant dysregulation of approximately 250 genes. Amongst these, the transcription factor Egr1 was consistently upregulated in mice deficient for miR-146a. Interestingly, transcriptional targets of Egr1 were enriched in both the high-throughput dataset and in a larger set of miR-146a deficient tumors. miR-146a overexpression led to downregulation of Egr1 and downstream targets with concomitant decrease in cell growth. Direct targeting of the human EGR1 by miR-146a was seen by luciferase assay. Together our findings illuminate a bona fide role for miR-146a in the modulation of B-cell oncogenesis and reveal the importance of understanding microRNA function in a cell- and disease-specific context. PMID- 25906748 TI - Multi-platform profiling of over 2000 sarcomas: identification of biomarkers and novel therapeutic targets. AB - BACKGROUND: Drug development in sarcoma has been hampered by the rarity and heterogeneity of the disease and lack of predictive biomarkers to therapies. We assessed protein expression and gene alterations in a large number of bone and soft tissue sarcomas in order to categorize the molecular alterations, identify predictive biomarkers and discover new therapeutic targets. METHODS: Data from sarcoma specimens profiled for protein expression, gene amplification/translocation and DNA sequencing was reviewed. RESULTS: 2539 sarcoma specimens of 22 subtypes were included. TOPO2A was the most overexpressed protein at 52.8%. There was overexpression or loss of other sarcoma relevant proteins such as SPARC, PTEN and MGMT. Approximately 50% of the sarcomas expressed PD-L1 by IHC and presented with PD-1+ TILs, notably the LMS, chondrosarcomas, liposarcomas and UPS. Gene amplification/rearrangement of ALK, cMYC, HER2, PIK3CA, TOPO2A and cMET was relatively uncommon. EGFR gene amplification occurred at a rate of 16.9%. DNA sequencing of 47 genes identified mutations in 47% of the samples. The most commonly mutated genes were TP53 (26.3%) and BRCA2 (17.6%). Overexpression of TOPO2A was associated with TP53 mutation (P = 0.0001). CONCLUSION: This data provides the landscape of alterations in sarcoma. Future clinical trials are needed to validate these targets. PMID- 25906747 TI - The prognostic value of the stem-like group in colorectal cancer using a panel of immunohistochemistry markers. AB - Colorectal cancer (CRC) is the second leading cause of cancer-related deaths in the Western world. It is becoming increasingly clear that CRC is a diverse disease, as exemplified by the identification of subgroups of CRC tumours that are driven by distinct biology. Recently, a number of studies have begun to define panels of diagnostically relevant markers to align patients into individual subgroups in an attempt to give information on prognosis and treatment response. We examined the immunohistochemical expression profile of 18 markers, each representing a putative role in cancer development, in 493 primary colorectal carcinomas using tissue microarrays. Through unsupervised clustering in stage II cancers, we identified two cluster groups that are broadly defined by inflammatory or immune-related factors (CD3, CD8, COX-2 and FOXP3) and stem-like factors (CD44, LGR5, SOX2, OCT4). The expression of the stem-like group markers was associated with a significantly worse prognosis compared to cases with lower expression. In addition, patients classified in the stem-like subgroup displayed a trend towards a benefit from adjuvant treatment. The biologically relevant and poor prognostic stem-like group could also be identified in early stage I cancers, suggesting a potential opportunity for the identification of aggressive tumors at a very early stage of the disease. PMID- 25906749 TI - Targeting pancreatitis blocks tumor-initiating stem cells and pancreatic cancer progression. AB - Recent development of genetically engineered mouse models (GEMs) for pancreatic cancer (PC) that recapitulates human disease progression has helped to identify new strategies to delay/inhibit PC development. We first found that expression of the pancreatic tumor-initiating/cancer stem cells (CSC) marker DclK1 occurs in early stage PC and in both early and late pancreatic intraepithelial neoplasia (PanIN) and that it increases as disease progresses in GEM and also in human PC. Genome-wide next generation sequencing of pancreatic ductal adenocarcinoma (PDAC) from GEM mice revealed significantly increased DclK1 along with inflammatory genes. Genetic ablation of cyclo-oxygenase-2 (COX-2) decreased DclK1 in GEM. Induction of inflammation/pancreatitis with cerulein in GEM mice increased DclK1, and the novel dual COX/5-lipoxygenase (5-LOX) inhibitor licofelone reduced it. Dietary licofelone significantly inhibited the incidence of PDAC and carcinoma in situ with significant inhibition of pancreatic CSCs. Licofelone suppressed pancreatic tumor COX-2 and 5-LOX activities and modulated miRNAs characteristic of CSC and inflammation in correlation with PDAC inhibition. These results offer a preclinical proof of concept to target the inflammation initiation to inhibit cancer stem cells early for improving the treatment of pancreatic cancers, with immediate clinical implications for repositioning dual COX/5-LOX inhibitors in human trials for high risk patients. PMID- 25906750 TI - FKBPL: a marker of good prognosis in breast cancer. AB - FK506-binding protein-like (FKBPL) has established roles as an anti-tumor protein, with a therapeutic peptide based on this protein, ALM201, shortly entering phase I/II clinical trials. Here, we evaluated FKBPL's prognostic ability in primary breast cancer tissue, represented on tissue microarrays (TMA) from 3277 women recruited into five independent retrospective studies, using immunohistochemistry (IHC). In a meta-analysis, FKBPL levels were a significant predictor of BCSS; low FKBPL levels indicated poorer breast cancer specific survival (BCSS) (hazard ratio (HR) = 1.30, 95% confidence interval (CI) 1.14 1.49, p < 0.001). The prognostic impact of FKBPL remained significant after adjusting for other known prognostic factors (HR = 1.25, 95% CI 1.07-1.45, p = 0.004). For the sub-groups of 2365 estrogen receptor (ER) positive patients and 1649 tamoxifen treated patients, FKBPL was significantly associated with BCSS (HR = 1.34, 95% CI 1.13-1.58, p < 0.001, and HR = 1.25, 95% CI 1.04-1.49, p = 0.02, respectively). A univariate analysis revealed that FKBPL was also a significant predictor of relapse free interval (RFI) within the ER positive patient group, but it was only borderline significant within the smaller tamoxifen treated patient group (HR = 1.32 95% CI 1.05-1.65, p = 0.02 and HR = 1.23 95% CI 0.99 1.54, p = 0.06, respectively). The data suggests a role for FKBPL as a prognostic factor for BCSS, with the potential to be routinely evaluated within the clinic. PMID- 25906752 TI - Contrast Echocardiography in Acutely Unwell Patients. PMID- 25906751 TI - Loss of Wave1 gene defines a subtype of lethal prostate cancer. AB - Genetic alterations involving TMPRSS2-ERG alterations and deletion of key tumor suppressor genes are associated with development and progression of prostate cancer (PCa). However, less defined are early events that may contribute to the development of high-risk metastatic prostate cancer. Bioinformatic analysis of existing tumor genomic data from PCa patients revealed that WAVE complex gene alterations are associated with a greater likelihood of prostate cancer recurrence. Further analysis of primary vs. castration resistant prostate cancer indicate that disruption of WAVE complex gene expression, and particularly WAVE1 gene (WASF1) loss, is also associated with castration resistance, where WASF1 is frequently co-deleted with PTEN and resists androgen deprivation therapy (ADT). Hence, we propose that WASF1 status defines a subtype of ADT-resistant patients. Better understanding of the effects of WAVE pathway disruption will lead to development of better diagnostic and treatment modalities. PMID- 25906753 TI - Feasibility and Reproducibility of Echocardiographic Measures in Children with Muscular Dystrophies. AB - BACKGROUND: Cardiac disease is a major cause of death in patients with muscular dystrophies. The use of feasible and reproducible echocardiographic measures of cardiac function is critical to advance the field of therapeutics for dystrophic cardiomyopathy. METHODS: Participants aged 8 to 18 years with genetically confirmed Duchenne muscular dystrophy (DMD), Becker muscular dystrophy, or limb girdle muscular dystrophy were enrolled at five centers, and standardized echocardiographic examinations were performed. Measures of systolic and diastolic function and speckle-tracking echocardiography-derived cardiac strain were reviewed independently by two central readers. Furthermore, echocardiographic measures from participants with DMD were compared with those from retrospective age-matched control subjects from a single site to assess measures of myocardial function. RESULTS: Forty-eight participants (mean age, 13.3 +/- 2.7 years) were enrolled. Shortening fraction had a greater interobserver correlation (intraclass correlation coefficient [ICC] = 0.63) compared with ejection fraction (ICC = 0.49). One reader could measure ejection fraction in only 53% of participants. Myocardial performance index measured by pulse-wave Doppler and Doppler tissue imaging showed similar ICCs (0.55 and 0.54). Speckle-tracking echocardiography showed a high ICC (0.96). Focusing on participants with DMD (n = 33), significantly increased mitral A-wave velocities, lower E/A ratios, and lower Doppler tissue imaging mitral lateral E' velocities were observed compared with age-matched control subjects. Speckle-tracking echocardiography demonstrated subclinical myocardial dysfunction with decreased average circumferential and longitudinal strain in three distinct subgroups: participants with DMD with normal shortening fractions, participants with DMD aged < 13 years, and participants with DMD with myocardial performance index scores < 0.40 compared with control subjects. CONCLUSIONS: In a muscular dystrophy cohort, assessment of cardiac function is feasible and reproducible using shortening fraction, diastolic measures, and myocardial performance index. Cardiac strain measures identified early myocardial disease in patients with DMD. PMID- 25906754 TI - Polyphenol-rich diets improve glucose metabolism in people at high cardiometabolic risk: a controlled randomised intervention trial. AB - AIM/HYPOTHESIS: Dietary polyphenols and long chain n-3 polyunsaturated fatty acids (LCn3) are associated with lower cardiovascular risk. This may relate to their influence on glucose metabolism and diabetes risk. We evaluated the effects of diets naturally rich in polyphenols and/or LCn3 of marine origin on glucose metabolism in people at high cardiometabolic risk. METHODS: According to a 2 * 2 factorial design, individuals with high waist circumference and at least one more component of the metabolic syndrome were recruited at the obesity outpatient clinic. Eighty-six participants were randomly assigned by MINIM software to an isoenergetic diet: (1) control, low in LCn3 and polyphenol (analysed n = 20); (2) rich in LCn3 (n = 19); (3) rich in polyphenols (n = 19); or (4) rich in LCn3 and polyphenols (n = 19). The assigned diets were known for the participants and blinded for people doing measurements. Before and after the 8 week intervention, participants underwent a 3 h OGTT and a test meal with a similar composition as the assigned diet for the evaluation of plasma glucose, insulin and glucagon-like peptide 1 (GLP-1) concentrations, and indices of insulin sensitivity and beta cell function. RESULTS: During OGTT, polyphenols significantly reduced plasma glucose total AUC (p = 0.038) and increased early insulin secretion (p = 0.048), while LCn3 significantly reduced beta cell function (p = 0.031) (two-factor ANOVA). Moreover, polyphenols improved post-challenge oral glucose insulin sensitivity (OGIS; p = 0.05 vs control diet by post hoc ANOVA). At test meal, LCn3 significantly reduced GLP-1 total postprandial AUC (p < 0.001; two-factor ANOVA). CONCLUSION/INTERPRETATION: Diets naturally rich in polyphenols reduce blood glucose response, likely by increasing early insulin secretion and insulin sensitivity. These effects may favourably influence diabetes and cardiovascular risk. The implications of the decrease in insulin secretion and postprandial GLP 1 observed with diets rich in marine LCn3 need further clarification. TRIAL REGISTRATION: ClinicalTrials.gov NCT01154478. FUNDING: The trial was funded by European Community's Seventh Framework Programme FP7/2009-2012 under grant agreement FP7-KBBE-222639, Etherpaths Project and 'Ministero Istruzione Universita e Ricerca' PRIN 2010-2011 - 2010JCWWKM. PMID- 25906755 TI - 50 years forward: mechanisms of hyperglycaemia-driven diabetic complications. AB - The advent of insulin treatment in 1923 meant fewer diabetes deaths from acute metabolic deterioration and sepsis and a progressive increase in the burden of disease caused by end-organ damage. These diabetic complications are the major cause of morbidity and premature mortality among diabetic subjects. Over the last 50 years it has become apparent that diabetic complications in disparate tissues may result from a combination of common pathological processes. Pathways activated by initial metabolic insults are promoted by co-factors such as renin angiotensin-aldosterone system activation, hyperinsulinaemia, underlying genetic susceptibility, and traditional vascular risk factors, particularly hypertension and lipids. These common pathways include AGE formation, reactive oxygen species overproduction, protein kinase C activation, mitochondrial dysfunction and activation of proinflammatory and profibrotic signalling cascades. Once established, these interlinked pathways become self-perpetuating. Many drugs acting against individual downstream targets in these pathways have failed due to lack of efficacy or adverse effects. Gains in the future may be made by better control of existing risk factors, more sophisticated modulation of tissue glucose and insulin signalling, and interventions to improve mitochondrial function and reduce oxidative stress. Epigenetic and microRNA research may lead to methods to disrupt the mechanisms whereby pathological pathways are perpetuated. Expansion in capacity and expertise in biomarker measurement and analysis may allow better targeting of therapies to patients who are most likely to benefit. This is one of a series of commentaries under the banner '50 years forward', giving personal opinions on future perspectives in diabetes, to celebrate the 50th anniversary of Diabetologia (1965-2015). PMID- 25906756 TI - Can mycophenolate mofetil be tapered safely in myasthenia gravis? A retrospective, multicenter analysis. AB - INTRODUCTION: Mycophenolate mofetil (MMF) is frequently used to treat myasthenia gravis, but there is little information to guide clinicians on the safety of reducing the dose in well-controlled patients. METHODS: This retrospective chart review at 3 institutions identified 92 patients who had undergone MMF taper after achieving either pharmacologic remission or minimal manifestations status. Statistical analysis was performed to assess differences in patient characteristics between patients who had successfully tapered MMF and those who relapsed. RESULTS: Of 92 patients undergoing a taper, 30 relapsed. The relapses were mild, transient, and usually responded to increased MMF dose. MG crisis did not occur. The mean dose at time of relapse was 888 mg/day. Patients with relapses were tapered more quickly (8.4 vs. 62.4 months). CONCLUSIONS: Tapering MMF appears safe after years of disease stability. Reducing the dose at a dose of only 500 mg/day every 12 months is recommended. PMID- 25906758 TI - Size-dependent penetration of carbon dots inside the ferritin nanocages: evidence for the quantum confinement effect in carbon dots. AB - The origin of the excitation wavelength (lambdaex)-dependent photoluminescence (PL) of carbon dots (CDs) is poorly understood and still remains obscured. This phenomenon is often explained on the basis of surface trap/defect states, while the effect of quantum confinement is highly neglected in the literature. Here, we have shown that the lambdaex-dependent PL of CDs is mainly due to the inhomogeneous size distribution. We have demonstrated the lambdaex-dependent PL quenching of CDs inside the ferritin nanocages through selective optical excitation of differently sized CDs. It has been observed that Fe(3+) ions of ferritin effectively quench the PL of CDs due to static electron transfer, which is driven by favorable electrostatic interactions. However, control experiment with aqueous Fe(3+) ions in bulk medium revealed lambdaex-independent PL quenching of CDs. The lambdaex-dependent PL quenching of CDs by Fe(3+) ions of ferritin has been rationalized on the basis of a different extent of accessibility of Fe(3+) ions by differently sized CDs through the funnel-shaped ferritin channels. PL microscopy of individual CDs has been performed to get further information about their inherent PL properties at single dot resolution. Our results have shown that these hydrophilic CDs can be used as potential iron sensors in biological macromolecules. PMID- 25906757 TI - 1,25(OH)2D3 downregulates the Toll-like receptor 4-mediated inflammatory pathway and ameliorates liver injury in diabetic rats. AB - BACKGROUND: Fatty acid deposition in the liver can activate a number of pro inflammatory signaling pathways such as the Toll-like receptor 4 (TLR4) pathway, which may be important in the pathogenesis of nonalcoholic steatohepatitis. 1,25(OH)2D3 downregulates the expression of TLR4 and may represent a novel treatment strategy for reducing hepatocyte injury. Therefore, in this study, we investigated the protective effects of 1,25(OH)2D3 on diabetic liver injury in vivo. METHODS: Streptozotocin (STZ)-induced diabetic rats were randomly divided into five groups and treated with low-dose 1,25(OH)2D3 (0.025 MUg/kg/day), medium dose 1,25(OH)2D3 (0.15 MUg/kg/day), high-dose 1,25(OH)2D3 (0.3 MUg/kg/day), insulin (protamine zinc insulin 16 U/kg/day, subcutaneous injection), or no intervention (the control group). Sixteen weeks later, the rats were killed, and blood samples were obtained to test lipid profiles and hepatic function. The infiltration of inflammatory cells, the level of fibrosis, and the expression levels of TLR4, nuclear factor-kappa B (NF-kappaB), and tumor necrosis factor alpha (TNF-alpha) in the liver were analyzed. The hepatocytes were treated with vehicle control, LPS (100 ng), high fat [DMEM + FFA (0.1 mM: palmitic acid, oleic acid, 1:2)], LPS + high fat, vehicle + 1,25(OH)2D3 (10(-7) M), LPS + 1,25(OH)2D3, high fat + 1,25(OH)2D3, or LPS + high fat + 1,25(OH)2D3. RNA and protein were extracted to detect the expression of TLR4 and downstream inflammatory factors such as NF-KappaB, TNF-alpha, and IL-6. Groups of data were compared by single factor variance analysis. RESULTS: High-dose 1,25(OH)2D3 administration for 16 weeks downregulated the expression of TLR4, NF-kappaB, and TNF-alpha in the liver tissue of diabetic rats and attenuated hepatic inflammation and fibrosis, as shown by immunohistochemical staining, hematoxylin and eosin staining, Masson's trichrome staining, reverse transcription polymerase chain reaction (RT-PCR), and western blotting. In vitro, hepatocytes treated with high fat or LPS exhibited significantly increased expression of TLR4, NF-kappaB, and downstream inflammatory factors (P < 0.05). Intervention with 1,25(OH)2D3 decreased the expression of TLR4, NF-kappaB, and inflammatory factors (P < 0.05). CONCLUSIONS: 1,25(OH)2D3 exhibited protective effects against diabetes-related liver injury, possibly through downregulation of components of the TLR4 signaling pathway. PMID- 25906759 TI - Molecular pathogenesis lessons from the world of infectious diseases research. AB - This Guest Editorial introduces this month's special Infectious Disease Theme Issue, a series of reviews focusing on the molecular pathogenic processes of four representative pathogens, including two bacteria (brucellae and Staphylococcus aureus), a virus (influenza), and a parasite (Trypanosoma cruzi). PMID- 25906760 TI - Case study interpretation: Report from the ICCS Annual Meeting, Seattle, 2014. AB - The Case Study Interpretation (CSI) cases presented at the 2014 International Clinical Cytometry Society (ICCS) meeting in Seattle illustrate the utility of state-of-the art multiparameter flow cytometry in the diagnosis of hematolymphoid neoplasms. Download the listmode files (Supporting Information) and test your analysis skills before reading the case reports, keeping in mind the following questions. How many separate abnormal mature B-cell populations can you identify, and how many of these represent different subtypes of B-cell neoplasm? How many separate abnormal mature T-cell populations can you identify, and do these represent different subtypes of T-cell neoplasm or phenotypic heterogeneity in one neoplasm? How many separate immature/blastic cell populations can you identify, and do they meet criteria for mixed phenotype leukemia? Is there a population of blasts that lacks T-cell, B-cell, and myeloid lineage defining antigens and if so, what entities should you consider and what additional antigens should you assess for? PMID- 25906761 TI - A magneto-electro-optical effect in a plasmonic nanowire material. AB - Electro- and magneto-optical phenomena play key roles in photonic technology enabling light modulators, optical data storage, sensors and numerous spectroscopic techniques. Optical effects, linear and quadratic in external electric and magnetic field are widely known and comprehensively studied. However, optical phenomena that depend on the simultaneous application of external electric and magnetic fields in conventional media are barely detectable and technologically insignificant. Here we report that a large reciprocal magneto electro-optical effect can be observed in metamaterials. In an artificial chevron nanowire structure fabricated on an elastic nano-membrane, the Lorentz force drives reversible transmission changes on application of a fraction of a volt when the structure is placed in a fraction-of-tesla magnetic field. We show that magneto-electro-optical modulation can be driven to hundreds of thousands of cycles per second promising applications in magneto-electro-optical modulators and field sensors at nano-tesla levels. PMID- 25906762 TI - Percutaneous carbon dioxide mist treatment has protective effects in experimental myocardial infarction. AB - Percutaneous treatment with carbon dioxide (CO2) mist, CO2 gas dissolved in water, contributes to improved cardiac function after myocardial infarction (MI). In this study, we investigated the effects of repeated pretreatment with CO2 mist on cardiac dysfunction after MI. The CO2 mist was generated by a dry mist production unit. The whole body of rats below the axilla was wrapped in a polyethylene bag, which was sealed and filled with the CO2 mist in the draft cabinet for 30 min daily for 7 days. MI was induced by ligation of the coronary artery in untreated (UT), CO2 gas-pretreated (CG), and CO2 mist-pretreated (CM) rats. The infarct size and the increase in oxidative stress due to MI were significantly smaller in the CM rats than in the UT rats. Furthermore, the expression of inflammation-related genes, such as monocyte chemoattractant protein-1, and fibrosis-related genes, such as transforming growth factor-beta1, was significantly suppressed in the CM rats. The CM rats had a better left ventricular ejection fraction than the UT rats 7 days after MI. These parameters in the CG rats were the same as in the UT group. Thus, CO2 mist preparative treatment may be potentially useful for the reduction of MI. PMID- 25906763 TI - Investigation of Optical Spectroscopic and Computational Binding Mode of Bovine Serum Albumin with 1, 4-Bis ((4-((4-Heptylpiperazin-1-yl) Methyl)-1H-1, 2, 3 Triazol-1-yl) Methyl) Benzene. AB - A newly synthesized 1, 4-bis ((4-((4-heptylpiperazin-1-yl) methyl)-1H-1, 2, 3 triazol-1-yl) methyl) benzene from the family of piperazine derivative has good anticancer activity, antibacterial and low toxic nature; its binding characteristics are therefore of huge interest for understanding pharmacokinetic mechanism of the drug. The binding of piperazine derivative to bovine serum albumin (BSA) was investigated using fluorescence spectroscopy. The molecular distance r between the donor (BSA) and acceptor (piperazine derivative) was estimated according to Forster's theory of nonradiative energy transfer. The physicochemical properties of piperazine derivative, which induced structural changes in BSA, have been studied by circular dichroism and those chemical environmental changes were probed using Raman spectroscopic analysis. Further, the binding dynamics was expounded by synchronous fluorescence spectroscopy and molecular modeling studies explored the hydrophobic interaction and hydrogen bonding results, which stabilize the interaction. PMID- 25906764 TI - Does haptic robot-assisted total hip arthroplasty better restore native acetabular and femoral anatomy? AB - BACKGROUND: The objective was to evaluate whether total hip arthroplasty (THA) using haptic robot assistance restores hip geometry better than the free-hand technique. METHODS: Twelve robot-assisted and 14 free-hand unilateral THA patients underwent CT scan for three-dimensional (3D) hip models. The anteversion, inclination and hip joint centre locations of the native and implanted hips in each patient were quantified and compared. RESULTS: Significant increase of combined anteversion by 19.1 +/- 11.7 degrees and 23.5 +/- 23.6 degrees and decrease of cup inclination by 16.5 +/- 6.0 degrees and 10.2 +/- 6.8 degrees were observed in the robot-assisted and the free-hand THAs, respectively. Less variation in the difference of the component orientations (max 11.1 vs 18.3 degrees ) and the femoral head centre (max 4.5 vs 6.3 mm) were found in the robot-assisted group. CONCLUSION: This study demonstrated that neither robot-assisted nor free-hand THAs had fully restored native hip geometry. However, the higher precision of the robot-assisted THA suggested that it has potential utility in restoring the native hip geometry. Copyright (c) 2015 John Wiley & Sons, Ltd. PMID- 25906765 TI - Sex and the lung: Observations, hypotheses, and future directions. AB - Sex-related differences in a variety of lung diseases in infants and young children are reviewed, including respiratory distress syndrome, and chronic lung disease of prematurity, lower respiratory tract illnesses and wheezing, asthma, diffuse, and interstitial lung diseases, and cystic fibrosis. Differences in anatomy and physiology, such as airway size, airway muscle bulk, airway reactivity, airway tone, and cough reflexes may explain much of these sex differences. Better understanding of sex-related lung differences could help personalize respiratory treatment. PMID- 25906766 TI - Patterns of change in cognitive function with anastrozole therapy. AB - BACKGROUND: The purpose of this study was to examine and compare the effects of the first 18 months of anastrozole therapy on cognitive function in women with breast cancer. METHODS: This large, longitudinal cohort study was composed of postmenopausal women with early-stage breast cancer who received chemotherapy plus anastrozole (n = 114) or anastrozole alone (n = 173) and a control group (n = 110). Cognitive function was assessed before systemic therapy and 6, 12, and 18 months after therapy initiation and at comparable time points in controls. RESULTS: The chemotherapy-anastrozole and anastrozole-alone groups had poorer executive function than the controls at nearly all time points (P < .0001 to P = .09). A pattern of deterioration in working memory and concentration was observed during the first 6 months of anastrozole therapy for the chemotherapy-anastrozole group (P < .0001 and P < .0009, respectively) and the anastrozole-alone group (P = .0008 and P = .0002, respectively). This was followed by improved working memory and concentration from 6 to 12 months in both groups. The anastrozole alone group had a second decline in working memory and concentration from 12 to 18 months after the initiation of therapy (P < .0001 and P = .02, respectively). CONCLUSIONS: Women with breast cancer had poorer executive functioning from the period before therapy through the entire first 18 months of therapy. A pattern of decline in working memory and concentration with initial exposure to anastrozole was observed. Women receiving anastrozole alone had a second deterioration in working memory and concentration from 12 to 18 months after therapy initiation. The longer term effects (>18 months) of anastrozole on cognitive function remain to be determined. PMID- 25906767 TI - Three-year-olds can predict a noun based on an attributive adjective: evidence from eye-tracking. AB - This paper investigates whether three-year-olds are able to process attributive adjectives (e.g., soft pillow) as they hear them and to predict the noun (pillow) on the basis of the adjective meaning (soft). This was investigated in an experiment by means of the Visual World Paradigm. The participants saw two pictures (e.g., a pillow and a book) and heard adjective-noun combinations, where the adjective was either informative (e.g., soft) or uninformative (e.g., new) about the head-noun. The properties described by the target adjectives were not visually apparent. When the adjective was uninformative, the looks at the target increased only upon hearing the noun. When the adjective was informative, however, the looks at the target increased upon hearing the adjective. Three-year olds were as fast as adult controls in predicting the upcoming noun. We conclude that toddlers process adjective-noun phrases incrementally and can predict the noun based on the prenominal adjective. PMID- 25906768 TI - Gaps in studies of global health education: an empirical literature review. AB - BACKGROUND: Global health has stimulated a lot of students and has attracted the interest of many faculties, thereby initiating the establishment of many academic programs on global health research and education. global health education reflects the increasing attention toward social accountability in medical education. OBJECTIVE: This study aims to identify gaps in the studies on global health education. DESIGN: A critical literature review of empirical studies was conducted using Boolean search techniques. RESULTS: A total of 238 articles, including 16 reviews, were identified. There had been a boom in the numbers of studies on global health education since 2010. Four gaps were summarized. First, 94.6% of all studies on global health education were conducted in North American and European countries, of which 65.6% were carried out in the United States, followed by Canada (14.3%) and the United Kingdom (9.2%). Only seven studies (2.9%) were conducted in Asian countries, five (2.1%) in Oceania, and two (0.8%) in South American/Caribbean countries. A total of 154 studies (64.4%) were qualitative studies and 64 studies (26.8%) were quantitative studies. Second, elective courses and training or programs were the most frequently used approach for global health education. Third, there was a gap in the standardization of global health education. Finally, it was mainly targeted at medical students, residents, and doctors. It had not granted the demands for global health education of all students majoring in medicine-related studies. CONCLUSIONS: Global health education would be a potentially influential tool for achieving health equity, reducing health disparities, and also for future professional careers. It is the time to build and expand education in global health, especially among developing countries. Global health education should be integrated into primary medical education. Interdisciplinary approaches and interprofessional collaboration were recommended. Collaboration and support from developed countries in global health education should be advocated to narrow the gap and to create further mutual benefits. PMID- 25906769 TI - Cost and impact of scaling up interventions to save lives of mothers and children: taking South Africa closer to MDGs 4 and 5. AB - BACKGROUND: South Africa has made substantial progress on child and maternal mortality, yet many avoidable deaths of mothers and children still occur. This analysis identifies priority interventions to be scaled up nationally and projects the potential maternal and child lives saved. DESIGN: We modelled the impact of maternal, newborn and child interventions using the Lives Saved Tools Projections to 2015 and used realistic coverage increases based on expert opinion considering recent policy change, financial and resource inputs, and observed coverage change. A scenario analysis was undertaken to test the impact of increasing intervention coverage to 95%. RESULTS: By 2015, with realistic coverage, the maternal mortality ratio (MMR) can reduce to 153 deaths per 100,000 and child mortality to 34 deaths per 1,000 live births. Fifteen interventions, including labour and delivery management, early HIV treatment in pregnancy, prevention of mother-to-child transmission and handwashing with soap, will save an additional 9,000 newborns and children and 1,000 mothers annually. An additional US$370 million (US$7 per capita) will be required annually to scale up these interventions. When intervention coverage is increased to 95%, breastfeeding promotion becomes the top intervention, the MMR reduces to 116 and the child mortality ratio to 23. CONCLUSIONS: The 15 interventions identified were adopted by the National Department of Health, and the Health Minister launched a campaign to encourage Provincial Health Departments to scale up coverage. It is hoped that by focusing on implementing these 15 interventions at high quality, South Africa will reach Millennium Development Goal (MDG) 4 soon after 2015 and MDG 5 several years later. Focus on HIV and TB during early antenatal care is essential. Strategic gains could be realised by targeting vulnerable populations and districts with the worst health outcomes. The analysis demonstrates the usefulness of priority setting tools and the potential for evidence-based decision making in the health sector. PMID- 25906770 TI - Fibrinogen concentrate versus placebo for treatment of postpartum haemorrhage: study protocol for a randomised controlled trial. AB - BACKGROUND: Postpartum haemorrhage (PPH) is a major cause of maternal morbidity. Bleeding is caused by a combination of physical causes, such as failure of the uterus to contract or operations, and is made worse by impairment of the blood clotting system. A number of studies have shown that low levels of the blood clotting factor fibrinogen are associated with progression of bleeding, the need for invasive interventions and transfusions of red blood cells and fresh frozen plasma (FFP). This trial will investigate whether early infusion of fibrinogen concentrate during a major PPH, with the aim of correcting a low fibrinogen to a level that is normal for delivery, based on the Fibtem test, reduces the total number of allogeneic blood products (red blood cells, FFP, cryoprecipitate and platelets) transfused after study medication until discharge, compared to placebo. METHODS/DESIGN: This is a prospective, randomised, double-blind placebo controlled trial. Women will enter an observational phase and if their Fibtem levels fall they will be randomised in the interventional phase. A total of 60 women will be randomised and women are eligible for the trial if they meet all of the following inclusion criteria: age 18 years or over, gestation >=24 + 0 weeks, haemorrhage of about 1500 ml and on-going bleeding without another complication or haemorrhage of about 1000 ml and caesarean section/uterine atony/placental abruption/placenta praevia/cardiovascular instability or microvascular oozing. Participants with a Fibtem A5 < 16 mm will be randomly allocated to receive either a bolus infusion of fibrinogen concentrate or placebo (isotonic saline). The dose of fibrinogen concentrate or placebo will be calculated based on the woman's ideal body weight for height and the measured Fibtem A5 with the aim of increasing the Fibtem A5 to 23 mm. DISCUSSION: The trial aims to provide evidence on the efficacy and safety of fibrinogen concentrate during acute bleeding in an obstetric setting. TRIAL REGISTRATION: ISRCTN ref: ISRCTN46295339 (01.07.2013); EudraCT: 2012-005511-11 (28.11.2012), UKCRN ref: 13940. PMID- 25906771 TI - Endogenous opioid inhibition of proliferation of T and B cell subpopulations in response to immunization for experimental autoimmune encephalomyelitis. AB - BACKGROUND: Experimental autoimmune encephalomyelitis (EAE), an animal model of multiple sclerosis, is induced by immunization of mice with myelin oligodendrocytic glycoprotein (MOG35-55) injections, and after 9 days, mice develop behavioral signs of chronic progressive EAE. Proliferation of T and B cells located in peripheral lymph tissues such as spleen and inguinal lymph nodes of C57BL/6J mice are stimulated. The opioid growth factor-opioid growth factor receptor (OGF-OGFr) axis has been shown to effectively limit progression of chronic EAE when mice are treated at the time of induction or at time of established disease. In addition to repressed behavioral profiles, spinal cord neuropathology is diminished in mice treated with OGF or low dosages of naltrexone (LDN). However, there is little or no information on peripheral lymphocyte dynamics following immunization of mice with MOG antigen and treatment with OGF or LDN. METHODS: Six-week old female mice were immunized with MOG35-55 and were injected intraperitoneally with OGF or a low dosage of naltrexone (LDN) beginning at the time of immunization; saline-injected immunized mice served as controls. Normal mice received saline for all injections. Periodically over a 2 week period, spleens and inguinal lymph nodes were removed, total lymphocytes counted, and subpopulations of CD4+ and CD8+ specific T-cells, as well as B lymphocytes, were determined by flow cytometry. On day 15 of treatment, lumbar spinal cord tissue was removed; CNS lymphocytes isolated, and assayed for Th1, Th2, and Th17 markers by flow cytometry. RESULTS: Exogenous OGF or endogenous OGF following LDN suppressed T and B lymphocyte proliferation in the spleen and inguinal lymph nodes of MOG-immunized mice. Suppression of peripheral immune cell CD4+ and CD8+ T cell proliferation at 5 and 12 days correlated with reductions in clinical behavior. EAE mice treated with OGF for 15 days displayed elevated Th1 and Th17 cells; no subpopulations of Th2-specific T cells were noted. CONCLUSIONS: OGF or LDN repress proliferation of CD4+ and CD8+T cells and B220+ B lymphocytes in the spleen and lymph nodes of immunized mice within a week of immunization. These data provide novel mechanistic pathways underlying the efficacy of OGF and LDN therapy for MS. PMID- 25906772 TI - Primary tumors of the patella. AB - The patella is an uncommon location for cancerous occurrence and development. The majority of tumors of the patella are benign, with a significant incidence of giant cell tumors and chondroblastoma. With the development of modern diagnostic technologies, there appear however many other histological types which raise challenges of diagnosis and treatment. In this article, we review the reported histological types of primary patellar tumors. Specifically, epidemiology, symptomatology, imageology, histopathology, and treatment options for these histological lesions will be discussed, respectively. As there is an increasing focus on the diagnosis and the treatment of these lesions, the availability of the integrated information about primary patellar tumors becomes more significant. PMID- 25906773 TI - The business of death: a qualitative study of financial concerns of widowed older women. AB - BACKGROUND: The feminisation of ageing and increasing number of widowed women in contemporary society has significant implications. Older women are at risk of poor health, social, and economic outcomes upon widowhood. The aim of the study was to describe women's experiences in the period soon after their husbands' death, including their financial issues and concerns, and the ways in which these experiences impacted on the transition to widowhood late in life. METHODS: This was a longitudinal study using serial in-depth semi-structured interviews with 21 community-dwelling women over the age of 65 in Australia. Verbatim transcripts underwent Interpretive Phenomenological Analysis. RESULTS: Thematic analysis revealed: 1) administrative burden increases vulnerability; 2) gender roles impact on transitions; and 3) financial adjustments render housing insecurity and health risk. High administrative burden within the context of significant grief and mourning was a defining feature of the early bereavement period. Complicated protracted administrative processes, insensitive interactions, and reminders of loss contributed to distress, anxiety and feelings of demoralisation. Several women identified assumption of household financial management as the most difficult aspect of coping with their husband's death. CONCLUSIONS: Older women may have unmet needs for assistance with administrative, financial, and legal issues immediately following spousal death and potentially for years afterward. Lack of familiarity and absence of instrumental support with financial and legal issues signal the need for policy reform, resources to improve financial literacy in women throughout the life course, increased advocacy, and consideration of different support and service models. PMID- 25906774 TI - The influence of nevirapine and efavirenz-based anti-retroviral therapy on the pharmacokinetics of lumefantrine and anti-malarial dose recommendation in HIV malaria co-treatment. AB - BACKGROUND: HIV-malaria co-infected patients in most parts of sub-Saharan Africa are treated with both artemether-lumefantrine (AL) and efavirenz (EFV) or nevirapine (NVP)-based antiretroviral therapy (ART). EFV, NVP, artemether and lumefantrine are substrates, inhibitors or inducers of CYP3A4 and CYP2B6, creating a potential for drug-drug interactions. The effect of EFV and/or NVP on lumefantrine pharmacokinetic profile among HIV-malaria co-infected patients on ART and treated with AL was investigated. Optimal lumefantrine dosage regimen for patients on EFV-based ART was determined by population pharmacokinetics and simulation. METHODS: This was a non-randomized, open label, parallel, prospective cohort study in which 128, 66 and 75 HIV-malaria co-infected patients on NVP based ART (NVP-arm), EFV-based ART (EFV-arm) and ART naive (control-am) were enrolled, respectively. Patients were treated with AL and contributed sparse venous plasma samples. Pharmacokinetic analysis of lumefantrine was done using non-linear mixed effect modelling. RESULTS: Of the evaluated models, a two compartment pharmacokinetic model with first order absorption and lag-time described well lumefantrine plasma concentrations time profile. Patients in the EFV-arm but not in the NVP-arm had significantly lower lumefantrine bioavailability compared to that in the control-arm. Equally, 32% of patients in the EFV-arm had day-7 lumefantrine plasma concentrations below 280 ng/ml compared to only 4% in the control-arm and 3% in the NVP-arm. Upon post hoc simulation of lumefantrine exposure, patients in the EFV-arm had lower exposure (median (IQR)) compared to that in the control-arm; AUC0-inf; was 303,130 (211,080-431,962) versus 784,830 (547,405-1,116,250); day-7 lumefantrine plasma concentrations was: 335.5 (215.8-519.5) versus 858.7 (562.3-1,333.8), respectively. The predictive model through simulation of lumefantrine exposure at different dosage regimen scenarios for patients on EFV-based ART, suggest that AL taken twice daily for five days using the current dose could improve lumefantrine exposure and consequently malaria treatment outcomes. CONCLUSIONS: Co-treatment of AL with EFV based ART but not NVP-based ART significantly reduces lumefantrine bioavailability and consequently total exposure. To ensure adequate lumefantrine exposure and malaria treatment success in HIV-malaria co-infected patients on EFV based ART, an extension of the duration of AL treatment to five days using the current dose is proposed. PMID- 25906775 TI - Use of antagonist muscle EMG in the assessment of neuromuscular health of the low back. AB - BACKGROUND: Non-specific low back pain (LBP) has been one of the most frequently occurring musculoskeletal problems. Impairment in the mechanical stability of the lumbar spine has been known to lower the safety margin of the spine musculature and can result in the occurrence of pain symptoms of the low back area. Previously, changes in spinal stability have been identified by investigating recruitment patterns of low back and abdominal muscles in laboratory experiments with controlled postures and physical activities that were hard to conduct in daily life. The main objective of this study was to explore the possibility of developing a reliable spine stability assessment method using surface electromyography (EMG) of the low back and abdominal muscles in common physical activities. METHODS: Twenty asymptomatic young participants conducted normal walking, plank, and isometric back extension activities prior to and immediately after maintaining a 10-min static upper body deep flexion on a flat bed. EMG data of the erector spinae, external oblique, and rectus abdominals were collected bilaterally, and their mean normalized amplitude values were compared between before and after the static deep flexion. Changes in the amplitude and co contraction ratio values were evaluated to understand how muscle recruitment patterns have changed after the static deep flexion. RESULTS: Mean normalized amplitude of antagonist muscles (erector spinae muscles while conducting plank; external oblique and rectus abdominal muscles while conducting isometric back extension) decreased significantly (P < 0.05) after the 10-min static deep flexion. Normalized amplitude of agonist muscles did not vary significantly after deep flexion. CONCLUSIONS: Results of this study suggest the possibility of using surface EMG in the evaluation of spinal stability and low back health status in simple exercise postures that can be done in non-laboratory settings. Specifically, amplitude of antagonist muscles was found to be more sensitive than agonist muscles in identifying changes in the spinal stability associated with the 10-min static deep flexion. Further research with various loading conditions and physical activities need to be performed to improve the reliability and utility of the findings of the current study. PMID- 25906776 TI - Targeting IL-33 in autoimmunity and inflammation. AB - Interleukin-33 (IL-33) belongs to the IL-1 family of cytokines. Whereas IL-1 is processed and released by live immune cells in response to infection or other triggers, IL-33 is mostly released as a danger signal ("alarmin") from damaged cells. IL-33 may also be processed and released from activated mast cells (MCs) with subsequent autocrine and paracrine actions. IL-33 augments the stimulatory effects of IgE and substance P on MCs but can also trigger release of cytokines from MCs on its own. Blood IL-33 levels are increased in asthma, atopic dermatitis, multiple sclerosis, rheumatoid arthritis, and Sjogren's syndrome. However, prolonged elevation of IL-33 downregulates FcepsilonRI and may be protective in atherosclerosis, suggesting different roles in immune-regulated diseases. Even though neutralizing IL-33, knocking-down its receptor, or using its soluble "decoy" receptor has resulted in anti-inflammatory effects, there appear to be different outcomes in different tissues. Hence, selective regulation of IL-33 synthesis, release, and signaling may be required to provide effective treatment options. PMID- 25906777 TI - Extracorporeal life support (ECLS) for cardiopulmonary resuscitation (CPR) with pulmonary embolism in surgical patients - a case series. AB - BACKGROUND: Extracorporeal life support (ECLS) devices maintain the circulation and oxygenation of organs during acute right ventricular failure and cardiogenic shock, bypassing the lungs. A pulmonary embolism can cause this life-threatening condition. ECLS is a considerably less invasive treatment than surgical embolectomy. Whether to bridge embolectomy or for a therapeutic purpose, ECLS is used almost exclusively following failure of all other therapeutic options. METHODS: From January 1, 2008 to June 30, 2014, five patients in cardiac arrest and with diagnosed pulmonary embolism (PE) were cannulated with the ECLS system. RESULTS: PE was diagnosed using computer tomography scanning or echocardiography. Cardiac arrest was witnessed in the hospital in all cases and CPR (cardiopulmonary resuscitation) was initiated immediately. Cannulation of the femoral vein and femoral artery was always performed under CPR conditions. Right heart failure regressed during the ECLS therapy, usually under a blood flow of 4 5 L/min after 48 hours. Three patients were weaned from ECLS and one patient became an organ donor. Finally, two of the five PE patients treated with ECLS were discharged from inpatient treatment without neurological dysfunction. The duration of ECLS therapy depends on the patient's condition. Irreversible damage to the organs after hypoxemia limits ECLS treatment and leads to futile multiorgan failure. Hemorrhages after thrombolysis and cerebral dysfunction were further complications. CONCLUSIONS: Veno-arterial cannulation for ECLS can be feasibly achieved and should be established during active CPR for cardiac arrest. In the case of PE, the immediate diagnosis and rapid implantation of the system are decisive for therapeutic success. PMID- 25906778 TI - The Effects of Low Self-Control and Delinquent Peers on Alcohol, Tobacco, and Drug Use in a Sample of Saudi Arabian Youth. AB - A considerable amount of research has examined patterns of substance use and the potential explanations of it among samples from the United States and other industrialized nations. To date, however, no research has explored these issues in a sample of Saudi Arabian youth. The current study addressed this gap in the literature and examined the lifetime use of drugs, alcohol, and tobacco among Saudi Arabian youth. We also examined whether key measures from social learning theory and low self-control theory were able to account for patterns of usage. Data drawn from a sample of nearly 500 youth residing in Jeddah, Saudi Arabia, were used. Analysis of the data revealed that 12.7% of youth had smoked cigarettes at least 1 time, 2.6% had consumed alcohol at least once, and 3.0% had used illegal drugs. Moreover, the results of rare-events logistic regression revealed that a measure of delinquent peers was the strongest and most consistent predictor of substance use, while a measure of low self-control was unrelated (or related in a direction opposite to that which was predicted) to the measures of substance use. PMID- 25906779 TI - Suspected acute coronary syndrome in the emergency room: Limited added value of heart type fatty acid binding protein point of care or ELISA tests: The FAME-ER (Fatty Acid binding protein in Myocardial infarction Evaluation in the Emergency Room) study. AB - BACKGROUND: Timely recognition of acute coronary syndrome remains a challenge as many biomarkers, including troponin, remain negative in the first hours following the onset of chest pain. We assessed the diagnostic accuracy of heart-type fatty acid binding protein (H-FABP), a cardiac biomarker with potential value immediately post symptom onset. METHODS AND RESULTS: Prospective monocentre diagnostic accuracy study of H-FABP bedside point of care (CardioDetect(r)) and ELISA tests in acute coronary syndrome suspected patients presenting within 24 hours of symptom onset to the emergency department, in addition to clinical findings, electrocardiography and the currently recommended biomarker high sensitivity troponin-T (hs-cTnT). The final diagnosis of acute coronary syndrome was adjudicated by two independent cardiologists, blinded to H-FABP results. Acute coronary syndrome was diagnosed in 149 (32.9%) of 453 unselected patients with suspected acute coronary syndrome (56% men, mean age 62.6 years). Negative predictive values were similar for H-FABP point of care and ELISA tests (79% vs. 78% respectively), but inferior to initial hs-cTnT (negative predictive value 86%). The addition of H-FABP point of care results to hs-cTnT increased the negative predictive value to 89%. In a multivariable logistic regression model, H FABP point of care and ELISA tests yielded relevant diagnostic information in addition to clinical findings and ECG (likelihood ratio test p<0.001) and increased area under the receiver operating characteristics curve (AUC; 0.82 vs. 0.84 and 0.84). This added value attenuated, however, after inclusion of hs-cTnT in the diagnostic model (AUC 0.88). CONCLUSIONS: In patients suspected of acute coronary syndrome presenting to the emergency department, H-FABP testing improves diagnostic accuracy in addition to clinical findings and electrocardiography. H FABP, however, has no additional diagnostic value when hs-cTnT measurements are also available. PMID- 25906780 TI - Assessment of current practice and barriers to antimicrobial prophylaxis in peritoneal dialysis patients. AB - BACKGROUND: Existing Australasian and international guidelines outline antibiotic and antifungal measures to prevent the development of treatment-related infection in peritoneal dialysis (PD) patients. Practice patterns and rates of PD-related infection vary widely across renal units in Australia and New Zealand and are known to vary significantly from guideline recommendations, resulting in PD technique survival rates that are lower than those achieved in many other countries. The aim of this study was to determine if there is an association between current practice and PD-related infection outcomes and to identify the barriers and enablers to good clinical practice. METHODS: This is a multicentre network study involving eight PD units in Australia and New Zealand, with a focus on adherence to guideline recommendations on antimicrobial prophylaxis in PD patients. Current practice was established by asking the PD unit heads to respond to a short survey about practice/protocols/policies and a 'process map' was constructed following a face-to-face interview with the primary PD nurse at each unit. The perceived barriers/enablers to adherence to the relevant guideline recommendations were obtained from the completion of 'cause and effect' diagrams by the nephrologist and PD nurse at each unit. Data on PD-related infections were obtained for the period 1 January 2011 to 31 December 2011. RESULTS: Perceived barriers that may result in reduced adherence to guideline recommendations included lack of knowledge, procedural lapses, lack of a centralized patient database, patients with non-English speaking background, professional concern about antibiotic resistance, medication cost and the inability of nephrologists and infectious diseases staff to reach consensus on unit protocols. The definitions of PD-related infections used by some units varied from those recommended by the International Society for Peritoneal Dialysis, particularly with exit-site infection (ESI). Wide variations were observed in the rates of ESI (0.06-0.53 episodes per patient-year) and peritonitis (0.31-0.86 episodes per patient-year). CONCLUSIONS: Despite the existence of strongly evidence-based guideline recommendations, there was wide variation in adherence to these recommendations between PD units which might contribute to PD-related infection rates, which varied widely between units. Although individual patient characteristics may account for some of this variability, inconsistencies in the processes of care to prevent infection in PD patients also play a role. PMID- 25906781 TI - The role of renin-angiotensin-aldosterone system genes in the progression of chronic kidney disease: findings from the Chronic Renal Insufficiency Cohort (CRIC) study. AB - BACKGROUND: We conducted single-marker, gene- and pathway-based analyses to examine the association between renin-angiotensin-aldosterone system (RAAS) variants and chronic kidney disease (CKD) progression among Chronic Renal Insufficiency Cohort study participants. METHODS: A total of 1523 white and 1490 black subjects were genotyped for 490 single nucleotide polymorphisms (SNPs) in 12 RAAS genes as part of the ITMAT-Broad-CARe array. CKD progression phenotypes included decline in estimated glomerular filtration rate (eGFR) over time and the occurrence of a renal disease event, defined as incident end-stage renal disease or halving of eGFR from baseline. Mixed-effects models were used to examine SNP associations with eGFR decline, while Cox proportional hazards models tested SNP associations with renal events. Gene- and pathway-based analyses were conducted using the truncated product method. All analyses were stratified by race, and a Bonferroni correction was applied to adjust for multiple testing. RESULTS: Among white and black participants, eGFR declined an average of 1.2 and 2.3 mL/min/1.73 m(2)/year, respectively, while renal events occurred in a respective 11.5 and 24.9% of participants. We identified strong gene- and pathway-based associations with CKD progression. The AGT and RENBP genes were consistently associated with risk of renal events in separate analyses of white and black participants (both P < 1.00 * 10(-6)). Driven by the significant gene-based findings, the entire RAAS pathway was also associated with renal events in both groups (both P < 1.00 * 10( 6)). No single-marker associations with CKD progression were observed. CONCLUSIONS: The current study provides strong evidence for a role of the RAAS in CKD progression. PMID- 25906782 TI - Association between perinatal methylation of the neuronal differentiation regulator HES1 and later childhood neurocognitive function and behaviour. AB - BACKGROUND: Early life environments induce long-term changes in neurocognitive development and behaviour. In animal models, early environmental cues affect neuropsychological phenotypes via epigenetic processes but, as yet, there is little direct evidence for such mechanisms in humans. METHOD: We examined the relation between DNA methylation at birth and child neuropsychological outcomes in two culturally diverse populations using a genome-wide methylation analysis and validation by pyrosequencing. RESULTS: Within the UK Southampton Women's Survey (SWS) we first identified 41 differentially methylated regions of interest (DMROI) at birth associated with child's full-scale IQ at age 4 years. Associations between HES1 DMROI methylation and later cognitive function were confirmed by pyrosequencing in 175 SWS children. Consistent with these findings, higher HES1 methylation was associated with higher executive memory function in a second independent group of 200 SWS 7-year-olds. Finally, we examined a pathway for this relationship within a Singaporean cohort (n = 108). Here, HES1 DMROI methylation predicted differences in early infant behaviour, known to be associated with academic success. In vitro, methylation of HES1 inhibited ETS transcription factor binding, suggesting a functional role of this site. CONCLUSIONS: Thus, our findings suggest that perinatal epigenetic processes mark later neurocognitive function and behaviour, providing support for a role of epigenetic processes in mediating the long-term consequences of early life environment on cognitive development. PMID- 25906784 TI - Health-Related Findings Among Twin Pairs Discordant for Leisure-Time Physical Activity for 32 Years: The TWINACTIVE Study Synopsis. AB - We are lacking very long-term and controlled intervention studies investigating the effects of habitual physical activity on health-related factors. To address this gap, we performed a natural experiment by identifying same-sex twin pairs in which the co-twins of each pair differed with respect to leisure-time physical activity habits throughout their adult life. Our criterion for the discordance was that the same co-twin had a higher leisure time-activity volume than that of the other member of the pair at the majority -- if not all -- of the follow-up time points according to reported/interviewed physical-activity data. Overall, we identified and conducted multidimensional health-related measurements (including fitness, body composition, cardiometabolic risk factor levels, bone and arterial status, and exercise motivation) of 16 twin pairs (seven monozygotic (MZ) and nine dizygotic (DZ) pairs, mean age 60 years) who had persistent discordance in leisure-time physical-activity habits over three decades (TWINACTIVE study). In our discordant-pair study design, after adjusting for sequence-level genes, both systemic-level metabolic, and site-specific structural findings differed significantly in the pairwise analysis in MZ pairs only. These findings included intrapair differences in accumulated fat depots and structure of heart, arteries, and bones. In addition, our study revealed intrapair differences in metabolic and regulatory pathways, which may partly explain the mechanistic links between long term physical activity, phenotypic changes, and decreased risk of cardiometabolic diseases. PMID- 25906783 TI - Prenatal mercury concentration is associated with changes in DNA methylation at TCEANC2 in newborns. AB - BACKGROUND: Human exposure to the widespread environmental contaminant mercury is a known risk factor for common diseases such as cancer, cardiovascular disease and neurological disorders through poorly characterized mechanisms. Evidence suggests mercury exposure may alter DNA methylation levels, but to date, the effects in early life on a genome-wide scale have not been investigated. METHODS: A study sample of 141 newborns was recruited in Baltimore, MD, USA and total mercury and methylmercury were measured in cord blood samples. We quantified genome-wide DNA methylation data using CHARM 2.0, an array-based method, and used region-finding analyses to identify concentration-associated differentially methylated regions (DMRs). To test for replication of these identified DMRs in the pilot, or Vanguard, phase of the National Children's Study (NCS), we compared bisulfite-pyrosequenced DNA at candidate regions from 85 whole cord blood samples with matched first trimester maternal mercury concentration measures. RESULTS: Total mercury concentration was associated with methylation at DMRs inside ANGPT2 and near PRPF18 genes [false discovery rate (FDR) < 0.05], as well as DMRs near FOXD2 and within TCEANC2 (FDR< 0.1) genes. Methylmercury concentration was associated with an overlapping DMR within TCEANC2 (FDR< 0.05). In NCS replication analyses, methylation levels at three of four cytosine-guanine DNA dinucleotides (CpG sites) within the TCEANC2 DMR were associated with total mercury concentration (P < 0.05), and this association was diminished after adjusting for estimated cell proportions. CONCLUSIONS: Evidence for an association between mercury and DNA methylation at the TCEANC2 region was found, which may represent a mercury-associated shift in cord blood cell composition or a change in methylation within blood cell types. Further confirmatory studies are needed. PMID- 25906785 TI - Analysis of Continuous Glucose Monitoring in Pregnant Women With Diabetes: Distinct Temporal Patterns of Glucose Associated With Large-for-Gestational-Age Infants. AB - OBJECTIVE: Continuous glucose monitoring (CGM) is increasingly used to assess glucose control in diabetes. The objective was to examine how analysis of glucose data might improve our understanding of the role temporal glucose variation has on large-for-gestational-age (LGA) infants born to women with diabetes. RESEARCH DESIGN AND METHODS: Functional data analysis (FDA) was applied to 1.68 million glucose measurements from 759 measurement episodes, obtained from two previously published randomized controlled trials of CGM in pregnant women with diabetes. A total of 117 women with type 1 diabetes (n = 89) and type 2 diabetes (n = 28) who used repeated CGM during pregnancy were recruited from secondary care multidisciplinary obstetric clinics for diabetes in the U.K. and Denmark. LGA was defined as birth weight >=90th percentile adjusted for sex and gestational age. RESULTS: A total of 54 of 117 (46%) women developed LGA. LGA was associated with lower mean glucose (7.0 vs. 7.1 mmol/L; P < 0.01) in trimester 1, with higher mean glucose in trimester 2 (7.0 vs. 6.7 mmol/L; P < 0.001) and trimester 3 (6.5 vs. 6.4 mmol/L; P < 0.01). FDA showed that glucose was significantly lower midmorning (0900-1100 h) and early evening (1900-2130 h) in trimester 1, significantly higher early morning (0330-0630 h) and throughout the afternoon (1130-1700 h) in trimester 2, and significantly higher during the evening (2030 2330 h) in trimester 3 in women whose infants were LGA. CONCLUSIONS: FDA of CGM data identified specific times of day that maternal glucose excursions were associated with LGA. It highlights trimester-specific differences, allowing treatment to be targeted to gestational glucose patterns. PMID- 25906786 TI - Incidence of Diabetes and Prediabetes and Predictors of Progression Among Asian Indians: 10-Year Follow-up of the Chennai Urban Rural Epidemiology Study (CURES). AB - OBJECTIVE: There are few data on the incidence rates of diabetes and prediabetes (dysglycemia) in Asian Indians. This article presents the incidence of diabetes and prediabetes and the predictors of progression in a population-based Asian Indian cohort. RESEARCH DESIGN AND METHODS: Data on progression to diabetes and prediabetes from 1,376 individuals, a subset of 2,207 of the Chennai Urban Rural Epidemiology Study (CURES) cohort (phase 3) with normal glucose tolerance (NGT) or prediabetes at baseline, who were followed for a median of 9.1 years (11,629 person-years), are presented. During follow-up, 534 died and 1,077 with NGT and 299 with prediabetes at baseline were reinvestigated in a 10-year follow-up study. Diabetes and prediabetes were diagnosed based on the American Diabetes Association criteria. Incidence rates were calculated and predictors of progression to prediabetes and/or diabetes were estimated using the Cox proportional hazards model. RESULTS: The incidence rates of diabetes, prediabetes, and "any dysglycemia" were 22.2, 29.5, and 51.7 per 1,000 person years, respectively. Among those with NGT, 19.4% converted to diabetes and 25.7% to prediabetes, giving an overall conversion rate to dysglycemia of 45.1%. Among those with prediabetes, 58.9% converted to diabetes. Predictors of progression to dysglycemia were advancing age, family history of diabetes, 2-h plasma glucose, glycated hemoglobin (HbA1c), low HDL cholesterol, and physical inactivity. CONCLUSIONS: Asian Indians have one of the highest incidence rates of diabetes, with rapid conversion from normoglycemia to dysglycemia. Public health interventions should target modifiable risk factors to slow down the diabetes epidemic in this population. PMID- 25906787 TI - Let's Empower and Prepare (LEAP): Evaluation of a Structured Transition Program for Young Adults With Type 1 Diabetes. AB - OBJECTIVE: To evaluate the efficacy of a structured transition program compared with usual care in improving routine follow-up, clinical, and psychosocial outcomes among young adults with type 1 diabetes. RESEARCH DESIGN AND METHODS: Eighty-one young adults in their last year of pediatric care were recruited from three clinics. Intervention group (IG) participants (n = 51) received a structured transition program incorporating tailored diabetes education, case management, group education classes, and access to a newly developed young adult diabetes clinic and transition website. Control group (CG) participants (n = 30) received usual care. The primary outcome was the number of routine clinic visits. Secondary outcomes included glycemic control, hypoglycemia, health care use, and psychosocial well-being. Assessments were conducted at baseline, and 6 and 12 months. RESULTS: Limitations in CG follow-up prevented direct comparisons of adult care visits; however, at the 12-month follow-up among IG participants discharged from pediatric care (n = 32), 78% had one or more adult visits. Among IG participants, the total number of clinic visits did not differ between those who transitioned and those who remained in pediatric care (3.0 +/- 1.24 vs. 3.11 +/- 0.94, P = 0.74). IG compared with CG participants had improved glycemic control (-0.40 +/- 1.16% vs. 0.42 +/- 1.51% [4.4 +/- 12.7 mmol/mol vs. 4.6 +/- 16.5 mmol/mol], P = 0.01), incidence of severe hypoglycemia (0.0% vs. 16%, P = 0.02), and global well-being (P = 0.02) at 12 months. CONCLUSIONS: A structured transition program was successful in facilitating transition to adult care without a decrease in clinical follow-up. Compared with usual care, the transition program facilitated improvements in glycemic control, hypoglycemia, and psychosocial well-being. PMID- 25906788 TI - Impact of post-stroke unilateral spatial neglect on goal-directed arm movements: systematic literature review. AB - BACKGROUND: Unilateral spatial neglect (USN), a highly prevalent post-stroke impairment, refers to one's inability to orient or respond to stimuli located in the contralesional visual hemispace. Unilateral spatial neglect has been shown to strongly affect motor performance in functional activities, including non affected upper extremity (UE) movements. To date, our understanding of the effects of USN on goal-directed UE movements is limited and comparing performance of individuals post-stroke with and without USN is required. OBJECTIVE: To determine, in individuals with stroke, how does the presence of USN, in comparison to the absence of USN, impacts different types of goal-directed movements of the non-affected UE. METHODS: The present review approach consisted of a comprehensive literature search, an assessment of the quality of the selected studies and qualitative data analysis. RESULTS: A total of 20 studies of moderate to high quality were selected. The USN-specific impairments were found in tasks that required a perceptual, memory-guided or delayed actions, and fewer impairments were found in tasks that required an immediate action to a predefined target. CONCLUSION: The results indicate that USN contributes to deficits observed in action execution with the non-effected UE that requires greater perceptual demands. PMID- 25906789 TI - A new polyoxygenated farnesylcyclohexenone from Fungus Penicillium sp. AB - A new polyoxygenated farnesylcyclohexenone, peniginsengin A (1), was isolated from the fermentation of Penicillium sp. YIM PH30003, an endophytic fungus associated with Panax notoginseng (Burk.) F. H. Chen. The structure was assigned based on a combination of 1 D and 2 D NMR and mass spectral data. The cytotoxicity and antimicrobial activities of compound 1 were investigated. PMID- 25906790 TI - Determinants of serum 25(OH)D concentration in young and middle-aged adults. The Cardiovascular Risk in Young Finns Study. AB - INTRODUCTION: We studied prevalence of hypovitaminosis D, its determinants, and whether achievement of recommended dietary vitamin D intake (10 MUg/d) is associated with absence of hypovitaminosis D in adults. METHODS: The study is part of the Cardiovascular Risk in Young Finns Study. We collected serum samples of 25-hydroxyvitamin D as part of the 27-year follow-up (994 men and 1,210 women aged 30-45 years). Hypovitaminosis was defined as vitamin D concentration <= 50 nmol/L. RESULTS: Hypovitaminosis D was found in 38% of men and 34% of women. Dietary vitamin D intake (OR 0.90, 95% CI 0.86-0.93), use of vitamin-mineral supplements (0.66, 0.51-0.85), sunny holiday (0.55, 0.41-0.75), and oral contraceptive use in women (0.45, 0.27-0.75) were independently associated with reduced odds of hypovitaminosis. Increase in body mass index (1.06, 1.03-1.09), being a smoker (1.36, 0.97-1.92), investigation month (December versus other) (1.35, 1.12-1.61), and risk alleles in genotypes rs12785878 (1.31, 1.00-1.70) and rs2282679 (2.08, 1.66-2.60) increased odds of hypovitaminosis. Hypovitaminosis D was common also when recommended dietary intake was obtained (men 29%, women 24%). CONCLUSION: Several factors were associated with hypovitaminosis D. The condition was common even when recommended vitamin D intake was reported. The results support the importance of vitamin D fortification and nutrient supplement use. PMID- 25906791 TI - Randomised controlled trial of the effectiveness of community group and home based falls prevention exercise programmes on bone health in older people: the ProAct65+ bone study. AB - BACKGROUND: exercise can reduce osteoporotic fracture risk by strengthening bone or reducing fall risk. Falls prevention exercise programmes can reduce fall incidence, and also include strengthening exercises suggested to load bone, but there is little information as to whether these programmes influence bone mineral density (BMD) and strength. OBJECTIVE: to evaluate the skeletal effects of home (Otago Exercise Programme, OEP) and group (Falls Exercise Management, FaME) falls prevention exercise programmes relative to usual care in older people. METHODS: men and women aged over 65 years were recruited through primary care. They were randomised by practice to OEP, FaME or usual care. BMD, bone mineral content (BMC) and structural properties were measured in Nottingham site participants before and after the 24-week intervention. RESULTS: participants were 319 men and women, aged mean(SD) 72(5) years. Ninety-two percentage of participants completed the trial. The OEP group completed 58(43) min/week of home exercise, while the FaME group completed 39(16) and 30(24) min/week of group and home exercise, respectively. Femoral neck BMD changes did not differ between treatment arms: mean (95% CI) effect sizes in OEP and FaME relative to usual care arm were 0.003(-0.011,0.005) and -0.002(-0.010,0.005) g cm(-2), respectively; P = 0.44 and 0.53. There were no significant changes in BMD or BMC at other skeletal sites, or in structural parameters. CONCLUSIONS: falls prevention exercise programmes did not influence BMD in older people. To increase bone strength, programmes may require exercise that exerts higher strains on bone or longer duration. PMID- 25906792 TI - Determining the effects of films with suicidal content: a laboratory experiment. AB - BACKGROUND: Media stories on suicide can increase suicidal ideation, but little is known about variations in media effects with regard to audience vulnerability and story contents. AIMS: We investigated the impact of three drama films with suicidal content that varied with regard to the final outcome (suicide completion, mastery of crisis and death by natural causes) and tested the moderating effect of baseline suicidality of the participants on the effects. METHOD: Within a laboratory setting, we randomly assigned 95 adults to three film groups. We used questionnaires to analyse the effects of the films on mood, depression, life satisfaction, self-worth, assumed benevolence of the world and suicidality, as well as identification with the protagonist. We stratified the sample into participants with suicidal tendencies above and below the sample median. RESULTS: The film that ended with the protagonist's suicide led to a deterioration of mood particularly in individuals with baseline suicidality below the median, who also experienced an increase in self-worth. Participants with stronger suicidal tendencies experienced a rise in suicidality that depended on their level of identification with the protagonist. The film featuring the main character positively coping with his crisis increased life satisfaction particularly among participants with higher suicidal tendencies. CONCLUSIONS: The effects of suicide-related media material seem to vary with individual vulnerability and with type of media portrayal. Individuals with lower vulnerability experience more emotional reactions when exposed to a film culminating in suicide, but individuals with higher vulnerability experience a rise in suicidal tendencies particularly if they identify with the protagonist who died by suicide. In contrast, portrayals of individual mastery of crisis may have beneficial effects in more vulnerable individuals. PMID- 25906793 TI - Psychosocial morbidity associated with bipolar disorder and borderline personality disorder in psychiatric out-patients: comparative study. AB - BACKGROUND: The morbidity associated with bipolar disorder is, in part, responsible for repeated calls for improved detection and recognition. No such commentary exists for the improved detection of borderline personality disorder. Clinical experience suggests that it is as disabling as bipolar disorder, but no study has directly compared the two disorders. AIMS: To compare the levels of psychosocial morbidity in patients with bipolar disorder and borderline personality disorder. METHOD: Patients were assessed with semi-structured interviews. We compared 307 patients with DSM-IV borderline personality disorder but without bipolar disorder and 236 patients with bipolar disorder but without borderline personality disorder. RESULTS: The patients with borderline personality disorder less frequently were college graduates, were diagnosed with more comorbid disorders, more frequently had a history of substance use disorder, reported more suicidal ideation at the time of the evaluation, more frequently had attempted suicide, reported poorer social functioning and were rated lower on the Global Assessment of Functioning. There was no difference between the two patient groups in history of admission to psychiatric hospital or time missed from work during the past 5 years. CONCLUSIONS: The level of psychosocial morbidity associated with borderline personality disorder was as great as (or greater than) that experienced by patients with bipolar disorder. From a public health perspective, efforts to improve the detection and treatment of borderline personality disorder might be as important as efforts to improve the recognition and treatment of bipolar disorder. PMID- 25906794 TI - A general psychopathology factor in early adolescence. AB - BACKGROUND: Recently, a general psychopathology dimension reflecting common aspects among disorders has been identified in adults. This has not yet been considered in children and adolescents, where the focus has been on externalising and internalising dimensions. AIMS: To examine the existence, correlates and predictive value of a general psychopathology dimension in young people. METHOD: Alternative factor models were estimated using self-reports of symptoms in a large community-based sample aged 11-13.5 years (N = 23 477), and resulting dimensions were assessed in terms of associations with external correlates and future functioning. RESULTS: Both a traditional two-factor model and a bi-factor model with a general psychopathology bi-factor fitted the data well. The general psychopathology bi-factor best predicted future psychopathology and academic attainment. Associations with correlates and factor loadings are discussed. CONCLUSIONS: A general psychopathology factor, which is equal across genders, can be identified in young people. Its associations with correlates and future functioning indicate that investigating this factor can increase our understanding of the aetiology, risk and correlates of psychopathology. PMID- 25906795 TI - Incision and stress regulation in borderline personality disorder: neurobiological mechanisms of self-injurious behaviour. AB - BACKGROUND: Patients with borderline personality disorder frequently show non suicidal self-injury (NSSI). In these patients, NSSI often serves to reduce high levels of stress. AIMS: Investigation of neurobiological mechanisms of NSSI in borderline personality disorder. METHOD: In total, 21 women with borderline personality disorder and 17 healthy controls underwent a stress induction, followed by either an incision into the forearm or a sham treatment. Afterwards participants underwent resting-state functional magnetic resonance imaging while aversive tension, heart rate and heart rate variability were assessed. RESULTS: We found a significant influence of incision on subjective and objective stress levels with a stronger decrease of aversive tension in the borderline personality disorder group following incision than sham. Amygdala activity decreased more and functional connectivity with superior frontal gyrus normalised after incision in the borderline personality disorder group. CONCLUSIONS: Decreased stress levels and amygdala activity after incision support the assumption of an influence of NSSI on emotion regulation in individuals with borderline personality disorder and aids in understanding why these patients use self-inflicted pain to reduce inner tension. PMID- 25906796 TI - Histological Evaluation of Allium sativum Oil as a New Medicament for Pulp Treatment of Permanent Teeth. AB - OBJECTIVE: The objective of this study was to evaluate the histo pathology effects of two medicaments Allium sativum oil and formocresol on the remaining pulp tissue of the permanent teething children. MATERIALS AND METHODS: A total of 18 premolars were included in this study. Two sound premolars were extracted and subjected to histological examination to show the normal pulp tissue. Pulpo tomy procedure was performed in the rest of the remaining 16 premolars; half of them using Allium sativum oil and the rest of the tested premolars were medicated using formocresol and all were sealed with suitable restoration. Then, premolars extracted at variable intervals (48 hours, 2 weeks, 1 month, 2 months), stained using hemotoxylin and eosin etain (H&E) and prepared for histopathology examination. RESULTS: Histological evaluation seemed far more promising for Allium sativum oil than formocresol. Histological evaluation revealed that teeth treated with Allium sativa oil showed infammatory changes that had been resolved in the end of the study. On the contrary, the severe chronic infammation of pulp tissue accompanied with formocresol eventually produced pulp necrosis with or without fibrosis. In addition, pulp calcification was evidenced in certain cases. CONCLUSION: Allium sativum oil is a biocompatible material that is compatible with vital human pulp tissue. It offers a good healing potential, leaving the remaining pulp tissue healthy and functioning. PMID- 25906797 TI - Deflection Evaluation of Thermoactivated Nickel-Titanium Archwires after Heat Treatment on their Distal Ends. AB - OBJECTIVE: This study evaluated in vitro the mechanical changes of 0.018" (0.45 mm) and 0.016 * 0.022" (0.40 * 0.55 mm) thermoactivated nickel-titanium archwires subjected to heat treatment on their distal ends. MATERIALS AND METHODS: Ten archwires in diameters 0.018" and 0.016 * 0.022" by different manufacturers Ormco, Morelli, Orthometric and Unitek were tested. Each tested archwire had an experimental side, submitted to heat treatment, and an annealing-free control. Tests for load/deflection were performed using a universal testing machine, with temperature control in the austenitic transformation phase through tempe rature controlled chamber. The variables showed normal distribution (Kolmogorov Smirnov), the t-student test was applied in order to observe the difference between the experi mental and control groups. Statistical significance was set at p < 0.05. RESULTS: There were no statistically significant differences between the groups. CONCLUSION: Heat treatment carried out in the region corresponding to the first molar distal region on thermoactivated nickel-titanium archwires did not influence the load/deflection values in adjacent portion. PMID- 25906798 TI - Solubility evaluation of different root canal sealing materials. AB - AIM: To evaluate the solubility of five different root canal sealers (AH Plus Jet, RealSeal SE, MTA Fillapex, Tubli-Seal, and Acroseal) in chloroform, eucalyptol and Endosolv-E solvents. MATERIALS AND METHODS: Ninety root canal sealer samples were prepared and then divided into three groups for immersion in a solvent for 2, 5 or 10 minutes. The mean values of the root canal sealers' dissolution in the solvents were obtained by the difference between the preimmersion original weight and the post-immersion weight on a digital analytical scale. Data were statistically analyzed by a Kruskal-Wallis test with a Bonferroni correction. RESULTS: Chloroform was a more effective solvent than eucaly-ptol or Endosolv E for all root canal sealers, except for RealSeal SE, at all time points (p < 0.003). RealSeal SE was the least soluble sealer in all solvents at all time points. CONCLUSION: Chloroform demonstrated a superior ability over other solvents in dissolving canal sealing materials, and eucaly ptol was found to be the least effective solvent in this study. CLINICAL SIGNIFICANCE: This study can help to the clinicians about which solvent should be preferred for solving the filling materials in retreatment cases. PMID- 25906799 TI - Antimicrobial activity of a tissue conditioner combined with a biocide polymer. AB - BACKGROUND: The characteristics of tissue conditioners support microorganism development that can threaten the health of the dentures user. PURPOSE: The object of this study was to evaluate the effect on antimicrobial activity, roughness and wettability surface of a tissue conditioners material combined with the antimicrobial polymer poly (2-tert-butilaminoethyl) methacrylate (PTBAEMA). MATERIALS AND METHODS: Specimens of tissue conditioner (Coe Soft((r))) were divided into three groups, according to the concentration of PTBAEMA incorporated (0, 10 and 25%). Antimicrobial activity was assessed by adherence assay of one of the microorganisms, Staphylococcus aureus, Streptococcus mutans and Candida albicans. Roughness measurements were made using a Mitutoyo SJ-400, and the mean arithmetic roughness values (Ra) obtained were used for the comparisons. The wettability properties were determined by contact angle measurements. RESULTS: The group containing 25% of PTBAEMA inhibited totally the S. aureus and S. mutans biofilm formation. A significant reduc tion in the S. aureus (Kruskal-Wallis, p = 0,001) and S. mutans (Kruscal-Wallis, p = 0,001) count for 10% PTBAEMA group compared with respective control group. No significant difference was found for C. albicans among PTBAEMA groups and control group (ANOVA, p > 0,05). Incorporating 10 and 25% PTBAEMA increased surface roughness and decreased contact angles (ANOVA and Tukey's post hoc tests, alpha = 5%). CONCLUSION: Incorporating 10% PTBAEMA into tissue conditioner increases wettability and roughness of tissue conditioner surface; and decreases the adhesion of S. mutans and S. aureus on material surface, but did not exhibit antimicrobial effect against C. albicans. SIGNIFICANCE: The PTBAEMA incorporated into tissue conditioner could prevent biofilm formation on elderly patient. PMID- 25906800 TI - Serum and Saliva MMP-3 in Patients with OLP and Oral SCC. AB - BACKGROUND: Matrix metalloproteinase-3 (MMP-3) plays a key role in development of cancer. The purpose of this study was to assess MMP-3 in the serum and saliva of patients with oral lichen planus (OLP) and oral squamous cell carcinoma (OSCC). MATERIALS AND METHODS: Thirty patients with OLP (8 reticular and 22 erosive forms), and 20 patients with OSCC (6 in low stage and 14 in advanced stage), were enrolled in this study, conducted at the Cancer Department, Clinic of Oral Medicine, Tehran University of Medical Sciences. The serum and saliva MMP-3 was assayed by ELISA method. Statistical analysis of the Student's t-test, ANOVA and Pearson correlation coefficient was performed. The mean saliva and serum levels of MMP-3 were significantly higher in patients with OSCC compared with OLP. RESULTS: The serum and saliva MMP-3 concentrations increased from reticular form of OLP to erosive form of OLP, and increased further to low stage of OSCC and advanced stage of OSCC. Serum MMP-3 correlated significantly with unstimulated (r = 0.310, p = 0.038) and stimulated (r = 0.365, p < 0.026) saliva MMP-3. CONCLUSION: Serum and saliva MMP-3 levels appear associated with OLP and OSCC. PMID- 25906801 TI - Anxiety, Depression and Quality of Life among Patients with Recurrent Aphthous Ulcers. AB - BACKGROUND: Recurrent aphtous ulcers (RAUs) are of the most painful and common oral mucosal diseases with uncertain etiology including trauma, genetics, stress, immune dysfunction, and vitamin deficiencies. The aim of this study was to investigate the relationship between oral health impacts, patients' oral health related quality of life and anxiety and depression in patients with recurrent aphtous ulcers. SUBJECTS AND METHODS: Sixty patients were diagnosed RAU (30 men and 30 women, mean age: 29.5 +/- 9.6 years) and sixty controls, who matched the patients with age and gender, participated in this study. Participants completed hospital anxiety and depression (HAD) scale, oral health impact profile (OHIP 14), and United Kingdom oral health related quality of life measure (OHQoL-UK). The statistically significance levels were set at p <= 0.05. RESULTS: Both patients and controls reported comparable depression and anxiety scores (p > 0.05). Ulcer patients reported worse oral health impacts and inferior quality of life in comparison to controls (p < 0.001). Among both groups, no relationships were detected between HAD scores on one hand and OHIP and/or OHQoL-UK on the other hand (p > 0.05). CONCLUSIONS: Recurrent aphthous ulcers increase the negative oral health impacts on patients and consequently cause inferior quality of life. Stressful situations and conditions (including anxiety and depression) were not related to oral health impacts and quality of life in patients with RAUs. PMID- 25906802 TI - Post-traumatic Stress Disorder in Facial Injuries: A Comparative Study. AB - AIM: The aim of the study was to identify the presence of post-traumatic stress disorder (PTSD) in patients who had sustained facial injuries, additionally, we aimed to identify other variables that may modify the psychological response to trauma that include gender, age and presence of disfigurement post-treatment and visible scars/orthopedic injuries. MATERIALS AND METHODS: Participants comprised of 460 patients from several multinodal trauma centers in Bengaluru City, Karnataka, who had sustained facial injuries that had healed either with or without significant disfigurement or scarring and with visible/orthopedic injuries. One hundred and eleven patients of the chosen 460 had sustained nondisfiguring facial injuries while 153 patients sustained disfiguring facial injuries, 64 patients who sustained facial injury (i.e. 19.5%) were lost to follow-up and were not included in the study. One hundred and thirty-two had sustained orthopedic/visible injuries; however, in this group, 18 (i.e. 13.6%) patients were lost to follow-up and were excluded from the study. The impact of events scale (IES) was used to check the presence of PTSD. RESULTS: Statistically significant higher means of IES were present in patients with disfiguring facial injuries compared to nondisfiguring facial injuries, female patients compared to male patients, patients with disfiguring facial injuries compared to orthopedic/visible injuries and patients who were younger than 50 years of age compared to patients who were older than 50 years of age and the results observed were similar at all three study intervals (date of discharge (DOD), 1 month and 6 months postoperatively). CONCLUSION: Patients with disfiguring facial injuries had significantly higher PTSD levels compared to patients with nondisfiguring facial injuries, patients with orthopedic/visible injuries had statistically significant lower IES scores which could not be strictly termed PTSD when compared to patients with disfiguring facial injuries who had high scores of IES corresponding to high levels of PTSD and these results were observed at all three study intervals (DOD, 1 and 6 months postoperatively). Female patients with disfiguring facial injuries had significantly higher PTSD levels compared to male patients (at all the study intervals) and patients younger than 50 years of age had significantly higher PTSD levels compared to older patients. PMID- 25906803 TI - Effect of Photo-Fenton Bleaching on Tetracycline-stained Dentin in vitro. AB - AIM: Tetracycline-stained tooth structure is difficult to bleach using nightguard tray methods. The possible benefits of in-office light-accelerated bleaching systems based on the photo-Fenton reaction are of interest as possible adjunctive treatments. This study was a proof of concept for possible benefits of this approach, using dentine slabs from human tooth roots stained in a reproducible manner with the tetracycline antibiotic demeclocycline hydrochloride. MATERIALS AND METHODS: Color changes overtime in tetra-cycline stained roots from single rooted teeth treated using gel (Zoom! WhiteSpeed((r))) alone, blue LED light alone, or gel plus light in combination were tracked using standardized digital photography. Controls received no treatment. Changes in color channel data were tracked overtime, for each treatment group (N = 20 per group). RESULTS: Dentin was lighter after bleaching, with significant improvements in the dentin color for the blue channel (yellow shade) followed by the green channel and luminosity. The greatest changes occurred with gel activated by light (p < 0.0001), which was superior to effects seen with gel alone. Use of the light alone did not significantly alter shade. CONCLUSION: This proof of concept study demonstrates that bleaching using the photo-Fenton chemistry is capable of lightening tetracycline-stained dentine. Further investigation of the use of this method for treating tetracycline-stained teeth in clinical settings appears warranted. CLINICAL SIGNIFICANCE: Because tetracycline staining may respond to bleaching treatments based on the photo-Fenton reaction, systems, such as Zoom! WhiteSpeed, may have benefits as adjuncts to home bleaching for patients with tetracycline staining. PMID- 25906804 TI - Effect of Self-etch Primer-adhesive and Conventional Adhesive Systems on the Shear Bond Strength and Bond Failure of Orthodontic Brackets: A Comparative Study. AB - BACKGROUND: Prompt-L-Pop is a sixth generation bonding system contains methacrylated phosphoric acid esters that combine an acidic component for etching the enamel and a primer, is an all-in-one adhesive. This study was undertaken to compare the bonding strength of brackets to enamel with traditional bonding technique and the new Prompt-L-Pop system using the same composite resin. MATERIALS AND METHODS: In this in vitro experimental study, 60 human premolar teeth extracted for orthodontic treatment were collected. The samples were randomly divided into three groups comprising of 20 teeth in each group. Shear bond strength and ARI scores for the specimens were measured. Comparison was done using one way ANOVA and Chi-square test. RESULTS: Fourth generation bonding adhesive system depicted similar bond strength to fifth generation bonding adhesive system. Both fourth and fifth generation exhibited higher shear bond strength as compared to sixth generation bonding adhesive system. CONCLUSION: Fourth and fifth generation exhibited higher shear bond strength as compared to sixth generation bonding adhesive system but the sixth generation has clinically acceptable shear bond strength. Also, it was found that sixth generation leaves less residual adhesive on the tooth after bracket removal. PMID- 25906805 TI - Comparison of Shade of Ceramic with Three Different Zirconia Substructures using Spectrophotometer. AB - OBJECTIVE: This study assessed how changing the Zirconia (Zr) substructure affected the color samples after they have been overlaid by the same shade of veneering ceramic. MATERIALS AND METHODS: Three commercial Zr materials were tested in this study: Prettau((r)) Zirconia (ZirKonZahn, Italy), Cercon (Dentsply, Germany) and InCoris ZI (Sirona, Germany). For each system, 15 disk shaped specimens (10 * 1 mm) were fabricated. Three shades of A1, A2 and A3.5 of porcelain (IPS e.MaxCeram, IvoclarVivadent, USA) were used for layering the specimens. Five specimens from each type of Zr were layered with same shade of ceramic. Color measurements were recorderd by a spectrophotometer Color-Eye((r)) 7000A (X-Rite, Grand Rapids, MI). Mean values of L, a, b color coordinates and DeltaE were recorded and comparisons were made. RESULTS: Differences in the DeltaE were recorded for the same porcelain shade with different Zr substructures and affected the color of the specimens (p < 0.01, ANOVA). The maximum difference between the DeltaE values for the A1, A2 and A3.5 shades with three types of Zr substructures was found to be 1.59, 1.69 and 1.45 respectively. Multiple comparisons of the DeltaE with PostHoc Tukey test revealed a statistically significant difference (p < 0.05) between the three types of Zr, except between Type 2 Zr and Type 3 Zr for the Shade A1. The mean values of L, a, b and DeltaE for the Prettau((r)) Zirconia substructure were found to be the least among the three types. CONCLUSIONS: The brand of Zr used influences the final color of the all ceramic Zr based restorations and this has clinical significance. PMID- 25906806 TI - Titanium Surface Roughing Treatments contribute to Higher Interaction with Salivary Proteins MG2 and Lactoferrin. AB - Some surface treatments performed on titanium can alter the composition of salivary pellicle formed on this abiotic surface. Such treatments modify the titanium's surface properties and can promote higher adsorption of proteins, which allow better integration of titanium to the biotic system. PURPOSE: This study aimed to evaluate the interactions between salivary proteins and titanium disks with different surface treatments. MATERIALS AND METHODS: Machined titanium disks (n = 48) were divided into four experimental groups (n = 12), according to their surface treatments: surface polishing (SP); acid etching (A); spot-blasting plus acid etching (SB-A); spot-blasting followed by acid etching and nano functionalization (SB-A-NF). Titanium surfaces were characterized by surface roughness and scanning electron microscopy (SEM). Specimens were incubated with human saliva extracted from submandibular and sublingual glands. Total salivary protein adsorbed to titanium was quantified and samples were submitted to western blotting for mucin glycoprotein 2 (MG2) and lactoferrin identification. RESULTS: Surface roughness was statistically higher for SB-A and SB-A-NF groups. Scanning electron microscopy images confirmed that titanium surface treatments increased surface roughness with higher number of porous and scratches for SB-A and SB-A-NF groups. Total protein adsorption was significantly higher for SB-A and SB-A-NF groups (p < 0.05), which also presented higher interactions with MG2 and lactoferrin proteins. CONCLUSION: The roughing of titanium surface by spot blasting plus acid etching treatments contribute to higher interaction with salivary proteins, such as MG2 and lactoferrin. CLINICAL SIGNIFICANCE: Titanium surface roughing increases the interactions of the substratum with salivary proteins, which can influence the integration of dental implants and their components to the oral environment. However, those treatments should be used carefully intraorally, avoiding increase biofilm formation. PMID- 25906807 TI - The Effect of Self-adhesive and Self-etching Resin Cements on the Bond Strength of Nonmetallic Posts in Different Root Thirds. AB - PURPOSE: The purpose of this study was to evaluate the effect of self-adhesive and self-etching resin cements on the bond strength of nonmetallic posts in different root regions. MATERIALS AND METHODS: Sixty single-rooted human teeth were decoronated, endodontically treated, post-space prepared, and divided into six groups. Glass-fiber (GF) posts (Exacto, Angelus) and fiber-reinforced composite (FRC) posts (EverStick, StickTeck) were cemented with self-adhesive resin cement (Breeze) (SA) (Pentral Clinical) and self-etching resin cement (Panavia-F) (SE) (Kuraray). Six 1-mm-thick rods were obtained from the cervical (C), middle (M), and apical (A) regions of the roots. The specimens were then subjected to microtensile testing in a special machine (BISCO; Schaumburg, IL, USA) at a crosshead speed of 0.5 mm/min. Microtensile bond strength data were analyzed with two-way ANOVA and Tukey's tests. RESULTS: Means (and SD) of the MPa were: GF/SA/C: 14.32 (2.84), GF/SA/M: 10.69 (2.72), GF/SA/A: 6.77 (2.17), GF/SE/C: 11.56 (4.13), GF/SE/M: 6.49 (2.54), GF/SE/A: 3.60 (1.29), FRC/SA/C: 16.89 (2.66), FRC/SA/M: 13.18 (2.19), FRC/SA/A: 8.45 (1.77), FRC/SE/C: 13.69 (3.26), FRC/SE/M: 9.58 (2.23), FRC/SE/A: 5.62 (2.12). The difference among the regions was statistically significant for all groups (p < 0.05). The self adhesive resin cement showed better results than the self-etching resin cement when compared to each post (p < 0.05). No statistically significant differences in bond strengths of the resin cements when comparable to each post (p > 0.05). CONCLUSION: The bond strength values were significantly affected by the resin cement and the highest values were found for self-adhesive resin cement. PMID- 25906808 TI - Horizontal-guided Bone Regeneration using a Titanium Mesh and an Equine Bone Graft. AB - AIM: The present work describes a horizontal ridge augmentation in which a titanium mesh was preshaped by adapting it to a stereolithographic model of the patient's jaw that was fabricated from CT scans. BACKGROUND: Guided bone regeneration (GBR) involves covering the augmentation site with a long-lasting barrier to protect it from the invasion of surrounding soft tissues. Among barriers, titanium meshes may provide a successful outcome, but the intraoperatory time needed to shape them is a disadvantage. CASE DESCRIPTION: The 54-year-old patient, missing the right mandibular second bicuspid, first molar, and second molar, had her atrophic ridge augmented with a 30:70 mixture of autogenous bone and equine, enzyme-deantigenic collagen-preserved bone substitute. Two conical implants were inserted concomitantly in the second bicuspid and first molar positions, and the site was protected with the preshaped mesh. Four months later, the titanium mesh was retrieved, a bone sample was collected, and histological and histomorphometric analyses were performed. Provisional and definitive prostheses were then delivered, and follow-up controls were performed for up to 24 months. CONCLUSION: Preshaping the mesh on a model of the patient's mandible shortened the surgical time and enabled faster mesh placement. Two years after surgery, the implants were perfectly functional, and the bone width was stable over time as shown by radiographic controls. Histological analysis of the bone sample showed the heterologous biomaterial to be biocompatible and undergoing advanced remodeling and replacement with newly formed bone. CLINICAL SIGNIFICANCE: Preshaping a titanium mesh over a stereolithographic model of the patient's jaw allowed for a significant reduction of the intraoperative time and may be therefore, advisable in routine practice. PMID- 25906809 TI - Hemisection: A Treatment Option for an Endodontically treated Molar with Vertical Root Fracture. AB - Vertical root fractures (VRF) in endodontically treated teeth have long been reported and pose diagnostic difficulties. A hemisection/root resection procedures removes the fractured fragments completely, and retains a portion of the compromized tooth offers a predictable treatment option. The key to this rests in ideal case selection involving balancing all indications and contraindications. The success of the treatment depends on careful case selection based on a firm set of guidelines. This article presents a case with VRF in an endodontic treated molar. This article describes the case of a 65-year-old man with a VRF on the mesial root and a healthy periodontium supporting the distal root making it ideal for retention as well as restoration and support of the final prosthesis. Also, the patient was motivated to try and save as much of the tooth as possible. Postoperatively no untoward complication was reported making it an alternative treatment option in patients with VRF in a molar, willing to retain the remaining tooth portion. With all other factors balanced, it allows for retaining the remaining intact portion of the tooth structure. PMID- 25906810 TI - Role of miRNA in the malignant transformation of oral lichen planus. PMID- 25906811 TI - Repetitive transcranial magnetic stimulation once a week induces sustainable long term relief of central poststroke pain. AB - OBJECTIVE: Central poststroke pain is a serious problem for some patients after stroke. Repetitive transcranial magnetic stimulation (rTMS) has been reported to relieve poststroke pain but its efficacy is still controversial. We tested the possibility that rTMS, when applied once a week, would induce sustainable relief of poststroke pain. MATERIALS AND METHODS: Eighteen patients with central poststroke pain were included in this study. rTMS (10 trains of 10-sec 5 Hz-rTMS) was delivered over the primary motor cortex on the affected side. The rTMS session was repeated once a week for 12 weeks, and for six patients the intervention was continued for one year. The degree of the pain was assessed before each weekly rTMS session to evaluate sustainable effects. RESULTS: The effects of the rTMS reached a plateau at the eighth week. At the 12th week, the rTMS was effective in 61.1% of the patients; 5 of the 18 patients showed more than 70% reduction based on a visual analog scale, 6 patients showed 40-69% reduction, and 7 remained at a pain reduction level of less than 40%. When patients were divided into two groups with or without severe dysesthesia, it was found that eight patients with severe dysesthesia showed less pain relief than those without. In the six patients who continued rTMS for one year, the pain relief effects also were sustained. CONCLUSION: Although this was an open-label study without a control group, our findings suggest that rTMS of the primary motor cortex, when maintained once a week, could help to relieve poststroke pain. PMID- 25906812 TI - Differences in inhibitory avoidance, cortisol and brain gene expression in TL and AB zebrafish. AB - Recently, we established an inhibitory avoidance paradigm in Tupfel Long-Fin (TL) zebrafish. Here, we compared task performance of TL fish and fish from the AB strain; another widely used strain and shown to differ genetically and behaviourally from TL fish. Whole-body cortisol and telencephalic gene expression related to stress, anxiety and fear were measured before and 2 h post-task. Inhibitory avoidance was assessed in a 3-day paradigm: fish learn to avoid swimming from a white to a black compartment where a 3V-shock is given: day 1 (first shock), day 2 (second shock) and day 3 (no shock, sampling). Tupfel Long Fin fish rapidly learned to avoid the black compartment and showed an increase in avoidance-related spatial behaviour in the white compartment across days. In contrast, AB fish showed no inhibitory avoidance learning. AB fish had higher basal cortisol levels and expression levels of stress-axis related genes than TL fish. Tupfel Long-Fin fish showed post-task learning-related changes in cortisol and gene expression levels, but these responses were not seen in AB fish. We conclude that AB fish show higher cortisol levels and no inhibitory avoidance than TL fish. The differential learning responses of these Danio strains may unmask genetically defined risks for stress-related disorders. PMID- 25906813 TI - Online and social media presence of Australian and New Zealand urologists. AB - OBJECTIVE: To assess the online and social media presence of all practising Australian and New Zealand urologists. SUBJECTS AND METHODS: In July 2014, all active members of the Urological Society of Australia and New Zealand (USANZ) were identified. A comprehensive search of Google and each social media platform (Facebook, Twitter, LinkedIn and YouTube) was undertaken for each urologist to identify any private websites or social media profiles. RESULTS: Of the 435 urologists currently practising in Australia and New Zealand, 305 (70.1%) have an easily identifiable social media account. LinkedIn (51.3%) is the most commonly used form of social media followed by Twitter (33.3%) and private Facebook (30.1%) accounts. About half (49.8%) have a private business website. The average number of social media accounts per urologist is 1.42 and 16 urologists (3.7%) have an account with all searched social media platforms. Over half of those with a Twitter account (55.9%) follow a dedicated urology journal club and have a median (range) number of 'followers' of 12 (1-2 862). Social media users had a median (range) of 2 (0-8 717) 'tweets' on Twitter, 2 (1-45) LinkedIn posts and 1 (1-14) YouTube video. CONCLUSION: This study represents a unique dataset not relying on selection or recall bias but using data freely available to patients and colleagues to gauge social media presence of urologists. Most Australian and New Zealand urologists have a readily identifiable online and social media presence, with widespread and consistent use across both countries. PMID- 25906814 TI - Fueling research on Chlamydomonas. PMID- 25906815 TI - Adverse Consequences of School Mobility for Children in Foster Care: A Prospective Longitudinal Study. AB - Few prospective studies have examined school mobility in children in foster care. This study described the school moves of 86 such children and 55 community comparison children (primarily Caucasian), living in a medium-sized metropolitan area in the Pacific Northwest who were approximately 3 to 6 years old at the study start. Additionally, the effects of moves from kindergarten through Grade 2 on academic and socioemotional competence in Grades 3 through 5 were examined. A greater number of early school moves was associated with poorer later socoemotional competence and partially mediated the effects of maltreatment and out-of-home placement on socioemotional competence. This was the case only for children with poorer early learning skills in kindergarten. Implications for preventive intervention are discussed. PMID- 25906816 TI - Safety and efficacy of a laparoscopic cholecystectomy in the morbid and super obese patients. AB - BACKGROUND: Although a laparoscopic cholecystectomy (LC) is the gold standard treatment for symptomatic cholelithiasis, its safety and efficacy in the morbidly/super obese patients is unknown. The aim of this study was to investigate the safety and efficacy of an elective LC in the morbid/super obese patients. METHODS: A retrospective review of the hospital electronic database and medical records was conducted searching for all elective LC from 2010 to 2013. The data collected included patient demographics and body mass index (BMI), length of hospital stay (LOS), duration of surgery (DOS), intra- and post operative complications, bile duct injuries, performance of an intra-operative cholangiogram, the incidence of open conversion and the seniority of the operator. RESULTS: A total of 799 patients (76% female) with a mean age of 46 years and BMI of 31 were included in this study. There were significant differences in the median DOS between the three BMI groups; BMI < 26 [64 min; interquartile range (IQR) 54-83]; BMI 26-40 (72 min, IQR 58-91) and BMI > 40 (82 min, IQR 63-104), P < 0.001. There were no statistically significant differences in the LOS, peri-operative complication rates, open conversions or bile duct injuries among the BMI groups. CONCLUSIONS: This study showed that LC can be performed safely in the morbid/super obese patients. PMID- 25906817 TI - History and current status of bariatric and metabolic surgeries in East Asia. AB - Morbid obesity and obesity-related comorbidities are major public health problems around the world, including in East Asia. Although Asian populations have been shown to have an elevated risk of type 2 diabetes mellitus, hypertension, and hyperlipidemia at a relatively lower BMI than Western populations, the Asian perspective on bariatric and metabolic surgeries has not been actively discussed until recently. Bariatric surgery in East Asia has undergone a paradigm shift since the first laparoscopic vertical bariatric surgery was performed in Taiwan in 1998, which was subsequently followed by the introduction of laparoscopic adjustable gastric banding, Roux-en-Y gastric bypass, and mini-gastric bypass. Since 2006, use of laparoscopic sleeve gastrectomy has remarkably increased because of its ease, speed, and safety. With regard to metabolic surgery, a randomized controlled trial in Taiwan demonstrated that laparoscopic Roux-en-Y gastric bypass is more effective than laparoscopic sleeve gastrectomy for surgical treatment of poorly controlled type 2 diabetes mellitus and metabolic syndrome. In this article, we describe the history of bariatric procedures, revision surgeries, weight-loss effect, and metabolic surgeries in Asian populations, and we also discuss minimally invasive bariatric surgery with some important citations. PMID- 25906818 TI - Effect of diuretics and sodium-restricted diet on sleep apnea severity: study protocol for a randomized controlled trial. AB - BACKGROUND: Obstructive sleep apnea occurs as a result of increased collapsibility of the upper airway. Overnight fluid displacement from the legs to the neck causes pharyngeal narrowing and increased apnea severity. Sodium intake is associated with apnea severity. We hypothesized that interventions that decrease bodily fluid content might reduce the severity of sleep apnea. METHODS/DESIGN: This is a randomized clinical trial including men with an apnea hypopnea index greater than 30 events/hour, previously diagnosed by full-night in laboratory polysomnography. A total of 54 men will be included and randomly assigned to three groups: Diuretic (n = 18), sodium-restricted diet (n = 18), and control (n = 18). The intervention will last one week. Intention-to-treat and per protocol analyses will be performed. The diuretic group will receive combined spironolactone 100 mg plus furosemide 20 mg daily, taken in the morning. The diet group will receive a regimen with a maximum intake of 3 g of sodium per day. The control group will receive a placebo pill and will maintain all eating habits while keeping a recall diary of their dietary behavior. The primary outcome measure will be change in apnea-hypopnea index. The secondary outcome measures will be variations of: anthropometric and bioelectrical impedance variables, office blood pressure, respiratory variables from in-home level III polysomnography, excessive daytime sleepiness, glycolipid profile, C-reactive protein, 24 h urinary variables, and adverse events. DISCUSSION: Despite the high efficacy of continuous positive airway pressure to reverse upper airway obstruction in sleep apnea, partial adherence to this form of treatment reduces its efficiency. Thus, additional forms of treating apnea need to be investigated. If the results of this proof-of-concept trial show that decreases in bodily fluid content, either by diuretic or dietary intervention, reduces the severity of sleep apnea, further investigation will be necessary before these results can be translated and adopted as an adjunct apnea therapy. TRIAL REGISTRATION: clinicaltrials.gov NCT01945801. PMID- 25906820 TI - Allergic children need more than diets, drugs, and creams. PMID- 25906821 TI - Transcriptome changes in Fusarium verticillioides caused by mutation in the transporter-like gene FST1. AB - BACKGROUND: Fusarium verticillioides causes an important seed disease on maize and produces the fumonisin group of mycotoxins, which are toxic to humans and livestock. A previous study discovered that a gene (FST1) in the pathogen affects fumonisin production and virulence. Although the predicted amino acid sequence of FST1 is similar to hexose transporters, previous experimental evidence failed to prove function. RESULTS: Three new phenotypes were identified that are associated with the FST1 mutant of F. verticillioides (Deltafst1), namely reduction in macroconidia production, increased sensitivity to hydrogen peroxide, and reduced mycelial hydrophobicity. A transcriptome comparison of the wild type and strain Deltafst1 grown on autoclaved maize kernels for six days identified 2677 genes that were differentially expressed. Through gene ontology analysis, 961 genes were assigned to one of 12 molecular function categories. Sets of down-regulated genes in strain Deltafst1 were identified that could account for each of the mutant phenotypes. CONCLUSION: The study provides evidence that disruption of FST1 causes several metabolic and developmental defects in F. verticillioides. FST1 appears to connect the expression of several gene networks, including those involved in secondary metabolism, cell wall structure, conidiogenesis, virulence, and resistance to reactive oxygen species. The results support our hypothesis that FST1 functions within the framework of environmental sensing. PMID- 25906822 TI - Assessing the implementability of telehealth interventions for self-management support: a realist review. AB - BACKGROUND: There is a substantial and continually growing literature on the effectiveness and implementation of discrete telehealth interventions for health condition management. However, it is difficult to predict which technologies are likely to work and be used in practice. In this context, identifying the core mechanisms associated with successful telehealth implementation is relevant to consolidating the likely elements for ensuring a priori optimal design and deployment of telehealth interventions for supporting patients with long-term conditions (LTCs). METHODS: We adopted a two-stage realist synthesis approach to identify the core mechanisms underpinning telehealth interventions. In the second stage of the review, we tested inductively and refined our understanding of the mechanisms. We reviewed qualitative papers focused on COPD, heart failure, diabetes, and behaviours and complications associated with these conditions. The review included 15 papers published 2009 to 2014. RESULTS: Three concepts were identified, which suggested how telehealth worked to engage and support health related work. Whether or not and how a telehealth intervention enables or limits the possibility for relationships with professionals and/or peers. Telehealth has the potential to reshape and extend existing relationships, acting as a partial substitute for the role of health professionals. The second concept is fit: successful telehealth interventions are those that can be well integrated into everyday life and health care routines and the need to be easy to use, compatible with patients' existing environment, skills, and capacity, and that do not significantly disrupt patients' lives and routines. The third concept is visibility: visualisation of symptoms and feedback has the capacity to improve knowledge, motivation, and a sense of empowerment; engage network members; and reinforce positive behaviour change, prompts for action and surveillance. CONCLUSIONS: Upfront consideration should be given to the mechanisms that are most likely to ensure the successful development and implementation of telehealth interventions. These include considerations about whether and how the telehealth intervention enables or limits the possibility for relationships with professionals and peers, how it fits with existing environment and capacities to self-manage, and visibility-enabling-enhanced awareness to self and others. PMID- 25906823 TI - Prospectively assessing risk for premature ovarian senescence in young females: a new paradigm. AB - BACKGROUND: Approximately 10% of women suffer from premature ovarian senescence (POS), ca. 9% as occult primary ovarian insufficiency (OPOI, also called premature ovarian aging, POA) and ca. 1% as primary ovarian insufficiency (POI, also called premature ovarian failure, POF). In a large majority of cases POS is currently only diagnosed at advanced clinical stages when women present with clinical infertility. METHODS: We here, based on published evidence, suggest a new diagnostic paradigm, which is based on identifying young women at increased risk for POS at much earlier stages. RESULTS: Risk factors for POS are known from the literature, and can be used to identify a sub-group of young women at increased risk, who then are followed sequentially with serial assessments of functional ovarian reserve (FOR) until a diagnosis of POS is either reached or refuted. At approximately 25% prevalence in general U.S. populations (and somewhat different prevalence rates in more homogenous Asian and African populations), so-called low (CGGn<26) mutations of the fragile X mental retardation 1 (FMR1) gene, likely, represents the most common known risk factor, including history-based risk factors from medical, genetic and family histories. CONCLUSIONS: Women so affirmatively diagnosed with POS at relative young ages, then have the opportunity to reconsider their reproductive planning and/or choose fertility preservation via oocyte or ovarian tissue cryopreservation at ages when such procedures are clinically much more effective and, therefore, also more cost effective. Appropriate validation studies will have to precede widespread utilization of this paradigm. PMID- 25906824 TI - Impact of the Centers for Medicare and Medicaid Services Hospital-Acquired Conditions Policy on Billing Rates for 2 Targeted Healthcare-Associated Infections. AB - BACKGROUND: The 2008 Centers for Medicare & Medicaid Services hospital-acquired conditions policy limited additional payment for conditions deemed reasonably preventable. OBJECTIVE: To examine whether this policy was associated with decreases in billing rates for 2 targeted conditions, vascular catheter associated infections (VCAI) and catheter-associated urinary tract infections (CAUTI). STUDY POPULATION: Adult Medicare patients admitted to 569 acute care hospitals in California, Massachusetts, or New York and subject to the policy. DESIGN We used an interrupted times series design to assess whether the hospital acquired conditions policy was associated with changes in billing rates for VCAI and CAUTI. RESULTS: Before the policy, billing rates for VCAI and CAUTI were increasing (prepolicy odds ratio per quarter for VCAI, 1.17 [95% CI, 1.11-1.23]; for CAUTI, 1.19 [1.16-1.23]). The policy was associated with an immediate drop in billing rates for VCAI and CAUTI (odds ratio for change at policy implementation for VCAI, 0.75 [95% CI, 0.69-0.81]; for CAUTI, 0.87 [0.79-0.96]). In the postpolicy period, we observed a decreasing trend in the billing rate for VCAI and a leveling-off in the billing rate for CAUTI (postpolicy odds ratio per quarter for VCAI, 0.98 [95% CI, 0.97-0.99]; for CAUTI, 0.99 [0.97-1.00]). CONCLUSIONS: The Centers for Medicare & Medicaid Services hospital-acquired conditions policy appears to have been associated with immediate reductions in billing rates for VCAI and CAUTI, followed by a slight decreasing trend or leveling-off in rates. These billing rates, however, may not correlate with changes in clinically meaningful patient outcomes and may reflect changes in coding practices. PMID- 25906825 TI - Stimulating the biosynthesis of antroquinonol by addition of effectors and soybean oil in submerged fermentation of Antrodia camphorata. AB - Antrodia camphorata is a precious medicinal mushroom that has attracted increasing attentions. Antroquinonol has been considered as being among the most biologically active components of A. camphorata. However, it was hardly biosynthesized via conventional submerged fermentation. Two approaches were applied to stimulate the biosynthesis of antroquinonol in submerged fermentation. On one hand, different kinds of effectors that may involve in the antroquinonol biosynthesis were investigated. Among the tested effectors, camphorwood leach liquor was the most effective for stimulating the antroquinonol production. On the other hand, because of the hydrophobic characteristics of antroquinonol, soybean oil was added to establish an extractive fermentation system for alleviating the product inhibition and resulting in enhanced productivity. The highest antroquinonol concentration could be achieved at 89.06 +/- 0.14 mg/L when 10% (v/v) soybean oil was added at the beginning of the fermentation. This study will be of great significance for the study of A. camphorata and the bioprocess regulation of antroquinonol production. PMID- 25906826 TI - Tuning the metal-support interaction by structural recognition of cobalt-based catalyst precursors. AB - Controlling the nature and size of cobalt(II) polynuclear precursors on gamma alumina and silica-alumina supports represents a challenge for the synthesis of optimal cobalt-based heterogeneous catalysts. By density functional theory (DFT) calculations, we show how after drying the interaction of cobalt(II) precursor on gamma-alumina is driven by a structural recognition phenomenon, leading to the formation of an epitaxial Co(OH)2 precipitate involving a Co-Al hydrotalcite-like interface. On a silica-alumina surface, this phenomenon is prevented due to the passivation effect of silica domains. This finding opens new routes to tune the metal-support interaction at the synthesis step of heterogeneous catalysts. PMID- 25906827 TI - An assessment of shear bond strength between ceramic repair systems and different ceramic infrastructures. AB - The purpose of this study was to evaluate of shear bond strengths between two ceramic repair systems and different ceramic infrastructure materials. One hundred cylindrical specimens of ceramic infrastructure were fabricated with non precious metal alloy, zirconia, alumina, galvano, and glass ceramic: 20 non precious metal alloy (NP), 20 zirconia (Z), 20 alumina (A), 20 galvano (G), and 20 glass ceramic (GC). Specimens were divided into 2 subgroups. One half of the specimens were applied by ClearfilTM (CR) repair system and, another half of that were applied by Cimara&Cimara((r)) Zircon (CZ) repair system. Bonded specimens were stored in 37 degrees C distilled water for 24 h and were thermocycled at 5 55 degrees C for 1,200 cycles with a 30-sec dwell time and 5-sec transfer time. Shear bond strengths were determined with a mechanical testing device. And mode of failure was recorded. Mann Whitney-U and Kruskal Wallis tests were applied to the data at 95% confidence interval level. Infrastructure groups displayed the following values in megapascals: NP = 10.70 +/- 1.88; Z = 9.15 +/- 0.80; A = 11.65 +/- 0.70; GC = 10.95 +/- 0.80; and G = 6.88 +/- 0.88. The Mann Whitney-U test results showed no significant difference between the repair systems. The Kruskal Wallis test results demonstrated significant difference between the infrastructures. The lowest bond strength values were observed in G group. In conclusion, average bond strength values were in accordance with previously reported values, therefore it can be suggested that intraoral repair of ceramic restorations can be temporary, but a satisfying alternative for patients. PMID- 25906828 TI - Seminal cyclooxygenase relationship with oxidative stress in infertile oligoasthenoteratozoospermic men with varicocele. AB - This study aimed to assess the relation of seminal cyclooxygenase COX-1, COX-2 with oxidative stress in infertile oligoasthenoteratozoospermic (OAT) men with varicocele (Vx). In all, 128 men were allocated into fertile men, fertile men with Vx, infertile OAT men without Vx and infertile OAT men with Vx. They were subjected to history taking, clinical examination and semen analysis. Also, seminal COX-1, COX-2, malondialdehyde (MDA) and glutathione peroxidase (GPx) were estimated. Mean levels of seminal COX-1, COX-2 were over-expressed, the mean level of seminal MDA was significantly increased, and the mean level of seminal GPx was significantly decreased in infertile OAT men with Vx compared with other groups. Seminal COX-1 and COX-2 were over-expressed in cases with Vx grade III compared with Vx grades I, II cases and in cases with bilateral Vx compared with unilateral Vx. There was significant negative correlation between seminal COX-1 and COX-2 with sperm concentration, sperm motility, sperm normal morphology, seminal GPx and significant positive correlation with seminal MDA. It is concluded that seminal COX-1 and COX-2 are over-expressed in infertile OAT men with Vx compared with fertile men with/without and infertile OAT men without Vx being associated with oxidative stress, Vx grade and Vx laterality. PMID- 25906829 TI - What makes the phenolphthalein still be a safe drug for patients in China? PMID- 25906830 TI - Centenary Celebration for Scottish Missionary Mary Slessor: A Lasting Legacy for Twins/Twin Research: Twins With Kleinfelter's Syndrome; Twin Research on Atopic Diseases; Twin Study of Autism; Psychotherapy with Twins / General Interest: Female Twin Pole-Vaulters; Longest Twin Birth Interval; Pair of Franco-Cuban Vocalists; Croatian Twin Models. AB - The centenary celebration for Scottish missionary, Mary Slessor, took place on February 14, 2015 in Melle, Belgium. Slessor saved many newborn twins and their mothers from death and disownment by members of their community, including their families, who believed twins harbored evil spirits. The events of this unusual and significant gathering are described. Next, twin research and reports concerning Kleinfelter's disease, atopic diseases, autism and psychotherapy are presented. General interest subjects include identical female twin pole-vaulters, the longest twin birth interval, Franco-Cuban twin vocalists, and Croatian twin models. PMID- 25906831 TI - Implementation of a clinical decision support system improves compliance with restrictive transfusion policies in hematology patients. AB - BACKGROUND: There is increasing evidence for restrictive red blood cell (RBC) transfusion but compliance with recommended transfusion triggers is variable. A clinical decision support system (CDSS) has been found to reduce unnecessary transfusion in some clinical settings when physicians are advised they are noncompliant with the current guidelines. The objective was to assess the impact of a CDSS for blood product ordering in patients with hematologic disease. STUDY DESIGN AND METHODS: All platelet (PLT) and RBC transfusions were identified in hematology patients in three periods: before (baseline), immediately after (CDSS1), and 7 months after implementation of CDSS for blood ordering (CDSS2). Compliance with the recommended transfusion triggers was monitored for all orders made by CDSS or non-CDSS methods during each period. RESULTS: Ninety-seven patients with a variety of hematologic diagnoses received 502 RBC and 572 PLT transfusions during the three periods with no significant difference in 1) the mean number of transfusions per patient, 2) the proportion of patients transfused, 3) posttransfusion hemoglobin (Hb), and 4) pre- and posttransfusion PLT count, although mean pretransfusion Hb decreased. The proportion of noncompliant RBC and PLT transfusion requests improved from baseline to CDSS2 (69.0% to 43.4% p <= 0.005 for RBCs; and 41.9% to 31.2%, p = 0.16 for PLT) when all orders were compared, although this improvement was not significant at the 5% level for PLTs. CONCLUSIONS: The introduction of CDSS for blood product ordering supported by education and physician feedback in the hematology setting had an immediate impact on improving compliance with guidelines for restrictive transfusion practice. PMID- 25906832 TI - Principles of minimal residual disease detection for hematopoietic neoplasms by flow cytometry. AB - Flow cytometry has become an indispensible tool for the diagnosis and classification of hematopoietic neoplasms. The ability to rapidly distinguish cellular subpopulations via multiparametric assessment of quantitative differences in antigen expression on single cells and enumerate the relative sizes of the resulting subpopulations is a key feature of the technology. More recently, these capabilities have been expanded to include the identification and enumeration of rare subpopulations within complex cellular mixtures, for example, blood or bone marrow, leading to the application for post-therapeutic monitoring or minimal residual disease detection. This review will briefly present the principles to be considered in the construction and use of flow cytometric assays for minimal residual disease detection including the use of informative antibody combinations, the impact of immunophenotypic instability, enumeration, assay sensitivity, and reproducibility. PMID- 25906834 TI - Alteration in the center of mass trajectory of patients after stroke. AB - BACKGROUND: The movement disorders due to stroke can alter the motion of the Center of Mass (CoM) of the body. Thus, the analysis of the CoM motion can be an alternative to diagnostic the stroke gait disturbances and has not been widely explored. OBJECTIVE: To identify and to analyze the alterations of CoM trajectory during both of gait cycles, affected and unaffected, of post-stroke patients comparing to healthy subjects. METHODS: The CoM trajectory was obtained using a gold standard method, the three-dimensional (3D) kinematics associate to anthropometry. Two experimental groups were compared: Hemiparetic Group (HG) consisted of fourteen chronic hemiparetic patients and Control Group (CG) by fourteen able-bodied subjects. RESULTS: The statistical analysis (P <= 0.05) revealed the following average gait alterations in the HG, in the stance phase of the affected side: higher lateral (midstance), lower vertical (midstance and terminal stance), and lower forward displacement (heel strike until terminal stance). In the swing phase of the affected side, HG showed higher lateral (preswing and initial swing) and vertical displacement (preswing until terminal swing), and lower forward (preswing until terminal swing) displacement of the CoM. There was also anticipation of the instants of maximum displacements in the lateral and vertical directions and lower total range in the forward direction. CONCLUSION: The CoM trajectory analysis pointed out that the gait after stroke was altered such in the affected as in the unaffected lower limbs, mainly in the single support phase of the affected side, but also in the swing phase of the gait cycle. PMID- 25906833 TI - Paths to health equity: Local area variation in progress toward eliminating breast cancer mortality disparities, 1990-2009. AB - BACKGROUND: US breast cancer deaths have been declining since 1989, but African American women are still more likely than white women to die of breast cancer. Black/white disparities in breast cancer mortality rate ratios have actually been increasing. METHODS: Across 762 US counties with enough deaths to generate reliable rates, county-level, age-adjusted breast cancer mortality rates were examined for women who were 35 to 74 years old during the period of 1989-2010. Twenty-two years of mortality data generated twenty 3-year rolling average data points, each centered on a specific year from 1990 to 2009. Mixed linear models were used to group each county into 1 of 4 mutually exclusive trend patterns. The most recent 3-year average black breast cancer mortality rate for each county was also categorized as being worse or not worse than the breast cancer mortality rate for the total US population. RESULTS: More than half of the counties (54%) showed persistent, unchanging disparities. Roughly 1 in 4 (24%) had a divergent pattern of worsening black/white disparities. However, 10.5% of the counties sustained racial equality over the 20-year period, and 11.7% of the counties actually showed a converging pattern from high disparities to greater equality. Twenty-three counties had 2008-2010 black mortality rates better than the US average mortality rate. CONCLUSIONS: Disparities are not inevitable. Four US counties have sustained both optimal and equitable black outcomes as measured by both absolute (better than the US average) and relative benchmarks (equality in the local black/white rate ratio) for decades, and 6 counties have shown a path from disparities to health equity. PMID- 25906835 TI - Modulation of protein synthesis by polyamines. AB - Polyamines are ubiquitous small basic molecules that play important roles in cell growth and viability. Since polyamines mainly exist as a polyamine-RNA complex, we looked for proteins whose synthesis is preferentially stimulated by polyamines at the level of translation, and thus far identified 17 proteins in Escherichia coli and 6 proteins in eukaryotes. The mechanisms of polyamine stimulation of synthesis of these proteins were investigated. In addition, the role of eIF5A, containing hypusine formed from spermidine, on protein synthesis is described. These results clearly indicate that polyamines and eIF5A contribute to cell growth and viability through modulation of protein synthesis. PMID- 25906836 TI - Pulmonary diffusing capacity in healthy African-American and Caucasian children. AB - Previous studies of pulmonary diffusing capacity in healthy children primarily focused upon Caucasian (C) subjects. Since lung volumes in African-Americans (AA) are smaller than lung volumes in C subjects of the same height, diffusing capacity values in AA children might be interpreted as low or abnormal using currently available equations without adjusting for race. Healthy AA (N = 151) and C (N = 301) children between 5 and 18 years of age performed acceptable measurements of single breath pulmonary diffusing capacity for carbon monoxide (DLCO ) and alveolar volume (VA ) according to current ATS/ERS guidelines. The natural log of DLCO and VA were associated with height, gender, age, and race; AA children had lower DLCO and VA compared to C children. Adjustment of DLCO for Hemoglobin (Hgb) resulted in no significant difference in DLCO among these healthy subjects with normal Hgb. In summary, we report prediction equations for DLCO and VA that include adjustment for race (C; AA) demonstrating that AA have lower DLCO and VA compared to C children for the same height, gender, and age. PMID- 25906837 TI - One-step synthesis of amorphous silver silicates with tunable light absorption spectra and photocatalytic activities in the visible region. AB - A series of amorphous silver silicates with different compositions were synthesized for the first time by one-step co-precipitation. Silicate ions were found to have important role on determining visible light absorption and photocatalytic activities of amorphous silver silicates, and the sample with Ag/Si ratio of 3.20 exhibits optimal photocatalytic activity. PMID- 25906838 TI - Selenium (Se) improves drought tolerance in crop plants--a myth or fact? AB - Climate change has emerged as one of the most complex challenges of the 21st century and has become an area of interest in the past few decades. Many countries of the world have become extremely vulnerable to the impacts of climate change. The scarcity of water is a serious concern for food security of these countries and climate change has aggravated the risks of extreme events like drought. Oxidative stress, caused by a variety of active oxygen species formed under drought stress, damages many cellular constituents, such as carbohydrates, lipids, nucleic acids and proteins, which ultimately reduces plant growth, respiration and photosynthesis. Se has become an element of interest to many biologists owing to its physiological and toxicological importance. It plays a beneficial role in plants by enhancing growth, reducing damage caused by oxidative stress, enhancing chlorophyll content under light stress, stimulating senesce to produce antioxidants and improving plant tolerance to drought stress by regulating water status. Researchers have adopted different strategies to evaluate the role of selenium in plants under drought stress. Some of the relevant work available regarding the role of Se in alleviating adverse effect of drought stress is discussed in this paper. PMID- 25906839 TI - New Insights into the Toxicity of n-Butanol to Trypsin: Spectroscopic and Molecular Docking Descriptions. AB - n-Butanol has been widely used and its residue exists extensively in the environment. It could lead to conformational and functional changes of trypsin by forming a complex with it. Docking method and spectrographic technique were employed to the study of the complex of trypsin and n-butanol. The fluorescence results indicated that n-butanol can form a complex with trypsin and change the distance between tryptophan and fluorescence quenchers. The conformational changes of trypsin were proved by UV-visible absorption and synchronous fluorescence spectroscopy indicating that n-butanol had little effect on the conformation of trypsin at a low concentration while denatured and coagulated the trypsin at a high concentration. The binding site was displayed by molecular modeling, which gave information about distances and binding forces between n butanol and trypsin. The results were in accordance with spectroscopic experiments. Besides, enzyme activity assay gave the dose-response relationship of n-butanol with trypsin. PMID- 25906840 TI - Total leisure noise exposure and its association with hearing loss among adolescents. AB - OBJECTIVE: To investigate total leisure noise exposure among adolescents and to assess its association with hearing. DESIGN: Based on self-reported time spent on 19 leisure activities and associated mean sound pressure levels reported in the literature, total leisure noise exposure was evaluated and compared to noise at work limits (> 85 dB(A) = hazardous) in a cross-sectional survey. Tympanometry and pure-tone audiometry was performed in sound isolated rooms. STUDY SAMPLE: The study sample consists of 2143 pupils attending grade nine in any school in a German city 2009-2011 (mean age: 15.4 years; range: 13-19 years). Audiometric data were available for 1837 (85.8%) pupils (53.9% girls). RESULTS: 41.9% of the 2143 adolescents who had provided self-reported data on leisure activities associated with noise exposure were estimated to be hazardously exposed to leisure time noise. The interaction of gender with total leisure time noise exposure was not significant. No association between leisure time noise exposure and audiometric notches could be detected. CONCLUSION: While hearing loss seems seldom in this age group, a high proportion of adolescents aged 15-16 years are exposed to noise levels during leisure time bearing long-term risks of hearing loss. PMID- 25906841 TI - Tests over time: Evaluating the currency of normative data in a complex multilingual environment. AB - BACKGROUND: Assessment of oral language skills is challenging in multilingual environments. With language policies promoting increased use of English and reduction of dialectal varieties of languages, rapid changes in language further confound assessment. PURPOSE: This study explores the currency of normative data on an expressive language screening tool in English for English-Mandarin bilingual Singaporean children. METHOD: Spoken language samples in English from 101 pre-school children were compared with those from 481 children in the original data collection in 2002. Scores for expressive vocabulary and morphosyntax were compared for the two main language groups. RESULT: Results indicate that the normative data for English-dominant children are still current. The data for younger Mandarin-dominant children showed improved test scores, indicating improvement in expressive morphosyntax in English. CONCLUSION: English language competency has changed over time for Mandarin-dominant children in Singapore, likely due to the influence of language policy on language use. This is a particular challenge in multilingual environments. Current literature emphasizes the need to develop language assessments specific to populations and language groups for standardized assessments to be valid and reliable. These results demonstrate the need to monitor normative data and characteristics of language over time and to update standardized language assessments accordingly. PMID- 25906843 TI - Methodological problems in the article comparing lung function profiles and aerobic capacity of adult cigarette and hookah smokers after 12 weeks intermittent training. PMID- 25906842 TI - Traditional Uighur Medicine Karapxa decoction, inhibits liver xanthine oxidase and reduces serum uric acid concentrations in hyperuricemic mice and scavenges free radicals in vitro. AB - BACKGROUND: Karapxa decoction (KD) is a Traditional Uighur Medicine used for hepatitis, cholecystitis, gastralgia, oedema, gout and arthralgia. Because of its purported effect in gout, its effects were tested in hyperuricemic mice models induced by yeast extract paste or potassium oxonate, as well as its capacity to scavenge free radicals in vitro. METHODS: Hyperuricemia was induced in mice by yeast extract paste or potassium oxonate. KD was given orally for 14 days at 200, 400 and 800 mg/kg/day, with Allopurinol 10 mg/kg/day as positive control. Serum uric acid (UA), and liver xanthine oxidase activity (XO) were measured. Scavenging activity of KD on 1, 1-diphenyl-2-picrylhydrazyl radicals (DPP*), nitric oxide (*NO), superoxide (O2*-), efficiency against lipid peroxidation, and XO inhibition were determined in vitro. RESULTS: KD inhibited liver XO activity and reduced serum uric acid in hyperuricemic mice. KD also showed noticeable antioxidant activity, scavenging free radicals (DPP*, *NO and O2*-). It was effective against lipid peroxidation and inhibited XO in vitro. CONCLUSIONS: This study supports the traditional use of Karapxa decoction to treat hyperuricemia and gout. PMID- 25906844 TI - Re-imagining the control of malaria in tropical Africa during the early years of the World Health Organization. AB - This paper grew out of a meeting organized in September 2014 in London on 'Re imagining malaria'. The focus of that meeting was on malaria today; only afterwards did the idea emerge that re-imagining the past might serve as a useful way for guiding present re-thinking. Sub-Saharan Africa is the logical place for such a re-examination for, as argued in this paper, the approaches that emerged following the collapse of the global eradication campaign were available to WHO in the 1950s, but these were not pursued as Africa was not encouraged to seek solutions outside those being advocated for eradication elsewhere. PMID- 25906845 TI - Evaluation of TV commercials using neurophysiological responses. AB - BACKGROUND: In recent years, neuroscientific knowledge has been applied to marketing as a novel and efficient means to comprehend the cognitive and behavioral aspects of consumers. A number of studies have attempted to evaluate media contents, especially TV commercials using various neuroimaging techniques such as electroencephalography (EEG). Yet neurophysiological examination of detailed cognitive and affective responses in viewers is still required to provide practical information to marketers. Here, this study develops a method to analyze temporal patterns of EEG data and extract affective and cognitive indices such as happiness, surprise, and attention for TV commercial evaluation. METHODS: Twenty participants participated in the study. We developed the neurophysiological indices for TV commercial evaluation using classification model. Specifically, these model-based indices were customized using individual EEG features. We used a video game for developing the index of attention and four video clips for developing indices of happiness and surprise. Statistical processes including one-way analyses of variance (ANOVA) and the cross validation scheme were used to select EEG features for each index. The EEG features were composed of the combinations of spectral power at selected channels from the cross validation for each individual. The Fisher's linear discriminant classifier (FLDA) was used to estimate each neurophysiological index during viewing four different TV commercials. Post hoc behavioral responses of preference, short-term memory, and recall were measured. RESULTS: Behavioral results showed significant differences for all preference, short-term memory rates, and recall rates between commercials, leading to a 'high-ranked' commercial group and a 'low-ranked' group (P < 0.05). Neural estimation of happiness results revealed a significant difference between the high-ranked and the low-ranked commercials in happiness index (P < 0.01). The order of rankings based on happiness and attention matched well with the order of behavioral response rankings. In the elapsed-time analysis of the highest-ranked commercial, we could point to visual and auditory semantic structures of the commercial that induced increases in the happiness index. CONCLUSIONS: Our results demonstrated that the neurophysiological indices developed in this study may provide a useful tool for evaluating TV commercials. PMID- 25906846 TI - A therapeutic challenge: catastrophic anti-phospholipid syndrome with diffuse alveolar haemorrhage. AB - Diffuse alveolar haemorrhage (DAH) complicating primary catastrophic anti phospholipid syndrome (CAPS) was diagnosed in a 50-year-old female patient. Treatment strategies are limited for this often life-threatening autoimmune disease that requires aggressive immunosuppression. In the absence of clinically validated treatment strategies, high-dose steroids associated with plasma exchange and eventually intravenous immunoglobulins were used to manage the disease. Its severity prompted the initiation of rituximab that was administered weekly for four consecutive weeks. Anticoagulation therapy, on the other hand, needed to be discontinued due to the major haemorrhagic episodes. This combination treatment provided an effective control of the CAPS-associated DAH and helped achieve clinical remission. PMID- 25906847 TI - 1.1 Child growth. PMID- 25906848 TI - 1.2.1 Clinical evaluation and anthropometry. 1.2 Nutritional assessment. PMID- 25906849 TI - 1.2.2 Diet history and dietary intake assessment. 1.2 Nutritional assessment. PMID- 25906850 TI - 1.2.3 Use of technical measurements in nutritional assessment. 1.2 Nutritional assessment. PMID- 25906851 TI - 1.2.4 Use Of laboratory measurements in nutritional assessment. 1.2 Nutritional assessment. PMID- 25906852 TI - 1.3.1. Nutrient intake values: concepts and applications. 1.3 Nutritional needs. PMID- 25906853 TI - 1.3.2 Energy requirements of infants, children and adolescents. 1.3 Nutritional needs. PMID- 25906854 TI - 1.3.3 Protein. 1.3 Nutritional needs. PMID- 25906855 TI - 1.3.4 Digestible and non-digestible carbohydrates. 1.3 Nutritional needs. PMID- 25906856 TI - 1.3.5 Fats. 1.3 Nutritional needs. PMID- 25906857 TI - 1.3.6 Fluid and electrolytes. 1.3 Nutritional needs. PMID- 25906858 TI - 1.3.7 Vitamins and trace elements. 1.3 Nutritional needs. PMID- 25906859 TI - 1.4 Physical activity, health and nutrition. PMID- 25906860 TI - 1.5 Early nutrition and long-term health. PMID- 25906861 TI - 1.6 Food safety. PMID- 25906862 TI - 1.7 Gastrointestinal development, nutrient digestion and absorption. PMID- 25906863 TI - 1.8 Gut microbiota in infants. PMID- 25906864 TI - 2.1 Breastfeeding. PMID- 25906865 TI - 2.2 Formula feeding. PMID- 25906866 TI - 2.3 Marketing of breast milk substitutes. PMID- 25906867 TI - 2.4 Complementary foods. PMID- 25906868 TI - 2.5 Allergy Prevention through Early Nutrition. PMID- 25906869 TI - 2.6 Toddlers, preschool and school children. PMID- 25906870 TI - 2.7 Adolescent nutrition. PMID- 25906871 TI - 2.8 Nutrition in pregnancy and lactation. PMID- 25906872 TI - 2.9 Vegetarian diets. PMID- 25906873 TI - 3.1 Primary and secondary malnutrition. PMID- 25906874 TI - 3.2 Micronutrient deficiencies in children. PMID- 25906875 TI - 3.3 Enteral nutritional support. PMID- 25906877 TI - 3.5 Management of child and adolescent obesity. PMID- 25906876 TI - 3.4 Parenteral nutritional support. PMID- 25906878 TI - 3.6 Reducing the burden of acute and prolonged childhood diarrhea. PMID- 25906879 TI - 3.7 HIV and AIDS. PMID- 25906880 TI - 3.8 Nutritional management in cholestatic liver disease. PMID- 25906881 TI - 3.9 Malabsorptive disorders and short bowel syndrome. PMID- 25906882 TI - 3.10 Celiac disease. PMID- 25906883 TI - 3.11 Food intolerance and allergy. PMID- 25906884 TI - 3.12 Regurgitation and gastroesophageal reflux. PMID- 25906885 TI - 3.13 Childhood feeding problems. PMID- 25906886 TI - 3.14 Preterm and low-birth-weight infants. PMID- 25906887 TI - 3.15 Nutritional management of diabetes in childhood. PMID- 25906888 TI - 3.16 Inborn errors of metabolism. PMID- 25906889 TI - 3.17 Hypercholesterolemia. PMID- 25906890 TI - 3.18 Enteral nutrition for paediatric inflammatory bowel disease. PMID- 25906891 TI - 3.19 Nutrition in cystic fibrosis. PMID- 25906892 TI - 3.20 Heart disease. PMID- 25906893 TI - 3.21 Nutritional management in children with chronic kidney disease. PMID- 25906894 TI - 3.22 Nutrition rehabilitation in eating disorders. PMID- 25906895 TI - 3.23 Haemato-oncology. PMID- 25906896 TI - 3.24 Intensive care. PMID- 25906897 TI - 4.1 The WHO Child Growth Standards. PMID- 25906898 TI - 4.2 The CDC and Euro Growth Charts. PMID- 25906899 TI - 4.3 Reference nutrient intakes of infants, children and adolescents. PMID- 25906900 TI - 4.4 Feeding my baby - advice for families. PMID- 25906901 TI - 4.5 Increasing dietary energy and nutrient supply. PMID- 25906902 TI - 4.6 Dietary assessment in children. PMID- 25906903 TI - How do you get your paper published more quickly in the British Journal of Oral and Maxillofacial Surgery? PMID- 25906904 TI - Commentary on: management of obstructive salivary disorders by sialendoscopy: a systematic review. PMID- 25906905 TI - Prevention of intraoperative pressure injuries caused by nasogastric tubes. PMID- 25906906 TI - Multiple, synchronous, unilateral parotid adenomas: a case series. AB - Most tumours of the major salivary glands are single and unilateral, and involve the parotid. It is uncommon for synchronous, multifocal tumours of the same histological type to affect one gland, and cases with multiple types are rare. Extracapsular dissection, an established technique for the safe removal of benign tumours of the parotid gland, has low rates of morbidity and recurrence, but relies on careful preoperative assessment and selection of cases. In a consecutive series of 70 cases of extracapsular dissection over 5 years by one surgeon, we found a 4% incidence (n=3) of synchronous, unilateral, multiple adenomas in the parotid gland. PMID- 25906907 TI - Bone Scan Index predicts outcome in patients with metastatic hormone-sensitive prostate cancer. AB - OBJECTIVE: To evaluate the Bone Scan Index (BSI) for prediction of castration resistance and prostate cancer-specific survival (PCSS). In this retrospective study, we used novel computer-assisted software for automated detection/quantification of bone metastases by BSI. Patients with prostate cancer are M-staged by whole-body bone scintigraphy (WBS) and categorised as M0 or M1. Within the M1 group, there is a wide range of clinical outcomes. The BSI was introduced a decade ago providing quantification of bone metastases by estimating the percentage of bone involvement. Being too time consuming, it never gained widespread clinical use. PATIENTS AND METHODS: In all, 88 patients with prostate cancer awaiting initiation of androgen-deprivation therapy due to metastases were included. WBS was performed using a two-headed gamma-camera. BSI was obtained using the automated platform EXINI bone (EXINI Diagnostics AB, Lund, Sweden). In Cox proportional hazard models, time to castration-resistant prostate cancer (CRPC) and PCSS were modelled as the dependent variables, whereas prostate specific antigen (PSA) level, Gleason score and BSI were used as explanatory factors. For Kaplan-Meier estimates, BSI groups were dichotomously split into: BSI <1 and BSI >=1. Discrimination between prognostic models was explored using the concordance index (C-index). RESULTS: The mean (range) age of the patients was 72 (52-92) years, the median (range) PSA level was 73 (4-5 740) ng/mL, the mean (range) Gleason score was 7.7 (2-10), and the mean (range) BSI was 1.0 (0 9.2). During a mean (range) follow-up of 26 (8-49) months, 48 patients became castration resistant and 15 had died; most (13) from prostate cancer. In multivariate analysis including PSA level, Gleason score and BSI, only prediction by BSI was statistically significant. This was true both for time to CRPC (hazard ratio [HR] 1.45, 95% confidence interval [CI] 1.22-1.74; C-index increase from 0.49 to 0.69) and for PCSS (HR 1.34, 95% CI 1.07-1.67; C-index increase from 0.76 to 0.95). CONCLUSION: BSI obtained using a novel automated computer-assisted algorithm appears to be a useful predictor of outcome for time to CRPC and PCSS in patients with hormone-sensitive metastatic prostate cancer. PMID- 25906908 TI - From zero to six double bonds: phospholipid unsaturation and organelle function. AB - Cellular phospholipids (PLs) differ by the nature of their polar heads as well as by the length and unsaturation level of their fatty acyl chains. We discuss how the ratio between saturated, monounsaturated, and polyunsaturated PLs impacts on the functions of such organelles as the endoplasmic reticulum, synaptic vesicles, and photoreceptor discs. Recent experiments and simulations suggest that polyunsaturated PLs respond differently to mechanical stress, including membrane bending, than monounsaturated PLs owing to their unique conformational plasticity. These findings suggest a rationale for PL acyl chain remodeling by acyltransferases and a molecular explanation for the importance of a balanced fatty acid diet. PMID- 25906909 TI - The demographics of the ubiquitin system. AB - The ubiquitin system is a major coordinator of cellular physiology through regulation of both protein degradation and signalling pathways. A key building block of a systems-level understanding has been generated by global proteomic studies, which provide copy number estimates for each component. The aggregate of ubiquitin, conjugating enzymes (E1, E2, and E3s), and deubiquitylases (DUBs) represents ~1.3% of total cellular protein. Complementary approaches have generated quantitative measurements of various ubiquitin pools and further subdivision into different ubiquitin chain topologies. Systematic studies aimed at associating specific enzymes (E2s and DUBs) with the dynamics of these different pools have also made significant progress. Here, we delineate the emerging picture of the most significant determinants of the cellular ubiquitin economy. PMID- 25906910 TI - Novel oral formulation approach for poorly water-soluble drug using lipocalin type prostaglandin D synthase. AB - Lipocalin-type prostaglandin D synthase (L-PGDS), a member of the lipocalin superfamily, possesses the function of forming complexes together with various small lipophilic molecules. In this study, we chose telmisartan as a model drug due to its pH dependent poor water solubility, and developed and characterized a novel solubilized formulation of telmisartan using a complex formulation with L PGDS. The solid state of the complex formulation was prepared using a spray drying process. The spray-dried formulation of telmisartan/L-PGDS powder showed a typical spray-dried particle without any change in the secondary and tertiary structures of L-PGDS. Furthermore, the complex formulation showed a high rate and level of drug release in pH 1.2, 5.0, and 6.8 solutions in comparison with the active pharmaceutical ingredient (API) and commercial product. To validate the potential for oral administration of the telmisartan/L-PGDS complex in vivo, the pharmacokinetic and pharmacodynamic profiles were assessed in spontaneous hypertensive rats. An animal study revealed that the complex formulation led to a significant improvement of AUC and Cmax as compared with API, and the prolonged pharmacologic effect on blood pressure reduction was comparable with the commercial product. These results, taken together, demonstrate that this novel approach is feasible for the solubilized solid oral formulation and it can be applied to poorly water-soluble drugs to enhance oral bioavailability. PMID- 25906911 TI - Bone block procedures in posterior shoulder instability. AB - PURPOSE: Posterior shoulder dislocation is often associated with bone defects. Surgical treatment is often necessary to address these lesions. The aim of the present systematic review was to analyse the available literature concerning bone block procedures in the treatment of bone deficiencies following posterior dislocation. In addition, the methodology of the articles has been evaluated through the Coleman methodology score. METHODS: A systematic review of the literature was performed using the keywords "posterior shoulder instability", "posterior shoulder dislocation", "bone loss", "bone defect", "bone block", and "bone graft" with no limit regarding the year of publication. All English language articles were evaluated using the Coleman methodology score. RESULTS: Fifty-four articles were identified, and 13 articles met inclusion criteria. The initial cohort included 208 shoulders, and 182 were reviewed at an average follow up of 72.7 months (+/-55.2). The average Coleman score was 57.2 (+/-8.0). The most lacking domains were the size of study population, the type of study, and the procedure for assessing outcomes. All the articles showed an increase in the outcome scores. Radiographic evaluation revealed degenerative changes such as osteoarthritis and graft lysis in most of the series. CONCLUSIONS: This review confirms the lack of studies with good methodological quality. However, bone grafting is a reliable option since significant improvement in all scores is reported. Although a low incidence of recurrence is generally described, there are concerns that the results may deteriorate over time as evidenced by graft lysis and glenohumeral osteoarthritis in up to one-third of patients. LEVEL OF EVIDENCE: Systematic review, Level IV. PMID- 25906912 TI - Anthropometric measurements of tibial plateau and correlation with the current tibial implants. AB - PURPOSE: The aim of the study was to make an anthropometric analysis at the resected surfaces of the proximal tibia in the Turkish population and to compare the data with the dimensions of tibial components in current use. We hypothesized that tibial components currently available on the market do not fulfil the requirements of this population and a new tibial component design may be required, especially for female patients with small stature. METHODS: Anthropometric data from the proximal tibia of 226 knees in 226 Turkish subjects were measured using magnetic resonance imaging. We measured the mediolateral, middle anteroposterior, medial and lateral anteroposterior dimensions and the aspect ratio of the resected proximal tibial surface. All morphological data were compared with the dimensions of five contemporary tibial implants, including asymmetric and symmetric design types. RESULTS: The dimensions of the tibial plateau of Turkish knees demonstrated significant differences according to gender (P < 0.05). Among the different tibial implants reviewed, neither asymmetric nor symmetric designs exhibited a perfect conformity to proximal tibial morphology in size and shape. The vast majority of tibial implants involved in this study tend to overhang anteroposteriorly, and a statistically significant number of women (21 %, P < 0.05) had tibial anteroposterior diameters smaller than the smallest available tibial component. CONCLUSION: Tibial components designed according to anthropometric measurements of Western populations do not perfectly meet the requirements of Turkish population. These data could provide the basis for designing the optimal and smaller tibial component for this population, especially for women, is required for best fit. LEVEL OF EVIDENCE: II. PMID- 25906913 TI - Lateral tibial plateau autograft in revision surgery for failed medial unicompartmental knee arthroplasty. AB - PURPOSE: Revision surgery for failed unicompartmental knee arthroplasty (UKA) with bone loss is challenging. Several options are available including cement augmentation, metal augmentation, and bone grafting. The aim of the present study was to describe a surgical technique for lateral tibial plateau autografting and report mid-term outcomes. METHODS: Eleven consecutive patients (median age 69.5 years) affected by posteromedial tibial plateau collapse after medial UKA were enrolled in the present study. The delay between UKA and revision surgery was 21 months (range 15-36 months). All patients were revised with a cemented posterior stabilized implant, with a tibial stem. Medial tibial plateau bone loss was treated with an autologous lateral tibial plateau bone graft secured with two absorbable screws. All patients were evaluated with the Oxford Knee Score (OKS), visual analogue scale for pain (VAS), and complete radiographic evaluation. RESULTS: At a median follow-up of 60 months (range 36-84 months), the OKS improved from 21.5 (range 16-26) to 34.5 (range 30-40) (p < 0.01) and the median VAS score improved from 8.0 (range 5-9) to 5.5 (range 3-7) (p < 0.01). No intraoperative complications were recorded. Partial reabsorption of the graft was observed in two cases at final follow-up. CONCLUSION: Lateral tibial plateau bone autograft is an alternative to metal wedge or cement augments in the treatment of medial plateau collapse after UKA. Primary fixation of the tibial plateau autograft can be achieved with absorbable screws and a tibial-stemmed implant. Further comparative studies with a larger series may be helpful to draw definitive conclusions. LEVEL OF EVIDENCE: Case series, Level IV. PMID- 25906914 TI - Circadian actigraphic rest-activity rhythms following surgery for endometrial cancer: A prospective, longitudinal study. AB - OBJECTIVE: To investigate (1) circadian rest-activity rhythm disturbances among endometrial cancer patients as they recover from surgery in comparison to a historical reference group of women with no cancer history and (2) health- and treatment-related predictors of dysregulated rest-activity rhythms in endometrial cancer patients. METHODS: 60 endometrial cancer patients participated in a prospective, longitudinal study with actigraphic assessment at 1week, 1month, and 4months post-surgery. 60 women without cancer from an epidemiological sample completed one actigraphic assessment, acting as a reference group. RESULTS: On average, results revealed initial significant rest-activity dysregulation at 1week and 1month post-surgery for the endometrial cancer group and then significant recovery in rest-activity patterns at 4months post-surgery. Similarly, the cancer group had significantly more impaired rhythms than the reference group at 1week post-surgery, but demonstrated comparable rhythms by 4months post-surgery. Among the health- and treatment-related variables examined, obesity and receipt of more invasive surgery were found to predict more impaired rhythms at all time points. CONCLUSION(S): The current study highlights significant disturbances in rest-activity patterns for endometrial cancer patients initially during surgical recovery followed by improvement in these patterns by 4months post-surgery; however, obese patients and those having more invasive surgery demonstrated more impaired rest-activity patterns throughout the 4-month recovery period. Further research is warranted to understand how more impaired rest-activity patterns relate to health and quality of life outcomes. PMID- 25906915 TI - Molecular subtypification of human papillomavirus in male adult individuals with recurrent respiratory papillomatosis. AB - OBJECTIVE: This study aimed to identify the isotype of human papillomavirus (HPV) in fresh tissue samples of 35 male adults with adult recurrent adult respiratory papillomatosis which may be important to define the precise etiology of the disease, and determine the therapeutic and prophylactic measures. METHODS: A total of 35 adult male patients diagnosed with active RRP who have been treated for several years were included in the study. DNA of patients was extracted from fresh biological samples and analyzed by PCR and a Linear Array(r) HPV Genotyping system. RESULTS: Most cases (95%) corresponded to adult-onset of RRP. A questionnaire was applied to obtain demographic and clinical data. Using a PCR based detection system all patients showed the presence of HPV; 80% were positive for HPV-6, 8% for HPV-11 and one for HPV-16. CONCLUSION: Most patients presented HPV-6 and consequently it was not feasible to correlate clinical and demographic characteristics with viral type. Besides, co-infections were not evident. This knowledge may be relevant to delineate therapeutic and preventive measures. PMID- 25906918 TI - External assessment of the Early Mortality Risk Score in patients with adenocarcinoma undergoing pancreaticoduodenectomy. AB - BACKGROUND: Pancreaticoduodenectomies (PD) still have a substantial mortality rate. Recently, different scores have been published to predict the mortality risk pre-operatively after PD. This retrospective study was designed to perform an external assessment of an Early Mortality Risk Score (EMRS). METHODS: From 2000 to 2012, all PD cases performed at our institution were documented. Only patients treated for pancreatic head adenocarcinomas were included. Survival time and EMRS (based on age, tumour size, tumour differentiation and comorbidities) were calculated for every patient. Relative risks (RR) of early death 9 and 12 months after PD were then calculated. RESULTS: Of 270 PD for various aetiologies, 120 PD for adenocarcinomas were included. The median follow-up was 37 months, and the overall median survival was 19 months. EMRS of 4 showed a mortality RR of 5.1 at 9 months (P = 0.048) and of 4.5 at 12 months (P = 0.020). CONCLUSIONS: EMRS of 4 is a predictor of tumour-related mortality at 9 and 12 months after PD for adenocarcinoma. The EMRS was externally assessed in our patient cohort and can be implemented in clinical practice. Clinical implications of this score still need to be studied. PMID- 25906919 TI - Selective Root Retreatment: A Novel Approach. AB - Root canal retreatment is traditionally considered an "all or none" treatment approach. It is typically recommended that all restorative and obturation materials be removed from all roots regardless of the presence or absence of periapical pathosis. In contrast, surgical endodontics is not viewed as an "all or none" treatment approach. Traditionally, only the diseased root(s) is addressed via root-end resection and root-end filling. The use of cone-beam computed tomographic imaging allows for a more accurate evaluation of the periapical status of individual roots associated with multirooted teeth. This information has introduced a novel and conservative treatment alternative for previously endodontically treated teeth with multiple roots presenting with post treatment disease. This new approach is termed selective root retreatment. Advanced imaging allows the clinician to make predictable treatment decisions with respect to the presence or absence of periapical pathosis of individual roots as opposed to making assumptions about the tooth as a whole. Selective root retreatment combines the approach of nonsurgical retreatment with the selectivity of surgical root resection. In this manner, retreatment could be limited to a single root or roots clearly showing periapical pathosis while leaving the root(s) with no visible or perceived pathosis untouched. PMID- 25906920 TI - Comparison of Bacterial Community Composition of Primary and Persistent Endodontic Infections Using Pyrosequencing. AB - INTRODUCTION: Elucidating the microbial ecology of endodontic infections (EIs) is a necessary step in developing effective intracanal antimicrobials. The aim of the present study was to investigate the bacterial composition of symptomatic and asymptomatic primary and persistent infections in a Greek population using high throughput sequencing methods. METHODS: 16S amplicon pyrosequencing of 48 root canal bacterial samples was conducted, and sequencing data were analyzed using an oral microbiome-specific and a generic (Greengenes) database. Bacterial abundance and diversity were examined by EI type (primary or persistent), and statistical analysis was performed by using non-parametric and parametric tests accounting for clustered data. RESULTS: Bacteroidetes was the most abundant phylum in both infection groups. Significant, albeit weak associations of bacterial diversity were found, as measured by UniFrac distances with infection type (analyses of similarity, R = 0.087, P = .005) and symptoms (analyses of similarity, R = 0.055, P = .047). Persistent infections were significantly enriched for Proteobacteria and Tenericutes compared with primary ones; at the genus level, significant differences were noted for 14 taxa, including increased enrichment of persistent infections for Lactobacillus, Streptococcus, and Sphingomonas. More but less abundant phyla were identified using the Greengenes database; among those, Cyanobacteria (0.018%) and Acidobacteria (0.007%) were significantly enriched among persistent infections. Persistent infections showed higher phylogenetic diversity (PD) (asymptomatic: PD = 9.2, standard error [SE] = 1.3; symptomatic: PD = 8.2, SE = 0.7) compared with primary infections (asymptomatic: PD = 5.9, SE = 0.8; symptomatic: PD = 7.4, SE = 1.0). CONCLUSIONS: The present study revealed a high bacterial diversity of EI and suggests that persistent infections may have more diverse bacterial communities than primary infections. PMID- 25906921 TI - The Effect of Surfactants on the Stability of Sodium Hypochlorite Preparations. AB - INTRODUCTION: The purpose of the present study was to assess the effect of the presence of surfactants over time on free available chlorine (FAC), pH, viscosity, and surface tension of sodium hypochlorite (NaOCl) preparations. METHODS: Three preparations containing surfactant (Chlor-XTRA 6% [Vista Dental Products, Racine, WI], Hypocelle 4% Forte [Dentalife, Ringwood, Australia], and White King Lemon [Pental, Shepparton, Australia]) and 2 without, Vista 6% (Vista Dental Products) and Hypocelle 4% Forte plain (Dentalife), were tested. The solutions were stored in closed plastic bottles and protected from light at a constant 20 degrees C for 213 days. FAC was measured using iodometric titration, whereas pH, surface tension, and viscosity were measured using a pH meter, pendant drop method, and rheometer, respectively. The influence of the type of solution and the presence of surfactant over time on FAC was compared with the aid of linear regression models. Two-way analysis of variance was used to evaluate the effect of passage of time and the type of solution on surface tension and the effect of the presence or absence of surfactant on the solutions. The Bonferroni test was used for multiple comparisons (post hoc) and to evaluate the effect of the presence of surfactant between solutions from the same manufacturer (alpha = 0.05). RESULTS: Degradation of available chlorine was faster in the presence of surfactant when comparing solutions from the same manufacturer [Chlor-XTRA versus Vista (P < .001) and for Hypocelle 4% Forte versus Hypocelle 4% Forte plain (P = .024)]. There was a gradual decline in pH over time, but viscosity remained stable. The surface tension of all products decreased over time (P = .025, F). CONCLUSIONS: The presence of surfactant hastened the degradation of FAC in all affected NaOCl solutions. The observed changes in pH and viscosity were minor, whereas their surface tension showed a significant decrease. PMID- 25906923 TI - A Survey of Zoonotic Pathogens Carried by Non-Indigenous Rodents at the Interface of the Wet Tropics of North Queensland, Australia. AB - In 1964, Brucella was isolated from rodents trapped in Wooroonooran National Park (WNP), in Northern Queensland, Australia. Genotyping of bacterial isolates in 2008 determined that they were a novel Brucella species. This study attempted to reisolate this species of Brucella from rodents living in the boundary area adjacent to WNP and to establish which endo- and ecto-parasites and bacterial agents were being carried by non-indigenous rodents at this interface. Seventy non-indigenous rodents were trapped [Mus musculus (52), Rattus rattus (17) and Rattus norvegicus (1)], euthanized and sampled on four properties adjacent to the WNP in July 2012. Organ pools were screened by culture for Salmonella, Leptospira and Brucella species, real-time PCR for Coxiella burnetii and conventional PCR for Leptospira. Collected ecto- and endo-parasites were identified using morphological criteria. The percentage of rodents carrying pathogens were Leptospira (40%), Salmonella choleraesuis ssp. arizonae (14.29%), ectoparasites (21.42%) and endoparasites (87%). Brucella and C. burnetii were not identified, and it was concluded that their prevalences were below 12%. Two rodent-specific helminthic species, namely Syphacia obvelata (2.86%) and Nippostrongylus brasiliensis (85.71%), were identified. The most prevalent ectoparasites belonged to Laelaps spp. (41.17%) followed by Polyplax spp. (23.53%), Hoplopleura spp. (17.65%), Ixodes holocyclus (17.64%) and Stephanocircus harrisoni (5.88%), respectively. These ectoparasites, except S. harrisoni, are known to transmit zoonotic pathogens such as Rickettsia spp. from rat to rat and could be transmitted to humans by other arthropods that bite humans. The high prevalence of pathogenic Leptospira species is of significant public health concern. This is the first known study of zoonotic agents carried by non-indigenous rodents living in the Australian wet-tropical forest interface. PMID- 25906922 TI - Distribution, source, and ecological risk assessment of polycyclic aromatic hydrocarbons (PAHs) in surface sediments from the Hun River, northeast China. AB - In this study, the occurrence and distribution of 16 polycyclic aromatic hydrocarbons (PAHs), listed by the United States Environmental Protection Agency (US EPA), were investigated in surface sediment samples from the Hun River, northeast China. The data was then used to assess the potential ecological risk. The results indicated 15 PAHs were detected in these sediments, and the total concentrations of the 15 PAHs (not including naphthalene) ranged from 82.96 to 39,292.95 ng g(-1) dry weight (dw), with an average value of 3705.54 ng g(-1) dw, and 4-ring PAHs were the dominant compounds at most sites. The diagnostic parameters such as anthracene/(anthracene + phenanthrene), fluoranthene/(fluoranthene + pyrene), and indeno[1,2,3-cd]pyrene/(indeno[1,2,3 cd]pyrene + benzo[g,h,i]perylene) showed that they had been emitted from a number of different sources, especially the pyrolytic emissions. The results of the ecological risk assessment, which compared the PAH concentrations with the effect range low (ERL) and the effect range median (ERM) values, indicated that several individual PAH concentrations at four sites in the downstream section of the Hun River were higher than the ERM, suggesting that there was a potential ecological risk in these areas. PMID- 25906924 TI - Immediate implant placement with simultaneous guided bone regeneration in the esthetic zone: 10-year clinical and radiographic outcomes. AB - AIM: To associate the dimension of the facial bone wall with clinical, radiological, and patient-centered outcomes at least 10 years after immediate implant placement with simultaneous guided bone regeneration in a retrospective study. MATERIAL AND METHODS: Primary endpoint was the distance from the implant shoulder (IS) to the first bone-to-implant contact (IS-BIC10y ). Secondary endpoints included the facial bone thickness (BT10y ) 2, 4, and 6 mm apical to the IS, and the implant position. At baseline, the horizontal defect width (HDWBL ) from the implant surface to the alveolar wall was recorded. At recall, distance from the IS to the mucosal margin (IS-MM10y ), degree of soft tissue coverage of the mesial and distal aspects of the implants (PISm10y , PISd10y ; Papilla Index), pocket probing depth (PPD10y ), and patient-centered outcomes were determined. Width of the keratinized mucosa (KM), Full-Mouth Plaque and Bleeding Score (FMPS, FMBS) were available for both time points. RESULTS: Of the 20 patients who underwent immediate implant placement with simultaneous guided bone regeneration and transmucosal healing, nine males and eight females with a median age of 62 years (42 min, 84 max) were followed up for a median period of 10.5 y (min 10.1 max 11.5). The 10-year implant survival rate was 100%. Multivariate regression analysis revealed a correlation of the IS-BIC10y , controlled for age and gender, with four parameters: HDWBL (P = 0.03), KMBL -10 (P = 0.02), BT10 4 mm (P = 0.01), and BT10 6 mm (P = 0.01). CONCLUSION: Within the conditions of the present study, the horizontal defect width was the main indicator for the vertical dimension of the facial bone. The facial bone dimension was further associated with a reduction in the width of the keratinized mucosa and the dimension of the buccal bone. PMID- 25906925 TI - Bidirectionality in Self-Regulation and Expressive Vocabulary: Comparisons Between Monolingual and Dual Language Learners in Preschool. AB - Significant differences in language and self-regulation skills exist among children when they enter formal schooling. Contributing to these language differences is a growing population of dual language learners (DLLs) in the United States. Given evidence linking self-regulatory processes and language development, this study explored bidirectional associations between English expressive vocabulary and self-regulation skills for monolingual English and DLL preschool children (N = 250) from mixed-income families in Los Angeles. Across three time points, findings provide initial support for bidirectionality between these developing skills for both monolinguals and DLLs. Results provide strong empirical support for vocabulary serving as a leading indicator of self regulation skills in preschool. Findings also suggest that early self-regulation skills play a particularly important role for vocabulary development. PMID- 25906926 TI - Editorial: Transformational experiences a key to improving global health: the role of the Peace Corps. PMID- 25906927 TI - Genetics and molecular biology of brain calcification. AB - Brain calcification is a common neuroimaging finding in patients with neurological, metabolic, or developmental disorders, mitochondrial diseases, infectious diseases, traumatic or toxic history, as well as in otherwise normal older people. Patients with brain calcification may exhibit movement disorders, seizures, cognitive impairment, and a variety of other neurologic and psychiatric symptoms. Brain calcification may also present as a single, isolated neuroimaging finding. When no specific cause is evident, a genetic etiology should be considered. The aim of the review is to highlight clinical disorders associated with brain calcification and provide summary of current knowledge of diagnosis, genetics, and pathogenesis of brain calcification. PMID- 25906928 TI - Assessment of morphology of patent foramen ovale with transesophageal echocardiography in symptomatic and asymptomatic patients. AB - BACKGROUND: The frequency of patent foramen ovale (PFO) is greater in patients who have had a stroke and transient ischemic attack (TIA) than that in the general population. However, it is not well defined, which PFO would cause stroke or TIA. In this trial, we aimed to evaluate whether there was a difference regarding morphologic features of PFO in patients who were symptomatic (cryptogenic stroke or history of TIA) or asymptomatic according to the neurologic findings. METHODS: Symptomatic patients with PFO and cryptogenic stroke or TIA and asymptomatic patients with PFO who were symptomatic in terms of neurologic findings as well as patients without any neurologic symptoms in whom PFO was diagnosed incidentally by transesophageal echocardiography were enrolled to this retrospective study on the condition that they were aged younger than 55 years. Not only the clinical and demographic characteristics of 2 groups were compared but also their morphological features were assessed. The morphologic features of PFO that were assessed included the length and height of tunnel, atrial septal excursion distance, thickness of septum primum, and thickness of septum secundum. RESULTS: One hundred fifty-six patients, 64 of whom were symptomatic, were enrolled to this study. The height of PFO (median, 3.0 [interquartile range, 2.0-3.8]mm versus 2.0 [2.0-2.0]mm, P < .001), thickness of septum secundum (5.0 [5.0-7.0] versus 3.0 [2.0-3.0], P < .001), and septal excursion distance (7.0 [6.0-10.5] versus 4.0 [4.0-5.0], P < .001) were found to be greater in the symptomatic group than those in the asymptomatic group. There was no significant difference regarding the length of tunnel and thickness of septum primum. The ratio of length to height of PFO tunnel was less in the symptomatic group (3.0 [3.0-3.23] versus 5.0 [4.0-6.25], P < .001). CONCLUSIONS: Our findings appear to indicate that a higher PFO tunnel, relatively greater interatrial septal mobility, thicker septum pellucidum, and the presence of an atrial septal aneurysm may help identifying the subjects at the age of or younger than 55 years with PFO who are at greater risk for cryptogenic stroke or TIA. PMID- 25906929 TI - Association of stroke clinical outcomes with coexistence of hyperglycemia and biomarkers of inflammation. AB - BACKGROUND: To investigate the association of short-term clinical outcomes with coexistence of hyperglycemia and elevated biomarkers of inflammation among acute ischemic stroke (AIS) patients. METHODS: We performed a retrospective study of 2675 patients diagnosed with AIS from January 2006 to December 2008. The study outcomes were defined as neurologic deficiency (National Institutes of Health Stroke Scale score >=5) at discharge or death during hospitalization. RESULTS: Compared with normoglycemia and without any elevated biomarkers, patients with hyperglycemia, elevated white blood cell (WBC) count, elevated neutrophils ratio (NEUR), and elevated erythrocyte sedimentation rate (ESR) had higher rates of study outcomes (all P < .05). Furthermore, patients with coexistence of hyperglycemia with any of elevated WBC count, NEUR, or ESR were more likely to have study outcomes (all P < .05). Compared with subjects with normoglycaemia and without any elevated biomarker, multivariate adjusted odds ratios (95% confidence interval) of study outcomes associated with hyperglycemia, elevated WBC count, elevated NEUR, elevated ESR, coexistences of hyperglycemia with elevated WBC count, elevated NEUR, and elevated ESR were 1.492 (1.139-1.955), 1.404 (1.048 1.881), 1.897 (1.411-2.551), 2.184 (1.339-3.564), 1.963 (1.337-2.883), 2.544(1.715- 3.775), and 2.687 (1.347-5.363), respectively. CONCLUSIONS: This study indicated that hyperglycemia and elevated biomarkers of inflammation were associated with short-term clinical outcomes, and individuals with coexistence of hyperglycemia and elevated biomarkers of inflammation had higher risk of poor clinical outcomes among AIS patients. PMID- 25906930 TI - Cognitive correlates of cerebral vasoreactivity on transcranial Doppler in older adults. AB - BACKGROUND: This study was performed to explore the possible contributions of cerebral hemodynamic changes to the cognitive impairment in patients with Alzheimer's disease (AD). METHODS: A total of 194 participants were included: 52 controls, 75 patients with mild cognitive impairment (MCI), and 67 patients with AD. Demographic characteristics, vascular risks, mini-mental state examination (MMSE), and clinical dementia rating (CDR) were assessed, and magnetic resonance imaging of the brain was performed to evaluate white matter hyperintensities (WMHs). Using transcranial Doppler (TCD) ultrasonography, cerebrovascular reactivity (CVR) was evaluated with a breath-holding test, in addition to the mean blood flow velocity (MFV), pulsatility index (PI), and resistance index (RI) of the middle cerebral artery. RESULTS: After adjusting for covariates such as age, education, WMH severity, and vascular risks, TCD parameters such as MFV, PI, and RI did not differ between the 3 groups. However, CVR was significantly reduced in the AD group (45.33 +/- 11.49%), compared with the other groups (56.36 +/- 14.65%, controls; 53.84 +/- 15.47%, MCI group; P < .001). Multiple regression analyses also showed that CVR was associated with MMSE scores. CVR differed according to the CDR scores (P < .001). CONCLUSIONS: Our finding may be suggestive of an underlying microangiopathic mechanism in AD patients. Furthermore, there was an association between the impaired function of cerebral microvessels and cognitive impairment. Further research is needed to fully establish whether altered cerebral hemodynamics may be considered an independent factor in predicting cognitive decline or an effect of pathologic processes involved in AD. PMID- 25906931 TI - Susceptibility Vessel Sign for Intra-arterial Thrombus in Acute Posterior Cerebral Artery Infarction. AB - BACKGROUND: Susceptibility vessel sign (SVS) on susceptibility-weighted imaging (SWI) has a high sensitivity and specificity to detect the intra-arterial thrombus in anterior circulation stroke. However, SVS has not been evaluated in posterior circulation stroke. METHODS: We reviewed the data from patients with acute posterior cerebral artery (PCA) infarction within 24 hours from stroke onset. To elucidate the usefulness of SVS for the detection of intraluminal thrombus in acute PCA infarction, the frequency and location of SVS were compared with those of occlusion on magnetic resonance angiography (MRA) and hyperdense PCA sign on computed tomography (CT). RESULTS: Twenty-five patients with acute PCA infarction were enrolled in the study. The SVS was found in 92% (23 of 25). MRA showed occlusions in 64% (16 of 25). The SVS was identified in 100% (16 of 16) of patients with occlusion on MRA. Patients without occlusion on MRA also showed the SVS in 78% (7 of 9; P = .0233). The positive SVS without occlusion on MRA was mainly identified in patients with occlusion of distal branches of PCA; P3 segment in 4 and P4 segment in 3. However, the hyperdense PCA sign on CT showed in only 8% (2 of 25) of all patients; its sensitivity was significantly lower than those of the SVS on SWI (P < .001). CONCLUSIONS: SWI is more sensitive than MRA for the detection of intraluminal thrombus, especially peripheral one, in patients with acute ischemic stroke of the PCA territory. In addition, irrespective of thrombus location, SWI is significantly superior to CT in detecting thrombus in acute PCA infarction. PMID- 25906932 TI - Beating the clock: time delays to thrombolytic therapy with advanced imaging and impact of optimized workflow. AB - BACKGROUND: The effectiveness of intravenous tissue plasminogen activator in the management of acute ischemic strokes diminishes significantly with time. Advanced computed tomography (CT) imaging can be helpful to identify candidates for neurointerventional procedures. We have successfully used a 320-slice Toshiba volume CT scanner since mid-2008. Other centers have forgone advanced imaging because of concerns of time delay. This study is to assess the time delay while using this scanner compared with our 64-slice scanner. METHODS: Treatment times of patients scanned with advanced imaging (CT head, dynamic CT angiography, and whole brain perfusion-group A) and patients scanned in a 64-slice scanner (CT head and traditional CT angiogram-group B) were compared. Two groups of stroke patients from November-March 2009-2010 (group 1) and 2012-2013 (group 2) were audited to assess temporal improvement. Multiple timing variables were analyzed. RESULTS: One hundred fifty-three cases from 2009/10 and 192 cases from 2012/13 were analyzed. The median door-to-needle time (DNT) for group 1A and group 2A was 57 minutes and 47 minutes, respectively. The median DNT for group 1B and group 2B was 54 minutes and 49 minutes, respectively. Decrease in the overall DNT with group A can be attributed to the "streamlining" of the stroke code process. There was no difference in the DNT for patients who presented during working hours versus those who presented during nonworking hours. CONCLUSIONS: With adequate experience and training, advanced stroke imaging with whole brain perfusion/dynamic CT angiography can be performed with treatment times that are comparable with traditional CT scanning. PMID- 25906934 TI - Bilateral central retinal artery occlusion in a patient with systemic lupus erythematosus. AB - Systemic lupus erythematosus (SLE) is associated with a wide range of ocular manifestations. We report a case of a 20-year-old woman with newly diagnosed SLE, who awoke with bilateral simultaneous central retinal artery occlusion (CRAO). Her antiphospholipid antibody panel was normal. Vision did not recover after treatment with steroids and anticoagulation. This case suggests that such patients may be in hypercoagulable status even with negative antiphospholipid antibodies. Severe ocular complication such as CRAO may occur during the early disease process. It is important to recognize this potential risk factor and treat vigorously and early. PMID- 25906933 TI - Incidental asymptomatic intracerebral hemorrhages and risk of subsequent cardiovascular events and cognitive decline in elderly persons. AB - BACKGROUND: The long-term prognostic significance of incidental asymptomatic intracerebral hemorrhages (aICHs) detected on brain magnetic resonance imaging (MRI) is unknown. METHODS: We analyzed clinical and baseline MRI data from the cohort of 5888 study participants aged 65 years and older recruited in the Cardiovascular Health Study from 4 US communities. We identified participants who had aICHs on MRI and selected 3 age- and gender-matched controls without aICHs. We compared the rates of cardiovascular events using logistic regression analysis including incident myocardial infarction, stroke, and death between those with and without aICHs. RESULTS: A total of 23 participants had aICHs classified as acute (n = 3), subacute (n = 4), and chronic (n = 16). During 14 years of follow up, the risk of incident stroke (relative risk [RR], .6; 95% confidence interval [CI], .2-2.0), myocardial infarction (RR, .3; 95% CI, .06-1.4), and death (RR, .6; 95% CI, .2-1.7) was not different between participants with aICHs compared with controls (n = 69). There was no difference between the 2 groups with regard to time to ischemic stroke or time to death by Kaplan-Meier analysis. CONCLUSIONS: The risks of stroke, myocardial infarction, and death were similar between persons with aICHs detected on MRI compared with age- and gender-matched controls. PMID- 25906935 TI - "Cardioembolic profile" in patients with ischemic stroke: data from the analysis of 1037 cases. AB - BACKGROUND: Basing on easily available clinical and instrumental data, we aimed to define an "atrial fibrillation profile" able to discriminate cases of stroke due to atrial fibrillation from cases due to atherothrombosis of large vessels or small-vessel disease. METHODS: A total of 1037 consecutive patients with ischemic stroke were enrolled. Cases with undetermined stroke, rare causes, and cardioembolic sources of emboli other than atrial fibrillation were excluded from further analysis. Thus, 653 patients were evaluated, dividing them into 2 groups for comparison (164 with stroke due to atrial fibrillation and 489 with atherothrombotic/lacunar stroke). Clinical, echocardiography, and neuroradiologic data were considered to characterize such groups. RESULTS: Atrial fibrillation and atherothrombotic-lacunar group presented a differential phenotypic profile. Binary multiple logistic regression identified age older than 75 years, female sex, left atrial dilation, cortical-subcortical cerebral index infarct, ischemic lesions in multiple vascular grounds, and spontaneous hemorrhagic transformation of brain infarction as significant predictors of cardioembolic stroke due to atrial fibrillation. CONCLUSIONS: A simple profile, based on commonly available data, seems suitable to characterize patients with stroke due to atrial fibrillation. If further validated, it may be useful to identify patients with undetermined stroke (or other well-defined causes of stroke) at high risk of being affected by undetected subclinical paroxysmal atrial fibrillation, prompting further diagnostic work-up and with potential therapeutic implication. PMID- 25906936 TI - Telephone and Teleradiology-Guided Thrombolysis Can Achieve Similar Outcome as Thrombolysis by Neurologist On-site. AB - BACKGROUND: Because of the limitation of on-site neurology workforce, telestroke was implemented to overcome this barrier. We explored the efficacy and safety of intravenous (IV) stroke thrombolysis service by telestroke when neurologist was not available on-site. METHODS: From January 2009 to December 2012, we compared patients treated with IV stroke thrombolysis by telestroke in the form of telephone consultation with teleradiology, to patients treated after in-person assessment by the same team of neurologists in a regional hospital. Door-to needle time, symptomatic intracranial hemorrhage, and functional outcome at 3 months were prospectively collected and compared between the groups. RESULTS: In all, 152 patients were treated with IV thrombolysis; 102 patients were treated with neurologist on-site; whereas 50 patients were treated by internists with telestroke. Fifty-two percent of the telemedical group achieved excellent outcome compared to 43% of the neurologist on-site group (P = .30). Symptomatic intracranial hemorrhage rate (4.0% versus 4.9%, P = 1.0) and mortality (8.3% versus 11.9%, P = .49) were comparable. Using the multiple logistic regression analysis, age, baseline stroke severity, and extent of early ischemic change on brain computed tomography scan, are independent predictors for excellent outcome, whereas the presence of neurologist on-site is not correlated with the outcome. CONCLUSIONS: Patients treated without neurologist on-site achieved similar outcome. Telephone consultation and teleradiology-guided IV stroke thrombolysis, with the support of on-site internist appeared safe and efficacious. PMID- 25906937 TI - Hospital differences in motor activity early after stroke: a comparison of 11 Norwegian stroke units. AB - BACKGROUND: Activity levels in patients early after stroke vary across the world. The primary aim of this study was to assess the variation in motor activity in patients admitted to multiple Norwegian stroke units and to identify factors which explained the variation between hospitals. METHODS: Eligible patients were those less than 14 days after stroke, more than 18 years, not receiving palliative care. Activity levels, people present, and location were recorded by the use of a standard method of observation between 8 am and 5 pm. Hospital policy on serving meals in communal areas was also registered. Mixed general binomial model was used to analyze, which factors explained variation in activity levels between hospitals, after adjusting for age and stroke severity. RESULTS: A total of 393 patients from 11 stroke units were included. The patients spent 44.1% of the day in bed, 43.2% sitting out of bed, and 8.3% in higher motor activities (4.4% were not observed). Increased physical activity was associated with spending more time with a physical therapist, odds ratio (OR), 1.05 (95% confidence interval [CI], 1.03-1.08, P < .001) and admitted to a hospital serving the meals in communal areas, OR, 1.46 (95% CI, 1.09-1.95, P = .011). CONCLUSIONS: Despite variation between the hospitals, patients admitted to Norwegian stroke units spend most of the day out of bed. Time spent with a physical therapist and hospitals having a policy of serving meals in communal areas explained most of the variation in activity between hospitals. PMID- 25906938 TI - Defining mild stroke: outcomes analysis of treated and untreated mild stroke patients. AB - BACKGROUND: Mild deficit is a relative contraindication to administration of intravenous recombinant tissue plasminogen activator (IV rtPA) for acute ischemic stroke. However, what constitutes "mild" deficit is vague. Prior studies showed patients with mild strokes have substantial disability rates at hospital discharge and at 90 days. We investigated whether the application of a new definition altered the rates of disability overall and assessed the effects of thrombolysis. METHODS: This analysis included all adult acute ischemic stroke patients from a prospective registry of consecutive patients (University of California San Diego Specialized Programs of Translational Research in Acute Stroke (SPOTRIAS) database, 2003-2014) with 90-day modified Rankin Scale (mRS) score available who were defined as "mild" using either: National Institutes of Health Stroke Scale (NIHSS) 0-5 or a "Re-examining Acute Eligibility for Thrombolysis" (TREAT) Task Force definition (NIHSS 0-5 and nondisabling based on prespecified syndromes). Dichotomized 90-day mRS were compared between treated and untreated patients using the 2 definitions. RESULTS: Of 802 ischemic stroke patients with mRS scores available, 184 had baseline mRS (0) and met TREAT criteria; 45 (24.5%) were rtPA treated. Among the treated patients, 35.6% had 90 day mRS (2-6), versus 28.8% in the untreated group, a nonsignificant difference after adjusting for baseline NIHSS (P = .47). None of the 45 treated patients had symptomatic hemorrhage. Outcomes were similar using the simpler NIHSS 0-5 definition. CONCLUSIONS: About one third of mild stroke patients were not functionally independent at 90 days, irrespective of treatment or mild definition applied, calling into question the treatment efficacy of IV rtPA for mild strokes and what constitutes an appropriate definition of "mild." Randomized studies are necessary to determine rtPA treatment efficacy in mild stroke patients. PMID- 25906939 TI - Circulatory and Respiratory Parameters during Acute Endovascular Stroke Therapy in Conscious Sedation or General Anesthesia. AB - BACKGROUND: Whether patients suffering from acute ischemic stroke and undergoing endovascular recanalization should be treated under general anesthesia (GA) or conscious sedation (CS) is a matter of debate. According to retrospective studies, GA appears to be associated with a worse outcome than CS. The underlying mechanisms are unknown, but hypotension and hypocapnia during GA have been suggested. There are no prospective data on this question. METHODS: We prospectively analyzed consecutive patients who were treated with endovascular recanalization from 11, 2013 to 03, 2014 regarding blood pressure, end-tidal carbon dioxide (etCO2), cerebral oximetry (by near-infrared spectroscopy), ventilation parameters, response to commands, basic parameters (age, gender, percentage of posterior circulation stroke, National Institutes of Health Stroke Scale score [NIHSSS] on admission, NIHSSS at discharge, rate of successful recanalization [thrombolysis in cerebral infarction scale >2a], duration of intervention, symptom-to-recanalization time, and door-to-needle time), and medication used. RESULTS: Forty-four patients (29 under GA and 15 in CS) were included. Significant differences between the groups (GA versus CS) were found in the median dose of norepinephrine (.4 mg/hour versus .1 mg/hour, P = .003), mean systolic blood pressure (139.67 mm Hg versus 155.00 mm Hg, P = .003), mean duration of relative hypotension (systolic blood pressure <140 mm Hg; 42.75 versus 15 minutes, P = .004), and mean etCO2 values (37.29 mm Hg versus 27.33 mm Hg, P = .004). CONCLUSIONS: In this small prospective study, patients under CS required less vasopressor medication and had a higher mean blood pressure than those under GA, but they also showed signs of hyperventilation. The impact of these physiological differences on outcome needs to be studied in randomized trials. PMID- 25906940 TI - Pre-admission CHADS2, CHA2DS2-VASc, and R2CHADS2 Scores on Severity and Functional Outcome in Acute Ischemic Stroke with Atrial Fibrillation. AB - BACKGROUND: We examined the association between pre-admission risk scores and severity on admission and functional outcome in acute ischemic stroke with atrial fibrillation (AF). METHODS: Between September 2011 and April 2014, we retrospectively extracted consecutive ischemic stroke patients with AF whose pre admission modified Rankin Scale (mRS) score was 2 or less from our prospective database. Pre-admission CHADS2, CHA2DS2-VASc, and R2CHADS2 scores were calculated in each patient, and their association with the National Institutes of Health Stroke Scale (NIHSS) score on admission or unfavorable outcome (mRS >= 3 at 3 months from the onset) was assessed. RESULTS: A total of 344 patients (189 were men; age, 77.7 +/- 10.0 years) were included in the analysis. The median pre admission CHADS2, CHA2DS2-VASc, and R2CHADS2 scores were 2, 4, and 4, respectively. NIHSS score on admission was positively correlated with pre admission CHADS2 (rho = .116, P = .031), CHA2DS2-VASc (rho = .166, P = .020), and R2CHADS2 scores (rho = .106, P = .049). Receiver operating characteristic (ROC) curve analysis revealed that pre-admission CHADS2 score of 2 or more (sensitivity, 80%; specificity, 45%; area under the ROC curve [AUC], .654), CHA2DS2-VASc score of 3 or more (sensitivity, 86%; specificity, 44%; AUC, .683), and R2CHADS2 score of 4 or more (sensitivity, 61%; specificity, 62%; AUC, .657) were associated with unfavorable outcome. The pre-admission CHA2DS2-VASc score was better than the pre-admission CHADS2 score in estimating unfavorable outcome (P = .017). In multivariate analysis, cutoffs of these scores, female sex, higher NIHSS score, and internal carotid artery occlusion were associated with unfavorable outcome. CONCLUSIONS: Pre-admission CHADS2, CHA2DS2-VASc, and R2CHADS2 scores were associated with onset severity and functional outcome in acute ischemic stroke with AF. PMID- 25906941 TI - Evolution, safety and efficacy of targeted temperature management after pediatric cardiac arrest. AB - BACKGROUND: It is unknown whether targeted temperature management (TTM) improves survival after pediatric out-of-hospital cardiac arrest (OHCA). The aim of this study was to assess the evolution, safety and efficacy of TTM (32-34 degrees C) compared to standard temperature management (STM) (<38 degrees C). METHODS: Retrospective, single center cohort study. Patients aged >one day up to 16 years, admitted to a UK Paediatric Intensive Care Unit (PICU) after OHCA (January 2004 December 2010). Primary outcome was survival to hospital discharge; efficacy and safety outcomes included: application of TTM, physiological, hematological and biochemical side effects. RESULTS: Seventy-three patients were included. Thirty eight patients (52%) received TTM (32-34 degrees C). Prior to ILCOR guidance adoption in January 2007, TTM was used infrequently (4/25; 16%). Following adoption, TTM (32-34 degrees C) use increased significantly (34/48; 71% Chi(2); p < 0.0001). TTM (32-34 degrees C) and STM (<38 degrees C) groups were similar at baseline. TTM (32-34 degrees C) was associated with bradycardia and hypotension compared to STM (<38 degrees C). TTM (32-34 degrees C) reduced episodes of hyperthermia (>38 degrees C) in the 1st 24h; however, excessive hypothermia (<32 degrees C) and hyperthermia (>38 degrees C) occurred in both groups up to 72 h, and all patients (n = 11) experiencing temperature <32 degrees C died. The study was underpowered to determine a difference in hospital survival (34% (TTM (32-34 degrees C)) versus 23% (STM (<38 degrees C)); p = 0.284). However, the TTM (32-34 degrees C) group had a significantly longer PICU length of stay. CONCLUSIONS: TTM (32-34 degrees C) was feasible but associated with bradycardia, hypotension, and increased length of stay in PICU. Temperature <32 degrees C had a universally grave prognosis. Larger studies are required to assess effect on survival. PMID- 25906942 TI - A performance improvement-based resuscitation programme reduces arrest incidence and increases survival from in-hospital cardiac arrest. AB - BACKGROUND: Traditional resuscitation training models are inadequate to achieving and maintaining resuscitation competency. This analysis evaluates the effectiveness of a novel, performance improvement-based inpatient resuscitation programme. METHODS: This was a prospective, before-and-after study conducted in an urban, university-affiliated hospital system. All inpatient adult cardiac arrest victims without an active Do Not Attempt Resuscitation order from July 2005 to June 2012 were included. The advanced resuscitation training (ART) programme was implemented in Spring 2007 and included a unique treatment algorithm constructed around the capabilities of our providers and resuscitation equipment, a training programme with flexible format and content including early recognition concepts, and a comprehensive approach to performance improvement feeding directly back into training. Our inpatient resuscitation registry and electronic patient care record were used to quantify arrest rates and survival-to hospital discharge before and after ART programme implementation. Multiple logistic regression analysis was used to adjust for age, gender, location of arrest, initial rhythm, and time of day. RESULTS: A total of 556 cardiac arrest victims were included (182 pre- and 374 post-ART). Arrest incidence decreased from 2.7 to 1.2 per 1000 patient discharges in non-ICU inpatient units, with no change in ICU arrest rate. An increase in survival-to-hospital discharge from 21 to 45% (p < 0.01) was observed following ART programme implementation. Adjusted odds ratios for survival-to-discharge (OR 2.2, 95% CI 1.4-3.4) and good neurological outcomes (OR 3.0, 95% CI 1.7-5.3) reflected similar improvements. Arrest-related deaths decreased from 2.1 to 0.5 deaths per 1000 patient discharges in non-ICU areas and from 1.5 to 1.3 deaths per 1000 patient discharges in ICU areas, and overall hospital mortality decreased from 2.2% to 1.8%. CONCLUSIONS: Implementation of a novel, performance improvement-based inpatient resuscitation programme was associated with a decrease in the incidence of cardiac arrest and improved clinical outcomes. PMID- 25906944 TI - Precision of image-based registration for intraoperative navigation in the presence of metal artifacts: Application to corrective osteotomy surgery. AB - Navigation for corrective osteotomy surgery requires patient-to-image registration. When registration is based on intraoperative 3-D cone-beam CT (CBCT) imaging, metal landmarks may be used that deteriorate image quality. This study investigates whether metal artifacts influence the precision of image-to patient registration, either with or without intermediate user intervention during the registration procedure, in an application for corrective osteotomy of the distal radius. A series of 3-D CBCT scans is made of a cadaver arm with and without metal landmarks. Metal artifact reduction (MAR) based on inpainting techniques is used to improve 3-D CBCT images hampered by metal artifacts. This provides three sets of images (with metal, with MAR, and without metal), which enable investigating the differences in precision of intraoperative registration. Gray-level based point-to-image registration showed a better correlation coefficient if intraoperative images with MAR are used, indicating a better image similarity. The precision of registration without intermediate user intervention during the registration procedure, expressed as the residual angulation and displacement error after repetitive registration was very low and showed no improvement when MAR was used. By adding intermediate user intervention to the registration procedure however, precision was very high but was not affected by the presence of metal artifacts in the specific application. PMID- 25906943 TI - Effect of a pharmacologically induced decrease in core temperature in rats resuscitated from cardiac arrest. AB - AIM: Hypothermia is recommended by international guidelines for treatment of unconscious survivors of cardiac arrest to improve neurologic outcomes. However, temperature management is often underutilized because it may be difficult to implement. The present study evaluated the efficacy of pharmacologically induced hypothermia on survival and neurological outcome in rats resuscitated from cardiac arrest. METHODS: Cardiac arrest was induced for 10 min in 120 rats. Sixty one rats were resuscitated and randomized to normothermia, physical cooling or pharmacological hypothermia 5 min after resuscitation. Pharmacological hypothermia rats received a combination of ethanol, vasopressin and lidocaine (HBN-1). Physical hypothermia rats were cooled with intravenous iced saline and cooling pads. Rats in the pharmacological hypothermia group received HBN-1 at ambient temperature (20 degrees C). Normothermic rats were maintained at 37.3 +/ 0.2 degrees C. RESULTS: HBN-1 (p < 0.0001) shortened the time (85 +/- 71 min) to target temperature (33.5 degrees C) versus physical hypothermia (247 +/- 142 min). The duration of hypothermia was 17.0 +/- 6.8h in the HBN-1 group and 17.3 +/- 7.5h in the physical hypothermia group (p = 0.918). Survival (p = 0.034), neurological deficit scores (p < 0.0001) and Morris Water Maze performance after resuscitation (p = 0.041) was improved in the HBN-1 versus the normothermic group. HBN-1 improved survival and early neurological outcome compared to the physical hypothermia group while there was no significant difference in performance in the Morris water maze. CONCLUSION: HBN-1 induced rapid and prolonged hypothermia improved survival with good neurological outcomes after cardiac arrest suggesting that pharmacologically induced regulated hypothermia may provide a practical alternative to physical cooling. PMID- 25906945 TI - The influence of stem taper re-use upon the failure load of ceramic heads. AB - Ceramic components are frequently used in total hip replacement due to their good tribological properties. In revision of broken ceramic heads clinical uncertainties arise, whether the taper of the stem can be re-used with a new ceramic head, especially if the stem is well fixed. Ceramic is a brittle material. Even small damage on the male stem taper can lead to stress concentrations causing premature failure of a new ceramic head. As a consequence, manufactures strictly prohibit stem taper re-use for ceramic heads. The aim of this study was to determine the fracture strength of ceramic heads assembled to re-used male stem tapers, which were subjected to prior head fracture. Five 12/14 Ti6Al4V male tapers and 15 Al2O3 ceramic heads (BIOLOX forte((r)); ? 28 mm, L) were used for three consecutive fracture tests. Before and after every fracture test, all components were inspected visually and the surface geometry was analyzed. Mean fracture force (52.5 kN) did not decrease with the number of taper re-uses (p >= 0.77) but the range increased significantly from initially 4.1 kN to 31.8 kN for the first and 52.6 kN for the second re-use due to some components failing at very low loads. Visual inspection was not sufficient to predict the reduced failure loads. Ceramic heads should therefore not be put on used male tapers without metal adapter sleeves. PMID- 25906946 TI - Platelet membrane variations and their effects on delta-granule secretion kinetics and aggregation spreading among different species. AB - Platelet exocytosis is regulated partially by the granular/cellular membrane lipids and proteins. Some platelets contain a membrane-bound tube, called an open canalicular system (OCS), which assists in granular release events and increases the membrane surface area for greater spreading. The OCS is not found in all species, and variations in membrane composition can cause changes in platelet secretion. Since platelet studies use various animal models, it is important to understand how platelets differ in both their composition and granular release to draw conclusions among various models. The relative phospholipid composition of the platelets with (mouse, rabbit) and without (cow) an OCS was quantified using UPLC-MS/MS. Cholesterol and protein composition was measured using an Amplex Red Assay and BCA Assay. TEM and dark field platelet images were gathered and analyzed with Image J. Granular release was monitored with single cell carbon fiber microelectrode amperometry. Cow platelets contained greater amounts of cholesterol and sphingomyelin. In addition, they yield greater serotonin release and longer delta granule secretion times. Finally, they showed greater spreading area with a greater range of spread. Platelets containing an OCS had more similarities in their membrane composition and secretion kinetics compared to cow platelets. However, cow platelets showed greater fusion pore stability which could be due to extra sphingomyelin and cholesterol, the primary components of lipid rafts. In addition, their greater stability may lead to many granules assisting in spreading. This study highlights fundamental membrane differences and their effects on platelet secretion. PMID- 25906947 TI - Thermosensing via transmembrane protein-lipid interactions. AB - Cell membranes are composed of a lipid bilayer containing proteins that cross and/or interact with lipids on either side of the two leaflets. The basic structure of cell membranes is this bilayer, composed of two opposing lipid monolayers with fascinating properties designed to perform all the functions the cell requires. To coordinate these functions, lipid composition of cellular membranes is tailored to suit their specialized tasks. In this review, we describe the general mechanisms of membrane-protein interactions and relate them to some of the molecular strategies organisms use to adjust the membrane lipid composition in response to a decrease in environmental temperature. While the activities of all biomolecules are altered as a function of temperature, the thermosensors we focus on here are molecules whose temperature sensitivity appears to be linked to changes in the biophysical properties of membrane lipids. This article is part of a Special Issue entitled: Lipid-protein interactions. PMID- 25906948 TI - Robust capsule endoscopy lesion quantification and localization systems. PMID- 25906949 TI - Effects of boron supplementation on the severity and duration of pain in primary dysmenorrhea. AB - BACKGROUND: Primary dysmenorrhea refers to painful menstrual cramps without pelvic pathology. The condition is highly prevalent among women and exerts negative effects on their quality of life. Considering the evidence for anti inflammatory properties of Boron, the present study aimed to determine the effects of Boron supplementation on the severity and duration of menstrual pain in female university students. METHODS: This triple-blind randomized clinical trial study recruited 113 university students. The participants were matched for the severity and duration of dysmenorrhea and randomly allocated into the case and control groups (n = 58 and 55, respectively). The case group consumed 10 mg/day Boron from two days before the menstrual flow until its third day. The control group received placebo capsules (similar to those distributed among the cases). All subjects were asked to take the capsules for two consecutive menstrual cycles. Pain severity (measured on a visual analog scale) and duration (in hours) were measured at baseline and during the two cycles. RESULTS: The two groups had no significant differences in the severity and duration of pain at baseline. After the intervention, however, the severity and duration of pain were significantly lower in the case group than in the control group (P < 0.05). CONCLUSION: Based on our findings, Boron supplementation can reduce the severity and duration of menstrual pain through exerting anti-inflammatory effects. In order to clarify the effects of Boron on dysmenorrhea, future studies are required to measure the levels of hormones and inflammatory biomarkers. PMID- 25906950 TI - Salvage high-dose-rate brachytherapy for esophageal cancer in previously irradiated patients: A retrospective analysis. AB - PURPOSE: To evaluate outcomes after exclusive salvage high-dose-rate (HDR) intraluminal esophageal brachytherapy given to previously irradiated patients with recurrent esophageal cancer. METHODS AND MATERIALS: We reviewed medical records of 30 patients who were treated by salvage HDR brachytherapy for local esophageal cancer. Brachytherapy delivered four to six fractions of 5-7 Gy at 5 mm from the applicator surface and 20 mm above and below the macroscopic tumor volume. RESULTS: Eighty percentage of patients received treatment as initially planned. Complete response rate, evaluated 1 month after brachytherapy by endoscopy and biopsy, was 53%. Squamous histology and complete endoscopic tumor response at 1 month were significantly associated with better local tumor control. Median local progression-free survival was 9.8 months. Overall survival was 31.5% and 17.5% at 1 and 2 years, respectively. On univariate analysis, preserved performance status and limited weight loss (<10%) before salvage brachytherapy were associated with better overall survival. Severe toxicity (Grade >=3) occurred in 7 patients (23%). CONCLUSIONS: Although esophageal cancer in previously irradiated patients is associated with poor outcomes, HDR brachytherapy may be a valuable salvage treatment for inoperable patients with locally limited esophageal cancer, particularly in the subset of patients with preserved performance status and limited weight loss (<=10%) before salvage brachytherapy. PMID- 25906951 TI - High-dose-rate vs. low-dose-rate intracavitary brachytherapy for carcinoma of the uterine cervix: Systematic review and meta-analysis. AB - PURPOSE: We performed a meta-analysis to compare the treatment outcomes between high-dose-rate (HDR) and low-dose-rate (LDR) intracavitary brachytherapy (ICBT) for the treatment of cervical cancer. METHODS AND MATERIALS: We searched the PubMed database for articles and the related referenced articles that compared HDR-ICBT and LDR-ICBT. A total of 15 published articles, 3 prospective randomized trials, and 12 retrospective studies performed between 1966 and December 2013 were selected using predefined inclusion and exclusion criteria for each study. The effect sizes were obtained from the odds ratios of the 5-year overall survival, 5-year disease-free survival (DFS), pelvic (locoregional) recurrence, and rectal and bladder complication rates in each study. The common effect sizes and 95% confidence intervals (CIs) were calculated using either the fixed or the random-effect model, according to the results of the homogeneity tests. RESULTS: We analyzed the outcome data for 18,937 patients, including 10,807 patients in the HDR-ICBT treatment group and 8,130 patients in the LDR-ICBT group. The common effect sizes (95% CI) for the 5-year survival rate, 5-year DFS rate, and pelvic recurrence rate were 1.1350 (0.9231-1.3955), 1.0777 (0.4896-2.3720), and 0.9521 (0.7624-1.1890), respectively. The common effect sizes (95% CI) for moderate-to severe complication rates of the rectum and the bladder were 0.7645 (0.5099 1.1463) and 0.9051 (0.6140-1.3342), respectively. There were no significant differences between HDR- and LDR-ICBT considering the 5-year survival, 5-year DFS, pelvic recurrence, and the rectal and bladder complication rates. CONCLUSION: The treatment outcome after HDR-ICBT seems to be equivalent to that following LDR-ICBT in terms of survival, pelvic recurrence, and major complications. PMID- 25906952 TI - Dexamethasone inhibits the differentiation of rat tendon stem cells into tenocytes by targeting the scleraxis gene. AB - Glucocorticoid-induced tendon rupture is very common in clinical practice, and the overall outcome of surgical suture repair is rather poor. The mechanism remains unclear, and effective treatments are still lacking. In the present study, we investigated the effect of dexamethasone on the differentiation of rat tendon stem cells (TSCs) to tenocytes and the underlying molecular mechanisms and found that dexamethasone inhibits the differentiation of TSCs to tenocytes by analyzing the development of long, spindle-shaped cells and detecting the expression of tenocyte markers type I collagen and tenomodulin (TNMD) at both the mRNA and protein levels. We also discovered that after treatment with dexamethasone, the scleraxis expression level is downregulated in vitro and in human specimen. Chromatin immunoprecipitation (ChIP)-PCR showed that dexamethasone promotes glucocorticoid receptor interacted with the TGGAAGCC sequence located between -734 and -726 base pairs (bp) upstream of the start codon of the scleraxis gene. Furthermore, TSCs were transfected with scleraxis knockdown or overexpression plasmids, and the results indicated that scleraxis plays a pivotal role in the differentiation of TSCs to tenocytes. In conclusion, dexamethasone inhibits the differentiation of TSCs to tenocytes by inhibiting the scleraxis gene. PMID- 25906953 TI - The Children's Health Insurance Program Reauthorization Act Evaluation Findings on Children's Health Insurance Coverage in an Evolving Health Care Landscape. AB - The Children's Health Insurance Program (CHIP) Reauthorization Act (CHIPRA) reauthorized CHIP through federal fiscal year 2019 and, together with provisions in the Affordable Care Act, federal funding for the program was extended through federal fiscal year 2015. Congressional action is required or federal funding for the program will end in September 2015. This supplement to Academic Pediatrics is intended to inform discussions about CHIP's future. Most of the new research presented comes from a large evaluation of CHIP mandated by Congress in the CHIPRA. Since CHIP started in 1997, millions of lower-income children have secured health insurance coverage and needed care, reducing the financial burdens and stress on their families. States made substantial progress in simplifying enrollment and retention. When implemented optimally, Express Lane Eligibility has the potential to help cover more of the millions of eligible children who remain uninsured. Children move frequently between Medicaid and CHIP, and many experienced a gap in coverage with this transition. CHIP enrollees had good access to care. For nearly every health care access, use, care, and cost measure examined, CHIP enrollees fared better than uninsured children. Access in CHIP was similar to private coverage for most measures, but financial burdens were substantially lower and access to weekend and nighttime care was not as good. The Affordable Care Act coverage options have the potential to reduce uninsured rates among children, but complex transition issues must first be resolved to ensure families have access to affordable coverage, leading many stakeholders to recommend funding for CHIP be continued. PMID- 25906954 TI - The Children's Health Insurance Program Strengthens Children's Health Care. PMID- 25906955 TI - The Children's Health Insurance Program and the Goldilocks Effect. PMID- 25906956 TI - The Children's Health Insurance Program Lessons for Health Reform. PMID- 25906957 TI - Support for the Children's Health Insurance Program Paves the Way for Broader Consensus on Coverage Policy. PMID- 25906958 TI - CHIP and Medicaid: Evolving to Meet the Needs of Children. AB - OBJECTIVE: To examine the evolution of Children's Health Insurance Program (CHIP) and Medicaid programs after passage of the Children's Health Insurance Program Reauthorization Act of 2009 (CHIPRA), focusing on policies affecting eligibility, enrollment, renewal, benefits, access to care, cost sharing, and preparation for health care reform. METHODS: Case studies were conducted in 10 states during 2012 which included key informant interviews and consumer focus groups-and a national survey of state CHIP program administrators was conducted in early 2013. RESULTS: Despite the recession that persisted during much of the study period, many states expanded children's coverage by raising upper income eligibility limits or by covering new groups made eligible by CHIPRA. Simplifying rules and procedures for enrollment and renewal continued to be a major priority for CHIP and Medicaid, and CHIPRA played a direct role in spurring innovation. CHIPRA's outreach grants played an important role in supporting and supplementing state outreach efforts. Important legacies of CHIPRA are the law's mandatory requirements for comprehensive dental benefits coverage and mental health parity for all types of CHIP programs. Although most states already offered generous coverage of these benefits, the mandate may have protected them from cuts during the economic downturn. Federal Maintenance of Effort rules were a crucial protection for CHIP, especially during the recession when state budget shortfalls could have led to program cuts. CONCLUSIONS: Passage of the Affordable Care Act has raised questions surrounding the future role of CHIP in a reformed health care system. A growing number of stakeholders have recommended a 2-year extension of federal CHIP funding to allow complex transition issues to be resolved. PMID- 25906959 TI - Children Eligible for Medicaid or CHIP: Who Remains Uninsured, and Why? AB - OBJECTIVE: To assess how many uninsured children are eligible for coverage through Medicaid or the Children's Health Insurance Program (CHIP) but not participating and examine the reasons low-income uninsured children are unenrolled. METHODS: Medicaid/CHIP eligibility and participation are estimated for a sample of over 1.4 million children in the 2008 and 2012 American Community Survey. Medicaid/CHIP experience and enrollment barriers are examined for 2300 uninsured children in families with incomes below 200% of the federal poverty level in the 2011-2012 National Survey of Children's Health. RESULTS: Despite increases in the number eligible for Medicaid or CHIP between 2008 and 2012, participation rose nationwide by 6 percentage points; by 2012, 21 states and the District of Columbia had participation rates for children of 90% or higher. The number of eligible but uninsured declined from 4.9 to 3.7 million, but 68% of uninsured children in 2012 qualified for Medicaid or CHIP. Interest in enrolling uninsured children in Medicaid or CHIP is high (more than 90% of parents say they would enroll their child), but despite the high rates of prior enrollment, many families had knowledge gaps and perceived difficulties with enrollment. CONCLUSIONS: Addressing enrollment/retention barriers and raising Medicaid/CHIP participation in low-performing states hold promise for reducing the number of eligible but uninsured children given the diverse set of states with high participation and the high expressed interest in enrolling children. PMID- 25906960 TI - Enrollment and Disenrollment Experiences of Families Covered by CHIP. AB - OBJECTIVE: To understand why families enroll in and disenroll from Children's Health Insurance Program (CHIP), their experience with the CHIP application and renewal process, and the insurance coverage of their children after disenrolling. METHODS: We conducted a large household telephone survey in 2012 of CHIP enrollees and disenrollees in 10 states. We used survey responses to assess the perceptions and experiences of families with the CHIP application and renewal process. In addition, we combined the survey data with CHIP/Medicaid administrative data to analyze coverage outcomes of children after disenrolling. RESULTS: A large majority of recent CHIP enrollees had positive impressions of the application process; 89% found the process very or somewhat easy, and 90% of those receiving assistance found it very helpful. Families had similarly favorable impressions of the renewal process, including those recently disenrolling from CHIP. After disenrolling, children were far more likely to gain Medicaid coverage (49%) than private insurance (18%), while a sizable percentage were uninsured (32%). The likelihood of becoming uninsured was especially high among 18- and 19-year-olds (62%), who lost CHIP coverage due to their age. CONCLUSIONS: Satisfaction with the CHIP application and renewal process is high among those with recent coverage, consistent with efforts by many states to simplify these processes for families. Medicaid is a critical source of coverage for those leaving CHIP, a role that may only increase as states expanding Medicaid through the Affordable Care Act create a new coverage option for older teens losing CHIP eligibility. PMID- 25906961 TI - Program Churning and Transfers Between Medicaid and CHIP. AB - OBJECTIVE: In the 10 states that are the focus of the Children's Health Insurance Program Reauthorization Act of 2009 evaluation, we analyze in detail the states' recent progress in retaining children in public coverage and public coverage churning. METHODS: We used administrative data spanning a five-and-a-half-year period collected from 10 study states-Alabama, California, Florida, Louisiana, Michigan, New York, Ohio, Texas, Utah, and Virginia-to analyze the extent to which children return to the same program a short time after disenrollment and the extent to which transfers between Medicaid and Children's Health Insurance Program (CHIP) lead to public coverage gaps. RESULTS: Our analysis yielded 3 key findings. First, many children moved between Medicaid and CHIP; while most transitioned seamlessly, coverage gaps occurred for as many as 40%, depending on the type of transition. Second, churning continued to be a concern for public coverage programs, with approximately 21% of Medicaid disenrollees and 10% of separate CHIP disenrollees returning to the same program within 7 months. Third, we found sizable differences in rates of program churning and nonseamless program transfers across the 10 study states. CONCLUSIONS: Notable variation existed across programs and states, which persisted over the period in public program churning. These results suggest the need for continued efforts to simplify renewal processes, particularly in state Medicaid programs, along with the adoption of processes that improve coordination across programs and policies that simplify these transfers. PMID- 25906962 TI - How Well Is CHIP Addressing Primary and Preventive Care Needs and Access for Children? AB - OBJECTIVE: To examine differences in primary care outcomes under the Children's Health Insurance Program (CHIP) compared to private coverage and being uninsured in 10 states. METHODS: We used data from a survey of parents of recent and established CHIP enrollees conducted from January 2012 through March 2013. We compared the primary care experiences of established CHIP enrollees to the preenrollment experiences of previously uninsured and privately insured recent CHIP enrollees to estimate differences in care outcomes. RESULTS: Parents of 4142 recent enrollees and 5518 established enrollees responded to the survey (response rates were 46% for recent enrollees and 51% for established enrollees). Compared to being uninsured, CHIP enrollees were more likely to have a well-child visit, receive a range of preventive care services, and have patient-centered care experiences. They were also more likely than uninsured children to have a regular source of care or provider, an easy time making appointments, and shorter wait times for those appointments. Relative to privately insured children, CHIP enrollees received preventive care services at similar rates and to be more likely to receive effective care coordination services. However, CHIP enrollees were less likely than privately insured children to have a regular source of care or provider and nighttime and weekend access to a usual source of care. CONCLUSIONS: CHIP continues to provide high levels of access to primary care, especially compared to uninsured children, and to provide benefits comparable to private insurance. PMID- 25906963 TI - The Children's Health Insurance Program as Adolescence Ends: Nearly 2 Decades of Children's Coverage. PMID- 25906964 TI - Children with Special Health Care Needs in CHIP: Access, Use, and Child and Family Outcomes. AB - OBJECTIVE: To assess how the Children's Health Insurance Program (CHIP) affects outcomes for children with special health care needs (CSHCN). METHODS: We used data from a survey of parents of recent and established CHIP enrollees conducted from January 2012 through March 2013 as part of a congressionally mandated evaluation of CHIP. We identified CSHCN in the sample using the Child and Adolescent Health Measurement Initiative's CSHCN screener. We compared the health care experiences of established CHIP enrollees to the pre-enrollment experiences of previously uninsured and privately insured recent CHIP enrollees, controlling for observable characteristics. RESULTS: Parents of 4142 recent enrollees and 5518 established enrollees responded to the survey (response rates, 46% recent enrollees and 51% established enrollees). In the 10 survey states, about one fourth of CHIP enrollees had a special health care need. Compared to being uninsured, parents of CSHCN who were established CHIP enrollees reported greater access to and use of medical and dental care, less difficulty meeting their child's health care needs, fewer unmet needs, and better dental health status for their child. Compared to having private insurance, parents of CSHCN who were established CHIP enrollees reported similar levels of access to and use of medical and dental care and unmet needs, and less difficulty meeting their child's health care needs. CONCLUSIONS: CHIP has significant benefits for eligible CSHCN and their families compared to being uninsured and appears to have some benefits compared to private insurance. PMID- 25906965 TI - Alabama's Perspective of the Child Health Insurance Program. PMID- 25906966 TI - Electronic stress tensor analysis of molecules in gas phase of CVD process for GeSbTe alloy. AB - We analyze the electronic structure of molecules which may exist in gas phase of chemical vapor deposition process for GeSbTe alloy using the electronic stress tensor, with special focus on the chemical bonds between Ge, Sb, and Te atoms. We find that, from the viewpoint of the electronic stress tensor, they have intermediate properties between alkali metals and hydrocarbon molecules. We also study the correlation between the bond order which is defined based on the electronic stress tensor, and energy-related quantities. We find that the correlation with the bond dissociation energy is not so strong while one with the force constant is very strong. We interpret these results in terms of the energy density on the "Lagrange surface," which is considered to define the boundary surface of atoms in a molecule in the framework of the electronic stress tensor analysis. PMID- 25906967 TI - Revisiting the solution structure of ceric ammonium nitrate. AB - Ceric ammonium nitrate (CAN) is a single-electron-transfer reagent with unparalleled utility in organic synthesis, and has emerged as a vital feedstock in diverse chemical industries. Most applications use CAN in solution where it is assigned a monomeric [Ce(IV) (NO3 )6 ](2-) structure; an assumption traced to half-century old studies. Using synchrotron X-rays and Raman spectroscopy we challenge this tradition, converging instead on an oxo-bridged dinuclear complex, even in strong nitric acid. Thus, one equivalent of CAN is recast as a two electron-transfer reagent and a redox-activated superbase, raising questions regarding the origins of its reactivity with organic molecules and giving new fundamental insight into the stability of polynuclear complexes of tetravalent ions. PMID- 25906968 TI - Social reform and a growing crisis for southern Myanmar's unique forests. PMID- 25906969 TI - Investigation of travel-related cases in a multinational outbreak: example of the Shiga-toxin producing E. coli outbreak in Germany, May-June 2011. AB - Early investigation of travel-related cases in an outbreak of an emerging infectious disease can provide useful information to epidemiologists to characterize the exposure, while they may differ in demographic profiles from cases reported in the country where the outbreak has occurred. During the spring 2011 E. coli outbreak in Germany, we proposed a methodological approach to collect a minimal set of demographic and clinical data that are relatively easy to obtain and available at an early stage of an outbreak investigation. Ninety eight STEC O104 travel-related cases were reported in a survey by seven EU countries, Switzerland, Canada and the USA. We found a mean incubation period (n = 50) of 8.5 days, which confirmed previous estimations communicated by the Robert Koch Institute. No significant association was found between the duration of the incubation period and possible demographic and clinical factors, although the older the age, the shorter the incubation period that was observed. Such approach and observations are informative for further investigations of outbreaks of enterohaemorrhagic E. coli or other emerging infectious diseases. PMID- 25906970 TI - Protective effect of thymoquinone against testicular torsion induced oxidative injury. AB - We aimed to determine the protective effects of thymoquinone (TQ), against ischaemia-reperfusion (I/R) injury in the testis tissue of rats. Twenty-seven male Wistar albino rats were randomly divided into three equal groups as follows: Group I, sham group; Group II, torsion group; and Group III, torsion + thymoquinone group. The ischaemia period was 2 h, and orchiectomy was performed after 30 min of detorsion. Testis tissue sections were analysed with the terminal transferase mediated dUTP-nick end labelling (TUNEL) assay to determine in situ apoptotic DNA fragmentation. Additionally, Caspase 3 and Bax proteins were analysed immunohistochemically. The superoxide dismutase (SOD), glutathione peroxidase (GSH-Px) and malondialdehyde (MDA) activity levels in the testis tissue were also measured. The superoxide dismutase activity and malondialdehyde levels in the torsion group were significantly higher than those of the sham group (P < 0.05). Thymoquinone administration significantly reduced these levels. Torsion significantly increased active-Caspase 3 and Bax expression, which was decreased by thymoquinone. The apoptotic index of the torsion group was significantly higher than that of the control group. However, thymoquinone significantly reduced the apoptotic index (P < 0.05). Our results indicate that thymoquinone plays a protective role in oxidative stress induced ischaemia reperfusion in the testis tissue of rats. PMID- 25906971 TI - Trends in opioid prescribing and co-prescribing of sedative hypnotics for acute and chronic musculoskeletal pain: 2001-2010. AB - PURPOSE: Characterize trends in opioid prescribing and co-prescribing of sedative hypnotics at acute and chronic musculoskeletal pain visits from 2001 to 2010. METHODS: We conducted a repeated cross-sectional analysis of 15 344 visits for acute pain and 19 958 visits for chronic pain in the National Ambulatory Medical Care Survey/National Hospital Ambulatory Medical Care Survey from 2001 to 2010. The primary outcome was receipt of an opioid, and secondary outcomes were co prescribing of a benzodiazepine or sedative hypnotic (benzodiazepine, muscle relaxant, or insomnia medications). We used multivariable logistic regression to assess temporal trends. RESULTS: Between 2001 and 2010, opioid prescribing at acute and chronic musculoskeletal pain visits increased by 50% (10.4% [95%CI 7.9 12.9%] to 15.6% [95%CI 12.5-18.6%]) and 79% (12.9% [95%CI 9.7-16.0%] to 23.1% [95%CI 18.3-27.9%]), respectively. For chronic pain visits, opioid prescribing plateaued between 2006 and 2010, and spline analysis detected a possible 2007 peak at 28.2% (95%CI 21.4-34.9%) of visits. Benzodiazepines were co-prescribed with opioids at 8.1% (95%CI 6.0-10.1%) of acute pain visits and 15.5% (95%CI 12.8 18.2%) of chronic pain visits. Sedative hypnotics were co-prescribed at 32.7% (95%CI 28.9-36.5%) of acute pain visits and 36.1% (95%CI 32.5-39.8%) of chronic pain visits. We found no evidence for decreased co-prescribing of opioids and sedative hypnotics by any of our measures. CONCLUSIONS: Opioid prescribing for acute and chronic musculoskeletal pain increased from 2001 to 2010, plateauing from 2006 to 2010 for chronic pain visits. Co-prescribing of opioids and sedative hypnotics is common and may represent a target for interventions to improve the safety of opioid prescribing. PMID- 25906972 TI - Vulnerability of Urban Homebound Older Adults in Disasters: A Survey of Evacuation Preparedness. AB - OBJECTIVE: Recent disasters within the United States, such as Hurricanes Katrina and Sandy, have highlighted the vulnerability of older adults, and recent litigation has upheld the responsibility of government in assisting the public during mandatory evacuations. Older adults designated as homebound due to their disabilities are at greatest risk of poor outcomes in disasters. This study aimed at assessing the willingness and ability of homebound older adults to evacuate, as well as categorizing their medical needs in the event they are relocated to an emergency shelter. METHODS: Fifty-six homebound older adults and medical decision surrogates from 1 homebound primary care practice in Philadelphia were assessed with a novel structured interview. RESULTS: Respondents reported limitations in both their ability and their willingness to evacuate their neighborhoods. Medical needs of homebound older adults were on par with those of nursing home residents. CONCLUSIONS: Many homebound older adults are unable or unwilling to evacuate in a mandatory evacuation situation, highlighting a need for public assistance. Their complex medical needs will require significant preparation by special needs shelters. PMID- 25906973 TI - The evolution of mate choice: a dialogue between theory and experiment. AB - Research on the evolution of mate choice has followed three avenues of investigation: (1) theoretical models of the evolution of preference and the preferred trait; (2) proposed models of mate choice; and (3) experiments and observations on mate choice, both in the laboratory and with free-ranging animals. However, there has been relatively little dialogue among these three areas. Most attempts to account for observations of mate choice using theoretical mate-choice models have focused only upon a subset of particular models and have generally failed to consider the difference between probabilistic and deterministic models. In this review, I outline the underlying reasoning of the commonly cited mate-choice models and review the conclusions of the empirical investigations. I present a brief outline of how one might go about testing these models. It remains uncertain if, in general, mate-choice models can be realistically analyzed. Although it is clear that females frequently discriminate among males, data also suggest that females may typically have a very limited number of males from which to choose. The extent to which female choice under natural conditions is relatively random because of limited opportunities remains an open question for the majority of species. PMID- 25906974 TI - Personalized versus standardized dosing strategies for the treatment of childhood amblyopia: study protocol for a randomized controlled trial. AB - BACKGROUND: Amblyopia is the commonest visual disorder of childhood in Western societies, affecting, predominantly, spatial visual function. Treatment typically requires a period of refractive correction ('optical treatment') followed by occlusion: covering the nonamblyopic eye with a fabric patch for varying daily durations. Recent studies have provided insight into the optimal amount of patching ('dose'), leading to the adoption of standardized dosing strategies, which, though an advance on previous ad-hoc regimens, take little account of individual patient characteristics. This trial compares the effectiveness of a standardized dosing strategy (that is, a fixed daily occlusion dose based on disease severity) with a personalized dosing strategy (derived from known treatment dose-response functions), in which an initially prescribed occlusion dose is modulated, in a systematic manner, dependent on treatment compliance. METHODS/DESIGN: A total of 120 children aged between 3 and 8 years of age diagnosed with amblyopia in association with either anisometropia or strabismus, or both, will be randomized to receive either a standardized or a personalized occlusion dose regimen. To avoid confounding by the known benefits of refractive correction, participants will not be randomized until they have completed an optical treatment phase. The primary study objective is to determine whether, at trial endpoint, participants receiving a personalized dosing strategy require fewer hours of occlusion than those in receipt of a standardized dosing strategy. Secondary objectives are to quantify the relationship between observed changes in visual acuity (logMAR, logarithm of the Minimum Angle of Resolution) with age, amblyopia type, and severity of amblyopic visual acuity deficit. DISCUSSION: This is the first randomized controlled trial of occlusion therapy for amblyopia to compare a treatment arm representative of current best practice with an arm representative of an entirely novel treatment regimen based on statistical modelling of previous trial outcome data. Should the personalized dosing strategy demonstrate superiority over the standardized dosing strategy, then its adoption into routine practice could bring practical benefits in reducing the duration of treatment needed to achieve an optimal outcome. TRIAL REGISTRATION: ISRCTN ISRCTN12292232. PMID- 25906975 TI - Henrik Sjobring and the concept of individual psychology in psychiatry. PMID- 25906976 TI - The routine leukocyte differential flow cytometry HematoFlowTM method: A new flagging system for automatic validation. AB - The complete blood cell count and white blood cell differential are the first step in the biological diagnosis of hematological diseases. Both are currently performed by automated instruments which control data and produce alerts. If such flags are activated, the automated differential cannot be validated and the operator must activate a visual blood smear review. Microscopic examination is still today the reference method despite its lack of sensitivity and reproducibility. The HematoFlowTM (Beckman Coulter) system is the first flow cytometry commercialized method designed for the routine differential. Using six markers in five colors and an automated gating strategy, it provides differentials proven to be reliable for 17 leukocyte subpopulations detection. Relying first on a retrospective analysis of 6,462 blood samples processed by HematoFlowTM, thresholds were determined to detect the presence of immature granulocytes and/or blast cells. All possible gating strategy misclassifications of leukocyte subpopulations were then summarized in a systematic nomenclature leading to the development of an original flag system based on the detection of aberrant localization of cell events in specific new bivariate histograms. Ultimately, more than 50% of the results could be automatically validated using the HematoFlowTM system, without any false negative, thereby dramatically contributing to an important decrease of technicians' workload. Moreover a noticeable help was given for smear review interpretation and new immunological flags led to the confirmation of blood disease after classical immunophenotyping. These results were confirmed in a second prospective study including 15,335 cases, where more than 50% of the results were automatically validated by this new flag system. MFC stands as being more and more essential for analyzing differentials in routine and this new flag system could greatly improve its implementation. PMID- 25906977 TI - Distal femoral condyle is more internally rotated to the patellar tendon at 90 degrees of flexion in normal knees. AB - BACKGROUND: The configuration of the distal surface of the femur would be more important in terms of the patellofemoral (PF) joint contact because the patella generally contacts with the distal surface of the femur in knee flexion. Some total knee arthroplasty (TKA) designs configurate medially prominent asymmetric femoral condyles. This difference in the design of distal femoral condyle may affect the PF joint congruity in knee flexion. Furthermore, some surgeons advocate a concept aligning the symmetric components parallel to the native joint inclination, not perpendicular to the mechanical axis. This concept would also make a difference on the PF joint congruity at the distal femur in knee flexion. However, no fundamental study has been reported on the PF congruity at the distal femur to discuss the theoretical priority of these concepts. The current study investigated the angular relationship between the tibial attachment of the patellar tendon and the distal surface of the femur at 90 degrees of flexion in normal knees. METHODS: The open magnetic resonance images of 45 normal knees at 90 degrees of flexion were used to measure the angles between the tibial attachment of the patellar tendon, the equatorial line of the patella, and the distal surface of femoral condyles. RESULTS: The distal surface of femoral condyles was internally rotated relative to the tibial attachment of the patellar tendon and the equatorial line of the patella in all the knees (8.2 degrees +/- 3.5 degrees and 5.8 degrees +/- 2.5 degrees , respectively), not parallel. CONCLUSIONS: Distal femoral condyle is internally rotated to the patellar tendon at 90 degrees of flexion in normal knees. When the symmetric femoral component is aligned perpendicular to the femoral mechanical axis, the patellar tendon would be possibly more twisted than the condition in normal knees, and the deviation of the PF contact force on the patellar component might be caused. The configuration and alignment of the distal condyle of the femoral component can affect the PF joint congruity in knee flexion. In this respect, our results provide important information in considering designs and alignment in the distal femur of TKA and the PF joint congruity in knee flexion. PMID- 25906978 TI - Egg clutch patterning in Lestes virens (Odonata, Lestidae) with evolutionary emphasis on endophytic oviposition in lestid dragonflies. AB - Egg deposition within plants is one of the most widely distributed and ancient behaviors in Odonata. The resulting clutch consists of eggs placed in peculiar pattern that can be a characteristic for certain groups of Odonata. Despite their importance for paleontological and evolutionary research, data on egg-clutch positioning are missing or insufficient for most species. Here, patterning of egg clutches in Lestes virens was measured and described in detail for the first time. The female usually produces a linear row of single eggs directed at an angle rightward or leftward to the longitudinal axis of plant substrate. Less often eggs are arranged in egg-sets consisting of up to 4 eggs. Apparently, the female insect follows the rigid behavior stereotypes during oviposition and is unable to easily switch to the alternate stereotypical behavior of single egg deposition or production of multiegg sets. Based on a literature review and original data, egg clutch patterning of European Lestidae is overlaid on preexisting phylogenies. The resulting evolutionary scenario of egg-clutch patterning can be considered in the framework of egg-laying behavior in Lestidae. PMID- 25906979 TI - Interleukin-1alpha and brain inflammation. AB - Acute brain injuries such as caused by stroke are amongst the leading causes of death and are the leading cause of disability. Despite this there are very limited therapeutic options, and new therapeutic strategies and targets are required. Inflammation is known to exacerbate brain injury and is now considered as a potential therapeutic target. The damaging inflammation that occurs after acute brain injury is driven by pro-inflammatory members of the interleukin (IL) 1 cytokine family, namely, IL-1alpha and IL-1beta. Previous research efforts have focussed on the biology and contribution of IL-1beta. However, we now recognise that IL-1alpha is an early and important mediator of inflammation after injury. This review focuses on what is known about IL-1alpha, its regulation and its contribution to brain injury. Inhibiting mechanisms regulating the processing and release of IL-1alpha may offer new therapeutic targets for the treatment of devastating acute brain injuries. PMID- 25906982 TI - The thermal reorganization of DNA immobilized at the silica/buffer interface: a vibrational sum frequency generation investigation. AB - We have monitored the interactions of DNA strands immobilized on silica at the buried solid/liquid interface using vibrational sum frequency generation. We find that the nucleobases exhibit net order even prior to hybridization for immobilized single strands. Moreover, varying the temperature of the hybridized samples leads to spectral changes from the thymine nucleobases that are consistent with duplex dissociation. PMID- 25906980 TI - Identification and functional characterization of the CYP51 gene from the yeast Xanthophyllomyces dendrorhous that is involved in ergosterol biosynthesis. AB - BACKGROUND: Xanthophyllomyces dendrorhous is a basidiomycetous yeast that synthesizes astaxanthin, a carotenoid with great biotechnological impact. The ergosterol and carotenoid synthetic pathways derive from the mevalonate pathway and involve cytochrome P450 enzymes. Among these enzymes, the CYP51 family, which is involved in ergosterol biosynthesis, is one of the most remarkable that has C14-demethylase activity. RESULTS: In this study, the CYP51 gene from X. dendrorhous was isolated and its function was analyzed. The gene is composed of ten exons and encodes a predicted 550 amino acid polypeptide that exhibits conserved cytochrome P450 structural characteristics and shares significant identity with the sterol C14-demethylase from other fungi. The functionality of this gene was confirmed by heterologous complementation in S. cerevisiae. Furthermore, a CYP51 gene mutation in X. dendrorhous reduced sterol production by approximately 40% and enhanced total carotenoid production by approximately 90% compared to the wild-type strain after 48 and 120 h of culture, respectively. Additionally, the CYP51 gene mutation in X. dendrorhous increased HMGR (hydroxy methylglutaryl-CoA reductase, involved in the mevalonate pathway) and crtR (cytochrome P450 reductase) transcript levels, which could be associated with reduced ergosterol production. CONCLUSIONS: These results suggest that the CYP51 gene identified in X. dendrorhous encodes a functional sterol C14-demethylase that is involved in ergosterol biosynthesis. PMID- 25906983 TI - Efficacy of robot-assisted fingers training in chronic stroke survivors: a pilot randomized-controlled trial. AB - BACKGROUND: While constraint-induced movement therapy (CIMT) is one of the most promising techniques for upper limb rehabilitation after stroke, it requires high residual function to start with. Robotic device, on the other hand, can provide intention-driven assistance and is proven capable to complement conventional therapy. However, with many robotic devices focus on more proximal joints like shoulder and elbow, recovery of hand and fingers functions have become a challenge. Here we propose the use of robotic device to assist hand and fingers functions training and we aim to evaluate the potential efficacy of intention driven robot-assisted fingers training. METHODS: Participants (6 to 24 months post-stroke) were randomly assigned into two groups: robot-assisted (robot) and non-assisted (control) fingers training groups. Each participant underwent 20 session training. Action Research Arm Test (ARAT) was used as the primary outcome measure, while, Wolf Motor Function Test (WMFT) score, its functional tasks (WMFT FT) sub-score, Fugl-Meyer Assessment (FMA), its shoulder and elbow (FMA-SE) sub score, and finger individuation index (FII) served as secondary outcome measures. RESULTS: Nineteen patients completed the 20-session training ( TRIAL REGISTRATION: HKClinicalTrials.com HKCTR-1554); eighteen of them came back for a 6-month follow-up. Significant improvements (p < 0.05) were found in the clinical scores for both robot and control group after training. However, only robot group maintained the significant difference in the ARAT and FMA-SE six months after the training. The WMFT-FT score and time post-training improvements of robot group were significantly better than those of the control group. CONCLUSIONS: This study showed the potential efficacy of robot-assisted fingers training for hand and fingers rehabilitation and its feasibility to facilitate early rehabilitation for a wider population of stroke survivors; and hence, can be used to complement CIMT. PMID- 25906984 TI - Geographical heterogeneity in the analysis of factors associated with leprosy in an endemic area of Brazil: are we eliminating the disease? AB - BACKGROUND: The leprosy transmission chain is very complex and, in order to intervene in this transmission, more must be known about the factors linked to falling ill. There are doubts as to the influence of population size, population density and the disease's magnitude in detection rate trends. This paper aimed to identify factors associated with detection of leprosy in an endemic municipality of Rio de Janeiro State, Brazil. METHODS: This ecological study in Duque de Caxias municipality, Rio de Janeiro State, Brazil, used neighbourhoods (bairros) as the unit of analysis. Selecting new cases of leprosy detected from 1998 to 2006, the analysis examined clinical, socioeconomic and service variables using a Poisson log-Normal model. RESULTS: In the municipality overall, 2572 new cases were detected, a rate of 3.70 cases/10,000 inhabitants. The results describe a heterogeneous distribution of cases and rates in the municipality. The final model displayed a significant association with indeterminate clinical form (beta = 2.599), proportion of homes with running water (beta = -2.334) and presence of a decentralised health care unit (beta = 0.524). CONCLUSION: Although the results indicate progress towards elimination of the disease in the municipality, high rates continue to be detected in municipal sub-regions. The following question can thus be posed: over how wide a geographical area could the disease be thoroughly eliminated, given this heterogeneity within a small municipality? PMID- 25906985 TI - Atomic structure of biodegradable Mg-based bulk metallic glass. AB - We have used highly accurate first-principles molecular dynamics simulations to elucidate the structure of Mg60Zn35Ca5 and Mg72Zn23Ca5 bulk metallic glasses, which are candidate materials for biomedical implants; these two compositions exhibit different behaviours when implanted. The environments of each species are different, and average coordination numbers are ~13 for Mg, ~11 for Zn and ~18-19 for Ca. A wide range of local environments were found and icosahedral motifs, often seen in bulk metallic glasses, were among the most common for both Mg and Zn. Through the computation of a chemical short-range order parameter, a moderate avoidance of Zn-Zn bonding over Zn-Mg or Zn-Ca was observed. No statistically significant difference in structure was observed between the two compositions. PMID- 25906986 TI - A {Co4 O4 } Cubane Incorporated within a Polyoxoniobate Cluster. AB - A novel octacobalt-containing polyoxoniobate, Na6 K12 [H2 Co8 O4 (Nb6 O19 )4 ]?39 H2 O, has been prepared by a combination of hydrothermal and diffusion methods. The polyanion [H2 Co8 O4 (Nb6 O19 )4 ](18-) incorporates a tetrameric assembly of Lindqvist-type [Nb6 O19 ](8-) fragments trapping a {Co(II) 4 Co(III) 4 } cluster which comprises a central {Co(III) 4 O4 } cubane core, surrounded by another four Co(II) ions linkers. Furthermore, magnetic measurements show that the compound exhibits antiferromagnetic interactions. PMID- 25906987 TI - Temperature and snowfall trigger alpine vegetation green-up on the world's roof. AB - Rapid temperature increase and its impacts on alpine ecosystems in the Qinghai Tibetan Plateau, the world's highest and largest plateau, are a matter of global concern. Satellite observations have revealed distinctly different trend changes and contradicting temperature responses of vegetation green-up dates, leading to broad debate about the Plateau's spring phenology and its climatic attribution. Large uncertainties in remote-sensing estimates of phenology significantly limit efforts to predict the impacts of climate change on vegetation growth and carbon balance in the Qinghai-Tibetan Plateau, which are further exacerbated by a lack of detailed ground observation calibration. Here, we revealed the spatiotemporal variations and climate drivers of ground-based herbaceous plant green-up dates using 72 green-up datasets for 22 herbaceous plant species at 23 phenological stations, and corresponding daily mean air temperature and daily precipitation data from 19 climate stations across eastern and southern parts of the Qinghai Tibetan Plateau from 1981 to 2011. Results show that neither the continuously advancing trend from 1982 to 2011, nor a turning point in the mid to late 1990s as reported by remote-sensing studies can be verified by most of the green-up time series, and no robust evidence for a warmer winter-induced later green-up dates can be detected. Thus, chilling requirements may not be an important driver influencing green-up responses to spring warming. Moreover, temperature-only control of green-up dates appears mainly at stations with relatively scarce preseason snowfall and lower elevation, while coupled temperature and precipitation controls of green-up dates occur mostly at stations with relatively abundant preseason snowfall and higher elevation. The diversified interactions between snowfall and temperature during late winter to early spring likely determine the spatiotemporal variations of green-up dates. Therefore, prediction of vegetation growth and carbon balance responses to global climate change on the world's roof should integrate both temperature and snowfall variations. PMID- 25906988 TI - Social media for lifelong learning. AB - Learning is ongoing, and can be considered a social activity. In this paper we aim to provide a review of the use of social media for lifelong learning. We start by defining lifelong learning, drawing upon principles of continuous professional development and adult learning theory. We searched Embase and MEDLINE from 2004-2014 for search terms relevant to social media and learning. We describe examples of lifelong learners using social media in medical education and healthcare that have been reported in the peer-reviewed literature. Medical or other health professions students may have qualities consistent with being a lifelong learner, yet once individuals move beyond structured learning environments they will need to recognize their own gaps in knowledge and skills over time and be motivated to fill them, thereby incorporating lifelong learning principles into their day-to-day practice. Engagement with social media can parallel engagement in the learning process over time, to the extent that online social networking fosters feedback and collaboration. The use of social media and online networking platforms are a key way to continuously learn in today's information sharing society. Additional research is needed, particularly rigorous studies that extend beyond learner satisfaction to knowledge, behaviour change, and outcomes. PMID- 25906989 TI - Social media, medicine and the modern journal club. AB - Medical media is changing along with the rest of the media landscape. One of the more interesting ways that medical media is evolving is the increased role of social media in medical media's creation, curation and distribution. Twitter, a microblogging site, has become a central hub for finding, vetting, and spreading this content among doctors. We have created a Twitter journal club for nephrology that primarily provides post-publication peer review of high impact nephrology articles, but additionally helps Twitter users build a network of engaged people with interests in academic nephrology. By following participants in the nephrology journal club, users are able to stock their personal learning network. In this essay we discuss the history of medical media, the role of Twitter in the current states of media and summarize our initial experience with a Twitter journal club. PMID- 25906990 TI - My three shrinks: Personal stories of social media exploration. AB - Three psychiatrist authors illustrate the impact of social media on their professional lives by reflecting on personal stories about their experiences with social media. They reflect on their experiences with listservs, chat rooms, online forums, blogs, podcasts, and other interactive media, while recounting actual stories involving those media. The impact of social media on professional advocacy across broad populations is addressed. In addition, the use of social media in educating psychiatric trainees and informing forensic evaluations is discussed. Finally, social media as a tool for enhancing consumer advocacy and addressing controversial patient safety procedures in emergency settings is discussed. PMID- 25906991 TI - Na(+) intercalation pseudocapacitance in graphene-coupled titanium oxide enabling ultra-fast sodium storage and long-term cycling. AB - Sodium-ion batteries are emerging as a highly promising technology for large scale energy storage applications. However, it remains a significant challenge to develop an anode with superior long-term cycling stability and high-rate capability. Here we demonstrate that the Na(+) intercalation pseudocapacitance in TiO2/graphene nanocomposites enables high-rate capability and long cycle life in a sodium-ion battery. This hybrid electrode exhibits a specific capacity of above 90 mA h g(-1) at 12,000 mA g(-1) (~36 C). The capacity is highly reversible for more than 4,000 cycles, the longest demonstrated cyclability to date. First principle calculations demonstrate that the intimate integration of graphene with TiO2 reduces the diffusion energy barrier, thus enhancing the Na(+) intercalation pseudocapacitive process. The Na-ion intercalation pseudocapacitance enabled by tailor-deigned nanostructures represents a promising strategy for developing electrode materials with high power density and long cycle life. PMID- 25906992 TI - V-cGAPs: attenuators of 3'3'-cGAMP signaling. AB - Cyclic GMP-AMPs (cGAMPs) are new members of the cyclic dinucleotide family of second messenger signaling molecules identified in both bacteria and mammalian cells. A recent study by Gao et al. published in Cell Research has identified and characterized three 3'3'-cGAMP-specific phosphodiesterases (termed as V cGAP1/2/3) in V. cholerae, thereby providing mechanistic insights into the function of these enzymes that degrade cGAMPs. PMID- 25906993 TI - A DNA ligase required for active DNA demethylation and genomic imprinting in Arabidopsis. PMID- 25906994 TI - Paternally contributed centrioles exhibit exceptional persistence in C. elegans embryos. PMID- 25906995 TI - Deficient plastidic fatty acid synthesis triggers cell death by modulating mitochondrial reactive oxygen species. AB - Programmed cell death (PCD) is of fundamental importance to development and defense in animals and plants. In plants, a well-recognized form of PCD is hypersensitive response (HR) triggered by pathogens, which involves the generation of reactive oxygen species (ROS) and other signaling molecules. While the mitochondrion is a master regulator of PCD in animals, the chloroplast is known to regulate PCD in plants. Arabidopsis Mosaic Death 1 (MOD1), an enoyl-acyl carrier protein (ACP) reductase essential for fatty acid biosynthesis in chloroplasts, negatively regulates PCD in Arabidopsis. Here we report that PCD in mod1 results from accumulated ROS and can be suppressed by mutations in mitochondrial complex I components, and that the suppression is confirmed by pharmaceutical inhibition of the complex I-generated ROS. We further show that intact mitochondria are required for full HR and optimum disease resistance to the Pseudomonas syringae bacteria. These findings strongly indicate that the ROS generated in the electron transport chain in mitochondria plays a key role in triggering plant PCD and highlight an important role of the communication between chloroplast and mitochondrion in the control of PCD in plants. PMID- 25906996 TI - Cryo-EM structure of SNAP-SNARE assembly in 20S particle. AB - N-ethylmaleimide-sensitive factor (NSF) and alpha soluble NSF attachment proteins (alpha-SNAPs) work together within a 20S particle to disassemble and recycle the SNAP receptor (SNARE) complex after intracellular membrane fusion. To understand the disassembly mechanism of the SNARE complex by NSF and alpha-SNAP, we performed single-particle cryo-electron microscopy analysis of 20S particles and determined the structure of the alpha-SNAP-SNARE assembly portion at a resolution of 7.35 A. The structure illustrates that four alpha-SNAPs wrap around the single left-handed SNARE helical bundle as a right-handed cylindrical assembly within a 20S particle. A conserved hydrophobic patch connecting helices 9 and 10 of each alpha-SNAP forms a chock protruding into the groove of the SNARE four-helix bundle. Biochemical studies proved that this structural element was critical for SNARE complex disassembly. Our study suggests how four alpha-SNAPs may coordinate with the NSF to tear the SNARE complex into individual proteins. PMID- 25906997 TI - Damage-tolerant nanotwinned metals with nanovoids under radiation environments. AB - Material performance in extreme radiation environments is central to the design of future nuclear reactors. Radiation induces significant damage in the form of dislocation loops and voids in irradiated materials, and continuous radiation often leads to void growth and subsequent void swelling in metals with low stacking fault energy. Here we show that by using in situ heavy ion irradiation in a transmission electron microscope, pre-introduced nanovoids in nanotwinned Cu efficiently absorb radiation-induced defects accompanied by gradual elimination of nanovoids, enhancing radiation tolerance of Cu. In situ studies and atomistic simulations reveal that such remarkable self-healing capability stems from high density of coherent and incoherent twin boundaries that rapidly capture and transport point defects and dislocation loops to nanovoids, which act as storage bins for interstitial loops. This study describes a counterintuitive yet significant concept: deliberate introduction of nanovoids in conjunction with nanotwins enables unprecedented damage tolerance in metallic materials. PMID- 25906998 TI - Age and gender differences in the influence of extrinsic product information on acceptability for RTD green tea beverages. AB - BACKGROUND: The introduction of ready-to-drink (RTD) green tea beverage has allowed diverse consumers to consume green teas and related products. Green tea that has been traditionally consumed for its delicate flavor characteristics is also widely consumed for its recognition as a healthy product. Because it is reported that age difference exists in consideration of health-related information, the objective of the study was to investigate how sensory and non sensory factors, in particular health-related information, price and packaging, would affect the flavor acceptability of green tea beverages, depending on consumers' age and gender. RESULTS: Regardless of the product information, old consumers preferred products that provided an indication of health beneficial effect. On the other hand, young consumers tended to be influenced by extrinsic product information such as packaging, brand/manufacturer and/or price, though these consumers were not so much influenced by health beneficial information as were the old consumers. CONCLUSION: The findings of the study implied that the influence of non-sensory information such as health beneficial information in flavor liking differed depending mostly on consumers' age, and little on gender, for RTD green tea beverages. PMID- 25906999 TI - Molecular analysis of the tlyA gene in Campylobacter lari. AB - Full-length tlyA gene and its adjacent genetic loci from the urease-positive thermophilic Campylobacter (UPTC) CF89-12 [approximately 15,000 base pairs (bp) in length], as well as a reference strain Campylobacter lari RM2100 (approximately 9,000 bp), were analyzed. The possible open-reading frame of tlyA from UPTC CF89-12 was shown to have 720 bp with a calculated molecular mass of approximately 26.7 kDa. Using a primer pair designed in silico, a total of approximately 1.1 kbp consisting of putative promoter region, structural gene for tlyA, and its adjacent genetic loci were identified in all 17 C. lari isolates [n = 13 for UPTC; n = 4 for urease-negative (UN) C. lari]. Although sequence differences were demonstrated at approximately 20 loci within the 90 bp non coding (NC) region, including the putative promoter structure candidates immediately upstream of the tlyA gene among the 18 isolates including C. lari RM2100, no sequence differences were identified within the NC region among the five UN C. lari isolates examined. A start codon ATG and a probable ribosome binding site, AGGC(T)GG(A), for the tlyA gene were identified in all 18 isolates, including C. lari RM2100. The putative intrinsic rho-independent transcriptional terminator structure candidate was also identified for the tlyA gene in both UPTC CF89-12 and C. lari RM2100. Additionally, the hemolysis assay was performed with some of the C. lari isolates. The tlyA gene nucleotide sequence data may possibly be useful for discrimination between UN C. lari and UPTC organisms, as well as for the differentiation among the four thermophilic Campylobacter species. PMID- 25907000 TI - Micro-vesicles derived from bone marrow stem cells protect the kidney both in vivo and in vitro by microRNA-dependent repairing. AB - AIMS: Micro-vesicles (MVs) from bone mesenchymal stem cells (MSCs) have been shown to contribute to the recovery of damaged kidney. The aims of the present study are to investigate the biological effects and repair mechanisms of MVs. METHODS: Micro-vesicles were obtained from MSC supernatants. In vitro, the proximal tubular epithelial cells (HK-2) were treated with transforming growth factor (TGF-beta1). The expressions of E-cadherin and alpha-smooth muscle actin (alpha-SMA) were evaluated. In vitro, the mice were divided into: control, unilateral ureteral obstruction (UUO), UUO+MSC, and UUO+MV group. MVs and MSCs were injected after surgery. The mice were killed 7/14 days after surgery and handled for further tests. The micro-RNA expressions were labeled using the miRCURY Hy3/Hy5 Power labeling kit and hybridized on the miRCURY LNA Array. RESULTS: In vitro, MV reversed transforming growth factor-beta1 (TGF-beta1) induced morphological changes, and firmed the expression of E-cadherin and reduced the secretion of alpha-SMA in HK2 cells. In vivo, the level of blood urea nitrogen (BUN) in the MV and MSC group was lower than the UUO (P < 0.01). The Scr level decreased after 7 days of MV treatment (P < 0.05). Administration of MSC and MV reduced Scr level at day 14 (P < 0.05). The level of serum UA decreased with MV administration (day 7,14, P < 0.01). Herein, a total of 503 expressed miRNAs were detected, of which, 266 were in MSC, including 237 in MVs. CONCLUSION: Micro-vesicles (MVs) protect kidneys both in vivo and vitro, and MVs are superior to MSCs in some respects. MVs can be a potential therapy in treatment of kidney diseases. PMID- 25907001 TI - Health disparities and underserved populations: a potential solution, medical school partnerships with free clinics to improve curriculum. AB - Health-care educators share the social responsibility to teach medical students about social determinants of health and health-care disparities and subsequently to encourage medical students to pursue residencies in primary care and medical practice in underserved communities. Free clinics provide care to underserved communities, yet collaborative partnerships with such organizations remain largely untapped by medical schools. Free clinics and medical schools in 10 US states demonstrate that such partnerships are geographically feasible and have the potential to mutually benefit both organizational types. As supported by prior research, students exposed to underserved populations may be more likely to pursue primary care fields and practice in underserved communities, improving health-care infrastructure. PMID- 25907002 TI - The educational value of ward rounds for junior trainees. AB - The ward round (WR) is a complex task and medical teachers are often faced with the challenge of finding a balance between service provision and clinical development of learners. The educational value of WRs is an under-researched area. This short communication aims to evaluate the educational role of WRs for junior trainees and provides insight into current practices. It also identifies obstacles to effective teaching/training in this setting and provides suggestions for improving the quality of WR teaching. PMID- 25907003 TI - Responder and health-related quality of life analyses in men with lower urinary tract symptoms treated with a fixed-dose combination of solifenacin and tamsulosin oral-controlled absorption system: results from the NEPTUNE study. AB - OBJECTIVE: To evaluate the effect of a fixed-dose combination (FDC) of solifenacin and an oral-controlled absorption system (OCASTM) formulation of tamsulosin (TOCAS) on health-related quality of life (HRQoL) in men with lower urinary tract symptoms associated with benign prostatic hyperplasia (LUTS/BPH). PATIENTS AND METHODS: Men with moderate-to-severe storage symptoms and voiding symptoms were treated for 12 weeks with a FDC of solifenacin 6 or 9 mg plus TOCAS (0.4 mg), TOCAS monotherapy (0.4 mg) or placebo in a randomised, double-blind study (NEPTUNE). The co-primary endpoints were Total Urgency Frequency Score (TUFS) and total International Prostate Symptom Score (IPSS). HRQoL was assessed by several secondary endpoints: IPSS QoL index, overactive bladder questionnaire (OAB-q), and Patient Global Impression (PGI) scale. The correlation between symptom improvement (TUFS) and HRQoL was assessed by Spearman rank correlation coefficients. Single and double responder analyses, using subjective and objective measures, were also performed. RESULTS: In the responder analyses, men treated with a FDC of solifenacin 6 mg plus TOCAS consistently had significantly improved outcomes compared with placebo (8/8 responder analyses performed) and TOCAS (6/8 responder analyses performed). There was a significant correlation (P < 0.001) between the reduction in TUFS and the improvement in HRQoL defined by IPSS QoL score, OAB-q symptom bother score, PGI overall bladder symptoms and PGI general health. CONCLUSIONS: In men with LUTS/BPH who have moderate-to-severe storage symptoms and voiding symptoms, the reduction in symptoms with a once daily FDC of solifenacin and TOCAS was associated with consistent patient relevant improvements in HRQoL compared with placebo and TOCAS monotherapy. PMID- 25907004 TI - Promoting a normal birth and a positive birth experience - Norwegian women's perspectives. AB - OBJECTIVE: the aim of this study is to gain a deeper understanding of a woman's internal factors and factors in her environment that are important for a normal birth and a positive birth experience. DESIGN/SETTING: a qualitative approach was selected for data collection, and the data presented are derived from in-depth interviews. Twelve healthy first time Norwegian mothers, aged 22-34, with a normal childbirth and a positive birth experience were interviewed five to six weeks after giving birth. All participants had given birth at a maternity unit, where 4000 births take place per year. The transcribed interviews were analysed through systematic text condensation. FINDINGS: the findings included two main themes: safe environment and emotional strength. Stability in everyday life and close relationships provided the women with the safe environment they needed. The women had a positive attitude to childbirth and they had all previously developed coping strategies. They highlighted that these acquired coping strategies contributed to higher emotional strength and a positive birth experience. CONCLUSIONS: the women experienced that a safe environment and network contributed to a sense of trust and emotional strength, which were positive factors promoting a normal birth and a positive birth experience. The women had a positive attitude towards the birth and used acquired coping strategies to deal with it, which in turn led to a positive birth experience. The natural vision the women had in connection with childbirth was part of their antenatal preparation, which also contributed to a positive experience of childbirth. PMID- 25907005 TI - Chondroitin-based nanoplexes as peptide delivery systems--Investigations into the self-assembly process, solid-state and extended release characteristics. AB - A new type of self-assembled polyelectrolyte complex nanocarrier composed of chondroitin (CHON) and protamine (PROT) was designed and the ability of the carriers to bind salmon calcitonin (sCT) was examined. The response of sCT-loaded CHON/PROT NPs to a change in the properties of the liquid medium, e.g. its pH, composition or ionic strength was studied and in vitro peptide release was assessed. The biocompatibility of the NPs was evaluated in Caco-2 cells. CHON/PROT NPs were successfully obtained with properties that were dependent on the concentration of the polyelectrolytes and their mixing ratio. X-ray diffraction determined the amorphous nature of the negatively charged NPs, while those with the positive surface potential were semi-crystalline. sCT was efficiently associated with the nanocarriers (98-100%) and a notably high drug loading (13-38%) was achieved. The particles had negative zeta potential values and were homogenously dispersed with sizes between 60 and 250 nm. CHON/PROT NPs released less than 10% of the total loaded peptide in the first hour of the in vitro release studies. The enthalpy of the decomposition exotherm correlated with the amount of sCT remaining in NPs after the release experiments. The composition of medium and its ionic strength was found to have a considerable influence on the release of sCT from CHON/PROT NPs. Complexation to CHON markedly reduced the toxic effects exerted by PROT and the NPs were compatible and well tolerated by Caco-2 cells. PMID- 25907006 TI - A new tablet brittleness index. AB - Brittleness is one of the important material properties that influences the success or failure of powder compaction. We have discovered that the reciprocal of diametrical elastic strain at fracture is the most suitable tablet brittleness indices (TBIs) for quantifying brittleness of pharmaceutical tablets. The new strain based TBI is supported by both theoretical considerations and a systematic statistical analysis of friability data. It is sufficiently sensitive to changes in both tablet compositions and compaction parameters. For all tested materials, it correctly shows that tablet brittleness increases with increasing tablet porosity for the same powder. In addition, TBI increases with increasing content of a brittle excipient, lactose monohydrate, in the mixtures with a plastic excipient, microcrystalline cellulose. A probability map for achieving less than 1% tablet friability at various combinations of tablet tensile strength and TBI was constructed. Data from marketed tablets validate this probability map and a TBI value of 150 is recommended as the upper limit for pharmaceutical tablets. This TBI can be calculated from the data routinely obtained during tablet diametrical breaking test, which is commonly performed for assessing tablet mechanical strength. Therefore, it is ready for adoption for quantifying tablet brittleness to guide tablet formulation development since it does not require additional experimental work. PMID- 25907007 TI - Monitoring of multiple solid-state transformations at tablet surfaces using multi series near-infrared hyperspectral imaging and multivariate curve resolution. AB - The assessment of the solid-state stability of active pharmaceutical ingredient (API) and/or excipients in solid dosage forms during manufacturing and storage is mandatory for safeguarding quality of the final products. In this work, the solid state transformations in tablets prepared as blends of piroxicam monohydrate, polyvinylpyrrolidone and the lactose forms monohydrate or anhydrate were studied when the tablets were exposed to the 23-120 degrees C range. Multi-series near infrared hyperspectral images were obtained from the surface of each sample for unveiling the local evolution of the solid-state transformations. The preprocessed spectra from the images (dataset) were arranged in augmented matrices, according to the composition of the tablets, and the profile of the overlapped compounds (relative concentration) along the solid-state transformations in the pixels was resolved by using multivariate curve resolution -alternating least squares (MCR-ALS). Therefore, the dehydration of piroxicam and lactose monohydrates could be mapped separately in the samples (explained variances by the models >96%) even when both compounds were being transformed simultaneously (80-120 degrees C). The images reproduced the same trends obtained from thermogravimetric analysis of the tablets, with the advantage that the pixel-to-pixel heterogeneity of each compound at the surface of the tablets was highlighted. PMID- 25907008 TI - Channeling the flood of meta-analyses. PMID- 25907009 TI - Functionalization of medical cotton by direct incorporation of silver nanoparticles. AB - Medical cotton is usually used to clean skin, pack wounds and in other surgical tasks. Such important usages make imparting the antibacterial property to medical cotton is so essential research. The current research focuses on functionalization of medical cotton by direct incorporation of silver nanoparticles (AgNPs) in two-step process namely, pre-alkalization followed by sorption. Decorative color and antibacterial action were accomplished for medical cotton after in situ incorporation of AgNPs without using any other external reducing agent. AgNPs were produced due to the reduction action of alcoholic and aldehydic groups of cotton's skeletal blocks. Cotton fibers were acquired a decorative color attributed to surface plasmon resonance of AgNPs. The treated cotton was characterized by using electron microscope. Results showed that Ag(0) with size distribution of 0-160 nm was formed in the cotton fibers and their size majority (70%) was less than 80 nm. The reduction of Ag(+) to Ag(0) was confirmed by measuring the carboxylic and aldehydic contents. The treated cotton exhibited excellent antibacterial action at low silver contents. The absorbency of cotton was not affected by treatment. The produced medical cotton could be used to safe cleaning of wounds without getting any microbial infections. PMID- 25907010 TI - Lycium barbarum polysaccharide attenuates type II collagen-induced arthritis in mice. AB - No curative treatment is yet available for rheumatoid arthritis (RA), wherein chronic synovitis progresses to cartilage and bone destruction. Considering the recently recognized anti-inflammatory properties of Lycium barbarum polysaccharide (LBP; a derivative of the goji berry), we established the collagen type II-induced arthritis (CIA) mouse model to investigate the potential therapeutic effects and mechanisms of LBP. The CIA-induced changes and LBP related effects were assessed by micro-computed tomography measurement of bone volume/tissue volume and by ELISA and western blotting detection of inflammatory mediators and matrix metalloproteinases (MMPs). The CIA mice showed substantial bone damage, bone loss, and increased concentrations of TNF-alpha, IL-6, IL-17, PGE2, MIP-1, anti-type II collagen IgG, MMP-1, and MMP-3. LBP treatments produced significant dose-dependent improvements in CIA-induced bone damage and bone loss, and significantly reduced CIA-stimulated expression of the inflammatory mediators and MMPs. Thus, LBP therapy can preserve bone integrity in CIA mice, possibly through down-regulation of inflammatory mediators. PMID- 25907011 TI - Hollow chitosan/alginate nanocapsules for bioactive compound delivery. AB - This work aimed at the development of biodegradable nanocapsules as carriers of two bioactive compounds, 5-aminosalycilic acid and glycomacropeptide. Nanocapsules were produced through layer-by-layer (LbL) deposition of chitosan (CH) and alginate (ALG) layers on polystyrene nanoparticles. The bioactive compounds were incorporated on the third layer of the nanocapsules being its encapsulation efficiency and release behaviour evaluated. The LbL deposition process, stability, morphology and size of the multilayer nanocapsules were monitored by means of zeta potential and transmission electron microscopy (TEM). The bioactive compounds release from the CH/ALG nanocapsules was successfully described by a mathematical model (linear superimposition model - LSM), which allowed concluding that bioactive compounds release is due to both Brownian motion and the polymer relaxation of the CH/ALG layers. Final results demonstrated that the synthesized LbL hollow nanocapsules presented spherical morphology and a good capacity to encapsulate different bioactive compounds, being the best results obtained for the system containing 5-aminosalycilic acid (with an encapsulation efficiency of approximately 70%). CH/ALG multilayer nanocapsules could be a promising carrier of bioactive compounds for applications in food and pharmaceutical industries. PMID- 25907012 TI - Interaction of bovine serum albumin with starch nanoparticles prepared by TEMPO mediated oxidation. AB - The objective of this study was to elucidate the interaction of starch nanoparticles prepared through TEMPO oxidation (TEMPO-SNPs) with protein (bovine serum albumin) by various spectroscopic techniques and transmission electron microscopy (TEM). The enhanced absorbance observed by UV spectra and the decrease in fluorescence spectroscopy of bovine serum albumin (BSA) induced by TEMPO-SNPs demonstrated the occurrence of an interaction between BSA and TEMPO-SNPs. The quenching constant was inversely correlated with temperature, showing that the quenching effect of TEMPO-SNPs was static quenching. Electrostatic force had a leading contribution to the binding roles of BSA on TEMPO-SNPs, which was confirmed by negative enthalpy change and positive entropy change. When interacting with TEMPO-SNPs at different concentrations, the content of the alpha helix structure in BSA decreased and beta-sheet and random coil structures increased, indicating that TEMPO-SNPs had an effect on the secondary conformation of BSA. Furthermore, TEM images suggested that nanoparticle-protein complexes were formed. PMID- 25907013 TI - Age-related changes of susceptibility-weighted imaging in subependymal nodules of neonates and children with tuberous sclerosis complex. AB - OBJECTIVES: To assess age-related changes in susceptibility-weighted imaging (SWI) and phase images of subependymal nodules (SENs) in neonates and children with tuberous sclerosis complex (TSC). METHODS: Images of 17 children (age range, 0-14years; mean, 5.5years) with TSC were retrospectively assessed. Changes in signals of SENs on SWI and filtered phase images were scored by two experienced radiologists using a three-point scale. The relation was assessed between patients' age and the average scores of SENs. The phase shift of SENs on the filtered phase image was also measured, and the correlation between age and phase shift was evaluated. Calcification in SENs on CT was compared to the finding on SWI and filtered phase image in four children. RESULTS: No change in signal was found in neonates in SENs on both SWI and filtered phase image. There was a positive correlation between the average scores of SENs and patients' age on both SWI and filtered phase image (Spearman rho=0.64, P=0.006; rho=0.71, P=0.001, respectively). There was a negative correlation between the patients' age and mean phase shift (Spearman rho=-0.86, P<0.001). Comparable or slight lower detectability of susceptibility changes was revealed in SENs on SWI and filtered phase image, compared to calcification on CT. CONCLUSIONS: There are age-related changes in susceptibility and phase in SENs, which may reflect the appearance of calcification in children with TSC. No magnetically susceptible changes were detected in neonates, suggesting a lack of calcification. PMID- 25907014 TI - Re-imagining malaria--a platform for reflections to widen horizons in malaria control. AB - Ongoing political-economic discussions that take stock of social and societal determinants of health present an opportunity for productive dialogue on why current approaches to malaria control and elimination need to be broadened, and how this may be accomplished. They invite us, for example, to look beyond malaria as a disease, to appreciate the experiences of malaria-afflicted populations, to transcend techno-centric approaches, to investigate social conflicts around malaria, to give voice to the communities engaged in bottom-up approaches, and to revisit lessons learned in the past. While contributions from all disciplines are invited to this discussion, social scientists are particularly encouraged to participate. They have struggled in the past to find an appropriate platform within the malaria community that provides them the opportunity to address researchers from other disciplines, malaria practitioners, and policy makers. The Malaria Journal's new thematic series on 're-imagining malaria' offers them this opportunity. The goal of the series is to encourage transdisciplinary thinking, to stimulate discussion, to promote constructive criticism, and to gather overlooked experiences that help to reflect on implicit assumptions. Overall it aims at widening horizons in malaria control. PMID- 25907015 TI - Time to take tension-type headache seriously. PMID- 25907016 TI - The burden of headache: global and regional prevalence of headache and its impact. AB - Headache is a universal symptom. However, despite its prevalence and implications for daily living, headache epidemiology and its public health impact have only been partially documented. Most research has focused on migraine, with data on tension-type headache (TTH) being relatively sparse, especially for countries outside Western Europe and North America. PMID- 25907017 TI - Headache: muscle tension, trigger points and referred pain. AB - Scientific interest in the pathogenesis of tension-type headache (TTH) has lagged behind that of migraine, although TTH is the most common headache disorder and considered the most important in terms of socioeconomic impact. As a result, understanding of the underlying mechanisms of TTH has remained relatively incomplete. PMID- 25907018 TI - Treatment guidelines: implications for community-based headache treatment. AB - Tension-type headache (TTH) is the most common form of headache in the community, affecting up to 80% of people from time to time. At least 10% of people experience episodic TTH on a frequent basis (up to 14 days per month) and the condition is chronic for 2- 3%. PMID- 25907019 TI - Community-based headache management. AB - Tension-type headache (TTH) - also known as 'regular' or 'ordinary' headache - is extremely common. The key symptom is a tight band or pressing pain felt on both sides of the head. The headache pain in TTH is mild or moderate and lasts from several hours up to a few days. TTH usually responds well to treatment with simple over-the-counter (OTC) analgesics such as ibuprofen and paracetamol. PMID- 25907020 TI - Speed, science and optimal pain relief. AB - Pain is a major global health problem. Six of the 11 most prevalent conditions worldwide are pain-related, with tension-type headache and migraine being the second and third most prevalent conditions. Pain also ranks high among the conditions that have the longest-lasting impact: five of the top 11 contributors to years lived with disability are pain-related. PMID- 25907021 TI - Analgesic safety - myths, mysteries and misconceptions. AB - Acute episodes of tension-type headache (TTH) are common and affect people of all ages, races and income levels. Two recommended and commonly used drugs for the treatment of this condition are ibuprofen and paracetamol. However, despite - or perhaps because of - their widespread use, many misconceptions persist about their comparative efficacy and safety. Are concerns about the gastrointenstinal (GI) safety of ibuprofen justified in the non-prescription over-the-counter (OTC) setting? Do low doses of ibuprofen - as used for TTH - increase the risk of heart attacks? Is the efficacy of ibuprofen and paracetamol really the same? PMID- 25907022 TI - Changing behaviours: interventions that count. AB - Many individuals affected by tension-type headache (TTH) choose the self-care route without seeking medical advice from their primary care doctor. As a result, community pharmacies play an important role in identifying patients with TTH, providing education and counselling on potential lifestyle trigger factors and recommending appropriate analgesics. PMID- 25907023 TI - Effects of seat surface inclination on respiration and speech production in children with spastic cerebral palsy. AB - BACKGROUND: Respiratory and speech problems are commonly observed in children with cerebral palsy (CP). The purpose of this study was to identify if inclination of seat surface could influence respiratory ability and speech production in children with spastic diplegic CP. METHODS: Sixteen children with spastic diplegic CP, ages 6 to 12 years old, participated in this study. The subjects' respiratory ability (forced vital capacity (FVC), forced expiratory volume in 1 s (FEV1), peak expiratory flow (PEF), and maximum phonation time (MPT)) were measured in three sitting conditions: a seat surface inclined 0 degrees , anterior 15 degrees , and posterior 15 degrees . RESULTS: FVC was significantly different across three inclinations of seat surface, F(2, 45) = 3.81, P = 0.03. In particular, the subjects' FVC at a seat surface inclined anterior 15 degrees was significantly greater than at a seat surface inclined posterior 15 degrees (P < 0.05). However, FEV1, PEF, and MPT were not significantly affected by seat surface inclination (P > 0.05). CONCLUSIONS: The results suggest that anterior inclination of seat surface may provide a positive effect on respiratory function in children with spastic diplegic CP. PMID- 25907024 TI - [High prevalence of physical inactivity among adolescents living with HIV/Aids]. AB - OBJECTIVE: To assess the prevalence of physical inactivity among adolescents with HIV/AIDS, as well as associated factors. METHODS: Ninety-one adolescents (from 10 to 19 years old) with HIV/AIDS who are patients at a university follow-up service were interviewed. Anthropometric data (weight, height, and waist circumference) were measured twice; clinical information was obtained from medical records, and habitual physical activity was assessed by a questionnaire proposed by Florindo et al. The cutoff point for sedentariness was 300minutes/week. RESULTS: The prevalence of inadequate height for age, malnutrition, and overweight/obesity was 15.4%, 9.9% and 12.1%, respectively. The most common physical activities were soccer (44.4%), volleyball (14.4%) and cycling (7.8%). The median times spent with physical activity and walking/bicycling to school were 141minutes and 39minutes, respectively. Most adolescents (71.4%) were sedentary and this proportion was higher among girls (p=0.046). CONCLUSIONS: A high prevalence of physical inactivity among adolescents with HIV/AIDS was observed, similarly to the general population. Promoting physical activity among adolescents, especially among girls with HIV/AIDS, as well as monitoring it should be part of the follow up routine of these patients. PMID- 25907025 TI - Where to cross? New insights into the location of meiotic crossovers. AB - During meiosis, the repair of induced DNA double-strand breaks (DSBs) produces crossovers (COs). COs are essential for the proper segregation of homologous chromosomes at the first meiotic division. In addition, COs generate new combinations of genetic markers in the progeny. CO localization is tightly controlled, giving rise to patterns that are specific to each species. The underlying mechanisms governing CO location, however, are poorly understood. Recent studies highlight the complexity of the multiple interconnected factors involved in shaping the CO landscape and demonstrate that the mechanisms that control CO distribution can vary from species to species. Here, we provide an overview of the recent findings related to CO distribution and discuss their impact on our understanding of the control of meiotic recombination. PMID- 25907026 TI - The effects of recombination, mutation and selection on the evolution of the Rp1 resistance genes in grasses. AB - Plant immune genes, or resistance genes, are involved in a co-evolutionary arms race with a diverse range of pathogens. In agronomically important grasses, such R genes have been extensively studied because of their role in pathogen resistance and in the breeding of resistant cultivars. In this study, we evaluate the importance of recombination, mutation and selection on the evolution of the R gene complex Rp1 of Sorghum, Triticum, Brachypodium, Oryza and Zea. Analyses show that recombination is widespread, and we detected 73 independent instances of sequence exchange, involving on average 1567 of 4692 nucleotides analysed (33.4%). We were able to date 24 interspecific recombination events and found that four occurred postspeciation, which suggests that genetic introgression took place between different grass species. Other interspecific events seemed to have been maintained over long evolutionary time, suggesting the presence of balancing selection. Significant positive selection (i.e. a relative excess of nonsynonymous substitutions (dN /dS >1)) was detected in 17-95 codons (0.42 2.02%). Recombination was significantly associated with areas with high levels of polymorphism but not with an elevated dN /dS ratio. Finally, phylogenetic analyses show that recombination results in a general overestimation of the divergence time (mean = 14.3%) and an alteration of the gene tree topology if the tree is not calibrated. Given that the statistical power to detect recombination is determined by the level of polymorphism of the amplicon as well as the number of sequences analysed, it is likely that many studies have underestimated the importance of recombination relative to the mutation rate. PMID- 25907027 TI - Number of Hydroxyl Groups on the B-Ring of Flavonoids Affects Their Antioxidant Activity and Interaction with Phorbol Ester Binding Site of PKCdelta C1B Domain: In Vitro and in Silico Studies. AB - Although flavonoids have been reported for their benefits and nutraceutical potential use, the importance of their structure on their beneficial effects, especially on signal transduction mechanisms, has not been well clarified. In this study, three flavonoids, pinocembrin, naringenin, and eriodictyol, were chosen to determine the effect of hydroxyl groups on the B-ring of flavonoid structure on their antioxidant activity. In vitro assays, including DPPH scavenging activity, ROS quantification by flow cytometer, and proteins immunoblotting, and in silico analysis by molecular docking between the flavonoids and C1B domain of PKCdelta phorbol ester binding site were both used to complete this study. Eriodictyol (10 MUM), containing two hydroxyl groups on the B-ring, exhibited significantly higher (p < 0.05) antioxidant activity than pinocembrin and naringenin. The IC50 values of eriodictyol, naringenin, and pinocembrin were 17.4 +/- 0.40, 30.2 +/- 0.61, and 44.9 +/- 0.57 MUM, respectively. In addition, eriodictyol at 10 MUM remarkably inhibited the phosphorylation of PKCdelta at 63.4% compared with PMA-activated RAW264.7, whereas pinocembrin and naringenin performed inhibition activity at 76.8 and 72.6%, respectively. According to the molecular docking analysis, pinocembrin, naringenin, and eriodictyol showed -CDOCKER_energy values of 15.22, 16.95, and 21.49, respectively, reflecting that eriodictyol could bind with the binding site better than the other two flavonoids. Interestingly, eriodictyol had a remarkably different pose to bind with the kinase as a result of the two hydroxyl groups on its B-ring, which consequently contributed to greater antioxidant activity over pinocembrin and naringenin. PMID- 25907028 TI - Foot-and-Mouth Disease in Red Deer - Experimental Infection and Test Methods Performance. AB - The aim of this study was to evaluate a number of foot-and-mouth disease (FMD) test methods for use in red deer. Ten animals were intranasally inoculated with the FMD virus (FMDV) O UKG 11/2001, monitored for clinical signs, and samples taken regularly (blood, serum, oral swabs, nasal swabs, probang samples and lesion swabs, if present) over a 4-week period. Only one animal, deer 1103, developed clinical signs (lesions under the tongue and at the coronary band of the right hind hoof). It tested positive by 3D and IRES real-time reverse transcription polymerase chain reaction (rRT-PCR) in various swabs, lesion materials and serum. In a non-structural protein (NSP) in-house ELISA (NSP-ELISA IH), one commercial ELISA (NSP-ELISA-PR) and a commercial antibody NSP pen side test, only deer 1103 showed positive results from day post-inoculation (dpi) 14 onwards. Two other NSP-ELISAs detected anti-NSP serum antibodies with lower sensitivity. It also showed rising antibody levels in the virus neutralization test (VNT), the in-house SPO-ELISA-IH and the commercial SPO-ELISA-PR at dpi 9, and in another two commercial SPO-ELISAs at dpi 12 (SPO-ELISA-IV) and dpi 19 (SPO ELISA-IZ), respectively. Six of the red deer that had been rRT-PCR and antibody negative were re-inoculated intramuscularly with the same O-serotype FMDV at dpi 14. None of these animals became rRT-PCR or NSP-ELISA positive, but all six animals became positive in the VNT, the in-house SPO-ELISA-IH and the commercial SPO-ELISA-PR. Two other commercial SPO-ELISAs were less sensitive or failed to detect animals as positive. The rRT-PCRs and the four most sensitive commercial ELISAs that had been used for the experimentally inoculated deer were further evaluated for diagnostic specificity (DSP) using 950 serum samples and 200 nasal swabs from non-infected animals. DSPs were 100% for the rRT-PCRs and between 99.8 and 100% for the ELISAs. PMID- 25907030 TI - A fully digital approach to replicate peri-implant soft tissue contours and emergence profile in the esthetic zone. AB - OBJECTIVE: This short communication reports on a novel digital technique designated - the "Fully Digital Technique (FDT)" - to take the impression of the peri-implant soft tissue and emergence profile with an intraoral scanner, digitally capturing both the three dimensional position of the implant platform and the coronal and gingival parts of the provisional retained restoration. MATERIALS AND METHODS: A first intraoral digital impression, which generated a standard triangulation language file (STL1), was taken using a standardized implant scanbody to detect the position of the implant. A second digital impression (STL2) with the provisional retained restoration in situ was performed in two steps: the first part of the scan captured all details of the vestibular and palatal sides of the provisional retained restoration and the adjacent teeth. The provisional retained restoration was then unscrewed, and the subgingival part of the restoration was scanned directly out of the mouth to determine its subgingival shape. STL1 and STL2 were imported into imaging software and superimposed using the "best fit" algorithm to achieve a new merged file (STL3) with the 3D implant position, the peri-implant mucosa, and emergence profile. The merged file was used to design the CAD/CAM customized abutment and to realize a stereolithographic model by 3D printing. RESULTS: The STL superimposition of digital impressions of the implant position and the provisional retained restoration constitute a novel technique to obtain a single STL file with the implant position and its peri-implant mucosal architecture. CONCLUSIONS: FDT is a rapid digital approach for achieving all information of the peri-implant soft tissue and emergence profile directly from the provisional retained restoration. PMID- 25907029 TI - Interpersonal Risk Profiles for Youth Depression: A Person-Centered, Multi-Wave, Longitudinal Study. AB - Independent lines of research illustrate the benefits of social support and the negative consequences of conflict and emotional neglect across family and peer contexts with regard to depression. However, few studies have simultaneously examined negative and positive interactions across relationships. We sought to address this gap in the literature by utilizing a person-centered approach to a) understand empirical, interpersonal profiles in youth and b) understand how these profiles confer risk for prospective depression. At baseline, 678 youth (380 females; 298 males) 3rd (N = 208), 6th (N = 245), and 9th graders (N = 225) completed self-report measures for self-perceived negative/positive relationships across family and peers, anxiety symptoms, and depressive symptoms in a laboratory setting. Next, youth were called every 3 months for 18 months and completed self-report depressive and anxiety symptom forms. Two-step cluster analyses suggested that children and adolescents fell into one of three interpersonal clusters, labeled: Support, Conflict, and Neglect. Our analyses supported a convergence model in which the quality of relationship was consistent across peers and family. Furthermore, mixed-level modeling (MLM) findings demonstrated that youth in the Conflict cluster were at increased risk for prospective depressive symptoms, while the Supported and Neglected profiles demonstrated similar symptom levels. Findings were unique to depressive symptoms and consistent across sex and age. Conflict seemed to uniquely confer risk for depression as findings concerning anxiety were not significant. These findings influence our interpersonal conceptualization of depression as well as clinical implications for how to assess and treat depression in youth. PMID- 25907031 TI - Carotid chemoreceptors do not mediate hypoxic-induced gasping and autoresuscitation in newborn rats. AB - Experiments were carried out on 48, 5-6-day-old rat pups to investigate the influence of carotid denervation on their time to last gasp during a single period of hypoxia, and on their ability to autoresuscitate from primary apnea during repeated hypoxic challenge. One group of pups was studied with intact carotid chemoreceptors and one group was studied following surgical denervation of the carotid chemoreceptors. Carotid denervation eliminated the early tachypneic phase during exposure to hypoxia and delayed the time to arousal/excitement but did not alter the time to primary apnea, the time to last gasp or the total number of gasps during exposure to a single period of unrelenting hypoxia. Furthermore, carotid denervation did not alter the number of successful autoresuscitations from primary apnea during repeated hypoxic exposure. Thus, the carotid chemoreceptors are not essential for the initiation or maintenance of gasping nor are they are integral to gasping effecting successful autoresuscitation from hypoxic-induced apnea in newborn rats. PMID- 25907032 TI - Long-lasting isolated freezing of gait with good response to methylphenidate: A patient with pantothenate kinase-associated neurodegeneration. PMID- 25907033 TI - Low-level GATA2 overexpression promotes myeloid progenitor self-renewal and blocks lymphoid differentiation in mice. AB - The transcription factor GATA2 is highly expressed in hematopoietic stem cells and is downregulated during lineage maturation. Gain of function mutations, loss of function mutations, and overexpression of GATA2 have been reported in acute myeloid leukemia. In previous studies, we and others showed that GATA2 overexpression at high levels, similar to that seen in hematopoietic stem cells, blocked differentiation of hematopoietic stem cells and progenitors. To better understand the effects of GATA2, we designed a Tamoxifen-inducible GATA2-estrogen receptor (ERT) vector. In the absence of Tamoxifen, small amounts of GATA2-ERT were still able to enter the nucleus in mouse bone marrow (BM) cells, providing us with a tool to test the effects of low-level GATA2 overexpression. We observed that this low-level GATA2 overexpression enhanced self-renewal of myeloid progenitors in vitro and resulted in immortalization of BM cells to myeloid cell lines. Continuous GATA2-ERT expression was required for the proliferation of these immortalized lines. Myeloid expansion and a block in T and B lineage differentiation were observed in mice transplanted with GATA2-ERT-expressing BM cells. Myeloid expansion occurred after the granulocyte monocyte progenitor stage, and lymphoid block was distal to the common lymphoid progenitor in transgenic mice. GATA2 appeared to induce growth via downstream activation of Nmyc and Hoxa9. Our results demonstrate that GATA2 overexpression at low level confers self-renewal capacity to myeloid progenitors and is relevant to myeloid leukemia development. PMID- 25907034 TI - Food-associated stimuli enhance barrier properties of gastrointestinal mucus. AB - Orally delivered drugs and nutrients must diffuse through mucus to enter the circulatory system, but the barrier properties of mucus and their modulation by physiological factors are generally poorly characterized. The main objective of this study was to examine the impact of physicochemical changes occurring upon food ingestion on gastrointestinal (GI) mucus barrier properties. Lipids representative of postprandial intestinal contents enhanced mucus barriers, as indicated by a 10-142-fold reduction in the transport rate of 200 nm microspheres through mucus, depending on surface chemistry. Physiologically relevant increases in [Ca(2+)] resulted in a 2-4-fold reduction of transport rates, likely due to enhanced cross-linking of the mucus gel network. Reduction of pH from 6.5 to 3.5 also affected mucus viscoelasticity, reducing particle transport rates approximately 5-10-fold. Macroscopic visual observation and micro-scale lectin staining revealed mucus gel structural changes, including clumping into regions into which particles did not penetrate. Histological examination indicated food ingestion can prevent microsphere contact with and endocytosis by intestinal epithelium. Taken together, these results demonstrate that GI mucus barriers are significantly altered by stimuli associated with eating and potentially dosing of lipid-based delivery systems; these stimuli represent broadly relevant variables to consider upon designing oral therapies. PMID- 25907035 TI - Mode of action of claudin peptidomimetics in the transient opening of cellular tight junction barriers. AB - In epithelial/endothelial barriers, claudins form tight junctions, seal the paracellular cleft, and limit the uptake of solutes and drugs. The peptidomimetic C1C2 from the C-terminal half of claudin-1's first extracellular loop increases drug delivery through epithelial claudin-1 barriers. However, its molecular and structural mode of action remains unknown. In the present study, >100 MUM C1C2 caused paracellular opening of various barriers with different claudin compositions, ranging from epithelial to endothelial cells, preferentially modulating claudin-1 and claudin-5. After 6 h incubation, C1C2 reversibly increased the permeability to molecules of different sizes; this was accompanied by redistribution of claudins and occludin from junctions to cytosol. Internalization of C1C2 in epithelial cells depended on claudin-1 expression and clathrin pathway, whereby most C1C2 was retained in recyclosomes >2 h. In freeze fracture electron microscopy, C1C2 changed claudin-1 tight junction strands to a more parallel arrangement and claudin-5 strands from E-face to P-face association - drastic and novel effects. In conclusion, C1C2 is largely recycled in the presence of a claudin, which explains the delayed onset of barrier and junction loss, the high peptide concentration required and the long-lasting effect. Epithelial/endothelial barriers are specifically modulated via claudin-1/claudin 5, which can be targeted to improve drug delivery. PMID- 25907036 TI - A transient cell-shielding method for viable MSC delivery within hydrophobic scaffolds polymerized in situ. AB - Cell-based therapies have emerged as promising approaches for regenerative medicine. Hydrophobic poly(ester urethane)s offer the advantages of robust mechanical properties, cell attachment without the use of peptides, and controlled degradation by oxidative and hydrolytic mechanisms. However, the application of injectable hydrophobic polymers to cell delivery is limited by the challenges of protecting cells from reaction products and creating a macroporous architecture post-cure. We designed injectable carriers for cell delivery derived from reactive, hydrophobic polyisocyanate and polyester triol precursors. To overcome cell death caused by reaction products from in situ polymerization, we encapsulated bone marrow-derived stem cells (BMSCs) in fastdegrading, oxidized alginate beads prior to mixing with the hydrophobic precursors. Cells survived the polymerization at >70% viability, and rapid dissolution of oxidized alginate beads after the scaffold cured created interconnected macropores that facilitated cellular adhesion to the scaffold in vitro. Applying this injectable system to deliver BMSCs to rat excisional skin wounds showed that the scaffolds supported survival of transplanted cells and infiltration of host cells, which improved new tissue formation compared to both implanted, pre-formed scaffolds seeded with cells and acellular controls. Our design is the first to enable injectable delivery of settable, hydrophobic scaffolds where cell encapsulation provides a mechanism for both temporary cytoprotection during polymerization and rapid formation of macropores post-polymerization. This simple approach provides potential advantages for cell delivery relative to hydrogel technologies, which have weaker mechanical properties and require incorporation of peptides to achieve cell adhesion and degradability. PMID- 25907037 TI - A cyanine-modified upconversion nanoprobe for NIR-excited imaging of endogenous hydrogen peroxide signaling in vivo. AB - Endogenous hydrogen peroxide is an important parameter associated with cellular signal transduction and homeostasis. However, abnormal H2O2 regulation in live systems has been implicated in many pathological conditions. Monitoring this signal in live systems is essential but challenging because current H2O2 probes are impractical for efficient bio-imaging due to UV/visible light as the excitation source. We herein present a novel design based on an organic fluorophore-attached lanthanide-doped upconversion nanoprobe (CYD1-UCNPs) for selective UCL detection of H2O2. This nanoprobe represents the next-generation imaging tool that features a robust UCL "turn-on" response to H2O2 with NIR excited ratiometric signals and has potential applications in ratiometric UCL imaging of endogenous H2O2 generating in living cells and whole-body animals. PMID- 25907038 TI - Transfer stamping of human mesenchymal stem cell patches using thermally expandable hydrogels with tunable cell-adhesive properties. AB - Development of stem cell delivery system with ability of control over mutilineage differentiation and improved engraft efficiency is imperative in regenerative medicine. We herein report transfer stamping of human mesenchymal stem cells (hMSCs) patches using thermally expandable hydrogels with tunable cell-adhesive properties. The hydrogels were prepared from functionalized four arm copolymer of Tetronic((r)), and the cell adhesion on the hydrogel was modulated by incorporation of fibronectin (FN) or cell-adhesive peptide (RGD). The resulting hydrogels showed spontaneous expansion in size within 10 min in response to the temperature reduction from 37 to 4 degrees C. The adhesion and proliferation of hMSCs on FN-hydrogels were positively tunable in proportion to the amount of FN within hydrogels with complete monolayer of hMSCs (hMSC patch) being successfully achieved. The hMSC patch on the hydrogel was faced to the target substrate, which was then easily detached and re-attached to the target when the temperature was reduced from 37 degrees C up to 4 degrees C. We found that the transfer stamping of cell patch was facilitated at lower temperature of 4 degrees C relative to 25 degrees C, with the use of thinner hydrogels (0.5 mm in thickness relatively to 1.0 or 1.5 mm) and longer transfer time (>15 min). Notably, the hMSC patch was simply transferred from the hydrogel to the subcutaneous mouse skin tissue within 15 min with cold saline solution being dropped to the hydrogel. The hMSC patch following osteogenic or adipogenic commitment was also achieved with long-term culture of hMSCs on the hydrogel, which was successfully detached to the target surface. These results suggest that the hydrogels with thermally expandable and tunable cell-adhesive properties may serve as a universal substrate to harvest hMSC patch in a reliable and effective manner, which could potentially be utilized in many cell-sheet based therapeutic applications. PMID- 25907039 TI - Simultaneous isolation and detection of circulating tumor cells with a microfluidic silicon-nanowire-array integrated with magnetic upconversion nanoprobes. AB - The development of sensitive and convenient methods for detection, enrichment, and analysis of circulating tumor cells (CTCs), which serve as an importance diagnostic indicator for metastatic progression of cancer, has received tremendous attention in recent years. In this work, a new approach characteristic of simultaneous CTC capture and detection is developed by integrating a microfluidic silicon nanowire (SiNW) array with multifunctional magnetic upconversion nanoparticles (MUNPs). The MUNPs were conjugated with anti-EpCAM antibody, thus capable to specifically recognize tumor cells in the blood samples and pull them down under an external magnetic field. The capture efficiency of CTCs was further improved by the integration with a microfluidic SiNW array. Due to the autofluorescence free nature in upconversion luminescence (UCL) imaging, our approach allows for highly sensitive detection of small numbers of tumor cells, which afterward could be collected for further analysis and re-culturing. We have further demonstrated that this approach can be applied to detect CTCs in clinical blood samples from lung cancer patients, and obtained consistent results by analyzing the UCL signals and the clinical outcomes of lung cancer metastasis. Therefore our approach represents a promising platform in CTC capture and detection with potential clinical utilization in cancer diagnosis and prognosis. PMID- 25907041 TI - Versatile preparation of intracellular-acidity-sensitive oxime-linked polysaccharide-doxorubicin conjugate for malignancy therapeutic. AB - Recently, chemotherapy has been one of the most important therapeutic approaches for malignant tumors. The tumor tissular or intracellular microenvironment sensitive polymer-doxorubicin (DOX) conjugates demonstrate great potential for improved antitumor efficacy and reduced side effects. In this work, the acid sensitive dextran-DOX conjugate (noted as Dex-O-DOX) was synthesized through the versatile efficient oximation reaction between the terminal aldehyde group of polysaccharide and the amino group in DOX in the buffer solution of sodium acetate/acetic acid. The insensitive one, i.e., Dex-b-DOX, was prepared similarly as Dex-O-DOX with a supplemented reduction reaction. The DOX release from Dex-O DOX was pH-dependent and accelerated by the decreased pH. The efficient intracellular DOX release from Dex-O-DOX toward the human hepatoma HepG2 cells was further confirmed. Furthermore, Dex-O-DOX exhibited a closer antiproliferative activity to free DOX.HCl as the extension of time. More importantly, compared with Dex-b-DOX, Dex-O-DOX exhibited higher antitumor activity and lower toxicity, which were further confirmed by the systemic histological and immunohistochemical analyses. Hence, the facilely prepared smart polysaccharide-DOX conjugates, i.e., Dex-O-DOX, exhibited great potential in the clinical chemotherapy of malignancy. PMID- 25907040 TI - Stiffening and unfolding of early deposited-fibronectin increase proangiogenic factor secretion by breast cancer-associated stromal cells. AB - Fibronectin (Fn) forms a fibrillar network that controls cell behavior in both physiological and diseased conditions including cancer. Indeed, breast cancer associated stromal cells not only increase the quantity of deposited Fn but also modify its conformation. However, (i) the interplay between mechanical and conformational properties of early tumor-associated Fn networks and (ii) its effect on tumor vascularization remain unclear. Here, we first used the Surface Forces Apparatus to reveal that 3T3-L1 preadipocytes exposed to tumor-secreted factors generate a stiffer Fn matrix relative to control cells. We then show that this early matrix stiffening correlates with increased molecular unfolding in Fn fibers, as determined by Forster Resonance Energy Transfer. Finally, we assessed the resulting changes in adhesion and proangiogenic factor (VEGF) secretion of newly seeded 3T3-L1s, and we examined altered integrin specificity as a potential mechanism of modified cell-matrix interactions through integrin blockers. Our data indicate that tumor-conditioned Fn decreases adhesion while enhancing VEGF secretion by preadipocytes, and that an integrin switch is responsible for such changes. Collectively, our findings suggest that simultaneous stiffening and unfolding of initially deposited tumor-conditioned Fn alters both adhesion and proangiogenic behavior of surrounding stromal cells, likely promoting vascularization and growth of the breast tumor. This work enhances our knowledge of cell - Fn matrix interactions that may be exploited for other biomaterials based applications, including advanced tissue engineering approaches. PMID- 25907042 TI - Guanidinylated block copolymers for gene transfer: A comparison with amine-based materials for in vitro and in vivo gene transfer efficiency. AB - There is currently no cure for neuron loss in the brain, which can occur due to traumatic injury or neurodegenerative disease. One proposed method to enhance brain neurogenesis is gene transfer to neural progenitor cells. In this work, a guanidine-based copolymer was synthesized and compared to an amine-based copolymer analog previously shown to effectively deliver genes in the murine brain. The guanidine-based copolymer was more efficient at gene transfer to immortalized, cultured cell lines; however, the amine-based copolymer was more effective at gene transfer in the brain. DNA condensation studies revealed that the nucleic acid complexes formed with the guanidine-based copolymer were more susceptible to unpackaging in the presence of anionic proteoglycans compared to complexes formed with the amine-based copolymer. Therefore, polyplexes formed from the amine-based copolymer may be more resistant to destabilization by the heparan sulfate proteoglycans present in the stem cell niches of the brain. PMID- 25907043 TI - Self healing hydrogels composed of amyloid nano fibrils for cell culture and stem cell differentiation. AB - Amyloids are highly ordered protein/peptide aggregates associated with human diseases as well as various native biological functions. Given the diverse range of physiochemical properties of amyloids, we hypothesized that higher order amyloid self-assembly could be used for fabricating novel hydrogels for biomaterial applications. For proof of concept, we designed a series of peptides based on the high aggregation prone C-terminus of Abeta42, which is associated with Alzheimer's disease. These Fmoc protected peptides self assemble to beta sheet rich nanofibrils, forming hydrogels that are thermoreversible, non-toxic and thixotropic. Mechanistic studies indicate that while hydrophobic, pi-pi interactions and hydrogen bonding drive amyloid network formation to form supramolecular gel structure, the exposed hydrophobic surface of amyloid fibrils may render thixotropicity to these gels. We have demonstrated the utility of these hydrogels in supporting cell attachment and spreading across a diverse range of cell types. Finally, by tuning the stiffness of these gels through modulation of peptide concentration and salt concentration these hydrogels could be used as scaffolds that can drive differentiation of mesenchymal stem cells. Taken together, our results indicate that small size, ease of custom synthesis, thixotropic nature makes these amyloid-based hydrogels ideally suited for biomaterial/nanotechnology applications. PMID- 25907044 TI - Correlation of the composition of biominerals with their ability of stimulating intracellular DNA sensors and inflammatory cytokines. AB - Biominerals (or microcalcification) deposited in soft tissues are associated with a number of pathogeneses and cancer progressions. Biominerals have also shown promise for DNA delivery and tissue engineering. Biominerals themselves may stimulate NALP3 inflammasomes, and DNA delivered by biominerals can potentially engage with intracellular DNA sensors, resulting in unwanted inflammatory responses. In this study, a library of biominerals doped with or without DNA is formed through surface-induced biomineralization. It is demonstrated that empty biominerals stimulate NALP3 inflammasomes and induce the production of IL-1beta. They are also able to activate mouse embryonic fibroblasts (MEFs) and induce inflammatory cytokines, i.e. IL-6. DNA delivered by biominerals escapes the detection of TLR9, but activates DAI and inflammasomes. Furthermore, it is shown that the level of both IL-1beta and IL-6 is correlated with the composition of biominerals, in particular the ratio of Mg(Sr) to Ca, and the pH sensitivity of biominerals. These results provide insights into the design of safe and effective DNA delivery systems and biocompatible implants as well as the understanding of the pathogeneses of biominerals deposited in soft tissues. PMID- 25907045 TI - In situ single step detection of exosome microRNA using molecular beacon. AB - In situ single step detection of microRNAs (miRNA) in a whole exosome has been developed as a novel diagnosis method that can be utilized for various diseases. Exosomes are small extracellular vesicles that contain biomarker miRNAs produced from their originating cells and are known to travel through the circulatory system. This makes exosomal miRNAs from the body fluids an attractive biomarker that can lead to a paradigm shift in the diagnosis of disease. However, current techniques, including real-time PCR analysis, are time-consuming and laborious, making them unsuitable for exosomal miRNA detection for diagnosis. Thus, the development of alternative methods is necessary. Herein, we have demonstrated that exosomal miRNAs can be detected directly using a nano-sized fluorescent oligonucleotide probe, molecular beacon. MiRNA-21 in exosomes from breast cancer cells were detected successfully by molecular beacons in a quantitative manner. Permeabilization by streptolysin O treatment further enhanced the delivery of molecular beacons into exosomes, giving significantly increased signals from target miRNAs. In addition, we selectively detected cancer cell-derived exosomal miRNA-21 among heterogeneous exosome mixtures and in human serum. The method developed in the article is simple, fast, and sensitive, so it will offer great opportunities for the high-throughput diagnosis and prognosis of diseases. PMID- 25907046 TI - Newly identified interfibrillar collagen crosslinking suppresses cell proliferation and remodelling. AB - Copper is becoming recognised as a key cation in a variety of biological processes. Copper chelation has been studied as a potential anti-angiogenic strategy for arresting tumour growth. Conversely the delivery of copper ions and complexes in vivo can elicit a pro-angiogenic effect. Previously we unexpectedly found that copper-stimulated intraperitoneal angiogenesis was accompanied by collagen deposition. Here, in hard tissue, not only was healing accelerated by copper, but again enhanced deposition of collagen was detected at 2 weeks. Experiments with reconstituted collagen showed that addition of copper ions post fibrillogenesis rendered plastically-compressed gels resistant to collagenases, enhanced their mechanical properties and increased the denaturation temperature of the protein. Unexpectedly, this apparently interfibrillar crosslinking was not affected by addition of glucose or ascorbic acid, which are required for crosslinking by advanced glycation end products (AGEs). Fibroblasts cultured on copper-crosslinked gels did not proliferate, whereas those cultured with an equivalent quantity of copper on either tissue culture plastic or collagen showed no effect compared with controls. Although non-proliferative, fibroblasts grown on copper-cross-linked collagen could migrate, remained metabolically active for at least 14 days and displayed a 6-fold increase in Mmps 1 and 3 mRNA expression compared with copper-free controls. The ability of copper ions to crosslink collagen fibrils during densification and independently of AGEs or Fenton type reactions is previously unreported. The effect on MMP susceptibility of collagen and the dramatic change in cell behaviour on this crosslinked ECM may contribute to shedding some light on unexplained phenomena as the apparent benefit of copper complexation in fibrotic disorders or the enhanced collagen deposition in response to localised copper delivery. PMID- 25907047 TI - Novel micropatterns mechanically control fibrotic reactions at the surface of silicone implants. AB - Over the past decade, various implantable devices have been developed to treat diseases that were previously difficult to manage such diabetes, chronic pain, and neurodegenerative disorders. However, translation of these novel technologies into clinical practice is often difficult because fibrotic encapsulation and/or rejection impairs device function after body implantation. Ideally, cells of the host tissue should perceive the surface of the implant being similar to the normal extracellular matrix. Here, we developed an innovative approach to provide implant surfaces with adhesive protein micropatterns. The patterns were designed to promote adhesion of fibroblasts and macrophages by simultaneously suppressing fibrogenic activation of both cell types. In a rat model, subcutaneously implanted silicone pads provided with the novel micropatterns caused 6-fold lower formation of inflammatory giant cells compared with clinical grade, uncoated, or collagen-coated silicone implants. We further show that micropatterning of implants resulted in 2-3-fold reduced numbers of pro-fibrotic myofibroblast by inhibiting their mechanical activation. Our novel approach allows controlled cell attachment to implant surfaces, representing a critical advance for enhanced biointegration of implantable medical devices. PMID- 25907048 TI - Tumor-environment biomimetics delay peritoneal metastasis formation by deceiving and redirecting disseminated cancer cells. AB - Peritoneal metastasis is life threatening and is the result of an extensive communication between disseminated cancer cells, mesothelial cells and cancer associated fibroblasts (CAF). CAFs secrete extracellular matrix (ECM) proteins creating a receptive environment for peritoneal implantation. Considering cancer as an ecosystem may provide opportunities to exploit CAFs to create biomimetic traps to deceive and redirect cancer cells. We have designed microparticles (MP) containing a CAF-derived ECM-surface that is intended to compete with natural niches. CAFs were encapsulated in alginate/gelatine beads (500-750 MUm in diameter) functionalised with a polyelectrolyte coating (MP[CAF]). The encapsulated CAFs remain viable and metabolically active (>=35 days), when permanently encapsulated. CAF-derived ECM proteins are retained by the non biodegradable coating. Adhesion experiments mimicking the environment of the peritoneal cavity show the selective capture of floating cancer cells from different tumor origins by MP[CAF] compared to control MP. MP[CAF] are distributed throughout the abdominal cavity without attachment to intestinal organs and without signs of inflammatory reaction. Intraperitoneal delivery of MP[CAF] and sequential removal redirects cancer cell adhesion from the surgical wound to the MP[CAF], delays peritoneal metastasis formation and prolongs animal survival. Our experiments suggest the use of a biomimetic trap based on tumor environment interactions to delay peritoneal metastasis. PMID- 25907049 TI - A DNA hybridization system for labeling of neural stem cells with SPIO nanoparticles for MRI monitoring post-transplantation. AB - Neural stem cells (NSCs) demonstrate encouraging results in cell replacement therapy for neurodegenerative disorders and traumatic injury in the central nervous system. Monitor the survival and migration of transplanted cells would provide us important information concerning the performance and integration of the graft during the therapy time course. Magnetic resonance imaging (MRI) allow us to monitor the transplanted cells in a non-invasive way. The only requirement is to use an appropriate contrast agent to label the transplanted cells. Superparamagnetic iron oxide (SPIO) nanoparticles are one of the most commonly used contrast agent for MRI detection of transplanted cells. SPIO nanoparticles demonstrated to be suitable for labeling several types of cells including NSCs. However, the current methods for SPIO labeling are non-specific, depending mostly on electrostatic interactions, demanding relatively high SPIO concentration, and long incubation time, which can affect the viability of cells. In this study, we propose a specific and relatively fast method to label NSCs with SPIO nanoparticles via DNA hybridization. Two short single stranded DNAs (ssDNAs), oligo[dT]20 and oligo[dA]20 were conjugated with a lipid molecule and SPIO nanoparticle respectively. The labeling process comprises two simple steps; first the cells are modified to present oligo[dT]20 ssDNA on the cell surface, then the oligo[dA]20 ssDNA conjugated with SPIO nanoparticles are presented to the modified cells to allow the oligo[dT]20-oligo[dA]20 hybridization. The method showed to be non-toxic at concentrations up to 50 MUg/mL oligo[dA]20-SPIO nanoparticles. Presence of SPIO nanoparticles at cell surface and cell cytoplasm was verified by transmission electron microscopy (TEM). SPIO labeling via DNA hybridization demonstrated to not interfere on NSCs proliferation, aggregates formation, and differentiation. NSCs labeled with SPIO nanoparticles via DNA hybridization system were successfully detected by MRI in vitro as well in vivo. Cells transplanted into the rat brain striatum could be detected by MRI scanning up to 1 month post-transplantation. PMID- 25907051 TI - Allogenic dendritic cell and tumor cell fused vaccine for targeted imaging and enhanced immunotherapeutic efficacy of gastric cancer. AB - Dendritic cells (DCs) have displayed the promising potential in cancer immunity. How to enhance DCs immunotherapeutic effect in cancer targeted immunotherapy and prevention is still a great challenge. Herein, we report for the first time the allogenic DCs and tumor cell fused vaccine combined with cytokine induced killing cells (CIKs) for targeted imaging and enhanced immunotherapeutic efficacy of gastric cancer (GC). The fused vaccine was prepared by PEG mediated fusion between mature DCs and inactive gastric cancer MGC803 cells. The immunotherapeutic and prophylactic potential of the fused cells (FCs) were evaluated in tumor-bearing, post-surgery and tumor free mice models. The migration and homing process of near infrared region quantum dots (NIR-QDs) labeled FCs were investigated by real-time animal imaging system. Results showed that the FCs and FC + CIKs could trigger the tumor-specific CTLs against GC cells, target the tumor tissue initiatively and enhance the prophylactic effects, suppress the tumor growth remarkably in vivo. The potential mechanism is also investigated. In conclusion, allogenic DCs and tumor cell fused vaccine can be used for targeted imaging and enhanced immunotherapeutic efficacy of GC, and the FC + CIKs strategy own great potential in clinical applications such as early therapy and prevention of tumor-metastasis and relapse in near future. PMID- 25907050 TI - Fabrication and characterization of medical grade polyurethane composite catheters for near-infrared imaging. AB - Peripherally inserted central catheters (PICCs) are hollow polymeric tubes that transport nutrients, blood and medications to neonates. To determine proper PICC placement, frequent X-ray imaging of neonates is performed. Because X-rays pose severe health risks to neonates, safer alternatives are needed. We hypothesize that near infrared (NIR) polymer composites can be fabricated into catheters by incorporating a fluorescent dye (IRDye 800CW) and visualized using NIR imaging. To fabricate catheters, polymer and dye are dry mixed and pressed, sectioned, and extruded to produce hollow tubes. We analyzed surface roughness, stiffness, dye retention, NIR contrast intensity, and biocompatibility. The extrusion process did not significantly alter the mechanical properties of the polymer composites. Over a period of 23 days, only 6.35 +/- 5.08% dye leached out of catheters. The addition of 0.025 wt% dye resulted in a 14-fold contrast enhancement producing clear PICC images at 1 cm under a tissue equivalent. The addition of IRDye 800CW did not alter the biocompatibility of the polymer and did not increase adhesion of cells to the surface. We successfully demonstrated that catheters can be imaged without the use of harmful radiation and still maintain the same properties as the unaltered medical grade equivalent. PMID- 25907052 TI - Long-term toxicity of reduced graphene oxide nanosheets: Effects on female mouse reproductive ability and offspring development. AB - Reduced graphene oxide (rGO) nanosheets have emerged as novel materials for cancer therapeutics. Their toxicity has attracted much attention since these nanomaterials may have great potential for clinical cancer treatment. Here we report the influence of rGO exposure on female mouse reproductive ability and offspring development. Mouse dams were injected with small or large rGO nanosheets at different doses and time points, pre- or post-fertilization. The sex hormone levels of adult female mice did not significantly change compared with the control group after intravenous injection with either small or large rGO, even at a high dose (25 mg/kg). Mouse dams could produce healthy offspring after treatment with rGO nanosheets before pregnancy and at an early gestational stage (~6 days). Despite the successful delivery of offspring, malformed fetuses were found among rGO-injected dam litters. All mice had abortions when injected with low (6.25 mg/kg) or intermediate (12.5 mg/kg) doses at a late gestational stage (~20 days); the majority of pregnant mice died when injected with the high dose of rGO at this stage of pregnancy. Interestingly, all surviving rGO-injected mouse mothers gave birth to another litter of healthy pups. The results presented in this work are important for a deeper understanding of the toxicity of rGO nanosheets on female reproductivity and their offspring development. PMID- 25907053 TI - Conversion of mouse fibroblasts into cardiomyocyte-like cells using small molecule treatments. AB - The possibility of controlling cell fates by overexpressing specific transcription factors has led to numerous studies in stem cell research. Small molecules can be used, instead of transcription factors, to induce the de differentiation of somatic cells or to induce pluripotent cells (iPSCs). Here we reported that combinations of small molecules could convert mouse fibroblasts into cardiomyocyte-like cell without requiring transcription factor expression. Treatment with specific combinations of small molecules that are enhancer for iPSC induction converted mouse fibroblasts into spontaneously contracting, cardiac troponin T-positive, cardiomyocyte-like cells. We specifically identified five small molecules that can induce mouse fibroblasts to form these cardiomyocyte-like cells. These cells are similar to primary cardiomyocytes in terms of marker gene expression, epigenetic status of cardiac-specific genes, and subcellular structure. Our findings indicate that lineage conversion can be induced not only by transcription factors, but also by small molecules. PMID- 25907055 TI - Real-Time Three-Dimensional Transesophageal Echocardiography in Multiple-Device Closure of a Ruptured Sinus of Valsalva Aneurysm. PMID- 25907054 TI - Collagen-mimetic peptide-modifiable hydrogels for articular cartilage regeneration. AB - Regenerative medicine strategies for restoring articular cartilage face significant challenges to recreate the complex and dynamic biochemical and biomechanical functions of native tissues. As an approach to recapitulate the complexity of the extracellular matrix, collagen-mimetic proteins offer a modular template to incorporate bioactive and biodegradable moieties into a single construct. We modified a Streptococcal collagen-like 2 protein with hyaluronic acid (HA) or chondroitin sulfate (CS)-binding peptides and then cross-linked with a matrix metalloproteinase 7 (MMP7)-sensitive peptide to form biodegradable hydrogels. Human mesenchymal stem cells (hMSCs) encapsulated in these hydrogels exhibited improved viability and significantly enhanced chondrogenic differentiation compared to controls that were not functionalized with glycosaminoglycan-binding peptides. Hydrogels functionalized with CS-binding peptides also led to significantly higher MMP7 gene expression and activity while the HA-binding peptides significantly increased chondrogenic differentiation of the hMSCs. Our results highlight the potential of this novel biomaterial to modulate cell-mediated processes and create functional tissue engineered constructs for regenerative medicine applications. PMID- 25907056 TI - Response to: Improving the Quality and Safety as Well as Reducing the Cost for Patients Undergoing Cardiac Surgery: Missing Some Issues? PMID- 25907057 TI - Dihomo-gamma-linolenic acid prevents the development of atopic dermatitis through prostaglandin D1 production in NC/Tnd mice. AB - BACKGROUND: Atopic dermatitis (AD) is a chronic and relapsing skin disorder with pruritic skin symptoms. We previously reported that dihomo-gamma-linolenic acid (DGLA) prevented the development of AD in NC/Tnd mice, though the mechanism remained unclear. OBJECTIVE: We attempted to investigate the mechanism of preventive effect of DGLA on AD development in NC/Tnd mice. METHODS: The clinical outcomes of NC/Tnd mice that were given diets containing DGLA, arachidonic acid, or eicosapentaenoic acid were compared. Lipid mediator contents in the skin in each group were also quantified. In addition, release of lipid mediators from RBL 2H3 mast cells treated with either DGLA or prostaglandin D1 (PGD1) was measured. Furthermore, effect of PGD1 on gene expression of thymic stromal lymphopoietin (TSLP) in PAM212 keratinocyte cells was determined. RESULTS: Only DGLA containing diet suppressed the development of dermatitis in vivo. By quantifying the 20 carbon fatty acid-derived eicosanoids in the skin, the application of DGLA was found to upregulate PGD1, which correlated with a better outcome in NC/Tnd mice. Moreover, we confirmed that mast cells produced PGD1 after DGLA exposure, thereby exerting a suppressive effect on immunoglobulin E-mediated degranulation. PGD1 also suppressed gene expression of TSLP in keratinocytes. CONCLUSION: These results suggest that oral administration of DGLA causes preventive effects on AD development in NC/Tnd mice by regulating the PGD1 supply. PMID- 25907058 TI - Necroptosis mediated by receptor interaction protein kinase 1 and 3 aggravates chronic kidney injury of subtotal nephrectomised rats. AB - Necroptosis, an alternative mode of programmed cell death, has crucial pathophysiological roles in many diseases, but its effect on chronic kidney disease (CKD) is poorly understood. Therefore, we assessed necroptosis and its pathophysiological effects in a widely used remnant-kidney rat model. We found that necroptotic cell death and the highest level of receptor interaction protein kinase 1 (RIP1) and receptor interaction protein kinase 3 (RIP3), critical signalling molecules for necroptosis, appeared 8 weeks after subtotal nephrectomy (SNX) surgery. After treatment with Necrostatin-1 (Nec-1), renal function and renal pathologic changes were significantly improved; the overexpression of RIP1, RIP3, mixed lineage kinase domain-like (MLKL) and dynamin-related protein 1 (Drp1) was reduced; and necroptosis was inhibited. These results indicated that necroptosis mediated by RIP1 and RIP3 participates in the loss of renal cells of subtotal nephrectomised rats and might be one of main causes of the excessive loss of renal cells during the sustained progression of renal fibrosis. PMID- 25907059 TI - When does the future begin? Time metrics matter, connecting present and future selves. AB - People assume they should attend to the present; their future self can handle the future. This seemingly plausible rule of thumb can lead people astray, in part because some future events require current action. In order for the future to energize and motivate current action, it must feel imminent. To create this sense of imminence, we manipulated time metric--the units (e.g., days, years) in which time is considered. People interpret accessible time metrics in two ways: If preparation for the future is under way (Studies 1 and 2), people interpret metrics as implying when a future event will occur. If preparation is not under way (Studies 3-5), they interpret metrics as implying when preparation should start (e.g., planning to start saving 4 times sooner for a retirement in 10,950 days instead of 30 years). Time metrics mattered not because they changed how distal or important future events felt (Study 6), but because they changed how connected and congruent their current and future selves felt (Study 7). PMID- 25907060 TI - Efficacy of Poly-Gamma-Glutamic Acid in Women with High-Risk Human Papillomavirus Positive Vaginal Intraepithelial Neoplasia: an Observational Pilot Study. AB - Poly-gamma-glutamic acid (gamma-PGA) is a natural polymer that is synthesized by Bacillus species and has been reported to have antitumor activity. The aim of this study was to investigate the effect of gamma-PGA on the treatment of vaginal intraepithelial neoplasia (VAIN). A retrospective observational study on gamma PGA therapy for biopsy-proven VAIN was conducted. The efficacy was assessed by evaluating the results of Pap cytology and the viral load of high-risk HPV at three time points: at enrollment, and at the first and second post-treatment visits. Of 17 patients treated with gamma-PGA, only 12 patients who had a high risk HPV infection were included in the analysis. Histology was VAIN1 in seven patients, VAIN2 in two patients, and VAIN3 in three patients. gamma-PGA was administered for newly diagnosed VAIN in five (41.7%) patients and persistent VAIN in seven (58.3%) patients for the mean time of 4.5 months. At the first and second post-treatment visits, cytological regression was observed in five (41.7%) and six (50%) patients, respectively. Regarding the HPV load, the overall response rate was 66.7%, and the mean level was 670.6 +/- 292.5 RLU at the first follow-up, which was lower than the initial viral load of 1,494.8 +/- 434.5 RLU (p = 0.084). At the second follow-up, the overall response rate was 58.3%, and the mean viral load level was 924.2 +/- 493.7 RLU. gamma-PGA may be helpful for the cytological regression and reduction of viral load in patients with high-risk HPV-positive VAIN, suggesting that gamma-PGA is a promising treatment option for primary or persistent VAIN. PMID- 25907061 TI - Enterococcus faecium LKE12 Cell-Free Extract Accelerates Host Plant Growth via Gibberellin and Indole-3-Acetic Acid Secretion. AB - The use of microbial extracts containing plant hormones is a promising technique to improve crop growth. Little is known about the effect of bacterial cell-free extracts on plant growth promotion. This study, based on phytohormonal analyses, aimed at exploring the potential mechanisms by which Enterococcus faecium LKE12 enhances plant growth in oriental melon. A bacterial strain, LKE12, was isolated from soil, and further identified as E. faecium by 16S rDNA sequencing and phylogenetic analysis. The plant growth-promoting ability of an LKE12 bacterial culture was tested in a gibberellin (GA)-deficient rice dwarf mutant (waito-C) and a normal GA biosynthesis rice cultivar (Hwayongbyeo). E. faecium LKE12 significantly improved the length and biomass of rice shoots in both normal and dwarf cultivars through the secretion of an array of gibberellins (GA1, GA3, GA7, GA8, GA9, GA12, GA19, GA20, GA24, and GA53), as well as indole-3-acetic acid (IAA). To the best of our knowledge, this is the first study indicating that E. faecium can produce GAs. Increases in shoot and root lengths, plant fresh weight, and chlorophyll content promoted by E. faecium LKE12 and its cell-free extract inoculated in oriental melon plants revealed a favorable interaction of E. faecium LKE12 with plants. Higher plant growth rates and nutrient contents of magnesium, calcium, sodium, iron, manganese, silicon, zinc, and nitrogen were found in cell-free extract-treated plants than in control plants. The results of the current study suggest that E. faecium LKE12 promotes plant growth by producing GAs and IAA; interestingly, the exogenous application of its cell-free culture extract can be a potential strategy to accelerate plant growth. PMID- 25907062 TI - A Novel Synthetic Compound, YH-1118, Inhibited LPS-Induced Inflammatory Response by Suppressing IkappaB Kinase/NF-kappaB Pathway in Raw 264.7 Cells. AB - For the search of a potent first-in-class compound to inactivate macrophages responsible for inflammatory responses, in the present study, we investigated the anti-inflammatory effects of YH-1118, a novel synthetic compound, in a lipopolysaccharide (LPS)-stimulated mouse macrophage cell line, Raw 264.7. YH 1118 inhibited LPS-induced nitric oxide (NO) production and inducible NO synthase (iNOS) expression at both the protein and mRNA levels. The suppression of LPS induced iNOS expression by YH-1118 was mediated via nuclear factor kappa B (NF kappaB), but not activator protein-1 (AP-1) transcription factor. This was supported by the finding that YH-1118 attenuated the phosphorylation of inhibitor of kappaBalpha (IkappaBalpha) and nuclear translocation and DNA binding activity of NF-kappaB. Through the mechanisms that YH- 1118 inhibited the activation of IkappaB kinases (IKKs), upstream activators of NF-kappaB, or p38 MAPK, YH-1118 significantly suppressed LPS-induced production of pro-inflammatory cytokines, tumor necrosis factor-alpha, interleukin-1beta (IL-1beta), and IL-6 (p < 0.05). In conclusion, our results suggest that YH-1118 inhibits LPS-induced inflammatory responses by blocking IKK and NF-kappaB activation in macrophages, and may be a therapeutic candidate for the treatment of various inflammatory diseases. PMID- 25907063 TI - Distribution of Pseudomonas-Derived Cephalosporinase and Metallo-beta-Lactamases in Carbapenem-Resistant Pseudomonas aeruginosa Isolates from Korea. AB - The emergence of carbapenem resistance among Pseudomonas aeruginosa is an increasing problem in many parts of the world. In particular, metallo-beta lactamases (MBLs) and AmpC beta- lactamases are responsible for high-level resistance to carbapenem and cephalosporin. We studied the diversity and frequency of beta-lactamases and characterized chromosomal AmpC beta- lactamase from carbapenem-resistant P. aeruginosa isolates. Sixty-one carbapenem-resistant P. aeruginosa isolates were collected from patients in a tertiary hospital in Daejeon, Korea, from January 2011 to June 2014. Minimum inhibitory concentrations (MICs) of four antimicrobial agents were determined using the agar-dilution method. Polymerase chain reaction and sequencing were used to identify the various beta-lactamase genes, class 1 integrons, and chromosomally encoded and plasmid-mediated ampC genes. In addition, the epidemiological relationship was investigated by multilocus sequence typing. Among 61 carbapenem-resistant P. aeruginosa isolates, 25 isolates (41.0%) were MBL producers. Additionally, 30 isolates producing PDC (Pseudomonas-derived cephalosporinase)-2 were highly resistant to ceftazidime (MIC50 = 256 MUg/ml) and cefepime (MIC50 = 256 MUg/ml). Of all the PDC variants, 25 isolates harboring MBL genes showed high levels of cephalosporin and carbapenem resistance, whereas 36 isolates that did not harbor MBL genes revealed relatively low-level resistance (ceftazidime, p < 0.001; cefepime, p < 0.001; imipenem, p = 0.003; meropenem, p < 0.001). The coexistence of MBLs and AmpC beta-lactamases suggests that these may be important contributing factors for cephalosporin and carbapenem resistance. Therefore, efficient detection and intervention to control drug resistance are necessary to prevent the emergence of P. aeruginosa possessing this combination of beta lactamases. PMID- 25907064 TI - Role of folP1 and folP2 Genes in the Action of Sulfamethoxazole and Trimethoprim Against Mycobacteria. AB - The combination of trimethoprim (TMP) and sulfamethoxazole (SMX) has been shown to be active against Mycobacterium tuberculosis (Mtb) in clinical tuberculosis (TB) treatment. However, the mechanism of action of TMP-SMX against Mtb is still unknown. To unravel this, we have studied the effect of TMP and SMX by deleting the folP2 gene in Mycobacterium smegmatis (Msm), and overexpressing the Mtb and Msm folP1/2 genes in Msm. Knocking out of the folP2 gene in Msm reduced the minimum inhibitory concentration of SMX 8-fold compared with wild type. Overexpression of the folP1 genes from Mtb and Msm increased the MICs by 4- and 2 fold in Msm for SMX and TMP, respectively. We show a strong correlation between the expression of folP1 and folP2 genes and TMP-SMX resistance in mycobacteria. This suggests that a combination of FolP2 inhibitor and SMX could be used for TB treatment with a better outcome. PMID- 25907065 TI - Anticancer Activity of the Antimicrobial Peptide Scolopendrasin VII Derived from the Centipede, Scolopendra subspinipes mutilans. AB - Previously, we performed de novo RNA sequencing of Scolopendra subspinipes mutilans using high-throughput sequencing technology and identified several antimicrobial peptide candidates. Among them, a cationic antimicrobial peptide, scolopendrasin VII, was selected based on its physicochemical properties, such as length, charge, and isoelectric point. Here, we assessed the anticancer activities of scolopendrasin VII against U937 and Jurkat leukemia cell lines. The results showed that scolopendrasin VII decreased the viability of the leukemia cells in MTS assays. Furthermore, flow cytometric analysis and acridine orange/ethidium bromide staining revealed that scolopendrasin VII induced necrosis in the leukemia cells. Scolopendrasin VII-induced necrosis was mediated by specific interaction with phosphatidylserine, which is enriched in the membrane of cancer cells. Taken together, these data indicated that scolopendrasin VII induced necrotic cell death in leukemia cells, probably through interaction with phosphatidylserine. The results provide a useful anticancer peptide candidate and an efficient strategy for new anticancer peptide development. PMID- 25907066 TI - Soluble Expression and Purification of the Catalytic Domain of Human Vascular Endothelial Growth Factor Receptor 2 in Escherichia coli. AB - Vascular endothelial growth factor (VEGF) plays a key role in angiogenesis through binding to its specific receptors, which mainly occurs to VEGF receptor 2 (VEGFR-2), a kinase insert domain-containing receptor. Therefore, the disruption of VEGFR-2 signaling provides a promising therapeutic approach for the treatment of cancer by inhibiting abnormal or tumorinduced angiogenesis. To explore this potential, we expressed the catalytic domain of VEGFR- 2 (VEGFR-2-CD) as a soluble active kinase in Escherichia coli. The recombinant protein was purified and the VEGFR-2-CD activity was investigated. The obtained VEGFR-2-CD showed autophosphorylation activity and phosphate transfer activity comparable to the commercial enzyme. Furthermore, the IC50 value of known VEGFR-2 inhibitor was determined using the purified VEGFR-2-CD. These results indicated a possibility for functional and economical VEGFR-2-CD expression in E. coli to use for inhibitor screening. PMID- 25907067 TI - Immobilization of Lactase onto Various Polymer Nanofibers for Enzyme Stabilization and Recycling. AB - Five different polymer nanofibers, namely, polyaniline nanofiber (PANI), magnetically separable polyaniline nanofiber (PAMP), magnetically separable DEAE cellulose fiber (DEAE), magnetically separable CM cellulose fiber (CM), and polystyrene nanofiber (PSNF), have been used for the immobilization of lactase (E.C. 3.2.1.23). Except for CM and PSNF, three polymers showed great properties. The catalytic activities (kcat) of the free, PANI, PAMP, and magnetic DEAE cellulose were determined to be 4.0, 2.05, 0.59, and 0.042 mM/min.mg protein, respectively. The lactase immobilized on DEAE, PANI, and PAMP showed improved stability and recyclability. PANI- and PAMP-lactase showed only a 0-3% decrease in activity after 3 months of vigorous shaking conditions (200 rpm) and at room temperature (25 degrees C). PANI-, PAMP-, and DEAE-lactase showed a high percentage of conversion (100%, 47%, and 12%) after a 1 h lactose hydrolysis reaction. The residual activities of PANI-, PAMP-, and DEAE-lactase after 10 times of recycling were 98%, 96%, and 97%, respectively. PMID- 25907068 TI - Construction and Characterization of Vitreoscilla Hemoglobin (VHb) with Enhanced Peroxidase Activity for Efficient Degradation of Textile Dye. AB - Pollution resulting from the discharge of textile dyes into water systems has become a major global concern. Because peroxidases are known for their ability to decolorize and detoxify textile dyes, the peroxidase activity of Vitreoscilla hemoglobin (VHb) has recently been studied. It is found that VHb and variants of this enzyme show great promise for enzymatic decolorization of dyes and may play a role in achieving their successful removal from industrial wastewater. The level of VHb peroxidase activity correlates with two amino acid residues present within the conserved distal pocket, at positions 53 and 54. In this work, sitedirected mutagenesis of these residues was performed and resulted in improved VHb peroxidase activity. The double mutant, Q53H/P54C, shows the highest dye decolorization and removal efficiency, with 70% removal efficiency within 5 min. UV spectral studies of Q53H/P54C reveals a more compact structure and an altered porphyrin environment (lambdaSoret = 413 nm) relative to that of wild-type VHb (lambdaSoret = 406), and differential scanning calorimetry data indicate that the VHb variant protein structure is more stable. In addition, circular dichroism spectroscopic studies indicate that this variant's increased protein structural stability is due to an increase in helical structure, as deduced from the melting temperature, which is higher than 90 degrees C. Therefore, the VHb variant Q53H/P54C shows promise as an excellent peroxidase, with excellent dye decolorization activity and a more stable structure than wild-type VHb under high temperature conditions. PMID- 25907069 TI - Effect of postnatal progesterone therapy following preterm birth on neurosteroid concentrations and cerebellar myelination in guinea pigs. AB - Allopregnanolone protects the fetal brain and promotes normal development including myelination. Preterm birth results in the early separation of the infant from the placenta and consequently a decline in blood and brain allopregnanolone concentrations. Progesterone therapy may increase allopregnanolone and lead to improved oligodendrocyte maturation. The objectives of this study were to examine the efficacy of progesterone replacement in augmenting allopregnanolone concentrations during the postnatal period and to assess the effect on cerebellar myelination - a region with significant postnatal development. Preterm guinea pig neonates delivered at 62 days of gestation by caesarean section received daily s.c. injections of vehicle (2-Hydroxypropyl-beta cyclodextrin) or progesterone (16 mg/kg) for 8 days until term-equivalent age (TEA). Term delivered controls (PND1) received vehicle. Neonatal condition/wellbeing was scored, and salivary progesterone was sampled over the postnatal period. Brain and plasma allopregnanolone concentrations were measured by radioimmunoassay; cortisol and progesterone concentrations were determined by enzyme immunoassay; and myelin basic protein (MBP), proteolipid protein (PLP), oligodendroctye transcription factor 2 (OLIG2) and platelet-derived growth factor receptor-alpha (PDGFRalpha) were quantified by immunohistochemistry and western blot. Brain allopregnanolone concentrations were increased in progesterone treated neonates. Plasma progesterone and cortisol concentrations were elevated in progesterone-treated male neonates. Progesterone treatment decreased MBP and PLP in lobule X of the cerebellum and total cerebellar OLIG2 and PDGFRalpha in males but not females at TEA compared with term animals. We conclude that progesterone treatment increases brain allopregnanolone concentrations, but also increases cortisol levels in males, which may disrupt developmental processes. Consideration should be given to the use of non-metabolizable neurosteroid agonists. PMID- 25907070 TI - An improved monocyte activation test using cryopreserved pooled human mononuclear cells. AB - The monocyte activation test (MAT) is a promising replacement of the currently used rabbit pyrogen test to detect the presence of pyrogens in injectable drugs. In the MAT, drugs are incubated with a source of human monocytes and production of pyrogenic cytokines used as readout. The best results are obtained with human mononuclear cells (MNC). However, donor variation requires testing on four different donors, and for most laboratories access to fresh MNCs is a problem. The current study shows how to overcome these problems using frozen pooled MNCs. The MAT is performed by thawing pooled MNC and co-culture overnight with a test substance, LPS or non-endotoxin pyrogens, with IL-6 production as the readout. The study demonstrates that fresh and frozen pooled MNC have comparable sensitivity. The reproducibility of the MAT performed with different batches of frozen pooled MNC was excellent. Different non-endotoxin pyrogens induce IL-6, confirming the ability of the MAT to detect a variety of pyrogens. In conclusion, the MAT using frozen pooled MNC is a highly sensitive, specific and reproducible pyrogen test, able to detect and quantify endotoxin and non-endotoxin pyrogenic contaminations in parenteral pharmaceuticals. PMID- 25907071 TI - Bovine macrophages sense Escherichia coli Shiga toxin 1. AB - Shiga toxin (Stx)-producing Escherichia coli (STEC) infections in cattle are asymptomatic; however, Stx impairs the initiation of an adaptive immune response by targeting bovine peripheral and intraepithelial lymphocytes. As presumptive bovine mucosal macrophages (Mo) are also sensitive to Stx, STEC may even exert immune modulatory effects by acting on steps preceding lymphocyte activation at the Mo level. We therefore studied the expression of the Stx receptor (CD77), cellular phenotype and functions after incubation of primary bovine monocyte derived Mo with purified Stx1. A significant portion of bovine Mo expressed CD77 on their surface, with the recombinant B-subunit of Stx1 binding to >50% of the cells. Stx1 down-regulated significantly surface expression of CD14, CD172a and co-stimulatory molecules CD80 and CD86 within 4 h of incubation, while MHC-II expression remained unaffected. Furthermore, incubation of Mo with Stx1 increased significantly numbers of transcripts for IL-4, IL-6, IL-10, IFN-gamma, TNF-alpha, IL-8 and GRO-alpha but not for IL-12, TGF-beta, MCP-1 and RANTES. In the course of bovine STEC infections, Stx1 appears to induce in Mo a mixed response pattern reminiscent of regulatory Mo, which may amplify the direct suppressive effect of the toxin on lymphocytes. PMID- 25907072 TI - Antimicrobial prescription patterns of veterinarians: introduction of a benchmarking approach. PMID- 25907073 TI - Detailed characterization of the first high-level azithromycin-resistant Neisseria gonorrhoeae cases in Ireland. PMID- 25907075 TI - Treg-specific demethylated region activity in isolated regulatory t lymphocytes is a surrogate for disease severity in hepatocellular carcinoma. AB - In certain unique conditions like viral infections of the liver like hepatitis B (HBV) and hepatitis C (HCV), activation of Tregs may be associated with chronicity of the viral infections and subsequent predisposition to development of hepatocellular carcinoma (HCC) by the integrated viral genome. In parallel, potential persistence of Tregs activity may lead to immune evasion of cancerous cells and thus persistence of the carcinomatous conditions. In this study, we hypothesized that although the relative proportions of Tregs may remain unaltered in HCC, persistence of activity of Tregs may lead to immune evasion in advanced stages of HCC. To examine the issue of activation of Treg in liver cancer pathogenesis, we obtained liver biopsy and peripheral blood samples from patients with advanced grades of HCC, isolated Tregs, and examined the methylation status of "Treg-specific demethylated region" (TSDR), a key region whose methylation suppresses Treg activity and demethylation stimulates its genomic activity. This study provides evidence of demethylation of TSDR, increased gene expression examined by luciferase assays, and nuclear translocation of key transcription factors that function as gene enhancers in CD4+CD25+FoxP3 regulatory T cells in advanced grades of HCC. PMID- 25907078 TI - [DBU-H]+ and H2 o as effective catalyst form for 2,3-dihydropyrido[2,3 d]pyrimidin-4(1H)-ones: A DFT Study. AB - DFT investigations are carried out to explore the effective catalyst forms of DBU and H(2)O and the mechanism for the formation of 2,3-dihydropyrido[2,3-d] pyrimidin-4(1H)-ones. Three main pathways are disclosed under unassisted, water catalyzed, DBU and water cocatalyzed conditions, which involves concerted nucleophilic addition and H-transfer, concerted intramolecular cyclization and H transfer, and Dimroth rearrangement to form the product. The results indicated that the DBU and water cocatalyzed pathway is the most favored one as compared to the rest two pathways. The water donates one H to DBU and accepts H from 2-amino nicotinonitrile (1), forming [DBU-H](+) -H(2)O as effective catalyst form in the proton migration transition state rather than [DBU-H](+) -OH(-) . The hydrogen bond between [DBU-H](+) ...H(2)O...1(-) decreases the activation barrier of the rate-determining step. Our calculated results open a new insight for the green catalyst model of DBU-H(2)O. PMID- 25907076 TI - Prescription sequence symmetry analysis: assessing risk, temporality, and consistency for adverse drug reactions across datasets in five countries. AB - BACKGROUND: Prescription sequence symmetry analysis (PSSA) is a signal detection method for adverse drug events. Its capacity to consistently detect adverse drug events across different settings has not been tested. We aimed to determine the consistency of PSSA results for detecting positive and negative control adverse drug events across different settings. METHODS: Using a distributed network model, we analyzed prescription dispensing data using PSSA in Australia, Hong Kong, Japan, Korea, and Taiwan. Positive control was amiodarone and thyroxine, as a marker of amiodarone-induced hypothyroidism, a known adverse event with a clear temporal relationship to amiodarone initiation. Negative controls were amiodarone and allopurinol, as a marker of amiodarone-induced gout and thyroxine and allopurinol, as a marker of thyroxine-induced gout. Gout is not recorded as an adverse event in product information for either medicine. Adjusted sequence ratios (ASR) were calculated for each country. Pooled estimates were obtained by using the generic inverse variance method. RESULTS: A positive association was identified between amiodarone and thyroxine in all settings with a pooled ASR 2.63 (95% confidence interval (CI) 1.47-4.72). Temporal analysis showed the effect occurred within the first few weeks of treatment. No significant associations were found for the negative controls in any setting; pooled ASR were 0.76 (95%CI 0.62-0.93) and 0.98 (95%CI 0.85-1.12) for amiodarone-allopurinol and thyroxine-allopurinol, respectively. CONCLUSION: Despite different health settings, different populations, and different patterns of medicine utilization, PSSA gave consistent estimates across countries for a well-known positive association and two negative control adverse events. PMID- 25907074 TI - mTOR activation is a biomarker and a central pathway to autoimmune disorders, cancer, obesity, and aging. AB - The mechanistic target of rapamycin (mTOR) is a ubiquitous serine/threonine kinase, which plays pivotal roles in integrating growth signals on a cellular level. To support proliferation and survival under stress, two interacting complexes that harbor mTOR, mTORC1 and mTORC2, promote the transcription of genes involved in carbohydrate metabolism and lipogenesis, enhance protein translation, and inhibit autophagy. Although rapamycin was originally developed as an inhibitor of T cell proliferation for preventing organ transplant rejection, its molecular target, mTOR, has been subsequently identified as a central regulator of metabolic cues that drive lineage specification in the immune system. Owing to oxidative stress, the activation of mTORC1 has emerged as a central pathway for the pathogenesis of systemic lupus erythematosus and other autoimmune diseases. Paradoxically, mTORC1 has also been identified as a mediator of the Warburg effect that allows cell survival under hypoxia. Rapamycin and new classes of mTOR inhibitors are being developed to block not only transplant rejection and autoimmunity but also to treat obesity and various forms of cancer. Through preventing these diseases, personalized mTOR blockade holds promise to extend life span. PMID- 25907079 TI - Using guided inquiry and the information search process to develop research confidence among first year anatomy students. AB - With the growing volume of obtainable medical information and scientific literature, it is crucial that students in the field of allied health professions develop and refine the research skill set necessary to effectively find, retrieve, analyze, and use this information. This skill set can be effectively developed using student inquiry; an active learning process where students answer questions using research and data analysis. Therefore, with the pedagogical goal of developing information literacy among a cohort of allied health professional trainees, first year students studying human anatomy completed inquiry-based projects that were structured within the framework of the Information Search Process. This article thoroughly describes the conceptualization, creation, improvement, implementation, and assessment of the projects beginning with version one, the Student Inquiry Projects. Following a pilot of the Student Inquiry Projects various evidence-based improvements resulted in the final project version called the Inquiry Guided Learning Projects (IGLPs). A full assessment of the IGLPs revealed that students' self-perceived confidence improved for all tested research skills including: research question development, research question selection, exploration of peer-review literature, acquisition of resources, effective communication of results, and literature citation (all P < 0.05). Furthermore, six months following project completion students retained improved confidence in research question development and effective communication of results, with 90% of students indicating the IGLPs were directly responsible for these improvements. By guiding students through the Information Search Process, the IGLPs successfully developed research confidence among allied health trainees. PMID- 25907080 TI - Radial Versus Femoral Access for Coronary Angiography/Intervention in Women With Acute Coronary Syndromes: Insights From the RIVAL Trial (Radial Vs femorAL access for coronary intervention). AB - OBJECTIVES: The purpose of this study was to determine the efficacy and safety of radial versus femoral access in women undergoing coronary angiography/intervention. BACKGROUND: The risk of bleeding and vascular access site complications are higher in women than in men. METHODS: In a pre-specified RIVAL (RadIal Vs femorAL access for coronary intervention) subgroup analysis, we compared outcomes in women (n=1,861) and men (n=5,160) randomized to radial versus femoral access. RESULTS: Overall, women were at higher risk of major vascular complications compared with men (4.7% vs. 1.7%; p<0.0001). Major vascular complications were significantly reduced with radial access in women (3.1% vs. 6.1%; hazard ratio [HR]: 0.5; 95% confidence interval [CI]: 0.32 to 0.78; p=0.002) and in men (0.7% vs. 2.8%; HR: 0.27; 95% CI: 0.17 to 0.45; p<0.0001; interaction p=0.092). Crossover rates were higher with radial compared with femoral access in women (11.1% vs. 1.9%; HR: 5.88; p<0.0001) and men (6.3% vs. 1.9%; HR: 3.32; p<0.0001; interaction p=0.054). Percutaneous coronary intervention (PCI) success rates were similar irrespective of access site (women: HR: 1.05; p=0.471; men: HR: 1.00; p=0.888; interaction p=0.674), with no differences in PCI complications. In multivariable analyses, female sex was an independent predictor of major vascular complications (HR: 2.39; 95% CI: 1.76 to 3.25; p<0.0001). There were consistent findings for women and men, with no difference for the primary composite endpoint of death, myocardial infarction, stroke, and non-coronary artery bypass grafting bleeding (women: 3.9% vs. 5.0%; HR: 0.77; 95% CI: 0.50 to 1.19; men: 3.54% vs. 3.5%; HR: 1.00; 95% CI: 0.75 to 1.34; interaction p=0.325). CONCLUSIONS: Women undergoing coronary angiography and PCI have a higher risk of vascular access site complications compared with men, and radial access is an effective method to reduce these complications. PMID- 25907081 TI - Radial artery access in women undergoing percutaneous coronary procedures. PMID- 25907083 TI - Bifurcation stenting techniques and outcomes in patients with stable coronary artery disease: more evidence suggesting simpler is safer. PMID- 25907082 TI - Randomized Comparisons Between Different Stenting Approaches for Bifurcation Coronary Lesions With or Without Side Branch Stenosis. AB - OBJECTIVES: This study sought to evaluate the optimal percutaneous coronary intervention techniques using drug-eluting stents for bifurcation coronary lesions. BACKGROUND: The optimal bifurcation stenting technique needs to be evaluated. METHODS: The trial included 2 randomization studies separated by the presence of side branch (SB) stenosis for patients having non-left main bifurcation lesions. For 306 patients without SB stenosis, the routine final kissing balloon or leave-alone approaches were compared. Another randomization study compared the crush or single-stent approaches for 419 patients with SB stenosis. RESULTS: Between the routine final kissing balloon and leave-alone groups for nondiseased SB lesions, angiographic restenosis occurred in 17.9% versus 9.3% (p=0.064), comprising 15.1% versus 3.7% for the main branch (p=0.004) and 2.8% versus 5.6% for the SB (p=0.50) from 214 patients (69.9%) receiving 8 month angiographic follow-up. Incidence of major adverse cardiac events including death, myocardial infarction, or target vessel revascularization over 1 year was 14.0% versus 11.6% between the routine final kissing balloon and leave-alone groups (p=0.57). In another randomization study for diseased SB lesions, 28.2% in the single-stent group received SB stents. From 300 patients (71.6%) receiving angiographic follow-up, between the crush and single-stent groups, angiographic restenosis rate was 8.4% versus 11.0% (p=0.44), comprising 5.2% versus 4.8% for the main branch (p=0.90) and 3.9% versus 8.3% for the SB (p=0.12). One-year major adverse cardiac events rate between the crush and single-stent groups was 17.9% versus 18.5% (p=0.84). CONCLUSIONS: Angiographic and clinical outcomes were excellent after percutaneous coronary intervention using drug-eluting stents with any stent technique for non-left main bifurcation lesions once the procedure was performed successfully. PMID- 25907085 TI - To Aspirate or Not to Aspirate: That Is the Question. PMID- 25907084 TI - Manual Thrombus Aspiration Is Not Associated With Reduced Mortality in Patients Treated With Primary Percutaneous Coronary Intervention: An Observational Study of 10,929 Patients With ST-Segment Elevation Myocardial Infarction From the London Heart Attack Group. AB - OBJECTIVES: This study aimed to assess the impact of thrombus aspiration on mortality in patients with ST-segment elevation myocardial infarction treated with primary percutaneous coronary intervention (PCI). BACKGROUND: The clinical effect of routine intracoronary thrombus aspiration before primary PCI in patients with ST-segment elevation myocardial infarction is uncertain. METHODS: We undertook an observational cohort study of 10,929 ST-segment elevation myocardial infarction patients from January 2005 to July 2011 at 8 centers across London, United Kingdom. Patients' details were recorded at the time of the procedure into local databases using the British Cardiac Intervention Society PCI dataset. Primary outcome was all-cause mortality at a median follow-up of 3.0 years (interquartile range: 1.2 to 4.6 years). RESULTS: In our cohort, 3,572 patients (32.7%) underwent thrombus aspiration during primary PCI. Patients who had thrombus aspiration were younger, had lower rates of previous myocardial infarction but were more likely to have poor left ventricular function. Procedural success rates were higher (90.9% vs. 89.2%; p=0.005) and in-hospital major adverse cardiac event rates were lower (4.4% vs. 5.5%; p=0.012) in patients undergoing thrombus aspiration. However, Kaplan-Meier analysis demonstrated no significant difference in mortality rates between patients with and without thrombus aspiration (14.8% aspiration vs. 15.3% PCI only; p=0.737) during the follow-up period. After multivariate Cox analysis (hazard ratio [HR]: 0.89, 95% confidence interval [CI]: 0.65 to 1.23) and the addition of propensity matching (HR: 0.85 95% CI: 0.60 to 1.20) thrombus aspiration was still not associated with decreased mortality. CONCLUSIONS: In this cohort of nearly 11,000 patients, routine thrombus aspiration was not associated with a reduction in long-term mortality in patients undergoing primary PCI, although procedural success and in hospital major adverse cardiac event rates were improved. PMID- 25907086 TI - Long-term outcome after transcatheter closure of atrial septal defect in older patients: impact of age at procedure. AB - OBJECTIVES: This study assessed long-term outcome after transcatheter atrial septal defect (ASD) closure in older patients, especially those older than 75 years of age. BACKGROUND: The clinical benefits of transcatheter ASD closure in this aged population are controversial. METHODS: A total of 244 patients older than 50 years of age were divided into 3 groups according to age at procedure (50 to 59 years: n=69; 60 to 74 years: n=120; 75 years and older: n=55). The primary endpoint was defined as all-cause mortality and hospitalization due to heart failure or stroke. Improvements in functional capacity and cardiac remodeling after the procedure were also assessed. RESULTS: During a median follow-up of 36 months, mortality and hospitalization due to heart failure or stroke occurred in 18 patients (7%). Among patients older than 75 years of age, 2 died of noncardiovascular disease, 2 were hospitalized due to heart failure, and 1 had a stroke. More than 90% of patients older than 75 years of age did not experience these events. Kaplan-Meier analysis showed that the event-free survival rate was not different among the 3 age groups (log-rank test, p=0.780). New York Heart Association functional class and right ventricular/left ventricular end-diastolic diameter ratio improved in patients older than 75 years of age, similar to the other age groups. CONCLUSIONS: Long-term outcome after transcatheter ASD closure in patients older than 75 years of age is similar to that in the other, relatively younger age groups. This suggests that transcatheter ASD closure can be considered a valuable therapeutic option in patients older than 75 years of age. PMID- 25907087 TI - Percutaneous Closure of Atrial Septal Defects: Contraindications Are Hard to Find These Days. PMID- 25907088 TI - Proximal versus distal embolic protection for carotid artery stenting: a national cardiovascular data registry analysis. AB - OBJECTIVES: The aim of this study was to compare the stroke/death rates between proximal embolic protection devices (P-EPDs) and distal filter embolic protection devices (F-EPDs) in elective carotid artery stenting (CAS). BACKGROUND: P-EPDs have theoretical advantages that may make them superior to F-EPDs for stroke prevention during CAS. METHODS: We examined 10,246 consecutive elective CAS procedures performed with embolic protection in the NCDR CARE registry between January 2009 and March 2013. We analyzed crude and propensity-matched rates of in hospital combined death/stroke in patients treated with P-EPDs versus F-EPDs. Secondary analyses included 30-day adverse event rates and stroke rates by the involved cerebrovascular territory. RESULTS: P-EPDs were used in 590 of 10,246 cases (5.8%). Patients treated with P-EPDs had higher rates of symptomatic lesion status (46.8% vs. 39.7%, p<0.001), atrial fibrillation/flutter (16.1% vs. 13.0%, p=0.03), and history of a neurological event (51.2% vs. 46.6%, p=0.03). In unadjusted and propensity-matched analyses, differences in in-hospital stroke/death between P-EPD and F-EPD cohorts were nonsignificant (1.5% vs. 2.4%, p=0.16 and 1.6% vs. 2.0%, p=0.56, respectively). For patients with available data (n=7,693, 75.1%), 30-day adverse events rates were similar for P-EPDs and F-EPDs before (2.5% vs. 4.2%, p=0.07) and after (2.7% vs. 4.0%, p=0.22) propensity matching. CONCLUSIONS: Use of a P-EPD during CAS was associated with low rates of in-hospital stroke/death similar to those with an F-EPD in the first comparative effectiveness study of the devices. An adequately powered randomized trial comparing clinical outcomes between these devices is unlikely to be feasible. PMID- 25907089 TI - Subclinical carotid atherosclerosis and early vascular aging from long-term low dose ionizing radiation exposure: a genetic, telomere, and vascular ultrasound study in cardiac catheterization laboratory staff. AB - OBJECTIVES: This study sought to assess the association between long-term radiation exposure in the catheterization laboratory (cath lab) and early signs of subclinical atherosclerosis. BACKGROUND: There is growing evidence of an excess risk of cardiovascular disease at low-dose levels of ionizing radiation exposure. METHODS: Left and right carotid intima-media thickness (CIMT) was measured in 223 cath lab personnel (141 male; age, 45 +/- 8 years) and 222 unexposed subjects (113 male; age, 44+/-10 years). Leukocyte telomere length (LTL) was evaluated by quantitative reverse transcriptase polymerase chain reaction. The DNA repair gene XRCC3 Thr241Met polymorphism was also analyzed to explore the possible interaction with radiation exposure. The occupational radiological risk score (ORRS) was computed for each subject on the basis of the length of employment, individual caseload, and proximity to the radiation source. A complete lifetime effective dose (mSv) was recorded for 57 workers. RESULTS: Left, right, and averaged CIMTs were significantly increased in high-exposure workers compared with both control subjects and low-exposure workers (all p values<0.04). On the left side, but not on the right, there was a significant correlation between CIMT and ORRS (p=0.001) as well as lifetime dose (p=0.006). LTL was significantly reduced in exposed workers compared with control subjects (p=0.008). There was a significant correlation between LTL and both ORRS (p=0.002) and lifetime dose (p=0.03). The XRCC3 Met241 allele presented a significant interaction with high exposure for right side (pinteraction=0.002), left side (pinteraction<0.0001), and averaged (pinteraction<0.0001) CIMTs. CONCLUSIONS: Long-term radiation exposure in a cath lab may be associated with increased subclinical CIMT and telomere length shortening, suggesting evidence of accelerated vascular aging and early atherosclerosis. PMID- 25907090 TI - Occupational health risks in interventional cardiology: expected inherent risk or preventable personal liability? PMID- 25907091 TI - Transradial PCI in Women: Zeroing in on Crossovers. PMID- 25907092 TI - Reply: Transradial PCI in Women: Zeroing in on Crossovers. PMID- 25907093 TI - Safety and Feasibility of Transradial Catheterization in Breast Cancer Survivors: A 2-Center International Experience. PMID- 25907094 TI - Coronary in-stent restenosis in patients treated with thoracic external beam radiation for cancer. PMID- 25907095 TI - Reply: coronary in-stent restenosis in patients treated with thoracic external beam radiation for cancer. PMID- 25907096 TI - Incredible India. PMID- 25907098 TI - Chemoselective Silylative Reduction of Conjugated Nitriles under Metal-Free Catalytic Conditions: beta-Silyl Amines and Enamines. AB - The B(C6F5)3-catalyzed silylative reduction of conjugated nitriles has been developed to afford synthetically valuable beta-silyl amines. The reaction is chemoselective and proceeds under mild conditions. Mechanistic elucidation indicates that it proceeds by rapid double hydrosilylation of the conjugated nitrile to an enamine intermediate which is subsequently reduced to the beta silyl amine, thus forming a new C(sp(3))-Si bond. Based on this mechanistic understanding, a preparative route to enamines was also established using bulky silanes. PMID- 25907097 TI - Presynaptic BK channel localization is dependent on the hierarchical organization of alpha-catulin and dystrobrevin and fine-tuned by CaV2 calcium channels. AB - BACKGROUND: Large conductance, calcium-activated BK channels regulate many important physiological processes, including smooth muscle excitation, hormone release and synaptic transmission. The biological roles of these channels hinge on their unique ability to respond synergistically to both voltage and cytosolic calcium elevations. Because calcium influx is meticulously regulated both spatially and temporally, the localization of BK channels near calcium channels is critical for their proper function. However, the mechanism underlying BK channel localization near calcium channels is not fully understood. RESULTS: We show here that in C. elegans the localization of SLO-1/BK channels to presynaptic terminals, where UNC-2/CaV2 calcium channels regulate neurotransmitter release, is controlled by the hierarchical organization of CTN-1/alpha-catulin and DYB 1/dystrobrevin, two proteins that interact with cortical cytoskeletal proteins. CTN-1 organizes a macromolecular SLO-1 channel complex at presynaptic terminals by direct physical interaction. DYB-1 contributes to the maintenance or stabilization of the complex at presynaptic terminals by interacting with CTN-1. We also show that SLO-1 channels are functionally coupled with UNC-2 calcium channels, and that normal localization of SLO-1 to presynaptic terminals requires UNC-2. In the absence of UNC-2, SLO-1 clusters lose the localization specificity, thus accumulating inside and outside of presynaptic terminals. Moreover, CTN-1 is also similarly localized in unc-2 mutants, consistent with the direct interaction between CTN-1 and SLO-1. However, localization of UNC-2 at the presynaptic terminals is not dependent on either CTN-1 or SLO-1. Taken together, our data strongly suggest that the absence of UNC-2 indirectly influences SLO-1 localization via the reorganization of cytoskeletal proteins. CONCLUSION: CTN-1 and DYB-1, which interact with cortical cytoskeletal proteins, are required for the presynaptic punctate localization of SLO-1 in a hierarchical manner. In addition, UNC-2 calcium channels indirectly control the fidelity of SLO-1 puncta localization at presynaptic terminals. We suggest that the absence of UNC-2 leads to the reorganization of the cytoskeletal structure that includes CTN-1, which in turn influences SLO-1 puncta localization. PMID- 25907099 TI - In vitro simulation research on the hoop stress of myocardial bridge--coronary artery. AB - AIMS: The aim of this study is to investigate how the myocardial bridge oppression affects the hoop stress of mural coronary artery. METHODS: The "myocardial bridge - coronary artery" simulative device records the hoop stress which is changed by adjusting the external pressure of the simulated coronary artery and the oppression degree of the respectively. RESULTS: Simulation experiment in vitro indicates that the abnormal hoop stress mainly occurs in the proximal end of mural coronary artery. As the oppression degree of myocardial bridge increases, the mean and the oscillatory value (maximum-minimum) of hoop stress in the proximal end increase markedly. CONCLUSIONS: The "myocardial bridge - coronary artery" simulation device can provide an experiment method of studying the hoop stress influence on mural coronary artery in vitro. PMID- 25907100 TI - In vitro polyclonal activation of conventional T cells with a CD28 superagonist protects mice from acute graft versus host disease. AB - Upon transplantation of T cells from a CD28 superagonist (CD28-SA) treated donor into an irradiated allogeneic host, the CD28-SA-induced activation and expansion of Treg cells inhibits acute graft versus host disease (aGvHD), while not abrogating the desired graft versus tumor effect. Human peripheral blood CD4(+) T cells, however, harbor only very few Treg cells. Therefore, we studied whether polyclonal in vitro prestimulation of conventional, that is Treg -cell-depleted, CD4(+) T cells of C57BL/6 mice with CD28-SA-coated paramagnetic beads is sufficient to protect recipient BALB/c mice from aGvHD. CD28-SA prestimulation of conventional CD4(+) T cells efficiently protected BALB/c recipient mice from aGvHD and CD28-SA-stimulated CD4(+) and CD8(+) T cells were capable of mediating long-term protection from the BCL1 lymphoma. The recently completed successful phase I testing of the human CD28-SA TGN1412/TAB08 should greatly facilitate further development of this straightforward method into a novel immunotherapy for patients. PMID- 25907101 TI - Systematic review of cigar smoking and all cause and smoking related mortality. AB - BACKGROUND: Cigars are a growing public health concern, given the changes in cigar use patterns in the US and elsewhere since the 1960s. We conducted a systematic review of published studies on current cigar smoking and all-cause and cause-specific mortality risks to inform potential regulatory approaches and future research that would strengthen the body of evidence. METHODS: Using 3 different databases and handsearching, we identified epidemiological studies published prior to June 2014 that examined the association between cigar smoking and all-cause mortality and smoking-related mortality. Detailed study characteristics as well as association-level characteristics, including effect estimates and 95% confidence intervals, were abstracted or calculated from each selected study. RESULTS: A total of 22 studies from 16 different prospective cohorts were identified. Primary cigar smoking (current, exclusive cigar smoking with no history of previous cigarette or pipe smoking) was associated with all cause-mortality, oral cancer, esophageal cancer, pancreatic cancer, laryngeal cancer, lung cancer, coronary heart disease (CHD), and aortic aneurysm. Strong dose trends by cigars per day and inhalation level for primary cigar smoking were observed for oral, esophageal, laryngeal, and lung cancers. Among primary cigar smokers reporting no inhalation, relative mortality risk was still highly elevated for oral, esophageal, and laryngeal cancers. CONCLUSIONS: In summary, cigar smoking carries many of the same health risks as cigarette smoking. Mortality risks from cigar smoking vary by level of exposure as measured by cigars per day and inhalation level and can be as high as or exceed those of cigarette smoking. The body of evidence would be strengthened by future studies that focus on the health effects of primary cigar smoking and incorporate more contemporary and diverse study populations to better reflect the current patterns of cigar use in the US. Ideally, these studies would also collect detailed information on cigar type, exposure level, and biomarkers of exposure and potential harm. PMID- 25907103 TI - Dienamine and Friedel-Crafts one-pot synthesis, and antitumor evaluation of diheteroarylalkanals. AB - An asymmetric synthesis of diheteroarylalkanals through one-pot dienamine and Friedel-Crafts reaction is presented. The reaction tolerates a large variety of substituents at different positions of the starting aldehyde and also in the indole nucleophile, and a range of diheterocyclic alkanals can be achieved. Furthermore, we have studied the antiproliferative activity of these new compounds in representative cancer tumor cell lines. PMID- 25907102 TI - Consensus guidelines for myeloma minimal residual disease sample staining and data acquisition. AB - BACKGROUND: Flow cytometric (FC) detection of minimal residual disease (MRD) in multiple myeloma (MM) is prognostic and predictive of response to therapy. Therefore, standardization of FC MM MRD testing is vital to ensure better and uniform assessment of response to therapy and clinical prognostication. The International Clinical Cytometry Society and European Society for Clinical Cell Analysis, recognizing the need for standardized FC approaches, organized a working group to develop consensus guidelines on good clinical practice in FC MM MRD. Consensus guidelines are presented for specimen quality, staining process, reagent combinations, and the data acquisition process, all key factors in achieving high quality FC MM MRD testing. METHODS: A group of eight flow cytometrists currently performing FC testing in MM evaluated available literature on FC MM MRD testing. A document presenting best practice was developed and reviewed in successive rounds until consensus was reached. RESULTS/CONCLUSION: The consensus on best practice for detection of MRD in MM is that CD38, CD138, and CD45 are analyzed in combination with CD19, CD56, CD27, CD81, and CD117. Consensus guidelines on acceptable specimen quality, staining procedures, panel design, and data acquisition were developed. PMID- 25907104 TI - Influence of the interface in quantum corrections on the low-temperature resistance of La(2/3)Sr(1/3)MnO3 trilayer masking thin films. AB - We report the low-temperature resistance upturn in sandwiched structures of La2/3Sr1/3MnO3/ZrO2/La2/3Sr1/3MnO3 and La2/3Sr1/3MnO3/LaMnO3/La2/3Sr1/3MnO3, while it disappeared when the interlayer was replaced by YBa2Cu3O7. The experimental data have been analyzed qualitatively and quantitatively. The results show that the low temperature resistance upturn is mainly due to the quantum correction effects driven by the weak localization and the electron electron interaction in such a strongly correlated system, and the contribution of each factor varies with grain boundaries. Moreover, the resistance upturns are suppressed by a local magnetic field. These findings will help to further understand the physical mechanism of low-temperature resistance upturn in colossal magnetoresistance manganites. Furthermore, it is also helpful to reveal the intrinsic transport mechanism at the interfaces of semiconductor/ferromagnetism and antiferromagnetism/ferromagnetism. PMID- 25907105 TI - Two-dimensional electron gas and its electric control at the interface between ferroelectric and antiferromagnetic insulator studied from first principles. AB - A multiferroic interface between the antiferromagnetic Slater insulator SrTcO3 and ferroelectric BaTiO3 (BTO) is studied from first principles. Although the interfacial magnetoelectric coupling of SrTcO3(001) is relatively small, we found that a two-dimensional electron gas (2DEG) appears for both BaO/TcO2 and TiO2/SrO terminations. The charge character of the carriers, induced in the band gap due to polar BTO, can be switched from electrons to holes by the reversal of the electric polarization in BTO. The 2DEG is robust and stable against the degree of electronic correlations, whereas the paraelectric state of BTO suppresses the 2DEG. The origin of the 2DEG at the BTO/SrTcO3 interface and its key factors are discussed. PMID- 25907106 TI - Preventing community-wide transmission of Cryptosporidium: a proactive public health response to a swimming pool-associated outbreak--Auglaize County, Ohio, USA. AB - The incidence of recreational water-associated outbreaks in the United States has significantly increased, driven, at least in part, by outbreaks both caused by Cryptosporidium and associated with treated recreational water venues. Because of the parasite's extreme chlorine tolerance, transmission can occur even in well maintained treated recreational water venues (e.g. pools) and a focal cryptosporidiosis outbreak can evolve into a community-wide outbreak associated with multiple recreational water venues and settings (e.g. childcare facilities). In August 2004 in Auglaize County, Ohio, multiple cryptosporidiosis cases were identified and anecdotally linked to pool A. Within 5 days of the first case being reported, pool A was hyperchlorinated to achieve 99.9% Cryptosporidium inactivition. A case-control study was launched to epidemiologically ascertain the outbreak source 11 days later. A total of 150 confirmed and probable cases were identified; the temporal distribution of illness onset was peaked, indicating a point-source exposure. Cryptosporidiosis was significantly associated with swimming in pool A (matched odds ratio 121.7, 95% confidence interval 27.4-infinity) but not with another venue or setting. The findings of this investigation suggest that proactive implementation of control measures, when increased Cryptosporidium transmission is detected but before an outbreak source is epidemiologically ascertained, might prevent a focal cryptosporidiosis outbreak from evolving into a community-wide outbreak. PMID- 25907108 TI - Hyperleptinaemia, insulin resistance and survival in peritoneal dialysis patients. AB - AIM: The aim of this study was to clarify the relationship between insulin resistance (IR) and glucose and lipid metabolism in peritoneal dialysis (PD) patients. The study also investigated the prognostic factors for survival in long term peritoneal dialysis patients. METHODS: Participants were recruited from July 1 to August 1, 2011, based on selection criteria. Patients were divided into two groups, high (H) and low (L) group according to the median value of homeostasis model assessment of IR (HOMA-IR). Type 2 diabetes mellitus (DM) patients were chosen as positive controls. Clinical, plasma biochemical and metabolic parameters were observed and recorded at the outset and follow-up of this study. Mortality related factors were also detected, and statistical analyses were performed. RESULTS: A total of 157 cases with an average age of 55 +/- 15 years were included. There were 26, 66 and 65 cases in the DM, H and L groups, respectively. Younger age, lower body mass index, high sensitive C-reactive protein (hsCRP) level, higher normalized protein catabolic rate (nPCR) were found in the L group compared with the other two groups. HOMA-IR positively correlated with age, leptin and triglyceride levels, and it negatively correlated with BMI. L group had better survival rate than H and DM groups. Dialysis duration, serum leptin level, nPCR and hsCRP were statistically associated with mortality. CONCLUSION: Insulin resistance may play an important role in the pathophysiology of glucose and lipid metabolism. Dialysis duration, leptin, nPCR and hsCRP may be risk factors for mortality in PD patients. PMID- 25907107 TI - GlyT-1 Inhibition Attenuates Attentional But Not Learning or Motivational Deficits of the Sp4 Hypomorphic Mouse Model Relevant to Psychiatric Disorders. AB - Serious mental illness occurs in 25% of the general population, with many disorders being neurodevelopmental, lifelong, and debilitating. The wide variation and overlap in symptoms across disorders increases the difficulty of research and treatment development. The NIMH Research Domain of Criteria initiative aims to improve our understanding of the molecular and behavioral consequences of specific neurodevelopmental mechanisms across disorders, enabling targeted treatment development. The transcription factor Specificity Protein 4 (SP4) is important for neurodevelopment and is genetically associated with both schizophrenia and bipolar disorder. Reduced Sp4 expression in mice (hypomorphic) reproduces several characteristics of psychiatric disorders. We further tested the utility of Sp4 hypomorphic mice as a model organism relevant to psychiatric disorders by assessing cognitive control plus effort and decision-making aspects of approach motivation using cross-species-relevant tests. Sp4 hypomorphic mice exhibited impaired attention as measured by the 5-Choice Continuous Performance Test, an effect that was attenuated by glycine type-1 transporter (GlyT-1) inhibition. Hypomorphic mice also exhibited reduced motivation to work for a reward and impaired probabilistic learning. These deficits may stem from affected anticipatory reward, analogous to anhedonia in patients with schizophrenia and other psychiatric disorders. Neither positive valence deficit was attenuated by GlyT-1 treatment, suggesting that these and the attentional deficits stem from different underlying mechanisms. Given the association of SP4 gene with schizophrenia and bipolar disorder, the present studies provide support that personalized GlyT-1 inhibition may treat attentional deficits in neuropsychiatric patients with low SP4 levels. PMID- 25907109 TI - Prevalence and predictors of persistent post-surgical pain 12 months after thoracotomy. AB - BACKGROUND: Persistent post-surgical pain is recognised as a major problem. Prevalence after different surgical procedures has been reported to range from 5% up to 85%. Limb amputation and thoracotomy have the highest reported prevalence. Prediction of persistent post-surgical pain has over the last decade caught attention. Several factors have been investigated, but in-depth knowledge is still scarce. The purpose of this study was to investigate the prevalence of persistent post-surgical pain, and predictive factors for persistent post surgical pain 12 months after thoracotomy. METHODS: A prospective longitudinal study was conducted. One-hundred and seventy patients were recruited before scheduled thoracotomy, and asked to answer a questionnaire. One-hundred and six patients completed the same questionnaire at 12-month follow-up. Regression analysis was performed to explore variables assumed predictive of persistent post surgical pain. RESULTS: One-hundred and six patients (62%) filled out the questionnaire at both time points. Preoperative, 34% reported muscle-skeletal related chronic pain. At 12-month follow-up, 50% of the patients reported persistent post-surgical pain. Of the variables explored in the logistic regression model, only preoperative pain (P < 0.001) and dispositional optimism (P = 0.04) were statistically significant. In this study, preoperative pain was a predominant predictor for persistent postoperative pain (OR 6.97, CI 2.40-20.21), while dispositional optimism (OR 0.36, CI 0.14-0.96) seem to have protective properties. CONCLUSION: Our results show that preoperative pain is a predominant predictor of future pain. This implies that patients presenting with a chronic pain condition prior to surgery should be assessed thoroughly preoperatively and have an individually tailored analgesic regimen. PMID- 25907110 TI - Polyphenols isolated from Broussonetia kazinoki prevent cytokine-induced beta cell damage and the development of type 1 diabetes. AB - The axis of nuclear factor kappaB (NF-kappaB)-inducible NO synthase (iNOS)-nitric oxide plays a key role in cytokine- and streptozotocin-mediated pancreatic beta cell damage. In this study, we investigated the effects of kazinol C and isokazinol D isolated from Broussonetia kazinoki on the beta-cell viability and function. RINm5F cells and primary islets were used for in vitro and ex vivo cytokine toxicity experiments, respectively. For type 1 diabetes induction, mice were injected with multiple low-dose streptozotocin (MLDS). Cytokine-induced toxicity was completely abolished in both RINm5F cells and islets that were pretreated with either kazinol C or isokazinol D. Both kazinols inhibited the NF kappaB signaling pathway, thereby inhibiting cytokine-mediated iNOS induction, nitric oxide production, apoptotic cell death and defects in insulin secretion. Moreover, the occurrence of diabetes in MLDS-treated mice was efficiently attenuated in kazinol-pretreated mice. Immunohistochemical analysis revealed that the numbers of terminal deoxynucleotidyl transferase dUTP nick end labeling positive apoptotic cells and nuclear p65-positive cells were significantly decreased in kazinol-pretreated mice. Our results suggest that kazinol C and isokazinol D block the NF-kappaB pathway, thus reducing the extent of beta-cell damage. Therefore, kazinol C and isokazinol D may have therapeutic value in delaying pancreatic beta-cell damage in type 1 diabetes. PMID- 25907111 TI - Bacterial versatility requires DEAD-box RNA helicases. AB - RNA helicases of the DEAD-box and DEAH-box families are important players in many processes involving RNA molecules. These proteins can modify RNA secondary structures or intermolecular RNA interactions and modulate RNA-protein complexes. In bacteria, they are known to be involved in ribosome biogenesis, RNA turnover and translation initiation. They thereby play an important role in the adaptation of bacteria to changing environments and to respond to stress conditions. PMID- 25907112 TI - Archaea associated with human surfaces: not to be underestimated. AB - Over 40 years ago, Carl Woese and his colleagues discovered the existence of two distinctly different groups of prokaryotes-Bacteria and Archaea. In the meantime, extensive research revealed that several hundred of bacterial species are intensely associated with humans' health and disease. Archaea, originally identified and described to occur mainly in extreme environments, have been shown to be ubiquitous and to appear frequently and in high numbers as part of human microbiota in recent years. Despite the improvement in methodologies leading to increased detection, archaea are often still not considered in many studies focusing on the interdependency between members of the microbiota and components of the human immune system. As a consequence, the knowledge on functional role(s) of archaeal species within the human body is mainly limited to their contribution to nutrient degradation in the intestine, and evidence for immunogenic properties of archaea as part of the human microbiota is generally rare. In this review, the current knowledge of human mucosa-associated archaeal species, their interaction with the human immune system and their potential contribution to humans' health and disease will be discussed. PMID- 25907114 TI - A pretty clue in pink: pink urine in a morbidly obese patient with lymphoma. PMID- 25907117 TI - Radiological features of metastases to the thyroid. AB - BACKGROUND: Thyroid metastases (TM) are uncommon. Dependent on study design, the reported frequency of TM is in the range of 0.1-6% in different analyses. While clinical and histopathological features of TM were well described in the literature, radiological publications consist predominantly of isolated case reports or small series. PURPOSE: To estimate the prevalence, clinical signs, and radiological appearances of TM. MATERIAL AND METHODS: From 1997 to 2013, a total of 8849 patients with various disorders of the thyroid gland were treated in our institution. In 33 patients TM were diagnosed. Ultrasound (US) images were available in all patients, computed tomography (CT) of the neck in 16 patients, and magnetic resonance imaging (MRI) in nine patients. RESULTS: Clinically, most patients (85%) presented with a painless neck mass. Primary tumors were renal cell carcinoma (79%), colorectal cancer (12%), lung cancer (3%), rhabdomyosarcoma (3%), and breast carcinoma (3%). On US, most lesions were irregular in shape with inhomogenous texture. On CT, all TM were hypodense. On T1-weighted images, most TM were inhomogenously iso-to-hyperintense in comparison to the normal thyroid tissue, and slightly hyperintense on T2-weighted images with an inhomogenous contrast enhancement. CONCLUSION: The prevalence of TM was 0.4%. Most of the TM originated from renal cell carcinoma. The identified radiological features of TM should be taken into consideration in the differential diagnosis of thyroid lesions. PMID- 25907113 TI - Giving structure to the biofilm matrix: an overview of individual strategies and emerging common themes. AB - Biofilms are communities of microbial cells that underpin diverse processes including sewage bioremediation, plant growth promotion, chronic infections and industrial biofouling. The cells resident in the biofilm are encased within a self-produced exopolymeric matrix that commonly comprises lipids, proteins that frequently exhibit amyloid-like properties, eDNA and exopolysaccharides. This matrix fulfils a variety of functions for the community, from providing structural rigidity and protection from the external environment to controlling gene regulation and nutrient adsorption. Critical to the development of novel strategies to control biofilm infections, or the capability to capitalize on the power of biofilm formation for industrial and biotechnological uses, is an in depth knowledge of the biofilm matrix. This is with respect to the structure of the individual components, the nature of the interactions between the molecules and the three-dimensional spatial organization. We highlight recent advances in the understanding of the structural and functional role that carbohydrates and proteins play within the biofilm matrix to provide three-dimensional architectural integrity and functionality to the biofilm community. We highlight, where relevant, experimental techniques that are allowing the boundaries of our understanding of the biofilm matrix to be extended using Escherichia coli, Staphylococcus aureus, Vibrio cholerae, and Bacillus subtilis as exemplars. PMID- 25907115 TI - Biodiversity enhances ecosystem multifunctionality across trophic levels and habitats. AB - The importance of biodiversity for the integrated functioning of ecosystems remains unclear because most evidence comes from analyses of biodiversity's effect on individual functions. Here we show that the effects of biodiversity on ecosystem function become more important as more functions are considered. We present the first systematic investigation of biodiversity's effect on ecosystem multifunctionality across multiple taxa, trophic levels and habitats using a comprehensive database of 94 manipulations of species richness. We show that species-rich communities maintained multiple functions at higher levels than depauperate ones. These effects were stronger for herbivore biodiversity than for plant biodiversity, and were remarkably consistent across aquatic and terrestrial habitats. Despite observed tradeoffs, the overall effect of biodiversity on multifunctionality grew stronger as more functions were considered. These results indicate that prior research has underestimated the importance of biodiversity for ecosystem functioning by focusing on individual functions and taxonomic groups. PMID- 25907118 TI - The value of anti-1-amino-3-18F-fluorocyclobutane-1-carboxylic acid PET/CT in the diagnosis of recurrent prostate carcinoma: a meta-analysis. AB - BACKGROUND: Anti-1-amino-3-[18F]fluorocyclobutane-1-carboxylic acid (anti-3-18F FACBC) positron emission tomography/computed tomography (PET/CT), 11 C-choline PET/CT, 111In-capromab pendetide, and T2-weighted magnetic resonance imaging (MRI) have been used for detecting prostate carcinoma relapse. PURPOSE: To systematically review and perform a meta-analysis of published data regarding the performance of 18F-FACBC PET/CT in the diagnosis of recurrent prostate carcinoma. MATERIAL AND METHODS: A comprehensive review of the literature regarding the role of 18F-FACBC PET/CT in the diagnosis of recurrent prostate carcinoma was performed. Pooled sensitivity, specificity, and the area under the receiver operating characteristic of 18F-FACBC PET/CT in the diagnosis of recurrent prostate carcinoma were calculated based on the included studies. RESULTS: Six studies comprising 251 patients, suspicious of prostate carcinoma recurrence, were included in this meta-analysis. 18F-FACBC PET/CT had an 87% pooled sensitivity, 66% pooled specificity, 0.93 the area under the receiver-operating characteristic curve on a per patient-based analysis in detecting prostate carcinoma recurrence. CONCLUSION: 18F-FACBC PET/CT was a non-invasive, metabolic imaging technique in the diagnosis of prostate carcinoma relapse. PMID- 25907116 TI - Severe acute respiratory syndrome coronavirus protein 6 mediates ubiquitin dependent proteosomal degradation of N-Myc (and STAT) interactor. AB - Severe acute respiratory syndrome coronavirus (SARS-CoV) encodes eight accessory proteins, the functions of which are not yet fully understood. SARS-CoV protein 6 (P6) is one of the previously studied accessory proteins that have been documented to enhance viral replication and suppress host interferon (IFN) signaling pathways. Through yeast two-hybrid screening, we identified eight potential cellular P6-interacting proteins from a human spleen cDNA library. For further investigation, we targeted the IFN signaling pathway-mediating protein, N Myc (and STAT) interactor (Nmi). Its interaction with P6 was confirmed within cells. The results showed that P6 can promote the ubiquitin-dependent proteosomal degradation of Nmi. This study revealed a new mechanism of SARS-CoV P6 in limiting the IFN signaling to promote SARS-CoV survival in host cells. PMID- 25907119 TI - Palliative endovascular treatment of cancer-related iliocaval obstructive disease: technical and clinical outcomes. AB - BACKGROUND: Cancer-related obstruction of large abdominal and pelvic veins might become symptomatic with clinical signs of lower limb venous congestion. Technical and clinical outcome after interventional treatment is not well studied yet. PURPOSE: To retrospectively assess the technical and clinical outcome of endovascular management of symptomatic cancer-related iliocaval venous obstructive disease. MATERIAL AND METHODS: From 1998 to 2013, 19 patients (15 men, 4 women; mean age, 63.6 years) referred for interventional treatment of cancer-related iliocaval obstructive disease were identified. Patients' symptoms included unilateral (n = 16; 84%) or bilateral (n = 3; 16%) painful swelling of the lower limbs. Patients' demographics as well as interventional and clinical outcome data were collected. RESULTS: All 19 patients underwent, under local anesthesia, stenting of the iliac vein (n = 16; 84%) or inferior vena cava (n = 3; 16%). Immediate technical success (n = 19) was 100%; immediate clinical success (n = 18) was 94.7%. During follow-up, seven patients (36.8%) presented with recurrent symptoms of painful limb swelling. Estimated survival after 3 and 6 months was 68.4% (95% confidence interval [CI], 47.8-82.3%) and 19.8% (95% CI, 11.9-29.2%), respectively. CONCLUSION: Endovascular stenting of cancer-related iliocaval venous obstructive disease is safe and results in immediate relief of symptoms. However, recurrent venous obstruction is common. At 3 months follow-up, the majority of patients with iliac vein stenting were still alive. PMID- 25907120 TI - Dual-energy computed tomography for evaluation of pulmonary nodules with emphasis on metastatic lesions. AB - BACKGROUND: The contrast enhancement of pulmonary nodules is a differential diagnostic criterion which can be helpful in staging investigations. PURPOSE: To investigate the impact of dual-energy computed tomography (DECT) with regards to the evaluation of pulmonary nodules with emphasis on metastatic lesions. MATERIAL AND METHODS: DECT scans of the thorax were performed in 70 consecutive patients. Data of the lung were acquired in the arterial and in delayed venous phase. The virtual native and overlay image data based on arterial and delayed venous phase of these lesions were compared using CT density values (HU) within the nodule tested for statistical significance. RESULTS: A total of 156 pulmonary lesions >=5 mm were identified on 70 DECT scans. There were no significant differences between the CT-value measurements in the virtual native images based on the arterial and delayed venous phase (27.9+/-3.9 HU vs.28.1+/-4.2 HU, P = 0.89) and between the CT-value measurements in the overlay images based on the arterial und delayed venous phase (35.5+/-6.8 HU vs. 36.6+/-5.0 HU, P = 0.75). Metastases of colorectal carcinoma (51.4+/-9.4 HU vs. 32.5+/-8.9 HU, P = 0.0001), malignant melanoma (56.1+/-6.4 HU vs. 34.2+/-1.6 HU, P = 0.0045), and thyroid cancer (53.5+/-15.5 HU vs. 15.7+/-4.2 HU, P = 0.001) showed a distinct wash-out, whereas metastases of lung cancer (23.1+/-6.3 HU vs. 58.6+/-4.8 HU, P = 0.001), salivary gland cancer (41.4+/-20.3 HU vs. 65.7+/-15.7 HU, P = 0.023), and sarcoma (56.2+/ 7.4 HU vs. 90.2+/-3.4 HU, P = 0.001) had an increased enhancement in the delayed venous phase. CONCLUSION: The contrast enhancement behavior of pulmonary metastases can be evaluated with DECT and depends on the type of the primary malignant tumor. PMID- 25907121 TI - Microbiological and chemical safety concerns regarding frozen fillets obtained from Pangasius sutchi and Nile tilapia exported to European countries. AB - BACKGROUND: Microbiological and chemical safety concerns regarding frozen fillets from pangasius catfish (Pangasius hypophthalmus) exported to Poland, Germany and Ukraine and Nile tilapia (Oreochromis niloticus) exported to Poland and Germany were investigated by analyzing heavy metal residues, microbiological hazards, biogenic amines, and thiobarbituric acid (TBA) and total volatile basic nitrogen (TVB-N) content. RESULTS: The heavy metal residues from all studied samples were far lower than the limits established by authorities. The most abundant biogenic amine found was histamine, with a maximum content of 9.6 mg 100 g(-1) , found in pangasius exported to Poland. The total viable counts were from 2.8 log cfu g(-1) in pangasius exported to Ukraine to 4.3 log cfu g(-1) in pangasius exported to Germany. Vibrio spp. were present in 70-80% of all studied pangasius groups, whereas there no Vibrio spp. were found in the studied tilapia samples. 30% of Pangasius fillets exported to Poland were contaminated with coagulase-positive staphylococci. No E. coli was found in any of the studied samples. Although the results of TBA analysis differed significantly between studied groups, the malonic aldehyde content in all studied groups was still very low. The TVB-N content in frozen fillets from pangasius was significantly lower than in frozen tilapia fillets. CONCLUSIONS: We reported that pangasius catfish frozen fillets were widely contaminated with Vibrio spp., which could prove hazardous for the final consumer if the fish is eaten raw or undercooked. The rest of the analysis showed no other reason for concern associated with Nile tilapia and Pangasius catfish frozen fillet consumption. PMID- 25907122 TI - Estimation of body size and growth patterns in Korean boys. AB - BACKGROUND: Anthropometric surveys devised by each country attempt to fulfill the requirements of the manufacturers, designers, and human welfare device production, providing them with data and tools and allowing them to face both the internal and export markets. To this end, national anthropometric data collections and comparisons including three-dimensional information, together with comparison of these data among countries, are conducted at both the domestic and global levels. METHODS: The anthropometric data of the Korean population measured in 2013 (Korean Agency for Technology and Standard (KATS) 2013 data) and the data collected from 2010 (KATS 2010 data) that was conducted on 710 males between the ages of 13 and 18 years were analyzed in this section to obtain information on Korean boys' physical features and growth. RESULTS: The mean height increased about 5 cm from 13 to 14 years which shows the early fast maturing somatotype. Also, the mean height of boys aged from 15 to 16 increased about 1 to 2 cm. For the results of body proportion rate index against height, they show 0.93, 0.81, 0.38, 0.99, and 0.26 times the height in eye height, shoulder height, fingertip height, and span and maximum shoulder breadth, respectively, in 16-year-old boys. For the body mass index, the weight is increased from the age of 16 years. CONCLUSIONS: There are several studies that cover growth features of the entire range from birth to maturity, and they have reported the comparison of the growth patterns among Europeans. Even though such researches have been made, as for the industry, the human modeling tools based on the anthropometric data and morphological features that cover all the countries should be developed for well-fit garments and other human-oriented design process. PMID- 25907123 TI - Thienopyridine use after coronary stenting in low income patients enrolled in Medicare part D receiving maintenance dialysis. PMID- 25907124 TI - Identifying predictors of cumulative healthcare costs in incident atrial fibrillation: a population-based study. AB - BACKGROUND: Atrial fibrillation (AF) has substantial impacts on healthcare resource utilization. Our objective was to understand the pattern and predictors of cumulative healthcare costs in AF patients after incident diagnosis in an emergency department (ED). METHODS AND RESULTS: Patients discharged after a first presentation of AF to an ED in Ontario, Canada, were identified from April 1, 2005, through March 31, 2010. Per-patient cumulative healthcare costs were determined until death or March 31, 2012. Join-point analyses identified clinically relevant cost phases. Hierarchical generalized linear models with a logarithmic link and gamma distribution determined predictors of cost per phase. Our cohort was 17 980 patients. During a mean follow-up of 3.9 years, 17.1% of patients died. Three distinct cost phases were identified: 2-month post-index ED visit phase, 12-month predeath phase, and a stable/chronic phase. The mean cost per patient in the first month post-index ED visit was $1876 (95% CI $1822 to $1931), $8050 (95% CI $7666 to $8434) in the month before death, and $640 (95% CI $624 to $655) per month for the stable/chronic phase. The main cost component in the post-index phase was physician services (32% of all costs) and hospitalizations for the predeath phase (72% of all costs). The CHA2DS2-VASc clinical risk score was a strong predictor of costs (rate ratio 1.91 and 5.08 for score of 7 versus score of 0 in predeath phase and postindex phase, respectively). CONCLUSIONS: There are distinct phases of resource utilization in AF, with highest costs in the predeath phase. PMID- 25907125 TI - Consumption of fried foods and risk of heart failure in the physicians' health study. AB - BACKGROUND: Consumption of fried foods is highly prevalent in the Western dietary pattern. Though limited studies have reported a positive association between frequency of fried food intake and risk of coronary artery disease, diabetes, or hypertension, other investigators failed to report such an association. It is unclear whether intake of fried foods is associated with a higher risk of heart failure (HF). Hence, we sought to examine the association between the frequency of fried food consumption and the risk of HF. METHODS AND RESULTS: This was a prospective cohort study of 15 362 participants from the Physicians' Health Study. Fried food intake frequency was assessed by a food frequency questionnaire (1997-2001), and incident HF was captured by annual questionnaires. We used Cox regression to calculate hazard ratios (HRs) of HF. After an average follow-up of 9.6 +/- 2.4 years, a total of 632 new HF cases occurred in this cohort. Compared to subjects who reported fried food consumption of <1 per week, HRs (95% CI) for HF were 1.24 (1.04 to 1.48), 1.28 (1.00 to 1.63), and 2.03 (1.37 to 3.02) for fried food intake of 1 to 3/week, 4 to 6/week, and 7+/week, respectively, after adjustment for age, energy intake, alcohol use, exercise, smoking, and overall diet score (P linear trend, 0.0002). Similar results were obtained for intake of fried foods at home or away from home and among subjects with higher dietary score or HF without antecedent myocardial infarction. CONCLUSIONS: Our data are consistent with a positive association of fried food intake frequency with incident HF in male physicians. PMID- 25907127 TI - Ethnic differences in family member diabetes involvement and psychological outcomes: results from the second Diabetes Attitudes, Wishes and Needs (DAWN2) study in the USA. AB - OBJECTIVE: To assess differences among USA ethnic groups in psychological status of adult family members (FMs) and their involvement with the diabetes of another adult. RESEARCH METHODS: Data are from the FM survey of the USA DAWN2 study, including 105 White non-Hispanics, 47 African Americans, 46 Hispanic Americans and 40 Chinese Americans. All FMs lived with and cared for an adult with diabetes. Analysis of covariance controlled for respondent and patient characteristics to assess ethnic group differences (P < 0.05). Multiple regression analyses identified significant (P < 0.05) independent correlates of psychological outcomes. MAIN OUTCOME MEASURES: FM psychological outcomes measured include well-being, quality of life (QoL), impact of diabetes on life domains, diabetes distress, and burden. CLINICAL TRIAL REGISTRATION: NCT01507116. RESULTS: White non-Hispanics reported less diabetes burden and distress, more negative life impact, and lower well-being than FMs from ethnic minority groups. African Americans reported the highest well-being and lowest negative life impact, Chinese Americans reported the most diabetes burden, Hispanic Americans reported the highest distress. There were no ethnic group differences in QoL. Ethnic minority FMs reported having more involvement with diabetes, greater support success, and more access to a diabetes support network than White non-Hispanics. Higher FM diabetes involvement was associated with negative psychological outcomes, while diabetes education, support success and diabetes support network size were associated with better psychological outcomes. Potential limitations are the sample sizes and representativeness. CONCLUSIONS: Minority ethnic FMs experienced both advantages and disadvantages in psychological outcomes relative to each other and to White non-Hispanics. Ethnic minority FMs had more involvement in diabetes care, support success and support from others, with the first associated with worse and the latter two with better psychological outcomes. Additional studies are needed with larger samples and broader representation of ethnic groups to better understand these associations and identify areas for intervention. PMID- 25907126 TI - Years of able life in older persons--the role of cardiovascular imaging and biomarkers: the Cardiovascular Health Study. AB - BACKGROUND: As the U.S. population grows older, there is greater need to examine physical independence. Previous studies have assessed risk factors in relation to either disability or mortality, but an outcome that combines both is still needed. METHODS AND RESULTS: The Cardiovascular Health Study is a population based, prospective study where participants underwent baseline echocardiogram, measurement of carotid intima-media thickness (IMT), and various biomarkers, then followed for up to 18 years. Years of able life (YAL) constituted the number of years the participant was able to perform all activities of daily living. Linear regression was used to model the relationship between selected measures and outcomes, adjusted for confounding variables. Among 4902 participants, mean age was 72.6 +/- 5.4 years, median YAL for males was 8.8 (interquartile range [IQR], 4.3 to 13.8) and 10.3 (IQR, 5.8 to 15.8) for females. Reductions in YAL in the fully adjusted model for females and males, respectively, were: -1.34 (95% confidence interval [CI], -2.18, -0.49) and -1.41 (95% CI, -2.03, -0.8) for abnormal left ventricular (LV) ejection fraction, -0.5 (95% CI, -0.78, -0.22) and -0.62 (95% CI, -0.87, -0.36) per SD increase in LV mass, -0.5 (95% CI, -0.7, 0.29) and -0.79 (95% CI, -0.99, -0.58) for IMT, -0.5 (95% CI, -0.64, -0.37) and 0.79 (95% CI, -0.94, -0.65) for N-terminal pro-brain natriuretic peptide, -1.08 (95% CI, -1.34, -0.83) and -0.73 (95% CI, -0.97, -0.5) for high-sensitivity troponin-T, and -0.26 (95% CI, -0.42, -0.09) and -0.23 (95% CI, -0.41, -0.05) for procollagen-III N-terminal propeptide. Most tested variables remained significant even after adjusting for incident cardiovascular (CV) disease. CONCLUSIONS: In this population-based cohort, variables obtained by CV imaging and biomarkers of inflammation, coagulation, atherosclerosis, myocardial injury and stress, and cardiac collagen turnover were associated with YAL, an important outcome that integrates physical ability and longevity in older persons. PMID- 25907128 TI - A clinical decision support system for the diagnosis of probable migraine and probable tension-type headache based on case-based reasoning. AB - BACKGROUND: The overlap between probable migraine (PM) and probable tension-type headache (PTTH) often confuses physicians in clinical practice. Although clinical decision support systems (CDSSs) have been proven to be helpful in the diagnosis of primary headaches, the existing guideline-based headache disorder CDSSs do not perform adequately due to this overlapping issue. Thus, in this study, a CDSS based on case-based reasoning (CBR) was developed in order to solve this problem. METHODS: First, a case library consisting of 676 clinical cases, 56.95% of which had been diagnosed with PM and 43.05% of which had been diagnosed with PTTH, was constructed, screened by a three-member panel, and weighted by engineers. Next, the resulting case library was used to diagnose current cases based on their similarities to the previous cases. The test dataset was composed of an additional 222 historical cases, 76.1% of which had been diagnosed with PM and 23.9% of which had been diagnosed with PTTH. The cases that comprised the case library as well as the test dataset were actual clinical cases obtained from the International Headache Center in Chinese PLA General Hospital. RESULTS: The results indicated that the PM and PTTH recall rates were equal to 97.02% and 77.78%, which were 34.31% and 16.91% higher than that of the guideline-based CDSS, respectively. Furthermore, the PM and PTTH precision rates were equal to 93.14% and 89.36%, which were7.09% and 15.68% higher than that of the guideline based CDSS, respectively. Comparing CBR CDSS and guideline-based CDSS, the p value of PM diagnoses was equal to 0.019, while that of PTTH diagnoses was equal to 0.002, which indicated that there was a significant difference between the two approaches. CONCLUSIONS: The experimental results indicated that the CBR CDSS developed in this study diagnosed PM and PTTH with a high degree of accuracy and performed better than the guideline-based CDSS. This system could be used as a diagnostic tool to assist general practitioners in distinguishing PM from PTTH. PMID- 25907129 TI - Using horizontal heel displacement to identify heel strike instants in normal gait. AB - Heel strike instants are an important component of gait analyses, yet accurate detection can be difficult without a force plate. This paper presents two novel techniques for kinematic heel strike instant (kHSI) detection which examined maximal resultant horizontal heel displacement (HHD). Each of these HHD techniques calculates HHD from a selected reference location of either the stance ankle or stance heel to the swing heel. The proposed techniques, along with other previously established techniques, were validated against a 10N force plate threshold. Fifty-four healthy adults walked overground at both normal and fast speeds while wearing athletic shoes. The reported true and absolute errors were as low as 3.2 (4.4) and 5.7 (3.4)ms, respectively, across 8678kHSI when using the stance ankle as a reference, which significantly outperformed (p<0.0001) the established techniques. Gait speed was shown to have a significant effect (p<0.0001) on HHD-determined kHSI, as well as the three other techniques evaluated, highlighting the need for condition-specific identification of kHSI. PMID- 25907130 TI - Development and validation of a Chinese outpatient satisfaction questionnaire: evidence from 46 public general hospitals and 5151 outpatients. AB - OBJECTIVE: To develop and test a reliable and practical self-administrated questionnaire in Chinese to evaluate outpatient satisfaction in China. DESIGN: In order to ensure content validity, the 19 items of this questionnaire were generated based on literature review, interview and group discussion. Acceptability was tested by the percentage of missing item responses and the time and operability of administration. Construct validity was evaluated using principal component exploratory factor analysis and item-total correlations. The reliability of the questionnaire was assessed using Cronbach's alpha coefficient and inter-subscale correlation. SETTING: This study was conducted in 46 public general hospitals that report directly to the Provincial Health Department in Hunan Province, China. SUBJECTS: In total, 5151 outpatients were selected at random and asked to complete the questionnaire after they finished their medical procedures in the outpatient area. RESULTS: The extremely low rate of missing data (0-0.04%) suggested good acceptability of the questionnaire. Factor analysis generated six dimensions, and all item-total coefficients were >0.8. Cronbach's alpha exceeded 0.7 for all dimensions, and the inter-subscale correlation coefficients were all lower than the Cronbach's alpha coefficients of the corresponding scale. According to the results, outpatients were least satisfied with waiting time (86.8%) and most satisfied with the quality of medical care (90.1%). CONCLUSION: The Chinese outpatient satisfaction questionnaire has good acceptability, validity and reliability. It was effective and efficient for measuring outpatient satisfaction in a Chinese population. PMID- 25907131 TI - [False aneurysm of the internal iliac artery in Behcet's disease]. AB - OBJECTIVES: This case illustrates a very rare localization of false aneurysm in Behcet's disease and demonstrates the importance of monitoring treated patients. CASE REPORT: The diagnosis of severe Behcet's disease was established in a young man after discovery of a cerebral venous thrombosis. One year later, the patient required emergency surgery for a symptomatic pseudoaneurysm of the internal iliac artery. RESULTS: Performed after a 3-day regimen of corticosteroid boluses, the pseudoaneurysm was treated by ligation of the hypogastric artery. Corticosteroids were then given for immunosuppression. DISCUSSION: Arterial involvement in Behcet's disease can be at the forefront of the clinical features and can cause potentially fatal complications. False aneurysm of the internal iliac artery is exceptional with only two cases reported in the literature. These false aneurysms occur on a fragile artery wall. Treatment requires the administration of immunosuppressive drugs. CONCLUSION: This rare clinical presentation highlights the importance of clinical and radiological monitoring in young patients with Behcet's disease. PMID- 25907132 TI - [Compression care for venous leg ulcers: Assessment of medical practices in 100 patients]. AB - INTRODUCTION: The etiologic treatment of venous ulcers is based on compression therapy in compliance with the new guidelines promulgated by the French National Authority for Health (HAS) in 2010. Prescriptions often originate from a request by the nurse delivering care in the patient's home. A recent French study demonstrated the positive impact of compression therapy on venous ulcer healing. The objective of this study was to evaluate medical practices in order to target corrective actions. MATERIALS AND METHODS: We conducted a single-center prospective observational study, using a standardized questionnaire from January to May 2014. Patients with venous ulcers who had an indication for compression therapy were included consecutively. The questionnaire collected demographic and clinical data and also recorded the results of complementary tests and the characteristics of the compression therapy. RESULTS: One hundred patients were included (61 women and 39 men). The average age was 76 years. Patients were recruited during consultations (n = 69), with a majority of patients living at home (n = 80) and receiving home care delivered by a nurse (n = 81). Thirteen patients were seen for the first time and 87 patients were receiving long-term care. The ulcers evolved for 5.7 years on average. Patients presented peri lesional edema (n = 58), ankle ankylosis (n = 49), autonomous mobilization (n = 40) and walking problems (n = 60). Physical therapy was prescribed for 39 patients and was effectively carried out for 24. The two main causes were venous varices (n = 66) and post-phlebitis disease (n = 18). Compression therapy was prescribed for 97 patients and the products delivered by the pharmacy were consistent with the prescription for 74 patients. Compliance with compression therapy was faulty for 28 patients because of poor tolerance, misunderstanding, manipulation problems, or inappropriate footwear. At assessment, 66 patients were wearing the bands, but not always correctly (starting at the base of the toes [n = 61], heel included [n = 43], proper stretching [n = 43] up to below the knee [n = 57]). Proper footwear was noted in 70 patients. CONCLUSION: Data are scarce on compliance with compression banding. This study shows that further efforts are needed to ensure proper patient education and professional training for physicians and allied profession concerning the installation of compression therapy. Total compliance was observed in only 35% of patients. In addition, the products delivered by the pharmacy were not consistent with the prescription in 26% of cases. Many discrepancies were observed between what was prescribed and what the patients achieved. Patient adherence is a crucial issue for compression therapy. PMID- 25907133 TI - Binding of imidazole, 1-methylimidazole and 4-nitroimidazole to yeast cytochrome c peroxidase (CcP) and the distal histidine mutant, CcP(H52L). AB - Imidazole, 1-methylimidazole and 4-nitroimidazole bind to yeast cytochrome c peroxidase (yCcP) with apparent equilibrium dissociation constants (KD(app)) of 3.3+/-0.4, 0.85+/-0.11, and ~0.2M, respectively, at pH7. This is the weakest imidazole binding to a heme protein reported to date and it is about 120 times weaker than imidazole binding to metmyoglobin. Spectroscopic changes associated with imidazole and 1-methylimidazole binding to yCcP suggest partial ionization of bound imidazole to imidazolate. The pKa for ionization of bound imidazole is estimated to be 7.4+/-0.2, about 7 units lower than that of free imidazole and about 3 units lower than imidazole bound to metmyoglobin. Equilibrium binding of imidazole to CcP(H52L) is biphasic with low- and high-affinity phases having KD(app) values of 9.5+/-4.5 and 0.13+/-0.04M, respectively. CcP(H52L) binding of 1-methylimidazole is monophasic with an affinity similar to those of yCcP and rCcP. Binding of 1-methylimidazole to rCcP is associated with two kinetic phases, the initial binding complete within 10s, followed by a process that is consistent with 1-methylimidazole binding to a cavity created by movement of Trp-191 from the interior of the protein to the surface. Both the equilibrium binding and kinetics of 1-methylimidazole binding to yCcP are pH dependent. yCcP has a four fold increase in 1-methylimidazole binding affinity on decreasing the pH from 7.5 to 4.0, an observation that is unique among the many studies on binding of imidazole and imidazole derivatives to heme proteins. PMID- 25907135 TI - Editorial Comment from Dr Miyata and Dr Sakai to Sulfoquinovosylacylpropanediol is a novel potent radiosensitizer in prostate cancer. PMID- 25907134 TI - Conservation and divergence of the cyclic adenosine monophosphate-protein kinase A (cAMP-PKA) pathway in two plant-pathogenic fungi: Fusarium graminearum and F. verticillioides. AB - The cyclic adenosine monophosphate-protein kinase A (cAMP-PKA) pathway is a central signalling cascade that transmits extracellular stimuli and governs cell responses through the second messenger cAMP. The importance of cAMP signalling in fungal biology has been well documented and the key conserved components, adenylate cyclase (AC) and the catalytic subunit of PKA (CPKA), have been functionally characterized. However, other genes involved in this signalling pathway and their regulation are not well understood in filamentous fungi. Here, we performed a comparative transcriptomics analysis of AC and CPKA mutants in two closely related fungi: Fusarium graminearum (Fg) and F. verticillioides (Fv). Combining available Fg transcriptomics and phenomics data, we reconstructed the Fg cAMP signalling pathway. We developed a computational program that combines sequence conservation and patterns of orthologous gene expression to facilitate global transcriptomics comparisons between different organisms. We observed highly correlated expression patterns for most orthologues (80%) between Fg and Fv. We also identified a subset of 482 (6%) diverged orthologues, whose expression under all conditions was at least 50% higher in one genome than in the other. This enabled us to dissect the conserved and unique portions of the cAMP PKA pathway. Although the conserved portions controlled essential functions, such as metabolism, the cell cycle, chromatin remodelling and the oxidative stress response, the diverged portions had species-specific roles, such as the production and detoxification of secondary metabolites unique to each species. The evolution of the cAMP-PKA signalling pathway seems to have contributed directly to fungal divergence and niche adaptation. PMID- 25907136 TI - A member of the Tlr family is involved in dsRNA innate immune response in Paracentrotus lividus sea urchin. AB - The innate immune response involves proteins such as the membrane receptors of the Toll-like family (TLRs), which trigger different intracellular signalling pathways that are dependent on specific stimulating molecules. In sea urchins, TLR proteins are encoded by members of a large multigenic family composed of 60 250 genes in different species. Here, we report a newly identified mRNA sequence encoding a TLR protein (referred to as Pl-Tlr) isolated from Paracentrotus lividus immune cells. The partial protein sequence contained the conserved Toll/IL-1 receptor (TIR) domain, the transmembrane domain and part of the leucine repeats. Phylogenetic analysis of the Pl-Tlr protein was accomplished by comparing its sequence with those of TLRs from different classes of vertebrates and invertebrates. This analysis was suggestive of an evolutionary path that most likely represented the course of millions of years, starting from simple organisms and extending to humans. Challenge of the sea urchin immune system with poly-I:C, a chemical compound that mimics dsRNA, caused time-dependent Pl-Tlr mRNA up-regulation that was detected by QPCR. In contrast, bacterial LPS injury did not affect Pl-Tlr transcription. The study of the Tlr genes in the sea urchin model system may provide new perspectives on the role of Tlrs in the invertebrate immune response and clues concerning their evolution in a changing world. PMID- 25907137 TI - A FOXM1 related long non-coding RNA contributes to gastric cancer cell migration. AB - Long non-coding RNAs (LncRNAs) have been reported that play important roles in the progression and metastasis of some carcinomas. In the present study, we identified a new LncRNA, FRLnc1, from a microarray analysis in which those LncRNAs were regulated by FOXM1, an oncogene widely studied in most malignancies. Quantitative real-time PCR (qRT-PCR) results in gastric cancer cell lines indicated FRLnc1 expression is positively correlated with FOXM1 level, supporting the microarray data. Furthermore, the RNA level of FRLnc1 is upregulated in 49% (20/41) of cancer samples compared with neighboring non-cancerous stomach tissues. The in vitro functional analyses demonstrated that FRLnc1 knockdown by RNA interference suppressed cell migration in MGC803 and AGS cells, whereas FRLnc1 overexpression promoted cell migration in BGC823 and SGC7901 cells. Moreover, FRLnc1 could enhance the distant metastasis of SGC7901 cells by tail vein injection approach in mice. We also identified TGFbeta1 and Twist as the downstream effectors of FRLnc1 in the regulation of cell migration by qRT-PCR analysis. Taken together, our findings suggest that FRLnc1 is involved in gastric cancer cell migration and for the first time set up the link between FOXM1 and LncRNA in cancer. PMID- 25907138 TI - Concentrations of doxycycline in cerebrospinal fluid in Whipple's disease. PMID- 25907139 TI - The antimicrobial potential of ionic liquids: A source of chemical diversity for infection and biofilm control. AB - Although described almost a century ago, interest in ionic liquids has flourished in the last two decades, with significant advances in the understanding of their chemical, physical and biological property sets driving their widespread application across multiple and diverse research areas. Significant progress has been made through the contributions of numerous research groups detailing novel libraries of ionic liquids, often 'task-specific' designer solvents for application in areas as diverse as separation technology, catalysis and bioremediation. Basic antimicrobial screening has often been included as a surrogate indication of the environmental impact of these compounds widely regarded as 'green' solvents. Obviating the biological properties, specifically toxicity, of these compounds has obstructed their potential application as sophisticated designer biocides. A recent tangent in ionic liquids research now aims to harness tuneable biological properties of these compounds in the design of novel potent antimicrobials, recognising their unparalleled flexibility for chemical diversity in a severely depleted antimicrobial arsenal. This review concentrates primarily on the antimicrobial potential of ionic liquids and aims to consolidate contemporary microbiological background information, assessment protocols and future considerations necessary to advance the field in light of the urgent need for antimicrobial innovation. PMID- 25907140 TI - Hypoxia inhibits semicarbazide-sensitive amine oxidase activity in adipocytes. AB - Semicarbazide-sensitive amine oxidase (SSAO), an enzyme highly expressed on adipocyte plasma membranes, converts primary amines into aldehydes, ammonium and hydrogen peroxide, and is likely involved in endothelial damage during the course of diabetes and obesity. We investigated whether in vitro, adipocyte SSAO was modulated under hypoxic conditions that is present in adipose tissue from obese or intensive care unit. Physical or pharmacological hypoxia decreased SSAO activity in murine adipocytes and human adipose tissue explants, while enzyme expression was preserved. This effect was time-, dose-dependent and reversible. This down-regulation was confirmed in vivo in subcutaneous adipose tissue from a rat model of hypoxia. Hypoxia-induced suppression in SSAO activity was independent of the HIF-1-alpha pathway or of oxidative stress, but was partially antagonized by medium acidification. Hypoxia-induced down-regulation of SSAO activity could represent an adaptive mechanism to lower toxic molecules production, and may thus protect from tissue injury during these harmful conditions. PMID- 25907141 TI - The role of the endothelin-1 pathway as a biomarker for donor lung assessment in clinical ex vivo lung perfusion. AB - BACKGROUND: Normothermic ex vivo lung perfusion (EVLP) is a preservation technique that allows reassessment of donor lungs before transplantation. We hypothesized that the endothelin-1 (ET-1) axis would be associated with donor lung performance during EVLP and recipient outcomes after transplantation. METHODS: ET-1, Big ET-1, endothelin-converting enzyme (ECE), and nitric oxide (NO) metabolites were quantified in the perfusates of donor lungs enrolled in a clinical EVLP trial. Lungs were divided into 3 groups: (I) Control: bilateral transplantation with good early outcomes defined as absence of primary graft dysfunction (PGD) Grade 3 (PGD3) ; (II) PGD3: bilateral lung transplantation with PGD3 any time within 72 hours; and (III) Declined: lungs rejected after EVLP. RESULTS: There were 25 lungs in Group I, 7 in Group II, and 16 in Group III. At 1 and 4 hours of EVLP, the perfusates of Declined lungs had significantly higher levels of ET-1 (3.1 +/- 2.1 vs. 1.8+/-2.3 pg/ml, p = 0.01; 2.7 +/- 2.2 vs. 1.3 +/ 1.1 pg/ml, p = 0.007) and Big ET-1 (15.8 +/- 14.2 vs. 7.0 +/- 6.5 pg/ml, p = 0.001; 31.7 +/- 17.4 vs. 19.4 +/- 9.5 pg/ml, p = 0.007) compared with Controls. Nitric oxide metabolite concentrations were significantly higher in Declined and PGD3 lungs than in Controls. For cases of donation after cardiac death, PGD3 and Declined lungs had higher ET-1 and Big ET-1 levels at 4 hours of perfusion compared with Controls. At this time point, Big ET-1 had excellent accuracy to distinguish PGD3 (96%) and Declined (92%) from Control lungs. CONCLUSIONS: In donation after cardiac death lungs, perfusate ET-1 and Big ET-1 are potential predictors of lung function during EVLP and after lung transplantation. They were also associated with non-use of lungs after EVLP and thus could represent useful biomarkers to improve the accuracy of donor lungs selection. PMID- 25907142 TI - Predicting protein-binding RNA nucleotides with consideration of binding partners. AB - In recent years several computational methods have been developed to predict RNA binding sites in protein. Most of these methods do not consider interacting partners of a protein, so they predict the same RNA-binding sites for a given protein sequence even if the protein binds to different RNAs. Unlike the problem of predicting RNA-binding sites in protein, the problem of predicting protein binding sites in RNA has received little attention mainly because it is much more difficult and shows a lower accuracy on average. In our previous study, we developed a method that predicts protein-binding nucleotides from an RNA sequence. In an effort to improve the prediction accuracy and usefulness of the previous method, we developed a new method that uses both RNA and protein sequence data. In this study, we identified effective features of RNA and protein molecules and developed a new support vector machine (SVM) model to predict protein-binding nucleotides from RNA and protein sequence data. The new model that used both protein and RNA sequence data achieved a sensitivity of 86.5%, a specificity of 86.2%, a positive predictive value (PPV) of 72.6%, a negative predictive value (NPV) of 93.8% and Matthews correlation coefficient (MCC) of 0.69 in a 10-fold cross validation; it achieved a sensitivity of 58.8%, a specificity of 87.4%, a PPV of 65.1%, a NPV of 84.2% and MCC of 0.48 in independent testing. For comparative purpose, we built another prediction model that used RNA sequence data alone and ran it on the same dataset. In a 10 fold cross validation it achieved a sensitivity of 85.7%, a specificity of 80.5%, a PPV of 67.7%, a NPV of 92.2% and MCC of 0.63; in independent testing it achieved a sensitivity of 67.7%, a specificity of 78.8%, a PPV of 57.6%, a NPV of 85.2% and MCC of 0.45. In both cross-validations and independent testing, the new model that used both RNA and protein sequences showed a better performance than the model that used RNA sequence data alone in most performance measures. To the best of our knowledge, this is the first sequence-based prediction of protein-binding nucleotides in RNA which considers the binding partner of RNA. The new model will provide valuable information for designing biochemical experiments to find putative protein-binding sites in RNA with unknown structure. PMID- 25907144 TI - Biosimilars and the long game. AB - Despite greater certainty for biosimilar markets and regulation, the change that was seen in the small-molecule pharmaceuticals market with the rapid entrance of emerging-country generics suppliers will not be replicated exactly. The long game has yet to be played out, and recent changes in regulation, science, and production technology are likely to impact on future patterns of partnership and production. PMID- 25907143 TI - Bacterial symbiont sharing in Megalomyrmex social parasites and their fungus growing ant hosts. AB - Bacterial symbionts are important fitness determinants of insects. Some hosts have independently acquired taxonomically related microbes to meet similar challenges, but whether distantly related hosts that live in tight symbiosis can maintain similar microbial communities has not been investigated. Varying degrees of nest sharing between Megalomyrmex social parasites (Solenopsidini) and their fungus-growing ant hosts (Attini) from the genera Cyphomyrmex, Trachymyrmex and Sericomyrmex allowed us to address this question, as both ant lineages rely on the same fungal diet, interact in varying intensities and are distantly related. We used tag-encoded FLX 454 pyrosequencing and diagnostic PCR to map bacterial symbiont diversity across the Megalomyrmex phylogenetic tree, which also contains free-living generalist predators. We show that social parasites and hosts share a subset of bacterial symbionts, primarily consisting of Entomoplasmatales, Bartonellaceae, Acinetobacter, Wolbachia and Pseudonocardia and that Entomoplasmatales and Bartonellaceae can co-infect specifically associated combinations of hosts and social parasites with identical 16S rRNA genotypes. We reconstructed in more detail the population-level infection dynamics for Entomoplasmatales and Bartonellaceae in Megalomyrmex symmetochus guest ants and their Sericomyrmex amabilis hosts. We further assessed the stability of the bacterial communities through a diet manipulation experiment and evaluated possible transmission modes in shared nests such as consumption of the same fungus garden food, eating of host brood by social parasites, trophallaxis and grooming interactions between the ants, or parallel acquisition from the same nest environment. Our results imply that cohabiting ant social parasites and hosts may obtain functional benefits from bacterial symbiont transfer even when they are not closely related. PMID- 25907145 TI - Effects of a movement training oriented rehabilitation program on symptoms, functional limitations and acromiohumeral distance in individuals with subacromial pain syndrome. AB - BACKGROUND: Multiple factors have been associated with the presence of a subacromial pain syndrome (SPS), including deficits in performance of scapular and glenohumeral muscles. Such deficits can lead to inadequate kinematics and decreased acromiohumeral distance (AHD). Exercises that aim at correcting these deficits, such as movement training, were suggested to improve symptoms and functional limitations. To date, few studies have assessed outcomes following an intervention focused on movement training. OBJECTIVES: Evaluate the effects of a rehabilitation program based on movement training on symptoms, functional limitations and AHD in individuals with SPS. DESIGN: Prospective single group pre post design. METHODS: Twenty-five participants with SPS (SPS group) participated in a 6-week program. Twenty asymptomatic volunteers were recruited for normative AHD values (control group). Outcomes of both groups were evaluated at baseline and 6 weeks, i.e. immediately following intervention for the SPS group. Changes in symptoms and functional limitations for SPS group were assessed using the Western Ontario Rotator Cuff (WORC) index and Disability of the Arm Shoulder and Hand (DASH) questionnaire. Changes in AHD for both groups were assessed using ultrasonographic measures. RESULTS: Following the rehabilitation program, the scores on WORC and DASH were significantly improved (p < 0.001). AHD increased significantly in the SPS group (p = 0.019), especially in a subgroup with initial deficits (p < 0.001). CONCLUSION: The rehabilitation program yielded improvements in symptoms and functional limitations in participants with SPS. Moreover, it led to an increase of the AHD--thus potentially decreasing subacromial compression, particularly in participants with an initially smaller AHD. The trial was registered at ClinicalTrials.gov: identifier--NCT02395770. PMID- 25907146 TI - Immediate combined effect of gastrocnemius stretching and sustained talocrural joint mobilization in individuals with limited ankle dorsiflexion: A randomized controlled trial. AB - BACKGROUND: Although gastrocnemius stretching and talocrural joint mobilization have been suggested as effective interventions to address limited ankle dorsiflexion passive range of motion (DF PROM), the effects of a combination of the two interventions have not been identified. OBJECTIVE: The aim of the present study was to compare the effects of gastrocnemius stretching combined with joint mobilization and gastrocnemius stretching alone. DESIGN: A randomized controlled trial. METHODS: In total, 24 individuals with limited ankle DF PROM were randomized to undergo gastrocnemius stretching combined with joint mobilization (12 feet in 12 individuals) or gastrocnemius stretching alone (12 feet in 12 individuals) for 5 min. Ankle kinematics during gait (time to heel-off and ankle DF before heel-off), ankle DF PROM, posterior talar glide, and displacement of the myotendinous junction (MTJ) of the gastrocnemius were assessed before and after the interventions. The groups were compared using two-way repeated measures analysis of variance. RESULTS/FINDINGS: Greater increases in the time to heel-off and ankle DF before heel-off during gait and posterior talar glide were observed in the stretching combined with joint mobilization group versus the stretching alone group. Ankle DF PROM and displacement of the MTJ of the gastrocnemius were increased significantly after the interventions in both groups, with no significant difference between them. CONCLUSIONS: These findings suggest that gastrocnemius stretching with joint mobilization needs to be considered to improve ankle kinematics during gait. PMID- 25907147 TI - Inhaled antimicrobial chemotherapy for respiratory tract infections: successes, challenges and the road ahead. PMID- 25907148 TI - Rollovers during play: Complementary perspectives. AB - In this commentary, we compare and contrast Norman et al.s' findings on rollovers during dog play (Norman et al., 2015; the "target article") with our work on dog play fighting (Bauer and Smuts, 2007; Ward et al., 2008). We first review our major findings and then correct some errors in the target article's descriptions of our work. We then further explore the concept of "defensive" rollovers proposed in the target article. We conclude that a combination of the target article's approach and ours should inform future investigations of dog rollovers. PMID- 25907149 TI - Reciprocation and altruism in social cooperation. AB - Altruistic behavior benefits other individuals at a cost to oneself. The purpose of the present experiment was to study altruistic behavior by players (P) in 2 person iterated prisoner's dilemma games in which reciprocation by the other player (OP) was impossible, and this impossibility was clear to P. Altruism by P could not therefore be attributed to expectation of reciprocation. The cost to P of altruistic behavior was constant throughout the study, but the benefit to OP from P's cooperation differed between groups and conditions. Rate of cooperation was higher when benefit to OP was higher. Thus altruism (not attributable to expectation of reciprocation) can be a significant factor in interpersonal relationships as studied in iterated prisoner's dilemma games, and needs to be taken into account in their analysis. PMID- 25907150 TI - Unraveling the adsorption mechanism of mono- and diaromatics in faujasite zeolite. AB - Monte Carlo simulations are performed to study the adsorption of aromatic molecules (toluene, styrene, o-xylene, m-xylene, p-xylene, 1,3,5 trimethylbenzene, and naphthalene) in all-silica faujasite (FAU) zeolite. For monoaromatics, a two-stage "ideal adsorption" and "insertion adsorption" mechanism is found by careful inspection of locations and distributions of the adsorbed toluene molecules. The validity of this mechanism is confirmed for all monoaromatics considered in the current study. Remarkably, the number of C atoms per unit cell corresponding to the inflection point of adsorbate loading (CI-P) is defined as a valid and convenient characterizing factor in the packing efficiency of monoaromatics in the FAU zeolite. For the case of naphthalene, a type of diaromatic, the three-stage mechanism is proposed, which consists of the first two stages and a third stage of "overideal adsorption". The so-called overideal adsorption is labeled because the naphthalene molecules start to occupy the S site nonideally at loadings that approach saturation, leading to a more localized feature of the adsorbates. The explicit adsorption mechanism can be used to understand the loading dependence of isosteric adsorption heat for the aromatics concerned. PMID- 25907151 TI - Electronic, bonding, and optical properties of 1d [CuCN]n (n = 1-10) chains, 2d [CuCN]n (n = 2-10) nanorings, and 3d [Cun (CN)n ]m (n = 4, m = 2, 3; n = 10, m = 2) tubes studied by DFT/TD-DFT methods. AB - The electronic, bonding, and photophysical properties of one-dimensional [CuCN](n) (n = 1-10) chains, 2-D [CuCN](n) (n = 2-10) nanorings, and 3-D [Cu(n)(CN)(n)](m) (n = 4, m = 2, 3; n = 10, m = 2) tubes are investigated by means of a multitude of computational methodologies using density functional theory (DFT) and time-dependent-density-functional theory (TD-DFT) methods. The calculations revealed that the 2-D [CuCN](n) (n = 2-10) nanorings are more stable than the respective 1-D [CuCN](n) (n = 2-10) linear chains. The 2-D [CuCN](n) (n = 2-10) nanorings are predicted to form 3-D [Cun (CN)(n)](m) (n = 4, m = 2, 3; n = 10, m = 2) tubes supported by weak stacking interactions, which are clearly visualized as broad regions in real space by the 3D plots of the reduced density gradient. The bonding mechanism in the 1-D [CuCN](n) (n = 1-10) chains, 2-D [CuCN](n) (n = 2-10) nanorings, and 3-D [Cu(n)(CN)(n)](m) (n = 4, m = 2, 3; n = 10, m = 2) tubes are easily recognized by a multitude of electronic structure calculation approaches. Particular emphasis was given on the photophysical properties (absorption and emission spectra) of the [CuCN](n) chains, nanorings, and tubes which were simulated by TD-DFT calculations. The absorption and emission bands in the simulated TD-DFT absorption and emission spectra have thoroughly been analyzed and assignments of the contributing principal electronic transitions associated to individual excitations have been made. PMID- 25907152 TI - Unusual clinical presentation of thoracic tuberculosis: the need for a better knowledge of illness. AB - BACKGROUND: Pulmonary tuberculosis (TB), a highly contagious infectious disease, is a significant public health problem all over the world and remains an important cause of preventable death in the adult population. Endobronchial TB is an unusual form of thoracic TB that may be complicated by tracheobronchial stenosis, and bronchoesophageal fistula formation is a very rare complication. Tubercular lymphadenitis can also lead to fistula formation through a process of caseum necrosis and opening of a fistula between the bronchus and oesophagus. CASE REPORT: We report an uncommon case of thoracic TB in an immunocompetent 73 year-old Caucasian man who presented several problems: bronchoesophageal fistula, endobronchial TB, and mediastinal lymphadenopathy in the absence of contemporary parenchymal consolidation. Furthermore, he presented a normal chest radiograph and mostly unclear and non-specific symptoms at onset. CONCLUSIONS: We emphasize the need for a better knowledge of this illness and awareness that it may have an unusual presentation. In these cases, diagnosis and proper treatment can be delayed, with severe complications for the patient. Pulmonary TB remains a real diagnostic challenge: a normal chest radiograph and nonspecific symptoms do not allow us to exclude this persistent infectious disease. PMID- 25907153 TI - Tuning hippocampal synapses by stress-hormones: Relevance for emotional memory formation. AB - While stress is often associated with an increased risk to develop (psycho) pathology, the initial response after exposure to stressors is often highly beneficial and allows individuals to optimally cope with challenging situations. Various neurotransmitters and neuromodulators - such as catecholamines and glucocorticoids - are released upon exposure to stressors and regulate behavioural adaptation to stress and enhance the storage of salient information. Studies over the past years have revealed that catecholamines and glucocorticoids regulate synaptic function and synaptic plasticity - which underlie memory formation - in a highly dynamic manner. In this brief review we will summarise how catecholamines and glucocorticoids regulate synaptic function and discuss how these effects may contribute to acquisition and storage of emotional information. This article is part of a Special Issue entitled SI: Brain and Memory. PMID- 25907154 TI - Laser Resurfacing for Latin Skins: The Experience with 665 Cases. AB - BACKGROUND: CO2 resurfacing and CO2 microfractionated laser systems are reliable tools to improve different facial pathologic skin conditions but are associated with a high rate of complications specially in Fitzpatrick III, IV, and V skin phototypes, predominant in the Latin population, which has pushed many surgeons to change technologies and abandon its use. OBJECTIVE: To compare patient results with the CO2 resurfacing laser and microfractionated CO2 laser resurfacing in all skin types and show similar results to those obtained worldwide in patients with phototypes III, IV, and V. METHODS: Standardized review of medical records from a database of private practice patients treated since January 1998 to July 2012 with SlimE30 MiXto SX((r)) CO2 laser. Evaluation of outcomes, complications, and satisfaction of three different modalities of treatment (CO2 ablative laser, CO2 microfractionated and a combination of both) was made. RESULTS: A total of 665 treated patients were included. Ablative CO2 was applied to 80.3 %, CO2 microfractionated to 15.1 %, and mixed treatment to 4.5 % of cases. Globally, hyperpigmentation rates were 30.4 % in the CO2 resurfacing group, 16.3 % when a combination of modalities was applied and 11 % in microfractionated CO2 cases. A steady increase of these rates is shown as the phototype becomes higher. Satisfaction rates were high for all groups: 86.7 % in the mixed group, 82.2 % in the microfractionated CO2, and 79.6 % in the CO2 ablative. CONCLUSIONS: Good results and an acceptable rate of complications in latin skins are obtainable after treating patients with CO2 ablative and microfractionated CO2 systems alone or in combination. Staged treatments and adequate post-procedure care reduce these complications. PMID- 25907155 TI - Massive Hemi-facial Edema After Permanent Filler Removal in an HIV-Positive Patient. Precautions and Patient Information. AB - HIV-related lipodystrophy and facial lipo-atrophy are well-described problems stigmatizing many HIV patients. As these patients often require large volumes of filler material, a more permanent solution is necessary. Before the popularization of lipofilling, synthetic permanent fillers have mostly been used. We describe a case report of a patient who had undergone removal of a permanent filler, polyacrylamide gel, because of dislocation of the filler, but who presented a massive hemi-facial edema immediately after the removal. Swelling subsided after 5 days. The use of permanent fillers has diminished due to frequent early and late complications, but a high awareness for permanent filler removal complications remains necessary. Possible pathways to explain these late complications are described. LEVEL OF EVIDENCE V: This journal requires that authors assign a level of evidence to each article. For a full description of these Evidence-Based Medicine ratings, please refer to the Table of Contents or the online Instructions to Authors www.springer.com/00266 . PMID- 25907156 TI - Depression relapse: importance of a long-term perspective. PMID- 25907157 TI - Effectiveness and cost-effectiveness of mindfulness-based cognitive therapy compared with maintenance antidepressant treatment in the prevention of depressive relapse or recurrence (PREVENT): a randomised controlled trial. AB - BACKGROUND: Individuals with a history of recurrent depression have a high risk of repeated depressive relapse or recurrence. Maintenance antidepressants for at least 2 years is the current recommended treatment, but many individuals are interested in alternatives to medication. Mindfulness-based cognitive therapy (MBCT) has been shown to reduce risk of relapse or recurrence compared with usual care, but has not yet been compared with maintenance antidepressant treatment in a definitive trial. We aimed to see whether MBCT with support to taper or discontinue antidepressant treatment (MBCT-TS) was superior to maintenance antidepressants for prevention of depressive relapse or recurrence over 24 months. METHODS: In this single-blind, parallel, group randomised controlled trial (PREVENT), we recruited adult patients with three or more previous major depressive episodes and on a therapeutic dose of maintenance antidepressants, from primary care general practices in urban and rural settings in the UK. Participants were randomly assigned to either MBCT-TS or maintenance antidepressants (in a 1:1 ratio) with a computer-generated random number sequence with stratification by centre and symptomatic status. Participants were aware of treatment allocation and research assessors were masked to treatment allocation. The primary outcome was time to relapse or recurrence of depression, with patients followed up at five separate intervals during the 24-month study period. The primary analysis was based on the principle of intention to treat. The trial is registered with Current Controlled Trials, ISRCTN26666654. FINDINGS: Between March 23, 2010, and Oct 21, 2011, we assessed 2188 participants for eligibility and recruited 424 patients from 95 general practices. 212 patients were randomly assigned to MBCT-TS and 212 to maintenance antidepressants. The time to relapse or recurrence of depression did not differ between MBCT-TS and maintenance antidepressants over 24 months (hazard ratio 0.89, 95% CI 0.67-1.18; p=0.43), nor did the number of serious adverse events. Five adverse events were reported, including two deaths, in each of the MBCT-TS and maintenance antidepressants groups. No adverse events were attributable to the interventions or the trial. INTERPRETATION: We found no evidence that MBCT-TS is superior to maintenance antidepressant treatment for the prevention of depressive relapse in individuals at risk for depressive relapse or recurrence. Both treatments were associated with enduring positive outcomes in terms of relapse or recurrence, residual depressive symptoms, and quality of life. FUNDING: National Institute for Health Research (NIHR) Health Technology Assessment (HTA) programme, and NIHR Collaboration for Leadership in Applied Health Research and Care South West Peninsula. PMID- 25907159 TI - Efficacy of idebenone in Duchenne muscular dystrophy. PMID- 25907158 TI - Efficacy of idebenone on respiratory function in patients with Duchenne muscular dystrophy not using glucocorticoids (DELOS): a double-blind randomised placebo controlled phase 3 trial. AB - BACKGROUND: Cardiorespiratory failure is the leading cause of death in Duchenne muscular dystrophy. Based on preclinical and phase 2 evidence, we assessed the efficacy and safety of idebenone in young patients with Duchenne muscular dystrophy who were not taking concomitant glucocorticoids. METHODS: In a multicentre phase 3 trial in Belgium, Germany, the Netherlands, Switzerland, France, Sweden, Austria, Italy, Spain, and the USA, patients (age 10-18 years old) with Duchenne muscular dystrophy were randomly assigned in a one-to-one ratio with a central interactive web response system with a permuted block design with four patients per block to receive idebenone (300 mg three times a day) or matching placebo orally for 52 weeks. Study personnel and patients were masked to treatment assignment. The primary endpoint was change in peak expiratory flow (PEF) as percentage predicted (PEF%p) from baseline to week 52, measured with spirometry. Analysis was by intention to treat (ITT) and a modified ITT (mITT), which was prospectively defined to exclude patients with at least 20% difference in the yearly change in PEF%p, measured with hospital-based and weekly home-based spirometry. This study is registered with ClinicalTrials.gov, number NCT01027884. FINDINGS: 31 patients in the idebenone group and 33 in the placebo group comprised the ITT population, and 30 and 27 comprised the mITT population. Idebenone significantly attenuated the fall in PEF%p from baseline to week 52 in the mITT (-3.05%p [95% CI -7.08 to 0.97], p=0.134, vs placebo -9.01%p [-13.18 to 4.84], p=0.0001; difference 5.96%p [0.16 to 11.76], p=0.044) and ITT populations (-2.57%p [-6.68 to 1.54], p=0.215, vs -8.84%p [-12.73 to -4.95], p<0.0001; difference 6.27%p [0.61 to 11.93], p=0.031). Idebenone also had a significant effect on PEF (L/min), weekly home-based PEF, FVC, and FEV1. The effect of idebenone on respiratory function outcomes was similar between patients with previous corticosteroid use and steroid-naive patients. Treatment with idebenone was safe and well tolerated with adverse event rates were similar in both groups. Nasopharyngitis and headache were the most common adverse events (idebenone, eight [25%] and six [19%] of 32 patients; placebo, nine [26%] and seven [21%] of 34 patients). Transient and mild diarrhoea was more common in the idebenone group than in the placebo group (eight [25%] vs four [12%] patients). INTERPRETATION: Idebenone reduced the loss of respiratory function and represents a new treatment option for patients with Duchenne muscular dystrophy. FUNDING: Santhera Pharmaceuticals. PMID- 25907160 TI - Elusive silane-alane complex [Si-H???Al]: isolation, characterization, and multifaceted frustrated Lewis pair type catalysis. AB - The super acidity of the unsolvated Al(C6F5)3 enabled isolation of the elusive silane-alane complex [Si-H???Al], which was structurally characterized by spectroscopic and X-ray diffraction methods. The Janus-like nature of this adduct, coupled with strong silane activation, effects multifaceted frustrated Lewis-pair-type catalysis. When compared with the silane-borane system, the silane-alane system offers unique features or clear advantages in the four types of catalytic transformations examined in this study, including: ligand redistribution of tertiary silanes into secondary and quaternary silanes, polymerization of conjugated polar alkenes, hydrosilylation of unactivated alkenes, and hydrodefluorination of fluoroalkanes. PMID- 25907162 TI - National income and environmental concern: Observations from 35 countries. AB - National income produces mixed impacts on public environmental concern. In a cross-national survey, environmental concern was measured in terms of propensity to act and environmental risk perception. Results of a multilevel regression analysis show that these two measures respond to gross domestic product per capita in opposite ways. Citizens of advanced industrial countries are more likely than those of lower-income countries to contribute to environmental protection. However, they are less likely to see the harmful impacts on the environment as very dangerous. Using an indicator of national adaptive capacity, this article demonstrates that environmental risk perception is a function of a country's estimated capacity for coping with condition changes. The stronger sense of collective security among citizens of wealthier nations offers a possible explanation for the negative effects of national income. These results indicate the complex relationship between development and public environmental concern across countries. PMID- 25907161 TI - Protective immunity against Schistosoma japonicum infection can be provided by IgG antibodies towards periodate-sensitive or periodate-resistant glycans. AB - BACKGROUND: It has been well accepted that glycans present in schistosomes are highly antigenic. However, it is not clear what kind of worm glycans can affect the infected host to mount IgG responses and whether mounted anti-glycan IgG responses are protective. METHODS: The contribution of antigenicity by glycans was measured by using competitive ELISA assay in sera from infected mice and humans. Monoclonal antibodies towards soluble Schistosoma japonicum egg antigens (SjEA) were generated from SjEA immunizated mice. The expression of glycans on surfaces of cercaria or young worm and their distributions were examined by immunofluorescence assay. The protective roles of glycans-specific mAbs were assayed by determination of the worm and egg burden in infected mice. RESULTS: Both periodate-resistant glycans and periodate-sensitive glycans are antigenic in schistosome infections. When monoclonal antibodies against either periodate sensitive or periodate-resistant glycans were administered prior to schistosome infections in mice, both kinds of anti-glycan antibodies were found to successfully provide protective immunity to infected mice. CONCLUSIONS: Both periodate-resistant and periodate-sensitive glycans are antigenic, and dominant anti-glycan IgG responses can play important roles in protective immunity in schistosome infected hosts. PMID- 25907163 TI - 'Imagining ourselves' as participating publics: An example from biodiversity conservation. AB - This article examines how residents in Natura 2000 sites in Southern Portugal 'imagine themselves' as publics participating in biodiversity conservation. Through nine focus groups (n = 49) it seeks to understand whether and how these self-imaginations reproduce and/or resist experts' highly shared, hegemonic, representations across two dimensions: the epistemic and the normative. Analysis of the groups' discussions shows that (1) reproduction is clearer in the normative dimension, conveyed through discursive formats that place 'people' as its actor and exempt the Ego from it; (2) resistance is clearer in the epistemic dimension, relying on vibrant claims of local knowledge, yet it can be maintained as hidden discourse; (3) the forms of reproduction or resistance that emerged were hybrid ones; and (4) self-imaginations are more fragmented and negative in normative matters and more unified and positive in epistemic matters. We discuss how these findings help understand how hegemonic representations are maintained/resisted in enduring public-expert relations. PMID- 25907164 TI - Non-steroidal anti-inflammatory drug administration after coronary artery bypass surgery: utilization persists despite the boxed warning. AB - PURPOSE: In 2005, the US Food and Drug Administration (FDA) issued a boxed warning against the administration of non-steroidal anti-inflammatory drugs (NSAIDs) after coronary artery bypass graft (CABG) surgery because of cardiovascular safety concerns. We assessed utilization rates before and after the advisory and evaluated predictors of NSAID administration following CABG. METHODS: We assembled a cohort of 277,576 patients who underwent CABG from 2004 to 2010. Temporal trends in NSAID exposure were evaluated, and predictors of postoperative NSAID use were identified using generalized estimating equations. RESULTS: Over the study period, 92,938 CABG patients (33.5%) received NSAIDs following surgery. The frequency of NSAID administration declined steadily over time, from a peak of 38.9% in 2004 to a low of 29.0% in 2010 (p < 0.0007). Ketorolac was the most frequent NSAID prescribed, commonly on the first postoperative day. Surgery performed after the boxed warning was independently associated with a 20% lower odds of NSAID administration [odds ratio (OR): 0.80; p = 0.0003]. Other factors that predicted a lower odds of NSAID use following surgery included a history of renal disease (OR: 0.33; p < 0.0001) and liver disease (OR: 0.66; p < 0.0001), and the need for concurrent valve surgery (OR: 0.78; p < 0.0001). A mammary graft at the time of surgery increased the odds of NSAID administration (OR: 1.23; p < 0.0001). CONCLUSIONS: The frequency of NSAID administration after CABG has declined since the FDA advisory, yet many patients continue to receive them in recent years. Our data highlight the need for future research initiatives to further define the risks associated with NSAID use in this population. PMID- 25907165 TI - In situ patch-clamp recordings from Merkel cells in rat whisker hair follicles, an experimental protocol for studying tactile transduction in tactile-end organs. AB - Mammals use tactile end-organs to perform sensory tasks such as environmental exploration, social interaction, and tactile discrimination. However, cellular and molecular mechanisms underlying tactile transduction in tactile end-organs remain poorly understood. The patch-clamp recording technique may be the most valuable approach for detecting and studying tactile transduction in tactile end organs, but it is technically challenging because tactile transduction elements in an end-organ are normally inaccessible by patch-clamp recording electrodes. Here we describe an in situ patch-clamp recording protocol for the study of tactile transduction in Merkel cells of rat whisker hair follicles, one of the most sensitive tactile end-organs in mammals. This technique offers an opportunity to explore the identities and properties of ion channels that are involved in tactile transduction in whisker hair follicles, and it may also lend a useful tool for researchers to study other tactile end-organs. The experimental protocol describes procedures for 1) tissue dissection and whisker hair follicle preparation, 2) device setup and steps for performing patch-clamp recordings from Merkel cells in a whisker hair follicle, 3) methods of delivering mechanical stimuli, and 4) intra-follicle microinjection for receptor knockdown in whisker hair follicles. The main procedures in this protocol, from tissue preparation to whole-cell patch-clamp recordings, can be completed in a few hours. PMID- 25907166 TI - Good teaching is good teaching: A narrative review for effective medical educators. AB - Educators have tried for many years to define teaching and effective teachers. More specifically, medical educators have tried to define what characteristics are common to successful teachers in the healthcare arena. The goal of teacher educators has long been to determine what makes an effective teacher so that they could do a better job of preparing future teachers to have a positive impact on the learning of their students. Medical educators have explored what makes some of their colleagues more able than others to facilitate the development of healthcare professionals who can successfully and safely meet the needs of future patients. Although there has historically been disagreement regarding the characteristics that need be developed in order for teachers to be effective, educational theorists have consistently agreed that becoming an effective teacher is a complex task. Such discussions have been central to deciding what education at any level is really all about. By exploring the literature and reflecting upon the personal experiences encountered in his lengthy career as a teacher, and as a teacher of teachers, the author reaches the conclusions that teaching is both art and science, that "good teaching is good teaching" regardless of the learning environment or the subject to be explored, and that the characteristics making up an effective medical educator are really not much different than those making up effective educators in any other area. PMID- 25907168 TI - Simultaneous Determination of Xylazine and 2,6-Xylidine in Blood and Urine by Auto Solid-Phase Extraction and Ultra High Performance Liquid Chromatography Coupled with Quadrupole-Time of Flight Mass Spectrometry. AB - Xylazine as veterinary medicine for sedation, but intoxication cases in humans were identified in the last few years. A highly sensitive method is required for analyzing xylazine and its metabolites in human blood and urine. This article presents an ultra high performance liquid chromatography coupled with quadrupole time of flight mass spectrometry (UHPLC-QTOF) study for simultaneous determination of xylazine and 2,6-dimethylaniline (DMA) in human blood and urine. The samples were extracted and cleaned up by Oasis MCX solid-phase extraction. The analysis is performed using an UHPLC-QTOF. Analysis precision, accuracy, sensitivity, linear range, limit of detection (LOD) and limit of quantification (LOQ) were validated for the proposed method. In the blood and urine samples, the linear calibration curves with high linearity are obtained over the range of 2.0 1,000.0 ng/mL. The LOD for xylazine and DMA in blood are 0.2 and 0.1 ng/mL, in urine are 0.4 and 0.2 ng/mL; the LOQ for xylazine and DMA in blood are 0.6 and 0.3 ng/mL, in urine are 1.0 and 0.6 ng/mL, respectively. The intra- and interday precision is better than 8.6 and 11.9%. In conclusion, the proposed method is highly sensitive and reproducible, thus suitable for accurate quantification of xylazine and its metabolites in blood and urine. PMID- 25907167 TI - Personalized medicine in diabetes mellitus: current opportunities and future prospects. AB - Diabetes mellitus affects approximately 382 million individuals worldwide and is a leading cause of morbidity and mortality. Over 40 and nearly 80 genetic loci influencing susceptibility to type 1 and type 2 diabetes, respectively, have been identified. In addition, there is emerging evidence that some genetic variants help to predict response to treatment. Other variants confer apparent protection from diabetes or its complications and may lead to development of novel treatment approaches. Currently, there is clear clinical utility to genetic testing to find the at least 1% of diabetic individuals who have monogenic diabetes (e.g., maturity-onset diabetes of the young and KATP channel neonatal diabetes). Diagnosing many of these currently underdiagnosed types of diabetes enables personalized treatment, resulting in improved and less invasive glucose control, better prediction of prognosis, and enhanced familial risk assessment. Efforts to enhance the rate of detection, diagnosis, and personalized treatment of individuals with monogenic diabetes should set the stage for effective clinical translation of current genetic, pharmacogenetic, and pharmacogenomic research of more complex forms of diabetes. PMID- 25907169 TI - Ethylene Glycol and Metabolite Concentrations in Fatal Ethylene Glycol Poisonings. AB - Ethylene glycol (EG) is used in antifreeze and other industrial products. It metabolizes to glycolic acid (GA) and oxalic acid (OX) that cause metabolic acidosis and are mainly responsible for the toxicity of EG. During 2010-2014, EG or GA was found in 25 postmortem cases in Finland. Of these cases, 21 were classified as fatal EG poisonings and 3 were classified as methanol (MeOH) poisonings. In this study, we report the concentrations of EG and GA in postmortem blood and urine samples of fatal EG or mixed MeOH/EG poisonings. In the fatal EG poisonings, the median EG and GA concentrations were 0.87 and 1.6 g/L in blood and 4.3 and 5.3 g/L in urine. The median urine-blood ratios were 3.8 and 3.1 for EG and GA. These results warrant the use of urine as a primary matrix for screening. In EG positive cases, the quantification of both EG and GA in blood is crucial as GA concentration appears to best indicate a fatal poisoning with an approximate threshold of 1.5 g/L. The measurement of urinary OX does not offer much additional value to toxic alcohol screening as it may originate from varying dietary conditions. PMID- 25907170 TI - Mycobacterium tuberculosis RpfE promotes simultaneous Th1- and Th17-type T-cell immunity via TLR4-dependent maturation of dendritic cells. AB - Reciprocal induction of the Th1 and Th17 immune responses is essential for optimal protection against Mycobacterium tuberculosis (Mtb); however, only a few Mtb antigens are known to fulfill this task. A functional role for resuscitation promoting factor (Rpf) E, a latency-associated member of the Rpf family, in promoting naive CD4(+) T-cell differentiation toward both Th1 and Th17 cell fates through interaction with dendritic cells (DCs) was identified in this study. RpfE induces DC maturation by increasing expression of surface molecules and the production of IL-6, IL-1beta, IL-23p19, IL-12p70, and TNF-alpha but not IL-10. This induction is mediated through TLR4 binding and subsequent activation of ERK, p38 MAPKs, and NF-kappaB signaling. RpfE-treated DCs effectively caused naive CD4(+) T cells to secrete IFN-gamma, IL-2, and IL-17A, which resulted in reciprocal expansions of the Th1 and Th17 cell response along with activation of T-bet and RORgammat but not GATA-3. Furthermore, lung and spleen cells from Mtb infected WT mice but not from TLR4(-/-) mice exhibited Th1 and Th17 polarization upon RpfE stimulation. Taken together, our data suggest that RpfE has the potential to be an effective Mtb vaccine because of its ability to activate DCs that simultaneously induce both Th1- and Th17-polarized T-cell expansion. PMID- 25907172 TI - Pharmacokinetics of sugammadex 16 mg/kg in healthy Chinese volunteers. AB - OBJECTIVE: Elimination of sugammadex occurs predominantly via the kidneys, with the majority of the drug excreted unchanged in the urine. To date, most studies with sugammadex have been performed in non-Asian populations. The objectives of this open-label study were to determine the pharmacokinetics (PK) and safety of single-dose sugammadex (16 mg/kg) in healthy Chinese adult volunteers. METHODS: 12 Chinese subjects (6 male; 6 female) received intravenous sugammadex (16 mg/kg) as a 10-second bolus infusion. Blood samples were collected pre-sugammadex and at regular intervals up to 24 hours post-sugammadex for PK assessment. Safety was assessed via AEs, vital signs, electrocardiogram, and laboratory parameters. RESULTS: Following sugammadex 16 mg/kg infusion, peak sugammadex concentration was 197 MUg/mL, clearance was 99.7 mL/min, and apparent volume of distribution at equilibrium was 10.5 L. Plasma sugammadex concentrations showed a polyexponential decline over time, with an overall geometric mean (CV%) terminal half-life of 145 minutes (17.9%) (139 minutes (17.7%) for males; 152 minutes (18.6%) for females). No influence of gender on the PK of sugammadex was observed. Three subjects experienced an adverse events (AE) (dysgeusia of mild intensity), which was considered possibly or probably related to sugammadex. There were no clinically significant changes in vital signs, electrocardiography or laboratory parameters. CONCLUSION: PK of sugammadex (16 mg/kg) was characterized in healthy Chinese subjects. Overall between-subject variability on clearance and apparent volume of distribution was ~ 10%. Sugammadex was generally well tolerated. PMID- 25907171 TI - Real-life use of budesonide/formoterol in clinical practice: a 12-month follow-up assessment in a multi-national study of asthma patients established on single inhaler maintenance and reliever therapy. AB - OBJECTIVE: The efficacy and safety of budesonide/formoterol maintenance and reliever therapy (MRT) has been demonstrated in phase III clinical studies, but limited data are available in a real-life setting. We examined the pattern of maintenance and as-needed inhaler use in routine clinical practice among patients with asthma receiving budesonide/formoterol MRT (NCT00505388). METHODS: This 12 month European observational study enrolled patients prescribed budesonide/formoterol MRT and grouped them based on regimen: 80/4.5 MUg one inhalation twice daily (b.i.d.); 160/4.5 MUg one inhalation b.i.d.; 160/4.5 MUg two inhalations b.i.d. (all plus as needed). Patient data were collected daily using an interactive voice- or web-response system. The primary outcome measure was total number of budesonide/formoterol inhalations/day. RESULTS: Overall, 4,581 patients were included (64% female; mean age 48.4 years; regimen: 80/4.5 MUg, n = 119; 160/4.5 MUg, n = 3,106; 2 x 160/4.5 MUg, n = 1,355). Mean (median) total numbers of budesonide/formoterol inhalations/day were 2.48 (2.11), 2.53 (2.14), and 4.27 (4.05) for 80/4.5 MUg b.i.d., 160/4.5 MUg b.i.d., and 2 x 160/4.5 MUg b.i.d., respectively; corresponding mean (median) number of as-needed inhalations/day were 0.68 (0.17), 0.73 (0.26), and 1.08 (0.45), respectively. As needed budesonide/formoterol use was generally low with a mean of 61 - 66% of reliever-free days; over 4 reliever inhalations/day occurred on a mean of 0.4 - 2.5% of days for all budesonide/formoterol MRT regimens. CONCLUSIONS: Inroutine clinical practice, all budesonide/formoterol MRT regimens were associated with a high proportion of reliever-free days and low incidence of high reliever-use days, indicating acceptable levels of asthma control with this symptom-adjusted controller regimen. PMID- 25907173 TI - A case of lacosamide-induced hepatotoxicity. AB - INTRODUCTION: Lacosamide is a novel antiepileptic drug that acts mainly via the selective enhancement of slow inactivation of voltage-gated sodium channels. It has been reported that lacosamide is effective and generally tolerable as an adjuvant treatment in patients with partial seizures. There are few reports regarding liver damage caused by lacosamide. We describe a case of a patient with drug-resistant epilepsy who developed symptomatic hepatotoxicity after lacosamide administration. RESULTS: A 22-year-old female with a 2-year history of temporal lobe epilepsy was admitted to our hospital because of nausea, dizziness, and abnormal liver function tests. Lacosamide was added for further seizure control 9 days before the current presentation. Her liver enzymes were markedly increased: aspartate aminotransferase, 635 U/L; alanine aminotransferase, 697 U/L. Lacosamide was ceased immediately, whereas other medications (zonisamide, clobazam, and tianeptine) were not withdrawn. The level of liver enzymes improved significantly within a few days, and a diagnosis of lacosamide-induced hepatitis was made based on the obvious temporal relationship. CONCLUSION: This case report demonstrates that hepatotoxicity may develop in association with lacosamide therapy. Liver function tests should be prompted in patients with symptoms suggestive of adverse effects after the initiation of lacosamide. Further research is required to identify predisposing factors of lacosamideinduced hepatotoxicity. PMID- 25907174 TI - Effective use of modeling and simulation in designing bioequivalence and comparability studies of large-molecule compounds: the case of erythropoietin. AB - OBJECTIVE: Bioequivalence and comparability studies are necessary for changing formulations of large-molecule drugs, such as antibody drugs and protein products, and in the development of their biosimilars. This study is the first application of modeling and simulation (M&S) in the design of bioequivalence and comparability studies of erythropoietin as an example of a large-molecule drug. METHODS: A novel population pharmacokinetic and pharmacodynamic (PPK/PD) model was developed for erythropoietin. Based on this PPK/PD model, the probabilities of success of bioequivalence and comparability studies were simulated with various numbers of subjects and samples. RESULTS: The simulation indicated that the minimum numbers of subjects and samples required to satisfy the criteria for bioequivalence and comparability studies were as follows: fewest for the area under the serum concentration-time curve, more for the area under the efficacy time curve, and most for the maximum serum concentration of erythropoietin. CONCLUSION: These results suggested that M&S could be successfully applied in the design of bioequivalence and comparability studies of large-molecule drugs. PMID- 25907175 TI - Acute severe back pain radiating to the whole body during intravenous administration of amiodarone. AB - Amiodarone represents an effective antiarrhythmic drug for cardioversion of recent-onset atrial fibrillation (AF) and maintenance of sinus rhythm. Acute low back and/or epigastric pain has been reported in the medical literature as a rare side effect of amiodarone, but most cases were Europeans, one was Chinese. We present the case of a Japanese patient who experienced acute severe back pain radiating to the whole body a few minutes after intravenous (IV) infusion of amiodarone. PMID- 25907176 TI - Pharmacokinetics and pharmacodynamics of once- and twice-daily multiple-doses of canagliflozin, a selective inhibitor of sodium glucose co-transporter 2, in healthy participants. AB - AIMS: Assess the steady-state pharmacokinetics, pharmacodynamics and safety of once-daily (q.d.) versus twice-daily (b.i.d.) dosing with canagliflozin at the same total daily doses of 100 and 300 mg in healthy participants. METHODS: 34 participants (17 in each cohort) were enrolled in this single-center, open-label, multiple-dose, 2-cohort, 2-way crossover study. Participants in each cohort received a total daily dose of either 100 or 300 mg canagliflozin for 5 days with q.d. then b.i.d. dosing or vice versa. Pharmacokinetics and pharmacodynamics were assessed on day 5 of each period. RESULTS: The canagliflozin Cmax,ss of 100 and 300 mg q.d. dosing were higher by 66% and 72% than corresponding morning Cmax,ss of the 50 mg and 150 mg b.i.d. regimen, respectively. The geometric mean ratios (90% CI) of b.i.d./q.d. for AUC0-24h,ss at total doses of 100 and 300 mg were 97.08 (94.08; 99.62) and 99.32 (94.71; 104.16) respectively. Median tmax and mean t1/2 were independent of dose and regimen. Mean (SE) 24-h mean renal glucose threshold values for b.i.d. and q.d. regimens were 59.2 (1.03) and 60.2 (1.03) mg/dL for the 100 mg daily doses and 51.0 (1.04) and 52.5 (1.04) mg/dL for the 300 mg daily doses. Mean (SE) values of 24-h urinary glucose excretion for b.i.d. and q.d. regimens were 52.8 (1.94) and 48.6 (1.94) g for the 100 mg daily doses and 58.6 (3.81) and 57.8 (3.81) g for the 300 mg daily doses. Both doses were safe and well tolerated. CONCLUSION: Pharmacokinetics and pharmacodynamics of canagliflozin administered q.d. relative to b.i.d. at the same 100 and 300 mg total daily doses were comparable. Overall, canagliflozin was well tolerated. PMID- 25907177 TI - Efficacy and prognosis of neoadjuvant chemotherapy is correlated with breast cancer molecular classification. AB - Breast cancer is one of the most common cancers affecting women globally. Recent studies have begun to investigate the possibility of customized treatment options for individuals based on the specific cancer type. Here, we sought to analyze the relationship between the molecular classification of breast cancer and the efficacy and prognosis of neoadjuvant chemotherapy (NCT). The study included 100 breast cancer patients treated with an NCT regimen of epirubicin and docetaxel (ET) who were divided into groups based on cancer subtype (luminal, HER2 over expression, and basal-like subtype). The nuclear classification, number of NCT cycles, pathological remission rate, and clinical curative effect, as well as the disease-free survival time (DFS) and the overall survival (OS), were compared across groups. The nuclear grade of participants in the basal-like group was significantly higher than those in the other groups but this group had fewer preoperative NCT cycles and lower pathological remission and clinical efficacy (Z=53.245, 50.077, 62.467, chi2=16.082, p<0.05). The OS and DFS of participants in the luminal subtype group were significantly higher than those in other groups while those in the basal-like subtype group were the lowest. The OS and DFS of participants who achieved pathological complete remission (pCR) through NCT treatment were significantly higher than those of the patients who had not achieved pCR through NCT treatment (chi2=9.558, 10.139, p<0.05). Therefore, we conclude that when NCT (ET regimen) is used in the treatment of breast cancer, the curative effects and prognosis appear to be correlated with the molecular classification of the tumor. Based on these results, clinicians should consider the molecular classification of the individual tumor to design the most effective treatment option. PMID- 25907178 TI - Management of rib pain in rowers: emerging issues. PMID- 25907179 TI - Twitterati and Paperati: evidence versus popular opinion in science communication. PMID- 25907180 TI - Terminology and definitions on groin pain in athletes: building agreement using a short Delphi method. AB - BACKGROUND: Groin pain in athletes occurs frequently and can be difficult to treat, which may partly be due to the lack of agreement on diagnostic terminology. OBJECTIVE: To perform a short Delphi survey on terminology agreement for groin pain in athletes by a group of experts. METHODS: A selected number of experts were invited to participate in a Delphi questionnaire. The study coordinator sent a questionnaire, which consisted of demographic questions and two 'real-life' case reports of athletes with groin pain. The experts were asked to complete the questionnaire and to provide the most likely diagnosis for each case. Questionnaire responses were analysed by an independent researcher. The Cohen's kappa statistic was used to evaluate the level of agreement between the diagnostic terms provided by the experts. RESULTS: Twenty-three experts participated (96% of those invited). For case 1, experts provided 9 different terms to describe the most likely diagnosis; for case 2, 11 different terms were provided to describe the most likely diagnosis. With respect to the terms provided for the most likely diagnosis, the Cohen's kappa was 0.06 and 0.002 for case 1 and 2, respectively. This heterogeneous taxonomy reflects only a slight agreement between the various diagnostic terms provided by the selected experts. CONCLUSIONS: This short Delphi survey of two 'typical, straightforward' cases demonstrated major inconsistencies in the diagnostic terminology used by experts for groin pain in athletes. These results underscore the need for consensus on definitions and terminology on groin pain in athletes. PMID- 25907181 TI - Interventions with potential to reduce sedentary time in adults: systematic review and meta-analysis. AB - CONTEXT: Time spent in sedentary behaviours (SB) is associated with poor health, irrespective of the level of physical activity. The aim of this study was to evaluate the effect of interventions which included SB as an outcome measure in adults. METHODS: Thirteen databases, including The Cochrane Library, MEDLINE and SPORTDiscus, trial registers and reference lists, were searched for randomised controlled trials until January 2014. Study selection, data extraction and quality assessment were performed independently. Primary outcomes included SB, proxy measures of SB and patterns of accumulation of SB. Secondary outcomes were cardiometabolic health, mental health and body composition. Intervention types were categorised as SB only, physical activity (PA) only, PA and SB or lifestyle interventions (PA/SB and diet). RESULTS: Of 8087 records, 51 studies met the inclusion criteria. Meta-analysis of 34/51 studies showed a reduction of 22 min/day in sedentary time in favour of the intervention group (95% CI -35 to -9 min/day, n=5868). Lifestyle interventions reduced SB by 24 min/day (95% CI -41 to -8 min/day, n=3981, moderate quality) and interventions focusing on SB only by 42 min/day (95% CI -79 to -5 min/day, n=62, low quality). There was no evidence of an effect of PA and combined PA/SB interventions on reducing sedentary time. CONCLUSIONS: There was evidence that it is possible to intervene to reduce SB in adults. Lifestyle and SB only interventions may be promising approaches. More high quality research is needed to determine if SB interventions are sufficient to produce clinically meaningful and sustainable reductions in sedentary time. PMID- 25907182 TI - Detecting and developing youth athlete potential: different strokes for different folks are warranted. AB - Sport talent identification and development (TI and TD) in youth continues to attract strong interest among coaches, sport scientists and sport administrators. TI for sport in youth with the anticipation of future elite level sport achievement is both an art and a science, and is strongly influenced by within athlete and extraneous-to-athlete factors (ecosystem of support or the lack of). The returns from investment on current TI and TD models of sport in youth are subpar in that few continue in the sport to achieve podium positions at the elite sport level in adulthood. Why, where and how one succeeds in sport, and what that success means to the athlete and stakeholders are dependent on the culture and context of the country. We advocate harnessing the power of sport to help in youth development, to be holistic in its nurturance, to allow for individual idiosyncratic expressions of the athletes, to provide for talent transfer across sport, and to facilitate key stakeholders to 'join' hands to work for the common interest and understanding for as many youth and adults so as to provide them with opportunities through support and coaching to compete at the different levels of competition in sport. Governments, policy makers and administrators of sport must decide, within their specific circumstances, if TI and TD in sport in youth is serving a meaningful purpose and is a viable return on investment; in short, is it mission possible or is it... a quest for the Holy Grail for a podium finish in elite level sport competition? PMID- 25907183 TI - Three distinct mechanisms predominate in non-contact anterior cruciate ligament injuries in male professional football players: a systematic video analysis of 39 cases. AB - BACKGROUND: Current knowledge on anterior cruciate ligament (ACL) injury mechanisms in male football players is limited. AIM: To describe ACL injury mechanisms in male professional football players using systematic video analysis. METHODS: We assessed videos from 39 complete ACL tears recorded via prospective professional football injury surveillance between 2001 and 2011. Five analysts independently reviewed all videos to estimate the time of initial foot contact with the ground and the time of ACL tear. We then analysed all videos according to a structured format describing the injury circumstances and lower limb joint biomechanics. RESULTS: Twenty-five injuries were non-contact, eight indirect contact and six direct contact injuries. We identified three main categories of non-contact and indirect contact injury situations: (1) pressing (n=11), (2) re gaining balance after kicking (n=5) and (3) landing after heading (n=5). The fourth main injury situation was direct contact with the injured leg or knee (n=6). Knee valgus was frequently seen in the main categories of non-contact and indirect contact playing situations (n=11), but a dynamic valgus collapse was infrequent (n=3). This was in contrast to the tackling-induced direct contact situations where a knee valgus collapse occurred in all cases (n=3). CONCLUSIONS: Eighty-five per cent of the ACL injuries in male professional football players resulted from non-contact or indirect contact mechanisms. The most common playing situation leading to injury was pressing followed by kicking and heading. Knee valgus was frequently seen regardless of the playing situation, but a dynamic valgus collapse was rare. PMID- 25907184 TI - Informal Caregivers of Palliative Oncohematologic Patients: The Invisible Guests: An Exhaustive Review of the Literature Available. AB - Informal caregivers are crucial members of the teams that care for palliative patients with cancer, including those with oncohematological malignancies. Publications concerning specific aspects of this latter group of carers are limited. This literature review indicates that palliative oncohematologic patients' caregivers do not differ from those of patients with solid tumors in ethical and related problems. However, there are specific problems for the former group with regard to negotiating the curative system, which are experienced as distressing, often without support from the health system and without offers of the possibility of being referred to palliative teams that they would have valued as very positive. Although this tendency seems to be changing, there is still considerable work to be done to improve the role of these carers. PMID- 25907186 TI - Winter chill of Geneva warmed by the WHO Executive Board. PMID- 25907185 TI - Accounting for quality: on the relationship between accounting and quality improvement in healthcare. AB - BACKGROUND: Accounting-that is, standardized measurement, public reporting, performance evaluation and managerial control-is commonly seen to provide the core infrastructure for quality improvement in healthcare. Yet, accounting successfully for quality has been a problematic endeavor, often producing dysfunctional effects. This has raised questions about the appropriate role for accounting in achieving quality improvement. This paper contributes to this debate by contrasting the specific way in which accounting is understood and operationalized for quality improvement in the UK National Health Service (NHS) with findings from the broadly defined 'social studies of accounting' literature and illustrative examples. DISCUSSION: This paper highlights three significant differences between the way that accounting is understood to operate in the dominant health policy discourse and recent healthcare reforms, and in the social studies of accounting literature. It shows that accounting does not just find things out, but makes them up. It shows that accounting is not simply a matter of substance, but of style. And it shows that accounting does not just facilitate, but displaces, control. The illumination of these differences in the way that accounting is conceptualized helps to diagnose why accounting interventions often fail to produce the quality improvements that were envisioned. This paper concludes that accounting is not necessarily incompatible with the ambition of quality improvement, but that it would need to be understood and operationalized in new ways in order to contribute to this end. Proposals for this new way of advancing accounting are discussed. They include the cultivation of overlapping and even conflicting measures of quality, the evaluation of accounting regimes in terms of what they do to practice, and the development of distinctively skeptical calculative cultures. PMID- 25907187 TI - Incidence of acute myocardial infarction in Islamic Republic of Iran: a study using national registry data in 2012. AB - Population-based data on myocardial infarction rates in the Islamic Republic of Iran have not been reported on a national or provincial scale. In a cross sectional study, data were collected on 20 750 new cases of myocardial infarction (ICD10 codes I21-22) admitted to hospitals and registered by the Iranian Myocardial Infarction Registry in 2012. The crude and age-adjusted incidence for the 31 provinces and the whole country were directly calculated per 100 000 people using the WHO standard population. Overall, males comprised 72.4% of cases and had a significantly lower mean age at incidence than women [59.6 (SD 13.3) years versus 65.4 (SD 12.6) years]. The male:female incidence ratio was 2.63. The age-standardized myocardial infarction incidence rate was 73.3 per 100 000 in the whole country (95% CI: 72.3%-74.3%) and varied significantly from 24.5 to 152.5 per 100 000 across the 31 provinces. The study provides baseline data for monitoring and managing cardiovascular diseases in the country. PMID- 25907188 TI - Epidemiological and chronological profile of preterm birth in the region of Monastir (Tunisia) between 1994 and 2012. AB - Data about the profile and risk factors of premature births in Tunisia are scarce. The objective of this study was to describe the epidemiological profile of preterm births in Monastir, Tunisia, and to study the chronological trends of associated factors over the years 1994-2012. A population-based study was conducted using data from the regional births database on all deliveries in public maternity units. The overall prevalence of preterm births among the 161 116 deliveries in the 19-year period was 5.60% (95% CI: 5.13%-6.07%). The rate of preterm births and of adequate prenatal care increased significantly over the study period. Extremes of maternal age (<= 19 and >= 35 years), having a twin pregnancy and the occurrence of complications during pregnancy were significant predictors of prematurity in the final regression model. Efforts should be made to improve the quality of health care in the region, especially for high-risk pregnancies. PMID- 25907189 TI - Problems of providing services to people affected by HIV/AIDS: service providers and recipients perspectives. AB - This qualitative study aimed to identify the health-care problems of people living with HIV (PLHIV) in 2 large cities: Tehran and Kermanshah. Two main groups of stakeholders - service providers (policy-makers, managers, physicians and counsellors) and service recipients (PLHIV and their relatives) - participated in focus group discussions and in-depth interviews. We identified 24 themes covering the major health problems of PLHIV, including: incomplete and inadequate coverage of health-care services; patients' substance abuse; patients' fear of stigma; occupational burnout of certain service providers; patients' dissatisfaction with some of the services provided by counselling centres/clinics; medical staff's failure to observe confidentiality; and patients' lack of access to required specialized services. The problems and needs identified can inform the design and implementation of health programmes in our country and elsewhere in the Eastern Mediterranean Region. PMID- 25907190 TI - Psychometric properties of the Persian version of the Sexual and Reproductive Health Needs Assessment Questionnaire. AB - No tools to assess women's general sexual and reproductive health needs have been validated in the Iranian context. This study in Sari in Mazandaran province of the Islamic Republic of Iran was conducted to evaluate the psychometric properties of a Persian version of the Sexual and Reproductive Health Needs Assessment Questionnaire (first developed for the International Organization for Migration and United Nations Population Fund). The Persian version of the questionnaire was found to have adequate face and content validity (quantitative and qualitative) for assessing sexual and reproductive health needs among women (content validity index = 0.88). The test-retest reliability showed that, except for the domain of sexually transmitted infections, all domains of the questionnaire had an acceptable reliability (intra-class correlation coefficients > 0.5). This questionnaire is a valid tool for assessing the sexual and reproductive health needs of Iranian women and planning/designing strategies to meet them. PMID- 25907191 TI - Herbal and nutritional supplement use among college students in Qatar. AB - There is increasing demand for herbal and nutritional supplements in the Middle East. This study aimed to examine the use of supplements by college students in Qatar and to elucidate users' views about them. A total of 419 college students completed a self-administered questionnaire. Almost half of the respondents (49.6%) had used supplements (ever users), with 32.7% reporting using them in the previous 6 months (current users). Of the latter, 27.7% had used herbal supplements, 56.2% vitamins and minerals and 56.9% non-vitamin, non-mineral, non herbal supplements. Many participants considered supplements to be safer and more effective than conventional medicines. Supplements were preferred over conventional medicines for the treatment of digestive conditions and common respiratory ailments and for weight management. Educating health-care providers about the benefits and risks of supplements is imperative and will enable health care practitioners to guide patients in making informed decisions about supplement use. PMID- 25907192 TI - Medical faculty members' perspectives on the components of cross-cultural competence in the Islamic Republic of Iran: a qualitative study. AB - Despite the importance of cultural competence in health care, there has been no research to develop a framework for cultural competence in the Iranian context. This qualitative study at Mashhad University of Medical Sciences aimed to elucidate the views of medical faculty staff on the components of cross-cultural competence and compare these with similar studies published in English. Using a combination of archival studies, semi-structured interviews and focus group discussions among faculty members 3 major domains (knowledge, attitude and behaviour) and 21 components were identified to describe the cross-cultural competence of faculty members in medical schools. Participants expressed the importance of knowledge as a precursor to changing attitudes and the 6 knowledge components related to knowledge and awareness of values, beliefs and norms of different ethnic, racial and cultural groups. Experts mostly emphasized the importance of interaction between faculty members and clients (students and patients). PMID- 25907193 TI - Risk factors influencing dentists' hepatitis B-related knowledge and attitudes and their willingness to treat hepatitis B positive patients. AB - This study assessed factors that could predict dentists' knowledge, attitudes and behaviour towards hepatitis B virus (HBV). A total of 300 dentists in Tehran, Islamic Republic of Iran were surveyed and their demographic, educational and office characteristics were analysed in relation to their scores on knowledge about HBV, self-reported attitudes towards treating people infected with HBV and actual behaviour towards treating simulated HBV-positive patients. Having a Master's degree, faculty membership, taking >= 3 continuing education courses, wearing eye-shields, spending more time on preparing dental units and higher self confidence about knowledge predicted better knowledge. A positive attitude was associated with having attended more courses and working in group practice. The number of courses and a shorter dental unit preparation time positively affected dentists' behaviour. PMID- 25907194 TI - Development, implementation and evaluation of a medication safety programme for schoolchildren in Qatar. AB - The objectives of this study were to assess the needs of schoolchildren relating to medication safety and to develop and implement a health promotion programme in Qatar. Semi-structured interviews were completed with teachers, nurses and school administrators at 2 primary schools in Doha. Two main themes were identified from these interviews, namely medication basics and medication safety. Subsequently, a 25-minute health promotion programme was developed and delivered to 11 groups of schoolchildren aged 6-10 years. The student groups contained both expatriate and local Qatari students. The programme was evaluated based on perceptions of site representatives, investigators and peer reviewers using a standardized evaluation form. All the evaluators agreed that the programme was beneficial and should be recommended to other schools in Qatar. This study can serve as a prototype for future programmes in the Eastern Mediterranean Region and elsewhere. PMID- 25907195 TI - WHO events addressing public health priorities. PMID- 25907197 TI - A lab-on-a-chip for hypoxic patch clamp measurements combined with optical tweezers and spectroscopy- first investigations of single biological cells. AB - The response and the reaction of the brain system to hypoxia is a vital research subject that requires special instrumentation. With this research subject in focus, a new multifunctional lab-on-a-chip (LOC) system with control over the oxygen content for studies on biological cells was developed. The chip was designed to incorporate the patch clamp technique, optical tweezers and absorption spectroscopy. The performance of the LOC was tested by a series of experiments. The oxygen content within the channels of the LOC was monitored by an oxygen sensor and verified by simultaneously studying the oxygenation state of chicken red blood cells (RBCs) with absorption spectra. The chicken RBCs were manipulated optically and steered in three dimensions towards a patch-clamp micropipette in a closed microfluidic channel. The oxygen level within the channels could be changed from a normoxic value of 18% O 2 to an anoxic value of 0.0-0.5% O 2. A time series of 3 experiments were performed, showing that the spectral transfer from the oxygenated to the deoxygenated state occurred after about 227 +/- 1 s and a fully developed deoxygenated spectrum was observed after 298 +/- 1 s, a mean value of 3 experiments. The tightness of the chamber to oxygen diffusion was verified by stopping the flow into the channel system while continuously recording absorption spectra showing an unchanged deoxygenated state during 5400 +/- 2 s. A transfer of the oxygenated absorption spectra was achieved after 426 +/- 1 s when exposing the cell to normoxic buffer. This showed the long time viability of the investigated cells. Successful patching and sealing were established on a trapped RBC and the whole-cell access (Ra) and membrane (Rm) resistances were measured to be 5.033 +/- 0.412 M Omega and 889.7 +/- 1.74 M Omega respectively. PMID- 25907198 TI - Hypolipidaemic and anti-oxidative potential of encapsulated herb (Terminalia arjuna) added vanilla chocolate milk in high cholesterol fed rats. AB - BACKGROUND: Atherosclerosis is associated with coronary artery disease and occurs in developing as well as developed countries. In the present investigation, hypolipidaemic and anti-oxidative properties of encapsulated herb (Terminalia arjuna, 1.8%) added vanilla chocolate dairy drink was evaluated in high cholesterol fed Wistar rats for 60 days. RESULTS: At the end of the experimental period, a significant decrease in the body weight gain by rats receiving the encapsulated herb extract was noted as compared to high cholesterol fed rats. Administration of microencapsulated herb showed a statistically significant decrease in organ weights (epididymal fat and liver). Moreover, a significant decrease in serum lipids such as triglycerides, total cholesterol, low-density lipoprotein cholesterol, very-low-density lipoprotein cholesterol and atherogenic index was observed with encapsulated Terminalia arjuna extract in high cholesterol fed group. Increases in reduced glutathione and decreases in TBARS levels were also reported in both liver and red blood cell lysates with encapsulated herb supplementation. CONCLUSION: The results demonstrated that the bioactive components (phytosterols, flavanoids, saponins and tannins etc.) which are present in the encapsulated T. arjuna not only withstand the processing conditions but also are effectively released in the intestine and show their effects, such as hypolipidaemic and antioxidant activities, for better treating cardiovascular disease. PMID- 25907199 TI - Beneficial effect of Danggui-Shaoyao-San, a traditional Chinese medicine, on drowsiness induced by chronic restraint stress. AB - Danggui-Shaoyao-San (DSS), a famous Chinese complex prescription, has a long history of treating dysmenorrhea in China. Recent studies showed that DSS had its therapeutic efficacy on depression. In the present study, the effects of aqueous extract of DSS were examined to investigate the pharmacological basis for its therapeutic efficacy on chronic restraint stress (CRS)-induced sleep disorder. Mice were treated with DSS by gavage administration at doses of 0.625g/kg, 1.25g/kg and 2.5g/kg for 10 days. Sleep time and sleep latency were measured 24h after the CRS procedures using the sodium pentobarbital-induced sleep test. Open field test was used to evaluate the mice locomotion and anxiety/depression levels. Body weight and food intake were determined as well. The results showed that DSS dose-dependently prolonged latency and decreased sleep time of CRS mice, reversed CRS-induced decrease of mean velocity, the percentage of center distance and time in central area, as well as decreased body weight and food intake. In conclusion, our results suggest that DSS has exerted measurable therapeutic effects in hypersomnia induced by chronic restraint stress. PMID- 25907200 TI - Similar patient outcomes yet different hospital costs between flowable hemostatic agents. AB - INTRODUCTION: SURGIFLO and FLOSEAL are absorbable gelatin-based products that form hemostatic matrices. These products are indicated as adjuncts to hemostasis when control of bleeding by conventional surgical techniques (such as suture, ligature or cautery) is ineffective or impractical. This study analyzed the effect of surgery time and the choice of product on cost to the hospital and patient outcomes. METHODS: The data source was the Premier Hospital database from January 1, 2010-June 30, 2012. Eligible patients were >=18 years of age with a spinal fusion or refusion surgery with either SURGIFLO (Ethicon Inc.) or FLOSEAL (Baxter International Inc.). The hospital Charge Master was used to identify the amount of flowable product, whether it included Thrombin, and the cost. Multivariable models were performed on overall cost and likelihood of surgical complications. All models were adjusted for patient demographics and severity as well as hospital, and surgical characteristics. RESULTS: A total of 24,882 patient records from 121 hospitals were analysed, which included 15,088 FLOSEAL records and 9794 SURGIFLO records, with 1498 SURGIFLO with Thrombin patients. Little or no differences in surgical complications were found between surgeries with SURGIFLO vs. surgery with FLOSEAL. Regression models showed a reduction in cost of $65 associated with use of SURGIFLO with Thrombin and an additional $21 reduction in hospital cost for each additional hour of surgery. Modeling which accounts for hospital fixed effects suggest that, in addition to a gap of ~$300 favoring SURGIFLO with Thrombin, every additional hour of surgery was associated with an additional reduction in hospital costs of ~$26. CONCLUSIONS: While the choice of flowable product had no effect on clinical outcomes, use of SURGIFLO was associated with hospital cost savings for flowable product. These savings increased with the length of surgery, even when controlling for the amount of flowable product (mL) used. PMID- 25907201 TI - Construction of the isocopalane skeleton: application of a desulfinylative 1,7 hydrogen atom transfer strategy. AB - Two attractive chirons, aldehyde 6 and chloride 7, exhibiting functionalized ent spongiane-type tricyclic skeletons (ABC ring system), have been constructed and their absolute configurations have been studied by NMR spectroscopy and confirmed by single-crystal X-ray diffraction. Both of these chirons are derived from commercially available andrographolide in good yield. Aldehyde 6 is obtained through a novel K2 S2 O8 -catalyzed aquatic ring-closing reaction of allylic sodium sulfonate and intramolecular 1,7-hydrogen atom transfer process. Further mechanistic investigations demonstrate that the 1,7-hydrogen atom transfer is a free-radical process, whereby hydrogen migrates from C18 to C17, as evidenced by double-18- deuterium-labeled isotope experiments. Prospective applications of these two chiral sources are also discussed. PMID- 25907202 TI - Assessment of multifocal contact lens over-refraction using an infrared, open field autorefractor: A preliminary study. AB - PURPOSE: To evaluate the usefulness of an infrared open-field autorefractor as a predictor of the refractive error when fitting multifocal contact lenses (MCL). METHODS: Objective and subjective measurements of the non-cycloplegic distance refractive error were compared in patients wearing MCL. We used the Grand Seiko WAM-5500 autorefractor for the objective measurements. Three commercially available MCL were tested. Twenty-one eyes of sixteen healthy adults were included in the study. Over-refraction was evaluated in terms of spherical equivalent (SE) and astigmatic vectors (J0 and J45). The mean difference+/-SD of each parameter was calculated. The Kolmogorov-Smirnov test was used to verify the normal distribution. Pearson's correlation, Bland and Altman plot and paired sample t test were used to compare the results obtained with both methods. RESULTS: The mean difference between objective and subjective results of the SE over-refraction was 0.13+/-0.42D; for astigmatic vectors J0 and J45 were 0.03+/ 0.32D and -0.00+/-0.17D, respectively. The Kolmogorov-Smirnov test showed a normal distribution for all parameters. The highest Pearson's correlation coefficients were obtained for the SE with values of 0.98 without MCL and 0.97 with MCL. The lowest were obtained for J45 with values of 0.65 without MCL and 0.75 with MCL. Significant correlations were obtained for each parameter. The paired sample t test failed to show significant differences in analyzed parameters except for J0 without MCL. CONCLUSIONS: The Grand Seiko WAM-5500 can be used as a screening method of over-refraction in the clinical fitting of MCL. PMID- 25907206 TI - The diagnostic accuracy of spectral-domain optical coherence tomography for neovascular age-related macular degeneration: a comparison with fundus fluorescein angiography. AB - PURPOSE: To evaluate the diagnostic accuracy of spectral-domain optical coherence tomography (SD-OCT) for neovascular age-related macular degeneration (nAMD): a comparison against fundus fluorescein angiography (FFA). METHODS: A retrospective review of SD-OCT, colour fundus photographs (FP), and FFA of 411 consecutive patients referred to a rapid access Macular Clinic over a 4-year period was performed. FFA images were reviewed non-stereoscopically. SD-OCT images were acquired using the Topcon 3D OCT-1000 instrument. All FFA and OCT images were graded by at least two ophthalmologists independently. Side-by-side grading took place with immediate open discussion and adjudication. If there was disagreement between the two grading ophthalmologists or they were not 90% confident of their assigned grade, then adjudication by a third ophthalmologist was performed. RESULTS: A total of 278 eyes were graded as having choroidal neovascularisation (CNV) with SD-OCT and 231 diagnosed with FFA. The main diagnostic CNV classifications on FFA were: classic no occult in 27 eyes, predominantly classic in 16, minimally classic in 50, occult in 129, and 9 peripapillary membranes. There were a total of 47 false positives with SD-OCT: a rate of 16.9%. The sensitivity and specificity of SD-OCT alone for detecting CNV was 100 and 80.8%, respectively. CONCLUSION: Our study confirms SD-OCT in comparison to the reference standard of non-stereoscopic FFA is highly sensitive at detecting newly presenting nAMD in the setting of a specialist AMD clinic where the investigations are interpreted by trained specialists. However, it does not seem accurate enough to replace FFA in the diagnosis on nAMD in current practice. PMID- 25907207 TI - Prevalence of gonococcal conjunctivitis in adults and neonates. AB - PURPOSE: To report the prevalence of gonococcal conjunctivitis (GC) presenting to a tertiary referral maternity hospital (NMH) and a tertiary referral ophthalmic hospital (RVEEH) from 2011 to 2013 and describe the demographics, clinical presentation, and antibiotic susceptibility of Neisseria gonorrhoeae ocular infections. METHODS: Demographic, clinical, and microbiological data were collected from patients with laboratory confirmed GC. RESULTS: There were 27 556 live births at NMH during the study period, and no case of neonatal GC was identified. Fourteen cases of GC were identified at RVEEH in this period, representing a prevalence of 0.19 cases per 1000 eye emergency attendees. Antibiotic susceptibility data were available on nine cases, of which, all were ceftriaxone- and ciprofloxacin sensitive. 64.3% of patients were male, with a mean age of 18 years. The mean duration of symptoms was 3 days. All patients presented with unilateral conjunctival injection and purulent discharge. Eight cases had visual impairment at presentation and their mean visual acuity was 6/15. Corneal involvement was present in 25% of patients. Uveitis was not detected. On receipt of positive culture and/or PCR results, treatment was altered in two thirds of patients. All patients were referred for full STI screening and all patients showed a full clinical recovery 1 week posttreatment. CONCLUSION: We observed that GC presented in young adults with a male predominance and was rare in neonates. In cases of unilateral purulent conjunctivitis, there should be a high clinical suspicion of GC, early swab for PCR and culture, and knowledge of current CDC-recommended antibiotic guidelines. PMID- 25907208 TI - Effect of cooling proparacaine 0.5% eye drops on patient's comfort during instillation. PMID- 25907209 TI - Neurotoxicity of intrathecal 6% hydroxyethyl starch 130/0.4 injection in a rat model. AB - Epidural blood patch is the gold standard treatment for post-dural puncture headache, although hydroxyethyl starch may be a useful alternative to blood if the latter is contraindicated. The aim of this experimental study was to assess whether hydroxyethyl starch given via an indwelling intrathecal catheter resulted in clinical or histopathological changes suggestive of neurotoxicity. The study was conducted in rats that were randomly allocated to receive three 10-MUl injections on consecutive days of either saline or hydroxyethyl starch administered via the intrathecal catheter. Eight rats were given injections of saline 0.9% and 11 were given 6% hydroxyethyl starch 130/0.4 derived from thin boiling waxy corn starch in 0.9% sodium chloride (Voluven). Daily clinical evaluation, activity measured by actimetry and neuropathological analysis of the spinal cord were subsequently performed to assess for signs of neurotoxicity. No clinical or actimetric changes were observed in either group following intrathecal saline or hydroxyethyl starch administration. Histopathological examination showed non-specific changes with no differences between the two groups. This experimental study in the rat suggests that repeated intrathecal injection of hydroxyethyl starch is not associated with neurotoxicity. PMID- 25907210 TI - Incidence of solid tumours among pesticide applicators exposed to the organophosphate insecticide diazinon in the Agricultural Health Study: an updated analysis. AB - OBJECTIVE: Diazinon, a common organophosphate insecticide with genotoxic properties, was previously associated with lung cancer in the Agricultural Health Study (AHS) cohort, but few other epidemiological studies have examined diazinon associated cancer risk. We used updated diazinon exposure and cancer incidence information to evaluate solid tumour risk in the AHS. METHODS: Male pesticide applicators in Iowa and North Carolina reported lifetime diazinon use at enrolment (1993-1997) and follow-up (1998-2005); cancer incidence was assessed through 2010(North Carolina)/2011(Iowa). Among applicators with usage information sufficient to evaluate exposure-response patterns, we used Poisson regression to estimate adjusted rate ratios (RRs) and 95% CI for cancer sites with >=10 exposed cases for both lifetime (LT) exposure days and intensity-weighted (IW) lifetime exposure days (accounting for factors impacting exposure). RESULTS: We observed elevated lung cancer risks (N=283) among applicators with the greatest number of LT (RR=1.60; 95% CI 1.11 to 2.31; P(trend)=0.02) and IW days of diazinon use (RR=1.41; 95% CI 0.98 to 2.04; P(trend)=0.08). Kidney cancer (N=94) risks were non-significantly elevated (RR(LT) days=1.77; 95% CI 0.90 to 3.51; P(trend)=0.09; RR(IW) days 1.37; 95% CI 0.64 to 2.92; P(trend)=0.50), as were risks for aggressive prostate cancer (N=656). CONCLUSIONS: Our updated evaluation of diazinon provides additional evidence of an association with lung cancer risk. Newly identified links to kidney cancer and associations with aggressive prostate cancer require further evaluation. PMID- 25907211 TI - Effects of partial sleep restriction and subsequent daytime napping on prolonged exertional heat strain. AB - OBJECTIVES: It is considered that sleep restriction is one of the risk factors for the development of exertional heat stroke and illness. However, how sleep restriction affects exertional heat strain and the nature of the coping strategy involved in this phenomenon remain unclear. METHODS: Fourteen healthy subjects were studied on four occasions: after a night of normal sleep (NS, 7-8 h) and after a night of partial sleep restriction (PSR, 4 h), each with or without taking a daytime nap during the subsequent experimental day. The laboratory test consisted of two 40 min periods of moderate walking in a hot room in the morning and the afternoon. RESULTS: The increase in rectal temperature during walking was significantly greater in PSR than in NS in the afternoon. The rating scores for physical and psychological fatigue and sleepiness were significantly greater in PSR than in NS, both in the morning and in the afternoon. The reaction times and lapses in the psychomotor vigilance task (PVT) after walking were significantly worse in PSR than in NS in the morning and after lunch. The nap intervention attenuated significantly the scores for fatigue and sleepiness in PSR. Furthermore, the decreased PVT response in PSR was significantly reversed by the nap. CONCLUSIONS: These results suggest that PSR augments physiological and psychological strain and reduces vigilance in the heat. Taking a nap seemed to be effective in reducing psychological strain and inhibiting the decrease in vigilance. PMID- 25907212 TI - Cleaning products and short-term respiratory effects among female cleaners with asthma. AB - OBJECTIVE: We evaluated the short-term effects of exposure to cleaning products on lung function and respiratory symptoms among professional cleaning women. METHODS: Twenty-one women with current asthma and employed as professional cleaners participated in a 15-day panel study. During 312 person-days of data collection, participants self-reported their use of cleaning products and respiratory symptoms in daily diaries and recorded their forced expiratory volume in 1 s (FEV1) and peak expiratory flow (PEF) three times per day using a handheld spirometer. We evaluated associations of cleaning product use with upper and lower respiratory tract symptoms using Poisson mixed regression models and with changes in FEV1 and PEF using linear mixed regression analyses. RESULTS: Participants reported using an average of 2.4 cleaning products per day, with exposure to at least one strong irritant (eg, ammonia, bleach, hydrochloric acid) on 56% of person-days. Among participants without atopy, lower respiratory tract symptoms were associated with the use of hydrochloric acid and detergents. Measurements of FEV1 and PEF taken in the evening were 174 mL (95% CI 34 to 314) and 37 L/min (CI 4 to 70), respectively, lower on days when three or more sprays were used. Evening and next morning FEV1 were both lower following the use of hydrochloric acid (-616 and -526 mL, respectively) and solvents (-751 and -1059 mL, respectively). Diurnal variation in FEV1 and PEF increased on days when ammonia and lime-scale removers were used. CONCLUSIONS: The use of specific cleaning products at work, mainly irritants and sprays, may exacerbate asthma. PMID- 25907213 TI - Metastasis: Spreading the seed. PMID- 25907214 TI - Tumorigenesis: A hairy and nervous start. PMID- 25907221 TI - Examining the utility of patient-derived xenograft mouse models. AB - Patient-derived xenograft (PDX) models are now being widely used in cancer research and have the potential to greatly inform our understanding of cancer biology. However, many questions remain, especially regarding the ability of PDX models to affect clinical decision making. With these points in mind, we asked three scientists to give their opinions on the generation and uses of PDX models and the future of this field. PMID- 25907219 TI - Mechanisms of aromatase inhibitor resistance. AB - Oestrogen receptor-positive (ER(+)) breast cancer is a major cause of cancer death in women. Although aromatase inhibitors suppress the function of ER and reduce the risk of recurrence, therapeutic resistance is common and essentially inevitable in advanced disease. This Review considers both genomic and cell biological explanations as to why ER(+) breast cancer cells persist, progress and cause an incurable, lethal, systemic disease. The design and outcomes of clinical trials are considered with the perspective that resistance mechanisms are heterogeneous, and therefore biomarker and somatic mutation-based stratification and eligibility will be essential for improvements in patient outcomes. PMID- 25907223 TI - Association of Serum 25-Hydroxyvitamin D and Parathyroid Hormone With Hypertension in Middle-Aged and Older Korean Adults. AB - BACKGROUND: Previous studies have suggested that serum 25-hydroxyvitamin D [25(OH)D] and parathyroid hormone (PTH) levels are associated with hypertension. However, the associations have yet to be studied in Koreans. This study explored the relationship among serum 25(OH)D, PTH concentrations, and the presence of hypertension in middle-aged and older Korean adults using the most recent nationally representative survey data. METHODS: A population-based, cross sectional study was conducted with data collected from 5,260 Korean adults (aged >=50 years) who participated in the 2010 and 2011 Korean National Health and Nutrition Examination Surveys. Hypertension was defined as a systolic blood pressure >=140 mm Hg, diastolic blood pressure >=90 mm Hg, or current use of antihypertensive medication. RESULTS: The prevalence of hypertension significantly increased according to the quartiles of serum PTH levels (P < 0.0001), but not of serum 25(OH)D levels. In multivariable logistic analysis, the adjusted odds ratios (ORs) for hypertension were significantly higher among participants in the highest quartile than among those in the lowest quartile of serum PTH level, after adjusting for potential confounders (OR = 1.26, 95% confidence interval: 1.02-1.56, P = 0.03). The adjusted ORs for hypertension tended to decrease across the quartiles of serum 25(OH)D level, but the associations were not significant. CONCLUSION: Serum 25(OH)D was not associated with the presence of hypertension, whereas serum PTH was positively associated, suggesting that serum PTH may be an independent risk factor for hypertension in middle-aged and older Korean adults. PMID- 25907222 TI - The reduction of circulating levels of IL-6 in pregnant women with preeclampsia by magnesium sulphate and nifedipine: In vitro evidence for potential mechanisms. AB - INTRODUCTION: Women with preeclampsia have elevated levels of inflammatory cytokines including IL-6. IL-6, which is known to activate endothelial cells and induce the production of necrotic trophoblastic debris from the placenta, may be important in the pathogenesis of preeclampsia. MgSO4 is a major therapy for the prevention of seizures in preeclampsia but it has been suggested to also have anti-inflammatory and vasodilatory properties. METHODS: 22 pregnant women with preeclampsia and 68 normotensive controls were recruited and circulating IL-6 levels in these women were measured before MgSO4 and nifedipine treatment and after delivery. In addition, endothelial cells were treated with IL-6 or necrotic trophoblastic debris, generated from first trimester placental explants in the presence or absence of MgSO4in vitro, and cell-surface ICAM-1 was measured by ELISA. The levels of IL-6 in the culture medium were also measured. Furthermore nitric oxide synthetase activity in endothelial cells that had been treated with IL-6 was measured using l-NAME. RESULTS: Circulating levels of IL-6 in preeclampsia were reduced significantly following administration of MgSO4. In vitro, MgSO4 reversed the activation of endothelial cells induced by IL-6 but not by necrotic trophoblastic debris. The effect of MgSO4 in reversing the IL-6 induced activation of endothelial cells was not dependent upon nitric oxide synthetase. Treating placental explants with MgSO4 prevented the production of necrotic trophoblastic debris induced by IL-6. DISCUSSION: we demonstrated that IL-6 levels drop following treatment with MgSO4 and nifedipine in vivo, and have identified several mechanisms by which this positive effect on IL-6 may occur in vitro. PMID- 25907220 TI - Replication stress and cancer. AB - Genome instability is a hallmark of cancer, and DNA replication is the most vulnerable cellular process that can lead to it. Any condition leading to high levels of DNA damage will result in replication stress, which is a source of genome instability and a feature of pre-cancerous and cancerous cells. Therefore, understanding the molecular basis of replication stress is crucial to the understanding of tumorigenesis. Although a negative aspect of replication stress is its prominent role in tumorigenesis, a positive aspect is that it provides a potential target for cancer therapy. In this Review, we discuss the link between persistent replication stress and tumorigenesis, with the goal of shedding light on the mechanisms underlying the initiation of an oncogenic process, which should open up new possibilities for cancer diagnostics and treatment. PMID- 25907224 TI - Effects of Arginase Inhibition in Hypertensive Hyperthyroid Rats. AB - BACKGROUND: This study analyzed the effects of chronic administration of N[omega] hydroxy-nor-l-arginine (nor-NOHA), an inhibitor of arginase, on the hemodynamic, oxidative stress, morphologic, metabolic, and renal manifestations of hyperthyroidism in rats. METHODS: Four groups of male Wistar rats were used: control, nor-NOHA-treated (10 mg/kg/day), thyroxine (T4)-treated (75 MUg/rat/day), and thyroxine- plus nor-NOHA-treated rats. All treatments were maintained for 4 weeks. Body weight, tail systolic blood pressure (SBP), and heart rate (HR) were recorded weekly. Finally, morphologic, metabolic, plasma, and renal variables were measured. Arginase I and II protein abundance and arginase activity were measured in aorta, heart, and kidney. RESULTS: The T4 group showed increased arginase I and II protein abundance, arginase activity, SBP, HR, plasma nitrates/nitrites (NOx), brainstem and urinary isoprostanes, proteinuria and cardiac and renal hypertrophy in comparison to control rats. In hyperthyroid rats, chronic nor-NOHA prevented the increase in SBP and HR and decreased proteinuria in association with an increase in plasma NOx and a decrease in brainstem and urinary isoprostanes. In normal rats, nor-NOHA treatment did not significantly change any hemodynamic, morphologic, or renal variables. Acute nor-NOHA administration did not affect renal or systemic hemodynamic variables in normal or T4-treated rats. CONCLUSION: Hyperthyroidism in rats is associated with the increased expression and activity of arginase in aorta, heart, and kidney. Chronic arginase inhibition with nor-NOHA suppresses the characteristic hemodynamic manifestations of hyperthyroidism in association with a reduced oxidative stress. These results indicate an important role for arginase pathway alterations in the cardiovascular and renal abnormalities of hyperthyroidism. PMID- 25907225 TI - Citosine-Adenine-Repeat Microsatellite of 11beta-hydroxysteroid dehydrogenase 2 Gene in Hypertensive Children. AB - BACKGROUND: The impairment of 11beta-hydroxysteroid dehydrogenase type 2 enzyme (11betaHSD2) results in an inefficient conversion of cortisol to cortisone, which triggers hypertension. Cytosine-adenine repeat (CA repeat) microsatellite has been associated with low HSD11B2 gene expression. AIM: To determine whether the CA-repeat length in intron 1 affect the serum cortisol to cortisone (F/E) ratio and/or blood pressure (BP) levels in pediatric subjects. SUBJECTS AND METHODS: Eighty-one hypertensive (HT) and 117 normotensive (NT) subjects participated in this study. We measured BP levels, as well as the F and E and F/E ratio in morning sera and 12-hour urine samples. The length of CA repeats was determined through fragment analysis. We compared the allele distribution between the HT and NT groups, and the patients were dichotomized into groups with short alleles (S) (<21 CA repeats) or long alleles (L), and also in groups according genotype (allele combination: S/S and S/L + L/L). RESULTS: We found no differences in the distribution of CA-repeat allelic length between the NT and HT groups (P = 0.7807), and there was no correlation between the CA-repeat allelic length and BP (P = 0.1151) levels or the serum F/E ratio (P = 0.6778). However, the serum F/E ratio was higher in the HT group than in the NT group (P = 0.0251). The serum F/E ratio was associated with systolic BP index independent of body mass index only in HT group. CONCLUSIONS: The CA-repeat length did not influence BP levels or serum F/E ratios in pediatric subjects. However, the serum F/E ratio was associated with BP, suggesting a role of 11betaHSD2 in mineralocorticoid hypertension. PMID- 25907227 TI - Composition-dependent buckling behaviour of hybrid boron nitride-carbon nanotubes. AB - The buckling of hybrid boron nitride-carbon nanotubes (BN-CNTs) with various BN compositions and locations of the BN domain is investigated using molecular dynamics. We find that BN-CNTs with large BN composition (>38%) only undergo local shell-like buckling in their BN domain. Although similar local shell-like buckling can occur in BN-CNTs with a relatively small BN composition, it can transfer to the global column-like buckling of the whole BN-CNT with increasing strains. The critical strains for local shell-like and global column-like buckling decrease with increasing BN composition. In addition, critical strains and buckling modes of the global column-like buckling of BN-CNTs also strongly depend on the location of their BN domain. As a possible application of the buckling of BN-CNTs, we demonstrate that the BN-CNT can serve as a water channel integrated with a local natural valve using the local buckling of its BN domain. PMID- 25907226 TI - Single-band upconversion nanoprobes for multiplexed simultaneous in situ molecular mapping of cancer biomarkers. AB - The identification of potential diagnostic markers and target molecules among the plethora of tumour oncoproteins for cancer diagnosis requires facile technology that is capable of quantitatively analysing multiple biomarkers in tumour cells and tissues. Diagnostic and prognostic classifications of human tumours are currently based on the western blotting and single-colour immunohistochemical methods that are not suitable for multiplexed detection. Herein, we report a general and novel method to prepare single-band upconversion nanoparticles with different colours. The expression levels of three biomarkers in breast cancer cells were determined using single-band upconversion nanoparticles, western blotting and immunohistochemical technologies with excellent correlation. Significantly, the application of antibody-conjugated single-band upconversion nanoparticle molecular profiling technology can achieve the multiplexed simultaneous in situ biodetection of biomarkers in breast cancer cells and tissue specimens and produce more accurate results for the simultaneous quantification of proteins present at low levels compared with classical immunohistochemical technology. PMID- 25907229 TI - Embryonic development of the cricket Gryllus bimaculatus. AB - Extensive research into Drosophila melanogaster embryogenesis has improved our understanding of insect developmental mechanisms. However, Drosophila development is thought to be highly divergent from that of the ancestral insect and arthropod in many respects. We therefore need alternative models for arthopod development that are likely to be more representative of basally-branching clades. The cricket Gryllus bimaculatus is such a model, and currently has the most sophisticated functional genetic toolkit of any hemimetabolous insect. The existing cricket embryonic staging system is fragmentary, and it is based on morphological landmarks that are not easily visible on a live, undissected egg. To address this problem, here we present a complementary set of "egg stages" that serve as a guide for identifying the developmental progress of a cricket embryo from fertilization to hatching, based solely on the external appearance of the egg. These stages were characterized using a combination of brightfield timelapse microscopy, timed brightfield micrographs, confocal microscopy, and measurements of egg dimensions. These egg stages are particularly useful in experiments that involve egg injection (including RNA interference, targeted genome modification, and transgenesis), as injection can alter the speed of development, even in control treatments. We also use 3D reconstructions of fixed embryo preparations to provide a comprehensive description of the morphogenesis and anatomy of the cricket embryo during embryonic rudiment assembly, germ band formation, elongation, segmentation, and appendage formation. Finally, we aggregate and schematize a variety of published developmental gene expression patterns. This work will facilitate further studies on G. bimaculatus development, and serve as a useful point of reference for other studies of wild type and experimentally manipulated insect development in fields from evo-devo to disease vector and pest management. PMID- 25907228 TI - Extra-embryonic Wnt3 regulates the establishment of the primitive streak in mice. AB - The establishment of the head to tail axis at early stages of development is a fundamental aspect of vertebrate embryogenesis. In mice, experimental embryology, genetics and expression studies have suggested that the visceral endoderm, an extra-embryonic tissue, plays an important role in anteroposterior axial development. Here we show that absence of Wnt3 in the posterior visceral endoderm leads to delayed formation of the primitive streak and that interplay between anterior and posterior visceral endoderm restricts the position of the primitive streak. Embryos lacking Wnt3 in the visceral endoderm, however, appear normal by E9.5. Our results suggest a model for axial development in which multiple signals are required for anteroposterior axial development in mammals. PMID- 25907230 TI - Neoadjuvant Radiotherapy Improves Survival in Patients With T2b/T3 Bladder Cancer: A Population-Based Analysis. AB - BACKGROUND: Neoadjuvant radiotherapy (NART) for muscle-invasive bladder cancer (MIBC) is currently underused. However, the outcomes for MIBC have remained suboptimal. We investigated the relationship of NART to cause-specific mortality (CSM) and overall mortality (OM) among patients with a diagnosis of MIBC. MATERIALS AND METHODS: The patients diagnosed with primary invasive urothelial carcinoma of the bladder from 1983 to 2008 with localized disease were included. Patients aged > 90 years, those diagnosed with T1 or T4 BC, and those with no information on tumor grade were excluded from the analysis. Kaplan-Meier, Cox regression, and competing risk methods were used in the analysis of OM and CSM. RESULTS: A total of 5562 patients were included in the cohort (115 NART and 5447 surgery alone). On univariate analysis, NART significantly decreased the OM for patients with high-grade BC (hazard ratio [HR], 0.8), stage T2b (HR, 0.74), and stage T2b/T3 (HR, 0.74). CSM was also lower for those with stage T2b disease (HR, 0.63). Multivariable analysis revealed that NART was associated with a significant decrease in CSM (P = .043) and OM (P = .0462) for those with T2b. Likewise, an improvement was seen in OM (P = .0337) for patients with T2b/T3 who had received NART. CONCLUSION: NART was significantly associated with decreased CSM and OM in patients with clinical T2b/T3 BC and OM for patients with T2b/T3. These data suggest that NART could be beneficial in patients with T2b/T3 BC. In the modern era, the greatest utility would potentially be for patients with an incomplete response to neoadjuvant chemotherapy or as an adjunct to chemotherapy to improve the complete response rates. PMID- 25907231 TI - Cessation of Primary Androgen Deprivation Therapy for Men With Localized Prostate Cancer. AB - INTRODUCTION: Substantial numbers of men with localized prostate cancer undergo long-term primary androgen deprivation therapy (ADT). Whether long-term ADT is required for patients with localized prostate cancer, especially elderly men, remains unknown. In the present study, we explored the possibility of ADT cessation after a favorable response to primary ADT in patients with localized prostate cancer. PATIENTS AND METHODS: We retrospectively reviewed men with localized prostate cancer who had achieved a good initial response to primary ADT and stopped it thereafter. Prostate-specific antigen (PSA) recurrence was defined as 2 consecutive increases > 4 ng/mL. A total of 34 patients (age, 62-89 years) were followed up for > 24 months after ADT cessation. RESULTS: The ADT duration and follow-up period after ADT cessation was 10 to 162 months (median, 33.5 months) and 24 to 95 months (median, 37 months), respectively. PSA recurrence was observed in 10 of 34 patients (29.4%), and the 5-year PSA progression-free rate was 66.2%. PSA recurrence was observed in 100% (6 of 6) and 14.3% (4 of 28) of men who had received ADT for < 16 months and > 16 months, respectively. ADT was reinstated in 5 patients after PSA recurrence; and their PSA levels declined rapidly, and no clinical progression was observed. The 5-year overall and disease specific survival rate was 65.1% and 100%, respectively. CONCLUSION: ADT can be stopped for men with localized prostate cancer, especially elderly men, after a favorable response to primary ADT. PMID- 25907232 TI - Statin intolerance - an attempt at a unified definition. Position paper from an International Lipid Expert Panel. AB - Statins are one of the most commonly prescribed drugs in clinical practice. They are usually well tolerated and effectively prevent cardiovascular events. Most adverse effects associated with statin therapy are muscle-related. The recent statement of the European Atherosclerosis Society (EAS) has focused on statin associated muscle symptoms (SAMS), and avoided the use of the term 'statin intolerance'. Although muscle syndromes are the most common adverse effects observed after statin therapy, excluding other side effects might underestimate the number of patients with statin intolerance, which might be observed in 10 - 15% of patients. In clinical practice, statin intolerance limits effective treatment of patients at risk of, or with, cardiovascular disease. Knowledge of the most common adverse effects of statin therapy that might cause statin intolerance and the clear definition of this phenomenon is crucial to effectively treat patients with lipid disorders. Therefore, the aim of this position paper was to suggest a unified definition of statin intolerance, and to complement the recent EAS statement on SAMS, where the pathophysiology, diagnosis and the management were comprehensively presented. PMID- 25907233 TI - The Contribution of Cell Blocks in the Diagnosis of Mediastinal Masses and Hilar Adenopathy Samples from Echobronchoscopy. PMID- 25907234 TI - Miliary Tuberculosis With Vertebral Involvement (Pott's Disease). PMID- 25907235 TI - Elevated Extravascular Lung Water Index (ELWI) as a Predictor of Failure of Continuous Positive Airway Pressure Via Helmet (Helmet-CPAP) in Patients With Acute Respiratory Failure After Major Surgery. AB - INTRODUCTION: NIV is increasingly used for prevention and treatment of respiratory complications and failure. Some of them are admitted to the PACU with advanced hemodynamic monitors which allow quantification of Extravascular Lung Water (EVLW) by transpulmonary thermodilution technique (TPTD) and Pulmonary Vascular Permeability (PVP) providing information on lung edema. AIM: The objective of this study was to ascertain if EVLW Index and PVP Index may predict failure (intubation) or success (non-intubation) in patients developing acute respiratory failure (ARF) in the postoperative period following major abdominal surgery, where the first line of treatment was non-invasive continuous positive airway pressure via a helmet. METHODS: Hemodynamic variables, EVLWI and PVPI were monitored with a transpulmonary thermodilution hemodynamic monitor device (PiCCOTM) before and after the application of CPAP. RESULTS: Avoidance of intubation was observed in 66% of patients with Helmet-CPAP. In these patients after the first hour of application of CPAP, PaO2/FiO2 ratio significantly increased (303.33+/-65.2 vs. 141.6+/-14.6, P<.01). Before starting Helmet-CPAP values of EVLWI and PVPI were significantly lower in non-intubated patients (EVLWI 8.6+/-1.08 vs. 11.8+/-0.99ml/kg IBW, P<.01 and PVPI 1.7+/-0.56 vs. 3.0+/ 0.88, P<.01). An optimal cut-off value for EVLWI was established at 9.5, and at 2.45 for PVPI (sensitivity of 0.7; specificity of 0.9, P<.01). CONCLUSION: In this type of patient the physiological parameters that predict the failure of Helmet-CPAP with the greatest accuracy were the value of the EVLWI and PVPI before Helmet-CPAP institution and the PaO2/FiO2 ratio and the respiratory rate after one hour of CPAP. PMID- 25907236 TI - Air pollution and respiratory health in childhood. PMID- 25907237 TI - Anesthetic Management of a Patient With a Giant Right Atrial Myxoma. AB - Cardiac myxomas account for 50% of all benign primary cardiac tumors. Rarely, these tumors occur in the right atrium (RA; 10% to 20%), with a stalk frequently attached to the interatrial septum. Right atrial myxomas can lead to RA enlargement, arrhythmias, functional tricuspid stenosis, right heart failure, and catastophic pulmonary embolization resulting in sudden cardiac death. Anesthetic management of patients with RA myxomas can be complicated by the mass effect of the myxoma, preload limitations, and the potential for cardiovascular collapse. Multimodal cardiac imaging inclusive of echocardiography, computed tomography, and magnetic resonance imaging helps with the diagnosis, preoperative optimization, and formulation of anesthetic and surgical plans. We present a case report highlighting the importance of multimodal imaging, adequate preoperative patient optimization, and the anesthetic considerations in the successful management of a patient with a giant 8.3 * 4.7 cm RA myxoma. PMID- 25907238 TI - D(-)-Salicin inhibits the LPS-induced inflammation in RAW264.7 cells and mouse models. AB - D(-)-Salicin is a traditional medicine which has been known to exhibit anti inflammation and other therapeutic activities. The present study aimed to investigate whether D(-)-Salicin inhibited the LPS-induced inflammation in vivo and in vitro. We evaluated the effect of D(-)-Salicin on cytokines (TNF-alpha, IL 1beta, IL-6 and IL-10) in vivo and in vitro by enzyme-linked immunosorbent assay and signaling pathways (MAPKs and NF-kappaB) in vivo by Western blot. The results showed that D(-)-Salicin markedly decreased TNF-alpha, IL-1beta and IL-6 concentrations and increased IL-10 concentration. In addition, western blot analysis indicated that D(-)-Salicin suppressed the activation of MAPKs and NF kappaB signaling pathways stimulated by LPS. To examine whether D(-)-Salicin ameliorated LPS-induced lung inflammation, inhibitors of MAPKs and NF-kappaB signaling pathways were administrated intraperitoneally to mice. Interference with specific inhibitors revealed that D(-)-Salicin-mediated cytokine suppression was through MAPKs and NF-kappaB pathways. In the mouse model of acute lung injury, histopathologic examination indicted that D(-)-Salicin suppressed edema induced by LPS. So it is suggest that D(-)-Salicin might be a potential therapeutic agent against inflammatory diseases. PMID- 25907239 TI - Non-neuronal cholinergic system in regulation of immune function with a focus on alpha7 nAChRs. AB - In 1929, Dale and Dudley described the first reported natural occurrence of acetylcholine (ACh) in an animal's body. They identified this ACh in the spleens of horses and oxen, which we now know suggests possible involvement of ACh in the regulation of lymphocyte activity and immune function. However, the source and function of splenic ACh were left unexplored for several decades. Recent studies on the source of ACh in the blood revealed ACh synthesis catalyzed by choline acetyltransferase (ChAT) in CD4(+) T cells. T and B cells, macrophages and dendritic cells (DCs) all express all five muscarinic ACh receptor subtypes (mAChRs) and several subtypes of nicotinic AChRs (nAChRs), including alpha7 nAChRs. Stimulation of these mAChRs and nAChRs by their respective agonists causes functional and biochemical changes in the cells. Using AChR knockout mice, we found that M(1)/M(5) mAChR signaling up-regulates IgG(1) and pro-inflammatory cytokine production, while alpha7 nAChR signaling has the opposite effect. These findings suggest that ACh synthesized by T cells acts in an autocrine/paracrine fashion at AChRs on various immune cells to modulate immune function. In addition, an endogenous allosteric and/or orthosteric alpha7 nAChR ligand, SLURP 1, facilitates functional development of T cells and increases ACh synthesis via up-regulation of ChAT mRNA expression. SLURP-1 is expressed in CD205(+) DCs residing in the tonsil in close proximity to T cells, macrophages and B cells. Collectively, these findings suggest that ACh released from T cells along with SLURP-1 regulates cytokine production by activating alpha7 nAChRs on various immune cells, thereby facilitating T cell development and/or differentiation, leading to immune modulation. PMID- 25907240 TI - Biosimilar vs biological agents in rheumatology: When are biosimilar agents similar enough? AB - With the introduction of biological agents, over the last two decades treatment prospects in many medical fields including Rheumatology have experienced an exciting revolution. The advent of biological therapy for specifically rheumatic diseases has provided more effective control of both the underlying disease, and sustained amelioration of disease activity, compared to the pre-biological era when only anti-inflammatory and immunosuppressant drugs were available. Although the importance of potential improved clinical outcome cannot be overstated, these efficacious treatments for rheumatic diseases are not without a high cost. Biological agents are expensive and rheumatological diseases are common. The patent and regulatory data protection periods for the first and second waves of biological agents based on recombinant proteins have begun to expire, leaving open the potential for development and regulatory approval of one or more "generic" versions of these biological therapies, termed "biosimilars" or "BSs" in Europe (the term we shall use from henceforth), "subsequent entry biologics" in Canada, or "follow-on-biologics" in US. We aimed to review the critical topics of efficacy, safety and regulatory approach of upcoming biosimilars. PMID- 25907241 TI - The role of chemokines in adjusting the balance between CD4+ effector T cell subsets and FOXp3-negative regulatory T cells. AB - Chemokines are small (~8-14 kDa) structurally-related chemotactic cytokines that regulate cell trafficking through interactions with specific seven-trans membrane, G protein-coupled receptors (GPCRs). One of the important features of G protein-coupled receptors (GPCRs) is their ability to transmit diverse signaling cascades upon binding different ligands. The current review focuses on the interplay between three ligands: CXCL9, CXCL10 and CXCL11 binding the same receptor (CXCR3) on CD4+ T cells, yet direct different signaling cascades to shape T cell mediated immunity. The review brings about a new concept regarding the biological activities of chemokines in shaping CD4+ T cell immunity, and also a new approach for applying chemokine based therapy of autoimmune diseases. PMID- 25907242 TI - Control of lymphocyte homeostasis and effector function by the aryl hydrocarbon receptor. AB - The adaptive immune system, composed of lymphocytes, recognizes diversified antigens and generates immunological memory. According to the canonical model, it is the innate immune system that captures pathogens and senses environment to activate adaptive lymphocytes through antigen presentation, costimulatory signals and cytokine milieu. Emerging evidence indicates that environmental cues can be directly conveyed to lymphocytes by the aryl hydrocarbon receptor (AhR). AhR is a ligand-activated transcription factor that widely expresses in many immune cell lineages and recognizes a broad range of ligands including endogenous and dietary metabolites, microbial derivatives and xenobiotics. This review will focus on the regulatory role of AhR in not only adaptive but also innate lymphocytes including recently discovered innate lymphoid cells. PMID- 25907243 TI - Biological drugs in ANCA-associated vasculitis. AB - The anti-neutrophil cytoplasmic antibody (ANCA) associated vasculitides granulomatosis with polyangiitis (GPA), eosinophilic granulomatosis with polyangiitis (EGPA) and microscopic polyangiitis (MPA) constitute a wide spectrum of clinical manifestations of systemic vasculitis which may range from limited disease to organ or life-threatening disease. The introduction of biologics for the management of severe ANCA-associated vasculitis and severe, relapsing disease refractory to conventional immunosuppressants, has significantly improved the clinical prognosis of these autoimmune disorders. Rituximab, an anti-CD20 monoclonal antibody is licenced for remission induction in severe GPA and MPA and the management of severe relapsing, refractory GPA and MPA. Belimumab, an anti-B lymphocyte stimulatory monoclonal antibody is in clinical trials for the management of the ANCA-associated vasculitis GPA. Mepolizumab and Omalizumab are biologics which have been reported to be efficacious in refractory asthma associated with EGPA. The role of anti-TNF therapy and T cell targeting drugs in ANCA-associated vasculitis is less clear due to limited study data. This review will summarise the clinical trials and clinical practice use of biologic treatment strategies for the management of ANCA-associated vasculitis. PMID- 25907244 TI - Upregulation of PD-1 on CD4+CD25+ T cells is associated with immunosuppression in liver of mice infected with Echinococcus multilocularis. AB - Alveolar echinococcosis is a zoonotic disease caused by Echinococcus multilocularis (E. multilocularis) infection. The relationship between PD-1/PD-L1 pathway and Tregs at different stages of E. multilocularis infection has rarely been reported. This study aims to investigate the role of PD-1/PD-L1 in immunosuppression of Tregs in E. multilocularis infection. Hematoxylin-eosin staining, flow cytometry, immunohistochemistry, quantitative RT-PCR analysis, cytometric bead array and MTT assay were used to analyze liver pathological changes, percentages of PD-1(+) Tregs and PD-L1(+) dendritic cells (DCs), expression levels of PD-1, PD-L1 and Foxp3, levels of interleukin-10 (IL-10) and transforming growth factor beta (TGF-beta) and proliferation of lymphocytes. During middle-late stage (day 30 to day 330) the percentages of PD-1(+) Tregs and PD-L1(+) DCs together with levels of Foxp3, IL-10 and TGF-beta increased significantly and maintained at high level. The expression of PD-1 and PD-L1 was increased with the enlarging erosion of E. multilocularis, and was mainly distributed in hepatic sinus, fibrous wall of alveolar hydatid and germinal layer around foci of infection. PD-1/PD-L1 promoted the secretion of IL-10 and TGF beta. Our results indicate that engagement of the PD-1 and PD-L1 correlates with inhibition of T-cell effector function, cytokine secretion and proliferation. High expression of PD-1/PD-L1 may play an important role in stimulating CD4(+)CD25(+) T cells, and maintaining peripheral tolerance and immune evasion during chronic infection of E. multilocularis. PMID- 25907245 TI - The probiotic mixture IRT5 ameliorates age-dependent colitis in rats. AB - To investigate the anti-inflammatory effect of probiotics, we orally administered IRT5 (1*10(9)CFU/rat) for 8 weeks to aged (16 months-old) Fischer 344 rats, and measured parameters of colitis. The expression levels of the inflammatory markers' inducible NO synthase (iNOS), cyclooxygenase-2 (COX2), tumor necrosis factor (TNF)-alpha, and interleukin (IL)-1beta were higher in the colons of normal aged rats (18 months-old) than in the colons of normal young rats (6 months-old). Treatment with IRT5 suppressed the age-associated increased expression of iNOS, COX2, TNF-alpha, and IL-1beta, and activation of NF-kappaB and mitogen-activated protein kinases. In a similar manner, the expression of tight junction proteins in the colon of normal aged rats was suppressed more potently than in normal young rats, and treatment of aged rats with IRT5 decreased the age-dependent suppression of tight junction proteins ZO-1, occludin, and claudin-1. Treatment with IRT5 suppressed age-associated increases in expressions of senescence markers p16 and p53 in the colon of aged rats, but increased age-suppressed expression of SIRT1. However, treatment with IRT5 inhibited age-associated increased myeloperoxidase activity in the colon. In addition, treatment with IRT5 lowered the levels of LPS in intestinal fluid and blood of aged rats, as well as the reduced concentrations of reactive oxygen species, malondialdehyde, and C-reactive protein in the blood. These findings suggest that IRT5 treatment may suppress age-dependent colitis by inhibiting gut microbiota LPS production. PMID- 25907247 TI - ZnO@Ag2S core-shell nanowire arrays for environmentally friendly solid-state quantum dot-sensitized solar cells with panchromatic light capture and enhanced electron collection. AB - A solid-state environmentally friendly Ag2S quantum dot-sensitized solar cell (QDSSC) is demonstrated. The photovoltaic device is fabricated by applying ZnO@Ag2S core-shell nanowire arrays (NWAs) as light absorbers and electron conductors, and poly-3-hexylthiophene (P3HT) as a solid-state hole conductor. Ag2S quantum dots (QDs) were directly grown on the ZnO nanowires by the successive ionic layer adsorption and reaction (SILAR) method to obtain the core shell nanostructure. The number of SILAR cycles for QD formation and the length of the core-shell NWs significantly affect the photocurrent. The device with a core-shell NWAs photoanode shows a power conversion efficiency increase by 32% compared with the device based on a typical nanoparticle-based photoanode with Ag2S QDs. The enhanced performance is attributed to enhanced collection of the photogenerated electrons utilizing the ZnO nanowire as an efficient pathway for transporting the photogenerated electrons from the QD to the contact. PMID- 25907246 TI - Antitumor activity of mHSP65-TTL enhanced by administration of low dose cyclophosphamide in pancreatic cancer-bearing mice. AB - Pancreatic cancer remains a lethal malignancy. Despite chemotherapy or/and radiotherapy after the surgery, the improvement on the overall survival of the patients has still been minimal. To develop novel therapeutic approaches, we tried to prepare mHSP65-TTL, a candidate vaccine prepared by mixing the recombinant mycobacterial heat shock protein 65 (mHSP65) with tumor tissue lysate (TTL) of Panc02 pancreatic cancer tissue. The mHSP65-TTL were used to immune the C57BL/6 mice implanted with the Panc02 cancer cells, in combination with or without low dose cyclophosphamide (CY). The results showed that mHSP65-TTL significantly prolonged the survival of the pancreatic cancer bearing mice and low dose CY enhanced the efficacy of the mHSP65-TTL. In addition, we detected mRNA expression of RORgammat and IL-17A in spleen cells of mice received mHSP65 TTL or mHSP65-TTL plus CY, and found that mHSP65-TTL up-regulated mRNA expressions of RORgammat and IL-17A, CY alone or mHSP65-TTL plus CY up-regulated mRNA expressions of RORgammat. The work could provide an insight into a combinational approach for the immunotherapy of pancreatic cancer. PMID- 25907248 TI - Placebo response in antipsychotic trials of patients with acute mania: Results of an individual patient data meta-analysis. AB - We examined the role of placebo response in acute mania trials. Specifically, whether placebo response: (1) predicts treatment effect, (2) can be predicted by patient and study characteristics, and (3) can be predicted by a parsimonious model. We performed a meta-analysis of individual patient data from 10 registration studies (n=1019) for the indication acute manic episode of bipolar disorder. We assessed the effect of 14 determinants on placebo response. Primary outcome measures were mean symptom change score (MCS) on the Young Mania Rating Scale (YMRS) and response rate (RR), defined as >= 50% YMRS symptom improvement from baseline to endpoint. The overall placebo response was 8.5 points improvement on the YMRS (=27.9%) with a RR of 32.8%. Placebo response was significantly associated with the overall treatment response. Five determinants significantly (p<0.05) predicted the placebo response. The multivariate prediction model, which consisted of baseline severity, psychotic features at baseline, number of geographic regions, and region, explained 10.4% and 5.5% of the variance in MSC and RR, respectively. Our findings showed that the placebo response in efficacy trials of antipsychotics for acute mania is substantial and an important determinant of treatment effect. Placebo response is influenced by patient characteristics (illness severity and presence of psychotic features) and by study characteristics (study year, number of geographic regions and region). However, the prediction model could only explain the placebo response to a limited extent. Therefore, limiting trials to certain patients in certain geographic regions seems not a viable strategy to improve assay sensitivity. PMID- 25907249 TI - Psychopharmacological treatment of 2195 in-patients with borderline personality disorder: A comparison with other psychiatric disorders. AB - Patients with borderline personality disorder (BPD) are usually prescribed a variety of psychotropic drugs; however, none is recommended in the guidelines nor has any been approved for this indication. As data on drug prescriptions for BPD are sparse, cross-sectional data from the European Drug Safety Project AMSP were used to analyse drug prescriptions of 2195 in-patients with BPD between 2001 and 2011, and the mean values, confidence intervals and regression analyses were calculated. 70% of all BPD patients were medicated with antipsychotics and/or antidepressants, 33% with anticonvulsants, 30% with benzodiazepines, and 4% with lithium; 90% received at least one, 80%>=2, and 54%>=3 psychotropic drugs concomitantly (mean: 2.8). Prescription rates for quetiapine, the single drug most often used in BPD (22%), increased significantly over time. In view of the high percentage of young females with BPD, 18-40 year-old female patients with BPD were compared with patients of the same age but with depression (unipolar and bipolar) and schizophrenia. Typical sedative antipsychotics and anticonvulsants were prescribed more often in BPD than in the other diagnostic groups, with the exception of bipolar depression; this was true for the single substances quetiapine, levomepromazine, chlorprothixene, carbamazepine, and valproate. A limitation of the study was the use of clinical data without verifying the diagnoses by structured interviews. Contrary to the guidelines, about 90% of in patients with BPD received psychotropic drugs. Polypharmacy was common, and antipsychotics with sedative profiles such as quetiapine and mood-stabilizing anticonvulsants such as valproate appear to be preferred. PMID- 25907250 TI - Differential effects of antipsychotic drugs on insight in first episode schizophrenia: Data from the European First-Episode Schizophrenia Trial (EUFEST). AB - Although antipsychotics are widely prescribed, their effect of on improving poor illness insight in schizophrenia has seldom been investigated and therefore remains uncertain. This paper examines the effects of low dose haloperidol, amisulpride, olanzapine, quetiapine, and ziprasidone on insight in first-episode schizophrenia, schizoaffective disorder, or schizophreniform disorder. The effects of five antipsychotic drugs in first episode psychosis on insight were compared in a large scale open randomized controlled trial conducted in 14 European countries: the European First-Episode Schizophrenia Trial (EUFEST). Patients with at least minimal impairments in insight were included in the present study (n=455). Insight was assessed with item G12 of the Positive and Negative Syndrome Scale (PANSS), administered at baseline and at 1, 3, 6, 9, and 12 months after randomization. The use of antipsychotics was associated with clear improvements in insight over and above improvements in other symptoms. This effect was most pronounced in the first three months of treatment, with quetiapine being significantly less effective than other drugs. Effects of spontaneous improvement cannot be ruled out due to the lack of a placebo control group, although such a large spontaneous improvement of insight would seem unlikely. PMID- 25907251 TI - Competing risks data analysis with high-dimensional covariates: an application in bladder cancer. AB - Analysis of microarray data is associated with the methodological problems of high dimension and small sample size. Various methods have been used for variable selection in high-dimension and small sample size cases with a single survival endpoint. However, little effort has been directed toward addressing competing risks where there is more than one failure risks. This study compared three typical variable selection techniques including Lasso, elastic net, and likelihood-based boosting for high-dimensional time-to-event data with competing risks. The performance of these methods was evaluated via a simulation study by analyzing a real dataset related to bladder cancer patients using time-dependent receiver operator characteristic (ROC) curve and bootstrap .632+ prediction error curves. The elastic net penalization method was shown to outperform Lasso and boosting. Based on the elastic net, 33 genes out of 1381 genes related to bladder cancer were selected. By fitting to the Fine and Gray model, eight genes were highly significant (P<0.001). Among them, expression of RTN4, SON, IGF1R, SNRPE, PTGR1, PLEK, and ETFDH was associated with a decrease in survival time, whereas SMARCAD1 expression was associated with an increase in survival time. This study indicates that the elastic net has a higher capacity than the Lasso and boosting for the prediction of survival time in bladder cancer patients. Moreover, genes selected by all methods improved the predictive power of the model based on only clinical variables, indicating the value of information contained in the microarray features. PMID- 25907252 TI - Species composition of phlebotomine sand flies and bionomics of Phlebotomus orientalis (Diptera: Psychodidae) in an endemic focus of visceral leishmaniasis in Tahtay Adiyabo district, Northern Ethiopia. AB - BACKGROUND: Visceral leishmaniasis (VL) is a neglected tropical disease, which is strongly associated with poverty. VL caused by Leishmania donovani and transmitted by Phlebotomus orientalis is endemic in various remote areas of north and north-west Ethiopia. The present study was designed to determine the sand fly fauna and bionomics of P. orientalis in the VL endemic focus of Tahtay Adiyabo district. METHODS: Sand flies were collected using CDC light traps (n = 602), sticky traps (n = 9,350) and indoor pyrethrum spray catches (n = 578 house visits) from indoor, peri-domestic and agricultural field habitats between May 2011 to April 2012. All sand fly specimens collected were identified to species level and counted. RESULTS: In total, 100,772 sand fly specimens, belonging to 25 sand fly species (nine Phlebotomus and sixteen Sergentomyia) were collected and identified. S. africana and P. orientalis made up 59.1% and 23.5% of the collected sand flies, respectively. As it could be determined from the proportion of collections from outdoor (peri-domestic and agricultural fields) and indoor locations, P. orientalis appears to exhibit increased exophilic behavior. The outdoor to indoor index was 79:1 on m(2) of sticky traps. Mean density of P. orientalis caught was significantly higher on horizontally placed sticky traps (mean = 60 +/- 14.56/m(2)/night) than vertically deployed sticky traps (12 +/- 3.57/m(2)/night). The highest abundance of P. orientalis occurred between March and April. Through July to September, there was a sharp decline in abundance of P. orientalis population. Regarding climatic variables, P. orientalis density in light traps and on sticky traps showed a significant positive and negative association with temperature and relative humidity, respectively. However, non significant negative correlation was observed with rainfall pattern. CONCLUSIONS: Overall, P. orientalis was found to be the most abundant Phlebotomus species, showing marked seasonal abundance that mainly peaks during the dry season (March to April). Likewise, the people in the area usually sleep in compounds during these months that potentially expose them to a high risk of peri-domestic VL transmission. PMID- 25907253 TI - Rapid and comprehensive 'shotgun' lipidome profiling of colorectal cancer cell derived exosomes. AB - There is an increasing recognition of the role that cancer cell derived exosomes play in intercellular signaling upon fusion or uptake with a target cell, including immune system evasion, tumor growth and metastasis. To date, however, although exosomal membrane and cargo lipids are expected to play a pivotal role in exosome biogenesis and secretion, as well as in fusion or uptake and target cell functional response, the detailed characterization of cancer cell derived exosome lipids across a range of different cancers has not yet been broadly explored. Here, a simple and straightforward lipidome analysis strategy consisting of optimized sample extraction and novel sample derivatization techniques, coupled with high-resolution 'shotgun' mass spectrometry and 'targeted' tandem mass spectrometry methods, is demonstrated for the rapid identification of >520 individual lipids in 36 lipid classes and sub classes from exosomes secreted by the colorectal cancer cell line, LIM1215. Relative quantification and comparison of exosome versus cellular lipid profiles reveals significant enrichment of certain lipid classes, as well as substantial lipid subclass remodeling and changes in abundance of individual lipids, including sphingolipids, sterol lipids, glycerolipids and glycerophospholipids, and particularly plasmalogen- and alkyl ether-containing glycerophospholipids. This analysis strategy therefore provides a platform for comprehensive lipidome profiling across a wide range of cancer cell or tissue derived exosomes, that will facilitate subsequent functional studies aimed at elucidating the role of specific cellular or exosome lipids in the onset and progression of colorectal cancer, or to identify specific lipid(s) that could serve as effective diagnostic or prognostic disease biomarkers. PMID- 25907254 TI - Advancing the screening of fibromyalgia in late-life depression: practical implications for psychiatric settings. AB - BACKGROUND: Fibromyalgia (FM) is common in older adults suffering from mood disorders. However, clinical diagnosis of FM is challenging, particularly in psychiatric settings. We examined the prevalence of FM and the sensitivity of three simple screeners for FM. METHODS: Using cross-sectional data, we evaluated three tests against the American College of Rheumatology (ACR) 1990 Criteria for the Classification of FM: a "Do you often feel like you hurt all over?" question, a pain map score, and the Pope and Hudson (PH) interview for FM. Participants were 185 community-dwelling adults >= 60 years old with comorbid depression and chronic low back pain evaluated at a late-life mental health clinic. RESULTS: Fifty three of 185 participants (29%) met the ACR 1990 FM criteria. Compared to those without FM, the FM group had more "yes" answers to the "hurt all over?" question and higher pain map scores. To reach a sensitivity of at least 0.90, the cut-off score for the pain map was 8. The sensitivity of the pain map, "hurt all over?" question, and PH criteria were 0.92 [95%CI 0.82-0.98], 0.91 [95%CI 0.79 0.97], and 0.94 [95%CI 0.843-0.99] respectively. CONCLUSIONS: Nearly one in three older adults suffering from depression and chronic low back pain met ACR 1990 FM criteria. Three short screening tests showed high sensitivity when compared to the ACR 1990 FM criteria. Implementation of one of the simple screeners for FM in geriatric psychiatry settings may guide the need for further diagnostic evaluation. PMID- 25907255 TI - Hypo-pharyngeal distension in an extremely low birth weight preterm infant. PMID- 25907256 TI - Exploring the Molecular Mechanism and Biomakers of Liver Cancer Based on Gene Expression Microarray. AB - Liver cancer is one of the most common cancers worldwide with high morbidity and mortality. Its molecular mechanism hasn't been fully understood though many studies have been conducted and thus further researches are still needed to improve the prognosis of liver cancer. Firstly, differentially expressed genes (DEGs) between six Mdr2-knockout (Mdr2-KO) mutant mice samples (3-month-old and 12-month-old) and six control mice samples were identified. Then, the enriched GO terms and KEGG pathways of those DEGs were obtained using the Database for Annotation, Visualization and Integrated Discovery (DAVID, http://david.abcc.ncifcrf.gov/). Finally, protein-protein interactions (PPI) network of those DEGs were constructed using STRING database ( http://www.string db.org/) and visualized by Cytoscape software, at the same time, genes with high degree were selected out. Several novel biomarkers that might play important roles in liver cancer were identified through the analysis of gene microarray in GEO. Also, some genes such as Tyrobp, Ctss and pathways such as Pathways in cancer, ECM-receptor interaction that had been researched previously were further confirmed in this study. Through the bioinformatics analysis of the gene microarray in GEO, we found some novel biomarkers of liver cancer and further confirmed some known biomarkers. PMID- 25907257 TI - [Preoperative and follow-up cardiac magnetic resonance imaging of candidates for surgical ventricular restoration]. AB - PURPOSE: To assess pre and post-operative cardiac MRI (CMR) findings in patients with left endoventriculoplasty repair for ventricular aneurysm due to ischemic heart disease. MATERIAL AND METHODS: Data were retrospectively gathered on 21 patients with diagnosis of ventricular aneurysm secondary to ischemic heart disease undergoing left endoventriculoplasty repair between January 2007 and March 2013. Pre and post-operative CMR was performed in 12 patients. The following data were evaluated in pre-operative and post-operative CMR studies: quantitative analysis of left ventricular ejection fraction (LVEF), left ventricular end-diastolic (LVEDV) and end-systolic (LVESV) volume index, presence of valvular disease and intracardiac thrombi. The time between surgery and post operative CRM studies was 3-24 months. RESULTS: Significant differences were found in the pre and post-operative LVEF, LVEDV and LVESV data. EF showed a median increase of 10% (IQR 2-15) (p=0.003). The LVEDV showed a median decrease of 38 ml/m(2) (IQR 18-52) (p=0.006) and the LVESV showed a median decrease of 45 ml/m(2) (IQR:12-60) (p=0.008). Post-operative ventricular volume reduction was significantly higher in those patients with preoperative LVESV >110 ml/m(2) (59 ml/m(2) and 12 ml/m(2), p=0.006). CONCLUSION: In patients with ischemic heart disease that are candidates for left endoventriculoplasty, CMR is a reliable non invasive and reproducible technique for the evaluation of the scar before the surgery and the ventricular volumes and its evolution after endoventricular surgical repair. PMID- 25907259 TI - Successful treatment of tuberous sclerosis with psychosis and obsessive compulsive disorder: A case report. PMID- 25907258 TI - FUS/TLS deficiency causes behavioral and pathological abnormalities distinct from amyotrophic lateral sclerosis. AB - INTRODUCTION: FUS/TLS is an RNA-binding protein whose genetic mutations or pathological inclusions are associated with neurological diseases including amyotrophic lateral sclerosis (ALS), frontotemporal lobar degeneration, and essential tremor (ET). It is unclear whether their pathogenesis is mediated by gain or loss of function of FUS/TLS. RESULTS: Here, we established outbred FUS/TLS knockout mice to clarify the effects of FUS/TLS dysfunction in vivo. We obtained homozygous knockout mice that grew into adulthood. Importantly, they did not manifest ALS- or ET-like phenotypes until nearly two years. Instead, they showed distinct histological and behavioral alterations including vacuolation in hippocampus, hyperactivity, and reduction in anxiety-like behavior. Knockout mice showed transcriptome alterations including upregulation of Taf15 and Hnrnpa1, while they have normal morphology of RNA-related granules such as Gems. CONCLUSIONS: Collectively, FUS/TLS depletion causes phenotypes possibly related to neuropsychiatric and neurodegenerative conditions, but distinct from ALS and ET, together with specific alterations in RNA metabolisms. PMID- 25907260 TI - Organocatalyzed CO2 Trapping Using Alkynyl Indoles. AB - The first organocatalyzed trapping of CO2 through C-C and C-O bond formation is reported. Alkynyl indoles together with catalytic amounts of an organic base and five equivalents of CO2 resulted in the formation new heterocyclic structures. These tricyclic indole-containing products were successfully prepared under mild reaction conditions from aromatic, heteroaromatic, and aliphatic alkynyl indoles with complete regioselectivity. Further investigations suggest that C-C bond formation is the initial intermolecular step, followed by lactone-forming C-O bond formation. PMID- 25907261 TI - Initial suboptimal CD4 reconstitution with antiretroviral therapy despite full viral suppression in a cohort of HIV-infected patients in Senegal. AB - OBJECTIVE: We determined the risk factors and incidence of clinical events associated with suboptimal immune reconstitution (SIR) defined by an increase in CD4 inferior to 50 cells/MUL, from inclusion up to six months of antiretroviral treatment (ARVT), in patients with an undetectable viral load (<50 copies/mL). METHODS: Logistic regression and Cox's proportional hazards model were used to examine risk factors for SIR and the association between SIR and the risk of new clinical events or death, respectively after six months of ARVT. RESULTS: One hundred and two (15.5%) of the 657 patients presented with SIR. Age > 40 years (aOR = 1.74, 95% CI = 1.10-2.75), baseline CD4 >= 100 cells/MUL (aOR = 2.06, 95% CI = 1.24-3.42), ARVT including AZT (aOR = 4.57, 95% CI=1.06-19.76), and the occurrence of a severe opportunistic infection during the first semester of ARVT (aOR = 2.38 95% CI= 1.49-3.80) were associated with SIR. After six months of ARVT and up to seven years of follow-up, 39 patients with SIR had presented with an opportunistic infection or death (rate= 9.78/100 person-years) compared to 168 with a normal recovery (rate = 7.75/100 person-years) but the difference was not statistically significant (aHR = 1.22, 95% CI = 0.85 to 1.74). CONCLUSION: SIR is less common in our country and is not associated with increased mortality or a greater incidence of opportunistic infections after six months of ARVT. PMID- 25907263 TI - Biphasic IDH1 phenotype in a diffusely infiltrating glioma: implications for pathogenesis, treatment and prognosis. AB - Recent studies suggest isocitrate dehydrogenase 1 (IDH1) mutations are early events in gliomagenesis, given their frequent occurrence in low-grade gliomas, diffuse expression within neoplastic cells, and lack of evidence for preceding TP53 mutations or 1p/19q co-deletion. We present an infiltrating glioma with mixed oligoastroglial morphology and biphasic molecular phenotype. Areas resembling oligodendroglioma by histology expressed mutant IDH1-R132H, and strong ATRX, Olig2, and PDGFR-alpha by immunohistochemistry. In contrast, astrocytic areas completely lacked the IDH1-R132H mutation, showed loss of nuclear ATRX expression, and only weakly expressed Olig2 and PDGFR-alpha. Co-deletion of 1p/19q was evident throughout, while p53 expression was largely negative. This case suggests that 1p/19q co-deletion may rarely precede IDH1 mutations or that IDH1 mutations may be secondarily lost, as demonstrated by IDH1-R132H positive and negative cells in a glioma with diffuse 1p/19q co-deletion. The uniquely biphasic molecular phenotype of this tumor supports the rare existence of true mixed oligoastrocytomas that may have significant prognostic and therapeutic implications. The case highlights the variable sequence of key molecular aberrations in gliomagenesis and the difficulty of targeting treatment to genetic profiles in inherently heterogeneous neoplasms. PMID- 25907262 TI - Forward lunge knee biomechanics before and after partial meniscectomy. AB - BACKGROUND: Patients following meniscectomy are at increased risk of developing knee osteoarthritis in the tibiofemoral compartment and at the patellofemoral joint. As osteoarthritis is widely considered a mechanical disease, it is important to understand the potential effect of arthroscopic partial meniscectomy (APM) on knee joint mechanics. The purpose of this study was to evaluate changes in knee joint biomechanics during a forward lunge in patients with a suspected degenerative meniscal tear from before to three months after APM. METHODS: Twenty two patients (35-55 years old) with a suspected degenerative medial meniscal tear participated in this study. Three dimensional knee biomechanics were assessed on the injured and contralateral leg before and three months after APM. The visual analogue scale was used to assess knee pain and the Knee Injury Osteoarthritis Outcome Score was used to assess sport/recreation function and knee-related confidence before and after APM. RESULTS: The external peak knee flexion moment reduced in the APM leg compared to the contralateral leg (mean difference (95% CI)) -1.08 (-1.80 to -0.35) (Nm/(BW * HT)%), p = 0.004. Peak knee flexion angle also reduced in the APM leg compared to the contralateral leg -3.94 (-6.27 to 1.60) degrees, p = 0.001. There was no change in knee pain between the APM leg and contralateral leg (p=0.118). Self-reported sport/recreation function improved (p = 0.004). CONCLUSIONS: Although patients self-reported less difficulty during strenuous tasks following APM, patients used less knee flexion, a strategy that may limit excessive patellar loads during forward lunge in the recently operated leg. PMID- 25907264 TI - Intraparenchymal mesenchymal chondrosarcoma of the frontal lobe--a case report and molecular detection of specific gene fusions from archival FFPE sample. AB - Mesenchymal chondrosarcoma is a rare tumor of cartilaginous origin characterized by its bimorphic pattern composed of highly undifferentiated small round cells separated by islands of well-differentiated hyaline cartilage. It exhibits higher malignancy and earlier occurrence in comparison to classic chondrosarcomas. Recently identified HEY1-NCOA2 and IRF2BP2-CDX1 gene fusions confirm their distinct molecular origin and pose a promising diagnostic marker. The majority of cases arise from craniofacial bones. In this study, we present a rare case of mesenchymal chondrosarcoma encompassed within the brain parenchyma of the frontal lobe without any dural or bone attachment. We demonstrate histopathological findings and confirm the HEY1-NCOA2 gene fusion in a formalin-fixed paraffin embedded archival sample using simple reverse transcription polymerase chain reaction (RT-PCR) method. IRF2BP2-CDX1 gene fusion was absent in the analyzed sample. The clinical follow-up is also presented with a review of treatment modalities for this entity. PMID- 25907265 TI - Chinese medicine Tongxinluo increases tight junction protein levels by inducing KLF5 expression in microvascular endothelial cells. AB - Tongxinluo (TXL) is a compound prescription formulated according to the meridian theory of traditional Chinese medicine. It may play an important role in cardiovascular protection by improving endothelial cell function. The aim of present study was to investigate whether endothelial protection with TXL is related to its regulation of tight junction protein expression. Human cardiac microvascular endothelial cells (HCMECs) were cultured and treated with 10(-7) mol l(-1) angiotensin II (Ang II) and the different doses of TXL; the expression of tight junction proteins occludin, claudin, VE-cadherin and beta-catenin was determined by Western blotting and real-time PCR. Gain-of-function and loss-of function of Kruppel-like factor 5 (KLF5) were carried out in HCMEC transfected with either KLF5 adenovirus pAd-KLF5 or siRNA specific for KLF5. Angiotensinogen transgenic mice were treated with TXL by oral administration of TXL of 0.75 g kg( 1) day(-1) , and immunohistochemical staining was performed with antioccludin, anticlaudin, anti-VE-cadherin, antibeta-catenin and anti-KLF5 antibodies. Ang II treatment significantly reduced the expression of tight junction proteins occludin, claudin, VE-cadherin and beta-catenin in cultured HCMECs. TXL pretreatment could abrogate the down-regulation of these tight junction proteins induced by Ang II. Ang II treatment also decreased KLF5 expression at the mRNA and protein levels; TXL pretreatment markedly reversed the inhibitory effect of Ang II on KLF5 expression. Gain-of-function and loss-of-function of KLF5 showed that KLF5 mediated the expression of tight junction proteins in HCMECs. TXL enhanced expression of the tight junction proteins was mediated by KLF5. In angiotensinogen transgenic mice, TXL also increased the tight junction protein levels by inducing KLF5 expression. Chinese medicine TXL increases tight junction protein levels by inducing KLF5 expression in microvascular endothelial cells. PMID- 25907266 TI - A novel HAC1-based dual-luciferase reporter vector for detecting endoplasmic reticulum stress and unfolded protein response in yeast Saccharomyces cerevisiae. AB - Unfolded protein response (UPR) is an important cellular phenomenon induced by over-accumulation of unfolded proteins in the endoplasmic reticulum (ER) lumen. ER stress and UPR are implicated in human diseases such as diabetes, atherosclerosis and neurodegenerative diseases. Current methods for measuring ER stress levels and UPR activation usually include cells lysis and other complicated procedures such as reverse transcription-PCR (RT-PCR). These methods typically have low sensitivity and are not suitable for live detection. In this study, we developed a dual-luciferase gene reporter system to monitor UPR activation in live cells of the yeast Saccharomyces cerevisiae by taking advantage of the HAC1 intron and its unconventional splicing-regulation mechanism. We showed that this reporter can be used to monitor UPR in live cells with high sensitivity. PMID- 25907267 TI - What is the animal doing? Tools for exploring behavioural structure in animal movements. AB - Movement data provide a window - often our only window - into the cognitive, social and biological processes that underlie the behavioural ecology of animals in the wild. Robust methods for identifying and interpreting distinct modes of movement behaviour are of great importance, but complicated by the fact that movement data are complex, multivariate and dependent. Many different approaches to exploratory analysis of movement have been developed to answer similar questions, and practitioners are often at a loss for how to choose an appropriate tool for a specific question. We apply and compare four methodological approaches: first passage time (FPT), Bayesian partitioning of Markov models (BPMM), behavioural change point analysis (BCPA) and a fitted multistate random walk (MRW) to three simulated tracks and two animal trajectories - a sea lamprey (Petromyzon marinus) tracked for 12 h and a wolf (Canis lupus) tracked for 1 year. The simulations - in which, respectively, velocity, tortuosity and spatial bias change - highlight the sensitivity of all methods to model misspecification. Methods that do not account for autocorrelation in the movement variables lead to spurious change points, while methods that do not account for spatial bias completely miss changes in orientation. When applied to the animal data, the methods broadly agree on the structure of the movement behaviours. Important discrepancies, however, reflect differences in the assumptions and nature of the outputs. Important trade-offs are between the strength of the a priori assumptions (low in BCPA, high in MRW), complexity of output (high in the BCPA, low in the BPMM and MRW) and explanatory potential (highest in the MRW). The animal track analysis suggests some general principles for the exploratory analysis of movement data, including ways to exploit the strengths of the various methods. We argue for close and detailed exploratory analysis of movement before fitting complex movement models. PMID- 25907268 TI - Amplified thrombin aptasensor based on alkaline phosphatase and hemin/G quadruplex-catalyzed oxidation of 1-naphthol. AB - An alkaline phosphatase (ALP)-based biosensor can in situ generate an electroactive product by enzymatic hydrolysis of inactive substrates. To obtain a higher signal-to-background ratio, a chemical redox cycling signal-amplified strategy based on the addition of a strong reducing agent has often be applied in the construction of ALP-based biosensors. However, the strong reducing agent not only affects the activity of ALP but also readily reacts with dissolved oxygen, leading to inaccurate results. In this work, a new signal-amplified strategy for a thrombin (TB) aptasensor based on the catalytic oxidation of ALP-generated products, 1-naphthol (NP), using hemin/G-quadruplex DNAzymes was reported. We implemented gold-nanoparticle-decorated zinc oxide nanoflowers (Au-ZnO) as the matrix for immobilizing ALP and TB aptamer (TBA) and then labeled it with hemin to form hemin/G-quadruplex/ALP/Au-ZnO bioconjugates (TBA II bioconjugates). Through a "sandwich" reaction, TBA II bioconjugates were captured on the electrode surface. The amplified signal was carried out in two steps: (i) an ALP catalyzed inactive substrate, 1-naphthyl phosphate (NPP), in situ produces NP on the surface of the electrode; (ii) on the one hand, NP as a new reactant could be directly electrooxidized and generated an electrochemical signal, but, on the other hand, NP could be oxidized by hemin/G-quadruplex in the presence of H2O2, resulting in amplification of the electrochemical signal. The proposed TB aptasensor achieved a linear range of 1 pM to 30 nM with a detection limit of 0.37 pM (defined as S/N = 3). PMID- 25907269 TI - Developing a roadmap for the translation of e-mental health services for depression. AB - OBJECTIVE: e-Mental health services have been shown to be effective and cost effective for the treatment of depression. However, to have optimal impact in reducing the burden of depression, strategies for wider reach and uptake are needed. METHOD: A review was conducted to assess the evidence supporting use of e mental health programmes for treating depression. From the review, models of dissemination and gaps in translation were identified, with a specific focus on characterising barriers and facilitators to uptake within the Australian healthcare context. Finally, recommendations for promoting the translation of e mental health services in Australia were developed. RESULTS: There are a number of effective and cost-effective e-health applications available for treating depression in community and clinical settings. Four primary models of dissemination were identified: unguided, health service-supported, private ownership and clinically guided. Barriers to translation include clinician reluctance, consumer awareness, structural barriers such as funding and gaps in the translational evidence base. CONCLUSION: Key strategies for increasing use of e-mental health programmes include endorsement of e-mental health services by government entities, education for clinicians and consumers, adequate funding of e-mental health services, development of an accreditation system, development of translation-focused activities and support for further translational research. The impact of these implementation strategies is likely to include economic gains, reductions in disease burden and greater availability of more interventions for prevention and treatment of mental ill-health complementary to existing health and efficient evidence-based mental health services. PMID- 25907270 TI - Treatment refractory chronic catatonia responsive to zolpidem challenge. PMID- 25907271 TI - Accuracy of clinician-clinical coder information handover following acute medical admissions: implication for using administrative datasets in clinical outcomes management. AB - BACKGROUND: We evaluated the accuracy, limitations and potential sources of improvement in the clinical utility of the administrative dataset for acute medicine admissions. METHODS: Accuracy of clinical coding in 8888 patient discharges following an emergency medical hospital admission to a teaching hospital and a district hospital over 3 years was ascertained by a coding accuracy audit team in respect of the primary and secondary diagnoses, morbidities and financial variance. RESULTS: There was at least one change to the original coding in 4889 admissions (55%) and to the primary diagnosis of at least one finished consultant episodes of 1496 spells (16.8%). There were significant changes in the number of secondary diagnoses and the Charlson morbidity index following the audit. Charlson score increased in 8.2% and decreased in 2.3% of patients. An income variance of L816 977 (+5.0%) or L91.92 per patient was observed. CONCLUSIONS: The importance and applications of coded healthcare big data within the NHS is increasing. The accuracy of coding is dependent on high fidelity information transfer between clinicians and coders, which is prone to subjectivity, variability and error. We recommend greater involvement of clinicians as part of multidisciplinary teams to improve data accuracy, and urgent action to improve abstraction and clarity of assignment of strategic diagnoses like pneumonia and renal failure. PMID- 25907272 TI - The influence of social context on the treatment outcomes of complementary and alternative medicine: the case of acupuncture and herbal medicine in Japan and the U.S. AB - BACKGROUND: Complementary and alternative medicine (CAM), such as acupuncture and herbal medicine, is popular in many countries. Yet, treatment outcomes of CAM are found to vary significantly between medical trials in different social environments. This paper addresses how the social organization of medicine affects medical treatment outcomes. In particular, it examines the extent to which two popular complementary and alternative medicine (CAM) interventions (acupuncture and herbal medicine) are coordinated with biomedicine and how coordination characteristics are related to the treatment outcomes of the two CAM interventions. METHODS: This paper conducts an archival analysis of the institutional settings of the CAM interventions in Japan and the U.S. It also conducts a systematic content analysis of the treatment outcomes in 246 acupuncture reports and 528 herbal medicine reports that are conducted in Japan or the U.S. and registered in the Cochrane Library's Central Register of Controlled Trials (CENTRAL), and 716 acupuncture reports and 3,485 herbal medicine reports that are from Japan or the U.S. and listed in MEDLINE. It examines the association between the treatment outcomes of the two interventions and the geographical location of the reports; it also explores how the institutional settings of the interventions are related to the treatment outcomes. RESULTS: Japanese herbal medicine is integrated into the national medical system the most and American herbal medicine the least; American acupuncture and Japanese acupuncture fall in the middle. Treatment outcomes are the most favorable for Japanese herbal medicine and the least favorable for American herbal medicine. The outcomes of American acupuncture and Japanese acupuncture fall in the middle. CONCLUSIONS: The co-utilization of CAM with biomedicine can produce difficulties due to tensions between CAM and biomedicine. These difficulties and subsequent CAM treatment outcomes vary, depending on how CAM is institutionalized in relation to biomedicine in the national medical system. Coordinated CAM interventions are more likely to be effective and synergic with biomedicine, when compared to uncoordinated ones. PMID- 25907275 TI - Antiviral treatment for Bell's palsy? PMID- 25907276 TI - Antiviral agents convey added benefit over steroids alone in Bell's palsy; decompression should be considered in patients who are not recovering. AB - BACKGROUND: The management of Bell's palsy has been the subject of much debate, with corticosteroids being the preferred medication. However, evidence also supports the use of antiviral drugs for severe cases and even decompression surgery in patients who, despite medical treatment, are not recovering. METHOD: A literature review was conducted on the management of Bell's palsy. RESULTS: This paper describes the background, statistical evidence, study results and pathophysiological theories that support more aggressive treatment for patients with severe palsy and those who have inadequate recovery. CONCLUSION: Combination therapy including antiviral medication significantly improves outcomes in patients with severe Bell's palsy. Decompression should be considered in patients who have not recovered with drug treatment. PMID- 25907273 TI - Perioperative lung protective ventilation in obese patients. AB - The perioperative use and relevance of protective ventilation in surgical patients is being increasingly recognized. Obesity poses particular challenges to adequate mechanical ventilation in addition to surgical constraints, primarily by restricted lung mechanics due to excessive adiposity, frequent respiratory comorbidities (i.e. sleep apnea, asthma), and concerns of postoperative respiratory depression and other pulmonary complications. The number of surgical patients with obesity is increasing, and facing these challenges is common in the operating rooms and critical care units worldwide. In this review we summarize the existing literature which supports the following recommendations for the perioperative ventilation in obese patients: (1) the use of protective ventilation with low tidal volumes (approximately 8 mL/kg, calculated based on predicted -not actual- body weight) to avoid volutrauma; (2) a focus on lung recruitment by utilizing PEEP (8-15 cmH2O) in addition to recruitment maneuvers during the intraoperative period, as well as incentivized deep breathing and noninvasive ventilation early in the postoperative period, to avoid atelectasis, hypoxemia and atelectrauma; and (3) a judicious oxygen use (ideally less than 0.8) to avoid hypoxemia but also possible reabsorption atelectasis. Obesity poses an additional challenge for achieving adequate protective ventilation during one lung ventilation, but different lung isolation techniques have been adequately performed in obese patients by experienced providers. Postoperative efforts should be directed to avoid hypoventilation, atelectasis and hypoxemia. Further studies are needed to better define optimum protective ventilation strategies and analyze their impact on the perioperative outcomes of surgical patients with obesity. PMID- 25907277 TI - Hearing loss following myringoplasty - implications for informed consent. AB - BACKGROUND: There are many reports of operations performed to successfully close ear drum perforations. Hearing deterioration after myringoplasty is not a widely published topic. This paper presents an audit of this complication. METHODS: A six-year retrospective analysis of a series of myringoplasty operations was performed using electronic patient records. Patients with post-operative hearing loss were identified and those with hearing loss greater than 10 dB were further scrutinised. RESULTS: Out of 187 patients who underwent myringoplasty procedures, 44 (23.53 per cent) experienced a reduction in hearing thresholds. In seven cases (3.74 per cent), the hearing loss was greater than 10 dB. A case note review revealed no obvious predictive factors, although posterior perforations and the possibility of ossicular chain manipulation were considered. CONCLUSION: Hearing loss following myringoplasty is not rare, and this may alter the consent process for this procedure. PMID- 25907274 TI - Persistent expression of activated notch in the developing hypothalamus affects survival of pituitary progenitors and alters pituitary structure. AB - BACKGROUND: As the pituitary gland develops, signals from the hypothalamus are necessary for pituitary induction and expansion. Little is known about the control of cues that regulate early signaling between the two structures. Ligands and receptors of the Notch signaling pathway are found in both the hypothalamus and Rathke's pouch. The downstream Notch effector gene Hes1 is required for proper pituitary formation; however, these effects could be due to the action of Hes1 in the hypothalamus, Rathke's pouch, or both. To determine the contribution of hypothalamic Notch signaling to pituitary organogenesis, we used mice with loss and gain of Notch function within the developing hypothalamus. RESULTS: We demonstrate that loss of Notch signaling by conditional deletion of Rbpj in the hypothalamus does not affect expression of Hes1 within the posterior hypothalamus or expression of Hes5. In contrast, expression of activated Notch within the hypothalamus results in ectopic Hes5 expression and increased Hes1 expression, which is sufficient to disrupt pituitary development and postnatal expansion. CONCLUSIONS: Taken together, our results indicate that Rbpj-dependent Notch signaling within the developing hypothalamus is not necessary for pituitary development, but persistent Notch signaling and ectopic Hes5 expression in hypothalamic progenitors affects pituitary induction and expansion. PMID- 25907278 TI - Spontaneous cerebrospinal fluid leaks in the anterior skull base: a surgical challenge. AB - OBJECTIVE: This retrospective study aimed to evaluate the effective closure rate for spontaneous cerebrospinal fluid leaks with functional endoscopic sinus surgery and identify patient characteristics that may be associated with a need for additional therapy. METHOD: A retrospective analysis of patients with spontaneous cerebrospinal fluid leaks was performed. Data on the nature of presentation, patient body mass index, defect location and size, intracranial pressure, clinical follow up, and complications were collected. RESULTS: Twenty five patients had spontaneous cerebrospinal fluid leaks with evidence of idiopathic intracranial hypertension. The most common sites were the cribriform plate, followed by the ethmoid roof and sphenoid lateral pterygoid recess. All patients underwent endonasal endoscopic surgery to repair the defect. Post operatively, all patients underwent lumbar drainage and acetazolamide therapy. CONCLUSION: Spontaneous cerebrospinal fluid leaks represent a surgical challenge because of their high recurrence rates. The most important factor for obtaining a successful repair in these patients is reducing their intracranial pressure through nutritional, medical or surgical means. PMID- 25907279 TI - Synergetic effect of temperature and pressure on energetic and structural characteristics of {ZIF-8 + water} molecular spring. AB - Metal-organic frameworks (MOFs) and particularly their subclass - Zeolite Imidazolate Frameworks (ZIFs) - are used for a variety of applications including particularly energy storage. Highly porous MOFs mixed with non-wetting liquids can be used to form molecular springs (MS) for efficient mechanical and thermal energy storage/transformation. In this paper by means of high-pressure calorimetry the energetic characteristics of {ZIF-8 + water} MS were investigated in wide temperature and pressure ranges. Unexpectedly XRD measurements show that the concomitant effects of temperature and pressure on {ZIF-8 + water} MS leads to an irreversible change of the ZIF-8 structure, transforming its symmetry from cubic to orthorhombic. Whereas, previous studies have demonstrated the stability of ZIF-8 under either high pressure or high temperature. PMID- 25907280 TI - Predicting neonatal pharmacokinetics from prior data using population pharmacokinetic modeling. AB - Selection of the first dose for neonates in clinical trials is very challenging. The objective of this analysis was to assess if a population pharmacokinetic (PK) model developed with data from infants to adults is predictive of neonatal clearance and to evaluate what age range of prior PK data is needed for informative modeling to predict neonate exposure. Two sources of pharmacokinetic data from 8 drugs were used to develop population models: (1) data from all patients > 2 years of age, and (2) data from all nonneonatal patients aged > 28 days. The prediction error based on the models using data from subjects > 2 years of age showed bias toward overprediction, with median average fold error (AFE) for CL predicted/CLobserved greater than 1.5. The bias for predicting neonatal PK was improved when using all prior PK data including infants as opposed to an assessment without infant PK data, with the median AFE 0.91. As an increased number of pediatric trials are conducted in neonates under the Food and Drug Administration Safety and Innovation Act, dose selection should be based on the best estimates of neonatal pharmacokinetics and pharmacodynamics prior to conducting efficacy and safety studies in neonates. PMID- 25907281 TI - Farmers' Willingness to Participate in the Next-Stage Grain-for-Green Project in the Three Gorges Reservoir Area, China. AB - The policy implications for success in the next-stage Grain-for-Green Project (GFGP) in China are analyzed from the perspectives of farmers' willingness. The ecological protection belt of the Three Gorges Reservoir Area was chosen as the case study area, where 1207 valid questionnaire surveys based on participatory rural appraisal were collected in 2012. Our study found that farmers with lower levels of education, older age, and higher livelihood dependency on farmland were more prone to reclamation if the compensation ended. Females and non-migrants were more reluctant to participate in the next GFGP than others. Nevertheless, traditional farming was no longer a preferred livelihood by all respondents. The majority of respondents (74.4%) wished to be liberated from the low-income farmland work through the next GFGP, and half of them (50.6%) hoped to get non cash compensation. The Willingness to Accept (WTA) values of the next GFGP showed significant social heterogeneity and regional difference, with an average of annual RMBY16,665 ha(-1), about 4.5 times the local compensation standard in 2000. By revealing some limitations of the uniform nationwide compensation standard system and the single payment form in adapting to evolving socioeconomic conditions, our study highlighted the importance of developing a region-based compensation standard system, integrating the next GFGP into regional sustainable development organically by more comprehensive alternative policy, and bonding a vertical partnership between the local community and the nation. Our study revealed some key elements for success in the future design of restoration projects in China. PMID- 25907282 TI - Implications from the Use of Non-timber Forest Products on the Consumption of Wood as a Fuel Source in Human-Dominated Semiarid Landscapes. AB - Little is known about what possible effects on wood resources might be caused by non-timber forest products (NTFPs). Here, we assessed the patterns of fuelwood consumption related to an NTFP (Caryocar coriaceum) oil extraction and how this non-domestic activity can indirectly increase the use pressure on fuelwood species in a protected area, semiarid of Brazil. We conducted semi-structured interviews, in situ inventories, phytosociological surveys, and analyses of wood quality to identify the set of woody plants used in oil production. Householders use large volumes of dry wood and a set of woody species, which are highly exploited. Additionally, many preferred species have low fuel potential and suffer much use pressure. The best fuelwood species are underused, what requires management strategies to improve their potential as a source of energy. As a result, we suggest some conservation and management actions of fuelwood resources related to the use of NTFPs. PMID- 25907283 TI - Microtubule affinity-regulating kinase 2 is associated with DNA damage response and cisplatin resistance in non-small cell lung cancer. AB - Microtubule affinity-regulating kinases (MARKs) are involved in several cellular functions but few studies have correlated MARK kinase expression with cancer, and none have explored their role in lung cancer. In this study, we identified MARK2 as frequently disrupted by DNA hypomethylation and copy gain, resulting in concordant overexpression in independent lung tumor cohorts and we demonstrate a role for MARK2 in lung tumor biology. Manipulation of MARK2 in lung cell lines revealed its involvement in cell viability and anchorage-independent growth. Analyses of both manipulated cell lines and clinical tumor specimens identified a potential role for MARK2 in cell cycle activation and DNA repair. Associations between MARK2 and the E2F, Myc/Max and NF-kappaB pathways were identified by luciferase assays and in-depth assessment of the NF-kappaB pathway suggests a negative association between MARK2 expression and NF-kappaB due to activation of non-canonical NF-kappaB signaling. Finally, we show that high MARK2 expression levels correlate with resistance to cisplatin, a standard first line chemotherapy for lung cancer. Collectively, our work supports a role for MARK2 in promoting malignant phenotypes of lung cancer and potentially modulating response to the DNA damaging chemotherapeutic, cisplatin. PMID- 25907284 TI - B cells generated by B-1 development can progress to chronic lymphocytic leukemia. AB - B cells generated early during fetal/neonatal B-1 development in mice include autoreactive cells with detectable CD5 upregulation induced by B cell receptor (BCR) signaling (B1a cells). A fraction of B1a cells are maintained by self renewal for life, with the potential risk of dysregulated growth and progression to chronic lymphocytic leukemia (CLL)/lymphoma during aging. In studies using the EMU-hTCL1 transgenic mouse system, it became clear that this B1a subset has a higher potential than other B cell subsets for progression to CLL. We have generated several autoreactive germline BCR gene models to compare B cells generated under conditions of natural exposure to autoantigen. Analysis of the mice has been key in understanding the importance of the BCR and BCR signaling for generating different B cell subsets and for investigating the cellular origin of B-CLL. PMID- 25907285 TI - 1,25-dihydroxyvitamin D3 regulates the development of chronic colitis by modulating both T helper (Th)1 and Th17 activation. AB - T helper (Th)1 and Th17 cells play a critical role in inflammatory bowel disease (IBD). 1,25-dihydroxyvitamin D3 (1,25(OH)2 D3 ) has emerged as a direct regulator of immune system function. Mice were grouped as follows: Control group (received PBS, n = 10), DSS group (received 2% DSS and PBS, n = 10), and DSS+VD group (received 2% DSS and 1,25(OH)2 D3 , n = 10). The disease activity index (DAI), colon length, and damage store of the mice were observed; the spleen length, weight, spleen index, and mononuclear cells of spleen were measured; mononuclear cells from mesenteric lymph nodes (MLN) were measured, and the levels of Th 1 and Th17 cytokines in the colon mucosa and spleen were measured. Mice in the DSS group developed severe diarrhea, rectal bleeding, and marked BW loss. Histological examination revealed extensive ulceration and inflammatory cell infiltration in the colon, and the structure of the spleen was disordered, infiltrated with inflammatory cytokines in red pulp. In the DSS group, mononuclear cell numbers from MLN and spleen were increased, and enhanced proteins and mRNA levels of Th 1 and Th17 cytokines were detected. In the DSS+VD group, 1,25(OH)2 D3 ameliorated the inflammation of the colon and spleen. In addition, 1,25(OH)2 D3 down-regulated the levels of Th 1 and Th17 cytokines. 1,25(OH)2 D3 represents a novel therapeutic drug for UC, which may correlate to inhibit the activation of Th1 and Th17 cells. PMID- 25907286 TI - Effect of intravitreal bevacizumab on retrobulbar blood flow of patients with diabetic macular edema. AB - PURPOSE: To determine the effect of intravitreal bevacizumab on retrobulbar blood flow of patients with diabetic macular edema. METHODS: Peak systolic velocity, end-diastolic velocity, resistance, and pulsatility indices of central retinal artery (CRA), nasal posterior ciliary artery (NPCA), temporal posterior ciliary artery (TPCA), and ophthalmic artery (OA) were assessed by color Doppler ultrasonography in injected and uninjected eyes of 37 patients at baseline and at day 1 and day 7 after the injection. RESULTS: At day 1 after the injection, peak systolic and end diastolic velocities of the CRA and NPCA in the injected eyes and peak systolic velocity of NPCA in the uninjected eyes decreased significantly (p<0.05, p = 0.025, respectively). Peak systolic and end diastolic velocities were not significantly different in the injected and uninjected eyes at day 7 after the injection (p>0.05). In the injected eyes, there was no significant change in resistance and pulsatility indices (p>0.05), but a decrease in resistance index of NPCA and resistance and pulsatility indices of TPCA occurred in uninjected eyes at day 7 after the injection (p = 0.016, p = 0.023, and p = 0.025, respectively). CONCLUSIONS: Intravitreal bevacizumab affects retrobulbar blood flow in injected and uninjected eyes of patients with diabetic macular edema. PMID- 25907287 TI - Effect of inhaled fluticasone propionate on retinal nerve fiber layer thickness in asthmatic children. AB - PURPOSE: Corticosteroids are under suspicion of playing an important role in the development of retinopathy. We aimed to determine peripapillary retinal nerve fiber layer (RNFL) thinning by spectral-domain optical coherence tomography (OCT) in children being treated with inhaled fluticasone propionate due to asthma. METHODS: Thirty-eight children diagnosed with allergic asthma (mean age 9.8 +/- 2.8 years, age range 6-13 years) and 40 age-similar controls were enrolled in this study. All children with asthma were taking inhaled fluticasone propionate at a dosage of 250 ug or more per day for at least 1 year. The RNFL thickness measurements were performed using Cirrus HD spectral-domain OCT 400. Central subfield thickness, cube average thickness, and cube volume were also measured. RESULTS: Among the 38 children with asthma and 40 healthy subjects who completed follow-up, children with asthma had similar mean peripapillary RNFL thicknesses compared with control children. The mean central subfield thickness was significantly higher than that of controls (248.8 +/- 23.4 vs 237.5 +/- 23.5, p<0.037). There was a positive linear relationship between cube average thickness and eosinophil count with a Pearson correlation coefficient of 0.336 (p<0.039) and a negative correlation was found between central subfield thickness and disease duration (r = -0.385, p = 0.017) in children with asthma. CONCLUSIONS: Asthmatic children have similar peripapillary RNFL measurements compared to controls on spectral-domain OCT. Raised eosinophil counts in asthmatic children were found to be significantly associated with cube average thickness. PMID- 25907288 TI - Epiretinal membrane and cystoid macular edema after retinal detachment repair with small-gauge pars plana vitrectomy. AB - PURPOSE: To evaluate the incidence rates of cystoid macular edema (CME) and epiretinal membrane (ERM) formation after uncomplicated primary 23-G and 25-G retinal detachment (RD) repair and to identify risk factors associated with postoperative CME and ERM formation. METHODS: This was a consecutive interventional case series of 587 eyes that underwent one RD repair with 23-G or 25-G pars plana vitrectomy (PPV) with scleral buckling. Epiretinal membrane and CME were confirmed by optical coherence tomography (OCT) and fluorescein angiography (FA). RESULTS: A total of 587 eyes with a mean follow-up of 404 days had incidence rates of 35.1% for ERM and 15.2% for CME. The incidence of ERM after combined PPV and scleral buckling (48.4%) (n = 61) was greater (p<0.0001) compared to that after PPV alone (31.2%) (n = 144). CONCLUSIONS: Epiretinal membrane and CME develop frequently after small-gauge RD repair. Pars plana vitrectomy combined with scleral buckling is associated with a higher incidence of ERM. Patients might benefit from increased use of OCT and FA to help rule out CME/ERM. PMID- 25907289 TI - Anterior segment morphologic changes related to alpha-1 adrenergic receptor antagonists use. AB - PURPOSE: To investigate possible changes in anterior segment parameters with the Pentacam in patients taking tamsulosin or doxazosin for benign prostatic hyperplasia. METHODS: This prospective, cross-sectional study was conducted at Necip Fazil City Hospital, Kahramanmaras, Turkey. Patients included in the study were grouped as follows: 29 patients treated with tamsulosin (group 1), 27 patients treated with doxazosin (group 2), and 40 untreated controls (group 3). Right eyes of each patient were included in the study. All patients underwent examination with the Pentacam under standard dim light conditions and with undilated pupils. Anterior chamber depth (ACD), anterior chamber volume (ACV), anterior chamber angle (ACA) width, central corneal thickness (CCT), corneal volume (CV), and pupil diameter (PD) were recorded. RESULTS: Mean duration of treatments was 2.7 +/- 1.2 (1-5) and 2.4 +/- 0.9 (1-5) years in groups 1 and 2 (p = 0.276). The ACD, ACV, ACA width, and PD were statistically significantly decreased in groups 1 and 2 when compared to group 3 (p<0.05). There were no statistically significant differences among the groups in mean values of CCT and CV. CONCLUSIONS: In this study, decreased ACD, ACV, ACA width, and PD values were detected in tamsulosin and doxazosin groups when compared to controls. These findings should be considered during anterior segment examinations and surgeries. PMID- 25907290 TI - Dexamethasone implants into the crystalline lens. PMID- 25907291 TI - A case of acute exudative polymorphous vitelliform maculopathy: follow-up and wide-field spectral-domain optical coherence tomography. AB - PURPOSE: To present a case of an HIV-positive patient with acute exudative polymorphous vitelliform maculopathy (AEPVM) and evaluate the presence of specific spectral-domain optical coherence tomography (SD-OCT) findings. METHODS: Case report. RESULTS: We reviewed the AEPVM cases reported in the literature and compared those to our patient to determine if there is a correspondence between the etiology that leads to the onset of AEPVM and clinical and SD-OCT findings. CONCLUSIONS: Acute exudative polymorphous vitelliform maculopathy is a disease that involves the outer retinal layers with lipofuscin deposits and serous detachment of the neuroepithelium with or without intraretinal cysts. Not much is known about the etiology and pathogenesis, and not many cases have been described. A review of the few clinical cases reported in the literature does not show a specific correspondence between etiology and SD-OCT findings. PMID- 25907292 TI - Femtosecond laser-assisted cataract surgery in Alport syndrome with anterior lenticonus. AB - PURPOSE: To report the surgical treatment of 3 eyes of 2 patients with bilateral anterior lenticonus due to Alport syndrome using femtosecond laser-assisted cataract surgery (FLACS). METHODS: Two patients with Alport syndrome presented to our department due to anterior lenticonus in both eyes. We performed FLACS with posterior chamber lens implantation in both eyes of one patient and in one eye of the other patient. Anterior segment morphologic changes were visualized with a Scheimpflug camera, and anterior segment optical coherence tomography preoperatively and 3 months after surgery. Ultrastructure of the cut capsule edges was observed with scanning electron microscopy and compared to the edge of femtosecond laser capsulotomy performed on an otherwise healthy patient with cataract (control). RESULTS: The intraocular lens (IOL) postoperative positioning parameters met the international requirements of aspherical and wavefront customized IOLs (tilt <10 degree, decentration <800 um). Scanning electron microscopy revealed the same characteristics of the cut capsule edges in the Alport and in the control eyes. CONCLUSIONS: Femtosecond laser cataract surgery can be a safe and successful method for optical rehabilitation of anterior lenticonus in patients with Alport syndrome. PMID- 25907293 TI - Correcting timolol prescribing in glaucoma management. PMID- 25907294 TI - Clinical assessment of retinal changes by spectral-domain OCT. AB - PURPOSE: To evaluate optical coherence tomography changes in patients with retinal thinning at the posterior pole. METHODS: In this cross-sectional and retrospective study, 648 files were reviewed, and 67 patients were selected. Optical coherence tomography images that showed an area with a retinal thickness reduction at the macular region by using the Asymmetry Analysis Map in Heidelberg Spectralis were selected. The presence of hemisphere asymmetry in the same eye and asymmetry between the paired eyes were calculated and used for the analysis. Retinal thickness was measured in 3 different retinal areas (squares): (1) the area (square) involved by the pathology (IA), (2) the specular area (square) in the opposite hemifield (SA), and (3) the corresponding IA in the contralateral eye (CIA) (area used to recruit the patients). Retinal layer morphology was analyzed observing the Spectralis screen. RESULTS: The thickness of the IA was 235.54 +/- 39.95 um (mean +/- standard deviation), while it was 269.84 +/- 36.16 um and 293.81 +/- 37.52 um for SA and CIA, respectively. CONCLUSIONS: Different retinal layers could be involved in reduction of the retinal thickness: a reduction of the inner layers was related to disease in which ciliary or retinal arterial vessel flow was involved, while a reduction of the outer retinal layer was related to pathologies related to choroidal flow diseases. PMID- 25907295 TI - Itraconazole and clarithromycin inhibit P-glycoprotein activity in primary human sinonasal epithelial cells. AB - BACKGROUND: Itraconazole and clarithromycin are clinically effective in the treatment of chronic rhinosinusitis (CRS) through incompletely understood anti inflammatory properties. P-glycoprotein (P-gp) is overexpressed in CRS and inhibition results in decreased inflammatory cytokine secretion. Both itraconazole and clarithromycin have also been shown to have P-gp inhibitory properties in other tissues, suggesting a novel explanation for their immunomodulatory effects in CRS. The purpose of this study is to therefore confirm whether these drugs are capable of inhibiting P-gp specifically in sinonasal epithelial cells. METHODS: This was an institutional review board (IRB) approved study in which primary sinonasal epithelial cells were cultured in 96 well plates. A Calcein AM assay was used to quantify P-gp inhibition as determined by an increase in intracellular fluorescence. A dose-response curve was generated for itraconazole and clarithromycin (maximal concentration 100 MUM) and compared to that of Zosuquidar, a highly specific known P-gp inhibitor. Results were compared using a Student t test with a significance defined as p < 0.05. RESULTS: Both itraconazole and clarithromycin demonstrated a dose-response curve for P-gp inhibition similar to that of Zosuquidar. The respective maximal inhibitory concentrations of Zosuquidar, itraconazole, and clarithromycin prior to induction of cytotoxicity were 0.31, 3.13, and 1.56 MUM, respectively, as demonstrated by a statistically significant increase in total intracellular fluorescence (p < 0.05 in all groups). CONCLUSION: Both itraconazole and clarithromycin are capable of inhibiting sinonasal epithelial cell associated P gp. The anti-inflammatory effects of these agents in CRS may be attributable, in part, to their heretofore unrecognized P-gp modulatory properties. PMID- 25907296 TI - S100A9 promotes human hepatocellular carcinoma cell growth and invasion through RAGE-mediated ERK1/2 and p38 MAPK pathways. AB - S100A9 belongs to the S100 family of calcium-binding proteins and is over expressed in many human tumors including hepatocellular carcinoma (HCC). Recent study demonstrated that S100A9 is significantly elevated and is associated with tumor differentiation and vascular invasion in HCC. The functional role of S100A9 is, however, poorly understood. Here, we demonstrated that S100A9 treatment increased viability, invasiveness and clone formation in three HCC cell lines (HepG2, SMMC-7721 and Huh7). S100A9 also promoted tumor growth in vivo by a xenograft mouse model. In addition, we observed a co-localization of S100A9 with receptor for advanced glycation end products (RAGE) in human HCC intratumoral tissues and an interaction of S100A9 with RAGE in vitro. Treatment with RAGE blocking antibody blocked the enhanced viability, invasion, clone formation and tumor growth in vivo resulted by S100A9, suggesting that these effects were mediated via RAGE ligation. In order to investigate the signaling pathways, mitogen-activated protein kinase (MAPK) phosphorylation was characterized. S100A9 caused a significant increase in p-p38 and p-ERK1/2 levels, and inhibition of which blocked enhanced invasion and viability resulted by S100A9, respectively. Furthermore, treatment with RAGE blocking antibodies also abrogated the S100A9 induced p38 and ERK1/2 activation, suggesting that S100A9-induced MAPK activation is mediated via RAGE ligation. Our data demonstrate that S100A9 binds to RAGE and stimulates RAGE-dependent MAPK signaling cascades, promoting cell growth and invasion in HCC. PMID- 25907298 TI - Serum posaconazole levels during acute myeloid leukaemia induction therapy: correlations with breakthrough invasive fungal infections. AB - The usefulness of posaconazole therapeutic drug monitoring (TDM) is still a matter of debate. A correlation between posaconazole serum levels and breakthrough invasive fungal infections (IFI) has not been clearly demonstrated so far. We analysed posaconazole serum levels in patients with acute myeloid leukaemia (AML) during induction therapy and correlated them with the incidence of breakthrough IFI and the need of systemic antifungal therapy. Overall, 77 AML patients receiving posaconazole were evaluated for serum levels; breakthrough IFI were observed in five with at least one posaconazole TDM (6.5%). Median serum level was 534 ng ml(-1) (IQ range: 298.5-750.5 ng ml(-1) ) and did not change significantly over time. Four of the 40 patients with median posaconazole levels <500 ng ml(-1) developed IFI, as compared with only 1 of the 37 patients with median levels >=500 (10% vs. 2.7%, P = 0.19). Median posaconazole levels on day 7 were 384.5 ng ml(-1) (IQ range: 207-659 ng ml(-1) ) and 560.5 ng ml(-1) (IQ range: 395-756 ng ml(-1) ) in patients requiring or not systemic antifungal treatment respectively (P = 0.067). These results seem to confirm that higher median serum levels of posaconazole correlate with higher prophylactic efficacy against proven/probable IFI and with lesser need of systemic antifungal therapy. PMID- 25907299 TI - Benefits of superdrainage using SIEV in DIEP flap breast reconstruction: A systematic review and meta-analysis. AB - BACKGROUND: Superdrainage using superficial inferior epigastric vein (SIEV) has been often used to overcome occasional venous insufficiency in deep inferior epigastric perforator (DIEP) flap. However, a consensus regarding its clinical benefits is lacking. The aim of this review was to evaluate the efficacy of superdrainage using SIEV on clinical outcome in DIEP flap breast reconstruction by meta-analytic methodology. METHODS: Medline, Ovid and Google Scholar were searched to obtain all relevant publications. Pooled risks for perfusion-related complications were compared between the superdrainage group and control group by Mantel-Haenszel test. RESULTS: Six studies representing 1,376 cases (842 superdrainage and 534 control group) were enrolled, all of which were retrospective cohort studies. Superdrainage had little influence on the risk of total flap loss (RR: 0.97, 95% CI: 0.36-2.57). There were trends toward decreasing risks of partial flap loss (RR: 0.59, 95% CI; 0.18-1.94) and fat necrosis (RR: 0.87, 95% CI: 0.58-1.30) in the superdrainage group, though they were not significant. The risk of partial flap necrosis in which partial flap loss and fat necrosis were combined, was reduced 20% in the superdrainage group, although statistical significance was not achieved (RR: 0.80, 95% CI: 0.57-1.11). The risk of flap congestion decreased significantly in the superdrainage group (RR: 0.06, 95% CI: 0.01-0.51). CONCLUSIONS: Although there is obvious benefit of SIEV superdrainage in reducing the risk of flap congestion, evidence supporting its use to prevent flap compromise is still insufficient. Further studies would be required. (c) 2014 Wiley Periodicals, Inc. Microsurgery 37:75-83, 2017. PMID- 25907297 TI - The progression from a lower to a higher invasive stage of bladder cancer is associated with severe alterations in glucose and pyruvate metabolism. AB - Cancer cells present a particular metabolic behavior. We hypothesized that the progression of bladder cancer could be accompanied by changes in cells glycolytic profile. We studied two human bladder cancer cells, RT4 and TCCSUP, in which the latter represents a more invasive stage. The levels of glucose, pyruvate, alanine and lactate in the extracellular media were measured by Proton Nuclear Magnetic Resonance. The protein expression levels of glucose transporters 1 (GLUT1) and 3 (GLUT3), monocarboxylate transporter 4 (MCT4), phosphofructokinase-1 (PFK1), glutamic-pyruvate transaminase (GPT) and lactate dehydrogenase (LDH) were determined. Our data showed that glucose consumption and GLUT3 levels were similar in both cell lines, but TCCSUP cells displayed lower levels of GLUT1 and PFK expression. An increase in pyruvate consumption, concordant with the higher levels of lactate and alanine production, was also detected in TCCSUP cells. Moreover, TCCSUP cells presented lower protein expression levels of GPT and LDH. These results illustrate that bladder cancer progression is associated with alterations in cells glycolytic profile, namely the switch from glucose to pyruvate consumption in the more aggressive stage. This may be useful to develop new therapies and to identify biomarkers for cancer progression. PMID- 25907300 TI - Fabrication of nanoscale heterostructures comprised of graphene-encapsulated gold nanoparticles and semiconducting quantum dots for photocatalysis. AB - Patterned growth of multilayer graphene shell encapsulated gold nanoparticles (GNPs) and their covalent linking with inorganic quantum dots are demonstrated. GNPs were grown using a xylene chemical vapor deposition process, where the surface oxidized gold nanoparticles catalyze the multilayer graphene shell growth in a single step process. The graphene shell encapsulating gold nanoparticles could be further functionalized with carboxylic groups, which were covalently linked to amine-terminated quantum dots resulting in GNP-quantum dot heterostructures. The compositions, morphologies, crystallinity, and surface functionalization of GNPs and their heterostructures with quantum dots were evaluated using microscopic, spectroscopic, and analytical methods. Furthermore, optical properties of the derived architectures were studied using both experimental methods and simulations. Finally, GNP-quantum dot heterostructures were studied for photocatalytic degradation of phenol. PMID- 25907301 TI - A model for energy transfer in collisions of atoms with highly excited molecules. AB - A model for energy transfer in the collision between an atom and a highly excited target molecule has been developed on the basis of classical mechanics and turning point analysis. The predictions of the model have been tested against the results of trajectory calculations for collisions of five different target molecules with argon or helium under a variety of temperatures, collision energies, and initial rotational levels. The model predicts selected moments of the joint probability distribution, P(Jf,DeltaE) with an R(2) ~ 0.90. The calculation is efficient, in most cases taking less than one CPU-hour. The model provides several insights into the energy transfer process. The joint probability distribution is strongly dependent on rotational energy transfer and conservation laws and less dependent on vibrational energy transfer. There are two mechanisms for rotational excitation, one due to motion normal to the intermolecular potential and one due to motion tangential to it and perpendicular to the line of centers. Energy transfer is found to depend strongly on the intermolecular potential and only weakly on the intramolecular potential. Highly efficient collisions are a natural consequence of the energy transfer and arise due to collisions at "sweet spots" in the space of impact parameter and molecular orientation. PMID- 25907303 TI - Analysis of human triallelic SNPs by next-generation sequencing. AB - Although single-nucleotide polymorphisms (SNPs) have become extremely useful in the study of geneticvariation, triallelic SNPs are still not fully understood. Next-generation sequencing (NGS) is a promising approach to identify triallelic sites in large populations. In this study, we explored exome sequencing data from 221 Chinese individuals, with an average depth of 70-fold. We identified 382,901 SNPs in the study samples, including 2,002 (0.52%) triallelic sites. Among the triallelic SNPs, 17.3% were coding SNPs (cSNPs) and 78.3% were novel. Comparison and analysis revealed that the variant alleles were more likely to result in nonsynonymous variation at triallelic sites. In addition, natural selection seemed to influence triallelic SNPs. However, with the limited sample size assessed, more studies will be required in order to fully characterize the features of triallelic SNPs. PMID- 25907302 TI - Optimal line of hepatotomy for left lateral living donor liver transplantation according to the anatomical variations of left hepatic duct system. AB - Multiple duct anastomoses during LLS transplantation increase the incidence of biliary complications. The optimal plane of hepatotomy that results in the least number of bile ducts at the surface was investigated according to LHD variations. Ducts of 30 human livers were injected with resin and LHD branching on 3D-CT reconstructions were analyzed. Ducts on the virtual hepatotomy surface were estimated in three splitting lines. Variations with subtypes were described. Ia (66.7%): ducts from segments (S.) II-III form a common trunk and S.IV duct joins it. Ib (10%): common trunk formed by ducts from S.II-S.III while S.IV duct joins the common hepatic duct. IIa (16.67%): S.IV duct drains into S.III duct. IIc (3.33%): S.IV duct drains into both S.II and S.III ducts. III (3.33%): trifurcation of S.II, S.III and S.IV ducts. When the virtual hepatotomy line was on the FL, there was a single duct for the anastomosis in 30% of cases but two, three, or four ducts in 53.3%, 10%, and 3.3%, respectively. Division 1 cm to the right of the FL resulted in one duct (70%), but S.IV duct injury may occur. LLS hepatotomy should not necessarily be performed along the FL. Variations must be taken into consideration to minimize the number of biliary anastomoses during liver implantation. PMID- 25907304 TI - EMR of a large, laterally spreading tumor. PMID- 25907305 TI - A rare cause of tarry stool and ileus. PMID- 25907306 TI - Redefining biorefinery: the search for unconventional building blocks for materials. AB - This review discusses different strategies for the upgrading of biomass into sustainable monomers and building blocks as scaffolds for the preparation of green polymers and materials. PMID- 25907307 TI - Insights on beer volatile profile: Optimization of solid-phase microextraction procedure taking advantage of the comprehensive two-dimensional gas chromatography structured separation. AB - The aroma profile of beer is crucial for its quality and consumer acceptance, which is modu-lated by a network of variables. The main goal of this study was to optimize solid-phase microextraction experimental parameters (fiber coating, extraction temperature, and time), taking advantage of the comprehensive two dimensional gas chromatography structured separation. As far as we know, it is the first time that this approach was used to the untargeted and comprehensive study of the beer volatile profile. Decarbonation is a critical sample preparation step, and two conditions were tested: static and under ultrasonic treatment, and the static condition was selected. Considering the conditions that promoted the highest extraction efficiency, the following parameters were selected: poly(dimethylsiloxane)/divinylbenzene fiber coating, at 40oC, using 10 min of pre-equilibrium followed by 30 min of extraction. Around 700-800 compounds per sample were detected, corresponding to the beer volatile profile. An exploratory application was performed with commercial beers, using a set of 32 compounds with reported impact on beer aroma, in which different patterns can be observed through the structured chromatogram. In summary, the obtained results emphasize the potential of this methodology to allow an in-depth study of volatile molecular composition of beer. PMID- 25907308 TI - Fungal colonization of the respiratory tract in allogeneic and autologous hematopoietic stem cell transplant recipients: a study of 573 transplanted patients. AB - BACKGROUND: Fungal colonization and infections remain a major cause of infection morbidity and mortality following hematopoietic stem cell transplantation (HSCT) in patients with hematological malignancies. The aim of this study was to analyze the spectrum of fungal microflora of the respiratory tract (oral cavity, pharynx, epiglottis, and sputum) in patients undergoing HSCT and to evaluate the relationship between HSCT type and incidence of mycotic colonization and infections. MATERIAL/METHODS: Retrospective analysis of fungal isolates collected from the respiratory tract (oral cavity, pharynx, epiglottis, and sputum) of 573 patients undergoing HSCT was performed. RESULTS: The overall rate of fungal colonization in patients undergoing HSCT was 8.7%. Patients undergoing allogeneic HSCT were statistically significantly more often colonized (12.95%) compared to autologous HSCT recipients (4.7%). Colonizing cultures were mainly C. albicans and C. krusei, and sporadically C. glabrata, C. famata, Aspergillus spp. and Saccharomyces cerevisiae. C. albicans was the most frequent species found in isolates from the pharynx, sputum, and oral cavity collected from patients undergoing HSCT. Aspergillosis was more common after allogeneic than after autologous HSCT. The pharynx was the most frequently colonized site. CONCLUSIONS: Allogeneic HSCT recipients are more susceptible to fungal infections compared to the autologous group. Selection of species during prophylaxis and antifungal therapy requires developing more effective prevention and treatment strategies based on new antifungal drugs and microbe-specific diagnoses. PMID- 25907310 TI - Preface. PMID- 25907311 TI - Introduction: Philosophers meet biologists. PMID- 25907309 TI - Deoxynybomycins inhibit mutant DNA gyrase and rescue mice infected with fluoroquinolone-resistant bacteria. AB - Fluoroquinolones are one of the most commonly prescribed classes of antibiotics, but fluoroquinolone resistance (FQR) is widespread and increasing. Deoxynybomycin (DNM) is a natural-product antibiotic with an unusual mechanism of action, inhibiting the mutant DNA gyrase that confers FQR. Unfortunately, isolation of DNM is difficult and DNM is insoluble in aqueous solutions, making it a poor candidate for development. Here we describe a facile chemical route to produce DNM and its derivatives. These compounds possess excellent activity against FQR methicillin-resistant Staphylococcus aureus and vancomycin-resistant Enterococci clinical isolates and inhibit mutant DNA gyrase in-vitro. Bacteria that develop resistance to DNM are re-sensitized to fluoroquinolones, suggesting that resistance that emerges to DNM would be treatable. Using a DNM derivative, the first in-vivo efficacy of the nybomycin class is demonstrated in a mouse infection model. Overall, the data presented suggest the promise of DNM derivatives for the treatment of FQR infections. PMID- 25907312 TI - One-step synthesis of [16]helicene. AB - A single-strand arylene-vinylene precursor containing four phenylene and three naphthylene units linked together with six vinylene spacers undergoes helical folding via sextuple photocyclization to give a [16]helicene core in a single step. The phenylene and naphthylene units are arranged in the precursor such that unfavorable side reactions (anthracene or benzoperylene formation) are avoided, and this is the key to the success of the one-step synthesis of [16]helicene, which is the longest [n]helicene that has been synthesized to date. PMID- 25907314 TI - Blood pressure reference values for normal-weight children: are they necessary? PMID- 25907313 TI - The metabolome profiling and pathway analysis in metabolic healthy and abnormal obesity. AB - OBJECTIVES: Mechanisms of the development of abnormal metabolic phenotypes among obese population are not yet clear. In this study, we aimed to screen metabolomes of both healthy and subjects with abnormal obesity to identify potential metabolic pathways that may regulate the different metabolic characteristics of obesity. METHODS: We recruited subjects with body mass index (BMI) over 25 from the weight-loss clinic of a central hospital in Taiwan. Metabolic healthy obesity (MHO) is defined as without having any form of hyperglycemia, hypertension and dyslipidemia, while metabolic abnormal obesity (MAO) is defined as having one or more abnormal metabolic indexes. Serum-based metabolomic profiling using both liquid chromatography-mass spectrometry and gas chromatography-mass spectrometry of 34 MHO and MAO individuals with matching age, sex and BMI was performed. Conditional logistic regression and partial least squares discriminant analysis were applied to identify significant metabolites between the two groups. Pathway enrichment and topology analyses were conducted to evaluate the regulated pathways. RESULTS: A differential metabolite panel was identified to be significantly differed in MHO and MAO groups, including L-kynurenine, glycerophosphocholine (GPC), glycerol 1-phosphate, glycolic acid, tagatose, methyl palmitate and uric acid. Moreover, several metabolic pathways were relevant in distinguishing MHO from MAO groups, including fatty acid biosynthesis, phenylalanine metabolism, propanoate metabolism, and valine, leucine and isoleucine degradation. CONCLUSION: Different metabolomic profiles and metabolic pathways are important for distinguishing between MHO and MAO groups. We have identified and discussed the key metabolites and pathways that may prove important in the regulation of metabolic traits among the obese, which could provide useful clues to study the underlying mechanisms of the development of abnormal metabolic phenotypes. PMID- 25907315 TI - Aryl hydrocarbon receptor deficiency protects mice from diet-induced adiposity and metabolic disorders through increased energy expenditure. AB - BACKGROUND/OBJECTIVES: Epidemics of obesity and diabetes are escalating. High calorie/high-fat food is a major cause for these global health issues, but molecular mechanisms underlying high-fat, diet-induced obesity are still not well understood. The aryl hydrocarbon receptor (AhR), a transcription factor that acts as a xenobiotic sensor, mediates environmental toxicant-induced obesity, insulin resistance and development of diabetes. AhR also influences lipid metabolism and diet-induced obesity. The effects of AhR deficiency on diet-induced obesity, hepatic steatosis and insulin resistance were examined. METHODS: Male wild-type (WT), AhR null (AhR(-/-)) and AhR heterozygote (AhR(+/-)) mice were fed a normal chow diet (NCD, 10% kcal from fat) or a high-fat diet (HFD, 60% kcal from fat) for up to 14 weeks. Adiposity, adipose and liver morphology, insulin signaling, metabolic parameters and gene profiles were assessed. RESULTS: AhR deficiency protected against HFD-induced obesity, hepatic steatosis, insulin resistance and inflammation. Moreover, AhR deficiency preserved insulin signaling in major metabolic tissues. These protective effects result from a higher energy expenditure in AhR-deficient mice compared with WT. Levels of transcript for both the thermogenic gene, uncoupling protein 1 (Ucp1), in brown adipose tissue and mitochondrial beta-oxidation genes in muscle were significantly higher in AhR(-/ ) and AhR(+/-) mice compared with WT. CONCLUSIONS: This work documents a physiologically relevant function for AhR in regulation of body weight, hepatic fat deposition, insulin sensitivity and energy expenditure under HFD exposure, suggesting that AhR signaling may be developed as a potential therapeutic target for treatment of obesity and metabolic disorders. PMID- 25907316 TI - Clustering of diet, physical activity and sedentary behaviour among Australian children: cross-sectional and longitudinal associations with overweight and obesity. AB - BACKGROUND/OBJECTIVES: Evidence suggests diet, physical activity (PA) and sedentary behaviour cluster together in children, but research supporting an association with overweight/obesity is equivocal. Furthermore, the stability of clusters over time is unknown. The aim of this study was to examine the clustering of diet, PA and sedentary behaviour in Australian children and cross sectional and longitudinal associations with overweight/obesity. Stability of obesity-related clusters over 3 years was also examined. SUBJECTS/METHODS: Data were drawn from the baseline (T1: 2002/2003) and follow-up waves (T2: 2005/2006) of the Health Eating and Play Study. Parents of Australian children aged 5-6 (n=87) and 10-12 years (n=123) completed questionnaires. Children wore accelerometers and height and weight were measured. Obesity-related clusters were determined using K-medians cluster analysis. Multivariate regression models assessed cross-sectional and longitudinal associations between cluster membership, and body mass index (BMI) Z-score and weight status. Kappa statistics assessed cluster stability over time. RESULTS: Three clusters, labelled 'most healthy', 'energy-dense (ED) consumers who watch TV' and 'high sedentary behaviour/low moderate-to-vigorous PA' were identified at baseline and at follow up. No cross-sectional associations were found between cluster membership, and BMI Z-score or weight status at baseline. Longitudinally, children in the 'ED consumers who watch TV' cluster had a higher odds of being overweight/obese at follow-up (odds ratio=2.8; 95% confidence interval: 1.1, 6.9; P<0.05). Tracking of cluster membership was fair to moderate in younger (K=0.24; P=0.0001) and older children (K=0.46; P<0.0001). CONCLUSIONS: This study identified an unhealthy cluster of TV viewing with ED food/drink consumption, which predicted overweight/obesity in a small longitudinal sample of Australian children. Cluster stability was fair to moderate over 3 years and is a novel finding. Prospective research in larger samples is needed to examine how obesity-related clusters track over time and influence the development of overweight and obesity. PMID- 25907317 TI - USP22 promotes tumor progression and induces epithelial-mesenchymal transition in lung adenocarcinoma. AB - OBJECTIVES: Our previous study showed that USP22 as an oncogene may mediate cancer development and progression in NSCLC, but the underlying molecular mechanism remains uncharacterized. Epithelial-mesenchymal transition (EMT) has been reported to play an important role in migration and invasion of the tumor cells. Thus, this study aims to determine the clinical significance and the possible roles of USP22 in EMT and progression of lung adenocarcinoma. METHODS: Immunohistochemistry was used to determine the expression of USP22 in clinical samples. The clinical correlations and prognostic significance of the aberrantly expressed proteins were evaluated by statistical analysis. Moreover, we evaluated whether USP22 could induce EMT in cultured lung cancer cells. RESULTS: The USP22 expression was positive in 76.03% of specimens and was correlated with advanced clinicopathologic classifications (differentiation, T and AJCC stages) and TGF beta1 expression (p=0.008). Multivariate Cox regression analysis revealed that USP22 expression level was an independent prognostic factor for both overall survival and disease-free survival (HR, 2.060; p=0.013 and HR, 1.993; p=0.016). In vitro study revealed that USP22 can regulate proliferation and invasive properties, and induce EMT of lung adenocarcinoma cells. Moreover, USP22 may up regulate TGF-beta1 expression. CONCLUSIONS: Our data indicated that USP22 may promote lung adenocarcinoma cell invasion by the induction of EMT. PMID- 25907318 TI - Insight into extravasation and internalization of nanoparticles. PMID- 25907319 TI - Palladium/Zinc Co-Catalyzed syn-Stereoselectively Asymmetric Ring-Opening Reaction of Oxabenzonorbornadienes with Phenols. AB - A new palladium/zinc co-catalyst system associated with chiral (R)-Difluorphos for asymmetric ring-opening reaction of oxabenzonorbornadienes with phenols is reported. This catalyst system allows the formation of cis-2-aryloxy-1,2 dihydronaphthalen-1-ol products in good yields (up to 95 % yield) with excellent enantioselectivities (up to 99 % ee). The cis-configuration of the product has been confirmed by X-ray crystal structure analysis. To the best of our knowledge, it represents the first example in ring-opening reactions of bicycloalkenes with heteronucleophiles in a syn-stereoselective manner. PMID- 25907320 TI - Synthesis of conducting asymmetric hydrogel particles showing autonomous motion. AB - In the present work, we introduce a new approach for the synthesis of asymmetric particles made from electrically conducting polyaniline-alginate hydrogels by using bipolar electrochemistry. Such an intrinsic break of symmetry allows the soft beads to exhibit tunable motion at the air/water interface when loaded with ethanol due to controllable directed release of the solvent. PMID- 25907321 TI - Gardner's Syndrome revisited: a clinical case and overview of the literature. AB - Gardner's syndrome (GS), a variant of familial adenomatous polyposis (FAP), remains a life-threatening condition of significant dental relevance. Clinicians can play an important role in the identification of this condition as the dental manifestations often precede the development of intestinal polyposis. This article describes a clinical case in which identification of the dental features of GS during routine orthodontic assessment resulted in the early diagnosis of this condition, which was previously unrecognised in a young female patient. PMID- 25907322 TI - Frailty and poor functional status are common in arterial vascular surgical patients and affect postoperative outcomes. AB - OBJECTIVES: Increasing numbers of older people are undergoing emergency and elective arterial vascular procedures. Many older patients are frail which is a recognised predictor of adverse postoperative outcomes in other surgical specialties. This study in older patients undergoing arterial vascular surgery examined; the prevalence of preoperative frailty; the clinical feasibility of preoperatively measuring frailty and functional status; the association between these characteristics and adverse postoperative outcome. METHODS: Prospective observational study in patients aged over 60 years undergoing elective and emergency arterial vascular surgery. Baseline measures of frailty (Edmonton Frail Scale), functional status (gait velocity, timed up and go, hand grip strength) and cognitive function (Montreal Cognitive Assessment) were obtained preoperatively. The primary outcome measure Length of Stay (LOS) and secondary outcome measures of postoperative morbidity (medical and surgical complications), functional status and postoperative in-hospital mortality were recorded. RESULTS: 125 patients were recruited. Frailty was common in this older surgical population (52% EFS score of >= 6.5) with high frailty scores observed (mean EFS 6.6, SD 3.05) and poor functional status (60% had TUG > 15 s, 45% had gait velocity of < 0.6 m/s). Higher preoperative EFS (> 6.5) was univariately associated with longer LOS (>= 12 days), composite measures of postoperative infections, postoperative medical complications and adverse functional outcomes. EFS >= 6.5 was predictive of LOS >= 12 days, adjusted for age (AUC 0.660, CI 0.541-0.779, p = 0.010). This association between EFS >= 6.5 and LOS >= 12 days was strengthened with the addition of MoCA < 24 (AUC 0.695, CI 0.584-0.806, p = 0.002). CONCLUSIONS: Patients aged over 60 years admitted for arterial vascular surgery were frail, had impaired functional status and were cognitively impaired. This combination of preoperative characteristics was predictive of longer hospital length of stay and associated with adverse postoperative outcome. PMID- 25907324 TI - A comparison between one-stage and two-stage procedures for the creation of brachiobasilic arteriovenous fistulas. AB - INTRODUCTION: Vascular access is essential to end-stage renal failure patients requiring haemodialysis. Many patients require multiple fistula formation attempts in order to gain good access, making secondary and tertiary fistula options vital. Brachiobasilic fistulas are well established, but there is little evidence to compare the different surgical techniques in creating them. This study aimed to determine the patency and complication rates associated with these procedures. METHODS: Retrospective data was collected by reviewing case notes to determine fistula survival time and surgical setting. Patency, complications and required interventions were recorded for each group at three time intervals. The Kaplan-Meier method was used to calculate survival for each cohort. RESULTS: 37 brachiobasilic arteriovenous fistulas were created in 35 patients. 17 fistulas were one-stage procedures; 20 fistulas were made in two stages. Survival proportions were measured as 70.6%, 58.8% and 51.5% for the one-stage procedure and 95%, 90% and 78% for the two-stage procedure at 1 month, 1 year and 2 years respectively with p = 0.0385. DISCUSSION: Native brachiobasilic fistulas have advantages over prosthetic grafts. There are technical aspects which make the two staged procedure preferable, including being more amenable to a day case surgery setting. Despite this, there is a lack of relative outcome differences in the literature, thus necessitating further work. CONCLUSION: Our data suggests creation of brachiobasilic fistulas using a two-staged procedure may result in improved patency rates. Complication rates were found to be statistically equivocal, with fistuloplasties and embolectomy shown to be effective in fistula salvage. PMID- 25907323 TI - The potential role of two appetite hormones in the early detection of pancreatic necrosis and severe acute pancreatitis: A biochemical aspect. PMID- 25907325 TI - Should we remove the normal-looking appendix during operations for borderline mucinous ovarian neoplasms?: A retrospective study of 129 cases. AB - INTRODUCTION: The aim of this study was to determine how often the appendix is involved or the primary source of cancer in women undergoing surgery for mucinous borderline ovarian tumour (mBOT) or invasive mucinous ovarian tumour (IMOT) and to evaluate whether appendectomy is necessary. METHODS: The hospital database was searched for women who underwent surgery and whose final diagnosis was mBOT, IMOT or mucinous appendix carcinoma between 1998 and 2014. RESULTS: One hundred and twenty-nine cases were identified, including 69 mBOT, 51 IMOT and nine primary mucinous appendix carcinomas. Of 97 appendectomies performed, nine lymphoid hyperplasia, two mucocele, one carcinoid tumour of the appendix, one mucinous tumour metastasis from the ovary and nine primary mucinous appendix carcinomas were found and all appendices were grossly abnormal. No recurrence was seen during the follow-up period in 28 patients who had no appendectomy performed for grossly normal appendix. Pathologic diagnosis was normal in all 65 patients whose appendix was noted to be grossly normal and who underwent appendectomy. No recurrence was detected during a median follow-up period of 7 years (range 1-16 years).Sensitivity, specificity, positive and negative predictive value of the macroscopic appearance of the appendix were 100%, 86.67%, 56.52% and 100.00%, respectively. DISCUSSION: If the appendix is grossly normal, it appears unnecessary to perform an appendectomy in patients operated for an adnexal mass and whose frozen section analysis was reported as mBOT or IMOT. CONCLUSION: Appendectomy should not be performed if the appendix is grossly normal. PMID- 25907326 TI - Surgical ergonomics. Analysis of technical skills, simulation models and assessment methods. AB - INTRODUCTION: Over the past two centuries the surgical profession has undergone a profound evolution in terms of efficiency and outcomes. Societal concerns in relation to quality assurance, patient safety and cost reduction have highlighted the issue of training expert surgeons. The core elements of a training model build on the basic foundations of gross and fine motor skills. In this paper we provide an analysis of the ergonomic principles involved and propose relevant training techniques. We have endeavored to provide both the trainer and trainee perspectives. METHODS: This paper is structured into four sections: 1) Pre operative preparation issues, 2) technical skills and instrument handling, 3) low fidelity simulation models and 4) discussion of current concepts in crew resource management, deliberate practice and assessment. DISCUSSION: Rehearsal, warm-up and motivation-enhancing techniques aid concentration and focus. Appropriate posture, comprehension of ergonomic principles in relation to surgical instruments and utilisation of the non-dominant hand are essential skills to master. Low fidelity models can be used to achieve significant progress through the early stages of the learning curve. Deliberate practice and innate ability are complementary to each other and may be considered useful adjuncts to surgical skills development. CONCLUSION: Safe medical care requires that complex patient interventions be performed by highly skilled operators supported by reliable teams. Surgical ergonomics lie at the heart of any training model that aims to produce professionals able to function as leaders of a patient safety oriented culture. PMID- 25907327 TI - Walking Clinic in ambulatory surgery--A patient based concept: A Portuguese pioneer project. AB - INTRODUCTION: Walking Clinic is an innovative, efficient and easily reproducible concept adapted to ambulatory surgery. It consists of a preoperative single day work-up, with a surgeon, an anesthetist and a nurse. The aim of this study was to evaluate patient satisfaction and its determinants. METHODS: A survey was applied to 171 patients (101 of the Walking Clinic group and 70 not engaged in this new concept). Patient satisfaction was assessed evaluating five major questionnaire items: secretariat (quality of the information and support given), physical space (overall comfort and cleanliness), nurses and medical staff (willingness and expertise), and patients (waiting time until pre-operative consults and exams, waiting time until being scheduled for surgery, surgery day waiting time and postoperative pain control). Furthermore, overall assessment of the received treatment, and probability of patient recommending or returning to our ambulatory unit were also analyzed. RESULTS: Walking Clinic group had overall better results in the five major questionnaire items assessed, with statistical significance, except for the physical space. It also showed better results regarding the sub items postoperative pain control, waiting time until being scheduled for surgery and surgery day waiting time. DISCUSSION: The results confirm better patient satisfaction with this new concept. CONCLUSION: The Walking Clinic concept complements all the tenets of ambulatory surgery, in a more efficient manner. PMID- 25907328 TI - Is robot-assisted laparoscopic right colectomy more effective than the conventional laparoscopic procedure? A meta-analysis of short-term outcomes. AB - AIM: The use of robotic technology procedures has proved to be safe and effective, arising as a helpful alternative to standard laparoscopic surgery in a variety of colorectal procedures. However, the role of robotic assistance in laparoscopic right colectomy is still not demonstrated. METHODS: A systematic review of the literature was carried out performing an unrestricted search in MEDLINE, EMBASE, the Cochrane Library and Google Scholar up to 30th August 2014. Reference lists of retrieved articles and review articles were manually searched for other relevant studies. We meta-analyzed the currently available data regarding the incidence of anastomotic leakage, operative time, intra-operative blood loss, conversion rate, retrieved lymphnodes, post-operative hemorrhage, intra-abdominal abscess, time to 1st flatus, post-operative ileus, wound infection, incisional hernia, not-surgical complications, total complications, hospital stay, post-operative mortality, surgery-related costs and total costs, in conventional laparoscopic right colectomy (LRC) compared to robot-assisted laparoscopic right colectomy (RRC). RESULTS: Overall 8 studies were included, thus resulting in 616 patients. The meta-analysis showed that the RRC decreases the intra-operative blood loss and the time to the 1st flatus, if compared to the LRC. On the other hand, the robotic assistance increases the operative time and the surgery-related costs. No statistically significant differences were found about the other post-operative outcomes. CONCLUSION: RRC may ensure limited improvements in post-operative outcome, thus increasing procedural costs and without a proved enhanced oncological accuracy to date, if compared to the LRC. PMID- 25907329 TI - Heart rate variability and arterial oxygen saturation response during extreme normobaric hypoxia. AB - The primary purpose of this study was to assess the response of autonomic cardiac activity and changes in the arterial oxygen saturation (SpO2) during normobaric hypoxia and subsequent recovery. Heart rate variability (HRV) and SpO2 were monitored in a supine position during hypoxia (FiO2=9.6%) for 10min, and normoxic recovery in 29 subjects. Spectral analysis of HRV quantified the autonomic cardiac activity by means of low frequency (LF) (0.05-0.15Hz) and high frequency (HF) (0.15-0.50Hz) power transformed by natural logarithm (Ln). Based on the SpO2 response to hypoxia, the subjects were divided into Resistant (RG, SpO2=80.8+/ 7.0%) or Sensitive (SG, SpO2=67.2+/-2.9%) group. The SpO2 and vagal activity (LnHF) significantly decreased during hypoxia in both groups. A withdrawal in vagal activity was significantly greater in SG compared to RG. Moreover, only in SG, a relative increase in sympathetic modulation (Ln LF/HF) during hypoxia occurred. Correlations (r=-0.461, and r=0.595, both P<0.05) between DeltaSpO2 (delta) and DeltaLn LF/HF, and DeltaLnHF were found. Based on results, it seems that SpO2 level could be an important factor that influences the autonomic cardiac response in hypoxia. PMID- 25907330 TI - Biochemical, structural and functional diversity between two digestive alpha amylases from Helicoverpa armigera. AB - BACKGROUND: Helicoverpa armigera (Lepidoptera) feeds on various plants using diverse digestive enzymes as one of the survival tool-kit. The aim of the present study was to understand biochemical properties of recombinant alpha-amylases of H. armigera viz., HaAmy1 and HaAmy2. METHODS: The open reading frames of HaAmy1 and HaAmy2 were cloned in Pichia pastoris and expressed heterologously. Purified recombinant enzymes were characterized for their biochemical and biophysical attributes using established methods. RESULTS: Sequence alignment and homology modeling showed that HaAmy1 and HaAmy2 were conserved in their amino acid sequences and structures. HaAmy1 and HaAmy2 showed optimum activity at 60 degrees C; however, they differed in their optimum pH. Furthermore, HaAmy2 showed higher affinity for starch and amylopectin whereas HaAmy1 had higher catalytic efficiency. HaAmy1 and HaAmy2 were inhibited to the same magnitude by a synthetic amylase inhibitor (acarbose) while wheat amylase inhibitor showed about 2-fold higher inhibition of HaAmy1 than HaAmy2 at pH7 while 6-fold difference at pH11. Interactions of HaAmy1 and HaAmy2 with wheat amylase inhibitor revealed 2:1 stoichiometric ratio and much more complex interaction with HaAmy1. CONCLUSIONS: The diversity of amylases in perspective of their biochemical and biophysical properties, and their differential interactions with amylase inhibitors signify the potential role of these enzymes in adaptation of H. armigera on diverse plant diets. GENERAL SIGNIFICANCE: Characterization of digestive enzymes of H. armigera provides the molecular basis for the polyphagous nature and thus could assist in designing future strategies for the insect control. PMID- 25907332 TI - Formation of fluorophores from the kynurenine pathway metabolite N formylkynurenine and cyclic amines involves transamidation and carbon-carbon bond formation at the 2-position of the amine. AB - BACKGROUND: Tryptophan catabolism along the kynurenine pathway is associated with a number of pathologies including cataract formation and cancer. Whilst the chemical reactions of kynurenine are well studied, less is known about the reactivity of its precursor N-formylkynurenine (NFK). We previously reported the generation of a strong fluorophore in an aqueous reaction of NFK with piperidine, and herein we describe its structure and mechanism of formation. METHODS: Compounds were identified using NMR, mass and UV spectroscopic techniques. The products from the reaction of amines with amino acids were quantified using HPLC MS. RESULTS: The novel fluorophore was identified as a tetrahydroquinolone adduct (PIP-THQ), where piperidine is N-formylated and attached at its 2-position to the quinolone. NFK is initially deaminated to generate an unsaturated enone, which forms an adduct with piperidine and is subsequently converted into the fluorophore. Testing of a variety of other secondary amines showed that only cyclic amines unsubstituted at both positions adjacent to nitrogen could form fluorophores efficiently. The amino acids tryptophan and kynurenine, which lack the formamide group do not form such fluorophores. CONCLUSIONS: NFK forms fluorophores in a not previously published reaction with cyclic amines. GENERAL SIGNIFICANCE: Our study is the first to provide evidence for concurrent transamidation and substitution at the 2-position of a cyclic amine occurring under moderately-heated aqueous conditions with no added catalysts. The high reactivity of NFK demonstrated here could result in formation of biologically relevant metabolites yet to be characterised. PMID- 25907331 TI - A comprehensive glycome profiling of Huntington's disease transgenic mice. AB - BACKGROUND: Huntington's disease (HD) is an autosomal, dominantly inherited and progressive neurodegenerative disease, nosologically classified as the presence of intranuclear inclusion bodies and the loss of GABA-containing neurons in the neostriatum and subsequently in the cerebellar cortex. Abnormal processing of neuronal proteins can result in the misfolding of proteins and altered post translational modification of newly synthesized proteins. Total glycomics, namely, N-glycomics, O-glycomics, and glycosphingolipidomics (GSL-omics) of HD transgenic mice would be a hallmark for central nervous system disorders in order to discover disease specific biomarkers. METHODS: Glycoblotting method, a high throughput glycomic protocol, and matrix-assisted laser desorption ionization time of flight/mass spectrometry (MALDI-TOF/MS) were used to study the total glycome expression levels in the brain tissue (3 mice of each sex) and sera (5 mice of each sex) of HD transgenic and control mice. All experiments were performed twice and differences in the expression levels of major glycoforms were compared between HD transgenic and control mice. RESULTS: We estimated the structure and expression levels of 87 and 58N-glycans in brain tissue and sera, respectively, of HD transgenic and control mice. The present results clearly indicated that the brain glycome and their expression levels are significantly gender specific when compared with those of other tissues and serum. Core fucosylated and bisecting-GlcNAc types of N-glycans were found in increased levels in the brain tissue HD transgenic mice. Accordingly, core-fucosylated and sialic acid (particularly N-glycolylneuraminic acid, NeuGc) for biantennary type glycans were found in increased amounts in the sera of HD transgenic mice compared to that of control mice. Core 3 type O-glycans were found in increased levels in male and in decreased levels in both the striatum and cortexes of female HD transgenic mice. Furthermore, serum levels of core 1 type O-glycans decreased and were undetected for core 2 type O-glycans for HD transgenic mice. In glycosphingolipids, GD1a in brain tissue and GM2-NeuGc serum levels were found to have increased and decreased, respectively, in HD transgenic mice compared to those of the control group mice. CONCLUSION: Total glycome expression levels are significantly different between HD transgenic and control group mice. GENERAL SIGNIFICANCE: Glycoblotting combined with MALDI-TOF/MS total glycomics warrants a comprehensive, effective, novel and versatile technique for qualitative and quantitative analysis of total glycome expression levels. Furthermore, glycome focused studies of both environmentally and genetically rooted neurodegenerative diseases are promising candidates for the discovery of potential disease glyco biomarkers in the post-genome era. PMID- 25907333 TI - Child welfare services involvement among the children of young parents in foster care. AB - Despite the high rate of early parenthood among youth in foster care as well as the increased risk of child maltreatment among children whose adolescent parents have been neglected or abused, very little is known about child welfare services involvement among children whose parents were in foster care when they were born. This study uses administrative data from the Illinois Department of Children and Family Services (DCFS) to examine the occurrence of child abuse and neglect investigations, indicated reports and out of home care placements among the children of youth in foster. Thirty-nine percent of the children were the subject of at least one CPS investigation, 17 percent had at least one indicated report and 11 percent were placed in out of home care at least once before their 5th birthday. Cox proportional hazard models are also estimated to identify characteristics of parenting foster youth and their placement histories associated with the risk of child welfare services involvement. Implications of the findings for policy and practice are discussed. PMID- 25907334 TI - Future treatment of gonorrhea--novel emerging drugs are essential and in progress? PMID- 25907337 TI - Dirk Gevers. PMID- 25907335 TI - IGF-1 levels across the spectrum of normal to elevated in acromegaly: relationship to insulin sensitivity, markers of cardiovascular risk and body composition. AB - PURPOSE: Activity of acromegaly is gauged by levels of GH and IGF-1 and epidemiological studies demonstrate that their normalization reduces acromegaly's excess mortality rate. However, few data are available linking IGF-1 levels to features of the disease that may relate to cardiovascular (CV) risk. Therefore, we tested the hypothesis that serum IGF-1 levels relative to the upper normal limit relate to insulin sensitivity, serum CV risk markers and body composition in acromegaly. METHODS: In this prospective, cross-sectional study conducted at a pituitary tumor referral center we studied 138 adult acromegaly patients, newly diagnosed and previously treated surgically, with fasting and post-oral glucose levels of endocrine and CV risk markers and body composition assessed by DXA. RESULTS: Active acromegaly is associated with lower insulin sensitivity, body fat and CRP levels than acromegaly in remission. %ULN IGF-1 strongly predicts insulin sensitivity, better than GH and this persists after adjustment for body fat and lean tissue mass. %ULN IGF-1 also relates inversely to CRP levels and fat mass, positively to lean tissue and skeletal muscle estimated (SM(E)) by DXA, but not to blood pressure, lipids, BMI or waist circumference. Gender interacts with the IGF-1-lean tissue mass relationship. CONCLUSIONS: Active acromegaly presents a unique combination of features associated with CV risk, reduced insulin sensitivity yet lower body fat and lower levels of some serum CV risk markers, a pattern that is reversed in remission. %ULN IGF-1 levels strongly predict these features. Given the known increased CV risk of active acromegaly, these findings suggest that of these factors insulin resistance is most strongly related to disease activity and potentially to the increased CV risk of active acromegaly. PMID- 25907340 TI - Cancer immunotherapy: Primed for a response. PMID- 25907341 TI - Cancer: Multifunctional nanodevice reverses drug resistance. PMID- 25907342 TI - Anticancer drugs: Advancing precision medicine in silico. PMID- 25907343 TI - CNS injury: Microtubule stabilizer repairs spinal cord injury. PMID- 25907345 TI - Cardiovascular disease: PDE9A inhibition mends broken hearts. PMID- 25907347 TI - Sexual health risks, service use, and views of rapid point-of-care testing among men who have sex with men attending saunas: a cross-sectional survey. AB - Guidelines highlight the need to increase HIV testing among men who have sex with men (MSM) and novel point-of-care testing provides new possibilities for delivery of care. However, it is unclear how point-of-care testing should be used to best effect. This study aimed to increase understanding of sexual risk-taking behaviour, service use, and attitudes to point-of-care testing among MSM sauna clients. Data were collected within two saunas for MSM in south west England using a self-completion survey (n = 134). Though this sample of MSM sauna clients are at high risk of acquiring a sexually transmitted infection, the testing frequency among the majority of those reporting unprotected anal intercourse is not in keeping with national guidelines. For almost all participants the introduction of rapid point-of-care testing for both genital and blood-borne infection was likely to increase testing and for the majority NHS specialist services was the preferred setting. PMID- 25907346 TI - Predicting drug metabolism: experiment and/or computation? AB - Drug metabolism can produce metabolites with physicochemical and pharmacological properties that differ substantially from those of the parent drug, and consequently has important implications for both drug safety and efficacy. To reduce the risk of costly clinical-stage attrition due to the metabolic characteristics of drug candidates, there is a need for efficient and reliable ways to predict drug metabolism in vitro, in silico and in vivo. In this Perspective, we provide an overview of the state of the art of experimental and computational approaches for investigating drug metabolism. We highlight the scope and limitations of these methods, and indicate strategies to harvest the synergies that result from combining measurement and prediction of drug metabolism. PMID- 25907348 TI - The utility of population-based surveys to describe the continuum of HIV services for key and general populations. AB - Monitoring the cascade or continuum of HIV services - ranging from outreach services to anti-retroviral treatment - has become increasingly important as the focus in prevention moves toward biomedical interventions, in particular, 'Treatment as Prevention.' The HIV continuum typically utilises clinic-based care and treatment monitoring data and helps identify gaps and inform programme improvements. This paper discusses the merits of a population-based survey informed continuum of services. Surveys provide individual-level, population based data by sampling persons both in and outside the continuum, which facilitate the estimation of population fractions, such as the proportion of people living with HIV in care, as well as the examination of determinants for being in or outside the continuum. Survey-informed cascades of services may especially benefit key populations at increased risk for HIV infection for who social marginalisation, criminalisation, and stigma result in barriers to access and retention in services, a low social visibility, mobility, and outreach-based services can compromise clinic-based monitoring. Adding CD4+ T-cell count and viral load measurements to such surveys may provide population-level information on viral load suppression, stage of disease, treatment needs, and population level transmission potential. While routine clinic-based reporting will remain the mainstay of monitoring, a survey-informed service cascade can address some of its limitations and offer additional insights. PMID- 25907349 TI - A Complication of Posterior Malleolar Fracture Fixation. AB - We present a case of tibial nerve impingement by an anteroposterior screw inserted for stabilization of a posterior malleolar fracture. This specific complication has not previously been described in published studies, although numerous reports have described various forms of peripheral nerve entrapment. We discuss the merits of fixation of these fractures using a posterolateral approach. PMID- 25907350 TI - Therapeutic effect of Avonex, Rebif and Betaferon on quality of life in multiple sclerosis. AB - AIMS: The aim of this study was to evaluate the effect of various disease modifying therapies (DMT) on quality of life in multiple sclerosis (MS). METHODS: This was a three-arm parallel study with balanced randomization in which 90 newly diagnosed, definite MS subjects referred to Ghaem Medical Center, Mashhad, Iran were enrolled between 2006 and 2009. Patients were randomly allocated into three DMT groups: Avonex, Rebif and Betaferon. Health-related quality of life was assessed in MS patients at baseline and 12 months after treatment with DMT using the MS Quality of Life-54 questionnaire. RESULTS: Both mental and physical health scores improved within all three treatment groups after 12 months of treatment; however, this increase was only significant in the mental health composite in the Betaferon group (P = 0.024). Betaferon had the highest mental health score change (14.04) while this change was 7.26 for Avonex (P = 0.031) and 5.08 for Rebif (P = 0.017). A physical health composite score comparison among the three treatment groups revealed no significant results. CONCLUSIONS: With a positive impact of DMT on mental and physical dimensions of QOL in MS patients, initiation of treatment soon after diagnosis is recommended. In MS patients with more mental issues and fewer physical disabilities, Betaferon might be considered as a better choice of treatment. PMID- 25907351 TI - Highly efficient quenching of tris(2,2'-bipyridyl)ruthenium(II) electrochemiluminescence by ozone using formaldehyde, methylglyoxal, and glyoxalate as co-reactants and its application to ozone sensing. AB - Most electrochemiluminescence (ECL) systems require high concentrations of quencher to totally quench ECL. In this study, we found that ozone can quench tris(2,2'-bipyridyl)ruthenium(II) ECL using formaldehyde, methylglyoxal, or glyoxalate as co-reactants at a glassy carbon electrode with remarkable efficiencies even when the concentration of ozone is merely 0.25% of that of the co-reactant. The strongest quenching is observed with the tris(2,2' bipyridyl)ruthenium(II)/formaldehyde ECL system. The tris(2,2' bipyridyl)ruthenium(II)/formaldehyde ECL intensities decrease linearly with the ozone concentration over the range of 0.025-25 MUM (r = 0.9947) with a limit of detection of 8 nM. The method is more sensitive and faster than most methods. It shows high selectivity in the presence of other ROS or oxidants and some metal ions, such as H2O2, ClO(-), Mg(2+), Ni(2+), etc. The method exhibits high recoveries for the detection of ozone in a ventilated photocopy room. PMID- 25907352 TI - Diagnostic and prognostic significance of ischemic electrocardiographic changes with regadenoson-stress myocardial perfusion imaging. AB - BACKGROUND: The diagnostic and prognostic value of regadenoson-induced ST-segment depression (ST?) is not defined. Due to the low incidence of ST? >=1.0 mm with vasodilator stress, a lower threshold to define ischemic ECG response may provide improved clinical utility. METHODS: We conducted a retrospective cohort study of patients who underwent regadenoson-stress SPECT myocardial perfusion imaging (MPI) followed by coronary angiography within 6 months. Ischemic ST? was defined as >=0.5 mm. The prevalence of angiographically severe coronary artery disease (CAD) and the rates of major adverse cardiac events (MACE) including cardiac death, myocardial infarction, and coronary revascularization were determined. RESULTS: In a diagnostic cohort of 629 subjects, 117 (18.6%) had ST? >=0.5 mm. Severe CAD was more prevalent in the ST? >=0.5 vs ST <0.5 group (13.7% vs 5.3%, P = .001). Among patients with normal MPI (n = 229), the prevalence of severe CAD was higher in the ST? >=0.5 group (8.2% vs 2.2%, P = .04). Adjusting for clinical and imaging covariates, ST? >=0.5 mm was independently predictive of severe CAD [odds ratio = 3.37, 95% confidence interval (CI) = 1.67-6.83, P = .001], and provided incremental diagnostic value (Chi square increment = 10.3, P = .001). In an outcome cohort of 748 subjects, after adjusting for clinical and imaging covariates, ST? >=0.5 mm was associated with increased MACE rate in the entire cohort [hazard ratio = 1.41, CI 1.01-1.96, P = .04] and in the subgroup of patients with normal MPI [hazard ratio = 2.2, CI 1.11-4.39, P = .02], and provided incremental prognostic value (Chi square increment = 3.9, P = .049). A diagnostic ST? threshold of 0.5 mm provided greater discriminatory capacity than a 1.0 mm cutoff (P = .03). CONCLUSIONS: Among patients selected to undergo coronary angiography, regadenoson-induced ST? >=0.5 mm was associated with higher rates of severe CAD and MACE, irrespective of MPI finding. PMID- 25907353 TI - Proceedings of the Cardiac PET Summit, 12 May 2014, Baltimore, MD : 3: Quantitation of myocardial blood flow. PMID- 25907354 TI - Proceedings of the ASNC Cardiac PET Summit, 12 May 2014, Baltimore, MD : 1: The value of PET: Integrating cardiovascular PET into the care continuum. PMID- 25907355 TI - Proceedings of the ASNC Cardiac PET Summit, 12 May 2014, Baltimore, MD. PMID- 25907356 TI - Fasciola hepatica: comparative metacercarial productions in experimentally infected Galba truncatula and Pseudosuccinea columella. AB - As large numbers of metacercariae of Fasciola hepatica are necessary for research, experimental infections of Galba truncatula and Pseudosuccinea columella with this digenean were carried out to determine the better intermediate host for metacercarial production and, consequently, the most profitable snail for decreasing the cost price of these larvae. Pre-adult snails (4 mm in shell height) originating from two populations per lymnaeid species were individually exposed to two or five miracidia, raised at 23 degrees C and followed for cercarial shedding up to their death. Compared to values noted in G. truncatula, the survival of P. columella on day 30 post-exposure was significantly greater, while the prevalence of F. hepatica infection was significantly lower. In the four P. columella groups, metacercarial production was significantly greater than that noted in the four groups of G. truncatula (347-453 per cercariae-shedding snail versus 163-275, respectively). Apart from one population of G. truncatula, the use of five miracidia per snail at exposure significantly increased the prevalence of F. hepatica in P. columella and the other population of G. truncatula, whereas it did not have any clear effect on the mean number of metacercariae. The use of P. columella for experimental infections with F. hepatica resulted in significantly higher metacercarial production than that noted with G. truncatula, in spite of a lower prevalence for the former lymnaeid. This finding allows for a significant decrease in the cost price of these larvae for commercial production. PMID- 25907357 TI - Dye-controlled interfacial electron transfer for high-current indium tin oxide photocathodes. AB - Efficient sensitized photocathodes are highly desired for solar fuels and tandem solar cells, yet the development is hindered by the scarcity of suitable p-type semiconductors. The generation of high cathodic photocurrents by sensitizing a degenerate n-type semiconductor (tin-doped indium oxide; ITO) is reported. The sensitized mesoporous ITO electrodes deliver cathodic photocurrents of up to 5.96+/-0.19 mA cm(-2), which are close to the highest record in conventional p type sensitized photocathodes. This is realized by the rational selection of dyes with appropriate energy alignments with ITO. The energy level alignment between the highest occupied molecular orbital of the sensitizer and the conduction band of ITO is crucial for efficient hole injection. Transient absorption spectroscopy studies demonstrate that the cathodic photocurrent results from reduction of the photoexcited sensitizer by free electrons in ITO. Our results reveal a new perspective toward the selection of electrode materials for sensitized photocathodes. PMID- 25907358 TI - Subfactors of oppositional defiant disorder: converging evidence from structural and latent class analyses. AB - BACKGROUND: Structural models of oppositional defiant disorder (ODD) symptoms have gained empirical support but await greater empirical scrutiny on issues such as reconciliation between competing models, evidence for gender differences, and delineation of external correlates. More extensive validation evidence is particularly necessary in consideration of their incorporation in psychiatric nomenclature. METHODS: We fitted previously proposed, but competing, models to ODD symptoms assessed with the Computerized Diagnostic Interview Schedule for Children (Shaffer et al., 2000, J. Am. Acad. Child Adolesc. Psychiatry, 39, 28) in a community sample and then fitted the best-fitting model in a replication sample (combined N = 730, Mage = 9.89, SD = 0.75). Analyses also examined potential classes based on resulting subfactors, gender differences, longitudinal associations with later behavioral problems, and concurrent personality associations. RESULTS: Burke's (2010) two-factor model composed of Irritability and Oppositionality subfactors best fit the data. Irritability and Oppositionality showed convergent and divergent patterns of association with personality traits at T1 and with externalizing and internalizing problems at T2. Latent class analyses revealed three classes (low severity, irritable/combined, and oppositional) which showed parallel divergence in externalizing and internalizing problem comorbidity. These findings were largely robust across gender and samples. CONCLUSIONS: These findings support Irritability/Oppositionality subfactors of ODD in two mixed-gender samples, demonstrate strong evidence for a lack of gender differences in such subfactors, and demonstrate their convergent and divergent validity in emergent latent classes, later behavioral problems, and personality correlates. PMID- 25907359 TI - Long-term atorvastatin-ezetimibe-probucol triple therapy for homozygous familial hypercholesterolaemia from early childhood. AB - In this observational case report, we share our experience of achieving >40% LDL cholesterol reduction in four Chinese homozygous familial hypercholesterolaemia children below 8 years of age with a triple combination of atorvastatin, probucol, and ezetimibe for >6 years. Within a follow-up duration of 6-13 years, this triple therapy achieved significant reduction of LDL cholesterol as well as an impressive regression of xanthomas in all paediatric cases. All the children remained free from treatment-related adverse responses and cardiovascular events throughout follow-up. PMID- 25907360 TI - Prognostic factors, patterns of recurrence and toxicity for patients with esophageal cancer undergoing definitive radiotherapy or chemo-radiotherapy. AB - The aim of this study was to evaluate the effectiveness and tolerability of definitive chemo-radiation or radiotherapy alone in patients with esophageal cancer. We retrospectively analyzed the medical records of n = 238 patients with squamous cell carcinoma or adenocarcinoma of the esophagus treated with definitive radiotherapy with or without concomitant chemotherapy at our institution between 2000 and 2012. Patients of all stages were included to represent actual clinical routine. We performed univariate and multivariate analysis to identify prognostic factors for overall survival (OS) and progression free survival (PFS). Moreover, treatment-related toxicity and patterns of recurrence were assessed. Patients recieved either chemo-radiation (64%), radiotherapy plus cetuximab (10%) or radiotherapy alone (26%). In 69%, a boost was applied, resulting in a median cumulative dose of 55.8 Gy; the remaining 31% received a median total dose of 50 Gy. For the entire cohort, the median OS and PFS were 15.0 and 11.0 months, respectively. In multivariate analysis, important prognostic factors for OS and PFS were T stage (OS: P = 0.005; PFS: P = 0.006), M stage (OS: P = 0.015; PFS: P = 0.003), concomitant chemotherapy (P < 0.001) and radiation doses of >55 Gy (OS: P = 0.019; PFS: P = 0.022). Recurrences occurred predominantly as local in-field relapse or distant metastases. Toxicity was dominated by nutritional impairment (12.6% with G3/4 dysphagia) and chemo associated side effects. Definitive chemo-radiation in patients with esophageal cancer results in survival rates comparable with surgical treatment approaches. However, local and distant recurrence considerably restrict prognosis. Further advances in radio-oncological treatment strategies are necessary for improving outcome. PMID- 25907362 TI - Handheld fluorescence imaging device detects subclinical wound infection in an asymptomatic patient with chronic diabetic foot ulcer: a case report. AB - Chronic wounds are a significant burden to global patient and health care infrastructures, and there is a need for better methods of early wound diagnosis and treatment. Traditional diagnosis of chronic wound infection by pathogenic bacteria, using clinical signs and symptoms, is based on visual inspection under white light and microbiological sampling (e.g. swabbing and/or biopsy) of the wound, which are subjective and suboptimal. Diagnosing microbial infection based on traditional clinical signs and symptoms in wounds of asymptomatic patients is especially challenging at the bedside. Bacteria are invisible to the unaided eye and wound sampling for diagnostic testing can cause unacceptable delays in diagnosis and treatment. To address this problem, we developed a new prototype handheld, portable fluorescence imaging device that enables non-contact, real time, high-resolution visualisation of pathogenic bacteria and tissues in wounds. Herein, we report the clinical use of this imaging device in detecting subsurface heavy bacterial load and subclinical local infection in an asymptomatic 50-year old patient with a non-healing diabetic foot ulcer. PMID- 25907361 TI - Further Confirmation of Germline Glioma Risk Variant rs78378222 in TP53 and Its Implication in Tumor Tissues via Integrative Analysis of TCGA Data. AB - We confirmed strong association of rs78378222:A>C (per allele odds ratio [OR] = 3.14; P = 6.48 * 10(-11) ), a germline rare single-nucleotide polymorphism (SNP) in TP53, via imputation of a genome-wide association study of glioma (1,856 cases and 4,955 controls). We subsequently performed integrative analyses on the Cancer Genome Atlas (TCGA) data for GBM (glioblastoma multiforme) and LUAD (lung adenocarcinoma). Based on SNP data, we imputed genotypes for rs78378222 and selected individuals carrying rare risk allele (C). Using RNA sequencing data, we observed aberrant transcripts with ~3 kb longer than normal for those individuals. Using exome sequencing data, we further showed that loss of haplotype carrying common protective allele (A) occurred somatically in GBM but not in LUAD. Our bioinformatic analysis suggests rare risk allele (C) disrupts mRNA termination, and an allelic loss of a genomic region harboring common protective allele (A) occurs during tumor initiation or progression for glioma. PMID- 25907363 TI - Biocompatible polymer-Peptide hybrid-based DNA nanoparticles for gene delivery. AB - Currently, research on polymers to be used as gene delivery systems is one of the most important directions in both polymer science and biomedicine. In this report, we describe a five-step procedure to synthesize a novel polymer-peptide hybrid system for gene transfection. The block copolymer based on the biocompatible polymer poly(2-methyl-2-oxazoline) (PMOXA) was combined with the biocleavable peptide block poly(aspartic acid) (PASP) and finally modified with diethylenetriamine (DET). PMOXA-b-PASP(DET) was produced in high yield and characterized by (1)H NMR and FT-IR. Our biopolymer complexed plasmid DNA (pDNA) efficiently, and highly uniform nanoparticles with a slightly negative zeta potential were produced. The polymer-peptide hybrid system was able to efficiently transfect HEK293 and HeLa cells with GFP pDNA in vitro. Unlike the commonly used polymer, 25 kDa branched poly(ethylenimine), our biopolymer had no adverse effects on cell growth and viability. In summary, the present work provides valuable information for the design of new polymer-peptide hybrid-based gene delivery systems with biocompatible and biodegradable properties. PMID- 25907365 TI - Synthesis of a hexahydropyrrolo indole (HPI) compound library. AB - Scaffolds of natural products represent promising starting points for the development of focused compound libraries. Here, we describe the development of a synthetic route to a compound library based on the hexahydropyrrolo indole (HPI) scaffold, the denoting structural motif of the HPI natural product family. To this end, a two-step approach consisting of a batch synthesis of an advanced functionalizable HPI intermediate followed by the establishment of reaction conditions that allow derivatization of this scaffold at three different positions is described. Subsequently, the optimized methods were applied to the synthesis of a 276-member library. PMID- 25907364 TI - A potent and selective inhibitor for the UBLCP1 proteasome phosphatase. AB - The ubiquitin-like domain-containing C-terminal domain phosphatase 1 (UBLCP1) has been implicated as a negative regulator of the proteasome, a key mediator in the ubiquitin-dependent protein degradation. Small molecule inhibitors that block UBLCP1 activity would be valuable as research tools and potential therapeutics for human diseases caused by the cellular accumulation of misfold/damaged proteins. We report a salicylic acid fragment-based library approach aimed at targeting both the phosphatase active site and its adjacent binding pocket for enhanced affinity and selectivity. Screening of the focused libraries led to the identification of the first potent and selective UBLCP1 inhibitor 13. Compound 13 exhibits an IC50 of 1.0MUM for UBLCP1 and greater than 5-fold selectivity against a large panel of protein phosphatases from several distinct families. Importantly, the inhibitor possesses efficacious cellular activity and is capable of inhibiting UBLCP1 function in cells, which in turn up-regulates nuclear proteasome activity. These studies set the groundwork for further developing compound 13 into chemical probes or potential therapeutic agents targeting the UBLCP1 phosphatase. PMID- 25907366 TI - Discovery of oxime-bearing naphthalene derivatives as a novel structural type of Nrf2 activators. AB - Recent studies have demonstrated that oxidative stress insult is one of major causes of tumor formation. Therefore, identify the effective anti-oxidative agents as a preventive approach to stop cancer progression has widely explored. Although, many potent anti-oxidative ingredients in the natural products have been identified but the amount from the nature source hindrances the clinical application. Compound which can activate Nrf2 signaling pathway result unregulated the cellular antioxidant-responses has been demonstrated as an effective chemopreventive approach for cancer treatment. In the present study, certain oxime-bearing naphthalene derivatives were synthesized and evaluated for their Nrf2 activation and anti-proliferative activities. Results indicated (E)-1 (naphthalen-2-yloxy)propan-2-one oxime (11) which increased 2.04-fold Nrf2/ARE driven luciferase activity was more active than its 1-substituted isomer 10 (1.17 fold) and t-BHQ (1.77-fold), the known Nrf2 activator. The activities were further increased by the replacement of the peripheral methyl group with the phenyl ring in which (Z)-2-(naphthalen-2-yloxy)-1-phenylethanone oxime (13a) exhibited 3.49-fold potency of the positive control. It is worth to mention that compounds 11, 13a, and 13b which showed significant Nrf2 activation are non cytotoxic to the tested cells with IC50>50MUM. This observation strongly suggested that these compounds can be used for chemoprevention. Mechanism studies indicated that these compounds were capable of inducing the phosphorylation of Nrf2 protein at serine 40 which led to the activation of the Nrf2 transcriptional activity. PMID- 25907367 TI - Light-switched inhibitors of protein tyrosine phosphatase PTP1B based on phosphonocarbonyl phenylalanine as photoactive phosphotyrosine mimetic. AB - Phosphopeptide mimetics containing the 4-phosphonocarbonyl phenylalanine (pcF) as a photo-active phosphotyrosine isoster are developed as potent, light-switchable inhibitors of the protein tyrosine phosphatase PTP1B. The photo-active inhibitors 6-10 are derived from phosphopeptide substrates and are prepared from the suitably protected pcF building block 12 by Fmoc-based solid phase peptide synthesis. All pcF-containing peptides are moderate inhibitors of PTP1B with KI values between 10 and 50MUM. Irradiation of the inhibitors at 365nm in the presence of the protein PTP1B amplify the inhibitory activity of pcF-peptides up to 120-fold, switching the KI values of the best inhibitors to the sub-micromolar range. Photo-activation of the inhibitors results in the formation of triplet intermediates of the benzoylphosphonate moiety, which deactivate PTP1B following an oxidative radical mechanism. Deactivation of PTP1B proceeds without covalent crosslinking of the protein target with the photo-switched inhibitors and can be reverted by subsequent addition of reducing agent dithiothreitol (DTT). PMID- 25907368 TI - Synthesis and discovery of (I-3,II-3)-biacacetin as a novel non-zinc binding inhibitor of MMP-2 and MMP-9. AB - Eleven biflavones (7a-b and 9a-i) were synthesised by a simple and efficient protocol and screened for MMP-2 and MMP-9 inhibitory activities. Amongst them, a natural product-like analog, (I-3,II-3)-biacacetin (9h) was found to be the most potent inhibitor. Molecular docking studies suggest that unlike most of the known inhibitors, 9h inhibits MMP-2 and MMP-9 through non-zinc binding interactions. PMID- 25907369 TI - Selaginellin and biflavonoids as protein tyrosine phosphatase 1B inhibitors from Selaginella tamariscina and their glucose uptake stimulatory effects. AB - As part of an ongoing search for new antidiabetic agents from medicinal plants, the methanol extract of the aerial parts of Selaginella tamariscina was found to possess stimulatory effect on glucose uptake in 3T3-L1 adipocyte cells. Thus, bioassay-guided isolation of this active extract yielded two new compounds (1 and 2) along with five known biflavonoids (3-7). Their structures were elucidated by extensive analysis of spectroscopic and physicochemical data. The absolute configuration of compound 2 was determined by specific rotation and CD data analysis. All isolates exhibited potent inhibitory effects on PTP1B enzyme with IC50 values ranging from 4.5+/-0.1 to 13.2+/-0.8MUM. Furthermore, the isolates (1 7) showed significant stimulatory effects on 2-NBDG uptake in 3T3-L1 adipocyte cells. Of these, compounds (1, 6, and 7) which exhibited mixed-competitive inhibition modes against PTP1B, showed potent stimulatory effects on 2-NBDG uptake. This result indicated the potential of these biflavonoids as lead molecules for development of antidiabetic agents and the beneficial use of S. tamariscina against hyperglycemia. PMID- 25907370 TI - Anti-HIV diarylpyrimidine-quinolone hybrids and their mode of action. AB - A molecular hybridization approach is a powerful tool in the design of new molecules with improved affinity and efficacy. In this context, a series of diarylpyrimidine-quinolone hybrids were synthesized and evaluated against both wt HIV-1 and mutant viral strains. The most active hybrid 5a displayed an EC50 value of 0.28+/-0.07MUM against HIV-1 IIIB. A couple of enzyme-based assays clearly pinpoint a RT-targeted mechanism of action. Docking studies revealed that these hybrids could be well located in the NNIBP of HIV-1 RT despite the bulky and polar properties of a quinolone 3-carboxylic acid moiety in the molecules. PMID- 25907371 TI - Connecting prosocial behavior to improved physical health: Contributions from the neurobiology of parenting. AB - Although a growing body of evidence suggests that giving to (helping) others is linked reliably to better health and longevity for the helper, little is known about causal mechanisms. In the present paper we use a recently developed model of caregiving motivation to identify possible neurophysiological mechanisms. The model describes a mammalian neurohormonal system that evolved to regulate maternal care, but over time may have been recruited to support a wide variety of helping behaviors in humans and other social animals. According to the model, perception of need or distress in others activates caregiving motivation, which in turn, can facilitate helping behavior. Motivational regulation is governed by the medial preoptic area of the hypothalamus, interacting with certain other brain regions, hormones, and neuromodulators (especially oxytocin and progesterone). Consideration of neurohormonal circuitry and related evidence raises the possibility that it is these hormones, known to have stress-buffering and restorative properties, that are responsible, at least in part, for health and longevity benefits associated with helping others. PMID- 25907372 TI - Becoming "someone" or "something". PMID- 25907373 TI - The need for a multidisciplinary approach to pain management in advanced cancer: A clinical case. AB - Advanced cancer patients are often affected by multiple complex symptoms brought about by persistent nociceptive stimuli and intense psychosocial distress. One such complex symptom, cancer pain, has continued to pose a challenge in medical management even though the concept of total pain was described several years ago by Cicely Saunders. Oftentimes, the application of a multidisciplinary approach is delayed after numerous opioid dose escalations and invasive procedures have been performed. The case presented here highlights the importance of timely multidisciplinary intervention and the use of an acute palliative care unit, which resulted in adequate pain control after multiple medical and invasive procedures that caused toxicities. PMID- 25907374 TI - Potential risk of misclassification HCV 2k/1b strains as HCV 2a/2c using VERSANT HCV Genotype 2.0 assay. AB - The performance of a hepatitis C virus (HCV) NS5B sequencing method described by Murphy et al. (Use of sequence analysis of the NS5B region for routine genotyping of hepatitis C virus with reference to C/E1 and 5' untranslated region sequences. J Clin Microbiol 2007;45(4):1102-12.) was compared with the VERSANT HCV Genotype 2.0 assay. The sequencing strategy led to detection of HCV recombinant genotype 2k/1b, previously identified as genotype 2a/2c, which reveals the importance of exact HCV genotyping and subtyping. PMID- 25907375 TI - Quantifying the yellow signal driver behavior based on naturalistic data from digital enforcement cameras. AB - The yellow signal driver behavior, reflecting the dilemma zone behavior, is analyzed using naturalistic data from digital enforcement cameras. The key variable in the analysis is the entrance time after the yellow onset, and its distribution. This distribution can assist in determining two critical outcomes: the safety outcome related to red-light-running angle accidents, and the efficiency outcome. The connection to other approaches for evaluating the yellow signal driver behavior is also discussed. The dataset was obtained from 37 digital enforcement cameras at non-urban signalized intersections in Israel, over a period of nearly two years. The data contain more than 200 million vehicle entrances, of which 2.3% (~5million vehicles) entered the intersection during the yellow phase. In all non-urban signalized intersections in Israel the green phase ends with 3s of flashing green, followed by 3s of yellow. In most non-urban signalized roads in Israel the posted speed limit is 90km/h. Our analysis focuses on crossings during the yellow phase and the first 1.5s of the red phase. The analysis method consists of two stages. In the first stage we tested whether the frequency of crossings is constant at the beginning of the yellow phase. We found that the pattern was stable (i.e., the frequencies were constant) at 18 intersections, nearly stable at 13 intersections and unstable at 6 intersections. In addition to the 6 intersections with unstable patterns, two other outlying intersections were excluded from subsequent analysis. Logistic regression models were fitted for each of the remaining 29 intersection. We examined both standard (exponential) logistic regression and four parameters logistic regression. The results show a clear advantage for the former. The estimated parameters show that the time when the frequency of crossing reduces to half ranges from1.7 to 2.3s after yellow onset. The duration of the reduction of the relative frequency from 0.9 to 0.1 ranged from 1.9 to 2.9s. PMID- 25907376 TI - Editorial for the Journal of Accident Analysis and Prevention Special Issue of ICTIS 2013. PMID- 25907377 TI - Mean corpuscular volume of control red blood cells determines the interpretation of eosin-5'-maleimide (EMA) test result in infants aged less than 6 months. AB - Eosin-5'-maleimide (EMA) binding test is a flow cytometric test used to detect hereditary spherocytosis (HS). To perform the test sample from patients, 5-6 reference samples of red blood are needed. Our aim was to investigate how the mean corpuscular volume (MCV) of red blood cells influences on the value of fluorescence of bounded EMA dye and how the choice of reference samples affects the test result. EMA test was performed in peripheral blood from 404 individuals, including 31 children suffering from HS. Mean fluorescence channel of EMA-RBCs was measured with Cytomics FC500 flow cytometer. Mean corpuscular volume of RBCs was assessed with LH750 Beckman Coulter. Statistical analysis was performed using Graph Pad Prism. The correlation Spearman coefficient between mean channel of fluorescence of EMA-RBCs and MCV was r = 0.39, p < 0.0001. Interpretation of EMA test depends on MCV of the reference samples. If reference blood samples have lower MCV than the patients MCV, EMA test result might be negative. Due to different MCV values of RBCs in infancy and ca. Three months later, EMA test in neonates might be interpreted falsely negative. Samples from children younger than 3 months old had EMA test result 86.1 +/- 11.7 %, whereas same samples that analyzed 4.1 +/- 2.1 later had results of 75.4 +/- 4.5 %, p < 0.05. Mean fluorescence of EMA-bound RBC depends on RBC's volume. MCV of reference samples affects EMA test results; thus, we recommend selection of reference samples with MCV in range of +/-2 fL compared to MCV of patient RBC's. PMID- 25907378 TI - In vivo assessment of the metabolic activity of CYP2D6 diplotypes and alleles. AB - AIMS: A prospectively enrolled patient cohort was used to assess whether the prediction of CYP2D6 phenotype activity from genotype data could be improved by reclassification of diplotypes or alleles. METHODS: Three hundred and fifty-five patients receiving tamoxifen 20 mg were genotyped for CYP2D6 and tamoxifen metabolite concentrations were measured. The endoxifen : N-desmethly-tamoxifen metabolic ratio, as a surrogate of CYP2D6 activity, was compared across four diplotypes (EM/IM, EM/PM, IM/IM, IM/PM) that are typically collapsed into an intermediate metabolizer (IM) phenotype. The relative metabolic activity of each allele type (UM, EM, IM, and PM) and each EM and IM allele was estimated for comparison with the activity scores typically assigned, 2, 1, 0.5 and 0, respectively. RESULTS: Each of the four IM diplotypes have distinct CYP2D6 activity from each other and from the EM and PM phenotype groups (each P < 0.05). Setting the activity of an EM allele at 1.0, the relative activities of a UM, IM and PM allele were 0.85, 0.67 and 0.52, respectively. The activity of the EM alleles were statistically different (P < 0.0001), with the CYP2D6*2 allele (scaled activity = 0.63) closer in activity to an IM than an EM allele. The activity of the IM alleles were also statistically different (P = 0.014). CONCLUSION: The current systems for translating CYP2D6 genotype into phenotype are not optimally calibrated, particularly in regards to IM diplotypes and the *2 allele. Additional research is needed to improve the prediction of CYP2D6 activity from genetic data for individualized dosing of CYP2D6 dependent drugs. PMID- 25907379 TI - Methylisothiazolinone: dermal and respiratory immune responses in mice. AB - Methylisothiazolinone (MI), a widely used chemical preservative in industrial and household products, and cosmetics, has been associated with allergic contact dermatitis. However, the asthmogenic capacity of MI is currently unknown. In this study, we investigated the capacity of MI to elicit asthma-like responses in a validated mouse model. On days 1 and 8, mice (C57Bl/6 and BALB/c) were dermally treated with MI or vehicle on each ear. On day 15, mice received a single intranasal challenge with MI or vehicle. Immediately after the challenge, the early ventilatory response was measured using a double chamber plethysmograph. One day later, airway hyperreactivity, pulmonary inflammation and immune-related parameters were assessed. Dermal treatment with MI in both C57Bl/6 and BALB/c mice induced increased T- and B-cell proliferation in the auricular lymph nodes, along with IFN-gamma production and limited increases in total serum IgE, confirming dermal sensitization. An airway challenge with MI led to an early ventilatory response (decreased breathing frequency), indicative for acute sensory irritation. However, 24h later no allergic respiratory response (no airway hyperreactivity (AHR) nor pulmonary inflammation) was found in either mouse strains. Our study indicates that MI can be classified as a strong dermal sensitizer and irritant, but not an asthmogen after initial dermal sensitization, followed by an airway challenge. PMID- 25907380 TI - Expression, purification and characterization of cold shock protein A of Corynebacterium pseudotuberculosis. AB - The gram-positive bacterium Corynebacterium pseudotuberculosis is the causative agent of different diseases that cause dramatically reduced yields of wool and milk, and results in weight loss, carcass condemnation and also death mainly in sheep, equids, cattle and goats and therefore globally results in considerable economical loss. Cold shock proteins are conserved in many bacteria and eukaryotic cells and they help to restore normal cell functions after cold shock in which some appear to have specific functions at normal growth temperature as well. Cold shock protein A from C. pseudotuberculosis was expressed in Escherichia coli and purified. The thermal unfolding/refolding process characterized by circular dichroism, differential scanning calorimetry and NMR spectroscopy techniques indicated that the refolding process was almost completely reversible. PMID- 25907382 TI - Colorectal adenocarcinoma with mucinous component: relation of MMP-13, EGFR, and E-cadherin expressions to clinicopathological features and prognosis. AB - The aim of this study was to compare colorectal adenocarcinoma with mucinous component, ordinary adenocarcinoma (OA) and mucinous adenocarcinoma (MA) regarding clinicopathological parameters, survival, EGFR, MMP-13, and E-cadherin. We studied tumor tissue specimens from 28 patients with adenocarcinoma with mucinous component, 47 with OA, and 56 with MA, who underwent radical surgery from January 2007 to January 2012 at the Gastroenterology Centre, Mansoura University, Egypt. High density manual tissue microarrays were constructed and immunohistochemistry for EGFR, MMP-13, and E-cadherin was done. Colorectal adenocarcinoma with mucinous component (AWMC) was significantly associated with more perineural invasion, lower EGFR, and MMP-13 expressions than OA, with no difference in E-cadherin expression. Conversely, only microscopic abscess formation was significantly more with colorectal AWMC than MC with no difference in EGFR, MMP-13 and E-cadherin expression between both groups. Colorectal AWMC showed a better survival than MA with no difference with OA. In a univariate analysis, EGFR, MMP-13, and E-cadherin expressions did not show a significant impact on disease-free or overall survival in patients with colorectal AWMC. Colorectal AWMC remains a vague entity that resembles OA in some clinicopathological and molecular respects as well as MA. PMID- 25907381 TI - Segmental expression and C-terminal labeling of protein ERp44 through protein trans-splicing. AB - Endoplasmic reticulum resident protein 44 (ERp44) is a member of the protein disulfide isomerase family and functions in oxidative protein folding in the endoplasmic reticulum. A structurally flexible C-terminal tail (C-tail) of ERp44 plays critical roles in dynamically regulating ERp44's function in protein folding quality control. The structure-function dynamics of ERp44's C-tail may be studied further using fluorescence and other techniques, if methods are found to label the C-tail site-specifically with a fluorescent group or segmentally with other desired labels. Here we have developed such methods, employing split inteins capable of protein trans-splicing, and identifying atypical S1 split inteins able to function efficiently at a suitable split site in the ERp44 sequence. One method demonstrated segmental expression of ERp44 for segmental labeling of the C-tail, another method efficiently added a commercially available fluorescent group to the C-terminus of ERp44, and both methods may also be generally useful for studying other proteins. PMID- 25907383 TI - Theoretical study of mechanism and dynamics on reaction of (CH3)2NH with CH3. AB - The mechanism and dynamics for the bimolecular reaction of (CH3)2NH with CH3 have been investigated based on the G3//MP2/6-311G(d,p) level of theory. Our calculations show that when the two reactants approach each other, three prereaction complexes, RC1, RC2, and RC3, can be formed through van der Waals force or hydrogen bonding. From RC1, RC2, and RC3, six routes have been established. Among the six routes, the two routes (R1 and R2) from van der Waals prereaction complex RC1 are the main routes for the title reaction. R1 and R2 are hydrogen abstractions routes associated with HN and HCalpha atoms in DMA, respectively. The calculated energy barriers for R1 and R2 are 12.3 and 13.7 kcal/mol, respectively. Both the potential energy surfaces of R1 and R2 locate a "reactant-like" transition state, as well as van der Waals complexes before and after the transition state. The slight preference of R1 over R2 might be related to the higher similarity between the structures of RC1 and the transition state for R1 (TS1), namely, the structure of TS1 is more "reactant-like". The rate constants of the two favorable H abstraction reaction routes, R1 and R2, are evaluated over a wide temperature range of 200-3000 K by the variational transition state theory (VTST) methods, which can be expressed as kR1 = 5.30 * 10(-13)(T/1000)(3.0) exp(-2883/T) cm(3) molecule(-1) s(-1) and kR2 = 8.34 * 10( 13)(T/1000)(4.5) exp(-3100/T) cm(3) molecule(-1) s(-1), respectively. The predicted rate constant of the HN abstraction (route R1) is in good agreement with the available experimental data. PMID- 25907384 TI - [Ventricular fibrillation and cardiorespiratory arrest during dexmedetomidine administration]. PMID- 25907385 TI - Spin crossover with thermal hysteresis: practicalities and lessons learnt. AB - The observation of spin crossover with thermal hysteresis loops of more than a few Kelvin remains relatively uncommon and unpredictable, so is a relatively underdeveloped, but important, area of spin crossover, particularly for memory applications. Lessons learnt regarding the origins, and the practicalities of the proper study and reporting, of thermal hysteresis loops are considered and explained, from a synthetic chemists perspective, after a general introduction to the field of spin crossover. PMID- 25907386 TI - Pre-hospital medications in total hip arthroplasty: risk factors for poor outcomes. AB - INTRODUCTION: The influence of co-morbidities on complication rates and length of hospitalisation after surgery is well recognised. Clinical instruments predicting this influence, are of increasing interest. We sought to determine whether a count of a patient's preoperative pharmaceuticals would be associated to postoperative outcomes. MATERIAL AND METHODS: In this retrospective, consecutive case series, 668 patients undergoing elective primary total hip arthroplasty (THA) were analysed. Age, gender, BMI, ASA-classification, nicotine or alcohol abuse, and the number and type of medications were documented. RESULTS: Mean age was 63 years (18-94), 53% were females. A total of 60 (8.9%) local and 19 (2.8%) systemic complications occurred during hospital stay. A total of 11 (1.6%) patients died, while 49 (7.3%) local complications occurred during the first postoperative year. Length of hospital stay, blood transfusions, and morbidity were found to be significantly related to the quantity of medications (p<0.001). While the risk of an extended hospital stay (>7 days) increased by a factor of 1.15 (CI: 1.08-1.22) with each medication, the risk of experiencing a complication within the first postoperative year was 1.19 times (CI: 1.07-1.29) for each additional medication. Type of medication also influenced morbidity: the odds ratio was 1.89 (CI: 1.05-3.41) for platelet inhibiting agents and 4.07 (CI: 1.96-8.42) for oral anticoagulants in early morbidity, which increased to 6.05 (CI:2.92-12.53) in 1-year follow-up. CONCLUSIONS: The investigation illustrated the significant influence of the number and/or type of medication on complications, morbidity and prolonged hospital stay. This predictive tool may be useful, for physicians and non-health professionals, in estimating particular outcomes after elective THA. PMID- 25907387 TI - A novel technique for identification of fractured ceramic acetabular liner in total hip arthroplasty: a case report. AB - In total hip arthroplasty ceramic bearings are liable to fracture. We present the case of an 82-year-old male with groin pain and an audible squeak 6 months post ceramic on ceramic hip arthroplasty. Initial plain radiography and examination under anaesthetic (EUA) were normal. Fluoroscopy with normal image exposure was also unremarkable. Over penetration of the image intensifier film demonstrated a fracture of the ceramic acetabular liner. The patient subsequently underwent a revision of both acetabular and femoral bearing surfaces.Displaced ceramic liner fractures are easy to identify with plain radiographs. We recommend the use of over penetration using image intensification as a technique to help identify subtle ceramic liner fractures. To our knowledge this has not been previously reported in the literature. PMID- 25907388 TI - The population attributable risk of nutrition and lifestyle on hip fractures. AB - INTRODUCTION: Norway is among the countries with the highest incidence of hip fractures, and how to reduce this incidence is a major public health concern. MATERIALS AND METHODS: The population attributable risk (PAR), which measures the portion of hip fracture incidences in the population that can be attributed to an exposure if there is a causal relationship, was assessed for the exposure to excessive alcohol consumption, being underweight, low calcium from dairy products, low physical activity and current tobacco smoking. The risk ratio (RR) of the exposures summarized from systematic reviews and meta-analyses, as well as their prevalence from national statistics or Norwegian population-based studies, were used to estimate PARs. RESULTS: Low physical activity and current tobacco smoking had the highest RR for hip fractures, with 1.65 (95% CI 1.50-1.81) and 1.52 (95% CI 1.41-1.63). Low physical activity had the highest prevalence in the population (27.4%) and the highest PAR (0.151), followed by tobacco smoking (PAR = 0.081) and excessive alcohol consumption (PAR = 0.01). By comparison, being underweight and low calcium from dairy products had negligible PAR estimates. CONCLUSIONS: From a public health perspective, increased daily physical activity is the most promising intervention to reduce the incidence of hip fractures. Reduced smoking and alcohol consumption are of relevance, but other health risks related to these exposures are of greater public health concern. Low body weight and nutritional calcium from dairy products seem to be of less importance. PMID- 25907389 TI - Revision of a single type of large metal head metal-on-metal hip prosthesis. AB - Large-head metal-on-metal (MoM) total hip arthroplasties were introduced because of their purported advantages. Inflammatory pseudotumours occasionally occur after MoM hip arthroplasty and often lead to revision. The purpose of this study was to assess the outcome of revision of large-head MoM total hip arthroplasties after an extensive screening protocol for all MoM articulations with a minimum 2 year follow-up. We identified 50 hips that had undergone large-head MoM total hip arthoplasty and required revision at a mean of 44 months after index operation. Of these, 38 were revised for pseudotumours, 7 for loosening, 2 for infection and 3 for instability. There was bone loss in 44 hips. The majority were revised to a 28 mm metal or ceramic head on a polyethylene-cemented cup. In 12 patients there was a complication. There was a decrease of whole blood cobalt from 20.8 ug/L preoperatively to 1.8 ug/L 1 year after revision. We found 6 residual masses on routine postoperative CT scans. The indication for revision of this cohort is inevitable but the clinical outcome 2 years after revision for pseudotumour is disappointing. Revising a MoM hip arthroplasty to a conventional cemented polyethylene or dual-mobility cup with bone impaction grafting and a 28 mm head can adequately treat the high ion levels and probably the disease of ARMD. PMID- 25907390 TI - Prospective evaluation of short and mid-term outcomes of total hip arthroplasty using the AccoladeTM stem. AB - PURPOSE: Cementless press-fit total hip arthroplasty (THA) with the Accolade stem (Stryker AccoladeTM TMZF, Mahwah, New Jersey) has demonstrated variable implant survivorship and outcomes. The purpose of this study was to analyse the: 1) implant survivorship; 2) complications; 3) functional outcomes; 4) overall quality of life; and 5) patient expectations and satisfaction following THA with this particular press-fit stem. METHODS: A prospectively collected database of 222 patients who underwent THA at 7 institutions between 2006 and 2009 using the Accolade stem (Stryker Inc. Mahwah, New Jersey) was evaluated. Harris Hip Score (HHS) and SF-12 were used to assess the outcomes at 2- and 5-year follow-up. Kaplan-Meier survivorship was calculated at 5 years of follow-up. RESULTS: The 5 year aseptic and all-cause survivorship rates were 99.4% (95% CI, 96.3 to 99.9%) and 97.9% (95% CI, 94.6 to 99.2%), respectively. At 2 and 5 years postoperatively, the patients demonstrated a mean HHS of approximately 89 points and 92 points, respectively. The mental and physical components of the SF-12 mean score increased with the physical component having a more marked increase. The mental and physical components of the SF-12 score increased to a mean of 46 and 45 points at 2 and 5 years, respectively. At 2-year follow-up, over 90% of patients were satisfied with their outcome in a majority of areas surveyed. DISCUSSION: Our results suggest that the use of this press-fit construct results in tremendous improvements in functional and quality of life outcomes, along with excellent survivorship at short- and mid-term follow-up. PMID- 25907391 TI - Arthroscopic ligamentum teres reconstruction of the hip in Ehlers-Danlos syndrome: a case study. AB - BACKGROUND: Ehlers-Danlos syndrome (EDS) is a genetic disorder that affects the structural integrity of collagen within the body. This presents clinically as a connective tissue disorder with increased elasticity of joints, muscles, and ligaments. Multiple joints are affected by hypermobility and joint injury is common in these patients. It is estimated that EDS occurs once in every 5,000 births worldwide. CASE REVIEW: This article focuses on reconstruction of the ligamentum teres (LT) of the hip using a tibialis anterior allograft to treat severe instability and pain in a 43 year-old female with EDS. The LT reconstruction was accompanied by labral repair and capsular plication. The patient was assessed pre- and postoperatively using modified Harris Hip Score (mHHS), Hip Outcome Score Activities of Daily Living (HOS-ADLS), Hip Outcome Score Sports Specific Subscale (HOS-SSS), Non Arthritic Hip Score (NAHS), Visual Analog Scale (VAS), and satisfaction. One year following surgery the patient has reported positive outcomes in terms of pain and instability. LITERATURE REVIEW: Ligament reconstruction has been reported in patients with Ehlers-Danlos syndrome for shoulders and knees with positive results and restoration of stability. Currently there is a paucity of literature regarding patients with EDS undergoing hip procedures. In addition, reconstruction of the ligamentum teres for hip instability and pain has rarely been reported in a normal patient cohort. CLINICAL RELEVANCE: This is the first study to report ligamentum teres reconstruction of the hip in a patient with Ehlers-Danlos syndrome and hip instability. The patient demonstrated satisfactory results 1 year from surgery. PMID- 25907392 TI - Highly cross-linked polyethylene improves wear and mid-term failure rates for young total hip arthroplasty patients. AB - We compared clinical outcomes and polyethylene wear for 2 young primary THA patient cohorts (<50 years of age) at mid-term follow-up. In total, 72 patients (84 hips) received a coventional polyethylene liner (CPE) and 84 patients (89 hips) received a highly cross-linked polyethylene liner (HXLPE). Mean Harris Hip Score improved to 81 points for both groups. UCLA activity scores were higher for HXLPE patients (6.0 vs 5.3, p = 0.03), with lower mean linear wear (0.02 vs 0.13 mm/year, p<0.001) and lower mean volumetric wear (75.1 vs 229.8 mm3, p<0.001) at an average of 70 months follow-up. No HXLPE patient required revision for wear related concerns, compared to 5 CPE patients with revision for aseptic loosening or impending radiographic failure (0% vs 5.9%, p = 0.02). HXLPE is associated with reduced wear among young, active THA patients without increased risk of early mechanical failure. PMID- 25907393 TI - Trends in the management of intertrochanteric femur fractures in the United States 2005-2011. AB - OBJECTIVES: In the last 2 decades, surgical treatment of intertrochanteric (IT) femur fractures has shown a continuing trend towards the increased use of intramedullary nails (IMN) and decreased use of sliding hip screws (SHS). Recent trends in the United States regarding the use of these implants, including charges and reimbursement, have not been investigated. METHODS: A national database of Medicare patients (PearlDiver, Inc.) was queried using Current Procedural Terminology (CPT) codes for patients with surgical dates from 2005 2011. RESULTS: A total of 34,759 SHS or IMN procedures for intertrochanteric femur fractures were identified from 2005-2011. There was a significant increase in the percentage of IMN compared to SHS, from 46.9% IMN in 2005 to 79.1% in 2011. The average charges for IMN and SHS increased. Statistically higher rates of PE (p<0.001), DVT (p<0.001), MI (p<0.001), respiratory failure (p<0.001), UTI (p<0.001), pneumonia (p<0.001), CVA (p<0.001) and blood transfusion (p<0.001) were noted in the IMN group. The SHS group had higher 1 year (4.3% vs 3.8%, p = 0.012) and 2 year (5.8% vs 5.0%, p = 0.002) mortality rates. CONCLUSIONS: The previously recognised trend of increasing use of IMN for IT femur fractures has continued. The overall incidence of operative IT femur fractures is not increasing at this time. The cost of IMN remains higher than SHS. PMID- 25907394 TI - Small diameter acetabulum and femoral head in total hip arthroplasty for developmental dysplasia of the hip, with no femoral osteotomy. AB - We present the results of 66 total hip arthroplasties in 62 patients of mean age 46 years (24-74 years), with developmental dysplasia of the hip. In all cases the centre of rotation of the new hip was positioned at the site of the true acetabulum. In all patients cementless press fit acetabular components of small diameter (42-44 mm) were used, articulating exclusively with a 22.25 mm modular metal femoral head, without the use of bone grafts or shortening osteotomies of the femur. Despite the use of small diameter femoral heads the rate of dislocation was 3%. After an average follow-up period of 9 years (4-18 years), no revisions were required for infection, loosening or wear or implant migration. Osteolytic lesions were seen in the periacetabular region in 3 patients who were symptom free. A total of 2 revisions were required for instability and 2 patients had the wires of their trochanteric osteotomy removed because of bursitis. Leg length inequality was improved in 55% of the patients and one postoperative transient sciatic nerve lesion settled within 4 months. We believe that in patients with painful dysplastic hips, the use of small diameter implants with the centre of rotation at the true acetabulum, can give very satisfactory results, without any supplementary procedures. PMID- 25907395 TI - Cementless total hip arthroplasty in developmental dysplasia of the hip with end stage osteoarthritis: 2-7 years' clinical results. AB - Between 2006 and 2011, 102 hips of 78 patients with end-stage osteoarthritis secondary to developmental dysplasia of the hip (DDH) underwent cementless total hip arthroplasty (THA). According to the Crowe's classification, 22 hips (21%) were type 1, 19 hips (18%) were type 2, 22 hips (21%) were type 3 and 39 hips (38%) were type 4 respectively. Functional and clinical analyses were performed by Harris Hip Scores (HHS). There were 73 (71%) excellent or good results according to HHS. The postoperative HHS was significantly lower in patients who underwent femoral shortening (p<0.01). We observed 25 (24.5%) complications in total, 15 (14.7%) of which required revision surgery. The authors concluded that THA for DDH is a safe and a reliable procedure with good clinical outcomes. PMID- 25907396 TI - A novel imidazopyridine derivative, X22, prevents the retinal ischemia reperfusion injury via inhibition of MAPKs. AB - Inflammation is a pathological hallmark of ischemia reperfusion (I/R) injury. The present study was conducted to explore the ability of a new anti-inflammatory compound, X22, to attenuate retinal I/R injury via cytokine-inhibitory mechanism. For the in vitro experiment, ARPE-19 cells were pretreated with X22 (5 or 10 MUM) or saline for 2 h, followed by stimulation with tert-butyl hydroperoxide (TBHP, 1000 MUM) for an indicated amount of time. The expression of inflammatory mediators, cell viability, and cell apoptosis were evaluated. For the in vivo experiment, the rats were randomized to receive treatment with saline or X22 (0.1 MUM/kg, 3 MUL) before the induction of I/R injury. Histological evaluation, apoptosis of retinal cells, macrophage infiltration, and retina functional changes were further determined. Our data showed that pretreatment with X22 significantly inhibited TBHP-induced inflammatory cytokine expression in ARPE-19 cells. The anti-inflammatory activity of X22 may be associated with its inhibition on MAPKs, rather than NF-kappaB. Subsequently, our data proved that TBHP induced apoptosis in ARPE-19 cells, while pretreatment of X22 significantly suppressed TBHP-caused ARPE-19 apoptosis. Finally, the in vivo data revealed that X22 administration maintained better inner retinal layer structures, reduced apoptosis of retinal ganglion cell, and improved retinal function in retinal I/R rat models, which were accompanied with a remarkable decrease in retinal macrophage infiltration. These results suggest that the novel compound X22 is a potential agent for the treatment of retinal I/R-related diseases via the MAPKs targeting anti-inflammatory mechanism and deserves the further development. PMID- 25907398 TI - A new stonemasonry surface adhesive causing occupational allergic contact dermatitis resulting from methyl methacrylate. PMID- 25907399 TI - Presentation, diagnosis, and management of early hepatic venous outflow complications in whole cadaveric liver transplant. AB - Early hepatic venous outflow obstruction (HVOO) can be a devastating complication leading to graft loss after liver transplantation (LT). A retrospective study on 777 adult LT recipients over a 5-year period (August 2007 to August 2012) was undertaken to determine the incidence of early HVOO presenting within 3 months of transplant, its clinical features and management, and potential technical risk factors related to the implanting technique. Cases of early HVOO were screened for by identifying recipients with problematic ascites within 3 months of transplant. Definitive diagnosis for HVOO was based on a wedge pressure of >12 mm Hg. Considering only whole livers, the incidence of early problematic ascites was 3% (20/695) of which more than one-third (35%, 7/20) were then confirmed to have HVOO. Overall, the incidence of early HVOO was 1% (7/695). Two hepatic veins (HVs) with extension piggybacks (PBs; n = 423) were the dominant implanting technique in the time period of study rather than the 3 HV PB (n = 182) and caval replacement techniques (n = 82). Considering the implantation technique, all cases of HVOO occurred after 2 HVs when extension PBs had been used with an incidence of 1.7% (7/423). Institutionally, early HVOO was mainly managed surgically by either cavoplasty within a month of transplant (n = 4) or retransplant (n = 1), and the remainder (n = 2) were medically managed with diuretics. In conclusion, early HVOO is rare, and there is no evidence from this study that a given implantation technique is at a higher risk of developing HVOO (2 HV with extension versus 3 HV and caval replacement; P = 0.11). However, early revisional surgery for HVOO can preserve graft function with retransplantation being reserved for when surgical cavoplasty or radiological stenting is technically not possible. PMID- 25907400 TI - All entities move and nothing remains still-Heraclitus. PMID- 25907401 TI - Survival benefit of physician-staffed Helicopter Emergency Medical Services (HEMS) assistance for severely injured patients. AB - BACKGROUND: Physician-staffed Helicopter Emergency Medical Services (HEMS) provide specialist medical care to the accident scene and aim to improve survival of severely injured patients. Previous studies were often underpowered and showed heterogeneous results, leaving the subject at debate. The aim of this retrospective, adequately powered, observational study was to determine the effect of physician-staffed HEMS assistance on survival of severely injured patients. METHODS: All consecutive severely injured trauma patients (ISS >15) between October 1, 2000 and February 28, 2013 were included. Assistance of physician-staffed HEMS was compared with assistance from the ambulance paramedic crew (i.e., EMS group) only. A regression model was constructed for calculating the expected survival and survival benefit. RESULTS: A total of 3543 polytraumatised patients with an ISS >15 were treated at the Emergency Department, of whom 2176 patients remained for analysis; 1495 (69%) were treated by EMS only and 681 (31%) patients received additional pre-hospital care of HEMS. The model with the best fit and diagnostic properties (H-L coefficient 2.959, p=0.937; AUC 0.888; PPV 71.4%; NPV 88.0%) calculated that 36 additional patients survived because of HEMS assistance. This resulted in an average of 5.33 additional lives saved per 100 HEMS dispatches for severely injured patients. CONCLUSION: The present study indicates an additional 5.33 lives saved per 100 dispatches of the physician-staffed HEMS. Given the excellent statistical power of this study (>90%), physician-staffed HEMS is confirmed to be an evidence-based valuable addition to the EMS systems in saving lives of severely injured patients. PMID- 25907402 TI - Predictors for moderate to severe paediatric head injury derived from a surveillance registry in the emergency department. AB - INTRODUCTION AND AIM: Head injuries are a common complaint among children presenting to the emergency department (ED). This study is part of an ongoing prospective surveillance of head injured children presenting to a paediatric ED. We aim to derive predictors for moderate to severe head injury in our population. MATERIALS AND METHODS: We performed an unmatched case-control study. Cases were defined as those who presented to the ED with moderate to severe head injury, during the period from 2006 to 2014. Controls were obtained from the prospective surveillance head injury database and were children who presented to the ED with head injury but who remained well on follow up. We compared variables from demographics, mechanism of injury, history, and physical examination. RESULTS: There were 39 cases and 1173 controls. In the prospective database, our event rate was 0.5% and our computed tomography (CT) rate was 1%. Among those with moderate to severe head injury, they were more likely to be involved in road traffic accidents, have a history of difficult arousal, confusion or disorientation and a history of seizure. On physical examination, cases were more likely to have the presence of altered mental status, base of skull fracture, scalp hematoma and anisocoria. On multivariable analysis, the following 4 predictors remained statistically significant: Involvement in road traffic accident (p<0.001), difficult arousal (p<0.001), vomiting (p=0.003) and signs of base of skull fracture (p<0.001). Using these 4 variables, the Area under Curve was 0.97 {Sensitivity 92.3% (79.1-98.4%), Specificity 93.0% (91.4-94.4%), positive predictive value 30.5% (22-40%), negative predictive value 99.7% (99.2 99.9%)}. CONCLUSION: Involvement in road traffic accident, difficult arousal, base of skull fracture and vomiting are independent predictors for moderate to severe head injury in our paediatric population. PMID- 25907403 TI - How useful are Primary Trauma Care courses in sub-Saharan Africa? AB - INTRODUCTION: More than five million deaths occur each year from injury with the vast majority occurring in low and middle-income countries (LMICs). Africa bears the highest road traffic related mortality rates in the world. Despite this, formal training in trauma management is not widely adopted in these countries. We report our results of 10 consecutive Primary Trauma Care (PTC) courses delivered in seven East and Central African countries, as part of the COSECSA Oxford Orthopaedic Link (COOL) initiative. METHODS: Candidate's knowledge and clinical confidence in trauma management were assessed using a multiple-choice questionnaire and a confidence matrix rating of eight clinical scenarios. We performed descriptive statistical analysis on knowledge and clinical confidence scores of candidates before and after the course. We sub-analysed these scores, examining specifically the difference that exist between gender, job-roles and instructors versus non-instructors. RESULTS: We have trained 345 new PTC providers and 99 new PTC instructors over the 10 courses. Data sets were complete for 322 candidates. Just under a third of candidates were women (n=94). Over two thirds of candidates (n=240) were doctors, while the remainder comprised of nurses, medical students and clinical officers. Overall, the median pre-course MCQ score was 70% which increased to 87% post course (p<0.05). Men achieved a higher MCQ score both pre- and post-course compared to women (p<0.05); however there was no significant difference in the degree of improvement of MCQ scores between gender. Instructors outperform non-instructors (p<0.05), and similarly doctors outperform non-doctors on final MCQ scores (post-course). However, it was the non-doctors who showed a statistically significant improvement in scores before and after the course (20% non-doctors vs 16% doctors, p<0.05). Candidate's clinical confidence also demonstrated significant improvement following the course (p<0.05). CONCLUSION: Our work demonstrates that COOL-funded PTC courses in the COSECSA region delivered to front-line health staff have helped improve their knowledge and confidence in trauma management, irrespective of their job roles and gender. Further follow-up is needed to establish the long-term impact of PTC courses in this region. PMID- 25907404 TI - Joint effect of unlinked genotypes: application to type 2 diabetes in the EPIC Potsdam case-cohort study. AB - Analyzing multiple single nucleotide polymorphisms (SNPs) is a promising approach to finding genetic effects beyond single-locus associations. We proposed the use of multilocus stepwise regression (MSR) to screen for allele combinations as a method to model joint effects, and compared the results with the often used genetic risk score (GRS), conventional stepwise selection, and the shrinkage method LASSO. In contrast to MSR, the GRS, conventional stepwise selection, and LASSO model each genotype by the risk allele doses. We reanalyzed 20 unlinked SNPs related to type 2 diabetes (T2D) in the EPIC-Potsdam case-cohort study (760 cases, 2193 noncases). No SNP-SNP interactions and no nonlinear effects were found. Two SNP combinations selected by MSR (Nagelkerke's R2 = 0.050 and 0.048) included eight SNPs with mean allele combination frequency of 2%. GRS and stepwise selection selected nearly the same SNP combinations consisting of 12 and 13 SNPs (Nagelkerke's R2 ranged from 0.020 to 0.029). LASSO showed similar results. The MSR method showed the best model fit measured by Nagelkerke's R2 suggesting that further improvement may render this method a useful tool in genetic research. However, our comparison suggests that the GRS is a simple way to model genetic effects since it does not consider linkage, SNP-SNP interactions, and no non-linear effects. PMID- 25907405 TI - Robust SiO2-modified CoFe2O4 hollow nanofibers with flexible room temperature magnetic performance. AB - A range of robust SiO2-modified CoFe2O4 hollow nanofibers with high uniformity and productivity were successfully prepared via polyvinylpyrrolidone-sol assisted electrospinning followed by annealing at a high temperature of 1000 degrees C, and they were characterized using scanning electron microscopy, transmission electron microscopy, vibrating sample magnetometry, X-ray diffraction and X-ray photoelectron spectroscopy in detail. It was demonstrated that amorphous SiO2 has a significant influence on not only the surface morphology, microstructure and crystalline size but also the room temperature magnetic performance of the inverse spinel CoFe2O4 nanofibers. The pure CoFe2O4 sample shows a particle chain rod-shape appearance but the SiO2-modified CoFe2O4 sample shows a robust hollow fibrous structure. With increasing SiO2 content, an increase at first and then a decrease in coercivity (Hc) and monotonously a decrease in saturation magnetization (Ms) have been determined in the obtained modified CoFe2O4 hollow nanofibers. A maximum Ms of about 80 emu g(-1) and a maximum Hc of about 1477 Oe could be, respectively, acquired from the pure CoFe2O4 nanorods and the modified CoFe2O4 hollow nanofibers with about 14.9% SiO2. The changes in Ms, Hc and the structure evolution mechanism of these SiO2-modified CoFe2O4 hollow nanofibers have been elaborated systematically. Furthermore, it is suggested that amorphous SiO2 enables effectively improving the structure endurance of 1D electrospun inorganic oxide hollow nanostructures being subjected to high temperatures. PMID- 25907406 TI - Effectiveness of a CBT Intervention for Persistent Insomnia and Hypnotic Dependency in an Outpatient Psychiatry Clinic. AB - OBJECTIVE: To test cognitive-behavioral therapy for insomnia (CBT-I) in patients who not only receive psychiatric treatment in a outpatient psychiatry clinic but also continue to experience chronic insomnia despite receiving pharmacological treatment for sleep. CBT-I included an optional module for discontinuing hypnotic medications. METHOD: Patients were randomized to 5 sessions of individual CBT-I (n = 13) or treatment as usual (n = 10). Sleep parameters were assessed using sleep diaries at pre- and posttreatment. Questionnaires measuring depression, anxiety, and health-related quality of life were also administered. RESULTS: CBT I was associated with significant improvement in sleep, with 46% obtaining normal global sleep ratings after treatment. However, no changes in secondary outcomes (depression, anxiety, quality of life) were obtained and no patients elected to discontinue their hypnotic medications. CONCLUSIONS: Patients with complex, chronic psychiatric conditions can obtain sleep improvements with CBT-I beyond those obtained with pharmacotherapy alone; however, sleep interventions alone may not have the same effect on mental health outcomes in samples with more severe and chronic psychiatric symptoms and dependency on hypnotic medications. PMID- 25907407 TI - Evaluation of the effect of food and gastric pH on the single-dose pharmacokinetics of cabozantinib in healthy adult subjects. AB - Cabozantinib is a small molecule tyrosine kinase inhibitor that has been approved for the treatment of patients with progressive, metastatic medullary thyroid cancer. Cabozantinib exhibits a pH-dependent solubility profile in vitro. Two phase 1 clinical pharmacology studies were conducted in healthy subjects to evaluate whether factors that may affect cabozantinib solubility and gastric pH could alter cabozantinib bioavailability: a food effect study (study 1) and a drug-drug interaction (DDI) study with the proton pump inhibitor (PPI) esomeprazole (study 2). Following a high-fat meal (study 1), cabozantinib Cmax and AUC were increased (40.5% and 57%, respectively), and the median tmax was delayed by 2 hours. Cabozantinib should thus not be taken with food (patients should not eat for at least 2 hours before and at least 1 hour after administration). In the DDI study (study 2), the 90% confidence intervals (CIs) around the ratio of least-squares means of cabozantinib with esomeprazole versus cabozantinib alone for AUC0-inf were within the 80%-125% limits; the upper 90%CI for Cmax was 125.1%. Because of the low apparent risk of a DDI, concomitant use of PPIs or weaker gastric pH-altering agents with cabozantinib is not contraindicated. PMID- 25907408 TI - Development and characterization of Haemophilus influenzae type b conjugate vaccine prepared using different polysaccharide chain lengths. AB - Capsular polysaccharide conjugates of Haemophilus influenzae type b (Hib) are important components of several mono- or multi-valent childhood vaccines. However, their access to the most needy people is limited due to their high cost. As a step towards developing a cost effective and more immunogenic Hib conjugate vaccine, we present a method for the preparation of Hib capsular polysaccharide (PRP)-tetanus toxoid (TT) conjugates using optimized PRP chain length and conjugation conditions. Reactive aldehyde groups were introduced into the polysaccharides by controlled periodate oxidation of the native polysaccharide, which were subsequently covalently linked to hydrazide derivatized tetanus toxoid by means of reductive amination. Native polysaccharides were reduced to average 100 or 50kDa polysaccharide and 10kDa oligosaccharides in a controlled manner. Various conjugates were prepared using Hib polysaccharide and oligosaccharide yielding conjugates with polysaccharide to protein ratios in the range of 0.25 0.5 (w/w) and free saccharide levels of less than 10%. Immunization of Sprague Dawley rats with the conjugates elicited specific antibodies to PRP. The low molecular weight PRP-TT conjugates were found to be more immunogenic as compared to their high molecular weight counterparts and the PRP-TT reference vaccine. PMID- 25907409 TI - Experimental in-vivo model of intravascular shunting for neurosurgical bypass. AB - BACKGROUND: Excessively long clamping time and suboptimal position of stitches can influence the anastomosis patency and the clinical outcome in cerebral bypass surgery. Coronary intravascular micro-shunts could represent an innovative solution for neurosurgical bypass, but the hemodynamic properties of these devices should be extensively studied before their translational application. We created an experimental in-vivo model and we analyzed the blood flow and pressure modification induced by the micro-shunt. METHODS: After laparotomy, an intravascular micro-shunt was placed into the aorta of 8 adult rats, simulating a neurosurgical setting in which the shunt is temporary placed inside the receiving cerebral vessel. A fiber-optic pressure sensor was placed in the femoral artery and the blood pressure continuously recorded during the procedure. Using an ultrasound vascular probe, blood flow velocity in aorta was measured at baseline and both proximally and distally to the shunt. RESULTS: After shunt positioning, no significant decrease in blood pressure was observed (mean value 68.57 versus 80.00 mmHg; P=0.48). Distal aortic blood flow, expressed as peak systolic velocity, showed a significant decrease after shunt positioning (mean value 51.88 versus 86.88 cm/sec; P=0.04), with a mean residual blood flow of 63%. Blood flow values recorded immediately upstream to the shunt did not differ from baseline. CONCLUSIONS: This is the first in-vivo experimental study concerning the hemodynamic properties of an intravascular micro-shunt. Our results demonstrate that this device provides a considerable blood out-flow without significant changes in blood pressure, suggesting that specific neurosurgical micro-shunts might be developed. PMID- 25907410 TI - Resecting diffuse low-grade gliomas to the boundaries of brain functions: a new concept in surgical neuro-oncology. AB - The traditional dilemma making surgery for diffuse low-grade gliomas (DLGGs) challenging is underlain by the need to optimize tumor resection in order to significantly increase survival versus the risk of permanent neurological morbidity. Development of neuroimaging led neurosurgeons to achieve tumorectomy according to the oncological limits provided by preoperative or intraoperative structural and metabolic imaging. However, this principle is not coherent, neither with the infiltrative nature of DLGGs nor with the limited resolution of current neuroimaging. Indeed, despite technical advances, MRI still underestimates the actual spatial extent of gliomas, since tumoral cells are present several millimeters to centimeters beyond the area of signal abnormalities. Furthermore, cortical and subcortical structures may be still crucial for brain functions despite their invasion by this diffuse tumoral disease. Finally, the lack of reliability of functional MRI has also been demonstrated. Therefore, to talk about "maximal safe resection" based upon neuroimaging is a non-sense, because oncological MRI does not show the tumor and functional MRI does not show critical neural pathways. This review proposes an original concept in neuro-oncological surgery, i.e. to resect DLGG to the boundaries of brain functions, thanks to intraoperative electrical mapping performed in awake patients. This paradigmatic shift from image-guided resection to functional mapping-guided resection, based upon an accurate study of brain connectomics and neuroplasticity in each patient throughout tumor removal has permitted to solve the classical dilemma, by increasing both survival and quality of life in DLGG patients. With this in mind, brain surgeons should also be neuroscientists. PMID- 25907412 TI - Computed tomography imaging practice patterns in adult chronic rhinosinusitis: survey of the American Academy of Otolaryngology-Head and Neck Surgery and American Rhinologic Society membership. AB - BACKGROUND: The objective of this study was to assess the current practice patterns of computed tomography (CT) imaging for diagnosis and management of adult chronic rhinosinusitis (CRS). METHODS: A 29-item, electronic, Web-based physician survey was disseminated to the American Academy of Otolaryngology-Head and Neck Surgery (AAO-HNS) and American Rhinologic Society (ARS) membership from November 2012 to January 2013. RESULTS: A total of 331 otolaryngologists completed the survey. Seventy-five percent of respondents did not obtain confirmatory CT imaging prior to initiating medical therapy for CRS. A typical diagnostic scan was considered to be a 3-mm coronal CT with or without 3-mm axial images for 50.6% of participants. On average, the respondents obtained 1 (58.8%) or 2 (36.6%) CT scans prior to proceeding with sinus surgery. CT scanning was most commonly performed in a hospital radiology department (76.4%), followed by a free-standing imaging center (44.5%). An in-office CT scanner was owned by 24.5% of the respondents, mostly commonly a cone beam CT (74.0%) scanner. Most respondents (87.1%) did not experience problems with carriers denying ability to image or reimbursing for scans. Overall, 68.4% of the respondents were unaware of the dosage of radiation delivered by the scanner used for CT acquisition. CONCLUSION: This survey provides a snapshot of the current utility of CT imaging in the management paradigm for CRS. Given that most are unaware of the delivered radiation dose, this clearly represents an important area of improvement in the knowledge gap. PMID- 25907411 TI - Radiolysis as a solution for accelerated ageing studies of electrolytes in Lithium-ion batteries. AB - Diethyl carbonate and dimethyl carbonate are prototype examples of eco-friendly solvents used in lithium-ion batteries. Nevertheless, their degradation products affect both the battery performance and its safety. Therefore, it is of paramount importance to understand the reaction mechanisms involved in the ageing processes. Among those, redox processes are likely to play a critical role. Here we show that radiolysis is an ideal tool to generate the electrolytes degradation products. The major gases detected after irradiation (H2, CH4, C2H6, CO and CO2) are identified and quantified. Moreover, the chemical compounds formed in the liquid phase are characterized by different mass spectrometry techniques. Reaction mechanisms are then proposed. The detected products are consistent with those of the cycling of Li-based cells. This demonstrates that radiolysis is a versatile and very helpful tool to better understand the phenomena occurring in lithium-ion batteries. PMID- 25907413 TI - 1H and 13C NMR spectral assignments of 18 novel polymethoxylated naphthochalcones bearing pyrazoline-1-carbothioamide groups. PMID- 25907414 TI - Identifying patients with Alzheimer's disease using resting-state fMRI and graph theory. AB - OBJECTIVE: Study of brain network on the basis of resting-state functional magnetic resonance imaging (fMRI) has provided promising results to investigate changes in connectivity among different brain regions because of diseases. Graph theory can efficiently characterize different aspects of the brain network by calculating measures of integration and segregation. METHOD: In this study, we combine graph theoretical approaches with advanced machine learning methods to study functional brain network alteration in patients with Alzheimer's disease (AD). Support vector machine (SVM) was used to explore the ability of graph measures in diagnosis of AD. We applied our method on the resting-state fMRI data of twenty patients with AD and twenty age and gender matched healthy subjects. The data were preprocessed and each subject's graph was constructed by parcellation of the whole brain into 90 distinct regions using the automated anatomical labeling (AAL) atlas. The graph measures were then calculated and used as the discriminating features. Extracted network-based features were fed to different feature selection algorithms to choose most significant features. In addition to the machine learning approach, statistical analysis was performed on connectivity matrices to find altered connectivity patterns in patients with AD. RESULTS: Using the selected features, we were able to accurately classify patients with AD from healthy subjects with accuracy of 100%. CONCLUSION: Results of this study show that pattern recognition and graph of brain network, on the basis of the resting state fMRI data, can efficiently assist in the diagnosis of AD. SIGNIFICANCE: Classification based on the resting-state fMRI can be used as a non-invasive and automatic tool to diagnosis of Alzheimer's disease. PMID- 25907416 TI - Rhodium-catalyzed enantioselective intramolecular C-H silylation for the syntheses of planar-chiral metallocene siloles. AB - Reported herein is the rhodium-catalyzed enantioselective C-H bond silylation of the cyclopentadiene rings in Fe and Ru metallocenes. Thus, in the presence of (S) TMS-Segphos, the reactions took place under very mild conditions to afford metallocene-fused siloles in good to excellent yields and with ee values of up to 97%. During this study it was observed that the steric hindrance of chiral ligands had a profound influence on the reactivity and enantioselectivity of the reaction, and might hold the key to accomplishing conventionally challenging asymmetric C-H silylations. PMID- 25907415 TI - Comparison of subdural and subgaleal recordings of cortical high-gamma activity in humans. AB - OBJECTIVE: The purpose of this study is to determine the relationship between cortical electrophysiological (CE) signals recorded from the surface of the brain (subdural electrocorticography, or ECoG) and signals recorded extracranially from the subgaleal (SG) space. METHODS: We simultaneously recorded several hours of continuous ECoG and SG signals from 3 human pediatric subjects, and compared power spectra of signals between a differential SG montage and several differential ECoG montages to determine the nature of the transfer function between them. RESULTS: We demonstrate the presence of CE signals in the SG montage in the high-gamma range (HG, 70-110 Hz), and the transfer function between 70 and 110 Hz is best characterized as a linear function of frequency. We also test an alternative transfer function, i.e. a single pole filter, to test the hypothesis of frequency dependent attenuation in that range, but find this model to be inferior to the linear model. CONCLUSIONS: Our findings indicate that SG electrodes are capable of recording HG signals without frequency distortion compared with ECoG electrodes. SIGNIFICANCE: HG signals could be recorded minimally invasively from outside the skull, which could be important for clinical care or brain-computer interface applications. PMID- 25907418 TI - Simultaneous detection of bacitracin and polymyxin B in livestock products using liquid chromatography with tandem mass spectrometry. AB - With the overarching aim to develop a simple and reliable method for the quantitative analysis of polypeptide antibiotics in various livestock products, the content of bacitracin, and polymyxin B in pork, beef, chicken, milk, and eggs was analyzed using colistin sulfate as an internal standard. The extracted samples were eluted via solid-phase extraction using 2% formic acid in acetonitrile/methanol (1:1, v/v). The two polypeptides were identified and quantified based on the intensities of mass fragments from the respective triply charged precursor ions (bacitracin: 474.97 amu and polymyxin B: 402 amu) at the defined retention time windows using liquid chromatography with electrospray ionization tandem mass spectrometry in time-scheduled multiple reaction monitoring mode. The calibration curves showed good linearity over the concentration range 50-2500 ng/mL with determination coefficients >= 0.991. The mean recoveries were in the range 80.3-88.8% with relative standard deviations <13% for all samples. The limits of quantitation ranged from 30-250 ng/g. The developed method was applied to market samples, but the target analytes were not detected in any of the samples. The developed method is reliable for the simultaneous detection of bacitracin and polymyxin B in pork, beef, chicken, milk, and eggs. PMID- 25907417 TI - The protective effect of caffeic acid on global cerebral ischemia-reperfusion injury in rats. AB - Ischemic stroke is a major cause of death and disability all over the world. Ischemic stroke results from a temporary or permanent reduction of cerebral blood flow that leads to functional and structural damage in different brain regions. Despite decades of intense research, the beneficial treatment of stroke remains limited. In light of this, the search for effective means ameliorating cerebral ischemia-reperfusion injury (CIRI) is one of the major problems of experimental medicine and biology. Recently, the 5-Lipoxygenase (5-LO, a key enzyme metabolizing arachidonic acid to produce leukotrienes) inhibitors have been showed to protect brain against ischemic damage in animal model of cerebral ischemia. Caffeic acid, an inhibitor of 5-LO, is a phenolic compound widely distributed in medicinal plants. The aim of this study was to investigate the effect of caffeic acid on global cerebral ischemia-reperfusion injury in rats. The study was carried out on 45 rats that were randomly divided into five groups: the sham group (n = 9), I/R non-treated group (n = 9), I/R-caffeic acid group (10 mg . kg(-1)) (n = 9), I/R-caffeic acid group (30 mg . kg(-1)) (n = 9) and I/R caffeic acid group (50 mg . kg(-1)) (n = 9). Global cerebral ischemia was induced by bilateral carotid artery occlusion for 20 min followed by reperfusion. Spatial learning and memory was evaluated using Morris water maze. Histopathological changes of hippocampus neurons was observed using HE staining. Superoxide dismutase (SOD, the antioxidant enzyme) activities and malondialdehyde (MDA, an oxidative stress biomarker) contents were detected. NF-kappaBp65 expression was detected by the methods of immunohistochemistry. Caffeic acid markedly reduced the escape latency, relieved hippocampal neurons injury and increased neuron count compared with those of I/R non-treated rat. NF-kappaBp65 expression and MDA content decreased significantly, and SOD activities increased significantly in hippocampus. Compared with sham group, 5-LO expression increase significantly in I/R non-treated group rat, and caffeic acid markedly reduced 5-LO expression. The results of the study suggest that caffeic acid has a significant protective effect on global cerebral ischemia-reperfusion injury in rats. The neuroprotective effects is likely to be mediated through the inhibition of 5-LO. PMID- 25907419 TI - Reduced age-related degeneration of the hippocampal subiculum in long-term meditators. AB - Normal aging is known to result in a reduction of gray matter within the hippocampal complex, particularly in the subiculum. The present study was designed to address the question whether the practice of meditation can amend this age-related subicular atrophy. For this purpose, we established the correlations between subicular volume and chronological age within 50 long-term meditators and 50 control subjects. High-resolution magnetic resonance imaging (MRI) scans were automatically processed combining cytoarchitectonically defined probabilistic maps with advanced tissue segmentation and registration methods. Overall, we observed steeper negative regression slopes in controls. The analysis further revealed a significant group-by-age interaction for the left subiculum with a significant negative correlation between age and subicular volume in controls, but no significant correlation in meditators. Altogether, these findings seem to suggest a reduced age-related atrophy of the left subiculum in meditators compared to healthy controls. Possible explanations might be a relative increase of subicular tissue over time through long-term training as meditation is a process that incorporates regular and ongoing mental efforts. Alternatively, because meditation is an established form of reducing stress, our observation might reflect an overall preservation of subicular tissue through a reduced neuronal vulnerability to negative effects of stress. PMID- 25907421 TI - Direct Aromatic C-H Trifluoromethylation via an Electron-Donor-Acceptor Complex. AB - A novel electron-donor-acceptor (EDA) complex-mediated direct C-H trifluoromethylation of arenes with Umemoto's reagent has been developed. This transformation has been enabled by an unprecedented EDA complex formed by Umemoto's reagent and an amine, which was supported by experiments and theoretical calculations. The radical-based methodology presented here allows to access highly-functionalized trifluoromethyl arenes in up to 81 % chemical yield. PMID- 25907420 TI - De novo deletion of HOXB gene cluster in a patient with failure to thrive, developmental delay, gastroesophageal reflux and bronchiectasis. AB - We report a female patient with a complex phenotype consisting of failure to thrive, developmental delay, congenital bronchiectasis, gastroesophageal reflux and bilateral inguinal hernias. Chromosomal microarray analysis revealed a 230 kilobase deletion in chromosomal region 17q21.32 (arr[hg19] 17q21.32(46 550 362 46 784 039)*1) encompassing only 9 genes - HOXB1 to HOXB9. The deletion was not found in her mother or father. This is the first report of a patient with a HOXB gene cluster deletion involving only HOXB1 to HOXB9 genes. By comparing our case to previously reported five patients with larger chromosomal aberrations involving the HOXB gene cluster, we can suppose that HOXB gene cluster deletions are responsible for growth retardation, developmental delay, and specific facial dysmorphic features. Also, we suppose that bilateral inguinal hernias, tracheo esophageal abnormalities, and lung malformations represent features with incomplete penetrance. Interestingly, previously published knock-out mice with targeted heterozygous deletion comparable to our patient did not show phenotypic alterations. PMID- 25907423 TI - Bendamustine and the immune system-a wolf in sheep's clothing ? PMID- 25907422 TI - Thromboelastography, thrombin generation test and thrombodynamics reveal hypercoagulability in patients with multiple myeloma. AB - Patients with multiple myeloma (MM) are at increased risk of venous thromboembolism. Therefore, adequate laboratory control of hemostasis and subsequent adjustments of anticoagulant therapy are necessary. We studied hemostasis changes using thromboelastography (TEG), thrombin generation test (TGT) and thrombodynamics (TD) in primary MM patients (PMMpt, n=25) and patients in remission (RMMpt, n=34) during blood stem cell (BSC) mobilization. TD and TEG reveal hypercoagulability in PMMpt (*p<0.05) in relation to healthy volunteers. There was no difference in any of the tests between PMMpt and RMMpt. We detected no heparin effect in 22% of patients one day after the onset of the prophylactic heparin treatment (500 IU/h) during BSC mobilization; tests shifted toward the hypercoagulability in 75% of patients one day after cyclophosphamide (4 g/m2) chemotherapy. Global hemostasis tests were in good agreement with each other, revealed hypercoagulability and heparin "resistance" in patients with MM and may be useful for therapy individualization. PMID- 25907424 TI - High serum concentration of L-kynurenine predicts unfavorable outcomes in patients with acute myeloid leukemia. AB - The immunomodulatory effects of indoleamine 2,3-dioxygenase (IDO) are ascribed to its ability to catalyze the breakdown of the L-tryptophan along the L-kynurenine pathway. Because blasts from patients with acute myeloid leukemia (AML) express IDO, the goal of this study was to investigate the role of L-kynurenine as a prognostic marker for AML. We enrolled 48 AML patients. L-kynurenine concentrations were measured by high-performance liquid chromatography. The median serum L-kynurenine level was 1.67 MUM. There was no significant difference in the complete remission rate between patients with L-kynurenine < 2.4 (77%) and >= 2.4 MUM (75%). However, 3-year overall survival (OS) rates were significantly better in patients with low L-kynurenine levels (76%) than in those with high L kynurenine levels (11%) (p < 0.0001). Furthermore, in intermediate-risk cytogenetics patients, only L-kynurenine was significantly associated with OS (p < 0.005). Multivariate analyses revealed that L-kynurenine and high leukocyte count were independent prognostic factors. PMID- 25907425 TI - Candida glabrata fungaemia at an Australian cancer centre: epidemiology, risk factors and therapy. PMID- 25907426 TI - Rapid lung MRI - paradigm shift in evaluation of febrile neutropenia in children with leukemia: a pilot study. AB - Immunocompromised children with hematological malignancies are at increased risk of developing potentially fatal pulmonary infections. Early detection and prompt treatment is critical to combat morbidity and mortality in these children. Twenty six children with leukemia (age range: 5-13years) presenting with fever and neutropenia were included in this prospective study, which was approved by the institutional ethics committee. All patients underwent HRCT and MRI of the chest on the same day. The findings of HRCT and MRI were compared, with HRCT as the standard of reference. There was perfect agreement between MRI and CT examinations findings by kappa test (kappa = 1). No significant difference was observed between the two modalities by the McNemar test (p > 0.05). Rapid lung MRI is technically feasible; has a high correlation, sensitivity and specificity to CT scan; and can emerge as the first line modality for the detection of pulmonary nodules in children with leukemia and persistent febrile neutropenia. PMID- 25907427 TI - The Revised International Prognostic Scoring System (IPSS-R) is not predictive of survival in patients with secondary myelodysplastic syndromes. PMID- 25907428 TI - Wound perimeter, area, and volume measurement based on laser 3D and color acquisition. AB - BACKGROUND: Wound measuring serves medical personnel as a tool to assess the effectiveness of a therapy and predict its outcome. Clinically used methods vary from measuring using rules and calipers to sophisticated methods, based on 3D measuring. Our method combines the added value of 3D measuring and well-known segmentation algorithms to enable volume calculation and achieve reliable and operator-independent analysis, as we demonstrate in the paper. METHODS: Developed 3D measuring system is based on laser triangulation with simultaneous color acquisition. Wound shape analysis is based on the edge-determination, virtual healthy skin approximation over the wound and perimeter, area, and volume calculation. In order to validate the approach, eight operators analyzed four different wounds using proposed method. Measuring bias was assessed by comparing measured values with expected values on an artificially modeled set of wounds. RESULTS: Results indicate that the perimeter, area, and volume are measured with a repeatability of 2.5 mm, 12 mm(2), and 30 mm(3), respectively, and with a measuring bias of -0.2 mm, -8.6 mm(2), 24 mm(3), respectively. CONCLUSIONS: According to the results of verification and the fact that typical wound analysis takes 20 seconds, the method for wound shape measurement can be clinically used as a precise tool for objectively monitoring the wound healing based on measuring its 3D shape and color. PMID- 25907429 TI - Stable underwater superoleophobic and low adhesive polypyrrole nanowire mesh in highly corrosive environments. AB - Underwater superoleophobic materials with low adhesion have been widely researched owing to their self-cleaning and anti-corrosive properties. In this study, polypyrrole (PPy) nanowire meshes have been successfully fabricated by in situ electrochemical polymerization on stainless steel mesh substrates in the presence of phosphate buffered saline as both an electrolyte and a dopant. PPy nanowire meshes have high oil contact angles (above 150 degrees ) and low sliding angles (less than 10 degrees ), and they show underwater superoleophobicity with an excellent self-cleaning performance, not only in pure water, but also in highly corrosive aqueous solutions, including salt solutions, strong acids or basic solutions. PPy nanowire meshes presented here show promise for potential applications in fields such as oil-water separation and marine oil spill clean up. PMID- 25907430 TI - The influence of biological rhythms on host-parasite interactions. AB - Biological rhythms, from circadian control of cellular processes to annual cycles in life history, are a main structural element of biology. Biological rhythms are considered adaptive because they enable organisms to partition activities to cope with, and take advantage of, predictable fluctuations in environmental conditions. A flourishing area of immunology is uncovering rhythms in the immune system of animals, including humans. Given the temporal structure of immunity, and rhythms in parasite activity and disease incidence, we propose that the intersection of chronobiology, disease ecology, and evolutionary biology holds the key to understanding host-parasite interactions. Here, we review host parasite interactions while explicitly considering biological rhythms, and propose that rhythms: influence within-host infection dynamics and transmission between hosts, might account for diel and annual periodicity in host-parasite systems, and can lead to a host-parasite arms race in the temporal domain. PMID- 25907432 TI - [Hepatitis C in 2014: responses to frequent questions in daily clinical practice]. PMID- 25907431 TI - Sagittal and vertical effects of transverse sagittal maxillary expander (TSME) in three different malocclusion groups. AB - BACKGROUND: The aim of this retrospective study was to cephalometrically evaluate the skeletal and dental effects of the transverse sagittal maxillary expander (TSME), for the correction of sagittal and transverse maxillary deficiency in class I, II, and III malocclusions. METHODS: The sample for this retrospective study included 45 patients (mean age, 8.4 years; 26 females, 19 males; 15 skeletal class I subjects, 15 skeletal class II subjects, and 15 skeletal class III subjects) with maxillary bilateral cross-bite. For each patient, a lateral cephalogram was obtained before treatment and at the end of the retention period. Changes in the groups during the observation period were calculated, compared, and statistically analyzed with a t-test. RESULTS: The cephalometric values before T0 and T1 showed significant changes. CONCLUSIONS: The TSME can produce skeletal changes due to the transverse force and sagittal effects on the maxillary alveolar process. These modifications have benefic effects in classes I, II, and III. The data obtained in this study permit us to underline the fact that TSME can be used in all of the skeletal classes, with good vertical and sagittal results. PMID- 25907433 TI - [Chronic hepatitis C: patients with mild disease]. AB - Chronic hepatitis C virus infection is usually asymptomatic. The severity of the hepatic lesion in these patients at diagnosis varies and, from the histopathologic point of view, most have mild disease. A series of factors have been described that correlate with the progression of fibrosis in patients with mild fibrosis: age at diagnosis, the duration of the infection, male sex, HIV coinfection, transaminase levels during follow-up, alcohol consumption, metabolic factors such as diabetes and overweight, necroinflammatory activity in the initial biopsy, and the degree of steatosis. In patients with genotype 1 hepatitis C infection, the standard treatment has been pegylated interferon and ribavirin. However, response rates are markedly increased by concomitant use of first-generation protease inhibitors, boceprevir or telaprevir. In patients with moderate fibrosis, these drugs are well tolerated, in addition to being effective. Currently, dual therapy should be reserved for patients with good baseline predictive factors of response and/or contraindications for treatment with telaprevir or boceprevir. In patients with genotypes other than genotype 1, the standard treatment continues to be the combination of pegylated interferon and ribavirin, although the development of new direct-acting antiviral agents such as sofosbuvir and simeprevir will change the strategies used in these patients. The decision to wait for the new treatments is complex because their release date is unknown; likewise, their high cost will limit the possibilities for their use. PMID- 25907434 TI - [Triple therapy in cirrhotic patients and those with advanced fibrosis: relevant aspects in clinical practice]. AB - The first-line option in the treatment of patients with advanced fibrosis and cirrhosis due to genotype 1 hepatitis C virus is currently triple therapy with boceprevir/telaprevir and pegylated interferon-ribavirin. However, certain limitations could constitute a barrier to starting treatment or achieving sustained viral response in these patients. These limitations include the patient's or physician's perception of treatment effectiveness in routine clinical practice-which can weight against the decision to start treatment-, the advanced stage of the disease with portal hypertension and comorbidity, treatment interruption due to poor adherence, and adverse effects, mainly anemia. In addition, it is now possible to identify patients who could benefit from a shorter therapeutic regimen with a similar cure rate. This review discusses these issues and their possible effect on the use of triple therapy. PMID- 25907435 TI - [Hepatitis C treatment in special patient groups]. AB - The treatment plan for chronic hepatitis C in special populations varies according to comorbidity and the current evidence on treatment. In patients with hepatitis C virus and HIV coinfection, the results of dual therapy (pegylated interferon plus ribavirin) are poor. In patients with genotype 1 infection, triple therapy (dual therapy plus boceprevir or telaprevir) has doubled the response rate, but protease inhibitors can interact with some antiretroviral drugs and provoke more adverse effects. These disadvantages are avoided by the new, second-generation, direct-acting antiviral agents. In patients who are candidates for liver transplantation or are already liver transplant recipients, the optimal therapeutic option at present is to combine the new antiviral agents, with or without ribavirin and without interferon. The treatment of patients under hemodialysis due to chronic renal disease continues to be dual therapy (often with reduced doses of pegylated interferon and ribavirin), since there is still insufficient information on triple therapy and the new antiviral agents. In mixed cryoglobulinemia, despite the scarcity of experience, triple therapy seems to be superior to dual therapy and may be used as rescue therapy in non-responders to dual therapy. However, a decision must always be made on whether antiviral treatment should be used concomitantly or after immunosuppressive therapy. PMID- 25907436 TI - Caring for the patient, caring for the record: an ethnographic study of 'back office' work in upholding quality of care in general practice. AB - BACKGROUND: The quality of information recorded about patient care is considered key to improving the overall quality, safety and efficiency of patient care. Assigning codes to patients' records is an important aspect of this documentation. Current interest in large datasets in which individual patient data are collated (e.g. proposed NHS care.data project) pays little attention to the details of how 'data' get onto the record. This paper explores the work of summarising and coding records, focusing on 'back office' practices, identifying contributors and barriers to quality of care. METHODS: Ethnographic observation (187 hours) of clinical, management and administrative staff in two UK general practices with contrasting organisational characteristics. This involved observation of working practices, including shadowing, recording detailed field notes, naturalistic interviews and analysis of key documents relating to summarising and coding. Ethnographic analysis drew on key sensitizing concepts to build a 'thick description' of coding practices, drawing these together in a narrative synthesis. RESULTS: Coding and summarising electronic patient records is complex work. It depends crucially on nuanced judgements made by administrators who combine their understanding of: clinical diagnostics; classification systems; how healthcare is organised; particular working practices of individual colleagues; current health policy. Working with imperfect classification systems, diagnostic uncertainty and a range of local practical constraints, they manage a moral tension between their idealised aspiration of a 'gold standard' record and a pragmatic recognition that this is rarely achievable in practice. Adopting a range of practical workarounds, administrators position themselves as both formally accountable to their employers (general practitioners), and informally accountability to individual patients, in a coding process which is shaped not only by the 'facts' of the case, but by ongoing working relationships which are co-constructed alongside the patient's summary. CONCLUSION: Data coding is usually conceptualised as either a technical task, or as mundane, routine work, and usually remains invisible. This study offers a characterisation of coding as a socially complex site of moral work through which new lines of accountability are enacted in the workplace, and casts new light on the meaning of coded data as conceptualised in the 'quality of care' discourse. PMID- 25907437 TI - Evidence-based design in an intensive care unit: end-user perceptions. AB - BACKGROUND: The objective of this study was to describe end-user impressions and experiences in a new intensive care unit built using evidence-based design. METHODS: This qualitative study was comprised of early (2-3 months after opening) and late (12-15 months after opening) phase individual interviews with end-users (healthcare providers, support staff, and patient family members) of the newly constructed Foothills Medical Centre intensive care unit in Calgary, Canada. The study unit was the recipient of the Society of Critical Care Medicine Design Citation award in 2012. RESULTS: We conducted interviews with thirty-nine ICU end users, twenty-four in the early phase and fifteen in the late phase. We identified four themes (eleven sub-themes): atmosphere (abundant natural light and low noise levels), physical spaces (single occupancy rooms, rooms clustered into clinical pods, medication rooms, and tradeoffs of larger spaces), family participation in care (family support areas and social networks), and equipment (usability, storage, and providers connectivity). Abundant natural light was the design feature most frequently associated with a pleasant atmosphere. Participants emphasized the tradeoffs of size and space, and reported that the benefits of additional space (e.g., fewer interruptions due to less noise) out weighed the disadvantages (e.g., greater distances between patients, families and providers). End-users advised that local patient care policies (e.g., number of visitors allowed at a time) and staffing needed to be updated to reflect the characteristics of the new facility design. CONCLUSIONS: End-users identified design elements for creating a pleasant atmosphere, attention to the tradeoffs of space and size, designing family support areas to encourage family participation in care, and updating patient care policies and staffing to reflect the new physical space as important aspects to consider when building intensive care units. Evidence-based design may optimize ICU structure for patients, patient families and providers. PMID- 25907438 TI - Grammar-based compression approach to extraction of common rules among multiple trees of glycans and RNAs. AB - BACKGROUND: Many tree structures are found in nature and organisms. Such trees are believed to be constructed on the basis of certain rules. We have previously developed grammar-based compression methods for ordered and unordered single trees, based on bisection-type tree grammars. Here, these methods find construction rules for one single tree. On the other hand, specified construction rules can be utilized to generate multiple similar trees. RESULTS: Therefore, in this paper, we develop novel methods to discover common rules for the construction of multiple distinct trees, by improving and extending the previous methods using integer programming. We apply our proposed methods to several sets of glycans and RNA secondary structures, which play important roles in cellular systems, and can be regarded as tree structures. The results suggest that our method can be successfully applied to determining the minimum grammar and several common rules among glycans and RNAs. CONCLUSIONS: We propose integer programming based methods MinSEOTGMul and MinSEUTGMul for the determination of the minimum grammars constructing multiple ordered and unordered trees, respectively. The proposed methods can provide clues for the determination of hierarchical structures contained in tree-structured biological data, beyond the extraction of frequent patterns. PMID- 25907439 TI - Synergistic effects of the sesquiterpene lactone, EPD, with cisplatin and paclitaxel in ovarian cancer cells. AB - BACKGROUND: Ovarian cancer remains still the leading cause of death of gynecological malignancy, in spite of first-line chemotherapy with cisplatin and paclitaxel. Although initial response is favorably, relapses are common and prognosis for women with advanced disease stays poor. Therefore efficacious approaches are needed. METHODS: Previously, an anti-cancer agent, EPD exhibited potent cytotoxic effects towards ovarian cancer and not towards normal cells. Cell viability and cell cycle analysis studies were performed with EPD, in combination with cisplatin and/or paclitaxel, using the ovarian carcinoma cell lines: SK-OV-3, OVCAR-3, JC, JC-pl and normal fibroblasts. Cell viability was measured using Presto Blue and cell cycle analysis using a flow cytometer. Apoptosis was measured in JC and JC-pl , using the caspase 3 assay kit. RESULTS: In JC-pl, SK-OV-3 and JC, synergistic interactions between either EPD and cisplatin or EPD and paclitaxel were observed. For the first time the effects of EPD on the cell cycle of ovarian cancer cells and normal cells was studied. EPD and combinations of EPD with cisplatin and/ or paclitaxel showed cell cycle arrest in the G2/M phase. The combination of EPD and cisplatin showed a significant synergistic effect in cell line JC-pl, while EPD with paclitaxel showed synergistic interaction in JC. Additionally, synergistic drug combinations showed increased apoptosis. CONCLUSIONS: Our results showed a synergistic effect of EPD and cisplatin in an ovarian drug resistant cell line as well as a synergistic effect of EPD and paclitaxel in two other ovarian cell lines. These results might enhance clinical efficacy, compared to the existing regimen of paclitaxel and cisplatin. PMID- 25907440 TI - Antidepressant action of HDAC inhibition in the prefrontal cortex. AB - Previous research has demonstrated antidepressant-like effects in rodents upon intracerebral inhibition of histone deacetylases (HDACs). Such effects have been reported for local HDAC inhibition in the nucleus accumbens, hippocampus, and amygdala. However, the effect of HDAC inhibition within the medial prefrontal cortex, which is integral to depression-related symptoms and their treatment, remains unknown. Here we show that local infusion of the highly selective HDAC inhibitor, MS-275, into the medial prefrontal cortex exerts robust antidepressant like effects in the chronic social defeat stress paradigm in mice. These findings provide further impetus for the assessment of HDAC inhibitors for the treatment of depression. PMID- 25907442 TI - Does the P300 reflect conscious perception or its consequences? AB - A common scientific strategy toward understanding consciousness is to study neural correlates of consciousness (NCC) for a particular conscious percept. This can be done by contrasting conditions in which subjects are aware and unaware of a particular visual stimulus. However, recent findings have been contradictory and this approach appears not to reveal only the NCC, but also the prerequisites or consequences of consciousness. The goal of the present study was to investigate whether the P300 component often claimed to be a key signature of conscious access might actually rather reflect the consequences of conscious perception. Subjects participated in an electroencephalography (EEG) experiment where most of the stimuli were clearly perceived and only a quarter of trials was associated with not perceiving the target. The visual masking paradigm used no discrimination task, always the same stimulus was presented and an additional task was given together with the target stimulus. Results indicate that trials where subjects reported to have seen the stimulus are associated with a more pronounced P300. Hence, the present data support the theories which claim that P300 is a marker of conscious perception. However, an earlier component, visual awareness negativity also tracks conscious perception reliably so that the P300 need not be the earliest correlate of conscious perception. PMID- 25907443 TI - Cognitive impairments and neuronal injury in different brain regions of a genetic rat model of absence epilepsy. AB - Growing numbers of evidence indicate that cognitive impairments are part of clinical profile of childhood absence epilepsy. Little is known on neuropathological changes accompanied by cognitive deficits in absence epilepsy. The aim of the present study was to investigate age-dependent neuropathological changes accompanied by learning and memory impairments in Wistar Albino Glaxo from Rijswijk (WAG/Rij) rat model of absence epilepsy. Experimental groups were divided into four groups of six rats of both WAG/Rij and Wistar strains with 2 and 6 months of age. The learning and memory performances were assessed using passive avoidance paradigm and neuropathological alterations were investigated by the evaluation of the number of dark neurons and apoptotic cells as well as the expression of caspase-3 in the neocortex, the hippocampus, and different regions of the thalamus. Results revealed a decline in learning and spatial memory of 6 month-old WAG/Rij rats compared to age-matched Wistar rats as well as 2-month-old WAG/Rij and Wistar rats. The mean number of dark neurons was significantly higher in the hippocampal CA1 and CA3 areas as well as in the laterodorsal, centromedial, and reticular thalamic nuclei and the somatosensory cortex of 6 month-old WAG/Rij rats. In addition, a higher number of apoptotic cells as well as a higher expression of caspase-3 was observed in the hippocampal CA1 and CA3 regions, the laterodorsal thalamic nucleus, and the somatosensory cortex of 6 month-old WAG/Rij rats compared to other animal groups. These results indicate significant enhancement of neuronal damage and cell death accompanied by memory deficits after seizure attacks in a rat model of absence epilepsy. Seizure induced neuronal injury and death may underlie cognitive impairments in absence epilepsy. PMID- 25907441 TI - 5-HT1B autoreceptors differentially modulate the expression of conditioned fear in a circuit-specific manner. AB - Located in the nerve terminals of serotonergic neurons, 5-HT1B autoreceptors are poised to modulate synaptic 5-HT levels with precise temporal and spatial control, and play an important role in various emotional behaviors. This study characterized two novel, complementary viral vector strategies to investigate the contribution of 5-HT1B autoreceptors to fear expression, displayed as freezing, during contextual fear conditioning. Increased expression of 5-HT1B autoreceptors throughout the brain significantly decreased fear expression in both wild-type (WT) and 5-HT1B knockout (1BKO) mice when receptor levels were increased with a cell-type-specific herpes simplex virus (HSV) vector injected into the dorsal raphe nucleus (DRN). Additional studies used an intersectional viral vector strategy, in which an adeno-associated virus containing a double-floxed inverted sequence for the 5-HT1B receptor (AAV-DIO-1B) was combined with the retrogradely transported canine adenovirus-2 expressing Cre (CAV-Cre) in order to increase 5 HT1B autoreceptor expression only in neurons projecting from the DRN to the amygdala. Surprisingly, selective expression of 5-HT1B autoreceptors in just this circuit led to an increase in fear expression in WT, but not 1BKO, mice. These results suggest that activation of 5-HT1B autoreceptors throughout the brain may have an overall effect of attenuating fear expression, but activation of subsets of 5-HT1B autoreceptors in particular brain regions, reflecting distinct projections of serotonergic neurons from the DRN, may have disparate contributions to the ultimate response. PMID- 25907444 TI - From cognitive motor preparation to visual processing: The benefits of childhood fitness to brain health. AB - The association between a fit body and a fit brain in children has led to a rise of behavioral and neuroscientific research. Yet, the relation of cardiorespiratory fitness on premotor neurocognitive preparation with early visual processing has received little attention. Here, 41 healthy, lower and higher fit preadolescent children were administered a modified version of the Eriksen flanker task while electroencephalography (EEG) and behavioral measures were recorded. Event-related potentials (ERPs) locked to the stimulus onset with an earlier than usual baseline (-900/-800 ms) allowed investigation of both the usual post-stimulus (i.e., the P1, N1 and P2) as well as the pre-stimulus ERP components, such as the Bereitschaftspotential (BP) and the prefrontal negativity (pN component). At the behavioral level, aerobic fitness was associated response accuracy, with higher fit children being more accurate than lower fit children. Fitness-related differences selectively emerged at prefrontal brain regions during response preparation, with larger pN amplitude for higher than lower fit children, and at early perceptual stages after stimulus onset, with larger P1 and N1 amplitudes in higher relative to lower fit children. Collectively, the results suggest that the benefits of being aerobically fit appear at the stage of cognitive preparation prior to stimulus presentation and the behavioral response during the performance of a task that challenges cognitive control. Further, it is likely that enhanced activity in prefrontal brain areas may improve cognitive control of visuo-motor tasks, allowing for stronger proactive inhibition and larger early allocation of selective attention resources on relevant external stimuli. PMID- 25907445 TI - Contrasting effects of Na+, K+-ATPase activation on seizure activity in acute versus chronic models. AB - Epilepsy is a life-shortening brain disorder affecting approximately 1% of the worldwide population. Most epilepsy patients are refractory to currently available antiepileptic drugs (AEDs). Knowledge about the mechanisms underlying seizure activity and probing for new AEDs is fundamental to the discovery of new therapeutic strategies. Brain Na(+), K(+)-ATPase activity contributes to the maintenance of the electrochemical gradients underlying neuronal resting and action potentials as well as the uptake and release of neurotransmitters. Accordingly, a decrease of Na(+), K(+)-ATPase increases neuronal excitability and may predispose to appearing of seizure activity. In the present study, we tested the hypothesis that activation of Na(+), K(+)-ATPase activity with a specific antibody (DRRSAb) raised against a regulatory site in the alpha subunit would decrease seizure susceptibility. We found that incubation of hippocampal homogenates with DRRSAb (1 MUM) increased total and alpha1 Na(+), K(+)-ATPase activities. A higher concentration (3 MUM) increased total, alpha1 and alpha2/alpha3 Na(+), K(+)-ATPase activities. Intrahippocampal injection of DRRSAb decreased the susceptibility of post status epilepticus animals to pentylenetetrazol (PTZ)-induced myoclonic seizures. In contrast, administration of DRRSAb into the hippocampus of naive animals facilitated the appearance of PTZ induced seizures. Quantitative analysis of hippocampal electroencephalography (EEG) recordings revealed that DRRSAb increased the percentage of total power contributed by the delta frequency band (0-3 Hz) to a large irregular amplitude pattern of hippocampal EEG. On the other hand, we found no DRRSAb-induced changes regarding the theta functional state. Further studies are necessary to define the potential of Na(+), K(+)-ATPase activation as a new therapeutic approach for seizure disorders. PMID- 25907446 TI - Effect of serotonin transporter blockade on L-DOPA-induced dyskinesia in animal models of Parkinson's disease. AB - Serotonin transporter blockade with selective serotonin reuptake inhibitors (SSRIs) was recently shown to counteract L-DOPA-induced dyskinesia in 6 hydroxydopamine (6-OHDA)-lesioned rats. However, this effect has never been described in Parkinson's disease (PD) patients, despite that they often receive SSRIs for the treatment of depression. In the present study, we investigated the efficacy of the SSRI citalopram against dyskinesia in two experimental models of PD, the 6-OHDA-lesioned rat and 1-methyl-4-phenyl 1,2,3,6-tetrahydropyridine (MPTP)-treated macaque. First, we studied the acute and chronic effect of citalopram, given at different time points before L-DOPA, in L-DOPA-primed parkinsonian rats. Moreover, the acute effect of citalopram was also evaluated in dyskinetic MPTP-treated macaques. In L-DOPA-primed rats, a significant and long lasting reduction of L-DOPA-induced dyskinesia (LID) was observed only when citalopram was given 30 min before L-DOPA, suggesting that the time of injection relative to L-DOPA is a key factor for the efficacy of the treatment. Interestingly, an acute challenge with the 5-HT1A/1B receptor agonist eltoprazine, given at the end of the chronic study, was equally effective in reducing LID in rats previously chronically treated with L-DOPA or L-DOPA plus citalopram, suggesting that no auto-receptor desensitization was induced by chronic citalopram treatment. In MPTP-treated macaques, citalopram produced a striking suppression of LID but at the expense of L-DOPA therapeutic efficacy, which represents a concern for possible clinical application. PMID- 25907447 TI - A single intracerebroventricular Abeta25-35 infusion leads to prolonged alterations in arginine metabolism in the rat hippocampus and prefrontal cortex. AB - While amyloid beta (Abeta) plays a central role in the development of Alzheimer's disease (AD), recent evidence suggests the involvement of arginine metabolism in AD pathogenesis. Earlier research has shown that a single intracerebroventricular (i.c.v.) infusion of pre-aggregated Abeta25-35 (the neurotoxic domain of the full length Abeta) altered arginine metabolism in the rat hippocampus (particularly the CA2/3 and dentate gyrus (DG) sub-regions) and prefrontal cortex (PFC) at the time point of 8 days post-infusion. The present study measured the levels of L arginine and its nine downstream metabolites (L-citrulline, L-ornithine, agmatine, putrescine, spermidine, spermine, glutamate, GABA and glutamine) in the hippocampus and PFC at the time points of 42 and 97 days following a single bilateral i.c.v. infusion of Abeta25-35 (30 nmol/rat) or Abeta35-25 (reverse peptide; 30 nmol/rat). At the 42-day time point, Abeta25-35 resulted in decreased levels of glutamate, glutamine and spermine in the CA2/3 sub-region of the hippocampus. At the 97-day time point, however, there were decreased L-ornithine, GABA and putrescine levels, but increased glutamate/GABA ratio, in the PFC and increased spermine levels in the DG sub-region. Cluster analyses showed that L arginine and its three main metabolites L-citrulline, L-ornithine and agmatine formed distinct groups, which changed as a function of Abeta25-35 at the 42-day and 97-day time points, particularly in the CA2/3 and PFC regions respectively. This study, for the first time, demonstrates that a single i.c.v. infusion of pre aggregated Abeta25-35 leads to prolonged alterations in arginine metabolism in a region-specific and time-dependent manner, which further supports the involvement of arginine metabolism in AD pathogenesis. PMID- 25907449 TI - Changes in the Blood Serum Levels of the Costimulatory Soluble B7-H4 Molecule in Pregnant Women During the Peripartal Phase. AB - PROBLEM: B7-H4, a transmembrane protein that negatively regulates T lymphocytes, seems to play a role in the suppression of the im?mune response at the maternal fetal interface. The aim of this study was to compare the blood serum concentration levels of soluble B7-H4 (sB7-H4) prepartal and postpartal in both women who experienced spontaneous onset of labor and those who underwent elective cesarian section. METHOD OF STUDY: Blood was obtained from 30 prepartal and postpartal women who delivered at the University Hospital of Essen between 2011 and 2012. These patients were further divided into two subgroups depending on the advancement of labor. The sB7-H4 blood serum concentration levels of the women in the groups were then determined by ELISA (BIOZOL, Eching, Germany). RESULTS: In women who underwent elective cesarian section, a significant increase in sB7-H4 blood serum concentration levels occurred postpartal, while in women who experienced spontaneous onset of labor, no differences between prepartal and postpartal concentration levels were observed. The sB7-H4 blood serum concentration levels on the day after delivery in the women who experienced spontaneous labor and those who underwent elective cesarian section were comparable; however, higher blood serum concentration levels of sB7-H4 were observed prepartal in women with spontaneous onset of labor compared to those found in the women about to undergo elective cesarian section. CONCLUSION: These changes in sB7-H4 blood serum concentration levels suggest that this protein is involved in immunological changes associated with the spontaneous onset of labor and post-delivery homeostasis. PMID- 25907448 TI - Neuroprotective and anti-inflammatory properties of a novel non-thiazolidinedione PPARgamma agonist in vitro and in MPTP-treated mice. AB - Peroxisome proliferator-activated receptor (PPAR)gamma is a potential pharmacological target for disease-modification in Parkinson's disease (PD), mainly acting by modulating the neuroinflammatory response. However, currently available agonists thiazolidinediones (TZDs) present limitations due to safety concerns. We evaluated a novel thiobarbituric-like compound MDG548, which acts as a functional PPARgamma agonist displaying higher and selective binding affinity as compared to TZDs. Neuroprotection by MDG548 was tested in vitro and in a mouse MPTP model of PD, and neuroinflammation was investigated as a putative underlying mechanism. Viability assay on rat cortical neurons showed lack of cytotoxic effect in the dose-range of 100 nM-10 MUM, which was therefore used for testing in vitro protection against H2O2 and MPP+ neurotoxicity. MDG548 dose-dependently increased cell viability of rat cortical neurons co-treated with H2O2 or pre exposed to MDG548 prior to H2O2. Moreover, MDG548 induced neuroprotection in MPP+ treated PC12 cells. NF-kB activation was investigated to assess anti-inflammatory activity. MDG548 dose-dependently decreased NF-kB activation induced by LPS (100 ng/100ml) in HEK-Blue-hTLR4 cells. Given the supposed cancer risk of other PPARgamma agonists, Ames test for genotoxicity was performed in Salmonella typhimurium TA100 and TA98 strains, showing that MDG548 was not genotoxic. In vivo, BL/6J mice were treated with MPTP (20mg/kg i.p. once/day for 4 days) in association with saline or MDG548 (2, 5, 10 mg/kg i.p.). Stereological counting showed that MDG548 prevented the MPTP-induced reduction in TH-positive cells in the substantia nigra compacta (SNc) at all doses tested. Moreover, MDG548 reduced reactive microglia and iNOS induction in the SNc. MDG548, being a non-TZD compound with high PPARgamma affinity, void of genotoxicity, and with in vitro as well as in vivo neuroprotective properties, provides a promising alternative in the search for safer PPARgamma agonists to be tested as potential disease modifying drugs in PD. PMID- 25907450 TI - Emerging paradigms in targeted treatments for Asian patients with NSCLC. AB - INTRODUCTION: EGFR-targeted drugs have been successfully approved in many countries and have demonstrated higher efficacy and lower toxicity than chemotherapy in molecularly defined subgroups of patients. Significant advances in clinical trials and studies focusing on targeted therapies have rapidly developed in Asia. AREAS COVERED: In the present review article, all of the published data or meeting abstracts on completed or ongoing trials of targeted treatment for Asian patients with NSCLC were collected and analyzed. EXPERT OPINION: Routine molecular testing has been used clinically to identify mutations/fusions and guide patient selection for targeted therapies. Based on the evidence presented, we provided up-to-date treatment recommendations for Asian patients with advanced NSCLC. Future directions, including dividing Del19 and L858R patients into two distinct populations, will optimize therapeutic strategies for L858R patients and may inform rational trial design by considering the proportion of type of sensitive EGFR mutation as a stratification factor. Another important aspect to consider involves how to monitor resistance to TKIs, which will improve the outcome for lung cancer patients with driver gene mutations. PMID- 25907451 TI - Reducing pain in acute herpes zoster with plain occlusive dressings: a case report. AB - INTRODUCTION: The pain of acute herpes zoster (shingles) is severe and difficult to control. The medications used to control pain have a variety of important and potentially serious side effects. To the best of my knowledge, this is the first case report of using a plain topical occlusive dressing to reduce the pain of herpes zoster, avoiding the use of medication. CASE PRESENTATION: A 40-year-old Caucasian man and a qualified physician (the author), developed a dermatomal vesicular rash consistent with herpes zoster. Applying plain topical occlusive dressings reduced the severity of his pain to an ignorable level. CONCLUSION: Plain topical occlusive dressings provide effective pain relief for acute herpes zoster, thereby avoiding the risks accompanying medication use. PMID- 25907452 TI - A study on the natural history of scanning behaviour in patients with visual field defects after stroke. AB - BACKGROUND: A visual field defect (VFD) is a common consequence of stroke with a detrimental effect upon the survivors' functional ability and quality of life. The identification of effective treatments for VFD is a key priority relating to life post-stroke. Understanding the natural evolution of scanning compensation over time may have important ramifications for the development of efficacious therapies. The study aims to unravel the natural history of visual scanning behaviour in patients with VFD. The assessment of scanning patterns in the acute to chronic stages of stroke will reveal who does and does not learn to compensate for vision loss. METHODS/DESIGN: Eye-tracking glasses are used to delineate eye movements in a cohort of 100 stroke patients immediately after stroke, and additionally at 6 and 12 months post-stroke. The longitudinal study will assess eye movements in static (sitting) and dynamic (walking) conditions. The primary outcome constitutes the change of lateral eye movements from the acute to chronic stages of stroke. Secondary outcomes include changes of lateral eye movements over time as a function of subgroup characteristics, such as side of VFD, stroke location, stroke severity and cognitive functioning. DISCUSSION: The longitudinal comparison of patients who do and do not learn compensatory scanning techniques may reveal important prognostic markers of natural recovery. Importantly, it may also help to determine the most effective treatment window for visual rehabilitation. PMID- 25907453 TI - A flow cytometer-based whole cell screening toolbox for directed hydrolase evolution through fluorescent hydrogels. AB - A high throughput whole cell flow cytometer screening toolbox was developed and validated by identifying improved variants (1.3-7-fold) for three hydrolases (esterase, lipase, cellulase). The screening principle is based on coupled enzymatic reaction using glucose derivatives which yield upon hydrolysis a fluorescent-hydrogel-layer on the surface of E. coli cells. PMID- 25907454 TI - Validation of a semiautomated liver segmentation method using CT for accurate volumetry. AB - RATIONALE AND OBJECTIVES: To compare the repeatability and agreement of a semiautomated liver segmentation method with manual segmentation for assessment of total liver volume on CT (computed tomography). MATERIALS AND METHODS: This retrospective, institutional review board-approved study was conducted in 41 subjects who underwent liver CT for preoperative planning. The major pathologies encountered were colorectal cancer metastases, benign liver lesions and hepatocellular carcinoma. This semiautomated segmentation method is based on variational interpolation and 3D minimal path-surface segmentation. Total and subsegmental liver volumes were segmented from contrast-enhanced CT images in venous phase. Two image analysts independently performed semiautomated segmentations and two other image analysts performed manual segmentations. Repeatability and agreement of both methods were evaluated with intraclass correlation coefficients (ICC) and Bland-Altman analysis. Interaction time was recorded for both methods. RESULTS: Bland-Altman analysis revealed an intrareader agreement of -1 +/- 27 mL (mean +/- 1.96 standard deviation) with ICC of 0.999 (P < .001) for manual segmentation and 12 +/- 97 mL with ICC of 0.991 (P < .001) for semiautomated segmentation. Bland-Altman analysis revealed an interreader agreement of -4 +/- 22 mL with ICC of 0.999 (P < .001) for manual segmentation and 5 +/- 98 mL with ICC of 0.991 (P < .001) for semiautomated segmentation. Intermethod agreement was found to be 3 +/- 120 mL with ICC of 0.988 (P < .001). Mean interaction time was 34.3 +/- 16.7 minutes for the manual method and 8.0 +/- 1.2 minutes for the semiautomated method (P < .001). CONCLUSIONS: A semiautomated segmentation method can substantially shorten interaction time while preserving a high repeatability and agreement with manual segmentation. PMID- 25907455 TI - Fasting and bed rest, even for a relatively short period, are risk factors for ceftriaxone-associated pseudolitiasis. AB - BACKGROUND: Cholelithiasis is one of the side-effects of ceftriaxone (CTRX). Reportedly, the cholelithiasis resolves relatively soon after cessation of CTRX, hence, it is called pseudolithiasis. Previous reports have suggested that biliary pseudolithiasis can cause not only gallstone attacks, but also severe adverse events, such as cholecystitis and pancreatitis. The purpose of this study was to prospectively elucidate the risk factors and clinical features of CTRX-associated pseudolithiasis in pediatric patients. METHODS: We prospectively examined the incidence and clinical outcome of CTRX-associated biliary pseudolithiasis. Subjects included infants and children who were admitted to hospital with acute disease. Ultrasonography was used to confirm the absence of stones and sludge in the gallbladder before CTRX therapy, and in assessment of pseudolithiasis on days 3, 5, 7 and 10 after initiation of CTRX in all subjects. The pseudolithiasis group was then compared with the non-pseudolithiasis group in terms of age, sex, CTRX dose, CTRX duration, duration of fever, fasting period, period of bed rest, and blood test results. RESULTS: Sixty patients were enrolled in the study. Eleven of them had biliary pseudolithiasis on ultrasonography (18.3%). Formation of biliary pseudolithiasis was prevalent in the fasting and bed rest groups, appearing relatively early in these groups. CONCLUSIONS: Special attention should be paid to the degree of oral intake and patient activity when CTRX is prescribed. We recommend regular ultrasonographic follow up of patients receiving CTRX, to evaluate the formation of biliary pseudolithiasis. PMID- 25907456 TI - Cytokines: An antagonistic family member. PMID- 25907457 TI - Immune regulation: Brain-fat axis in adaptive immunity. PMID- 25907458 TI - Infection: Virus boosts protection. PMID- 25907460 TI - Smoking prevalence, reduction, and cessation during pregnancy and associated factors: a cross-sectional study in public maternities, Rio de Janeiro, Brazil. AB - BACKGROUND: Smoking epidemic in Brazilian women has later onset, smaller magnitude, and slower decreasing trend, compared to men. Among pregnant women, smoking has an additional deleterious effect. The purpose of this study was to analyze smoking prevalence during pregnancy and associated factors, and to describe the frequency of smoking reduction and cessation in public maternities of Rio de Janeiro State, southeastern Brazil, in 2011. METHODS: A cross-sectional study was conducted in two maternities located at public hospitals in two cities of the Rio de Janeiro state, Niteroi (maternity A) and of Rio de Janeiro (maternity B). Data were gathered by interviews 12 hours after the delivery, and analyses of prenatal cards and medical records. Smoking prevalence according to maternal characteristics, adequacy of prenatal care, and proportions of smoking reduction and cessation during pregnancy were calculated. Factors associated to smoking during pregnancy were estimated by logistic regression analysis. RESULTS: Smoking prevalence at maternity A (24.8%, 95% CI: 21.1-29.0) and maternity B (17.9%, 95% CI: 15.8-20.1) were high. Prevalence rates were greater in women aged 20-34 years, mainly without partner, multiparous and brown or black skin color. Low education (OR = 2.14, 95% CI 1.21, 3.79) and multiparity (OR = 3.48, 95% CI 1.78, 6.81), at maternity A; adolescence (OR = 0.44, 95% CI 0.26, 0.75), black skin color (OR = 1.71, 95% CI 1.06, 2.74), low education (OR = 1.61, 95% CI 1.08, 2.40), and multiparity (OR = 1.58, 95% CI 1.03, 2.44), at maternity B, were associated with smoking in multivariable analysis. Adequacy of prenatal care and smoking prevalence showed an inverse association. More than half of the smokers kept the smoking habits during pregnancy. Reduction occurred mainly between the 1(st) and 2(nd) trimesters of pregnancy. CONCLUSION: Smoking prevalence during pregnancy was higher for multiparous and less educated women. Population and individual strategies for smoking prevention and control must include actions specific for women, especially during the reproductive period. PMID- 25907462 TI - The incidence, success rate, and complications of awake tracheal intubation in 1,554 patients over 12 years: an historical cohort study. AB - PURPOSE: Awake tracheal intubation is one recommended option to address select situations in the management of a patient with an anticipated difficult airway. A scarcity of data exists on how often awake intubation is performed or whether its use is changing over time, particularly with the increasingly widespread availability of video laryngoscopy. This retrospective database review was undertaken to determine the incidence, success, and complications of awake intubation and the incidence of other tracheal intubation techniques in the operating room over a 12-yr period (2002-2013) at our institution. METHODS: The Anesthesia Information Management System in use at a Canadian tertiary care centre was searched for all awake intubations that occurred during the years 2002 2013. Records were also searched to identify airway methods other than direct laryngoscopy that may have been used after the induction of general anesthesia. Changes in both the incidence of awake intubation and in the use of video laryngoscopy over the 12 years were analyzed using linear regression modelling. RESULTS: Of 146,252 cases performed under general anesthesia with endotracheal intubation, 1,554 intubations (1.06%) were performed awake. There was no significant change in the rate of awake intubation over the studied years (slope 1.4(-4) incidence.year(-1); 95% confidence interval [CI]: -3.0(-4) to 3.0(-5); P = 0.102). The relatively steady rate of awake intubation occurred despite a significant increase in the use of video laryngoscopy over the same time (slope 0.080 incidence.year(-1); 95% CI: 0.076 to 0.083; P < 0.001), particularly from 2009 onwards. Attempted awake intubation failed in 31 (2%) of the cases. Self reported complications occurred in 15.7% of successful procedures. In addition, in a convenience sample of three years (2011-2013), the rate at which each of 49 attending staff performed awake intubation varied widely from 0-3.4 awake intubations per 100 cases of general anesthesia with endotracheal intubation. CONCLUSIONS: At our tertiary care centre, we did not find a significant change in the use of awake tracheal intubation over the studied years 2002-2013 despite increasing availability and use of video laryngoscopy. It appears that awake tracheal intubation retains an important and consistent role in the management of the difficult airway. PMID- 25907463 TI - Magnetic resonance imaging markers of suicide attempt and suicide risk in adolescents. AB - More than 36,000 people in the United States die from suicide annually, and suicide is the third leading cause of death in adolescence. Adolescence is a time of high risk for suicidal behavior, as well as a time that intervention and treatment may have the greatest impact because of structural brain changes and significant psychosocial development during this period. Functional and structural neuroimaging studies in adults who have attempted suicide suggest distinct gray matter volume abnormalities in cortical regions, as well as prefrontal cortical and dorsal anterior cingulate gyrus neural circuitry differences compared with affective and healthy adult controls. Recent functional neuroimaging studies in adolescents with a history of suicide attempt suggest differences in the attention and salience networks compared with adolescents with depression and no history of suicide attempt and healthy controls when viewing angry faces. In contrast, no abnormalities are seen in these areas in the absence of emotional stimuli. These networks may represent promising targets for future neuroimaging studies to identify markers of risk for future suicide attempt in adolescents. PMID- 25907459 TI - The impact of diet on asthma and allergic diseases. AB - The incidence of allergic diseases is increasing, both in developed and developing countries, concomitantly with the rise in living standards and the adoption of a 'western lifestyle'. For two decades, the hygiene hypothesis - which proposes that the lack of early childhood exposure to infectious agents increases susceptibility to allergic diseases in later life - provided the conceptual framework for unravelling the mechanisms that could account for the increased incidence of allergic diseases. In this Review, we discuss recent evidence that highlights the role of diet as a key factor influencing immune homeostasis and the development of allergic diseases through a complex interplay between nutrients, their metabolites and immune cell populations. Although further investigations are still required to understand these complex relationships, recent data have established a possible connection between metabolic homeostasis and allergic diseases. PMID- 25907464 TI - Challenges of microtome-based serial block-face scanning electron microscopy in neuroscience. AB - Serial block-face scanning electron microscopy (SBEM) is becoming increasingly popular for a wide range of applications in many disciplines from biology to material sciences. This review focuses on applications for circuit reconstruction in neuroscience, which is one of the major driving forces advancing SBEM. Neuronal circuit reconstruction poses exceptional challenges to volume EM in terms of resolution, field of view, acquisition time and sample preparation. Mapping the connections between neurons in the brain is crucial for understanding information flow and information processing in the brain. However, information on the connectivity between hundreds or even thousands of neurons densely packed in neuronal microcircuits is still largely missing. Volume EM techniques such as serial section TEM, automated tape-collecting ultramicrotome, focused ion-beam scanning electron microscopy and SBEM (microtome serial block-face scanning electron microscopy) are the techniques that provide sufficient resolution to resolve ultrastructural details such as synapses and provides sufficient field of view for dense reconstruction of neuronal circuits. While volume EM techniques are advancing, they are generating large data sets on the terabyte scale that require new image processing workflows and analysis tools. In this review, we present the recent advances in SBEM for circuit reconstruction in neuroscience and an overview of existing image processing and analysis pipelines. PMID- 25907465 TI - Isomerization of Olefins Triggered by Rhodium-Catalyzed C-H Bond Activation: Control of Endocyclic beta-Hydrogen Elimination. AB - Five-membered metallacycles are typically reluctant to undergo endocyclic beta hydrogen elimination. The rhodium-catalyzed isomerization of 4-pentenals into 3 pentenals occurs through this elementary step and cleavage of two C-H bonds, as supported by deuterium-labeling studies. The reaction proceeds without decarbonylation, leads to trans olefins exclusively, and tolerates other olefins normally prone to isomerization. Endocyclic beta-hydrogen elimination can also be controlled in an enantiodivergent reaction on a racemic mixture. PMID- 25907467 TI - The added value of PET/Ce-CT/DW-MRI fusion in assessment of hepatic focal lesions: PET/Ce-CT/DW-MRI fusion in hepatic focal lesion. AB - INTRODUCTION: The liver hosts a variety of benign and malignant tumors. Accurate diagnosis can be challenging in certain cases, especially in patients with a history of malignancy or in those with underlying liver pathology, such as cirrhosis. OBJECTIVES: To evaluate the added clinical value of multi-modality liver imaging utilizing PET/Ce-CT/DW-MRI for characterization of hepatic focal lesions (HFL) and compare it with each diagnostic modality when interpreted alone. METHODS: The study included 35 patients with HFL. They were 7 females & 28 males; their age ranged from 41 to 78years, all patients underwent PET/Ce-CT and DW-MRI scans. Ce-CT, PET and DW-MR images were reviewed independently, and then combined PET/Ce-CT, PET/DW-MRI and PET/Ce-CT/DW-MRI scans were analyzed. The results were correlated with histopathology or clinical/imaging follow-up. RESULTS: The 35 patients had 98 focal lesions. Fifty-three lesions were finally diagnosed as primary hepatocellular carcinoma, 18 lesions were metastases, 7 lesions were lymphoma and 20 lesions were benign. On a patient based analysis; the sensitivity, specificity, PPV, NPV and accuracy were 100%, 67%, 94%, 100% and 94% for PET/Ce-CT compared to 97%, 83%, 97%, 83% and 94 % for DW-MRI, respectively. Combined PET/Ce-CT/DW-MR scans raise those parameters up to 100%. On a lesion based analysis; the sensitivity, specificity, PPV, NPV and accuracy were 94%, 75%, 94%, 75%, 90% for PET/Ce-CT compared to 94%, 95%, 99%, 97% and 94 % for DW-MRI, respectively. All these parameters were 100 % with PET/Ce-CT/DW MRI. CONCLUSIONS: The addition of DW-MRI to PET/Ce-CT is valuable in the characterization of hepatic focal lesions. PMID- 25907466 TI - Performant Mutation Identification Using Targeted Next-Generation Sequencing of 14 Thoracic Aortic Aneurysm Genes. AB - At least 14 causative genes have been identified for both syndromic and nonsyndromic forms of thoracic aortic aneurysm/dissection (TAA), an important cause of death in the industrialized world. Molecular confirmation of the diagnosis is increasingly important for gene-tailored patient management but consecutive, conventional molecular TAA gene screening is expensive and labor intensive. To circumvent these problems, we developed a TAA gene panel for next generation sequencing of 14 TAA genes. After validation, we applied the assay to 100 Marfan patients. We identified 90 FBN1 mutations, 44 of which were novel. In addition, Multiplex ligation-dependent probe amplification identified large deletions in six of the remaining samples, whereas false-negative results were excluded by Sanger sequencing of FBN1, TGFBR1, and TGFBR2 in the last four samples. Subsequently, we screened 55 syndromic and nonsyndromic TAA patients. We identified causal mutations in 15 patients (27%), one in each of the six following genes: ACTA2, COL3A1, TGFBR1, MYLK, SMAD3, SLC2A10 (homozygous), two in NOTCH1, and seven in FBN1. We conclude that our approach for TAA genetic testing overcomes the intrinsic hurdles of consecutive Sanger sequencing of all candidate genes and provides a powerful tool for the elaboration of clinical phenotypes assigned to different genes. PMID- 25907468 TI - The first detection of white spot syndrome virus in naturally infected cultured Chinese mitten crabs, Eriocheir sinensis in China. AB - An epidemic with a high mortality rate (80-100%) recently occurred in the cultured Chinese mitten crab, Eriocheir sinensis, which is a very important economic crustacean species in China. Using negative stain, histopathology and nested PCR supplemented by sequencing we identified white spot syndrome virus (WSSV) in these crabs. Challenge experiments revealed that the disease was caused by WSSV and confirmed the crab's susceptibility to this virus, which was consistent with previous laboratory-based studies. A cumulative mortality of 100% was observed within 10 days post WSSV injection. This is the first report of WSSV associated disease outbreaks in the Chinese mitten crab, which is normally reported as an important penaeid-shrimp viral pathogen. Furthermore, this is only the second report to describe a significant pathogen in pond-cultured E. sinensis. These results will enhance the early diagnosis of WSSV in the crab farms and help in monitoring efforts directed at determining the prevalence of the virus in E. sinensis. PMID- 25907469 TI - Development and validation of a multiplex reverse transcription quantitative PCR (RT-qPCR) assay for the rapid detection of Citrus tristeza virus, Citrus psorosis virus, and Citrus leaf blotch virus. AB - A single real-time multiplex reverse transcription quantitative polymerase chain reaction (RT-qPCR) assay for the simultaneous detection of Citrus tristeza virus (CTV), Citrus psorosis virus (CPsV), and Citrus leaf blotch virus (CLBV) was developed and validated using three different fluorescently labeled minor groove binding qPCR probes. To increase the detection reliability, coat protein (CP) genes from large number of different isolates of CTV, CPsV and CLBV were sequenced and a multiple sequence alignment was generated with corresponding CP sequences from the GenBank and a robust multiplex RT-qPCR assay was designed. The capacity of the multiplex RT-qPCR assay in detecting the viruses was compared to singleplex RT-qPCR designed specifically for each virus and was assessed using multiple virus isolates from diverse geographical regions and citrus species as well as graft-inoculated citrus plants infected with various combination of the three viruses. No significant difference in detection limits was found and specificity was not affected by the inclusion of the three assays in a multiplex RT-qPCR reaction. Comparison of the viral load for each virus using singleplex and multiplex RT-qPCR assays, revealed no significant differences between the two assays in virus detection. No significant difference in Cq values was detected when using one-step and two-step multiplex RT-qPCR detection formats. Optimizing the RNA extraction technique for citrus tissues and testing the quality of the extracted RNA using RT-qPCR targeting the cytochrome oxidase citrus gene as an RNA specific internal control proved to generate better diagnostic assays. Results showed that the developed multiplex RT-qPCR can streamline viruses testing of citrus nursery stock by replacing three separate singleplex assays, thus reducing time and labor while retaining the same sensitivity and specificity. The three targeted RNA viruses are regulated pathogens for California's mandatory "Section 3701: Citrus Nursery Stock Pest Cleanliness Program". Adopting a compatible multiplex RT-qPCR testing protocol for these viruses as well as other RNA and DNA regulated pathogens will provide a valuable alternative tool for virus detection and efficient program implementation. PMID- 25907470 TI - Development and application of an indirect ELISA for the detection of antibodies to novel duck reovirus. AB - A novel duck reovirus (N-DRV) disease emerged in China in 2000 and it has become an epidemic genotype. A test for detection of virus-specific antibodies in serum samples would be useful for epidemiological investigations. Currently, Currently, serological assays for N-DRV diagnosis are not available. A test for detection of virus-specific antibodies in serum samples would be useful for epidemiological investigations. In this study, a highly sensitive and specific indirect enzyme linked immunosorbent assay (ELISA) for the detection of antibodies to N-DRV was developed. The outer capsid (sigmaC) of N-DRV was cloned and expressed in Escherichia coli as a coating antigen. The antigen concentration and serum dilution were optimized using a checkerboard titration. Furthermore, the specificity of sigmaC-ELISA assay was confirmed by cross checking with other duck viral pathogens. In comparison with the western blot, the sensitivity and specificity of the sigmaC-ELISA was 92.6% and 88.9%, respectively, and agreement of two tests was excellent with kappa value of 0.786 (p < 0.05). A serological survey was performed using the assay on serum samples from different age and species of duck flocks in the Zhejiang and Jiangsu Province, China. The seropositive rate of the 1209 serum samples was 57.7%. In conclusion, the developed sigmaC-ELISA assay is a very specific and sensitive test that will be useful for large-scale serological survey in N-DRV infection and monitoring antibodies titers against N-DRV. PMID- 25907471 TI - Detection, discrimination and discovery of a new Tobacco streak virus strain. AB - Soybean plants that exhibited symptoms of virus infection were sampled from different counties of Oklahoma. These plants were tested serologically for 15 viruses known to infect soybean plants. Fifty-seven samples that exhibited typical virus-like symptoms did not test positive for any of the 15 viruses used in a dot-immunobinding assay (DIBA). Four samples were pooled and used for next generation sequencing using the 454-Roche protocol. Sequence and phylogenetic analysis of the sequences obtained revealed infection with a distinct strain of Tobacco streak virus (TSV). TSV was one of the 15 viruses initially tested for using DIBA and had tested negative. TSV belongs to the genus Ilarvirus and has been reported as a causal agent of bud blight in soybean crops in Brazil and the United States. Out of 10 reported primer pairs for TSV reverse transcription polymerase chain reaction (RT-PCR), only two had the potential, based on sequence similarity, to amplify part of the genome of the distinct strain of TSV found in Oklahoma and only one was actually able to amplify the region. In this study, a new primer pair, specific to all known TSV and capable of amplifying the Oklahoma strain (TSV-OK), was designed from a highly conserved region of coat protein (CP) sequences and end-point PCR and quantitative RT-PCR detection methods were developed and their sensitivity assayed. This is the first report of specific primers designed from this highly conserved region in the CP of TSV for detection of TSV. Twenty-three of the 57 DIBA soybean samples that initially tested negative were retested with the new specific end-point PCR method and found positive for TSV infection. PMID- 25907472 TI - [Innovation in succession:leading the way of prevention and control of cardiovascular disease with Chinese characteristics]. PMID- 25907473 TI - [A centennial development of invasive cardiology in China]. PMID- 25907474 TI - [A centennial development of coronary artery disease in China]. PMID- 25907475 TI - [Epidemiology, diagnosis and treatment of hypertension in China: 60 years development history]. PMID- 25907476 TI - [Heart failure in China: review and prospect]. PMID- 25907477 TI - [A centennial development of electrocardiology in China]. PMID- 25907478 TI - [Retrospect on the development of clinical electrophysiology in China]. PMID- 25907479 TI - [A centennial retrospect and outlook in clinical dyslipidemia and atherosclerosis]. PMID- 25907480 TI - [Bright beginning of Chinese cardiac rehabilitation post a rough road]. PMID- 25907481 TI - [Development history of cardiovascular imaging in China: retrospect and expectation]. PMID- 25907482 TI - [Spiritual monument of dedicators]. PMID- 25907483 TI - [Erectile dysfuction in men with atherosclerotic cardiovascular disease]. PMID- 25907484 TI - [Postmenopausal estrogen, lipid metabolism and atherosclerosis]. PMID- 25907485 TI - [Association of human epicardial adipose tissue volume and inflammatory mediators with atherosclerosis and vulnerable coronary atherosclerotic plaque]. AB - OBJECTIVE: To investigate the relation of epicardial adipose tissue volume (EATV) determined by dual-source CT (DSCT) cardiac angiography and EAT-derived inflammatory factors to coronary heart disease (CHD) and vulnerable plaque. METHODS: A total of 260 patients underwent cardiac computed tomography to evaluate stenosis of coronary artery, and blood samples were obtained from each patient. CHD was confirmed in 180 patients by DSA and CHD was excluded in the remaining 80 patients (NCHD). Vascular remodeling index and plaque vulnerability parameters (fatty volume, fibrous volume and calcification volume and fiber volume) were measured in CHD patients and correlation with EATV was analyzed. Epicardial adipose tissue (EAT) and intrathoracic adipose tissue (TAT) were collected from 40 CHD patients undergoing CABG surgery, and, mRNA and protein expressions of leptin and MMP9 were detected by RT-PCR and Western blot analysis. RESULTS: (1) The EATV was significantly higher in the CHD group than in NCHD group ((121.2 +/- 40.6) mm3 vs. (74.7 +/- 18.1) mm3, P = 0.01). (2) Subgroup analysis of the CHD patients demonstrated that EATV was significantly higher in patients with positive remodeling than in patients without positive remodeling ((97.6 +/- 42.0) cm3 vs. (75.5 +/- 25.4) cm3, P = 0.01). Lipid plaque volume was positively correlated with EATV (r = 0.34, P = 0.002); however, fiber plaque volume was negatively correlated with EATV (r = -0.30, P = 0.008). (3) Logistic regression analysis indicated that EATV was an independent risk factor for positive vascular remodeling (OR = 2.01, 95% CI: 1.30-2.32, P = 0.01). (4) mRNA and protein expression of leptin and MMP9 in EAT was significantly upregulated in 40 CHD patients who received CABG surgery compared to 40 NCHD patients (P < 0.01). However, there was no significant difference (P > 0.05) in mRNA and protein expression of leptin and MMP9 from the SAT between CHD and NCHD patients. (5) In the CHD group, leptin and MMP9 levels in EAT and EATV were positively correlated with lipid plaque volume and fibrous plaque volume (P < 0.05). CONCLUSIONS: EATV is an independent risk factors of coronary heart disease and plaque vulnerability; EAT secretion of inflammatory cytokines from CHD patients is significant increased compared to NCHD patients, EAT secretion of inflammatory cytokines are positively correlated with EATV, both of which are determinants affecting vascular remodeling. Reducing EATV might help to attenuate inflammation and plaque vulnerability and reduce the risk of coronary heart disease. PMID- 25907486 TI - [High insulin level promotes the degradation of high density lipoprotein generation-related functional protein ABCA1 through calpain and proteasome pathway in 3T3-L1 adipocytes]. AB - OBJECTIVE: To explore effects and potential mechanisms of high insulin environment on high density lipoprotein (HDL) generation-related functional protein ABCA1. METHODS: [(3)H] labeled cholesterol efflux from mature 3T3-L1 adipocytes was detected by liquid scintillation counting. ABCA1 mRNA and protein expression in mature 3T3-L1 adipocytes post stimulation with various concentrations of insulin was detected by real-time fluorescence-based quantitative techniques and Western blot, respectively, in the absence and presence of CHX (cycloheximide, CHX), calpeptin (calpain pathway inhibitor) or MG 132 (proteasome pathway inhibitor). RESULTS: Cholesterol efflux rates were reduced post insulin stimulation in a dose-dependent manner ((7.06 +/- 0.27)%, (6.59 +/- 0.30)%, (6.34 +/- 0.24)%, (5.07 +/- 0.40)%, and (4.71 +/- 0.40)% at 0, 1, 10, 102, and 103 nmol/L of insulin, P < 0.05). Cholesterol efflux rates decreased in a time-dependent manner post 103 nmol/L insulin stimulation (6.52 +/ 0.30)%, (5.59 +/- 0.71)%, (5.44 +/- 0.37)%, (4.52 +/- 0.32)%, and (4.38 +/- 0.33)% at 0, 2, 4, 6, 12 h, respectively). ABCA1mRNA levels were not affected by insulin (P > 0.05). ABCA1 protein level was significantly downregulated in 103 nmol/L insulin group compared to 0 nmol/L insulin group (P < 0.01). Compared with the 0 h group, ABCA1 protein level was significantly reduced in 6 h group (P < 0.05) and further reduced in 12 h group (P < 0.01). Both calpeptin and MG-132 could partly reduce insulin-induced degradation of ABCA1. Compared with the negative control group, ABCA1 protein levels were significantly upregulated by cotreatment with calpeptin and MG-132, respectively (both P < 0.01). CONCLUSION: Our data suggest that high insulin level could promote the ABCA1 protein degradation and reduce cholesterol efflux from mature 3T3-L1 adipocytes through calpain and proteasome pathway, thus, produce a circumference not suitable for nascent HDL formation in 3T3-L1 adipocytes. PMID- 25907487 TI - [Macrophage content detection in an experimental rabbit model of atherosclerotic plaque by optical coherence tomography]. AB - OBJECTIVE: To evaluate the feasibility of detecting macrophage content on atherosclerotic plaques by optical coherence tomography (OCT) technique. METHODS: Thirty New Zealand white rabbits were equally divided into 3 groups at random: Control group (fed normal rabbit chow, n = 10); lipid diet group (fed regular chow supplemented with cholesterol, n = 10) and balloon injury+ lipid diet group (balloon catheter injury of the common carotid artery after 2 weeks lipid diet, n = 10). After 12 weeks, all rabbits underwent pharmacological triggering with Chinese Russell's viper venom (CRVV, 15 mg/kg, i.p.) and histamine (0.02 mg/kg, i.v.). Common carotid arteries were detected with OCT and the Movat pentachrome stain respectively. OCT and histological examination results were compared and the correlation was analyzed. RESULTS: The intra thickness measured by Movat pentachrome stain and by the OCT was (15.2 +/- 0.9) um and (20.2 +/- 7.6) um, the medial thickness was (434.2 +/- 86.5) um and (453.8 +/- 87.2) um, the plaque thickness was (330.2 +/- 87.1) um and (392.2 +/- 134.5) um, the fibrous cap thickness was (58.3 +/- 5.6) um and (61.2 +/- 4.9) um, respectively (all P > 0.05). The normalized standard deviation of the OCT signal (NSD) was compared with immunohistochemical detection. The OCT signal within the cap is relatively homogeneous for low macrophage density in high lipid diet group. For the raw OCT data, a correlation of r = 0.846 (P < 0.01) was found between OCT NSD and a CD68 area<10%, whereas for the base 10 logarithm OCT data, a correlation of r = 0.646 (P < 0.05) was found between OCT NSD and a CD68 area<10%. In balloon injury + high lipid diet group, the OCT signal within the cap was relatively heterogeneous for high macrophage content. For the raw OCT data, a correlation of r = 0.906 (P < 0.01) was found between OCT NSD and a CD68 area >10%, whereas for the base 10 logarithm OCT data, a correlation of r = 0.593 (P < 0.05) was found between OCT NSD and a CD68 area >10%. For the raw OCT signal NSD, a range of NSDs (7.12% to 7.35%) demonstrated 100% sensitivity and specificity (Kappa value 1.0) for differentiating caps containing >10% CD68 staining. For the base 10 logarithm OCT signal, NSD values ranging from 7.81% to 7.92% provided 70% sensitivity and 75% specificity (value 0.44) for identifying caps containing >10% CD68 staining. CONCLUSIONS: OCT is an effective tool to determine macrophage content in this model. OCT imaging can clearly visualize different types of atherosclerotic plaques and provide detailed information on plaque characteristics. PMID- 25907488 TI - [Clinical intervention research on mental stress-induced myocardial ischemia]. AB - OBJECTIVE: To observe the impact of Xinkeshu on top of standard medication on psychological stress-related emotional and biophysiological parameters in patients with mental stress-induced myocardial ischemia (MSIMI). METHODS: A randomized controlled clinical trial was conducted on 40 patients with MSIMI and patients were randomized into treatment group (n = 21) and control group (n = 19) by random number table method. Patients in the treatment group received Xinkeshu (12 capsules/d) on top of standard therapy, and the control group received placebo on top of standard therapy. Serum homocysteine (Hcy), Patient Health Questionnaire-9 (PHQ-9), Generalized Anxiety Disorder-7 (GAD-7), left ventricular ejection fraction (LVEF) and left ventricular fractional shortening (LVFS) were compared between the groups at baseline and after 8 weeks therapy. RESULTS: (1) Baseline data were similar between the 2 groups (all P > 0.05). (2) After 8 weeks, LVFS was significantly increased (from (34.62 +/- 5.76)% to (35.90 +/- 4.99) %, P = 0.027) and serum Hcy (from (18.08 +/- 1.81) umol/L to (16.06 +/- 10.10) umol/L), PHQ-9 (from 8.14 +/- 3.98 to 6.28 +/- 2.87) and GAD-7 (from 9.52 +/- 4.98 to 6.48 +/- 3.84) were significantly reduced in treatment group (all P < 0.05) compared to baseline. In the control group, only GAD-7 was significantly reduced (from 8.89 +/- 5.06 to 6.74 +/- 4.80, P = 0.003) after 8 weeks therapy compared to baseline (P < 0.05) while other parameters remained unchanged (all P > 0.05). CONCLUSION: Xinkeshu on the top of standard therapy can improve the emotional state and left ventricular systolic function in patients with MSIMI. PMID- 25907489 TI - [Stromal interaction molecule 1 silencing attenuates the proliferation and migration capacities of endothelial progenitor cells]. AB - OBJECTIVE: The purpose of this study is to explore the impact of stromal interaction molecule 1 (STIM1) knockdown on the proliferation and migration capacities of endothelial progenitor cells (EPCs). METHODS: The rat bone marrow derived EPCs were obtained and divided into three groups: adenovirus negative control (NSC) group, rat STIM1 adenovirus vector transfection (si/rSTIM1) group and rat and human recombinant STIM1 adenovirus transfection (si/rSTIM1+hSTIM1) group. The STIM1 expressions in each group were detected by reverse transcription PCR after transfection. The cell proliferation was tested by [(3)H] thymidine incorporation assay ((3)H-TdR). Cell cycle was analyzed by flow cytometry. The cells migration activity was detected by Boyden assay. Calcium ion concentration was detected by confocal laser scanning microscopy. RESULTS: 48 h after transfection, the expression level of STIM1 in si/rSTIM1 group was significantly lower than that in NSC group (0.21 +/- 0.12 vs. 1.01 +/- 0.01, P < 0.05), and number of EPCs at G1 phase in si/rSTIM1 group ((93.31 +/- 0.24)%) was significantly higher than that in NSC group ((78.03 +/- 0.34)%, P < 0.05), and EPCs' migration activity in si/rSTIM1 group (10.03 +/- 0.33) was significantly lower than that in NSC group (32.11 +/- 0.54, P < 0.05), and EPCs calcium ion concentration in EPCs in si/rSTIM1 group (38.03 +/- 0.13) was significantly lower than that in NSC group (98.11 +/- 0.34, P < 0.05), while there was no significant difference between si/rSTIM1+hSTIM1 group and NSC group on the above four indexes. CONCLUSION: Silencing STIM1 could attenuate EPCs proliferation and migration capacities by modulating the calcium ion concentration in EPCs. PMID- 25907490 TI - [Impacts and mechanisms of kruppel like factor 15 in pressure overload induced cardiac remodeling and angiogenesis in rats]. AB - OBJECTIVE: To explore the impact of kruppel like factor 15 (KLF15) on cardiac fibroblasts on angiogenesis in a pressure overload rat model. METHODS: Pressure overload was induced in female rats by aortic constriction for 3 and 6 weeks. After 6 weeks aortic banding, rats underwent aortic debanding for 3 or 6 weeks. Sham rats were observed for 3 and 6 weeks (n = 10 each). Cardiac function, myocardial pathological changes, interstitial angiogenesis and KLF15 expression during rat myocardial overloading-unloading process were determined. Cardiac fibroblasts and vascular endothelial cells were cultured in vitro in the absence or presence of KLF15-shRNA recombinant adenovirus and the regulation effect of KLF15 on vascular endothelial cells and angiogenesis was observed on a three dimensional angiogenesis in vitro model. RESULTS: The ascending aorta diameter, ejection fraction, fractional shortening, left ventricular systolic pressure and the KLF15 protein expression level were significantly lower but the left ventricular end-diastolic pressure was significantly higher in pressure overloaded rats than in Sham rats (all P < 0.01) after 6 weeks. At the same time, increased myocardial hypertrophy and fibrosis as well as reduced angiogenesis density were observed in pressure overloaded rats. These changes were significantly attenuated post aortic debanding. In vitro, KLF15-shRNA recombinant adenovirus transfection into cardiac fibroblasts significantly downregulated the protein expression of KLF15 compared with the control group (4 922 +/- 430 vs. 7 034 +/- 178, P < 0.01). The formation of tubular structure of vascular endothelial cells was shorter after KLF15-shRNA recombinant adenovirus transfection and the structure was incomplete when compared with the control group. CONCLUSION: Our results suggest that upregulation of KLF15 expression in myocardial fibroblasts might promote vascular generation, alleviate the myocardial interstitial fibrosis and improve cardiac function in this pressure overload rat model. PMID- 25907491 TI - [Tanshinone attenuates myocardial injury via activating JAK2/STAT1 pathway in a murine model of viral myocarditis]. AB - OBJECTIVE: To explore the effects of tanshinone and JAK2/STAT1 signaling pathway related mechanism in CVB3-induced myocarditis in murine. METHODS: A total of 110 inbred male Balb/c mice which were 4 to 6 weeks-old were randomly divided into five groups: normal control (N, n = 10), myocarditis control (C, n = 25), tanshinone group (T, 15 mg . kg-1 . d-1, i.p., n = 25), janus kinase 2 inhibitor AG490 group (A, 10 mg . kg-1 . d-1, i.p., n = 25), T+A group (H, n = 25). Myocarditis was induced by 0.5 ml 10(-9.51) TCID50/ml CVB3 i.p. injection for 10 days in group C, T and H. Myocardial histopathologic changes were observed and phospho-STAT1 expressions were detected by immunohistochemistry and Western blot analysis. The levels of serum cardiac troponin I were detected with chemiluminescence immunoassay. RESULTS: (1) Compared with group C, the histopathologic scores were significantly higher in group A and H (3.35 +/- 0.57 and 3.34 +/- 0.54 vs. 2.12 +/- 0.39, P < 0.01), but lower in group T (1.40 +/- 0.34 vs.2.12 +/- 0.39, P < 0.01). (2) The expression of p-STAT1 protein was similar in group A and H compared to group N (P > 0.05), but was significantly lower than that in group C (0.017 +/- 0.010 and 0.020 +/- 0.010 vs. 0.246 +/- 0.010, P < 0.01). The expression of p-STAT1 protein was significantly higher in group T than in group C (P < 0.01). (3) The levels of serum cardiac troponin I in group C, A, T and H were significantly higher than in group N ((0.42 +/- 0.06), (1.17 +/- 0.25), (0.23 +/- 0.05) and (1.04 +/- 0.19) ug/L vs. (0.02 +/- 0.01) ug/L, all P < 0.01). The levels of serum cardiac troponin I were significantly higher in group A and H compared with group C ((1.17 +/- 0.25) and (1.04 +/- 0.19) ug/L vs. (0.42 +/- 0.06) ug/L, P < 0.01), but were significantly lower in group T than in group C ((0.23 +/- 0.05) ug/L vs. (0.42 +/- 0.06) ug/L, P < 0.01). (4) There was a negative correlation between the expression level of p STAT1 and the histopathologic scores (y = -4.503 x + 3.371, R2 = 0.738, P < 0.01), but a positive correlation between the levels of serum cardiac troponin I and the histopathologic scores (y = 1.935x + 1.165, R2 = 0.766, P < 0.01). CONCLUSION: Tanshinone could attenuate myocardial injury via upregulating the JAK2/STAT1 signaling pathway in this murine viral myocarditis model. PMID- 25907492 TI - [The optimal cutoff point of waist-to-hip ratio for screening Uyghur population aged 35 years and over at high-risk of cardiovascular diseases in Xinjiang]. AB - OBJECTIVE: To explore the appropriate waist-to-hip ratio (WHR) cutoffs to identify people at high risk of cardiovascular disease of Uygur population aged 35 years and over in Xinjiang. METHODS: The cardiovascular risk survey (CRS) in Xinjiang was conducted from October 2007 to March 2010, using 4-stagestratified random sampling method and 14 618 representative participated this survey, and the questionnaire survey, anthropometric data, blood pressure, serum total cholesterol, triglyceride, low density lipoprotein (LDL-C), high density lipoprotein (HDL-C) and fasting glucose were measured. A total of 4 657 participants aged 35 years and over with complete anthropometric data were analyzed. The sensitivity, specificity and distance on the receiver operating characteristic (ROC) curve of different WHR levels predicting risk factors of cardiovascular disease were calculated. The analysis method of ROC curve was used to determine the optimum cut-off point of WHR predicting risk factors of cardiovascular disease. RESULTS: (1) There were significantly differences in prevalence of hypertension, diabetes mellitus, hypercholesterolemia, low HDL-C level, and hypertriglyceridemia between WHR < 0.75,0.75 <= WHR < 0.80,0.80 <= WHR < 0.85,0.85 <= WHR < 0.90,0.90 <= WHR < 0.95,0.95 <= WHR < 1.00, WHR >= 1.00 in male participants (P < 0.01 or 0.05), LDL-C level was similar among groups in males (P = 0.139). There were significantly differences in prevalence of hypertension, diabetes mellitus, hypercholesterolemia and hypertriglyceridemia between WHR < 0.75,0.75 <= WHR < 0.80,0.80 <= WHR < 0.85,0.85 <= WHR < 0.90,0.90 <= WHR < 0.95,0.95 <= WHR < 1.00, WHR >= 1.00 in female participants (all P < 0.01), and there were no significantly differences in prevalence of high LDL-C level and low HDL-C level among groups in females (both P > 0.05). (2) ROC analysis for hypertension, dyslipidemia, diabetes and >= 2 of these risk factors suggested a WHR cutoff of 0.92 for men and 0.90 for women as the optimal cutoff value for predicting high risk of cardiovascular disease of Uygur population aged 35 years and over in Xinjiang. CONCLUSION: Higher WHR cutoffs are needed for screening people at high risk of cardiovascular disease among Uygur population aged 35 years and over in Xinjiang. PMID- 25907493 TI - [Surveillance on the incidence of acute coronary events in the permanent residents aged 25 years and more from 2010 to 2012 in Zhejiang province]. AB - OBJECTIVE: To survey the incidence of acute coronary events (nonfatal acute myocardial infarction and death from coronary heart disease), and analyze the trend and distribution characteristics in permanent residents aged 25 years and more across 30 surveillance regions of Zhejiang province from 2010 to 2012. METHODS: Through databases matching and duplicate checking, this study incorporated the register module of coronary disease and the cause of death register module in Zhejiang provincial information system for chronic non communicable diseases surveillance and management. The distribution of incidence was calculated across gender, age groups, regions and times. RESULTS: A total of 31 872 person-time acute coronary events were identified. The gender- and age standardized mean annual incidence was 81.56 per 100 000 people in overall population, with 94.33 in males and 68.27 in females. Age-standardized incidence was 87.90 and 77.36 per 100 000 people in urban and rural area, respectively. Urban area had higher incidence rate than rural in each of the three years, and had obvious trend of increasing (P < 0.001) compared with rural area (P = 0.331). Incidence rate also increased significantly with age (P < 0.001).In addition, compared with women, men had higher incidence in each age group (all P < 0.001). The incidence rate increased rapidly in population older than 75 years old. The highest incidence was observed in age group >= 85 years old, with 2 371.67 and 1 873.92 per 100 000 in males and females, respectively. Apparent seasonal trend was observed for acute coronary events, which was low in summer and high in winter. CONCLUSIONS: Quantity and incidence for acute coronary events in residents aged 25 years and more of Zhejiang surveillance regions increased during 2010 to 2012. Male had higher incidence than female, and the incidence in urban areas was higher compared with rural areas. Residents older than 75 years old were high risk population of events, and winter was the high-occurrence season. PMID- 25907494 TI - [Clinical manifestations, diagnosis and treatments of 4 cases of Brucella endocarditis]. PMID- 25907495 TI - [A case of successful transcatheter aortic valve implantation for severe noncalcified aortic regurgitation]. PMID- 25907496 TI - [Small conductance Ca(2+)-activated K(+) channels and their association with arrhythmias]. PMID- 25907497 TI - [Radiotherapy in patients with cardiac implantable electronic devices]. PMID- 25907498 TI - Incidence of electronic cigarette exposures in children skyrockets in Arizona. PMID- 25907499 TI - The worst amnesia of your life. PMID- 25907500 TI - Reconsidering the effectiveness and safety of carotid sinus massage as a therapeutic intervention in patients with supraventricular tachycardia. AB - OBJECTIVE: The objectives of our investigation were to review the evidence for the efficacy and safety of carotid sinus massage in terminating supraventricular tachycardia and to determine if other potentially less harmful interventions have been established to be safer and more effective. METHODS: A search using PubMed, Ovid, and COCHRANE databases was performed using the terms supraventricular tachycardia, carotid sinus massage, SVT, and CSM. Articles not written in English were excluded. There was a paucity of randomized controlled trials comparing various supraventricular tachycardia (SVT) interventions. However, articles of highest quality were selected for review and inclusion. In addition, articles examining potential hazards of carotid sinus massage in case report format were reviewed, even when performed for other indications other than SVT, as the maneuver is identically performed. Selected articles were reviewed by both authors for relevance to the topic. RESULTS: Summarizing the findings of this review leads to these 3 fundamental conclusions. First, a therapeutic intervention should only be performed when the benefit of the procedure outweighs its risk. Carotid sinus massage exposes the patient to rare but potentially devastating iatrogenic harm. Second, a therapeutic intervention should be efficacious. The efficacy of carotid sinus massage in terminating supraventricular tachycardia appears to be modest at best. Third, other readily available, easily mastered, and potentially safer and more efficacious alternative interventions are available such as Valsalva maneuver and pharmacologic therapy. CONCLUSION: Based on the limited evidence available, we believe that carotid sinus massage should be reconsidered as a first-line therapeutic intervention in the termination of SVT. PMID- 25907501 TI - Diagnostic value of platelet indexes for pulmonary embolism. AB - AIM: The aims of the study are to investigate the changes in platelet indexes, including platelet count, platelet distribution width (PDW), and mean platelet volume (MPV), in patients with pulmonary embolism (PE) and to evaluate their diagnostic values in relation to this disease. METHODS: The study included 70 patients with PE as the observation group and 75 patients without PE as the control group. The differences in platelet count, PDW, MPV, d-dimer, and other indicators between the 2 groups were retrospectively analyzed. RESULTS: Platelet distribution width and MPV were significantly higher in patients with PE than in the controls (16.40% [13.70%-16.85%] vs 16.00% [11.28%-16.60%], P = .023; 9.91 +/ 1.40 fL. vs 8.84 +/- 1.68 fL, P < .001, respectively). Multivariate logistic regression analysis showed that MPV and d-dimer were independent influencing factors for the diagnosis of PE. Receiver operating characteristic curve analysis showed that MPV (with the cut-off value set at 8.45 fL) had a sensitivity of 88.7%, negative predictive value of 78.7%, specificity of 50.0%, and positive predictive value of 61.9%. d-Dimer (with the cut-off value set at 835.5 MUg/L) had a sensitivity of 80.6%, negative predictive value of 77.8%, specificity of 62.1%, and positive predictive value of 66.7%. The combination of d-dimer and MPV resulted in an increase in the area under the curve (0.799; 95% confidence interval, 0.724-0.874; P < .001). CONCLUSION: Higher PDW and MPV levels are noticed in patients with PE. The combined application of MPV can improve the diagnostic value of d-dimer for PE. PMID- 25907502 TI - A new paradigm in cardiac resynchronization therapy? PMID- 25907503 TI - Status of systemic to pulmonary arterial collateral flow after the fontan procedure. AB - The investigators recently validated a method of quantifying systemic-to pulmonary arterial collateral flow using phase-contrast magnetic resonance imaging velocity mapping. Cross-sectional data suggest decreased collateral flow in patients with total cavopulmonary connections (TCPCs) compared with those with superior cavopulmonary connections (SCPCs). However, no studies have examined serial changes in collateral flow from SCPCs to TCPCs in the same patients. The aim of this study was to examine differences in collateral flow between patients with SCPCs and those with TCPCs. Collateral flow was quantified by 2 independent measures from 250 single-ventricle studies in 219 different patients (115 SCPC and 135 TCPC studies, 31 patients with both) and 18 controls, during routine studies using through-plane phase-contrast magnetic resonance imaging. Collateral flow was indexed to body surface area, aortic flow, and pulmonary venous flow. Regardless of indexing method, SCPC patients had significantly higher collateral flow than TCPC patients (1.64 +/- 0.8 vs 1.03 +/- 0.8 L/min/m(2), p <0.001). In 31 patients who underwent serial examinations, collateral flow as a fraction of aortic flow increased early after TCPC completion. In TCPC patients, indexed collateral flow demonstrated a significant negative correlation with time from TCPC. In conclusion, SCPC and TCPC patients demonstrate substantial collateral flow, with SCPC patients having higher collateral flow than TCPC patients overall. On the basis of the paired subset analysis, collateral flow does not decrease in the short term after TCPC completion and trends toward an increase. In the long term, however, collateral flow decreases over time after TCPC completion. PMID- 25907504 TI - A Systematic Review of the Usefulness of Statin Therapy in HIV-Infected Patients. AB - HIV-infected patients have a greater prevalence of dyslipidemia, earlier incidence and progression of atherosclerosis, and a nearly twofold increased risk for myocardial infarction compared with those not infected with HIV. Pre-existing cardiovascular risk factors, viral replication, and antiviral treatments all contribute to this accelerated and increased risk for cardiovascular disease in HIV-infected subjects. Given this risk and the proven benefit of statins reducing cardiovascular events across numerous patient groups, statin therapy might be particularly beneficial for patients with HIV. However, safety concerns and a dearth of quality trial data evaluating clinical outcomes in HIV-infected patients on simultaneous antiretroviral therapy (ART) and statin therapy have likely limited statin use in HIV-infected patients chronically taking ART. We performed a systematic review evaluating 18 clinical trials of statins in HIV infected subjects receiving ART. Simvastatin is contraindicated in the setting of protease inhibitor use because of toxic drug-drug interactions when the 2 drugs are taken concomitantly. Meanwhile, atorvastatin appears to be relatively safe at submaximal doses if monitored. Pravastatin, rosuvastatin, and pitavastatin appear to have the most benign safety profiles among statins when co-administered with ART and may not require dose adjustment. In conclusion, clinicians should be mindful of the elevated risk for atherosclerotic cardiovascular disease in HIV infected patients when assessing the need for lifestyle interventions and statin therapy. PMID- 25907506 TI - Current approaches to atherosclerotic obstructive renal artery stenosis. AB - Increased lifespan in the last few decades has substantially changed the scenario for renal artery stenosis. Indeed, because older populations show a higher prevalence of atherosclerotic disease, the incidence of atheromatous renal artery stenosis has also increased. Intuitively, one could surmise that stenosis removal should void both the hypertension and the kidney damage resulting from the obstructive stenosis. Surprisingly, a number of important clinical trials have failed to show the reversion seen in experimental models. The reasons for these differences may be linked to chronicity and inflammation associated with the atherosclerotic lesion. However, the failure to obtain a favorable response may also be related to abnormalities in the contralateral kidney. Indeed, this apparently normal kidney should work to compensate the hemodynamic effects of the ipsilateral stenosed kidney. Instead, structure and function in the contralateral kidney can be altered in renal artery stenosis to the point that this nonstenotic kidney may sustain both, hypertension and progressive kidney disease. Certainly, comparing the effects of clip removal in the Goldblatt model to angioplasty in clinical settings with atherosclerotic lesions may be totally inappropriate. Nevertheless, there remain certain clinical situations such as bilateral renal arterial disease, congestive heart failure, and progressive renal failure, where angioplasty may be an alternative. These approaches however are yet to be tested. PMID- 25907507 TI - Galanin is Co-Expressed with Substance P, Calbindin and Corticotropin-Releasing Factor (CRF) in The Enteric Nervous System of the Wild Boar (Sus scrofa) Small Intestine. AB - Galanin is a neuropeptide widely present in the enteric nervous system of numerous animal species and exhibiting neurotransmittery/neuromodulatory roles. Colocalization patterns of galanin with substance P (SP), corticotropin-releasing factor (CRF) and calbindin were studied in the small intestine of the wild boar using immunofluorescence technique. We demonstrated the presence of SP in substantial populations of galanin-immunoreactive (IR) submucous neurons. Additionally, different amounts of nerve fibres exhibiting simultaneous presence of galanin and SP were noted in the small intestinal smooth musculature, submucous ganglia, lamina muscularis mucosae and mucosa. In the wild boar duodenum, jejunum and ileum, the co-expression of galanin and calbindin was limited to minor populations of submucous neurons only. Single galanin-/CRF-IR nerve fibres were exclusively present in the duodenal and jejunal (but not ileal) mucosa. These results strongly suggest that galanin participates in neuronal control of the wild boar small intestine also by functional co-operation with other biologically active neuropeptides. PMID- 25907508 TI - Modulation of Regorafenib effects on HCC cell lines by epidermal growth factor. AB - PURPOSE: Blood platelet numbers are correlated to growth and aggressiveness of several tumor types, including hepatocellular carcinoma (HCC). We previously found that platelet lysates (hPLs) also stimulated growth and migration, and antagonized the growth-inhibitory and apoptotic effects of both Sorafenib and Regorafenib, two multikinase inhibitors, on three HCC cell lines. In this study, in vitro function of human epidermal growth factor (EGF) with and without Sorafenib or Regorafenib was investigated. METHODS: An ELISA kit was used to evaluate the EGF concentrations in hPLs. In vitro function of EGF was assessed with proliferation MTT test. Apoptosis assay, scratch assays, and Transwell assays were performed for apoptosis, invasion, and migration, respectively. MAPK Activation Kit was used to explore MAPK phosphorylation. RESULTS: EGF antagonized the growth inhibition of Regorafenib on three HCC cell lines. Regorafenib mediated growth inhibition was blocked by 70 % when the cells were pre-treated with EGF. EGF also blocked Regorafenib-induced apoptosis, as well as Regorafenib induced decreases in cell migration and invasion. The EGF effects were in turn antagonized by concomitant addition to the cultures of EGF receptor antagonist Erlotinib, showing that the EGF receptor was involved in the mechanisms of EGF mediated blocking of Regorafenib effects. Erlotinib also partially blocked the effects of hPLs in antagonizing Regorafenib-mediated growth inhibition, showing that EGF was an important component of hPL actions. CONCLUSIONS: All these results show that EGF antagonized Regorafenib-mediated growth and migration inhibition and apoptosis induction in HCC cells and reinforce the idea that microenvironment can influence cancer drug actions. PMID- 25907509 TI - Size analysis of nanoparticles extracted from W/O emulsions. AB - Nanosized particles are frequently used in many different applications, especially TiO2 nanoparticles as physical filters in sunscreens to protect the skin from UV radiation. However, concerns have arisen about possible health issues caused by nanoparticles and therefore, the assessment of the occurrence of nanoparticles is important in pharmaceutical and cosmetic formulations. In a previous work of our group, a method was presented to extract nanoparticles from O/W emulsions. But to respond to the needs of dry and sensitive skin, sunscreens of the water-in-oil emulsion type are available. In these, assessment of present nanoparticles is also an important issue, so the present study offers a method for extracting nanoparticles from W/O emulsions. Both methods emanate from the same starting point, which minimizes both effort and cost before the beginning of the assessment. By addition of NaOH pellets and centrifugation, particles were extracted from W/O emulsions and measured for their size and surface area by laser diffraction. With the simple equation Q=A/S a distinction between nanoparticles and microparticles was achieved in W/O emulsions, even in commercially available samples. The present method is quick and easy to implement, which makes it cost-effective. PMID- 25907510 TI - Profile of the intermolecular forces governing the interaction of drugs with mucin. AB - The study highlights the balance of the intermolecular forces governing the interaction between drugs and mucin. The interaction strength is expressed as a retention factor k (data retrieved from the literature (Gargano et al., 2014)) obtained by a new bio-affinity chromatographic method in which the stationary phase is based on covalently immobilized mucin (porcine gastric mucin, PGM). A quantitative structure-property relationship (QSPR) between logk and 82 VolSurf+ descriptors was established and mechanistically interpreted. Results evidence that all blocks contribute similarly to the model; moreover, hydrogen bonding donor (HBD) properties of solutes favor the interaction with mucin; and thus, support their detrimental role on drug permeability. PMID- 25907511 TI - Anticancer effect of gene/peptide co-delivery system using transferrin-grafted LMWSC. AB - A series of ternary complex was designed to deliver psiRNA-bcl2 and (KLA)4 peptide into cancer cells for cancer therapy. The delivered psiRNA-bcl2 induced gene-silencing in a nucleus of cancer cells, while (KLA)4 peptide inhibited cancer growth via mitochondrial apoptosis, indicating that the ternary complexes exerted very strong synergistic effects on cancer growth suppression by acting on psiRNA-bcl2 and (KLA)4 peptide simultaneously. The ternary complexes having a targeting-ligand, transferrin (TfP), were found to be especially effective at binding to the TfP receptor rich cancer cells, HCT119. The plasmid DNA (pDNA) in ternary complexes was completely condensed at various content of LMWSC-PEG-TfP (32-64 times more than pDNA) and released into cells. pDNA in the complexes was protected from DNase present on the exterior of cells. The size (165-248 nm) of ternary complexes with LMWSC-PEG-TfP was increased, but surface charges (3-4.5 mV) were decreased. These results likely occurred because the free amine-group of LMWSC decreased in response to conjugated transferrin. Moreover, transfected ternary complexes with LMWSC-PEG-TfP were not expressed in the normal cells (HEK293), but were over expressed in HCT119 cells. These findings indicate that the ternary complexes can be specifically targeted to HCT119 cancer cells. The useful complexes for gene and peptide delivery had high anticancer activities via a synergistic effect due to co-operative action of psiRNA and (KLA)4 peptide in HCT119 cells. PMID- 25907512 TI - Treatment of severe radial club hand by distraction using an articulated mini rail fixator and transfixing pins. AB - INTRODUCTION: Treatment of severe radial club hand is difficult. Several authors have emphasized the importance of preliminary soft-tissue distraction before centralization. HYPOTHESIS: Treatment of severe radial club hand by articulated mini-rail allowing prior soft-tissue distraction improves results. MATERIAL AND METHODS: Thirteen patients were treated sequentially, with an initial step of distraction and a second step of centralization. The first step consisted in fitting 2 mini-fixators, one in the concavity and the other in the convexity of the deformity. Four transfixing wires through the ulna and metacarpal bone connected the 2 fixators. After this preliminary distraction, the fixator was removed and a centralization wire was introduced percutaneously, with ulnar osteotomy if necessary. Sagittal and coronal correction was measured on the angle between forearm and hand. RESULTS: Mean age at treatment was 37.5 months (range, 9-120 months). Mean distraction time was 53.2 days (26-90 days). Ulnar osteotomy was required in 8 cases (61%). There were no major complications requiring interruption of distraction. Sagittal and coronal correction after centralization reduced mean residual forearm/hand angulation to<12 degrees . DISCUSSION: Soft tissue distraction in the concavity ahead of centralization is essential to good correction, avoiding extensive soft-tissue release and hyperpressure on the distal ulnar growth plate. There have been several studies of distraction; the present technique, associating 2 mini-fixators connected by threaded K-wires, provided sufficient distraction in the concavity of the deformity to allow satisfactory correction in all cases. Subsequent complications (breakage or displacement of the centralization wires) testify to the complexity of long-term management. CONCLUSION: The present study confirms the interest of a preliminary soft-tissue distraction step in treating severe radial club hand. PMID- 25907513 TI - Inferior tilt fixation of the glenoid component in reverse total shoulder arthroplasty: A biomechanical study. AB - BACKGROUND: Glenoid component fixation with an inferior tilt has been suggested to decrease scapular notching, but this remains controversial. We aimed here to evaluate the effect of glenoid component inferior tilt in reverse total shoulder arthroplasty (RSA) on micromotion and loss of fixation of the glenoid component by biomechanical testing. HYPOTHESIS: Increased inferior reaming of the glenoid for inferiorly tilted implantation of the glenoid component will decrease glenoid bone stock and compromise the fixation of RSA. MATERIALS AND METHODS: The micromotions of the glenoid components attached to 14 scapulae from fresh frozen cadavers were measured and compared between neutral and 10 degrees inferior tilts in 0.7- and 1-body weight cyclic loading tests using digital-image analysis. The incidence of bone breakage or loss of fixation was assessed in the 1-body weight fatigue-loading test. RESULTS: Micromotion was higher with a 10 degrees inferior tilt than with a neutral tilt during both the 0.7-body weight (36 +/- 11 MUm vs. 22 +/- 5 MUm; P = 0.028) and 1-body weight (44 +/- 16 MUm vs. 28 +/- 9 MUm; P = 0.045) cyclic loading. The incidence of bone breakage or loss of fixation was 17% and 60% with a neutral and 10 degrees inferior tilt, respectively. DISCUSSION: Glenoid component inferior tilt fixation in RSA may reduce primary stability and increase mechanical failure of the glenoid component, thereby reducing longevity of the prosthesis. Accordingly, we recommend careful placement of the glenoid component when an inferior tilt is used. PMID- 25907514 TI - Outcome of Bankart repair in contact versus non-contact athletes. AB - BACKGROUND: The clinical results of arthroscopic Bankart repair for contact athletes varies according to published reports. The purposes of this study were to analyze the clinical outcome of open or arthroscopic Bankart repair and to investigate the results in contact and non-contact athletes. HYPOTHESIS: Clinical outcome of arthroscopic Bankart repair is similar to that of open procedure. PATIENTS AND METHODS: One hundred patients with recurrent anterior shoulder dislocation without a large bony defect were retrospectively reviewed. Fifty-one contact and 49 non-contact athletes were found with a mean follow-up of 17 months. Forty-nine shoulders underwent arthroscopic Bankart repairs; 51 shoulders had open Bankart repairs. RESULTS: In non-contact athletes, there was a 5% (1/22 cases) recurrence rate in the open group and 4% (1/27 cases) in the arthroscopic group. In contrast, in contact athletes, there was a 10% (3/29 cases) recurrence rate in the open group and 14% (3/22 cases) in the arthroscopic group. There was no significant difference in the recurrence rate between contact and non-contact athletes, although contact athletes showed two to three times a higher recurrence rate than that of non-contact athletes. The Rowe score and Constant score showed no significant difference between the two procedures and between the contact and non-contact athletes. The rate of the complete return to sports showed no significant difference between contact and non-contact athletes. CONCLUSION: The recurrence rate of Bankart repair in the contact athletes was 2 times higher in the open group and 3 times higher in the arthroscopic group than in the non contact athletes. Clinical outcome of arthroscopic Bankart repair was similar to that of open procedure. PMID- 25907515 TI - Prone and direct posterior approach for management of posterior column tibial plateau fractures. AB - INTRODUCTION: The three-column fixation concept is becoming popular in orthopedic practice. Posterior column fracture is an uncommon type of tibial plateau fracture. The supine position for the surgical approach is familiar to most surgeons; however, it is difficult to achieve good reduction and fixation in posterior column fracture. HYPOTHESES: The prone position and direct posterior approach can achieve proper reduction and fixation for posterior column tibial plateau fracture, yielding good functional outcome. MATERIALS AND METHODS: Between January 2010 and January 2012, 184 tibial plateau fractures were diagnosed and operated on in our institution. Sixteen posterior column tibial plateau fractures (10 male and 6 female patients, with a mean age of 41.5 +/- 14.3 years) were diagnosed by preoperative plain films and CT scans. Ten patients presented with fracture-dislocation of the knee joint. A direct posterior approach in prone position was used to reduce the tibial condyle and fix it with an anti-glide buttress plate. Radiographic evaluation included reduction quality and bone union. Functional evaluation included Lysholm score and Tegner activity score. RESULTS: All fractures healed within 6 months, without secondary displacement. Ten knees had postoperative anatomic reduction (0mm step-off) and 6 had acceptable reduction (< 2mm step-off). At 34.4 +/- 9.6 months, median extension was 3 (5-10) and flexion 135 (100-145). The mean Lysholm score was 95 (75-100) and the mean Tegner activity score was 6 (5-8). All patients were satisfied with the operation. No cases of post-traumatic osteoarthritis of the knee occurred during follow-up. CONCLUSIONS: The prone position and direct posterior approach has great advantages in terms of reduction and stable fixation, yielding good results. PMID- 25907516 TI - Multiple nucleophilic elbows leading to multiple active sites in a single module esterase from Sorangium cellulosum. AB - The catalytic residues in carbohydrate esterase enzyme families constitute a highly conserved triad: serine, histidine and aspartic acid. This catalytic triad is generally located in a very sharp turn of the protein backbone structure, called the nucleophilic elbow and identified by the consensus sequence GXSXG. An esterase from Sorangium cellulosum Soce56 that contains five nucleophilic elbows was cloned and expressed in Escherichia coli and the function of each nucleophilic elbowed site was characterized. In order to elucidate the function of each nucleophilic elbow, site directed mutagenesis was used to generate variants with deactivated nucleophilic elbows and the functional promiscuity was analyzed. In silico analysis together with enzymological characterization interestingly showed that each nucleophilic elbow formed a local active site with varied substrate specificities and affinities. To our knowledge, this is the first report presenting the role of multiple nucleophilic elbows in the catalytic promiscuity of an esterase. Further structural analysis at protein unit level indicates the new evolutionary trajectories in emerging promiscuous esterases. PMID- 25907517 TI - Nucleophosmin overexpression is associated with poor survival in astrocytoma. AB - The multiple functions of the protein nucleophosmin (NPM) include the regulation and balance of cell growth, proliferation, and apoptosis. Many cancers have suspected associations with overexpression of NPM or with mutation of the NPM gene. Although NPM and anaplastic lymphoma kinase fusion proteins are known to be related to the Janus Kinase/Signal Transduction and Activator of Transcription (JAK/STAT) signaling pathway, the relationships of NPM, JAK2, and STAT5 to astrocytoma remain unclear. Therefore, this study performed histochemical analyses of expressions of NPM, p-JAK2, and STAT5B proteins in patients with astrocytoma. The results showed that high NPM expression was significantly associated with high tumor grade (p = 0.000), old age (p = 0.000), low Karnofsky Performance Scale (KPS) score (p = 0.000), and tumor recurrence (p = 0.045). High p-JAK2 expression was significantly associated with old age (p = 0.000), high tumor grade (p = 0.000), low KPS score (p = 0.000), and tumor recurrence (p = 0.036). Expression of STAT5B was significantly correlated with tumor grade (p = 0.018) and KPS score (p = 0.002). High expressions of NPM, p-JAK2, and STAT5B were associated with a short survival time (p = 0.035, 0.003 and 0.002, respectively). In multivariable analysis, STAT5B expression was a significant predictor of survival time (p = 0.003). In conclusion, NPM and p-JAK2/STAT5B may have important roles in tumor progression, and STAT5B is an independent prognostic marker of astrocytoma. PMID- 25907518 TI - Identifying Corticothalamic Network Epicenters in Patients with Idiopathic Generalized Epilepsy. AB - BACKGROUND AND PURPOSE: Corticothalamic networks are considered core pathologic substrates for idiopathic generalized epilepsy; however, the predominant epileptogenic epicenters within these networks are still largely unknown. The current study aims to identify these epicenters by resting-state functional connectivity. MATERIALS AND METHODS: To identify epicenters within the corticothalamic networks in idiopathic generalized epilepsy, we retrospectively studied a large cohort of patients with this condition (n = 97) along with healthy controls (n = 123) by resting-state functional MR imaging. The thalamus was functionally divided into subregions corresponding to distinct cortical lobes for 5 parallel corticothalamic networks. The functional connectivity between each voxel in the cortical lobe and the corresponding thalamic subregion was calculated, and functional connectivity strength was used to evaluate the interconnectivity of voxels in the cortex and thalamus. RESULTS: The projection of 5 cortical lobes to the thalamus is consistent with previous histologic findings in humans. Compared with controls, patients with idiopathic generalized epilepsy showed increased functional connectivity strength in 4 corticothalamic networks: 1) the supplementary motor area, pulvinar, and ventral anterior nucleus in the prefrontal-thalamic network; 2) the premotor cortex and ventrolateral nucleus in motor/premotor-thalamic networks; 3) the visual cortex, posterior default mode regions, and pulvinar in parietal/occipital-thalamic networks; and 4) the middle temporal gyrus in the temporal-thalamic network. CONCLUSIONS: Several key nodes were distinguished in 4 corticothalamic networks. The identification of these epicenters refines the corticothalamic network theory and provides insight into the pathophysiology of idiopathic generalized epilepsy. PMID- 25907519 TI - Mesial Temporal Sclerosis: Accuracy of NeuroQuant versus Neuroradiologist. AB - BACKGROUND AND PURPOSE: We sought to compare the accuracy of a volumetric fully automated computer assessment of hippocampal volume asymmetry versus neuroradiologists' interpretations of the temporal lobes for mesial temporal sclerosis. Detecting mesial temporal sclerosis (MTS) is important for the evaluation of patients with temporal lobe epilepsy as it often guides surgical intervention. One feature of MTS is hippocampal volume loss. MATERIALS AND METHODS: Electronic medical record and researcher reports of scans of patients with proved mesial temporal sclerosis were compared with volumetric assessment with an FDA-approved software package, NeuroQuant, for detection of mesial temporal sclerosis in 63 patients. The degree of volumetric asymmetry was analyzed to determine the neuroradiologists' threshold for detecting right-left asymmetry in temporal lobe volumes. RESULTS: Thirty-six patients had left lateralized MTS, 25 had right-lateralized MTS, and 2 had bilateral MTS. The estimated accuracy of the neuroradiologist was 72.6% with a kappa statistic of 0.512 (95% CI, 0.315-0.710) [moderate agreement, P < 3 * 10(-6)]), whereas the estimated accuracy of NeuroQuant was 79.4% with a kappa statistic of 0.588 (95% CI, 0.388-0.787) [moderate agreement, P < 2 * 10(-6)]). This discrepancy in accuracy was not statistically significant. When at least a 5%-10% volume discrepancy between temporal lobes was present, the neuroradiologists detected it 75%-80% of the time. CONCLUSIONS: As a stand-alone fully automated software program that can process temporal lobe volume in 5-10 minutes, NeuroQuant compares favorably with trained neuroradiologists in predicting the side of mesial temporal sclerosis. Neuroradiologists can often detect even small temporal lobe volumetric changes visually. PMID- 25907521 TI - Statin therapy does not affect the radiographic and clinical profile of patients with TIA and minor stroke. AB - BACKGROUND AND PURPOSE: Acute statin therapy improves neurologic outcome and diminishes infarct growth in animal models of stroke. Clinical studies suggest that premorbid and early statin use is associated with improved outcome after major stroke. We studied the association between statin therapy and radiographic and clinical outcomes in patients with high-risk TIA and minor stroke. MATERIALS AND METHODS: Patients with high-risk TIA and minor stroke (NIHSS <=3) were prospectively enrolled within 24 hours of symptom onset. Patients were followed clinically for 3 months, and a subset had a repeat MR imaging at 90 days. RESULTS: Of 418 patients, 23% were prescribed statins before their stroke. Statins were continued in 20% and initiated in 42%. Patients on prior statin therapy were older and more hypertensive, treated with aspirin, and more likely to have symptomatic carotid disease compared with those not on statin. Adjusting for these differences, prior statin treatment was not associated with DWI positivity (adjusted OR = 1.3; 95% CI, 0.77-2.1; P = .32) or smaller median baseline infarct volume, 1.1 mL (interquartile range = 4) versus 1 mL (interquartile range = 2.5; P = .56). Early or continued treatment with statins did not improve the risk of clinical deterioration (adjusted OR = 0.66; 95% CI, 0.27-1.6; P = .35) or poor functional outcome at 3 months (adjusted OR = 0.66; 95% CI, 0.35-1.24; P = .19). CONCLUSIONS: Prestroke or early-stroke statin therapy was not associated with a reduction in the number of DWI lesions, infarct volume, or improved clinical or functional outcome at 3 months. The effect of acute statin treatment in patients with ischemic stroke/TIA remains unclear and needs further investigation. PMID- 25907520 TI - ASFNR recommendations for clinical performance of MR dynamic susceptibility contrast perfusion imaging of the brain. AB - MR perfusion imaging is becoming an increasingly common means of evaluating a variety of cerebral pathologies, including tumors and ischemia. In particular, there has been great interest in the use of MR perfusion imaging for both assessing brain tumor grade and for monitoring for tumor recurrence in previously treated patients. Of the various techniques devised for evaluating cerebral perfusion imaging, the dynamic susceptibility contrast method has been employed most widely among clinical MR imaging practitioners. However, when implementing DSC MR perfusion imaging in a contemporary radiology practice, a neuroradiologist is confronted with a large number of decisions. These include choices surrounding appropriate patient selection, scan-acquisition parameters, data-postprocessing methods, image interpretation, and reporting. Throughout the imaging literature, there is conflicting advice on these issues. In an effort to provide guidance to neuroradiologists struggling to implement DSC perfusion imaging in their MR imaging practice, the Clinical Practice Committee of the American Society of Functional Neuroradiology has provided the following recommendations. This guidance is based on review of the literature coupled with the practice experience of the authors. While the ASFNR acknowledges that alternate means of carrying out DSC perfusion imaging may yield clinically acceptable results, the following recommendations should provide a framework for achieving routine success in this complicated-but-rewarding aspect of neuroradiology MR imaging practice. PMID- 25907523 TI - Photolysis of nitric acid at 308 nm in the absence and in the presence of water vapor. AB - We have re-examined the NOx channels from the 308 nm gas-phase photolysis of nitric acid (HNO3) by using excimer laser photolysis combined with cavity ring down spectroscopy. The photolysis products were monitored in the 552-560 and 640 648 nm regions. Direct comparison of the photolysis product spectrum in the 640 648 nm region with literature vibronic band origins and line intensities in electronically excited NO2 (NO2*) suggests that NO2* is not formed from HNO3 photolysis at 308 nm. A comparison of the photolysis product spectrum in the 552 560 nm region with a standard NO2 spectrum indicates that ground-state NO2 is a photolysis product. We have determined the NO2 quantum yield from the 308 nm HNO3 photolysis. We also investigated HNO3 photolysis in the presence of water vapor. For equilibrated HNO3/H2O mixtures, we did not observe significant variation of product absorption around 552 nm with delay times between the firing of the photolysis and the probe lasers. Transient product absorption measurements at 342.0 and 343.5 nm (respective wavelengths where the peak and valley of HONO absorptions are located) are consistent with ground-state NO2 being the predominant NOx product from the 308 nm photolysis of a HNO3/H2O mixture. Atmospheric implications are also discussed. PMID- 25907522 TI - Predictors of reperfusion in patients with acute ischemic stroke. AB - BACKGROUND AND PURPOSE: Ischemic stroke studies emphasize a difference between reperfusion and recanalization, but predictors of reperfusion have not been elucidated. The aim of this study was to evaluate the relationship between reperfusion and recanalization and identify predictors of reperfusion. MATERIALS AND METHODS: From the Dutch Acute Stroke Study, 178 patients were selected with an MCA territory deficit on admission CTP and day 3 follow-up CTP and CTA. Reperfusion was evaluated on CTP, and recanalization on CTA, follow-up imaging. Reperfusion percentages were calculated in patients with and without recanalization. Patient admission and treatment characteristics and admission CT imaging parameters were collected. Their association with complete reperfusion was analyzed by using univariate and multivariate logistic regression. RESULTS: Sixty percent of patients with complete recanalization showed complete reperfusion (relative risk, 2.60; 95% CI, 1.63-4.13). Approximately one-third of patients showed some discrepancy between recanalization and reperfusion status. Lower NIHSS score (OR, 1.06; 95% CI, 1.01-1.11), smaller infarct core size (OR, 3.11; 95% CI, 1.46-6.66; and OR, 2.40; 95% CI, 1.14-5.02), smaller total ischemic area (OR, 4.20; 95% CI, 1.91-9.22; and OR, 2.35; 95% CI, 1.12-4.91), lower clot burden (OR, 1.35; 95% CI, 1.14-1.58), distal thrombus location (OR, 3.02; 95% CI, 1.76-5.20), and good collateral score (OR, 2.84; 95% CI, 1.34-6.02) significantly increased the odds of complete reperfusion. In multivariate analysis, only total ischemic area (OR, 6.12; 95% CI, 2.69-13.93; and OR, 1.91; 95% CI, 0.91-4.02) was an independent predictor of complete reperfusion. CONCLUSIONS: Recanalization and reperfusion are strongly associated but not always equivalent in ischemic stroke. A smaller total ischemic area is the only independent predictor of complete reperfusion. PMID- 25907524 TI - Sympathectomy for glaucoma: Its rise and fall (1898-1910). AB - The influence of the sympathetic nervous system upon intraocular pressure (IOP) has been a subject of great interest since 1727, when the first experimental ocular sympathetic paralysis was produced in dogs. By the middle of the 19th century, it was known that excision of the superior cervical sympathetic ganglion lowered, and that electrical stimulation of the sympathetic nerve trunk raised IOP in various animals. From these observations, it was thought that excision of this ganglion could replace or supplement the available operations for glaucoma of which iridectomy was the most popular. Iridectomy was acknowledged to be of great value in acute and subacute glaucoma, but less useful in chronic glaucoma. Iridectomy, however, was associated with major surgical complications and long term failure, so that there was considerable appeal of an extraocular operation that avoided the risks of intraocular surgery. Beginning in 1898, cervical sympathectomy became a widely performed operation around the world, with most surgeons enthusiastic about its results, at least initially, and many publications from 1898 to 1905 claimed excellent results for various types of glaucoma. Opponents of the procedure emphasized that the effect on IOP was transient, and that the published reports of successful results were poorly documented. The popularity of sympathectomy gradually diminished and by 1910 it was abandoned. I discuss the reasons why cervical sympathectomy received such initial enthusiasm but was then questioned and discarded. These included bias from the surgeons promoting this surgery; the placebo effect; short follow-up; inaccurate, subjective, and variable measures of the surgical results; and the development of more effective procedures such as filtering surgery and cyclodialysis. PMID- 25907526 TI - Understanding corrosion inhibition with van der Waals DFT methods: the case of benzotriazole. AB - The corrosion of materials is an undesirable and costly process affecting many areas of technology and everyday life. As such, considerable effort has gone into understanding and preventing it. Organic molecule based coatings can in certain circumstances act as effective corrosion inhibitors. Although they have been used to great effect for more than sixty years, how they function at the atomic-level is still a matter of debate. In this work, computer simulation approaches based on density functional theory are used to investigate benzotriazole (BTAH), one of the most widely used and studied corrosion inhibitors for copper. In particular, the structures formed by protonated and deprotonated BTAH molecules on Cu(111) have been determined and linked to their inhibiting properties. It is found that hydrogen bonding, van der Waals interactions and steric repulsions all contribute in shaping how BTAH molecules adsorb, with flat-lying structures preferred at low coverage and upright configurations preferred at high coverage. The interaction of the dehydrogenated benzotriazole molecule (BTA) with the copper surface is instead dominated by strong chemisorption via the azole moiety with the aid of copper adatoms. Structures of dimers or chains are found to be the most stable structures at all coverages, in good agreement with scanning tunnelling microscopy results. Benzotriazole thus shows a complex phase behaviour in which van der Waals forces play an important role and which depends on coverage and on its protonation state and all of these factors feasibly contribute to its effectiveness as a corrosion inhibitor. PMID- 25907525 TI - The interactions of genes, age, and environment in glaucoma pathogenesis. AB - Glaucoma, a progressive degenerative condition that results in the death of retinal ganglion cells, is one of the leading causes of blindness, affecting millions worldwide. The mechanisms underlying glaucoma are not well understood, although years of studies have shown that the largest risk factors are elevated intraocular pressure, age, and genetics. Eleven genes and multiple loci have been identified as contributing factors. These genes act by a number of mechanisms, including mechanical stress, ischemic/oxidative stress, and neurodegeneration. We summarize the recent advances in the understanding of glaucoma and propose a unified hypothesis for glaucoma pathogenesis. Glaucoma does not result from a single pathological mechanism, but rather a combination of pathways that are influenced by genes, age, and environment. In particular, we hypothesize that, in the presence of genetic risk factors, exposure to environment stresses results in an earlier age of onset for glaucoma. This hypothesis is based upon the overlap of the molecular pathways in which glaucoma genes are involved. Because of the interactions between these processes, it is likely that there are common therapies that may be effective for different subtypes of glaucoma. PMID- 25907527 TI - Investigating the Frequency and Nature of Medication-Related Problems in the Women's Health Unit of an Australian Tertiary Teaching Hospital. AB - BACKGROUND: Despite the large burden medication-related morbidity and mortality places on the Australian health care system, there is little known about the extent of this problem in a women's health (obstetric and gynecology) setting. OBJECTIVE: Determine the frequency and nature of medication-related problems (MRPs) occurring in a women's health unit (WHU) of an Australian teaching hospital. METHODS: A prospective audit of consecutive cases of patients treated in the WHU at a tertiary-level teaching hospital was undertaken by a clinical pharmacist over a 5-week period. Data collected included the following: patient characteristics, type of MRP (using a modified version of the Hepler-Strand classification system), medication involved (according to the World Health Organisation Anatomical Therapeutic Chemical classification system), and clinical significance (using a 2-level severity index). RESULTS: A total of 454 potential MRPs were identified over the 5-week period among 241 patients. A total of 39 MRPs (8.6%) identified were deemed to be of moderate/high clinical significance. The highest number of MRPs (221; 49%) was identified among women admitted following a cesarean delivery, with 83 of 85 women in this group experiencing at least 1 MRP. Additional factors associated with an increased likelihood of patients experiencing a MRP included increased age, length of hospital stay, and number of regular medications taken prior to and during admission (P < 0.05). CONCLUSION: The widespread nature of identified MRPs in this setting suggests that various approaches to minimizing these problems and mitigating the associated burden on the health care system are warranted. PMID- 25907528 TI - Pharmacist leadership in ICU quality improvement: coordinating spontaneous awakening and breathing trials. AB - BACKGROUND: Coordinating efforts across disciplines in the intensive care unit is a key component of quality improvement (QI) efforts. Spontaneous awakening trials (SATs) and spontaneous breathing trials (SBTs) are considered key components of guidelines, yet unfortunately are often not done or coordinated properly. OBJECTIVE: To determine if a pharmacist-driven awakening and breathing coordination (ABC) QI program would improve compliance (ie, process measures) as compared with the previous protocol, which did not involve pharmacists. METHODS: The QI program included pharmacist-led education, daily discussion on rounds, and weekly performance reports to staff. Using a pre-QI versus during-QI versus post QI intervention design, we compared data from 500 control ventilator-days (pre-QI period) versus 580 prospective ventilator-days (during-QI period). We then evaluated the sustainability of the QI program in 216 ventilator-days in the post QI period. RESULTS: SAT safety screens were performed on only 20% pre-QI patient days versus 97% of during-QI patient-days (P < 0.001) and 100% of post-QI patient days (P = 0.25). The rates of passing the SAT safety screen in pre-QI and during QI periods were 63% versus 78% (P = 0.03) and 81% in the post-QI period (P = 0.86). The rates of SATs among eligible patients on continuous infusions were only 53% in the pre-QI versus 85% in the during-QI (P = 0.0001) and 87% in the post-QI (P = 1) periods. CONCLUSIONS: In this QI initiative, a pharmacist-driven, interdisciplinary ABC protocol significantly improved process measures compliance, comparing the pre-QI versus during-QI rates of screening, performing, and coordinating SAT and SBTs, and these results were sustained in the 8-month follow-up period post-QI program. PMID- 25907529 TI - Alternate Routes of Administration of Antidepressant and Antipsychotic Medications. AB - OBJECTIVE: To review the administration of antidepressant and antipsychotic medications via inhaled, intranasal, buccal, sublingual, transdermal, and rectal routes. DATA SOURCES: A PubMed search was conducted for all data through March 31, 2015 to identify pertinent literature. Search terms included the generic name of each antidepressant and antipsychotic medication in combination with the following terms: alternate routes of administration, inhaled, intranasal, buccal, sublingual, transdermal, and rectal. STUDY SELECTION AND DATA EXTRACTION: English language case reports, studies, and reviews describing medication administration in human subjects were included. DATA SYNTHESIS: Commercially available products that use an alternative route of administration include loxapine for inhalation, asenapine for sublingual administration, and selegiline for transdermal administration. Case reports and studies describe intranasal, sublingual, and transdermal routes of administration of antipsychotic medications as well as buccal, sublingual, transdermal, and rectal administration of antidepressant medications. The concordance between the physicochemical properties possessed by some antipsychotic and antidepressant agents and the physicochemical properties required for nontraditional routes of administration suggest that administration via alternative routes may be feasible for some of these drugs. Further exploration of drug absorption via alternative routes in addition to consideration of patient and formulation factors may yield improvements in medication therapy for patients with psychiatric illnesses. CONCLUSIONS: For patients unable to tolerate oral or injectable therapy, administration of psychotropic medications via nontraditional routes may be feasible. The development of alternative routes of drug delivery could prevent discontinuation of needed medication therapy. PMID- 25907530 TI - Serum interleukin 17 as an early prognostic biomarker of severe acute pancreatitis receiving continuous blood purification. AB - BACKGROUND: Severe acute pancreatitis (SAP) is associated with systemic inflammation, immunoparalysis, and sepsis, and may lead to vital organ failure and death. We evaluated the efficacy of serum interleukin 17 (IL-17) concentration for predicting eventual SAP severity and the clinical benefits of removing IL-17 by continuous veno-venous hemofiltration (CVVH). METHODS: Patients were divided into 2 groups according to severity: Grade 1 (n = 18, SAP without organ dysfunction) and Grade 2 (n = 18, SAP with organ dysfunction). 20 healthy volunteers served as controls. All patients underwent 24-h CVVH and blood samples were taken at 0, 6, 12, and 24 h for measurement of bacterial load and serum IL 17, IL-6, and endotoxin. Clinical condition was graded by the sequential organ failure assessment (SOFA) score. RESULTS: Baseline IL-17, IL-6, endotoxin, and bacterial load were higher in Grade 2 patients. SOFA scores improved significantly, and serum IL-17, IL-6, endotoxin, and bacterial load decreased significantly in all patients after CVVH. Serum IL-17 was significantly and positively correlated with IL-6, bacterial load, and endotoxin during CVVH treatment. In addition, post-CVVH serum IL-17 was directly correlated with SOFA scores on days 1 and 7, and with duration of hospital stay. Non-survivors showed both higher SOFA scores on day 1 and higher baseline IL-17 than survivors. CONCLUSIONS: Earlier and higher serum IL-17 elevation predicted prolonged hospitalization, organ failure, and death, possibly by disrupting gut barrier function. CVVH can remove inflammatory cytokines from serum, including IL-17 and IL-6, thereby attenuating the inflammatory response and diminishing associated systemic complications. PMID- 25907531 TI - Associated risk factors for chronic kidney disease of unknown etiologies in 241 patients. AB - BACKGROUND: Apart from the well-known etiologies, there are still a high proportion of patients with chronic kidney disease of unknown etiology (CKDu), which has rarely been reported on. In this study, we explored the potential associated risk factors for CKDu and identified those that occur in childhood. METHODS: 700 patients with CKD we were selected randomly from 4 hospitals in Chengdu and 241 were screened for CKDu. The following clinical information was analyzed: demographic data, life style, personal and family history, nephrotoxic drugs, exposure to poison, allergies, and recurrent respiratory infections in childhood. RESULTS: Among 700 CKD patients, 34.43% (241/700) were CKDu. Of the 241 patients, there were 67.63% (163/241) with at least 1 associated risk factor and 56.44% (92/163) with more than 1. Patients with a personal history of an associated risk factor represented the largest proportion (31.95%, 77/241), while 28.63% (69/241) of the CKDu patients had risk factors appearing in childhood. Logistic regression analysis supported the results. CONCLUSIONS: The study demonstrated that most so-called CKDu patients do have an identifiable etiology, and that several associated risk factors contribute to it. Of all the risk factors, age >60 years, nephrotoxic drugs, exposure to poison, and alcohol consumption were the independent significant factors for CKDu. Furthermore, many risk factors that caused kidney injury started in childhood. PMID- 25907532 TI - The immune response to crosslinked tissue is reduced in decellularized xenogeneic and absent in decellularized allogeneic heart valves. AB - BACKGROUND: The degeneration and failure of xenogeneic heart valves, such as the Matrix P Plus valve (MP-V) consisting of decellularized porcine valves (dec-pV) and equine glutaraldehyde-fixed conduits (ga-eC) have been linked to tissue immunogenicity accompanied by antibody formation. In contrast, decellularized allograft valves (dec-aV) are well-tolerated. Here, we determined tissue-specific antibody levels in patients after implantation of MP-V or dec-aV and related them to valve failure or time period after implantation. METHODS AND RESULTS: Specific antibodies toward whole tissue-homogenates or alphaGal were determined retrospectively by ELISA analyses from patients who received MP-V with an uneventful course of 56.1 +/- 5.1 months (n = 15), or with valve failure after 25.3 +/- 14.6 months (n = 3), dec-aV for various times from 4 to 46 months (n = 14, uneventful) and from healthy controls (n = 4). All explanted valves were assessed histopathologically.MP-V induced antibodies toward both tissue components with significantly higher levels toward ga-eC than toward dec-pV (68.7 and 26.65 ug/ml IgG). In patients with valve failure, levels were not significantly higher and were related to inflammatory tissue infiltration. Anti Gal antibodies in MP-V patients were significantly increased in both, the uneventful and the failure group. In contrast, in dec-aV patients only a slight tissue-specific antibody formation was observed after 4 months (6.24 ug/ml) that normalized to control levels after 1 year. CONCLUSIONS: The strong humoral immune response to glutaraldehyde-fixed tissues is reduced in decellularized xenogeneic valves and almost absent in decellularized allogeneic tissue up to 4.5 years after implantation. PMID- 25907533 TI - Endocarditis and spondylodiscitis associated with tunneled cuffed hemodialysis catheters: hospitalizations with poor outcomes. AB - INTRODUCTION: Patients undergoing chronic hemodialysis using tunneled cuffed catheters (TCCs) are at increased risk of metastatic infections, namely endocarditis and spondydodiscitis, and mortality is high in this group. The aim of this study was to determine the clinical features, causative organisms, its susceptibility and outcomes in patients hospitalized with these infections from a single center. METHODS: All consecutive patients with TCC and endocarditis and/or spondylodiscitis treated at the authors' institution between 2005 and 2011 were selected retrospectively. RESULTS: A total of 7 cases of endocarditis and 7 cases of spondylodiscitis were diagnosed. Concurrent infection was present in 1 patient. The mean age was 63.4 years, 53.8% were male, 23% had diabetes and 31% had previous immunosuppression. The average time on hemodialysis was 24 months. Those patients with endocarditis presented with fever, and 43% had previous valvular disease; mitral valve involvement was the most common. Early surgery was performed in 2 patients.Concerning spondylodiscitis, the median time from first symptom to diagnosis was 48 days. The first manifestation was back pain in 86% percent of patients, and 71% had an epidural or paraspinous abscess demonstrated by neuroimaging. One patient underwent surgical drainage of the abscess. Regarding both infections, staphylococcus aureus was the most common causative agent with a lower rate of negative blood cultures. All patients received intravenous antibiotics for a mean duration of six weeks. The mortality rate was 46%. CONCLUSIONS: A high index of suspicion is critical in the early recognition and management of both of these infections. PMID- 25907534 TI - Biventricular failure in dextro-transposition of the great arteries corrected with the Mustard procedure: VAD support of the systemic ventricle is enough. AB - INTRODUCTION: Miniaturization and surgical progress in the field of ventricular assist device (VAD) therapy will lead to an increasing use in grown-up patients with congenital heart disease (GUCH). VAD implantation in such patients, especially biventricular VAD (BVAD) placement, can be very challenging, potentially associated with high morbidity and mortality. METHODS AND RESULTS: We report on a 47-year-old male patient in terminal biventricular failure with pulmonary hypertension 40 years after a Mustard procedure. The patient was successfully provided with a HVAD (HeartWare; HeartWare Inc., Framingham, MA, USA) into the systemic ventricle as bridge to transplantation, with the sub pulmonary ventricle left unsupported. DISCUSSION: We present our institutional strategy for VAD selection in these patients and highlight intra-corporeal VAD implantation technique. PMID- 25907535 TI - Opposite expression of CYP51A1 and its natural antisense transcript AluCYP51A1 in adenovirus type 37 infected retinal pigmented epithelial cells. AB - Cytochrome P450 family member CYP51A1 is a key enzyme in cholesterol biosynthesis whose deregulation is implicated in numerous diseases, including retinal degeneration. Here we describe that HAdV-37 infection leads to downregulation of CYP51A1 expression and overexpression of its antisense non-coding Alu element (AluCYP51A1) in retinal pigment epithelium (RPE) cells. This change in gene expression is associated with a reversed accumulation of a positive histone mark at the CYP51A1 and AluCYP51A1 promoters. Further, transient AluCYP51A1 RNA overexpression correlates with reduced CYP51A1 mRNA accumulation. Collectively, our data suggest that AluCYP51A1 might control CYP51A1 gene expression in HAdV-37 infected RPE cells. PMID- 25907536 TI - Protein phosphatase PP1-NIPP1 activates mesenchymal genes in HeLa cells. AB - The deletion of the protein phosphatase-1 (PP1) regulator known as Nuclear Inhibitor of PP1 (NIPP1) is embryonic lethal during gastrulation, hinting at a key role of PP1-NIPP1 in lineage specification. Consistent with this notion we show here that a mild, stable overexpression of NIPP1 in HeLa cells caused a massive induction of genes of the mesenchymal lineage, in particular smooth/cardiac-muscle and matrix markers. This reprogramming was associated with the formation of actin-based stress fibers and retracting filopodia, and a reduced proliferation potential. The NIPP1-induced mesenchymal transition required functional substrate and PP1-binding domains, suggesting that it involves the selective dephosphorylation of substrates of PP1-NIPP1. PMID- 25907537 TI - TRIM35 negatively regulates TLR7- and TLR9-mediated type I interferon production by targeting IRF7. AB - Toll-like receptor 7 (TLR7) and TLR9 sense viral nucleic acids and induce type I IFN production, which must be properly controlled to avoid autoimmune diseases. Here, we report the negative regulation of TLR7/9-mediated type I IFN production by TRIM35. TRIM35 expression is induced by TLR7/9 stimulation and then interacts with IRF7, which is the master regulator of type I IFN response. Furthermore, TRIM35 promotes the K48-linked ubiquitination of IRF7 and induces its degradation via a proteasome-dependent pathway. Therefore, TRIM35 is a negative feedback regulator of TLR7/9-mediated type I IFN production due to its ability to suppress the stability of IRF7. PMID- 25907538 TI - Adverse effect of urease on salt stress during seed germination in Arabidopsis thaliana. AB - Seed germination is a critical stage in the development of crops that grow in saline soils. We noticed that seeds of an Arabidopsis urease mutant have significantly increased salt stress tolerance. To understand why, we treated the wild type (WT) with a urease inhibitor and found that its salt stress tolerance was also improved. We hypothesized that urease acting on urea generates NH4+, which probably exacerbates salt stress. As expected, the urease inhibitor significantly decreased the NH4+ level in WT seeds. These findings suggest that blocking urease activity improves salt tolerance during seed germination by lowering the concentration of NH4+. PMID- 25907539 TI - Restoring esophageal continuity following a failed colonic interposition for long gap esophageal atresia. AB - The Foker process is a method of esophageal lengthening through axial tension induced growth, allowing for subsequent primary reconstruction of the esophagus in esophageal atresia (EA). In this unique case, the Foker process was used to grow the remaining esophageal segment long enough to attain esophageal continuity following failed colonic interpositions for long-gap esophageal atresia (LGEA). Initially developed for the treatment of LGEA in neonates, this case demonstrates that (i) an active esophageal lengthening response may still be present beyond the neonate time-period; and, (ii) the Foker process can be used to restore esophageal continuity following a failed colonic interposition if the lower esophageal segment is still present. PMID- 25907540 TI - Bronchogenic cyst associated with congenital absence of the pericardium. AB - We report a rare case of bronchogenic cyst associated with congenital complete absence of the pericardium. A 17-year-old male was admitted to the hospital for surgical resection of a growing cystic lesion located in the middle mediastinum. The patient was asymptomatic and no significant findings were found on physical examination. Resection of the mediastinal cyst was performed by video-assisted thoracoscopic surgery. The complete absence of the pericardium was immediately observed along with a cystic tumor arising from the mediastinum. After the resection of the cyst, no additional procedure to reconstruct the absence of the left pericardium was performed. Pathological diagnosis was a bronchogenic cyst. Congenital absence of the pericardium may be associated with the bronchogenic cyst and complete absence of the pericardium requires no additional surgical reconstruction, if remaining space in the pleural cavity is small enough to avoid cardiac disposition after surgical resection of the cyst. PMID- 25907541 TI - Allergic nickel dermatitis following an occupational accident involving a mechanical rodeo bull. PMID- 25907542 TI - Geriatric conditions, rather than multimorbidity, as predictors of disability and mortality among octogenarians: A population-based cohort study. AB - AIM: To examine the impact of geriatric conditions and multimorbidity on the risk of incident disability and mortality among young-old and old-old adults. METHODS: The present study used nationally-representative data from the "Survey of Health and Living Status of the Elderly in Taiwan" for the years 2003 and 2007. Non disabled older adults were divided into two age groups (65-79 years and >=80 years). Chronic morbidities and geriatric conditions were assessed in 2003. Incident disability was defined as dependency in one or more activities of daily living in 2007. Vital statistics of the participants was linked to death registration data through 31 December 2007. Multivariable logistic regression and Cox regression were used to determine the effect of multimorbidity and geriatric conditions on health outcomes. RESULTS: Among those aged 65-79 years (n = 1874), the presentation of multimorbidity or two or more geriatric conditions was related to incident disability. Among octogenarians, the presentation of one or more geriatric conditions, but not multimorbidity, was shown to be independently associated with the risk of disability. Multimorbidity was related to a higher adjusted risk of mortality in the young-old group (hazard ratio 1.54; 95% confidence interval 1.1-2.2) but not in the old-old group. Among octogenarians, those with two or more geriatric conditions had a higher adjusted risk of mortality (hazard ratio 1.7; 95% confidence interval 1.2-2.5), compared with those with 0-1 geriatric conditions. CONCLUSIONS: The risk of incident disability and mortality increased in octogenarians with geriatric conditions, but not in cases with multimorbidity. PMID- 25907543 TI - Eliminating transplant tourism in the United States as a means to decrease wait list mortality of US residents. PMID- 25907544 TI - Social justice for the mentally ill. PMID- 25907545 TI - Adaptation difficulties among immigrants. PMID- 25907546 TI - Validation of the revised international prognostic scoring system (IPSS-R) in patients with lower-risk myelodysplastic syndromes: a report from the prospective European LeukaemiaNet MDS (EUMDS) registry. AB - Baseline characteristics, disease-management and outcome of 1000 lower-risk myelodysplastic syndrome (MDS) patients within the European LeukaemiaNet MDS (EUMDS) Registry are described in conjunction with the validation of the revised International Prognostic Scoring System (IPSS-R). The EUMDS registry confirmed established prognostic factors, such as age, gender and World Health Organization 2001 classification. Low quality of life (EQ-5D visual analogue scale score) was significantly associated with reduced survival. A high co-morbidity index predicted poor outcome in univariate analyses. The IPSS-R identified a large group of 247 patients with Low (43%) and Very low (23%) risk score within the IPSS intermediate-1 patients. The IPSS-R also identified 32 High or Very high risk patients within the IPSS intermediate-1 patients. IPSS-R was superior to the IPSS for predicting both disease progression and survival. Seventy percent of patients received MDS-specific treatment or supportive care, including red blood cell transfusions (51%), haematopoietic growth factors (58%) and iron chelation therapy (8%), within 2 years of diagnosis; while 30% of the patients only required active monitoring. The IPSS-R proved its utility as a more refined risk stratification tool for the identification of patients with a very good or poor prognosis and in this lower-risk MDS population. PMID- 25907547 TI - 2D trajectory estimation during free walking using a tiptoe-mounted inertial sensor. AB - An estimation method for a two-dimensional walking trajectory during free walking, such as forward walking, side stepping and backward walking, was investigated using a tiptoe-mounted inertial sensor. The horizontal trajectory of the toe-tip is obtained by double integration of toe-tip acceleration during the moving phase in which the sensor is rotated before foot-off or after foot contact, in addition to the swing phase. Special functions that determine the optimum moving phase as the integral duration in every one step are developed statistically using the gait cycle and the resultant angular velocity of dorsi/planter flexion, pronation/supination and inversion/eversion so that the difference between the estimated trajectory and actual one gives a minimum value during free walking with several cadences. To develop the functions, twenty healthy volunteers participated in free walking experiments in which subjects performed forward walking, side stepping to the right, side stepping to the left, and backward walking at 39 m down a straight corridor with several predetermined cadences. To confirm the effect of the developed functions, five healthy subjects participated in the free walking experiment in which each subject performed free walking with different velocities of normal, fast, and slow based on their own assessment in a square course with 7 m side. The experimentally obtained results of free walking with a combination of forward walking, backward walking, and side stepping indicate that the proposed method produces walking trajectory with high precision compared with the constant threshold method which determines swing phase using the size of the angular velocity. PMID- 25907548 TI - In vitro flow investigations in the aortic arch during cardiopulmonary bypass with stereo-PIV. AB - The cardiopulmonary bypass is related to complications like stroke or hypoxia. The cannula jet is suspected to be one reason for these complications, due to the sandblast effect on the vessel wall. Several in silico and in vitro studies investigated the underlying mechanisms, but the applied experimental flow measurement techniques were not able to address the highly three-dimensional flow character with a satisfying resolution. In this work in vitro flow measurements in a cannulated and a non-cannulated aortic silicone model are presented. Stereo particle image velocimetry measurements in multiple planes were carried out. By assembling the data of the different measurement planes, quasi 3D velocity fields with a resolution of~1.5*1.5*2.5 mm(3) were obtained. The resulting velocity fields have been compared regarding magnitude, streamlines and vorticity. The presented method shows to be a suitable in vitro technique to measure and address the three-dimensional aortic CPB cannula flow with a high temporal and spatial resolution. PMID- 25907549 TI - A finite element strategy to investigate the free expansion behaviour of a biodegradable polymeric stent. AB - Bioresorbable stents represent a promising technological development within the field of cardiovascular angioplasty because of their ability to avoid long-term side effects of conventional stents such as in-stent restenosis, late stent thrombosis and fatigue induced strut fracture. Finite element simulations have proven to present a useful research tool for the design and mechanical analysis of stents. However, biodegradable stents pose new challenges because of their transitional mechanical behaviour. For polymeric biodegradable stents, viscoplastic effects have to be accounted for. This paper presents a method to analyse the mechanical behaviour of polymeric bioresorbable stents using an implicit finite-element solver. As an example, we investigate the mechanical behaviour of a commercially available bioresorbable stent. We examine how, due to the visco-elastic properties of the stent material, the balloon deployment rate influences the mechanical integrity of the stent. PMID- 25907550 TI - Lubricin deficiency in the murine lumbar intervertebral disc results in elevated torsional apparent modulus. AB - The purpose of this study was to investigate the mechanical consequences of proteoglycan 4 (Prg4) deficiency on intervertebral disc mechanics using a Prg4 knockout mouse model. Prg4, also called lubricin, was first identified as the boundary lubricant in synovial fluid but has subsequently been localized within a number of musculoskeletal tissues in areas subjected to shear and tensile stresses, including the intervertebral disc. The function of lubricin in the intervertebral disc has not been determined. Lumbar level 1-2 vertebral body-disc vertebral body motion segments were isolated from Prg4 null mice and wild type (WT) litter mate controls. Disc dimensions were measured and motion segments were tested in axial loading and torsion. Torque measurements and disc dimensions were used to calculate the torsional apparent modulus for discs from Prg4 null and WT discs. Discs from Prg4 null mice had a significantly smaller mean transverse disc area (p=0.0057), with a significantly larger proportion of this area occupied by the nucleus pulposus (p<0.0001), compared to WT specimens. Apparent torsional moduli were found to be elevated in Prg4 null lumbar discs compared to WT controls at 10-10 degrees (p=0.0048) and 10-30 degrees (p=0.0127) rotation. This study suggests a functional role for Prg4 in the murine intervertebral disc. The absence of Prg4 was associated with an increased apparent torsional modulus and the structural consequences of Prg4 deficiency in the intervertebral disc, with expansion of the area of the nucleus pulposus relative to the transverse disc area in Prg4 null specimens. PMID- 25907552 TI - Tuning the switching behavior of binary oxide-based resistive memory devices by inserting an ultra-thin chemically active metal nanolayer: a case study on the Ta2O5-Ta system. AB - The common nonpolar switching behavior of binary oxide-based resistive random access memory devices (RRAMs) has several drawbacks in future application, such as the requirements for a high forming voltage, a large reset current, and an additional access device to settle the sneak-path issue. Herein, we propose the tuning of the switching behavior of binary oxide-based RRAMs by inserting an ultra-thin chemically active metal nanolayer, and a case study on Ta2O5-Ta systems is provided. The devices are designed to be Pt/Ta2O5(5 - x/2)/Ta(x)/Ta2O5(5 - x/2)/Pt with x = 0, 2, or 4 nm. The reference devices without the Ta nanolayer exhibit an expected nonpolar switching behavior with a high forming voltage of ~-4.5 V and a large reset current of >10 mA. In contrast, a self-compliance bipolar switching behavior with a low forming voltage of ~-2 V and a small reset current of <1 mA is observed after inserting a 2 nm Ta nanolayer. When the Ta nanolayer is increased to 4 nm, a complementary resistive switching (CRS) behavior is found, which can effectively settle the sneak-path issue. The appearance of CRS behavior suggests that a thin Ta nanolayer of 4 nm is robust enough to act as an inner electrode. Besides, the behind switching mechanisms are thoroughly discussed with the help of a transmission electron microscope and temperature-dependent electrical measurements. All these results demonstrate the feasibility of tuning switching behavior of binary oxide-based RRAMs by inserting an ultra-thin chemically active metal nanolayer and might help to advance the commercialization of binary oxide-based RRAMs. PMID- 25907551 TI - Assessment of hemoglobin responsiveness to epoetin alfa in patients on hemodialysis using a population pharmacokinetic pharmacodynamic model. AB - A population pharmacokinetic pharmacodynamic (PK/PD) model describing the effect of epoetin alfa on hemoglobin (Hb) response in hemodialysis patients was developed. Epoetin alfa pharmacokinetics was described using a linear 2 compartment model. PK parameter estimates were similar to previously reported values. A maturation-structured cytokinetic model consisting of 5 compartments linked in a catenary fashion by first-order cell transfer rates following a zero order input process described the Hb time course. The PD model described 2 subpopulations, one whose Hb response reflected epoetin alfa dosing and a second whose response was unrelated to epoetin alfa dosing. Parameter estimates from the PK/PD model were physiologically reasonable and consistent with published reports. Numerical and visual predictive checks using data from 2 studies were performed. The PK and PD of epoetin alfa were well described by the model. PMID- 25907553 TI - A Novel Peroxisome Proliferator-activated Receptor (PPAR)alpha Agonist and PPARgamma Antagonist, Z-551, Ameliorates High-fat Diet-induced Obesity and Metabolic Disorders in Mice. AB - A novel peroxisome proliferator-activated receptor (PPAR) modulator, Z-551, having both PPARalpha agonistic and PPARgamma antagonistic activities, has been developed for the treatment of obesity and obesity-related metabolic disorders. We examined the effects of Z-551 on obesity and the metabolic disorders in wild type mice on the high-fat diet (HFD). In mice on the HFD, Z-551 significantly suppressed body weight gain and ameliorated insulin resistance and abnormal glucose and lipid metabolisms. Z-551 inhibited visceral fat mass gain and adipocyte hypertrophy, and reduced molecules involved in fatty acid uptake and synthesis, macrophage infiltration, and inflammation in adipose tissue. Z-551 increased molecules involved in fatty acid combustion, while reduced molecules associated with gluconeogenesis in the liver. Furthermore, Z-551 significantly reduced fasting plasma levels of glucose, triglyceride, free fatty acid, insulin, and leptin. To elucidate the significance of the PPAR combination, we examined the effects of Z-551 in PPARalpha-deficient mice and those of a synthetic PPARgamma antagonist in wild-type mice on the HFD. Both drugs showed similar, but weaker effects on body weight, insulin resistance and specific events provoked in adipose tissue compared with those of Z-551 as described above, except for lack of effects on fasting plasma triglyceride and free fatty acid levels. These findings suggest that Z-551 ameliorates HFD-induced obesity, insulin resistance, and impairment of glucose and lipid metabolisms by PPARalpha agonistic and PPARgamma antagonistic activities, and therefore, might be clinically useful for preventing or treating obesity and obesity-related metabolic disorders such as insulin resistance, type 2 diabetes, and dyslipidemia. PMID- 25907554 TI - Maternal and Zygotic Sphingosine Kinase 2 Are Indispensable for Cardiac Development in Zebrafish. AB - Sphingosine 1-phosphate (S1P) is synthesized from sphingosine by sphingosine kinases (SPHK1 and SPHK2) in invertebrates and vertebrates, whereas specific receptors for S1P (S1PRs) selectively appear in vertebrates, suggesting that S1P acquires novel functions in vertebrates. Because the developmental functions of SPHK1 and SPHK2 remain obscure in vertebrates, we generated sphk1 or sphk2 gene disrupted zebrafish by introducing premature stop codons in their coding regions using transcription activator-like effector nucleases. Both zygotic sphk1 and sphk2 zebrafish mutants exhibited no obvious developmental defects and grew to adults. The maternal-zygotic sphk2 mutant (MZsphk2), but not the maternal-zygotic sphk1 mutant and maternal sphk2 mutant, had a defect in the cardiac progenitor migration and a concomitant decrease in S1P level, leading to a two-heart phenotype (cardia bifida). Cardia bifida in MZsphk2, which was rescued by injecting sphk2 mRNA, was a phenotype identical to that of zygotic mutants of the S1P transporter spns2 and S1P receptor s1pr2, indicating that the Sphk2-Spns2 S1pr2 axis regulates the cardiac progenitor migration in zebrafish. The contribution of maternally supplied lipid mediators during vertebrate organogenesis presents as a requirement for maternal-zygotic Sphk2. PMID- 25907555 TI - The Influence of Nitric Oxide on Soluble Guanylate Cyclase Regulation by Nucleotides: ROLE OF THE PSEUDOSYMMETRIC SITE. AB - Activation of soluble guanylate cyclase (sGC) by the signaling molecule nitric oxide (NO) leads to formation of the second messenger cGMP, which mediates numerous physiological processes. NO activates sGC by binding to the ferrous heme cofactor; the relative amount of NO with respect to sGC heme affects the enzyme activity. ATP can also influence the activity by binding to an allosteric site, most likely the pseudosymmetric site located in the catalytic domain. Here, the role of the pseudosymmetric site on nucleotide regulation was investigated by point mutations at this site. ATP inhibition kinetics of wild type and a pseudosymmetric site (alpha1-C594A/beta1-D477A) variant of sGC was determined at various levels of NO. Results obtained show that in the presence of less than 1 eq of NO, there appears to be less than complete activation and little change in the nucleotide binding parameters. The most dramatic effects are observed for the addition of excess NO, which results in an increase in the affinity of GTP at the catalytic site and full activation of sGC. The pseudosymmetric site mutation only affected nucleotide affinities in the presence of excess NO; there was a decrease in the affinity for ATP in both the allosteric and catalytic sites. These observations led to a new kinetic model for sGC activity in the presence of excess NO. This model revealed that the active and allosteric sites show cooperativity. This new comprehensive model gives a more accurate description of sGC regulation by NO and nucleotides in vivo. PMID- 25907556 TI - The Interaction of Heparin Tetrasaccharides with Chemokine CCL5 Is Modulated by Sulfation Pattern and pH. AB - Interactions between chemokines such as CCL5 and glycosaminoglycans (GAGs) are essential for creating haptotactic gradients to guide the migration of leukocytes into inflammatory sites, and the GAGs that interact with CCL5 with the highest affinity are heparan sulfates/heparin. The interaction between CCL5 and its receptor on monocytes, CCR1, is mediated through residues Arg-17 and -47 in CCL5, which overlap with the GAG-binding (44)RKNR(47) "BBXB" motifs. Here we report that heparin and tetrasaccharide fragments of heparin are able to inhibit CCL5 CCR1 binding, with IC50 values showing strong dependence on the pattern and extent of sulfation. Modeling of the CCL5-tetrasaccharide complexes suggested that interactions between specific sulfate and carboxylate groups of heparin and residues Arg-17 and -47 of the protein are essential for strong inhibition; tetrasaccharides lacking the specific sulfation pattern were found to preferentially bind CCL5 in positions less favorable for inhibition of the interaction with CCR1. Simulations of a 12-mer heparin fragment bound to CCL5 indicated that the oligosaccharide preferred to interact simultaneously with both (44)RKNR(47) motifs in the CCL5 homodimer and engaged residues Arg-47 and -17 from both chains. Direct engagement of these residues by the longer heparin oligosaccharide provides a rationalization for its effectiveness as an inhibitor of CCL5-CCR1 interaction. In this mode, histidine (His-23) may contribute to CCL5 GAG interactions when the pH drops just below neutral, as occurs during inflammation. Additionally, an examination of the contribution of pH to modulating CCL5-heparin interactions suggested a need for careful interpretation of experimental results when experiments are performed under non-physiological conditions. PMID- 25907557 TI - The Us3 Protein of Herpes Simplex Virus 1 Inhibits T Cell Signaling by Confining Linker for Activation of T Cells (LAT) Activation via TRAF6 Protein. AB - Herpes simplex virus 1 (HSV-1) is the most prevalent human virus and causes global morbidity because the virus is able to infect multiple cell types. Remarkably, HSV infection switches between lytic and latent cycles, where T cells play a critical role. However, the precise way of virus-host interactions is incompletely understood. Here we report that HSV-1 productively infected Jurkat T cells and inhibited antigen-induced T cell receptor activation. We discovered that HSV-1-encoded Us3 protein interrupted TCR signaling and interleukin-2 production by inactivation of the linker for activation of T cells. This study unveils a mechanism by which HSV-1 intrudes into early events of TCR-mediated cell signaling and may provide novel insights into HSV infection, during which the virus escapes from host immune surveillance. PMID- 25907558 TI - Stress-activated Dendritic Cells (DC) Induce Dual Interleukin (IL)-15- and IL1beta-mediated Pathways, Which May Elicit CD4+ Memory T Cells and Interferon (IFN)-stimulated Genes. AB - The prevailing evidence suggests that immunological memory does not require antigenic re-stimulation but is maintained by low level tonic stimulation. We examined the hypothesis that stress agents contribute to tonic cellular activation and maintain immunological memory. Stimulation of monocyte-derived dendritic cells (DC) with stress agents elicits reactive oxygen species and HSP70. NFkappaB is activated, which up-regulates membrane-associated (ma) IL-15, caspase-1 and IL-1beta. Co-culture of stress-treated DC with mononuclear cells activates IL-15 and IL-1beta receptors on CD4(+) T cells, eliciting CD40L, proliferation, and up-regulation of CD45RO(+) memory T cells. The transcription factors Tbet(high) and RORgammat are up-regulated, whereas FoxP3 is down regulated, resulting in enhanced Th1 and Th17 expression and the corresponding cytokines. The interaction between maIL-15 expressed by DC and IL-15R on CD4(+) T cells results in one pathway and the corresponding cells expressing IL-1beta and IL1betaR as a second pathway. Importantly, inhibition studies with IL-15 antibodies and IL-1betaR inhibitor suggest that both pathways may be required for optimum CD4(+) CD45RO(+) memory T cell expression. Type 1 IFN expression in splenic CD11c DC of stress-treated mice demonstrated a significant increase of IFN-alpha in CD11c CD317(+) and CD8alpha(+) DC. Analysis of RNA in human CD4(+) memory T cells showed up-regulation of type 1 IFN-stimulated genes and inhibition with histone methyltransferase inhibitor. We suggest the paradigm that stress induced tonic stimulation might be responsible for the robust persistence of the immune response in vaccination and that epigenetic changes are involved in maintaining CD4(+) T cell memory. PMID- 25907559 TI - Deletion of the Proposed Iron Chaperones IscA/SufA Results in Accumulation of a Red Intermediate Cysteine Desulfurase IscS in Escherichia coli. AB - In Escherichia coli, sulfur in iron-sulfur clusters is primarily derived from L cysteine via the cysteine desulfurase IscS. However, the iron donor for iron sulfur cluster assembly remains elusive. Previous studies have shown that, among the iron-sulfur cluster assembly proteins in E. coli, IscA has a unique and strong iron-binding activity and that the iron-bound IscA can efficiently provide iron for iron-sulfur cluster assembly in proteins in vitro, indicating that IscA may act as an iron chaperone for iron-sulfur cluster biogenesis. Here we report that deletion of IscA and its paralog SufA in E. coli cells results in the accumulation of a red-colored cysteine desulfurase IscS under aerobic growth conditions. Depletion of intracellular iron using a membrane-permeable iron chelator, 2,2'-dipyridyl, also leads to the accumulation of red IscS in wild-type E. coli cells, suggesting that the deletion of IscA/SufA may be emulated by depletion of intracellular iron. Purified red IscS has an absorption peak at 528 nm in addition to the peak at 395 nm of pyridoxal 5'-phosphate. When red IscS is oxidized by hydrogen peroxide, the peak at 528 nm is shifted to 510 nm, which is similar to that of alanine-quinonoid intermediate in cysteine desulfurases. Indeed, red IscS can also be produced in vitro by incubating wild-type IscS with excess L-alanine and sulfide. The results led us to propose that deletion of IscA/SufA may disrupt the iron delivery for iron-sulfur cluster biogenesis, therefore impeding sulfur delivery by IscS, and result in the accumulation of red IscS in E. coli cells. PMID- 25907561 TI - Genetic risk loci for Parkinson's disease: Moving from state to trait? PMID- 25907560 TI - MicroRNA-26a/-26b-COX-2-MIP-2 Loop Regulates Allergic Inflammation and Allergic Inflammation-promoted Enhanced Tumorigenic and Metastatic Potential of Cancer Cells. AB - Cyclooxgenase-2 (COX-2) knock-out mouse experiments showed that COX-2 was necessary for in vivo allergic inflammation, such as passive cutaneous anaphylaxis, passive systemic anaphylaxis, and triphasic cutaneous allergic reaction. TargetScan analysis predicted COX-2 as a target of miR-26a and miR-26b. miR-26a/-26b decreased luciferase activity associated with COX-2-3'-UTR. miR-26a/ 26b exerted negative effects on the features of in vitro and in vivo allergic inflammation by targeting COX-2. ChIP assays showed the binding of HDAC3 and SNAIL, but not COX-2, to the promoter sequences of miR-26a and miR-26b. Cytokine array analysis showed that the induction of chemokines, such as MIP-2, in the mouse passive systemic anaphylaxis model occurred in a COX-2-dependent manner. ChIP assays showed the binding of HDAC3 and COX-2 to the promoter sequences of MIP-2. In vitro and in vivo allergic inflammation was accompanied by the increased expression of MIP-2. miR-26a/-26b negatively regulated the expression of MIP-2. Allergic inflammation enhanced the tumorigenic and metastatic potential of cancer cells and induced positive feedback involving cancer cells and stromal cells, such as mast cells, macrophages, and endothelial cells. miR-26a mimic and miR-26b mimic negatively regulated the positive feedback between cancer cells and stromal cells and the positive feedback among stromal cells. miR-26a/-26b negatively regulated the enhanced tumorigenic potential by allergic inflammation. COX-2 was necessary for the enhanced metastatic potential of cancer cells by allergic inflammation. Taken together, our results indicate that the miR26a/-26b COX-2-MIP-2 loop regulates allergic inflammation and the feedback relationship between allergic inflammation and the enhanced tumorigenic and metastatic potential. PMID- 25907562 TI - Evaluating the Multifactor Structure of the Long and Short Versions of the Self Compassion Scale in a Clinical Sample. AB - OBJECTIVE: There has been a growing interest in the concept of self-compassion in Eastern psychology. The aim of the present study was to explore the dimensionality of the widely used Self-Compassion Scale (SCS; long and short versions) in both clinical and nonclinical samples METHOD: Several confirmatory factor analyses (CFAs) were computed in a mixed clinical (n = 316) and a nonclinical sample (n = 1128) from the Portuguese population. Also, differences were tested between the groups in the SCS 6 factors. RESULTS: The CFA supported both a 6-factor model and a hierarchical model in both samples. The SCS also showed good psychometric properties, with good internal consistency, test-retest reliability, and convergent validity. Our study further suggests that individuals with several psychopathological disorders showed significantly lower self compassionate abilities. CONCLUSIONS: The SCS (long and short versions) is thus a reliable instrument to assess self-compassion and is useful for research and, in particular, clinical practice. PMID- 25907563 TI - Homology-based method for detecting regions of interest in colonic digital images. AB - BACKGROUND: A region of interest (ROI) is a part of tissue that contains important information for diagnosis. To use many image analysis methods efficiently, a technique that would allow for ROI identification is required. For the colon, ROIs are characterized by areas of stronger color intensity of hematoxylin. Since malignant tumors grow in the innermost layer, most ROIs will be located in the colonic mucosa and will be an accumulation of tumor cells and/or integrated cells with distorted architecture. METHODS: Using homology theory, our group proposed a method to estimate the contact degree of elements in a unit area of tissue. Homology is a concept that is used in many branches of algebra and topology, and it can quantify the contact degree. Due to the lack of contact inhibition of cancer cells, an area with unusual contact degree is expected to be a potential ROI. RESULTS: The current work verifies the accuracy of this method against the results of pathological diagnosis, based on 1825 colonic images provided by the Osaka Medical Center for Cancer and Cardiovascular Diseases. Although we have many false positives and there is a possibility of missing undifferentiated types of cancer, this system is very effective for detecting ROIs. CONCLUSIONS: The mathematical system proposed by our group successfully detects ROIs and is a potentially useful tool for differentiating tumor areas in microscopic examination very quickly. Because we use only the information from low-power field images, there is room for further improvement. This system could be used to screen for not only colon cancer but other cancers as well. More sophisticated and more efficient automated pathological diagnosis systems can be developed by integrating various techniques available today. VIRTUAL SLIDE: The virtual slide(s) for this article can be found here: http://www.diagnosticpathology.diagnomx.eu/vs/7129390011429407 . PMID- 25907564 TI - Effect of intranasal dexamethasone on endogenous cortisol level and intraocular pressure. AB - BACKGROUND: Medical treatment of chronic rhinosinusitis with nasal polyposis (CRSwNP) centers on the administration of steroids. High-dose topical nasal steroids (HDTNS) have shown promising results with less systemic effects than oral steroids. One promising HDTNS is 0.132% dexamethasone nasal spray. We investigated whether intranasal dexamethasone was associated with changes in serum cortisol and/or intraocular pressure (IOP). METHODS: Patients with CRSwNP were treated with dexamethasone sodium phosphate 0.132% nasal spray twice daily. Morning serum cortisol and IOP were checked after at least 6 weeks of therapy. RESULTS: Twenty-eight patients met study criteria. The average serum cortisol level after at least 6 weeks of therapy (average duration of 38.3 weeks) was 9.8 MUg/dL (normal range, 4 to 22 MUg/dL). Ten patients had suppressed cortisol levels (average, 2.5 MUg/dL). Ten patients underwent IOP measurements and none revealed ocular hypertension on tonometry. CONCLUSION: High-dose dexamethasone nasal spray given for a period of at least 6 weeks does appear to have the potential to cause a decrease in serum cortisol levels; however, future studies with greater power are necessary to support this claim. Additionally, similar administration of high-dose dexamethasone nasal spray did not reveal IOP diagnostic of ocular hypertension on single-measurement tonometry readings. PMID- 25907565 TI - HAG3, a Histone Acetyltransferase, Affects UV-B Responses by Negatively Regulating the Expression of DNA Repair Enzymes and Sunscreen Content in Arabidopsis thaliana. AB - Histone acetylation is regulated by histone acetyltransferases and deacetylases. In Arabidopsis, there are 12 histone acetyltransferases and 18 deacetylases. Histone acetyltransferases are organized in four families: the GNAT/HAG, the MYST, the p300/CBP and the TAFII250 families. Previously, we demonstrated that Arabidopsis mutants in the two members of the MYST acetyltransferase family show increased DNA damage after UV-B irradiation. To investigate further the role of other histone acetyltransferases in UV-B responses, a putative role for enzymes of the GNAT family, HAG1, HAG2 and HAG3, was analyzed. HAG transcripts are not UV B regulated; however, hag3 RNA interference (RNAi) transgenic plants show a lower inhibition of leaf and root growth by UV-B, higher levels of UV-B-absorbing compounds and less UV-B-induced DNA damage than Wassilewskija (Ws) plants, while hag1 RNAi transgenic plants and hag2 mutants do not show significant differences from wild-type plants. Transcripts for UV-B-regulated genes are highly expressed under control conditions in the absence of UV-B in hag3 RNAi transgenic plants, suggesting that the higher UV-B tolerance may be due to increased levels of proteins that participate in UV-B responses. Together, our data provide evidence that HAG3, directly or indirectly, participates in UV-B-induced DNA damage repair and signaling. PMID- 25907566 TI - Transport Function of Rice Amino Acid Permeases (AAPs). AB - The transport function of four rice (Oryza sativa) amino acid permeases (AAPs), OsAAP1 (Os07g04180), OsAAP3 (Os06g36180), OsAAP7 (Os05g34980) and OsAAP16 (Os12g08090), was analyzed by expression in Xenopus laevis oocytes and electrophysiology. OsAAP1, OsAAP7 and OsAAP16 functioned, similarly to Arabidopsis AAPs, as general amino acid permeases. OsAAP3 had a distinct substrate specificity compared with other rice or Arabidopsis AAPs. OsAAP3 transported the basic amino acids lysine and arginine well but selected against aromatic amino acids. The transport of basic amino acids was further analyzed for OsAAP1 and OsAAP3, and the results support the transport of both neutral and positively charged forms of basic amino acids by the rice AAPs. Cellular localization using the tandem enhanced green fluorescent protein (EGFP)-red fluorescent protein (RFP) reporter pHusion showed that OsAAP1 and OsAAP3 localized to the plasma membrane after transient expression in onion epidermal cells or stable expression in Arabidopsis. PMID- 25907567 TI - Spatial Regulation of the Gene Expression Response to Shade in Arabidopsis Seedlings. AB - The shade avoidance response, which allows plants to escape from nearby competitors, is triggered by a reduction in the PFR form of phytochrome in response to shade. Classic physiological experiments have demonstrated that the shade signal perceived by the leaves is transmitted to the other parts of the plant. Recently, a simple method was developed to analyze the transcriptome in a single microgram tissue sample. In the present study, we adopted this method to conduct organ-specific transcriptomic analysis of the shade avoidance response in Arabidopsis seedlings. The shoot apical samples, which contained the meristem, basal parts of leaf primordia and short fragments of vasculature, were collected from the topmost part of the hypocotyl and subjected to RNA sequencing analysis. Unexpectedly, many more genes were up-regulated in the shoot apical region than in the cotyledons. Spotlight irradiation demonstrated that the apex-responsive genes were mainly controlled by phytochrome in the cotyledons. In accordance with the involvement of many auxin-responsive genes in this category, auxin biosynthesis was genetically shown to be essential for this response. In contrast, organ-autonomous regulation was more important for the genes that were up-regulated preferentially either in the cotyledons or in both the cotyledons and the apical region. Their responses to shade depended variously on auxin and PIFs (phytochrome-interacting factors), indicating the mechanistic diversity of the organ-autonomous response. Finally, we examined the expression of the auxin synthesis genes, the YUC genes, and found that three YUC genes, which were differently spatially regulated, co-ordinately elevated the auxin level within the shoot apical region. PMID- 25907568 TI - Auxin Biosynthesis, Accumulation, Action and Transport are Involved in Stress Induced Microspore Embryogenesis Initiation and Progression in Brassica napus. AB - Isolated microspores are reprogrammed in vitro by stress, becoming totipotent cells and producing embryos and plants via a process known as microspore embryogenesis. Despite the abundance of data on auxin involvement in plant development and embryogenesis, no data are available regarding the dynamics of auxin concentration, cellular localization and the expression of biosynthesis genes during microspore embryogenesis. This work involved the analysis of auxin concentration and cellular accumulation; expression of TAA1 and NIT2 encoding enzymes of two auxin biosynthetic pathways; expression of the PIN1-like efflux carrier; and the effects of inhibition of auxin transport and action by N-1 naphthylphthalamic acid (NPA) and alpha-(p-chlorophenoxy) isobutyric acid (PCIB) during Brassica napus microspore embryogenesis. The results indicated de novo auxin synthesis after stress-induced microspore reprogramming and embryogenesis initiation, accompanying the first cell divisions. The progressive increase of auxin concentration during progression of embryogenesis correlated with the expression patterns of TAA1 and NIT2 genes of auxin biosynthetic pathways. Auxin was evenly distributed in early embryos, whereas in heart/torpedo embryos auxin was accumulated in apical and basal embryo regions. Auxin efflux carrier PIN1 like gene expression was induced in early multicellular embryos and increased at the globular/torpedo embryo stages. Inhibition of polar auxin transport (PAT) and action, by NPA and PCIB, impaired embryo development, indicating that PAT and auxin action are required for microspore embryo progression. NPA also modified auxin embryo accumulation patterns. These findings indicate that endogenous auxin biosynthesis, action and polar transport are required in stress-induced microspore reprogramming, embryogenesis initiation and progression. PMID- 25907569 TI - Global Transcriptome Analysis Reveals Acclimation-Primed Processes Involved in the Acquisition of Desiccation Tolerance in Boea hygrometrica. AB - Boea hygrometrica resurrection plants require a period of acclimation by slow soil-drying in order to survive a subsequent period of rapid desiccation. The molecular basis of this observation was investigated by comparing gene expression profiles under different degrees of water deprivation. Transcripts were clustered according to the expression profiles in plants that were air-dried (rapid desiccation), soil-dried (gradual desiccation), rehydrated (acclimated) and air dried after acclimation. Although phenotypically indistinguishable, it was shown by principal component analysis that the gene expression profiles in rehydrated, acclimated plants resemble those of desiccated plants more closely than those of hydrated acclimated plants. Enrichment analysis based on gene ontology was performed to deconvolute the processes that accompanied desiccation tolerance. Transcripts associated with autophagy and alpha-tocopherol accumulation were found to be activated in both air-dried, acclimated plants and soil-dried non acclimated plants. Furthermore, transcripts associated with biosynthesis of ascorbic acid, cell wall catabolism, chaperone-assisted protein folding, respiration and macromolecule catabolism were activated and maintained during soil-drying and rehydration. Based on these findings, we hypothesize that activation of these processes leads to the establishment of an optimal physiological and cellular state that enables tolerance during rapid air-drying. Our study provides a novel insight into the transcriptional regulation of critical priming responses to enable survival following rapid dehydration in B. hygrometrica. PMID- 25907570 TI - Ubiquitin-Mediated Proteasomal Degradation of Oleosins is Involved in Oil Body Mobilization During Post-Germinative Seedling Growth in Arabidopsis. AB - In oleaginous seeds, lipids--stored in organelles called oil bodies (OBs)--are degraded post-germinatively to provide carbon and energy for seedling growth. To date, little is known about how OB coat proteins, known as oleosins, control OB dynamics during seed germination. Here, we demonstrated that the sequential proteolysis of the five Arabidopsis thaliana oleosins OLE1-OLE5 begins just prior to lipid degradation. Several post-translational modifications (e.g. phosphorylation and ubiquination) of oleosins were concomitant with oleosin degradation. Phosphorylation occurred only on the minor OLE5 and on an 8 kDa proteolytic fragment of OLE2. A combination of immunochemical and proteomic approaches revealed ubiquitination of the four oleosins OLE1-OLE4 at the onset of OB mobilization. Ubiquitination topology was surprisingly complex. OLE1 and OLE2 were modified by three distinct and predominantly exclusive motifs: monoubiquitin, K48-linked diubiquitin (K48Ub(2)) and K63-linked diubiquitin. Ubiquitinated oleosins may be channeled towards specific degradation pathways according to ubiquitination type. One of these pathways was identified as the ubiquitin-proteasome pathway. A proteasome inhibitor (MG132) reduced oleosin degradation and induced cytosolic accumulation of K48Ub(2)-oleosin aggregates. These results indicate that K48Ub(2)-modified oleosins are selectively extracted from OB coat and degraded by the proteasome. Proteasome inhibition also reduced lipid hydrolysis, providing in vivo evidence that oleosin degradation is required for lipid mobilization. PMID- 25907571 TI - Limitation of Cell Elongation in Barley (Hordeum vulgare L.) Leaves Through Mechanical and Tissue-Hydraulic Properties. AB - The aim of the present study was to assess the mechanical and hydraulic limitation of growth in leaf epidermal cells of barley (Hordeum vulgare L.) in response to agents which affect cellular water (mercuric chloride, HgCl(2)) and potassium (cesium chloride, CsCl; tetraethylammonium, TEA) transport, pump activity of plasma membrane H(+)-ATPase and wall acidification (fusicoccin, FC). Cell turgor (P) was measured with the cell pressure probe, and cell osmotic pressure (pi) was analyzed through picoliter osmometry of single-cell extracts. A wall extensibility coefficient (M) and tissue hydraulic conductance coefficient (L) were derived using the Lockhart equation. There was a significant positive linear relationship between relative elemental growth rate and P, which fit all treatments, with an overall apparent yield threshold of 0.368 MPa. Differences in growth between treatments could be explained through differences in P. A comparison of L and M showed that growth in all except the FC treatment was co limited through hydraulic and mechanical properties, though to various extents. This was accompanied by significant (0.17-0.24 MPa) differences in water potential (DeltaPsi) between xylem and epidermal cells in the leaf elongation zone. In contrast, FC-treated leaves showed DeltaPsi close to zero and a 10-fold increase in L. PMID- 25907572 TI - Model demonstrates functional purpose of the nasal cycle. AB - BACKGROUND: Despite the occurrence of the nasal cycle being well documented, the functional purpose of this phenomenon is not well understood. This investigation seeks to better understand the physiological objective of the nasal cycle in terms of airway health through the use of a computational nasal air-conditioning model. METHOD: A new state-variable heat and water mass transfer model is developed to predict airway surface liquid (ASL) hydration status within each nasal airway. Nasal geometry, based on in-vivo magnetic resonance imaging (MRI) data is used to apportion inter-nasal air flow. RESULTS: The results demonstrate that the airway conducting the majority of the airflow also experiences a degree of ASL dehydration, as a consequence of undertaking the bulk of the heat and water mass transfer duties. In contrast, the reduced air conditioning demand within the other airway allows its ASL layer to remain sufficiently hydrated so as to support continuous mucociliary clearance. CONCLUSIONS: It is quantitatively demonstrated in this work how the nasal cycle enables the upper airway to accommodate the contrasting roles of air conditioning and the removal of entrapped contaminants through fluctuation in airflow partitioning between each airway. PMID- 25907573 TI - Heme precursor injection is effective for Arthromyces ramosus peroxidase fusion protein production by a silkworm expression system. AB - Recombinant peroxidase from Arthromyces ramosus, fused with domains of antibody binding proteins, was successfully obtained by a silkworm larvae expression system. The catalytic activity of the fusion peroxidase was increased 6-fold with the injection of 5-aminolevulinic acid into silkworm larvae as a heme precursor. PMID- 25907574 TI - Transcription activator-like effector nucleases mediated metabolic engineering for enhanced fatty acids production in Saccharomyces cerevisiae. AB - Targeted engineering of microbial genomes holds much promise for diverse biotechnological applications. Transcription activator-like effector nucleases (TALENs) and clustered regularly interspaced short palindromic repeats/Cas9 systems are capable of efficiently editing microbial genomes, including that of Saccharomyces cerevisiae. Here, we demonstrate the use of TALENs to edit the genome of S. cerevisiae with the aim of inducing the overproduction of fatty acids. Heterodimeric TALENs were designed to simultaneously edit the FAA1 and FAA4 genes encoding acyl-CoA synthetases in S. cerevisiae. Functional yeast double knockouts generated using these TALENs over-produce large amounts of free fatty acids into the cell. This study demonstrates the use of TALENs for targeted engineering of yeast and demonstrates that this technology can be used to stimulate the enhanced production of free fatty acids, which are potential substrates for biofuel production. This proof-of-principle study extends the utility of TALENs as excellent genome editing tools and highlights their potential use for metabolic engineering of yeast and other organisms, such as microalgae and plants, for biofuel production. PMID- 25907575 TI - Comparison of manual and automated cultures of bone marrow stromal cells for bone tissue engineering. AB - The development of an automated cell culture system would allow stable and economical cell processing for wider clinical applications in the field of regenerative medicine. However, it is crucial to determine whether the cells obtained by automated culture are comparable to those generated by manual culture. In the present study, we focused on the primary culture process of bone marrow stromal cells (BMSCs) for bone tissue engineering and investigated the feasibility of its automation using a commercially available automated cell culture system in a clinical setting. A comparison of the harvested BMSCs from manual and automated cultures using clinically acceptable protocols showed no differences in cell yields, viabilities, surface marker expression profiles, and in vivo osteogenic abilities. Cells cultured with this system also did not show malignant transformation and the automated process was revealed to be safe in terms of microbial contamination. Taken together, the automated procedure described in this report provides an approach to clinical bone tissue engineering. PMID- 25907576 TI - A planarized triphenylborane mesogen: discotic liquid crystals with ambipolar charge-carrier transport properties. AB - A discotic liquid-crystalline (LC) material, consisting of a planarized triphenylborane mesogen, was synthesized. X-ray diffraction analysis confirmed that this compound forms a hexagonal columnar LC phase with an interfacial distance of 3.57 A between the discs. At ambient temperature, this boron-centered discotic liquid crystal exhibited ambipolar carrier transport properties with electron and hole mobility values of approximately 10(-3) and 3*10(-5) cm(2) V( 1) s(-1), respectively. PMID- 25907577 TI - Improving preoperative medication compliance with standardized instructions. AB - BACKGROUND: Patient medication adherence in the perioperative setting is challenging, and failure to comply with medication instructions has serious clinical consequences. Many factors contribute to medication nonadherence, but a modifiable cause is inadequate physician instruction of patients. Variable formats, language and legibility impede patient-physician communication regarding proper use of medications. We hypothesized that the use of a standardized, electronic medical record (EMR)-derived medication instruction template would improve medication compliance on the day of surgery. METHODS: As part of an ongoing quality improvement program, our institution surveyed patient's compliance with preoperative medication instructions. A standardized template was then created within the EMR and implemented by all providers in the preoperative evaluation clinic. Compliance with medications on the morning of surgery was then reassessed by preoperative nursing staff for three months shortly after the intervention and again two years later. RESULTS: Patient adherence to preoperative medication instructions improved significantly immediately after the implementation of the template (from 83.7% to 89.7%, P=0.025). This improvement was also sustained at the two-year follow-up. Although patients' had overall good medication compliance (90% after the intervention), 71% of medication errors were made with medications with significant potential for causing complications (e.g., antithrombotic therapy). CONCLUSION: Use of standardized, EMR-generated preoperative instructions improves patient medication adherence on the morning of surgery. Even with this intervention, medication nonadherence most often involves medications that could seriously interfere with perioperative care. PMID- 25907578 TI - Early vascular complications after percutaneous cannulation for extracorporeal membrane oxygenation for cardiac assist. AB - BACKGROUND: Extracorporeal membrane oxygenation (VA ECMO) demonstrated an advantage in survival and neurological outcome in patients with cardiogenic shock and, in selected population, in victims of refractory cardiac arrest. The incidence of vascular complications ranges in recent series from 10 to 70% including both early and late complications. The aim of the present study was to determine the incidence of early vascular complications and the effectiveness of the prevention of limb ischemia by the insertion of a catheter for distal perfusion. METHODS: Data from our registry of 100 patients treated with VA ECMO implanted via percutaneous femoral approach for cardiogenic shock or refractory cardiac arrest were analyzed. If the leg perfusion was inadequate, an additional 7-9 Fr percutaneous catheter distal to the ECMO arterial cannula was placed into the femoral artery to prevent limb ischemia. RESULTS: Thirty-five patients had early vascular complications. Thirty patients with early ischemia were cannulated with a small reperfusion cannula to obtain antegrade perfusion of the limb. Twenty-six had an effective reperfusion. Seven patients developed a compartment syndrome of the leg requiring urgent fasciotomy that led to clinical improvement and recovery in five, while the other two patients progressed to irreversible ischemia requiring amputation of the limb. CONCLUSION: The majority of ischemic episodes were resolved with the insertion of a distal perfusion catheter. We did not observe any mortal vascular complication, nor any of the observed complications was related to increased mortality. PMID- 25907579 TI - A new training approach in endoscopic percutaneous tracheostomy using a simulation model based on biological tissue. AB - BACKGROUND: Ciaglia et al. originally proposed the percutaneous tracheostomy in 1985 as an alternative to the surgical approach. Several variants have been developed in the years with a convincing evidence that, compared to surgical tracheostomy, the percutaneous approach is more cost-effective without compromising safety. However the procedure is not immune from complications and requires procedural skills and adequate level of expertise with a steep learning curve. In this contest, to optimize safety and efficacy of percutaneous tracheostomy in different clinical scenarios, physicians should be familiar with the different available percutaneous techniques. Traditionally, the training has been performed using manikins or animal models. However, by definition the manikin is not able to replicate the complex anatomy and does not provide a realist model for learning. METHODS: A sheep model was implemented and was tested in a simulation-based course for percutaneous dilational tracheostomy and cricothyrotomy organized by the Department of Surgical Sciences of University of Turin at the Special Educational Section of the Veterinary Sciences Department (University of Turin). RESULTS: From September 2012 to December 2014, 2 sessions of the training course were performed. Thirty-two anesthesiologists (16 men and 16 women, mean (SD) age 40.4 (SD 8.6) attended the course. A quality assessment of the course was then collected by participants. CONCLUSIONS: The biological model we implemented proved to be adequate and effective. Future studies are required to compare its efficacy with previously proposed training methods. PMID- 25907580 TI - Upgrading the anesthesiologists' main tool: using the endotrachial tube as a large bore suction catheter for removal of a large tracheal blood clot: a technical note on a life-saving rescue maneuvre. PMID- 25907581 TI - Impact of charge transport on current-voltage characteristics and power conversion efficiency of organic solar cells. AB - This work elucidates the impact of charge transport on the photovoltaic properties of organic solar cells. Here we show that the analysis of current voltage curves of organic solar cells under illumination with the Shockley equation results in values for ideality factor, photocurrent and parallel resistance, which lack physical meaning. Drift-diffusion simulations for a wide range of charge-carrier mobilities and illumination intensities reveal significant carrier accumulation caused by poor transport properties, which is not included in the Shockley equation. As a consequence, the separation of the quasi Fermi levels in the organic photoactive layer (internal voltage) differs substantially from the external voltage for almost all conditions. We present a new analytical model, which considers carrier transport explicitly. The model shows excellent agreement with full drift-diffusion simulations over a wide range of mobilities and illumination intensities, making it suitable for realistic efficiency predictions for organic solar cells. PMID- 25907582 TI - The role of institutions on the effectiveness of malaria treatment in the Ghanaian health sector. AB - BACKGROUND: The Ghanaian health sector has undertaken several policies to help improve the quality of care received by patients. This includes the construction of several health facilities, the increase in the training of health workers, especially nurses, and the introduction of incentive packages (such as salary increase) to motivate health workers. The important question is to what extent does the institutional arrangement between the health facilities and the government as well as between health workers and public health facility administration affect the quality of care? The objective of this study is to find the effect of institutional factors on the quality of care. The institutional factors examined were mainly the extent of decentralization between government and health facilities, as well as between health workers and facility administration, the hiring procedure, and job satisfaction. METHODS: The study used primary data on former patients from sixty six health facilities in three administrative regions of Ghana: the Northern, the Ashanti and the Greater Accra regions. The quality indicator used was effectiveness of treatment as determined by the patient. Ordered logit regression was run for the indicator with patient and health facility characteristics as well as institutional factors as independent variables. The sample size was 2248. RESULTS: The results showed that the patient's level of formal education had a strong influence on the effectiveness of treatment. In addition, effectiveness of treatment differed according to the administrative region in which the facility was located, and according to the extent of decentralization between health facility and government. The quality of instruments used for treatment, the working conditions for health workers, and job satisfaction had no effect on the effectiveness of treatment. CONCLUSION: Decentralization, the flow of information from government to health facilities and from health facility administrators to health workers are important in ensuring effectiveness. The study recommends further decentralization between health facilities as well as between health workers and administrators. In addition, the study recommends the involvement of health facilities in malaria programs to ensure the flow of information needed for effectiveness of treatment. PMID- 25907583 TI - Can obtaining informed consent alter self-reported drinking behaviour? A methodological experiment. AB - BACKGROUND: Informed consent is the foundation of the ethical conduct of health research. Obtaining informed consent may unwittingly interfere with the data collected in research studies, particularly if they concern sensitive behaviours that participants are requested to report on. To address gaps in evidence on such research participation effects, we conducted a methodological experiment evaluating the impact of the informed consent procedure on participants' reporting behaviour, specifically on their self-report of drinking behaviour as measured by Alcohol Use Disorder Identification Test (AUDIT). METHODS: A two arm double blinded randomised controlled trial was used. University students present in London student unions at the time of recruitment were contacted in two phases (an initial run-in phase followed by the main phase). Those providing positive responses to verbal questions: 1) "are you a student?"; 2) "do you drink alcohol?"; 3) "would you like to take part in a brief health survey, which will take around 5 minutes?" were recruited. Participants received one of the two envelopes by chance, with the sequence generated by an online random sequence generator. One contained the participant information sheet, informed consent form and the AUDIT questionnaire (the intervention group), while the other contained only the AUDIT questionnaire (the comparator group). The primary outcome was the mean AUDIT score, which ranges from 0 to 40. The secondary outcome was the proportion of participants in each group scoring 8 or more on the AUDIT, the threshold score for hazardous and harmful drinking warranting intervention. RESULTS: A total of 380 participants were successfully recruited, resulting in 190 participants in each group, of which 378 were included in the final analysis. There is no evidence of any statistically significant difference between groups in the primary outcome. A statistically significant difference in the secondary outcome was found in the run-in phase only, and not in the main phase, or overall. Moreover, between-group outcome differences between the two phases suggest an important influence of setting on reporting behaviour. CONCLUSIONS: There is no strong evidence that completion of informed consent itself alters self-reporting behaviour with regards to alcohol, though the effect of settings needs to be further studied. PMID- 25907584 TI - Multiple antibiotic susceptibility of polyphosphate kinase mutants (ppk1 and ppk2) from Pseudomonas aeruginosa PAO1 as revealed by global phenotypic analysis. AB - BACKGROUND: Pseudomonas aeruginosa is known to be a multidrug resistant opportunistic pathogen. Particularly, P. aeruginosa PAO1 polyphosphate kinase mutant (ppk1) is deficient in motility, quorum sensing, biofilm formation and virulence. FINDINGS: By using Phenotypic Microarrays (PM) we analyzed near 2000 phenotypes of P. aeruginosa PAO1 polyP kinase mutants (ppk1 and ppk2). We found that both ppk mutants shared most of the phenotypic changes and interestingly many of them related to susceptibility toward numerous and different type of antibiotics such as Ciprofloxacin, Chloramphenicol and Rifampicin. CONCLUSIONS: Combining the fact that ppk1 mutants have reduced virulence and are more susceptible to antibiotics, polyP synthesis and particularly PPK1, is a good target for the design of molecules with anti-virulence and anti-persistence properties. PMID- 25907585 TI - Separation and purification of five alkaloids from Aconitum duclouxii by counter current chromatography. AB - C19 -diterpenoid alkaloids are the main components of Aconitum duclouxii Levl. The process of separation and purification of these compounds in previous studies was tedious and time consuming, requiring multiple chromatographic steps, thus resulted in low recovery and high cost. In the present work, five C19 diterpenoid alkaloids, namely, benzoylaconine (1), N-deethylaconitine (2), aconitine (3), deoxyaconitine (4), and ducloudine A (5), were efficiently prepared from A. duclouxii Levl (Aconitum L.) by ethyl acetate extraction followed with counter-current chromatography. In the process of separation, the critical conditions of counter-current chromatography were optimized. The two phase solvent system composed of n-hexane/ethyl acetate/methanol/water/NH3 .H2 O (25%) (1:1:1:1:0.1, v/v) was selected and 148.2 mg of 1, 24.1 mg of 2, 250.6 mg of 3, 73.9 mg of 4, and 31.4 mg of 5 were obtained from 1 g total Aconitum alkaloids extract, respectively, in a single run within 4 h. Their purities were found to be 98.4, 97.2, 98.2, 96.8, and 96.6%, respectively, by ultra-high performance liquid chromatography analysis. The presented separation and purification method was simple, fast, and efficient, and the obtained highly pure alkaloids are suitable for biochemical and toxicological investigation. PMID- 25907586 TI - Omega-3 supplements for patients in chemotherapy and/or radiotherapy: A systematic review. AB - BACKGROUND & AIMS: Eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA), in vitro and in vivo, used along with anticancer drugs, have improved cancer treatment outcome. Clinical studies have reported positive results with omega-3 supplements in oncologic patients. We summarized only randomized controlled clinical trials involving the administration of DHA and/or EPA during chemotherapy and/or radiotherapy to assess the effects on treatment outcomes. METHODS: We conducted a systematic literature search using specific terms. Of 157 publications, 10 were selected on the basis of their methodological quality, according to the Oxford Quality Scale and the Cochrane Concealment Assessment. Outcome included body weight and composition, peripheral neuropathy, immune, inflammatory and oxidative status, quality of life, and membrane omega-3 fatty acids incorporation. RESULTS: Treatment regimens included radiotherapy (1), chemotherapy (8), and chemoradiotherapy (1). The number of patients ranged from 11 to 92 and the daily dose of EPA and/or DHA from 600 mg to 3.6 g. For high quality methodology studies only, the combination of omega-3 fatty acids supplements with conventional chemotherapy was beneficial. None of the studies reported a worse outcome for the supplement patients. CONCLUSIONS: There are beneficial effects of omega-3 fatty acids supplements in patients undergoing chemotherapy and/or radiotherapy on different outcomes, being the preservation of body composition the most evident. Some important outcome like decrease tumor size and prolonging patient survival, are not observed. PMID- 25907587 TI - Enantioselective Synthesis of Tertiary Propargylic Alcohols under N-Heterocyclic Carbene Catalysis. AB - A straightforward procedure to carry out the enantioselective benzoin reaction between aldehydes and ynones by employing a chiral N-heterocyclic carbene (NHC) as catalyst was developed. Under the optimized reaction conditions, these ynones undergo a clean and selective 1,2-addition with the catalytically generated Breslow intermediate, not observing any byproduct arising from competitive Stetter-type reactivity. This procedure allows the preparation of tertiary alkynyl carbinols as highly enantioenriched materials, which have the remarkable potential to be used as chiral building blocks in organic synthesis. PMID- 25907588 TI - [Bilateral neuroretinitis secondary to Takayasu's arteritis in a young girl]. PMID- 25907589 TI - [Asteroid hyalosis]. PMID- 25907590 TI - [A documented case of pigmented paravenous chorioretinal atrophy]. PMID- 25907591 TI - [Haab's striae on optical coherence tomography]. PMID- 25907592 TI - [Shaken baby syndrome: Retcam findings]. PMID- 25907593 TI - The Neuroimaging Spectrum of Septum Posticum Derangement and Associated Thoracic Myelopathy. AB - BACKGROUND: Arachnoid cysts and meningeal membranes are among the differential diagnostic considerations of extra-medullary causes of thoracic myelopathy. In this case series of 7 patients, we present compressive meningeal membranes mimicking dorsal arachnoid cyst. The propensity of the meningeal membranes for the dorsal aspect of upper thoracic spine may reflect derangements of the septum posticum. OBJECTIVE: To provide the spectrum of imaging appearances and clinical presentations of pathology of the septum posticum to improve imaging utilization and to better guide treatment planning. METHODS: Seven patients aged 40 to 75 with MRI findings of ventral displacement and dorsal cord compression in the upper thoracic spine were further evaluated with CT-myelograms. The primary indication was to exclude dorsal arachnoid cyst. Two patients with progressive symptoms and lower extremity weakness were operated for decompression. RESULTS: CT-myelogram excluded space occupying lesions and cord herniation in all cases. Intradural dorsal meningeal webs and membranes were inconsistently visualized. In the 2 operated cases, thick coalescing membranes and hyperdynamic turbulent CSF flow were severely compressing the thoracic cord. CONCLUSION: Derangements of septum posticum may present a spectrum of findings that should be considered in the differential of thoracic myelopathy. Flattening of the posterior cord margin is a reliable imaging clue for a dorsal extra-medullary compressive lesion. Cord compression results from combination of adhesive membranes and turbulent CSF flow. The clinical course may be difficult to predict. Periodic imaging follow up can be helpful to confirm stability of findings in expectantly managed cases. PMID- 25907594 TI - A model of vesicle tubulation and pearling induced by adsorbing particles. AB - We study the basic theoretical model of a deformable vesicle immersed in a solution of particles that can adsorb onto one of the two surfaces of a membrane. The model consists of an adsorption energy gain for the adsorbing particles and the Canham-Helfrich membrane bending energy, in which the spontaneous curvature is coupled with the adsorption area. We demonstrate that bud, pearling, and tube conformations can be stabilized after minimizing the free energy and that the pearling-tubulation transition has the characteristics of an abrupt structural transition. PMID- 25907595 TI - Everyday cold exposure and urgency in translation. PMID- 25907596 TI - Heat shock at higher cell densities improves measles hemagglutinin translocation and human GRP78/BiP secretion in Saccharomyces cerevisiae. AB - The yield of heterologous proteins is often limited by several bottlenecks in the secretory pathway of yeast Saccharomyces cerevisiae. It was shown earlier that synthesis of measles virus hemagglutinin (MeH) is inefficient mostly due to a bottleneck in the translocation of viral protein precursors into the endoplasmic reticulum (ER) of yeast cells. Here we report that heat shock with subsequent induction of MeH expression at 37 degrees C improved translocation of MeH precursors when applied at higher cell densities. The amount of MeH glycoprotein increased by about 3-fold after heat shock in the late-log phases of both glucose and ethanol growth. The same temperature conditions increased both secretion titer and yield of another heterologous protein human GRP78/BiP by about 50%. Furthermore, heat shock at the late-log glucose growth phase also improved endogenous invertase yield by approximately 2.7-fold. In contrast, a transfer of yeast culture to lower temperature at diauxic shift followed by protein expression at 20 degrees C almost totally inhibited translocation of MeH precursors. The difference in amounts of MeH glycoprotein under expression at 37 degrees C and 20 degrees C was about 80-fold, while amounts of unglycosylated MeH polypeptides were similar under both conditions. Comparative proteomic analysis revealed that besides over-expressed ER-resident chaperone Kar2, an increased expression of several cytosolic proteins (such as Hsp104, Hsp90 and eEF1A) may contribute to improved translocation of MeH. PMID- 25907597 TI - Critical determinant of intestinal permeability and oral bioavailability of pegylated all trans-retinoic acid prodrug-based nanomicelles: Chain length of poly (ethylene glycol) corona. AB - Pegylation method is widely used to prolong the blood circulation time of proteins and nanoparticles after intravenous administration, but the effect of surface poly (ethylene glycol) (PEG) chain length on oral absorption of the pegylated nanoparticles is poorly reported. The aim of our study was to investigate the influence of PEG corona chain length on membrane permeability and oral bioavailability of the amphiphilic pegylated prodrug-based nanomicelles, taking all trans-retinoic acid (ATRA) as a model drug. The amphiphilic ATRA-PEG conjugates were synthesized by esterification reaction between all trans-retinoic acid and mPEGs (mPEG500, mPEG1000, mPEG2000, and mPEG5000). The conjugates could self-assemble in aqueous medium to form nanomicelles by emulsion-solvent evaporation method. The resultant nanomicelles were in spherical shape with an average diameter of 13-20 nm. The drug loading efficiency of ATRA-PEG500, ATRA PEG1000, ATRA-PEG2000, and ATRA-PEG5000 was about 38.4, 26.6, 13.1, and 5.68 wt%, respectively. With PEG chain length ranging from 500 to 5000, ATRA-PEG nanomicelles exhibited a bell shape of chemical stability in different pH buffers, intestinal homogenate and plasma. More importantly, they were all rapidly hydrolyzed into the parent drug in hepatic homogenate, with the half-time values being 0.3-0.4h. In comparison to ATRA solution and ATRA prodrug-based nanomicelles, ATRA-PEG1000 showed the highest intestinal permeability. After oral administration, ATRA-PEG2000 and ATRA-PEG5000 nanomicelles were not nearly absorbed, while the oral bioavailability of ATRA-PEG500 and ATRA-PEG1000 demonstrated about 1.2- and 2.0-fold higher than ATRA solution. Our results indicated that PEG1000 chain length of ATRA-PEG prodrug nanomicelles has the optimal oral bioavailability probably due to improved stability and balanced mucus penetration capability and cell binding, and that the PEG chain length on a surface of nanoparticles cannot exceed a key threshold with the purpose of enhancement in oral bioavailability. PMID- 25907598 TI - Combined nitric oxide-releasing poly(vinyl alcohol) film/F127 hydrogel for accelerating wound healing. AB - Nitric oxide (NO) releasing biomaterials represent a potential strategy for use as active wound dressings capable of accelerating wound healing. Topical NO releasing poly(vinyl alcohol) (PVA) films and Pluronic F127 hydrogels (F127) have already exhibited effective skin vasodilation and wound healing actions. In this study, we functionalized PVA films with SNO groups via esterification with a mixture of mercaptosucinic acid (MSA) and thiolactic acid (TLA) followed by S nitrosation of the SH moieties. These films were combined with an underlying layer of poly(ethylene oxide)-poly(propylene oxide)-poly(ethylene oxide), i.e., PEO-PPO-PEO (Pluronic F127) hydrogel and used for the topical treatment of skin lesions in an animal model. The mixed esterification of PVA with MSA and TLA led to chemically crosslinked PVA-SNO films with a high swelling capacity capable of spontaneously releasing NO. Real time NO-release measurements revealed that the hydrogel layer reduces the initial NO burst from the PVA-SNO films. We demonstrate that the combination of PVA-SNO films with F127 hydrogel accelerates wound contraction, decreases wound gap and cellular density and accelerates the inflammatory phase of the lesion. These results were reflected in an increase in myofibroblastic differentiation and collagen type III expression in the cicatricial tissue. Therefore, PVA-SNO films combined with F127 hydrogel may represent a new approach for active wound dressings capable of accelerating wound healing. PMID- 25907599 TI - Television viewing time and risk of eating disorders in Spanish adolescents: AVENA and AFINOS studies. AB - BACKGROUND: Effective preventive interventions for both eating disorders and obesity in adolescence should be focused on shared risk factors. We analyzed the association between television (TV) viewing time and the risk of eating disorders, as well as the potential role of obesity in this association. METHODS: The sample consisted of a total of 3458 Spanish adolescents, aged 13-18.5 years, from the Food and Assessment of the Nutritional Status of Adolescents (AVENA) and Physical Activity as a Preventive Measure of the Development of Overweight, Obesity, Allergies, Infections, and Cardiovascular Risk Factors in Adolescents (AFINOS) studies. Adolescents' TV time was assessed by self-report. Body mass index was calculated and the adolescents were classified into non-overweight and overweight-obesity. The risk of eating disorders was evaluated using the SCOFF questionnaire. RESULTS: Adolescents who watched TV >1 h/day had a higher risk for eating disorders, compared with those adolescents who watch TV <1 h/day. Also, overweight-obese adolescents had a higher risk for eating disorders than those who were non-overweight. Analyses across groups of TV viewing time and weight status showed similar trends, so that the higher the time spent in TV viewing, the higher the risk of eating disorders, regardless of weight status. CONCLUSIONS: TV viewing time might be a focal point for prevention of both eating disorders and obesity in adolescence. PMID- 25907600 TI - Deep molecular response in chronic myelogenous leukemia: ensuring accuracy and consistency. PMID- 25907601 TI - Creating extra pores in microporous carbon via a template strategy for a remarkable enhancement of ambient-pressure CO2 uptake. AB - In this work, we illustrate a template strategy to create extra pores in microporous carbon for enhancing ambient-pressure CO2 uptake, as exemplified in the context of carbonizing the silicon-containing POP, PPN-4, followed by removal of the silicon template. The resultant PPN-4/C600 demonstrates a remarkable enhancement of CO2 uptake capacity at 295 K and 1 bar by a factor of 2.3 compared to the parent PPN-4. PMID- 25907602 TI - A qualitative study of discourses on heterosexual anal sexual practice among key, and general populations in Tanzania: implications for HIV prevention. AB - BACKGROUND: The risk of contracting HIV through heterosexual anal sex (HAS) is significantly higher than from vaginal intercourse. Little has been done to understand the discourses around HAS and terms people use to describe the practice in Tanzania. A better understanding of discourses on HAS would offer useful insights for measurement of the practice as well as designing appropriate interventions to minimise the risks inherent in the practice. METHODS: This study employed qualitative approaches involving 24 focus group discussions and 81 in depth interviews. The study was conducted in 4 regions of Tanzania, and included samples from the general population and among key population groups (fishermen, truck drivers, sex workers, food and recreational facilities workers). Discourse analysis was conducted with the aid of NVIVO versions 8 and 10 software. RESULTS: Six discourses were delineated in relation to how people talked about HAS. Secrecy versus openness discourse describes the terms used when talking about HAS. "Other" discourse involved participants' perception of HAS as something practiced by others unrelated to them and outside their communities. Acceptability/trendiness discourse: young women described HAS as something trendy and increasingly gaining acceptability in their communities. Materiality discourse: describes HAS as a practice that was more profitable than vaginal sex. Masculinity discourse involved discussions on men proving their manhood by engaging in HAS especially when women initiated the practice. Masculine attitudes were also reflected in how men described the practice using a language that would be considered crude. Public health discourse: describes HAS as riskier for HIV infection than vaginal sex. The reported use of condoms was low due to the perceptions that condoms were unsuitable for anal sex, but also perceptions among some participants that anal sex was safer than vaginal sex. CONCLUSION: Discourses among young women and adult men across the study populations were supportive of HAS. These findings provide useful insights in understanding how different population groups talked about HAS and offer a range of terms that interventions and further research on magnitude of HAS could draw on when addressing health risks of HAS among different study populations. PMID- 25907603 TI - Post-translational modifications: Crotonylation versus acetylation. PMID- 25907610 TI - Mechanotransduction: VE-cadherin lets it flow. PMID- 25907611 TI - The ribosome prophecy. PMID- 25907614 TI - The unravelling of the ubiquitin system. AB - Today, many scientific discoveries are made using a top-down experimental approach. The ubiquitin system was discovered using a 'classic' bottom-up approach to tackle the question: 'how are cellular proteins selectively degraded?' A simple proteolytic assay, which used a crude cell-extract, was all that was required to address this question; it was followed by fractionation and reconstitution experiments to decipher the role of the components in this multi step process. This 'biochemistry at its best' approach, which was published in a periodical that today would not be regarded as highly visible, provided magnificent findings. PMID- 25907615 TI - Transformed mycosis fungoides: bridging to allogeneic stem cell transplantation with brentuximab vedotin. PMID- 25907612 TI - Regulation of RAF protein kinases in ERK signalling. AB - RAF family kinases were among the first oncoproteins to be described more than 30 years ago. They primarily act as signalling relays downstream of RAS, and their close ties to cancer have fuelled a large number of studies. However, we still lack a systems-level understanding of their regulation and mode of action. The recent discovery that the catalytic activity of RAF depends on an allosteric mechanism driven by kinase domain dimerization is providing a vital new piece of information towards a comprehensive model of RAF function. The fact that current RAF inhibitors unexpectedly induce ERK signalling by stimulating RAF dimerization also calls for a deeper structural characterization of this family of kinases. PMID- 25907613 TI - Somatic stem cell heterogeneity: diversity in the blood, skin and intestinal stem cell compartments. AB - Somatic stem cells replenish many tissues throughout life to repair damage and to maintain tissue homeostasis. Stem cell function is frequently described as following a hierarchical model in which a single master cell undergoes self renewal and differentiation into multiple cell types and is responsible for most regenerative activity. However, recent data from studies on blood, skin and intestinal epithelium all point to the concomitant action of multiple types of stem cells with distinct everyday roles. Under stress conditions such as acute injury, the surprising developmental flexibility of these stem cells enables them to adapt to diverse roles and to acquire different regeneration capabilities. This paradigm shift raises many new questions about the developmental origins, inter-relationships and molecular regulation of these multiple stem cell types. PMID- 25907616 TI - A murine model of acute myeloid leukemia with Evi1 overexpression and autocrine stimulation by an intracellular form of GM-CSF in DA-3 cells. AB - The poor treatment response of acute myeloid leukemia (AML) overexpressing high risk oncogenes such as EVI1, demands specific animal models for new treatment evaluations. Evi1 is a common site of activating integrations in murine leukemia virus (MLV)-induced AML and in retroviral and lentiviral gene-modified HCS. Still, a model of overt AML induced by Evi1 has not been generated. Cell lines from MLV-induced AML are growth factor-dependent and non-transplantable. Hence, for the leukemia maintenance in the infected animals, a growth factor source such as chronic immune response has been suggested. We have investigated whether these leukemias are transplantable if provided with growth factors. We show that the Evi1(+)DA-3 cells modified to express an intracellular form of GM-CSF, acquired growth factor independence and transplantability and caused an overt leukemia in syngeneic hosts, without increasing serum GM-CSF levels. We propose this as a general approach for modeling different forms of high-risk human AML using similar cell lines. PMID- 25907617 TI - Bayes' syndrome: the association between interatrial block and supraventricular arrhythmias. AB - The past few years have given rise to extensive research on atrial conduction disorders and their clinical relevance. Most notably, an association between interatrial block and supraventricular arrhythmias has been discovered. This disorder, recently termed 'Bayes' syndrome', has important clinical implications. In this article, the authors review normal atrial conduction and associated disorders. A particular focus is placed on Bayes' syndrome and the relationship between interatrial block and supraventricular arrhythmias in different clinical scenarios. The report also outlines the current progress in the study of this syndrome and highlights areas requiring further investigation. PMID- 25907618 TI - Strategies for managing aortoiliac occlusions: access, treatment and outcomes. AB - Treatment of severe aortoiliac disease has dramatically evolved from a dependence on open aortobifemoral grafting to hybrid and endovascular only approaches. Open surgery has been the gold standard treatment of severe aortoiliac disease with excellent patency rates, but with increased length of stay and major complications. In contrast, endovascular interventions can successfully treat almost any lesion with decreased risk, compared to open surgery. Although primary patency rates remain inferior, secondary endovascular interventions are often minor procedures resulting in comparable long-term outcomes. The risks of renal insufficiency, embolization and access complications are not insignificant; however, most can be prevented or managed without significant clinical consequence. Endovascular therapies should be considered a first-line treatment option for all patients with aortoiliac disease, especially those with high-risk cardiovascular comorbidities. PMID- 25907619 TI - Metastatic Pancreatic Adenocarcinoma Treatment Patterns, Health Care Resource Use, and Outcomes in France and the United Kingdom Between 2009 and 2012: A Retrospective Study. AB - PURPOSE: In Europe, pancreatic cancer (PC) accounts for approximately 2.6% of all new cancer cases and is the fourth leading cause of cancer-related death. Despite substantial morbidity and mortality, limited data are available describing real world treatment patterns and health care resource use in any European country. We evaluated PC-related treatment patterns and associated health care resource use among patients with metastatic PC in the United Kingdom and France. METHODS: One hundred three oncology specialists (53 in France and 50 in the United Kingdom) abstracted data from medical records of 400 patients whom they treated for metastatic PC. Eligible patients had a diagnosis of metastatic PC at age 18 years or older between January 1, 2009, and December 31, 2012; had >=3 months of follow up time beginning at metastatic diagnosis; and received at least 1 cancer directed therapy for metastatic disease. Information on patient demographics, Eastern Cooperative Oncology Group performance status, location of primary tumor, presence of comorbidities, adverse events, and complications were collected. Data on cancer-directed treatments and supportive care measures were evaluated. All analyses were descriptive. FINDINGS: Approximately two thirds of patients were men, and median age at metastatic disease diagnosis was 62.2 years. Nearly all patients (97.3%) received chemotherapy to treat metastatic disease, 9.3% received radiation therapy, and 7.8% received a targeted therapy. Overall, the most frequently administered first-line regimens for metastatic disease were gemcitabine alone (46.0%), a combination chemotherapy regimen consisting of oxaliplatin, irinotecan, fluorouracil, and leucovorin (FOLFIRINOX; 20.1%); gemcitabine/capecitabine (10.8%); and gemcitabine/oxaliplatin (9.5%). Approximately 40% of patients in France and 15% of patients in the United Kingdom received second-line systemic therapy, whereas 20% of patients in France and 3.4% of patients in the United Kingdom received third-line systemic therapy for metastatic disease. Overall, 52.5% of patients experienced at least one complication of PC. More than two thirds of patients had >=1 office visit unrelated to chemotherapy administration, 54.0% had >=1 inpatient hospitalization, 36.8% had >=1 emergency department visit, and 25.3% had >=1 pain management clinic visit. A total of 26.5% of patients in France and 42.5% in the United Kingdom entered hospice or long-term care. IMPLICATIONS: This study provides new, detailed information for patients with metastatic PC in real-world settings in 2 European countries. A small proportion of patients received >1 line of systemic therapy for metastatic disease, which is likely due to the aggressiveness of this disease and the lack of effective therapeutic options. PMID- 25907620 TI - Translational intracerebral hemorrhage: a need for transparent descriptions of fresh tissue sampling and preclinical model quality. AB - For years, strategies have been proposed to improve translational success in stroke research by improving the quality of animal studies. However, articles that report preclinical intracerebral hemorrhage (ICH) studies continue to lack adequate qualitative and quantitative descriptions of fresh brain tissue collection. They also tend to lack transparency about animal model quality. We conducted a systematic review of 82 ICH research articles to determine the level of detail reported for brain tissue collection. We found that only 24 (29 %) reported the volume, weight, or thickness of tissue collected and a specific description of the anatomical location. Thus, up to 71 % of preclinical ICH research articles did not properly define how fresh specimens were collected for biochemical measurements. Such omissions may impede reproducibility of results between laboratories. Although existing criteria have improved the quality of preclinical stroke studies, ICH researchers need to identify specific guidelines and strategies to avoid pitfalls, minimize bias, and increase reproducibility in this field. PMID- 25907621 TI - Commentary on: "Ipilimumab versus placebo after radiotherapy in patients with metastatic castration-resistant prostate cancer that had progressed after docetaxel chemotherapy (CA184-043): A multicentre, randomised, double-blind, phase 3 trial." Kwon ED, Drake CG, Scher HI, Fizazi K, Bossi A, van den Eertwegh AJ, Krainer M, Houede N, Santos R, Mahammedi H, Ng S, Maio M, Franke FA, Sundar S, Agarwal N, Bergman AM, Ciuleanu TE, Korbenfeld E, Sengelov L, Hansen S, Logothetis C, Beer TM, McHenry MB, Gagnier P, Liu D, Gerritsen WR, CA184-043 Investigators. Departments of Urology and Immunology and Mayo Clinic Comprehensive Cancer Center, Mayo Clinic, Rochester, MN, USA, Electronic address: kwon.eugene@mayo.edu; Johns Hopkins Sidney Kimmel Comprehensive Cancer Center and Brady Urological Institute, Baltimore, MD, USA; Memorial Sloan Kettering Cancer Center and Weill Cornell Medical College, New York, NY, USA; Institut Gustave Roussy, University of Paris-Sud, Villejuif, France; Institut Gustave Roussy, Villejuif, France; VU University Medical Centre, Amsterdam, Netherlands; Vienna General Hospital, Medical University Vienna, Vienna, Austria; Institut Bergonie, Bordeaux, France; CHU Caremeau, Nimes, France; Centro Medico Austral, Buenos Aires, Argentina; Centre Jean Perrin, Clermont-Ferrand, France; St John of God Hospital, Subiaco, WA, Australia; University Hospital of Siena, Istituto Toscano Tumori, Siena, Italy; Hospital de Caridade de Ijui, Ijui, Brazil; Nottingham University Hospital, Nottingham, UK; Huntsman Cancer Institute, University of Utah, Salt Lake City, UT, USA; Netherlands Cancer Institute and Antoni van Leeuwenhoek Hospital, Amsterdam, Netherlands; Institute of Oncology Ion Chiricuta and University of Medicine and Pharmacy Iuliu Hatieganu, Cluj-Napoca, Romania; Hospital Britanico de Buenos Aires, Buenos Aires, Argentina; Herlev Hospital, Herlev, Denmark; Odense University Hospital, Odense, Denmark; University of Texas MD Anderson Cancer Center, Houston, AB - BACKGROUND: Ipilimumab is a fully human monoclonal antibody that binds cytotoxic T-lymphocyte antigen 4 to enhance antitumour immunity. Our aim was to assess the use of ipilimumab after radiotherapy in patients with metastatic castration resistant prostate cancer that progressed after docetaxel chemotherapy. METHODS: We did a multicentre, randomised, double-blind, phase 3 trial in which men with at least one bone metastasis from castration-resistant prostate cancer that had progressed after docetaxel treatment were randomly assigned in a 1:1 ratio to receive bone-directed radiotherapy (8Gy in one fraction) followed by either ipilimumab 10mg/kg or placebo every 3 weeks for up to four doses. Non-progressing patients could continue to receive ipilimumab at 10mg/kg or placebo as maintenance therapy every 3 months until disease progression, unacceptable toxic effect, or death. Patients were randomly assigned to either treatment group via a minimisation algorithm, and stratified by Eastern Cooperative Oncology Group performance status, alkaline phosphatase concentration, haemoglobin concentration, and investigator site. Patients and investigators were masked to treatment allocation. The primary endpoint was overall survival, assessed in the intention-to-treat population. This trial is registered with ClinicalTrials.gov, number NCT00861614. FINDINGS: From May 26, 2009, to Feb 15, 2012, 799 patients were randomly assigned (399 to ipilimumab and 400 to placebo), all of whom were included in the intention-to-treat analysis. Median overall survival was 11.2 months (95% CI: 9.5-12.7) with ipilimumab and 10.0 months (8.3-11.0) with placebo (hazard ratio [HR] = 0.85, 0.72-1.00; P = 0.053). However, the assessment of the proportional hazards assumption showed that it was violated (P = 0.0031). A piecewise hazard model showed that the HR changed over time: the HR for 0-5 months was 1.46 (95% CI: 1.10-1.95), for 5-12 months was 0.65 (0.50-0.85), and beyond 12 months was 0.60 (0.43-0.86). The most common grade 3-4 adverse events were immune-related, occurring in 101 (26%) patients in the ipilimumab group and 11 (3%) of patients in the placebo group. The most frequent grade 3-4 adverse events included diarrhoea (64 [16%] of 393 patients in the ipilimumab group vs seven [2%] of 396 in the placebo group), fatigue (40 [11%] vs 35 [9%]), anaemia (40 [10%] vs 43 [11%]), and colitis (18 [5%] vs 0). Four (1%) deaths occurred because of toxic effects of the study drug, all in the ipilimumab group. INTERPRETATION: Although there was no significant difference between the ipilimumab group and the placebo group in terms of overall survival in the primary analysis, there were signs of activity with the drug that warrant further investigation. FUNDING: Bristol-Myers Squibb. PMID- 25907622 TI - Clinical outcomes in a contemporary series of "young" patients with castration resistant prostate cancer who were 60 years and younger. AB - BACKGROUND: The prognosis of younger patients with prostate cancer is unclear, and the very few studies assessing those with metastatic castration-resistant prostate cancer (mCRPC) have mainly involved patients treated with older therapies. The aim of this observational study was to evaluate the clinical outcomes of a contemporary series of docetaxel-treated patients with mCRPC who were 60 years and younger. PATIENTS AND METHODS: We retrospectively identified 134 patients who were 60 years and younger who were treated with docetaxel in 25 Italian hospitals and recorded their predocetaxel history of prostate cancer, their characteristics at the start of chemotherapy, and their postdocetaxel treatment history and outcomes. RESULTS: Most of the 134 consecutive patients with mCRPC received the standard 3-week docetaxel schedule; median progression free survival (PFS) was 7 months, and 90 patients underwent further therapies after progression. The median overall survival (OS) from the start of docetaxel treatment was 21 months, but OS was significantly prolonged by the postprogression treatments, particularly those based on the new agents such as cabazitaxel, abiraterone acetate, or enzalutamide. OS was significantly shorter in the patients with a shorter interval between the diagnosis of prostate cancer and the start of docetaxel treatment; those who received hormonal treatment for a shorter period; those with shorter prostate-specific antigen doubling times; and those with lower hemoglobin levels, a worse performance status, and higher lactate dehydrogenase levels before starting treatment with docetaxel. CONCLUSIONS: The findings of this first study of clinical outcomes in a contemporary series of younger patients with mCRPC showed that their survival is similar to that expected in unselected patients with mCRPC who were of any age. PMID- 25907623 TI - Commentary on "Comparison of abiraterone acetate versus ketoconazole in patients with metastatic castration resistant prostate cancer refractory to docetaxel." Peer A, Gottfried M, Sinibaldi V, Carducci MA, Eisenberger MA, Sella A, Leibowitz Amit R, Berger R, Keizman D, Department of Oncology, Rambam Medical Center, Haifa, Israel.: Prostate 2014 Apr;74(4):433-40; doi:10.1002/pros.22765. [Epub 2013 Dec 11]. AB - BACKGROUND: Abiraterone, a potent CYP 17 inhibitor, is standard treatment in docetaxel refractory, metastatic castrate resistant prostate cancer (mCRPC). However, in countries where abiraterone has not been approved yet, or for patients who cannot afford it, ketoconazole is used as an alternative CYP 17 inhibitor. Although preclinical data suggests that ketoconazole is a less potent inhibitor of CYP 17, there are limited clinical data comparing both agents. We aimed to compare the clinical effectiveness of abiraterone versus ketoconazole in docetaxel refractory mCRPC. METHODS: Records from mCRPC patients treated with ketoconazole (international multicenter database, n = 162) were reviewed retrospectively. Twenty-six patients treated post docetaxel were individually matched by clinicopathologic factors to patients treated with abiraterone (national multicenter database, n = 140). We compared the PSA response, biochemical and radiological progression free survival (PFS), and overall survival (OS) between the groups. PFS and OS were determined by Cox regression. RESULTS: The groups were matched by Gleason score, pre-treatment disease extent, ECOG PS, pre-treatment risk category (Keizman, Oncologist 2012). Furthermore, they were balanced regarding other known confounding risk factors. In the groups of abiraterone versus ketoconazole, PSA response was 46% versus 19% (OR 4.3, P = 0.04), median biochemical PFS 7 versus 2 months (HR 1.54, P = 0.02), median radiological PFS 8 versus 2.5 months (HR 1.8, P = 0.043), median OS 19 versus 11 months (HR 0.53, P = 0.79), and treatment interruption d/t severe adverse events 8% (n = 2) versus 31% (n = 8) (OR 0.6, P = 0.023). CONCLUSIONS: In docetaxel refractory mCRPC, the outcome of abiraterone treatment may be superior to ketoconazole. PMID- 25907624 TI - Sources of variation in follow-up expenditure after radical cystectomy. AB - BACKGROUND: Follow-up care after radical cystectomy is poorly defined, with extensive variation in practice patterns. We sought to determine sources of these variations in care as well as examine the economic effect of standardization of care to guideline-recommended care. METHODS: Using linked Surveillance, Epidemiology, and End Results (SEER)-Medicare data from 1992 to 2007, we determined follow-up care expenditures (time and geography standardized) for 24 months after surgery. Accounted expenditures included office visits, imaging studies, urine tests, and blood work. A multilevel model was implemented to determine the effect of region, surgeon, and patient factors on care delivery. We then compared the actual expenditures on care in the Medicare system (interquartile range) with the expenditures if patients received care recommended by current clinical guidelines. RESULTS: Expenditures over 24 months of follow-up were calculated per month and per patient. The mean and median total expenditures per patient were $1108 and $805 respectively (minimum $0, maximum $9,805; 25th 75th percentile $344-$1503). Variations in expenditures were most explained at the patient level. After accounting for surgeon and patient levels, we found no regional-level variations in care. Adherence to guidelines would lead to an increase in expenditures by 0.80 to 10.6 times the expenditures exist in current practice. CONCLUSION: Although some regional-level and surgeon-level variations in care were found, the most variation in expenditure on follow-up care was at the patient level, largely based on node positivity, chemotherapy status, and final cancer stage. Standardization of care to current established guidelines would create higher expenditures on follow-up care than current practice patterns. PMID- 25907625 TI - Targeted Detection of G-Quadruplexes in Cellular RNAs. AB - The G-quadruplex (G4) is a non-canonical nucleic acid structure which regulates important cellular processes. RNA G4s have recently been shown to exist in human cells and be biologically significant. Described herein is a new approach to detect and map RNA G4s in cellular transcripts. This method exploits the specific control of RNA G4-cation and RNA G4-ligand interactions during reverse transcription, by using a selective reverse transcriptase to monitor RNA G4 mediated reverse transcriptase stalling (RTS) events. Importantly, a ligation amplification strategy is coupled with RTS, and enables detection and mapping of G4s in important, low-abundance cellular RNAs. Strong evidence is provided for G4 formation in full-length cellular human telomerase RNA, offering important insights into its cellular function. PMID- 25907626 TI - Assessment of cytotoxicity and AhR-mediated toxicity in tropical fresh water sediments under the influence of an oil refinery. AB - Oil refinery effluents contain many chemicals at variable concentrations. Therefore, it is difficult to predict potential effects on the environment. The Atibaia River (SP, Brazil), which serves as a source of water supply for many municipalities, receives the effluents of one of the biggest oil refinery of this country. The aim of this study was to identify the (eco)toxicity of fresh water sediments under the influence of this oil refinery through neutral red (cytotoxicity) and ethoxyresorufin-O-deethylase (EROD) assays (AhR-mediated toxicity) in RTL-W1 cells (derived from fish liver). Once the refinery captures the waters of Jaguari River for the development of its activities and discharges its effluents after treatment into the Atibaia River, which then flows into Piracicaba River, sediments from both river systems were also investigated. The samples showed a high cytotoxic potential, even when compared to well-known pollution sites. However, the cytotoxicity of samples collected downstream the effluent was not higher than that of sediments collected upstream, which suggested that the refinery discharges are not the main source of pollution in those areas. No EROD activity could be recorded, which could be confirmed by chemical analyses of polycyclic aromatic hydrocarbons (PAHs) that revealed a high concentration of phenanthrene, anthracene, fluoranthene, and pyrene, which are not EROD inducers in RTL-W1 cells. In contrast, high concentrations of PAHs were found upstream the refinery effluent, corroborating cytotoxicity results from the neutral red assay. A decrease of PAHs was recorded from upstream to downstream the refinery effluent, probably due to dilution of compounds following water discharges. On the other hand, these discharges apparently contribute specifically to the amount of anthracene in the river, since an increase of anthracene concentrations could be recorded downstream the effluent. Since the extrapolation of results from acute toxicity to specific toxic effects with different modes of action is a complex task, complementary bioassays covering additional specific effects should be applied in future studies for better understanding of the overall ecotoxicity of those environments. PMID- 25907627 TI - An appraisal of biological responses and network of environmental interactions in non-mining and mining impacted coastal waters. AB - The coastal waters of Goa and Ratnagiri lying on the West coast of India are influenced by terrestrial influx. However, Goa is influenced anthropogenically by iron-ore mining, while Ratnagiri is influenced by deposition of heavy minerals containing iron brought from the hinterlands. We hypothesize that there could be a shift in biological response along with changes in network of interactions between environmental and biological variables in these mining and non-mining impacted regions, lying 160 nmi apart. Biological and environmental parameters were analyzed during pre-monsoon season. Except silicates, the measured parameters were higher at Goa and related significantly, suggesting bacteria centric, detritus-driven region. At Ratnagiri, phytoplankton biomass related positively with silicate suggesting a region dominated by primary producers. This dominance perhaps got reflected as a higher tertiary yield. Thus, even though the regions are geographically proximate, the different biological response could be attributed to the differences in the web of interactions between the measured variables. PMID- 25907628 TI - Restoring ecosystem services to littoral zones of rivers in the urban core of Chongqing, China. AB - Two examples of the creation of naturalized areas in the littoral zone of the Three Gorges Reservoir in the urban core of Chongqing City, China, are described. The areas were created for the purpose of restoring ecological functions and services. Plants were selected based on surveys of natural wetland vegetation in the region, and experiments were conducted to discover the capacity of species of interest to survive the sometimes extreme hydrological regimes at the sites. Novel methods were developed to stabilize the plants against the rigors of extreme summer floods and constant swash, notably zigzag berms of rocks wrapped in iron mesh. The areas include native reeds, grasses, shrubs, and trees. Plant communities in the areas are zoned according to flooding stress, and their structure is less stable at lower elevations that are subjected to greater stress. The tall grass Saccharum spontaneum (widespread in Southern Asia) and the tree Pterocarya stenoptera (native to Southwest China) are notable for their utility at these sites in the center of a large city. Communities of tall reeds and grasses have become so dense and stable that they now provide the ecosystem services of capturing river sediments and resisting erosion of the river banks. It is recommended that extensive greening of the riparian zones in urban areas of the Three Gorges Reservoir be conducted for the purpose of providing ecosystem services, based in part on the experiences described here. PMID- 25907629 TI - Virulency of novel nanolarvicide from Trichoderma atroviride against Aedes aegypti (Linn.): a CLSM analysis. AB - Aedes aegypti is the vector for transmitting dengue, chikungunya, and yellow fever. These diseases' transmission has increased predominantly in urban and semi urban areas as a major public health concern. In present investigation, Trichoderma atroviride culture filtrates were used for the synthesis of silver nanoparticle. Moreover, T. atroviride is a free-living and rapidly growing fungi common in soil and root ecosystem. This fungi is an exceptionally good model for biocontrol and more significant as a bioagent. T. atroviride was grown in malt extract. T. atroviride culture filtrates were exposed to silver nitrates solution for 24 h at 25 degrees C for the synthesis of silver nanoparticles (AgNPs). These AgNPs were characterized to find their unique properties with UV-visible spectrophotometer and transmission electron microscope (TEM) analysis. The T. atroviride culture filtrates have formed hexagonal (diamond shape) AgNPs with the range of size of 14.01-21.02 nm. These AgNPs have shown significant efficacies against first, second, third, and fourth instar larvae of A. aegypti. The LC90 and LC99 values for the first instar were 1 and 3 ppm, second instar 2 and 3.18 ppm, third instar 3.12 and 4.12 ppm, and fourth instar 6.30 and 6.59 ppm, respectively, after an exposure of 7 h. The confocal laser scanning microscopy (CLSM) studies were verdict that these AgNPs embedded in the cuticle of larvae and cause instant lethality in 7 h. Present investigations have demonstrated that the AgNPs of T. atroviride culture filtrates synthesized can be used for larvae control of A. aegypti. T. atroviride is synthesized to silver nanoparticles to be a promising new candidate for application in mosquito control. We therefore suggested that the ability of T. atroviride culture filtrates in synthesis can also be explored for synthesizing silver nanoparticles for commercial exploitation. PMID- 25907630 TI - Phototransformation of mefenamic acid induced by nitrite ions in water: mechanism, toxicity, and degradation pathways. AB - Here, we evidenced the photo-induced degradation of mefenamic acid, a nonsteroidal anti-inflammatory drug, through the 254-nm light excitation of nitrite. The results demonstrated that the photodegradation of mefenamic acid was enhanced, and the mefenamic acid photodegradation rate significantly increased, from 0.00627 to 0.0350 min(-1) as the nitrite was increased from 0 to 0.5 mmol L( 1). The photodegradation rate increased from 0.0287 to 0.0512 min(-1) as the pH was elevated, from 5.0 to 10.0. The actual second-order rate constant for the reaction of mefenamic acid with .OH was investigated to 1.079 * 10(10) M(-1) s( 1) according to steady-state .OH concentration of 3.5 * 10(-14) mmol L(-1) and the contribution to the rate of .OH of 67.1%. The photoproducts were identified using HPLC/MS/MS, and possible nitrite-induced photodegradation pathways were proposed by hydroxylation, dehydrogenation, hydration, nitrosylation, and ketonized reactions. The toxicity of the phototransformation products was evaluated using the Microtox test, which revealed that the photoproducts were more toxic than mefenamic acid for the generation of nitrosation aromatic compounds. PMID- 25907632 TI - The KM-parkin-DB: A Sub-set MutationView Database Specialized for PARK2 (PARKIN) Variants. AB - We previously isolated PARKIN (PARK2) as a gene responsible for a unique sort of Parkinson disease, namely Autosomal Recessive Juvenile Parkinsonism (ARJP). In this study, we surveyed all the available literature describing PARK2 gene/Parkin protein mutations found in Parkinson disease patients. Only carefully evaluated data were deposited in the graphical database MutationView (http://mutview.dmb.med.keio.ac.jp) to construct KM-parkin-DB, an independent sub set database. Forty-four articles were selected for data curation regarding clinical information such as ethnic origins, manifested symptoms, onset age, and hereditary patterns as well as mutation details including base changes and zygosity. A total of 366 cases were collected from 39 ethnic origins and 96 pathogenic mutations were found. PARK2 gene mutations were found also in some general Parkinson disease patients. The majority (63%) of mutations in PARK2 were restricted to two particular domains (UBL and RING1) of the Parkin protein. In these domains, two major mutations, a large deletion (DelEx3) and a point mutation (p.Arg275Trp), were located. PMID- 25907631 TI - The anti-inflammatory effect of combined complement and CD14 inhibition is preserved during escalating bacterial load. AB - Combined inhibition of complement and CD14 is known to attenuate bacterial induced inflammation, but the dependency of the bacterial load on this effect is unknown. Thus, we investigated whether the effect of such combined inhibition on Escherichia coli- and Staphylococcus aureus-induced inflammation was preserved during increasing bacterial concentrations. Human whole blood was preincubated with anti-CD14, eculizumab (C5-inhibitor) or compstatin (C3-inhibitor), or combinations thereof. Then heat-inactivated bacteria were added at final concentrations of 5 * 10(4) -1 * 10(8) /ml (E. coli) or 5 * 10(7) -4 * 10(8) /ml (S. aureus). Inflammatory markers were measured using enzyme-linked immunosorbent assay (ELISA), multiplex technology and flow cytometry. Combined inhibition of complement and CD14 significantly (P < 0.05) reduced E. coli-induced interleukin (IL)-6 by 40-92% at all bacterial concentrations. IL-1beta, IL-8 and macrophage inflammatory protein (MIP)-1alpha were significantly (P < 0.05) inhibited by 53 100%, and the effect was lost only at the highest bacterial concentration. Tumour necrosis factor (TNF) and MIP-1beta were significantly (P < 0.05) reduced by 80 97% at the lowest bacterial concentration. Monocyte and granulocyte CD11b were significantly (P < 0.05) reduced by 63-91% at all bacterial doses. Lactoferrin was significantly (P < 0.05) attenuated to the level of background activity at the lowest bacterial concentration. Similar effects were observed for S. aureus, but the attenuation was, in general, less pronounced. Compared to E. coli, much higher concentrations of S. aureus were required to induce the same cytokine responses. This study demonstrates generally preserved effects of combined complement and CD14 inhibition on Gram-negative and Gram-positive bacterial induced inflammation during escalating bacterial load. The implications of these findings for future therapy of sepsis are discussed. PMID- 25907633 TI - Value of utilizing both ASPECTS and CT angiography collateral score for outcome prediction in acute ischemic stroke. AB - BACKGROUND: Alberta Stroke Program Early CT Score (ASPECTS) represents the extent of irreversibly damaged tissue; while CT angiography collateral score (CTA-CS) denotes the degree of collaterals. AIMS: We investigated whether there is cumulative value in using both ASPECTS and CTA-CS for outcome prediction and attempted to determine the specific subgroup of patients who could benefit from successful reperfusion using these scores. METHODS: This is a retrospective observational study of stroke patients treated with intra-arterial reperfusion therapy for unilateral arterial occlusion in the anterior circulation. A favorable outcome was defined as modified Rankin Scale <= 2 at three-months. Receiver operating characteristic comparison analysis was performed to decide whether outcome predictability increases when ASPECTS and CTA-CS are used together. Classification and regression tree (CART) analysis was done to identify the variables that best predict outcome and define the specific subgroup of patients who could benefit from successful reperfusion. RESULTS: A total of 91 consecutive patients were included. Outcome predictability of ASPECTS with CTA-CS was better than that of ASPECTS (P = 0.088) or that of CTA-CS (P = 0.049). CART analysis revealed that ASPECTS > 5 was the primary determinant of favorable outcome, followed by CTA-CS > 1. Among 19 patients with ASPECTS <= 5, none had a favorable outcome. Successful reperfusion was associated significantly with favorable outcome in the 51 patients with ASPECTS > 5 and CTA-CS > 1, but not in the 21 patients with ASPECTS > 5 and CTA-CS <= 1. CONCLUSIONS: Outcome predictability improves when using ASPECTS and CTA-CS together. PMID- 25907635 TI - The appropriateness of treating psychopathic disorders. AB - The received wisdom is that there is no known effective treatment for psychopathic disorders. Although outcome studies have not identified an effective programmatic treatment for psychopathic disorders, such studies tend to leave the question open. If behavioral science has not established that psychopathic disorders respond to a particular programmatic approach, neither are psychopathic disorders convincingly proven to be absolutely resistant to treatment. If no treatment is known to be effective in psychopathic disorders, then any treatment seems to squander resources. What is often missing from the discussion is effective therapeutic measures to treat other behaviors that often co-occur, if they do not represent a domain of pathology of psychopathic disorders, such as impulsive aggression. After a brief summary of results of programmatic treatment of psychopathic offenders, this review focuses on the pharmacotherapy of impulsive aggression in psychopathic disorders. If the impulsive aggression that occurs with psychopathic disorders can be better controlled, treatment can have substantial benefits and would be most appropriate. PMID- 25907634 TI - Multi-Institution Validation of an Emergency Ultrasound Image Rating Scale-A Pilot Study. AB - BACKGROUND: As bedside ultrasound (BUS) is being increasingly taught and incorporated into emergency medicine practice, measurement of BUS competency is becoming more important. The commonly adopted experiential approach to BUS competency has never been validated on a large scale, and has some limitations by design. OBJECTIVE: Our aim was to introduce and report preliminary testing of a novel emergency BUS image rating scale (URS). METHODS: Gallbladder BUS was selected as the test case. Twenty anonymous BUS image sets (still images and clips) were forwarded electronically to 16 reviewers (13 attendings, 3 fellows) at six training sites across the United States. Each reviewer rated the BUS sets using the pilot URS that consisted of three components, with numerical values assigned to each of the following aspects: Landmarks, Image Quality, and Annotations. Reviewers also decided whether or not each BUS set would be "Clinically Useful." Kendall taus were calculated as a measure of concordance among the reviewers. RESULTS: Among the 13 attendings, image review experience ranged from 2-15 years, 5-300 scans per week, and averaged 7.8 years and 60 images. Kendall taus for each aspect of the URS were: Landmarks: 0.55; Image Quality: 0.57; Annotation: 0.26; Total Score: 0.63, and Clinical Usefulness: 0.45. All URS elements correlated significantly with clinical usefulness (p < 0.001). The correlation coefficient between each attending reviewer and the entire group ranged from 0.48-0.69, and was independent of image review experience beyond fellowship training. CONCLUSION: Our novel URS had moderate-to good inter-rater agreement in this pilot study. Based on these results, the URS will be modified for use in future investigations. PMID- 25907636 TI - The potential application of photodynamic therapy in drug-resistant tuberculosis. AB - Tuberculosis (TB) is an infectious bacterial disease that has historically created a high global health burden. Unfortunately, the emergence of drug resistant TB (DR-TB), which includes multidrug-resistant TB (MDR-TB) and extensively drug-resistant TB (XDR-TB), has greatly affected the treatment of TB. Anti-TB chemotherapy drugs are classified into five groups to facilitate application of effective guidelines for the treatment regimen. However, chemotherapy has a limited ability to treat DR-TB, and therefore a novel alternative treatment for DR-TB is required. In this review, we focused on photodynamic therapy (PDT) as potential treatment for DR-TB. PDT is a widely used cancer treatment that combines photosensitizers and harmless laser light to produce reactive oxygen species that selectively damage the target cells. Initially, PDT was originally developed to target pathogenic microorganisms but fell into disuse because of adverse reactions. Recently, photodynamic antimicrobial chemotherapy is attracting attention again as an alternative treatment for bacterial infections. In our previous study, we suggested that PDT could be a novel option to treat MDR- and XDR-TB in vitro. Despite the limited previous studies regarding PDT in TB models, fast-developing bronchoscopic technologies and clinician experience will soon facilitate the clinical application of safe and minimally invasive PDT for TB. PMID- 25907637 TI - Capripox disease in Ethiopia: Genetic differences between field isolates and vaccine strain, and implications for vaccination failure. AB - Sheeppox virus (SPPV), goatpox virus (GTPV) and lumpy skin disease virus (LSDV) of the genus Capripoxvirus (CaPV) cause capripox disease in sheep, goats and cattle, respectively. These viruses are not strictly host-specific and their geographical distribution is complex. In Ethiopia, where sheep, goats and cattle are all affected, a live attenuated vaccine strain (KS1-O180) is used for immunization of both small ruminants and cattle. Although occurrences of the disease in vaccinated cattle are frequently reported, information on the circulating isolates and their relation to the vaccine strain in use are still missing. The present study addressed the parameters associated with vaccination failure in Ethiopia. Retrospective outbreak data were compiled and isolates collected from thirteen outbreaks in small ruminants and cattle at various geographical locations and years were analyzed and compared to the vaccine strain. Isolates of GTPV and LSDV genotypes were responsible for the capripox outbreaks in small ruminants and cattle, respectively, while SPPV was absent. Pathogenic isolates collected from vaccinated cattle were identical to those from the non-vaccinated ones. The vaccine strain, genetically distinct from the outbreak isolates, was not responsible for these outbreaks. This study shows capripox to be highly significant in Ethiopia due to low performance of the local vaccine and insufficient vaccination coverage. The development of new, more efficient vaccine strains, a GTPV strain for small ruminants and a LSDV for cattle, is needed to promote the acceptance by farmers, thus contribute to better control of CaPVs in Ethiopia. PMID- 25907638 TI - Simple and effective label-free capillary electrophoretic analysis of sugars by complexation using quinoline boronic acids. AB - An effective separation and detection procedure for sugars by capillary electrophoresis (CE) using a complexation between quinolineboronic acid (QBA) and multiple hydroxyl structure of sugar alcohol is reported. We investigated the variation of fluorescence spectra of a variety of QBAs with sorbitol at a wide range of pH conditions and then found that 5-isoQBA strongly enhanced the fluorescence intensity by the complexation at basic pH conditions. The other sugar alcohols having multiple hydroxyls also revealed the enhancement of the fluorescence intensity with 5-isoQBA, whereas the alternation of the intensity was not found in the sugars such as glucose. After optimization of the 5-isoQBA concentration and pH of the buffered solution in CE analysis, 6 sugar alcohols were successfully separated in the order based on the formation constants with 5 isoQBA, which were calculated from the variation of the fluorescence intensity with each sugar alcohol and 5-isoQBA. Furthermore, the limits of detection for sorbitol and xylitol by the CE method were estimated at 15 and 27 MUM, respectively. PMID- 25907639 TI - Reply: To PMID 25476703. PMID- 25907640 TI - Reconstruction techniques in comparison for reverse shoulder trauma prosthesis in the elderly: a follow-up between 2 and 4 years. AB - INTRODUCTION: The aim of this study was to evaluate the clinical outcome of a bone graft technique called bCAT (bone Collar And Tie), in which the fractured humeral head is modelled into a collar shape versus puzzle piece reconstruction (PPR) in elderly patients with complex proximal humeral fractures. MATERIALS AND METHODS: Between 2005 and 2011, we have performed 46 reverse shoulder prosthesis in patients with a mean age of 73.8 years (range 69-95) affected by shoulder complex fracture. A Delta CTA Depuy prosthesis was used in two patients, and a Lima SMR modular shoulder system in 44. To obtain a homogeneous group we compared the cases in which was used the same prosthesis with a similar follow-up. In a series of patients, we reconstructed tuberosities with the PPR technique (group A), while in another series we used the bCAT technique (group B). RESULTS: The results were evaluated in 20 of group A and 20 of group B patients (mean clinical and radiological follow-up: 45.8 months). Average range of motion in group A was 111 degrees anterior elevation, 90 degrees abduction, 16 degrees extrarotation and intrarotation till the sacral bone. The corresponding values in group B were 150 degrees , 110 degrees , 44 degrees and L4. The mean absolute and age adjusted Constant-Murley score were 55 and 67.85 %, respectively, in group A and 70.8 and 83.85 % in group B. Tuberosity resorption occurred in 40 % of group A versus 15 % in group B. CONCLUSION: The PPR and the bCAT techniques promoted the healing and correct positioning of the tuberosities thereby resulting in good functioning of the residual cuff. The bCAT technique resulted in better clinical function particularly in abduction and extrarotation and in terms of radiological outcome of reverse prosthesis surgery. PMID- 25907641 TI - The enkephalinergic nervous system and its immunomodulation on the developing immune system during the ontogenesis of oyster Crassostrea gigas. AB - Enkephalinergic neuroendocrine-immune regulatory system is one of the most important neuroendocrine-immune systems in both vertebrates and invertebrates for its significant role in the immune regulation. In the present study, the early onset of enkephalinergic nervous system and its immunomodulation on the developing immune system during the ontogenesis of oyster Crassostrea gigas were investigated to illustrate the function of neural regulation on the innate immune system in oyster larvae. [Met(5)]-enkephalin (Met-ENK) was firstly observed on the marginal of the dorsal half of D-hinged larvae. Six immune-related molecules, including four PRRs (CgCTL-1, CgCTL-2, CgCTL-4, CgNatterin-3) and two immune effectors (CgTNF-1 and CgEcSOD) were detected in the early developmental stages of trochophore, D-hinged and umbo larvae of oyster. After incubated with [Met(5)] enkephalin, the mRNA expression level of all the PRRs changed significantly (p < 0.05). In trochophore larvae, the expression level of CgNatterin-3 decreased dramatically (p < 0.05) at 6 h, and the expression level of CgCTL-4 was significantly down-regulated at 3 h and 6 h (p < 0.05), respectively. In D-hinged and umbo larvae, only CgCTL-1 was significantly down-regulated and the differences were significant at 3 h and 6 h (p < 0.05), while the expression level of CgCTL-2 and CgCTL-4 increased significantly at 3 h after treatment (p < 0.05). Moreover, the expression levels of immune effectors were up-regulated significantly at 3 h and 6 h in trochophore larvae (p < 0.05). The expression level of CgTNF-1 in both blank and experiment groups was up-regulated but there was no significant difference in D-hinged larvae stage. On the contrary, the expression level of CgEcSOD in D-hinged larvae decreased dramatically at 3 h and 6 h after [Met(5)]-enkephalin incubation (p < 0.05). In umbo larvae, the expression level of CgTNF-1 and CgEcSOD in the experiment group increased significantly at 6 h after [Met(5)]-enkephalin treatment (p < 0.05), while no significant difference was found in the blank group. In addition, the anti bacterial activities of the total protein extract from trochophore, D-hinged and umbo larvae increased significantly (p < 0.05) at both 3 h and 6 h after [Met(5)] enkephalin incubation compared to that in the blank group, and PO activities of both D-hinged and umbo larvae total protein extract increased significantly (p < 0.05) while no significant difference was observed in trochophore larvae. The PO activities of the total protein extract in all the experiment groups decreased after the treatment with [Met(5)]-enkephalin for 6 h, but no significant difference was observed when compared to the blank group. Furthermore, after incubation for 6 h, the concentration of both CgTNF-1 and CgIL17-5 increased dramatically compared to that in the blank group (p < 0.05). These results together indicated that the enkephalinergic nervous system of oyster was firstly appeared in D-hinged larvae, while the primitive immune defense system existed in the region of prototroch in trochophore larvae and developed maturely after D hinged larvae. The developing immune system could be regulated by the neurotransmitter [Met(5)]-enkephalin released by the neuroendocrine system in oyster C. gigas. PMID- 25907642 TI - Immunotoxicological effects of environmental contaminants on marine bivalves. AB - Coastal areas are complex environments frequently contaminated by numerous pollutants that represent a potential threat to marine organisms, especially bivalves. These pollutants may have major ecological consequences. Although effects of different environmental contaminants on the immune system in marine bivalves have been already reported, a few of reviews summarizes these effects. The main purpose of this chapter relies on summarizing recent body of data on immunotoxicity in bivalves subjected to contaminants. Immune effects of heavy metals, pesticides, HAP, PCB and pharmaceuticals are presented and discussed and a particular section is devoted to nanoparticle effects. A large body of literature is now available on this topic. Finally, the urgent need of a better understanding of complex interactions between contaminants, marine bivalves and infectious diseases is noticed. PMID- 25907643 TI - Cause-specific or relative survival setting to estimate population-based net survival from cancer? An empirical evaluation using women diagnosed with breast cancer in Geneva between 1981 and 1991 and followed for 20 years after diagnosis. AB - BACKGROUND: Both cause-specific and relative survival settings can be used to estimate net survival, the survival that would be observed if the only possible underlying cause of death was the disease under study. Both resulting net survival estimators are biased by informative censoring and prone to biases related to the data settings within which each is derived. We took into account informative censoring to derive theoretically unbiased estimators and examine which of the two data settings was the most robust against incorrect assumptions in the data. PATIENTS AND METHODS: We identified 2489 women in the Geneva Cancer Registry, diagnosed with breast cancer between 1981 and 1991, and estimated net survival up to 20-years using both cause-specific and relative survival settings, by tackling the informative censoring with weights. To understand the possible origins of differences between the survival estimates, we performed sensitivity analyses within each setting. We evaluated the impact of misclassification of cause of death and of using inappropriate life tables on survival estimates. RESULTS: Net survival was highest using the cause-specific setting, by 1% at one year and by up to around 11% twenty years after diagnosis. Differences between both sets of net survival estimates were eliminated after recoding between 15% and 20% of the non-specific deaths as breast cancer deaths. By contrast, a dramatic increase in the general population mortality rates was needed to see the survival estimates based on relative survival setting become closer to those derived from cause-specific setting. CONCLUSION: Net survival estimates derived using the cause-specific setting are very sensitive to misclassification of cause of death. Net survival estimates derived using the relative-survival setting were robust to large changes in expected mortality. The relative survival setting is recommended for estimation of long-term net survival among patients with breast cancer. PMID- 25907644 TI - Analyzing the evolution of young people's brain cancer mortality in Spanish provinces. AB - OBJECTIVES: To analyze the spatio-temporal evolution of brain cancer relative mortality risks in young population (under 20 years of age) in Spanish provinces during the period 1986-2010. METHODS: A new and flexible conditional autoregressive spatio-temporal model with two levels of spatial aggregation was used. RESULTS: Brain cancer relative mortality risks in young population in Spanish provinces decreased during the last years, although a clear increase was observed during the 1990s. The global geographical pattern emphasized a high relative mortality risk in Navarre and a low relative mortality risk in Madrid. Although there is a specific Autonomous Region-time interaction effect on the relative mortality risks this effect is weak in the final estimates when compared to the global spatial and temporal effects. CONCLUSIONS: Differences in mortality between regions and over time may be caused by the increase in survival rates, the differences in treatment or the availability of diagnostic tools. The increase in relative risks observed in the 1990s was probably due to improved diagnostics with computerized axial tomography and magnetic resonance imaging techniques. PMID- 25907645 TI - Proteomic analysis of the kidney filtration barrier--Problems and perspectives. AB - Diseases of the glomerular filter of the kidney are a leading cause of end-stage renal failure. The kidney filter is localized within the renal glomeruli, small microvascular units that are responsible for ultrafiltration of about 180 liters of primary urine every day. The renal filter consists of three layers, fenestrated endothelial cells, glomerular basement membrane, and the podocytes, terminally differentiated, arborized epithelial cells. This review demonstrates the use of proteomics to generate insights into the regulation of the renal filtration barrier at a molecular level. The advantages and disadvantages of different glomerular purification methods are examined, and the technical limitations that have been significantly improved by in silico or biochemical approaches are presented. We also comment on phosphoproteomic studies that have generated considerable molecular-level understanding of the physiological regulation of the kidney filter. Lastly, we conclude with an analysis of urinary exosomes as a potential filter-derived resource for the noninvasive discovery of glomerular disease mechanisms. PMID- 25907646 TI - Association between falls and depressive symptoms or visual impairment among Japanese young-old adults. AB - AIM: To investigate the association between falls and self-reported depressive symptoms or visual impairment among young-old adults. METHODS: A total of 1904 participants (986 men and 918 women) aged 64 years from the New Integrated Suburban Seniority Investigation Project from 1996 to 2005, an age-specific cohort study in Nisshin, Japan, took part in the present study. Depressive symptoms were evaluated using the Geriatric Depression Scale. Visual impairment was assessed using a self-administered questionnaire. The outcome variable was self-reported injurious falls at the age of 70 years. Multivariate odds ratios (OR) and 95% confidence intervals (CI) of depressive symptoms and visual impairment for the incidence of falls were calculated using logistic regression models and adjusted for possible confounding factors. RESULTS: Overall, 77 (7.8%) men and 126 (13.7%) women reported falls within the past 1 year at age 70 years. Among women, depressive symptoms and visual impairment were significantly associated with falls after adjusting for potential confounders (OR 1.70, 95% CI 1.09-2.62; OR 2.34, 95% CI 1.45-3.71, respectively), but not among men. Women with both conditions had a significantly increased risk of falls after adjusting for potential confounders (OR 3.50, 95% CI 1.65-7.13) compared with those with neither condition; the association was not significant among men. CONCLUSIONS: Depressive symptoms and visual impairment at age 64 years were significantly associated with an increased risk of falls at age 70 years in Japanese women but not in men. The combination of the two symptoms had an even greater association with fall risk. PMID- 25907647 TI - Cyberbullying and bullying must be studied within a broader peer victimization framework. PMID- 25907648 TI - Adolescent presentations of inborn errors of metabolism. AB - Several studies have shown that a large percentage of inborn errors of metabolism is present in adolescent patients. Individually, each diagnosis in this category of diseases is rare; therefore, there is often a significant delay in determining the etiology of a patient's complaints. These disorders can have a wide variety of multisystemic presentations, several of which overlap with more common disorders of adolescence. This review highlights the red-flag findings on history and physical examination indicating a possible inborn error of metabolism. In addition, a systematic approach for evaluating and categorizing these disorders is introduced and demonstrated through case examples. Primary care physicians play a crucial role in the early detection and prompt treatment of patients with late-onset inborn errors of metabolism. PMID- 25907650 TI - Mental Health Difficulties in Early Adolescence: A Comparison of Two Cross Sectional Studies in England From 2009 to 2014. AB - PURPOSE: To examine the changes in mental health difficulties in early adolescence between 2009 and 2014 in England. METHODS: Analysis reports on data from two cross-sectional samples of adolescents (aged 11-13 years) collected 5 years apart in 2009 and 2014 in secondary schools across England. Samples were matched using propensity scoring, resulting in a total pooled sample of 3,366 adolescents. Mental health difficulties were reported by participants using the Strengths and Difficulties Questionnaire. RESULTS: Overall, there were similar levels of mental health difficulties experienced by adolescents in 2009 and 2014. Notable exceptions were a significant increase in emotional problems in girls and a decrease in total difficulties in boys in 2014 compared to 2009. CONCLUSIONS: The increased prevalence of emotional problems in girls mirrors a trend found in other similar studies, and the results are discussed in the context of recent economic and societal changes. The small decrease in total difficulties in boys, although promising, clearly warrants further research. PMID- 25907651 TI - Tripling use of electronic cigarettes among New Zealand adolescents between 2012 and 2014. AB - PURPOSE: Use of electronic cigarettes (e-cigarettes) among adults has flourished in recent years. However, little is known about their use among adolescents. This article reports on data collected from a New Zealand national youth tobacco use survey in 2012 and 2014. METHODS: The Youth Insights Survey is a biennial self complete survey of Year 10 students (predominately aged 14-15 years), with a sample size of 3,127 in 2012 and 2,919 in 2014. Ever-use of e-cigarettes was self reported by participants in both years, and in 2014, e-cigarette ever-users also reported their reasons for first trying e-cigarettes. RESULTS: The rate of e cigarette ever-use tripled from 7.0% in 2012 to 20.0% in 2014. After adjusting for sociodemographic variables, smoking status (including susceptibility), and other factors associated with tobacco smoking uptake, e-cigarette ever-use was associated with gender, smoking status, close friends' smoking behavior, and risky substance use. Among smokers, desire for a cigarette, quit intention, or past-year quit attempts did not predict e-cigarette ever-use. Irrespective of smoking status, curiosity was the most commonly cited reason for trying e cigarettes. CONCLUSIONS: In 2014, one in five 14- to 15-year-olds had used e cigarettes. Our data suggest that for adolescent smokers, cessation was not the main reason for trying e-cigarettes. Instead, most adolescents (smokers and nonsmokers) tried e-cigarettes out of curiosity. Our findings signal a need to continue monitoring the uptake of e-cigarettes among adolescents, including both experimental and long-term use. Controlling access and exposure to e-cigarettes among this young age group is also required. PMID- 25907649 TI - Discrimination, racial identity, and cytokine levels among African-American adolescents. AB - PURPOSE: Low-grade inflammation, measured by circulating levels of cytokines, is a pathogenic mechanism for several chronic diseases of aging. Identifying factors related to inflammation among African-American youths may yield insights into mechanisms underlying racial disparities in health. The purpose of the study was to determine whether (1) reported racial discrimination from ages 17-19 years forecasts heightened cytokine levels at the age of 22 years and (2) this association is lower for youths with positive racial identities. METHODS: A longitudinal research design was used with a community sample of 160 African Americans who were aged 17 years at the beginning of the study. Discrimination and racial identity were measured with questionnaires, and blood was drawn to measure basal cytokine levels. Ordinary least squares regression analyses were used to examine the hypotheses. RESULTS: After controlling for socioeconomic risk, life stress, depressive symptoms, and body mass index, racial discrimination (beta = .307; p < .01), racial identity (beta = -.179; p < .05), and their interaction (beta = -.180; p < .05) forecast cytokine levels. Youths exposed to high levels of racial discrimination evinced elevated cytokine levels 3 years later. This association was not significant for young adults with positive racial identities. CONCLUSIONS: High levels of interpersonal racial discrimination and the development of a positive racial identity operate jointly to determine low-grade inflammation levels that have been found to forecast chronic diseases of aging, such as coronary disease and stroke. PMID- 25907652 TI - Social and cultural environment factors influencing physical activity among african-american adolescents. AB - PURPOSE: African-American youth are at high risk for physical inactivity. This study explored social and cultural environment facilitators of physical activity among 12- to 14-year-old African-American adolescents living in a metropolitan area in the Southeast. METHODS: Youth (n = 51; 45% male) participated in brainstorming focus groups responding to the prompt, "What about your family, friends, and community, encourages you to be physically active?" In a second meeting, participants (n = 56; 37.5% male) sorted statements (n = 84) based on similarity in meaning and rated statements on relative importance. Statement groups and ratings were entered into Concept Systems software where multidimensional scaling and hierarchical cluster analysis were used to create graphical representation of ideas. Finally, researchers named clusters according to the gestalt of grouped statements. RESULTS: The total sample included 28.9% of youth with household incomes <=$30,000 (area median income = $30,701), 29% who perceived themselves as overweight, and 14.5% who reported being active for 60+ minutes everyday. Nine clusters, in rank order, emerged as follows: access/availability of physical activity resources; family and friend support; physical activity with friends; physical activity with family members; inspiration to/from others; parental reinforcement; opportunities in daily routine; pressure from social networks; and seeing consequences of activity/inactivity. Themes analyzed by gender were very similar (r = .90); however, "pressure from social networks" was more important for girls than boys (r = .10). CONCLUSIONS: Clear patterns of social and cultural facilitators of physical activity are perceived by African-American adolescents. Interventions targeting this group may benefit by incorporating these themes. PMID- 25907653 TI - Parental separation, parental alcoholism, and timing of first sexual intercourse. AB - PURPOSE: We examined timing of first voluntary sexual intercourse as a joint function of parental separation during childhood and parental history of alcoholism. METHODS: Data were drawn from a birth cohort of female like-sex twins (n = 569 African ancestry [AA]; n = 3,415 European or other ancestry [EA]). Cox proportional hazards regression was conducted predicting age at first sex from dummy variables coding for parental separation and parental alcoholism. Propensity score analysis was also employed to compare intact and separated families, stratified by predicted probability of separation. RESULTS: Earlier sex was reported by EA twins from separated and alcoholic families, compared to EA twins from intact nonalcoholic families, with effects most pronounced through the age of 14 years. Among AA twins, effects of parental separation and parental alcoholism were largely nonsignificant. Results of propensity score analyses confirmed unique risks from parental separation in EA families, where consistent effects of parental separation were observed across predicted probability of separation. For AA families, there was poor matching on risk factors presumed to predate separation, which limited interpretability of survival-analytic findings. CONCLUSIONS: In European American families, parental separation during childhood is an important predictor of early-onset sex, beyond parental alcoholism and other correlated risk factors. To characterize risk for African Americans associated with parental separation, additional research is needed where matching on confounders can be achieved. PMID- 25907654 TI - Alcohol mixed with energy drink use among u.s. 12th-grade students: prevalence, correlates, and associations with unsafe driving. AB - PURPOSE: The consumption of alcohol mixed with energy drinks (AmED) is a risky drinking behavior, most commonly studied using college samples. We know little about rates of AmED use and its associations with other risk behaviors, including unsafe driving, among high school students. This study examined the prevalence and correlates of AmED use among high school seniors in the United States. METHODS: Nationally representative analytic samples included 6,498 12th-grade students who completed Monitoring the Future surveys in 2012 and 2013. Focal measures included AmED use, sociodemographic characteristics, academic and social factors, other substance use, and unsafe driving (i.e., tickets/warnings and accidents) after alcohol consumption. RESULTS: Approximately one in four students (24.8%) reported AmED use during the past 12 months. Rates of AmED use were highest among males and white students. Using multivariable logistic regression models controlling for sociodemographic characteristics, results indicate that students who cut class, spent more evenings out for fun and recreation, and reported binge drinking, marijuana use, and illicit drug use had a greater likelihood of AmED use. AmED use was also associated with greater odds of alcohol related unsafe driving, even after controlling for sociodemographic, academic, and social factors and other substance use. CONCLUSIONS: AmED use among 12th grade students is common and associated with certain sociodemographic, academic, social, and substance use factors. AmED use is also related to alcohol-related unsafe driving, which is a serious public health concern. PMID- 25907656 TI - Primary chicken embryo fibroblasts seeded acellular dermal matrix (3-D ADM) improve regeneration of full thickness skin wounds in rats. AB - Rat skins were deepithelialized and decellularized by hypertonic saline and sodium deoxycholate (SDC), respectively. Primary chicken embryo fibroblasts (P CEF) were cultured and seeded on prepared acellular dermal matrix (ADM). A full thickness skin defect (20*20 mm(2)) was created in thirty-six rats and randomly divided into three equal groups. Defect was left open, repaired with ADM and ADM seeded with P-CEF (3-D ADM) in groups 1, 2 and 3, respectively. By day 28, the treated wounds healed completely without scar. By day 7 hydroxyproline contents was higher in group 3 as compared to groups 1 and 2. There was slightly more B cell response in animals implanted with ADM and 3-D ADM. At day 21, stimulation index was lower with acellular dermis antigen as compared to 3-D ADM antigen. In group 1 on day 3, the granulation tissue showed more inflammatory reaction, fibroplasia and neovascularization as compared to group 2 and 3. By day 28, there was complete epithelization was observed in all groups over. However, a large scar was observed in group 1. The graft was completely absorbed and replaced with densely thick and best arranged collagen fibers. On day 7, malonyldialdehyde and superoxide dismutase levels were significantly (P<0.05) increased in group 1. Reduced glutathione values increased and reached to near normal in groups 2 and 3. Catalase values were significantly (P<0.05) higher in group 1 at different time intervals. SEM samples of group 2 showed ingrowth of fibroblasts into acellular matrix at host graft junction. However, in group 3 fibroblasts were infiltrated within the pores of graft. It was concluded that P-CEF cells seeded ADM facilitated early and better healing. PMID- 25907655 TI - Selection of branded alcoholic beverages by underage drinkers. AB - PURPOSE: The purpose of this study was to identify reasons why youth choose to drink specific brands of alcohol and to determine if these reasons are associated with problem drinking patterns and outcomes. METHODS: We conducted an Internet survey of 1,031 youth aged 13-20 years who reported drinking within the past 30 days. Of these, 541 youth who reported having a choice of multiple brands of alcohol the last time they drank stated (yes/no) whether each of 16 different reasons had influenced their choice of a specific brand. We reduced these 16 reasons to three principal components and used latent class modeling to identify five groups of youth with similar reasons for selecting a brand, which we then profiled. RESULTS: We grouped respondents into the following brand selection groups: "Brand Ambassadors" who were distinguished from other clusters by selecting a brand because they identified with it (32.5% of respondents), "Tasters" who selected a brand because they expected it to taste good (27.2%), "Bargain Hunters" who selected a brand because it was inexpensive (18.5%), "Copycats" who selected a brand because they had seen adults drinking it or seen it consumed in movies or other media (10.4%), and "Others" (11.5%). Brand ambassadors and copycats reported the largest amount of alcohol consumed and had the greatest prevalence of both heavy episodic drinking and negative alcohol related health consequences. CONCLUSIONS: Underage drinkers who cite marketing influences and adult or media modeling of brand choices as their reasons for selecting alcohol brands are likely to drink more and incur adverse consequences from drinking. PMID- 25907657 TI - Nucleobindin-1 encodes a nesfatin-1-like peptide that stimulates insulin secretion. AB - Nesfatin-1 (82 amino acid) is an anorexigenic and insulinotropic peptide encoded in a secreted precursor, nucleobindin-2 (NUCB2). Nucleobindin-1 (NUCB1) is a protein with very high sequence similarity to NUCB2. We hypothesized that a nesfatin-1 like peptide (NLP) is encoded in NUCB1, and this peptide is biologically active. In silico analysis found a signal peptide cleavage site at position 25 (Arginine) and 26 (Valine) preceding the NLP region in NUCB1 sequence, and potential proprotein convertase cleavage sites at Lys-Arg (KR), forming a 77 amino acid NLP. RT-PCR studies found NUCB1 mRNA in both pancreas and MIN6 cells. NUCB1-like immunoreactivity was detected in mouse insulinoma (MIN6) cells, and pancreatic islet beta cells of mice. In order to determine the biological activity of NLP, MIN6 cells were incubated with synthetic rat NLP. NLP (10nM and 100nM) upregulated preproinsulin mRNA expression and insulin secretion at 1h post-incubation. In identical experiments using MIN6 cells, a scrambled peptide based on the NLP sequence did not elicit any effects on preproinsulin mRNA expression or insulin secretion. From this result, it is clear that an intact NLP sequence is required for its biological activity. NLP appears as another endogenous insulinotropic peptide encoded in NUCB1. PMID- 25907658 TI - Urotensin II upregulates migration and cytokine gene expression in leukocytes of the African clawed frog, Xenopus laevis. AB - Urotensin II (UII) exhibits diverse physiological actions including vasoconstriction, locomotor activity, osmoregulation, and immune response via the UII receptor (UTR) in mammals. However, in amphibians the function of the UII-UTR system remains unknown. In the present study, we investigated the potential immune function of UII using leukocytes isolated from the African clawed frog, Xenopus laevis. Stimulation of male frogs with lipopolysaccharide increased mRNA expression of UII and UTR in leukocytes, suggesting that inflammatory stimuli induce activation of the UII-UTR system. Migration assays showed that both UII and UII-related peptide enhanced migration of leukocytes in a dose-dependent manner, and that UII effect was inhibited by the UTR antagonist urantide. Inhibition of Rho kinase with Y-27632 abolished UII-induced migration, suggesting that it depends on the activation of RhoA/Rho kinase. Treatment of isolated leukocytes with UII increased the expression of several cytokine genes including tumor necrosis factor-alpha, interleukin-1beta, and macrophage migration inhibitory factor, and the effects were abolished by urantide. These results suggest that in amphibian leukocytes the UII-UTR system is involved in the activation of leukocyte migration and cytokine gene expression in response to inflammatory stimuli. PMID- 25907659 TI - Fibular giant cell-rich osteosarcoma virtually indistinguishable radiographically and histopathologically from giant cell tumor-analysis of subtle differentiating features. AB - Giant cell-rich osteosarcoma by its abundance of osteoclastic giant cells and paucity of tumor osteoid, leads to its easy confusion with giant cell tumor during biopsy interpretation. In this report, we describe a unique case of upper fibular metaphyseal giant cell-rich osteosarcoma in a 12-year-old boy; the radiographic and histopathologic features of the biopsy and initial resected tumor are virtually indistinguishable from conventional giant cell tumor. The tumor rapidly recurred 7 months after resection with metastasis to the groin lymph nodes, was resistant to first-line chemotherapy and pursued an aggressive course, developing disseminated metastasis to the lung, liver, pelvis, scapula and clavicle, and resulted in the death of the patient 21 months after initial presentation. The subtle features alerting one to the possibility of giant cell rich osteosarcoma are retrospectively evaluated in comparison with cases of metaphyseal conventional giant cell tumors, four from our records and those from literature review. We conclude that the occurrence of a giant cell-rich lesion in the metaphysis of a skeletally immature individual merits careful assessment for the presence of periosteal reaction, permeative infiltrative margins, lacelike osteoid formation, high mitotic activity or Ki67 proliferative index, and extra tumoral lymphovascular permeation, since the possibility of an aggressive lesion notably giant cell-rich osteosarcoma probably increases with the number of such features. PMID- 25907660 TI - Adaptation and Evaluation of a Nonviolent Resistance Intervention for Foster Parents: A Progress Report. AB - Foster care faces serious challenges, such as behavioral problems in foster children and parental stress and ineffective parenting behavior in foster parents. The results of a pilot study that evaluated a training program for foster parents based on nonviolent resistance are described. In a pretest posttest design, data were collected from 25 families. Significant reductions in externalizing, internalizing, and total problem behavior in the foster children and in parenting stress were found. Using a reliable change index, significant improvements in externalizing, internalizing, and total problem behavior were found in, respectively, 72, 44, and 80% of the cases. Most improvements proved to be clinically relevant. Effect sizes ranged from medium to large for problem behavior, and from small to medium for parenting stress. PMID- 25907662 TI - Correlation of miRNA expression profiling in surgical pathology materials, with Ki-67, HER2, ER and PR in breast cancer patients. AB - BACKGROUND: New molecular markers related to prognosis and/or clinical outcome have been extensively studied in breast cancer. In particular, microRNA (miRNA) has attracted the interest of both basic and clinical investigators as one of the promising molecular markers of breast cancer patients. MiRNAs are a class of short noncoding RNAs that regulate mRNAs at posttranscriptional level and are deregulated in various human malignancies. Previous studies have reported that miRNAs were stably conserved in 10% formalin-fixed paraffin-embedded tissues without significant degradation, in contrast to more fragile RNA. METHODS: Therefore, in this study, we examined 21 surgical breast cancer specimens using the Human Cancer microRNA PCR Array system (QIAGEN) to explore potential molecular targets of miRNAs. RESULTS: Profiling of miRNA expression in archival materials demonstrated that a group of deregulated miRNAs was associated with clinicopathological parameters of the patients, such as Ki-67, HER2, ER and PR. For instance, an abundant expression of multiple let-7 miRNA family, also known as tumor suppressor, was detected in low Ki-67 and HER2 groups. Elevated expression of 8 miRNAs overlapped between Ki-67+/HER2+/ER+/PR+ groups, including several known oncogenic miRNAs such as miR-148b, miR-15b, miR-200c, miR-150, miR 191, miR-96, miR-25 and miR-21. CONCLUSIONS: These results all indicated that when analyzing miRNAs in surgical pathology specimens of breast cancer as a biomarker, they should be examined as a cluster through miRNA profiling, rather than relying on the analysis of a single miRNA. PMID- 25907661 TI - Preclinical assessments of the MEK inhibitor PD-0325901 in a mouse model of Neurofibromatosis type 1. AB - BACKGROUND: Neurofibromatosis type 1 (NF1) is a genetic disorder that predisposes affected individuals to formation of benign neurofibromas, peripheral nerve tumors that can be associated with significant morbidity. Loss of the NF1 Ras-GAP protein causes increased Ras-GTP, and we previously found that inhibiting MEK signaling downstream of Ras can shrink established neurofibromas in a genetically engineered murine model. PROCEDURES: We studied effects of MEK inhibition using 1.5 mg/kg/day PD-0325901 prior to neurofibroma onset in the Nf1 (flox/flox); Dhh Cre mouse model. We also treated mice with established tumors at 0.5 and 1.5 mg/kg/day doses of PD-0325901. We monitored tumor volumes using MRI and volumetric measurements, and measured pharmacokinetic and pharmacodynamic endpoints. RESULTS: Early administration significantly delayed neurofibroma development as compared to vehicle controls. When treatment was discontinued neurofibromas grew, but no rebound effect was observed and neurofibromas remained significantly smaller than controls. Low dose treatment of mice with PD-0325901 resulted in neurofibroma shrinkage equivalent to that observed at higher doses. Tumor cell proliferation decreased, although less than at higher doses with drug. Tumor blood vessels per area correlated with tumor shrinkage. CONCLUSIONS: Neurofibroma development was not prevented by MEK inhibition, beginning at 1 month of age, but tumor size was controlled by early treatment. Moreover, treatment with PD-0325901 at very low doses may shrink neurofibromas while minimizing toxicity. These studies highlight how genetically engineered mouse models can guide clinical trial design. PMID- 25907663 TI - hOGG1 C1245G gene polymorphism associated with prostate cancer: a meta-analysis. AB - BACKGROUND: Prostate cancer (Pca) is one of the most frequently encountered multifactorial malignant diseases worldwide. The human oxoguanine glycosylase 1 (hOGG1) C1245G polymorphism (rs1052133) has been found to be associated with Pca. However, the conclusions have been controversial. METHODS: Based on the PubMed, Embase, HuGENet and Chinese National Knowledge Infrastructure (CNKI) databases, this meta-analysis was conducted with 4 models. Eleven qualified studies were included. RESULTS: Although no positive relation was discovered in the pooled analysis, significant associations between rs1052133 and Pca were found in the Asian population (recessive: odds ratio [OR] = 1.580, 95% confidence interval [95% CI], 1.189-2.098; GG vs. GC: OR = 1.504, 95% CI, 1.114-2.030; GG vs. CC: OR = 1.677, 95% CI, 1.201-2.342; allele analysis: OR = 1.249, 95% CI, 1.077-1.449), whites (dominant: OR = 2.138, 95% CI, 1.483-3.083; recessive: OR = 3.143, 95% CI, 1.171-8.437; GG vs. CC: OR = 3.992, 95% CI, 1.891-8.431; allele analysis: OR = 1.947, 95% CI, 1.467-2.586) and mixed populations (recessive: OR = 0.636, 95% CI, 0.484-0.834; GG vs. GC: OR = 0.654, 95% CI, 0.492-0.871; GG vs. CC: OR = 0.624, 95% CI, 0.473-0.823; allele analysis: OR = 0.857, 95% CI, 0.771-0.954). After excluding studies deviating from the Hardy-Weinberg equilibrium, a significant association was also found in the same ethnic groups. In addition, a new positive relation was identified in the "other country" subgroup (with China, South Korea and Australia included) (dominant: OR = 1.622, 95% CI, 1.163-2.261; recessive: OR = 1.773, 95% CI, 1.308-2.404; GG vs. GC: OR = 1.614, 95% CI, 1.169-2.230; GG vs. CC: OR = 2.108, 95% CI, 1.456-3.051; allele analysis: OR = 1.494, 95% CI, 1.235 1.808) and among the Chinese-Korean population. CONCLUSIONS: In conclusion, we suggest that the hOGG1 C1245G polymorphism might be potentially associated with Pca risk in different ethnicities and countries, especially among Asians. Further studies are needed to confirm these relations. PMID- 25907664 TI - Determination of mutagenicity and genotoxicity of indium tin oxide nanoparticles using the Ames test and micronucleus assay. AB - In this study, the mutagenicity and genotoxicity of indium tin oxide (ITO) nanomaterial were assessed using two standard genotoxicity assays, the Salmonella reverse mutation assay (Ames test) and the in vitro micronucleus (MN) assay. Seven different concentrations (12.5, 25, 50, 75, 100, 125, and 150 ug/plate) of this nanomaterial were tested using the Ames test on the TA98 and TA100 strains in the presence and absence of the S9 mixture. At all the concentrations tested, this substance did not significantly increase the number of revertant colonies compared with the control with or without S9 mixture. The genotoxic effects of ITO were investigated in human peripheral lymphocytes treated with 125, 250, 500, and 750 ug/ml concentrations of this substance for 24- and 48-h treatment periods using an MN test. Nuclear division index (NDI) was also calculated in order to determine the cytotoxicity of ITO. It was determined that ITO increased MN frequency in the 750 ug/ml concentration in 24- and 48-h treatments. In addition, ITO dose dependently decreased the NDI significantly for two treatment periods. PMID- 25907666 TI - An improved multiple flame photometric detector for gas chromatography. AB - An improved multiple flame photometric detector (mFPD) is introduced, based upon interconnecting fluidic channels within a planar stainless steel (SS) plate. Relative to the previous quartz tube mFPD prototype, the SS mFPD provides a 50% reduction in background emission levels, an orthogonal analytical flame, and easier more sensitive operation. As a result, sulfur response in the SS mFPD spans 4 orders of magnitude, yields a minimum detectable limit near 9*10( 12)gS/s, and has a selectivity approaching 10(4) over carbon. The device also exhibits exceptionally large resistance to hydrocarbon response quenching. Additionally, the SS mFPD uniquely allows analyte emission monitoring in the multiple worker flames for the first time. The findings suggest that this mode can potentially further improve upon the analytical flame response of sulfur (both linear HSO, and quadratic S2) and also phosphorus. Of note, the latter is nearly 20-fold stronger in S/N in the collective worker flames response and provides 6 orders of linearity with a detection limit of about 2.0*10(-13)gP/s. Overall, the results indicate that this new SS design notably improves the analytical performance of the mFPD and can provide a versatile and beneficial monitoring tool for gas chromatography. PMID- 25907667 TI - Considerations on the determination of the limit of detection and the limit of quantification in one-dimensional and comprehensive two-dimensional gas chromatography. AB - Methods based on the blank signal as proposed by IUPAC procedure and on the signal to noise ratio (S/N) as listed in the ISO-11843-1 norm for determination of the limit of detection (LOD) and quantitation (LOQ) in one-dimensional capillary gas chromatography (1D-GC) and comprehensive two-dimensional capillary gas chromatography (CG*GC) are described in detail and compared for both techniques. Flame ionization detection was applied and variables were the data acquisition frequency and, for CG*GC, also the modulation time. It has been stated that LOD and LOQ estimated according to IUPAC might be successfully used for 1D-GC-FID method. Moreover, LOD and LOQ decrease with decrease of data acquisition frequency (DAF). For GC*GC-FID, estimation of LOD by IUPAC gave poor reproducibility of results while for LOQ reproducibility was acceptable (within +/-10% rel.). The LOD and LOQ determined by the S/N concept both for 1D-GC-FID and GC*GC-FID methods are ca. three times higher than those values estimated by the standard deviation of the blank. Since the distribution pattern of modulated peaks for any analyte separated by GC*GC is random and cannot be predicted, LOQ and LOD may vary within 30% for 3s modulation time. Concerning sensitivity, 1D-GC FID at 2Hz and of GC*GC-FID at 50Hz shows a ca. 5 times enhancement of sensitivity in the modulated signal output. PMID- 25907668 TI - Application of a new nanocarbonaceous sorbent in electromembrane surrounded solid phase microextraction for analysis of amphetamine and methamphetamine in human urine and whole blood. AB - Application of a new carbon-based sorbent was studied for the first time for extraction and quantification of amphetamine and methamphetamine as model analytes by means of electromembrane surrounded solid phase microextraction (EM SPME). Since the basis of this microextraction method is adsorption of target analytes on the sorbent surface (after transferring across a supported liquid membrane) in an electrical field, the sorbent, which also performs the electrical potential, should have a conductive nature. On the other hand, using a synthesized fiber is a suitable solution to eliminate the interfering compounds existing in the fiber. To extract the model analytes from acidic sample solution through a thin layer of organic phase and into the aqueous acceptor phase and their final adsorption, 150V electrical potential was applied for 15min. Regardless of the high sample cleanup ability of the proposed method, which makes the analysis of complicated biological fluids possible, admissible extraction recoveries (9.0-18.8%) and suitable detection limits (less than 2.0ngmL(-1)) were obtained. Repeatability and reproducibility of the method were studied and intra- and inter-assay precisions were in the ranges of 2.0-7.3% and 7.5-12.5%, respectively. Coefficients of determination larger than 0.9964 were achieved by scrutinizing of the linearity up to 500ngmL(-1) and calibration curves were utilized for quantification of analytes of interest in human urine and whole blood samples. PMID- 25907665 TI - Dysregulated arginine metabolism and cardiopulmonary dysfunction in patients with thalassaemia. AB - Pulmonary hypertension (PH) commonly develops in thalassaemia syndromes, but is poorly characterized. The goal of this study was to provide a comprehensive description of the cardiopulmonary and biological profile of patients with thalassaemia at risk for PH. A case-control study of thalassaemia patients at high versus low PH-risk was performed. A single cross-sectional measurement for variables reflecting cardiopulmonary status and biological pathophysiology were obtained, including Doppler-echocardiography, 6-min-walk-test, Borg Dyspnoea Score, New York Heart Association functional class, cardiac magnetic resonance imaging (MRI), chest-computerized tomography, pulmonary function testing and laboratory analyses targeting mechanisms of coagulation, inflammation, haemolysis, adhesion and the arginine-nitric oxide pathway. Twenty-seven thalassaemia patients were evaluated, 14 with an elevated tricuspid-regurgitant jet-velocity (TRV) >= 2.5 m/s. Patients with increased TRV had a higher frequency of splenectomy, and significantly larger right atrial size, left atrial volume and left septal-wall thickness on echocardiography and/or MRI, with elevated biomarkers of abnormal coagulation, lactate dehydrogenase (LDH) levels and arginase concentration, and lower arginine-bioavailability compared to low-risk patients. Arginase concentration correlated significantly to several echocardiography/MRI parameters of cardiovascular function in addition to global arginine-bioavailability and biomarkers of haemolytic rate, including LDH, haemoglobin and bilirubin. Thalassaemia patients with a TRV >= 2.5 m/s have additional echocardiography and cardiac-MRI parameters suggestive of right and left-sided cardiac dysfunction. In addition, low arginine bioavailability may contribute to cardiopulmonary dysfunction in beta-thalassaemia. PMID- 25907669 TI - Associations between responses to interferon therapy and genetic variation in interleukin-28B and the core region of hepatitis C virus genotype 3a. AB - The single-nucleotide polymorphism (SNP) of interleukin-28B (IL-28B) and mutations in the core region of hepatitis C virus (HCV) genotype 1b have been associated with response to interferon (IFN) therapy. However, whether this IL 28B SNP affects responses to INF therapy for HCV genotype 3a is not known. The aim of this study is to investigate whether this IL-28B SNP (rs8099917) and specific missense mutations in the HCV core region affect the response to IFN therapy for HCV genotype 3a. Patients (n = 19; median age 44.5) infected with HCV genotype 3a who received IFN therapy were studied. Of the 19 patients, 12 (63.1%) achieved sustained virological response. Of those 12 patients, 11 had the TT genotype (11/16; 68.7%), and one had the TG genotype (1/3; 33.3%). The difference in the sustained virological response rate between IL-28B genotype groups was not significant (P = 0.5232). HCV core region was well conserved; however, polymorphisms at position 72 were identified. Of the 19 HCV samples; 15 carried a glutamic acid at position 72, and these were defined as E type; the others (4/19) were defined as non-E type. Notably, there was a significant difference in the sustained virological response rate between E type and non-E-type; 12 of the 15 patients with E-type achieved sustained virological response, but none of the four patients with non-E-type achieved sustained virological response (P = 0.009). A glutamic acid at position 72 in the core region of HCV genotype 3a was associated with a good response to IFN therapy. J. Med. Virol. 87:1361-1367, 2015. (c) 2015 Wiley Periodicals, Inc. PMID- 25907670 TI - 1D-3D mixed-ligand frameworks with an unusual dmp topology tuned by intersection angles of isomeric benzenedicarboxylates: magnetic properties, gas-dependent calcination-thermolysis and energy storage performances. AB - In this work, three isomeric benzenedicarboxylates, 1,2-benzenedicarboxylic acid (o-H2bdc), 1,3-benzenedicarboxylic acid (m-H2bdc), and 1,4-benzenedicarboxylic acid (p-H2bdc) have been utilized as the ancillary ligands to perform a systematic study on the structural diversity of mixed-ligand frameworks. The solvothermal reactions of Co(NO3)2 with these aromatic acids and the primary ligand 4,4'-bis(imidazolyl)biphenyl (bibp) afford three novel coordination polymers, {[Co6(bibp)3(o-bdc)6(H2O)](CH3CN)1.5}infinity (1), [Co(bibp)(m bdc)]infinity (2), and [Co(bibp)(p-bdc)]infinity (3). Owing to the different orientations of the carboxylate groups, the benzenedicarboxylates adopt various bridging modes to connect the Co(II) ions into a series of 1D carboxylate?cobalt architectures based on the 1D chain, binuclear and single-ion magnetic units, respectively. These 1D architectures are further decorated by the bibp ligand to afford a 1D belt for , 2D double-bridging (4,4) sheet for 2, and an unusual 3D dmp framework for 3. Significantly in 3, three equivalent frameworks are interlocked with each other to represent an unprecedented three-fold interpenetrating dmp network. The structural diversity indicates that the benzenedicarboxylate plays an essential role in the assembly of mixed-ligand frameworks, and the orientation of the carboxylate group exerts an important influence on the nucleation, dimensionality and also interpenetration. Furthermore, the magnetic properties of 1 and 2 have been studied by fitting the experimental data as possible, and the magneto-structural correlation of 2 has also been well discussed. Importantly, CoO and Co3O4 were obtained from the controllable thermolysis of crystals of 1 via simple calcination treatment under different gas environments. The as-synthesized cobalt oxides display good crystallinity and appear as micro- or nanoparticles, which can be applied as supercapacitor electrodes as demonstrated by their energy storage performance in 2 M KOH electrolyte. PMID- 25907671 TI - Prevalence of Perceived Dysphonia and Its Correlation With the Prevalence of Clinically Diagnosed Laryngeal Disorders: The Korea National Health and Nutrition Examination Surveys 2010-2012. AB - OBJECTIVE: This study investigated the prevalence of perceived dysphonia and its correlation with the prevalence of clinically diagnosed laryngeal disorders. METHODS: Subjects were 8713 non-institutionalized civilian adults over the age of 19 (3810 men and 4912 women) who completed the laryngeal examination of the fifth Korea National Health and Nutrition Examination Survey. A Poisson regression was used to examine the association between perceived dysphonia and laryngeal disorders. RESULTS: Adjusting for covariates (age, sex, education level, income, occupation, alcohol drinking, and self-reported health status), those with perceived voice problems were 4.8 times (OR=4.75, 95% CI, 3.77-5.99) more likely to have laryngeal disorders than those without voice problems. In particular, the vocal fold pathology correlated with perceived dysphonia was: vocal fold nodules (OR=5.32, 95% CI, 3.43-8.26), vocal polyps (OR=3.73, 95% CI, 1.57-8.86), vocal cysts (OR=11.97, 95% CI, 1.97-72.72), Reinke's edema (OR=9.27, 95% CI, 4.77 18.00), laryngeal paralysis (OR=3.58, 95% CI, 1.56-8.26), laryngeal granulomas (OR=4.31, 95% CI, 1.01-18.80), epiglottic cyst (OR=2.94, 95% CI, 1.21-7.13), and laryngitis (OR=4.07, 95% CI, 2.91-5.69). CONCLUSION: People with self-perceived dysphonia had a high risk of laryngeal disorders. PMID- 25907673 TI - Pilot Study of Droxidopa With Carbidopa in Adults With ADHD. AB - OBJECTIVE: We conducted a two-period (open-label and double-blind) pilot investigation of droxidopa, with and without carbidopa, for ADHD. METHOD: Twenty adult ADHD patients received open-label droxidopa titrated from 200 to 600 mg 3 times per day (TID; Weeks 1-3), then open-label droxidopa plus carbidopa titrated from 25 or 50 mg TID (Weeks 4-6). In Weeks 7 to 8, patients were randomized to continued co-treatment or matching placebo substitution. RESULTS: Improvements in mean total Adult ADHD Investigator Symptom Report Scale (AISRS) scores were seen at Week 1 (p < .0001) and Week 3 (p < .0001). Improvements were maintained but not increased with carbidopa. Thirteen of 20 patients completed open-label treatment. In the double-blind period, mean total AISRS scores were similar between the co-treatment (n = 6) and placebo (n = 5) groups. No serious adverse events were reported. CONCLUSION: These preliminary findings indicate that droxidopa can improve adult ADHD symptoms. Further studies are warranted to examine the efficacy and safety of droxidopa in ADHD. PMID- 25907672 TI - Determinants of ventilation and pulmonary artery pressure during early acclimatization to hypoxia in humans. AB - Pulmonary ventilation and pulmonary arterial pressure both rise progressively during the first few hours of human acclimatization to hypoxia. These responses are highly variable between individuals, but the origin of this variability is unknown. Here, we sought to determine whether the variabilities between different measures of response to sustained hypoxia were related, which would suggest a common source of variability. Eighty volunteers individually underwent an 8-h isocapnic exposure to hypoxia (end-tidal P(O2)=55 Torr) in a purpose-built chamber. Measurements of ventilation and pulmonary artery systolic pressure (PASP) assessed by Doppler echocardiography were made during the exposure. Before and after the exposure, measurements were made of the ventilatory sensitivities to acute isocapnic hypoxia (G(pO2)) and hyperoxic hypercapnia, the latter divided into peripheral (G(pCO2)) and central (G(cCO2)) components. Substantial acclimatization was observed in both ventilation and PASP, the latter being 40% greater in women than men. No correlation was found between the magnitudes of pulmonary ventilatory and pulmonary vascular responses. For G(pO2), G(pCO2) and G(cC O2), but not the sensitivity of PASP to acute hypoxia, the magnitude of the increase during acclimatization was proportional to the pre-acclimatization value. Additionally, the change in G(pO2) during acclimatization to hypoxia correlated well with most other measures of ventilatory acclimatization. Of the initial measurements prior to sustained hypoxia, only G(pCO2) predicted the subsequent rise in ventilation and change in G(pO2) during acclimatization. We conclude that the magnitudes of the ventilatory and pulmonary vascular responses to sustained hypoxia are predominantly determined by different factors and that the initial G(pCO2) is a modest predictor of ventilatory acclimatization. PMID- 25907674 TI - Arsenic Inhibits DNA Mismatch Repair by Promoting EGFR Expression and PCNA Phosphorylation. AB - Both genotoxic and non-genotoxic chemicals can act as carcinogens. However, while genotoxic compounds lead directly to mutations that promote unregulated cell growth, the mechanism by which non-genotoxic carcinogens lead to cellular transformation is poorly understood. Using a model non-genotoxic carcinogen, arsenic, we show here that exposure to arsenic inhibits mismatch repair (MMR) in human cells, possibly through its ability to stimulate epidermal growth factor receptor (EGFR)-dependent tyrosine phosphorylation of proliferating cellular nuclear antigen (PCNA). HeLa cells exposed to exogenous arsenic demonstrate a dose- and time-dependent increase in the levels of EGFR and tyrosine 211 phosphorylated PCNA. Cell extracts derived from arsenic-treated HeLa cells are defective in MMR, and unphosphorylated recombinant PCNA restores normal MMR activity to these extracts. These results suggest a model in which arsenic induces expression of EGFR, which in turn phosphorylates PCNA, and phosphorylated PCNA then inhibits MMR, leading to increased susceptibility to carcinogenesis. This study suggests a putative novel mechanism of action for arsenic and other non-genotoxic carcinogens. PMID- 25907675 TI - Cyclin D1 in well differentiated thyroid tumour of uncertain malignant potential. AB - BACKGROUND: Encapsulated follicular tumours with equivocal papillary thyroid carcinoma (PTC) type nuclear features continue to remain a challenge despite the recent attempts to classify these borderline lesions. The term 'well differentiated tumour of uncertain malignant potential (WDT-UMP)' was introduced to classify these tumours. The present study aimed to evaluate the role of a cell cycle regulator like cyclin D1 in these tumours along with assessment of other well established PTC markers like galectin-3, HBME-1, CK19. METHODS: Thirteen cases of metastatic PTC, papillary microcarcinoma and follicular variant of PTC (FVPTC) were identified from a histological review of 510 cases. In addition, 13 cases of a subset of follicular adenomatoid nodules with focal areas showing nuclear features characteristic of PTC, identified as WDT-UMP, were also analyzed. Immunohistochemical analysis of galectin-3, HBME-1, CK19 and the proliferation markers Ki67 and cyclin D1 was performed. Lesions were analyzed for cyclin D1 gene amplification by fluorescent in-situ hybridization. RESULTS: All WDT-UMP lesions showed immunolabelling of cyclin D1, Ki67; 11/ 13 cases showed immunolabelling of CK19; 10/13 cases showed immunolabelling of HBME-1 and 4/13 cases showed immunolabelling of galectin-3. Surrounding benign adenomatoid areas showed no to faint focal staining in all thirteen cases of cyclin D1, HBME-1 and galectin-3. A low rate of cyclin D1 gene amplification was identified in a significant proportion of cells in the WDT-UMP lesions as compared to surrounding benign adenomatoid areas. CONCLUSIONS: Increased expression of cyclin D1 and amplification of its gene along with immunolabelling of HBME-1 in WDT-UMP lesions showing cytological features of papillary thyroid carcinoma within follicular adenomatoid nodules suggest that these areas could correspond to a precursor lesion of follicular variant of PTC. Overexpression of cyclin D1, associated with the amplification of the gene suggests that these WDT-UMP lesions are an intermediate between the benign and malignant groups making this group of lesions a reliable precursor of FVPTC. VIRTUAL SLIDES: The virtual slide(s) for this article can be found here: http://www.diagnosticpathology.diagnomx.eu/vs/1851820807142117. PMID- 25907676 TI - Expression of heme oxygenase-1 in eosinophilic and non-eosinophilic chronic rhinosinusitis with nasal polyps: modulation by cytokines. AB - BACKGROUND: Oxidative stress is characteristic of chronic airway inflammatory diseases such as asthma, chronic obstructive pulmonary disease and chronic rhinosinusitis with nasal polyps (CRSwNP). Heme oxygenase (HO)-1 has been proposed to be a cytoprotective enzyme against oxidative stress in CRSwNP. However, the expression and regulation of HO-1 in eosinophilic CRSwNP (ECRS) and non-eosinophilic CRSwNP (non-ECRS) subsets has not been well documented. METHODS: Nasal polyps and uncinate process tissues were enrolled from 40 CRSwNP patients (ECRS, 17; non-ECRS, 23) and 20 control subjects, respectively. The messenger RNA (mRNA) and protein expression of HO-1 was examined using qRT-PCR, immunohistochemistry, and Western blot staining. Moreover, the stimulatory effects of several cytokines (interferon gamma [IFN-gamma], interleukin [IL]-5, and IL-13, etc.) on HO-1 mRNA expression in cultured nasal explants were evaluated. RESULTS: The mRNA and protein expression of HO-1 was significantly increased in polyp tissues compared with healthy controls (p < 0.05), and the non ECRS subset showed significantly increased HO-1 expression compared with the ECRS subset (p < 0.05). Moreover, in cultured nasal explant, HO-1 mRNA was significantly upregulated in the presence of IFN-gamma, IL-27, IL-5, IL-13, and IL-17A, but was significantly inhibited by transforming growth factor beta1 (TGF beta1) (p < 0.05). CONCLUSION: Our findings indicate that HO-1 was differentially expressed and regulated in ECRS and non-ECRS patients. PMID- 25907678 TI - Hospital-associated microbiota and implications for nosocomial infections. AB - The rise of high-throughput sequencing technologies and culture-independent microbial surveys has the potential to revolutionize our understanding of how microbes colonize, move about, and evolve in hospital environments. Genome analysis of individual organisms, characterization of population dynamics, and microbial community ecology are facilitating the identification of novel pathogens, the tracking of disease outbreaks, and the study of the evolution of antibiotic resistance. Here we review the recent applications of these methods to microbial ecology studies in hospitals and discuss their potential to influence hospital management policy and practice and to reduce nosocomial infections and the spread of antibiotic resistance. PMID- 25907679 TI - P2-Na0.6[Cr0.6Ti0.4]O2 cation-disordered electrode for high-rate symmetric rechargeable sodium-ion batteries. AB - Most P2-type layered oxides exhibit Na(+)/vacancy-ordered superstructures because of strong Na(+)-Na(+) interaction in the alkali metal layer and charge ordering in the transition metal layer. These superstructures evidenced by voltage plateaus in the electrochemical curves limit the Na(+) ion transport kinetics and cycle performance in rechargeable batteries. Here we show that such Na(+)/vacancy ordering can be avoided by choosing the transition metal ions with similar ionic radii and different redox potentials, for example, Cr(3+) and Ti(4+). The designed P2-Na(0.6)[Cr(0.6)Ti(0.4)]O2 is completely Na(+)/vacancy-disordered at any sodium content and displays excellent rate capability and long cycle life. A symmetric sodium-ion battery using the same P2-Na(0.6)[Cr(0.6)Ti(0.4)]O2 electrode delivers 75% of the initial capacity at 12C rate. Our contribution demonstrates that the approach of preventing Na(+)/vacancy ordering by breaking charge ordering in the transition metal layer opens a simple way to design disordered electrode materials with high power density and long cycle life. PMID- 25907677 TI - Evaluation of an open access software for calculating glucose variability parameters of a continuous glucose monitoring system applied at pediatric intensive care unit. AB - BACKGROUND: Continuous Glucose Monitoring (CGM) has become an increasingly investigated tool, especially with regards to monitoring of diabetic and critical care patients. The continuous glucose data allows the calculation of several glucose variability parameters, however, without specific application the interpretation of the results is time-consuming, utilizing extreme efforts. Our aim was to create an open access software [Glycemic Variability Analyzer Program (GVAP)], readily available to calculate the most common parameters of the glucose variability and to test its usability. METHODS: The GVAP was developed in MATLAB(r) 2010b environment. The calculated parameters were the following: average area above/below the target range (Avg. AUC-H/L); Percentage Spent Above/Below the Target Range (PATR/PBTR); Continuous Overall Net Glycemic Action (CONGA); Mean of Daily Differences (MODD); Mean Amplitude of Glycemic Excursions (MAGE). For verification purposes we selected 14 CGM curves of pediatric critical care patients. Medtronic(r) Guardian(r) Real-Time with Enlite(r) sensor was used. The reference values were obtained from Medtronic(r)(')s own software for Avg. AUC-H/L and PATR/PBTR, from GlyCulator for MODD and CONGA, and using manual calculation for MAGE. RESULTS: The Pearson and Spearman correlation coefficients were above 0.99 for all parameters. The initial execution took 30 minutes, for further analysis with the Windows(r) Standalone Application approximately 1 minute was needed. CONCLUSIONS: The GVAP is a reliable open access program for analyzing different glycemic variability parameters, hence it could be a useful tool for the study of glycemic control among critically ill patients. PMID- 25907680 TI - Hydrophilic interaction liquid chromatography for the separation of acidic agricultural compounds. AB - Organic acids with very low pKa require extremely low pH conditions to achieve adequate retention in reversed-phase liquid chromatography, but an extremely low pH mobile phase can cause instrument reliability problems and limit the choice of columns. Hydrophilic interaction chromatography is a potential alternative to reversed-phase liquid chromatography for the separation of organic acids using more moderate conditions. However, the hydrophilic interaction chromatography separation mechanism is known to be very complex and involves multiple competing mechanisms. In the present study, a hydrophilic interaction chromatography column packed with bare silica core-shell particles was used as the separation column and six agricultural organic acids were used as model analytes to evaluate the effects of buffer concentration, buffer pH, and temperature on sample loading capacity, selectivity, retention, and repeatability. It was found that using a higher concentration of buffer can lead to a significant improvement in the overall performance and reproducibility of the separation. Investigation of column equilibration time revealed that a very long equilibration time is needed when changing mobile phase conditions in between runs. This limitation needs to be acknowledged in hydrophilic interaction chromatography method development and sufficient equilibration time needs to be allowed in method scouting. PMID- 25907682 TI - Predicting Persistence of Nonsuicidal Self-Injury in Suicidal Adolescents. AB - Prospective predictors of persistent nonsuicidal self-injury (NSSI) were examined in adolescents admitted to an inpatient psychiatric unit for suicidal behaviors and followed naturalistically for 6 months. Seventy-one (77%) participants reported NSSI at baseline, and 40 (56%) persisted at the 6 month follow-up. Those who endorsed automatic positive reinforcement (APR) as the predominant reason for NSSI were more likely to persist in NSSI. Depression over follow-up, but not at baseline, also predicted persistence. These results suggest that helping high risk adolescents to identify alternative ways of generating emotion(s) to counter the effects of APR that may accompany NSSI should be a high priority treatment target. PMID- 25907681 TI - Expression of leukemia inhibitory factor in Muller glia cells is regulated by a redox-dependent mRNA stability mechanism. AB - BACKGROUND: Photoreceptor degeneration is a main hallmark of many blinding diseases making protection of photoreceptors crucial to prevent vision loss. Thus, regulation of endogenous neuroprotective factors may be key for cell survival and attenuation of disease progression. Important neuroprotective factors in the retina include H2O2 generated by injured photoreceptors, and leukemia inhibitory factor (LIF) expressed in Muller glia cells in response to photoreceptor damage. RESULTS: We present evidence that H2O2 connects to the LIF response by inducing stabilization of Lif transcripts in Muller cells. This process was independent of active gene transcription and p38 MAPK, but relied on AU-rich elements (AREs), which we identified within the highly conserved Lif 3'UTR. Affinity purification combined with quantitative mass spectrometry identified several proteins that bound to these AREs. Among those, interleukin enhancer binding factor 3 (ILF3) was confirmed to participate in the redox dependent Lif mRNA stabilization. Additionally we show that KH-type splicing regulatory protein (KHSRP) was crucial for maintaining basal Lif expression levels in non-stressed Muller cells. CONCLUSIONS: Our results suggest that H2O2 induced redox signaling increases Lif transcript levels through ILF3 mediated mRNA stabilization. Generation of H2O2 by injured photoreceptors may thus enhance stability of Lif mRNA and therefore augment neuroprotective LIF signaling during degenerative conditions in vivo. PMID- 25907683 TI - Palladium-Catalyzed Construction of Heteroatom-Containing pi-Conjugated Systems by Intramolecular Oxidative C-H/C-H Coupling Reaction. AB - Synthesis of heteroatom-containing ladder-type pi-conjugated molecules was successfully achieved via a palladium-catalyzed intramolecular oxidative C-H/C-H cross-coupling reaction. This reaction provides a variety of pi-conjugated molecules bearing heteroatoms, such as nitrogen, oxygen, phosphorus, and sulfur atoms, and a carbonyl group. The pi-conjugated molecules were synthesized efficiently, even in gram scale, and larger pi-conjugated molecules were also obtained by a double C-H/C-H cross-coupling reaction and successive oxidative cycloaromatization. PMID- 25907684 TI - Genetic evaluation of the evolutionary distinctness of a federally endangered butterfly, Lange's Metalmark. AB - BACKGROUND: The Mormon Metalmark (Apodemia mormo) species complex occurs as isolated and phenotypically variable colonies in dryland areas across western North America. Lange's Metalmark, A. m. langei, one of the 17 subspecies taxonomically recognized in the complex, is federally listed under the U.S. Endangered Species Act of 1973. Metalmark taxa have traditionally been described based on phenotypic and ecological characteristics, and it is unknown how well this nomenclature reflects their genetic and evolutionary distinctiveness. Genetic variation in six microsatellite loci and mitochondrial cytochrome oxidase subunit I sequence was used to assess the population structure of the A. mormo species complex across 69 localities, and to evaluate A. m. langei's qualifications as an Evolutionarily Significant Unit. RESULTS: We discovered substantial genetic divergence within the species complex, especially across the Continental Divide, with population genetic structure corresponding more closely with geographic proximity and local isolation than with taxonomic divisions originally based on wing color and pattern characters. Lange's Metalmark was as genetically divergent as several other locally isolated populations in California, and even the unique phenotype that warranted subspecific and conservation status is reminiscent of the morphological variation found in some other populations. CONCLUSIONS: This study is the first genetic treatment of the A. mormo complex across western North America and potentially provides a foundation for reassessing the taxonomy of the group. Furthermore, these results illustrate the utility of molecular markers to aid in demarcation of biological units below the species level. From a conservation point of view, Apodemia mormo langei's diagnostic taxonomic characteristics may, by themselves, not support its evolutionary significance, which has implications for its formal listing as an Endangered Species. PMID- 25907685 TI - N-glycosylation profile analysis of Trastuzumab biosimilar candidates by Normal Phase Liquid Chromatography and MALDI-TOF MS approaches. AB - The pharmaceutical market has entered an era in which the production of new therapeutics is being often replaced by "biosimilars", copies of already commercialized products waiting for the patents to expire in order to be distributed in a more competitive and affordable manners. Due to its relevance, the ErbB2-targeted monoclonal antibody Trastuzumab (Herceptin) used as breast cancer therapy is one of the main targets in the production of biosimilars. A major challenge is to produce antibodies with the same or the closest N glycosylation pattern seen in the commercialized drug. Several factors, such as growing conditions or cell types employed, can determine the final composition and structure of the glycans, significantly affecting the properties of the generated antibodies. Therefore, an appropriate characterization is essential. In the present study, we describe two different but complementary strategies to characterize the N-glycosylation of two biosimilar candidates of Trastuzumab. In the first case, N-glycans are fluorescently labeled and separated by Normal Phase HPLC. Different sugars will elute at different times and can be identified using specific oligosaccharide standards. In the second approach, released glycans are permethylated and analyzed by MALDI-TOF MS, being able to determine the structure because of the differential sugar masses. BIOLOGICAL SIGNIFICANCE: The characterization of the N-glycosylation sites of therapeutic recombinant monoclonal antibodies (mAbs) is usually one of the most critical and time consuming steps in the developing process of biosimilars or any other glycosylated drug. Herein we describe two different but complementary approaches to characterize mAbs glycosylation patterns, the use of glycan fluorescence labeling coupled to HPLC and MALDI-TOF MS profile analysis. This article is part of a Special Issue entitled: HUPO 2014. PMID- 25907686 TI - Differential dependencies on [Ca2+] and temperature of the monolayer spontaneous curvatures of DOPE, DOPA and cardiolipin: effects of modulating the strength of the inter-headgroup repulsion. AB - Biomembranes assume nonlamellar structures in many cellular events, with the tendency of forming a nonlamellar structure quantified by the monolayer spontaneous curvature, C(0), and with many of these events involving the acts of Ca(2+). Despite this biologically important intimacy, how C(0) is affected by [Ca(2+)] is unknown. In this study, we use the X-ray diffraction technique and the reconstruction of electron density profiles to measure the C(0)s of a zwitterionic phospholipid, DOPE, and two anionic phospholipids, DOPA and 18 : 1 (9Z) cardiolipin, at temperatures from 20 degrees C to 40 degrees C and [Ca(2+)]s from 0 mM to 100 mM; these phospholipids are chosen to examine the contributions of the electric charge density per molecule. While showing a strong dependence on temperature, C(0,DOPE) is nearly independent of [Ca(2+)]. In contrast, C(0,DOPA) and C(0),cardiolipin are almost unresponsive to the temperature change but affected by the [Ca(2+)] variation; and C(0,DOPA) varies with [Ca(2+)] ~1.5 times more strongly than C(0,cardiolipin), with the phase preferences of DOPA and cardiolipin shifting to the H(II) phase and remaining on the Lalpha phase, respectively, at [Ca(2+)] = 100 mM. From these observations, we reveal the effects of modulating the strength of the inter-headgroup repulsion and discuss the mechanisms underlying the phase behaviour and cellular functions of the investigated phospholipids. Most importantly, this study recognizes that the headgroup charge density is dominant in dictating the phase behaviour of the anionic phospholipids, and that the unique molecular characteristics of cardiolipin are critically needed both for maintaining the structural integrity of cardiolipin-rich biomembranes and for fulfilling the biological roles of the phospholipid. PMID- 25907687 TI - The problem with emotion: Comment on "The quartet theory of human emotions: An integrative and neurofunctional model" by S. Koelsch et al. PMID- 25907688 TI - Perfusion MRI in the Evaluation of Suspected Glioblastoma Recurrence. AB - PURPOSE: Treatment-related changes (TRC) often imitate tumor progression in glioblastomas. Increased regional cerebral blood volume (rCBV) can differentiate tumor progression from TRC after the standardized first-line radiochemotherapy, but information about diagnostic accuracy of rCBV for patients without any clinical selection criteria is limited. Therefore, we aimed to evaluate if rCBV can differentiate between TRC and tumor progression irrespective of preceding therapies and number of tumor progressions. METHODS: We analyzed mean and maximum rCBV from the enhancing areas normalized to the contralateral white matter in 44 pretreated glioblastomas with MR-morphological tumor progression. The diagnosis (real progression vs. TRC) was determined by histopathology or by clinical/MRI follow-up. We performed nonparametric tests, receiver operating characteristics (ROC), and Kaplan-Meier analysis. RESULTS: Significant differences between tumor progression (N = 37) and TRC (N = 7) were found for rCBVmean (2.44 +/- 1.05 vs. 1.69 +/- .56, P < .03) and rCBVmax (3.40 +/- 1.25 vs. 2.21 +/- .62, P < .0007). A rCBVmax of 2.6 had 78% sensitivity and 86% specificity to detect tumor progression. Neither rCBVmean nor rCBVmax was predictive for the patient overall survival (OS). There were no statistically different rCBVmean and rCBVmax between the first and further tumor progressions. CONCLUSIONS: The rCBVmax differentiates tumor progression from TRC in unselected recurrent glioblastomas, but it is not predictive for the OS. PMID- 25907689 TI - Decreased melatonin secretion is associated with increased intestinal permeability and marker of endotoxemia in alcoholics. AB - Chronic heavy alcohol use is known to cause gut leakiness and alcoholic liver disease (ALD), but only 30% of heavy drinkers develop increased intestinal permeability and ALD. The hypothesis of this study was that disruption of circadian rhythms is a potential risk factor in actively drinking alcoholics for gut leakiness and endotoxemia. We studied 20 subjects with alcohol use disorder (AD) and 17 healthy controls (HC, 6 day workers, 11 night workers). Subjects wore a wrist actiwatch for 7 days and underwent a 24-h dim light phase assessment and urine collection for intestinal permeability. The AD group had significantly less total sleep time and increased fragmentation of sleep (P < 0.05). AD also had significantly lower plasma melatonin levels compared with the HC [mean area under the curve (AUC) 322.78 +/- 228.21 vs. 568.75 +/- 304.26 pg/ml, P = 0.03]. In the AD group, AUC of melatonin was inversely correlated with small bowel and colonic intestinal permeability (lactulose-to-mannitol ratio, r = -0.39, P = 0.03; urinary sucralose, r = -0.47, P = 0.01). Cosinor analysis of lipopolysaccharide binding protein (marker of endotoxemia) and lipopolysaccharide every 4 h for 24 h in HC and AD subjects had a midline estimating statistic of rhythm of 5,026.15 +/ 409.56 vs. 6,818.02 +/- 628.78 ng/ml (P < 0.01) and 0.09 +/- 0.03 vs. 0.15 +/- 0.19 EU/ml (P < 0.05), respectively. We found plasma melatonin was significantly lower in the AD group, and lower melatonin levels correlated with increased intestinal permeability and a marker of endotoxemia. Our study suggests the suppression of melatonin in AD may promote gut leakiness and endotoxemia. PMID- 25907690 TI - A new role for reticulon-4B/NOGO-B in the intestinal epithelial barrier function and inflammatory bowel disease. AB - Inflammatory bowel disease (IBD) is characterized by an impaired intestinal barrier function. We aimed to investigate the role of reticulon-4B (RTN-4B/NOGO B), a structural protein of the endoplasmic reticulum, in intestinal barrier function and IBD. We used immunohistochemistry, confocal microscopy, real-time PCR, and Western blotting to study tissue distribution and expression levels of RTN-4B/NOGO-B in control and IBD samples from mouse and humans. We also targeted RTN-4B/NOGO-B using siRNAs in cultured human intestinal epithelial cell (IECs). Epithelial barrier permeability was assessed by transepithelial electrical resistance (TEER) measurement. RTN-4B/NOGO-B is expressed in the intestine mainly by IECs. Confocal microscopy revealed a colocalization of RTN-4B, E-cadherin, and polymerized actin fibers in tissue and cultured IECs. RTN-4B mRNA and protein expression were lower in the colon of IL-10(-/-) compared with wild-type mice. Colocalization of RTN-4B/E-cadherin/actin was reduced in the colon of IL-10(-/-) mice. Analysis of endoscopic biopsies from IBD patients showed a significant reduction of RTN-4B/NOGO-B expression in inflamed mucosa compared with control. Treatment of IECs with H2O2 reduced TEER values and triggered phosphorylation of RTN-4B in serine 107 residues as well as downregulation of RTN-4B expression. Acute RTN-4B/NOGO-B knockdown by siRNAs resulted in a decreased TEER values and reduction of E-cadherin and alpha-catenin expression and in the amount of F-actin rich filaments in IECs. Epithelial RTN-4B/NOGO-B was downregulated in human and experimental IBD. RTN-4B participates in the intestinal epithelial barrier function, most likely via its involvement in E-cadherin, alpha-catenin expression, and actin cytoskeleton organization at sites of cell-to-cell contacts. PMID- 25907692 TI - Topical protection of human esophageal mucosal integrity. AB - Patients with nonerosive reflux disease exhibit impaired esophageal mucosal integrity, which may underlie enhanced reflux perception. In vitro topical application of an alginate solution can protect mucosal biopsies against acid induced changes in transepithelial electrical resistance (TER). We aimed to confirm this finding in a second model using 3D cell cultures and to assess prolonged protection in a biopsy model. We assessed the protective effect of a topically applied alginate solution 1 h after application. 3D cell cultures were grown by using an air-liquid interface and were studied in Ussing chambers. The apical surface was "protected" with 200 MUl of either alginate or viscous control or was unprotected. The tissue was exposed to pH 3 + bile acid solution for 30 min and TER change was calculated. Distal esophageal mucosal biopsies were taken from 12 patients and studied in Ussing chambers. The biopsies were coated with either alginate or viscous control solution. The biopsies were then bathed in pH 7.4 solution for 1 h. The luminal chamber solution was replaced with pH 2 solution for 30 min. Percentage changes in TER were recorded. In five biopsies fluorescein-labeled alginate solution was used to allow immunohistological localization of the alginate after 1 h. In the cell culture model, alginate solution protected tissue against acid-induced change in TER. In biopsies, 60 min after protection with alginate solution, the acidic exposure caused a -8.3 +/- 2.2% change in TER compared with -25.1 +/- 4.5% change after protection with the viscous control (P < 0.05). Labeled alginate could be seen coating the luminal surface in all cases. In vitro, alginate solutions can adhere to the esophageal mucosa for up to 1 h and exert a topical protectant effect. Durable topical protectants can be further explored as first-line/add-on therapies for gastroesophageal reflux disease. PMID- 25907691 TI - The small molecule ferristatin II induces hepatic hepcidin expression in vivo and in vitro. AB - Previous studies have shown that administration of ferristatin II to rats is associated with decreased serum iron, reduced transferrin saturation, and increased hepatic hepcidin expression. BMP and IL-6 signaling act via Smad and Stat3 transcription factors, respectively, to increase expression of hepcidin, the master regulator of iron metabolism. In this study, we aimed to explore the underlying mechanism of ferristatin II action on hepcidin production. We found that ferristatin II greatly increased hepcidin expression both in vivo and in vitro. In the rat liver, ferristatin II treatment decreased expression of Smad downstream targets Smad7 and Id1 and increased expression of Stat3 downstream targets alpha-2-macroglobulin, alpha-1-acid glycoprotein, and C-reactive peptide. Ferristatin II also increased Stat3 phosphorylation in the rat liver without affecting serum or hepatic IL-6 levels. It is unclear whether the Stat3 activation observed in vivo is a cause or a consequence to hepcidin induction. Reporter gene expression studies demonstrated that ferristatin II synergized with BMP6 and IL-6 to enhance hepcidin expression in vitro. However, this synergy was not due to activation of either Smad or Stat3 signaling, raising the possibility that ferristatin II may activate a novel pathway for hepcidin regulation. PMID- 25907693 TI - Which prognostic score in MDS? Both! PMID- 25907694 TI - Mechanochemical surface functionalisation of superparamagnetic microparticles with in situ formed crystalline metal-complexes: a fast novel core-shell particle formation method. AB - An innovative mechanochemical method is reported for the in situ formation of crystalline metal-complexes on the surface of superparamagnetic nanocomposite microparticles. The process is demonstrated for coating Fe3O4 multicore-silica matrix particles with the 1,2,4-1H-triazole complex [ZnCl2(TzH)2]. The use of mechanochemistry demonstrates a flexible process to obtain functional shells on magnetic particle cores without the need for complicated surface functionalisation reactions in solution. Simple mixing of the desired shell precursors ZnCl2 and 1,2,4-1H-triazole (TzH) with the magnetic particles in a ball mill is sufficient to tailor the particle surfaces with novel functionalities while retaining the superparamagnetic behaviour. PMID- 25907695 TI - Adult metanephric adenoma presumed to be all benign? A clinical perspective. AB - BACKGROUND: In most documented literature, metanephric adenoma (MA) is described as a benign tumour. Nevertheless, the nature of MA remains unclear and the clinical criteria of different MA subtypes are not well established. In the present study, we investigated the clinicopathological characteristics of MA, especially those of the uncommon histological subtypes. METHODS: A cohort study was performed on 18 patients with pathologically proven MA in our institute from January 2004 to June 2014. The patients' clinicopathological and radiological data were retrospectively analysed and evaluated with an emphasis on the corresponding subtypes. RESULTS: The patient population had a female: male ratio of 1:1 and mean age of 50 years (range, 18-66 years). The mean tumour size was 3.9 cm (range, 1.4-9.0 cm). There were no pathognomonic radiological features that posed a challenge for a preoperative diagnosis of MA. Fourteen patients underwent radical nephrectomy, and the other four underwent partial nephrectomy. Three histological subtypes were observed: classic MA (n = 10), malignant MA (n = 2), and composite MA with coexistence of different malignant components (n = 6). Despite the presence of atypical histological features and malignant components among the patients, only one patient developed distant metastasis (median postoperative follow-up, 56 months; range, 30-86 months). CONCLUSIONS: MAs are a heterogeneous group of neoplasms with different biological characteristics. The correct identification of this entity and its subtypes would facilitate stratification of optimal management protocols and accurate assessment of the prognosis. PMID- 25907696 TI - Clinical performance of biodegradable polymer-coated sirolimus-eluting stents in unselected real-world population with coronary artery disease: results from the multicenter CORE Registry. AB - BACKGROUND: The main aim of the CORE Registry was to evaluate clinical performance of the Supralimus-Core(r) biodegradable polymer-coated sirolimus eluting cobalt-chromium stent (Sahajanand Medical technologies Pvt. Ltd., Surat, India) in unselected real-world patients. METHODS: This was a multicenter, retrospective, non-randomized, single-arm study. A total of 376 consecutive patients treated with the Supralimus-Core(r) between April 2010 and June 2014 were enrolled. The primary-end point of the registry was major adverse cardiac events (MACE), which is a composite of cardiac death, target lesion revascularization (TLR), target vessel revascularization (TVR), myocardial infarction (MI) and stent thrombosis (ST). Clinical follow-up were scheduled at 30-day and 6-month. RESULTS: The mean age of enrolled patients was 54.6+/-10.3 years. A total of 444 lesions were treated successfully with 457 stents (1.0+/ 0.2 per lesion). The average stent length and diameter was 24.0+/-8.0 mm and 3.0+/-0.33 mm, respectively. Out of total patients, 300 (79.8%) were male. Diabetes, hypertension and chronic totally occluded lesions were found in 95 (25.3%), 102 (27.1%) and 125 (28.2%) patients, respectively, reflecting high-risk patients involvement. The incidence of MACE at 30-day and 6-month was found to be in 4 (1.1 %) and 4 (1.1%) patients, respectively. The TLR and ST was found in 1 (0.3 %) and 1 (0.3 %) patient respectively at 6-month follow-up. CONCLUSIONS: The lower incidence of MACE, TLR and ST clearly delineates safety and efficacy of Supralimus-Core sirolimus-eluting stent in "real-world" patients with complex coronary lesions. PMID- 25907701 TI - Therapy: Facing up to biosimilar agents--the ACR position. PMID- 25907699 TI - Genetic architectures of seropositive and seronegative rheumatic diseases. AB - Rheumatoid arthritis, systemic lupus erythematosus, ankylosing spondylitis and some other rheumatic diseases are genetically complex, with evidence of familial clustering, but not of Mendelian inheritance. These diseases are thought to result from contributions and interactions of multiple genetic and nongenetic risk factors, which have small effects individually. Genome-wide association studies (GWAS) of large collections of data from cases and controls have revealed many genetic factors that contribute to non-Mendelian rheumatic diseases, thus providing insights into associated molecular mechanisms. This Review summarizes methods for the identification of gene variants that influence genetically complex diseases and focuses on what we have learned about the rheumatic diseases for which GWAS have been reported. Our review of the disease-associated loci identified to date reveals greater sharing of risk loci among the groups of seropositive (diseases in which specific autoantibodies are often present) or seronegative diseases than between these two groups. The nature of the shared and discordant loci suggests important similarities and differences among these diseases. PMID- 25907702 TI - Rheumatoid arthritis: IL-6 inhibition in RA--deja vu all over again? PMID- 25907700 TI - The IL-23-IL-17 axis in inflammatory arthritis. AB - The discovery that the IL-23-IL-17 immune pathway is involved in many models of autoimmune disease has changed the concept of the role of T-helper cell subsets in the development of autoimmunity. In addition to TH17 cells, IL-17 is also produced by other T cell subsets and innate immune cells; which of these IL-17 producing cells have a role in tissue inflammation, and the timing, location and nature of their role(s), is incompletely understood. The current view is that innate and adaptive immune cells expressing the IL-23 receptor become pathogenic after exposure to IL-23, but further investigation into the role of IL-23 and IL 17 at different stages in the development and progression of chronic (destructive) inflammatory diseases is needed. Rheumatoid arthritis (RA) and spondyloarthritis (SpA) are the two most common forms of chronic immune-mediated inflammatory arthritis, and the IL-23-IL-17 axis is thought to have a critical role in both. This Review discusses the basic mechanisms of these cytokines in RA and SpA on the basis of findings from disease-specific animal models as well as human ex vivo studies. Promising therapeutic applications to modulate this immune pathway are in development or have already been approved. Blockade of IL-17 and/or TH17-cell activity in combination with anti-TNF therapy might be a successful approach to achieving stable remission or even prevention of chronic immune-mediated inflammatory diseases. PMID- 25907703 TI - Kawasaki disease: insights into pathogenesis and approaches to treatment. AB - This Review summarizes recent advances in understanding of the pathologic processes and pathophysiologic mechanisms leading to coronary arteritis in Kawasaki disease, and describes current approaches to its treatment. Kawasaki disease is the most common cause of acquired heart disease among children in developed countries, in whom the resulting coronary artery abnormalities can cause myocardial ischaemia, infarction and even death. Epidemiologic data strongly suggest an infectious aetiology, although the causative agent has yet to be identified. Genetic factors also increase susceptibility to Kawasaki disease, as indicated by its strikingly high incidence rate in children of Asian ethnicity and by an increased incidence in first-degree family members. The treatment of Kawasaki disease is based on timely administration of intravenous immunoglobulin and aspirin. However, the management of patients who do not respond to this standard therapy remains challenging; although several options are available, comparative data on which to base treatment decisions are scarce. The added value of adjunctive therapy with corticosteroids in patients at particularly high risk of coronary complications has been demonstrated in Japanese populations, but identification of high-risk patients has proven to be difficult in ethnically diverse populations. PMID- 25907705 TI - Axitinib in metastatic renal cell carcinoma. AB - Axitinib is the most recent targeted therapy approved by the US FDA and EMA in the treatment of metastatic renal cell carcinoma (mRCC). It is a second generation, orally available, potent tyrosine kinase inhibitor targeting selectively VEGF receptor (VEGFR)-1, -2 and -3, resulting in inhibition of angiogenesis, metastasis and tumor growth. Based on the results of a randomized pivotal Phase III clinical trial, axitinib stands as one of the two recommended agents for patients with mRCC who progressed after first-line tyrosine kinase inhibitor therapy. Its potent and selective inhibition of VEGFR was the rationale for its development in the second-line setting after failure of prior cytokines or sunitinib. Here we examine the preclinical and clinical data of axitinib for mRCC, and its use in the treatment algorithm. PMID- 25907704 TI - The role of sleep in pain and fibromyalgia. AB - Fibromyalgia is a common cause of chronic widespread pain, characterized by reduced pressure pain thresholds with hyperalgesia and allodynia. In addition to pain, common symptoms include nonrestorative sleep, fatigue, cognitive dysfunction, stiffness and mood disturbances. The latest research indicates that the dominant pathophysiology in fibromyalgia is abnormal pain processing and central sensitization. Neuroimaging studies have shown that patients with fibromyalgia have similar neural activation to healthy age-matched and gender matched individuals; however, they have a lower pressure-pain threshold. Polysomnography data has demonstrated that these patients have reduced short-wave sleep and abnormal alpha-rhythms, suggestive of wakefulness during non-REM (rapid eye movement) sleep. Sleep deprivation in healthy individuals can cause symptoms of fibromyalgia, including myalgia, tenderness and fatigue, suggesting that sleep dysfunction might be not only a consequence of pain, but also pathogenic. Epidemiological studies indicate that poor sleep quality is a risk factor for the development of chronic widespread pain among an otherwise healthy population. Mechanistically, sleep deprivation impairs descending pain-inhibition pathways that are important in controlling and coping with pain. Clinical trials of pharmacological and nonpharmacological therapies have shown that improving sleep quality can reduce pain and fatigue, further supporting the hypothesis that sleep dysfunction is a pathogenic stimulus of fibromyalgia. PMID- 25907706 TI - Extra-CNS metastasis from glioblastoma: a rare clinical entity. AB - Extra-CNS metastasis from glioblastoma (ECMGBM) is an emerging but little known clinical entity. We review pre-clinical and translational publications assessing the ability of GBM to spread locally and outside the CNS. Reported cases demonstrating ECMGBM are reviewed providing a summary of presentations for the entity. Special attention is placed on transmission of GBM through organ transplantation. Finally, predictions are made as to the future significance of ECMGBM, especially in the context of better outcomes in CNS GBM. PMID- 25907707 TI - [Antimicrobial photodynamic therapy in dermatology. Part I: Bacterial and fungal infections]. PMID- 25907710 TI - Design, synthesis, and application of a chiral sulfinamide phosphine catalyst for the enantioselective intramolecular Rauhut-Currier reaction. AB - A novel class of chiral sulfinamide phosphine catalysts (Xiao-Phos) are reported, which can be easily prepared from inexpensive commercially available starting materials. The Xiao-Phos catalysts showed good performance in enantioselective intramolecular Rauhut-Currier reactions, generating alpha-methylene-gamma butyrolactones in high yields with up to 99% ee under mild conditions. Moreover, kinetic resolution and parallel kinetic resolution were also observed with the use of two different substituted racemic precursors. PMID- 25907709 TI - Patients' perspective of barriers and facilitators to taking long-term controller medication for asthma: a novel taxonomy. AB - BACKGROUND: Although asthma morbidity can be prevented through long-term controller medication, most patients with persistent asthma do not take their daily inhaled corticosteroid. The objective of this study was to gather patients' insights into barriers and facilitators to taking long-term daily inhaled corticosteroids as basis for future knowledge translation interventions. METHODS: We conducted a collective qualitative case study. We interviewed 24 adults, adolescents, or parents of children, with asthma who had received a prescription of long-term inhaled corticosteroids in the previous year. The one-hour face-to face interviews revolved around patients' perceptions of asthma, use of asthma medications, current self-management, prior changes in self-management, as well as patient-physician relationship. We sought barriers and facilitators to optimal asthma management. Interviews were transcribed verbatim and transcripts were analyzed using a thematic approach. RESULTS: Patients were aged 2-76 years old and 58% were female. Nine patients were followed by an asthma specialist (pulmonologist or allergist), 13 patients by family doctors or pediatricians, and two patients had no regular follow-up. Barriers and facilitators to long-term daily inhaled corticosteroids were classified into the following loci of responsibility and its corresponding domains: (1) patient (cognition; motivation, attitudes and preferences; practical implementation; and parental support); (2) patient-physician interaction (communication and patient-physician relationship); and (3) health care system (resources and services). Patients recognized that several barriers and facilitators fell within their own responsibility. They also underlined the crucial impact (positive or negative) on their adherence of the quality of patient-physician interaction and health care system accessibility. CONCLUSIONS: We identified a close relationship between reported barriers and facilitators to adherence to long-term daily controller medication for asthma within three loci of responsibility. As such, patients' adherence must be approached as a multi-level phenomenon; moreover, interventions targeting the patient, the patient-physician interaction, and the health care system are recommended. The present study offers a potential taxonomy of barriers and facilitators to adherence to long-term daily inhaled corticosteroids therapy that, once validated, may be used for planning a knowledge translation intervention and may be applicable to other chronic conditions. PMID- 25907711 TI - Mitochondrial genome of the intertidal acorn barnacle Tetraclita serrata Darwin, 1854 (Crustacea: Sessilia): Gene order comparison and phylogenetic consideration within Sessilia. AB - The complete mitochondrial genome of the intertidal barnacle Tetraclita serrata Darwin, 1854 (Crustacea: Maxillopoda: Sessilia) is presented. The genome is a circular molecule of 15,200 bp, which encodes 13 PCGs, 2 ribosomal RNA genes, and 22 transfer RNA genes. All non-coding regions are 591 bp in length, with the longest one speculated as the control region (389 bp), which is located between srRNA and trnK. The overall A+T content of the mitochondrial genome of T. serrata is 65.4%, which is lowest among all the eight mitochondrial genomes reported from sessile barnacles. There are variations of initiation and stop codons in the reported sessile barnacle mitochondrial genomes. Large-scale gene rearrangements are found in these genomes as compared to the pancrustacean ground pattern. ML and Bayesian analyses of all 15 complete mitochondrial genomes available from Maxillopoda lead to identical phylogenies. The phylogenetic tree based on mitochondrial PCGs shows that Argulus americanus (Branchiura) cluster with Armillifer armillatus (Pentastomida), distinct from all ten species from Cirripedia. Within the order Sessilia, Amphibalanus amphitrite (Balanidae) clusters with Striatobalanus amaryllis (Archaeobalanidae), and Nobia grandis (Pyrgomatidae). However, the two Megabalanus (Balanidae) are separated from the above grouping, resulting in non-monophyly of the family Balanidae. Moreover, the two Megabalanus have large-scale rearrangements as compared to the gene order shared by former three species. Therefore, both phylogenetic analysis using PCG sequences and gene order comparison suggest that Balanidae is not a monophyletic group. Given the limited taxa and moderate support values of the internal branches, the non-monophyly of the family Balanidae requires further verification. PMID- 25907712 TI - Effects of combined exercise on gait variability in community-dwelling older adults. AB - Training that focuses on strength, balance, and endurance, the so-called combined exercise, can enhance physical function, including gait, according to a literature review. However, the effects of combined exercise on improving gait variability are limited. The objective of this study is to investigate the effects of 12 weeks of combined exercise comprised of resistance, endurance, and balance training on gait performance in older adults. Twenty-nine community dwelling older adults were recruited and assigned to either the experimental group (n = 17) or the control group (n = 12). The 12-week intervention was a combined exercise program at 1 h per day and 3 days per week. The participants received an assessment for both a 6-min walk and gait during both habitual walking and fast walking conditions at pre-intervention and after 8 and 12 weeks of exercise. The 6-min walk was used to assess gait endurance. GAITRite was used to evaluate gait. An analysis of covariance with the pretest score as the covariate was used to determine the difference in each dependent variable between groups. The level of significance was set as p less than 0.05. Our results showed significant between-group effects in the 6-min walk and velocity, stride time, and stride length in both conditions after 8 weeks of exercise and significant between-group effects in the 6-min walk test and all selected gait parameters in both conditions after 12 weeks of exercise. Our findings demonstrate that a 12 week combined exercise program may positively affect gait endurance and gait performance including gait variability in habitual walking and fast walking conditions among older adults. The current study provides important evidence of short-term combined exercise effects on improvements in gait performance. PMID- 25907715 TI - [Prevalence of dyslipidemia among non-overweight adults and related factors in Zhejiang]. AB - OBJECTIVE: To understand the prevalence of dyslipidemia among non-overweight adults and related factors in Zhejiang province. METHODS: A total of 10 868 non overweight adults (aged >=18 years and BMI<24.0 kg/m2) included in a population based cross-sectional survey on metabolic syndrome in Zhejiang province in 2010 were selected to conduct questionnaire survey, health examination and blood fat detection. RESULTS: The overall prevalence of dyslipidemia in this population was 41.38%. The prevalence was significantly higher in males (43.19%) than in females (39.84%) (chi2 = 12.53, P < 0.001). The prevalence of dyslipidemia significantly decreased in males (trend chi2 = 47.61, P < 0.001) but increased in females (trend chi2 = 3.88, P < 0.05) with age. There was no significant difference in the prevalence between urban area (41.21%) and rural area (41.49%) (chi2 = 0.08, P = 0.774). Multiple logistic regression analysis showed that sex, family history of chronic diseases, smoking, alcohol use, high meat and egg diet, cooking with animal oil, physical activity, central obesity and BMI were factors related to prevalence of dyslipidemia. CONCLUSION: The prevalence of dyslipidemia was high among the non-overweight adults in Zhejiang, and family history, smoking, high fat diet, physical inactivity, central obesity seemed to be the major risk factors. PMID- 25907714 TI - Targeted IgA Fc receptor I (FcalphaRI) therapy in the early intervention and treatment of pristane-induced lupus nephritis in mice. AB - The Fc receptor I for IgA (FcalphaRI) down-regulates humoral immune responses and modulates the risk of autoimmunity. This study aimed to investigate whether FcalphaRI targeting can affect progression of pristine-induced lupus nephritis. In the first experiment (early intervention), four groups of animals were evaluated: untreated FcalphaRI/FcRgamma transgenic (Tg) mice and Tg mice administered control antibody (Ctr Fab), saline and anti-FcalphaRI Fab [macrophage inflammatory protein (MIP)-8a], respectively, three times a week for 29 weeks, after being injected once intraperitoneally with 0.5 ml pristane. In the second experiment, antibody injection started after the onset of nephritis and was carried out for 2 months, with similar groups as described above. MIP-8a improved proteinuria, decreased the amounts of glomerular injury markers, serum interleukin (IL)-6, IL-1 and monocyte chemoattractant protein (MCP)-1, and F4/80 macrophages in the interstitium and glomeruli, in both experiments. When MIP-8a was used as early intervention, a decrease in mouse serum anti-nuclear antibody (ANA) titres and reduced deposition of immunoglobulins in glomeruli were observed. This effect was associated with reduced serum titres of immunoglobulin (Ig)G2a but not IgG1, IgG2b and IgG3. Furthermore, pathological analysis showed lower glomerular activity index and less fibronectin in MIP-8a treated mice. This study suggests that FcalphaRI targeting could halt disease progression and lupus activation by selective inhibition of cytokine production, leucocyte recruitment and renal inflammation. Our findings provide a basis for the use of FcalphaRI as a molecular target for the treatment of lupus. PMID- 25907716 TI - [Birth weight and subsequent risk of type 2 diabetes across two generations in Chinese females]. AB - OBJECTIVE: To evaluate the association between birth weight and subsequent risk of type 2 diabetes (T2DM) across two generations in Chinese females. METHODS: A cross-sectional survey was conducted among 10 324 blood-related females in Shanghai from November 2012 to January 2013. A structured questionnaire was used to collect data about demographic information, birth weight, lifestyle factors and diagnosis of T2DM. Path analysis was performed to estimate the maternal effect of birth weight and diabetes status on their offspring, and mediation analysis was conducted to test whether birth weight mediates the association between maternal and daughters' diabetes status. RESULTS: A positive association was observed between maternal and daughters' birth weight. One kg increase in maternal birth weight was associated with an average of 0.335 (95% CI: 0.307 0.363) kg elevated birth weight in female offspring. Maternal diabetes status was also related with an average of 0.066 (95% CI:0.025-0.107) kg increase in birth weight and tripled risk of subsequent T2DM (OR = 3.173, 95% CI: 1.946-5.174) in female offspring. In all subjects aged >= 20 years, no significant relationship was observed between birth weight and risk of T2DM subsequently after adjusting for age. Offspring's birth weight, as a mediator of maternal and daughters' diabetes status, explained 2.8% of their association. CONCLUSION: Maternal birth weight and diabetes status may influence their female offspring's birth weight and subsequent risk of T2DM. PMID- 25907713 TI - Mutation Update of the CLCN5 Gene Responsible for Dent Disease 1. AB - Dent disease is a rare X-linked tubulopathy characterized by low molecular weight proteinuria, hypercalciuria, nephrocalcinosis and/or nephrolithiasis, progressive renal failure, and variable manifestations of other proximal tubule dysfunctions. It often progresses over a few decades to chronic renal insufficiency, and therefore molecular characterization is important to allow appropriate genetic counseling. Two genetic subtypes have been described to date: Dent disease 1 is caused by mutations of the CLCN5 gene, coding for the chloride/proton exchanger ClC-5; and Dent disease 2 by mutations of the OCRL gene, coding for the inositol polyphosphate 5-phosphatase OCRL-1. Herein, we review previously reported mutations (n = 192) and their associated phenotype in 377 male patients with Dent disease 1 and describe phenotype and novel (n = 42) and recurrent mutations (n = 24) in a large cohort of 117 Dent disease 1 patients belonging to 90 families. The novel missense and in-frame mutations described were mapped onto a three dimensional homology model of the ClC-5 protein. This analysis suggests that these mutations affect the dimerization process, helix stability, or transport. The phenotype of our cohort patients supports and extends the phenotype that has been reported in smaller studies. PMID- 25907717 TI - [Change trend of birth weight of twins in China, 1995-2012]. AB - OBJECTIVE: To understand the change trend of birth weight of twins in China from 1995 to 2012. METHODS: A total of 10 827 twins born between 1995 and 2012 registered in national twin registry system in 8 provinces in China were included in this study. A retrospective study was conducted to analyze the change trend of twin's birth weight. RESULTS: Mean birth weight of twins decreased by 0.01 kg every five years after adjusting sex, ovum type and place of birth (P = 0.041). The birth weight decreased both in superior twin and in inferior twin over time. After 2007, the birth weight of superior twin decreased by 0.008 kg each year, while the birth weight of inferior twin decreased by 0.014 kg each year. Mean relative difference in birth weight and birth weight discordant rate decreased before 2002, then increased from the lowest point 8.16% and 16.20% to highest point 9.99% and 22.40% respectively. CONCLUSION: The birth weight of twins in China decreased between 1995 and 2012, while the birth weight discordant rate increased, suggesting that close attention should be paid to the discordance of twin body weight to reduce the risk of adverse health outcome. PMID- 25907718 TI - [Impact of intervention on tobacco related knowledge, attitudes and practice of smokers]. AB - OBJECTIVE: To evaluate the impact of intervention on tobacco related knowledge, attitudes and practice of smokers. METHODS: An observational study was conducted among the smokers seeking counsel at smoking cessation clinic in our hospital from October 2008 to August 2013. First, a face to face counsel and mental intervention for more than 30 minutes was given to smoker, then 4 interventions through telephone call for 15-20 minutes for each time were conducted 1 week later, 1 month later, 3 months later and 6 months later, respectively. The controls were smokers receiving health examination in our hospital. No interventions were conducted among them. The tobacco related knowledge, attitudes and practice at baseline survey and follow up 1 year later were compared between intervention group and control group. RESULTS: The intervention group included 414 smokers and the control group included 213 smokers. Intentional analysis indicated that the awareness/acceptance rates of 5 items about tobacco related knowledge and attitudes at follow up 1 year later was higher than those at baseline survey in intervention group. The smoking cessation rate was 27.3% in intervention group and 4.7% in control group. Multivariate logistic regression analysis indicated that the smoking cessation rate was positively correlated with intervention, female, highly nicotine dependence and positive change of tobacco related knowledge and attitudes (smoking can cause heart disease, all kinds of tobacco advertisements should be prohibited, smoking waste money and restaurant should be smoking free) with OR (95% CI): 2.85 (2.00-4.07), 3.34 (1.23-9.07), 2.78 (1.64-4.72), 2.30 (1.03-5.15), 5.33 (1.47-19.32), 6.32 (1.56-25.62) and 10.47 (2.25-48.84), respectively. CONCLUSION: The awareness rate of tobacco related harm was high among the smokers seeking counsel at smoking cessation clinic. Systematic smoking cessation intervention can improve smokers' tobacco related knowledge and attitudes and increase smoking cessation rate. PMID- 25907719 TI - [Effect of antiretroviral therapy in reducing deaths among patients co-infected with Mycobacterium tuberculosis and human immunodeficiency virus in Guangxi]. AB - OBJECTIVE: To understand the effect of antiretroviral therapy (ART) in reducing deaths among patients co-infected with Mycobacterium tuberculosis and human immunodeficiency virus (TB/HIV), and provide data-based evidence for improving ART in TB/HIV patients. METHODS: The information about TB patients who were HIV positive confirmed previously or recently in Guangxi were collected, and the TB/HIV patients were confirmed by using the related data from national AIDS prevention and treatment information system. Then a retrospective case control study was conducted to understand the survivals and deaths in the patients receiving ART or receiving no ART by using Kaplan-Meier method and estimate the ART protective rate within 1 year after TB treatment initiation. RESULTS: Among 519 TB/HIV patients, 100 received ART (19.3%); Among 84 TB/HIV patients who died within 1 year after TB treatment, 8 (9.5%) received ART, while 76 (90.5%) received no ART. Compared with the 18.7% mortality rate in non-ART group, TB/HIV patients mortality rate in ART group was only 8.08%, the difference was statistical significant (P < 0.05). Kaplan-Meier survival curve showed that the survival rate in patients receiving ART was higher than that in patients receiving no ART within 1 year after TB treatment, the difference was statistical significant (Log-rank = 4.96, P = 0.02). Compared with patients receiving ART, the OR value was 2.31 times higher than that in patients receiving no ART;ART could protect 56.7% of TB/HIV patients against death during the first year of anti-TB therapy. CONCLUSION: In the first year of anti-TB therapy, the risk of death in TB/HIV patients receiving no ART was much higher than that in TB/HIV patients receiving ART, and the survival time was longer in the patients receiving ART. The ART coverage should be expanded in TB/HIV patients. PMID- 25907720 TI - [Effect of anti-tuberculosis treatment in tuberculosis patients co-infected with human immunodeficiency virus in seven counties,Yunnan]. AB - OBJECTIVE: To understand the potential risk factors influencing the effect of standard anti-tuberculosis (TB) treatment for TB patients co-infected with human immunodeficiency virus (HIV) and provide evidence for the improvement of anti TB therapy. METHODS: A retrospective study was conducted among 445 TB/HIV patients diagnosed and registered in 7 counties in Yunnan province from January 2010 to June 2012. A structured questionnaire was used to collect the patients' demographic characteristics, diagnosis and treatment information after informed consent. Chi-square test was conducted to compare successful rate of anti TB treatment among the patients with different demographic characteristics. Multivariate logistic regression analysis was conducted to identify risk factors influencing the effect of anti TB treatment. Adjusted OR>1 means the risk factor of treatment failure. P value less than 0.05 was set as significant level. RESULTS: After standard anti TB treatment, 397 patients were cured. The five risk factors influencing treatment effect were the existing of 4 suspected TB symptoms when seeking medical care for the first time (adjusted OR = 2.208), TB/HIV patients detected in HIV/AIDS screening (adjusted OR = 5.856), severe case (adjusted OR = 4.607), non-full-course supervision during treatment (in intensive phase adjusted OR = 4.129, full-course management adjusted OR = 8.090) and interruption of therapy (adjusted OR = 21.517). CONCLUSION: Early detection of TB/HIV patients and conducting full course supervision during treatment can improve the effect of anti TB treatment. It is necessary to strengthen the early detection of TB/HIV patients and standarded treatment in Yunnan province. PMID- 25907721 TI - [Analysis on willingness to pay for HIV antibody saliva rapid test and related factors]. AB - OBJECTIVE: To understand the willingness to pay for HIV antibody saliva rapid test and its influential factors among people seeking counsel and HIV test, STD clinic patients, university students, migrant people, female sex workers (FSWs), men who have sex with men (MSM) and injecting drug users (IDUs). METHODS: An anonymous questionnaire survey was conducted among 511 subjects in the 7 groups selected by different sampling methods, and 509 valid questionnaires were collected. RESULTS: The majority of subjects were males (54.8%) and aged 20-29 years (41.5%). Among the subjects, 60.3% had education level of high school or above, 55.4% were unmarried, 37.3% were unemployed, 73.3% had monthly expenditure <2 000 Yuan RMB, 44.2% had received HIV test, 28.3% knew HIV saliva test, 21.0% were willing to receive HIV saliva test, 2.0% had received HIV saliva test, only 1.0% had bought HIV test kit for self-test, and 84.1% were willing to pay for HIV antibody saliva rapid test. Univariate logistic regression analysis indicated that subject group, age, education level, employment status, monthly expenditure level, HIV test experience and willingness to receive HIV saliva test were correlated statistically with willingness to pay for HIV antibody saliva rapid test. Multivariate logistic regression analysis showed that subject group and monthly expenditure level were statistically correlated with willingness to pay for HIV antibody saliva rapid test. CONCLUSION: The willingness to pay for HIV antibody saliva rapid test and acceptable price of HIV antibody saliva rapid test varied in different areas and populations. Different populations may have different willingness to pay for HIV antibody saliva rapid test;the affordability of the test could influence the willingness to pay for the test. PMID- 25907722 TI - [Prevalence rate of ovine hepatic cystic echinococcosis in Quaker Wusu area of Bayinbuluke of Xinjiang, 2014]. AB - OBJECTIVE: To investigate the prevalence rate of ovine hepatic cystic echinococcosis (HCE) in sheep in Quaker Wusu area of Bayinbuluke of Xinjiang by ultrasonography and provide evidence for the prevention and control of HCE in sheep. METHODS: The prevalence screening of HCE in sheep was conducted based on ultrasound images in this area in July 2014. The sheep were divided into different groups by dental age to calculate the age specific prevalence rate of HCE and analyzed the correlation between the dental age and the prevalence rate. RESULTS: The total prevalence rate of HCE in sheep in this area was 36.9%. The prevalence rates of none-calcified HCE and calcified HCE were 7.3% and 29.6%, respectively. The prevalence rates of none-calcified HCE in different age groups were 1.2% (1-2 years old), 1.4% (2-3 years old), 14.0% (3-4 years old), 10.0% (4 5 years old), 15.6% (5-6 years old) and 4.2% (>6 years old) respectively. The prevalence rate of calcified HCE in different age groups were 9.9% (1-2 years old), 16.2% (2-3 years old), 31.6% (3-4 years old), 47.8% (4-5 years old), 42.2% (5-6 years old) and 41.7% (>6 years old) respectively. The prevalence rate of HCE in 1-2 years old group was lower than those in other groups, the prevalence rate of HCE in age groups >3 years increased significantly. There was positive correlation between the prevalence rate of HCE and dental age (r = 0.372, R(2) = 0.107, F = 44.176, P = 0.000). CONCLUSION: HCE is highly endemic in Quaker Wusu area. The prevalence rate of HCE is low in sheep with young age and high in sheep aged 3-4 years. It is necessary to conduct early prevention of HCE in sheep in this area. PMID- 25907723 TI - [Factors related to household rodent abundance in rodent-borne disease foci in western Yunnan]. AB - OBJECTIVE: To analyze the factors related to the household abundance of rodents in rodent-borne disease foci in the western part of Yunnan province. METHODS: From July 2011 to October 2012, 800 households (20 households in 1 village) were randomly selected in 40 natural villages of 10 counties in western Yunnan where rodent borne disease was endemic to conduct a study on relationship between rodent abundance and environmental factors. Five cages were placed in each household for 3 consecutive nights to capture rodents. The rodent species were identified based on their morphological characteristics. The data on potential factors related to rodent abundance were collected through questionnaires and field observation. A dataset was established by using EpiData software and the analysis was performed with hurdle regression model under R software. RESULTS: A total of 421 rodents were captured in 800 households, belonging to 9 species, 6 genera, 2 families, 2 orders. Rattus tanezumi was the predominant species (66.03%). The final hurdle regression model showed that the probability of capturing rodents in the households where family member had high education level and the garbage was placed outside declined by 50%-68% ;The probability of capturing rodents in the households of Dai and Yi ethnic groups increased by 2.16 2.87 times;The probability of capturing rodents in the households where rodents were observed or vegetables grown near houses increased by 1.54-1.59 times;In the households where many rodents were believed to exist, the probability of capturing rodents and the number of rodents captured increased by 1.59 and 1.84 times respectively. The number of rodents captured in the houses with cement or tile floor increased by 3.62 times. CONCLUSION: The household abundance of rodents in the area in western Yunnan, where the rodent-borne disease survey was conducted, seemed to be closely related to the social economy status, human intervention and ecological environment. To control the abundance of rodents effectively, it is necessary to take these factors into consideration. PMID- 25907724 TI - [Analysis on morbidity and mortality of viral hepatitis in China, 2004-2013]. AB - OBJECTIVE: To understand the incidence and death patterns of viral hepatitis in China and provide evidence for the prevention and control of viral hepatitis. METHODS: The analysis was conducted on the incidence and death data of viral hepatitis published by National Health and Family Planning Commission during 2004 2013. RESULTS: The incidences of viral hepatitis in Guizhou,Yunnan, Tibet, Gansu, Qinghai,Ningxia and Xinjiang provinces (autonomous region) were high. The major forms were hepatitis B (80.63/100 000) and hepatitis C (9.68/100 000), accounting for 80.90% and 9.25% of the total reported viral hepatitis cases respectively. The incidences of hepatitis A and unidentified hepatitis decreased and the incidence of hepatitis B, C and E increased during this period. During the 10 years, 10 008 deaths caused by viral hepatitis were reported (1 001 deaths per year). The reported deaths caused by hepatitis A, hepatitis E and unidentified hepatitis decreased during this period. The reported deaths caused by hepatitis B were in a downward trend, but the constituent in total cases remained high. The reported deaths caused by hepatitis C were in an upward trend. CONCLUSION: During 2004-2013, the overall incidence of viral hepatitis showed no downward trend in China. The incidence of hepatitis B remained high, and the incidence of hepatitis C showed an obvious upward trend. The overall death rate and case fatality rate of viral hepatitis showed a downward trend, but hepatitis B remained the main cause of viral hepatitis related death, and the death caused by hepatitis C was in increase. Hepatitis B and hepatitis C are the major targets in the prevention and treatment of viral hepatitis in China, and the 7 western provinces (autonomous region) with high incidences are the key regions of the prevention and control. PMID- 25907725 TI - [Analysis on genotype distribution and mutation of major hydroponic region of hepatitis B virus in Liaoning]. AB - OBJECTIVE: To understand the genotype and the mutation of amino acid (aa) in the major hydrophilic region (MHR) of hepatitis B virus (HBV) among the hepatitis B cases under surveillance in Liaoning province. METHODS: The serum samples were collected from hepatitis B cases under surveillance in Liaoning. The complete S gene of HBV were amplified and sequenced. The aa sequences were analyzed with bioinformatics software. RESULTS: A total of 81 sequences of S gene of HBV were ontained, including 7 sequences of genotype B (8.64%), 70 sequences of genotype C (86.42%) and 4 sequences of genotype D (4.94%). The mutation rate of aa of MHR of S gene was 4.87%. The mutation rate of T126I was highest (8.64%). The overall prevalence of mutant strain of MHR was 49.38% (40/81), and it was 42.86% for genotype B (3/7), 47.14% for genotype C (33/70) and 100% for genotype D (4/4). Statistical analysis revealed that there was no age, sex, genotypes and anti-HBc IgM (+/-) specific significant differences in aa mutant strains prevalence, while the difference between ALT abnormal group (ALT >= 43 IU/L) and ALT normal group (ALT<43 IU/L) was significant (P < 0.05). CONCLUSION: Among the hepatitis B cases under surveillance in Liaoning, HBV genotype C predominant, followed by genotype B and genotype D. The mutation of aa in MHR of HBV detected in this study was consistent with previous research results. It is necessary to strengthen the surveillance for HBV mutation to provide accurate information for the development of hepatitis B prevention and control measures. PMID- 25907726 TI - [Change trend of HIV/AIDS related risk factors and influencing factors among men who have sex with men in Yunnan, 2010-2013]. AB - OBJECTIVE: To understand the change trend of the awareness rate of HIV/AIDS related knowledge, risk behaviors among men who have sex with men (MSM) in Yunnan and the factors influencing their condom use, and evaluate the effect of comprehensive intervention. METHODS: The data about the MSM's demographic information, HIV/AIDS related knowledge awareness, and sex behavior, condom use, drug use and intervention receiving were obtained from AIDS sentinel surveillance among MSM in Yunnan province during 2010-2013 to conduct change trend and influencing factor analysis. RESULTS: A total of 9 073 MSM were surveyed. The awareness rate of the HIV/AIDS related knowledge, homosexual behavior and condom use rate increased year by year (P < 0.01). The condom use rate was lower in heterosexual behavior, and the drug use rate and sexually transmitted disease prevalence declined with year (P < 0.01). Multivariate logistic regression analysis indicated that cohabiting, low awareness of HIV/AIDS related knowledge, being from other provinces, local residence for <1 year, low education level, receiving no intervention, frequent anal sex and receiving no HIV/AIDS detection were the risk factors influencing persistent condom use among MSM. CONCLUSION: The effect of HIV/AIDS comprehensive intervention was observed after 4 years implantation, but most of the index were at low level. More attention should be paid to the intervention among MSM with cohabiting habit, low education level, frequent anal sex, and heterosexual sex. It is necessary to expand intervention coverage, strengthen HIV test and promote condom use among MSM. PMID- 25907727 TI - [HIV infection status among men who have sex with men in Henan, 2008-2013]. AB - OBJECTIVE: To understand the infection status of HIV among men who have sex with men (MSM) in Henan province and provide scientific evidence for the development of AIDS prevention and control measures. METHODS: The analysis was conducted on the data about incidence of HIV infection and related risk factors among MSM in Henan from 2008 to 2013, which were obtained from AIDS reporting information system and AIDS survey in MSM. RESULTS: The constituent of HIV infection in MSM increased from 1.3% in 2008 to 17.1% in 2013. The HIV infection rate in MSM increased from 4.69% in 2008 to 8.33% in 2013 (trend chi2 = 39.24, P < 0.001). Univariate analysis indicated that the risk factors related with HIV infection included age (chi2 = 21.03, P < 0.001), education level (chi2 = 31.66, P < 0.001), occupation (chi2 = 14.59, P = 0.01), condom use in the last anal sex (chi2 = 134.97, P < 0.001), condom use in anal sex during past 6 months (chi2 = 97.15, P < 0.001), STI history (chi2 = 67.21, P < 0.001) and syphilis prevalence (chi2 = 163.60, P < 0.001). Multivariate analysis indicated that HIV infection related risk factors included age, STD history, syphilis prevalence and poor awareness of AIDS related knowledge. CONCLUSION: The incidence of HIV infection among MSM in Henan increased rapidly, and homosexual transmission has become the major route of HIV infection. HIV infection related risk behavior is prevalent among MSM, therefore, it is necessary to take effective measures to prevent and control HIV/AIDS in MSM. PMID- 25907728 TI - [Recent HIV infection among men who have sex with men in Hubei, 2010-2013]. AB - OBJECTIVE: To understand the HIV infection status among MSM in Hubei province and provide scientific evidence for the development of intervention strategy. METHODS: A total of 11 438 samples were collected from MSM in sentinel surveillance during 2010-2013 to detect HIV-1 antibody. BED-CEIA was used to identify the recent HIV infection, and the recent HIV infection rate among the MSM was estimated. The age, group and area specific recent infection rate and condom use rate were analyzed. RESULTS: The annual HIV positive rates among MSM were 3.34% , 3.74% , 2.96% and 3.15% respectively and the annual recent infection rates were 2.31% , 1.91% , 1.53% and 1.71% respectively during 2010-2013. The HIV positive rate in age group <= 30 years was lower than that in age group >30 years, but the recent HIV incidence rate was higher in age group <= 30 years than in age group >30 years. The detection rate of recent HIV infection varied with sample source, the highest detection rate was among the samples form work group/CDC and public bathroom (3.54% and 3.49%, respectively). The recent HIV i nfection rate in Wuhan was highest (5.73%). The proportion of MSM using condoms in each homosexual behavior during past six months was 38.91% . Multiple logistic regression analysis indicated that the factors related to recent HIV infection included sample source (OR = 0.344-0.713), area (OR = 3.581-9.577) and condom usage (OR = 6.686). CONCLUSION: The HIV-1 infection rate in MSM was at a high level in Hubei, especially in some areas. The condom use rate was low, it is necessary to strengthen the prevention and control of HIV infection in MSM. PMID- 25907729 TI - [Differences in anthropometric measurements between Mongolia boys and Han boys in China]. AB - OBJECTIVE: To analyze the difference in anthropometric measurements between Mongolia boys and Han boys in China and understand the characteristics of children's physical development in two ethnic groups. METHODS: The data on anthropometric measurements of Mongolia boys and Han boys in Inner Mongolia were obtained from the National Survey on Student's Constitution and Health (CNSSCH) conducted in 2010, the data included body height, sitting height, chest circumference, body weight, triceps skinfold thickness (TST), scapular skinfold thickness (SST), abdominal skinfold thickness (AST), living area (urban area or rural area), and having spermatorrhea or not. The boys in two ethnic groups were divided into two groups according to the data about spermatorrhea, the living area specific difference in the anthropometric measurements between the boys in two ethnic groups were analyzed. RESULTS: The proportions of Han boys having spermatorrhea at 11, 12, 14 years old (0, 3.2% , 62.5%) were higher than those of Mongolia boys (8.1%, 15.3%, 76.0%, all P < 0.05). In the boys who had had no spermatorrhea (11-14 years old), the body height of Han boys was 1.4 cm higher than that of Mongolia boys (P < 0.01), however, there were no significant differences in sitting height, chest circumference, body weight, TST, SST,AST and BMI between Han boys and Mongolia boys (all P > 0.05). In the boys who had had spermatorrhea (12-17 years old), the body height, sitting height, chest circumference, body weight, SST, BMI of Han boys were 1.8 cm,0.6 cm, 3.1 cm, 3.1 kg, 1.7 mm and 0.7 kg/m(2) higher than those of Mongolia boys, respectively (all P < 0.05), however, the differences in TST and AST between Han boys and Mongolia boys were not statistical significant (all P > 0.05). CONCLUSION: The body height of Han boys might be higher than that of Mongolia boys, and in those who had had spermatorrhea, the sitting height, chest circumference, body weight, SST and BMI of Han boys might be higher than those of Mongolia boys, the differences in anthropometric measurements between Mongolia boys and Han boys who had had spermatorrhea or not might be different. PMID- 25907730 TI - [Outbreak of tuberculosis in a high school in Zhejiang, China]. AB - OBJECTIVE: To identify precipitating factors of a tuberculosis (TB) outbreak in a school and discuss the importance of index case detection on outbreak monitoring, follow up and related control measures. METHODS: A case survey of the index patient was conducted to evaluate the illness severity and infectious duration of the case. The initial response to this case was surveyed to understand the factors leading to the outbreak. RESULTS: A total of 25 TB cases were detected in the outbreak, including 14 cases in one class. The risk of catching TB among the classmates of the index case was 10.74 times higher than that among students in other classes (chi2 = 42.31, P < 0.001). Although the index case had typical TB symptom of cough and expectoration, TB was not diagnosed until pulmonary cavity was detected by chest radiograph one month later. Among 64 close contacts, 56 (87.5%) completed TB screening, 52 (92.9%) were purified protein derivative positive. No TB cases were detected. CONCLUSION: The factors leading to the outbreak included delayed diagnoses of the index case, no chemoprophylaxis taken by the close contacts;poor surveillance and follow-up for close contacts. PMID- 25907731 TI - [Comparison of clinical outcomes of vitrified-thawed embryo transfer and fresh embryos transfer]. AB - OBJECTIVE: To understand the clinical outcomes of frozen embryo transfer and fresh embryo transfer. METHODS: A retrospective analysis was conducted on the clinical data of 870 cases receiving embryo transfer at the Reproductive Medical Center of Sun Yat-Sen Memorial Hospital from January 2013 to March 2014, including 577 cases of in vitro fertilization and fresh embryo transfer, 118 cases of intracytoplasmic sperm injection and fresh embryo transfer and 175 cases of frozen thawed embryo transfer, to compare the clinical characteristics and outcomes between fresh embryo transfer group and frozen embryo transfer group (the patients who had received unsuccessful fresh embryo transfer). The frozen embryo transfer group was divided into pregnant subgroup and non pregnant subgroup to further comparison. Binary logistic regression analyses was performed to identify the influencing factors of pregnancy. RESULTS: The implantation rate and clinical pregnancy rate were significantly lower in frozen embryo transfer group than in fresh embryo transfer group (26.27% vs. 31.98%, P = 0.01 and 47.43% vs. 65.18%, P < 0.001). The differences in abortion rate, biochemical pregnancy rate and fetal birth weight had no statistical significance between the two groups (P = 0.63, P = 0.17 and P = 0.33). The difference in age between pregnant subgroup and non pregnant subgroup was statistical significant (30.69 +/- 3.37 years vs. 32.00 +/- 5.09 years, P = 0.03), but no significant differences were found in BMI, duration of infertility and basic endocrine between the two subgroups. Binary logistic regression analysis showed that receiving frozen embryo transfer or not (P < 0.001), wife's age (P < 0.001), BMI (P = 0.011) and number of top quality embryos (P < 0.001) were influencing factors of pregnancy. CONCLUSION: Lower implantation rate and clinical pregnancy rate was observed in the patients in frozen embryo transfer group, who had received unsuccessful fresh embryo transfer, but no increase of abortion rate, influence on fetal birth weight and adverse pregnancy outcome were observed. PMID- 25907732 TI - [Reinfection of Schistosoma japonicum and related risk factors in Chinese: Meta analysis]. AB - OBJECTIVE: To study the dynamics of the reinfection of Schistosoma japonicum and related risk factors among the people in schistosomiasis endemic areas in China. METHODS: Literature retrieval was conducted by using databases of PubMed, CNKI,VIP and Wanfang to collected all the data about the human re-infection of Schistosoma japonicum and related risk factors in the endemic areas in China. And a Mata-analysis was conducted on the literatures met the inclusion standards. RESULTS: Eighteen studies involving 12 604 people for infection survey and 3 128 people for re-infection survey were included in the analysis. The overall infection rate was 20.8%, and the overall re-infection rate was 21.0% . The difference had no statistical significance (Z = 1.12, P = 0.26). The re-infection related factors included baseline infection intensity (OR = 3.58, 95% CI: 1.56 8.22); the index of contaminated water OR = 2.37, 95% CI: 1.08-5.22); distance from house to river-side (OR = 1.72, 95% CI: 0.41-7.30) and age (OR = 0.48, 95% CI: 0.19-1.23). CONCLUSION: The baseline infection intensity, the index of contaminated water and distance from house to river-side were the risk factors related to the re-infection of Schistosoma japonicum and age was a protective factor. PMID- 25907733 TI - [Statistical methods for comparing survival rates at a fixed time point]. AB - Comparison of survival curves between two groups is an important part of disease prognosis study. Log-rank test is commonly used, but when the two curves' later intersecting opening is too large, the proportion of assumptions is not established, thus the Log-rank test is ineffective. We introduces five statistical tests to compare two survival curves at a fixed time points: classic method, logarithmic transformation, cloglog transformation, arcsine transformation and logit transformation. Through the study we found that if the overall survival curves are difficult to compare between groups tested with Log rank test method or Two-stage test method, the fixed time point test can effectively determine whether there was significant difference in survival rate at a fixed time point. Among the five fixed time point tests, cloglog transformation could give more precise result. PMID- 25907734 TI - [Research progress on estimation of influenza associated mortality burden based on sample data]. PMID- 25907735 TI - Risk factors for ischemic stroke and its subtypes in Chinese vs. Caucasians: Systematic review and meta-analysis. AB - BACKGROUND: Chinese populations are reported to have a different distribution of ischemic stroke subtypes compared with Caucasians. AIMS: To understand this better, we aimed to evaluate the differences in prevalence of risk factors in ischemic stroke and their distributions among ischemic stroke subtypes in Chinese vs. Caucasians. SUMMARY OR REVIEW: We systematically sought studies conducted since 1990 with data on frequency of risk factors among ischemic stroke subtypes in Chinese or Caucasians. For each risk factor, we calculated study-specific and random effects pooled estimates in Chinese and Caucasians separately for: prevalence among ischemic stroke; odds ratios, comparing prevalence for each ischemic stroke subtype vs. all others. We included seven studies among 16,199 Chinese, and eleven among 16,189 Caucasian ischemic stroke patients. Risk factors studied were hypertension, diabetes, atrial fibrillation, ischemic heart disease, hypercholesterolemia, smoking and alcohol. Chinese ischemic stroke patients had younger onset of stroke than Caucasians, similar prevalence of hypertension, diabetes, smoking and alcohol, and significantly lower prevalence of atrial fibrillation, ischemic heart disease and hypercholesterolemia. Risk factor associations with ischemic stroke subtypes were mostly similar among Chinese and Caucasian ischemic stroke patients. Compared with all other ischemic subtypes, diabetes was more common in large artery stroke, atrial fibrillation and ischemic heart disease in cardioembolic stroke, and hypertension and diabetes in lacunar stroke. CONCLUSION: Our study showed a lower prevalence of atrial fibrillation, ischemic heart disease and hypercholesterolemia in Chinese, and mostly similar risk factor associations in Chinese and Caucasian ischemic stroke patients. Further analyses of individual patient data to allow adjustment for confounders are needed to confirm and extend these findings. PMID- 25907737 TI - Influences of health literacy, judgment skills, and empowerment on asthma self management practices. AB - Asthma self-management has been recognized as an essential factor for the improvement of asthma outcomes and patients' quality of life (WHO, 2013). Likewise, empowerment and health literacy have been noted as important elements for the management of chronic diseases. OBJECTIVE: To study the influence of health literacy and empowerment on asthma self-management. METHODS: This cross sectional study used a self-reported questionnaire assessing health literacy, judgment skills, empowerment, and asthma self-management; 236 patients were recruited from medical offices in Switzerland and Italy. RESULTS: Judgment skills (B=2.28, p<0.001) and empowerment (B=0.19, p<0.05) have a significant and positive influence on several asthma self-management practices such as use of medicines, timely medical consultation, and asthma triggers control whereas health literacy (B=-0.15, p<0.175) appeared to have a negative effect on self management practices. However, this was not significant. CONCLUSIONS: These findings suggest that empowered patients with adequate judgment skills carry out key self-management tasks more appropriately, which in turn will potentially result in better asthma control. PRACTICE IMPLICATIONS: This study recommends that both empowerment and judgment skills should be addressed in patient education as they serve as essential motivators to engage patients in these behaviors. PMID- 25907736 TI - Recurrent gain of function mutation in calcium channel CACNA1H causes early-onset hypertension with primary aldosteronism. AB - Many Mendelian traits are likely unrecognized owing to absence of traditional segregation patterns in families due to causation by de novo mutations, incomplete penetrance, and/or variable expressivity. Genome-level sequencing can overcome these complications. Extreme childhood phenotypes are promising candidates for new Mendelian traits. One example is early onset hypertension, a rare form of a global cause of morbidity and mortality. We performed exome sequencing of 40 unrelated subjects with hypertension due to primary aldosteronism by age 10. Five subjects (12.5%) shared the identical, previously unidentified, heterozygous CACNA1H(M1549V) mutation. Two mutations were demonstrated to be de novo events, and all mutations occurred independently. CACNA1H encodes a voltage-gated calcium channel (CaV3.2) expressed in adrenal glomerulosa. CACNA1H(M1549V) showed drastically impaired channel inactivation and activation at more hyperpolarized potentials, producing increased intracellular Ca(2+), the signal for aldosterone production. This mutation explains disease pathogenesis and provides new insight into mechanisms mediating aldosterone production and hypertension. PMID- 25907738 TI - Expanding research on decentering as measured by the Portuguese version of the experiences questionnaire. AB - For long decentering has been regarded as a crucial process for well-being and health. Thus, reliable measures are needed to assess decentering. This study aimed at examining the psychometric characteristics of the Portuguese version of the Experiences Questionnaire (EQ), and to contribute to gather new evidence on the role of this particular measure of decentering on the well-known relationship between rumination and depressive symptoms. The EQ factorial structure was assessed through a Confirmatory Factor Analysis (CFA) conducted in 709 participants (66% women; 34% men). CFA' results supported a 10-item solution (chi2/df = 2.62; CFI = .96; TLI = .95; RMSEA = .05, CI = .04 to .06) with high internal consistency (alpha = .81), test-retest reliability (r = .86; p < .010) and construct validity. Two path analyses were further conducted in a subsample exploring the indirect effect of rumination on depression through the mechanism of decentering as assessed by the specific measure of EQ, and by the non-specific measure of decentering TMS. Decentering, only when measured by EQ, significantly emerged as a mechanism through which the relationship between rumination and depressive symptoms also operates (R 2 = .22). Findings highlight the importance of using EQ as a specific measure of this transdiagnostic process in research and clinical settings. PMID- 25907739 TI - Biology and immunology of cancer stem(-like) cells in head and neck cancer. AB - Immunological approaches against tumors including head and neck squamous cell carcinoma (HNSCC) have been investigated for about 50 years. Such immunotherapeutic treatments are still not sufficiently effective for therapy of HNSCC. Despite the existence of immunosurveillance tumor cells may escape from the host immune system by a variety of mechanisms. Recent findings have indicated that cancer stem(-like) cells (CSCs) in HNSCC have the ability to reconstitute the heterogeneity of the bulk tumor and contribute to immunosuppression and resistance to current therapies. With regard to the CSC model, future immunotherapy possibly in combination with other modes of treatment should target this subpopulation specifically to reduce local recurrence and metastasis. In this review, we will summarize recent research findings on immunological features of CSCs and the potential of immune targeting of CSCs. PMID- 25907740 TI - Remote ischemic post-conditioning improves neurological function by AQP4 down regulation in astrocytes. AB - Cerebral ischemia is a primary cause of human death and long-term disability. Previous studies have suggested that remote ischemic post-conditioning (RIPC) is a potential useful tool for cerebral ischemic treatment. However, the protective mechanism of RIPC is not very clear. This study verified the hypothesis that, in remote post-conditioning of cerebral ischemic rats, down-regulation of aquaporin 4 (AQP4), which is an important player for water hemostasis in astrocytes, could attenuate cerebral damage after transient middle cerebral artery occlusion (MCAO). In this study, RIPC model was established after MCAO. Each hind limb of rat was clamped by small rubber tubes for 10 min, and then the tubes were opened for 10 min. The clamping and opening were operated for a total of three cycles to block the hind limbs blood flow. The results showed that, RIPC could significantly improve neurological function, decrease the percentage of the infarct volume and edema, and elevate the integrity of blood-brain barrier (BBB). In addition, the numbers of AQP4 and glial fibrillary acidic protein (GFAP) positive cells were significantly lower in the RIPC group. Moreover, we found that AQP4 expression decreased in response to ischemia/reperfusion in the RIPC group. Our findings indicated that RIPC could attenuate focal cerebral ischemia/reperfusion injury, and the neuroprotective mechanism was related with the down-regulation of AQP4 in astrocytes. PMID- 25907741 TI - Pharmacological characterization of the nociceptin/orphanin FQ receptor on ethanol-mediated motivational effects in infant and adolescent rats. AB - Activation of nociceptin/orphanin FQ (NOP) receptors attenuates ethanol drinking and prevents relapse in adult rodents. In younger rodents (i.e., infant rats), activation of NOP receptors blocks ethanol-induced locomotor activation but does not attenuate ethanol intake. The aim of the present study was to extend the analysis of NOP modulation of ethanol's effects during early ontogeny. Aversive and anxiolytic effects of ethanol were measured in infant and adolescent rats via conditioned taste aversion and the light-dark box test; whereas ethanol-induced locomotor activity and ethanol intake was measured in adolescents only. Before these tests, infant rats were treated with the natural ligand of NOP receptors, nociceptin (0.0, 0.5 or 1.0 MUg) and adolescent rats were treated with the specific agonist Ro 64-6198 (0.0, 0.1 or 0.3 mg/kg). The activation of NOP receptors attenuated ethanol-induced anxiolysis in adolescents only, and had no effect on ethanol's aversive effects. Administration of Ro 64-6198 blocked ethanol-induced locomotor activation but did not modify ethanol intake patterns. The attenuation of ethanol stimulating and anxiolytic effect by activation of NOP receptors indicates a modulatory role of this receptor on ethanol effects, which is expressed early in ontogeny. PMID- 25907742 TI - Inflammation and increased IDO in hippocampus contribute to depression-like behavior induced by estrogen deficiency. AB - Estrogen deficiency is involved in the development of depression. However, the mechanism underlying estrogen modulates depression-like behavior remains largely unknown. Inflammation and indoleamine-2,3-dioxygenase (IDO) have been shown to play pivotal roles in various depression models. The objective of the present study was to investigate whether estrogen deficiency-induced depression-like behavior is associated with inflammation and IDO activation in brain. The results showed that ovariectomy resulted in depression-like behavior in female rats and caused a decrease in 5-HT content and an increase in levels of IDO, IFN-gamma, IL 6, toll like receptor (TLR)-4 and phosphorylated NF-kappaB (p65 subunit) in hippocampus but not in prefrontal cortex (PFC). 17beta-Estradiol (E2) treatment ameliorated depression-like behavior and restored above neurochemical alternations in hippocampus in ovariectomized rats. Partial correlation analysis showed that the levels of phosphorylated p65, IFN-gamma and IL-6 in hippocampus correlated to serum E2 level. Our study suggests that estrogen inhibits inflammation and activates of IDO and maintains 5-HT level in hippocampus, thereby ameliorating depression-like behavior. PMID- 25907743 TI - Reduced prefrontal dopaminergic activity in valproic acid-treated mouse autism model. AB - Previous studies suggest that dysfunction of neurotransmitter systems is associated with the pathology of autism in humans and the disease model rodents, but the precise mechanism is not known. Rodent offspring exposed prenatally to VPA shows autism-related behavioral abnormalities. The present study examined the effect of prenatal VPA exposure on brain monoamine neurotransmitter systems in male and female mice. The prenatal VPA exposure did not affect the levels of dopamine (DA), noradrenaline (NA), serotonin (5-HT) and their metabolites in the prefrontal cortex and striatum, while it significantly reduced methamphetamine (METH) (1.0 mg/kg)-induced hyperlocomotion in male offspring. In vivo microdialysis study demonstrated that prenatal VPA exposure attenuated METH induced increases in extracellular DA levels in the prefrontal cortex, while it did not affect those in extracellular NA and 5-HT levels. Prenatal VPA exposure also decreased METH-induced c-Fos expression in the prefrontal cortex and the mRNA levels of DA D1 and D2 receptors in the prefrontal cortex. These effects of VPA were not observed in the striatum. In contrast to male offspring, prenatal VPA exposure did not affect METH-induced increases in locomotor activity and prefrontal DA levels and the D1 and D2 receptor mRNA levels in the prefrontal cortex in female offspring. These findings suggest that prenatal VPA exposure causes hypofunction of prefrontal DA system in a sex-dependent way. PMID- 25907745 TI - Sensation-seeking: Dopaminergic modulation and risk for psychopathology. AB - Sensation-seeking (SS) is a personality trait that refers to individual differences in motivation for intense and unusual sensory experiences. It describes a facet of human behaviour that has direct relevance for several psychopathologies associated with high social cost. Here, we first review ways of measuring SS behaviour in both humans and animals. We then present convergent evidence that implicates dopaminergic neurotransmission (particularly via D2-type receptors) in individual differences in SS trait. Both high tonic dopamine levels and hyper-reactive midbrain dopaminergic responses to signals of forthcoming reward are evident in higher sensations-seekers. We propose that differences in the efficacy of striatal dopaminergic transmission may result in differential expression of approach-avoidance reactions to same intensity stimuli. This constitutes a quantitative trait of intensity preference for sensory stimulation that may underlie core features of the SS personality. We review the evidence that high trait SS is a vulnerability factor for psychopathologies related to changes in brain dopamine function, in particular substance and gambling addictions. Conversely, we consider the possibility that increased tolerance of high intensity stimulation may represent a protective mechanism against the development of trauma-related psychopathologies (e.g. post-traumatic stress disorder) in high sensation-seeking individuals. Further understanding of the brain mechanisms underlying SS trait might not only to shed light on the aetiology of these disorders, but also aid in developing individualised therapies and prevention strategies for psychopathologies. PMID- 25907744 TI - Age-related differences in conditioned pain modulation of sensitizing and desensitizing trends during response dependent stimulation. AB - The current study evaluated age differences in conditioned pain modulation using a test stimulus that provided the opportunity to evaluate changes in heat pain sensitivity, sensitization, and desensitization within the same paradigm. During this psychophysical test, pain intensity clamping uses REsponse Dependent STIMulation (REDSTIM) methodology to automatically adjust stimulus intensity to maintain a desired pain rating set-point. Specifically, stimulus intensity increases until a pre-defined pain rating (the setpoint) is exceeded, and then decreases until pain ratings fall below the setpoint, with continued increases and decreases dictated by ratings. The subjects are blinded in terms of the setpoint and stimulus intensities. Younger and older subjects completed two test sessions of two REDSTIM trials, with presentation of conditioning cold stimulation between the trials of one session but not the other. The results indicated that conditioning cold stimulation similarly decreased the overall sensitivity of younger and older subjects, as measured by the average temperature that maintained a setpoint rating of 20 (on a scale of 0-100). The conditioning stimulus also significantly enhanced sensitization following ascending stimulus progressions and desensitization following descending stimulus progressions in older subjects relative to younger subjects. Thus, older subjects experienced greater swings in sensitivity in response to varying levels of painful stimulation. These results are discussed in terms of control over pain intensity by descending central modulatory systems. These findings potentially shed new light on the central control over descending inhibition and facilitation of pain. PMID- 25907746 TI - Lesions of the hippocampus or dorsolateral striatum disrupt distinct aspects of spatial navigation strategies based on proximal and distal information in a cued variant of the Morris water task. AB - The hippocampus and dorsolateral striatum are critically involved in spatial navigation based on extra-maze and intra-maze cues, respectively. Previous reports from our laboratory suggest that behavior in the Morris water task may be guided by both cue types, and rats appear to switch from extra-pool to intra-pool cues to guide navigation in a sequential manner within a given trial. In two experiments, rats with hippocampal or dorsolateral striatal lesions were trained and tested in water task paradigms that involved translation and removal of a cued platform within the pool and translations of the pool itself with respect to the extra-pool cue reference frame. In the first experiment, moment-to-moment analyses of swim behavior indicate that hippocampal lesions disrupt initial trajectories based on extra-pool cues at the beginning of the trial, while dorsolateral striatal lesions disrupt subsequent swim trajectories based on the location of the cued platform at the end of the trial. In the second experiment, lesions of the hippocampus, but not the dorsolateral striatum, impaired directional responding in situations where the pool was shifted within the extra pool cue array. These results are important for understanding the cooperative interactions between the hippocampus and dorsolateral striatum in spatial learning and memory and establish that these brain areas are continuously involved in goal-directed spatial navigation. These results also highlight the importance of the hippocampus in directional responding in addition to place navigation. PMID- 25907748 TI - Acute caffeine administration affects zebrafish response to a robotic stimulus. AB - Zebrafish has been recently proposed as a valid animal model to investigate the fundamental mechanisms regulating emotional behavior and evaluate the modulatory effects exerted by psychoactive compounds. In this study, we propose a novel methodological framework based on robotics and information theory to investigate the behavioral response of zebrafish exposed to acute caffeine treatment. In a binary preference test, we studied the response of caffeine-treated zebrafish to a replica of a shoal of conspecifics moving in the tank. A purely data-driven information theoretic approach was used to infer the influence of the replica on zebrafish behavior as a function of caffeine concentration. Our results demonstrate that acute caffeine administration modulates both the average speed and the interaction with the replica. Specifically, zebrafish exposed to elevated doses of caffeine show reduced locomotion and increased sensitivity to the motion of the replica. The methodology developed in this study may complement traditional experimental paradigms developed in the field of behavioral pharmacology. PMID- 25907749 TI - The degeneration of dopaminergic synapses in Parkinson's disease: A selective animal model. AB - Available evidence increasingly suggests that the degeneration of dopamine neurons in Parkinson's disease starts in the striatal axons and synaptic terminals. A selective procedure is described here to study the mechanisms involved in the striatal denervation of dopaminergic terminals. This procedure can also be used to analyze mechanisms involved in the dopaminergic re innervation of the striatum, and the role of astrocytes and microglia in both processes. Adult Sprague-Dawley rats were injected in the lateral ventricles with increasing doses of 6-hydroxydopamine (12-50 MUg), which generated a dose dependent loss of dopaminergic synapses and axons in the striatum, followed by an axonal sprouting (weeks later) and by a progressive recovery of striatal dopaminergic synapses (months later). Both the degeneration and regeneration of the dopaminergic terminals were accompanied by astrogliosis. Because the experimental manipulations did not induce unspecific damage in the striatal tissue, this method could be particularly suitable to study the basic mechanisms involved in the distal degeneration and regeneration of dopaminergic nigrostriatal neurons, and the possible role of astrocytes and microglia in the dynamics of both processes. PMID- 25907750 TI - Role of the D3 dopamine receptor in nicotine sensitization. AB - Adolescent cigarette use is associated with reduced quitting success and continued smoking in adulthood. Interestingly, polymorphisms of the dopamine D3 receptor (DRD3) gene have been associated with smoking behavior, and the receptor is expressed in an age- and brain region-dependent manner that suggests relevance to addiction. Here, we investigate the possible role of dopamine-related receptors, including DRD3 and an intriguing splice variant known as D3nf, in nicotine-induced sensitization. In adolescent and adult male rats, we examined (1) alterations occurring in dopamine receptor-related mRNAs (DRD1, DRD2, DRD3 and D3nf) at two time points during a sensitizing regimen of nicotine and (2) whether DRD3 antagonism either during the initial treatment (induction) or at a later challenge exposure (expression) is able to block nicotine sensitization. Nicotine-induced changes were seen for DRD3 and D3nf mRNAs in the nucleus accumbens shell early in repeated exposure in both age groups. DRD3 antagonism only blocked the induction of sensitization in adolescents and did not block the expression of sensitization in either age group. Adolescents and adults showed opposite DRD1 mRNA responses to nicotine treatment, while no age- and nicotine related changes in DRD2 mRNA were observed. These data reveal important age dependent regulation of DRD1- and DRD3-related mRNAs during the course of nicotine exposure. Furthermore, they highlight a requirement for DRD3 signaling in the development of adolescent nicotine sensitization, suggesting it may represent an appropriate target in the prevention of nicotine dependence initiated at this age. PMID- 25907751 TI - State-based functional connectivity changes associate with cognitive decline in amnestic mild cognitive impairment subjects. AB - Episodic memory (EM) dysfunction is a central characteristic of amnestic mild cognitive impairment (aMCI) subjects, and has a high risk of converting to Alzheimer's disease (AD). However, it is unknown how the EM network is modulated when a situation is switched. Twenty-six aMCI and twenty-two cognitively normal (CN) subjects were enrolled in this study. All of the subjects completed multi dimensional neuropsychological tests and underwent functional magnetic resonance imaging scans during a resting-state and an episodic memory retrieval task state. The EM network was constructed using a seed-based functional connectivity (FC) approach. AMCI subjects showed poorer cognitive performances in the episodic memory and executive function. We demonstrated that connectivity of the left posterior parahippocampal gyrus (LpPHG) connected to the left ventral medial prefrontal cortex and the right postcentral gyrus (RPCG) was significantly decreased in aMCI subjects compared to CN subjects. Meanwhile, there was increased connectivity of the LpPHG to the right dorsal medial prefrontal cortex (RDMPFC), RPCG, left inferior parietal cortex, and bilateral superior parietal lobe in all of the subjects that changed from a resting-state to a task-state. Interestingly, the changed LpPHG-RDMPFC connectivity strength was significantly correlated with EM scores and executive function in the aMCI subjects. As a result, general brain regions are functionally organized and integrated into the EM network, and this strongly suggests that more cognitive resources are mobilized to meet the challenge of cognitive demand in the task state. These findings extend our understanding of the underlying mechanisms of EM deficits in aMCI subjects. PMID- 25907752 TI - Seize the moment that is thine: how should we define seizures? PMID- 25907747 TI - Basal ganglia circuit loops, dopamine and motivation: A review and enquiry. AB - Dopamine neurons located in the midbrain play a role in motivation that regulates approach behavior (approach motivation). In addition, activation and inactivation of dopamine neurons regulate mood and induce reward and aversion, respectively. Accumulating evidence suggests that such motivational role of dopamine neurons is not limited to those located in the ventral tegmental area, but also in the substantia nigra. The present paper reviews previous rodent work concerning dopamine's role in approach motivation and the connectivity of dopamine neurons, and proposes two working models: One concerns the relationship between extracellular dopamine concentration and approach motivation. High, moderate and low concentrations of extracellular dopamine induce euphoric, seeking and aversive states, respectively. The other concerns circuit loops involving the cerebral cortex, basal ganglia, thalamus, epithalamus, and midbrain through which dopaminergic activity alters approach motivation. These models should help to generate hypothesis-driven research and provide insights for understanding altered states associated with drugs of abuse and affective disorders. PMID- 25907753 TI - Cognitive auditory evoked potentials in coma: can you hear me? PMID- 25907754 TI - Where and what is the PPN and what is its role in locomotion? PMID- 25907755 TI - New criteria for Alzheimer's disease: which, when and why? PMID- 25907756 TI - An Up to 12-Year Retrospective Follow-Up on Immediately Loaded, Surface-Modified Implants in the Edentulous Mandible. AB - PURPOSE: The study aims to evaluate the long-term clinical outcome of immediate loading of implants in the edentulous mandible. MATERIALS AND METHODS: Patients were treated at least 1 year prior to evaluation, with four to five implants and an immediate provisional bridge in the edentulous mandible. They were invited for a clinical examination, which included the removal of the bridge, probing, perio testing, clinical photographs, and a new radiograph to determine the bone level. Also, patients were requested to answer the OHIP-14 questionnaire to rate their satisfaction with the treatment. RESULTS: Forty-six patients (21 men, 25 women), mean age 60 years (SD 8.5, range 43-77), were treated with 211 implants. One implant failed to integrate, resulting in a survival rate of 99.5%. After a mean follow-up of 90 months (SD 45, range 17-143), the mean bone level was 1.17 mm (SD 0.49, range 0.36-4.88). The mean Periotest value was -5.48 (SD 0.883, range -2 to -7). The mean probing depth was 2.04 mm (SD 0.71, range 1.00-8.25). There were 83.3% of the implants that demonstrated no bleeding at probing. Calculus was observed at 13.9% of the abutments. Around one implant (0.5%), suppuration was seen after probing. There was a highly significant correlation between bone loss and probing depth (p < .001). Overall, patients were very satisfied, with 69.6% scoring their treatment as excellent. CONCLUSION: Immediate loading of surface enhanced implants is a highly predictable and successful treatment modality in the edentulous mandible. PMID- 25907757 TI - Seminal Plasma Promotes Lesion Development in a Xenograft Model of Endometriosis. AB - The factors that predispose one-tenth of reproductive-aged women to endometriosis are poorly understood. We determined that genetic deficiency in transforming growth factor beta1 impairs endometriosis-like lesion growth in mice. Given that seminal plasma is an abundant source of transforming growth factor beta, we evaluated the effect of exposure to seminal plasma on the growth of endometrial lesions. Human endometrial explants were exposed to seminal plasma or to control medium before transfer to Prkdc(scid)-mutant (severe combined immunodeficient) mice. Xenografts exposed to seminal plasma showed an eightfold increase in volume and a 4.3-fold increase in weight after 14 days. These increases were associated with increased proliferation of endometrial epithelial cells and enhanced survival and proliferation of human stromal cells compared with those in control lesions, in which human stromal cell persistence was negligible. Although the distribution of macrophages was altered, their number and activation status did not change in response to seminal plasma. Seminal plasma stimulated the production of a variety of cytokines in endometrial tissue, including growth regulated oncogene, granulocyte macrophage colony-stimulating factor, and IL 1beta. These data suggest that seminal plasma enhances the formation of endometriosis-like lesion via a direct effect on endometrial cell survival and proliferation, rather than via macrophage-mediated mechanisms. These findings raise the possibility that endometrial exposure to seminal plasma could contribute to endometriotic disease progression in women. PMID- 25907759 TI - Clarifying the role of theory of mind areas during visual perspective taking: Issues of spontaneity and domain-specificity. AB - Visual perspective taking is a fundamental feature of the human social brain. Previous research has mainly focused on explicit visual perspective taking and contrasted brain activation for other- versus self-perspective judgements. This produced a conceptual gap to theory of mind studies, where researchers mainly compared activation for taking another's mental perspective to non-mental control conditions. We compared brain activation for visual perspective taking to activation for non-mental control conditions where the avatar was replaced by directional (arrow, lamp) or non-directional (brick-wall) objects. We found domain-specific activation linked to the avatar's visual perspective in right TPJ, ventral mPFC and ventral precuneus. Interestingly, we found that these areas are spontaneously processing information linked to the other's perspective during self-perspective judgements. Based on a review of the visual perspective taking literature, we discuss how these findings can explain some of the inconsistent/negative results found in previous studies comparing other- versus self-perspective judgements. PMID- 25907758 TI - Changing the concepts of immune-mediated glomerular diseases through proteomics. AB - Standard classification of glomerular diseases is based on histopathologic abnormalities. The recent application of proteomic technologies has resulted in paradigm changes in the understanding and classification of idiopathic membranous nephropathy and membranoproliferative glomerulonephritis. Those examples provide evidence that proteomics will lead to advances in understanding of the molecular basis of other glomerular diseases, such as lupus nephritis. Proof of principle experiments show that proteomics can be applied to patient renal biopsy specimens. This viewpoint summarizes the advances in immune-mediated glomerular diseases that have relied on proteomics, and potential future applications are discussed. PMID- 25907760 TI - Unplanned readmission following foot and ankle surgery. PMID- 25907761 TI - Incidence of revision after primary implantation of the Salto (r) mobile version and Salto Talaris TM total ankle prostheses: a systematic review. AB - The incidence of revision of total ankle replacement prostheses remains unclear. We undertook a systematic review to identify the material relating to the incidence of revision after implantation of the Salto((r)) mobile version and Salto TalarisTM total ankle prostheses. Studies were eligible for inclusion only if they had involved primary total ankle replacement with these prostheses and had included the incidence of revision. Eight studies involving 1,209 Salto((r)) mobile version prostheses, with a weighted mean follow-up period of 55.2 months, and 5 studies involving 212 Salto TalarisTM total ankle prostheses, with a weighted mean follow-up period of 34.9 months, were included. Forty-eight patients with Salto((r)) mobile version prostheses (4%) underwent revision, of whom 24 (70.5%) underwent ankle arthrodesis, 9 (26.5%) metallic component replacement, and 1 (3%) below-the-knee amputation. Five (2.4%) Salto TalarisTM total ankle prostheses underwent revision (3 metallic component replacement and 2 ankle arthrodeses). Restricting the data to the inventor, design team, or disclosed consultants, the incidence of revision was 5.2% for the Salto((r)) mobile version and 2.6% for the Salto TalarisTM total ankle prostheses. In contrast, data that excluded these individuals had an incidence of revision of 2.8% for the Salto((r)) mobile version and 2.0% for the Salto TalarisTM total ankle prostheses. We could not identify any obvious difference in the etiology responsible for the incidence of revision between these mobile- and fixed-bearing prostheses. The incidence of revision for the Salto((r)) mobile version and Salto TalarisTM total ankle prostheses was lower than those reported through systematic review for the AgilityTM and Scandinavian Total Ankle ReplacementTM systems without obvious selection (inventor) or publication (conflict of interest) bias. PMID- 25907762 TI - Electron acceptors for energy generation in microbial fuel cells fed with wastewaters: A mini-review. AB - Microbial fuel cells (MFCs) have gained tremendous global interest over the last decades as a device that uses bacteria to oxidize organic and inorganic matters in the anode with bioelectricity generation and even for purpose of bioremediation. However, this prospective technology has not yet been carried out in field in particular because of its low power yields and target compounds removal which can be largely influenced by electron acceptors contributing to overcome the potential losses existing on the cathode. This mini review summarizes various electron acceptors used in recent years in the categories of inorganic and organic compounds, identifies their merits and drawbacks, and compares their influences on performance of MFCs, as well as briefly discusses possible future research directions particularly from cathode aspect. PMID- 25907763 TI - Can percutaneous endoscopic gastrostomy be carried out safely in the elderly? AB - AIM: Percutaneous endoscopic gastrostomy (PEG) is carried out commonly for patients with dysphagia. Clinicians, however, are often reluctant to carry out PEG in the elderly because of concerns about complications and short life expectancy. The present study aimed to assess the safety of PEG in elderly patients. METHODS: The medical records of 116 patients who received PEG from October 2005 to May 2012 were reviewed retrospectively. Among them, 63 patients were aged 65 years and older (the elderly group), and 53 were aged less than 65 years (the younger group). RESULTS: Baseline characteristics showed no significant difference in both groups, except that pulmonary comorbidities was more common in the elderly group (P = 0.003). Overall, PEG-related complications occurred in 23 (19.8%) patients. Wound infections were the most common (15 patients), and followed by gastrointestinal bleeding, esophageal injury, pneumomediastinum and buried bumper syndrome. Although there was no difference in the overall complications, wound infections were less frequent in the elderly group than in the younger group (4 [6.3%] out of 63 vs 11 [20.8%] out of 53, P = 0.027). There were 17 (14.7%) cases of mortality, with three patients (2.5%) dying within 30 days after the procedure and the causes of deaths were unrelated to PEG. No significant difference in mortality rate was observed between the two groups (13 [20.6%] vs 4 [7.5%], P = 0.065). CONCLUSIONS: PEG can be carried out safely in elderly patients, as procedure-related complications and mortality did not increase compared with those of younger patients. PMID- 25907764 TI - A Comprehensive Immunoreceptor Phosphotyrosine-based Signaling Network Revealed by Reciprocal Protein-Peptide Array Screening. AB - Cells of the immune system communicate with their environment through immunoreceptors. These receptors often harbor intracellular tyrosine residues, which, when phosphorylated upon receptor activation, serve as docking sites to recruit downstream signaling proteins containing the Src Homology 2 (SH2) domain. A systematic investigation of interactions between the SH2 domain and the immunoreceptor tyrosine-based regulatory motifs (ITRM), including inhibitory (ITIM), activating (ITAM), or switching (ITSM) motifs, is critical for understanding cellular signal transduction and immune function. Using the B cell inhibitory receptor CD22 as an example, we developed an approach that combines reciprocal or bidirectional phosphopeptide and SH2 domain array screens with in solution binding assays to identify a comprehensive SH2-CD22 interaction network. Extending this approach to 194 human ITRM sequences and 78 SH2 domains led to the identification of a high-confidence immunoreceptor interactome containing 1137 binary interactions. Besides recapitulating many previously reported interactions, our study uncovered numerous novel interactions. The resulting ITRM SH2 interactome not only helped to fill many gaps in the immune signaling network, it also allowed us to associate different SH2 domains to distinct immune functions. Detailed analysis of the NK cell ITRM-mediated interactions led to the identification of a network nucleated by the Vav3 and Fyn SH2 domains. We showed further that these SH2 domains have distinct functions in cytotoxicity. The bidirectional protein-peptide array approach described herein may be applied to the numerous other peptide-binding modules to identify potential protein-protein interactions in a systematic and reliable manner. PMID- 25907766 TI - Mass Spectrometry-Based Proteomics Identification of Enteropathogenic Escherichia coli Pedestal Constituents. AB - Enteropathogenic Escherichia coli (EPEC) co-opt host signaling pathways and recruit numerous host proteins to motile morphological structures, called pedestals, at sites of bacterial attachment. These pedestals are hallmarks of EPEC-based disease, and the identification and characterization of the functions of pedestal proteins continue to steadily increase. To identify additional constituents in an unbiased manner, we developed a strategy where EPEC pedestals were elongated artificially, severed, and then concentrated prior to their analysis by mass spectrometry (MS)-based proteomics. We identified >90 unique mammalian proteins over multiple experimental trials from our preparations. Seventeen predicted molecules were significantly higher in abundance (p < 0.05) when compared to both the negative controls and sample means. Validation of two identified proteins (cyclophilin A [nonactin-associated] and transgelin [actin associated]) by immunolocalization was used to confirm our analysis, and both showed enrichment at EPEC pedestals. The EPEC pedestal concentration technique developed here together with the identification of novel pedestal proteins not only provides a resource for the further characterization of molecular components within these structures but also demonstrates that EPEC pedestals can be used as a model system for the identification of novel functions of proteins not normally thought to be at actin-based structures. PMID- 25907767 TI - Crosstalk of EGFR signalling with Notch and Hippo pathways to regulate cell specification, migration and proliferation in cockroach panoistic ovaries. AB - BACKGROUND INFORMATION: Epidermal growth factor receptor (EGFR) signalling is crucial for the regulation of multiple developmental processes. Its function in relation to insect oogenesis has been thoroughly studied in the fly Drosophila melanogaster, which possesses ovaries of the highly modified meroistic type. Conversely, studies in other insect species with different ovary types are scarce. We have studied EGFR functions in the oogenesis of the cockroach Blattella germanica, a phylogenetically basal insect with panoistic ovaries. RESULTS: In this cockroach, depletion of EGFR expression aborts oocyte maturation and prevents oviposition, as affects the distribution of F-actins in the follicular cells of the basal ovarian follicle, which triggers premature apoptosis. In the younger ovarian follicles within the ovariole, depletion of EGFR expression reduces the number of follicular cells, possibly because the Hippo pathway is altered; moreover, the concomitant reduction of Notch expression results in the absence of stalk. Finally, depletion of EGFR determines an increase in the number of germinal cells. CONCLUSIONS: In the panoistic ovary of B. germanica, EGFR plays a role in the control of cell proliferation through interaction with Hippo and Notch pathways. PMID- 25907765 TI - Functional Proteomics Identifies Acinus L as a Direct Insulin- and Amino Acid Dependent Mammalian Target of Rapamycin Complex 1 (mTORC1) Substrate. AB - The serine/threonine kinase mammalian target of rapamycin (mTOR) governs growth, metabolism, and aging in response to insulin and amino acids (aa), and is often activated in metabolic disorders and cancer. Much is known about the regulatory signaling network that encompasses mTOR, but surprisingly few direct mTOR substrates have been established to date. To tackle this gap in our knowledge, we took advantage of a combined quantitative phosphoproteomic and interactomic strategy. We analyzed the insulin- and aa-responsive phosphoproteome upon inhibition of the mTOR complex 1 (mTORC1) component raptor, and investigated in parallel the interactome of endogenous mTOR. By overlaying these two datasets, we identified acinus L as a potential novel mTORC1 target. We confirmed acinus L as a direct mTORC1 substrate by co-immunoprecipitation and MS-enhanced kinase assays. Our study delineates a triple proteomics strategy of combined phosphoproteomics, interactomics, and MS-enhanced kinase assays for the de novo identification of mTOR network components, and provides a rich source of potential novel mTOR interactors and targets for future investigation. PMID- 25907768 TI - Cytometric analysis, genetic manipulation and antibiotic selection of the snail embryonic cell line Bge from Biomphalaria glabrata, the intermediate host of Schistosoma mansoni. AB - The invertebrate cell line, Bge, from embryos of the snail Biomphalaria glabrata, remains to date the only established cell line from any species of the Phylum Mollusca. Since its establishment in 1976 by Eder Hansen, few studies have focused on profiling its cytometrics, growth characteristics or sensitivity to xenobiotics. Bge cells are reputed to be challenging to propagate and maintain. Therefore, even though this cell line is a noteworthy resource, it has not been studied widely. With growing interest in functional genomics, including genetic transformation, to elucidate molecular aspects of the snail intermediate hosts responsible for transmission of schistosomiasis, and aiming to enhance the convenience of maintenance of this molluscan cell line, we deployed the xCELLigene real time approach to study Bge cells. Doubling times for three isolates of Bge, termed CB, SL and UK, were longer than for mammalian cell lines longer than 40 h in complete Bge medium supplemented with 7% fetal bovine serum at 25 degrees C, ranging from ~42 h to ~157 h when 40,000 cells were seeded. To assess the potential of the cells for genetic transformation, antibiotic selection was explored. Bge cells were sensitive to the aminonucleoside antibiotic puromycin (from Streptomyces alboniger) from 5 MUg/ml to 200 ng/ml, displaying a half maximal inhibitory concentration (IC50) of ~1.91 MUg/ml. Sensitivity to puromycin, and a relatively quick kill time (<48 h in 5 MUg/ml) facilitated use of this antibiotic, together with the cognate resistance gene (puromycin N-acetyl-transferase) for selection of Bge cells transformed with the PAC gene (puroR). Bge cells transfected with a plasmid encoding puroR were partially rescued when cultured in the presence of 5 MUg/ml of puromycin. These findings pave the way for the development of functional genomic tools applied to the host-parasite interaction during schistosomiasis and neglected tropical trematodiases at large. PMID- 25907769 TI - Microbes of the tonsils in PFAPA (Periodic Fever, Aphtous stomatitis, Pharyngitis and Adenitis) syndrome - a possible trigger of febrile episodes. AB - Periodic Fever, Aphtous stomatitis, Pharyngitis, and Adenitis (PFAPA) is a childhood febrile syndrome that is often cured by tonsillectomy (TE). We hypothesized that microbes present in the tonsils may act as a trigger for the activation of inflammasomes and investigated the microbiology of the tonsils in PFAPA patients and controls. We recruited 31 consecutive children who underwent TE due to PFAPA; 24 children who underwent TE due to other reasons served as controls. We cultured all the samples for bacteria, mycobacteria, yeasts, and viruses and used PCR for 15 viruses. Also biofilm formation and histologic findings were identified. The samples of the patients yielded Candida albicans more often than did the controls (16 vs 0%, p = 0.003). Staphylococcus aureus occurred in only 10% of the patients, but in 38% of the controls (p = 0.01). Varicella zoster and Herpes simplex viruses occurred less often in patients than in controls. Biofilm was present in 55% of PFAPA tonsils, but in only 24% of the controls (p = 0.03). The microbes found in the tonsils of PFAPA patients showed significant differences from those of controls. This may in part explain the efficacy of TE in PFAPA. PMID- 25907770 TI - Image Analysis-Based Approaches for Scoring Mouse Models of Colitis. AB - Mouse models of inflammatory bowel disease are critical for basic and translational research that is advancing the understanding and treatment of this disease. Assessment of these mouse models frequently relies on histologic endpoints. In recent years, whole slide imaging and digital pathology-based image analysis platforms have become increasingly available for implementation into the pathology workflow. These automated image analysis approaches allow for nonbiased quantitative assessment of histologic endpoints. In this study, the authors sought to develop an image analysis workflow using a commercially available image analysis platform that requires minimal training in image analysis or programming, and this workflow was used to score 2 mouse models of colitis that are primarily characterized by immune cell infiltrates in the lamina propria. Although the software was unable to accurately and consistently segment hematoxylin and eosin-stained sections, automated quantification of CD3 immunolabeling resulted in strong correlations with the pathologist's score in all studies and allowed for the identification of 8 of the 9 differences among treatment groups that were identified by the pathologist. These results demonstrate not only the ability to incorporate solutions based on image analysis into the pathologist's workflow but also the importance of immunohistochemical or histochemical surrogates for the incorporation of image analysis in histologic assessments. PMID- 25907771 TI - Review of transposed basilic vein access for hemodialysis. AB - BACKGROUND: There is ongoing debate about the use of transposed basilic vein (TBV) fistula and the choice between it and prosthetic arteriovenous graft (AVG). This paper reviews the available literature relating to TBV fistula in terms of surgical technique, patency rates, complications, access survival and compares it with prosthetic AVG for hemodialysis (HD). METHODS: Review of English language publications on TBV during the last two decades. FINDINGS: The rate of fistula maturation was higher in the two-stage group, although the mean diameter of the basilic vein was smaller. Dialysis via central venous catheters at time of surgery was most prevalent in patients undergoing staged procedures-14% in one stage TBV and 43% in two-stage TBV. Several authors report 1-year cumulative patency rate of 47% to 96% and 59% to 90% for TBV and AVG, respectively. TBV provides a more cost-effective option and should be considered the next choice when primary autogenous fistulae are not possible, whereas AVGs are easier to create, can be punctured earlier and have a greater reintervention rate if the access fails. CONCLUSIONS: This analysis shows that TBV has several advantages over AVG and provides a valuable access for HD but raises the need for a comparative trial between TBV and the newer generation AVGs. There is no clear superiority of the one-stage over the two-stage procedure. PMID- 25907772 TI - Use of double-lumen peripherally inserted central catheters for safer perioperative management of esophageal cancer patients. AB - PURPOSE: As a step to large-scale clinical trials, we conducted a small-scale exploratory study to clarify whether the secondary lumen of the double-lumen (DL) peripherally inserted central catheters (PICCs) could perform as well as the secondary lumen of the DL centrally inserted central catheters (CICCs), with an acceptable complication rate in the perioperative surgery period. METHODS: Forty thoracic esophageal cancer patients requiring central venous catheterization during the perioperative period were assigned to the DL-PICC (4.5-French, 60-cm) group or the DL-CICC (16-gauge, 30-cm) group, with 1:1 randomization. The primary endpoint was the completion rate of continuous catecholamine infusion via the secondary lumen during the observation period. RESULTS: Thirty-two cases (14 cases in the PICC group and 18 cases in the CICC group) were analyzed. Continuous catecholamine infusion via the secondary lumen was completed in all 32 cases. No major complications related to PICC/CICC placement/maintenance were noted in the groups during the median observation period of 6 days. CONCLUSIONS: The secondary lumen of the DL-PICCs performed as well as the secondary lumen of the DL-CICCs with acceptable safety during the relatively short perioperative period of these thoracic esophageal cancer patients (UMIN Clinical Trial Registry UMIN000008131). PMID- 25907773 TI - Hemodialysis catheter-related infection: prophylaxis, diagnosis and treatment. AB - PURPOSE: Infectious complications associated with central venous catheters (CVCs) are a major source of morbidity and mortality among hemodialysis (HD) patients. This review aims to discuss prevention, diagnosis criteria and management of CVC related infections in HD patients. METHODS: We searched Medline for articles published in the last 10 years, with the keywords "catheter," "hemodialysis," "infection," "treatment," "diagnosis," "prophylaxis" and "adults." Only English language articles were reviewed. We reviewed prophylaxis and surveillance protocols, diagnosis criteria, including new molecular tools, and the management of catheter-related infections, including antibiotic regimen, empiric and according to causal agents, lock therapy, catheter salvage or removal choice and treatment of complications. RESULTS: To prevent infectious complications, first of all we need to avoid using catheters. If we need CVC, adoption of prophylaxis and surveillance protocols, and antibiotic ointment at the exit site reduce infectious complications. The diagnosis of CVC-related infections should be made with drainage and/or blood cultures. Empiric systemic antibiotics should cover Gram-positive and -negative microorganisms, and final regimen should be based on culture results. In selected cases, salvage of site, by CVC exchange over wire, or salvage of catheter, using antibiotic lock, under the cover of systemic antibiotics, could be attempted. CONCLUSIONS: The best approach to prevent CVC related infection would be to avoid the use of CVC. However, in patients for whom it is impossible, the adoption of adequate prophylaxis protocols, early diagnosis and effective treatment of infectious complications are essential to improve outcomes. PMID- 25907774 TI - Gene expression of OCT4, SOX2, KLF4 and MYC (OSKM) induced pluripotent stem cells: identification for potential mechanisms. AB - BACKGROUND: Somatic cells could be reprogrammed to induced pluripotent stem cells (iPS) by ectopic expression of OCT4, SOX2, KLF4 and MYC (OSKM). We aimed to gain insights into the early mechanisms underlying the induction of pluripotency. METHODS: GSE28688 containing 14 gene expression profiles were downloaded from GEO, including untreated human neonatal foreskin fibroblasts (HFF1) as control, OSKM-induced HFF1 (at 24, 48, 72 h post-transduction of OSKM encoding viruses), two iPS cell lines, and two embryonic stem (ES) cell lines. Differentially expressed genes (DEGs) were screened between different cell lines and the control by Limma package in Bioconductor. KEGG pathway enrichment analysis was performed by DAVID. The STRING database was used to construct protein-protein interaction (PPI) network. Activities and regulatory networks of transcription factors (TFs) were calculated and constructed by Fast Network Component Analysis (FastNCA). RESULTS: Compared with untreated HFF1, 117, 347, 557, 2263 and 2307 DEGs were obtained from three point post-transduction HFF1, iPS and ES cells. Meanwhile, up regulated DEGs in first two days of HFF1 were mainly enriched in RIG-I-like receptor (RLR) and Toll-like receptor (TLR) signaling pathways. Down-regulated DEGs at 72 h were significantly enriched in focal adhesion pathway which was similar to iPS cells. Moreover, ISG15, IRF7, STAT1 and DDX58 were with higher degree in PPI networks during time series. Furthermore, the targets of six selected TFs were mainly enriched in screened DEGs. CONCLUSION: In this study, screened DEGs including ISG15, IRF7 and CCL5 participated in OSKM-induced pluripotency might attenuate immune response post-transduction through RLR and TLR signaling pathways. VIRTUAL SLIDES: The virtual slide(s) for this article can be found here: http://www.diagnosticpathology.diagnomx.eu/vs/2503890341543007 . PMID- 25907776 TI - Cerebrospinal Fluid Monoamine Metabolite Analysis in Pediatric Movement Disorders. AB - Abnormal concentrations of dopamine and serotonin metabolites in the cerebrospinal fluid is the diagnostic hallmark of a group of treatable conditions known as the monoamine neurotransmitter disorders. We assessed cerebrospinal fluid dopamine and serotonin metabolite concentrations in a series of 69 patients affected by movement disorders of unknown etiology. Abnormal results were disclosed in 13/69 subjects (19%). Both primary and secondary monoamine neurotransmitter disorders were observed. The clinical presentation of both forms was hypokinetic-rigid syndrome or dystonia. L-Dopa treatment resulted in significant improvement of the clinical picture in the majority of primary neurotransmitter disorders. Eight patients presented a secondary neurotransmitter disorder. One suffered from a GM2 gangliosidosis and one from infantile bilateral striatal necrosis. Etiologic diagnoses were not established in the others. L-Dopa was started in four patients, leading to a significant improvement of hypokinesia in the patient suffering from GM2 gangliosidosis and a slight improvement in 3 unclassified patients. PMID- 25907775 TI - Eating out is different from eating at home among individuals who occasionally eat out. A cross-sectional study among middle-aged adults from eleven European countries. AB - Eating out has been linked to the current obesity epidemic, but the evaluation of the extent to which out of home (OH) dietary intakes are different from those at home (AH) is limited. Data collected among 8849 men and 14,277 women aged 35-64 years from the general population of eleven European countries through 24-h dietary recalls or food diaries were analysed to: (1) compare food consumption OH to those AH; (2) describe the characteristics of substantial OH eaters, defined as those who consumed 25 % or more of their total daily energy intake at OH locations. Logistic regression models were fit to identify personal characteristics associated with eating out. In both sexes, beverages, sugar, desserts, sweet and savoury bakery products were consumed more OH than AH. In some countries, men reported higher intakes of fish OH than AH. Overall, substantial OH eating was more common among men, the younger and the more educated participants, but was weakly associated with total energy intake. The substantial OH eaters reported similar dietary intakes OH and AH. Individuals who were not identified as substantial OH eaters reported consuming proportionally higher quantities of sweet and savoury bakery products, soft drinks, juices and other non-alcoholic beverages OH than AH. The OH intakes were different from the AH ones, only among individuals who reported a relatively small contribution of OH eating to their daily intakes and this may partly explain the inconsistent findings relating eating out to the current obesity epidemic. PMID- 25907777 TI - Dutcher bodies in multiple myeloma are highly associated with translocation t(4;14) and IgA isotype. PMID- 25907779 TI - Prescription of emergency antiepileptic medication after a first childhood seizure: analysis of routine administrative data. AB - AIM: UK guidelines do not recommend prescribing emergency antiepileptic drugs after first simple febrile seizures or for single afebrile seizures. Non adherence to the guidelines could result in substantial health service cost. METHODS: Scottish national hospital discharge records were used to identify children aged one month to 4 years admitted for a first febrile seizures or single afebrile seizures between April 2009 and March 2012. Prescriptions for antiepileptic drugs within 12 months of index admission were identified on the national community prescribing database by matching unique patient identifiers. RESULTS: There were 1,978 and 663 children admitted for febrile seizures and single afebrile seizures, respectively. One percent of children admitted with febrile seizures and 1.7% with single afebrile seizures had a subsequent community prescription record for emergency antiepileptic drugs within 12 months of index admission. Total cost of emergency antiepileptic drugs following febrile seizures and single afebrile seizures for the study period was just over L900. CONCLUSION: Health care providers and policy makers can be reassured that emergency antiepileptic drugs are not being inappropriately overprescribed for febrile seizures and single afebrile seizures. PMID- 25907778 TI - Successful behavior change in obesity interventions in adults: a systematic review of self-regulation mediators. AB - BACKGROUND: Relapse is high in lifestyle obesity interventions involving behavior and weight change. Identifying mediators of successful outcomes in these interventions is critical to improve effectiveness and to guide approaches to obesity treatment, including resource allocation. This article reviews the most consistent self-regulation mediators of medium- and long-term weight control, physical activity, and dietary intake in clinical and community behavior change interventions targeting overweight/obese adults. METHODS: A comprehensive search of peer-reviewed articles, published since 2000, was conducted on electronic databases (for example, MEDLINE) and journal reference lists. Experimental studies were eligible if they reported intervention effects on hypothesized mediators (self-regulatory and psychological mechanisms) and the association between these and the outcomes of interest (weight change, physical activity, and dietary intake). Quality and content of selected studies were analyzed and findings summarized. Studies with formal mediation analyses were reported separately. RESULTS: Thirty-five studies were included testing 42 putative mediators. Ten studies used formal mediation analyses. Twenty-eight studies were randomized controlled trials, mainly aiming at weight loss or maintenance (n = 21). Targeted participants were obese (n = 26) or overweight individuals, aged between 25 to 44 years (n = 23), and 13 studies targeted women only. In terms of study quality, 13 trials were rated as "strong", 15 as "moderate", and 7 studies as "weak". In addition, methodological quality of formal mediation analyses was "medium". Identified mediators for medium-/long-term weight control were higher levels of autonomous motivation, self-efficacy/barriers, self-regulation skills (such as self-monitoring), flexible eating restraint, and positive body image. For physical activity, significant putative mediators were high autonomous motivation, self-efficacy, and use of self-regulation skills. For dietary intake, the evidence was much less clear, and no consistent mediators were identified. CONCLUSIONS: This is the first systematic review of mediational psychological mechanisms of successful outcomes in obesity-related lifestyle change interventions. Despite limited evidence, higher autonomous motivation, self efficacy, and self-regulation skills emerged as the best predictors of beneficial weight and physical activity outcomes; for weight control, positive body image and flexible eating restraint may additionally improve outcomes. These variables represent possible targets for future lifestyle interventions in overweight/obese populations. PMID- 25907780 TI - The impact of viral dynamics on the clinical severity of infants with respiratory syncytial virus bronchiolitis. AB - The impact of dynamic respiratory syncytial virus (RSV) load on the clinical severity of hospitalized infants with bronchiolitis has not been clarified. Nasopharyngeal aspirates were obtained from 60 infants who were diagnosed with bronchiolitis within 96 hr of wheezing onset upon admission and on days 3, 5, and 7 in the hospital, and 17 respiratory viruses were detected. The RSV load was quantified by real-time qPCR for RSV subtypes A and B at different time points. Scoring criteria were used to evaluate the degree of severity. A total of 40 infants were determined to be RSV-positive, nine were identified as RSV subtype A (RSVA), and 31 were RSV subtype B (RSVB). The peak RSV load was observed upon admission, and the RSV load decreased significantly over time; in addition, this decrease began to have significant differences on day 5. There was a positive correlation between the RSV load and the clinical score (r(2) = 0.121 and P < 0.001). According to the clinical scores, the infants in the severe group tended to have higher RSV loads than those in the moderate and mild groups. Multivariate logistic regression models revealed that the viral load on day 3 was independently associated with the degree of severity. This study elucidated that a higher mean RSV load was associated with a more severe disease and a longer duration of hospitalization and symptoms. This study also clarified RSV replication in infants and provides a theoretical basis for specifying an anti RSV therapy strategy. PMID- 25907782 TI - Microfiber cloths reduce the transfer of Clostridium difficile spores to environmental surfaces compared with cotton cloths. AB - BACKGROUND: Environmental surfaces in health care facilities contaminated with Clostridium difficile spores can be a reservoir that contribute to transmission of hospital-acquired infections. Microfiber cleaning cloths may improve the effectiveness of surface cleaning. The objective of this study was to assess the removal and transfer of C difficile spores on surfaces cleaned by microfiber compared with cotton cloths. METHODS: C difficile spores (approximately 4.2 log(10)/site) were applied to ceramic surfaces. Microfiber or cotton cloths were used to wipe the surfaces that were sprayed with either buffer or a nonsporicidal cleaning agent. To ensure reproducible pressure and surface contact time, a drill apparatus was used. The pressure was 1.5-1.77 N, and the total number of rotations was 10. Viable counts were used to assess the efficiency of microfiber and cotton cloths in removing and transferring spores. RESULTS: Of 4.4 log(10)C difficile spores inoculated on a ceramic surface, microfiber and cotton cloths removed 2.4 and 1.7 log(10), respectively. Microfiber cloths containing 4.2 log(10)C difficile spores transferred 1.7 log(10) C difficile spores when used to wipe a ceramic surface compared with cotton cloths that transferred 2.4 log(10). Similarly microfiber wipes transferred fewer spores on consecutive surfaces wiped compared with cotton cloths (0.8 log(10) vs 1.80 log(10)). CONCLUSION: The use of microfiber cloths may reduce the risk of C difficile spore transfer during surface cleaning. PMID- 25907783 TI - Environmental contamination by multidrug-resistant microorganisms after daily cleaning. AB - We analyzed 91 samples of high-touch surfaces obtained within the first hour after daily cleaning in intensive care unit rooms occupied with patients with multidrug-resistant organisms (MDROs). We determined that 22% of high-touch surfaces in rooms with methicillin-resistant Staphylococcus aureus patients and 5% of high-touch surfaces in rooms with multiresistant Pseudomonas aeruginosa patients were colonized with the same strain as the patient. We postulated that textile cleaning wipes could be contaminated with MDROs and may contribute to its spreading within the room. PMID- 25907781 TI - Association between biomarkers of endothelial injury and hypocoagulability in patients with severe sepsis: a prospective study. AB - INTRODUCTION: Patients with severe sepsis often present with concurrent coagulopathy, microcirculatory failure and evidence of vascular endothelial activation and damage. Given the critical role of the endothelium in balancing hemostasis, we investigated single-point associations between whole blood coagulopathy by thrombelastography (TEG) and plasma/serum markers of endothelial activation and damage in patients with severe sepsis. METHODS: A post-hoc multicenter prospective observational study in a subgroup of 184 patients from the Scandinavian Starch for Severe Sepsis/Septic Shock (6S) Trial. Study patients were admitted to two Danish intensive care units. Inclusion criteria were severe sepsis, pre-intervention whole blood TEG measurement and a plasma/serum research sample available from baseline (pre-intervention) for analysis of endothelial derived biomarkers. Endothelial-derived biomarkers were measured in plasma/serum by enzyme-linked immunosorbent assay (syndecan-1, thrombomodulin, protein C (PC), tissue-type plasminogen activator and plasminogen activator inhibitor-1). Pre intervention TEG, functional fibrinogen (FF) and laboratory and clinical data, including mortality, were retrieved from the trial database. RESULTS: Most patients presented with septic shock (86%) and pulmonary (60%) or abdominal (30%) focus of infection. The median (IQR) age was 67 years (59 to 75), and 55% were males. The median SOFA and SAPS II scores were 8 (6 to 10) and 56 (41 to 68), respectively, with 7-, 28- and 90-day mortality rates being 21%, 39% and 53%, respectively. Pre-intervention (before treatment with different fluids), TEG reaction (R)-time, angle and maximum amplitude (MA) and FF MA all correlated with syndecan-1, thrombomodulin and PC levels. By multivariate linear regression analyses, higher syndecan-1 and lower PC were independently associated with TEG and FF hypocoagulability at the same time-point: 100 ng/ml higher syndecan-1 predicted 0.64 minutes higher R-time (SE 0.25), 1.78 mm lower TEG MA (SE 0.87) and 0.84 mm lower FF MA (SE 0.42; all P < 0.05), and 10% lower protein C predicted 1.24 mm lower TEG MA (SE 0.31). CONCLUSIONS: In our cohort of patients with severe sepsis, higher circulating levels of biomarkers of mainly endothelial damage were independently associated with hypocoagulability assessed by TEG and FF. Endothelial damage is intimately linked to coagulopathy in severe sepsis. TRIAL REGISTRATION: Clinicaltrials.gov number: NCT00962156. Registered 13 July 2009. PMID- 25907784 TI - Precision-cut rat, mouse, and human intestinal slices as novel models for the early-onset of intestinal fibrosis. AB - Intestinal fibrosis (IF) is a major complication of inflammatory bowel disease. IF research is limited by the lack of relevant in vitro and in vivo models. We evaluated precision-cut intestinal slices (PCIS) prepared from human, rat, and mouse intestine as ex vivo models mimicking the early-onset of (human) IF. Precision-cut intestinal slices prepared from human (h), rat (r), and mouse (m) jejunum, were incubated up to 72 h, the viability of PCIS was assessed by ATP content and morphology, and the gene expression of several fibrosis markers was determined. The viability of rPCIS decreased after 24 h of incubation, whereas mPCIS and hPCIS were viable up to 72 h of culturing. Furthermore, during this period, gene expression of heat shock protein 47 and plasminogen activator inhibitor 1 increased in all PCIS in addition to augmented expression of synaptophysin in hPCIS, fibronectin (Fn2) and TGF-beta1 in rPCIS, and Fn2 and connective tissue growth factor (Ctgf) in mPCIS. Addition of TGF-beta1 to rPCIS or mPCIS induced the gene expression of the fibrosis markers Pro-collagen1a1, Fn2, and Ctgf in both species. However, none of the fibrosis markers was further elevated in hPCIS. We successfully developed a novel ex vivo model that can mimic the early-onset of fibrosis in the intestine using human, rat, and mouse PCIS. Furthermore, in rat and mouse PCIS, TGF-beta1 was able to even further increase the gene expression of fibrosis markers. This indicates that PCIS can be used as a model for the early-onset of IF. PMID- 25907785 TI - Exercise training reduces insulin resistance in postmyocardial infarction rats. AB - Myocardial infarction (MI) induces cardiac dysfunction and insulin resistance (IR). This study examines the effects of MI-related IR on vasorelaxation and its underlying mechanisms, with a specific focus on the role of exercise in reversing the impaired vasorelaxation. Adult male Sprague-Dawley rats were divided into three groups: Sham, MI, and MI+Exercise. MI+Exercise rats were subjected to 8 weeks of treadmill training. Cardiac contraction, myocardial and arterial structure, vasorelaxation, levels of inflammatory cytokines, expression of eNOS and TNF-alpha, and activation of PI3K/Akt/eNOS and p38 mitogen-activated protein kinase (p38 MAPK) were determined in aortas. MI significantly impaired endothelial structure and vasodilation (P < 0.05-0.01), as indicated by decreased arterial vasorelaxation to ACh and insulin. MI also attenuated the myocardial contractile response, decreased aortic PI3K/Akt/eNOS expression and phosphorylation by insulin, and increased IL-1beta, IL-6, and TNF-alpha expression and p38 MAPK activity (P < 0.05-0.01). Exercise improved insulin sensitivity in aortas, facilitated myocardial contractile response and arterial vasorelaxation to ACh and insulin, and increased arterial PI3K/Akt/eNOS activity. Moreover, exercise markedly reversed increased p38 MAPK activity and normalized inflammatory cytokines in post-MI arteries. Inhibition of PI3K with LY-294002, and eNOS with L-NAME significantly blocked arterial vasorelaxation and PI3K/Akt/eNOS phosphorylation in response to insulin. In conclusion, these results demonstrate that endothelial dysfunction in response to insulin plays an important role in MI-related IR. The reversal of IR by exercise is most likely associated with normalizing inflammatory cytokines, increasing the activation of PI3K/Akt/eNOS, and reducing the activation of p38 MAPK. PMID- 25907786 TI - Vocal development in dystonic rats. AB - Vocal production, which requires the generation and integration of laryngeal and respiratory motor patterns, can be impaired in dystonia, a disorder believed due to dysfunction of sensorimotor pathways in the central nervous system. Herein, we analyze vocal and respiratory abnormalities in the dystonic (dt) rat, a well characterized model of generalized dystonia. The dt rat is a recessive mutant with haploinsufficiency of Atcay which encodes the neuronally restricted protein caytaxin. Olivocerebellar functional abnormalities are central to the dt rat's truncal and appendicular dystonia and could also contribute to vocal and respiratory abnormalities in this model system. Differences in vocal repertoire composition were found between homozygote and wild-type dt rat pups developing after 3 weeks of life. Those spectro-temporal differences were not paralleled by differences in vocal activity or maximum lung pressures during quiet breathing and vocalization. However, breathing rhythm was slower in homozygote pups. This slower breathing rhythm persisted into adulthood. Given that cerebellectomy eliminates truncal and appendicular dystonia in the dt rat, we hypothesize that the altered breathing patterns stem either from a disturbance in the maturation of respiratory pattern generators or from deficient extracerebellar caytaxin expression affecting normal respiratory pattern generation. The altered breathing rhythm associated with vocal changes in the murine model resembles aspects of vocal dysfunction that are seen in humans with sporadic dystonia. PMID- 25907787 TI - Disruption of action potential and calcium signaling properties in malformed myofibers from dystrophin-deficient mice. AB - Duchenne muscular dystrophy (DMD), the most common and severe muscular dystrophy, is caused by the absence of dystrophin. Muscle weakness and fragility (i.e., increased susceptibility to damage) are presumably due to structural instability of the myofiber cytoskeleton, but recent studies suggest that the increased presence of malformed/branched myofibers in dystrophic muscle may also play a role. We have previously studied myofiber morphology in healthy wild-type (WT) and dystrophic (MDX) skeletal muscle. Here, we examined myofiber excitability using high-speed confocal microscopy and the voltage-sensitive indicator di-8 butyl-amino-naphthyl-ethylene-pyridinium-propyl-sulfonate (di-8-ANEPPS) to assess the action potential (AP) properties. We also examined AP-induced Ca(2+) transients using high-speed confocal microscopy with rhod-2, and assessed sarcolemma fragility using elastimetry. AP recordings showed an increased width and time to peak in malformed MDX myofibers compared to normal myofibers from both WT and MDX, but no significant change in AP amplitude. Malformed MDX myofibers also exhibited reduced AP-induced Ca(2+) transients, with a further Ca(2+) transient reduction in the branches of malformed MDX myofibers. Mechanical studies indicated an increased sarcolemma deformability and instability in malformed MDX myofibers. The data suggest that malformed myofibers are functionally different from myofibers with normal morphology. The differences seen in AP properties and Ca(2+) signals suggest changes in excitability and remodeling of the global Ca(2+) signal, both of which could underlie reported weakness in dystrophic muscle. The biomechanical changes in the sarcolemma support the notion that malformed myofibers are more susceptible to damage. The high prevalence of malformed myofibers in dystrophic muscle may contribute to the progressive strength loss and fragility seen in dystrophic muscles. PMID- 25907788 TI - Appetite regulation is independent of the changes in ghrelin levels in pregnant rats fed low-protein diet. AB - Gestational protein restriction causes hypertension in the adult offspring. Very little is known about the food intake regulation and ghrelin signaling in pregnant dams fed a low-protein (LP) diet. We hypothesized that diet intake and ghrelin signaling are altered in pregnant rats fed the low-protein diet. Sprague Dawley rats were fed a control (CT) or LP diet from Day 3 of pregnancy. Diet intake and body weight were monitored daily. Expression of ghrelin production related genes in the stomach and appetite-related genes in the hypothalamus was analyzed by real-time PCR. Plasma levels of total and active ghrelin, growth hormone and leptin were measured by ELISA. Main results include: (1) Daily diet intake was greater in the LP group than in the CT group in early pregnancy, but substantially lower in late pregnancy; (2) Daily gain in body weight was substantially lower in the LP group in late pregnancy; (3) Expression of ghrelin production-related genes in the stomach and plasma total ghrelin levels were increased in LP group in late pregnancy; (4) Plasma active ghrelin levels were elevated in the LP group at mid-late pregnancy, but growth hormone and leptin levels were uncorrelated with active ghrelin in late pregnancy; and (5) Hypothalamic expression of ghrelin-stimulated genes in LP rats was unassociated with the changes in both plasma ghrelin levels and the diet intake. Taken together, the appetite in LP rats is greater in early pregnancy but reduced at late pregnancy, possibly due to ghrelin insensitivity in appetite regulation. PMID- 25907789 TI - Studying cerebral hemodynamics and metabolism using simultaneous near-infrared spectroscopy and transcranial Doppler ultrasound: a hyperventilation and caffeine study. AB - Caffeine is one of the most widely consumed psycho-stimulants in the world, yet little is known about its effects on brain oxygenation and metabolism. Using a double-blind, placebo-controlled, randomized cross-over study design, we combined transcranial Doppler ultrasound (TCD) and near-infrared spectroscopy (NIRS) to study caffeine's effect on middle cerebral artery peak blood flow velocity (Vp), brain tissue oxygenation (StO2), total hemoglobin (tHb), and cerebral oxygen metabolism (CMRO2) in five subjects. Hyperventilation-induced hypocapnia served as a control to verify the sensitivity of our measurements. During hypocapnia (~16 mmHg below resting values), Vp decreased by 40.0 +/- 2.4% (95% CI, P < 0.001), while StO2 and tHb decreased by 2.9 +/- 0.3% and 2.6 +/- 0.4%, respectively (P = 0.003 and P = 0.002, respectively). CMRO2, calculated using the Fick equation, was reduced by 29.3 +/- 9% compared to the isocapnic-euoxia baseline (P < 0.001). In the pharmacological experiments, there was a significant decrease in Vp, StO2, and tHb after ingestion of 200 mg of caffeine compared with placebo. There was no significant difference in CMRO2 between caffeine and placebo. Both showed a CMRO2 decline compared to baseline showing the importance of a placebo control. In conclusion, this study showed that profound hypocapnia impairs cerebral oxidative metabolism. We provide new insight into the effects of caffeine on cerebral hemodynamics. Moreover, this study showed that multimodal NIRS/TCD is an excellent tool for studying brain hemodynamic responses to pharmacological interventions and physiological challenges. PMID- 25907790 TI - Transient early food restriction leads to hypothalamic changes in the long-lived crowded litter female mice. AB - Transient nutrient restriction in the 3 weeks between birth and weaning (producing "crowded litter" or CL mice) leads to a significant increase in lifespan and is associated with permanent changes in energy homeostasis, leptin, and insulin sensitivity. Here, we show this brief period of early food restriction leads to permanent modulation of the arcuate nucleus of the hypothalamus (ARH), markedly increasing formation of both orexigenic agouti related peptide (AgRP) and anorexigenic proopiomelanocortin (POMC) projections to the paraventricular nucleus of the hypothalamus (PVH). An additional 4 weeks of caloric restriction, after weaning, does not further intensify the formation of AgRP and POMC projections. Acute leptin stimulation of 12-month-old mice leads to a stronger increase in the levels of hypothalamic pStat3 and cFos activity in CL mice than in controls, suggesting that preweaning food restriction leads to long lasting enhancement of leptin signaling. In contrast, FoxO1 nuclear exclusion in response to insulin is equivalent in young adult CL and control mice, suggesting that hypothalamic insulin signaling is not modulated by the crowded litter intervention. Markers of hypothalamic reactive gliosis associated with aging, such as Iba1-positive microglia and GFAP-positive astrocytes, are significantly reduced in CL mice as compared to controls at 12 and 22 months of age. Lastly, age-associated overproduction of TNF-alpha in microglial cells is reduced in CL mice than in age-matched controls. Together, these results suggest that transient early life nutrient deprivation leads to long-term hypothalamic changes which may contribute to the longevity of CL mice. PMID- 25907791 TI - Bicarbonate exchangers SLC26A3 and SLC26A6 are localized at the apical membrane of porcine vas deferens epithelium. AB - The goal of this study was to test for expression of HCO3 (-) exchangers SLC26A3 and SLC26A6 in primary cultures of porcine vas deferens epithelial cells (1 degrees PVD) and native porcine vas deferens. Quantitative RT-PCR revealed that mRNA coding for SLC26A6 was six times more abundant than mRNA coding for SLC26A3 in 1 degrees PVD cells. Western blot analyses combined with surface biotinylation of 1 degrees PVD demonstrated SLC26A3 and SLC26A6 immunoreactivities in whole cell lysates and apical surfaces of monolayers. Laser scanning confocal microscopy (LSCM) of the 1 degrees PVD cell monolayers demonstrated that SLC26A3 immunoreactivity was primarily in the apical region but present throughout the basal-apical cellular axis, whereas SLC26A6 immunoreactivity was present in the apical region and sometimes accumulated in the nuclear region. LSCM also demonstrated SLC26A3 and SLC26A6 immunoreactivities present along the entire apical lining of the native porcine vas deferens epithelium and in basal cells. The patterns and apparent abundance of SLC26A3 and SLC26A6 immunoreactivities in the proximal vas deferens were not different from the corresponding immunoreactivities in the distal region. There is no evidence of preferential expression of SLC26A3 or SLC26A6 in any portion of the vas deferens, as has been proposed for epithelia that secrete HCO3 (-) in other duct systems. Thus, vas deferens epithelia express transporters throughout the duct that can contribute to rapid alkalinization of the luminal contents as it has been demonstrated in vivo. PMID- 25907792 TI - Ascorbic acid attenuates the pressor response to voluntary apnea in postmenopausal women. AB - We recently demonstrated that postmenopausal women have an augmented blood pressure response to voluntary apnea compared to premenopausal women. Both obstructive sleep apnea (OSA) and healthy aging are associated with increased oxidative stress, which may impair cardiovascular function. Restoring physiological responses could have clinical relevance since transient surges in blood pressure are thought to be an important stimulus for end-organ damage in aging and disease. We tested the hypothesis that acute antioxidant infusion improves physiological responses to voluntary apnea in healthy postmenopausal women (n = 8, 64 +/- 2 year). We measured beat-by-beat mean arterial pressure (MAP), heart rate (HR), and brachial artery blood flow velocity (BBFV, Doppler ultrasound) following intravenous infusion of normal saline and ascorbic acid (~3500 mg). Subjects performed maximal voluntary end-expiratory apneas and changes (Delta) from baseline were compared between infusions. The breath hold duration and oxygen saturation nadir were similar between saline (29 +/- 6 sec, 94 +/- 1%) and ascorbic acid (29 +/- 5 sec, 94 +/- 1%). Ascorbic acid attenuated the pressor response to voluntary apnea (DeltaMAP: 6 +/- 2 mmHg) as compared to saline (DeltaMAP: 12 +/- 2 mmHg, P = 0.034) and also attenuated forearm vasoconstriction (DeltaBBFV: 4 +/- 9 vs. -12 +/- 7%, P = 0.049) but did not affect DeltaHR. We conclude that ascorbic acid lowers the blood pressure response to voluntary apnea in postmenopausal women by inhibiting vasoconstriction in the limb vasculature. Whether ascorbic acid has similar effects in OSA patients remains to be prospectively tested. PMID- 25907793 TI - Exercise-induced changes in tumour LDH-B and MCT1 expression are modulated by oestrogen-related receptor alpha in breast cancer-bearing BALB/c mice. AB - KEY POINTS: Monocarboxylate transporters (MCTs) and lactate dehydrogenase A (LDH A) play important roles in sustaining the glycolytic phenotype seen in cancer. Endurance training improves aerobic capacity; however, whether endurance training alters the metabolic phenotype of a solid tumour, from the perspective of lactate metabolism, is yet to be proven. This study showed that endurance training decreases expression of the MCT1 basigin (CD147) and LDH-A , and also increases LDH-B expression in solid tumours and attenuates tumour lactate metabolism. Similar results for MCT1 and LDH-B were found with inhibition of the oestrogen related receptor alpha (ERRalpha). The training effects were not additive to the ERRalpha effects on MCT1 and LDH-B expression in the tumour, which indicated that exercise-induced alterations in MCT1 and LDH-B expression were modulated by ERRalpha. These results suggest that endurance training could be a useful tool in cancer therapy, especially in basal-like and luminal-like breast carcinomas. ABSTRACT: Several factors, including overexpression of lactate dehydrogenase (LDH) and monocarboxylate transporters (MCTs), promote an aerobic lactate production that allows some cancer cells to sustain higher proliferation rates in hostile environments outside the cell. To elucidate the effect of endurance training on the metabolic phenotype of solid tumours, we focused on the tumour expression of LDH-A, LDH-B, MCT1, MCT4, oestrogen-related receptor alpha (ERRalpha) and LDH isozymes in control (C), trained (T), control+XCT790 (CX) and trained+XCT790 (TX) mice. First, we found that the metabolically altered tumours from the trained animals exhibited lower values for lactate concentration than the control group. The decreased lactate concentration was associated with a shift in the tumour LDH isozyme profile towards LDH-1. These exercise-induced changes were also associated with decreases in the expression of the tumour MCT1, ERRalpha and CD147 in the trained animals. Secondly, the inhibition of ERRalpha by treatment of MC4-L2 human breast cancer cells with XCT790 (inverse agonist ligand of ERRalpha) before injection into the animals not only increased LDH-B expression in the tumour, but also decreased MCT1 expression in the CX group in comparison to the C group. The effects of ERRalpha inhibition were not additive to the training effects on the expressions of MCT1 and LDH-B in the solid tumours. In conclusion, our results suggest that exercise-induced suppression of ERRalpha expression modulates alterations in solid tumour expression of LDH-B and MCT1 and contributes towards the prevention of tumour development. PMID- 25907795 TI - Clinical update on frontotemporal dementia: diagnosis and treatment. AB - OBJECTIVES: To provide a clinical update for general psychiatrists on frontotemporal dementias (FTDs) using a selective narrative review of recent findings and advances in conceptualising, diagnosing and treating FTD. CONCLUSIONS: General psychiatrists can apply their skills to support patients, carers, GPs and allied health workers in comprehensive care of persons with FTD. PMID- 25907794 TI - Ubiquitination of the Dishevelled DIX domain blocks its head-to-tail polymerization. AB - Dishevelled relays Wnt signals from the plasma membrane to different cytoplasmic effectors. Its signalling activity depends on its DIX domain, which undergoes head-to-tail polymerization to assemble signalosomes. The DIX domain is ubiquitinated in vivo at multiple lysines, which can be antagonized by various deubiquitinases (DUBs) including the CYLD tumour suppressor that attenuates Wnt signalling. Here, we generate milligram quantities of pure human Dvl2 DIX domain mono-ubiquitinated at two lysines (K54 and K58) by genetically encoded orthogonal protection with activated ligation (GOPAL), to investigate their effect on DIX polymerization. We show that the ubiquitination of DIX at K54 blocks its polymerization in solution, whereas DIX58-Ub remains oligomerization-competent. DUB profiling identified 28 DUBs that cleave DIX-ubiquitin conjugates, half of which prefer, or are specific for, DIX54-Ub, including Cezanne and CYLD. These DUBs thus have the potential to promote Dvl polymerization and signalosome formation, rather than antagonize it as previously thought for CYLD. PMID- 25907796 TI - The abandonment of the RANZCP OCI--and why we may live to regret it. AB - OBJECTIVE: The objective of this article is to explore the tension between what should be complementary notions of medical education and professional identity formation, referencing a major recent change to the assessment program of the Royal Australian and New Zealand College of Psychiatrists (RANZCP). The College recently determined that the observed clinical interview (OCI) is to cease with equivalent skills assessed by multiple workplace-based assessments within a competency-based education program. The literature relating to the change is briefly reviewed. The shortcomings of the OCI include concerns regarding reliability, validity, sustainability and transparency. Arguments in favour of keeping the OCI are then considered, including those made on grounds of reliability of the new instruments, validity of the new assessment program as a whole, the importance of professional identity formation and cultural considerations within the specialty. CONCLUSION: Education and professional identity formation are not synonymous. Applying educational evidence alone to assessment design may mean an opportunity for trainees to demonstrate qualities previously assessed at the OCI is lost. This may have negative consequences for the quality of RANZCP trained psychiatrists and for our patients. The OCI is a flawed instrument but the new system will be flawed in different and possibly more important ways. PMID- 25907797 TI - Vortioxetine: A multimodal antidepressant or another selective serotonin reuptake inhibitor? AB - OBJECTIVE: The treatment of depressive disorders remains unsatisfactory for many patients with regard to efficacy and tolerability. Vortioxetine has been registered by regulatory authorities for the treatment of major depressive disorder. This paper aims to provide clinicians with a brief overview of vortioxetine and its place in treatment. CONCLUSIONS: Vortioxetine is a serotonin reuptake inhibitor with additional serotonergic receptor effects of uncertain significance; hence, its classification as 'multimodal'. The half-life is about 2.75 days and steady state requires about 14 days. Metabolism is hepatic and involves cytochromes 2D6 and 3A4/5. Antidepressant efficacy in major depressive disorder has been established in registration studies, but the effectiveness of vortioxetine in 'real world' patients and in comparison to other antidepressants needs further investigation. The recommended dose range is 5-20 mg. Nausea, constipation and vomiting are the most common side effects. Sexual dysfunction may occur at higher doses but there appears to be low risk of weight gain and sedation. There is still much to learn about this drug, particularly whether it has unique characteristics in comparison to existing antidepressants. At present, vortioxetine can be considered as an antidepressant option in patients with established major depressive disorder who have not responded adequately to other antidepressants. PMID- 25907798 TI - Template-dependent photochemical reactivity of molecular metal oxides. AB - A combined experimental and theoretical study shows that the photooxidative activity of two isostructural metal oxide clusters depends on their internal templates. To this end, two halide-templated bismuth vanadium oxide clusters [X(Bi(dmso)3 )2 V12 O33 ](-) (X=Cl(-) , Br(-) ) are reported and fully characterized. The two clusters show similar absorption features and illustrate that bismuth incorporation results in increased visible-light absorption. Significantly higher photooxidative activity is observed for the bromide templated cluster compared with the chloride-templated one. Detailed photophysical assays and complementary DFT calculations suggest that the more efficient triplet excited state formation in the Br(-) -containing cluster is the decisive step in the photocatalysis and is due to the heavy-atom effect of the bromide. This concept can therefore open new pathways towards the optimization of photocatalytic activity in metal oxide clusters. PMID- 25907799 TI - Analysis of amicarbazone and its two metabolites in grains and soybeans by liquid chromatography with tandem mass spectrometry. AB - A sensitive, simple and reliable analytical method based on a modified quick, easy, cheap, effective, rugged, safe sample preparation and liquid chromatography with tandem mass spectrometry detection was developed for the simultaneous determination of amicarbazone and its two major metabolites desamino amicarbazone and isopropyl-2-hydroxy-desamino amicarbazone residues in grains (rice, wheat, corn, buckwheat) and soybean. Several parameters, including liquid chromatography and tandem mass spectrometry conditions, extraction approaches and the adsorbents for clean-up, which might influence the accuracy of the method, were extensively investigated. The established method was further validated by determining the linearity (R(2) > 0.99), fortified recovery (79-118%), precision (1-12%) and sensitivity (limit of quantification, 5 MUg/kg for amicarbazone and desamino amicarbazone, and 10 MUg/kg for isopropyl-2-hydroxy-desamino amicarbazone). Finally, the established method was successfully applied to determine the residues of amicarbazone and its metabolites in 49 real samples of grain and soybean. PMID- 25907802 TI - Radiotherapy following surgery in keloid treatment: our protocol. AB - BACKGROUND: Despite the wide availability of literature on keloids, their onset is not completely understood. Several protocols have been described to treat keloids, but none are considered to be a gold standard. In this paper, we will report our experience treating recurrent keloids with surgical excision, followed by immediate postoperative radiotherapy, focusing on the irradiation protocol, to better define the treatment schedule, dose, and results. METHODS: From September 2009 to July 2012, 10 patients were referred to our department because of unresponsive keloids. All patients underwent 6-MeV electron beam radiotherapy, up to a total dose of 20 Gy, 24-48 hours after radical surgical keloid excision. RESULTS: Three patients had excellent results, while 5 patients had good results and 2 had moderate results; none of the cases had poor results. No major adverse events were observed. Small keloids can be treated with non-surgical therapy or radical excision, although followed by an adjuvant therapy. Radiotherapy seems to be a better adjuvant approach. The mechanism for the radiotherapeutic prevention of keloids is still poorly understood. It may act by controlling collagen synthesis through the elimination of abnormally-activated fibroblasts. CONCLUSIONS: From our results, postoperative electron radiotherapy is an effective and well-tolerated treatment to prevent keloid recurrence, especially in patients with bulky keloids or recurrent disease. PMID- 25907800 TI - Enterobacteria-secreted particles induce production of exosome-like S1P containing particles by intestinal epithelium to drive Th17-mediated tumorigenesis. AB - Gut-associated inflammation plays a crucial role in the progression of colon cancer. Here, we identify a novel pathogen-host interaction that promotes gut inflammation and the development of colon cancer. We find that enteropathogenic bacteria-secreted particles (ET-BSPs) stimulate intestinal epithelium to produce IDENs (intestinal mucosa-derived exosome-like nanoparticles) containing elevated levels of sphingosine-1-phosphate, CCL20 and prostaglandin E2 (PGE2). CCL20 and PGE2 are required for the recruitment and proliferation, respectively, of Th17 cells, and these processes also involve the MyD88-mediated pathway. By influencing the recruitment and proliferation of Th17 cells in the intestine, IDENs promote colon cancer. We demonstrate the biological effect of sphingosine-1 phosphate contained in IDENs on tumour growth in spontaneous and transplanted colon cancer mouse models. These findings provide deeper insights into how host microbe relationships are mediated by particles secreted from both bacterial and host cells. PMID- 25907801 TI - Proinflammatory mediators alter expression of nuclear factor kappa B-regulating deubiquitinases in sinonasal epithelial cells. AB - BACKGROUND: Nuclear factor kappaB (NF-kappaB) is a vital transcription factor that is activated by numerous inflammatory stimuli. Its activity is tightly regulated by a family of deubiquitinating enzymes (A20, Cezanne, cylindromatosis [CYLD]) that function in a negative-feedback loop, a process that prevents chronic and systemic inflammation. This study seeks to characterize the expression and functional role of NF-kappaB-regulating deubiquitinases in the sinonasal epithelium. METHODS: Expression of A20, Cezanne, and CYLD was assessed in normal sinonasal tissue using immunohistochemistry. Cultured sinonasal epithelial cells (SNECs) were stimulated with proinflammatory cytokines (tumor necrosis factor alpha [TNF-alpha], interleukin 4 [IL]-4, IL-13) or lipopolysaccharide (LPS) and changes in NF-kappaB activation and deubiquitinase expression were assessed using Western blots and quantitative real-time polymerase chain reaction (qRT-PCR), respectively. RESULTS: NF-kappaB was activated in response to LPS and TNF-alpha, but not IL-4 or IL-13. A20, Cezanne, and CYLD were all expressed in sinonasal tissue, primarily along the apical surface of the epithelium. Proinflammatory mediators primarily affected expression of A20, with upregulation by LPS and TNF-alpha and downregulation by IL-4 and IL-13. CONCLUSION: The NF-kappaB-regulating deubiquitinases A20, Cezanne, and CYLD are expressed in sinonasal tissue and are differentially induced by proinflammatory cytokines and the microbial antigen, LPS. These results suggest an important role for NF-kappaB-regulating deubiquitinases in mucosal immunity and homeostasis. PMID- 25907803 TI - Atomic scale study of CU clustering and pseudo-homogeneous Fe-Si nanocrystallization in soft magnetic FeSiNbB(CU) alloys. AB - A local electrode atom probe has been employed to trace the onset of Cu clustering followed by their coarsening and subsequent growth upon rapid (10s) annealing of an amorphous Fe73.5Si15.5Cu1Nb3B7 alloy. It has been found that the clustering of Cu atoms introduces heterogeneities in the amorphous matrix, leading to the formation of Fe rich regions which crystallizes pseudo homogeneously into Fe-Si nanocrystals upon annealing. In this paper, we present the data treatment method that allows for the visualization of these different phases and to understand their morphology while still quantifying them in terms of their size, number density and volume fraction. The crystallite size of Fe-Si nanocrystals as estimated from the atom probe data are found to be in good agreement with other complementary techniques like XRD and TEM, emphasizing the importance of this approach towards accurate structural analysis. In addition, a composition driven data segmentation approach has been attempted to determine and distinguish nanocrystalline regions from the remaining amorphous matrix. Such an analysis introduces the possibility of retrieving crystallographic information from extremely fine (2-4 nm sized) nanocrystalline regions of very low volume fraction (< 5 Vol%) thereby providing crucial in-sights into the chemical heterogeneity induced crystallization process of amorphous materials. PMID- 25907804 TI - Functional characterization of different ORFs including luciferase-like monooxygenase genes from the mensacarcin gene cluster. AB - The biologically active compound mensacarcin is produced by Streptomyces bottropensis. The cosmid cos2 contains a large part of the mensacarcin biosynthesis gene cluster. Heterologous expression of this cosmid in Streptomyces albus J1074 led to the production of the intermediate didesmethylmensacarcin (DDMM). In order to gain more insights into the biosynthesis, gene inactivation experiments were carried out by lambda-Red/ET-mediated recombination, and the deletion mutants were introduced into the host S. albus. In total, 23 genes were inactivated. Analysis of the metabolic profiles of the mutant strains showed the complete collapse of DDMM biosynthesis, but upon overexpression of the SARP regulatory gene msnR1 in each mutant new intermediates were detected. The compounds were isolated, and their structures were elucidated. Based on the results the specific functions of several enzymes were determined, and a pathway for mensacarcin biosynthesis is proposed. PMID- 25907806 TI - Hyperthermia-induced seizures alter adenosine A1 and A2A receptors and 5' nucleotidase activity in rat cerebral cortex. AB - Febrile seizure is one of the most common convulsive disorders in children. The neuromodulator adenosine exerts anticonvulsant actions through binding adenosine receptors. Here, the impact of hyperthermia-induced seizures on adenosine A1 and A2A receptors and 5'-nucleotidase activity has been studied at different periods in the cerebral cortical area by using radioligand binding, real-time PCR, and 5' nucleotidase activity assays. Hyperthermic seizures were induced in 13-day-old rats using a warmed air stream from a hair dryer. Neonates exhibited rearing and falling over associated with hindlimb clonus seizures (stage 5 on Racine scale criteria) after hyperthermic induction. A significant increase in A1 receptor density was observed using [(3) H]DPCPX as radioligand, and mRNA coding A1 was observed 48 h after hyperthermia-induced seizures. In contrast, a significant decrease in A2A receptor density was detected, using [(3) H]ZM241385 as radioligand, 48 h after hyperthermia-evoked convulsions. These short-term changes in A1 and A2A receptors were also accompanied by a loss of 5'-nucleotidase activity. No significant variations either in A1 or A2A receptor density or 5' nucleotidase were observed 5 and 20 days after hyperthermic seizures. Taken together, both regulation of A1 and A2A receptors and loss of 5'-nucleotidase in the cerebral cortex suggest the existence of a neuroprotective mechanism against seizures. Febrile seizure is one of the most common convulsive disorders in children. The consequences of hyperthermia-induced seizures (animal model of febrile seizures) on adenosine A1 and A2A receptors and 5'-nucleotidase activity have been studied at different periods in cerebral cortical area. A significant increase in A1 receptor density and mRNA coding A1 was observed 48 h after hyperthermia-induced seizures. In contrast, a significant decrease in A2A receptor density and 5'-nucleotidase activity was detected 48 h after convulsions evoked by hyperthermia. These changes suggest the possible existence of a neuroprotective mechanism against seizures. PMID- 25907807 TI - Bimodal Programming: A Survey of Current Clinical Practice. AB - PURPOSE: The purpose of this study was to determine the current clinical practice in approaches to bimodal programming in the United States. To be specific, if clinicians are recommending bimodal stimulation, who programs the hearing aid in the bimodal condition, and what method is used for programming the hearing aid? METHOD: An 11-question online survey was created and sent via email to a comprehensive list of cochlear implant programming centers in the United States. The survey was sent to 360 recipients. RESULTS: Respondents in this study represented a diverse group of clinical settings (response rate: 26%). Results indicate little agreement about who programs the hearing aids, when they are programmed, and how they are programmed in the bimodal condition. Analysis of small versus large implant centers indicated small centers are less likely to add a device to the contralateral ear. CONCLUSIONS: Although a growing number of cochlear implant recipients choose to wear a hearing aid on the contralateral ear, there is inconsistency in the current clinical approach to bimodal programming. These survey results provide evidence of large variability in the current bimodal programming practices and indicate a need for more structured clinical recommendations and programming approaches. PMID- 25907805 TI - MicroRNA-135b regulates ERalpha, AR and HIF1AN and affects breast and prostate cancer cell growth. AB - MicroRNAs (miRNAs) regulate a wide range of cellular signaling pathways and biological processes in both physiological and pathological states such as cancer. We have previously identified miR-135b as a direct regulator of androgen receptor (AR) protein level in prostate cancer (PCa). We wanted to further explore the relationship of miR-135b to hormonal receptors, particularly estrogen receptor alpha (ERalpha). Here we show that miR-135b expression is lower in ERalpha-positive breast tumors as compared to ERalpha-negative samples in two independent breast cancer (BCa) patient cohorts (101 and 1302 samples). Additionally, the miR-135b expression is higher in AR-low PCa patient samples (47 samples). We identify ERalpha as a novel miR-135b target by demonstrating miR 135b binding to the 3'UTR of the ERalpha and decreased ERalpha protein and mRNA level upon miR-135b overexpression in BCa cells. MiR-135b reduces proliferation of ERalpha-positive BCa cells MCF-7 and BT-474 as well as AR-positive PCa cells LNCaP and 22Rv1 when grown in 2D. To identify other genes regulated by miR-135b we performed gene expression studies and found a link to the hypoxia inducible factor 1alpha (HIF1alpha) pathway. We show that miR-135b influences the protein level of the inhibitor for hypoxia inducible factor 1alpha (HIF1AN) and is able to bind to HIF1AN 3'UTR. Our study demonstrates that miR-135b regulates ERalpha, AR and HIF1AN protein levels through interaction with their 3'UTR regions, and proliferation in ERalpha-positive BCa and AR-positive PCa cells. PMID- 25907808 TI - Separation of liquid domains in model membranes induced with high hydrostatic pressure. AB - We have imaged the formation of membrane microdomains immediately after their induction using a novel technology platform coupling high hydrostatic pressure to fluorescence microscopy. After formation, the ordered domains are small and highly dynamic. This will enhance links between model lipid assemblies and dynamic processes in cellular membranes. PMID- 25907813 TI - Predictors of depression outcomes among abstinent methamphetamine-dependent individuals exposed to an exercise intervention. AB - BACKGROUND AND OBJECTIVES: This paper expands on a study investigating depression outcomes in response to an 8-week exercise intervention among methamphetamine (MA) dependent individuals in early recovery. METHODS: A total of 135 MA dependent individuals enrolled in residential treatment were randomly assigned to either a structured exercise intervention or a structured health education control group. Both groups were similar in format: 60-minute sessions, offered three times a week over an 8-week study period. RESULTS: Results showed that at the 8-week trial endpoint, participants randomized to the exercise intervention showed significantly greater reduction in depression symptom scores than participants randomized to the health education group, and that participants who attended the greatest number of exercise sessions derived the greatest benefit. This paper further analyzes study data to uncover individual predictors of depression response to exercise and finds that among participants randomized to exercise treatment, individuals with the most severe medical, psychiatric, and addiction disease burden at baseline showed the most significant improvement in depressive symptoms by study endpoint. CONCLUSIONS: Our findings suggest that exercise in moderate dose is effective at treating depressive symptoms in individuals in early recovery from addiction, and furthermore, that treatment with exercise appears to be particularly beneficial to individuals who suffer from severe medical, psychiatric, and addictive disorders. PMID- 25907814 TI - Enforced abstinence from tobacco during in-patient dual-diagnosis treatment improves substance abuse treatment outcomes in smokers. AB - BACKGROUND AND OBJECTIVES: Although the prevalence of tobacco use in those in substance abuse treatment is known to be quite high, most treatment programs do not address tobacco. The purpose of this study was to determine substance abuse recovery rates a year after treatment in a fully integrated, 90-day inpatient, dual diagnosis treatment program where patients are required to quit tobacco use in addition to drug and alcohol use for the duration of their 3 month stay. Tobacco is treated in the same way as other drugs and alcohol. METHODS: One hundred fifty-four patients enrolled in a yearlong follow-up after treatment study consisting of monthly phone contact to assess recovery from substance abuse. RESULTS: One hundred forty (n=140) patients completed the year follow-up. At the time of entry into the program 120 (86%) were using tobacco daily. At the end of the year this decreased to 102 (73%). Patients who were using tobacco were more likely to relapse to other drugs or alcohol (p = .01). Patients who actively attempted to abstain from tobacco after treatment were significantly more likely to remain continuously abstinent throughout the year (p = .03). CONCLUSIONS: This study demonstrates that tobacco use is correlated with relapse and addressing tobacco in treatment as seriously as and in the same fashion as other drugs, improves outcomes. SCIENTIFIC SIGNIFICANCE: When provided with a tobacco free treatment environment for 90 days, patients with substance abuse and mental illness can and do make the decision to quit tobacco and stay quit, aiding their ability to remain sober. PMID- 25907820 TI - Survivorship - searching for new directions. PMID- 25907815 TI - Baseline characteristics of patients predicting suitability for rapid naltrexone induction. AB - BACKGROUND AND OBJECTIVES: Extended-release (XR) injection naltrexone has proved promising in the treatment of opioid dependence. Induction onto naltrexone is often accomplished with a procedure known as rapid naltrexone induction. The purpose of this study was to evaluate pre-treatment patient characteristics as predictors of successful completion of a rapid naltrexone induction procedure prior to XR naltrexone treatment. METHODS: A chart review of 150 consecutive research participants (N = 84 completers and N = 66 non-completers) undergoing a rapid naltrexone induction with the buprenorphone-clonidine procedure were compared on a number of baseline demographic, clinical and psychosocial factors. Logistic regression was used to identify client characteristics that may predict successful initiation of naltrexone after a rapid induction-detoxification. RESULTS: Patients who failed to successfully initiate naltrexone were younger (AOR: 1.040, CI: 1.006, 1.075), and using 10 or more bags of heroin (or equivalent) per day (AOR: 0.881, CI: 0.820, 0.946). Drug use other than opioids was also predictive of failure to initiate naltrexone in simple bivariate analyses, but was no longer significant when controlling for age and opioid use level. CONCLUSIONS: Younger age, and indicators of greater substance dependence severity (more current opioid use, other substance use) predict difficulty completing a rapid naltrexone induction procedure. Such patients might require a longer period of stabilization and/or more gradual detoxification prior to initiating naltrexone. SCIENTIFIC SIGNIFICANCE: Our study findings identify specific characteristics of patients who responded positively to rapid naltrexone induction. PMID- 25907821 TI - Prevalence and management of pulmonary comorbidity in patients with lung and head and neck cancer. AB - BACKGROUND: The simultaneous presence of cancer and other medical conditions (comorbidity) is frequent. Cigarette smoking is the major risk factor for as well head and neck cancer (HNC) and lung cancer (LC) as chronic obstructive pulmonary disease (COPD). COPD is the most common comorbidity in LC patients, and presence of COPD worsens the prognosis of HNC and LC. COPD is under-diagnosed and under treated in the Danish population. The aims of this study were to determine the prevalence of COPD in a HNC and LC population, and to determine the need and feasibility of a randomized controlled phase II trial comparing usual care with optimized medical treatment of COPD in cancer patients. MATERIAL AND METHODS: All patients with HNC or LC referred for oncologic treatment in a university hospital during a 10-month period were invited to attend a pulmonary clinic for evaluation of lung function. Patients who were found to have concomitant COPD were randomized to intervention or usual care. Primary endpoints were prevalence of COPD among the referred patients with either LC or HNC, and further whether the patients that were diagnosed with COPD already received treatment in accordance with Danish COPD guidelines. Secondary outcome was feasibility, i.e. the proportion of eligible patients that accepted follow-up in the pulmonary clinic for 24 weeks in addition to oncological treatment. The design of the randomized trail is described in detail. RESULTS: In total 130 patients of whom 65% had LC and 35% HNC have been screened during the first seven months of this ongoing trial. Sixty-eight percent of LC patients and 22% of HNC patients had COPD. All but one of 68 eligible patients accepted randomization. Nearly one third (31%) of the LC and HNC patients with COPD were diagnosed prior to study entry, and of these, only 33% were receiving correct treatment according to current guidelines. CONCLUSION: For patients with LC, and to a lesser extend HNC, there is a need for improved diagnosis and treatment of concomitant COPD. Furthermore, patients found it acceptable to be scheduled for a 24-week follow-up in a pulmonary clinic along with their oncological treatment. PMID- 25907822 TI - A longitudinal study of follow-up activities after curative treatment for head and neck cancer. AB - PURPOSE: To test the hypothesis that head and neck cancer (HNC) patients are in need of specialized follow-up (FU). This was done by an evaluation of the FU activities in a cohort of patients followed longitudinally for five years with focus on optimal duration and interval of post-therapeutic follow-up. METHODS: The study evaluated a cohort consisting of 197 consecutive patients with HNC treated at Aarhus University Hospital from 1 January to 31 December 2009. The inclusion criteria was that patients should be deemed free of disease two months after completed primary curative intended treatment or after primary curative salvage. It left 141 patients available for analysis. Data were collected through a medical chart review and from the Danish Head and Neck Cancer Group (DAHANCA) database. Parameters recorded were: regular or extraordinary visit, alarm symptoms, late morbidity and the consequences of these. RESULTS: The 141 patients underwent 1408 FU visits. Only 15 of the 141 patients had no tumor problems or morbidity issues raised at any FU visit. Suspicion of recurrent disease was observed at 207 of the 1408 FU visits, involving 97 patients and resulted in a total of 370 diagnostic procedures; 170 (82%) visits with suspicion of recurrence occurred within 31/2 years after end of treatment. A recurrence was verified in 30 patients. Additionally four new primary head and neck cancer was diagnosed during follow-up. There were 1150 visits (82%) involving 135 patients in which late treatment-related morbidity was recorded. Actions taken related to morbidity happened in 71 patients, but no new problems appeared after three years. CONCLUSION: The study document the need of specialized FU, as 86% of all HNC survivors have tumor or severe morbidity issues during FU. The data suggest that 31/2-year FU after ended therapy may be sufficient for the majority of patients. PMID- 25907823 TI - [Determinants of participation in a program for diabetes education in children]. PMID- 25907824 TI - Validation of the composite autonomic symptom scale 31 (COMPASS-31) in patients with and without small fiber polyneuropathy. AB - BACKGROUND AND PURPOSE: The recently developed composite autonomic symptom score 31 (COMPASS-31) is a questionnaire that assess symptoms of dysautonomia. It was distilled from the well-established Autonomic Symptom Profile questionnaire. COMPASS-31 has not yet been externally validated. To do so, its psychometric properties and convergent validity in patients with and without objective diagnosis of small fiber polyneuropathy (SFPN) were assessed. METHODS: Internal validity and reliability of COMPASS-31 were assessed in participants with or without SFPN spanning the full range of severity of autonomic symptoms. Convergent validity was assessed by comparing results of the COMPASS-31 with the "gold standard" autonomic function testing that measures cardiovagal, adrenergic and sudomotor functions. Additionally, relationships between COMPASS-31 and the Short Form McGill Pain Questionnaire, Short Form Health Survey and 0-10 numeric pain scale were measured. COMPASS-31 and all other questionnaire results were compared between patients with or without evidence of SFPN, objectively confirmed by distal-leg PGP9.5-immunolabeled skin biopsy. RESULTS: Amongst 66 participants (28 SFPN+, 38 SFPN-), COMPASS-31 total scores had excellent internal validity (Cronbach's alpha = 0.919), test-retest reliability (r(s) = 0.886; P < 0.001) and good convergent validity (r(s) = 0.474; P < 0.001). COMPASS-31 scores differed between subjects with or without SFPN (Z = -3.296, P < 0.001) and demonstrated fair diagnostic accuracy. Area under the Receiver Operating Characteristic curve was 0.749 (P = 0.01, 95% confidence interval 0.627-0.871). CONCLUSIONS: COMPASS 31 has good psychometric properties in the population of patients being evaluated for SFPN and thus it might be useful as an initial screening tool for the more expensive SFPN objective tests. PMID- 25907825 TI - Protecting the fair trial rights of mentally disordered defendants in criminal proceedings: Exploring the need for further EU action. AB - Using the new legal basis provided by the Lisbon Treaty, the Council of the European Union has endorsed the 2009 Procedural Roadmap for strengthening the procedural rights of suspected or accused persons in criminal proceedings. This Roadmap has so far resulted in six measures from which specific procedural minimum standards have been and will be adopted or negotiated. So far, only Measure E directly touches on the specific issue of vulnerable persons. This Measure has recently produced a tentative result through a Commission Recommendation on procedural safeguards for vulnerable persons in criminal proceedings. This contribution aims to discuss the need for the introduction of binding minimum standards throughout Europe to provide additional protection for mentally disordered defendants. The paper will examine whether or not the member states adhere to existing fundamental norms and standards in this context, and whether the application of these norms and standards should be made more uniform. For this purpose, the procedural situation of mentally disordered defendants in Belgium and England and Wales will be thoroughly explored. The research establishes that Belgian law is unsatisfactory in the light of the Strasbourg case law, and that the situation in practice in England and Wales indicates not only that there is justifiable doubt about whether fundamental principles are always adhered to, but also that these principles should become more anchored in everyday practice. It will therefore be argued that there is a need for putting Measure E into practice. The Commission Recommendation, though only suggestive, may serve as a necessary and inspirational vehicle to improve the procedural rights of mentally disordered defendants and to ensure that member states are able to cooperate within the mutual recognition framework without being challenged on the grounds that they are collaborating with peers who do not respect defendants' fundamental fair trial rights. Throughout this contribution the term 'defendant' will be used, and no difference will be made in terminology between suspected and accused persons. This contribution only covers the situation of mentally disordered adult defendants. PMID- 25907827 TI - Asymmetric total synthesis of mycoleptodiscin A. AB - The first total synthesis of mycoleptodiscin A, a structurally unusual indolosesquiterpenoid possessing an ortho-benzoquinone motif, has been accomplished. A sulfone alkylation coupled two readily available fragments to give an aryl triene intermediate. The tetracyclic core of the molecule was assembled through a highly enantioselective iridium-catalyzed polyene cyclization. The benzylic homologation was achieved by a cationic cyanation. The indole motif was constructed via a copper-mediated intramolecular C-N bond formation at a late stage. PMID- 25907826 TI - The design evolution of interbody cages in anterior cervical discectomy and fusion: a systematic review. AB - BACKGROUND: Anterior cervical discectomy with fusion is a common surgical procedure for patients experiencing pain and/or neurological deficits due to cervical spondylosis. Although iliac crest bone graft remains the gold standard today, the associated morbidity has inspired the search for alternatives, including allograft, synthetic and factor/cell-based grafts; and has further led to a focus on cage fusion technology. Compared to their graft counterparts, cage interbody implants have enhanced biomechanical properties, with designs constantly improving to maximise biocompatibility and osseointegration. We present a systematic review examining the historical progress of implant designs and performance, as well as an update on the currently available designs, and the potential future of cervical interbody implants. METHODS: We performed a systematic review using the keywords "cervical fusion implant design", with no limits on year of publication. Databases used were PubMed, Medline, Embase and Cochrane. In addition, the search was extended to the reference lists of selected articles. RESULTS: 180 articles were reviewed and 64 articles were eligible for inclusion. Exclusion criteria were based around study design, implant information and patient cohorts. The evolution of cage implant design has been shaped by improved understanding of ideal anatomy, progress in materials research and continuing experimentation of structural design. Originally, designs varied primarily in their choice of structure, however long-term studies have displayed the overall advantages of non-threaded, wedge shaped cages in complementing healthy anatomical profiles, and thus focus has shifted to refining material utilisation and streamlining anterior fixation. CONCLUSIONS: Evolution of design has been dramatic over the past decades; however an ideal cage design has yet to be realised. Current research is focusing on the promotion of osseointegration through bioactiviation of surface materials, as well as streamlining anterior fixation with the introduction of integrated screws and zero profile designs. Future designs will benefit from a combination of these advances in order to achieve ideal disc heights, cervical alignments and fusions. PMID- 25907829 TI - Hemorrhage as a sign of treatment failure after intra-arterial chemotherapy in retinoblastoma. AB - Intra-arterial melphalan chemotherapy (IAC) continues to demonstrate excellent utility in the treatment of retinoblastoma. We present the case of a 3-month-old boy diagnosed with with unilateral, advanced stage 5B retinoblastoma and a Coats' response in the right eye. After laser therapy he received 3 doses of IAC. Intraretinal hemorrhaging, first noted after the second dose and worsening after the third, preceded complex exudative retinal detachment. With little visual potential and evidence of atropy, the eye was enucleated. This case illustrates that intraretinal hemorrhage may serve as an early predictor of treatment failure. PMID- 25907828 TI - Transcriptomic responses of corpuscle of Stannius gland of Japanese eels (Anguilla japonica) to changes in water salinity. AB - Physiological studies of a unique endocrine gland in fish, named corpuscles of Stannius (CS), described a Ca2(+)-regulatory function for this gland mediated by stanniocalcin-1, a hypocalcemic polypeptide hormone. However, to date, the endocrine functions of the glands have not been completely elucidated.We hypothesized that other unidentified active principles in the glands are involved in the regulation of plasma ion (Na(+), Ca2(+)) and/or blood pressure. In this study, transcriptome sequencing of CS glands was performed using Japanese eels (Anguilla japonica) adapted to freshwater (FW) or seawater (SW) to reveal the presence and differential expression of genes encoding proteins related to the ion-osmoregulatory and pressor functions. We acquired a total of 14.1 Mb and 12.1 Mb quality-trimmed reads from the CS glands collected from FW and SW adapted eels, respectively. The de novo assembly resulted in 9254 annotated genes. Among them, 475 genes were differentially expressed with 357 up- and 118 down-regulated in the SW group. Gene ontology analysis further demonstrated the presence of natriuresis and pressor related genes. In summary, ours is the first study using high-throughput sequencing to identify gene targets that could explain the physiological importance of the CS glands. PMID- 25907830 TI - Ultrasound evaluation of glaucoma drainage devices in children. AB - This study evaluated B-scan ultrasound as a technique for assessing glaucoma drainage device (GDD) patency/function in refractory pediatric glaucoma. We retrospectively evaluated 70 eyes of 52 patients after Ahmed (n = 40 eyes), Baerveldt (n = 27 eyes) and Molteno (n = 5 eyes) GDD implantation; 2 eyes each had 2 GDDs. Median age was 6.5 years. Glaucoma diagnoses included primary congenital glaucoma (n = 19) and secondary glaucoma associated with aphakia (n = 16), aniridia (n = 5), Peters anomaly (n = 3), uveitis (n = 2), and other conditions (n = 7). B-scan ultrasound evaluation proved helpful to clinical assessment when the GDD tube was not seen because of opaque corneas (n = 20 eyes), the bleb was not visualized (n = 21 eyes), or IOP was elevated (n = 28 eyes). Ultrasound findings suggesting a nonpatent or malfunctioning GDD were further confirmed by subsequent intraoperative bleb needling (n = 2 eyes) and GDD revision (n = 7 eyes). B-scan ultrasound evaluation can serve as a useful adjunct in evaluating GDD patency/function in selected eyes with refractory pediatric glaucoma and may aid in clinical management. PMID- 25907832 TI - The PTEN-AKT-mTOR/RICTOR Pathway in Nasal Natural Killer Cell Lymphoma Is Activated by miR-494-3p via PTEN But Inhibited by miR-142-3p via RICTOR. AB - Nasal natural killer (NK) cell lymphoma (NNL) is an Epstein-Barr virus-associated lymphoma of cytotoxic NK cell origin. The Epstein-Barr virus-encoded miR-BART20 5p inhibits T-bet (TBX21), the master transcription factor of cytotoxic NK cells. To further explore the roles of miRNAs in NNLs, we measured the miRNA expression profiles of 36 NNLs. miR-21, miR-142-3p, miR-126, miR-451, and miR-494-3p were the top five miRNAs with the highest expression levels. By using pathway analysis, we identified associations between all of the five miRNAs with the PTEN AKT-mTOR pathway, in which PTEN suppresses the oncogenic AKT, and mTOR mediates the oncogenic effects of AKT. YT and NK92 cells derived from NK cell lymphomas were used. miR-494-3p inhibited PTEN with secondary activation of AKT in NK92 cells, and miR-142-3p inhibited RICTOR, a key component of the mTOR complex, with secondary suppression of AKT in YT cells. Significantly, T-bet inhibited the PTEN AKT-mTOR/RICTOR pathway through induction of PTEN and suppression of RICTOR. Therefore, a molecular circuit of T-bet, PTEN, AKT, and RICTOR is regulated by miR-BART20-5p, miR-494-3p, and miR-142-3p. This circuit is involved in the pathogenesis of NNL. Hence, antagomirs to miR-BART20-5p or miR-494-3p, miR-142-3p mimics, or AKT inhibitors may be useful in NNL therapy. PMID- 25907831 TI - Loss of FOXA1 Drives Sexually Dimorphic Changes in Urothelial Differentiation and Is an Independent Predictor of Poor Prognosis in Bladder Cancer. AB - We previously found loss of forkhead box A1 (FOXA1) expression to be associated with aggressive urothelial carcinoma of the bladder, as well as increased tumor proliferation and invasion. These initial findings were substantiated by The Cancer Genome Atlas, which identified FOXA1 mutations in a subset of bladder cancers. However, the prognostic significance of FOXA1 inactivation and the effect of FOXA1 loss on urothelial differentiation remain unknown. Application of a univariate analysis (log-rank) and a multivariate Cox proportional hazards regression model revealed that loss of FOXA1 expression is an independent predictor of decreased overall survival. An ubiquitin Cre-driven system ablating Foxa1 expression in urothelium of adult mice resulted in sex-specific histologic alterations, with male mice developing urothelial hyperplasia and female mice developing keratinizing squamous metaplasia. Microarray analysis confirmed these findings and revealed a significant increase in cytokeratin 14 expression in the urothelium of the female Foxa1 knockout mouse and an increase in the expression of a number of genes normally associated with keratinocyte differentiation. IHC confirmed increased cytokeratin 14 expression in female bladders and additionally revealed enrichment of cytokeratin 14-positive basal cells in the hyperplastic urothelial mucosa in male Foxa1 knockout mice. Analysis of human tumor specimens confirmed a significant relationship between loss of FOXA1 and increased cytokeratin 14 expression. PMID- 25907833 TI - Comparing multi-module connections in membrane chromatography scale-up. AB - Membrane chromatography is increasingly used for protein purification in the biopharmaceutical industry. Membrane adsorbers are often pre-assembled by manufacturers as ready-to-use modules. In large-scale protein manufacturing settings, the use of multiple membrane modules for a single batch is often required due to the large quantity of feed material. The question as to how multiple modules can be connected to achieve optimum separation and productivity has been previously approached using model proteins and mass transport theories. In this study, we compare the performance of multiple membrane modules in series and in parallel in the production of a protein antigen. Series connection was shown to provide superior separation compared to parallel connection in the context of competitive adsorption. PMID- 25907834 TI - Increased mannosylphosphorylation of N-glycans by heterologous expression of YlMPO1 in glyco-engineered Saccharomyces cerevisiae for mannose-6-phosphate modification. AB - Mannosylphosphorylated N-glycans found in yeasts can be converted to those containing mannose-6-phosphate, which is a key factor for lysosomal targeting. In the traditional yeast Saccharomyces cerevisiae, both ScMNN4 and ScMNN6 genes are required for efficient mannosylphosphorylation. ScMnn4 protein has been known to be a positive regulator of ScMnn6p, a real enzyme for mannosylphosphorylation. On the other hand, YlMpo1p, a ScMnn4p homologue, mediates mannosylphosphorylation in Yarrowia lypolytica without the involvement of ScMnn6p homologues. In this study, we show that heterologous expression of YlMpo1p can perform and enhance mannosylphosphorylation in S. cerevisiae in the absence of ScMnn4p and ScMnn6p. Moreover, the level of mannosylphosphorylation of N-glycans enhanced by YlMpo1p overexpression is much higher than that with ScMnn4p overexpression, and this is highlighted further in Scmnn4- and Scmnn6-disrupted mutants. When YlMpo1p overexpression is applied to glyco-engineered S. cerevisiae in which the synthesis of immunogenic glycans is abolished, a great increase of bi mannosylphosphorylated glycan is observed. Through an in vitro process involving the uncapping of the outer mannose residue, this bi-mannosylphosphorylated structure is changed to a bi-phosphorylated structure with high affinity for mannose-6-phosphate receptor. The superior ability of YlMpo1p to increase bi mannosylphosphorylated glycan in yeast shows promise for the production of therapeutic enzymes with improved lysosomal targeting capability. PMID- 25907835 TI - Beneficial effects of finasteride on hepatic and pulmonary immune response after trauma hemorrhage in mice. AB - The literature reveals evidence for a gender specific outcome after major trauma and hemorrhage. Increased levels of male sex hormones such as testosterone and even more dihydrotestosterone (DHT) mediate negative effects on the posttraumatic immune response. Pretreatment with finasteride several days before trauma hemorrhage (TH) led to improved outcomes in mice. We hypothesized that finasteride mediates its protective effects also when administered after TH within the resuscitation process. METHODS: Male C57BL/6N-mice underwent TH (blood pressure: 35 mmHg, 90 min) followed by finasteride application and fluid resuscitation. Plasma cytokines (MIP-1beta, TNF-alpha, MCP-1, MCP-3, IL-6), productive capacity of alveolar macrophages (AM) and hepatic Kupffer cells (KC) and systemic DHT levels were determined 4 h and 24 h thereafter. Pulmonary and hepatic infiltration of PMN was determined by immunohistochemical staining. RESULTS: Finasteride treatment resulted in reduced levels of systemic cytokines. This was accompanied by a reduced posttraumatic cytokine secretion of AM as well as Kupffer cells, thereby reducing hepatic distant organ damage as measured by reduced PMN infiltration. Systemic DHT levels were decreased following finasteride treatment. CONCLUSION: Finasteride exerts salutary effects on the pulmonary and hepatic immune response using a therapeutic approach following TH in mice. Therefore, finasteride might represent a potential agent following multiple trauma and hemorrhage. PMID- 25907836 TI - The Potential Application of Mitochondrial Medicine in Toxicologic Poisoning. AB - The advancement of biomolecular techniques has continued to advance in the area of mitochondrial medicine. This has allowed clinicians and researchers to more effectively study the bioenergetics of the mitochondria in various disease states. One potential technique in mitochondrial medicine is the generation of cytoplasmic hybrids. A cytoplasmic hybrid or cybrid are created by introducing mitochondrial DNA (mtDNA) of interest into cells depleted of mtDNA. A cybrid is therefore a hybrid cell that mixes the nuclear genome from one cell with the mitochondrial genes from another cell. Cybrids are currently utilized in mitochondrial research to demonstrate mitochondrial involvement in a wide range of diseases that include diabetes, Parkinson's disease and inherited diseases. At this time the use of cybrids to study toxicologic poisoning is limited and offers a potential avenue of research in this area. PMID- 25907837 TI - [Hematological malignancy development from China perspective: past to present]. PMID- 25907839 TI - [The clinical significance of serum Epstein-Barr virus-determined nuclear antigen 1 (EBNA1)/latent membrane protein 1 (LMP1) assay in patients with nasal type extranodal NK/T-cell lymphoma]. AB - OBJECTIVE: To explore the clinical significance of the serum Epstein-Barr virus determined nuclear antigen 1 (EBNA1)/latent membrane protein 1 (LMP1) in patients with extranodal NK/T-cell lymphoma, nasal type (ENKL). METHODS: The serum EBNA1 and LMP1 were detected by real-time PCR in 36 ENKL patients hospitalized in Beijing Tongren Hospital from August 2010 to August 2013. Twenty healthy volunteers were recruited as controls. RESULTS: The median serum EBNA1 was 1.9*10(4) (ranged from 0 to 11.0*10(4)) copies/ul in ENKL patients and 8.0 (ranged from 0 to 43.8) copies/ul in healthy volunteers. The median serum LMP1 was 3.9*10(3) (ranged from 118.3 to 24.0*10(3)) copies/ul in ENKL patients and 3.3 (ranged from 0 to 33.3) copies/ul in healthy volunteers. Both EBNA1 and LMP1 were higher in ENKL patients than healthy volunteers (all P < 0.01). The median EBNA1 and LMP1 in ENKL patients posttreatment were 1.0*10(3) (ranged from 0 to 2.0 * 10(3)) copies/ul and 300.8 (ranged from 0 to 825.7) copies/ul respectively, which were both significantly decreased than pretreatment (all P < 0.05). The EBNA1 and LMP1 were decreased in effective treatment group versus ineffective treatment group (P < 0.05). The serum EBNA1 and LMP1 were positively correlated with lactic dehydrogenase (LDH) level (r = 0.364,0.546; P = 0.040,0.012). CONCLUSIONS: (1) The measurement of EBNA1/LMP1 may be useful in evaluating the therapeutic effect. (2) The serum EBNA1/LMP1 may reflect the tumor load in ENKL patients. PMID- 25907838 TI - [Cytomegalovirus specific cytotoxic T lymphocytes for treatment of refractory cytomegalovirus infection in patients following allogeneic hematopoietic stem cell transplantation]. AB - OBJECTIVE: To explore the efficacy and safety of expanding cytomegalovirus specific cytotoxic T lymphocytes (CMV-CTL) in vitro on refractory cytomegalovirus (CMV) infection. METHODS: A total of twenty-eight patients with refractory CMV infection following stem cell transplant (SCT) were treated with CMV-specific T cells, of which 19 cases were from hematopoietic stem cell donors and 9 from third-party donors. In the first course, CTL was infused once or twice and the efficacy and adverse effects were evaluated. If CMV infection relapsed after complete remission (CR), the second course would be given. RESULTS: Twenty-one patients with refractory CMV viremia and seven with CMV diseases were eligible for adoptive T-cell transfer. After a median of 76 (39-321) days post-transplant, patients received a median dose of 1.0 (0.5-10.0) * 10(7) CTL infusion in the first course. All twenty-one patients with CMV viremia and four patients with CMV diseases achieved CR after using 9 (3-23) and 7 (4-18) days respecitvely. Six patients with CMV viremia and one with CMV disease received the second course after recurrence. Another four patients with viremia and one with CMV disease had reached CR again. Five patients exhibited graft-versus-host diseases (GVHD), all experiencing mild to moderate skin involvement. Six patients died of CMV infection and 2 of other transplantation-related complications. CONCLUSION: Our preliminary results have shown that CMV-CTL infusion is effective against refractory cytomegalovirus infection following SCT, but therapeutic schedule still needs to be improved in further study. PMID- 25907840 TI - [A clinical observation of treatment of peripheral T-cell lymphoma with L asparaginase-containing combination chemotherapy]. AB - OBJECTIVE: To investigate the efficacy and adverse effects of L-asparaginase (L ASP) containing regimens in patients with newly diagnosed peripheral T-cell lymphoma. METHODS: A total of 102 newly diagnosed patients with peripheral T-cell lymphoma who received combination chemotherapy with or without L-ASP were enrolled in the study between January 2011 and December 2013 in our hospital. Therapeutic and adverse effects were retrospectively analyzed, including the short-term efficacy such as complete remission (CR) rate, partial remission (PR) rate, overall remission (OR) rate, and long-term efficacy such as overall survival (OS) rate, progressive free survival (PFS) rate. RESULTS: The OR rate in patients treated with L-ASP containing regimens (L-ASP group) was apparently higher than the patients treated without L-ASP (non L-ASP group) [83.3% (35/42) vs 61.7% (37/60), P = 0.016]. Furthermore, the difference was especially significant in patients with stage III/IV [82.4% (28/34) vs 54.0% (27/50), P = 0.007] or IPI score >= 2 [82.1% (23/28) vs 50.0% (21/42), P = 0.006]. The 3-year OS rate of L-ASP group and non L-ASP group were 48.9% and 65.0% respectively (P = 0.974). Three-year PFS rate of L-ASP group and non L-ASP group were 40.8% and 61.0% respectively (P = 0.479). Neither had statistical significance. Although the incidence of adverse effects was higher in L-ASP group, most of them were mild and controllable after supportive treatment. There was no significant difference in serious infections caused by III-IV degree neutropenia between the two groups (P = 0.777). Other severe side-effects in L-ASP group such as hematencephalon and acute pancreatitis were only seen in one case respectively. CONCLUSIONS: Combination chemotherapy with L-ASP showed better short-term efficacy in newly diagnosed peripheral T-cell lymphoma patients and the adverse effects were controllable. Large scale prospective clinical trial of using L-ASP in peripheral T-cell lymphoma is worthy of developing and further studying. PMID- 25907841 TI - [A multicenter study of correlation between peripheral lymphocyte counts and CD(+)4T cell counts in HIV/AIDS patients]. AB - OBJECTIVE: To evaluate the accuracy of lymphocyte count as a surrogate for CD(+)4T cell count in treatment-naive HIV-infected adults. METHODS: A total of 2 013 HIV-infected patients were screened at 23 sites in China. CD(+)4T cell counts were measured by flow cytometry. Correlation between CD(+)4T cell count and peripheral lymphocyte count were analyzed by spearman coefficient. AUCROC were used to evaluate the performance of lymphocyte count as a surrogate for CD(+)4T cell count. RESULTS: The lymphocyte count and CD(+)4T cell count of these 2 013 patients were (1 600 +/- 670) * 10(6)/L and (244 +/- 148) * 10(6)/L respectively. CD(+)4T cell count were positively correlated with lymphocyte count (r = 0.482, P < 0.000 1). AUCROC of lymphocyte count as a surrogate for CD(+)4T cell counts of <100*10(6)/L, <200*10(6)/L and <350*10(6)/L were 0.790 (95%CI 0.761-0.818, P < 0.000 1), 0.733 (95%CI 0.710-0.755, P < 0.000 1) and 0.732 (95%CI 0.706-0.758, P < 0.000 1) respectively. CONCLUSION: Lymphocyte count could be considerad as a potential surrogate marker for CD(+)4T cell count in HIV/AIDS patients not having access to T cell subset test by flowcytometry. PMID- 25907842 TI - [The association between angiogenin gene variations and familial amyotrophic lateral sclerosis in Chinese Han patients]. AB - OBJECTIVE: To investigate effect of genetic variants in angiogenin (ANG) on the susceptibility of familial amyotrophic lateral sclerosis (FALS) in Han Chinese. METHODS: Thirty-one FALS families from 2009 to 2012 were collected and ANG gene was screened in the probands using PCR and direct sequencing. RESULTS: All 31 ALS families were autosomal dominant inheritance. No mutations and single nucleotide polymorphism were detectable in ANG gene in the 31 probands. CONCLUSION: Our study suggests that ANG gene variations may be rare in Chinese Han FALS. PMID- 25907843 TI - [A retrospective clinical analysis of 16 patients with scleroderma renal crisis]. AB - OBJECTIVE: To analyze the clinical features, laboratory tests, treatments and outcome of patients with scleroderma renal crisis (SRC). METHODS: We retrospectively reviewed the clinical and laboratory data of 16 patients with scleroderma renal crisis in Peking Union Medical College Hospital from May 2004 to May 2013. The treatment and outcome of SRC patients were also retrospectively analyzed. RESULTS: There were a total of 16 SRC patients including 5 male patients and 11 females. The median age at SRC onset was (49.9 +/- 12.3) years. It usually took 3.2 years from the diagnosis of systemic sclerosis (SSc) to SRC attack. Ten SRC patients belonged to diffuse cutaneous systemic sclerosis (dcSSc), and 6 patients were limited cutaneous systemic sclerosis (lcSSc). Among SRC patients, 16/16 were negative of anti-centromere antibodies (ACAs). All these 16 patients had hypertension and renal insufficiency, including 8 dialysis dependent after the onset of SRC and 7 with thrombotic microangiopathy. There were 3 patients receiving renal biopsy. The pathological findings were mainly summarized as intimal thickening and stenosis of renal arterioles. Among 13 patients with long-term followed-up, 11 patients received angiotensin converting enzyme inhibitors (ACEI), 5 patients died, 2 patients were dialysis dependent. Only 1 patient stopped dialysis after the combination treatment of ACEI and endothelin receptor antagonist. Another 5 patients didn't need dialysis. CONCLUSION: SRC usually occurred at the early course of SSc. dcSSc was more frequent than lcSSc. ACAs were rarely found in SRC patients. The immediate and sufficient use of ACEIs was still the cornerstone of SRC treatment. Future studies are needed to evaluate the efficacy of endothelin receptor antagonist in the treatment of SRC. PMID- 25907844 TI - [The prediction value of noninvasive bioreactance-based passive leg raising test in assessing fluid responsiveness in elderly patients with sepsis]. AB - OBJECTIVE: To investigate the value of bioreactance-based passive leg raising (PLR) test predicting fluid responsiveness of elderly patients with sepsis. METHODS: This prospective and self-controlled clinical study included 31 elderly patients with sepsis in the Department of Intensive Care Medicine of Zhejiang Hospital. Hemodynamic parameters including cardiac output (CO), stroke volume variation (SVV) were continuously recorded by bioreactance-based device (noninvasive cardiac output monitoring, NICOM) before and after PLR and volume expansion (VE) test. Patients were defined as responders if CO increased >= 10% after VE. RESULTS: A total of 100 PLR and VE tests in these 31 patients were evaluated.In 28 responders, CO[(5.11 +/- 2.10) L/min vs (5.91 +/- 2.45) L/min, P < 0.05; (5.06 +/- 2.06) L/min vs (5.77 +/- 2.47) L/min, P < 0.05] and SV [(59.61 +/- 18.22) ml vs (69.29 +/- 21.32) ml, P < 0.05; (60.10 +/- 15.95) ml vs (70.06 +/- 17.96) ml, P < 0.05] were obviously increased both after PLR and VE. The DeltaCO after PLR (DeltaCOPLR) and DeltaCOVE was highly correlated (r = 0.819, P = 0.001) while the SVV before VE and Delta COVE was uncorrelated (r = -0.218, P = 0.059). The areas under the ROC curve of DeltaCOPLR, SVV predicting fluid responsiveness were 0.859 and 0.459 respectively. The DeltaCOPLR >= 10% was found to predict fluid responsiveness with a sensitivity and specificity of 85% and 83% respectively. CONCLUSION: Compared with SVV, PLR test is a simple, effective method for accurately predicting fluid responsiveness of elderly patients with sepsis. PMID- 25907845 TI - [The expression and significance of microtubule-associated protein 1 light chain 3-related protein-1 (LC3) mRNA in peripheral blood mononuclear cells in patients with systemic lupus erythematosus]. AB - OBJECTIVE: Increasing evidence supports the involvement of autophagy in the etiopathology of autoimmune diseases. Systemic lupus erythematosus (SLE) is a potentially fatal autoimmune disease characterized by production of multiple autoantibodies through poorly understood mechanism. In order to explore the role of autophagy in the development of SLE, the expression of autophagy related gene microtubule-associated protein 1 light chain 3 (MAPLC3) in peripheral blood mononuclear cells (PBMCs) was measured in patients with SLE. METHODS: The mRNA levels of LC3 in PBMCs from 56 SLE patients and 45 healthy individuals were detected by real-time quantitative polymerase chain reaction (qPCR) technique. Autophagy in PBMCs was also determined by flow cytometry (FACs) in 20 SLE patients and 15 healthy controls. The correlation between LC3 mRNA expression and disease activity of SLE (SLEDAI) was then analyzed. RESULTS: The mRNA level of LC3 (RQ) in SLE patients was obviously downregulated compared with that in healthy population (1.30 +/- 0.10 vs 1.35 +/- 0.09; P = 0.029), paralleled with the decreased autophagy rate detected by flow cytometry in PBMCs of SLE patients [(2.21 +/- 1.07) % vs (9.91 +/- 4.01) %;P = 0.047]. Moreover, LC3 mRNA expression level was negatively correlated with SLEDAI (r = -0.337, P = 0.023). However, when the clinical features of 27 SLE patients with decreased LC3 mRNA expression (RQ<1.351) were compared with those of other 29 SLE patients with normal or high LC3 mRNA expression (RQ>1.351), increasing rates of arthritis, serositis, hematological abnormalities were noted in patients with decreased LC3 mRNA expression yet without statistically significance. However, there was a significant difference between two groups in the incidence of renal involvement (P = 0.028). CONCLUSION: The impaired autophagy due to downregulated LC3 mRNA level in SLE patients indicates that autophagy plays a role in mediating the occurrence and development of SLE. PMID- 25907846 TI - Effects of different processing methods of flaxseed on ruminal degradability and in vitro post-ruminal nutrient disappearance. AB - The aim of the study was to determine the effects of different heat-processing methods of flaxseed on the in situ effective dry matter degradability (EDMD) and the in situ effective crude protein degradability (ECPD). The treatments included roasting, steep roasting, rolled roasting, rolled steep roasting, microwave irradiation and extrusion. Three rumen-fistulated sheep were used for in situ incubations. Furthermore, the effects of heat-processing methods on post-ruminal in vitro nutrient disappearance and total tract disappearance were measured by a three-step in vitro technique. The seeds were roasted and extruded at 140 degrees C to 145 degrees C. One lot of roasted seeds was gradually cooled for about 1 h (roasting) and another lot was held in temperature isolated barrels for 45 min (steep roasting). Moreover, roasted and steep roasted flaxseed was rolled in a roller mill. The lowest and highest EDMD was observed for unheated and extruded flaxseed, respectively (p < 0.05). The highest ECPD was observed for extruded flaxseed (p < 0.05). Roasting and microwave irradiation reduced ECPD of flaxseed (p < 0.05). In vitro post-ruminal disappearance of crude nutrients including fibre fractions was highest for rolled-roasted and rolled steep-roasted flaxseed (p < 0.05). The lowest and highest total tract disappearance rates of crude nutrients and fibre fractions were estimated for unheated and extruded flaxseed, respectively (p < 0.05). The post-ruminal disappearance of crude nutrients was also increased by roasting, in which rolling enhanced this effect. In conclusion, all investigated heat treatments had significant effects on in situ and in vitro degradability of nutrients. As well, rolling of roasted flaxseed enhanced the respective effects. Therefore, different methods of heat processing can be used to modify the feed value of flaxseed for specific purposes. PMID- 25907847 TI - All-solution-processed PbS quantum dot solar modules. AB - A rapid increase in power conversion efficiencies in colloidal quantum dot (QD) solar cells has been achieved recently with lead sulphide (PbS) QDs by adapting a heterojunction architecture, which consists of small-area devices associated with a vacuum-deposited buffer layer with metal electrodes. The preparation of QD solar modules by low-cost solution processes is required to further increase the power-to-cost ratio. Herein we demonstrate all-solution-processed flexible PbS QD solar modules with a layer-by-layer architecture comprising polyethylene terephthalate (PET) substrate/indium tin oxide (ITO)/titanium oxide (TiO2)/PbS QD/poly(3-hexylthiophene) (P3HT)/poly(3,4-ethylenedioxythiophene) : poly(styrene sulfonate) (PEDOT : PSS)/Ag, with an active area of up to 30 cm(2), exhibiting a power conversion efficiency (PCE) of 1.3% under AM 1.5 conditions (PCE of 2.2% for a 1 cm(2) unit cell). Our approach affords trade-offs between power and the active area of the photovoltaic devices, which results in a low-cost power source, and which is scalable to larger areas. PMID- 25907848 TI - Teaching reading to children with neurofibromatosis type 1: a clinical trial with random assignment to different approaches. AB - AIM: Neurofibromatosis type 1 (NF1) is a genetic disorder with a cognitive profile that includes visual-spatial perception deficits and a high incidence of reading disability. There is a paucity of information about how this cognitively complex population responds to mainstream reading interventions. The clinical trial goals were to determine whether children and adolescents with NF1 and reading deficits (NF+RD) benefit from mainstream remedial reading programs and whether responsiveness varies with differences in program-related visual-spatial demands. METHOD: Forty-nine participants (28 males, 21 females; aged 8-14y) with either NF+RD (n=17, 11 males, six females) or idiopathic reading deficit (IRD) (n=32, 17 males, 15 females) were randomly assigned to intensive remedial teaching using one of two multisensory reading programs: one with greater kinesthetic demands and the other with greater visual-spatial demands. Two control groups - wait-list IRD (n=14, 11 males, three females) and typically developing readers (n=26, 13 males, 13 females) - received no treatment. Repeated measures and multivariate ANOVA analyses compared each group's growth in reading achievement from pre- to post-testing. RESULTS: Treated groups showed significant growth whereas untreated groups did not. Comparing treated groups, the IRD group responded equally well to both interventions, whereas the NF+RD group showed a better response to the more kinesthetic approach. INTERPRETATION: Results suggest that multisensory remedial reading teaching that emphasizes kinesthetic demands more than visual-spatial demands is suitable for students with NF+RD. PMID- 25907850 TI - Necessity of repeat head computed tomography after isolated skull fracture in the pediatric population. AB - BACKGROUND: Head injuries are common in the pediatric population, but when an isolated skull fracture is found, there are no guidelines for repeat imaging. This study evaluated the need for repeat head computed tomography (CT) for isolated skull fracture. METHODS: A 10-year retrospective review was conducted of patients 17 years and younger with isolated skull fractures. Data included demographics, injury severity score (ISS), fracture location, clinical indicators of head trauma, intracranial hemorrhage, and mortality. RESULTS: Of the 65 patients in this study, mean age was 4.2 years, ISS was 7.2, and head/neck abbreviated injury score was 2.3. Most injuries were from falls (69.2%) and motor vehicle collisions (23.1%). The most common clinical indicators associated with skull fractures were nonfrontal scalp hematoma (40.0%), severe mechanism (30.8%), and loss of consciousness (30.8%). One patient who developed intracranial hemorrhage after the initial head CT showed no bleed. There were no deaths. CONCLUSION: Isolated skull fractures in the pediatric population do not necessitate a repeat head CT as long as they do not develop worsening clinical indicators of head injury. PMID- 25907849 TI - Maximizing Effectiveness Trials in PTSD and SUD Through Secondary Analysis: Benefits and Limitations Using the National Institute on Drug Abuse Clinical Trials Network "Women and Trauma" Study as a Case Example. AB - Recent federal legislation and a renewed focus on integrative care models underscore the need for economical, effective, and science-based behavioral health care treatment. As such, maximizing the impact and reach of treatment research is of great concern. Behavioral health issues, including the frequent co occurrence of substance use disorders (SUD) and posttraumatic stress disorder (PTSD), are often complex, with a myriad of factors contributing to the success of interventions. Although treatment guides for comorbid SUD/PTSD exist, most patients continue to suffer symptoms following the prescribed treatment course. Further, the study of efficacious treatments has been hampered by methodological challenges (e.g., overreliance on "superiority" designs (i.e., designs structured to test whether or not one treatment statistically surpasses another in terms of effect sizes) and short term interventions). Secondary analyses of randomized controlled clinical trials offer potential benefits to enhance understanding of findings and increase the personalization of treatment. This paper offers a description of the limits of randomized controlled trials as related to SUD/PTSD populations, highlights the benefits and potential pitfalls of secondary analytic techniques, and uses a case example of one of the largest effectiveness trials of behavioral treatment for co-occurring SUD/PTSD conducted within the National Drug Abuse Treatment Clinical Trials Network (NIDA CTN) and producing 19 publications. The paper concludes with implications of this secondary analytic approach to improve addiction researchers' ability to identify best practices for community based treatment of these disorders. Innovative methods are needed to maximize the benefits of clinical studies and better support SUD/PTSD treatment options for both specialty and non-specialty healthcare settings. Moving forward, planning for and description of secondary analyses in randomized trials should be given equal consideration and care to the primary outcome analysis. PMID- 25907851 TI - Does the amount of time medical students spend in the operating room during the general surgery core clerkship affect their career decision? AB - BACKGROUND: The amount of time medical students (MS) spend in the operating room (OR) during their general surgery core clerkship has not been previously studied as a predictor for choosing a career in surgery. We hypothesize that MS choosing a career in surgery spend more time in the OR. METHODS: Operative records for surgery cases at our institution from 2009 to 2013 were linked to the schedules of MS from classes of 2010 to 2014. Total number of minutes, cases, and average number of minutes in the OR were calculated and compared with the match lists. Univariate analysis was conducted to assess for associations (P < .05). RESULTS: A total of 117 students and 1,524 procedures were included. Twenty-two MS chose a surgical career (19%). An average of 2,018.5 minutes per rotation was spent in the OR (81.2 min/d), but neither the amount of time nor the number of cases was associated with choosing a career in surgery. CONCLUSIONS: Quality of the educational experience trumps quantity regarding what most influences MS career decision. PMID- 25907852 TI - Personality traits, future time perspective and adaptive behavior in adolescence. AB - Several studies provide evidence of the importance of future time perspective (FTP) for individual success. However, little research addresses the relationship between FTP and personality traits, particularly if FTP can mediate their influence on behavior. In this study we analyze the mediating of FTP in the influence of personality traits on the way adolescents live their life at school. Sample consisted in 351 students, aged from 14 to 18 years-old, at different schooling levels. Instruments were the Portuguese version of the MMPI-A, particularly the PSY-5 dimensions (Aggressiveness, Psychoticism, Disconstraint, Neuroticism, Introversion), a FTP questionnaire, and a survey on school life, involving several indicators of achievement, social integration, and overall satisfaction. With the exception of Neuroticism, the results show significant mediation effects (p < .001) of FTP on most relationships between PSY-5 dimensions and school life variables. Concerning Disconstraint, FTP mediated its influence on overall satisfaction (beta = -.125) and school achievement (beta = .106). In the case of Introversion, significant mediation effects occurred for interpersonal difficulties (beta = .099) and participation in extracurricular activities (beta = -.085). FTP was also a mediator of Psychoticism influence in overall satisfaction (beta = -.094), interpersonal difficulties (beta = .057), and behavior problems (beta = .037). Finally, FTP mediated the influence of Aggressiveness on overall satisfaction (beta = -.061), interpersonal difficulties (beta = .040), achievement (beta = -.052), and behavior problems (beta = .023). Results are discussed considering the importance of FTP in the impact of some personality structural characteristics in students' school adaptation. PMID- 25907853 TI - ICARUSS, the Integrated Care for the Reduction of Secondary Stroke trial: rationale and design of a randomized controlled trial of a multimodal intervention to prevent recurrent stroke in patients with a recent cerebrovascular event, ACTRN = 12611000264987. AB - BACKGROUND: The majority of strokes, both ischaemic and haemorrhagic, are attributable to a relatively small number of risk factors which are readily manageable in primary care setting. Implementation of best-practice recommendations for risk factor management is calculated to reduce stroke recurrence by around 80%. However, risk factor management in stroke survivors has generally been poor at primary care level. A model of care that supports long term effective risk factor management is needed. AIM: To determine whether the model of Integrated Care for the Reduction of Recurrent Stroke (ICARUSS) will, through promotion of implementation of best-practice recommendations for risk factor management reduce the combined incidence of stroke, myocardial infarction and vascular death in patients with recent stroke or transient ischaemic attack (TIA) of the brain or eye. DESIGN: A prospective, Australian, multicentre, randomized controlled trial. SETTING: Academic stroke units in Melbourne, Perth and the John Hunter Hospital, New South Wales. SUBJECTS: 1000 stroke survivors recruited as from March 2007 with a recent (<3 months) stroke (ischaemic or haemorrhagic) or a TIA (brain or eye). RANDOMIZATION: Randomization and data collection are performed by means of a central computer generated telephone system (IVRS). INTERVENTION: Exposure to the ICARUSS model of integrated care or usual care. PRIMARY OUTCOME: The composite of stroke, MI or death from any vascular cause, whichever occurs first. SECONDARY OUTCOMES: Risk factor management in the community, depression, quality of life, disability and dementia. STATISTICAL POWER: With 1000 patients followed up for a median of one year, with a recurrence rate of 7-10% per year in patients exposed to usual care, the study will have at least 80% power to detect a significant reduction in primary end-points CONCLUSION: The ICARUSS study aims to recruit and follow up patients between 2007 and 2013 and demonstrate the effectiveness of exposure to the ICARUSS model in stroke survivors to reduce recurrent stroke or vascular events and promote the implementation of best practice risk factor management at primary care level. PMID- 25907854 TI - Thermal unfolding of apolipoprotein A-1. Evaluation of methods and models. AB - Human apolipoprotein A-1 (Apo A-1) was used as a model protein to compare experimental methods and theoretical models for protein unfolding. Thermal unfolding was investigated in aqueous buffer, in beta-octylglucoside solution, and with phospholipid bilayer vesicles. The alpha-helix content of Apo A-1 increased from 50% in aqueous buffer to 75% in the presence of lipid vesicles, but remained constant in solutions of beta-octyl glucoside. Differential scanning calorimetry (DSC) measured the thermodynamic properties of the unfolding process and was our reference method. The increased heat capacity of the unfolded protein made an important contribution to the total enthalpy of unfolding. The structural properties of Apo A-1 were studied with circular dichroism (CD) spectroscopy. The CD-recorded unfolding transitions were broader than the corresponding DSC transitions and were shifted toward higher temperatures. DSC and CD data were analyzed with the two-state model and the Zimm-Bragg theory. The two-state model assumes just two species in solution, native (N) and unfolded (U) Apo A-1. However, Apo A-1 unfolding is a highly cooperative event with helical amino acid residues unfolding and refolding rapidly. For such a sequential process, the Zimm Bragg theory provides an alternative and physically more realistic model. The Zimm-Bragg theory allowed perfect simulations of the DSC and CD experiments. In contrast, incorrect thermodynamic results were obtained with the two-state model. The Zimm-Bragg theory also provided a physically well-defined analysis of the cooperativity of the folding ? unfolding equilibrium. The cooperative unfolding of Apo A-1 increased upon addition of lipids and decreased in detergent solution. PMID- 25907855 TI - Behavioral effects of neonatal lesions on the cerebellar system. AB - Several rodent models with spontaneous mutations causing cerebellar pathology are impaired in motor functions during the neonatal period, including Grid2(Lc), Rora(sg), Dab1(scm), Girk2(Wv), Lmx1a(dr-sst), Myo5a(dn), Inpp4a(wbl), and Cacna1a(rol) mice as well as shaker and dystonic rats. Deficits are also evident in murine null mutants such as Zic1, Fgfr1/FgFr2, and Xpa/Ercc8. Behavioral deficits are time-dependent following X-irradiated- or aspiration-induced lesions of the cerebellum in rats. In addition, motor functions are deficient after lesions in cerebellar-related pathways. As in animal subjects, sensorimotor disturbances have been described in children with cerebellar lesions. These results underline the importance of the cerebellum and its connections in the development of motor functions. PMID- 25907856 TI - Investigation on the potential of Mueller matrix imaging for digital staining. AB - Digital staining based on Mueller matrix measurements and their derivatives was investigated. Mueller matrix imaging was performed at the microscopic level on gastric tissue sections. Full Mueller matrices (4 * 4) were reconstructed using recorded images, followed by the extraction of polarization parameters. The most effective parameters and their combinations were extracted from Mueller matrix elements, principal component scores and polarization parameters respectively to classify samples into three categories - i.e. cancer, dysplasia and intestinal metaplasia/normal glands for various regions of interest sizes. It was observed that two-step classification yielded higher classification accuracy than the traditional one-step classification and that pixel classification based on Mueller matrix elements yielded higher accuracy than that based on polarization parameters and derived principal components. Moreover, Mueller matrix images with a lower spatial resolution generated higher classification accuracy but those with a higher spatial resolution revealed more morphological details.ns. The original stained image (top) and the digital staining image (bottom). PMID- 25907857 TI - Psychiatric symptoms and personality dimensions in patients younger than 65 years admitted for acute coronary syndrome. PMID- 25907858 TI - Sensitivity and negative predictive value of treadmill exercise stress testing for the diagnosis of catecholaminergic polymorphic ventricular tachycardia. PMID- 25907859 TI - Importance of sudden cardiac death risk stratification in hypertrophic cardiomyopathy. Response. PMID- 25907860 TI - Knee osteoarthritis patients with severe nocturnal pain have altered proximal tibial subchondral bone mineral density. AB - OBJECTIVE: Our objective was to investigate relationships between proximal tibial subchondral bone mineral density (BMD) and nocturnal pain in patients with knee osteoarthritis (OA). METHODS: The preoperative knee of 42 patients booked for knee arthroplasty was scanned using quantitative computed tomography (QCT). Pain was measured using the Western Ontario and McMaster Universities Arthritis Index (WOMAC) and participants were categorized into three groups: 'no pain', 'moderate pain', and 'severe pain' while lying down at night. We used depth-specific image processing to assess tibial subchondral BMD at normalized depths of 0-2.5 mm, 2.5 5.0 mm and 5-10 mm relative to the subchondral surface. Regional analyses of each medial and lateral plateau included total BMD and maximum BMD within a 10 mm diameter core or 'focal spot'. The association between WOMAC pain scores and BMD measurements was assessed using Spearman's rank correlation. Regional BMD was compared pairwise between pain and no pain groups using multivariate analysis of covariance using age, sex, and BMI as covariates and Bonferroni adjustment for multiple comparisons. RESULTS: Lateral focal BMD at the 2.5-5 mm depth was related to nocturnal pain (rho = 0.388, P = 0.011). The lateral focal BMD was 33% higher in participants with 'severe pain' than participants with 'no pain' at 2.5 5 mm depth (P = 0.028) and 32% higher at 5-10 mm depth (P = 0.049). There were no BMD differences at 0-2.5 mm from the subchondral surface. CONCLUSION: This study suggests that local subchondral bone density may have a role in elucidating OA related pain pathogenesis. PMID- 25907861 TI - Association of mucoid degeneration of anterior cruciate ligament with knee meniscal and cartilage damage. AB - OBJECTIVE: To assess the prevalence of anterior cruciate ligament (ACL) mucoid degeneration in patients referred for routine knee magnetic resonance (MR) imaging, and its association with age and structural joint damage. METHOD: Four independent radiologists assessed 413 consecutive knee MR examinations for the presence of a normal or ruptured ACL, or ACL mucoid degeneration. Knees with ACL mucoid degeneration were frequency matched by age, sex, and MR field strength with consecutive control knees with a normal ACL (1:2 ratio). Differences in meniscal and cartilage damage of the tibiofemoral compartments, as determined by the Whole-Organ MR Imaging Score (WORMS) system, were compared by Mann-Whitney U tests. Multivariable logistic regression analysis identified the association of ACL mucoid degeneration with severe MTFC cartilage damage (WORMS>=5). RESULTS: Patients with ACL mucoid degeneration (n = 36; 36% males; median age 55.5 years, range: 26-81) were older than patients with a normal (P < 0.001) or ruptured ACL (P < 0.001), without sex predilection (P = 0.76), and were more frequently diagnosed at 3 T (12%) compared to 1.5 T (2%). Knees with ACL mucoid degeneration had statistically significantly more medial meniscal (P < 0.001) and central and posterior medial tibiofemoral compartment (MTFC) cartilage (P < 0.001) damage compared with control knees (n = 72), but there were no differences in patients <=50 years (P = 0.09 and 0.32, respectively). In multivariable logistic regression, severe MTFC cartilage damage (WORMS>=5) was significantly associated with ACL mucoid degeneration (odds ratio 4.09, 95% confidence interval 1.29 12.94, P = 0.016). CONCLUSION: There is a strong association between ACL mucoid degeneration and cartilage damage in the central and posterior MTFC, especially in patients >50 years. PMID- 25907862 TI - Fibroblast growth factor signalling in multiple sclerosis: inhibition of myelination and induction of pro-inflammatory environment by FGF9. AB - Remyelination failure plays an important role in the pathophysiology of multiple sclerosis, but the underlying cellular and molecular mechanisms remain poorly understood. We now report actively demyelinating lesions in patients with multiple sclerosis are associated with increased glial expression of fibroblast growth factor 9 (FGF9), which we demonstrate inhibits myelination and remyelination in vitro. This inhibitory activity is associated with the appearance of multi-branched 'pre-myelinating' MBP+ / PLP+ oligodendrocytes that interact with axons but fail to assemble myelin sheaths; an oligodendrocyte phenotype described previously in chronically demyelinated multiple sclerosis lesions. This inhibitory activity is not due to a direct effect of FGF9 on cells of the oligodendrocyte lineage but is mediated by factors secreted by astrocytes. Transcriptional profiling and functional validation studies demonstrate that these include effects dependent on increased expression of tissue inhibitor of metalloproteinase-sensitive proteases, enzymes more commonly associated with extracellular matrix remodelling. Further, we found that FGF9 induces expression of Ccl2 and Ccl7, two pro-inflammatory chemokines that contribute to recruitment of microglia and macrophages into multiple sclerosis lesions. These data indicate glial expression of FGF9 can initiate a complex astrocyte-dependent response that contributes to two distinct pathogenic pathways involved in the development of multiple sclerosis lesions. Namely, induction of a pro-inflammatory environment and failure of remyelination; a combination of effects predicted to exacerbate axonal injury and loss in patients. PMID- 25907863 TI - Outcomes in 132 patients following laparoscopic total mesorectal excision (TME) for rectal cancer with greater than 5-year follow-up. AB - INTRODUCTION: The role of laparoscopic TME for rectal cancer is still questioned as a safe and adequate cancer operation. Currently, multicenter randomized prospective trials are underway to evaluate this. We analyze our long-term results using laparoscopic TME in the treatment of rectal cancer to evaluate its oncologic outcomes. METHODS: A prospective laparoscopic database was queried to identify all patients operated upon for rectal cancer from April 1997 to September 2007. In total, 151 patients were identified. Metastatic disease excluded 19 patients, leaving 132 patients to be analyzed for perioperative and 5 year oncologic outcomes. Procedures included LAR, n = 35; transanal abdominal transanal proctosigmoidectomy, n = 77; and APR, n = 20. All surgeries were TME or pTME. RESULTS: Laparoscopic TME was performed on 89 men (67%), mean age 61 (22 85). Preoperative chemoradiation was administered in 119 (90.2 %) with median dose of 5500 cGy (3800-10,080). Mean EBL was 300 ml, and 4.5% were transfused. Seven patients (5.3%) underwent conversion, 5 to lap-assisted, with a 1.5% conversion rate to open. Pathologic stage of disease: complete response: 24%; I: 36%; II: 22%; III: 18%. There were no mortalities. Overall morbidity was 23.5%, with no anastomotic leaks and 5 (3.8%) delayed anastomotic stricture/fistula. There were no port site recurrences. Mean follow-up was 69.4 months (7.6-168.0). Overall LR was 5.3% (n = 7). There was only one isolated LR (0.8%). Mean time to local recurrence was 13.9 months. Metastatic rate was 18.2%. By stage, disease specific survival was: CR 86.3%; I: 87.4%; II: 86.4%; III: 77.4%. Overall, 5-year survival was 84.8%. CONCLUSION: The long-term data confirm that laparoscopic TME can be performed with lasting low local recurrence (5.3 %) and excellent 5-year survival (84.8%). This report's importance stems from it representing one of the largest experiences of rectal cancer treated by laparoscopic TME with greater than 5-year follow-up reported in the literature. PMID- 25907864 TI - Atypical postcesarean epithelioid trophoblastic lesion with cyst formation: a case report and literature review. AB - We report an extremely rare case of atypical postcesarean epithelioid trophoblastic lesion with cyst formation. A 41-year-old Chinese woman presented with lower abdominal pain and menstrual disorder. Her serum human chorionic gonadotropin (hCG) was low (0.373 IU/L), and her urine hCG was negative. Ultrasound images showed a 3.7*2.8*2.5 cm(3) mass on the surface of the lower uterine segment, and a laparoscopy indicated a cystic mass in the serosal surface of the lower uterine segment. Histology indicated a cystic lesion consisting of epithelioid trophoblastic cells with an intermediate pattern between a classical placental site nodule and an epithelioid trophoblastic tumor; thus, the term atypical postcesarean epithelioid trophoblastic lesion with cyst formation was appropriate. As in atypical placental site nodule, serum hCG monitoring after treatment is necessary. PMID- 25907865 TI - Epstein-Barr virus-positive nodal T/NK-cell lymphoma: an analysis of 15 cases with distinct clinicopathological features. AB - Nodal peripheral T-cell lymphoma, not otherwise specified, is a heterogeneous entity with variable biologic behavior. We analyze the clinicopathological features of 15 patients with Epstein-Barr virus-positive (EBV+) nodal T/NK-cell lymphoma, including 9 males and 6 females, with a median age of 64 years. All patients presented with multiple lymphadenopathy with common B symptoms (80%, 12/15) at an advanced Ann Arbor stage (III, IV) (87%, 13/15). The International Prognostic Index was high or high/intermediate in 87% (13/15) of patients, and the prognostic index for peripheral T-cell lymphoma was group 3 or 4 in 73% (11/15). Spleen and liver involvement was observed in 73% (11/15) and 60% (9/15) of patients, respectively. In contrast, extranodal involvement was infrequent, with no more than 1 site in 71% (10/15) of patients. Moreover, none had nasal lesions, and only 1 had mucocutaneous involvement. The cell lineage of EBV+ tumor cells was determined to be T cell in all except 1 patient, who was NK-cell lineage. Cytotoxic molecules were expressed in all cases, and 64% (9/14) of patients expressed the alphabetaT-cell receptor. Moreover, most patients (67%, 10/15) showed CD8 positivity, with 2 of them being CD4CD8 double positive; the others were CD4 positive (n = 2) or CD4CD8 double negative (n = 3). The clinical course was very aggressive, with a median survival time of 3.5 months, and 10 patients died within 6 months of diagnosis. Taken together, our data demonstrate that EBV+ nodal T/NK-cell lymphoma is a distinct clinicopathological entity characterized by cytotoxic molecule expression, a frequent CD8-positive alphabetaT-cell lineage, and a very aggressive clinical behavior. PMID- 25907866 TI - MicroRNA-144 suppresses tumorigenesis and tumor progression of astrocytoma by targeting EZH2. AB - Our previous study demonstrated that enhancer of zeste homolog 2 (EZH2) overexpression may be associated with aggressive tumor progression and poor prognosis in human astrocytoma. The aim of this study was to investigate the underlying mechanisms of EZH2 on astrocytoma tumorigenesis. An online program miRWalk (http://www.umm.uni-heidelberg.de/apps/zmf/mirwalk/) was used to predict possible microRNAs (miRNAs) that might target EZH2 messenger RNA (mRNA). Then the functions of the miRNA-EZH2 mRNA axis in astrocytoma cell proliferation, invasion, and migration were also assessed. We further evaluated the clinical value of the miRNA-EZH2 mRNA axis in astrocytomas. As a result, we identified EZH2 as a target gene of miR-144. In addition, forced expression of miR-144 suppressed astrocytoma cell proliferation, invasion, and migration by down regulating EZH2. Moreover, miR-144 down-regulation and EZH2 mRNA up-regulation were both significantly associated with advanced World Health Organization grades and low Karnofsky performance status score of astrocytoma patients. Importantly, survival analysis identified the combined expression of miR-144 and EZH2 (miR 144/EZH2) as an independent prognostic factor for overall survival in astrocytoma patients. In conclusion, miR-144 may function as a tumor suppressor by regulating EZH2 expression, and miR-144/EZH2 expression may be a highly sensitive marker for the prognosis in astrocytoma patients. PMID- 25907867 TI - Our lives as surgeons: finding a sense of place and purpose. PMID- 25907868 TI - Early resuscitation with fresh frozen plasma for traumatic brain injury combined with hemorrhagic shock improves neurologic recovery. AB - BACKGROUND: We have shown that early administration of fresh frozen plasma (FFP) reduces the size of brain lesions 6 hours after injury in a large animal model of traumatic brain injury (TBI) and hemorrhagic shock (HS). To examine long-term outcomes, we hypothesized that early treatment with FFP would result in faster neurologic recovery and better long-term outcomes in a combined TBI and HS model. STUDY DESIGN: Anesthetized Yorkshire swine underwent combined TBI and volume controlled hemorrhage (40% blood volume). After 2 hours of shock, animals were randomized (n = 5/group) to normal saline (3* shed blood) or FFP (1* shed blood) treatment. A neurologic severity score was assessed for 30 days. Magnetic resonance imaging of the brain was performed at days 3, 10, and 24. Cognitive function was tested by training animals to retrieve food from color-coded boxes. RESULTS: Neurologic impairment was lower and speed of recovery was considerably faster in the FFP-treated animals. There was a trend toward a smaller lesion size in FFP-treated animal at days 3 and 10, but this did not reach statistical significance. Both groups reached baseline performance on the cognitive testing; however, FFP-treated animals were able to participate, on average, 8 days earlier due to quicker recovery. CONCLUSIONS: This is the first study to demonstrate the beneficial effects of FFP treatment in a long-term survival model of combined TBI and HS. Our data show that early treatment with FFP substantially attenuates the degree of neurologic impairment, improves the rate of recovery, and preserves the cognitive functions. PMID- 25907869 TI - Use and Outcomes of Laparoscopic Sleeve Gastrectomy vs Laparoscopic Gastric Bypass: Analysis of the American College of Surgeons NSQIP. AB - BACKGROUND: Laparoscopic sleeve gastrectomy is gaining popularity in the United States. However, few studies have examined outcomes of sleeve gastrectomy compared with those of the "gold standard" bariatric operation: Roux-en-Y gastric bypass. STUDY DESIGN: Using the American College of Surgeons National Surgical Quality Improvement Program database, clinical data were obtained for all patients who underwent laparoscopic sleeve gastrectomy or laparoscopic gastric bypass between 2010 and 2011. Main outcomes measures were risk-adjusted 30-day serious morbidity and mortality. RESULTS: We analyzed 24,117 patients who underwent laparoscopic sleeve gastrectomy or laparoscopic gastric bypass for the treatment of morbid obesity. Gastric bypass comprised 79.5% of cases and sleeve gastrectomy comprised 20.5%; the proportion of sleeve gastrectomy cases increased from 14.6% in 2010 to 25.8% in 2011. On univariate analysis, sleeve gastrectomy had a shorter mean operative time (101 vs 133 minutes, p < 0.01), a lower rate of blood loss requiring transfusion (0.6% vs 1.5%, p < 0.01), a lower rate of deep wound infections (0.06% vs 0.20%, p = 0.05), lower serious morbidity rate (3.8% vs 5.8%, p < 0.01), and 30-day reoperation rate (1.6% vs 2.5%, p < 0.01), but a higher rate of deep venous thrombosis (0.47% vs 0.21%, p < 0.01). Compared with sleeve gastrectomy, gastric bypass patients had higher risk-adjusted 30-day serious morbidity (odds ratio [OR] 1.32; 95% CI1.11 to 1.56, p < 0.01). Patients who were older, had higher BMI, smoked, or had hypertension were at significantly greater risk of serious morbidity. The 30-day mortality was similar between groups (0.10% for sleeve vs 0.15% for bypass). CONCLUSIONS: Use of laparoscopic sleeve gastrectomy is increasing on a national level. Compared with laparoscopic gastric bypass, laparoscopic sleeve gastrectomy is associated with lower 30-day risk-adjusted serious morbidity and equivalent 30-day mortality. PMID- 25907870 TI - Report of a Simplified Frailty Score Predictive of Short-Term Postoperative Morbidity and Mortality. AB - BACKGROUND: Frailty is an objective method of quantifying a patient's fitness for surgery. Its clinical use is limited by the time needed to complete, as well as a lack of evidence-based interventions to improve outcomes in identified frail patients. The purpose of this study was to critically analyze the components of the Fried Frailty Criteria, among other preoperative variables, to create a simplified risk assessment amenable to a busy clinical setting, while maintaining prognostic ability for surgical outcomes. STUDY DESIGN: We performed a prospective evaluation of patients that included the 5-component Fried Frailty Criteria, traditional surgical risk assessments, biochemical laboratory values, and clinical and demographic data. Thirty-day postoperative outcomes were the outcomes of interest. RESULTS: There were 351 consecutive patients undergoing major intra-abdominal operations enrolled. Analysis demonstrated that shrinking and grip strength alone hold the same prognostic information as the full 5 component Fried Frailty Criteria for 30-day morbidity and mortality. The addition of American Society of Anesthesia (ASA) score and serum hemoglobin creates a composite risk score, which facilitates easy classification of patients into discrete low (ref), intermediate (odds ratio [OR] 1.974, 95% CI 1.006 to 3.877, p = 0.048), and high (OR 4.889, 95% CI 2.220 to 10.769, p < 0.001) risk categories, with a corresponding stepwise increase in risk for 30-day postoperative complications. Internal validation by bootstrapping confirmed the results. CONCLUSIONS: This study demonstrated that 2 components of the Fried Frailty Criteria, shrinking and grip strength, hold the same predictive value as the full frailty assessment. When combined with American Society of Anesthesiologists score and serum hemoglobin, they form a straightforward, simple risk classification system with robust prognostic information. PMID- 25907871 TI - Nationwide analysis of outcomes of bowel preparation in colon surgery. AB - BACKGROUND: There are limited data comparing the outcomes of preoperative oral antibiotic bowel preparation (OBP) and mechanical bowel preparation (MBP) in colorectal surgery. We sought to identify the relationship between preoperative bowel preparations (BP) and postoperative complications in colon cancer surgery. STUDY DESIGN: The NSQIP database was used to examine the clinical data of colon cancer patients undergoing scheduled colon resection during 2012 to 2013. Multivariate regression analysis was performed to identify correlations between BP and postoperative complications. RESULTS: We evaluated a total of 5,021 patients who underwent elective colon resection. Of these, 44.8% had only MBP, 2.3% had only OBP, 27.6% had both MBP and OBP, and 25.3% of patients did not have any type of BP. In multivariate analysis of data, MBP and OBP were not associated with decreased risk of postoperative complications in right side (adjusted odds ratio [AOR] 0.80, 0.30, p = 0.08, 0.10, respectively) or left side colon resections (AOR 1.02, 0.68, p = 0.81, 0.24, respectively). However, the combination of MBP and OBP before left side colon resections resulted in a significantly decreased risk of overall morbidity (AOR 0.63, p < 0.01), superficial surgical site infection (AOR 0.31, p < 0.01), anastomosis leakage (AOR 0.44, p < 0.01), and intra-abdominal infections (AOR 0.44, p < 0.01). CONCLUSIONS: Our analysis revealed that solitary mechanical bowel preparation and solitary oral bowel preparation had no significant effects on major postoperative complications after colon cancer resection. However, a combination of mechanical and oral antibiotic preparations showed a significant decrease in postoperative morbidity. PMID- 25907872 TI - A flexible postoperative debriefing process can effectively provide formative resident feedback. AB - BACKGROUND: Providing residents with formative operative feedback is one of the ongoing challenges in modern surgical education. This is highlighted by the recent American Board of Surgery requirement for formal operative assessments. A flexible and adaptable procedure feedback process may allow attending surgeons to provide qualitative and quantitative feedback to residents while encouraging surgeons-in-training to critically reflect on their own performance. STUDY DESIGN: We designed and implemented a flexible feedback process in which residents initiated a postoperative feedback discussion and completed a Procedure Feedback Form (PFF) with their supervising attending surgeon. Comparisons were made between the quantitative and qualitative assessments of attending and resident surgeons. Free text statements describing strengths and weaknesses were analyzed using grounded theory with constant comparison. RESULTS: We identified 346 assessments of 48 surgery residents performing 38 different cases. There was good inter-rater reliability between resident and attending surgeons' quantitative assessment, Goodman and Kruskal gamma > 0.65. Key themes identified on qualitative analysis included flow, technique, synthesis/decision, outcomes, knowledge, and communication/attitudes. Subthematic analysis demonstrated that our novel debriefing procedure was easily adaptable to a wide variety of clinical settings and grew more individualized for senior learners. CONCLUSIONS: This procedure feedback process is easily adaptable to a wide variety of cases and supports resident self-reflection. The process grows in nuance and complexity with the learner and may serve as a guide for a flexible and widely applicable postoperative feedback process. PMID- 25907873 TI - Early hiatal hernia recurrence rates. PMID- 25907874 TI - American Academy of Emergency Medicine Response to "Optimal Resources for Children's Surgical Care in the United States". PMID- 25907875 TI - Laparoscopic paraesophageal hernia repair: in reply to Falk. PMID- 25907876 TI - Emergency physicians are experts in managing childhood emergencies. PMID- 25907877 TI - Optimal Resources for Children's Surgical Care: In Reply to: Reiter and Gerardi. PMID- 25907878 TI - Methodologic approach to accurate prediction of anastomotic leakage after colorectal surgery using plasma markers for intestinal damage and inflammation. PMID- 25907879 TI - Intraoperative nerve monitoring and vocal cord paralysis: have rates really risen after the adoption of intraoperative nerve monitoring? PMID- 25907880 TI - Confounding factors of increased calprotectin levels: in reply to Agilli and Aydin. PMID- 25907881 TI - Intraoperative Nerve Monitoring and Vocal Cord Paralysis: Controlling Bias: In reply to Nguyen and Wang. PMID- 25907882 TI - The Time Might Have Come to Change the Standard Procedure for Primary Hepatocellular Carcinomas within the Milan Criteria from the Open to Laparoscopic Approach for Skilled Surgeons: In reply to Di Carlo and Toro. PMID- 25907883 TI - Is it Time to Change the Standard Procedure for Hepatocellular Carcinoma from an Open to a Laparoscopic Approach? PMID- 25907884 TI - Renal cystic disease and liver abnormalities: polycystic kidney and hepatic disease and the association with Caroli disease. PMID- 25907885 TI - Perioperative strategy for severe nutritional risk-related frail patients. PMID- 25907886 TI - Patient safety. PMID- 25907888 TI - Biologic monitoring and surveillance results for the department of veterans affairs' depleted uranium cohort: Lessons learned from sustained exposure over two decades. AB - BACKGROUND: A small group of Gulf War I veterans wounded in depleted uranium (DU) friendly fire incidents have been monitored in a clinical surveillance program at the Veterans Affairs Medical Center, Baltimore since 1994. METHODS: An in-patient clinical surveillance protocol was performed on 35 members of the cohort, including exposure monitoring for total and isotopic uranium concentrations in urine and a comprehensive assessment of health outcomes. RESULTS: Although urine U concentrations continue to be elevated in this group, illustrating on-going in situ mobilization of U from embedded fragments, no consistent U-related health effects have been observed. CONCLUSIONS: Now more than 20 years since first exposure to DU, an aging cohort of military veterans continues to show no U related health effects in known target organs of U toxicity. As tissue concentrations continue to accrue with exposure duration, critical tissue specific U concentration thresholds may be reached, thus recommending on-going surveillance of this veteran cohort. PMID- 25907889 TI - Software solutions for the livestock genomics SNP array revolution. AB - Since the beginning of the genomic era, the number of available single nucleotide polymorphism (SNP) arrays has grown considerably. In the bovine species alone, 11 SNP chips not completely covered by intellectual property are currently available, and the number is growing. Genomic/genotype data are not standardized, and this hampers its exchange and integration. In addition, software used for the analyses of these data usually requires not standard (i.e. case specific) input files which, considering the large amount of data to be handled, require at least some programming skills in their production. In this work, we describe a software toolkit for SNP array data management, imputation, genome-wide association studies, population genetics and genomic selection. However, this toolkit does not solve the critical need for standardization of the genotypic data and software input files. It only highlights the chaotic situation each researcher has to face on a daily basis and gives some helpful advice on the currently available tools in order to navigate the SNP array data complexity. PMID- 25907890 TI - Negative regulation of juvenile hormone analog for ecdysteroidogenic enzymes. AB - Disruption of the appropriate balance between juvenile hormone (JH) and ecdysteroids causes abnormal insect development. The application of a JH analog (JHA) during the early days of the final (fifth) instar induces dauer larvae with low ecdysteroid titers in insects, but the mechanism that underlies the action of JHA remains unclear. In this study, we clarified the negative effects of JHA on ecdysteroidogenic enzymes. JHA application to Bombyx mori larvae during the early stage of the fifth instar suppressed the expression of four enzymes, i.e., neverland (nvd), spook, phantom, and disembodied but not non-molting glossy and shadow. Furthermore, JHA application reduced the amount of 7-dehydrocholesterol, a metabolite produced by Nvd, in both the prothoracic glands and hemolymph, indicating JHA can disrupt ecdysteroidogenic pathway from the first step. Neck ligation resulted in increased nvd expression, whereas JHA application reversed this increase. These results suggest that the endogenous JH represses ecdysteroidogenesis during the early days in final instar larvae. Neck ligation and JHA application had no substantial effects on the expression of a transcription factor, ftz-f1, or a prothoracicotropic hormone receptor, torso; therefore, the inhibitory regulation of JHA may not involve these factors. Further analysis is required to clarify the regulation of JHA in ecdysteroidogenesis, but this study showed that JHA, and probably endogenous JH, can suppress the transcription of four of six ecdysteroidogenic enzymes. This regulation may be essential for maintaining the appropriate balance between JH and ecdysone during insect development. PMID- 25907891 TI - Posterior choroidal leiomyoma: a rare case report and literature review. AB - We report a literature review and detailed evaluation of a rare case of posterior choroidal leiomyoma to emphasize the importance of differentiating this from other choroidal tumors. A 30-year-old male presented with variable blurred vision in his right eye secondary to a choroidal tumor. Clinical examinations were performed including fundus photography, optical coherence tomography, B scans, fluorescein and indocyanine green angiography, computed tomography, and magnetic resonance imaging. Preoperative examination revealed a suspected choroidal melanoma and enucleation was performed. However, a definitive diagnosis of choroidal leiomyoma was made following postoperative pathological light microscopy and immunohistochemical studies. Published case reports were collected and the common characteristics and distinctive features were compared with the current case. Posterior choroidal leiomyoma was summarized from the literature, and beneficial information for diagnosis and treatment was obtained. In conclusion, posterior choroidal leiomyoma is rare and should be differentiated from amelanotic melanomas. Despite the benign nature, an explanation regarding the rare incidence and difficult diagnosis of posterior choroidal leiomyoma must be provided to patients, prior to enucleation or detrimental treatment. PMID- 25907892 TI - Tunable hydrogel thin films from reactive synthetic polymers as potential two dimensional cell scaffolds. AB - This article describes the formation of cross-linked 10-200-nm-thick polymer hydrogel films by alternating the spin-coating of two mutually reactive polymers from organic solutions, followed by hydrolysis of the resulting multilayer film in aqueous buffer. Poly(methyl vinyl ether-alt-maleic anhydride) (PMM) was deposited from acetonitrile solution, and poly(N-3-aminopropylmethacrylamide-co-N 2-hydroxypropylmethacrylamide) (PAPMx, where x corresponds to the 3 aminopropylmethacrylamide content ranging from 10 to 100%) was deposited from methanol. Multilayer films were formed in up to 20 deposition cycles. The films cross-linked during formation by reaction between the amine groups of PAPMx and the anhydride groups of PMM. The resulting multilayer films were covalently postfunctionalized by exposure to fluoresceinamine, decylamine, d-glucamine, or fluorescently labeled PAPMx solutions prior to the hydrolysis of residual anhydride in aqueous PBS buffer. This allowed tuning the hydrophobicity of the film to give static water contact angles ranging from about 5 to 90 degrees . Increasing the APM content in PAPMx from 10 to 100% led to apparent Young's moduli from 300 to 700 kPa while retaining sufficient anhydride groups to allow postfunctionalization of the films. This allowed the resulting (PMM/PAPMx) multilayer films to be turned into adhesion-promoting or antifouling surfaces for C2C12 mouse myoblasts and MCF 10A premalignant human mammary epithelial cells. PMID- 25907893 TI - Emergency embolization of actively bleeding small renal angiomyolipoma with a fast growth in four months. AB - Angiomyolipoma (AML) is the most common benign tumour of the kidney and is composed of smooth muscle cells, blood vessels and fat elements. AMLs are usually casually discovered when the kidneys are imaged for other reasons. Their first presentation is often a spontaneous retroperitoneal haemorrhage or bleeding into the urinary collection system, which can be life-threatening. The bleeding tendency is related to the irregular, aneurysmal, tortuous blood vessels that compose the tumor. The greatest risks for bleeding are tumour size and grade of the vascular component of the tumour. Moreover, the risk of bleeding is proportional to the size of the lesion (it is higher in AMLs with a diameter more than 4 cm). Shock due to a grave haemorrhage from AML rupture is called Wunderlich syndrome that is clinically characterized by the Lenk's triad: acute flank pain, a flank mass and hypovolemic shock.Other symptoms and signs may be present: haematuria, palpable mass, flank pain, urinary tract infections, renal failure or hypertension. Small AMLs usually require no therapy, although follow up is recommended in order to follow its growth. Larger or symptomatic lesions can be electively embolized and/or resected with a partial nephrectomy. AMLs that present with retroperitoneal haemorrhage frequently require emergency embolization. We describe a case of an actively bleeding small renal AML, with a rapid growth, without any evidence for big aneurysmal vessels, who underwent an emergency embolization at our hospital. PMID- 25907894 TI - [Statistical tests in medical research: traditional methods vs. multivariate NPC permutation tests]. AB - Statistical tests in medical research: traditional methods vs. multivariate npc permutation tests.Within medical research, a useful statistical tool is based on hypotheses testing in terms of the so-called null, that is the treatment has no effect, and alternative hypotheses, that is the treatment has some effects. By controlling the risks of wrong decisions, empirical data are used in order to possibly reject the null hypotheses in favour of the alternative, so that demonstrating the efficacy of a treatment of interest. The multivariate permutation tests, based on the nonparametric combination - NPC method, provide an innovative, robust and effective hypotheses testing solution to many real problems that are commonly encountered in medical research when multiple end points are observed. This paper discusses the various approaches to hypothesis testing and the main advantages of NPC tests, which consist in the fact that they require much less stringent assumptions than traditional statistical tests. Moreover, the related results may be extended to the reference population even in case of selection-bias, that is non-random sampling. In this work, we review and discuss some basic testing procedures along with the theoretical and practical relevance of NPC tests showing their effectiveness in medical research. Within the non-parametric methods, NPC tests represent the current "frontier" of statistical research, but already widely available in the practice of analysis of clinical data. PMID- 25907895 TI - On the partiality of procreative beneficence: a critical note. AB - The aim of this paper is to criticise the well-discussed principle of Procreative Beneficence (PB) lately refined by Julian Savulescu and Guy Kahane. First, it is argued that advocates of PB leave us with an implausible justification for the moral partiality towards the child (or children) which reproducers decide to bring into existence as compared with all other individuals. This is implausible because the reasons given in favour of the partiality of PB, which are based on practical reason and common-sense morality, can just as well be used to guide reproducers to make choices that do not support partiality towards one's possible children. This seems to be true as least in some situations. Second, it is argued that Jakob Elster's recent critique of PB is problematic and specifically that a counterexample designed by Elster to criticise PB because of its partiality towards one's own children misses the target. Finally, a genuine counterexample to PB is developed in order to show that the partiality of PB leads to the wrong answer in a specific case. PMID- 25907896 TI - The role of multicomponent therapy in the metabolic syndrome, inflammation and cardiovascular risk in obese adolescents. AB - Obesity is characterised by low-grade inflammation, which increases the metabolic syndrome (MetS) and cardiovascular risks. The aim of the present study was to verify the role of multicomponent therapy in controlling the MetS, inflammation and carotid intima-media thickness (cIMT) in obese adolescents. The second aim was to investigate the relationships between adipokines, the MetS parameters and cIMT. A total of sixty-nine obese adolescents participated in the present study and completed 1 year of multicomponent therapy (a combination of strategies involving nutrition, psychology, physical exercise and clinical therapy), and were divided according to their MetS diagnosis as follows: MetS (n 19); non-MetS (n 50). Blood analyses of glucose, lipid and adipokine concentrations (adiponectin, leptin, plasminogen activator inhibitor 1 (PAI-1) and C-reactive protein) were collected. Insulin resistance was assessed using the homeostasis model assessment for insulin resistance, quantitative insulin sensitivity check index and homeostasis model assessment-adiponectin. cIMT and visceral and subcutaneous fat were estimated using ultrasonography. At baseline, the MetS group presented higher waist circumference, glucose and insulin levels, and systolic and median blood pressures compared with the non-MetS group. After therapy, both groups showed improvements in the anthropometric profile, body composition, insulin level, insulin resistance, insulin sensibility, TAG and VLDL cholesterol, adiponectin, leptin and PAI-1 levels, blood pressure and cIMT. The prevalence of the MetS was reduced from 27.5 to 13.0 %. Metabolic syndrome patients showed resistance in the attenuation of total cholesterol and LDL cholesterol (LDL-C) levels and leptin:adiponectin and adiponectin:leptin ratios. In the MetS group, the variation in the adiponectin:leptin ratio was correlated with variations in glucose, insulin sensibility, total cholesterol, LDL-c and systolic blood pressure. Additionally, the number of MetS parameters was correlated with the carotid measurement. Moreover, the variation in cIMT was correlated with the variations in insulin sensibility, total cholesterol and LDL c. For the entire group, the number of MetS alterations was correlated with the leptin level and leptin:adiponectin ratio and adiponectin:leptin ratio after therapy. In conclusion, multicomponent therapy was effective in controlling the MetS, inflammation and cIMT in the obese adolescents. However, the MetS patients showed resistance in the attenuation of the atherogenic lipid profile and leptin:adiponectin ratio and adiponectin:leptin ratio. These results suggest that the MetS patients have increased cardiovascular risks, and that it is important to attempt to control the inflammatory process that occurs due to obesity in clinical practice in order to improve the health of adolescents. PMID- 25907897 TI - Front-line, dose-escalated immunochemotherapy is associated with a significant progression-free survival advantage in patients with double-hit lymphomas: a systematic review and meta-analysis. AB - 'Double-hit lymphomas' (DHL), defined by concurrent MYC and BCL2 (or, alternatively, BCL6) rearrangements, have a very poor outcome compared to standard-risk, diffuse large B-cell lymphomas (DLBCL). Consequently, dose intensive (DI) therapies and/or consolidation with high-dose therapy and transplant have been explored in DHL, although benefit has been debated. This meta-analysis compared survival outcomes in DHL patients receiving dose-escalated regimens [DI: R-Hyper-CVAD (rituximab, cyclophosphamide, vincristine, doxorubicin, dexamethasone) or R-CODOX-M/IVAC (rituximab, cyclophosphamide, doxorubicin, vincristine, methotrexate/ifosfamide, etoposide, high dose cytarabine); or intermediate-dose: R-EPOCH (rituximab, etoposide, doxorubicin, cyclophosphamide, vincristine, prednisone)] versus standard-dose regimens (R CHOP; rituximab, cyclophosphamide, doxorubicin, vincristine, prednisone) in the first-line setting. Data were synthesized to estimate hazard ratios of dose escalated treatments versus R-CHOP using a Weibull proportional hazards model within a Bayesian meta-analysis framework. Eleven studies examining 394 patients were included. Patients were treated with either front-line R-CHOP (n = 180), R EPOCH (n = 91), or R-Hyper-CVAD/rituximab, methotrexate, cytarabine (R-M/C), R CODOX-M/R-IVAC (DI) (n = 123). Our meta-analysis revealed that median progression free survival (n = 350) for the R-CHOP, R-EPOCH and DI groups was 12.1, 22.2, and 18.9 months, respectively. First-line treatment with R-EPOCH significantly reduced the risk of a progression compared with R-CHOP (relative risk reduction of 34%; P = 0.032); however, overall survival (n = 374) was not significantly different across treatment approaches. A subset of patients might benefit from intensive induction with/without transplant. Further investigation into the role of transplant and novel therapy combinations is necessary. PMID- 25907898 TI - Nanotopographical control of human embryonic stem cell differentiation into definitive endoderm. AB - Derivation of definitive endoderm (DE) from human embryonic stem cells (hESCs) can address the needs of regenerative medicine for endoderm-derived organs such as the pancreas and liver. Fibrous substrates which topographically recapitulate native extracellular matrix have been known to promote the stem cell differentiation. However, the optimal fiber diameter remains to be determined for the desired differentiation. Here, we have developed a simple method to precisely fabricate electrospun poly(epsilon-caprolactone) fibers with four distinct average diameters at nano- and microscale levels (200, 500, 800, and 1300 nm). Human ESCs were cultured as clumps or single cells and induced into DE differentiation to determine the optimal topography leading to the promoted differentiation compared with planar culture plates. Gene expression analysis of the DE-induced cells showed significant upregulation of DE-specific genes exclusively on the 200-nm fibers. By Western blot analysis, significant expression of DE-specific proteins was found when hESCs were cultured on the 200 nm substrate as single cells rather than clumps, probably due to more efficient cell-matrix interaction realized by morphological observations of the cell colonies. The results indicated that nanofibrillar substrates, only at ultrathin fiber diameters, provided a better environment for DE differentiation of hESC, which holds great promise in prospective tissue engineering applications. PMID- 25907899 TI - Association of cardiovascular and biochemical risk factors with tibial artery calcification. AB - The cardiovascular risk factors that contribute to coronary calcification have been extensively studied while those related to tibial artery calcium are less well defined. We sought to determine the associations between cardiovascular risk factors and tibial artery calcification in a cohort of patients with and without significant peripheral atherosclerosis. A total of 222 patients without end-stage renal disease were identified in a prospectively maintained database containing tibial artery calcification (TAC) scores, and demographic, cardiovascular, and biochemical risk factor information. Patients with prevalent tibial artery calcification were more likely to be older, male, and have a history positive for hypertension, hyperlipidemia, diabetes, and tobacco use. Patients with an abnormal ankle-brachial index (ABI) or symptoms of peripheral artery disease (PAD) were also more likely to have higher calcium values. In analyses using multivariable logistic regression, age, gender, diabetes, and tobacco use maintained their association with prevalent tibial calcification while hypertension, hyperlipidemia and body mass index did not. These associations remained when PAD was added to the model. After adjusting for relevant cardiovascular risk factors, we found that only abnormal ABI, current PAD symptoms, and lower serum calcium values were associated with the presence of tibial artery calcification. In conclusion, in patients without end-stage renal disease, tibial artery calcification has risk factors that are similar but not identical to those for coronary artery calcification and peripheral atherosclerosis. PMID- 25907900 TI - Sickle cell and silent spleen. AB - In this issue of Blood, in a first-rate example of collaboration between academia (University of California) and industry (Sangamo), Hoban et al show in situ gene correction of sickle cell anemia (SCA), a prototypical hemoglobinopathy. PMID- 25907901 TI - Osteoblast ablation burns out functional stem cells. AB - In this issue of Blood, Bowers et al report that osteoblasts maintain a subset of quiescent stem cells and that osteoblast ablation converts bone marrow into a proliferation-promoting environment for both normal and malignant stem cells. PMID- 25907902 TI - Disabling the platelet's brakes to promote thrombosis. AB - In this issue of Blood, Magwenzi et al from the University of Hull report a novel mechanistic connection between oxidized low-density lipoprotein (oxLDL)-induced prothrombotic platelet signaling and the inhibition of endogenous platelet anti activating signaling mediated by the nitric oxide (NO)/guanosine 3',5'-cyclic monophosphate (cGMP)/protein kinase G (PKG) pathway. PMID- 25907903 TI - GVHD clears the Aire in thymic selection. AB - In this issue of Blood, Dertschnig et al describe the development of autoreactive T cells from the thymus in mice that had previously developed acute graft-versus host-disease (aGVHD). PMID- 25907904 TI - CCMCL1: a new model of aggressive mantle cell lymphoma. PMID- 25907905 TI - NHLBI Strategic Visioning: setting an agenda together for the NHLBI of 2025. PMID- 25907906 TI - The influence of SnoN gene silencing by siRNA on the cell proliferation and apoptosis of human pancreatic cancer cells. AB - BACKGROUND: The prognosis for pancreatic cancer (PC) is very poor. The SnoN gene may have a role in cell proliferation and apoptosis in human cancer. However, the influence of SnoN on cell proliferation and apoptosis in human PC cells remains unknown. METHODS: SnoN expression was assessed in SW1990 PC cell lines using real time polymerase chain reaction (PCR). A luciferase reporter assay was used to confirm the target associations. The effect of SnoN on cell proliferation in vitro was confirmed using Cell Counting Kit-8. Apoptosis was confirmed using flow cytometry. Gene and protein expression were examined using real time PCR and Western blotting, respectively. RESULTS: SnoN siRNA significantly inhibited the growth of SW1990 cells by decreasing cell proliferation (P < 0.05) and increasing cell apoptosis (P < 0.05), compared with the blank group and the negative control group. The highest inhibition of cell proliferation appeared at 3 days post transfection. Cell apoptosis more obvious at 48 h after transfection. CONCLUSIONS: In summary, our results reveal that the RNAi-mediated downregulation of SnoN effectively inhibited the proliferation of PC cells. SnoN-siRNA also enhanced SW1990 PC cell apoptosis. These findings indicate that SnoN gene plays an important role in pancreatic cancer development, and might serve as a potential therapeutic target for pancreatic cancer. However, further in vivo studies are needed to clarify the influence of SnoN gene silencing by siRNA on pancreatic cancer therapy. VIRTUAL SLIDES: The virtual slide(s) for this article can be found here: http://www.diagnosticpathology.diagnomx.eu/vs/7609324661510147. PMID- 25907907 TI - Detection and characterization of a human G9P[4] rotavirus strain in Japan. AB - In a surveillance system in Osaka City, Japan, 48 sporadic rotavirus A (RVA) infections were detected during 2008/2009-2011/2012 seasons. The G/P-genotypes of detected RVAs were G1P[8], G2P[4], G3P[8], G9P[4], and G9P[8]. Although G9P[4] is a rare genotype that had not been reported in Japan, it was the second most prevalent genotype, following G1P[8], and accounted for 35.3% of RVA cases in the 2011/2012 season. Further genotyping revealed that the G9P[4] strain had genotype 2 internal protein genes except for NSP3: G9-P[4]-I2-R2-C2-M2-A2-N2-T1-E2-H2. Among detected RVA strains, G9P[4] and some G9P[8] strains shared high nucleotide identity in VP7 and NSP3 genes. Phylogenetic and BLAST search analyses showed that the G9P[4] strain in Japan shared high nucleotide identity in genotype 2 genes with common G2P[4] strains circulating globally, but was distinct from other G9P[4] strains circulating worldwide. These results suggest that the G9P[4] strain in Japan may have emerged through an independent reassortment between G9P[8] and G2P[4]. Finally, the role of NSP3 protein in the circulating RVA from an amino acid comparison between T1- and T2-type NSP3 is discussed. These findings provide an important insight into less problematic combinations of circulating RVA genes derived from different genotypes. PMID- 25907908 TI - Diagnostic evaluation for nontraumatic intracerebral hemorrhage. AB - Intracerebral hemorrhage (ICH) is a devastating condition with multiple possible underlying causes. Early diagnosis of ICH associated with a precise diagnostic work-up is mandatory. Clinical signs may give clues to diagnosis but are not reliable enough and imaging remains the cornerstone of management. Noncontrast computed tomography and magnetic resonance imaging (MRI) are highly sensitive for ICH identification. Additionally, MRI may disclose brain parenchymal biomarkers that can contribute to the etiologic diagnosis. Vessel examination should be carried out whenever there is a clinical suspicion of underlying structural lesions, such as vascular malformations or tumors. To date, conventional angiography remains the gold standard to detect intracranial vascular malformations in patients with ICH. PMID- 25907909 TI - Antiplatelet and anticoagulant therapy after intracerebral hemorrhage. AB - Management of patients with an indication for long-term oral antithrombotic therapy who have an intracerebral hemorrhage (ICH) presents a therapeutic dilemma. Should antithrombotic therapy be resumed, and if so, when, using what agent, and for whom? There is no consensus for answers to these questions. In the absence of randomized trials, management of antithrombotic therapy after ICH is based on a combination of observational data, pathophysiologic concepts, and decision analysis. At the heart of the decision is an assessment of the individual patient's risk of thromboembolism off antithrombotic therapy versus risk of ICH recurrence on antithrombotic therapy. PMID- 25907911 TI - Acute treatment of blood pressure after ischemic stroke and intracerebral hemorrhage. AB - Blood pressure elevation in the setting of acute ischemic stroke and intracerebral hemorrhage is common. Controversy exists as to the optimal management of elevated blood pressure in this patient population. This article reviews the available clinical data that guides acute blood pressure management and how this may affect clinical outcomes. Furthermore, it examines how these data have led to controversies in their clinical application. PMID- 25907910 TI - Management of unbled brain arteriovenous malformation study. AB - In a recent trial limited to arteriovenous malformations discovered not to have bled, medical management was superior to medical management plus intervention. The trial was halted after 226 randomizations and a mean follow-up of 3.3 years owing to a disparity favoring the medical arm. Eligible patients were selected as suitable for lesion eradication. The initial sample size of 800 and follow-up plans for a mean of 7 years were lowered and shortened, respectively, by the outcome data. An application for extended follow-up was given poor priority scores owing to estimations that the disparities in outcomes would not change significantly. PMID- 25907912 TI - Expansion of Intravenous Tissue Plasminogen Activator Eligibility Beyond National Institute of Neurological Disorders and Stroke and European Cooperative Acute Stroke Study III Criteria. AB - Intravenous tPA is the standard treatment for acute ischemic stroke. Multiple contraindications for thrombolysis developed during the design of the clinical trials may be overly cautious and limit the number of patients who may be eligible and potentially benefit from treatment. As clinicians have become more comfortable with off-label use of tPA, new data on the safety of thrombolysis have become available and shaped the current guidelines. This article updates our knowledge on the evidence available for these contraindications to help guide the clinician in choosing the optimal approach to some of the most commonly encountered clinical scenarios. PMID- 25907913 TI - Endovascular treatment of acute ischemic stroke. AB - Endovascular therapy for acute stroke has evolved with the use of intra-arterial thrombolytics, intravenous/intra-arterial bridging strategies, and mechanical thrombectomy/aspiration devices. Despite widespread use in clinical practice, randomized trials of first-generation devices failed to demonstrate improved outcomes compared with standard care. New-generation stent retriever devices demonstrate higher rates of revascularization and clinical outcomes compared with first-generation devices. Additional randomized trials are underway and have the potential to confirm clinical efficacy of new-generation devices compared with standard care. The role of additional advanced imaging for patient selection remains unclear, and further trials are needed to demonstrate the role of these techniques for patient selection. PMID- 25907914 TI - Diagnosis and treatment of cervical artery dissection. AB - Cervical artery dissection (CAD) is a major cause of stroke in the young. A mural hematoma is detected in most CAD patients. The intramural blood accumulation should not be considered a reason to withhold intravenous thrombolysis in patients with CAD-related stroke. Because intravenous-thrombolyzed CAD patients might not recover as well as other stroke patients, acute endovascular treatment is an alternative. Regarding the choice of antithrombotic agents, this article discusses the findings of 4 meta-analyses across observational data, the current status of 3 randomized controlled trials, and arguments and counterarguments favoring anticoagulants over antiplatelets. Furthermore, the role of stenting and surgery is addressed. PMID- 25907915 TI - Management of asymptomatic carotid stenosis. AB - With modern intensive medical therapy, the risk of ipsilateral stroke in patients with asymptomatic carotid stenosis (ACS) is below the risk of either carotid stenting or endarterectomy. Routine intervention for ACS is therefore not justified; approximately 90% of patients with ACS would be better off with intensive medical therapy. The few who could benefit can be identified by transcranial Doppler embolus detection or features of vulnerable plaque that can be imaged by 3-dimensional ultrasound, MRI or positron emission tomography/computed tomography; some of these methods are still in development. PMID- 25907916 TI - Stenting or endarterectomy for patients with symptomatic carotid stenosis. AB - Carotid artery stenting is a less invasive alternative to endarterectomy to treat symptomatic carotid stenosis. Clinical trials showed a higher periprocedural risk of nondisabling stroke with stenting, and a higher periprocedural risk of myocardial infarction, cranial nerve palsy, and access site hematoma with endarterectomy. The excess in procedure-related strokes with stenting is mainly seen in patients aged 70 and over. After the procedural period, stenting and endarterectomy are equally effective in preventing stroke and recurrent carotid stenosis in the medium to long term. The choice of stenting versus endarterectomy should take into account risks of both procedures in individual patients. PMID- 25907917 TI - Recurrent Stroke while on Antiplatelet Therapy. AB - Of the ~795,000 strokes in the United States annually, 185,000 are recurrent. A third to half of them occur while on antiplatelet therapy. Multiple reasons could explain breakthrough stroke while on antiplatelet therapy. Management of recurrent stroke requires a meticulous search for the cause and mechanism of stroke. At present, there is no indication for antiplatelet resistance testing in ischemic stroke, or adjusting medications based on its results. Recent trials have shown the effectiveness of dual antiplatelet therapy in the acute period after an ischemic event, but no benefit has been found with this regimen for long term secondary prevention. PMID- 25907918 TI - Prevention of recurrent stroke in patients with patent foramen ovale. AB - Patent foramen ovale (PFO) is common and only rarely related to stroke. The high PFO prevalence in healthy individuals makes for difficult decision making when a PFO is found in the setting of a cryptogenic stroke, because the PFO may be an incidental finding. Recent clinical trials of device-based PFO closure have had negative overall summary results; these trials have been limited by low recurrence rates. The optimal antithrombotic strategy for these patients is also unknown. Recent work has identified a risk score that estimates PFO-attributable fractions based on individual patient characteristics, although whether this score can help direct therapy is unclear. PMID- 25907919 TI - The therapeutic value of laboratory testing for hypercoagulable states in secondary stroke prevention. AB - Although screening for hypercoagulable states is commonly performed as part of the evaluation of first arterial ischemic stroke in young adults, available evidence does not support this as a routine practice, even in patients with cryptogenic stroke and a positive family history of early thrombotic events or in patients with a patent foramen ovale. Testing for antiphospholipid antibodies is a possible exception because persistent antibodies are associated with an increased risk of recurrent stroke. Despite the lack of supporting data, screening for hypercoagulable states in recurrent early-onset cryptogenic cerebral ischemia could be considered. PMID- 25907920 TI - Primary angiitis of the central nervous system: diagnostic criteria. AB - Primary angiitis of the central nervous system (PACNS) is a vasculitis of small arteries and veins of unknown cause restricted to the central nervous system (CNS), and controversy and disagreement exist over the means to establish the diagnosis. Cerebral arteriography, cerebrospinal fluid examination, and MRI singly or in combination do not have sufficiently demonstrated positive predictive value to establish the diagnosis. An alternative diagnosis is established at biopsy in 35% of cases. Histologic confirmation is required for the diagnosis of PACNS. Patients without histologic confirmation should not be included in case reports, case series, or reviews. PMID- 25907921 TI - Cerebrovascular diseases: controversies and challenges. PMID- 25907922 TI - Note on levels of clinical efficacy. PMID- 25907923 TI - A metabolomic study of adipose tissue in mice with a disruption of the circadian system. AB - Adipose tissue functions in terms of energy homeostasis as a rheostat for blood triglyceride, regulating its concentration, in response to external stimuli. In addition it acts as a barometer to inform the central nervous system of energy levels which can vary dramatically between meals and according to energy demand. Here a metabolomic approach, combining both Mass Spectrometry and Nuclear Magnetic Resonance spectroscopy, was used to analyse both white and brown adipose tissue in mice with adipocyte-specific deletion of Arntl (also known as Bmal1), a gene encoding a core molecular clock component. The results are consistent with a peripheral circadian clock playing a central role in metabolic regulation of both brown and white adipose tissue in rodents and show that Arntl induced global changes in both tissues which were distinct for the two types. In particular, anterior subcutaneous white adipose tissue (ASWAT) tissue was effected by a reduction in the degree of unsaturation of fatty acids, while brown adipose tissue (BAT) changes were associated with a reduction in chain length. In addition the aqueous fraction of metabolites in BAT were profoundly affected by Arntl disruption, consistent with the dynamic role of this tissue in maintaining body temperature across the day-night cycle and an upregulation in fatty acid oxidation and citric acid cycle activity to generate heat during the day when rats are inactive (increases in 3-hydroxybutyrate and glutamate), and increased synthesis and storage of lipids during the night when rats feed more (increased concentrations of glycerol, choline and glycerophosphocholine). PMID- 25907924 TI - The association of perioperative autologous blood transfusion with the early postoperative cognitive dysfunction in aged patients following lumbar surgery. AB - PURPOSE: Intraoperation autologous blood transfusion is an effective method that is used in surgeries with an important blood loss. Several studies suggest that massive blood transfusion is one of the independent risks for postoperative cognitive dysfunction (POCD). Whether the autologous blood is one of the risk factor for POCD or not, we retrospectively examined the incidence of POCD and the probable risk factors in patients undergoing lumbar surgery in our hospital, with the same aged non-POCD patients as controls. METHODS: Eighty-one patients who underwent lumbar surgery were included. Perioperative data were examined for association with POCD on the 7 postoperative days by a Mini-Mental State Test. Multivariable logistic regression analysis was conducted to determine the probable risks associated with POCD. RESULTS: POCD was found in 21 patients. Participants who developed POCD were more likely to had a lower eduction level, more likely to had more blood loss, higher incidence of preoperative anemia, and perioperative allogeneic blood transfusion of more than 3 units as independent risk factors for POCD 7 d postoperatively (P < 0.05). Otherwise, there is no significant difference of the patients received autologous blood or not (P > 0.05). CONCLUSION: Autologous blood transfusion is not a risk factor for POCD in aged patients following lumbar surgery. Autologous blood is likely to be a better method of intraoperative blood transfusion during lumbar spine surgery. PMID- 25907926 TI - [Big data: the progress and applications of antibody repertoire sequencing]. AB - Antibody, the major effector in adaptive immunity, plays key roles in protective and pathogenic immune responses. Integrative analyses of antibody development, differentiation, and maturation promote the research in immune mechanism, vaccine design, and therapies for autoimmune disorders. The development of next generation sequencing technologies has enabled large-scale characterization of functional antibody repertoires. With the advantages of next generation sequencing, antibody and antibody repertoire analysis have been successfully used in identification of HIV-1-broadly neutralizing antibodies, design of rationale structure-based vaccine, and development of immunology. With increasing sequence length and precision, improvement of experimental protocols and bioinformatics analyses, and development of single cell sequencing technology, antibody repertoire sequencing will expedite the research in antibody-related immune response, and thus facilitates vaccine design for infectious diseases, clinical diagnosis and interference of autoimmune diseases. This review introduces the technologies, progresses, applications, and caveats of antibody repertoire sequencing. PMID- 25907925 TI - The clinical implications of thrombocytopenia in adults with severe falciparum malaria: a retrospective analysis. AB - BACKGROUND: Thrombocytopenia is a common finding in adults with severe falciparum malaria, but its clinical and prognostic utility is incompletely defined. METHODS: Clinical and laboratory data from 647 adults with severe falciparum malaria were analysed retrospectively to determine the relationship between a patient's platelet count on admission to hospital and their subsequent clinical course. RESULTS: On admission, 614 patients (94.9%) were thrombocytopenic (platelet count <150 * 10(9)/L) and 328 (50.7%) had a platelet count <50 * 10(9)/L. The admission platelet count was inversely correlated with parasite biomass (estimated from plasma PfHRP2 concentrations, rs = -0.28, P = 0.003), the degree of microvascular sequestration (measured with orthogonal polarizing spectral imaging, rs = -0.31, P = 0.001) and disease severity (the number of World Health Organization severity criteria satisfied by the patient, rs = -0.21, P <0.001). Platelet counts were lower on admission in the patients who died (median: 30 (interquartile range 22 to 52) * 10(9)/L versus 50 (34 to 78) * 10(9)/L in survivors; P <0.001), but did not predict outcome independently from other established laboratory and clinical prognostic indices. The 39 patients (6%) with profound thrombocytopenia (platelet count <20 * 10(9)/L) were more likely to die (odds ratio: 5.00, 95% confidence interval: 2.56 to 9.75) than patients with higher platelet counts, but these high-risk patients could be identified more rapidly with simple bedside clinical assessment. The admission platelet count did not reliably identify the 50 patients (7.7%) with major bleeding during the study. CONCLUSIONS: Thrombocytopenia is a marker of disease severity in adults with falciparum malaria, but has limited utility in prognostication, triage and management. PMID- 25907927 TI - [Role of CD44 in monocyte transmigration across Cryptococcus neoformans-infected blood-brain barrier in vitro]. AB - OBJECTIVE: To explore the role of CD44 in monocyte adhesion to human brain microvascular endothelial cells (HBMECs) and monocyte migration across an in vitro model of blood-brain barrier (BBB) infected by Cryptococcus neoformans (Cn). METHODS: An in vitro blood-brain barrier model was constructed using a transwell chamber covered with a HBMEC monolayer. The wild-type strain of Cn B4500FO2, TYCC645#32 strain with CPS1 gene deletion and PCIP strain with CPS1 complementation were chosen to infect the monolayer HBMECs. THP-1 cells were added to the upper chamber of transwell, and the relative migration rate was determined by counting the number of the cells entering the lower chambers. The inhibitory effects of anti-CD44 monoclonal antibody and the CD44 inhibitor bikunin were examined on THP-1 binding to and migration across HBMECs. RESULTS: Cn infection of the HBMECs caused markedly enhanced THP-1 cell adhesion and migration across the monolyers (P<0.01) dependent on Cn concentration and exposure time. Addition of anti-CD44 monoclonal antibody and bikunin significantly lowered THP-1 adhesion and migration rates in the BBB model with Cn infected HBMECs (P<0.01) with a dose dependence of the antibody (within 0-1 ug) and inhibitor (within 0-20 nmol/L). Both THP-1 adhesion rate and migration rate were lowered in the BBB model infected with CPS1 gene-deleted Cn but increased in the model infected with the complemented strain compared with those in the wild type strain-infected model. CONCLUSION: In the in vitro BBB model, CD44 expressed on HBMECs may play an essential role in monocyte adhesion to and migration across the BBB. The capsular hyaluronic acid may mediate Cn-induced monocyte adhesion and migration. PMID- 25907928 TI - [Incorporation of TV regularization in deconvolution for partial volume correction in PET imaging]. AB - OBJECTIVE: We propose a method using total variation (TV) regularization in deconvolution for partial volume correction in PET imaging. In the degraded image model, we used TV regularization procedure in Van Cittert (VC) and Richardson Lucy (RL) deconvolution algorithms. These methods were tested in simulated NCAT images and images of NEMA NU4-2008 IQ phantom and tumor-bearing mouse scanned by Simens Invoen microPET. The simulated experiment and tumor-bearing mouse experiment showed that the algorithms using TV regularization provided superior qualitative and quantitative appearance compared with traditional VC and RL algorithms. When the mean intensity of the tumor increased by (10+/-1.8)%, the SD increase percentage was decreased from 49.98% to 14.26% and from 42.76% to 4.70%, suggesting the efficiency of the proposed algorithms for reducing PVEs in PET. PMID- 25907929 TI - [Comparison of clinical outcomes of blastocysts derived from non-top quality embryos and cleavage-stage high-quality embryos in frozen-thawed embryo transfer cycles]. AB - OBJECTIVE: To explore the developmental potential of embryos at different developmental days and provide evidence for blastocyst culture of non-top quality cleavage stage embryos in frozen-thawed embryo transfer (FET) cycles. METHODS: The clinical data of 687 FET cycles were retrospectively analyzed. According to the embryo freezing time, the patients were divided into day 5 (D5) blastocyst group (n=87), day 6 (D6) blastocyst group (n=111) and day 3 cleavage-stage embryo (D3) group (n=489) with hormone replacement cycles or natural cycles for endometrial preparation. The clinical pregnancy rates, miscarriage rates, and implantation rates were compared between the 3 groups. RESULTS: The clinical pregnancy rate, miscarriage rate and implantation rate per transfer were 58.6%, 9.8%, and 42.9% in D5 group, 32.4%, 19.4%, and 23.3% in D6 group, and 44.9%, 16.4%, and 26.9% in D3 group, respectively. The clinical pregnancy rate and implantation rate were significantly higher in D5 group than in the other two groups (P<0.05). CONCLUSION: The D5 blastocysts derived from non-top quality D3 embryos after cryopreservation can have better clinical outcomes than those derived from D3 cleavage-stage embryos and D6 blastocysts, and are therefore a better option than D3 cleavage-stage embryos in FET cycles. PMID- 25907930 TI - [Activation of phospholipase C-independent protein kinase C signaling pathway of parathyroid hormone enhances CITED1 expression in mouse osteoblasts]. AB - OBJECTIVE: To explore the functions of phospholipase C (PLC)-independent protein kinase C signaling pathway (PTH/nonPLC/PKC) of parathyroid hormone (PTH) and its role in bone metabolism. METHODS: Osteoblasts isolated from the calvaria of 2- or 3-day-old C57BL mice, identified by alkaline phosphatase staining and Alizarin red staining, were treated for 4 h with 100 nmol/L [Gly(1), Arg(19)]hPTH(1-28) plus 10 nmol/L RP-cAMP, 10 nmol/L [Gly(1), Arg(19)]hPTH(1-34) plus 10 nmol/L RP cAMP , 10 nmol/L PTH(1-34), or and 0.1% trifluoroacetic acid (TFA). The total RNA was then isolated for screening differentially expressed genes related to PTH/nonPLC/PKC pathway using Affymetrix mouse 12x135K gene expression profile microarray, and the identified genes were confirmed by real-time quantitative PCR. MC3T3-E1 cells treated with [Gly(1), Arg(19)]hPTH(1-28)+RP-cAMP, [Gly(1), Arg(19)]hPTH(1-34)+RP-cAMP, [Gly(1), Arg(19)]hPTH(1-34)+ RP-cAMP +100 nmol/L Go6983, or 0.1% TFA were also examined for GR(1-28)- or GR(1-34)-mediated gene expression changes using real-time quantitative PCR. RESULTS: Alizarin red staining visualized red mineralized nodules in the osteoblasts at 28 days of culture. According to the genechip results, we selected 56 target genes related to PTH/nonPLC/PKC pathway, among which CITED1 showed higher expressions in [Gly(1), Arg(19)]hPTH(1-34)+ RP-cAMP group than in both the control group and [Gly(1), Arg(19)]hPTH(1-28)+RP-cAMP group (P<0.05), and its expression was the highest in PTH(1-34) group (P<0.05). RT-PCR of MC3T3-E1 cells yielded consist results with those in the primary osteoblasts, and the cells treated with Go6983 (a PKC inhibitor) did not show GR(1-28)- or GR(1-34)-mediated differential expression of CITED1. CONCLUSION: The activation of PLC-independent protein kinase C signaling pathway of PTH enhances the expression of CITED1 in mouse osteoblasts to mediate the effect of PTH on bone metabolism, and this pathway is not dependent on the activation of PLC or PKA signaling. PMID- 25907931 TI - [Key frames extraction and application in intravascular ultrasound pullback sequences based on manifold learning]. AB - OBJECTIVE: We propose an image-based key frames gating method for intravascular ultrasound (IVUS) sequence based on manifold learning to reduce motion artifacts in IVUS longitudinal cuts. METHODS: We achieved the gating with Laplacian eigenmaps, a manifold learning technique, to determine the low-dimensional manifold embedded in the high-dimensional image space. A distance function was constructed by the low-dimensional feature vectors to reflect the heart movement. The IVUS images were classified as end-diastolic and non-end-diastolic based on the distance function, and the IVUS images collected in end-diastolic stage constitutes the key frames gating sequences. RESULTS: We tested the algorithm on 13 in vivo clinical IVUS sequences (images 915+/-142 frames, coronary segments length 15.24+/-2.37 mm) to calculate the vessel volume, lumen volume, and the mean plaque burden of the original and gated sequences. Statistical results showed that both the vessel volume and lumen volume measured from the gated sequences were significantly smaller than the original ones, indicating that the gated sequences were more stable; the mean plaque burden was comparable between the original and gated sequences to meet the need in clinical diagnosis and treatment. In the longitudinal views, the gated sequences had less saw tooth shape than the original ones with a similar trend and a good continuity. We also compared our method with an existing gating method. CONCLUSION: The proposed algorithm is simple and robust, and the gating sequences can effectively reduce motion artifacts in IVUS longitudinal cuts. PMID- 25907932 TI - [Effect of Tripterygium glycosides on expression of hypoxia inducible factor 1alpha and endothelin-1 in kidney of diabetic rats]. AB - OBJECTIVE: To observe the effect of Tripterygium glycosides (TG) on the expression of hypoxia-inducible factor-1alpha and endothelin-1 in the kidney of diabetic rats and explore the possible mechanism underlying the protective effect of TG against diabetic nephropathy. METHODS: Sixty 8-week-old male SD rats were randomly divided into normal control group (n=10) and streptozotocin-induced diabetes mellitus (DM) model group (n=50). The diabetic model rats were then randomly divided into DM group, low-dose (8 mg/kg) and high-dose (16 mg/kg) TG treatment groups, and Irbesartan (50 mg/kg) treatment group. After 8 weeks, the levels of blood glucose (BG), 24-h urine protein (24 h Upro), serum creatinine (Scr) and blood urea nitrogen (BUN) were measured. The pathological changes in the renal tissues were examined by optical microscopy, and the mean glomerular area (MGA) and mean glomerular volume (MGV) were measured with pathological image analysis. Immunohistochemical and Western blotting were used to detect the expression of HIF-1alpha and ET-1 protein in the renal tissue, and their mRNA expressions were detected using real-time fluorescence quantitative PCR. RESULTS: HIF-1alpha and ET-1 expression increased in the kidney of diabetic rats. Compared with the diabetic model rats, the rats receiving TG and Irbesartan treatment showed decreased levels of Scr, BUN, 24h Upro, MGA and MGV, improved renal histopathology, and reduced expression of HIF-1alpha and ET-1 mRNA and protein in the renal tissue. These changes were more obvious in high-dose TG treatment group. Correlation analysis showed that the expression of HIF-1alpha was positively correlated with that of ET-1, and they were both positively correlated with kidney weight index (KW/BW), 24 h Upro, MGA, and MGV. CONCLUSION: HIF-1alpha and ET-1 are overexpressed in the kidney of diabetic rats. TG can improve kidney damage in diabetic rats and delay the development of diabetic nephropathy by inhibiting the HIF-1alpha and ET-1 expression. PMID- 25907933 TI - [Changes in serum level of carboxy-terminal telopeptide of type I collagen in patients with coronary heart disease]. AB - OBJECTIVE: To investigate the serum level of carboxy-terminal telopeptide of type I collagen (ICTP) and explore its correlation with MMP-2 and MMP-9 in patients with coronary artery disease (CHD). METHODS: A total of 103 CHD patients treated in our hospital between October, 2013 and May, 2014 were enrolled, including 39 with stable angina pectoris (SAP), 39 with unstable angina (UA), and 25 with acute myocardial infarction (AMI), with 38 non-CHD volunteers as the control group. The serum levels of ICTP, MMP-2, and MMP-9 were detected in all the subjects using enzyme-linked immunosorbent assay (ELISA). RESULTS: No significant difference in serum levels of MMP-2, MMP-9, or ICTP was found between the control and SAP groups or between UA and AMI groups (P>0.05), but the latter two groups had significantly higher serum levels of MMP-2, MMP-9, and ICTP than the former two groups (P<0.05). Serum ICTP level was found to negatively correlated with the fibrotic area and positively with the lipid component in the plaques (P<0.05). Regression analysis revealed significant positive correlations of serum ICTP with MMP-2 and MMP-9 (P<0.05). CONCLUSION: An elevated serum ICTP level is indicative of the presence of unstable plaques in CHD patients. Serum ICTP is more strongly correlated with MMP-2 than with MMP-9, and can be used as a non-invasive marker for assessing vulnerable plaques in patients with acute coronary syndrome. PMID- 25907934 TI - [Mechanism of thioridazine-induced apoptosis of human colorectal cancer SW480 cells]. AB - OBJECTIVE: To study the effect of thioridazine on the proliferation and apoptosis of human colorectal cancer SW480 cells. METHODS: SW480 cells were treated with different concentrations of thioridazine, and MTT assay was used to evaluate the cell inhibition rate. Hoechst 33342 staining was performed to demonstrate the cell morphology changes. Flow cytometry was used to determine the cell apoptosis and cell cycle changes. RT-qPCR was used to detect PDCD4, c-MYC, BCL2, CCND1, CASPASE3, PARP1, CDK4 and EIF4A mRNA expressions, and Western blotting was employed to assay AKT, p-AKT, and PDCD4 protein expression levels. RESULTS: MTT results showed that thioridazine inhibits the proliferation of SW480 cells. SW480 cells treated with thioridazine presented with such typical features of apoptosis of karyopyknosis, chromatin condensation and nuclear fragmentation. Flow cytometry showed that thioridazine was a cell cycle-specific drug and caused cell cycle arrest at G(1)/G(0) phase and an increased cell apoptosis rate. Thioridazine treatment of the cells resulted in up-regulated PDCD4 mRNA expression and down-regulated mRNA expressions of CCND1, CDK4, c-MYC, BCL2, CASPASE3, PARP1 and EIF4A, increased PDCD4 protein expression and reduced p-AKT protein expression. CONCLUSION: Thioridazine inhibits the proliferation and induces apoptosis of SW480 cells by up-regulating PDCD4 and inhibiting PI3K/Akt pathway. PMID- 25907935 TI - [A competency model of rural general practitioners: theory construction and empirical study]. AB - OBJECTIVE: To perform theory construction and empirical study of the competency model of rural general practitioners. METHODS: Through literature study, job analysis, interviews, and expert team discussion, the questionnaire of rural general practitioners competency was constructed. A total of 1458 rural general practitioners were surveyed by the questionnaire in 6 central provinces. The common factors were constructed using the principal component method of exploratory factor analysis and confirmatory factor analysis. The influence of the competency characteristics on the working performance was analyzed using regression equation analysis. RESULTS: The Cronbach 's alpha coefficient of the questionnaire was 0.974. The model consisted of 9 dimensions and 59 items. The 9 competency dimensions included basic public health service ability, basic clinical skills, system analysis capability, information management capability, communication and cooperation ability, occupational moral ability, non-medical professional knowledge, personal traits and psychological adaptability. The rate of explained cumulative total variance was 76.855%. The model fitting index were Chi(2)/df 1.88, GFI=0.94, NFI=0.96, NNFI=0.98, PNFI=0.91, RMSEA=0.068, CFI=0.97, IFI=0.97, RFI=0.96, suggesting good model fitting. Regression analysis showed that the competency characteristics had a significant effect on job performance. CONCLUSIONS: The rural general practitioners competency model provides reference for rural doctor training, rural order directional cultivation of medical students, and competency performance management of the rural general practitioners. PMID- 25907936 TI - [Preparation and characterization of rabbit anti-mouse zona pellucida 2 antibodies]. AB - OBJECTIVE: To prepare rabbit anti-mouse zona pellucida 2 (mZP2) polyclonal antibodies and test their immunoactivity. METHODS: Recombinant proteins of mZP2 expressed in Rosetta transformant was separated by SDS-PAGE, and the gel strips containing the recombinant mZP2 were cut out and emulsified to immunize New Zealand white rabbits. The antibody response of the antiserum was detected by ELISA, and the specificity of the antiserum was verified by immunohistochemical assay. The effect of the antiserum on the binding of oocytes with acrosomal reacted sperm was tested by sperm-egg binding assay. RESULTS: ELISA results showed that the immunized rabbit produced anti-mZP2 antiserum. The antiserum reacted specifically with the zona pellucida of mouse ovarian sections. Sperm-egg binding assay showed that treatment of the oocytes with the anti-mZP2 antiserum caused decreased binding of zona pellucida with the acrosomal reacted sperm by 43.7%. CONCLUSION: We obtained rabbit anti-mouse ZP2 polyclonal antibodies that can inhibit the binding of oocytes with acrosomal reacted sperm. PMID- 25907937 TI - [Detection of PLA2R1 in renal biopsy specimens of patients with idiopathic membranous nephropathy]. AB - OBJECTIVE: To investigate the prevalence of PLA2R1 in renal biopsy specimens of patients with idiopathic membranous nephropathy (IMN) and explore the relationship between PLA2R1 and IMN. METHODS: A total of 108 adult patients with biopsy-proved glomerular diseases were enrolled in this study, including 41 with IMN, 2 with hepatitis B-associated membranous nephropathy, 8 with V lupus nephritis, 27 with IgA nephropathy, 19 with minimal change nephropathy, 5 with mild mesangial proliferative glomerulonephritis, and 6 with focal segmental glomeruloselerosis (FSGS). Indirect immunofluorescence assay was used to detect PLA2R1 in the biopsy specimens and the clinical variables of the IMN patients were analyzed. RESULTS: In 35 of the 41 (85.37%) patients with IMN, PLA2R1 was detected with a fine granular pattern in the subepithelial deposits along the glomerular capillary loops. PLA2R1 antigen was not detected in patients with other glomerulopathies. No significant differences were found in age, serum creatinine, serum albumin, or 24-h urinary protein level between PLA2R1-positive and negative patients with IMN (P>0.05). CONCLUSION: According to our results, 85.37% of adult patients with biopsy-proven IMN are positive for PLA2R1 antigen, which, however, does not contribute to variations of the patients' clinical manifestations. PMID- 25907939 TI - [Changes of masseter muscle asymmetry due to unilateral mastication after intervention: a electromyographic analysis]. AB - OBJECTIVE: To explore the effect of intervention with unilateral mastication on masseter muscle asymmetry. METHODS: Forty-three subjects (19 males and 24 females, mean age 20.0?0.5 years) with unilateral chewing were divided into group A0 with motivation and without intervention, group A1 with motivation and intervention, group B0 without motivation or intervention, and group B1 without motivation but with intervention. In groups A0 and A1, the motivation was removed and groups A1 and group B1 received interventions. Surface electromyography was recorded using surface electromyography in all the subjects in mandible postural position (MPP), with maximum clenching in intercuspal position (ICP) and during chewing. The sEMG of the left and right masseter muscle were separately recorded to assess the asymmetry index of the masseter muscles (ASMM) and its changes after intervention. RESULTS: In groupA0, the ASMM at MPP, during maximum clenching and chewing had no obvious changes after removal of the motivation. In group A1, the ASMM at MPP, during maximum clenching and chewing were obviously decreased after intervention. In group B0, the ASMM at MPP and during maximum clenching showed no obvious changes but ASMM during chewing significantly increased after removal of the motivation. In group B1, the ASMM at MPP, during maximum clenching and chewing all decreased obviously after intervention. CONCLUSION: Interventions can significantly improve the bilateral symmetry of the masseter muscles in subjects with unilateral chewing, and the motivation for unilateral chewing should be removed before intervention. PMID- 25907938 TI - [Ursolic acid inhibits corneal graft rejection following orthotopic allograft transplantation in rats]. AB - OBJECTIVE: To investigate the effects of ursolic acid on corneal graft rejection in a rat model of othotopic corneal allograft transplantation. METHODS: Forty eight recipient Wistar rats were divided into normal control group with saline treatment (group A), autograft group with saline treatment (group B), SD rat allograft group with saline treatment (group C), and SD rat allograft group with intraperitoneal ursolic acid (UA) treatment group (group D). The rats received saline or UC (20 mg.kg(-1).d(-1)) treatment for 12 days following othotopic graft transplantation. The grafts were evaluated using the Larkin corneal rejection rating system, and the graft survival was assessed with Kaplan-Meier analysis. On day 14, the grafts were harvested for histological examination, Western blotting, and assessment of expressions of interlukin-2 (IL-2), interferon-gamma (IFN gamma), nuclear transcription factor-kappaB (NF-kappaB) p65, vascular endothelial growth factor (VEGF) and intercellular adhesion molecule-1 (ICAM-1). RESULTS: The allograft survival was significantly longer in group D than in group C (29.12+/ 9.58 vs 9.67+/-2.16 days, P<0.05). UC treatment obviously reduced the expression levels of IL-2, IFN-gamma, NF-kappaBp65, ICAM-1 and VEGF and increased inhibitory kappa B alpha (IkappaB-alpha) expression in the grafts, where no obvious inflammatory cell infiltration or corneal neovascularization was found. CONCLUSION: As a NF-kappaB inhibitor, ursolic acid can prevent corneal neovascularization and corneal allograft rejection to promote graft survival in rats following orthotopic corneal allograft transplantation. PMID- 25907940 TI - [Effect of resveratrol on constrictions of human intrapulmonary arteries ex vivo]. AB - OBJECTIVE: To determine the effect of resveratrol on constrictions of isolated human intrapulmonary arteries and its mechanisms. METHODS: Intrapulmonary arteries (1-1.5 mm in diameter) were dissected and cut into rings (1.8-2.0 mm in length) under microscope, and were then mounted in a Multi Myograph system. The rings were stimulated with 100 nmol/L U46619, 30 nmol/L endothelin-1, or 60 mmol/L KCl to produce sustained contraction of the intrapulmonary arteries, after which resveratrol was applied cumulatively. Endothelium denudation, L-NAME and indomethecin were used to investigate the effect of resveratrol on constrictions of the isolated arteries, suing DMSO as the control. RESULTS: Resveratrol induced concentration-dependent relaxations in endothelium-intact rings that contracted in response to stimulations with U46619, ET-1 and KCl, with pD2 of 3.82+/-0.20, 3.84+/-0.57, and 3.68+/-0.27, Emax of (99.58+/-0.83)%, 100%, and (99.65+/-0.98)%, respectively. Treatment of the arterial rings with the eNOS inhibitor L-NAME, but not with indomethecin or endothelium denudation, obviously affected the relaxant effects of resveratrol. CONCLUSION: Resveratrol can concentration-dependently produce relaxant effect on human intrapulmonary arteries independent of the endothelium possibly by promoting synthesis and release of NO. PMID- 25907941 TI - [Human soluble dendritic cell-specific intercellular adhesion molecule 3-grabbing nonintegrin inhibits phagocytosis of Staphylococcus aureus by immature dendritic cells]. AB - OBJECTIVE: To study the effect and mechanism of soluble dendritic cell-specific intercellular adhesion molecule 3-grabbing nonintegrin (sDC-SIGN) on the phagocytosis of Staphylococcus aureus (S. aureus) by immature dendritic cells (imDCs). METHODS: Flow cytometry was employed to examine the effect of sDC-SIGN on the phagocytosis of S. aureus by imDCs. Enzyme-linked immunosorbent assay (ELISA) was used to analyze the binging of sDC-SIGN to S. aureus, lipoteichoic acid (LTA) and lipopolysaccharides (LPS) and investigate the effect of the ligands mannan and LTA and anti-DC-SIGN antibodies 1C6 and 4H3 on the binging of sDC-SIGN to S. aureus. RESULTS: sDC-SIGN inhibited the phagocytosis of S. aureus by imDCs. sDC-SIGN bound to S. aureus in a Ca(2+)-dependent manner. sDC-SIGN concentration-dependently bound to LTA, but not to LTA, and the binging of sDC SIGN to S. aureus was blocked by mannan, LTA, 1C6 and 4H3. CONCLUSION: sDC-SIGN preferentially binds to the carbohydrate constituents on S. aureus to affect the binding between membrane-bound DC-SIGN and S. aureus, thus suppressing the phagocytosis of S. aureus by imDCs. PMID- 25907942 TI - [Effects of hydrogen sulfide on myocardial fibrosis and MAPK1/3 and MMP-8 expression in diabetic rats]. AB - OBJECTIVE: To explore the effects of hydrogen sulfide (H(2)S) on myocardial fibrosis and expressions of MAPK1/3 and MMP-8 in diabetic rats. METHODS: Forty adult male SD rats were randomized into 4 groups, namely the control group, diabetes mellitus group (STZ group), diabetes mellitus with H(2)S treatment group (STZ+H(2)S group), and normal rats with H(2)S treatment group (H(2)S group). Diabetes was induced by intraperitoneal injections of 40 mg/kg streptozotocin (STZ). The rats in the control group received daily intraperitoneal injections of saline, and those in STZ+H(2)S group and H(2)S group were given NaHS (100 umol/kg) injections. After 8 weeks, the pathologies of cardiac fibrosis were examined with HE staining, and the expressions of collagen I, MAPK1/3 and MMP-8 were analyzed with Western blotting. RESULTS: Compared with the control group, the diabetic rats showed increased collagen content and obvious interstitial fibrosis in the myocardial tissue with significantly increased expression levels of collagen I, MAPK1/3 and MMP-8 (P<0.05); all these changes were obviously reversed by treatment with H(2)S (P<0.05). Collagen I, MAPK1/3 and MMP-8 expression levels and the degree of myocardial fibrosis were comparable between H(2)S group and control group (P>0.05). CONCLUSION: Hydrogen sulfide can attenuate cardiac fibrosis in diabetic rats, and the mechanism may involve the inhibition of MAPK1/3/MMP-8 signal pathway. PMID- 25907943 TI - [Clinical features and genotype analysis in a case of dyskeratosis congenita]. AB - OBJECTIVE: To analyze the clinical features and genotype in a 8-year-old boy with dyskeratosis congenita (DC). METHODS: We reviewed the clinical data of the case and amplified 7 DC-related genes (including DKC1,TERT,TERC,TINF2,NOP10, NHP2 and WRAP53) using polymerase chain reaction for DNA sequence analysis to identify the abnormal exons. RESULTS: DNA sequence analysis showed a c.85-15T>C mutation in DKC1 gene of the patient. His mother was a carrier of the mutated gene and presented with partial clinical features such as abnormal nails. CONCLUSION: The mutation of c.85-15T>C in DKC1 gene was reported for the first time in China. The diagnosis of DC should be considered if a young patient presents with mucocutaneous abnormalities, bone marrow failure, cancer susceptibility and a family history of cancer. Early genetic tests can improve the diagnosis rates and reduce misdiagnosis and missed diagnosis. PMID- 25907944 TI - [Changes of left ventricular function in cirrhotic patients and their correlation with the model for end-stage liver disease score]. AB - OBJECTIVE: To investigate the changes of left ventricular structure and function in patients with liver cirrhosis and their correlation with the model for end stage liver disease (MELD) score. METHODS: A total of 89 cirrhotic patients admitted between June, 2012 and June, 2014 and 30 healthy control subjects were enrolled in the study. According to MELD score, the cirrhotic patients were divided into 3 groups with MELD scores <=9, between 10 and 19, and >=20. The parameters of the left ventricle in resting state were measured using Doppler echocardiography, including left ventricular end systolic diameter (LVESD), left ventricular end diastolic diameter (LVEDD), interventricular septal thickness (IVST), left ventricular posterior wall thickness (LVPWT), left atrial diameter (LAD), ejection fraction (LVEF), cardiac output (CO), mitral flow velocity, and E wave deceleration time (DT), and evaluated their relationship with MELD score. RESULTS: Compared with the control subjects, the cirrhotic patients showed significantly increased LVESD, LVEDD, IVST, LAD, CO and DT but reduced VE/VA ratio (P<0.05 or 0.01). The values of LVESD, LVEDD, IVST, LAD and DT increased gradually with MELD scores (P<0.05 or 0.01). VE/VA ratio was higher in patients with MELD score of 10-19 than in those with MELD score <=9, and decreased significantly in those with MELD score >=20. Of the cirrhotic patients, 55% were found to have left atrial enlargement and 44% had a VE/VA ratio <=1; left atrial enlargement and a VE/VA ratio below 1 were more common in patients with a MELD score >=20 than in those with lower MELD scores. The LAD, LVEDD and DT were positively correlated with MELD scores (r=0.208, 0.319 and 0.197, respectively; P<0.05 or 0.01). CONCLUSIONS: The patients with liver cirrhosis can have cardiac function deficiency manifested mainly by left ventricular diastolic dysfunction in positive correlation with the severity of liver disease. PMID- 25907945 TI - [Perioperative immunomodulatory therapy does not decrease postoperative recurrence rate of rectal cancer]. AB - OBJECTIVE: To study the effect of perioperative immunomodulatory therapy on postoperative recurrence of rectal cancer. METHODS: This prospective study was conducted among 238 rectal/anal cancer patients undergoing intersphincteric resection at our center between January, 2010 and January, 2011, among whom 150 were eligible to be included and completed the study. The 150 patients were randomized in a double-blinded fashion into 3 equal groups to receive immunomodulatory therapy with 8 mg/kg celecoxib (group A), 0.4 mg/kg Sou-Medrol (group B), or placebo (group C), given daily from 5 days before surgery to 5 days after surgery, and the postoperative cancer recurrence were compared. RESULTS: At 3 days after the operation, the 3 groups showed significantly different C reactive protein (CRP) levels, which decreased obviously in all the 3 groups compared with those at 1 day following the operation (P=0.022), especially in group B. The levels of interleukin-6 (IL-6) at 3 days after the operation also differed significantly between the 3 groups but were lower in all the 3 groups than those at 1 day after the operation (P=0.046), and this reduction was the most obvious in group A. COX-2 expression differed significantly between the 3 groups (P=0.017), among which group A showed the most obvious suppression of COX 2 expression. During the follow-up for a mean of 45 months, no significant difference in the recurrence rate was found between the 3 groups (P=0.549). CONCLUSION: With a lower efficacy than Sou-Medrol in decreasing postoperative inflammation, celecoxib produces a better effect in inhibiting COX-2 expression, but it does not lower postoperative recurrence rate of rectal cancer. PMID- 25907946 TI - [Biocompatibility of poly-L-lactic acid/Bioglass-guided bone regeneration membranes processed with oxygen plasma]. AB - OBJECTIVE: To prepare and characterize a nano-scale fibrous hydrophilic poly-L lactic acid/ Bioglass (PLLA/BG) composite membrane and evaluate its biocompatibility as a composite membrane for guiding bone regeneration (GBR). METHODS: PLLA/BG-guided bone regeneration membrane was treated by oxygen plasma to improved its hydrophilicity. The growth of MG-63 osteoblasts on the membrane was observed using Hoechst fluorescence staining, and the biocompatibility of the membrane was evaluated by calculating the cells adhesion rate and proliferation rate. Osteogenesis of MG-63 cells was assessed by detecting alkaline phosphatase (ALP), and the formation of calcified nodules and cell morphology changes were observed using scanning electron microscope (SEM). RESULTS: The cell adhesion rates of PLLA/BG-guided bone regeneration membrane treated with oxygen plasma were (30.570+/-0.96)%, (47.27+/-0.78)%, and (66.78+/-0.69)% at 1, 3, and 6 h, respectively, significantly higher than those on PLLA membrane and untreated PLLA/BG membrane (P<0.01). The cell proliferation rates on the 3 membranes increased with time, but highest on oxygen plasma-treated PLLA/BG membrane (P<0.01). Hoechst fluorescence staining revealed that oxygen plasma treatment of the PLLA/BG membrane promoted cell adhesion. The membranes with Bioglass promoted the matrix secretion of the osteoblasts. Under SEM, the formation of calcified nodules and spindle-shaped cell morphology were observed on oxygen plasma-treated PLLA/BG membrane. CONCLUSION: Oxygen plasma-treated PLLA/BG composite membrane has good biocompatibility and can promote adhesion, proliferation and osteogenesis of the osteoblasts. PMID- 25907947 TI - [Effect of aluminum phosphate gel and Kangfuxin on esophageal pathology and IL-8 and PGE2 expressions in a rat model of reflux esophagitis]. AB - OBJECTIVE: To explore the effect of aluminum phosphate gel and Kangfuxin on esophageal pathology and expressions of interleukin-8 (IL-8) and prostaglandin E2 (PGE2) in rats with reflux esophagitis and explore the possible mechanisms. METHODS: Sixty SD rats were randomized into aluminum phosphate gel group (n=10), Kangfuxin group (n=10), aluminum phosphate gel+Kangfuxin group (n=10), model group (n=20), and control group (n=10). Except for those in the control group, all the rats were subjected to infusion of diluted lysolecithin with hydrochloric acid in the esophagus for 14 days. Ten rats in the model group and those in the control group were sacrificed to examine the pathological changes and contents of IL-8 and PGE2 in the esophagus using optical and electron microscopes and radioimmunoassay. The next day the rest rats were given corresponding treatments (saline in model group) administered into the esophagus on a daily basis for 14 days, after which esophageal pathologies and IL-8 and PGE2 contents were examined. RESULTS: The model rats showed obvious esophageal pathologies including inflammatory cell infiltration, vacuolar degeneration of the epithelial cells, esophageal erosion and even ulceration, with severe detachment of the epithelial cells. The rats in all the intervention groups showed lessened esophageal pathologies and lowered esophageal IL-8 and PGE2 contents compared with those in the model group. Esophageal mucosal injury index and IL-8 and PGE2 contents were all significantly lower in rats receiving combined treatment with aluminum phosphate and Kangfuxin than in those receiving either of the treatments (P<0.05). CONCLUSIONS: Both Kangfuxin and aluminum phosphate gel are effective in the treatment for reflux esophagitis induced by lysolecithin and hydrochloric acid, and their therapeutic effects are achieved possibly by reducing IL-8 and PGE2 levels in the esophagus. PMID- 25907948 TI - [Prophylactic antibiotics: a necessity in totally percutaneous thoracic endovascular aortic repair?]. AB - OBJECTIVE: To study the benefit of prophylactic antibiotics (PA) in totally percutaneous aortic endovascular repair (PEVAR) in the catheterization laboratory for reducing stent-graft infection and postimplantation syndrome (PIS). METHODS: The clinical data were analyzed of patients undergoing thoracic endovascular aortic repairs. The patients were divided into non-PA group and PA group according to the use of prophylactic antibiotics before PEVAR. The diagnosis of infection was made by two senior physicians with reference to Hospital Acquired Infection Diagnostic Criteria Assessment released by the Ministry of Health of China. RESULTS: The 95 enrolled patients included 35 with PA and 60 without PA group, who were comparable for baseline characteristics. Infection-related deaths occurred in 1 case in non-PA group and retrograde Stanford type A dissection and death occurred in 1 case in PA group (1.67% vs 2.85%, P=1.00). The PA and non-PA groups showed no significant difference in the incidence of postoperative infection (5% vs 2.86%, P=1.000), hospital stay (9.30+/-7.21 vs 10.06+/-5.69, P=0.094), infection-related mortality (1.67% vs 0%, P=1.00), or postoperative fever (70.90% vs 91.43%, P=0.20). The body temperature showed significant variations at different time points after procedure (F=19.831, P<0.001) irrelevant to the use of prophylactic antibiotics (F=0.978, P=0.326). CONCLUSION: The current data do not support the benefit of PA in reducing postoperative infection and PIS in patients undergoing PEVAR, but the patients without PA may have worse clinical outcomes in the event of postoperative infections. PMID- 25907949 TI - [Therapeutic effect of hemin on gestational hypertension in rats and the mechanism]. AB - OBJECTIVE: To investigate the therapeutic effects of hemin, an inducer of heme oxygenase, in a rat model of gestational hypertension and explore the possible mechanism. METHODS: Eighteen pregnant SD rats at day 12 of gestation were randomized equally into gestational hypertension model group, hemin treatment group, and normal pregnancy (control) group. In the former two groups, the rats were subjected to daily nitro-L-arginine methyl ester (L-NAME, 80 mg/kg) gavage since gestational day 14 for 7 consecutive days to induce gestational hypertension; saline was administered in the same manner in the control rats. The rats in hemin group received daily intraperitoneal injection of hemin (30 mg/kg) starting from gestational day 16. HO activity and carboxyhemoglobin (COHb) level in rat placental tissue were detected with spectrophotometric method, and soluble vascular endothelial growth factor receptor-1 (sFlt-1) and vascular endothelial growth factor (VEGF) level in the placental tissue homogenate supernatant were detected using ELSIA. RESULTS: At gestational day 20, the blood pressure and 24-h urinary protein were significantly higher in the model group than in the other two groups (P<0.05), and were higher in hemin group than in the control group (P<0.05); HO activity and COHb content in the placenta tissue were the lowest in the model group (P<0.05), and was lower in hemin group than in the control group (P<0.05). The level of sFlt-1 was significantly higher and VEGF level significantly lower in the model group than in the other two groups (P<0.05); sFlt-1 level remained higher and VEGF lower in hemin group than in the control group (P<0.05). CONCLUSION: Hemin can reduce blood pressure and urinary protein in rats with gestational hypertension possibly by up-regulating HO activity, enhancing carbon monoxide production, reducing sFlt-1 and increasing VEGF in the placental tissue. PMID- 25907950 TI - [Expression of helicase DDX41 in human dental pulp tissues and cells]. AB - OBJECTIVE: To detect the expression of D-E-A-D-box polypeptide 41 (DDX41) in human dental pulp tissues and cells. METHODS: The mRNA and protein expressions of DDX41 in human dental pulp cells were detected by RT-PCR and immunocytochemistry, and the expression of DDX41 in human dental pulp tissues was investigated by immunohistochemistry. RESULTS: Strong expressions of DDX41 mRNA and protein were detected in dental pulp cells. In dental pulp tissues, DDX41 was expressed in the cytoplasm and nucleus of odontoblasts. CONCLUSION: DDX41/STING-dependent TBK1 IRF3-IFN-beta signaling pathway may play a role in innate immune responses of the dental pulp to caries and pulpitis. PMID- 25907951 TI - [Reconstruction of a digital three-dimensional model of fetal heart]. AB - OBJECTIVE: To explore the methods for constructing the digital three-dimensional model of fetal heart. METHODS: Original two-dimensional CT image data sets were collected from 4 abortion fetuses with fetal malformations but not heart malformation or chromosomal abnormalities. The three-dimensional fetal heart model was reconstructed using Mimics14.0 software. RESULTS: In the reconstructed three-dimensional fetal heart, the left atrium, left ventricle, right atrium, right ventricle, the ascending aorta, the main pulmonary and their branches, the superior cava and inferior vena cava were marked with different colors, and these structures could be displayed individually or with other structures. This model also allowed three-dimensional arbitrary scaling, shifting or rotation at any angle, and the diameter of the each vessel could be measured with the software. CONCLUSION: The fetal heart model can be successfully reconstructed from the CT datasets using three-dimensional reconstruction software to facilitate clinical and anatomical teaching. PMID- 25907952 TI - [Establishment of a rabbit model of scoliosis induced by asymmetric load using springs]. AB - OBJECTIVE: To establish rabbit model of scoliosis induced with stable asymmetric lumbar loads. METHODS: Scoliosis was induced in 10 two-month-old New Zealand rabbits using 316L stainless steel springs placed between the unilateral transverse processes of L2 and L5. Serial radiographs were documented before and at 1, 4, 8, 9 and 12 weeks after the operation. At weeks, the rabbits were randomly divided into SR group (n=5) with the spring removed and SK group (n=5) without spring removal. RESULTS: All the rabbits survived the experiment with Cobb angle all greater than 10 degree at the end of the experiment. Significant changes were found in the Cobb angles and kyphotic angles at 1, 4 and 8 weeks after the operation (P<0.05). At 8 weeks, the Cobb angle, the kyphotic angle and the length of the spring were similar between SR and SK groups (P>0.05), and in the 4 weeks following spring removal in SR group, the Cobb angle and the kyphosis decreased significantly compared with those in SK group (P<0.05). Micro-CT showed that the BV/TV of the concave side was greater than that of the convex side. The length of the spring did not show obvious changes during the experiment (P>0.05). CONCLUSIONS: Asymmetric lumbar loading is a convenient, time-saving, and highly reproducible approach for establishing rabbit models of scoliosis. PMID- 25907953 TI - [Effect of prenatal alcohol exposure on rhythmic respiratory discharge activity in medullary slices of neonatal rats]. AB - OBJECTIVE: To investigate the effects of prenatal alcohol exposure on rhythmic respiratory discharge activity (RRDA) in the medullary slices of neonatal rats. METHODS: Ten pregnant female SD rats were exposed to 0, 4%, 6%, 8%, and 10% alcohol in drinking water from 1 week before till 3 days after delivery. The medullary slices of the neonatal rats containing the medial region of the nucleus retrofacialis (mNRF) with the hypoglossal nerve rootlets were prepared and perfused with modified Kreb's solution to record RRDA from the hypoglossal nerve rootlets using suction electrodes. RESULTS: No significant difference was found in RRDA in 50 min among the neonatal rats with prenatal exposure to 0, 4%, 6%, and 8% alcohol, but the RRDA in 10% alcohol exposure group became irregular. Prenatal exposure to increased alcohol concentrations caused attenuated RRDA attenuated in the neonatal rats, shown by shortened inspiratory time (TI), decreased respiratory frequency (RF), and reduced integral amplitude (IA) as compared with those in the control group. CONCLUSION: Prenatal alcohol exposure inhibits RRDA in medullary slices of neonatal rats, which might be a mechanism by which maternal alcohol exposure causes suppressed offspring respiratory functions. PMID- 25907954 TI - [Regulatory T cells in the treatment of autoimmune myositis in mice: efficacy and mechanism]. AB - OBJECTIVE: To investigate effect of CD4(+) CD25(+) Foxp3(+) Tregs in the treatment of autoimmune myositis (EAM) in mice and explore the possible mechanisms. METHODS: Mouse models of EAM were divided randomly into model group and treatment group, and the latter received infusion of CD4(+) CD25(+) Foxp3(+) Tregs separated from normal mouse spleen by magnetic activated cell sorting. The changes of muscle pathology was observed, and the expression of PD-1 and CTLA-4 in spleen CD4(+) CD25(+) Foxp3(+) Tregs was analyzed using flow cytometry; peripheral blood IL-10 and TGF-beta levels were tested using double antibody sandwich ELISA. RESULTS: Compare with the model group, the mice in the treatment group showed significantly reduced muscular inflammatory cell infiltration, increased blood levels of IL-10 and TGF-beta (P<0.05), and increased expression of PD-1 and CTLA-4 in spleen CD4(+) CD25(+) Foxp3(+) Tregs (P<0.05). CONCLUSION: CD4(+) CD25(+) Foxp3(+) Tregs reinfusion produces therapeutic effect in mice with EAM by increasing peripheral blood IL-10 and TGF-beta levels and PD-1 and CTLA-4 expressions in spleen CD4(+) CD25(+) Foxp3(+) Tregs. PMID- 25907955 TI - [Risk factors for capillary leak syndrome in children with hematological malignancies]. AB - OBJECTIVE: To investigate the risk factors for capillary leak syndrome (CLS) in children with malignant hematologic diseases. METHODS: Thirty children with hematological malignancies complicated with CLS were analyzed with multiple logistic regression analysis. RESULTS: At the test level of 0.05, hypoxemia and septicemia were found to significantly correlate with CLS in these children, and the number of white blood cells before CLS and severe bone marrow suppression were near the test level. CONCLUSION: Hypoxemia and septicemia are risk factors for CLS in children with malignant hematologic diseases. PMID- 25907956 TI - [Predictive value of serum iron level for in-hospital acute heart failure after acute ST-elevated myocardial infarction]. AB - OBJECTIVE: To evaluate the predictive value of serum iron level for in-hospital acute heart failure (AHF) after acute ST-elevated myocardial infarction (STEMI). METHODS: This retrospective study involved 287 patients with STEMI stratified by quartiles of admission serum iron concentration. The incidence of AHF was assessed by serum iron quartiles. We evaluated the association of serum iron levels with B-type natriuretic peptide (BNP), cardiac troponin I (cTnI), and high sensitivity C-reactive protein (hs-CRP) levels on admission, and analyzed the correlation of serum iron levels with in-hospital AHF, death, and duration of hospital stay. RESULTS: The average serum iron level on admission of the 287 STEMI patients was 10.20 umol/L (6.90-14.40 umol/L), and the quartiles (Q) of serum iron levels were <=6.90 umol/L (Q(1)), 6.91-10.19 umol/L (Q(2)), 10.20 14.39 umol/L (Q(3)), and >=14.40 umol/L (Q(4)). The incidences of in-hospital AHF from Q(1) to Q(4) were 79.5%, 64.3%, 50.0% and 45.9%, respectively (P<0.001). Univariate logistic regression analysis showed that low admission serum iron level (Q(1)) was an independent predictor for in-hospital AHF (OR=3.358, 95%CI 1.791- 6.294, P<0.001), and multivariate logistic regression analysis showed a similar result (OR=2.316, 95%CI 1.205-4.453, P=0.012). CONCLUSIONS: A lower admission serum iron level is an independent predictor of AHF in STEMI patients during hospitalization. PMID- 25907957 TI - [Effect of thermal cycling on surface microstructure of different light-curing composite resins]. AB - OBJECTIVE: To evaluate the effect of thermal cycling on surface microstructure of different light-curing composite resins. METHODS: A nanofilled composite (Z350) and 4 microhybrid composites (P60, Z250, Spectrum, and AP-X) were fabricated from lateral to center to form cubic specimens. The lateral surfaces were abrased and polished before water storage and 40 000 thermal cycles (5/55 degrees celsius;). The mean surface roughness (Ra) were measured and compared before and after thermal cycling, and the changes of microstructure were observed under scanning electron microscope (SEM). RESULTS: Significant decreases of Ra were observed in the composites, especially in Spectrum (from 0.164+/-0.024 um to 0.140+/-0.017 um, P<0.001) and Z250 (from 0.169+/-0.035 um to 0.144+/-0.033 um, P<0.001), whose Ra approximated that of P60 (0.121+/-0.028 um) with smoothly polished surface. SEM revealed scratches and shallower pits on the surface of all the 5 resins, and fissures occurred on Z350 following the thermal cycling. CONCLUSION: Water storage and thermal cycling may produce polishing effect on composite resins and cause fissures on nanofilled composite resins. PMID- 25907959 TI - Low voltage and high ON/OFF ratio field-effect transistors based on CVD MoS2 and ultra high-k gate dielectric PZT. AB - MoS2 and other atomic-level thick layered materials have been shown to have a high potential for outperforming Si transistors at the scaling limit. In this work, we demonstrate a MoS2 transistor with a low voltage and high ON/OFF ratio. A record small equivalent oxide thickness of ~1.1 nm has been obtained by using ultra high-k gate dielectric Pb(Zr0.52Ti0.48)O3. The low threshold voltage (<0.5 V) is comparable to that of the liquid/gel gated MoS2 transistor. The small sub threshold swing of 85.9 mV dec(-1), the high ON/OFF ratio of ~10(8) and the negligible hysteresis ensure a high performance of the MoS2 transistor operating at 1 V. The extracted field-effect mobility of 1-10 cm(2) V(-1) s(-1) suggests a high crystalline quality of the CVD-grown MoS2 flakes. The combination of the two dimensional layered semiconductor and the ultra high-k dielectric may enable the development of low-power electronic applications. PMID- 25907958 TI - Co-deleting Pten with Rb in retinal progenitor cells in mice results in fully penetrant bilateral retinoblastomas. AB - BACKGROUND: Rb1 is the most frequently mutated gene in the pediatric cancer retinoblastoma, and its loss causes E2F transcription factors to induce proliferation related genes. However, high E2F levels following pRB loss also induce apoptosis-promoting genes as a safeguard mechanism to suppress emergent tumors. Although p53 accumulation and apoptosis induction is believed to be a primary mechanism to eliminate cells with excess E2F activity, p53 deletion doesn't suppress RB/E2F induced apoptosis in vivo in the retina. This prompted us to test the PTEN/PI3K/AKT signaling pathway on RB/E2F apoptosis suppression in vivo, to ascertain if the PI3K pathway may provide a potential avenue for retinoblastoma therapy. METHODS: We developed a mouse model in which Rb1 and Pten were conditionally deleted from retinal progenitor cells using Chx10-Cre, whereas Rbl1 (p107) was constitutively deleted. Pathway components were also tested individually by in vivo electroporation into newborn retinas for an effect on apoptosis and tumor initiation. Mouse retinal tissues were analyzed by immunohistochemistry (IHC) for proliferation, apoptosis, and pathway activation. ShRNAs were used in vitro to assess effects on apoptosis and gene expression. RESULTS: Co-deleting Pten with Rb1 and Rbl1 in mouse retinal progenitor cells (RPCs) causes fully penetrant bilateral retinoblastomas by 30 days and strongly suppresses Rb/E2F-induced apoptosis. In vivo electroporation of constitutively active (ca)-Pik3ca, ca-Akt, or dominant-negative (dn)-Foxo1 into apoptosis prone newborn murine retina with deleted Rb/p107 eliminate Rb/E2F induced apoptosis and induce retinoblastoma emergence. Retinal deletion of Pten activates p-AKT and p FOXO1 signaling in incipient retinoblastoma. An unbiased shRNA screen focusing on Akt phosphorylation targets identified FOXOs as critical mediators of Rb/E2F induced apoptosis and expression of Bim and p73 pro-apoptotic genes. CONCLUSIONS: These data indicate that we defined a key molecular trigger involving E2F/FOXO functioning to control retinal progenitor cell homeostasis and retinoblastoma tumor initiation. We anticipate that our findings could provide contextual understanding of the proliferation of other progenitor cells, considering the high frequency of co-altered signaling from RB/E2F and PTEN/PI3K/AKT pathways in a wide variety of normal and malignant settings. PMID- 25907960 TI - Bh3 induced conformational changes in Bcl-Xl revealed by crystal structure and comparative analysis. AB - Apoptosis or programmed cell death is a regulatory process in cells in response to stimuli perturbing physiological conditions. The Bcl-2 family of proteins plays an important role in regulating homeostasis during apoptosis. In the process, the molecular interactions among the three members of this family, the pro-apoptotic, anti-apoptotic and BH3-only proteins at the mitochondrial outer membrane define the fate of a cell. Here, we report the crystal structures of the human anti-apoptotic protein Bcl-XL in complex with BH3-only BID(BH3) and BIM(BH3) peptides determined at 2.0 A and 1.5 A resolution, respectively. The BH3 peptides bind to the canonical hydrophobic pocket in Bcl-XL and adopt an alpha helical conformation in the bound form. Despite a similar structural fold, a comparison with other BH3 complexes revealed structural differences due to their sequence variations. In the Bcl-XL-BID(BH3) complex we observed a large pocket, in comparison with other BH3 complexes, lined by residues from helices alpha1, alpha2, alpha3, and alpha5 located adjacent to the canonical hydrophobic pocket. These results suggest that there are differences in the mode of interactions by the BH3 peptides that may translate into functional differences in apoptotic regulation. PMID- 25907961 TI - A network approach for identifying and delimiting biogeographical regions. AB - Biogeographical regions (geographically distinct assemblages of species and communities) constitute a cornerstone for ecology, biogeography, evolution and conservation biology. Species turnover measures are often used to quantify spatial biodiversity patterns, but algorithms based on similarity can be sensitive to common sampling biases in species distribution data. Here we apply a community detection approach from network theory that incorporates complex, higher-order presence-absence patterns. We demonstrate the performance of the method by applying it to all amphibian species in the world (c. 6,100 species), all vascular plant species of the USA (c. 17,600) and a hypothetical data set containing a zone of biotic transition. In comparison with current methods, our approach tackles the challenges posed by transition zones and succeeds in retrieving a larger number of commonly recognized biogeographical regions. This method can be applied to generate objective, data-derived identification and delimitation of the world's biogeographical regions. PMID- 25907962 TI - A Review: The Pharmacology of Isoliquiritigenin. AB - Isoliquiritigenin (ISL) is one of the bioactive ingredients isolated from the roots of plants belonging to licorice, including Glycyrrhiza uralensis, Mongolian glycyrrhiza, Glycyrrhiza glabra, and so forth. Liquiritigenin is available in common foods and alternative medicine, and its derivative-ISL is applied into food additives and disease treatment like cancer therapy, antibiotic therapy, and so on. This review aims at providing a comprehensive summary of the pharmacological activities of ISL. The information published between 1972 and 2014 from a number of reliable sources including PubMed, ScienceDirect, Springer, and Wiley-Blackwell. The practical application of ISL on the various disease prevention and treatments may stem from its numerous pharmacological properties such as antiinflammatory, anti-microbial, anti-oxidative, anticancer activities, immunoregulatory, hepatoprotective, and cardioprotective effects. However, further studies are needed to verify the target-organ toxicity or side effects investigation. PMID- 25907963 TI - Studies on the tempo of bubble formation in recently cavitated vessels: a model to predict the pressure of air bubbles. AB - A cavitation event in a vessel replaces water with a mixture of water vapor and air. A quantitative theory is presented to argue that the tempo of filling of vessels with air has two phases: a fast process that extracts air from stem tissue adjacent to the cavitated vessels (less than 10 s) and a slow phase that extracts air from the atmosphere outside the stem (more than 10 h). A model was designed to estimate how water tension (T) near recently cavitated vessels causes bubbles in embolized vessels to expand or contract as T increases or decreases, respectively. The model also predicts that the hydraulic conductivity of a stem will increase as bubbles collapse. The pressure of air bubbles trapped in vessels of a stem can be predicted from the model based on fitting curves of hydraulic conductivity versus T. The model was validated using data from six stem segments each of Acer mono and the clonal hybrid Populus 84 K (Populus alba * Populus glandulosa). The model was fitted to results with root mean square error less than 3%. The model provided new insight into the study of embolism formation in stem tissue and helped quantify the bubble pressure immediately after the fast process referred to above. PMID- 25907968 TI - Personality and risk of adult asthma in a prospective cohort study. AB - OBJECTIVE: Traits conceptualized according to the five-factor model of personality have been found to predict numerous health outcomes and may also be predictive of asthma. Prior longitudinal studies on personality and asthma remain however sparse, have been restricted to only two traits (i.e., neuroticism and extraversion), and yielded inconsistent results. We therefore aimed to examine the potential relationships of all five-factor personality traits with incident asthma. METHODS: We combined the 2009 and 2011 data from the population-based German Socio-Economic Panel study for longitudinal analyses (n=12,202). Personality traits were measured by an established 15-item version of the Big Five Inventory. Asthma was measured by participant-reports of having ever received such a diagnosis by a physician. We estimated multivariable risk ratios (RRs) and corresponding 95% confidence intervals (CIs) of trait-specific scores (continuous or categorized by tertiles) and incident asthma by Poisson regression. RESULTS: Neuroticism was the only trait which was predictive of asthma (RR for the z-score=1.17, 95% CI=1.02-1.34; RR for the highest versus the lowest tertile=1.59, 95% CI=1.12-2.25). Associations between personality traits and asthma risk did not differ by sex (p-values for interaction >=0.07). There were no two-way interactions between personality traits when we tested all potential combinations (all p-values for interaction >=0.20). CONCLUSION: The present study suggests that high levels of neuroticism may predispose adults to develop asthma. Future longitudinal studies are needed to confirm our findings and to shed light on the potential psychophysiological processes underlying the observed association. PMID- 25907969 TI - Re-infection outcomes following one- and two-stage surgical revision of infected hip prosthesis in unselected patients: protocol for a systematic review and an individual participant data meta-analysis. AB - BACKGROUND: Several aggregate published reviews have compared the effectiveness of one- and two-stage surgical revision to prevent re-infection following prosthetic hip infection and have reported inconsistent results. In addition, there were several features of these previous reviews which limited the validity of the findings. In the absence of a well-designed clinical trial, we propose the Global Infection Orthopaedic Management (INFORM) collaboration, a worldwide collaborative systematic review and meta-analysis of individual participant data (IPD) to address the existing uncertainties. METHODS: Cohort studies (prospective or retrospective) and randomised controlled trials conducted in unselected patients with infection treated exclusively by one- or two-stage revision and reporting re-infection outcomes within 2 years of revision will be retrieved by searching the following databases: MEDLINE, EMBASE, Web of Science, Cochrane Database of Systematic Reviews, Cochrane Central Register of Controlled Trials and the WHO International Clinical Trials Registry Platform. Reference lists of relevant studies will be manually scanned and there will be email contact with investigators of grey literature and conference abstracts. Investigators will be invited to join the Global INFORM collaboration and share their individual level data. The primary outcome of the analyses will be incidence of re-infection within 2 years of commencement of revision surgery. Primary analyses will be conducted comparing the one-stage to the two-stage surgical revision. IPD analyses will be based on Cox proportional hazard (PH) models estimated for each study separately. Study-specific log hazard ratios will be combined using random effects meta-analysis with fixed-effects meta-analysis in subsidiary analyses. Hazard ratios for re-infection according to different individual level characteristics such as sex, age groups, body mass index and comorbidities will also be assessed. DISCUSSION: The analyses will enable a consistent approach to the definition of re-infection outcomes, more detailed analyses under a broader range of circumstances and exploration of potential sources of heterogeneity and produce much more valid and precise estimates of re-infection outcomes. SYSTEMATIC REVIEW REGISTRATION: PROSPERO 2015: CRD42015016664. PMID- 25907970 TI - Low-buoyancy thermochemical plumes resolve controversy of classical mantle plume concept. AB - The Earth's biggest magmatic events are believed to originate from massive melting when hot mantle plumes rising from the lowermost mantle reach the base of the lithosphere. Classical models predict large plume heads that cause kilometre scale surface uplift, and narrow (100 km radius) plume tails that remain in the mantle after the plume head spreads below the lithosphere. However, in many cases, such uplifts and narrow plume tails are not observed. Here using numerical models, we show that the issue can be resolved if major mantle plumes contain up to 15-20% of recycled oceanic crust in a form of dense eclogite, which drastically decreases their buoyancy and makes it depth dependent. We demonstrate that, despite their low buoyancy, large enough thermochemical plumes can rise through the whole mantle causing only negligible surface uplift. Their tails are bulky (>200 km radius) and remain in the upper mantle for 100 millions of years. PMID- 25907971 TI - Frequency and distribution of Notch mutations in tumor cell lines. AB - BACKGROUND: Deregulated Notch signaling is linked to a variety of tumors and it is therefore important to learn more about the frequency and distribution of Notch mutations in a tumor context. METHODS: In this report, we use data from the recently developed Cancer Cell Line Encyclopedia to assess the frequency and distribution of Notch mutations in a large panel of cancer cell lines in silico. RESULTS: Our results show that the mutation frequency of Notch receptor and ligand genes is at par with that for established oncogenes and higher than for a set of house-keeping genes. Mutations were found across all four Notch receptor genes, but with notable differences between protein domains, mutations were for example more prevalent in the regions encoding the LNR and PEST domains in the Notch intracellular domain. Furthermore, an in silico estimation of functional impact showed that deleterious mutations cluster to the ligand-binding and the intracellular domains of NOTCH1. For most cell line groups, the mutation frequency of Notch genes is higher than in associated primary tumors. CONCLUSIONS: Our results shed new light on the spectrum of Notch mutations after in vitro culturing of tumor cells. The higher mutation frequency in tumor cell lines indicates that Notch mutations are associated with a growth advantage in vitro, and thus may be considered to be driver mutations in a tumor cell line context. PMID- 25907973 TI - Letter to the editor. PMID- 25907972 TI - Outcomes of complete vs targeted approaches to endoscopic sinus surgery. AB - BACKGROUND: Functional endoscopic sinus surgery (FESS) was historically predicated on targeted widening of narrow anatomic structures that caused postobstructive persistent sinus inflammation. It is now clear that chronic rhinosinusitis (CRS) is a multifactorial disease with subsets of patients which may require a more extensive surgical approach. This study compares quality-of life (QOL) and disease severity outcomes after FESS based on the extent of surgical intervention. METHODS: Participants with CRS were prospectively enrolled into an ongoing, multi-institutional, observational, cohort study. Surgical extent was determined by physician discretion. Participants undergoing bilateral frontal sinusotomy, ethmoidectomy, maxillary antrostomy, and sphenoidotomy were considered to have undergone "complete" surgery, whereas all other participants were categorized as receiving "targeted" surgery. Improvement was evaluated between surgical subgroups with at least 6-month follow-up using the 22-item Sino Nasal Outcome Test (SNOT-22) and the Brief Smell Inventory Test (B-SIT). RESULTS: A total of 311 participants met inclusion criteria with 147 subjects undergoing complete surgery and 164 targeted surgery. A higher prevalence of asthma, acetylsalicylic acid (ASA) sensitivity, nasal polyposis, and a history of prior sinus surgery (p <= 0.002) was present in participants undergoing complete surgery. Mean improvement in SNOT-22 (28.1 +/- 21.9 vs 21.9 +/- 20.6; p = 0.011) and B-SIT (0.8 +/- 3.1 vs 0.2 +/- 2.4; p = 0.005) was greater in subjects undergoing complete surgery. Regression models demonstrated a 5.9 +/- 2.5 greater relative mean improvement on SNOT-22 total scores with complete surgery over targeted approaches (p = 0.016). CONCLUSION: Complete surgery was an independent predictor of greater postoperative SNOT-22 score improvement, yet did not achieve clinical significance. Further study is needed to determine the optimal surgical extent. PMID- 25907974 TI - Exploring bacterial heparinase II activities with defined substrates. AB - Bacterial heparinases that cleave heparan sulfate (HS) and heparin are widely used to generate low-molecular-weight heparins (LMWHs) and to structurally and functionally characterise heparin and HS biomolecules. We provide novel insights into the substrate specificity of heparinase II from two different bacteria: Pedobacter heparinus (formerly Flavobacterium heparinum) and Bacteroides eggerthii. The activity towards various well-defined HS oligosaccharides was investigated by (1) H NMR spectroscopy; this revealed distinct specificities for the two heparinases. Heparinase II from P. heparinus appears to be more active and displays a broader substrate specificity than B. eggerthii heparinase II. Furthermore, HS di- and tetrasaccharides inhibited B. eggerthii heparinase II activity. A better understanding of heparinase substrate specificity will contribute to the production of homogenous LMWHs, provide better characterisation of heparin and HS and assist therapeutic applications. PMID- 25907975 TI - Improved surgical management through optimized imaging of pelvic endometriosis. AB - Deep infiltrating endometriosis is a frequent benign pathology that is found in 10-15% of fertile women and in 20% of infertile women. It has an impact on fertility but also on everyday life. In case of failure of medical treatment, surgical treatment can be offered to the patient. To provide adequate treatment and give the clearest information to patients, it seems essential to achieve optimal preoperative imaging. The aim of this work was to define for each compartment the surgeon's expectations and the indications of iconographic work ups before surgical management of pelvic endometriosis. We do not discuss technical examinations nor surgical indications and techniques. PMID- 25907976 TI - [Predictors of mean blood glucose control and its variability in diabetic hospitalized patients]. AB - INTRODUCTION: This study was intended to assess the effectiveness and predictors factors of inpatient blood glucose control in diabetic patients admitted to medical departments. MATERIAL AND METHODS: A retrospective, analytical cohort study was conducted on patients discharged from internal medicine with a diagnosis related to diabetes. Variables collected included demographic characteristics, clinical data and laboratory parameters related to blood glucose control (HbA1c, basal plasma glucose, point-of-care capillary glucose). The cumulative probability of receiving scheduled insulin regimens was evaluated using Kaplan-Meier analysis. Multivariate regression models were used to select predictors of mean inpatient glucose (MHG) and glucose variability (standard deviation [GV]). RESULTS: The study sample consisted of 228 patients (mean age 78.4 (SD 10.1) years, 51% women). Of these, 96 patients (42.1%) were treated with sliding-scale regular insulin only. Median time to start of scheduled insulin therapy was 4 (95% CI, 2-6) days. Blood glucose control measures were: MIG 181.4 (SD 41.7) mg/dL, GV 56.3 (SD 22.6). The best model to predict MIG (R(2): .376; P<.0001) included HbA1c (b=4.96; P=.011), baseline plasma glucose (b=.056; P=.084), mean capillary blood glucose in the first 24hours (b=.154; P<.0001), home treatment (versus oral agents) with basal insulin only (b=13.1; P=.016) or more complex (pre-mixed insulin or basal-bolus) regimens (b=19.1; P=.004), corticoid therapy (b=14.9; P=.002), and fasting on admission (b=10.4; P=.098). CONCLUSION: Predictors of inpatient blood glucose control which should be considered in the design of DM management protocols include home treatment, HbA1c, basal plasma glucose, mean blood glucose in the first 24hours, fasting, and corticoid therapy. PMID- 25907977 TI - Intramolecular thiol-yne cyclisation as a novel strategy for thioglycal synthesis. AB - A novel intramolecular thiol-yne cyclisation strategy has been developed for the synthesis of thioglycals. Both ionic and radical mediated cyclisation pathways have been investigated for D- and L-sugars. The ionic cyclisation provides exclusive access to 5-exo products directly from the thioesters whereas the radical cyclisation provides access to both 5-exo and 6-endo products upon photochemical irradiation of the free thiols. These are the first examples of intramolecular thiol-yne cyclisation reactions applied to thiosugar synthesis. PMID- 25907978 TI - A community-based early intervention program for toddlers with autism spectrum disorders. AB - This study examined Pathways Early Autism Intervention, a community-based, parent mediated, intensive behavioral and developmental intervention program for children with autism spectrum disorders that could be used as a model for state funded early intervention programs. A single-subject, multiple-baseline, across participants design was used. Four boys with autism spectrum disorder and their mothers participated. Interventionists made weekly home visits and worked with caregivers to establish and maintain face-to-face reciprocal social interaction and eye contact. Each session included a 10-min video of parent-child interaction. Evidence of intervention effectiveness was measured by percentage of nonoverlapping data points. Social validity was measured using questionnaire items in regard to parents' perception of the intervention. The intervention was effective for the measures of eye contact, social engagement, and verbal reciprocity but not for nonverbal turn taking. Parents perceived the intervention as beneficial and easy to learn and incorporate into daily life. PMID- 25907979 TI - Elements affecting wound healing time: An evidence based analysis. AB - The purpose of this study was to identify the predominant client factors and comorbidities that affected the time taken for wounds to heal. A prospective study design used the Mobile Wound Care (MWC) database to capture and collate detailed medical histories, comorbidities, healing times and consumable costs for clients with wounds in Gippsland, Victoria. There were 3,726 wounds documented from 2,350 clients, so an average of 1.6 wounds per client. Half (49.6%) of all clients were females, indicating that there were no gender differences in terms of wound prevalence. The clients were primarily older people, with an average age of 64.3 years (ranging between 0.7 and 102.9 years). The majority of the wounds (56%) were acute and described as surgical, crush and trauma. The MWC database categorized the elements that influenced wound healing into 3 groups--factors affecting healing (FAH), comorbidities, and medications known to affect wound healing. While there were a multitude of significant associations, multiple linear regression identified the following key elements: age over 65 years, obesity, nonadherence to treatment plan, peripheral vascular disease, specific wounds associated with pressure/friction/shear, confirmed infection, and cerebrovascular accident (stroke). Wound healing is a complex process that requires a thorough understanding of influencing elements to improve healing times.(c) 2015 by the Wound Healing Society. PMID- 25907980 TI - Simultaneous determination of seven anthraquinones in rat plasma by Ultra High Performance Liquid Chromatography-tandem Mass Spectrometry and pharmacokinetic study after oral administration of Semen Cassiae extract. AB - ETHNOPHARMACOLOGICAL RELEVANCE: Semen Cassiae, called Juemingzi in China, is the seed of the annual Cassia obtusifolia L., of the leguminosae family. It has been used as healthy drinks to alleviate constipation and improve eyesight for many years in China. AIM OF THE STUDY: A simple sensitive UHPLC-MS/MS method has been developed and validated for the simultaneous determination and pharmacokinetic study of chrysophanol, emodin, aloe-emodin, rhein, physcion, obtusifolin and aurantio-obtusin in rat plasma. MATERIALS AND METHODS: Chromatographic separation was accomplished on a C18 column with a 5min gradient elution. A tandem mass spectrometric detection was conducted using multiple reaction monitoring (MRM) via an electrospray ionization (ESI) source and operating in the negative ionization mode. The samples were prepared by LLE with ethyl acetate after being spiked with an internal standard (butylparaben). RESULTS: The current UHPLC-MS/MS assay was validated for linearity, intra-day and inter-day precisions, accuracy, extraction recovery and stability. The method was linear for all analytes over investigated range with all correlation coefficients greater than 0.9900. The lower limit of quantification (LLOQ) of each analyte was lower than 5ng/mL. Intra day and inter-day precisions were less than 14.99%. The relative errors of accuracies were in the range of -14.60% to 5.11%. The mean recoveries and matrix effects of anthraquinones were higher than 65.54% and 93.26%, respectively. After oral administration 1.25g/kg of Semen Cassiae extract, the maximum plasma concentration (Cmax) was 1189.25+/-333.40ng/mL for chrysophanol, 38.48+/ 3.15ng/mL for emodin, 79.20+/-34.76ng/mL for aloe-emodin, 152.70+/-23.91ng/mL for rhein, 461.85+/-266.77ng/mL for physcion, 243.59+/-22.71ng/mL for obtusifolin and 1950.44+/-638.86ng/mL for aurantio-obtusin, respectively. The time to reach the maximum plasma concentration (Tmax) was 0.333+/-0.071h for chrysophanol, 0.333+/ 0.059h for emodin, 0.333+/-0.009h for aloe-emodin, 0.333+/-0.09h for rhein, 0.167+/-0.002h for physcion, 0.5+/-0.074h for obtusifolin and 0.333+/-0.06h for aurantio-obtusin, respectively. CONCLUSION: The proposed method was further applied to investigate the pharmacokinetics of seven anthraquinones after oral administration of Semen Cassia extract to rats. PMID- 25907981 TI - The protective effect of piperine on dextran sulfate sodium induced inflammatory bowel disease and its relation with pregnane X receptor activation. AB - ETHNOPHARMACOLOGICAL RELEVANCE: Inflammatory bowel disease (IBD) is associated with chronic inflammation of the intestinal tract. Piperine (1 peperoylpiperidine), the primary lipophilic component in black pepper (Piper nigrum) and long pepper (Piper longum), has been reported to be effective for anti-inflammatory. Rencently, several ethnopharmacological purity compounds, such as baicalin and artemisinin, are reported to have potentially therapeutic role in treating IBD. In the present study, the effects of piperine on pregnane X receptor (PXR)-mediated CYP3A expression and its therapeutic role in IBD were investigated. MATERIALS AND METHODS: LS174T cells and C57BL/6J mice were treated by the piperine. Gene expressions were analyzed by real-time PCR, Western blot analysis, transient transfections assay and histological analysis. RESULTS: Data indicated that treatment of LS174T cells with piperine markedly increased both CYP3A4 and PXR mRNA and protein. Transient transfection experiments indicated that transcriptional activation of the CYP3A4 gene via piperine was PXR dependent. Data show that pre-administration of piperine decreased clinical hallmarks of colitis in DSS-treated PXR mice as measured by body weight loss and assessment of diarrhea, rectal bleeding, colon length, and histology. Inflammatory mediators (CCR2, ICAM-1, IL-1beta, IL-6, IL-10, iNOS, MCP-1, and TNFalpha) after DSS treatment were significantly decreased in mice pretreated with piperine but corresponding conditions did not occur in mice with down regulation of PXR by small interfering RNA (siRNA). CONCLUSION: Piperine is a potential agonist of PXR and an inducer of PXR, which may induce CYP3A4 gene expression at the mRNA and protein levels. These results establish that piperine may contribute to prevention or reduction of colonic inflammation. PMID- 25907982 TI - Medial percutaneous hemi-epiphysiodesis improves the valgus tilt of the femoral head in developmental dysplasia of the hip (DDH) type-II avascular necrosis. AB - BACKGROUND AND PURPOSE: Avascular necrosis (AVN) is a major cause of disability after treatment of developmental dysplasia of the hip (DDH), leading to femoral head deformity, acetabular dysplasia, and osteoarthritis in adult life. Type-II AVN is characterized by retarded growth in the lateral aspect of the physis or by premature lateral fusion, which produces a valgus deformity of the head on the neck of the femur. We investigated the effect of medial percutaneous hemi epiphysiodesis as a novel technique in the treatment of late-diagnosed type-II AVN. PATIENTS AND METHODS: 9 patients (11 hips) with a diagnosis of type-II AVN who underwent medial percutaneous hemi-epiphysiodesis after the surgical treatment for DDH were included in the study. 10 patients (12 hips) with the same diagnosis but who did not undergo hemi-epiphysodesis were chosen as a control group. Preoperative and postoperative articulotrochanteric distances, head-shaft angles, CE (center-edge) angles, and physeal inclination angles were measured. The treatment group underwent medial hemi-epiphysodesis at a mean age of 8 years. The mean ages of the treatment group and the control group at final follow-up were 14 and 12 years respectively. The mean duration of follow-up was 5.7 years in the treatment group and 8.3 years in the control group. RESULTS: Preoperative articulotrochanteric distance, head-shaft angle, and functional outcome at the final follow-up assessment were similar in the 2 groups. However, preoperative and postoperative CE angles and physeal inclination angles differed significantly in the treatment group (p < 0.05). The final epiphyseal valgus angles were better in the treatment group than in the control group (p = 0.05). The treatment group improved after the operation. INTERPRETATION: Medial percutaneous epiphysiodesis performed through a mini-incision under fluoroscopic control is a worthwhile modality in terms of changing the valgus tilt of the femoral head. PMID- 25907983 TI - A simulation study of the interception of prescribing errors by clinical pharmacists in an acute hospital setting. AB - RATIONALE, AIMS AND OBJECTIVES: To evaluate the performance of several pharmacists in the same department who analysed the same prescriptions in a simulation study. METHODS: One hundred prescriptions were retrospectively extracted from the prospective database of our hospital. Five clinical pharmacists working in the same department were asked to analyse individually the order lines of each prescription as if it were part of their routine daily practice. Afterward, an independent committee of five other clinical pharmacists reviewed the same 100 prescriptions. We calculated the sensitivity and the specificity of error detection in a line order by using the results of the committee as the gold standard. RESULTS: A total of 908 order lines were analysed (mean 9 +/- 3 order lines per prescription). Fifty-one medication errors were identified by the committee (5.6%), including 23 related to laboratory test results: renal failure, or therapeutic concentrations being too low or too high. The sensitivity of the five pharmacists ranged between 19.6% and 56.9% and the specificity between 92.8% and 98.7%. The rates of agreement between each pharmacist and the committee, assessed using kappa coefficient, were between 0.20 and 0.39. The main factors affecting sensitivity and/or specificity in univariate analysis were the number of drugs per prescription, type of drug prescribed (ATC classification) and the glomerular filtration rate. CONCLUSION: Discrepancies between the performances of pharmacists exist, as there are between other health care professionals. Pharmacist training, standardization of the pharmaceutical analysis of drug prescription, and implementation of a clinical decision support system allowing biological values to be linked to drug prescriptions could improve individual performance. PMID- 25907984 TI - Choosing ACE-inhibitors instead of sartans: encouraging results of an evidence based policy in Emilia-Romagna, Italy. PMID- 25907985 TI - Effects of a long-term lifestyle intervention program with Mediterranean diet and exercise for the management of patients with metabolic syndrome in a primary care setting. AB - BACKGROUND: The impact of a lifestyle intervention (LSI) program for the long term management of subjects with metabolic syndrome in a primary care setting is not known. METHODS: This 3-year prospective controlled trial randomized adult subjects with metabolic syndrome to receive intensive LSI or to usual care in a community health centre in Malaga, Spain. LSI subjects received instruction on Mediterranean diet and a regular aerobic exercise program by their primary care professionals. Primary outcome included changes from baseline on different components of metabolic syndrome (abdominal circumference, blood pressure, HDL cholesterol, fasting plasma glucose and triglycerides). RESULTS: Among the 2,492 subjects screened, 601 subjects with metabolic syndrome (24.1%) were randomized to LSI (n = 298) or to usual care (n = 303); of them, a 77% and a 58%, respectively, completed the study. At the end of the study period, LSI resulted in significant differences vs. usual care in abdominal circumference (-0.4 +/- 6 cm vs. + 2.1 +/- 6.7 cm, p < 0.001), systolic blood pressure (-5.5 +/- 15 mmHg vs. -0.6 +/- 19 mmHg, p = 0.004), diastolic blood pressure (-4.6 +/- 10 mmHg vs. 0.2 +/- 13 mmHg, p < 0.001) and HDL-cholesterol (+4 +/- 12 mg/dL vs. + 2 +/- 12 mg/dL, p = 0.05); however, there were no differences in fasting plasma glucose and triglyceride concentration (-4 +/- 35 mg/dl vs. -1 +/- 32 mg/dl, p = 0.43 and -0.4 +/- 83 mg/dl vs. +6 +/- 113 mg/dl, p = 0.28). CONCLUSION: Intensive LSI counseling provided by primary care professionals resulted in significant improvements in abdominal circumference, blood pressure and HDL-cholesterol but had limited effects on glucose and triglyceride levels in patients with metabolic syndrome. PMID- 25907986 TI - The utility of a caseload registry: perceptions of behavioral health clinicians working in an integrated primary care and mental health program. AB - OBJECTIVES: This study evaluated the perceived benefits and limitations of a Web based clinical support tool for behavioral health clinicians serving patients in an integrated primary care and mental health program in Washington State community health centers. METHODS: We surveyed 71 clinicians who utilize a Web based clinical support tool ("the caseload registry") in treating patients. Follow-up interviews were scheduled with a subset (n=32) of respondents. Comments made during these interviews were analyzed using qualitative methods. RESULTS: Survey responses were favorable on 4 of 7 questions regarding specific benefits of the caseload registry. Notably, clinicians agreed that the caseload registry helps track patients and their clinical progress. Clinicians also agreed that the caseload registry adds an additional documentation burden to their work duties. The most common positive themes identified during follow-up interviews were that the registry is useful and improves care. The most common critical themes identified were that the tool is burdensome and sometimes does not encompass important elements of care. CONCLUSIONS: Behavioral health clinicians working in an integrated primary care and mental health program report that use of a caseload registry adds value and improves care. They express that it helps provide more comprehensive care and tracks patient progress. PMID- 25907987 TI - Catalytic Enantioselective Synthesis of N,C(alpha),C(alpha)-Trisubstituted alpha Amino Acid Derivatives Using 1H-Imidazol-4(5H)-ones as Key Templates. AB - 1H-Imidazol-4(5H)-ones are introduced as novel nucleophilic alpha-amino acid equivalents in asymmetric synthesis. These compounds not only allow highly efficient construction of tetrasubstituted stereogenic centers, but unlike hitherto known templates, provide direct access to N-substituted (alkyl, allyl, aryl) alpha-amino acid derivatives. PMID- 25907988 TI - [The legacy of Jean Delay in psychiatry]. PMID- 25907990 TI - Animal models for prion-like diseases. AB - Prion diseases or Transmissible Spongiform Encephalopathies (TSEs) are a group of fatal neurodegenerative disorders affecting several mammalian species being Creutzfeldt-Jacob Disease (CJD) the most representative in human beings, scrapie in ovine, Bovine Spongiform Encephalopathy (BSE) in bovine and Chronic Wasting Disease (CWD) in cervids. As stated by the "protein-only hypothesis", the causal agent of TSEs is a self-propagating aberrant form of the prion protein (PrP) that through a misfolding event acquires a beta-sheet rich conformation known as PrP(Sc) (from scrapie). This isoform is neurotoxic, aggregation prone and induces misfolding of native cellular PrP. Compelling evidence indicates that disease specific protein misfolding in amyloid deposits could be shared by other disorders showing aberrant protein aggregates such as Alzheimer's Disease (AD), Parkinson's Disease (PD), Amyotrophic lateral sclerosis (ALS) and systemic Amyloid A amyloidosis (AA amyloidosis). Evidences of shared mechanisms of the proteins related to each disease with prions will be reviewed through the available in vivo models. Taking prion research as reference, typical prion-like features such as seeding and propagation ability, neurotoxic species causing disease, infectivity, transmission barrier and strain evidences will be analyzed for other protein-related diseases. Thus, prion-like features of amyloid beta peptide and tau present in AD, alpha-synuclein in PD, SOD-1, TDP-43 and others in ALS and serum alpha-amyloid (SAA) in systemic AA amyloidosis will be reviewed through models available for each disease. PMID- 25907989 TI - SIRTain regulators of premature senescence and accelerated aging. AB - The sirtuin proteins constitute class III histone deacetylases (HDACs). These evolutionarily conserved NAD(+)-dependent enzymes form an important component in a variety of cellular and biological processes with highly divergent as well as convergent roles in maintaining metabolic homeostasis, safeguarding genomic integrity, regulating cancer metabolism and also inflammatory responses. Amongst the seven known mammalian sirtuin proteins, SIRT1 has gained much attention due to its widely acknowledged roles in promoting longevity and ameliorating age associated pathologies. The contributions of other sirtuins in the field of aging are also gradually emerging. Here, we summarize some of the recent discoveries in sirtuins biology which clearly implicate the functions of sirtuin proteins in the regulation of premature cellular senescence and accelerated aging. The roles of sirtuins in various cellular processes have been extrapolated to draw inter linkage with anti-aging mechanisms. Also, the latest findings on sirtuins which might have potential effects in the process of aging have been reviewed. PMID- 25907991 TI - The amino acid residues at 102 and 104 in GP5 of porcine reproductive and respiratory syndrome virus regulate viral neutralization susceptibility to the porcine serum neutralizing antibody. AB - Porcine reproductive and respiratory syndrome virus (PRRSV) is mainly responsible for the heavy economic losses in pig industry in the world. A number of neutralizing epitopes have been identified in the viral structural proteins GP3, GP4, GP5 and M. In this study, the important amino acid (aa) residues of HP-PRRSV strain BB affecting neutralization susceptibility of antibody were examined using resistant strains generated under neutralizing antibody (NAb) pressure in MARC 145 cells, reverse genetic technique and virus neutralization assay. HP-PRRSV strain BB was passaged under the pressure of porcine NAb serum in vitro. A resistant strain BB34s with 102 and 104 aa substitutions in GP5, which have been predicted to be the positive sites for pressure selection (Delisle et al., 2012), was cloned and identified. To determine the effect of the two aa residues on neutralization, eight recombinant PRRSV strains were generated, and neutralization assay results confirmed that the aa residues 102 and 104 in GP5 played an important role in NAbs against HP-PRRSV in MARC-145 cells and porcine alveolar macrophages. Alignment of GP5 sequences revealed that the variant aa residues at 102 and 104 were frequent among type 2 PRRSV strains. It may be helpful for understanding the mechanism regulating the neutralization susceptibility of PRRSV to the NAbs and monitoring the antigen variant strains in the field. PMID- 25907992 TI - Four-dimensional computed tomography in accelerated partial breast irradiation planning: single series from a phase III trial. AB - PURPOSE: The aim of our study was to evaluate the usefulness of the four dimensional computed tomography (4DCT) in accelerated partial breast irradiation (aPBI) planning. MATERIALS AND METHODS: At our Institute, we have been treating the index quadrant with external intensity-modulated radiation therapy in a phase III trial. For this study, we selected a sample of 10 patients with right- or left-sided breast cancer and surgical clips at the excision site. Contouring of the target was performed both using three-dimensional computed tomography (3DCT) and 4DCT imaging. On both 3DCT and 4DCT, we recorded the clinical target volume (CTV) and the planning target volume (PTV) and the coordinates of the PTV centroid. We calculated the treatment plans, according to our protocol, using the contours drawn on the 3DCT and 4DCT and evaluated target coverage and sparing of organs at risk (OAR). RESULTS: Median age of the patients was 63.5 years (range 52-75). The comparison between the 3DCT and 4DCT PTV volumes was not statistically significant (p = 0.79). Concerning centroid coordinates, the average absolute differences were 0.1 mm in the latero-lateral, 0.7 mm in the antero-posterior and 0.3 mm in the supero-inferior direction. No statistically significant differences were observed both in PTV coverage and OAR sparing; the 4D PTV contour is adequately covered when the plan based on the 3D contours is used. Target coverage was reduced on average by 1 % and no statistically significant difference was observed (p = 0.93). CONCLUSIONS: In our experience, no significant differences between PTV volumes, PTV coverage, OAR sparing and centroid position are evidenced when comparing 3DCT and 4DCT plans. Conventional 3DCT-based planning is adequate for aPBI. PMID- 25907995 TI - [Glaucoma in China: where we are and what the future is]. AB - In the last 5 years, great achievements have been made in glaucoma clinics and research field in China. The main Chinese glaucoma research progresses were selected by Chinese Ophthalmology Society. Among them, some research works have reached the international level. But we should clearly realize that Chinese glaucoma research work has a long way to go and the development plan should be made carefully.In the future, we need to establish the national clinical standards of glaucoma diagnosis and treatment to improve the research level, so as to enhance our international influence in glaucoma field. PMID- 25907993 TI - MR imaging of primary hepatic neuroendocrine neoplasm and metastatic hepatic neuroendocrine neoplasm: a comparative study. AB - PURPOSE: To investigate MR characteristics in differentiating primary hepatic neuroendocrine neoplasm (PHNEN) from metastatic hepatic neuroendocrine neoplasm (MHNEN). MATERIALS AND METHODS: Thirty-nine patients with histopathologically proven liver neuroendocrine neoplasm were retrospectively analyzed. The morphological and MR signal features on T1, T2-weighted, dynamic-enhanced, and diffusion-weighted imaging were evaluated and compared between the PHNEN group (n = 12) and the MHNEN group (n = 27). RESULTS: The tumor size (P = 0.0084), number (P = 0.017), distribution (P = 0.000), contour (P = 0.041), the presence of capsule-like enhancement (P = 0.034), tumor homogeneity (P = 0.018) and the apparent diffusion coefficient (ADC) values (P = 0.024) were different between PHNENs and MHNENs. Large, solitary or massive-growing nodules with lobulated or irregular contour, capsule-like enhancement, heterogeneous signals or lower ADC values supported the diagnosis of PHNEN compared with MHNEN. ROC analysis demonstrated an area under the curve of 0.746, when the optimal cutoff value of 1.049 * 10(-3) mm(2)/s was used, a sensitivity of 63.0 % (95 % CI, 44.2-79.4 %), a specitivity of 80.0 % (95 % CI, 50.1-96.4 %), a positive predictive value of 89.5 % (95 % CI, 70.9-98.2 %), and a negative predictive value of 44.4 % (95 % CI, 23.4-67.0 %) can be achieved. CONCLUSIONS: MRI may provide valuable information for the diagnosis and differential diagnosis of PHNENs and MHNENs. PMID- 25907994 TI - Bioimpedance spectroscopy for swelling evaluation following total knee arthroplasty: a validation study. AB - BACKGROUND: The evaluation of swelling is important for the outcome of total knee arthroplasty (TKA) surgery. The circumference or volume measurements are applicable at the bedside of the patient but are altered by muscular atrophy and the post-surgical dressing. Bioimpedance spectroscopy might overcome these limitations; however, it should be validated. This study aimed to explore the validity, the reliability and the responsiveness of bioimpedance spectroscopy for measuring swelling after TKA. METHODS: The degree of swelling in 25 patients undergoing TKA surgery was measured using bioimpedance spectroscopy (BIS R0), knee circumference and limb volume. The measurements were performed on D-1 (day before surgery), D + 2 (2 days after surgery) and D + 8 (8 days after surgery). The BIS R0 measurements were repeated twice, alternating between two evaluators. The percentage of the difference between the limbs was calculated for BIS R0, circumference and volume. The intra- and inter-observer intraclass correlation coefficients (ICCs), limits of agreement (LOA), effect size (Cohen's d), correlations between the methods and diagnostic sensitivity were calculated. RESULTS: BIS R0, circumference and volume detected swelling < 3.5% at D-1. The swelling at D2 and D8 was greater with BIS R0 [mean (SD) 29.9% (+/-9.8) and 38.27 (+/-7.8)] than with volume [14.7 (+/-9.5) and 14.9 (+/-8.2)] and circumference [11.1 (+/-5.7) and 11.7 (+/-4.1)]. The BIS R0 intra- and inter-evaluator ICCs ranged from 0.89 to 0.99, whereas the LOA were < 5.2%. The BIS R0 correlation was 0.73 with volume and 0.75 with circumference. The BIS R0 Cohen's d was 3.32 for the D-1-D2 evolution. The diagnostic sensitivity was 83% D2 and 96% at D8. CONCLUSION: Bioimpedance is a valid method for the evaluation of swelling following TKA. BIS R0 also demonstrated excellent intra- and inter-evaluator reliability. The diagnostic sensitivity and responsiveness is superior to that of concurrent methods. BIS R0 is an efficient method for post-surgical follow up at the bedside of the patient. The measurement of BIS R0 is a straightforward, valid, reliable and responsive method for lower limb swelling following TKA surgery that could be used in clinics and research. TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT00627770. PMID- 25907996 TI - [Insist on the nature of evidence-based medicine for the development of glaucoma clinical trial]. AB - Evidence-based medicine (EBM) has markedly promoted the development of ophthalmology.Glaucoma clinical trials have been developed rapidly. Clinical trial papers have been tremendously increasing in the decade, but unhealthy tendency deviating from the nature of EBM---"conscientious, explicit and judicious" has come into notice by the medical society. It is the time to develop patient based medicine, combining with experience-based, experiment-based, ethics based, economy-based medicine. Only face up to the fundamental problems can we avoid misleading clinicians and provide better health care of affordable, accessible, accountable medical service for patients. This is the intrinsic value of evidence-based medicine. PMID- 25907997 TI - [Is increased choroidal thickness a risk factor for primary angle-closure glaucoma]. AB - Primary angle-closure glaucoma (PACG) is the main form of glaucoma in China. The pathological mechanism of PACG is not yet well understood. Traditional anatomic disorders are characterized by biometric factors such as shallow anterior chamber depth, narrow anterior chamber angle, short axial length, and thick crystalline lens.Newly found potential risk factors include dynamic changes of iris and choroid.With the development of enhanced depth imaging spectral-domain optical coherence tomography (EDI-OCT) and swept source OCT (SS-OCT), it is possible to measure choroidal thickness accurately.Several studies have found the choroid of PACG eyes was thicker than that of primary open-angle glaucoma (POAG) and normal subject eyes, which suggests that increased choroidal thickness might be another risk factor for PACG. PMID- 25907998 TI - [Focus on the ethics problem in glaucoma management]. AB - Due to the different goals of current glaucoma treatments, various treatment methods have their pros and cons. Therefore, their applications are affected by factors inside and outside medical category, thus prone to a series of problems.In clinical practice, in addition to following the related clinical guidelines and standards, medical ethics problems must be considered. And besides, based on the principles of nonmaleficence, beneficence, respect and justice in medical ethics, the treatments should be carefully selected to weigh the advantages and disadvantages to the patients.Only in this way, the efficacy and safety of glaucoma treatment can be improved, and the medical and social missions of glaucoma specialists can be more reasonably completed. PMID- 25907999 TI - [Randomized parallel group study of 0.0015% tafluprost ophthalmic solution in patients with primary open-angle glaucoma or ocular hypertension (comparison with 0.005% latanoprost ophthalmic solution)]. AB - OBJECTIVE: To confirm the non-inferiority of the IOP-lowering effect of the 0.0015% Tafluprost ophthalmic solution to the 0.005% Latanoprost ophthalmic solution in patients with primary open-angle glaucoma or ocular hypertension.Safety was also compared between two groups. METHODS: This study was conducted from August 2008 to December 2009, at five clinical trial sites in China. Patients of this study population was diagnosed with primary open-angle glaucoma or ocular hypertension in both eyes.Subjects were randomized into 0.0015% Tafluprost group or 0.005% Latanoprost group.Intraocular pressure (IOP) measurement by Goldmann applanation tonometer, slit-lamp microscopy, Gonioscopy, Fundascopy, Visual acuity test, Perimetry, Blood pressure and pulse rate, Subjective symptoms were compered between two groups at Week 0, Week 2 and Week 4.For main effectiveness evaluation index adopt the bad effect evaluation, safety evaluation index by Fisher's exact test probability method. RESULTS: The 246 subjects/246 eyes were randomized (Tafluprost group:122 subjects/122 eyes, Latanoprost group:124 subjects/ 124 eyes). Change in the IOP at 17:00 of Week 2 is (8.8 +/- 3.8) mmHg and (8.9 +/- 4.4) mmHg (1 mmHg = 0.133 kPa) in Tafluprost group and Latanoprost group. Percent change in the IOP at 17:00 of Week 2 is (33.2 +/- 12.8)% and (34.4 +/- 14.1)% in Tafluprost group and Latanoprost group. Change in the IOP at 17:00 at the end of treatment is (9.8 +/- 4.0) mmHg and (9.2 +/- 4.1) mmHg in Tafluprost group and Latanoprost group. Percent change in the IOP at 17:00 at the end of treatment is 37.2% +/- 13.4% group and 35.7% +/- 13.0% in Tafluprost and Latanoprost group.In addition, distribution of subjects with percentage decrease of IOP > 30% was 72.5% in Tafluprost group higher than 63.8% in Latanoprost group. The major adverse reactions were conjunctival hyperemia, eye irritation, eye pain and foreign body sensation. The incidence of adverse reactions is 31.7% in Tafluprost group and 20.8% in Latanoprost group. The inter group difference had no statistical significance. CONCLUSION: Efficacy and safety of Tafluprost ophthalmic solution are no less than Latanoprost ophthalmic solution in patients with primary open-angle glaucoma or ocular hypertension. PMID- 25908000 TI - [Distribution of peak intraocular pressure in 24-hour and correlation between peak nocturnal intraocular pressure with diurnal intraocular pressure level in primary open angle glaucoma patients]. AB - OBJECTIVE: To study the distribution of peak intraocular pressure (IOP) in 24 hour in untreated primary open angle glaucoma (POAG) patients, and to explore the correlation between nocturnal peak IOP and office hour or diurnal IOP level. METHODS: A Cross-sectional study.One hundred and twenty-one untreated POAG patients (121 eyes), including 78 normal tension patients (78 eyes) and 43 hyper tension patients (43 eyes), were enrolled in this study. All the patients underwent 24-hour IOP monitoring with non-contact tonometer. The distribution of peak IOP in 24-hour and the correlation between nocturnal peak IOP and office hour or diurnal mean and peak IOP were evaluated. Categorical variables were described as frequency and constituent ratio, and analyzed by chi-square test. Continuous variables were described as mean, standard deviation, range, and analyzed by independent samples t test, pearson correlation test and linear regression. RESULTS: In all glaucoma patients, peak IOP occurred mainly from 8:00 to 10:00 and 8:00 to 10:00.In normal tension group, peak IOP appeared mainly from 8:00 to 10:00 and from 0:00 to 6:00, the highest frequency showed at 8:00 (17 eyes 18.48%).In hyper-tension group, the probability of IOP reaching peak was more in night time, mainly from 0:00 to 6:00, the highest frequency showed at 2:00 (10 eyes 21.28%). If only the peak IOP during office hours or diurnal hours were considered, then only 32.55% (14/43) and 44.19% (19/43) patients could be correctly diagnosed. The remaining patients would be missed because of low IOP and/or mild structure and/or functional damages. There were good linear correlations between office hours or diurnal peak and mean IOP and nocturnal peak IOP in glaucoma patients. CONCLUSIONS: More than 50% peak IOP occurred out of office hour in POAG patients. There is a good correlation between peak nocturnal IOP and office hour or diurnal IOP level. PMID- 25908001 TI - [A prospective randomized study of selective laser trabeculoplasty (SLT) as a replacement for medical therapy in primary open-angle glaucoma]. AB - OBJECTIVE: To evaluate the efficacy and safety of selective laser trabeculoplasty (SLT) as a replacement for medical therapy in primary open-angle glaucoma (POAG). METHODS: A prospective, randomized, controlled study.SLT treatment with SOLO SLT Nd: YAG laser was provided to 45 participants with advanced POAG (67 eyes, IOP <= 21 mmHg, 1 mmHg = 0.133 kPa) under anti-glaucomatous medications control). A table of random numbers was created by simple randomization method. Participants were randomly divided into two groups: the standard-energy group (34 eyes), which received a 270 degrees standard-energy SLT treatment and the sub-threshold energy group (33 eyes), which received a 360 degrees sub-threshold energy treatment. The intraocular pressure (IOP) before and after SLT, daytime IOP curve, dosage of anti-glaucoma drugs and treatment complications were observed, which were be followed up for 6-9 months (average 6.4 months). Two-tailed t-test or paired t test was used when the continuous variables were normal distribution, such as the basic data, daily fluctuations of IOP, laser energy. Non-parametric Mann-Whitney U test or Wilcoxon rank test was used when data was not distributed normally, such as drug category. Chi-square or Fisher's exact test was used when count variables such as success rate and complications were analyzed. RESULTS: The number of anti-glaucomatous drugs used in the standard-energy group and the sub-threshold energy group before SLT was (2.3 +/- 0.5) and (2.1 +/- 0.4), respectively; whereas, after the last treatment, it reduced to (1.3 +/- 0.5) and (1.1 +/- 0.3), respectively (Z = -5.477, -5.396; P < 0.05). The success rate of the standard-energy group and the sub-threshold energy group was 91.1%, and 87.9%, respectively, which was not significant different (P = 0.70). Laser treatment was found to reduce the IOP fluctuation during the daytime.IOP fluctuation decreased from (3.6 +/- 1.0) mmHg to (2.3 +/- 1.0) mmHg in the standard-energy group, and decreased from (3.9 +/- 1.4) mmHg to (2.4 +/- 0.9) mmHg in the sub-threshold energy group, which was significant different (t = 4.911, 4.679; P < 0.05). The total laser energy of the standard-energy group (47.8 +/- 6.0) mJ was higher than the sub-threshold energy group (43.2 +/- 5.1) mJ (t = 12.006, 3.233; P < 0.05). However, there was no significant difference in the daily IOP fluctuations, success rate, reduction of medication categories, preoperative and postoperative IOP, and adverse reactions between the two groups. CONCLUSIONS: SLT is a safe and effective replacement for medical therapy in primary open-angle glaucoma treatment. SLT could reduce the applications of anti glaucoma drugs. There was no significant difference between therapeutic effects of which eyes received 360 degrees sub-threshold energy and 270 degrees standard-energy. PMID- 25908002 TI - [Preliminary investigation on the safety and efficacy of Trabectome]. AB - OBJECTIVE: To evaluate the safety and efficacy of ab interno trabeculectomy (Trabectome) surgery in Chinese open angle glaucoma patients. METHODS: Prospective non-comparative case series study. A total of 41 cases (34 primary open angle glaucoma patients, 3 developmental glaucoma patients and 4 pigmentary glaucoma patients) were included in the study. All the cases underwent Trabectome, including 9 cases combined with phacoemulsification cataract extraction. Major outcomes include intraocular pressure (IOP), number of glaucoma medications, secondary glaucoma surgery and postoperative complications. Criteria for successful operation were defined as IOP <= 21 mmHg (1 mmHg = 0.133 kPa), at least 20% IOP reduction in any two consecutive visits after 3 months with or without IOP-lowering drugs and no additional glaucoma surgery. IOP and number of glaucoma medications were compared to baseline using Wilcoxon signed-rank test with Bonferroni correction. Kaplan-Meier analysis was performed to analyze the success rate of surgery. RESULTS: In the all 41 patients, 21 cases (51.2%) were followed up for up to 12 months. IOP was reduced from (22.5 +/- 8.1) mmHg to (17.6 +/- 6.4) mmHg (P = 0.02), meanwhile number of glaucoma medications was reduced from 2.0 +/- 0.9 to 1.2 +/- 0.9 (P = 0.02) at 12 months. The success rate at one year was 85% and 4 cases required additional glaucoma surgery. CONCLUSIONS: Trabectome has many advantages, such as shorter surgery time, simple post-operative care, less intraoperative and postoperative complications and clear IOP-lowering effect. But it slong-term efficacy is still need a large sample, long-term follow-up to verify. PMID- 25908003 TI - [Study of thioredoxin antioxidative system in lateral geniculate body of chronic intraocular hypertension rat]. AB - OBJECTIVE: To investigate the dynamic changes and molecular mechanisms of thioredoxin system in lateral geniculate body of chronic intraocular hypertension rats. METHOD: Glaucoma model was established by cauterizing rat's episclera veins. Right eye is the treatment group, while left eye is the sham operation group, vein of which is just isolated not be cauterized. There were 25 rats in high intraocular pressure group, and 4 rats in control group. The expression of Trx, Trx1, Trx2, Sesn2, Srxn1, Txnip was detected by Western blot and RT-PCR at different time points after intraocular pressure rose (1, 3, 7, 14, 28 d), and were grouped according to the time points. Paired t test was used in the data analysis within each time group and one-way ANOVA was used in the comparisons among different time groups. RESULT: After 3 days of glaucoma induction, the gray scale value of thioredoxin (0.83 +/- 0.02) was statistically significant decreased (F = 4.871, P = 0.005), compared with the control group (1.02 +/- 0.04). After 14 days, TRX1 related expression level reduced to 0.63 +/- 0.04, while the control group level was 0.96 +/- 0.03 (t = 13.647, P < 0.05). The related expression level of SESN2 was 0.53 +/- 0.11, but the control group expression was 0.96 +/- 0.03 (t = 13.812, P < 0.05). SRXN1 decreased to 0.71 +/- 0.05 and 0.49 +/- 0.03 after 7 days and 14 days respectively, while the expression of control group were 0.97 +/- 0.02 and 0.96 +/- 0.02 respectively. (Group 7 d, t = 9.451, P < 0.05; group 14 d, t = 13.611, P < 0.01).On the contrary, expression of TXINP was upregulated to 1.83 +/- 0.04 and 2.37 +/- 0.03 respectively, while the expression of control group were 1.00 +/- 0.02 and, 0.95 +/- 0.03 (Group 7 d, t = 7.924, P < 0.05;14 d t = 12.637, P < 0.01) respectively. CONCLUSIONS: Oxidative stress existed in lateral geniculate body of chronic intraocular hypertension rat model, and the down-regulated expression of Trx, Trx2 of the Trx system in lateral geniculate body was inhibited by multiple pathways when oxidative damage occurs. The inhibitor genes on up-stream increased while promoting genes diminished. PMID- 25908004 TI - [Efficacy of intravitreal carboplatin plus bevacizumab in refractory retinoblastoma]. AB - OBJECTIVES: To evaluate the efficacy of intravitreal carboplatin plus bevacizumab in refractory retinoblastoma. METHODS: Perspective study.Eleven patients (11 eyes) with the diagnosis of refractory retinoblastoma were enrolled in Department of Ophthalmology of Peking University People's Hospital from June 2013 to March 2014. They underwent intravitreal carboplatin plus bevacizumab every 4 weeks, an average of 4.5 times of treatment.Observe for 3 months after the last treatment. Aqueous humor was taken for cytological and VEGF detection and retinal funds were taken photos for observation.Statistical analyses between experimental group and control group and before and after intravitreal injection within experimental group were performed with independent samples t test. RESULTS: Tumor in vitreous cavity reduced significantly in seven patients, however, poor control in four cases, and three of them were recurrent after first-line treatment. Cytology detection for aqueous humor showed no tumor cells in all of them. Aqueous VEGF of patients with retinoblastoma (60.65 +/- 6.20) was significantly higher than the control group (21.98 +/- 6.91). The difference was statistically significant (t = 13.80, P < 0.01). And the aqueous VEGF content decreased significantly after treatment (t = 2.12, P < 0.05). CONCLUSION: Intravitreal carboplatin plus bevacizumab, is a relatively safe, effective treatment for refractory retinoblastoma, however, ineffective for recurrent tumor. PMID- 25908005 TI - [Protective effect of Salidroside on oxidative damage to human lens epithelial cells]. AB - OBJECTIVE: The aim of the experiment was to investigate the effects of salidroside (Sal) on oxidative damage to human lens epithelial cells (HLEC). METHODS: Experimental study. The cultured HLECwas intervened with hydrogen peroxide (H2O2) which created oxidative damage model to observe the effect of Sal on HLECs. The cultured cells during the logarithmic phase were interposed by different concentrations Sal (0 umol/L, 10 umol/L, 30 umol/L, 50 umol/L, 100 umol/L, 200 umol/L) for 24 h. Then the viability of cells was detected by cell counting Kit-8 (CCK-8) assay. The cells were divided into 5 groups:control group, H2O2 group, Sal low dose group (30 umol/L Sal+ H2O2 group), Sal middle dose group (50 umol/L Sal+H2O2 group), Sal high dose group (100 umol/L Sal+ H2O2 group). The effects of Sal on the apoptosis of the HLEC were determined by Hoechst 33258 staining and flow cytometry assay.Reverse transcriptase-polymerase chain reaction (RT-PCR) was used to detect B cell lymphoma-2 associated X protein (Bax), B-cell lymphoma-2 (Bcl-2) and Cysteinyl aspartate specific proteinase 3 (Caspase-3) expression. Data between groups were analyzed using one-way analysis of variance (ANOVA), while LSD-t test was used for further comparison between every two groups. RESULTS: CCK-8 result showed that when the concentration of H2O2 was 200 umol/L, the survival of HLEC inhibition rate was 49.56% +/- 7.07%, which was close to the half of the cell survival inhibition rate (IC50). So 200 umol/L was chosen as the concentration of H2O2 in follow-up experiments. Different concentrations of Sal had no inhibitive influence on HLEC viability. After 24 hours cultivated with Sal (10 umol/L, 30 umol/L, 50 umol/L, 100 umol/L, 200 umol/L), the survival rate of HLEC were 100.24% +/- 2.07%, 101.18% +/- 2.14%, 101.32% +/- 2.48%, 101.76% +/- 1.93% and 99.28% +/- 1.74% correspondingly. There was no significant difference comparing with that of the control group 99.84% +/- 2.21% (F = 1.044, P = 0.415; all P > 0.05). Hoechst 33258 staining showed that the chromatin of H2O2 group aggregated and concentrated obviously. And Sal could reduce the aggregation of chromatin of HLEC obviously. FCM results indicated that the apoptosis rate of HLEC was 2.26% +/- 0.29% in control group and 44.56% +/- 4.28% in H2O2 group. After interposal with Sal (30 umol/L, 50 umol/L, 100 umol/L), the apoptosis rate of HLEC reduced to 31.52% +/- 3.05%, 24.06% +/- 4.25% and 17.16% +/- 2.75%. The differences of apoptosis rates had statistical significance between the five groups (F = 117.082, P < 0.001). The HLEC apoptosis rate decreased with higher Sal concentreations (F = 117.082, P < 0.01). The expression of Bax and Caspase-3 in H2O2 group were higher and the expression of Bcl-2 were lower than that in the control group (P < 0.01). Compared with the control group, the expression of Bcl-2 in three Sal dose groups was higher and the expression of Bax, Caspase-3 was lower, especially the high dose Sal group (Bax:F = 493.554, P < 0.01; Bcl-2:F = 827.820, P < 0.01; Caspase-3:F = 537.237, P < 0.01). CONCLUSIONS: The Sal takes the protective effect on the oxidative damage to HLEC.It could decrease the apoptosis of HLEC. PMID- 25908006 TI - [Posture change and intraocular pressure fluctuation]. AB - Although the pathogenesis of glaucoma is complicated and multifactorial, elevated intraocular pressure (IOP) remains the most important known risk factor. The higher the IOP and the larger the IOP fluctuation, the more damage to the optic nerve. IOP fluctuation can be affected by many factors, such as emotion, exercise and circadian rhythm, etc. Recently, the effects of postural change on IOP fluctuation are receiving more and more attention. This article reviews the effects of different body positions on IOP fluctuation, the effects of surgery, medications and aging on posture-induced IOP fluctuation and the effects of postural change on IOP fluctuation of certain special groups. The possible mechanisms of posture-induced IOP fluctuation are also discussed in this article. PMID- 25908007 TI - [Uveitic macular edema and the pharmacotherapy]. AB - Macular edema represents a major cause of visual loss in uveitis and its adequate management is crucial for the maintenance of useful vision in patients with uveitis. Corticosteroid is the first choice for UME treatment.Long term and sustained release implantation is the newest administration for medical therapy. The immunosuppressant such as cyclosporine, methotrexate, azathioprine and mycophenolate mofetil can be used specially for chronic and intractable UME. Moreover, these years, some newly developed biological agents, for example, anti VEGF, interferon-alpha, anti-TNF and acetazolamide will provide new options for UME pharmacotherapy. PMID- 25908008 TI - [Clinical evaluation of ocriplasmin as a vitreolytic agent]. AB - Incomplete perifoveal posterior vitreous detachment (PVD) associated with abnormal vitreomacular adhesion (VMA) can cause vitreomacular traction (VMT) and macular hole (MH) formation, which require vitrectomy treatment. Pharmacologic vitreolysis, which is intravitreal injection with vitreolytic enzymes to resolve VMA, may be used as an alternative therapy.Ocriplasmin, formerly known as microplasmin, is a recombinant truncated form of plasmin with proteolytic activity against fibronectin and laminin.It was recently approved for VMA treatment in the European Union and USA. Phase III studies indicated that ocriplasmin injection was a safe and effective treatment for selected cases of symptomatic VMA and MH. VMA release was achieved in 26.5% of ocriplasmin-injected eyes versus 10.1% of the placebo group. MH closure was achieved in 40.6% as compared with 10.6% of the placebo group.In comparison with the outcome after vitrectomy, the success rate of ocriplasmin was still far below expectation. Ocular adverse events included vitreous floaters, photopsia and profound visual decline. Its efficacy and safety need to be further evaluated in more clinical trials. PMID- 25908009 TI - Effects of low dietary protein on the metabolites and microbial communities in the caecal digesta of piglets. AB - Thirty-six healthy piglets (weighing 10 +/- 1 kg; three animals per pen) were randomly allocated to two treatments: (i) a low protein diet (14% crude protein [CP]) supplemented with lysine, methionine, threonine and tryptophan (Group LP) and (ii) a normal protein diet (20% CP, Group NP), resulting in six replicate pens per treatment. One piglet from each pen was slaughtered at days 10, 25 and 45 of the experiment. For the whole experimental period of 45 d, Group LP had lower feed intake and daily gain and a higher feed-to-gain ratio compared with Group NP. At day 10, no effects on measured caecum metabolites were observed, but at days 25 and 45 in Group LP the concentration of ammonia-N, cadaverine, branched chain fatty acids and acetate were reduced. This was also true for the concentration of short chain fatty acids at day 45. The results of denaturing gradient gel electrophoresis showed that microbial diversity in Group LP was less abundant at day 25, but there was no difference at days 10 and 45. An unweighted pair group mean average analysis showed that the similarities were lower between Groups LP and NP at day 10 and higher at days 25 and 45. Quantitation results indicated that the numbers of Firmicutes and Clostridium cluster IV were lower in Group LP than in Group NP at day 25, but there were no differences at days 10 and 45. In conclusion, the low protein diet markedly reduced the metabolites of protein and carbohydrate fermentation and altered microbial communities in the caecal digesta of piglets. PMID- 25908010 TI - Morbidity and mortality after surgery for cancer of the oesophagus and gastro oesophageal junction: A randomized clinical trial of neoadjuvant chemotherapy vs. neoadjuvant chemoradiation. AB - OBJECTIVE: To compare the incidence and severity of postoperative complications after oesophagectomy for carcinoma of the oesophagus and gastro-oesophageal junction (GOJ) after randomized accrual to neoadjuvant chemotherapy (nCT) or neoadjuvant chemoradiotherapy (nCRT). BACKGROUND: Neoadjuvant therapy improves long-term survival after oesophagectomy. To date, evidence is insufficient to determine whether combined nCT, or nCRT alone, is the most beneficial. METHODS: Patients with carcinoma of the oesophagus or GOJ, resectable with a curative intention, were enrolled in this multicenter trial conducted at seven centres in Sweden and Norway. Study participants were randomized to nCT or nCRT followed by surgery with two-field lymphadenectomy. Three cycles of cisplatin/5-fluorouracil was administered in all patients, while 40 Gy of concomitant radiotherapy was administered in the nCRT group. RESULTS: Of the randomized 181 patients, 91 were assigned to nCT and 90 to nCRT. One-hundred-and-fifty-five patients, 78 nCT and 77 nCRT, underwent resection. There was no statistically significant difference between the groups in the incidence of surgical or nonsurgical complications (P value = 0.69 and 0.13, respectively). There was no 30-day mortality, while the 90 day mortality was 3% (2/78) in the nCT group and 6% (5/77) in the nCRT group (P = 0.24). The median Clavien-Dindo complication severity grade was significantly higher in the nCRT group (P = 0.001). CONCLUSION: There was no significant difference in the incidence of complications between patients randomized to nCT and nCRT. However, complications were significantly more severe after nCRT. REGISTRATION TRIAL DATABASE: The trial was registered in the Clinical Trials Database (registration number NCT01362127). PMID- 25908011 TI - The effect of diverting stoma on postoperative morbidity after low anterior resection for rectal cancer in patients treated within an ERAS program. AB - BACKGROUND: Anastomotic leakage (AL) is a serious complication after low anterior resection (LAR) with total mesorectal excision (TME) for rectal cancer. Whether the Enhanced Recovery After Surgery (ERAS)-protocol influences the risk of short term morbidity in relation to the use of a diverting stoma is unclear. METHODS: Between 2002 and 2011, 287 consecutive patients underwent LAR with TME for rectal cancer at Ersta Hospital, Sweden. All patients were treated according to the ERAS program and thereby included. Between 2002 and 2006 15% had a diverting stoma compared to 91 %, 2007 to 2011. RESULTS: One hundred and thirty-nine patients were operated with a diverting stoma at primary surgery (S+), 148 patients were not (S-). The groups were comparable regarding pre- and peroperative data and patients' characteristics. Postoperative morbidity within 30 days after surgery (S+ 53% vs. S- 43%) and hospital stay (S+ 11 days vs. S- 9 days) did not differ. AL occurred in 22% of all patients. In a multivariate analysis, no significant difference in AL was found in relation to the use of a diverting stoma (S+ vs. S , OR 0.64, 95% CI 0.34-1.19). Eleven patients (8%) in the S+ group underwent relaparotomy versus 22 (15%) in the S- group (p = 0.065). Total overall compliance to the ERAS program was 65%. Patients in S- had faster postoperative recovery. CONCLUSION: A diverting stoma did not affect postoperative morbidity in this large cohort of patients undergoing LAR within an ERAS program. However, the routine use of a diverting stoma could be expected to delay postoperative recovery. PMID- 25908012 TI - On the evolutionary interplay between dispersal and local adaptation in heterogeneous environments. AB - Dispersal, whether in the form of a dandelion seed drifting on the breeze, or a salmon migrating upstream to breed in a nonnatal stream, transports genes between locations. At these locations, local adaptation modifies the gene frequencies so their carriers are better suited to particular conditions, be those of newly disturbed soil or a quiet river pool. Both dispersal and local adaptation are major drivers of population structure; however, in general, their respective roles are not independent and the two may often be at odds with one another evolutionarily, each one exhibiting negative feedback on the evolution of the other. Here, we investigate their joint evolution within a simple, discrete-time, metapopulation model. Depending on environmental conditions, their evolutionary interplay leads to either a monomorphic population of highly dispersing generalists or a collection of rarely dispersing, locally adapted, polymorphic sub-populations, each adapted to a particular habitat type. A critical value of environmental heterogeneity divides these two selection regimes and the nature of the transition between them is determined by the level of kin competition. When kin competition is low, at the transition we observe discontinuities, bistability, and hysteresis in the evolved strategies; however, when high, kin competition moderates the evolutionary feedback and the transition is smooth. PMID- 25908013 TI - Individual recovery profiles in basketball players. AB - In the sport context, recovery has been characterized as a multifactor process (physiological, psychological, behavioral, social, etc.). This study takes a multidisciplinary approach to find psychophysiological markers of the stress recovery process. It aims to determine how athletes' specific recovery actions relate to their perceptions of recovery, and Heart Rate Variability (HRV). A total of 196 assessments were analyzed from 6 players on a men's professional basketball team within the Liga LEB Oro basketball federation (2012/2013 season). Perceptions of recovery, recovery strategies, and HRV were recorded. The results show a pattern of individual differences in behavior related to athletes' recovery actions and HRV profiles throughout the season (p < .05). Moreover, we observed that each player had different recovery needs. In light of these results, we suggest an individualistic approach to evaluating and monitoring recovery to attend more accurately to each player's recovery needs. PMID- 25908014 TI - Stability of Language and Literacy Profiles of Children With Language Impairment in the Public Schools. AB - PURPOSE: The present study focused on the identification and stability of language and literacy profiles of primary school children receiving school-based language therapy over the course of one academic year. METHOD: Participants included 272 early elementary school-age children (144 boys, 128 girls) who had been clinically identified as having a language impairment. A latent profile analysis was used to identify distinct profiles on the basis of a battery of language and literacy assessments in the fall and spring of the academic year. RESULTS: Four profiles were identified in both fall and spring that could be best described as representing high, average, and low overall abilities. Two average groups were identified that differentiated according to phonological awareness abilities. Children's profile membership was variable from fall to spring with nearly 60% of children shifting into a higher profile. The results of t tests comparing children who shifted into higher profiles from those who remained stable in profile membership revealed group differences regarding language severity, socio-economic status, and proportion of therapy sessions received in the classroom. CONCLUSION: These results provide further evidence regarding the heterogeneity of children with language impairment served in the public schools, indicating that differences may be best conceptualized along a continuum of severity. PMID- 25908015 TI - Laser speckle spatiotemporal variance analysis for noninvasive widefield measurements of blood pulsation and pulse rate on a camera-phone. AB - Photoplethysmography is a well-established technique for the noninvasive measurement of blood pulsation. However, photoplethysmographic devices typically need to be in contact with the surface of the tissue and provide data from a single contact point. Extensions of conventional photoplethysmography to measurements over a wide field-of-view exist, but require advanced signal processing due to the low signal-to-noise-ratio of the photoplethysmograms. Here, we present a noncontact method based on temporal sampling of time-integrated speckle using a camera-phone for noninvasive, widefield measurements of physiological parameters across the human fingertip including blood pulsation and resting heart-rate frequency. The results show that precise estimation of these parameters with high spatial resolution is enabled by measuring the local temporal variation of speckle patterns of backscattered light from subcutaneous skin, thereby opening up the possibility for accurate high resolution blood pulsation imaging on a camera-phone. Camera-phone laser speckle imager along with measured relative blood perfusion maps of a fingertip showing skin perfusion response to a pulse pressure applied to the upper arm. The figure is for illustration only; the imager was stabilized on a stand throughout the experiments. PMID- 25908016 TI - The use of VA Disability Compensation and Social Security Disability Insurance among working-aged veterans. AB - BACKGROUND: Although there is substantial disability among veterans, relatively little is known about working-aged veterans' uptake of Department of Veterans Affairs (VA) Disability Compensation and Social Security Disability Insurance (DI). OBJECTIVES: This study identifies levels of veteran participation in VA disability and/or DI benefit programs, examines transitions into and out of VA and DI programs among veterans, and estimates the size and composition of the veteran population receiving VA and/or DI benefits over time. METHODS: Data from the 1992, 1993, 1996, 2001, 2004, and 2008 Survey of Income and Program Participation (SIPP) are used to describe VA and DI program participation among veterans under the age of 65. RESULTS: The majority of working-aged veterans do not receive VA or DI benefits and joint participation is low, but use of these programs has increased over time. A higher percentage of veterans receive VA compensation, which ranges from 4.9% in 1992 to 13.2% in 2008, than DI compensation, which ranges from 2.9% in 1992 to 6.7% in 2008. The rate of joint participation ranges from less than 1% in 1992 to 3.6% in 2008. Veterans experience few transitions between VA and DI programs during the 36-48 months they are observed. The number of veterans receiving benefits from VA and/or DI nearly doubled between 1992 and 2008. There have been substantial shifts in the composition of veterans using these programs, as cohorts who served prior to 1964 are replaced by those who served after 1964. CONCLUSIONS: The findings suggest potential gaps in veterans' access to disability programs that might be addressed through improved coordination of VA and DI benefits. PMID- 25908017 TI - Geo-social and health disparities among persons with disabilities living in Monterrey, Nuevo Leon and Dallas, Texas. AB - BACKGROUND: In low and high income countries alike, disability exacerbates social, economic, and health disparities, in spite of their differences. OBJECTIVE: This study seeks to identify factors that predict the circumstances people with disabilities face, including poverty. METHODS: A cross-sectional study design was employed using census track level data for the cities of Monterrey, Nuevo Leon, and Dallas, Texas, from Mexico 2010 and USA 2000 census data collections. Two methods, spatial autocorrelation and geographically weighted regression were used to identify spatial patterns of disability and to explore the relation between disability and context-specific socio-demographic factors. RESULTS: Results indicated that people with disabilities living below the poverty line experience high segregation levels in the semi-central zones of Dallas. In Monterrey, people with disabilities clustered in central areas of the city. A Geographically Weighted Regression (GWR) from both data analyses reported high goodness of fit (R >= 0.8 for Dallas data and R >= 0.7 for Monterrey data, respectively) and predictability of disability prevalence when social disadvantage factors such as unemployment, housing insecurity, household living conditions, and lack of education were present. CONCLUSIONS: The divergent and sometimes conflicting trends in practices and policies addressing disability in low and high income environments renders a reexamination of the framework of disability. An understanding of local characteristics joins a grounded socio cultural understanding of the various contexts that shape location-based social networks and political decisions in providing such an analysis. PMID- 25908018 TI - Health Literacy Predicts Morbidity and Mortality in Rural Patients With Heart Failure. AB - BACKGROUND: Patients hospitalized with heart failure are often readmitted. Health literacy may play a substantial role in the high rate of readmissions. The purpose of this study was to examine the association of health literacy with the composite end point of heart failure readmission rates and all-cause mortality in patients with heart failure living in rural areas. METHODS AND RESULTS: Rural adults (n = 575), hospitalized for heart failure within the past 6 months, completed the Short Test of Functional Health Literacy in Adults (STOFHLA) to measure health literacy and were followed for >=2 years. The percentage of patients with the end point of heart failure readmission or all-cause death was different (P = .001) among the 3 STOFHLA score levels. Unadjusted analysis revealed that patients with inadequate and marginal health literacy were 1.94 (95% confidence interval [CI] 1.43-2.63; P < .001) times, and 1.91 (95% CI 1.36 2.67; P < .001) times, respectively, more likely to experience the outcome. After adjustment for covariates, health literacy remained a predictor of outcomes. Of the other covariates, worse functional class, higher comorbidity burden, and higher depression score predicted worse outcomes. CONCLUSIONS: Inadequate or marginal health literacy is a risk factor for heart failure rehospitalization or all-cause mortality among rural patients with heart failure. PMID- 25908019 TI - Frequent mild cognitive deficits in several functional domains in elderly patients with heart failure without known cognitive disorders. AB - BACKGROUND: The objective of the present study was to investigate whether mild cognitive deficits are present in patients with heart failure (HF) despite absence of any known cognitive disorder. METHODS AND RESULTS: A well defined group of patients (n = 40) with heart failure completed a cognitive screening check list, a depression screening questionnaire, and a battery consisting of neuropsychological tests assessing 5 different cognitive domains: speed/attention, episodic memory, visuospatial functions, language, and executive functions. The neuropsychological results were compared with those from a group of healthy control subjects (n = 41). The patients with HF displayed cognitive impairment compared with the control group within the domains speed and attention, episodic memory, visuospatial functions, and language. Among them, 34 HF patients (85%) could be classified with mild cognitive impairment (MCI), the majority as nonamnestic MCI, ie, with no memory impairment. CONCLUSIONS: Considering the high occurrence of mild cognitive deficits among HF patients without known cognitive disorders, closer attention should be paid to their self care and compliance. Inadequate self-care and compliance could lead to more frequent hospitalizations. Furthermore, the HF patients may be at increased risk of dementia. PMID- 25908020 TI - Vegetation ecology meets ecosystem science: Permanent grasslands as a functional biogeography case study. AB - The effect of biodiversity on ecosystem functioning has been widely acknowledged, and the importance of the functional roles of species, as well as their diversity, in the control of ecosystem processes has been emphasised recently. However, bridging biodiversity and ecosystem science to address issues at a biogeographic scale is still in its infancy. Bridging this gap is the primary goal of the emerging field of functional biogeography. While the rise of Big Data has catalysed functional biogeography studies in recent years, comprehensive evidence remains scarce. Here, we present the rationale and the first results of a country-wide initiative focused on the C3 permanent grasslands. We aimed to collate, integrate and process large databases of vegetation releves, plant traits and environmental layers to provide a country-wide assessment of ecosystem properties and services which can be used to improve regional models of climate and land use changes. We outline the theoretical background, data availability, and ecoinformatics challenges associated with the approach and its feasibility. We provide a case study of upscaling of leaf dry matter content averaged at ecosystem level and country-wide predictions of forage digestibility. Our framework sets milestones for further hypothesis testing in functional biogeography and earth system modelling. PMID- 25908021 TI - Letter to the Editor concerning "Does whole-spine lateral radiograph with clavicle positioning reflect the correct cervical sagittal alignment?" by Park SM et al. (Eur Spine J 24(1):57-62). PMID- 25908022 TI - A Rickettsiales symbiont of amoebae with ancient features. AB - The Rickettsiae comprise intracellular bacterial symbionts and pathogens infecting diverse eukaryotes. Here, we provide a detailed characterization of 'Candidatus Jidaibacter acanthamoeba', a rickettsial symbiont of Acanthamoeba. The bacterium establishes the infection in its amoeba host within 2 h where it replicates within vacuoles. Higher bacterial loads and accelerated spread of infection at elevated temperatures were observed. The infection had a negative impact on host growth rate, although no increased levels of host cell lysis were seen. Phylogenomic analysis identified this bacterium as member of the Midichloriaceae. Its 2.4 Mb genome represents the largest among Rickettsiales and is characterized by a moderate degree of pseudogenization and a high coding density. We found an unusually large number of genes encoding proteins with eukaryotic-like domains such as ankyrins, leucine-rich repeats and tetratricopeptide repeats, which likely function in host interaction. There are a total of three divergent, independently acquired type IV secretion systems, and 35 flagellar genes representing the most complete set found in an obligate intracellular Alphaproteobacterium. The deeply branching phylogenetic position of 'Candidatus Jidaibacter acanthamoeba' together with its ancient features place it closely to the rickettsial ancestor and helps to better understand the transition from a free-living to an intracellular lifestyle. PMID- 25908023 TI - Successful treatment of a massive metoprolol overdose using intravenous lipid emulsion and hyperinsulinemia/euglycemia therapy. AB - Adrenergic beta-antagonists, commonly known as beta-blockers, are prescribed for many indications including hypertension, heart failure, arrhythmias, and migraines. Metoprolol is a moderately lipophilic beta-blocker that in overdose causes direct myocardial depression leading to bradycardia, hypotension, and the potential for cardiovascular collapse. We describe the case of a 59-year-old man who intentionally ingested ~7.5 g of metoprolol tartrate. Initial treatment of bradycardia and hypotension included glucagon, atropine, dopamine, and norepinephrine. Despite these treatment modalities, the patient developed cardiac arrest. Intravenous lipid emulsion (ILE) and hyperinsulinemia/euglycemia (HIE) therapies were initiated during advanced cardiac life support and were immediately followed by return of spontaneous circulation. Further treatment included gastric lavage, activated charcoal, continued vasopressor therapy, and a repeat bolus of ILE. The patient was weaned off vasoactive infusions and was extubated within 24 hours. HIE therapy was continued for 36 hours after metoprolol ingestion. A urine beta-blocker panel using mass spectrometry revealed a metoprolol concentration of 120 ng/ml and the absence of other beta-blocking agents. To date, no clear treatment guidelines are available for beta-blocker overdose, and the response to toxic concentrations is highly variable. In this case of a life-threatening single-agent metoprolol overdose, the patient was successfully treated with HIE and ILE therapy. Due to the increasing frequency with which ILE and HIE are being used for the treatment of beta-blocker overdose, clinicians should be aware of their dosing strategies and indications. PMID- 25908024 TI - Quantitative trait loci segregating in crosses between New Hampshire and White Leghorn chicken lines: IV. Growth performance. AB - Reciprocal crosses between the inbred lines New Hampshire (NHI) and White Leghorn (WL77) comprising 579 F2 individuals were used to map QTL for body weight and composition. Here, we examine the growth performance until 20 weeks of age. Linkage analysis provided evidence for highly significant QTL on GGA1, 2, 4, 10 and 27 which had specific effects on early or late growth. The highest QTL effects, accounting for 4.6-25.6% of the phenotypic F2 variance, were found on the distal region of GGA4 between 142 and 170 cM (F >= 13.68). The NHI QTL allele increased body mass by 141.86 g at 20 weeks. Using body weight as a covariate in the analysis of body composition traits provided evidence for genes in the GGA4 QTL region affecting fat mass independently of body mass. The QTL effect size differed between sexes and depended on the direction of cross. TBC1D1, CCKAR and PPARGC1A are functional candidate genes in the QTL peak region. Our study confirmed the importance of the distal GGA4 region for chicken growth performance. The strong effect of the GGA4 QTL makes fine mapping and gene discovery feasible. PMID- 25908025 TI - Secretion, blood levels and cutaneous expression of TL1A in psoriasis patients. AB - TL1A is a TNF-like cytokine which has been shown to co-stimulate TH1 and TH17 responses during chronic inflammation. The expression of this novel cytokine has been investigated in inflammatory disorders like rheumatoid arthritis and inflammatory bowel disease, but little is known about expression and induction in psoriasis. Indeed, the pathogenesis in psoriasis is still not fully understood and it is speculated that cytokines other than TNF-alpha are important in subsets of patients. Also, for patients with severe disease that are treated with systemic anti-TNF-alpha blockade, novel candidates to be used as disease and response biomarkers are of high interest. Here, we demonstrate TL1A expression in biopsies from psoriatic lesions. Also, we investigated spontaneous and induced TL1A secretion from PBMCs and blood levels from a cohort of psoriasis patients. Here, increased spontaneous secretion from PBMCs was observed as compared to healthy controls and a small subset of patients had highly elevated TL1A in the blood. Interestingly, activation of PBMCs with various cytokines showed a decreased sensitivity for TL1A activation in psoriasis patients compared to healthy controls.TL1A levels in blood and biopsies could not be correlated with disease activity with this patient cohort. Thus, additional large-scale studies are warranted to investigate TL1A as a biomarker. PMID- 25908026 TI - Loss of p27 phosphorylation at Ser10 accelerates early atherogenesis by promoting leukocyte recruitment via RhoA/ROCK. AB - Reduced phosphorylation of the tumor suppressor p27(Kip1) (p27) at serine 10 (Ser10) is a hallmark of advanced human and mouse atherosclerosis. Apolipoprotein E-null mice defective for this posttranslational modification (apoE(-/ )p27Ser10Ala) exhibited increased atherosclerosis burden at late disease states. Here, we investigated the regulation of p27 phosphorylation in Ser10 at the very initial stages of atherosclerosis and its impact on endothelial-leukocyte interaction and early plaque formation. Hypercholesterolemia in fat-fed apoE(-/-) mice is associated with a rapid downregulation of p27-phospho-Ser10 in primary endothelial cells (ECs) and in aorta prior to the development of macroscopically visible lesions. We find that lack of p27 phosphorylation at Ser10 enhances the expression of adhesion molecules in aorta of apoE(-/-) mice and ECs, and augments endothelial-leukocyte interactions and leukocyte recruitment in vivo. These effects correlated with increased RhoA/Rho-associated coiled-coil containing protein kinase (ROCK) signaling in ECs, and inhibition of this pathway with fasudil reduced leukocyte-EC interactions to control levels in the microvasculature of p27Ser10Ala mice. Moreover, apoE(-/-)p27Ser10Ala mice displayed increased leukocyte recruitment and homing to atherosusceptible arteries and augmented early plaque development, which could be blunted with fasudil. In conclusion, our studies demonstrate a very rapid reduction in p27 phospho-Ser10 levels at the onset of atherogenesis, which contributes to early plaque build-up through RhoA/ROCK-induced integrin expression in ECs and enhanced leukocyte recruitment. PMID- 25908027 TI - Image-guided radiotherapy for prostate cancer using 3 different techniques: localization data of 186 patients. AB - AIMS AND BACKGROUND: This study evaluates 3 different imaging modalities- ultrasound (US), stereoscopic X-ray imaging of implanted markers (Visicoils) (X ray), and kV cone-beam computed tomography (CBCT)--to assess interfraction and intrafraction localization error during conformal radiation therapy of prostate cancer. METHODS AND STUDY DESIGN: The study population consisted of 186 consecutive prostate cancer patients treated with an image-guided radiotherapy (IGRT) hypofractionated protocol using 3 techniques: 32 with X-ray, 30 with CBCT, and 124 with US. Treatment dose of 70.2 Gy was delivered in 26 fractions with a conformal dynamic arcs technique. Interfraction prostate localization errors were determined for the 3 techniques. Moreover, interfraction and intrafraction prostate motion in terms of translations and rotations, as well as residual errors, were determined with X-ray. RESULTS: The systematic and random components of the prostate localization errors were as follows: (1) with X-ray 3.0 +/- 3.4, 2.3 +/- 2.7, 1.8 +/- 2.3 mm in anterior-posterior (AP), superior-inferior (SI), and left-right (LR) directions and 1.8 degrees +/- 1.2 degrees , 2.3 degrees +/ 1.5 degrees , 2.7 degrees +/- 3.1 degrees , for the yaw, roll, and pitch rotations; (2) with CBCT 3.5 +/- 4.2, 3.3 +/- 3.3, 2.5 +/- 3.1 mm in AP, SI, and LR directions; (3) with US 3.7 +/- 4.7, 3.4 +/- 4.3, 2.3 +/- 3.5 mm in AP, SI, and LR directions. Residual errors with X-ray were less than 1 mm in all directions. Intrafraction prostate motion of less than 0.5 mm in LR and of the order of 1 mm in AP and SI directions was found. This led to a significant reduction of the margins, potentially important for dose escalation studies. CONCLUSIONS: Daily on-line IGRT with stereoscopic X-ray imaging allowed a consistent PTV margin reduction considering residual interfraction prostate localization error and intrafraction motion. X-ray offers the best compromise among accuracy, reliability, dose to the patient, and time investment for daily IGRT treatment of prostate. PMID- 25908028 TI - Role of multidetector computed tomography in evaluating incidentally detected breast lesions. AB - AIMS AND BACKGROUND: Computed tomography (CT) does not represent the primary method for the evaluation of breast lesions; however, it can detect breast abnormalities, even when performed for other reasons related to thoracic structures. The aim of this study is to evaluate the potential benefits of 320 row multidetector CT (MDCT) in evaluating and differentiating incidentally detected breast lesions by using vessel probe and 3D analysis software with net enhancement value. METHODS AND STUDY DESIGN: Sixty-two breast lesions in 46 patients who underwent 320-row chest CT examination were retrospectively evaluated. CT scans were assessed searching for the presence, location, number, morphological features, and density of breast nodules. Net enhancement was calculated by subtracting precontrast density from the density obtained by postcontrast values. The sensitivity, specificity, positive predictive value (PPV), negative predictive value (NPV), and diagnostic accuracy of CT were calculated for morphological features and net enhancement. RESULTS: Thirty of 62 lesions were found to be malignant at histological examination and 32 were found to be benign. When morphological features were considered, the sensitivity, specificity, accuracy, PPV, and NPV of CT were 87%, 100%, 88%, 100%, and 50%, respectively. Based on net enhancement, CT reached a sensitivity, specificity, accuracy, PPV, and NPV of 100%, 94%, 97%, 94%, and 100%, respectively. CONCLUSIONS: MDCT allows to recognize and characterize breast lesions based on morphological features. Net enhancement can be proposed as an additional accurate feature of CT. PMID- 25908029 TI - BDE-99 (2,2',4,4',5-pentabromodiphenyl ether) triggers epithelial-mesenchymal transition in colorectal cancer cells via PI3K/Akt/Snail signaling pathway. AB - PURPOSE: The gut is in direct contact with BDE-99 (2,2',4,4',5-pentabromodiphenyl ether), one of the most abundant PBDE congeners in the environment and in human tissues. The objective of the present study was to investigate the effects of BDE 99 on colorectal cancer (CRC) cells. METHODS: The effects of BDE-99 on cell proliferation were measured by CCK-8 assay in the CRC cell line HCT-116. Wound healing and transwell migration/invasion assays were used to test the migration and invasion of CRC cells. Factors related to epithelial-to-mesenchymal transition (EMT) were measured by real-time PCR and Western blot analysis for mRNA and protein levels, respectively. RESULTS: BDE-99 was found to increase migration and invasion and trigger EMT in HCT-116 cells; EMT was characterized by cells acquiring mesenchymal spindle-like morphology and by increased expression of N-cadherin with a concomitant decrease in E-cadherin. BDE-99 treatment also increased the protein and mRNA levels of the transcription factor Snail, but not Slug, Twist, and ZEB1. Knockdown of Snail by siRNA significantly attenuated BDE 99-induced EMT in HCT-116 cells, suggesting that Snail plays a crucial role in BDE-99-induced EMT. The PI3K/Akt inhibitor LY294002 completely blocked BDE-99 induced Snail and invasion of HCT-116 cells. CONCLUSIONS: Our results revealed that BDE-99 can trigger the EMT of colon cancer cells via the PI3K/AKT/Snail signaling pathway. This study provides new insight into the tumorigenesis and metastasis of CRC stimulated by BDE-99 and possibly other PBDE congeners. PMID- 25908030 TI - Bronchiolitis obliterans organizing pneumonia after radiation therapy for lung cancer: a case report. AB - Bronchiolitis obliterans organizing pneumonia (BOOP), also known as cryptogenic organizing pneumonia, has mainly been described in patients with breast cancer who received radiotherapy after breast-conserving surgery. In this rare case, a 70-year-old man with left apical squamous lung cancer developed BOOP after radiotherapy and only one cycle of concomitant chemotherapy.This case report draws attention to the development of this syndrome in the unusual setting of lung cancer, advising prompt steroid treatment when diagnostic images reveal the characteristic signs of the disease. PMID- 25908031 TI - Comparison of stereotactic body radiation therapy for biopsy-proven versus radiographically diagnosed early-stage non-small lung cancer: a single institution experience. AB - INTRODUCTION: Histological confirmation of non-small cell lung cancer (NSCLC) is often required before patients are offered stereotactic body radiation therapy (SBRT) as a treatment option. Many patients, however, are unsuitable to undergo a biopsy procedure because of comorbidity. Our objective is to compare the outcomes of patients with biopsy-proven (BxPr) or clinically/radiographically diagnosed (RadDx) early-stage NSCLC treated with SBRT. METHODS: Records of 88 patients treated with SBRT at a single institution were reviewed. Sixty-five patients had BxPr early-stage NSCLC. Twenty-three patients were RadDx with early-stage NSCLC based on an FDG-avid chest nodule on PET scan, serial sequential CT-findings compatible with NSCLC, and consensus of a multidisciplinary team. Outcomes of patients with BxPr and RadDx NSCLC were evaluated in regard to local control, regional lymph node metastasis-free and distant metastasis-free rates, and overall survival using Kaplan-Meier survival curves. RESULTS: Median follow-up for all patients was 29 months (range, 4-82 months). Cumulative local progression free rate after 3 years for the BxPr group was 93.1% (95% confidence interval [CI], 85.2%-97.6%) and 94.10% (95% CI, 73.2%-97.6%) for the RadDx group (p = 0.98). No differences regarding regional lymph node metastasis-free and distant metastasis-free rates by subgroup were observed. The overall 3-year survival rate for the BxPr group was 59.9% (95% CI, 44.8%-68.2%) and 58.9% (95% CI, 40.1% 77.8%) for the RadDx group (p = 0.46). CONCLUSIONS: SBRT is a practical treatment modality for patients with RadDx early-stage NSCLC. Outcomes of patients RadDx with NSCLC mirror the results of patients treated with BxPr disease. PMID- 25908032 TI - Risk patterns of subsequent primary cancers following esophagectomy in early stage thoracic esophageal squamous cell cancer patients. AB - AIMS AND BACKGROUND: Subsequent primary cancers (SPCs) have been demonstrated to be the major causes of death among patients with thoracic esophageal squamous cell cancer (ESCC) negative for lymph node involvement. We designed this study to investigate clinical characteristics and risk patterns of SPCs following esophagectomy in patients with early-stage thoracic ESCC. METHODS: We retrospectively analyzed clinical factors in 512 patients with early-stage thoracic ESCC collected from 3 independent hospitals over a 10-year interval. RESULTS: The overall standard incidence rate (SIR) of SPCs was 3.84 (95% confidence interval 2.98-4.95). The most common SPCs were head and neck cancers, lung cancer, and stomach cancer. The risk patterns of SPCs varied across organs. A 3-phase risk pattern with a U-shaped curve between 2 rising phases was seen for head and neck cancers, while for the other cancers, the risk patterns all displayed as an approximately linear upward trend. It was further noted that sex, smoking habits, and cancer histories among first-degree relatives were 3 significant independent risk factors in the development of SPCs. CONCLUSIONS: We observed significant associations between early-stage ESCC and SPCs arising from anatomically adjacent sites. The different risk patterns of SPCs indicated that follow-up strategies should be established accordingly in different organs at different times, with particularly close follow-up for head and neck cancers in the first 5 years and beyond 15 years after diagnosis of ESCC. PMID- 25908033 TI - A commentary on interstitial pneumonitis induced by docetaxel: clinical cases and systematic review of the literature. AB - BACKGROUND: Pulmonary toxicity is a well-known complication observed with several anticancer drugs. Docetaxel, a taxane chemotherapy drug widely used in the treatment of many types of solid tumors including non-small cell lung cancer (NSCLC), rarely causes infiltrative pneumonitis. The exact mechanism by which docetaxel develops this side effect is not well understood; probably it is produced by type I and IV hypersensitivity responses. Here we describe 2 cases of infiltrative pneumonitis induced by docetaxel as second-line chemotherapy in advanced NSCLC. MATERIALS AND METHODS: Two patients with advanced NSCLC were treated with weekly docetaxel as second-line chemotherapy. After 3 courses of chemotherapy, restaging computed tomography (CT) of the chest revealed bilateral diffuse ground-glass opacities with a peribronchial distribution possibly indicative of hypersensitivity pneumonitis. No evidence of pulmonary embolus or pleural effusion was found. Fiberoptic bronchoscopy showed normal bronchi without lymphangitis; biopsies showed interstitial fibrosis without tumor cells. Bronchial tissue laboratory tests for fungi or bacilli were negative. No malignant cells were found at bronchoalveolar lavage. The patients were given high-dose corticosteroid therapy with prednisone 0.7 mg per kilogram per day. RESULTS: After 1 month of therapy, contrast-enhanced chest CT showed complete disappearance of the pulmonary changes in both patients. Spirometry and blood gas analysis revealed complete recovery of pulmonary function. The patients continued their oncological follow-up program. CONCLUSIONS: Pulmonary injury is a rare adverse event during docetaxel chemotherapy. Prompt treatment with high-dose corticosteroids is needed to avoid worsening of respiratory performance. PMID- 25908034 TI - Breast metastasis from cutaneous malignant melanoma mimicking a breast cancer. AB - INTRODUCTION: Breast metastases are very uncommon, either from solid tumors or malignant melanoma. CASE REPORT: We present the case of a 42-year-old woman with a history of cutaneous melanoma of the shoulder excised 21 years ago. She presented with a palpable lump in the upper outer quadrant of the right breast. Ultrasound demonstrated a solid mass within a cystic lesion. A core biopsy was taken and first histology reported a poorly differentiated primary breast cancer suspected to be triple negative. MRI detected a satellite lesion in the same breast, a focus of suspected enhancement in the other breast, and the extramammary finding of an enhancing pulmonary lesion. Staging computed tomography detected widespread metastases to the lungs, brain, subcutaneous left shoulder, liver, pancreas, and hepatorenal recess. A core biopsy was taken from the left breast lesion and the previous slides were reviewed; histopathology and immunohistochemistry were in keeping with metastasis from melanoma. CONCLUSIONS: The possibility of a metastatic lesion to the breast should be taken into account in any patient presenting with a breast lump and a previous history of melanoma. Breast involvement cannot be considered an isolated finding, as it might be the first manifestation of widespread disease. PMID- 25908035 TI - Helical tomotherapy for the treatment of anal canal cancer: a dosimetric comparison with 3D conformal radiotherapy. AB - AIMS AND BACKGROUND: The standard treatment of anal canal cancer (ACC) is combined chemotherapy and radiation therapy (RT), which is complex because of the shape of the target volumes and the need to minimize the irradiation of normal pelvic structures. In this study we compared the dosimetric results of helical tomotherapy (HT) plans with traditional 3D conformal RT (3DRT) plans for the treatment of ACC. METHODS AND STUDY DESIGN: Twelve patients (median age 57 years, range 38-83; F/M 8/4) treated with HT and concurrent chemotherapy for locally advanced ACC were selected. All had histologically confirmed squamous-cell carcinoma. A clinical target volume including the tumor and pelvic and inguinal lymph nodes was treated with HT to a total dose of 36 Gy in 1.8-Gy daily fractions. Then a sequential boost of 23.4 Gy in 1.8-Gy daily fractions (total dose 59.4 Gy) was delivered to the tumor and involved nodes. For all 12 patients, 3DRT plans were generated for comparison. Treatment plans were evaluated by means of standard dose-volume histograms. Dose coverage of the planning target volumes (PTVs), homogeneity index (HI), and mean doses to organs at risk (OARs) were compared. RESULTS: The coverage of PTV was comparable between the two treatment plans. HI was better in the HT vs. 3DRT plans (1.25 and 3.57, respectively; p<0.0001). HT plans resulted in better sparing of OARs (p<0.0001). CONCLUSIONS: HT showed superior target dose conformality and significant sparing of pelvic structures compared with 3DRT. Further investigation should determine if these dosimetric improvements will improve clinical outcomes regarding locoregional control, survival, and treatment-related acute and late morbidity. PMID- 25908036 TI - Neoadjuvant chemotherapy in locally advanced gastric cancer: what to avoid. Preliminary analysis of a consecutive series of patients. AB - AIMS AND BACKGROUND: The role of neoadjuvant (NAD) chemotherapy (CHT) in patients with locally advanced gastric cancer (LAGC) is validated. However, some important limitations emerged from the literature, including patient selection, quality of surgery, and pathologic response evaluation. Neoadjuvant CHT for LAGC has been evaluated with a focus on safety and efficacy of the preoperative approach in terms of patient compliance, surgical outcomes, and pathologic response. METHODS AND STUDY DESIGN: Ninety-one patients with gastric adenocarcinoma were prospectively observed. All patients received computed tomography scan and laparoscopy staging. Ten patients with LAGC (including 2 with LAGC suspected for cM+/lapM+) had been recruited in the preoperative ECF/EOX CHT protocol and were compared with 61 patients who underwent surgery alone. RESULTS: The overall compliance for the preoperative CHT group was higher than compliance for adjuvant CHT observed in both the NAD CHT group and the surgery alone group. There were 2 treatment shifts to FOLFOX in the preoperative regimen. In the preoperative CHT group, D2-gastrectomy was possible only in 6/10 of cases, with a R0 resection rate of 67% (versus 64% in the LAGC patients treated by surgery alone). The postoperative mortality and morbidity were 0% and 17% in the NAD CHT group versus 2% and 26% in the surgery alone group. The overall pathologic response rate after NAD CHT was 83% (5/6). CONCLUSIONS: Staging and CHT management problems can negatively affect patient outcomes. In the LAGC setting, when well applied, NAD CHT could be considered a valuable treatment option. PMID- 25908037 TI - Outcome of crizotinib treatment in a young woman with heavily pretreated ROS1 positive lung cancer. AB - Non-small-cell lung cancer is a term that encompasses a number of subtypes of lung cancer. In recent years, several intracellular pathways have been studied in order to discover a potential target for novel anticancer therapies such as anaplastic lymphoma kinase (ALK) and reactive oxygen species 1 (ROS1). Increased interest in oncologic treatment research has resulted from the observation that ALK- and ROS1-associated tyrosine kinases show molecular analogies in some of their domains. This discovery led to the hypothesis that target therapy against ALK translocation could have efficacy also in ROS1-positive tumors. Crizotinib is an oral tyrosine kinase inhibitor that binds the ALK tyrosine kinase domain, blocking its function. We report the case of a woman with heavily pretreated metastatic lung adenocarcinoma harboring ROS1 positivity who experienced a prolonged and dramatic clinical benefit from crizotinib therapy. PMID- 25908038 TI - Hyponatremia in cancer patients. AB - Hyponatremia is the most frequent electrolyte disorder in hospitalized patients but also a well known poor prognostic factor in cancer patients. Syndrome of inappropriate secretion of antidiuretic hormone (SIADH) is often misdiagnosed by oncologist because of difficulties in the interpretation of laboratory tests. Etiology is heterogeneous but the predominant cause is represented by the unbalance between excessive presence of water and serum sodium deficiency. Ectopic production of arginine vasopressin (AVP) develops more frequently in small cell lung cancer but it is not so rare in other malignancies. Neurological impairment may range from subclinical to life-threating symptoms depending by the rate of serum sodium deficiency. Appropriate diagnosis is essential to set a proper therapy. When hyponatremia is caused by SIADH, hypertonic saline infusion is indicated for acute presentation whereas fluid restriction is preferred in case of chronic asymptomatic evolution. Other options include vaptans, vasopressin receptor antagonists, targeted specifically for the correction of euvolemic hyponatremia. The aim of this brief report is to provide concise and specific informations for the management of SIADH in oncology clinical practice. PMID- 25908040 TI - Single synchronous pulmonary metastasis from placental site trophoblastic tumor and teratoma. AB - Placental site trophoblastic tumor (PSTT) is a rare variant of gestational trophoblastic tumor (GTN), accounting for 1-2% of all GTNs. Primary testicular PSTTs are extremely rare. Thirty percent of patients with PSTT show multiple lung and brain metastases at the time of diagnosis. We present the first case of a synchronous single pulmonary trophoblastic placental tumor metastasis together with a teratoma and a mixed germinal tumor of the testis, treated with minimally invasive lung metastasectomy. PMID- 25908039 TI - Transformation to small cell lung cancer as an acquired resistance mechanism in EGFR-mutant lung adenocarcinoma: a case report of complete response to etoposide and cisplatin. AB - First-line epidermal growth factor receptor tyrosine kinase inhibitors (EGFR TKIs) for patients with advanced non-small cell lung cancer who were selected on the basis of EGFR mutations have improved the progression-free survival with acceptable toxicity compared to standard chemotherapy. However, acquired resistance to EGFR-TKIs has been identified as an important clinical problem. Transformation to small cell lung cancer (SCLC) is a rare mechanism of resistance to EGFR-TKI therapy. We describe the case of a 61-year-old man who presented transformation from adenocarcinoma to SCLC as the manifestation of acquired resistance after EGFR-TKI treatment. He underwent chemotherapy with etoposide and cisplatin and achieved a complete response. PMID- 25908041 TI - A case of Hodgkin lymphoma in a patient with a history of bone pain and an initial diagnosis of chronic osteomyelitis. AB - Hodgkin lymphoma (HL) is an uncommon monoclonal lymphoid malignancy consisting of 2 main entities: classical HL and nodular lymphocyte predominant. Hodgkin lymphoma usually presents with peripheral lymphadenopathies, while extranodal involvement is rare. Prevalent osseous presentation is rare and still misdiagnosed, despite improvements in diagnostic techniques. Here we report the case of a 30-year-old man with multifocal HL bone involvement initially misdiagnosed as chronic recurrent osteomyelitis. This case emphasizes the difficulties in the diagnosis of HL presenting with bone pain and with radiologic skeletal findings not specific for lymphoma. These patients often have diagnostic delays and misdiagnosis. Repeated investigations and clinical suspicion of unusual presentations may be helpful in order to establish a correct diagnosis and start an effective treatment in this highly curable disease. PMID- 25908042 TI - Stereotactic body radiotherapy with CyberKnife for cardiac malignancies. AB - AIMS AND BACKGROUND: Radiobiological and technical considerations have traditionally limited the role of radiation therapy in the context of primary and secondary cardiac malignancies. Stereotactic body radiotherapy (SBRT) is a promising modality for the delivery of focused high-dose radiation with ablative potential to complex targets such as small, deep-seated, moving lesions, allowing also for re-irradiation. METHODS: Between January 2013 and October 2013, 3 patients underwent SBRT for cardiac lesions: 2 patients had recurrent, previously irradiated cardiac angiosarcomas (PCA) and 1 patient had a cardiac metastasis from melanoma. They were treated with fiducial-guided robotic radiotherapy with CyberKnife. As for dose prescription, 24 Gy in 3 fractions (80% isodose) and 30 Gy in 5 fractions (80% isodose) were administered to the recurrent PCAs and cardiac metastasis, respectively. RESULTS: At 2 months after SBRT, cardiac MRI showed a partial response in the patients treated for recurrent PCA while the cardiac metastasis remained stable. In all cases, absence of local progression was subsequently confirmed by contrast-enhanced cardiac MRI after 6 months, without any evidence of treatment-related side effects. CONCLUSIONS: Fiducial guided SBRT proved to be feasible and effective in preventing local disease progression in selected patients with cardiac malignancies. PMID- 25908043 TI - Knowledge, opinions and attitudes of Italian mothers towards HPV vaccination and Pap test. AB - AIM: This study evaluated the knowledge and attitudes of Italian mothers - whose daughters had been vaccinated in 2012 - towards primary (anti-HPV vaccination) and secondary (Pap test screening) cervical cancer prevention, as well as sources of information and mother-daughter communication on health issues. METHODS: The survey - part of a multicenter study carried out in 4 Italian cities (Ferrara, Rome, Cassino and Palermo) - was conducted through self-administered questionnaires. The first univariate analysis evaluated differences between mothers of under-18s and over-18s relative to knowledge and attitudes on HPV vaccination and Pap test. The second univariate analysis evaluated differences between the 2 groups of mothers and possible geographical variations regarding the sources of information on HPV and Pap test. RESULTS: The sample proved knowledgeable about the correlation between HPV and cervical cancer (>85%) but less aware of other HPV-related diseases. HPV vaccination should be administered before first sexual intercourse according to mothers of over-18s, and to 14- to 17-year-olds according to mothers of under-18s. Up to 88% of mothers of under-18s and 80% of mothers of over-18s declared that the vaccine should be given free of charge. More mothers of under-18s consulted a general practitioner (GP) or gynecologist before deciding to vaccinate their daughters. Mothers of under-18s received information on HPV vaccination mainly from GPs and gynecologists, while mothers of over-18s were informed through TV and books/journals. Over 80% of the sample declared satisfaction with the information received from their gynecologist during the Pap test. CONCLUSIONS: The findings provide useful information for the development of effective public health interventions that may help improve acceptance of HPV vaccination among mothers. PMID- 25908044 TI - Outcomes of patients with squamous cell carcinoma of esophagus who did not receive surgical resection after neoadjuvant radiochemotherapy. AB - AIMS AND BACKGROUND: The primary objective was to assess the different reasons for refusal of surgical resection (SR) in patients with esophageal squamous cell cancer (ESCC), who were initially planned for neoadjuvant radiochemotherapy (N RCT) + SR, but SR was not performed after N-RCT. METHODS AND STUDY DESIGN: From 1988 to 2011, 311 patients with ESCC were treated with N-RCT in a tertiary referral center for esophageal diseases. Fifty-three patients were analyzed who received RCT with 40-45 Gy and concomitant chemotherapy in neoadjuvant intention, but in whom the treatment was stopped or switched to definitive RCT due to progression, patient decision, or new findings. RESULTS: The reasons for refusal of SR for these 53 patients were as follows: (1) patients' or physicians' preference for the planned treatment was changed during the N-RCT, such that RCT was continued to a curative dose without a break (group 1, n = 23, 44%); (2) patients were restaged after 4 weeks, and the tumor board decided to continue RCT because R0 resection was unlikely and/or patients were medically unfit (group 2, n = 15, 28%); (3) patients refused continuation of any treatment (group 3, n = 15, 28%). Refusal of SR was significantly more likely in patients with longitudinal tumor dimension >8 cm and those with an Eastern Cooperative Oncology Group performance status score of 2. Median follow-up time from the start of N RCT was 57 months (range 1-137 months). The survival rates at 2 and 5 years were 36 +/- 7% and 27 +/- 7%, respectively. Group 1 had significantly longer survival. CONCLUSIONS: The planned N-RCT+SR could not be completed in a considerable number of patients in a tertiary referral center. More strict selection criteria for multimodality treatment including SR could spare some of these patients an incomplete treatment and probably lead to increased utilization of definitive RCT. PMID- 25908045 TI - Ampulla of Vater carcinoma in real-world clinical practice: a case series. AB - AIMS AND BACKGROUND: The aim of this report was to describe the way in which a rare and niche disease like ampulla of Vater carcinoma (AVC) was treated in real world clinical practice. METHODS AND STUDY DESIGN: A retrospective analysis of consecutive patients with a diagnosis of AVC treated at our medical oncology unit between August 2004 and August 2013 was performed. RESULTS: We evaluated 8 consecutive patients with a median age of 60 years (range 56-84). At the last follow-up, 4 patients were alive without evidence of disease and 4 patients had died. The median follow-up time was 21.51 months (range 1-100.43), the median overall survival 23.19 months (range 7.07-102.2), and the median disease-free survival 18.26 months (range 0-102.2). Six patients underwent surgery, which consisted of pylorus-preserving pancreaticoduodenectomy, R0 in all cases. Tumor histology was adenocarcinoma in all patients. Two patients presented with locally advanced disease. Only 1 patient presented with metastases while 3 patients subsequently developed metastases. Two patients received chemotherapy for metastatic disease; in both cases disease progression was observed at the first disease evaluation. CONCLUSIONS: We can consider AVC as a pathology niche and pancreaticoduodenectomy as the effective treatment for these patients. PMID- 25908046 TI - PIK3CA mutations in small bowel adenocarcinoma. AB - AIMS AND BACKGROUND: PIK3CA mutations involving exons 9 and 20 are among the most common aberrations seen in human malignancies. The identification of PIK3CA mutations in small bowel adenocarcinoma (SBA) is sparse. There is some evidence that tumors with this mutation may be a good target for inhibitors of the PI3K pathway. CASE REPORT: We report an exon 9 (G1624A: E542K) hot spot mutation in a 69-year-old man with sporadic jejunal cancer (T3, N1). A systemic search was made for other reports using Medline/Embase along with Sangers Institute Cancer Genome Project database. We analyzed and describe this mutation in these patients, including one of ours. RESULTS AND CONCLUSION: A total of 8 tumor samples with confirmed somatic mutations out of a total of 86 samples were noted: rate 9.3% (95% confidence interval 4.5% to 17.5%). Overall, PIK3CA mutations were more common in duodenum (62.5%) and located most commonly on exon 9. The significance of PIK3CA mutation in SBA is unclear. Further studies on mutation analysis in larger cohorts with SBA are in order to identify and confirm relationships between these mutations and various clinical and pathologic variables such as age, lymph node status, distant metastasis, stage, and progression-free survival and association with other gene mutations. PMID- 25908047 TI - Investigation of prognostic factors affecting efficacy in carboplatin- and paclitaxel-based first-line chemotherapies for advanced non-small-cell lung cancer. AB - AIMS AND BACKGROUND: First-line chemotherapies for advanced non-small-cell lung cancer (NSCLC) are platinum-based regimens. An analysis of efficacy outcomes has not yet been systematically performed and fully evaluated using large patient cohorts in each of the platinum-based chemotherapies. The present meta-analysis aims to investigate prognostic factors affecting overall survival (OS), progression-free survival (PFS) or time to progression (TTP), and overall response rate (ORR) in carboplatin and paclitaxel-based first-line chemotherapies for advanced NSCLC. METHODS: We performed a literature search in PubMed for randomized phase II and III clinical trials in patients with NSCLC treated with carboplatin and paclitaxel as first-line chemotherapy published from January 2000 to December 2013 to investigate prognostic factors affecting OS, PFS or TTP, and ORR by linear regression analysis and logistic regression analysis. RESULTS: We identified 61 treatment arms in 53 phase II and III clinical trials for the analysis. Asian region was found to be a prognostic factor that affects longer OS in treatment with carboplatin and paclitaxel as first-line chemotherapy. In addition, we identified weekly administration schedule of paclitaxel, Asian region, and lower percentage of patients with adenocarcinoma as factors affecting higher ORR. CONCLUSIONS: Our findings of prognostic factors affecting ORR and OS in carboplatin and paclitaxel-based chemotherapies as first-line therapy should be considered in the interpretation of efficacy results in global phase II and III clinical trials. PMID- 25908048 TI - Loss of YAP protein in prostate cancer is associated with Gleason score increase. AB - AIMS AND BACKGROUND: To investigate the expression of YAP protein by immunohistochemistry in prostate cancer tissues and hyperplasia or normal prostate tissues adjacent to cancer, and establish the correlation of YAP expression with Gleason score. METHODS AND STUDY DESIGN: The expression of YAP protein was evaluated in tissue microarray by immunohistochemistry. The samples included 66 radical prostatectomy specimens with clinically detected prostate cancer and 54 hyperplasia or normal prostate tissues adjacent to cancer. RESULTS: YAP expression was present mainly in the nuclei of basal cells in both prostate cancer tissues and normal prostate or hyperplasia tissues adjacent to cancer. Cytoplasmic expression of YAP was weaker than nuclear expression in both malignant and nonmalignant luminal epithelial cells. YAP expression was decreased or lost in prostate cancer tissues; hyperplasia or normal prostate tissues adjacent to cancer exhibited stronger nuclear and cytoplasmic expression of YAP (p = 0.0001). Downregulation of YAP expression in prostate cancer samples correlated with Gleason score increase (p = 0.002). CONCLUSIONS: This immunohistochemical study expands our knowledge of the expression and localization of YAP in prostate cancer tissue and nonmalignant prostate tissue adjacent to cancer. YAP might function as a tumor suppressor in prostate cancer. Such information may provide the foundation for the treatment of preneoplastic and neoplastic lesions of the prostate. PMID- 25908049 TI - Multifraction radiotherapy for palliation of painful bone metastases: 20 Gy versus 30 Gy. AB - AIMS AND BACKGROUND: To compare 2 multifraction radiotherapy schedules in the palliation of painful bone metastases. METHODS AND STUDY DESIGN: We retrospectively analyzed clinical data of 105 patients with a total of 140 painful bone metastases who were treated with 20 Gy in 5 fractions or 30 Gy in 10 fractions. The primary tumors were breast (30%), lung (28%), and prostate (14%). The main sites of irradiation were spine (n = 79) and sacrum or pelvis (n = 39). Pain was graded by patients according to the pain numeric rating scale just before and 1 month after radiotherapy. Pain progression was defined as an increase >=2 on pain scale after an initial response. RESULTS: The overall response rate at 1 month was 88.6%. Overall response rate was 89.6% in the 20-Gy arm and 87.3% in the 30-Gy arm (p = 0.669). The rate of complete response was statistically better in patients treated with 30 Gy (p = 0.019). The mean reduction in pain was 3.2 in the 20-Gy group and 3.6 in the 30-Gy group. Pain progression was 6.5% and 1.6%, respectively. The incidence of acute toxicity was statistically significantly higher in the 30-Gy arm (23.8%) than in the 20-Gy arm (2.6%) (p = 0.001). One pathologic fracture of the irradiated bone was observed in the 30-Gy arm. Two lesions, one in each group, were re-irradiated for pain recurrence. Pain progression was found in 6.5% of the irradiated lesions in the 20-Gy arm and in 1.6% in the 30-Gy arm. CONCLUSIONS: In our series, both regimens achieved high rate of pain relief, although the group treated with higher total dose reported better complete response rate. The 30-Gy arm had a significantly higher rate of acute toxicity. PMID- 25908050 TI - Inferior mesenteric artery chemoembolization and chemotherapy for advanced rectal cancer: report of a clinical case. AB - Patients with advanced and incurable colorectal cancer have a very poor prognosis. Curative-intent resection was performed in 70%-90% of cases in reported series of colorectal cancer, sometimes after neoadjuvant chemotherapy and radiotherapy. The remaining 10%-30% of patients are treated with palliative intent, where treatment is aimed at relieving disease-related symptoms and improving quality of life. The provision of palliative care for these patients is complicated and outcomes are often disappointing. Although there are many available options including a variety of surgical and nonsurgical interventions, the best management remains controversial. Transarterial chemoembolization with irinotecan-loaded drug-eluting beads (DEBIRI) is an effective, minimally invasive procedure performed by interventional radiologists that allows intra-arterial drug delivery to stop vascular feeding and exert local cytotoxic effects. We here report on a patient treated with DEBIRI followed by systemic chemotherapy with the FOLFOX regimen for locally advanced, inoperable colorectal cancer. PMID- 25908051 TI - Management of oropharyngeal mycosis in head and neck cancer occurring during (chemo) radiotherapy: an Italian radio-oncologist survey. AB - AIMS AND BACKGROUND: Oropharyngeal candidiasis is a common disorder in head and neck cancer patients (HNCPs) who underwent (chemo)-radiotherapy. An Italian survey was conducted in order to investigate radiation oncologists' behavior in regard to diagnosis, prevention, and treatment of oral candidiasis. METHODS AND STUDY DESIGN: Between April and May 2013, a national online 18-question survey was sent to major Italian radiotherapy centers. RESULTS: All Italian regions were represented and 86 radiation oncologists were involved. Eighty-three percent of responders estimated that oropharyngeal candidiasis occurred in 30%-40% of their HNCPs. The majority of responders were able to recognize oral mycosis when it occurred in a localized pseudomembranous form and all responders agreed with the fact that oral candidiasis was always associated with mucositis. A prophylactic therapy was prescribed occasionally by 35% and routinely by 20% of responders. Forty percent prescribed an antifungal drug in the case of suspected mycotic infection and 20% waited for symptomatic clinical evidence before prescribing a therapy. In the presence of candidiasis, mainly topical fluconazole (59%) and itraconazole (36%) were prescribed. Concomitant chemo-radiotherapy was first identified as a risk factor for mycosis occurrence and development. Ninety-nine percent of responders believed that oral mycosis was associated with increased toxicity and 44% of them interrupted treatment due to candidiasis. CONCLUSIONS: A variety of approaches to oropharyngeal candidiasis emerges from this survey; further clinical trials are necessary to identify the best approach for oral mycosis prevention and treatment and to establish specific international guidelines for HNCPs. PMID- 25908052 TI - Perioperative medicine--the second round will need a change of tactics. PMID- 25908053 TI - RNA interference-aided knockdown of a putative saccharopine dehydrogenase leads to abnormal ecdysis in the brown planthopper, Nilaparvata lugens (Stal) (Hemiptera: Delphacidae). AB - The brown planthopper Nilaparvata lugens is a serious phloem-feeding pest of rice in China. The current study focuses on a saccharopine dehydrogenase (SDH) that catalyzes the penultimate reaction in biosynthesis of the amino acid lysine (Lys), which plays a role in insect growth and carnitine production (as a substrate). The protein, provisionally designated as NlylsSDH [a SDH derived from yeast-like symbiont (YLS) in N. lugens], had a higher transcript level in abdomens, compared with heads, wings, legs and thoraces, which agrees with YLS distribution in N. lugens. Ingestion of Nlylssdh targeted double-stranded RNA (dsNlylssdh) for 5, 10 and 15 days decreased the mRNA abundance in the hoppers by 47, 70 and 31%, respectively, comparing with those ingesting normal or dsegfp diets. Nlylssdh knockdown slightly decreased the body weights, significantly delayed the development of females, and killed approximately 30% of the nymphs. Moreover, some surviving adults showed two apparent phenotypic defects: wing deformation and nymphal cuticles remained on tips of the legs and abdomens. The brachypterours/macropterours and sex ratios (female/male) of the adults on the dsRNA diet were lowered compared with the adults on diets without dsRNA. These results suggest that Nlylssdh encodes a functional SDH protein. The adverse effect of Nlylssdh knockdown on N. lugens implies the importance of Lys in hopper development. This study provides a proof of concept example that Nlylssdh could serve as a possible dsRNA-based pesticide for planthopper control. PMID- 25908054 TI - Aleukaemic leukaemia cutis. PMID- 25908055 TI - 3p14 deletion is a rare contiguous gene syndrome: report of 2 new patients and an overview of 14 patients. AB - Interstitial deletions of chromosome 3p14p12 are a rare chromosome rearrangement. Twenty-six patients have been reported in the literature to date, however, a specific clinical phenotype has not yet been delineated. We describe three patients (two new) with overlapping chromosome 3p14p12 deletions and review the clinical and molecular data of 11 well-characterized, published cases. These patients had a number of features in common, such as short stature, failure to thrive, facial dysmorphism, congenital heart defects, urogenital abnormalities, neurological problems, hearing loss, and global developmental delay, suggesting that the interstitial chromosome 3p14p12 deletion gives rise to a multiple congenital anomaly syndrome. Some of the patients show clinical overlap with other complex syndromes such as CHARGE syndrome. Genotype-phenotype analysis revealed candidate genes for parts of the clinical features suggesting that the 3p14 deletion is a contiguous gene syndrome. PMID- 25908056 TI - Metabolic fates and effects of nitrite in brown trout under normoxic and hypoxic conditions: blood and tissue nitrite metabolism and interactions with branchial NOS, Na+/K+-ATPase and hsp70 expression. AB - Nitrite secures essential nitric oxide (NO) bioavailability in hypoxia at low endogenous concentrations, whereas it becomes toxic at high concentrations. We exposed brown trout to normoxic and hypoxic water in the absence and presence of added ambient nitrite to decipher the cellular metabolism and effects of nitrite at basal and elevated concentrations under different oxygen regimes. We also tested hypotheses concerning the influence of nitrite on branchial nitric oxide synthase (NOS), Na(+)/K(+)-ATPase (nka) and heat shock protein (hsp70) mRNA expression. Basal plasma and erythrocyte nitrite levels were higher in hypoxia than normoxia, suggesting increased NOS activity. Nitrite exposure strongly elevated nitrite concentrations in plasma, erythrocytes, heart tissue and white muscle, which was associated with an extensive metabolism of nitrite to nitrate and to iron-nitrosylated and S-nitrosated compounds. Nitrite uptake was slightly higher in hypoxia than normoxia, and high internal nitrite levels extensively converted blood hemoglobin to methemoglobin and nitrosylhemoglobin. Hypoxia increased inducible NOS (iNOS) mRNA levels in the gills, which was overruled by a strong inhibition of iNOS expression by nitrite in both normoxia and hypoxia, suggesting negative-feedback regulation of iNOS gene expression by nitrite. A similar inhibition was absent for neuronal NOS. Branchial NKA activity stayed unchanged, but mRNA levels of the nkaalpha1a subunit increased with hypoxia and nitrite, which may have countered an initial NKA inhibition. Nitrite also increased hsp70 gene expression, probably contributing to the cytoprotective effects of nitrite at low concentrations. Nitrite displays a concentration dependent switch between positive and negative effects similar to other signaling molecules. PMID- 25908057 TI - Scaling of left ventricle cardiomyocyte ultrastructure across development in the kangaroo Macropus fuliginosus. AB - The heart and left ventricle of the marsupial western grey kangaroo Macropus fuliginosus exhibit biphasic allometric growth, whereby a negative shift in the trajectory of cardiac growth occurs at pouch exit. In this study, we used transmission electron microscopy to examine the scaling of left ventricle cardiomyocyte ultrastructure across development in the western grey kangaroo over a 190-fold body mass range (0.355-67.5 kg). The volume-density (%) of myofibrils, mitochondria, sarcoplasmic reticuli and T-tubules increase significantly during in-pouch growth, such that the absolute volume (ml) of these organelles scales with body mass (Mb; kg) with steep hyperallometry: 1.41Mb (1.38), 0.64Mb (1.29), 0.066Mb (1.45) and 0.035Mb (1.87), respectively. Maturation of the left ventricle ultrastructure coincides with pouch vacation, as organelle volume-densities scale independent of body mass across post-pouch development, such that absolute organelle volumes scale in parallel and with relatively shallow hypoallometry: 4.65Mb (0.79), 1.75Mb (0.77), 0.21Mb (0.79) and 0.35Mb (0.79), respectively. The steep hyperallometry of organelle volumes and volume-densities across in-pouch growth is consistent with the improved contractile performance of isolated cardiac muscle during fetal development in placental mammals, and is probably critical in augmenting cardiac output to levels necessary for endothermy and independent locomotion in the young kangaroo as it prepares for pouch exit. The shallow hypoallometry of organelle volumes during post-pouch growth suggests a decrease in relative cardiac requirements as body mass increases in free-roaming kangaroos, which is possibly because the energy required for hopping is independent of speed, and the capacity for energy storage during hopping could increase as the kangaroo grows. PMID- 25908058 TI - Oxidative stress as an indicator of the costs of reproduction among free-ranging rhesus macaques. AB - Sex differences in longevity may reflect sex-specific costs of intra-sexual competition and reproductive effort. As male rhesus macaques experience greater intrasexual competition and die younger, we predicted that males would experience greater oxidative stress than females and that oxidative stress would reflect sex specific measures of reproductive effort. Males, relative to females, had higher concentrations of 8-OHdG and malondialdehyde, which are markers of DNA oxidative damage and lipid peroxidation, respectively. Older macaques had lower 8-OHdG levels than younger ones, suggesting that oxidative stress decreases in parallel with known age-related declines in reproductive investment. Among males, a recent period of social instability affected oxidative status: males who attacked others at higher rates had higher 8-OHdG levels. Multiparous lactating females with daughters had higher 8-OHdG levels than those with sons. No differences in antioxidant capacity were found. These results lend initial support for the use of oxidative stress markers to assess trade-offs between reproductive effort and somatic maintenance in primates. PMID- 25908059 TI - Dynamic changes in global and gene-specific DNA methylation during hibernation in adult thirteen-lined ground squirrels, Ictidomys tridecemlineatus. AB - Hibernating mammals conserve energy in the winter by undergoing prolonged bouts of torpor, interspersed with brief arousals back to euthermia. These bouts are accompanied by a suite of reversible physiological and biochemical changes; however, much remains to be discovered about the molecular mechanisms involved. Given the seasonal nature of hibernation, it stands to reason that underlying plastic epigenetic mechanisms should exist. One such form of epigenomic regulation involves the reversible modification of cytosine bases in DNA by methylation. DNA methylation is well known to be a mechanism that confers upon DNA its cellular identity during differentiation in response to innate developmental cues. However, it has recently been hypothesized that DNA methylation also acts as a mechanism for adapting genome function to changing external environmental and experiential signals over different time scales, including during adulthood. Here, we tested the hypothesis that DNA methylation is altered during hibernation in adult wild animals. This study evaluated global changes in DNA methylation in response to hibernation in the liver and skeletal muscle of thirteen-lined ground squirrels along with changes in expression of DNA methyltransferases (DNMT1/3B) and methyl binding domain proteins (MBDs). A reduction in global DNA methylation occurred in muscle during torpor phases whereas significant changes in DNMTs and MBDs were seen in both tissues. We also report dynamic changes in DNA methylation in the promoter of the myocyte enhancer factor 2C (mef2c) gene, a candidate regulator of metabolism in skeletal muscle. Taken together, these data show that genomic DNA methylation is dynamic across torpor-arousal bouts during winter hibernation, consistent with a role for this regulatory mechanism in contributing to the hibernation phenotype. PMID- 25908060 TI - Internal carbonic anhydrase activity in the tissue of scleractinian corals is sufficient to support proposed roles in photosynthesis and calcification. AB - Reef-building corals import inorganic carbon (Ci) to build their calcium carbonate skeletons and to support photosynthesis by the symbiotic algae that reside in their tissue. The internal pathways that deliver Ci for both photosynthesis and calcification are known to involve the enzyme carbonic anhydrase (CA), which interconverts CO2 and HCO3 (-). We have developed a method for absolute quantification of internal CA (iCA) activity in coral tissue based on the rate of (18)O-removal from labeled Ci. The method was applied to three Caribbean corals (Orbicella faveolata, Porites astreoides and Siderastrea radians) and showed that these species have similar iCA activities per unit surface area, but that S. radians has ~10-fold higher iCA activity per unit tissue volume. A model of coral Ci processing shows that the measured iCA activity is sufficient to support the proposed roles for iCA in Ci transport for photosynthesis and calcification. This is the case even when iCA activity is homogeneously distributed throughout the coral, but the model indicates that it would be advantageous to concentrate iCA in the spaces where calcification (the calcifying fluid) and photosynthesis (the oral endoderm) take place. We argue that because the rates of photosynthesis and calcification per unit surface area are similar among the corals studied here, the areal iCA activity used to deliver Ci for these reactions should also be similar. The elevated iCA activity per unit volume of S. radians compared with that of the other species is probably due to the thinner effective tissue thickness in this species. PMID- 25908061 TI - Sexual differences in exploration behavior in Xenopus tropicalis? AB - The two sexes of a species often differ in many ways. How sexes differ depends on the selective context, with females often investing more in reproductive output and males in territory defense and resource acquisition. This also implies that behavioral strategies may differ between the two sexes, allowing them to optimize their fitness in a given ecological context. Here, we investigated whether males and females differ in their exploration behavior in an aquatic frog (Xenopus tropicalis). Moreover, we explored whether females show different behavioral strategies in the exploration of a novel environment as has been demonstrated previously for males of the same species. Our results show significant sex differences, with males exploring their environment more than females. Yet, similar to males, female exploratory behavior varied significantly among individuals and broadly fell into three categories: shy, intermediate and bold. Moreover, like in males, behavioral strategies are decoupled from morphology and performance. Our results suggest that females are more sedentary than males, with males engaging in greater risk taking by exploring novel environments more. Male and female behaviors could, however, be classified into similar groups, with some individuals being bolder than others and displaying more exploration behavior. The decoupling of morphology and performance from behavior appears to be a general feature in the species and may allow selection to act on both types of traits independently. PMID- 25908062 TI - Relationship between HPV 16, 18, 31, 33, 45 DNA detection and quantitation and E6/E7 mRNA detection among a series of cervical specimens with various degrees of histological lesions. AB - Better understanding of the correlation between high-risk HPV DNA testing, viral load quantitation, and E6/E7 mRNA detection is required. The aim of this study was to assess the relationship between these markers and the severity of cervical lesions. One-hundred and fifty one directed cervical specimens were analysed (normal, cervical intraepithelial neoplasia, and cancer). HPV types 16, 18, 31, 33, and 45 DNA detection and quantititation and E6/E7 mRNA detection were performed. DNA was detected in 87 (57.6%) samples and increased from 0% (normal) to 93.9% (cancer). E6/E7 mRNA was detected in 65 (43%) samples and increased with the severity of the lesions from 0% (normal) to 78.8% (26/33) (cancers) (P < 0.001). HPV DNA and E6/E7 mRNA detection were compared in the 141 samples harbouring HPV16, 18, 31, 33, or 45 infection: 45.4% (64/141) of specimens were DNA-/mRNA-, 46% (65/141) were DNA + /mRNA+ and 8.5% (12/141) were DNA + /mRNA-. The proportion of DNA + /mRNA+ specimens increased with the severity of the lesions (P < 0.001). All normal cervix specimens were DNA-/mRNA-. Among grade 2 cervical intraepithelial neoplasia, prevalence of DNA was higher than that of mRNA: 41.6% (5/12) versus 25% (3/12), whereas it was 79.3% (46/58) versus 62% (36/58) among grade 3 cervical intraepithelial neoplasia. Full concordance was observed in cancers as all the 26 DNA+ specimens were mRNA +. Median overall HPV load was higher in DNA + /mRNA+ than in DNA + /mRNA- specimens (1.41 * 10(6) vs. 9.1 * 10(2) copies per million cells, P < 0.001). Both E6/E7 mRNA detection and concordant DNA + /mRNA+ detection increases with the severity of the lesions and with the HPV DNA load. PMID- 25908063 TI - Reply from authors to the letter to the editor that reference to paper "Prevalence of renal stones in Andalusian population: Results of PreLiRenA study". PMID- 25908064 TI - Safety and Efficacy of the Totally Subcutaneous Implantable Defibrillator: 2-Year Results From a Pooled Analysis of the IDE Study and EFFORTLESS Registry. AB - BACKGROUND: The entirely subcutaneous implantable cardioverter-defibrillator (S ICD) is the first implantable defibrillator that avoids placing electrodes in or around the heart. Two large prospective studies (IDE [S-ICD System IDE Clinical Investigation] and EFFORTLESS [Boston Scientific Post Market S-ICD Registry]) have reported 6-month to 1-year data on the S-ICD. OBJECTIVES: The objective of this study was to evaluate the safety and efficacy of the S-ICD in a large diverse population. METHODS: Data from the IDE and EFFORTLESS studies were pooled. Shocks were independently adjudicated, and complications were measured with a standardized classification scheme. Enrollment date quartiles were used to assess event rates over time. RESULTS: Eight hundred eighty-two patients who underwent implantation were followed for 651+/-345 days. Spontaneous ventricular tachyarrhythmia (VT)/ventricular fibrillation (VF) events (n=111) were treated in 59 patients; 100 (90.1%) events were terminated with 1 shock, and 109 events (98.2%) were terminated within the 5 available shocks. The estimated 3-year inappropriate shock rate was 13.1%. Estimated 3-year, all-cause mortality was 4.7% (95% confidence interval: 0.9% to 8.5%), with 26 deaths (2.9%). Device related complications occurred in 11.1% of patients at 3 years. There were no electrode failures, and no S-ICD-related endocarditis or bacteremia occurred. Three devices (0.3%) were replaced for right ventricular pacing. The 6-month complication rate decreased by quartile of enrollment (Q1: 8.9%; Q4: 5.5%), and there was a trend toward a reduction in inappropriate shocks (Q1: 6.9% Q4: 4.5%). CONCLUSIONS: The S-ICD demonstrated high efficacy for VT/VF. Complications and inappropriate shock rates were reduced consistently with strategic programming and as operator experience increased. These data provide further evidence for the safety and efficacy of the S-ICD. (Boston Scientific Post Market S-ICD Registry [EFFORTLESS]; NCT01085435; S-ICD(r) System IDE Clinical Study; NCT01064076). PMID- 25908065 TI - The subcutaneous implantable cardioverter-defibrillator: when less is more. PMID- 25908066 TI - Duration of Triple Therapy in Patients Requiring Oral Anticoagulation After Drug Eluting Stent Implantation: The ISAR-TRIPLE Trial. AB - BACKGROUND: Patients receiving oral anticoagulation (OAC) who undergo drug eluting stent (DES) implantation require additional dual antiplatelet therapy with aspirin and clopidogrel. Such triple therapy confers an elevated bleeding risk, and its optimal duration is not known. OBJECTIVES: The goal of this study was to evaluate whether shortening the duration of clopidogrel therapy from 6 months to 6 weeks after DES implantation was associated with a superior net clinical outcome in patients receiving concomitant aspirin and OAC. METHODS: In this randomized, open-label trial, we enrolled patients receiving OAC who underwent DES implantation at 3 European centers between September 2008 and December 2013. A total of 614 patients receiving concomitant aspirin and OAC were randomized to either 6-week clopidogrel therapy (n=307) or 6-month clopidogrel therapy (n=307). The primary endpoint was a composite of death, myocardial infarction (MI), definite stent thrombosis, stroke, or Thrombolysis In Myocardial Infarction (TIMI) major bleeding at 9 months. RESULTS: The primary endpoint occurred in 30 patients (9.8%) in the 6-week group compared with 27 patients (8.8%) in the 6-month group (hazard ratio [HR]: 1.14; 95% CI: 0.68 to 1.91; p=0.63). There were no significant differences for the secondary combined ischemic endpoint of cardiac death, MI, definite stent thrombosis, and ischemic stroke (12 [4.0%] vs. 13 [4.3%]; HR: 0.93; 95% CI: 0.43 to 2.05; p=0.87) or the secondary bleeding endpoint of TIMI major bleeding (16 [5.3%] vs. 12 [4.0%]; HR: 1.35; 95% CI: 0.64 to 2.84; p=0.44). CONCLUSIONS: Six weeks of triple therapy was not superior to 6 months with respect to net clinical outcomes. These results suggest that physicians should weigh the trade-off between ischemic and bleeding risk when choosing the shorter or longer duration of triple therapy. (Triple Therapy in Patients on Oral Anticoagulation After Drug Eluting Stent Implantation [ISAR-TRIPLE]; NCT00776633). PMID- 25908067 TI - When Is a Double Better Than a TRIPLE?: Stenting in Patients With Atrial Fibrillation. PMID- 25908068 TI - Cholesterol guidelines do not endorse "one size fits all": the strategy begins with a discussion. PMID- 25908069 TI - Long-term prognosis in patients with type 1 and 2 diabetes mellitus after coronary artery bypass grafting. AB - BACKGROUND: Patients with diabetes mellitus (DM) have an increased risk of adverse outcomes after coronary artery bypass grafting (CABG). Previous studies have reported prognosis in relation to treatment with or without insulin, and not to the type of diabetes. OBJECTIVES: This study investigated long-term survival in patients with type 1 DM (T1DM) and type 2 DM (T2DM) following CABG. METHODS: We included all patients from the SWEDEHEART (Swedish Web-System for Enhancement and Development of Evidence-Based Care in Heart Disease Evaluated According to Recommended Therapies) register who underwent primary isolated CABG in Sweden during 2003 through 2013. We identified patients with T1DM or T2DM in the Swedish National Diabetes Register. We calculated hazard ratios (HRs) with 95% confidence intervals (CIs) for all-cause mortality in patients with T1DM or T2DM. RESULTS: In total, 39,235 patients were included, of whom 725 (1.8%) had T1DM and 8,208 (21%) had T2DM. Patients with TDM1 were younger (59 vs. 67 years), had reduced kidney function (31% vs. 24%), and had peripheral vascular disease (21% vs. 11%) more often than patients with TDM2 or no diabetes. During a mean follow-up of 5.9+/-3.2 years (230,085 person-years), 6,765 (17%) patients died. Among patients with T1DM, 152 (21%) died, and among patients with T2DM, 1,549 (19%) died. Adjusted hazard ratio (95% confidence interval) for death in patients with T1DM and T2DM, compared with patients without diabetes, were 2.04 (1.72 to 2.42), and 1.11 (1.05 to 1.18), respectively. CONCLUSIONS: Patients with T1DM had more than double the long-term risk of death after CABG compared with patients without diabetes. The long-term risk of death in patients with T2DM was only slightly increased. PMID- 25908070 TI - Impact of Type 1 and 2 Diabetes Mellitus on Long-Term Outcomes After CABG. PMID- 25908071 TI - Implications of Introducing High-Sensitivity Cardiac Troponin T Into Clinical Practice: Data From the SWEDEHEART Registry. AB - BACKGROUND: Cardiac troponin is the preferred biomarker for diagnosing myocardial infarction (MI). OBJECTIVES: The aim of this study was to examine the implications of introducing high-sensitivity cardiac troponin T (hs-cTnT) into clinical practice and to define at what hs-cTnT level risk starts to increase. METHODS: We analyzed data from 48,594 patients admitted because of symptoms suggesting an acute coronary syndrome and who were entered into a large national registry. Patients were divided into Group 1, those with hs-cTnT<6 ng/l; Group 2, those with hs-cTnT 6 to 13 ng/l; Group 3, those with hs-cTnT 14 to 49 ng/l (i.e., a group in which most patients would have had a negative cardiac troponin T with older assays); and Group 4, those with hs-cTnT>=50 ng/l. RESULTS: There were 5,790 (11.9%), 6,491 (13.4%), 10,476 (21.6%), and 25,837 (53.2%) patients in Groups 1, 2, 3, and 4, respectively. In Groups 1 to 4, the proportions with MI were 2.2%, 2.6%, 18.2%, and 81.2%. There was a stepwise increase in the proportion of patients with significant coronary stenoses, left ventricular systolic dysfunction, and death during follow-up. When dividing patients into 20 groups according to hs-cTnT level, the adjusted mortality started to increase at an hs-cTnT level of 14 ng/l. CONCLUSIONS: Introducing hs-cTnT into clinical practice has led to the recognition of a large proportion of patients with minor cardiac troponin increases (14 to 49 ng/l), the majority of whom do not have MI. Although a heterogeneous group, these patients remain at high risk, and the adjusted mortality rate started to increase at the level of the 99th percentile in healthy controls. PMID- 25908072 TI - What to expect when measuring high-sensitivity troponin: practical advice for clinicians. PMID- 25908075 TI - A challenge: let us strive to be #2. PMID- 25908074 TI - Endogenous Fibrinolysis: An Important Mediator of Thrombus Formation and Cardiovascular Risk. AB - Most acute cardiovascular events are attributable to arterial thrombosis. Plaque rupture or erosion stimulates platelet activation, aggregation, and thrombosis, whilst simultaneously activating enzymatic processes that mediate endogenous fibrinolysis to physiologically maintain vessel patency. Interplay between these pathways determines clinical outcome. If proaggregatory factors predominate, the thrombus may propagate, leading to vessel occlusion. However, if balanced by a healthy fibrinolytic system, thrombosis may not occur or cause lasting occlusion. Despite abundant evidence for the fibrinolytic system regulating thrombosis, it has been overlooked compared with platelet reactivity, partly due to a lack of techniques to measure it. We evaluate evidence for endogenous fibrinolysis in arterial thrombosis and review techniques to assess it, including biomarkers and global assays, such as thromboelastography and the Global Thrombosis Test. Global assays, simultaneously assessing proaggregatory and fibrinolytic pathways, could play a role in risk stratification and in identifying impaired fibrinolysis as a potential target for pharmacological modulation. PMID- 25908073 TI - Patient selection in heart failure with preserved ejection fraction clinical trials. AB - Recent clinical trials in patients with heart failure with preserved ejection fraction (HFpEF) have provided important insights into participant selection strategies. Historically, HFpEF trials have included patients with relatively preserved left ventricular ejection fraction ranging from 40% to 55% and a clinical history of heart failure. Contemporary HFpEF trials have also incorporated inclusion criteria such as hospitalization for HFpEF, altered functional capacity, cardiac structural and functional abnormalities, and abnormalities in neurohormonal status (e.g., elevated natriuretic peptide levels). Careful analyses of the effect of these patient selection criteria on outcomes in prior trials provide valuable lessons for future trial design. We review recent and ongoing HFpEF clinical trials from a patient selection perspective and appraise trial patient selection methodologies in relation to outcomes. This review reflects discussions between clinicians, scientists, trialists, regulators, and regulatory representatives at the 10th Global CardioVascular Clinical Trialists Forum in Paris, France, on December 6, 2013. PMID- 25908076 TI - Challenges for research publications: what is journal quality and how to measure it? PMID- 25908077 TI - Transitioning the External Applicant Into a Cardiology Training Program. PMID- 25908078 TI - Depression 1 Year After CABG Is Predicted by Acute Inflammatory Responses. PMID- 25908079 TI - Association between journal citation distribution and impact factor: a novel application of the Gini coefficient. PMID- 25908080 TI - Relationship between vulnerable plaque and coronary artery stenosis. PMID- 25908081 TI - Elevated serum fibrinogen: an independent link between diabetes mellitus, impaired on-clopidogrel platelet inhibition, and major adverse cardiac events after percutaneous coronary intervention. PMID- 25908082 TI - Reply: elevated serum fibrinogen: an independent link between diabetes mellitus, impaired on-clopidogrel platelet inhibition, and major adverse cardiac events after percutaneous coronary intervention. PMID- 25908083 TI - Is CABG Superior to DES for Repeat Revascularization in Patients With Isolated Proximal LAD Disease? PMID- 25908084 TI - Has Prasugrel Been Compared Correctly With Clopidogrel in Non-ST-Segment Elevation Acute Coronary Syndrome? PMID- 25908085 TI - Reply: Is CABG Superior to DES for Repeat Revascularization in Patients With Isolated Proximal LAD Disease? PMID- 25908086 TI - Reply: Has Prasugrel Been Compared Correctly With Clopidogrel in Non-ST-Segment Elevation Acute Coronary Syndrome? PMID- 25908087 TI - Not All NSTEMIs Are Created Equal. PMID- 25908088 TI - Reply: Not All NSTEMIs Are Created Equal. PMID- 25908089 TI - Stenting versus medical treatment in patients with symptomatic vertebral artery stenosis: a randomised open-label phase 2 trial. AB - BACKGROUND: Patients with a recent vertebrobasilar transient ischaemic attack or ischaemic stroke and vertebral artery stenosis of at least 50% have a high risk of future vertebrobasilar stroke. Stenting of vertebral artery stenosis is promising, but of uncertain benefit. We investigated the safety and feasibility of stenting of symptomatic vertebral artery stenosis of at least 50%, and assessed the rate of vascular events in the vertebrobasilar supply territory to inform the design of a phase 3 trial. METHODS: Between Jan 22, 2008, and April 8, 2013, patients with a recent transient ischaemic attack or minor stroke associated with an intracranial or extracranial vertebral artery stenosis of at least 50% were enrolled from seven hospitals in the Netherlands in a phase 2 open label trial with masked assessment of outcome. Patients were randomly allocated in a 1:1 ratio to stenting plus best medical treatment or best medical treatment alone by the local investigators using a web-based randomisation system. The primary outcome was the composite of vascular death, myocardial infarction, or any stroke within 30 days after the start of treatment. The secondary outcomes were stroke in the supply territory of the symptomatic vertebral artery during follow-up, the composite outcome during follow-up, and the degree of stenosis in the symptomatic vertebral artery at 12 months. The trial is registered, number ISRCTN29597900. FINDINGS: The trial was stopped after inclusion of 115 patients because of new regulatory requirements, including the use of a few prespecified stent types and external monitoring, for which no funding was available. 57 patients were assigned to stenting and 58 to medical treatment alone. Three patients in the stenting group had vascular death, myocardial infarction, or any stroke within 30 days after the start of treatment (5%, 95% CI 0-11) versus one patient in the medical treatment group (2%, 0-5). During a median follow-up of 3 years (IQR 1.3-4.1), seven (12%, 95% CI 6-24) patients in the stenting group and four (7%, 2-17) in the medical treatment group had a stroke in the territory of the symptomatic vertebral artery; 11 (19%) patients in the stenting group and ten (17%) in the medical treatment group had vascular death, myocardial infarction, or any stroke. The small size of the vertebral artery and stent artifacts did not allow exact grading of restenosis on CT angiography. During the complete period of follow-up, there were 60 serious adverse events (eight strokes) in the stenting group and 56 (seven strokes) in the medical treatment alone group. INTERPRETATION: Stenting of symptomatic vertebral artery stenosis is associated with a major periprocedural vascular complication in about one in 20 patients. In the population we studied, the risk of recurrent vertebrobasilar stroke under best medical treatment alone was low, questioning the need for and feasibility of a phase 3 trial. FUNDING: Dutch Heart Foundation. PMID- 25908090 TI - Status epilepticus in adults. AB - Status epilepticus is a common neurological emergency with considerable associated health-care costs, morbidity, and mortality. The definition of status epilepticus as a prolonged seizure or a series of seizures with incomplete return to baseline is under reconsideration in an effort to establish a more practical definition to guide management. Clinical research has focused on early seizure termination in the prehospital setting. The approach of early escalation to anaesthetic agents for refractory generalised convulsive status epilepticus, rather than additional trials of second-line anti-epileptic drugs, to avoid neuronal injury and pharmaco-resistance associated with prolonged seizures is gaining momentum. Status epilepticus is also increasingly identified in the inpatient setting as the use of extended electroencephalography monitoring becomes more commonplace. Substantial further research to enable early identification of status epilepticus and efficacy of anti-epileptic drugs will be important to improve outcomes. PMID- 25908091 TI - Yet again no benefit of stenting over medical therapy. PMID- 25908092 TI - Globalization of continuing professional development by journal clubs via microblogging: a systematic review. AB - BACKGROUND: Journal clubs are an essential tool in promoting clinical evidence based medical education to all medical and allied health professionals. Twitter represents a public, microblogging forum that can facilitate traditional journal club requirements, while also reaching a global audience, and participation for discussion with study authors and colleagues. OBJECTIVE: The aim of the current study was to evaluate the current state of social media-facilitated journal clubs, specifically Twitter, as an example of continuing professional development. METHODS: A systematic review of literature databases (Medline, Embase, CINAHL, Web of Science, ERIC via ProQuest) was performed according to Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines. A systematic search of Twitter, the followers of identified journal clubs, and Symplur was also performed. Demographic and monthly tweet data were extracted from Twitter and Symplur. All manuscripts related to Twitter-based journal clubs were included. Statistical analyses were performed in MS Excel and STATA. RESULTS: From a total of 469 citations, 11 manuscripts were included and referred to five Twitter-based journal clubs (#ALiEMJC, #BlueJC, #ebnjc, #urojc, #meded). A Twitter-based journal club search yielded 34 potential hashtags/accounts, of which 24 were included in the final analysis. The median duration of activity was 11.75 (interquartile range [IQR] 19.9, SD 10.9) months, with 7 now inactive. The median number of followers and participants was 374 (IQR 574) and 157 (IQR 272), respectively. An overall increasing establishment of active Twitter-based journal clubs was observed, resulting in an exponential increase in total cumulative tweets (R(2)=.98), and tweets per month (R(2)=.72). Cumulative tweets for specific journal clubs increased linearly, with @ADC_JC, @EBNursingBMJ, @igsjc, @iurojc, and @NephJC, and showing greatest rate of change, as well as total impressions per month since establishment. An average of two tweets per month was estimated for the majority of participants, while the "Top 10" tweeters for @iurojc showed a significantly lower contribution to overall tweets for each month (P<.005). A linearly increasing impression:tweet ratio was observed for the top five journal clubs. CONCLUSIONS: Twitter-based journal clubs are free, time-efficient, and publicly accessible means to facilitate international discussions regarding clinically important evidence-based research. PMID- 25908093 TI - Immunohistochemical expression of sulfhydryl oxidase (QSOX1) in pediatric medulloblastomas. AB - BACKGROUND: Medulloblastoma is a malignant, invasive embryonal tumor of the cerebellum and accounts for 20% of intracranial tumors in children. QSOX1, whose functions include formation of disulphide bridges, which are needed for correct protein folding and stability, formation of the extracellular matrix, regulation of the redox status and cell cycle control, appears to be involved in apoptosis in pathological states such as cancer. Thus, the aim of this study was to investigate the immunohistochemical expression of QSOX1 in medulloblastomas and nonneoplastic cerebellum. METHODS: Histology blocks of pediatric medulloblastomas were separated and two representative areas of the tumors and non-neoplastic cerebellum samples were used to construct tissue microarrays (TMAs) that were stained with an anti-QSOX1 antibody, and the slides were read using image analysis software. RESULTS: QSOX1 immunoexpression was observed in the non neoplastic cerebellum samples and the medulloblastoma samples. There was no statistically significant relationship between QSOX1 immunopositivity in the medulloblastoma samples and the clinical and pathological variables. CONCLUSIONS: Although QSOX1 did not prove useful for stratifying patients into risk groups, tumor cells and the fibrillar extracellular matrix were positive for this marker, indicating that this enzyme may be involved in the pathogenesis of medulloblastoma. VIRTUAL SLIDES: The virtual slide(s) for this article can be found here: http://www.diagnosticpathology.diagnomx.eu/vs/1822040654139436. PMID- 25908094 TI - Municipal solid waste management health risk assessment from air emissions for China by applying life cycle analysis. AB - This study is to quantify and objectively evaluate the extent of environmental health risks from three waste treatment options suggested by the national municipal solid waste management enhancing strategy (No [2011] 9 of the State Council, promulgated on 19 April 2011), which includes sanitary landfill, waste to-energy incineration and compost, together with the material recovery facility through a case study in Zhangqiu City of China. It addresses potential chronic health risks from air emissions to residential receptors in the impacted area. It combines field survey, analogue survey, design documents and life cycle inventory methods in defining the source strength of chemicals of potential concern. The modelling of life cycle inventory and air dispersion is via integrated waste management(IWM)-2 and Screening Air Dispersion Model (Version 3.0) (SCREEN3). The health risk assessment is in accordance with United States Environmental Protection Agency guidance Risk Assessment Guidance for Superfund (RAGS), Volume I: Human Health Evaluation Manual (Part F, Supplemental Guidance for Inhalation Risk Assessment). The exposure concentration is based on long-term exposure to the maximum ground level contaminant in air under the 'reasonable worst situation' emissions and then directly compared with reference for concentration and unit risk factor/cancer slope factor derived from the national air quality standard (for a conventional pollutant) and toxicological studies (for a specific pollutant). Results from this study suggest that the option of compost with material recovery facility treatment may pose less negative health impacts than other options; the sensitivity analysis shows that the landfill integrated waste management collection rate has a great influence on the impact results. Further investigation is needed to validate or challenge the findings of this study. PMID- 25908095 TI - REGgamma is critical for skin carcinogenesis by modulating the Wnt/beta-catenin pathway. AB - Here we report that mice deficient for the proteasome activator, REGgamma, exhibit a marked resistance to TPA (12-O-tetradecanoyl-phorbol-13-acetate) induced keratinocyte proliferation, epidermal hyperplasia and onset of papillomas compared with wild-type counterparts. Interestingly, a massive increase of REGgamma in skin tissues or cells resulting from TPA induces activation of p38 mitogen-activated protein kinase (MAPK/p38). Blocking p38 MAPK activation prevents REGgamma elevation in HaCaT cells with TPA treatment. AP-1, the downstream effector of MAPK/p38, directly binds to the REGgamma promoter and activates its transcription in response to TPA stimulation. Furthermore, we find that REGgamma activates Wnt/beta-catenin signalling by degrading GSK-3beta in vitro and in cells, increasing levels of CyclinD1 and c-Myc, the downstream targets of beta-catenin. Conversely, MAPK/p38 inactivation or REGgamma deletion prevents the increase of cyclinD1 and c-Myc by TPA. This study demonstrates that REGgamma acts in skin tumorigenesis mediating MAPK/p38 activation of the Wnt/beta catenin pathway. PMID- 25908096 TI - Iron acquisition and oxidative stress response in aspergillus fumigatus. AB - BACKGROUND: Aspergillus fumigatus is a ubiquitous airborne fungal pathogen that presents a life-threatening health risk to individuals with weakened immune systems. A. fumigatus pathogenicity depends on its ability to acquire iron from the host and to resist host-generated oxidative stress. Gaining a deeper understanding of the molecular mechanisms governing A. fumigatus iron acquisition and oxidative stress response may ultimately help to improve the diagnosis and treatment of invasive aspergillus infections. RESULTS: This study follows a systems biology approach to investigate how adaptive behaviors emerge from molecular interactions underlying A. fumigatus iron regulation and oxidative stress response. We construct a Boolean network model from known interactions and simulate how changes in environmental iron and superoxide levels affect network dynamics. We propose rules for linking long term model behavior to qualitative estimates of cell growth and cell death. These rules are used to predict phenotypes of gene deletion strains. The model is validated on the basis of its ability to reproduce literature data not used in model generation. CONCLUSIONS: The model reproduces gene expression patterns in experimental time course data when A. fumigatus is switched from a low iron to a high iron environment. In addition, the model is able to accurately represent the phenotypes of many knockout strains under varying iron and superoxide conditions. Model simulations support the hypothesis that intracellular iron regulates A. fumigatus transcription factors, SreA and HapX, by a post-translational, rather than transcriptional, mechanism. Finally, the model predicts that blocking siderophore mediated iron uptake reduces resistance to oxidative stress. This indicates that combined targeting of siderophore-mediated iron uptake and the oxidative stress response network may act synergistically to increase fungal cell killing. PMID- 25908098 TI - A study of T1 relaxation time as a measure of liver fibrosis and the influence of confounding histological factors. AB - Liver biopsy is the standard test for the assessment of fibrosis in liver tissue of patients with chronic liver disease. Recent studies have used a non-invasive measure of T1 relaxation time to estimate the degree of fibrosis in a single slice of the liver. Here, we extend this work to measure T1 of the whole liver and investigate the effects of additional histological factors such as steatosis, inflammation and iron accumulation on the relationship between liver T1 and fibrosis. We prospectively enrolled patients who had previously undergone liver biopsy to have MR scans. A non-breath-holding, fast scanning protocol was used to acquire MR relaxation time data (T1 and T2*), and blood serum was used to determine the enhanced liver fibrosis (ELF) score. Areas under the receiver operator curves (AUROCs) for T1 to detect advanced fibrosis and cirrhosis were derived in a training cohort and then validated in a second cohort. Combining the cohorts, the influence of various histology factors on liver T1 relaxation time was investigated. The AUROCs (95% confidence interval (CI)) for detecting advanced fibrosis (F >= 3) and cirrhosis (F = 4) for the training cohort were 0.81 (0.65-0.96) and 0.92 (0.81-1.0) respectively (p < 0.01). Inflammation and iron accumulation were shown to significantly alter T1 in opposing directions in the absence of advanced fibrosis; inflammation increasing T1 and iron decreasing T1. A decision tree model was developed to allow the assessment of early liver disease based on relaxation times and ELF, and to screen for the need for biopsy. T1 relaxation time increases with advanced fibrosis in liver patients, but is also influenced by iron accumulation and inflammation. Together with ELF, relaxation time measures provide a marker to stratify patients with suspected liver disease for biopsy. PMID- 25908097 TI - Melatonin modulates the fetal cardiovascular defense response to acute hypoxia. AB - Experimental studies in animal models supporting protective effects on the fetus of melatonin in adverse pregnancy have prompted clinical trials in human pregnancy complicated by fetal growth restriction. However, the effects of melatonin on the fetal defense to acute hypoxia, such as that which may occur during labor, remain unknown. This translational study tested the hypothesis, in vivo, that melatonin modulates the fetal cardiometabolic defense responses to acute hypoxia in chronically instrumented late gestation fetal sheep via alterations in fetal nitric oxide (NO) bioavailability. Under anesthesia, 6 fetal sheep at 0.85 gestation were instrumented with vascular catheters and a Transonic flow probe around a femoral artery. Five days later, fetuses were exposed to acute hypoxia with or without melatonin treatment. Fetal blood was taken to determine blood gas and metabolic status and plasma catecholamine concentrations. Hypoxia during melatonin treatment was repeated during in vivo NO blockade with the NO clamp. This technique permits blockade of de novo synthesis of NO while compensating for the tonic production of the gas, thereby maintaining basal cardiovascular function. Melatonin suppressed the redistribution of blood flow away from peripheral circulations and the glycemic and plasma catecholamine responses to acute hypoxia. These are important components of the fetal brain sparing response to acute hypoxia. The effects of melatonin involved NO-dependent mechanisms as the responses were reverted by fetal treatment with the NO clamp. Melatonin modulates the in vivo fetal cardiometabolic responses to acute hypoxia by increasing NO bioavailability. PMID- 25908099 TI - Parecoxib for the prevention of shivering after general anesthesia. AB - BACKGROUND: Shivering is the most common complication during the recovery period after general anesthesia, and there is no clear consensus about the best strategy for its prophylactic. The aim of the study was to evaluate the efficacy of parecoxib in prevention of postoperative shivering. METHODS: Eighty patients with American Society of Anesthesiologists physical status I-II, who were scheduled for minor urological surgeries under general anesthesia, were randomly assigned to two groups (n = 40 in each group): group P received 40 mg of parecoxib by intravenous bolus injection and group S received the same volume of normal saline in the same way just after the induction of anesthesia. Hemodynamic parameters and body temperatures including tympanic and axillary temperature were monitored. The occurrence of shivering and pain intensity score were recorded during the recovery period. RESULTS: Parecoxib significantly reduced the incidence and severity of shivering in comparison with the placebo. Postoperative shivering was observed in 22 patients in group S (55%), compared with nine in group P (22.5%) (P = 0.003). In addition, pain intensity scores were lower in group P during recovery period; consequently, less rescue analgesics were required in group P when compared with group S (P = 0.001). Regarding the body temperature, it was found that core temperature decreased but peripheral temperature increased significantly in both groups. There was no significant difference between groups in all time intervals. CONCLUSIONS: Prophylactic administration of parecoxib produces dual effects on antishivering and postoperative analgesia. This implies that cyclooxygenase 2-prostaglandin E2 pathways may be involved in the regulation of shivering. PMID- 25908100 TI - Daidzein pretreatment improves survival in mouse model of sepsis. AB - BACKGROUND: The aim of the present study was to assess the effect of seven days daidzein pretreatment in cecal ligation and puncture (CLP) model of sepsis. METHODS: We assessed the survival benefit of daidzein and its effect on lung injury in CLP-induced sepsis in mice and determined the bacterial load in peritoneal fluid, blood, and lung homogenates. Tumor necrosis factor alpha (TNF alpha) and corticosterone levels were measured by enzyme-linked immunosorbent assay; relative mRNA expression was estimated by real-time polymerase chain reaction, and standard biochemical techniques were used to measure nitrite level, myeloperoxidase activity, and vascular permeability. RESULTS: Daidzein pretreatment for seven days at a dose of 1 mg/kg body weight subcutaneously increased the survival time of septic mice. Daidzein decreased the bacterial load in peritoneal fluid, blood, and lungs, reduced the tumor necrosis factor alpha and nitrite level in plasma, and partially suppressed lung injury by reducing vascular permeability and myeloperoxidase activity in septic mice. Further, it restored the relative mRNA expressions of inducible nitric oxide synthase, glucocorticoid receptor alpha, and glucocorticoid receptor beta genes in septic lungs were restored by daidzein pretreatment. CONCLUSIONS: Daidzein pretreatment for 7 d in sepsis increased the survival time in mice, which may be relate to decrease in bacterial load, anti-inflammatory effect, and protection from lung injury. PMID- 25908101 TI - Hospital and procedure incidence of pediatric retained surgical items. AB - BACKGROUND: Prevention of retained surgical items (RSIs) is the main objective of the World Health Organization "Guidelines for Safe Surgery" (WHO/GSS) 2008 to improve patient safety. METHODS: We analyzed Kids' Inpatient Database 1997-2009 for RSI in patients aged <18 y. Incidence of RSI was calculated by per 100,000 admissions and per 100,000 procedures. The incidence was analyzed based on hospital bedsize, teaching status, region, and ownership and rural versus metropolitan location based on per 100,000 admissions. RESULTS: Overall, 713 cases were identified with a mean (standard deviation) age of 8.31 y (6.62), length of stay of 13 d (20), and total charges of $91,321 (155,054). RSI occurred at a rate of 2.22 per 100,000 admissions and 1.93 per 100,000 procedures; both rates decreased post-WHO/GSS implementation versus pre-WHO/GSS, P < 0.005. On average, public or children's hospitals reported the highest RSI rates (8.89 and 6.07/100,000 admissions, respectively). Small and medium bedsize hospitals had lower rates of RSI post-WHO/GSS, P < 0.05. Nonteaching, non-children's, or public hospitals reported lower rates post-WHO/GSS, P < 0.003. Private (nonprofit) hospitals reported higher rates post-WHO/GSS, P < 0.001. Facilities in the southern United States or in metropolitan areas reported lower rates post WHO/GSS, P < 0.02. A subanalysis of 107 cases requiring surgical removal demonstrated that fundoplications had the highest rate of RSI, followed by gastric procedures, laparotomy, bile duct procedures, lysis of adhesions, and abdominal wall repair. CONCLUSIONS: RSI rates have decreased overall after the introduction of the WHO/GSS. The largest reductions have occurred in public or nonteaching hospitals. Only private (nonprofit) hospitals reported increases in RSI since 2008. Higher rates of RSI are associated with fundoplications and other gastric procedures. PMID- 25908102 TI - Getting satisfaction: drivers of surgical Hospital Consumer Assessment of Health care Providers and Systems survey scores. AB - BACKGROUND: Hospital consumer assessment of health care providers and systems (HCAHPS) survey scores formally recognize that patients are central to health care, shifting quality metrics from the physician to patient perspective. This study describes clinical predictors of patient satisfaction in surgical patients. METHODS: Analysis of a single institution's Surgical Department HCAHPS responses was performed from March 2011-October 2012. The end points were top box satisfaction on two global domains. Multivariable regression was used to determine satisfaction predictors including HCAHPS domains, demographics, and clinical variables such as comorbidities, intensive care unit stay, emergency case, discharge day, floor transfers, complications, and ancillary procedures. RESULTS: In total, 978 surveys were evaluated representing admissions to Acute care and/or Trauma (n = 177, 18.1%), Thoracic (n = 169, 17.3%), Colorectal (n = 107, 10.9%), Transplant (n = 95, 9.7%), Vascular (n = 92, 9.4%), Oncology (n = 88, 9.0%), Plastic (n = 49, 5.0%), and Cardiac (n = 201, 20.6%) divisions. Overall, 658 patients (67.3%) had high satisfaction and 733 (74.9%) gave definite hospital recommendations. Hospital satisfaction was positively associated with an intensive care unit admission (odds ratio [OR] = 1.64, confidence interval [CI]: 1.20-2.23, P = 0.002) and satisfaction with provider and pain domains. Factors associated with decreased satisfaction were race (non-black minority compared with whites; OR = 0.41, CI: 0.21-0.83, P = 0.012), self-reported poor health (OR = 0.43, CI: 0.27-0.68, P < 0.001), >= 2 floor transfers (OR = 0.50, CI: 0.25 0.99, P = 0.046), and postoperative complications (OR = 0.67, CI: 0.55-0.82, P < 0.0001). In addition, weekend discharge (OR = 1.76, CI: 1.02-3.02, P = 0.041) was associated with hospital recommendation. CONCLUSIONS: Clinical course, particularly complications, impacts patient satisfaction. However, more important than what happens is how it happens, as evidenced by the much greater influence of surgeon and nurse-patient interactions. These results help inform future quality improvement and resource allocation. PMID- 25908103 TI - IL-6, through p-STAT3 rather than p-STAT1, activates hepatocarcinogenesis and affects survival of hepatocellular carcinoma patients: a cohort study. AB - BACKGROUND: Biologic activities of functional mediators activate downstream transducers regulating inflammation and carcinogenesis. Correlation among mediators (IL-6, IL-27, TNF-alpha, and VEGF) with STAT proteins at diverse clinical-pathologic stages of hepatocellular carcinoma (HCC) remains limited. METHODS: Serum mediators assayed from 147 untreated HCC cases (HCC-total group) included 70 HBV-infected (HCC-HBV group), 64 HCV-infected (HCC-HCV group), and 13 without HBV-/HCV-infection (HCC-NBNC group). Another 156 non-HCC individuals comprised 54 healthy individuals (HG) and 102 chronic hepatitis patients (CH total group) as control group. To correlate with serum mediators, 86-paired liver tissues (CH: 52 and HCC: 34 cases) served for p-STATs proteins immunostain. RESULTS: Although four mediators (IL-6, IL-27, TNF-alpha, and VEGF) significantly over-expressed, IL-6 presented the strongest correlation in HCC-total versus CH total or HG groups (HCC-total versus CH-total: P < 0.001; HCC-total versus HG: P < 0.001). Over-expressed IL-6 concentration linked with poor liver function (Albumin: r = -0.383, P < 0.001; Bilirubin: r = 0.280, P = 0.001; INR: r = 0.299, P < 0.001; AST: 0.212, P = 0.016), tumor progression (TNM system: r = 0.370; P < 0.001), clinical condition severity (BCLC system: r = 0.471; P < 0.001; terminal- versus early-stage HCC, P = 0.001; advanced- versus early-stage HCC, P = 0.007; terminal- versus intermediate- stage HCC P = 0.003; advanced- versus intermediate stage HCC P = 0.019), and 6-month mortality (P = 0.024). Likewise, serum IL-6 (r = 0.501, P = 0.003) as compared to IL-27 (r = 0.052, P = 0.770), TNF-alpha (r = 0.019, P = 0.917), and VEGF (r = 0.096, P = 0.595) expression reflected positive correlation with activation of tissues p-STAT3 rather than p-STAT1. CONCLUSIONS: Serum IL-6, through p-STAT3 rather than p-STAT1 signal pathway, affected hepatic function, tumor progression, and determine HCC patient survival. PMID- 25908104 TI - Podoplanin and CLEC-2 drive cerebrovascular patterning and integrity during development. AB - Mice with a constitutive or platelet-specific deletion of the C-type-lectin-like receptor (CLEC-2) exhibit hemorrhaging in the brain at mid-gestation. We sought to investigate the basis of this defect, hypothesizing that it is mediated by the loss of CLEC-2 activation by its endogenous ligand, podoplanin, which is expressed on the developing neural tube. To induce deletion of podoplanin at the 2-cell stage, we generated a podoplanin(fl/fl) mouse crossed to a PGK-Cre mouse. Using 3-dimensional light-sheet microscopy, we observed cerebral vessels were tortuous and aberrantly patterned at embryonic (E) day 10.5 in podoplanin- and CLEC-2-deficient mice, preceding the formation of large hemorrhages throughout the fore-, mid-, and hindbrain by E11.5. Immunofluorescence and electron microscopy revealed defective pericyte recruitment and misconnections between the endothelium of developing blood vessels and surrounding pericytes and neuro epithelial cells. Nestin-Cre-driven deletion of podoplanin on neural progenitors also caused widespread cerebral hemorrhaging. Hemorrhaging was also seen in the ventricles of embryos deficient in the platelet integrin subunit glycoprotein IIb or in embryos in which platelet alpha-granule and dense granule secretion is abolished. We propose a novel role for podoplanin on the neuro-epithelium, which interacts with CLEC-2 on platelets, mediating platelet adhesion, aggregation, and secretion to guide the maturation and integrity of the developing vasculature and prevent hemorrhage. PMID- 25908105 TI - Association between BDNF levels and suicidal behaviour: a systematic review protocol. AB - BACKGROUND: Suicide is a worldwide public health concern that claims close to 1 million lives each year. Suicidal behaviour is a significant risk factor for completed suicide and is much more prevalent than completed suicide. Many internal and external factors contribute to the risk of suicidal behaviour. Recent research has focused on biological markers in suicide risk, including brain-derived neurotrophic factor (BDNF). BDNF is a protein involved in the growth, function, and maintenance of the nervous system. It has been implicated in psychiatric disorders and suicide. While some evidence suggests that reduced levels of BDNF are associated with suicide, the precise relationship has yet to be determined. The aim of this study is to review the literature examining the relationship between levels of BDNF and suicidal behaviour. METHODS: A predefined search strategy will be implemented to search the following electronic databases: PubMed/MEDLINE, Excerpta Medica Database (EMBASE), PsycINFO, and Cumulative Index to Nursing and Allied Health Literature (CINAHL) from inception. The articles will be screened by two independent authors (RE and SP) using predetermined inclusion and exclusion criteria. Discrepancies will be resolved by consensus, or by a third author (ZS) in cases of disagreement. The primary outcome will be the association between levels of BDNF and suicidal behaviour. A meta-analysis will be conducted if appropriate. Quality of evidence and risk of bias will be evaluated. DISCUSSION: The findings of this review will assist in identifying and treating individuals at increased risk of suicide. SYSTEMATIC REVIEW REGISTRATION: PROSPERO CRD42015015871 . PMID- 25908106 TI - Does comorbid anxiety predict quality of life outcomes in patients with chronic rhinosinusitis following endoscopic sinus surgery? AB - BACKGROUND: Approximately 25% of patients with chronic rhinosinusitis (CRS) have comorbid anxiety and both conditions independently decrease quality of life (QOL). QOL outcomes for CRS and depression have garnered the majority of research attention, but efforts to better understand the impact of anxiety disorders on QOL are increasing. We evaluated the role of comorbid anxiety in patients with CRS undergoing endoscopic sinus surgery (ESS). METHODS: Adult patients (n = 148) with CRS with and without comorbid anxiety were prospectively enrolled into a treatment outcomes investigation. History of comorbid anxiety was retrospectively identified (n = 30; 20%) and preoperative and postoperative QOL (Rhinosinusitis Disability Index [RSDI], and 22-item Sino-Nasal Outcome Test [SNOT-22]) scores were compared to patients without comorbid anxiety. RESULTS: Compared to patients without anxiety, patients with anxiety were found to be younger (p = 0.02) and have a higher prevalence of female gender (p = 0.05), diabetes mellitus (p < 0.001), depression (p < 0.001), and tobacco use (p = 0.03). Participants with comorbid anxiety reported significantly worse preoperative psychological dysfunction as measured by SNOT-22 subdomain scores (p = 0.02), as well as worse preoperative functional (p = 0.04) and emotional (p = 0.001) impairment as evaluated by RSDI subdomain scores. After adjustment for other cofactors, patients with anxiety improved significantly less on SNOT-22 total scores compared to participants without anxiety after ESS (p = 0.02). CONCLUSION: Anxiety occurs with higher prevalence in patients with CRS and the presence of comorbid anxiety is associated with worse preoperative QOL and reduced QOL improvement following ESS. These findings warrant improvement in screening, diagnosis, and treatment for patients with CRS and comorbid anxiety. PMID- 25908107 TI - L-Type amino acid transporter 1 (LAT1) expression in lymph node metastasis of gastric carcinoma: Its correlation with size of metastatic lesion and Ki-67 labeling. AB - L-Type amino acid transporter 1 (LAT1) is one of the major amino acid transporters. High levels of LAT1 expression have been reported in various tumors, which can act as a novel prognostic marker. Previously, we demonstrated that LAT1 is highly expressed in advanced gastric carcinoma with lymph node metastasis, and proposed that LAT1 is an independent prognostic factor in non scirrhous gastric carcinoma. The aim of the present study was to investigate the relationship between LAT1 expression and the size of lymph node metastatic lesions in gastric carcinoma. LAT1 and Ki-67 expression was immunohistochemically analyzed in 64 cases of advanced gastric carcinoma with lymph node metastasis. LAT1 expression in the metastatic lymph nodes was correlated with that in the primary lesions. The high LAT1 expression group showed a larger size of metastatic lesion and a higher Ki-67 labeling index than the low LAT1 expression group. LAT1 expression had a weak association with Ki-67 labeling index and tumor diameter of lymph nodes. These results suggest that LAT1 expression is associated with disease progression in gastric carcinoma. We proposed that LAT1 could be a potential therapeutic target for gastric carcinoma cases with large lymph node metastasis. PMID- 25908108 TI - Gelsolin, NF-kappaB, and p53 expression in clear cell renal cell carcinoma: Impact on outcome. AB - OBJECTIVES: To examine the prognostic significance of Gelsolin, NF-kappaB, and p53 in clear cell renal cell carcinoma (CRCC), which has an unpredictable behavior and tendency for recurrence and metastasis. MATERIALS AND METHODS: Immunohistochemistry was performed on 100 consecutive cases of CRCC using antibodies against Gelsolin, NF-kappaB, and p53. Tumors were grouped by nuclear grade (NG) as low NG (NG1, 2) or high NG (NG3, 4), and by pathological stage as localized (pT1, 2) or locally invasive (pT3, 4). Clinical stage was grouped as early stage (stage I, II) or late stage (stage III, IV). Evaluation was based on cytoplasmic (NF-kappaB(Cyt)) and nuclear (NF-kappaB(Nuc)) expression for NF kappaB, nuclear expression for p53, membranous and cytoplasmic expression for Gelsolin. RESULTS: Gelsolin expression correlated with high NG (p = 0.001), metastasis (p = 0.003), late stage (p = 0.008), and cancer death (p = 0.001). NF kappaB(Cyt) expression correlated with high NG (p = 0.002), perirenal invasion (p = 0.010), local invasion (p = 0.020), and late stage (p= 0.003). NF-kappaB(Nuc) expression failed to predict the prognosis of CRCC. p53 expression correlated with high NG (p = 0.045), lymphovascular invasion (p = 0.05), metastasis (p = 0.001), late stage (p = 0.028), and cancer death (p = 0.034). However, only Gelsolin was found to correlate with disease-specific survival, (p = 0.006), and neither NF-kappaB nor p53 showed such relation. CONCLUSION: Expressions of Gelsolin, NF-kappaB(Cyt), and p53 associated with aggressive behavior of CRCC, while Gelsolin expression specifically indicated poor disease-specific survival. The results of the present study served to determine biomarkers for predicting high-risk patients with CRCC, expected to show aggressive phenotype. PMID- 25908109 TI - Both respiration and photosynthesis determine the scaling of plankton metabolism in the oligotrophic ocean. AB - Despite its importance to ocean-climate interactions, the metabolic state of the oligotrophic ocean has remained controversial for >15 years. Positions in the debate are that it is either hetero- or autotrophic, which suggests either substantial unaccounted for organic matter inputs, or that all available photosynthesis (P) estimations (including (14)C) are biased. Here we show the existence of systematic differences in the metabolic state of the North (heterotrophic) and South (autotrophic) Atlantic oligotrophic gyres, resulting from differences in both P and respiration (R). The oligotrophic ocean is neither auto- nor heterotrophic, but functionally diverse. Our results show that the scaling of plankton metabolism by generalized P:R relationships that has sustained the debate is biased, and indicate that the variability of R, and not only of P, needs to be considered in regional estimations of the ocean's metabolic state. PMID- 25908110 TI - Group versus Individual Professional Antenatal Breastfeeding Education for Extending Breastfeeding Duration and Exclusivity: A Systematic Review. AB - Although breastfeeding initiation rates have increased substantially in many developed countries over the past several decades, breastfeeding duration and exclusivity remain suboptimal. In the antenatal period, both group and individual education interventions have been implemented to improve breastfeeding. The purpose of this review was to compare the effectiveness of group and individual antenatal professional education on breastfeeding exclusivity and duration. A systematic search of the literature was conducted using Medline (1946-June 2014), PubMed (1883-June 2014), the Cumulative Index to Nursing and Allied Health Literature (1947-June 2014), EMBASE (1947-June 2014), British Nursing Index (1994 June 2014), Google Scholar, and the Cochrane Library. Included studies were limited to health care professional-conducted education delivered to pregnant women only. Only studies reporting breastfeeding duration or exclusivity were included. Nineteen studies were included, of which 13 evaluated antenatal group education, 5 evaluated individual antenatal education, and 1 evaluated both a group and an individual antenatal education. When compared with standard care, 4 out of 12 studies supported the effectiveness of antenatal group education on breastfeeding duration or exclusivity, whereas 4 out of 6 studies supported the effectiveness of antenatal individual education. Two studies compared antenatal group education with peer-led education and neither study showed a significant difference in breastfeeding outcomes. The methodological heterogeneity and the small number of high quality studies limited our ability to draw firm conclusions about the effectiveness of either mode of antenatal education. PMID- 25908111 TI - Improving adherence rate of extended prophylaxis for venous thromboembolic disease after abdominal and pelvic oncologic surgery: a pilot educational study. AB - BACKGROUND: Venous thromboembolic disease (VTE) is higher among patients with cancer. For those undergoing abdominal or pelvic surgery for cancer, it is suggested to extend thromboprophylaxis during 4 weeks with low-molecular-weight heparin over limited-duration of 7 days. There is no published local data from our country about compliance with recommended guidelines of extended prophylaxis (EP) in patients with cancer undergoing surgical procedures. Our aim was to evaluate the adherence rate to extended pharmacological thromboprophylaxis after abdominal-pelvic surgery for cancer, before and after an educational intervention program (EIP) geared toward surgeons. METHODS: Prospective cross-sectional study before and after an EIP aimed for surgeons. All consecutive patients older than 65 years who underwent surgery for abdominal-pelvic neoplasm, at the Hospital Italiano de Buenos Aires, Argentina, between September 2013 and May 2014, were evaluated for inclusion. RESULTS: A total of 120 patients were included, 60 before and 60 after the EIP aimed for surgeons. None of the initial 60 patients received EP, while 13 (21.6%) of 60 patients received prophylaxis for 28 days (all with colon or rectal cancer) after the intervention. There were no bleeding or death during 90 days of follow-up, and there were 7 of 120 VTE events, none in the group receiving extended thromboprophylaxis. CONCLUSION: The EIP for the surgical team significantly improved their adherence but only in the colon-rectal surgeries. The adherence to the recommended guidelines is still low. Reasons could be the subjective perception of elevated bleeding risk and the variable grade of recommendation in different guidelines. PMID- 25908112 TI - Estimating Glenoid Width for Instability-Related Bone Loss: A CT Evaluation of an MRI Formula. AB - BACKGROUND: Determining the magnitude of glenoid bone loss in cases of shoulder instability is an important step in selecting the optimal reconstructive procedure. Recently, a formula has been proposed that estimates native glenoid width based on magnetic resonance imaging (MRI) measurements of height (1/3 * glenoid height + 15 mm). This technique, however, has not been validated for use with computed tomography (CT), which is often the preferred imaging modality to assess bone deficiencies. PURPOSE: The purpose of this project was 2-fold: (1) to determine if the MRI-based formula that predicts glenoid width from height is valid with CT and (2) to determine if a more accurate regression can be resolved for use specifically with CT data. STUDY DESIGN: Descriptive laboratory study. METHODS: Ninety normal shoulder CT scans with preserved osseous anatomy were drawn from an existing database and analyzed. Measurements of glenoid height and width were performed by 2 observers on reconstructed 3-dimensional models. After assessment of reliability, the data were correlated, and regression models were created for male and female shoulders. The accuracy of the MRI-based model's predictions was then compared with that of the CT-based models. RESULTS: Intra- and interrater reliabilities were good to excellent for height and width, with intraclass correlation coefficients of 0.765 to 0.992. The height and width values had a strong correlation of 0.900 (P < .001). Regression analyses for male and female shoulders produced CT-specific formulas: for men, glenoid width = 2/3 * glenoid height + 5 mm; for women, glenoid width = 2/3 * glenoid height + 3 mm. Comparison of predictions from the MRI- and CT-specific formulas demonstrated good agreement (intraclass correlation coefficient = 0.818). The CT-specific formulas produced a root mean squared error of 1.2 mm, whereas application of the MRI-specific formula to CT images resulted in a root mean squared error of 1.5 mm. CONCLUSION: Use of the MRI-based formula on CT scans to predict glenoid width produced estimates that were nearly as accurate as the CT-specific formulas. The CT-specific formulas, however, are more accurate at predicting native glenoid width when applied to CT data. CLINICAL RELEVANCE: Imaging-specific (CT and MRI) formulas have been developed to estimate glenoid bone loss in patients with instability. The CT-specific formula can accurately predict native glenoid width, having an error of only 2.2% of average glenoid width. PMID- 25908113 TI - Evidence for the Durability of Autologous Tenocyte Injection for Treatment of Chronic Resistant Lateral Epicondylitis: Mean 4.5-Year Clinical Follow-up. AB - BACKGROUND: Chronic lateral epicondylitis (LE) induces cell apoptosis and autophagy, which lead to the reduction of tendon-derived cells in the torn tendon. Our previous study has shown that ultrasound-guided autologous tenocyte injection (ATI) to the torn tendon in patients with chronic resistant LE significantly improves pain, function, and structural repair at 1 year. This report is the continued assessment of the clinical outcomes of these patients at mean 4.5-year follow-up. HYPOTHESIS: Improvements in LE clinical function and structural repair after ATI will be maintained at mean 4.5-year follow-up. STUDY DESIGN: Case series; Level of evidence, 4. METHODS: Patients with severe refractory LE underwent clinical evaluation and MRI before intervention. A patellar tendon needle biopsy was performed under local anesthetic, and tendon cells were expanded by in vitro culture. Autologous tenocytes were injected into the central tendinopathy identified at the common extensor tendon origin under ultrasound guidance on a single occasion. Patients underwent serial clinical evaluations for up to 5 years after ATI, including the visual analog scale (VAS) for pain, Quick Disabilities of the Arm, Shoulder and Hand (QuickDASH), Upper Extremity Functional Scale (UEFS), and grip strength. Post-ATI MRI scanning was performed at 1 year and final follow-up. RESULTS: A total of 16 patients (9 male, 7 female), aged between 37 and 63 years, were included in the study. The mean duration of symptoms before study recruitment was 29.24 months (range, 6-240 months). One patient elected to proceed to surgery 3 months after ATI due to reinjury at work, and 1 patient died of prostate cancer with metastases during the follow-up period. The mean final follow-up time for the remaining 15 patients was 4.51 years (range, 3.08-5.17 years). No complications were observed at the patellar tendon biopsy site for any patient. No adverse events, infection, or excessive fibroblastic reactions were observed in any patient at the injection site. Clinical evaluation revealed significant (P < .001) improvement in mean VAS pain score from 5.73 at initial assessment to 1.21 (78% improvement) at final follow-up. Mean QuickDASH, UEFS, and grip strength scores also significantly (P < .001) improved from initial assessment to final follow-up (from 45.88 to 6.61 [84%], from 31.73 to 9.20 [64%], and from 19.85 to 46.60 [208%], respectively). There was no difference in mean QuickDASH and UEFS scores at 1 year and final follow-up (P > .05); however, grip strength continued to improve (P < .001). A validated MRI scoring system indicated that the mean grade of tendinopathy at the common extensor origin improved significantly (P < .001) from initial assessment (4.31) to 1 year (2.88) and was maintained (P > .05) at final follow-up (2.87). At final follow-up, 93% of patients were either highly satisfied or satisfied with their ATI treatment. CONCLUSION: ATI significantly improved clinical function and MRI tendinopathy scores for up to 5 years in patients with chronic resistant LE who had previously undergone unsuccessful nonsurgical treatment. This study provides evidence for the midterm durability of ATI for treatment of LE tendinopathy. PMID- 25908115 TI - Microengine-assisted electrochemical measurements at printable sensor strips. AB - A new microengine-based built-in-platform exploiting a surprising dual action with solution mixing and control of the reaction parameters, has been applied for accelerating chemical reactions (organophosphorous nerve agents hydrolysis) and electrochemical detection of non-hazardous by-product (p-nitrophenol) using printable sensor strip. PMID- 25908114 TI - Midregional proadrenomedullin predicts mortality and major adverse cardiac events in patients presenting with chest pain: results from the CHOPIN trial. AB - OBJECTIVES: Chest pain is a common complaint to emergency departments (EDs) and clinical risk factors are used to predict which patients are at risk for worse outcomes and mortality. The goal was to assess the novel biomarker midregional proadrenomedullin (MR-proADM) in prediction of mortality and major adverse cardiac events (MACE). METHODS: This was a subanalysis of the CHOPIN study, a 16 center prospective trial that enrolled 2,071 patients presenting with chest pain within 6 hours of onset. The primary endpoint was 6-month all-cause mortality and the secondary endpoint was 30-day and 6-month MACE: ED visits or hospitalization for acute myocardial infarction, unstable angina, reinfarction, revascularization, and heart failure. RESULTS: MR-proADM performed similarly to troponin (cTnI; c-statistic = 0.845 and 0.794, respectively) for mortality prediction in all subjects and had similar results in those with noncardiac diagnoses. MR-proADM concentrations were stratified by decile, and the cohort in the top decile had a 9.8% 6-month mortality risk versus 0.9% risk for those in the bottom nine deciles (p < 0.0001). MR-proADM, history of coronary artery disease (CAD), and hypertension were predictors of short-term MACE, while history of CAD, hypertension, cTnI, and MR-proADM were predictors of long-term MACE. CONCLUSIONS: In patients with chest pain, MR-proADM predicts mortality and MACE in all-comers with chest pain and has similar prediction in those with a noncardiac diagnosis. This exploratory analysis is primarily hypotheses generating and future prospective studies to identify its utility in risk stratification should be considered. PMID- 25908116 TI - Spectroscopic Observation of Calcium-Induced Reorientation of Cellobiose Dehydrogenase Immobilized on Electrodes and its Effect on Electrocatalytic Activity. AB - Cellobiose dehydrogenase catalyzes the oxidation of various carbohydrates and is considered as a possible anode catalyst in biofuel cells. It has been shown that the catalytic performance of this enzyme immobilized on electrodes can be increased by presence of calcium ions. To get insight into the Ca(2+) -induced changes in the immobilized enzyme we employ surface-enhanced vibrational (SERR and SEIRA) spectroscopy together with electrochemistry. Upon addition of Ca(2+) ions electrochemical measurements show a shift of the catalytic turnover signal to more negative potentials while SERR measurements reveal an offset between the potential of heme reduction and catalytic current. Comparing SERR and SEIRA data we propose that binding of Ca(2+) to the heme induces protein reorientation in a way that the electron transfer pathway of the catalytic FAD center to the electrode can bypass the heme cofactor, resulting in catalytic activity at more negative potentials. PMID- 25908117 TI - Doing justice to allosteric regulation. AB - Jacques Monod gave us not only our first regulatory system, but also our first smart molecules - i.e., he gave us allosteric proteins. But both of these contributions hung in a certain tension with his primary commitments. In particular, I focus here on the ways in which his ontological commitments constrained his thinking about the power of allostery. Although he wrote that "so far as regulation through allosteric interaction is concerned, everything is possible", for him, not everything was conceivable. In particular, what was not conceivable was a challenge to the primacy of DNA. PMID- 25908120 TI - Correction for Sun et al., Nucleation of metastable aragonite CaCO3 in seawater. PMID- 25908118 TI - Impact of polyploidy on fertility variation of Mediterranean Arundo L. (Poaceae). AB - Failure of seed production in the genus Arundo L. (Poaceae) is often attributed to polyploidy. This study tested the impact of two ploidy levels (2n=12 and 18x) on the fertility of four Mediterranean Arundo. Viable pollen was screened from its production to its germination, and seed occurrence was monitored in admixture or isolated conditions. In addition, insights on restructuration of polyploid genomes were analysed using molecular cytogenetics. Our results show that high ploidy levels do not automatically induce failure of sexual reproduction. The two ploidy levels are able to produce viable pollen and seed set depending on species and cultural conditions. The sterility of A. micrantha (2n=12x) and A. donax (2n=18x) is due to the early failures of gametogenesis steps. For 18x cytotypes of A. donaciformis and A. plinii, seed absence for isolated genotype vs. seed production in admixed culture support their auto-incompatibility. PMID- 25908119 TI - Emergence of homeostatic epithelial packing and stress dissipation through divisions oriented along the long cell axis. AB - Cell division plays an important role in animal tissue morphogenesis, which depends, critically, on the orientation of divisions. In isolated adherent cells, the orientation of mitotic spindles is sensitive to interphase cell shape and the direction of extrinsic mechanical forces. In epithelia, the relative importance of these two factors is challenging to assess. To do this, we used suspended monolayers devoid of ECM, where divisions become oriented following a stretch, allowing the regulation and function of epithelial division orientation in stress relaxation to be characterized. Using this system, we found that divisions align better with the long, interphase cell axis than with the monolayer stress axis. Nevertheless, because the application of stretch induces a global realignment of interphase long axes along the direction of extension, this is sufficient to bias the orientation of divisions in the direction of stretch. Each division redistributes the mother cell mass along the axis of division. Thus, the global bias in division orientation enables cells to act collectively to redistribute mass along the axis of stretch, helping to return the monolayer to its resting state. Further, this behavior could be quantitatively reproduced using a model designed to assess the impact of autonomous changes in mitotic cell mechanics within a stretched monolayer. In summary, the propensity of cells to divide along their long axis preserves epithelial homeostasis by facilitating both stress relaxation and isotropic growth without the need for cells to read or transduce mechanical signals. PMID- 25908121 TI - Characteristics of the use of 3-MMC and other new psychoactive drugs in Slovenia, and the perceived problems experienced by users. AB - BACKGROUND: The study presents the characteristics of the use of new psychoactive substances (NPS), the perceived problems experienced by users, and the reasons for cessation or cutting down. The research focused mainly on synthetic cathinones and the use of 3-MMC in Slovenia. METHODS: In order to research the characteristics of NPS use, we used a questionnaire which had been developed to determine the characteristics of the use of ATS and cocaine in the context of nightlife and was elaborated in our study on the use of mephedrone. The final non representative sample included 249 users of NPS from Slovenia, who had completed an on-line survey over a period of 5 months in 2014. Part of the sampling was conducted on the ground and with the help of peer-groups. DrogArt's outreach workers and correspondents visited open public places, clubs, and discotheques to encourage users to participate in the survey. RESULTS: Most users of NPS in Slovenia have tried NPS from the groups of synthetic cathinones and amphetamines. Most respondents included in the sample (67.9%) have tried 3-MMC, while 43.0% have tried methylone and 37.3% have tried mephedrone (4-MMC). Users attributed greater risks to the use of new drugs and preferred the effects of traditional drugs to those of new drugs. The most frequently reported problems were depression (55.2% of users), concentration difficulties (44.0%), damage to the mucous membrane of the nose and to the throat (39.8%), feelings of fear and anxiety (39.4%), and tingling in the arms or legs (34.4%). The main reasons for cutting down or discontinuing the use of NPS were 'fear of the health consequences', 'actual health consequences', and 'growing weary of using'. Among users of NPS, 7% have sought help, while 9.1% have considered doing so. The results also highlight differences between the NPS drug markets in Slovenia and the United Kingdom. CONCLUSIONS: In 2014, the most frequently used NPS in Slovenia were synthetic cathinones such as 3-MMC. Users experienced various problems related to the use of NPS. However, they are familiar with recommendations on harm reduction and want additional information on the harmful effects of the use of NPS. Based on the obtained results, we can develop specific interventions in the area of harm reduction. PMID- 25908122 TI - Draft Genome Sequences of 53 Genetically Distinct Isolates of Bordetella bronchiseptica Representing 11 Terrestrial and Aquatic Hosts. AB - Bordetella bronchiseptica infects a variety of mammalian and avian hosts. Here, we report the genome sequences of 53 genetically distinct isolates acquired from a broad range of terrestrial and aquatic animals. These data will greatly facilitate ongoing efforts to better understand the evolution, host adaptation, and virulence mechanisms of B. bronchiseptica. PMID- 25908123 TI - Genome Sequences of Three Helicobacter pylori Strains from Patients with Gastric Mucosa-Associated Lymphoid Tissue Lymphoma. AB - Most of the published complete genome sequences of Helicobacter pylori strains are limited to clinical isolates associated with gastritis, peptic ulcers, or gastric cancer. The genome sequences of three H. pylori strains isolated from patients with gastric mucosa-associated lymphoid tissue (MALT) lymphoma are presented here to facilitate studies of H. pylori-associated MALT lymphomagenesis. PMID- 25908124 TI - Complete coding sequences of eastern equine encephalitis virus and venezuelan equine encephalitis virus strains isolated from human cases. AB - We obtained the complete coding genome of an eastern equine encephalitis virus (EEEV) strain, EEEV V105-00210, and the complete genome of a Venezuelan equine encephalitis virus (VEEV) strain, VEEV INH-9813. They were obtained from human cases and are proposed as reference challenge strains for vaccine and therapeutic development in animal models. PMID- 25908125 TI - Genome Sequence of Methanosarcina soligelidi SMA-21, Isolated from Siberian Permafrost-Affected Soil. AB - Here, we announce the genome sequence of Methanosarcina soligelidi SMA-21, an anaerobic methanogenic archaeon that was previously isolated from Siberian permafrost-affected soil. The sequencing of strain SMA-21 yielded a 4.06-Mb genome with 41.5% G+C content, containing a total of 2,647 open reading frames. PMID- 25908126 TI - Genome Sequences of Beak and Feather Disease Virus in Urban Rainbow Lorikeets (Trichoglossus haematodus). AB - Beak and feather disease viral genomes were recovered from two deceased juvenile urban rainbow lorikeets (Trichoglossus haematodus) that lacked tail feathers. These genomes share ~95% pairwise identity with two beak and feather disease virus (BFDV) genomes identified in wild and captive Australian T. haematodus birds and ~92% identity to those in wild New Caledonian T. haematodus deplanchii birds. PMID- 25908127 TI - Complete genome sequence of a hop latent virus infecting hop plants. AB - The hop latent virus is a single-stranded RNA virus that mainly infects hop plants. Here, we report the complete genome sequence of a hop latent virus, which was de novo assembled by RNA sequencing (RNA-seq). Our study indicates that transcriptome data are useful for identifying a complete viral genome. PMID- 25908128 TI - Draft Genome Sequence of Clostridium beijerinckii Ne1, Clostridia from an Enrichment Culture Obtained from Australian Subterranean Termite, Nasutitermes exitiosus. AB - The draft genome of Clostridium beijerinckii strain Ne1 was reconstructed from the metagenomic sequence of a mixed-microbial consortium that produced commercially significant quantities of hydrogen from xylan as a sole feedstock. The organism possesses relatively limited hemicellulolytic capacity and likely requires the action of other organisms to completely degrade xylan. PMID- 25908129 TI - Draft Genome Sequence of Clostridium sp. Ne2, Clostridia from an Enrichment Culture Obtained from Australian Subterranean Termite, Nasutitermes exitiosus. AB - The draft genome sequence of Clostridium sp. Ne2 was reconstructed from a metagenome of a hydrogenogenic microbial consortium. The organism is most closely related to Clostridium magnum and is a strict anaerobe that is predicted to ferment a range of simple sugars. PMID- 25908130 TI - Draft Genome Sequence of Ruminoclostridium sp. Ne3, Clostridia from an Enrichment Culture Obtained from Australian Subterranean Termite, Nasutitermes exitiosus. AB - The draft genome sequence of Ruminoclostridium sp. Ne3 was reconstructed from the metagenome of a hydrogenogenic microbial consortium growing on xylan. The organism is likely the primary hemicellulose degrader within the consortium. PMID- 25908131 TI - Complete genome sequence of duck tembusu virus isolated from pekin ducks in shanghai, china. AB - We report here the complete genomic sequence of the duck Tembusu virus (DTMUV) SH001 strain, isolated from Pekin ducks in Shanghai, China, in 2013. The genome of SH001 is 10,990 nucleotides (nt) in length and contains a single open reading frame encoding a putative polyprotein of 3,425 amino acids. PMID- 25908132 TI - Genome Sequence of a Copper-Resistant Strain of Acidovorax citrulli Causing Bacterial Fruit Blotch of Melons. AB - Bacterial fruit blotch (BFB) of melons is a seed-borne disease caused by Acidovorax citrulli. We determined the draft genome of A. citrulli Tw6. The strain was isolated from a watermelon collected from Beijing, China. The A. citrulli Tw6 genome contains 5,080,614 bp and has a G+C content of 68.7 mol%. PMID- 25908133 TI - Whole-Genome Sequences of Eight Campylobacter jejuni Isolates from Wild Birds. AB - We present here the draft genome sequences of 8 Campylobacter jejuni strains isolated from wild birds. The strains were initially isolated from swabs taken from resident wild birds in the Tokachi area of Japan. The genome sizes range from 1.65 to 1.77 Mbp. PMID- 25908134 TI - Complete Genome Sequence of Streptococcus iniae YSFST01-82, Isolated from Olive Flounder in Jeju, South Korea. AB - Streptococcus iniae is associated with morbidity in commercial fish species, especially in olive flounders (Paralichthys olivaceus), and was recently identified as an emerging human pathogen. Here, we report the complete 2.09-Mb genome sequence of S. iniae strain YSFST01-82, isolated from an olive flounder with streptococcosis disease in Jeju, South Korea. PMID- 25908135 TI - Genome Sequence of Phlebopus portentosus Strain PP33, a Cultivated Bolete. AB - Phlebopus portentosus can form fruiting bodies, both independently as a saprophyte and in association with plants as an ectomycorrhizal symbiont. It thus offers an excellent model from which to examine the genetic basis of lifestyle adaptations and transitions for mushrooms. This paper reports the genome sequence of a homokaryotic strain of P. portentosus, PP33. PMID- 25908136 TI - Genome Sequence of Acidovorax citrulli Group 1 Strain pslb65 Causing Bacterial Fruit Blotch of Melons. AB - Acidovorax citrulli is typed into two groups, mainly based on the host. We determined the draft genome of A. citrulli group 1 strain pslb65. The strain was isolated from melon collected from Xinjiang province, China. The A. citrulli pslb65 genome contains 4,903,443 bp and has a G+C content of 68.8 mol%. PMID- 25908137 TI - Complete Genome Sequence of Mycoplasma yeatsii Strain GM274B (ATCC 43094). AB - Mycoplasma yeatsii is a goat mycoplasma species that, although an obligate parasite, accommodates this lifestyle as an inapparent commensalist. High frequency transformation has also been reported for this species. The complete 895,051-bp genome sequence of strain GM274B has been determined, enabling an analysis of the features of this potential cloning host. PMID- 25908138 TI - Draft Genome Sequence of Pseudoalteromonas sp. Strain ECSMB14103, Isolated from the East China Sea. AB - Pseudoalteromonas sp. strain ECSMB14103 was isolated from marine biofilms formed on the East China Sea. The draft genome sequence comprises 4.11 Mp with a G+C content of 39.7%. The information from the draft genome will contribute to an understanding of bacteria-animal interaction. PMID- 25908139 TI - Draft Genome Sequences of Agrobacterium nepotum Strain 39/7T and Agrobacterium sp. Strain KFB 330. AB - Tumorigenic strains of Agrobacterium spp. are responsible for crown gall disease of numerous plant species. We present here draft genome sequences of nonpathogenic Agrobacterium nepotum strain 39/7(T) (CFBP 7436(T), LMG 26435(T)), isolated from crown gall tumor on Prunus cerasifera, and tumorigenic Agrobacterium sp. strain KFB 330 (CFBP 8308, LMG 28674), isolated from galls on raspberry. PMID- 25908140 TI - Complete genome sequences of human respiratory syncytial virus genotype a and B isolates from South Korea. AB - There is a paucity of complete genome sequence information for human respiratory syncytial virus (HRSV). To this end, we sequenced the complete genome sequences of HRSV genotype A (HRSV-A/IC688/12) and genotype B (HRSV-B/GW0047/14 and HRSV B/IC0027/14). This information will increase the understanding of HRSV genetic diversity, evolution, pathogenicity, antigenicity, and transmissibility. PMID- 25908141 TI - Genome Sequences of Four Staphylococcus aureus Strains Isolated from Bovine Mastitis. AB - Staphylococcus aureus is a major causative agent of mastitis in dairy cows. The pathogenicity of S. aureus may vary; it is able to cause severe clinical mastitis, but most often it is associated with chronic subclinical mastitis. Here, we present the genome assemblies of four S. aureus strains from bovine mastitis. PMID- 25908142 TI - Complete Genome Sequence of a Western Siberian Lymantria dispar Multiple Nucleopolyhedrovirus Isolate. AB - A novel strain of Lymantria dispar multiple nucleopolyhedrovirus (LdMNPV-27) was isolated from dead larvae of a Western Siberian (WS) population of gypsy moths (Lymantria dispar L.). We report the complete genome sequence of this strain, comprising 164,108 bp and double-stranded circular DNA encoding 162 predicted open reading frames. PMID- 25908143 TI - Complete Genome Sequencing of Protease-Producing Novel Arthrobacter sp. Strain IHBB 11108 Using PacBio Single-Molecule Real-Time Sequencing Technology. AB - A previously uncharacterized species of the genus Arthrobacter, strain IHBB 11108 (MCC 2780), is a Gram-positive, strictly aerobic, nonmotile, cold-adapted, and protease-producing alkaliphilic actinobacterium, isolated from shallow undersurface water from Chandra Tal Lake, Lahaul-Spiti, India. The complete genome of the strain is 3.6 Mb in size with an average 58.97% G+C content. PMID- 25908144 TI - Genome Sequence of Jannaschia aquimarina GSW-M26, a Member of the Roseobacter Clade. AB - The Gram-negative alphaproteobacterium Jannaschia aquimarina GSW-M26 (DSM 28248) is a member of the Roseobacter clade. The size of the draft genome is 4.1 Mb. Genome analysis revealed the presence of genes encoding a complete gene transfer agent and aerobic anoxygenic photosynthesis. The latter indicated a photoheterotrophic lifestyle. PMID- 25908145 TI - Complete Genome Sequence of Paenibacillus sp. Strain IHBB 10380 Using PacBio Single-Molecule Real-Time Sequencing Technology. AB - The complete genome sequence of 5.77 Mb is reported for Paenibacillus sp. strain IHBB 10380, isolated from the cold desert area of the northwestern Himalayas and exhibiting amylase and cellulase activities. The gene-coding clusters predicted the presence of genes for hydrolytic enzymes in the genome. PMID- 25908146 TI - Complete Genome Sequence of Fish Pathogen Aeromonas hydrophila AL06-06. AB - Aeromonas hydrophila occurs in freshwater environments and infects fish and mammals. Here, we report the complete genome sequence of Aeromonas hydrophila AL06-06, which was isolated from diseased goldfish and is being used for comparative genomic studies with A. hydrophila strains that cause bacterial septicemia in channel catfish aquaculture. PMID- 25908147 TI - Draft Genome Sequence of Erythromycin-Resistant Streptococcus gallolyticus subsp. gallolyticus NTS 31106099 Isolated from a Patient with Infective Endocarditis and Colorectal Cancer. AB - Streptococcus gallolyticus subsp. gallolyticus is known for its close association with infective endocarditis and colorectal cancer in humans. Here, we report the draft genome sequence of highly erythromycin-resistant strain NTS 31106099 isolated from a patient with infective endocarditis and colorectal cancer. PMID- 25908148 TI - Draft Genome Sequences of Paenibacillus polymyxa NRRL B-30509 and Paenibacillus terrae NRRL B-30644, Strains from a Poultry Environment That Produce Tridecaptin A and Paenicidins. AB - Paenibacillus polymyxa NRRL B-30509 and Paenibacillus terrae NRRL B-30644 produce tridecaptin A that is inhibitory to Campylobacter jejuni, as well as lantibiotics in the paenicidin family. Here, we report the draft genome sequences of P. polymyxa NRRL B-30509 and P. terrae NRRL B-30644 that contain gene clusters for various nonribosomal lipopeptides. PMID- 25908149 TI - Genome Sequence of Mucoid Pseudomonas aeruginosa Strain FRD1. AB - Pseudomonas aeruginosa is an important opportunistic pathogen. Strain FRD1 is a mucoid isolate from the sputum of a cystic fibrosis patient. It has been widely studied and has many different phenotypes compared to nonmucoid strains. Here, we present the draft genome sequence of P. aeruginosa strain FRD1 to gain insight into mucoid isolates. PMID- 25908150 TI - Draft genome sequence of a novel culturable marine chroococcalean cyanobacterium from the South atlantic ocean. AB - The novel chroococcalean cyanobacterium strain CENA595 was isolated from the deep chlorophyll maximum layer of the continental shelf of the South Atlantic Ocean. Here, we report the draft genome sequence for this strain, consisting of 60 contigs containing a total of 5,265,703 bp and 3,276 putative protein-coding genes. PMID- 25908151 TI - Genome Sequence of a Versatile Aromatic Hydrocarbon-Degrading Bacterium, Arthrobacter sp. W1. AB - Arthrobacter sp. W1 is a versatile aromatic-degrading strain which can directly or cometabolically degrade various organic pollutants, such as phenol, naphthalene, carbazole, dibenzofuran, and dibenzothiophene. Here, we present a 3.8-Mb draft genome sequence of strain W1, which may provide comprehensive genetic information for the application in environmental pollution remediation. PMID- 25908152 TI - Complete Genome Sequence of Kluyveromyces marxianus NBRC1777, a Nonconventional Thermotolerant Yeast. AB - We determined the genome sequence of the thermotolerant yeast Kluyveromyces marxianus strain NBRC1777. The genome of strain NBRC1777 is composed of 4,912 open reading frames (ORFs) on 8 chromosomes, with a total size of 10,895,581 bp, including mitochondrial DNA. PMID- 25908153 TI - 2014 presidential address: stop diabetes--it is up to us. AB - This address was delivered by Elizabeth R. Seaquist, MD, President, Medicine & Science, of the American Diabetes Association (ADA) at the Association's 74th Scientific Sessions in San Francisco, CA, on 15 June 2014. Dr. Seaquist is a professor of medicine at the University of Minnesota in Minneapolis, where she holds the Pennock Family Chair in Diabetes Research. She has been an ADA volunteer since 1987 and has served on several national committees and chaired the Association's workgroup on Hypoglycemia in Diabetes. At the local level, she served a 2-year term as cochair of the ADA EXPO in Minneapolis. Dr. Seaquist is a clinical investigator interested in the complications of diabetes. Her research focuses on the effect of diabetes on brain metabolism structure and function. She directs the University of Minnesota site for the Action to Control Cardiovascular Risk in Diabetes (ACCORD) and Glycemia Reduction Approaches in Diabetes: A Comparative Effectiveness Study(GRADE) trials and has an active clinical practice. She was the 2009 recipient of the ADA's Distinguished Clinical Scientist Award. Dr. Seaquist holds a Bachelor of Arts degree from Vassar College in Poughkeepsie, NY, and a doctorate in medicine from the University of Minnesota. She is board certified in internal medicine and endocrinology, diabetes, and metabolism. The ADA and Diabetes Care thank Dr. Seaquist for her outstanding leadership and service to the Association. PMID- 25908154 TI - Erratum. Serum 25-hydroxyvitamin d levels and prediabetes among subjects free of diabetes. Diabetes care 2011;34:1114-1119. PMID- 25908155 TI - Erratum. Association Between Serum IGF-1 and Diabetes Among U.S. Adults. Diabetes Care 2010;33:2257-2259. PMID- 25908157 TI - Patient-reported outcomes and continuous glucose monitoring: can we do better with artificial pancreas devices? PMID- 25908158 TI - Pancreatic Amylase and Lipase Plasma Concentrations Are Unaffected by Increments in Endogenous GLP-1 Levels Following Liquid Meal Tests. PMID- 25908159 TI - Cardiovascular disease protection in long-duration type 1 diabetes and sex differences. PMID- 25908160 TI - Pregnancy and delivery in a woman with type 1 diabetes, gastroparesis, and a gastric neurostimulator. PMID- 25908161 TI - Pioglitazone improves fat tissue distribution and hyperglycemia in a case of cockayne syndrome with diabetes. PMID- 25908162 TI - Diabetes prevalence and risk factors among vietnamese adults: findings from community-based screening programs. PMID- 25908163 TI - Use of highly purified synthetic calcium sulfate impregnated with antibiotics for the management of diabetic foot ulcers complicated by osteomyelitis. PMID- 25908164 TI - Comment on Cefalu et Al. The alarming and rising costs of diabetes and prediabetes: a call for action! Diabetes care 2014;37:3137-3138. PMID- 25908165 TI - Response to comment on Cefalu et Al. The alarming and rising costs of diabetes and prediabetes: a call for action! Diabetes care 2014;37:3137-3138. PMID- 25908166 TI - The bystander cell-killing effect mediated by nitric oxide in normal human fibroblasts varies with irradiation dose but not with radiation quality. AB - PURPOSE: To investigate the dependence of the bystander cell-killing effect on radiation dose and quality, and to elucidate related molecular mechanisms. MATERIALS AND METHODS: Normal human fibroblast WI-38 cells were irradiated with 0.125 - 2 Gy of gamma-rays or carbon ions and were co-cultured with non irradiated cells. Survival rates of bystander cells were investigated using the colony formation assays, and nitrite concentrations in the medium were measured using the modified Saltzman method. RESULTS: Survival rates of bystander cells decreased with doses of gamma-rays and carbon ions of <= 0.5 Gy. Treatment of the specific nitric oxide (NO) radical scavenger prevented reductions in survival rates of bystander cells. Moreover, nitrite concentrations increased with doses of less than 0.25 Gy (gamma-rays) and 1 Gy (carbon ions). The dose responses of increased nitrite concentrations as well as survival reduction were similar between gamma-rays and carbon ions. In addition, negative relationships were observed between survival rates and nitrite concentrations. CONCLUSION: The bystander cell-killing effect mediated by NO radicals in normal human fibroblasts depends on irradiation doses of up to 0.5 Gy, but not on radiation quality. NO radical production appears to be an important determinant of gamma-ray- and carbon-ion-induced bystander effects. PMID- 25908167 TI - Dr. H. Rodney Withers (1932 - 2015). PMID- 25908169 TI - Transient changes of enzyme activities and expression of stress proteins in the small intestine of piglets after weaning. AB - To determine the transient effects of weaning on the small intestine, 16 piglets were slaughtered at days 0, 1, 4 and 7 after weaning. Jejunal samples were collected to examine different enzyme activities and mRNA expressions of two stress protein families, namely, heat-shock proteins (HSP) and trefoil factors (TFF). Results showed that the activities of ceruloplasmin, alkaline phosphatase and lactate dehydrogenase, were significantly changed at Day 1 and/or Day 4. The mRNA expressions of HSP10, HSP60 and HSP90 showed a pattern of increased expression with time after weaning. Expression significantly differed between Day 0 and Day 7 after weaning. The mRNA expression of HSP70 was significantly increased on Day 1 only. Similarly, the mRNA expressions of TFF1 and TFF2 were significantly increased on Day 7 compared with those on Day 0. Expression of TFF3 was not affected by time after weaning. In conclusion, the present study indicated that weaning induced transient injury to small intestinal morphology and function. Particularly it changed enzyme activities and gene expression of stress proteins in the small intestine of piglets. At first time, a change in the gene expression of HSP10 and a gene overexpression of TFF1 in the small intestine of piglets after weaning was found. PMID- 25908170 TI - Antiviral activity of an N-allyl acridone against dengue virus. AB - BACKGROUND: Dengue virus (DENV), a member of the family Flaviviridae, is at present the most widespread causative agent of a human viral disease transmitted by mosquitoes. Despite the increasing incidence of this pathogen, there are no antiviral drugs or vaccines currently available for treatment or prevention. In a previous screening assay, we identified a group of N-allyl acridones as effective virus inhibitors. Here, the antiviral activity and mode of action targeted to viral RNA replication of one of the most active DENV-2 inhibitors was further characterized. RESULTS: The compound 10-allyl-7-chloro-9(10H)-acridone, designated 3b, was active to inhibit the in vitro infection of Vero cells with the four DENV serotypes, with effective concentration 50% (EC50) values in the range 12.5-27.1 MUM, as determined by virus yield inhibition assays. The compound was also effective in human HeLa cells. No cytotoxicity was detected at 3b concentrations up to 1000 MUM. Mechanistic studies demonstrated that virus entry into the host cell was not affected, whereas viral RNA synthesis was strongly inhibited, as quantified by real time RT-PCR. The addition of exogenous guanosine together with 3b rescued only partially the infectivity of DENV-2. CONCLUSIONS: The acridone derivative 3b selectively inhibits the infection of Vero cells with the four DENV serotypes without a direct interaction with the host cell or the virion but interfering specifically with the intracellular virus multiplication. The mode of antiviral action for this acridone apparently involves the cellular enzyme inosine-monophospahe dehydrogenase together with another still unidentified target related to DENV RNA synthesis. PMID- 25908171 TI - Manganese oxide and docetaxel co-loaded fluorescent polymer nanoparticles for dual modal imaging and chemotherapy of breast cancer. AB - Multifunctional nanoparticles (NPs) have found important applications in diagnosis, chemotherapy, and image-guided surgery of tumors. In this work, we have developed polymeric theranostic NPs (PTNPs) containing the anticancer drug docetaxel (DTX), a fluorescent dye, and magnetic manganese oxide (MnO) NPs for dual modal imaging and chemotherapy. PTNPs ~150 nm in diameter were synthesized by co-loading hydrophobic DTX and MnO NPs ~5 nm in diameter, into the matrix of a fluorescent dye-labeled amphiphilic polymer. The PTNPs enabled high loading efficiency and sustained in vitro release of DTX. Energy-dependent cellular uptake and extended cytoplasmic retention of the PTNPs in MDA-MB-231 human breast cancer cells were observed by fluorescence microscopy examination. DTX-loaded PTNPs exhibited higher cytotoxicity than free DTX with a 3 to 4.4-fold decrease in drug dose required for 50% cell growth inhibition. The hydrophilic backbone of the amphiphilic polymer improved the fluidity of PTNPs which enhanced the longitudinal relaxivity (r1) of loaded MnO NPs by 2.7-fold with r1=2.4mM(-1)s( 1). Whole body fluorescence imaging (FI) and magnetic resonance imaging (MRI) showed significant accumulation and prolonged retention of PTNPs in orthotopic MDA-MB-231 breast tumors. These results suggest that the new amphiphilic polymer based PTNP system, able to simultaneously deliver a poorly soluble anticancer drug, enhance MRI contrast, and stain tumor tissue by fluorescence, is a good candidate for cancer theranostic applications. PMID- 25908172 TI - Bioinformatics analyses of significant prognostic risk markers for thyroid papillary carcinoma. AB - This study was aimed to identify the prognostic risk markers for thyroid papillary carcinoma (TPC) by bioinformatics. The clinical data of TPC and their microRNAs (miRNAs) and genes expression profile data were downloaded from The Cancer Genome Atlas. Elastic net-Cox's proportional regression hazards model (EN COX) was used to identify the prognostic associated factors. The receiver operating characteristic (ROC) curve and Kaplan-Meier (KM) curve were used to screen the significant prognostic risk miRNA and genes. Then, the target genes of the obtained miRNAs were predicted followed by function prediction. Finally, the significant risk genes were performed literature mining and function analysis. Total 1046 miRNAs and 20531 genes in 484 cases samples were identified after data preprocessing. From the EN-COX model, 30 prognostic risk factors were obtained. Based on the 30 risk factors, 3 miRNAs and 11 genes were identified from the ROC and KM curves. The target genes of miRNA-342 such as B-cell CLL/lymphoma 2 (BCL2) were mainly enriched in the biological process related to cellular metabolic process and Disease Ontology terms of lymphoma. The target genes of miRNA-93 were mainly enriched in the pathway of G1 phase. Among the 11 prognostic risk genes, v maf avian musculoaponeurotic fibrosarcoma oncogene homologue F (MAFF), SRY (sex determining region Y)-box 4 (SOX4), and retinoic acid receptor, alpha (RARA) encoded transcription factors. Besides, RARA was enriched in four pathways. These prognostic markers such as miRNA-93, miRNA-342, RARA, MAFF, SOX4, and BCL2 may be used as targets for TPC chemoprevention. PMID- 25908173 TI - Japonicone A inhibits the growth of non-small cell lung cancer cells via mitochondria-mediated pathways. AB - Japonicone A, which is a natural product isolated from the aerial part of Inula japonica Thunb., has a wide range of clinical applications, including anti inflammation and anti-oxidation. This study investigated the effects of japonicone A on the growth of non-small cell lung cancer (NSCLC) cell lines. The results showed that japonicone A significantly inhibited the growth of NSCLC cell lines in a dose- and time-dependent manner. This product also blocked cell cycle progression at S phase and induced mitochondrial-related apoptosis by upregulating Bax, cleaved caspase-9, cleaved caspase-3, and cleaved poly(ADP ribose) polymerase (PARP) protein levels and by downregulating Bcl-2, cyclin D1, CDC25A, and CDK2 protein levels. In vivo, japonicone A suppressed tumor growth via the same mechanism as that observed in vitro. In conclusion, our study is the first to report that japonicone A has an inhibitory effect on the growth of NSCLC cells, indicating that japonicone A administration is a potential therapeutic approach for future NSCLC treatments. PMID- 25908174 TI - A novel long noncoding RNA LINC01133 is upregulated in lung squamous cell cancer and predicts survival. AB - Lung adenocarcinoma (LAD) and lung squamous cell cancer (LSCC) are two major histological types of non-small cell lung cancer. LSCC differs greatly from LAD in many aspects. Accumulating evidence has shown that long noncoding RNA (lncRNA) plays an important role in the process of carcinogenesis and tumor progression. Expression of lncRNA is highly tissue-specific and could be biomarkers for cancer diagnosis and prognosis. Here, we identified differentially expressed lncRNA between LSCC and LAD by data mining of Affymetrix HG-U133 Plus 2.0 microarray. A set of 1646 differentially expressed lncRNA transcripts were identified. Among these lncRNAs, a novel lncRNA, LINC01133, showed the largest fold change among large intergenic noncoding RNAs. Quantitative real-time polymerase chain reaction (PCR) assay confirmed that LINC01133 was upregulated in LSCC (increasing fold 6.4, P < 0.01) but not in the LAD samples. LSCC patients with higher expression level of LINC01133 had shorter survival time (hazard ratio = 2.383; 95 % confidence interval 1.023-5.547, P = 0.044). Wound-healing and transwell assays demonstrated that silence of LINC01133 by small interfering RNA (siRNA) inhibited invasion ability of LSCC cell line. Thus, a set of lncRNA was differentially expressed between LAD and LSCC and could serve as potential biomarkers. PMID- 25908175 TI - Adipose cells promote resistance of breast cancer cells to trastuzumab-mediated antibody-dependent cellular cytotoxicity. AB - INTRODUCTION: Trastuzumab has been used in the treatment of human epidermal growth factor receptor 2 (HER2)-expressing breast cancer, but its efficacy is limited by de novo or acquired resistance. Although many mechanisms have been proposed to explain resistance to trastuzumab, little is known concerning the role of the tumor microenvironment. Given the importance of antibody-dependent cellular cytotoxicity (ADCC) in the antitumor effect of trastuzumab and the abundance of adipose tissue in the breast, we investigated the impact of adipocytes on ADCC. METHODS: We set up a coculture system to study the effect of adipocytes on ADCC in vitro. The results were validated in vivo in a mouse xenograft model. RESULTS: We found that adipocytes, as well as preadipocytes, inhibited trastuzumab-mediated ADCC in HER2-expressing breast cancer cells via the secretion of soluble factors. The inhibition of ADCC was not due to titration or degradation of the antibody. We found that adipose cells decreased the secretion of interferon-gamma by natural killer cells, but did not alter natural killer cells' cytotoxicity. Preincubation of breast cancer cells with the conditioned medium derived from adipocytes reduced the sensitivity of cancer cells to ADCC. Using a transcriptomic approach, we found that cancer cells undergo major modifications when exposed to adipocyte-conditioned medium. Importantly, breast tumors grafted next to lipomas displayed resistance to trastuzumab in mouse xenograft models. CONCLUSIONS: Collectively, our findings underline the importance of adipose tissue in the resistance to trastuzumab and suggest that approaches targeting the adipocyte-cancer cell crosstalk may help sensitize cancer cells to trastuzumab-based therapy. PMID- 25908176 TI - Comparative in vitro biological evaluation of daunorubicin containing GnRH-I and GnRH-II conjugates developed for tumor targeting. AB - Hormone based drug targeting is a promising tool for selective tumor therapy. In this study, synthesis and systematic comparative biological evaluation of novel drug containing analogs of gonadotropin-releasing hormone GnRH-I and GnRH-II is reported demonstrating their suitability for tumor targeting. The cytotoxic conjugates were prepared by the attachment of the chemotherapeutical agent daunorubicin (Dau) to GnRH analogs directly or through an enzyme-labile spacer with oxime linkage. All conjugates were found to be proteolytically stable under circumstances applied in biological assays. Both GnRH-I and GnRH-II were able to bind similarly to high-affinity GnRH-I receptors on human pituitary and human prostate cancer cells. The in vitro long-term cytotoxic effect of the conjugates was comparable with that of the free drug in human breast and colon cancer cell lines. Furthermore, a concentration-dependent cellular uptake profile was observed. The in vitro apoptotic effect of the compounds was evaluated by flow cytometry analysis using annexin-V. Our results show that both the GnRH-I and the GnRH-II based analogs might be applied for targeted tumor therapy. PMID- 25908177 TI - Role of disgust proneness in Parkinson's disease: a voxel-based morphometry study. AB - The knowledge about personality traits in Parkinson's disease (PD) is still limited. In particular, disgust proneness has not been investigated as well as its neuronal correlates. Although several morphometric studies demonstrated that PD is associated with gray matter volume (GMV) reduction in olfactory and gustatory regions involved in disgust processing, a possible correlation with disgust proneness has not been investigated. We conducted a voxel-based morphometry analysis to compare GMV between 16 cognitively normal male PD patients with mild to moderate symptoms and 24 matched control subjects. All participants had answered questionnaires for the assessment of disgust proneness, trait anger and trait anxiety. We correlated questionnaire scores with GMV in both groups. The clinical group reported selectively reduced disgust proneness toward olfactory stimuli associated with spoilage. Moreover, they showed GMV reduction in the central olfactory system [orbitofrontal cortex (OFC) and piriform cortex]. Disgust items referring to olfactory processing were positively correlated with OFC volume in PD patients. Our data suggest an association between PD-associated neurodegeneration and olfactory related facets of the personality trait disgust proneness. PMID- 25908178 TI - Proceedings from the 7th Annual International Society for Musculoskeletal Imaging in Rheumatology (ISEMIR) conference. AB - The International Society for Musculoskeletal Imaging in Rheumatology (ISEMIR) was founded in 2005 with the goal of discussing matters related to imaging in rheumatology, particularly, validation, education, and use in clinical practice and research. Because the field of musculoskeletal (MSK) imaging is rapidly evolving, continuous education in the field is imperative. ISEMIR's international faculty and world-renowned experts presented the newest information as it relates to the use of magnetic resonance imaging (MRI) and ultrasound (US) at the 7th annual ISEMIR meeting which took place on April 12-14, 2014 in Santa Monica, California. Presentations from the meeting can be viewed at www.isemir.org. PMID- 25908179 TI - Rituximab for eosinophilic granulomatosis with polyangiitis with severe vasculitic neuropathy: Case report and review of current clinical evidence. AB - OBJECTIVE: Rituximab is approved for the treatment of granulomatosis with polyangiitis and microscopic polyangiitis. Our objective was to review published clinical evidence on the efficacy of rituximab in the treatment of eosinophilic granulomatosis and polyangiitis (EGPA). METHODS: We describe a case of refractory EGPA with severe vasculitic neuropathy, which responded impressively to B-cell depleting therapy. A systematic search of the English literature was also performed to capture all available clinical evidence on the use of rituximab in EGPA. RESULTS: We identified a total of 73 EGPA patients who have been treated with rituximab, all data coming from case series or isolated case reports. The majority of patients (85.1%) were treated for refractory or relapsing disease; a mean (SD) of 2.1 (0.9) different immunosuppressive agents were used prior to rituximab administration. Efficacy of RTX therapy was significant in the majority of cases and in a wide variety of disease manifestations; however, a lack of standardized assessment of disease activity before and after treatment was observed in many reports. Overall, 54.0% of patients were treated with a single cycle of rituximab and only 10.8% experienced relapses of the disease. Few significant side effects were observed during a highly variable period of follow up (3 months to 5 years), mainly severe infections and allergic reactions. CONCLUSIONS: RTX seems to be effective in cases of severe EGPA refractory to standard of care immunosuppressive treatment, although support comes from case reports and non-controlled studies. PMID- 25908180 TI - Quetiapine-induced ischemic colitis. A case report. PMID- 25908181 TI - [Endoscopic resection of a dermoid rectal cyst]. PMID- 25908182 TI - Commentary for Special Issue "Public health is new in Saudi Arabia. With this degree, I can go back and help to develop the field there."--Naif Mohammed Alraihan, King Abdullah Fellow, Rollins School of Public Health, 2015. PMID- 25908183 TI - Integrated care scheme for older people will roll out across England. PMID- 25908184 TI - Meta-analyses triggered by previous (false-)significant findings: problems and solutions. AB - BACKGROUND: Meta-analyses are typically triggered by a (potentially false significant) finding in one of the preceding primary studies. We studied consequences of meta-analysis investigating effects when primary studies that triggered such meta-analysis are also included. METHODS: We analytically determined the bias of the treatment effect estimates obtained by meta-analysis, conditional on the number of included primary and false-significant studies. The type I error rate and power of the meta-analysis were assessed using simulations. We applied a method for bias-correction, by subtracting an analytically derived bias from the treatment effect estimated in meta-analysis. RESULTS: Bias in meta analytical effects and type I error rates increased when increasing numbers of primary studies with false-significant effects were included. When 20% of the primary studies showed false-significant effects, the bias was 0.33 (z-score) instead of 0, and the type I error rate was 23% instead of 5%. After applying a bias-correction, the type I error rate became indeed 5%. CONCLUSIONS: Inclusion of primary studies with false-significant effects leads to biased effect estimates and inflated type I error rates in the meta-analysis, depending on the number of false-significant studies. This bias can be adjusted for. PMID- 25908185 TI - Self-induced metabolic state switching by a tunable cell density sensor for microbial isopropanol production. AB - Chemicals production by engineered microorganisms often requires induction of target gene expression at an appropriate cell density to reduce conflict with cell growth. The lux system in Vibrio fischeri is a well-characterized model for cell density-dependent regulation of gene expression termed quorum sensing (QS). However, there are currently no reports for application of the lux system to microbial chemical production. Here, we constructed a synthetic lux system as a tunable cell density sensor-regulator using a synthetic lux promoter and a positive feedback loop in Escherichia coli. In this system, self-induction of a target gene expression is driven by QS-signal, and its threshold cell density can be changed depending on the concentration of a chemical inducer. We demonstrate auto-redirection of metabolic flux from central metabolic pathways toward a synthetic isopropanol pathway at a desired cell density resulting in a significant increase in isopropanol production. PMID- 25908187 TI - [Cariology update and research direction]. PMID- 25908186 TI - Rational design of 'controller cells' to manipulate protein and phenotype expression. AB - Coordination between cell populations via prevailing metabolic cues has been noted as a promising approach to connect synthetic devices and drive phenotypic or product outcomes. However, there has been little progress in developing 'controller cells' to modulate metabolic cues and guide these systems. In this work, we developed 'controller cells' that manipulate the molecular connection between cells by modulating the bacterial signal molecule, autoinducer-2, that is secreted as a quorum sensing (QS) signal by many bacterial species. Specifically, we have engineered Escherichia coli to overexpress components responsible for autoinducer uptake (lsrACDB), phosphorylation (lsrK), and degradation (lsrFG), thereby attenuating cell-cell communication among populations. Further, we developed a simple mathematical model that recapitulates experimental data and characterizes the dynamic balance among the various uptake mechanisms. This study revealed two controller 'knobs' that serve to increase AI-2 uptake: overexpression of the AI-2 transporter, LsrACDB, which controls removal of extracellular AI-2, and overexpression of the AI-2 kinase, LsrK, which increases the net uptake rate by limiting secretion of AI-2 back into the extracellular environment. We find that the overexpression of lsrACDBFG results in an extraordinarily high AI-2 uptake rate that is capable of completely silencing QS mediated gene expression among wild-type cells. We demonstrate utility by modulating naturally occurring processes of chemotaxis and biofilm formation. We envision that 'controller cells' that modulate bacterial behavior by manipulating molecular communication, will find use in a variety of applications, particularly those employing natural or synthetic bacterial consortia. PMID- 25908188 TI - [Morphology study of mandibular incisive canal in adults based on cone-beam computed tomography]. AB - OBJECTIVE: To investigate the mandibular incisive canal (MIC) with cone-beam computed tomography (CBCT). METHODS: Fifty adults were selected and CBCT was taken. The CBCT data were reconstructed to evaluate the visibility, shape, diameter, length of the MIC and its relationship with mandible. RESULTS: MIC could be identified in 100% (100/100) of CBCT with good clarity in 71% (71/100). The diameters (horizontal diameter versus vertical diameter) of MIC became smaller from origin to end (left origin of MIC was 2.17 mm*2.22 mm, left end was 0.82 mm*0.92 mm; right origin of MIC was 2.14 mm*2.08 mm, right end was 0.87 mm*0.86 mm). The left and right mean length of MIC was 17.84 mm and 17.73 mm respectively. In bucca-lingual direction, MIC was close to buccal cortical border, and in vertical direction, MIC was close to lower margin of mandible. The distance from MIC to apex of root was shortest in canine. CONCLUSIONS: CBCT can identify MIC with high visibility and prominent clarity. In the interforaminal region of mandible, MIC was close to buccal and lower margin of mandible. PMID- 25908189 TI - [Variations of sulfhydryl compounds of saliva and plasma in healthy population of different ages]. AB - OBJECTIVE: To analyze the effect of age and gender on sulfhydryl compounds content in saliva and plasma in healthy population and to study the relationship between sulfhydryl compounds content of saliva and plasma to provide a basis for clinical examination of saliva sulfhydryl compounds. METHODS: Sulfhydryl compounds content of saliva and plasma were measured in 306 healthy adults from the Department of Clinical Laboratory of Health Management lnstitute of General Hospital of Chinese PLA (151 female and 155 male) who were divided into young group (20-44 years old, n = 106, 48 female and 58 male), middle-aged group (45-59 years old, n = 109, 63 female and 46 male) and elderly group (60-79 years old, n = 91, 40 female and 51 male). RESULTS: Sulfhydryl compounds content in saliva and plasma in 306 healthy adults were (123+/-27) and (427+/-124) umol/L respectively. Sulfhydryl compounds content in saliva and plasma were significantly decreased as age increased (both P < 0.01). Significant differences of sulfhydryl compounds content of saliva and plasma among the young group, middle-aged group and elderly group were found (P < 0.01). No sex difference was observed in saliva sulfhydryl compounds content (P = 0.451), however the sex difference was significant in plasma sulfhydryl compounds content (P = 0.006). There was a significantly positive correlation between sulfhydryl compounds content in saliva and plasma (r = 0.5050, P < 0.01). CONCLUSIONS: Saliva sulfhydryl compounds content can roughly reflect plasma sulfhydryl compounds content. Saliva sulfhydryl compounds test is a promising biological index of aging which could be an alternative of plasma test. PMID- 25908190 TI - [A cone-beam computed tomography evaluation of maxillary protraction with repetitive rapid palatal expansions and constrictions]. AB - OBJECTIVE: To investigate the effects of maxillary protraction combined with repetitive rapid palatal expansions and constrictions (RPE/C) vs. rapid palatal expansion (RPE) alone using cone-beam computed tomography (CBCT). METHODS: Twenty four subjects with maxillary retrusion were recruited and block randomized into either the control group (n = 12) or the RPE/C (n = 12) group. CONTROL GROUP: facemask protraction after RPE. RPE/C group: facemask protraction after RPE/C. 3D reconstruction, landmarks identifying, superimposition and cephalometric analysis were performed to compare the pre-treatment and post- treatment CBCT images. RESULTS: One subject in the RPE/C group was lost to follow up during the treatment. Maxilla moved forward [(2.5+/-1.0) mm] after maxillary protraction with RPE/C, which was significantly greater than that in the control group [(1.6+/-0.8) mm] (P < 0.05). The distance of basion to subspinale (Ba-A) increased [(3.1+/-1.0) mm] in the RPE/C group, which was significantly greater than that in the control group [(2.2 +/- 0.9) mm] (P < 0.05). The amount of forward movement of upper first molars was significantly greater in the RPE/C group (P < 0.05). CONCLUSIONS: Maxillary protraction with RPE/C might positively affect the forward movement of maxilla compared with the RPE alone protocol with the early treatment of maxillary retrusion patients. PMID- 25908191 TI - [Three-dimensional finite element analysis on En mass intrusion and retraction of maxillary anterior teeth with J-hook headgear]. AB - OBJECTIVE: To investigate the biomechanics of J-hook headgear in En mass intrusion and retraction of maxillary anterior teeth and provide guidance for clinical treatment. METHODS: A three-dimensional finite element model of maxillary teeth, periodontium, straight wire appliance and maxillary bone was established in ANSYS 14.0. En mass retraction of anterior teeth with force of 1.5 N through J-hook headgear was stimulated. Force was applied mesial to lateral incisor in group A and distal to lateral incisor in group B. The force direction was 30 degrees to the sagittal plane and 20 degrees to 60 degrees to the occlusal plane. Force direction to the occlusal plane was changed every 5 degrees and 18 cases were calculated. Displacement of upper anterior teeth and stress distribution in the periodontium were analyzed. RESULTS: As the degrees of force direction to the occlusal plane increased, the moving pattern of upper anterior teeth changed from clockwise rotation (lingual movement with intrusion) to bodily retraction and intrusion, and counter- clockwise rotation (intrusion with labial movement). With the force direction of 35 degrees to occlusal plane applied mesial to lateral incisor or force direction of 45 degrees to the occlusal plane applied distal to lateral incisor, bodily movement of upper anterior teeth without rotation was achieved. CONCLUSIONS: Placement of J-hook mesial to lateral incisor enable orthodontists to maintain better en mass intrusion and retraction of upper anterior teeth. The direction of J-hook should be adjusted according to individual condition and treatment objective. PMID- 25908192 TI - [Effect of hypoxia on the proliferation and expressions of hypoxia-inducible factor-1alpha, vascular endothelial growth factor and matrix metalloproteinase-9 in keratinocytes obtained from oral lichen planus lesions]. AB - OBJECTIVE: To investigate the effect of hypoxia on the proliferation and expressions of hypoxia-inducible factor-1alpha (HIF-1alpha), vascular endothelial growth factor (VEGF) and matrix metalloproteinase-9 (MMP-9) in keratinocytes obtained from oral lichen planus (OLP) lesions. METHODS: Hypoxia environment was induced by a airtight incubator. Five groups were included, normoxia control group, hypoxia control group (12, 24, 36, 48 h). The effect of different treatment time of hypoxia on cellular proliferation was determined with cell counting kit-8 (CCK-8). The mRNA and protein expressions of HIF-1alpha, VEGF and MMP-9 were analyzed respectively by quantitative real-time polymerase chain reaction with SYBR Green I and Western blotting. RESULTS: The growth activity of keratinocytes obtained from OLP lesions in the hypoxia groups (0.340+/-0.002, 0.415+/-0.006, 0.546+/-0.006) was reduced than that in control (0.431+/-0.001, 0.620+/-0.004, 1.022+/-0.005) (P < 0.01). The mRNA levels of VEGF (2.087+/-0.291, 3.189+/-0.573, 5.402+/-0.563) and MMP-9 (2.936+/-0.500, 4.083+/-0.300, 6.374+/ 0.858) were elevated by hypoxia (P < 0.05). The protein levels of HIF- 1alpha (0.414+/-0.093, 0.751+/-0.056, 0.875+/-0.040), VEGF (0.393+/-0.046, 0.557+/ 0.078, 0.767+/-0.045) and MMP-9 (0.250+/-0.053, 0.384+/-0.038, 0.611+/-0.092) were all remarkably elevated by hypoxia (P < 0.05). However, hypoxia had no effect on HIF-1alpha mRNA expression. The mRNA expression of HIF-1alpha after hypoxia exposure for 36 h (1.412+/-0.094) and 48 h (1.417+/-0.446) was higher than that of control group, however, there was no significant difference. A positive correlation was noted between HIF-1alpha and VEGF in protein level (r = 0.905, P = 0.000), and the same correlation found between HIF-1alpha and MMP-9 (r = 0.881, P = 0.000). CONCLUSIONS: Hypoxia conditions may inhibit the proliferation of keratinocytes obtained from OLP lesions. Hypoxia conditions can promote the protein expressions of HIF-1alpha and both the mRNA and protein expression of VEGF and MMP-9 in keratinocytes obtained from OLP lesions exposed to hypoxia. The relative high expression of HIF-1alpha may be involved in multiple aspects of OLP progression through the regulation of its downstream target genes. PMID- 25908193 TI - [Evaluation of the esthetic effect of resin cements on the final color of ceramic veneer restorations]. AB - OBJECTIVE: To evaluate the influence of various shades of resin cements on the final color of an improved lithium-disilicate pressed glass ceramic veneers and analyze the agreement of resin cements and corresponding try-in pastes. METHODS: Forty-eight artificial maxillary central incisor teeth were sequenced according to the measured color parameters and divided at random into 8 groups (n = 6). These artificial teeth were prepared following veneer preparation protocol. An improved lithium- disilicate pressed glass ceramic materials (IPS e.max Press, Ivoclar Vivadent) were selected as the veneer material. The shape and curvature of each veneer wax pattern were duplicated with the same impression to guarantee the similarity. The ceramic veneer specimens were delivered on the artificial teeth using the corresponding try-in pastes of 8 shades (Variolink Veneer, shades of LV-3, LV-2, MV, HV+2, HV+3; and 3M RelyXTM Veneer, shades of WO, TR, A3) and bonded with the resin cements. A clinical spectrophotometer was used to measure the color parameters of the ceramic veneers before the try-in, during the try-in procedure, and after cementation. DeltaE values and C*ab values were calculated. RESULTS: The result of one-way ANOVA indicated that the color changes of ceramic veneer cementation with resin cements were statistically significantly different in the shades of resin cements (P < 0.001). The DeltaE values of ceramic veneer after cementation ranged from 0.93 to 6.79. The color changes of ceramic veneer specimens using the shades of LV-3, HV+3, WO were 3.31, 4.90 and 6.79, respectively (DeltaE>3.3). The DeltaE values of the ceramic veneer specimens between the resin cements and corresponding try-in pastes were from 0.72 to 1.79 (except the shade of HV+3). CONCLUSIONS: The LV-3, HV+3, WO shades were able to change the final color of a ceramic veneer. The color of resin cements and corresponding try-in pastes achieved high agreement (except the shade of HV+3). PMID- 25908194 TI - [Effect of parathyroid hormone (1-34) and coralline hydroxyapatite on bone regeneration of peri-implant bone defects]. AB - OBJECTIVE: To evaluate the effect of parathyroid hormone (1-34) [PTH(1-34)] and coralline hydroxyapatite (CHA) on bone regeneration of peri- implant bone defects. METHODS: Two implant sites were prepared on both sides of tibia in 8 mongrel dogs. The bone defect was created along one bone wall of each implant site. Implants were implanted into the implant sites, then CHA was grafted into the bone defects. After surgery, the animals were randomly divided into two groups. PTH (1-34) (40 ug/kg) was used for subcutaneous injection to the experimental group for three consecutive days, meanwhile the same amount of saline was given to the control group. Half of the animals of each group were sacrificed after 4 weeks and 8 weeks respectively. Specimens were subjected to implant pull- out strength tests, X-ray picture and histological observation. RESULTS: The bone density of bone defects in the experimental group were higher than that in the control group. No low-density images was observed between the implants and bone at 4 weeks and 8 weeks. The maximum pull-out force value of the experimental group (199.8 N, 411.5 N) was higher at 4 weeks and 8 weeks than that of the control group (100.1 N, 184.5 N) (P < 0.05). The pull-out force value of the experimental group at 4 weeks and the pull-out force value of the control group at 8 weeks were similar. The new bone trabecular around CHA of experimental group was thicker at 4 weeks. Implant surface contacted to the new bone directly without fiber. CHA granules of the experimental group at 8 weeks were fewer than that of the control group. New bone tissue of the experimental group was denser. The contact area between implant surface and new bone was wider in experimental group than in the control group. CONCLUSIONS: PTH (1-34) and CHA can promote bone regeneration of peri-implant bone defects, shorten the implants and bone healing cycle and improve the implants osseointegration. PMID- 25908195 TI - [The capacity and biological characteristic of the p75 neurotrophin receptor positive ectomesenchymal stem cell in vitro]. AB - OBJECTIVE: To investigate the biological characteristic of ectomesenchymal stem cells (EMSC) and the differentiation of p75(+)EMSC and influencing factors. METHODS: The immunohistochemical staining method was used to observe the migration of EMSC from 12.5 d SD rat embryonic facial process. Then EMSC was labeled by p75 neurotrophin receptor, and the cell cycle and stem cell surface antigens of the p75(+) EMSC was examined. RESULTS: Immunohistochemical staining showed that stem cells from the cranial neural crest migrated to embryonic rat facial process at 12.5 days. The sorting rate of the p75(+)EMSC was 6.1%. The proportion of the p75(+)EMSCs' S/G2/M phase was stable during subculture. The special substances CD29, CD146 and Stro-1 were marked for p75(+)EMSC, and the expressions of the markers were all higher (> 90%) in p75(+) EMSC. CONCLUSIONS: The embryonic tooth did not start to grow on the conception 12.5 days of SD rats. The p75(+) EMSC after sorting had stable proliferation ability and had stem cell characteristics during subculture and didn't start differentiation. PMID- 25908196 TI - [Acne fulminans associated with the osteolytic lesion of alveolar bone for ten years follow-up]. PMID- 25908197 TI - [Modified dextrose prolotherapy for the treatment of recurrent temporomandibular joint dislocation]. PMID- 25908198 TI - [Bisphosphonate drugs and dental implant]. PMID- 25908199 TI - [Development of the molecular mechanism in the pathogenesis of infantile haemangioma]. PMID- 25908200 TI - [Summary of annual conference 2014 of the chinese stomatological association professional committee of the oral mucosa disease and the combination of chinese traditional and Western medicine, and the interdisciplinary symposiun on the combination of oral and general health]. PMID- 25908201 TI - [Klippel-Feil syndrome with thenar hypoplasia:a case report and literature review]. PMID- 25908202 TI - [Analysis of subcutaneous emphysema during root canal preparation in pediatric dentistry with cone-beam CT]. PMID- 25908203 TI - [Surgical excision of Langerhans cell histocytosis in condyloid process in adult]. PMID- 25908204 TI - Modelling cell cycle synchronisation in networks of coupled radial glial cells. AB - Radial glial cells play a crucial role in the embryonic mammalian brain. Their proliferation is thought to be controlled, in part, by ATP mediated calcium signals. It has been hypothesised that these signals act to locally synchronise cell cycles, so that clusters of cells proliferate together, shedding daughter cells in uniform sheets. In this paper we investigate this cell cycle synchronisation by taking an ordinary differential equation model that couples the dynamics of intracellular calcium and the cell cycle and extend it to populations of cells coupled via extracellular ATP signals. Through bifurcation analysis we show that although ATP mediated calcium release can lead to cell cycle synchronisation, a number of other asynchronous oscillatory solutions including torus solutions dominate the parameter space and cell cycle synchronisation is far from guaranteed. Despite this, numerical results indicate that the transient and not the asymptotic behaviour of the system is important in accounting for cell cycle synchronisation. In particular, quiescent cells can be entrained on to the cell cycle via ATP mediated calcium signals initiated by a driving cell and crucially will cycle in near synchrony with the driving cell for the duration of neurogenesis. This behaviour is highly sensitive to the timing of ATP release, with release at the G1/S phase transition of the cell cycle far more likely to lead to near synchrony than release during mid G1 phase. This result, which suggests that ATP release timing is critical to radial glia cell cycle synchronisation, may help us to understand normal and pathological brain development. PMID- 25908205 TI - The leg stiffnesses animals use may improve the stability of locomotion. AB - Despite a wide diversity of running animals, their leg stiffness normalized by animal size and weight (a relative leg stiffness) resides in a narrow range between 7 and 27. Here we determine if the stability of locomotion could be a driving factor for the tight distribution of animal leg stiffness. We simulated an established physics-based model (the actuated Spring-Loaded Inverted Pendulum model) of animal running and found that, with the same energetic cost, perturbations to locomotion are optimally corrected when relative leg stiffness is within the biologically observed range. Here we show that the stability of locomotion, in combination with energetic cost, could be a significant factor influencing the nearly universally observed animal relative leg stiffness range. The energetic cost of locomotion has been widely acknowledged as influencing the evolution of physiology and locomotion behaviors. Specifically, its potential importance for relative leg stiffness has been demonstrated. Here, we demonstrate that stability of locomotion may also be a significant factor influencing relative leg stiffness. PMID- 25908206 TI - iPPI-Esml: An ensemble classifier for identifying the interactions of proteins by incorporating their physicochemical properties and wavelet transforms into PseAAC. AB - A cell contains thousands of proteins. Many important functions of cell are carried out through the proteins therein. Proteins rarely function alone. Most of their functions essential to life are associated with various types of protein protein interactions (PPIs). Therefore, knowledge of PPIs is fundamental for both basic research and drug development. With the avalanche of proteins sequences generated in the postgenomic age, it is highly desired to develop computational methods for timely acquiring this kind of knowledge. Here, a new predictor, called "iPPI-Emsl", is developed. In the predictor, a protein sample is formulated by incorporating the following two types of information into the general form of PseAAC (pseudo amino acid composition): (1) the physicochemical properties derived from the constituent amino acids of a protein; and (2) the wavelet transforms derived from the numerical series along a protein chain. The operation engine to run the predictor is an ensemble classifier formed by fusing seven individual random forest engines via a voting system. It is demonstrated with the benchmark dataset from Saccharomyces cerevisiae as well as the dataset from Helicobacter pylori that the new predictor achieves remarkably higher success rates than any of the existing predictors in this area. The new predictor' web-server has been established at http://www.jci-bioinfo.cn/iPPI Esml. For the convenience of most experimental scientists, we have further provided a step-by-step guide, by which users can easily get their desired results without the need to follow the complicated mathematics involved during its development. PMID- 25908207 TI - New virus dynamics in the presence of multiple infection. AB - While most aspects of virus dynamics are well understood in standard models, the phenomenon of multiple infection (or coinfection) can change the properties of the dynamics, and this has so far not been fully explored. An important parameter in determining the properties of the model is the virus output from multiply infected cells compared to that from singly infected cells. If the amount of virus produced by infected cells during their life-span is independent of the infection multiplicity, then multiple infection does not change the dynamics. If, however, multiply infected cells produce more virus during their life-span than singly infected cells, then the properties of the dynamics can change fundamentally. This paper presents a detailed mathematical analysis of this scenario. We demonstrate that under some realistic conditions, the equilibrium structure of the solutions acquires novel properties. In particular, infection can persist even for values of the basic reproductive number, R0, smaller than unity. In this regime, we observe the phenomenon of bistability, when two stable equilibria are present simultaneously, and the outcome is determined by the initial conditions. The two possible solutions are the virus-free equilibrium, which is exactly the same as the one observed in the absence of multiple infection, and a novel infection equilibrium. In the presence of this outcome, it is clear that the meaning of the parameter R0 changes, as it no longer simply indicates the possibility of successful infection. This adds to our understanding and interpretation of R0 in virus dynamics models, and also provides further insights about conditions that can lead to virus extinction rather than persistence. It turns out that conditions for bistability depend (in a fully specified way) on the model structure, particularly on the way the infection term is formulated. We provide a general condition that informs us whether or not bistability occurs, and define what needs to be measured when examining the dynamics of multiple infection in specific biological systems. PMID- 25908208 TI - Piecewise virus-immune dynamic model with HIV-1 RNA-guided therapy. AB - Clinical studies have used CD4 T cell counts to evaluate the safety or risk of plasma HIV-1 RNA-guided structured treatment interruptions (STIs), aimed at maintaining CD4 T cell counts above a safe level and plasma HIV-1 RNA below a certain level. However, quantifying and evaluating the impact of STIs on the control of HIV replication and on activation of the immune response remains challenging. Here we extend the virus-immune dynamic system by including a piecewise smooth function to describe the elimination of HIV viral loads and the activation of effector cells under plasma HIV-1 RNA-guided therapy, in order to quantitatively explore the STI strategies. We theoretically investigate the global dynamics of the proposed Filippov system. Our main results indicate that HIV viral loads could either go to infinity or be maintained below a certain level or stabilize at a previously given level, depending on the threshold level and initial HIV virus loads and effector cell counts. This suggests that proper combinations of threshold and initial HIV virus loads and effector cell counts, based on threshold policy, can successfully preclude exceptionally high growth of HIV virus and, in particular, maximize the controllable region. PMID- 25908209 TI - Freedom of Choice About Incidental Findings Can Frustrate Participants' True Preferences. AB - Ethicists, regulators and researchers have struggled with the question of whether incidental findings in genomics studies should be disclosed to participants. In the ethical debate, a general consensus is that disclosed information should benefit participants. However, there is no agreement that genetic information will benefit participants, rather it may cause problems such as anxiety. One could get past this disagreement about disclosure of incidental findings by letting participants express their preferences in the consent form. We argue that this freedom of choice is problematic. In transferring the decision to participants, it is assumed that participants will understand what they decide about and that they will express what they truly want. However, psychological findings about people's reaction to probabilities and risk have been shown to involve both cognitive and emotional challenges. People change their attitude to risk depending on what is at stake. Their mood affects judgments and choices, and they over- and underestimate probabilities depending on whether they are low or high. Moreover, different framing of the options can steer people to a specific choice. Although it seems attractive to let participants express their preferences to incidental findings in the consent form, it is uncertain if this choice enables people to express what they truly prefer. In order to better understand the participants' preferences, we argue that future empirical work needs to confront the participant with the complexity of the uncertainty and the trade-offs that are connected with the uncertain predictive value of genetic risk information. PMID- 25908210 TI - Regulation by gut commensal bacteria of carcinoembryonic antigen-related cell adhesion molecule expression in the intestinal epithelium. AB - Carcinoembryonic antigen-related cell adhesion molecule (CEACAM) 1 and CEACAM20, immunoglobulin superfamily members, are predominantly expressed in intestinal epithelial cells (IECs) and co-localized at the apical surface of these cells. We here showed that the expression of mouse CEACAM1 and CEACAM20 at both mRNA and protein levels was markedly reduced in IECs of the small intestine by the treatment of mice with antibiotics against Gram-positive bacteria. The expression of both proteins was also decreased in IECs of the small intestine from germ-free mice, compared with that from control specific-pathogen-free mice. Exposure of intestinal organoids to IFN-gamma markedly increased the expression of either CEACAM1 or CEACAM20, whereas the exposure to TNF-alpha increased the expression of the former protein, but not that of the latter. In contrast, the expression of CEACAM20, but not of CEACAM1, in intestinal organoids was markedly increased by exposure to butyrate, a short-chain fatty acid produced by bacterial fermentation in the intestine. Collectively, our results suggest that Gram-positive bacteria promote the mRNA expression of CEACAM1 or CEACAM20 in the small intestine. Inflammatory cytokines or butyrate likely participates in such effects of commensal bacteria. PMID- 25908211 TI - Outcome of gastric emptying and gastrointestinal symptoms after liver transplantation for hereditary transthyretin amyloidosis. AB - BACKGROUND: Hereditary transthyretin amyloid (ATTR) amyloidosis is a rare but fatal autosomal dominant condition that is present all over the world. A liver transplantation has been shown to halt the progress of the disease in selected patients and is currently considered to be the standard treatment. Gastrointestinal manifestations are common in hereditary ATTR amyloidosis and are important for the patients' morbidity and mortality. The aim of this study was to evaluate the long-term outcome of gastric emptying, gastrointestinal symptoms and nutritional status after liver transplantation for the disease. METHODS: Swedish patients with hereditary ATTR amyloidosis transplanted between 1990 and 2012 were included. A standardized method for measuring gastric emptying with a Tc(99m) labelled meal followed by scintigraphy was utilized. Validated questionnaires were used to assess gastrointestinal symptoms and the modified body mass index (mBMI), in which BMI is multiplied by s-albumin, was used to evaluate nutritional status. Non-parametrical statistical tests were used. RESULTS: Gastric emptying rates and nutritional statuses were evaluated approximately eight months before and two and five years after liver transplantation, whereas gastrointestinal symptoms were assessed in median nine months before and two and nine years after transplantation. No significant change was found in gastric emptying (median half time 137 vs. 132 vs. 125 min, p = 0.52) or nutritional status (median mBMI 975 vs. 991 vs. 973, p = 0.75) after transplantation. Gastrointestinal symptom scores, however, had increased significantly over time (median score 7 vs. 10 vs. 13, p < 0.01). CONCLUSIONS: Gastric emptying and nutritional status were maintained after liver transplantation for hereditary ATTR amyloidosis, although gastrointestinal symptom scores had increased over time. PMID- 25908212 TI - Cholestatic Liver Injury After Biliary Reconstruction Impairs Transplanted Islet Viability and Function. AB - Islet autotransplantation following total pancreatectomy differs from allograft transplantation with respect to the requirement of biliary reconstruction. Although it is known that careful consideration should be given to postoperative cholestatic liver injury after biliary reconstruction, its direct effects on transplanted islets have not been completely elucidated. In this study, we developed a murine model of postoperative cholestatic liver injury after biliary reconstruction with islet autotransplantation that involved syngeneic intraportal islet transplantation into chemically induced diabetic mice and common bile duct ligation. We assessed the viability and function of the transplanted islets. The impaired viability of transplanted islets and increased blood glucose levels indicated restoration of the diabetic state after common bile duct ligation in this murine model. Furthermore, impaired islet viability and function occurred earlier in the transplanted islets than in the surrounding liver tissues, which was consistent with the faster and higher expression of oxidative stress markers in the transplanted islets. Transplanted islets may be more vulnerable to oxidative stress caused by cholestatic liver injury than the surrounding liver tissue. Therefore, patients should be intensively managed after total pancreatectomy with islet autotransplantation to preserve viability and function of the transplanted islets. PMID- 25908213 TI - Synthesis and Characterization of a Gold Vinylidene Complex Lacking pi-Conjugated Heteroatoms. AB - Hydride abstraction from the gold (disilyl)ethylacetylide complex [(P)Au{eta(1) C=CSi(Me)2CH2CH2SiMe2H}] (P=P(tBu)2o-biphenyl) with triphenylcarbenium tetrakis(pentafluorophenyl)borate at -20 degrees C formed the cationic gold (beta,beta-disilyl)vinylidene complex [(P)Au=C=CSi(Me)2CH2CH2Si(Me)2](+)B(C6F5)4( ) with >=90% selectivity. (29)Si NMR analysis of this complex pointed to delocalization of positive charge onto both the beta-silyl groups and the (P)Au fragment. The C1 and C2 carbon atoms of the vinylidene complex underwent facile interconversion (DeltaG(?)=9.7 kcal mol(-1)), presumably via the gold pi disilacyclohexyne intermediate [(P)Au{eta(2) C=CSi(Me)2CH2CH2Si(Me)2}](+)B(C6F5)4(-). PMID- 25908214 TI - [Illness and jaundice. Copalchi toxic hepatitis]. PMID- 25908215 TI - MicroRNA-218 increases cellular sensitivity to Rapamycin via targeting Rictor in cervical cancer. AB - We previously reported that microRNA-218 was frequently lost in cervical cancer and restoration of microRNA-218 increased cellular radio-sensitivity via inhibiting. Herein, we aim to investigate the effects of microRNA-218 on cellular response to mTOR inhibition. The expression of microRNA-218 and Rictor were measured by Taqman PCR and real time PCR in a panel of 15 cervical cancer tissues. MicroRNA-218 was stably overexpressed in four cervical cancer cell lines and a series of in vitro and in vivo experiments were performed to investigate cellular sensitivity to Rapamycin. In primary cultured cervical cancer cells, the expression of microRNA-218 was negatively correlated with the mRNA level of Rictor, which predicted cellular sensitivity to Rapamycin (p = 0.002, R(2) = 0.6810). In vitro, overexpression of microRNA-218 significantly reduced the level of Rictor and enhanced the growth-inhibition, cell cycle arrest, and apoptosis induced by Rapamycin. In vivo, overexpression of microRNA-218 further enhanced the suppressive effects of Rapamycin on tumor growth. In conclusion, we demonstrated that microRNA-218 could re-sensitize cervical cancer to Rapamycin through targeting Rictor. Moreover, patients with loss of microRNA-218 presented notable resistance to Rapamycin, indicating that microRNA-218 might be a valid marker for patients-stratification in future clinical trials. PMID- 25908216 TI - Estimate variable importance for recurrent event outcomes with an application to identify hypoglycemia risk factors. AB - Recurrent event data are an important data type for medical research. In particular, many safety endpoints are recurrent outcomes, such as hypoglycemic events. For such a situation, it is important to identify the factors causing these events and rank these factors by their importance. Traditional model selection methods are not able to provide variable importance in this context. Methods that are able to evaluate the variable importance, such as gradient boosting and random forest algorithms, cannot directly be applied to recurrent events data. In this paper, we propose a two-step method that enables us to evaluate the variable importance for recurrent events data. We evaluated the performance of our proposed method by simulations and applied it to a data set from a diabetes study. PMID- 25908217 TI - Effect of Acupuncture on the Notch Signaling Pathway in Rats with Brain Injury. AB - OBJECTIVE: To observe the effect of acupuncture on the Notch signaling pathway in rats with traumatic brain injury and to explore the pathogenesis of acupuncture intervention on traumatic brain injury. METHODS: Feeney's freefall epidural impact method was used to establish a traumatic brain injury model in rats; the rats were randomly divided into a normal group, sham operation group, model group and acupuncture group. Acupuncture was performed in the Baihui (DU 20), Shuigou (DU 26), Fengfu (DU 16), Yamen (DU 15) and Hegu (LI 4) acupoints in the rat, and Yamen was punctured via Fengfu. Then, the rats in each group were randomly divided into three subgroups, namely the day 3 subgroup, day 7 subgroup and day 14 subgroup according to treatment duration. The modified neurological severity scores (mNss) method was used to perform neurobehavioral scoring for evaluating the degree of injury in the rats. The hematoxylin-eosin (HE) staining method was used to observe the pathological change in the brain tissue of rats in each group. Real-time fluorescent quantitative polymerase chain reaction (Q-PCR) technology was used to detect changes in the Notch1, Hes1 and Hes5 gene expression levels in the cortex on the injured side. Western blot was used to detect the protein expression changes. RESULTS: One day after modeling, the mNss scores in the model group and in the acupuncture group were significantly higher than those in the normal and sham operation groups (P<0.01) ; there was no statistically significant difference between the normal group and the sham operation group. The scores decreased with increased treatment time, and the scores in the acupuncture group decreased more significantly than those in the model group (P<0.01). The pathological examination by the HE staining method demonstrated that the brain tissue of the rats in the acupuncture and model groups relatively significantly changed. The Notch1 gene expression level in the acupuncture group was significantly higher than the level in all of the other groups (P<0.01) ; the Hes1 and Hes5 gene expression levels were also higher in the acupuncture group. The expression changes of the Notch1 and Hes1 protein were consistent with that of mRNA. In each experimental group, the mNss score and the pathological results by the HE staining method were consistent with the mRNA results. CONCLUSION: Acupuncture could significantly promote high expression levels of Notch1, Hes1 and Hes5 in the brain tissue of traumatic brain injury rats. Therefore, acupuncture might be an important intervention for inducing endogenous stem cell proliferation and for promoting nerve repair. PMID- 25908218 TI - Effect of Puerarin on the Pharmacokinetics of Baicalin in Gegen Qinlian Decoction () in Mice. AB - OBJECTIVE: To study the pharmacokinetics of puerarin (PUE) in Gegen Qinlian Decoction (, GQD), and the effects of PUE dosage variations on the pharmacokinetics of baicalin (BAL) in mice. METHODS: GQD is composed of the concentrated granules of four Chinese herbs. Three dosages with different levels of PUE, including GQD, GQD co-administered with PUE, and GQD co-administration with two times the amount of PUE, were used to research the pharmacokinetics of PUE and BAL in mice. The indirect competitive enzyme-linked immunosorbent assay (icELISA) methods based on an anti PUE-monoclonal antibody (MAb)and BAL-MAb were employed to determine the concentration of PUE and BAL in mice blood. RESULTS: After the co-administration of GQD with PUE, the area under the curves (AUC0-14h) of PUE increased 2.8 times compared with GQD. At the dose of GQD co administration at two times that of PUE, the (AUC0-14h) of PUE was almost equal to that of GQD co-administration of PUE, showing non-linear pharmacokinetics. The (AUC0-48h) of BAL showed a good dose-related increase of PUE (r=0.993) in the range from 100 to 300 mg/kg, indicating that PUE dramatically affects the absorption of BAL in mice. There was no significant difference in the other pharmacokinetic parameters, such as the first time of maximum concentration (Tmax), the second Tmax, or the mean residence time. CONCLUSIONS: The icELISA methods were successfully applied to pharmacokinetic studies of PUE and BAL in GQD in mice. The dosage variability of PUE of the main ingredient in GQD affects its own pharmacokinetic characteristics and the absorption characteristics of BAL. PMID- 25908219 TI - MnCo2O4 nanowires anchored on reduced graphene oxide sheets as effective bifunctional catalysts for Li-O2 battery cathodes. AB - A hybrid composite system of MnCo2 O4 nanowires (MCO NWs) anchored on reduced graphene oxide (RGO) nanosheets was prepared as the bifunctional catalyst of a Li O2 battery cathode. The catalysts can be obtained from the hybridization of one dimensional MCO NWs and two-dimensional RGO nanosheets. As O2 -cathode catalysts for Li-O2 cells, the MCO@RGO composites showed a high initial discharge capacity (ca. 11092.1 mAh gcarbon (-1) ) with a high rate performance. The Li-O2 cells could run for more than 35 cycles with high reversibility under a limited specific capacity of 1000 mAh gcarbon (-1) with a low potential polarization of 1.36 V, as compared with those of pure Ketjenblack and MCO NWs. The high cycling stability, low potential polarization, and rate capability suggest that the MCO@RGO composites prepared here are promising catalyst candidates for highly reversible Li-O2 battery cathodes. PMID- 25908220 TI - Haemostatic and inflammatory alterations in familial hypercholesterolaemia, and the impact of angiotensin II infusion. AB - INTRODUCTION: We examined potential prothrombotic and proinflammatory effects of angiotensin II in 16 otherwise healthy familial hypercholesterolaemia subjects and 16 matched controls. METHODS: Markers of fibrinolysis, thrombin generation and inflammation were assessed in plasma before, during and 1h after a 3h intravenous infusion of angiotensin II. In addition, placebo experiments with saline infusion were carried out. RESULTS: Baseline plasminogen activator inhibitor type-1 activity and plasmin-antiplasmin-complex concentrations were similar in FH and controls, as were interleukin-6, leukocyte counts and C reactive protein. Fibrinogen levels were higher in FH, and we observed a greater thrombin generating potential in FH (calibrated automated thrombogram), but no signs of elevated thrombin generation in vivo (prothrombin fragment 1+2). During angiotensin infusion plasminogen activator inhibitor type-1 activity decreased and plasmin-antiplasmin-complex concentrations increased similarly in FH and controls. Total and maximal amount of thrombin generated was unchanged, as were prothrombin-fragment-1+2 levels. Interleukin-6 and leukocyte counts increased similarly in both groups during angiotensin infusion, while fibrinogen tended to increase in FH and increased in controls. During saline infusion plasminogen activator inhibitor type-1 activity and prothrombin fragment 1+2 concentrations fell, whereas other markers were unchanged. CONCLUSIONS: FH exhibits an increased thrombin generation potential, an intact fibrinolysis, and has no convincing signs of inflammation. Angiotensin has proinflammatory effects, and might have minor profibrinolytic and procoagulatory effects. PMID- 25908221 TI - The use of the 25 Sprotte needle markedly reduces post-dural puncture headache in routine neurological practice. AB - OBJECTIVES: The objectives of this article are to test the feasibility of lumbar puncture (LP) using 25-gauge (G) needles in daily neurological practice and to compare the risk of post-dural puncture headache (PDPH) with four types of needles. METHODS: In a prospective rater-blind study, pros and cons of four different LP needles, the 20G Quincke (20Q), 22G Sprotte (22S), 25G Whitacre (25W) and 25G Sprotte (25S), were evaluated in 394 LPs performed by seven neurologists. The neurologist performing the LP recorded the type and size of needle, intensity of pain, safety, time of the procedure and failure or success. Between five and 15 days later another neurologist, blind to the type of needle used, completed an ad-hoc questionnaire for PDPH. RESULTS: PDPH developed in 35.9% patients when using a 20Q needle, and in 12.9%, 6.8% and 1.6%, respectively, when using a 22S, 25W or 25S needle. The difference in incidence of PDPH following LP performed with the 20Q needle and the 25S or 22S was statistically significant (p < 0.001 and p = 0.008, respectively) and it approached significance when comparing the 25S and 25W (p = 0.06). As 25W and 25S needles need CSF aspiration, LP requires more time and skill. Pain caused by LP was similar with the four needles. CONCLUSION: The use of the 25S needle in diagnostic LP reduces the frequency and severity of PDPH. PMID- 25908222 TI - Populations adapt to fluctuating selection using derived and ancestral allelic diversity. AB - Populations can adapt to changing environments by using allelic diversity, yet whether diversity is recently derived or ancestral is often debated. Although evolution could productively use both types of diversity in a changing environment, their relative frequency has not been quantified. We address this question experimentally using budding yeast strains that harbor a tandem repeat containing URA3 gene, which we expose to cyclical selection and counterselection. We characterize and quantify the dynamics of frameshift events in the URA3 gene in eight populations over 12 cycles of selection and find that ancestral alleles account for 10-20% of all adaptive events. Using a general model of fluctuating selection, we determine how these results depend on mutation rates, population sizes, and fluctuation timescales. We quantify the contribution of derived alleles to the adaptation process using the de novo mutation rate along the population's ancestral lineage, a novel measure that is applicable in a wide range of settings. We find that the adaptive dynamics undergoes a sharp transition from selection on ancestral alleles to selection on derived alleles as fluctuation timescales increase. Our results demonstrate that fluctuations can select between different modes of adaptation over evolutionary timescales. PMID- 25908223 TI - [Management of new oral anticoagulants in gastrointestinal bleeding and endoscopy]. AB - New oral direct anticoagulants agents are alternatives to warfarin for long-term anticoagulation in a growing number of patients that require long-term anticoagulation for atrial fibrillation, deep venous thrombosis and pulmonary embolism. These new agents with predictable pharmacokinetic and pharmacodynamics profiles offer a favorable global safety profile, but increased gastrointestinal bleeding compared to the vitamin K antagonists. Many gastroenterologists are unfamiliar and may be wary of these newer drugs, since Clinical experience is limited and no specific antidote is available to reverse their anticoagulant effect. In this article the risk of these new agents and, how to manage these agents in both the presence of acute gastrointestinal bleeding and in patients undergoing endoscopic procedures is reviewed. PMID- 25908224 TI - [Upper gastrointestinal bleeding due to an uncommon lymphoproliferative process]. PMID- 25908225 TI - Cellulosome stoichiometry in Clostridium cellulolyticum is regulated by selective RNA processing and stabilization. AB - The mechanism, physiological relevance and evolutionary implication of selective RNA processing and stabilization (SRPS) remain elusive. Here we report the genome wide maps of transcriptional start sites (TSs) and post-transcriptional processed sites (PSs) for Clostridium cellulolyticum. The PS-associated genes are preferably associated with subunits of heteromultimeric protein complexes, and the intergenic PSs (iPSs) are enriched in operons exhibiting highly skewed transcript-abundance landscape. Stem-loop structures associated with those iPSs located at 3' termini of highly transcribed genes exhibit folding free energy negatively correlated with transcript-abundance ratio of flanking genes. In the cellulosome-encoding cip-cel operon, iPSs and stem-loops precisely regulate structure and abundance of the subunit-encoding transcripts processed from a primary polycistronic RNA, quantitatively specifying cellulosome stoichiometry. Moreover, cellulosome evolution is shaped by the number, position and biophysical nature of TSs, iPSs and stem-loops. Our findings unveil a genome-wide RNA-encoded strategy controlling in vivo stoichiometry of protein complexes. PMID- 25908226 TI - Phonological Priming With Nonwords in Children With and Without Specific Language Impairment. AB - PURPOSE: The cross-modal picture-word interference task is used to examine contextual effects on spoken-word production. Previous work has documented lexical-phonological interference in children with specific language impairment (SLI) when a related distractor (e.g., bell) occurs prior to a picture to be named (e.g., a bed). In the current study, the authors examined whether interference also arises with nonwords as distractors. METHOD: In Study 1, children with SLI (N = 20; ages 7;1 [years;months] to 11;0) and age-matched controls named pictures accompanied by (a) phonologically related nonwords, (b) unrelated nonwords, or (c) the word go (baseline). Stimulus asynchrony (SA) varied across blocks with distractors occurring prior to (-300 ms, -100 ms) or after (+100 ms, +300 ms) the pictures. In Study 2, a cross-sectional sample of children (N = 48, 5;3 to 10;9) and adults (N = 16) performed the same task. RESULTS: Child and adult control participants showed phonological priming (not interference) at early and late SAs, whereas children with SLI showed priming only at late SAs. Effect sizes correlated with language skills (Clinical Evaluation of Language Fundamentals-Fourth Edition scores; Semel, Wiig, & Secord, 2003). In the cross-sectional sample, anticipatory priming at SA -300 varied with age, with larger effects in older children. CONCLUSIONS: Children with SLI utilize phonological information when it is available just in time for word production but fail to anticipate upcoming stimuli. Poor anticipatory processing may adversely affect language fluency in children with SLI. PMID- 25908227 TI - Pollinator communities in strawberry crops - variation at multiple spatial scales. AB - Predicting potential pollination services of wild bees in crops requires knowledge of their spatial distribution within fields. Field margins can serve as nesting and foraging habitats for wild bees and can be a source of pollinators. Regional differences in pollinator community composition may affect this spill over of bees. We studied how regional and local differences affect the spatial distribution of wild bee species richness, activity-density and body size in crop fields. We sampled bees both from the field centre and at two different types of semi-natural field margins, grass strips and hedges, in 12 strawberry fields. The fields were distributed over four regions in Northern Europe, representing an almost 1100 km long north-south gradient. Even over this gradient, daytime temperatures during sampling did not differ significantly between regions and did therefore probably not impact bee activity. Bee species richness was higher in field margins compared with field centres independent of field size. However, there was no difference between centre and margin in body-size or activity density. In contrast, bee activity-density increased towards the southern regions, whereas the mean body size increased towards the north. In conclusion, our study revealed a general pattern across European regions of bee diversity, but not activity-density, declining towards the field interior which suggests that the benefits of functional diversity of pollinators may be difficult to achieve through spill-over effects from margins to crop. We also identified dissimilar regional patterns in bee diversity and activity-density, which should be taken into account in conservation management. PMID- 25908228 TI - Single-fraction radiation therapy in patients with metastatic Merkel cell carcinoma. AB - Merkel cell carcinoma (MCC) is an aggressive, polyomavirus-associated cancer with limited therapeutic options for metastatic disease. Cytotoxic chemotherapy is associated with high response rates, but responses are seldom durable and toxicity is considerable. Here, we report our experience with palliative single fraction radiotherapy (SFRT) in patients with metastatic MCC. We conducted retrospective analyses of safety and efficacy outcomes in patients that received SFRT (8 Gy) to MCC metastases between 2010 and 2013. Twenty-six patients were treated with SFRT to 93 MCC tumors located in diverse sites that included skin, lymph nodes, and visceral organs. Objective responses were observed in 94% of the measurable irradiated tumors (86/92). Complete responses were observed in 45% of tumors (including bulky tumors up to 16 cm). "In field" lesion control was durable with no progression in 77% (69/89) of treated tumors during median follow up of 277 days among 16 living patients. Clinically significant toxicity was seen in only two patients who had transient side effects. An exploratory analysis suggested a higher rate of in-field progression in patients with an immunosuppressive comorbidity or prior recent chemotherapy versus those without (30% and 9%, respectively; P = 0.03). Use of SFRT in palliating MCC patients was associated with an excellent in field control rate and durable responses at treated sites, and with minimal toxicity. SFRT may represent a convenient and appealing alternative to systemic chemotherapy for palliation, for which most patients with oligometastatic MCC are eligible. SFRT may also synergize with emerging systemic immune stimulants by lowering tumor burden and enhancing presentation of viral/tumor antigens. PMID- 25908229 TI - Neurologic Manifestations of Chronic Liver Disease and Liver Cirrhosis. AB - The normal functioning of brain is intimately as well as intricately interrelated with normal functioning of the liver. Liver plays a critical role of not only providing vital nutrients to the brain but also of detoxifying the splanchnic blood. Compromised liver function leads to insufficient detoxification thus allowing neurotoxins (such as ammonia, manganese, and other chemicals) to enter the cerebral circulation. In addition, portosystemic shunts, which are common accompaniments of advanced liver disease, facilitate free passage of neurotoxins into the cerebral circulation. The problem is compounded further by additional variables such as gastrointestinal tract bleeding, malnutrition, and concurrent renal failure, which are often associated with liver cirrhosis. Neurologic damage in chronic liver disease and liver cirrhosis seems to be multifactorial primarily attributable to the following: brain accumulation of ammonia, manganese, and lactate; altered permeability of the blood-brain barrier; recruitment of monocytes after microglial activation; and neuroinflammation, that is, direct effects of circulating systemic proinflammatory cytokines such as tumor necrosis factor, IL-1beta, and IL-6. Radiologist should be aware of the conundrum of neurologic complications that can be encountered in liver disease, which include hepatic encephalopathy, hepatocerebral degeneration, hepatic myelopathy, cirrhosis-related parkinsonism, cerebral infections, hemorrhage, and osmotic demyelination. In addition, neurologic complications can be exclusive to certain disorders, for example, Wilson disease, alcoholism (Wernicke encephalopathy, alcoholic cerebellar degeneration, Marchiafava-Bignami disease, etc). Radiologist should be aware of their varied clinical presentation and radiological appearances as the diagnosis is not always straightforward. PMID- 25908230 TI - Intraorbital Cystic Lesions: An Imaging Spectrum. AB - Presence of a cyst or a cystic component in an intraorbital mass often narrows the list of differential diagnoses to specific entities. Such a lesion in the orbit may arise from structures within the orbit, globe, and lacrimal system or from neighboring paranasal sinuses or meninges. Common congenital and developmental lesions encountered within the orbit include dermoids and epidermoids, and infrequently coloboma. Parasitic cysts (cysticercus), orbital abscess, mucocele, and vascular lesions are the most common acquired pathologies giving rise to fluid-containing lesions within the orbit. The role of a radiologist is crucial in expediting the diagnosis of orbital lesions with the help of characteristic imaging features on ultrasound, computed tomography, or magnetic resonance imaging. It also helps in identifying complications in others where formulation of an early and effective management strategy is vital for preserving vision. PMID- 25908231 TI - WITHDRAWN: SEPT9 DNA methylation as an early diagnostic marker in colorectal cancer. AB - The publisher regrets that this article has been temporarily removed. A replacement will appear as soon as possible in which the reason for the removal of the article will be specified, or the article will be reinstated. The full Elsevier Policy on Article Withdrawal can be found at http://www.elsevier.com/locate/withdrawalpolicy. PMID- 25908233 TI - Comparison of acquisition schemes for hyperpolarised 13C imaging. AB - The aim of this study was to characterise and compare widely used acquisition strategies for hyperpolarised (13)C imaging. Free induction decay chemical shift imaging (FIDCSI), echo-planar spectroscopic imaging (EPSI), IDEAL spiral chemical shift imaging (ISPCSI) and spiral chemical shift imaging (SPCSI) sequences were designed for two different regimes of spatial resolution. Their characteristics were studied in simulations and in tumour-bearing rats after injection of hyperpolarised [1-(13)C]pyruvate on a clinical 3-T scanner. Two or three different sequences were used on the same rat in random order for direct comparison. The experimentally obtained lactate signal-to-noise ratio (SNR) in the tumour matched the simulations. Differences between the sequences were mainly found in the encoding efficiency, gradient demand and artefact behaviour. Although ISPCSI and SPCSI offer high encoding efficiencies, these non-Cartesian trajectories are more prone than EPSI and FIDCSI to artefacts from various sources. If the encoding efficiency is sufficient for the desired application, EPSI has been proven to be a robust choice. Otherwise, faster spiral acquisition schemes are recommended. The conclusions found in this work can be applied directly to clinical applications. PMID- 25908234 TI - Association between urinary biomarkers of exposure to organophosphate insecticides and serum reproductive hormones in men from NHANES 1999-2002. AB - Exposure to organophosphate (OP) insecticides may alter reproductive hormone levels in men and increase the risk for poor reductive health and other adverse health outcomes. However, relevant epidemiology studies in men are limited. We evaluated urinary concentrations of OP metabolites (3,5,6-trichloro-2-pyridinol and six dialkyl phosphates) in relation to serum concentrations of testosterone (T) and estradiol among 356 men aged 20-55 years old from the U.S. National Health and Nutrition Examination Survey. Biomarkers were detected in greater than 50% of the samples, except for diethyldithiophosphate, dimethylphosphate, and dimethyldithiophosphate. In adjusted regression models, we observed a statistically significant inverse relationship between diethyl phosphate (DEP) and T when DEP was modeled as either a continuous or categorical variable. These findings add to the limited evidence that exposure to certain OP insecticides is linked to altered T in men, which may have important implications for male health. PMID- 25908235 TI - Internet-Based Cognitive Behavioral Therapy for Residual Symptoms in Bipolar Disorder Type II: A Single-Subject Design Pilot Study. AB - BACKGROUND: Bipolar disorder is a chronic condition with recurring episodes that often lead to suffering, decreased functioning, and sick leave. Pharmacotherapy in the form of mood stabilizers is widely available, but does not eliminate the risk of a new depressive or (hypo)manic episode. One way to reduce the risk of future episodes is to combine pharmacological treatment with individual or group psychological interventions. However, access to such interventions is often limited due to a shortage of trained therapists. In unipolar depression there is now robust evidence of the effectiveness of Internet-based psychological interventions, usually comprising psychoeducation and cognitive behavioral therapy (CBT). Internet-based interventions for persons suffering from bipolar disorder could increase access to psychological treatment. OBJECTIVE: The aim of this study was to investigate the feasibility of an Internet-based intervention, as well as its effect on residual depressive symptoms in persons diagnosed with bipolar disorder type II (BP-II). The most important outcomes were depressive symptoms, treatment adherence, and whether the patient perceived the intervention as helpful. METHODS: A total of 7 patients diagnosed with bipolar disorder type II at a Swedish psychiatric outpatient clinic were offered the opportunity to participate. Of the 7 patients, 3 (43%) dropped out before treatment began, and 4 (57%) were treated by means of an online, Internet-based intervention based on CBT (iCBT). The intervention was primarily aimed at psychoeducation, treatment of residual depressive symptoms, emotion regulation, and improved sleep. All patients had ongoing pharmacological treatment at recruitment and established contact with a psychiatrist. The duration of BP-II among the treated patients was between 6 and 31 years. A single-subject design was used and the results of the 4 participating patients were presented individually. RESULTS: Initiating treatment was perceived as too demanding under current life circumstances for 3 patients who consequently dropped out during baseline assessment. Self-ratings using the Montgomery-Asberg Depression Rating Scale-Self-rated (MADRS-S) showed symptom reduction in 3 (75%) of the 4 treated cases during iCBT. In the evaluation of the treatment, 2 patients reported that they perceived that the treatment had reduced symptoms a little, 1 that it had reduced symptoms very much, and 1 not at all. Treatment adherence (ie, module completion) was fairly high in 3 cases. In general, the modules were perceived as fairly helpful or very helpful by the patients. In one case, there was a reliable change-according to the Reliable Change Index-in self-rated symptoms of depression and perseverative thinking. CONCLUSIONS: The treatment seemed to have acceptable feasibility. The iCBT intervention could be an effective way to treat residual symptoms in some patients with bipolar disorder type II. This should be investigated in a larger study. TRIAL REGISTRATION: ClinicalTrials.gov NCT01742351; https://clinicaltrials.gov/ct2/show/NCT01742351 (Archived by WebCite at http://www.webcitation.org/6XnVpv4C3). PMID- 25908236 TI - Haplotype analysis finds linkage disequilibrium in the IL-12 gene in patients with HCV. AB - HCV is a major cause of liver disease worldwide. IL-12 plays an essential role in the balance of T helper 1 (Th1) differentiation versus a T helper 2 (Th2) driven response from its naive precursor. Linkage disequilibrium measures the degree to which alleles at two loci are associated and the non-random associations between alleles at two loci. Haplotypes of the three IL-12B loci studied were determined in the patient cases and the normal healthy control subjects. The frequency of the 12 possible IL-12B haplotypes on the 3 loci was determined in subjects heterozygous at only one of the loci within the studied haplotype. Haplotype frequencies were compared between the patient groups and controls (n = 49) to determine if any preferential combination of markers occurred using chi-squared and applying the Bonferroni correction. 45 HCV RNA negative patients; 88 HCV RNA positive patients; and 15 uninfected cases at high risk of HCV infection (EU) were studied. The haplotype "C" SNP of the 3'UTR with the "E" 4 bp deletion of the intron 4 region was in linkage disequilibrium (chi(2) = 45.15, P < 0.001, 95% CL). The haplotype analysis of the insertion allele of the promoter with the deletion allele of the intron 4("E") IL-12B polymorphism showed linkage disequilibrium (chi(2) = 5.64, P = 0.02). Linkage disequilibrium of polymorphisms is reported in the IL-12 gene in patients with HCV infection and contributes to the understanding of patient genotype and expected production of IL-12, responding to infection. PMID- 25908237 TI - Synthesis and Properties of a Novel Pyridineoxazoline Containing Optically Active Helical Polymer as a Catalyst Ligand for Asymmetric Diels-Alder Reaction. AB - A novel pyridineoxazoline (PyOx) containing helical polymer, poly{(-)-(S)-4-tert butyl-2-[5-(4-tert-butylphenyl)-3-vinylpyridin-2-yl]-oxazoline} (PA), was designed and synthesized to approach the effect of chain conformation on the catalytic property. Its complex with Cu(OTf)(2) , i.e., Cu(II)-PA, was employed to catalyze the homogeneous Diels-Alder (D-A) reaction of alkenoyl pyridine N oxides with cyclopentadiene in tetrahydrofuran. Compared with the previously reported copper complex, Cu(II)-P1 (RSC Advances, 2015, 5, 2882), which was derived from a nonhelical poly[(-)-(S)-4-tert-butyl-2-(3-vinylpyridin-2-yl) oxazoline], Cu(II)-PA exhibited a remarkably enhanced enantioselectivity and reaction rate. However, its enantioselectivity was lower than the Cu(II) complex of (-)-(S)-4-tert-butyl-2-[5-(4-tert-butylphenyl)-3-vinylpyridin-2-yl]-oxazoline (Cu(II)-A), a low molar mass model compound. PMID- 25908238 TI - A quantitative study of the interactive effects of glycine and serine with threonine and choline on growth performance in broilers. AB - Differences in the optimal dietary concentrations of Gly (glycine) and Ser (serine) in broiler diets may be due to levels of endogenous Gly precursors that differ in literature. Therefore, we measured the extent of the interactive effects between equivalents of Gly and Ser (Glyequi) and the endogenous Gly precursors choline and Thr (threonine) on growth performance. A fractional central composite design included concentrations of 15-25 g/kg DM, 0.6-2.0 g/kg DM, and 6.4-10.4 g/kg DM for Glyequi, choline, and Thr, respectively, in 5 levels each. The various concentrations were achieved by adding Gly, choline chloride, and l-Thr to a basal mix. Except for 20 replicates of the central diet, all treatments were tested with 5 replicates, each with 10 birds. Food was provided for ad libitum consumption throughout the experiment. The data were evaluated using artificial neural networks. Digestibility was studied for selected diets using separate birds. Since average daily feed intake (ADFI) varied between replicates, the intake of prececal digestible Glyequi, choline, and prececal digestible Thr were more adequate independent variables than the dietary concentration of each amino acid. From d 1 to d 7, no treatment effects on G:F and average daily gain (ADG) were detected; subsequent results refer to the period from d 7 to d 21. Increasing prececal digestible Thr intake considerably decreased the need for prececal digestible Glyequi to achieve certain levels of G:F and ADG. The extent of this effect cannot be explained only by the endogenous metabolism of Thr to Gly. Since essential amino acids were present above the recommended levels, Thr probably limited performance, and excessive intake of other essential amino acids prompted a Gly-dissipating process. Choline exerted a considerable effect on the required intake of prececal digestible Glyequi and prececal digestible Thr to achieve certain levels of G:F and ADG. The results of this study partly explain the previously reported variations in response to dietary Thr, Gly, and Ser. PMID- 25908239 TI - An Arabidopsis thaliana copper-sensitive mutant suggests a role of phytosulfokine in ethylene production. AB - To increase our understanding of the adaptation for copper (Cu) deficiency, Arabidopsis mutants with apparent alterations under Cu deficiency were identified. In this report, a novel mutant, tpst-2, was found to be more sensitive than wild-type (Col-0) plants to Cu deficiency during root elongation. The positional cloning of tpst-2 revealed that this gene encodes a tyrosylprotein sulfotransferase (TPST). Moreover, the ethylene production of tpst-2 mutant was higher than that of Col-0 under Cu deficiency, and adding the ethylene response inhibitor AgNO3 partially rescued defects in root elongation. Interestingly, peptide hormone phytosulfokine (PSK) treatment also repressed the ethylene production of tpst-2 mutant plants. Our results revealed that TPST suppressed ethylene production through the action of PSK. PMID- 25908240 TI - How cell wall complexity influences saccharification efficiency in Miscanthus sinensis. AB - The production of bioenergy from grasses has been developing quickly during the last decade, with Miscanthus being among the most important choices for production of bioethanol. However, one of the key barriers to producing bioethanol is the lack of information about cell wall structure. Cell walls are thought to display compositional differences that lead to emergence of a very high level of complexity, resulting in great diversity in cell wall architectures. In this work, a set of different techniques was used to access the complexity of cell walls of different genotypes of Miscanthus sinensis in order to understand how they interfere with saccharification efficiency. Three genotypes of M. sinensis displaying different patterns of correlation between lignin content and saccharification efficiency were subjected to cell wall analysis by quantitative/qualitative analytical techniques such as monosaccharide composition, oligosaccharide profiling, and glycome profiling. When saccharification efficiency was correlated negatively with lignin, the structural features of arabinoxylan and xyloglucan were found to contribute positively to hydrolysis. In the absence of such correlation, different types of pectins, and some mannans contributed to saccharification efficiency. Different genotypes of M. sinensis were shown to display distinct interactions among their cell wall components, which seem to influence cell wall hydrolysis. PMID- 25908241 TI - Augmentation therapy of alpha-1 antitrypsin deficiency associated emphysema. AB - INTRODUCTION: Alpha-1 antitrypsin, secreted by the liver, inhibits neutrophil elastase. Its deficiency favours the development of emphysema. Restoring a "protective" serum level in deficient patients should make it possible to inhibit the development of emphysema. STATE OF THE ART: Human plasma-derived alpha-1 antitrypsin is a blood-derived drug sold in France under the name Alfalastin((r)). The recommended posology is an I.V. administration of 60 mg/kg once a week. Human plasma-derived alpha-1 antitrypsin restores anti-elastase protection in the lower lung and prevents experimental emphysema induced by the elastasis of human neutrophils in hamster. The low number of patients with alpha 1 antitrypsin deficiency is one of the difficulties to perform sufficiently powerful randomised studies. However, randomised studies have reported the efficacy of human plasma-derived alpha-1 antitrypsin perfusions on mortality, FEV1 decline and the frequency of exacerbations. Randomised control trials have demonstrated the efficacy of human plasma-derived alpha-1 antitrypsin perfusions on the loss of lung density assessed by CT scan. CONCLUSION: Augmentation therapy is simple in its conception and implementation, but it is expensive. However, there are currently no other solutions. PMID- 25908242 TI - Validity and reliability of the session-RPE method for quantifying training load in karate athletes. AB - AIM: To test the construct validity and reliability of the session rating of perceived exertion (sRPE) method by examining the relationship between RPE and physiological parameters (heart rate: HR and blood lactate concentration: [La --] ) and the correlations between sRPE and two HR--based methods for quantifying internal training load (Banister's method and Edwards's method) during karate training camp. METHODS: Eighteen elite karate athletes: ten men (age: 24.2 +/- 2.3 y, body mass: 71.2 +/- 9.0 kg, body fat: 8.2 +/- 1.3% and height: 178 +/- 7 cm) and eight women (age: 22.6 +/- 1.2 y, body mass: 59.8 +/- 8.4 kg, body fat: 20.2 +/- 4.4%, height: 169 +/- 4 cm) were included in the study. During training camp, subjects participated in eight karate--training sessions including three training modes (4 tactical--technical, 2 technical--development, and 2 randori training), during which RPE, HR, and [La -- ] were recorded. RESULTS: Significant correlations were found between RPE and physiological parameters (percentage of maximal HR: r = 0.75, 95% CI = 0.64--0.86; [La --] : r = 0.62, 95% CI = 0.49- 0.75; P < 0.001). Moreover, individual sRPE was significantly correlated with two HR--based methods for quantifying internal training load ( r = 0.65--0.95; P < 0.001). The sRPE method showed the high reliability of the same intensity across training sessions (Cronbach's alpha = 0.81, 95% CI = 0.61--0.92). CONCLUSION: This study demonstrates that the sRPE method is valid for quantifying internal training load and intensity in karate. PMID- 25908244 TI - The lncRNA MIR31HG regulates p16(INK4A) expression to modulate senescence. AB - Oncogene-induced senescence (OIS) can occur in response to oncogenic insults and is considered an important tumour suppressor mechanism. Here we identify the lncRNA MIR31HG as upregulated in OIS and find that knockdown of MIR31HG promotes a strong p16(INK4A)-dependent senescence phenotype. Under normal conditions, MIR31HG is found in both nucleus and cytoplasm, but following B-RAF expression MIR31HG is located mainly in the cytoplasm. We show that MIR31HG interacts with both INK4A and MIR31HG genomic regions and with Polycomb group (PcG) proteins, and that MIR31HG is required for PcG-mediated repression of the INK4A locus. We further identify a functional enhancer, located between MIR31HG and INK4A, which becomes activated during OIS and interacts with the MIR31HG promoter. Data from melanoma patients show a negative correlation between MIR31HG and p16(INK4A) expression levels, suggesting a role for this transcript in cancer. Hence, our data provide a new lncRNA-mediated regulatory mechanism for the tumour suppressor p16(INK4A). PMID- 25908245 TI - Reduced somatosensory impairment by piezosurgery during orthognathic surgery of the mandible. AB - PURPOSE: This clinical trial aimed to test the hypothesis that piezosurgery causes reduced nerval irritations and, thus, reduced somatosensory impairment when used in orthognathic surgery of the mandible. METHODS: To this end, 37 consecutive patients with Angle Class II and III malocclusion were treated using bilateral sagittal split osteotomies (BSSO) of the mandible. In a split mouth design, randomized one side of the mandible was operated using a conventional saw, while a piezosurgery device was used on the contralateral side. In order to test the individual qualities of somatosensory function, quantitative sensory testings (QSTs) were performed 1 month, 6 months and 1 year after surgery. RESULTS: A comparison of the data using a two-way analysis of variance (ANOVA) revealed a significant reduction in postoperative impairment in warm detection threshold (WDT) (P = 0.046), a decreased dynamic mechanical allodynia (ALL) (P = 0.002) and a decreased vibration detection threshold (VDT) (P = 0.030) on the piezosurgery side of the mandible as opposed to the conventionally operated control side. In the remaining QSTs, minor deviations from the preoperative baseline conditions and a more rapid regression could be observed. CONCLUSIONS: Piezosurgery caused reduced somatosensory impairment and a faster recovery of somatosensory functions in the present investigation. PMID- 25908246 TI - Solute Carrier Family of the Organic Anion-Transporting Polypeptides 1A2- Madin Darby Canine Kidney II: A Promising In Vitro System to Understand the Role of Organic Anion-Transporting Polypeptide 1A2 in Blood-Brain Barrier Drug Penetration. AB - Organic anion-transporting polypeptide (OATP) 1A2 has the potential to be a target for central nervous system drug delivery due to its luminal localization at the human blood-brain barrier and broad substrate specificity. We found OATP1A2 mRNA expression in the human brain to be comparable to breast cancer resistance protein and OATP2B1 and much higher than P-glycoprotein (P-gp), and confirmed greater expression in the brain relative to other tissues. The goal of this study was to establish a model system to explore OATP1A2-mediated transcellular transport of substrate drugs and the interplay with P-gp. In vitro (human embryonic kidney 293 cells stably expressing Oatp1a4, the closest murine isoform) and in vivo (naive and Oatp1a4 knock-out mice) studies with OATP1A2 substrate triptan drugs demonstrated that these drugs were not Oatp1a4 substrates. This species difference demonstrates that the rodent is not a good model to investigate the active brain uptake of potential OATP1A2 substrates. Thus, we constructed a novel OATP1A2 expressing Madin-Darby canine kidney (MDCK) II wild type and an MDCKII-multidrug resistance protein 1 (MDR1) system using BacMam virus transduction. The spatial expression pattern of OATP1A2 after transduction in MDCKII-MDR1 cells was superimposed to P-gp, confirming apical membrane localization. OATP1A2-mediated uptake of zolmitriptan, rosuvastatin, and fexofenadine across monolayers increased with increasing OATP1A2 protein expression. OATP1A2 counteracted P-gp efflux for cosubstrates zolmitriptan and fexofenadine. A three-compartment model incorporating OATP1A2-mediated influx was used to quantitatively describe the time- and concentration-dependent apical-to basolateral transcellular transport of rosuvastatin across OATP1A2 expressing the MDCKII monolayer. This novel, simple and versatile experimental system is useful for understanding the contribution of OATP1A2-mediated transcellular transport across barriers, such as the blood-brain barrier. PMID- 25908247 TI - Bilateral adrenal histoplasmosis in a man with chronic alcoholism. PMID- 25908248 TI - Two new triterpenoids from the resin of Styrax tonkinensis. AB - Two new triterpenoids, 3beta,6beta-dihydroxy-12-oxo-13Halpha-olean-28,19beta olide (1) and 3-oxo-olean-11,13(18)-dien-28,19beta-olide (2) were isolated from the resin of Styrax tonkinensis (Pier.) Craib. The structures of both triterpenoids were determined by physicochemical and spectroscopic methods. Compound 1 is the second triterpene found with cis-fused C/D ring from the resin, which is rarely observed in oleanane-type triterpenes. PMID- 25908243 TI - Do circulating tumor cells, exosomes, and circulating tumor nucleic acids have clinical utility? A report of the association for molecular pathology. AB - Diagnosing and screening for tumors through noninvasive means represent an important paradigm shift in precision medicine. In contrast to tissue biopsy, detection of circulating tumor cells (CTCs) and circulating tumor nucleic acids provides a minimally invasive method for predictive and prognostic marker detection. This allows early and serial assessment of metastatic disease, including follow-up during remission, characterization of treatment effects, and clonal evolution. Isolation and characterization of CTCs and circulating tumor DNA (ctDNA) are likely to improve cancer diagnosis, treatment, and minimal residual disease monitoring. However, more trials are required to validate the clinical utility of precise molecular markers for a variety of tumor types. This review focuses on the clinical utility of CTCs and ctDNA testing in patients with solid tumors, including somatic and epigenetic alterations that can be detected. A comparison of methods used to isolate and detect CTCs and some of the intricacies of the characterization of the ctDNA are also provided. PMID- 25908249 TI - Reliability and validity of the Portuguese version of the Generalized Anxiety Disorder (GAD-7) scale. AB - BACKGROUND: Generalized anxiety disorder has a strong impact on health-related quality of life. For this reason, it seems relevant to develop strategies allowing early diagnoses in order to promote appropriate treatments. The objective of this study was to culturally adapt and validate the GAD-7 for the Portuguese patients with generalized anxiety disorder. METHODS: For the cultural adaptation of the Portuguese version of the GAD-7 scale we started with a previous translation made by Mapi Institute and decided to perform a clinical review followed by a cognitive debriefing with patients. Once piloted, this version was then tested in a larger sample for feasibility and reliability (1 week test-retest). Construct validity was assessed by the relationship between GAD-7 and socio-demographic and clinical variables. Its unidimensionality was tested by principal component factor analysis. Criterion validity was assessed by comparing GAD-7 scores with those obtained by HADS, and EQ-5D. STAI was mainly used as a screening indicator for patient inclusion. RESULTS: GAD-7 was considered feasible with a mean completion time of 2.3 minutes and no major floor or ceiling effects. We found an excellent Cronbach's alpha internal consistency score (0.880) and the test-retest and interclass correlation coefficients were also very good. Regarding the construct validity, younger patients, those with higher education, employed and without anxiety symptoms revealed lower GAD-7 scores, meaning better health. The unidimensionality of GAD-7 index was also confirmed by principal component factor analysis. At last, GAD-7 was significantly correlated with other health outcome indices and the classification levels created by it and by HADS showed to be dependent. CONCLUSION: The excellent metric properties confirmed the cultural adaptation and validity of GAD 7 into Portuguese population, allowing the clinicians an early detection and treatment of these patients. PMID- 25908250 TI - Estimation of bonding nature using diamagnetic susceptibility. AB - A chemical bond includes both covalent and ionic characteristics. We develop an experimental method to estimate the degree of each contribution based on magnetic susceptibility measurements, in which Pascal's scheme for Larmor diamagnetism is combined with electronegativity. The applicability to metal hydrides is also shown. PMID- 25908252 TI - Photocatalytic Activity of Au/TiO2 Photocatalysts for H2 Evolution: Role of the Au Nanoparticles as a Function of the Irradiation Wavelength. AB - An investigation of hydrogen production with a series of Au/TiO2 photocatalysts reveals that the Au nanoparticles play different roles depending on the wavelength of the light irradiation. Under visible-light irradiation, the photoactivity is primarily controlled by the intensity of the Au surface plasmon band, whereas under UV irradiation the Au nanoparticles act as co-catalysts with TiO2 . PMID- 25908254 TI - Rituximab treatment did not aggravate ongoing progressive multifocal leukoencephalopathy in a patient with multiple sclerosis. AB - A multiple sclerosis (MS) patient developed progressive multifocal leukoencephalopathy (PML) after 43 months of natalizumab treatment. New clinical and magnetic resonance imaging (MRI) findings were initially misinterpreted as breakthrough MS disease activity and natalizumab treatment was replaced by rituximab treatment. The patient had a single infusion of rituximab 1000 mg before a definite PML diagnosis was confirmed. Despite undetectable levels of B cells, JC virus DNA became undetectable in the cerebrospinal fluid by quantitative polymerase chain reaction. The patient partially recovered without any clinical or MRI signs of new MS activity. These findings suggest that B-cell depletion in a non-immune compromised individual did not prevent the patient from clearing the JC virus infection. PMID- 25908253 TI - Meloxicam prevents COX-2-mediated post-surgical inflammation but not pain following laparotomy in mice. AB - BACKGROUND: Inflammation is thought to be a major contributor to post-surgical pain, so non-steroidal anti-inflammatory drugs (NSAIDs) are commonly used analgesics. However, compared to rats, considerably less is known as to how successfully these prevent pain in mice. METHODS: A fluorescent COX-2 selective probe was used for the first time to evaluate the post-surgical anti-inflammatory effects of meloxicam, and automated behaviour analyses (HomeCageScan; HCS), the Mouse Grimace Scale (MGS) and body weight changes to assess its pain-preventative properties. Groups of 8-9 BALB/c mice were subcutaneously injected with saline (0.3 mL) or meloxicam at (1, 5 or 20 mg/kg) 1 h before a 1.5-cm midline laparotomy. The probe or a control dye (2 mg/kg) was injected intravenously 3 h later. Imaging was used to quantify inflammation at 7, 24 and 48 h following surgery. HCS data and MGS scores were respectively obtained from video recordings and photographs before surgery and 24 h later. RESULTS: Post-surgical inflammation was dose dependently reduced by meloxicam; with 5 or 20 mg/kg being most effective compared to saline. However, all mice lost weight, MGS scores increased and behavioural activity was reduced by surgery for at least 24 h with no perceivable beneficial effect of meloxicam on any of these potentially pain associated changes. CONCLUSIONS: Although meloxicam prevented inflammation, even large doses did not prevent post-laparotomy pain possibly arising due to a range of factors, including, but not limited to inflammation. MGS scoring can be applied by very naive assessors and so should be effective for cage-side use. PMID- 25908255 TI - Multitarget intervention of Fasudil in the neuroprotection of dopaminergic neurons in MPTP-mouse model of Parkinson's disease. AB - Recent studies have demonstrated that activation of the Rho-associated kinase (ROCK) pathway participates in the dopaminergic neuron degeneration and possibly in Parkinson's disease (PD). In the current study, we tried to observe the therapeutic potential of ROCK inhibitor Fasudil against dopaminergic neuron injury in 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-mouse model of PD, and explore possible molecular mechanisms by enzyme-linked immunosorbent assay (ELISA), western blot and immunofluorescent assays. The results showed that MPTP PD mice presented motor deficits, dopaminergic neuron loss, activation of inflammatory response and oxidative stress as well as ROCK and glycogen synthase kinase 3beta (GSK-3beta) signaling pathways. The administration of Fasudil exhibited neuroprotective effects against the dopaminergic neurons and improved the motor function recovery in the MPTP-PD mice, accompanied by the suppression of inflammatory responses (IL-1beta, TNF-alpha, NF-kappaB-p65 and TLR-2), and oxidative stress (iNOS and gp91Phox), which might be associated with the inhibition of ROCK and GSK-3beta activity. Simultaneously, the administration of Fasudil resulted in the shift from inflammatory M1 to anti inflammatory/neurorepair M2 microglia. Additionally, Fasudil intervention enhanced the expression of anti-oxidative factors such as NF-E2-related factor 2 (Nrf2), Hmox as well as neurotrophic factor including GDNF. Our observations defined the neuroprotective effects of Fasudil in MPTP-PD mice, and we found a series of novel effector molecules and pathways for explaining the neuroprotective effects against dopaminergic neurons. However, a lot of investigations are warranted to further elucidate the crosstalk among Fasudil, oxidative stress, inflammatory response, GDNF and ROCK/NF-kB/Nrf2 pathways in the therapeutic potential of PD. PMID- 25908256 TI - Cytomegalovirus Preventive Strategies in Liver Transplant. PMID- 25908257 TI - The complex modulation of lysosomal degradation pathways by cannabinoid receptors 1 and 2. AB - The two main receptors of the endocannabinoid system, cannabinoid receptors 1 (CB1R) and 2 (CB2R), were described in the early 1990s. Since then, different physiological functions have been revealed that are linked to the activity of these two G-protein-coupled receptors. CB1R and CB2R activities influence signal cascades, which are known to play a role in the regulation of the cellular "self digestion" process called autophagy. A variety of these signaling pathways are integrated by the mammalian target of rapamycin complex 1 (mTORC1) that acts as an inhibitor of autophagy. Others, like AMP-activated protein kinase dependent signaling pathway, are able to bypass mTORC1 to modulate the autophagic activity directly. In the recent years, several scientific reports demonstrate an involvement of CB1R and CB2R signaling in the control of the autophagic activity in different paradigms. In this review, we summarize the recent literature on this topic, which is in part contradictory and therefore, it is of great importance to illuminate the results of the single reports in the physiological context of the model systems used in these studies. Utilizing CB1R and CB2R as pharmacological targets to modulate the autophagic activity is a promising strategy for the treatment of different patho-physiological conditions and disease. PMID- 25908258 TI - Four Ways Life Extension will Change Our Relationship with Death. AB - Discussions of life extension ethics have focused mainly on whether an extended life would be desirable to have, and on the social consequences of widely available life extension. I want to explore a different range of issues: four ways in which the advent of life extension will change our relationship with death, not only for those who live extended lives, but also for those who cannot or choose not to. Although I believe that, on balance, the reasons in favor of developing life extension outweigh the reasons against doing so (something I won't argue for here), most of these changes probably count as reasons against doing so. First, the advent of life extension will alter the human condition for those who live extended lives, and not merely by postponing death. Second, it will make death worse for those who lack access to life extension, even if those people live just as long as they do now. Third, for those who have access to life extension but prefer to live a normal lifespan because they think that has advantages, the advent of life extension will somewhat reduce some of those advantages, even if they never use life extension. Fourth, refusing life extension turns out to be a form of suicide, and this will force those who have access to life extension but turn it down to choose between an extended life they don't want and a form of suicide they may (probably mistakenly) consider immoral. PMID- 25908259 TI - Neuritogenic militarinone-inspired 4-hydroxypyridones target the stress pathway kinase MAP4K4. AB - Progressive loss and impaired restoration of neuronal activity are hallmarks of neurological diseases, and new small molecules with neurotrophic activity are in high demand. The militarinone alkaloids and structurally simplified analogues with 4-hydroxy-2-pyridone core structure induce pronounced neurite outgrowth, but their protein target has not been identified. Reported herein is the synthesis of a militarinone-inspired 4-hydroxy-2-pyridone collection, its investigation for enhancement of neurite outgrowth, and the discovery of the stress pathway kinase MAP4K4 as a target of the discovered neuritogenic pyridones. The most potent 4 hydroxy-2-pyridone is a selective ATP-competitive inhibitor of MAP4K4 but not of the other stress pathway related kinases, as proven by biochemical analysis and by a crystal structure of the inhibitor in complex with MAP4K4. The findings support the notion that MAP4K4 may be a new target for the treatment of neurodegenerative diseases. PMID- 25908260 TI - Acute changes in kinematic and muscle activity patterns in habitually shod rearfoot strikers while running barefoot. AB - The aim of this study was to observe changes in the kinematics and muscle activities when barefoot running was initially adopted by six habitually shod, recreational rearfoot striking runners. Participants ran on a treadmill shod for 5 min, completed 3 * 10-min intervals of barefoot running and then completed a final minute of shod running at a self-selected pace. Dependent variables (speed, joint angles at foot-contact, joint range of motion (ROM), mean and peak electromyography (EMG) activity) were compared across conditions using repeated measures ANOVAs. Anterior pelvic tilt and hip flexion significantly decreased during barefoot conditions at foot contact. The ROM for the trunk, pelvis, knee and ankle angles decreased during the barefoot conditions. Mean EMG activity was reduced for biceps femoris, gastrocnemius lateralis and tibialis anterior during barefoot running. The peak activity across the running cycle decreased in biceps femoris, vastus medialis, gastrocnemius medialis and tibialis anterior during barefoot running. During barefoot running, tibialis anterior activity significantly decreased during the pre-activation and initial contact phases; gastrocnemius lateralis and medialis activity significantly decreased during the push-off phase. Barefoot running caused immediate biomechanical and neuromuscular adaptations at the hip and pelvis, which persisted when the runners donned their shoes, indicating that some learning had occurred during an initial short bout of barefoot running. PMID- 25908251 TI - The genomes of two key bumblebee species with primitive eusocial organization. AB - BACKGROUND: The shift from solitary to social behavior is one of the major evolutionary transitions. Primitively eusocial bumblebees are uniquely placed to illuminate the evolution of highly eusocial insect societies. Bumblebees are also invaluable natural and agricultural pollinators, and there is widespread concern over recent population declines in some species. High-quality genomic data will inform key aspects of bumblebee biology, including susceptibility to implicated population viability threats. RESULTS: We report the high quality draft genome sequences of Bombus terrestris and Bombus impatiens, two ecologically dominant bumblebees and widely utilized study species. Comparing these new genomes to those of the highly eusocial honeybee Apis mellifera and other Hymenoptera, we identify deeply conserved similarities, as well as novelties key to the biology of these organisms. Some honeybee genome features thought to underpin advanced eusociality are also present in bumblebees, indicating an earlier evolution in the bee lineage. Xenobiotic detoxification and immune genes are similarly depauperate in bumblebees and honeybees, and multiple categories of genes linked to social organization, including development and behavior, show high conservation. Key differences identified include a bias in bumblebee chemoreception towards gustation from olfaction, and striking differences in microRNAs, potentially responsible for gene regulation underlying social and other traits. CONCLUSIONS: These two bumblebee genomes provide a foundation for post-genomic research on these key pollinators and insect societies. Overall, gene repertoires suggest that the route to advanced eusociality in bees was mediated by many small changes in many genes and processes, and not by notable expansion or depauperation. PMID- 25908261 TI - The free-radical scavenger edaravone accelerates thrombolysis with alteplase in an experimental thrombosis model. AB - BACKGROUND AND PURPOSE: Reperfusion injury after thrombolytic therapy can have adverse neurologic effects. The free-radical scavenger edaravone is used in combination with the recombinant tissue plasminogen activator alteplase to treat acute ischemic stroke. However, basic investigations of this combination use remain inadequate. Here, we used an in vivo model to investigate the effects of edaravone on alteplase-induced thrombolysis. METHODS: Thrombolysis was evaluated by using a He-Ne-laser-induced thrombosis model in rat mesenteric microvessels. Changes in thrombus volume were analyzed with the image analysis software Image Pro Plus (Media Cybernetics, USA). There were three experimental groups (placebo, alteplase 0.6 mg/kg, alteplase 0.6 mg/kg + edaravone 10.5 mg/kg). Sequential changes (0 to 60 min) in thrombus volume were compared by using a relative optical density method that we had used previously. RESULTS: In the placebo group, the thrombus volume at 60 min, reflecting the extent of thrombolysis, was 97.2% +/- 5.7% of the initial value. In the alteplase group, thrombus volume decreased to 70.7% +/- 4.1% (P<0.01) after 20 min and 14.2% +/- 6.6% after 60 min. In the alteplase+edaravone group, thrombus volume decreased to 66.9% +/- 7.2% (P<0.001) after 10 min and 10.9% +/- 2.3% after 60 min. CONCLUSIONS: These results support the hypothesis that edaravone accelerates thrombolysis by alteplase. PMID- 25908262 TI - Familial liability to schizophrenia and mood disorders and cognitive impairment in psychosis. AB - Schizophrenia and other psychoses are complex disorders with high rates of cognitive impairment and a considerable degree of genetic and environmental influence on its etiology. Whether cognitive impairment is related to dimensional scores of familial liability is still matter of debate. We conducted a cross sectional study including 169 patients with psychotic disorders and 26 healthy controls. Attention, memory and executive functions were assessed, and familial loading scores for schizophrenia and mood disorders were calculated. The relationships between familial liability and neuropsychological performance were examined with Spearman's correlation coefficients. In addition, patients were classified into three groups by family loading tertiles, and comparisons were performed between the patients in the top and bottom tertiles. Low familial loading scores for schizophrenia showed a significant association with poor executive functioning and delayed visual memory. And these results were also achieved when the subset of psychotic patients in the two extreme tertiles of family loadings of schizophrenia and mood disorders were compared. Low familial liability to schizophrenia seems to be a contributing factor for the severity of cognitive impairment in patients with a broad putative schizophrenia spectrum diagnosis. PMID- 25908263 TI - Mapping non suicidal self-injury in adolescence: Development and confirmatory factor analysis of the Impulse, Self-harm and Suicide Ideation Questionnaire for Adolescents (ISSIQ-A). AB - Non-suicidal self-injury (NSSI) is the deliberate, self-inflicted destruction of body tissue without suicidal intent and an important clinical phenomenon. Rates of NSSI appear to be disproportionately high in adolescents and young adults, and is a risk factor for suicidal ideation and behavior. The present study reports the psychometric properties of the Impulse, Self-harm and Suicide Ideation Questionnaire for Adolescents (ISSIQ-A), a measure designed to comprehensively assess the impulsivity, NSSI behaviors and suicide ideation. An additional module of this questionnaire assesses the functions of NSSI. Results of Confirmatory Factor Analysis (CFA) of the scale on 1722 youths showed items' suitability and confirmed a model of four different dimensions (Impulse, Self-harm, Risk-behavior and Suicide ideation) with good fit and validity. Further analysis showed that youth's engagement in self-harm may exert two different functions: to create or alleviate emotional states, and to influence social relationships. Our findings contribute to research and assessment on non-suicidal self-injury, suggesting that the ISSIQ-A is a valid and reliable measure to assess impulse, self-harm and suicidal thoughts, in adolescence. PMID- 25908264 TI - School refusal behavior in South Korean first graders: A prospective observational community-based study. AB - Refusing to attend school is a serious problem that could lead to psychopathology. We aimed to: (1) prospectively observe the actual development of school refusal behavior according to a history of separation anxiety symptoms (SAS) and (2) explore factors for predicting school refusal behavior in children who were just beginning primary school. The participants were 277 children, aged 6-7 years, who were expected to enter primary school in 2 months. The parents were surveyed about the child's history of SAS and their behavior. The children were questioned about anxiety symptoms. The children were surveyed about whether school refusal behavior developed or not after they entered primary school. Of the 248 children who responded to the follow-up survey, 7.66% of children met the criteria for school refusal behavior during the 3 months after entering school. We found no significant differences in the occurrence of school refusal behavior according to the children's SAS history. Familial risk factors for school refusal behavior included low parental educational level and a working mother. School refusal behavior by first graders cannot be fully explained by the expression of SAS and could be implicated in a more complex psychopathology. PMID- 25908265 TI - Patterns and correlates of attempted suicide amongst heroin users: 11-year follow up of the Australian treatment outcome study cohort. AB - Lifetime and recent rates of attempted suicide and suicidal ideation amongst the Australian Treatment Outcome Study cohort of heroin users at 11-year follow-up were examined. The mean elapsed time since heroin initiation was 20.4 years. At 11-year follow-up, 42.2% of the cohort reported ever having made a suicide attempt, 11.1% having made a first attempt subsequent to baseline. In the year preceding 11-year follow-up, 1.6% had made an attempt, suicidal ideation was reported by 10.4%, and 4.2% had a current suicide plan. After controlling for other variables, past 12 month attempts, current ideation or plans were independently associated with a current diagnosis of Major Depression (odds ratios (OR) 1.67) and more extensive polydrug use (OR 1.39), while each standard deviation higher on the SF12 physical health scale (reflecting better health) was associated with reduced odds (OR 0.66). Suicide and suicidal ideation remained a significant clinical issue for heroin users, some 20 years after their heroin use commenced. PMID- 25908266 TI - Current maternal depression moderates the relation between critical expressed emotion in mothers and depressive symptoms in their adolescent daughters. AB - Prior studies have examined critical expressed emotion (EE-Crit) in mothers in the intergenerational transmission of depression. However, the potential moderating effect of maternal depression diagnostic status in relation to EE-Crit and youth depressive symptoms has yet to be determined. A total of N=121 biological mother/daughter dyads that differed in maternal depression diagnostic status were recruited for the present study: (1) currently depressed mothers (current depression, n=29); (2) formerly depressed mothers (past depression, n=39); and (3) mothers free from any psychiatric history (healthy controls, n=53). Mothers were administered structured clinical interviews and completed self-report measures of EE-Crit and psychopathology, and daughters self-reported depressive symptoms. Results indicated no significant group differences in EE Crit; however, current maternal depression status moderated EE-Crit such that the magnitude of the relation between EE-Crit and adolescent depressive symptoms was significantly greater in daughters of currently depressed mothers. These findings highlight the importance of considering current maternal depression, rather than a history of maternal depression, in relation to EE-Crit and adolescent depressive symptoms, providing impetus for future investigations. PMID- 25908267 TI - Multi-disease analysis of maternal antibody decay using non-linear mixed models accounting for censoring. AB - Biomedical studies often generate repeated measures of multiple outcomes on a set of subjects. It may be of interest to develop a biologically intuitive model for the joint evolution of these outcomes while assessing inter-subject heterogeneity. Even though it is common for biological processes to entail non linear relationships, examples of multivariate non-linear mixed models (MNMMs) are still fairly rare. We contribute to this area by jointly analyzing the maternal antibody decay for measles, mumps, rubella, and varicella, allowing for a different non-linear decay model for each infectious disease. We present a general modeling framework to analyze multivariate non-linear longitudinal profiles subject to censoring, by combining multivariate random effects, non linear growth and Tobit regression. We explore the hypothesis of a common infant specific mechanism underlying maternal immunity using a pairwise correlated random-effects approach and evaluating different correlation matrix structures. The implied marginal correlation between maternal antibody levels is estimated using simulations. The mean duration of passive immunity was less than 4 months for all diseases with substantial heterogeneity between infants. The maternal antibody levels against rubella and varicella were found to be positively correlated, while little to no correlation could be inferred for the other disease pairs. For some pairs, computational issues occurred with increasing correlation matrix complexity, which underlines the importance of further developing estimation methods for MNMMs. PMID- 25908268 TI - Control of temporal activation of hepatitis C virus-induced interferon response by domain 2 of nonstructural protein 5A. AB - BACKGROUND & AIMS: Hepatitis C virus (HCV) nonstructural protein 5A (NS5A) is a multifunctional protein playing a crucial role in diverse steps of the viral replication cycle and perturbing multiple host cell pathways. We showed previously that removal of a region in domain 2 (D2) of NS5A (mutant NS5A(D2Delta)) is dispensable for viral replication in hepatoma cell lines. By using a mouse model and immune-competent cell systems, we studied the role of D2 in controlling the innate immune response. METHODS: In vivo replication competence of NS5A(D2Delta) was studied in transgenic mice with human liver xenografts. Results were validated using primary human hepatocytes (PHHs) and mechanistic analyses were conducted in engineered Huh7 hepatoma cells with reconstituted innate signaling pathways. RESULTS: Although the deletion in NS5A removed most of the interferon (IFN) sensitivity determining-region, mutant NS5A(D2Delta) was as sensitive as the wild type to IFN-alpha and IFN-lambda in vitro, but severely attenuated in vivo. This attenuation could be recapitulated in PHHs and was linked to higher activation of the IFN response, concomitant with reduced viral replication and virus production. Importantly, immune-reconstituted Huh7-derived cell lines revealed a sequential activation of the IFN-response via RIG-I (retinoic acid-inducible gene I) and MDA5 (Myeloma differentiation associated factor 5), respectively, that was significantly higher in the case of the mutant lacking most of NS5A D2. CONCLUSIONS: Our study reveals an important role of NS5A D2 for suppression of the IFN response that is activated by HCV via RIG-I and MDA5 in a sequential manner. PMID- 25908269 TI - Gas6/Axl pathway is activated in chronic liver disease and its targeting reduces fibrosis via hepatic stellate cell inactivation. AB - BACKGROUND & AIMS: Liver fibrosis, an important health concern associated to chronic liver injury that provides a permissive environment for cancer development, is characterized by accumulation of extracellular matrix components mainly derived from activated hepatic stellate cells (HSCs). Axl, a receptor tyrosine kinase and its ligand Gas6, are involved in cell differentiation, immune response and carcinogenesis. METHODS: HSCs were obtained from WT and Axl(-/-) mice, treated with recombinant Gas6 protein (rGas6), Axl siRNAs or the Axl inhibitor BGB324, and analyzed by western blot and real-time PCR. Experimental fibrosis was studied in CCl4-treated WT and Axl(-/-) mice, and in combination with Axl inhibitor. Gas6 and Axl serum levels were measured in alcoholic liver disease (ALD) and hepatitis C virus (HCV) patients. RESULTS: In primary mouse HSCs, Gas6 and Axl levels paralleled HSC activation. rGas6 phosphorylated Axl and AKT prior to HSC phenotypic changes, while Axl siRNA silencing reduced HSC activation. Moreover, BGB324 blocked Axl/AKT phosphorylation and diminished HSC activation. In addition, Axl(-/-) mice displayed decreased HSC activation in vitro and liver fibrogenesis after chronic damage by CCl4 administration. Similarly, BGB324 reduced collagen deposition and CCl4-induced liver fibrosis in mice. Importantly, Gas6 and Axl serum levels increased in ALD and HCV patients, inversely correlating with liver functionality. CONCLUSIONS: The Gas6/Axl axis is required for full HSC activation. Gas6 and Axl serum levels increase in parallel to chronic liver disease progression. Axl targeting may be a therapeutic strategy for liver fibrosis management. PMID- 25908270 TI - The Hippo pathway effector YAP controls mouse hepatic stellate cell activation. AB - BACKGROUND & AIMS: Hepatic stellate cell activation is a wound-healing response to liver injury. However, continued activation of stellate cells during chronic liver damage causes excessive matrix deposition and the formation of pathological scar tissue leading to fibrosis and ultimately cirrhosis. The importance of sustained stellate cell activation for this pathological process is well recognized, and several signalling pathways that can promote stellate cell activation have been identified, such as the TGFbeta-, PDGF-, and LPS-dependent pathways. However, the mechanisms that trigger and drive the early steps in activation are not well understood. METHODS AND RESULTS: We identified the Hippo pathway and its effector YAP as a key pathway that controls stellate cell activation. YAP is a transcriptional co-activator and we found that it drives the earliest changes in gene expression during stellate cell activation. Activation of stellate cells in vivo by CCl4 administration to mice or activation in vitro caused rapid activation of YAP as revealed by its nuclear translocation and by the induction of YAP target genes. YAP was also activated in stellate cells of human fibrotic livers as evidenced by its nuclear localization. Importantly, knockdown of YAP expression or pharmacological inhibition of YAP prevented hepatic stellate cell activation in vitro and pharmacological inhibition of YAP impeded fibrogenesis in mice. CONCLUSIONS: YAP activation is a critical driver of hepatic stellate cell activation and inhibition of YAP presents a novel approach for the treatment of liver fibrosis. PMID- 25908272 TI - Evidence supporting a beneficial role of vitamin D in chronic hepatitis C. PMID- 25908273 TI - Expected long-term impact of the German screening colonoscopy programme on colorectal cancer prevention: analyses based on 4,407,971 screening colonoscopies. AB - AIM: Endoscopy based screening programmes for colorectal cancer (CRC) are being implemented in an increasing number of countries. In Germany, screening colonoscopy at age 55 or older has been offered since the end of 2002. We aimed to estimate the long-term impact of this offer on CRC prevention. METHODS: We estimated numbers of prevented CRC cases by expected age and year of their (prevented) occurrence over four decades (2005-2045) by four state Markov models (non-advanced adenoma, advanced adenoma, preclinical CRC, clinically manifest CRC). Estimates are based on screening colonoscopies reported to the German screening colonoscopy registry in 2003-2012 (N=4,407,971), transition rates between the four states and general population mortality rates. RESULTS: Numbers of prevented clinically manifest CRC cases are projected to increase from <100 in 2005 to approximately 6500 in 2015, 12,600 in 2025, 15,400 in 2035 and 16,000 in 2045, compared to approximately 58,000 incident cases observed in 2003. The annual number of prevented cases is expected to be higher among men than among women and to strongly vary by age. The vast majority of prevented cases would have occurred at age 75 or older. CONCLUSIONS: Despite modest participation rates, the German screening colonoscopy programme will lead to substantial reductions in the CRC burden. The reductions will be fully disclosed in the long run only and predominantly affect numbers of incident cases above 75years of age. Screening offers would need to start at younger ages in order to achieve more effective CRC prevention at younger ages. PMID- 25908274 TI - MiR-21, miR-34a, miR-198 and miR-217 as diagnostic and prognostic biomarkers for chronic pancreatitis and pancreatic ductal adenocarcinoma. AB - BACKGROUND: Pancreatic ductal adenocarcinoma is an aggressive malignancy with late presentation, metastatic potential and very poor prognosis. Therefore, there is an urgent need for novel diagnostic and prognostic biomarkers. MicroRNAs are small non-coding RNAs that post-transcriptionally regulate gene expression. Altered expression of microRNAs has been reported in wide range of malignancies, including pancreatic ductal adenocarcinoma. The aim of this study was to analyze the expression of selected microRNAs in normal pancreas, chronic pancreatitis and pancreatic ductal adenocarcinoma tissues and evaluate their diagnostic and prognostic potential. FINDINGS: Using quantitative real-time PCR, expression levels of 4 microRNAs were examined in 74 tumor tissues, 18 tissues of chronic pancreatitis and 9 adjacent normal tissues and correlated with clinicopathological features of patients. Expression levels of miR-21, miR-34a and miR-198 were significantly higher, whereas levels of miR-217 were significantly lower in pancreatic ductal adenocarcinomas compared to healthy tissues and tissues of chronic pancreatitis. Moreover, increased expression of miR-21 and miR-198 was significantly associated with shorter disease free survival and overall survival. CONCLUSIONS: Our data suggest that altered expression of examined microRNAs is related to neoplastic transformation and progression of the disease and these microRNAs could serve as diagnostic and prognostic biomarkers for pancreatic ductal adenocarcinoma. VIRTUAL SLIDES: The virtual slide(s) for this article can be found here: http://www.diagnosticpathology.diagnomx.eu/vs/1373952531543898. PMID- 25908277 TI - [Offer early attention and intervention to patients with valvular heart disease]. AB - As a key feature of the updates, early intervention of valvular heart disease is highlighted in the 2014 AHA/ACC guideline for the management of patients with valvular heart disease. This article reviewed the new guideline in regards to the issue of early intervention of diseases such as aortic stenosis, aortic insufficiency, mitral stenosis, mitral insufficiency, tricuspid insufficiency, and infective endocarditis, with discussion on the related topics according to the authors' understanding and practical experience in China. We conclude that valvular heart disease should receive early intervention and attention should also be paid on the progress of disease. PMID- 25908276 TI - Ethnic differences in dietary intake at age 12 and 18 months: the Born in Bradford 1000 Study. AB - OBJECTIVE: To compare the intake of key indicator foods at age 12 months and 18 months between infants of Pakistani and White British origin. DESIGN: Logistic regression was used to model associations between ethnicity and consumption of key indicator foods defined by high or low energy density using an FFQ at age 12 and 18 months. SETTING: Born in Bradford 1000 study, Bradford, UK. SUBJECTS: Infants (n 1259; 38 % White British, 49 % Pakistani), mean age 12.7 (sd 1.0) months and toddlers (n 1257; 37 % White British, 49 % Pakistani), mean age 18.7 (sd1.0) months. RESULTS: At 12 months, Pakistani infants consumed more commercial sweet baby meals than White British infants, with greater odds for being above average consumers (adjusted OR (AOR)=1.90; 95 % CI 1.40, 2.56), more chips/roast potatoes (AOR=2.75; 95 % CI 2.09, 3.62), less processed meat products (AOR=0.11; 95 % CI 0.08, 0.15), more fruit (AOR=2.20; 95 % CI 1.70, 2.85) and more sugar sweetened drinks (AOR=1.68; 95 % CI 1.29, 2.18). At 18 months these differences persisted, with Pakistani infants consuming more commercial sweet baby meals (AOR=4.57; 95 % CI 2.49, 8.39), more chips/roast potato shapes (AOR=2.26; 95 % CI 1.50, 3.43), more fruit (AOR=1.40; 95 % CI 1.08, 1.81), more sugar-sweetened drinks (AOR=2.03; 95 % CI 1.53, 2.70), more pure fruit juice (AOR=1.82; 95 % CI 1.40, 2.35), more water (AOR=3.24; 95 % CI 2.46, 4.25) and less processed meat (AOR=0.10; 95 % CI 0.06, 0.15) than White British infants. CONCLUSIONS: Dietary intake during infancy and the early toddlerhood period is associated with ethnicity, suggesting the importance of early and culturally adapted interventions aimed at establishing healthy eating behaviours. PMID- 25908275 TI - Identification and visualization of multidimensional antigen-specific T-cell populations in polychromatic cytometry data. AB - An important aspect of immune monitoring for vaccine development, clinical trials, and research is the detection, measurement, and comparison of antigen specific T-cells from subject samples under different conditions. Antigen specific T-cells compose a very small fraction of total T-cells. Developments in cytometry technology over the past five years have enabled the measurement of single-cells in a multivariate and high-throughput manner. This growth in both dimensionality and quantity of data continues to pose a challenge for effective identification and visualization of rare cell subsets, such as antigen-specific T cells. Dimension reduction and feature extraction play pivotal role in both identifying and visualizing cell populations of interest in large, multi dimensional cytometry datasets. However, the automated identification and visualization of rare, high-dimensional cell subsets remains challenging. Here we demonstrate how a systematic and integrated approach combining targeted feature extraction with dimension reduction can be used to identify and visualize biological differences in rare, antigen-specific cell populations. By using OpenCyto to perform semi-automated gating and features extraction of flow cytometry data, followed by dimensionality reduction with t-SNE we are able to identify polyfunctional subpopulations of antigen-specific T-cells and visualize treatment-specific differences between them. PMID- 25908278 TI - [Retrospective analysis of 553 patients with posttraumatic elbow stiffness]. AB - OBJECTIVE: To investigate the etiology of posttraumatic elbow stiffness and distinguish features of the patients by retrospective analyzing their records. METHODS: This was a retrospective analysis of 553 patients with posttraumatic elbow stiffness who underwent arthrolysis performed in Beijing Jishuitan Hospital from January 1997 to December 2013. The patients' clinical and radiographic results were collected, and encoded into a survey database. RESULTS: Total 366 male and 189 female patients were treated by the same treating team. The average age of 553 cases was 35 years (12-76 years). And the largest number of >30-40 years old group was 166 (30.8%). There were 301 cases (54.4%) causing by low energy injury and 227 cases (41.1%) by high-energy injury. The patients of extra articular fractures and injuries were 60 cases (10.8%) with average 6.1 weeks' immobilization, and the patients of intra-articular fractures or dislocations were 493 cases (89%) with average 4.9 weeks' immobilization. The mean range of motion of extension and flexion was 30 degrees (0 degrees -110 degrees ). Four hundreds and fifty-seven patients (82.6%) were diagnosed with Heterotopic Ossification (HO), the other 96 patients without HO. CONCLUSIONS: Elbow stiffness commonly occurs following trauma. More attention needs to pay on the treatment procedures for minor injuries, extra-articular fractures and simple intra articular fractures. It is not appropriate to immobilize the elbow more than 3 weeks, even for those complicated elbow fracture and dislocation. Heterotopic ossification has significant negative impact on the function of elbow. However its pathogenesis is still not clear, which need more fundamental research. PMID- 25908279 TI - [An anatomic study of glenoid regarding anchor insertion posion and direction]. AB - OBJECTIVE: To investigate normal bony anatomy of the glenoid rim, to measure inner glenoid rim angle and outer glenoid rim angle, and the angles for successful anchor insertion for arthroscopic labral repairs. METHODS: Twelve unpaired isolated human glenoids (6 right, 6 left) without any evidence of trauma were for studying. The glenoid specimens were scanned using 320-slice CT (Aquilion ONE), then reconstruction glenoid to a three dimensional model using materialise's interactive medical image control system (Mimics) and to obtain cross-sectional images in 6 different planes, mark the right glenoid rim with clockwise tag, the left with counterclockwise tag. Inner glenoid rim angle marked as angle alpha and outer glenoid rim angle marked as angle beta were measured from the cross-sectional images of the glenoids at 8 positions: 2-, 3-, 4-, 5-, 6 , 7-, 8- and 9-o'clock positions. Glenoid morphology was noted for each position. Using 12 mm as radius, measured the minimum insertion angle of anchor, marked as angle gamma. Normal distribution of the data was confirmed with Kolmogorov Smirnov test. Paired t-test was performed to detect differences in the angles between two locations. Two independent samples t-test was performed to detect differences in the angles between same location of left and right. Analysis of variance (ANOVA) was performed to detect differences in the angles between right and left, and different locations of the glenoid rim. RESULTS: The smallest alpha was at the 4-o'clock position (right 50 degrees +/- 6 degrees , left 52 degrees +/- 9 degrees ), significant difference were seen when compared with the 6 o'clock position (t = 10.466, P = 0.000) or the 5-o'clock position (t = 3.754, P = 0.003), no significant difference exist between 4-o'clock position and 3 o'clock posion (t = 0.926, P = 0.374). The smallest beta was at the 3-o'clock position (right 50 degrees +/- 6 degrees , left 53 degrees +/- 10 degrees ), significant difference were seen when compared with the 6-o'clock position (t = 9.862, P = 0.000) or the 5-o'clock position (t = 3.634, P = 0.003), no significant difference exist between 4-o'clock position and 3-o'clock posion (t = 0.697, P = 0.501). Asymmetric morphology of the glenoid was noted with an almost straight line extending medially from the rim at the 3-o'clock position, whereas a concave morthology was noted at the 9-o'clock position. Similary at the 4- and 5-o'clock position, the scapular bony surface did not curve toward the base as markedly as it did at the corresponding posterior 8- and 7-o'clock position. Angle gamma from the 3-o'clock to the 9-o'clock were 25 degrees +/- 4 degrees , 54 degrees +/- 6 degrees , 83 degrees +/- 4 degrees , 119 degrees +/- 2 degrees at right side, 23 degrees +/- 4 degrees , 57 degrees +/- 4 degrees , 89 degrees +/- 7 degrees , 119 degrees +/- 4 degrees at left side. No significant difference of any angle at the same position was noted between left and right (alpha:t = 0.283-1.785, P > 0.05;beta:t = 0.369-2.067, P > 0.05;gamma:t = 0.145-0.492, P > 0.05). CONCLUSIONS: The available bone mass for the anchor insertion is found to vary depending on the position of the glenoid rim. The smallest inner and outer glenoid rim angle are at the 4- and 3-o'clock position. The minimum insertion angles of anchor differ at different position. Both rim angle and glenoid morthology for each position must be considered when selecting the ideal anchor insertion angle for Bankart repair. Meanwhile, minimum insertion angle of anchor should also be considered before anchor insertion. PMID- 25908280 TI - [Cervical flexion F-waves in the patients with Hirayama diseases]. AB - OBJECTIVE: To identify whether there is significant changes between the cervical neutral F-waves and cervical flexion F-waves in the patients with Hirayama disease. METHODS: This study was performed on 25 normal subjects and 22 male patients with identified Hirayama disease (age: 15 to 44 years; height: 165 to 183 cm; duration: 6 to 240 months) between May 2010 and March 2014. Both cervical flexion F-wave (cervical flexion 45 degrees , 30 minutes) and conventional F waves to median nerve stimulation and to ulnar nerve stimulation were performed in all subjects bilaterally. RESULTS: were analyzed by t-test or Fisher exact probability. RESULTS: In the normal subjects, all measurements of the bilateral F waves didn't have any difference between the cervical flexion position and the cervical neutral position. On the cervical neutral position, the persistence (t = 5.209, P = 0.000), average latencies (t = 4.731, P = 0.022) and minimal latencies (t = 23.843, P = 0.006) of ulnar F-wave on the symptomatic heavier side from the patients with identified Hirayama disease were significantly lower or longer than those from the normal subjects, and the repeat F-waves were found in 3 patients (13.6%). On the symptomatic lighter side, the ulnar F-waves only had lower persistence (t = 22.306, P = 0.001) along with 5 repeat F-waves. Only lower persistence were found in the median F-wave on the both side (higher side t = 23.696, P = 0.000; lighter side t = 23.998, P = 0.000), along with 5 (22.7%) repeat F-waves on the symptomatic heavier side and 6 (27.3%) ones on the symptomatic lighter side. After cervical flexion maintaining 30 minutes, the increased maximal amplitudes (t = -2.552, P = 0.019), average amplitudes (t = 3.322, P = 0.003), duration (t = -3.323, P = 0.00), persistence (t = -2.604, P = 0.017) and frequency of repeat F-waves (9/22, 41%) (P = 0.044) were found on the symptomatic heavier side of ulnar F-wave, and 5 of 10 absent ulnar F-wave on the cervical neutral position were also recover. The median F-wave on the symptomatic heavier side mainly had increased maximal amplitude (t = -3.847, P = 0.001), average amplitudes (t = -2.188, P = 0.040) and persistence (t = -2.421, P = 0.025), and 1 of 6 absent median F-wave on the cervical neutral position were also recover after cervical flexion. CONCLUSION: The cervical flexion F-waves have significant regular changes compared to the cervical neutral F-waves in patients with Hirayama diseases, especially maximal and average amplitudes of F waves. PMID- 25908281 TI - [Study of a preoperative deep venous thrombosis predictor score for patients with fresh lower extremity fractures]. AB - OBJECTIVE: To establish a preoperative deep venous thrombosis predictor score for patients with fresh lower extremity fractures by statistical analysis. METHODS: From January 2011 to December 2012, 1 705 patients with fresh lower extremity fractures were admitted to department of orthopaedic trauma, Beijing Jishuitan Hospital. They were randomly divided into two groups, the group 1 (n = 879) was used to screen risk factors and derived a predictive models based on logistic regression, the group 2 (n = 826) validated the models. RESULTS: Among the patients, there were 1 106 male and 599 female patients, with an average age of (50 +/- 18) years.Variables related to preoperative deep venous thrombosis were age, length of time before surgery, cause of injury, low/high-energy injury, location of injury, history of cardiovascular and cerebrovascular diseases, and D Dimer. The scores based on OR were: age <= 35 years: 1 point, > 35- < 65 years: 4 points, >= 65 years: 6 points; length of time before surgery, < 8 days:1 point, >= 8 days:2 points;low-energy injury:1 point, high energy injury:3 points;location of injury, foot and ankle:1 point, calf:3 points, around the knee: 5 points, femoral diaphysis and proximal femur:7 points, pelvis and acetabulum:4 points, >= 2 sites:6 point;history of cardiovascular and cerebrovascular diseases, yes:2 points, no:1 point. D-Dimer < 600 ug/L:1 point, >= 600 ug/L:3 points. Area under receiver operating characteristic curve was 0.79, critical point 15.5 points, sensitivity was 77.00%, specificity was 68.17%. CONCLUSION: The score can predict the preoperative deep venous thrombosis for patients with fresh lower extremity fractures, but limited. PMID- 25908282 TI - [Postoperative complications and revision surgery following primary total knee arthroplasty after midterm follow-up]. AB - OBJECTIVE: To determine the postoperative complications of primary total knee arthroplasty (TKA) within 30 postoperative days, and the different causes for revision surgery during follow-up. METHODS: Between January 2001 and December 2012, a total of 1 920 patients underwent 2 779 primary TKA with fixed bearing platform in Peking Union Medical College Hospital, with 323 for male and 1 607 for female. The revision surgery at index time and the hemophiliac arthropathy were excluded for this study. The average age was (66 +/- 9) years (from 25 to 86 years).Osteoarthritis accounted for 1 720 cases (89.58%), rheumatoid arthritis for 168 cases (8.75%), ankylosing spondylitis for 12 cases (0.63%), secondary arthritis for 20 cases (1.04%). The postoperative complications with 30 postoperative days and revision surgery during follow-up were recorded. RESULTS: Follow-up was concluded at December 2013. Totally, 1 854 patients (2 693 knees) were successfully followed-up.Forty-one patients experienced systemic complication within 30 postoperative days, with the rate of 2.21%. The most common reasons of systemic complication were the respiratory complication and cardiovascular complication in origin, with the rate of 0.49% (9/1 854) and 0.38% (7/1 854) respectively. The average rate of deep venous thrombosis in this group was 3.02% (56/1 854). The local complication rate within 30 days was 1.29% in this group. Totally 59 knees experienced the revision surgeries during average 67 months follow-up. The most common causes for revision surgery in relative values were septic loosening, with the rate of 1.19% (32 in 2 693 knees), followed by postoperative stiffness, with the rate of 0.37% (10 in 2 693 knees). CONCLUSIONS: The most common reasons of systemic complication with 30 postoperative days after primary TKA procedure are the respiratory complication and cardiovascular complication in origin. The most common reason for revision surgery during mid term follow-up for primary TKA is septic loosening. PMID- 25908283 TI - [Restoration of the difference value of pelvic incidence and lumbar lordosis in degenerative scoliosis patients: its influence in maintaining sagittal profile and improving quality of life]. AB - OBJECTIVE: To evaluate the role that post-operative difference value of pelvic incidence and lumbar lordosis (PI-LL) played on loss of correction, implant failure and health-related quality of life during follow-up in degenerative scoliosis patients. METHODS: Retrospective review of 62 patients (average age (57 +/- 10) years, 11 male and 51 female patients) with degenerative scoliosis who underwent one stage posterior surgical instrumentation in the affiliated Drum Tower Hospital of Nanjing University Medical School from January 2005 to December 2011. The mean follow-up duration was 4.2 years. Long-cassette standing upright sagittal radiographs were obtained before and after operation and at the last follow-up. At the last follow-up, visual analogue scale and Oswestry disability index were collected. Based on post-operative PI-LL, patients were divided into two groups: group A (-9 degrees < post-operative PI-LL<9 degrees ) and group B (post-operative PI-LL < -9 degrees or post-operative PI-LL>9 degrees ). Independent t test and chi(2) test were performed for statistical analysis. For all statistical analysis, the level of significance was set at P < 0.05. RESULTS: No difference was observed in terms of loss of correction between two groups during follow-up. More implant failure were observed in group B (15.63% vs. 6.7%, chi(2) = 21.85, P = 0.012). In addition, patients with better PI-LL matching came with better visual analogue scale (3.9 +/- 2.4 vs. 5.2 +/- 3.3, F = 0.089, P = 0.024). CONCLUSION: Worse quality of life and increased risk for implant failure during follow-up may be related to mismatched PI-LL. PMID- 25908284 TI - [Association between the expression of Aggrecan and the distribution of Aggrecan gene variable number of tandem repeats with symptomatic lumbar disc herniation]. AB - OBJECTIVE: To study the expression of Aggrecan and the relationship between the variable number of tandem repeats (VNTR) of Aggrecan and lumbar disc herniation (LDH). METHODS: The disease group comprised of 74 patients already diagnosed with symptomatic LDH. The control group consisted of 15 patients restricted to spinal trauma and 113 healthy blood donors without symptoms of LDH who were not diagnosed with LDH. Disc tissue samples were obtained from surgical operations and blood samples were donated from all participants. The Aggrecan expression in isolated tissues was assessed by western blot using specific antibodies. The Aggrecan gene VNTR region was analyzed by PCR. RESULTS: The Aggrecan expression positive rate of control group was statistically and significantly higher (control group:86.67%, disease group:13.51%;chi(2) = 34.83, P < 0.05) than that of the disease group. Moreover, there was a statistically significant higher frequency of Allele 25 or Allele 21 in disease group compared to controls (A25disease group = 22.97%, A25control group = 12.11%, chi(2)A25 = 8.20, PA25 = 0.004; A21disease group = 6.76%, A21control group = 0.39%, chi(2)A21 = 14.35, PA21 = 0.000). Compared to the participants with 2 Alleles>25 repeats, subjects with 1 or 2 Alleles <= 25 repeats statistically and significantly over represented the disease group without the expression of Aggrecan (chi(2) = 5.69, P = 0.017). CONCLUSIONS: The findings suggest a relationship between Aggrecan and symptomatic LDH, where symptomatic LDH has a tendency of allele 21 and allele 25 repeats.In addition, an association between the distribution of Aggrecan gene VNTR polymorphism and the expression of Aggrecan is observed in symptomatic LDH. PMID- 25908285 TI - [Total en-bloc spondylectomy for recurrence spinal tumor]. AB - OBJECTIVE: To evaluate the clinical outcomes of total en-bloc spondylectomy (TES) in recurrence spinal tumor. METHODS: The study was a retrospective study of recurrence spinal tumor from January 2010 to October 2013. A total of 6 patients with recurrent spinal tumor underwent TES procedures, with 5 cases located in thoracic spine and 1 case located in L1. There were 3 male and 3 female patients, with a mean age of 33.2 years. Pathological diagnosis included giant cell tumor of bone in 3 cases, breast cancer, lung cancer and nasopharyngeal carcinoma with 1 case in each. The operation time, bleeding loss, resected segments, cutting edge, spinal cord function and complications was evaluated. RESULTS: Single segment resected in 1 case, 2 segments resected in 2 cases and 3 segments resected in 3 cases. The average operation time was 8.9 hours (7.5 to 12.0 hours). The average blood loss was 3 116 ml (2 500 to 4 500 ml). The average follow-up period was 23.2 months (12 to 47 months) without recurrence. There was no spinal cord injury during operation. The neurologic function was significantly improved in 2 cases (American Spinal Injury Association (ASIA) grade C to grade D), unchanged in 1 cases (ASIA grade B) and no deteriorated case in 3 cases (ASIA grade E). There was no perioperative deaths case. Complications included 2 cases pleural rupture, 1 case dural tear and 1 case massive haemothorax. No peri operation death case. CONCLUSION: Some of the recurrent spinal tumors are still suitable for en-bloc resection and TES procedure with the extent of its applicability under strict control. PMID- 25908286 TI - [Clinical features of hip fractures with combined fractures in adults of the Third Hospital of Hebei Medical University from 2008 to 2012]. AB - OBJECTIVE: To investigate the clinical characteristics and analyze the proportions of adult hip fracture patients combined with other sites of fractures. METHODS: Adult patients with hip fractures admitted to the Third Hospital of Hebei Medical University were retrospectively collected from January 2008 to December 2012. The proportions of patients combined with other fractures were calculated and the clinical features of gender, age and combined fracture sites were analyzed. RESULTS: A total of 3 310 patients with hip fracture were included, and 328 patients of them were combined with other site fractures, therefore with the proportions of 9.91%, and 13.93% for males, 6.40% for females respectively. The patients aged >= 30 and < 40 years account for the highest (26.88%) proportion of combined fractures, with the single summit for incident age. The most amount of hip fracture patients with other site fractures were aged >= 70 and < 80 years (56 patients). Which were aged >= 30 and < 40 years, >= 40 and < 50 years for males (41 patients), while aged >= 80 years for females (32 patients). There were a total of 536 combined fracture sites with 1.63 sites per patient, and 1.73 sites per males, 1.45 sites per females. The highest of average sites per patient (2.22 sites/person) was occurred at age >= 16 and < 20 years. For youth or males patients, the most common combined fracture sites were diaphyseal femur fracture, tibia and fibula and ankle fractures, foot fractures. While for elderly or female patients, it were thoracolumbar fractures and distal radius and ulna fractures. CONCLUSIONS: The young or male patients have the most possibility to combine with other sites of fractures. For youth or males, the most common combined fracture sites are concentrated in the lower limbs. While for elderly or female patients, thoracolumbar fractures and distal radius and ulna fractures are more commonly. PMID- 25908287 TI - [The method and result analyses of pathogenic bacteria culture on chronic periprosthetic joint infection after total knee arthroplasty and total hip arthroplasty]. AB - OBJECTIVE: To analyze the results of pathogenic bacteria culture on chronic periprosthetic joint infection after total knee arthroplasty (TKA) and total hip arthroplasty (THA). METHODS: The medical data of 23 patients with chronic periprosthetic joint infection after TKA or THA from September 2010 to March 2014 were reviewed. Fifteen cases of TKA and 8 cases of THA were included in this study. There were 12 male and 11 female patients with the mean age of 62 years (range from 32 to 79 years), and among them 9 patients with sinus. All patients discontinued antibiotic therapy for a minimum of 2 weeks before arthrocentesis, taking pathogenic bacteria culture and antimicrobial susceptibility test by using synovial fluid taken preoperatively and intraoperatively of revision. Common pathogenic bacteria culture and pathological biopsy were taken on tissues intraoperatively of revision. Culture-negative specimens were prolonged the period of incubation for 2 weeks. RESULTS: The overall culture-positive rate of all 23 patients for 1 week before revision was 30.4% (7/23), and the positive rate of culture-negative samples which prolonged for 2 weeks was 39.1% (9/23). The overall culture-positive rate of patients for 1 week intraoperatively of revision was 60.9% (14/23), and the positive rate of culture-negative samples which prolonged for 2 weeks was 82.6% (19/23). The incubation results of 7 cases (30.4%) preoperatively conformed to that of intraoperation. CONCLUSION: The culture-positive rate of pathogenic bacteria culture can be increased evidently by discontinuing antimicrobial therapy for a minimum of 2 weeks prior to the definite diagnosis. PMID- 25908288 TI - [Surgical management of incidental gallbladder cancer discovered during or after laparoscopic cholecystectomy]. AB - OBJECTIVE: To analyze the surgical management of incidental gallbladder cancer (IGBC) discovered during or after laparoscopic cholecystectomy (LC) and to evaluate the associated factors of survival. METHODS: A retrospective analysis of patients with IGBC between January 2002 and December 2013 was performed. A total of 10 080 consecutive patients underwent LC operation for presumed gallbladder benign disease in Chinese People's Liberation Army General hospital. And among them, 83 patients were histologically diagnosed as IGBC. Data covering clinical characteristics, surgery records, local pathological stage, histological features and factors for long term survival were reviewed. The survival analysis was performed using Kaplan-Meier method, and the results were examined using the log rank test.For multivariate statistical analyses of prognostic factors, a Cox proportional hazards model was carried out. RESULTS: A total of 83 patients with IGBC:68.7% females (57/83), median age of 61 years (range 34-83 years). There were 47 cases accepted the initial simple LC, 18 cases converted to open extended radical cholecystectomy, 16 cases with radical second resection, and 2 cases with re-laparotomy; the 5-year survival rates for each group were 89.4%, 38.9%, 87.5%, and 0, respectively. The 5-year survival rates in T1a, T1b, T2, and T3 stage patients were 95.7% (22/23), 90.0% (18/20), 75.0% (15/20), and 40.0% (8/20), respectively. Univariate analysis for prognostic factors associated with cancer specific death showed that depth of invasion, lymph-node status, vascular or neural invasion, tumor differentiation, extent of resection, bile spillage during prior LC and type of surgery were statistically significant.In multivariate analysis, depth of invasion, extent of resection and bile spillage were the most important prognostic factors related to both cancer-specific mortality and disease relapse (P < 0.05). CONCLUSIONS: Simple LC is appropriate for T1a patients with clear margin and unbroken gallbladder. An extended radical resection in patients with T1b or more is highly recommended, and provided as a potentially curative R0 resection only if it is necessary. PMID- 25908289 TI - [Hybrid treatment of aortic arch disease with ascending aorta to carotid artery revascularization and subsequent endovascular repair]. AB - OBJECTIVE: To summarize the experience of treating aortic arch disease with ascending aorta to carotid artery revascularization and subsequent endovascular repair. METHODS: From January 2002 to June 2013, 10 high risk patients with aortic arch disease were treated with ascending aorta to carotid artery revascularization with subsequent endovascular repair in the First Affiliated Hospital, Sun Yat-sen University. There were 9 male and 1 female patients with a mean age of (54 +/- 14) years (ranging from 34 to 71 years). Of the 10 patients, 8 were aortic dissection and 2 were thoracic aortic aneurysm. All aortic arch debranching was performed with mid-sternotomy, including 7 ascending aorta to innominate artery and left common carotid artery bypass, and 3 ascending aorta to left common carotid artery and left subclavian artery bypass.Subsequently, simultaneous (n = 5) and staged (n = 5, mean interval (7 +/- 4) days) endovascular repair were performed via femoral artery. RESULTS: Technical success rate was 10/10. The 30 day-mortality was 3/10, including 1 brain stem infarction, 1 circulatory failure and 1 aorto-tracheal fistula. Complication included 1 type II endoleak. The median time of follow-up was 24 (14) months. CT scanning was performed at 1, 3 months and annually thereafter. There was no death and no occlusion of bypass during follow-up.No complication occurred except 1 existing type II endoleak. CONCLUSION: Ascending aorta to carotid artery revascularization with subsequent endovascular repair is suitable for high risk aortic arch pathology patients in poor general condition with little tolerance to aortic arch replacement. PMID- 25908290 TI - [Surgical treatment of multiple intracranial aneurysms]. AB - OBJECTIVE: To discuss the surgical strategies and analyze the clinical outcomes of multiple intracranial aneurysms (MIA). METHODS: The clinical data of 49 MIA patients surgically treated between January 2009 and December 2013 was analyzed retrospectively. Among the 49 patients, 12 patients were male and 37 were female, mean age (49 +/- 11) years. Thirty-five patients had ruptured aneurysms, and 14 had unruptured aneurysms. Treatment strategies included one-stage operation (MIA were treated in one-stage with an unilateral approach), two-stage treatment (MIA were treated stage by stage) and partial treatment (only ruptured aneurysm was treated). Postoperative CT angiograms (CTA) or digital subtraction angiograms (DSA) were reviewed and the Glasgow Outcome Scale (GOS) scores were evaluated during follow-up period. RESULTS: Thirty-two patients (65.3%) underwent one-stage operation, 9 patients (18.4%) underwent two-stage treatment, and 8 patients (16.3%) underwent partial treatment. Forty-seven patients were followed up 4-49 months, mean (22 +/- 7) months. Postoperative CTA or DSA showed no aneurysm recurrence. According to the GOS scores, 41 patients (83.7%) with good outcomes (GOS 4, 5), 6 patients (12.2%) were disabled (GOS 2, 3) and 2 patients (4.1%) were dead (GOS 1). CONCLUSION: Selecting the right patients for surgery and making personalized surgical strategies based on the characteristics of patients and aneurysms could improve the surgical outcomes of MIA. PMID- 25908291 TI - [Comparison of sufentanil-tramadol PCIA between laparoscopic cholecystectomy and gynecological laparoscopy]. AB - OBJECTIVE: To compare the differences of postoperative patient-controlled intravenous analgesia for laparoscopic cholecystectomy and gynecological laparoscopy in female patients. METHODS: This retrospective study included 645 female patients received laparoscopic cholecystectomy or gynecological laparoscopy (laparoscopic oophorocystectomy/myomectomy) between January 2011 and July 2012 in Tongji Hospital. Among them, 207 cases of sufentanil-tramadol patient-controlled intravenous analgesia (PCIA) were enrolled and divided into 2 groups:77 cases in laparoscopic cholecystectomy group, and 130 cases in gynecological laparoscopy group. The pressing frequency and consumption of PCIA, localization and quality of postoperative pain, visual analogue scale (VAS) at 4 6 h, 8-12 h, 18-24 h after surgery, and adverse effect were compared by t test,chi(2) test, Fisher exact test or Mann-Whitney test. RESULTS: There was no statistical difference of age, body mass index, and operation time between the two groups (all P > 0.05). As compared with the gynecological laparoscopy group (3 (4)), PCIA pressing frequency was higher in the laparoscopic cholecystectomy group (5 (7)), but there was no statistical difference (Z = -1.747, P = 0.081). PCIA consumption in the laparoscopic cholecystectomy group (79 (33) ml) was higher than that in the gynecological laparoscopy group (48 (30) ml) (Z = -6.267, P = 0.000). The postoperative pain localization and quality were different in the two groups, the patients in the laparoscopic cholecystectomy group experienced dull pain in lower abdomen, but the ones in the gynecological laparoscopy group had distending pain in upper abdomen and piercing pain around scapula. The differences of 4-6 h, 8-12 h, 18-24 h VAS scores in the two groups had no statistical significance (all P > 0.05). The total incidence of postoperative adverse effect between the two groups had no statistical significant difference (laparoscopic cholecystectomy group:11.7%, gynecological laparoscopy group:16.2%) (chi(2) = 0.778, P = 0.378). The incidence of dizziness was higher in the gynecological laparoscopy group (6.2%) than that in the laparoscopic cholecystectomy group (0) (Fisher exact test:P < 0.05). CONCLUSION: In the case of sufentanil-tramadol PCIA, laparoscopic cholecystectomy needs more postoperative analgesia, while gynecological laparoscopy has higher incidence of dizziness. PMID- 25908292 TI - [The clinical application of near-infrared light imaging mediated by indocyanine green in liver cancer surgery]. AB - In recent years, the emerging optical imaging technologies have shown their unique value in diagnosis of disease and surgical navigation. This article focus on describing the optical imaging technology mediated by the only one near infrared light imaging molecule--indocyanine green which has already been approved by FDA to use in clinical and inmates a characteristics of passive targeting liver cancer tissue. This article reviews the application of the technology in liver cancer surgery and demonstrates the value, deficiency and possible improvements of this technology. PMID- 25908293 TI - [Research advances on the evaluation of regional liver function based on the demand of precise liver surgery]. AB - Surgical resection is the best treatment for hepatocarcinoma. With the rapid development and cooperation of multi-disciplines, the liver surgery gradually towards a precise stage, and accurate evaluation of regional liver function preoperatively is demand for the development of precise liver surgery. Methods to assess function of liver at present include serological liver function and biochemical examination, clinical liver function scoring system, quantitative liver function test and imaging examination. Nuclide imaging technology and liver specificity enhanced MRI contrast agent are expected to achieve to evaluate regional liver function. PMID- 25908294 TI - Predictors of Health-Related Quality of Life After Bariatric Surgery. AB - BACKGROUND: Bariatric surgery is typically associated with improvement in health related quality of life (HRQoL). However, recent reports are conflicting, and the aim of this study was to determine factors that would be predictive for long-term outcomes after bariatric procedures. METHODS: One thousand five hundred and seventy-three patients at one Midwestern academic medical center who underwent any type of bariatric surgery were sent the SF-36 survey. Three hundred and fifty completed surveys collected over a 3-month period were returned. Multivariate analysis was conducted. RESULTS: The physical and mental component scores were significantly lower than the norm population mean. Age at time of surgery, pre surgical body mass index (BMI) and duration since surgery were negatively related to HRQoL. CONCLUSIONS: Improvements in HRQoL following bariatric surgery do not appear to be sustained over the long term. Older patients and those with high pre surgical obesity do not appear to have the same benefits in HRQoL over time. PMID- 25908295 TI - Malignant glomus tumor with oncocytic features: an unusual presentation of dysphagia. AB - Glomus tumors in the gastrointestinal tract are unusual, as the previous series in the literature have been mainly limited to the stomach. Less than 10 cases of esophageal glomus tumors have been described in the literature. Oncocytic glomus tumors are a recently identified, rare variant of the glomus tumor. We report a 47-year-old female who presented with an approximately 3-month history of dysphagia and weight loss. Upper gastrointestinal endoscopy showed a black purple, hypervascular, protruding lesion measuring approximately 65 mm at the 37th cm of the esophagus. The patient underwent an Ivor Lewis operation via open thoracotomy. The resected specimen had a protuberant, ulcerated mass measuring 80 * 35 mm in the posterior wall of the esophagus. Based on the histopathological, immunohistochemical and electron microscope findings, the final diagnosis was a malignant glomus tumor with oncocytic features. To our knowledge, this is the first report of a malignant glomus tumor with oncocytic features in an esophageal location. PMID- 25908296 TI - Prostatosymphyseal fistula and osteomyelitis pubis following transurethral resection of the prostate: CT and MRI findings. AB - We present a very rare case of osteomyelitis pubis in a 75-year-old male patient due to a prostatosymphyseal fistula, which constituted a few weeks after trans urethral resection of the prostate. The patient had a previous history of prostatic carcinoma treated by radiotherapy, which may have played a role in the development of the fistula. Computed tomography with excretory phase and magnetic resonance imaging were performed and enabled to make the final diagnosis. PMID- 25908297 TI - NHS faces biggest challenge "for many years" amid mounting deficits and declining morale. PMID- 25908298 TI - Response to the letter to the editor: Barasheed et al., 'No evidence of MERS-CoV in Ghanaian Hajj pilgrims: cautious interpretation is needed'. PMID- 25908299 TI - Corticosteroids for the management of cancer-related pain in adults. AB - BACKGROUND: One of the most feared symptoms associated with cancer is pain. Opioids remain the mainstay of pain treatment but corticosteroids are often used concurrently as co- or adjuvant analgesics. Due to their anti-inflammatory mechanism of action, corticosteroids are said to provide effective analgesia for pain associated with inflammation and in the management of cancer-related complications such as brain metastasis and spinal cord compression. However, corticosteroids have a wide range of adverse effects that are dose and time dependent. OBJECTIVES: To evaluate the efficacy of corticosteroids in treating cancer-related pain in adults. SEARCH METHODS: We searched the Cochrane Central Register of Controlled Trials (CENTRAL 2014, Issue 4), MEDLINE (OVID) (1966 to 29 September 2014), EMBASE (OVID) (1970 to 29 September 2014), CINAHL (1982 to 29 September 2014), Science Citation Index (Web of Science) (1899 to 29 September 2014) and Conference Proceedings Citation Index - Science (Web of Science) (1990 to 29 September 2014). SELECTION CRITERIA: Any randomised or prospective controlled trial that included patients over 18 years with cancer-related pain were eligible for the review. Corticosteroids were compared to placebo or usual treatment and/or supportive care. DATA COLLECTION AND ANALYSIS: All review authors independently assessed trial quality and extracted data. We used arithmetic means and standard deviations for each outcome to report the mean difference (MD) with 95% confidence interval (CI). MAIN RESULTS: Fifteen studies met the inclusion criteria, enrolling 1926 participants. The trial size varied from 20 to 598 patients. Most studies compared corticosteroids, particularly dexamethasone, to standard therapy. We included six studies with data at one week in the meta-analysis for pain intensity; no data were available at that time point for the remaining studies. Corticosteroid therapy resulted in less pain (measured on a scale of 0 to 10 with a lower score indicating less pain) compared to control at one week (MD 0.84 lower pain, 95% CI 1.38 to 0.30 lower; low quality evidence). Adverse events were poorly documented. Factors limiting statistical analysis included the lack of standardised measurements of pain and the use of different agents, dosages, comparisons and routes of drug delivery. Subgroup analysis according to type of cancer was not possible. The quality of this evidence was limited by the risk of bias of the studies and small sample size. The results were also compromised by attrition, with data missing for the enrolled patients. AUTHORS' CONCLUSIONS: The evidence for the efficacy of corticosteroids for pain control in cancer patients is weak. Significant pain relief was noted in some studies, albeit only for a short period of time. This could be important for patients with poor clinical status. Further trials, with increased numbers of participants, are needed to evaluate the safety and effectiveness of corticosteroids for the management cancer pain in adults, and to establish an ideal dose, duration of therapy and route of administration. PMID- 25908300 TI - Geographic region and racial variations in polypharmacy in the United States. AB - PURPOSE: Medications can have unintended effects. High medication use populations may benefit from increased regimen oversight. Limited knowledge exists concerning racial and regional polypharmacy variation. We estimated total medication distributions (excluding supplements) of American black and white adults and assessed racial and regional polypharmacy variation. METHODS: REasons for Geographic And Racial Differences in Stroke (REGARDS) cohort data (n = 30,239 U.S. blacks and whites aged >=45 years) were analyzed. Home pill bottle inspections assessed the last two weeks' medications. Polypharmacy (>=8 medications) was determined by summing prescription and/or over-the-counter ingredients. Population-weighted logistic regression assessed polypharmacy's association with census region, race, and sex. RESULTS: The mean ingredient number was 4.12 (standard error = 0.039), with 15.7% of REGARDS using 8 ingredients or more. In crude comparisons, women used more medications than men, and blacks and whites reported similar mean ingredients. A cross-sectional, logistic model adjusting for demographics, socioeconomics, and comorbidities showed increased polypharmacy prevalence in whites versus blacks (OR [95% CI]: 0.63, [0.55-0.72]), women (1.94 [1.68-2.23]), and Southerners (broadly Southeasterners and Texans; 1.48 [1.17-1.87]) versus Northeasterners (broadly New England and upper Mid-Atlantic). Possible limitations include polypharmacy misclassification and model misspecification. CONCLUSION: Polypharmacy is common. Race and geography are associated with polypharmacy variation. Further study of underlying factors explaining these differences is warranted. PMID- 25908302 TI - Effect of acute and chronic DSS induced colitis on plasma eicosanoid and oxylipin levels in the rat. AB - Eicosanoids and oxylipins are potent lipid mediators involved in the regulation of inflammation. In order to evaluate their role and suitability as biomarkers in colitis, we analyzed their systemic levels in the acute and chronic phase of dextran sulfate sodium (DSS) induced colitis. Male Fischer 344 rats were treated in three cycles with 4% DSS in the drinking water (4 days followed by 10 days recovery) and blood was drawn 3 days prior to the first DSS treatment and on days 4, 11, 32 and 39. Histopathological evaluation of the colon tissue after 42 days showed that the animals developed a mild to severe chronic colitis. Consistently, prostaglandin levels were massively (twofold) elevated in the colonic tissue. LC MS based targeted metabolomics was used to determine plasma oxylipin levels at the different time points. In the acute phase of inflammation directly after DSS treatment, epoxy-fatty acid (FA), dihydroxy-FA and hydroxy-FA plasma concentrations were uniformly elevated. With each treatment cycle the increase in these oxylipin levels was more pronounced. Our data suggest that in the acute phase of colitis release of polyunsaturated FAs from membranes in the inflamed tissue is reflected by a uniform increase of oylipins formed in different branches of the arachidonic acid cascade. However, during the recovery phases the systemic oxylipin pattern is not or only moderately altered and does not allow to evaluate the onset of chronic inflammation in the colon. PMID- 25908301 TI - Soluble epoxide hydrolase null mice exhibit female and male differences in regulation of vascular homeostasis. AB - Increased CYP epoxygenase activity and consequently up regulation of epoxyeicosatrienoic acids (EETs) levels provides protection against metabolic syndrome and cardiovascular diseases. Conversion of arachidonic acid epoxides to diols by soluble epoxide hydrolase (sEH) diminishes the beneficial cardiovascular properties of these epoxyeicosanoids. We therefore examined the possible biochemical consequences of sEH deletion on vascular responses in male and female mice. Through the use of the sEH KO mouse, we provide evidence of differences in the compensatory response in the balance between nitric oxide (NO), carbon monoxide (CO), EETs and the vasoconstrictor 20-HETE in male and female KO mice. Serum levels of adiponectin, TNFalpha, IL-1b and MCP1 and protein expression in vascular tissue of p-AMPK, p-AKT and p-eNOS were measured. Deletion of sEH caused a significant (p<0.05) decrease in body weight, and an increase in adiponectin, pAMPK and pAKT levels in female KO mice compared to male KO mice. Gene deletion resulted in a higher production of renal EETs in female KO compared to male KO mice and, concomitantly, we observed an increase in renal 20-HETEs levels and superoxide anion production only in male KO mice. sEH deletion increased p-AKT and p-eNOS protein expression but decreased p-AMPK levels in female KO mice. Increased levels of p-eNOS at Thr-495 were observed only in KO male mice. While p eNOS at 1177 were not significantly different between male and female. Nitric oxide production was unaltered in male KO mice. These results provide evidence of gender differences in the preservation of vascular homeostasis in response to sEH deletion which involves regulation of phosphorylation of eNOS at the 495 site. PMID- 25908303 TI - Impact of colonic mucosal lipoxin A4 synthesis capacity on healing in rats with dextran sodium sulfate-induced colitis. AB - Ulcerative colitis is a chronic inflammatory disease of the colon. This study evaluates the role of colonic mucosal lipoxin A4 (LXA4) synthesis in an experimental rat model of dextran sodium sulfate (DSS)-induced colitis. Wistar rats were randomly assigned to four groups: healthy controls, DSS-induced colitis with no or vehicle therapy, misoprostol or 5-aminosalicylic acid (5-ASA) therapy groups. Disease severity and colonic mucosal LXA4 synthesis was assessed specifically during the acute phase (day 5), chronic phase (day 15) and healing phases (day 19). Both misoprostol and 5-ASA reduced histopathologic score during the acute phase and reduced disease activity score at the healing phase. In addition, misoprostol reduced histopathologic score and colon weight/length ratio during the healing phase. Only misoprostol therapy increased colonic mucosal LXA4 synthesis. Furthermore, LXA4 levels correlated negatively with disease progression (R=-0.953). Collectively, our findings suggest that misoprostol induced LXA4 synthesis may be favorable for the healing of ulcerative colitis. PMID- 25908304 TI - A potential role of PUFAs and COXIBs in cancer chemoprevention. AB - Polyunsaturated fatty acids (PUFAs), particularly the omega-3 PUFAs and COXIBs have been associated with decreased inflammation and the prevention of tumorigenesis. omega-3 PUFAs have shown to display multiple antitumour actions, while omega-6 PUFAs and its derived eicosanoids promote the effects in cancer cell growth, angiogenesis, and invasion. omega-3 PUFAs may act by suppressing the metabolism of arachidonic acid to form proinflammatory mediators or as a precursors of novel lipid mediators with pro-resolving activity, while COXIBs are able to modulate inflammatory response by inhibiting cyclooxygenase 2 (COX-2), an inducible prostaglandin synthase overexpressed in several human cancers. As recently has been postulated, the anti-inflammation and pro-resolution processes are not equivalent. A family of lipid mediators from omega-3 PUFAs can act as agonist promoting resolution, while antinflammatory agents such as COXIBs may act as antagonists limiting the inflammatory response. The present paper reviews the current knowledge about the role of PUFAs and its derivatives (metabolites), as well as the COXIBs activity in cancer process as a sinergic therapeutic alternative for cancer treatment. PMID- 25908305 TI - [Detecting patients at risk of malnutrition. Can we improve?]. PMID- 25908306 TI - Adaptation in a variable environment: Phenotypic plasticity and bet-hedging during egg diapause and hatching in an annual killifish. AB - Two ways in which organisms adapt to variable environments are phenotypic plasticity and bet-hedging. Theory suggests that bet-hedging is expected to evolve in unpredictable environments for which reliable cues indicative of future conditions (or season length) are lacking. Alternatively, if reliable cues exist indicating future conditions, organisms will be under selection to produce the most appropriate phenotype -that is, adaptive phenotypic plasticity. Here, we experimentally test which of these modes of adaptation are at play in killifish that have evolved an annual life cycle. These fish persist in ephemeral pools that completely dry each season through the production of eggs that can remain in developmental arrest, or diapause, buried in the soil, until the following rainy season. Consistent with diversified bet-hedging (a risk spreading strategy), we demonstrate that the eggs of the annual killifish Nothobranchius furzeri exhibit variation at multiple levels-whether or not different stages of diapause are entered, for how long diapause is entered, and the timing of hatching-and this variation persists after controlling for both genetic and environmental sources of variation. However, we show that phenotypic plasticity is also present in that the proportion of eggs that enter diapause is influenced by environmental factors (temperature and light level) that vary seasonally. In nature there is typically a large parameter zone where environmental cues are somewhat correlated with seasonality, but not perfectly so, such that it may be advantageous to have a combination of both bet-hedging and plasticity. PMID- 25908308 TI - Electrocatalytic hydrogenation of 5-hydroxymethylfurfural in acidic solution. AB - Electrocatalytic hydrogenation of 5-hydroxymethylfurfural (HMF) is studied on solid metal electrodes in acidic solution (0.5 M H2 SO4 ) by correlating voltammetry with on-line HPLC product analysis. Three soluble products from HMF hydrogenation are distinguished: 2,5-dihydroxymethylfuran (DHMF), 2,5 dihydroxymethyltetrahydrofuran (DHMTHF), and 2,5-dimethyl-2,3-dihydrofuran (DMDHF). Based on the dominant reaction products, the metal catalysts are divided into three groups: (1) metals mainly forming DHMF (Fe, Ni, Cu, and Pb), (2) metals forming DHMF and DMDHF depending on the applied potentials (Co, Ag, Au, Cd, Sb, and Bi), and (3) metals forming mainly DMDHF (Pd, Pt, Al, Zn, In, and Sb). Nickel and antimony are the most active catalysts for DHMF (0.95 mM cm(-2) at ca. -0.35 VRHE and -20 mA cm(-2) ) and DMDHF (0.7 mM cm(-2) at -0.6 VRHE and 5 mA cm(-2) ), respectively. The pH of the solution plays an important role in the hydrogenation of HMF: acidic condition lowers the activation energy for HMF hydro-genation and hydrogenates the furan ring further to tetrahydrofuran. PMID- 25908307 TI - Long-range evolutionary constraints reveal cis-regulatory interactions on the human X chromosome. AB - Enhancers can regulate the transcription of genes over long genomic distances. This is thought to lead to selection against genomic rearrangements within such regions that may disrupt this functional linkage. Here we test this concept experimentally using the human X chromosome. We describe a scoring method to identify evolutionary maintenance of linkage between conserved noncoding elements and neighbouring genes. Chromatin marks associated with enhancer function are strongly correlated with this linkage score. We test >1,000 putative enhancers by transgenesis assays in zebrafish to ascertain the identity of the target gene. The majority of active enhancers drive a transgenic expression in a pattern consistent with the known expression of a linked gene. These results show that evolutionary maintenance of linkage is a reliable predictor of an enhancer's function, and provide new information to discover the genetic basis of diseases caused by the mis-regulation of gene expression. PMID- 25908309 TI - Grammatical Planning Units During Real-Time Sentence Production in Speakers With Agrammatic Aphasia and Healthy Speakers. AB - PURPOSE: Grammatical encoding (GE) is impaired in agrammatic aphasia; however, the nature of such deficits remains unclear. We examined grammatical planning units during real-time sentence production in speakers with agrammatic aphasia and control speakers, testing two competing models of GE. We queried whether speakers with agrammatic aphasia produce sentences word by word without advanced planning or whether hierarchical syntactic structure (i.e., verb argument structure; VAS) is encoded as part of the advanced planning unit. METHOD: Experiment 1 examined production of sentences with a predefined structure (i.e., "The A and the B are above the C") using eye tracking. Experiment 2 tested production of transitive and unaccusative sentences without a predefined sentence structure in a verb-priming study. RESULTS: In Experiment 1, both speakers with agrammatic aphasia and young and age-matched control speakers used word-by-word strategies, selecting the first lemma (noun A) only prior to speech onset. However, in Experiment 2, unlike controls, speakers with agrammatic aphasia preplanned transitive and unaccusative sentences, encoding VAS before speech onset. CONCLUSIONS: Speakers with agrammatic aphasia show incremental, word-by word production for structurally simple sentences, requiring retrieval of multiple noun lemmas. However, when sentences involve functional (thematic to grammatical) structure building, advanced planning strategies (i.e., VAS encoding) are used. This early use of hierarchical syntactic information may provide a scaffold for impaired GE in agrammatism. PMID- 25908310 TI - What would it take to prevent stunted growth in children in sub-Saharan Africa? AB - There is increasing agreement among the nutrition community about the use of length/height-for-age as the indicator to monitor the long-term impact of chronic nutritional deficiencies. Stunting, an indicator of linear growth failure, has both long- and short-term consequences affecting growth and development and adult work potential. The number of stunted children in sub-Saharan Africa is expected to increase by 2025 if the current trends remain. Stunting among African children peaks during the complementary feeding period, which coincides with the period when children are no longer on exclusive breastfeeding and infections are frequent. Addressing stunting has become the focus of global efforts. The World Health Assembly in 2012 set a 40 % reduction in the number of stunted children by 2025. To effectively address the issues of stunting in sub-Saharan Africa is it appropriate to examine the issue of what it takes. The WHO Multicentre Growth Reference Study (MGRS) conducted in several regions of the world, including Africa has lessons on what it would take to prevent in African children. The children in the MGRS had good socioeconomic background characteristics reflected by years of maternal education and availability of basic amenities, such as potable water and sanitary conditions. The prescription of exclusive breastfeeding, high-quality diversified diets and attention to care were critical factors contributing to healthy growth for the African children. Preventing stunting in sub-Saharan Africa is possible. It requires governments to put in place policies that would create the conducive environment needed. The complex and multiple causes of stunting offer the opportunity to address stunting in a multisectoral and within a food systems approach. The global resolve to make food systems deliver on healthy diet requires all stakeholders to work together to achieve the global goal of reducing stunting. This review highlights the key elements contributing to adequate growth in the Africa cohort of the WHO-MGRS and how these provide lessons for addressing stunting in children in sub-Saharan Africa. PMID- 25908311 TI - A phase II RCT and economic analysis of three exercise delivery methods in men with prostate cancer on androgen deprivation therapy. AB - BACKGROUND: Androgen deprivation therapy is commonly used to treat prostate cancer, the most common visceral cancer in men. However, various side effects often worsen physical functioning and reduce well-being among men on this treatment. Based on existing evidence, both resistance and aerobic training provide benefits for this population yet adherence rates are often low. The method of exercise delivery (supervised in-center or home-based) may be important, yet few studies have compared different models. Additionally, long term exercise adherence is critical to achieve sustained benefits but long-term adherence data and predictors of adherence are lacking. The primary aim of this phase II, non-inferiority randomized controlled trial is to determine whether three exercise training delivery models are equivalent in terms of benefits in quality of life and physical fitness in this population. Secondary aims include examination of long-term adherence and cost-effectiveness. DESIGN: Men diagnosed with prostate cancer, starting or continuing on androgen deprivation therapy for at least 6 months, fluent in English, and living close to one of two experienced Canadian study centers are eligible. Participants complete five assessments over one year, including a fitness assessment and self-report questionnaires. Socio demographic and clinical data collection occur at baseline, bone mineral density testing at two time points, and blood work is performed at three time points. Participants are randomized in a 1:1:1 fashion to supervised personal training, supervised group training, or home-based smartphone- and health coach-supported training. Each participant receives a detailed exercise manual, including illustrations of exercises and safety precautions. Participants are asked to complete 4 to 5 exercise sessions per week, incorporating aerobic, resistance and flexibility training. Participant intensity levels will be monitored. The intervention duration is 6 months, with 6 months additional follow-up. Outcomes include: body composition, fitness testing, quality of life and fatigue, biological outcomes, and program adherence. Cost information will be obtained using patient diary-based self-report. DISCUSSION: The goals of this study are to gain a better understanding of health benefits and costs associated with commonly used yet currently not compared exercise delivery models as well as an increased understanding of adherence to exercise. TRIAL REGISTRATION: The trial has been registered at clinicaltrials.gov (Registration # NCT02046837), registered January 20(th), 2014. PMID- 25908312 TI - Performance of new alternative providers of primary care services in England: an observational study. AB - OBJECTIVES: Health system reforms in England are opening broad areas of clinical practice to new providers of care. As part of these reforms, new entrants- including private companies--have been allowed into the primary care market under 'alternative provider of medical services' contracting mechanisms since 2004. The characteristics and performance of general practices working under new alternative provider contracts are not well described. We sought to compare the quality of care provided by new entrant providers to that provided by the traditional model of general practice. DESIGN: Open cohort study of English general practices. We used linear regression in cross-sectional and time series analyses, adjusting for practice and population characteristics, to compare quality in practices using alternative provider contracts to traditional practices. We created regression models using practice fixed effects to estimate the impact of practices changing to the new contract type. SETTING: The English National Health Service. PARTICIPANTS: All general practices open from 2008/2009 to 2012/2013. MAIN OUTCOME MEASURES: Seventeen established quality indicators- covering clinical effectiveness, efficiency, access and patient experience. RESULTS: In total, 4.1% (347 of 8300) of general practices in England were run by alternative contract providers. These practices tended to be smaller, and serve younger, more diverse and more deprived populations than traditional providers. Practices run by alternative providers performed worse than traditional providers on 15 of 17 indicators after adjusting for practice and population characteristics (p < 0.01 for all). Switching to a new alternative provider contract did not result in improved performance. CONCLUSIONS: The introduction of new alternative providers to deliver primary care services in England has not led to improvements in quality and may have resulted in worse care. Regulators should ensure that new entrants to clinical provider markets are performing to adequate standards and at least as well as traditional providers. PMID- 25908313 TI - The need to improve patient care through discriminate use of intracytoplasmic sperm injection (ICSI) and improved understanding of spermatozoa, oocyte and embryo biology. PMID- 25908314 TI - Announcing the 2014 andrology award. PMID- 25908315 TI - Lessons in Andrology: many paths to success. PMID- 25908318 TI - The Causal Meaning of Genomic Predictors and How It Affects Construction and Comparison of Genome-Enabled Selection Models. AB - The term "effect" in additive genetic effect suggests a causal meaning. However, inferences of such quantities for selection purposes are typically viewed and conducted as a prediction task. Predictive ability as tested by cross-validation is currently the most acceptable criterion for comparing models and evaluating new methodologies. Nevertheless, it does not directly indicate if predictors reflect causal effects. Such evaluations would require causal inference methods that are not typical in genomic prediction for selection. This suggests that the usual approach to infer genetic effects contradicts the label of the quantity inferred. Here we investigate if genomic predictors for selection should be treated as standard predictors or if they must reflect a causal effect to be useful, requiring causal inference methods. Conducting the analysis as a prediction or as a causal inference task affects, for example, how covariates of the regression model are chosen, which may heavily affect the magnitude of genomic predictors and therefore selection decisions. We demonstrate that selection requires learning causal genetic effects. However, genomic predictors from some models might capture noncausal signal, providing good predictive ability but poorly representing true genetic effects. Simulated examples are used to show that aiming for predictive ability may lead to poor modeling decisions, while causal inference approaches may guide the construction of regression models that better infer the target genetic effect even when they underperform in cross validation tests. In conclusion, genomic selection models should be constructed to aim primarily for identifiability of causal genetic effects, not for predictive ability. PMID- 25908317 TI - Fine-Tuning of the Actin Cytoskeleton and Cell Adhesion During Drosophila Development by the Unconventional Guanine Nucleotide Exchange Factors Myoblast City and Sponge. AB - The evolutionarily conserved Dock proteins function as unconventional guanine nucleotide exchange factors (GEFs). Upon binding to engulfment and cell motility (ELMO) proteins, Dock-ELMO complexes activate the Rho family of small GTPases to mediate a diverse array of biological processes, including cell motility, apoptotic cell clearance, and axon guidance. Overlapping expression patterns and functional redundancy among the 11 vertebrate Dock family members, which are subdivided into four families (Dock A, B, C, and D), complicate genetic analysis. In both vertebrate and invertebrate systems, the actin dynamics regulator, Rac, is the target GTPase of the Dock-A subfamily. However, it remains unclear whether Rac or Rap1 are the in vivo downstream GTPases of the Dock-B subfamily. Drosophila melanogaster is an excellent genetic model organism for understanding Dock protein function as its genome encodes one ortholog per subfamily: Myoblast city (Mbc; Dock A) and Sponge (Spg; Dock B). Here we show that the roles of Spg and Mbc are not redundant in the Drosophila somatic muscle or the dorsal vessel. Moreover, we confirm the in vivo role of Mbc upstream of Rac and provide evidence that Spg functions in concert with Rap1, possibly to regulate aspects of cell adhesion. Together these data show that Mbc and Spg can have different downstream GTPase targets. Our findings predict that the ability to regulate downstream GTPases is dependent on cellular context and allows for the fine-tuning of actin cytoskeletal or cell adhesion events in biological processes that undergo cell morphogenesis. PMID- 25908319 TI - Acknowledging the work of manuscript reviewers. PMID- 25908320 TI - Understanding Overrepresentation of Indigenous Children in Child Welfare Data: An Application of the Drake Risk and Bias Models. AB - Child welfare data collected for administrative purposes are often used as a source of information for understanding the population impact of child abuse and neglect (CA/N). This study used administrative data linked at the individual level for a cohort of Aotearoa New Zealand (NZ) children to follow and extend a model developed by Drake et al. In this investigation, we aimed to build an understanding of the high representation of indigenous NZ children in administratively sourced measures of CA/N. Variation in rate ratios (RRs) within infant mortality and birth outcomes considered as possible proxies for actual CA/N RRs leaves open a range of interpretations. Our findings indicate that a more nuanced interpretation of the overrepresentation of indigenous children in administratively recorded maltreatment statistics is required. Rather than considering risk and bias as competing explanations, we suggest an acknowledgment of the impact of colonization and the existence of systemic bias generating increased risk as key drivers. As linked administrative data are increasingly used for research and evaluation, and considered for use in supporting decision making, there is a need for a deeper understanding of the drivers of administratively recorded CA/N in order to effectively address the needs of indigenous populations. PMID- 25908321 TI - Examining the factor structure of the Clinical Opiate Withdrawal Scale: A secondary data analysis from the National Drug Abuse Treatment Clinical Trials Network (CTN) 0003. AB - BACKGROUND: The Clinical Opiate Withdrawal Scale (COWS) is used to assess withdrawal in clinical trials and practice. The aims of this study were to examine the inter-item correlations and factor structure of the COWS in opioid dependent men and women. METHODS: This is a secondary data analysis of the National Drug Abuse Treatment Clinical Trials Network 0003, a randomized clinical trial that compared buprenorphine/naloxone tapering strategies. The trial included 11 sites in 10 US cities. Participants were opioid-dependent individuals (n=516) that had data on the COWS. The COWS at study baseline was analyzed in this study. RESULTS: Inter-item correlations showed weak to moderate relationships among the items. A 1-factor model did not fit the data for men (comparative fit index (CFI)=.801, root mean square error of approximation (RMSEA)=.073, weighted root mean square residual (WRMR)=1.132) or women (CFI=.694, RMSEA=.071, WRMR=.933), where resting pulse rate was not related to withdrawal for men, and yawning and gooseflesh skin was not related to withdrawal for women. A reduced model comprised of only the 8 items that were significantly related to the construct of withdrawal in both men and women, and an exploratory 2-factor model, were also assessed but not retained due to inconsistencies across gender. CONCLUSIONS: When traditional psychometric models are applied to the COWS, it appears that the scale may not relate to a single underlying construct of withdrawal. Further research testing the hypothesized factor structure in other opioid-dependent samples is needed. PMID- 25908322 TI - Peak ages of risk for starting nonmedical use of prescription stimulants. AB - BACKGROUND: To produce population-level, year- and age-specific risk estimates of first time nonmedical use of prescription stimulants among young people in the United States. METHODS: Data are from the National Surveys on Drug Use and Health 2004-2012; a nationally representative probability sample survey administered each year. Subpopulations included youths aged 12 to 21 years (n=240,160) who had not used prescription stimulants nonmedically prior to their year of survey assessment. A meta-analytic approach was used to produce population-level age-, year-, and cohort-specific risk estimates of first time nonmedical use of prescription stimulants. RESULTS: Peak risk of starting nonmedical use of prescription stimulants was concentrated between ages 16 and 19 years, when an estimated 0.7% to 0.8% of young people reported nonmedical use of these medicines for the first time in the past twelve months. Smaller risk estimates ranging from 0.1% to 0.6% were observed at ages 12 to 15 years and 20 to 21 years. Compared with males, females were more likely to have started nonmedical use of prescription stimulants (odds ratio=1.35; 95% CI, 1.13-1.62), particularly between the ages of 14 and 19. Females showed a peak annual incidence rate of 1% at age 18, while males the same age showed an incidence rate of 0.5%. CONCLUSIONS: Peak annual incidence rates for nonmedical use of prescription stimulants were observed between the ages of 16 and 19 years. There is reason to initiate interventions during the earlier adolescent years to prevent youths from starting nonmedical use of prescription stimulants. PMID- 25908324 TI - Breast tomosynthesis: Dosimetry and image quality assessment on phantom. AB - PURPOSE: To evaluate using phantom study the average glandular dose (AGD) and image quality in breast tomosynthesis. MATERIALS AND METHODS: The study was performed with a full-field digital mammography system (Mammomat Inspiration((r)), Siemens, Erlangen, Germany) combined with tomosynthesis equipment (3D). For AGD evaluation, polymethyl methacrylate (PMMA) plates and a dosimeter were used to directly measure the absorbed doses in 2D and in 3D. The doses were then compared to the doses displayed on the equipment using the Mann Whitney test. Three phantoms, accredited for 2D digital mammography (MTM 100, ACR RMI 156, BR3D), were imaged three times in 2D then in 3D. For each acquisition, the AGD was recorded. For image quality assessment, scores, defined by the rate of visible inserts, obtained for each acquisition both in 2D and in 3D, and for each phantom, were compared (Kruskall-Wallis and post-hoc Dunn tests). RESULTS: There was no significant difference between the measured and displayed AGD, both in 2D and in 3D imaging (P>0.05). With identical acquisition parameters, AGD were significantly greater in 3D than in 2D P<0.01). For phantoms MTM 100 and ACR RMI 156, there was no significant difference between the rate of visible inserts in 2D and in 3D (P=0.06 and P=0.36, respectively). However for phantom BR3D, the rate was significantly higher in 3D than in 2D (P<0.0001). CONCLUSION: Doses are significantly greater in 3D than in 2D. With tomosynthesis, out of the three phantoms tested, only phantom BR3D showed a higher rate of visible inserts. PMID- 25908323 TI - Change in psychiatric symptomatology after benfotiamine treatment in males is related to lifetime alcoholism severity. AB - BACKGROUND: Severe alcoholism can be associated with significant nutritional and vitamin deficiency, especially vitamin B1 (thiamine) which is associated with neurological deficits impacting mood and cognition. Alcohol consumption was reduced among female but not male alcoholics after supplementation with the high potency thiamine analog benfotiamine (BF). We examined the relationship between lifetime alcoholism severity, psychiatric symptoms and response to BF among the alcohol dependent men from this cohort. METHODS: Eighty-five adult men (mean age=48+/-8 years) meeting DSM-IV-TR criteria for a current alcohol use disorder who were abstinent <30days participated in a randomized, double-blind, placebo controlled trial of 600mg BF vs placebo (PL) for 6 months. Psychometric testing included a derived Lifetime Alcoholism Severity Score (AS), Symptom Checklist 90R (SCL-90R), and the Barratt Impulsivity Scale (BIS) at baseline and at 6 months. RESULTS: Baseline SCL-90-R scale scores for men with high alcoholism severity (AS>=24; N=46 HAS) were significantly greater than for men with low alcoholism severity (AS<24; N=39 LAS), but BIS scores did not differ. MANOVA modeling at follow-up (N=50 completed subjects) identified a significant treatment effect (F=2.5, df=10, p<0.03) and treatment*alcoholism severity level interaction (F=2.5, dfnum=10, dfden=30, p<0.03) indicating reduced SCL-90-R scores among BF treated, HAS males. Above normal plasma thiamine levels at follow-up predicted reduced depression scores in a BF-treated subset (F=3.2, p<0.09, N=26). CONCLUSION: BF appears to reduce psychiatric distress and may facilitate recovery in severely affected males with a lifetime alcohol use disorder and should be considered for adjuvant therapy in alcohol rehabilitation. TRIAL REGISTRATION: #NCT00680121 High Dose Vitamin B1 to Reduce Abusive Alcohol Use. PMID- 25908325 TI - Electrographic status epilepticus and neurobehavioral outcomes in critically ill children. AB - PURPOSE: Electrographic seizures (ESs) and electrographic status epilepticus (ESE) are common in children with acute neurologic conditions in pediatric intensive care units (PICUs), and ESE is associated with worse functional and quality-of-life outcomes. As an exploratory study, we aimed to determine if ESE was associated with worse outcomes using more detailed neurobehavioral measures. METHODS: Three hundred children with an acute neurologic condition and altered mental status underwent clinically indicated EEG monitoring and were enrolled in a prospective observational study. We obtained follow-up data from subjects who were neurodevelopmentally normal prior to PICU admission. We evaluated for associations between ESE and adaptive behavior (Adaptive Behavior Assessment System-II, ABAS-II), behavioral and emotional problems (Child Behavior Checklist, CBCL), and executive function (Behavior Rating Inventory of Executive Function, BRIEF) using linear regression analyses. A p-value of <0.05 was considered significant. RESULTS: One hundred thirty-seven of 300 subjects were neurodevelopmentally normal prior to PICU admission. We obtained follow-up data from 36 subjects for the CBCL, 32 subjects for the ABAS-II, and 20 subjects for the BRIEF. The median duration from admission to follow-up was 2.6 years (IQR: 1.2-3.8). There were no differences in the acute care variables (age, sex, mental status category, intubation status, paralysis status, acute neurologic diagnosis category, seizure category, EEG background category, or short-term outcome) between subjects with and without follow-up data for any of the outcome measures. On univariate analysis, significant differences were not identified for CBCL total problem (ES coefficient: -4.1, p = 0.48; ESE coefficient: 8.9, p = 0.13) or BRIEF global executive function (ES coefficient: 2.1, p = 0.78; ESE coefficient: 14.1, p = 0.06) scores, although there were trends toward worse scores in subjects with ESE. On univariate analysis, ESs were not associated with worse scores (coefficient: -21.5, p = 0.051), while ESE (coefficient: -29.7, p = 0.013) was associated with worse ABAS-II adaptive behavioral global composite scores. On multivariate analysis, when compared to subjects with no seizures, both ESs (coefficient: -28, p=0.014) and ESE (coefficient: -36, p = 0.003) were associated with worse adaptive behavioral global composite scores. DISCUSSION: Among previously neurodevelopmentally normal children with acute neurologic disorders, ESs and ESE were associated with worse adaptive behavior and trends toward worse behavioral-emotional and executive function problems. This was a small exploratory study, and the impact of ESs and ESE on these neurobehavioral measures may be clarified by subsequent larger studies. This article is part of a Special Issue entitled "Status Epilepticus". PMID- 25908332 TI - Evaluating the performance of the focus HerpeSelect(r) HSV-2 IgG in veterans with chronic hepatitis C infection. AB - Epidemiologic links between chronic hepatitis C and herpes simplex type-2 infection have been suggested; however, type-specific tests for HSV-2 infection have not been validated in patients with chronic hepatitis C infection. The Focus HerpeSelect((r)) HSV-2 IgG (Cypress, California) assay and the Biokit HSV-2 rapid assay (Biokit USA, Lexington, MA) were performed on serum samples obtained from 84 veterans with chronic hepatitis C who demonstrated a previously positive HSV-2 serologic test in their medical records. Using the Biokit HSV-2 as the comparator assay, the positive predictive value, and specificity for the HerpeSelect((r)) HSV-2 assay were 62.1% (95%CI: 49.3-73.8) and 41.9% (95%CI: 27.0-57.9), respectively. Increasing the HerpeSelect((r)) HSV-2 index value defining a positive test result from >1.1 to >=2.89 increased the assay's specificity to 97.7% (95%CI: 87.7-99.6) and the positive predictive value to 94.1%(95%CI: 71.2 99.0). J. Med. Virol. 9999: 1-5, 2015. (c) 2015 Wiley Periodicals, Inc. In veterans with chronic hepatitis C infection, HerpeSelect((r)) HSV-2 index values between 1.1 and 2.89 should be confirmed with an alternate test for HSV-2 infection. PMID- 25908333 TI - Bilateral hydronephrosis with urinary tract infection in a Campbell's hamster (Phodopus campbelli). PMID- 25908331 TI - Localization and regulation of reproductive steroid receptors in the raphe serotonin system of male macaques. AB - We previously showed that tryptophan hydroxylase 2 (TPH2) and serotonin reuptake transporter (SERT) mRNAs are increased by the androgens, testosterone (T) and dihydrotestosterone (DHT) in serotonin neurons of male macaques. In addition, we observed that serotonin in axons of a terminal region were markedly decreased by aromatase inhibition and lack of estradiol (E) from metabolism of T. These observations implicated androgen receptors (AR) and estrogen receptors (ER) in the transduction of steroid hormone actions in serotonin neurons. Due to the longer treatment period employed, the expression of the cognate nuclear receptors was sought. We used single and double immunohistochemistry to quantitate and phenotypically localize AR, ERalpha and ERbeta in the dorsal raphe of male macaques. Male Japanese macaques (Macaca fuscata) were castrated for 5-7 months and then treated for 3 months with [1] placebo, [2] T, [3] DHT (non-aromatizable androgen) plus ATD (steroidal aromatase inhibitor), or [4] Flutamide (FLUT; androgen antagonist) plus ATD (n = 5/group). After single labeling of each receptor, quantitative image analysis was applied and receptor positive neurons were counted. Double-label of raphe neurons for each receptor plus TPH2 determined whether the receptors were localized in serotonin neurons. There were significantly more AR-positive neurons in T- and DHT+ATD-treated groups (p = 0.0014) compared to placebo or FLUT+ATD-treated groups. There was no difference in the number of positive-neurons stained for ERalpha or ERbeta? Double immunohistochemistry revealed that serotonin neurons did not contain AR. Rather, AR-positive nuclei were found in neighboring cells that are likely neurons. However, approximately 40% of dorsal raphe serotonin neurons contained ERalpha or ERbeta? In conclusion, the stimulatory effect of androgens on TPH2 and SERT mRNA expression is mediated indirectly by neighboring neurons contain AR. The stimulatory effect of E, derived from T metabolism, on serotonin transport is partially mediated directly via nuclear ERs. PMID- 25908334 TI - Development of chiral building blocks having a bicyclo[3.3.0]octane framework using a diastereomeric resolution-selective deprotection. AB - A protocol is presented for an efficient and practical approach to the synthesis of enantiomerically pure bicyclo[3.3.0]octane derivatives from achiral Cs symmetric bicyclo[3.3.0]octane-2,8-dione using a diastereomeric resolution selective deprotection method. This method affords chiral building blocks having bicyclo[3.3.0]octane framework with the same site of diastereotopic carbonyl functional group. PMID- 25908336 TI - Having a voice. PMID- 25908335 TI - Two-Stage Cementless Revision Total Hip Arthroplasty for Infected Primary Hip Arthroplasties. AB - The main purpose of the present study was to analyze the clinical features, the most common infective agents, and the results of two-stage total hip revision using a teicoplanin-impregnated spacer. Between January 2005 and July 2011, 41 patients were included. At the clinical status analysis, physical examination was performed, Harris hip score was noted, isolated microorganisms were recorded, and the radiographic evaluation was performed. The mean Harris hip score was improved from 38.9 +/- 9.6 points to 81.8 +/- 5.8 points (P<0.05). Infection was eradicated in 39 hips. Radiographic evidence of stability was noted in 37 acetabular revision components, and all femoral stems. Two-stage revision of the infected primary hip arthroplasty is a time-consuming but a reliable procedure with high rates of success. PMID- 25908337 TI - Acidic saliva substitutes. PMID- 25908338 TI - Periodontology: A little caution. PMID- 25908339 TI - Preventive dentistry: Early childhood caries in infants. PMID- 25908340 TI - Oral cancer: Two cancer cases in a career? PMID- 25908341 TI - The overriding objective. PMID- 25908342 TI - Dental regulation: In conflict with the GMC. PMID- 25908343 TI - Dental public health: Community action. PMID- 25908344 TI - The power of data. PMID- 25908345 TI - Equipment quality: Counterfeit cables. PMID- 25908347 TI - Mustering motivation. PMID- 25908349 TI - Dentist triumphs to stay on the Dentist's Register. PMID- 25908352 TI - BDA museum: Anatomical model on trip to Paris. PMID- 25908355 TI - Paul Brocklehurst: 'It's about optimising how much health and care we can deliver for patients'. PMID- 25908356 TI - Glove wearing: an assessment of the evidence. AB - Infection control is ubiquitous in current dental practice. However, it might not always be best practice to take the 'you can't be too safe' route without first weighing up all the available evidence, risks and benefits. This article will discuss the balance between the conflicting priorities in relation to glove wearing and infection control within the dental setting. PMID- 25908357 TI - Evaluation of a pilot oral health promotion programme 'Keep Smiling': perspectives from GDPs, health champions and school staff. AB - OBJECTIVE: To evaluate a pilot oral health promotion programme (fluoride varnish and tooth brushing), targeting 3-7-year-olds in primary schools in a deprived area of London. METHOD: A pilot programme was conducted among five primary schools targeting 3-7-year-old children in a deprived area of London. The programme consisted of a fluoride varnish application and tooth brushing sessions. Outcome (participation rates) and process evaluations were carried out using semi-structured interviews with school staff, health champions and dentists. RESULTS: Overall, 79.2% of the targeted children participated in tooth brushing and 68.6% of children received fluoride varnish. The programme received positive feedback from school staff, dental teams and health champions. It raised awareness of dental health among all stakeholders and provided children with a unique experience, creating a positive image of dental teams. CONCLUSIONS: Community engagement and collaboration between health, education and the voluntary sector is feasible and integral in developing oral health promotion programmes aimed at children attending primary schools in a deprived area of London. PMID- 25908358 TI - Producing guidance for the management of patients with chronic periodontal disease in general dental practice. AB - The vast majority of patients will experience gingival-related disease at some point in their life, and up to a quarter of those are susceptible to advanced periodontal disease. This makes its effective management an important part of general dental practice. This paper provides guidance on management which incorporates periodontal assessment, management and recall according to patient's oral hygiene and modifiable risk factors. This has been produced in flow diagram format to aid non-surgical management of chronic gingival and periodontal disease in general dental practice. PMID- 25908359 TI - Erratum. PMID- 25908360 TI - A nomogram to calculate the maximum dose of local anaesthetic in a paediatric dental setting. AB - While local anaesthetic agents are usually safe and are used ubiquitously, inadvertent overdoses may have potentially fatal consequences. Errors in the dosing of local anaesthetics frequently occur due to inherent difficulties in remembering the toxic dosage limits, difficulties in performing the appropriate calculations correctly, and errors in estimating patient weight. We have developed a simple graphical calculation aid (nomogram) to overcome these problems and facilitate rapid cross-checking of the maximum safe dose for a variety of local anaesthetic agents in common use. Standard mathematical techniques were used to draft the nomogram. A randomised blinded study using simulated patient data and Bland-Altman analysis was used to assess the accuracy and precision of the nomogram. The nomogram was found to have a bias of 0.0 ml, with limits of agreement -0.05-0.04 ml. It was found to be easy to use and suitably accurate for clinical use. PMID- 25908363 TI - Social media and dentistry: some reflections on e-professionalism. AB - The proliferation of digital technology is impacting on the training and development of healthcare professionals. Research on the online behaviour of medical and pharmacy students indicates that social media poses a number of risks to the professional practice of healthcare professionals. General Dental Council guidelines on the use of social media also suggest that it has the potential to expose dental professionals to a variety of breaches of professional conduct. This paper explores the various ways social media can help, as well as hinder, the practice of dental professionalism. However, the lack of primary research on the social media behaviour of dental students and qualified dental practitioners alike acts as a barrier to increasing social media awareness within dentistry. The paper concludes by calling for more research-led discussion on the role social media plays in shaping our understanding of dental professionalism in the twenty-first century. PMID- 25908364 TI - The value of inter-professional education: a comparative study of dental technology students' perceptions across four countries. AB - The ability to function as an effective member of a dental care team is a highly desirable--frequently mandated--attribute of dental technology (DT) graduates. Currently, there is little rigorous examination of how the learning of team working skills might best be structured in a DT curriculum. This research compares DT curricula, and students' attitudes and perceptions regarding collaboration in practice, from four countries. Students (n=376) were invited to complete an education profile questionnaire, and the standardised measure--the shared learning scale. There were 196 (52%) responses. Students given opportunities to engage with others had better perceptions of inter-professional learning (IPL). Most believed that team-work and collaborative skills were best acquired by learning together with other dental care professionals, preferably sharing cases for real patients. Curricula should maximise opportunities for dental technology students to experience authentic IPL. Collaboration and team work needs to be embedded through the whole undergraduate programme. PMID- 25908381 TI - Alan Sweetman. PMID- 25908382 TI - Surgeon Rear Admiral (D) David A. Coppock CB OSTJ. PMID- 25908383 TI - Current UK dental sedation practice and the 'National Institute for Health and Care Excellence' (NICE) guideline 112: sedation in children and young people. AB - AIM: Describe current dental sedation practice for under 19-year-olds in the UK and compare it with the recommendations of NICE guidance 112. METHOD: Members of the Society for the Advancement of Anaesthesia in Dentistry and members of the Dental Sedation Teachers Group were invited to participate in an online survey. RESULTS: Two hundred and sixty-six dentists and doctors completed the survey. Eighty-two percent were operator and sedationist (operator-sedationist). Ninety five percent provided written information and 94% obtained written consent. Eighty-four percent kept a written or electronic sedation record. Eighty-six percent complied with life support training expectations. Eighty-six percent had immediate access to resuscitation equipment. Sixty-seven percent of sedationists reported that treatment could not be completed under sedation for <10% of cases during the previous year. When sedation was unsuccessful, 61% said they would schedule general anaesthesia and 54.5% would schedule advanced sedation care. Forty-nine percent believed that a dentist was an appropriate person to provide advanced sedation for 12-18 years. Only 24% thought a dentist should provide advanced sedation for children<12 years, with 75% preferring an anaesthetist. The appropriate setting for advanced sedation was thought to be primary care by 33% and secondary care by 68%. CONCLUSIONS: We found good agreement between the current practice of sedation and the recommendations of the NICE guidance 112. PMID- 25908384 TI - Evolutionary games of condensates in coupled birth-death processes. AB - Condensation phenomena arise through a collective behaviour of particles. They are observed in both classical and quantum systems, ranging from the formation of traffic jams in mass transport models to the macroscopic occupation of the energetic ground state in ultra-cold bosonic gases (Bose-Einstein condensation). Recently, it has been shown that a driven and dissipative system of bosons may form multiple condensates. Which states become the condensates has, however, remained elusive thus far. The dynamics of this condensation are described by coupled birth-death processes, which also occur in evolutionary game theory. Here we apply concepts from evolutionary game theory to explain the formation of multiple condensates in such driven-dissipative bosonic systems. We show that the vanishing of relative entropy production determines their selection. The condensation proceeds exponentially fast, but the system never comes to rest. Instead, the occupation numbers of condensates may oscillate, as we demonstrate for a rock-paper-scissors game of condensates. PMID- 25908385 TI - Association of TLR4 gene polymorphisms with sporadic Parkinson's disease in a Han Chinese population. AB - Parkinson's disease (PD) is considered as a multifactorial disorder involving complex interactions between genetic and environmental factors, while previous studies point to a pivotal role of neuroinflammation in the pathophysiology of PD. As a member of pattern recognition receptors, TLR4 plays an important role in the immune response and inflammatory responses. Growing evidences suggest that mutation of TLR4 gene may be connected with the development of PD. The objective of this study was to evaluate whether genetic polymorphisms of the TLR4 gene are associated with PD susceptibility. We genotyped three single-nucleotide polymorphisms of the TLR4 gene (rs1927911, rs1927914 and rs10116253) by polymerase chain reaction and restriction fragment length polymorphism (PCR-RFLP) in unrelated 380 PD patients and 380 healthy-matched controls. Our study revealed that rs1927914 C allele carriers and C allele were probably related to a decreased risk of PD (p = 0.032 and p = 0.028, respectively) as well as male PD (p = 0.034) and early-onset PD (EOPD) (p = 0.023). In addition, there were significant differences in genotype and allele distribution in male PD patients and its healthy-matched control subgroup (p = 0.035 and p = 0.012, respectively). For rs1927911 and rs10116253 polymorphisms, genotype or allele frequencies did not differ between groups. Our data suggest that the TLR4 gene might contribute to the risk of developing PD in Han Chinese and rs1927914 polymorphism may be a protective factor for sporadic PD, male PD and EOPD. PMID- 25908386 TI - [Temporal triangular alopecia]. PMID- 25908387 TI - The flow of power law fluids in elastic networks and porous media. AB - The flow of power law fluids, which include shear thinning and shear thickening as well as Newtonian as a special case, in networks of interconnected elastic tubes is investigated using a residual-based pore scale network modeling method with the employment of newly derived formulae. Two relations describing the mechanical interaction between the local pressure and local cross-sectional area in distensible tubes of elastic nature are considered in the derivation of these formulae. The model can be used to describe shear dependent flows of mainly viscous nature. The behavior of the proposed model is vindicated by several tests in a number of special and limiting cases where the results can be verified quantitatively or qualitatively. The model, which is the first of its kind, incorporates more than one major nonlinearity corresponding to the fluid rheology and conduit mechanical properties, that is non-Newtonian effects and tube distensibility. The formulation, implementation, and performance indicate that the model enjoys certain advantages over the existing models such as being exact within the restricting assumptions on which the model is based, easy implementation, low computational costs, reliability, and smooth convergence. The proposed model can, therefore, be used as an alternative to the existing Newtonian distensible models; moreover, it stretches the capabilities of the existing modeling approaches to reach non-Newtonian rheologies. PMID- 25908388 TI - Genericity of confined chemical garden patterns with regard to changes in the reactants. AB - The growth of chemical gardens is studied experimentally in a horizontal confined geometry when a solution of metallic salt is injected into an alkaline solution at a fixed flow rate. Various precipitate patterns are observed-spirals, flowers, worms or filaments-depending on the reactant concentrations. In order to determine the relative importance of the chemical nature of the reactants and physical processes in the pattern selection, we compare the structures obtained by performing the same experiment using different pairs of reactants of varying concentrations with cations of calcium, cobalt, copper, and nickel, and anions of silicate and carbonate. We show that although the transition zones between different patterns are not sharply defined, the morphological phase diagrams are similar in the various cases. We deduce that the nature of the chemical reactants is not a key factor for the pattern selection in the confined chemical gardens studied here and that the observed morphologies are generic patterns for precipitates possessing a given level of cohesiveness when grown under certain flow conditions. PMID- 25908389 TI - Pituitary tumor transforming gene: a novel therapeutic target for glioma treatment. AB - Glioma which has strong proliferation and angiogenesis ability is the most common and malignant primary tumor in central nervous system. Pituitary tumor transforming gene (PTTG) is found in pituitary tumor, and plays important role in cell proliferation, cell cycle, cell apoptosis, and angiogenesis. However, the role of PTTG in glioma is still incompletely investigated. Here, we explored the correlation between PTTG and glioma grade, as well as micro-vessel density (MVD). In addition, siRNA was used to silence PTTG expression in glioma cell lines including U87MG, U251, and SHG44. Cell proliferation, apoptosis, invasion, and angiogenesis were studied both in vitro and in vivo. Our results demonstrated that PTTG expression was significantly up-regulated in glioma, and had positive correlation with glioma grade and MVD. Silencing of PTTG inhibited glioma cell proliferation, migration/invasion, and angiogenesis, induced cell apoptosis, suppressed cell invasion, and arrested cell cycle at G0/G1 stage. Silencing of PTTG could also inhibit tumor growth, invasion, and angiogenesis in vivo. Our data indicated that PTTG might be a potential target for glioma treatment. PMID- 25908390 TI - Immobilization of Distinctly Capped CdTe Quantum Dots onto Porous Aminated Solid Supports. AB - Immobilization of quantum dots (QDs) onto solid supports could improve their applicability in the development of sensing platforms and solid-phase reactors by allowing the implementation of reusable surfaces and the execution of repetitive procedures. As the reactivity of QDs relies mostly on their surface chemistry, immobilization could also limit the disruption of solution stability that could prevent stable measurements. Herein, distinct strategies to immobilize QDs onto porous aminated supports, such as physical adsorption and the establishment of chemical linking, were evaluated. This work explores the influence of QD capping and size, concentration, pH, and contact time between the support and the QDs. Maximum QD retention was obtained for physical adsorption assays. Freundlich and Langmuir isotherms were used to analyze the equilibrium data. Gibbs free energy, enthalpy, and entropy were calculated and the stability of immobilized QDs was confirmed. PMID- 25908391 TI - Mice Brain Tissue Injury Induced by Diisononyl Phthalate Exposure and the Protective Application of Vitamin E. AB - As a widely used plasticizer in plastic industry, the data of diisononyl phthalate (DINP) toxicity due to exposure are insufficient. This work investigated the brain tissue injury induced by DINP exposure. Through oral exposure to DINP, oxidative stress, inflammatory responses, apoptosis, and hippocampus pathological alterations were found in the mice brain. And through the Morris water maze test, cognitive deficits were tested. Our data also showed that these exacerbations were counteracted by vitamin E. These results above indicated that oral exposure of mice to DINP induced brain damage, and oxidative stress, inflammation, and the consequential apoptosis jointly constituted the potential mechanisms of such induced toxicity. PMID- 25908392 TI - Foul wind, spirits and witchcraft: illness conceptions and health-seeking behaviour for malaria in the Gambia. AB - BACKGROUND: As the disease burden in the Gambia has reduced considerably over the last decade, heterogeneity in malaria transmission has become more marked, with infected but asymptomatic individuals maintaining the reservoir. The identification, timely diagnosis and treatment of malaria-infected individuals are crucial to further reduce or eliminate the human parasite reservoir. This ethnographic study focused on the relationship between local beliefs of the cause of malaria and treatment itineraries of suspected cases. METHODS: An ethnographic qualitative study was conducted in twelve rural communities in the Upper River Region and the Central River Region in the Gambia. The data collection methods included in-depth interviews, participant observation, informal conversations, and focus group discussions. RESULTS: While at first glance, the majority of people seek biomedical treatment for 'malaria', there are several constraints to seeking treatment at health centres. Certain folk illnesses, such as Jontinooje and Kajeje, translated and interpreted as 'malaria' by healthcare professionals, are often not considered to be malaria by local populations but rather as self limiting febrile illnesses--consequently not leading to seeking care in the biomedical sector. Furthermore, respondents reported delaying treatment at a health centre while seeking financial resources, and consequently relying on herbal treatments. In addition, when malaria cases present symptoms, such as convulsions, hallucinations and/or loss of consciousness, the illness is often interpreted as having a supernatural aetiology, leading to diagnosis and treatment by traditional healers. CONCLUSION: Although malaria diagnostics and treatment-seeking in the biomedical sector has been reported to be relatively high in the Gambia compared to other sub-Saharan African countries, local symptom interpretation and illness conceptions can delay or stop people from seeking timely biomedical treatment, which may contribute to maintaining a parasite reservoir of undiagnosed and untreated malaria patients. PMID- 25908394 TI - The Diabetes Shared Care Program and Risks of Cardiovascular Events in Type 2 Diabetes. AB - OBJECTIVE: The Diabetes Shared Care Program (DSCP) is an integrated diabetes care model designed to increase the quality of diabetes care in Taiwan. The efficacy of this program is unknown. Therefore, we evaluated whether participating patients had reduced risks of cardiovascular events, including coronary heart disease, stroke, and all-cause mortality. METHODS: All 120,000 diabetes patients' data in this retrospective cohort study were obtained from Taiwan's National Health Insurance Research Database. DSCP participants received integrated care from a physician, diabetes educator, and dietitian. Otherwise, non-DSCP participants visited a physician without instruction from a diabetes educator or dietitian. We followed these patients until the first hospitalizations due to cardiovascular events. The Kaplan-Meier method was used to estimate the survival curves, and the Cox proportional hazards model was applied to determine the risk of cardiovascular events. RESULTS: A total of 4458 participants and 4458 matched controls were enrolled in this study. Mean age of both participants and nonparticipants was 56 years. DSCP participants had significantly lower risks of cardiovascular events (hazard ratio [HR] 0.86; 95% confidence interval [CI], 0.78 0.95), including stroke (HR 0.84; 95% CI, 0.73-0.98) and all-cause mortality (HR 0.78; 95% CI, 0.63-0.95), compared with nonparticipants. Older age, male, history of hypertension, chronic lung disease, and prescription for insulin secretagogues or insulin tended to have higher cardiovascular risks. Nevertheless, the following drugs reduced the cardiovascular risks: biguanides, alpha-glucosidase inhibitors, and thiazolidinediones. CONCLUSIONS: Participation in the DSCP was associated with lower risks of cardiovascular events, stroke, and all-cause mortality. PMID- 25908393 TI - American Heart Association's Life's Simple 7: Avoiding Heart Failure and Preserving Cardiac Structure and Function. AB - BACKGROUND: Many people may underappreciate the role of lifestyle in avoiding heart failure. We estimated whether greater adherence in middle age to American Heart Association's Life's Simple 7 guidelines-on smoking, body mass, physical activity, diet, cholesterol, blood pressure, and glucose-is associated with lower lifetime risk of heart failure and greater preservation of cardiac structure and function in old age. METHODS: We studied the population-based Atherosclerosis Risk in Communities Study cohort of 13,462 adults ages 45-64 years in 1987-1989. From the 1987-1989 risk factor measurements, we created a Life's Simple 7 score (range 0-14, giving 2 points for ideal, 1 point for intermediate, and 0 points for poor components). We identified 2218 incident heart failure events using surveillance of hospital discharge and death codes through 2011. In addition, in 4855 participants free of clinical cardiovascular disease in 2011-2013, we performed echocardiography from which we quantified left ventricular hypertrophy and diastolic dysfunction. RESULTS: One in four participants (25.5%) developed heart failure through age 85 years. Yet, this lifetime heart failure risk was 14.4% for those with a middle-age Life's Simple 7 score of 10-14 (optimal), 26.8% for a score of 5-9 (average), and 48.6% for a score of 0-4 (inadequate). Among those with no clinical cardiovascular event, the prevalence of left ventricular hypertrophy in late life was approximately 40% as common, and diastolic dysfunction was approximately 60% as common, among those with an optimal middle age Life's Simple 7 score, compared with an inadequate score. CONCLUSIONS: Greater achievement of American Heart Association's Life's Simple 7 in middle age is associated with a lower lifetime occurrence of heart failure and greater preservation of cardiac structure and function. PMID- 25908395 TI - Impact of a Doctor's Invitation on Participation in Colorectal Cancer Screening: A Cluster Randomized Trial. AB - BACKGROUND: There is a need to improve participation in colorectal cancer screening. Our objective was to assess the impact of a signature from the patient's general practitioner on a letter inviting patients to participate in a colorectal cancer screening. METHOD: We conducted a cluster randomized controlled trial with 57 general practitioners established in Paris for more than 5 years, randomized to intervention or usual-care arms. There were 3422 patients included, ages 50-74 years, from general practitioner patient files, and eligible for an invitation letter or a reminder letter to participate in the national population based screening program. In the intervention arm, patients received a standard letter signed by their general practitioner inviting them to visit the general practitioner's office for a fecal occult blood test if they were eligible. Control patients received the standard invitation letter or the standard reminder. All letters were sent by the district screening organization. The main outcome was the proportion of patients who took the fecal occult blood test within 6 months after the invitation. RESULTS: Among patients eligible for the study, 508 (14.8%) took a fecal occult blood test after being invited; 285 (15%; 95% confidence interval [CI], 13.5-16.7) in the intervention group and 223 (14.6%; 95% CI, 12.9-16.5) in the control group, with no statistical difference between the 2 groups (odds ratio 1.04; 95% CI, 0.83-1.31; P = .731). CONCLUSIONS: The addition of a general practitioner's signature to a standard letter inviting patients to take a fecal occult blood test had no impact on the frequency of patients taking the fecal occult blood test in the Paris program of colorectal cancer screening. PMID- 25908396 TI - Staphylococcus aureus haem biosynthesis: characterisation of the enzymes involved in final steps of the pathway. AB - Haem is a life supporting molecule that is ubiquitous in all major kingdoms. In Staphylococcus aureus, the importance of haem is highlighted by the presence of systems both for the exogenous acquisition and endogenous synthesis of this prosthetic group. In this work, we show that in S. aureus the formation of haem involves the conversion of coproporphyrinogen III into coproporphyrin III by coproporphyrin synthase HemY, insertion of iron into coproporphyrin III via ferrochelatase HemH, and oxidative decarboxylation of Fe-coproporphyrin III into protohaem IX by Fe-coproporphyrin oxidase/dehydrogenase HemQ. Together, this route represents a transitional pathway between the classic pathway and the more recently acknowledged alternative biosynthesis machinery. The role of the haem biosynthetic pathway in the survival of the bacterium was investigated by testing for inhibitors of HemY. Analogues of acifluorfen are shown to inhibit the flavin containing HemY, highlighting this protein as a suitable target for the development of drugs against S. aureus. Moreover, the presence of a transitional pathway for haem biosynthesis within many Gram positive pathogenic bacteria suggests that this route has the potential not only for the design of antimicrobials but also for the selective discrimination between bacteria operating different routes to the biosynthesis of haem. PMID- 25908397 TI - Infused Bone Marrow Fails to Prevent Vascularized Composite Allograft Rejection in Nonhuman Primates. PMID- 25908398 TI - In Favour of Medical Dissensus: Why We Should Agree to Disagree About End-of-Life Decisions. AB - End-of-life decision-making is controversial. There are different views about when it is appropriate to limit life-sustaining treatment, and about what palliative options are permissible. One approach to decisions of this nature sees consensus as crucial. Decisions to limit treatment are made only if all or a majority of caregivers agree. We argue, however, that it is a mistake to require professional consensus in end-of-life decisions. In the first part of the article we explore practical, ethical, and legal factors that support agreement. We analyse subjective and objective accounts of moral reasoning: accord is neither necessary nor sufficient for decisions. We propose an alternative norm for decisions - that of 'professional dissensus'. In the final part of the article we address the role of agreement in end-of-life policy. Such guidelines can ethically be based on dissensus rather than consensus. Disagreement is not always a bad thing. PMID- 25908400 TI - The coupling interface and pore domain codetermine the single-channel activity of the alpha7 nicotinic receptor. AB - Ligand-gated ion channels play a role in mediating fast synaptic transmission for communication between neurons. However, the structural basis for the functional coupling of the binding and pore domains, resulting in channel opening, remains a topic of intense investigation. Here, a series of alpha7 nicotinic receptor mutants were constructed for expression in cultured mammalian cells, and their single-channel properties were examined using the patch-clamp technique combined with radio ligand binding and the fluorescence staining technique. We demonstrated that the replacement of the four pore-lining residues in the channel domain of the alpha7 nicotinic receptor with the hydrophilic residue serine prolongs the open-channel lifetime, although the conductance of these mutants decreases. At the coupling interface between the extracellular and transmembrane domains, when the VRW residues in the Cys-loop were substituted with the corresponding residues (i.e., IYN) in the 5-HT3A receptor, the single-channel activity elicited by acetylcholine is impaired. This effect occurred despite the expression of the mutant receptors on the cell surface and despite the fact that the apparent Kd values were much lower than those of the wild-type alpha7 receptor. When we further lowered the channel-gating barrier of this chimera to enhance the open-channel probability, the loss of function was rescued. Overall, we explored the microscopic mechanisms underlying the interplay between the channel domains and the coupling interface that affect the channel activity, and we generated an allosteric gating model for the alpha7 receptor. This model shows that the gating machinery and coupling assembly codetermine the single-channel gating kinetics. These results likely apply to all channels in the Cys-loop receptor family. PMID- 25908401 TI - Heterologous expression and nonsense suppression provide insights into agonist behavior at alpha6beta2 nicotinic acetylcholine receptors. AB - The alpha6-containing subtypes of the nicotinic acetylcholine receptor (nAChR) are localized to presynaptic terminals of the dopaminergic pathways of the central nervous system. Selective ligands for these nAChRs are potentially useful in both Parkinson's disease and addiction. For these and other goals, it is important to distinguish the binding behavior of agonists at the alpha6-beta2 binding site versus other subtypes. To study this problem, we apply nonsense suppression-based non-canonical amino acid mutagenesis. We report a combination of four mutations in alpha6beta2 that yield high-level heterologous expression in Xenopus oocytes. By varying mRNA injection ratios, two populations were observed with unique characteristics, likely due to differing stoichiometries. Responses to nine known nAChR agonists were analyzed at the receptor, and their corresponding EC50 values and efficacies are reported. The system is compatible with nonsense suppression, allowing structure-function studies between Trp149 - a conserved residue on loop B found to make a cation-pi interaction at several nAChR subtypes - and several agonists. These studies reveal that acetylcholine forms a strong cation-pi interaction with the conserved tryptophan, while nicotine and TC299423 do not, suggesting a unique pharmacology for the alpha6beta2 nAChR. PMID- 25908399 TI - Dopaminergic and cholinergic modulation of striatal tyrosine hydroxylase interneurons. AB - The recent electrophysiological characterization of TH-expressing GABAergic interneurons (THINs) in the neostriatum revealed an unexpected degree of diversity of interneurons in this brain area (Ibanez-Sandoval et al., 2010, Unal et al., 2011, 2015). Despite being relatively few in number, THINs may play a significant role in transmitting and distributing extra- and intrastriatal neuromodulatory signals in the striatal circuitry. Here we investigated the dopaminergic and cholinergic regulation of THINs in vitro. We found that the dominant effect of dopamine was a dramatic enhancement of the ability of THINs to generate long-lasting depolarizing plateau potentials (PPs). Interestingly, the same effect could also be elicited by amphetamine-induced release of endogenous dopamine suggesting that THINs may exhibit similar responses to changes in extracellular dopamine concentration in vivo. The enhancement of PPs in THINs is perhaps the most pronounced effect of dopamine on the intrinsic excitability of neostriatal neurons described to date. Further, we demonstrate that all subtypes of THINSs tested also express nicotinic cholinergic receptors. All THIS responded, albeit differentially, with depolarization, PPs and spiking to brief application of nicotinic agonists. Powerful modulation of the nonlinear integrative properties of THINs by dopamine and the direct depolarization of these neurons by acetylcholine may play important roles in mediating the effects of these neuromodulators in the neostriatum with potentially important implications for understanding the mechanisms of neuropsychiatric disorders affecting the basal ganglia. PMID- 25908402 TI - Benzothiazepine CGP37157 and its 2'-isopropyl analogue modulate Ca2+ entry through CALHM1. AB - CALHM1 is a Ca(2+) channel discovered in 2008, which plays a key role in the neuronal electrical activity, among other functions. However, there are no known efficient blockers able to modulate its Ca(2+) handling ability. We herein describe that benzothiazepine CGP37157 and its newly synthesized analogue ITH12575 reduced Ca(2+) influx through CALHM1 at low micromolar concentrations. These results could serve as a starting point for the development of more selective CALHM1 ligands using CGP37157 as a hit compound, which would help to study the physiological role of CALHM1 in the control of [Ca(2+)]cyt in excitable cells, as well as its implication in CNS diseases. PMID- 25908404 TI - Radical covalent organic frameworks: a general strategy to immobilize open accessible polyradicals for high-performance capacitive energy storage. AB - Ordered pi-columns and open nanochannels found in covalent organic frameworks (COFs) could render them able to store electric energy. However, the synthetic difficulty in achieving redox-active skeletons has thus far restricted their potential for energy storage. A general strategy is presented for converting a conventional COF into an outstanding platform for energy storage through post synthetic functionalization with organic radicals. The radical frameworks with openly accessible polyradicals immobilized on the pore walls undergo rapid and reversible redox reactions, leading to capacitive energy storage with high capacitance, high-rate kinetics, and robust cycle stability. The results suggest that channel-wall functional engineering with redox-active species will be a facile and versatile strategy to explore COFs for energy storage. PMID- 25908403 TI - Cardiac depression induced by cocaine or cocaethylene is alleviated by lipid emulsion more effectively than by sulfobutylether-beta-cyclodextrin. AB - OBJECTIVES: Cocaine intoxication leads to over 500,000 emergency department visits annually in the United States and ethanol cointoxication occurs in 34% of those cases. Cardiotoxicity is an ominous complication of cocaine and cocaethylene overdose for which no specific antidote exists. Because infusion of lipid emulsion (Intralipid) can treat lipophilic local anesthetic toxicity and cocaine is an amphipathic local anesthetic, the authors tested whether lipid emulsion could attenuate cocaine cardiotoxicity in vivo. The effects of lipid emulsion were compared with the metabolically inert sulfobutylether-beta cyclodextrin (SBE-beta-CD; Captisol) in an isolated heart model of cocaine and cocaethylene toxicity to determine if capture alone could exert similar benefit as lipid emulsion, which exhibits multimodal effects. The authors then tested if cocaine and cocaethylene, like bupivacaine, inhibit lipid-based metabolism in isolated cardiac mitochondria. METHODS: For whole animal experiments, Sprague Dawley rats were anesthetized, instrumented, and pretreated with lipid emulsion followed by a continuous infusion of cocaine to assess time of onset of cocaine toxicity. For ex vivo experiments, rat hearts were placed onto a nonrecirculating Langendorff system perfused with Krebs-Henseleit solution. Heart rate, left ventricle maximum developed pressure (LVdevP), left ventricle diastolic pressure, maximum rate of contraction (+dP/dtmax), maximum rate of relaxation (-dP/dtmax), rate-pressure product (RPP = heart rate * LVdevP), and line pressure were monitored continuously during the experiment. A dose response to cocaine (10, 30, 50, and 100 MUmol/L) and cocaethylene (10, 30, and 50 MUmol/L) was generated in the absence or presence of either 0.25% lipid emulsion or SBE-beta-CD. Substrate specific rates of oxygen consumption were measured in interfibrillar cardiac mitochondria in the presence of cocaine, cocaethylene, ecgonine, and benzoylecgonine. RESULTS: Treatment with lipid emulsion delayed onset of hypotension (140 seconds vs. 279 seconds; p = 0.008) and asystole (369 seconds vs. 607 seconds; p = 0.02) in whole animals. Cocaine and cocaethylene induced dose-dependent decreases in RPP, +dP/dtmax, and -dP/dtmaxabs (p < 0.0001) in Langendorff hearts; line pressure was increased by cocaine and cocaethylene infusion, but not altered by treatment. Lipid emulsion attenuated cocaine- and cocaethylene-induced cardiac depression. SBE-beta-CD alone evoked a mild cardiodepressant effect (p < 0.0001) but attenuated further cocaine- and cocaethylene-induced decrements in cardiac contractility at high concentrations of drug (100 MUmol/L; p < 0.001). Finally, both cocaine and cocaethylene, but not ecgonine and benzoylecgonine, inhibited lipid-dependent mitochondrial respiration by blocking carnitine exchange (p < 0.05). CONCLUSIONS: A commercially available lipid emulsion was able to delay progression of cocaine cardiac toxicity in vivo. Further, it improved acute cocaine- and cocaethylene-induced cardiac toxicity in rat isolated heart while SBE-beta-CD was effective only at the highest cocaine concentration. Further, both cocaine and cocaethylene inhibited lipid-dependent mitochondrial respiration. Collectively, this suggests that scavenging independent effects of lipid emulsion may contribute to reversal of acute cocaine and cocaethylene cardiotoxicity, and the beneficial effects may involve mitochondrial lipid processing. PMID- 25908405 TI - Intrinsic Chirality of CdSe/ZnS Quantum Dots and Quantum Rods. AB - A new class of chiral nanoparticles is of great interest not only for nanotechnology, but also for many other fields of scientific endeavor. Normally the chirality in semiconductor nanocrystals is induced by the initial presence of chiral ligands/stabilizer molecules. Here we report intrinsic chirality of ZnS coated CdSe quantum dots (QDs) and quantum rods (QRs) stabilized by achiral ligands. As-prepared ensembles of these nanocrystals have been found to be a racemic mixture of d- and l-nanocrystals which also includes a portion of nonchiral nanocrystals and so in total the solution does not show a circular dichroism (CD) signal. We have developed a new enantioselective phase transfer technique to separate chiral nanocrystals using an appropriate chiral ligand and obtain optically active ensembles of CdSe/ZnS QDs and QRs. After enantioselective phase transfer, the nanocrystals isolated in organic phase, still capped with achiral ligands, now display circular dichroism (CD). We propose that the intrinsic chirality of CdSe/ZnS nanocrystals is caused by the presence of naturally occurring chiral defects. PMID- 25908407 TI - In women with gestational diabetes requiring drug treatment, glibenclamide may be inferior to insulin and metformin: metformin (plus insulin when required) performs better than insulin. PMID- 25908408 TI - Infantile Frey's syndrome. AB - Frey's syndrome in children is rare and often erroneously attributed to food allergy. Here we describe a case of Frey's syndrome in an infant and provide a review of the literature. Awareness of this condition is important for the Otolaryngologist in order to avoid unnecessary medical costs and procedures and provide reassurance to both parents and primary care providers in the setting of this benign condition. PMID- 25908406 TI - A depauperate immune repertoire precedes evolution of sociality in bees. AB - BACKGROUND: Sociality has many rewards, but can also be dangerous, as high population density and low genetic diversity, common in social insects, is ideal for parasite transmission. Despite this risk, honeybees and other sequenced social insects have far fewer canonical immune genes relative to solitary insects. Social protection from infection, including behavioral responses, may explain this depauperate immune repertoire. Here, based on full genome sequences, we describe the immune repertoire of two ecologically and commercially important bumblebee species that diverged approximately 18 million years ago, the North American Bombus impatiens and European Bombus terrestris. RESULTS: We find that the immune systems of these bumblebees, two species of honeybee, and a solitary leafcutting bee, are strikingly similar. Transcriptional assays confirm the expression of many of these genes in an immunological context and more strongly in young queens than males, affirming Bateman's principle of greater investment in female immunity. We find evidence of positive selection in genes encoding antiviral responses, components of the Toll and JAK/STAT pathways, and serine protease inhibitors in both social and solitary bees. Finally, we detect many genes across pathways that differ in selection between bumblebees and honeybees, or between the social and solitary clades. CONCLUSIONS: The similarity in immune complement across a gradient of sociality suggests that a reduced immune repertoire predates the evolution of sociality in bees. The differences in selection on immune genes likely reflect divergent pressures exerted by parasites across social contexts. PMID- 25908409 TI - Modulation of (14) C-labeled glucose metabolism by zinc during aluminium induced neurodegeneration. AB - Aluminium (Al) is one of the most prominent metals in the environment and is responsible for causing several neurological disorders, including Alzheimer's disease. On the other hand, zinc (Zn) is an essential micronutrient that is involved in regulating brain development and function. The present study investigates the protective potential of Zn in the uptake of (14) C-labeled amino acids and glucose and their turnover in rat brain slices during Al intoxication. Male Sprague Dawley rats (140-160 g) were divided into four different groups: normal control, Al treated (100 mg/kg body weight/day via oral gavage), Zn treated (227 mg/liter in drinking water), and Al + Zn treated. Radiorespirometric assay revealed an increase in glucose turnover after Al exposure that was attenuated after Zn treatment. Furthermore, the uptake of (14) C-labeled glucose was increased after Al treatment but was appreciably decreased upon Zn supplementation. In addition, the uptakes of (14) C-lysine, (14) C-leucine, and (14) C-aspartic acid were also found to be elevated following Al exposure but were decreased after Zn treatment. Al treatment also caused alterations in the neurohistoarchitecture of the brain, which were improved after Zn coadministration. Therefore, the present study suggests that Zn provides protection against Al-induced neurotoxicity by regulating glucose and amino acid uptake in rats, indicating that Zn could be a potential candidate for the treatment of various neurodegenerative disorders. PMID- 25908410 TI - Exploring the Alzheimer amyloid-beta peptide conformational ensemble: A review of molecular dynamics approaches. AB - Alzheimer's disease is one of the most common dementia among elderly worldwide. There is no therapeutic drugs until now to treat effectively this disease. One main reason is due to the poorly understood mechanism of Abeta peptide aggregation, which plays a crucial role in the development of Alzheimer's disease. It remains challenging to experimentally or theoretically characterize the secondary and tertiary structures of the Abeta monomer because of its high flexibility and aggregation propensity, and its conformations that lead to the aggregation are not fully identified. In this review, we highlight various structural ensembles of Abeta peptide revealed and characterized by computational approaches in order to find converging structures of Abeta monomer. Understanding how Abeta peptide forms transiently stable structures prior to aggregation will contribute to the design of new therapeutic molecules against the Alzheimer's disease. PMID- 25908411 TI - A short history, principles, and types of ELISA, and our laboratory experience with peptide/protein analyses using ELISA. AB - Playing a critical role in the metabolic homeostasis of living systems, the circulating concentrations of peptides/proteins are influenced by a variety of patho-physiological events. These peptide/protein concentrations in biological fluids are measured using various methods, the most common of which is enzymatic immunoassay EIA/ELISA and which guide the clinicians in diagnosing and monitoring diseases that inflict biological systems. All the techniques where enzymes are employed to show antigen-antibody reactions are generally referred to as enzymatic immunoassay EIA/ELISA method. Since the basic principles of EIA and ELISA are the same. The main objective of this review is to present an overview of the historical journey that had led to the invention of EIA/ELISA, an indispensible method for medical and research laboratories, types of ELISA developed after its invention [direct (the first ELISA method invented), indirect, sandwich and competitive methods], problems encountered during peptide/protein analyses (pre-analytical, analytical and post-analytical), rules to be followed to prevent these problems, and our laboratory experience of more than 15 years. PMID- 25908412 TI - Hydrothermal upgrading of algae paste in a continuous flow reactor. AB - This investigation demonstrates the utility of a novel laboratory scale continuous plug flow reactor for fast Hydrothermal Liquefaction (HTL) of microalgae in a quartz lined chamber. Reactions were carried out between 300 and 380 degrees C and residence times of 0.5-4 min. Cyclohexane was used as a co solvent to enhance extraction and prevent char formation. Highest biocrude yield of 38 wt.% was achieved at 380 degrees C and 30 s as well as Water Soluble Fraction containing up to 60 wt.% matter recovered. Analysis of the biocrude showed that the extent of deoxygenation and denitrogenation after HTL varied and is dependent on the reaction conditions, Fourier Transform Infrared Spectroscopy analysis showed that biocrude contains similar functional moieties with only a small difference observed at different reaction conditions. Conversely, the Simulated Distillation and Size Exclusion Chromatography data showed that harsher conditions produced marginally better biocrude with improved boiling point profile and lower molecular weight compounds, respectively which was confirmed using Gas Chromatography-Mass Spectrometry. PMID- 25908413 TI - Asthma control in pregnancy is associated with pre-conception dietary patterns. AB - OBJECTIVE: To examine pre-conception dietary patterns in pregnant asthmatic women and to identify associations between maternal diet and asthma control during pregnancy. DESIGN: Cross-sectional study. Pre-conception food frequency data were collected retrospectively. Asthma control was assessed using the Global Initiative for Asthma guidelines. Dietary patterns were derived using factor analysis. Binary logistic regression analyses were used to test the association between uncontrolled asthma and each dietary pattern (Z-score), with values presented as odds ratio and 95 % confidence interval. SETTING: Antenatal clinic in a tertiary hospital, Adelaide, Australia, May 2009-July 2013. SUBJECTS: One hundred and fifty-eight asthmatic pregnant women. RESULTS: Three dietary patterns were identified: (i) 'high protein/fruit' (strong food group loadings for fish, meat, chicken, fruit); (ii) 'high fat/sugar/takeaway' (takeaway foods, crisps, refined grains); and (iii) 'vegetarian-type' (vegetables, fruit, soya milk, whole grains). A 1 sd increase in score on the high fat/sugar/takeaway pattern was associated with increased likelihood of uncontrolled asthma (adjusted OR=1.54; 95 % CI 1.07, 2.23; P=0.022). Women with uncontrolled asthma (n 115) had higher energy-adjusted intakes of saturated fat, monounsaturated fat, carbohydrate, sugar and fibre compared with women with controlled asthma (n 43, all P<=0.05). CONCLUSIONS: Pre-pregnancy dietary patterns may influence maternal asthma control. Our work highlights the importance of achieving a healthy diet before pregnancy that is low in saturated fat, sugar and takeaway foods, and therefore higher in lean meats, poultry and fish, as well as fruits, vegetables and whole grains. A healthy dietary pattern should be encouraged in all asthmatic women who are of childbearing age, and should additionally be promoted before pregnancy and beyond. PMID- 25908415 TI - [The close attention should be paid to study and use of pre-screening tools for COPD in the primary care setting]. PMID- 25908414 TI - Lower serum zinc levels are associated with unhealthy metabolic status in normal weight adults: The 2010 Korea National Health and Nutrition Examination Survey. AB - AIM: This study investigated whether serum zinc concentration is associated with glucose tolerance, insulin resistance and metabolic health status in Korean adults. METHODS: Subjects with available serum zinc levels were recruited from the fifth Korea National Health and Nutrition Examination Survey (KNHANESV) cohort. Those in the highest quartile on homoeostasis model assessment for insulin resistance (HOMA-IR) and with a body mass index (BMI) of 18.5-25kg/m(2) were classified as metabolically obese and normal weight (MONW). RESULTS: A total of 1813 subjects with a mean age of 45.2+/-0.5 years and a mean BMI of 24.01+/ 0.11kg/m(2) were enrolled. Those in the lower serum zinc quartiles exhibited higher levels of fasting blood glucose and insulin resistance indices compared with those in the higher quartiles. However, these associations were positive only in normal-weight subjects. Those categorized as MONW exhibited significantly lower serum zinc levels than the metabolically healthy and normal weight (MHNW) subjects (131.6+/-3.0MUg/dL vs 141.7+/-2.8MUg/dL, respectively; P=0.0026), whereas serum zinc levels did not differ according to metabolic health in obese subjects. The odds ratio for being categorized as MONW was 4.12 (95% CI: 1.75, 9.72) among those in the lowest serum zinc quartile compared with those in the highest quartile even after adjusting for possible confounding factors. CONCLUSION: Lower serum zinc levels were associated with unhealthy metabolic status in normal-weight adults. Further prospective studies are required to define the role of zinc in metabolic health. PMID- 25908416 TI - [Efficacy and safety of nebulized corticosteroids in the treatment for acute exacerbation of chronic obstructive pulmonary disease]. PMID- 25908417 TI - [The risk factors of chronic obstructive pulmonary disease in Heilongjiang province]. AB - OBJECTIVE: To study the prevalence and risk factors of chronic obstructive pulmonary disease (COPD) in Heilongjiang province. METHODS: This was a population based and cross-sectional survey on prevalence of COPD in Heilongjiang province from September 2013 to March 2014. The stratified-cluster-random sampling method was performed to collect the data from 4 478 people in 5 cities (Jixi, Daqing, Suihua, Yichun and Jiagedaqi). The subjects were interviewed with questionnaires and tested with spirometry. A post-bronchodilator FEV1/FVC<70% was defined as diagnostic of COPD. RESULTS: Completed and qualified data were obtained from 4 059 participants. The average prevalence of COPD was 7.3% (urban 6.0%; rural 8.8%; men 8.6%; women 6.5%). When using SPSS18.0 for the single factors logistic regression analysis, results indicated that sex (OR = 0.700, 95%CI:0.540-0.907), age >= 50 (OR = 1.236, 95%CI:0.758-2.017), lower education level (OR = 1.551, 95%CI:0.929-2.590), biomass for cooking (compared with electricity, OR = 2.744, 95%CI:1.429-5.271), biomass (compared with centralized heat supply, OR = 1.229, 95%CI:0.120-12.546)and coal (compared with centralized heat supply, OR = 4.661, 95%CI:0.474-45.840) for heating, respiratory diseases (OR = 3.594, 95%CI:2.738 4.716), combined with cardiovascular disease (OR = 1.370, 95%CI:1.058-1.776) were the risk factors of COPD in Heilongjiang province. CONCLUSION: Higher risk for COPD was related with sex, age, education level, cooking fuel, heating methods, respiratory diseases and combined with cardiovascular disease. PMID- 25908418 TI - [Sarcoidosis related pleural effusion: 6 case reports and literatures review]. AB - OBJECTIVE: To summarize the clinical features and the diagnosis-treatment points of sarcoidosis related pleural effusion. METHODS: Six typical sarcoidosis related pleural effusion cases with pathological evidence were reviewed, and the clinical data of these cases were retrospectively analyzed and the related literatures were reviewed. The literature review was carried out respectively with "sarcoidosis", "pleural disease" and "pleural effusion" as the keywords in CNKI and PubMed database by January 2014. RESULTS: Six cases, including 1 male and 5 females, with sarcoidosis related pleural effusions were reported. 3 cases had bilateral effusions, 2 cases had left effusion and 1 case had right effusion. The pleural effusion routine test had a low specificity, which demonstrated that the fluid was exudate and consisted with large number of lymphocytes. 3 of these cases were diagnosed by medical thoracoscopy. Medical thoracoscopy revealed that pleural involvement was variable with multiple nodulespresent in some cases and subtle change in others. A total of 28 literatures and 92 cases with pleural involvement in sarcoidosis were retrieved from CNKI and PubMed database (time range: 2004.1-2014.1), including 59 cases of pleural effusion, 29 cases of pleural thickening, 3 cases of pneumothorax and 1 case of nodules in pleura. CONCLUSIONS: Pleural involvement in sarcoidosis was often misdiagnosed or mistreated as tuberculous pleurisy because the routine tests regarding pleural effusion usually had a low specificity. Medical thoracoscopy could provide clinicians with important clues to assist differentiation of the cause for non conclusive pleural effusion in this situation. PMID- 25908419 TI - [Application of melting curve assay in the quality assessment of drug susceptibility test on Mycobacterium tuberculosis]. AB - OBJECTIVE: To evaluate the feasibility of melting curve assay technologies in quality assessment of drug susceptibility test (DST) on Mycobacterium tuberculosis. METHODS: During May 2009 to September 2012, a total of 2 204 MTB isolates were collected in Shanghai Songjiang District and 5 other county level TB institutes. DST results of these isolates were verified by the melting curve assay. Isolates with inconsistent phenotype and genotype results were retested and sequenced for any drug resistance mutations. RESULTS: Evaluation at Songjiang District showed high consistency of the melting curve assay with rifampicin and isoniazid DST results (kappa = 0.97 and 0.99, respectively). Consistency of the two methods were 97.6% (41/42), 100% (757/757) and 99.9% (788/799) in rifampicin resistant, susceptible, and total cases, respectively. As for isoniazid resistance detection, the consistency were 100% (72/72), 99.9% (726/727), and 99.9% (798/799) in resistant, susceptible, and total cases, respectively. Blinded re-examination of isolates with inconsistent genotype and phenotype resistance confirmed the good reproducibility of melting curve assay, which yielded the same results as the first test. Quality assessment at institutes A,B, C,D and E, however, showed consistency of only 87.5% (21/24), 80.8% (21/26), 87.5% (14/16), 82.9% (29/35), 60.9% (14/23) in rifampicinresistant cases, and 88.2% (30/34), 65.6% (21/32), 85.0% (17/20), 68.3% (41/60), 62.5% (15/24) in isoniazid resistant cases. As the reliability of DST results significantly varied among different areas, our finding indicated that there were misdiagnosed drug resistant cases in some field sites. CONCLUSION: The melting curve assay for MTB DST is fast, easy to use, reproducible, and able to identify mistakes in daily work. Therefore, it is a suitable tool for the quality assessment of conventional DST results. PMID- 25908420 TI - [The clinical significance of the levels of serum KL-6 mucin and interleukin-13 in pulmonary alveolar proteinosis]. AB - OBJECTIVE: To explore the serum levels of KL-6 mucin and interleukin 13 (IL-13) in patients with pulmonary alveolar proteinosis (PAP) and to investigate their clinical significance. METHODS: The serum levels of KL-6 and IL-13 were measured in 54 patients with PAP and in 50 healthy volunteers. The relationships among clinical features, chest high resolution computed tomography image scores, serum KL-6 levels and serum IL-13 levels were analyzed. RESULTS: The serum levels of IL 13 in PAP patients were significantly higher than those in healthy controls [(23 +/- 14) ng/L vs. (13 +/- 9) ng/L, t = 3.71, P < 0.05]. The serum levels of IL-13 did not associate with lung function and image scores. The serum levels of KL-6 [median (inter quartile range) U/ml] were higher in PAP patients than those in healthy controls [3 498.50 (1 160.50-9 337.75) U/ml vs. 177.00 (147.50-255.00) U/ml, U = 6.00, P < 0.05]. The value of KL-6 negatively correlated with FVC % predicted, FEV1 % predicted, DLCO% predicted, and PaO2 (r = -0.591, -0.563, 0.529, and -0.618, P < 0.05) ; however positively correlated with serum lactate dehydrogenase, the degree of lung opacification opacity, ground glass opacity extent, ground glass opacity severity and reticulation extent (r = 0.645, 0.733, 0.500, 0.751 and 0.753, respectively, P < 0.05). The serum levels of KL-6 were higher in patients with PAP who required whole lung lavage (WLL) or inhalation of granulocyte-macrophage colony-stimulating factor (GM-CSF) than those who did not [5 592.00 (1 738.00-9 982.00) U/ml vs.1 329.00 (1 017.75-3 543.75) U/ml, U = 101.00, P < 0.05]. CONCLUSION: PAP patients had significantly higher levels of serum IL-13 and KL-6. The serum levels of KL-6 may reflect the severity of the disease and be taken as a marker of the necessity of treatment in PAP patients. PMID- 25908421 TI - [Significance of fractional exhaled nitric oxide in the diagnosis of asthma in pregnant women]. AB - OBJECTIVE: To assess the variability of fractional exhaled nitric oxide (FeNO) and to explore the significances of FeNO in the diagnosis and treatment of asthma in pregnant women. METHODS: In a prospective study, 65 healthy pregnant women, 55 asthmatic non-pregnant women, 40 asthmatic pregnant women and 60 healthy non pregnant women were enrolled in the study from Oct 2012 to Apr 2014.FeNO levels of the 4 groups were compared, and the variability of FeNO in different pregnancy periods of 15 healthy pregnant women were examined.We also analyzed the correlation between the level of FeNO, FEV1% pred, asthma control test (ACT) scores andblood eosinophils in patients of asthmatic pregnant women. RESULTS: The difference in the levels of FeNO between healthy pregnant women (12 +/- 6) ppb and healthy non-pregnant women (14 +/- 5) ppb were no significant (t = 0.508, P > 0.05) . The levels of FeNO in different pregnancy periods of healthy pregnant women were not significantly different (F = 0.656, P > 0.05). Compared with healthy pregnant women (12 +/- 6) ppb, the level of FeNO was significantly higher in asthmatic pregnant patients (43 +/- 21) ppb (t = 2.981, P < 0.05) , but the difference of the levels of FeNO between asthmatic non-pregnant (51 +/- 32) ppb and pregnant patients (43 +/- 21) ppb were no significant (t = 0.366, P > 0.05) . There was no significant correlation between FeNO level and FEV1% pred (r = 0.164, P > 0.05), nor between FeNO level and ACT scores (r = 0.272, P > 0.05) , but there was significant correlation between FeNO level and eosinophils (r = 0.723, P < 0.05). CONCLUSIONS: FeNO level is not influenced by pregnancy and different gestation periods.FeNO level in asthmatic pregnant women is increased, and FeNO is an important examination in the diagnosis of asthma during pregnancy. PMID- 25908422 TI - [mRNA expression of Follistatin and follistatin-like 3, bone morphogenetic protein-4 antagonists in lung tissues of hypoxic mice]. AB - OBJECTIVE: To observe the expression changes of Follistatin (FSN) and follistatin like 3 (FSRP) mRNA, both of bone morphogenetic protein-4(BMP4) antagonists, in mice lung tissue under different hypoxic time and its relation with BMP4. METHODS: Thirty BMP4+/+ C57BL/6J wild type mice were randomly divided into normoxic control group, and 4 groups including 1 day, 3 days, 7 days and 21 days under hypoxic condition. The hypoxic animal model was established by exposing the mice to hypoxic condition for different time. The expressing level of FSN and FSRP mRNA in lung tissues were measured by Quantitative Real-Time PCR. RESULTS: FSN and FSRP mRNA increased in hypoxic 1 day group as (28.0 +/- 9.4) and (2.0 +/- 0.4), in hypoxic 3 day group, FSN mRNA increased by (6.3 +/- 3.2) and FSRP mRNA by (1.67 +/- 0.7) (P < 0. 05). Compared with the normoxic group (1.77 +/- 0.36) and (1.22 +/- 0.15) (P < 0. 01), FSN and FSRP mRNA up-regulated in hypoxic 7 day group. The positive degree of FSN and FSRP mRNA in hypoxic 21 day group were (1.04 +/- 0.27) and (0.85 +/- 0.10) (P < 0. 05). In normoxic 1 day group, FSN mRNA of lung tissues of BMP4+/- C57BL/6J mice was (0.95 +/- 0.05); FSRP mRNA was (1.11 +/- 0.03) (P < 0. 05). In BMP4+/- C57BL/6J mice lung tissues, FSN mRNA were (1.10 +/- 0.40) (P < 0. 05); FSRP mRNA were (0.85 +/- 0.18). CONCLUSIONS: The expression of FSN and FSRP mRNA in hypoxic 1;3;7 day mice lung tissues increased obviously, and FSN may play an important role in the hypoxic pulmonary hypertension through BMP4. PMID- 25908423 TI - [Electrocardiographic and chronic obstructive pulmonary disease]. PMID- 25908424 TI - [A review for voltage-gated potassium channels in the pathogenesis of pulmonary hypertension]. PMID- 25908425 TI - [The progress of study and application in Medical Thoracoscopy]. PMID- 25908426 TI - Baker's Yeast Deficient in Storage Lipid Synthesis Uses cis-Vaccenic Acid to Reduce Unsaturated Fatty Acid Toxicity. AB - The role of cis-vaccenic acid (18:1n-7) in the reduction of unsaturated fatty acids toxicity was investigated in baker's yeast Saccharomyces cerevisiae. The quadruple mutant (QM, dga1Delta lro1Delta are1Delta are2Delta) deficient in enzymes responsible for triacylglycerol and steryl ester synthesis has been previously shown to be highly sensitive to exogenous unsaturated fatty acids. We have found that cis-vaccenic acid accumulated during cultivation in the QM cells but not in the corresponding wild type strain. This accumulation was accompanied by a reduction in palmitoleic acid (16:1n-7) content in the QM cells that is consistent with the proposed formation of cis-vaccenic acid by elongation of palmitoleic acid. Fatty acid analysis of individual lipid classes from the QM strain revealed that cis-vaccenic acid was highly enriched in the free fatty acid pool. Furthermore, production of cis-vaccenic acid was arrested if the mechanism of fatty acids release to the medium was activated. We also showed that exogenous cis-vaccenic acid did not affect viability of the QM strain at concentrations toxic for palmitoleic or oleic acids. Moreover, addition of cis-vaccenic acid to the growth medium provided partial protection against the lipotoxic effects of exogenous oleic acid. Transformation of palmitoleic acid to cis-vaccenic acid is thus a rescue mechanism enabling S. cerevisiae cells to survive in the absence of triacylglycerol synthesis as the major mechanism for unsaturated fatty acid detoxification. PMID- 25908427 TI - Neutrophil-to-lymphocyte ratio in head and neck cancer. AB - INTRODUCTION: The neutrophil-to-lymphocyte ratio (NLR) is an index of systemic inflammatory burden in malignancy. An elevated NLR has been associated with poor prognosis in a number of cancer sites. We investigated its role in a cohort of patients with locally advanced head and neck cancer. METHODS: Eligible patients had primary mucosal squamous cell carcinoma treated with chemoradiotherapy and a minimum follow-up of 12 months (unless deceased). NLR was analysed as <5 vs. >=5 and above and below the median. The primary endpoint was overall survival (OS) and secondary endpoints metastasis free survival and locoregional relapse free survival. Actuarial Kaplan-Meier statistics and log rank test were used. Univariate analysis for age (continuous), Eastern Cooperative Oncology Group performance status (0 vs. 1), gender (male vs. female), smoking (yes vs. no), American Joint Committee on Cancer stage (III vs. IV) and NLR (<5 vs. >=5 and <3.3 vs. >=3.3) were performed. RESULTS: Forty-six patients were included in this analysis. Median NLR was 3.3 (0.4-22.8). After a median follow-up of 34 months (13-47 months), the 2-year estimated OS, metastasis free survival and locoregional relapse free survival for NLR <5 vs. >=5 were 89% vs. 61% (p = 0.017), 84% vs. 64% (p = 0.083) and 81% vs. 70% (p = 0.17) respectively. On univariate analysis NLR >=5 (p = 0.025), older age (p = 0.01) and ECOG 1 (p = 0.025) were significant for OS. CONCLUSION: In this cohort of locally advanced head and neck cancer patients treated with chemoradiotherapy, pre-treatment NLR >=5 was prognostic for mortality. Further studies are required to confirm these results and to assess the interaction with other prognostic factors. PMID- 25908428 TI - Surgical versus non-surgical interventions in people with adolescent idiopathic scoliosis. AB - BACKGROUND: Adolescent idiopathic scoliosis (AIS) is a three-dimensional deformity of the spine. While AIS can progress during growth and cause a surface deformity, it is usually not symptomatic. However, if the final spinal curvature surpasses a certain critical threshold, the risk of health problems and curve progression is increased. Interventions for the prevention of AIS progression include scoliosis-specific exercises, bracing, and surgery. The main aims of all types of interventions are to correct the deformity and prevent further deterioration of the curve and to restore trunk asymmetry and balance, while minimising morbidity and pain, allowing return to full function. Surgery is normally recommended for curvatures exceeding 40 to 50 degrees to stop curvature progression with a view to achieving better truncal balance and cosmesis. Short term results of the surgical treatment of people with AIS demonstrate the ability of surgery to improve various outcome measures. However there is a clear paucity of information on long-term follow-up of surgical treatment of people with AIS. OBJECTIVES: To examine the impact of surgical versus non-surgical interventions in people with AIS who have severe curves of over 45 degrees, with a focus on trunk balance, progression of scoliosis, cosmetic issues, quality of life, disability, psychological issues, back pain, and adverse effects, at both the short term (a few months) and the long term (over 20 years). SEARCH METHODS: We searched the Cochrane Back Review Group Trials Register, the Cochrane Central Register of Controlled Trials (CENTRAL), MEDLINE, EMBASE, four other databases, and three trials registers up to August 2014 with no language limitations. We also checked the reference lists of relevant articles and conducted an extensive handsearch of the grey literature. SELECTION CRITERIA: We searched for randomised controlled trials (RCTs) and prospective controlled trials comparing spinal fusion surgery with non-surgical interventions in people with AIS with a Cobb angle greater than 45 degrees. We were interested in all types of instrumented surgical interventions with fusion that aimed to provide curve correction and spine stabilisation. DATA COLLECTION AND ANALYSIS: We found no RCTs or prospective controlled trials that met our inclusion criteria. MAIN RESULTS: We did not identify any evidence comparing surgical to non-surgical interventions for AIS with severe curves of over 45 degrees. AUTHORS' CONCLUSIONS: We cannot draw any conclusions. PMID- 25908429 TI - Genome-wide identification of SSR and SNP markers from the non-heading Chinese cabbage for comparative genomic analyses. AB - BACKGROUND: Non-heading Chinese cabbage (NHCC), belonging to Brassica, is an important leaf vegetable in Asia. Although genetic analyses have been performed through conventional selection and breeding efforts, the domestication history of NHCC and the genetics underlying its morphological diversity remain unclear. Thus, the reliable molecular markers representative of the whole genome are required for molecular-assisted selection in NHCC. RESULTS: A total of 20,836 simple sequence repeats (SSRs) were detected in NHCC, containing repeat types from mononucleotide to nonanucleotide. The average density was 62.93 SSRs/Mb. In gene regions, 5,435 SSRs were identified in 4,569 genes. A total of 5,008 primer pairs were designed, and 74 were randomly selected for validation. Among these, 60 (81.08%) were polymorphic in 18 Cruciferae. The number of polymorphic bands ranged from two to five, with an average of 2.70 for each primer. The average values of the polymorphism information content, observed heterozygosity, Hardy Weinberg equilibrium, and Shannon's information index were 0.2970, 0.4136, 0.5706, and 0.5885, respectively. Four clusters were classified according to the unweighted pair-group method with arithmetic average cluster analysis of 18 genotypes. In addition, a total of 1,228,979 single nucleotide polymorphisms (SNPs) were identified in the NHCC through a comparison with the genome of Chinese cabbage, and the average SNP density in the whole genome was 4.33/Kb. The number of SNPs ranged from 341,939 to 591,586 in the 10 accessions, and the average heterozygous SNPs ratio was ~42.53%. All analyses showed these markers were high quality and reliable. Therefore, they could be used in the construction of a linkage map and for genetic diversity studies for NHCC in future. CONCLUSIONS: This is the first systematic and comprehensive analysis and identification of SSRs in NHCC and 17 species. The development of a large number of SNP and SSR markers was successfully achieved for NHCC. These novel markers are valuable for constructing genetic linkage maps, comparative genome analysis, quantitative trait locus (QTL) mapping, genome-wide association studies, and marker-assisted selection in NHCC breeding system research. PMID- 25908430 TI - Shear bond strength of Biodentine, ProRoot MTA, glass ionomer cement and composite resin on human dentine ex vivo. AB - INTRODUCTION: The aim of this study was to compare the shear bond strength of Biodentine, ProRoot MTA (MTA), glass ionomer cement (GIC) and composite resin (CR) on dentine. METHODS: 120 extracted human third molars were embedded in cold cured-resin and grinned down to the dentine. For each material 30 specimens were produced in standardised height and width and the materials were applied according to manufacturers' instructions on the dentine samples. Only in the CR group a self-etching dentine-adhesive was used. In all other groups the dentine was not pre-treated. All specimens were stored at 37.5 degrees C and 100% humidity for 2d, 7d and 14d. With a testing device the shear bond strength was determined (separation of the specimens from the dentine surface). The statistical evaluation was performed using ANOVA and Tukey-test (p < 0.05). RESULTS: At all observation periods the CR showed the significant highest shear bond strength (p < 0.05). After 2d significant differences in the shear bond strength were detectable between all tested materials, whereby CR had the highest and MTA the lowest values (p < 0.05). After 7d and 14d the shear bond strengths of MTA and Biodentine increased significantly compared to the 2d investigation period (p < 0.05). Biodentine showed a significantly higher shear bond strength than MTA (p < 0.05), while the difference between Biodentine and GIC was not significant (p > 0.05). CONCLUSIONS: After 7d Biodentine showed comparable shear bond values than GIC, whereas the shear bond values for MTA were significantly lower even after 14d. The adhesion of Biodentine to dentine surface seams to be superior compared to that of MTA. PMID- 25908432 TI - [Ensure to reassure]. PMID- 25908431 TI - Spectrum of enteropathogens detected by the FilmArray GI Panel in a multicentre study of community-acquired gastroenteritis. AB - The European, multicentre, quarterly point-prevalence study of community-acquired diarrhoea (EUCODI) analysed stool samples received at ten participating clinical microbiology laboratories (Austria, Finland, France, Germany, Greece, Ireland, Italy, Portugal, Romania, and the UK) in 2014. On four specified days, each local laboratory submitted samples from <=20 consecutive patients to the Austrian Study Centre for further testing with the FilmArray GI Panel (BioFire Diagnostics, Salt Lake City, UT, USA). Of the 709 samples from as many patients received, 325 (45.8%) tested negative, 268 (37.8%) yielded only one organism, and 116 (16.4%) yielded multiple organisms. Positivity rates ranged from 41% (30 of 73 samples) in France to 74% (59 of 80 samples) in Romania. With the exception of Entamoeba histolytica and Vibrio cholerae, all of the 22 targeted pathogens were detected at least once. Enteropathogenic Escherichia coli, Campylobacter species, toxigenic Clostridium difficile, enteroaggregative E. coli, norovirus and enterotoxigenic E. coli were the six most commonly detected pathogens. When tested according to local protocols, seven of 128 positive samples (5.5%) yielded multiple organisms. Overall, the FilmArray GI Panel detected at least one organism in 54.2% (384/709) of the samples, as compared with 18.1% (128/709) when testing was performed with conventional techniques locally. This underlines the considerable potential of multiplex PCR to improve routine stool diagnostics in community-acquired diarrhoea. Classic culture methods directed at the isolation of specific pathogens are increasingly becoming second-line tools, being deployed when rapid molecular tests give positive results. This optimizes the yield from stool examinations and dramatically improves the timeliness of diagnosis. PMID- 25908433 TI - [A difficult swallowing]. PMID- 25908434 TI - The fitness effect of mutations across environments: Fisher's geometrical model with multiple optima. AB - When are mutations beneficial in one environment and deleterious in another? More generally, what is the relationship between mutation effects across environments? These questions are crucial to predict adaptation in heterogeneous conditions in a broad sense. Empirical evidence documents various patterns of fitness effects across environments but we still lack a framework to analyze these multivariate data. In this article, we extend Fisher's geometrical model to multiple environments determining distinct peaks. We derive the fitness distribution, in one environment, among mutants with a given fitness in another and the bivariate distribution of random mutants' fitnesses across two or more environments. The geometry of the phenotype-fitness landscape is naturally interpreted in terms of fitness trade-offs between environments. These results may be used to fit/predict empirical distributions or to predict the pattern of adaptation across heterogeneous conditions. As an example, we derive the genomic rate of substitution and of adaptation in a metapopulation divided into two distinct habitats in a high migration regime and show that they depend critically on the geometry of the phenotype-fitness landscape. PMID- 25908436 TI - Systematic reviews from the 2nd International Consensus Conference on Laparoscopic Liver Resection. PMID- 25908435 TI - DNMT1 is essential for mammary and cancer stem cell maintenance and tumorigenesis. AB - Mammary stem/progenitor cells (MaSCs) maintain self-renewal of the mammary epithelium during puberty and pregnancy. DNA methylation provides a potential epigenetic mechanism for maintaining cellular memory during self-renewal. Although DNA methyltransferases (DNMTs) are dispensable for embryonic stem cell maintenance, their role in maintaining MaSCs and cancer stem cells (CSCs) in constantly replenishing mammary epithelium is unclear. Here we show that DNMT1 is indispensable for MaSC maintenance. Furthermore, we find that DNMT1 expression is elevated in mammary tumours, and mammary gland-specific DNMT1 deletion protects mice from mammary tumorigenesis by limiting the CSC pool. Through genome-scale methylation studies, we identify ISL1 as a direct DNMT1 target, hypermethylated and downregulated in mammary tumours and CSCs. DNMT inhibition or ISL1 expression in breast cancer cells limits CSC population. Altogether, our studies uncover an essential role for DNMT1 in MaSC and CSC maintenance and identify DNMT1-ISL1 axis as a potential therapeutic target for breast cancer treatment. PMID- 25908437 TI - Why do cancer drugs get such an easy ride? PMID- 25908438 TI - An Examination of Strategy Implementation During Abstract Nonlinguistic Category Learning in Aphasia. AB - PURPOSE: Our purpose was to study strategy use during nonlinguistic category learning in aphasia. METHOD: Twelve control participants without aphasia and 53 participants with aphasia (PWA) completed a computerized feedback-based category learning task consisting of training and testing phases. Accuracy rates of categorization in testing phases were calculated. To evaluate strategy use, strategy analyses were conducted over training and testing phases. Participant data were compared with model data that simulated complex multi-cue, single feature, and random pattern strategies. Learning success and strategy use were evaluated within the context of standardized cognitive-linguistic assessments. RESULTS: Categorization accuracy was higher among control participants than among PWA. The majority of control participants implemented suboptimal or optimal multi cue and single-feature strategies by testing phases of the experiment. In contrast, a large subgroup of PWA implemented random patterns, or no strategy, during both training and testing phases of the experiment. CONCLUSIONS: Person-to person variability arises not only in category learning ability but also in the strategies implemented to complete category learning tasks. PWA less frequently developed effective strategies during category learning tasks than control participants. Certain PWA may have impairments of strategy development or feedback processing not captured by language and currently probed cognitive abilities. PMID- 25908439 TI - Validation of the Identification and Intervention for Dementia in Elderly Africans (IDEA) cognitive screen in Nigeria and Tanzania. AB - BACKGROUND: We have previously described the development of the Identification and Intervention for Dementia in Elderly Africans (IDEA) cognitive screen for use in populations with low levels of formal education. The IDEA cognitive screen was developed and field-tested in an elderly, community-based population in rural Tanzania with a relatively high prevalence of cognitive impairment. The aim of this study was to validate the IDEA cognitive screen as an assessment of major cognitive impairment in hospital settings in Nigeria and Tanzania. METHODS: In Nigeria, 121 consecutive elderly medical clinic outpatients reviewed at the University College Hospital, Ibadan were screened using the IDEA cognitive screen. In Tanzania, 97 consecutive inpatients admitted to Mawenzi Regional Hospital (MRH), Moshi, and 108 consecutive medical clinic outpatients attending the geriatric medicine clinic at MRH were screened. Inter-rater reliability was assessed in Tanzanian outpatients attending St Joseph's Hospital in Moshi using three raters. A diagnosis of dementia or delirium (DSM-IV criteria) was classified as major cognitive impairment and was provided independently by a physician blinded to the results of the screening assessment. RESULTS: The area under the receiver operating characteristic (AUROC) curve in Nigerian outpatients, Tanzanian outpatients and Tanzanian inpatients was 0.990, 0.919 and 0.917 respectively. Inter-rater reliability was good (intra-class correlation coefficient 0.742 to 0.791). In regression models, the cognitive screen did not appear to be educationally biased. CONCLUSIONS: The IDEA cognitive screen performed well in these populations and should prove useful in screening for dementia and delirium in other areas of sub-Saharan Africa. PMID- 25908441 TI - Clinical nutrition staffing benchmarks for acute care hospitals. PMID- 25908440 TI - Dietary intake of children attending full-time child care: What are they eating away from the child-care center? AB - BACKGROUND: The Academy of Nutrition and Dietetics recommends children attending full-time child care obtain one-half to two-thirds of daily nutrient needs during their time at the child-care center, leaving one-third to one-half to be consumed away from the center. Although there are guidelines to optimize dietary intake of children attending child care, little is known about what these children consume away from the center. OBJECTIVE: To describe the dietary intake away from the child-care center for preschool-aged children relative to the expected one-third to one-half proportion of recommended intake, and to examine the relationships between energy intake away from the center with weight status, food group consumption, and low-income status. DESIGN: Cross-sectional study conducted between November 2009 and January 2011. PARTICIPANTS/SETTING: Participants (n=339) attended 30 randomly selected, licensed, full-time child-care centers in Hamilton County, OH. MAIN OUTCOME MEASURES: Child weight status and dietary intake (food/beverages consumed outside the child-care setting from the time of pickup from the center to the child's bedtime), including energy and servings of fruits, vegetables, milk, 100% juice, sugar-sweetened beverages, and snack foods. STATISTICAL ANALYSES PERFORMED: Generalized linear mixed models were used to examine independent associations of food group servings and low-income status to energy intake and energy intake to child weight status. RESULTS: The mean energy intake consumed away from the center (685+/-17 kcal) was more than the recommended target range (433 to 650 kcal). Intakes of fruits, vegetables, and milk were less than recommended. Food group servings and overweight/obesity status were positively associated with energy intake while away from the center. CONCLUSIONS: Preschool-aged children consume more energy and less fruits, vegetables, and milk outside of child-care centers than recommended. Overweight status was associated with children's dietary intake after leaving the child-care center. It may be beneficial to include parents in obesity prevention efforts targeting children attending child-care centers. PMID- 25908442 TI - Understanding millennial grocery shoppers' behavior and the role of the registered dietitian nutritionist. PMID- 25908443 TI - Outcome of Immediate Breast Reconstruction in Patients With Nonendocrine Responsive Breast Cancer: A Monoinstitutional Case-Control Study. AB - BACKGROUND: The long-term prognostic relevance of immediate breast reconstruction (IBR) for patients with estrogen receptor (ER)-negative breast cancer (BC) has not been fully elucidated. PATIENTS AND METHODS: The study population included 444 patients with ER-negative BC who underwent total mastectomy with complete axillary dissection between 1995 and 2006, 339 patients with and 105 patients without IBR. The median follow-up was 8.6 years. RESULTS: Patients treated with IBR were younger (P < .001) and received surgery more recently (2003-2006: 53.1% vs. 39%; P = .0003), and had a lower number of metastatic lymph nodes (>4 lymph nodes involvement: 29.5% vs. 45.7%; P = .0026), smaller tumors (pT1/2: 15% vs. 26.7%; P = .0007), and lower extent of peritumoral vascular invasion (15.9% vs. 21%; P = .032). The 5-year cumulative incidence of locoregional recurrence was 7.1% in the IBR group and 11.7% in the no IBR group (hazard ratio [HR], 0.81; P = .63). The 5-year cumulative incidence of distant metastases were similar in the 2 groups (P = .79). The 5-year overall and disease-free survival proportions were 79.9% versus 69.5% (HR, 1.11; P = .67) and 66.6% versus 54.1% (HR, 1.04; P = .83) in the IBR group and no IBR group, respectively. CONCLUSION: IBR intervention does not significantly affect prognosis of ER-negative BC patients. PMID- 25908444 TI - Novel mechanisms for superoxide-scavenging activity of human manganese superoxide dismutase determined by the K68 key acetylation site. AB - Superoxide is the primary reactive oxygen species generated in the mitochondria. Manganese superoxide dismutase (SOD2) is the major enzymatic superoxide scavenger present in the mitochondrial matrix and one of the most crucial reactive oxygen species-scavenging enzymes in the cell. SOD2 is activated by sirtuin 3 (SIRT3) through NAD(+)-dependent deacetylation. However, the exact acetylation sites of SOD2 are ambiguous and the mechanisms underlying the deacetylation-mediated SOD2 activation largely remain unknown. We are the first to characterize SOD2 mutants of the acetylation sites by investigating the relative enzymatic activity, structures, and electrostatic potential of SOD2 in this study. These SOD2 mutations affected the superoxide-scavenging activity in vitro and in HEK293T cells. The lysine 68 (K68) site is the most important acetylation site contributing to SOD2 activation and plays a role in cell survival after paraquat treatment. The molecular basis underlying the regulation of SOD2 activity by K68 was investigated in detail. Molecular dynamics simulations revealed that K68 mutations induced a conformational shift of residues located in the active center of SOD2 and altered the charge distribution on the SOD2 surface. Thus, the entry of the superoxide anion into the coordinated core of SOD2 was inhibited. Our results provide a novel mechanistic insight, whereby SOD2 acetylation affects the structure and charge distribution of SOD2, its tetramerization, and p53-SOD2 interactions of SOD2 in the mitochondria, which may play a role in nuclear mitochondrial communication during aging. PMID- 25908446 TI - Metformin increases peroxisome proliferator-activated receptor gamma Co-activator 1alpha and utrophin a expression in dystrophic skeletal muscle. AB - INTRODUCTION: Metformin (MET) stimulates skeletal muscle AMP-activated protein kinase (AMPK), a key phenotype remodeling protein with emerging therapeutic relevance for Duchenne muscular dystrophy (DMD). Our aim was to identify the mechanism of impact of MET on dystrophic muscle. METHODS: We investigated the effects of MET in cultured C2 C12 muscle cells and mdx mouse skeletal muscle. Expression of potent phenotypic modifiers was assessed, including peroxisome proliferator-activated receptor (PPAR)gamma coactivator-1alpha (PGC-1alpha), PPARdelta, and receptor-interacting protein 140 (RIP140), as well as that of the dystrophin-homolog, utrophin A. RESULTS: In C2 C12 cells, MET augmented expression of PGC-1alpha, PPARdelta, and utrophin A, whereas RIP140 content was reciprocally downregulated. MET treatment of mdx mice increased PGC-1alpha and utrophin A and normalized RIP140 levels. CONCLUSIONS: In this study we identify the impact of MET on skeletal muscle and underscore the timeliness and importance of investigating MET and other AMPK activators as relevant therapeutics for DMD. PMID- 25908445 TI - The superoxide dismutase 1 3'UTR maintains high expression of the SOD1 gene in cancer cells: The involvement of the RNA-binding protein AUF-1. AB - Superoxide dismutase 1 (SOD1) is ubiquitously expressed and the predominant dismutase in the cytoplasm. Whereas transcriptional regulation of the SOD1 gene has been well characterized, posttranscriptional regulation of the gene remains largely unknown in eukaryotes. In this study, a full-length 3'UTR of the SOD1 transcript was cloned and characterized for its ability to regulate SOD1 gene expression in human cancer cells. Inclusion of the SOD1 3'UTR in the pGL3 reporter construct dramatically enhanced the reporter activity by 10- to 220-fold in various cell lines. RT-PCR analysis, however, indicated that the reporter gene mRNA levels were only modestly altered by the SOD1 3'UTR, suggesting that the SOD1 3'UTR enhances the reporter gene activity not simply by stabilizing the mRNA but primarily by promoting translation of the protein. Bioinformatics analysis showed multiple stem and loop structures of the SOD1 3'UTR, and alterations in this secondary structure led to remarkably reduced reporter gene activity. Importantly, introducing the SOD1 3'UTR into cancer cells attenuated endogenous SOD1 expression in a concentration-dependent manner, indicating the involvement of RNA trans-acting factors in this process. Using siRNA and RNA immunoprecipitation techniques, we identified AUF-1, an RNA-binding protein, as a positive regulator of SOD1 expression through its 3'UTR. Consequently, AUF-1 was found to regulate redox balance in our cell model systems. Furthermore, in human ovarian, esophageal, and pancreatic cancer tissues, the expression of SOD1 was significantly correlated with that of AUF-1, further supporting the importance of AUF-1 in regulating SOD1 gene expression. PMID- 25908447 TI - Evaluation of in-hospital electrocardiography versus 24-hour Holter for rate control in dogs with atrial fibrillation. AB - OBJECTIVES: To determine if the in-clinic ECG-derived heart rate could predict the at-home Holter-derived 24-hour average heart rate (Holter24h ), and whether it is useful to identify slow versus fast atrial fibrillation in dogs. MATERIALS AND METHODS: 82 pairs of 1-minute ECGs and 24-hour Holter recordings were acquired in 34 dogs with atrial fibrillation. The initial 24-hour Holter was used to test if the ECG heart rate can identify dogs with "slow" versus "fast" atrial fibrillation based on a Holter24h threshold value of 140 bpm. RESULTS: ECG heart rate overestimated Holter24h by 26 bpm (95% CI: 3 bpm, 48 bpm; P < 0 . 015) with a 95% limit of agreement of -21 to 83 bpm. The in-clinic ECG-derived heart rate A155 bpm had a sensitivity of 73% and a specificity of 100% for identifying a Holter24h HR A140 bpm; an in-clinic ECG-derived HR <160 bpm had a sensitivity and specificity of 91% each. CLINICAL SIGNIFICANCE: In-clinic ECG assessment of heart rate in dogs with atrial fibrillation does not reliably predict the heart rate in their home environment. However, an in-clinic heart rate greater than 155 bpm is useful in identifying "fast" atrial fibrillation, allowing clinicians to stratify which case may benefit from antiarrhythmic therapy. PMID- 25908448 TI - Synthesis of triazine-based materials by functionalization with alkynes. AB - In this contribution, we report on novel functionalized triazines, which represent new precursors for C/N/(H) compounds or suitable building blocks for carbon-based functional networks. Our results provide insights into the structural properties of molecular carbon nitride materials and their design principles. Tris(1-propynyl)-1,3,5-triazine (C3 N3 (C3 H3 )3 ) and tris(1 butynyl)-1,3,5-triazine (C3 N3 (C4 H5 )3 ) were prepared by substitution reactions of cyanuric chloride (C3 N3 Cl3 ) with prop-1-yne and but-1-yne. The crystal structure of tris(1-propynyl)-1,3,5-triazine was solved in the orthorhombic space group Pbcn (Z=4, a=1500.06 (14), b=991.48(10), c=754.42(6) pm, V=1122.03(18)*10(6) pm(3) ), whereas tris(1-butynyl)-1,3,5-triazine crystallized in the triclinic space group P-1 (Z=6, a=1068.36(12), b=1208.68(12), c=1599.38(16) pm, alpha=86.67(3), beta=86.890(4), gamma=86.890(4) degrees , V=1997.7(4)*10(6) pm(3) ). For both structures, planar triazine units and layerlike packing of the molecules were observed. Tris(1-propynyl)-1,3,5-triazine is built up from hydrogen-bonded zig-zag strands, whereas tris(1-butynyl)-1,3,5 triazine shows parallel layered arrangements. Both compounds were investigated by NMR spectroscopy, IR spectroscopy, and differential thermal analysis/thermogravimetric analysis, which provided insights into their structural, chemical, and thermal properties. In addition, tris(1-propynyl)-1,3,5 triazine was pyrolyzed and a new polymeric triazine-based compound containing mesitylene units was obtained. Its structural features and properties are discussed in detail. PMID- 25908450 TI - Structural priming in Spanish as evidence of implicit learning. AB - This study uses a structural priming technique with young Spanish speakers to test whether exposure to a rare syntactic form in Spanish (fue-passive) would increase the production and comprehension of that form. In Study 1, 14 six-year old Spanish speakers described pictures of transitive scenes. This baseline study revealed that fue-passives were virtually non-existent in children's spontaneous speech. Using the priming technique in Study 2, an additional 56 Spanish-speaking children were exposed to fue-passive or active picture descriptions; we varied whether children repeated the modeled form. With repetition, production of fue passives increased past baseline usage. When not asked to repeat, comprehension and production of fue-passives was no different than chance. Results extend the existing literature by experimentally testing input effects on the production and comprehension of infrequently used constructions, further corroborating the relation between input frequency and language skill. Findings are consistent with the view that an implicit learning mechanism guides language learning. PMID- 25908449 TI - Systematic interaction network filtering identifies CRMP1 as a novel suppressor of huntingtin misfolding and neurotoxicity. AB - Assemblies of huntingtin (HTT) fragments with expanded polyglutamine (polyQ) tracts are a pathological hallmark of Huntington's disease (HD). The molecular mechanisms by which these structures are formed and cause neuronal dysfunction and toxicity are poorly understood. Here, we utilized available gene expression data sets of selected brain regions of HD patients and controls for systematic interaction network filtering in order to predict disease-relevant, brain region specific HTT interaction partners. Starting from a large protein-protein interaction (PPI) data set, a step-by-step computational filtering strategy facilitated the generation of a focused PPI network that directly or indirectly connects 13 proteins potentially dysregulated in HD with the disease protein HTT. This network enabled the discovery of the neuron-specific protein CRMP1 that targets aggregation-prone, N-terminal HTT fragments and suppresses their spontaneous self-assembly into proteotoxic structures in various models of HD. Experimental validation indicates that our network filtering procedure provides a simple but powerful strategy to identify disease-relevant proteins that influence misfolding and aggregation of polyQ disease proteins. PMID- 25908451 TI - The receptor for advanced glycation end products (RAGE) enhances autophagy and neutrophil extracellular traps in pancreatic cancer. AB - Neutrophil extracellular traps (NETs) are formed when neutrophils expel their DNA, histones and intracellular proteins into the extracellular space or circulation. NET formation is dependent on autophagy and is mediated by citrullination of histones to allow for the unwinding and subsequent expulsion of DNA. NETs have an important role in the pathogenesis of several sterile inflammatory diseases, including malignancy, therefore we investigated the role of NETs in the setting of pancreatic ductal adenocarcinoma (PDA). Neutrophils isolated from two distinct animal models of PDA had an increased propensity to form NETs following stimulation with platelet activating factor (PAF). Serum DNA, a marker of circulating NET formation, was elevated in tumor bearing animals as well as in patients with PDA. Citrullinated histone H3 expression, a marker of NET formation, was observed in pancreatic tumors obtained from murine models and patients with PDA. Inhibition of autophagy with chloroquine or genetic ablation of receptor for advanced glycation end products (RAGE) resulted in decreased propensity for NET formation, decreased serum DNA and decreased citrullinated histone H3 expression in the pancreatic tumor microenvironment. We conclude that NETs are upregulated in pancreatic cancer through RAGE-dependent/autophagy mediated pathways. PMID- 25908452 TI - Identification of commonly dysregulated genes in colorectal cancer by integrating analysis of RNA-Seq data and qRT-PCR validation. AB - The progression of colorectal cancer (CRC) is a multistep process and metastatic CRC is always incurable; consequently, CRC is the leading cause of cancer-related deaths. There is therefore an urgent need for identifying useful biomarkers with enough sensitivity and specificity to detect this disease at early stages, which will significantly reduce the mortality for this malignancy. In this study, we performed an integrating analysis of different RNA-Seq data sets to find new candidate biomarkers for diagnosis, prognosis and as therapeutic targets for this malignancy, as well as to elucidate the molecular mechanisms of CRC carcinogenesis. We identified 883 differentially expressed genes (DEGs) across the studies between CRC and normal control (NC) tissues by combining five RNA-Seq data sets. Gene function analysis revealed high correlation with carcinogenesis. The top 10 most significantly DEGs were further evaluated by quantitative real time polymerase chain reaction (qRT-PCR) in both rectal cancer (RC) and colon cancer (CC), and the results matched well with integrating data, suggesting that the method of integrating analysis of different RNA-seq data sets is acceptable. Therefore, integrating analysis of different RNA-seq data sets may be a useful way to overcome the limitation of small sample size in a single RNA-seq study. In addition, our study showed that some genes, such as SIM2, ADAMTS6, FOXD4L4 and DNAH5, may have an important role in the development of CRC, which could be applied for diagnosis, prognosis and as therapy for this malignancy. Our findings would also help to understand the pathology of CRC. PMID- 25908453 TI - A transfection method of PS-asODNs targeting ANGPTL4 in multicellular structures of hepatocarcinoma cell line. AB - To find an efficient transfection method for metastatic cancer cells, we established a three-dimensional (3D) growth model for solid tumor cells to mimic the metastatic cancer cells in the vascular system and compared the efficiency of several transfection methods in vitro. We found that it was optimal to transfect two-dimensional cells in vitro and detach them for 3D growth 6 h later. The transfection efficiency of this method was high, and the results were reliable. This method can be used to deliver several types of small molecules into the 3D metastatic cell model. Using this method, we increased our understanding of why drugs that are effective in vitro cannot treat the disease in vivo. If this phenomenon occurs due to the resistance of the cells to the drug, other treatment agents for the disease must be identified. However, if this occurs because the agent cannot reach the cells inside the 3D aggregate, we can improve the delivery efficiency by using methods that target the agent to all cells. Briefly, the method introduced in this study will contribute to future research focusing on the 3D metastatic cell model as well as on drug development for various solid tumors. PMID- 25908454 TI - Knockdown of c-MET induced apoptosis in ABCB1-overexpressed multidrug-resistance cancer cell lines. AB - Inappropriate c-MET signaling in cancer can enhance tumor cell proliferation, survival, motility, and invasion. Inhibition of c-MET signaling induces apoptosis in a variety of cancers. It has also been recognized as a novel anticancer therapy approach. Furthermore, reports have also indicated that constitutive expression of P-glycoprotein (ABCB1) is involved in the HGF/c-MET-related pathway of multidrug resistance ABCB1-positive human hepatocellular carcinoma cell lines. We previously reported that elevated expression levels of PKCdelta and AP-1 downstream genes, and HGF receptor (c-MET) and ABCB1, in the drug-resistant MES SA/Dx5 cells. Moreover, leukemia cell lines overexpressing ABCB1 have also been shown to be more resistant to the tyrosine kinase inhibitor imatinib mesylate. These findings suggest that chemoresistant cancer cells may also develop a similar mechanism against chemotherapy agents. To circumvent clinical complications arising from drug resistance during cancer therapy, the present study was designed to investigate apoptosis induction in ABCB1-overexpressed cancer cells using c-MET-targeted RNA interference technology in vitro and in vivo. The results showed that cell viability decreased and apoptosis rate increased in c-MET shRNA-transfected HGF/c-MET pathway-positive MES-SA/Dx5 and MCF-7/ADR2 cell lines in a dose-dependent manner. In vivo reduction of tumor volume in mice harboring c-MET shRNA-knockdown MES-SA/Dx5 cells was clearly demonstrated. Our study demonstrated that downregulation of c-MET by shRNA induced apoptosis in a multidrug resistance cell line. PMID- 25908456 TI - Reperfusion versus recanalization: the winner is.... PMID- 25908455 TI - Long-term exposure to fine particulate matter, residential proximity to major roads and measures of brain structure. AB - BACKGROUND AND PURPOSE: Long-term exposure to ambient air pollution is associated with cerebrovascular disease and cognitive impairment, but whether it is related to structural changes in the brain is not clear. We examined the associations between residential long-term exposure to ambient air pollution and markers of brain aging using magnetic resonance imaging. METHODS: Framingham Offspring Study participants who attended the seventh examination were at least 60 years old and free of dementia and stroke were included. We evaluated associations between exposures (fine particulate matter [PM2.5] and residential proximity to major roadways) and measures of total cerebral brain volume, hippocampal volume, white matter hyperintensity volume (log-transformed and extensive white matter hyperintensity volume for age), and covert brain infarcts. Models were adjusted for age, clinical covariates, indicators of socioeconomic position, and temporal trends. RESULTS: A 2-MUg/m(3) increase in PM2.5 was associated with -0.32% (95% confidence interval, -0.59 to -0.05) smaller total cerebral brain volume and 1.46 (95% confidence interval, 1.10 to 1.94) higher odds of covert brain infarcts. Living further away from a major roadway was associated with 0.10 (95% confidence interval, 0.01 to 0.19) greater log-transformed white matter hyperintensity volume for an interquartile range difference in distance, but no clear pattern of association was observed for extensive white matter. CONCLUSIONS: Exposure to elevated levels of PM2.5 was associated with smaller total cerebral brain volume, a marker of age-associated brain atrophy, and with higher odds of covert brain infarcts. These findings suggest that air pollution is associated with insidious effects on structural brain aging even in dementia- and stroke-free persons. PMID- 25908457 TI - Patterns of poststroke brain damage that predict speech production errors in apraxia of speech and aphasia dissociate. AB - BACKGROUND AND PURPOSE: Acquired apraxia of speech (AOS) is a motor speech disorder caused by brain damage. AOS often co-occurs with aphasia, a language disorder in which patients may also demonstrate speech production errors. The overlap of speech production deficits in both disorders has raised questions on whether AOS emerges from a unique pattern of brain damage or as a subelement of the aphasic syndrome. The purpose of this study was to determine whether speech production errors in AOS and aphasia are associated with distinctive patterns of brain injury. METHODS: Forty-three patients with history of a single left hemisphere stroke underwent comprehensive speech and language testing. The AOS Rating Scale was used to rate speech errors specific to AOS versus speech errors that can also be associated with both AOS and aphasia. Localized brain damage was identified using structural magnetic resonance imaging, and voxel-based lesion impairment mapping was used to evaluate the relationship between speech errors specific to AOS, those that can occur in AOS or aphasia, and brain damage. RESULTS: The pattern of brain damage associated with AOS was most strongly associated with damage to cortical motor regions, with additional involvement of somatosensory areas. Speech production deficits that could be attributed to AOS or aphasia were associated with damage to the temporal lobe and the inferior precentral frontal regions. CONCLUSIONS: AOS likely occurs in conjunction with aphasia because of the proximity of the brain areas supporting speech and language, but the neurobiological substrate for each disorder differs. PMID- 25908458 TI - Dietary intake of sugar substitutes aggravates cerebral ischemic injury and impairs endothelial progenitor cells in mice. AB - BACKGROUND AND PURPOSE: In our current food supply, sugar substitutes are widely used in beverages and other food products. However, there is limited information about the link between dietary consumption of sugar substitutes and stroke to date. This study sought to determine the effect of various sugar substitutes on the cerebral ischemic injury and endothelial progenitor cells, which have been implicated to play an important role in vascular repair and revascularization in ischemic brain tissues, in mice. METHODS: After treatment with sucrose and various sugar substitutes (the doses are in the range of corresponding acceptable daily intake levels) and vehicle for 6 weeks, mice were subjected to permanent left middle cerebral artery occlusion, and the infarct volumes, angiogenesis, and neurobehavioral outcomes were determined. In addition, the number and function of endothelial progenitor cells were also examined. RESULTS: After long-term treatment with fructose, erythritol (sugar alcohols), acesulfame K (artificial sweeteners), or rebaudioside A (rare sugars), the cerebral ischemic injury (both infarct volumes and neurobehavioral outcomes) was significantly aggravated, angiogenesis in ischemic brain was reduced, and endothelial progenitor cell function was impaired in mice compared with control. However, the similar impairments were not found in sucrose (with the same dose as fructose's)-treated mice. CONCLUSIONS: Long-term consumption of sugar substitutes aggravated cerebral ischemic injury in mice, which might be partly attributed to the impairment of endothelial progenitor cells and the reduction of angiogenesis in ischemic brain. This result implies that dietary intake of sugar substitutes warrants further attention in daily life. PMID- 25908459 TI - Resveratrol Preconditioning Protects Against Cerebral Ischemic Injury via Nuclear Erythroid 2-Related Factor 2. AB - BACKGROUND AND PURPOSE: Nuclear erythroid 2 related factor 2 (Nrf2) is an astrocyte-enriched transcription factor that has previously been shown to upregulate cellular antioxidant systems in response to ischemia. Although resveratrol preconditioning (RPC) has emerged as a potential neuroprotective therapy, the involvement of Nrf2 in RPC-induced neuroprotection and mitochondrial reactive oxygen species production after cerebral ischemia remains unclear. The goal of our study was to study the contribution of Nrf2 to RPC and its effects on mitochondrial function. METHODS: We used rodent astrocyte cultures and an in vivo stroke model with RPC. An Nrf2 DNA binding ELISA and protein analysis via Western blotting of downstream Nrf2 targets were performed to determine RPC-induced activation of Nrf2 in rat and mouse astrocytes. After RPC, mitochondrial function was determined by measuring reactive oxygen species production and mitochondrial respiration in both wild-type and Nrf2-/- mice. Infarct volume was measured to determine neuroprotection, whereas protein levels were measured by immunoblotting. RESULTS: We report that Nrf2 is activated by RPC in rodent astrocyte cultures, and that loss of Nrf2 reduced RPC-mediated neuroprotection in a mouse model of focal cerebral ischemia. In addition, we observed that wild-type and Nrf2-/- cortical mitochondria exhibited increased uncoupling and reactive oxygen species production after RPC treatments. Finally, Nrf2-/- astrocytes exhibited decreased mitochondrial antioxidant expression and were unable to upregulate cellular antioxidants after RPC treatment. CONCLUSIONS: Nrf2 contributes to RPC-induced neuroprotection through maintaining mitochondrial coupling and antioxidant protein expression. PMID- 25908460 TI - Left atrial enlargement and stroke recurrence: the Northern Manhattan Stroke Study. AB - BACKGROUND AND PURPOSE: Although left atrial enlargement (LAE) increases incident stroke risk, the association with recurrent stroke is less clear. Our aim was to determine the association of LAE with recurrent stroke most likely related to embolism (cryptogenic and cardioembolic) and all ischemic stroke recurrences. METHODS: We followed 655 first ischemic stroke patients in the Northern Manhattan Stroke Study for <=5 years. LA size from 2D echocardiography was categorized as normal LAE (52.7%), mild LAE (31.6%), and moderate-severe LAE (15.7%). We used Cox proportional hazard models to calculate the hazard ratios and 95% confidence intervals for the association of LA size and LAE with recurrent cryptogenic/cardioembolic and total recurrent ischemic stroke. RESULTS: LA size was available in 529 (81%) patients. Mean age at enrollment was 69+/-13 years; 45.8% were male, 54.0% Hispanic, and 18.5% had atrial fibrillation. Over a median of 4 years, there were 65 recurrent ischemic strokes (29 were cardioembolic or cryptogenic). In multivariable models adjusted for confounders, including atrial fibrillation and heart failure, moderate-severe LAE compared with normal LA size was associated with greater risk of recurrent cardioembolic/cryptogenic stroke (adjusted hazard ratio 2.83, 95% confidence interval 1.03-7.81), but not total ischemic stroke (adjusted hazard ratio 1.06, 95% confidence interval, 0.48-2.30). Mild LAE was not associated with recurrent stroke. CONCLUSION: Moderate to severe LAE was an independent marker of recurrent cardioembolic or cryptogenic stroke in a multiethnic cohort of ischemic stroke patients. Further research is needed to determine whether anticoagulant use may reduce risk of recurrence in ischemic stroke patients with moderate to severe LAE. PMID- 25908461 TI - White matter perivascular spaces on magnetic resonance imaging: marker of cerebrovascular amyloid burden? AB - BACKGROUND AND PURPOSE: We investigated the relationship between magnetic resonance imaging-visible centrum semiovale perivascular spaces (CSO-PVS), a biomarker of impaired interstitial fluid drainage, and positron emission tomography-based amyloid-beta burden across a wide range of cerebrovascular amyloid deposition. METHODS: Thirty-one nondemented subjects (11 probable cerebral amyloid angiopathy patients and 10 healthy subjects>=60 years; 10 older individuals, <60 years) had brain magnetic resonance imaging and Pittsburgh compound B-positron emission tomography. CSO-PVS was evaluated on T2-magnetic resonance imaging using a 4-point scale. The association between Pittsburgh compound B and CSO-PVS was assessed in linear regression. RESULTS: In multivariable analyses adjusted for age, microbleeds and white matter hyperintensities, whole cortex Pittsburgh compound B binding was associated with CSO-PVS degree both as continuous (coefficient, 0.11; 95% confidence interval, 0.01-0.22; P=0.040) and as dichotomous variable (coefficient, 0.27; 95% confidence interval, 0.11-0.44; P=0.002). The median Pittsburgh compound B retention was higher in high versus low CSO-PVS degree (P=0.0007). CONCLUSIONS: This pilot study suggests a possible association between cerebrovascular amyloid deposition and CSO-PVS, with potential pathophysiological implications. PMID- 25908462 TI - Short-term blood pressure variability in acute stroke: post hoc analysis of the controlling hypertension and hypotension immediately post stroke and continue or stop post-stroke antihypertensives collaborative study trials. AB - BACKGROUND AND PURPOSE: Short-term blood pressure variability (BPV) may predict outcome in acute stroke. We undertook a post hoc analysis of data from 2 randomized controlled trials to determine the effect of short-term BPV on 2-week outcome. METHODS: Controlling Hypertension and Hypotension Immediately Post Stroke (CHHIPS) was a trial of BP-lowering, enrolling 179 acute stroke patients (onset<36 hours). Continue or Stop Post-Stroke Antihypertensives Collaborative Study (COSSACS) compared a strategy of continuation versus temporarily stopping prestroke antihypertensive therapy in 763 acute stroke patients (onset<48 hours). BPV at baseline (defined as SD, coefficient of variation, variation independent of the mean, and average real variability) was derived from standardized casual cuff BP measures (6 readings<30 minutes). Adjusted logistic regression models were used to assess the relation between BPV and death and disability (modified Rankin scale>3) at 2 weeks. RESULTS: Seven hundred six (92.5%) and 171 (95.5%) participants were included in the analysis for the COSSACS and CHHIPS data sets, respectively. Adjusted logistic regression analyses revealed no statistically significant associations between any of the included BPV parameters with 2-week death or disability in either study data set: COSSACS, odds ratio SD systolic BP 0.98 (0.78-1.23); CHHIPS, odds ratio SD systolic BP 0.97 (0.90-1.11). CONCLUSIONS: When derived from casual cuff BP measures, short-term BPV is not a useful predictor of early (2 weeks) outcome after acute stroke. Differing methodology may account for the discordance with previous studies indicating long term (casual BPV) and short-term (beat-to-beat BPV) prognostic value. CLINICAL TRIAL REGISTRATION: COSSACS was registered on the International Standard Randomised Controlled Trial Register; URL: http://www.isrctn.com. Unique identifier: ISRCTN89712435. CHHIPS was registered on the National Research Register; URL: http://public.ukcrn.org.uk. Unique identifier: N0484128008. PMID- 25908464 TI - Hypertension in CKD: Sodium still at the nexus. PMID- 25908463 TI - Reperfusion within 6 hours outperforms recanalization in predicting penumbra salvage, lesion growth, final infarct, and clinical outcome. AB - BACKGROUND AND PURPOSE: The relative merits of reperfusion versus recanalization to predict tissue and clinical outcomes in anterior circulation stroke have been previously assessed using data acquired >12 hours postonset. To avoid late occurring confounders such as non-nutritional reperfusion, futile recanalization and no-reflow phenomenon, we performed ultraearly assessment of reperfusion and recanalization. METHODS: From a multicenter prospective database, 46 patients with acute magnetic resonance angiography-visible occlusion and in whom both reperfusion and recanalization were assessed on follow-up magnetic resonance imaging <=6 hours of symptom onset were identified. Multiple linear regressions modeled salvaged penumbra, diffusion-weighted imaging lesion growth, and final infarct at 1 month using baseline clinical and imaging parameters and acute reperfusion or recanalization. Best predictors were determined with the Akaike information criterion. Univariate and multivariate logistic regressions identified the clinical and imaging predictors of clinical outcome. RESULTS: Admission magnetic resonance imaging showed M1 occlusion in 15 (33%) patients; median penumbra volume was 13.4 mL. Acute reperfusion was observed in 27 (59%) patients; 42% of nonrecanalized patients demonstrated reperfusion. The dichotomized classification of reperfusion and recanalization was discordant (P=0.0002). Reperfusion<=6 hours was a significant (P<0.05) predictor of increased penumbra salvage, reduced lesion growth, and final infarct size. Recanalization did not improve model accuracy. Reperfusion, but not recanalization, was significantly associated with good clinical outcome in logistic regressions. CONCLUSIONS: Reperfusion<=6 hours was consistently superior to recanalization in predicting tissue and clinical outcome. Reperfusion without recanalization was frequent and probably related to retrograde reperfusion through leptomeningeal collaterals. Acute reperfusion was the strongest predictor of, and may therefore, represent a reliable surrogate for, clinical outcome. PMID- 25908465 TI - Secondary hypertension: beginnings and transitions. PMID- 25908467 TI - Mineralocorticoid and apparent mineralocorticoid syndromes of secondary hypertension. AB - The mineralocorticoid aldosterone is a key hormone in the regulation of plasma volume and blood pressure in man. Excessive levels of this mineralocorticoid have been shown to mediate metabolic disorders and end-organ damage more than what can be attributed to its effects on blood pressure alone. Inappropriate excess levels of aldosterone contribute significantly to the cardiorenal metabolic syndrome and target organ injury that include atherosclerosis, myocardial hypertrophy, fibrosis, heart failure, and kidney disease. The importance of understanding the role of excess mineralocorticoid hormones such as aldosterone in resistant hypertension and in those with secondary hypertension should be visited. Primary aldosteronism is one of the commonly identified causes of hypertension and is treatable and/or potentially curable. We intend to review the management of mineralocorticoid-induced hypertension in the adult population along with other disease entities that mimic primary aldosteronism. PMID- 25908466 TI - Sodium retention and volume expansion in nephrotic syndrome: implications for hypertension. AB - Sodium retention is a major clinical feature of nephrotic syndrome. The mechanisms responsible for sodium retention in this setting have been a subject of debate for years. Excessive sodium retention occurs in some individuals with nephrotic syndrome in the absence of activation of the renin-angiotensin aldosterone system, suggesting an intrinsic defect in sodium excretion by the kidney. Recent studies have provided new insights regarding mechanisms by which sodium transporters are activated by factors present in nephrotic urine. These mechanisms likely have a role in the development of hypertension in nephrotic syndrome, where hypertension may be difficult to control, and provide new therapeutic options for the management of blood pressure and edema in the setting of nephrotic syndrome. PMID- 25908468 TI - Outcomes of drug-based and surgical treatments for primary aldosteronism. AB - Treatments for primary aldosteronism (PA) aim to correct or prevent the deleterious consequences of hyperaldosteronism: hypertension, hypokalemia, and direct target organ damage. Patients with unilateral PA considered fit for surgery can undergo laparoscopic adrenalectomy, which significantly decreases blood pressure (BP) and medications in most cases and cures hypertension in about 40%. Mineralocorticoid receptor antagonists (MRA) are used to treat patients with bilateral PA and those with unilateral PA if surgery is not possible or not desired. Spironolactone is more potent than eplerenone, but high doses are poorly tolerated in men. MRA can be replaced or complemented with epithelial sodium channel blockers, such as amiloride. Thiazide diuretics and calcium channel blockers are used when the first-line drugs are insufficient to control BP. Dietary sodium restriction should be implemented in all cases because the deleterious consequences of hyperaldosteronism are dependent on salt loading. Several studies comparing the results of surgery and MRA have reported no differences in terms of BP, serum potassium concentration, or cardiovascular and kidney outcomes, although the benefits of treatment tend to be observed sooner with surgery. Patients with PA display relative glomerular hyperfiltration, which is reversed by specific treatment, revealing CKD in 30% of patients. However, further kidney damage is lessened by the treatment of PA. PMID- 25908469 TI - The intrarenal renin-angiotensin system in hypertension. AB - The renin-angiotensin system (RAS) is a well-studied hormonal cascade controlling fluid and electrolyte balance and blood pressure through systemic actions. The classical RAS includes renin, an enzyme catalyzing the conversion of angiotensinogen to angiotensin (Ang) I, followed by angiotensin-converting enzyme (ACE) cleavage of Ang I to II, and activation of AT1 receptors, which are responsible for all RAS biologic actions. Recent discoveries have transformed the RAS into a far more complex system with several new pathways: the (des aspartyl(1))-Ang II (Ang III)/AT2 receptor pathway, the ACE-2/Ang (1-7)/Mas receptor pathway, and the prorenin-renin/prorenin receptor/mitogen-activated protein kinase pathway, among others. Although the classical RAS pathway induces Na(+) reabsorption and increases blood pressure, several new pathways constitute a natriuretic/vasodilator arm of the system, opposing detrimental actions of Ang II through Ang II type 1 receptors. Instead of a simple circulating RAS, several independently functioning tissue RASs exist, the most important of which is the intrarenal RAS. Several physiological characteristics of the intrarenal RAS differ from those of the circulating RAS, autoamplifying the activity of the intrarenal RAS and leading to hypertension. This review will update current knowledge on the RAS with particular attention to the intrarenal RAS and its role in the pathophysiology of hypertension. PMID- 25908470 TI - Obesity and insulin resistance in resistant hypertension: implications for the kidney. AB - There is recognition that the obesity epidemic contributes substantially to the increasing incidence of CKD and resistant hypertension (HTN). The mechanisms by which obesity promotes resistance are an area of active interest and intense investigation. It is thought that increases in visceral adiposity lead to a proinflammatory, pro-oxidative milieu that promote resistance to the metabolic actions of insulin. This resistance to insulin at the level of skeletal muscle tissue impairs glucose disposal/utilization through actions on the endothelium that include vascular rarefaction, reductions in vascular relaxation, and vascular remodeling. Insulin resistance derived from increased adipose tissue and obesity has system-wide implications for other tissue beds such as the kidney that affects blood pressure regulation. The additional autocrine and paracrine activities of adipose tissue contribute to inappropriate activation of the renin angiotensin-aldosterone system and the sympathetic nervous system that promote kidney microvascular remodeling, stiffness, and sodium (Na(+)) retention that in turn promote HTN and in the CKD patient, resistance. In this review, we will summarize the important mechanisms that link obesity to CKD as they relate to resistant HTN. PMID- 25908471 TI - Catecholamine excess: pseudopheochromocytoma and beyond. AB - Symptoms of catecholamine excess or pseudopheochromocytoma can be clinically indistinguishable from pheochromocytoma. Patients usually present with paroxysmal or episodic hypertension and have a negative evaluation for pheochromocytoma. It is important to exclude other causes of catecholamine excess that can be induced by stress, autonomic dysfunction due to baroreflex failure, medications, and drugs. Patients with pseudopheochromocytoma appear to have an amplified cardiovascular responsiveness to catecholamines with enhanced sympathetic nervous stimulation. The exact mechanism is not well understood and increased secretion of dopamine, epinephrine, and norepinephrine, and their metabolites have been identified as potentiating this clinical scenario leading to differing hemodynamic presentations depending on which catecholamine is elevated. Management of this condition is often difficult and frustrating for both the physician and the patient. Most patients respond reasonably well to medications that reduce sympathetic nervous system activity. Anxiolytics, antidepressants, and psychotherapy also play an important role in managing these patients' symptoms. PMID- 25908472 TI - Atherosclerotic renal artery stenosis: current status. AB - Atherosclerotic renal artery stenosis (ARAS) remains a major cause of secondary hypertension and kidney failure. Randomized prospective trials show that medical treatment should constitute the main therapeutic approach in ARAS. Regardless of intensive treatment and adequate blood pressure control, however, renal and extrarenal complications are not uncommon. Yet, the precise mechanisms, accurate detection, and optimal treatment in ARAS remain elusive. Strategies oriented to early detection and targeting these pathogenic pathways might prevent development of clinical end points. Here, we review the results of recent clinical trials, current understanding of the pathogenic mechanisms, novel imaging techniques to assess kidney damage in ARAS, and treatment options. PMID- 25908474 TI - Our own worst enemy: pharmacologic mechanisms of hypertension. AB - Drug-induced hypertension is often an unrecognized cause of resistant or secondary hypertension. It is defined as hypertension resulting from the unintended effect of a drug or from a drug's antagonistic effect on antihypertensive medications. The main mechanisms of drug-induced hypertension, when categorized broadly, include volume retention and sympathomimetic effects. These mechanisms along with management strategies will be further discussed in this article. PMID- 25908477 TI - Ochronosis and Osteoporosis: A Case Report. PMID- 25908475 TI - Saccharina genomes provide novel insight into kelp biology. AB - Seaweeds are essential for marine ecosystems and have immense economic value. Here we present a comprehensive analysis of the draft genome of Saccharina japonica, one of the most economically important seaweeds. The 537-Mb assembled genomic sequence covered 98.5% of the estimated genome, and 18,733 protein-coding genes are predicted and annotated. Gene families related to cell wall synthesis, halogen concentration, development and defence systems were expanded. Functional diversification of the mannuronan C-5-epimerase and haloperoxidase gene families provides insight into the evolutionary adaptation of polysaccharide biosynthesis and iodine antioxidation. Additional sequencing of seven cultivars and nine wild individuals reveal that the genetic diversity within wild populations is greater than among cultivars. All of the cultivars are descendants of a wild S. japonica accession showing limited admixture with S. longissima. This study represents an important advance toward improving yields and economic traits in Saccharina and provides an invaluable resource for plant genome studies. PMID- 25908478 TI - Erratum. PMID- 25908476 TI - Image-guided, microsurgical topographic anatomy of the endolymphatic sac and vestibular aqueduct via a suboccipital retrosigmoid approach. AB - The endolymphatic sac (ES) and the vestibular aqueduct (VA) are often in the surgical field when posterior fossa lesions are targeted using retrosigmoid approaches. The purpose of this work is to validate neuronavigator accuracy in predicting VA location as well as to give guidelines to preserve the ES and VA. A retrosigmoid approach was performed bilaterally in six specimens in the semisitting position. Preoperatively, we registered in the CT scans the position of the VA genu (virtual genu). After the approach execution, ES and VA genu topographic relationships with evident posterolateral cranial base structures were measured using neuronavigation. Next, we exposed the VA genu: its position coincided with the virtual VA genu in all the specimens. On the average, the ES was 17.93 mm posterosuperolateral to the XI nerve in the jugular foramen, 12.26 mm posterolateral to the internal acoustic meatus, 20.13 mm anteromedial to the petro-sigmoid intersection at a point 13.30 mm inferior to the petrous ridge. The VA genu was located 7.23 mm posterolateral to the internal acoustic meatus, 18.11 mm superolateral to the XI nerve in the jugular foramen, 10.27 mm inferior to the petrous ridge, and 6.28 mm anterolateral to the endolymphatic ledge at a depth of 3.46 mm from the posterior pyramidal wall. Our study demonstrates that is possible to use neuronavigation to reliably predict the location of the VA genu. In addition, neuronavigation may be effectively used to create a topographical framework that may help maintaining the integrity of the ES/VA during retrosigmoid approaches. PMID- 25908473 TI - Endogenous cardiotonic steroids in kidney failure: a review and an hypothesis. AB - In response to progressive nephron loss, volume and humoral signals in the circulation have increasing relevance. These signals, including plasma sodium, angiotensin II, and those related to volume status, activate a slow neuromodulatory pathway within the central nervous system (CNS). The slow CNS pathway includes specific receptors for angiotensin II, mineralocorticoids, and endogenous ouabain (EO). Stimulation of the pathway leads to elevated sympathetic nervous system activity (SNA) and increased circulating EO. The sustained elevation of circulating EO (or ouabain) stimulates central and peripheral mechanisms that amplify the impact of SNA on vascular tone. These include changes in synaptic plasticity in the brain and sympathetic ganglia that increase preganglionic tone and amplify ganglionic transmission, amplification of the impact of SNA on arterial tone in the vascular wall, and the reprogramming of calcium signaling proteins in arterial myocytes. These increase SNA, raise basal and evoked arterial tone, and elevate blood pressure (BP). In the setting of CKD, we suggest that sustained activation/elevation of the slow CNS pathway, plasma EO, and the cardiotonic steroid marinobufagenin, comprises a feed-forward system that raises BP and accelerates kidney and cardiac damage. Block of the slow CNS pathway and/or circulating EO and marinobufagenin may reduce BP and slow the progression to ESRD. PMID- 25908479 TI - Pregnancies in women receiving renal transplant for lupus nephritis: description of nine pregnancies and review of the literature. AB - BACKGROUND: Few data are available on pregnancy in renal transplanted women for lupus nephritis (LN). METHODS: Among 38 women with LN who received a renal transplant in our Unit, three had nine pregnancies. During the pregnancies, patients were followed by a multidisciplinary team including gynecologists and nephrologists. RESULTS: Two patients received a living related and one a deceased kidney transplant. The immunosuppressive therapy consisted of steroids calcinurin inhibithors and mycophenolate mofetil. The last drug was substituted with azathioprine in prevision of pregnancy. All patients had normal renal function and urinalysis. In two patients some signs of immunological activity persisted after transplantation. Five pregnancies ended in miscarriage and four in live births. Two pregnancies were uneventful. Pre-eclampsia occurred in a hypertensive patient in two pregnancies that ended in preterm delivery in one case and in a small for gestation age in both cases. And finally, follow-up graft function and urinalysis continued to be normal in all patients. CONCLUSIONS: After renal transplantation our LN women continue to have frequent miscarriages. The other pregnancies ended in live births and, with the exception of pre-eclampsia in a hypertensive patient, no renal or extra-renal complications occurred during or after pregnancy, even in cases with active immunological tests. PMID- 25908480 TI - Associations between the functional CD40 rs4810485 G/T polymorphism and susceptibility to rheumatoid arthritis and systemic lupus erythematosus: a meta analysis. AB - OBJECTIVE: The aim of this study was to determine whether the functional CD40 rs4810485 G/T polymorphism is associated with susceptibility to rheumatoid arthritis (RA) or with susceptibility to systemic lupus erythematosus (SLE). METHODS: A series of meta-analyses were conducted to test for association between the CD40 rs4810485 G/T polymorphism and RA or SLE. RESULTS: A total of 21 comparisons involving 15,095 patients and 27,050 controls for RA, and 1353 patients and 2342 controls for SLE were considered. Meta-analysis showed a significant association between the CD40 rs4810485 T allele and RA in all subjects (odds ratio (OR) 0.890, 95% confidence interval (CI) 0.846-0.936, p = 5.5 * 10(-7)). After stratification by ethnicity, the CD40 T allele was found to be significantly associated with RA in Europeans (OR 0.879, 95% CI 0.848-0.901, p = 3.0 * 10(-9)). A similar pattern of association was observed between the CD40 T allele and RA when the analysis was performed using the recessive, dominant, and additive models. Meta-analysis also showed a significant association between the CD40 polymorphism and SLE in Europeans (OR for the T allele 0.715, 95% CI 0.641 0.832, p = 1.4 * 10(-6)). CONCLUSIONS: Our meta-analyses confirm that the CD40 rs4810485 G/T polymorphism is associated with susceptibility to RA and SLE in Europeans. PMID- 25908481 TI - In situ PM-IRRAS of a glassy carbon electrode/deep eutectic solvent interface. AB - The interface of a 1 : 2 molar choline chloride/ethylene glycol deep eutectic solvent with a glassy carbon electrode has been investigated by polarization modulation reflection-absorption spectroscopy (PM-IRRAS). Temporal spectral changes at open circuit potential show the experiments to be surface sensitive and indicate slow adsorption of electrolyte molecules on the electrode surface. In situ spectroelectrochemical PM-IRRAS measurements reveal characteristic potential-dependent changes of band intensities and wavenumber-shifts in the surface spectra. The potential dependent spectral changes are discussed in terms of adsorption, reduction, desorption and reorientation of choline cations at the interface. Analogies are drawn to the ionic layer structure proposed for the architecture of electrode/ionic liquid interfaces. The results show that in situ PM-IRRAS is generally applicable to glassy carbon electrodes and to electrode interfaces with deep eutectic solvents. PMID- 25908482 TI - Reply to Farkouh RA et al. Comment on "Cost-Effectiveness Evaluation of the 10 Valent Pneumococcal Non-Typeable Haemophilus Influenzae Protein D Conjugate Vaccine and 13-Valent Pneumococcal Vaccine in Japanese Children". PMID- 25908483 TI - Comment on: "Cost-Effectiveness Evaluation of the 10-Valent Pneumococcal Non Typeable Haemophilus influenzae Protein D Conjugate Vaccine and 13-Valent Pneumococcal Vaccine in Japanese Children". PMID- 25908484 TI - Intramolecular Hydrogen Bonds Enhance Disparity in Reactivity between Isomers of Photoswitchable Sorbents and CO2 : A Computational Study. AB - Reducing the emission of greenhouse gases, such as CO2 , requires efficient and reusable capture materials. The energy for regenerating sorbents is critical to the cost of CO2 capture. Here, we design a series of photoswitchable CO2 capture molecules by grafting Lewis bases, which can covalently bond CO2 , to azo-based backbones that can switch configurations upon light stimulation. The first principles calculations demonstrate that intramolecular hydrogen bonds are crucial for enlarging the difference of CO2 binding strengths to the cis and trans isomers. As a result, the CO2 -sorbent interaction can be light-adjusted from strong chemical bonding in one configuration to weak bonding in the other, which may lead to a great energy reduction in sorbent regeneration. PMID- 25908485 TI - Bone Marrow and Adipose-Derived Mesenchymal Stem Cells Alleviate Methotrexate Induced Pulmonary Fibrosis in Rat: Comparison with Dexamethasone. AB - The present study examined the therapeutic effects of bone marrow mesenchymal stem cells (BM-MSCs) and adipose-derived mesenchymal stem cells (AD-MSCs) in methotrexate (MTX)-induced pulmonary fibrosis in rats as compared with dexamethasone (Dex). MTX (14 mg/kg, as a single dose/week for 2 weeks, p.o.) induced lung fibrosis as marked by elevation of relative lung weight, malondialdehyde, nitrite/nitrate, interleukin-4, transforming growth factor beta1, deposited collagen, as well as increased expression of Bax along with the reduction of reduced glutathione content and superoxide dismutase activity. These deleterious effects were antagonized after treatment either with BM-MSCs or AD MSCs (2 * 10(6) cells/rat) 2 weeks after MTX to even a better extent than Dex (0.5 mg/kg/ for 7 days, p.o.). In conclusion, BM-MSC and AD-MSCs possessed antioxidant, antiapoptotic, as well as antifibrotic effects, which will probably introduce them as remarkable candidates for the treatment of pulmonary fibrosis. PMID- 25908487 TI - Multimodal Approach to Monitoring and Investigating Cone Structure and Function in an Inherited Macular Dystrophy. AB - PURPOSE: To examine a female subject, her father, and a brother harboring a missense mutation of the retinitis pigmentosa 1-like 1 (RP1L1) gene, over 2 years of follow-up. DESIGN: Observational case series. METHODS: setting: Fondazione G.B. Bietti IRCCS, Rome, Italy. STUDY POPULATION: RP1L1 family members and controls. MAIN OUTCOME MEASURES: Images of the cone mosaic acquired with an adaptive optics retinal camera, spectral-domain optical coherence tomography (SD OCT), and full-field and multifocal electroretinography (mfERG). RESULTS: In the proband, best-corrected visual acuity (<=0.7 logMAR) was stable in both eyes during follow-up, though analysis of adaptive optics images showed decreased cone density in the central 9 degrees from the fovea with respect to controls (P < .05) and cone density loss in the parafoveal area (2 degrees; <12%-16%) during follow-up. Texture analysis of SD OCT images identified abnormalities of the ellipsoid zone in the central 7 degrees, while mfERG response amplitudes were reduced only in the central 5 degrees relative to controls. In the proband's father, who had 0.0 logMAR visual acuity, significant cone loss was found in the central 7 degrees from the fovea (P < .05); abnormal SD OCT and mfERG values with respect to controls were found in corresponding retinal areas. No defects in the cone structure and function were found in the proband's brother, who had 0.0 logMAR visual acuity. CONCLUSIONS: Occult macular dystrophy was diagnosed based on genetic and multimodal ophthalmic findings. The quantitative assessment of photoreceptor survival or loss, based on analysis of adaptive optics retinal images, was valuable to monitor disease progression at a cellular level. PMID- 25908486 TI - Pro-Permeability Factors After Dexamethasone Implant in Retinal Vein Occlusion; the Ozurdex for Retinal Vein Occlusion (ORVO) Study. AB - PURPOSE: To correlate aqueous vasoactive protein changes with macular edema after dexamethasone implant in retinal vein occlusion (RVO). DESIGN: Prospective, interventional case series. METHODS: Twenty-three central RVO (CRVO) and 17 branch RVO (BRVO) subjects with edema despite prior anti-vascular endothelial growth factor (VEGF) treatment had aqueous taps at baseline and 4 and 16 weeks after dexamethasone implant. Best-corrected visual acuity (BCVA) and center subfield thickness were measured every 4 weeks. Aqueous vasoactive protein levels were measured by protein array or enzyme-linked immunosorbent assay. RESULTS: Thirty-two vasoactive proteins were detected in aqueous in untreated eyes with macular edema due to RVO. Reduction in excess foveal thickness after dexamethasone implant correlated with reduction in persephin and pentraxin 3 (Pearson correlation coefficients = 0.682 and 0.638, P = .014 and P = .003). Other protein changes differed among RVO patients as edema decreased, but >=50% of patients showed reductions in hepatocyte growth factor, endocrine gland VEGF, insulin-like growth factor binding proteins, or endostatin by >=30%. Enzyme linked immunosorbent assay in 18 eyes (12 CRVO, 6 BRVO) showed baseline levels of hepatocyte growth factor and VEGF of 168.2 +/- 20.1 pg/mL and 78.7 +/- 10.0 pg/mL, and each was reduced in 12 eyes after dexamethasone implant. CONCLUSIONS: Dexamethasone implants reduce several pro-permeability proteins providing a multitargeted approach in RVO. No single protein in addition to VEGF can be implicated as a contributor in all patients. Candidates for contribution to chronic edema in subgroups of patients that deserve further study include persephin, hepatocyte growth factor, and endocrine gland VEGF. PMID- 25908488 TI - Microplastics in the Solent estuarine complex, UK: An initial assessment. AB - Microplastics are known to be an increasing component found within both marine sediments and the water column. This study carried out an initial assessment of the levels of microplastics present within the Solent estuarine complex, focusing specifically on the water column. A plankton net trawl survey was carried out, with samples analysed using visual observation and Fourier Transform Infrared Spectroscopy (FT-IR). The study identified significant quantities of plastics, ranging in shape, with hot spots found at confluence points within the estuary. Though the FT-IR analysis was inconclusive, the nature of the samples indicates the effect of oceanographic conditions on the prevalent types of microplastics found, which in turn identifies key local sources such as wastewater treatment plants and the plastics industry as being the dominant inputs. PMID- 25908489 TI - Clinical Practice of Steroid Avoidance in Pediatric Kidney Transplantation. AB - Steroid-avoidance protocols have recently gained popularity in pediatric kidney transplantation. We investigated the clinical practice of steroid avoidance among 9494 kidney transplant recipients at 124 transplant centers between 2000 and 2012 in the Organ Procurement and Transplantation Network database. The practice of steroid avoidance increased during the study period and demonstrated significant variability among transplant centers. From 2008 to 2012, 39% of transplant centers used steroid avoidance in <10% of all discharged transplant recipients. Twenty-one percent of transplant centers practiced steroid avoidance in 10-40% of transplant recipients, and 40% of transplant centers used steroid avoidance in >40% of discharged patients. Children receiving steroid avoidance more frequently received induction with lymphocyte-depleting agents. Repeat kidney transplants were the least likely to receive steroid avoidance. Children who received a deceased donor kidney, underwent pretransplant dialysis, were highly sensitized, or had glomerular kidney disease or delayed graft function were also less likely to receive steroid avoidance. The variation in practice between centers remained highly significant (p < 0.0001) after adjustment for all patient- and center level factors in multivariate analysis. We conclude that significant differences in the practice of steroid avoidance among transplant centers remain unexplained and may reflect uncertainty about the safety and efficacy of steroid-avoidance protocols. PMID- 25908490 TI - Prescribing Posttraumatic Growth. AB - This article introduces questions in psychiatric ethics regarding the substantial field of qualitative and quantitative research into 'posttraumatic growth', which investigates how, after devastating experiences, individuals can come to feel that they have developed warmer relationships, increased spirituality, or a clearer vision of their priorities. In one area of this research, researchers of posttraumatic growth outline strategies for clinicians interested in assisting their patients in achieving such growth. In this article, I articulate two ethical concerns about this account of posttraumatic growth and the practice of growth-oriented therapy. The first is a concern about the status and effects of the ideal of posttraumatic health implicit in their account, and the second a concern about the ethical implications of the clinical recommendations for the post-trauma patient. I argue for the need for more attention to the hazardous implications of relating to patients as though they are on their way to, and themselves largely in control of, their own posttraumatic growth. PMID- 25908491 TI - Stimulus rate increases lateralisation in linguistic and non-linguistic tasks measured by functional transcranial Doppler sonography. AB - Studies to date that have used fTCD to examine language lateralisation have predominantly used word or sentence generation tasks. Here we sought to further assess the sensitivity of fTCD to language lateralisation by using a metalinguistic task which does not involve novel speech generation: rhyme judgement in response to written words. Line array judgement was included as a non-linguistic visuospatial task to examine the relative strength of left and right hemisphere lateralisation within the same individuals when output requirements of the tasks are matched. These externally paced tasks allowed us to manipulate the number of stimuli presented to participants and thus assess the influence of pace on the strength of lateralisation. In Experiment 1, 28 right handed adults participated in rhyme and line array judgement tasks and showed reliable left and right lateralisation at the group level for each task, respectively. In Experiment 2 we increased the pace of the tasks, presenting more stimuli per trial. We measured laterality indices (LIs) from 18 participants who performed both linguistic and non-linguistic judgement tasks during the original 'slow' presentation rate (5 judgements per trial) and a fast presentation rate (10 judgements per trial). The increase in pace led to increased strength of lateralisation in both the rhyme and line conditions. Our results demonstrate for the first time that fTCD is sensitive to the left lateralised processes involved in metalinguistic judgements. Our data also suggest that changes in the strength of language lateralisation, as measured by fTCD, are not driven by articulatory demands alone. The current results suggest that at least one aspect of task difficulty, the pace of stimulus presentation, influences the strength of lateralisation during both linguistic and non-linguistic tasks. PMID- 25908492 TI - Alterations in Th17 and the Respective Cytokine Levels in Helicobacter pylori Induced Stomach Diseases. AB - BACKGROUND: Infections by Helicobacter can cause the stimulation of sophisticated immune response in mucosal immunity. Among the different lymphocytes, Th17 plays an important role in the defense against H. pylori and may cause gastritis and peptic ulcer due to the increased activation of Th17 and cytokine changes. AIM: To find a relationship between Th17 and IL-17A, IL-21, IL-22, IL-23, TGF-beta in the patients with H. pylori infection having signs including gastritis and peptic ulcer. METHODS: A total of 36 samples from the patients [24 Hp+ and 12 Hp- cases] with dyspepsia symptoms were collected. The percentage of Th17 was measured by flow cytometry. The levels of Th17-associated cytokines in the sera and supernatants of peripheral blood mononuclear cells (PBMCs) which were stimulated with the H. pylori antigen, phytohemagglutinin (PHA), or Dynabeads were measured by ELISA. RESULTS: Patients were divided into two groups of having either H. pylori infected (peptic ulcer, gastritis (mild, moderate)) or being uninfected. The percentage of Th17 in the patients with peptic ulcer and gastritis was significantly higher than their uninfected counterparts (p <= .001). The serum levels of IL-17A, IL-23, and TGF-beta in the peptic ulcer and gastritis groups were significantly higher compared with the corresponding levels in the uninfected population (p < .05). A significant association of TGF-beta, IL-21, and Th17 was observed with low levels of IL-17A in the mild gastritis patients (p < .05). Significantly higher levels of IL-22, IL-17A, IL-23, and higher Th17 frequencies were detected in the moderate gastritis patients, as compared with the uninfected patients (p <= .001). CONCLUSION: It can be concluded that among the cytokines associated with Th17, the two cytokines of IL-21 and TGF-beta play a more critical role in peptic ulcer and gastritis in the individuals infected with H. pylori. Furthermore, inflammation varies depending on the type of the cytokine and its secreted level. PMID- 25908493 TI - Rate and equilibrium constants for the addition of N-heterocyclic carbenes into benzaldehydes: a remarkable 2-substituent effect. AB - Rate and equilibrium constants for the reaction between N-aryl triazolium N heterocyclic carbene (NHC) precatalysts and substituted benzaldehyde derivatives to form 3-(hydroxybenzyl)azolium adducts under both catalytic and stoichiometric conditions have been measured. Kinetic analysis and reaction profile fitting of both the forward and reverse reactions, plus onwards reaction to the Breslow intermediate, demonstrate the remarkable effect of the benzaldehyde 2-substituent in these reactions and provide insight into the chemoselectivity of cross-benzoin reactions. PMID- 25908494 TI - Insomnia and health-related quality of life in stroke. AB - BACKGROUND: Insomnia is a common complaint in stroke survivors. Insomnia after stroke is correlated with physical disability, dementia, anxiety, depression, and fatigue. However, the influence of insomnia following stroke on health-related quality of life (HRQoL) has not been investigated. OBJECTIVES: The current study aimed to examine the effect of insomnia on HRQoL in stroke survivors 3 months after their index stroke over and above confounding variables. METHOD: Three hundred and thirty-six patients were recruited from the acute stroke unit in a regional hospital in Hong Kong. Insomnia was ascertained by a single item on a locally validated, seven-item insomnia questionnaire. HRQoL was measured by the total score and the 12 domain scores of the Stroke Specific Quality of Life (SSQoL) scale. Demographic and clinical characteristics were obtained using the following scales: National Institutes of Health Stroke Scale (NIHSS), Barthel Index (BI), Mini-Mental State Examination (MMSE), and Geriatric Depression Scale (GDS). RESULTS: Forty-four percent of stroke survivors reported experiencing insomnia in the past month; they were more likely to be female and to have a higher GDS score. The insomnia group had significantly lower overall SSQoL, energy and thinking scores after adjusting for sex, BI, and GDS scores. CONCLUSION: The findings show that stroke survivors who experienced insomnia had a reduced overall HRQoL and were impaired in the energy and thinking domains of HRQoL. Early screening for sleep disturbance would be beneficial to prevent later development of post-stroke insomnia. Pharmacological and non-pharmacological interventions are suggested to improve HRQoL in stroke patients with insomnia. PMID- 25908495 TI - Visible-Light-Promoted Vinylation of Tetrahydrofuran with Alkynes through Direct C-H Bond Functionalization. AB - Mild and direct C-H bond functionalizations and vinylations of tetrahydrofuran with alkynes have been accomplished through visible light photocatalysis, yielding a range of vinyl tetrahydrofurans under the synergistic actions of organic dye-type photocatalyst eosin Y, tert-butyl hydroperoxide (t-BuOOH), and a 45 W household lightbulb. A significant kinetic isotope effect (KIE) was recorded, which helps shed light on the mechanistic course. PMID- 25908496 TI - Neuronal Circuits for Fear Expression and Recovery: Recent Advances and Potential Therapeutic Strategies. AB - Recent technological developments, such as single unit recordings coupled to optogenetic approaches, have provided unprecedented knowledge about the precise neuronal circuits contributing to the expression and recovery of conditioned fear behavior. These data have provided an understanding of the contributions of distinct brain regions such as the amygdala, prefrontal cortex, hippocampus, and periaqueductal gray matter to the control of conditioned fear behavior. Notably, the precise manipulation and identification of specific cell types by optogenetic techniques have provided novel avenues to establish causal links between changes in neuronal activity that develop in dedicated neuronal structures and the short and long-lasting expression of conditioned fear memories. In this review, we provide an update on the key neuronal circuits and cell types mediating conditioned fear expression and recovery and how these new discoveries might refine therapeutic approaches for psychiatric conditions such as anxiety disorders and posttraumatic stress disorder. PMID- 25908497 TI - Oxytocin Conditions Intergroup Relations Through Upregulated In-Group Empathy, Cooperation, Conformity, and Defense. AB - Humans live in, rely on, and contribute to groups. Evolution may have biologically prepared them to quickly identify others as belonging to the in group (vs. not), to decode emotional states, and to empathize with in-group members; to learn and conform to group norms and cultural practices; to extend and reciprocate trust and cooperation; and to aggressively protect the in-group against outside threat. We review evidence that these components of human group psychology rest on and are modulated by the hypothalamic neuropeptide oxytocin. It appears that oxytocin motivates and enables humans to 1) like and empathize with others in their groups, 2) comply with group norms and cultural practices, and 3) extend and reciprocate trust and cooperation, which may give rise to intergroup discrimination and sometimes defensive aggression against threatening (members of) out-groups. We explore the possibility that deficiencies in (components of) group psychology, seen in autistic spectrum disorder, schizophrenia, and borderline personality and social anxiety disorders, may be reduced by oxytocin administration. Avenues for new research are highlighted, and implications for the role of oxytocin in cooperation and competition within and between groups are discussed. PMID- 25908498 TI - Re-imagining malaria: heterogeneity of human and mosquito behaviour in relation to residual malaria transmission in Cambodia. AB - BACKGROUND: In certain regions in Southeast Asia, where malaria is reduced to forested regions populated by ethnic minorities dependent on slash-and-burn agriculture, malaria vector populations have developed a propensity to feed early and outdoors, limiting the effectiveness of long-lasting insecticide-treated nets (LLIN) and indoor residual spraying (IRS). The interplay between heterogeneous human, as well as mosquito behaviour, radically challenges malaria control in such residual transmission contexts. This study examines human behavioural patterns in relation to the vector behaviour. METHODS: The anthropological research used a sequential mixed-methods study design in which quantitative survey research methods were used to complement findings from qualitative ethnographic research. The qualitative research existed of in-depth interviews and participant observation. For the entomological research, indoor and outdoor human landing collections were performed. All research was conducted in selected villages in Ratanakiri province, Cambodia. RESULTS: Variability in human behaviour resulted in variable exposure to outdoor and early biting vectors: (i) indigenous people were found to commute between farms in the forest, where malaria exposure is higher, and village homes; (ii) the indoor/outdoor biting distinction was less clear in forest housing often completely or partly open to the outside; (iii) reported sleeping times varied according to the context of economic activities, impacting on the proportion of infections that could be accounted for by early or nighttime biting; (iv) protection by LLINs may not be as high as self-reported survey data indicate, as observations showed around 40% (non-treated) market net use while (v) unprotected evening resting and deep forest activities impacted further on the suboptimal use of LLINs. CONCLUSIONS: The heterogeneity of human behaviour and the variation of vector densities and biting behaviours may lead to a considerable proportion of exposure occurring during times that people are assumed to be protected by the distributed LLINs. Additional efforts in improving LLIN use during times when people are resting in the evening and during the night might still have an impact on further reducing malaria transmission in Cambodia. PMID- 25908499 TI - Dementia informal caregiver obtaining and engaging in food-related information and support services. AB - As dementia progresses, caregivers increasingly have to manage the decline of food-related abilities with little outside information or input from support services The provision of food coping skills and knowledge can lessen the burden on caregivers. However, there is little research on caregivers' perspectives on food-related services. This paper reports on a qualitative study to investigate informal caregivers' experiences of, and views on, food-related information and support services in dementia. Twenty informal caregivers were interviewed and the transcripts from these interviews were analysed using both deductive and inductive thematic analysis. Four categories emerged. 'Direct food-related Information', covers written material, training, 'Direct food-related informal support': lunch clubs, 'Indirect non-food related formal support services' covers respite services and domestic help at home. Finally 'no services required' covers those who did not feel they needed any form of intervention due to confidence in managing food-related processes or having no change in dementia progression and food responsibility. Most caregivers will need different levels of information and support at different stages of dementia. It is necessary therefore to undertake ongoing individual assessment of food information and support needs. PMID- 25908500 TI - Presence redefined: The reciprocal nature of engagement between elder-clowns and persons with dementia. AB - Elder-clowns are a recent innovation in arts-based approaches to person-centred dementia care. They use improvisation, humour, and empathy, as well as song, dance, and music. We examined elder-clown practice and techniques through a 12 week programme with 23 long-term care residents with moderate to severe dementia in Ontario, Canada. Analysis was based on qualitative interviews and ethnographic observations of video-recorded clown-resident interactions and practice reflections. Findings highlight the reciprocal nature of clown-resident engagement and the capacity of residents to initiate as well as respond to verbal and embodied engagement. Termed relational presence, this was achieved and experienced through affective relationality, reciprocal playfulness, and coconstructed imagination. These results highlight the often overlooked capacity of individuals living with dementia to be deliberately funny, playful, and imaginative. Relational presence offers an important perspective with which to rethink care relationships between individuals living with dementia and long-term care staff. PMID- 25908501 TI - Effect of therapeutic massage on pain in patients with dementia. AB - Introduction The aim was to investigate whether therapeutic massage was effective in relieving pain in elderly residents with dementia. Methods A randomized controlled study was conducted in an aged care facility. Ten participants with dementia or advanced dementia were allocated to an intervention group or a control group. The intervention group received 10 min of massage (effleurage, kneading, and trigger point therapy) four times per week for 4 weeks. The Pain Assessment in Advanced Dementia scale was used as the outcome measure. Results No significant changes in mean outcome measure scores were found post intervention (Intervention mean = 5.0 +/- 3.49; Control mean = 5.2 +/- 3.49: t(8) = 0.09, p = 0.93). However, the Intervention Group had a greater magnitude of change (1.200 +/- 1.78) when compared to the control group (0.800 +/- 2.16). Conclusion Therapeutic massage may provide a useful adjunct to the current pain management plan of patients with dementia. PMID- 25908502 TI - Up-front systemic chemotherapy is a feasible option compared to primary tumor resection followed by chemotherapy for colorectal cancer with unresectable synchronous metastases. AB - BACKGROUND: In stage IV colorectal cancer (CRC) with unresectable metastases, whether or not resection of the primary tumor should be indicated remains controversial. We aim to determine the impact of primary tumor resection on the survival of stage IV CRC patients with unresectable metastases. METHODS: We retrospectively investigated 103 CRC patients with stage IV colorectal cancer with metastases, treated at Hiroshima University Hospital between 2007 and 2013. Of these, those who had resectable primary tumor but unresectable metastases and received any chemotherapy were included in the study. We analyzed the overall survival (OS) and short-term outcomes between the patients who received up-front systemic chemotherapy (USC group) and those who received primary tumor resection followed by chemotherapy (PTR group). RESULTS: Of the 57 included patients, 15 underwent USC and 42 PTR. The median survival times were 13.4 and 23.9 months in the USC and PTR groups, respectively (P = 0.093), but multivariate analysis for the overall survival showed no significant difference between the two groups (hazard ratio, 1.30; 95% confidence interval (CI), 0.60 to 2.73, P = 0.495). In the USC group, the disease control rate of primary tumor was observed in 12 patients (80.0%), but emergency laparotomy was required for 1 patient. Morbidity in the PTR group was observed in 18 cases (42.9%). CONCLUSIONS: The overall survival did not differ significantly between the USC and PTR groups. USC may help avoid unnecessary resection and consequently the high morbidity rate associated with primary tumor resection for stage IV CRC with unresectable metastases. PMID- 25908503 TI - Metabolic engineering of cyanobacteria for the synthesis of commodity products. AB - Through metabolic engineering cyanobacteria can be employed in biotechnology. Combining the capacity for oxygenic photosynthesis and carbon fixation with an engineered metabolic pathway allows carbon-based product formation from CO(2), light, and water directly. Such cyanobacterial 'cell factories' are constructed to produce biofuels, bioplastics, and commodity chemicals. Efforts of metabolic engineers and synthetic biologists allow the modification of the intermediary metabolism at various branching points, expanding the product range. The new biosynthesis routes 'tap' the metabolism ever more efficiently, particularly through the engineering of driving forces and utilization of cofactors generated during the light reactions of photosynthesis, resulting in higher product titers. High rates of carbon rechanneling ultimately allow an almost-complete allocation of fixed carbon to product above biomass. PMID- 25908504 TI - Selenium biomineralization for biotechnological applications. AB - Selenium (Se) is not only a strategic element in high-tech electronics and an essential trace element in living organisms, but also a potential toxin with low threshold concentrations. Environmental biotechnological applications using bacterial biomineralization have the potential not only to remove selenium from contaminated waters, but also to sequester it in a reusable form. Selenium biomineralization has been observed in phylogenetically diverse microorganisms isolated from pristine and contaminated environments, yet it is one of the most poorly understood biogeochemical processes. Microbial respiration of selenium is unique because the microbial cells are presented with both soluble (SeO(4)(2-) and SeO(3)(2-)) and insoluble (Se(0)) forms of selenium as terminal electron acceptor. Here, we highlight selenium biomineralization and the potential biotechnological uses for it in bioremediation and wastewater treatment. PMID- 25908505 TI - Modeling cancer processes with CRISPR-Cas9. AB - CRISPR-Cas9 is an RNA-guided site-specific DNA editing tool which, together with its reprogrammed versions such as nickase Cas9 and dead Cas9, enables quick modeling of desired combinations of cancer-associated genomic and/or epigenetic aberrations simultaneously or sequentially, thus facilitating massive functional interrogations and therapy testing. PMID- 25908506 TI - Effect of Vitamin D3 Supplementation in Combination with Weight Loss on Inflammatory Biomarkers in Postmenopausal Women: A Randomized Controlled Trial. AB - Obesity and vitamin D deficiency are associated with risk for several cancers, possibly through inflammation and adipokine-related pathways. Two hundred and eighteen postmenopausal women with BMI > 25 kg/m(2) and low serum 25 hydroxyvitamin D (25(OH)D; >=10-<32 ng/mL), were randomized to 12 months of either (i) weight-loss intervention + 2000 IU/day oral vitamin D3 or (ii) weight loss intervention + daily placebo. Serum adiponectin, leptin, TNFalpha, IL6, IL1beta, IL8, and IL10, were measured by immunoassay, and a composite inflammatory biomarker score calculated. Using generalized estimating equations, mean changes in outcomes were compared between arms (intent-to-treat), adjusted for possible confounders. Analyses were also stratified by weight-loss (gained/no weight-loss; <5%; 5% to 10%; >=10%). At 12 months, there were no significant differences in analyte changes between arms. In stratified analyses, participants randomized to vitamin D3 who lost 5% to 10% of baseline weight, versus participants who gained weight/had no weight-loss, had significantly greater decreases in levels of IL6 compared with those randomized to placebo: absolute change -0.75 pg/mL (-17.2%), placebo versus -1.77 pg/mL (-37.3%), vitamin D, P = 0.004. Similar but attenuated results were observed for participants who lost >=10% of baseline weight: -0.41 pg/mL (-13.6%), placebo versus -0.67 pg/mL ( 17.3%), vitamin D, P = 0.02. Effects of vitamin D3 supplementation on levels of IL1beta were inconsistent when stratified by weight loss. There were no intervention effects on IL10, TNFalpha, IL8, the composite score, adiponectin, or leptin, when stratified by weight-loss. In conclusion, vitamin D3 supplementation in combination with weight-loss of at least 5% of baseline weight was associated with significant reductions in levels of IL6. PMID- 25908507 TI - Genetic Manipulation of Homologous Recombination In Vivo Attenuates Intestinal Tumorigenesis. AB - Although disruption of DNA repair capacity is unquestionably associated with cancer susceptibility in humans and model organisms, it remains unclear if the inherent tumor phenotypes of DNA repair deficiency syndromes can be regulated by manipulating DNA repair pathways. Loss-of-function mutations in BLM, a member of the RecQ helicase family, cause Bloom's syndrome (BS), a rare, recessive genetic disorder that predisposes to many types of cancer. BLM functions in many aspects of DNA homeostasis, including the suppression of homologous recombination (HR) in somatic cells. We investigated whether BLM overexpression, in contrast with loss of-function mutations, attenuated the intestinal tumor phenotypes of Apc(Min/+) and Apc(Min/+);Msh2(-/-) mice, animal models of familial adenomatous polyposis coli (FAP). We constructed a transgenic mouse line expressing human BLM (BLM-Tg) and crossed it onto both backgrounds. BLM-Tg decreased adenoma incidence in a dose-dependent manner in our Apc(Min/) (+) model of FAP, although levels of GIN were unaffected and concomitantly increased animal survival over 50%. It did not reduce intestinal tumorigenesis in Apc(Min/) (+);Msh2(-/-) mice. We used the pink eyed unstable (p(un)) mouse model to demonstrate that increasing BLM dosage in vivo lowered endogenous levels of HR by 2-fold. Our data suggest that attenuation of the Min phenotype is achieved through a direct effect of BLM-Tg on the HR repair pathway. These findings demonstrate that HR can be manipulated in vivo to modulate tumor formation at the organismal level. Our data suggest that lowering HR frequencies may have positive therapeutic outcomes in the context of specific hereditary cancer predisposition syndromes, exemplified by FAP. PMID- 25908508 TI - Effect of Metformin, Rapamycin, and Their Combination on Growth and Progression of Prostate Tumors in HiMyc Mice. AB - In this study, we compared the effect of oral administration of metformin (MET) and rapamycin (RAPA) alone or in combination on prostate cancer development and progression in HiMyc mice. MET (250 mg/kg body weight in the drinking water), RAPA (2.24 mg/kg body weight microencapsulated in the diet), and the combination inhibited progression of prostatic intraepithelial neoplasia lesions to adenocarcinomas in the ventral prostate (VP). RAPA and the combination were more effective than MET at the doses used. Inhibition of prostate cancer progression in HiMyc mice by RAPA was associated with a significant reduction in mTORC1 signaling that was further potentiated by the combination of MET and RAPA. In contrast, treatment with MET alone enhanced AMPK activation, but had little or no effect on mTORC1 signaling pathways in the VP of HiMyc mice. Further analyses revealed a significant effect of all treatments on prostate tissue inflammation as assessed by analysis of the expression of cytokines, the presence of inflammatory cells and NFkappaB signaling. MET at the dose used appeared to reduce prostate cancer progression primarily by reducing tissue inflammation whereas RAPA and the combination appeared to inhibit prostate cancer progression in this mouse model via the combined effects on both mTORC1 signaling as well as on tissue inflammation. Overall, these data support the hypothesis that blocking mTORC1 signaling and/or tissue inflammation can effectively inhibit prostate cancer progression in a relevant mouse model of human prostate cancer. Furthermore, combinatorial approaches that target both pathways may be highly effective for prevention of prostate cancer progression in men. PMID- 25908509 TI - Chronic lymphocytic leukemia: 2015 Update on diagnosis, risk stratification, and treatment. AB - DISEASE OVERVIEW: Chronic lymphocytic leukemia (CLL) is the commonest leukemia in western countries. The disease typically occurs in elderly patients and has a highly variable clinical course. Leukemic transformation is initiated by specific genomic alterations that impair apoptosis of clonal B-cells. DIAGNOSIS: The diagnosis is established by blood counts, blood smears, and immunophenotyping of circulating B-lymphocytes, which identify a clonal B-cell population carrying the CD5 antigen as well as B-cell markers. PROGNOSIS: Two prognostic staging systems exist, the Rai and Binet staging systems, which are established by physical examination and blood counts. Various biological and genetic markers also have prognostic value. Deletions of the short arm of chromosome 17 (del(17p)) predict resistance to available chemotherapies. Comprehensive prognostic scores are currently being developed. THERAPY: Patients with active or symptomatic disease or with advanced Binet or Rai stages require therapy. For physical fit patients, chemoimmunotherapy with fludarabine, cyclophosphamide, and rituximab remains the current standard therapy. For unfit patients, treatment with an anti-CD20 antibody (obinutuzumab or rituximab or ofatumumab) plus a milder chemotherapy (Chlorambucil) may be applied. At relapse, the initial treatment may be repeated, if the treatment-free interval exceeds two to three years. If the disease relapses earlier, therapy should be changed using alternative agents such as bendamustine (plus rituximab), alemtuzumab, lenalidomide, ofatumumab, ibrutinib, or idelalisib. Patients with a del(17p) or TP53 mutation can be treated with ibrutinib or a combination of idelalisib and rituximab. An allogeneic SCT may be considered in relapsing patients with TP53 mutations or del(17p) or patients that are refractory to repeated chemoimmunotherapies. Future challenges: Several new agents (e.g., ibrutinib, idelalisib, obinutuzumab) hold the potential to improve the outcome of patients with CLL. However, their optimal use (in terms of combination, sequence, and duration) is unknown. Therefore, CLL patients should be treated in clinical trials whenever possible. PMID- 25908510 TI - Improving the power of long term rodent carcinogenicity bioassays by adjusting the experimental design. AB - Since long term rodent carcinogenicity studies are used to test a very large number of potential tumor endpoints, finding a balance between the control of Type 1 and Type 2 error is challenging. As a result, these studies can suffer from very low power to detect effects of regulatory significance. In the present paper, a new design is proposed in order address this problem. This design is a simple modification of the existing standard designs and uses the same number of animals. Where it differs from the currently used designs is that it uses just three treatment groups rather than four, with the animals concentrated in the control and high dose groups, rather than being equally distributed among the groups. This new design is tested, in a pair of simulation studies over a range of scenarios, against two currently used designs, and against a maximally powerful two group design. It consistently performs at levels close to the optimal design, and except in the case of relatively modest effects and very rare tumors, is found to increase power by 10%-20% over the current designs while maintaining or reducing the Type 1 error rate. PMID- 25908511 TI - Consumer exposure modelling under REACH: Assessing the defaults. AB - Consumer exposure to chemicals from products and articles is rarely monitored. Since an assessment of consumer exposure has become particularly important under the European REACH Regulation, dedicated modelling approaches with exposure assessment tools are applied. The results of these tools are critically dependent on the default input values embedded in the tools. These inputs were therefore compiled for three lower tier tools (ECETOC TRA (version 3.0), EGRET and REACT)) and benchmarked against a higher tier tool (ConsExpo (version 4.1)). Mostly, conservative input values are used in the lower tier tools. Some cases were identified where the lower tier tools used less conservative values than ConsExpo. However, these deviations only rarely resulted in less conservative exposure estimates compared to ConsExpo, when tested in reference scenarios. This finding is mainly due to the conservatism of (a) the default value for the thickness of the product layer (with complete release of the substance) used for the prediction of dermal exposure and (b) the complete release assumed for volatile substances (i.e. substances with a vapour pressure ?10Pa) for inhalation exposure estimates. The examples demonstrate that care must be taken when changing critical defaults in order to retain conservative estimates of consumer exposure to chemicals. PMID- 25908512 TI - Development of a risk management tool for prioritizing chemical hazard-food pairs and demonstration for selected mycotoxins. AB - We developed a simple tool for ranking chemical hazard-food pairs to assist policy makers and risk managers selecting the hazard-food pairs that deserve more attention and need to be monitored during food safety inspections. The tool is based on the derivation of a "Priority Index" (PI) that results from the ratio of the potency of the hazard and the consumer exposure. The potency corresponds to a toxicity reference value of the hazard, whereas the exposure results from the combination of the concentration of the hazard in the food, and the food consumption. Tool's assumptions and limitations are demonstrated and discussed by ranking a dataset of 13 mycotoxins in 26 food items routinely analyzed in Switzerland. The presented ranking of mycotoxin-food pairs has to be considered as relative due to scarce exposure data availability, and uncertainties in toxicity reference values. However, this representative example allows demonstrating the simplicity and the ability of the PI tool to prioritize chemical hazard-food pairs. PMID- 25908513 TI - The making of eusociality: insights from two bumblebee genomes. AB - The genomes of two bumblebee species characterized by a lower level of sociality than ants and honeybees provide new insights into the origin and evolution of insect societies. PMID- 25908514 TI - Identification of lead compounds for (99m)Tc and (18)F GPR91 radiotracers. AB - To develop the first radiotracer targeting GPR91, a cell membrane-bound receptor that modulates the cellular response to hyperglycemia and hypoxia, we designed and prepared a small series of compounds based on a published series of 1,8 naphthyridines with high affinity to GPR91. Our approach provides a mechanism to incorporate radioactive atoms ((99m)Tc and (18)F) into the GPR91 pharmacophore as the final synthetic step. Pharmacological assays confirmed lead compounds for (99m)Tc and (18)F GPR91 radiotracers within the series. PMID- 25908515 TI - Synthesis and anti-mycobacterial activity of 2-chloronicotinaldehydes based novel 1H-1,2,3-triazolylbenzohydrazides. AB - 1H-1,2,3-Triazolylbenzohydrazides (6a-h and 11a-l) were synthesized from 2 chloronicotinaldehydes and evaluated for anti-mycobacterial activity against Mycobacterium tuberculosis H37Rv strain (ATCC-27294). Seven compounds 6b, 6e,f, 11d, 11h, 11j and 11l displayed potent anti-mycobacterial activity (MIC 2.8-6.2 MUM). Potent anti-mycobacterial compounds were chosen for cytotoxicity studies by MTT protein assay against normal cell lines (PBMC and Raw 264.7) and shown low cytotoxicity. This is the first Letter assigning anti-mycobacterial activity, cytotoxicity and structure activity relationship for 1H-1,2,3 triazolylbenzohydrazides. PMID- 25908516 TI - Design, synthesis and biological evaluation of deuterated Tivozanib for improving pharmacokinetic properties. AB - Tivozanib is a potent and selective tyrosine kinase inhibitor of vascular endothelial growth factor receptor-1(VEGFR1), -2(VEGFR2), and -3(VEGFR3). Analog of Tivozanib with deuterium-for-hydrogen replacement in metabolically active site was prepared and evaluated in vitro. Compared to its prototype, deuterated Tivozanib compound HC-1144 retained in vitro activity against VEGFR tyrosine kinases. In vivo pharmacokinetic studies indicated HC-1144 clearly altered the blood circulation behavior, which was proved by significantly prolonged blood circulation half life time (t1/2) and increased AUC0-infinity. Therefore, HC-1144 has the potential to be a novel inhibitor against VEGFR tyrosine kinases with long-acting plasma exposure. PMID- 25908517 TI - Discovery of novel indirubin-3'-monoxime derivatives as potent inhibitors against CDK2 and CDK9. AB - Indirubin-3'-monoxime (IM) is a potent cyclin-dependent kinase (CDK) inhibitor. Twenty novel IM derivatives were prepared to investigate the structure-activity relationships (SAR) of this compound class. Six compounds showed significant inhibition against both CDK2/cyclin E1 and CDK9/cyclin T1. The most potent compound 7t exhibited IC50 values at submicromolar level. Preliminary SAR trends were suggested and cytotoxicity of these compounds was investigated. Molecular docking studies on compounds 7l and 7t provided conducive clues for further structural optimization. PMID- 25908518 TI - Using gold aggregation to probe the inhibition and destruction of the G quadruplex structure by TT-dimerization. AB - Thrombin binding G-quadruplex oligonucleotide containing two TT-dimer fragments and a gold attachment (ODN G1-G) was designed and synthesized with the aim of understanding the TT-dimer effect in G-quadruplex formation. Our results showed that TT-dimer mutation induced by UV light inhibits the formation of and even destroys the G-quadruplex structure, as confirmed by UV, CD and melting temperature measurements. The structural change resulting from TT-dimer formation with DNA was additionally probed and was found to be accompanied by significant gold aggregation that was observed in the form of a signal change from red to blue. PMID- 25908519 TI - Intensive symptom control of opioid-refractory dyspnea in congestive heart failure: Role of milrinone in the palliative care unit. AB - OBJECTIVE: We describe an exemplary case of congestive heart failure (CHF) symptoms controlled with milrinone. We also analyze the benefits and risks of milrinone administration in an unmonitored setting. METHOD: We describe the case of a patient with refractory leukemia and end-stage CHF who developed severe dyspnea after discontinuation of milrinone. At that point, despite starting opioids, she had been severely dyspneic and anxious, requiring admission to the palliative care unit (PCU) for symptom control. After negotiation with hospital administrators, milrinone was administered in an unmonitored setting such as the PCU. A multidisciplinary team approach was also provided. RESULTS: Milrinone produced a dramatic improvement in the patient's symptom scores and performance status. The patient was eventually discharged to home hospice on a milrinone infusion with excellent symptom control. SIGNIFICANCE OF RESULTS: This case suggests that milrinone may be of benefit for short-term inpatient administration for dyspnea management, even in unmonitored settings and consequently during hospice in do-not-resuscitate (DNR) patients. This strategy may reduce costs and readmissions to the hospital related to end-stage CHF. PMID- 25908520 TI - [The testicular microtubule-associated protein Tau: Where, when during spermatogenesis?]. AB - The Tau protein (Tubulin Associated Unit) is a phosphoprotein of the microtubule associated protein family (MAPs). Its role is the regulation of the microtubule polymerization. The Tau protein is naturally present in brain, heart, muscle, lung, kidney, pancreas and liver. An expression of Tau protein and RNA messengers was also highlighted in the testis that is an organ rich in microtubules. The role of microtubules is essential in the stabilization of the cellular shape and in cell divisions. In the testis, Tau protein could be involved in the division process of the spermatogenesis by acting on the microtubular dynamics in the arrangement of the spermatozoon polarity. This review synthesizes the current knowledge, the localization and the main functions of the Tau protein focused on the testis. The localization and the potential roles of the Tau protein during the spermatogenesis are discussed by emphasizing the link with the microtubular structures of seminiferous tubules. PMID- 25908521 TI - Development and validation of receptor occupancy pharmacodynamic assays used in the clinical development of the monoclonal antibody vedolizumab. AB - BACKGROUND: Vedolizumab is a monoclonal antibody approved for use in ulcerative colitis and Crohn's disease. By specifically binding to alpha4 beta7 integrin, vedolizumab prevents trafficking of lymphocytes to the gut, thereby interfering with disease pathology. During the clinical development program, the pharmacodynamic effect of vedolizumab was evaluated by 2 flow cytometry receptor occupancy assays: act-1 (ACT-1) and mucosal addressin cell adhesion molecule-1 (MAdCAM-1). Here we describe the development and validation of these assays. METHODS: The ACT-1 assay is a receptor occupancy free-site assay that uses a monoclonal antibody with the same binding epitope as vedolizumab to detect free (unbound) sites on alpha4 beta7 integrin. The MAdCAM-1 assay used a soluble version of the natural ligand for alpha4 beta7 integrin to detect free sites. The assays were validated using a fit-for-purpose approach throughout the clinical development of vedolizumab. RESULTS: Both the ACT-1 assay and the MAdCAM-1 assay demonstrated acceptable reproducibility and repeatability. The assays were sufficiently stable to allow for clinical use. During clinical testing the assays demonstrated that vedolizumab was able to saturate peripheral cells at all doses tested. CONCLUSIONS: Two pharmacodynamic receptor occupancy assays were developed and validated to assess the effect of vedolizumab on peripheral blood cells. The results of these assays demonstrated the practical use of flow cytometry to examine pharmacodynamic response in clinical trials. PMID- 25908523 TI - Promoting Health and Wellness: Implications for Physical Therapist Practice. AB - The leading cause of morbidity and mortality in the United States is chronic, or noncommunicable, diseases. The impact of chronic diseases on health and wellness can be significantly altered by individual health and behavior choices or modifications. Furthermore, the burden of chronic disease goes beyond health and the health care system and may influence an individual's wellness. The purposes of this article are: (1) to provide a basis for understanding the terms "health" and "wellness," (2) to identify the knowledge and skills physical therapists need to address behaviors that promote health and wellness and treat and protect against chronic disease, and (3) to discuss barriers and opportunities associated with integrating the promotion of health and wellness into physical therapist practice. PMID- 25908522 TI - Assessing the Psychometric Properties of an Activity Pacing Questionnaire for Chronic Pain and Fatigue. AB - BACKGROUND: Therapists frequently advise the use of activity pacing as a coping strategy to manage long-term conditions (eg, chronic low back pain, chronic widespread pain, chronic fatigue syndrome/myalgic encephalomyelitis). However, activity pacing has not been clearly operationalized, and there is a paucity of empirical evidence regarding pacing. This paucity of evidence may be partly due to the absence of a widely used pacing scale. To address the limitations of existing pacing scales, the 38-item Activity Pacing Questionnaire (APQ-38) was previously developed using the Delphi technique. OBJECTIVE: The aims of this study were: (1) to explore the psychometric properties of the APQ-38, (2) to identify underlying pacing themes, and (3) to assess the reliability and validity of the scale. DESIGN: This was a cross-sectional questionnaire study. METHODS: Three hundred eleven adult patients with chronic pain or fatigue participated, of whom 69 completed the test-retest analysis. Data obtained for the APQ-38 were analyzed using exploratory factor analysis, internal and test-retest reliability, and validity against 2 existing pacing subscales and validated measures of pain, fatigue, anxiety, depression, avoidance, and mental and physical function. RESULTS: Following factor analysis, 12 items were removed from the APQ-38, and 5 themes of pacing were identified in the resulting 26-item Activity Pacing Questionnaire (APQ-26): activity adjustment, activity consistency, activity progression, activity planning, and activity acceptance. These themes demonstrated satisfactory internal consistency (Cronbach alpha=.72-.92), test retest reliability (intraclass correlation coefficient=.50-.78, P<=.001), and construct validity. Activity adjustment, activity progression, and activity acceptance correlated with worsened symptoms; activity consistency correlated with improved symptoms; and activity planning correlated with both improved and worsened symptoms. LIMITATIONS: Data were collected from self-report questionnaires only. CONCLUSIONS: Developed to be widely used across a heterogeneous group of patients with chronic pain or fatigue, the APQ-26 is multifaceted and demonstrates reliability and validity. Further study will explore the effects of pacing on patients' symptoms to guide therapists toward advising pacing themes with empirical benefits. PMID- 25908524 TI - Risk Adjustment for Lumbar Dysfunction: Comparison of Linear Mixed Models With and Without Inclusion of Between-Clinic Variation as a Random Effect. AB - BACKGROUND: Valid comparison of patient outcomes of physical therapy care requires risk adjustment for patient characteristics using statistical models. Because patients are clustered within clinics, results of risk adjustment models are likely to be biased by random, unobserved between-clinic differences. Such bias could lead to inaccurate prediction and interpretation of outcomes. PURPOSE: The purpose of this study was to determine if including between-clinic variation as a random effect would improve the performance of a risk adjustment model for patient outcomes following physical therapy for low back dysfunction. DESIGN: This was a secondary analysis of data from a longitudinal cohort of 147,623 patients with lumbar dysfunction receiving physical therapy in 1,470 clinics in 48 states of the United States. METHODS: Three linear mixed models predicting patients' functional status (FS) at discharge, controlling for FS at intake, age, sex, number of comorbidities, surgical history, and health care payer, were developed. Models were: (1) a fixed-effect model, (2) a random-intercept model that allowed clinics to have different intercepts, and (3) a random-slope model that allowed different intercepts and slopes for each clinic. Goodness of fit, residual error, and coefficient estimates were compared across the models. RESULTS: The random-effect model fit the data better and explained an additional 11% to 12% of the between-patient differences compared with the fixed-effect model. Effects of payer, acuity, and number of comorbidities were confounded by random clinic effects. LIMITATIONS: Models may not have included some variables associated with FS at discharge. The clinics studied may not be representative of all US physical therapy clinics. CONCLUSIONS: Risk adjustment models for functional outcome of patients with lumbar dysfunction that control for between clinic variation performed better than a model that does not. PMID- 25908525 TI - Therapist-Designed Adaptive Riding in Children With Cerebral Palsy: Results of a Feasibility Study. AB - BACKGROUND: It is debatable whether adaptive riding (AR) in children with cerebral palsy (CP) improves postural control and gross motor development. OBJECTIVE: The study aim was to explore the feasibility of an extensive assessment protocol for a randomized controlled trial of therapist-designed adaptive riding (TDAR) in children with CP, with the goals of assessing the effect on child outcomes and evaluating working mechanisms of sitting postural control. DESIGN: A pretest-posttest group design with 2 baseline measurements was used. METHODS: Six children (1 girl, 5 boys; age range=6-12 years, median age=8 years 9 months) with bilateral spastic CP (Gross Motor Function Classification System level III) participated. Outcomes were evaluated 3 times (T0, T1, and T2) at 6-week intervals. T0 and T1 were baseline measurements; between T1 and T2, a TDAR intervention including an integrated program of postural challenge exercises (2 times per week for 1 hour) was applied. The complex protocol included the 88 item Gross Motor Function Measure (GMFM-88) and electromyographic (EMG) recording of postural muscle activity during reaching while sitting (EMG recording at T1 and T2 only). RESULTS: The protocol was feasible. Median GMFM-88 scores changed from 64.4 at T0 to 66.7 at T1 and from 66.7 at T1 to 73.2 at T2. The change scores for all children exceeded the minimal clinically important difference of the GMFM-88. Five of 6 children showed a decrease in stereotyped top-down recruitment between T1 and T2. LIMITATIONS: Study limitations included the lack of a control group, small sample size, and potential assessor bias for all but the EMG parameters. CONCLUSIONS: The feasibility of the complex protocol was established. The data suggested that a 6-week TDAR intervention may improve gross motor function and may reduce stereotyped postural adjustments in children with CP. The limited results warrant replication in a well-powered randomized controlled trial. PMID- 25908527 TI - A comparative MRI study of cartilage damage in gout versus rheumatoid arthritis. AB - INTRODUCTION: Magnetic resonance imaging (MRI) is useful for detecting joint inflammation and damage in the inflammatory arthropathies. This study aimed to investigate MRI cartilage damage and its associations with joint inflammation in patients with gout compared with a group with rheumatoid arthritis (RA). METHODS: Forty patients with gout and 38 with seropositive RA underwent 3T-MRI of the wrist with assessment of cartilage damage at six carpal sites, using established scoring systems. Synovitis and bone oedema (BME) were graded according to Rheumatoid Arthritis MRI Scoring System criteria. Cartilage damage was compared between the groups adjusting for synovitis and disease duration using logistic regression analysis. RESULTS: Compared with RA, there were fewer sites of cartilage damage and lower total damage scores in the gout group (P = 0.02 and 0.003), adjusting for their longer disease duration and lesser degree of synovitis. Cartilage damage was strongly associated with synovitis in both conditions (R = 0.59, P < 0.0001 and R = 0.52, P = 0.0045 respectively) and highly correlated with BME in RA (R = 0.69, P < 0.0001) but not in gout (R = 0.095, P = 0.56). CONCLUSIONS: Cartilage damage is less severe in gout than in RA, with fewer sites affected and lower overall scores. It is associated with synovitis in both diseases, likely indicating an effect of pro-inflammatory cytokine production on cartilage integrity. However, the strong association between cartilage damage and BME observed in RA was not identified in gout. This emphasizes differences in the underlying pathophysiology of joint damage in these two conditions. PMID- 25908526 TI - Rethinking Hospital-Associated Deconditioning: Proposed Paradigm Shift. AB - Physical therapists often treat older adults with marked deficits in physical function secondary to an acute hospitalization. These deficits are often collectively defined as hospital-associated deconditioning (HAD). However, there is a paucity of evidence that objectively demonstrates the efficacy of physical therapy for older adults with HAD. Older adults with HAD represent a highly variable and complex population and thus may be difficult to study and develop effective interventions for using our current rehabilitation strategies. This perspective article outlines an innovative framework to operationalize and treat older adults with HAD. This framework may help therapists apply emerging exercise strategies to this population and facilitate additional research to support the total value of physical therapy for older adults in postacute care settings-with value measured not only by improvements in physical performance but perhaps also by reduced rates of disability development, rehospitalization, and institutionalization. PMID- 25908528 TI - Dyslexia and voxel-based morphometry: correlations between five behavioural measures of dyslexia and gray and white matter volumes. AB - In voxel-based morphometry studies of dyslexia, the relation between causal theories of dyslexia and gray matter (GM) and white matter (WM) volume alterations is still under debate. Some alterations are consistently reported, but others failed to reach significance. We investigated GM alterations in a large sample of Dutch students (37 dyslexics and 57 non-dyslexics) with two analyses: group differences in local GM and total GM and WM volume and correlations between GM and WM volumes and five behavioural measures. We found no significant group differences after corrections for multiple comparisons although total WM volume was lower in the group of dyslexics when age was partialled out. We presented an overview of uncorrected clusters of voxels (p < 0.05, cluster size k > 200) with reduced or increased GM volume. We found four significant correlations between factors of dyslexia representing various behavioural measures and the clusters found in the first analysis. In the whole sample, a factor related to performances in spelling correlated negatively with GM volume in the left posterior cerebellum. Within the group of dyslexics, a factor related to performances in Dutch-English rhyme words correlated positively with GM volume in the left and right caudate nucleus and negatively with increased total WM volume. Most of our findings were in accordance with previous reports. A relatively new finding was the involvement of the caudate nucleus. We confirmed the multiple cognitive nature of dyslexia and suggested that experience greatly influences anatomical alterations depending on various subtypes of dyslexia, especially in a student sample. PMID- 25908530 TI - The Role of Modulators in Controlling Layer Spacings in a Tritopic Linker Based Zirconium 2D Microporous Coordination Polymer. AB - A 2D zirconium-based microporous coordination polymer derived from the tritopic linker 1,3,5-(4-carboxylphenyl)benzene, UMCM-309a, has been synthesized. This noninterpenetrated material possesses a Zr6(MU3-O)4(MU3-OH)4(RCO2)6(OH)6(H2O)6 cluster with six hexagonal-planar-coordinated linkers. UMCM-309a is stable in an aqueous HCl solution for over 4 months. The use of different monocarboxylates as modulators leads to similar 2D structures with different layer spacings; moreover, removal of the modulator yields the parent UMCM-309a. PMID- 25908529 TI - Predictors of posttraumatic stress and appetitive aggression in active soldiers and former combatants. AB - BACKGROUND: During the period between 1993 and 2005, the people of Burundi were trapped within a violent civil war. In post-conflict regions, symptoms of posttraumatic stress disorder (PTSD) were found to be widespread. At the same time, combatants often reported having perceived committing violence as exciting and appealing, an experience referred to as appetitive aggression. Both of these phenomena hamper the building of a functional and peaceful society. OBJECTIVE: This study aims to investigate the factors that are associated with the level of PTSD and appetitive aggression in former and still active combatants. METHODS: Semi-structured interviews were conducted with 948 male Burundians: 556 active soldiers and 392 ex-combatants. PTSD symptom severity was assessed using the PTSD Symptom Scale Interview, while appetitive aggression was assessed using the Appetitive Aggression Scale. RESULTS: Linear regression analyses revealed that the number of traumatic events, childhood maltreatment, and their interaction predicted PTSD symptom severity, whereas self-committed violence did not. The number of traumatic events and self-committed violence were associated with appetitive aggression. Childhood maltreatment alone was not associated with appetitive aggression; however, its interaction with self-committed violence did predict appetitive aggression. When controlling for predictors, ex-combatants reported a higher degree of PTSD symptomatology, whereas active soldiers reported a higher degree of appetitive aggression. CONCLUSION: We conclude that childhood maltreatment is an additional, significant risk factor that exacerbates the psychological consequences of violent conflicts. Self-committed violence may not necessarily engender trauma-related disorders, but is highly related to appetitive aggression. PMID- 25908531 TI - Chromatin mechanisms in the developmental control of imprinted gene expression. AB - Hundreds of protein-coding genes and regulatory non-coding RNAs (ncRNAs) are subject to genomic imprinting. The mono-allelic DNA methylation marks that control imprinted gene expression are somatically maintained throughout development, and this process is linked to specific chromatin features. Yet, at many imprinted genes, the mono-allelic expression is lineage or tissue-specific. Recent studies provide mechanistic insights into the developmentally-restricted action of the 'imprinting control regions' (ICRs). At several imprinted domains, the ICR expresses a long ncRNA that mediates chromatin repression in cis (and probably in trans as well). ICRs at other imprinted domains mediate higher-order chromatin structuration that enhances, or prevents, transcription of close-by genes. Here, we present how chromatin and ncRNAs contribute to developmental control of imprinted gene expression and discuss implications for disease. This article is part of a Directed Issue entitled: Epigenetics dynamics in development and disease. PMID- 25908532 TI - A randomized controlled trial of the effects of n-3 fatty acids on resolvins in chronic kidney disease. AB - BACKGROUND AND OBJECTIVE: The high incidence of cardiovascular disease (CVD) in chronic kidney disease (CKD) is related partially to chronic inflammation. n-3 Fatty acids have been shown to have anti-inflammatory effects and to reduce the risk of CVD. Specialized Proresolving Lipid Mediators (SPMs) derived from the n-3 fatty acids, eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) actively promote the resolution of inflammation. This study evaluates the effects of n-3 fatty acid supplementation on plasma SPMs in patients with CKD. METHODS: In a double-blind, placebo-controlled intervention of factorial design, 85 patients were randomized to either n-3 fatty acids (4 g), Coenzyme Q10 (CoQ) (200 mg), both supplements, or control (4 g olive oil), daily for 8 weeks. The SPMs 18 HEPE, 17-HDHA, RvD1, 17R-RvD1, and RvD2, were measured in plasma by liquid chromatography-tandem mass spectrometry before and after intervention. RESULTS: Seventy four patients completed the 8 weeks intervention. n-3 Fatty acids but not CoQ significantly increased (P < 0.0001) plasma levels of 18-HEPE and 17-HDHA, the upstream precursors to the E- and D-series resolvins, respectively. RvD1 was significantly increased (P = 0.036) after n-3 fatty acids, but no change was seen in other SPMs. In regression analysis the increase in 18-HEPE and 17-HDHA after n 3 fatty acids was significantly predicted by the change in platelet EPA and DHA, respectively. CONCLUSION: SPMs are increased after 8 weeks n-3 fatty acid supplementation in patients with CKD. This may have important implications for limiting ongoing low grade inflammation in CKD. PMID- 25908533 TI - "Of mice and (wo)men": The need to confirm results of animal experimentations with solid clinical data. PMID- 25908534 TI - Physical activity as a risk factor for prostate cancer diagnosis: a prospective biopsy cohort analysis. AB - OBJECTIVES: To assess the association between physical activity, evaluated by the Physical Activity Scale for the Elderly (PASE) questionnaire, and prostate cancer risk in a consecutive series of men undergoing prostate biopsy. PATIENTS AND METHOD: From 2011 onwards, consecutive men undergoing 12-core prostate biopsy were enrolled into a prospective database. Indications for a prostatic biopsy were a prostate-specific antigen (PSA) value of >=4 ng/mL and/or a positive digital rectal examination. Body mass index (BMI) and waist circumferences were measured before the biopsy. Fasting blood samples were collected before biopsy and tested for: total PSA, glucose, high-density lipoprotein cholesterol, and trygliceride levels. Blood pressure was recorded. Metabolic syndrome (MetS) was defined according to the Adult Treatment panel III. The PASE questionnaire was completed before the biopsy. RESULTS: In all, 286 patients were enrolled with a median (interquartile range, IQR) age and PSA level of 68 (62-74) years and 6.1 (5-8.8) ng/mL, respectively. The median (IQR) BMI was 26.4 (24.6-29) kg/m(2) and waist circumference was 102 (97-108) cm, with 75 patients (26%) presenting with MetS. In all, 106 patients (37%) had prostate cancer at biopsy. Patients with prostate cancer had higher PSA levels (median [IQR] 6.7 [5-10] vs 5.6 [4.8-8] ng/mL; P = 0.007) and lower LogPASE scores (median [IQR] 2.03 [1.82-2.18] vs 2.10 [1.92-2.29]; P = 0.005). On multivariate analysis, in addition to well-recognised risk factors such as age, PSA level and prostate volume, LogPASE score was an independent risk factor for prostate cancer diagnosis (odds ratio [OR] 0.146, 95% confidence interval [CI] 0.037-0.577; P = 0.006]. LogPASE score was also an independent predictor of high-grade cancer (OR 0.07, 95% CI 0.006-0.764; P = 0.029). CONCLUSION: In our single-centre study, increased physical activity, evaluated by the PASE questionnaire, is associated with a reduced risk of prostate cancer and of high-grade prostate cancer at biopsy. Further studies should clarify the molecular pathways behind this association. PMID- 25908535 TI - Desired crystal oriented LiFePO4 nanoplatelets in situ anchored on a graphene cross-linked conductive network for fast lithium storage. AB - Electron transfer and lithium ion diffusion rates are the key factors limiting the lithium ion storage in anisotropic LiFePO4 electrodes. In this work, we employed a facile solvothermal method to synthesize a "platelet-on-sheet" LiFePO4/graphene composite (LFP@GNs), which is LiFePO4 nanoplatelets in situ grown on graphene sheets with highly oriented (010) facets of LiFePO4 crystals. Such a two-phase contact mode with graphene sheets cross-linked to form a three dimensional porous network is favourable for both fast lithium ion and electron transports. As a result, the designed LFP@GNs displayed a high rate capability (~56 mA h g(-1) at 60 C) and long life cycling stability (~87% capacity retention over 1000 cycles at 10 C). For comparison purposes, samples ex situ modified with graphene (LFP/GNs) as well as pure LiFePO4 platelets (LFP) were also prepared and investigated. More importantly, the obtained LFP@GNs can be used as a basic unit for constructing more complex structures to further improve electrochemical performance, such as coating the exposed LFP surface with a thin layer of carbon to build a C@LFP@GN composite to further enhance its cycling stability (~98% capacity retention over 1000 cycles at 10 C). PMID- 25908536 TI - The Meaning of the Sperm Donor for Heterosexual Couples: Confirming the Position of the Father. AB - In the literature, relatively little attention has been paid to the meaning of donor involvement in the intimate couple dyad. The current study aimed to enrich our understanding of couples' meaning-making regarding the anonymous sperm donor and how they dealt with the donor involvement. Semi-structured interviews were conducted with nine couples, who had at least one child conceived through sperm donation. Our thematic analysis showed that the donor conception was seen as a different path to create a normal family. Once the family was formed, most couples avoided talking about the donor because it was perceived as disrupting men's growing confidence in their position as father. Participants tried to confirm the position of the father to protect the family relationships. Uncertainties about how they were perceived as parents showed the continuing dominance of genetic ties within our social discourse. Participants also dealt with reminders of the donor in their daily life. Overall, they tried to manage the space taken up by the donor and to protect the position of the father. We relate our findings to literature on topic avoidance and shared obliviousness in families. For counseling practice, it could be useful to explore couples' meaning making about the donor as this seemed to serve family functioning. PMID- 25908538 TI - Teaching a Child With Autism to Request Breaks While Concurrently Increasing Task Engagement. AB - PURPOSE: An intervention package, including teaching break requests and tolerance for delay in reinforcement delivery to increase task engagement, was implemented with a 4-year-old child with an autism spectrum disorder who did not engage for a duration commensurate with individual education program team expectations. METHOD: A multiple-probe design across tasks was implemented. Dependent measures taken included engagement duration and the production of spoken break requests after work completion. Intervention was implemented with tasks involving short periods of engagement prior to the learner's disengagement. The possibility of the learner's overgeneralized production of break requests with tasks originally associated with longer engagement was also examined. RESULTS: The participant learned to request breaks in short engagement tasks. In addition, engagement increased dramatically without off-task behavior. Overgeneralized use of break requests with long engagement tasks did not occur. Generalization of break requests to untrained short engagement tasks that were not the focus of intervention (but were associated with escape and short engagement) did not occur until the intervention package was implemented. CONCLUSIONS: The combination of teaching break requests and tolerance for delay in reinforcement delivery was effective in addressing problem behavior. Implications for enhancing properly generalized and moderated use of break requests across different tasks or contexts are discussed. PMID- 25908539 TI - US Environmental Protection Agency sued over toxic air pollutants. PMID- 25908540 TI - Disruptive behavior within the workplace. AB - INTRODUCTION: The aim of this study was to determine the incidence of disruptive behavior among nurses in the healthcare workplace, the details that are associated with its occurrence, and the organizational procedures utilized when disruptive incidents occur. BACKGROUND: Healthcare workers have a higher risk of experiencing disruptive behavior among staff in the workplace compared to other industries, and nurses are more susceptible than other healthcare workers. METHOD: A quantitative, descriptive, survey design asked nurses if they had experienced disruptive behavior within the past 12 months and how this was handled by their organization. Disruptive behavior included any type of verbal abuse, electronic or e-mail abuse, or physical abuse within the work environment. RESULTS: There were 2,821 participants that validated the occurrence of verbal, electronic, and physical disruptive behavior, and the majority rated their overall work environment to be at high risk of experiencing disruptive behavior at least once every 6 months. DISCUSSION: Twenty-four statistically significant relationships were found with strongest associations (<0.001) between: age and electronic abuse; position and verbal abuse; position and physical abuse; years of experience and electronic abuse; susceptibility of the organization to workplace violence and position as well as education; missing work due to disruptive behavior and position; and feeling comfortable reporting the abuse and position as well as education. CONCLUSION: It is evident that disruptive behavior exists verbally, electronically, and physically, and that the overall work environment is felt to be at high risk of experiencing repeated disruptive behavior. PMID- 25908537 TI - A dominant role for the methyl-CpG-binding protein Mbd2 in controlling Th2 induction by dendritic cells. AB - Dendritic cells (DCs) direct CD4(+) T-cell differentiation into diverse helper (Th) subsets that are required for protection against varied infections. However, the mechanisms used by DCs to promote Th2 responses, which are important both for immunity to helminth infection and in allergic disease, are currently poorly understood. We demonstrate a key role for the protein methyl-CpG-binding domain-2 (Mbd2), which links DNA methylation to repressive chromatin structure, in regulating expression of a range of genes that are associated with optimal DC activation and function. In the absence of Mbd2, DCs display reduced phenotypic activation and a markedly impaired capacity to initiate Th2 immunity against helminths or allergens. These data identify an epigenetic mechanism that is central to the activation of CD4(+) T-cell responses by DCs, particularly in Th2 settings, and reveal methyl-CpG-binding proteins and the genes under their control as possible therapeutic targets for type-2 inflammation. PMID- 25908541 TI - Using non-invasive assessment methods to predict the risk of metabolic syndrome. AB - This study aimed to develop non-invasive assessment indicators for predicting the risk of metabolic syndrome. A cross-sectional study design with 154 convenient subjects recruited from the family clinics was used for this study. Physical assessment sheet, lifestyle profile, the heart rate variability assessment and standard blood sample tests were used to measure variables. The subjects were categorized into four groups based on the number of factors meeting the criteria for metabolic syndrome. After excluding invasive blood tests, the results of multivariate logistic regression identified non-invasive assessment (blood pressure, body mass index and very lower frequency of heart rate variability) were the significantly predictors of the risks of metabolic syndrome. When invasive blood test cannot be performed, community health care providers can use the non-invasive physical assessments to predict the risk of early-stage metabolic syndrome, consequently enabling them to implement related health education and interventions. PMID- 25908542 TI - Factors associated with falls in hospitalized adult patients. AB - INTRODUCTION: Despite efforts in hospitals to identify patients at risk for falls and to prevent these incidents, falls among hospitalized patients are not a rare event and continue to be a major health care concern, occurring in approximately 700,000-1,000,000 hospitalized patients per year. PURPOSE: The purpose of this study was to examine intrinsic, extrinsic, and workforce factors that contribute to falls among hospitalized adult patients. METHODS: A retrospective correlational design was used to examine 160 patients admitted to a medical surgical unit over the year 2012. Analytical weighting was applied to the study sample to conduct bivariate and multivariate analysis. FINDINGS: In multivariate analysis, the variables age, narcotic/sedative use, and overnight shift, significantly predicted the likelihood of a fall during the hospitalization. Cardiovascular disease, neuromusculoskeletal disease, evening shift, the implementation of fall prevention strategies and higher RN to unlicensed assistive personnel staffing ratios decreased the likelihood of a fall during the hospitalization. In addition, patients at high risk for falls using the Hendrich I fall scale were nearly 17% more likely to fall during the hospitalization. CONCLUSIONS: Many factors influence the occurrence of a fall in hospitalized patients. Fall risk assessment and the implementation of fall prevention strategies are both effective strategies in the clinical area to identify and decrease the probability of a fall. The presence of the RN is significant in fall prevention in medical-surgical patients. PMID- 25908543 TI - An introduction to key event mapping: A primer for nurse researchers. AB - To fully understand the events leading to a diagnosis, retrospective recall can help nurse researchers reconstruct important health behavior-related events. However, retrospective recall can be a challenge. Key event mapping offers nurse researchers a method beyond retrospective chart review to elicit date data to explore the pre-diagnosis time frame of an illness. The purpose of this paper is to introduce the key event mapping method to nurse researchers in search of a method of eliciting date data from participants when designing research studies that include a retrospective recall component. PMID- 25908544 TI - Support supplied by Parkinson's disease specialist nurses to Parkinson's disease patients and their spouses. AB - AIM: The purpose of the study was to identify the role of the Parkinson's disease specialist nurse in providing support both for people with Parkinson's disease (PD) and their spouses. BACKGROUND: PD is a neurodegenerative disease with symptoms that affect many aspects of daily life. In Sweden, specialised nurses called Parkinson's disease specialist nurses (PD specialist nurses) have been working for over a decade to support PD patients and their families. METHOD: A qualitative approach was taken using dyad interviews with each PD patient and spouse. The analysis was conducted using conventional qualitative content analysis. FINDINGS: The analysis resulted in the identification of one overarching category; competent, professional practice, tailored for the individual. Four categories: professional competence, nursing practice, continuity of contact and emotional support, are distinct but related to each other and show different nuances of the same phenomenon. CONCLUSION: The work of PD specialist nurses in providing support to PD patients and their relatives should be tailored to individual patients and their families as well as including skilled nursing care to relieve the impact of the disease on daily life. PMID- 25908545 TI - Ebola and ethics: autopsy of a failure. PMID- 25908546 TI - A comparison between egg trancriptomes of cod and salmon reveals species-specific traits in eggs for each species. AB - Fish in use in aquaculture display large variation in gamete biology. To reach better understanding around this issue, this study aims at identifying if species specific "egg life history traits" can be hidden in the unfertilized egg. This was done by investigating egg transcriptome differences between Atlantic salmon and Atlantic cod. Salmon and cod eggs were selected due to their largely differencing phenotypes. An oligo microarray analysis was performed on ovulated eggs from cod (n = 8) and salmon (n = 7). The arrays were normalized to a similar spectrum for both arrays. Both arrays were re-annotated with SWISS-Prot and KEGG genes to retrieve an official gene symbol and an orthologous KEGG annotation, in salmon and cod arrays this represented 14,009 and 7,437 genes respectively. The probe linked to the highest gene expression for that particular KEGG annotation was used to compare expression between species. Differential expression was calculated for genes that had an annotation with score >300, resulting in a total of 2,457 KEGG annotations (genes) being differently expressed between the species (FD > 2). This analysis revealed that immune, signal transduction and excretory related pathways were overrepresented in salmon compared to cod. The most overrepresented pathways in cod were related to regulation of genetic information processing and metabolism. To conclude this analysis clearly point at some distinct transcriptome repertoires for cod and salmon and that these differences may explain some of the species-specific biological features for salmon and cod eggs. PMID- 25908548 TI - Pyrosequencing analysis of microbial communities reveals dominant cosmopolitan phylotypes in deep-sea sediments of the eastern Mediterranean Sea. AB - The deep eastern basin of the Mediterranean Sea is considered to be one of the world's most oligotrophic areas in the world. Here we performed pyrosequenicng analysis of bacterial and archaeal communities in oxic nutrient-poor sediments collected from the eastern Mediterranean at 1025-4393 m depth. Microbial communities were surveyed by targeting the hypervariable V5-V6 regions of the 16S ribosomal RNA gene using bar-coded pyrosequencing. With a total of 13,194 operational taxonomic units (OTUs) or phylotypes at 97% sequence similarities, the phylogenetic affiliation of microbes was assigned to 23 bacterial and 2 archaeal known phyla, 23 candidate divisions at the phylum level and distributed into 186 families. It was further revealed that the microbial consortia inhabiting all sampling sites were highly diverse, but dominated by phylotypes closely related to members of the genus Pseudomonas and Marine Group I archaea. Such pronounced and widespread enrichment probably manifests the cosmopolitan character of these species and raises questions about their metabolic adaptation to the physical stressors and low nutrient availability of the deep eastern Mediterranean Sea. PMID- 25908549 TI - Mechanism of thyroxine deiodination by naphthyl-based iodothyronine deiodinase mimics and the halogen bonding role: a DFT investigation. AB - This paper deals with a systematic density functional theory (DFT) study aiming to unravel the mechanism of the thyroxine (T4) conversion into 3,3',5 triiodothyronine (rT3) by using different bio-inspired naphthyl-based models, which are able to reproduce the catalytic functions of the type-3 deiodinase ID 3. Such naphthalenes, having two selenols, two thiols, and a selenol-thiol pair in peri positions, which were previously synthesized and tested in their deiodinase activity, are able to remove iodine selectively from the inner ring of T4 to produce rT3. Calculations were performed including also an imidazole ring that, mimicking the role of the His residue, plays an essential role deprotonating the selenol/thiol moiety. For all the used complexes, the calculated potential energy surfaces show that the reaction proceeds via an intermediate, characterized by the presence of a X-I-C (X=Se, S) halogen bond, whose transformation into a subsequent intermediate in which the C-I bond is definitively cleaved and the incipient X-I bond is formed represents the rate determining step of the whole process. The calculated trend in the barrier heights of the corresponding transition states allows us to rationalize the experimentally observed superior deiodinase activity of the naphthyl-based compound with two selenol groups. The role of the peri interactions between chalcogen atoms appears to be less prominent in determining the deiodination activity. PMID- 25908550 TI - Diagnostic utility of somatosensory evoked potentials in chronic polyradiculopathy without electrodiagnostic signs of peripheral demyelination. AB - INTRODUCTION: Diagnosis of chronic inflammatory demyelinating polyneuropathy (CIDP) remains uncertain when nerve conduction studies (NCS) fail to show demyelination. METHODS: We conducted a retrospective study of patients who presented with clinical criteria of CIDP in whom electrodiagnostic (EDx) criteria of definite or probable CIDP were missing [axonal sensorimotor neuropathy (n = 23), normal EDx with pure sensory presentation (n = 3)]. All patients received immunomodulatory treatment. Twenty-six patients were evaluated with somatosensory evoked potentials (SSEPs), MRI of spinal roots, cerebrospinal fluid analysis, and/or nerve biopsy. Diagnosis of CIDP was considered to be confirmed in patients who responded to immunotherapy. RESULTS: Twenty-two of 26 patients (85%) had SSEPs reflecting abnormal proximal conduction in sensory fibers, including 14 who had only clinical and SSEP data in favor of CIDP. SSEPs were abnormal in 16 of 20 responders (80%) to immunotherapy. CONCLUSION: SSEP recording contributes to the diagnosis of CIDP when nerve conduction studies fail to detect peripheral demyelination. PMID- 25908551 TI - Shape-controllable and versatile synthesis of copper nanocrystals with amino acids as capping agents. AB - Thanks to their outstanding properties and a wide range of promising applications, the development of a versatile and convenient preparation method for metallic copper nanocrystals with controllable shape is of primary significance. Different from the literature that utilized a capping agent bearing only one kind of Cu binding functionality, either an amino or a carboxylic unit, for their preparation and shape control, this contribution reports a convenient method to engage both amino and carboxylic binding units at the same time. In this method, natural amino acids have been chosen as capping agents and demonstrated their versatile capabilities for the preparation of both Cu nanoparticles and nanowires. Detailed X-ray photoelectron spectroscopy revealed that the binding mode between amino acids and the Cu surface is highly dependent on their chemical structures. Interestingly, the produced Cu nanocrystals, exhibited an extraordinarily excellent anti-oxidation power. Furthermore, it was found that the multiple functionalities of amino acids not only have a great impact on the properties of their capped nanocrystals, such as solvent dispersibility, but also provide a convenient route for their further modification and functionalization. PMID- 25908552 TI - Real-time submillisecond single-molecule FRET dynamics of freely diffusing molecules with liposome tethering. AB - Single-molecule fluorescence resonance energy transfer (smFRET) is one of the powerful techniques for deciphering the dynamics of unsynchronized biomolecules. However, smFRET is limited in its temporal resolution for observing dynamics. Here, we report a novel method for observing real-time dynamics with submillisecond resolution by tethering molecules to freely diffusing 100-nm-sized liposomes. The observation time for a diffusing molecule is extended to 100 ms with a submillisecond resolution, which allows for direct analysis of the transition states from the FRET time trace using hidden Markov modelling. We measure transition rates of up to 1,500 s(-1) between two conformers of a Holliday junction. The rapid diffusional migration of Deinococcus radiodurans single-stranded DNA-binding protein (SSB) on single-stranded DNA is resolved by FRET, faster than that of Escherichia coli SSB by an order of magnitude. Our approach is a powerful method for studying the dynamics and movements of biomolecules at submillisecond resolution. PMID- 25908553 TI - Epidemiology of digital amputation and replantation in Taiwan: A population-based study. AB - BACKGROUND: Publications on digital amputation and replantation have been mostly derived from case series in high-volume hand surgery practices, and epidemiological studies are few. This study used a population-based dataset to illustrate the incidence of digital amputation, patient and hospital characteristics, and their relationships with replantation. METHODS: A claim for reimbursement dataset (2008) was provided as a research database by the Bureau of National Health Insurance, Taiwan. Patients with ICD-9-CM coded as digital amputation (885 and 886) were included. These were cross-referenced with procedure codes for replantation procedures (84.21 and 84.22). We defined the patients who underwent thumb replantation (84.21) and thumb amputation (84.01) during a single hospitalization as replantation failure. Patient and hospital characteristics were studied with statistical analysis. RESULTS: In total, 2358 patients with digital amputation were admitted (1859 male, 499 female), mean age 39.2 +/- 15.5 years. The incidence was 10.2/100,000 person-years. The highest incidence was 14.7/100,000 person-years in the age group 45-54 years. Machinery and powered hand tools caused 68.8% of digital amputations. Thumb amputation [odds ratio (OR): 1.35, p = 0.01], private hospital (OR: 1.40, p = 0.01), medical center (OR: 2.38, p < 0.001), regional hospital (OR: 2.41, p < 0.001) and hospitals with an annual volume >20 digital amputations (OR: 4.23, p < 0.001) were associated with higher attempt rates for replantation. Elderly patients (age >65 years) had higher risk of thumb replantation failure (OR: 32.30, p = 0.045), while hospitals with >20 annual replantations had lower risk (OR: 0.11, p = 0.02). CONCLUSION: Our study of the National Health Insurance database characterized the epidemiology of digital amputation patients undergoing replantation and the facilities in Taiwan where these procedures are performed. The hospitals treating more digital amputation patients had higher attempt rates and lower thumb failure rates. PMID- 25908554 TI - DNA damage induced by bare and loaded microporous coordination polymers from their ground and electronic excited states. AB - We report on interactions of cell free double-stranded DNA (dsDNA) with a selected subgroup of Microporous Coordination Polymers (MCPs). In particular, we have studied the influence of different metal ion constituents and chemically modified linkers using a set of five benzene carboxylate-based MCPs. Our results suggest that the DNA moiety can be structurally modified in two different ways: by direct MCPs-dsDNA interaction and/or through photosensitized processes. The extent of the observed damage was found to be strongly dependent on the charge density of the material. The potential use of the MCPs tested as inert carriers of photosensitizers was demonstrated by analyzing the interaction between dsDNA and harmine-loaded Cr-based materials, both in the absence of light and upon UVA irradiation. PMID- 25908556 TI - Iridium- and Osmium-decorated Reduced Graphenes as Promising Catalysts for Hydrogen Evolution. AB - Renewable energy sources are highly sought after as a result of numerous worldwide problems concerning the environment and the shortage of energy. Currently, the focus in the field is on the development of catalysts that are able to provide water splitting catalysis and energy storage for the hydrogen evolution reaction (HER). While platinum is an excellent material for HER catalysis, it is costly and rare. In this work, we investigated the electrocatalytic abilities of various graphene-metal hybrids to replace platinum for the HER. The graphene materials were doped with 4f metals, namely, iridium, osmium, platinum and rhenium, as well as 3d metals, namely, cobalt, iron and manganese. We discovered that a few hybrids, in particular iridium- and osmium doped graphenes, have the potential to become competent electrocatalysts owing to their low costs and-more importantly-to their promising electrochemical performances towards the HER. One of the more noteworthy observations of this work is the superiority of these two hybrids over MoS2 , a well-known electrocatalyst for the HER. PMID- 25908555 TI - Defining breast cancer intrinsic subtypes by quantitative receptor expression. AB - PURPOSE: To determine intrinsic breast cancer subtypes represented within categories defined by quantitative hormone receptor (HR) and HER2 expression. METHODS: We merged 1,557 cases from three randomized phase III trials into a single data set. These breast tumors were centrally reviewed in each trial for quantitative ER, PR, and HER2 expression by immunohistochemistry (IHC) stain and by reverse transcription-quantitative polymerase chain reaction (RT-qPCR), with intrinsic subtyping by research-based PAM50 RT-qPCR assay. RESULTS: Among 283 HER2-negative tumors with <1% HR expression by IHC, 207 (73%) were basal-like; other subtypes, particularly HER2-enriched (48, 17%), were present. Among the 1,298 HER2-negative tumors, borderline HR (1%-9% staining) was uncommon (n = 39), and these tumors were heterogeneous: 17 (44%) luminal A/B, 12 (31%) HER2 enriched, and only 7 (18%) basal-like. Including them in the definition of triple negative breast cancer significantly diminished enrichment for basal-like cancer (p < .05). Among 106 HER2-positive tumors with <1% HR expression by IHC, the HER2 enriched subtype was the most frequent (87, 82%), whereas among 127 HER2-positive tumors with strong HR (>10%) expression, only 69 (54%) were HER2-enriched and 55 (43%) were luminal (39 luminal B, 16 luminal A). Quantitative HR expression by RT qPCR gave similar results. Regardless of methodology, basal-like cases seldom expressed ER/ESR1 or PR/PGR and were associated with the lowest expression level of HER2/ERBB2 relative to other subtypes. CONCLUSION: Significant discordance remains between clinical assay-defined subsets and intrinsic subtype. For identifying basal-like breast cancer, the optimal HR IHC cut point was <1%, matching the American Society of Clinical Oncology and College of American Pathologists guidelines. Tumors with borderline HR staining are molecularly diverse and may require additional assays to clarify underlying biology. PMID- 25908557 TI - Uptake of raft components into amyloid beta-peptide aggregates and membrane damage. AB - Amyloid aggregation and deposition of amyloid beta-peptide (Abeta) are pathologic characteristics of Alzheimer's disease (AD). Recent reports have shown that the association of Abeta with membranes containing ganglioside GM1 (GM1) plays a pivotal role in amyloid deposition and the pathogenesis of AD. However, the molecular interactions responsible for membrane damage associated with Abeta deposition are not fully understood. In this study, we microscopically observed amyloid aggregation of Abeta in the presence of lipid vesicles and on a substrate supported planar membrane containing raft components and GM1. The experimental system enabled us to observe lipid-associated aggregation of Abeta, uptake of the raft components into Abeta aggregates, and relevant membrane damage. The results indicate that uptake of raft components from the membrane into Abeta deposits induces macroscopic heterogeneity of the membrane structure. PMID- 25908558 TI - Agarose gel shift assay reveals that calreticulin favors substrates with a quaternary structure in solution. AB - Here we present an agarose gel shift assay that, in contrast to other electrophoresis approaches, is loaded in the center of the gel. This allows proteins to migrate in either direction according to their isoelectric points. Therefore, the presented assay enables a direct visualization, separation, and prefractionation of protein interactions in solution independent of isoelectric point. We demonstrate that this assay is compatible with immunochemical methods and mass spectrometry. The assay was used to investigate interactions with several potential substrates for calreticulin, a chaperone that is involved in different biological aspects through interaction with other proteins. The current analytical assays used to investigate these interactions are mainly spectroscopic aggregation assays or solid phase assays that do not provide a direct visualization of the stable protein complex but rather provide an indirect measure of interactions. Therefore, no interaction studies between calreticulin and substrates in solution have been investigated previously. The results presented here indicate that calreticulin has a preference for substrates with a quaternary structure and primarily beta-sheets in their secondary structure. It is also demonstrated that the agarose gel shift assay is useful in the study of other protein interactions and can be used as an alternative method to native polyacrylamide gel electrophoresis. PMID- 25908559 TI - A recommended workflow for DNase I footprinting using a capillary electrophoresis genetic analyzer. AB - Fragment analysis was developed to determine the sizes of DNA fragments relative to size standards of known lengths using a capillary electrophoresis genetic analyzer. This approach has since been adapted for use in DNA footprinting. However, DNA footprinting requires accurate determination of both fragment length and intensity, imposing specific demands on the experimental design. Here we delineate essential considerations involved in optimizing the fragment analysis workflow for use in DNase I footprinting to ensure that changes in DNase I cleavage patterns may be reliably identified. PMID- 25908560 TI - Development of an enzyme-linked immunosorbent assay for thiacloprid in soil and agro-products with phage-displayed peptide. AB - A monoclonal antibody (3A5) that can recognize thiacloprid was produced, and a linear 8-residue peptide phage library was constructed. Six phage-displayed peptides were isolated from the linear 8-residue peptide phage library and a cyclic 8-residue peptide phage library. A phage enzyme-linked immunosorbent assay (ELISA) was developed to detect thiacloprid using a phage-displayed peptide. Under the optimal conditions, the half-maximal inhibition concentration (IC50) and the limit of detection (IC10) of the developed phage ELISA were 8.3 and 0.7 MUg/L, respectively. Compared with the conventional ELISA, the sensitivity was improved more than 3-fold. The cross-reactivity (CR) was less than 0.08% for the tested structural analogues and was regarded as negligible. The recoveries of thiacloprid ranged from 80.3% to 116.3% in environmental and agricultural samples, which conformed to the requirements for residue detection. The amount of thiacloprid detected by phage ELISA in the samples was significantly correlated with that detected by high-performance liquid chromatography. The current study indicates that isolating phage-displayed peptides from phage display libraries is an alternative method for the development of a sensitive immunoassay and that the developed assay is a potentially useful tool for detecting thiacloprid in environmental and agricultural samples. PMID- 25908561 TI - Conditions for (13)C NMR detection of 2-hydroxyglutarate in tissue extracts from isocitrate dehydrogenase-mutated gliomas. AB - (13)C NMR (nuclear magnetic resonance) spectroscopy of extracts from patient tumor samples provides rich information about metabolism. However, in isocitrate dehydrogenase (IDH)-mutant gliomas, (13)C labeling is obscured in oncometabolite 2-hydroxyglutaric acid (2 HG) by glutamate and glutamine, prompting development of a simple method to resolve the metabolites. J-coupled multiplets in 2 HG were similar to glutamate and glutamine and could be clearly resolved at pH 6. A cryogenically cooled (13)C probe, but not J-resolved heteronuclear single quantum coherence spectroscopy, significantly improved detection of 2 HG. These methods enable the monitoring of (13)C-(13)C spin-spin couplings in 2 HG expressing IDH mutant gliomas. PMID- 25908562 TI - Cloning, expression, and characterization of a thermostable l-arginase from Geobacillus thermodenitrificans NG80-2 for l-ornithine production. AB - Arginase (l-arginine amidinohydrolase, EC 3.5.3.1) can efficiently catalyze conversion of arginine to ornithine. Therefore, this enzyme can be used to produce l-ornithine from l-arginine. In this article, the l-arginase gene encoding the Geobacillus thermodenitrificans NG80-2 was cloned and overexpressed in Escherichia coli. The specific activity of the purified enzyme was 138.3 U/mg. The molecular mass of the l-arginase was approximately 33.0 kDa as estimated by SDS-PAGE and 192.0 kDa as determined by gel-filtration chromatography. Manganese ions were the optimum metal cofactor for activity, whereas the enzyme was slightly inhibited by Mg(2+) , Cu(2+) , Ba(2+) , Ca(2+) , and Zn(2+) . Activity was optimal at pH 9.0 and 80 degrees C, and the protein was stable at 40 and 50 degrees C. The recombinant enzyme was a uricotelic arginase. Using arginine as the substrate, the Michaelis-Menten constant (Km ) and catalytic efficiency (kcat /Km ) were measured to be 171.9 mM and 3.8 mM(-1) s(-1) , respectively. Trp and His residues were directly involved in the l-arginase activity evaluated by inactivation agents. The biosynthesis yield of l-ornithine by the purified enzyme was 36.9 g/L, and the molar yield was 97.2%. PMID- 25908563 TI - Imposed rate and extent of weight loss in obese men and adaptive changes in resting and total energy expenditure. AB - OBJECTIVES: Weight loss (WL) is associated with a decrease in total and resting energy expenditure (EE). We aimed to investigate whether (1) diets with different rate and extent of WL determined different changes in total and resting EE and if (2) they influenced the level of adaptive thermogenesis, defined as the decline in total or resting EE not accounted by changes in body composition. METHODS: Three groups of six, obese men participated in a total fast for 6 days to achieve a 5% WL and a very low calorie (VLCD, 2.5 MJ/day) for 3 weeks or a low calorie (LCD, 5.2 MJ/day) diet for 6 weeks to achieve a 10% WL. A four-component model was used to measure body composition. Indirect calorimetry was used to measure resting EE. Total EE was measured by doubly labelled water (VLCD, LCD) and 24 hour whole-body calorimetry (fasting). RESULTS: VLCD and LCD showed a similar degree of metabolic adaptation for total EE (VLCD = -6.2%; LCD = -6.8%). Metabolic adaptation for resting EE was greater in the LCD (-0.4 MJ/day, -5.3%) compared to the VLCD (-0.1 MJ/day, -1.4%) group. Resting EE did not decrease after short-term fasting and no evidence of adaptive thermogenesis (+0.4 MJ/day) was found after 5% WL. The rate of WL was inversely associated with changes in resting EE (n = 30, r = 0.-42, p=0.01). CONCLUSIONS: The rate of WL did not appear to influence the decline in total EE in obese men after 10% WL. Approximately 6% of this decline in total EE was explained by mechanisms of adaptive thermogenesis. PMID- 25908565 TI - Porous Carbon Fibers Containing Pores with Sizes Controlled at the Angstrom Level by the Cavity Size of Pillar[6]arene. AB - We report a new synthesis method of fibrous carbon material with pores sizes that are precisely controlled at the Angstrom level, by carbonization of two dimensional (2D) porous sheets of pillar[6]arenes. The 2D porous sheets were prepared by 2D supramolecular polymerization induced by oxidation of hydroquinone units of pillar[6]arenes. Owing to the hexagonal structure of pillar[6]arene, the assembly induced by 2D supramolecular polymerization gave hexagonal 2D porous sheets, and the highly ordered structure of the 2D porous sheets formed regular fibrous structures. Then, carbonization of the 2D porous sheets afforded fibrous carbon materials with micropores. The micropore size of the fibrous porous carbon prepared from pillar[6]arene was the same size as that of the starting material pillar[6]arene assembly. PMID- 25908564 TI - Distributional Cost-Effectiveness Analysis: A Tutorial. AB - Distributional cost-effectiveness analysis (DCEA) is a framework for incorporating health inequality concerns into the economic evaluation of health sector interventions. In this tutorial, we describe the technical details of how to conduct DCEA, using an illustrative example comparing alternative ways of implementing the National Health Service (NHS) Bowel Cancer Screening Programme (BCSP). The 2 key stages in DCEA are 1) modeling social distributions of health associated with different interventions, and 2) evaluating social distributions of health with respect to the dual objectives of improving total population health and reducing unfair health inequality. As well as describing the technical methods used, we also identify the data requirements and the social value judgments that have to be made. Finally, we demonstrate the use of sensitivity analyses to explore the impacts of alternative modeling assumptions and social value judgments. PMID- 25908566 TI - Patterns of Adherence of Helicobacter pylori Clinical Isolates to Epithelial Cells, and its Association with Disease and with Virulence Factors. AB - BACKGROUND AND AIM: Adherence to the gastric epithelium is one of the most important steps of Helicobacter pylori to remain and cause disease. The aim of this study was to analyze whether H. pylori isolates from patients with different gastroduodenal diseases present differences in the pattern of adherence to gastric epithelial cells (AGS), in the ability to induce IL-8, and in the presence of virulence genes. METHODS: We tested 75 H. pylori strains isolated from nonatrophic gastritis, gastric cancer, and duodenal ulcer patients. The adhesion pattern and IL-8 induction were determined in AGS cells, and invasion of AGS cells was studied using a gentamicin protection assay. The IL-8 levels induced were determined by ELISA. RESULTS: Helicobacter pylori strains presented diffuse adherence (DA) and localized (LA) adherence patterns, similar to those described for enteropathogenic E. coli (EPEC), were observed in AGS cells. A DA pattern was observed in 57% and LA in 43% of the strains, and DA was more frequent in isolates from patients with gastric cancer (p = 0.044). Strains with a LA pattern induced higher levels of IL-8 (p = 0.042) in AGS cells. CONCLUSION: The adherence pattern was not associated with neither invasiveness nor with the presence of virulence genes. Our study shows that H. pylori strains present adherence patterns to AGS cells resembling those observed in EPEC and that these patterns may be associated with disease and with activity on AGS cells. PMID- 25908568 TI - Meeting Report on Experimental Approaches to Evolution and Ecology Using Yeast and Other Model Systems. PMID- 25908567 TI - Improved Detection and Characterization of Copy Number Variations Among Diverse Pig Breeds by Array CGH. AB - As a major component of genomic variation, copy number variations (CNVs) are considered as promising markers for some phenotypic and economically important traits in domestic animals. Using a custom-designed 1M array CGH (aCGH), we performed CNV discovery in 12 pig samples from one Asian wild boar population, six Chinese indigenous breeds, and two European commercial breeds. In total, we identified 758 CNV regions (CNVRs), covering 47.43 Mb of the pig genome sequence. Of the total porcine genes, 1295 genes were completely or partially overlapped with the identified CNVRs, which enriched in the terms related to sensory perception of the environment, neurodevelopmental processes, response to external stimuli, and immunity. Further probing the potential functions of these genes, we also found a suite of genes related important traits, which make them a promising resource for exploring the genetic basis of phenotype differences among diverse pig breeds. Compared with previous relevant studies, the current study highlights that different platforms can complement each other, and the combined implementation of different platforms is beneficial to achieve the most comprehensive CNV calls. CNVs detected in diverse populations herein are essentially complementary to the CNV map in the pig genome, which would be helpful for understanding the pig genome variants and investigating the associations between various phenotypes and CNVs. PMID- 25908570 TI - Diabetic cardiomyopathy: An expression of stage B heart failure with preserved ejection fraction. AB - Heart failure is now recognized as a progressive disease in which patients transition through the stages of being at risk of heart failure (stage A), to asymptomatic structural heart disease (stage B), to clinical manifestations of heart failure (stage C) and finally end-stage or refractory heart failure (stage D). This review outlines the key role of diabetes mellitus as a stage A risk factor for heart failure with preserved ejection fraction, and asymptomatic diabetic cardiomyopathy, referring to the presence of left ventricular diastolic dysfunction in diabetic patients without coronary artery disease, hypertension or other potential aetiologies, as an expression of stage B heart failure with preserved ejection fraction at high risk of transitioning to symptomatic stage C heart failure with preserved ejection fraction. The data presented call for better recognition of the unique phenotype of diabetic cardiomyopathy with preserved ejection fraction and elevated diastolic stiffness as a manifestation of stage B heart failure with preserved ejection fraction that should be targeted for risk management and preventive strategies. PMID- 25908571 TI - Copper-Catalyzed Intermolecular Trifluoromethylthiocyanation of Alkenes: Convenient Access to CF3-Containing Alkyl Thiocyanates. AB - A highly selective and efficient approach for the direct trifluoromethylthiocyanation of alkenes has been developed using trimethylsilyl isothiocyanate (TMSNCS) as the thiocyanating agent and Togni reagent as the CF3 source in the presence of copper(I) catalyst. Both activated and unactivated alkenes work well to deliver various CF3-containing thiocyanates. PMID- 25908569 TI - Development of a 63K SNP Array for Cotton and High-Density Mapping of Intraspecific and Interspecific Populations of Gossypium spp. AB - High-throughput genotyping arrays provide a standardized resource for plant breeding communities that are useful for a breadth of applications including high density genetic mapping, genome-wide association studies (GWAS), genomic selection (GS), complex trait dissection, and studying patterns of genomic diversity among cultivars and wild accessions. We have developed the CottonSNP63K, an Illumina Infinium array containing assays for 45,104 putative intraspecific single nucleotide polymorphism (SNP) markers for use within the cultivated cotton species Gossypium hirsutum L. and 17,954 putative interspecific SNP markers for use with crosses of other cotton species with G. hirsutum. The SNPs on the array were developed from 13 different discovery sets that represent a diverse range of G. hirsutum germplasm and five other species: G. barbadense L., G. tomentosum Nuttal * Seemann, G. mustelinum Miers * Watt, G. armourianum Kearny, and G. longicalyx J.B. Hutchinson and Lee. The array was validated with 1,156 samples to generate cluster positions to facilitate automated analysis of 38,822 polymorphic markers. Two high-density genetic maps containing a total of 22,829 SNPs were generated for two F2 mapping populations, one intraspecific and one interspecific, and 3,533 SNP markers were co-occurring in both maps. The produced intraspecific genetic map is the first saturated map that associates into 26 linkage groups corresponding to the number of cotton chromosomes for a cross between two G. hirsutum lines. The linkage maps were shown to have high levels of collinearity to the JGI G. raimondii Ulbrich reference genome sequence. The CottonSNP63K array, cluster file and associated marker sequences constitute a major new resource for the global cotton research community. PMID- 25908572 TI - Use of an anti-GnRF vaccine to suppress estrus in crossbred Iberian female pigs. AB - Antibodies against GnRF elicited by vaccination with Improvac are expected to have the same effects on the gonads of female pigs as those observed in males and thus suppress estrus. The objective of this study was to evaluate whether a 3- or a 4-dose regimen of Improvac was effective in inducing and maintaining suppression of estrus in intact Iberian female pigs through 14 months of age. Sixty 18-week-old gilts were randomly assigned to one of the following three treatment groups: control (PBS injected), V3 (3-dose Improvac regimen), and V4 (4 dose Improvac regimen). Animals were tested for the presence of standing estrus in the presence of a boar three times per week until study completion at 60 weeks of age. Blood samples were regularly collected to determine the serum levels of anti-GnRF antibodies and progesterone. The weight and size of the uterus and the weight and activity of the ovaries were assessed at the time of euthanasia. For both treatment groups V3 and V4, a large reduction in the incidence of standing estrus was observed when compared to the control group (P < 0.0001). No significant differences between the V3 and V4 groups were observed. Both V3 and V4 groups had higher serum anti-GnRF antibody levels than the control group from 28 days after the first vaccination until the end of the study. In addition, both V3 and V4 groups had lower levels of progesterone than the control group from Day 112 until the end of the study (P < 0.0001 in all cases). Mean ovary weights at study end in treatment groups V3 and V4 were significantly lower (P < 0.0001) than those for the control group and not significantly different between the V3 and V4 groups. An onset of immunity of 2 weeks after the second vaccination and a long-lasting immunity of at least 20 weeks after the third vaccination were observed. In summary, both the 3-and 4-dose Improvac regimens were efficacious in reducing the incidence of standing estrus, serum progesterone levels, and the development of the uterus and ovaries. PMID- 25908574 TI - Making consequentialism more appealing. PMID- 25908573 TI - Does active application of universal adhesives to enamel in self-etch mode improve their performance? AB - OBJECTIVES: To evaluate the effect of adhesion strategy on the enamel microshear bond strengths (MUSBS), etching pattern, and in situ degree of conversion (DC) of seven universal adhesives. METHODS: 84 extracted third molars were sectioned in four parts (buccal, lingual, proximal) and divided into 21 groups, according to the combination of the main factors adhesive (AdheSE Universal [ADU], All-Bond Universal [ABU], Clearfil Universal [CFU], Futurabond U [FBU], G-Bond Plus [GBP], Prime&Bond Elect (PBE), and Scotchbond Universal Adhesive [SBU]), and adhesion strategy (etch-and-rinse, active self-etch, and passive self-etch). Specimens were stored in water (37 degrees C/24h) and tested at 1.0mm/min (MUSBS). Enamel resin interfaces were evaluated for DC using micro-Raman spectroscopy. The enamel etching pattern was evaluated under a field-emission scanning electron microscope (direct and replica techniques). Data were analyzed with two-way ANOVA and Tukey's test (alpha=0.05). RESULTS: Active self-etch application increased MUSBS and DC for five out of the seven universal adhesives when compared to passive application (p<0.001). A deeper enamel-etching pattern was observed for all universal adhesives in the etch-and-rinse strategy. A slight improvement in etching ability was observed in active self-etch application compared to that of passive self-etch application. Replicas of GBP and PBE applied in active self etch mode displayed morphological features compatible with water droplets. The DC of GBP and PBE were not affected by the application/strategy mode. CONCLUSIONS: In light of the improved performance of universal adhesives when applied actively in SE mode, selective enamel etching with phosphoric acid may not be crucial for their adhesion to enamel. CLINICAL SIGNIFICANCE: The active application of universal adhesives in self-etch mode may be a practical alternative to enamel etching in specific clinical situations. PMID- 25908576 TI - Pathophysiologically relevant in vitro tumor models for drug screening. AB - The alarming rate of failure of clinical trials is a major hurdle in cancer therapy that partly results from the inadequate use of in vitro tumor models for the screening of promising hits and leads in preclinical studies. 2D cultures of cancer cell lines that are primarily used for drug screening do not adequately recapitulate tumor microenvironment (TME) complexities compared with 3D cancer cell cultures and tumor-derived primary cell cultures. In this review, we focus on the potential use of in vitro tumor models that reproduce in vivo tumor complexities for effective drug selection in the preclinical stages of drug development. PMID- 25908577 TI - A history of drug development in four acts. PMID- 25908578 TI - High-content analysis for drug delivery and nanoparticle applications. AB - High-content analysis (HCA) provides quantitative multiparametric cellular fluorescence data. From its origins in discovery toxicology, it is now addressing fundamental questions in drug delivery. Nanoparticles (NPs), polymers, and intestinal permeation enhancers are being harnessed in drug delivery systems to modulate plasma membrane properties and the intracellular environment. Identifying comparative mechanistic cytotoxicity on sublethal events is crucial to expedite the development of such systems. NP uptake and intracellular routing pathways are also being dissected using chemical and genetic perturbations, with the potential to assess the intracellular fate of targeted and untargeted particles in vitro. As we discuss here, HCA is set to make a major impact in preclinical delivery research by elucidating the intracellular pathways of NPs and the in vitro mechanistic-based toxicology of formulation constituents. PMID- 25908579 TI - Patient-centered drug discovery as the means to improved R&D productivity. PMID- 25908580 TI - [Aortic dissection in pregnancy]. AB - During pregnancy, the occurrence of aortic dissection is a rare event immediately threatening fetal and maternal prognosis. Its occurrence is more common in cases of connective tissue disease. But the absence risk factor shall not exclude or delay diagnosis. We must learn to think about it, because the prognosis is highly dependent on time management. The clinical presentation of this medical and surgical emergency varies, and pregnancy adds its own symptoms. We have to ask without hesitation that echocardiography or chest CT be performed since these diagnostic methods are both reliable and available. PMID- 25908581 TI - Role of the cardio-pulmonary exercise test and six-minute walking test in the evaluation of exercise performance in patients with late-onset Pompe disease. AB - In patients with late-onset Pompe disease, we explored the role of the Cardiopulmonary Exercise Test (CPET) and the Six-Minute Walking Test (6MWT) in the assessment of exercise capacity and in the evaluation of the effects of enzyme replacement therapy (ERT). Eight patients affected by late-onset Pompe disease, followed up at the Centre for Neuromuscular Diseases and treated with ERT, underwent a baseline evaluation with a spirometry, a CPET and a 6MWT. Four of them were restudied after 36 months of treatment. Three patients showed a reduction in exercise capacity as evaluated by peak oxygen uptake (VO2) measured at the CPET and Distance Walked (DW) measured at the 6MWT (median % predicted: 67.1 [range 54.3-99.6] and 67.3 [56.6-82.6], respectively). Cardiac and respiratory limitations revealed by the CPET were correlated to peak VO2, but not to the DW. Nevertheless, percent of predicted values of peak VO2 and DW were strongly correlated (rho = 0.85, p = 0.006), and close to identity. In the longitudinal evaluation forced vital capacity decreased, while peak VO2 and DW showed a trend to a parallel improvement. We concluded that although only the CPET revealed causes of exercise limitation, which partially differed among patients, CPET and 6MWT showed a similar overall degree of exercise impairment. That held true in the longitudinal assessment during ERT, where both tests demonstrated similar small improvements, occurring despite deterioration in forced vital capacity. PMID- 25908582 TI - Influence of production system in local and conventional pig breeds on stress indicators at slaughter, muscle and meat traits and pork eating quality. AB - Sensory quality of pork is a complex phenotype determined by interactions between genetic and environmental factors. This study aimed at describing the respective influences of breed and production system on the development of pork quality. Plasma stress indicators and Longissimus muscle (LM) composition, physicochemical and sensory quality traits were determined in two contrasted breeds - the conventional Large White (LW, n=40) and the French local Basque (B, n=60). Pigs were reared in either a conventional (C; n=20 per breed), alternative (A; sawdust bedding and outdoor area, n=20 per breed) or extensive system (E; free-range, n=20 B). All the pigs from A and C systems were slaughtered at the same slaughterhouse, whereas B pigs from the E system were slaughtered at a local commercial abattoir. Major breed differences were found for almost all traits under study. LM from B pigs exhibited higher lipid, lower water and collagen concentrations, as well as lower collagen thermal solubility (P0.05) influence plasma stress indicators, LM chemical composition and physicochemical or sensory traits of pork. In contrast, within the B pigs, the E system affected the meat quality more. Lower plasma cortisol levels (P<0.05), but higher plasma lactate, creatine kinase and lactate dehydrogenase activities, and more skin lesions (P<0.05), indicating higher muscular activity during pre-slaughter handling, were found in pigs produced in the E compared with the C system. E pigs exhibited higher meat pH1 and pHu values and shear force (P<0.01) and exhibited lower lightness, hue angle and drip and thawing losses (P<0.01) compared with the C pigs, whereas LM lipid, protein or collagen concentrations were not affected. Regarding sensory traits, the E system produced redder meat, but did not impact the eating quality of pork. Altogether, this study demonstrates that differences in meat quality between B and LW breeds can be modulated by extensive pig production system. PMID- 25908584 TI - Multi-muscle activation strategies during walking in female post-operative total joint replacement patients. AB - Dynamic knee joint function requires coordinated multi-muscle activation patterns (MMP) that may be adversely affected by total knee arthroplasty (TKA). This study identified MMP changes in post-operative female TKA patients using a Support Vector Machine (SVM). It was hypothesised that TKA patients can successfully be classified and display significant alterations in temporal and spectral muscle activation characteristics. 19 female subjects (10 unilateral gender-specific TKA, 62.2+/-8.6yrs, BMI 28.2+/-5.4; and 9 healthy controls, 61.4+/-7.4yrs, BMI 25.6+/-2.4) were recruited. Surface electromyograms (EMG) were obtained for 7 lower limb muscles during walking. Stance phase (+/-30%) EMG data were processed using a wavelet transform and normalized to total power. Data across all muscles were combined to form MMPs and analyzed using a SVM. Recognition rates for all subjects were computed for MMPs and individual muscles. A binomial test was used to establish statistical significance (p<0.05). The results supported the hypothesis indicating significantly altered muscle activations for vastus medialis (recognition rate ~68.4%) and biceps femoris (recognition rate ~73.7%). Further analysis identified distinct between group differences across temporal, spectral and intensity domains. Application of a combined SVM and MMP approach may be beneficial for the future assessment of post-surgical dynamic muscle function. PMID- 25908585 TI - Training-related changes in the EMG-moment relationship during isometric contractions: Further evidence of improved control of muscle activation in strength-trained men? AB - The possibility of using electromyography (EMG) to track muscle activity has raised the question of its relationship with the effort exerted by the muscles around the joints. However, the EMG-moment relationship is yet to be fully defined, and increasing knowledge of this topic could contribute to research in motor control and to the development of EMG-based algorithms and devices. With regards the training-related adaptations at the peripheral and central level, the present study investigated the effect of strength training on EMG-moment relationship. Our aim was to clarify its nature and gain further understanding of how morphological and neural factors may affect its form. The EMG-moment relationship was determined during knee flexion and extension isometric contractions performed by strength-trained male athletes and untrained male participants. The results showed that strength training induced linearity of the EMG-moment relationship concomitantly with enhanced maximum force production capacity and decreased co-activation of knee agonist-antagonist muscle pair. These results clarified discordant results regarding the linear or curved nature of the EMG-moment in isometric conditions and suggested that the remarkable linearity of the EMG-moment found in trained participants could indicate improved control of muscle activation. PMID- 25908586 TI - G-CSF Promotes Neuroblastoma Tumorigenicity and Metastasis via STAT3-Dependent Cancer Stem Cell Activation. AB - Increasing evidence suggests that inflammatory cytokines play a critical role in tumor initiation and progression. A cancer stem cell (CSC)-like subpopulation in neuroblastoma is known to be marked by expression of the G-CSF receptor (G-CSFR). Here, we report on the mechanistic contributions of the G-CSFR in neuroblastoma CSCs. Specifically, we demonstrate that the receptor ligand G-CSF selectively activates STAT3 within neuroblastoma CSC subpopulations, promoting their expansion in vitro and in vivo. Exogenous G-CSF enhances tumor growth and metastasis in human xenograft and murine neuroblastoma tumor models. In response to G-CSF, STAT3 acts in a feed-forward loop to transcriptionally activate the G CSFR and sustain neuroblastoma CSCs. Blockade of this G-CSF-STAT3 signaling loop with either anti-G-CSF antibody or STAT3 inhibitor depleted the CSC subpopulation within tumors, driving correlated tumor growth inhibition, decreased metastasis, and increased chemosensitivity. Taken together, our results define G-CSF as a CSC activating factor in neuroblastoma, suggest a comprehensive reevaluation of the clinical use of G-CSF in these patients to support white blood cell counts, and suggest that direct targeting of the G-CSF-STAT3 signaling represents a novel therapeutic approach for neuroblastoma. PMID- 25908587 TI - Effects of Sorafenib Dose on Acquired Reversible Resistance and Toxicity in Hepatocellular Carcinoma. AB - Acquired evasive resistance is a major limitation of hepatocellular carcinoma (HCC) treatment with the tyrosine kinase inhibitor (TKI) sorafenib. Recent findings suggest that resistance to sorafenib may have a reversible phenotype. In addition, loss of responsiveness has been proposed to be due to a gradual decrease in sorafenib plasma levels in patients. Here, the possible mechanisms underlying reversible sorafenib resistance were investigated using a Hep3B-hCG orthotopic human xenograft model of locally advanced HCC. Tissue and plasma sorafenib and metabolite levels, downstream antitumor targets, and toxicity were assessed during standard and dose-escalated sorafenib treatment. Drug levels were found to decline significantly over time in mice treated with 30 mg/kg sorafenib, coinciding with the onset of resistance but a greater magnitude of change was observed in tissues compared with plasma. Skin rash also correlated with drug levels and tended to decrease in severity over time. Drug level changes appeared to be partially tumor dependent involving induction of tumoral CYP3A4 metabolism, with host pretreatment alone unable to generate resistance. Escalation from 30 to 60 mg/kg sorafenib improved antitumor efficacy but worsened survival due to excessive body weight loss. Microvessel density was inhibited by sorafenib treatment but remained suppressed over time and dose increase. In conclusion, tumor CYP3A4 induction by sorafenib is a novel mechanism to account for variability in systemic drug levels; however, declining systemic sorafenib levels may only be a minor resistance mechanism. Escalating the dose may be an effective treatment strategy, provided toxicity can be controlled. PMID- 25908588 TI - Reply to: 'Harder but smarter? Co-designing together' by Robert and Donetto. PMID- 25908589 TI - Response to: 'A 'work smarter, not harder' approach to improving healthcare quality' by Hayes et al. PMID- 25908591 TI - PET after chemotherapy identifies Hodgkin's lymphoma patients who can avoid radiotherapy. PMID- 25908590 TI - Mechanisms of splicing-dependent trans-synaptic adhesion by PTPdelta-IL1RAPL1/IL 1RAcP for synaptic differentiation. AB - Synapse formation is triggered through trans-synaptic interaction between pairs of pre- and postsynaptic adhesion molecules, the specificity of which depends on splice inserts known as 'splice-insert signaling codes'. Receptor protein tyrosine phosphatase delta (PTPdelta) can bidirectionally induce pre- and postsynaptic differentiation of neurons by trans-synaptically binding to interleukin-1 receptor accessory protein (IL-1RAcP) and IL-1RAcP-like-1 (IL1RAPL1) in a splicing-dependent manner. Here, we report crystal structures of PTPdelta in complex with IL1RAPL1 and IL-1RAcP. The first immunoglobulin-like (Ig) domain of IL1RAPL1 directly recognizes the first splice insert, which is critical for binding to IL1RAPL1. The second splice insert functions as an adjustable linker that positions the Ig2 and Ig3 domains of PTPdelta for simultaneously interacting with the Ig1 domain of IL1RAPL1 or IL-1RAcP. We further identified the IL1RAPL1-specific interaction, which appears coupled to the first-splice-insert-mediated interaction. Our results thus reveal the decoding mechanism of splice-insert signaling codes for synaptic differentiation induced by trans-synaptic adhesion between PTPdelta and IL1RAPL1/IL-1RAcP. PMID- 25908592 TI - Predictors of systolic blood pressure in post-menopausal euthyroid women: A study of the NHANES continuous survey data 2007-2012. AB - There is an increased risk of cardiovascular disease and higher rate of hypertension in post-menopausal (compared to pre-menopausal women). We analysed the cross-sectional National Health and Nutritional Examination and Survey 2007 2012 to look at the factors that affect systolic blood pressure in post menopausal women. We also performed a linear regression with systolic blood pressure as the dependent variable and age, body mass index, total cholesterol, triglycerides, A1C and serum creatinine as independent variables. In the regression model, only body mass index was a significant predictor of systolic blood pressure (adjusted r (2) of 0. 100, F(6, 740) = 14.74, standard error beta = 0.08, standardized coefficient B = 0.31, p < 0.01). PMID- 25908593 TI - On the design and characterization of a new cold atmospheric pressure plasma jet and its applications on cancer cells treatment. AB - In this paper, a new configuration of a cold atmospheric pressure plasma jet has been designed and constructed. Poly-methyl-methacrylate was used as a new dielectric in this configuration which in comparison to other dielectrics is inexpensive, more resistant against break, and also more shapeable. Then, the plasma jet parameters such as plume temperature, rotational and vibrational temperatures, power, electrical behavior (voltage and current profile), electron density, and the produced reactive species were characterized. In order to determine the jet temperature and the amount of reactive species, effects of applied voltage, gas flow rate, and distance from the nozzle were studied. The power of the jet was specified using Lissajous curve approach. The plume temperature of the plasma jet was about the room temperature. Optical emission spectroscopy determined the type of reactive species, and also electron density and its corresponding plasma frequency (~6.4 * 10(13) cm(-3) and 4.52 * 10(11) Hz). Because of producing different reactive species, the device can be used in different applications, especially in plasma medicine. Thus, 4T1 cancer cells were treated using this plasma jet. The results showed that this plasma jet has a great potential to kill one of the most aggressive and resistant cancerous cell lines. PMID- 25908594 TI - Procedures for Obtaining and Analyzing Writing Samples of School-Age Children and Adolescents. AB - PURPOSE: Many students' writing skills are below grade-level expectations, and students with oral language difficulties are at particular risk for writing difficulties. Speech-language pathologists' (SLPs') expertise in language applies to both the oral and written modalities, yet evidence suggests that SLPs' confidence regarding writing assessment is low. Writing samples are a clinically useful, criterion-referenced assessment technique that is relevant to helping students satisfy writing-related requirements of the Common Core State Standards (National Governors Association Center for Best Practices and Council of Chief State School Officers, 2010a). This article provides recommendations for obtaining and analyzing students' writing samples. METHOD: In this tutorial, the authors provide a comprehensive literature review of methods regarding (a) collection of writing samples from narrative, expository (informational/explanatory), and persuasive (argument) genres; (b) variables of writing performance that are useful to assess; and (c) manual and computer-aided techniques for analyzing writing samples. The authors relate their findings to expectations for writing skills expressed in the Common Core State Standards (National Governors Association Center for Best Practices & Council of Chief State School Officers, 2010a). CONCLUSION: SLPs can readily implement many techniques for obtaining and analyzing writing samples. The information in this article provides SLPs with recommendations for the use of writing samples and may help increase SLPs' confidence regarding written language assessment. PMID- 25908595 TI - Parental provision of alcohol: a TPB-framed review of the literature. AB - There is evidence that parents are a common source of alcohol provision for teenagers, and increasing evidence that this provision is associated with current and future drinking. This review examines the current literature on parental provision of alcohol to children and teenagers, through the lens of the Theory of Planned Behavior: attitudes, subjective norms and perceived behavioral control. A search of the databases ProQuest, PsycINFO, Medline, Expanded Academic, Scopus and PBSC identified 826 articles. Of these, 810 did not meet the inclusion criteria, and 16 were included in the review. In summary, the reviewed articles demonstrated positive attitudes toward parental supply of alcohol (often driven by misperceptions), strong subjective norms, but little exploration of perceived behavioral control There is a need for further research which clearly differentiates between adolescents of different ages and genders, and which explores the predictors and role of perceived behavioral control. There is also a need for further research to more fully understand this behavior and to develop appropriate interventions which address all three predictors (attitudes, subjective norms and perceived behavioral control). PMID- 25908596 TI - Electronic cigarettes: analysis of FDA adverse experience reports in non-users. PMID- 25908597 TI - SEATCA Tobacco Industry Interference Index: a tool for measuring implementation of WHO Framework Convention on Tobacco Control Article 5.3. AB - OBJECTIVE: To measure the implementation of WHO Framework Convention on Tobacco Control (FCTC) Article 5.3 at country level using a new Tobacco Industry Interference Index and to report initial results using this index in seven Southeast Asian countries. METHODS: Score sheet based on WHO FCTC Article 5.3 Guidelines sent to correspondents in seven Southeast Asian countries, using a scoring system designed with the help of tobacco control experts and validated through focused group discussions. RESULTS: The seven countries ranked from the lowest level of interference to the highest are Brunei, Thailand, Lao PDR, Cambodia, Philippines, Malaysia and Indonesia. Countries that face high levels of unnecessary interaction with the tobacco industry also face high levels of tobacco industry influence in policy development. Most governments do not allow any tobacco industry representatives on their delegation to sessions of the Conference of the Parties or its subsidiary bodies nor accept their sponsorship for delegates, but most governments still accept or endorse offers of assistance from the tobacco industry in implementing tobacco control policies. Most governments also receive tobacco industry contributions (monetary or in kind) or endorse industry corporate social responsibility activities. Governments do not have a procedure for disclosing interactions with the tobacco industry, but Lao PDR, Philippines and Thailand have instituted measures to prevent or reduce industry interference. CONCLUSIONS: This Tobacco Industry Interference Index, based on the WHO FCTC Article 5.3 Guidelines, is a useful advocacy tool for identifying both progress and gaps in national efforts at implementing WHO FCTC Article 5.3. PMID- 25908598 TI - Preface. PMID- 25908599 TI - Create a clinical chief executive role in hospitals. PMID- 25908600 TI - A young woman with recurrent perianal sepsis. PMID- 25908601 TI - Exposure age and ice-sheet model constraints on Pliocene East Antarctic ice sheet dynamics. AB - The Late Pliocene epoch is a potential analogue for future climate in a warming world. Here we reconstruct Plio-Pleistocene East Antarctic Ice Sheet (EAIS) variability using cosmogenic nuclide exposure ages and model simulations to better understand ice sheet behaviour under such warm conditions. New and previously published exposure ages indicate interior-thickening during the Pliocene. An ice sheet model with mid-Pliocene boundary conditions also results in interior thickening and suggests that both the Wilkes Subglacial and Aurora Basins largely melted, offsetting increased ice volume. Considering contributions from West Antarctica and Greenland, this is consistent with the most recent IPCC AR5 estimate, which indicates that the Pliocene sea level likely did not exceed +20 m on Milankovitch timescales. The inception of colder climate since ~3 Myr has increased the sea ice cover and inhibited active moisture transport to Antarctica, resulting in reduced ice sheet thickness, at least in coastal areas. PMID- 25908602 TI - Challenges in initiating and conducting personalized cancer therapy trials: perspectives from WINTHER, a Worldwide Innovative Network (WIN) Consortium trial. AB - Advances in 'omics' technology and targeted therapeutic molecules are together driving the incorporation of molecular-based diagnostics into the care of patients with cancer. There is an urgent need to assess the efficacy of therapy determined by molecular matching of patients with particular targeted therapies. WINTHER is a clinical trial that uses cutting edge genomic and transcriptomic assays to guide treatment decisions. Through the lens of this ambitious multinational trial (five countries, six sites) coordinated by the Worldwide Innovative Networking Consortium for personalized cancer therapy, we discovered key challenges in initiation and conduct of a prospective, omically driven study. To date, the time from study concept to activation has varied between 19 months at Gustave Roussy Cancer Campus in France to 30 months at the Segal Cancer Center, McGill University (Canada). It took 3+ years to be able to activate US sites due to national regulatory hurdles. Access to medications proposed by the molecular analysis remains a major challenge, since their availability through active clinical trials is highly variable over time within sites and across the network. Rules regarding the off-label use of drugs, or drugs not yet approved at all in some countries, pose a further challenge, and many biopharmaceutical companies lack a simple internal mechanism to supply the drugs even if they wish to do so. These various obstacles should be addressed to test and then implement precision medicine in cancer. PMID- 25908603 TI - FOLFIRI plus bevacizumab as second-line therapy in patients with metastatic colorectal cancer after first-line bevacizumab plus oxaliplatin-based therapy: the randomized phase III EAGLE study. AB - BACKGROUND: A targeted agent combined with chemotherapy is the standard treatment in patients with metastatic colorectal cancer (mCRC). The present phase III study was conducted to compare two doses of bevacizumab combined with irinotecan, 5 fluorouracil/leucovorin (FOLFIRI) in the second-line setting after first-line therapy with bevacizumab plus oxaliplatin-based therapy. PATIENTS AND METHODS: Patients were randomly assigned to receive FOLFIRI plus bevacizumab 5 or 10 mg/kg in 2-week cycles until disease progression. The primary end point was progression free survival (PFS), and secondary end points included overall survival (OS), time to treatment failure (TTF), and safety. RESULTS: Three hundred and eighty seven patients were randomized between September 2009 and January 2012 from 100 institutions in Japan. Baseline patient characteristics were well balanced between the two groups. Efficacy was evaluated in 369 patients (5 mg/kg, n = 181 and 10 mg/kg, n = 188). Safety was evaluated in 365 patients (5 mg/kg, n = 180 and 10 mg/kg, n = 185). The median PFS was 6.1 versus 6.4 months (hazard ratio, 0.95; 95% confidence interval [CI] 0.75-1.21; P = 0.676), and median TTF was 5.2 versus 5.2 months (hazard ratio, 1.01; 95% CI 0.81-1.25; P = 0.967), respectively, for the bevacizumab 5 and 10 mg/kg groups. Follow-up of OS is currently ongoing. Adverse events, including hypertension and hemorrhage, occurred at similar rates in both groups. CONCLUSION: Bevacizumab 10 mg/kg plus FOLFIRI as the second-line treatment did not prolong PFS compared with bevacizumab 5 mg/kg plus FOLFIRI in patients with mCRC. If bevacizumab is continued after first-line therapy in mCRC, a dose of 5 mg/kg is appropriate for use as second-line treatment. CLINICAL TRIAL IDENTIFIER: UMIN000002557. PMID- 25908604 TI - Titration of signalling output: insights into clinical combinations of MEK and AKT inhibitors. AB - BACKGROUND: We aimed to understand the relative contributions of inhibiting MEK and AKT on cell growth to guide combinations of these agents. MATERIALS AND METHODS: A panel of 20 cell lines was exposed to either the MEK inhibitor, PD0325901, or AKT inhibitor, AKT 1/2 inhibitor. p-ERK and p-S6 ELISAs were used to define degrees of MEK and AKT inhibition, respectively. Growth inhibition to different degrees of MEK and AKT inhibition, either singly or in combination using 96-h sulphorhodamine assays was then studied. RESULTS: A significantly greater growth inhibition was seen in BRAF(M) and PIK3CA(M) cells upon maximal MEK (P = 0.004) and AKT inhibition (P = 0.038), respectively. KRAS(M) and BRAF/PIK3CA/KRAS(WT) cells were not significantly more likely to be sensitive to MEK or AKT inhibition. Significant incremental growth inhibition of the combination of MEK + AKT over either MEK or AKT inhibition alone was seen when MEK + AKT was inhibited maximally and not when sub-maximal inhibition of both MEK + AKT was used (11/20 cell lines versus 1/20 cell lines; P = 0.0012). CONCLUSIONS: KRAS(M) cells are likely to benefit from combinations of MEK and AKT inhibitors. Sub-maximally inhibiting both MEK and AKT within a combination, in a majority of instances, does not significantly increase growth inhibition compared with maximally inhibiting MEK or AKT alone and alternative phase I trial designs are needed to clinically evaluate such combinations. PMID- 25908606 TI - Neonatal Body Composition: Measuring Lean Mass as a Tool to Guide Nutrition Management in the Neonate. AB - Neonatal nutrition adequacy is often determined by infant weight gain. The aim of this review is to summarize what is currently known about neonatal body composition and the use of body composition as a measure for adequate neonatal nutrition. Unlike traditional anthropometric measures of height and weight, body composition measurements account for fat vs nonfat mass gains. This provides a more accurate picture of neonatal composition of weight gain. Providing adequate neonatal nutrition in the form of quantity and composition can be a challenge, especially when considering the delicate balance of providing adequate nutrition to preterm infants for catch-up growth. Monitoring weight gain as fat mass and nonfat mass while documenting dietary intake of fat, protein, and carbohydrate in formulas may help provide the medical community the tools to provide optimal nutrition for catch-up growth and for improved neurodevelopmental outcomes. Tracking body composition in term and preterm infants may also provide critical future information concerning the nutritional state of infants who go on to develop future disease such as obesity, hypertension, and hyperlipidemia as adolescents or adults. PMID- 25908605 TI - A randomized phase III trial of oral S-1 plus cisplatin versus docetaxel plus cisplatin in Japanese patients with advanced non-small-cell lung cancer: TCOG0701 CATS trial. AB - BACKGROUND: Platinum-based two-drug combination chemotherapy has been standard of care for patients with advanced nonsmall-cell lung cancer (NSCLC). The primary aim was to compare overall survival (OS) of patients with advanced NSCLC between the two chemotherapy regimens. Secondary end points included progression-free survival (PFS), response, safety, and quality of life (QoL). PATIENTS AND METHODS: Patients with previously untreated stage IIIB or IV NSCLC, an Eastern Cooperative Oncology Group performance status of 0-1 and adequate organ function were randomized to receive either oral S-1 80 mg/m(2)/day on days 1-21 plus cisplatin 60 mg/m(2) on day 8 every 4-5 weeks, or docetaxel 60 mg/m(2) on day 1 plus cisplatin 80 mg/m(2) on day 1 every 3-4 weeks, both up to six cycles. RESULTS: A total of 608 patients from 66 sites in Japan were randomized to S-1 plus cisplatin (n = 303) or docetaxel plus cisplatin (n = 305). OS for oral S-1 plus cisplatin was noninferior to docetaxel plus cisplatin [median survival, 16.1 versus 17.1 months, respectively; hazard ratio = 1.013; 96.4% confidence interval (CI) 0.837-1.227]. Significantly higher febrile neutropenia (7.4% versus 1.0%), grade 3/4 neutropenia (73.4% versus 22.9%), grade 3/4 infection (14.5% versus 5.3%), and grade 1/2 alopecia (59.3% versus 12.3%) were observed in the docetaxel plus cisplatin than in the S-1 plus cisplatin. There were no differences found in PFS or response between the two arms. QoL data investigated by EORTC QLQ-C30 and LC-13 favored the S-1 plus cisplatin. CONCLUSION: Oral S-1 plus cisplatin is not inferior to docetaxel plus cisplatin and is better tolerated in Japanese patients with advanced NSCLC. CLINICAL TRIAL NUMBER: UMIN000000608. PMID- 25908607 TI - Finding the Best Waist Circumference Measurement Protocol in Patients With Nonalcoholic Fatty Liver Disease. AB - BACKGROUND: Central fat accumulation is important in nonalcoholic fatty liver disease (NAFLD) etiology. It is unknown whether any commonly used waist circumference measurement protocol (WCmp), as a whole and central fat accumulation marker, is preferable for patients with NAFLD. The present study sought to find a preferable WCmp to be used in patients with NAFLD, based on 3 fold criteria. METHODS: Body fat (BF) was assessed through dual-energy x-ray absorptiometry in 28 patients with NAFLD (19 men, 51 +/- 13 years; 9 women, 47 +/ 13 years). WC was measured with 4 types of WCmp: WC1, narrowest torso; WC2, just above iliac crest; WC3, middistance between iliac crest and last rib; WC4, at the umbilicus. RESULTS: All WC measurements were highly correlated with central BF depots, including trunk BF (r = 0.78, r = 0.82, r = 0.82, r = 0.84 for WC1, WC2, WC3, and WC4, respectively), abdominal BF (r = 0.78, r = 0.78, r = 0.80, r = 0.72 for WC1, WC2, WC3, and WC4, respectively), and central abdominal BF (r = 0.76, r = 0.77, r = 0.78, r = 0.68 for WC1, WC2, WC3, and WC4, respectively), controlling for age, sex, and body mass index. There were no differences between the correlation coefficients obtained between all studied waist circumference measurements and each whole and central analyzed BF variable. CONCLUSIONS: All studied WCmps seem suitable for use in patients with NAFLD, particularly as a central BF clinical assessment tool, though not interchangeably. Hence, biological and precision criteria alone did not sanction the superiority of any WCmp. Practical criteria may endorse WC measured at the iliac crest. PMID- 25908608 TI - An update on human immunodeficiency virus vaccine preparedness studies. AB - Human immunodeficiency virus (HIV) vaccine preparedness studies (VPSs) have taken place in both the Organisation for Economic Co-operation and Development (OECD) countries and the non-OECD countries. HIV VPSs are conducted to assess the feasibility of phase 3 HIV vaccine trials. This descriptive review is an update of HIV VPSs in the non-OECD countries, and examines the willingness to participate (WTP) in hypothetical HIV vaccine trials, as well as retention. Few VPSs have been published in the OECD countries since the discontinuation of the STEP/Phambili HIV vaccine trials. Barriers to participation in the non-OECD countries after the STEP/Phambili studies include safety issues and side effects, vaccine-induced seropositivity (VISP) and mistrust among key informants (KIs). HIV VPSs indicate that HIV vaccine trials are still feasible in the non-OECD countries, but barriers must be overcome to improve feasibility. Hypothetical WTP in a VPS may not translate into actual WTP in an HIV vaccine trial. PMID- 25908610 TI - Scientists warn that Paris summit is last chance to prevent fatal temperature rise. PMID- 25908611 TI - Mechanism-Based Classification of PAH Mixtures to Predict Carcinogenic Potential. AB - We have previously shown that relative potency factors and DNA adduct measurements are inadequate for predicting carcinogenicity of certain polycyclic aromatic hydrocarbons (PAHs) and PAH mixtures, particularly those that function through alternate pathways or exhibit greater promotional activity compared to benzo[a]pyrene (BaP). Therefore, we developed a pathway-based approach for classification of tumor outcome after dermal exposure to PAH/mixtures. FVB/N mice were exposed to dibenzo[def,p]chrysene (DBC), BaP, or environmental PAH mixtures (Mix 1-3) following a 2-stage initiation/promotion skin tumor protocol. Resulting tumor incidence could be categorized by carcinogenic potency as DBC >> BaP = Mix2 = Mix3 > Mix1 = Control, based on statistical significance. Gene expression profiles measured in skin of mice collected 12 h post-initiation were compared with tumor outcome for identification of short-term bioactivity profiles. A Bayesian integration model was utilized to identify biological pathways predictive of PAH carcinogenic potential during initiation. Integration of probability matrices from four enriched pathways (P < .05) for DNA damage, apoptosis, response to chemical stimulus, and interferon gamma signaling resulted in the highest classification accuracy with leave-one-out cross validation. This pathway-driven approach was successfully utilized to distinguish early regulatory events during initiation prognostic for tumor outcome and provides proof-of concept for using short-term initiation studies to classify carcinogenic potential of environmental PAH mixtures. These data further provide a 'source-to outcome' model that could be used to predict PAH interactions during tumorigenesis and provide an example of how mode-of-action-based risk assessment could be employed for environmental PAH mixtures. PMID- 25908612 TI - Embedded Performance Validity on the CVLT-C for Youth with Neurological Disorders. AB - Embedded validity measures can screen for possible noncredible performance, but there is a paucity of literature with youth who have neurological disorders. The purpose of this study is to examine the California Verbal Learning Test, Children's Version (CVLT-C) recognition discriminability (RD) score as an embedded validity marker in a sample of youth with neurological diagnoses. Youth between 5-16 years old (N = 294; mean age = 11.3, SD = 3.4) completed the CVLT-C and the Test of Memory Malingering (TOMM). Overall, 5.4% (n = 16) scored below the established cutoff on the TOMM; they were younger, had lower intellectual abilities, and worse performance on nearly all CVLT-C scores than those who scored above the TOMM cutoff. Using the CVLT-C RD score of z <= -0.5 (Baker et al. 2004), our sample had a sensitivity = .81 and specificity = .67. Using z <= 3.0 provided sensitivity at .44 with specificity at .90. A lower cutoff score of z <= -3.0 for CVLT-C RD is necessary in youth with neurological diagnoses. PMID- 25908613 TI - Visuoperceptual assessments for differentiating dementia with Lewy bodies and Alzheimer's disease: illusory contours and other neuropsychological examinations. AB - We examined the utility of illusory contours (ICs) for the differentiation of dementia with Lewy bodies (DLB) from Alzheimer's disease (AD). Thirty-five probable DLB patients, 35 probable AD patients controlled by age, years of education, and Mini-Mental State Examination (MMSE) score, and 30 cognitively normal subjects controlled by age and years of education underwent visuoperceptual examinations including ICs, pentagon copying in MMSE, overlapping figures, clock drawing test, cube copying, and line orientation. Four items in ICs (ICs-4) were found to be significantly impaired in DLB compared with AD, and a sensitivity and a specificity of total score of ICs-4 were 88.6% and 37.1%, respectively. When a score of ICs-4 is combined with a 10-point scaled score of pentagon copying in MMSE, a sensitivity and a specificity were 77.1% and 82.9%, respectively. The present study suggests that ICs-4 can be included in neuropsychological examinations to assess visuoperceptual impairment in DLB. PMID- 25908614 TI - Short-Term Practice Effects and Brain Hypometabolism: Preliminary Data from an FDG PET Study. AB - Practice effects are improvements in cognitive test scores due to repeated exposure to the same tests. Typically viewed as error, short-term practice effects have been shown to provide valuable clinical information about diagnosis, prognosis, and treatment outcomes in older patients with mild cognitive impairments. This study examined short-term practice effects across one week and brain hypometabolism on fluoro-2-deoxyglucose (FDG) positron emission tomography (PET) in 25 older adults (15 intact, 10 Mild Cognitive Impairment). Averaged cerebral brain metabolism on FDG PET was correlated with multiple cognitive scores at baseline in those with Mild Cognitive Impairment, and short-term practice effects accounted for additional variance in these same subjects. The relationship between brain metabolism and cognition (either at baseline or practice effects) was minimal in the intact individuals. Although needing replication in larger samples, short-term practice effects on tests of executive functioning and memory may provide valuable information about biomarkers of Alzheimer's disease. PMID- 25908615 TI - Alu-mediated diverse and complex pathogenic copy-number variants within human chromosome 17 at p13.3. AB - Alu repetitive elements are known to be major contributors to genome instability by generating Alu-mediated copy-number variants (CNVs). Most of the reported Alu mediated CNVs are simple deletions and duplications, and the mechanism underlying Alu-Alu-mediated rearrangement has been attributed to non-allelic homologous recombination (NAHR). Chromosome 17 at the p13.3 genomic region lacks extensive low-copy repeat architecture; however, it is highly enriched for Alu repetitive elements, with a fraction of 30% of total sequence annotated in the human reference genome, compared with the 10% genome-wide and 18% on chromosome 17. We conducted mechanistic studies of the 17p13.3 CNVs by performing high-density oligonucleotide array comparative genomic hybridization, specifically interrogating the 17p13.3 region with ~150 bp per probe density; CNV breakpoint junctions were mapped to nucleotide resolution by polymerase chain reaction and Sanger sequencing. Studied rearrangements include 5 interstitial deletions, 14 tandem duplications, 7 terminal deletions and 13 complex genomic rearrangements (CGRs). Within the 17p13.3 region, Alu-Alu-mediated rearrangements were identified in 80% of the interstitial deletions, 46% of the tandem duplications and 50% of the CGRs, indicating that this mechanism was a major contributor for formation of breakpoint junctions. Our studies suggest that Alu repetitive elements facilitate formation of non-recurrent CNVs, CGRs and other structural aberrations of chromosome 17 at p13.3. The common observation of Alu-mediated rearrangement in CGRs and breakpoint junction sequences analysis further demonstrates that this type of mechanism is unlikely attributed to NAHR, but rather may be due to a recombination-coupled DNA replicative repair process. PMID- 25908616 TI - The mutant Moonwalker TRPC3 channel links calcium signaling to lipid metabolism in the developing cerebellum. AB - The Moonwalker (Mwk) mouse is a model of dominantly inherited cerebellar ataxia caused by a gain-of-function mutation in the transient receptor potential (TRP) channel TRPC3. Here, we report impairments in dendritic growth and synapse formation early on during Purkinje cell development in the Mwk cerebellum that are accompanied by alterations in calcium signaling. To elucidate the molecular effector pathways that regulate Purkinje cell dendritic arborization downstream of mutant TRPC3, we employed transcriptomic analysis of developing Purkinje cells isolated by laser-capture microdissection. We identified significant gene and protein expression changes in molecules involved in lipid metabolism. Consistently, lipid homeostasis in the Mwk cerebellum was found to be disturbed, and treatment of organotypic cerebellar slices with ceramide significantly improved dendritic outgrowth of Mwk Purkinje cells. These findings provide the first mechanistic insights into the TRPC3-dependent mechanisms, by which activated calcium signaling is coupled to lipid metabolism and the regulation of Purkinje cell development in the Mwk cerebellum. PMID- 25908618 TI - Exposure Therapy. PMID- 25908619 TI - UK research paper of the year. PMID- 25908617 TI - Specific variants in WDR35 cause a distinctive form of Ellis-van Creveld syndrome by disrupting the recruitment of the EvC complex and SMO into the cilium. AB - Most patients with Ellis-van Creveld syndrome (EvC) are identified with pathogenic changes in EVC or EVC2, however further genetic heterogeneity has been suggested. In this report we describe pathogenic splicing variants in WDR35, encoding retrograde intraflagellar transport protein 121 (IFT121), in three families with a clinical diagnosis of EvC but having a distinctive phenotype. To understand why WDR35 variants result in EvC, we analysed EVC, EVC2 and Smoothened (SMO) in IFT-A deficient cells. We found that the three proteins failed to localize to Wdr35(-/-) cilia, but not to the cilium of the IFT retrograde motor mutant Dync2h1(-/-), indicating that IFT121 is specifically required for their entry into the ciliary compartment. Furthermore expression of Wdr35 disease cDNAs in Wdr35(-/-) fibroblasts revealed that the newly identified variants lead to Hedgehog signalling defects resembling those of Evc(-/-) and Evc2(-/-) mutants. Together our data indicate that splicing variants in WDR35, and possibly in other IFT-A components, underlie a number of EvC cases by disrupting targeting of both the EvC complex and SMO to cilia. PMID- 25908620 TI - Phytochemical progress made in investigations of Angelica sinensis (Oliv.) Diels. AB - The phytochemical progress on Angelica sinensis (Oliv.) Diels over the past decades is summarized. Since 1970s, 165 chemical constituents, including phthalides, phenylpropanoids, terpenoids and essential oils, aromatic compounds, alkaloids, alkynes, sterols, fatty acids, and polysaccharides have been isolated or detected from the various parts of the title plant. PMID- 25908621 TI - Ethanol promotes saturated fatty acid-induced hepatoxicity through endoplasmic reticulum (ER) stress response. AB - Serum palmitic acid (PA), a type of saturated fatty acid, causes lipid accumulation and induces toxicity in hepatocytes. Ethanol (EtOH) is metabolized by the liver and induces hepatic injury and inflammation. Herein, we analyzed the effects of EtOH on PA-induced lipotoxicity in the liver. Our results indicated that EtOH aggravated PA-induced apoptosis and lipid accumulation in primary rat hepatocytes in dose-dependent manner. EtOH intensified PA-caused endoplasmic reticulum (ER) stress response in vitro and in vivo, and the expressions of CHOP, ATF4, and XBP-1 in nucleus were significantly increased. EtOH also increased PA caused cleaved caspase-3 in cytoplasm. In wild type and CHOP(-/-) mice treated with EtOH and high fat diet (HFD), EtOH worsened the HFD-induced liver injury and dyslipidemia, while CHOP knockout blocked toxic effects of EtOH and PA. Our study suggested that targeting UPR-signaling pathways is a promising, novel approach to reducing EtOH and saturated fatty acid-induced metabolic complications. PMID- 25908622 TI - Pre-treatment with puerarin affects pharmacokinetics of warfarin, but not clopidogrel, in experimental rats. AB - The present study was designed to determine the effects of puerarin pre-treatment on the pharmacokinetics of the oral anticoagulant agent warfarin and the antiplatelet agent clopidogrel in rats. In the treatment group, rats was gavaged with warfarin or clopidogrel after repeated treatment with puerarin at intraperitoneal doses of 20, 60, or 200 mg.kg(-1) for 7 days, while rats in the control group were administrated only with the same dose warfarin or clopidogrel. Plasma samples were obtained at the prescribed times and analyzed by liquid chromatography tandem mass spectrometry (LC-MS/MS). The results showed that rats treated with puerarin at all the test doses of 20, 60 and 200 mg.kg(-1) were found to affect the pharmacokinetics of warfarin, but not clopidogrel, suggesting a potential herb-drug interaction between puerarin and warfarin. PMID- 25908623 TI - Scutellarin attenuates endothelium-dependent aasodilation impairment induced by hypoxia reoxygenation, through regulating the PKG signaling pathway in rat coronary artery. AB - Scutellarin (SCU), a flavonoid from a traditional Chinese medicinal plant. Our previous study has demonstrated that SCU relaxes mouse aortic arteries mainly in an endothelium-depend-ent manner. In the present study, we investigated the vasoprotective effects of SCU against HR-induced endothelial dysfunction (ED) in isolated rat CA and the possible mechanisms involving cyclic guanosine monophosphate (cGMP) dependent protein kinase (PKG). The isolated endothelium intact and endothelium-denuded rat CA rings were treated with HR injury. Evaluation of endothelium-dependent and -independent vasodilation relaxation of the CA rings were performed using wire myography and the protein expressions were assayed by Western blotting. SCU (10-1 000 MUmol.L(-1)) could relax the endothelium-intact CA rings but not endothelium-denuded ones. In the intact CA rings, the PKG inhibitor, Rp-8-Br-cGMPS (PKGI-rp, 4 MUmol.L(-1)), significantly blocked SCU (10-1 000 MUmol.L(-1))-induced relaxation. The NO synthase (NOS) inhibitor, NO-nitro-L-arginine methylester (L-NAME, 100 MUmol.L(-1)), did not significantly change the effects of SCU (10-1 000 MUmol.L(-1)). HR treatment significantly impaired ACh-induced relaxation, which was reversed by pre incubation with SCU (500 MUmol.L(-1)), while HR treatment did not altered NTG induced vasodilation. PKGI-rp (4 MUmol.L(-1)) blocked the protective effects of SCU in HR-treated CA rings. Additionally, HR treatment reduced phosphorylated vasodilator-stimulated phosphoprotein (p-VASP, phosphorylated product of PKG), which was reversed by SCU pre-incubation, suggesting that SCU activated PKG phosphorylation against HR injury. SCU induces CA vasodilation in an endothelium dependent manner to and repairs HR-induced impairment via activation of PKG signaling pathway. PMID- 25908624 TI - Prophylactic effects of asiaticoside-based standardized extract of Centella asiatica (L.) Urban leaves on experimental migraine: Involvement of 5HT1A/1B receptors. AB - The present study aimed at evaluation of prophylactic efficacy and possible mechanisms of asiaticoside (AS) based standardized extract of Centella asiatica (L.) Urban leaves (INDCA) in animal models of migraine. The effects of oral and intranasal (i.n.) pretreatment of INDCA (acute and 7-days subacute) were evaluated against nitroglycerine (NTG, 10 mg.kg(-1), i.p.) and bradykinin (BK, 10 MUg, intra-arterial) induced hyperalgesia in rats. Tail flick latencies (from 0 to 240 min) post-NTG treatment and the number of vocalizations post-BK treatment were recorded as a measure of hyperalgesia. Separate groups of rats for negative (Normal) and positive (sumatriptan, 42 mg.kg(-1), s.c.) controls were included. The interaction of INDCA with selective 5-HT1A, 5-HT1B, and 5-HT1D receptor antagonists (NAN-190, Isamoltane hemifumarate, and BRL-15572 respectively) against NTG-induced hyperalgesia was also evaluated. Acute and sub-acute pre treatment of INDCA [10 and 30 mg.kg(-1) (oral) and 100 MUg/rat (i.n.) showed significant anti-nociception activity, and reversal of the NTG-induced hyperalgesia and brain 5-HT concentration decline. Oral pre-treatment with INDCA (30 mg.kg(-1), 7 d) showed significant reduction in the number of vocalization. The anti-nociceptive effects of INDCA were blocked by 5-HT1A and 5-HT1B but not 5 HT1D receptor antagonists. In conclusion, INDCA demonstrated promising anti nociceptive effects in animal models of migraine, probably through 5-HT1A/1B medicated action. PMID- 25908625 TI - Ginsenoside Ro suppresses interleukin-1beta-induced apoptosis and inflammation in rat chondrocytes by inhibiting NF-kappaB. AB - This study investigated effects of Ginsenoside Ro (Ro) on interleukin-1beta (IL 1beta)-induced apoptosis and inflammation in rat chondrocytes. The rat chondrocytes were co-treated with IL-1beta (10 ng.kg(-1)) and Ro (50, 100 and 200 MUmol.L(-1)) for 48 h. Chondrocytes viability was detected by the MTT assay and Annexin V-FITC/PI dual staining assay. Caspase 3 activity was measured by using caspase 3 colorimetric assay kit. Apoptosis related proteins Bax, Bad, Bcl-xL, PCNA, p53 and phospho-p53, along with inflammation related protein MMP 3, MMP 9 and COX-2, and the expression of phospho-NF-kappaB p65 were assayed by western blotting analyses. Ro could improve IL-1beta-induced chondrocytes viability. Ro could suppress IL-1beta-induced apoptosis by inhibiting levels of Bax and Bad, decreasing p53 phosphorylation and promoting the expression of Bcl-xL and PCNA. Ro inhibited caspase 3 activity. IL-1beta-induced inflammation and matrix degration were also alleviated by Ro with down-regulating the expression of MMP 3, MMP 9 and COX-2. Moreover, Ro inhibited NF-kappaB p65 phosphorylation induced by IL-1beta. In conclusion, these results suggested Ro exerted anti-apoptosis and anti-inflammation in IL-1beta-induced rat chondrocytes, which might be related to NF-kappaB signal pathway. Therefore, we propose that Ro might be a potential novel drug for the treatment of osteoarthritis. PMID- 25908626 TI - Structural elucidation of two new megastigmane glycosides from the leaves of Aquilaria sinensis. AB - The present study was designed to determine the chemical constituents and identify new components of the leaves of Aquilaria sinensis (Lour.) Gilg. The compounds were isolated and purified by repeated silica gel, Sephadex LH-20, and ODS column chromatography and their structures were elucidated by NMR and HR-ESI MS spectrometry. Eight megastigmane glycosides and two cucurbitacins were isolated and identified as (9S) megastigma-4,7-diene-2,3,9-triol 9-O-beta-D glucopyranoside (1), (9S) megastigma-4(13),7-diene-3,6,9-triol 9-O-beta-D glucopyranoside (2), macarangloside D (3), corchoionoside C (4), staphylionoside H (5), (+) 3-oxo-alpha-ionol-beta-D-glucopyranoside (6), (-) 3-oxo-alpha-ionol beta-D-glucopyranoside (7), citroside B (8), 2-O-beta-D-glucopyranosyl cucurbitacin I (9), bryoamaride (10). Compounds 1 and 2 were newly identified megstigmane glucosides and reported from this genus for the first time. PMID- 25908627 TI - A new polyphenol, 1, 3-di-O-caffeoyl-5-O-(1-methoxyl-2-O-caffeoyl-4-maloyl) quinic acid, isolated from cultured cells of Saussurea involucrata. AB - The present study was designed to isolate the polyphenol constituents of cultured cells of Saussurea involucrata. The polyphenol type constituents were isolated using chromatography methods, and then characterized by spectral analysis. 1,1 Diphenyl-2-picrylhydrazyl radical 2,2-Diphenyl-1-(2,4,6-trinitrophenyl)-hydrazyl (DPPH) and 2,2'-azinobis-(3-ethylbenzothiazoline-6-sulfonic acid (ABTS) free radical scavenging were assayed using Vitamin C as the positive control. One new polyphenol 18, 1, 3-di-O-caffeoyl-5-O-(1-methoxyl-2-O-caffeoyl-4-maloyl)-quinic acid, together with 17 known compounds, was isolated and characterized. In conclusion, Compound 18 was a new caffeoyl maloyl quinic acid type polyphenol and showed desired vitro anti-oxidant activity. Compounds 1-5, 9, 10, 14, 15, and 17 were isolated from cultured cells of Saussurea involucrata for the first time. PMID- 25908628 TI - Two new conjugated ketonic fatty acids from the stem bark of Juglans mandshurica. AB - The present study was designed to isolate and characterize novel chemical constituents of the stem bark of Juglans mandshurica Maxim. (Juglandaceae). The chemical constituents were isolated and purified by various chromatographic techniques. The structures of the compounds were elucidated on the basis of spectral data (1D and 2D NMR, HR-ESI-MS, CD, UV, and IR) and by the comparisons of spectroscopic data with the reported values in the literatures. Two long chain polyunsaturated fatty acids (1 and 2) were obtained and identified as (S) (8E,10E)-12-hydroxy-7-oxo-8,10-octadecadienoic acid (1) and (S)-(8E, 10E)-12 hydroxy-7-oxo-8,10-octadecadienoic acid methyl ester (2). To the best of our knowledge, this is the first report on the isolation and structural elucidation of the two new conjugated ketonic fatty acids from this genus. PMID- 25908629 TI - A novel 12, 23-epoxy dammarane saponin from Panax notoginseng. AB - The present study investigated the chemical constituents of the roots and rhizomes of Panax notoginseng. Compounds were isolated by various column chromatographic methods, and their structures were elucidated by the extensive analysis of spectroscopic data and chemical evidences. A novel 12, 23-epoxy dammarane-type saponin, named epoxynotoginsenoside A (1), together with four known compounds (2-5), was isolated and characterized. PMID- 25908630 TI - Antibacterial constituents from Melodinus suaveolens. AB - To investigate the non-alkaloidal chemical constituents of the stems and leaves of Melodinus suaveolens and their antibacterial activities. Compounds were isolated and purified by repeated silica gel, Sephadex LH-20, RP18, and preparative HPLC. Their structures were elucidated by comparison with published spectroscopic data, as well as on the basis of extensive spectroscopic analysis. The antibacterial screening assays were performed by the dilution method. Fourteen compounds were isolated, and identified as lycopersene (1), betulinic aldehyde (2), 3beta-acetoxy-22,23,24,25,26,27-hexanordammaran-20-one (3), 3a acetyl-2, 3, 5-trimethyl-7a-hydroxy-5-(4,8,12-trimethyl-tridecanyl)-1,3a,5,6,7,7a hexahydro-4-oxainden-1-one (4), 3beta-hydroxy-28-norlup-20(29)-ene-17beta hydroperoxide (5), 3beta-hydroxy-28-norlup-20(29)-ene-17alpha-hydroperoxide (6), beta-sitosterol (7), 28-nor-urs-12-ene-3beta, 17beta-diol (8), alpha-amyrin (9), ergosta-4,6,8(14),22-tetraen-3-one (10), 3beta-hydroxy-urs-11-en-28,13beta-olide (11), betulin (12), obtusalin (13), and ursolic acid (14). Among the isolates, compounds 1, 2, 6, 8, 10, and 14 showed potent antibacterial activities against the four bacteria. This is the first report of the antibacterial activity of the constituents of Melodinus suaveolens. PMID- 25908631 TI - Synthesis and cytotoxicity of longistylin C derivatives. AB - The present study was designed to identify potent anti-tumor compounds from a series of new longistylin C derivatives. Ten longistylin C derivatives were synthesized and their structures were confirmed by (1)H NMR, MS, and elemental analyses. Their cytotoxicity in vitro against three human cancer cell lines (A549, HepG2, and MCF-7) were evaluated by the MTT assay. Among these compounds, DT-6 and DT-9 displayed much better cytotoxicity against A549, HepG2, and MCF-7 cells, DT-1 exhibited selective cytotoxicity against HepG2, and the structure activity relationships were investigated. In conclusion, Compounds DT-6 and DT-9 may serve as potential lead compounds for the discovery of new anti-cancer drugs. PMID- 25908632 TI - Evaluation of the value of near infrared (NIR) spectromicroscopy for the analysis of glycyrrizhic acid in licorice. AB - It has been reported that hyperspectral data could be employed to qualitatively elucidate the spatial composition of tablets of Chinese medicinal plants. To gain more insights into this technology, a quantitative profile provided by near infrared (NIR) spectromicroscopy was further studied by determining the glycyrrhizic acid content in licorice, Glycyrrhiza uralensis. Thirty-nine samples from twenty-four different origins were analyzed using NIR spectromicroscopy. Partial least squares, interval partial least square (iPLS), and least squares support vector regression (LS-SVR) methods were used to develop linear and non linear calibration models, with optimal calibration parameters (number of interval numbers, kernel parameter, etc.) being explored. The root mean square error of prediction (RMSEP) and the coefficient of determination (R(2)) of the iPLS model were 0.717 7% and 0.936 1 in the prediction set, respectively. The RMSEP and R(2) of LS-SVR model were 0.515 5% and 0.951 4 in the prediction set, respectively. These results demonstrated that the glycyrrhizic acid content in licorice could barely be analyzed by NIR spectromicroscopy, suggesting that good quality quantitative data are difficult to obtain from microscopic NIR spectra for complicated Chinese medicinal plant materials. PMID- 25908633 TI - Insights into the regulation of neuronal viability by nucleophosmin/B23. AB - The vastness of the neuronal network that constitutes the human brain proves challenging when trying to understand its complexity. Furthermore, due to the senescent state they enter into upon maturation, neurons lack the ability to regenerate in the face of insult, injury or death. Consequently, their excessive death can be detrimental to the proper functioning of the brain. Therefore, elucidating the mechanisms regulating neuronal survival is, while challenging, of great importance as the incidence of neurological disease is becoming more prevalent in today's society. Nucleophosmin/B23 (NPM) is an abundant and ubiquitously expressed protein that regulates vital cellular processes such as ribosome biogenesis, cell proliferation and genomic stability. As a result, it is necessary for proper embryonic development, but has also been implicated in many cancers. While highly studied in the context of proliferative cells, there is a lack of understanding NPM's role in post-mitotic neurons. By exploring its role in healthy neurons as well as its function in the regulation of cell death and neurodegeneration, there can be a better understanding of how these diseases initiate and progress. Owing to what is thus far known about its function in the cell, NPM could be an attractive therapeutic target in the treatment of neurodegenerative diseases. PMID- 25908634 TI - Laboratory diagnosis of melioidosis: past, present and future. AB - Melioidosis is an emerging, potentially fatal disease caused by Burkholderia pseudomallei, which requires prolonged antibiotic treatment to prevent disease relapse. However, difficulties in laboratory diagnosis of melioidosis may delay treatment and affect disease outcomes. Isolation of B. pseudomallei from clinical specimens has been improved with the use of selective media. However, even with positive cultures, identification of B. pseudomallei can be difficult in clinical microbiology laboratories, especially in non-endemic areas where clinical suspicion is low. Commercial identification systems may fail to distinguish between B. pseudomallei and closely related species such as Burkholderia thailandensis. Genotypic identification of suspected isolates can be achieved by sequencing of gene targets such as groEL which offer higher discriminative power than 16S rRNA. Specific PCR-based identification of B. pseudomallei has also been developed using B. pseudomallei-specific gene targets such as Type III secretion system and Tat-domain protein. Matrix-assisted laser desorption ionization time of-flight mass spectrometry, a revolutionary technique for pathogen identification, has been shown to be potentially useful for rapid identification of B. pseudomallei, although existing databases require optimization by adding reference spectra for B. pseudomallei. Despite these advances in bacterial identification, diagnostic problems encountered in culture-negative cases remain largely unresolved. Although various serological tests have been developed, they are generally unstandardized "in house" assays and have low sensitivities and specificities. Although specific PCR assays have been applied to direct clinical and environmental specimens, the sensitivities for diagnosis remain to be evaluated. Metabolomics is an uprising tool for studying infectious diseases and may offer a novel approach for exploring potential diagnostic biomarkers. The metabolomics profiles of B. pseudomallei culture supernatants can be potentially distinguished from those of related bacterial species including B. thailandensis . Further studies using bacterial cultures and direct patient samples are required to evaluate the potential of metabolomics for improving diagnosis of melioidosis. PMID- 25908635 TI - Cytoskeletal prestress regulates nuclear shape and stiffness in cardiac myocytes. AB - Mechanical stresses on the myocyte nucleus have been associated with several diseases and potentially transduce mechanical stimuli into cellular responses. Although a number of physical links between the nuclear envelope and cytoplasmic filaments have been identified, previous studies have focused on the mechanical properties of individual components of the nucleus, such as the nuclear envelope and lamin network. The mechanical interaction between the cytoskeleton and chromatin on nuclear deformability remains elusive. Here, we investigated how cytoskeletal and chromatin structures influence nuclear mechanics in cardiac myocytes. Rapid decondensation of chromatin and rupture of the nuclear membrane caused a sudden expansion of DNA, a consequence of prestress exerted on the nucleus. To characterize the prestress exerted on the nucleus, we measured the shape and the stiffness of isolated nuclei and nuclei in living myocytes during disruption of cytoskeletal, myofibrillar, and chromatin structure. We found that the nucleus in myocytes is subject to both tensional and compressional prestress and its deformability is determined by a balance of those opposing forces. By developing a computational model of the prestressed nucleus, we showed that cytoskeletal and chromatin prestresses create vulnerability in the nuclear envelope. Our studies suggest the cytoskeletal-nuclear-chromatin interconnectivity may play an important role in mechanics of myocyte contraction and in the development of laminopathies by lamin mutations. PMID- 25908636 TI - Expression and promoter methylation status of hMLH1, MGMT, APC, and CDH1 genes in patients with colon adenocarcinoma. AB - Colorectal cancer (CRC) is the third most common cancer in men and the second in women worldwide. CRC development is the result of genetic and epigenetic alterations accumulation in the epithelial cells of colon mucosa. In the present study, DNA methylation, an epigenetic event, was evaluated in tumoral and matching normal epithelium in a cohort of 61 CRC patients. The results confirmed and expanded knowledge for the tumor suppressor genes hMLH1, MGMT, APC, and CDH1. Promoter methylation was observed for all the examined genes in different percentage. A total of 71% and 10% of the examined cases were found to be methylated in two or more and in all genes, respectively. mRNA and protein levels were also evaluated. Promoter methylation of hMLH1, MGMT, APC, and CDH1 genes was present at the early stages of tumor's formation and it could also be detected in the normal mucosa. Correlations of the methylated genes with patient's age and tumor's clinicopathological characteristics were also observed. Our findings suggest that DNA methylation is a useful marker for tumor progression monitoring and that promoter methylation in certain genes is associated with more advanced tumor stage, poor differentiation, and metastasis. PMID- 25908637 TI - The Role of Racial Discrimination in the Economic Value of Education Among Urban, Low-Income Latina/o Youth: Ethnic Identity and Gender as Moderators. AB - The present study used resilience theory to explore relationships among perceived racial discrimination, ethnic identity, gender, and economic value of education (EVE) among urban, low-income, Latina/o youth. It was expected that racial discrimination would predict poorer perceptions of the EVE among Latina/o adolescents. Ethnic identity was hypothesized to buffer the negative effect of racial discrimination on Latina/o students' EVE. The participants in this study were 396 urban, low-income Latina/o high school students from a large, Midwestern city who completed surveys in both 9th- and 10th-grade. Structural equation modeling was used to test the relationships among racial discrimination, ethnic identity, and EVE. Results supported a protective model of resilience. Specifically, ethnic identity served as a protective factor by buffering the negative effect of perceived racial discrimination on EVE for male participants. The present study is the first to examine ethnic identity as a buffer of racial discrimination on EVE among Latina/o high school students. Future directions and implications are discussed. PMID- 25908638 TI - Ethical concerns and dilemmas of Finnish and Dutch health professionals. AB - BACKGROUND: Healthcare professionals encounter ethical dilemmas and concerns in their practice. More research is needed to understand these ethical problems and to know how to educate professionals to respond to them. RESEARCH OBJECTIVE: To describe ethical dilemmas and concerns at work from the perspectives of Finnish and Dutch healthcare professionals studying at the master's level. RESEARCH DESIGN: Exploratory, qualitative study that used the text of student online discussions of ethical dilemmas at work as data. METHOD: Participants' online discussions were analyzed using inductive content analysis. PARTICIPANTS: The sample consisted of 49 students at master's level enrolled in professional ethics courses at universities in Finland and the Netherlands. ETHICAL CONSIDERATIONS: Permission for conducting the study was granted from both universities of applied sciences. All students provided their informed consent for the use of their assignments as research data. FINDINGS: Participants described 51 problematic work situations. Among these, 16 were found to be ethical dilemmas, and the remaining were work issues with an ethical concern and did not meet criteria of a dilemma. The most common problems resulted from concerns about quality care, safety of healthcare professionals, patients' rights, and working with too few staff and inadequate resources. DISCUSSION: The results indicated that participants were concerned about providing quality of care and raised numerous questions about how to provide it in challenging situations. The results show that it was difficult for students to differentiate ethical dilemmas from other ethical work concerns. CONCLUSION: Online discussions among healthcare providers give them an opportunity to relate ethical principles to real ethical dilemmas and problems in their work as well as to critically analyze ethical issues. We found that discussions with descriptions of ethical dilemmas and concerns by health professionals provide important information and recommendations not only for education and practice but also for health policy. PMID- 25908639 TI - Nurse moral disengagement. AB - BACKGROUND: Ethics is a founding component of the nursing profession; however, nurses sometimes find it difficult to constantly adhere to the required ethical standards. There is limited knowledge about the factors that cause a committed nurse to violate standards; moral disengagement, originally developed by Bandura, is an essential variable to consider. RESEARCH OBJECTIVES: This study aimed at developing and validating a nursing moral disengagement scale and investigated how moral disengagement is associated with counterproductive and citizenship behaviour at work. RESEARCH DESIGN: The research comprised a qualitative study and a quantitative study, combining a cross-validation approach and a structural equation model. PARTICIPANTS AND RESEARCH CONTEXT: A total of 60 Italian nurses (63% female) involved in clinical work and enrolled as students in a postgraduate master's programme took part in the qualitative study. In 2012, the researchers recruited 434 nurses (76% female) from different Italian hospitals using a convenience sampling method to take part in the quantitative study. ETHICAL CONSIDERATIONS: All the organisations involved and the university gave ethical approval; all respondents participated on a voluntary basis and did not receive any form of compensation. FINDINGS: The nursing moral disengagement scale comprised a total of 22 items. Results attested the mono-dimensionality of the scale and its good psychometric properties. In addition, results highlighted a significant association between moral disengagement and both counterproductive and citizenship behaviours. DISCUSSION: Results showed that nurses sometimes resort to moral disengagement in their daily practice, bypassing moral and ethical codes that would normally prevent them from enacting behaviours that violate their norms and protocols. CONCLUSION: The nursing moral disengagement scale can complement personnel monitoring and assessment procedures already in place and provide additional information to nursing management for designing interventions aimed at increasing compliance with ethical codes by improving the quality of the nurses' work environment. PMID- 25908640 TI - Rabies kills 59,000 people worldwide each year, study estimates. PMID- 25908641 TI - The molecular mechanism of ligand unbinding from the human telomeric G-quadruplex by steered molecular dynamics and umbrella sampling simulations. AB - G-quadruplexes are attractive drug targets in cancer therapy. Understanding the mechanisms of the binding-unbinding processes involving biomolecules and molecular recognition is essential for designing new drugs of G-quadruplexes. We performed steered molecular dynamics and umbrella sampling simulations to investigate the molecular mechanism and kinetics of ligand unbinding processes of the basket, propeller and hybrid G-quadruplex structures. Our studies of the ligand charge effect showed that Coulomb interaction plays a significant role in stabilizing the G-quadruplex structure in the unbinding process. The free energy profiles were carried out and the free energy changes associated with the unbinding process were computed quantitatively, whereas these results could help to identify accessible binding sites and transient interactions. The dynamics of the hydration shell water molecules around the G-quadruplex exhibits an abnormal Brownian motion, and the thickness and free energy of the hydration shell were estimated. A two-step relaxation scheme was theoretically developed to describe the kinetic reaction of BMVC and G-quadruplex interactions. Our computed results fall in a reasonable range of experimental data. The present investigation could be helpful in the structure-based drug design. PMID- 25908642 TI - HIV positive men as fathers: Accounts of displacement, ir/responsibility and paternal emergence. AB - It is now apparent that socio-cultural constructions of masculinity variously impact men's experiences of their HIV positive status, yet how being a father can feature in this mix remains under-researched. This study employed in-depth semi structured interviews and Foucauldian-informed discourse analysis to explore the accounts of six self-identifying heterosexual fathers (four Black African migrants, two White European) who had been living with HIV from 5 to 24 years. While the HIV-related literature calls for the need to subvert 'traditional' expressions of masculinity as a means of promoting HIV prevention and HIV health, we argue that the lived experience for HIV positive men as fathers is more socially, discursively and thus more psychologically nuanced. We illustrate this by highlighting ways in which HIV positive men as fathers are not simply making sense of themselves as a HIV positive man for whom the modern (new) man and father positions are useful strategies for adapting to HIV and combating associated stigma. Discourses of modern and patriarchal fatherhoods, a gender specific discourse of irresponsibility and the neoliberal conflation of heath and self-responsibility are also at work in the sense-making frames that HIV positive men, who are also fathers, can variously deploy. Our analysis shows how this discursive mix can underpin possibilities of often conflicted meaning and identity when living as a man and father with HIV in the United Kingdom, and specifically how discourses of fatherhood and HIV 'positive' health can complicate these men's expressions and inhabitations of masculinity. PMID- 25908643 TI - Mitoflash altered by metabolic stress in insulin-resistant skeletal muscle. AB - Central to bioenergetics and reactive oxygen species (ROS) signaling, the mitochondrion plays pivotal roles in the pathogenesis of metabolic diseases. Recent advances have shown that mitochondrial flash ("mitoflash") visualized by the biosensor mt-cpYFP affords a frequency-coded, optical readout linked to mitochondrial ROS production and energy metabolism, at the resolution of a single mitochondrion. To investigate possible mitoflash responses to metabolic stress in insulin resistance (IR), we generated an mt-cpYFP-expressing db/db mouse model with the obesity and IR phenotypes unaltered. In conjunction with in vivo imaging of skeletal muscles, we uncovered a progressive increase of mitoflash frequency along with its morphological changes. Interestingly, enhanced mitochondrial networking occurred at 12 weeks of age, and this was followed by mitochondrial fragmentation at 34 weeks. Pioglitazone treatment normalized mitoflash frequency and morphology while restored mitochondrial respiratory function and insulin sensitivity in 12 weeks mt-cpYFP db/db mice. Mechanistic study revealed that the mitoflash remodeling was associated with altered expression of proteins involved in mitochondrial dynamics and quality control. These findings indicate that mitoflash activity may serve as an optical functional readout of the mitochondria, a robust and sensitive biomarker to gauge IR stresses and their amelioration by therapeutic interventions. KEY MESSAGE: * In vivo detection of mitochondrial flashes in mt-cpYFP-expressing db/db mouse. * Mitoflash frequency increased progressively with disease development. * Mitoflash morphology revealed a biphasic change in mitochondrial networking. * Mitoflash abnormalities and mitochondrial defects are restored by pioglitazone. * Mitoflash may serve as a unique biomarker to gauge metabolic stress in insulin resistance. PMID- 25908644 TI - A novel prostate cancer therapeutic strategy using icaritin-activated arylhydrocarbon-receptor to co-target androgen receptor and its splice variants. AB - Persistent androgen receptor (AR) signaling is the key driving force behind progression and development of castration-resistant prostate cancer (CRPC). In many patients, AR COOH-terminal truncated splice variants (ARvs) play a critical role in contributing to the resistance against androgen depletion therapy. Unfortunately, clinically used antiandrogens like bicalutamide (BIC) and enzalutamide (MDV), which target the ligand binding domain, have failed to suppress these AR variants. Here, we report for the first time that a natural prenylflavonoid, icaritin (ICT), can co-target both persistent AR and ARvs. ICT was found to inhibit transcription of key AR-regulated genes, such as KLK3 [prostate-specific antigen (PSA)] and ARvs-regulated genes, such as UBE2C and induce apoptosis in AR-positive prostate cancer (PC) cells. Mechanistically, ICT promoted the degradation of both AR and ARvs by binding to arylhydrocarbon receptor (AhR) to mediate ubiquitin-proteasomal degradation. Therefore, ICT impaired AR transactivation in PC cells. Knockdown of AhR gene restored AR stability and partially prevented ICT-induced growth suppression. In clinically relevant murine models orthotopically implanted with androgen-sensitive and CRPC cells, ICT was able to target AR and ARvs, to inhibit AR signaling and tumor growth with no apparent toxicity. Our results provide a mechanistic framework for the development of ICT, as a novel lead compound for AR-positive PC therapeutics, especially for those bearing AR splice variants. PMID- 25908646 TI - Melatonin: Physiological effects in humans. AB - Melatonin is a methoxyindole synthesized and secreted principally by the pineal gland at night under normal light/dark conditions. The endogenous rhythm of secretion is generated by the suprachiasmatic nuclei and entrained to the light/dark cycle. Light is able to either suppress or synchronize melatonin production according to the light schedule. The nycthohemeral rhythm of this hormone can be evaluated by repeated measurement of plasma or saliva melatonin or urine sulfatoxymelatonin, the main hepatic metabolite. The primary physiological function of melatonin, whose secretion adjusts to night length, is to convey information concerning the daily cycle of light and darkness to body structures. This information is used for the organisation of functions, which respond to changes in the photoperiod such as the seasonal rhythms. Seasonal rhythmicity of physiological functions in humans related to possible alteration of the melatonin message remains, however, of limited evidence in temperate areas under field conditions. Also, the daily melatonin secretion, which is a very robust biochemical signal of night, can be used for the organisation of circadian rhythms. Although functions of this hormone in humans are mainly based on correlations between clinical observations and melatonin secretion, there is some evidence that melatonin stabilises and strengthens coupling of circadian rhythms, especially of core temperature and sleep-wake rhythms. The circadian organisation of other physiological functions depend also on the melatonin signal, for instance immune, antioxidant defences, haemostasis and glucose regulation. The difference between physiological and pharmacological effects of melatonin is not always clear but is based upon consideration of dose and not of duration of the hormone message. It is admitted that a "physiological" dose provides plasma melatonin levels in the same order of magnitude as a nocturnal peak. Since the regulating system of melatonin secretion is complex, following central and autonomic pathways, there are many pathophysiological situations where melatonin secretion can be disturbed. The resulting alteration could increase the predisposition to disease, add to the severity of symptoms or modify the course and outcome of the disorder. Since melatonin receptors display a very wide distribution in the body, putative therapeutic indications of this compound are multiple. Great advances in this field could be achieved by developing multicentre trials in a large series of patients, in order to establish efficacy of melatonin and absence of long-term toxicity. PMID- 25908645 TI - Circulating immune/inflammation markers in Chinese workers occupationally exposed to formaldehyde. AB - BACKGROUND: Formaldehyde has been classified as a human myeloid leukemogen. However, the mechanistic basis for this association is still debated. OBJECTIVES: We aimed to evaluate whether circulating immune/inflammation markers were altered in workers occupationally exposed to formaldehyde. METHODS: Using a multiplexed bead-based assay, we measured serum levels of 38 immune/inflammation markers in a cross-sectional study of 43 formaldehyde-exposed and 51 unexposed factory workers in Guangdong, China. Linear regression models adjusting for potential confounders were used to compare marker levels in exposed and unexposed workers. RESULTS: We found significantly lower circulating levels of two markers among exposed factory workers compared with unexposed controls that remained significant after adjusting for potential confounders and multiple comparisons using a false discovery rate of 10%, including chemokine (C-X-C motif) ligand 11 (36.2 pg/ml in exposed versus 48.4 pg/ml in controls, P = 0.0008) and thymus and activation regulated chemokine (52.7 pg/ml in exposed versus 75.0 pg/ml in controls, P = 0.0028), suggesting immunosuppression among formaldehyde-exposed workers. CONCLUSIONS: Our findings are consistent with recently emerging understanding that immunosuppression might be associated with myeloid diseases. These findings, if replicated in a larger study, may provide insights into the mechanisms by which formaldehyde promotes leukemogenesis. PMID- 25908647 TI - Single-dose dexamethasone for the prevention of pemetrexed associated cutaneous adverse reactions. AB - Pemetrexed (Alimta(r)) is a novel anti-folate antimetabolite agent that is used in combination with cisplatin for the treatment of patients with unresectable malignant pleural mesothelioma and as a single agent or in combination with cisplatin for patients with locally advanced or metastatic non-small-cell-lung cancer. Cutaneous adverse reactions are common side effects of pemetrexed for which the manufacturer recommends 3-day premedication with dexamethasone 4 mg by mouth twice daily-(the day before, the day of, and the day after treatment). Patients' adherence to this premedication regimen is of concern. We report 14 cases of metastatic non-small-cell-lung-cancer patients who were premedicated with a single dose of dexamethasone 20 mg prior to pemetrexed or pemetrexed-based chemotherapy. None of these patients reported a grade 3 or above skin reactions over the course of their treatments. These findings suggest that a single dose of dexamethasone 20 mg may be an alternative premedication regimen in patients with metastatic non small cell lung cancer receiving pemetrexed or pemetrexed-based chemotherapy. PMID- 25908648 TI - Drug treatment for adults with HIV infection. PMID- 25908649 TI - IL-9: a new culprit in atherosclerosis? PMID- 25908650 TI - Candida parapsilosis complex induces local inflammatory cytokines in immunocompetent mice. AB - Despite the increasing incidence of the Candida parapsilosis complex in the clinical setting and high mortality rates associated with disseminated infection, the host-fungus interactions regarding Candida parapsilosis sensu stricto and the closely related species C. orthopsilosis and C. metapsilosis remains blurred. In this study, we analyzed inflammatory cytokines levels and histopathology as well as fungal burden in spleen, kidney and lung of mice infected with six strains of the "psilosis" group with different enzymatic profiles. Strong interleukin 22 (IL 22) and tumor necrosis factor alpha (TNF-alpha) responses were observed in analyzed organs from infected mice (P < .0001) regardless of the species and enzymatic profile. TNF-alpha and IL-22 levels were related with spleen inflammation and fungal load. Fungal cells were detected only in spleen and kidney of infected mice, especially by day 2 post-challenge. The kidney showed glomerular retraction and partial destruction of renal tubules. Our data suggest that a strong inflammatory response, mainly of IL-22 and TNF-alpha, could be involved in Candida parapsilosis complex infection control. PMID- 25908651 TI - Phaeohyphomycosis in transplant recipients: Results from the Transplant Associated Infection Surveillance Network (TRANSNET). AB - Transplant recipients are at a high risk for developing invasive fungal infections. The agents of phaeohyphomycosis are environmental molds found worldwide, and they cause a broad spectrum of disease including skin and subcutaneous lesions, pneumonia, central nervous system disease, fungemia, and disseminated disease. Using data from the Transplant Associated Infection Surveillance Network (TRANSNET), we evaluated patients with proven and probable phaeohyphomycosis. Centers collected data on demographics, co-morbid conditions, clinical features, treatment, and three-month mortality. Fifty-six patients with phaeohyphomycosis were identified from 15 centers, comprising 26 stem cell transplant (SCT) and 30 solid organ transplant (SOT) recipients. Median time to diagnosis post-transplant was 358 days (SCT 100 days; SOT 685 days; P = <.001). The most frequent pathogen was Alternaria species (32%). Disseminated disease was found in 55.4%. Cutaneous infection was more common in SOT (53.3% vs 23.1%; P = .021), while pulmonary disease was more common in SCT (57.7 vs. 26.7; P = .019). Voriconazole (44.6%) and amphotericin B preparations (37.5%) were the most common antifungal therapies. Overall mortality was 25% and was higher in SCT than in SOT (42% vs 10%; P = <.001). A wide variety of organisms encompass phaeohyphomycosis contributing to varying types of infection in transplant recipients. Site of infection, time to disease, and mortality varies significantly between SCT and SOT recipients. Lipid formulations of amphotericin B and voriconazole were the most common antifungals used to treat this disorder. PMID- 25908652 TI - Molecular identification of Coccidioides immitis in formalin-fixed, paraffin embedded (FFPE) tissues from a Colombian patient. AB - Coccidioides immitis and C. posadasii are the etiologic agents of coccidioidomycosis, an endemic fungal disease of the Americas. In Colombia, this mycosis is uncommon, and only five cases, two of them imported, have been documented.By means of DNA sequencing, C. immitis was identified in formalin fixed, paraffin-embedded archival tissues samples from the 5th Colombian patient diagnosed in 1997. The patient was born in Pinto, Department of Magdalena, and had never visited other geographic regions, a reason to consider that the mycosis had been acquired locally.This species is primarily found in California although it has been occasionally reported in other geographic areas such as Mexico and Brazil. This is the first indigenous report of C. immitis-associated coccidioidomycosis in a Colombian patient. PMID- 25908653 TI - Spatial epidemiology of blastomycosis hospitalizations: detecting clusters and identifying environmental risk factors. AB - Blastomycosis is a disease caused by endemic fungi that ranges from severe pulmonary or disseminated to mild or asymptomatic. Environmental factors associated with it are not well described throughout the endemic area. We used the intramural State Inpatient Database from the Agency for Healthcare Research and Quality and ArcMap GIS to identify geographic high-risk clusters of blastomycosis hospitalizations in 13 states in the US endemic regions (AR, IA, IL, IN, KY, LA, MI, MN, MO, MS, OH, TN, and WI). We then used logistic regression to identify risk factors associated with these high-risk clusters. We describe six clusters of counties in which there was an elevated incidence of blastomycosis hospitalizations. We identified maximum mean annual temperature, percentage of persons aged >=65 years, and mercury and copper soil content as being associated with high-risk clusters. Specifically, the odds of a county being part of a high-risk cluster was associated with increasing percentage of population over age 65, decreasing maximum temperature, increasing mercury, and decreasing copper soil content. Healthcare providers should be aware of these high-risk areas so that blastomycosis can be included, as appropriate, in a differential diagnosis for patients currently or previously residing in these areas. PMID- 25908654 TI - Role of root microbiota in plant productivity. AB - The growing human population requires increasing amounts of food, but modern agriculture has limited possibilities for increasing yields. New crop varieties may be bred to have increased yields and be more resistant to environmental stress and pests. However, they still require fertilization to supplement essential nutrients that are normally limited in the soil. Soil microorganisms present an opportunity to reduce the requirement for inorganic fertilization in agriculture. Microorganisms, due to their enormous genetic pool, are also a potential source of biochemical reactions that recycle essential nutrients for plant growth. Microbes that associate with plants can be considered to be part of the plant's pan-genome. Therefore, it is essential for us to understand microbial community structure and their 'metagenome' and how it is influenced by different soil types and crop varieties. In the future we may be able to modify and better utilize the soil microbiota potential for promoting plant growth. PMID- 25908655 TI - Lack of replication of four candidate SNPs implicated in human male fertility traits: a large-scale population-based study. AB - STUDY QUESTION: Are the four candidate loci (rs7867029, rs12870438, rs7174015 and rs724078) for human male fertility traits, identified in a genome-wide association study (GWAS) of a Hutterite population in the USA, associated with semen quality traits in a Japanese population? SUMMARY ANSWER: The four single nucleotide polymorphisms (SNPs) rs7867029, rs12870438, rs7174015 and rs724078 have no association with semen parameters in a meta-analysis of two Japanese male cohorts. WHAT IS KNOWN ALREADY: Four (rs7867029, rs12870438, rs7174015 and rs724078) of the SNPs associated with family size or birth rate in the GWAS of a Hutterite population in the USA were associated with semen parameters in ethnically diverse men from Chicago, USA. STUDY DESIGN, SIZE, DURATION: This is a replication study in a total of 2015 Japanese subjects, including 791 fertile men and 1224 young men from the general population. PARTICIPANTS/MATERIALS, SETTING, METHODS: We performed a replication study in two cohorts to assess whether the SNPs rs7867029, rs12870438, rs7174015 and rs724078 are associated with sperm concentration, semen volume, total sperm numbers, total motile sperm numbers or sperm motility. The rs12870438 SNP was detected by restriction fragment length polymorphism PCR while rs7174015, rs724078 and rs7867029 SNPs were genotyped using TaqMan probes. MAIN RESULTS AND THE ROLE OF CHANCE: This study indicated that none of the four SNPs rs7867029, rs12870438, rs7174015 and rs724078 displayed a significant association with semen parameters in the meta-analysis of two Japanese male cohorts. LIMITATIONS, REASONS FOR CAUTION: Only four SNPs identified in the Hutterite GWAS were examined for associations with semen quality traits in a Japanese population. In addition, the linkage disequilibrium structures around the testing markers were different between ethnic groups. WIDER IMPLICATIONS OF THE FINDINGS: Locus mapping studies using a set of tagging SNPs across the loci will be necessary in populations with larger sample sizes in order to understand the contribution of specific genes to semen quality. STUDY FUNDING/COMPETING INTEREST S: This study was supported in part by the Ministry of Health and Welfare of Japan (1013201) (to T.I.), Grant-in-Aids for Scientific Research (C) (23510242) (to A.Ta.) from the Japan Society for the Promotion of Science, the European Union (BMH4-CT96-0314) (to T.I.), and the Takeda Science Foundation (to A.Ta.). None of the authors has any competing interests to declare. PMID- 25908656 TI - An association study of four candidate loci for human male fertility traits with male infertility. AB - STUDY QUESTION: Are the four candidate loci (rs7867029, rs7174015, rs12870438 and rs724078) for human male fertility traits, identified in a genome-wide association study (GWAS) of a Hutterite population in the USA, associated with male infertility in a Japanese population? SUMMARY ANSWER: rs7867029, rs7174015 and rs12870438 are significantly associated with the risk of male infertility in a Japanese population. WHAT IS KNOWN ALREADY: Recently, a GWAS of a Hutterite population in the USA revealed that 41 single-nucleotide polymorphisms (SNPs) were significantly correlated with family size or birth rate. Of these, four SNPs (rs7867029, rs7174015, rs12870438 and rs724078) were found to be associated with semen parameters in ethnically diverse men from Chicago. STUDY DESIGN, SIZE, DURATION: This is a case-control association study in a total of 917 Japanese subjects, including 791 fertile men, 76 patients with azoospermia and 50 patients with oligozoospermia. PARTICIPANTS/MATERIALS, SETTING, METHODS: Azoospermia was diagnosed on the basis of semen analysis (the absence of sperm in ejaculate), serum hormone levels and physical examinations. Oligozoospermia was defined as a sperm concentration of <20 * 10(6)/ml. We excluded patients with any known cause of infertility (i.e. obstructive azoospermia, varicocele, cryptorchidism, hypogonadotropic hypogonadism, karyotype abnormalities or complete deletion of AZF a, b or c). The SNPs rs7867029, rs7174015, rs12870438 and rs724078 were genotyped using DNA from peripheral blood samples and either restriction fragment length polymorphism PCR or TaqMan probes. Genetic associations between the four SNPs and male infertility were assessed using a logistic regression analysis under three different comparative models (additive, recessive or dominant). MAIN RESULTS AND THE ROLE OF CHANCE: The genotypes of all four SNPs were in Hardy Weinberg equilibrium in the fertile controls. The SNPs rs7867029 and rs7174015 are associated with oligozoospermia [rs7867029: odds ratio (OR) = 1.70, 95% confidence interval (CI) = 1.07-2.68, P = 0.024 (log-additive); rs7174015: OR = 6.52, 95% CI = 1.57-27.10, P = 0.0099 (dominant)] and rs12870438 is associated with azoospermia (OR = 10.90, 95% CI = 2.67-44.60, P = 0.00087 (recessive)] and oligozoospermia [OR = 8.54, 95% CI = 1.52-47.90, P = 0.015 (recessive)]. The association between rs7174015 and oligozoospermia under a dominant model and between rs12870438 and azoospermia under additive and recessive models remained after correction for multiple testing. There were no associations between rs724078 and azoospermia or oligozoospermia. LIMITATIONS, REASONS FOR CAUTION: Even though the sample size of case subjects was not very large, we found that three SNPs were associated with the risk of male infertility in a Japanese population. WIDER IMPLICATIONS OF THE FINDINGS: The three infertility-associated SNPs may be contributing to a quantitative reduction in spermatogenesis. STUDY FUNDING/COMPETING INTERESTS: This study was supported in part by the Ministry of Health and Welfare of Japan (1013201) (to T.I.), Grant-in-Aids for Scientific Research (C) (23510242) (to A.Ta.) from the Japan Society for the Promotion of Science, the European Union (BMH4-CT96-0314) (to T. I.) and the Takeda Science Foundation (to A.Ta.). None of the authors has any competing interests to declare. PMID- 25908657 TI - Quality of life outcomes in women with endometriosis are highly influenced by recruitment strategies. AB - STUDY QUESTION: To what extent are outcome measures in endometriosis-related quality of life studies influenced by the setting in which patient recruitment is performed? SUMMARY ANSWER: Quality of life outcomes in women with endometriosis are highly influenced by recruitment strategies. WHAT IS KNOWN ALREADY: Most studies on quality of life in women with endometriosis are conducted in tertiary care centres or patient associations. It is conceivable that the setting in which patient recruitment is performed influences the quality of life results. This has not been investigated before. STUDY DESIGN, SIZE, DURATION: Retrospective questionnaire based cohort study (part of the World Endometriosis Research Foundation (WERF) EndoCost study). The investigated women were recruited in three settings: a tertiary care centre for endometriosis (n = 135); five secondary care centres (n = 63); an endometriosis patient association (n = 291). PARTICIPANTS/MATERIALS, SETTING, METHODS: The secondary and tertiary care population included women with a laparoscopic and/or histological diagnosis of endometriosis. The patient association population consisted of women with a self reported diagnosis of surgically confirmed endometriosis. MAIN RESULTS AND THE ROLE OF CHANCE: The populations did not differ in terms of age, co-morbidities and education level. Delay of diagnosis was the longest in the patient association (median 7 years) (tertiary care 2 years; secondary care 1.5 years) (P < 0.001). The tertiary care population reported more laparotomies (64%) than the other populations (secondary care 43%; patient association 47%) (P = 0.002). Affected job was least prevalent in the secondary care setting (35%) (patient association 64%; tertiary care 56%) (P < 0.001). Affected relationships were most prevalent in the patient association setting (52%) (tertiary care 38%; secondary care 22%) (P < 0.001). Chronic pain was least prevalent in patients in secondary care (44%) (tertiary care 65%; patient association 61%) (P = 0.009). Substantial differences in quality of life were detected between secondary care (median physical component 50.4, mental component 49.6); tertiary care (physical component 46.2, mental component 46.2) and the patient association (physical component 45.0, mental component 44.6) (P < 0.001, P = 0.018). LIMITATIONS, REASONS FOR CAUTION: The response rate was relatively low (35%). Analysis of the hospital populations revealed that non-responders and responders did not differ with respect to age or revised American Fertility Society classification, indicating that the non-responder bias is limited. However, other factors, such as social and marital status or symptomatology, might be different for non responders. Missing values were analysed as if the symptom was not present. Missing values never exceeded 10%, except for one value. Therefore, it can be expected that the effect of missing data on the outcome is negligible. Twenty five patients belonged to more than one category. A sensitivity analysis showed that the influence of assigning patients to another category was limited. WIDER IMPLICATIONS OF THE FINDINGS: Outcomes regarding quality of life are highly influenced by recruitment strategy. None of the groups appeared to be a representative selection of the total population of women with endometriosis. An alternative strategy for creating a representative population for cost and quality of life studies is probably to recruit women who live in a specific geographic area rather than women that visit a specific hospital or are a member of a patient association. STUDY FUNDING/COMPETING INTERESTS: The WERF EndoCost study was funded by the World Endometriosis Research Foundation. The sponsors did not have a role in the design and conduct of this study: collection, management, analysis, interpretation of the data; preparation, review, approval of the manuscript. L.H. is the chief executive and T.M.D. was a board member of WERF at the time of funding. T.M.D holds the Merck-Serono Chair and the Ferring Chair in Reproductive Medicine in Leuven, Belgium and has served as consultant for Merck Serono, Schering-Plough, Astellas, and Arresto. TRIAL REGISTRATION NUMBER: Not applicable. PMID- 25908658 TI - Trans people's experiences with assisted reproduction services: a qualitative study. AB - STUDY QUESTION: What are the experiences of trans persons (i.e. those whose gender identity does not match the gender assigned to them at birth) who sought or accessed assisted reproduction (AR) services in Ontario, Canada, between 2007 and 2010? SUMMARY ANSWER: The majority of trans persons report negative experiences with AR service providers. WHAT IS KNOWN ALREADY: Apart from research examining desire to have children among trans people, most of the literature on this topic has debated the ethics of assisting trans persons to become parents. To-date, all of the published research concerning trans persons' experiences with AR services is solely from the perspective of service providers; no studies have examined the experiences of trans people themselves. STUDY DESIGN, SIZE, DURATION: Secondary qualitative research study of data from nine trans-identified people and their partners (total n = 11) collected as part of a community-based study of access to AR services for sexual and gender minority people between 2010 and 2012. PARTICIPANTS/MATERIALS, SETTING, METHODS: Trans-identified volunteers (and their partners, when applicable) who had used or attempted to access AR services since 2007 from across Ontario, Canada, participated in a 60-90 minute, semi-structured qualitative interview. Qualitative analysis was performed using a descriptive phenomenological approach. Emerging themes were continually checked against the data as part of an iterative process. MAIN RESULTS AND THE ROLE OF CHANCE: The data highlight barriers to accessing AR services for trans people. Participant recommendations for improving AR service provision to better meet the needs of this population are presented. These recommendations address the following areas: (i) AR service provider education and training; (ii) service provider and clinic practices and (iii) clinic environment. LIMITATIONS, REASONS FOR CAUTION: The majority of study participants were trans people who identified as men and who resided in major urban areas; those living in smaller communities may have different experiences that were not adequately captured in this analysis. WIDER IMPLICATIONS OF THE FINDINGS: While existing literature debates the ethics of assisting trans people to become parents through the use of AR, our study demonstrates that they are already accessing or attempting to access these services. This reality necessitates a shift toward exploring the ways in which AR services can be improved to better meet the needs of this population, from the perspectives of both service users and service providers. STUDY FUNDING/COMPETING INTERESTS: This project was supported by the Canadian Institutes of Health Research-Institute of Gender and Health, in partnership with the Assisted Human Reproduction Canada: Catalyst Grant: Psychosocial Issues Associated with Assisted Human Reproduction (FRN-103595). S.M. was supported by a Canada Graduate Scholarship from the Social Science and Humanities Research Council, as well as research funding from Osgoode Hall Law School, York University. S.J.-A. was supported by an Ontario Graduate Scholarship funded by the Province of Ontario and the University of Toronto. TRIAL REGISTRATION NUMBER: N/A. PMID- 25908659 TI - Volcanology. The Yellowstone magmatic system from the mantle plume to the upper crust. AB - The Yellowstone supervolcano is one of the largest active continental silicic volcanic fields in the world. An understanding of its properties is key to enhancing our knowledge of volcanic mechanisms and corresponding risk. Using a joint local and teleseismic earthquake P-wave seismic inversion, we revealed a basaltic lower-crustal magma body that provides a magmatic link between the Yellowstone mantle plume and the previously imaged upper-crustal magma reservoir. This lower-crustal magma body has a volume of 46,000 cubic kilometers, ~4.5 times that of the upper-crustal magma reservoir, and contains a melt fraction of ~2%. These estimates are critical to understanding the evolution of bimodal basaltic rhyolitic volcanism, explaining the magnitude of CO2 discharge, and constraining dynamic models of the magmatic system for volcanic hazard assessment. PMID- 25908660 TI - Archaeology. The makers of the Protoaurignacian and implications for Neandertal extinction. AB - The Protoaurignacian culture is pivotal to the debate about the timing of the arrival of modern humans in western Europe and the demise of Neandertals. However, which group is responsible for this culture remains uncertain. We investigated dental remains associated with the Protoaurignacian. The lower deciduous incisor from Riparo Bombrini is modern human, based on its morphology. The upper deciduous incisor from Grotta di Fumane contains ancient mitochondrial DNA of a modern human type. These teeth are the oldest human remains in an Aurignacian-related archaeological context, confirming that by 41,000 calendar years before the present, modern humans bearing Protoaurignacian culture spread into southern Europe. Because the last Neandertals date to 41,030 to 39,260 calendar years before the present, we suggest that the Protoaurignacian triggered the demise of Neandertals in this area. PMID- 25908661 TI - Anthropology. Chronicling modern human's arrival in Europe. PMID- 25908662 TI - Mitosis. Microtubule detyrosination guides chromosomes during mitosis. AB - Before chromosomes segregate into daughter cells, they align at the mitotic spindle equator, a process known as chromosome congression. Centromere-associated protein E (CENP-E)/Kinesin-7 is a microtubule plus-end-directed kinetochore motor required for congression of pole-proximal chromosomes. Because the plus-ends of many astral microtubules in the spindle point to the cell cortex, it remains unknown how CENP-E guides pole-proximal chromosomes specifically toward the equator. We found that congression of pole-proximal chromosomes depended on specific posttranslational detyrosination of spindle microtubules that point to the equator. In vitro reconstitution experiments demonstrated that CENP-E dependent transport was strongly enhanced on detyrosinated microtubules. Blocking tubulin tyrosination in cells caused ubiquitous detyrosination of spindle microtubules, and CENP-E transported chromosomes away from spindle poles in random directions. Thus, CENP-E-driven chromosome congression is guided by microtubule detyrosination. PMID- 25908664 TI - Commercial Sexual Exploitation of Children and State Child Welfare Systems. AB - In several states, commercial sexual exploitation of children (CSEC) is now a reportable child abuse offense. Illinois has taken the lead in tackling the issue and the Illinois experience illuminates valuable lessons. This article delineates the protection, practice, and policy implications that evolve when CSEC falls under a state child welfare system. The specific aims are to (a) discuss CSEC, its victims, risks, harms, and challenges inherent in providing effective care; (b) use Illinois as an exemplar to explicate the consequences and implementation challenges of establishing a state reporting system that frames CSEC as a child welfare issue; (c) recommend strategies for developing effective state reporting models, and (d) demonstrate how nurses are well poised to advocate for victims of human trafficking on both state and national levels. Recommendations for improving the identification of CSEC victims and overcoming challenges to state implementation are offered. PMID- 25908663 TI - Immune tolerance. Group 3 innate lymphoid cells mediate intestinal selection of commensal bacteria-specific CD4+ T cells. AB - Inflammatory CD4(+) T cell responses to self or commensal bacteria underlie the pathogenesis of autoimmunity and inflammatory bowel disease (IBD), respectively. Although selection of self-specific T cells in the thymus limits responses to mammalian tissue antigens, the mechanisms that control selection of commensal bacteria-specific T cells remain poorly understood. Here, we demonstrate that group 3 innate lymphoid cell (ILC3)-intrinsic expression of major histocompatibility complex class II (MHCII) is regulated similarly to thymic epithelial cells and that MHCII(+) ILC3s directly induce cell death of activated commensal bacteria-specific T cells. Further, MHCII on colonic ILC3s was reduced in pediatric IBD patients. Collectively, these results define a selection pathway for commensal bacteria-specific CD4(+) T cells in the intestine and suggest that this process is dysregulated in human IBD. PMID- 25908665 TI - A Critical Discourse Analysis of Provincial Policies Impacting Shelter Service Delivery to Women Exposed to Violence. AB - Shelters for abused women function within a broad context that includes intersecting social structures, policies, and resources, which may constrain and limit the options available to abused women and tacitly reinforce the cycle of abuse. This feminist, qualitative study combined in-depth interviews and focus groups conducted with 37 staff and four executive directors from four shelters in Ontario, Canada, along with a critical discourse analysis of salient policy texts. Together, the interviews and critical discourse analysis formed an integrated analysis of the dialectic between policy as written and enacted. The study findings illuminate the complexity of the system and its impact on women, shelters, and the community and highlight how specific types of social policies and various social system subsystems and structures, and system configuration, shape the day to day reality of shelter service delivery and impact outcomes for abused women and their children. Collectively, these findings offer direction regarding where these policies could be improved and provide a basis for shelters, policy makers, advocates, and the community to strengthen current services and policies, potentially enhancing outcomes for women. PMID- 25908666 TI - Diversity of MHC DQB and DRB Genes in the Endangered Australian Sea Lion (Neophoca cinerea). AB - Major histocompatibility complex (MHC) class II molecules have an important role in vertebrate adaptive immunity, being responsible for recognizing, binding, and presenting specific antigenic peptides to T lymphocytes. Here, we study the MHC class II DQB and DRB exon 2 genes of the Australian sea lion (Neophoca cinerea), an endangered pinniped species that experiences high pup mortality. Following characterization of N. cinerea DQB and DRB by molecular cloning, and evaluation of diversity in pups across 2 colonies using variant screening (n = 47), 3 DQB alleles and 10 DRB variants (including 1 pseudogene allele) were identified. The higher diversity at DRB relative to DQB is consistent with other studies in marine mammals. Despite overall lower MHC class II allelic diversity relative to some other pinniped species, we observed similar levels of nucleotide diversity and selection in N. cinerea. In addition, we provide support for recent divergence of MHC class II alleles. The characterization of MHC class II diversity in the Australian sea lion establishes a baseline for further investigation of associations with disease, including endemic hookworm infection, and contributes to the conservation management of this species. PMID- 25908667 TI - Species Introductions and Their Cascading Impacts on Biotic Interactions in desert riparian ecosystems. AB - Desert riparian ecosystems of North America are hotspots of biodiversity that support many sensitive species, and are in a region experiencing some of the highest rates of climatic alteration in North America. Fremont cottonwood, Populus fremontii, is a foundation tree species of this critical habitat, but it is threatened by global warming and regional drying, and by a non-native tree/shrub, Tamarix spp., all of which can disrupt the mutualism between P. fremontii and its beneficial mycorrhizal fungal communities. Specialist herbivorous leaf beetles (Diorhabda spp.) introduced for biocontrol of Tamarix are altering the relationship between this shrub and its environment. Repeated episodic feeding on Tamarix foliage by Diorhabda results in varying rates of dieback and mortality, depending on genetic variation in allocation of resources, growing conditions, and phenological synchrony between herbivore and host plant. In this article, we review the complex interaction between climatic change and species introductions and their combined impacts on P. fremontii and their associated communities. We anticipate that (1) certain genotypes of P. fremontii will respond more favorably to the presence of Tamarix and to climatic change due to varying selection pressures to cope with competition and stress; (2) the ongoing evolution of Diorhabda's life cycle timing will continue to facilitate its expansion in North America, and will over time enhance herbivore impact to Tamarix; (3) defoliation by Diorhabda will reduce the negative impact of Tamarix on P. fremontii associations with mycorrhizal fungi; and (4) spatial variability in climate and climatic change will modify the capacity for Tamarix to survive episodic defoliation by Diorhabda, thereby altering the relationship between Tamarix and P. fremontii, and its associated mycorrhizal fungal communities. Given the complex biotic/abiotic interactions outlined in this review, conservation biologists and riparian ecosystem managers should strive to identify and conserve the phenotypic traits that underpin tolerance and resistance to stressors such as climate change and species invasion. Such efforts will greatly enhance conservation restoration efficacy for protecting P. fremontii forests and their associated communities. PMID- 25908668 TI - Eco-evo-devo in the Study of Adaptive Divergence: Examples from Threespine Stickleback (Gasterosteus aculeatus). AB - The tight fit between form and function in organisms suggests the influence of adaptive evolution in biomechanics; however, the prevalence of adaptive traits, the mechanisms by which they arise and the corresponding responses to selection are subjects of extensive debate. We used three-dimensional microcomputed tomography and geometric morphometrics to characterize the structure of phenotypic covariance within the G. aculeatus trophic apparatus and its supporting structures in wild and controlled crosses of fish from two different localities. Our results reveal that while the structure of phenotypic covariance is conserved in marine and freshwater forms, it may be disrupted in the progeny of artificial crosses or during rapid adaptive divergence events. We discuss these results within the context of integrating covariance structure with quantitative genetics, toward establishing predictive links between genes, development, biomechanics, and the environment. PMID- 25908669 TI - Dopamine D1/D2 Receptor Activity in the Nucleus Accumbens Core But Not in the Nucleus Accumbens Shell and Orbitofrontal Cortex Modulates Risk-Based Decision Making. AB - BACKGROUND: It is well known that brain dopamine (DA) signals support risk-based decision making; however, the specific terminal regions of midbrain DA neurons through which DA signals mediate risk-based decision making are unknown. METHODS: Using microinfusions of the D1/D2 receptor antagonist flupenthixol, we sought to explore the role of D1/D2 receptor activity in the rat orbitofrontal cortex (OFC) and core and shell regions of the nucleus accumbens (AcbC and AcbS, respectively) in the regulation of risky choices. A risk-discounting task was used that involves choices between a certain small-reward lever that always delivered 1 pellet or a risky large-reward lever which delivered 4 pellets but had a decreasing probability of receiving the reward across 4 subsequent within-session trial blocks (100%, 50%, 25%, 12.5%). To validate task sensitivity to experimental manipulations of DA activity, we also examined the effects of systemic amphetamine and flupenthixol. RESULTS: Systemic amphetamine increased while systemic flupenthixol reduced risky choices. Results further demonstrate that rats that received intra-AcbC flupenthixol were able to track increasing risk associated with the risky lever but displayed a generally reduced preference for the risky lever across all trial blocks, including in the initial trial block (large reward at 100%). Microinfusions of flupenthixol into the AcbS or OFC did not alter risk-based decision making. CONCLUSIONS: Our data suggest that intra AcbC D1/D2 receptor signaling does not support the ability to track shifts in reward probabilities but does bias risk-based decision making. That is, it increased the rats' preference for the response option known to be associated with higher risk-related costs. PMID- 25908670 TI - Maintenance and Loss of Duplicated Genes by Dosage Subfunctionalization. AB - Whole-genome duplications (WGDs) have contributed to gene-repertoire enrichment in many eukaryotic lineages. However, most duplicated genes are eventually lost and it is still unclear why some duplicated genes are evolutionary successful whereas others quickly turn to pseudogenes. Here, we show that dosage constraints are major factors opposing post-WGD gene loss in several Paramecium species that share a common ancestral WGD. We propose a model where a majority of WGD-derived duplicates preserve their ancestral function and are retained to produce enough of the proteins performing this same ancestral function. Under this model, the expression level of individual duplicated genes can evolve neutrally as long as they maintain a roughly constant summed expression, and this allows random genetic drift toward uneven contributions of the two copies to total expression. Our analysis suggests that once a high level of imbalance is reached, which can require substantial lengths of time, the copy with the lowest expression level contributes a small enough fraction of the total expression that selection no longer opposes its loss. Extension of our analysis to yeast species sharing a common ancestral WGD yields similar results, suggesting that duplicated-gene retention for dosage constraints followed by divergence in expression level and eventual deterministic gene loss might be a universal feature of post-WGD evolution. PMID- 25908671 TI - Comparative Genomics Reveals the Origins and Diversity of Arthropod Immune Systems. AB - Insects are an important model for the study of innate immune systems, but remarkably little is known about the immune system of other arthropod groups despite their importance as disease vectors, pests, and components of biological diversity. Using comparative genomics, we have characterized the immune system of all the major groups of arthropods beyond insects for the first time--studying five chelicerates, a myriapod, and a crustacean. We found clear traces of an ancient origin of innate immunity, with some arthropods having Toll-like receptors and C3-complement factors that are more closely related in sequence or structure to vertebrates than other arthropods. Across the arthropods some components of the immune system, such as the Toll signaling pathway, are highly conserved. However, there is also remarkable diversity. The chelicerates apparently lack the Imd signaling pathway and beta-1,3 glucan binding proteins--a key class of pathogen recognition receptors. Many genes have large copy number variation across species, and this may sometimes be accompanied by changes in function. For example, we find that peptidoglycan recognition proteins have frequently lost their catalytic activity and switch between secreted and intracellular forms. We also find that there has been widespread and extensive duplication of the cellular immune receptor Dscam (Down syndrome cell adhesion molecule), which may be an alternative way to generate the high diversity produced by alternative splicing in insects. In the antiviral short interfering RNAi pathway Argonaute 2 evolves rapidly and is frequently duplicated, with a highly variable copy number. Our results provide a detailed analysis of the immune systems of several important groups of animals for the first time and lay the foundations for functional work on these groups. PMID- 25908672 TI - Violence against Congolese refugee women in Rwanda and mental health: a cross sectional study using latent class analysis. AB - OBJECTIVE: To examine patterns of conflict-related violence and intimate partner violence (IPV) and their associations with emotional distress among Congolese refugee women living in Rwanda. DESIGN: Cross-sectional study. SETTING: Two Congolese refugee camps in Rwanda. PARTICIPANTS: 548 ever-married Congolese refugee women of reproductive age (15-49 years) residing in Rwanda. PRIMARY OUTCOME MEASURE: Our primary outcome was emotional distress as measured using the Self-Report Questionnaire-20 (SRQ-20). For analysis, we considered participants with scores greater than 10 to be experiencing emotional distress and participants with scores of 10 or less not to be experiencing emotional distress. RESULTS: Almost half of women (49%) reported experiencing physical, emotional or sexual violence during the conflict, and less than 10% of women reported experiencing of any type of violence after fleeing the conflict. Lifetime IPV was reported by approximately 22% of women. Latent class analysis derived four distinct classes of violence experiences, including the Low All Violence class, the High Violence During Conflict class, the High IPV class and the High Violence During and After Conflict class. In multivariate regression models, latent class was strongly associated with emotional distress. Compared with women in the Low All Violence class, women in the High Violence During and After Conflict class and women in the High Violence During Conflict had 2.7 times (95% CI 1.11 to 6.74) and 2.3 times (95% CI 1.30 to 4.07) the odds of experiencing emotional distress in the past 4 weeks, respectively. Furthermore, women in the High IPV class had a 4.7 times (95% CI 2.53 to 8.59) greater odds of experiencing emotional distress compared with women in the Low All Violence class. CONCLUSIONS: Experiences of IPV do not consistently correlate with experiences of conflict-related violence, and women who experience high levels of IPV may have the greatest likelihood for poor mental health in conflict-affected settings. PMID- 25908673 TI - Medium-term cost-effectiveness of an automated non-invasive ventilation outpatient set-up versus a standard fixed level non-invasive ventilation inpatient set-up in obese patients with chronic respiratory failure: a protocol description. AB - INTRODUCTION: Obesity is an escalating issue, with an accompanying increase in referrals of patients with obesity-related respiratory failure. Currently, these patients are electively admitted to hospital for initiation of non-invasive ventilation (NIV), but it is unknown whether outpatient initiation is as effective as inpatient set-up. We hypothesise that outpatient set-up using an autotitrating NIV device will be more cost-effective than a nurse-led inpatient titration and set-up. METHODS AND ANALYSIS: We will undertake a multinational, multicentre randomised controlled trial. Participants will be randomised to receive the usual inpatient set-up, which will include nurse-led initiation of NIV or outpatient set-up with an automated NIV device. They will be stratified according to the trial site, gender and previous use of NIV or continuous positive airway pressure. Assuming a 10% dropout rate, a total sample of 82 patients will be required. Cost-effectiveness will be evaluated using standard treatment costs and health service utilisation as well as health-related quality of life measures (severe respiratory insufficiency (SRI) and EuroQol-5 dimensions (EQ-5D)). A change in the SRI questionnaire will be based on the analysis of covariance adjusting for the baseline measurements between the two arms of patients. ETHICS AND DISSEMINATION: This study has been approved by the Westminster National Research Ethics Committee (11/LO/0414) and is the trial registered on the UKCRN portfolio. The trial is planned to start in January 2015 with publication of the trial results in 2017. TRIAL REGISTRATION NUMBER: ISRCTN 51420481. PMID- 25908675 TI - The role of cognitive function in the relationship between age and health literacy: a cross-sectional analysis of older adults in Chicago, USA. AB - OBJECTIVES: To investigate how 3 measures of health literacy correlate with age and the explanatory roles of fluid and crystallised cognitive abilities in these relationships among older adults. DESIGN: Cross-sectional baseline analysis of the 'LitCog' cohort study. SETTING: 1 academic internal medicine clinic and 5 federally qualified health centres in Chicago, USA. PARTICIPANTS: English speaking adults (n=828) aged 55-74 years, recruited from August 2008 through October 2011. OUTCOME MEASURES: Health literacy was measured by the Test of Functional Health Literacy in Adults (TOFHLA) and the Newest Vital Sign (NVS), both of which assess reading comprehension and numeracy in health contexts, and by the Rapid Estimate of Adult Literacy in Medicine (REALM), which assesses medical vocabulary. Fluid cognitive ability was assessed through the cognitive domains of processing speed, inductive reasoning, and working, prospective and long-term memories, and crystallised cognitive ability through the verbal ability domain. RESULTS: TOFHLA and NVS scores were lower at ages 70-74 years compared with all other age groups (p<0.05 for both tests). The inverse association between age and TOFHLA score was attenuated from beta=-0.39 (95% CI -0.55 to 0.22) to beta=-0.06 (95% CI -0.20 to 0.08) for ages 70-74 vs 55-59 years when fluid cognitive ability was added to the model (85% attenuation). Similar results were seen with NVS scores (68% attenuation). REALM scores did not differ by age group (p=0.971). Crystallised cognitive ability was stable across age groups, and did not influence the relationships between age and TOFHLA or NVS performance. CONCLUSIONS: Health literacy skills show differential patterns of age-related change, which may be explained by cognitive ageing. Researchers should select health literacy tests appropriate for their purposes when assessing the health literacy of older adults. Clinicians should be aware of this issue to ensure that health self-management tasks for older patients have appropriate cognitive and literacy demands. PMID- 25908674 TI - Clinical characteristics, precipitating factors, management and outcome of patients with prior stroke hospitalised with heart failure: an observational report from the Middle East. AB - OBJECTIVES: The purpose of this study is to report the prevalence, clinical characteristics, precipitating factors, management and outcome of patients with prior stroke hospitalised with acute heart failure (HF). DESIGN: Retrospective analysis of prospectively collected data. SETTING: Data were derived from Gulf CARE (Gulf aCute heArt failuRe rEgistry), a prospective multicentre study of consecutive patients hospitalised with acute HF in 2012 in seven Middle Eastern countries and analysed according to the presence or absence of prior stroke; demographics, management and outcomes were compared. PARTICIPANTS: A total of 5005 patients with HF. OUTCOME MEASURES: In-hospital and 1-year outcome. RESULTS: The prevalence of prior stroke in patients with HF was 8.1%. Patients with stroke with HF were more likely to be admitted under the care of internists rather than cardiologists. When compared with patients without stroke, patients with stroke were more likely to be older and to have diabetes mellitus, hypertension, atrial fibrillation, hyperlipidaemia, chronic kidney disease, ischaemic heart disease, peripheral arterial disease and left ventricular dysfunction (p=0.001 for all). Patients with stroke were less likely to be smokers (0.003). There were no significant differences in terms of precipitating risk factors for HF hospitalisation between the two groups. Patients with stroke with HF had a longer hospital stay (mean+/-SD days; 11+/-14 vs 9+/-13, p=0.03), higher risk of recurrent strokes and 1-year mortality rates (32.7% vs 23.2%, p=0.001). Multivariate logistic regression analysis showed that stroke is an independent predictor of in-hospital and 1-year mortality. CONCLUSIONS: This observational study reports high prevalence of prior stroke in patients hospitalised with HF. Internists rather than cardiologists were the predominant caregivers in this high risk group. Patients with stroke had higher risk of in-hospital recurrent strokes and long-term mortality rates. TRIAL REGISTRATION NUMBER: NCT01467973. PMID- 25908676 TI - Systematic review of the effects of iodised salt and iodine supplements on prenatal and postnatal growth: study protocol. AB - INTRODUCTION: Iodine is an essential micronutrient and component of the thyroid hormones. Sufficient ingestion of iodine is necessary for normal growth and development. If iodine requirements are not met, growth can be impaired. Salt iodisation and supplementation with iodine can prevent iodine deficiency disorders and stunted growth. No systematic review has yet collated the evidence linking iodine to growth. With an increased emphasis on stunting within the WHO Global Nutrition Targets for 2025, we propose a systematic review to address this question. METHODS AND ANALYSIS: We will undertake a systematic review, and if appropriate, meta-analyses, evaluating the effects of iodised salt or iodine supplements on prenatal and postnatal somatic growth, until age 18. We will search a number of databases, including MEDLINE, EMBASE, Web of Science, CINAHL, PsychINFO, the Cochrane Library, including the CENTRAL register of Controlled Trials and also the WHO library and ICTRP (International Clinical Trials Registry Platform), which includes the Clinicaltrials.gov repository. We will also search Wanfang Data and the China Knowledge Resource Integrated Database. Included studies must have compared exposure to iodised salt, iodine supplements or iodised oil, to placebo, non-iodised salt or no intervention. Primary outcomes will be continuous and categorical markers of prenatal and postnatal somatic growth. Secondary outcomes will cover further measures of growth, including growth rates and indirect markers of growth such as insulin-like growth factor-1 (IGF-1). ETHICS AND DISSEMINATION: The systematic review will be published in a peer-reviewed journal, and will be sent directly to the WHO, United Nations Children's Fund, International Council for the Control of Iodine Deficiency Disorders and other stakeholders. The results generated from this systematic review will provide evidence to support future programme recommendations regarding iodine fortification or supplementation and child growth. TRIAL REGISTRATION NUMBER: PROSPERO CRD42014012940. PMID- 25908677 TI - The diagnostic performance evaluation of the SD BIOLINE HIV/syphilis Duo rapid test in southern Ethiopia: a cross-sectional study. AB - OBJECTIVE: To determine the diagnostic performance of the SD BIOLINE HIV/syphilis Duo rapid test. DESIGN: A hospital-based cross-sectional study. SETTING: This evaluation was conducted at one of the largest hospitals in southern Ethiopia. PARTICIPANTS: Serum samples obtained from clients attending the antiretroviral therapy and voluntary counselling and testing centres were used. Sera were originally collected for the purpose of investigating syphilis epidemiology. The performance of the test to detect HIV was evaluated using 400 sera (200 HIV positives and 200 HIV negatives). Also, its performance to detect syphilis was evaluated using 85 syphilis positive and 100 syphilis negative serum samples. Individuals <15 years of age or syphilis treated or those with <=50 cells/uL CD4 cell count were originally excluded. OUTCOME MEASURES: HIV screening was carried out according to the national rapid diagnostic testing (RDT) algorithm: Shenghai Kehua Bioengineering (KHB) test kit as a screening test, followed by the HIV1/2 STAT-PAK assay if positive. Where the result of the STAT-PAK is discordant with KHB, Unigold HIV is used as a tiebreaker to determine the result. We also used ELISA to resolve discordant HIV results. Syphilis serostatus was determined using the Treponema pallidum haemagglutination assay (TPHA). RESULTS: The respective sensitivity, specificity, positive predictive value and negative predictive value of the SD BIOLINE HIV/syphilis Duo test were 100, 99.5, 99.5 and 100% for HIV and 97.6, 96, 95.4 and 98% for syphilis testing, respectively. In reference to TPHA, the test kit reported 4 false positives and 2 false negative results for syphilis. The kappa values were 0.99 for HIV testing and 0.94 for syphilis testing. CONCLUSIONS: The excellent performance of the SD BIOLINE HIV/syphilis Duo test to detect HIV as well as syphilis facilitates the integration of syphilis testing and treatment to the already established HIV prevention programme, ultimately contributing to the dual HIV and syphilis elimination goal. PMID- 25908678 TI - Interprofessional education in the care of people diagnosed with dementia: protocol for a systematic review. AB - INTRODUCTION: Interprofessional education (IPE) offers a possible way to improve interprofessional collaboration and patient care. Current research addressing the effectiveness of IPE in dementia care is limited. A protocol is described for a systematic review to investigate the evidence for the influence of IPE on collaborative knowledge and skills; interprofessional practice and the delivery of dementia care. METHODS AND ANALYSIS: We will search the following electronic databases: PubMed, EMBASE, The Cochrane Library, PsycINFO CINAHL, Applied Social Sciences Index and Abstracts (ASSIA), ERIC British Education Index (BEI) and the Healthcare Management Information Consortium (HMIC). Additional studies will be identified by manually searching relevant journals and the reference list of selected studies. The selection of the studies, data collection and quality appraisal will be performed independently by two reviewers. Data will be initially analysed through a narrative synthesis method. If a subset of data we analyse appears comparable, we will investigate the possibility of pooling such data via formal meta-analysis analytical techniques. ETHICS AND DISSEMINATION: Ethics approval will not be required as this is a protocol for a systematic review. This systematic review aims to establish the effectiveness of IPE programmes on collaborative professional practice and the delivery of care for people with dementia. The findings of this systematic review may also identify specific gaps in the evidence informing a future agenda for research, policy and practice. It will be published in a peer-reviewed journal. TRIAL REGISTRATION NUMBER: PROSPERO CRD42014015075. PMID- 25908679 TI - Medication incidents in primary care medicine: protocol of a study by the Swiss Federal Sentinel Reporting System. AB - BACKGROUND/RATIONALE: Patient safety is a major concern in healthcare systems worldwide. Although most safety research has been conducted in the inpatient setting, evidence indicates that medical errors and adverse events are a threat to patients in the primary care setting as well. Since information about the frequency and outcomes of safety incidents in primary care is required, the goals of this study are to describe the type, frequency, seasonal and regional distribution of medication incidents in primary care in Switzerland and to elucidate possible risk factors for medication incidents. METHODS AND ANALYSIS: STUDY DESIGN AND SETTING: We will conduct a prospective surveillance study to identify cases of medication incidents among primary care patients in Switzerland over the course of the year 2015. PARTICIPANTS: Patients undergoing drug treatment by 167 general practitioners or paediatricians reporting to the Swiss Federal Sentinel Reporting System. INCLUSION CRITERIA: Any erroneous event, as defined by the physician, related to the medication process and interfering with normal treatment course. EXCLUSION CRITERIA: Lack of treatment effect, adverse drug reactions or drug-drug or drug-disease interactions without detectable treatment error. PRIMARY OUTCOME: Medication incidents. RISK FACTORS: Age, gender, polymedication, morbidity, care dependency, hospitalisation. STATISTICAL ANALYSIS: Descriptive statistics to assess type, frequency, seasonal and regional distribution of medication incidents and logistic regression to assess their association with potential risk factors. Estimated sample size: 500 medication incidents. LIMITATIONS: We will take into account under-reporting and selective reporting among others as potential sources of bias or imprecision when interpreting the results. ETHICS AND DISSEMINATION: No formal request was necessary because of fully anonymised data. The results will be published in a peer-reviewed journal. TRIAL REGISTRATION NUMBER: NCT0229537. PMID- 25908680 TI - Antibacterial drug shortages from 2001 to 2013: implications for clinical practice. AB - BACKGROUND: Previous studies have described drug shortages; however, there has been no comprehensive evaluation focusing on US antibacterial shortages. METHODS: Drug shortage data from the University of Utah Drug Information Service database were analyzed, with a focus on antibacterial agents from 2001 to 2013. We used descriptive statistics to describe trends in drug shortages, analyze drug classes commonly affected, and investigate whether drugs experienced multiple periods of shortages. RESULTS: One hundred forty-eight antibacterial drugs were on shortage over the 13-year study period, with 26 drugs still active on shortage as of December 2013. The median number of new shortages per year was 10 (interquartile range [IQR], 7). The number of drugs on shortage increased at a rate of 0.35 additional drugs every month (95% confidence interval, .22-.49) from July 2007 to December 2013 (P < .001). The median shortage duration was 188 days (IQR, 366.5). Twenty-two percent of drugs experienced multiple shortage periods. CONCLUSIONS: There were a substantial number of drug shortages from 2001 to 2013, with a dramatic rise in shortages since 2007. Shortages of agents used to treat multidrug-resistant infections are of concern due to continued transmission and limited treatment options. PMID- 25908681 TI - Editorial Commentary: Unmasking the Bare Bones of HIV Preexposure Prophylaxis. PMID- 25908683 TI - Characteristics and Clinical Outcome of Bone and Joint Tuberculosis From 1994 to 2011: A Retrospective Register-based Study in Denmark. AB - BACKGROUND: Most information on bone-joint (BJ)-tuberculosis is based on data from high-incidence areas. We conducted a nationwide register-based analysis of BJ-tuberculosis in Denmark from 1994 to 2011. METHODS: We linked data from the national tuberculosis surveillance system on BJ-tuberculosis, hospital records, the Danish Hospital and Civil Registration System. RESULTS: We identified 282 patients with BJ-tuberculosis, 3.6% of all tuberculosis cases (n = 7936). Spinal tuberculosis was found in 153 of 282 patients (54.3%); 83.3% of all cases were immigrants. Danes were older and had higher Charlson comorbidity index scores than immigrants (P < .01). C-reactive protein and erythrocyte sedimentation rates were elevated in most cases. Median time to diagnosis after first hospital contact was 19.5 days for spinal tuberculosis and 28 days for other forms of BJ tuberculosis (P = .01). Of patients with spinal tuberculosis, 54/133 (40.6%) had neurologic deficits at admission and 17.3% presented with cauda equina. Diagnosis was culture verified in 87%. (Resistance to any drug was found in 10.2%). Median time on antituberculous treatment for patients with spinal and other forms of BJ tuberculosis was 9 months and 7 months, respectively (P < .01). Surgery was required in 44.4% patients with spinal tuberculosis and in 32.6% patients with other forms of BJ-tuberculosis (P = .04). Sequelae were reported in 57.5% of patients with spinal tuberculosis and 29.1% of patient with other forms of BJ tuberculosis (P < .01). One-year mortality was 25.5% among Danes compared with 1.3% among immigrants (P < .01). CONCLUSIONS: BJ-tuberculosis was rare and seen mainly in younger immigrants in Denmark. More than half of cases were spinal tuberculosis, presenting with more severe symptoms and worse outcome, compared with other forms of BJ-tuberculosis. PMID- 25908682 TI - Effects of Emtricitabine/Tenofovir on Bone Mineral Density in HIV-Negative Persons in a Randomized, Double-Blind, Placebo-Controlled Trial. AB - BACKGROUND: Daily preexposure prophylaxis (PrEP) with oral emtricitabine and tenofovir disoproxil fumarate (FTC/TDF) decreases the risk of human immunodeficiency virus (HIV) acquisition. Initiation of TDF decreases bone mineral density (BMD) in HIV-infected people. We report the effect of FTC/TDF on BMD in HIV-seronegative men who have sex with men and in transgender women. METHODS: Dual-energy X-ray absorptiometry was performed at baseline and 24-week intervals in a substudy of iPrEx, a randomized, double-blind, placebo-controlled trial of FTC/TDF PrEP. Plasma and intracellular tenofovir concentrations were measured in participants randomized to FTC/TDF. RESULTS: In 498 participants (247 FTC/TDF, 251 placebo), BMD in those randomized to FTC/TDF decreased modestly but statistically significantly by 24 weeks in the spine (net difference, -0.91% [95% confidence interval {CI}, -1.44% to -.38%]; P = .001) and hip (-0.61% [95% CI, .96% to -.27%], P = .001). Changes within each subsequent 24-week interval were not statistically significant. Changes in BMD by week 24 correlated inversely with intracellular tenofovir diphosphate (TFV-DP), which was detected in 53% of those randomized to FTC/TDF. Net BMD loss by week 24 in participants with TFV-DP levels indicative of consistent dosing averaged -1.42% +/- 29% and -0.85% +/- 19% in the spine and hip, respectively (P < .001 vs placebo). Spine BMD tended to rebound following discontinuation of FTC/TDF. There were no differences in fractures (P = .62) or incidence of low BMD. CONCLUSIONS: In HIV-uninfected persons, FTC/TDF PrEP was associated with small but statistically significant decreases in BMD by week 24 that inversely correlated with TFV-DP, with more stable BMD thereafter. CLINICAL TRIALS REGISTRATION: NCT00458393. PMID- 25908684 TI - Risk of cardiovascular events associated with current exposure to HIV antiretroviral therapies in a US veteran population. AB - BACKGROUND: To characterize the association of antiretroviral drug combinations on risk of cardiovascular events. METHODS: Certain antiretroviral medications for human immunodeficiency virus (HIV) have been implicated in increasing risk of cardiovascular disease. However, antiretroviral drugs are typically prescribed in combination. We characterized the association of current exposure to antiretroviral drug combinations on risk of cardiovascular events including myocardial infarction, stroke, percutaneous coronary intervention, and coronary artery bypass surgery. We used the Veterans Health Administration Clinical Case Registry to analyze data from 24 510 patients infected with HIV from January 1996 through December 2009. We assessed the association of current exposure to 15 antiretroviral drugs and 23 prespecified combinations of agents on the risk of cardiovascular event by using marginal structural models and Cox models extended to accommodate time-dependent variables. RESULTS: Over 164 059 person-years of follow-up, 934 patients had a cardiovascular event. Current exposure to abacavir, efavirenz, lamivudine, and zidovudine was significantly associated with increased risk of cardiovascular event, with odds ratios ranging from 1.40 to 1.53. Five combinations were significantly associated with increased risk of cardiovascular event, all of which involved lamivudine. One of these-efavirenz, lamivudine, and zidovudine-was the second most commonly used combination and was associated with a risk of cardiovascular event that is 1.60 times that of patients not currently exposed to the combination (odds ratio = 1.60, 95% confidence interval, 1.25 2.04). CONCLUSIONS: In the VA cohort, exposure to both individual drugs and drug combinations was associated with modestly increased risk of a cardiovascular event. PMID- 25908685 TI - Myostatin Neutralization Results in Preservation of Muscle Mass and Strength in Preclinical Models of Tumor-Induced Muscle Wasting. AB - Skeletal muscle wasting occurs in a great majority of cancer patients with advanced disease and is associated with a poor prognosis and decreased survival. Myostatin functions as a negative regulator of skeletal muscle mass and has recently become a therapeutic target for reducing the loss of skeletal muscle and strength associated with clinical myopathies. We generated neutralizing antibodies to myostatin to test their potential use as therapeutic agents to attenuate the skeletal muscle wasting due to cancer. We show that our neutralizing antimyostatin antibodies significantly increase body weight, skeletal muscle mass, and strength in non-tumor-bearing mice with a concomitant increase in mean myofiber area. The administration of these neutralizing antibodies in two preclinical models of cancer-induced muscle wasting (C26 colon adenocarcinoma and PC3 prostate carcinoma) resulted in a significant attenuation of the loss of muscle mass and strength with no effect on tumor growth. We also show that the skeletal muscle mass- and strength-preserving effect of the antibodies is not affected by the coadministration of gemcitabine, a common chemotherapeutic agent, in both non-tumor-bearing mice and mice bearing C26 tumors. In addition, we show that myostatin neutralization with these antibodies results in the preservation of skeletal muscle mass following reduced caloric intake, a common comorbidity associated with advanced cancer. Our findings support the use of neutralizing antimyostatin antibodies as potential therapeutics for cancer-induced muscle wasting. PMID- 25908686 TI - A primer on network meta-analysis with emphasis on mental health. AB - OBJECTIVE: A quantitative synthesis of evidence via standard pair-wise meta analysis lies on the top of the hierarchy for evaluating the relative effectiveness or safety between two interventions. In most healthcare problems, however, there is a plethora of competing interventions. Network meta-analysis allows to rank competing interventions and evaluate their relative effectiveness even if they have not been compared in an individual trial. The aim of this paper is to explain and discuss the main features of this statistical technique. METHODS: We present the key assumptions underlying network meta-analysis and the graphical methods to visualise results and information in the network. We used one illustrative example that compared the relative effectiveness of 15 antimanic drugs and placebo in acute mania. RESULTS: A network plot allows to visualise how information flows in the network and reveals important information about network geometry. Discrepancies between direct and indirect evidence can be detected using inconsistency plots. Relative effectiveness or safety of competing interventions can be presented in a league table. A contribution plot reveals the contribution of each direct comparison to each network estimate. A comparison adjusted funnel plot is an extension of simple funnel plot to network meta analysis. A rank probability matrix can be estimated to present the probabilities of all interventions assuming each rank and can be represented using rankograms and cumulative probability plots. CONCLUSIONS: Network meta-analysis is very helpful in comparing the relative effectiveness and acceptability of competing treatments. Several issues, however, still need to be addressed when conducting a network meta-analysis for the results to be valid and correctly interpreted. PMID- 25908687 TI - Common childhood neurodevelopmental disorders are associated with increased risk of psychotic experiences in early adolescence. PMID- 25908688 TI - Providing assessable information on effectiveness of maintenance treatments for bipolar disorder to psychiatrists and patients. PMID- 25908689 TI - Sustained antipsychotic effect and delayed self-esteem improvement of metacognitive training for schizophrenia. PMID- 25908690 TI - Improving outcome of paediatric depression with cognitive-behavioural therapy (CBT) after initial improvement on antidepressant medication. PMID- 25908691 TI - Focal atrial tachycardia surrounding the anterior septum: strategy for mapping and catheter ablation. AB - BACKGROUND: Focal atrial tachycardias (ATs) surrounding the anterior atrial septum (AAS) have been successfully ablated from the right atrial septum (RAS), the aortic cusps, and the aortic mitral junction. However, the strategy for mapping and ablation of AAS-ATs has not been well defined. METHODS AND RESULTS: Of 227 consecutive patients with AT, 47 (20.7%; mean age, 56.3+/-11.6 years) with AAS-ATs were studied; among them, initial ablation was successful at RAS in only 5 of 14 patients and at noncoronary cusp (NCC) in 28 of 33 patients. In 45 of the 47 patients, the 46 of 48 AAS-ATs were eliminated at RAS in 8 patients, NCC in 35 patients (earliest activation time at NCC was later than that at RAS by 5-10 ms in 6 patients), and aortic mitral junction in 3 patients (all with negative P wave in lead aVL and positive P wave in the inferior leads), including 1 patient whose 2 ATs were eliminated separately from the NCC and the aortic mitral junction. CONCLUSIONS: Most of the ATs surrounding the AAS can be eliminated from within the NCC, which is usually the preferential ablation site. Ablation at the RAS and aortic mitral junction should be considered when supported by P-wave morphologies on surface ECG and results of activation mapping and ablation. PMID- 25908693 TI - Ateplase for ischaemic stroke: increased risk of intracranial haemorrhage is balanced by improved stroke outcomes, particularly if treated within 3-4.5 h of onset. PMID- 25908692 TI - Small conductance calcium-activated potassium current is important in transmural repolarization of failing human ventricles. AB - BACKGROUND: The transmural distribution of apamin-sensitive small conductance Ca(2+)-activated K(+) (SK) current (IKAS) in failing human ventricles remains unclear. METHODS AND RESULTS: We optically mapped left ventricular wedge preparations from 12 failing native hearts and 2 rejected cardiac allografts explanted during transplant surgery. We determined transmural action potential duration (APD) before and after 100 nmol/L apamin administration in all wedges and after sequential administration of apamin, chromanol, and E4031 in 4 wedges. Apamin prolonged APD from 363 ms (95% confidence interval [CI], 341-385) to 409 (95% CI, 385-434; P<0.001) in all hearts, and reduced the transmural conduction velocity from 36 cm/s (95% CI, 30-42) to 32 cm/s (95% CI, 27-37; P=0.001) in 12 native failing hearts at 1000 ms pacing cycle length (PCL). The percent APD prolongation is negatively correlated with baseline APD and positively correlated with PCL. Only 1 wedge had M-cell islands. The percentages of APD prolongation in the last 4 hearts at 2000 ms PCL after apamin, chromanol, and E4031 were 9.1% (95% CI, 3.9-14.2), 17.3% (95% CI, 3.1-31.5), and 35.9% (95% CI, 15.7-56.1), respectively. Immunohistochemical staining of subtype 2 of SK protein showed increased expression in intercalated discs of myocytes. CONCLUSIONS: SK current is important in the transmural repolarization in failing human ventricles. The magnitude of IKAS is positively correlated with the PCL, but negatively correlated with APD when PCL is fixed. There is abundant subtype 2 of SK protein in the intercalated discs of myocytes. PMID- 25908694 TI - Comparison of intracoronary versus intravenous administration of adenosine for measurement of coronary fractional flow reserve. AB - BACKGROUND: Measurement of fractional flow reserve (FFR) constitutes the current gold standard to evaluate the hemodynamic significance of coronary stenoses. Limited data validate the intracoronary application of adenosine against standard intravenous infusion. We systematically compared FFR measurements during intracoronary and intravenous application of adenosine about agreement and reproducibility. METHODS AND RESULTS: We included 114 patients with an intermediate degree of stenosis in coronary angiography. Two FFR measurements were performed during intracoronary bolus injection (40 MUg for the right and 80 MUg for the left coronary artery, FFRic), and 2 FFR measurements during continuous intravenous infusion of adenosine (140 MUg/kg per minute, FFRiv). FFR value, the time to reach FFR and patient discomfort (on a subjective scale from 0 for no symptoms to 5 for maximal discomfort) were recorded for each measurement. Mean time to FFR was 100 +/- 27 s for continuous intravenous infusion versus 23 +/- 14 s for intracoronary bolus administration of adenosine (P < 0.001). Reported discomfort after intracoronary application was significantly lower compared with intravenous adenosine (subjective scale > 0 in 35.1% versus 87.7% of the patients; P < 0.001). Correlation between FFRiv and FFRic was extremely close (r = 0.99; P < 0.001) with no systematic bias in Bland-Altman analysis (bias 0.002 [confidence interval, -0.001 to 0.005]) and low intermethod variability (1.56%). Intramethod variability was not different between intravenous and intracoronary administration (1.47% versus 1.33%; P=0.5). CONCLUSIONS: Intracoronary bolus injection of adenosine (40 MUg for the right and 80 MUg for the left coronary artery) yields identical FFR results compared with intravenous infusion (140 MUg/kg per minute), while requiring less time and offering superior patient comfort. PMID- 25908695 TI - Surgical anatomy relevant to the transpalpebral subperiosteal elevation of the midface. AB - BACKGROUND: The surgical anatomy of the midface relevant to its subperiosteal elevation and repositioning is assessed. OBJECTIVES: The aim of this study is to give more details on the anatomy relevant to the midface lift. METHODS: Twenty hemifacial dissections were performed. The location of the zygomatic branches of the facial nerve (ZBFN) and the terminal branches of the infraorbital nerve (ION) were dissected. The location of the masseteric and zygomatic ligaments and the elevation of midface following their release were documented. RESULTS: On average, there were 3 branches of the facial nerve innervating the zygomatic major muscle and 1.8 branches entering the muscle superior to the caudal origin of the zygomaticomaxillary (ZM) suture. The most superior ZBFN was found to lie at an average of 6.2 +/- 1.6 mm cranial to ZM suture and 1.4 +/- 0.4 mm superficial to the bone. The most inferior branch was at a mean of 4.8 +/- 3.3 mm inferior to ZM suture. On average the ION had 5.2 branches that traveled for 10.2 mm above the periosteum before they passed into a superficial plane. Division of the zygomatico-masseteric retaining ligaments allowed for elevation of the midface by 4.8 +/- 1.0 mm medially and 5.5 +/- .9 mm laterally. CONCLUSIONS: Branches of the ZBFN and ION lie in close proximity to the subperiosteal plane in the midface. These branches are at risk for damage during release of the upper zygomatic ligaments and placement of the periosteal suspension sutures during midface elevation procedures. PMID- 25908696 TI - The plunging tip: analysis and surgical treatment. AB - BACKGROUND: The plunging tip refers to a deformity in which the nasal tip plunges on smiling. OBJECTIVES: To understand the plunging tip, we have updated our series of 25 cosmetic rhinoplasty patients who complained of a plunging tip with a focus on the anatomic changes of the nose on smiling. METHODS: Twenty-five female cosmetic primary rhinoplasty patients who complained of a nasal tip that plunged on smiling were photographed in static and smiling sequences preoperatively and one year postoperatively. Different nasal angles and landmarks were measured to study changes of the nose. RESULTS: Pre- and postoperatively, there was no statistically significant difference in the changes in the nasal angles and landmarks on smiling. At one year postoperatively, 2 patients had nasal tips that continued to plunge on smiling; these patients had requested no increase in tip rotation preoperatively. Only 2 patients had columellar base muscles cut for reasons other than treating the plunging tip. CONCLUSIONS: This is the first prospective, evidence-based study on the plunging tip. Measurements of the nose before and after surgery demonstrate that the nasal tip moves less than 1 mm and 1 degree on smiling. Treatment of the plunging tip illusion was effective by increasing the tip angle in repose. No columellar base muscles were cut to treat the plunging tip, and the nose moved just as much after surgery as before. Cutting or manipulating muscles is not necessary for treatment. To treat the illusion, the surgeon must increase tip rotation. PMID- 25908697 TI - Autologous fat grafting for cosmetic breast augmentation: a systematic review. AB - BACKGROUND: Breast augmentation is one of the most popular aesthetic surgical procedures. The only potential alternative is autologous fat grafting (AFG), which is not new in principle. This procedure has been used on native breasts since 2009, following the recommendations of some learned societies. OBJECTIVES: We performed a systematic review to determine the current worldwide status of fat grafting for aesthetic breast augmentation. METHODS: A systematic review of the literature following the Preferred Reporting Items for Systematic Reviews and Meta-Analysis criteria was conducted using the PubMed, EmBASE, and Cochrane library databases. This protocol was registered at the National Institute for Health Research, Prospective Register of Systematic Reviews. RESULTS: A total of 42 articles published between 1987 and July 2014 were included. Most of the studies had a low level of evidence, with only one level 2 study, published by Spear (2014), a prospective cohort study which included 10 patients. The publications were from North America, Europe, and Asia. The indications were aesthetic augmentation (92.4%) and congenital malformation (7.6%). Two cases of cancer were reported among the 2023 patients included (0.09%), with a mean follow up of 22 months, although the follow-up was insufficient for medium- and long term cancer diagnoses. CONCLUSIONS: AFG seems to be a major tool in this field, but we must remain cautious about its systematization for this indication. Preoperative patient selection is essential but underreported. AFG appears particularly relevant in breast malformations. We believe that this method should be practiced within the scope of a national or international registry with proper follow-up of patients. PMID- 25908698 TI - Correction of small volume breast asymmetry using deep parenchymal resection and identical silicone implants: an early experience. AB - BACKGROUND: Virtually all patients presenting for augmentation mammaplasty will exhibit some degree of asymmetry. The use of asymmetric implants to address small volume breast asymmetry introduces uncontrolled variables into the longevity of postoperative results. OBJECTIVES: We described a novel method of addressing small-volume asymmetry using deep parenchymal resection (DPR) to achieve symmetry prior to insertion of identical implants. We also compared our results with this technique to a cohort of standard augmentation mammaplasty patients. METHODS: All patients underwent 3-dimensional (3D) imaging during consultation. In patients with small-volume breast asymmetry, a uniform disk of deep parenchymal tissue was resected from the base of the larger breast cone through an inframammary incision. A standard submuscular augmentation was then completed. Five patients (DPR group) with appreciable small-volume asymmetry underwent DPR in the larger breast prior to insertion of identical implants. Fifty-six consecutive patients with no appreciable volume asymmetry (standard group) underwent standard submuscular breast augmentation. RESULTS: Using 3D imaging preoperatively, DPR group patients had an estimated breast volume asymmetry of 86 +/- 58 g and had 55 +/- 27 g excised from the larger breast intraoperatively, allowing for insertion of identical implants in each patient. Complications in the standard group included 1 case of rippling and 2 cases of malposition. One case of malposition was noted in the DPR group. No other complications were recorded in either group over 6 months. CONCLUSIONS: Our novel method of addressing small-volume breast asymmetry allows for the use of identical implants and presents no increase in early complications. PMID- 25908699 TI - Labia minora reduction techniques: a comprehensive literature review. AB - BACKGROUND: Many studies of techniques to reduce the labia minora have been published in recent decades, including case reports and retrospective case series. However, to date, there has been no study of the overall complications or satisfaction rates associated with the broad spectrum of techniques. OBJECTIVES: The authors performed a comprehensive literature review to determine outcomes and complications of labiaplasty techniques, including patient satisfaction. METHODS: A search on PubMed/Medline was performed with the keywords labiaplasty, labioplasty, labial hypertrophy, and techniques plus labia minora reduction. The inclusion criterion was clinical studies in which techniques of labia minora reduction were described. Excluded from the study were publications not dealing with surgical procedures and review articles. RESULTS: Thirty-eight studies, published from 1971 through 2014, were included; this represented 1981 treated patients. Eight labiaplasty techniques were identified from these studies: edge resection, wedge resection, deepithelialization, W-plasty, laser labiaplasty, custom flask, fenestration, and composite reduction. Satisfactory results, judged from clinical examination, were observed with all 8 techniques. Few postoperative complications occurred. In a small number of cases, complications required surgical revision or secondary resection. CONCLUSIONS: All 8 labiaplasty techniques resulted in good outcomes, including high patient satisfaction and low morbidity. PMID- 25908700 TI - Commentary on: Labia Minora Reduction Techniques: A Comprehensive Literature Review. PMID- 25908701 TI - Lipoabdominoplasty without drains or progressive tension sutures: an analysis of 100 consecutive patients. AB - BACKGROUND: Subcutaneous surgical drains are commonly used in abdominoplasties to prevent seromas but are not tolerated well by patients and add additional discomfort after the procedure. The lipoabdominoplasty modification may create a more favorable surgical field to reduce the need for surgical drains without increasing seroma formation. OBJECTIVES: The goal of this review was to determine if surgical drains can be completely eliminated in lipoabdominoplasty procedures without an increased risk of seromas. METHODS: The authors conducted a retrospective chart review of 100 consecutive standard, extended, and circumferential lipoabdominoplasty patients done by a single surgeon with at least a 3-month follow-up period. RESULTS: Seroma was identified in 5% of patients, hematoma and abscess each in 2% of patients, and granuloma, cellulitis, and delayed wound healing each in 1% of patients. CONCLUSIONS: The use of discontinuous undermining with liposuction, limited direct undermining in the midline, preservation of a thin layer of fibrofatty tissue on the superficial abdominal wall fascia, and targeted surgical site compression can eliminate the need for surgical drains without increasing seroma rates. PMID- 25908702 TI - Commentary on: Lipoabdominoplasty Without Drains or Progressive Tension Sutures: An Analysis of 100 Consecutive Patients. PMID- 25908703 TI - A blinded, randomized, split-face pilot study of bruising and pain with hyaluronic acid for correction of perioral lines using no lidocaine, lidocaine alone, and lidocaine and epinephrine. AB - BACKGROUND: Hyaluronic acid (HA) fillers are sometimes mixed with lidocaine to mitigate pain. Whether the addition of epinephrine to lidocaine provides greater benefits in bruising and pain has not been fully reported. OBJECTIVES: The investigators explored the severity of bruising and pain in patients treated with the cohesive polydensified matrix HA (CPMHA) in 3 different preparations: CPMHA (Belotero Balance [BEL]), CPMHA with lidocaine (BEL-L), and CPMHA with lidocaine and epinephrine (BEL-LE). METHODS: In a blinded, split-face, 14-day study, 30 patients were divided into groups of 10. One group received 1.0 mL BEL in the perioral lines on 1 side and 1.0 mL of BEL-LE on the other side. A second group received 1.0 mL of BEL on 1 side and 1.0 mL of BEL-L on the other side. The third group received 1.0 mL of BEL-L on 1 side and 1.0 mL of BEL-LE on the other side. Over 3 visits, the treating investigator, the patients, and a blinded investigator rated the bruising. RESULTS: Bruising occurred in each treatment group by day 1 but resolved for half of the patients by day 7 and for all patients by day 14. Split-face comparison did not reveal a significant difference in pain and bruising scores among the 3 preparations. CONCLUSIONS: No significant difference was found in bruising or pain in patients treated with BEL, BEL-L, and BEL-LE. Studies with a considerably larger sample size are warranted to determine statistically significant and clinically meaningful differences between and among the various formulations. PMID- 25908704 TI - Factors influencing judicial decisions on medical disputes in plastic surgery. AB - BACKGROUND: Recently, more lawsuits have been filed by patients against their plastic surgeons, often leading to social and financial losses for the physicians involved. OBJECTIVES: The authors sought to determine the factors that influence judicial decisions against plastic surgeons. METHODS: Data from 98 malpractice claims filed between January 1 2000 and December 31 2008 were obtained from a state court of justice in Brazil. The authors selected 39 closed cases for this study. The following parameters were reviewed for each case: date of decision, complaint(s), conclusions of expert report, presence/absence of informed consent, medical records, and judicial decision. The chi-square test, Cramer's V coefficient, Fisher's exact test, and Cochran-Armitage test were utilized to compare data. Significance was defined as P <= .05. RESULTS: Most lawsuits pertained to breast surgery (32%), abdominoplasty (24%), rhinoplasty (22%), and liposuction (22%). The most common complaints were scars and resulting contour (48.9%), general dissatisfaction (25.6%), and complications (25.2%). In all cases with medical records considered of "good quality" by the judge (n = 17), the surgeon was acquitted. There was a significant correlation between decisions favoring the surgeon and the presence of written informed consent documentation. "Not guilty" verdicts also were associated with expert report conclusions favoring the physician. Surgeons were found guilty of malpractice in cases that failed to meet at least 2 of these 3 conditions (good-quality medical record, informed consent, expert report favoring the surgeon). CONCLUSIONS: Factors that heavily influenced judicial decisions were the quality of medical records, informed consent, and expert report conclusions. PMID- 25908705 TI - Commentary on: Factors Influencing Judicial Decisions on Medical Disputes in Plastic Surgery. PMID- 25908706 TI - Aquipuribacter nitratireducens sp. nov., isolated from a soil sample of a mud volcano. AB - A novel Gram-stain-positive, coccoid, non-motile bacterium, designated strain AMV4T, was isolated from a soil sample collected from a mud volcano located in the Andaman Islands, India. The colony was pale orange. Strain AMV4T was positive for oxidase, aesculinase, lysine decarboxylase and ornithine decarboxylase activities and negative for amylase, catalase, cellulase, protease, urease and lipase activities. 16S rRNA gene sequence analysis indicated that strain AMV4T was a member of the order Actinomycetales and was closely related to Aquipuribacter hungaricus with a sequence similarity of 97.13% (pairwise alignment). Phylogenetic analyses showed that strain AMV4T clustered with Aquipuribacter hungaricus and was distantly related to the other genera of the family Intrasporangiaceae. DNA-DNA hybridization between strains AMV4T and Aquipuribacter hungaricus IV-75T showed a relatedness of 28%. The predominant cellular fatty acids were iso-C15 : 0 (6.9%), anteiso-C15 : 0 (25.3%), C16 : 0 (12.9%), anteiso-C16 : 0 (5.6%), C18 : 1omega9c (19.8%) and C18 : 3omega6,9,12c (9.1%). The diagnostic diamino acid in the cell-wall peptidoglycan of strain AMV4T was meso-diaminopimelic acid. Strain AMV4T contained MK-10(H4) as the predominant respiratory quinone. The polar lipids consisted of phosphatidylglycerol, one unidentified glycolipid, two unidentified phospholipids and five unidentified lipids. The DNA G+C content of strain AMV4T was 74.3 mol%. Based on data from this taxonomic study using a polyphasic approach, it is proposed that strain AMV4T represents a novel species of the genus Aquipuribacter, with the suggested name Aquipuribacter nitratireducens sp. nov. The type strain is AMV4T ( = CCUG 58430T = DSM 22863T = NBRC 107137T). PMID- 25908707 TI - The status of the species Bacillus aerius. Request for an Opinion. AB - During a recent study assessing the diversity of the species Bacillus licheniformis, it became apparent that the type strain of Bacillus aerius was not available from any established culture collection or from the authors who originally described it. Other authors have reported similar findings when trying to obtain the strain (Lai et al., 2014), therefore, this species cannot currently be included in any further scientific studies. It is proposed that, if suitable replacements for type strains are not found or neotype strains are not proposed within two years following the publication of this Request for an Opinion, the Judicial Commission of the International Committee of Systematics of Prokaryotes place the name B. aerius on the list of rejected names. PMID- 25908708 TI - Bacillus caseinilyticus sp. nov., an alkali- and thermotolerant bacterium isolated from a soda lake. AB - A novel Gram-stain-positive, rod-shaped, motile, endospore-forming and proteolytic bacterial strain, SPT, was isolated from Lonar soda lake, in India. On the basis of 16S rRNA gene sequence analysis it was identified as belonging to the class Firmibacteria and was most closely related to Bacillus cellulosilyticus DSM 2522T (96.7%) and other members of the genus Bacillus ( < 95.9%). Strain SPT was catalase- and oxidase-positive. The cell-wall peptidoglycan of strain SPT contained meso-diaminopimelic acid. Polar lipids included diphosphatidylglycerol, phosphatidylglycerol, phosphatidylethanolamine, three phospholipids, two aminolipids and two unknown lipids. The predominant isoprenoid quinone was MK-7. Anteiso-C15 : 0 (26.8%) was the predominant fatty acid and significant proportions (>5%) of iso-C15 : 0 (20.9%), C16 : 1omega7c alcohol (6.3%), iso-C16 : 0 (6.3%) and anteiso-C17 : 0 (5.3 %) were also detected in strain SPT. The DNA G+C content of strain SPT was 38.9 mol%. The results of phylogenetic, chemotaxonomic and biochemical tests allowed a clear differentiation of strain SPT from all other members of the genus Bacillus. Strain SPT represents a novel member of the genus Bacillus, for which the name Bacilluscaseinilyticus sp. nov. is proposed. The type strain is SPT ( = MCC 2612T = JCM 30246T). PMID- 25908709 TI - Fuchsiella ferrireducens sp. nov., a novel haloalkaliphilic, lithoautotrophic homoacetogen capable of iron reduction, and emendation of the description of the genus Fuchsiella. AB - Two strains of haloalkaliphilic homoacetogenic bacteria capable of iron reduction, Z-7101T and Z-7102, were isolated from soda lake Tanatar III (Altai, Russia). Cells of both strains were flexible, motile, Gram-negative, spore forming rods. The strains were mesophilic and obligately alkaliphilic: the pH range for growth was 8.5-10.2 (pHopt 9.8). Growth depended on carbonate and chloride ions. The strains were able to grow chemolithoautotrophically on H2+CO2, producing acetate as the only metabolic product. In medium with carbonates as the only potential electron acceptor, the following substrates were utilized for chemo-organotrophic growth: pyruvate, lactate, ethanol, 1-propanol, ethylene glycol and 1-butanol. Strain Z-7101T was able to reduce nitrate, selenate, thiosulfate and anthraquinone 2,6-disulfonate with ethanol as an electron donor. It was also able to reduce synthesized ferrihydrite to siderite with molecular hydrogen or organic compounds, including acetate and formate, as electron donors. It was able to reduce S0 with acetate or formate as electron donors. The DNA G+C content of strain Z-7101T was 34.6 mol%. 16S rRNA gene sequence analysis showed that strains Z-7101T and Z-7102 were members of the order Halanaerobiales and family Halobacteroidaceae, clustering with Fuchsiella alkaliacetigena Z-7100T (98.9-98.4% similarity). DNA-DNA hybridization was 63.0% between strain Z-7101T and F. alkaliacetigena Z-7100T. Based on morphological and physiological differences from F. alkaliacetigena Z-7100T and the results of phylogenetic analysis and DNA-DNA hybridization, it is proposed to assign strains Z-7101T and Z-7102 ( = DSM 26052 = VKM B-2790) to the novel species Fuchsiellaferrireducens sp. nov. The type strain is strain Z-7101T ( = DSM 26031T = VKM B-2766T). PMID- 25908710 TI - Detection and identification of a novel 16SrXIII subgroup phytoplasma associated with strawberry red leaf disease in Argentina. AB - Strawberry red leaf phytoplasma was found in strawberry plants from production fields in Lules (Tucuman province) and Bella Vista (Corrientes province), Argentina. Characteristic strawberry red leaf symptoms were stunting, young leaves with yellowing at the edges, mature leaves which curled and were reddish at the abaxial face, flower and fruit deformation and death. The pathogen was detected with phytoplasma-universal primer pairs P1/P7 followed by R16F2n/R16R2 as nested primers in 13 diseased plants. Based on RFLP and sequence analysis of the amplified 16S rRNA gene, the phytoplasma was related to the 16SrXIII group (Mexican periwinkle virescence). In silico the RFLP profile of all the samples analysed revealed the presence of a unique pattern, showing that the novel phytoplasma is different from all the phytoplasmas currently composing the 16SrXIII group. The phylogenetic analysis was consistent with RFLP analysis as the strawberry red leaf phytoplasma was grouped within the 16SrXIII group, but formed a particular cluster. On this basis, the Strawberry red leaf phytoplasma associated with strawberry red leaf disease was assigned to a new subgroup, 16SrXIII-F. PMID- 25908711 TI - Lysinibacillus alkaliphilus sp. nov., an extremely alkaliphilic bacterium, and emended description of genus Lysinibacillus. AB - A novel aerobic, alkaliphilic, Gram-staining-positive, endospore-forming bacterium, strain OMN17T, was isolated from a typical sandy loam soil under long term OMN fertilization (half organic manure N plus half mineral N fertilizer) in northern China and was subjected to a polyphasic taxonomic study. The best growth was achieved at 30 degrees C and pH 8-10 in medium containing 0.5% (w/v) NaCl. The cell-wall peptidoglycan of strain OMN17T was type A4alpha; (l-Lys-Gly-d-Asp) and the cell-wall sugars were ribose, traces of galactose and arabinose. The only respiratory quinone found in strain OMN17T was menaquinone 7 (MK-7). The major cellular fatty acids were iso-C15 : 0 and anteiso-C15 : 0. The major polar lipids were found to be phosphatidylethanolamine, phosphatidylglycerol and diphosphatidylglycerol. Phylogenetic analysis of strain OMN17T based on the 16S rRNA gene sequence showed that the strain was most closely related to Lysinibacillus halotolerans (97.8%), Lysinibacillus sinduriensis (97.5%), Lysinibacillus chungkukjangi (97.4%) and Lysinibacillus xylanilyticus (97.0%). The DNA-DNA hybridization results indicated that this strain was distinct from other species of the genus Lysinibacillus, the degree of relatedness being 21.8 +/- 0.2% with L. halotolerans, 45.6 +/- 1.8% with L. sinduriensis, 33.7 +/- 1.2% with L. chungkukjangi and 23.7 +/- 0.7% with L. xylanilyticus. The DNA G+C content of strain OMN17T was 38.1 mol%. The phenotypic, chemotaxonomic and genetic analyses identified strain OMN17T as a novel species of the genus Lysinibacillus, for which the name Lysinibacillus alkaliphilus sp. nov. is proposed. The type strain is OMN17T ( = DSM 28019T = CCTCC AB 2014073T). An emended description of the genus Lysinibacillus is also provided. PMID- 25908712 TI - Mangrovibacter yixingensis sp. nov., isolated from farmland soil. AB - A Gram-staining-negative, facultatively anaerobic, rod-shaped, nitrogen-fixing bacterial strain, designated TULL-AT, was isolated from a farmland soil sample in Yixing, China. The optimal conditions for growth were 30 degrees C, pH 7.0-8.0 and 0% (w/v) NaCl. Q8 was the dominant respiratory quinone and the major polar lipids were phosphatidylethanolamine, phosphatidylglycerol and aminophospholipid. Phylogenetic analysis of 16S rRNA gene sequences showed that strain TULL-AT was most closely related to Mangrovibacter plantisponsor MSSRF40T (99.6%), followed by Salmonella enterica subsp. diarizonae DSM 14847T (96.8%) and Cronobacter condimenti 1330T (96.8 %). Sequence analysis of the genes rpoB, gyrB and hsp60 revealed that those of strain TULL-AT also exhibit high sequence similarity with those of the species M. plantisponsor MSSRF40T (95.5, 94.1 and 93.4%). The genomic DNA G+C content was 52 mol%. The major fatty acids of strain TULL-AT were C16 : 0, C16 : 1omega7c and/or C16 : 1omega6c, C18 : 1omega7c /C18 : 1omega6c, C14 : 0, C14 : 0 3-OH/iso-C16 : 1 I and iso-C17 : 1 I and/or anteiso-C17 : 1 B. Strain TULL-AT showed low DNA-DNA relatedness with M. plantisponsor MSSRF40T (35.10 +/- 1.41%). Based on the multiple genotypic and phenotypic data, strain TULL-AT is considered to represent a novel species of the genus Mangrovibacter, for which the name Mangrovibacter yixingensis sp. nov. is proposed. The type strain is TULL-AT ( = ACCC 19709T = KCTC 42181T). PMID- 25908713 TI - Alkalimicrobium pacificum gen. nov., sp. nov., a marine bacterium in the family Rhodobacteraceae. AB - A Gram-stain-negative, aerobic, non-motile, rod-shaped bacterium, designated strain F15T, was isolated from a deep-sea sediment of the western Pacific Ocean. The temperature, pH and NaCl ranges for growth were 4-50 degrees C, pH 6-11 and 0-10 % (w/v), respectively. Strain F15T showed the highest 16S rRNA gene sequence similarity to Sagittula stellata E-37T (96.4%), followed by Ponticoccus litoralis CL-GR66T (96.4%), Antarctobacter heliothermus EL-219T (96.3%) and Thalassococcus lentus YCS-24T (96.0%). Phylogenetic analysis based on 16S rRNA gene sequence data showed that strain F15T formed a lineage within the family Rhodobacteraceae of the class Alphaproteobacteria. The polar lipid profile of strain F15T comprised significant amounts of phosphatidylethanolamine, phosphatidylglycerol, phosphatidylcholine, one unidentified glycolipid and one unidentified phospholipid. The predominant cellular fatty acids were summed feature 8 (C18 : 1omega7c and/or C18 : 1omega6c, 40.2%), anteiso-C15 : 0 (30.4%) and anteiso-C17 : 0 (9.7%). The genomic DNA G+C content of strain F15T was 60.2 mol% and the major respiratory quinone was Q-10. On the basis of phenotypic, phylogenetic and chemotaxonomic data, strain F15T is considered to represent a novel species of a new genus within the family Rhodobacteraceae, for which the name Alkalimicrobium pacificum gen. nov., sp. nov. is proposed. The type strain is F15T ( = LMG 28107T = JCM 19851T = CGMCC 1.12763T = MCCC 1A09948T). PMID- 25908714 TI - When free healthcare is not free. Corruption and mistrust in Sierra Leone's primary healthcare system immediately prior to the Ebola outbreak. AB - INTRODUCTION: Sierra Leone is one of three countries recently affected by Ebola. In debates surrounding the circumstances that contributed to the initial failure to contain the outbreak, the word 'trust' is often used: In December 2014, WHO director Margret Chan used 'lack of trust in governments'; The Lancet's Editor-in Chief, wrote how Ebola has exposed the '... breakdown of trust between communities and their governments.' This article explores the lack of trust in public healthcare providers in Sierra Leone, predating the Ebola outbreak, apparently linked to widespread petty corruption in primary healthcare facilities. It compares four NGO-supported accountability interventions targeting Sierra Leone's primary health sector. METHODS: Field research was conducted in Kailahun, Kono and Tonkolili Districts, based on interviews with health workers and focus group discussions with primary healthcare users. RESULTS: Field research showed that in most clinics, women and children entitled to free care routinely paid for health services. CONCLUSIONS: A lack of accountability in Sierra Leone's health sector appears pervasive at all levels. Petty corruption is rife. Understaffing leads to charging for free care in order to pay clinic-based 'volunteers' who function as vaccinators, health workers and birth attendants. Accountability interventions were found to have little impact on healthworker (mis)behaviour. PMID- 25908715 TI - Prevalence of pneumonia and associated factors among indigenous children in Brazil: results from the First National Survey of Indigenous People's Health and Nutrition. AB - BACKGROUND: Based on data from a nationally representative sample of indigenous villages in Brazilian indigenous reserves, the study sought to estimate the prevalence of pneumonia and evaluate associated factors among indigenous children under 5 years of age. METHODS: Sociodemographic, clinical and reported data on child respiratory health from the First National Survey of Indigenous People's Health and Nutrition in Brazil were collected for 6128 children. Prevalence of pneumonia was calculated for independent variables and hierarchical multivariate analyses were performed to assess associations. RESULTS: The overall prevalence proportions of cough, nasal congestion, pneumonia, and pneumonia with fever were 44.4%, 31.0%, 2.63%, and 1.28%, respectively. In the multivariate model, pneumonia was more frequent among children living in the South/Southeast and North regions of Brazil. Children living in larger households or houses with wood or thatch roofing, as well those with low birthweight or stunting, presented higher risk of pneumonia. Pneumonia was less prevalent among children living in houses with wood flooring and those presenting low weight-for-age. CONCLUSIONS: The study results demonstrate that pneumonia is an important cause of illness among indigenous children throughout Brazil. The association between pneumonia and household characteristics suggests that indoor home environment is closely related to the respiratory health of indigenous children. PMID- 25908716 TI - The characteristics of, and risk factors for, child injuries in Andhra Pradesh, India: the Young Lives project. AB - BACKGROUND: Injuries are an emerging public health issue among children worldwide, and one of the leading causes of disability-adjusted life years lost for children aged 0-14 years. Few studies, particularly in low- and middle-income countries, have analysed characteristics and risk factors for these injuries. METHODS: This study examined the occurrence and risk factors of serious non-fatal injuries in children aged 7-9 years (n=1820) from Andhra Pradesh, India. Logistic regression models were used to explore potential risk factors for these injuries. RESULTS: Based on a 3-year recall period, 336 (18.5%) children reported serious non-fatal injuries. Incidence was higher among males (209/971; 21.5%) compared to females (127/849; 15.0%). Of the most serious non-fatal injuries reported, falls (n=186, 55.4%) were the major cause of injuries, followed by road traffic injuries (50, 14.9%), and assaults/blows/hits (26, 7.7%). Twenty children (6.0%) did not fully recover from their injuries, and 14 (4.2%) had long-term health problems as a result of their injuries. The logistic regression analyses indicated that being male (AOR 1.59; 95% CI: 1.25-2.05), in poor health (AOR 2.50; 95% CI: 1.88-3.31), and having a caregiver with low education (AOR 1.53; 95% CI: 1.15-2.05) were associated with an increased risk of non-fatal injury. CONCLUSIONS: Urgent attention is needed to reduce child injuries and address risk factors according to local context. PMID- 25908717 TI - Vaccination in inflammatory bowel disease patients: attitudes, knowledge, and uptake. AB - BACKGROUND: Immunomodulators and biological agents, used to treat inflammatory bowel disease [IBD], are associated with an increased risk of infection, including vaccine-preventable infections. We assessed patient attitudes towards vaccination, knowledge of vaccine recommendations, and uptake of recommended vaccines. METHODS: Patients attending IBD clinics completed a self-administered, structured, paper-based questionnaire. We collected demographic data, medical and immunisation history, self-reported patient uptake, knowledge, and perceptions of childhood and adult vaccinations. RESULTS: The prevalence of treatment with biologicals, steroids, thiopurines, and methotrexate among the 300 respondents were 37.3%, 16.0%, 16.0%, and 5.7%, respectively. Self-reported vaccine completion was reported by 45.3% of patients. Vaccination uptake rates were 61.3% for influenza, 10.3% for pneumococcus, 61.0% for hepatitis B, 52.0% for hepatitis A, 26.0% for varicella, 20.7% for meningococcus, 5.3% for herpes zoster, and 11.0% for herpes papilloma virus [females only]. Significant predictors of vaccine completion were annual vaccination review by family physician (odds ratio [OR] = 1.82) or gastroenterologist [OR = 1.72], current steroid use [OR = 1.28], and current or prior treatment with biologicals [OR = 1.42]. The majority of patients reported that the primary responsibility to ensure vaccine completion lies with the patient [41.7%] and the family physician [32.3%]. Uncertainty about indications, fears of side effects, and concerns regarding vaccine safety were the most commonly reported reasons for non-uptake [22.0%, 20.7%, and 5.3%, respectively]. CONCLUSIONS: Uptake of recommended vaccines among IBD patients is suboptimal. Annual vaccination reviews by both family physician and gastroenterologist may improve vaccine uptake. Interventions targeted at improving vaccination uptake in IBD patients are needed. PMID- 25908718 TI - Development of Red Flags Index for Early Referral of Adults with Symptoms and Signs Suggestive of Crohn's Disease: An IOIBD Initiative. AB - BACKGROUND AND AIMS: Diagnostic delay is frequent in patients with Crohn's disease (CD). We developed a tool to predict early diagnosis. METHODS: A systematic literature review and 12 CD specialists identified 'Red Flags', i.e. symptoms or signs suggestive of CD. A 21-item questionnaire was administered to 36 healthy subjects, 80 patients with irritable bowel syndrome (non-CD group) and 85 patients with recently diagnosed (<18 months) CD. Patients with CD were asked to recall symptoms and signs they experienced during the 12 months before diagnosis. Multiple logistic regression analyses selected and weighted independent items to construct the Red Flags index. A receiver operating characteristic curve was used to assess the threshold that discriminated CD from non-CD. Association with the Red Flags index relative to this threshold was expressed as the odds ratios (OR). RESULTS: Two hundred and one subjects, CD and non-CD, answered the questionnaire. The multivariate analysis identified eight items independently associated with a diagnosis of CD. A minimum Red Flags index value of 8 was highly predictive of CD diagnosis with sensitivity and specificity bootstrap estimates of 0.94 (95% confidence interval 0.88-0.99) and 0.94 (0.90 0.97), respectively. Positive and negative likelihood ratios were 15.1 (9.3-33.6) and 0.066 (0.013-0.125), respectively. The association between CD diagnosis and a Red Flags index value of >=8 corresponds to an OR of 290 (p < 0.0001). CONCLUSIONS: The Red Flags index using early symptoms and signs has high predictive value for the diagnosis of CD. These results need prospective validation prior to introduction into clinical practice. PMID- 25908719 TI - Psoriasis Phenotype in Inflammatory Bowel Disease: A Case-Control Prospective Study. AB - BACKGROUND AND AIMS: Whether inflammatory bowel disease [IBD] is associated with specific psoriasis phenotypes is undefined. In a case-control prospective study, we aimed to assess the severity and phenotype of psoriasis in IBD vs matched non IBD controls with psoriasis [non-IBD]. METHODS: From 2011 to 2013, dermatological assessment was performed in all IBD patients showing lesions requiring characterisation. In patients with psoriasis, assessment included: presence, characteristics, and severity. Each IBD patient with psoriasis was matched [gender, ethnicity, age +/- 5 years] with one non-IBD patient with psoriasis. STATISTICAL ANALYSIS: data were expressed as median [range], chi-square, Student's t test. RESULTS: Dermatological assessment was performed in 251 IBD patients [115 females, age 47 [16-85]; IBD duration 9 years [1-46]]: 158 Crohn's disease [CD] [63%], 93 ulcerative colitis [UC] [37%]. Psoriasis was detected in 62 [25%] IBD patients: 36 [58%] CD, 26 UC [42%; p = 0.44]. Clinical characteristics were comparable between IBD patients with or without psoriasis: age 50 [23-72] vs 47 [16-85]; IBD duration 9.5 [1-46] vs 9 [1-41]; p = non significant]. The non-IBD group included 62 patients with psoriasis: 35 male; age 47 [18-75]. Mild psoriasis was more frequent in IBD vs non-IBD [87% vs 53%; p < 0.0001], whereas moderate and severe psoriasis were more frequent in non-IBD vs IBD [37% vs 13%, p = 0.004; 10% vs 0%; p = 0.036]. Plaque-type psoriasis was the most common phenotype in both IBD and non-IBD [p < 0.0001 vs others phenotypes].The frequency of plaque-type, nail psoriasis and psoriatic arthritis was lower in IBD vs non-IBD [p = 0.008; p < 0.0001; p = 0.006]. Psoriasis occurred after anti-tumour necrosis factor [TNF]alpha treatment in six CD patients [7%]. CONCLUSIONS: Severity and phenotypes of psoriasis may differ between patients with IBD and their matched non-IBD controls. PMID- 25908720 TI - Rectal hypersensitivity in patients with quiescent ulcerative colitis. PMID- 25908721 TI - Value of faecal calprotectin for inflammatory bowel disease at first presentation. PMID- 25908722 TI - A case of molluscum contagiosum infection in a patient with Crohn's disease, receiving combination therapy with azathioprine and adalimumab. PMID- 25908723 TI - Smad2/3 linker phosphorylation is a possible marker of cancer stem cells and correlates with carcinogenesis in a mouse model of colitis-associated colorectal cancer. AB - BACKGROUND: Epithelial cells affected by somatic mutations undergo transition from a tumour-suppressive to a carcinogenic Smad pathway during sporadic colorectal carcinogenesis, and the specific linker threonine phosphorylation of Smad2/3 in colon epithelial cells indicates stem-like cells. This study extends previous observations to a model of colitis-associated colorectal cancer. METHODS: After Crl:CD-1 mice received an administration of azoxymethane [AOM], the mice were given dextran sodium sulfate [DSS] for 7 days. AOM/DSS-treated mice [AOM/DSS mice] were killed at 10 or 20 weeks. After macroscopic observations, a histopathological analysis was conducted. Immunohistochemical staining was performed using the avidin-biotin immunoperoxidase method [pSmad3C-Ser, pSmad3L Ser, c-Myc] and immunofluorescent methods [Ki67, beta-catenin, CDK4, cyclin D1, Sox9, pSmad2/3L-Thr]. RESULTS: The colons from AOM/DSS mice were shorter than those from control mice. The number of colon tumours at Week 20 was higher than at Week 10. The inflammation scores for AOM/DSS mice were greater than those for control mice. Immunostaining-positive cells (staining by Ki67, beta-catenin [nuclear and cytoplasmic], cyclin D1, and Sox9) were diffusely distributed in colon tumours. The percentage of pSmad3L-Ser-positive cells in colon tumours was higher than in sites of pre-neoplastic colitis, and that in sites of pre neoplastic colitis was higher than in control mice. pSmad2/3L-Thr-positive cells were sparsely detected around crypt bases in non-neoplastic colon epithelia and at the tops of tumours, and immunohistochemical co-localisation of pSmad2/3L-Thr with Ki67 was not observed. Immunohistochemical co-localisation of pSmad2/3L-Thr with beta-catenin and CDK4 was observed. CONCLUSIONS: pSmad3L-Ser signalling is an early event in colitis-associated colorectal cancer, and pSmad2/3L-Thr immunostaining-positive cells might be cancer stem cells. PMID- 25908724 TI - A compendium on peripheral arterial disease. PMID- 25908725 TI - Epidemiology of peripheral artery disease. AB - New data on the epidemiology of peripheral artery disease (PAD) are available, and they should be integrated with previous data. We provide an updated, integrated overview of the epidemiology of PAD, a focused literature review was conducted on the epidemiology of PAD. The PAD results were grouped into symptoms, diagnosis, prevalence, and incidence both in the United States and globally, risk factors, progression, coprevalence with other atherosclerotic disease, and association with incident cardiovascular morbidity and mortality. The most common symptom of PAD is intermittent claudication, but noninvasive measures, such as the ankle-brachial index, show that asymptomatic PAD is several times more common in the population than intermittent claudication. PAD prevalence and incidence are both sharply age-related, rising >10% among patients in their 60s and 70s. With aging of the global population, it seems likely that PAD will be increasingly common in the future. Prevalence seems to be higher among men than women for more severe or symptomatic disease. The major risk factors for PAD are similar to those for coronary and cerebrovascular disease, with some differences in the relative importance of factors. Smoking is a particularly strong risk factor for PAD, as is diabetes mellitus, and several newer risk markers have shown independent associations with PAD. PAD is strongly associated with concomitant coronary and cerebrovascular diseases. After adjustment for known cardiovascular disease risk factors, PAD is associated with an increased risk of incident coronary and cerebrovascular disease morbidity and mortality. PMID- 25908726 TI - Pathogenesis of the limb manifestations and exercise limitations in peripheral artery disease. AB - Patients with peripheral artery disease have a marked reduction in exercise performance and daily ambulatory activity irrespective of their limb symptoms of classic or atypical claudication. This review will evaluate the multiple pathophysiologic mechanisms underlying the exercise impairment in peripheral artery disease based on an evaluation of the current literature and research performed by the authors. Peripheral artery disease results in atherosclerotic obstructions in the major conduit arteries supplying the lower extremities. This arterial disease process impairs the supply of oxygen and metabolic substrates needed to match the metabolic demand generated by active skeletal muscle during walking exercise. However, the hemodynamic impairment associated with the occlusive disease process does not fully account for the reduced exercise impairment, indicating that additional pathophysiologic mechanisms contribute to the limb manifestations. These mechanisms include a cascade of pathophysiological responses during exercise-induced ischemia and reperfusion at rest that are associated with endothelial dysfunction, oxidant stress, inflammation, and muscle metabolic abnormalities that provide opportunities for targeted therapeutic interventions to address the complex pathophysiology of the exercise impairment in peripheral artery disease. PMID- 25908727 TI - Lower extremity manifestations of peripheral artery disease: the pathophysiologic and functional implications of leg ischemia. AB - Lower extremity peripheral artery disease (PAD) is frequently underdiagnosed, in part because of the wide variety of leg symptoms manifested by patients with PAD and in part because of the high prevalence of asymptomatic PAD. In primary care medical practices, 30% to 60% of patients with PAD report no exertional leg symptoms and ~45% to 50% report exertional leg symptoms that are not consistent with classic intermittent claudication. The prevalence and extent of functional impairment and functional decline in PAD may also be underappreciated. Functional impairment and functional decline are common in PAD, even among those who are asymptomatic. Lower extremity ischemia is also associated with pathophysiologic changes in calf skeletal muscle, including smaller calf muscle area, increased calf muscle fat content, impaired leg strength, and impaired metabolic function. People with severe PAD have poorer peroneal nerve conduction velocity compared with people with mild PAD or no PAD. The degree of ischemia-related pathophysiologic changes in lower extremity muscles and peripheral nerves of people with PAD are associated with the degree of functional impairment. New interventions are needed to improve functional performance and prevent mobility loss in the large number of patients with PAD, including in those who are asymptomatic or who have exertional leg symptoms other than claudication. PMID- 25908728 TI - The genetic basis of peripheral arterial disease: current knowledge, challenges, and future directions. AB - Several risk factors for atherosclerotic peripheral arterial disease (PAD), such as dyslipidemia, diabetes mellitus, and hypertension, are heritable. However, predisposition to PAD may be influenced by genetic variants acting independently of these risk factors. Identification of such genetic variants will provide insights into underlying pathophysiologic mechanisms and facilitate the development of novel diagnostic and therapeutic approaches. In contrast to coronary heart disease, relatively few genetic variants that influence susceptibility to PAD have been discovered. This may be, in part, because of greater clinical and genetic heterogeneity in PAD. In this review, we (1) provide an update on the current state of knowledge about the genetic basis of PAD, including results of family studies and candidate gene, linkage as well as genome wide association studies; (2) highlight the challenges in investigating the genetic basis of PAD and possible strategies to overcome these challenges; and (3) discuss the potential of genome sequencing, RNA sequencing, differential gene expression, epigenetic profiling, and systems biology in increasing our understanding of the molecular genetics of PAD. PMID- 25908730 TI - Pharmacological treatment and current management of peripheral artery disease. AB - Patients with peripheral artery disease (PAD) are at heightened risk of both systemic cardiovascular adverse events, as well as limb-related morbidity. The optimal management of patients with PAD requires a comprehensive treatment strategy incorporating both lifestyle changes, including smoking cessation and exercise, as well as optimal medical therapy. Pharmacological therapies for patients with PAD are targeted both at modifying broad risk factors for major adverse cardiovascular events, as well as reducing limb-related morbidity. Observational data suggest that indicated pharmacological treatments are greatly underutilized in PAD, underscoring the need for improvements in patient identification and care delivery. Ongoing trials of novel therapies in patients with PAD will further inform pharmacological strategies to reduce both systemic cardiovascular risk and limb-related morbidity. PMID- 25908729 TI - Modulating the vascular response to limb ischemia: angiogenic and cell therapies. AB - The age-adjusted prevalence of peripheral arterial disease in the US population has been estimated to approach 12%. The clinical consequences of occlusive peripheral arterial disease include pain on walking (claudication), pain at rest, and loss of tissue integrity in the distal limbs; the latter may ultimately lead to amputation of a portion of the lower extremity. Surgical bypass techniques and percutaneous catheter-based interventions may successfully reperfuse the limbs of certain patients with peripheral arterial disease. In many patients, however, the anatomic extent and distribution of arterial occlusion is too severe to permit relief of pain and healing of ischemic ulcers. No effective medical therapy is available for the treatment of such patients, for many of whom amputation represents the only hope for alleviation of symptoms. The ultimate failure of medical treatment and procedural revascularization in significant numbers of patients has led to attempts to develop alternative therapies for ischemic disease. These strategies include administration of angiogenic cytokines, either as recombinant protein or as gene therapy, and more recently, to investigations of stem/progenitor cell therapy. The purpose of this review is to provide an outline of the preclinical basis for angiogenic and stem cell therapies, review the clinical research that has been done, summarize the lessons learned, identify gaps in knowledge, and suggest a course toward successfully addressing an unmet medical need in a large and growing patient population. PMID- 25908732 TI - Surgical intervention for peripheral arterial disease. AB - The prevalence of peripheral arterial disease (PAD) is increasing worldwide, with recent global estimates exceeding 200 million people. Advanced PAD leads to a decline in ambulatory function and diminished quality of life. In its most severe form, critical limb ischemia, rest pain, and tissue necrosis are associated with high rates of limb loss, morbidity, and mortality. Revascularization of the limb plays a central role in the management of symptomatic PAD. Concomitant with advances in the pathogenesis, genetics, and medical management of PAD during the last 20 years, there has been an ongoing evolution of revascularization options. The increasing application of endovascular techniques has resulted in dramatic changes in practice patterns and has refocused the question of which patients should be offered surgical revascularization. Nonetheless, surgical therapy remains a cornerstone of management for advanced PAD, providing versatile and durable solutions to challenging patterns of disease. Although there is little high-quality comparative effectiveness data to guide patient selection, existing evidence suggests that outcomes are dependent on definable patient factors such as distribution of disease, status of the limb, comorbid conditions, and conduit availability. As it stands, surgical revascularization remains the standard against which emerging percutaneous techniques are compared. This review summarizes the principles of surgical revascularization, patient selection, and expected outcomes, while highlighting areas in need of further research and technological advancement. PMID- 25908731 TI - Endovascular intervention for peripheral artery disease. AB - Advances in endovascular therapies during the past decade have broadened the options for treating peripheral vascular disease percutaneously. Endovascular treatment offers a lower risk alternative to open surgery in many patients with multiple comorbidities. Noninvasive physiological tests and arterial imaging precede an endovascular intervention and help localize the disease and plan the procedure. The timing and need for revascularization are broadly related to the 3 main clinical presentations of claudication, critical limb ischemia, and acute limb ischemia. Many patients with claudication can be treated by exercise and medical therapy. Endovascular procedures are considered when these fail to improve quality of life and function. In contrast, critical limb ischemia and acute limb ischemia threaten the limb and require more urgent revascularization. In general, endovascular treatments have greater long-term durability for aortoiliac disease than femoral popliteal disease. Infrapopliteal revascularization is generally reserved for critical and acute limb ischemia. Balloon angioplasty and stenting are the mainstays of endovascular therapy. New well-tested innovations include drug-eluting stents and drug-coated balloons. Adjunctive devices for crossing chronic total occlusions or debulking plaque with atherectomy are less rigorously studied and have niche roles. Patients receiving endovascular procedures need a structured surveillance plan for follow-up care. This includes intensive treatment of cardiovascular risk factors to prevent myocardial infarction and stroke, which are the main causes of death. Limb surveillance aims to identify restenosis and new disease beyond the intervened segments, both of which may jeopardize patency and lead to recurrent symptoms, functional impairment, or a threatened limb. PMID- 25908734 TI - Emerging single-cell technologies in immunology. AB - During evolution, the immune system has diversified to protect the host from the extremely wide array of possible pathogens. Until recently, immune responses were dissected by use of global approaches and bulk tools, averaging responses across samples and potentially missing particular contributions of individual cells. This is a strongly limiting factor, considering that initial immune responses are likely to be triggered by a restricted number of cells at the vanguard of host defenses. The development of novel, single-cell technologies is a major innovation offering great promise for basic and translational immunology with the potential to overcome some of the limitations of traditional research tools, such as polychromatic flow cytometry or microscopy-based methods. At the transcriptional level, much progress has been made in the fields of microfluidics and single-cell RNA sequencing. At the protein level, mass cytometry already allows the analysis of twice as many parameters as flow cytometry. In this review, we explore the basis and outcome of immune-cell diversity, how genetically identical cells become functionally different, and the consequences for the exploration of host-immune defense responses. We will highlight the advantages, trade-offs, and potential pitfalls of emerging, single-cell-based technologies and how they provide unprecedented detail of immune responses. PMID- 25908736 TI - Badger culling: BVA withdraws support for controlled shooting. PMID- 25908733 TI - Using light to shape chemical gradients for parallel and automated analysis of chemotaxis. AB - Numerous molecular components have been identified that regulate the directed migration of eukaryotic cells toward sources of chemoattractant. However, how the components of this system are wired together to coordinate multiple aspects of the response, such as directionality, speed, and sensitivity to stimulus, remains poorly understood. Here we developed a method to shape chemoattractant gradients optically and analyze cellular chemotaxis responses of hundreds of living cells per well in 96-well format by measuring speed changes and directional accuracy. We then systematically characterized migration and chemotaxis phenotypes for 285 siRNA perturbations. A key finding was that the G-protein Gialpha subunit selectively controls the direction of migration while the receptor and Gbeta subunit proportionally control both speed and direction. Furthermore, we demonstrate that neutrophils chemotax persistently in response to gradients of fMLF but only transiently in response to gradients of ATP. The method we introduce is applicable for diverse chemical cues and systematic perturbations, can be used to measure multiple cell migration and signaling parameters, and is compatible with low- and high-resolution fluorescence microscopy. PMID- 25908735 TI - Enhancement of neutrophil autophagy by an IVIG preparation against multidrug resistant bacteria as well as drug-sensitive strains. AB - Autophagy occurs in human neutrophils after the phagocytosis of multidrug resistant bacteria and drug-sensitive strains, including Escherichia coli and Pseudomonas aeruginosa. The present study detected autophagy by immunoblot analysis of LC3B conversion, by confocal scanning microscopic examination of LC3B aggregate formation and by transmission electron microscopic examination of bacteria-containing autophagosomes. Patients with severe bacterial infections are often treated with IVIG alongside antimicrobial agents. Here, we showed that IVIG induced neutrophil-mediated phagocytosis of multidrug-resistant strains. Compared with untreated neutrophils, neutrophils exposed to IVIG showed increased levels of bacterial cell killing, phagocytosis, O(2)(-) release, MPO release, and NET formation. IVIG also increased autophagy in these cells. Inhibiting the late phase of autophagy (fusion of lysosomes with autophagosomes) with bafilomycin A1 reduced, neutrophil-mediated bactericidal activity. These findings indicate that autophagy plays a critical role in the bactericidal activity mediated by human neutrophils. Furthermore, the autophagosomes within the neutrophils contained bacteria only and their organelles only, or both bacteria and their organelles, a previously undocumented observation. Taken together, these results suggest that the contents of neutrophil autophagosomes may be derived from specific autophagic systems, which provide the neutrophil with an advantage. Thus, IVIG promotes the neutrophil-mediated killing of multidrug-resistant bacteria as well as drug sensitive strains. PMID- 25908737 TI - Eradication of peste des petits ruminants 'within reach'. PMID- 25908738 TI - RCVS sets framework for accrediting overseas veterinary nurses. PMID- 25908739 TI - Getting ready for compulsory microchipping. PMID- 25908740 TI - Statue to symbolise Herriot legacy fund. PMID- 25908741 TI - Where should the profession be heading? PMID- 25908742 TI - Vets encouraged to neuter cats at four months old as 'the norm'. PMID- 25908743 TI - Opening doors to animal adoption. PMID- 25908744 TI - Supporting scientific research in Africa. PMID- 25908745 TI - Questions of identity. PMID- 25908746 TI - Welfare in horse breeding. AB - Welfare problems related to the way horses are bred, whether by coitus or by the application of artificial reproduction techniques (ARTs), have been given no discrete consideration within the academic literature. This paper reviews the existing knowledge base about welfare issues in horse breeding and identifies areas in which data is lacking. We suggest that all methods of horse breeding are associated with potential welfare problems, but also that the judicious use of ARTs can sometimes help to address those problems. We discuss how negative welfare effects could be identified and limited and how positive welfare effects associated with breeding might be maximised. Further studies are needed to establish an evidence base about how stressful or painful various breeding procedures are for the animals involved, and what the lifetime welfare implications of ARTs are for future animal generations. PMID- 25908747 TI - TB testing. PMID- 25908748 TI - Lungworm in dogs. PMID- 25908749 TI - Cats indoors and out. PMID- 25908757 TI - Correction. PMID- 25908758 TI - One Health and a world of opportunity. PMID- 25908759 TI - Prevalence of MLH1 constitutional epimutations as a cause of Lynch syndrome in unselected versus selected consecutive series of patients with colorectal cancer. AB - BACKGROUND: The prevalence of MLH1 constitutional epimutations in the general population is unknown. We sought to analyse the prevalence of MLH1 constitutional epimutations in unselected and selected series of patients with colorectal cancer (CRC). METHODS: Patients with diagnoses of CRC (n=2123) were included in the unselected group. For comparison, a group of 847 selected patients with CRC who fulfilled the revised Bethesda guidelines (rBG) were also included. Somatic and constitutional MLH1 methylation was assayed via methylation-specific multiplex ligation-dependent probe amplification of cases lacking MLH1 expression. Germline alterations in mismatch-repair (MMR) genes were assessed via Sanger sequencing and methylation-specific multiplex ligation-dependent probe amplification. RESULTS: Loss of MLH1 expression occurred in 5.5% of the unselected series and 12.5% of the selected series (p<0.0001). No constitutional epimutations in MLH1 were detected in the unselected population (0/62); five cases from the selected series were positive for MLH1 epimutations (15.6%, 5/32; p=0.004). CONCLUSIONS: Our results suggest a negligible prevalence of MLH1 constitutional epimutations in unselected cases of CRC. Therefore, MLH1 constitutional epimutation analysis should be conducted only for patients who fulfil the rBG and who lack MLH1 expression with methylated MLH1. PMID- 25908760 TI - Forkhead box O-1 modulation improves endothelial insulin resistance in human obesity. AB - OBJECTIVE: Increased visceral adiposity has been closely linked to insulin resistance, endothelial dysfunction, and cardiometabolic disease in obesity, but pathophysiological mechanisms are poorly understood. We sought to investigate mechanisms of vascular insulin resistance by characterizing depot-specific insulin responses and gain evidence that altered functionality of transcription factor forkhead box O-1 (FOXO-1) may play an important role in obesity-related endothelial dysfunction. APPROACH AND RESULTS: We intraoperatively collected paired subcutaneous and visceral adipose tissue samples from 56 severely obese (body mass index, 43 +/- 7 kg/m(2)) and 14 nonobese subjects during planned surgical operations, and characterized depot-specific insulin-mediated responses using Western blot and quantitative immunofluorescence techniques. Insulin signaling via phosphorylation of FOXO-1 and consequent endothelial nitric oxide synthase stimulation was selectively impaired in the visceral compared with subcutaneous adipose tissue and endothelial cells of obese subjects. In contrast, tissue actions of insulin were preserved in nonobese individuals. Pharmacological antagonism with AS1842856 and biological silencing using small interfering RNA mediated FOXO-1 knockdown reversed insulin resistance and restored endothelial nitric oxide synthase activation in the obese. CONCLUSIONS: We observed profound endothelial insulin resistance in the visceral adipose tissue of obese humans which improved with FOXO-1 inhibition. FOXO-1 modulation may represent a novel therapeutic target to diminish vascular insulin resistance. In addition, characterization of endothelial insulin resistance in the adipose microenvironment may provide clues to mechanisms of systemic disease in human obesity. PMID- 25908761 TI - Downregulation of dynamin-related protein 1 contributes to impaired autophagic flux and angiogenic function in senescent endothelial cells. AB - OBJECTIVE: Recent studies have shown that altered mitochondrial dynamics impairs the function in senescent endothelial cells (ECs). However, the underlying molecular mechanism remains to be elucidated. Herein, we investigated the role and underlying mechanism of mitochondrial fission protein dynamin-related protein 1 (DRP1) in vascular aging. APPROACH AND RESULTS: We found that DRP1 expression is decreased in senescent ECs, accompanied with long interconnected mitochondria and impaired angiogenic function. In addition, there was marked increase of autophagosomes but not of autolysosomes (assessed as punctate dual fluorescent mCherry-GFP (green fluorescent protein) tandem-tagged light chain 3 expression) in senescent ECs, indicating impaired autophagic flux. DRP1 knockdown or pharmacological inhibition in young ECs resulted in elongated mitochondria, suppressed autophagic flux, premature senescence, and impaired angiogenic function. In contrast, adenoviral-mediated overexpression of DRP1 in senescent ECs restored autophagic flux and improved angiogenic function. EC senescence was associated with the increase of mitochondrial reactive oxygen species and antioxidant N-acetyl-cysteine restored autophagosome clearance and improved angiogenic function. Consistently, en face staining of old rat thoracic aorta revealed a decrease of DRP1 expression and increase of autophagosomes accumulation. Furthermore, in vivo knockdown of Drp1 in common carotid arteries significantly impaired the autophagosome clearance. Importantly, downregulation of Drp1 directly abrogated microvessels outgrowth from ex vivo aortic rings. CONCLUSIONS: These results suggest that loss of DRP1 during senescence exacerbates ECs dysfunction by increasing mitochondrial reactive oxygen species and subsequently inhibiting autophagic flux. PMID- 25908763 TI - Class IA Phosphatidylinositol 3-Kinase Isoform p110alpha Mediates Vascular Remodeling. AB - OBJECTIVE: Neointima formation after vascular injury remains a significant problem in clinical cardiology, and current preventive strategies are suboptimal. Phosphatidylinositol 3'-kinase is a central downstream mediator of growth factor signaling, but the role of phosphatidylinositol 3'-kinase isoforms in vascular remodeling remains elusive. We sought to systematically characterize the precise role of catalytic class IA phosphatidylinositol 3'-kinase isoforms (p110alpha, p110beta, p110delta), which signal downstream of receptor tyrosine kinases, for vascular remodeling in vivo. APPROACH AND RESULTS: Western blot analyses revealed that all 3 isoforms are abundantly expressed in smooth muscle cells. To analyze their significance for receptor tyrosine kinases-dependent cellular responses, we used targeted gene knockdown and isoform-specific small molecule inhibitors of p110alpha (PIK-75), p110beta (TGX-221), and p110delta (IC-87114), respectively. We identified p110alpha to be crucial for receptor tyrosine kinases signaling, thus affecting proliferation, migration, and survival of rat, murine, and human smooth muscle cells, whereas p110beta and p110delta activities were dispensable. Surprisingly, p110delta exerted noncatalytic functions in smooth muscle cell proliferation, but had no effect on migration. Based on these results, we generated a mouse model of smooth muscle cell-specific p110alpha deficiency (sm p110alpha(-/-)). Targeted deletion of p110alpha in sm-p110alpha(-/-) mice blunted growth factor-induced cellular responses and abolished neointima formation after balloon injury of the carotid artery in mice. In contrast, p110delta deficiency did not affect vascular remodeling in vivo. CONCLUSIONS: Receptor tyrosine kinases-induced phosphatidylinositol 3'-kinase signaling via the p110alpha isoform plays a central role for vascular remodeling in vivo. Thus, p110alpha represents a selective target for the prevention of neointima formation after vascular injury, whereas p110beta and p110delta expression and activity do not play a significant role. PMID- 25908762 TI - 2013 scientific sessions Sol Sherry distinguished lecture in thrombosis: polyphosphate: a novel modulator of hemostasis and thrombosis. AB - Polyphosphate is a highly anionic, linear polymer of inorganic phosphates that is found throughout biology, including in many infectious microorganisms. Recently, polyphosphate was discovered to be stored in a subset of the secretory granules of human platelets and mast cells, and to be secreted on activation of these cells. Work from our laboratory and others has now shown that polyphosphate is a novel, potent modulator of the blood clotting and complement systems that likely plays roles in hemostasis, thrombosis, inflammation, and host responses to pathogens. Therapeutics targeting polyphosphate may have the potential to limit thrombosis with fewer hemorrhagic complications than conventional anticoagulant drugs that target essential proteases of the blood clotting cascade. PMID- 25908764 TI - Involvement of interleukin-1 receptor-associated kinase-1 in vascular smooth muscle cell proliferation and neointimal formation after rat carotid injury. AB - OBJECTIVE: Reduced frequency of atherosclerotic plaques is observed in interleukin-1 receptor-associated kinase-1 (IRAK1)-deficient mice; however, the underlying mechanism is not clear. Therefore, this study investigate the role of IRAK1 in vascular smooth muscle cell proliferation and neointimal hyperplasia. APPROACH AND RESULTS: Stimulation of rat primary vascular smooth muscle cells with fetal bovine serum (10%) or platelet-derived growth factor-BB (20 ng/mL) for 15 minutes to 24 hours induced a time-dependent increase in IRAK1 and extracellular signal-regulated kinase (ERK) activation, proliferating cell nuclear antigen upregulation and p27Kip1 downregulation as assessed by Western blotting. Inhibitors of ERK pathway (U0126, 10 MUmol/L), IRAK (IRAK1/4, 3 MUmol/L), protein kinase C (PKC; Ro-31-8220, 1 MUmol/L), siRNA of toll-like receptor-4 (200 nmol/L), and PKC-epsilon (200 nmol/L) significantly attenuated these changes. Platelet-derived growth factor induced endogenous IRAK-ERK-PKC epsilon association in a toll-like receptor-4 and PKC-epsilon-dependent manner. A time-dependent increase in IRAK1 and ERK activation was observed after 15 minutes, 30 minutes, 1 hour, 6 hours, 12 hours, and 24 hours of carotid balloon injury in rats. Balloon injury induced endogenous IRAK-ERK-PKC-epsilon interaction. Perivascular application of IRAK1/4 inhibitor (100 MUmol/L), U0126 (100 MUmol/L), and IRAK1 siRNA (220 and 360 nmol/L) in pluronic gel abrogated balloon injury-induced ERK phosphorylation, activation, and p27Kip1 downregulation. Hematoxylin and eosin staining and immunohistochemistry of proliferating cell nuclear antigen and smooth muscle actin demonstrated that balloon injury-induced intimal thickening and neointimal vascular smooth muscle cell proliferation were significantly abrogated in the presence of IRAK1/4 inhibitor, IRAK1 siRNA, and U0126. CONCLUSIONS: IRAK1 mediates vascular smooth muscle cell proliferation and neointimal hyperplasia by regulating PKC-epsilon IRAK1-ERK axis. PMID- 25908765 TI - GLP-1 Receptor Agonist Exenatide Increases Capillary Perfusion Independent of Nitric Oxide in Healthy Overweight Men. AB - OBJECTIVE: The insulinotropic gut-derived hormone glucagon-like peptide-1 (GLP-1) increases capillary perfusion via a nitric oxide-dependent mechanism in rodents. This improves skeletal muscle glucose use and cardiac function. In humans, the effect of clinically used GLP-1 receptor agonists (GLP-1RAs) on capillary density is unknown. We aimed to assess the effects of the GLP-1RA exenatide on capillary density as well as the involvement of nitric oxide in humans. APPROACH AND RESULTS: We included 10 healthy overweight men (age, 20-27 years; body mass index, 26-31 kg/m(2)). Measurements were performed during intravenous infusion of placebo (saline 0.9%), exenatide, and a combination of exenatide and the nonselective nitric oxide-synthase inhibitor L-N(G)-monomethyl arginine. Capillary videomicroscopy was performed, and baseline and postocclusive (peak) capillary densities were counted. Compared with placebo, exenatide increased baseline and peak capillary density by 20.1% and 8.3%, respectively (both P=0.016). Concomitant L-N(G)-monomethyl arginine infusion did not alter the effects of exenatide. Vasomotion was assessed using laser Doppler fluxmetry. Exenatide nonsignificantly reduced the neurogenic domain of vasomotion measurements (R=-5.6%; P=0.092), which was strongly and inversely associated with capillary perfusion (R=-0.928; P=0.036). Glucose levels were reduced during exenatide infusion, whereas levels of insulin were unchanged. CONCLUSIONS: Acute exenatide infusion increases capillary perfusion via nitric oxide-independent pathways in healthy overweight men, suggesting direct actions of this GLP-1RA on microvascular perfusion or interaction with vasoactive factors. PMID- 25908766 TI - Novel protein glycan side-chain biomarker and risk of incident type 2 diabetes mellitus. AB - OBJECTIVES: Enzymatically glycosylated proteins partake in multiple biological processes, including glucose transport and inflammation. We hypothesized that a novel biomarker (GlycA) of N-acetyl methyl groups originating mainly from N acetylglucosamine moieties of acute-phase glycoproteins is related to incident type 2 diabetes mellitus and compared it with high-sensitivity C-reactive protein. APPROACH AND RESULTS: In 26,508 initially healthy women free of diabetes mellitus, baseline GlycA and high-sensitivity C-reactive protein were quantified by nuclear magnetic resonance spectroscopy and immunoturbidimetry, respectively. During median follow-up of 17.2 years, 2087 type 2 diabetes mellitus cases occurred. In Cox models with adjustment for age, race, smoking, alcohol, activity, menopausal status, hormone use, family history, and body mass index, quartile 4 versus 1 hazard ratios and 95% confidence intervals were 2.67 (2.26 3.14) for GlycA and 3.93 (3.24-4.77) for high-sensitivity C-reactive protein; both P trend <0.0001. Associations for GlycA and high-sensitivity C-reactive protein were attenuated after additionally adjusting for lipids: 1.65 (1.39-1.95) and 2.83 (2.32-3.44), respectively, both P trend <0.0001, and after mutual adjustment: 1.11 (0.93-1.33; P trend=0.10) and 2.57 (2.09-3.16; P trend<0.0001), respectively. CONCLUSIONS: Our finding of an association between a consensus glycan sequence common to a host of acute-phase reactants and incident type 2 diabetes mellitus provides further support for inflammation in the development of type 2 diabetes mellitus. Additional studies exploring the role of enzymatic glycosylation in the prevention of type 2 diabetes mellitus are warranted. CLINICAL TRIAL REGISTRATION: URL: http://www.clinicaltrials.gov. Unique identifier: NCT00000479. PMID- 25908769 TI - Optical imaging innovations for atherosclerosis research: multiphoton microscopy and optical nanoscopy. AB - Cardiovascular disease is the leading cause of death and morbidity worldwide. Improving vascular prevention and therapy based on a refined mechanistic pervasion of atherosclerosis as the underlying pathology could limit the effect of vascular disease in aging societies. During the past decades, microscopy has contributed greatly to a better understanding of vascular physiology and pathology by allowing imaging of living specimen with subcellular resolution and high specificity. An important advance has been accomplished through the application of multiphoton microscopy in the vascular domain, a technological development that enabled multidimensional and dynamic imaging deep into the cellular architecture of intact tissue under physiological conditions. To identify and validate new targets for treating atherosclerosis, novel imaging strategies with nanoscale resolution will be essential to visualize molecular processes in intracellular and extracellular compartments. This review will discuss the current use of 2-photon microscopy and will provide an overview and outlook on options for introducing nanoscopic optical imaging modalities in atherosclerosis research. PMID- 25908768 TI - Platelet CD40L Modulates Thrombus Growth Via Phosphatidylinositol 3-Kinase beta, and Not Via CD40 and IkappaB Kinase alpha. AB - OBJECTIVE: To investigate the roles and signaling pathways of CD40L and CD40 in platelet-platelet interactions and thrombus formation under conditions relevant for atherothrombosis. APPROACH AND RESULTS: Platelets from mice prone to atherosclerosis lacking CD40L (Cd40lg(-/-)Apoe(-/-)) showed diminished alphaIIbbeta3 activation and alpha-granule secretion in response to glycoprotein VI stimulation, whereas these responses of CD40-deficient platelets (Cd40(-/ )Apoe(-/-)) were not decreased. Using blood from Cd40lg(-/-)Apoe(-/-) and Cd40(-/ )Apoe(-/-) mice, the glycoprotein VI-dependent formation of dense thrombi was impaired on atherosclerotic plaque material or on collagen, in comparison with Apoe(-/-) blood. In all genotypes, addition of CD40L to the blood enhanced the growth of dense thrombi on plaques and collagen. Similarly, CD40L enhanced glycoprotein VI-induced platelet aggregation, even with platelets deficient in CD40. This potentiation was antagonized in Pik3cb(R/R) platelets or by inhibiting phosphatidylinositol 3-kinase beta (PI3Kbeta). Addition of CD40L also enhanced collagen-induced Akt phosphorylation, which was again antagonized by absence or inhibition of PI3Kbeta. Finally, platelets from Chuk1(A/A)Apoe(-/-) mice deficient in IkappaB kinase alpha (IKKalpha), implicated in CD40 signaling to nuclear factor (NF) kappaB, showed unchanged responses to CD40L in aggregation or thrombus formation. CONCLUSIONS: Under atherogenic conditions, CD40L enhances collagen-induced platelet-platelet interactions by supporting integrin alphaIIbbeta3 activation, secretion and thrombus growth via PI3Kbeta, but not via CD40 and IKKalpha/NFkappaB. This role of CD40L exceeds the no more than modest role of CD40 in thrombus formation. PMID- 25908767 TI - Asthma predicts cardiovascular disease events: the multi-ethnic study of atherosclerosis. AB - OBJECTIVES: To identify and characterize an association between persistent asthma and cardiovascular disease (CVD) risk in the Multi-Ethnic Study of Atherosclerosis (MESA). APPROACH AND RESULTS: MESA is a longitudinal prospective study of an ethnically diverse cohort of individuals free of known CVD at its inception. The presence and severity of asthma were assessed in the MESA at examination 1. Persistent asthma was defined as asthmatics using controller medications (inhaled corticosteroids, leukotriene inhibitors, and oral corticosteroids) and intermittent asthma as asthmatics not using controller medications. Participants were followed up for a mean (SD) of 9.1 (2.8) years for development of incident CVD (coronary death, myocardial infarction, angina, stroke, and CVD death). Multivariable Cox regression models were used to assess associations of asthma and CVD. The 6792 participants were 62.2 (SD, 10.2) years old: 47% men (28% black, 22% Hispanic, and 12% Chinese). Persistent asthmatics (n=156), compared with intermittent (n=511) and nonasthmatics (n=6125), respectively, had higher C-reactive protein (1.2 [1.2] versus 0.9 [1.2] versus 0.6 [1.2] mg/L) and fibrinogen (379 [88] versus 356 [80] versus 345 [73] mg/dL) levels. Persistent asthmatics had the lowest unadjusted CVD-free survival rate of 84.1%, 95% confidence interval (78.9%-90.3%) compared with intermittent asthmatics 91.1% (88.5%-93.8%) and nonasthmatics 90.2% (89.4%-91%). Persistent asthmatics had greater risk of CVD events than nonasthmatics (hazard ratio [95% confidence interval], 1.6 [1.01-2.5]; P=0.040]), even after adjustment for age, sex, race, CVD risk factors, and antihypertensive and lipid medication use. CONCLUSIONS: In this large multiethnic cohort, persistent asthmatics had a higher CVD event rate than nonasthmatics. PMID- 25908771 TI - Revision of the Jones Criteria for the diagnosis of acute rheumatic fever in the era of Doppler echocardiography: a scientific statement from the American Heart Association. AB - BACKGROUND: Acute rheumatic fever remains a serious healthcare concern for the majority of the world's population despite its decline in incidence in Europe and North America. The goal of this statement was to review the historic Jones criteria used to diagnose acute rheumatic fever in the context of the current epidemiology of the disease and to update those criteria to also take into account recent evidence supporting the use of Doppler echocardiography in the diagnosis of carditis as a major manifestation of acute rheumatic fever. METHODS AND RESULTS: To achieve this goal, the American Heart Association's Council on Cardiovascular Disease in the Young and its Rheumatic Fever, Endocarditis, and Kawasaki Disease Committee organized a writing group to comprehensively review and evaluate the impact of population-specific differences in acute rheumatic fever presentation and changes in presentation that can result from the now worldwide availability of nonsteroidal anti-inflammatory drugs. In addition, a methodological assessment of the numerous published studies that support the use of Doppler echocardiography as a means to diagnose cardiac involvement in acute rheumatic fever, even when overt clinical findings are not apparent, was undertaken to determine the evidence basis for defining subclinical carditis and including it as a major criterion of the Jones criteria. This effort has resulted in the first substantial revision to the Jones criteria by the American Heart Association since 1992 and the first application of the Classification of Recommendations and Levels of Evidence categories developed by the American College of Cardiology/American Heart Association to the Jones criteria. CONCLUSIONS: This revision of the Jones criteria now brings them into closer alignment with other international guidelines for the diagnosis of acute rheumatic fever by defining high-risk populations, recognizing variability in clinical presentation in these high-risk populations, and including Doppler echocardiography as a tool to diagnose cardiac involvement. PMID- 25908770 TI - Efficacy of Long-Term beta-Blocker Therapy for Secondary Prevention of Long-Term Outcomes After Coronary Artery Bypass Grafting Surgery. AB - BACKGROUND: Conflicting results from recent observational studies have raised questions concerning the benefit of beta-blockers for patients undergoing coronary artery bypass grafting (CABG). Furthermore, the efficacy of long-term beta-blocker therapy in CABG patients after hospital discharge is uncertain. METHODS AND RESULTS: The study included 5926 consecutive patients who underwent CABG and were discharged alive. The prevalence and consistency of beta-blocker use were determined in patients with and without a history of myocardial infarction (MI). beta-Blockers were always used in 1280 patients (50.9%) with and 1642 patients (48.1%) without previous MI after CABG. Compared with always users (n=2922, 49.3%), the risk of all-cause death was significantly higher among inconsistent beta-blocker users (hazard ratio [HR], 1.96; 95% confidence interval [CI], 1.50-2.57), and never using beta-blockers was associated with increased risk of both all-cause death (HR, 1.42; 95% CI, 1.01-2.00) and the composite of adverse cardiovascular events (HR, 1.29; 95% CI, 1.10-1.50). In the cohort without MI, the HR for all-cause death was 1.70 (95% CI, 1.17-2.48) in inconsistent users and 1.23 (95% CI, 0.76-1.99) in never users. In the MI cohort, mortality was higher for inconsistent users (HR, 2.14; 95% CI, 1.43-3.20) and for never users (HR, 1.59; 95% CI, 1.07-2.63). Consistent results were obtained in equivalent sensitivity analyses. CONCLUSIONS: In patients with or without previous MI undergoing CABG, the consistent use of beta-blockers was associated with a lower risk of long-term mortality and adverse cardiovascular events. Strategies should be developed to understand and improve discharge prescription of beta-blockers and long-term patient adherence. PMID- 25908772 TI - Are patients with cardiac implants protected against electromagnetic interference in daily life and occupational environment? AB - Utilization of cardiac implants such as pacemakers and implantable cardioverter defibrillators is now commonplace among heart disease patients. The ever increasing technological complexity of these devices is matched by the near omnipresent exposure to electric, magnetic, and electromagnetic fields (EMFs), both in everyday life and the occupational environment. Given that electromagnetic interferences (EMIs) are associated with potential risk in device patients, physicians are increasingly confronted with managing device patients with intermittent EMI and chronic occupational exposure. The current review aims to provide a contemporary overview of cardiovascular implantable electronic devices, their function and susceptibility of non-medical EMFs and provide recommendations for physicians caring for cardiac device patients presenting with EMI. PMID- 25908773 TI - Cardiac rehabilitation: why is it an underused therapy? PMID- 25908776 TI - The effect of duration of follow-up and presence of competing risk on lifespan gain from implantable cardioverter defibrillator therapy: who benefits the most? AB - BACKGROUND: In at-risk patients with left ventricular dysfunction, implantable cardioverter defibrillators (ICDs) prolong life. Implantable cardioverter defibrillators are increasingly implanted for primary prevention and therefore into lower risk patients. Trial data have demonstrated the benefit of these devices but does not provide an estimate of potential lifespan-gain over longer time periods, e.g. a patient's lifespan. METHODS: Using data from landmark ICD trials, lifespan-gain was plotted against baseline annual mortality in the individual trials. Lifespan-gain was then extrapolated to a time-horizon of >20 years while adjusting for increasing 'competing' risk from ageing and non-sudden cardiac death (pump failure). RESULTS: At 3 years, directly observed lifespan gain was strongly dependent on baseline event rate (r = 0.94, P < 0.001). However, projecting beyond the duration of the trial, lifespan-gain increases rapidly and non-linearly with time. At 3 years, it averages 1.7 months, but by 10 years up to 9-fold more. Lifespan-gain over time horizons >20 years were greatest in lower risk patients (~5 life-years for 5% baseline mortality, ~2 life-years for 15% baseline mortality). Increased competing risks significantly reduce lifespan-gain from ICD implantation. CONCLUSION: While high-risk patients may show the greatest short-term gain, the dramatic growth of lifespan-gain over time means that it is the lower risk patients, e.g. primary prevention ICD implantation, who gain the most life-years over their lifetime. Benefit is underestimated when only trial data are assessed as trials can only maintain randomization over limited periods. Lifespan-gain may be further increased through advances in ICD device programming. PMID- 25908777 TI - Moral repugnance, moral distress, and organ sales. AB - Many still oppose legalizing markets in human organs on the grounds that they are morally repugnant. I will argue in this paper that the repugnance felt by some persons towards sales of human organs is insufficient to justify their prohibition. Yet this rejection of the view that markets in human organs should be prohibited because some persons find them to be morally repugnant does not imply that persons' feelings of distress at the possibility of organ sales are irrational. Eduardo Rivera-Lopez argues that such instinctive distress is an appropriate response to the (rationally defensible) perception that certain kinds of arguments that are offered in favor of legalizing organ sales are "in an important sense, illegitimate." Having argued that repugnance should not ground the prohibition of markets in human organs, I will also argue that the moral distress that some feel towards certain arguments that favor such markets is not rationally defensible, either. PMID- 25908774 TI - Randomized trial of atrial arrhythmia monitoring to guide anticoagulation in patients with implanted defibrillator and cardiac resynchronization devices. AB - AIMS: Atrial tachyarrhythmias (ATs) detected by implanted devices are often atrial fibrillation or flutter (AF) associated with stroke. We hypothesized that introduction and termination of anticoagulation based upon AT monitoring would reduce both stroke and bleeding. METHODS AND RESULTS: We randomized 2718 patients with dual-chamber and biventricular defibrillators to start and stop anticoagulation based on remote rhythm monitoring vs. usual office-based follow up with anticoagulation determined by standard clinical criteria. The primary analysis compared the composite endpoint of stroke, systemic embolism, and major bleeding with the two strategies. The trial was stopped after 2 years median follow-up based on futility of finding a difference in primary endpoints between groups. A total of 945 patients (34.8%) developed AT, 264 meeting study anticoagulation criteria. Adjudicated atrial electrograms confirmed AF in 91%; median time to initiate anticoagulation was 3 vs. 54 days in the intervention and control groups, respectively (P < 0.001). Primary events (2.4 vs. 2.3 per 100 patient-years) did not differ between groups (HR 1.06; 95% CI 0.75-1.51; P = 0.732). Major bleeding occurred at 1.6 vs. 1.2 per 100 patient-years (HR 1.39; 95% CI 0.89-2.17; P = 0.145). In patients with AT, thromboembolism rates were 1.0 vs. 1.6 per 100 patient-years (relative risk -35.3%; 95% CI -70.8 to 35.3%; P = 0.251). Although AT burden was associated with thromboembolism, there was no temporal relationship between AT and stroke. CONCLUSION: In patients with implanted defibrillators, the strategy of early initiation and interruption of anticoagulation based on remotely detected AT did not prevent thromboembolism and bleeding. CLINICAL TRIAL REGISTRATION: IMPACT ClinicalTrials.gov identifier: NCT00559988 ( http://clinicaltrials.gov/ct2/show/NCT00559988?term=NCT00559988&rank=1 ). PMID- 25908775 TI - Predicting sudden cardiac death using common genetic risk variants for coronary artery disease. AB - AIMS: Genome-wide association studies (GWAS) have identified many variants associating with an increased risk of coronary artery disease (CAD). We studied the possible association between these variants and the risk of sudden cardiac death (SCD). METHODS AND RESULTS: A weighted genetic risk score (GRSCAD) was formed from variants most strongly associating with CAD identified by the CARDIoGRAMplusC4D Consortium explaining 10.6% of the heritability of CAD [153 single-nucleotide polymorphisms with r(2) < 0.2]. The association between GRSCAD and the occurrence of SCD was studied in three independent autopsy series of consecutive cases combining altogether 1035 autopsies with 306 SCDs due to CAD (SCDCAD). The results were replicated in a prospective follow-up study of 2321 patients (mean follow-up time of 6.2 years with 48 incident SCDs of which 39 due to CAD) undergoing clinical exercise test at baseline. In a meta-analysis of the autopsy series, GRSCAD associated significantly with the risk of SCDCAD with age, body mass index, and sex adjusted odds ratio (OR) of 1.042 (1.023-1.061, P = 9.1 * 10(-6)) for one allele increase in GRSCAD. The same association was seen in both sexes. GRSCAD predicted significantly the risk of SCDCAD also in a prospective study setting (Cox regression analysis adjusted with all relevant clinical data): hazard ratio 1.049 (1.010-1.090, P = 0.014). In meta-analysis of all cohorts (adjusting further for other genetic markers related to traditional risk factors and QT-interval), the association was highly significant [OR 1.045 (1.028-1.063), P = 1.7 * 10(-7)]. CONCLUSION: Genetic risk estimate for CAD may also be used to predict SCD. PMID- 25908778 TI - A replication defect of pseudorabies virus induced by targeted alpha-helix distortion in the syntaxin-like bundle of glycoprotein H (V275P) is corrected by an adjacent compensatory mutation (V271A). AB - Glycoprotein gH is essential for herpesvirus-induced membrane fusion during entry and cell-to-cell spread. Structural analyses of gH homologues revealed a conserved syntaxin-like bundle motif composed of three alpha-helices. Previous studies showed that targeted disruption of any of these helices strongly impaired maturation, cell surface expression and fusion activity of pseudorabies virus gH, as well as formation and spread of infectious virus. After passaging of one corresponding mutant (pPrV-gH-V275P) these replication defects were widely corrected by an adjacent spontaneous amino acid substitution (V271A). Although the doubly mutated gH was still non-functional in fusion assays, its targeted reinsertion into the cloned virus genome (pPrV-gH-V275P-V271A) led to a 200-fold increase in plaque sizes and 10,000-fold higher virus titres, compared with pPrV gH-V275P. Thus, our results demonstrate that structural requirements for gH function in in vitro assays and virus replication are different, and that minor amounts of mature gH in virions are sufficient for productive replication. PMID- 25908779 TI - Genotype-specific neutralization determinants in envelope protein: implications for the improvement of Japanese encephalitis vaccine. AB - Japanese encephalitis remains the leading cause of viral encephalitis in children in Asia and is expanding its geographical range to larger areas in Asia and Australasia. Five genotypes of Japanese encephalitis virus (JEV) co-circulate in the geographically affected areas. In particular, the emergence of genotype I (GI) JEV has displaced genotype III (GIII) as the dominant circulating genotype in many Asian regions. However, all approved vaccine products are derived from GIII strains. In the present study, bioinformatic analysis revealed that GI and GIII JEV strains shared two distinct amino acid residues within the envelope (E) protein (E222 and E327). By using reverse genetics approaches, A222S and S327T mutations were demonstrated to decrease live-attenuated vaccine (LAV) SA14-14-2 induced neutralizing antibodies in humans, without altering viral replication. A222S or S327T mutations were then rationally engineered into the infectious clone of SA14-14-2, and the resulting mutant strains retained the same genetic stability and attenuation characteristics as the parent strain. More importantly, immunization of mice with LAV-A222S or LAV-S327T elicited increased neutralizing antibodies against GI strains. Together, these results demonstrated that E222 and E327 are potential genotype-related neutralization determinants and are critical in determining the protective efficacy of live Japanese encephalitis vaccine SA14 14-2 against circulating GI strains. Our findings will aid in the rational design of the next generation of Japanese encephalitis LAVs capable of providing broad protection against all JEV strains belonging to different genotypes. PMID- 25908780 TI - Boosting Cancer Immunotherapy with Anti-CD137 Antibody Therapy. AB - In the past 5 years, immunomodulatory antibodies have revolutionized cancer immunotherapy. CD137, a member of the tumor necrosis factor receptor superfamily, represents a promising target for enhancing antitumor immune responses. CD137 helps regulate the activation of many immune cells, including CD4(+) T cells, CD8(+) T cells, dendritic cells, and natural killer cells. Recent studies indicate that the antitumor efficacy of therapeutic tumor-targeting antibodies can be augmented by the addition of agonistic antibodies targeting CD137. As ligation of CD137 provides a costimulatory signal in multiple immune cell subsets, combination therapy of CD137 antibody with therapeutic antibodies and/or vaccination has the potential to improve cancer treatment. Recently, clinical trials of combination therapies with agonistic anti-CD137 mAbs have been launched. In this review, we discuss the recent advances and clinical promise of agonistic anti-CD137 monoclonal antibody therapy. PMID- 25908781 TI - Pan-HER, an Antibody Mixture Simultaneously Targeting EGFR, HER2, and HER3, Effectively Overcomes Tumor Heterogeneity and Plasticity. AB - PURPOSE: Accumulating evidence indicates a high degree of plasticity and compensatory signaling within the human epidermal growth factor receptor (HER) family, leading to resistance upon therapeutic intervention with HER family members. EXPERIMENTAL DESIGN/RESULTS: We have generated Pan-HER, a mixture of six antibodies targeting each of the HER family members EGFR, HER2, and HER3 with synergistic pairs of antibodies, which simultaneously remove all three targets, thereby preventing compensatory tumor promoting mechanisms within the HER family. Pan-HER induces potent growth inhibition in a range of cancer cell lines and xenograft models, including cell lines with acquired resistance to therapeutic antibodies. Pan-HER is also highly efficacious in the presence of HER family ligands, indicating that it is capable of overcoming acquired resistance due to increased ligand production. All three target specificities contribute to the enhanced efficacy, demonstrating a distinct benefit of combined HER family targeting when compared with single-receptor targeting. CONCLUSIONS: Our data show that simultaneous targeting of three receptors provides broader efficacy than targeting a single receptor or any combination of two receptors in the HER family, especially in the presence of HER family ligands. Pan-HER represents a novel strategy to deal with primary and acquired resistance due to tumor heterogeneity and plasticity in terms of HER family dependency and as such may be a viable alternative in the clinic. PMID- 25908782 TI - Repair of acute type A aortic dissection: moving towards a more aggressive approach but keeping the old gold standards. PMID- 25908783 TI - Safety of recombinant factor VIIa in patients under extracorporeal membrane oxygenation. AB - OBJECTIVES: To address the safety (rate of thromboembolic events and circuit complications) and efficacy (rate of bleeding control) of recombinant activated coagulation factor VII (rFVIIa) to treat severe bleeding refractory to all surgical and medical treatments in patients under veno-arterial (VA) or veno venous (VV) extracorporeal membrane oxygenation (ECMO) support. METHODS: In a tertiary referral University Cardiothoracic Surgery Centre including three intensive care units, 30 patients received the rFVIIa during ongoing VA or VV ECMO support (8.6% of ECMO activity from 2005 to 2014; N = 347). Early and late clinical results were analysed (retrospective analysis of prospectively collected data). In a substudy, a case-matching procedure was performed among ECMO patients who received (Group A) or did not receive (Group B) rFVIIa treatment. RESULTS: The mediastinum was the most common site of refractory bleeding (after heart transplantation or other cardiac surgery; 90%); 90% (n = 27) of patients were on VA ECMO and the remainder on VV ECMO. The survival rate at ECMO explantation and at the 30th post-implantation day was 67 and 50%, respectively. The final efficacy rate of rFVIIa in stopping bleeding was 93.3%. The rate of thromboembolic events was 3.3% (1 case) and the rate of circuit change was 16.7% (without instances of overt circuit clotting). After case-matching, Group A comprised 23 patients and Group B included 43 patients. No statistically significant differences were observed among groups in terms of thromboembolic events (P = 0.99), circuit change, ventilation time (P = 0.71), infectious complications (P = 06) and survival at both ECMO explantation and the 30th post implantation day. Late survival was comparable (Kaplan-Meier analysis; P = 0.42). CONCLUSIONS: In case of life-threatening bleeding refractory to all conventional therapies, rFVIIa presents an acceptable safety profile in patients under ECMO support. No circuit dysfunctions and limited rates of thromboembolism are observed. PMID- 25908784 TI - Outcomes of In-Hospital Cardiopulmonary Resuscitation in Maintenance Dialysis Patients. AB - Outcomes of cardiopulmonary resuscitation (CPR) in hospitalized patients with ESRD requiring maintenance dialysis are unknown. Outcomes of in-hospital CPR in these patients were compared with outcomes in the general population using data from the Nationwide Inpatient Sample (NIS; 2005-2011). The study population included all adults (>= 18 years old) from the general population and those with a history of ESRD. Baseline characteristics, in-hospital complications, and discharge outcomes were compared between the two groups. The effects of in hospital CPR on mortality, length of stay, hospitalization charges, and discharge destination were analyzed. Yearly national trends in survival, discharge to home, and length of stay were also examined using the Cochran-Armitage trend test. During the study period, 56,069 patients with ESRD underwent in-hospital CPR compared with 323,620 patients from the general population. Unadjusted in hospital mortality rates were higher in patients with ESRD (73.9% versus 71.8%, P<0.001) on univariate analysis. After adjusting for age, gender, and potential confounders, patients with ESRD had higher odds of mortality (odds ratio, 1.24; 95% confidence interval, 1.11 to 1.3; P<0.001). Survival after CPR improved in the year 2011 compared with 2005 (31% versus 21%, P<0.001). Multivariate analysis also revealed that a greater proportion of patients with ESRD who survived were discharged to skilled nursing facilities. In conclusion, outcomes after in hospital CPR are improving in patients with ESRD but remain worse than outcomes in the general population. Patients with ESRD who survive are more likely to be discharged to nursing homes. PMID- 25908785 TI - Targeting chromatin binding regulation of constitutively active AR variants to overcome prostate cancer resistance to endocrine-based therapies. AB - Androgen receptor (AR) variants (AR-Vs) expressed in prostate cancer (PCa) lack the AR ligand binding domain (LBD) and function as constitutively active transcription factors. AR-V expression in patient tissues or circulating tumor cells is associated with resistance to AR-targeting endocrine therapies and poor outcomes. Here, we investigated the mechanisms governing chromatin binding of AR Vs with the goal of identifying therapeutic vulnerabilities. By chromatin immunoprecipitation and sequencing (ChIP-seq) and complementary biochemical experiments, we show that AR-Vs display a binding preference for the same canonical high-affinity androgen response elements (AREs) that are preferentially engaged by AR, albeit with lower affinity. Dimerization was an absolute requirement for constitutive AR-V DNA binding and transcriptional activation. Treatment with the bromodomain and extraterminal (BET) inhibitor JQ1 resulted in inhibition of AR-V chromatin binding and impaired AR-V driven PCa cell growth in vitro and in vivo. Importantly, this was associated with a novel JQ1 action of down-regulating AR-V transcript and protein expression. Overall, this study demonstrates that AR-Vs broadly restore AR chromatin binding events that are otherwise suppressed during endocrine therapy, and provides pre-clinical rationale for BET inhibition as a strategy for inhibiting expression and chromatin binding of AR-Vs in PCa. PMID- 25908787 TI - Stock-based detection of protein oligomeric states in jsPISA. AB - A new version of the popular software PISA for the analysis of macromolecular interfaces and identification of biological assemblies (complexes) from macromolecular crystal structures is presented. The new web server jsPISA has a substantially improved user interface, based on modern JavaScript technologies, and also new elements of analysis: assembly stock and interaction radar. The new elements help interpretation of PISA results in difficult and ambiguous cases, for example, when the oligomeric state depends on protein concentration, or when the biologically relevant interaction is weak and cannot be easily discriminated from superficial crystal contacts. jsPISA is maintained by CCP4 at http://www.ccp4.ac.uk/pisa. There are no login requirements for using the server. PMID- 25908786 TI - Identification of recurrent regulated alternative splicing events across human solid tumors. AB - Cancer is a complex disease that involves aberrant gene expression regulation. Discriminating the modified expression patterns driving tumor biology from the many that have no or little contribution is important for understanding cancer molecular basis. Recurrent deregulation patterns observed in multiple cancer types are enriched for such driver events. Here, we studied splicing alterations in hundreds of matched tumor and normal RNA-seq samples of eight solid cancer types. We found hundreds of cassette exons for which splicing was altered in multiple cancer types and identified a set of highly frequent altered splicing events. Specific splicing regulators, including RBFOX2, MBNL1/2 and QKI, appear to account for many splicing alteration events in multiple cancer types. Together, our results provide a first global analysis of regulated splicing alterations in cancer and identify common events with a potential causative role in solid tumor development. PMID- 25908788 TI - Identification of novel post-transcriptional features in olfactory receptor family mRNAs. AB - Olfactory receptor (Olfr) genes comprise the largest gene family in mice. Despite their importance in olfaction, how most Olfr mRNAs are regulated remains unexplored. Using RNA-seq analysis coupled with analysis of pre-existing databases, we found that Olfr mRNAs have several atypical features suggesting that post-transcriptional regulation impacts their expression. First, Olfr mRNAs, as a group, have dramatically higher average AU-content and lower predicted secondary structure than do control mRNAs. Second, Olfr mRNAs have a higher density of AU-rich elements (AREs) in their 3'UTR and upstream open reading frames (uORFs) in their 5 UTR than do control mRNAs. Third, Olfr mRNAs have shorter 3' UTR regions and with fewer predicted miRNA-binding sites. All of these novel properties correlated with higher Olfr expression. We also identified striking differences in the post-transcriptional features of the mRNAs from the two major classes of Olfr genes, a finding consistent with their independent evolutionary origin. Together, our results suggest that the Olfr gene family has encountered unusual selective forces in neural cells that have driven them to acquire unique post-transcriptional regulatory features. In support of this possibility, we found that while Olfr mRNAs are degraded by a deadenylation dependent mechanism, they are largely protected from this decay in neural lineage cells. PMID- 25908790 TI - MultiMeta: an R package for meta-analyzing multi-phenotype genome-wide association studies. AB - As new methods for multivariate analysis of genome wide association studies become available, it is important to be able to combine results from different cohorts in a meta-analysis. The R package MultiMeta provides an implementation of the inverse-variance-based method for meta-analysis, generalized to an n dimensional setting. AVAILABILITY AND IMPLEMENTATION: The R package MultiMeta can be downloaded from CRAN. CONTACT: dragana.vuckovic@burlo.trieste.it; vi1@sanger.ac.uk SUPPLEMENTARY INFORMATION: Supplementary data are available at Bioinformatics online. PMID- 25908791 TI - ESPRESSO: taking into account assessment errors on outcome and exposures in power analysis for association studies. AB - MOTIVATION: Very large studies are required to provide sufficiently big sample sizes for adequately powered association analyses. This can be an expensive undertaking and it is important that an accurate sample size is identified. For more realistic sample size calculation and power analysis, the impact of unmeasured aetiological determinants and the quality of measurement of both outcome and explanatory variables should be taken into account. Conventional methods to analyse power use closed-form solutions that are not flexible enough to cater for all of these elements easily. They often result in a potentially substantial overestimation of the actual power. RESULTS: In this article, we describe the Estimating Sample-size and Power in R by Exploring Simulated Study Outcomes tool that allows assessment errors in power calculation under various biomedical scenarios to be incorporated. We also report a real world analysis where we used this tool to answer an important strategic question for an existing cohort. AVAILABILITY AND IMPLEMENTATION: The software is available for online calculation and downloads at http://espresso-research.org. The code is freely available at https://github.com/ESPRESSO-research. CONTACT: louqman@gmail.com SUPPLEMENTARY INFORMATION: Supplementary data are available at Bioinformatics online. PMID- 25908789 TI - A new transcription factor for mitosis: in Schizosaccharomyces pombe, the RFX transcription factor Sak1 works with forkhead factors to regulate mitotic expression. AB - Mitotic genes are one of the most strongly oscillating groups of genes in the eukaryotic cell cycle. Understanding the regulation of mitotic gene expression is a key issue in cell cycle control but is poorly understood in most organisms. Here, we find a new mitotic transcription factor, Sak1, in the fission yeast Schizosaccharomyces pombe. Sak1 belongs to the RFX family of transcription factors, which have not previously been connected to cell cycle control. Sak1 binds upstream of mitotic genes in close proximity to Fkh2, a forkhead transcription factor previously implicated in regulation of mitotic genes. We show that Sak1 is the major activator of mitotic gene expression and also confirm the role of Fkh2 as the opposing repressor. Sep1, another forkhead transcription factor, is an activator for a small subset of mitotic genes involved in septation. From yeasts to humans, forkhead transcription factors are involved in mitotic gene expression and it will be interesting to see whether RFX transcription factors may also be involved in other organisms. PMID- 25908794 TI - Transthoracic three-dimensional echocardiography visualization of functional anatomy of double-orifice mitral valve. PMID- 25908792 TI - Living Donor Kidney Transplantation: Facilitating Education about Live Kidney Donation--Recommendations from a Consensus Conference. AB - The Best Practice in Live Kidney Donation Consensus Conference held in June of 2014 included the Best Practices in Living Donor Education Workgroup, whose charge was to identify best practice strategies in education of living donors, community outreach initiatives, commercial media, solicitation, and state registries. The workgroup's goal was to identify critical content to include in living kidney donor education and best methods to deliver educational content. A detailed summary of considerations regarding educational content issues for potential living kidney donors is presented, including the consensus that was reached. Educational topics that may require updating on the basis of emerging studies on living kidney donor health outcomes are also presented. Enhancing the educational process is important for increasing living donor comprehension to optimize informed decision-making. PMID- 25908793 TI - Focus group study of public opinion about paying living kidney donors in Australia. AB - BACKGROUND AND OBJECTIVES: The unmet demand for kidney transplantation has generated intense controversy about introducing incentives for living kidney donors to increase donation rates. Such debates may affect public perception and acceptance of living kidney donation. This study aims to describe the range and depth of public opinion on financial reimbursement, compensation, and incentives for living kidney donors. DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS: Twelve focus groups were conducted with 113 participants recruited from the general public in three Australian states in February 2013. Thematic analysis was used to analyze the transcripts. RESULTS: Five themes were identified: creating ethical impasses (commodification of the body, quandary of kidney valuation, pushing moral boundaries), corrupting motivations (exposing the vulnerable, inevitable abuse, supplanting altruism), determining justifiable risk (compromising kidney quality, undue harm, accepting a confined risk, trusting protective mechanisms, right to autonomy), driving access (urgency of organ shortage, minimizing disadvantage, guaranteeing cost-efficiency, providing impetus, counteracting black markets), and honoring donor deservingness (fairness and reason, reassurance and rewards, merited recompense). Reimbursement and justifiable recompense are considered by the Australian public as a legitimate way of supporting donors and reducing disadvantage. Financial payment beyond reimbursement is regarded as morally reprehensible, with the potential for exploitative commercialism. Some contend that regulated compensation could be a defensible strategy to increased donation rates provided that mechanisms are in place to protect donors. CONCLUSIONS: The perceived threat to community values of human dignity, goodwill, and fairness suggests that there could be strong public resistance to any form of financial inducements for living kidney donors. Policy priorities addressing the removal of disincentives may be more acceptable to the public. PMID- 25908795 TI - Epicardial fat volume is related to atherosclerotic calcification in multiple vessel beds. AB - AIM: To investigate relationships between epicardial fat volume and atherosclerosis in multiple major vessel beds. METHODS AND RESULTS: From the population-based Rotterdam Study, 2298 participants underwent computed tomography examinations to quantify epicardial fat volume and atherosclerotic calcification volume in the coronary arteries, aortic arch, and extracranial and intracranial internal carotid arteries. Using linear regression modelling, we investigated relationships of epicardial fat volume with atherosclerotic calcification volume in each vessel bed, adjusting for conventional cardiovascular risk factors (waist circumference, systolic and diastolic blood pressure, total and high-density lipoprotein cholesterol, smoking, diabetes, and usage of blood pressure-lowering and lipid-lowering medication). To test whether associations of epicardial fat with calcification per vessel bed were independent of calcification elsewhere, we created a model in which all vessel beds were entered together. We found that a larger epicardial fat volume was associated with larger calcification volumes in the coronary arteries, aortic arch, and extracranial carotid arteries in both sexes. After adjustment for cardiovascular risk factors, larger epicardial fat volume was related to coronary and extracranial carotid artery calcification volume in males only [difference in calcification volume per SD increase in epicardial fat volume: 0.12 (95% confidence interval, CI: 0.04; 0.19) and 0.14 (95% CI: 0.06; 0.22)]. These associations remained unchanged after entering all vessel beds into one model. CONCLUSION: Larger volumes of epicardial fat are associated with larger amounts of coronary and extracranial carotid artery atherosclerosis in males, independent of cardiovascular risk factors. This could imply that epicardial fat also exerts a systemic effect on atherosclerosis development. Future longitudinal research is warranted to further disentangle these relationships with a specific focus on sex differences. PMID- 25908796 TI - Big science is hard but worth it. PMID- 25908798 TI - Neuroscience. Seeking tests for a contested brain disease. PMID- 25908800 TI - Research funding. House science chief unveils contentious vision for science. PMID- 25908799 TI - Europe. Plan for E.U. research funds raises ire. PMID- 25908801 TI - Medical research. Clinical trials get practical. PMID- 25908802 TI - Ecology. Inbred wolf population on Isle Royale collapses. PMID- 25908804 TI - A space icon turns 25. PMID- 25908803 TI - Scientific publishing. NIH's peer review stands up to scrutiny. PMID- 25908805 TI - After Hubble. PMID- 25908806 TI - Hubble on steroids. PMID- 25908807 TI - Evolutionary biology. Evolving new organisms via symbiosis. PMID- 25908808 TI - Geochemistry. Biogeochemical tales told by isotope clumps. PMID- 25908809 TI - Self-assembled materials. Supramolecular lattices from tetrahedral nanobuilding blocks. PMID- 25908810 TI - Physiology. Calcilytics for asthma relief. PMID- 25908811 TI - Protein synthesis. The delicate dance of translation and folding. PMID- 25908812 TI - Sustainability. Ecosystem services lost to oil and gas in North America. PMID- 25908813 TI - A path to recruiting more STEM teachers. PMID- 25908814 TI - Editor's note. PMID- 25908815 TI - A Chinese physics institute's defense. PMID- 25908816 TI - Galaxy evolution. Isolated compact elliptical galaxies: stellar systems that ran away. AB - Compact elliptical galaxies form a rare class of stellar system (~30 presently known) characterized by high stellar densities and small sizes and often harboring metal-rich stars. They were thought to form through tidal stripping of massive progenitors, until two isolated objects were discovered where massive galaxies performing the stripping could not be identified. By mining astronomical survey data, we have now found 195 compact elliptical galaxies in all types of environment. They all share similar dynamical and stellar population properties. Dynamical analysis for nonisolated galaxies demonstrates the feasibility of their ejection from host clusters and groups by three-body encounters, which is in agreement with numerical simulations. Hence, isolated compact elliptical and isolated quiescent dwarf galaxies are tidally stripped systems that ran away from their hosts. PMID- 25908817 TI - Organic chemistry. A rhodium catalyst for single-step styrene production from benzene and ethylene. AB - Rising global demand for fossil resources has prompted a renewed interest in catalyst technologies that increase the efficiency of conversion of hydrocarbons from petroleum and natural gas to higher-value materials. Styrene is currently produced from benzene and ethylene through the intermediacy of ethylbenzene, which must be dehydrogenated in a separate step. The direct oxidative conversion of benzene and ethylene to styrene could provide a more efficient route, but achieving high selectivity and yield for this reaction has been challenging. Here, we report that the Rh catalyst ((Fl)DAB)Rh(TFA)(eta(2)-C2H4) [(Fl)DAB is N,N'-bis(pentafluorophenyl)-2,3-dimethyl-1,4-diaza-1,3-butadiene; TFA is trifluoroacetate] converts benzene, ethylene, and Cu(II) acetate to styrene, Cu(I) acetate, and acetic acid with 100% selectivity and yields >=95%. Turnover numbers >800 have been demonstrated, with catalyst stability up to 96 hours. PMID- 25908818 TI - Self-assembly. Selective assemblies of giant tetrahedra via precisely controlled positional interactions. AB - Self-assembly of rigid building blocks with explicit shape and symmetry is substantially influenced by the geometric factors and remains largely unexplored. We report the selective assembly behaviors of a class of precisely defined, nanosized giant tetrahedra constructed by placing different polyhedral oligomeric silsesquioxane (POSS) molecular nanoparticles at the vertices of a rigid tetrahedral framework. Designed symmetry breaking of these giant tetrahedra introduces precise positional interactions and results in diverse selectively assembled, highly ordered supramolecular lattices including a Frank-Kasper A15 phase, which resembles the essential structural features of certain metal alloys but at a larger length scale. These results demonstrate the power of persistent molecular geometry with balanced enthalpy and entropy in creating thermodynamically stable supramolecular lattices with properties distinct from those of other self-assembling soft materials. PMID- 25908819 TI - Isotope geochemistry. Biological signatures in clumped isotopes of O2. AB - The abundances of molecules containing more than one rare isotope have been applied broadly to determine formation temperatures of natural materials. These applications of "clumped" isotopes rely on the assumption that isotope-exchange equilibrium is reached, or at least approached, during the formation of those materials. In a closed-system terrarium experiment, we demonstrate that biological oxygen (O2) cycling drives the clumped-isotope composition of O2 away from isotopic equilibrium. Our model of the system suggests that unique biological signatures are present in clumped isotopes of O2-and not formation temperatures. Photosynthetic O2 is depleted in (18)O(18)O and (17)O(18)O relative to a stochastic distribution of isotopes, unlike at equilibrium, where heavy isotope pairs are enriched. Similar signatures may be widespread in nature, offering new tracers of biological and geochemical cycling. PMID- 25908820 TI - Research funding. Big names or big ideas: do peer-review panels select the best science proposals? AB - This paper examines the success of peer-review panels in predicting the future quality of proposed research. We construct new data to track publication, citation, and patenting outcomes associated with more than 130,000 research project (R01) grants funded by the U.S. National Institutes of Health from 1980 to 2008. We find that better peer-review scores are consistently associated with better research outcomes and that this relationship persists even when we include detailed controls for an investigator's publication history, grant history, institutional affiliations, career stage, and degree types. A one-standard deviation worse peer-review score among awarded grants is associated with 15% fewer citations, 7% fewer publications, 19% fewer high-impact publications, and 14% fewer follow-on patents. PMID- 25908821 TI - Genome editing. The mutagenic chain reaction: a method for converting heterozygous to homozygous mutations. AB - An organism with a single recessive loss-of-function allele will typically have a wild-type phenotype, whereas individuals homozygous for two copies of the allele will display a mutant phenotype. We have developed a method called the mutagenic chain reaction (MCR), which is based on the CRISPR/Cas9 genome-editing system for generating autocatalytic mutations, to produce homozygous loss-of-function mutations. In Drosophila, we found that MCR mutations efficiently spread from their chromosome of origin to the homologous chromosome, thereby converting heterozygous mutations to homozygosity in the vast majority of somatic and germline cells. MCR technology should have broad applications in diverse organisms. PMID- 25908822 TI - Protein folding. Translational tuning optimizes nascent protein folding in cells. AB - In cells, biosynthetic machinery coordinates protein synthesis and folding to optimize efficiency and minimize off-pathway outcomes. However, it has been difficult to delineate experimentally the mechanisms responsible. Using fluorescence resonance energy transfer, we studied cotranslational folding of the first nucleotide-binding domain from the cystic fibrosis transmembrane conductance regulator. During synthesis, folding occurred discretely via sequential compaction of N-terminal, alpha-helical, and alpha/beta-core subdomains. Moreover, the timing of these events was critical; premature alpha subdomain folding prevented subsequent core formation. This process was facilitated by modulating intrinsic folding propensity in three distinct ways: delaying alpha-subdomain compaction, facilitating beta-strand intercalation, and optimizing translation kinetics via codon usage. Thus, de novo folding is translationally tuned by an integrated cellular response that shapes the cotranslational folding landscape at critical stages of synthesis. PMID- 25908823 TI - SARM1 activation triggers axon degeneration locally via NAD+ destruction. AB - Axon degeneration is an intrinsic self-destruction program that underlies axon loss during injury and disease. Sterile alpha and TIR motif-containing 1 (SARM1) protein is an essential mediator of axon degeneration. We report that SARM1 initiates a local destruction program involving rapid breakdown of nicotinamide adenine dinucleotide (NAD(+)) after injury. We used an engineered protease sensitized SARM1 to demonstrate that SARM1 activity is required after axon injury to induce axon degeneration. Dimerization of the Toll-interleukin receptor (TIR) domain of SARM1 alone was sufficient to induce locally mediated axon degeneration. Formation of the SARM1 TIR dimer triggered rapid breakdown of NAD(+), whereas SARM1-induced axon destruction could be counteracted by increased NAD(+) synthesis. SARM1-induced depletion of NAD(+) may explain the potent axon protection in Wallerian degeneration slow (Wld(s)) mutant mice. PMID- 25908825 TI - To work or not shouldn't be a question. PMID- 25908824 TI - Ribosome. Mechanical force releases nascent chain-mediated ribosome arrest in vitro and in vivo. AB - Protein synthesis rates can affect gene expression and the folding and activity of the translation product. Interactions between the nascent polypeptide and the ribosome exit tunnel represent one mode of regulating synthesis rates. The SecM protein arrests its own translation, and release of arrest at the translocon has been proposed to occur by mechanical force. Using optical tweezers, we demonstrate that arrest of SecM-stalled ribosomes can indeed be rescued by force alone and that the force needed to release stalling can be generated in vivo by a nascent chain folding near the ribosome tunnel exit. We formulate a kinetic model describing how a protein can regulate its own synthesis by the force generated during folding, tuning ribosome activity to structure acquisition by a nascent polypeptide. PMID- 25908826 TI - Multilayer assembly. Technology-driven layer-by-layer assembly of nanofilms. AB - Multilayer thin films have garnered intense scientific interest due to their potential application in diverse fields such as catalysis, optics, energy, membranes, and biomedicine. Here we review the current technologies for multilayer thin-film deposition using layer-by-layer assembly, and we discuss the different properties and applications arising from the technologies. We highlight five distinct routes of assembly-immersive, spin, spray, electromagnetic, and fluidic assembly-each of which offers material and processing advantages for assembling layer-by-layer films. Each technology encompasses numerous innovations for automating and improving layering, which is important for research and industrial applications. Furthermore, we discuss how judicious choice of the assembly technology enables the engineering of thin films with tailor-made physicochemical properties, such as distinct-layer stratification, controlled roughness, and highly ordered packing. PMID- 25908827 TI - Multimodality and molecular imaging of matrix metalloproteinase activation in calcific aortic valve disease. AB - Calcific aortic valve disease (CAVD) is the most common cause of aortic stenosis. Matrix metalloproteinases (MMPs) are upregulated in CAVD and contribute to valvular remodeling and calcification. We investigated the feasibility and correlates of MMP-targeted molecular imaging for detection of valvular biology in CAVD. METHODS: Apolipoprotein E-deficient (apoE(-/-)) mice were fed a Western diet (WD) for 3, 6, and 9 mo (n = 108) to induce CAVD. Wild-type mice served as the control group (n = 24). The development of CAVD was tracked with CT, echocardiography, MMP-targeted small-animal SPECT imaging using (99m)Tc-RP805, and histologic analysis. RESULTS: Key features of CAVD-leaflet thickening and valvular calcification-were noted after 6 mo of WD and were more pronounced after 9 mo. These findings were associated with a significant reduction in aortic valve leaflet separation and a significant increase in transaortic valve flow velocity. On in vivo SPECT/CT images, MMP signal in the aortic valve area was significantly higher at 6 mo in WD mice than in control mice and decreased thereafter. The specificity of the signal was demonstrated by blocking, using an excess of nonlabeled precursor. Similar to MMP signal, MMP activity as determined by in situ zymography and valvular inflammation by CD68 staining were maximal at 6 mo. In vivo (99m)Tc-RP805 uptake correlated significantly with MMP activity (R(2) = 0.94, P < 0.05) and CD68 expression (R(2) = 0.98, P < 0.01) in CAVD. CONCLUSION: MMP-targeted imaging detected valvular inflammation and remodeling in a murine model of CAVD. If this ability is confirmed in humans, the technique may provide a tool for tracking the effect of emerging medical therapeutic interventions and for predicting outcome in CAVD. PMID- 25908828 TI - Reply: Modifying the Poor Prognosis Associated with 18F-FDG-Avid NET with Peptide Receptor Chemo-Radionuclide Therapy (PRCRT). PMID- 25908830 TI - Reconstruction-Incorporated Respiratory Motion Correction in Clinical Simultaneous PET/MR Imaging for Oncology Applications. AB - Simultaneous PET and MR imaging is a promising new technique allowing the fusion of functional (PET) and anatomic/functional (MR) information. In the thoracic abdominal regions, respiratory motion is a major challenge leading to reduced quantitative and qualitative image accuracy. Correction methodologies include the use of gated frames that lead to low signal-to-noise ratio considering the associated low statistics. More advanced correction approaches, previously developed for PET/CT imaging, consist of either registering all the reconstructed gated frames to the reference frame or incorporating motion parameters into the iterative reconstruction process to produce a single motion-compensated PET image. The goal of this work was to compare these two-previously implemented in PET/CT-correction approaches within the context of PET/MR motion correction for oncology applications using clinical 4-dimensional PET/MR acquisitions. Two different correction approaches were evaluated comparing the incorporation of elastic transformations extracted from 4-dimensional MR imaging datasets during PET list-mode image reconstruction to a postreconstruction image-based approach. METHODS: Eleven patient datasets acquired on a PET/MR system were used. T1 weighted 4D MR images were registered to the end-expiration image using a nonrigid B-spline registration algorithm to derive deformation matrices accounting for respiratory motion. The derived matrices were subsequently incorporated within a PET image reconstruction of the original emission list-mode data (reconstruction space [RS] method). The corrected images were compared with those produced by applying the deformation matrices in the image space (IS method) followed by summing the realigned gated frames, as well as with uncorrected motion-averaged images. RESULTS: Both correction techniques led to significant improvement in accounting for respiratory motion artifacts when compared with uncorrected motion-averaged images. These improvements included signal-to-noise ratio (mean increase of 28.0% and 24.2% for the RS and IS methods, respectively), lesion size (reduction of 60.4% and 47.9%, respectively), lesion contrast (increase of 70.1% and 57.2%, respectively), and lesion position (changes of 60.9% and 46.7%, respectively). CONCLUSION: Our results demonstrate significant respiratory motion compensation using both methods, with superior results from a 4D PET RS approach. PMID- 25908829 TI - Repeatability of 18F-FDG PET/CT in Advanced Non-Small Cell Lung Cancer: Prospective Assessment in 2 Multicenter Trials. AB - PET/CT with the glucose analog (18)F-FDG has several potential applications for monitoring tumor response to therapy in patients with non-small cell lung cancer (NSCLC). A prerequisite for many of these applications is detailed knowledge of the repeatability of quantitative parameters derived from (18)F-FDG PET/CT studies. METHODS: The repeatability of the (18)F-FDG signal was evaluated in 2 prospective multicenter trials. Patients with advanced NSCLC (tumor stage III-IV) underwent two (18)F-FDG PET/CT studies while not receiving therapy. Tumor (18)F FDG uptake was quantified by measurement of the maximum standardized uptake value within a lesion (SUVmax) and the average SUV within a small volume of interest around the site of maximum uptake (SUVpeak). Analysis was performed for the lesion in the chest with the highest (18)F-FDG uptake and a size of at least 2 cm (target lesion) as well as for up to 6 additional lesions per patient. Repeatability was assessed by Bland-Altman plots and calculation of 95% repeatability coefficients (RCs) of the log-transformed SUV differences. RESULTS: Test-retest repeatability was assessed in 74 patients (34 from the ACRIN 6678 trial and 40 from the Merck MK-0646-008 trial). SUVpeak was 11.57 +/- 7.89 g/mL for the ACRIN trial and 6.89 +/- 3.02 for the Merck trial. The lower and upper RCs were -28% (95% confidence interval [CI], -35% to -23%) and +39% (95% CI, 31% to 54%) in the ACRIN trial, indicating that a decrease of SUVpeak by more than 28% or an increase by more than 39% has a probability of less than 2.5%. The corresponding RCs from the Merck trial were -35% (95% CI, -42% to -29%) and +53% (95% CI, 41% to 72%). Repeatability was similar for SUVmax of the target lesion, averaged SUVmax, and averaged SUVpeak of up to 6 lesions per patient. CONCLUSION: The variability of repeated measurements of tumor (18)F-FDG uptake in patients with NSCLC is somewhat larger than previously reported in smaller single-center studies but comparable to that of gastrointestinal malignancies in a previous multicenter trial. The variability of measurements supports the definitions of tumor response according to PET Response Criteria in Solid Tumors. PMID- 25908831 TI - Predicting Aortic Aneurysm Expansion by PET. PMID- 25908832 TI - 64Cu-Labeled Divalent Cystine Knot Peptide for Imaging Carotid Atherosclerotic Plaques. AB - The rupture of vulnerable atherosclerotic plaques that lead to stroke and myocardial infarction may be induced by macrophage infiltration and augmented by the expression of integrin alphavbeta3. Indeed, atherosclerotic angiogenesis may be a promising marker of inflammation. In this study, an engineered integrin alphavbeta3-targeting PET probe, (64)Cu-NOTA-3-4A, derived from a divalent knottin miniprotein was evaluated in a mouse model for carotid atherosclerotic plaques. METHODS: Atherosclerotic plaques in BALB/C mice, maintained on a high fat diet, were induced with streptozotocin injection and carotid artery ligation and verified by MR imaging. Knottin 3-4A was synthesized by solid-phase peptide synthesis chemistry and coupled to 1,4,7-triazacyclononane-1,4,7-triacetic acid (NOTA) before radiolabeling with (64)Cu. PET probe stability in mouse serum was evaluated. Mice with carotid atherosclerotic plaques were injected via the tail vein with (64)Cu-NOTA-3-4A or (18)F-FDG, followed by small-animal PET/CT imaging at different time points. Receptor targeting specificity of the probe was verified by coinjection of c(RGDyK) administered in molar excess. Subsequently, carotid artery dissection and immunofluorescence staining were performed to evaluate target expression. RESULTS: (64)Cu-NOTA-3-4A was synthesized in high radiochemical purity and yield and demonstrated molecular stability in both phosphate-buffered saline and mouse serum at 4 h. Small-animal PET/CT showed that (64)Cu-NOTA-3-4A accumulated at significantly higher levels in the neovasculature of carotid atherosclerotic plaques (7.41 +/- 1.44 vs. 0.67 +/- 0.23 percentage injected dose/gram, P < 0.05) than healthy or normal vessels at 1 h after injection. (18)F-FDG also accumulated in atherosclerotic lesions at 0.5 and 1 h after injection but at lower plaque-to-normal tissue ratios than (64)Cu-NOTA-3 4A. For example, plaque-to-normal carotid artery ratios for (18)F-FDG and (64)Cu NOTA-3-4A at 1 h after injection were 3.75 and 14.71 (P < 0.05), respectively. Furthermore, uptake of (64)Cu-NOTA-3-4A in atherosclerotic plaques was effectively blocked (~90% at 1 h after injection) by coinjection of c(RGDyK). Immunostaining confirmed integrin alphavbeta3 expression in both the infiltrating macrophages and the neovasculature of atherosclerotic plaques. CONCLUSION: (64)Cu NOTA-3-4A demonstrates specific accumulation in carotid atherosclerotic plaques in which macrophage infiltration and angiogenesis are responsible for elevated integrin alphavbeta3 levels. Therefore, (64)Cu-NOTA-3-4A may demonstrate clinical utility as a PET probe for atherosclerosis imaging or for the evaluation of therapies used to treat atherosclerosis. PMID- 25908834 TI - Simplified Quantification Method for In Vivo SPECT Imaging of the Vesicular Acetylcholine Transporter with 123I-Iodobenzovesamicol. AB - (123)I-iodobenzovesamicol is a SPECT radioligand selective for the vesicular acetylcholine transporter (VAChT) and used to assess the integrity of cholinergic pathways in various neurologic disorders. The current noninvasive method for quantitative analysis of (123)I-iodobenzovesamicol, based on multilinear reference tissue model 2 (MRTM2), requires repeated scans for several hours, limiting its application in clinical trials. Our objective was to validate a simplified acquisition method based on a single (123)I-iodobenzovesamicol static scan preserving the quantification accuracy. Three acquisition times were tested comparatively to a kinetic analysis using MRTM2. METHODS: Six healthy volunteers underwent a dynamic SPECT acquisition comprising 14 frames over 28 h and an MR imaging scan. MR images were automatically segmented, providing the volumes of 19 regions of interest (ROIs). SPECT datasets were coregistered with MR images, and regional time-activity curves were derived. For each ROI, a complete MRTM2 pharmacokinetic analysis, using the cerebellar hemispheres as the reference region, led to the calculation of a (123)I-iodobenzovesamicol-to-VAChT binding parameter, the nondisplaceable binding potential (BP(ND-MRTM2)). A simplified analysis was also performed at 5, 8, and 28 h after injection, providing a simplified BP(ND), given as BP(ND-t) = C(ROI) - C(cerebellar hemispheres)/C(cerebellar hemispheres), with C being the averaged radioactive concentration. RESULTS: No significant difference was found among BP(ND-5 h), BP(ND-8 h), and BP(ND-MRTM2) in any of the extrastriatal regions explored. BP(ND 28 h) was significantly higher than BP(ND-5 h), BP(ND-8 h), and BP(ND-MRTM2) in 9 of the 17 regions explored (P < 0.05). BP(ND-5 h), BP(ND-8 h), and BP(ND-28 h) correlated significantly with BP(ND-MRTM2) (P < 0.05; rho = 0.99, 0.98, and 0.92, respectively). In the striatum, BP(ND-28 h) was significantly higher than BP(ND-5 h) and BP(ND-8 h). BP(ND-5 h) differed significantly from BP(ND-MRTM2) (P < 0.05), with BP(ND-5 h) being 43.6% lower. CONCLUSION: In the extrastriatal regions, a single acquisition at 5 or 8 h after injection provides quantitative results similar to a pharmacokinetic analysis. However, with the highest correlation and accuracy, 5 h is the most suitable time to perform an accurate (123)I-iodobenzovesamicol quantification. In the striatum, none of the 3 times has led to an accurate quantification. PMID- 25908833 TI - Small-Animal PET Imaging of Pancreatic Cancer Xenografts Using a 64Cu-Labeled Monoclonal Antibody, MAb159. AB - Overexpression of the GRP78 receptor on cell surfaces has been linked with tumor growth, metastasis, and resistance to therapy. We developed a (64)Cu-labeled probe for PET imaging of tumor GRP78 expression based on a novel anti-GRP78 monoclonal antibody, MAb159. METHODS: MAb159 was conjugated with the (64)Cu chelator DOTA through lysines on the antibody. DOTA-human IgG was also prepared as a control that did not bind to GRP78. The resulting PET probes were evaluated in BXPC3 pancreatic cancer xenografts in athymic nude mice. RESULTS: The radiotracer was synthesized with a specific activity of 0.8 MBq/MUg of antibody. In BXPC3 xenografts, (64)Cu-DOTA-MAb159 demonstrated prominent tumor accumulation (4.3 +/- 1.2, 15.4 +/- 2.6, and 18.3 +/- 1.0 percentage injected dose per gram at 1, 17, and 48 after injection, respectively). In contrast, (64)Cu-DOTA-human IgG had low BXPC3 tumor accumulation (4.8 +/- 0.5, 7.5 +/- 0.7, and 4.6 +/- 0.8 percentage injected dose per gram at 1, 17, and 48 h after injection, respectively). CONCLUSION: We demonstrated that GRP78 can serve as a valid target for pancreatic cancer imaging. The success of this approach will be valuable for evaluating disease course and therapeutic efficacy at the earliest stages of anti GRP78 treatment. Moreover, these newly developed probes may have important applications in other types of cancer overexpressing GRP78. PMID- 25908836 TI - A review of the surgical options for the correction of presbyopia. AB - Presbyopia is an age-related eye condition where one of the signs is the reduction in the amplitude of accommodation, resulting in the loss of ability to change the eye's focus from far to near. It is the most common age-related ailments affecting everyone around their mid-40s. Methods for the correction of presbyopia include contact lens and spectacle options but the surgical correction of presbyopia still remains a significant challenge for refractive surgeons. Surgical strategies for dealing with presbyopia may be extraocular (corneal or scleral) or intraocular (removal and replacement of the crystalline lens or some type of treatment on the crystalline lens itself). There are however a number of limitations and considerations that have limited the widespread acceptance of surgical correction of presbyopia. Each surgical strategy presents its own unique set of advantages and disadvantages. For example, lens removal and replacement with an intraocular lens may not be preferable in a young patient with presbyopia without a refractive error. Similarly treatment on the crystalline lens may not be a suitable choice for a patient with early signs of cataract. This article is a review of the options available and those that are in development stages and are likely to be available in the near future for the surgical correction of presbyopia. PMID- 25908835 TI - Early diagnosis and successful treatment of paraneoplastic melanocytic proliferation. AB - BACKGROUND: Paraneoplastic melanocytic proliferation (bilateral diffuse uveal melanocytic proliferation, BDUMP) is a rare but devastating disease that causes progressive visual loss in patients who usually have an occult malignancy. Visual loss occurs as a result of paraneoplastic changes in the uveal tissue. METHODS: In a masked fashion, the serum of two patients with BDUMP was evaluated for the presence of cultured melanocyte elongation and proliferation (CMEP) factor using cultured human melanocytes. We evaluated the efficacy of plasmapheresis as a treatment modality early in the disease in conjunction with radiation and chemotherapy. RESULTS: The serum of the first case patient was investigated after plasmapheresis and did not demonstrate proliferation of cultured human melanocytes. The serum of the second case was evaluated prior to treatment with plasmapheresis and did induce this proliferation. These findings are in accordance with the diminution of CMEP factor after plasmapheresis. Treatment with plasmapheresis managed to stabilise the ocular disease progression in both patients. CONCLUSIONS: In the past, visual loss due to paraneoplastic melanocytic proliferation was considered progressive and irreversible. We treated two patients successfully with plasmapheresis and demonstrated a relation between CMEP factor in the serum of these patients and proliferation of cultured melanocytes. PMID- 25908837 TI - The mental health of UK ex-servicemen with a combat-related or a non-combat related visual impairment: does the cause of visual impairment matter? AB - AIMS: Since the start of the conflicts in Iraq and Afghanistan, the numbers of young service personnel who have sustained a combat-related visual impairment have increased. This cross-sectional study examined the mental well-being of ex servicemen (aged 22-55 years) with a visual impairment and determined if the mental health of those with a combat-related visual impairment differed from those whose visual impairment is not combat-related. METHODS: Male ex-service personnel with a visual impairment completed a telephone interview assessing the presence of depressive symptomatology, probable anxiety disorder, post-traumatic stress disorder (PTSD) symptomatology and alcohol misuse. Data were analysed using descriptive statistics. RESULTS: 77 participants were included in the study, reflecting a response rate of 76.2%. Of those with complete data (n=74), 20 ex-servicemen had a combat-related visual impairment. Among ex-service personnel with a combat-related visual impairment, 10.0% (95% CI 0 to 23.2) screened positive for a probable depression, 25.0% (95% CI 6.0 to 44.0) for probable anxiety and 10.0% (95% CI 0 to 23.2) for probable PTSD. The prevalence of probable depression and probable PTSD differed among those with a non-combat related visual impairment, namely 18.5% (95% CI 8.1 to 28.9) and 16.7% (95% CI 6.8 to 26.7), respectively. Probable anxiety was 18.5% (95% CI 8.1 to 28.9) among non-combat-related visually impaired ex-service personnel. 45.0% (95% CI 23.2 to 66.8) of combat-related visually impaired personnel reported hazardous drinking, compared with 20.4% (95% CI 9.7 to 31.2) of those with a non-combat-related visual impairment. CONCLUSIONS: Mental health problems were prevalent among visually impaired younger ex-servicemen. No statistically significant differences were found in the prevalence of mental health problems among ex-servicemen with a combat-related visual impairment compared with those with a non-combat-related visual impairment. PMID- 25908838 TI - Biological variation of cardiac troponin in stable haemodialysis patients. AB - BACKGROUND: Patients with end-stage renal failure exhibit a chronic elevation of serum cardiac troponin (cTn) concentration. In order to facilitate the diagnosis of myocardial infarction in these patients, it is necessary to distinguish an increased cTn concentration due to an acute event, from that being a manifestation of chronic elevation. The aim of this study was to gather biological variation data relating to two serum cTn assays, one, a hs-cTnT assay, the other a contemporary sensitive cTnI assay, among stable haemodialysis patients. It was hoped that this might inform as to the best way to use cTn assays to assist in the diagnosis of myocardial infarction in patients with end stage renal failure. METHODS: Eighteen stable haemodialysis patients were recruited, of whom 16 completed the study. Predialysis blood samples were collected weekly for 10 weeks during the second dialysis session of the week. Analytical CV (CVA), within-subject biological variation (CVI), between-subject biological variation (CVG), reference change value (RCV) and index of individuality (II) were determined for both assays. RESULTS: All samples had a serum hs-cTnT concentration above the 99th percentile for a healthy population compared to 29.4% for cTnI. For hs-cTnT, the long-term CVA was 2.1%, CVI 10.5%, CVG 64.2%, RCV 28.1% and log-normal RCV (rise/fall) 34.4%/-25.6%. The corresponding values for cTnI were 7.1, 20.2, 100.5 and 79.8%/-44.4%. The II was 0.17 and 0.2 for hs-cTnT and cTnI, respectively. CONCLUSION: Long-term biological variation of cTn in stable haemodialysis patients is similar to that in healthy individuals and in patients with stable coronary arterial disease. The low II for cTnI and hs-cTnT in stable haemodialysis patients indicates that population-based decision points are of limited value. Serial measurements are required to detect significant changes in cTn concentrations and support diagnosis of myocardial infarction in these patients. PMID- 25908839 TI - Controlled induction of human pancreatic progenitors produces functional beta like cells in vitro. AB - Directed differentiation of human pluripotent stem cells into functional insulin producing beta-like cells holds great promise for cell replacement therapy for patients suffering from diabetes. This approach also offers the unique opportunity to study otherwise inaccessible aspects of human beta cell development and function in vitro. Here, we show that current pancreatic progenitor differentiation protocols promote precocious endocrine commitment, ultimately resulting in the generation of non-functional polyhormonal cells. Omission of commonly used BMP inhibitors during pancreatic specification prevents precocious endocrine formation while treatment with retinoic acid followed by combined EGF/KGF efficiently generates both PDX1(+) and subsequent PDX1(+)/NKX6.1(+) pancreatic progenitor populations, respectively. Precise temporal activation of endocrine differentiation in PDX1(+)/NKX6.1(+) progenitors produces glucose-responsive beta-like cells in vitro that exhibit key features of bona fide human beta cells, remain functional after short-term transplantation, and reduce blood glucose levels in diabetic mice. Thus, our simplified and scalable system accurately recapitulates key steps of human pancreas development and provides a fast and reproducible supply of functional human beta-like cells. PMID- 25908840 TI - Sox2, Tlx, Gli3, and Her9 converge on Rx2 to define retinal stem cells in vivo. AB - Transcriptional networks defining stemness in adult neural stem cells (NSCs) are largely unknown. We used the proximal cis-regulatory element (pCRE) of the retina specific homeobox gene 2 (rx2) to address such a network. Lineage analysis in the fish retina identified rx2 as marker for multipotent NSCs. rx2-positive cells located in the peripheral ciliary marginal zone behave as stem cells for the neuroretina, or the retinal pigmented epithelium. We identified upstream regulators of rx2 interrogating the rx2 pCRE in a trans-regulation screen and focused on four TFs (Sox2, Tlx, Gli3, and Her9) activating or repressing rx2 expression. We demonstrated direct interaction of the rx2 pCRE with the four factors in vitro and in vivo. By conditional mosaic gain- and loss-of-function analyses, we validated the activity of those factors on regulating rx2 transcription and consequently modulating neuroretinal and RPE stem cell features. This becomes obvious by the rx2-mutant phenotypes that together with the data presented above identify rx2 as a transcriptional hub balancing stemness of neuroretinal and RPE stem cells in the adult fish retina. PMID- 25908842 TI - RIP1 negatively regulates basal autophagic flux through TFEB to control sensitivity to apoptosis. AB - In a synthetic lethality/viability screen, we identified the serine-threonine kinase RIP1 (RIPK1) as a gene whose knockdown is highly selected against during growth in normal media, in which autophagy is not critical, but selected for in conditions that increase reliance on basal autophagy. RIP1 represses basal autophagy in part due to its ability to regulate the TFEB transcription factor, which controls the expression of autophagy-related and lysosomal genes. RIP1 activates ERK, which negatively regulates TFEB though phosphorylation of serine 142. Thus, in addition to other pro-death functions, RIP1 regulates cellular sensitivity to pro-death stimuli by modulating basal autophagy. PMID- 25908841 TI - Forward engineering neuronal diversity using direct reprogramming. AB - The nervous system is comprised of a vast diversity of distinct neural cell types. Differences between neuronal subtypes drive the assembly of neuronal circuits and underlie the subtype specificity of many neurological diseases. Yet, because neurons are irreversibly post-mitotic and not readily available from patients, it has not been feasible to study specific subtypes of human neurons in larger numbers. A powerful means to study neuronal diversity and neurological disease is to establish methods to produce desired neuronal subtypes in vitro. Traditionally this has been accomplished by treating pluripotent or neural stem cells with growth factors and morphogens that recapitulate exogenous developmental signals. These approaches often require extended periods of culture, which can limit their utility. However, more recently, it has become possible to produce neurons directly from fibroblasts using transcription factors and/or microRNAs. This technique referred to as direct reprogramming or transdifferentiation has proven to be a rapid, robust, and reproducible method to generate mature neurons of many different subtypes from multiple cell sources. Here, we highlight recent advances in generating neurons of specific subtypes using direct reprogramming and outline various scenarios in which induced neurons may be applied to studies of neuronal function and neurological disease. PMID- 25908843 TI - GSTO1-1 modulates metabolism in macrophages activated through the LPS and TLR4 pathway. AB - Macrophages mediate innate immune responses that recognise foreign pathogens, and bacterial lipopolysaccharide (LPS) recruits a signalling pathway through Toll like receptor 4 (TLR4) to induce pro-inflammatory cytokines and reactive oxygen species (ROS). LPS activation also skews the metabolism of macrophages towards a glycolytic phenotype. Here, we demonstrate that the LPS-triggered glycolytic switch is significantly attenuated in macrophages deficient for glutathione transferase omega-1 (GSTO1, note that GSTO1-1 refers to the dimeric molecule with identical type 1 subunits). In response to LPS, GSTO1-1-deficient macrophages do not produce excess lactate, or dephosphorylate AMPK, a key metabolic stress regulator. In addition, GSTO1-1-deficient cells do not induce HIF1alpha, which plays a key role in maintaining the pro-inflammatory state of activated macrophages. The accumulation of the TCA cycle intermediates succinate and fumarate that occurs in LPS-treated macrophages was also blocked in GSTO1-1 deficient cells. These data indicate that GSTO1-1 is required for LPS-mediated signalling in macrophages and that it acts early in the LPS-TLR4 pro-inflammatory pathway. PMID- 25908844 TI - Regulation of Cdc42 polarization by the Rsr1 GTPase and Rga1, a Cdc42 GTPase activating protein, in budding yeast. AB - Cdc42 plays a central role in establishing polarity in yeast and animals, yet how polarization of Cdc42 is achieved in response to spatial cues is poorly understood. Using live-cell imaging, we found distinct dynamics of Cdc42 polarization in haploid budding yeast in correlation with two temporal steps of the G1 phase. The position at which the Cdc42-GTP cluster develops changes rapidly around the division site during the first step but becomes stabilized in the second step, suggesting that an axis of polarized growth is determined in mid G1. Cdc42 polarization in the first step and its proper positioning depend on Rsr1 and its GTPase-activating protein (GAP) Bud2. Interestingly, Rga1, a Cdc42 GAP, exhibits transient localization to a site near the bud neck and to the division site during cytokinesis and G1, and this temporal change of Rga1 distribution is necessary for determination of a proper growth site. Mathematical modeling suggests that a proper axis of Cdc42 polarization in haploid cells might be established through a biphasic mechanism involving sequential positive feedback and transient negative feedback. PMID- 25908845 TI - SUMOylation regulates ciliary localization of olfactory signaling proteins. AB - Cilia are evolutionarily conserved organelles found on many mammalian cell types, including neuronal populations. Although neuronal cilia, including those on olfactory sensory neurons (OSNs), are often delineated by localization of adenylyl cyclase 3 (AC3, also known as ADCY3), the mechanisms responsible for targeting integral membrane proteins are largely unknown. Post-translational modification by small ubiquitin-like modifier (SUMO) proteins plays an important role in protein localization processes such as nuclear-cytosolic transport. Here, we identified through bioinformatic analysis that adenylyl cyclases harbor conserved SUMOylation motifs, and show that AC3 is a substrate for SUMO modification. Functionally, overexpression of the SUMO protease SENP2 prevented ciliary localization of AC3, without affecting ciliation or cilia maintenance. Furthermore, AC3-SUMO mutants did not localize to cilia. To test whether SUMOylation is sufficient for cilia entry, we compared localization of ANO2, which possesses a SUMO motif, and ANO1, which lacks SUMOylation sites and does not localize to cilia. Introduction of SUMOylation sites into ANO1 was not sufficient for ciliary entry. These data suggest that SUMOylation is necessary but not sufficient for ciliary trafficking of select constituents, further establishing the link between ciliary and nuclear import. PMID- 25908846 TI - The structure of the complex between alpha-tubulin, TBCE and TBCB reveals a tubulin dimer dissociation mechanism. AB - Tubulin proteostasis is regulated by a group of molecular chaperones termed tubulin cofactors (TBC). Whereas tubulin heterodimer formation is well characterized biochemically, its dissociation pathway is not clearly understood. Here, we carried out biochemical assays to dissect the role of the human TBCE and TBCB chaperones in alpha-tubulin-beta-tubulin dissociation. We used electron microscopy and image processing to determine the three-dimensional structure of the human TBCE, TBCB and alpha-tubulin (alphaEB) complex, which is formed upon alpha-tubulin-beta-tubulin heterodimer dissociation by the two chaperones. Docking the atomic structures of domains of these proteins, including the TBCE UBL domain, as we determined by X-ray crystallography, allowed description of the molecular architecture of the alphaEB complex. We found that heterodimer dissociation is an energy-independent process that takes place through a disruption of the alpha-tubulin-beta-tubulin interface that is caused by a steric interaction between beta-tubulin and the TBCE cytoskeleton-associated protein glycine-rich (CAP-Gly) and leucine-rich repeat (LRR) domains. The protruding arrangement of chaperone ubiquitin-like (UBL) domains in the alphaEB complex suggests that there is a direct interaction of this complex with the proteasome, thus mediating alpha-tubulin degradation. PMID- 25908848 TI - The P2Y2 receptor promotes Wnt3a- and EGF-induced epithelial tubular formation by IEC6 cells by binding to integrins. AB - Epithelial tubular structures are essential units in various organs. Here, we used rat intestinal epithelial IEC6 cells to investigate tubulogenesis and we found that tubular formation was induced by a combination of Wnt3a and EGF signaling during three-dimensional culture. Wnt3a and EGF induced the expression of the P2Y2 receptor (P2Y2R, also known as P2RY2), and knockdown of P2Y2R suppressed tubular formation. A P2Y2R mutant that lacks nucleotide responsiveness rescued the phenotypes resulting from P2Y2R knockdown, suggesting that nucleotide dependent responses are not required for P2Y2R functions in tubular formation. The Arg-Gly-Asp (RGD) sequence of P2Y2R has been shown to interact with integrins, and a P2Y2R mutant lacking integrin-binding activity was unable to induce tubular formation. P2Y2R expression inhibited the interaction between integrins and fibronectin, and induced cell morphological changes and proliferation. Inhibition of integrin and fibronectin binding by treatment with the cyclic RGD peptide and fibronectin knockdown induced tubular formation in the presence of EGF alone, but a fibronectin coat suppressed Wnt3a- and EGF-induced tubular formation. These results suggest that Wnt3a- and EGF-induced P2Y2R expression causes tubular formation by preventing the binding of integrins and fibronectin rather than by mediating nucleotide responses. PMID- 25908847 TI - The small GTPase Arl8b regulates assembly of the mammalian HOPS complex on lysosomes. AB - The homotypic fusion and protein sorting (HOPS) complex is a multi-subunit complex conserved from yeast to mammals that regulates late endosome and lysosome fusion. However, little is known about how the HOPS complex is recruited to lysosomes in mammalian cells. Here, we report that the small GTPase Arl8b, but not Rab7 (also known as RAB7A), is essential for membrane localization of the human (h)Vps41 subunit of the HOPS complex. Assembly of the core HOPS subunits to Arl8b- and hVps41-positive lysosomes is guided by their subunit-subunit interactions. RNA interference (RNAi)-mediated depletion of hVps41 resulted in the impaired degradation of EGFR that was rescued upon expression of wild-type but not an Arl8b-binding-defective mutant of hVps41, suggesting that Arl8b dependent lysosomal localization of hVps41 is required for its endocytic function. Furthermore, we have also identified that the Arl8b effector SKIP (also known as PLEKHM2) interacts with and recruits HOPS subunits to Arl8b and kinesin positive peripheral lysosomes. Accordingly, RNAi-mediated depletion of SKIP impaired lysosomal trafficking and degradation of EGFR. These findings reveal that Arl8b regulates the association of the human HOPS complex with lysosomal membranes, which is crucial for the function of this tethering complex in endocytic degradation. PMID- 25908849 TI - HGF-induced serine 897 phosphorylation of EphA2 regulates epithelial morphogenesis of MDCK cells in 3D culture. AB - Expression of EphA2 is upregulated in various cancers that are derived from epithelial cells and correlates with the ability of a cancer cell to undergo migration and invasion. Here we have investigated the role of EphA2 in the epithelial morphogenesis of Madin-Darby canine kidney (MDCK) cells in three dimensional culture. We show that EphA2 is phosphorylated on serine residue 897 through hepatocyte growth factor (HGF) stimulation using a phosphatidylinositol 3 kinase (PI3K)-Akt-dependent mechanism and that this phosphorylation is required for the formation of extensions, the first step of tubulogenesis, in MDCK cysts. By contrast, stimulation using the ligand ephrinA1 dephosphorylates EphA2 on serine residue 897 and suppresses the HGF-induced morphological change. Furthermore, activation of the small GTPase RhoG is involved in the HGF-induced formation of extensions downstream of EphA2. These observations suggest that a ligand-independent activity of EphA2 contributes to epithelial morphogenesis. PMID- 25908850 TI - Protection of Drosophila chromosome ends through minimal telomere capping. AB - In Drosophila, telomere-capping proteins have the remarkable capacity to recognize chromosome ends in a sequence-independent manner. This epigenetic protection is essential to prevent catastrophic ligations of chromosome extremities. Interestingly, capping proteins occupy a large telomere chromatin domain of several kilobases; however, the functional relevance of this to end protection is unknown. Here, we investigate the role of the large capping domain by manipulating HOAP (encoded by caravaggio) capping-protein expression in the male germ cells, where telomere protection can be challenged without compromising viability. We show that the exhaustion of HOAP results in a dramatic reduction of other capping proteins at telomeres, including K81 [encoded by ms(3)K81], which is essential for male fertility. Strikingly however, we demonstrate that, although capping complexes are barely detected in HOAP-depleted male germ cells, telomere protection and male fertility are not dramatically affected. Our study thus demonstrates that efficient protection of Drosophila telomeres can be achieved with surprisingly low amounts of capping complexes. We propose that these complexes prevent fusions by acting at the very extremity of chromosomes, reminiscent of the protection conferred by extremely short telomeric arrays in yeast or mammalian systems. PMID- 25908851 TI - The transcriptional activator Gli2 modulates T-cell receptor signalling through attenuation of AP-1 and NFkappaB activity. AB - Different tissues contain diverse and dynamic cellular niches, providing distinct signals to tissue-resident or migratory infiltrating immune cells. Hedgehog (Hh) proteins are secreted inter-cellular signalling molecules, which are essential during development and are important in cancer, post-natal tissue homeostasis and repair. Hh signalling mediated by the Hh-responsive transcription factor Gli2 also has multiple roles in T-lymphocyte development and differentiation. Here, we investigate the function of Gli2 in T-cell signalling and activation. Gene transcription driven by the Gli2 transcriptional activator isoform (Gli2A) attenuated T-cell activation and proliferation following T-cell receptor (TCR) stimulation. Expression of Gli2A in T-cells altered gene expression profiles, impaired the TCR-induced Ca(2+) flux and nuclear expression of NFAT2, suppressed upregulation of molecules essential for activation, and attenuated signalling pathways upstream of the AP-1 and NFkappaB complexes, leading to reduced activation of these important transcription factors. Inhibition of physiological Hh-dependent transcription increased NFkappaB activity upon TCR ligation. These data are important for understanding the molecular mechanisms of immunomodulation, particularly in tissues where Hh proteins or other Gli activating ligands such as TGFbeta are upregulated, including during inflammation, tissue damage and repair, and in tumour microenvironments. PMID- 25908852 TI - The nucleus is an intracellular propagator of tensile forces in NIH 3T3 fibroblasts. AB - Nuclear positioning is a crucial cell function, but how a migrating cell positions its nucleus is not understood. Using traction-force microscopy, we found that the position of the nucleus in migrating fibroblasts closely coincided with the center point of the traction-force balance, called the point of maximum tension (PMT). Positioning of the nucleus close to the PMT required nucleus cytoskeleton connections through linker of nucleoskeleton-to-cytoskeleton (LINC) complexes. Although the nucleus briefly lagged behind the PMT following spontaneous detachment of the uropod during migration, the nucleus quickly repositioned to the PMT within a few minutes. Moreover, traction-generating spontaneous protrusions deformed the nearby nucleus surface to pull the nuclear centroid toward the new PMT, and subsequent retraction of these protrusions relaxed the nuclear deformation and restored the nucleus to its original position. We propose that the protruding or retracting cell boundary transmits a force to the surface of the nucleus through the intervening cytoskeletal network connected by the LINC complexes, and that these forces help to position the nucleus centrally and allow the nucleus to efficiently propagate traction forces across the length of the cell during migration. PMID- 25908853 TI - FilGAP, a Rho-ROCK-regulated GAP for Rac, controls adherens junctions in MDCK cells. AB - Rho family small GTPases are essential for the formation of adherens junctions in epithelial cells. Here, we found that FilGAP (also known as ARHGAP24), a Rac specific Rho GTPase-activating protein, promoted the formation of adherens junctions in Madin-Darby canine kidney (MDCK) cells. Knockdown of FilGAP by siRNA stimulated the disassembly and migration of MDCK cells induced by hepatocyte growth factor (HGF). By contrast, forced expression of FilGAP induced accumulation of E-cadherin at adherens junctions. Endogenous FilGAP colocalized with E-cadherin at adherens junctions, and depletion of FilGAP reduced the amount of E-cadherin expressed at the surface. The Rac GAP domain of FilGAP was necessary for the suppression of cell scattering induced by HGF. In agreement with this, siRNA-mediated knockdown of both Rac1 and FilGAP suppressed cell scattering induced by HGF. Forced expression of Rho kinase (ROCK, of which there are two isoforms ROCK1 and ROCK2) induced the accumulation of E-cadherin at the adherens junction, and depletion of FilGAP prevented the accumulation of E cadherin. Moreover, wild-type FilGAP but not a non-phosphorylatable FilGAP mutant rescued the accumulation of E-cadherin at adherens junctions. These results suggest that FilGAP might regulate cell-cell adhesion through inactivation of Rac downstream of Rho-ROCK-signaling in MDCK cells. PMID- 25908854 TI - The Drosophila fragile X mental retardation protein participates in the piRNA pathway. AB - RNA metabolism controls multiple biological processes, and a specific class of small RNAs, called piRNAs, act as genome guardians by silencing the expression of transposons and repetitive sequences in the gonads. Defects in the piRNA pathway affect genome integrity and fertility. The possible implications in physiopathological mechanisms of human diseases have made the piRNA pathway the object of intense investigation, and recent work suggests that there is a role for this pathway in somatic processes including synaptic plasticity. The RNA binding fragile X mental retardation protein (FMRP, also known as FMR1) controls translation and its loss triggers the most frequent syndromic form of mental retardation as well as gonadal defects in humans. Here, we demonstrate for the first time that germline, as well as somatic expression, of Drosophila Fmr1 (denoted dFmr1), the Drosophila ortholog of FMRP, are necessary in a pathway mediated by piRNAs. Moreover, dFmr1 interacts genetically and biochemically with Aubergine, an Argonaute protein and a key player in this pathway. Our data provide novel perspectives for understanding the phenotypes observed in Fragile X patients and support the view that piRNAs might be at work in the nervous system. PMID- 25908855 TI - ENTH and ANTH domain proteins participate in AP2-independent clathrin-mediated endocytosis. AB - Clathrin-mediated endocytosis (CME) is a major route of entry into eukaryotic cells. A core of evolutionarily ancient genes encodes many components of this system but much of our mechanistic understanding of CME is derived from a phylogenetically narrow sampling of a few model organisms. In the parasite Trypanosoma brucei, which is distantly related to the better characterised animals and fungi, exceptionally fast endocytic turnover aids its evasion of the host immune system. Although clathrin is absolutely essential for this process, the adaptor protein complex 2 (AP2) has been secondarily lost, suggesting mechanistic divergence. Here, we characterise two phosphoinositide-binding monomeric clathrin adaptors, T. brucei (Tb)EpsinR and TbCALM, which in trypanosomes are represented by single genes, unlike the expansions present in animals and fungi. Depletion of these gene products reveals essential, but partially redundant, activities in CME. Ultrastructural analysis of TbCALM and TbEpsinR double-knockdown cells demonstrated severe defects to clathrin-coated pit formation and morphology associated with a dramatic inhibition of endocytosis. Depletion of TbCALM alone, however, produced a distinct lysosomal segregation phenotype, indicating an additional non-redundant role for this protein. Therefore, TbEpsinR and TbCALM represent ancient phosphoinositide binding proteins with distinct and vital roles in AP2-independent endocytosis. PMID- 25908856 TI - Amorphous Ca2+ polyphosphate nanoparticles regulate the ATP level in bone-like SaOS-2 cells. AB - Polyphosphate (polyP) is a physiologically occurring polyanion that is synthesized especially in bone-forming osteoblast cells and blood platelets. We used amorphous polyP nanoparticles, complexed with Ca(2+), that have a globular size of ~100 nm. Because polyP comprises inorganic orthophosphate units that are linked together through high-energy phosphoanhydride bonds, we questioned whether the observed morphogenetic effect, elicited by polyP, is correlated with the energy-generating machinery within the cells. We show that exposure of SaOS-2 osteoblast-like cells to polyP results in a strong accumulation of mitochondria and a parallel translocation of the polyP-degrading enzyme alkaline phosphatase to the cell surface. If SaOS-2 cells are activated by the mineralization activation cocktail (comprising beta-glycerophosphate, ascorbic acid and dexamethasone) and additionally incubated with polyP, a tenfold intracellular increase of the ATP level occurs. Even more, in those cells, an intensified release of ATP into the extracellular space is also seen. We propose and conclude that polyP acts as metabolic fuel after the hydrolytic cleavage of the phosphoanhydride linkages, which contributes to hydroxyapatite formation on the plasma membranes of osteoblasts. PMID- 25908857 TI - Dendrite arborization requires the dynein cofactor NudE. AB - The microtubule-based molecular motor dynein is essential for proper neuronal morphogenesis. Dynein activity is regulated by cofactors, and the role(s) of these cofactors in shaping neuronal structure are still being elucidated. Using Drosophila melanogaster, we reveal that the loss of the dynein cofactor NudE results in abnormal dendrite arborization. Our data show that NudE associates with Golgi outposts, which mediate dendrite branching, suggesting that NudE normally influences dendrite patterning by regulating Golgi outpost transport. Neurons lacking NudE also have increased microtubule dynamics, reflecting a change in microtubule stability that is likely to also contribute to abnormal dendrite growth and branching. These defects in dendritogenesis are rescued by elevating levels of Lis1, another dynein cofactor that interacts with NudE as part of a tripartite complex. Our data further show that the NudE C-terminus is dispensable for dendrite morphogenesis and is likely to modulate NudE activity. We propose that a key function of NudE is to enhance an interaction between Lis1 and dynein that is crucial for motor activity and dendrite architecture. PMID- 25908858 TI - Localization of cofilin mRNA to the leading edge of migrating cells promotes directed cell migration. AB - mRNA trafficking, which enables the localization of mRNAs to particular intracellular targets, occurs in a wide variety of cells. The importance of the resulting RNA distribution for cellular functions, however, has been difficult to assess. We have found that cofilin-1 mRNA is rapidly localized to the leading edge of human lung carcinoma cells and that VICKZ family RNA-binding proteins help mediate this localization through specific interactions with the 3'UTR of cofilin mRNA. Using a phagokinetic assay for cell motility, we have been able to quantify the effect of mRNA localization on the rescue of lung carcinoma cells in which cofilin was knocked down by using short hairpin RNA (shRNA). Although restoring cofilin protein to normal endogenous levels rescues general lamellipodia formation around the periphery of the cell, only when the rescuing cofilin mRNA can localize to the leading edge is it capable of also fully rescuing directed cell movement. These results demonstrate that localization of an mRNA can provide an additional level of regulation for the function of its protein product. PMID- 25908859 TI - Induction of stable ER-plasma-membrane junctions by Kv2.1 potassium channels. AB - Junctions between cortical endoplasmic reticulum (cER) and the plasma membrane are a subtle but ubiquitous feature in mammalian cells; however, very little is known about the functions and molecular interactions that are associated with neuronal ER-plasma-membrane junctions. Here, we report that Kv2.1 (also known as KCNB1), the primary delayed-rectifier K(+) channel in the mammalian brain, induces the formation of ER-plasma-membrane junctions. Kv2.1 localizes to dense, cell-surface clusters that contain non-conducting channels, indicating that they have a function that is unrelated to membrane-potential regulation. Accordingly, Kv2.1 clusters function as membrane-trafficking hubs, providing platforms for delivery and retrieval of multiple membrane proteins. Using both total internal reflection fluorescence and electron microscopy we demonstrate that the clustered Kv2.1 plays a direct structural role in the induction of stable ER-plasma membrane junctions in both transfected HEK 293 cells and cultured hippocampal neurons. Glutamate exposure results in a loss of Kv2.1 clusters in neurons and subsequent retraction of the cER from the plasma membrane. We propose Kv2.1 induced ER-plasma-membrane junctions represent a new macromolecular plasma membrane complex that is sensitive to excitotoxic insult and functions as a scaffolding site for both membrane trafficking and Ca(2+) signaling. PMID- 25908860 TI - PML induces compaction, TRF2 depletion and DNA damage signaling at telomeres and promotes their alternative lengthening. AB - The alternative lengthening of telomeres (ALT) mechanism allows cancer cells to escape senescence and apoptosis in the absence of active telomerase. A characteristic feature of this pathway is the assembly of ALT-associated promyelocytic leukemia (PML) nuclear bodies (APBs) at telomeres. Here, we dissected the role of APBs in a human ALT cell line by performing an RNA interference screen using an automated 3D fluorescence microscopy platform and advanced 3D image analysis. We identified 29 proteins that affected APB formation, which included proteins involved in telomere and chromatin organization, protein sumoylation and DNA repair. By integrating and extending these findings, we found that APB formation induced clustering of telomere repeats, telomere compaction and concomitant depletion of the shelterin protein TRF2 (also known as TERF2). These APB-dependent changes correlated with the induction of a DNA damage response at telomeres in APBs as evident by a strong enrichment of the phosphorylated form of the ataxia telangiectasia mutated (ATM) kinase. Accordingly, we propose that APBs promote telomere maintenance by inducing a DNA damage response in ALT-positive tumor cells through changing the telomeric chromatin state to trigger ATM phosphorylation. PMID- 25908861 TI - Sphingolipids inhibit vimentin-dependent cell migration. AB - The sphingolipids, sphingosine 1-phosphate (S1P) and sphingosylphosphorylcholine (SPC), can induce or inhibit cellular migration. The intermediate filament protein vimentin is an inducer of migration and a marker for epithelial mesenchymal transition. Given that keratin intermediate filaments are regulated by SPC, with consequences for cell motility, we wanted to determine whether vimentin is also regulated by sphingolipid signalling and whether it is a determinant for sphingolipid-mediated functions. In cancer cells where S1P and SPC inhibited migration, we observed that S1P and SPC induced phosphorylation of vimentin on S71, leading to a corresponding reorganization of vimentin filaments. These effects were sphingolipid-signalling-dependent, because inhibition of either the S1P2 receptor (also known as S1PR2) or its downstream effector Rho associated kinase (ROCK, for which there are two isoforms ROCK1 and ROCK2) nullified the sphingolipid-induced effects on vimentin organization and S71 phosphorylation. Furthermore, the anti-migratory effect of S1P and SPC could be prevented by expressing S71-phosphorylation-deficient vimentin. In addition, we demonstrated, by using wild-type and vimentin-knockout mouse embryonic fibroblasts, that the sphingolipid-mediated inhibition of migration is dependent on vimentin. These results imply that this newly discovered sphingolipid-vimentin signalling axis exerts brake-and-throttle functions in the regulation of cell migration. PMID- 25908862 TI - Arabidopsis KCBP interacts with AIR9 but stays in the cortical division zone throughout mitosis via its MyTH4-FERM domain. AB - The preprophase band of microtubules performs the crucial function of marking the plane of cell division. Although the preprophase band depolymerises at the onset of mitosis, the division plane is 'memorized' by a cortical division zone to which the phragmoplast is attracted during cytokinesis. Proteins have been discovered that are part of the molecular memory but little is known about how they contribute to phragmoplast guidance. Previously, we found that the microtubule-associated protein AIR9 is found in the cortical division zone at preprophase and returns during cell plate insertion but is absent from the cortex during the intervening mitosis. To identify new components of the preprophase memory, we searched for proteins that interact with AIR9. We detected the kinesin like calmodulin-binding protein, KCBP, which can be visualized at the predicted cortical site throughout division. A truncation study of KCBP indicates that its MyTH4-FERM domain is required for linking the motor domain to the cortex. These results suggest a mechanism by which minus-end-directed KCBP helps guide the centrifugally expanding phragmoplast to the cortical division site. PMID- 25908863 TI - Inhibiting IkappaBbeta-NFkappaB signaling attenuates the expression of select pro inflammatory genes. AB - Multiple mediators of septic shock are regulated by the transcription factor nuclear factor kappaB (NFkappaB). However, complete NFkappaB inhibition can exacerbate disease, necessitating evaluation of targeted strategies to attenuate the pro-inflammatory response. Here, we demonstrate that in murine macrophages, low-dose NFkappaB inhibitors specifically attenuates lipopolysaccharide (LPS) induced IkappaBbeta degradation and the expression of a select subset of target genes (encoding IL1beta, IL6, IL12beta). Gain- and loss-of-function experiments demonstrate the necessary and sufficient role of inhibitor of NFkappaB family member IkappaBbeta (also known as NFKBIB) in the expression of these genes. Furthermore, both fibroblasts and macrophages isolated from IkappaBbeta overexpressing mice demonstrate attenuated LPS-induced IkappaBbeta-NFkappaB signaling and IL1beta, IL6 and IL12beta expression. Further confirming the role of IkappaBbeta and its NFkappaB subunit binding partner cRel in LPS-induced gene expression, pre-treatment of wild-type mouse embryonic fibroblasts with a cell permeable peptide containing the cRel nuclear localization sequence attenuated IL6 expression. We prove that LPS-induced IkappaBbeta-NFkappaB signaling can be selectively modulated to attenuate the expression of select pro-inflammatory target genes, thus providing therapeutic insights for patients exposed to systemic inflammatory stress. PMID- 25908865 TI - Essential role of flotillin-1 palmitoylation in the intracellular localization and signaling function of IGF-1 receptor. AB - Here, we explored flotillin-1-mediated regulation of insulin-like growth factor-1 (IGF-1) signaling. Flotillin-1-deficient cells exhibited a reduction in the activation of IGF-1 receptor (IGF-1R), ERK1/2 and Akt pathways, and the transcriptional activation of Elk-1 and the proliferation in response to IGF-1 were reduced in these cells. We found that IGF-1-independent flotillin-1 palmitoylation at Cys34 in the endoplasmic reticulum (ER) was required for the ER exit and the plasma membrane localization of flotillin-1 and IGF-1R. IGF-1 dependent depalmitoylation and repalmitoylation of flotillin-1 sustained tyrosine kinase activation of the plasma-membrane-targeted IGF-1R. Dysfunction and blocking the turnover of flotillin-1 palmitoylation abrogated cancer cell proliferation after IGF-1R signaling activation. Our data show that flotillin-1 palmitoylation is a new mechanism by which the intracellular localization and activation of IGF-1R are controlled. PMID- 25908864 TI - Traction forces mediated by integrin signaling are necessary for definitive endoderm specification. AB - Pluripotent embryonic stem cells (ESCs) exert low-traction forces on their niche in vitro whereas specification to definitive endoderm in vivo coincides with force-mediated motility, suggesting a differentiation-mediated switch. However, the onset of contractility and extent to which force-mediated integrin signaling regulates fate choices is not understood. To address the requirement of tractions forces for differentiation, we examined mouse embryonic stem cell (ESC) specification towards definitive endoderm on fibrillar fibronectin containing a deformation-sensitive FRET probe. Inhibiting contractility resulted in an increase in the observed fibronectin FRET intensity ratio but also decreased the amount of phosphorylated nuclear SMAD2, leading to reduced expression of the definitive endoderm marker SOX17. By contrast ESCs maintained in pluripotency medium did not exert significant tractions against the fibronectin matrix. When laminin-111 was added to fibrillar matrices to improve the efficiency of definitive endoderm induction, ESCs decreased their fibronectin traction forces in a laminin-dependent manner; blocking the laminin-binding alpha3-integrin restored fibronectin matrix deformation and reduced SOX17 expression and SMAD2 phosphorylation, probably because of compensation of inhibitory signaling from SMAD7 after 5 days in culture. These data imply that traction forces and integrin signaling are important regulators of early fate decisions in ESCs. PMID- 25908866 TI - Non-coding stem-bulge RNAs are required for cell proliferation and embryonic development in C. elegans. AB - Stem bulge RNAs (sbRNAs) are a family of small non-coding stem-loop RNAs present in Caenorhabditis elegans and other nematodes, the function of which is unknown. Here, we report the first functional characterisation of nematode sbRNAs. We demonstrate that sbRNAs from a range of nematode species are able to reconstitute the initiation of chromosomal DNA replication in the presence of replication proteins in vitro, and that conserved nucleotide sequence motifs are essential for this function. By functionally inactivating sbRNAs with antisense morpholino oligonucleotides, we show that sbRNAs are required for S phase progression, early embryonic development and the viability of C. elegans in vivo. Thus, we demonstrate a new and essential role for sbRNAs during the early development of C. elegans. sbRNAs show limited nucleotide sequence similarity to vertebrate Y RNAs, which are also essential for the initiation of DNA replication. Our results therefore establish that the essential function of small non-coding stem-loop RNAs during DNA replication extends beyond vertebrates. PMID- 25908867 TI - Probing microtubule polymerisation state at single kinetochores during metaphase chromosome motion. AB - Kinetochores regulate the dynamics of attached microtubule bundles (kinetochore fibres, K-fibres) to generate the forces necessary for chromosome movements in mitosis. Current models suggest that poleward-moving kinetochores are attached to depolymerising K-fibres and anti-poleward-moving kinetochores to polymerising K fibres. How the dynamics of individual microtubules within the K-fibre relate to poleward and anti-poleward movements is poorly understood. To investigate this, we developed a live-cell imaging assay combined with computational image analysis that allows eGFP-tagged EB3 (also known as MAPRE3) to be quantified at thousands of individual metaphase kinetochores as they undergo poleward and anti-poleward motion. Surprisingly, we found that K-fibres are incoherent, containing both polymerising and depolymerising microtubules - with a small polymerisation bias for anti-poleward-moving kinetochores. K-fibres also display bursts of EB3 intensity, predominantly on anti-poleward-moving kinetochores, equivalent to more coherent polymerisation, and this was associated with more regular oscillations. The frequency of bursts and the polymerisation bias decreased upon loss of kinesin-13, whereas loss of kinesin-8 elevated polymerisation bias. Thus, kinetochores actively set the balance of microtubule polymerisation dynamics in the K-fibre while remaining largely robust to fluctuations in microtubule polymerisation. PMID- 25908869 TI - Linking environmental prokaryotic viruses and their host through CRISPRs. AB - The ecological pressure that viruses place on microbial communities is not only based on predation, but also on gene transfer. In order to determine the potential impact of viruses and transduction, we need a better understanding of the dynamics of interactions between viruses and their hosts in the environment. Data on environmental viruses are scarce, and methods for tracking their interactions with prokaryotes are needed. Clustered regularly interspaced short palindromic repeats (CRISPRs), which contain viral sequences in bacterial genomes, might help document the history of virus-host interactions in the environment. In this study, a bioinformatics network linking viruses and their hosts using CRISPR sequences obtained from metagenomic data was developed and applied to metagenomes from Arctic glacial ice and soil. The application of our network approach showed that putative interactions were more commonly detected in the ice samples than the soil which would be consistent with the ice viral bacterial interactions being more dynamic than those in soil. Further analysis of the viral sequences in the CRISPRs indicated that Ralstonia phages might be agents of transduction in the Arctic glacial ice. PMID- 25908868 TI - Laser-treated stainless steel mini-screw implants: 3D surface roughness, bone implant contact, and fracture resistance analysis. AB - BACKGROUND/OBJECTIVES: This study investigated the biomechanical properties and bone-implant intersurface response of machined and laser surface-treated stainless steel (SS) mini-screw implants (MSIs). MATERIAL AND METHODS: Forty eight 1.3mm in diameter and 6mm long SS MSIs were divided into two groups. The control (machined surface) group received no surface treatment; the laser-treated group received Nd-YAG laser surface treatment. Half in each group was used for examining surface roughness (Sa and Sq), surface texture, and facture resistance. The remaining MSIs were placed in the maxilla of six skeletally mature male beagle dogs in a randomized split-mouth design. A pair with the same surface treatment was placed on the same side and immediately loaded with 200 g nickel titanium coil springs for 8 weeks. After killing, the bone-implant contact (BIC) for each MSI was calculated using micro computed tomography. Analysis of variance model and two-sample t test were used for statistical analysis with a significance level of P <0.05. RESULTS: The mean values of Sa and Sq were significantly higher in the laser-treated group compared with the machined group (P <0.05). There were no significant differences in fracture resistance and BIC between the two groups. LIMITATION: animal study CONCLUSIONS/IMPLICATIONS: Laser treatment increased surface roughness without compromising fracture resistance. Despite increasing surface roughness, laser treatment did not improve BIC. Overall, it appears that medical grade SS has the potential to be substituted for titanium alloy MSIs. PMID- 25908870 TI - Lactobacillus fermentum 3872 genome sequencing reveals plasmid and chromosomal genes potentially involved in a probiotic activity. AB - In this report we describe a Lactobacillus fermentum 3872 plasmid (pLF3872) not previously found in any other strain of this species. The analysis of the complete sequence of this plasmid revealed the presence of a gene encoding a large collagen-binding protein (CBP), as well as the genes responsible for plasmid maintenance and conjugation. Potential roles of CBP and a chromosomally encoded fibronectin-binding protein (FbpA) in probiotic activity are discussed. PMID- 25908871 TI - Effects of Listeria monocytogenes EGD-e and Salmonella enterica ser. Typhimurium LT2 chitinases on intracellular survival in Dictyostelium discoideum and mammalian cell lines. AB - Some bacterial pathogens produce chitinases as virulence factors during host infection. The molecular target of such enzymes in non-chitinous hosts remains uncertain. We studied the importance of Listeria monocytogenes EGD-e and Salmonella enterica ser. Typhimurium LT2 chitinases for intracellular survival in Dictyostelium discoideum, and for Salmonella, also infection of mammalian cell lines, and a mouse model. The Salmonella chitinase did not contribute significantly to infection of D. discoideum, mammalian cell lines or mice. However, survival in D. discoideum was clearly reduced for Listeria mutants deficient of ChiB (8-fold) or deficient of both ChiA and ChiB (22-fold). Our findings suggest that chitinases from the two species play different roles in virulence. PMID- 25908872 TI - Advances in risk prediction of type 2 diabetes: integrating genetic scores with Framingham risk models. PMID- 25908873 TI - Brain IL-6--Where Amylin and GLP-1 Antiobesity Signaling Congregate. PMID- 25908875 TI - Enterovirus infection and type 1 diabetes: closing in on a link? PMID- 25908874 TI - Ghrelin: a new incretin enhancer therapy? PMID- 25908876 TI - Bilirubin: striking gold in diabetic vasculopathy? PMID- 25908877 TI - To Lose Weight or Not to Lose Weight, That Is the Big Question--in Obesity Related Heart Failure. PMID- 25908878 TI - Puzzling about partial glucagon responses to hypoglycemia in intrahepatic islet recipients: missing pieces. PMID- 25908880 TI - Comment on Balestrieri et al. Sirtuin 6 expression and inflammatory activity in diabetic atherosclerotic plaques: effects of incretin treatment. Diabetes 2015;64:1395-1406. PMID- 25908881 TI - Response to comment on Balestrieri et al. Sirtuin 6 expression and inflammatory activity in diabetic atherosclerotic plaques: effects of incretin treatment. Diabetes 2015;64:1395-1406. PMID- 25908882 TI - Long-distance communication facilitates cooperation among wild spotted hyaenas, Crocuta crocuta. AB - Calls that catalyse group defence, as in the mobbing of predators, appear to facilitate cooperation by recruiting receivers to act collectively. However, even when such signals reliably precede cooperative behaviour, the extent to which the calls function as recruitment signals is unclear. Calls might simply arouse listeners' attention, setting off a cascade of independent responses to the threat. By contrast, they might convey information, for example, about signaller identity and the nature of a threat that affects receivers' decisions to participate. We explored this distinction by investigating a possible long distance recruitment call used by spotted hyaenas. These social carnivores live in fission-fusion clans and individuals disperse widely within their territories. Putative recruitment calls must therefore attract receivers that are distant from the inciting threat and free to opt out of risky collective aggression. Hyaenas compete with lions over food, and neighbouring clans sometimes engage in violent border clashes. These high-stakes contests are decided based on numerical asymmetries, so hyaenas can only protect critical resources if the dispersed clan can converge quickly at conflict sites. We recorded and analysed whoop bouts produced in multiple contexts and found that bouts produced in response to signs of lion-hyaena conflict had shorter inter-whoop intervals than spontaneous 'display' bouts. In subsequent field playback experiments, resting hyaenas were significantly more likely to move in response to 'recruitment' bouts with shortened intervals than to otherwise identical 'display' bouts. Whereas only stimulus type predicted movement, lower-ranked subjects responded most quickly, perhaps because their feeding opportunities depend on arriving early at any kill site. Results demonstrate that hyaenas possess a signal that can reliably recruit allies across long distances, despite moderating effects of individual circumstances on the strength of receivers' responses. PMID- 25908883 TI - Pyrrolidine catalyzed reactions of cyclopentadiene with alpha,beta-unsaturated carbonyl compounds: 1,2- versus 1,4-additions. AB - A systematic study of the reactions of cyclopentadiene with alpha,beta unsaturated carbonyl compounds in the presence of catalytic pyrrolidine-H2O revealed that the reactions can either proceed with a Michael attack at the beta carbon of enone, or 1,2-addition to the carbonyl, leadingeither to 4 cyclopentadienyl-2-butanones or 6-vinylfulvenes. The former can be isolated and/or converted to the corresponding 1,2-dihydropentalenes with base (or in one pot at longer reaction times). Substitution pattern on the enones on the competing pathways have been studied and consistent mechanisms are proposed. PMID- 25908884 TI - Ecology and functional roles of biological soil crusts in semi-arid ecosystems of Spain. AB - Biological soil crusts (BSCs), composed of lichens, cyanobacteria, mosses, liverworts and microorganisms, are key biotic components of arid and semi-arid ecosystems worldwide. Despite they are widespread in Spain, these organisms have been historically understudied in this country. This trend is beginning to change as a recent wave of research has been identifying BSCs as a model ecological system. Many studies and research projects carried out in Spain have explored the role of BSCs on water, carbon and nitrogen fluxes, the interactions between BSCs and vascular plants, their dynamics after disturbances, and their response to global change, among other topics. In this article we review the growing body of research on BSCs available from semi-arid areas of Spain, highlighting its importance for increasing our knowledge on this group of organisms. We also discuss how it is breaking new ground in emerging research areas on the ecology of BSCs, and how it can be use to guide management and restoration efforts. Finally, we provide directions for future research on the ecology of BSCs in Spain and abroad. PMID- 25908885 TI - Person * Environment Interactions on Adolescent Delinquency: Sensation Seeking, Peer Deviance and Parental Monitoring. AB - Sensation seeking is a personality trait that is robustly correlated with delinquent behavior in adolescence. The current study tested specific contextual factors hypothesized to facilitate, exacerbate or attenuate this risk factor for adolescent delinquency. Individual differences in sensation seeking, peer deviance, parental monitoring and self-reported delinquent behavior were assessed in a sample of 470 adolescents. Peer deviance partially mediated the effects of sensation seeking and parental monitoring on adolescent delinquency. We also found evidence for a three-way interaction between sensation seeking, peer deviance and parental monitoring, such that the highest rates of delinquency occurred from the concurrence of high sensation seeking, high peer deviance, and low levels of parental monitoring. Results highlight the importance of considering peer- and family-level processes when evaluating personality risk and problematic adolescent behavior. PMID- 25908887 TI - A framework for ensuring competence and credibility in cancer rehabilitation services. PMID- 25908886 TI - Learning-related skills and academic achievement in academically at-risk first graders. AB - Using an academically at-risk, ethnically diverse sample of 744 first-grade children, this study tested a multi-method (i.e., child performance measures, teacher ratings, and peer ratings) measurement model of learning-related skills (i.e., effortful control [EC], behavioral self-regulation [BSR], and social competence [SC]), and their shared and unique contributions to children's reading and math achievement, above the effect of demographic variables. The hypothesized correlated factor measurement model demonstrated relatively good fit, with BSR and SC correlated highly with one another and moderately with EC. When entered in separate regression equations, EC and BSR each predicted children's reading and math achievement; SC only predicted reading achievement. When considered simultaneously, neither EC, BSR, nor SC contributed independently to reading achievement; however, EC had a direct effect on math achievement and an indirect effect on reading achievement via both BSR and SC. Implications for research and early intervention efforts are discussed. PMID- 25908888 TI - Clinician's commentary on Blonski et al.(1). PMID- 25908889 TI - Clinical commentary on mistry et Al.(1). PMID- 25908890 TI - What Does the Cochrane Collaboration Say about Pelvic Floor Muscle Training? PMID- 25908891 TI - Physiotherapy Canada volume 66, Annual Index-2014. PMID- 25908892 TI - Clinician's Commentary on Pak et al.(1). PMID- 25908893 TI - Clinician's Commentary on Duncan et al.(1). PMID- 25908894 TI - Clinician's Commentary on Bech et al.(1). PMID- 25908895 TI - What Does the Cochrane Collaboration Say about the Use of Botulinum in Rehabilitation? PMID- 25908896 TI - Letter to the editor. PMID- 25908897 TI - Deep-water fossorial shrimps from the Oligocene Kiscell Clay of Hungary: Taxonomy and palaeoecology. AB - We describe deep-water ghost shrimp assemblages from the otherwise well known Oligocene Kiscell Clay in Hungary. The described fossorial shrimps (Decapoda: Callianassidae and Ctenochelidae) include: Ctenocheles rupeliensis (younger synonym Callianassa nuda) and Lepidophthalmus crateriferus (younger synonym Callianassa brevimanus). The fossil material of the former species is assigned to Ctenocheles based on the morphology of the major cheliped, particularly the pectinate fingers, bulbous propodus, cup-shaped carpus and elongated merus. Lepidophthalmus crateriferus from the Oligocene of Hungary is the first unequivocal fossil record of the genus, which is distinguished in the fossil record on the basis of the presence of a meral blade and meral hook on the major cheliped. Lepidophthalmus is today known exclusively from shallow-water environments. The finding of a deep-water fossil representative of Lepidophthalmus therefore appears to be a reverse of the common pattern of groups shifting environments from onshore to offshore over geological time, as seen in many taxa. The presence of Lepidophthalmus crateriferus comb. nov. in the Kiscell Clay therefore suggests different ecological requirements for at least some populations of this genus in the geological past. PMID- 25908898 TI - Peptidomic analysis of healthy and subclinically mastitic bovine milk. AB - A variety of proteases release hundreds of endogenous peptide fragments from intact bovine milk proteins. Mass spectrometry-based peptidomics allows for high throughput sequence assignment of a large number of these peptides. Mastitis is known to result in increased protease activity in the mammary gland. Therefore, we hypothesized that subclinically mastitic milks would contain higher concentrations of released peptides. In this work, milks were sampled from three cows and, for each, one healthy and one subclinically mastitic teat were sampled for milk. Peptides were analyzed by nano-liquid chromatography quadrupole time of flight tandem mass spectrometry and identified with database searching. In total, 682 peptides were identified. The total number of released peptides increased 146% from healthy to subclinically mastitic milks (p < 0.05), and the total abundance of released peptides also increased significantly (p < 0.05). Bioinformatic analysis of enzyme cleavage revealed increases in activity of cathepsin D and elastase (p < 0.05) with subclinical mastitis. PMID- 25908899 TI - VARYING COEFFICIENT MODELS FOR DATA WITH AUTO-CORRELATED ERROR PROCESS. AB - Varying coefficient model has been popular in the literature. In this paper, we propose a profile least squares estimation procedure to its regression coefficients when its random error is an auto-regressive (AR) process. We further study the asymptotic properties of the proposed procedure, and establish the asymptotic normality for the resulting estimate. We show that the resulting estimate for the regression coefficients has the same asymptotic bias and variance as the local linear estimate for varying coefficient models with independent and identically distributed observations. We apply the SCAD variable selection procedure (Fan and Li, 2001) to reduce model complexity of the AR error process. Numerical comparison and finite sample performance of the resulting estimate are examined by Monte Carlo studies. Our simulation results demonstrate the proposed procedure is much more efficient than the one ignoring the error correlation. The proposed methodology is illustrated by a real data example. PMID- 25908901 TI - Incautiously Optimistic: Positively-Valenced Cognitive Avoidance in Adult ADHD. AB - Clinicians who conduct cognitive-behavioral therapy (CBT) targeting attention deficit/hyperactivity disorder (ADHD) in adulthood have noted that their patients sometimes verbalize overly positive automatic thoughts and set overly optimistic goals. These cognitions are frequently related to failure to engage in compensatory behavioral strategies emphasized in CBT. In this paper, we offer a functional analysis of this problematic pattern, positively-valenced cognitive avoidance, and suggest methods for addressing it within CBT for adult ADHD. We propose that maladaptive positive cognitions function to relieve aversive emotions in the short-term and are therefore negatively reinforced but that, in the long-term, they are associated with decreased likelihood of active coping and increased patterns of behavioral avoidance. Drawing on techniques from Behavioral Activation (BA), we offer a case example to illustrate these concepts and describe step-by-step methods for clinicians to help patients recognize avoidant patterns and engage in more active coping. PMID- 25908900 TI - Mindfulness Meditation Training for Attention-Deficit/Hyperactivity Disorder in Adulthood: Current Empirical Support, Treatment Overview, and Future Directions. AB - Research examining nonpharmacological interventions for adults diagnosed with attention-deficit/hyperactivity disorder (ADHD) has expanded in recent years and provides patients with more treatment options. Mindfulness-based training is an example of an intervention that is gaining promising preliminary empirical support and is increasingly administered in clinical settings. The aim of this review is to provide a rationale for the application of mindfulness to individuals diagnosed with ADHD, describe the current state of the empirical basis for mindfulness training in ADHD, and summarize a treatment approach specific to adults diagnosed with ADHD: the Mindful Awareness Practices (MAPs) for ADHD Program. Two case study examples are provided to demonstrate relevant clinical issues for practitioners interested in this approach. Directions for future research, including mindfulness meditation as a standalone treatment and as a complementary approach to cognitive-behavioral therapy, are provided. PMID- 25908902 TI - Alterations in cancer cell mechanical properties after fluid shear stress exposure: a micropipette aspiration study. AB - Over 90% of cancer deaths result not from primary tumor development, but from metastatic tumors that arise after cancer cells circulate to distal sites via the circulatory system. While it is known that metastasis is an inefficient process, the effect of hemodynamic parameters such as fluid shear stress (FSS) on the viability and efficacy of metastasis is not well understood. Recent work has shown that select cancer cells may be able to survive and possibly even adapt to FSS in vitro. The current research seeks to characterize the effect of FSS on the mechanical properties of suspended cancer cells in vitro. Nontransformed prostate epithelial cells (PrEC LH) and transformed prostate cancer cells (PC-3) were used in this study. The Young's modulus was determined using micropipette aspiration. We examined cells in suspension but not exposed to FSS (unsheared) and immediately after exposure to high (6,400 dyn/cm2) and low (510 dyn/cm2) FSS. The PrEC LH cells were ~140% stiffer than the PC-3 cells not exposed to FSS. Post-FSS exposure, there was an increase of ~77% in Young's modulus after exposure to high FSS and a ~47% increase in Young's modulus after exposure to low FSS for the PC-3 cells. There was no significant change in the Young's modulus of PrEC LH cells post-FSS exposure. Our findings indicate that cancer cells adapt to FSS, with an increased Young's modulus being one of the adaptive responses, and that this adaptation is specific only to PC-3 cells and is not seen in PrEC LH cells. Moreover, this adaptation appears to be graded in response to the magnitude of FSS experienced by the cancer cells. This is the first study investigating the effect of FSS on the mechanical properties of cancer cells in suspension, and may provide significant insights into the mechanism by which some select cancer cells may survive in the circulation, ultimately leading to metastasis at distal sites. Our findings suggest that biomechanical analysis of cancer cells could aid in identifying and diagnosing cancer in the future. PMID- 25908903 TI - Thrombocytopenia absent radius syndrome with Tetralogy of Fallot: a rare association. AB - Thrombocytopenia absent radius (TAR) syndrome is a very rare and infrequently seen congenital disorder with an approximate frequency of 0.42/100,000 live births. It is associated with bilateral absence of radii, hypo-megakaryocytic thrombocytopenia, and presence of both thumbs. The other systems which are affected by TAR syndrome include skeletal, hematologic, and cardiac systems. Intracranial hemorrhages due to thrombocytopenia and cardiac disorders are a common association usually seen with this syndrome and are usual cause of death. We describe a 3-month-old infant who was diagnosed with TAR syndrome on the basis of clinical features (thrombocytopenia and bilateral absent radius bone and confirmed by genetic analysis). The patient was diagnosed to have Tetralogy of Fallot, for which the infant was managed with definitive repair and thrombocytopenia was managed with platelet transfusion. Infants with TAR syndrome should be assessed for other associated malformations of various systems and followed up regularly and parents should be counseled for associated expected complications in these patients. We report an infant with TAR syndrome with Tetralogy of Fallot, which has not been reported in medical literature until now and this is the first case of its type. PMID- 25908904 TI - The value-for-money of adjuvant aromatase inhibitors: time to put the debate to rest? PMID- 25908905 TI - Ethnicity and breast cancer stage at diagnosis: an issue of health equity. PMID- 25908906 TI - Physician-assisted death is not palliative care. PMID- 25908907 TI - Economic evaluation of hormonal therapies for postmenopausal women with estrogen receptor-positive early breast cancer in Canada. AB - BACKGROUND: Aromatase inhibitor (ai) therapy has been subjected to numerous cost effectiveness analyses. However, with most ais having reached the end of patent protection and with maturation of the clinical trials data, a re-analysis of ai cost-effectiveness and a consideration of ai use as part of sequential therapy is desirable. Our objective was to assess the cost-effectiveness of the 5-year upfront and sequential tamoxifen (tam) and ai hormonal strategies currently used for treating patients with estrogen receptor (er)-positive early breast cancer. METHODS: The cost-effectiveness analysis used a Markov model that took a Canadian health system perspective with a lifetime time horizon. The base case involved 65 year-old women with er-positive early breast cancer. Probabilistic sensitivity analyses were used to incorporate parameter uncertainties. An expected-value-of perfect-information test was performed to identify future research directions. Outcomes were quality-adjusted life-years (qalys) and costs. RESULTS: The sequential tam-ai strategy was less costly than the other strategies, but less effective than upfront ai and more effective than upfront tam. Upfront ai was more effective and less costly than upfront tam because of less breast cancer recurrence and differences in adverse events. In an exploratory analysis that included a sequential ai-tam strategy, ai-tam dominated based on small numerical differences unlikely to be clinically significant; that strategy was thus not used in the base-case analysis. CONCLUSIONS: In postmenopausal women with er positive early breast cancer, strategies using ais appear to provide more benefit than strategies using tam alone. Among the ai-containing strategies, sequential strategies using tam and an ai appear to provide benefits similar to those provided by upfront ai, but at a lower cost. PMID- 25908909 TI - Patient-expressed perceptions of wait-time causes and wait-related satisfaction. AB - BACKGROUND: This study set out to identify patterns in the causes of waits and wait-related satisfaction. METHODS: We conducted qualitative interviews with urban, semi-urban, and rural patients (n = 60) to explore their perceptions of the waits they experienced in the detection and treatment of their breast, prostate, lung, or colorectal cancer. We asked participants to describe their experiences from the onset of symptoms to the start of treatment at the cancer clinic and their satisfaction with waits at various intervals. Interview transcripts were coded using a thematic approach. RESULTS: Patients identified five groups of wait-time causes: Patient-related (beliefs, preferences, and non cancer health issues)Treatment-related (natural consequences of treatment)System related (the organization or functioning of groups, workforce, institution, or infrastructure in the health care system)Physician-related (a single physician responsible for a specific element in the patient's care)Other causes (disruptions to normal operations of a city or community as a whole) With the limited exception of physician-related absences, the nature of the cause was not linked to overall satisfaction or dissatisfaction with waits. CONCLUSIONS: Causes in themselves do not explain wait-related satisfaction. Further work is needed to explore the underlying reasons for wait-related satisfaction or dissatisfaction. Although our findings shed light on patient experiences with the health system and identify where interventions could help to inform the expectations of patients and the public with respect to wait time, more research is needed to understand wait-related satisfaction among cancer patients. PMID- 25908908 TI - A population-based study of ethnicity and breast cancer stage at diagnosis in Ontario. AB - BACKGROUND: Breast cancer stage at diagnosis is an important predictor of survival. Our goal was to compare breast cancer stage at diagnosis (by American Joint Committee on Cancer criteria) in Chinese and South Asian women with stage at diagnosis in the remaining general population in Ontario. METHODS: We used the Ontario population-based cancer registry to identify all women diagnosed with breast cancer during 2005-2010, and we applied a validated surname algorithm to identify South Asian and Chinese women. We used logistic regression to compare, for Chinese or South Asian women and for the remaining general population, the frequency of diagnoses at stage ii compared with stage i and stages ii-iv compared with stage i. RESULTS: The registry search identified 1304 Chinese women, 705 South Asian women, and 39,287 women in the remaining general population. The Chinese and South Asian populations were younger than the remaining population (mean: 54, 57, and 61 years respectively). Adjusted for age, South Asian women were more often diagnosed with breast cancer at stage ii than at stage i [odds ratio (or): 1.28; 95% confidence interval (ci): 1.08 to 1.51] or at stages ii-iv than at stage i (or: 1.27; 95% ci: 1.08 to 1.48); Chinese women were less likely to be diagnosed at stage ii than at stage i (or: 0.82; 95% ci: 0.72 to 0.92) or at stages ii-iv than at stage i (or: 0.73; 95% ci: 0.65 to 0.82). CONCLUSIONS: Breast cancers were diagnosed at a later stage in South Asian women and at an earlier stage in Chinese women than in the remaining population. A more detailed analysis of ethnocultural factors influencing breast screening uptake, retention, and care-seeking behavior might be needed to help inform and evaluate tailored health promotion activities. PMID- 25908910 TI - Establishing a clinic-based pancreatic cancer and periampullary tumour research registry in Quebec. AB - BACKGROUND: Enrolling patients in studies of pancreatic ductal adenocarcinoma (pdac) is challenging because of the high fatality of the disease. We hypothesized that a prospective clinic-based study with rapid ascertainment would result in high participation rates. Using that strategy, we established the Quebec Pancreas Cancer Study (qpcs) to investigate the genetics and causes of pdac and other periampullary tumours (pats) that are also rare and underrepresented in research studies. METHODS: Patients diagnosed with pdac or pat were introduced to the study at their initial clinical encounter, with a strategy to enrol participants within 2 weeks of diagnosis. Patient self referrals and referrals of unaffected individuals with an increased risk of pdac were also accepted. Family histories, epidemiologic and clinical data, and biospecimens were collected. Additional relatives were enrolled in families at increased genetic risk. RESULTS: The first 346 completed referrals led to 306 probands being enrolled, including 190 probands affected with pdac, who represent the population focus of the qpcs. Participation rates were 88.4% for all referrals and 89.2% for pdac referrals. Family history, epidemiologic and clinical data, and biospecimens were ascertained from 91.9%, 54.6%, and 97.5% respectively of patients with pdac. Although demographics and trends in risk factors in our patients were consistent with published statistics for patients with pdac, the qpcs is enriched for families with French-Canadian ancestry (37.4%), a population with recurrent germ-line mutations in hereditary diseases. CONCLUSIONS: Using rapid ascertainment, a pdac and pat research registry with high participation rates can be established. The qpcs is a valuable research resource and its enrichment with patients of French-Canadian ancestry provides a unique opportunity for studies of heredity in these diseases. PMID- 25908911 TI - Management of egfr tki-induced dermatologic adverse events. AB - Targeting the epidermal growth factor receptor (egfr) pathway has become standard practice for the treatment of advanced non-small-cell lung cancer. Compared with chemotherapy, egfr tyrosine kinase inhibitors (tkis) have been associated with improved efficacy in patients with an EGFR mutation. Together with the increase in efficacy comes an adverse event (ae) profile different from that of chemotherapy. That profile includes three of the most commonly occurring dermatologic aes: acneiform rash, stomatitis, and paronychia. Currently, no randomized clinical trials have evaluated the treatments for the dermatologic aes that patients experience when taking egfr tkis. Based on the expert opinion of the authors, some basic strategies have been developed to manage those key dermatologic aes. Those strategies have the potential to improve patient quality of life and compliance and to prevent inappropriate dose reductions. PMID- 25908912 TI - Canadian consensus recommendations on the management of venous thromboembolism in patients with cancer. Part 1: prophylaxis. AB - Patients with cancer are at increased risk of venous thromboembolism (vte). Anticoagulation therapy has been shown to prevent vte; however, unique clinical circumstances in patients with cancer can often complicate the decisions surrounding the administration of prophylactic anticoagulation. No national Canadian guidelines on the prevention of cancer-associated thrombosis have been published. We therefore aimed to develop a consensus-based, evidence-informed guideline on the topic. PubMed was searched for clinical trials and meta-analyses published between 2002 and 2013. Reference lists of key articles were hand searched for additional publications. Content experts from across Canada were assembled to review the evidence and make recommendations. Low molecular weight heparin can be used prophylactically in cancer patients at high risk of developing vte. Direct oral anticoagulants are not recommended for vte prophylaxis at this time. Specific clinical scenarios, including renal insufficiency, thrombocytopenia, liver disease, and obesity can warrant modifications in the administration of prophylactic anticoagulant therapy. There is no evidence to support the monitoring of anti-factor Xa levels in clinically stable cancer patients receiving prophylactic anticoagulation; however, factor Xa levels could be checked at baseline and periodically in patients with renal insufficiency. The use of anticoagulation therapy to prolong survival in cancer patients without the presence of risk factors for vte is not recommended. PMID- 25908913 TI - Canadian consensus recommendations on the management of venous thromboembolism in patients with cancer. Part 2: treatment. AB - Patients with cancer are at increased risk of venous thromboembolism (vte). Anticoagulation therapy is used to treat vte; however, patients with cancer have unique clinical circumstances that can often make decisions surrounding the administration of therapeutic anticoagulation complicated. No national Canadian guidelines on the management of established cancer-associated thrombosis have been published. We therefore aimed to develop a consensus-based, evidence informed guideline on the topic. PubMed was searched for clinical trials and meta analyses published between 2002 and 2013. Reference lists of key articles were hand-searched for additional publications. Content experts from across Canada were assembled to review the evidence and make recommendations. Low molecular weight heparin is the treatment of choice for cancer patients with established vte. Direct oral anticoagulants are not recommended for the treatment of vte at this time. Specific clinical scenarios, including the presence of an indwelling venous catheter, renal insufficiency, and thrombocytopenia, warrant modifications in the therapeutic administration of anticoagulation therapy. Patients with recurrent vte should receive extended (>3 months) anticoagulant therapy. Incidental vte should generally be treated in the same manner as symptomatic vte. There is no evidence to support the monitoring of anti-factor Xa levels in clinically stable cancer patients receiving prophylactic anticoagulation; however, levels of anti-factor Xa could be checked at baseline and periodically thereafter in patients with renal insufficiency. Follow-up and education about the signs and symptoms of vte are important components of ongoing patient care. PMID- 25908914 TI - Canadian cancer screening disparities: a recent historical perspective. AB - Across Canada, introduction of the Pap test for cervical cancer screening, followed by mammography for breast cancer screening and, more recently, the fecal occult blood test for colorectal cancer screening, has contributed to a reduction in cancer mortality. However, another contribution of screening has been disparities in cancer mortality between certain populations. Here, we explore the disparities associated with breast and cervical cancer screening and preliminary data concerning disparities in colorectal cancer screening. Although some disparities in screening utilization have been successfully reduced over time (for example, mammography and Pap test screening in rural and remote populations), screening utilization data for other populations (for example, low income groups) clearly indicate that disparities have existed and continue to exist across Canada. Organized screening programs in Canada have been able to successfully engage 80% of women for regular cervical cancer screening and 70% of women for regular mammography screening, but of the women who remain to be reached or engaged in regular screening, those with the least resources, those who are the most isolated, and those who are least culturally integrated into Canadian society as a whole are over-represented. Population differences are also observed for utilization of colorectal cancer screening services. The research literature on interventions to promote screening utilization provides some evidence about what can be done to increase participation in organized screening by vulnerable populations. Adaption and adoption of evidence-based screening promotion interventions can increase the utilization of available screening services by populations that have experienced the greatest burden of disease with the least access to screening services. PMID- 25908915 TI - Guidelines on the use of cytoreductive surgery and hyperthermic intraperitoneal chemotherapy in patients with peritoneal surface malignancy arising from colorectal or appendiceal neoplasms. AB - To meet the needs of patients, Canadian surgical and medical oncology leaders in the treatment of peritoneal surface malignancies (psms), together with patient representatives, formed the Canadian HIPEC Collaborative Group (chicg). The group is dedicated to standardizing and improving the treatment of psm in Canada so that access to treatment and, ultimately, the prognosis of Canadian patients with psm are improved. Patients with resectable psm arising from colorectal or appendiceal neoplasms should be reviewed by a multidisciplinary team including surgeons and medical oncologists with experience in treating patients with psm. Cytoreductive surgery and hyperthermic intraperitoneal chemotherapy should be offered to appropriately selected patients and performed at experienced centres. The aim of this publication is to present guidelines that we recommend be applied across the country for the treatment of psm. PMID- 25908917 TI - Analysis of sebum lipid composition and the development of acneiform rash before and after administration of egfr inhibitor. AB - Treatment with an epidermal growth factor receptor inhibitor (egfri) in patients having non-small-cell lung cancer can cause frequent and diverse skin toxicities, an acneiform rash being one of the commonest. Although the exact pathophysiology of this rash and its development mechanisms remain unknown, investigators have noted that egfri-induced skin toxicity might be partly associated with sebaceous gland function. Sebum is composed mainly of the lipids squalene (sq), wax ester (we), triglyceride, free fatty acid, and cholesterol, which are secreted mostly from the sebaceous glands and by keratinocytes. We therefore investigated the lipid composition of sebum before and after administration of egfri and whether sebum composition was associated with the development of acneiform rash. To investigate any associated changes in sebum gland activity, we focused especially on alterations in the amounts of sq and we, which are secreted solely from the sebaceous glands. In contrast to our expectations, we observed no substantial changes in the lipid composition of sebum before and after administration of egfri. Composition varies with the individual; however, the proportion of sq and we derived from the sebaceous glands was significantly lower in regions that did not develop acneiform rash than in regions that did. Our results suggest that development of an acneiform rash after administration of egfri could be related to sebaceous gland activity. Measurement of the lipid composition of sebum before therapy with egfri might predict which patients will be prone to acneiform rash. PMID- 25908916 TI - Consensus statement: the 16th Annual Western Canadian Gastrointestinal Cancer Consensus Conference; Saskatoon, Saskatchewan; September 5-6, 2014. AB - The 16th annual Western Canadian Gastrointestinal Cancer Consensus Conference was held in Saskatoon, Saskatchewan, September 4-5, 2014. The Consensus Conference is an interactive, multidisciplinary event attended by health care professionals from across western Canada (British Columbia, Alberta, Saskatchewan, and Manitoba) involved in the care of gastrointestinal cancer. Surgical, medical, and radiation oncologists; pathologists; radiologists; and allied health care professionals participated in presentation and discussion sessions for the purposes of developing the recommendations presented here. This consensus statement addresses current issues in the management of colorectal cancer. PMID- 25908918 TI - A case of transfusion independence in a patient with myelodysplastic syndrome using deferasirox, sustained for two years after stopping therapy. AB - Patients with myelodysplastic syndrome (mds) experience clinical complications related to progressive marrow failure and have an increased risk of developing acute myeloid leukemia. Frequent red blood cell transfusion can lead to clinical iron overload and is associated with decreased survival in mds patients. Iron chelation therapy reduces markers of iron overload and prevents end-organ damage. Here, we present the case of a patient with low-risk mds with transfusional iron overload. He was treated for 2 years with an oral iron chelator, deferasirox, and after 12 months of treatment, he experienced a hemoglobin increase of more than 50 g/L, becoming transfusion-independent. He has remained transfusion independent, with a normal hemoglobin level, for more than 2 years since stopping chelation therapy. Hematologic and erythroid responses have previously been reported in mds patients treated with iron chelation. The durability of our patient's response suggests that iron chelation might alter the natural history of mds in some patients. PMID- 25908919 TI - Erratum: Tumour inflammatory response: adding fuel to the fire? AB - [This corrects the article on p. 7 in vol. 22, PMID: 25684982.]. PMID- 25908920 TI - Using the Cancer Risk Management Model to evaluate colorectal cancer screening options for Canada. AB - BACKGROUND: Several screening methods for colorectal cancer (crc) are available, and some have been shown by randomized trials to be effective. In the present study, we used a well-developed population health simulation model to compare the risks and benefits of a variety of screening scenarios. Tests considered were the fecal occult blood test (fobt), the fecal immunochemical test (fit), flexible sigmoidoscopy, and colonoscopy. Outcomes considered included years of life gained, crc cases and deaths prevented, and direct health system costs. METHODS: A natural history model of crc was implemented and calibrated to specified targets within the framework of the Cancer Risk Management Model (crmm) from the Canadian Partnership Against Cancer. The crmm-crc permits users to enter their own parameter values or to use program-specified base values. For each of 23 screening scenarios, we used the crmm-crc to run 10 million replicate simulations. RESULTS: Using base parameter values and some user-specified values in the crmm-crc, and comparing our screening scenarios with no screening, all screening scenarios were found to reduce the incidence of and mortality from crc. The fobt was the least effective test; it was not associated with lower net cost. Colonoscopy screening was the most effective test; it had net costs comparable to those for several other strategies considered, but required more than 3 times the colonoscopy resources needed by other approaches. After colonoscopy, strategies based on the fit were predicted to be the most effective. In sensitivity analyses performed for the fobt and fit screening strategies, fobt parameter values associated with high-sensitivity formulations were associated with a substantial increase in test effectiveness. The fit was more cost-effective at the 50 ng/mL threshold than at the 100 ng/mL threshold. CONCLUSIONS: The crmm-crc provides a sophisticated and flexible environment in which to evaluate crc control options. All screening scenarios considered in this study effectively reduced crc mortality, although sensitivity analyses demonstrated some uncertainty in the magnitude of the improvements. Where possible, local data should be used to reduce uncertainty in the parameters. PMID- 25908921 TI - Use of bevacizumab as a first-line treatment for metastatic breast cancer. AB - OBJECTIVE: During clinical practice, it can be challenging, given the lack of response biomarkers, to identify the patients with metastatic breast cancer (mbca) who would benefit most from the addition of bevacizumab to first-line standard chemotherapy. The aim of the present review was to summarize the relevant scientific evidence and to discuss the experience of a group of experts in using bevacizumab to treat mbca. METHODS: A panel of 17 Spanish oncology experts met to discuss the literature and their experience in the use of bevacizumab as first-line treatment for mbca. During the meeting, discussions focused on three main issues: the profile of the patients who could benefit most from bevacizumab, the optimal bevacizumab treatment duration, and the safety profile of bevacizumab. RESULTS: The subset of mbca patients who would benefit the most from the addition of bevacizumab to first-line standard chemotherapy are those with clinically defined aggressive disease. Treatment with bevacizumab should be maintained until disease progression or the appearance of unacceptable toxicity. In the mbca setting, the toxicity profile of bevacizumab is well known and can be managed in clinical practice after adequate training. CONCLUSIONS: This expert group recommends administering bevacizumab as first-line treatment in patients with clinically aggressive disease. PMID- 25908922 TI - Adherence to and uptake of clinical practice guidelines: lessons learned from a clinical practice guideline on chemotherapy concomitant with radiotherapy in head and-neck cancer. AB - BACKGROUND: Clinical practice guidelines (cpgs) are systematically developed statements designed to assist practitioners and patients in making decisions about appropriate heath care interventions. Clinical practice guidelines are expensive and time-consuming to create. A cpg on concurrent chemotherapy with radiation therapy (ccrt) was developed in Ontario at a time when treatment approaches for head-and-neck cancer were changing significantly. METHODS: An assessment of treatments and outcomes based on electronic and chart data obtained from a population-based study of 571 patients with oropharynx cancer treated in Ontario (2003-2004) was combined with a review of relevant knowledge transfer (publications and presentations at major meetings) to understand variation in adherence to a cpg. RESULTS: In 9 Ontario cancer treatment centres, ccrt was used for 55% of all patients with oropharyngeal cancer; however, at the centres individually, that proportion ranged from 82% to 39%. Furthermore, there was no agreement on the chemotherapy regimen: 2-4 years later (a period during which newer regimens were emerging), only 4 of 9 centres were following the guideline for most patients. When outcomes of treated patients were compared for centres with "higher" and "lower" use of ccrt, no difference in survival was observed (p = 0.64). CONCLUSIONS: At a time of treatment evolution, the new guideline was controversial, and there are many reasons for the mixed adherence. An estimation of adherence should be included during both development and review of guidelines. PMID- 25908923 TI - Access to oncology consultation in a cancer cohort in northeastern Ontario. AB - BACKGROUND: To enhance cancer symptom management for residents of Sudbury Manitoulin District, an ambulatory palliative clinic (pac) was established at the Northeast Cancer Centre of Health Sciences North. The pac is accessed from a medical or radiation oncology consultation. The primary purpose of the present population-based retrospective study was to estimate the percentage of cancer patients who died without ever having a medical or radiation oncology consultation. A secondary purpose was to determine factors associated with never having received one of those specialized consultations. METHODS: Administrative data was obtained through the Ontario Cancer Data Linkage Project. For each index case, we constructed a timeline, in days, of all Ontario Health Insurance Plan billing codes and associated service dates starting with the primary cancer diagnosis and ending with death. RESULTS: Within the 5-year study period (2004 2008), 6683 people in the area of interest with a valid record of primary cancer diagnosis died from any cause. Most (n = 5988, 89.6%) had 1 primary cancer diagnosis. For that subgroup, excluding those with a disease duration of 0 days (n = 67), about 18.4% (n = 1088) never had a consultation with a medical or radiation oncologist throughout their disease trajectory. Patients who were older or who resided in a rural area were significantly less likely to have had a consultation. CONCLUSIONS: Specific strategies directed toward older and rural patients might help to address this important access-to-care issue. PMID- 25908924 TI - Acute toxicity of hypofractionated intensity-modulated radiotherapy for prostate cancer. AB - BACKGROUND: Dose-escalated hypofractionated radiotherapy (hfrt) using intensity modulated radiotherapy (imrt), with inclusion of the pelvic lymph nodes (plns), plus androgen suppression therapy (ast) in high-risk prostate cancer patients should improve patient outcomes, but acute toxicity could limit its feasibility. METHODS: Our single-centre phase ii prospective study enrolled 40 high-risk prostate cancer patients. All patients received hfrt using imrt with daily mega voltage computed tomography imaging guidance, with 95% of planning target volumes (ptv68 and ptv50) receiving 68 Gy and 50 Gy (respectively) in 25 daily fractions. The boost volume was targeted to the involved plns and the prostate (minus the urethra plus 3 mm and minus 3 mm from adjacent rectal wall) and totalled up to 75 Gy in 25 fractions. Acute toxicity scores were recorded weekly during and 3 months after radiotherapy (rt) administration. RESULTS: For the 37 patients who completed rt and the 3-month follow-up, median age was 65.5 years (range: 50-76 years). Disease was organ-confined (T1c-T2c) in 23 patients (62.1%), and node positive in 5 patients (13.5%). All patients received long-term ast. Maximum acute genitourinary (gu) and gastrointestinal (gi) toxicity peaked at grade 2 in 6 of 36 evaluated patients (16.6%) and in 4 of 31 evaluated patients (12.9%) respectively. Diarrhea and urinary frequency were the chief complaints. Dose volume parameters demonstrated no correlation with toxicity. The ptv treatment objectives were met in 36 of the 37 patients. CONCLUSIONS: This hfrt dose escalation trial in high-risk prostate cancer has demonstrated the feasibility of administering 75 Gy in 25 fractions with minimal acute gi and gu toxicities. Further follow-up will report late toxicities and outcomes. PMID- 25908925 TI - Secular trends in the survival of patients with laryngeal carcinoma, 1995-2007. AB - BACKGROUND: Recent reports suggest a decline over time in the survival of patients newly diagnosed with laryngeal cancer in spite of developments in treatment practices. Our study set out to determine whether the survival of patients with laryngeal cancer in Ontario has changed over time. METHODS: This population-based cohort study of patients diagnosed with laryngeal cancer in the province of Ontario between 1995 and 2007 used data extracted from linked provincial administrative and registry databases. Its main outcomes were overall survival, laryngectomy-free survival, and survival ratio relative to an age- and sex-matched general population. RESULTS: The 4298 patients newly diagnosed with laryngeal cancer during the period of interest were predominantly men (n = 3615, 84.1%) with glottic cancer (n = 2787, 64.8%); mean age in the group was 66 years (interquartile range: 59-74 years). Patient demographics did not significantly change over time. Overall, 5-year survival was 57.4%; laryngectomy-free survival was 45.4%. Comparing patients from three eras (1995-1998, 1999-2003, 2004-2007) and adjusting for age, sex, and comorbidity status, we observed no differences in overall survival or laryngectomy-free survival over time. The 5-year relative survival ratio for patients with laryngeal cancer compared with an age- and sex matched group from the general population was 81.1% for glottic cancer and 44.5% for supraglottic cancer. CONCLUSIONS: In patients with a new diagnosis of laryngeal cancer, overall and laryngectomy-free survival have remained unchanged since the mid-1990s. New methods to improve survival and the rate of laryngeal preservation in this patient population are needed. PMID- 25908926 TI - B7-H3 promotes aggression and invasion of hepatocellular carcinoma by targeting epithelial-to-mesenchymal transition via JAK2/STAT3/Slug signaling pathway. AB - BACKGROUND: B7-homologue 3 (B7-H3), a recently identified immunoregulatory protein, has been shown to be overexpressed in human hepatocellular carcinoma (HCC). However, whether the dynamic expression pattern of B7-H3 contributes to early invasion of HCC is largely unknown. In addition, the biological roles of B7 H3 in HCC are still unclear. Herein, we are going to examine B7-H3 expression profile and its clinicopathological significance in primary and metastatic HCC, and further determine whether B7-H3 knockdown simulates different pathological states of HCC progression and metastasis. METHODS: Using immunohistochemistry, B7 H3 expression was studied on 116 HCC containing primary and metastatic HCCs. Survival curves and log-rank tests were used to test the association of B7-H3 expression with survival. HCC cells with B7-H3 depletion were established by RNA interference to investigate the effect of B7-H3 on cell proliferation, apoptosis, migration and invasion in vitro. RESULTS: Statistical analysis of clinical cases revealed that B7-H3 high expression group had inclinations towards late TNM stage, the presence of vascular invasion, lymph metastasis, and the formation of microsatellite tumors. Increased intensity of tumor B7-H3 staining was detected more significantly in metastatic HCC tumors. Consistently in experiments performed in vitro, B7-H3 was able to stimulate the wound healing, metastasis and invasion of hepatoma cells by targeting epithelial-to-mesenchymal transition (EMT) via JAK2/Stat3/Slug signaling pathway, while no obvious influence on cell growth and apoptosis. CONCLUSION: B7-H3 in the regulation of the metastatic capacity of HCC cells makes itself a promising therapeutic target for anti metastasis therapy. PMID- 25908927 TI - Neutrophil-to-lymphocyte ratio, calprotectin and YKL-40 in patients with chronic obstructive pulmonary disease: correlations and 5-year mortality - a cohort study. AB - BACKGROUND: Chronic obstructive pulmonary disease (COPD) is characterized by chronic inflammation and progressive decline in pulmonary function. Neutrophil-to lymphocyte ratio (NLR), YKL-40 and calprotectin are biomarkers of inflammation and predict mortality in patients with different inflammatory diseases. We aimed to investigate the correlation between levels of these three biomarkers and neutrophil granulocyte and lymphocyte count in patients with moderate to very severe COPD stratified by use of systemic glucocorticoids. Furthermore, we studied the ability of these biomarkers to predict all-cause mortality. METHODS: 386 patients with moderate to very severe COPD were followed prospectively for 10 years. Patients were divided into two groups according to systemic glucocorticoid use at baseline. Correlations between biomarkers were assessed by Spearman's Rho, and mortality was evaluated in uni- and multivariate Cox regression analyses with hazard ratios (HR) and 95% confidence intervals (CI). RESULTS: Plasma calprotectin was positively correlated with neutrophil granulocyte count and NLR. No significant association was found between plasma YKL-40 and the cellular biomarkers, irrespective of glucocorticoid treatment. In the group not treated with systemic glucocorticoids, plasma calprotectin [HR 1.002 (95% CI 1.000 - 1.004)], NLR [HR 1.090 (1.036 - 1.148)] and lymphocyte count [HR 0.667 (0.522 - 0.851)] were significantly associated with higher mortality. In the group treated with systemic glucocorticoids, higher plasma YKL-40 was significantly associated with mortality in univariate Cox regression analysis [HR 1.006 (1.003 - 1.008)]. CONCLUSIONS: Calprotectin was related to neutrophil granulocyte count and NLR in patients with moderate to very severe COPD in stable phase and not in treatment with systemic glucocorticoids. Lymphopenia, higher plasma calprotectin and higher NLR were independent predictors of increased all-cause mortality in this group. Our data also suggests that treatment with systemic glucocorticoids has a significant impact on the ability of inflammatory biomarkers to predict all-cause mortality. TRIAL REGISTRATION: ClinicalTrials.gov NCT00132860. PMID- 25908928 TI - Valproic acid attenuates intercellular adhesion molecule-1 and E-selectin through a chemokine ligand 5 dependent mechanism and subarachnoid hemorrhage induced vasospasm in a rat model. AB - BACKGROUND: Up-regulation of regulated upon activation, normal T-cell expressed and secreted (RANTES/CCL5) and adhesion molecules is observed in the serum of animals following experimental subarachnoid hemorrhage (SAH). The present study was to examine the effect of valproic acid (VPA) on RANTES and alternation of adhesion molecules in this model. METHODS: A rodent SAH model was employed. Animals were randomly assigned into six groups. Basilar artery (BA) was harvested for intercellular adhesion molecule-1 (ICAM-1), vascular cell adhesion molecule-1 (VCAM-1), and E-selectin evaluation (western blotting) and RANTES (rt-PCR). 1 ng CCL5 recombinant protein intrathecal injection was performed in the VPA + SAH groups. (N = 5). RESULTS: Convoluted internal elastic lamina, distorted endothelial wall, and smooth muscle micro-necrosis was prominently observed in the SAH groups, which is absent in the VPA treatment and the healthy controls. Treatment with VPA dose-dependently reduced the ICAM-1, E-selectin and RANTES level, compared with the SAH group (p <0.01). The administration of CCL5 significantly increased CD45(+) glia and ICAM-1 level in the VPA treatment groups. CONCLUSION: VPA exerts its anti-vasospastic effect through the dual effect of inhibiting RANTES expression and reduced adhesion molecules. Besides, VPA also decreased CD45(+) cells transmigrated to the vascular wall. The administration of CCL5 significantly reversed the inhibitory effect of this compound on CD45(+) monocytes, E-selectin, and ICAM-1 level. This study also lends credence to support this compound could attenuate SAH induced adhesion molecules and neuro-inflammation in a CCL5 dependent mechanism. PMID- 25908929 TI - Systemic lupus erythematosus and thrombosis. AB - Systemic Lupus Erythematosus (SLE) is an acquired, multiorgan, autoimmune disease. Clinical presentation is extremely variable and heterogeneous. It has been shown that SLE itself is an independent risk factor for developing both arterial and venous thrombotic events since SLE patients have an Odds Ratio (OR) for thrombosis that varies depending on the clinical and laboratory characteristics of each study cohort. The risk of developing a thrombotic event is higher in this setting than in the general population and may further increase when associated with other risk factors, or in the presence of inherited or acquired pro-thrombotic abnormalities, or trigger events. In particular, a striking increase in the number of thrombotic events was observed when SLE was associated with antiphospholipid antibodies (aPL). The presence of aPLs has been described in about 50% of SLE patients, while about 20% of antiphospholipid syndrome (APS) patients have SLE. While APS patients (with or without an autoimmune disease) have been widely studied in the last years, fewer studies are available for SLE patients and thrombosis in the absence of APS. Although the available literature undoubtedly shows that SLE patients have a greater prevalence of thrombotic events as compared to healthy subjects, it is difficult to obtain a definite result from these studies because in some cases the study cohort was too small, in others it is due to the varied characteristics of the study population, or because of the different (and very copious) laboratory assays and methods that were used. When an SLE patient develops a thrombotic event, it is of great clinical relevance since it is potentially life threatening. Moreover, it worsens the quality of life and is a clinical challenge for the clinician. PMID- 25908930 TI - The risks of self-made diets: the case of an amateur bodybuilder. AB - BACKGROUND: Following DIY (do it yourself) diets as well as consuming supplements exceeding by far the recommended daily intake levels, is common among athletes; these dietary habits often lead to an overconsumption of some macro and/or micronutrients, exposing athletes to potential health risks. The aim of this study is to document the development of possible adverse effects in a 33 year-old amateur bodybuilder who consumed for 16 years a DIY high protein diet associated to nutrient supplementation. Body composition, biochemical measures and anamnestic findings were evaluated. We present this case to put on alert about the possible risks of such behavior repeated over time, focusing on the adverse gastrointestinal effects. We discuss the energy and nutrient composition of his DIY diet as well as the use of supplements. CONCLUSION: This study provides preliminary data of the potential risks of a long-term DIY dietary supplementation and a high protein diet. In this case, permanent abdominal discomfort was evidenced in an amateur body builder with an intake exceeding tolerable upper limit for vitamin A, selenium and zinc, according to our national and updated recommendations. As many amateur athletes usually adopt self-made diets and supplementation, it would be advisable for them to be supervised in order to prevent health risks due to a long-term DIY diet and over supplementation. PMID- 25908931 TI - Prenatal recruitment of participants for a birth cohort study including cord blood collection: results of a feasibility study in Bremen, Germany. AB - BACKGROUND: Prospective birth cohort studies comprising follow up of children from pregnancy or birth over a long period of time, and collecting various biological samples at different times through the life-course offer a promising approach to enhance etiologic knowledge of various diseases. Especially for those where early lifetime exposures and conditions are thought to play an important role. The collection and storage of biological samples is a critical component in epidemiological studies, notably for research regarding prenatal exposures to various environmental factors as well as for DNA extraction. Our feasibility study for a birth cohort within the scope of etiology of childhood leukemia with prospective sampling of mothers and their future newborns aimed to investigate the willingness of pregnant women to participate in a birth cohort study involving collection of blood and umbilical cord blood samples. The overall aim was to develop practice-based research recommendations for a possible German birth cohort study. METHODS: The study was conducted in Bremen, Germany, between January 2012 and March 2013. Pregnant women were eligible for recruitment if (i) their expected date of delivery was during the study recruitment phase (September 2012-February 2013), (ii) they planned to give birth at the cooperating hospital's obstetric unit and (iii) their knowledge of the German language was sufficient to understand study materials, details of participation and to fill out the prenatal self-administered questionnaire. Maternal blood and umbilical cord blood samples to be used for later research activities were collected and stored at a stem cell bank already collaborating with the hospital. 22 primary care gynecologists were invited to enroll pregnant women for the study and cooperation with one hospital was established. Expectant women were recruited during the last trimester of pregnancy, either during one of their prenatal care visits at their primary care gynecologist or later on in hospital by the attending obstetricians or project staff. RESULTS: Of the 22 invited primary care gynecologists requested to enroll pregnant women for the study, 8 gynecologists actually collaborated. A total of 200 eligible women were invited to participate in the study, 48 (24%) of whom agreed. 34 women were enrolled by primary care gynecologists, with one gynecologist enrolling 26 women. Twelve of 14 women recruited via hospitals were enrolled by study staff. A total of 41 women consented to the collection of umbilical cord blood and maternal blood samples, and samples could be stored for 54% of them. Reason for non-participation were the uncertainty whether or not the full study would be conducted and the fact that the participants were not willing to decide for their children whether or not genetic information (cord blood) can be stored for research purposes. CONCLUSION: Enrolling parents in a birth cohort study that includes biosampling is a challenge, but participation can be improved through close collaboration with primary care gynecologists and maternity hospitals. Cord blood collection may impede participation, especially when maternity hospitals offer an alternative option for cord blood donation. PMID- 25908932 TI - Factors associated with smoking in immigrants from non-western to western countries - what role does acculturation play? A systematic review. AB - INTRODUCTION: We aimed to identify factors associated with smoking among immigrants. In particular, we investigated the relationship between acculturation and smoking, taking into consideration the stage of the 'smoking epidemic' in the countries of origin and host countries of the immigrants. METHODS: We searched PubMed for peer-reviewed quantitative studies. Studies were included if they focused on smoking among adult immigrants (foreign-born) from non-western countries now residing in the USA, Canada, Ireland, Germany, the Netherlands, Norway, the UK, and Australia. Studies were excluded if, among others, a distinction between immigrants and their (native-born) offspring was not made. RESULTS: We retrieved 27 studies published between 1998 and 2013. 21 of the 27 studies focused on acculturation (using bidimensional multi-item scales particularly designed for the immigrant group under study and/or proxy measures such as language proficiency or length of stay in host country) and 16 of those found clear differences between men and women: whereas more acculturated women were more likely to smoke than less acculturated women, the contrary was observed among men. CONCLUSION: Immigrants' countries of origin and host countries have reached different stages of the 'smoking epidemic' where, in addition, smoking among women lags behind that in men. Immigrants might 'move' between the stages as (I) the (non-western) countries of origin tend to be in the early phase, (II) the (western) host countries more in the advanced phase of the epidemic and (III) the arrival in the host countries initiates the acculturation process. This could explain the 'imported' high (men)/low (women) prevalence among less acculturated immigrants. The low (men)/high (women) prevalence among more acculturated immigrants indicates an adaptation towards the social norms of the host countries with ongoing acculturation. PMID- 25908933 TI - Dietary exposures and allergy prevention in high-risk infants: a joint position statement of the Canadian Society of Allergy and Clinical Immunology and the Canadian Paediatric Society. AB - Allergic conditions in children are a prevalent health concern in Canada. The burden of disease and the societal costs of proper diagnosis and management are considerable, making the primary prevention of allergic conditions a desirable health care objective. This position statement reviews current evidence on dietary exposures and allergy prevention in infants at high risk of developing allergic conditions. It revisits previous dietary recommendations for pregnancy, breastfeeding and formula-feeding, and provides an approach for introducing solid foods to high-risk infants. While there is no evidence that delaying the introduction of any specific food beyond six months of age helps to prevent allergy, the protective effect of early introduction of potentially allergenic foods (at four to six months) remains under investigation. Recent research appears to suggest that regularly ingesting a new, potentially allergenic food may be as important as when that food is first introduced. This article has already been published (Paediatr Child Health. 2013 Dec;18(10):545-54), and is being re-published with permission from the original publisher, the Canadian Paediatric Society. PMID- 25908934 TI - Expression of activating receptors on natural killer cells from AIDS-related lymphoma patients. AB - BACKGROUND: Abnormal NK phenotype and cytotoxic functions have been described in acute myeloid leukemia, chronic lymphocytic leukemia, myeloma and myelodysplastic syndromes. Defective NK cytotoxicity is due to decreased expression of the Natural Cytotoxicity Receptors (NCRs), 2B4/CD244/p38, or NKG2D. This prompted us to test the expression of these molecules on circulating NK cells from patients with AIDS-related lymphomas (RL) in comparison with HIV + patients without lymphoma, healthy subjects and HIV-negative patients with lymphoma. METHODS: Blood samples were analyzed by flow cytometry for NCRs, 2B4/CD244/p38 and NKG2D expression on NK cells defined as CD3-/CD56+ lymphocytes. We also analyzed by quantitative PCR specific RNA for NKp30/NCR3 and NKp46/NCR1. RESULTS: We could not detect any defect in NKp46/NCR1 expression between all groups. NKp44/NCR2, NKp30/NCR3 and NKG2D had lower expression in AIDS-RL in comparison with HIV + patients without lymphoma when compared to patients with similar (>0.3 G/L) CD4+ lymphocyte levels. Expression of 2B4/CD244/p38 was lower in AIDS-RL than in HIV negative lymphoma. Comparison of specific NKp30/NCR3 and NKp46/NCR1 RNA showed increased steady state levels, despite decreased surface expression for NKp30/NCR3, suggesting abnormal post-transcriptional regulatory mechanisms. CONCLUSIONS: We show a more pronounced defect in NK activating molecule when HIV infection is associated with lymphoma than when only one condition (HIV positivity or lymphoma) is present. Defective NK phenotype, in addition to CD4+ depletion and dysfunction, may participate to the increased incidence of lymphoma in HIV patients. PMID- 25908936 TI - TETX: a novel nuclear selection marker for Chlamydomonas reinhardtii transformation. AB - BACKGROUND: Transformation of microalgae to obtain recombinant proteins, lipids or metabolites of economic value is of growing interest due to low costs associated with culture growth and scaling up. At present there are only three stable nuclear selection markers for the transformation of Chlamydomonas reinhardtii, which is the most commonly transformed microalgae, specifically: the aminoglycoside phosphotransferaseses aph7and aphVIII and the phleomycin resistance ble gene. As several microalgae are resistant to some of the antibiotics associated with the mentioned resistance genes, we have developed another alternative, tetX, a NADP-requiring Oxidoreductase that hydroxylates tetracycline substrates. We provide evidence that tetX can be used to obtain nuclear transformants of Chlamydomonas reinhardtii. RESULTS: We obtained nuclear transformants harbouring the tetX gene under the control of beta 2 tubulin or HSP70ARBCS2 promoters at an efficiency of transformation of 3.28 and 6.18 colony forming units/MUg DNA respectively. This is the first report of a eukaryotic cell transformed using tetracycline as a selectable marker. CONCLUSIONS: We developed a protocol for the nuclear transformation of Chlamydomonas reinhardtii using tetX as a selectable marker that confers stable resistance to tetracycline up to 100 MUg/mL. We believe tetX can be used to transform Chlamydomonas reinhardtii chloroplasts, related microalgae and other aerobic organisms sensitive to any tetracycline antibiotic. PMID- 25908935 TI - Guidelines for antiretroviral therapy in HIV-1 infected adults and adolescents 2014, Thailand. AB - New evidence has emerged regarding when to commence antiretroviral therapy (ART), optimal treatment regimens, management of HIV co-infection with opportunistic infections, and management of ART failure. The 2014 guidelines were developed by the collaborations of the Department of Disease Control, Ministry of Public Health (MOPH) and the Thai AIDS Society (TAS). One of the major changes in the guidelines included recommending to initiating ART irrespective of CD4 cell count. However, it is with an emphasis that commencing HAART at CD4 cell count above 500 cell/mm(3) is for public health, in term of preventing HIV transmission and personal benefit. In tuberculosis co-infected patients with CD4 cell counts <=50 cells/mm(3) or with CD4 cell counts >50 cells/mm(3) who have severe clinical disease, ART should be initiated within 2 weeks of starting tuberculosis treatment. The preferred initial ART regimen in treatment naive patients is efavirenz combined with tenofovir and emtricitabine or lamivudine. Plasma HIV viral load assessment should be done twice a year until achieving undetectable results; and will then be monitored once a year. CD4 cell count should be monitored every 6 months until CD4 cell count >=350 cells/mm(3) and with plasma HIV viral load <50 copies/mL; then it should be monitored once a year afterward. HIV drug resistance genotypic test is indicated when plasma HIV viral load >1,000 copies/mL while on ART. Ritonavir-boosted lopinavir or atazanavir in combination with optimized two nucleoside-analogue reverse transcriptase inhibitors is recommended after initial ART regimen failure. Long-term ART-related safety monitoring has also been included in the guidelines. PMID- 25908937 TI - CSGM Designer: a platform for designing cross-species intron-spanning genic markers linked with genome information of legumes. AB - BACKGROUND: Genetic markers are tools that can facilitate molecular breeding, even in species lacking genomic resources. An important class of genetic markers is those based on orthologous genes, because they can guide hypotheses about conserved gene function, a situation that is well documented for a number of agronomic traits. For under-studied species a key bottleneck in gene-based marker development is the need to develop molecular tools (e.g., oligonucleotide primers) that reliably access genes with orthology to the genomes of well characterized reference species. RESULTS: Here we report an efficient platform for the design of cross-species gene-derived markers in legumes. The automated platform, named CSGM Designer (URL: http://tgil.donga.ac.kr/CSGMdesigner), facilitates rapid and systematic design of cross-species genic markers. The underlying database is composed of genome data from five legume species whose genomes are substantially characterized. Use of CSGM is enhanced by graphical displays of query results, which we describe as "circular viewer" and "search within-results" functions. CSGM provides a virtual PCR representation (eHT-PCR) that predicts the specificity of each primer pair simultaneously in multiple genomes. CSGM Designer output was experimentally validated for the amplification of orthologous genes using 16 genotypes representing 12 crop and model legume species, distributed among the galegoid and phaseoloid clades. Successful cross species amplification was obtained for 85.3% of PCR primer combinations. CONCLUSION: CSGM Designer spans the divide between well-characterized crop and model legume species and their less well-characterized relatives. The outcome is PCR primers that target highly conserved genes for polymorphism discovery, enabling functional inferences and ultimately facilitating trait-associated molecular breeding. PMID- 25908938 TI - A shifting paradigm in the aetiology of oral and pharyngeal cancer in Sri Lanka: a case-control study providing serologic evidence for the role of oncogenic HPV types 16 and 18. AB - BACKGROUND: Oral and pharyngeal cancer (OPC) of multifactorial aetiology is a major health problem globally. Ranking first in all cancers, OPC poses a significant impact on the Sri Lankan male population. As Human Papillomavirus (HPV) high risk (HR) types are found to be significant risk factors for OPC globally, the current study was undertaken to examine the association between HR HPV16 and 18 types with OPC in Sri Lanka. MATERIALS AND METHODS: Serum samples of 78 OPC patients and 51 non-cancer controls were assayed for the presence of anti HPV16 and anti-HPV18 IgG antibodies using in-house established Enzyme Linked Immunosorbent Assays (ELISAs). The association between OPC and its risk factors i.e. HPV, smoking, alcohol, betel quid, poor dentition, was established using Chi square test. Logistic regression was used to calculate odds ratios (OR), adjusted for the influence of other risk factors. RESULTS: This prototype study in Sri Lanka showed a significant risk of 15 fold in developing OPC due to HPV16/18 seropositivity after removing variability due to other factors. Oncogenic HPV18 showed a higher rate of seropositivity being detected in 32% of OPC patients, and also in 2% of non-cancer control subjects. HR-HPV16 was detected in 23% of OPC patients and in 5.88% of controls. Moreover, seven OPC patients were detected with both anti-HPV16 and anti-HPV18 antibodies. According to the logistic regression models HPV18 seropositivity was associated with a 28 fold risk in developing OPC while that of HPV16 was associated with a 6 fold increase in risk for the development of OPC. A 5 fold risk of developing OPC was also pronounced among smokers while alcohol, betel and poor dentition was not significantly associated with OPC. Statistically significant differences with regard to age, gender, smoking, alcohol, betel use, poor dentition and site specificity of the tumour was not observed between HPV seropositive and seronegative OPC patients. CONCLUSIONS: Both in-house developed ELISAs detected significant proportions of HPV seropositives within the OPC study population suggestive of HPV as a strong risk factor for oral and pharyngeal carcinogenesis in Sri Lanka. PMID- 25908939 TI - Relationship between duration of illness and cardiac autonomic nervous activity in anorexia nervosa. AB - BACKGROUND: The mortality rate associated with anorexia nervosa (AN) is high, and death is mainly attributable to cardiac events. A wide range of autonomic nervous system disturbances may be mechanisms underlying the increased cardiovascular mortality and sudden death of patients with AN. Heart rate variability (HRV) has been proven to be a reliable noninvasive method for quantitative assessment of sympathetic and parasympathetic regulation of heart rate (HR). The longer the duration of illness of AN patients, the higher the mortality rate. However, there have been few reports on the relationship between the duration of illness and HRV in AN. Hence, the aims of this study were to compare the cardiac autonomic nervous activity (CANA) of female patients with AN and age-matched female controls and to evaluate the relationship between the duration of illness and the CANA of the AN patients. METHODS: We studied 14 female patients with AN and 22 age-matched healthy women. Beat-to-beat heart rate variability, recorded in a supine position, was investigated using power spectral analysis. RESULT: Mean heart rate was positively correlated with normalized high-frequency (HF: 0.15 to 0.40 Hz) power and negatively correlated with the low-frequency (LF: 0.04 to 0.15 Hz)/HF power (LF/HF) ratio of the controls. On the other hand, duration of illness was negatively correlated with normalized HF power and positively correlated with the LF/HF ratio of the AN patients. CONCLUSIONS: These results suggest that, given that the LF/HF ratio is an estimate of cardiac sympathovagal balance, anorectic patients with a long illness duration display lower vagal tone (parasympathetic withdrawal) and high sympathetic tone. PMID- 25908940 TI - Synthesis, crystal structures and docking studies of 2,7-diphenyl-1,4-diazepan-5 one derivatives. AB - BACKGROUND: 1,4-Diazepine derivatives are the seven membered, nitrogen containing heterocyclic ring systems possessing a wide range of therapeutic applications. 1,4-Diazepines attracted the attention of chemists and druggists due to their biological and medicinal properties, such as antimicrobial, anti-HIV and anticancer activities. Herein, we report the preparation, crystal structure determined by X-ray crystallographic methods and docking of the molecules with the potential target protein NS5B RNA polymerase. RESULTS: The crystal structures and conformational studies of 1,4-diazepine [t-3, t-6-dimethyl-r-2,c-7-diphenyl 1,4-diazepan-5-one(DIAZ1)] and its nitroso derivative [t-3, t-6-dimethyl-1 nitroso-r-2,c-7-diphenyl-1,4-diazepan-5-one(DIAZ2)] are reported. The analyses of the molecules reveal that the seven membered diazepine ring systems adopt chair and boat conformations in compounds DIAZ1 & DIAZ2, respectively. In DIAZ2, the oxygen O2A is disordered over two positions with the refined occupancies of 0.792(7): 0.208(7) in the nitroso group. In both DIAZ1 & DIAZ2, the symmetry related molecules form a hetero/homo-dimer through N-H...O hydrogen bonds. CONCLUSION: In this study, the crystal structures of two new 1,4-diazepines, namely t-3, t-6-dimethyl-r-2,c-7-diphenyl-1,4-diazepan-5-one and t-3, t-6 dimethyl-1-nitroso-r-2,c-7-diphenyl-1,4-diazepan-5-one were synthesized and characterized by X-ray crystallographic methods. The docking studies show that the compounds inhibit at the active site of the target protein and can be utilized as potential drug molecules. In both the compounds, N-H...O hydrogen bonds lead to dimer formation. In DIAZ2, additionally a couple of C-H...O interactions are noted between the molecules. Graphical AbstractStructure and docking studies of 1,4-diazapine derivatives. PMID- 25908942 TI - HLAreporter: a tool for HLA typing from next generation sequencing data. AB - Human leukocyte antigen (HLA) typing from next generation sequencing (NGS) data has the potential for widespread applications. Here we introduce a novel tool (HLAreporter) for HLA typing from NGS data based on read-mapping using a comprehensive reference panel containing all known HLA alleles, followed by de novo assembly of the gene-specific short reads. Accurate HLA typing at high-digit resolution was achieved when it was tested on publicly available NGS data, outperforming other newly developed tools such as HLAminer and PHLAT. HLAreporter can be downloaded from http://paed.hku.hk/genome/. PMID- 25908941 TI - Rare thyroid non-neoplastic diseases. AB - Rare diseases are usually defined as entities affecting less than 1 person per 2,000. About 7,000 different rare entities are distinguished and, among them, rare diseases of the thyroid gland. Although not frequent, they can be found in the everyday practice of endocrinologists and should be considered in differential diagnosis. Rare non-neoplastic thyroid diseases will be discussed. Congenital hypothyroidism's frequency is relatively high and its early treatment is of vital importance for neonatal psychomotor development; CH is caused primarily by thyroid dysgenesis (85%) or dyshormonogenesis (10-15%), although secondary defects - hypothalamic and pituitary - can also be found; up to 40% of cases diagnosed on neonatal screening are transient. Inherited abnormalities of thyroid hormone binding proteins (TBG, TBP and albumin) include alterations in their concentration or affinity for iodothyronines, this leads to laboratory test abnormalities, although usually with normal free hormones and clinical euthyroidism. Thyroid hormone resistance is most commonly found in THRB gene mutations and more rarely in THRA mutations; in some cases both genes are unchanged (non-TR RTH). Recently the term 'reduced sensitivity to thyroid hormones' was introduced, which encompass not only iodothyronine receptor defects but also their defective transmembrane transport or metabolism. Rare causes of hyperthyroidism are: activating mutations in TSHR or GNAS genes, pituitary adenomas, differentiated thyroid cancer or gestational trophoblastic disease; congenital hyperthyroidism cases are also seen, although less frequently than CH. Like other organs and tissues, the thyroid can be affected by different inflammatory and infectious processes, including tuberculosis and sarcoidosis. In most of the rare thyroid diseases genetic factors play a key role, many of them can be classified as monogenic disorders. Although there are still some limitations, progress has been made in our understanding of rare thyroid diseases etiopathogenesis, and, thanks to these studies, also in our understanding of how normal thyroid gland functions. PMID- 25908943 TI - Reliability of isometric subtalar pronator and supinator strength testing. AB - BACKGROUND: Due to the specific anatomy of the subtalar joint with its oblique axis, isometric pronator and supinator strength is not well documented. The purpose of this study was to determine intra- and between-session reliability of pronator and supinator strength and lower leg muscle activity measurements during maximum voluntary isometric contractions (MVIC). METHODS: Pronator and supinator peak torques (PT), with and without supplementary visual muscle strength biofeedback (FB), and muscular activities of peroneus longus (PL) and tibialis anterior (TA) were assessed twice 3 days apart by the same examiner in 21 healthy young male adults (mean age: 27.6 years; SD = 3.9). Limits of agreement (LoA) and minimum detectable change (MDC) were evaluated. RESULTS: By applying FB, reliability of both pronator and supinator PT was improved: LoA were reduced from 32% to 26% and from 20% to 18% and MDC from 20% to 15% and from 16% to 12% in supinator and pronator PT, respectively. Learning effects in pronator and supinator PT (p < 0.05), which were present without FB, were eliminated using FB. Except for TA during pronation, muscle activities showed low reliability indicated by LoA of 51% to 79%. CONCLUSIONS: Using supplementary biofeedback, isometric subtalar pronator and supinator strength testing is reliable in healthy subjects. LoA of 18% and 26% have to be exceeded for pronator and supinator PT, respectively, to detect relevant effects in repeated measures. PMID- 25908944 TI - How do Australian podiatrists manage patients with diabetes? The Australian diabetic foot management survey. AB - BACKGROUND: Diabetic foot complications are the leading cause of lower extremity amputation and diabetes-related hospitalisation in Australia. Studies demonstrate significant reductions in amputations and hospitalisation when health professionals implement best practice management. Whilst other nations have surveyed health professionals on specific diabetic foot management, to the best of the authors' knowledge this appears not to have occurred in Australia. The primary aim of this study was to examine Australian podiatrists' diabetic foot management compared with best practice recommendations by the Australian National Health Medical Research Council. METHODS: A 36-item Australian Diabetic Foot Management survey, employing seven-point Likert scales (0 = Never; 7 = Always) to measure multiple aspects of best practice diabetic foot management was developed. The survey was briefly tested for face and content validity. The survey was electronically distributed to Australian podiatrists via professional associations. Demographics including sex, years treating patients with diabetes, employment-sector and patient numbers were also collected. Chi-squared and Mann Whitney U tests were used to test differences between sub-groups. RESULTS: Three hundred and eleven podiatrists responded; 222 (71%) were female, 158 (51%) from the public sector and 11-15 years median experience. Participants reported treating a median of 21-30 diabetes patients each week, including 1-5 with foot ulcers. Overall, participants registered median scores of at least "very often" (>6) in their use of most items covering best practice diabetic foot management. Notable exceptions were: "never" (1 (1 - 3)) using total contact casting, "sometimes" (4 (2 - 5)) performing an ankle brachial index, "sometimes" (4 (1 - 6)) using University of Texas Wound Classification System, and "sometimes" (4 (3 6) referring to specialist multi-disciplinary foot teams. Public sector podiatrists reported higher use or access on all those items compared to private sector podiatrists (p < 0.01). CONCLUSIONS: This study provides the first baseline information on Australian podiatrists' adherence to best practice diabetic foot guidelines. It appears podiatrists manage large caseloads of people with diabetes and are generally implementing best practice guidelines recommendations with some notable exceptions. Further studies are required to identify barriers to implementing these recommendations to ensure all Australians with diabetes have access to best practice care to prevent amputations. PMID- 25908945 TI - Minimally invasive surgery for pedal digital deformity: an audit of complications using national benchmark indicators. AB - BACKGROUND: There is increasing global interest and performance of minimally invasive foot surgery (MIS) however, limited evidence is available in relation to complications associated with MIS for digital deformity correction. The aim of this prospective audit is to report the surgical and medical complications following MIS for digital deformity against standardised clinical indicators. METHODS: A prospective clinical audit of 179 patients who underwent MIS to reduce simple and complex digital deformities was conducted between June 2011 and June 2013. All patients were followed up to a minimum of 12 months post operatively. Data was collected according to a modified version of the Australian Council of Healthcare standards (ACHS) clinical indicator program. The audit was conducted in accordance with the National Research Ethics Service (NRES) guidelines on clinical audit. RESULTS: The surgical complications included 1 superficial infection (0.53%) and 2 under-corrected digits (0.67%), which required revision surgery. Two patients who underwent isolated complex digital corrections had pain due to delayed union (0.7%), which resolved by 6 months post-op. No neurovascular compromise and no medical complications were encountered. The results compare favourably to rates reported in the literature for open reduction of digital deformity. CONCLUSION: This audit has illustrated that performing MIS to address simple and complex digital deformity results in low complication rates compared to published standards. MIS procedures were safely performed in a range of clinical settings, on varying degrees of digital deformity and on a wide range of ages and health profiles. Further studies investigating the effectiveness of these techniques are warranted and should evaluate long term patient reported outcome measures, as well as developing treatment algorithms to guide clinical decision making. PMID- 25908946 TI - Genome-wide methylation and transcriptome analysis in penile carcinoma: uncovering new molecular markers. AB - BACKGROUND: Despite penile carcinoma (PeCa) being a relatively rare neoplasm, it remains an important public health issue for poor and developing countries. Contrary to most tumors, limited data are available for markers that are capable of assisting in diagnosis, prognosis, and treatment of PeCa. We aimed to identify molecular markers for PeCa by evaluating their epigenomic and transcriptome profiles and comparing them with surrounding non-malignant tissue (SNT) and normal glans (NG). RESULTS: Genome-wide methylation analysis revealed 171 hypermethylated probes in PeCa. Transcriptome profiling presented 2,883 underexpressed and 1,378 overexpressed genes. Integrative analysis revealed a panel of 54 genes with an inverse correlation between methylation and gene expression levels. Distinct methylome and transcriptome patterns were found for human papillomavirus (HPV)-positive (38.6%) and negative tumors. Interestingly, grade 3 tumors showed a distinct methylation profile when compared to grade 1. In addition, univariate analysis revealed that low BDNF methylation was associated with lymph node metastasis and shorter disease-free survival. CpG hypermethylation and gene underexpression were confirmed for a panel of genes, including TWIST1, RSOP2, SOX3, SOX17, PROM1, OTX2, HOXA3, and MEIS1. CONCLUSIONS: A unique methylome signature was found for PeCa compared to SNT, with aberrant DNA methylation appearing to modulate the expression of specific genes. This study describes new pathways with the potential to regulate penile carcinogenesis, including stem cell regulatory pathways and markers associated to a worse prognosis. These findings may be instrumental in the discovery and application of new genetic and epigenetic biomarkers in PeCa. PMID- 25908948 TI - In response to the article "joubert syndrome imaging features and illustration of a case"; pol j radiol, 2015; 80: 381-83. PMID- 25908949 TI - The Role of MR Imaging in the Assessment of Clinical Outcomes in Children with X Linked Adrenoleukodystrophy after Allogeneic Haematopoietic Stem Cell Transplantation. AB - BACKGROUND: The aim of the study was to analyse MR images of the brain, including advanced MR techniques, such as single voxel spectroscopy (MRS) and diffusion tensor imaging (DTI), in children with X-linked adrenoleukodystrophy (X-ALD) before and after haematopoietic stem cell transplantation (HSCT) and to establish the imaging criteria which may be helpful in the assessment of disease staging, qualification to HSCT and follow-up. MATERIAL/METHODS: Seven boys, aged 5-10 years, (mean 8.14 years) with biochemically proved X-ALD, underwent plain MR imaging with a 1.5 T unit before and after HSCT. Structural images were analyzed using an MRI severity scale (Loes scale). In one patient the follow-up examinations included MRS with the assessment of metabolite ratios (NAA/Cr, Cho/Cr, mI/Cr), as well as DTI with evaluation of fractional anisotropy (FA) and apparent diffusion coefficient (ADC) in several white matter tracts. RESULTS: Two boys had an MRI severity score before HSCT equal to <8 points, and after HSCT they showed no clinical or radiological progression. In 5 patients with a higher severity score (from 8 to 16 points, mean 10.9) before HSCT, clinical and radiological progression was observed (MRI severity score from 17 to 25 points, mean 20.9). Follow-up advanced MRI techniques in one boy showed metabolic alterations, as well as decreased FA and ADC values in all evaluated areas. CONCLUSIONS: Children at an early stage of X-ALD (below 8 points in MRI severity scale) are more likely to benefit from HSCT. DTI and MRS seem to be more useful imaging methods to assess the progression of X-ALD. PMID- 25908950 TI - CT of Hepatic Sarcoidosis: Small Nodular Lesions Simulating Metastatic Disease. AB - BACKGROUND: Sarcoidosis is a multisystemic inflammatory disease of unknown origin. The lymphoid system and the lungs are the most commonly involved organs. The frequency of signs or symptoms of hepatic involvement is very low. CASE REPORT: We present a case of symptomatic granulomatous liver disease secondary to sarcoidosis, mimicking a metastatic disease on ultrasonography and CT. CONCLUSIONS: Hepatic involvement in sarcoidosis might be a perplexing diagnostic problem. The decisive CT finding with respect to the differential diagnosis was the absence of a mass effect and intact vascular architecture around the lesions. PMID- 25908951 TI - Enhanced olfactory sensitivity in autism spectrum conditions. AB - BACKGROUND: People with autism spectrum conditions (ASC) report heightened olfaction. Previous sensory experiments in people with ASC have reported hypersensitivity across visual, tactile, and auditory domains, but not olfaction. The aims of the present study were to investigate olfactory sensitivity in ASC, and to test the association of sensitivity to autistic traits. METHODS: We recruited 17 adult males diagnosed with ASC and 17 typical adult male controls and tested their olfactory sensitivity using the Alcohol Sniff Test (AST), a standardised clinical evaluation of olfactory detection. The AST involves varying the distance between subject and stimulus until an odour is barely detected. Participants with ASC also completed the Autism Spectrum Quotient (AQ) as a measure of autism traits. RESULTS: The ASC group detected the odour at a mean distance of 24.1 cm (SD =11.5) from the nose, compared to the control group, who detected it at a significantly shorter mean distance of 14.4 cm (SD =5.9). Detection distance was independent of age and IQ for both groups, but showed a significant positive correlation with autistic traits in the ASC group (r =0.522). CONCLUSIONS: This is the first experimental demonstration, as far as the authors are aware, of superior olfactory perception in ASC and showing that greater olfactory sensitivity is correlated with a higher number of autistic traits. This is consistent with results from previous findings showing hypersensitivity in other sensory domains and may help explain anecdotal and questionnaire accounts of heightened olfactory sensitivity in ASC. Results are discussed in terms of possible underlying neurophysiology. PMID- 25908952 TI - Is it me? Self-recognition bias across sensory modalities and its relationship to autistic traits. AB - BACKGROUND: Atypical self-processing is an emerging theme in autism research, suggested by lower self-reference effect in memory, and atypical neural responses to visual self-representations. Most research on physical self-processing in autism uses visual stimuli. However, the self is a multimodal construct, and therefore, it is essential to test self-recognition in other sensory modalities as well. Self-recognition in the auditory modality remains relatively unexplored and has not been tested in relation to autism and related traits. This study investigates self-recognition in auditory and visual domain in the general population and tests if it is associated with autistic traits. METHODS: Thirty nine neurotypical adults participated in a two-part study. In the first session, individual participant's voice was recorded and face was photographed and morphed respectively with voices and faces from unfamiliar identities. In the second session, participants performed a 'self-identification' task, classifying each morph as 'self' voice (or face) or an 'other' voice (or face). All participants also completed the Autism Spectrum Quotient (AQ). For each sensory modality, slope of the self-recognition curve was used as individual self-recognition metric. These two self-recognition metrics were tested for association between each other, and with autistic traits. RESULTS: Fifty percent 'self' response was reached for a higher percentage of self in the auditory domain compared to the visual domain (t = 3.142; P < 0.01). No significant correlation was noted between self-recognition bias across sensory modalities (tau = -0.165, P = 0.204). Higher recognition bias for self-voice was observed in individuals higher in autistic traits (tau AQ = 0.301, P = 0.008). No such correlation was observed between recognition bias for self-face and autistic traits (tau AQ = -0.020, P = 0.438). CONCLUSIONS: Our data shows that recognition bias for physical self representation is not related across sensory modalities. Further, individuals with higher autistic traits were better able to discriminate self from other voices, but this relation was not observed with self-face. A narrow self-other overlap in the auditory domain seen in individuals with high autistic traits could arise due to enhanced perceptual processing of auditory stimuli often observed in individuals with autism. PMID- 25908953 TI - Enhanced prey capture skills in Astyanax cavefish larvae are independent from eye loss. AB - BACKGROUND: Enhanced food-finding efficiency is an obvious adaptive response to cave environments. Here, we have compared the food-finding abilities of Astyanax surface fish and blind cavefish young larvae in their first month of life, in the dark. RESULTS: Our results show that enhanced prey capture skills of cavefish are already in effect in fry soon after the yolk is depleted and the young larvae must find food for themselves. Moreover, using prey capture competition assays on surface fish fry with lensectomies, we showed that eye-dependent developmental processes are not the main determinant for enhanced prey capture skills. Finally, using F2 hybrid larvae resulting from crosses between surface fish and cavefish, we found that reduced eyes do not confer a selective advantage for prey capture by fry in the dark. CONCLUSION: We discuss these data with regards to our current developmental and genetic understanding of cavefish morphological and behavioral evolution. PMID- 25908947 TI - EPMA position paper in cancer: current overview and future perspectives. AB - At present, a radical shift in cancer treatment is occurring in terms of predictive, preventive, and personalized medicine (PPPM). Individual patients will participate in more aspects of their healthcare. During the development of PPPM, many rapid, specific, and sensitive new methods for earlier detection of cancer will result in more efficient management of the patient and hence a better quality of life. Coordination of the various activities among different healthcare professionals in primary, secondary, and tertiary care requires well defined competencies, implementation of training and educational programs, sharing of data, and harmonized guidelines. In this position paper, the current knowledge to understand cancer predisposition and risk factors, the cellular biology of cancer, predictive markers and treatment outcome, the improvement in technologies in screening and diagnosis, and provision of better drug development solutions are discussed in the context of a better implementation of personalized medicine. Recognition of the major risk factors for cancer initiation is the key for preventive strategies (EPMA J. 4(1):6, 2013). Of interest, cancer predisposing syndromes in particular the monogenic subtypes that lead to cancer progression are well defined and one should focus on implementation strategies to identify individuals at risk to allow preventive measures and early screening/diagnosis. Implementation of such measures is disturbed by improper use of the data, with breach of data protection as one of the risks to be heavily controlled. Population screening requires in depth cost-benefit analysis to justify healthcare costs, and the parameters screened should provide information that allow an actionable and deliverable solution, for better healthcare provision. PMID- 25908954 TI - Cellular dynamics during regeneration of the flatworm Monocelis sp. (Proseriata, Platyhelminthes). AB - BACKGROUND: Proseriates (Proseriata, Platyhelminthes) are free-living, mostly marine, flatworms measuring at most a few millimetres. In common with many flatworms, they are known to be capable of regeneration; however, few studies have been done on the details of regeneration in proseriates, and none cover cellular dynamics. We have tested the regeneration capacity of the proseriate Monocelis sp. by pre-pharyngeal amputation and provide the first comprehensive picture of the F-actin musculature, serotonergic nervous system and proliferating cells (S-phase in pulse and pulse-chase experiments and mitoses) in control animals and in regenerates. RESULTS: F-actin staining revealed a strong body wall, pharynx and dorsoventral musculature, while labelling of the serotonergic nervous system showed an orthogonal pattern and a well developed subepidermal plexus. Proliferating cells were distributed in two broad lateral bands along the anteroposterior axis and their anterior extension was delimited by the brain. No proliferating cells were detected in the pharynx or epidermis. Monocelis sp. was able to regenerate the pharynx and adhesive organs at the tip of the tail plate within 2 or 3 days of amputation, and genital organs within 8 to 10 days. Posterior pieces were not able to regenerate a head. The posterior regeneration blastema was found to be a centre of cell proliferation, whereas within the pharynx primordium, little or no proliferation was detected. The pharynx regenerated outside of the blastema and was largely, but not solely formed by cells that were proliferating at the time of amputation. CONCLUSIONS: Our findings suggest that proliferating cells or their offspring migrated to the place of organ differentiation and then stopped proliferating at that site. This mode of rebuilding organs resembles the mode of regeneration of the genital organs in another flatworm, Macrostomum lignano. Pharynx regeneration resembles embryonic development in Monocelis fusca and hints at the vertically directed pharynx being plesiomorphic in proseriates. Proliferation within the regeneration blastema has been detected in anterior and posterior blastemas of other flatworms, but is notably missing in triclads. The phylogenetic relationships of the flatworms studied indicate that proliferation within the blastema is the plesiomorphic condition in Platyhelminthes. PMID- 25908955 TI - Toll signals regulate dorsal-ventral patterning and anterior-posterior placement of the embryo in the hemipteran Rhodnius prolixus. AB - BACKGROUND: Insect embryonic dorso-ventral patterning depends greatly on two pathways: the Toll pathway and the Bone Morphogenetic Protein pathway. While the relative contribution of each pathway has been investigated in holometabolous insects, their role has not been explored in insects with a hemimetabolous type of development. The hemimetabolous insect Rhodnius prolixus, an important vector of Chagas disease in the Americas, develops from an intermediate germ band and displays complex movements during katatrepsis that are not observed in other orders. However, little is known about the molecular events that regulate its embryogenesis. Here we investigate the expression and function of genes potentially involved in the initial patterning events that establish the embryonic dorso-ventral axis in this hemipteran. RESULTS: We establish a staging system for early embryogenesis that allows us to correlate embryo morphology with gene expression profiles. Using this system, we investigate the role of Toll pathway genes during embryogenesis. Detailed analyses of gene expression throughout development, coupled with functional analyses using parental RNA interference, revealed that maternal Toll is required to establish germ layers along the dorso-ventral axis and for embryo placement along the anterior posterior axis. Interestingly, knockdown of the Toll pathway effector Rp-dorsal appears to regulate the expression of the Bone Morphogenetic Protein antagonist Rp-short-gastrulation. CONCLUSIONS: Our results indicate that Toll signals are the initiating event in dorso-ventral patterning during Rhodnius embryogenesis, and this is the first report of a conserved role for Toll in a hemipteran. Furthermore, as Rp-dorsal RNA interference generates anteriorly misplaced embryos, our results indicate a novel role for Toll signals in establishment of the anterior-posterior axis in Rhodnius. PMID- 25908956 TI - Molecular conservation of metazoan gut formation: evidence from expression of endomesoderm genes in Capitella teleta (Annelida). AB - BACKGROUND: Metazoan digestive systems develop from derivatives of ectoderm, endoderm and mesoderm, and vary in the relative contribution of each germ layer across taxa and between gut regions. In a small number of well-studied model systems, gene regulatory networks specify endoderm and mesoderm of the gut within a bipotential germ layer precursor, the endomesoderm. Few studies have examined expression of endomesoderm genes outside of those models, and thus, it is unknown whether molecular specification of gut formation is broadly conserved. In this study, we utilize a sequenced genome and comprehensive fate map to correlate the expression patterns of six transcription factors with embryonic germ layers and gut subregions during early development in Capitella teleta. RESULTS: The genome of C. teleta contains the five core genes of the sea urchin endomesoderm specification network. Here, we extend a previous study and characterize expression patterns of three network orthologs and three additional genes by in situ hybridization during cleavage and gastrulation stages and during formation of distinct gut subregions. In cleavage stage embryos, Ct-otx, Ct-blimp1, Ct-bra and Ct-nkx2.1a are expressed in all four macromeres, the endoderm precursors. Ct otx, Ct-blimp1, and Ct-nkx2.1a are also expressed in presumptive endoderm of gastrulae and later during midgut development. Additional gut-specific expression patterns include Ct-otx, Ct-bra, Ct-foxAB and Ct-gsc in oral ectoderm; Ct-otx, Ct blimp1, Ct-bra and Ct-nkx2.1a in the foregut; and both Ct-bra and Ct-nkx2.1a in the hindgut. CONCLUSIONS: Identification of core sea urchin endomesoderm genes in C. teleta indicates they are present in all three bilaterian superclades. Expression of Ct-otx, Ct-blimp1 and Ct-bra, combined with previously published Ct foxA and Ct-gataB1 patterns, provide the most comprehensive comparison of these five orthologs from a single species within Spiralia. Each ortholog is likely involved in endoderm specification and midgut development, and several may be essential for establishment of the oral ectoderm, foregut and hindgut, including specification of ectodermal and mesodermal contributions. When the five core genes are compared across the Metazoa, their conserved expression patterns suggest that 'gut gene' networks evolved to specify distinct digestive system subregions, regardless of species-specific differences in gut architecture or germ layer contributions within each subregion. PMID- 25908957 TI - POU genes are expressed during the formation of individual ganglia of the cephalopod central nervous system. AB - BACKGROUND: Among the Lophotrochozoa, cephalopods possess the highest degree of central nervous system (CNS) centralization and complexity. Although the anatomy of the developing cephalopod CNS has been investigated, the developmental mechanisms underlying brain development and evolution are unknown. POU genes encode key transcription factors controlling nervous system development in a range of bilaterian species, including lophotrochozoans. In this study, we investigate the expression of POU genes during early development of the pygmy squid Idiosepius notoides and make comparisons with other bilaterians to reveal whether these genes have conserved or divergent roles during CNS development in this species. RESULTS: POU2, POU3, POU4 and POU6 orthologs were identified in transcriptomes derived from developmental stages and adult brain tissue of I. notoides. All four POU gene orthologs are expressed in different spatiotemporal combinations in the early embryo. Ino-POU2 is expressed in the gills and the palliovisceral, pedal, and optic ganglia of stage 19 to 20 embryos, whereas the cerebral and palliovisceral ganglia express Ino-POU3. Ino-POU4 is expressed in the optic and palliovisceral ganglia and the arms/intrabrachial ganglia of stage 19 to 20 individuals. Ino-POU6 is expressed in the palliovisceral ganglia during early development. In stage 25 embryos expression domains include the intrabrachial ganglia (Ino-POU3) and the pedal ganglia (Ino-POU6). All four POU genes are strongly expressed in large areas of the brain of stage 24 to 26 individuals. Expression could not be detected in late prehatching embryos (approximately stage 27 to 30). CONCLUSIONS: The expression of four POU genes in unique spatiotemporal combinations during early neurogenesis and sensory organ development of I. notoides suggests that they fulfill distinct tasks during early brain development. Comparisons with other bilaterian species reveal that POU gene expression is associated with anteriormost neural structures, even between animals for which these structures are unlikely to be homologous. Within lophotrochozoans, POU3 and POU4 are the only two genes that have been comparatively investigated. Their expression patterns are broadly similar, indicating that the increased complexity of the cephalopod brain is likely due to other unknown factors. PMID- 25908958 TI - Pattern and process in the evolution of the sole dioecious member of Brassicaceae. AB - BACKGROUND: Lepidium sisymbrioides, a polyploid New Zealand endemic, is the sole dioecious species in Brassicaceae and therefore the closest dioecious relative of the model plant Arabidopsis thaliana. The attractiveness of developing this system for future studies on the genetics of sex determination prompted us to investigate historical and developmental factors surrounding the evolution of its unisexual flowers. Our goal was to determine the evolutionary pattern of polyploidization of L. sisymbrioides and the timing and process of flower reproductive organ abortion. To that end, we used a combination of phylogenetics to place this species within the complex history of polyploidization events in Lepidium and histology to compare its floral ontogeny to that of its closest hermaphroditic relatives and to A. thaliana. RESULTS: Using a nuclear locus (PISTILLATA), we reconstructed the gene tree among Lepidium taxa and applied a phylogenetic network analysis to identify ancestral genomes that contributed to the evolution of L. sisymbrioides. Combining this phylogenetic framework with cytological and genome size data, we estimated L. sisymbrioides as an allo octoploid resulting from three hybridization events. Our investigations of flower development showed that unisexual flowers appear to abort reproductive organs by programmed cell death in female flowers and by developmental arrest in male flowers. This selective abortion occurs at the same floral developmental stage in both males and females, corresponding to Arabidopsis stage nine. CONCLUSIONS: Dioecy in Brassicaceae evolved once in L. sisymbrioides following several allopolyploidization events, by a process of selective abortion of reproductive organs at intermediate stages of flower development. Different developmental processes, but similar timing of abortions, affect male versus female flower development. An increased understanding of how and when reproductive organs abort in this species, combined with our estimates of ancestral genome contributions, ploidy and genome size, lay the foundation for future efforts to examine the genetic mechanisms involved in the evolution of unisexual flowers in the closest dioecious relative of the best studied model plant. PMID- 25908959 TI - HoxA and HoxD expression in a variety of vertebrate body plan features reveals an ancient origin for the distal Hox program. AB - BACKGROUND: Hox genes are master regulatory genes that specify positional identities during axial development in animals. Discoveries regarding their concerted expression patterns have commanded intense interest due to their complex regulation and specification of body plan features in jawed vertebrates. For example, the posterior HoxD genes switch to an inverted collinear expression pattern in the mouse autopod where HoxD13 switches from a more restricted to a less restricted domain relative to its neighboring gene on the cluster. We refer to this program as the 'distal phase' (DP) expression pattern because it occurs in distal regions of paired fins and limbs, and is regulated independently by elements in the 5' region upstream of the HoxD cluster. However, few taxa have been evaluated with respect to this pattern, and most studies have focused on pectoral fin morphogenesis, which occurs relatively early in development. RESULTS: Here, we demonstrate for the first time that the DP expression pattern occurs with the posterior HoxA genes, and is therefore not solely associated with the HoxD gene cluster. Further, DP Hox expression is not confined to paired fins and limbs, but occurs in a variety of body plan features, including paddlefish barbels - sensory adornments that develop from the first mandibular arch (the former 'Hox-free zone), and the vent (a medial structure that is analogous to a urethra). We found DP expression of HoxD13 and HoxD12 in the paddlefish barbel; and we present the first evidence for DP expression of the HoxA genes in the hindgut and vent of three ray-finned fishes. The HoxA DP expression pattern is predicted by the recent finding of a shared 5' regulatory architecture in both the HoxA and HoxD clusters, but has not been previously observed in any body plan feature. CONCLUSIONS: The Hox DP expression pattern appears to be an ancient module that has been co-opted in a variety of structures adorning the vertebrate bauplan. This module provides a shared genetic program that implies deep homology of a variety of distally elongated structures that has played a significant role in the evolution of morphological diversity in vertebrates. PMID- 25908960 TI - Comparative developmental osteology of the seahorse skeleton reveals heterochrony amongst Hippocampus sp. and progressive caudal fin loss. AB - BACKGROUND: Seahorses are well known for their highly derived head shape, prehensile tail and armoured body. They belong to the family of teleosts known as Syngnathidae, which also includes the pipefishes, pipehorses and seadragons. Very few studies have investigated the development of the skeleton of seahorses because larvae are extremely difficult to obtain in the wild and breeding in captivity is rarely successful. Here we compare the developmental osteology of Hippocampus reidi over an ontogenetic series spanning the first 93 days after release from the brood pouch to that of a smaller series of Hippocampus; namely H. subelongatus. RESULTS: We compare the osteology in these two species over growth to the published description of the dwarf species, H. zosterae. We show that ossification onset in H. subelongatus is earlier than in H. reidi, despite similar sizes at parturition. Interestingly, the timing of development of the bony skeleton in H. zosterae is similar to that of the larger species, H. subelongatus. Furthermore, we show that the growth rate of all three species is similar up until about 30 days post pouch release. From this stage onwards in the life history, the size of the dwarf species H. zosterae remains relatively constant whilst the other two species continue growing with an accelerated growth phase. CONCLUSION: This data together with a phylogenetic assessment suggests that there has been a heterochronic shift (a delay) in the timing of ossification in H. reidi and accelerated bonedevelopment in H. zosterae. That is, H. zosterae is not a developmentally truncated dwarf species but rather a smaller version of its larger ancestor, "a proportioned dwarf" species. Furthermore, we show that caudal fin loss is incomplete in Hippocampus seahorses. This study shows that these three species of Hippocampus seahorses have evolved (either directly or indirectly) different osteogenic strategies over the last 20-30 million years of seahorse evolution. PMID- 25908962 TI - Evaluation of immunosuppressive function of regulatory T cells using a novel in vitro cytotoxicity assay. AB - Naturally occurring regulatory T cells (Tregs) play a pivotal role in the maintenance of self-tolerance due to their intrinsic immunosuppressive activity. Currently, a number of human clinical trials are being conducted to investigate the roles of Tregs in treating various immune-mediated disorders. Traditionally, the suppressive activity of Tregs is measured using either a thymidine incorporation assay, which is a radioactive assay; or CFSE based flow cytometry assay, which requires a relatively large number of cells. Consequently, there is an increasing need to develop novel alternative bioassays that can characterize various aspects of the immunosuppressive function of Tregs in vitro. In this study, using murine clonal CD8(+) T cells specific for an islet antigen as responder T cells, we first established a novel, sensitive and quantitative in vitro luminescence based cell viability assay to measure cytotoxicity. Then we used this assay to measure if Tregs could inhibit the cytotoxicity of CD8 effector T cells. This assay does not involve the use of radioisotopes and only needs relatively low number of Tregs. Since normally Tregs only constitute 5-10% of peripheral CD4(+) T cells, this advantage is noteworthy compared with other methods. With the assay we developed, we demonstrated that regulatory T cells (Tregs) could inhibit the antigen-specific killing of an adherent target cell monolayer by the CD8(+) cytotoxic T cells. We observed more inhibition when Tregs and CD8 killer T cells were incubated during the in vitro activation (stimulation) stage of the cytotoxic T lymphocytes (CTL) than when they were added later at the start of the effector phase. Interestingly, Tregs from B6 mice demonstrated higher suppression of CD8(+) T cell killing than Tregs from NOD mice. Moreover, IL-2/anti-IL-2 mAb complexes induced expansion of Tregs in vivo, as well as enhancing the Treg's suppressive activity per cell. Therefore, this novel non-radioactive, luminescence based cytotoxicity assay mediated by clonal islet antigen-specific CD8 T cells can be used to measure, characterize, and quantitate the immunosuppressive activity of natural Tregs, representing a useful approach to characterize the functions of Tregs in the setting of autoimmune diseases and to elucidate the mechanisms for Treg cell-mediated immunoregulation. PMID- 25908961 TI - Treating medullary thyroid cancer in the age of targeted therapy. AB - Medullary thyroid carcinoma (MTC) is a rare neuroendocrine tumor deriving from the thyroid parafollicular cell. Thyroidectomy continues to serve as the primary initial treatment for this cancer. Because standard cytotoxic chemotherapy has proven ineffective, reoperation and external beam radiation therapy had been the only tools to treat recurrences or distant disease. The discovery that aberrant activation of RET, a receptor tyrosine kinase, is a primary driver of MTC tumorigenesis led to clinical trials using RET-targeting tyrosine kinase inhibitors. The successes of those trials led to the approval of vandetanib and cabozantinib for treating patients with progressive or symptomatic MTC. The availability of these drugs, along with additional targeted therapies in development, requires a thoughtful reconsideration of the approach to treating patients with unresectable locally advanced and/or metastatic progressive MTC. PMID- 25908963 TI - A 2-methoxyestradiol bis-sulphamoylated derivative induces apoptosis in breast cell lines. AB - INTRODUCTION: Research involving antimitotic compounds identified 2 methoxyestradiol (2ME2), as a promising anticancer endogenous metabolite. Owing to its low bioavailability, several in silico-designed 2ME2 analogues were synthesized. Structure-activity relationship studies indicated that an already existing 17-beta-estradiol analogue, namely (8R,13S,14S,17S)-2-ethyl-13-methyl 7,8,9,11,12,13,14,15,16,17-decahydro-6H-cyclopenta[a]phenanthrane-3,17-diyl bis(sulphamate) (EMBS) to exert potential in vitro anticancer activity. METHODS: This study investigated the in vitro apoptotic influence of EMBS in an estrogen receptor-positive breast adenocarcinoma epithelial cell line (MCF-7); an estrogen receptor-negative breast epithelial cell line (MDA-MB-231) and a non-tumorigenic breast cell line (MCF-12A). Cell cycle progression, a phosphatidylserine flip, caspase 6-, 7- and 8 enzyme activity levels, Bcl-2 phosphorylation status at serine 70 and Bcl-2- and p53 protein levels were investigated to identify a possible action mechanism for apoptotic induction. RESULTS: The xCELLigence real time label-independent approach revealed that EMBS exerted antiproliferative activity in all three cell lines after 24 h of exposure. A G2M block was observed and apoptosis induction was verified by means of flow cytometry using propidium iodide and Annexin V-FITC respectively. EMBS-treated cells demonstrated a reduced mitochondrial membrane potential. EMBS exposure resulted in a statistically significant increase in p53 protein expression, decreased Bcl-2 protein expression and a decrease in pBcl-2(s70) phosphorylation status in all three cell lines. Results support the notion that EMBS induces apoptosis in all three cell lines. CONCLUSION: This study includes investigation into the apoptotic hallmarks exerted by EMBS after exposure of three cell lines namely MCF-7-, MDA-MDA-231- and MCF-12A cells. Increased caspase 6-, caspase 7- and caspase 8 activities, upregulation of p53 protein expression and a decrease in phosphorylation status of Bcl-2 at serine 70 in tumorigenic and non-tumorigenic lines were demonstrated. PMID- 25901279 TI - Fused embryos and pre-metamorphic conjoined larvae in a broadcast spawning reef coral. AB - Fusion of embryos or larvae prior to metamorphosis is rarely known to date in colonial marine organisms. Here, we document for the first time that the embryos of the broadcast spawning coral Platygyra daedalea could fuse during blastulation and further develop into conjoined larvae, and the settlement of conjoined larvae immediately resulted in inborn juvenile colonies. Fusion of embryos might be an adaptive strategy to form pre-metamorphic chimeric larvae and larger recruits, thereby promoting early survival. However, future studies are needed to explore whether and to what extent fusion of coral embryos occurs in the field, and fully evaluate its implications. PMID- 25908965 TI - Impact of livestock-associated MRSA in a hospital setting. AB - OBJECTIVES: The Netherlands is known for a stringent search and destroy policy to prevent spread of MRSA. In the hospital setting, livestock-associated MRSA (LA MRSA) is frequently found in patients coming from the high density farming area in the south of the Netherlands. The aim of the study was to determine the contribution of LA-MRSA in the epidemiology of MRSA in cases found following the Dutch search and destroy policy. PATIENTS AND METHODS: From two hospitals serving a population of 550,000 persons all data on MRSA cultures and subsequent control measures from 2008 and 2009 were retrospectively collected and analyzed. RESULTS: A total of 3856 potential index patients were screened for MRSA, 373 (9.7%) were found to be positive, 292 ( 78%) LA-MRSA and 81 (22%) non-LA-MRSA respectively. No secondary cases were found among contact research in persons exposed to LA MRSA (0/416), whereas similar contact research for non-LA-MRSA resulted in 83 (2.5%) secondary cases. LA-MRSA were rarely found to cause infections. CONCLUSIONS: LA-MRSA is more prevalent than non-LA-MRSA in Dutch Hospitals in the South of the Netherlands. However, retrospectively studied cases show that the transmission rate for LA-MRSA was much lower than for non-LA-MRSA. This suggest that infection control practices for LA-MRSA may possibly be less stringent than for non-LA-MRSA. PMID- 25908966 TI - Multidrug resistant and carbapenemase producing Enterobacteriaceae among patients with urinary tract infection at referral Hospital, Northwest Ethiopia. AB - BACKGROUND: Updates on the epidemiology of antibiotic resistance bacterial pathogens is important. This is because the spread of multidrug resistant enterobacteriaceae (MDRE) and recently carbapenemase producing enterobacteriaceae (CPE) have emerged as a major public health concern in patients with urinary tract infections (UTIs). This study is therefore, aimed to assess the prevalence and associated risk factors of MDR and CPE among patients with UTIs. METHODS: A cross sectional study was conducted among 442 symptomatic UTI suspected patients. Data on socio-demographic characteristics, clinical information and possible risk factors were collected using structured questionnaire. Early morning mid-stream urine samples were collected and processed to characterize bacterial isolates. Disk diffusion method was used to determine the antibiotic susceptibility patterns of isolates. Carbapenemase producing strains were detected using CHROMagar KPC medium. Data were entered and analyzed using SPSS version 20. P value <0.05 was considered as statistical significant. RESULTS: Among 442 patients enrolled a total of 183 Enterobacteriaceae were recovered. Of these isolates; 160 (87.4%) were MDRE; the most common isolates were K. pneumoniae and E.coli. Five (2.73%) of the isolates were found to be carbapenemase producers and all of CPE strains were 100% ESBL producers. Significant drug resistances were observed among CPE compared to other MDRE, low resistance rates were noted to ciprofloxacin (20%). Being female (OR 4.46; P = 0.018), age (OR 1.08; P = 0.001), hospitalization (OR 5.23; P = 0.006), and prior antibiotic use (OR 3.98; P = 0.04) were associated risk factors for MDRE. CONCLUSION AND RECOMMENDATION: High rates of MDR (87.4%) were observed among enterobacteriaceae uropathogens; K. pneumoniae and E.coli were the principal MDR isolates. Overall prevalence of CPE was 2.73% and all of these strains were 100% ESBL producer. Attributing risk factors for MDR UTIs were found to be sex (female), age, hospitalization, and history of antibiotic therapy. Therefore, efforts should be made to reduce patient hospital stay and maximize rational use of drugs. Additional and vigorous investigation especially on CPE should be encouraged. PMID- 25908967 TI - Predicting mouse vertebra strength with micro-computed tomography-derived finite element analysis. AB - As in clinical studies, finite element analysis (FEA) developed from computed tomography (CT) images of bones are useful in pre-clinical rodent studies assessing treatment effects on vertebral body (VB) strength. Since strength predictions from microCT-derived FEAs (MUFEA) have not been validated against experimental measurements of mouse VB strength, a parametric analysis exploring material and failure definitions was performed to determine whether elastic MUFEAs with linear failure criteria could reasonably assess VB strength in two studies, treatment and genetic, with differences in bone volume fraction between the control and the experimental groups. VBs were scanned with a 12-MUm voxel size, and voxels were directly converted to 8-node, hexahedral elements. The coefficient of determination or R (2) between predicted VB strength and experimental VB strength, as determined from compression tests, was 62.3% for the treatment study and 85.3% for the genetic study when using a homogenous tissue modulus (E t) of 18 GPa for all elements, a failure volume of 2%, and an equivalent failure strain of 0.007. The difference between prediction and measurement (that is, error) increased when lowering the failure volume to 0.1% or increasing it to 4%. Using inhomogeneous tissue density-specific moduli improved the R (2) between predicted and experimental strength when compared with uniform E t=18 GPa. Also, the optimum failure volume is higher for the inhomogeneous than for the homogeneous material definition. Regardless of model assumptions, MUFEA can assess differences in murine VB strength between experimental groups when the expected difference in strength is at least 20%. PMID- 25908968 TI - Bone specific immunity and its impact on metastasis. AB - Bone is one of the most common sites of metastasis in solid malignancy. Contributing to this osteotropism are the dynamic interactions between tumor cells and the numerous cell types resident in the normal bone, particularly osteoclasts and osteoblasts, which create a tumor supporting microenvironment. However, disseminated cells are detected in the bone marrow long before evidence of metastatic outgrowth, and it is likely that prolonged survival is also reliant on immunoescape. Compared with other peripheral organs such as the lung and spleen, the bone marrow constitutes a unique immune cell compartment that likely provides an immune privileged niche for disseminated tumor cells. This includes the large proportions of immunosuppressive cells, including myeloid derived suppressor cells and regulatory T cells, that blunt the activity of cytotoxic lymphocytes involved in tumor immunosurveillance. This review highlights key aspects of the osteoimmune landscape and emerging mechanisms by which tumor cells create or co-opt an immunosuppressed niche to support their outgrowth in bone. Future studies in this field are likely to shed light on the differences in immunoregulation between the bone and other sites including the primary tumor, and the potential for immunotherapeutics in treating disseminated disease in the bone. However, more immunocompetent models, that recapitulate tumor heterogeneity and bone metastasis need to be developed to accelerate this field. PMID- 25908969 TI - Bone remodeling markers and bone metastases: From cancer research to clinical implications. AB - Bone metastasis is a frequent finding in the natural history of several types of cancers. However, its anticipated risk, diagnosis and response to therapy are still challenging to assess in clinical practice. Markers of bone metabolism are biochemical by-products that provide insight into the tumor-bone interaction, with potential to enhance the clinical management of patients with bone metastases. In fact, these markers had a cornerstone role in the development of bone-targeted agents; however, its translation to routine practice is still unclear, as reflected by current international guidelines. In this review, we aimed to capture several of the research and clinical translational challenges regarding the use of bone metabolism markers that we consider relevant for future research in bone metastasis. PMID- 25908970 TI - Bone marrow stroma-derived miRNAs as regulators, biomarkers and therapeutic targets of bone metastasis. AB - MicroRNAs (miRNAs) are short, endogenous RNA molecules that have essential roles in regulating gene expression. They control numerous physiological and cellular processes, including normal bone organogenesis and homeostasis, by enhancing or inhibiting bone marrow cell growth, differentiation, functional activity and crosstalk of the multiple cell types within the bone. Hence, elucidating miRNA targets in bone marrow stromal cells has revealed novel regulations during bone development and maintenance. Moreover, recent studies have detailed the capacity for bone stromal miRNAs to influence bone metastasis from a number of primary carcinomas by interfering with bone homeostasis or by directly influencing metastatic tumor cells. Owing to the current lack of good diagnostic biomarkers of bone metastases, such changes in bone stromal miRNA expression in the presence of metastatic lesions may become useful biomarkers, and may even serve as therapeutic targets. In particular, cell-free and exosomal miRNAs shed from bone stromal cells into circulation may be developed into novel biomarkers that can be routinely measured in easily accessible samples. Taken together, these findings reveal the significant role of bone marrow stroma-derived miRNAs in the regulation of bone homeostasis and bone metastasis. PMID- 25908971 TI - Effects of a multi-enzyme complex on growth performance, nutrient utilization and bone mineralization of meat duck. AB - BACKGROUND: Previous studies with broiler have shown dietary supplementation with multi-enzyme complex containing non-starch polysaccharides (NSP) degrading enzymes and phytase is efficient in releasing phosphorus (P), calcium (Ca), energy and amino acids from corn-soybean meal diets or corn-sorghum diets, hence compensating considerable levels of nutrients in formulation. Notwithstanding, such potentials have not been well defined in duck nutrition. Giving China being the largest duck producing country, we conducted this study to establish adequate specifications of major nutrients along with multi-enzyme complex to meat duck from day-old to slaughter, focusing on performance, utilization of nutrients and bone mineralization. Five dietary treatments were: Positive control (PC,T1 ): the nutrients concentration of diet for 1 to 14 d of age were apparent metabolizable energy(AME) 2,800 kcal/kg, crude protein (CP)19.39%, Ca 0.85%, available phosphorus (avP) 0.42%; for 15 to 35 d of age these parameters were AME 2,900 kcal/kg, CP 16.47%,Ca 0.76%,avP 0.38%; Negative control 1(NC1,T2), the AME and digestible amino acids (DAA) were reduced by 70 kcal/kg and 2.0%, avP and Ca by 1.0 g/kg from PC diet; Negative control 2( NC2,T4), the down-spec from PC diet was AME 100 kcal/kg, DAA 2.5%, avP 1.5 g/kg and Ca 1.2 g/kg; The enzyme complex was added at the same dosage (200 mL/ 1,000 kg) on NC1 (T3) and NC2 (T5) diets. RESULTS: Comparing with the ducks fed on T1, T3 and T5 diets, the birds fed on NC2 diet showed the lowest (P < 0.05) body weight ( d 14 and 35), feed intake (d 35), tibia ash, Ca and P contents (d 14 and 35), and the utilization of nutrients (P < 0.05). The supplementation with the enzyme complex to the NC diets restored growth rate, utilization of nutrients and bone mineralization to the level of the PC diet, and increased AME by 60 kcal/kg and 117 kcal/kg, respectively for the NC1 and NC2 diets. CONCLUSION: These results suggest that down-spec AME by 100 kcal/kg, DAA by 2.5%, avP by 1.5 g/kg and Ca by 1.2 g/kg caused detrimental effects on duck performance compared with those fed on the PC diet, and these performance losses can be compensated by the addition of the multiple-enzyme complex. PMID- 25908972 TI - Factors controlling nutrient availability to the developing fetus in ruminants. AB - Inadequate delivery of nutrients results in intrauterine growth restriction (IUGR), which is a leading cause of neonatal morbidity and mortality in livestock. In ruminants, inadequate nutrition during pregnancy is often prevalent due to frequent utilization of exensive forage based grazing systems, making them highly susceptible to changes in nutrient quality and availability. Delivery of nutrients to the fetus is dependent on a number of critical factors including placental growth and development, utero-placental blood flow, nutrient availability, and placental metabolism and transport capacity. Previous findings from our laboratory and others, highlight essential roles for amino acids and their metabolites in supporting normal fetal growth and development, as well as the critical role for amino acid transporters in nutrient delivery to the fetus. The focus of this review will be on the role of maternal nutrition on placental form and function as a regulator of fetal development in ruminants. PMID- 25908973 TI - Characterization of energy and performance of swine fed a novel corn-soybean extruded product. AB - BACKGROUND: A novel extruded product was characterized with a metabolism and lactation trial to establish the product's energy content, and its effects on lactating sow performance. The product was composed of a 60:40 corn-soybean blend, which was then extruded. This product containing the co-extruded 60:40 corn-soybean blend was commercially developed and is used extensively in swine diets in southwest Minnesota. GE of dietary treatments were determined by isoperibol bomb calorimetry. Twelve barrows (59.9 +/- 1.4 kg), were used to determine the digestible and metabolizable energy of the extruded product. DE of treatments was determined by subtracting fecal energy from GE provided to barrows by each respective treatment. ME was determined by subtracting urinary energy from calculated digestible energy. Sixty-three sows were used for the lactation trial. Three dietary treatments were utilized: CONTROL (an industry standard diet); PRODUCT (contained the product, vitamins and minerals); OIL (matched the lysine:ME ratio of PRODUCT by addition of soy oil). Sow weight, backfat thickness at the right and left last ribs, body condition score, number of piglets, and litter weights were recorded on the date of farrowing (d 0), (d 9), and at weaning. Blood and milk samples were obtained at weaning, and blood was analyzed for plasma urea nitrogen (PUN), milk was analyzed for total protein and fat content. RESULTS: On a dry-matter basis, the test diet provided 3,908 kcal/kg DE and 3,833 kcal/kg ME, which was significantly greater than the basal diet, which provided 3,633 kcal/kg DE and 3,567 kcal/kg ME (P < 0.0001). These data were used to establish the DE and ME of the product, which were 3,882 kcal/kg and 3,798 kcal/kg, respectively, on an as-fed basis. No effect of diet was observed for changes in sow backfat (RBF P = 0.24; LBF P = 0.07) or body condition score (P = 0.12) during lactation. Milk total protein (P = 0.69), fat (P = 0.66), PUN, average piglet gain (P = 0.55) and piglet mortality (P = 0.70) did not differ between treatments. CONCLUSIONS: While the novel extruded product was higher in energy content than traditional feedstuffs, it resulted in the same lactational sow performance. Thus, the co-extruded corn-soybean product is a reasonable inclusion in sow lactation diets. PMID- 25908974 TI - Effect of inhaled hydrosoluble curcumin on inflammatory markers in broncho alveolar lavage fluid of horses with LPS-induced lung neutrophilia. AB - BACKGROUND: Horses commonly suffer from chronic respiratory disease and are also used in large animal models of spontaneous or induced airway inflammation. The anti-inflammatory properties of curcumin are largely described but its low bioavailability precludes its clinical use. NDS27, a lysin salt of curcumin incorporated in beta-cyclodextrine, has high bioavailability and can be administered by inhalation. The aim of this study was to investigate the effects of inhaled NDS27 on inflammatory cytokines and proteins in the broncho-alveolar lavage fluid using a model of neutrophilic airway inflammation. METHODS: Airway neutrophilia was induced in eight horses by inhalation of lipopolysaccharides (LPS). Horses were treated with either inhalation of NDS27 or with placebo in a randomized cross-over design. Broncho-alveolar lavages were performed 6 hours after stimulation with LPS. Percentage of neutrophils, concentrations of IL 1beta, TNF-alpha, IL-6, Club cell secretory protein, myeloperoxidase (MPO) and elastase (ELT) concentrations were determined. RESULTS: LPS stimulation induced significant increases in neutrophil counts and concentrations of IL-6 (70.2 +/- 66.0 pg/ml), TNF-alpha (43.9 +/- 31.2 pg/ml), MPO (580.9 +/- 327.0 ng/ml) and ELT (27.6 +/- 16.7 ng/ml). Treatment with NDS27 significantly prevented the increase in active and total MPO (216.4 +/- 118.1 ng/ml) and ELT (5.9 +/- 3.2 ng/ml) while there was a trend towards reduced IL-6 concentration. CONCLUSIONS: Results show that, although not reducing neutrophil recruitment, NDS27 largely abolishes LPS induced neutrophil degranulation. Reduced levels of ELT and MPO, as well as reduced MPO activity may have beneficial effects via a reduced production of reactive oxygen species implicated in chronic inflammation and airway remodeling. PMID- 25908975 TI - Tackling challenges of TB/MDRTB in China: concerted actions are imperative. AB - China is the second largest TB epidemic with the most number of people infected with multi-drug resistant (MDR). Over the past decade, a large number of TB control projects have been funded by the government of China and international organizations, and epidemic in China has been effectively controlled. However TB control in China still faced many challenges. Strategies to address these challenges may include integrating the national TB control program into health insurance schemes, strengthening TB case management through involving the Chinese hospital in national TB control program, and reforming payment methods for TB care as part of health system reform in China. PMID- 25908976 TI - Disordered eating behaviors in university students in Hanoi, Vietnam. AB - BACKGROUND: The aim of the study was to examine disordered eating behaviors in university students in Vietnam. METHODS: A total of 244 female university students participated, and 203 data could be analyzed. The Body Mass Index, the SCOFF screening questionnaire and the Eating Disorder Inventory 2 were used to explore disordered eating behaviors. RESULTS: 45.3% of the participants were underweight, 53.2% were normal weight and 1.5% were overweight. 48.8% of students reported two or more yes-responses on the SCOFF screening questionnaire which indicates a high possibility of having eating disorder symptoms. The mean score for underweight subjects (M = 14.79, SD = 6.81) indicated a lower level on the drive for thinness scale of the EDI-2 compared to normal weight subjects (M = 24.65, SD = 6.86) and overweight subjects (M = 31.33, SD = 6.66). Additionally, underweight subjects (M = 27.24, SD = 7.57) were less dissatisfied with their body than normal weight subjects (M = 35.94, SD = 8.67) and overweight subjects (M = 43.33, SD = 11.24). A significant positive correlation appeared between the BMI and the EDI-2. The SCOFF questionnaire showed a statistically significant negative correlation with the BMI and the EDI-2. CONCLUSIONS: Despite some limitations the current study shows a tendency in young females in urban Vietnam to be underweight and to develop disordered eating symptoms such as drive for thinness and body dissatisfaction. However, more studies using the SCOFF and the EDI-2 would be needed to verify these findings. PMID- 25908977 TI - Dually degradable click hydrogels for controlled degradation and protein release. PMID- 25908978 TI - Evaluating the fundamental critical care support course in critical care education in Japan: a survey of Japanese fundamental critical care support course experience. AB - BACKGROUND: The Fundamental Critical Care Support (FCCS) course has been introduced after minimal adaptation according to Japanese clinical settings. The original course in the USA is often used to prepare residents for rotations in the intensive care unit (ICU). Therefore, the FCCS program can be appropriate for the basic training of critical care in Japan to standardize critical care management. The purpose of this study is to evaluate whether Japanese FCCS course is useful and has a possibility to deserve a basis of critical care management in Japan. METHODS: The course program was provided with the form of lecture and skills stations. Pre- and post-training knowledge was assessed. After completion of the 2-day course, a questionnaire survey was administered to all course participants. Participants were asked to fill out the questions regarding socio demographic characteristics. Participants were also asked to identify which lectures or skill stations they thought to be useful for clinical practice. Then, they were asked to rate their performance of each field: 'Assessment,' 'Diagnosis,' 'Recognition,' 'Response,' and 'Transfer'. RESULTS: The number of participants increased year after year and reached 1,804 during the past 4 years. Nearly 70% of the participants were physicians. Most of the others were nurses. In the established year, the percentage of physicians who had clinical experience more than 5 years exceeded 50%, however, this percentage gradually decreased. On the contrary, the percentages of residents and nurses increased. Regarding useful sessions, nearly half of the participants thought that mechanical ventilation was the most useful. With regard to the results of pre- and post-tests, the participants had already shown a high average mark (78.8 +/- 14.1) at the pre test. Furthermore, the score at the post-test was significantly improved (82.0 +/ 6.6, p < 0.01). The participants' confidence in any field regarding critical care management was almost 4 points (5-point scale). CONCLUSIONS: It is considered that Japanese FCCS course is useful and has a promising basis of critical care management in Japan. Therefore, it is reasonable to think that Japanese FCCS mission has been successfully achieved. PMID- 25908979 TI - Effects of epinephrine administration in out-of-hospital cardiac arrest based on a propensity analysis. AB - BACKGROUND: Epinephrine administration has been advocated for cardiopulmonary resuscitation (CPR) for decades. Despite the fact that epinephrine administration during CPR is internationally accepted, the effects of the prehospital epinephrine administration still remain controversial. We investigated the effects of epinephrine administration on patients with out-of-hospital cardiac arrest based on a propensity analysis with regard to the 'CPR time'. METHODS: From April 1, 2007, to December 31, 2009, 633 out-of-hospital cardiac arrest patients with bystander witnesses were included in the present study. To rule out any survival bias, we used the propensity scores, which included CPR time. CPR time was defined as the time span from when the emergency medical technicians started CPR until either the return of spontaneous circulation or arrival at the hospital. After performing propensity score matching, the epinephrine and no-drug groups each included 141 patients. The primary study endpoint was a favorable neurological outcome at 30 days after cardiac arrest. RESULTS: After propensity score matching, the frequency of the return of spontaneous circulation before arrival at the hospital in the matched epinephrine group was higher than that in the matched no-drug group (27% vs. 13%, P = 0.002). However, the frequency of a favorable neurological state did not differ between the two groups. With regard to the frequency of a favorable neurological state in the patients, the adjusted odds ratio of the time span from cardiac arrest to the first epinephrine administration was 0.917 (95% confidence interval 0.850-0.988, P = 0.023) per minute. CONCLUSIONS: In patients with witnessed out-of-hospital cardiac arrest, prehospital epinephrine administration was associated with increase of the return of spontaneous circulation before arrival at the hospital. Moreover, the early administration of epinephrine might improve the overall neurological outcome. PMID- 25908980 TI - Respiratory support with nasal high-flow therapy helps to prevent recurrence of postoperative atelectasis: a case report. AB - Postoperative atelectasis should be avoided in surgical patients with impaired pulmonary function. Nasal high-flow (NHF) therapy delivered by the OptiflowTM system (Fisher & Paykel Healthcare Ltd., Auckland, New Zealand) is a new, simple device that supplies heated and humidified oxygen gas at >30 L/min via a large bore nasal cannula. We herein describe a case in which respiratory support with NHF therapy was useful for the prevention of postoperative atelectasis recurrence. A 67-year-old man with an upper digestive tract perforation underwent emergency laparoscopic surgery. He appeared malnourished because of severe untreated diabetes mellitus. The proposed surgery was uneventfully completed. On postoperative day (POD) 5, he experienced massive atelectasis of the left lower lobe with desaturation to <90%. After restoration of normal oxygenation by tracheal suction and postural drainage, noninvasive positive-pressure ventilation (NPPV) at a continuous positive airway pressure (CPAP) of 8 cm H2O was conducted to prevent repeated atelectasis. Fifteen hours after the cessation of NPPV on POD 7, he developed recurrence of massive atelectasis. Bronchoscopic suction removed a mucous plaque in the tracheobronchial tree, and NHF therapy at 40 L/min was subsequently performed, delivering a low level of CPAP instead of NPPV. Under the respiratory support with NHF therapy, his condition was more stable than with NPPV, and his respiratory rehabilitation continued uneventfully. In addition, the NHF therapy delivered optimally humidified gas, which improved the bronchial secretion quality. No further atelectasis occurred throughout the remaining stay in the intensive care unit. We conclude that respiratory support with NHF therapy may contribute to the prevention of postoperative atelectasis by delivering CPAP in combination with progressive respiratory rehabilitation. PMID- 25908981 TI - ICU service in Taiwan. AB - BACKGROUND: The aim of the study was to understand the current status of intensive care unit (ICU) in order to optimize the resources achieving the best possible care. METHODS: The study analyzed the status of ICU settings based on the Taiwan National Health Insurance database between March 2004 and February 2009. RESULTS: A total of 1,028,364 ICU patients were identified. The age was 65 +/- 18 years, and 61% of the patients were male. The total ICU bed occupancy rate was 83.8% which went up to 87.3% during winter. The ICU bed occupancy was 94.4% in major medical centers. The ICU stay was 6.5 +/- 0.5 days, and the overall ICU mortality rate was 20.2%. The hospital stay was 16.4 +/- 16.8 days, and the average cost of total hospital stay was approximately US$5,186 per patient. CONCLUSIONS: The rate of ICU bed occupancy was dependent on seasonal changes, and it reached near full capacity in major medical centers in Taiwan. The ICU beds were distributed based on the categories of hospitals in order to achieve a reasonable cost efficiency. ICU faces many challenges to maintain and improve quality care because of the increasing cost of state-of-the-art technologies and dealing with aging population. PMID- 25908982 TI - Patient questionnaire following closure of tracheotomy fistula: percutaneous vs. surgical approaches. AB - BACKGROUND: Tracheotomy is an indispensable component in intensive care management. Doctors in charge of the intensive care unit (ICU) usually decide whether tracheotomy should be performed. However, long-term follow-up of a closed fistula by these doctors is rarely continued in most cases. Doctors in charge of the ICU should be interested in the long-term prognosis of tracheotomy. The purpose of this study was to evaluate whether different tracheotomy procedures affect the long-term outcome of a closed tracheal fistula. METHODS: We mailed questionnaires to patients undergoing tracheotomy in Fukushima Medical University Hospital between January 2008 and December 2010. Questions concerned problems related to perception, laryngeal function, and the appearance of a closed fistula. Patients were classified into percutaneous tracheotomy (PT) group and surgical tracheotomy (ST) group. We evaluated the statistical significance of differences in the frequency and degree of each problem between the two groups. A door-to-door objective evaluation using the original scoring system was then performed for patients who replied to the mailed questionnaire. We evaluated the percentage of patients with high scores as well as the mean scores for problems with function and appearance. RESULTS: We received completed questionnaires from 28/40 patients in the PT group and 35/55 patients in the ST group. There were no significant differences in age, mean hospital stay, or APACHE II score between the groups. Regarding problems with appearance, the outcomes of PT were significantly better than those of ST with respect to self-evaluation (p = 0.04) and the frequency (p = 0.03) and degree (p = 0.02) of scar unevenness according to door-to-door evaluation. However, there were no significant differences in the frequency or degree of self-evaluation in problems with perception and function between the two groups. There were no significant differences in the frequency or degree of door-to-door evaluation of problems with function. CONCLUSIONS: This study shows that PT might be superior to ST with respect to problems with long term appearance. Continuous follow-up of closed tracheal fistulas can help assure that patients recovering from a critical condition experience a better return to their former lives. A systematic follow-up of post-critical-care patients is required. PMID- 25908983 TI - Clinical characteristics of yamakagashi (Rhabdophis tigrinus) bites: a national survey in Japan, 2000-2013. AB - BACKGROUND: Yamakagashi (Rhabdophis tigrinus) is a species of pit viper present throughout Russia and Eastern Asia. Although R. tigrinus venom is known to induce life-threatening hemorrhagic symptoms, the clinical characteristics and effective treatment of R. tigrinus bites remain unknown. The present study aimed to clarify these issues. METHODS: Records in the Japan Snake Institute between 2000 and 2013 were retrospectively investigated. The following were determined: patient characteristics, coagulation and fibrinolytic system abnormalities, effect of antivenom treatment, and outcomes. RESULTS: Nine patients (all males; median age, 38 years) with R. tigrinus bites were identified. On admission, the median levels of fibrinogen and fibrinogen degradation products, and platelet counts were 50 mg/dL, 295 MUg/mL, and 107,000/mm(3), respectively. The median (minimum-maximum) disseminated intravascular coagulation (DIC) score defined by the Japanese Association of Acute Medicine was 8 (1-8). Antivenom was administered to seven patients, with a median interval of 35 h between bite and antivenom administration. All patients treated with antivenom survived, and the in-hospital mortality rate was 11%. CONCLUSIONS: Patients with R. tigrinus bites presented with DIC of a fibrinolytic phenotype, which can result in life-threatening injury unless appropriate antivenom and DIC treatment are provided. PMID- 25908984 TI - IV injection of polystyrene beads for mouse model of sepsis causes severe glomerular injury. AB - BACKGROUND: Infusion fluids may be contaminated with different types of particulates that are a potential health hazard. Particulates larger than microvessels may cause an embolism by mechanical blockage and inflammation; however, it has been reported that particulates smaller than capillary diameter are relatively safe. Against such a background, one report showed that polystyrene beads smaller than capillary diameter decreased tissue perfusion in ischemia-reperfusion injury. This report suggested that polystyrene beads from 1.5- to 6-MUm diameter (dia.) may have unfavorable effects after pretreatment. Here, we investigated whether injection of polystyrene beads (3- and 6-MUm dia.) as an artificial contaminant of intravenous fluid after lipopolysaccharide (LPS) injection affected mortality and organ damage in mice. METHODS: Mice were divided into four groups and injected: polystyrene beads only, LPS only, polystyrene beads 30 min after LPS, or saline. A survival study, histology, blood examination, and urine examination were performed. RESULTS: The survival rate after LPS and polystyrene bead (6-MUm dia.) injection was significantly lower than that of the other three groups. In the kidney sections, injured glomeruli were significantly higher with LPS and polystyrene bead injection than that of the other three groups. LPS and polystyrene bead injection decreased the glomerular filtration rate and led to renal failure. Inflammatory reactions induced with LPS were not significantly different between with or without polystyrene beads. Polystyrene beads were found in urine after LPS and polystyrene bead injection. CONCLUSIONS: Injection of polystyrene beads after LPS injection enhanced glomerular structural injury and caused renal function injury in a mouse sepsis model. PMID- 25908985 TI - Hyperammonemia due to urea cycle disorders: a potentially fatal condition in the intensive care setting. AB - Disorders of the urea cycle are secondary to a defect in the system that converts ammonia into urea, resulting in accumulation of ammonia and other products. This results in encephalopathy, coma, and death if not recognized and treated rapidly. Late-onset urea cycle disorders may be precipitated by acute disease and can be difficult to recognize because patients are already ill. Diagnosis of urea cycle disorders is based on clinical suspicion and determination of blood ammonia in suspected patients with neurological symptoms in the intensive care setting. Treatment is based on the removal of ammonia by dialysis or hemofiltration, reduction of the catabolic state, abolishment of nitrogen administration, and use of pharmacological nitrogen scavenging agents. PMID- 25908986 TI - Neurological outcomes after extracorporeal cardiopulmonary resuscitation in patients with out-of-hospital cardiac arrest: a retrospective observational study in a rural tertiary care center. AB - BACKGROUND: In a rural region with few medical resources, we have promoted the strategy that if an out-of-hospital cardiac arrest (OHCA) patient is likely reversible, he or she should be transported directly from the scene of cardiac arrest to the only tertiary care center where extracorporeal cardiopulmonary resuscitation (ECPR) is readily available. We investigated 1-month survival and neurological outcomes after ECPR in OHCA patients at this center. METHODS: We implemented a retrospective review of OHCA patients of heterogeneous origin in whom ECPR was performed. Demographic characteristics, cardiopulmonary resuscitation, ECPR details, and neurological outcomes were evaluated. Cerebral performance categories were used to assign each patient to favorable or unfavorable outcome groups. RESULTS: Fifty OHCA patients underwent ECPR. Presumed causes of OHCA were cardiac etiology in 32 patients, accidental hypothermia in 7 patients, and other causes in 11 patients. Overall, 13 patients (26%) survived and 10 patients (20%) had favorable outcomes. Of the 32 patients with OHCA of cardiac origin, 5 patients (16%) had favorable outcomes. Of the seven patients with OHCA of hypothermic origin, five patients (71%) had favorable outcomes. No clinically reliable predictors to identify ECPR candidates were found. However, all nine OHCA patients over 70 years of age had unfavorable outcomes (P = 0.224). In addition, all seven patients who satisfied the basic life support termination of-resuscitation rule had unfavorable outcomes (P = 0.319). CONCLUSIONS: ECPR can be a useful means to rescue OHCA patients who are unresponsive to conventional cardiopulmonary resuscitation in a rural tertiary care center, in a manner similar to that observed in the urban regions. PMID- 25908987 TI - Decrease in cuff pressure during the measurement procedure: an experimental study. AB - BACKGROUND: To prevent endotracheal tube (ETT)-related complications during mechanical ventilation, ETT cuff pressure should be kept within proper range. In clinical settings, cuff pressure often decreases from target values. METHODS: We performed an experimental study to investigate the effects of measuring devices and endotracheal tubes on change in cuff pressure. We continuously measured cuff pressure by inserting a three-way stopcock in the middle of an ETT pilot balloon system. After adjusting the cuff pressure to 24 cmH2O, we disconnected and reconnected each cuff inflator to the inflation valve of the ETT and measured the changes in the cuff pressure. We measured the change in cuff pressure with different ETT sizes, cuff shapes, brands of cuff inflator, and with and without added extension tubes. RESULTS: The cuff pressure decreased, on average, by 6.6 cmH2O (standard deviation 1.9), when connecting the cuff inflator to the pilot balloon. The measured cuff pressure was less than 20 cmH2O in 67% of the tests. The cuff pressure decreased more when an extension tube was used. The brand of cuff inflator made no difference to the pressure loss. The cuff pressure decreased more with ETTs of smaller size and with ETTs with pyriform cuffs. CONCLUSIONS: Procedures to connect cuff inflators to inflation valves resulted in the loss of cuff pressure by 6.6 cmH2O on average. PMID- 25908988 TI - Markedly elevated procalcitonin in early postoperative period in pediatric open heart surgery: a prospective cohort study. AB - BACKGROUND: We encountered markedly elevated procalcitonin (PCT) among pediatric patients during the early postoperative period of open heart surgery. The purpose of this study is to investigate what factors are associated with the PCT elevation. METHODS: Fifty-two pediatric patients undergoing cardiac surgery with cardiopulmonary bypass (CPB) were enrolled. Plasma PCT, aspartate aminotransferase/alanine aminotransferase (AST/ALT), creatinine, lactate, and C reactive protein (CRP) were measured on admission to ICU and during the postoperative period. The patients were categorized into high (group H) and low (group L) groups according to their peak PCT levels. Aorta cross-clamp (ACC), CPB time, ICU stay, mechanical ventilation period, peak AST/ALT, creatinine, lactate, and CRP levels were compared. RESULTS: ACC and CPB times, ICU stay period, and mechanical ventilation period were significantly longer in group H compared with group L (118.7 +/- 51.6 vs. 49.4 +/- 43.5 min, 244.5 +/- 65.7 vs. 122.9 +/- 63.0 min, 7.9 +/- 4.6 vs. 4.0 +/- 4.5 days, and 6.3 +/- 4.1 vs. 2.9 +/- 4.2 days, respectively; p < 0.01). Peak AST and creatinine were significantly higher in group H compared with group L (999.0 +/- 1,990.3 vs. 88.3 +/- 43.0 U/l and 0.84 +/- 0.77 vs. 0.41 +/- 0.17 mg/dl, respectively; p < 0.05). CONCLUSIONS: ACC and CPB time-related perioperative stress is associated with elevated PCT; an association between ICU stay and mechanical ventilation period, liver enzymes, and creatinine levels was observed. PCT may be a good predictor of postoperative severity and organ dysfunction. PMID- 25908989 TI - Association of serum chloride concentration with outcomes in postoperative critically ill patients: a retrospective observational study. AB - BACKGROUND: Although chloride is one of the major electrolytes measured routinely in dairy practice, the amount of attention chloride receives in critically ill patients is limited. There are still a few studies reporting the incidence of derangements of chloride and its association with patients' outcomes. Accordingly, we conducted a retrospective study to assess the prevalence of abnormality of serum chloride level in postoperative patients in the intensive care unit on the early phase of surgery and its association with outcome. METHODS: We conducted a single-center retrospective observational study. All adult patients who underwent elective thoracic or abdominal surgery and required postoperative intensive care for more than 48 h between 2007 and 2011 were included. Chloride levels were measured on each morning of postoperative day 1 and day 2 in the intensive care unit. We defined all-cause hospital death as the primary outcome and compared serum chloride levels on postoperative day 1 and day 2 between hospital survivors and non-survivors. Comparisons among groups were conducted using the chi-square test for equal proportion, Mann-Whitney U tests, or Kruskal-Wallis test. RESULTS: Among 98 patients included in this study, hypochloremia (less than 98 mmol/L) during the first 48 h occurred in 14 patients (14.3%). The mortality in hypochloremia patients was 28.6%, which is significantly higher than 6.0% in patients with normal chloride concentration (p = 0.007). Even after being adjusted for severity of illness, the incidence of hypochloremia was independently associated with the risk of hospital death (adjusted odds ratio 5.8 (1.1, 30.2), p = 0.04). Hyperchloremia (more than 112 mmol/L) occurred in one patient (1.0%), who was discharged from the hospital at day 9. There was no significant difference in the total volume of infused fluid (p = 0.30), sum of chloride administration (p = 0.33), and use of furosemide (p = 0.75) from intensive care unit admission to the morning of postoperative day 2 between survivors and non-survivors. CONCLUSIONS: Hypochloremia observed within 48 h after surgery was not rare and was independently associated with the increased risk of hospital death. Hypochloremia might be a useful indicator of prognosis for patients in the postoperative intensive care unit. PMID- 25908990 TI - The effect of leg compression garments on the mechanical characteristics and performance of single-leg hopping in healthy male volunteers. AB - BACKGROUND: Compression garments (CG) are commonly used by athletes to improve motor performance and recovery during or following exercise. Numerous studies have investigated the effect of CG on physiological and physical parameters with variable results as to their efficacy. A possible effect of commercially available CG may be to induce a change in leg mechanical characteristics during repetitive tasks to fatigue. This investigation determined the effect of CG on performance and vertical stiffness during single-leg-hopping to exhaustion. METHODS: Thirty-eight healthy, male participants, mean (SD) 22.1 (2.8) years of age performed single-leg hopping at 2.2 Hz to volitional exhaustion with a CG, without CG and with a sham. Differences in total duration of hopping (1-way repeated ANOVA) and dependant variables for the start and end periods (2-way repeated ANOVA) including duration of flight (tf), loading (tl) and contact (tc) phases, vertical height displacement during flight (zf) and loading (zl) phases, normalised peak vertical ground reaction force (FzN) and normalised vertical stiffness (k N), were determined. Bonferroni correction was performed to reduce the risk of type 1 error. RESULTS: There was no significant difference (p = 0.73) in the total duration of hopping between conditions (CG (mean (SD)) 89.6 (36.3) s; without CG 88.5 (27.5) s; sham 91.3 (27.7) s). There were no significant differences between conditions for spatiotemporal or kinetic characteristics (p > 0.05). From the start to the end periods there was no significant difference in tl (p = 0.15), significant decrease in tf (p < 0.001), zf and zl (p < 0.001) and increase in tc (p < 0.001). There was also a significant increase in k N from start to end periods (p < 0.01) ranging from 9.6 to 14.2%. CONCLUSIONS: This study demonstrates that commercially available CG did not induce a change in spatiotemporal or vertical stiffness during a fatiguing task. The finding that vertical stiffness increased towards the end of the task, while hopping frequency and duration of loading were maintained, may indicate that there was an alteration to the motor control strategy as fatigue approached. TRIAL REGISTRATION: Current Controlled Trials ACTRN12615000240549. Registered 17 March 2015. PMID- 25908991 TI - Laccase-catalyzed decolorization and detoxification of Acid Blue 92: statistical optimization, microtoxicity, kinetics, and energetics. AB - BACKGROUND: In recent years, enzymatic-assisted removal of hazardous dyes has been considered as an alternative and eco-friendly method compared to those of physicochemical techniques. The present study was designed in order to obtain the optimal condition for laccase-mediated (purified from the ascomycete Paraconiothyrium variabile) decolorization of Acid Blue 92; a monoazo dye, using response surface methodology (RSM). So, a D-optimal design with three variables, including pH, enzyme activity, and dye concentration, was applied to optimize the decolorization process. In addition, the kinetic and energetic parameters of the above mentioned enzymatic removal of Acid Blue 92 was investigated. RESULTS: Decolorization of Acid Blue 92 was maximally (94.1% +/- 2.61) occurred at pH 8.0, laccase activity of 2.5 U/mL, and dye concentration of 75 mg/mL. The obtained results of kinetic and energetic studies introduced the laccase-catalyzed decolorization of Acid Blue 92 as an endothermic reaction (Ea, 39 kJ/mol; DeltaS, 131 J/mol K; and DeltaH, 40 kJ/mol) with K m and V max values of 0.48 mM and 227 mM/min mg, respectively. Furthermore, the results of microtoxicity study revealed that the toxicity of laccase-treated dye was significantly reduced compared to the untreated dye. CONCLUSIONS: To sum up, the present investigation introduced the Paraconiothyrium variabile laccase as an efficient biocatalyst for decolorization of synthetic dye Acid Blue 92. PMID- 25908992 TI - Photocatalytic degradation of Metronidazole with illuminated TiO2 nanoparticles. AB - Metronidazole (MNZ) is a brand of nitroimidazole antibiotic, which is generally used in clinical applications and extensively used for the treatment of infectious diseases caused by anaerobic bacteria and protozoans. The aim of this investigation was to degrade MNZ with illuminated TiO2 nanoparticles at different catalyst dosage, contact time, pH, initial MNZ concentration and lamp intensity. Maximum removal of MNZ was observed at near neutral pH. Removal efficiency was decreased by increasing dosage and initial MNZ concentration. The reaction rate constant (k obs ) was decreased from 0.0513 to 0.0072 min(-1) and the value of electrical energy per order (EEo) was increased from 93.57 to 666.67 (kWh/m(3)) with increasing initial MNZ concentration from 40 to 120 mg/L, respectively. The biodegradability estimated from the BOD5/COD ratio was increased from 0 to 0.098. The photocatalyst demonstrated proper photocatalytic activity even after five successive cycles. Finally, UV/TiO2 is identified as a promising technique for the removal of antibiotic with high efficiency in a relatively short reaction time. PMID- 25908993 TI - Risk assessment of gastric cancer associated with asbestosis: a case report. AB - BACKGROUND: The International Agency for Research on Cancer classifies asbestos as belonging to Carcinogen Group 2A for gastric cancer. We herein report a case of gastric cancer associated with asbestosis and describe the work-related and risk assessments of asbestos exposure for gastric cancer. CASE PRESENTATION: The 66-year-old male patient in our case worked in asbestos spinning factories. His level of cumulated asbestos fiber exposure was estimated to be 38.0-71.0 f-yr/cc. Thus, the Excess Life Cancer Risk for lung cancer associated with asbestos exposure was 9,648*10(-5), almost 9,600 times the value recommended by the United States of America Environmental Protection Agency (1 * 10(-5)). The relative risk of developing lung cancer for this patient was more than 25 f-yr/cc, a well-known criterion for doubling the risk of lung cancer. CONCLUSION: The patient's exposure to high-dose asbestos was sufficient to increase his risk of gastric cancer because as the risk of lung cancer increased, the risk of gastric cancer was due to increase as well. Therefore, occupational asbestos fiber exposure might be associated with gastric cancer in this case. PMID- 25908994 TI - Identification of nasal colonization with beta-lactamase-producing Enterobacteriaceae in patients, health care workers and students in Madagascar. AB - This study assesses the nasal occurrence of beta-lactamase-producing Enterobacteriaceae both in patients in a hospital department of infectious diseases at admission and in healthy Madagascan students and health care workers. Nasal swabs from 681 students, 824 health care workers, and 169 patients were obtained in Antananarivo, Madagascar, and transferred to Germany. Screening for beta-lactamase (ESBL, ampC) producing Enterobacteriaceae was performed by cultural and molecular approaches, comprising Brilliance ESBL agar, E-testing, ABCD-testing, and commercial hyplex ESBL and SuperBug ID PCR. Regarding ESBL positive strains and strains with resistance against at least three out of the four tested bactericidal antibiotic drugs, 0.3% (five out of 1541) of the students and health care workers group showed nasal colonization, whereas colonization was observed in 7.1% (12 out of 169) of the hospitalized patients at admission. No appreciably reduced detection rates after sample storage and intercontinental transport were observed. A considerable proportion of nasal colonization with cephalosporin-resistant Enterobacteriaceae was demonstrated in Madagascan hospital patients at admission, posing a risk of developing future endogenous infections. The nasal colonization of healthy individuals was negligible. Good storage and transport stability of Enterobacteriaceae will allow for future studies even in areas difficult to access. PMID- 25908995 TI - Response to Pneumococcal Polysaccharide Vaccination in Newly Diagnosed HIV Positive Individuals. AB - BACKGROUND: Newly diagnosed HIV-positive individuals are 35 to 100-fold more susceptible to Streptococcus pneumoniae infection compared to non-infected individuals. Therefore, the 23-valent pneumococcal polysaccharide vaccine (PPV23) has previously been recommended, though efficacy and effectiveness of vaccination remains controversial. Early severe B cell dysfunction is a central feature of HIV infection. The specific nature of the immune cells involved in the production of protective antigen-specific antibodies in HIV-positive individuals remains to be elucidated. OBJECTIVES: Evaluate the antibody and antigen-specific B cell response to the 23-valent pneumococcal polysaccharide vaccine in newly diagnosed HIV-positive patients. Moreover, determine if newly diagnosed patients with CD4<200 cells/MUl benefit from 6-12 months of HAART, allowing partial viral suppression and immune reconstitution, prior to immunization. METHODS: Newly diagnosed HIV-positive patients with CD4>200 cells/MUl and CD4<200 cells/MUl were immunized with PPV23. Patients with CD4<200 cells/MUl received either immediate or delayed immunization following 6-12 months of HAART. Antibody responses, opsonophagocytic activity and phenotypic analysis of pneumococcal polysaccharide specific B cells were studied. RESULTS: Newly diagnosed HIV-positive patients demonstrated CD4-dependent increases in antibody and opsonophagocytic titers thought to be commensurate with protection. Functional opsonophagocytic titers of patients with CD4<200 cells/MUl immunized immediately compared to patients with CD4<200 cells/MUl receiving HAART for 6-12 months were not significantly different. Pneumococcal polysaccharide-specific B cells were distributed evenly between IgM memory and switched memory B cells for all groups, but IgM memory B cells were significantly lower than in HIV-negative individuals. CONCLUSIONS: Despite CD4-dependent pneumococcal polysaccharide-specific deficiencies in newly diagnosed HIV-positive patients, vaccination was beneficial based on opsonophagocytic titers for all newly diagnosed HIV-positive groups. In HIV positive patients with CD4<200 cells/MUl, 6-12 months of HAART did not improve opsonophagocytic titers or antibody concentrations. Based on these findings, immunization with the 23-valent pneumococcal polysaccharide vaccine should not be delayed in newly diagnosed HIV-positive patients with CD4<200 cells/MUl. PMID- 25908996 TI - Response to Pneumococcal Polysaccharide Vaccination in HIV-Positive Individuals on Long Term Highly Active Antiretroviral Therapy. AB - BACKGROUND AND OBJECTIVES: Streptococcus pneumoniae continues to cause serious infections in HIV-positive individuals in the era of highly active anti retroviral therapy. This led to the recommendation to revaccinate HIV-positive individuals with PPV23 five years after primary vaccination. The benefits of revaccination and the impact of long term highly active anti-retroviral therapy (HAART) on antigen-specific B cell reconstitution have remained unclear thus far and were investigated. DESIGN AND METHODS: We assessed antibody levels, opsonophagocytic activity and phenotype of pneumococcal polysaccharide (PPS) specific-B cells post-revaccination in long term HAART cohorts stratified according to CD4 count as group A (CD4>200) and group B (CD4<200). Anti-PPS IgG, IgM and functional antibody response against vaccine serotypes 14 and 23F were measured by ELISA and opsonophagocytic assay followed by phenotypic analysis of PPS14 and 23F-specific B cells using fluorescently labeled PPS. RESULTS: Significant increases in total and functional antibody titers were noted in groups A and B post-vaccination concomitant with significant rise in PPS-specific IgM memory B cells, a critical B cell subset required for protection against PPS although the overall response remained significantly diminished compared to HIV negative volunteers. CONCLUSION: Comparable increases in opsonophagocytic titers between study groups A and B concomitant with a comparable rise in PPS-specific IgM memory B cells indicate revaccination to be beneficial regardless of the degree of CD4 T cell reconstitution. These findings emphasize the importance of defining effective vaccination practices amongst high-risk individuals. PMID- 25908997 TI - Analyzing three-dimensional ultrastructure of human cervical tissue using optical coherence tomography. AB - During pregnancy, the uterine cervix is the mechanical barrier that prevents delivery of a fetus. The underlying cervical collagen ultrastructure, which influences the overall mechanical properties of the cervix, plays a role in maintaining a successful pregnancy until term. Yet, not much is known about this collagen ultrastructure in pregnant and nonpregnant human tissue. We used optical coherence tomography to investigate the directionality and dispersion of collagen fiber bundles in the human cervix. An image analysis tool has been developed, combining a stitching method with a fiber orientation measurement, to study axially sliced cervix samples. This tool was used to analyze the ultrastructure of ex-vivo pregnant and non-pregnant hysterectomy tissue samples taken at the internal os, which is the region of the cervix adjacent to the uterus. With this tool, directionality maps of collagen fiber bundles and dispersion of collagen fiber orientation were analyzed. It was found that that the overall preferred directionality of the collagen fibers for both the nonpregnant and pregnant samples were circling around the inner cervical canal. Pregnant samples showed greater dispersion than non-pregnant samples. Lastly, we observed regional differences in collagen fiber dispersion. Fibers closer to the inner canal showed more dispersion than the fibers on the radial edges. PMID- 25908998 TI - Q-r curve of thermal tomography and its clinical application on breast tumor diagnosis. AB - Heat is the product following the metabolism of cells, and the metabolism is closely related with the pathological information of living organism. So, there are strong ties between the heat distribution and the pathological state in living organism. In this paper, the mathematical function delta is introduced in the classical Pennes bio-heat transfer equation as the point heat source. By simplifying the boundary conditions, a novel bio-heat transfer model is established and solved in a spherical coordinate system. Based on the temperature distribution of human body surface, the information of heat source is mined layer by layer, and the corresponding q-r curve of heat intensity varying with depth is acquired combining the fitting method of Lorentz curve. According to a large number of clinical confirmed cases and statistics, the diagnostic criteria judging diseases by q-r curve are proposed. Five typical clinical practices are performed and four of the diagnosis results are very consistent with those of molybdenum target (MT) X-ray, B-ultrasonic images and pathological examination, one gives the result of early stage malignant tumor that MT X-ray and B ultrasonic can't check out. It is a radiation-free green method with noninvasive diagnostic procedure and accurate diagnosis result. PMID- 25908999 TI - Anisotropic aberration correction using region of interest based digital adaptive optics in Fourier domain OCT. AB - In this paper a numerical technique is presented to compensate for anisotropic optical aberrations, which are usually present across the lateral field of view in the out of focus regions, in high resolution optical coherence tomography and microscopy (OCT/OCM) setups. The recorded enface image field at different depths in the tomogram is digitally divided into smaller sub-regions or the regions of interest (ROIs), processed individually using subaperture based digital adaptive optics (DAO), and finally stitched together to yield a final image with a uniform diffraction limited resolution across the entire field of view (FOV). Using this method, a sub-micron lateral resolution is achieved over a depth range of 218 [Formula: see text]for a nano-particle phantom sample imaged using a fiber based point scanning spectral domain (SD) OCM system with a limited depth of focus (DOF) of ~7 [Formula: see text]at a numerical aperture (NA) of 0.6. Thus, an increase in DOF by ~30x is demonstrated in this case. The application of this method is also shown in ex vivo mouse adipose tissue. PMID- 25909000 TI - Identification of cancerous gastric cells based on common features extracted from hyperspectral microscopic images. AB - We construct a microscopic hyperspectral imaging system to distinguish between normal and cancerous gastric cells. We study common transmission-spectra features that only emerge when the samples are dyed with hematoxylin and eosin (H&E) stain. Subsequently, we classify the obtained visible-range transmission spectra of the samples into three zones. Distinct features are observed in the spectral responses between the normal and cancerous cell nuclei in each zone, which depend on the pH level of the cell nucleus. Cancerous gastric cells are precisely identified according to these features. The average cancer-cell identification accuracy obtained with a backpropagation algorithm program trained with these features is 95%. PMID- 25909001 TI - Ultrahigh speed en face OCT capsule for endoscopic imaging. AB - Depth resolved and en face OCT visualization in vivo may have important clinical applications in endoscopy. We demonstrate a high speed, two-dimensional (2D) distal scanning capsule with a micromotor for fast rotary scanning and a pneumatic actuator for precision longitudinal scanning. Longitudinal position measurement and image registration were performed by optical tracking of the pneumatic scanner. The 2D scanning device enables high resolution imaging over a small field of view and is suitable for OCT as well as other scanning microscopies. Large field of view imaging for screening or surveillance applications can also be achieved by proximally pulling back or advancing the capsule while scanning the distal high-speed micromotor. Circumferential en face OCT was demonstrated in living swine at 250 Hz frame rate and 1 MHz A-scan rate using a MEMS tunable VCSEL light source at 1300 nm. Cross-sectional and en face OCT views of the upper and lower gastrointestinal tract were generated with precision distal pneumatic longitudinal actuation as well as proximal manual longitudinal actuation. These devices could enable clinical studies either as an adjunct to endoscopy, attached to an endoscope, or as a swallowed tethered capsule for non-endoscopic imaging without sedation. The combination of ultrahigh speed imaging and distal scanning capsule technology could enable both screening and surveillance applications. PMID- 25909002 TI - Miniature forward-viewing common-path OCT probe for imaging the renal pelvis. AB - We demonstrate an ultrathin flexible cone-scanning forward-viewing OCT probe which can fit through the working channel of a flexible ureteroscope for renal pelvis imaging. The probe is fabricated by splicing a 200 um section of core-less fiber and a 150 um section of gradient-index (GRIN) fiber to the end of a single mode (SM) fiber. The probe is designed for common-path OCT imaging where the back reflection of the GRIN fiber/air interface is used as the reference signal. Optimum sensitivity was achieved with a 2 degree polished probe tip. A correlation algorithm was used to correct image distortion caused by non-uniform rotation of the probe. The probe is demonstrated by imaging human skin in vivo and porcine renal pelvis ex vivo and is suitable for imaging the renal pelvis in vivo for cancer staging. PMID- 25909003 TI - Kernel regression based segmentation of optical coherence tomography images with diabetic macular edema. AB - We present a fully automatic algorithm to identify fluid-filled regions and seven retinal layers on spectral domain optical coherence tomography images of eyes with diabetic macular edema (DME). To achieve this, we developed a kernel regression (KR)-based classification method to estimate fluid and retinal layer positions. We then used these classification estimates as a guide to more accurately segment the retinal layer boundaries using our previously described graph theory and dynamic programming (GTDP) framework. We validated our algorithm on 110 B-scans from ten patients with severe DME pathology, showing an overall mean Dice coefficient of 0.78 when comparing our KR + GTDP algorithm to an expert grader. This is comparable to the inter-observer Dice coefficient of 0.79. The entire data set is available online, including our automatic and manual segmentation results. To the best of our knowledge, this is the first validated, fully-automated, seven-layer and fluid segmentation method which has been applied to real-world images containing severe DME. PMID- 25909004 TI - Efficient method to suppress artifacts caused by tissue hyper-reflections in optical microangiography of retina in vivo. AB - Optical microangiography (OMAG) is an optical coherence tomography (OCT)-based imaging technique that is capable of achieving the angiographic imaging of biological tissues in vivo with a high imaging resolution and no need for dye injection. OMAG has a potential to become a clinical tool for the diagnosis and treatment monitoring of various retinopathies. In principle, OMAG extracts blood flow information based on a direct differentiation of complex or intensity OCT signals between repeated B-scans acquired at the same cross section, which is sensitive to blood cell movement. In practice, this method is prone to artifacts due to tissue hyper-reflection, commonly seen in retinal diseases such as diabetic retinopathy. In this paper, we propose a novel method to suppress the artifacts induced by hyper-reflection. We propose to scale OMAG flow signals by a weighting factor that is motion-sensitive but hyper-reflection insensitive. We show that this simple weighting approach is effective in suppressing the artifacts due to tissue hyper-reflections while still maintaining the detected capillary networks with high fidelity, especially in deeper retina. The effectiveness of the proposed technique is demonstrated by a phantom study and case studies on patients' eyes with hyper-reflective foci. Finally we discuss potential applications of this technique. PMID- 25909005 TI - Evaluation of area-based collagen scoring by nonlinear microscopy in chronic hepatitis C-induced liver fibrosis. AB - In this paper we analyze a fibrosis scoring method based on measurement of the fibrillar collagen area from second harmonic generation (SHG) microscopy images of unstained histological slices from human liver biopsies. The study is conducted on a cohort of one hundred chronic hepatitis C patients with intermediate to strong Metavir and Ishak stages of liver fibrosis. We highlight a key parameter of our scoring method to discriminate between high and low fibrosis stages. Moreover, according to the intensity histograms of the SHG images and simple mathematical arguments, we show that our area-based method is equivalent to an intensity-based method, despite saturation of the images. Finally we propose an improvement of our scoring method using very simple image processing tools. PMID- 25909007 TI - Influence of absorption induced thermal initiation pathway on irradiance threshold for laser induced breakdown. AB - We investigated the influence of thermal initiation pathway on the irradiance threshold for laser induced breakdown in transparent, absorbing and scattering phantoms. We observed a transition from laser-induced optical breakdown to laser induced thermal breakdown as the absorption coefficient of the medium is increased. We found that the irradiance threshold after correction for the path length dependent absorption and scattering losses in the medium is lower due to the thermal pathway for the generation of seed electrons compared to the laser induced optical breakdown. Furthermore, irradiance threshold gradually decreases with the increase in the absorption properties of the medium. Creating breakdown with lower irradiance threshold that is specific at the target chromophore can provide intrinsic target selectivity and improve safety and efficacy of skin treatment methods that use laser induced breakdown. PMID- 25909006 TI - Spectral and lifetime domain measurements of rat brain tumors. AB - During glioblastoma surgery, delineation of the brain tumor margins is difficult because the infiltrated and normal tissues have the same visual appearance. We use a fiber-optical fluorescence probe for spectroscopic and time domain measurements to assist surgeon in differentiating the healthy and the infiltrated tissues. First study was performed on rats that were previously injected with tumorous cells. Measurements of endogenous tissue fluorescence were performed on fresh and fixed rat tumor brain slices. Spectral characteristics, fluorescence redox ratios and fluorescence lifetime measurements were analyzed. The study aimed at defining an optical index that can act as an indicator for discriminating healthy from tumorous tissue. PMID- 25909008 TI - High speed, line-scanning, fiber bundle fluorescence confocal endomicroscopy for improved mosaicking. AB - A significant limitation of fiber bundle endomicroscopy systems is that the field of view tends to be small, usually only several hundred micrometers in diameter. Image mosaicking techniques can increase the effective image size, but require careful manipulation of the probe to ensure sufficient overlap between adjacent frames. For confocal endomicroscopes, which typically have frame rates on the order of 10 fps, this is particularly challenging. In this paper we demonstrate that line-scanning confocal endomicroscopy can, by use of a high speed linear CCD camera, achieve a frame rate of 120 fps while maintaining sufficient resolution and signal-to-noise ratio to allow imaging of topically stained gastrointestinal tissues. This leads to improved performance of a cross-correlation based mosaicking algorithm when compared with lower frame-rate systems. PMID- 25909009 TI - Mesoscopic in vivo 3-D tracking of sparse cell populations using angular multiplexed optical projection tomography. AB - We describe an angular multiplexed imaging technique for 3-D in vivo cell tracking of sparse cell distributions and optical projection tomography (OPT) with superior time-lapse resolution and a significantly reduced light dose compared to volumetric time-lapse techniques. We demonstrate that using dual axis OPT, where two images are acquired simultaneously at different projection angles, can enable localization and tracking of features in 3-D with a time resolution equal to the camera frame rate. This is achieved with a 200x reduction in light dose compared to an equivalent volumetric time-lapse single camera OPT acquisition with 200 projection angles. We demonstrate the application of this technique to mapping the 3-D neutrophil migration pattern observed over ~25.5 minutes in a live 2 day post-fertilisation transgenic LysC:GFP zebrafish embryo following a tail wound. PMID- 25909010 TI - Superresolved labeling nanoscopy based on temporally flickering nanoparticles and the K-factor image deshadowing. AB - Localization microscopy provides valuable insights into cellular structures and is a rapidly developing field. The precision is mainly limited by additive noise and the requirement for single molecule imaging that dictates a low density of activated emitters in the field of view. In this paper we present a technique aimed for noise reduction and improved localization accuracy. The method has two steps; the first is the imaging of gold nanoparticles that labels targets of interest inside biological cells using a lock-in technique that enables the separation of the signal from the wide spread spectral noise. The second step is the application of the K-factor nonlinear image decomposition algorithm on the obtained image, which improves the localization accuracy that can reach 5nm and enables the localization of overlapping particles at minimal distances that are closer by 65% than conventional methods. PMID- 25909011 TI - Assessing breast tumor margin by multispectral photoacoustic tomography. AB - An unmet need exists in high-speed and highly-sensitive intraoperative assessment of breast cancer margin during conservation surgical procedures. Here, we demonstrate a multispectral photoacoustic tomography system for breast tumor margin assessment using fat and hemoglobin as contrasts. This system provides ~3 mm tissue depth and ~125 MUm axial resolution. The results agreed with the histological findings. A high sensitivity in margin assessment was accomplished, which opens a compelling way to intraoperative margin assessment. PMID- 25909012 TI - Straylight, lens yellowing and aberrations of eyes in Type 1 diabetes. AB - Straylight, lens yellowing and ocular aberrations were assessed in a group of people with type 1 diabetes and in an age matched control group. Most of the former had low levels of neuropathy. Relative to the control group, the type 1 diabetes group demonstrated greater straylight, greater lens yellowing, and differences in some higher-order aberration co-efficients without significant increase in root-mean-square higher-order aberrations. Differences between groups did not increase significantly with age. The results are similar to the findings for ocular biometry reported previously for this group of participants, and suggest that age-related changes in the optics of the eyes of people with well controlled diabetes need not be accelerated. PMID- 25909013 TI - Laser tissue coagulation and concurrent optical coherence tomography through a double-clad fiber coupler. AB - Double-clad fiber (DCF) is herein used in conjunction with a double-clad fiber coupler (DCFC) to enable simultaneous and co-registered optical coherence tomography (OCT) and laser tissue coagulation. The DCF allows a single channel fiber-optic probe to be shared: i.e. the core propagating the OCT signal while the inner cladding delivers the coagulation laser light. We herein present a novel DCFC designed and built to combine both signals within a DCF (>90% of single-mode transmission; >65% multimode coupling). Potential OCT imaging degradation mechanisms are also investigated and solutions to mitigate them are presented. The combined DCFC-based system was used to induce coagulation of an ex vivo swine esophagus allowing a real-time assessment of thermal dynamic processes. We therefore demonstrate a DCFC-based system combining OCT imaging with laser coagulation through a single fiber, thus enabling both modalities to be performed simultaneously and in a co-registered manner. Such a system enables endoscopic image-guided laser marking of superficial epithelial tissues or laser thermal therapy of epithelial lesions in pathologies such as Barrett's esophagus. PMID- 25909014 TI - Nodal lymph flow quantified with afferent vessel input function allows differentiation between normal and cancer-bearing nodes. AB - Morbidity and complexity involved in lymph node staging via surgical resection and biopsy could ideally be improved using node assay techniques that are non invasive. While visible blue dyes are often used to locate the sentinel lymph nodes from draining lymphatic vessels near a tumor, they do not provide an in situ metric to evaluate presence of cancer. In this study, the transport kinetics of methylene blue were analyzed to determine the potential for better in situ information about metastatic involvement in the nodes. A rat model with cancer cells in the axillary lymph nodes was used, with methylene blue injection to image the fluorescence kinetics. The lymphatic flow from injection sites to nodes was imaged and the relative kinetics from feeding lymphatic ducts relative to lymph nodes was quantified. Large variability existed in raw fluorescence and transport patterns within each cohort resulting in no systematic difference between average nodal uptake in normal, sham control and cancer-bearing nodes. However, when the signal from the afferent lymph vessel fluorescence was used to normalize the signal of the lymph nodes, the high signal heterogeneity was reduced. Using a model, the lymph flow through the nodes [Formula: see text] was estimated to be 1.49 +/- 0.64 ml/g/min in normal nodes, 1.53 +/- 0.45 ml/g/min in sham control nodes, and reduced to 0.50 +/- 0.24 ml/g/min in cancer-cell injected nodes. This summarizes the significant difference (p = 0.0002) between cancer free and cancer-bearing nodes in normalized flow. This process of normalized flow imaging could be used as an in situ tool to detect metastatic involvement in nodes. PMID- 25909015 TI - Characterizing the beam steering and distortion of Gaussian and Bessel beams focused in tissues with microscopic heterogeneities. AB - Bessel beams have recently been investigated as a means of improving deep-tissue microscopy in highly scattering and heterogeneous media. It has been suggested that the long depth-of-field and self-reconstructing property of a Bessel beam enables an increased penetration depth of the focused beam in tissues compared to a conventional Gaussian beam. However, a study is needed to better quantify the magnitude of the beam steering as well as the distortion of focused Gaussian and Bessel beams in tissues with microscopic heterogeneities. Here, we have developed an imaging method and quantitative metrics to evaluate the motion and distortion of low-numerical-aperture (NA) Gaussian and Bessel beams focused in water, heterogeneous phantoms, and fresh mouse esophagus tissues. Our results indicate that low-NA Bessel beams exhibit reduced beam-steering artifacts and distortions compared to Gaussian beams, and are therefore potentially useful for microscopy applications in which pointing accuracy and beam quality are critical, such as dual-axis confocal (DAC) microscopy. PMID- 25909016 TI - Spectral discrimination between healthy people and cold patients using spontaneous photon emission. AB - In this paper, ultra-weak photon emission (UPE) was used to distinguish cold patients from healthy subjects. The UPE intensity of fingertips of two hands from healthy subjects and cold patients was measured using a two-hand UPE detecting system and a group of cut-off filters. We found a significant difference in the maximum spectral peak and photon emission ratio between the filter of 550nm and 495nm, which can be used in distinguish cold patients from healthy people. Methods and results in this work could be useful for developing a new optical diagnostic tool for early disease diagnosis in the future. PMID- 25909017 TI - High-performance multi-megahertz optical coherence tomography based on amplified optical time-stretch. AB - As the key prerequisite of high-speed volumetric structural and functional tissue imaging in real-time, scaling the A-scan rate beyond MHz has been one of the major pursuits in the development of optical coherence tomography (OCT). Along with a handful of techniques enabling multi-MHz, amplified optical time-stretch OCT (AOT-OCT) has recently been demonstrated as a viable alternative for ultrafast swept-source OCT well above MHz without the need for the mechanical wavelength-tuning mechanism. In this paper, we report a new generation of AOT-OCT demonstrating superior performance to its older generation and all other time stretch-based OCT modalities in terms of shot-to-shot stability, sensitivity (~90dB), roll-off performance (>4 mm/dB) and A-scan rate (11.5 MHz). Such performance is mainly attributed to the combined contribution from the stable operation of the broadband and compact mode-locked fiber laser as well as the optical amplification in-line with the time-stretch process. The system allows us, for the first time, to deliver volumetric time-stretch-based OCT of biological tissues with the single-shot A-scan rate beyond 10 MHz. Comparing with the existing high-speed OCT systems, the inertia-free AOT-OCT shows promises to realize high-performance 3D OCT imaging at video rate. PMID- 25909019 TI - A new strategy for label-free detection of lymphoma cancer cells. AB - In this paper, a new strategy for highly selective and sensitive direct detection of lymphoma cells by exploiting the interaction between a peptide and its B-cell receptor, has been evaluated. In particular, an idiotype peptide, able to specifically bind the B-cell receptor of A20 cells in mice engrafted with A20 lymphoma, has been used as molecular probe. The new detection technique has been demonstrated on a planar crystalline silicon chip. Coverage of 85% of silicon surface and detection efficiency of 8.5 * 10(-3) cells/MUm(2) were obtained. The recognition strategy promises to extend its application in studying the interaction between ligands and their cell-surface receptors. PMID- 25909020 TI - Ex vivo catheter-based imaging of coronary atherosclerosis using multimodality OCT and NIRAF excited at 633 nm. AB - While optical coherence tomography (OCT) has been shown to be capable of imaging coronary plaque microstructure, additional chemical/molecular information may be needed in order to determine which lesions are at risk of causing an acute coronary event. In this study, we used a recently developed imaging system and double-clad fiber (DCF) catheter capable of simultaneously acquiring both OCT and red excited near-infrared autofluorescence (NIRAF) images (excitation: 633 nm, emission: 680nm to 900nm). We found that NIRAF is elevated in lesions that contain necrotic core - a feature that is critical for vulnerable plaque diagnosis and that is not readily discriminated by OCT alone. We first utilized a DCF ball lens probe and a bench top setup to acquire en face NIRAF images of aortic plaques ex vivo (n = 20). In addition, we used the OCT-NIRAF system and fully assembled catheters to acquire multimodality images from human coronary arteries (n = 15) prosected from human cadaver hearts (n = 5). Comparison of these images with corresponding histology demonstrated that necrotic core plaques exhibited significantly higher NIRAF intensity than other plaque types. These results suggest that multimodality intracoronary OCT-NIRAF imaging technology may be used in the future to provide improved characterization of coronary artery disease in human patients. PMID- 25909021 TI - Complete 360 degrees circumferential gonioscopic optical coherence tomography imaging of the iridocorneal angle. AB - Clinically, gonioscopy is used to provide en face views of the ocular angle. The angle has been imaged with optical coherence tomography (OCT) through the corneoscleral limbus but is currently unable to image the angle from within the ocular anterior chamber. We developed a novel gonioscopic OCT system that images the angle circumferentially from inside the eye through a custom, radially symmetric, gonioscopic contact lens. We present, to our knowledge, the first 360 degrees circumferential volumes (two normal subjects, two subjects with pathology) of peripheral iris and iridocorneal angle structures obtained via an internal approach not typically available in the clinic. PMID- 25909022 TI - Dispersion compensation in three-photon fluorescence microscopy at 1,700 nm. AB - Signal generation in three-photon microscopy is proportional to the inverse squared of the pulse width. Group velocity dispersion is anomalous for water as well as many glasses near the 1,700 nm excitation window, which makes dispersion compensation using glass prism pairs impractical. We show that the high normal dispersion of a silicon wafer can be conveniently used to compensate the dispersion of a 1,700 nm excitation three-photon microscope. We achieved over a factor of two reduction in pulse width at the sample, which corresponded to over a 4x increase in the generated three-photon signal. This signal increase was demonstrated during in vivo experiments near the surface of the mouse brain as well as 900 MUm below the surface. PMID- 25909023 TI - Feasibility of terahertz reflectometry for discrimination of human early gastric cancers. AB - We have investigated the feasibility of THz time-domain reflectometry for the discrimination of human early gastric cancer (EGC) from the normal gastric region. Eight fresh EGC tissues, which were resected by endoscopic submucosal dissection, were studied. Of them, six lesions were well discriminated on THz images and the regions well correlated with tumor regions on pathologically mapped images. Four THz parameters could be suggested for quantitative discrimination of EGCs. PMID- 25909024 TI - Imaging of retinal vasculature using adaptive optics SLO/OCT. AB - We use our previously developed adaptive optics (AO) scanning laser ophthalmoscope (SLO)/ optical coherence tomography (OCT) instrument to investigate its capability for imaging retinal vasculature. The system records SLO and OCT images simultaneously with a pixel to pixel correspondence which allows a direct comparison between those imaging modalities. Different field of views ranging from 0.8 degrees x0.8 degrees up to 4 degrees x4 degrees are supported by the instrument. In addition a dynamic focus scheme was developed for the AO-SLO/OCT system in order to maintain the high transverse resolution throughout imaging depth. The active axial eye tracking that is implemented in the OCT channel allows time resolved measurements of the retinal vasculature in the en-face imaging plane. Vessel walls and structures that we believe correspond to individual erythrocytes could be visualized with the system. PMID- 25909025 TI - Real-time tissue differentiation based on optical emission spectroscopy for guided electrosurgical tumor resection. AB - Complete surgical removal of cancer tissue with effective preservation of healthy tissue is one of the most important challenges in modern oncology. We present a method for real-time, in situ differentiation of tissue based on optical emission spectroscopy (OES) performed during electrosurgery not requiring any biomarkers, additional light sources or other excitation processes. The analysis of the optical emission spectra, enables the differentiation of healthy and tumorous tissue. By using multi-class support vector machine (SVM) algorithms, distinguishing between tumor types also seems to be possible. Due to its fast reaction time (0.05s) the method can be used for real-time navigation helping the surgeon achieve complete resection. The system's easy realization has been proven by successful integration in a commercial electro surgical unit (ESU). In a first step the method was verified by using ex vivo tissue samples. The histological analysis confirmed, 95% of correctly classified tissue types. PMID- 25909026 TI - Quantitative microvascular hemoglobin mapping using visible light spectroscopic Optical Coherence Tomography. AB - Quantification of chromophore concentrations in reflectance mode remains a major challenge for biomedical optics. Spectroscopic Optical Coherence Tomography (SOCT) provides depth-resolved spectroscopic information necessary for quantitative analysis of chromophores, like hemoglobin, but conventional SOCT analysis methods are applicable only to well-defined specular reflections, which may be absent in highly scattering biological tissue. Here, by fitting of the dynamic scattering signal spectrum in the OCT angiogram using a forward model of light propagation, we quantitatively determine hemoglobin concentrations directly. Importantly, this methodology enables mapping of both oxygen saturation and total hemoglobin concentration, or alternatively, oxyhemoglobin and deoxyhemoglobin concentration, simultaneously. Quantification was verified by ex vivo blood measurements at various pO2 and hematocrit levels. Imaging results from the rodent brain and retina are presented. Confounds including noise and scattering, as well as potential clinical applications, are discussed. PMID- 25909027 TI - Temporal and spatial temperature distributions on glabrous skin irradiated by a 1940 nm continuous-wave laser stimulator. AB - For predicting pain stimulation effects and avoiding damage in 1940nm laser evoked potentials (LEPs) experiments, a 2-layer finite element model (FEM-2) was constructed. A series of experiments were conducted on ex-vivo pig skin pieces to verify temperature distribution predicted by this model. Various laser powers and beam radii were employed. Experimental data of time-dependent temperature responses in different sub-skin depths and space-dependent surface temperature was recorded by thermocouple instrument. By comparing with the experimental data and model results, FEM-2 model was proved to predict temperature distributions accurately. A logarithmic relationship between laser power density and temperature increment was revealed by the results. It is concluded that power density is an effective parameter to estimate pain and damage effect. The obtained results also indicated that the proposed FEM-2 model can be extended to predict pain and damage thresholds of human skin samples and thus contribute to LEPs study. PMID- 25909028 TI - Differential diagnosis of human bladder mucosa pathologies in vivo with cross polarization optical coherence tomography. AB - Quantitative image analysis and parameter extraction using a specific implementation of polarization-sensitive optical coherence tomography (OCT) provides differential diagnosis of mucosal pathologies in in-vivo human bladders. We introduce a cross-polarization (CP) OCT image metric called Integral Depolarization Factor (IDF) to enable automatic diagnosis of bladder conditions (assessment the functional state of collagen fibers). IDF-based diagnostic accuracy of identification of the severe fibrosis of normal bladder mucosa is 79%; recurrence of carcinoma on the post-operative scar is 97%; and differentiation between neoplasia and acute inflammation is 75%. The promising potential of CP OCT combined with image analysis in human urology is thus demonstrated in vivo. PMID- 25909029 TI - Long-term two-photon neuroimaging with a photostable AIE luminogen. AB - In neuroscience, fluorescence labeled two-photon microscopy is a promising tool to visualize ex vivo and in vivo tissue morphology, and track dynamic neural activities. Specific and highly photostable fluorescent probes are required in this technology. However, most fluorescent proteins and organic fluorophores suffer from photobleaching, so they are not suitable for long-term imaging and observation. To overcome this problem, we utilize tetraphenylethene triphenylphosphonium (TPE-TPP), which possesses aggregation-induced emission (AIE) and two-photon fluorescence characteristics, for neuroimaging. The unique AIE feature of TPE-TPP makes its nanoaggregates resistant to photobleaching, which is useful to track neural cells and brain-microglia for a long period of time. Two-photon fluorescence of TPE-TPP facilitates its application in deep in vivo neuroimaging, as demonstrated in the present paper. PMID- 25909030 TI - Measuring the optical characteristics of medulloblastoma with optical coherence tomography. AB - Medulloblastoma is the most common malignant pediatric brain tumor. Standard treatment consists of surgical resection, followed by radiation and high-dose chemotherapy. Despite these efforts, recurrence is common, leading to reduced patient survival. Even with successful treatment, there are often severe long term neurologic impacts on the developing nervous system. We present two quantitative techniques that use a high-resolution optical imaging modality: optical coherence tomography (OCT) to measure refractive index, and the optical attenuation coefficient. To the best of our knowledge, this study is the first to demonstrate OCT analysis of medulloblastoma. Refractive index and optical attenuation coefficient were able to differentiate between normal brain tissue and medulloblastoma in mouse models. More specifically, optical attenuation coefficient imaging of normal cerebellum displayed layers of grey matter and white matter, which were indistinguishable in the structural OCT image. The morphology of the tumor was distinct in the optical attenuation coefficient imaging. These inherent properties may be useful during neurosurgical intervention to better delineate tumor boundaries and minimize resection of normal tissue. PMID- 25909031 TI - Broadband miniature optical ultrasound probe for high resolution vascular tissue imaging. AB - An all-optical ultrasound probe for vascular tissue imaging was developed. Ultrasound was generated by pulsed laser illumination of a functionalized carbon nanotube composite coating on the end face of an optical fiber. Ultrasound was detected with a Fabry-Perot (FP) cavity on the end face of an adjacent optical fiber. The probe diameter was < 0.84 mm and had an ultrasound bandwidth of ~20 MHz. The probe was translated across the tissue sample to create a virtual linear array of ultrasound transmit/receive elements. At a depth of 3.5 mm, the axial resolution was 64 um and the lateral resolution was 88 um, as measured with a carbon fiber target. Vascular tissues from swine were imaged ex vivo and good correspondence to histology was observed. PMID- 25909032 TI - Development of a graded index microlens based fiber optical trap and its characterization using principal component analysis. AB - We demonstrate a miniaturized single beam fiber optical trapping probe based on a high numerical aperture graded index (GRIN) micro-objective lens. This enables optical trapping at a distance of 200MUm from the probe tip. The fiber trapping probe is characterized experimentally using power spectral density analysis and an original approach based on principal component analysis for accurate particle tracking. Its use for biomedical microscopy is demonstrated through optically mediated immunological synapse formation. PMID- 25909033 TI - Polarized light spatial frequency domain imaging for non-destructive quantification of soft tissue fibrous structures. AB - The measurement of soft tissue fiber orientation is fundamental to pathophysiology and biomechanical function in a multitude of biomedical applications. However, many existing techniques for quantifying fiber structure rely on transmitted light, limiting general applicability and often requiring tissue processing. Herein, we present a novel wide-field reflectance-based imaging modality, which combines polarized light imaging (PLI) and spatial frequency domain imaging (SFDI) to rapidly quantify preferred fiber orientation on soft collagenous tissues. PLI utilizes the polarization dependent scattering property of fibers to determine preferred fiber orientation; SFDI imaging at high spatial frequency is introduced to reject the highly diffuse photons and to control imaging depth. As a result, photons scattered from the superficial layer of a multi-layered sample are highlighted. Thus, fiber orientation quantification can be achieved for the superficial layer with optical sectioning. We demonstrated on aortic heart valve leaflet that, at spatial frequency of f = 1mm( 1) , the diffuse background can be effectively rejected and the imaging depth can be limited, thus improving quantification accuracy. PMID- 25909034 TI - Lactate, a putative survival factor for myeloma cells, is incorporated by myeloma cells through monocarboxylate transporters 1. AB - BACKGROUND: Lactate levels within tumors are correlated with metastases, tumor recurrence, and radioresistance, thus apparently contributing to poor outcomes in patients with various cancers. We previously reported that high-level production of lactate by multiple myeloma (MM) cell lines is associated with high-level LDH activity within such MM cells. However, the kinetics of lactate remains to be studied. In the present study, we attempted to elucidate the mechanism of lactate incorporation into MM cells. METHODS: Six MM cell lines and stromal cells obtained through long-term culture of bone marrow samples from MM patients were employed. Incorporation of lactate was quantified using C(14)-labeled lactate. The role of MCT1, a member of the monocarboxylate transporters (MCTs), expressed on MM cells, was examined in the presence of its inhibitor (alpha-cyano-4 hydroxycinnamic acid: CHC) and by using gene-silencing technique. RESULTS: MM cell lines as well as stromal cells were found to produce lactate. Incorporation of C(14)-labeled lactate into MM cells occurred in all 6 MM cell lines analyzed. Inhibition of MCT1 by using CHC or MCT1-targeting siRNA reduced lactate incorporation and caused apoptosis in MM cells. This apoptosis was enhanced when the activity of pyruvate dehydrogenase kinase was blocked by dichroloacetate. Survival of normal peripheral blood mononuclear cells was not influenced by MCT1 inhibition. CONCLUSIONS: The present data suggest that lactate is produced by MM cell lines and stromal cells, and contributes to the survival of such MM cells in autocrine or paracrine manners. Suppression of lactate incorporation by targeting MCT1 may provide a novel therapeutic strategy for MM which may be applicable for other B-cell neoplasms. PMID- 25909035 TI - Confocal Adaptive Optics Imaging of Peripapillary Nerve Fiber Bundles: Implications for Glaucomatous Damage Seen on Circumpapillary OCT Scans. AB - PURPOSE: To improve our understanding of glaucomatous damage as seen on circumpapillary disc scans obtained with frequency-domain optical coherence tomography (fdOCT), fdOCT scans were compared to images of the peripapillary retinal nerve fiber (RNF) bundles obtained with an adaptive optics-scanning light ophthalmoscope (AO-SLO). METHODS: The AO-SLO images and fdOCT scans were obtained on 6 eyes of 6 patients with deep arcuate defects (5 points <=-15 db) on 10-2 visual fields. The AO-SLO images were montaged and aligned with the fdOCT images to compare the RNF bundles seen with AO-SLO to the RNF layer thickness measured with fdOCT. RESULTS: All 6 eyes had an abnormally thin (1% confidence limit) RNF layer (RNFL) on fdOCT and abnormal (hyporeflective) regions of RNF bundles on AO SLO in corresponding regions. However, regions of abnormal, but equal, RNFL thickness on fdOCT scans varied in appearance on AO-SLO images. These regions could be largely devoid of RNF bundles (5 eyes), have abnormal-appearing bundles of lower contrast (6 eyes), or have isolated areas with a few relatively normal appearing bundles (2 eyes). There also were local variations in reflectivity of the fdOCT RNFL that corresponded to the variations in AO-SLO RNF bundle appearance. CONCLUSIONS: Relatively similar 10-2 defects with similar fdOCT RNFL thickness profiles can have very different degrees of RNF bundle damage as seen on fdOCT and AO-SLO. TRANSLATIONAL RELEVANCE: While the results point to limitations of fdOCT RNFL thickness as typically analyzed, they also illustrate the potential for improving fdOCT by attending to variations in local intensity. PMID- 25909036 TI - Effects of Detergent-Based Protocols on Decellularization of Corneas With Sclerocorneal Limbus. Evaluation of Regional Differences. AB - PURPOSE: In this work, we decellularized whole porcine corneas including the sclerocorneal limbus (SCL) and we evaluated regional differences in order to identify an efficient method to decellularize whole corneas for future clinical use. METHODS: We analyzed the efficiency of four decellularization protocols based on benzalkonium chloride (BAK), Igepal, sodium dodecyl sulfate (SDS), and Triton X-100 detergents on whole porcine corneas. RESULTS: Results showed that the decellularization efficiency of most protocols was low, with the specific protocol resulting in more efficient levels of decellularization being 0.1% SDS for 48 hours, especially in the medium and posterior cornea regions. A significant correlation was found between the decellularization efficiency and the concentration of agent used (P = 0.0174; r = 0.1540), but not for the incubation time (P > 0.05). The analysis of cornea components preservation demonstrated that all protocols were able to preserve the integrity of the Bowman's layer and Descemet's membrane. Although the collagen structure was partially altered, the global decellularization groups showing highest preservation of the ECM collagen contents and orientation were Igepal and SDS, with differences among the three regions of the cornea. All global groups showed high levels of proteoglycan and glycoprotein preservation after decellularization, with the best results were found in the SDS group followed by the Igepal group. CONCLUSIONS: These results suggest that very powerful protocols are necessary for whole-cornea decellularization. For the generation of lamelar corneas for clinical use, decellularization regional differences should be taken into account. TRANSLATIONAL RELEVANCE: Decellularized whole corneas may be potential therapeutic agents for lamelar keratoplasty. PMID- 25909037 TI - Alkaline and ultrasonic dissolution of biological materials for trace silicon determination. AB - A simple method for trace elemental determination in biological tissue has been developed. Novel nanomaterials with biomedical applications necessitate the determination of the in vivo fate of the materials to understand their toxicological profile. Hollow iron-doped calcined silica nanoshells have been used as a model to demonstrate that potassium hydroxide and bath sonication at 50 degrees C can extract elements from alkaline-soluble nanomaterials. After alkali digestion, nitric acid is used to adjust the pH into a suitable range for analysis using techniques such as inductively coupled plasma optical emission spectrometry which require neutral or acidic analytes. In chicken liver phantoms injected with the nanoshells, 96% of the expected silicon concentration was detected. This value was in good agreement with the 94% detection efficiency of nanoshells dissolved in aqueous solution as a control for potential sample matrix interference. Nanoshell detection was further confirmed in a mouse 24 h after intravenous administration; the measured silica above baseline was 35 times greater or more than the standard deviations of the measurements. This method provides a simple and accurate means to quantify alkaline-soluble nanomaterials in biological tissue. PMID- 25909038 TI - Water availability as an agent of selection in introduced populations of Arabidopsis thaliana: impacts on flowering time evolution. AB - Flowering is one of the most influential events in the life history of a plant and one of the main determinants of reproductive investment and lifetime fitness. It is also a highly complex trait controlled by dozens of genes. Understanding the selective pressures influencing time to flowering, and being able to reliably predict how it will evolve in novel environments, are unsolved challenges for plant evolutionary geneticists. Using the model plant species, Arabidopsis thaliana, we examined the impact of simulated high and low winter precipitation levels on the flowering time of naturalized lines from across the eastern portion of the introduced North American range, and the fitness consequences of early versus late flowering. Flowering time order was significantly correlated across two environments-in a previous common garden experiment and in environmental chambers set to mimic mid-range photoperiod and temperature conditions. Plants in low water flowered earlier, had fewer basal branches and produced fewer fruits. Selection in both treatments favored earlier flowering and more basal branches. Our analyses revealed an interaction between flowering time and water treatment for fitness, where flowering later was more deleterious for fitness in the low water treatment. Our results are consistent with the hypothesis that differences in winter precipitation levels are one of the selective agents underlying a flowering time cline in introduced A. thaliana populations. PMID- 25909039 TI - Natural variation in teosinte at the domestication locus teosinte branched1 (tb1). AB - The teosinte branched1(tb1) gene is a major QTL controlling branching differences between maize and its wild progenitor, teosinte. The insertion of a transposable element (Hopscotch) upstream of tb1 is known to enhance the gene's expression, causing reduced tillering in maize. Observations of the maize tb1 allele in teosinte and estimates of an insertion age of the Hopscotch that predates domestication led us to investigate its prevalence and potential role in teosinte. We assessed the prevalence of the Hopscotch element across an Americas wide sample of 837 maize and teosinte individuals using a co-dominant PCR assay. Additionally, we calculated population genetic summaries using sequence data from a subset of individuals from four teosinte populations and collected phenotypic data using seed from a single teosinte population where Hopscotch was found segregating at high frequency. Genotyping results indicate the Hopscotch element is found in a number of teosinte populations and linkage disequilibrium near tb1 does not support recent introgression from maize. Population genetic signatures are consistent with selection on the tb1 locus, revealing a potential ecological role, but a greenhouse experiment does not detect a strong association between the Hopscotch and tillering in teosinte. Our findings suggest the role of Hopscotch differs between maize and teosinte. Future work should assess tb1 expression levels in teosinte with and without the Hopscotch and more comprehensively phenotype teosinte to assess the ecological significance of the Hopscotch insertion and, more broadly, the tb1 locus in teosinte. PMID- 25909040 TI - Optical sectioning and 3D reconstructions as an alternative to scanning electron microscopy for analysis of cell shape. AB - PREMISE OF THE STUDY: Visualizing flower epidermal cells is often desirable for investigating the interaction between flowers and their pollinators, in addition to the broader range of ecological interactions in which flowers are involved. We developed a protocol for visualizing petal epidermal cells without the limitations of the commonly used method of scanning electron microscopy (SEM). METHODS: Flower material was collected and fixed in glutaraldehyde, followed by dehydration in an ethanol series. Flowers were dissected to collect petals, and subjected to a Histo-Clear series to remove the cuticle. Material was then stained with aniline blue, mounted on microscope slides, and imaged using a compound fluorescence microscope to obtain optical sections that were reconstructed into a 3D image. RESULTS: This optical sectioning method yielded high-quality images of the petal epidermal cells with virtually no damage to cells. Flowers were processed in larger batches than are possible using common SEM methods. Also, flower size was not a limiting factor as often observed in SEM studies. Flowers up to 5 cm in length were processed and mounted for visualization. CONCLUSIONS: This method requires no special equipment for sample preparation prior to imaging and should be seen as an alternative method to SEM. PMID- 25909041 TI - MarkerMiner 1.0: A new application for phylogenetic marker development using angiosperm transcriptomes. AB - PREMISE OF THE STUDY: Targeted sequencing using next-generation sequencing (NGS) platforms offers enormous potential for plant systematics by enabling economical acquisition of multilocus data sets that can resolve difficult phylogenetic problems. However, because discovery of single-copy nuclear (SCN) loci from NGS data requires both bioinformatics skills and access to high-performance computing resources, the application of NGS data has been limited. METHODS AND RESULTS: We developed MarkerMiner 1.0, a fully automated, open-access bioinformatic workflow and application for discovery of SCN loci in angiosperms. Our new tool identified as many as 1993 SCN loci from transcriptomic data sampled as part of four independent test cases representing marker development projects at different phylogenetic scales. CONCLUSIONS: MarkerMiner is an easy-to-use and effective tool for discovery of putative SCN loci. It can be run locally or via the Web, and its tabular and alignment outputs facilitate efficient downstream assessments of phylogenetic utility, locus selection, intron-exon boundary prediction, and primer or probe development. PMID- 25909042 TI - Characterization of 23 polymorphic SSR markers in Salix humboldtiana (Salicaceae) using next-generation sequencing and cross-amplification from related species. AB - PREMISE OF THE STUDY: We present a set of 23 polymorphic nuclear microsatellite loci, 18 of which are identified for the first time within the riparian species Salix humboldtiana (Salicaceae) using next-generation sequencing. METHODS AND RESULTS: To characterize the 23 loci, up to 60 individuals were sampled and genotyped at each locus. The number of alleles ranged from two to eight, with an average of 4.43 alleles per locus. The effective number of alleles ranged from 1.15 to 3.09 per locus, and allelic richness ranged from 2.00 to 7.73 alleles per locus. CONCLUSIONS: The new marker set will be used for future studies of genetic diversity and differentiation as well as for unraveling spatial genetic structures in S. humboldtiana populations in northern Patagonia, Argentina. PMID- 25909043 TI - Microsatellite primers for vulnerable and thriving Acacia (Fabaceae) species from Australia's arid zone. AB - PREMISE OF THE STUDY: Microsatellite markers were developed for the common arid Australian shrub Acacia ligulata (Fabaceae) and the threatened overstory trees A. melvillei and A. pendula. METHODS AND RESULTS: DNA sequence data generated by 454 sequencing were used to identify microsatellite nucleotide repeat motifs. Including previously developed primer sets, we report on the development of 10 polymorphic microsatellite loci for each species. Six of these were novel for A. melvillei and A. ligulata, and five were novel for A. pendula, while five more each were transferred from primers developed for related species (A. carneorum and A. loderi). We found three to 17 alleles per locus for each species, with high multilocus genotypic diversity within each of two A. ligulata and A. pendula stands, and one A. melvillei population. A second A. melvillei stand appeared to be monoclonal. CONCLUSIONS: These markers will allow assessment of population genetics, mating systems, and connectedness of populations of these and possibly other arid-zone acacias. PMID- 25909044 TI - Development of microsatellites from Fothergilla *intermedia (Hamamelidaceae) and cross transfer to four other genera within Hamamelidaceae. AB - PREMISE OF THE STUDY: We developed microsatellites from Fothergilla *intermedia to establish loci capable of distinguishing species and cultivars, and to assess genetic diversity for use by ornamental breeders and to transfer within Hamamelidaceae. METHODS AND RESULTS: We sequenced a small insert genomic library enriched for microsatellites to develop 12 polymorphic microsatellite loci. The number of alleles detected ranged from four to 15 across five genera within Hamamelidaceae. Shannon's information index ranged from 0.07 to 0.14. CONCLUSIONS: These microsatellite loci provide a set of markers to evaluate genetic diversity of natural and cultivated collections and assist ornamental plant breeders for genetic studies of five popular genera of woody ornamental plants. PMID- 25909045 TI - Development and characterization of EST-SSR markers in Bombax ceiba (Malvaceae). AB - PREMISE OF THE STUDY: Bombax ceiba (Malvaceae), commonly known as silk cotton tree, is a multipurpose tree species of tropical forests. Novel expressed sequence tag-simple sequence repeat (EST-SSR) markers were developed and characterized for the species using transcriptome analysis. METHODS AND RESULTS: A total of 33 new EST-SSR markers were developed for B. ceiba, of which 13 showed polymorphisms across the 24 individuals from four distant populations tested in the study. The results showed that the number of alleles per polymorphic locus ranged from two to four, and the expected heterozygosity and observed heterozygosity per locus varied from 0.043 to 0.654 and from 0 to 0.609, respectively. CONCLUSIONS: These newly developed EST-SSR markers can be used in phylogeographic and population genetic studies to investigate the origin of B. ceiba populations. Furthermore, these EST-SSR markers could also greatly promote the development of molecular breeding studies pertaining to silk cotton tree. PMID- 25909046 TI - Development and characterization of microsatellite loci for the endangered scrub lupine, Lupinus aridorum (Fabaceae). AB - PREMISE OF THE STUDY: Microsatellite primers were developed in scrub lupine (Lupinus aridorum, Fabaceae), an endemic species to Florida that is listed as endangered in the United States, to assess connectivity among populations, identify hybrids, and examine genetic diversity. METHODS AND RESULTS: We isolated and characterized 12 microsatellite loci polymorphic in scrub lupine or in closely related species (i.e., sky-blue lupine [L. diffusus] and Gulf Coast lupine [L. westianus]). Loci showed low to moderate polymorphism, ranging from two to 14 alleles per locus and 0.01 to 0.86 observed heterozygosity. CONCLUSIONS: These loci are the first developed for Florida species of lupine and will be used to determine differentiation among species and to aid in conservation of the endangered scrub lupine. PMID- 25909047 TI - Targeted Maximum Likelihood Estimation for Dynamic and Static Longitudinal Marginal Structural Working Models. AB - This paper describes a targeted maximum likelihood estimator (TMLE) for the parameters of longitudinal static and dynamic marginal structural models. We consider a longitudinal data structure consisting of baseline covariates, time dependent intervention nodes, intermediate time-dependent covariates, and a possibly time-dependent outcome. The intervention nodes at each time point can include a binary treatment as well as a right-censoring indicator. Given a class of dynamic or static interventions, a marginal structural model is used to model the mean of the intervention-specific counterfactual outcome as a function of the intervention, time point, and possibly a subset of baseline covariates. Because the true shape of this function is rarely known, the marginal structural model is used as a working model. The causal quantity of interest is defined as the projection of the true function onto this working model. Iterated conditional expectation double robust estimators for marginal structural model parameters were previously proposed by Robins (2000, 2002) and Bang and Robins (2005). Here we build on this work and present a pooled TMLE for the parameters of marginal structural working models. We compare this pooled estimator to a stratified TMLE (Schnitzer et al. 2014) that is based on estimating the intervention-specific mean separately for each intervention of interest. The performance of the pooled TMLE is compared to the performance of the stratified TMLE and the performance of inverse probability weighted (IPW) estimators using simulations. Concepts are illustrated using an example in which the aim is to estimate the causal effect of delayed switch following immunological failure of first line antiretroviral therapy among HIV-infected patients. Data from the International Epidemiological Databases to Evaluate AIDS, Southern Africa are analyzed to investigate this question using both TML and IPW estimators. Our results demonstrate practical advantages of the pooled TMLE over an IPW estimator for working marginal structural models for survival, as well as cases in which the pooled TMLE is superior to its stratified counterpart. PMID- 25909048 TI - The impact of treatment decisions on the diagnosis of bipolar disorders. PMID- 25909049 TI - Are renal tumors associated with lithium treatment? PMID- 25909050 TI - Clinical characteristics of bipolar disorder: a comparative study between Argentina and the United States. AB - BACKGROUND: Bipolar disorder presents with diverse clinical manifestations. Numerous investigators have sought to identify variables that may predict a more severe illness course. METHODS: With the objective of studying the clinical characteristics of bipolar patients between South and North America, a comparison was performed between a sample from Argentina (n = 449) and a sample from the United States (n = 503) with respect to demographics and clinical characteristics, including presence of comorbidities. RESULTS: The Argentinian sample had more unfavorable demographics and higher rates of prior psychiatric hospitalization and prior suicide attempt but a better social outcome. However, the sample from the United States had a higher rate of prior year rapid cycling, as well as younger bipolar disorder onset age (mean +/- SD, 17.9 +/- 8.4 vs. 27.1 +/- 11.4 years) and more severe clinical morbidity, though there was no significant difference in terms of the total duration of the illness. Argentinian compared to American patients were taking more mood stabilizers and benzodiazepines/hypnotics, but fewer antipsychotics and other psychotropic medications, when considering patients in aggregate as well as when stratifying by illness subtype (bipolar I versus bipolar II) and by illness onset age (<=21 vs. >21 years). However, there was no significant difference in rate of antidepressant prescription between the two samples considered in aggregate. CONCLUSIONS: Although possessing similar illness durations, these samples presented significant clinical differences and distinctive prescription patterns. Thus, though the Argentinian compared to North American patients had more unfavorable demographics, they presented a better social outcome and, in several substantive ways, more favorable illness characteristics. In both samples, early onset (age <= 21 years) was a marker for poor prognosis throughout the illness course, although this phenomenon appeared more robust in North America. PMID- 25909051 TI - Daily Patterns of Physical Activity by Type 2 Diabetes Definition: Comparing Diabetes, Prediabetes, and Participants with Normal Glucose Levels in NHANES 2003 2006. AB - OBJECTIVE: Diabetes is associated with low levels of physical activity (PA), but detailed objective information about how PA patterns vary by diabetes definition is lacking. METHODS: PA was measured with Actigraph accelerometers in older (60+) adults from the 2003-2006 National Health and Nutrition Examination Survey (n= 1,043) and analyzed in 2014. Diabetes definition (normal glucose levels, prediabetes, diabetes) was assessed (fasting glucose, hemoglobin A1C, and self report). Accelerometer data were used to characterize total activity counts (TAC) per day and hour-by-hour activity counts by diabetes definition. Multiple linear regression models explored the relationship between diabetes definition and TAC. RESULTS: Despite similar patterns of PA, diabetes participants had significantly lower TAC compared to participants with normal glucose levels and prediabetes. Diabetes participants' activity counts per hour declined more rapidly after 12 pm, with the biggest differences between the groups occurring at 4 pm. Participants with normal glucose levels and prediabetes had similar TAC and daily PA profiles. CONCLUSION: Our novel methodology provides information about PA patterns by diabetes definition. Significantly lower TAC in the diabetes group, their significant drop in afternoon PA, and the similarity of PA between participants with normal glucose levels and prediabetes provide insight into potential targets for intervention. PMID- 25909052 TI - Effects of a granulocyte colony stimulating factor, Neulasta, in mini pigs exposed to total body proton irradiation. AB - Astronauts could be exposed to solar particle event (SPE) radiation, which is comprised mostly of proton radiation. Proton radiation is also a treatment option for certain cancers. Both astronauts and clinical patients exposed to ionizing radiation are at risk for loss of white blood cells (WBCs), which are the body's main defense against infection. In this report, the effect of Neulasta treatment, a granulocyte colony stimulating factor, after proton radiation exposure is discussed. Mini pigs exposed to total body proton irradiation at a dose of 2 Gy received 4 treatments of either Neulasta or saline injections. Peripheral blood cell counts and thromboelastography parameters were recorded up to 30 days post irradiation. Neulasta significantly improved WBC loss, specifically neutrophils, in irradiated animals by approximately 60% three days after the first injection, compared to the saline treated, irradiated animals. Blood cell counts quickly decreased after the last Neulasta injection, suggesting a transient effect on WBC stimulation. Statistically significant changes in hemostasis parameters were observed after proton radiation exposure in both the saline and Neulasta treated irradiated groups, as well as internal organ complications such as pulmonary changes. In conclusion, Neulasta treatment temporarily alleviates proton radiation-induced WBC loss, but has no effect on altered hemostatic responses. PMID- 25909053 TI - Reactive Secondary Sequence Oxidative Pathology Polymer Model and Antioxidant Tests. AB - AIMS: To provide common Organic Chemistry/Polymer Science thermoset free-radical crosslinking Sciences for Medical understanding and also present research findings for several common vitamins/antioxidants with a new class of drugs known as free-radical inhibitors. STUDY DESIGN: Peroxide/Fenton transition-metal redox couples that generate free radicals were combined with unsaturated lipid oils to demonstrate thermoset-polymer chain growth by crosslinking with the alpha-beta unsaturated aldehyde acrolein into rubbery/adhesive solids. Further, Vitamin A and beta carotene were similarly studied for crosslink pathological potential. Also, free-radical inhibitor hydroquinone was compared for antioxidant capability with Vitamin E. PLACE AND DURATION OF STUDY: Department of Materials Science and Engineering and Department of Biomaterials, University of Alabama at Birmingham, between June 2005 and August 2012. METHODOLOGY: Observations were recorded for Fenton free-radical crosslinking of unsaturated lipids and vitamin A/beta carotene by photography further with weight measurements and percent-shrinkage testing directly related to covalent crosslinking of unsaturated lipids recorded over time with different concentrations of acrolein. Also, hydroquinone and vitamin E were compared at concentrations from 0.0-7.3wt% as antioxidants for reductions in percent-shrinkage measurements, n = 5. RESULTS: Unsaturated lipid oils responded to Fenton thermoset-polymer reactive secondary sequence reactions only by acrolein with crosslinking into rubbery-type solids and different non solid gluey products. Further, molecular oxygen crosslinking was demonstrated with lipid peroxidation and acrolein at specially identified margins. By peroxide/Fenton free-radical testing, both vitamin A and beta-carotene demonstrated possible pathology chemistry for chain-growth crosslinking. During lipid/acrolein testing over a 50 hour time period at 7.3wt% antioxidants, hydroquinone significantly reduced percent shrinkage greatly compared to the standard antioxidant vitamin E, %shrinkage at 11.6 +/-1.3 for hydroquinone and 27.8 +/-2.2 for vitamin E, P = .001. CONCLUSION: Free radicals crosslinked unsaturated lipid fatty acids into thermoset polymers through Fenton reactions when combined with acrolein. Further, hydroquinone was a superior antioxidant to vitamin E. PMID- 25909055 TI - Factors affecting the attractiveness of medical tourism destination: an empirical study on India- review article. AB - BACKGROUND: In this edge, medical tourism is not a new idea. Medical treatment is one of the essential demands of human beings and it requires high quality and intensive care. Beside western world, few developing countries are playing key roles as medical tourism destinations. India is one of the leading names among these countries. The purpose of the paper is to find the factors influencing the attractiveness of India as a health tourism destination. METHODS: The study has found the major contributing factors and their relative importance in the attractiveness of the health tourism destination that is India from consumers' perspectives by conducting survey with an application of structural equation modelling approach. RESULTS: In Indian context, medical tourists consider service quality and cost mostly to select any medical destination. In addition they also give value to the destination competitiveness but tourist attitude is less important in comparison with other factors affecting their destination choice. Since the study has used structural equation modelling approach to test the hypothesis and figure out the relative importance of the factors, the fundamental indices such as Normed Chi square(less than 3), RMSEA (less than 0.08) and CFI (more than 0.90) values show the overall model fit of the proposed model. CONCLUSION: In order to transform a country such as India as an attractive and competitive medical tourist destination in this time of globalization, a step should be taken to control cost ensuring the quality of services. PMID- 25909054 TI - Type 2 diabetes mellitus and risk of malignant melanoma: a systematic review and meta-analysis of cohort studies. AB - BACKGROUND: Epidemiology studies have demonstrated inconsistent associations between type 2 diabetes mellitus and the risk of malignant melanoma. To this end, the aim was to perform a meta-analysis of cohort studies. METHOD: Medline, PubMed, Embase and the Cochrane Library were searched up to February 2014. Cohort studies addressing the relative risk of type 2 diabetes mellitus on malignant melanoma were included in this meta-analysis. The Newcastle-Ottawa Scale was applied for quality evaluation. The pooled relative risks with the corresponding 95% confidence intervals (95% CIs) were calculated by using random-effects or random-effects model. Heterogeneity and publication bias were evaluated by I (2) and funnel plot analysis, respectively. Data was analyzed using STATA 11.0. RESULTS: A total of 9 independent cohorts from 8 manuscripts were entered this meta-analysis. Type 2 diabetes mellitus was slightly associated with an increased risk of malignant melanoma, and the pooled relative risk was 1.15 (95% CI, 1.00 1.32) in diabetes compared with non-diabetes with significant evidence of heterogeneity among these studies (P=0.016, I (2) =57.6%). For the studies adjusted for age, gender and obesity, the relative risks were 1.21 (95% CI, 1.03 1.42), 1.17 (95% CI, 1.01-1.35) and 1.11 (95% CI, 1.00-1.24), respectively. For the population-based studies in which case cohort established, the relative risk was 1.85 (95% CI, 1.31-2.62). CONCLUSION: Type 2 diabetes might be an independent risk factor for malignant melanoma. Further studies are needed to specifically test the effect, and fully elucidate the underlying pathophysiologic mechanisms. PMID- 25909056 TI - Association between beta2-Adrenergic Receptor-16Arg/Gly Gene Polymorphism and Chronic Obstructive Pulmonary Disease Risk:Systematic Review and Meta-Analysis. AB - BACKGROUND: The association between beta2-adrenergic receptor (ADRB2) -16Arg/Gly polymorphism (rs1042713) and chronic obstructive pulmonary disease (COPD) risk has been investigated in many published studies. However, the results were inconclusive. A meta-analysis was performed to make a more precise estimation of the relationship. METHODS: The PubMed, EMBASE, ISI web of science, the Cochrane Database of Systematic Reviews, and Chinese databases (CNKI, Wanfang Data, CBM, VIP) were searched for published literature. Odds ratios (OR) with 95% confidence interval (CI) were used to assess the strength of association. RESULTS: Eleven studies, comprising 1,128 COPD patients and 1,182 controls, were included in the meta-analysis. Overall, there was no significant association between the ADRB2 16Arg/Gly polymorphism and COPD risk in general population. In the stratification analysis by potential confounding variables, significant associations were observed between the ADRB2-16Arg/Gly polymorphism and COPD risk among smoking Asians under the dominant genetic model and allele model (Arg vs. Gly) (dominant model: OR = 1.45, 95% CI = 1.04-2.01, P = 0.311 for heterogeneity, z = 2.22, P = 0.026 for OR; allele model: OR = 1.27, 95% CI = 1.03-1.57, P = 0.209 for heterogeneity, z = 2.20, P = 0.028 for OR), but not in other subgroups. CONCLUSION: This meta-analysis suggested that the ADRB2-16Arg/Gly polymorphism might be a potential risk factor for the development of COPD in smoking Asian populations, but not in European descendents, and tobacco smoking probably increased the genetic susceptibility. More studies with larger sample sizes are needed to validate the results. PMID- 25909057 TI - Development a comprehensive food safety system in serbia- a narrative review article. AB - BACKGROUND: Food safety issues are not a new issue in science, but due to the dynamic changes in the modern world it is as equally important as decades ago. The aim of the study was to address the efforts in the development of a comprehensive food safety system in Serbia, and make specific recommendations regarding the improvement of epidemiological investigation capacity as a useful tool which contributes to improving the public health by joint efforts of epidemiologists and law enforcement. METHODS: We used the methodology appropriate for social sciences. RESULTS: The findings show the current state-of-affairs in the area of food safety and health care system and present some most important weaknesses which have to be overcome. Policy makers need timely and reliable information so that they can make informed decisions to improve the population health in an ongoing process of seeking full membership in the European Union. CONCLUSION: Serbia has to apply significant changes in practice because the current state-of-affairs in the area of food safety and health care system is not so favourable due to numerous both objective and subjective factors. Hence, the policy-makers must work on the development of epidemiological investigation capacities as a firm basis for greater efficiency and effectiveness. Epidemiologists would not stay alone in their work. Law enforcement as well as many other stakeholders should recognize their new role in the process of the development of epidemiological investigation capacity as a tool for the development of a comprehensive food safety system in Serbia. PMID- 25909058 TI - Which type of social activities decrease depression in the elderly? An analysis of a population-based study in South Korea. AB - BACKGROUND: The aim of this study was to examine whether formal and informal social activities are associated with a lower risk of depression. Besides, we investigated which type of social activities may protect against late-life depression by gender using data from a population-based study of older Korean adults. METHODS: Data for analysis were drawn from the 2010 Korean Longitudinal Study of Aging. Study sample included 3968 Korean adults aged >= 65 years. Depression was measured using the 10-item Center for Epidemiological Studies. Depression scale. Multivariate logistic regression analyses were used. RESULTS: Among the informal activities, frequent contact by phone or letters with adult children is significantly associated with a lower risk of depression among older Korean adults, even after adjusting for potentially confounding factors. Face to face contact with close friends was negatively associated with depression in women, but not in men. Face to face contacts with adult children were not significantly associated with depression. All of formal social activities (attending religious activities, volunteering, and participating in alumni society or family councils, political or interest groups) were not significantly associated with depression in both men and women. CONCLUSIONS: Informal social activities (contact by phone/letters with children and contact with friends) may have a greater impact on geriatric depression than formal social activities in this population. Researchers need to consider gender differences when examining the relationship between social activity and depression. More research is warranted to examine the direction of associations between particular types of social activities and late-life depression across time. PMID- 25909059 TI - Socioeconomic status and overweight prevalence in polish adolescents: the impact of single factors and a complex index of socioeconomic status in respect to age and sex. AB - BACKGROUND: The aim of this study was to analyze the association between overweight prevalence and socioeconomic status (SES) measured by complex SES index and single SES factors in Polish adolescents in respect to age and sex. METHODS: This cross-sectional study was conducted in 2010-2011. A total of 1,176 adolescents aged 13.0-18.9 years were included. The respondents were students of junior-high and high schools from northern, eastern and central Poland. Quota sampling by sex and age was used. The SES was determined by: place of residence, self-declared economic situation, and parental education level. Respondents with low, average or high SES index (SESI) were identified. The level of overweight was assessed using Polish and international standards. RESULTS: The odds ratio (OR) for overweight prevalence in the oldest girls (aged 17.0-18.9 years) with high SESI was 0.34 (95%CI:0.13-0.92; P < 0.05) by Polish standards and 0.22 (95%CI:0.05-0.95; P < 0.05) by international standards, in comparison to the reference group (low SESI). In total girls who had mothers with higher education level, the OR adjusted for age was 0.44 (95%CI:0.21-0.90; P <0.05) by Polish standards and 0.35 (95%CI:0.15-0.81; P < 0.05) by international standards, in comparison to the reference group (maternal elementary education). The other single SES factors were not significant for overweight prevalence. CONCLUSIONS: The relationship between socioeconomic status and prevalence of overweight was related to sex and age. The high socioeconomic status strongly lowered the risk of overweight prevalence in the oldest girls, but not in boys, irrespective of age. Maternal education level lowered risk of overweight prevalence in girls. PMID- 25909060 TI - Organ Donation Campaigns: Perspective of Dialysis Patient's Family Members. AB - BACKGROUND: Solving the dilemma of the organ shortage in Malaysia requires educating Malaysians about organ donation and transplantation. This paper aims at exploring the average Malaysian households ' preferred channels of campaigns and the preferred campaigners in a family setting, targeting at the dialysis family members. METHODS: We analyzed the responses of 350 respondents regarding organ donation campaigns. The respondents are 2 family members of 175 dialysis patients from 3 different institutions. The information on respondents' willingness to donate and preferred method and channel of organ donation campaign were collected through questionnaire. RESULTS: Malaysian families have a good tendency to welcome campaigns in both the public and private (their homes) spheres. We also found that campaigns facilitated by the electronic media (Television and Radio) and executed by experienced doctors are expected to optimize the outcomes of organ donation, in general. Chi-square tests show that there are no significant differences in welcoming campaigns among ethnics. However, ethnics preferences over the campaign methods and campaigners are significantly different (P <0.05). CONCLUSION: Ethnic differences imply that necessary modifications on the campaign channels and campaigners should also be taken under consideration. By identifying the preferred channel and campaigners, this study hopes to shed some light on the ways to overcome the problem of organ shortage in Malaysia. PMID- 25909061 TI - Changes in Physiological Parameters after Combined Exercise according to the I/D Polymorphism of hUCP2 Gene in Middle-Aged Obese Females. AB - BACKGROUND: The purpose of this study was to determine whether a 45 bp insertion/deletion (I/D) polymorphism in human uncoupling protein 2 (hUCP2) gene was associated with changes in several cardiovascular risk and physical fitness factors in response to combined exercise during 12 weeks in Korean middle-aged women. The changes in physiological parameters after combined exercise during 12 weeks were compared between each genotype subgroups of hUCP2 gene to clarify the inter-individual differences in exercised-induced changes according to genetic predisposition. METHODS: A total of 185 women aged over 40 years living in Seoul, Korea were participated in this study, and analyzed before and after 12 weeks on combined exercise including aerobic exercise and strength training for body composition, hemodynamic parameters, physical fitness and metabolic variables. A 45 bp I/D polymorphism in hUCP2 gene was genotyped by polymerase chain reaction (PCR) amplification and agarose gel electrophoresis method. RESULTS: Combined exercise program during 12 weeks indicated the significant health-promoting effects for our participants on multiple body composition, hemodynamic parameters, physical fitness factors and metabolic parameters, respectively. With respect to a 45 bp I/D polymorphism in hUCP2 gene, this polymorphism was significantly associated with baseline %body fat of our participants (P <.05). Moreover, this polymorphism was significantly associated with the changes in %body fat and serum triglyceride(TG) level after combined exercise program during 12 weeks(P <.05). CONCLUSION: Our data suggest that a 45 bp I/D polymorphism in hUCP2 gene may at least in part contribute to the inter-individual differences on the changes in some clinical and metabolic parameters following combined exercise in middle-aged women. PMID- 25909062 TI - Etiology of Acute Diarrhea in Tunisian Children with Emphasis on Diarrheagenic Escherichia coli: Prevalence and Identification of E. coli Virulence Markers. AB - BACKGROUND: Diarrheal diseases can be caused by viral, bacterial and parasitic infections. This paper provides a preliminary image of diarrhea with regards to etiology and epidemiologic factors in Tunisian children less than five years of age. METHODS: Overall, 124 diarrhoeal stools were collected from patients suffering from acute diarrhea and 54 stool samples from healthy children. All stools were examined for the presence of enteric pathogens. RESULTS: In diarrheagenic children, 107 pathogenic bacteria were isolated (12 Salmonella spp. (9.7%) and 95 diarrheagenic Escherichia coli strains (76.6%): 29 enteroaggregative E.coli (EAEC) (23.4%), 15 enteroinvasive E.coli (EIEC) (12.1%), 17 enteropathogenic E.coli (EPEC) (13.7%), 26 enterotoxigenic E.coli (ETEC) (21%) and 2 enterohemoragic E.coli (EHEC) (1.6%). However, in the control group, 23 pathogenic E.coli strains were isolated (42.6%): 8 EAEC (14.8%), 12 EIEC (22.2%) and 3 EPEC (5.5%). Among diarrheagenic E.coli (DEC), only ETEC strains were significantly recovered from diarrheagenic children than from healthy controls (P < 0.0003). Group A rotavirus was identified in 33.9% (n=42) of diarrheagenic children and in 11.1% among the control group (n=6). Concerning norovirus, 8.9% (n=11) of the samples collected from diarrheagenic children and 9.2% (n=5) from the control group were positive. The prevalence of rotaviruses and Salmonella spp were also significantly higher in patients with diarrhea than in controls (P = 0.002 and P < 0.019, respectively). Finally, enteropathogenic parasites (Entamoeba coli and cryptosporidium Oocystes) were isolated from 4.8% and 9.2% of diarrheagenic and control children, respectively. CONCLUSION: These results provide baseline data about the relative importance of different enteropathogens in Tunisian children. PMID- 25909063 TI - Trend in cataract surgical rate in iran provinces. AB - BACKGROUND: The aim of this study was to determine the trend of changes in Cataract Surgical Rate (CSR) in the provinces of Iran during 2006 to 2010 and identify high risk areas. METHODS: This report is part of the national Iranian CSR Study. The percentage change in CSR in 2010 compared to 2006 was conducted in each province, retrospectively. One hundred and ten centers were chosen from all provinces, to determine CSR in each, the weight of major (>3,000 annual surgeries) and minor (3,000 annual surgeries or less) centers was calculated based on the number of selected centers, and multiplied by the number of surgeries in each province. RESULTS: In eight provinces, CSR was decreased by 1 60%. One province (Booshehr) showed no change. Eighteen provinces had 2-79% increase. No 2006 data was available in three provinces. North Khorasan had the most decrease while Kerman had the most increase in CSR. Six of these 8 provinces had CSR>3,000 despite a decrease in 2010, but North Khorasan had CSR<3,000 over the whole 5 year period. In 4 provinces, CSR had a gap from 3,000 despite an ascending trend, and in two, the gap was quite considerable. CONCLUSION: Although CSR has an improving trend in most provinces in Iran, it is decreasing in some provinces, and despite an already low CSR, the exacerbation continues. The growing population of over 50 year olds calls for prompt measures in such provinces. Even in improving provinces, some lag behind the minimum recommended by WHO, and the growth rate of the over 50 population reveals the necessity of immediate planning. PMID- 25909064 TI - Research's Practice and Barriers of Knowledge Translation in Iran. AB - BACKGROUND: Knowledge Translation is a process that includes synthesis, dissemination, exchange and application of knowledge to improve the health, services and products In this study we have attempted to examine the knowledge translation practice and its perceived barriers on the universalities and research institutes (research sector) in Iran. METHODS: Both qualitative and quantitative approaches were used. In the quantitative section, a questionnaire had prepared for this study was completed by 88 authors country wide from randomly selected papers. In the qualitative section 13 in-depth interviews and 6 focus group discussions were held with managers and policy makers, clinical and health service providers, and researchers. RESULTS: Twenty four percent of the authors had no interaction whatsoever with the target audience. Lack of expectation toward creating change in the target audience, researchers' incentives, low level of trust among researchers and decision makers, absence of a predefined mechanism for delivery of research results and inappropriate research priorities were among the most important barriers identified in the qualitative section. CONCLUSION: Translation of research findings into some concrete outputs which can affect health of people is not in mandate of researchers and subsequently they are not prepared for this as well. Based on the barriers identified, it seems that the following interventions are necessary: cooperation among policy makers at macro and meso (organizational) level and the research sector; establishing networks for researchers and decision makers in choosing the research topic, priority setting, and building trust among researchers and policy makers. PMID- 25909065 TI - Association of ABO and Rh Blood Groups to Blood-Borne Infections among Blood Donors in Tehran-Iran. AB - BACKGROUND: The aim of this study was to investigate the prevalence of hepatitis B, hepatitis C, HIV and syphilis infections in blood donors referred to Tehran Blood Transfusion Center (TBTC), and determine any association between blood groups and blood- borne infections between the years of 2005 and 2011. METHODS: This was a retrospective study conducted at TBTC. All of the donor serum samples were screened for HBV, HCV, HIV and syphilis by using third generation ELISA kits and RPR test. Initial reactive samples were tested in duplicate. Confirmatory tests were performed on all repeatedly reactive donations. Blood group was determined by forward and reverse blood grouping. The results were subjected to chi square analysis for determination of statistical difference between the values among different categories according to SPSS program. RESULTS: Overall, 2031451 donor serum samples were collected in 2005-2011. Totally, 10451 were positive test for HBV, HCV, HIV and syphilis. The overall seroprevalence of HBV, HCV, HIV, and syphilis was 0.39%, 0.11%, 0.005%, and 0.010%, respectively. Hepatitis B and HIV infections were significantly associated with blood group of donors (P <0.05) ; percentage of HIV Ag/Ab was higher in donors who had blood group "A" and percentage of HBs Ag was lower in donors who had blood group O. There was no significant association between Hepatitis C and syphilis infections with ABO and Rh blood groups (P>0.05). CONCLUSION: Compared with neighboring countries and the international standards, prevalence of blood-borne infections is relatively low. PMID- 25909066 TI - Natural history of chronic hepatitis B virus infection based on laboratory testing. AB - BACKGROUND: Understanding of the natural history of chronic HBV infection is useful for presenting the optimal management of chronic HBV infection. The aim of this study was to evaluate the natural history of chronic hepatitis B infection. METHODS: In this cross sectional study, 219 untreated chronic hepatitis B patients from Jan. 2010 to Aug. 2012 were included. The subjects were classified in four groups based on serological, biochemical and molecular testing, Serological tests for HBeAg and HBeAb were performed by ELISA method. HBV DNA viral loads were detected by using Light Cycler instrument and ALT/AST levels were assessed by automatic analyzer. RESULTS: The majority of subjects (94.1%) were HBeAg negative. Of 13 HBeAg positive patients, 5 (2.3%) and 8(3.7%) were considered as immunetolerant and immune reactive, respectively. Of 206 HBeAg negative patients, there were 142 (64.8%) patients in inactive or low replicative phase and 64(29.2%) were in HBeAg negative chronic hepatitis B phase. DISCUSSION: The lowest rate of subjects were in immunetolerant phase and most of them had above 20 years old that confirmed successful neonatal vaccines in our country. The highest rate of chronic HBV infected patients were in low replicative phase of chronic hepatitis B infection. Although, it is not recommended to treat these patients, but liver function and also liver biopsy should be considered in patients above 40 years of age. PMID- 25909067 TI - Activity Assay of Glutathione S-Transferase (GSTs) Enzyme as a Diagnostic Biomarker for Liver Hydatid Cyst in Vitro. AB - BACKGROUND: The aim of this study was to detect the Glutathione S Transferase(GST) enzyme activity of healthy / cystic liver as a diagnostic biomarker for hydatidosis. In order to compare with liver tissue, the level of the GSTs enzyme activity of parasite was also determined. METHODS: Parasites were collected from sheep liver tissue with hydatid cysts at a local abattoir and washed with PBS buffer. Collected parasites and liver tissues were sonicated or homogenized respectively. Extract solution samples were centrifuged and stored at - 20 degrees C. GST enzyme activities were measured in the extract of parasite and liver tissue samples (healthy and infected livers). Protein amounts and protein bands were detected using Bradford and sodium dodecyl sulfate polyacrylamide gel electrophoresis (SDS-PAGE) methods respectively. To determine significant difference between two groups, two-sample t-test was performed. RESULTS: GST specific activities of healthy / infected livers and parasites were estimated 304, 1297 and 146 U/ml/mg respectively. Significant higher GST specific activities in cystic liver than healthy liver was observed (P <0.05). T-test analysis showed GST activity of parasite was lower than healthy liver tissue. SDS PAGE showed GST protein bands with 24 kDa in parasite samples and25 kDa in liver tissues. CONCLUSION: GST activity incystic liver tissue could be concerned as a biomarker for hydatid cyst diagnosis with other hydatid disease parameters. PMID- 25909068 TI - Termination of twin pregnancies with hydatidiform moles: a case series of four patients. AB - P A twin pregnancy with a complete hydatidiform mole with a coexistent foetus (CHMF) is a rare condition that typically results in poor pregnancy outcomes. For patients with refractory vaginal bleeding, termination of pregnancy is more appropriate. However, unified methods for termination remain to be explored. In the present study, we reviewed the termination measures in four cases of twin pregnancy with CHMF. Additional understanding of this condition will aid in the treatment of women with this condition and improve their pregnancy outcomes. PMID- 25909069 TI - Increasing skyscrapers: possibility of new disaster. PMID- 25909070 TI - Reliability of Spirometric Tests during the Different Menstrual Cycle Phases in Healthy Women. PMID- 25909071 TI - Challenges for molecular diagnosis of familial early-onset diabetes in unexplored populations. PMID- 25909072 TI - Small Bite, Big Threat: The Burden of Vector-borne Diseases. PMID- 25909073 TI - The most important species of nosocomial infection and the most important wards susceptible to nosocomial infection. PMID- 25909074 TI - Application of hydrogen producing microorganisms in radiotherapy: an idea. PMID- 25909075 TI - Regional disparities in the distribution of health care facilities: building evidence for evidence-based policy making. PMID- 25909076 TI - Association of 18bp insertion/deletion polymorphism, at -2549 position of VEGF gene, with diabetic nephropathy in type 2 diabetes mellitus patients of North Indian population. AB - BACKGROUND: Vascular endothelial growth factor (VEGF) is a potent multifunctional cytokine which plays a key role in the pathogenesis of diabetic micro-vascular complications. Human VEGF gene is said to be highly polymorphic. Insertion/deletion (I/D) polymorphism of the 18 bp fragment at -2549 position of the promoter region in VEGF gene is said to be of particular interest. The study was aimed to evaluate association of Insertion/deletion (I/D) polymorphism of the 18 bp fragment at -2549 position of the promoter region in VEGF gene, with diabetic nephropathy in type 2 diabetes mellitus. METHODS: This cross sectional study enrolled 40 subjects each of diabetic nephropathy (DN), diabetes mellitus without nephropathy (DM) and normal control subjects. DNA was isolated from peripheral blood leukocytes. Genotyping of the VEGF gene insertion/ deletion (I/D) polymorphism was done by the polymerase chain reaction (PCR) methods. The frequency of VEGF alleles and genotype distribution were compared in diabetic nephropathy, uncomplicated diabetic and control groups. RESULTS: DD genotype and D allele were found to be significantly associated with DN group (p = 0.009 and 0.02 respectively) in comparison to DM group. Also DD genotype conferred significant risk of diabetic nephropathy in DM group (OR = 4.2) (against combined frequency of ID and II genotype) so does D allele 2.09 (against I allele). CONCLUSION: DD genotype and D allele in I/D polymorphism at -2549 position of VEGF gene is associated with increased susceptibility to diabetic nephropathy in north Indian population. PMID- 25909077 TI - Haplotype analysis of the Apolipoprotein A5 gene in Moroccan patients with the metabolic syndrome. AB - BACKGROUND: In this case-control study we investigated the relative contribution of commons APOA5 polymorphisms and haplotypes to the risk of metabolic syndrome in Moroccan patients. METHODS: Using the International Diabetes Federation (IDF) criteria for metabolic syndrome, the study included 176 patients and 105 controls. We genotyped APOA5 polymorphisms (-1131 T > C, c.56C > G, c.553G > T and c.1259 T > C) by PCR-RFLP analysis. The effects of APOA5 polymorphisms and constructed haplotypes on metabolic syndrome were estimated using logistic regression analyses. RESULTS: The statistical analysis showed a significant association between APOA5 -1131 T > C and APOA5 c.56C > G polymorphisms with metabolic syndrome in both Codominant and Dominant models. The APOA5 -1131 T > C polymorphism was associated with increased fasting glucose (p = 0.0295) and reduced HDL levels (p = 0.0091). Carriers of the APOA5 c.56G allele had increased triglyceride levels (p = 0.0435) and waist circumference (p = 0.0122). Similarly the APOA5 1259 T > C variant was associated with increased waist circumference (p = 0.0463). The haplotypes CCGT (OR = 3.223; p = 0.00278) and CGGT (OR = 8.234; p = 0.00534) were significantly associated with susceptibility to metabolic syndrome. CONCLUSIONS: Our results confirms the association of APOA5 -1131 T > C and c.56C > G variants with the predisposition to metabolic syndrome complications. PMID- 25909078 TI - The association of circulating adiponectin and + 45 T/G polymorphism of adiponectin gene with gestational diabetes mellitus in Iranian population. AB - BACKGROUND: Adiponectin is an adipokine with insulin-sensitizing effects. We investigated the relationship between the single nucleotide polymorphism (SNP) +45 T > G ( rs 2241766 ;Gly15Gly) in the adiponectin gene, serum adiponectin levels, insulin resistance and risk of gestational diabetes (GDM) in Iranian population. METHODS: 65 GDM patients and 70 healthy pregnant women were enrolled in this study. Genotyping for SNP +45 T > G in the adiponectin gene ( rs 2241766 ) was performed by the polymerase chain reaction-restriction fragment length polymorphism method. The level of fasting serum adiponectin, insulin, glucose, and lipid levels were measured. Insulin resistance was estimated using homeostasis model of assessment for insulin resistance (HOMA-IR). RESULTS: The G allele and TG/GG genotype of rs 2241766 were more frequent than the T allele and TT genotype in GDM patients compared to the controls (p < 0.05). Multiple logistic regression analysis revealed that the risk of GDM was significantly higher in subjects with the TG/GG genotype to those with TT genotype [odds ratio = 2.38, 95% CI 1.09-5.22, p = 0.030]. No significant association was observed between genotypes of rs 2241766 and circulating concentrations of adiponectin. Multiple regression analysis showed that serum adiponectin levels was negatively associated with HOMA-IR in GDM patients (beta = -0.385, p <0.01). CONCLUSION: The findings demonstrated that TG/GG genotype of rs 2241766 was an independent risk factor of GDM in our population. Furthermore, circulating adiponectin level was negatively correlated with insulin resistance in GDM patients. PMID- 25909079 TI - HIF-1alpha Mediates Isoflurane-Induced Vascular Protection in Subarachnoid Hemorrhage. AB - OBJECTIVE: Outcome after aneurysmal subarachnoid hemorrhage (SAH) depends critically on delayed cerebral ischemia (DCI) - a process driven primarily by vascular events including cerebral vasospasm, microvessel thrombosis, and microvascular dysfunction. This study sought to determine the impact of postconditioning - the phenomenon whereby endogenous protection against severe injury is enhanced by subsequent exposure to a mild stressor - on SAH-induced DCI. METHODS: Adult male C57BL/6 mice were subjected to sham, SAH, or SAH plus isoflurane postconditioning. Neurological outcome was assessed daily via sensorimotor scoring. Contributors to DCI including cerebral vasospasm, microvessel thrombosis, and microvascular dysfunction were measured 3 days later. Isoflurane-induced changes in hypoxia-inducible factor 1alpha (HIF-1alpha) dependent genes were assessed via quantitative polymerase chain reaction. HIF 1alpha was inhibited pharmacologically via 2-methoxyestradiol (2ME2) or genetically via endothelial cell HIF-1alpha-null mice (EC-HIF-1alpha-null). All experiments were performed in a randomized and blinded fashion. RESULTS: Isoflurane postconditioning initiated at clinically relevant time points after SAH significantly reduced cerebral vasospasm, microvessel thrombosis, microvascular dysfunction, and neurological deficits in wild-type (WT) mice. Isoflurane modulated HIF-1alpha-dependent genes - changes that were abolished in 2ME2-treated WT mice and EC-HIF-1alpha-null mice. Isoflurane-induced DCI protection was attenuated in 2ME2-treated WT mice and EC-HIF-1alpha-null mice. INTERPRETATION: Isoflurane postconditioning provides strong HIF-1alpha-mediated macro- and microvascular protection in SAH, leading to improved neurological outcome. These results implicate cerebral vessels as a key target for the brain protection afforded by isoflurane postconditioning, and HIF-1alpha as a critical mediator of this vascular protection. They also identify isoflurane postconditioning as a promising novel therapeutic for SAH. PMID- 25909080 TI - Dissociated multimodal hubs and seizures in temporal lobe epilepsy. AB - OBJECTIVE: Brain connectivity at rest is altered in temporal lobe epilepsy (TLE), particularly in "hub" areas such as the posterior default mode network (DMN). Although both functional and anatomical connectivity are disturbed in TLE, the relationships between measures as well as to seizure frequency remain unclear. We aim to clarify these associations using connectivity measures specifically sensitive to hubs. METHODS: Connectivity between 1000 cortical surface parcels was determined in 49 TLE patients and 23 controls with diffusion and resting state functional magnetic resonance imaging. Two types of hub connectivity were investigated across multiple brain modules (the DMN, motor system, etcetera): (1) within-module connectivity (a measure of local importance that assesses a parcel's communication level within its own subnetwork) and (2) between-module connectivity (a measure that assesses connections across multiple modules). RESULTS: In TLE patients, there was lower overall functional integrity of the DMN as well as an increase in posterior hub connections with other modules. Anatomical between-module connectivity was globally decreased. Higher DMN disintegration (DD) coincided with higher anatomical between-module connectivity, whereas both were associated with increased seizure frequency. DD related to seizure frequency through mediating effects of anatomical connectivity, but seizure frequency also correlated with anatomical connectivity through DD, indicating a complex interaction between multimodal networks and symptoms. INTERPRETATION: We provide evidence for dissociated anatomical and functional hub connectivity in TLE. Moreover, shifts in functional hub connections from within to outside the DMN, an overall loss of integrative anatomical communication, and the interaction between the two increase seizure frequency. PMID- 25909081 TI - Identification of distinct circulating exosomes in Parkinson's disease. AB - OBJECTIVE: Whether circulating microvesicles convey bioactive signals in neurodegenerative diseases remains currently unknown. In this study, we investigated the biochemical composition and biological function of exosomes isolated from sera of patients with Parkinson's disease (PD). METHODS: Proteomic analysis was performed on microvesicle preparations from grouped samples of patients with genetic and sporadic forms of PD, amyotrophic lateral sclerosis, and healthy subjects. Nanoparticle-tracking analysis was used to assess the number and size of exosomes between patient groups. To interrogate their biological effect, microvesicles were added to primary rat cortical neurons subjected to either nutrient deprivation or sodium arsenite. RESULTS: Among 1033 proteins identified, 23 exosome-associated proteins were differentially abundant in PD, including the regulator of exosome biogenesis syntenin 1. These protein changes were detected despite similar exosome numbers across groups suggesting that they may reflect exosome subpopulations with distinct functions. Accordingly, we showed in models of neuronal stress that Parkinson's-derived microvesicles have a protective effect. INTERPRETATION: Collectively, these data suggest for the first time that immunophenotyping of circulating exosome subpopulations in PD may lead to a better understanding of the systemic response to neurodegeneration and the development of novel therapeutics. PMID- 25909082 TI - Endplate denervation correlates with Nogo-A muscle expression in amyotrophic lateral sclerosis patients. AB - OBJECTIVE: Data from mouse models of amyotrophic lateral sclerosis (ALS) suggest early morphological changes in neuromuscular junctions (NMJs), with loss of nerve muscle contact. Overexpression of the neurite outgrowth inhibitor Nogo-A in muscle may play a role in this loss of endplate innervation. METHODS: We used confocal and electron microscopy to study the structure of the NMJs in muscle samples collected from nine ALS patients (five early-stage patients and four long term survivors). We correlated the morphological results with clinical and electrophysiological data, and with Nogo-A muscle expression level. RESULTS: Surface electromyography assessment of neuromuscular transmission was abnormal in 3/9 ALS patients. The postsynaptic apparatus was morphologically altered for almost all NMJs (n = 430) analyzed using confocal microscopy. 19.7% of the NMJs were completely denervated (fragmented synaptic gutters and absence of nerve terminal profile). The terminal axonal arborization was usually sparsely branched and 56.8% of innervated NMJs showed a typical reinnervation pattern. Terminal Schwann cell (TSC) morphology was altered with extensive cytoplasmic processes. A marked intrusion of TSCs in the synaptic cleft was seen in some cases, strikingly reducing the synaptic surface available for neuromuscular transmission. Finally, high-level expression of Nogo-A in muscle was significantly associated with higher extent of NMJ denervation and negative functional outcome. INTERPRETATION: Our results support the hypothesis that morphological alterations of NMJs are present from early-stage disease and may significantly contribute to functional motor impairment in ALS patients. Muscle expression of Nogo-A is associated with NMJ denervation and thus constitutes a therapeutic target to slow disease progression. PMID- 25909083 TI - Comparative efficacy of switching to natalizumab in active multiple sclerosis. AB - OBJECTIVE: To compare treatment efficacy and persistence in patients who switched to natalizumab versus those who switched between glatiramer acetate (GA) and interferon-beta (IFNbeta) after an on-treatment relapse on IFNbeta or GA using propensity score matched real-world datasets. METHODS: Patients included were registered in MSBase or the TYSABRI Observational Program (TOP), had relapsed on IFNbeta or GA within 12 months prior to switching to another therapy, and had initiated natalizumab or IFNbeta/GA treatment <=6 months after discontinuing prior therapy. Covariates were balanced across post switch treatment groups by propensity score matching at treatment initiation. Relapse, persistence, and disability measures were compared between matched treatment arms in the total population (n = 869/group) and in subgroups defined by prior treatment history (IFNbeta only [n = 578/group], GA only [n = 165/group], or both IFNbeta and GA [n = 176/group]). RESULTS: Compared to switching between IFNbeta and GA, switching to natalizumab reduced annualized relapse rate in year one by 65-75%, the risk of first relapse by 53-82% (mean follow-up 1.7-2.2 years) and treatment discontinuation events by 48-65% (all P <= 0.001). In the total population, switching to natalizumab reduced the risk of confirmed disability progression by 26% (P = 0.036) and decreased the total disability burden by 1.54 EDSS-years (P < 0.0001) over the first 24 months post switch. INTERPRETATION: Using large, real world, propensity-matched datasets we demonstrate that after a relapse on IFNbeta or GA, switching to natalizumab (rather than between IFNbeta and GA) led to superior outcomes for patients in all measures assessed. Results were consistent regardless of the prior treatment identity. PMID- 25909084 TI - Blocking GluR2-GAPDH ameliorates experimental autoimmune encephalomyelitis. AB - OBJECTIVE: Multiple sclerosis (MS) is the most common disabling neurological disease of young adults. The pathophysiological mechanism of MS remains largely unknown and no cure is available. Current clinical treatments for MS modulate the immune system, with the rationale that autoimmunity is at the core of MS pathophysiology. METHODS: Experimental autoimmune encephalitis (EAE) was induced in mice with MOG35-55 and clinical scoring was performed to monitor signs of paralysis. EAE mice were injected intraperitoneally with TAT-fusion peptides daily from day 10 until day 30 after immunization, and their effects were measured at day 17 or day 30. RESULTS: We report a novel target for the development of MS therapy, which aimed at blocking glutamate-mediated neurotoxicity through targeting the interaction between the AMPA (2-amino-3-(3 hydroxy-5-methyl-isoxazol-4-yl) propanoic acid) receptor and an interacting protein. We found that protein complex composed of the GluR2 subunit of AMPA receptors and GAPDH (glyceraldehyde-3-phosphate dehydrogenase) was present at significantly higher levels in postmortem tissue from MS patients and in EAE mice, an animal model for MS. Next, we developed a peptide that specifically disrupts the GluR2 -GAPDH complex. This peptide greatly improves neurological function in EAE mice, reduces neuron death, rescues demyelination, increases oligodendrocyte survival, and reduces axonal damage in the spinal cords of EAE mice. More importantly, our peptide has no direct suppressive effect on naive T cell responses or basal neurotransmission. INTERPRETATION: The GluR2 -GAPDH complex represents a novel therapeutic target for the development of medications for MS that work through a different mechanism than existing treatments. PMID- 25909085 TI - Methionine increases BDNF DNA methylation and improves memory in epilepsy. AB - OBJECTIVE: Temporal lobe epilepsy (TLE) patients exhibit signs of memory impairments even when seizures are pharmacologically controlled. Surprisingly, the underlying molecular mechanisms involved in TLE-associated memory impairments remain elusive. Memory consolidation requires epigenetic transcriptional regulation of genes in the hippocampus; therefore, we aimed to determine how epigenetic DNA methylation mechanisms affect learning-induced transcription of memory-permissive genes in the epileptic hippocampus. METHODS: Using the kainate rodent model of TLE and focusing on the brain-derived neurotrophic factor (Bdnf) gene as a candidate of DNA methylation-mediated transcription, we analyzed DNA methylation levels in epileptic rats following learning. After detection of aberrant DNA methylation at the Bdnf gene, we investigated functional effects of altered DNA methylation on hippocampus-dependent memory formation in our TLE rodent model. RESULTS: We found that behaviorally driven BdnfDNA methylation was associated with hippocampus-dependent memory deficits. Bisulfite sequencing revealed that decreased BdnfDNA methylation levels strongly correlated with abnormally high levels of BdnfmRNA in the epileptic hippocampus during memory consolidation. Methyl supplementation via methionine (Met) increased BdnfDNA methylation and reduced BdnfmRNA levels in the epileptic hippocampus during memory consolidation. Met administration reduced interictal spike activity, increased theta rhythm power, and reversed memory deficits in epileptic animals. The rescue effect of Met treatment on learning-induced BdnfDNA methylation, Bdnf gene expression, and hippocampus-dependent memory, were attenuated by DNA methyltransferase blockade. INTERPRETATION: Our findings suggest that manipulation of DNA methylation in the epileptic hippocampus should be considered as a viable treatment option to ameliorate memory impairments associated with TLE. PMID- 25909087 TI - Short pulse width widens the therapeutic window of subthalamic neurostimulation. AB - We explored the impact of pulse durations <60 MUsec on the therapeutic window of subthalamic neurostimulation in Parkinson's disease. Current thresholds for full rigidity control and first muscle contractions were evaluated at pulse durations between 20 and 120 MUsec during a monopolar review session in four patients. The average therapeutic window was 2.16 mA at 60 MUsec, which proportionally increased by 182% at 30 MUsec, while decreasing by 46% at 120 MUsec. Measured chronaxies and model data suggest, that pulse durations <60 MUsec lead to a focusing of the neurostimulation effect on smaller diameter axons close to the electrode while avoiding stimulation of distant pyramidal tract fibers. PMID- 25909088 TI - Progressive decline of glucocerebrosidase in aging and Parkinson's disease. AB - The principal risk factor for developing most adult onset neurodegenerative diseases is aging, with incidence rising significantly after age 50. Despite research efforts, the causes of Parkinson's disease (PD) remain unknown. As neurons age, they show signs of diminished lysosomal and mitochondrial function, including increased oxidative stress and accumulation of misfolded proteins, and these changes become exacerbated PD. We show that activity of the lysosomal hydrolase glucocerebrosidase gradually diminishes with age in the substantia nigra and putamen of healthy controls. This reduction is comparable to glucocerebrosidase activity in GBA1-mutation carrier PD patients. These data, demonstrate for the first time that an age-dependent reduction in glucocerebrosidase activity may lower the threshold for developing PD. PMID- 25909086 TI - Variants associated with Gaucher disease in multiple system atrophy. AB - OBJECTIVE: Glucocerebrosidase gene (GBA) variants that cause Gaucher disease are associated with Parkinson disease (PD) and dementia with Lewy bodies (DLB). To investigate the role of GBA variants in multiple system atrophy (MSA), we analyzed GBA variants in a large case-control series. METHODS: We sequenced coding regions and flanking splice sites of GBA in 969 MSA patients (574 Japanese, 223 European, and 172 North American) and 1509 control subjects (900 Japanese, 315 European, and 294 North American). We focused solely on Gaucher disease-causing GBA variants. RESULTS: In the Japanese series, we found nine carriers among the MSA patients (1.65%) and eight carriers among the control subjects (0.89%). In the European series, we found three carriers among the MSA patients (1.35%) and two carriers among the control subjects (0.63%). In the North American series, we found five carriers among the MSA patients (2.91%) and one carrier among the control subjects (0.34%). Subjecting each series to a Mantel-Haenszel analysis yielded a pooled odds ratio (OR) of 2.44 (95% confidence interval [CI], 1.14-5.21) and a P-value of 0.029 without evidence of significant heterogeneity. Logistic regression analysis yielded similar results, with an adjusted OR of 2.43 (95% CI 1.15-5.37) and a P-value of 0.022. Subtype analysis showed that Gaucher-disease-causing GBA variants are significantly associated with MSA cerebellar subtype (MSA-C) patients (P = 7.3 * 10(-3)). INTERPRETATION: The findings indicate that, as in PD and DLB, Gaucher-disease-causing GBA variants are associated with MSA. PMID- 25909089 TI - Long survival in a child with a mutated K27M-H3.3 pilocytic astrocytoma. AB - We report the first case of a child with a H3F3A K27M mutated pilocytic astrocytoma, who presented with a 10 years survival, and underwent spontaneous malignant transformation. The complex tumoral chromosomal rearrangements were consistent for genomic instability and for the histopathological features of malignant transformation into glioblastoma. H3F3A K27M mutations are rarely observed in benign neoplasms and may be associated with an adverse outcome. This mutation might not be the major driver that led to the onset of tumorigenesis, and we could consider that the associated TP53 mutation, would be required for malignant transformation. PMID- 25909091 TI - The growing spectrum of antibody-associated inflammatory brain diseases in children. AB - OBJECTIVE: To describe the clinical spectrum, diagnostic evaluation, current management, and neurologic outcome of pediatric antibody-associated inflammatory brain diseases (AB-associated IBrainD). METHODS: We performed a single-center retrospective cohort study of consecutive patients aged <=18 years diagnosed with an AB-associated IBrainD at The Hospital for Sick Children, Toronto, Ontario, Canada, between January 2005 and June 2013. Standardized clinical data, laboratory test results, neuroimaging features, and treatment regimens were captured. RESULTS: Of 169 children (93 female, 55%) diagnosed with an IBrainD, 16 (10%) had an AB-associated IBrainD. Median age at presentation was 13.3 years (range 3.1-17.9); 11 (69%) were female. Nine patients (56%) had anti-NMDA receptor encephalitis, 4 (25%) had aquaporin-4 autoimmunity, 2 (13%) had Hashimoto encephalitis, and 1 (6%) had anti-glutamic acid decarboxylase 65 (GAD65) encephalitis. The key presenting features in children with anti-NMDA receptor encephalitis, Hashimoto encephalopathy, and anti-GAD65 encephalitis included encephalopathy, behavioral symptoms, and seizures; patients with aquaporin-4 autoimmunity showed characteristic focal neurologic deficits. Six patients (38%) required intensive care unit admission at presentation. Median time from symptom onset to diagnosis was 55 days (range 6-358). All but 1 patient received immunosuppressive therapy. One child with anti-NMDA receptor encephalitis died due to multiorgan failure. At last follow-up, after a median follow-up time of 1.7 years (range 0.8-3.7), 27% of the children had function limiting neurologic sequelae. CONCLUSIONS: Children with AB-associated IBrainD represent an increasing subgroup among IBrainD; 1 in 4 children has function limiting residual neurologic deficits. Awareness of the different clinical patterns is important in order to facilitate timely diagnosis and initiate immunosuppressive treatment. PMID- 25909092 TI - Observability of Neuronal Network Motifs. AB - We quantify observability in small (3 node) neuronal networks as a function of 1) the connection topology and symmetry, 2) the measured nodes, and 3) the nodal dynamics (linear and nonlinear). We find that typical observability metrics for 3 neuron motifs range over several orders of magnitude, depending upon topology, and for motifs containing symmetry the network observability decreases when observing from particularly confounded nodes. Nonlinearities in the nodal equations generally decrease the average network observability and full network information becomes available only in limited regions of the system phase space. Our findings demonstrate that such networks are partially observable, and suggest their potential efficacy in reconstructing network dynamics from limited measurement data. How well such strategies can be used to reconstruct and control network dynamics in experimental settings is a subject for future experimental work. PMID- 25909093 TI - A MULTISCALE COMPUTATIONAL MODEL FOR THE GROWTH OF THE CRANIAL VAULT IN CRANIOSYNOSTOSIS. AB - Craniosynostosis is a condition defined by premature closure of cranial vault sutures, which is associated with abnormalities of the brain and skull. Many causal relationships between discovered mutations and premature suture closure have been proposed but an understanding of the precise mechanisms remains elusive. This article describes a computational framework of biological processes underlying cranial growth that will enable a hypothesis driven investigation of craniosynostosis phenotypes using reaction-diffusion-advection methods and the finite element method. Primary centers of ossification in cranial vault are found using activator-substrate model that represents the behavior of key molecules for bone formation. Biomechanical effects due to the interaction between growing bone and soft tissue is investigated to elucidate the mechanism of growth of cranial vault. PMID- 25909094 TI - Where dentistry is headed. PMID- 25909095 TI - Assessment of the physicochemical conditions sediments in a polluted tidal flat colonized by microbial mats in Bahia Blanca Estuary (Argentina). AB - The aim of this work is to assess the physicochemical conditions of the supratidal sediments colonized by microbial mats at two sites from Rosales Harbor (Bahia Blanca Estuary, Argentina) close to sewage discharge. Both sites differed in the size grain. No differences in pH, Eh and temperature were observed. Moisture retention and chlorophyll a concentration were significantly different between sites and sediment layers. Heavy metals and organic matter content were significantly higher in SII. No statistical differences were found in porewater nutrients concentration, being higher in SI (except DSi). The presence of Escherichia coli in water and sediment (1000 CFU/100 mL - uncountable and 35-40 CFU g(-1) dw, respectively) evidenced microbial contamination in the study area. The relationships between the physicochemical parameters evaluated and the influence of the sewage discharge allow defining two different areas in the Rosales Harbor despite the proximity and the presence of microbial mats. PMID- 25909098 TI - Cardiovascular risks associated with non-aspirin non-steroidal anti-inflammatory drug use. PMID- 25909099 TI - Mediation--an alternative to litigation in medical malpractice. PMID- 25909100 TI - Clinical and pathology disciplines. PMID- 25909101 TI - Bureaucracy and clinical performance. PMID- 25909102 TI - A puzzling case of cryptococcal meningitis. PMID- 25909103 TI - Dr Mary Gordon. PMID- 25909105 TI - Emergency care doctors--'off-task and in the wrong places'. PMID- 25909104 TI - Ebola global response: 'not in my back yard'. PMID- 25909106 TI - The smell of coffee, blood and disinfectant ... . PMID- 25909107 TI - Discard the placenta at your peril, pathologist warns doctors. PMID- 25909108 TI - Blood-borne infections in healthcare workers in South Africa. AB - The risks associated with infection of healthcare workers and students with blood borne pathogens, specifically HIV, hepatitis B virus and hepatitis C virus, are often neglected. South Africa (SA) currently has no official policies or guidelines in place for the prevention and management of these infections. This article reviews the available data and international guidelines with regard to infected healthcare practitioners and makes minimum recommendations for the SA setting. PMID- 25909109 TI - Impressions of defensive medical practice and medical litigation among South African neurosurgeons. AB - From a litigation perspective, neurosurgery is considered a 'super high-risk' field, and this has been associated with rapidly increasing malpractice cover costs. In 2013 the annual Medical Protection Society fee for cover was R250,900. We wished to determine whether high malpractice cover was influencing how neurosurgeons managed patients. A 40-question online survey asking questions on defensive medicine was distributed to determine perceptions around liability risk and whether these influenced how patients were managed. Eighty-four per cent of respondents agreed that a medicolegal crisis existed, and over half (53.8%) had been sued for malpractice during their career. Altering practice behaviour to minimise the risk of a lawsuit is common. The increasing number of legal claims against respondents in this survey has resulted in most neurosurgeons practising defensive medicine. Arguably this will result in increased healthcare costs, inferior patient care and decreased access to skilled surgeons. PMID- 25909110 TI - The impact of the Consumer Protection Act on pharmacists. AB - The Consumer Protection Act of 2008 has had far-reaching consequences for suppliers of goods and services in South Africa. The implementation of the Act has important implications for all suppliers who enter into 'consumer transactions.' This article aims to stimulate awareness of the legal consequences of the Act arising from day-to-day situations occurring in the pharmacy, and to highlight the compliance obligations that the Act creates for pharmacists. PMID- 25909111 TI - Interference with the clinical independence of doctors in hospitals faced with a shortage of resources: what should doctors do? AB - In the face of interference with their clinical independence in hospitals with a shortage of resources, what should doctors do? The question can be answered by considering: (i) the constitutional right to healthcare and emergency treatment; (ii) the common-law position regarding unlawful homicide and the doctrine of 'superior orders'; (iii) the ethical rules of the Health Professions Council of South Africa; and (iv) whether there is any protection for doctors who refuse to carry out unprofessional, unethical or unlawful directives from their superiors. While this article focuses on the public sector, some of the legal principles, where relevant, apply equally to doctors in the private sector. PMID- 25909112 TI - Recommendations for the management of sickle cell disease in South Africa. AB - The spectrum of sickle cell disease (SCD) encompasses a heterogeneous group of disorders that include: (I) homozygous SCD (HbSS), also referred to as sickle cell anaemia; (ii) heterozygous SCD (HbAS), also referred to as sickle cell trait; and (iii) compound heterozygous states such as HbSC disease, HbSbeta thalassaemia, etc. Homozygous or compound heterozygous SCD patients manifest with clinical disease of varying severity that is influenced by biological and environmental factors, whereas subject with sickle cell trait are largely asymptomatic. SCD is characterized by vaso-occlusive episodes that result in tissue ischaemia and pain in the affected region. Repeated infarctive episodes cause organ damage and may eventually lead to organ failure. For effective management, regular follow-up with support from a multidisciplinary healthcare team is necessary. The chronic nature of the disease, the steady increase in patient numbers, and relapsing acute episodes have cost implications that are likely to impact on provincial and national health budgets. Limited resources mandate local management protocols for the purposes of consistency and standardisation, which could also facilitate sharing of resources between centres for maximal utility. These recommendations have been developed for the South African setting, and it is intended to update them regularly to meet new demands and challenges. PMID- 25909113 TI - Public somnambulism: a general lack of awareness of the consequences of increasing medical negligence litigation. PMID- 25909114 TI - Ebola virus disease in West Africa--South African perspectives. PMID- 25909115 TI - Compensation for research injuries: thoughts from a human research ethics committee chair. PMID- 25909116 TI - Who will guard the guards? Medical leadership and conflict of interest in South African healthcare. PMID- 25909117 TI - Compensation for research-related harm: the implications of Venter v Roche Products (Pty) Limited and Others for research ethics committees. AB - BACKGROUND: The issue of what type of compensation a research participant would be entitled to in a clinical trial when they have signed an informed consent document excluding certain forms of compensation recently came before our courts in the matter of Venter v Roche Products (Pty) Limited and Others (Case No. 12285/08). In this case, the court had to consider whether the plaintiff, Mr Venter, was entitled to claim for non-medical costs such as pain and suffering, loss of income and general damages, even though the informed-consent document expressly excluded such claims. OBJECTIVES: To set out the facts, issues and judgment in the case, concluding with a discussion of the implications of the judgment for research ethics committees (RECs). METHODS: Critical review of a judgment of the Western Cape High Court. RESULTS: The court concluded that Mr Venter's application for damages should be dismissed because he had voluntarily agreed to the limited compensation as set out in the informed consent form that had been approved by both the local RECs and the Medicines Control Council. CONCLUSIONS: The Venter case has shown that delictual claims for research-related injuries will not be successful if plaintiffs have agreed to limit their own rights through signing an informed-consent form that limits compensation. This places an important obligation on RECs to ensure that they carefully review compensation clauses in informed-consent documents and that these are made clear to potential research participants. PMID- 25909118 TI - Appropriateness of computed tomography and magnetic resonance imaging scans in the Eden and Central Karoo districts of the Western Cape Province, South Africa. AB - INTRODUCTION: Computed tomography (CT) and magnetic resonance imaging (MRI) are an essential part of modern healthcare. Marked increases in clinical demand for these imaging modalities are straining healthcare expenditure and threatening health system sustainability. The number of CT and MRI scans requested in the Eden and Central Karoo districts of the Western Cape Province, South Africa (SA), almost doubled from 2011 to 2013. OBJECTIVE: To determine the appropriateness of CT and MRI scans and relate this to the requesting department and clinician. METHODS: This was a retrospective analytical cohort study. All scans during October 2012 were analysed as a sample. Appropriateness of scans was determined using the American College of Radiologists (ACR) Appropriateness Criteria and the Royal College of Radiology Guidelines. Appropriateness was also correlated back to the requesting department and clinician. RESULTS: Of a total of 219 scans, 53.0% were abnormal. Overall 6.4% of scans were considered inappropriate. Interns and registrars requested no inappropriate scans. The orthopaedics department scored the highest rate of appropriate scans (80.0%) and the oncology department the highest rate of inappropriate scans (20.8%). CONCLUSION: The limited resources available for healthcare in a developing country like SA should be a motivation to implement control mechanisms aimed at appropriate utilisation of imaging examinations. The Eden and Central Karoo districts have a low rate of inappropriate scans (6.4%). We recommend that the current preauthorisation system by consultants and other senior clinicians continues, but with increased clinician awareness of the ACR Appropriateness Criteria and the Royal College guidelines. PMID- 25909119 TI - A laboratory-based study to identify and speciate non-tuberculous mycobacteria isolated from specimens submitted to a central tuberculosis laboratory from throughout KwaZulu-Natal Province, South Africa. AB - BACKGROUND: Non-tuberculous mycobacteria (NTM) are important environmental pathogens capable of causing a spectrum of infection. The different species exhibit varied geographical prevalence worldwide. Identification of the infecting organism may be helpful in determining the clinical significance of the isolate. OBJECTIVE: To describe the spectrum of NTM isolated from clinical specimens received at the National Health Laboratory Service central tuberculosis laboratory in KwaZulu-Natal Province, South Africa. METHOD: In a laboratory-based prospective study, 200 suspected NTM were randomly selected over a period of 1 year and identified to species level using a commercially available DNA strip assay (GenoType Mycobacterium, CM/AS; Hain Lifescience, Germany). RESULTS: Of the 200 suspected NTM, 133 (66.5%) were confirmed to be NTM by the molecular test. The most frequently isolated NTM species were Mycobacterium intracellulare (45.9%), M. avium subspecies (11.3%), M. gordonae (6.0%) and M. kansasii (4.5%). CONCLUSION: It is important for laboratories to document the local spectrum of NTM because of the geographical variation in the different NTM species isolated. Although molecular tests for identifying NTM are relatively expensive, they have the advantage of providing rapid and accurate identification of the various NTM species. PMID- 25909120 TI - Immunology as a medical discipline in South Africa: why, how and what form? PMID- 25909121 TI - Superheroes in autoimmune warfare: biologic therapies in current South African practice. AB - Biologic drugs targeting immune cells or cytokines underlying systemic inflammation have dramatically improved outcomes in patients with rheumatological and autoimmune diseases. Nine biologic drugs are currently available in South Africa (SA)--all showing good efficacy and safety profiles. Their high cost and potential adverse events preclude them from being used as first-line agents. They are therefore indicated for severe disease refractory to standard therapies, and their use must be initiated by a specialist. The most important adverse effect of this class of drugs is infection and, in SA, tuberculosis is of particular concern. As new targets in the immune system are identified, new biologics will be developed. The current challenges are to optimise standard care for all patients with autoimmune diseases, and to offer the appropriate biologic to patients with refractory disease. PMID- 25909122 TI - [Identification the risk of preterm labor :the role of fetal fibronectin]. AB - Fibronectins represent a group of glycoproteins, which form "molecular glue" and are necessary in the interaction between a cell and a cell. The existence of fetal fibronectin in pregnant woman's vagina up to 22 g.w. is normal. In a normally proceeding pregnancy between 22 g.w. and 35 g.w. there is not supposed to be found fetal fibronectin in cervico-vaginal secretion. Its presence is a highly informative biological marker for the risk of premature birth. AIM: The aim of this research was to determine the risk for premature birth through applying fetal fibronectin test as a specific marker to pregnant women with or withthout symptoms of threatened birth. METHODS: A prospective longitudinal study has been carried out. The tests have been applied to hospitalized patients in University hospital "Majchin dom", Clinic of Pathologic pregnancy and Delivery room. Tests have been applied on 116 patients in totally). The pregnant have been separated in two groups depending on the fact of presence or absence of premature birth symptoms. The screening methods used were: the fFN test and the cervical length measurement by transvaginal according to an established protocol. CONCLUSION: From the total of 116 patients, in 78 we have received positive tests for fetal fibronectin; in 38 - negative test. With asymptomatic patients, having higher risk of preterm birth, the percent of positive tests has been lower (14%). With asymptomatic patients with higher percent of risk factors have been: short cervix (38%), multiple pregnancy (29%), followed by patients with diagnosis of preterm birth in the past (25%) and bleeding in earlier terms. Estimating positive and negative predictive rate, we have achieved following results: The test for fetal fibronectin has excellent predictive rate - 97%, which coincides with the great deal of research until this moment in the world. Referring to the positive predictive rate--it is not sufficient--only 19%. PMID- 25909123 TI - [Inadequate antenatal care as a factor for prematurity]. AB - The study aims to analyze the impact of the implementation of the program "Maternal Health" as a factor for the premature birth in town of Pleven, 2007. A case-control study among preterm and term infants and their mothers regarding the implementation of the "Maternal Health" during pregnancy were conducted. Studied factors increase the likelihood of a premature birth are: late coverage (timing) of the program "Maternal Health" (OR = 4.23 95% CI 1.41-12.69); less than 5 visits to the specialist (OR = 4.96 95% CI 1.65-14.95); 2 ultrasound examination (OR = 2.45 95% CI = 1.27-4.71); perform additional tests OR = (6.02 95% CI 2.08 17.42). Quality and overall performance of the "Maternal Health" program and adequate antenatal care are the leading factor for the prevention of prematurity. PMID- 25909124 TI - [Ca-125 in diagnosis and monitoring of patients with ovarian cancer]. AB - The carbohydrated antigen Ca-125 is identified by Bast et al. in 1981. The cut off value of 35 KU/l for serum levels of the marker covers in fact 98-99% of the healthy women. There are some variations in the levels of pre- and post menopausal women, and also some race- dependent and cycle-dependent differences. Although Ca-125 is the only one accepted tumor marker for ovarian cancer, its screening usage is controversial, because of the high percentage of false positive results. Ca-125 and HE4 are both validated serum markers for differential diagnose of pelvic masses. The Ca-125 main role is monitoring patients, having ovarian cancer in their chemotherapy, early recurrence finding and progression. Ca-125 rising values in monitoring patients are predictor of image or clinical recurrence in 59-96% of the cases. FDG PET/CT gave a new standard in ovarian cancer staging, especially in patients, having high levels of Ca-125, but negative conventional imaging examinations. PMID- 25909125 TI - [Surgical staging and lymph node status in patients with invasive cervical cancer]. AB - Lymph node matastases (LNM) are the most important prognostic factor of the cervical cancer regardless the stage and other prognostic factors. Lymph node status is the basis for tailoring the management strategies. In negative for metastases lymph nodes adjuvant radiotherapy can be omitted, as well as the risk for complications. LNM can be detected by histopathologic examination after meticulous lymphadenectomy. Other methods for detection of LNM such as PET/CT, CT, MRI, frozen section, sentinel lymph node biopsy have low sensitivity. PMID- 25909126 TI - [Fertility-sparing surgery in borderline ovarian tumours]. AB - Borderline ovarian tumours (BOTs) account for 10-15% of all ovarian tumours. They affect a younger age group than the ovarian carcinoma and have a much better prognosis. Over the last decades, the management of borderline ovarian tumors has changed from radical surgery to more conservative therapy as a result of the need for fertility-sparing surgery and the increasing use of laparoscopy. Fertility sparing surgery is defined as surgery with complete staging, but where the uterus and at least a part of one ovary are preserved. It presents a good option in young patients with early-stage disease or in selected cases with noninvasive implants, since long-term survival does not seem to be negatively influenced by conservative surgery. This review will outline the most recent information regarding fertility sparing surgery and controversial issues of BOT. PMID- 25909127 TI - [Management in advanced germ-cell tumors--report of two cases]. AB - The germ-cells tumors are the most common ovarian malignancy in young women between 15-25 years. Often advanced disease is present at the time of diagnosis. The management and treatment approaches of disgerminoma and immature teratoma, as most common germ-cells tumors (GST), are presented. Two clinical cases of advanced stages of GST with complete remision after conservative surgical treatment and chemotherapy have been reviewed. PMID- 25909128 TI - [Prenatal diagnosis and fetoscopic tracheal occlusion (FETO) for severe congenital diaphragmatic hernia. Case report]. AB - We present a case of severe isolated congenital diaphragmatic hernia (CDH) diagnosed at 19 weeks of gestation and treated at 28 weeks with Fetal Endoscopic Tracheal Occlusion (FETO). The CDH was left-sided with part of the liver in the thorax and lung area to head circumference ratio (LHR) of 0.9. The FETO was successfully performed under spinal anesthesia. The pregnancy is progressing uneventfully and ultrasound examination 10 days after the FETO demonstrated an increased LHR to 1.1. Treatment with FETO for severe CDH has been performed for the first time in Bulgaria and this procedure addressed several questions for optimal management by an experienced interdisciplinary team. PMID- 25909129 TI - [Leiomyosarcoma of the vagina: a case report and review from the literature]. AB - Leiomiosarcoma of the vagina is a very rare condition and that is why there is no standard treatment of this disease. We describe a 35 year old woman with vaginal leiomyosarcoma to whom was accomplished a complete surgical treatment and no postoperative radiation or chimiotherapy. Tumor recurrence was not detected for the last 6 months. PMID- 25909130 TI - [Breast metastasis of a squamous cell carcinoma of the uterine cervix. A case report]. AB - The breast is an extremely rare target organ for metastasis of extramammary neoplasms. The occurence varies between 1.7% to 6.6% in autopsies; between 1.2% and 2% in clinical cases; and around 2.7% in sputum series. In accordance with the primary tumor localization, it is more common to find metastases of lymphoma, melanoma, rhabdomyosarcoma, tumors of the lung and ovarian tumors. Breast metastasis of the uterine cervix is a very seldomly found. According to the published literature so far there have been around 30 documented cases with such pathology. This study presents the case of a 48-year-old female with a squamous cell carcinoma of the uterine cervix, which was histologically verified in 2010. Three years after the initial tumor diagnosis, radiotherapy and chemotherapy, the patient was found to have a cystic tumor formation in one of her breasts. The formation was painful to pressure. Quadrantectomy with an open bisopsy was performed to the patient. Histological and immunohistochemical diagnosis rejected primary squamous cell carcinoma of the breast. The differential diagnosis of metastatic lesions in the breast is problematic and requires careful clinical history, immunohistochemical study and multidisciplinary approach in the management. Mammary metastases are a bad predictor and they serve as an indicator of generalized dissemination of the primary tumor process. PMID- 25909131 TI - [A case of gynandroblastoma in a 16-year old girl and review of literature]. AB - An ovarian tumor (gynandroblastoma) in a 16-year old girl is reported. Clinical presentation include abdominal pain, signs of virilization and irregular menstrual cycles. Ultrasound scan examination reveals a cystic mass in a left ovary. The patient underwent a left ovariosalpingectomy. Grossly, a cystic mass (73 x 42 x 36 mm) with smooth outer surface and with many cysts was found in the left ovary. The intraoperative diagnosis was ovarian adenocarcinoma. Postoperative histological examination reveals that the tumor was presented by two patterns- nodules and nests of juvenile granulose cell pattern admixed with Sertoli-Leydig pattern as tubules and cyst and scanty Sertoli cells. On immunohistochemical staining the Granulosa cells were negative for cytokeratin AE1-AE3 and positive for Vimentin. The Sertoli cells were androgen receptor positive. A year after operation the patient had no abdominal pain, the menstrual cycles are regular but the virilization persist. Histogenesis and differential diagnosis are discussed. PMID- 25909132 TI - [Malignant vascular tumors of the vulva]. AB - Due to the increased vascularity as well as the unique anatomical structure, vascular lesions, which occur in the female reproductive system are common observed and diverse by their morphology. The majority of them are benign, including vascular malformations, lesions due to vascular hyperplasia, tumors with significant vascular component and others. Malignant vascular tumors are rare in the area of the vulva accounting about 1% of all vulvar lesions with vascular origin. Kaposi sarcoma, epithelioid hemangioepithelioma and epithelioid angiosarcoma have been reported with vulvar localization. With a view to their rare incidence, nonspecific clinical manifestation and aggressive behavior associated with high mortality, we present the most common malignant tumors of vascular origin arising in the vulva, as we emphasize on their epidemiology and clinical features, differential diagnosis and therapeutic algorithms for this rare type of malignancies. PMID- 25909133 TI - [New screening method for aneuploidies based on analysis of cell-free DNA in the maternal blood]. AB - The national program of screening for aneuploidies in Bulgaria is based on first trimester combined test, second trimester biochemical test and/or the combination between first and second trimester integrated test. OBJECTIVE: To review the literature for studies analyzing cell-free (cf) DNA in the maternal blood and to report the clinical implementation and validation of the method in the clinical practice. Literature search and study selection extracted studies since 2011 when the first article was published. The data source included searches from PubMed and Medline. The reported results for detection rates (DR) and false positive rates (FPR) in singleton pregnancies were about 99.0% and 0.08% respectively, for trisomy 21, 96.8% and 0.15% for trisomy 18, 92.1% and 0.20% for trisomy 13, 88.6% and 0.12% for monosomy X. For twin pregnancies, the DR was 94.4% and FPR was 0% for trisomy 21. CONCLUSION: Analysis of cell-free DNA in the maternal blood is an effective method of screening for aneuploidies. PMID- 25909134 TI - [Types of hospital property and the relative rate of cesarean section occurrence]. AB - AIM: To determine the influential significance of types of hospital property over methods of delivery and other related medical issues METHODS AND MATERIALS: The research includes 61 662 deliveries over the period of 01.01.2013-31.12.2013, registered in the Birth Information System (BIS) maintained by the National Center of Public Health and Analyses . It is a retrospective research that compares the portion of cesarean sections (C-sections), premature births, the birth weight of newborns, and APGAR scores at the first minute after birth in three types of hospitals, divided by their property types--municipal, state owned, and private. Alternate analysis has been used--comparison of relative portion indices. We used t-test to determine significant differences among surveyed indicators with established level of significance p < 0.05. RESULTS: The rate of C-sections out of all deliveries for the period of 2013 totals 38.40%. One can determine important differences in this rate among different types of hospitals, the highest rate reaching 59.63% in private hospitals. Health institutions with more than 1000 deliveries per year also show a greater amount of accomplished c-sections. The percentage of birth before 37 weeks of gestation and of birth weight below 2500 g is greatest in state owned hospitals, and the portion of newborns with APGAR scores measuring above 7 is greatest in municipal hospitals. CONCLUSIONS: There is a tendency in the rise of the portion of c sections, and from 2012 to 2013 this rise runs up to 2.39%. However, there is a lack of data to relate significant greater proportion of c-section deliveries in private hospitals to any medical reasons. Therefore, some additional research should be done to give a more objective explanation to the reasons as well as the consequences that follow a change in obstetrical behavior that eventually leads to a rise in c-section deliveries. PMID- 25909135 TI - [Breast cancer developing during pregnancy--clinical cases and review of the literature]. AB - The goal of the present paper is to discuss diagnosis, treatment approaches and histopathologic characteristics of breast cancer developing during pregnancy, based on our results and published literature data. We retrospectively evaluated clinical and pathologic features of tumors, treatment methods, decisions related to pregnancy and final outcome by eight pregnant patients with breast cancer. The patients' age varied from 26 to 36 years. At the last medical examination in October 2013, three among all eight patients were alive, two of them were without local and distant recurrence, and one patient has distant metastases and is carrying out a treatment. The aim of this paper was to discuss the characteristics of breast cancer developing during pregnancy. Retrospectively have been analyzed clinical-pathological characteristics of the tumors in eight pregnant women with breast cancer, the treatment, the management of the pregnancy, and the final outcome. The results are analyzed by comparing with data published in the literature. PMID- 25909136 TI - [Histological subtypes of ovarian carcinoma and their importance for clinical prognosis]. AB - Ovarian cancer is one of the most common and most lethal cancers. For Bulgaria (2012) it occupies third place in the structure of gynecological malignancies with a share of 22.6 percent, while regarding mortality is at first place with 35.7 percent. New cases are 838 with crude incidence 22.3 x 10(5), and the deaths are 463 with crude mortality 12.3 x 10(5). Ovarian tumors, even when they are of the same histological type clearly differ in their cellular differentiation, molecular characteristiques and subsequently in their biological behavior. In this review, we discuss the frequency origin, morphology and molecular characteristiques of the five major subtypes of ovarian cancer--serous low and high grade, mucinous, endometroid and and clear cell. The role of different risk and prognostic factors for the efficiency of the treatment and control of disease been discussed. PMID- 25909137 TI - [Uterine smooth muscle tumors--direction of differentiation and morphological features]. AB - Uterine smooth muscle tumors /USMT/ are the most common tumors of the female reproductive system. The main aim of the clinical histological classification and the grading of MGMT is to predict their progression. The diagnosis of USMT has of the following stages: the determination of the direction of differentiation of the tumor and the defining the morphological features (the mitotic index, the tumor necrosis and the cellular atypia). In each of them there are specific problems. This indicates, that the USMT are therapeutic and clinical challenge. PMID- 25909138 TI - [Squamous cell carcinoma (SCC)--nature and usage in patients with cervical carcinoma]. AB - Squamous cell carcinoma antigen (SCC) is isolated as a heterologic antiserum against cells of cervical carcinoma in 1977 by Kato u Torigoe. It is not specific for cervical carcinoma and rises up in cases of carcinoma vulvae, esophageal carcinoma, carcinoma pulmonum, ext. High levels are detected also in psoriasis, sarcoidosis, liver and kidney diseases. SCC is not a reliable marker in diagnosis and screening. Some trials show a correlation between the preterapeutic levels of SCC and the prognosis, but none of them is randomized. So the predictive value of SCC, except the nodal metastasis, stays on a low level of evidence and recommendation. On the contrary is the data for SCC as a monitoring marker for a local recurrence in patients after primary treatment. The sensitivity and specificity of the marker for a cervical carcinoma recurrence varies between 56 and 86% sensitivity and 83 and 100% specificity. A new possibility for an early recurrence finding in patients with rising SCC gives FDG PET/CT. The method is highly potent in detection of local recurrence and distant metastasis in patients with cervical carcinoma and is suitable for staging, restaging and monitoring of these patients. PMID- 25909139 TI - [Fertility--preserve approaches in the surgery of cervical cancer]. AB - Review was made of the literature about the long time used techniques Vaginal radical trachelectomy (VRT) and abdominal radical trachelectomy (ART) in respect of the following items--oncological results, obstetric outcomes, complications. PMID- 25909140 TI - [Molecular based targets and endometrial cancer]. AB - In recent years, increasing attention has been paid to the rate of spread of endometrial carcinoma, especially in the postmenopausal period. Along with routine diagnostic methods, giving information on the location and progression of the disease, there are some morphological methods determining very accurately the correlations in the development of this type of cancer and his prognosis. Moreover--in recent years, the accumulated information about the molecular profile of this type of cancer made it possible to implement a number of new drugs against the so-called molecular therapy -'targets' in the neoplastic process. Significant proportion of cases show response rates, it is more hope in the development of more successful formulas and target -based therapy. In this review, we present and discuss the role of certain molecular markers as potential indicators of prognosis and development, as well as determining the target treatment of endometrial carcinoma. PMID- 25909141 TI - [Hyperandrogenism in multiple pregnancy]. AB - Hyperandrogenism caused by pregnancy is an extremely rare condition. One of the most common reasons is the hyperreactio luteinalis (LH). The literature describes 51 cases of LH where 8 of them have occurred during spontaneous multiple pregnancy. LH is a result of increased serum concentrations of human chorion gonadotropin (beta-hCG) and increased receptors' sensitivity to beta-hCG. It is characterized by a typical ultrasound image: most often bilaterally massively enlarged ovaries that consist of many of thin-walled small theca-lutein cysts, giving it the appearance of a "spoke wheel". We present a case of a 36 year old woman pregnant for the first time with spontaneously occurred twin pregnancy, who has hyperandrogenism and high blood pressure resistant to therapy. The conducted imaging studies showed enlarged polycystic ovaries resembling cancerous ovarian neoplasia. Recognition of this condition is important as radical surgery, resulting in removal of the ovaries is wrong and incorrect. PMID- 25909142 TI - [Case of encapsulated solid papillary carcinoma with triple-negative and basal like phenotype occurred in pregnant woman with review of the literature]. AB - The term breast cancer in pregnant women is used when the disease has been diagnosed during pregnancy or within first 12 months after delivery. The frequency of this type of breast cancer is about 7% of all cases in reproductive period. We present a case of breast cancer that occurred in pregnant 35 year old woman. We performed histological and immunohistochemical tests of excised tumor formation. We did not find sufficient evidence of both carcinoma in situ and invasive ductal carcinoma. The lesion was consisted with encapsulated/intracystic carcinoma, solid papillary variant with a low degree of differentiation-G3. Young age of patient, receptor status of the tumor the characteristic morphology of hereditary cancer, the presence of inflammatory infiltrates intratumorally, absence of reaction to IHC protein product of the tumor suppressor gene BRCA1 in combination with a positive p53 IHC makes this case suitable for genetic testing of BRCA1/BRCA2 susceptibility genes. The case is interesting because of the rarity of the histological variant, the young age of the patient, the combination with BC and pregnancy and the triple-negative phenotype. PMID- 25909143 TI - [Vulvar melanoma]. AB - Malignant melanoma of the vulva is a rare disease with aggressive behavior and poor prognosis. It consist < 5% of all cases of melanoma in females, as the ratio of its manifestation, compared with the cutaneous melanoma is 1:71. Higher risk of developing melanoma of the vulva is established in white women, as the peak of the incidence is between 60 and 70 years of age. Clinically, MM of the vulva manifests as asymptomatic pigmented, rarely a pigmented lesion, as the usual clinical form is superficial spreading MM and much less common nodular MM, which is associated with a poorer prognosis in. general. The diagnosis is confirmed by histological examination. Conduction of PCR and DNA analysis for detection of BRAF mutations, NRAS mutations and KIT amplification is also appropriate. Advanced age, black race, tumor size, tumor thickness, ulceration, presence of satellite lesions, involvement of adjacent organs (vagina, urethra), and the presence of regional or distant metastases are identified as the most important prognostic markers. Radical wide excision followed by bilateral lymphadenectomy id considered as the optimal therapeutic approach. PMID- 25909145 TI - Correction to "Cyclization Cascades via N-Amidyl Radicals toward Highly Functionalized Heterocyclic Scaffolds". PMID- 25909144 TI - Neuropsychological Language Tests in Dementia Diagnosis in English-Speaking Hispanic and Non-Hispanic White Outpatients. AB - Neuropsychological language tests have limitations (e.g., unrepresentative norms) when applied to "Hispanics" and clinicians are likely aware that these tests may lead to inaccurate dementia diagnoses. Therefore, it was hypothesized that language tests would be weaker diagnostic predictors in Hispanics versus "Non Hispanic Whites." Participants included 436 English-speaking Hispanic and 436 Non Hispanic White (randomly selected from 10,937) outpatients classified as having dementia or normal cognition at initial evaluation. When covarying for age, sex, education, and functional abilities, vegetable fluency significantly predicted diagnosis among Non-Hispanic Whites (odds ratio = 0.80, 95% confidence interval [0.69, 0.94], p < .01). Animal fluency and an abbreviated (30-item) Boston Naming Test (BNT) comparably predicted diagnosis across groups. Results remained similar when covarying for primary language among Hispanics. Findings suggest that vegetable fluency, but not animal fluency, was relatively unimportant in diagnosis for the English-speaking Hispanics in this study possibly because of cultural influences on the familiarity, salience, and relevance of this category's items. Additionally, clinicians may have informally adjusted Hispanics' 30-item BNT and animal fluency scores and discounted vegetable fluency to account for their limitations. Animal fluency and BNT may be preferable language tests when assessing dementia in English across groups, as they comparably predicted diagnosis in both groups. PMID- 25909146 TI - Genetic variation at 15 autosomal STR loci in Bhil tribal population of Central India. AB - AIMS: Genotypic polymorphism studies at 15 highly polymorphic short tandem repeat (STR) loci were carried out in Bhil tribal population of Madhya Pradesh, in central region of India. METHODS: The analysis of 15 autosomal STR loci (TH01, D3S1358, vWA, D21S11, TPOX, D7S820, D19S433, D5S818, D2S1338, D16S539, CSF1PO, D13S317, FGA, D18S51, D8S1179) was done in 183 unrelated individuals of the Bhil tribe. RESULTS: Heterozygosity among the studied 15 autosomal STR loci ranged from 63.5-86.5%. The loci D2S1338 and FGA were found to be mostly polymorphic. All loci fall under Hardy-Weinberg equilibrium, except loci D18S51 and D7S820. These STR loci were highly informative and discriminating, with CPD > 0.99999. CONCLUSION: The clustering pattern of the NJ tree and the PCA plot showed grouping of the Bhil population with previously reported tribes of central India. PMID- 25909147 TI - Spectrum of Radiation-Induced Clustered Non-DSB Damage - A Monte Carlo Track Structure Modeling and Calculations. AB - The aim of this report is to present the spectrum of initial radiation-induced cellular DNA damage [with particular focus on non-double-strand break (DSB) damage] generated by computer simulations. The radiation types modeled in this study were monoenergetic electrons (100 eV-1.5 keV), ultrasoft X-ray photons Ck, AlK and TiK, as well as some selected ions including 3.2 MeV/u proton; 0.74 and 2.4 MeV/u helium ions; 29 MeV/u nitrogen ions and 950 MeV/u iron ions. Monte Carlo track structure methods were used to simulate damage induction by these radiation types in a cell-mimetic condition from a single-track action. The simulations took into account the action of direct energy deposition events and the reaction of hydroxyl radicals on atomistic linear B-DNA segments of a few helical turns including the water of hydration. Our results permitted the following conclusions: a. The absolute levels of different types of damage [base damage, simple and complex single-strand breaks (SSBs) and DSBs] vary depending on the radiation type; b. Within each damage class, the relative proportions of simple and complex damage vary with radiation type, the latter being higher with high-LET radiations; c. Overall, for both low- and high-LET radiations, the ratios of the yields of base damage to SSBs are similar, being about 3.0 +/- 0.2; d. Base damage contributes more to the complexity of both SSBs and DSBs, than additional SSB damage and this is true for both low- and high-LET radiations; and e. The average SSB/DSB ratio for low-LET radiations is about 18, which is about 5 times higher than that for high-LET radiations. The hypothesis that clustered DNA damage is more difficult for cells to repair has gained currency among radiobiologists. However, as yet, there is no direct in vivo experimental method to validate the dependence of kinetics of DNA repair on DNA damage complexity (both DSB and non-DSB types). The data on the detailed spectrum of DNA damage presented here, in particular the non-DSB type, provide a good basis for testing mechanistic models of DNA repair kinetics such as base excision repair. PMID- 25909148 TI - Subfemtosecond quantum nuclear dynamics in water isotopomers. AB - Subfemtosecond quantum dynamics studies of all water isotopomers in the X (2)B1 and A (2)A1 electronic states of the cation formed by Franck-Condon ionization of the neutral ground electronic state are reported. Using the ratio of the autocorrelation functions for the isotopomers as obtained from the solution of the time-dependent Schrodinger equation in a grid representation, high-order harmonic generation signals are calculated as a function of time. The results are found to be in agreement with the available experimental findings and with our earlier study for D2O(+)/H2O(+). Maxima are predicted in the autocorrelation function ratio at various times. Their origin and occurrence is explained by calculating expectation values of the bond lengths and bond angle of the water isotopomers as a function of time. The values so calculated for the (2)B1 and (2)A1 electronic states of the cation show quasiperiodic oscillations that can be associated with the time at which the nuclear wave packet reaches the minima of the potential energy surface, there being responsible for the peaks in the HHG signals. PMID- 25909149 TI - Lactobacillus gasseri KS-13, Bifidobacterium bifidum G9-1, and Bifidobacterium longum MM-2 Ingestion Induces a Less Inflammatory Cytokine Profile and a Potentially Beneficial Shift in Gut Microbiota in Older Adults: A Randomized, Double-Blind, Placebo-Controlled, Crossover Study. AB - OBJECTIVE: This study determined whether older adults who consumed a probiotic mixture would have a greater proportion of circulating CD4+ lymphocytes, altered cytokine production, and a shift in intestinal microbiota toward a healthier microbial community. METHODS: Participants (70 +/- 1 years [mean +/- SEM]; n = 32) consumed a probiotic (Lactobacillus gasseri KS-13, Bifidobacterium bifidum G9 1, and Bifidobacterium longum MM2) or a placebo twice daily for 3 weeks with a 5 week washout period between intervention periods. Blood and stools were collected before and after each intervention. The percentage of circulating CD4+ lymphocytes and ex vivo mitogen-stimulated cell cytokine production were measured. In stools, specific bacterial targets were quantified via quantitative polymerase chain reaction (qPCR) and community composition was determined via pyrosequencing. RESULTS: During the first period of the crossover the percentage of CD4+ cells decreased with the placebo (48% +/- 3% to 31% +/- 3%, p < 0.01) but did not change with the probiotic (44% +/- 3% to 42% +/- 3%) and log-transformed concentrations of interleukin-10 increased with the probiotic (1.7 +/- 0.2 to 3.4 +/- 0.2, p < 0.0001) but not the placebo (1.7 +/- 0.2 to 2.1 +/- 0.2). With the probiotic versus the placebo a higher percentage of participants had an increase in fecal bifidobacteria (48% versus 30%, p < 0.05) and lactic acid bacteria (55% versus 43%, p < 0.05) and a decrease in Escherichia coli (52% versus 27%, p < 0.05). Several bacterial groups matching Faeacalibactierium prausnitzii were more prevalent in stool samples with the probiotic versus placebo. CONCLUSIONS: The probiotic maintained CD4+ lymphocytes and produced a less inflammatory cytokine profile possibly due to the changes in the microbial communities, which more closely resembled those reported in healthy younger populations. PMID- 25909151 TI - Structure Elucidation, Relative LC-MS Response and In Vitro Toxicity of Azaspiracids 7-10 Isolated from Mussels (Mytilus edulis). AB - Azaspiracids (AZAs) are marine biotoxins produced by dinoflagellates that can accumulate in shellfish, which if consumed can lead to poisoning events. AZA7-10, 7-10, were isolated from shellfish and their structures, previously proposed on the basis of only LC-MS/MS data, were confirmed by NMR spectroscopy. Purified AZA4-6, 4-6, and 7-10 were accurately quantitated by qNMR and used to assay cytotoxicity with Jurkat T lymphocyte cells for the first time. LC-MS(MS) molar response studies performed using isocratic and gradient elution in both selected ion monitoring and selected reaction monitoring modes showed that responses for the analogues ranged from 0.3 to 1.2 relative to AZA1, 1. All AZA analogues tested were cytotoxic to Jurkat T lymphocyte cells in a time- and concentration dependent manner; however, there were distinct differences in their EC50 values, with the potencies for each analogue being: AZA6 > AZA8 > AZA1 > AZA4 ~ AZA9 > AZA5 ~ AZA10. This data contributes to the understanding of the structure activity relationships of AZAs. PMID- 25909152 TI - Using phosphate supplementation to reverse hypophosphatemia and phosphate depletion in neurological disease and disturbance. AB - Hypophosphatemia (HP) with or without intracellular depletion of inorganic phosphate (Pi) and adenosine triphosphate has been associated with central and peripheral nervous system complications and can be observed in various diseases and conditions related to respiratory alkalosis, alcoholism (alcohol withdrawal), diabetic ketoacidosis, malnutrition, obesity, and parenteral and enteral nutrition. In addition, HP may explain serious muscular, neurological, and haematological disorders and may cause peripheral neuropathy with paresthesias and metabolic encephalopathy, resulting in confusion and seizures. The neuropathy may be improved quickly after proper phosphate replacement. Phosphate depletion has been corrected using potassium-phosphate infusion, a treatment that can restore consciousness. In severe ataxia and tetra paresis, complete recovery can occur after adequate replacement of phosphate. Patients with multiple risk factors, often with a chronic disease and severe HP that contribute to phosphate depletion, are at risk for neurologic alterations. To predict both risk and optimal phosphate replenishment requires assessing the nutritional status and risk for re-feeding hypophosphatemia. The strategy for correcting HP depends on the severity of the underlying disease and the goal for re-establishing a phosphate balance to limit the consequences of phosphate depletion. PMID- 25909153 TI - Uncoupling protein-2 mRNA expression in mice subjected to intermittent hypoxia. AB - OBJECTIVE: To investigate the effect of intermittent hypoxia-a model of obstructive sleep apnea (OSA)-on pancreatic expression of uncoupling protein-2 (UCP2), as well as on glycemic and lipid profiles, in C57BL mice. METHODS: For 8 h/day over a 35-day period, male C57BL mice were exposed to intermittent hypoxia (hypoxia group) or to a sham procedure (normoxia group). The intermittent hypoxia condition involved exposing mice to an atmosphere of 92% N and 8% CO2 for 30 s, progressively reducing the fraction of inspired oxygen to 8 +/- 1%, after which they were exposed to room air for 30 s and the cycle was repeated (480 cycles over the 8-h experimental period). Pancreases were dissected to isolate the islets. Real-time PCR was performed with TaqMan assays. RESULTS: Expression of UCP2 mRNA in pancreatic islets was 20% higher in the normoxia group than in the hypoxia group (p = 0.11). Fasting serum insulin was higher in the hypoxia group than in the normoxia group (p = 0.01). The homeostasis model assessment of insulin resistance indicated that, in comparison with the control mice, the mice exposed to intermittent hypoxia showed 15% lower insulin resistance (p = 0.09) and 21% higher pancreatic beta-cell function (p = 0.01). Immunohistochemical staining of the islets showed no significant differences between the two groups in terms of the area or intensity of alpha- and beta-cell staining for insulin and glucagon. CONCLUSIONS: To our knowledge, this is the first report of the effect of intermittent hypoxia on UCP2 expression. Our findings suggest that UCP2 regulates insulin production in OSA. Further study of the role that UCP2 plays in the glycemic control of OSA patients is warranted. PMID- 25909154 TI - Cognitive impairment in COPD: a systematic review. AB - The objectives of this study were to characterize and clarify the relationships between the various cognitive domains affected in COPD patients and the disease itself, as well as to determine the prevalence of impairment in the various cognitive domains in such patients. To that end, we performed a systematic review using the following databases: PubMed, Scopus, and ScienceDirect. We included articles that provided information on cognitive impairment in COPD patients. The review of the findings of the articles showed a significant relationship between COPD and cognitive impairment. The most widely studied cognitive domains are memory and attention. Verbal memory and learning constitute the second most commonly impaired cognitive domain in patients with COPD. The prevalence of impairment in visuospatial memory and intermediate visual memory is 26.9% and 19.2%, respectively. We found that cognitive impairment is associated with the profile of COPD severity and its comorbidities. The articles reviewed demonstrated that there is considerable impairment of the cognitive domains memory and attention in patients with COPD. Future studies should address impairments in different cognitive domains according to the disease stage in patients with COPD. PMID- 25909155 TI - Lymphadenopathy and fever in a chef during a stay in Europe. AB - This case illustrates a rare presentation (as lymphadenopathy and fever) of one of the most common zoonotic diseases worldwide--brucellosis--in a 22-year-old Brazilian male (a chef) who had recently returned to Brazil after having lived in and traveled around Europe for one year. The histopathology, clinical history, and response to treatment were all consistent with a diagnosis of brucellosis, which was confirmed by PCR in a urine sample. We also review some aspects of brucellosis, such as the clinical features, diagnosis, and management. PMID- 25909156 TI - Risk factors for respiratory complications after adenotonsillectomy in children with obstructive sleep apnea. AB - OBJECTIVE: To identify risk factors for respiratory complications after adenotonsillectomy in children <= 12 years of age with obstructive sleep apnea who were referred to the pediatric ICU (PICU). METHODS: A cross-sectional historical cohort study analyzing 53 children after adenotonsillectomy who met predetermined criteria for PICU referral in a tertiary level teaching hospital. The Student's t-test, Mann-Whitney test, and chi-square test were used to identify risk factors. RESULTS: Of the 805 children undergoing adenotonsillectomy between January of 2006 and December of 2012 in the teaching hospital, 53 were referred to the PICU. Twenty-one children (2.6% of all those undergoing adenotonsillectomy and 39.6% of those who were referred to the PICU) had respiratory complications. Of those 21, 12 were male. The mean age was 5.3 +/- 2.6 years. A high apnea-hypopnea index (AHI; p = 0.0269), a high oxygen desaturation index (ODI; p = 0.0082), a low SpO2 nadir (p = 0.0055), prolonged orotracheal intubation (p = 0.0011), and rhinitis (p = 0.0426) were found to be independent predictors of respiratory complications. Some of the complications observed were minor (SpO2 90-80%), whereas others were major (SpO2 <= 80%, laryngospasm, bronchospasm, acute pulmonary edema, pneumonia, and apnea). CONCLUSIONS: Among children up to 12 years of age with OSA, those who have a high AHI, a high ODI, a low SpO2 nadir, or rhinitis are more likely to develop respiratory complications after adenotonsillectomy than are those without such characteristics. PMID- 25909157 TI - Microfluidic analysis of extracellular matrix-bFGF crosstalk on primary human myoblast chemoproliferation, chemokinesis, and chemotaxis. AB - Exposing myoblasts to basic fibroblast growth factor (bFGF), which is released after muscle injury, results in receptor phosphorylation, faster migration, and increased proliferation. These effects occur on time scales that extend across three orders of magnitude (10(0)-10(3) minutes). Finite element modeling of Transwell assays, which are traditionally used to assess chemotaxis, revealed that the bFGF gradient formed across the membrane pore is short-lived and diminishes 45% within the first minute. Thus, to evaluate bFGF-induced migration over 10(2) minutes, we employed a microfluidic assay capable of producing a stable, linear concentration gradient to perform single-cell analyses of chemokinesis and chemotaxis. We hypothesized that the composition of the underlying extracellular matrix (ECM) may affect the behavioral response of myoblasts to soluble bFGF, as previous work with other cell types has suggested crosstalk between integrin and fibroblast growth factor (FGF) receptors. Consistent with this notion, we found that bFGF significantly reduced the doubling time of myoblasts cultured on laminin but not fibronectin or collagen. Laminin also promoted significantly faster migration speeds (13.4 MUm h(-1)) than either fibronectin (10.6 MUm h(-1)) or collagen (7.6 MUm h(-1)) without bFGF stimulation. Chemokinesis driven by bFGF further increased migration speed in a strictly additive manner, resulting in an average increase of 2.3 MUm h(-1) across all ECMs tested. We observed relatively mild chemoattraction (~67% of myoblast population) in response to bFGF gradients of 3.2 ng mL(-1) mm(-1) regardless of ECM identity. Thus, while ECM-bFGF crosstalk did impact chemoproliferation, it did not have a significant effect on chemokinesis or chemotaxis. These data suggest that the main physiological effect of bFGF on myoblast migration is chemokinesis and that changes in the surrounding ECM, resulting from aging and/or disease may impact muscle regeneration by altering myoblast migration and proliferation. PMID- 25909158 TI - Oligomers of Parkinson's Disease-Related alpha-Synuclein Mutants Have Similar Structures but Distinctive Membrane Permeabilization Properties. AB - Single-amino acid mutations in the human alpha-synuclein (alphaS) protein are related to early onset Parkinson's disease (PD). In addition to the well-known A30P, A53T, and E46K mutants, recently a number of new familial disease-related alphaS mutations have been discovered. How these mutations affect the putative physiological function of alphaS and the disease pathology is still unknown. Here we focus on the H50Q and G51D familial mutants and show that like wild-type alphaS, H50Q and G51D monomers bind to negatively charged membranes, form soluble partially folded oligomers with an aggregation number of ~30 monomers under specific conditions, and can aggregate into amyloid fibrils. We systematically studied the ability of these isolated oligomers to permeabilize membranes composed of anionic phospholipids (DOPG) and membranes mimicking the mitochondrial phospholipid composition (CL:POPE:POPC) using a calcein release assay. Small-angle X-ray scattering studies of isolated oligomers show that oligomers formed from wild-type alphaS and the A30P, E46K, H50Q, G51D, and A53T disease-related mutants are composed of a similar number of monomers. However, although the binding affinity of the monomeric protein and the aggregation number of the oligomers formed under our specific protocol are comparable for wild-type alphaS and H50Q and G51D alphaS, G51D oligomers cannot disrupt negatively charged and physiologically relevant model membranes. Replacement of the membrane immersed glycine with a negatively charged aspartic acid at position 51 apparently abrogates membrane destabilization, whereas a mutation in the proximal but solvent-exposed part of the membrane-bound alpha-helix such as that found in the H50Q mutant has little effect on the bilayer disrupting properties of oligomers. PMID- 25909159 TI - The kinetics of fluoride sorption by zeolite: Effects of cadmium, barium and manganese. AB - Industrial wastewaters often consist of a complex chemical cocktail with treatment of target contaminants complicated by adverse chemical reactions. The impact of metal ions (Cd(2+), Ba(2+) and Mn(2+)) on the kinetics of fluoride removal from solution by natural zeolite was investigated. In order to better understand the kinetics, the pseudo-second order (PSO), Hill (Hill 4 and Hill 5) and intra-particle diffusion (IPD) models were applied. Model fitting was compared using the Akaike Information Criterion (AIC) and the Schwarz Bayesian Information Criterion (BIC). The Hill models (Hill 4 and Hill 5) were found to be superior in describing the fluoride removal processes due to the sigmoidal nature of the kinetics. Results indicate that the presence of Mn (100 mg L(-1)) and Cd (100 mg L(-1)) respectively increases the rate of fluoride sorption by a factor of ~28.3 and ~10.9, the maximum sorption capacity is increased by ~2.2 and ~1.7. The presence of Ba (100 mg L(-1)) initially inhibited fluoride removal and very poor fits were obtained for all models. Fitting was best described with a biphasic sigmoidal model with the degree of inhibition decreasing with increasing temperature suggesting that at least two processes are involved with fluoride sorption onto natural zeolite in the presence of Ba. PMID- 25909160 TI - IL-32alpha suppresses colorectal cancer development via TNFR1-mediated death signaling. AB - Inflammation is associated with cancer-prone microenvironment, leading to cancer. IL-32 is expressed in chronic inflammation-linked human cancers. To investigate IL-32alpha in inflammation-linked colorectal carcinogenesis, we generated a strain of mice, expressing IL-32 (IL-32alpha-Tg). In IL-32alpha-Tg mice, azoxymethane (AOM)-induced colon cancer incidence was decreased, whereas expression of TNFR1 and TNFR1-mediated apoptosis was increased. Also, IL-32alpha increased ROS production to induce prolonged JNK activation. In colon cancer patients, IL-32alpha and TNFR1 were increased. These findings indicate that IL 32alpha suppressed colon cancer development by promoting the death signaling of TNFR1. PMID- 25909161 TI - TRAIL-R2 promotes skeletal metastasis in a breast cancer xenograft mouse model. AB - Despite improvements in detection, surgical approaches and systemic therapies, breast cancer remains typically incurable once distant metastases occur. High expression of TRAIL-R2 was found to be associated with poor prognostic parameters in breast cancer patients, suggesting an oncogenic function of this receptor. In the present study, we aimed to determine the impact of TRAIL-R2 on breast cancer metastasis. Using an osteotropic variant of MDA-MB-231 breast cancer cells, we examine the effects of TRAIL-R2 knockdown in vitro and in vivo. Strikingly, in addition to the reduced levels of the proliferation-promoting factor HMGA2 and corresponding inhibition of cell proliferation, knockdown of TRAIL-R2 increased the levels of E-Cadherin and decreased migration. In vivo, these cells were strongly impaired in their ability to form bone metastases after intracardiac injection. Evaluating possible underlying mechanisms revealed a strong downregulation of CXCR4, the receptor for the chemokine SDF-1 important for homing of cancers cells to the bone. In accordance, cell migration towards SDF-1 was significantly impaired by TRAIL-R2 knockdown. Conversely, overexpression of TRAIL-R2 upregulated CXCR4 levels and enhanced SDF-1-directed migration. We therefore postulate that inhibition of TRAIL-R2 expression could represent a promising therapeutic strategy leading to an effective impairment of breast cancer cell capability to form skeletal metastases. PMID- 25909162 TI - Cleaved CD44 intracellular domain supports activation of stemness factors and promotes tumorigenesis of breast cancer. AB - CD44 plays a role in the progression of tumors and is expressed in cancer stem cells (CSCs). However, the mechanisms underlying the crosstalk of CD44 with stemness genes in CSC maintenance remains unclear. In this study, we demonstrated how the cleaved intracellular domain of CD44 (CD44ICD) activates stemness factors such as Nanog, Sox2 and Oct4, and contributes to the tumorigenesis of breast cancer. We have found that the overexpression of CD44ICD increased mammosphere formation in breast cancer cells. Treatment with a gamma-secretase inhibitor (GSI), which blocks the cleavage of CD44ICD, interfered with mammosphere formation. Interestingly, CD44ICD decreased the expression levels and nuclear localization of stemness factors, but overexpression of CD44ICD reversed these effects. In addition, we showed that nuclear localization of CD44ICD is important for transcriptional activation of the stemness factors. Furthermore, CD44ICD overexpressed cells exhibited strong tumorigenecity and greater metastatic potential than did the control cells or CD44-depleted cells in vivo in mice models. Taken together, it was supposed that CD44 promotes tumorigenesis through the interaction and nuclear-translocation of its intracellular domain and stemness factors. We suggest that the prevention of cleavage and nuclear translocation of CD44ICD is a potential target in treating breast cancer. PMID- 25909163 TI - Metformin potentiates rapamycin and cisplatin in gastric cancer in mice. AB - Here we showed that pAMPKalpha and PTEN were down-regulated and p-mTOR, p-S6, p 4EBP1, MMP7, and DCN1 were up-regulated in human gastric cancer tissue samples as compared to that in the noncancerous tissues. Metformin inhibited tumor growth in mice. Also it enhanced cisplatin- or rapamycin-induced reduction of tumor growth as compared with treatment of either drug alone. In addition to activation of AMPK and suppression of the mTOR pathway, a series of increased and decreased genes expression were induced by metformin, including PTEN, MMP7, and FN1. We suggest that metformin could potentially be used for the treatment of gastric cancer especially in combination with cisplatin or rapamycin. PMID- 25909164 TI - Podoplanin-expressing cancer-associated fibroblasts inhibit small cell lung cancer growth. AB - Cancer-associated fibroblasts (CAFs) expressing podoplanin (PDPN) are a favorable prognosticator in surgically resected small cell lung cancer (SCLC). Here we explore whether CAFs expressing PDPN influence proliferation of SCLC cells. Compared with control group (SCLC cells co-cultured with CAFs-Ctrl), numbers of SCLC cells co-cultured with CAFs overexpressing PDPN were decreased. Suppression of PDPN expression by shRNA in CAFs resulted in increased numbers of SCLC cells. In surgically resected human SCLC specimens, the frequency of Geminin-positive cancer cells was significantly higher in the cases with PDPN-positive CAFs than in the cases with PDPN-negative CAFs. Thus CAFs expressing PDPN inhibit growth of SCLC cells, suggesting that CAFs expressing PDPN represent a tumor inhibitory stromal cell component in SCLC. PMID- 25909165 TI - Flotillin-2 promotes nasopharyngeal carcinoma metastasis and is necessary for the epithelial-mesenchymal transition induced by transforming growth factor-beta. AB - Transforming growth factor-beta (TGF-beta) promotes cancer metastasis via the epithelial-mesenchymal transition (EMT) but the underlying mechanisms in nasopharyngeal carcinoma (NPC) remain unclear. Flotillin-2 (Flot2), a specialized lipid raft domain in cellular membrane, was reported to promote cancer metastasis. Recently, in neuropathy, it was also suggested that Flot2 was involved in Src activation, which is known as the downstream signal of TGF-beta. Therefore, we intended to find out the relationship between Flot2 and TGF-beta in the process of nasopharyngeal carcinoma (NPC) metastasis. In this study, we found that Flot2 expression level positively correlated with the cancer stage in NPC tissues. Elevated Flot2 in tumor tissue was an independent prognostic marker, and higher Flot2 expression level showed shorter overall survival time in 181 NPC patients. In NPC cells, silencing Flot2 reversed the metastatic effect induced by TGF-beta. Moreover, TGF-beta-induced Src phosphorylation was significantly inhibited by Flot2 knocking down. As the consequence of Flot2 inhibition, the expression of the epithelial biomarker E-cadherin was upregulated, while the mesenchymal marker vimentin and signaling transducer beta-catenin was suppressed. In conclusions, Flot2 is an indispensable member for TGF-beta signaling, which is essential for the EMT process in NPC metastasis. Suppressing Flot2 may be a novel way against TGF-beta-induced EMT. PMID- 25909166 TI - Netrin-4 as a biomarker promotes cell proliferation and invasion in gastric cancer. AB - Gastric cancer (GC) is the second most common cause of cancer-related death with limited serum biomarkers for diagnosis and prognosis. Netrin-4 (Ntn4) is a laminin-related secreted molecule found to regulate tumor progression and metastasis. However, it is completely unknown whether Ntn4 has roles in GC development. Here, we first reported Ntn4 knockdown significantly suppressed cell proliferation and motility, while overexpression or addition of exogenous Ntn4 reversed these effects. In addition, Ntn4 receptor, neogenin (Neo) was also found highly expressed in GC cells and mediated the Ntn4-induced cell proliferation and invasion. Moreover, Ntn4 or Neo silencing decreased the phosphorylation of Stat3, ERK, Akt and p38, indicating multi-oncogenic pathways (Jak/Stat, PI3K/Akt, and ERK/MAPK) were involved in Ntn4-induced effects on the GC cells. Importantly, Ntn4 level was significantly increased in 82 tumor tissues (p = 0.001) and 52 serum samples (p < 0.0001) from GC patients and positively correlated with Neo expression (p = 0.003). Ntn4 expression was negatively correlated with the survival period (p = 0.038), and positively associated with the severity of pathological stages of the tumors (p = 0.008). Taken together, Ntn4 promoted the proliferation and motility of GC cells which was mediated by its receptor Neo and through further activation of multi-oncogenic pathways. Elevated Ntn4 was detected in both tumor tissues and serum samples of GC patients and suggested a relatively poor survival, indicating Ntn4 may be used as a potential non-invasive biomarker for diagnosis and prognosis of GC. PMID- 25909167 TI - High frequency of loss of PTEN expression in human solid salivary adenoid cystic carcinoma and its implication for targeted therapy. AB - Salivary gland tumor (SGT) is one of the least studied cancers due to its rarity and heterogeneous histological types. Here, we reported that loss of PTEN expression was most frequently found in the poorly differentiated, high grade solid adenoid cystic carcinomas. Loss of PTEN expression correlated with activation of mTOR by increased phosphorylated S6 ribosome protein. We further functionally studied the role of PTEN in a pair of human SACC cell lines, SACC-83 and SACC-LM. Reduced PTEN level was correlated with the metastasis potential. When we knocked down PTEN in the SACC-83 cell line, we observed increased proliferation and enhanced migration/invasion in vitro, and increased tumor size in vivo. We further tested the therapeutical effect by applying a PI3K/mTOR inhibitor NVP-BEZ235 to both SACC cell lines. Decreased cell proliferation, increased apoptosis, as well as reduced cell migration/invasion were observed in both cell lines upon the NVP-BEZ235 treatment. Moreover, the NVP-BEZ235 treatment in a SGT xenograft mouse model significantly reduced primary tumor size and lung metastasis. Taken together, our results demonstrated that PTEN is a potent tumor suppressor in human SGTs, and targeting PI3K/mTOR pathway may be effective in the targeted therapy for human SGT patients with loss of PTEN expression. PMID- 25909168 TI - Epigenetic silencing of BCL6B inactivates p53 signaling and causes human hepatocellular carcinoma cell resist to 5-FU. AB - BCL6B is a potential tumor suppressor in human gastric cancer, but the regulation and mechanism of BCL6B in human hepatocellular carcinogenesis remain unclear. This study is to explore the epigenetic change and mechanism of BCL6B in human hepatocellular carcinoma (HCC). Nineteen hepatic cancer cell lines, 50 cases of adjacent tissue and 149 cases of HCC samples were employed. BCL6B is methylated in 100% (19/19) of human HCC cell lines, 40.0% (20/50) of adjacent tissue samples and 86.6% (129/149) of primary cancer samples. Methylation of BCL6B is associated with HBV positive (p < 0.05). But no association was found with age, sex, tumor size, differentiation, TNM stage, recurrence and survival. Loss of BCL6B expression was found in 19 of completely methylated HCC cell lines. BCL6B was re expressed after 5-aza-2'-deoxycytidine treatment. Restoration of BCL6B expression suppressed cell proliferation, induced apoptosis and G1/S arrest in HCC cells. The expression of EGR1, a key component of p53 signaling, was increased after re expression BCL6B in HCC cells. Re-expression of BCL6B activated p53 signaling and sensitized HCC cells to 5-fluorouracil. BCL6B is frequently methylated in human HCC and the expression of BCL6B is regulated by promoter region hypermethylation. BCL6B activates p53 signaling by increasing EGR1 expression in HCC. PMID- 25909169 TI - Implications for selecting local excision in locally advanced rectal cancer after preoperative chemoradiation. AB - Local excision may offer the possibility of organ preservation for the management of locally advanced rectal cancer after neoadjuvant chemoradiotherapy (CRT). However, the oncological outcomes of this strategy have been largely associated with the risk of nodal metastases. In this study, Surveillance, Epidemiology, and End Results Program (SEER)-registered rectal cancer patients, and patients from Fudan University Shanghai Cancer Center (FUSCC) after preoperative chemoradiation were combined to analyze the incidence of lymph node metastasis. The results showed that there was a high risk for residual lymph node metastasis among patients even with complete pathologic response of primary tumor after preoperative CRT (12.6-13.2%). However, in the selected group of patients with pre-CRT MRI staging cN0 rectal cancer, there was only one ypN+ case (3.3%) in ypT0-1 group. These results suggest that pre-CRT MRI staging cN0 patients achieved ypT0-1 of bowel wall tumor may be suitable for local resection. PMID- 25909170 TI - HSPA12B: a novel facilitator of lung tumor growth. AB - Lung tumor progression is regulated by proangiogenic factors. Heat shock protein A12B (HSPA12B) is a recently identified regulator of expression of proangiogenic factors. However, whether HSPA12B plays a role in lung tumor growth is unknown. To address this question, transgenic mice overexpressing HSPA12B (Tg) and wild type littermates (WT) were implanted with Lewis lung cancer cells to induce lung tumorigenesis. Tg mice showed significantly higher number and bigger size of tumors than WT mice. Tg tumors exhibited increased angiogenesis and proliferation while reduced apoptosis compared with WT tumors. Interestingly, a significantly enhanced upregulation of Cox-2 was detected in Tg tumors than in WT tumors. Also, Tg tumors demonstrated upregulation of VEGF and angiopoietin-1, downregulation of AKAP12, and increased eNOS phosphorylation compared with WT tumors. Celecoxib, a selective Cox-2 inhibitor, suppressed the HSPA12B-induced increase in lung tumor burden. Moreover, celecoxib decreased angiogenesis and proliferation whereas increased apoptosis in Tg tumors. Additionally, celecoxib reduced angiopoietin-1 expression and eNOS phosphorylation but increased AKAP12 levels in Tg tumors. Our results indicate that HSPA12B stimulates lung tumor growth via a Cox-2-dependent mechanism. The present study identified HSPA12B as a novel facilitator of lung tumor growth and a potential therapeutic target for the treatment of lung cancer. PMID- 25909171 TI - Identification of a novel TGF-beta-miR-122-fibronectin 1/serum response factor signaling cascade and its implication in hepatic fibrogenesis. AB - Transforming growth factor-beta (TGF-beta) is a potent cytokine that promotes the development of fibrogenic cells, stimulates the expression of fibrosis-related genes, and consequently results in hepatic fibrogenesis. The involvement of miRNAs in this process remains largely unknown. We showed that miR-122 was substantially expressed in hepatic stellate cells (HSCs) and fibroblasts, the major sources of fibrogenic cells in liver tissues. Notably, exposure to TGF-beta led to significant downregulation of miR-122. Furthermore, reintroduction of miR 122 suppressed TGF-beta-induced expression of fibrosis-related genes, including alpha smooth muscle actin (alpha-SMA), fibronectin 1 (FN1) and alpha1 type I collagen (COL1A1), in HSCs and fibroblasts. Subsequent mechanism investigations revealed that miR-122 directly inhibited FN1 expression by binding to its 3' untranslated region and indirectly reduced the transcription of alpha-SMA and COL1A1 by inhibiting the expression of serum response factor (SRF), a key transcription factor that mediated the activation of fibrogenic cells. Further in vivo studies disclosed that intravenous injection of miR-122-expressing lentivirus successfully increased miR-122 level and reduced the amount of collagen fibrils, FN1 and SRF in the livers of CCl4-treated mice. These findings disclose a novel TGF-beta-miR-122-FN1/SRF signaling cascade and its implication in hepatic fibrogenesis, and suggest miR-122 as a promising molecular target for anti-fibrosis therapy. PMID- 25909172 TI - Selective killing of breast cancer cells expressing activated CD44 using CD44 ligand-coated nanoparticles in vitro and in vivo. AB - The cell surface glycoprotein CD44 is expressed in cancer cells and has been used as a therapeutic target in preclinical studies. However, the ubiquitous expression of CD44 in numerous cell types, including hematopoietic cells, has hindered its application in targeted therapy. Here, we demonstrated that CD44 was activated on breast cancer cells but was inactive on normal cells in vitro and in vivo. We analyzed 34 clinical primary tumor and normal breast tissues and demonstrated that CD44 was in an active state on breast cancer cells but in an inactive state on normal cells. Furthermore, based on the binding property of CD44 with its ligand hyaluronan (HA), we self-assembled HA-coated nanoparticles and studied their selective targeting efficacy. Our results indicate that HA coated nanoparticles bearing the CD44 ligand selectively targeted cancer cells both in vitro and in vivo, killing breast cancer cells while sparing normal cells. Our study suggested that the active state of CD44 plays a crucial role in the selective targeting of breast cancer cells by avoiding nonspecific toxicity to CD44-quiescent normal cells. These findings may provide a new idea for the selective targeting of cancer cells in other human cancers. PMID- 25909173 TI - CXCL16/CXCR6 chemokine signaling mediates breast cancer progression by pERK1/2 dependent mechanisms. AB - Our previous studies demonstrate that CXCL6/CXCR6 chemokine axis induces prostate cancer progression by the AKT/mTOR signaling pathway; however, its role and mechanisms underlying invasiveness and metastasis of breast cancer are yet to be elucidated. In this investigation, CXCR6 protein expression was examined using high-density tissue microarrays and immunohistochemistry. Expression of CXCR6 shows a higher epithelial staining in breast cancer nest site and metastatic lymph node than the normal breast tissue, suggesting that CXCR6 may be involved in breast cancer (BC) development. In vitro and in vivo experiments indicate that overexpression of CXCR6 in BC cells has a marked effect on increasing cell migration, invasion and metastasis. In contrast, reduction of CXCR6 expression by shRNAs in these cells greatly reduce its invasion and metastasis ability. Mechanistic analyses show that CXCL16/CXCR6 chemokine axis is capable of modulating activation of RhoA through activating ERK1/2 signaling pathway, which then inhibits the activity of cofilin, thereby enhancing the stability of F actin, responsible for invasiveness and metastasis of BC. Taken together, our data shows for the first time that the CXCR6 / ERK1/2/ RhoA / cofilin /F-actin pathway plays a central role in the development of BC. Targeting the signaling pathway may prove beneficial to prevent metastasis and provide a more effective therapeutic strategy for BC. PMID- 25909175 TI - Clinical evaluation of red cell distribution width and contrast-induced acute kidney injury in percutaneous coronary interventions. PMID- 25909174 TI - A novel derivative of betulinic acid, SYK023, suppresses lung cancer growth and malignancy. AB - Herein, we evaluated the anti-cancer effect and molecular mechanisms of a novel betulinic acid (BA) derivative, SYK023, by using two mouse models of lung cancer driven by KrasG12D or EGFRL858R. We found that SYK023 inhibits lung tumor proliferation, without side effects in vivo or cytotoxicity in primary lung cells in vitro. SYK023 triggered endoplasmic reticulum (ER) stress. Blockage of ER stress in SYK023-treated cells inhibited SYK023-induced apoptosis. In addition, we found that the expression of cell cycle-related genes, including cyclin A2, B1, D3, CDC25a, and CDC25b decreased but, while those of p15INK4b, p16INK4a, and p21CIP1 increased following SYK023 treatment. Finally, low doses of SYK023 significantly decreased lung cancer metastasis in vitro and in vivo. Expression of several genes related to cell migration, including synaptopodin, were downregulated by SYK023, thereby impairing F-actin polymerization and metastasis. Therefore, SYK023 may be a potentially therapeutic treatment for metastatic lung cancer. PMID- 25909176 TI - Plasma nuclear and mitochondrial DNA levels in acute myocardial infarction patients. PMID- 25909177 TI - Anisotropic modulation of magnetic properties and the memory effect in a wide band (011)-Pr0.7Sr0.3MnO3/PMN-PT heterostructure. AB - Memory effect of electric-field control on magnetic behavior in magnetoelectric composite heterostructures has been a topic of interest for a long time. Although the piezostrain and its transfer across the interface of ferroelectric/ferromagnetic films are known to be important in realizing magnetoelectric coupling, the underlying mechanism for nonvolatile modulation of magnetic behaviors remains a challenge. Here, we report on the electric-field control of magnetic properties in wide-band (011) Pr0.7Sr0.3MnO3/0.7Pb(Mg1/3Nb2/3)O3-0.3PbTiO3 heterostructures. By introducing an electric-field-induced in-plane anisotropic strain field during the cooling process from room temperature, we observe an in-plane anisotropic, nonvolatile modulation of magnetic properties in a wide-band Pr0.7Sr0.3MnO3 film at low temperatures. We attribute this anisotropic memory effect to the preferential seeding and growth of ferromagnetic (FM) domains under the anisotropic strain field. In addition, we find that the anisotropic, nonvolatile modulation of magnetic properties gradually diminishes as the temperature approaches FM transition, indicating that the nonvolatile memory effect is temperature dependent. By taking into account the competition between thermal energy and the potential barrier of the metastable magnetic state induced by the anisotropic strain field, this distinct memory effect is well explained, which provides a promising approach for designing novel electric-writing magnetic memories. PMID- 25909178 TI - Tri- and tetra-substituted cyclen based lanthanide(III) ion complexes as ribonuclease mimics: a study into the effect of log Ka, hydration and hydrophobicity on phosphodiester hydrolysis of the RNA-model 2-hydroxypropyl-4 nitrophenyl phosphate (HPNP). AB - A series of tetra-substituted 'pseudo' dipeptide ligands of cyclen (1,4,7,10, tetraazacyclododecane) and a tri-substituted 3'-pyridine ligand of cyclen, and the corresponding lanthanide(III) complexes were synthesised and characterised as metallo-ribonuclease mimics. All complexes were shown to promote hydrolysis of the phosphodiester bond of 2-hydroxypropyl-4-nitrophenyl phosphate (HPNP, tau1/2 = 5.87 * 10(3) h), a well known RNA mimic. The La(III) and Eu(III) tri substituted 3'-pyridine lanthanide(III) complexes being the most efficient in promoting such hydrolysis at pH 7.4 and at 37 degrees C; with tau1/2 = 1.67 h for La(III) and 1.74 h for Eu(III). The series was developed to provide the opportunity to investigate the consequences of altering the lanthanide(III) ion, coordination ability and hydrophobicity of a metallo-cavity on the rate of hydrolysis using the model phosphodiester, HPNP, at 37 degrees C. To further provide information on the role that the log Ka of the metal bound water plays in phosphodiester hydrolysis the protonation constants and the metal ion stability constants of both a tri and tetra-substituted 3'pyridine complex were determined. Our results highlighted several key features for the design of lanthanide(III) ribonucelase mimics; the presence of two metal bound water molecules are vital for pH dependent rate constants for Eu(III) complexes, optimal pH activity approximating physiological pH (~7.4) may be achieved if the log Ka values for both MLOH and ML(OH)2 species occur in this region, small changes to hydrophobicity within the metallo cavity influence the rate of hydrolysis greatly and an amide adjacent to the metal ion capable of forming hydrogen bonds with the substrate is required for achieving fast hydrolysis. PMID- 25909179 TI - The studies on the toxicity mechanism of environmentally hazardous natural (IAA) and synthetic (NAA) auxin--The experiments on model Arabidopsis thaliana and rat liver plasma membranes. AB - This paper concerns the studies towards membrane-damage effect of two auxins: indole-3-acetic acid - IAA and 1-naphthaleneacetic acid - NAA on plant (Arabidopsis thaliana) and animal (rat liver) model membranes. The foregoing auxins are plant growth regulators widely used in agriculture to control the quality of the crop. However, their accumulation in the environment makes them hazardous for the living organisms. The aim of our investigations was to compare the effect of natural (IAA) vs. synthetic (NAA) auxin on the organization of plant and animal model membranes and find a possible correlation between membrane disturbing effect of these compounds and their toxicity. The collected data evidenced that auxins cause destabilization of membranes, decrease their condensation and weakens interactions of molecules. The alterations in the morphology of model systems were also noticed. The foregoing effects of auxins are concentration-dependent and additionally NAA was found to act on animal vs. plant membranes more selectively than IAA. Interestingly, both IAA and NAA induce the strongest disordering in model lipid system at the concentration, which is frequently reported as toxic to animal and plants. Based on the above findings it was proposed that membrane-damage effect induced by IAA and NAA may be important from the point of view of the mechanism of toxicity of these compounds and cannot be ignored in further investigations in this area. PMID- 25909180 TI - Megaporous poly(hydroxy ethylmethacrylate) based poly(glycidylmethacrylate-N methacryloly-(L)-tryptophan) embedded composite cryogel. AB - One-step activation, purification, and stabilization of lipase enzyme were performed by using composite hydrophobic support at low ionic strength with increased surface area during embedding process. A novel hydrophobic poly(hydroxyethylmethacrylate) [PHEMA] based, poly(glycidyl methacrylate-N methacryloly-(L)-tryptophan) [PGMATrp] bead embedded composite cryogel membrane having specific surface area of 195m(2)/g was used as hydrophobic matrix for adsorption of commercial Candida Rugosa lipase in a continuous system. PGMATrp embedded PHEMA cryogel membrane with 60-100 MUm pore size was obtained by dispersion polymerization of GMA and MATrp to form PGMATrp beads followed by embedding of PGMATrp to HEMA via APS and TEMED redox pair. The introduction of hydrophobic MATrp monomer into bead structure aiming to increase interaction between lipase and composite membrane was estimated using nitrogen stoichiometry of elemental analysis and found to be 239 MUmol/g of polymer. Hydophobicity increment due to embedding process was confirmed by measuring contact angle, it was found 42 degrees and 48.4 degrees for the PHEMA and PHEMA/PGMATrp composite cryogel respectively. Some parameters i.e. pH, flow-rate, protein concentration, temperature, salt type and ionic intensity were evaluated on the adsorption capacity in a continuous system. Fast protein liquid chromatography (FPLC) studies were performed for specific adsorption of lipase onto the PHEMA/PGMATrp embedded composite cryogel membrane. PMID- 25909181 TI - Sequential and competitive adsorption of peptides at pendant PEO layers. AB - Earlier work provided direction for development of responsive drug delivery systems based on modulation of the structure, amphiphilicity, and surface density of bioactive peptides entrapped within pendant polyethylene oxide (PEO) brush layers. In this work, we describe the sequential and competitive adsorption behavior of such peptides at pendant PEO layers. Three cationic peptides were used for this purpose: the arginine-rich, amphiphilic peptide WLBU2, a peptide chemically identical to WLBU2 but of scrambled sequence (S-WLBU2), and the non amphiphilic peptide poly-L-arginine (PLR). Optical waveguide lightmode spectroscopy (OWLS) was used to quantify the rate and extent of peptide adsorption and elution at surfaces coated with PEO. UV spectroscopy and time-of flight secondary ion mass spectrometry (TOF-SIMS) were used to quantify the extent of peptide exchange during the course of sequential and competitive adsorption. Circular dichroism (CD) was used to evaluate conformational changes after adsorption of peptide mixtures at PEO-coated silica nanoparticles. Results indicated that amphiphilic peptides are able to displace adsorbed, non amphiphilic peptides in PEO layers, while non-amphiphilic peptides were not able to displace more amphiphilic peptides. In addition, peptides of greater amphiphilicity dominated the adsorption at the PEO layer from mixtures with less amphiphilic or non-amphiphilic peptides. PMID- 25909182 TI - Control of biomimetic hydroxyapatite deposition on polymer substrates using different protein adsorption abilities. AB - We recently developed a system for coating polystyrene (PS) substrates with hydroxyapatite (HAp) by utilizing serum protein adsorption layers as mediators to induce the heterogeneous nucleation of HAp in simulated body fluids (SBFs). In this study, the selective deposition of HAp on polymer substrate surfaces with different protein adsorption abilities was investigated using PS and poly(methyl methacrylate) (PMMA). Atomic force microscopic observations and the results of a quantitative analysis using a quartz-crystal microbalance (QCM) revealed that the amounts of proteins such as human serum albumin (HSA) and human immunoglobulin G (hIgG) adsorbed on PS substrate surfaces were markedly greater than those on PMMA substrate surfaces. A markedly larger amount of HAp was deposited on protein treated PS substrate surfaces than on PMMA substrate surfaces, reflecting protein adsorption to polymers. We also revealed that the deposition of HAp on protein adsorbed PS substrate surfaces was enhanced by aqueous calcium chloride treatments before immersion in 1.5SBF. In the case of 2.5 M calcium chloride treatment, these surfaces were completely covered with deposits. PMID- 25909183 TI - Bio-physical evaluation and in vivo delivery of plant proteinase inhibitor immobilized on silica nanospheres. AB - Recombinant expression of Capsicum annuum proteinase inhibitors (CanPI-13) and its application via synthetic carrier for the crop protection is the prime objective of our study. Herein, we explored proteinase inhibitor peptide immobilization on silica based nanospheres and rods followed by its pH mediated release in vitro and in vivo. Initial studies suggested silica nanospheres to be a suitable candidate for peptide immobilization. Furthermore, the interactions were characterized biophysically to ascertain their conformational stability and biological activity. Interestingly, bioactive peptide loading at acidic pH on nanospheres was found to be 62% and showed 56% of peptide release at pH 10, simulating gut milieu of the target pest Helicoverpa armigera. Additionally, in vivo study demonstrated significant reduction in insect body mass (158 mg) as compared to the control insects (265 mg) on 8th day after feeding with CanPI-13 based silica nanospheres. The study confirms that peptide immobilized silica nanosphere is capable of affecting overall growth and development of the feeding insects, which is known to hamper fecundity and fertility of the insects. Our study illustrates the utility and development of peptide-nanocarrier based platform in delivering diverse biologically active complexes specific to gut pH of H. armigera. PMID- 25909184 TI - Co-regulation of translation in protein complexes. AB - BACKGROUND: Co-regulation of gene expression has been known for many years, and studied widely both globally and for individual genes. Nevertheless, most analyses concerned transcriptional control, which in case of physically interacting proteins and protein complex subunits may be of secondary importance. This research is the first quantitative analysis that provides global-scale evidence for translation co-regulation among associated proteins. RESULTS: By analyzing the results of our previous quantitative model of translation, we have demonstrated that protein production rates plus several other translational parameters, such as mRNA and protein abundance, or number of produced proteins from a gene, are well concerted between stable complex subunits and party hubs. This may be energetically favorable during synthesis of complex building blocks and ensure their accurate production in time. In contrast, for connections with regulatory particles and date hubs translational co-regulation is less visible, indicating that in these cases maintenance of accurate levels of interacting particles is not necessarily beneficial. CONCLUSIONS: Similar results obtained for distantly related model organisms, Saccharomyces cerevisiae and Homo sapiens, suggest that the phenomenon of translational co-regulation applies to the variety of living organisms and concerns many complex constituents. This phenomenon was also observed among the set of functionally linked proteins from Escherichia coli operons. This leads to the conclusion that translational regulation of a protein should always be studied with respect to the expression of its primary interacting partners. PMID- 25909185 TI - What happens after inbreeding avoidance? Inbreeding by rejected relatives and the inclusive fitness benefit of inbreeding avoidance. AB - Avoiding inbreeding, and therefore avoiding inbreeding depression in offspring fitness, is widely assumed to be adaptive in systems with biparental reproduction. However, inbreeding can also confer an inclusive fitness benefit stemming from increased relatedness between parents and inbred offspring. Whether or not inbreeding or avoiding inbreeding is adaptive therefore depends on a balance between inbreeding depression and increased parent-offspring relatedness. Existing models of biparental inbreeding predict threshold values of inbreeding depression above which males and females should avoid inbreeding, and predict sexual conflict over inbreeding because these thresholds diverge. However, these models implicitly assume that if a focal individual avoids inbreeding, then both it and its rejected relative will subsequently outbreed. We show that relaxing this assumption of reciprocal outbreeding, and the assumption that focal individuals are themselves outbred, can substantially alter the predicted thresholds for inbreeding avoidance for focal males. Specifically, the magnitude of inbreeding depression below which inbreeding increases a focal male's inclusive fitness increases with increasing depression in the offspring of a focal female and her alternative mate, and it decreases with increasing relatedness between a focal male and a focal female's alternative mate, thereby altering the predicted zone of sexual conflict. Furthermore, a focal male's inclusive fitness gain from avoiding inbreeding is reduced by indirect opportunity costs if his rejected relative breeds with another relative of his. By demonstrating that variation in relatedness and inbreeding can affect intra- and inter-sexual conflict over inbreeding, our models lead to novel predictions for family dynamics. Specifically, parent-offspring conflict over inbreeding might depend on the alternative mates of rejected relatives, and male-male competition over inbreeding might lead to mixed inbreeding strategies. Making testable quantitative predictions regarding inbreeding strategies occurring in nature will therefore require new models that explicitly capture variation in relatedness and inbreeding among interacting population members. PMID- 25909186 TI - Structural Analysis of the 14-3-3zeta/Chibby Interaction Involved in Wnt/beta Catenin Signaling. AB - The partially disordered Chibby (Cby) is a conserved nuclear protein that antagonizes the Wnt/beta-catenin signaling pathway. By competing with the Tcf/Lef family proteins for binding to beta-catenin, Cby abrogates the beta-catenin mediated transcription of Wnt signaling genes. Additionally, upon phosphorylation on S20 by the kinase Akt, Cby forms a complex with 14-3-3 to facilitate the nuclear export of beta-catenin, which represents another crucial mechanism for the regulation of Wnt signaling. To obtain a mechanistic understanding of the 14 3-3/Cby interaction, we have extensively characterized the complex using X-ray crystallography, nuclear magnetic resonance (NMR) spectroscopy, and isothermal titration calorimetry (ITC). The crystal structure of the human 14-3-3zeta/Cby protein-peptide complex reveals a canonical binding mode; however the residue at the +2 position from the phosphorylated serine is shown to be uniquely oriented relative to other solved structures of 14-3-3 complexes. Our ITC results illustrate that although the phosphorylation of S20 is essential for Cby to recognize 14-3-3, residues flanking the phosphorylation site also contribute to the binding affinity. However, as is commonly observed in other 14-3 3/phosphopeptide crystal structures, residues of Cby flanking the 14-3-3 binding motif lack observable electron density. To obtain a more detailed binding interface, we have completed the backbone NMR resonance assignment of 14-3-3zeta. NMR titration experiments reveal that residues outside of the 14-3-3 conserved binding cleft, namely a flexible loop consisting of residues 203-210, are also involved in binding Cby. By using a combined X-ray and NMR approach, we have dissected the molecular basis of the 14-3-3/Cby interaction. PMID- 25909187 TI - Multiplex Eukaryotic Transcription (In)activation: Timing, Bursting and Cycling of a Ratchet Clock Mechanism. AB - Activation of eukaryotic transcription is an intricate process that relies on a multitude of regulatory proteins forming complexes on chromatin. Chromatin modifications appear to play a guiding role in protein-complex assembly on chromatin. Together, these processes give rise to stochastic, often bursting, transcriptional activity. Here we present a model of eukaryotic transcription that aims to integrate those mechanisms. We use stochastic and ordinary differential-equation modeling frameworks to examine various possible mechanisms of gene regulation by multiple transcription factors. We find that the assembly of large transcription factor complexes on chromatin via equilibrium-binding mechanisms is highly inefficient and insensitive to concentration changes of single regulatory proteins. An alternative model that lacks these limitations is a cyclic ratchet mechanism. In this mechanism, small protein complexes assemble sequentially on the promoter. Chromatin modifications mark the completion of a protein complex assembly, and sensitize the local chromatin for the assembly of the next protein complex. In this manner, a strict order of protein complex assemblies is attained. Even though the individual assembly steps are highly stochastic in duration, a sequence of them gives rise to a remarkable precision of the transcription cycle duration. This mechanism explains how transcription activation cycles, lasting for tens of minutes, derive from regulatory proteins residing on chromatin for only tens of seconds. Transcriptional bursts are an inherent feature of such transcription activation cycles. Bursting transcription can cause individual cells to remain in synchrony transiently, offering an explanation of transcriptional cycling as observed in cell populations, both on promoter chromatin status and mRNA levels. PMID- 25909189 TI - Correction: Cell-Penetrating Peptide Derived from Human Eosinophil Cationic Protein Inhibits Mite Allergen Der p 2 Induced Inflammasome Activation. PMID- 25909188 TI - Early systemic microvascular damage in pigs with atherogenic diabetes mellitus coincides with renal angiopoietin dysbalance. AB - BACKGROUND: Diabetes mellitus (DM) is associated with a range of microvascular complications including diabetic nephropathy (DN). Microvascular abnormalities in the kidneys are common histopathologic findings in DN, which represent one manifestation of ongoing systemic microvascular damage. Recently, sidestream dark field (SDF) imaging has emerged as a noninvasive tool that enables one to visualize the microcirculation. In this study, we investigated whether changes in the systemic microvasculature induced by DM and an atherogenic diet correlated spatiotemporally with renal damage. METHODS: Atherosclerotic lesion development was triggered in streptozotocin-induced DM pigs (140 mg/kg body weight) by administering an atherogenic diet for approximately 11 months. Fifteen months following induction of DM, microvascular morphology was visualized in control pigs (n = 7), non-diabetic pigs fed an atherogenic diet (ATH, n = 5), and DM pigs fed an atherogenic diet (DM+ATH, n = 5) using SDF imaging of oral mucosal tissue. Subsequently, kidneys were harvested from anethesized pigs and the expression levels of well-established markers for microvascular integrity, such as Angiopoietin-1 (Angpt1) and Angiopoietin-2 (Angpt2) were determined immunohistochemically, while endothelial cell (EC) abundance was determined by immunostaining for von Willebrand factor (vWF). RESULTS: Our study revealed an increase in the capillary tortuosity index in DM+ATH pigs (2.31+/-0.17) as compared to the control groups (Controls 0.89+/-0.08 and ATH 1.55+/-0.11; p<0.05). Kidney biopsies showed marked glomerular lesions consisting of mesangial expansion and podocyte lesions. Furthermore, we observed a disturbed Angpt2/Angpt1 balance in the cortex of the kidney, as evidenced by increased expression of Angpt2 in DM+ATH pigs as compared to Control pigs (p<0.05). CONCLUSION: In the setting of DM, atherogenesis leads to the augmentation of mucosal capillary tortuosity, indicative of systemic microvascular damage. Concomitantly, a dysbalance in renal angiopoietins was correlated with the development of diabetic nephropathy. As such, our studies strongly suggest that defects in the systemic microvasculature mirror the accumulation of microvascular damage in the kidney. PMID- 25909190 TI - Climatic and Catchment-Scale Predictors of Chinese Stream Insect Richness Differ between Taxonomic Groups. AB - Little work has been done on large-scale patterns of stream insect richness in China. We explored the influence of climatic and catchment-scale factors on stream insect (Ephemeroptera, Plecoptera, Trichoptera; EPT) richness across mid latitude China. We assessed the predictive ability of climatic, catchment land cover and physical structure variables on genus richness of EPT, both individually and combined, in 80 mid-latitude Chinese streams, spanning a 3899-m altitudinal gradient. We performed analyses using boosted regression trees and explored the nature of their influence on richness patterns. The relative importance of climate, land cover, and physical factors on stream insect richness varied considerably between the three orders, and while important for Ephemeroptera and Plecoptera, latitude did not improve model fit for any of the groups. EPT richness was linked with areas comprising high forest cover, elevation and slope, large catchments and low temperatures. Ephemeroptera favoured areas with high forest cover, medium-to-large catchment sizes, high temperature seasonality, and low potential evapotranspiration. Plecoptera richness was linked with low temperature seasonality and annual mean, and high slope, elevation and warm-season rainfall. Finally, Trichoptera favoured high elevation areas, with high forest cover, and low mean annual temperature, seasonality and aridity. Our findings highlight the variable role that catchment land cover, physical properties and climatic influences have on stream insect richness. This is one of the first studies of its kind in Chinese streams, thus we set the scene for more in-depth assessments of stream insect richness across broader spatial scales in China, but stress the importance of improving data availability and consistency through time. PMID- 25909191 TI - A systematic review of medication exposure assessment in prospective cohort studies of community dwelling older australians. AB - INTRODUCTION: It is not known to what extent medication use has been comprehensively assessed in prospective cohort studies of older Australians. Understanding the varying methods to assess medication use is necessary to establish comparability and to understand the opportunities for pharmacoepidemiological analysis. The objective of this review was to compare and contrast how medication-related data have been collected in prospective cohorts of community-dwelling older Australians. METHODS: MEDLINE and EMBASE (1990-2014) were systematically searched to identify prospective cohorts of >=1000 older participants that commenced recruitment after 1990. The data collection tools used to assess medication use in each cohort were independently examined by two investigators using a structured approach. RESULTS: Thirteen eligible cohorts were included. Baseline medication use was assessed in participant self-completed surveys (n = 3), by an investigator inspecting medications brought to a clinic interview (n = 7), and by interviewing participants in their home (n = 3). Five cohorts sought participant consent to access administrative claims data. Six cohorts used multiple methods to assess medication use across one or more study waves. All cohorts assessed medication use at baseline and 12 cohorts in follow up waves. Twelve cohorts recorded prescription medications by trade or generic name; 12 cohorts recorded medication strength; and 9 recorded the daily medication dose in at least one wave of the cohort. Seven cohorts asked participants about their "current" medication use without providing a definition of "current"; and nine cohorts asked participants to report medication use over recall periods ranging from 1-week to 3-months in at least one wave of the cohort. Sixty-five original publications, that reported the prevalence or outcomes of medication use, in the 13 cohorts were identified (median = 3, range 1-21). CONCLUSION: There has been considerable variability in the assessment of medication use within and between cohorts. This may limit the comparability of medication data collected in these cohorts. PMID- 25909192 TI - Predictors of time to recovery in infants with probable serious bacterial infection. AB - INTRODUCTION: Serious bacterial infections continue to be an important cause of death and illness among infants in developing countries. Time to recovery could be considered a surrogate marker of severity of the infection. We therefore aimed to identify clinical and laboratory predictors of time to recovery in infants with probable serious bacterial infection (PSBI). METHODS: We used the dataset of 700 infants (7-120 days) enrolled in a randomised controlled trial in India in which 10mg of oral zinc or placebo was given to infants with PSBI. PSBI was defined as signs/symptoms of possible serious bacterial infection along with baseline C-reactive protein(CRP) level >12mg/L. Time to recovery was defined as time from enrolment to the end of a 2-day period with no symptoms/signs of PSBI and daily weight gain of at least 10g over 2 succesive days on exclusive oral feeding. Cox proportional hazard regression was used to measure the associations between relevant variables and time to recovery. RESULTS: Infants who were formula fed prior to illness episode had 33% longer time to recovery (HR-0.67, 95%CI-0.52, 0.87) than those who were not. Being underweight (HR-0.84, 95%CI 0.70, 0.99), lethargic (HR-0.77, 95%CI-0.62, 0.96) and irritable (HR-0.81, 95%CI 0.66, 0.99) were independent predictors of time to recovery. Baseline CRP was significantly associated with time to recovery (P<0.001), higher CRP was associated with longer time to recovery and this association was nearly linear. CONCLUSION: Simple clinical and laboratory parameters such as formula feeding prior to the illness, being underweight, lethargic, irritable and having elevated CRP levels could be used for early identification of infants with PSBI at risk for protracted illness and could guide prompt referral to higher centers in resource limited settings. This also provides prognostic information to clinicians and family as longer recovery time has economic and social implications on the family in our setting. TRIAL REGISTRATION: ClinicalTrials.gov NCT00347386. PMID- 25909193 TI - Biological Activities of QIAPI 1 as a Melanin Precursor and Its Therapeutic Effects in Wistar Rats Exposed to Arsenic Poisoning. AB - The chemical process initiated by QIAPI 1 has been deemed to be the most important biological reaction associated with human photosynthesis, and possibly neuroprotective effects under various inflammatory events. However, the detailed biological activities of QIAPI 1 as a melanin precursor are still unknown. In the present work, cytotoxicity test was done by MTT assay to determine cell viability of various cell lines (WI-38, A549, HS 683) like proliferation tests and its effect on cytokine production. Arsenic poisoning is an often-unrecognized cause of renal insufficiency. No prophylactic and/or therapeutic compounds have shown promising results against kidney diseases. The pathogenesis of Arsenic-induced nephropathy is not clear. Arsenic, as itself, does not degrade over time in the environment, and its accumulation may induce toxic effects. In this study, we also report the histological findings of the kidney in 3 groups of Wistar rats, a control group, a group exposed to arsenic in the water; and a group exposed to arsenic and treated with QIAPI 1 simultaneously. The findings of the current evidence indicates a potential therapeutic ability of QIAPI 1. PMID- 25909195 TI - Thoughts on breast cancer in Brazil. PMID- 25909194 TI - High Prevalence of the BIM Deletion Polymorphism in Young Female Breast Cancer in an East Asian Country. AB - BACKGROUND: A rapid surge of female breast cancer has been observed in young women in several East Asian countries. The BIM deletion polymorphism, which confers cell resistance to apoptosis, was recently found exclusively in East Asian people with prevalence rate of 12%. We aimed to evaluate the possible role of this genetic alteration in carcinogenesis of breast cancer in East Asians. METHOD: Female healthy volunteers (n = 307), patients in one consecutive stage I III breast cancer cohort (n = 692) and one metastatic breast cancer cohort (n = 189) were evaluated. BIM wild-type and deletion alleles were separately genotyped in genomic DNAs. RESULTS: Both cancer cohorts consistently showed inverse associations between the BIM deletion polymorphism and patient age (<=35 y vs. 36 50 y vs. >50 y: 29% vs. 22% vs. 15%, P = 0.006 in the consecutive cohort, and 40% vs. 23% vs. 13%, P = 0.023 in the metastatic cohort). In healthy volunteers, the frequencies of the BIM deletion polymorphism were similar (13%-14%) in all age groups. Further analyses indicated that the BIM deletion polymorphism was not associated with specific clinicopathologic features, but it was associated with poor overall survival (adjusted hazard ratio 1.71) in the consecutive cohort. CONCLUSIONS: BIM deletion polymorphism may be involved in the tumorigenesis of the early-onset breast cancer among East Asians. PMID- 25909198 TI - Femoral neck fracture in children: treatment and complications. PMID- 25909199 TI - Treatment of prostate cancer with intensity modulated radiation therapy (IMRT). PMID- 25909200 TI - Chondroma of the falx cerebri. PMID- 25909201 TI - Natriuretic peptides, obesity and cardiovascular diseases. AB - Obesity, hypertension and heart failure are conditions commonly associated with each other. Recent investigations have demonstrated that low plasmatic levels of natriuretic peptides are linked with obesity. Thus, knowing the actions of these hormones in water and salt homeostasis, it is possible to establish that low levels of natriuretic peptides may be the common denominator among obesity, hypertension and heart failure. Knowledge on this topic is crucial to develop further investigation for definitive conclusions. PMID- 25909202 TI - The importance of modernizing the specialty societies. PMID- 25909203 TI - Is there any increase in newborn morbidity in elective C-sections performed before the 39th week of pregnancy? PMID- 25909204 TI - Rio Grande do Norte, Brazil, voluntary bone marrow donors registry analysis. AB - OBJECTIVE: this study aimed to report the allele and haplotype frequencies of volunteer bone marrow donors (VBMD) from the state of Rio Grande do Norte (RN) who were enrolled in the Brazilian Volunteer Bone Marrow Donor Registry (REDOME). METHODS: the sample comprised 12,973 VBMD who had their allele and haplotype frequencies calculated by Arlequin 3.5.1.2. A multivariate analysis of the data was obtained through a principal component analysis (PCA) and hierarchical cluster analysis (HCA) performed with SPSS 8.0. RESULTS: the most frequent allelic group was HLA-A*02, followed by -DRB1*13, -DRB1*04, -DRB1*07, -B*44, B*35, -A*24 and -DRB1*01. Of the 2,701 haplotypes observed, the three most frequent were HLA-A*01 B*08 DRB1*03 (1.62%), -A*29 B*44 DRB1*07 (1.56%) and -A*02 B*44 DRB1*04 (1.29%). These haplotypes were in linkage disequilibrium. RN allele and haplotype frequencies were very similar to those in other Brazilian states in which similar studies have been performed. The PCA revealed that RN is highly genetically similar to Caucasian populations, especially those from Iberian countries, which strongly influenced the state's ethnic composition. Africans and Amerindians also influenced the RN population structure, to a lesser extent. CONCLUSION: the HCA reinforced the conclusion that, despite its highly admixed profile, the RN population is genetically similar to European and European descended populations. The PCA also showed that RN cities do not contribute to the same extent to REDOME, with less populous cities being underrepresented, indicating the need to enroll more VBMD from these smaller cities to faithfully depict the state's population structure in the database. PMID- 25909205 TI - Diazepam or midazolam for orotracheal intubation in the ICU? AB - OBJECTIVE: to compare clinical and cost effectiveness of midazolam and diazepam for urgent intubation. METHODS: patients admitted to the Central ICU of the Santa Casa Hospital Complex in Porto Alegre, over the age of 18 years, undergoing urgent intubation during 6 months were eligible. Patients were randomized in a single-blinded manner to either intravenous diazepam or midazolam. Diazepam was given as a 5 mg intravenous bolus followed by aliquots of 5 mg each minute. Midazolam was given as an intravenous bolus of 5 mg with further aliquots of 2.5 mg each minute. Ramsay sedation scale 5-6 was considered adequate sedation. We recorded time and required doses to reach adequate sedation and duration of sedation. RESULTS: thirty four patients were randomized, but one patient in the diazepam group was excluded because data were lost. Both groups were similar in terms of illness severity and demographics. Time for adequate sedation was shorter (132 +/- 87 sec vs. 224 +/- 117 sec, p = 0.016) but duration of sedation was similar (86 +/- 67 min vs. 88 +/- 50 min, p = 0.936) for diazepam in comparison to midazolam. Total drug dose to reach adequate sedation after either drugs was similar (10.0 [10.0-12.5] mg vs. 15.0 [10.0-17.5] mg, p = 0.248). Arterial pressure and sedation intensity reduced similarly overtime with both drugs. Cost of sedation was lower for diazepam than for midazolam (1.4[1.4-1.8] vs. 13.9[9.4-16.2] reais, p <0.001). CONCLUSIONS: intubation using intravenous diazepam and midazolam is effective and well tolerated. Sedation with diazepam is associated to a quicker sedation time and to lower costs. PMID- 25909206 TI - In-hospital mortality risk factors in patients with ascites due to cirrhosis. AB - INTRODUCTION: ascites is one of the most common complications of cirrhosis associated with a high rate of mortality. Although several scores have been developed in order to assess the prognosis of the disease, they were designed for predicting liver transplantation requirements and mortality in the short term, but not while in hospital. The aim of this study was to weigh risk factors for in hospital mortality in adult patients with ascites due to alcoholic cirrhosis. MATERIAL AND METHODS: we performed a cross-sectional study in 180 adult patients with diagnosis of cirrhosis with portal hypertension associated with high alcohol intake. The diagnosis of cirrhosis was made by liver echography and portal hypertension was defined by clinical features plus serum-ascites albumin gradient. Sampled individuals were subjected to complete clinical examination. Child Pugh and the MELD scores were applied in all the patients. RESULTS: nineteen patients died while in-hospital. Mortality was associated with increased levels of serum white blood cell, urea, creatinine, prolonged prothrombin time, aspartate aminotransferase and alanine aminotransferase. We conducted a multiple binary logistic to predict in-hospital mortality which yielded that serum urea, creatinine and prothrombin time made a significant contribution to prediction with an OR 14 (95% CI 12.8 - 16.7 p = 0.03), 2 (95% CI 0.5 - 3.47, p = 0.04), and 2 (95% CI 1.03 - 2.31, p = 0.01) linearly-related. CONCLUSIONS: our results suggest that acute renal failure and prolonged prothrombin time are predictors of in-hospital mortality in patients with portal hypertension due to alcoholic cirrhosis. PMID- 25909207 TI - Reducing the length of hospital stay after total knee arthroplasty: influence of femoral and sciatic nerve block. AB - OBJECTIVE: the aim of this study is to evaluate the change in length of hospital stay postoperatively for Total Knee Arthroplasty after using femoral and sciatic nerve block. MATERIALS AND METHODS: the medical records of 287 patients were evaluated, taking into account the number of hours of admission, the percentage and the reason for re-hospitalization within 30 days, as well as associated complications. All patients were divided into two groups according or not to whether they were admitted to ICU or not. During the years 2009 and 2010, isolated spinal anesthesia was the method used in the procedure. From 2011 on, femoral and sciatic nerve blocking was introduced. RESULTS: between the years 2009 and 2012, the average length of stay ranged from 74 hours in 2009 to 75.2 hours in 2010. The average length of stay in 2011 was 56.52 hours and 53.72 hours in 2012, all in the group of patients who did not remain in the ICU postoperatively. In the same period, among those in the group that needed ICU admission, the average length of stay was 138.7 hours in 2009, 90.25 hours in 2010, 79.8 hours in 2011, and 52.91 hours in 2012. During 2009 and 2010, the rate of re-hospitalization was 0%, while in 2011 and 2012, were 3.44% and 1%, respectively. CONCLUSION: according to this study, the use of femoral and sciatic nerve blocking after total knee arthroplasty allowed significant reduction in hospital stay. PMID- 25909208 TI - Generic versus branded enoxaparin in prophylaxis and treatment of vein thrombosis. AB - OBJECTIVES: to compare the biological efficacy of generic enoxaparin (HeptronTM) versus branded Sanofi-Aventis enoxaparin for prophylaxis and treatment of lower extremity deep venous thrombosis (DVT) in a prospective, randomized, open-label study. METHODS: patients with diagnosed lower-extremity DVT (therapeutic branch, n=57) and patients requiring venous thromboembolism (VTE) prophylaxis after arterial vascular surgery or major lower-extremity amputations (prophylactic branch, n=57) were randomized to receive generic or branded enoxaparin for up to seven days. Enoxaparin activity was measured by estimating blood anti-factor Xa levels at the peak plasma concentration. As secondary outcomes, development or progression of VTE events, major adverse events and major bleeding events were considered for efficacy and safety comparisons. RESULTS: DVT therapy: twenty-five patients received generic enoxaparin while 32 received branded enoxaparin (subcutaneous, 1 mg/kg BID). Mean percentages of anti-factor Xa levels within the target ranges were 62 +/- 35.4% and 67.5 +/- 24.7%, respectively (p= .035 for non inferiority). No patient presented DVT progression, clinically detectable pulmonary embolism, or major bleeding events in any subgroup. DVT prophylaxis: Thirty patients received generic enoxaparin and 27 received branded enoxaparin (subcutaneous, 40 mg/day). Mean percentages of anti-factor Xa levels within the target ranges were 77.9 +/- 30.9% and 77.8 +/- 32.9%, respectively (p = .009 for non-inferiority). There were no cases of VTE or major bleeding events in any subgroup. CONCLUSION: generic and branded enoxaparins exhibited similar in vivo responses as measured by the anti-factor Xa activity, as well as similar clinical efficacy and safety outcomes. PMID- 25909209 TI - Delinquency and association with behavioral disorders and substance abuse. AB - OBJECTIVE: to determine the incidence and associations of attention deficit hyperactivity disorder (ADHD), conduct disorder (CD), and substance abuse disorder (SAD) in adolescents in conflict with the law in a Brazilian cohort. METHODS: the Brazilian version of the Schedule for Affective Disorders and Schizophrenia for School Aged-Children (K-SADS-PL) was administered to 69 adolescent boys who were incarcerated for 45 days in the city of Curitiba, Brazil. RESULTS: mean age was 15.5 years (range, 12-16.9 years) and most adolescents originated from disadvantaged social classes (87%). They resided in neighborhoods on the outskirts of the city or towns in the greater metropolitan area. Truancy and low educational achievement were common, with 73.9% not currently attending school and 43.4% not having finished the 5th grade. The great majority lived in single-parent families and many had relatives who themselves had problems with the law. Psychiatric disorders were apparent in 81.1% of the subjects, with the most common disorders being CD (59.4%), SAD (53.6%), and ADHD (43.5%). Both ADHD (p <0.001) and CD (p <0.01) had significant associations with substance abuse. CONCLUSION: in male adolescents in conflict with the law, ADHD, CD, and SAD were all found to be associated with delinquency. PMID- 25909210 TI - Inflammatory biomarker kinetics after mechanical and bioprosthetic valve replacement. AB - INTRODUCTION: valve disease is an important cause of heart failure. There is a direct relationship between valve deterioration and the patient's inflammatory status and cytokines: interleukin-6, interleukin-1, tumor necrosis factor, and C reactive protein, involved in this major state of inflammation. OBJECTIVE: to report a series of cases of valve replacement, using a bioprosthetic or mechanical valve, and the inflammatory profile of them. METHODS: patients older than 18 years and with bioprosthetic or mechanical valve placed for a minimum of 6 months and maximum of 2 years were included. In addition to the demographic characteristics of each patient, inflammatory markers were measured and a comparison was made of echocardiographic results before (based on medical records) and after surgery. A total of 46 patients were enrolled, 23 with mechanical valve and 23 with bioprosthetic valve. RESULTS: of the 46 patients, 20 presented complete data were included, 12 with bioprosthetic and 8 with mechanical valve. There was no difference between types of prosthesis or implant site for the values of inflammatory markers although they were all above reference range. DISCUSSION: patients undergoing aortic mechanical valve implant benefited more than those undergoing bioprosthetic implant and both with much better results than those of valve replacements performed on mitral valve. In short, there was no difference in relation to inflammatory biomarkers. PMID- 25909211 TI - Characteristics of motorcyclists involved in accidents between motorcycles and automobiles. AB - INTRODUCTION: traffic accidents are one of the main causes of death and disability, with motorcyclists representing the great majority of both the victims and the perpetrators. OBJECTIVE: this work studied the characteristics of motorcyclists injured in accidents involving motorcycles and automobiles. METHOD: this study sought to interview 100 motorcyclists who had been injured in collisions between motorcycles and automobiles, and who were undergoing emergency hospital treatment in the region of Belo Horizonte, Brazil. The questionnaires included demographic information (age, gender, skin color, education level, profession) and questions about years of licensed driving practice, how often they would drive an automobile, how long they had had a motorcycle driver's license, how often they would ride a motorcycle, the number of prior accidents involving a car, and the number of prior accidents not involving a car. RESULTS: of the 100 consecutive accidents studied, 91 occurred with men and 9 with women, aged between 16 and 79 (m = 29 +/- 11) years. Regarding their reason for using a motorcycle, 83% reported using it for transport, 7% for work, and 10% for leisure. Most of these accident victims had secondary or higher education (47%). Of the motorcyclists who held a car driver's license, 68.3% drove the vehicle daily or weekly and held the license for more than one year. Sixty-seven percent of the accident victims used a motorcycle daily and had a motorcycle driver's license for at least one year. CONCLUSION: among the motorcyclists injured, most were men aged 20 years or older, with complete secondary education, and experienced in driving both motorcycles and cars, indicating that recklessness while driving the motorcycle is the main cause of traffic accidents. PMID- 25909212 TI - Extracorporeal shock wave lithotripsy in the treatment of renal and ureteral stones. AB - The use of certain technical principles and the selection of favorable cases can optimize the results of extracorporeal shock wave lithotripsy (ESWL). The aim of this study is to review how ESWL works, its indications and contraindications, predictive factors for success, and its complications. A search was conducted on the Pubmed(r) database between January 1984 and October 2013 using "shock wave lithotripsy" and "stone" as key-words. Only articles with a high level of evidence, in English, and conducted in humans, such as clinical trials or review/meta-analysis, were included. To optimize the search for the ESWL results, several technical factors including type of lithotripsy device, energy and frequency of pulses, coupling of the patient to the lithotriptor, location of the calculus, and type of anesthesia should be taken into consideration. Other factors related to the patient, stone size and density, skin to stone distance, anatomy of the excretory path, and kidney anomalies are also important. Antibiotic prophylaxis is not necessary, and routine double J stent placement before the procedure is not routinely recommended. Alpha-blockers, particularly tamsulosin, are useful for stones >10mm. Minor complications may occur following ESWL, which generally respond well to clinical interventions. The relationship between ESWL and hypertension/diabetes is not well established. PMID- 25909213 TI - Relationship between adiponectin, obesity and insulin resistance. AB - OBJECTIVES: the conditions of obesity and overweight pose a major risk for a number of comorbidities, including clinical syndromes resulting from atherosclerotic disease. Recent studies strongly indicate that adipose tissue is an active endocrine organ that secretes bioactive factors such as adipokines. Adiponectin appears to have a regulatory role in the mechanism of insulin resistance and in the development of atherosclerosis. This systematic review aims to evaluate the anti-atherogenic effects of adiponectin and its properties to improve and mimic metabolic and vascular actions of insulin and its influence on endothelial function. METHODS: a qualitative, exploratory and literature review was performed in the PubMed, Portal Capes and Scielo databases using as key-words "adiponectin", "obesity", "insulin resistance", "anti-inflammatory", "therapeutic strategies" and "future prospects". RESULTS: evidence suggests that adiponectin has anti-atherogenic properties with anti-inflammatory effects on the vascular wall. Moreover, it modifies the vascular intracellular signaling and has indirect antioxidant effects on the human myocardium. On the other hand, there are studies suggesting that increased levels of adiponectin are paradoxically associated with a worse prognosis in heart failure syndrome, although the mechanisms are not clear. CONCLUSION: it is not clear whether adiponectin levels have any clinical significance for risk stratification in cardiovascular disease or if they simply reflect the activation of complex underlying mechanisms. Changes in lifestyle and some drug treatments for hypertension and coronary heart disease have shown significant effect to increase adiponectin levels, and simultaneously decrease in insulin resistance and endothelial dysfunction. PMID- 25909214 TI - Adhesion molecules in breast carcinoma: a challenge to the pathologist. AB - The role of adhesion molecules is very important both in the activation of carcinogenesis and in the differentiation of subtypes of breast carcinoma, aiding in diagnosis, prognosis and therapeutic choice in these tumors. Therefore, understanding the functions and interrelationships among these molecules is crucial to the pathologist, who often uses these factors as a resource to differentiate tumors and further classify them according to a molecular point of view. Our goal is to describe the applicability and the difficulties encountered by the pathologist in the diagnosis of breast carcinoma, discussing the most commonly used markers of adhesion in routine analyses. PMID- 25909215 TI - Cancer stem cells: a new approach to tumor development. AB - Many theories have been proposed to explain the origins of cancer. Currently, evidences show that not every tumor cell is capable of initiating a tumor. Only a small part of the cancer cells, called cancer stem cells (CSCs), can generate a tumor identical to the original one, when removed from human tumors and transplanted into immunosuppressed mice. The name given to these cells comes from the resemblance to normal stem cells, except for the fact that their ability to divide is infinite. These cells are also affected by their microenvironment. Many of the signaling pathways, such as Wnt, Notch and Hedgehog, are altered in this tumoral subpopulation, which also contributes to abnormal proliferation. Researchers have found several markers for CSCs; however, much remains to be studied, or perhaps a universal marker does not even exist, since they vary among tumor types and even from patient to patient. It was also found that cancer stem cells are resistant to radiotherapy and chemotherapy. This may explain the re emergence of the disease, since they are not completely eliminated and minimal amounts of CSCs can repopulate a tumor. Once the diagnosis in the early stages greatly increases the chances of curing cancer, identifying CSCs in tumors is a goal for the development of more effective treatments. The objective of this article is to discuss the origin of cancer according to the theory of stem cell cancer, as well as its markers and therapies used for treatment. PMID- 25909216 TI - Deficiency of caspase 3 in tumor xenograft impairs therapeutic effect of measles virus Edmoston strain. AB - The oncolytic measles virus Edmonston (MV-Edm) strain shows considerable oncolytic activity against a variety of human tumors. In this study, we report MV Edm is able to trigger apoptosis pathways in infected tumor cells and elucidate the roles of cellular apoptosis in the whole oncolytic process. We also show that activated caspase 3, a key executioner of apoptosis, plays key roles in the oncolytic virotherapy. Activated caspase 3 can accelerate viral replication in cervical cancer cells and enhance the killing effects of the virus. Deficiency of caspase 3 either in tumor cells or in tumor xenograft significantly desensitized tumor to oncolysis with MV-Edm. In the infected cells, caspase 3 regulates interferon alpha release, which can inhibit viral replication in neighboring tumor cells. We propose that caspase-3 activation enhances the oncolytic effects of MV-Edm, thus inhibiting tumor growth in mice. PMID- 25909218 TI - Molecular stratification of metastatic melanoma using gene expression profiling: Prediction of survival outcome and benefit from molecular targeted therapy. AB - Melanoma is currently divided on a genetic level according to mutational status. However, this classification does not optimally predict prognosis. In prior studies, we have defined gene expression phenotypes (high-immune, pigmentation, proliferative and normal-like), which are predictive of survival outcome as well as informative of biology. Herein, we employed a population-based metastatic melanoma cohort and external cohorts to determine the prognostic and predictive significance of the gene expression phenotypes. We performed expression profiling on 214 cutaneous melanoma tumors and found an increased risk of developing distant metastases in the pigmentation (HR, 1.9; 95% CI, 1.05-3.28; P=0.03) and proliferative (HR, 2.8; 95% CI, 1.43-5.57; P=0.003) groups as compared to the high-immune response group. Further genetic characterization of melanomas using targeted deep-sequencing revealed similar mutational patterns across these phenotypes. We also used publicly available expression profiling data from melanoma patients treated with targeted or vaccine therapy in order to determine if our signatures predicted therapeutic response. In patients receiving targeted therapy, melanomas resistant to targeted therapy were enriched in the MITF-low proliferative subtype as compared to pre-treatment biopsies (P=0.02). In summary, the melanoma gene expression phenotypes are highly predictive of survival outcome and can further help to discriminate patients responding to targeted therapy. PMID- 25909217 TI - Targeting Hsp90 in urothelial carcinoma. AB - Urothelial carcinoma, or transitional cell carcinoma, is the most common urologic malignancy that carries significant morbidity, mortality, recurrence risk and associated health care costs. Despite use of current chemotherapies and immunotherapies, long-term remission in patients with muscle-invasive or metastatic disease remains low, and disease recurrence is common. The molecular chaperone Heat Shock Protein-90 (Hsp90) may offer an ideal treatment target, as it is a critical signaling hub in urothelial carcinoma pathogenesis and potentiates chemoradiation. Preclinical testing with Hsp90 inhibitors has demonstrated reduced proliferation, enhanced apoptosis and synergism with chemotherapies and radiation. Despite promising preclinical data, clinical trials utilizing Hsp90 inhibitors for other malignancies had modest efficacy. Therefore, we propose that Hsp90 inhibition would best serve as an adjuvant treatment in advanced muscle-invasive or metastatic bladder cancers to potentiate other therapies. An overview of bladder cancer biology, current treatments, molecular targeted therapies, and the role for Hsp90 inhibitors in the treatment of urothelial carcinoma is the focus of this review. PMID- 25909219 TI - Fasting induces anti-Warburg effect that increases respiration but reduces ATP synthesis to promote apoptosis in colon cancer models. AB - Tumor chemoresistance is associated with high aerobic glycolysis rates and reduced oxidative phosphorylation, a phenomenon called "Warburg effect" whose reversal could impair the ability of a wide range of cancer cells to survive in the presence or absence of chemotherapy. In previous studies, Short-term starvation (STS) was shown to protect normal cells and organs but to sensitize different cancer cell types to chemotherapy but the mechanisms responsible for these effects are poorly understood. We tested the cytotoxicity of Oxaliplatin (OXP) combined with a 48hour STS on the progression of CT26 colorectal tumors. STS potentiated the effects of OXP on the suppression of colon carcinoma growth and glucose uptake in both in vitro and in vivo models. In CT26 cells, STS down regulated aerobic glycolysis, and glutaminolysis, while increasing oxidative phosphorylation. The STS-dependent increase in both Complex I and Complex II dependent O(2) consumption was associated with increased oxidative stress and reduced ATP synthesis. Chemotherapy caused additional toxicity, which was associated with increased succinate/Complex II-dependent O(2) consumption, elevated oxidative stress and apoptosis .These findings indicate that the glucose and amino acid deficiency conditions imposed by STS promote an anti-Warburg effect characterized by increased oxygen consumption but failure to generate ATP, resulting in oxidative damage and apoptosis. PMID- 25909220 TI - Fasting potentiates the anticancer activity of tyrosine kinase inhibitors by strengthening MAPK signaling inhibition. AB - Tyrosine kinase inhibitors (TKIs) are now the mainstay of treatment in many types of cancer. However, their benefit is frequently short-lived, mandating the search for safe potentiation strategies. Cycles of fasting enhance the activity of chemo radiotherapy in preclinical cancer models and dietary approaches based on fasting are currently explored in clinical trials. Whether combining fasting with TKIs is going to be potentially beneficial remains unknown. Here we report that starvation conditions increase the ability of commonly administered TKIs, including erlotinib, gefitinib, lapatinib, crizotinib and regorafenib, to block cancer cell growth, to inhibit the mitogen-activated protein kinase (MAPK) signaling pathway and to strengthen E2F-dependent transcription inhibition. In cancer xenografts models, both TKIs and cycles of fasting slowed tumor growth, but, when combined, these interventions were significantly more effective than either type of treatment alone. In conclusion, cycles of fasting or of specifically designed fasting-mimicking diets should be evaluated in clinical studies as a means to potentiate the activity of TKIs in clinical use. PMID- 25909221 TI - miR-497 and miR-34a retard lung cancer growth by co-inhibiting cyclin E1 (CCNE1). AB - Cyclin E1, encoded by the CCNE1 gene, promotes G1/S transition, chromosome instability, and oncogenesis. Here, we show that miR-497 and miR-34a target the 3'-UTR of CCNE1. miR-497 and miR-34a are downregulated in cancer cells and their ectopic expression inhibited cell proliferation and colony formation in vitro, and inhibited tumor growth in a xenograft model. The effect of simultaneous overexpression of miR-497 and miR-34a on the inhibition of cell proliferation, colony formation, and tumor growth, and the downregulation of cyclin E1 was stronger than the effect of each miRNA alone. The synergistic actions of miR-497 and miR-34a partly correlated with cyclin E1 levels. When cells stably expressing CCNE1 were transfected with the Hi-miR-497/34a plasmid, there was no effect on colony formation, compared with that of cells transfected with either Hi-miR497 or Hi-miR34a. These results indicate cyclin E1 is downregulated by both miR-497 and miR-34a, which synergistically retard the growth of human lung cancer cells. PMID- 25909222 TI - Enhanced tumorigenicity by mitochondrial DNA mild mutations. AB - To understand how mitochondria are involved in malignant transformation we have generated a collection of transmitochondrial cybrid cell lines on the same nuclear background (143B) but with mutant mitochondrial DNA (mtDNA) variants with different degrees of pathogenicity. These include the severe mutation in the tRNALys gene, m.8363G>A, and the three milder yet prevalent Leber's hereditary optic neuropathy (LHON) mutations in the MT-ND1 (m.3460G>A), MT-ND4 (m.11778G>A) and MT-ND6 (m.14484T>C) mitochondrial genes. We found that 143B rho0 cells devoid of mtDNA and cybrids harboring wild type mtDNA or that causing severe mitochondrial dysfunction do not produce tumors when injected in nude mice. By contrast cybrids containing mild mutant mtDNAs exhibit different tumorigenic capacities, depending on OXPHOS dysfunction.The differences in tumorigenicity correlate with an enhanced resistance to apoptosis and high levels of NOX expression. However, the final capacity of the different cybrid cell lines to generate tumors is most likely a consequence of a complex array of pro-oncogenic and anti-oncogenic factors associated with mitochondrial dysfunction.Our results demonstrate the essential role of mtDNA in tumorigenesis and explain the numerous and varied mtDNA mutations found in human tumors, most of which give rise to mild mitochondrial dysfunction. PMID- 25909223 TI - MiR-200b/200c/429 subfamily negatively regulates Rho/ROCK signaling pathway to suppress hepatocellular carcinoma metastasis. AB - MiR-200 family is an important regulator of epithelial-mesenchymal transition and has been implicated in human carcinogenesis. However, their expression and functions in human cancers remain controversial. In the work presented here, we showed that miR-200 family members were frequently down-regulated in hepatocellular carcinoma (HCC). Although all five members of miR-200 family inhibited ZEB1/2 expression in HCC cell lines, we showed that overexpression only of the miR-200b/200c/429 subfamily, but not the miR-200a/141 subfamily, resulted in impeded HCC cell migration. Further investigations led to the identification of RhoA and ROCK2 as specific down-stream targets of the miR-200b/200c/429 subfamily. We demonstrated that the miR-200b/200c/429 subfamily inhibited HCC cell migration through modulating Rho/ROCK mediated cell cytoskeletal reorganization and cell-substratum adhesion. Re-expression of miR-200b significantly suppressed lung metastasis of HCC cells in an orthotopic liver implantation model in vivo. In conclusion, our findings identified the miR 200b/200c/429 subfamily as metastasis suppressor microRNAs in human HCC and highlighted the functional discrepancy among miR-200 family members. PMID- 25909224 TI - High USP22 expression indicates poor prognosis in hepatocellular carcinoma. AB - Ubiquitin-specific protease 22 (USP22) removes ubiquitin from histones, thus regulating gene transcription. The expression frequency and expression levels of USP22 were significantly higher in hepatocellular carcinoma (HCC) than in normal liver tissues. High USP22 expression in HCC was significantly correlated with clinical stage and tumor grade. Kaplan-Meier analysis showed that elevated USP22 expression predicted poorer overall survival and recurrence-free survival. High USP22 expression was also associated with shortened survival time in patients at advanced tumor stages and with high grade HCC. Multivariate analyses revealed that USP22 expression is an independent prognostic parameter in HCC. These findings provide evidence that high USP22 expression might be important in tumor progression and serves as an independent molecular marker for poor HCC prognosis. Thus, USP22 overexpression identifies patients at high risk and represents a novel therapeutic molecular target for this tumor. PMID- 25909225 TI - PBK/TOPK enhances aggressive phenotype in prostate cancer via beta-catenin TCF/LEF-mediated matrix metalloproteinases production and invasion. AB - A current challenge in prostate cancer treatment is how to differentiate aggressive disease from indolent prostate cancer. There is an urgent need to identify markers that would accurately distinguish indolent prostate cancer from aggressive disease. The aim of this study was to evaluate the role of PDZ Domain binding kinase (PBK) in prostate cancer and to determine if PBK expression enhances aggressiveness in prostate cancer. Using archival tissue samples, gain of-function and loss-of-function studies, we show that PBK expression is up regulated in prostate cancer, and its expression level is commensurate with invasiveness. Modulation of PBK expression and function causally regulates the invasive ability of prostate cancer cells. Production of matrix metalloproteinases-2 and -9, which are key players in metastatic invasion, is up regulated, and the promoters of these genes are transcriptionally activated by PBK via increased beta-catenin-TCF/LEF signaling. Prostate cancer tissue specimens show that PBK's expression correlates with aggressive disease and distant metastasis in bone, lymph node and abdomen. Our in vitro and in situ data are in agreement that PBK could be a prognostic biomarker for prostate cancer that would discriminate aggressive prostate cancer from indolent disease, and is a potential target for the therapeutic intervention of aggressive prostate cancer in men. PMID- 25909226 TI - Comprehensive characterization of chemotherapeutic efficacy on metastases in the established gastric neuroendocrine cancer patient derived xenograft model. AB - The HuPrime(r) human gastric neuroendocrine carcinoma derived xenograft model GA0087 was established in this study. GA0087 PDX model showed high gene expression of vascular endothelial growth factors (VEGF)-A and B, and high potential of lung metastasis. Circulating tumor cells (CTCs) with either large or small size, circulating tumor microemboli (CTM) and lung metastatic lesions were detected in GA0087 PDX mice. The number of CTC correlated to the number of metastatic nodules in lung. Both primary tumor growth and metastasis in terms of the number of dynamically monitored CTCs and metastatic nodules were effectively suppressed by Cisplatin. Diverse subtypes of CTCs in the context of sensitivity to Cisplatin were specifically identified by subtraction enrichment (SE) integrated with in situ Phenotyping of cytokeratin 18 (CK18) and Karyotyping of chromosome 8 (in situ PK CTC by CK-iFISH). All the CK18-/diploid and majority of CK18+/diploid CTC subtypes were chemosensitive, whereas a higher percentage of CK18+/multiploid subtype of CTC were Cisplatin-insensitive. Combined histopathological examination of metastatic lesion and in situ PK CTC in a metastatic PDX (mPDX) tumor model are of particular significance, and may provide an unique and robust platform for cancer research as well as pre-clinical evaluation of therapeutic efficacy of new anti-cancer drugs. PMID- 25909228 TI - Tilt behavior of an octa-peptide nanotube in POPE and affects on the transport characteristics of channel water. AB - MD simulations have been carried out for studying the tilt behaviors of the 8 * (WL)4-CPNT embedded in the POPE bilayer in a water environment and under an anhydrous condition, respectively. Besides, the dependences of the transport characteristics of channel water on the extent of the CPNT tilt were explored. The results indicate that the presence of water may exacerbate the CPNT tilt but plays an important role in maintaining the integrity of the CPNT by forming water bridges in the end-gaps. Cation-pi interactions between the indole rings of Trp residues and lipid headgroups are the major factor causing the CPNT tilt under an anhydrous condition, while H-bonded interactions between water molecules and the indole rings are primary in a water environment. The dipole orientations of channel water molecules except those in the last end-gap are gradually oriented and eventually only take "+dipole" states under 20 degrees of the CPNT tilt. The average residence time of channel water gradually increases with the intensifying of the CPNT tilt. PMID- 25909227 TI - MicroRNA-21 plays an oncogenic role by targeting FOXO1 and activating the PI3K/AKT pathway in diffuse large B-cell lymphoma. AB - The prognostic implications of miR-21, miR-17-92 and miR-155 were evaluated in diffuse large B-cell lymphoma (DLBCL) patients, and novel mechanism by which miR 21 contributes to the oncogenesis of DLBCL by regulating FOXO1 and PI3K/AKT/mTOR pathway was investigated. The expressions of miR-21, miR-17-92 and miR-155 measured by quantitative reverse-transcription-PCR were significantly up regulated in DLBCL tissues (n=200) compared to control tonsils (P=0.012, P=0.001 and P<0.0001). Overexpression of miR-21 and miR-17-92 was significantly associated with shorter progression-free survival (P=0.003 and P=0.014) and overall survival (P=0.004 and P=0.012). High miR-21 was an independent prognostic factor in DLBCL patients treated with rituximab-combined chemotherapy. MiR-21 level was inversely correlated with the levels of FOXO1 and PTEN in DLBCL cell lines. Reporter-gene assay showed that miR-21 directly targeted and suppressed the FOXO1 expression, and subsequently inhibited Bim transcription in DLBCL cells. MiR-21 also down-regulated PTEN expression and consequently activated the PI3K/AKT/mTOR pathway, which further decreased FOXO1 expression. Moreover, miR-21 inhibitor suppressed the expression and activity of MDR1, thereby sensitizing DLBCL cells to doxorubicin. These data demonstrated that miR-21 plays an important oncogenic role in DLBCL by modulating the PI3K/AKT/mTOR/FOXO1 pathway at multiple levels resulting in strong prognostic implication. Therefore, targeting miR-21 may have therapeutic relevance in DLBCL. PMID- 25909231 TI - Message from the guest editors. PMID- 25909232 TI - Millon's Contributions to the International Society for the Study of Personality Disorders (ISSPD). AB - In this article we highlight the pivotal role of Dr. Theodore Millon in the founding of the International Society for the Study of Personality Disorders (ISSPD). This historical outline of Millon's contribution to the ISSPD also contains previously unpublished transcripts of his talks at ISSPD congresses based on transcripts from the first author's audio recordings throughout the years. PMID- 25909229 TI - Structural features of a 3' splice site in influenza a. AB - Influenza A is an RNA virus with a genome of eight negative sense segments. Segment 7 mRNA contains a 3' splice site for alternative splicing to encode the essential M2 protein. On the basis of sequence alignment and chemical mapping experiments, the secondary structure surrounding the 3' splice site has an internal loop, adenine bulge, and hairpin loop when it is in the hairpin conformation that exposes the 3' splice site. We report structural features of a three-dimensional model of the hairpin derived from nuclear magnetic resonance spectra and simulated annealing with restrained molecular dynamics. Additional insight was provided by modeling based on (1)H chemical shifts. The internal loop containing the 3' splice site has a dynamic guanosine and a stable imino (cis Watson-Crick/Watson-Crick) GA pair. The adenine bulge also appears to be dynamic with the A either stacked in the stem or forming a base triple with a Watson Crick GC pair. The hairpin loop is a GAAA tetraloop closed by an AC pair. PMID- 25909230 TI - The Relationship of Mucus Concentration (Hydration) to Mucus Osmotic Pressure and Transport in Chronic Bronchitis. AB - RATIONALE: Chronic bronchitis (CB) is characterized by persistent cough and sputum production. Studies were performed to test whether mucus hyperconcentration and increased partial osmotic pressure, in part caused by abnormal purine nucleotide regulation of ion transport, contribute to the pathogenesis of CB. OBJECTIVES: We tested the hypothesis that CB is characterized by mucus hyperconcentration, increased mucus partial osmotic pressures, and reduced mucus clearance. METHODS: We measured in subjects with CB as compared with normal and asymptomatic smoking control subjects indices of mucus concentration (hydration; i.e., percentage solids) and sputum adenine nucleotide/nucleoside concentrations. In addition, sputum partial osmotic pressures and mucus transport rates were measured in subjects with CB. MEASUREMENTS AND RESULTS: CB secretions were hyperconcentrated as indexed by an increase in percentage solids and total mucins, in part reflecting decreased extracellular nucleotide/nucleoside concentrations. CB mucus generated concentration-dependent increases in partial osmotic pressures into ranges predicted to reduce mucus transport. Mucociliary clearance (MCC) in subjects with CB was negatively correlated with mucus concentration (percentage solids). As a test of relationships between mucus concentration and disease, mucus concentrations and MCC were compared with FEV1, and both were significantly correlated. CONCLUSIONS: Abnormal regulation of airway surface hydration may slow MCC in CB and contribute to disease pathogenesis. PMID- 25909233 TI - The glass is half full: evidence for efficacy of alcohol-wise at one university but not the other. AB - This research extends the growing literature about online alcohol prevention programs for first-year college students. Two independent randomized control studies, conducted at separate universities, evaluated the short-term effectiveness of Alcohol-Wise, an online alcohol prevention program not previously studied. It was hypothesized the prevention program would increase alcohol knowledge and reduce alcohol consumption, including high-risk alcohol related behaviors, among first-year college students. At both universities, the intervention significantly increased alcohol-related knowledge. At one university, the prevention program also significantly reduced alcohol consumption and high-risk drinking behaviors, such as playing drinking games, heavy drinking, and extreme ritualistic alcohol consumption. Implications for the use of online alcohol prevention programs and student affairs are discussed. PMID- 25909234 TI - Efficacy and safety of topical diquafosol ophthalmic solution for treatment of dry eye: a systematic review of randomized clinical trials. AB - PURPOSE: To evaluate the efficacy and safety of topical diquafosol ophthalmic solution for treatment of dry eye. METHODS: Randomized clinical trials (RCTs) from MEDLINE, EMBASE, and Cochrane Central Register of Controlled Trials (CENTRAL) were identified to evaluate the efficacy and safety of topical administration of diquafosol to patients with dry eyes. Data evaluation was based on endpoints including Schirmer test, tear film break-up time, ocular surface staining score, subjective symptom score, and adverse events. RESULTS: A total of 8 RCTs involving 1516 patients were selected based on the prespecified criteria. Significant improvement of Schirmer test values and tear film break-up time were reported in 40% (2 of 5) and 80% (4 of 5) studies, respectively. Ocular surface staining scores significantly decreased in 100% (fluorescein corneal staining, 6 of 6; Rose Bengal corneal and conjunctival staining, 4 of 4) RCTs. Symptoms significantly improved in 75% (6 of 8) RCTs in patients with dry eyes. No severe adverse events were reported with the concentration of diquafosol from 0.5% to 5%. Heterogeneity in study design prevented meta-analysis from statistical integration and summarization. CONCLUSIONS: Topical diquafosol seems to be a safe therapeutic option for the treatment of dry eye. The high variability of the selected RCTs compromised the strength of evidence and limits the determination of efficacy. However, the topical administration of diquafosol seems to be beneficial in improving the integrity of the epithelial cell layer of the ocular surface and mucin secretion in patients with dry eyes. This review indicates a need for standardized criteria and methods for evaluation to assess the efficacy of diquafosol in the future clinical trials. PMID- 25909235 TI - Intraoperative review of different bubble types formed during pneumodissection (big-bubble) deep anterior lamellar keratoplasty. AB - PURPOSE: To evaluate the preoperative factors and intraoperative complications of the 2 bubble types formed during big-bubble deep anterior lamellar keratoplasty (DALK). METHODS: This is a retrospective review of medical records of a series of patients who underwent DALK using the big-bubble technique from September 2009 to March 2014. RESULTS: A total of 134 eyes were included in this study-89 eyes with advanced keratoconus, 35 eyes with post-microbial keratitis corneal scars, 8 eyes with stromal dystrophies, and 2 eyes with post-laser in situ keratomileusis ectasia. A type 1 bubble (white margin) was achieved in 56 eyes (41.8%), whereas a type 2 bubble (clear margin) was formed in 14 eyes (10.4%) and a mixed bubble was formed in 2 eyes (1.5%). Big-bubble formation failed in 62 (46.3%). All eyes with the type 1 bubble were completed as DALK; microperforation occurred in 4 eyes. Twelve of 14 eyes with the type 2 bubble were converted to penetrating keratoplasty because of large perforations. CONCLUSIONS: The type 2 bubble is more likely to form in elderly patients and those with deep corneal scars and thin corneas. Because of the high rate of conversion to penetrating keratoplasty, better surgical strategies may be needed to manage type 2 bubbles. PMID- 25909236 TI - Effect of oral omega-3 Fatty Acid supplementation on contrast sensitivity in patients with moderate meibomian gland dysfunction: a prospective placebo controlled study. AB - PURPOSE: To evaluate the effect of oral supplementation with omega-3 (omega-3) fatty acids (FAs) in improving contrast sensitivity (CS) of patients with moderate meibomian gland dysfunction (MGD). METHODS: In this prospective study, 60 patients with moderate MGD were allocated alternately to treatment and control groups. Both groups received warm compresses, lid massage, and artificial tear substitutes. The treatment group also received oral supplements of 1.2 g omega-3 FAs per day. All parameters were recorded at baseline and at 12 weeks and included Ocular Surface Disease Index scores, CS testing at 3, 6, 12, and 18 cycles per degree (cpd), tear break-up time, Schirmer test I without anesthesia, corneal and conjunctival staining scores, and meibum quality and expressibility. RESULTS: At the end of 12 weeks, significant improvement in CS was seen in the treatment group in 7 of the 8 testing conditions (3, 6, 12, and 18 cpd photopic and 6, 12, and 18 cpd mesopic), whereas in the placebo group, significant improvement was seen only in 3 of the 8 testing conditions (3 cpd photopic, 6 and 18 cpd mesopic). Ocular Surface Disease Index, tear break-up time, ocular surface staining, and meibum quality and expressibility improved significantly in both groups, but more so in the treatment group. Schirmer scores showed no significant improvement in either group. CONCLUSIONS: Oral supplementation with omega-3 FAs significantly improved CS under both photopic and mesopic testing conditions in patients with moderate MGD. Tear film stability also improved significantly, whereas no effect was seen on aqueous tear production. PMID- 25909237 TI - Utility of Assessing Nerve Morphology in Central Cornea Versus Whorl Area for Diagnosing Diabetic Peripheral Neuropathy. AB - PURPOSE: To compare small nerve fiber damage in the central cornea and whorl area in participants with diabetic peripheral neuropathy (DPN) and to examine the accuracy of evaluating these 2 anatomical sites for the diagnosis of DPN. METHODS: A cohort of 187 participants (107 with type 1 diabetes and 80 controls) was enrolled. The neuropathy disability score (NDS) was used for the identification of DPN. The corneal nerve fiber length at the central cornea (CNFLcenter) and whorl (CNFLwhorl) was quantified using corneal confocal microscopy and a fully automated morphometric technique and compared according to the DPN status. Receiver operating characteristic analyses were used to compare the accuracy of the 2 corneal locations for the diagnosis of DPN. RESULTS: CNFLcenter and CNFLwhorl were able to differentiate all 3 groups (diabetic participants with and without DPN and controls) (P < 0.001). There was a weak but significant linear relationship for CNFLcenter and CNFLwhorl versus NDS (P < 0.001); however, the corneal location * NDS interaction was not statistically significant (P = 0.17). The area under the receiver operating characteristic curve was similar for CNFLcenter and CNFLwhorl (0.76 and 0.77, respectively, P = 0.98). The sensitivity and specificity of the cutoff points were 0.9 and 0.5 for CNFLcenter and 0.8 and 0.6 for CNFLwhorl. CONCLUSIONS: Small nerve fiber pathology is comparable at the central and whorl anatomical sites of the cornea. Quantification of CNFL from the corneal center is as accurate as CNFL quantification of the whorl area for the diagnosis of DPN. PMID- 25909238 TI - Correlation of Tear Film Osmolarity and 2 Different MMP-9 Tests With Common Dry Eye Tests in a Cohort of Non-Dry Eye Patients. AB - PURPOSE: Given that early-stage dry eye is difficult to diagnose, the purpose of this study was to evaluate the performance of matrix metalloproteinase 9 (MMP-9) and tear film osmolarity (TFO) in a cohort of elderly patients with potential dry eye disease (DED). METHODS: A group of 20 patients, aged 60 years and above, previously undiagnosed with DED were selected. The following DED tests were performed: tear osmolarity, MMP-9 (InflammaDry), Schirmer test, tear film break up time, Ocular Surface Disease Index (OSDI) questionnaire, corneal fluorescein staining, and conjunctival lissamine green staining. MMP-9 concentrations in tears collected through Schirmer strips were analyzed by an MMP-9 enzyme-linked immunosorbent assay [ELISA]. Subjects were classified by symptoms (classification A: OSDI >=10, n = 9), based on suspected mild dry eye (classification B: n = 14), TFO difference >8 mOsm/L between both eyes (classification C: n = 13), and TFO cutoff at 308 mOsm/L (classification D: >308 mOsm/L, n = 11). RESULTS: Eleven percent (1/9) of the symptomatic and 14% (2/14) of the suspected mild dry eye were positive for MMP-9. InflammaDry MMP-9 tests were confirmed to be accurate through an ELISA. Sixty-seven percent (6/9) of the symptomatic and 64% (9/14) of the suspected mild dry eye were positive for tear osmolarity. None of the evaluated tear film parameters showed a significant correlation, although tear osmolarity and symptoms trended toward significance (r = 0.433, P = 0.06), whereas MMP-9 and corneal staining showed a positive association (r = 0.376, P = 0.10). CONCLUSIONS: Similar to corneal staining, the MMP-9 is likely a late-stage sign that is rarely overexpressed in mild subjects, whereas tear osmolarity tends to be a more frequent early indicator of ocular surface disequilibrium within mild subjects. PMID- 25909239 TI - Visual performance and the use of colored filters in children who are deaf. AB - PURPOSE: To assess visual performance and the effects of color overlays on reading in children who were deaf and children who could hear. METHODS: Thirty one children who were deaf (mean [+/- SD] age, 14 [+/- 1.99] years) and 39 children who could hear (mean [+/- SD] age, 13.58 [+/- 3.09] years) underwent an optometric examination with specific emphasis on near vision. Participants chose an overlay with color optimal for clarity and comfort and completed the Wilkins Rate of Reading Test both with and without an overlay of this color. Nineteen of the participants who were deaf were retested a year later with a modified rate of reading test that used only words that can readily be signed. This modified rate of reading test was repeated 1 week after its first administration. RESULTS: Participants who were deaf had greater ametropia (p = 0.003), a more distant near point of convergence (p = 0.002), and reduced amplitude of accommodation (p < 0.001) compared with normal-hearing participants. All the children who were deaf chose a color overlay, with 45% choosing a yellow overlay, which increased the rate of reading by 18%. Only 66% of the participants who could hear chose an overlay, and it had no effect on reading speed. With the modified reading test, 7 of 19 (37%) again chose yellow. These participants showed a 9% increase in reading speed with the yellow overlay, which was repeatable 1 week later. The remainder showed no increase in rate of reading with their chosen overlay. CONCLUSIONS: An eye examination of children who are deaf needs to include a comprehensive assessment of near visual function so that deficiencies of amplitude of accommodation, near point convergence, and ametropia can be treated. A yellow overlay improved reading speed in the participants who were deaf, whereas other colors did not, a finding at variance with earlier work on hearing populations. PMID- 25909240 TI - Disc hemorrhages and their risk factors in an urban South Korean population. AB - PURPOSE: The aim of this study was to estimate the prevalence of disc hemorrhage (DH) and evaluate its related risk factors in an urban South Korean population. METHODS: This retrospective cross-sectional study included subjects who underwent health screening at the Health Screening Center of Kangbuk Samsung Hospital from August 2012 to July 2013. All fundus photographs were first reviewed by two ophthalmologists and then by two glaucoma specialists and one retina specialist to determine the presence of DHs. In addition to fundus photographs, each participant completed systemic examination as well as sociodemographic and behavioral questionnaires. RESULTS: Fundus photographs were available for 164,029/168,044 (97.61%) subjects 20 years and older. The prevalence of DH was 226/164,029 (0.14%; 95% confidence interval, 0.12 to 0.16) per subject. A large proportion (61.5%) of eyes with DH had localized wedge-shaped retinal nerve fiber layer defects indicative of glaucoma. There was also a slight increase in DH prevalence with age, but no other statistically significant associations were found. CONCLUSIONS: The prevalence of DH was 0.14% in urban South Korean subjects 20 years and older. Older age and the presence of glaucomatous retinal nerve fiber layer defects were associated with higher prevalence of DH. These findings suggest that the presence of a DH in an eye implies a high likelihood of glaucoma, although its absence does not indicate that glaucoma is absent. PMID- 25909241 TI - Corneal Confocal Microscopy in Dry Eye Treated with Corticosteroids. AB - PURPOSE: To evaluate, by in vivo laser scanning confocal microscopy (LSCM), the corneal findings in moderate-to-severe dry eye patients before and after treatment with topical corticosteroid and to associate the confocal findings to the clinical response. METHODS: Fifty eyes of 50 patients with moderate-to-severe dry eye were included in this open-label, masked study. Exclusion criteria were any systemic or ocular condition (other than dry eye) and any systemic or topical treatment (except artificial tears), ongoing or performed in the previous 3 months, with known effect on the ocular surface. All patients were treated with loteprednol etabonate ophthalmic suspension 0.5% qid for 4 weeks. Baseline and follow-up (day 30 +/- 2) visits included Ocular Surface Disease Index (OSDI) questionnaire, full eye examination, and central cornea LSCM. We compared data obtained before and after treatment and looked for associations between baseline data and steroid-induced changes. Based on the previously validated OSDI Minimal Clinically Important Difference, we reanalyzed the baseline findings comparing those patients clinically improved after steroids to patients not clinically improved after steroids. RESULTS: Ocular Surface Disease Index score and LSCM dendritic cell density (DCD) significantly decreased after treatment. Baseline DCD correlated with both OSDI and DCD steroid-related changes (r = -0.44, p < 0.05 and r = -0.70, p < 0.01, respectively; Spearman) and was significantly higher in patients clinically improved after steroids than in patients not clinically improved after steroids (164.1 +/- 109.2 vs. 72.4 +/- 45.5 cells/mm2, p < 0.01; independent samples t test). CONCLUSIONS: Laser scanning confocal microscopy examination of DCD allows detection of treatment-related inflammation changes and shows previously unknown associations between confocal finding and symptoms improvement after treatment. These promising preliminary data suggest the need for future studies testing the predictive value of DCD for a clinical response to topical corticosteroids. PMID- 25909242 TI - Conjunctival diverticuli in Stevens-Johnson syndrome. AB - PURPOSE: To report a patient with a history of eye involving Stevens-Johnson syndrome (SJS) who developed chronic bilateral purulent discharge attributed to conjunctival diverticuli. CASE REPORT: A 75-year-old woman with SJS presented with bilateral chronic relapsing purulent conjunctivitis secondary to inferior conjunctival diverticuli. The symptoms resolved after marsupialization of the diverticuli. CONCLUSIONS: The conjunctival scarring associated with SJS can lead to sequestration of conjunctival epithelium that may in turn lead to the formation of a diverticulum. The presence of a diverticulum should be considered in patients with a history of SJS who develop chronic relapsing purulent conjunctivitis. PMID- 25909243 TI - Frontal mucocele with intracranial extension causing frontal lobe syndrome. AB - PURPOSE: Mucoceles are mucus-containing cysts that form in paranasal sinuses; although mucoceles themselves are benign, this case report highlights the extensive damage they can cause as their expansion may lead to bony erosion and extension of the mucocele into the orbit and cranium; it also presents a rarely reported instance of frontal sinus mucocele leading to frontal lobe syndrome. A thorough discussion and review of mucoceles is included. CASE REPORT: A 68-year old white man presented with intermittent diplopia and a pressure sensation in the right eye. He had a history of chronic sinusitis and had had endoscopic sinus surgery 5 years prior. A maxillofacial computed tomography scan revealed a large right frontal sinus mucocele, which had caused erosion along the medial wall of the right orbit and the outer and inner tables of the right frontal sinus. The mucocele had protruded both into the right orbit and intracranially, causing mass effect on the frontal lobe, which led to frontal lobe syndrome. The patient was successfully treated with endoscopic right ethmoidectomy, radial frontal sinusotomy, marsupialization of the mucocele, and transcutaneous irrigation. CONCLUSIONS: Paranasal sinus mucoceles may expand and lead to bony erosion and can become very invasive in surrounding structures such as the orbit and cranium. This case not only exhibits a very rare presentation of frontal sinus mucocele with intracranial extension and frontal lobe mass effect causing a frontal lobe syndrome but also demonstrates many of the ocular and visual complications commonly associated with paranasal sinus mucoceles. Early identification and surgical intervention is vital for preventing and reducing morbidity associated with invasive mucoceles, and the patient must be followed regularly to monitor for recurrence. PMID- 25909244 TI - Spray deposited beta-Bi2O3 nanostructured films with visible photocatalytic activity for solar water treatment. AB - Bismuth oxide thin films were obtained by the spray pyrolysis method using bismuth acetate as the precursor salt. The films were characterized by X-ray diffraction (XRD), Fourier Transform Infrared (FTIR), UV-vis diffuse reflectance, X-ray Photoelectron Spectroscopy (XPS) and Scanning Electron Microscopy (SEM). The XRD patterns indicated that the pure beta phase is obtained at 450 degrees C and was also confirmed by FTIR. This phase presents a nanoplate morphology which is adequate for the photocatalytic reactions. Moreover, the band gap value was 2.6 eV indicating a good capacity of visible light absorption. The photocatalytic degradation of the Methyl Orange (MO) dye was pH dependent, an acid solution being easier to degrade. However, the Bi2O3 films were easily converted into BiOCl when they were in contact with a solution containing HCl. In order to preserve the beta-Bi2O3 phase, the Acid Blue 113 dye with its natural pH of 8 was used to evaluate the stability of the photocatalytic activity after five degradation cycles. The photoactivity was practically stable indicating a good performance of the material. This encouraged us to test the films in a continuous flow solar reactor prototype for the degradation of the dye solution using sunlight radiation exclusively. The good performance of the beta-Bi2O3 films indicates that they can be used for sustainable water treatment applications. PMID- 25909245 TI - Integrated proteomic platforms for the comparative characterization of medulloblastoma and pilocytic astrocytoma pediatric brain tumors: a preliminary study. AB - A top-down/bottom-up integrated proteomic approach based on LC-MS and 2-DE analysis was applied for comparative characterization of medulloblastoma and pilocytic astrocytoma posterior cranial fossa pediatric brain tumor tissues. Although rare, primary brain tumors are the most frequent solid tumors in the pediatric age. Among them the medulloblastoma is the prevalent malignant tumor in childhood while pilocytic astrocytoma is the most common, rarely showing a malignant progression. Due to the limited availability of this kind of sample, the study was applied to pooled tumor tissues for a preliminary investigation. The results showed different proteomic profiles of the two tumors and evidenced interesting differential expression of several proteins and peptides. Top-down proteomics of acid-soluble fractions of brain tumor homogenates ascribed a potential biomarker role of malignancy to beta- and alpha-thymosins and their truncated proteoforms and to C-terminal truncated (des-GG) ubiquitin, resulting exclusively detected or over-expressed in the highly malignant medulloblastoma. The bottom-up proteomics of the acid-soluble fraction identified several proteins, some of them in common with 2-DE analysis of acid-insoluble pellets. Peroxiredoxin-1, peptidyl-prolyl cis-trans isomerase A, triosephosphate isomerase, pyruvate kinase PKM, tubulin beta and alpha chains, heat shock protein HSP-90-beta and different histones characterized the medulloblastoma while the Ig kappa chain C region, serotransferrin, tubulin beta 2A chain and vimentin the pilocytic astrocytoma. The two proteomic strategies, with their pros and cons, well complemented each other in characterizing the proteome of brain tumor tissues and in disclosing potential disease biomarkers to be validated in a future study on individual samples of both tumor histotypes. PMID- 25909247 TI - Losing Weight on Reality TV: A Content Analysis of the Weight Loss Behaviors and Practices Portrayed on The Biggest Loser. AB - A number of weight loss-related reality television programs chronicle the weight loss experience of obese individuals in a competitive context. Although highly popular, such shows may misrepresent the behavior change necessary to achieve substantial weight loss. A systematic, quantitative content analysis of Seasons 10-13 (n = 66 episodes) of The Biggest Loser was conducted to determine the amount of time and number of instances that diet, physical activity, or other weight management strategies were presented. The average episode was 78.8 +/- 15.7 min in length. Approximately 33.3% of an episode, representing 1,121 segments, portrayed behavioral weight management-related content. Within the episode time devoted to weight management content, 85.2% was related to physical activity, 13.5% to diet, and 1.2% to other. Recent seasons of The Biggest Loser suggest that substantial weight loss is achieved primarily through physical activity, with little emphasis on modifying diet and eating behavior. Although physical activity can impart substantial metabolic health benefits, it may be difficult to create enough of an energy deficit to induce significant weight loss in the real world. Future studies should examine the weight loss attitudes and behaviors of obese individuals and health professionals after exposure to reality television shows focused on weight loss. PMID- 25909246 TI - Chemical proteomic identification of T-plastin as a novel host cell response factor in HCV infection. AB - Hepatitis C virus (HCV) infection is the leading cause of chronic liver disease that currently affects at least 170 million people worldwide. Although significant efforts have been focused on discovering inhibitors of a viral polymerase (NS5B) or protease (NS3), strategies to cure HCV infection have been hampered by the limited therapeutic target proteins. Thus, discovery of a novel target remains a major challenge. Here, we report a method that combines transcriptome expression analysis with unbiased proteome reactivity profiling to identify novel host cell response factors in HCV infection. A chemical probe for non-directed proteomic profiling was selected based on genome-wide transcriptome expression analysis after HCV infection, which revealed noticeable alterations related to disulfide bond metabolism. On the basis of this result, we screened the proteome reactivity using chemical probes containing thiol-reactive functional groups and discovered a unique labeling profile in HCV-infected cells. A subsequent quantitative chemical proteomic mapping study led to the identification of a target protein, T-plastin (PLST), and its regulation of HCV replication. Our approach demonstrates both a straightforward strategy for selecting chemical probes to discriminate disease states using a model system and its application for proteome reactivity profiling for novel biomarker discovery. PMID- 25909248 TI - Protozoan infections in farmed fish from Brazil: diagnosis and pathogenesis. AB - The Phylum Protozoa brings together several organisms evolutionarily different that may act as ecto or endoparasites of fishes over the world being responsible for diseases, which, in turn, may lead to economical and social impacts in different countries. Apart from the recent advances for the diagnosis of fish diseases in Brazil, little is known on the protozoan parasites and their relationship with environment and host. This revision presents the most important protozoan parasites found in farmed fish from Brazil, not only with emphasis on its diagnosis, biology, transmission and host-parasite relationship, but also on some information that may be useful to researchers in determining the correct diagnosis in fish farms. PMID- 25909249 TI - Parasites in the mangrove oyster Crassostrea rhizophorae cultivated in the estuary of the Graciosa River in Taperoa, Bahia. AB - In this work, parasites associated with the mangrove oyster Crassostrea rhizophorae were studied at a cultivation unit in the estuary of the Graciosa River in Taperoa, Bahia. On a monthly basis, between April 2011 and March 2012, 20 oysters were collected, measured and fixed in 10% formaldehyde. In order to identify the parasites, routine histological techniques were used. The specimens were embedded in paraffin and sections, 7 um thick, were cut. These were then stained with Harris hematoxylin and eosin and were examined using an optical microscope. The parameters analyzed to investigate water quality showed that the temperature ranged from 23.9 degrees C to 29.3 degrees C, water salinity from 0.4 to 24.2 Practical Salinity Units PSU and recorded rainfall from 80 mm to 406.4 mm/month. During the parasitological analyses, infestation of the polychaete Neanthes succinea was observed in 41% of the oysters. Through histological techniques, the following parasites were identified: colonies of Rickettsia-like organisms (RLOs); the protozoa Nematopsis sp. and Ancistrocoma sp.; the turbellarian Urastoma sp.; the metacestode Tylocephalum sp. and an unidentified tapeworm. The data collected showed that there was low-intensity infection with and prevalence of parasites, except for Nematopsis sp., thus attesting that these cultivated oysters were in a healthy condition. PMID- 25909250 TI - A serological and molecular survey of Babesia vogeli, Ehrlichia canis and Rickettsia spp. among dogs in the state of Maranhao, northeastern Brazil. AB - This study evaluated exposure and infection by tick-borne agents (Babesia vogeli, Ehrlichia canis and Rickettsia spp.) in 172 dogs in rural areas and 150 dogs in urban areas of the municipality of Chapadinha, state of Maranhao, northeastern Brazil, using molecular and serological methods. Overall, 16.1% of the sampled dogs (52/322) were seroreactive to B. vogeli, with endpoint titers ranging from 40 to 640. For E. canis, 14.6% of the dogs (47/322) were seroreactive, with endpoint titers from 80 to 163,840. Antibodies reactive to at least one of the five species of Rickettsia were detected in 18.9% of the dogs (61/322), with endpoint titers ranging from 64 to 4,096. High endpoint titers were observed for Rickettsia amblyommii. Three (0.9%) and nine (2.8%) canine blood samples were PCR positive for Babesia spp. and E. canis. The ticks collected from urban dogs were all Rhipicephalus sanguineus sensu lato, whereas the rural dogs were infested by R. sanguineus s.l, Amblyomma cajennense sensu lato and Amblyomma ovale. One A. ovale tick was found to be infected by Rickettsia bellii. This study provides an epidemiological background for controlling and preventing canine tick-borne diseases in a neglected region of Brazil. PMID- 25909251 TI - Chemical composition and insecticidal activity of Cymbopogon citratus essential oil from Cuba and Brazil against housefly. AB - Essential oil of Cymbopogon citratus collected from Brazil and Cuba was tested to a chemical characterization and then was tested on the post-embryonic development of Musca domestica. The chemical composition analysis by GC-MS of the oils from Brazil/Cuba allowed the identification of 13 and 12 major constituents respectively; nine of them common to both. In the both oils, the main components were the isomers geranial and neral, which together form the compound citral. This corresponds to a total of 97.92%/Brazil and 97.69%/Cuba of the compounds identified. The monoterpene myrcene, observed only in the sample of Cuba, presented a large relative abundance (6.52%). The essential oil of C. citratus (Brazil/Cuba) was dissolved in DMSO and tested at concentrations of 5, 10, 25, 50, 75 and 100% and citral was prepared by mixing 16.8 mg with 960 uL DMSO. Both essential oils and monoterpene citral were applied topically to newly-hatched larvae (1uL/larva). The results showed a lethal concentration (LC50) of 4.25 and 3.24% for the Brazilian and Cuban essential oils, respectively. Mortalities of larval and newly-hatched larvae to adult periods were dose-dependent for the two both oils as for monoterpene citral, reaching 90%. Both essential oils and citral caused morphological changes in adult specimens. PMID- 25909252 TI - Hypertension and its correlation with renal lesions in dogs with leishmaniosis. AB - To evaluate the prevalence of hypertension and its correlation with the severity of renal injury and proteinuria in dogs with leishmaniosis, sixty-six dogs were divided into two groups. Group 1 (G1) was composed of 54 dogs included in stage 1 of chronic kidney disease (CKD), and group 2 (G2) of twelve dogs in stages 2 and 3 of CKD. Prevalence of hypertension was 28.8%, comprising 22.2% of the dogs from G1 and 58.3% from G2 (P=0.011). The mean arterial blood pressure (BP) of dogs from G1 (135.7 +/- 20.5) was lower than from G2 (170.0 +/- 26.3) (P <0.001). Urine protein-creatinine ratio (UP/C) revealed values above 0.5 in 75.7% of the dogs, with 34% presenting hypertension. All dogs with hypertension had histopathological and laboratory evidence of glomerular disease. Although there was no statistically significant correlation between elevated BP and the severity of glomerular lesions (P=0.408), there was a statistically significant correlation between elevated BP and increased UP/C in the studied population (P=0.002). Thus, dogs with leishmaniosis and renal disease must be screened for the presence of hypertension so that treatment may be instituted as early as possible, in countries where treatment is allowed, to prevent the progression of renal damage. PMID- 25909253 TI - Survey of Ehrlichia canis, Babesia spp. and Hepatozoon spp. in dogs from a semiarid region of Brazil. AB - This study assessed the occurrence of Ehrlichia spp., Babesia spp. and Hepatozoon spp. infections in 100 tick-harboring dogs from a semiarid region of the State of Paraiba, Northeastern Brazil. Blood samples and ticks were collected from the animals, and a questionnaire was submitted to dog owners to obtain general data. Blood samples were used to perform hemogram, direct blood smear and immunological and molecular hemoparasite detection. The 1,151 ticks collected were identified as Rhipicephalus sanguineus; direct smears revealed E. canis-like morulae in the monocytes of 4% (4/100) of the non-vaccinated female dogs, and 34% and 25% of the dogs tested positive for Ehrlichia canis by indirect immunofluorescence assay (IFA) and polymerase chain reaction (PCR), respectively. Blood smear examination revealed Babesia-suggestive merozoites in the erythrocytes of 2% (2/100) of the animals. Babesia vogeli was detected by PCR in ten animals (10%) and was correlated with young age (p = 0.007) and thrombocytopenia (p = 0.01). None of the animals showed Hepatozoon spp. positivity. These results indicate that E. canis is the main tick-borne canine pathogen in the study area and provide the first report of B. vogeli infection in dogs from Paraiba State. PMID- 25909254 TI - Seasonal prevalence and mean intensity of Psoroptes ovis infestation in goats in the Brazilian semiarid region. AB - To determine the prevalence and seasonal variation of Psoroptes ovis (Delafond, 1858) mange in goats in the semiarid region of Paraiba, 541 crossbred goats of both sexes and different ages were examined between June 1999 and May 2001 and between August 2011 and December 2012, by washing their ear canals. The monthly prevalence of the infestation varied between 66.66% and 100% without significant differences (p = 0.10) among months and years. The intensity of infestation was higher between 2011-2012 (p < 0.05), with an annual rainfall of 123 mm, than between 1999-2000, which had an annual rainfall of 614.9 mm. By the Spearman test there was a negative correlation between the relative humidity and the rainfall of the intensity of the P. ovis infestation. It is concluded that parasitism by P. ovis occurs at a similar prevalence rate during the entire year but increases during dry years. PMID- 25909255 TI - Effect of dietary supplementation with propolis and Aloe barbadensis extracts on hematological parameters and parasitism in Nile tilapia. AB - This study evaluated the influence of diet supplementation with propolis and Aloe barbadensis on hematological parameters and parasitism in tilapia. One hundred and eighty fish were distributed among 12 water tanks forming four treatments: fish supplemented with a 1:1 mixture of 0%, 0.5%, 1% and 2% propolis and aloe extracts. After the fish had been fed on the experimental diets for 15 and 21 days, blood samples were taken and parasites collected. The monogeneans Cichlidogyrus sclerosus, C. halli, C. thurstonae and Scutogyrus longicornis were identified in the gills. Between the sampling times, there were increases in the numbers of erythrocytes, leukocytes, thrombocytes and lymphocytes, as observed after 21 days, possibly due to the stress level over the course of the assay and/or accumulation of substances in the organism. Supplementation with the mixture of propolis and aloe for 15 days showed the highest efficacy against the parasites. This was possibly due to the association between the two compounds. The results demonstrated that supplementation with mixtures of extracts did not produce hematological alterations and also favored a significant reduction in the number of gill parasites. The best results were achieved after 15 days of feeding with a diet with 0.5% and 1% supplementation with the extract mixture, which increased efficiency by 83 and 85% respectively. PMID- 25909256 TI - Anisakidae and Raphidascarididae larvae parasitizing Selene setapinnis (Mitchill, 1815) in the State of Rio de Janeiro, Brazil. AB - Between February and August, 2012, thirty specimens of Atlantic moonfish, Selene setapinnis, were purchased in local markets in Niteroi, State of Rio de Janeiro, Brazil, with the aim of analyzing the presence of anisakid nematodes, establishing their rates of parasitism and infection sites, due to importance in the sanitary inspection. A total of sixty nematode larvae, belonging to at least two species were found: nine larvae of Terranova sp., Anisakidae, with prevalence (P) of 13.3%, mean intensity (MI) of 2.25, mean abundance (MA) of 0.30 and range of infection intensity (RI) from 1 to 6; and 51 larvae of Hysterothylacium fortalezae, Raphidascarididae, with P = 26.7%, MI = 6.40, MA = 1.70, and RI = 1 17. The infection sites for Terranova sp. were the mesentery and liver serosa; and for H. fortalezae, the infection sites were the mesentery, abdominal cavity and liver serosa. New morphological data from scanning electron microscopy, on the external structures of H. fortalezae (mainly at the posterior end), are presented. This is the first report of H. fortalezae parasitizing S. setapinnis. PMID- 25909257 TI - Occurrence of Ehrlichia canis in free-living primates of the genus Callithrix. AB - Bacteria of the genus Ehrlichia are Gram-negative and coccoid-shaped microorganisms that cause ehrlichiosis - a serious infectious disease that often leads to death. These bacteria present a strong zoonotic potential and primates may act as reservoir hosts. This study involved a molecular analysis to detect these microorganisms in blood samples collected from nineteen primates of the genus Callithrix living free in an Atlantic Forest fragment in the municipality of Vicosa, state of Minas Gerais, Brazil. One of the 19 primates was found to be infected with Ehrlichia canis. This finding points to a new wild host of E. canis with a strong potential for transmission to humans because of its increasing contact with people. This is the first report of Ehrlichia spp. in primate of the genus Callithrix. PMID- 25909258 TI - Parasitic infections in ornamental cichlid fish in the Peruvian Amazon. AB - The aim of this study was to evaluate the prevalence and seasonal distribution of the main parasite species in Amazonian ornamental cichlids that affect their trade. The study was conducted from August 2007 to September 2009. We sampled 3042 specimens from 9 different species, of which 9.47% had at least one type of external parasite. 81.25% of the cases occurred in the dry season. Crenicichla anthurus (28.57%) was the most parasitized, followed by Aequidens diadema (26.32%), Pterophyllum scalare (22.69%), Cichlasoma sp. (9.52%), Apistogramma sp. (3.88%) and Symphysodon aequifasciatus (3.66%). Monogenea was the most abundant group of parasites, occurring in 66.67% of the cases, of which 96.88% occurred in the dry season. This parasite infested 95.68% of Pterophyllum scalare, 76.67% of Apistogramma sp, 33.33% of Cichlasoma sp. and 23.81% of Symphysodon aequifasciatus cases. Ichthyophthirius multifiliis infested 100% of Aequidens diadema, 76.19% of Symphysodon aequifasciatus, 66.67% of Cichlasoma sp, 41.67% of Crenicichla anthurus and 23.33% of Apistogramma sp cases. Myxosporidia infested 58.33% of Crenicichla anthurus. Trichodina infested 4.32% of Pterophyllum scalare. The prevalence of these parasites is related to the season, preferred habitat, fish behavior, individual susceptibility and handling of animals during transportation by fishermen. PMID- 25909259 TI - Parasitological survey on birds at some selected brazilian zoos. AB - A parasitological survey was conducted at some zoos in the states of Sao Paulo and Parana, Brazil, from 2009 to 2011. Several groups of birds were surveyed for fecal samples, but the most important was Psittacidae. Among the parasites, Eimeria (coccidian) and Capillaria, Ascaridia and Heterakis (nematodes) were observed in almost one third of the samples. Presence of a rich parasite fauna associated with captive birds seems to be an effect of captivity, since data on free-ranging birds indicate few or virtually no parasites at all. The discovery of new coccidian species during this survey reveals the need of more research on the subject as even well-known bird species have unknown parasites, but caution must be exercised in order to avoid descriptions of pseudoparasites. PMID- 25909260 TI - Leishmania (infantum) chagasi in canine urinary sediment. AB - Canine visceral leishmaniasis (CVL) is difficult to diagnosis, mainly due to the presence of asymptomatic animals, the diversity of clinical symptoms and the difficulty in obtaining diagnostic evidence of high sensitivity and specificity. The purpose of this study was to diagnose CVL in urinary sediment of 70 dogs of different breeds, sexes and ages from the veterinary hospital of the Federal University of Piaui and Zoonosis Control Center of Teresina, Brazil. The serological tests were TR DPP(r) for CVL and enzyme-linked immunosorbent assay (ELISA) for CVL, parasitological exams of bone marrow and lymph nodes and urine sediment cultures. Leishmania was detected in the bone marrow and/or lymph node of 61.0% of the animals (43/70), and urine sediment culture was positive in 9.30% (4/43) of these animals. In the serological exams, 70.0% (49/70) were reactive using the DPP and 78.2% (55/70) were reactive using ELISA. The goal of this study was to diagnose the presence of L. (infantum) chagasi in a culture of urinary sediment. PMID- 25909261 TI - Antibodies to Neospora caninum in sheep from slaughterhouses in the state of Sao Paulo, Brazil. AB - Neosporosis is an emergent disease responsible for considerable economic impact due to reproductive losses. Its zoonotic potential remains unknown. This study involved a survey of antibodies to Neospora caninum in slaughtered sheep and their association with epidemiological variables. Serum samples from 596 sheep from the states of Sao Paulo and Rio Grande do Sul, Brazil, were collected in two slaughterhouses located in Sao Paulo and evaluated by indirect fluorescence antibody test (IFAT), using cut-off titers of 25. Among these samples, 353/596 (59.23%; 95%CI 55.23-63.10) were positive and 263/353 (74.50%; 95%CI 69.71 78.77%) were from Rio Grande do Sul. Statistical associations were determined in the univariate analysis between the serological results and sex, breed and municipality of origin. Sheep that came from extensive breeding system showed higher chance (OR=2.09) of presenting antibodies to N. caninum in relation to those from semi-intensive system. Higher chance was also observed for the different studied breeds, except Bergamacia, in relation to Hampshire Down. The results revealed the presence of infection by N. caninum in sheep from slaughterhouses. PMID- 25909263 TI - Occurrence of Chandleronema longigutturata (Nematoda: Acuariidae) in Procyon cancrivorus in the Neotropical region. AB - Procyon cancrivorus is a wild animal that is found from Central America to Uruguay and northeastern Argentina. It is one of the least studied carnivore species in Brazil. For the purpose of identifying helminths that parasitize P. cancrivorus, individuals of this species that had been run over and killed by motor vehicles were collected from highways in the southern part of the state of Rio Grande do Sul. At necropsy, their organs, along with organ contents and mucous membranes, were examined for parasite collection. The nematodes found in the stomachs of these Procyonidae were cleared with lactophenol and Chandleronema longigutturata was identified. This report provides the first record of occurrences of C. longigutturata in the Neotropical region and its parasitism in P. cancrivorus. PMID- 25909262 TI - Caryospora bigenetica (Apicomplexa: Eimeriidae) in South America: new hosts and distribution records. AB - The coccidian Caryospora bigenetica was first described in the snake Crotalus horridus (Viperidae) from United States of America. This study represents the first record of the occurrence of C. bigenetica in snakes in South America. Feces were sampled between November 2013 and May 2014 from 256 wild snakes maintained in scientific breeding facilities in the states of Mato Grosso do Sul (MS; n = 214) and Rio de Janeiro (RJ; n = 42), Brazil. Caryospora bigenetica was found in 14 (5.6%) snakes, all belonging to the family Viperidae. Ten Bothrops moojeni and two Crotalus durissus from MS were infected. The coccidian was also found in one C. durissus and in one Bothrops jararacussu from the state of RJ. The oocysts were spherical with a double wall, the exterior lightly mammillated, striations apparent in transverse view, 13.0 um (12 - 14); polar granule fixed in the internal wall. Sporocysts oval or pyriform, 10.0 * 8.0 um (9 - 11 * 8 - 9); Stieda body discoid; sub-Stieda body present; sporocyst residuum present, formed by a group of spheroid bodies between sporozoites. This study increases the number of viperid hosts of C. bigenetica and expands the geographical distribution to South America. PMID- 25909264 TI - Evaluation of Kato-Katz and spontaneous sedimentation methods for the diagnosis of platynosomiasis in Neotropical primates. AB - Platynosomiasis is a parasitic infection reported in non-human primates, including marmosets, and is frequently difficult to diagnose. In this study, the Kato-Katz method and the spontaneous sedimentation method were evaluated for their usefulness in identifying Platynosomum eggs in fecal samples from Callithrix penicillata that naturally harbor Platynosomum illiciens. Spontaneous sedimentation allowed the diagnosis of 41.7% (5/12) and 66.7% (8/12) of infected marmosets from one and three slides, respectively, prepared from the same fecal sample. The examination of a single Kato-Katz thick smear detected 83.3% (10/12) of infection cases. The analysis of feces on three different days increased the rate of diagnosis, since 75% (9/12) and 100% (12/12) of the primates with platynosomiasis were identified using serial spontaneous sedimentation (3 slides/day) and the Kato-Katz method, respectively. The mean number of Platynosomum eggs per gram of feces determined via the Kato-Katz method was 71.7 (8-240). The spontaneous sedimentation method when performed in series is acceptable for the diagnosis of platynosomiasis. However, the Kato-Katz method, which was here used for the first time to detect this infection, has a higher diagnostic sensitivity and the advantage that a quantitative analysis of the eggs released in the host feces is possible. PMID- 25909265 TI - Editorial. PMID- 25909266 TI - Adsorption and transformation mechanism of NO2 on NaCl(100) surface: A density functional theory study. AB - To understand the heterogeneous reactions between NO2 and sea salt particles in the atmosphere of coastal areas, the absorption of an NO2 molecule on the NaCl(100) surface, the dimerization of NO2 molecules and the hydrolysis of N2O4 isomers at the (100) surface of NaCl are investigated by density functional theory. Calculated results show that the most favorable adsorption geometry of isolated NO2 molecule is found to reside at the bridge site (II-1) with the adsorption energy of -14.85 kcal/mol. At the surface of NaCl(100), three closed shell dimers can be identified as sym-O2N-NO2, cis-ONO-NO2 and trans-ONO-NO2. The reactions of H2O with sym-O2N-NO2 on the (100) surface of NaCl are difficult to occur because of the high barrier (33.79 kcal/mol), whereas, the reactions of H2O with cis-ONONO2 and trans-ONONO2 play the key role in the hydrolysis process. The product, HONO, is one of the main atmospheric sources of OH radicals which drive the chemistry of the troposphere. PMID- 25909267 TI - Personal exposure to black carbon during commuting in peak and off-peak hours in Shanghai. AB - A study on a commuter's exposure to black carbon (BC) in five different traffic modes (taxi, bus, subway, cycling and walking) was conducted in Xuhui District, Shanghai. A commuter's real-time exposure concentrations were recorded by MicroAeth AE51 BC monitors, and the average BC exposure concentration and inhalation dose were analyzed. Data collected by cyclist was applied to characterize the micro-variability in relation to traffic density and street topology. The distance to the traffic and the street topology as well as the volume of heavy diesel trucks were the dominant factors influencing the BC concentrations. In this study, a high variability of BC concentrations between streets and even within streets was observed, and also between days and hour of the day. The average BC exposure concentrations were 5.59+/-1.02 MUg/m(3), 6.58+/ 1.78 MUg/m(3), 7.28+/-1.87 MUg/m(3), 8.62+/-4.13 MUg/m(3) and 9.43+/-2.89 MUg/m(3) for walking, cycling, bus, taxi and subway trips, respectively. Exposure levels of in-vehicle microenvironments were 8.66+/-3.66 MUg/m(3), 9.39+/-6.98 MUg/m(3) and 10.96+/-2.72 MUg/m(3) for bus, taxi and subway, respectively. While inhalation doses were 0.68+/-0.33 MUg, 0.95+/-0.29 MUg, 1.36+/-0.37 MUg, 1.50+/ 0.39 MUg and 1.58+/-0.29 MUg for taxi, subway, cycling, bus and walking, respectively. BC exposure level of walking was the lowest among all the traffic modes, but its inhalation dose was the highest. PMID- 25909268 TI - Mercury in sediment, water, and fish in a managed tropical wetland-lake ecosystem. AB - Mercury pollution has not been well documented in the inland lakes or fishes of Mexico, despite the importance of freshwater fish as a source of protein in local diets. Total mercury and methylmercury in waters, sediments, and the commercial fish catch were investigated in Lake Zapotlan, Mexico. Concentrations of total and methylmercury were very high in runoff and wastewater inputs, but very low in sediments and surface waters of the open water area of the lake. Concentrations of total mercury in tilapia and carp were very low, consistent with the low concentrations in lake water and sediments. Particle settling, sorption, the biogeochemical environment, and/or bloom dilution are all plausible explanations for the significant reductions in both total mercury and methylmercury. Despite very high loading of mercury, this shallow tropical lake was not a mercury impaired ecosystem, and these findings may translate across other shallow, alkaline tropical lakes. Importantly, the ecosystem services that seemed to be provided by peripheral wetlands in reducing mercury inputs highlight the potential for wetland conservation or restoration in Mexico. PMID- 25909269 TI - Giant pseudomeningocele causing urinary obstruction in a patient with Marfan syndrome. AB - Defective collagen biosynthesis in Marfan syndrome predisposes to dural defects such as dural ectasia, meningocele, and pseudomeningocele; thus, an increased index of suspicion for these conditions should be present in the clinical setting of Marfan syndrome. The authors describe a young woman with Marfan syndrome who was being treated with anticoagulants for a prosthetic heart valve and who presented with a spontaneous retroperitoneal hemorrhage requiring surgical evacuation. No CSF leak was encountered at surgery, but she developed progressively more severe positional headaches over the following year. She then experienced the sudden onset of acute urinary obstruction, at which time CT revealed a 17 * 15 * 13-cm presacral pseudomeningocele communicating with the thecal sac through a sacral bone defect. An anterior surgical approach was used for drainage of the pseudomeningocele as well as for primary closure of the dural defect with a bovine pericardial patch and autologous subcutaneous fat graft. After a short period of lumbar subarachnoid drainage of the CSF, the patient was able to resume normal activity without recurrent symptoms. To the authors' knowledge, such a pseudomeningocele in a patient with Marfan syndrome has been reported only twice, and this case features the largest pseudomeningocele to date. They also review the pertinent literature regarding presentation, diagnosis, and management of these lesions. PMID- 25909270 TI - Cervical laminoplasty developments and trends, 2003-2013: a systematic review. AB - OBJECT: Despite extensive clinical experience with laminoplasty, the efficacy of the procedure and its advantages over laminectomy remain unclear. Specific clinical elements, such as incidence or progression of kyphosis, incidence of axial neck pain, postoperative cervical range of motion, and incidence of postoperative C-5 palsies, are of concern. The authors sought to comprehensively review the laminoplasty literature over the past 10 years while focusing on these clinical elements. METHODS: The authors conducted a literature search of articles in the Medline database published between 2003 and 2013, in which the terms "laminoplasty," "laminectomy," and "posterior cervical spine procedures" were used as key words. Included was every single case series in which patient outcomes after a laminoplasty procedure were reported. Excluded were studies that did not report on at least one of the above-mentioned items. RESULTS: A total of 103 studies, the results of which contained at least 1 of the prespecified outcome variables, were identified. These studies reported 130 patient groups comprising 8949 patients. There were 3 prospective randomized studies, 1 prospective nonrandomized alternating study, 15 prospective nonrandomized data collections, and 84 retrospective reviews. The review revealed a trend for the use of miniplates or hydroxyapatite spacers on the open side in Hirabayashi-type laminoplasty or on the open side in a Kurokawa-type laminoplasty. Japanese Orthopaedic Association (JOA) scoring was reported most commonly; in the 4949 patients for whom a JOA score was reported, there was improvement from a mean (+/ SD) score of 9.91 (+/- 1.65) to a score of 13.68 (+/- 1.05) after a mean follow up of 44.18 months (+/- 35.1 months). The mean preoperative and postoperative C2 7 angles (available for 2470 patients) remained stable from 14.17 degrees (+/- 0.19 degrees ) to 13.98 degrees (+/- 0.19 degrees ) of lordosis (average follow up 39 months). The authors found significantly decreased kyphosis when muscle/posterior element-sparing techniques were used (p = 0.02). The use of hardware in the form of hydroxyapatite spacers or miniplates did not influence the progression of deformity (p = 0.889). An overall mean (calculated from 2390 patients) of 47.3% loss of range of motion was reported. For the studies that used a visual analog scale score (totaling 986 patients), the mean (cohort size adjusted) postoperative pain level at a mean follow-up of 29 months was 2.78. For the studies that used percentages of patients who complained of postoperative axial neck pain (totaling 1249 patients), the mean patient number-adjusted percentage was 30% at a mean follow-up of 51 months. The authors found that 16% of the studies that were published in the last 10 years reported a C-5 palsy rate of more than 10% (534 patients), 41% of the studies reported a rate of 5%-10% (n = 1006), 23% of the studies reported a rate of 1%-5% (n = 857), and 12.5% reported a rate of 0% (n = 168). CONCLUSIONS: Laminoplasty remains a valid option for decompression of the spinal cord. An understanding of the importance of the muscle-ligament complex, plus the introduction of hardware, has led to progress in this type of surgery. Reporting of outcome metrics remains variable, which makes comparisons among the techniques difficult. PMID- 25909271 TI - Sagittal balance of the cervical spine: an analysis of occipitocervical and spinopelvic interdependence, with C-7 slope as a marker of cervical and spinopelvic alignment. AB - OBJECT: Sagittal malalignment of the cervical spine has been associated with worsened postsurgical outcomes. For better operative planning of fusion and alignment restoration, improved knowledge of ideal fusion angles and interdependences between upper and lower cervical spine alignment is needed. Because spinal and spinopelvic parameters might play a role in cervical sagittal alignment, their associations should be studied in depth. METHODS: The authors retrospectively analyzed digital lateral standing cervical radiographs of 145 patients (34 asymptomatic, 74 symptomatic; 37 surgically treated), including full standing radiographs obtained in 45 of these patients. Sagittal measurements were as follows: C2-7, occiput (Oc)-C2, C1-2 Cobb angles, and C-7 slope (the angle between the horizontal line and the superior endplate of C-7), as well as T4-12 and L1-S1 Cobb angles, sacral slope, pelvic incidence, and C-7 sagittal vertical axis (SVA). A correlation analysis was performed, and linear regression models were developed. RESULTS: Statistical analyses revealed significant correlations between C2-7 and Oc-C2 (r = -0.4, p < 0.01), Oc-C2 (r = -0.3, p < 0.01), and C1-2 angle (r = -0.3, p < 0.01). C-7 slope was significantly correlated with C2-7 (r = -0.5, p < 0.01) and with Oc-C2 angle (r = 0.2, p = 0.02). Total cervical (Oc-C7) lordosis was 30.2 degrees and did not differ significantly among asymptomatic, symptomatic, and surgically treated patients. Correlations between C2-7 and Oc-C2 alignment were stronger in asymptomatic patients (r = -0.5, p < 0.01) and surgically treated patients (r = -0.5, p < 0.01) than in symptomatic patients (r = -0.3, p = 0.01), but the between-group difference was not significant (p > 0.1). Comparing cervical and spinopelvic alignment revealed a significant correlation between sacral slope and C-7 slope (r = -0.3, p = 0.04) and C2-7 (r = 0.4, p < 0.01). The C-7 SVA correlated significantly with the C-7 slope (r = 0.4, p < 0.01). The interdependences were stronger within the occipitocervical parameters than between the cervical and remaining spinal parameters. CONCLUSIONS: Significant correlations between the upper and lower cervical spine exist, confirming the existence of inherent compensatory mechanisms to maintain overall balance; no significant differences were found among asymptomatic, symptomatic, and surgically treated patients. The C-7 slope is a useful marker of overall sagittal alignment, acting as a link between the occipitocervical and thoracolumbar spine. PMID- 25909272 TI - A single-stage posterior approach with open reduction and pedicle screw fixation in subaxial cervical facet dislocations. AB - OBJECT: The optimal treatment for cervical facet dislocations is controversial, but the generally accepted process recommends an initial closed reduction with the next step determined according to the success of the closed reduction and the presence of traumatic disc herniation. This study aimed to show the efficacy of a posterior approach performed with an open reduction and pedicle screw fixation with removal of disc particles, if required, in the management of subaxial cervical dislocations. METHODS: Between March 2012 and September 2013, 21 consecutive patients with cervical facet dislocations were enrolled. The affected levels were as follows: 4 at C3-4; 2 at C4-5; 5 at C5-6; and 10 at the C6-7 level. Seven patients had traumatic disc herniations. Closed reduction was not attempted; a prompt posterior cervical surgery was performed instead. After open reduction, pedicle screw fixation was performed. In cases with traumatic disc herniation, herniated disc fragments were excised via a posterolateral approach and successful decompressions were determined by postoperative MRI studies. Clinical outcomes were assessed using the American Spinal Injury Association (ASIA) grading system. Radiological outcomes were assessed by comparing the degree of subluxation and the angle of segmental lordosis between pre- and postoperative CT scans. RESULTS: All patients improved neurologically. The mean segmental angles improved from 7.3 degrees +/- 8.68 degrees to -5.9 degrees +/ 4.85 degrees . The mean subluxation improved from 23.4% +/- 16.52% to 2.6% +/- 7.19%. Disc fragments were successfully removed from the 7 patients with herniated discs, as shown on MRI. CONCLUSIONS: Open reduction followed by pedicle screw fixation or posterolateral removal of herniated disc fragments is a good treatment option for cervical facet dislocations. PMID- 25909273 TI - A minimally invasive pericoccygeal approach to resection of a large presacral schwannoma: case report. AB - Resection of large presacral schwannomas can present a challenge. The posterior approach is commonly associated with coccygeal disarticulation, partial sacral resection, and muscular disarticulation, which can all result in significant morbidity. Minimally invasive surgery may obviate some of the morbidity traditionally associated with this approach. The authors present the case of a morbidly obese 49-year-old man with an enlarging presacral schwannoma. The patient refused laparoscopic resection because of the morbidity he had experienced with a previous laparoscopic surgery. The tumor was resected using a minimally invasive paracoccygeal approach, which affords improved access with minimal morbidity. PMID- 25909274 TI - Expanded eggshell procedure combined with closing-opening technique (a modified vertebral column resection) for the treatment of thoracic and thoracolumbar angular kyphosis. AB - OBJECT: The purpose of this study was to determine the efficacy of a modified vertebral column resection for the treatment of thoracolumbar angular kyphosis. METHODS: A total of 13 patients (8 male, 5 female) with thoracolumbar kyphosis (kyphotic angle > 60 degrees ) were included in this study (Group A). There were 3 patients with failure of spinal formation (Type 1 deformity), 6 patients with old thoracic or lumbar compression fracture, and 4 patients with old spinal tuberculosis (including 1 case of T3-5 vertebral malunion). The average preoperative kyphotic angle was 67.3 degrees (range 62 degrees -75 degrees ). Each patient underwent an expanded eggshell procedure combined with the closing opening technique for the treatment of thoracolumbar angular kyphosis. Sixteen patients who were previously treated with a closing-opening wedge osteotomy in the same spine classification group (kyphotic angle > 60 degrees ) were used as a control group (Group B). RESULTS: In Group A, the average (+/- SD) operative time was 400 +/- 60 minutes, and the average blood loss was 960 +/- 120 ml. There were no surgery-related complications observed during or after the operations. The average local kyphotic angle was 20.3 degrees (range 18 degrees -24.5 degrees ), and the average correction rate was 68.7%. In Group B, the average operative time was 470 +/- 90 minutes, and the average blood loss was 2600 +/- 1600 ml (range 1200-8200 ml). There were segmental vessels and spinal canal venous plexus injury in 1 case, spinal cord injury in 1 case, dural tearing in 2 cases, pleural rupture in 2 cases, and hemothorax and pneumothorax in 1 case. Each patient had more than 2 years of follow-up. At the latest follow-up examination, the average regional kyphotic angle was 19.9 degrees +/- 9.1 degrees (range 19 degrees -34 degrees ), and there was no significant loss of correction (p > 0.05). There was greater blood loss and a higher complication rate in Group B than in Group A (p < 0.05). CONCLUSIONS: An expanded eggshell procedure combined with the closing opening technique for the treatment of thoracolumbar angular kyphosis resulted in significant reduction of the kyphotic angle, few complications, and good follow up results. However, a larger series of patients and long-term follow-up results is still required to verify the effectiveness and safety of this method. PMID- 25909275 TI - Clinical presentation and surgical outcomes of intramedullary neurenteric cysts. AB - OBJECT: Intramedullary neurenteric cysts (NECs) are exceedingly rare lesions and have been previously reported in case reports. The aim of this study was to determine the clinical manifestations, radiological features, and long-term prognosis of patients with such lesions. METHODS: The authors retrospectively reviewed the records of 13 patients with an intramedullary NEC. Each patient underwent MRI, laminotomy, and microsurgery. The accurate diagnosis was based on imaging and pathology findings. Each patient's follow-up status was determined through individual office visits and a structured telephone interview. RESULTS: The series included 7 male and 6 female patients. Progressive or intermittent motor deficit was the main symptom associated with or without pain or sensory disturbance. Five cysts were located in the cervical cord, 1 in the cervicothoracic cord, 3 in the thoracic cord, and 4 in the conus medullaris. Concurrent malformations included scoliosis (3 cases), fusion of rib (1 case), enlarged spinal canal (1 case), tethered spinal cord (1 case), and ectocardia (1 case). Gross-total resection of the cyst was achieved in 8 cases, and subtotal resection (STR) was achieved in 5 cases. All patients were followed up, with a mean duration of 66.5 months. Cyst recurrence was observed in 4 cases after STR. In 2 cases the patients underwent reoperation; the other 2 patients remained clinically stable and did not undergo reoperation. At the last evaluation, neurological function was improved in 11 patients and remained stable in 2 patients. CONCLUSIONS: Intramedullary NECs should be considered in the differential diagnosis of a middle-aged patient with intermittent neurological symptoms and concurrent malformations. Early surgery is advocated to prevent permanent neurological deficits. When gross-total resection cannot be achieved, maximally safe removal under the protection of intraoperative neuromonitoring is advised. Because of the high risk of cyst recurrence, routine follow-up MRI is needed. If a residual cyst shows obvious regrowth and results in neurological deficits, timely reoperation with a goal of STR should be performed. PMID- 25909277 TI - The rate of prosthetic joint infection is underestimated in the arthroplasty registers. PMID- 25909276 TI - A new family of hybrid virophages from an animal gut metagenome. AB - Search of metagenomics sequence databases for homologs of virophage capsid proteins resulted in the discovery of a new family of virophages in the sheep rumen metagenome. The genomes of the rumen virophages (RVP) encode a typical virophage major capsid protein, ATPase and protease combined with a Polinton type, protein primed family B DNA polymerase. The RVP genomes appear to be linear molecules, with terminal inverted repeats. Thus, the RVP seem to represent virophage-Polinton hybrids that are likely capable of formation of infectious virions. Virion proteins of mimiviruses were detected in the same metagenomes as the RVP suggesting that the virophages of the new family parasitize on giant viruses that infect protist inhabitants of the rumen. PMID- 25909278 TI - Improved DNA equilibrium binding affinity determinations of platinum(II) complexes using synchrotron radiation circular dichroism. AB - The binding affinity of a series of square planar platinum(II) compounds of the type [Pt(A(L))(I(L))](2+), where A(L) is 1,2-diaminoethane and I(L) are 1,10 phenanthroline (phen), 4-methyl-1,10-phenanthroline (4Mephen), 5-methyl-1,10 phenanthroline (5Mephen), 4,7-dimethyl-1,10-phenanthroline (47Me2phen), 5,6 dimethyl-1,10-phenanthroline (56Me2phen) or 3,4,7,8-tetramethyl-1,10 phenanthroline (3478Me4phen) has been reinvestigated using Synchrotron Radiation Circular Dichroism (SRCD) spectroscopy. The additional peaks exhibited considerably greater intensity than those observed between 200 and 400 nm affording additional binding affinity determinations. In addition, the authors have reviewed the various mathematical approaches used to estimate equilibrium binding constants and thereby demonstrate that their mathematical approach, implemented with Wolfram Mathematica, has merit over other methods. PMID- 25909279 TI - Discovery of potent indenoisoquinoline topoisomerase I poisons lacking the 3 nitro toxicophore. AB - 3-Nitroindenoisoquinoline human topoisomerase IB (Top1) poisons have potent antiproliferative effects on cancer cells. The undesirable nitro toxicophore could hypothetically be replaced by other functional groups that would retain the desired biological activities and minimize potential safety risks. Eleven series of indenoisoquinolines bearing 3-nitro bioisosteres were synthesized. The molecules were evaluated in the Top1-mediated DNA cleavage assay and in the National Cancer Institute's 60 cell line cytotoxicity assay. The data reveal that fluorine and chlorine may substitute for the 3-nitro group with minimal loss of Top1 poisoning activity. The new information gained from these efforts can be used to design novel indenoisoquinolines with improved safety. PMID- 25909281 TI - Multiscale characterization of ageing and cancer progression by a novel network entropy measure. AB - We characterize different cell states, related to cancer and ageing phenotypes, by a measure of entropy of network ensembles, integrating gene expression profiling values and protein interaction network topology. In our case studies, network entropy, that by definition estimates the number of possible network instances satisfying the given constraints, can be interpreted as a measure of the "parameter space" available to the cell. Network entropy was able to characterize specific pathological conditions: normal versus cancer cells, primary tumours that developed metastasis or relapsed, and extreme longevity samples. Moreover, this approach has been applied at different scales, from whole network to specific subnetworks (biological pathways defined on a priori biological knowledge) and single nodes (genes), allowing a deeper understanding of the cell processes involved. PMID- 25909280 TI - Genetic Variation along the Histamine Pathway in Children with Allergic versus Nonallergic Asthma. AB - Histamine is an important mediator in the pathogenesis of asthma. Variation in genes along the histamine production, response, and degradation pathway may be important in predicting response to antihistamines. We hypothesize that differences exist among single-nucleotide polymorphisms (SNPs) in genes of the histamine pathway between children with allergic versus nonallergic asthma. Children (7-18 yr of age; n = 202) with asthma were classified as allergic or nonallergic based on allergy skin testing. Genotyping was performed to detect known SNPs (n = 10) among genes (HDC, HNMT, ABP1, HRH1, and HRH4) within the histamine pathway. Chi square tests and Cochran-Armitage Trend were used to identify associations between genetic variants and allergic or nonallergic asthma. Significance was determined by P < 0.05 and false-positive report probability. After correction for race differences in genotype were observed, HRH1-17 TT (6% allergic versus 0% nonallergic; P = 0.04), HNMT-464 TT (41% allergic versus 29% nonallergic; P = 0.04), and HNMT-1639 TT (30% allergic versus 20% nonallergic; P = 0.04) were overrepresented among children with allergic asthma. Genotype differences specifically among the African-American children were also observed: HRH1-17 TT (13% allergic versus 0% nonallergic; P = 0.04) and HNMT-1639 TT (23% allergic versus 3% nonallergic; P = 0.03) genotypes were overrepresented among African-American children with allergic asthma. Our study suggests that genetic variation within the histamine pathway may be associated with an allergic versus nonallergic asthma phenotype. Further studies are needed to determine the functional significance of identified SNPs and their impact on antihistamine response in patients with asthma and allergic disease. PMID- 25909282 TI - Synergistic protection of N-acetylcysteine and ascorbic acid 2-phosphate on human mesenchymal stem cells against mitoptosis, necroptosis and apoptosis. AB - Human mesenchymal stem cells (hMSCs) contribute to ischemic tissue repair, regeneration, and possess ability to self-renew. However, poor viability of transplanted hMSCs within ischemic tissues has limited its therapeutic efficiency. Therefore, it is urgent to explore new method to improve the viability of the grafted cells. By using a systematic analysis, we reveal the mechanism of synergistic protection of N-acetylcysteine (NAC) and ascorbic acid 2 phosphate (AAP) on hMSCs that were under H2O2-induced oxidative stress. The combined treatment of NAC and AAP (NAC/AAP) reduces reactive oxygen species (ROS) generation, stabilizes mitochondrial membrane potential and decreases mitochondrial fission/fragmentation due to oxidative stress. Mitochondrial fission/fragmentation is a major prologue of mitoptosis. NAC/AAP prevents apoptotic cell death via decreasing the activation of BAX, increasing the expression of BCL2, and reducing cytochrome c release from mitochondria that might lead to the activation of caspase cascade. Stabilization of mitochondria also prevents the release of AIF, and its nuclear translocation which may activate necroptosis via H2AX pathway. The decreasing of mitoptosis is further studied by MicroP image analysis, and is associated with decreased activation of Drp1. In conclusion, NAC/AAP protects mitochondria from H2O2-induced oxidative stress and rescues hMSCs from mitoptosis, necroptosis and apoptosis. PMID- 25909283 TI - Fibulin-5 inhibits Wnt/beta-catenin signaling in lung cancer. AB - Metastatic lung cancer is incurable and a leading cause of cancer death in the United States. However, the molecular mechanism by which lung cancer cells invade other tissues has remained unclear. We previously identified fibulin-5, an extracellular matrix protein, as a frequently silenced gene in lung cancer and a suppressor of cell invasion. In this study, we found fibulin-5 functions by inhibiting the Wnt/beta-catenin pathway. The Cancer Genome Atlas (TCGA) datasets show a strong association between loss of fibulin-5 expression and poor outcomes of lung cancer patients, and also activation of the Wnt target genes MMP-7 and c Myc. Fibulin-5 impedes Wnt/beta-catenin signaling by inhibiting extracellular signal-regulated kinase (ERK) to activate glycogen synthase kinase-3 beta (GSK3beta), which downregulates beta-catenin and prevents its nuclear accumulation, leading to suppression of MMP-7 and c-Myc expression. These effects of fibulin-5 are mediated by its amino-terminal integrin-binding RGD motif. Fibulin-5 also blocks Wnt/beta-catenin signaling in vivo in H460 metastasis and H1299 tumor models. Furthermore, knockdown of beta-catenin suppresses metastasis of H460 tumors, while knockdown of GSK3beta promotes metastasis of fibulin-5 expressing H1752 tumors. Together, our results suggest that fibulin-5 functions as a metastasis suppressor in lung cancer by modulating tumor microenvironment to suppress Wnt/beta-catenin signaling. PMID- 25909284 TI - Macrolide analog F806 suppresses esophageal squamous cell carcinoma (ESCC) by blocking beta1 integrin activation. AB - The paucity of new drugs for the treatment of esophageal squamous cell carcinoma (ESCC) limits the treatment options. This study characterized the therapeutic efficacy and action mechanism of a novel natural macrolide compound F806 in human ESCC xenograft models and cell lines. F806 inhibited growth of ESCC, most importantly, it displayed fewer undesirable side effects on normal tissues in two human ESCC xenograft models. F806 inhibited proliferation of six ESCC cells lines, with the half maximal inhibitory concentration (IC50) ranging from 9.31 to 16.43 MUM. Furthermore, F806 induced apoptosis of ESCC cells, contributing to its growth-inhibitory effect. Also, F806 inhibited cell adhesion resulting in anoikis. Mechanistic studies revealed that F806 inhibited the activation of beta1 integrin in part by binding to a novel site Arg610 of beta1 integrin, suppressed focal adhesion formation, decreased cell adhesion to extracellular matrix and eventually triggered apoptosis. We concluded that F806 would potentially be a well-tolerated anticancer drug by targeting beta1 integrin, resulting in anoikis in ESCC cells. PMID- 25909285 TI - Foretinib inhibits angiogenesis, lymphangiogenesis and tumor growth of pancreatic cancer in vivo by decreasing VEGFR-2/3 and TIE-2 signaling. AB - Foretinib, a multiple kinase inhibitor undergoing clinical trials, could suppress the activity of hepatocyte growth factor (HGF) receptor c-MET and vascular endothelial growth factor receptor-2 (VEGFR-2). In addition, Foretinib may inhibit two critical lymphangiogenic signaling receptors VEGFR-3 and TIE-2. However, the effect of Foretinib on lymphatic endothelial cells (LECs) in vitro and lymphangiogenesis in vivo is still unknown. We found Foretinib decreased basal- and HGF-induced c-MET activity at low concentrations. However, Foretinib only reduced the proliferation of pancreatic cancer cells at high concentration reflecting the intrinsic chemoresistance of pancreatic cancer cells. Foretinib inhibited VEGF-A, VEGF-C and Angiopoetin-2 (ANG-2)-stimulated tube formation and sprouting of LECs by reducing VEGFR-2, VEGFR-3 and TIE-2 activation and increased apoptosis of LECs. In xenograft animal study, Foretinib suppressed tumor growth by inhibiting proliferation, angiogenesis and lymphangiogenesis. Additionally, Foretinib inhibited angiogenesis and lymphangiogenesis more significantly and exhibited low detrimental effect in orthotopic animal study. Collectively, we suggested that Foretinib simultaneously inhibits cancer cells and LECs to reduce pancreatic tumor growth in vivo and demonstrated for the first time that Foretinib suppresses angiogenesis and lymphangiogenesis by blocking VEGFR-2/3 and TIE-2 signaling. PMID- 25909286 TI - TIMP-1 activated carcinoma-associated fibroblasts inhibit tumor apoptosis by activating SDF1/CXCR4 signaling in hepatocellular carcinoma. AB - Tissue inhibitor of metalloproteinase 1 (TIMP-1) is an endogenous inhibitor for MMPs that regulates the remodeling and turnover of the ECM during normal development and pathological conditions. Intriguingly, recent studies have shown that TIMP-1 plays a dual role in cancer progression. In this study, we found that TIMP-1 expression in HCC tissues is associated with advanced TNM stage, intrahepatic metastasis, portal vein invasion, and vasculature invasion. Notably, TIMP-1 expression in HCC tissue is significantly related to worse overall survival for patients with HCC after liver resection. Ectopic TIMP1 expression promoted the growth of HCC xenografts in nude mice. Both co-culture with Huh7 cells with a high level of TIMP-1 and TIMP1 treatment resulted in up-regulation of hallmarks of carcinoma-associated fibroblasts (CAFs) and accelerated cell proliferation, migration and invasion in immortalized liver fibroblasts (LFs) isolated from human normal liver tissue. By co-culture with CAFs, SDF 1/CXCR4/PI3K/AKT signaling was activated and apoptosis was markedly repressed with an increased Bcl-2/BAX ratio in Huh7 cells. Taken together, our observations suggest that TIMP-1 induces the trans-differentiation of LFs into CAFs, suppresses apoptosis via SDF-1/CXCR4/PI3K/AKT signaling and then promotes HCC progression. This protein may be a potential prognostic biomarker and therapeutic target for HCC. PMID- 25909287 TI - Loss of the N-terminal methyltransferase NRMT1 increases sensitivity to DNA damage and promotes mammary oncogenesis. AB - Though discovered over four decades ago, the function of N-terminal methylation has mostly remained a mystery. Our discovery of the first mammalian N-terminal methyltransferase, NRMT1, has led to the discovery of many new functions for N terminal methylation, including regulation of DNA/protein interactions, accurate mitotic division, and nucleotide excision repair (NER). Here we test whether NRMT1 is also important for DNA double-strand break (DSB) repair, and given its previously known roles in cell cycle regulation and the DNA damage response, assay if NRMT1 is acting as a tumor suppressor. We find that NRMT1 knockdown significantly enhances the sensitivity of breast cancer cell lines to both etoposide treatment and gamma-irradiation, as well as, increases proliferation rate, invasive potential, anchorage-independent growth, xenograft tumor size, and tamoxifen sensitivity. Interestingly, this positions NRMT1 as a tumor suppressor protein involved in multiple DNA repair pathways, and indicates, similar to BRCA1 and BRCA2, its loss may result in tumors with enhanced sensitivity to diverse DNA damaging chemotherapeutics. PMID- 25909288 TI - OGFOD1 is required for breast cancer cell proliferation and is associated with poor prognosis in breast cancer. AB - 2-oxogluatrate and Fe(II)-dependent oxygenase domain-containing protein 1 (OGFOD1) was recently revealed to be a proline hydroxylase of RPS23 for translational termination. However, OGFOD1 is nuclear, whereas translational termination occurs in the cytoplasm, raising the possibility of another function of OGFOD1 in the nucleus. In this study, we demonstrate that OGFOD1 is involved in cell cycle regulation. OGFOD1 knockdown in MDA-MB-231 breast cancer cells significantly impeded cell proliferation and resulted in the accumulation of G1 and G2/M cells by decreasing the mRNA levels of G1/S transition- and G2/M-related transcription factors and their target genes. We also confirmed that OGFOD1 is highly expressed in breast cancer tissues by bioinformatic analysis and immunohistochemistry. Thus, we propose that OGFOD1 is required for breast cancer cell proliferation and is associated with poor prognosis in breast cancer. PMID- 25909289 TI - JARID1B promotes metastasis and epithelial-mesenchymal transition via PTEN/AKT signaling in hepatocellular carcinoma cells. AB - JARID1B is a member of the family of JmjC domain-containing proteins that removes methyl residues from methylated lysine 4 on histone H3 lysine 4 (H3K4). JARID1B has been proposed as an oncogene in many types of tumors; however, its role and underlying mechanisms in hepatocellular carcinoma (HCC) remain unknown. Here we show that JARID1B is elevated in HCC and its expression level is positively correlated with metastasis. In addition Kaplan-Meier survival analysis showed that high expression of JARID1B was associated with decreased overall survival of HCC patients. Overexpression of JARID1B in HCC cells increased proliferation, epithelial-mesenchymal transition, migration and invasion in vitro, and enhanced tumorigenic and metastatic capacities in vivo. In contrast, silencing JARID1B in aggressive and invasive HCC cells inhibited these processes. Mechanistically, we found JARID1B exerts its function through modulation of H3K4me3 at the PTEN gene promoter, which was associated with inactive PTEN transcription. PTEN overexpression blocked JARID1B-driven proliferation, EMT, and metastasis. Our results, for the first time, portray a pivotal role of JARID1B in stimulating metastatic behaviors of HCC cells. Targeting JARID1B may thus be a useful strategy to impede HCC cell invasion and metastasis. PMID- 25909290 TI - Expression alterations define unique molecular characteristics of spinal ependymomas. AB - Ependymomas are glial tumors that originate in either intracranial or spinal regions. Although tumors from different regions are histologically similar, they are biologically distinct. We therefore sought to identify molecular characteristics of spinal ependymomas (SEPN) in order to better understand the disease biology of these tumors. Using gene expression profiles of 256 tumor samples, we identified increased expression of 1,866 genes in SEPN when compared to intracranial ependymomas. These genes are mainly related to anterior/posterior pattern specification, response to oxidative stress, glial cell differentiation, DNA repair, and PPAR signalling, and also significantly enriched with cellular senescence genes (P = 5.5 * 10-03). In addition, a high number of significantly down-regulated genes in SEPN are localized to chromosome 22 (81 genes from chr22: 43,325,255 - 135,720,974; FDR = 1.77 * 10-23 and 22 genes from chr22: 324,739 - 32,822,302; FDR = 2.07 * 10-09) including BRD1, EP300, HDAC10, HIRA, HIC2, MKL1, and NF2. Evaluation of NF2 co-expressed genes further confirms the enrichment of chromosome 22 regions. Finally, systematic integration of chromosome 22 genes with interactome and NF2 co-expression data identifies key candidate genes. Our results reveal unique molecular characteristics of SEPN such as altered expression of cellular senescence and chromosome 22 genes. PMID- 25909291 TI - 5-Fluorouracil sensitizes colorectal tumor cells towards double stranded DNA breaks by interfering with homologous recombination repair. AB - Malignant tumors of the rectum are treated by neoadjuvant radiochemotherapy. This involves a combination of 5-fluorouracil (5-FU) and double stranded DNA-break (DSB)-inducing radiotherapy. Here we explored how 5-FU cooperates with DSB induction to achieve sustainable DNA damage in colorectal cancer (CRC) cells. After DSB induction by neocarzinostatin, phosphorylated histone 2AX (gamma-H2AX) rapidly accumulated but then largely vanished within a few hours. In contrast, when CRC cells were pre-treated with 5-FU, gammaH2AX remained for at least 24 hours. GFP-reporter assays revealed that 5-FU decreases the efficiency of homologous recombination (HR) repair. However, 5-FU did not prevent the initial steps of HR repair, such as the accumulation of RPA and Rad51 at nuclear foci. Thus, we propose that 5-FU interferes with the continuation of HR repair, e. g. the synthesis of new DNA strands. Two key mediators of HR, Rad51 and BRCA2, were found upregulated in CRC biopsies as compared to normal mucosa. Inhibition of HR by targeting Rad51 enhanced DNA damage upon DSB-inducing treatment, outlining an alternative way of enhancing therapeutic efficacy. Taken together, our results strongly suggest that interfering with HR represents a key mechanism to enhance the efficacy when treating CRC with DNA-damaging therapy. PMID- 25909292 TI - Assessment of folate receptor-beta expression in human neoplastic tissues. AB - Over-expression of folate receptor alpha on cancer cells has been frequently exploited for delivery of folate-targeted imaging and therapeutic agents to tumors. Because limited information exists on expression of the beta isoform of the folate receptor in human cancers (FR-beta), we have evaluated the immunohistochemical staining pattern of FR-beta in 992 tumor sections from 20 different human cancer types using a new anti-human FR-beta monoclonal antibody. FR-beta expression was shown to be more pronounced in cells within the stroma, primarily macrophages and macrophage-like cells than cancer cells in every cancer type studied. Moreover, FR-beta expression in both cancer and stromal cells was found to be statistically more prominent in females than males. A significant positive correlation was also observed between FR-beta expression on stromal cells and both the stage of the cancer and the presence of lymph node metastases. Based on these data we conclude FR-beta may constitute a good target for specific delivery of therapeutic agents to activated macrophages and that accumulation of FR-beta positive macrophages in the stroma could serve as a useful indicator of a tumor's metastatic potential. PMID- 25909293 TI - Intracellular HMGB1: defender of client proteins and cell fate. PMID- 25909294 TI - Series of quinone-containing nanosensors for biologically relevant redox potential determination by surface-enhanced Raman spectroscopy. AB - Redox potential is of key importance in the control and regulation of cellular function and lifecycle, and previous approaches to measuring the biological redox potential noninvasively in real time are limited to areas of hypoxia or normoxia. In this paper, we extend our previous work on nanoparticle-based intracellular nanosensors to cover a much wider redox potential range of -470 to +130 mV vs NHE, which includes the redox potential range occupied by cells in a state of oxidative stress. The nanosensors are rationally designed to target different areas of this redox potential range and are monitored by surface-enhanced Raman spectroscopy, which will permit noninvasive real-time imaging of cells undergoing oxidative stress. PMID- 25909295 TI - Cardiovascular events and all-cause mortality in a cohort of 57,946 patients with type 2 diabetes: associations with renal function and cardiovascular risk factors. AB - BACKGROUND: Diabetes and chronic kidney disease (CKD) are independent predictors of death and cardiovascular events and their concomitant prevalence has increased in recent years. The aim of this study was to characterize the effect of the estimated glomerular filtration rate (eGFR) and other factors on the risk of death and cardiovascular events in patients with type 2 diabetes. METHODS: A cohort of 57,946 patients with type 2 diabetes who were aged 20-89 years in 2000 2005 was identified from The Health Improvement Network, a UK primary care database. Incidence rates of death, myocardial infarction (MI), and ischemic stroke or transient ischemic attack (IS/TIA) were calculated overall and by eGFR category at baseline. eGFR was calculated using the Modification of Diet in Renal Disease (MDRD) study equation. Death, MI and IS/TIA cases were detected using an automatic computer search and IS/TIA cases were further ascertained by manual review of medical records. Hazard ratios (HRs) and their corresponding 95% confidence intervals (CIs) for death, MI, and IS/TIA associated with eGFR category and other factors were estimated using Cox regression models adjusted for potential confounders. RESULTS: Overall incidence rates of death (mean follow up time of 6.76 years), MI (6.64 years) and IS/TIA (6.56 years) were 43.65, 9.26 and 10.39 cases per 1000 person-years, respectively. A low eGFR (15-29 mL/min) was associated with an increased risk of death (HR: 2.79; 95% CI: 2.57-3.03), MI (HR: 2.33; 95% CI: 1.89-2.87) and IS/TIA (HR: 1.77; 95% CI: 1.43-2.18) relative to eGFR >= 60 mL/min. Other predictors of death, MI and IS/TIA included age, longer duration of diabetes, poor control of diabetes, hyperlipidemia, smoking and a history of cardiovascular events. CONCLUSIONS: In patients with type 2 diabetes, management of cardiovascular risk factors and careful monitoring of eGFR may represent opportunities to reduce the risks of death, MI and IS/TIA. PMID- 25909296 TI - The Posteromedial Thigh Flap for Head and Neck Reconstruction: Anatomical Basis, Surgical Technique, and Clinical Applications. AB - BACKGROUND: The authors present the posteromedial thigh flap as an alternative source for head and neck reconstruction, and the perforator patterns and vascular anatomy of this flap were further investigated. METHODS: From March to August of 2014, 23 patients underwent head and neck reconstruction with 23 posteromedial thigh flaps. The numbers, locations, and types of perforators were measured. The surgical technique and the results after reconstruction were evaluated. RESULTS: Most perforators were located 8 to 10 cm away from the pubic crease on the reference line between the perineum and the insertion of the semitendinosus muscle. The average number of perforators was 1.7 (range, 1 to 3), and the average pedicle length was 10.3 cm (range, 8 to 13 cm). Eighty percent of the perforators (32 of 40) were musculocutaneous, and 20 percent (8 of 40) were septocutaneous. Ninety-five percent of the perforators (38 of 40) originated from the profunda femoris artery, and 5 percent (two of 40) originated from the medial circumflex femoral artery. The flap survival rate was 95.6 percent; one flap failed due to pedicle thrombosis. The donor sites were all closed primarily. CONCLUSIONS: The location of the perforators of the posteromedial thigh flap is consistent, and the pedicle length is sufficient to reach the neck region. Different reconstruction demands can be met by incorporating various soft-tissue components. The donor-site scar is well concealed, with minimal morbidity. The above advantages make the posteromedial thigh flap an excellent option for head and neck reconstruction. CLINICAL QUESTION/LEVEL OF EVIDENCE: Therapeutic, IV. PMID- 25909297 TI - Reply: Tuberous Breast Deformity: Classification and Treatment Strategy for Improving Consistency in Aesthetic Correction. PMID- 25909298 TI - Reply: Latissimus Dorsi Flap for Total Autologous Immediate Breast Reconstruction without Implants. PMID- 25909299 TI - A Systematic Review of Topical Vasodilators for the Treatment of Intraoperative Vasospasm in Reconstructive Microsurgery. AB - BACKGROUND: Intraoperative vasospasm during reconstructive microsurgery is common, often unpredictable, and potentially devastating with regard to flap survival. Current methods of pharmacologic management vary, and may be shifting as a result of changes in the availability of individual medications. This review aims to provide a concise examination of the published literature regarding use, efficacy, and adverse effects of the agents described for local management of vascular spasm during microsurgery. METHODS: A systematic review of the literature was performed to identify articles relevant to pharmacologic treatment of intraoperative vasospasm in vivo. An additional review of the literature was performed with regard to each agent identified in order to provide clinical background information. RESULTS: Systematic review identified 20 articles, in which 14 vasodilator agents were evaluated. Drugs were classified into five pharmacologic categories: phosphodiesterase inhibitors (papaverine, pentoxifylline, and amrinone), local anesthetics (lidocaine), calcium channel blockers (nicardipine, verapamil, nifedipine, and magnesium sulfate), direct vasodilators (sodium nitroprusside, prostaglandin E1, nitroglycerin, and hydralazine), and alpha antagonists (phentolamine and chlorpromazine). Despite a variety of methods, these studies indicate some degree of experimental evidence of efficacy for each of these agents. CONCLUSIONS: Available literature regarding use of topical vasodilating agents for intraoperative management of vasospasm during microsurgery is limited and largely based on animal models, which may not reliably generalize to the reconstructive patient population. Well-controlled translational study in clinically applicable and reproducible models is needed to guide evidence-based clinical management of this important phenomenon. PMID- 25909300 TI - Algorithm for the Management of Intracranial Hypertension in Children with Syndromic Craniosynostosis. AB - BACKGROUND: The purpose of this study was to examine the relationship of head growth, obstructive sleep apnea, and intracranial hypertension in patients with syndromic or complex craniosynostosis, and to evaluate the authors' standardized treatment protocol for the management of intracranial hypertension in these patients. METHODS: The authors conducted a prospective observational cohort study of patients with syndromic craniosynostosis at a national referral center, treated according to a standardized protocol. Measurements included occipitofrontal head circumference, with growth arrest defined as downward deflection in occipitofrontal head circumference trajectory greater than or equal to a 0.5 SD fall from baseline over 2 years, or lack of change in occipitofrontal head circumference growth curve; sleep studies, with results dichotomized into no/mild versus moderate/severe obstructive sleep apnea; and funduscopy to indicate papilledema, supplemented by optical coherence tomography and/or intracranial pressure monitoring to identify intracranial hypertension. RESULTS: The authors included 62 patients, of whom 21 (33.9 percent) had intracranial hypertension, 39 (62.9 percent) had obstructive sleep apnea, and 20 (32.3 percent) had occipitofrontal head circumference growth arrest during the study. Age at which intracranial hypertension first occurred was 2.0 years (range, 0.4 to 6.0 years). Preoperatively, 13 patients (21.0 percent) had intracranial hypertension, which was associated only with moderate/severe obstructive sleep apnea (p = 0.012). In the first year after surgery, intracranial hypertension was particularly related to occipitofrontal head circumference growth arrest (p = 0.006). Beyond 1 year after surgery, intracranial hypertension was associated with a combination of occipitofrontal head circumference growth arrest (p < 0.001) and moderate/severe obstructive sleep apnea (p = 0.007). CONCLUSIONS: Children with syndromic craniosynostosis are at risk of intracranial hypertension. The major determinant of this after vault expansion is impaired head growth, which may occur at varying ages. The presence of moderate/severe obstructive sleep apnea also significantly increases the risk of intracranial hypertension. CLINICIAL QUESTION/LEVEL OF EVIDENCE: Risk, III. PMID- 25909302 TI - Face-Lift Satisfaction Using the FACE-Q. AB - BACKGROUND: Face lifting is one of the most common operative procedures for facial aging and perhaps the procedure most synonymous with plastic surgery in the minds of the lay public, but no verifiable documentation of patient satisfaction exists in the literature. This study is the first to examine face lift outcomes and patient satisfaction using a validated questionnaire. METHODS: One hundred five patients undergoing a face lift performed by the senior author (C.H.T.) using a high, extended-superficial musculoaponeurotic system with submental platysma approximation technique were asked to complete anonymously the FACE-Q by e-mail. FACE-Q scores were assessed for each domain (range, 0 to 100), with higher scores indicating greater satisfaction with appearance or superior quality of life. RESULTS: Fifty-three patients completed the FACE-Q (50.5 percent response rate). Patients demonstrated high satisfaction with facial appearance (mean +/- SD, 80.7 +/- 22.3), and quality of life, including social confidence (90.4 +/- 16.6), psychological well-being (92.8 +/- 14.3), and early life impact (92.2 +/- 16.4). Patients also reported extremely high satisfaction with their decision to undergo face lifting (90.5 +/- 15.9). On average, patients felt they appeared 6.9 years younger than their actual age. Patients were most satisfied with the appearance of their nasolabial folds (86.2 +/- 18.5), cheeks (86.1 +/- 25.4), and lower face/jawline (86.0 +/- 20.6), compared with their necks (78.1 +/ 25.6) and area under the chin (67.9 +/- 32.3). CONCLUSION: Patients who responded in this study were extremely satisfied with their decision to undergo face lifting and the outcomes and quality of life following the procedure. PMID- 25909301 TI - Patient-Reported Satisfaction and Quality of Life following Breast Reconstruction in Thin Patients: A Comparison between Microsurgical and Prosthetic Implant Recipients. AB - BACKGROUND: Patients undergoing autologous breast reconstruction have higher long term satisfaction rates compared with those undergoing prosthetic reconstruction. Regardless, most patients still undergo prosthetic reconstruction. The authors compared outcomes of microsurgical reconstruction to those of prosthetic reconstruction in thin patients and evaluated the effect of reconstructive type on quality of life. METHODS: After institutional review board approval was obtained, the authors reviewed all patients undergoing breast reconstruction at a single institution from November of 2007 to May of 2012. Thin patients (body mass index <22 kg/m) were included for analysis and divided into two cohorts: microsurgical reconstruction and tissue expander/implant reconstruction. Once identified, patients were mailed a BREAST-Q survey for response; a retrospective chart review was also conducted. RESULTS: A total of 273 patients met inclusion criteria: 81.7 percent (n = 223) underwent tissue expander/implant reconstruction and 18.3 percent (n = 50) underwent microsurgical reconstruction. Of the patients undergoing microsurgical reconstruction, 50 percent (n = 25) responded to the BREAST-Q survey, whereas 48.4 percent of patients (n = 108) with implant reconstruction were responders. Microsurgical patients required more secondary revision [48 percent (n = 12) versus 25.9 percent (n = 28)] and autologous fat grafting [32 percent (n = 8) versus 16.9 percent (n = 19)] and a greater volume of fat per injection (147.85 ml versus 63.9 ml; p < 0.001). Furthermore, BREAST-Q responses showed that these patients were more satisfied with their breasts (71.1 percent versus 64.9 percent; p = 0.004), but had similar overall satisfaction with reconstruction (73.0 percent versus 74.8 percent; p = 0.54). CONCLUSIONS: Microsurgical breast reconstruction is efficacious in patients with a body mass index less than 22 kg/m and, when compared with prosthetic reconstruction, results in higher satisfaction with breasts. However, it requires more secondary revision surgery and the use of autologous fat grafting as an adjunct. CLINICAL QUESTION/LEVEL OF EVIDENCE: Therapeutic, III. PMID- 25909303 TI - A 5-Year Cost-Effectiveness Analysis of Silicone Metacarpophalangeal Arthroplasty in Patients with Rheumatoid Arthritis. AB - BACKGROUND: There is a paucity of research evaluating the cost-effectiveness of surgical interventions for rheumatoid arthritis patients. Previous reports have challenged the sustainability of improved outcomes after silicone metacarpophalangeal arthroplasty. The authors conducted an economic evaluation of the long-term health outcomes after silicone metacarpophalangeal arthroplasty. METHODS: The authors performed a 5-year prospective cohort study of 170 patients with rheumatoid arthritis (73 surgical and 97 nonsurgical). Objective functional measurements and patient-rated outcomes using the Michigan Hand Outcomes Questionnaire and the Arthritis Impact Measurement Scale 2 were collected at 3 and 5 years. A cost-effectiveness analysis using direct costs from Medicare outpatient claims data (2006 to 2010) was performed to estimate the incremental cost-effectiveness ratios for both the Michigan and Arthritis Impact Measurement Scale 2 measurements. RESULTS: At 5 years, the authors observed a statistically significant difference in upper extremity outcomes (Michigan Hand Outcomes Questionnaire) between the two groups, with surgical patients having higher outcomes. Costs associated with improved outcomes 5 years after surgery were $787 to $1150 when measured by the Michigan Hand Outcomes Questionnaire and $49,843 to $149,530 when measured by the Arthritis Impact scale. The incremental cost effectiveness ratios did not substantially increase with their observed surgical revision rate of 5.5 percent (approximately 4 percent increase in incremental cost-effectiveness ratio) or with previously published long-term revision rates of 6.2 percent (approximately 6 percent increase in incremental cost effectiveness ratio). CONCLUSIONS: Short-term improvements in upper extremity outcomes after silicone metacarpophalangeal arthroplasty are maintained over the 5-year follow-up period. These outcomes are achieved at a relatively low cost, even with the addition of potential surgical complications. PMID- 25909304 TI - Development of drug delivery systems and quality by design. PMID- 25909305 TI - Goals of goal-directed sedation. PMID- 25909306 TI - Shortage of intensive care specialists in the United States: recent insights and proposed solutions. PMID- 25909307 TI - Caring for the critically ill in developing countries: a perspective from India. PMID- 25909308 TI - What happens to the fluid balance during and after recovering from septic shock? AB - OBJECTIVE: We aimed to evaluate the cumulative fluid balance during the period of shock and determine what happens to fluid balance in the 7 days following recovery from shock. METHODS: A prospective and observational study in septic shock patients. Patients with a mean arterial pressure >= 65 mmHg and lactate < 2.0 mEq/L were included < 12 hours after weaning from vasopressor, and this day was considered day 1. The daily fluid balance was registered during and for seven days after recovery from shock. Patients were divided into two groups according to the full cohort's median cumulative fluid balance during the period of shock: Group 1 <= 4.4 L (n = 20) and Group 2 > 4.4 L (n = 20). RESULTS: We enrolled 40 patients in the study. On study day 1, the cumulative fluid balance was 1.1 [0.6 3.4] L in Group 1 and 9.0 [6.7 - 13.8] L in Group 2. On study day 7, the cumulative fluid balance was 8.0 [4.5 - 12.4] L in Group 1 and 14.7 [12.7 - 20.6] L in Group 2 (p < 0.001 for both). Afterwards, recovery of shock fluid balance continued to increase in both groups. Group 2 had a more prolonged length of stay in the intensive care unit and hospital compared to Group 1. CONCLUSION: In conclusion, positive fluid balances are frequently seen in patients with septic shock and may be related to worse outcomes. During the shock period, even though the fluid balance was previously positive, it becomes more positive. After recovery from shock, the fluid balance continues to increase. The group with a more positive fluid balance group spent more time in the intensive care unit and hospital. PMID- 25909309 TI - Patient stress in intensive care: comparison between a coronary care unit and a general postoperative unit. AB - OBJECTIVE: To evaluate and compare stressors identified by patients of a coronary intensive care unit with those perceived by patients of a general postoperative intensive care unit. METHODS: This cross-sectional and descriptive study was conducted in the coronary intensive care and general postoperative intensive care units of a private hospital. In total, 60 patients participated in the study, 30 in each intensive care unit. The stressor scale was used in the intensive care units to identify the stressors. The mean score of each item of the scale was calculated followed by the total stress score. The differences between groups were considered significant when p < 0.05. RESULTS: The mean ages of patients were 55.63 +/- 13.58 years in the coronary intensive care unit and 53.60 +/- 17.47 years in the general postoperative intensive care unit. For patients in the coronary intensive care unit, the main stressors were "being in pain", "being unable to fulfill family roles" and "being bored". For patients in the general postoperative intensive care unit, the main stressors were "being in pain", "being unable to fulfill family roles" and "not being able to communicate". The mean total stress scores were 104.20 +/- 30.95 in the coronary intensive care unit and 116.66 +/- 23.72 (p = 0.085) in the general postoperative intensive care unit. When each stressor was compared separately, significant differences were noted only between three items. "Having nurses constantly doing things around your bed" was more stressful to the patients in the general postoperative intensive care unit than to those in the coronary intensive care unit (p = 0.013). Conversely, "hearing unfamiliar sounds and noises" and "hearing people talk about you" were the most stressful items for the patients in the coronary intensive care unit (p = 0.046 and 0.005, respectively). CONCLUSION: The perception of major stressors and the total stress score were similar between patients in the coronary intensive care and general postoperative intensive care units. PMID- 25909310 TI - The reality of patients requiring prolonged mechanical ventilation: a multicenter study. AB - OBJECTIVE: The number of patients who require prolonged mechanical ventilation increased during the last decade, which generated a large population of chronically ill patients. This study established the incidence of prolonged mechanical ventilation in four intensive care units and reported different characteristics, hospital outcomes, and the impact of costs and services of prolonged mechanical ventilation patients (mechanical ventilation dependency >= 21 days) compared with non-prolonged mechanical ventilation patients (mechanical ventilation dependency < 21 days). METHODS: This study was a multicenter cohort study of all patients who were admitted to four intensive care units. The main outcome measures were length of stay in the intensive care unit, hospital, complications during intensive care unit stay, and intensive care unit and hospital mortality. RESULTS: There were 5,287 admissions to the intensive care units during study period. Some of these patients (41.5%) needed ventilatory support (n = 2,197), and 218 of the patients met criteria for prolonged mechanical ventilation (9.9%). Some complications developed during intensive care unit stay, such as muscle weakness, pressure ulcers, bacterial nosocomial sepsis, candidemia, pulmonary embolism, and hyperactive delirium, were associated with a significantly higher risk of prolonged mechanical ventilation. Prolonged mechanical ventilation patients had a significant increase in intensive care unit mortality (absolute difference = 14.2%, p < 0.001) and hospital mortality (absolute difference = 19.1%, p < 0.001). The prolonged mechanical ventilation group spent more days in the hospital after intensive care unit discharge (26.9 +/- 29.3 versus 10.3 +/- 20.4 days, p < 0.001) with higher costs. CONCLUSION: The classification of chronically critically ill patients according to the definition of prolonged mechanical ventilation adopted by our study (mechanical ventilation dependency >= 21 days) identified patients with a high risk for complications during intensive care unit stay, longer intensive care unit and hospital stays, high death rates, and higher costs. PMID- 25909311 TI - Blood transfusions in septic shock: is 7.0 g/dL really the appropriate threshold? AB - OBJECTIVE: To evaluate the immediate effects of red blood cell transfusion on central venous oxygen saturation and lactate levels in septic shock patients with different transfusion triggers. METHODS: We included patients with a diagnosis of septic shock within the last 48 hours and hemoglobin levels below 9.0 g/dL Patients were randomized for immediate transfusion with hemoglobin concentrations maintained above 9.0 g/dL (Group Hb9) or to withhold transfusion unless hemoglobin felt bellow 7.0 g/dL (Group Hb7). Hemoglobin, lactate, central venous oxygen saturation levels were determined before and one hour after each transfusion. RESULTS: We included 46 patients and 74 transfusions. Patients in Group Hb7 had a significant reduction in median lactate from 2.44 (2.00 - 3.22) mMol/L to 2.21 (1.80 - 2.79) mMol/L, p = 0.005, which was not observed in Group Hb9 [1.90 (1.80 - 2.65) mMol/L to 2.00 (1.70 - 2.41) mMol/L, p = 0.23]. Central venous oxygen saturation levels increased in Group Hb7 [68.0 (64.0 - 72.0)% to 72.0 (69.0 - 75.0)%, p < 0.0001] but not in Group Hb9 [72.0 (69.0 - 74.0)% to 72.0 (71.0 - 73.0)%, p = 0.98]. Patients with elevated lactate or central venous oxygen saturation < 70% at baseline had a significant increase in these variables, regardless of baseline hemoglobin levels. Patients with normal values did not show a decrease in either group. CONCLUSION: Red blood cell transfusion increased central venous oxygen saturation and decreased lactate levels in patients with hypoperfusion regardless of their baseline hemoglobin levels. Transfusion did not appear to impair these variables in patients without hypoperfusion. ClinicalTrials.gov NCT01611753. PMID- 25909312 TI - Causes of non-adherence to therapeutic guidelines in severe community-acquired pneumonia. AB - OBJECTIVE: To assess the adherence to Infectious Disease Society of America/American Thoracic Society guidelines and the causes of lack of adherence during empirical antibiotic prescription in severe pneumonia in Latin America. METHODS: A clinical questionnaire was submitted to 36 physicians from Latin America; they were asked to indicate the empirical treatment in two fictitious cases of severe respiratory infection: community-acquired pneumonia and nosocomial pneumonia. RESULTS: In the case of community acquired pneumonia, 11 prescriptions of 36 (30.6%) were compliant with international guidelines. The causes for non-compliant treatment were monotherapy (16.0%), the unnecessary prescription of broad-spectrum antibiotics (40.0%) and the use of non-recommended antibiotics (44.0%). In the case of nosocomial pneumonia, the rate of adherence to the Infectious Disease Society of America/American Thoracic Society guidelines was 2.8% (1 patient of 36). The reasons for lack of compliance were monotherapy (14.3%) and a lack of dual antibiotic coverage against Pseudomonas aeruginosa (85.7%). If monotherapy with an antipseudomonal antibiotic was considered adequate, the antibiotic treatment would be adequate in 100% of the total prescriptions. CONCLUSION: The compliance rate with the Infectious Disease Society of America/American Thoracic Society guidelines in the community-acquired pneumonia scenario was 30.6%; the most frequent cause of lack of compliance was the indication of monotherapy. In the case of nosocomial pneumonia, the compliance rate with the guidelines was 2.8%, and the most important cause of non adherence was lack of combined antipseudomonal therapy. If the use of monotherapy with an antipseudomonal antibiotic was considered the correct option, the treatment would be adequate in 100% of the prescriptions. PMID- 25909313 TI - Septic shock: a major cause of hospital death after intensive care unit discharge. AB - OBJECTIVE: To assess the causes and factors associated with the death of patients between intensive care unit discharge and hospital discharge. METHODS: The present is a pilot, retrospective, observational cohort study. The records of all patients admitted to two units of a public/private university hospital from February 1, 2013 to April 30, 2013 were assessed. Demographic and clinical data, risk scores and outcomes were obtained from the Epimed monitoring system and confirmed in the electronic record system of the hospital. The relative risk and respective confidence intervals were calculated. RESULTS: A total of 581 patients were evaluated. The mortality rate in the intensive care unit was 20.8% and in the hospital was 24.9%. Septic shock was the cause of death in 58.3% of patients who died after being discharged from the intensive care unit. Of the patients from the public health system, 73 (77.6%) died in the intensive care unit and 21 (22.4%) died in the hospital after being discharged from the unit. Of the patients from the Supplementary Health System, 48 (94.1%) died in the intensive care unit and 3 (5.9%) died in the hospital after being discharged from the unit (relative risk, 3.87%; 95% confidence interval, 1.21 - 12.36; p < 0.05). The post discharge mortality rate was significantly higher in patients with intensive care unit hospitalization time longer than 6 days. CONCLUSION: The main cause of death of patients who were discharged from the intensive care unit and died in the ward before hospital discharge was septic shock. Coverage by the public healthcare system and longer hospitalization time in the intensive care unit were factors associated with death after discharge from the intensive care unit. PMID- 25909314 TI - Management of severe community-acquired pneumonia in Brazil: a secondary analysis of an international survey. AB - OBJECTIVE: This study aimed to evaluate Brazilian physicians' perceptions regarding the diagnosis, severity assessment, treatment and risk stratification of severe community-acquired pneumonia patients and to compare those perceptions to current guidelines. METHODS: We conducted a cross-sectional international anonymous survey among a convenience sample of critical care, pulmonary, emergency and internal medicine physicians from Brazil between October and December 2008. The electronic survey evaluated physicians' attitudes towards the diagnosis, risk assessment and therapeutic interventions for patients with severe community-acquired pneumonia. RESULTS: A total of 253 physicians responded to the survey, with 66% from Southeast Brazil. The majority (60%) of the responding physicians had > 10 years of medical experience. The risk assessment of severe community-acquired pneumonia was very heterogeneous, with clinical evaluation as the most frequent approach. Although blood cultures were recognized as exhibiting a poor diagnostic performance, these cultures were performed by 75% of respondents. In contrast, the presence of urinary pneumococcal and Legionella antigens was evaluated by less than 1/3 of physicians. The vast majority of physicians (95%) prescribe antibiotics according to a guideline, with the combination of a 3rd/4th generation cephalosporin plus a macrolide as the most frequent choice. CONCLUSION: This Brazilian survey identified an important gap between guidelines and clinical practice and recommends the institution of educational programs that implement evidence-based strategies for the management of severe community-acquired pneumonia. PMID- 25909315 TI - Swallowing rehabilitation of dysphagic tracheostomized patients under mechanical ventilation in intensive care units: a feasibility study. AB - OBJECTIVE: The aim of the present study was to assess the feasibility of the early implementation of a swallowing rehabilitation program in tracheostomized patients under mechanical ventilation with dysphagia. METHODS: This prospective study was conducted in the intensive care units of a university hospital. We included hemodynamically stable patients under mechanical ventilation for at least 48 hours following 48 hours of tracheostomy and with an appropriate level of consciousness. The exclusion criteria were previous surgery in the oral cavity, pharynx, larynx and/or esophagus, the presence of degenerative diseases or a past history of oropharyngeal dysphagia. All patients were submitted to a swallowing rehabilitation program. An oropharyngeal structural score, a swallowing functional score and an otorhinolaryngological structural and functional score were determined before and after swallowing therapy. RESULTS: We included 14 patients. The mean duration of the rehabilitation program was 12.4 +/ 9.4 days, with 5.0 +/- 5.2 days under mechanical ventilation. Eleven patients could receive oral feeding while still in the intensive care unit after 4 (2 - 13) days of therapy. All scores significantly improved after therapy. CONCLUSION: In this small group of patients, we demonstrated that the early implementation of a swallowing rehabilitation program is feasible even in patients under mechanical ventilation. PMID- 25909316 TI - Therapeutic hypothermia as a bridge to transplantation in patients with fulminant hepatic failure. AB - The most important topics in fulminant hepatic failure are cerebral edema and intracranial hypertension. Among all therapeutic options, systemic induced hypothermia to 33 - 34oC has been reported to reduce the high pressure and increase the time during which patients can tolerate a graft. This review discusses the indications and adverse effects of hypothermia. PMID- 25909317 TI - Recurrent rhabdomyolysis secondary to hyponatremia in a patient with primary psychogenic polydipsia. AB - Rhabdomyolysis is characterized by the destruction of skeletal muscle tissue, and its main causes are trauma, toxic substances and electrolyte disturbances. Among the latter is hyponatremia-induced rhabdomyolysis, a rare condition that occurs mainly in patients with psychogenic polydipsia. Psycogenic polydipsia mostly affects patients with schizophrenia, coursing with hyponatremia in almost 25% of the cases. It is also in this context that rhabdomyolysis secondary to hyponatremia occurs most often. In this article, the case of a 49-year-old male with a history of schizophrenia, medicated with clozapine, and brought to the emergency room in a state of coma and seizures is described. Severe hypoosmolar hyponatremia with cerebral edema was found on a computed tomography examination, and a subsequent diagnosis of hyponatremia secondary to psychogenic polydipsia was made. Hyponatremia correction therapy was started, and the patient was admitted to the intensive care unit. After the hyponatremia correction, the patient presented with analytical worsening, showing marked rhabdomyolysis with a creatine phosphokinase level of 44.058 UI/L on day 3 of hospitalization. The condition showed a subsequent progressive improvement with therapy, with no occurrence of kidney damage. This case stresses the need for monitoring rhabdomyolysis markers in severe hyponatremia, illustrating the condition of rhabdomyolysis secondary to hyponatremia induced by psychogenic polydipsia, which should be considered in patients undergoing treatment with neuroleptics. PMID- 25909318 TI - To: Fulminant myocarditis associated with the H1N1 influenza virus: case report and literature review. PMID- 25909319 TI - Authors' response. PMID- 25909320 TI - Randomized controlled trial of a mobile phone intervention for improving adherence to naltrexone for alcohol use disorders. AB - BACKGROUND: Naltrexone is a front-line treatment for alcohol use disorders, but its efficacy is limited by poor medication adherence. This randomized controlled trial evaluated whether a mobile health intervention could improve naltrexone adherence. METHODS: Treatment-seeking participants with an alcohol use disorder (N = 76) were randomized to intervention and control conditions. All participants received naltrexone (50 mg/day) with a medication event monitoring system (MEMS) and a prepaid smartphone, and received a daily text message querying medication side effects, alcohol use, and craving. Those in the intervention arm received additional medication reminders and adherence assessment via text message. RESULTS: The primary outcome, proportion of participants with adequate adherence (defined as >=80% of prescribed doses taken through Week 8), did not differ between groups in intent-to-treat analyses (p = .34). Mean adherence at study midpoint (Week 4) was 83% in the intervention condition and 77% in the control condition (p = .35). Survival analysis found that the intervention group sustained adequate adherence significantly longer (M = 19 days [95% CI = 0.0 44.0]) than those in the control group (M = 3 days [95% CI = 0.0-8.1]) during the first month of treatment (p = .04). Medication adherence did not predict drinking outcomes. CONCLUSIONS: These results suggest that in the context of daily monitoring and assessment via cell phone, additional text message reminders do not further improve medication adherence. Although this initial trial does not provide support for the efficacy of text messaging to improve adherence to pharmacotherapy for alcohol use disorders, additional trials with larger samples and alternate designs are warranted. TRIAL REGISTRATION: ClinicalTrials.gov: NCT01349985. PMID- 25909321 TI - Exploring risk and protective factors with a community sample of American Indian adolescents who attempted suicide. AB - American Indian adolescents are at disproportionate risk for suicide, and community-based studies of this population, which allow a deeper understanding of risks and resilience to inform interventions, are rare. This is a cross-sectional study of N = 71 Apache adolescents. Strengths include the role of the community and American Indian paraprofessionals in the design, implementation, and interpretation of findings. Participants were M = 16.0 years old, 65% female, and 69% multiple attempters. Risks included suicidal behavior among peers and family (68%), caregivers with substance problems (62%), and participant substance use history, namely alcohol (91%) and marijuana (88%). Areas of resiliency included lower depression scores (M = 23.1) and cultural activity participation. A multi tiered intervention at individual, family, and community levels is needed. PMID- 25909322 TI - Classification of circulating tumor cells by epithelial-mesenchymal transition markers. AB - In cancer, epithelial-mesenchymal transition (EMT) is associated with metastasis. Characterizing EMT phenotypes in circulating tumor cells (CTCs) has been challenging because epithelial marker-based methods have typically been used for the isolation and detection of CTCs from blood samples. The aim of this study was to use the optimized CanPatrol CTC enrichment technique to classify CTCs using EMT markers in different types of cancers. The first step of this technique was to isolate CTCs via a filter-based method; then, an RNA in situ hybridization (RNA-ISH) method based on the branched DNA signal amplification technology was used to classify the CTCs according to EMT markers. Our results indicated that the efficiency of tumor cell recovery with this technique was at least 80%. When compared with the non-optimized method, the new method was more sensitive and more CTCs were detected in the 5-ml blood samples. To further validate the new method, 164 blood samples from patients with liver, nasopharyngeal, breast, colon, gastric cancer, or non-small-cell lung cancer (NSCLC) were collected for CTC isolation and characterization. CTCs were detected in 107 (65%) of 164 blood samples, and three CTC subpopulations were identified using EMT markers, including epithelial CTCs, biophenotypic epithelial/mesenchymal CTCs, and mesenchymal CTCs. Compared with the earlier stages of cancer, mesenchymal CTCs were more commonly found in patients in the metastatic stages of the disease in different types of cancers. Circulating tumor microemboli (CTM) with a mesenchymal phenotype were also detected in the metastatic stages of cancer. Classifying CTCs by EMT markers helps to identify the more aggressive CTC subpopulation and provides useful evidence for determining an appropriate clinical approach. This method is suitable for a broad range of carcinomas. PMID- 25909323 TI - Evaluating interactions of forest conservation policies on avoided deforestation. AB - We estimate the effects on deforestation that have resulted from policy interactions between parks and payments and between park buffers and payments in Costa Rica between 2000 and 2005. We show that the characteristics of the areas where protected and unprotected lands are located differ significantly. Additionally, we find that land characteristics of each of the policies and of the places where they interact also differ significantly. To adequately estimate the effects of the policies and their interactions, we use matching methods. Matching is implemented not only to define adequate control groups, as in previous research, but also to define those groups of locations under the influence of policies that are comparable to each other. We find that it is more effective to locate parks and payments away from each other, rather than in the same location or near each other. The high levels of enforcement inside both parks and lands with payments, and the presence of conservation spillovers that reduce deforestation near parks, significantly reduce the potential impact of combining these two policies. PMID- 25909325 TI - Metabarcoding of benthic eukaryote communities predicts the ecological condition of estuaries. AB - DNA-derived measurements of biological composition have the potential to produce data covering all of life, and provide a tantalizing proposition for researchers and managers. We used metabarcoding to compare benthic eukaryote composition from five estuaries of varying condition. In contrast to traditional studies, we found biotic richness was greatest in the most disturbed estuary, with this being due to the large volume of extraneous material (i.e. run-off from aquaculture, agriculture and other catchment activities) being deposited in the system. In addition, we found strong correlations between composition and a number of environmental variables, including nutrients, pH and turbidity. A wide range of taxa responded to these environmental gradients, providing new insights into their sensitivities to natural and anthropogenic stressors. Metabarcoding has the capacity to bolster current monitoring techniques, enabling the decisions regarding ecological condition to be based on a more holistic view of biodiversity. PMID- 25909324 TI - MicroRNA let-7c Inhibits Cell Proliferation and Induces Cell Cycle Arrest by Targeting CDC25A in Human Hepatocellular Carcinoma. AB - Down-regulation of the microRNA let-7c plays an important role in the pathogenesis of human hepatocellular carcinoma (HCC). The aim of the present study was to determine whether the cell cycle regulator CDC25A is involved in the antitumor effect of let-7c in HCC. The expression levels of let-7c in HCC cell lines were examined by quantitative real-time PCR, and a let-7c agomir was transfected into HCC cells to overexpress let-7c. The effects of let-7c on HCC proliferation, apoptosis and cell cycle were analyzed. The in vivo tumor inhibitory efficacy of let-7c was evaluated in a xenograft mouse model of HCC. Luciferase reporter assays and western blotting were conducted to identify the targets of let-7c and to determine the effects of let-7c on CDC25A, CyclinD1, CDK6, pRb and E2F2 expression. The results showed that the expression levels of let-7c were significantly decreased in HCC cell lines. Overexpression of let-7c repressed cell growth, induced cell apoptosis, led to G1 cell cycle arrest in vitro, and suppressed tumor growth in a HepG2 xenograft model in vivo. The luciferase reporter assay showed that CDC25A was a direct target of let-7c, and that let-7c inhibited the expression of CDC25A protein by directly targeting its 3' UTR. Restoration of CDC25A induced a let-7c-mediated G1-to-S phase transition. Western blot analysis demonstrated that overexpression of let-7c decreased CyclinD1, CDK6, pRb and E2F2 protein levels. In conclusion, this study indicates that let-7c suppresses HCC progression, possibly by directly targeting the cell cycle regulator CDC25A and indirectly affecting its downstream target molecules. Let-7c may therefore be an effective therapeutic target for HCC. PMID- 25909326 TI - Induction of c-Jun by air particulate matter (PM10) of Mexico city: Participation of polycyclic aromatic hydrocarbons. AB - The carcinogenic potential of urban particulate matter (PM) has been partly attributed to polycyclic aromatic hydrocarbons (PAHs) content, which activates the aryl hydrocarbon receptor (AhR). Here we report the effect of PM with an aerodynamic size of 10 MUm (PM10) on the induction of AhR pathway in A549 cells, evaluating its downstream targets CYP1B1, IL-6, IL-8 and c-Jun. Significant increases in CYP1B1 protein and enzyme activity; IL-6 and IL-8 secretion and c Jun protein were found in response to PM10. The formation of PAH-DNA adducts was also detected. The involvement of AhR pathway was confirmed with Resveratrol as AhR antagonist, which reversed CYP1B1 and c-Jun induction. Nevertheless, in IL-6 and IL-8 secretion, the Resveratrol was ineffective, suggesting an effect independent of this pathway. Considering the role of c-Jun in oncogenesis, its induction by PM may be contributing to its carcinogenic potential through induction of AhR pathway by PAHs present in PM10. PMID- 25909327 TI - The unrecognized effects of phosphodiesterase 4 on epithelial cells in pulmonary inflammation. AB - Acute pulmonary inflammation is characterized by migration of polymorphonuclear neutrophils (PMNs) into the different compartments of the lung, passing an endothelial and epithelial barrier. Recent studies showed evidence that phosphodiesterase (PDE)4-inhibitors stabilized endothelial cells. PDE4B and PDE4D subtypes play a pivotal role in inflammation, whereas blocking PDE4D is suspected to cause gastrointestinal side effects. We thought to investigate the particular role of the PDE4-inhibitors roflumilast and rolipram on lung epithelium. Acute pulmonary inflammation was induced by inhalation of LPS. PDE4-inhibitors were administered i.p. or nebulized after inflammation. The impact of PDE4-inhibitors on PMN migration was evaluated in vivo and in vitro. Microvascular permeability, cytokine levels, and PDE4B and PDE4D expression were analyzed. In vivo, both PDE4 inhibitors decreased transendothelial and transepithelial migration even when administered after inflammation, whereas roflumilast showed a superior effect compared to rolipram on the epithelium. Both inhibitors decreased TNFalpha, IL6, and CXCL2/3. CXCL1, the strong PMN chemoattractant secreted by the epithelium, was significantly more reduced by roflumilast. In vitro assays with human epithelium also emphasized the pivotal role of roflumilast on the epithelium. Additionally, LPS-induced stress fibers, an essential requirement for a direct migration of PMNs into the alveolar space, were predominantly reduced by roflumilast. Expression of PDE4B and PDE4D were both increased in the lungs by LPS, PDE4-inhibitors decreased mainly PDE4B. The topical administration of PDE4 inhibitors was also effective in curbing down PMN migration, further highlighting the clinical potential of these compounds. In pulmonary epithelial cells, both subtypes were found coexistent around the nucleus and the cytoplasm. In these epithelial cells, LPS increased PDE4B and, to a lesser extend, PDE4D, whereas the effect of the inhibitors was prominent on the PDE4B subtype. In conclusion, we determined the pivotal role of the PDE4-inhibitor roflumilast on lung epithelium and emphasized its main effect on PDE4B in hyperinflammation. PMID- 25909328 TI - Quantifying spike train oscillations: biases, distortions and solutions. AB - Estimation of the power spectrum is a common method for identifying oscillatory changes in neuronal activity. However, the stochastic nature of neuronal activity leads to severe biases in the estimation of these oscillations in single unit spike trains. Different biological and experimental factors cause the spike train to differentially reflect its underlying oscillatory rate function. We analyzed the effect of factors, such as the mean firing rate and the recording duration, on the detectability of oscillations and their significance, and tested these theoretical results on experimental data recorded in Parkinsonian non-human primates. The effect of these factors is dramatic, such that in some conditions, the detection of existing oscillations is impossible. Moreover, these biases impede the comparison of oscillations across brain regions, neuronal types, behavioral states and separate recordings with different underlying parameters, and lead inevitably to a gross misinterpretation of experimental results. We introduce a novel objective measure, the "modulation index", which overcomes these biases, and enables reliable detection of oscillations from spike trains and a direct estimation of the oscillation magnitude. The modulation index detects a high percentage of oscillations over a wide range of parameters, compared to classical spectral analysis methods, and enables an unbiased comparison between spike trains recorded from different neurons and using different experimental protocols. PMID- 25909329 TI - Analysis of conformational motions and related key residue interactions responsible for a specific function of proteins with elastic network model. AB - Protein collective motions play a critical role in many biochemical processes. How to predict the functional motions and the related key residue interactions in proteins is important for our understanding in the mechanism of the biochemical processes. Normal mode analysis (NMA) of the elastic network model (ENM) is one of the effective approaches to investigate the structure-encoded motions in proteins. However, the motion modes revealed by the conventional NMA approach do not necessarily correspond to a specific function of protein. In the present work, a new analysis method was proposed to identify the motion modes responsible for a specific function of proteins and then predict the key residue interactions involved in the functional motions by using a perturbation approach. In our method, an internal coordinate that accounts for the specific function was introduced, and the Cartesian coordinate space was transformed into the internal/Cartesian space by using linear approximation, where the introduced internal coordinate serves as one of the axes of the coordinate space. NMA of ENM in this internal/Cartesian space was performed and the function-relevant motion modes were identified according to their contributions to the specific function of proteins. Then the key residue interactions important for the functional motions of the protein were predicted as the interactions whose perturbation largely influences the fluctuation along the internal coordinate. Using our proposed methods, the maltose transporter (MalFGK2) from E. Coli was studied. The functional motions and the key residue interactions that are related to the channel-gating function of this protein were successfully identified. PMID- 25909330 TI - "They know, they agree, but they don't do"--the paradox of tuberculosis case notification by private practitioners in Alappuzha district, Kerala, India. AB - BACKGROUND: Despite being a recognized standard of tuberculosis (TB) care internationally, mandatory TB case notification brings forth challenges from the private sector. Only three TB cases were notified in 2013 by private practitioners compared to 2000 TB cases notified yearly from the public sector in Alappuzha district. The study objective was to explore the knowledge, opinion and barriers regarding TB Notification among private practitioners offering TB services in Alappuzha, Kerala state, India. METHODS & FINDINGS: This was a mixed methods study with quantitative (survey) and qualitative components conducted between December 2013 and July 2014. The survey, using a structured questionnaire, among 169 private practitioners revealed that 88% were aware of mandatory notification. All patient-related details requested in the notification form (except government-issued identification number) were perceived to be important and easy to provide by more than 80% of practitioners. While more than 95% felt that notification should be mandatory, punitive action in case of failure to notify was considered unnecessary by almost two third. General practitioners (98%) were more likely to be aware of notification than specialists (84 %). (P<0.01). Qualitative purposive personal interviews (n=34) were carried out among private practitioners and public health providers. On thematic framework analysis of the responses, barriers to TB notification were grouped into three themes: 'private provider misconceptions about notification', 'patient confidentiality, and stigma and discrimination 'and 'lack of cohesion and coordination between public and private sector'. Private practitioners did not consider it necessary to notify TB cases treated with daily regimen. CONCLUSION: Communication strategies like training, timely dissemination of information of policy changes and one-to-one dialogue with private practitioners to dispel misconceptions may enhance TB notification. Trust building strategies like providing feedback about referred cases from private sector, health personnel visit or a liaison private doctor may ensure compliance to public health activities. PMID- 25909332 TI - Correction: Retinal Vessel Segmentation: an Efficient Graph Cut Approach with Retinex and Local Phase. PMID- 25909331 TI - Alternative Protein Secretion in the Malaria Parasite Plasmodium falciparum. AB - Plasmodium falciparum invades human red blood cells, residing in a parasitophorous vacuole (PV), with a parasitophorous vacuole membrane (PVM) separating the PV from the host cell cytoplasm. Here we have investigated the role of N-myristoylation and two other N-terminal motifs, a cysteine potential S palmitoylation site and a stretch of basic residues, as the driving force for protein targeting to the parasite plasma membrane (PPM) and subsequent translocation across this membrane. Plasmodium falciparum adenylate kinase 2 (Pf AK2) contains these three motifs, and was previously proposed to be targeted beyond the parasite to the PVM, despite the absence of a signal peptide for entry into the classical secretory pathway. Biochemical and microscopy analyses of PfAK2 variants tagged with green fluorescent protein (GFP) showed that these three motifs are involved in targeting the protein to the PPM and translocation across the PPM to the PV. It was shown that the N-terminal 37 amino acids of PfAK2 alone are sufficient to target and translocate GFP across the PPM. As a control we examined the N-myristoylated P. falciparum ADP-ribosylation factor 1 (PfARF1). PfARF1 was found to co-localise with a Golgi marker. To determine whether or not the putative palmitoylation and the cluster of lysine residues from the N-terminus of PfAK2 would modulate the subcellular localization of PfARF1, a chimeric fusion protein containing the N-terminus of PfARF1 and the two additional PfAK2 motifs was analysed. This chimeric protein was targeted to the PPM, but not translocated across the membrane into the PV, indicating that other features of the N-terminus of PfAK2 also play a role in the secretion process. PMID- 25909333 TI - Adjustable Gastric Band Surgery or Medical Management in Patients With Type 2 Diabetes: A Randomized Clinical Trial. AB - CONTEXT: Recommendations for surgical, compared with lifestyle and pharmacologically based, approaches for type 2 diabetes (T2D) management remain controversial. OBJECTIVE: The objective was to compare laparoscopic adjustable gastric band (LAGB) to an intensive medical diabetes and weight management (IMWM) program for T2D. DESIGN: This was designed as a prospective, randomized clinical trial. SETTING: The setting was two Harvard Medical School-affiliated academic institutions. INTERVENTIONS AND PARTICIPANTS: A 12-month randomized trial comparing LAGB (n = 23) vs IMWM (n = 22) in persons aged 21-65 years with body mass index of 30-45 kg/m(2), T2D diagnosed more than 1 year earlier, and glycated hemoglobin (HbA(1c)) >= 6.5% on antihyperglycemic medication(s). MAIN OUTCOME MEASURE: The proportion meeting the prespecified primary glycemic endpoint, defined as HbA(1c) < 6.5% and fasting glucose < 7.0 mmol/L at 12 months, on or off medication. RESULTS: After randomization, five participants did not undergo the surgical intervention. Of the 40 initiating intervention (22 males/18 females; age, 51 +/- 10 y; body mass index, 36.5 +/- 3.7 kg/m(2); diabetes duration, 9 +/- 5 y; HbA(1c), 8.2 +/- 1.2%; 40% on insulin), the proportion meeting the primary glycemic endpoint was achieved in 33% of the LAGB patients and 23% of the IMWM patients (P = .457). HbA(1c) reduction was similar between groups at both 3 and 12 months (-1.2 +/- 0.3 vs -1.0 +/- 0.3%; P = .496). Weight loss was similar at 3 months but greater 12 months after LAGB (-13.5 +/- 1.7 vs 8.5 +/- 1.6 kg; P = .027). Systolic blood pressure reduction was greater after IMWM than LAGB, whereas changes in diastolic blood pressure, lipids, fitness, and cardiovascular risk scores were similar between groups. Patient-reported health status, assessed using the Short Form-36, Impact of Weight on Quality of Life, and Problem Areas in Diabetes, all improved similarly between groups. CONCLUSIONS: LAGB and a multidisciplinary IMWM program have similar 1-year benefits on diabetes control, cardiometabolic risk, and patient satisfaction, which should be considered in the context of other factors, such as personal preference, when selecting treatment options with obese T2D patients. Longer duration studies are important to understand emergent differences. PMID- 25909334 TI - Efficacy of Leukadherin-1 in the Prevention of Hyperoxia-Induced Lung Injury in Neonatal Rats. AB - Lung inflammation plays a key role in the pathogenesis of bronchopulmonary dysplasia (BPD), a chronic lung disease of premature infants. The challenge in BPD management is the lack of effective and safe antiinflammatory agents. Leukadherin-1 (LA1) is a novel agonist of the leukocyte surface integrin CD11b/CD18 that enhances leukocyte adhesion to ligands and vascular endothelium and thus reduces leukocyte transendothelial migration and influx to the injury sites. Its functional significance in preventing hyperoxia-induced neonatal lung injury is unknown. We tested the hypothesis that administration of LA1 is beneficial in preventing hyperoxia-induced neonatal lung injury, an experimental model of BPD. Newborn rats were exposed to normoxia (21% O2) or hyperoxia (85% O2) and received twice-daily intraperitoneal injection of LA1 or placebo for 14 days. Hyperoxia exposure in the presence of the placebo resulted in a drastic increase in the influx of neutrophils and macrophages into the alveolar airspaces. This increased leukocyte influx was accompanied by decreased alveolarization and angiogenesis and increased pulmonary vascular remodeling and pulmonary hypertension (PH), the pathological hallmarks of BPD. However, administration of LA1 decreased macrophage infiltration in the lungs during hyperoxia. Furthermore, treatment with LA1 improved alveolarization and angiogenesis and decreased pulmonary vascular remodeling and PH. These data indicate that leukocyte recruitment plays an important role in the experimental model of BPD induced by hyperoxia. Targeting leukocyte trafficking using LA1, an integrin agonist, is beneficial in preventing lung inflammation and protecting alveolar and vascular structures during hyperoxia. Thus, targeting integrin mediated leukocyte recruitment and inflammation may provide a novel strategy in preventing and treating BPD in preterm infants. PMID- 25909335 TI - Flexible and waterproof micro-sensors to uncover zebrafish circadian rhythms: The next generation of cardiac monitoring for drug screening. AB - Flexible electronics are the next generation of sensors for mobile health and implantation. Zebrafish (Danio rerio) is an emergent strategy for pre-clinical drug development and toxicity testing. To address the confounding effects from sedation of fish and removal from the aquatic habitat for micro-electrocardiogram (uECG) measurements, we developed waterproof and wearable sensors to uncover the circadian variation in heart rate (HR) and heart rate variability (HRV) (Massin et al., 2000). The parylene-C based ECG sensor consisted of an ultra-soft silicone integrated jacket designed to wrap around the fish during swimming. The Young's modulus of this silicone jacket matched with the fish surface, and an extended parylene cable connected the underwater chest electrodes with the out-of water electronics. In addition, embedded micro-glass spheres in the silicone effectively reduced the effective density of the jacket to ~1 g cm(-3). These innovations enabled physiological ECG telemetry in the fish's natural habitat without the need for sedation. Furthermore, a set of non-linear signal processing techniques filtered out the breathing and electromagnetic artifacts from the recorded signals. We observed a reduction in mean HR and an increase in HRV over 24h at 10 dpa, accompanied by QT prolongation as well as diurnal variations, followed by normalization in mean HR and QT intervals at 26 days post ventricular amputation (dpa). We revealed Amiodarone-mediated QTc prolongation, HR reduction and HRV increase otherwise masked by sedation. The novel features of the flexible silicon jacket for uECG telemetry unraveled the biological clock and normalization of QT intervals at 26 dpa, providing the first evidence of new physiological phenomena during cardiac injury and repair as well as cardiac drug mediated aberrant rhythms. Thus, the light weight and waterproof design holds promise to advance the next generation of mobile health and drug discovery. PMID- 25909336 TI - Novel electrochemical dual-aptamer-based sandwich biosensor using molybdenum disulfide/carbon aerogel composites and Au nanoparticles for signal amplification. AB - A new electrochemical aptamer biosensor for the platelet-derived growth factor BB (PDGF-BB) detection has been developed based on the signal amplification of MoS2/carbon aerogel composites (MoS2/CA) and sandwich assay. A facile hydrothermal route assisted by L-cysteine was applied to synthesize CA incorporated flower-like MoS2 with the large surface active sites and good conductivity. The electrochemical aptasensor was constructed by sandwiching the PDGF-BB between a glassy carbon electrode modified with thiol-terminated PDGF-BB aptamer-1 (Apt1)/gold nanoparticles (AuNPs)/MoS2/CA and the AuNPs with thiol terminated PDGF-BB aptamer-2 (Apt2) and 6-ferrocenyl hexanethiol (Fc). Fc-AuNPs Apt2 acted as tracer and AuNPs/MoS2/CA were utilized as the biosensor platform to immobilize a large amount of capture aptamers, owing to their layered structure and high surface-to-volume ratio. Based on the sandwich format, a dual signal amplification strategy had been successfully developed with a wide linear response in the range of 0.001-10nM and a limit of detection of 0.3 pM. The developed assay demonstrated good selectivity and high sensitivity, indicating potential applications in bioanalysis and biomedicine. PMID- 25909337 TI - Bioelectronic nose combined with a microfluidic system for the detection of gaseous trimethylamine. AB - A bioelectronic nose based on a novel microfluidic system (MUBN) was fabricated to detect gaseous trimethylamine (TMA) in real-time. Single-walled carbon nanotube-field effect transistors (SWNT-FETs) were functionalized with olfactory receptor-derived peptides (ORPs) that can recognize the TMA molecules. The ORP coated SWNT-FETs were assembled with a microfluidic channel and were sealed with top and bottom frames. This simple process was used to complete the MUBNs, and a well-defined condition was achieved to detect the gaseous molecules. The MUBNs allowed us to detect gaseous TMA molecules down to 10 parts per trillion (ppt) in real-time and showed high selectivity when distinguishing gaseous TMA from other gaseous odorants. The sensor was used to determine the quality of seafood (oysters), and spoiled seafood and other types of spoiled foods were also successfully discriminated without any pretreatment processes. These results indicate that portable-scale platforms can be manufactured by using MUBNs and can be applicable for real-time on-site gas analysis. PMID- 25909338 TI - Ultrasensitive detection and rapid identification of multiple foodborne pathogens with the naked eyes. AB - In this study, a novel approach for ultrasensitive detection and rapid high throughput identification of a panel of common foodborne pathogens with the naked eyes is presented. As a proof-of-concept application, a multiple pathogen analysis array is fabricated through immobilizing three specific polyT-capture probes which can respectively recognize rfbE gene (Escherichia coli O157:H7), invA gene (Salmonella enterica), inlA gene (Listeria monocytogenes) on the plastic substrates. PCR has been developed for amplification and labeling target genes of rfbE, invA, inlA with biotin. The biotinated target DNA is then captured onto the surface of plastic strips through specific DNA hybridization. The succeeding staining of biotinated DNA duplexes with avidin-horseradish peroxidise (AV-HRP) and biotinated anti-HRP antibody greatly amplifies the detectable signal through the multiple cycle signal amplification strategy, and thus realizing ultrasensitive and specific detection of the above three pathogens in food samples with the naked eyes. Results showed approximately 5 copies target pathogenic DNA could be detected with the naked eyes. This simple but very efficient colorimetric assay also show excellent anti-interference capability and good stability, and can be readily applied to point-of-care diagnosis. PMID- 25909339 TI - A facile and sensitive electrochemiluminescence biosensor for Hg2+ analysis based on a dual-function oligonucleotide probe. AB - In this study, a sensitive electrochemiluminescent (ECL) biosensor for the detection of Hg(2+) was easily prepared by self-assembling mercury-specific oligonucleotide on the surface of gold nanoparticles (AuNPs) modified indium tin oxide (ITO) electrode. A conformation change of the oligonucleotide from linear chain to hairpin occurs upon the binding of Hg(2+) through thymine-Hg(2+)-thymine coordination. The dual-function oligonucleotide serves as the probe to Hg(2+) but also a carrier of signal-generating molecules, [Ru(bpy)2(dppz)](BF4)2. It was estimated that one oligonucleotide was able to load with eight ECL signal molecules; a ratio of four or five oligonucleotides per gold nanoparticle was obtained basing on the calculation with surface density. Without tedious multiple labeling procedures and special modification of oligonucleotide probe for signal transduction/amplification, a detection limit of 5.1 pM Hg(2+) was outstanding from the interference of other ten metal ions. Results of spiked water samples were in good agreement with that obtained by atomic fluorescent spectrometry. PMID- 25909340 TI - Hollow PDA-Au nanoparticles-enabled signal amplification for sensitive nonenzymatic colorimetric immunodetection of carbohydrate antigen 125. AB - A novel colorimetric immunoassay was designed for the sensitive detection of carbohydrate antigen 125 (CA125). The success of this immunoassay relies on the use of hollow polydopamine-gold nanoparticles (PDA-Au) for signal amplification to achieve sensitive nonenzymatic colorimetric detection. In particular, PDA-Au was used as a stable and sensitive label and aminated-Fe3O4 magnetic nanoparticles (Fe3O4 NPs) were employed to immobilize capture antibody (Ab1) and acted as a separable immunosensing probe. PDA-Au exhibited high catalytic performance towards p-nitrophenol reduction and thus resulted in significant color change and UV/vis signal variations. The immunoassay was performed based on sandwich protocol. As compared to pure Au nanoparticles, the signal amplification and sensitivity of PDA-Au-based assay was significantly improved. For instance, the dynamic range of the developed colorimetric immunoassay for CA125 was 0.1-100 U/mL with a detection limit of 0.1 U/mL at S/N=3. In addition, this immunoassay was also tested for the analysis of clinical serum samples, which demonstrated its potential for practical diagnostic applications. PMID- 25909341 TI - Increased mortality after upper extremity fracture requiring inpatient care. AB - BACKGROUND AND PURPOSE: Increased mortality after hip fracture is well documented. The mortality after hospitalization for upper extremity fracture is unknown, even though these are common injuries. Here we determined mortality after hospitalization for upper extremity fracture in patients aged >=16 years. PATIENTS AND METHODS: We collected data about the diagnosis code (ICD10), procedure code (NOMESCO), and 7 additional characteristics of 5,985 patients admitted to the trauma ward of Central Finland Hospital between 2002 and 2008. During the study, 929 women and 753 men sustained an upper extremity fracture. The patients were followed up until the end of 2012. Mortality rates were calculated using data on the population at risk. RESULTS: By the end of follow-up (mean duration 6 years), 179 women (19%) and 105 men (14%) had died. The standardized mortality ratio (SMR) for all patients was 1.5 (95% CI: 1.4-1.7). The SMR was higher for men (2.1, CI: 1.7-2.5) than for women (1.3, CI: 1.1-1.5) (p < 0.001). The SMR decreased with advancing age, and the mortality rate was highest for men with humerus fractures. INTERPRETATION: In men, the risk of death related to proximal humerus fracture was even higher than that reported previously for hip fracture. Compared to the general population, the SMR was double for humerus fracture patients, whereas wrist fracture had no effect on mortality. PMID- 25909342 TI - Blood, sweat, and tears: developing clinically relevant protein biosensors for integrated body fluid analysis. AB - Biosensors are being developed to provide rapid, quantitative, diagnostic information to clinicians in order to help guide patient treatment, without the need for centralised laboratory assays. The success of glucose monitoring is a key example of where technology innovation has met a clinical need at multiple levels - from the pathology laboratory all the way to the patient's home. However, few other biosensor devices are currently in routine use. Here we review the challenges and opportunities regarding the integration of biosensor techniques into body fluid sampling approaches, with emphasis on the point-of care setting. PMID- 25909343 TI - Standardization and quality control in quantifying non-enzymatic oxidative protein modifications in relation to ageing and disease: Why is it important and why is it hard? AB - Post-translational modifications (PTM) of proteins determine the activity, stability, specificity, transportability and lifespan of a protein. Some PTM are highly specific and regulated involving various enzymatic pathways, but there are other non-enzymatic PTM (nePTM), which occur stochastically, depend on the ternary structure of proteins and can be damaging. It is often observed that inactive and abnormal proteins accumulate in old cells and tissues. The nature, site and extent of nePTM give rise to a population of that specific protein with alterations in structure and function ranging from being fully active to totally inactive molecules. Determination of the type and the amount (abundance) of nePTM is essential for establishing connection between specific protein structure and specific biological role. This article summarizes analytical demands for reliable quantification of nePTM, including requirements for the assay performance, standardization and quality control, and points to the difficulties, uncertainties and un-resolved issues. PMID- 25909344 TI - Tributyltin induces mitochondrial fission through NAD-IDH dependent mitofusin degradation in human embryonic carcinoma cells. AB - Organotin compounds, such as tributyltin (TBT), are well-known endocrine disruptors. TBT acts at the nanomolar level through genomic pathways via the peroxisome proliferator activated receptor (PPAR)/retinoid X receptor (RXR). We recently reported that TBT inhibits cell growth and the ATP content in the human embryonic carcinoma cell line NT2/D1 via a non-genomic pathway involving NAD(+) dependent isocitrate dehydrogenase (NAD-IDH), which metabolizes isocitrate to alpha-ketoglutarate. However, the molecular mechanisms by which NAD-IDH mediates TBT toxicity remain unclear. In the present study, we evaluated the effects of TBT on mitochondrial NAD-IDH and energy production. Staining with MitoTracker revealed that nanomolar TBT levels induced mitochondrial fragmentation. TBT also degraded the mitochondrial fusion proteins, mitofusins 1 and 2. Interestingly, apigenin, an inhibitor of NAD-IDH, mimicked the effects of TBT. Incubation with an alpha-ketoglutarate analogue partially recovered TBT-induced mitochondrial dysfunction, supporting the involvement of NAD-IDH. Our data suggest that nanomolar TBT levels impair mitochondrial quality control via NAD-IDH in NT2/D1 cells. Thus, mitochondrial function in embryonic cells could be used to assess cytotoxicity associated with metal exposure. PMID- 25909345 TI - Ddx1 knockout results in transgenerational wild-type lethality in mice. AB - DEAD box 1 (DDX1) is a member of the DEAD box family of RNA helicases which are involved in all aspects of RNA metabolism. DDX1 has been implicated in a variety of biological processes, including 3'-end processing of mRNA, DNA repair, microRNA processing, tRNA maturation and mRNA transport. To study the role of DDX1 during development, we have generated mice carrying a constitutive Ddx1 knock-out allele. Ddx1(+/-) mice have no obvious phenotype and express similar levels of DDX1 as wild-type mice indicating compensation from the intact Ddx1 allele. Heterozygote matings produce no viable Ddx1(-/-) progeny, with Ddx1(-/-) embryos dying prior to embryonic day (E) 3.5. Intriguingly, the number of wild type progeny is significantly decreased in heterozygote crosses, with two different heterozygote populations identified based on parental genotype: (i) normal Ddx1(+/-) mice which generate the expected number of wild-type progeny and (ii) Ddx1*(/-) mice (with * signifying a non-genetically altered allele) which generate a significantly reduced number of wild-type mice. The transgenerational inheritance of wild-type lethality observed upon crossing Ddx1*(/-) mice is independent of parental sex and occurs in cis through a mechanism that is different from other types of previously reported transgenerational epigenetic inheritance. PMID- 25909346 TI - Dew harvesting efficiency of four species of cacti. AB - Four species of cacti were chosen for this study: Copiapoa cinerea var. haseltoniana, Ferocactus wislizenii, Mammillaria columbiana subsp. yucatanensis and Parodia mammulosa. It has been reported that dew condenses on the spines of C. cinerea and that it does not on the spines of F. wislizenii, and our preliminary observations of M. columbiana and P. mammulosa revealed a potential for collecting dew water. This study found all four cacti to harvest dew on their stems and spines (albeit rarely on the spines of F. wislizenii). Dew harvesting experiments were carried out in the UK, recording an increase in cacti mass on dewy nights. By applying a ranking relative to a polymethyl methacrylate (Plexiglas) reference plate located nearby, it was found that C. cinerea collected the most airborne moisture followed by M. columbiana, P. mammulosa and F. wislizenii respectively, with mean efficiency ratio with respect to the Plexiglas reference of 3.48 +/- 0.5, 2.44 +/- 0.06, 1.81 +/- 0.14 and 1.27 +/- 0.49 on observed dewy nights. A maximum yield of normalized performance of 0.72 +/- 0.006 l/m(-2) on one dewy night was recorded for C. cinerea. Removing the spines from M. columbiana was found to significantly decrease its dew harvesting efficiency. The spines of three of the species were found to be hydrophilic in nature, while F. wislizenii was hydrophobic; the stems of all four species were hydrophilic. The results of this study could be translated into designing a biomimetic water collecting device that utilizes cactus spines and their microstructures. PMID- 25909347 TI - Kinetic Monte Carlo Simulation of Statistical Mechanical Models and Coarse Grained Mesoscale Descriptions of Catalytic Reaction-Diffusion Processes: 1D Nanoporous and 2D Surface Systems. PMID- 25909348 TI - Re: Identification of Risk Factors for the Occurrence of Cement Leakage During Percutaneous Vertebroplasty for Painful Osteoporotic or Malignant Vertebral Fracture. PMID- 25909349 TI - Re: Lu Y, Guzman JZ, Purmessur D, et al. Nonoperative management of discogenic back pain. Spine (Phila Pa 1976) 2014;39:1314-24. PMID- 25909350 TI - Li S, Qi M, Yuan W, et al. The Impact of the Depression and Anxiety on Prognosis of Cervical Total Disc Replacement. Spine (Phila Pa 1976) 2015;40(5):E266-71. PMID- 25909351 TI - Occipital condyles congenital dislocation and condylus tertius: an unstable association revealing a new abnormality of the craniocervical junction. AB - STUDY DESIGN: A case report. OBJECTIVE: To describe a unique craniocervical junction anomaly and its implications both on mobility and stability of the skull base. SUMMARY OF BACKGROUND DATA: Congenital variations in the craniocervical junction (CVJ) are rare and frequently symptomless. Mild traumas may commonly rouse symptoms which help to unveil such anomalies through radiological investigations. METHODS: A 73-year-old woman developed a monoparesis of the right arm after a mild craniofacial trauma. Neurological examination revealed hyper reflexia in the upper limbs, confirming the strength impairment in the right one. Radiology showed a post-traumatic bulbo-medullary contusion sustained by a unique and unstable association of the first occipital condyles congenital dislocation ever reported with a rare condylus tertius. The patient underwent posterior decompression and occipitocervical screw-rod fixation and fusion. Clinico radiological follow-up highlighted a gradual recovery of the neurologic impairment and the posterior decompression with resolution of the spinal cord contusion. RESULTS: Although apparently stable the hyperostosis and the irregularly shaped condylar surfaces behind the 3-points mechanism of skull base support played a critical role in determining axial instability. The imbalance due to skull-cervical spine malpositioning may consequently trigger a vicious cycle of development of osteophytes leading to spinal cord narrowing with neurologic decline. A surgical strategy providing for posterior decompression and fixation satisfied the need to solve both bulbo-medullary constriction and skull base instability. CONCLUSION: Clinical evidences about CVJ anomalies are lacking and symptoms, when present, tend to be vague. Although extremely rare clinicians should be aware of CVJ variations by engaging to improve their knowledge of imaging anatomy, embryology, CVJ basic craniometry and anatomic relationships. Studies on developmental control genes may offer future perspectives of early diagnosis and targeted treatments. LEVEL OF EVIDENCE: 4. PMID- 25909352 TI - The clinical importance of lumbosacral transitional vertebra in patients with adolescent idiopathic scoliosis. AB - STUDY DESIGN: Retrospective review of radiographs. OBJECTIVE: The objective of this study was to (1) determine the prevalence of lumbosacral transitional vertebra (LSTV) with computed tomography (CT) and (2) correlate LSTV presence with lumbar disc degeneration at each level by magnetic resonance imaging. SUMMARY OF BACKGROUND DATA: LSTV is a frequently observed abnormality. Although its prevalence in patients with adolescent idiopathic scoliosis (AIS) has been shown, no studies have yet examined the clinical importance of LSTV in patients with AIS. METHODS: This study included 385 consecutive patients who underwent surgery for AIS at a single center. Plain radiographs and CT scans were used to detect LSTV. Disc degeneration was analyzed at the L3-4, L4-5, and L5-S1 disc levels with magnetic resonance imaging. The difference in disc degeneration at each level by the presence of LSTV was also analyzed. The effect of lumbar curve type on the disc degeneration of each level was then determined. To minimize confounding factors, logistic regression analysis was performed. RESULTS: The overall prevalence of LSTV in patients with AIS confirmed by CT scans was 12.2% (47/385). The proportion of grade II or more disc degeneration at the L4-5 level was higher in the LSTV(+) group than in the LSTV(-) group (29.8% vs.19.2%) although it was not statistically significant (P = 0.093). Large lumbar curves showed a positive correlation with disc degeneration at the L5-S1 level (P = 0.022). CONCLUSION: The prevalence of LSTV in patients with AIS was 12.2%. A trend of early degeneration in L4-5 level discs was found in patients with AIS with LSTV although it was not statistically confirmed. Disc degeneration at the L5-S1 level is related to a large lumbar curve. If patients with AIS with large lumbar curves have LSTV, consideration should be given to stopping the distal fusion at L3 instead of L4. LEVEL OF EVIDENCE: 4. PMID- 25909353 TI - Re: The Anatomy of Failure in Lumbar Disc Herniation. PMID- 25909354 TI - Mitochondrial Membrane Potential and Nuclear and Gene Expression Changes During Human Disc Cell Apoptosis: In Vitro and In Vivo Annulus Findings. AB - STUDY DESIGN: A study using cultured human annulus cells and human annular tissue. OBJECTIVE: To further explore and define mitochondrial mechanisms related to disc cell apoptosis in vitro and in vivo. SUMMARY OF BACKGROUND DATA: Mitochondrial-dependent intrinsic signaling pathways are a well-recognized component of apoptosis (programmed cell death). Disc cell apoptosis is important because it is a major mechanism by which cell numbers decrease during disc degeneration. Our objective was to further explore and define mitochondrial mechanisms related to disc cell apoptosis. METHODS: High-content screening techniques were used to study nuclear morphology and mitochondrial membrane potentials in cultured annulus cells. Gene expression in annulus tissue was studied with microarray analysis. RESULTS: Cultured cells showed significantly increased nuclear size (an indicator of apoptosis) with increasing Thompson grade (P < 0.00001 by analysis of variance). A significant negative correlation for mitochondrial potential (which results from the difference in electrical potential generated by the electrochemical gradient across the inner membrane of the mitochondrion) versus Thompson grade was identified in cultured human annulus cells in control conditions (r = 0.356, P < 0.0001). When exposed to the K ionophore valinomycin at sublethal levels to induce apoptosis, a significant reduction in mitochondrial potential was identified versus nontreated cells. Gene expression patterns in more degenerated Thompson grade III, IV, and V discs versus healthier grade I and II discs showed significant upregulation of a number of genes with well-recognized apoptosis roles in mitochondrial potential decline (ITM2B, beta-2-microglobulin, and cathepsin B, DAP, GAS1, and PDCD5) and TNF alpha associations (cathepsin B, RAC1, and PPT1). CONCLUSION: Data presented here show the in vivo expression of apoptosis-related genes associated with the loss of mitochondrial membrane integrity and decreased mitochondrial membrane potential with increasing Thompson scores. These data, which mimic our novel, direct cell-based in vitro findings, stress the importance of mitochondrial changes related to apoptosis and TNF-alpha during human disc degeneration. LEVEL OF EVIDENCE: N/A. PMID- 25909355 TI - Perceptions on the right to adequate food after a major landslide disaster: a cross-sectional survey of two districts in Uganda. AB - BACKGROUND: Despite the instruments on the right to adequate food adopted by the United Nations, there exists limited information on how this right is perceived. Following a major 2010 landslide disaster in the Bududa district of Eastern Uganda and the resettlement of some affected households into the Kiryandongo district in Western Uganda, we surveyed both districts to explore perceptions about the right to adequate food among households with different experiences; disaster-affected and controls. METHODS: We deployed qualitative and quantitative techniques to a cross-sectional survey. The index respondent was the head of each randomly selected household from the landslide affected communities and controls from a bordering sub-county. Data was collected by interviews and focus group discussions (FGDs). Structured entries were tested statistically to report associations using Pearson's Chi-square at the 95% CI. Information from FGDs was transcribed, coded, sequenced and patterned. Findings from both techniques were triangulated to facilitate interpretations. RESULTS: Analysis included 1,078 interview entries and 12 FGDs. Significant differences between the affected and control households (P < 0.05) were observed with: age; education level; religious affiliation; existence of assets that complement food source; and having received relief food. Analysis between groups showed differences in responses on: whether everyone has a right to adequate food; who was supposed to supply relief food; whether relief food was adequate; and preferred choice on the means to ensure the right to adequate food. FGDs emphasized that access to land was the most important means to food and income. Affected households desired remedial interventions especially alternative land for livelihood. Despite the provision of adequate relief food being a state's obligation, there was no opportunity to exercise choice and preference. Comprehension and awareness of accountability and transparency issues was also low. CONCLUSION: Though a significant proportion of participants affirmed they have a right to adequate food, relief food was largely perceived as insufficient. Given the high regard for land as a preferred remedy, a resettlement policy is of the essence to streamline post-landslide displacement and resettlement. Information materials need to be assembled and disseminated to stimulate awareness and debate on the right to adequate food. PMID- 25909357 TI - Establishing a proactive safety and health risk management system in the fire service. AB - BACKGROUND: Formalized risk management (RM) is an internationally accepted process for reducing hazards in the workplace, with defined steps including hazard scoping, risk assessment, and implementation of controls, all within an iterative process. While required for all industry in the European Union and widely used elsewhere, the United States maintains a compliance-based regulatory structure, rather than one based on systematic, risk-based methodologies. Firefighting is a hazardous profession, with high injury, illness, and fatality rates compared with other occupations, and implementation of RM programs has the potential to greatly improve firefighter safety and health; however, no descriptions of RM implementation are in the peer-reviewed literature for the North American fire service. METHODS: In this paper we describe the steps used to design and implement the RM process in a moderately-sized fire department, with particular focus on prioritizing and managing injury hazards during patient transport, fireground, and physical exercise procedures. Hazard scoping and formalized risk assessments are described, in addition to the identification of participatory-led injury control strategies. Process evaluation methods were conducted to primarily assess the feasibility of voluntarily instituting the RM approach within the fire service setting. RESULTS: The RM process was well accepted by the fire department and led to development of 45 hazard specific interventions. Qualitative data documenting the implementation of the RM process revealed that participants emphasized the: value of the RM process, especially the participatory bottom-up approach; usefulness of the RM process for breaking down tasks to identify potential risks; and potential of RM for reducing firefighter injury. CONCLUSIONS: As implemented, this risk-based approach used to identify and manage occupational hazards and risks was successful and is deemed feasible for U.S. (and other) fire services. While several barriers and challenges do exist in the implementation of any intervention such as this, recommendations for adopting the process are provided. Additional work will be performed to determine the effectiveness of select controls strategies that were implemented; however participants throughout the organizational structure perceived the RM process to be of high utility while researchers also found the process improved the awareness and engagement in actively enhancing worker safety and health. PMID- 25909356 TI - Grazoprevir-Elbasvir Combination Therapy for Treatment-Naive Cirrhotic and Noncirrhotic Patients With Chronic Hepatitis C Virus Genotype 1, 4, or 6 Infection: A Randomized Trial. AB - BACKGROUND: Novel interferon- and ribavirin-free regimens are needed to treat hepatitis C virus (HCV) infection. OBJECTIVE: To evaluate the safety and efficacy of grazoprevir (NS3/4A protease inhibitor) and elbasvir (NS5A inhibitor) in treatment-naive patients. DESIGN: Randomized, blinded, placebo-controlled trial. (ClinicalTrials.gov: NCT02105467). SETTING: 60 centers in the United States, Europe, Australia, Scandinavia, and Asia. PATIENTS: Cirrhotic and noncirrhotic treatment-naive adults with genotype 1, 4, or 6 infection. INTERVENTION: Oral, once-daily, fixed-dose grazoprevir 100 mg/elbasvir 50 mg for 12 weeks, stratified by fibrosis and genotype. Patients were randomly assigned 3:1 to immediate or deferred therapy. MEASUREMENTS: Proportion of patients in the immediate-treatment group achieving unquantifiable HCV RNA 12 weeks after treatment (SVR12); adverse events in both groups. RESULTS: Among 421 participants, 194 (46%) were women, 157 (37%) were nonwhite, 382 (91%) had genotype 1 infection, and 92 (22%) had cirrhosis. Of 316 patients receiving immediate treatment, 299 of 316 (95% [95% CI, 92% to 97%]) achieved SVR12, including 144 of 157 (92% [CI, 86% to 96%]) with genotype 1a, 129 of 131 (99% [CI, 95% to 100%]) with genotype 1b, 18 of 18 (100% [CI, 82% to 100%]) with genotype 4, 8 of 10 (80% [CI, 44% to 98%]) with genotype 6, 68 of 70 (97% [CI, 90% to 100%]) with cirrhosis, and 231 of 246 (94% [CI, 90% to 97%]) without cirrhosis. Virologic failure occurred in 13 patients (4%), including 1 case of breakthrough infection and 12 relapses, and was associated with baseline NS5A polymorphisms and emergent NS3 or NS5A variants or both. Serious adverse events occurred in 9 (2.8%) and 3 (2.9%) patients in the active and placebo groups, respectively (difference <0.05 percentage point [CI, -5.4 to 3.1 percentage points]); none were considered drug related. The most common adverse events in the active group were headache (17%), fatigue (16%), and nausea (9%). LIMITATION: The study lacked an active-comparator control group and included relatively few genotype 4 and 6 infections. CONCLUSION: Grazoprevir elbasvir achieved high SVR12 rates in treatment-naive cirrhotic and noncirrhotic patients with genotype 1, 4, or 6 infection. This once-daily, all-oral, fixed combination regimen represents a potent new therapeutic option for chronic HCV infection. PRIMARY FUNDING SOURCE: Merck & Co. PMID- 25909358 TI - Physical Activity, Sedentary Behaviors, and Nutritional Risk Profiles and Relations to Body Mass Index, Obesity, and Overweight in Eighth Grade. AB - The objective of this article was to determine (1) the existence of individually varying patterns of physical activity, sedentary behavior, and nutrition intake risk; and (2) how these risk-patterns relate to youth's demographics, Body mass index (BMI) and psychosocial functioning. Participants (N = 9,304) from the 2007 8th Grade Early Childhood Longitudinal Study Cohort completed the revised Self Description Questionnaire II. Age, sex, height, and weight were used to calculate body mass index (BMI) z scores and percentiles. Three risk profiles emerged via Latent Profile Analyses: "Active + Healthy Diet" (AHD; 16.3% Obese); "Sedentary + Unbalanced Diet" (SUD; 21.3% Obese); and "Screen-Time + Recreational Food" (STRF; 25.0% Obese). Significant differences in BMIs, psychosocial factors, and demographic characteristics were found across the profiles. Differential patterns of physical activity, sedentary behavior, and nutritional choices were found to predict BMI and psychosocial functioning. These findings may be helpful to refine and develop modular-based prevention and weight control intervention programs. PMID- 25909359 TI - Training program for the management of two obstetric emergencies within a French perinatal care network. AB - OBJECTIVES: To evaluate the effectiveness of an interdisciplinary team training program based on simulated scenarios and focusing on two obstetrical emergency situations: shoulder dystocia and complicated breech vaginal delivery (CBVD). These situations are rare, so there are few opportunities for real-life training, yet their competent and efficient management is crucial to minimizing the risks to mother and child. STUDY DESIGN: The target population for training comprised the 450 professionals working in the French regional perinatal care network ELENA. An expert committee defined the topics for the training program, selected the simulated scenarios and developed the evaluation grids. The training sessions were conducted by two qualified and experienced professionals in each maternity unit. They comprised a theoretical introduction followed by practical exercises in management of simulated emergency situations by the participant teams, with the aid of a mannequin. Each team completed the exercises twice, their performances being filmed, reviewed and evaluated in each case. RESULTS: The training sessions took place over 9 months between September 2012 and June 2013. A total of 298 professionals (obstetricians, residents in obstetrics, midwives and nursery nurses) were trained, representing 75% of the staff working in the ELENA perinatal care network. The results showed substantial and significant increases in the overall scores for management of the two emergency situations (from 74.5% to 91.4% for shoulder dystocia [p<0.0001], and from 67.2% to 88.4% [p<0.0001] for CBVD) as well as in the scores for all the specific areas of expertise assessed: safety, know-how, technique, team communication and communication with the patient. CONCLUSION: This study demonstrated the value of multidisciplinary team training for obstetric emergencies, encouraging the ELENA perinatal care network to implement an annual training program for its staff. Over and above our experience, the future establishment of a national education program to optimize the management of obstetric emergencies seems to be essential. PMID- 25909360 TI - Evolutionary Comparison of Two Combinatorial Regulators of SBP-Box Genes, MiR156 and MiR529, in Plants. AB - A complete picture of the evolution of miRNA combinatorial regulation requires the synthesis of information on all miRNAs and their targets. MiR156 and miR529 are two combinatorial regulators of squamosa promoter binding protein-like (SBP box) genes. Previous studies have clarified the evolutionary dynamics of their targets; however, there have been no reports on the evolutionary patterns of two miRNA regulators themselves to date. In this study, we investigated the evolutionary differences between these two miRNA families in extant land plants. Our work found that miR529 precursor, especially of its mature miRNA sequence, has a higher evolutionary rate. Such accelerating evolution of miR529 has significantly effects on its structural stability, and sequence conservation against existence of itself. By contrast, miR156 evolves more rapidly in loop region of the stable secondary structure, which may contribute to its functional diversity. Moreover, miR156 and miR529 genes have distinct rates of loss after identical duplication events. MiR529 genes have a higher average loss rate and asymmetric loss rate in duplicated gene pairs, indicating preferred miR529 gene losses become another predominant mode of inactivation, that are implicated in the contraction of this family. On the contrary, duplicated miR156 genes have a low loss rate, and could serve as another new source for functional diversity. Taken together, these results provide better insight into understanding the evolutionary divergence of miR156 and miR529 family in miRNA combinational regulation network. PMID- 25909361 TI - Differential Impact of Relative Dose-Intensity Reductions in Diffuse Large B-Cell Lymphoma Treated with R-CHOP21 or R-CHOP14. AB - DLBCL is an aggressive lymphoma treated with R-CHOP. Recently, attempts have been made to improve the outcome by increasing both dose-density and intensity but there have been no benefits in terms of survival. When treating malignancies RDI is important to consider but there is little published information on DLBCL. The purpose of this study was to analyze the differential prognostic impact of RDI in two cohorts of DLBCL patients treated with R-CHOP21 or R-CHOP14. From January 2001 to August 2013 we included DLBCL patients homogenously treated with R-CHOP21 or R-CHOP14, with or without radiotherapy, at University Hospital Son Espases, Hospital Son Llatzer of Palma and Hospital del Mar of Barcelona (N = 157). In order to avoid selection bias the patients were retrospectively identified from the Pathology Department and Pharmacy registries. Median follow-up was 68 months. There was no difference in the response or survival between the two cohorts. In the R-CHOP21 group, both a reduction higher than 15% in RDI (RR 7.41) and R-IPI (RR 2.99) were independently associated with OS. However, a reduction higher than 15% in RDI (RR 4.41) was only noted for PFS. In the R-CHOP14 group, NCCN-IPI (RR 7.09) and B-symptoms (RR 5.37) for OS; AA stage III-IV (RR 6.26) and bulky disease (RR 4.05) for PFS. There was a trend towards a higher rate of RDI reduction observed in the R-CHOP14 group but it only made an impact in the R CHOP21 group. We conclude that R-CHOP21 and R-CHOP14 are equivalent regimens in terms of response and survival, but only if RDI reductions are avoided. For patients receiving R-CHOP21 we recommend using clinical and support measures in order to avoid RDI reductions. PMID- 25909362 TI - Determination of plasma heparin level improves identification of systemic mast cell activation disease. AB - Diagnosis of mast cell activation disease (MCAD), i.e. systemic mastocytosis (SM) and idiopathic systemic mast cell activation syndrome (MCAS), usually requires demonstration of increased mast cell (MC) mediator release. Since only a few MC mediators are currently established as biomarkers of MCAD, the sensitivity of plasma heparin level (pHL) as an indicator of increased MC activation was compared with that of serum tryptase, chromogranin A and urinary N methylhistamine levels in 257 MCAD patients. Basal pHL had a sensitivity of 41% in MCAS patients and 27% in SM patients. Non-pharmacologic stimulation of MC degranulation by obstruction of venous flow for 10 minutes increased the sensitivity of pHL in MCAS patients to 59% and in SM patients to 47%. In MCAS patients tryptase, chromogranin A, and N-methylhistamine levels exhibited low sensitivities (10%, 12%, and 22%, respectively), whereas sensitivities for SM were higher (73%, 63%, and 43%, respectively). Taken together, these data suggest pHL appears more sensitive than the other mediators for detecting systemic MC activity in patients with MCAS. The simple, brief venous occlusion test appears to be a useful indicator of the presence of pathologically irritable MCs, at least in the obstructed compartment of the body. PMID- 25909363 TI - The Malaysian Medication Adherence Scale (MALMAS): Concurrent Validity Using a Clinical Measure among People with Type 2 Diabetes in Malaysia. AB - Medication non-adherence is a prevalent problem worldwide but up to today, no gold standard is available to assess such behavior. This study was to evaluate the psychometric properties, particularly the concurrent validity of the English version of the Malaysian Medication Adherence Scale (MALMAS) among people with type 2 diabetes in Malaysia. Individuals with type 2 diabetes, aged 21 years and above, using at least one anti-diabetes agent and could communicate in English were recruited. The MALMAS was compared with the 8-item Morisky Medication Adherence Scale (MMAS-8) to assess its convergent validity while concurrent validity was evaluated based on the levels of glycated hemoglobin (HbA1C). Participants answered the MALMAS twice: at baseline and 4 weeks later. The study involved 136 participants. The MALMAS achieved acceptable internal consistency (Cronbach's alpha=0.565) and stable reliability as the test-retest scores showed fair correlation (Spearman's rho=0.412). The MALMAS has good correlation with the MMAS-8 (Spearman's rho=0.715). Participants who were adherent to their anti diabetes medications had significantly lower median HbA1C values than those who were non-adherence (7.90 versus 8.55%, p=0.032). The odds of participants who were adherent to their medications achieving good glycemic control was 3.36 times (95% confidence interval: 1.09-10.37) of those who were non-adherence. This confirms the concurrent validity of the MALMAS. The sensitivity of the MALMAS was 88.9% while its specificity was 29.6%. The findings of this study further substantiates the reliability and validity of the MALMAS, in particular its concurrent validity and sensitivity for assessing medication adherence of people with type 2 diabetes in Malaysia. PMID- 25909365 TI - Diphtheria in Lao PDR: Insufficient Coverage or Ineffective Vaccine? AB - BACKGROUND: During late 2012 and early 2013 several outbreaks of diphtheria were notified in the North of the Lao People's Democratic Republic. The aim of this study was to determine whether the re-emergence of this vaccine-preventable disease was due to insufficient vaccination coverage or reduction of vaccine effectiveness within the affected regions. METHODS: A serosurvey was conducted in the Huaphan Province on a cluster sampling of 132 children aged 12-59 months. Serum samples, socio-demographic data, nutritional status and vaccination history were collected when available. Anti-diphtheria and anti-tetanus IgG antibody levels were measured by ELISA. RESULTS: Overall, 63.6% of participants had detectable diphtheria antibodies and 71.2% tetanus antibodies. Factors independently associated with non-vaccination against diphtheria were the distance from the health centre (OR: 6.35 [95% CI: 1.4-28.8], p = 0.01), the Lao Theung ethnicity (OR: 12.2 [95% CI:1,74-85, 4], p = 0.01) and the lack of advice on vaccination given at birth (OR: 9.8 [95% CI: 1.5-63.8], (p = 0.01) while the level of maternal edu-cation was a protective factor (OR: 0.08 [95% CI: 0.008 0.81], p = 0.03). Most respondents claimed financial difficulties as the main reason for non-vaccination. Out of 55 children whose vaccination certificates stated that they were given all 3 doses of diphtheria-containing vaccine, 83.6% had diphtheria antibodies and 92.7% had tetanus antibodies. Furthermore, despite a high prevalence of stunted and underweight children (53% and 25.8%, respectively), the low levels of anti-diphtheria antibodies were not correlated to the nutritional status. CONCLUSIONS: Our data highlight a significant deficit in both the vaccination coverage and diphtheria vaccine effectiveness within the Huaphan Province. Technical deficiencies in the methods of storage and distribution of vaccines as well as unreliability of vaccination cards are discussed. Several hypotheses are advanced to explain such a decline in immunity against diphtheria and recommendations are provided to prevent future outbreaks. PMID- 25909364 TI - Spatio-temporal remodeling of functional membrane microdomains organizes the signaling networks of a bacterium. AB - Lipid rafts are membrane microdomains specialized in the regulation of numerous cellular processes related to membrane organization, as diverse as signal transduction, protein sorting, membrane trafficking or pathogen invasion. It has been proposed that this functional diversity would require a heterogeneous population of raft domains with varying compositions. However, a mechanism for such diversification is not known. We recently discovered that bacterial membranes organize their signal transduction pathways in functional membrane microdomains (FMMs) that are structurally and functionally similar to the eukaryotic lipid rafts. In this report, we took advantage of the tractability of the prokaryotic model Bacillus subtilis to provide evidence for the coexistence of two distinct families of FMMs in bacterial membranes, displaying a distinctive distribution of proteins specialized in different biological processes. One family of microdomains harbors the scaffolding flotillin protein FloA that selectively tethers proteins specialized in regulating cell envelope turnover and primary metabolism. A second population of microdomains containing the two scaffolding flotillins, FloA and FloT, arises exclusively at later stages of cell growth and specializes in adaptation of cells to stationary phase. Importantly, the diversification of membrane microdomains does not occur arbitrarily. We discovered that bacterial cells control the spatio-temporal remodeling of microdomains by restricting the activation of FloT expression to stationary phase. This regulation ensures a sequential assembly of functionally specialized membrane microdomains to strategically organize signaling networks at the right time during the lifespan of a bacterium. PMID- 25909366 TI - Certolizumab pegol - A new therapeutic option for refractory disseminated pyoderma gangrenosum associated with Crohn's disease. AB - Systemic steroids, in association or not with cyclosporin, are indicated for the treatment of large or widespread Pyoderma gangrenosum (PG). We report the case of a 27-year-old woman with a 15-year history of severe Crohn's disease, who developed a severe and disseminated PG, refractory to multiple lines of treatment. Infliximab and adalimumab were contraindicated, either because of allergy or of ineffectiveness on Crohn's disease. The addition of certolizumab pegol to the baseline treatment, associating systemic steroids and tacrolimus, finally allowed the complete healing of PG. Oral prednisone was stopped and tacrolimus was decreased, without any cutaneous or digestive relapse. Certolizumab pegol could be an alternative therapy in the treatment of PG in case of intolerance or ineffectiveness of the other anti-tumor necrosis factor (anti TNF) therapies. PMID- 25909367 TI - A massive neglected giant basal cell carcinoma in a schizophrenic patient treated successfully with vismodegib. AB - The small molecule vismodegib is a great treatment alternative to patients challenged, e.g. psychiatric disorders, suffering from severe basal cell carcinoma of the skin in which surgery or other treatment modalities is not possible because of patient's wish or condition. We present a case of a 73-year old schizophrenic patient with a 15-year history of a neglected tumour located at the forehead and scalp, admitted to hospital in a state of inanition because of tumour expansion to the meninges and severe anaemia caused by bleeding, treated successfully with vismodegib. PMID- 25909368 TI - Combination therapy of methotrexate plus NBUVB phototherapy is more effective than methotrexate monotherapy in the treatment of chronic plaque psoriasis. AB - BACKGROUND: The efficacy of methotrexate (MTX) plus narrowband ultraviolet B (NBUVB) phototherapy in treatment of chronic plaque psoriasis has been rarely assessed. OBJECTIVES: The objective of this study is to compare the efficacy of MTX/NBUVB phototherapy versus MTX monotherapy in treatment of chronic plaque psoriasis. METHODS: Forty patients with psoriasis were enrolled into the study and classified into group A receiving oral MTX and group B receiving oral MTX plus NBUVB. Onset of improvement was <=70% of baseline PASI. End point clearance was 90 % reduction in PASI or up to 6 months. Side effects were reported. Follow up for 12 weeks for assessment of relapse was done. RESULTS: Of 40 patients, 35 completed the study. A higher clearance rate was achieved in patients of group B versus group A (100% versus 83%). A significant difference was reported regarding the onset of improvement and the duration required for clearance (p < 0.001) in favor of the MTX/NBUVB group. Patients in group B had a highly significant lower cumulative dose of MTX than the monotherapy group (p < 0.05). No significant difference as regard side effects and relapse was reported. CONCLUSION: MTX remains the mainstay in the treatment of psoriasis in developing countries and its combination with NBUVB offers a cheap and a beneficial therapeutic option. PMID- 25909369 TI - Long-term use of a 4% sodium cromoglicate cutaneous emulsion in the treatment of moderate to severe atopic dermatitis in children. AB - INTRODUCTION: Sodium cromoglicate (SCG), a chromone with anti-inflammatory, anti itch and anti-allergic properties. We report a long-term study of a 4% aqueous solution of SCG in children with moderate to severe atopic dermatitis (AD). MATERIALS AND METHODS: Children aged 1 to 12 years with AD were entered into a 12 week randomised clinical trial (RCT), followed by 12 months open treatment with known 4% SCG emulsion (Altocrom(r)). Primary endpoint was change in SCORAD score. Secondary endpoints included symptom severity, Quality of Life, concomitant treatment usage, global assessments. RESULTS: One hundred and seventy-seven subjects entered, 118 treated with 4% SCG emulsion and 59 with vehicle: 128 completed 12 months in open study. SCORAD score reduced during RCT by -15.3 ( 33%) on 4% SCG emulsion and -18.0 (-39%) on vehicle: p = 0.2331. After 12 months reduction was 56%. No secondary endpoint showed differences between treatments during RCT. Thirty-two subjects reported treatment related events during RCT and open trial. Eleven (7%) reported application site discomfort. Most were reported as mild and most resolved without intervention and the study drug was stopped in one case only. CONCLUSIONS: SCG 4% cutaneous emulsion was well tolerated in children treated for 15 months. PMID- 25909371 TI - Impact of polymethylmethacrylate additives on methicillin-resistant Staphylococcus pseudintermedius biofilm formation in vitro. AB - OBJECTIVE: To evaluate the impact of gentamicin, silver, or both additives in polymethylmethacrylate (PMMA) beads on methicillin-resistant Staphylococcus pseudintermedius (MRSP) biofilm formation in vitro. SAMPLE: 4 preparations of PMMA beads (formed with no additive [control], gentamicin, silver, and gentamicin and silver). PROCEDURES: Beads from each group were exposed to 10 MRSP isolates known to be strong biofilm formers. Following incubation, the beads were rinsed to remove planktonic bacteria, then sonicated to dislodge biofilm-associated bacteria. Resulting suspensions were serially diluted, plated on blood agar, and incubated overnight; CFUs were counted. Variance of mean CFU counts following log10 transformation was analyzed among PMMA groups. RESULTS: None of the PMMA additives tested completely inhibited MRSP biofilm formation. There was a significant effect of gentamicin and gentamicin plus silver on this variable, compared with controls, but not of silver alone. There was no difference between gentamicin and gentamicin plus silver. When only isolates not susceptible to gentamicin were evaluated, there were no significant differences among PMMA additive groups. Within gentamicin-susceptible isolates, there was an impact of gentamicin and gentamicin plus silver, but no impact of silver alone and no difference between gentamicin and gentamicin plus silver. CONCLUSIONS AND CLINICAL RELEVANCE: Gentamicin-impregnated PMMA was effective at reducing biofilm formation of gentamicin-susceptible MRSP isolates but had no effect on isolates not susceptible to gentamicin. Silver-impregnated PMMA had no effect on MRSP biofilm formation. Results suggested that gentamicin-impregnated PMMA may not be effective in vivo against MRSP isolates not susceptible to gentamicin. Antibacterial efficacy of silver should not be assumed without proper testing of the target bacteria and specific silver compound. PMID- 25909372 TI - Effect of screw position on single cycle to failure in bending and torsion of a locking plate-rod construct in a synthetic feline femoral gap model. AB - OBJECTIVE: To evaluate the effect of screw position on strength and stiffness of a combination locking plate-rod construct in a synthetic feline femoral gap model. SAMPLE: 30 synthetic long-bone models derived from beechwood and balsa wood. PROCEDURES: 3 constructs (2 locking plate-rod constructs and 1 locking plate construct; 10 specimens/construct) were tested in a diaphyseal bridge plating configuration by use of 4-point bending and torsion. Variables included screw position (near the fracture gap and far from the fracture gap) and application of an intramedullary pin. Constructs were tested to failure in each loading mode to determine strength and stiffness. Failure was defined as plastic deformation of the plate or breakage of the bone model or plate. Strength, yield angle, and stiffness were compared by use of a Wilcoxon test. RESULTS: Placement of screws near the fracture gap did not increase bending or torsional stiffness in the locking plate-rod constructs, assuming the plate was placed on the tension side of the bone. Addition of an intramedullary pin resulted in a significant increase in bending strength of the construct. Screw positioning did not have a significant effect on any torsion variables. CONCLUSIONS AND CLINICAL RELEVANCE: Results of this study suggested that, in the investigated plate-rod construct, screw insertion adjacent to the fracture lacked mechanical advantages over screw insertion at the plate ends. For surgeons attempting to minimize soft tissue dissection, the decision to make additional incisions for screw placement should be considered with even more caution. PMID- 25909373 TI - Mechanical strength of four allograft fixation techniques for ruptured cranial cruciate ligament repair in dogs. AB - OBJECTIVE: To test ex vivo mechanical properties of 4 allograft fixation techniques for cranial cruciate ligament (CCL) replacement. SAMPLE: 30 stifle joints from canine cadavers. PROCEDURES: CCL-deficient stifle joints repaired by 1 of 4 techniques (n = 6/group) and CCL-intact stifle joints (control group; 6) were mechanically tested. Three repair techniques involved a patella-patella ligament segment (PPL) allograft: a tibial and femoral interference screw (PPL 2S), a femoral interference screw and the patella seated in a tapering bone tunnel in the tibia (PPL-1S), or addition of a suture and a bone anchor to the PPL-1S (PPL-SL). The fourth technique involved a deep digital flexor tendon (DDFT) allograft secured with transverse femoral fixation and stabilized with a tibial interference screw and 2 spiked washers on the tibia (DDFT-TF). The tibia was axially loaded at a joint angle of 135 degrees . Loads to induce 3, 5, and 10 mm of femoral-tibia translation; stiffness; and load at ultimate failure with the corresponding displacement were calculated. Group means were compared with a multivariate ANOVA. RESULTS: Mean +/- SD load for the intact (control) CCL was 520.0 +/- 51.3 N and did not differ significantly from the load needed to induce 3 mm of femoral-tibial translation for fixation techniques PPL-SL (422.4 +/- 46.3 N) and DDFT-TF (654.2 +/- 117.7 N). Results for the DDFT-TF were similar to those of the intact CCL for all outcome measures. CONCLUSIONS AND CLINICAL RELEVANCE: The DDFT-TF yielded mechanical properties similar to those of intact CCLs and may be a viable technique to test in vivo. PMID- 25909374 TI - Stability of hemostatic proteins in canine fresh-frozen plasma thawed with a modified commercial microwave warmer or warm water bath. AB - OBJECTIVE: To compare stability of hemostatic proteins in canine fresh-frozen plasma (FFP) thawed with a modified commercial microwave warmer (MCM) or warm water bath (37 degrees C; WWB) or at room temperature (22 degrees C). SAMPLE: Fresh-frozen plasma obtained from 8 canine donors of a commercial blood bank. PROCEDURES: A commercial microwave warmer was modified with a thermocouple to measure surface temperature of bags containing plasma. The MCM and a WWB were each used to concurrently thaw a 60-mL bag of plasma obtained from the same donor. Two 3-mL control aliquots of FFP from each donor were thawed to room temperature without use of a heating device. Concentrations of hemostatic proteins, albumin, and D-dimers; prothrombin time (PT); and activated partial thromboplastin time (aPTT) were determined for all samples. RESULTS: Significant decreases in concentrations of factors II, IX, X, XI, fibrinogen, von Willebrand factor, antithrombin, protein C, and albumin and significant increases in PT and aPTT were detected for plasma thawed with the MCM, compared with results for samples thawed with the WWB. Concentrations of factors VII, VIII, and XII were not significantly different between plasma thawed with the MCM and WWB. Concentrations of D-dimers were above the reference range for all thawed samples regardless of thawing method. No significant differences in factor concentrations were detected between control and WWB-thawed samples. CONCLUSIONS AND CLINICAL RELEVANCE: Significant differences in hemostatic protein concentrations and coagulation times were detected for plasma thawed with an MCM but not between control and WWB-thawed samples. Clinical importance of these changes should be investigated. PMID- 25909375 TI - Ultrasonographic detection of early atrophy of the intrinsic laryngeal muscles of horses. AB - OBJECTIVE: To describe the ultrasonographic changes in the cricoarytenoideus dorsalis (CAD) and cricoarytenoideus lateralis (CAL) muscles of horses before and at various times during the 32 weeks after unilateral neurectomy of the right recurrent laryngeal nerve. ANIMALS: 28 healthy Standardbreds. PROCEDURES: For each horse, the appearance of the CAD and CAL muscles on the right (neurectomized) and left (control) sides was serially monitored ultrasonographically by percutaneous (CAD and CAL) and transesophageal (CAD) approaches. The ultrasonographic images were assessed to determine the mean pixel intensity, muscle thickness, and appearance grade, and comparisons were made between the muscles of the neurectomized and control sides. RESULTS: The muscle appearance grade and mean pixel intensity for the CAL and CAD muscles on the neurectomized side were significantly increased by 2 and 4 weeks, respectively, after the neurectomy. The transesophageal approach enhanced the ultrasonographic visibility of the CAD muscle and allowed us to detect a significant decrease in the thickness of the CAD muscle on the neurectomized side over time, compared with thickness of the CAD muscle on the control side. CONCLUSIONS AND CLINICAL RELEVANCE: Results suggested ultrasonography can be used to successfully assess the CAL and CAD muscles of horses. A qualitative grading scheme was sufficient for successful detection and monitoring of muscle atrophy and reduced the need for image standardization. The transesophageal approach described for assessment of the CAD muscle warrants further investigation. PMID- 25909376 TI - Evaluation of a thyrotropin-releasing hormone solution stored at room temperature for pituitary pars intermedia dysfunction testing in horses. AB - OBJECTIVE: To determine whether plasma ACTH concentrations vary following administration of a thyrotropin-releasing hormone (TRH) solution prepared for research purposes and stored at -20 degrees C (rTRH) or prepared by a compounding pharmacy and stored at room temperature (approx 22 degrees C; cTRH). ANIMALS: 34 adult horses. PROCEDURES: The study consisted of 2 experiments. In experiment 1, each horse underwent 2 TRH stimulation tests separated by 24 hours; 10 horses were administered cTRH for the first test and rTRH for the second test (group 1), 10 horses were administered rTRH for the first test and cTRH for the second test (group 2), and 10 horses were administered rTRH for both tests (group 3). Plasma ACTH concentrations were measured at 0 (baseline) and 30 minutes after TRH administration and the delta ACTH responses (change in ACTH concentration after TRH administration) were calculated. In experiment 2, the design was the same as that for experiment 1 except there were 14 days between tests, ACTH was measured at 0 and 10 minutes after TRH administration, and 11, 9, and 10 horses were assigned to groups 1, 2, and 3, respectively. RESULTS: Adverse effects associated with TRH administration included transient coughing and yawning. In experiment 1, the median delta ACTH response for the second test was significantly lower than that for the first test for all groups. In experiment 2, the median delta ACTH response did not differ significantly between the first and second tests for any group, ACTH concentrations after rTRH administration were positively correlated (rs = 0.95) with those after cTRH administration, and the mean +/- SD bias in post-TRH ACTH concentration between rTRH and cTRH was 2.9 +/- 12.4 pg/mL. CONCLUSIONS AND CLINICAL RELEVANCE: Results indicated that the TRH stimulation test should not be repeated within 24 hours, and cTRH solution stored at room temperature could be used to effectively perform TRH stimulation testing in horses. PMID- 25909377 TI - Pharmacologic evaluation of ammonium tetrathiomolybdate after intravenous and oral administration to healthy dogs. AB - OBJECTIVE: To evaluate pharmacokinetics of ammonium tetrathiomolybdate (TTM) after IV and oral administration to dogs and effects of TTM administration on trace mineral concentrations. ANIMALS: 8 adult Beagles and Beagle crossbreds (4 sexually intact males and 4 sexually intact females). PROCEDURES: Dogs received TTM (1 mg/kg) IV and orally in a randomized crossover study. Serum molybdenum and copper concentrations were measured via inductively coupled plasma mass spectrometry in samples obtained 0 to 72 hours after administration. Pharmacokinetics was determined via noncompartmental analysis. RESULTS: For IV administration, mean +/- SD terminal elimination rate constant, maximum concentration, area under the curve, and half-life were 0.03 +/- 0.01 hours(-1), 4.9 +/- 0.6 MUg/mL, 30.7 +/- 5.4 MUg/mL*h, and 27.7 +/- 6.8 hours, respectively. For oral administration, mean +/- SD terminal elimination rate constant, time to maximum concentration, maximum concentration, area under the curve, and half-life were 0.03 +/- 0.01 hours(-1), 3.0 +/- 3.5 hours, 0.2 +/- 0.4 MUg/mL, 6.5 +/- 8.0 MUg/mL*h, and 26.8 +/- 8.0 hours, respectively. Oral bioavailability was 21 +/- 22%. Serum copper concentrations increased significantly after IV and oral administration. Emesis occurred after IV (2 dogs) and oral administration (3 dogs). CONCLUSIONS AND CLINICAL RELEVANCE: Pharmacokinetics for TTM after a single IV and oral administration was determined for clinically normal dogs. Absorption of TTM after oral administration was variable. Increased serum copper concentrations suggested that TTM mobilized tissue copper. Further studies will be needed to evaluate the potential therapeutic use of TTM in copper-associated chronic hepatitis of dogs. PMID- 25909378 TI - Posaconazole pharmacokinetics after administration of an intravenous solution, oral suspension, and delayed-release tablet to dogs. AB - OBJECTIVE: To determine pharmacokinetics of posaconazole in dogs given an IV solution, oral suspension, and delayed-release tablet. ANIMALS: 6 healthy dogs. PROCEDURES: Posaconazole was administered IV (3 mg/kg) and as an oral suspension (6 mg/kg) to dogs in a randomized crossover study. Blood samples were collected before (time 0) and for 48 hours after each dose. In an additional experiment, 5 of the dogs received posaconazole delayed-release tablets (mean dose, 6.9 mg/kg); blood samples were collected for 96 hours. Plasma concentrations were analyzed with high-performance liquid chromatography. RESULTS: IV solution terminal half life (t1/2) was 29 hours (coefficient of variation [CV], 23%). Clearance and volume of distribution were 78 mL/h/kg (CV, 59%) and 3.3 L/kg (CV, 38%), respectively. Oral suspension t1/2 was 24 hours (CV, 42%). Maximum plasma concentration (Cmax) of 0.42 MUg/mL (CV, 56%) was obtained at 7.7 hours (CV, 92%). Mean bioavailability was 26% (range, 7.8% to 160%). Delayed-release tablet t1/2 was 42 hours (CV, 25%), with a Cmax of 1.8 MUg/mL (CV, 44%) at 9.5 hours (CV, 85%). Mean bioavailability of tablets was 159% (range, 85% to 500%). Bioavailability of delayed-release tablets was 497% (range, 140% to 1,800%) relative to that of the oral suspension. CONCLUSIONS AND CLINICAL RELEVANCE: Absorption of posaconazole oral suspension in dogs was variable. Absorption of the delayed-release tablets was greater than absorption of the oral suspension, with a longer t1/2 that may favor its clinical use in dogs. Administration of delayed-release tablets at a dosage of 5 mg/kg every other day can be considered for future studies. PMID- 25909379 TI - Effect of long-term oral administration of a low dosage of clenbuterol on body fat percentage in working and nonworking adult horses. AB - OBJECTIVE: To determine the anabolic and lipolytic effects of a low dosage of clenbuterol administered orally in working and nonworking equids. ANIMALS: 8 nonworking horses and 47 polo ponies in active training. PROCEDURES: Each polo pony continued training and received either clenbuterol (0.8 MUg/kg) or an equal volume of corn syrup (placebo) orally twice daily for 21 days, and then was evaluated for another 21-day period. Nonworking horses received clenbuterol or placebo at the same dosage for 21 days in a crossover trial (2 treatments/horse). For working and nonworking horses, percentage body fat (PBF) was estimated before treatment and then 2 and 3 times/wk, respectively. Body weight was measured at intervals. RESULTS: Full data sets were not available for 8 working horses. For working horses, a significant treatment effect of clenbuterol was detected by day 3 and continued through the last day of treatment; at day 21, the mean change in PBF from baseline following clenbuterol or placebo treatment was -0.80% (representing a 12% decrease in PBF) and -0.32%, respectively. By day 32 through 42 (without treatment), PBF change did not differ between groups. When treated with clenbuterol, the nonworking horses had a similar mean change in PBF from baseline from day 6 onward, which peaked at -0.75% on day 18 (an 8% decrease in PBF). Time and treatment had no significant effect on body weight in either experiment. CONCLUSIONS AND CLINICAL RELEVANCE: Among the study equids, long-term low-dose clenbuterol administration resulted in significant decreases in body fat with no loss in body weight. PMID- 25909380 TI - In vitro evaluation of bursting pressure and intestinal luminal area of three jejunostomy tube placement techniques in dogs. AB - OBJECTIVE: To compare pursestring, Witzel (seromuscular inversion), and seromuscular incision jejunostomy tube placement techniques in vitro. SAMPLE: Jejunal specimens from 10 dogs. PROCEDURES: Jejunal segments (50 cm) were harvested immediately prior to euthanasia from 10 mixed-breed dogs Specimens were harvested with the orad and aborad ends clamped and stored in saline (0.9% NaCl) solution-soaked towels during instrumentation. Three jejunostomy tubes were placed via 3 techniques (pursestring, Witzel, and seromuscular incision), and 2 double lumen central venous catheters were placed at each intestinal end for luminal filling and leak testing. Intestinal luminal area was measured ultrasonographically with specimens suspended in a warm undyed saline solution bath with the intestinal lumen filled with dyed saline solution (intraluminal pressure, 6 mm Hg). Leak testing was performed by means of infusion of dyed saline solution (4 mL/min) until each jejunostomy site failed. Intestinal luminal area and leakage pressure were compared between the 3 tube placement techniques. RESULTS: The Witzel and seromuscular incision techniques decreased the intestinal luminal area measured at the tube insertion site, albeit nonsignificantly. For the seromuscular incision technique, a significant decrease in intestinal luminal area at the intraluminal site of measurement was found. For 2/30 specimens (1/10 pursestring and 1/10 seromuscular incision), failure occurred at pressures within the range of previously reported peak peristaltic pressure for dogs. Failure occurred at supraphysiologic peristaltic pressures for the remaining 28 specimens, including all 10 specimens for the Witzel technique. CONCLUSIONS AND CLINICAL RELEVANCE: In this in vitro study, all specimens for the Witzel technique withstood physiologic peristaltic pressures during leak testing. Both tunneling techniques (Witzel and seromuscular incision) created a decrease in intestinal luminal area. Further investigation, including in vivo testing, is indicated to evaluate the clinical relevance of these findings. PMID- 25909381 TI - Turnover rates of hepatic collagen and circulating collagen-associated proteins in humans with chronic liver disease. AB - Accumulation and degradation of scar tissue in fibrotic liver disease occur slowly, typically over many years. Direct measurement of fibrogenesis, the rate of scar tissue deposition, may provide valuable therapeutic and prognostic information. We describe here results from a pilot study utilizing in vivo metabolic labeling to measure the turnover rate of hepatic collagen and collagen associated proteins in plasma for the first time in human subjects. Eight subjects with chronic liver disease were labeled with daily oral doses of 2H2O for up to 8 weeks prior to diagnostic liver biopsy and plasma collection. Tandem mass spectrometry was used to measure the abundance and fractional synthesis rate (FSR) of proteins in liver and blood. Relative protein abundance and FSR data in liver revealed marked differences among subjects. FSRs of hepatic type I and III collagen ranged from 0.2-0.6% per day (half-lives of 4 months to a year) and correlated significantly with worsening histologic fibrosis. Analysis of plasma protein turnover revealed two collagen-associated proteins, lumican and transforming growth factor beta-induced-protein (TGFBI), exhibiting FSRs that correlated significantly with FSRs of hepatic collagen. In summary, this is the first direct measurement of liver collagen turnover in vivo in humans and suggests a high rate of collagen remodeling in advanced fibrosis. In addition, the FSRs of collagen-associated proteins in plasma are measurable and may provide a novel strategy for monitoring hepatic fibrogenesis rates. PMID- 25909382 TI - Prevalence and associated factors of hypertension: a crossectional community based study in northwest ethiopia. AB - BACKGROUND: Hypertension, being the root cause of many of the body sytem and organs failure, remains to be a major public health challenge globally. Though the problem is huge in both developed and developing countries, data are scarce in developing countries like Ethiopia. Therefore, this study was aimed to determine the magnitude and associated factors of hypertension in North West Ethiopia. METHODS: A cross-sectional survey was conducted on adults aged 35 years and above in the rural and urban communities of Dabat district and Gondar town in 2012. The data were collected using the WHO STEPwise strategy. Hypertension was defined as having a Systolic blood pressure of >=140 mmHg and/ or a Diastolic BP of >= 90mmHg or a reported use of anti-hypertensive medications for raised blood pressure. Prevalence was computed with a 95% confidence interval. Selected risk factors were assessed using a biviarete logistic regression. RESULTS: A total of 2200 participants were included in the study. The median age (+/-SD) was 47 (+/ 12.4) years. The overall prevalence of hypertension was found to be 27.9% [95% CI 26.0, 29.8], with the proportion in the urban and rural residents being 30.7% and 25.3% respectively. The prevalence of hypertension was 29.3% for women and 26.3% for men. Out of the 598 hypertensive patients 241 (40.3%) had blood pressure measurements, and 99 (16.6%) had known hypertension and were on treatment. The proportion of systolic and diastolic hypertension in this subgroup of adults was 133(6.2%). The multivariable logistic regression analysis showed older age (AOR = 1.06; 1.05, 1.07), raised fasting glucose (AOR = 1.01; 1.001, 1.01), alcohol consumption (AOR = 1.71; 1.24, 2.36), and raised BMI (AOR =1.07; 1.04, 1.10) were significantly associated with hypertension. CONCLUSION: The prevalence of hypertension was considerably higher in rural areas than previously reported. The health system needs to develop strategies to increase the reach of relevant screening and diagnostic services to both rural and urban populations. PMID- 25909383 TI - Islet formation in mice and men: lessons for the generation of functional insulin producing beta-cells from human pluripotent stem cells. AB - The Islets of Langerhans are crucial 'micro-organs' embedded in the glandular exocrine pancreas that regulate nutrient metabolism. They not only synthesize, but also secrete endocrine hormones in a modulated fashion in response to physiologic metabolic demand. These highly sophisticated structures with intricate organization of multiple cell types, namely endocrine, vascular, neuronal and mesenchymal cells, have evolved to perform this task to perfection over time. Not surprisingly, islet architecture and function are dissimilar between humans and typically studied model organisms, such as rodents and zebrafish. Further, recent findings also suggest noteworthy differences in human islet development from that in mouse, including delayed appearance and gradual resolution of key differentiation markers, a single-phase of endocrine differentiation, and prenatal association of developing islets with neurovascular milieu. In light of these findings, it is imperative that a systematic study is undertaken to compare islet development between human and mouse. Illuminating inter-species differences in islet development will likely be critical in furthering our pursuit to generate an unlimited supply of truly functional and fully mature beta-cells from human pluripotent stem cell (hPSC) sources for therapeutic purposes. PMID- 25909384 TI - Bacterial Cooperation Causes Systematic Errors in Pathogen Risk Assessment due to the Failure of the Independent Action Hypothesis. AB - The Independent Action Hypothesis (IAH) states that pathogenic individuals (cells, spores, virus particles etc.) behave independently of each other, so that each has an independent probability of causing systemic infection or death. The IAH is not just of basic scientific interest; it forms the basis of our current estimates of infectious disease risk in humans. Despite the important role of the IAH in managing disease interventions for food and water-borne pathogens, experimental support for the IAH in bacterial pathogens is indirect at best. Moreover since the IAH was first proposed, cooperative behaviors have been discovered in a wide range of microorganisms, including many pathogens. A fundamental principle of cooperation is that the fitness of individuals is affected by the presence and behaviors of others, which is contrary to the assumption of independent action. In this paper, we test the IAH in Bacillus thuringiensis (B.t), a widely occurring insect pathogen that releases toxins that benefit others in the inoculum, infecting the diamondback moth, Plutella xylostella. By experimentally separating B.t. spores from their toxins, we demonstrate that the IAH fails because there is an interaction between toxin and spore effects on mortality, where the toxin effect is synergistic and cannot be accommodated by independence assumptions. Finally, we show that applying recommended IAH dose-response models to high dose data leads to systematic overestimation of mortality risks at low doses, due to the presence of synergistic pathogen interactions. Our results show that cooperative secretions can easily invalidate the IAH, and that such mechanistic details should be incorporated into pathogen risk analysis. PMID- 25909385 TI - Growth modulation with a medial malleolar screw for ankle valgus deformity. 79 children with 125 affected ankles followed until correction or physeal closure. AB - BACKGROUND AND PURPOSE: Growth modulation with a medial malleolar screw is used to correct ankle valgus deformity in children with a wide spectrum of underlying etiologies. It is unclear whether the etiology of the deformity affects the angular correction rate with this procedure. PATIENTS AND METHODS: 79 children (20 girls) with ankle valgus deformity had growth modulation by a medial malleolar screw (125 ankles). To be included, patients had to have undergone screw removal at the time of skeletal maturity or deformity correction, or a minimum follow-up of 18 months, and consistent radiographs preoperatively and at the time of screw removal and/or follow-up. The patients were assigned to 1 of 7 groups according to their underlying diagnoses. The lateral distal tibial angle (LDTA) was analyzed preoperatively, at screw removal, and at follow-up. RESULTS: Mean age at operation was 11.7 (7.4-16.5) years. The average lateral distal tibial angle normalized from 80 degrees (67-85) preoperatively to 89 degrees (73-97) at screw removal. The screws were removed after an average time of 18 (6 46) months, according to an average rate of correction of 0.65 degrees (0.1-2.2) per month. No significant differences in the correction rate per month were found between the groups (p = 0.3). INTERPRETATION: Growth modulation with a medial malleolar screw is effective for the treatment of ankle valgus deformity in patients with a wide spectrum of underlying diagnoses. The individual etiology of the ankle valgus does not appear to affect the correction rate after growth modulation. Thus, the optimal timing of growth modulation mainly depends on the remaining individual growth and on the extent of the deformity. PMID- 25909387 TI - Simple and fast electrochemical detection of sequence-specific DNA via click chemistry-mediated labeling of hairpin DNA probes with ethynylferrocene. AB - A universal and straightforward electrochemical biosensing strategy for the detection and identification of sequence-specific DNA via click chemistry mediated labeling of hairpin DNA probes (hairpins) with ethynylferrocene was reported. In the target-unbound form, the immobilized hairpins were kept in the folded stem-loop configuration with their azido terminals held in close proximity of the electrode surface, making them difficult to be labeled with ethynylferrocene due to the remarkable steric hindrance of the densely packed hairpins. Upon hybridization, they were unfolded and underwent a large conformational change, thus enabling the azido terminals to become available for its subsequent conjugation with ethynylferrocene via the Cu(I)-catalyzed azide alkyne cycloaddition (CuAAC). After that, the quantitatively labeled ethynylferrocene could be exploited as the electroactive probes to monitor the DNA hybridization. As the unfolded hairpins were labeled in a stoichiometric ratio of 1 : 1, the electrochemical measurement based on differential pulse voltammetry enabled a reliable quantification of sequence-specific DNA. Under optimal conditions, the strategy could detect target single-stranded DNA (ssDNA) down to 0.296 pM with a good linear response over the range from 1 pM to 1 nM, and had excellent specificity in the genotyping of single-nucleotide polymorphisms. Furthermore, it also exhibited good detection reliability in serum samples and required no complicated protocols. More importantly, the simplicity of this strategy together with its compatibility with microfluidic chips makes it show great potential in clinical applications, where simple procedures are generally preferred. PMID- 25909386 TI - 5'-Silylated 3'-1,2,3-triazolyl Thymidine Analogues as Inhibitors of West Nile Virus and Dengue Virus. AB - West Nile virus (WNV) and Dengue virus (DENV) are important human pathogens for which there are presently no vaccine or specific antivirals. We report herein a 5'-silylated nucleoside scaffold derived from 3'-azidothymidine (AZT) consistently and selectively inhibiting WNV and DENV at low micromolar concentrations. Further synthesis of various triazole bioisosteres demonstrated clear structure-activity relationships (SARs) in which the antiviral activity against WNV and DENV hinges largely on both the 5'-silyl group and the substituent of 3'-triazole or its bioisosteres. Particularly interesting is the 5' silyl group which turns on the antiviral activity against WNV and DENV while abrogating the previously reported antiviral potency against human immunodeficiency virus (HIV-1). The antiviral activity was confirmed through a plaque assay where viral titer reduction was observed in the presence of selected compounds. Molecular modeling and competitive S-adenosyl-l-methionine (SAM) binding assay suggest that these compounds likely confer antiviral activity via binding to methyltransferase (MTase). PMID- 25909388 TI - Enforcement avoidance behavior near automated speed enforcement areas in Korean expressways. AB - Automated speed enforcement system (ASES) has been deployed as a safety countermeasure on Korean roadways to reduce speeding-related traffic crashes; information on ASES locations is mandated to be open to the public. However, because drivers are alerted about enforcement via on-board navigation systems and roadside signs, they can avoid enforcement by momentarily reducing their speeds near ASES locations. This enforcement avoidance behavior (EAB) can induce sudden changes in speed near the enforcement locations and thereby increase risk of crash occurrence. In light of this situation, the present study evaluates the effects of ASES on traffic behavior and safety. An analysis of traffic data shows that drivers indeed diminish their speeds near enforcement locations, and accelerate shortly after passing the locations. To investigate how this behavior affects safety performance, this study, by using Empirical Bayes analysis with comparison groups, compares crash occurrences along a certain section before and after the installation of ASES. The comparative analysis shows that overall crash occurrence dropped by 7.6% on average near the enforcement locations, although the reduction was not significant. However, an average 11% non-significant increase in crash occurrence is also observed in the upstream segment, where enforcement is announced to drivers and traffic starts to diminish speed. The findings suggest that the sudden changes in traffic speed induced by EAB substantially negate the benefits of ASES. Therefore, modification of the design of current ASES is required to mitigate EAB and further improve the effectiveness of ASES. PMID- 25909389 TI - Identifying behaviour patterns of construction safety using system archetypes. AB - Construction safety management involves complex issues (e.g., different trades, multi-organizational project structure, constantly changing work environment, and transient workforce). Systems thinking is widely considered as an effective approach to understanding and managing the complexity. This paper aims to better understand dynamic complexity of construction safety management by exploring archetypes of construction safety. To achieve this, this paper adopted the ground theory method (GTM) and 22 interviews were conducted with participants in various positions (government safety inspector, client, health and safety manager, safety consultant, safety auditor, and safety researcher). Eight archetypes were emerged from the collected data: (1) safety regulations, (2) incentive programs, (3) procurement and safety, (4) safety management in small businesses (5) production and safety, (6) workers' conflicting goals, (7) blame on workers, and (8) reactive and proactive learning. These archetypes capture the interactions between a wide range of factors within various hierarchical levels and subsystems. As a free-standing tool, they advance the understanding of dynamic complexity of construction safety management and provide systemic insights into dealing with the complexity. They also can facilitate system dynamics modelling of construction safety process. PMID- 25909390 TI - "Crashing the gates" - selection criteria for television news reporting of traffic crashes. AB - This study investigates which crash characteristics influence the probability that the crash is reported in the television news. To this purpose, all news items from the period 2006-2012 about traffic crashes from the prime time news of two Belgian television channels are linked to the official injury crash database. Logistic regression models are built for the database of all injury crashes and for the subset of fatal crashes to identify crash characteristics that correlate with a lower or higher probability of being reported in the news. A number of significant biases in terms of crash severity, time, place, types of involved road users and victims' personal characteristics are found in the media reporting of crashes. More severe crashes are reported in the media more easily than less severe crashes. Significant fluctuations in media reporting probability through time are found in terms of the year and month in which the crash took place. Crashes during week days are generally less reported in the news. The geographical area (province) in which the crash takes place also has a significant impact on the probability of being reported in the news. Crashes on motorways are significantly more represented in the news. Regarding the age of the involved victims, a clear trend of higher media reporting rates of crashes involving young victims or young fatalities is observed. Crashes involving female fatalities are also more frequently reported in the news. Furthermore, crashes involving a bus have a significantly higher probability of being reported in the news, while crashes involving a motorcycle have a significantly lower probability. Some models also indicate a lower reporting rate of crashes involving a moped, and a higher reporting rate of crashes involving heavy goods vehicles. These biases in media reporting can create skewed perceptions in the general public about the prevalence of traffic crashes and eventually may influence people's behaviour. PMID- 25909391 TI - Safety assessment of the conversion of toll plazas to all-electronic toll collection system. AB - Traditional mainline toll plaza (TMTP) is considered the most high-risk location on the toll roads. Conversion from TMTP or hybrid mainline toll plaza (HMTP) to an all-electronic toll collection (AETC) system has demonstrated measured improvement in traffic operations and environmental issues. However, there is a lack of research that quantifies the safety impacts of these new tolling systems. This study evaluated the safety effectiveness of the conversion from TMTP or HMTP to AETC system. An extensive data collection was conducted that included hundred mainline toll plazas located on more than 750 miles of toll roads in Florida. Various observational before-after studies including the empirical Bayes method were applied. The results indicated that the conversion from the TMTP to an AETC system resulted in an average crash reduction of 76, 75, and 68% for total, fatal and-injury and property damage only (PDO) crashes, respectively; for rear end and lane change related (LCR) crashes the average reductions were 80 and 74%, respectively. The conversion from HMTP to AETC system enhanced traffic safety by reducing crashes by 24, 28 and 20% of total, fatal-and-injury, and PDO crashes respectively; also, for rear end and LCR crashes, the average reductions were 15 and 22%, respectively. Overall, this paper provided an up-to-date safety impact of using different toll collection systems. The results proved that the AETC system significantly improved traffic safety for all crash categories; and changed toll plazas from the highest risk on Expressways to be similar to regular segments. PMID- 25909392 TI - An in vivo study of electrical charge distribution on the bacterial cell wall by atomic force microscopy in vibrating force mode. AB - We report an in vivo electromechanical atomic force microscopy (AFM) study of charge distribution on the cell wall of Gram+ Rhodococcus wratislaviensis bacteria, naturally adherent to a glass substrate, under physiological conditions. The method presented in this paper relies on a detailed study of AFM approach/retract curves giving the variation of the interaction force versus distance between the tip and the sample. In addition to classical height and mechanical (as stiffness) data, mapping of local electrical properties, such as bacterial surface charge, was proved to be feasible at a spatial resolution better than a few tens of nanometers. This innovative method relies on the measurement of the cantilever's surface stress through its deflection far from (>10 nm) the repulsive contact zone: the variations of surface stress come from the modification of electrical surface charge of the cantilever (as in classical electrocapillary measurements) likely stemming from its charging during contact of both the tip and the sample electrical double layers. This method offers an important improvement in local electrical and electrochemical measurements at the solid/liquid interface, particularly in high-molarity electrolytes when compared to techniques focused on the direct use of electrostatic force. It thus opens a new way to directly investigate in situ biological electrical surface processes involved in numerous practical applications and fundamental problems such as bacterial adhesion, biofilm formation, microbial fuel cells, etc. PMID- 25909393 TI - Extremely high brightness from polymer-encapsulated quantum dots for two-photon cellular and deep-tissue imaging. AB - Materials possessing high two photon absorption (TPA) are highly desirable for a range of fields, such as three-dimensional data storage, TP microscopy (TPM) and photodynamic therapy (PDT). Specifically, for TPM, high TP excitation (TPE) brightness (sigma * phi, where sigma is TPA cross-sections and phi is fluorescence quantum yield), excellent photostability and minimal cytotoxicity are highly desirable. However, when TPA materials are transferred to aqueous media through molecule engineering or nanoparticle formulation, they usually suffer from the severely decrease of quantum yield (QY). Here, we report a convenient and efficient method for preparing polymer-encapsulated quantum dots (P-QD). Interestingly, the QY was considerably enhanced from original 0.33 (QDs in THF) to 0.84 (P-QD in water). This dramatic enhancement in QY is mainly from the efficiently blocking nonradiative decay pathway from the surface trap states, according to the fluorescence decay lifetimes analysis. The P-QD exhibits extremely high brightness (sigma * phi up to 6.2 * 10(6) GM), high photostability, excellent colloidal stability and minimal cytotoxicity. High quality cellular TP imaging with high signal-to-background ratio (> 100) and tissue imaging with a penetration depth of 2200 MUm have been achieved with P-QD as probe. PMID- 25909395 TI - From the editor. PMID- 25909394 TI - Effects of sensilla morphology on mechanosensory sensitivity in the crayfish. AB - Crustaceans contain a great variety of sensilla along their antennules that enable them to sense both hydrodynamic and chemical stimuli in aquatic environments, and can be used to inspire the design of engineered sensing systems. For example, along the antennule of the freshwater crayfish, Procambarus clarkii, four predominant mechanosensory sensilla morphologies are found. To study their response to upstream flow perturbations, atomic force microscopy was utilized to determine P. clarkii sensilla bending in response to an applied force and a mean torsional stiffness, k(t) = 1 * 10(-12) N m degree(-1) was found. A numerical model was developed to quantify the deformation of the four sensilla morphologies due to flow perturbations within their surrounding fluid. These flow perturbations were intended to mimic predator and ambient fluid movements. Results show that upstream fluid motion causes alterations in velocity near the sensilla, accompanied by corresponding variations in pressure along the sensilla surface. The feathered and filamentous sensilla, which are hydrodynamic sensilla, were found to be highly sensitive to flow perturbations. The beaked and asymmetric sensilla, which are bimodal chemo-mechanoreceptors, were found to be much less sensitive to hydrodynamic disturbances. Results also show that sensilla are most sensitive to fluid movement in the along-axis plane of the antennule, with a sharp drop in sensitivity perpendicular to this axis. This sensitivity agrees well with neural responses measured directly from the paired sensory neurons associated with each sensillum. Greater along-axis sensitivity is likely beneficial for determining the direction of fluid movements, which may be important for both aquatic organisms and biomimetic sensing systems. PMID- 25909396 TI - Using a facilitation model to achieve patient-centered medical home recognition. AB - This article describes how a facilitation model that included a partnership between a Community Care of North Carolina network and undergraduates at a regional university supported rural primary care practices in transforming their practices to become National Committee for Quality Assurance-recognized patient centered medical homes. Health care management and preprofessional undergraduate students worked with 14 rural primary care practices to redesign practice processes and complete the patient-centered medical home application. Twelve of the practices participated in the evaluation of the student contribution. A semistructured interview guide containing questions about practice characteristics, student competencies, and the value of the student's contribution to their practice's achievement of patient-centered medical home recognition was used to interview practice managers or their designee. Analysis included item-descriptive statistics and qualitative analysis of narrative content. All 12 participating practices achieved 2011 National Committee for Quality Assurance patient-centered medical home recognition, with 4 practices achieving level 3, 5 practices achieving level 2, and 3 practices achieving level 1. The facilitation model using partnerships between health care agencies and universities might be an option for enhancing a practice's internal capacity for successful transformation and should be explored further. PMID- 25909397 TI - Has competition increased hospital technical efficiency? AB - Hospital competition and managed care have affected the hospital industry in various ways including technical efficiency. Hospital efficiency has become an important topic, and it is important to properly measure hospital efficiency in order to evaluate the impact of policies on the hospital industry. The primary independent variable is hospital competition. By using the 2001-2004 inpatient discharge data from Florida, we calculate the degree of hospital competition in Florida for 4 years. Hospital efficiency scores are developed using the Data Envelopment Analysis and by using the selected input and output variables from the American Hospital Association's Annual Survey of Hospitals for those acute care general hospitals in Florida. By using the hospital efficiency score as a dependent variable, we analyze the effects of hospital competition on hospital efficiency from 2001 to 2004 and find that when a hospital was located in a less competitive market in 2003, its technical efficiency score was lower than those in a more competitive market. PMID- 25909398 TI - Manager-employee interaction in ambulance services: an exploratory study of employee perspectives on management communication. AB - Managers of ambulance stations face many communicative challenges in their interaction with employees working in prehospital first-line services. The article presents an exploratory study of how paramedics experience these challenges in communication with station leaders. On the basis of a dialogue perspective in qualitative method, 24 paramedics were interviewed in one-to-one and focus group settings. Naturalistic and phenomenological approaches were used to analyze the interviews. All the paramedics said that they wished to be more involved in decision processes and that station managers should provide better explanations of information "from above." The paramedics understood that it was difficult for the managers to find time for extensive dialogue, but many thought that the managers should give more priority to communication. The paramedics' views correspond to theoretical assumptions in human resource management. According to this model, employees should be involved in decision processes on management levels, as long as it is realistically possible to do so. Furthermore, expressing emotional support and positive attitudes does not take much time, and the study suggests that many ambulance managers should focus more on interpersonal relations to employees. It has been extensively documented that management communication affects organizational performance. The study indicates that managers of ambulance stations should be more aware of how their leadership style affects professional commitment and motivation in the first-line services. PMID- 25909399 TI - International Classification of Diseases, 10th Revision, coding for prematurity: need for standardized nomenclature. AB - The International Classification of Diseases, Ninth Revision, Clinical Modification was introduced in the United States in 1979 as a coding system to document inpatient diagnostic and procedural codes. However, transition to International Classification of Diseases, 10th Revision (ICD-10) has been federally mandated by October 2015 due to advances in medical technology and procedures in medicine. This includes ICD-10, Clinical Modification and ICD-10, Procedure Coding System. The ICD-10 coding set is more detailed and specific and will add 54 000 diagnosis codes and 83 000 procedure codes to the International Classification of Diseases, Ninth Revision, Clinical Modification code set, thereby accounting for increased granularity of codes needed for evidence-based medicine. This article describes the importance of need for specificity of the codes and emphasizes the role of training in preparing for implementation of the ICD-10 coding system. An example is made for the need for accuracy in ICD-10 codes for prematurity as regards defining the premature population using standardized nomenclature. PMID- 25909400 TI - Robotic joint replacement surgery: does technology improve outcomes? AB - Osteoarthritis is a common disease that leads patients to seek total joint replacement (TJR). Component misalignment leads to failure of TJR. Computer navigation enhances the precision of component alignment, but the addition of robotic guidance can boost TJR to a higher level of accuracy. Some 29 English language peer-reviewed articles from 2002 to 2013 and 1 Web site were reviewed. A conceptual framework was adapted to explain benefits and barriers of adoption of robotic TJR. A total of 10 studies were reviewed with focus on more precise alignment, outcomes, length of stay, and costs. Cost to obtain robotic surgical equipment was found to be about $1 million with maintenance costs approaching $350 000. Robotic techniques compared with conventional orthopedic surgery showed slight variances in favor of robotic procedures. Although hospitals have the potential to reduce costs and improve outcomes with robotic TJR, the expenditure and maintenance have not been proven a clear return on investment. As surgical robotic technology evolves in accuracy and accessibility, joint replacement surgery may benefit from improved precision and decreased health care costs. However, equipment purchase and upkeep costs and surgeon training may impede use to its full potential in orthopedic surgery in the United States. PMID- 25909402 TI - Health care leader competencies and the relevance of emotional intelligence. AB - As health care leader competencies continue to be refined and emphasized in health care administration educational programs, the "soft skills" of emotional intelligence have often been implied, but not included explicitly. The purpose of this study was to better understand what relationship, if any, could be identified between health care leader competencies and emotional intelligence. A quantitative correlational method of study was used, utilizing self-assessments and 360-degree assessments of both constructs. There were 43 valid participants in the study, representing the various types of health care delivery systems. Correlational analysis suggested there was a positive relationship; for each unit of increase in emotional intelligence, there was a 0.6 increase in overall health care leadership competence. This study did not suggest causation, but instead suggested that including the study and development of emotional intelligence in health care administration programs could have a positive impact on the degree of leader competence in graduates. Some curricula suggestions were provided, and further study was recommended. PMID- 25909403 TI - Community health needs assessment: a pathway to the future and a vision for leaders. AB - There is a need to implement evidence-based public health practice that integrates targeted and specific strategies and actions with community preferences to improve the health of populations. A community health needs assessment (CHNA) is vital to identifying the health concerns of communities, to learn about the factors that influence their health and the assets, resources, and challenges that impact those factors. It is required for tax-exempt entities to conduct a CHNA and adopt an implementation strategy to meet the identified community health needs. The goal of this article is to chart a pathway for health system leaders utilizing a CHNA process to address disparities in racial/ethnic groups and other medically underserved populations and to meet legal requirements. The efforts of the H. Lee Moffitt Cancer Center and Research Institute in developing its CHNA will be highlighted to provide clear evidence to health system leaders for why and how to conduct a thorough and compelling CHNA to meaningfully address health disparities locally and respond to longstanding historical health inequities at the health system level. PMID- 25909404 TI - Hospital budget increase for information technology during phase 1 meaningful use. AB - Federal policies have a significant effect on how businesses spend money. The 2009 HITECH (Health Information Technology for Economic and Clinical Health Act) authorized incentive payments through Medicare and Medicaid to clinicians and hospitals when they use certified electronic health records privately and securely to achieve specified improvements in care delivery. Federal incentive payments were offered in 2011 for hospitals that had satisfied "meaningful use" criteria. A longitudinal study of nonfederal hospital information technology (IT) budgets (N = 493) during the years 2009 to 2011 found increases in the percentage of hospital annual operating budgets allocated to IT in the years leading up to these federal incentives. This increase was most pronounced among hospitals receiving high proportions of their reimbursements from Medicaid, followed by hospitals receiving high proportions of their reimbursements from Medicare, possibly indicating a budget shift during this period to more IT spending to achieve meaningful-use policy guidelines. PMID- 25909405 TI - The manager and the merger: adjusting to functioning in a blended organization. AB - Once a cottage industry consisting of many scattered providers, health care has become an industry of large organizations and multi-institutional systems. Various organizational combinations continue to occur, especially in the form of mergers, affiliations, and the creation and expansion of health care systems. In the midst of this ongoing dramatic change, the role of the individual manager remains essentially unchanged in concept, but the arena in which that role is pursued is rapidly changing. Areas of responsibility are becoming broader, the groups overseen by individual managers are becoming larger, and many of the older "principles" of management are being tested and strained. Today's health care manager is learning that survival and success depend more than ever on flexibility and adaptability. PMID- 25909407 TI - Evaluation of the safety and feasibility of resuscitative endovascular balloon occlusion of the aorta. AB - BACKGROUND: Resuscitative endovascular balloon occlusion of the aorta (REBOA) is one of the ultimately invasive procedures for managing a noncompressive torso injury. Since it is less invasive than resuscitative open aortic cross-clamping, its clinical application is expected. METHODS: We retrospectively evaluated the safety and clinical feasibility of REBOA (intra-aortic occlusion balloon, MERA, Tokyo, Japan) using the Seldinger technique to control severe hemorrhage. Of 5,230 patients admitted to our trauma center in Japan from 2007 to 2013, we included 24 who underwent REBOA primarily. The indications for REBOA were a pelvic ring fracture or hemoperitoneum with hemodynamically instability and impending cardiac arrest. Emergency hemostasis was performed during REBOA in all patients. RESULTS: All 24 patients had a blunt injury, the median age was 59 (interquartile range, 41-71 years), the median Injury Severity Score (ISS) was 47 (interquartile range, 37-52), the 30-day survival rate was 29.2% (n = 7), and the median probability survival rate was 12.5%. Indications for REBOA were hemoperitoneum and pelvic ring fracture in 15 cases and overlap in 8 cases. In 10 cases of death, the balloon could not be deflated in 5 cases. In 19 cases in which the balloon was deflated, the median duration of aortic occlusion was shorter in survivors than in deaths (21 minutes vs. 35 minutes, p = 0.05). The mean systolic blood pressure was significantly increased by REBOA (from 53.1 [21] mm Hg to 98.0 [26.6] mm Hg, p < 0.01). There were three cases with complications (12.5%), one external iliac artery injury and two lower limb ischemias in which lower limb amputation was necessary in all cases. Acute kidney injury developed in all three cases, but failure was not persistent. CONCLUSION: REBOA seems to be feasible for trauma resuscitation and may improve survivorship. However, the serious complication of lower limb ischemia warrants more research on its safety. LEVEL OF EVIDENCE: Therapeutic/care management, level V. PMID- 25909406 TI - Ketamine/propofol admixture (ketofol) at induction in the critically ill against etomidate (KEEP PACE trial): study protocol for a randomized controlled trial. AB - BACKGROUND: Endotracheal intubation (ETI) is commonly performed as a life-saving procedure in the intensive care unit (ICU). It is often associated with significant hemodynamic perturbations and can severely impact the outcome of ICU patients. Etomidate is often chosen by many critical care providers for the patients who are hypotensive because of its superior hemodynamic profile compared to other induction medications. However, recent evidence has raised concerns about the increased incidence of adrenal insufficiency and mortality associated with etomidate use. A combination of ketamine and propofol (known as ketofol) has been studied in various settings as an alternative induction agent. In recent years, studies have shown that this combination may provide adequate sedation while maintaining hemodynamic stability, based on the balancing of the hemodynamic effects of these two individual agents. We hypothesized that ketofol may offer a valuable alternative to etomidate in critically ill patients with or without hemodynamic instability. METHODS/DESIGN: A randomized controlled parallel group clinical trial of adult critically ill patients admitted to either a medical or surgical ICU at Mayo Clinic in Rochester, MN will be conducted. As part of planned emergency research, informed consent will be waived after appropriate community consultation and notification. Patients undergoing urgent or emergent ETI will receive either etomidate or a 1:1 admixture of ketamine and propofol (ketofol). The primary outcome will be hemodynamic instability during the first 15 minutes following drug administration. Secondary outcomes will include ICU length of stay, mortality, adrenal function, ventilator-free days and vasoactive medication use, among others. The planned sample size is 160 total patients. DISCUSSION: The overall goal of this trial is to assess the hemodynamic consequences of a ketamine-propofol combination used in critically ill patients undergoing urgent or emergent ETI compared to etomidate, a medication with an established hemodynamic profile. The trial will address a crucial gap in the literature regarding the optimal induction agent for ETI in patients that may have potential or established hemodynamic instability. Greater experience with planned emergency research will, hopefully, pave the way for future prospective randomized clinical trials in the critically ill population. TRIAL REGISTRATION: Clinicaltrials.gov: NCT02105415. 31 March 2014. PMID- 25909408 TI - The impact of tranexamic acid on mortality in injured patients with hyperfibrinolysis. AB - BACKGROUND: In 2011, supported by data from two separate trauma centers, we implemented a protocol to administer tranexamic acid (TXA) in trauma patients with evidence of hyperfibrinolysis (HF) on admission. The purpose of this study was to examine whether the use of TXA in patients with HF determined by admission rapid thrombelastography was associated with improved survival. METHODS: Following institutional review board approval, we evaluated all trauma patients 16 years or older admitted between September 2009 and September 2013. HF was defined as LY-30 of 3% or greater. Patients with LY-30 less than 3.0% were excluded. Patients were divided into those who received TXA (TXA group) and those who did not (no-TXA group). After univariate analyses, a purposeful, logistic regression model was developed a priori to evaluate the impact of TXA on mortality (controlling for age, sex, Injury Severity Score (ISS), arrival physiology, and base deficit). RESULTS: A total of 1,032 patients met study criteria. Ninety-eight (10%) received TXA, and 934 (90%) did not. TXA patients were older (median age, 37 years vs. 32 years), were more severely injured (median ISS, 29 vs. 14), had a lower blood pressure (median systolic blood pressure 103 mm Hg vs. 125 mm Hg), and were more likely to be in shock (median, base excess, -5 mmol/dL vs. -2 mmol/dL), all p < 0.05. Twenty-three percent of the patients had a repeat thrombelastography within 6 hours; 8.8% of the TXA patients had LY-30 of 3% or greater on repeat rapid thrombelastography (vs. 10.1% in the no-TXA group, p = 0.679). Unadjusted in-hospital mortality was higher in the TXA group (40% vs. 17%, p < 0.001). There were no differences in venous thromboembolism (3.3% vs. 3.8%). Logistic regression failed to find a difference in in-hospital mortality among those receiving TXA (odds ratio, 0.74; 95% confidence interval, 0.38-1.40; p 0.80). CONCLUSION: In the current study, the use of TXA was not associated with a reduction in mortality. Further studies are needed to better define who will benefit from an administration of TXA. LEVEL OF EVIDENCE: Therapeutic study, level IV. PMID- 25909410 TI - Does unit designation matter? A dedicated trauma intensive care unit is associated with lower postinjury complication rates and death after major complication. AB - BACKGROUND: Recent data suggest that specialty intensive care units (ICUs) have outcomes better than those of mixed ICUs. The cause for this apparent discrepancy has not been well established. We hypothesized that trauma patients admitted to a dedicated trauma ICU (TICU) would have a lower complication rate as well as death after complication (failure to rescue [FTR]). METHODS: This was a retrospective review of the ICUs of two Level I trauma centers covered by one group of surgical intensivists. One center has a dedicated TICU, while the other has a mixed ICU. Demographic and clinical characteristics were stratified into TICU and ICU groups. The primary outcomes were postinjury complications and FTR. Multivariate regression was used to derive factors associated with complications and FTR. RESULTS: During the 5-year study period, 3,833 patients were analyzed. TICU patients were older (57.8 vs. 47.0 years, p < 0.0001), had higher Charlson score (2 vs. 1, p = 0.001), had more severe head injuries (Head Abbreviated Injury Scale [AIS] score >= 3, 50.0% vs. 37.5%, p < 0.0001), and had greater injury burden (Injury Severity Score [ISS] > 16, 49.6% vs. 38.6%, p < 0.0001) than those admitted to the mixed ICU. Need for immediate operative intervention was similar (18.0% vs. 17.6%, p = 0.788). Overall complications were significantly higher in trauma patients admitted to the mixed ICU (27.5% vs. 17.0%, p < 0.0001), as well as FTR (3.7% vs. 1.8%, p < 0.0001). Trauma patients admitted to a dedicated TICU had significantly lower chance of developing a postinjury complication (adjusted odds ratio [AOR], 0.5; p < 0.0001), FTR (AOR, 0.3; p < 0.0001), and overall mortality (AOR, 0.4; p < 0.0001). CONCLUSION: Admission of critically ill trauma patients to a TICU staffed by a surgical intensivist is associated with a lower complication rate and FTR. Factors such as trauma nursing experience, education, and unit management structure should be further explored to elucidate the observed improved outcomes. LEVEL OF EVIDENCE: Prognostic study, level III. PMID- 25909409 TI - Impact of specific postoperative complications on the outcomes of emergency general surgery patients. AB - BACKGROUND: The relative contribution of specific postoperative complications on mortality after emergency operations has not been previously described. Identifying specific contributors to postoperative mortality following acute care surgery will allow for significant improvement in the care of these patients. METHODS: Patients from the 2005 to 2011 American College of Surgeons' National Surgical Quality Improvement Program database who underwent emergency operation by a general surgeon for one of seven diagnoses (gallbladder disease, gastroduodenal ulcer disease, intestinal ischemia, intestinal obstruction, intestinal perforation, diverticulitis, and abdominal wall hernia) were analyzed. Postoperative complications (pneumonia, myocardial infarction, incisional surgical site infection, organ/space surgical site infection, thromboembolic process, urinary tract infection, stroke, or major bleeding) were chosen based on surgical outcome measures monitored by national quality improvement initiatives and regulatory bodies. Regression techniques were used to determine the independent association between these complications and 30-day mortality, after adjustment for an array of patient- and procedure-related variables. RESULTS: Emergency operations accounted for 14.6% of the approximately 1.2 million general surgery procedures that are included in American College of Surgeons' National Surgical Quality Improvement Program but for 53.5% of the 19,094 postoperative deaths. A total of 43,429 emergency general surgery patients were analyzed. Incisional surgical site infection had the highest incidence (6.7%). The second most common complication was pneumonia (5.7%). Stroke, major bleeding, myocardial infarction, and pneumonia exhibited the strongest associations with postoperative death. CONCLUSION: Given its disproportionate contribution to surgical mortality, emergency surgery represents an ideal focus for quality improvement. Of the potential postoperative targets for quality improvement, pneumonia, myocardial infarction, stroke, and major bleeding have the strongest associations with subsequent mortality. Since pneumonia is both relatively common after emergency surgery and strongly associated with postoperative death, it should receive priority as a target for surgical quality improvement initiatives. LEVEL OF EVIDENCE: Prognostic and epidemiologic study, level III. PMID- 25909411 TI - The pediatric trauma center and the inclusive trauma system: Impact on splenectomy rates. AB - BACKGROUND: Before 2006, the Delaware Trauma System (DTS) did not include a designated pediatric trauma center (PTC). In 2006, the Delaware Trauma System designated and the American College of Surgeons Committee on Trauma verification/consultation program verified Nemours AI DuPont Hospital for Children, a freestanding children's hospital, as a PTC. We evaluated the impact of the addition of the PTC to the state trauma system on pediatric traumatic splenectomy rates. METHODS: The study cohort comprised DTS trauma registry recorded children younger than 16 years with spleen injury (ICD-9 codes 865.0 865.9) from January 1998 through December 2012. This cohort was categorized into pre-PTC (1998-2005) and post-PTC (2006-2012) groups. Penetrating injuries were excluded. Comparisons between groups included age, gender, length of stay, organ specific injury grade, Injury Severity Score, incidence of polytrauma, splenectomy rate, and admitting hospital. Management, operative versus nonoperative, of low grade (Organ Injury Scale [OIS] score, 1-3) and high grade (OIS score, 4-5) were also compared. Pearson's chi analysis was performed for categorical variables. Continuous variables were reported as mean (standard deviation) and compared by Student's t test for independent normally distributed samples. Mann-Whitney U-test was used for non-normally distributed variables. A value of p < 0.05 was considered significant. RESULTS: Of the 231 pediatric spleen injuries, 118 occurred pre-PTC and 113 occurred post-PTC. There were no significant differences in age, gender, length of stay, Injury Severity Score, OIS grade, or incidence of polytrauma. Splenectomy rates decreased from 11% (13 of 118) pre-PTC to 2.7% (3 of 113) post-PTC (p = 0.012). CONCLUSION: The addition of an American College of Surgeons-verified PTC within an inclusive trauma system that was previously without one was associated with a significant reduction in the rate of blunt trauma-related splenectomy. Integration of a verified PTC is an influential factor in achieving spleen preservation rates equivalent to published American Pediatric Surgery Association benchmarks within a trauma system. LEVEL OF EVIDENCE: Therapeutic study, level IV; epidemiologic study, level III. PMID- 25909412 TI - Trends in pediatric spleen management: Do hospital type and ownership still matter? AB - BACKGROUND: Nonoperative management of traumatic blunt splenic injury is preferred over splenectomy because of improved outcomes and reduced complications. However, variability in treatment is previously reported with respect to hospital profit types and ownership. METHODS: Our study objectives were to investigate the past decade's trends in pediatric splenic injury management and to determine whether previously reported disparities by hospital type have changed. We analyzed data from the Kid's Inpatient Database from Healthcare Cost and Utility Project for Years 2000, 2003, 2006, and 2009. Multivariable logistic regression was used to investigate the likelihood of receiving splenectomy in different hospital profit and ownership types. Patients 18 years and younger admitted with blunt splenic injury (DRG International Classification of Diseases-9th Rev.-Clinical Modification code 865) were included. Treatment was dichotomized into nonoperative management, defined as initial attempt at nonoperative management, and operative management, defined as splenectomy within 1 day of admission. RESULTS: Of 17,044 patient records, 11,893 participants were studied. Not-for-profit hospitals demonstrated a higher rate of nonoperative management than for-profit hospitals in 2000 (83.8% vs. 71.0 %). Both not-for-profit and for-profit hospitals increased the use of nonoperative management, with a narrower disparity observed by 2009 (87.5% vs. 84.6%). The use of splenectomy was reduced significantly between 2000 and 2003 (odds ratio, 0.66; weighted 95% confidence interval, 0.54-0.81). The rate of nonoperative management in children's hospitals remained very high across the study period (98.6% in 2009) and continued to be the benchmark for pediatric spleen injury management. CONCLUSION: Improvement was observed in nonoperative management rates for pediatric spleen injuries in both not-for-profit and for-profit hospitals. However, general hospitals still fail to reach the target of 90% nonoperative management. Further investigations are needed to facilitate optimal management of such children in general hospitals. LEVELS OF EVIDENCE: Epidemiologic and prognostic study, level III. PMID- 25909413 TI - Absence of clinical findings reliably excludes unstable cervical spine injuries in children 5 years or younger. AB - BACKGROUND: Increased accessibility and rapidity of computed tomography (CT) have led to increased use and radiation exposure to pediatric trauma patients. The thyroid is radiosensitive and therefore at risk for developing malignancy from radiation exposure during cervical spine CT. This analysis aimed to determine which preelementary trauma patients warrant cervical spine CT by defining incidence and clinical characteristics of preelementary cervical spine injury. METHODS: This was a retrospective review of pre-elementary trauma patients from 1998 to 2010 with cervical spine injury admitted to a Level I trauma center. Patients were identified from the trauma registry using DRG International Classification of Diseases-9th Rev. codes and reviewed for demographics, mechanism of injury, clinical presentation, injury location, injury type, treatment, and outcome. RESULTS: A total of 2,972 preelementary trauma patients were identified. Twenty-two (0.74%) had confirmed cervical spine injuries. Eleven (50%) were boys, and the mean (SD) age was 3 (1.7) years. The most common mechanism of injury was motor vehicle collision (n = 16, 73%). The majority (59%) were in extremis, and 12 (55%) arrived intubated. The median Glasgow Coma Scale (GCS) score was 3 (interquartile range, 3-10); the median Injury Severity Score (ISS) was 33 (interquartile range, 17-56). Nineteen injuries (76%) were at the level of C4 level and higher. The mortality rate was 50%. All patients had clinical findings suggestive of or diagnostic for cervical spine injury; 18 (82%) had abnormal neurologic examination result, 2 (9%) had torticollis, and 2 (9%) had neck pain. CONCLUSION: The incidence of cervical spine injury in preelementary patients was consistent with previous reports. Missing a cervical spine injury in asymptomatic preelementary patients is extremely low. Reserving cervical spine CT to symptomatic preelementary patients would decrease unnecessary radiation exposure to the thyroid. LEVEL OF EVIDENCE: Therapeutic study, level IV. PMID- 25909414 TI - The implementation of a multinational "walking blood bank" in a combat zone: The experience of a health service team deployed to a medical treatment facility in Afghanistan. AB - BACKGROUND: We present here a description of the experience in whole-blood transfusion of a health service team deployed to a medical treatment facility in Afghanistan from June 2011 to October 2011. The aim of our work was to show how a "walking blood bank" could provide a sufficient supply. METHODS: We gathered the blood-group types of military personnel deployed to the theater of operations to evaluate our "potential walking blood bank," and we compared these data with our needs. RESULTS: Blood type frequencies among our "potential walking blood bank" were similar to those observed in European or American countries. Our resources could have been limited because of a low frequency of B blood type and negative rhesus in our "potential walking blood bank." Because of the large number of potential donors in the theater of operations, the risk of blood shortage was quite low and we did not face blood shortage despite significant transfusion requirements. Actually, 93 blood bags were collected, including rare blood types like AB and B blood types. CONCLUSION: In our experience, this international "walking blood bank" provided a quick, safe, and sufficient blood supply. More research in this area is needed, and our results should be confirmed by further prospective trials. LEVEL OF EVIDENCE: Therapeutic study, level V. PMID- 25909415 TI - Acute traumatic coagulopathy: Whole blood thrombelastography measures the tip of the iceberg. AB - BACKGROUND: Thrombelastography (TEG) is suggested as an optimal instrument for the identification of acute traumatic coagulopathy-induced alterations in coagulation status. Patient whole blood (WB) used in TEG analysis is generally collected from a large blood vessel containing representative systemic blood, often close to 40% hematocrit (Hct). Trauma patients often exhibit bleeding from the microvasculature. This study examines early coagulation function changes at the simulated microvascular level based on altered Hct and pH in vitro through TEG analyses of normal donor blood. METHODS: Anticoagulated normophysiologic fresh human blood was centrifuged. Individual component effects on coagulation were investigated through variable recombination groups: platelet-rich plasma (PRP), platelet-poor plasma (PPP), and red blood cells (RBCs), which were compared with WB. Acute traumatic coagulopathy-induced acidic microvascular environment was simulated and investigated using tissue factor-activated TEG analysis of variable Hct (40%, 30%, 20%, and 0%) samples and variable [H]. Incremental replacement of RBC with either PPP or normal saline (NS) simulated resuscitation in vitro was also conducted under similar conditions. RESULTS: Only acidified PRP reflected loss of clot strength. Acidified PRP and PPP were delayed equally in clot time. In all groups, inclusion of RBCs normalized clot time. RBC replacement with PPP significantly delayed clot time when samples were acid challenged, signifying greater acid effect in low Hct microvascular beds. NS simulated resuscitation incurred even greater clotting delays. CONCLUSION: Acidemia-induced coagulopathy at the level of the capillary Hct (1) is more severe than at higher Hct levels (larger blood vessels), (2) shows that simulated resuscitation with NS causes greater increases in clot time and decreases in clot strength beyond that which occurs with plasma replacement, and (3) may not accurately be portrayed through common TEG practice of testing systemic WB of greater than 30% Hct. PMID- 25909416 TI - Feasibility and utility of population-level geospatial injury profiling: prospective, national cohort study. AB - BACKGROUND: Geospatial analysis is increasingly being used to evaluate the design and effectiveness of trauma systems, but there are no metrics to describe the geographic distribution of incidents. The aim of this study, therefore, was to evaluate the feasibility and utility of using spatial analysis to characterize, at scale, the geospatial profile of an injured population. METHODS: This is a prospective national cohort study of all trauma patients attended to by the Scottish Ambulance Service in a complete year (between July 1, 2013, and June 30, 2014). Incident location and severity were collected at source. Incident distribution was evaluated using geostatistical techniques. RESULTS: There were 80,391 recorded incidents involving traumatic injury. Incident density was highest in the central Southern part of the country and along the East coast, broadly following the population distribution and road network. The overall distribution was highly clustered, and centered on the central Southern and Eastern parts of the country. When analyzed by triage category, the distribution of incidents triaged to major trauma center care was slightly less clustered than that of incidents triaged to trauma unit or local emergency hospital care, but the spread was similar. When analyzed by type of injury, assaults and falls were more clustered than incidents relating to traffic and transportation. CONCLUSION: This study demonstrates the feasibility and power of describing the geographic distribution of a group of injured patients. The methodology described has potential application for injury surveillance and trauma system design and evaluation. PMID- 25909417 TI - A pilot single-institution predictive model to guide rib fracture management in elderly patients. AB - BACKGROUND: Rib fractures (RFx) remain the most prevalent injury in an elderly population that will increase from 40 to 81 million for the next 30 years. We sought to create an accurate cost-effective algorithm to triage elderly patients with RFx that accounted for both frailty and trauma burden. METHODS: Retrospective analysis evaluated 400 patients older than 55 years with RFx admitted to a level 1 trauma center from 2007 to 2012. Comorbidities included chronic obstructive pulmonary disease, congestive heart failure, tobacco use, obesity, and nutrition and functional status. Trauma burden included RFx, tube thoracostomy, pulmonary contusions, and spine and extremity fractures. Patients with Glasgow Coma Scale scores lower than 13, thoracoabdominal surgery, or deaths from other causes were excluded. Comparative analysis used bivariate and logistic regression. Variables contributing to intubation (INT) and pneumonia (PNA) were then used to create a scoring system to predict the need for intensive care unit (ICU) admission. RESULTS: Six variables increased the risk for INT or PNA: chronic obstructive pulmonary disease, low albumin, assisted status, tube thoracostomy, Injury Severity Score, and RFx (p < 0.05). These six variables and congestive heart failure (odds ratio, 1.9; p = 0.06) were used to create a predictive model with the following scores assigned respectively: 1.4, 1.1, 1, 0.9, 0.1(n), 0.1(n), and 0.6. A score lower than 3.7 had a sensitivity and specificity of 78.5% and 78.9%. The negative predictive value was 94.5% for INT or PNA, suggesting a low risk for ICU requirement. Ninety-two ICU admissions had a score lower than 3.7. Forty had no other indication for ICU admission aside from RFx. These patients had an average ICU length of stay of 1.7 days, resulting in an increased cost of $2,200 per patient. CONCLUSION: A scoring system combining frailty and trauma burden may provide more accurate and cost-effective triage of the elderly trauma patient with RFx. Further prospective studies are required to verify our scoring system. LEVEL OF EVIDENCE: Prognostic and epidemiologic study, level III. PMID- 25909418 TI - Ventilator gas delivery wave form substantially impacts plateau pressure and peak to-plateau pressure gradient determination. AB - BACKGROUND: To determine whether plateau pressure (Pplat) measurement is lowered and peak airway pressure (Pawpeak)-to-Plat gradient is increased by measurement on a decelerating compared with square gas delivery wave form. METHODS: Prospective before and after study of mechanically ventilated injured and critically ill patients in an adult surgical intensive care unit. Pplat, Pawpeak, and Pawpeak-to-Pplat gradient were measured on decelerating and square gas delivery wave forms. RESULTS: Pplat and other routine ventilator parameters were measured in 82 (47 trauma, 35 emergency general surgery) consecutive convenience sampled adult intensive care unit patients on decelerating and then square gas delivery wave forms. Peak gas flow was fixed at 40 L/min; all other parameters (rate, tidal volume, positive end-expiratory pressure) were held constant. All patients were managed on assist control volume cycled ventilation using fentanyl and midazolam or propofol; no neuromuscular blockade was used. Patients with Pawpeak more than 35 cm H2O were excluded. Comparing decelerating with square gas delivery, mean Pawpeak was lower (25.1 +/- 2.3 cm H2O vs. 33.1 +/- 2.1 cm H2O; p < 0.0001) and mean Pplat was lower (21.3 +/- 1.9 cm H2O vs. 24.8 +/- 2.5 cm H2O; p < 0.0001), resulting in a decreased Pawpeak-to-Pplat gradient (3.8 +/- 2.1 vs. 8.3 +/- 2.3; p < 0.0001). CONCLUSION: Changing from a decelerating to a square gas delivery wave form significantly increases Pplat and Pawpeak, thereby increasing the Pawpeak-to-Pplat gradient. This increase may prompt unwarranted therapy aimed at reducing the gradient to its normal value of 4 cm H2O pressure or less. Conversely, patients with a high Pawpeak on a square wave form may benefit from transitioning to a decelerating wave form before changing ventilation parameters. LEVEL OF EVIDENCE: Diagnostic study, level III. PMID- 25909419 TI - Recombinant human brain natriuretic peptide ameliorates trauma-induced acute lung injury via inhibiting JAK/STAT signaling pathway in rats. AB - BACKGROUND: JAK/STAT signal pathway plays an important role in the inflammation process of acute lung injury (ALI). This study aimed to investigate the correlation between recombinant human brain natriuretic peptide (rhBNP) and the JAK/STAT signaling pathway and to explore the protective mechanism of rhBNP against trauma-induced ALI. METHODS: The arterial partial pressure in oxygen, lung wet-dry weight ratios, protein content in bronchoalveolar lavage fluid, the histopathologic of the lung, as well as the protein expressions of STAT1, JAK2, and STAT3 were detected. RESULTS: Sprague-Dawley rats were randomly divided into five groups: a control group, a sham-operated group, an ALI group, an ALI + rhBNP group, and an ALI + AG490 group. At 4 hours, 12 hours, 1 day, 3 days, and 7 days after injury, injured lung specimens were harvested. rhBNP pretreatment significantly ameliorated hypoxemia and histopathologic changes and alleviated pulmonary edema in trauma-induced ALI rats. rhBNP pretreatment reduced the phosphorylated protein and total protein level of STAT1. Similarly to JAK specific inhibitor AG490, rhBNP was shown to significantly inhibit the phosphorylation of JAK2 and STAT3 in rats with trauma-induced ALI. CONCLUSION: Our experimental findings indicated that rhBNP can protect rats against trauma induced ALI and that its underlying mechanism may be related to the inhibition of JAK/STAT signaling pathway activation. PMID- 25909420 TI - Early acute kidney injury in military casualties. AB - BACKGROUND: While acute kidney injury (AKI) has been well studied in a variety of patient settings, there is a paucity of data in patients injured in the course of the recent wars in Iraq and Afghanistan. We sought to establish the rate of early AKI in this population and to define risk factors for its development. METHODS: We combined the results of two studies performed at combat support hospitals in Afghanistan. Only US service members who required care in the intensive care unit were included for analysis. Data on age, race, sex, Injury Severity Score (ISS), first available lactate, and requirement for massive transfusion were collected. Univariate analyses were performed to identify factors associated with the subsequent development of early AKI. Multivariable Cox regression was used to adjust for potential confounders. RESULTS: The two observational cohorts yielded 134 subjects for analysis. The studies had broadly similar populations but differed in terms of age and need for massive transfusion. The rate of early AKI in the combined cohort was 34.3%, with the majority (80.5%) occurring within the first two hospital days. Patients with AKI had higher unadjusted mortality rates than those without AKI (21.7% vs. 2.3%, p < 0.001). After adjustment, ISS (hazard ratio, 1.02; 95% confidence interval, 1.00-1.03; p = 0.046) and initial lactate (hazard ratio, 1.16; 95% confidence interval, 1.03-1.31; p = 0.015) were independently associated with the development of AKI. CONCLUSION: AKI is common in combat casualties enrolled in two prospective intensive care unit studies, occurring in 34.3%, and is associated with crude mortality. ISS and initial lactate are independently associated with the subsequent development of early AKI. LEVEL OF EVIDENCE: Prognostic and epidemiologic study, level III. PMID- 25909421 TI - Influence of intra-abdominal pressure on the specificity of pulse pressure variations to predict fluid responsiveness. AB - BACKGROUND: The positive predictive value of pulse pressure variations (DeltaPP) to discriminate patients who should respond to volume expansion (VE) may be altered in mechanically ventilated patients. Our goal was to determine whether intra-abdominal pressure (IAP) measurements could discriminate patients with true positive DeltaPP values versus patients with false-positive DeltaPP values. METHODS: We designed a prospective pathophysiologic study in a mixed intensive care unit of a university hospital. Sixteen mechanically ventilated patients with hypotension (SAP, <90 mm Hg) and with DeltaPP of 13% or more were included. Cardiac output was assessed using Doppler echocardiography before and after VE; IAP was measured using the bladder pressure method. Patients were classified into two groups according to their response to a standardized VE (500 mL of NaCl 0.9%): responders (>=15% increase in cardiac output) and nonresponders. RESULTS: Nine patients (57%) were responders, and seven patients (43%) were nonresponders. Before VE, IAP was statistically higher in nonresponders (15 [11-22] mm Hg vs. 9 [6.5-11] mm Hg; p = 0.008). The area under the curve of the receiver operating characteristic curve was 0.9 +/- 0.08. In patients with DeltaPP of 13% or more, an IAP cutoff value of 10.5 mm Hg discriminated between responders and nonresponders with a sensitivity of 100% (59-100%) and a specificity of 78% (40 97%). CONCLUSION: An increase in IAP of more than 10.5 mm Hg can decrease the positive predictive value of DeltaPP. Hence, in patients prone to present abnormal IAP values, IAP should be measured before performing VE directed by the DeltaPP marker. LEVEL OF EVIDENCE: Diagnostic study, level II. PMID- 25909422 TI - An open, parallel, randomized, comparative, multicenter investigation evaluating the efficacy and tolerability of Mepilex Ag versus silver sulfadiazine in the treatment of deep partial-thickness burn injuries. AB - BACKGROUND: Partial-thickness burns are among the most frequently encountered types of burns, and numerous dressing materials are available for their treatment. A multicenter, open, randomized, and parallel study was undertaken to determine the efficacy and tolerability of silver sulfadiazine (SSD) compared with an absorbent foam silver dressing, Mepilex Ag, on patients aged between 5 years and 65 years with deep partial-thickness thermal burn injuries (2.5-25% total body surface area). METHODS: Patients were randomly assigned to either SSD (n = 82) applied daily or a Mepilex Ag dressing (n = 71) applied every 5 days to 7 days. The treatment period was up to 4 weeks. RESULTS: There was no significant difference between the two treatment groups with respect to the primary end point of time to healing, which occurred in 56 (79%) of 71 patients after a median follow-up time of 15 days in the Mepilex Ag group compared with 65 (79%) of 82 patients after a median follow-up time of 16 days in the SSD group (p = 0.74). There was also no significant difference in the percentage of study burn healed. Patients in the Mepilex Ag group had 87.1% of their study burn healed (out of the total burn area) compared with 85.2% of patients in the SSD group. However, the mean total number of dressings used was significantly more in the SSD group (14.0) compared with the Mepilex Ag group (3.06, p < 0.0001). There was no significant difference in the time until skin graft was performed between the two study groups. CONCLUSION: There was no difference in healing rates between Mepilex Ag and SSD, with both products well tolerated. The longer wear time of Mepilex Ag promotes undisturbed healing and makes it easier for patients to continue with their normal lives sooner. LEVEL OF EVIDENCE: Therapeutic study, level III. PMID- 25909423 TI - Validation of the quality of ultrasound imaging and competence (QUICk) score as an objective assessment tool for the FAST examination. AB - BACKGROUND: The Focused Assessment with Sonography for Trauma (FAST) examination has become a valuable tool in trauma resuscitation. Despite the widespread use of FAST training among traumatologists, no evidence-based guidelines exist to support optimal training requirements or to provide quantitative objective assessments of imaging capabilities. Both Task-Specific Checklist (TSC) and Global Rating Scale (GRS) have been validated as objective skill assessment tools; we developed both types of scoring checklist and assessed them for construct validity with the FAST examination. METHODS: Two scoring checklists, collectively termed the Quality of Ultrasound Imaging and Competence (QUICk) Score, were developed and subjected to a modified Delphi consensus process. Two cohorts of 12 novice and 12 expert sonographers performed the FAST examination and were evaluated by two experts according to the QUICk model. Total scores as well as anatomic subsets were compared via comparison of means, and logistic regression modeling was used to determine sensitivity and specificity. RESULTS: Experts achieved significantly higher total scores than novices on both scoring systems (17.2 vs. 11.1 of 24, p < 0.01 TSC, 29.8 vs. 18.4 of 40, p < 0.01 GRS). Sensitivity (85.7% TSC, 92.9% GRS) and specificity (75.0% TSC, 91.7% GRS) as well as area under the receiver operating characteristic curve (89.9% TSC, 97.6% GRS) were consistent with a highly discriminant tool. CONCLUSION: The QUICk Score is the first validated objective tool for assessment of the quality of FAST examination imaging. Use of this tool may be instrumental in developing an evidence-based minimum-performance standard and for assessing quality-improvement modifications in FAST examination training. PMID- 25909424 TI - Improved survival in UK combat casualties from Iraq and Afghanistan: 2003-2012. AB - BACKGROUND: The United Kingdom was at war in Iraq and Afghanistan for more than a decade. Despite assertions regarding advances in military trauma care during these wars, thus far, no studies have examined survival in UK troops during this sustained period of combat. The aims of this study were to examine temporal changes of injury patterns defined by body region and survival in a population of UK Military casualties between 2003 and 2012 in Iraq and Afghanistan. METHODS: The UK Military Joint Theatre Trauma Registry was searched for all UK Military casualties (survivors and fatalities) sustained on operations between January 1, 2003, and December 31, 2012. The New Injury Severity Score (NISS) was used to stratify injury severity. RESULTS: There were 2,792 UK Military casualties sustaining 14,252 separate injuries during the study period. There were 608 fatalities (22% of all casualties). Approximately 70% of casualties injured in hostile action resulted from explosive munitions. The extremities were the most commonly injured body region, involved in 43% of all injuries. The NISS associated with a 50% chance of survival rose each year from 32 in 2003 to 60 in 2012. CONCLUSION: An improvement in survival during the 10-year period is demonstrated. A majority of wounds are a result of explosive munitions, and the extremities are the most commonly affected body region. The authors recommend the development of more sophisticated techniques for the measuring of the performance of combat casualty care systems to include measures of morbidity and functional recovery as well as survival. LEVEL OF EVIDENCE: Epidemiologic study, level III. PMID- 25909425 TI - Upper extremity injuries in motorcyclists: Implications for mortality and need for rehabilitation services. AB - BACKGROUND: Motorcycle crashes (MCCs) constitute a disproportionately high number of road accidents that result in mortality and injury, compared with other motor vehicle collisions. Distribution and characteristics of upper extremity injuries sustained by motorcyclists and their implications are not well established. We sought to determine the epidemiology of upper extremity injuries in motorcyclists and the independent effects of the injuries on mortality and need for rehabilitative services. METHODS: All motorcyclist admissions at our Level I trauma center from 2006 through 2010 were retrospectively reviewed. We identified and categorized all upper extremity injuries. Demographic data, in-hospital mortality, disposition to a rehabilitation facility, and other potential confounding covariates were recorded. Propensity score-adjusted logistic regression models quantified the effects of upper limb injuries on mortality and transfer to rehabilitation facilities. RESULTS: Thirty-five percent (759 of 2,151 patients) involved in MCCs sustained upper extremity injury. Shoulder girdle injuries were most common (n = 433), followed by forearm fractures (n = 272). Mortality rate was 4% (87 of 2,151 patients) for all MCC admissions. Propensity score-adjusted logistic regression models showed that injuries distal to the humerus had an independent odds ratio for mortality of 0.41 (95% confidence interval, 0.21-0.8). Odds of requiring rehabilitation after discharge were 1.82 times (95% confidence interval, 1.47-2.26) higher when any upper extremity injury was sustained. CONCLUSION: Upper extremity injuries are common in MCCs. Distal injuries are associated with lower mortality rates possibly because of a "crumple zone effect" of distal upper extremities sparing the head and neck region from direct impact in head-first injuries. MCC patients with upper extremity injuries are more likely to require rehabilitation services. LEVEL OF EVIDENCE: Epidemiologic study, level III. PMID- 25909426 TI - Trauma care does not discriminate: The association of race and health insurance with mortality following traumatic injury. AB - BACKGROUND: Previous studies have reported that black race and lack of health insurance coverage are associated with increased mortality following traumatic injury. However, the association of race and insurance status with trauma outcomes has not been examined using contemporary, national, population-based data. METHODS: We used data from the National Inpatient Sample on 215,615 patients admitted to 1 of 836 hospitals following traumatic injury in 2010. We examined the effects of race and insurance coverage on mortality using two logistic regression models, one for patients younger than 65 years and the other for older patients. RESULTS: Unadjusted mortality was low for white (2.71%), black (2.54%), and Hispanic (2.03%) patients. We found no difference in adjusted survival for nonelderly black patients compared with white patients (adjusted odds ratio [AOR], 1.04; 95% confidence interval [CI], 0.90-1.19; p = 0.550). Elderly black patients had a 25% lower odds of mortality compared with elderly white patients (AOR, 0.75; 95% CI, 0.63-0.90; p = 0.002). After accounting for survivor bias, insurance coverage was not associated with improved survival in younger patients (AOR, 0.91; 95% CI, 0.77-1.07; p = 0.233). CONCLUSION: Black race is not associated with higher mortality following injury. Health insurance coverage is associated with lower mortality, but this may be the result of hospitals' inability to quickly obtain insurance coverage for uninsured patients who die early in their hospital stay. Increasing insurance coverage may not improve survival for patients hospitalized following injury. LEVEL OF EVIDENCE: Epidemiologic and prognostic study, level III. PMID- 25909427 TI - SIRT1 mediates a primed response to immune challenge after traumatic lung injury. AB - BACKGROUND: Pulmonary contusion (PC) is a common, potentially lethal injury that results in priming for exaggerated inflammatory responses to subsequent immune challenge like infection (second hit). The molecular mechanism of priming and the second hit phenomenon after PC remain obscure. With the use of a mouse model of PC, this study explores the role of sirtuin 1 (SIRT1), an NAD+-dependent deacetylase, in priming for a second hit after injury. METHODS: With the use of a mouse model of PC, injury-primed second-hit host responses were tested at 24 hours after PC by (1) in vivo infectious challenge of injured mice or (2) ex vivo inflammatory challenge of isolated immune cells from injured mice. SIRT activators or repressors were used to test for SIRT1 participation in these second-hit responses. RESULTS: PC-injured mice given an in vivo infectious challenge by cecal ligation and puncture (CLP) had significantly increased mortality compared with injury or infectious challenge alone. Isolated bronchoalveolar lavage (BAL) cells from injured mice given an ex vivo inflammatory challenge with bacterial lipopolysaccharide (LPS) had increased levels of tumor necrosis factor alpha messenger RNA compared with uninjured mice. We found that PC reduced SIRT1 protein, messenger RNA, and SIRT1 enzymatic activity in injured lung tissue. We also found decreased SIRT1 protein levels in BAL cells from injured mice. We further found that injured mice treated with a SIRT1 activator, resveratrol, showed significantly decreased polymorphonuclear leukocytes (PMN) in the BAL in response to intratracheal LPS and increased survival from CLP. CONCLUSION: These results showed that PC decreased SIRT1 levels in the lung correlated with enhanced responses to infectious or inflammatory stimuli in injured mice. Treatment of injured mice with a SIRT1 activator, resveratrol, decreased LPS inflammatory response and increased survival after CLP. Our results suggest that SIRT1 participates in the second-hit response after injury. PMID- 25909428 TI - Acute outcomes of isolated cerebral contusions in children with Glasgow Coma Scale scores of 14 to 15 after blunt head trauma. AB - BACKGROUND: Little data exist to guide the management of children with cerebral contusions after minor blunt head trauma. We therefore aimed to determine the risk of acute adverse outcomes in children with minor blunt head trauma who had cerebral contusions and no other traumatic brain injuries on computed tomography (i.e., isolated cerebral contusions). METHODS: We conducted a secondary analysis of a public use data set originating from a prospective cohort study performed in 25 PECARN (Pediatric Emergency Care Applied Research Network) emergency departments of children younger than 18 years with blunt head trauma resulting from nontrivial injury mechanisms and with Glasgow Coma Scale (GCS) scores of 14 or 15. In this analysis, we included only children with isolated cerebral contusions. We defined a normal mental status as a GCS score of 15 and no other signs of abnormal mental status. Acute adverse outcomes included intubation longer than 24 hours because of the head trauma, neurosurgery, or death from the head injury. RESULTS: Of 14,983 children with GCS scores of 14 or 15 who received cranial computed tomography scans in the parent study, 152 (1.0%; 95% confidence interval, 0.8-1.2%) had cerebral contusions, of which 54 (35.8%) of 151 with available data were isolated. The median age of those with isolated cerebral contusions was 9 years (interquartile range, 1-13); 31 (57.4%) had a normal mental status. Of 36 patients with available data on isolated cerebral contusion size, 34 (94.4%) were described as small. 43 (79.6%) of 54 patients with isolated cerebral contusions were hospitalized, including 16 (29.6%) of 54 to an intensive care unit. No patients with isolated cerebral contusions died, were intubated longer than 24 hours for head trauma, or required neurosurgery (95% confidence interval for all outcomes, 0-6.6%). CONCLUSION: Children with small isolated cerebral contusions after minor blunt head trauma are unlikely to require further acute intervention, including neurosurgery, suggesting that neither intensive care unit admission nor prolonged hospitalization is generally required. LEVEL OF EVIDENCE: Epidemiologic study, level IV. PMID- 25909429 TI - Abdominal compliance: A bench-to-bedside review. AB - Abdominal compliance (AC) is an important determinant and predictor of available workspace during laparoscopic surgery. Furthermore, critically ill patients with a reduced AC are at an increased risk of developing intra-abdominal hypertension and abdominal compartment syndrome, both of which are associated with high morbidity and mortality. Despite this, AC is a concept that has been neglected in the past.AC is defined as a measure of the ease of abdominal expansion, expressed as a change in intra-abdominal volume (IAV) per change in intra-abdominal pressure (IAP):AC = DeltaIAV / DeltaIAPAC is a dynamic variable dependent on baseline IAV and IAP as well as abdominal reshaping and stretching capacity. Whereas AC itself can only rarely be measured, it always needs to be considered an important component of IAP. Patients with decreased AC are prone to fulminant development of abdominal compartment syndrome when concomitant risk factors for intra-abdominal hypertension are present.This review aims to clarify the pressure volume relationship within the abdominal cavity. It highlights how different conditions and pathologies can affect AC and which management strategies could be applied to avoid serious consequences of decreased AC.We have pooled all available human data to calculate AC values in patients acutely and chronically exposed to intra-abdominal hypertension and demonstrated an exponential abdominal pressure-volume relationship. Most importantly, patients with high level of IAP have a reduced AC. In these patients, only small reduction in IAV can significantly increase AC and reduce IAPs.A greater knowledge on AC may help in selecting a better surgical approach and in reducing complications related to intra-abdominal hypertension. PMID- 25909430 TI - The role of REBOA in the control of exsanguinating torso hemorrhage. AB - The management of patients with exsanguinating torso hemorrhage is challenging. Emergency surgery, with the occasional use of resuscitative thoracotomy for patient in extremis, is the current standard. Recent reports of REBOA (resuscitative endovascular balloon occlusion of the aorta) have led to discussions about changing paradigms in the management of patients in both civilian and military are nas. We submit that broad and liberal application of this technique is premature given the current data and in light of historical experience. We propose an algorithm for the management of patients with exsanguinating torso hemorrhage, as well as a set of research questions that we feel can help clarify the role of REBOA in modern trauma care in a variety of trauma settings. PMID- 25909431 TI - ICD-9-CM and ICD-10-CM mapping of the AAST Emergency General Surgery disease severity grading systems: Conceptual approach, limitations, and recommendations for the future. AB - The American Association for the Surgery of Trauma (AAST) recently established a grading system for uniform reporting of anatomic severity of several emergency general surgery (EGS) diseases. There are five grades of severity for each disease, ranging from I (lowest severity) to V (highest severity). However, the grading process requires manual chart review. We sought to evaluate whether International Classification of Diseases, 9th and 10th Revisions, Clinical Modification (ICD-9-CM, ICD-10-CM) codes might allow estimation of AAST grades for EGS diseases. The Patient Assessment and Outcomes Committee of the AAST reviewed all available ICD-9-CM and ICD-10-CM diagnosis codes relevant to 16 EGS diseases with available AAST grades. We then matched grades for each EGS disease with one or more ICD codes. We used the Official Coding Guidelines for ICD-9-CM and ICD-10-CM and the American Hospital Association's "Coding Clinic for ICD-9 CM" for coding guidance. The ICD codes did not allow for matching all five AAST grades of severity for each of the 16 diseases. With ICD-9-CM, six diseases mapped into four categories of severity (instead of five), another six diseases into three categories of severity, and four diseases into only two categories of severity. With ICD-10-CM, five diseases mapped into four categories of severity, seven diseases into three categories, and four diseases into two categories. Two diseases mapped into discontinuous categories of grades (two in ICD-9-CM and one in ICD-10-CM). Although resolution is limited, ICD-9-CM and ICD-10-CM diagnosis codes might have some utility in roughly approximating the severity of the AAST grades in the absence of more precise information. These ICD mappings should be validated and refined before widespread use to characterize EGS disease severity. In the long-term, it may be desirable to develop alternatives to ICD-9-CM and ICD 10-CM codes for routine collection of disease severity characteristics. PMID- 25909432 TI - AAMS response to Habib et al, Probable cause in helicopter emergency medical services crashes. PMID- 25909433 TI - Rethinking "time to rethink" distracting injuries. PMID- 25909436 TI - Emotion Regulation and Mentalization in People at Risk for Food Addiction. AB - Researchers investigated the association among food addiction, difficulties in emotion regulation, and mentalization deficits in a sample of 322 Italian adults from the general population. All participants were administered the Italian versions of the Yale Food Addiction Scale (I-YFAS), the Difficulties in Emotion Regulation Scale, the Mentalization Questionnaire, the Binge Eating Scale, and the Michigan Alcohol Screening Test. Of respondents, 7.1% reported high food addiction symptoms (ie, 3 or more symptoms of food addiction on the I-YFAS). In bivariate analyses, high food-addiction symptoms were associated with more difficulties in emotion regulation and mentalization deficits. In the multivariate analysis, high food-addiction symptoms remained independently associated with mentalization deficits, but not with difficulties in emotion regulation. Our data suggest that mentalization may play an important role in food addiction by making it difficult for an individual to understand his or her own inner mental states as well as the mental states of others, especially when powerful emotions arise. PMID- 25909437 TI - Vaccination Week in the Americas, 2011: an opportunity to assess the routine vaccination program in the Bolivarian Republic of Venezuela. AB - BACKGROUND: Vaccination Week in the Americas (VWA) is an annual initiative in countries and territories of the Americas every April to highlight the work of national expanded programs on immunization (EPI) and increase access to vaccination services for high-risk population groups. In 2011, as part of VWA, Venezuela targeted children aged less than 6 years in 25 priority border municipalities using social mobilization to increase institution-based vaccination. Implementation of social communication activities was decentralized to the local level. We conducted a survey in one border municipality of Venezuela to evaluate the outcome of VWA 2011 and provide a snapshot of the overall performance of the routine EPI at that level. METHODS: We conducted a coverage survey, using stratified cluster sampling, in the Venezuelan municipality of Bolivar (bordering Colombia) in August 2011. We collected information for children aged <6 years through caregiver interviews and transcription of vaccination card data. We estimated each child's eligibility to receive a specific vaccine dose during VWA 2011 and whether or not they were actually vaccinated during VWA activities. We also estimated baseline vaccination coverage, timeliness and 95% confidence intervals (CI), and used chi-square tests to compare coverage across age cohorts, taking into account the sampling design. RESULTS: We surveyed 839 children from 698 households; 93% of children had a vaccination card. Among households surveyed, 216 (31%) caregivers reported having heard about a vaccination activity during April or May 2011. Of the 528 children eligible to receive a vaccine during VWA, 24% received at least one dose, while 13% received all doses due. Overall, baseline coverage with routine vaccines, as measured by the survey, was >85%, with a few exceptions. CONCLUSION: Low levels of VWA awareness among caregivers probably contributed to the limited vaccination of eligible children during the VWA activities in Bolivar in 2011. However, vaccine coverage for most EPI vaccines was high. Additionally, high vaccination card availability and high participation in VWA among those caregivers aware of it in 2011 suggest public trust in the EPI program in the municipality. Health authorities have used survey findings to inform changes to the routine EPI and better VWA implementation in subsequent years. PMID- 25909438 TI - Histamine H4 Receptor Antagonists: A New Approach for Tinnitus Treatment? AB - Tinnitus, a disorder with disruptive sound perception in the head without an external source, affects around 15 % of the worldwide adult population. Since there is no approved drug for the treatment for this symptom, novel strategies need to be developed to provide relief for the patient. A patent from the small French start-up company Sensorion suggests the use of histamine H4 receptor (H4R) inhibitors as potential treatment. Since histamine and its receptor subtypes are strongly involved in neuronal and inflammatory processes in vestibular areas, targeting the H4R could be a novel way to gain a treatment for tinnitus. Although mRNA and protein levels of H4R have been demonstrated on isolated spiral ganglion neurons from mice, the methods of receptor detection as well as the species relevance of the data are under discussion and require considerable further verification, especially on a disease with a high medical need like tinnitus. PMID- 25909439 TI - Design rules for successful governmental payments for ecosystem services: Taking agri-environmental measures in Germany as an example. AB - In recent years, increasing attention has been paid to financial environmental policy instruments that have played important roles in solving agri-environmental problems throughout the world, particularly in the European Union and the United States. The ample and increasing literature on Payments for Ecosystem Services (PES) and agri-environmental measures (AEMs), generally understood as governmental PES, shows that certain single design rules may have an impact on the success of a particular measure. Based on this research, we focused on the interplay of several design rules and conducted a comparative analysis of AEMs' institutional arrangements by examining 49 German cases. We analyzed the effects of the design rules and certain rule combinations on the success of AEMs. Compliance and noncompliance with the hypothesized design rules and the success of the AEMs were surveyed by questioning the responsible agricultural administration and the AEMs' mid-term evaluators. The different rules were evaluated in regard to their necessity and sufficiency for success using Qualitative Comparative Analysis (QCA). Our results show that combinations of certain design rules such as environmental goal targeting and area targeting conditioned the success of the AEMs. Hence, we generalize design principles for AEMs and discuss implications for the general advancement of ecosystem services and the PES approach in agri-environmental policies. Moreover, we highlight the relevance of the results for governmental PES program research and design worldwide. PMID- 25909440 TI - Microbial colonization affects the efficiency of photovoltaic panels in a tropical environment. AB - Sub-aerial biofilm (SAB) development on solar panels was studied in Sao Paulo. After 6, 12 and 18 months' exposure, photovoltaic panels were covered by increasing proportions of organic matter (42%, 53% and 58%, respectively). Fungi were an important component of these biofilms; very few phototrophs were found. Major microorganisms detected were melanised meristematic ascomycetes and pigmented bacterial genera Arthrobacter and Tetracoccus. While diverse algae, cyanobacteria and bacteria were identified in biofilms at 6 and 12 months, diversity at a later stage was reduced to that typical for SAB: the only fungal group detected in 18 month biofilm was the meristematic Dothideomycetes and the only phototrophs Ulothrix and Chlorella. Photovoltaic modules showed significant power reductions after 6, 12 (both 7%) and 18 (11%) months. The lack of difference in power reduction between 6 and 12 months reflects the dual nature of soiling, which can result from the deposition of particulates as well as from SAB fouling. Although 12-month old SAB demonstrated an almost 10-fold increase in fungal colonization and a higher organic content, the larger non-microbial particles (above 10 MUm), which were important for efficiency reduction of lightly-biofilmed panels, were removed by high rainfall just before the 12-month sampling. PMID- 25909441 TI - Applying Climate Compatible Development and economic valuation to coastal management: A case study of Kenya's mangrove forests. AB - Mangrove forests are under global pressure. Habitat destruction and degradation persist despite longstanding recognition of the important ecological functions of mangroves. Hence new approaches are needed to help stakeholders and policy-makers achieve sound management that is informed by the best science. Here we explore how the new policy concept of Climate Compatible Development (CCD) can be applied to achieve better outcomes. We use economic valuation approaches to combine socio economic data, projections of forest cover based on quantitative risk mapping and storyline scenario building exercises to articulate the economic consequences of plausible alternative future scenarios for the mangrove forests of the South Kenya coast, as a case study of relevance to many other areas. Using data from 645 household surveys, 10 focus groups and 74 interviews conducted across four mangrove sites, and combining these with information on fish catches taken at three landing sites, a mangrove carbon trading project and published data allowed us to make a thorough (although still partial) economic valuation of the forests. This gave a current value of the South Coast mangroves of USD 6.5 million, or USD 1166 ha(-1), with 59% of this value on average derived from regulating services. Quantitative risk mapping, projecting recent trends over the next twenty years, suggests a 43% loss of forest cover over that time with 100% loss at the most vulnerable sites. Much of the forest lost between 1992 and 2012 has not been replaced by high value alternative land uses hence restoration of these areas is feasible and may not involve large opportunity costs. We invited thirty eight stakeholders to develop plausible storyline scenarios reflecting Business as Usual (BAU) and CCD - which emphasises sustainable forest conservation and management - in twenty years time, drawing on local and regional expert knowledge of relevant policy, social trends and cultures. Combining these scenarios with the quantitative projections and economic baseline allowed the modelling of likely value added and costs avoided under the CCD scenario. This suggests a net present value of more than US$20 million of adoption of CCD rather than BAU. This work adds to the economic evidence for mangrove conservation and helps to underline the importance of new real and emerging markets, such as for REDD + projects, in making this case for carbon-rich coastal habitats. It demonstrates a policy tool - CCD - that can be used to engage stakeholders and help to co ordinate policy across different sectors towards mangrove conservation. PMID- 25909442 TI - Factors affecting adoption of improved management practices in the pastoral industry in Great Barrier Reef catchments. AB - Substantial efforts are being made by industry and government in Australia to reduce adverse impacts of pastoral operations on water quality draining to the Great Barrier Reef. A key target is to achieve rapid adoption of better management practices by landholders, but current theoretical frameworks provide limited guidance about priorities for improving adoption. In this study information from direct surveys with landholders in the two largest catchments draining into the Great Barrier Reef has been collected and analysed. Study outcomes have important implications for policy settings, because they confirm that substantial variations in adoption drivers exist across landholders, enterprises and practices. The results confirm that the three broad barriers to adoption of information gaps, financial incentives and risk perceptions are relevant. This implies that different policy mechanisms, including extension and incentive programs, remain important, although financial incentives were only identified as important to meet capital and transformational costs rather than recurrent costs. PMID- 25909444 TI - Properties of soil pore space regulate pathways of plant residue decomposition and community structure of associated bacteria. AB - Physical protection of soil carbon (C) is one of the important components of C storage. However, its exact mechanisms are still not sufficiently lucid. The goal of this study was to explore the influence of soil structure, that is, soil pore spatial arrangements, with and without presence of plant residue on (i) decomposition of added plant residue, (ii) CO2 emission from soil, and (iii) structure of soil bacterial communities. The study consisted of several soil incubation experiments with samples of contrasting pore characteristics with/without plant residue, accompanied by X-ray micro-tomographic analyses of soil pores and by microbial community analysis of amplified 16S-18S rRNA genes via pyrosequencing. We observed that in the samples with substantial presence of air-filled well-connected large (>30 um) pores, 75-80% of the added plant residue was decomposed, cumulative CO2 emission constituted 1,200 um C g(-1) soil, and movement of C from decomposing plant residue into adjacent soil was insignificant. In the samples with greater abundance of water-filled small pores, 60% of the added plant residue was decomposed, cumulative CO2 emission constituted 2,000 um C g(-1) soil, and the movement of residue C into adjacent soil was substantial. In the absence of plant residue the influence of pore characteristics on CO2 emission, that is on decomposition of the native soil organic C, was negligible. The microbial communities on the plant residue in the samples with large pores had more microbial groups known to be cellulose decomposers, that is, Bacteroidetes, Proteobacteria, Actinobacteria, and Firmicutes, while a number of oligotrophic Acidobacteria groups were more abundant on the plant residue from the samples with small pores. This study provides the first experimental evidence that characteristics of soil pores and their air/water flow status determine the phylogenetic composition of the local microbial community and directions and magnitudes of soil C decomposition processes. PMID- 25909443 TI - Chlamydia trachomatis Infection Leads to Defined Alterations to the Lipid Droplet Proteome in Epithelial Cells. AB - The obligate intracellular bacterium Chlamydia trachomatis is a major human pathogen and a main cause of genital and ocular diseases. During its intracellular cycle, C. trachomatis replicates inside a membrane-bound vacuole termed an "inclusion". Acquisition of lipids (and other nutrients) from the host cell is a critical step in chlamydial replication. Lipid droplets (LD) are ubiquitous, ER-derived neutral lipid-rich storage organelles surrounded by a phospholipids monolayer and associated proteins. Previous studies have shown that LDs accumulate at the periphery of, and eventually translocate into, the chlamydial inclusion. These observations point out to Chlamydia-mediated manipulation of LDs in infected cells, which may impact the function and thereby the protein composition of these organelles. By means of a label-free quantitative mass spectrometry approach we found that the LD proteome is modified in the context of C. trachomatis infection. We determined that LDs isolated from C. trachomatis-infected cells were enriched in proteins related to lipid metabolism, biosynthesis and LD-specific functions. Interestingly, consistent with the observation that LDs intimately associate with the inclusion, a subset of inclusion membrane proteins co-purified with LD protein extracts. Finally, genetic ablation of LDs negatively affected generation of C. trachomatis infectious progeny, consistent with a role for LD biogenesis in optimal chlamydial growth. PMID- 25909445 TI - Simple Amine-Directed Meta-Selective C-H Arylation via Pd/Norbornene Catalysis. AB - Herein we report a highly meta-selective C-H arylation using simple tertiary amines as the directing group. This method takes advantage of Pd/norbornene catalysis, offering a distinct strategy to control the site selectivity. The reaction was promoted by commercially available AsPh3 as the ligand and a unique "acetate cocktail". Aryl iodides with an ortho electron-withdrawing group were employed as the coupling partner. A wide range of functional groups, including some heteroarenes, are tolerated under the reaction conditions. In addition, the amine directing group can be easily installed and transformed to other common versatile functional groups. We expect this C-H functionalization mode to have broad implications for developing other meta-selective transformations beyond this work. PMID- 25909446 TI - Sociological fidelity: keeping the patient at the heart of interprofessional learning. PMID- 25909447 TI - Gene Electrotransfer of Plasmid with Tissue Specific Promoter Encoding shRNA against Endoglin Exerts Antitumor Efficacy against Murine TS/A Tumors by Vascular Targeted Effects. AB - Vascular targeted therapies, targeting specific endothelial cell markers, are promising approaches for the treatment of cancer. One of the targets is endoglin, transforming growth factor-beta (TGF-beta) co-receptor, which mediates proliferation, differentiation and migration of endothelial cells forming neovasculature. However, its specific, safe and long-lasting targeting remains the challenge. Therefore, in our study we evaluated the transfection efficacy, vascular targeted effects and therapeutic potential of the plasmid silencing endoglin with the tissue specific promoter, specific for endothelial cells marker endothelin-1 (ET) (TS plasmid), in comparison to the plasmid with constitutive promoter (CON plasmid), in vitro and in vivo. Tissue specificity of TS plasmid was demonstrated in vitro on several cell lines, and its antiangiogenic efficacy was demonstrated by reducing tube formation of 2H11 endothelial cells. In vivo, on a murine mammary TS/A tumor model, we demonstrated good antitumor effect of gene electrotransfer (GET) of either of both plasmids in treatment of smaller tumors still in avascular phase of growth, as well as on bigger tumors, already well vascularized. In support to the observations on predominantly vascular targeted effects of endoglin, histological analysis has demonstrated an increase in necrosis and a decrease in the number of blood vessels in therapeutic groups. A significant antitumor effect was observed in tumors in avascular and vascular phase of growth, possibly due to both, the antiangiogenic and the vascular disrupting effect. Furthermore, the study indicates on the potential use of TS plasmid in cancer gene therapy since the same efficacy as of CON plasmid was determined. PMID- 25909448 TI - Vigorous Exercise Can Cause Abnormal Pulmonary Function in Healthy Adolescents. AB - RATIONALE: Although exercise-induced bronchoconstriction is more common in adolescents with asthma, it also manifests in healthy individuals without asthma. The steady-state exercise protocol is widely used and recommended by the American Thoracic Society (ATS) as a method to diagnose exercise-induced bronchoconstriction. Airway narrowing in response to exercise is thought to be related to airway wall dehydration secondary to hyperventilation. More rigorous exercise protocols may have a role in detecting exercise-induced bronchoconstriction in those who otherwise have a normal response to steady-state exercise challenge. OBJECTIVES: The objective of this study was to determine the effect of two different exercise protocols--a constant work rate protocol and a progressive ramp protocol--on pulmonary function testing in healthy adolescents. We hypothesized that vigorous exercise protocols would lead to reductions in lung function in healthy adolescents. METHODS: A total of 56 healthy adolescents (mean age, 15.2 +/- 3.3 [SD] years) were recruited to perform two exercise protocols: constant work rate exercise test to evaluate for exercise-induced bronchoconstriction (as defined by ATS) and standardized progressive ramp protocol. Pulmonary function abnormalities were defined as a decline from baseline in FEV1 of greater than 10%. MEASUREMENTS AND MAIN RESULTS: Ten participants (17.8%) had a significant drop in FEV1. Among those with abnormal lung function after exercise, three (30%) were after the ATS test only, five (50%) were after the ramp test only, and two (20%) were after both ATS and ramp tests. CONCLUSION: Healthy adolescents demonstrate subtle bronchoconstriction after exercise. This exercise-induced bronchoconstriction may be detected in healthy adolescents via constant work rate or the progressive ramp protocol. In a clinical setting, ramp testing warrants consideration in adolescents suspected of having exercise-induced bronchoconstriction and who have normal responses to steady-state exercise testing. PMID- 25909449 TI - Strain Specific Phage Treatment for Staphylococcus aureus Infection Is Influenced by Host Immunity and Site of Infection. AB - The response to multi-drug resistant bacterial infections must be a global priority. While mounting resistance threatens to create what the World Health Organization has termed a "post-antibiotic era", the recent discovery that antibiotic use may adversely impact the microbiome adds further urgency to the need for new developmental approaches for anti-pathogen treatments. Methicillin resistant Staphylococcus aureus (MRSA), in particular, has declared itself a serious threat within the United States and abroad. A potential solution to the problem of antibiotic resistance may not entail looking to the future for completely novel treatments, but instead looking into our history of bacteriophage therapy. This study aimed to test the efficacy, safety, and commercial viability of the use of phages to treat Staphylococcus aureus infections using the commercially available phage SATA-8505. We found that SATA 8505 effectively controls S. aureus growth and reduces bacterial viability both in vitro and in a skin infection mouse model. However, this killing effect was not observed when phage was cultured in the presence of human whole blood. SATA 8505 did not induce inflammatory responses in peripheral blood mononuclear cultures. However, phage did induce IFN gamma production in primary human keratinocyte cultures and induced inflammatory responses in our mouse models, particularly in a mouse model of chronic granulomatous disease. Our findings support the potential efficacy of phage therapy, although regulatory and market factors may limit its wider investigation and use. PMID- 25909450 TI - The relation between self-reported PTSD and depression symptoms and the psychological distance of positive and negative events. AB - BACKGROUND AND OBJECTIVES: Psychological distance refers to how far and how long ago an event feels to a person and how distant this person feels from their past self who experienced the event. Psychological distance is related to the recollective experience of the memory, but people with PTSD and depression remember positive and negative events differently. Whereas people with depression tend to have over-general memory, people with PTSD often relive traumatic experiences (i.e., intrusive memories). These findings suggest that people with PTSD might feel close to negative events and that people with depression might feel distant from positive events. METHOD: In the present study, students (N = 103) reported their PTSD and depression symptoms and the psychological distance of highly positive and highly negative events. RESULTS: In line with previous work, participants generally felt close to positive experiences and distant from negative experiences. However, this study is the first one to show that participants with more depression symptoms feel psychologically distant from positive events and participants with more PTSD symptoms feel psychologically close to negative events. LIMITATIONS: Although we did not establish whether the negative event was traumatic and whether the participants with many PTSD and depression symptoms suffered from these disorders, these limitations can be addressed in future research. CONCLUSIONS: The results emphasize the important role of identifying with positive events in depression and they support the idea that PTSD is caused by the fact that the traumatic event has become central to a person's life story. PMID- 25909451 TI - Maintenance of glia in the optic lamina is mediated by EGFR signaling by photoreceptors in adult Drosophila. AB - The late onset of neurodegeneration in humans indicates that the survival and function of cells in the nervous system must be maintained throughout adulthood. In the optic lamina of the adult Drosophila, the photoreceptor axons are surrounded by multiple types of glia. We demonstrated that the adult photoreceptors actively contribute to glia maintenance in their target field within the optic lamina. This effect is dependent on the epidermal growth factor receptor (EGFR) ligands produced by the R1-6 photoreceptors and transported to the optic lamina to act on EGFR in the lamina glia. EGFR signaling is necessary and sufficient to act in a cell-autonomous manner in the lamina glia. Our results suggest that EGFR signaling is required for the trafficking of the autophagosome/endosome to the lysosome. The loss of EGFR signaling results in cell degeneration most likely because of the accumulation of autophagosomes. Our findings provide in vivo evidence for the role of adult neurons in the maintenance of glia and a novel role for EGFR signaling in the autophagic flux. PMID- 25909453 TI - Effects of feedstock ratio and organic loading rate on the anaerobic mesophilic co-digestion of rice straw and cow manure. AB - In order to investigate the effects of feedstock ratio and organic loading rate (OLR) on the anaerobic mesophilic co-digestion of rice straw (RS) and cow manure (CM), batch tests (2.5L) were carried out at volatile solid (VS) ratios of 0:1, 1:2, 1:1, 2:1, and 1:0 (RS/CM), and continuous bench experiments (40 L) were carried out at OLRs of 3.0, 3.6, 4.2, 4.8, 6.0, 8.0, and 12.0 kg VS/(m(3) d) with optimal VS ratio. The optimal VS ratio was found to be 1:1. Stable and efficient co-digestion with average specific biogas production of 383.5L/kg VS and volumetric biogas production rate of 2.30 m(3)/(m(3) d) was obtained at an OLR of 6 kg VS/(m(3) d). Anaerobic co-digestion was severely inhibited by the accumulation of volatile fatty acids instead of ammonia when the OLR was 12 kg VS/(m(3) d). Further, significant foaming was observed at OLR ? 8 kg VS/(m(3) d). PMID- 25909452 TI - Characterization of chromosomal and megaplasmid partitioning loci in Thermus thermophilus HB27. AB - BACKGROUND: In low-copy-number plasmids, the partitioning loci (par) act to ensure proper plasmid segregation and copy number maintenance in the daughter cells. In many bacterial species, par gene homologues are encoded on the chromosome, but their function is much less understood. In the two-replicon, polyploid genome of the hyperthermophilic bacterium Thermus thermophilus, both the chromosome and the megaplasmid encode par gene homologues (parABc and parABm, respectively). The mode of partitioning of the two replicons and the role of the two Par systems in the replication, segregation and maintenance of the genome copies are completely unknown in this organism. RESULTS: We generated a series of chromosomal and megaplasmid par mutants and sGFP reporter strains and analyzed them with respect to DNA segregation defects, genome copy number and replication origin localization. We show that the two ParB proteins specifically bind their cognate centromere-like sequences parS, and that both ParB-parS complexes localize at the cell poles. Deletion of the chromosomal parAB genes did not apparently affect the cell growth, the frequency of cells with aberrant nucleoids, or the chromosome and megaplasmid replication. In contrast, deletion of the megaplasmid parAB operon or of the parB gene was not possible, indicating essentiality of the megaplasmid-encoded Par system. A mutant expressing lower amounts of ParABm showed growth defects, a high frequency of cells with irregular nucleoids and a loss of a large portion of the megaplasmid. The truncated megaplasmid could not be partitioned appropriately, as interlinked megaplasmid molecules (catenenes) could be detected, and the ParBm-parSm complexes in this mutant lost their polar localization. CONCLUSIONS: We show that in T. thermophilus the chromosomal par locus is not required for either the chromosomal or megaplasmid bulk DNA replication and segregation. In contrast, the megaplasmid Par system of T. thermophilus is needed for the proper replication and segregation of the megaplasmid, and is essential for its maintenance. The two Par sets in T. thermophilus appear to function in a replicon-specific manner. To our knowledge, this is the first analysis of Par systems in a polyploid bacterium. PMID- 25909454 TI - Global spectrum of copy number variations reveals genome organizational plasticity and proposes new migration routes. AB - Global spectrum of CNVs is required to catalog variations to provide a high resolution on the dynamics of genome-organization and human migration. In this study, we performed genome-wide genotyping using high-resolution arrays and identified 44,109 CNVs from 1,715 genomes across 12 populations. The study unraveled the force of independent evolutionary dynamics on genome-organizational plasticity across populations. We demonstrated the use of CNV tool to study human migration and identified a second major settlement establishing new migration routes in addition to existing ones. PMID- 25909457 TI - Theoretical study of electronic and tribological properties of h-BNC2/graphene, h BNC2/h-BN and h-BNC2/h-BNC2 bilayers. AB - Density functional theory based methods are used to investigate the interlayer sliding energy landscape (ISEL), binding energy and interlayer spacing between h BNC2/graphene (I), h-BNC2/h-BN (II) and h-BNC2/h-BNC2 (III) bilayer structures for three, six and fourteen different stacking patterns, respectively. Our results show that, in the studied cases, increasing the atomic variety of the ingredient monolayers leads to an ISEL corrugation increase as well. For the studied bilayers the ISEL is obtained by means of the registry index. For sufficiently large flakes of h-BNC2 on graphene sheets with the largest incommensurability and the least monolayer anisotropy, a robust superlubricity occurs regardless of the relative interlayer orientation. On the other hand, for the h-BNC2/h-BNC2 bilayer exhibiting the least incommensurability and the most monolayer anisotropy, the occurrence of robust superlubricity depends on the relative interlayer orientation. PMID- 25909456 TI - Regulation of Cadmium-Induced Proteomic and Metabolic Changes by 5-Aminolevulinic Acid in Leaves of Brassica napus L. AB - It is evident from previous reports that 5-aminolevulinic acid (ALA), like other known plant growth regulators, is effective in countering the injurious effects of heavy metal-stress in oilseed rape (Brassica napus L.). The present study was carried out to explore the capability of ALA to improve cadmium (Cd2+) tolerance in B. napus through physiological, molecular, and proteomic analytical approaches. Results showed that application of ALA helped the plants to adjust Cd2+-induced metabolic and photosynthetic fluorescence changes in the leaves of B. napus under Cd2+ stress. The data revealed that ALA treatment enhanced the gene expressions of antioxidant enzyme activities substantially and could increase the expression to a certain degree under Cd2+ stress conditions. In the present study, 34 protein spots were identified that differentially regulated due to Cd2+ and/or ALA treatments. Among them, 18 proteins were significantly regulated by ALA, including the proteins associated with stress related, carbohydrate metabolism, catalysis, dehydration of damaged protein, CO2 assimilation/photosynthesis and protein synthesis/regulation. From these 18 ALA regulated proteins, 12 proteins were significantly down-regulated and 6 proteins were up-regulated. Interestingly, it was observed that ALA-induced the up regulation of dihydrolipoyl dehydrogenase, light harvesting complex photo-system II subunit 6 and 30S ribosomal proteins in the presence of Cd2+ stress. In addition, it was also observed that ALA-induced the down-regulation in thioredoxin-like protein, 2, 3-bisphosphoglycerate, proteasome and thiamine thiazole synthase proteins under Cd2+ stress. Taken together, the present study sheds light on molecular mechanisms involved in ALA-induced Cd2+ tolerance in B. napus leaves and suggests a more active involvement of ALA in plant physiological processes than previously proposed. PMID- 25909455 TI - Early subsidence of shape-closed hip arthroplasty stems is associated with late revision. A systematic review and meta-analysis of 24 RSA studies and 56 survival studies. AB - BACKGROUND AND PURPOSE: Few studies have addressed the association between early migration of femoral stems and late aseptic revision in total hip arthroplasty. We performed a meta-regression analysis on 2 parallel systematic reviews and meta analyses to determine the association between early migration and late aseptic revision of femoral stems. PATIENTS AND METHODS: Of the 2 reviews, one covered early migration data obtained from radiostereometric analysis (RSA) studies and the other covered long-term aseptic revision rates obtained from survival studies with endpoint revision for aseptic loosening. Stems were stratified according to the design concept: cemented shape-closed, cemented force-closed, and uncemented. A weighted regression model was used to assess the association between early migration and late aseptic revision, and to correct for confounders. Thresholds for acceptable and unacceptable migration were determined in accordance with the national joint registries (<= 5% revision at 10 years) and the NICE criteria (<= 10% revision at 10 years). RESULTS: 24 studies (731 stems) were included in the RSA review and 56 studies (20,599 stems) were included in the survival analysis review. Combining both reviews for the 3 design concepts showed that for every 0.1-mm increase in 2-year subsidence, as measured with RSA, there was a 4% increase in revision rate for the shape-closed stem designs. This association remained after correction for age, sex, diagnosis, hospital type, continent, and study quality. The threshold for acceptable migration of shape-closed designs was defined at 0.15 mm; stems subsiding less than 0.15 mm in 2 years had revision rates of less than 5% at 10 years, while stems exceeding 0.15 mm subsidence had revision rates of more than 5%. INTERPRETATION: There was a clinically relevant association between early subsidence of shape-closed femoral stems and late revision for aseptic loosening. This association can be used to assess the safety of shape-closed stem designs. The published research is not sufficient to allow us to make any conclusions regarding such an association for the force-closed and uncemented stems. PMID- 25909458 TI - It's Never over until It's over: How Can Age and Ovarian Reserve Be Mathematically Bound through the Measurement of Serum AMH-A Study of 5069 Romanian Women. AB - Wide regional differences in the age-related Anti Mullerian hormone (AMH) regression patterns or age at onset of natural menopause have been reported, possibly reflecting genetic, socioeconomic, environmental, racial or ethnic peculiarities. Moreover, adaptation of AMH levels from different assays using regression functions may lack accuracy and externally defined references for AMH levels may not fully comply with a specific geographical area. The current study aimed to establish an accurate mathematical relationship between AMH serum values and age in a large group of women from Romania, as any consistent difference from previously reported regression models may aid in building specific profiles for the AMH decline with age in this geographical region. Our study pointed out to the quadratic regression as the most fitted pattern of correlation for all the age groups between 24 and 45. To our knowledge the current manuscript is based on the singular study carried out in this geographical region, generating a particular age-related pattern of association between age and serum AMH levels in women, regardless of their subjacent pathologies. PMID- 25909460 TI - Unusual ferromagnetism enhancement in ferromagnetically optimal manganite La0.7 yCa0.3+yMn1-yRuyO3 (0<=y<0.3): the role of Mn-Ru t2g super-exchange. AB - The eg-orbital double-exchange mechanism as the core of physics of colossal magnetoresistance (CMR) manganites is well known, which usually covers up the role of super-exchange at the t2g-orbitals. The role of the double-exchange mechanism is maximized in La0.7Ca0.3MnO3, leading to the concurrent metal insulator transition and ferromagnetic transition as well as CMR effect. In this work, by a set of synchronous Ru-substitution and Ca-substitution experiments on La0.7-yCa0.3+yMn1-yRuyO3, we demonstrate that the optimal ferromagnetism in La0.7Ca0.3MnO3 can be further enhanced. It is also found that the metal-insulator transition and magnetic transition can be separately modulated. By well-designed experimental schemes with which the Mn(3+)-Mn(4+) double-exchange is damaged as weakly as possible, it is revealed that this ferromagnetism enhancement is attributed to the Mn-Ru t2g ferromagnetic super-exchange. The present work allows a platform on which the electro-transport and magnetism of rare-earth manganites can be controlled by means of the t2g-orbital physics of strongly correlated transition metal oxides. PMID- 25909461 TI - Manipulating the glass transition behavior of sulfonated polystyrene by functionalized nanoparticle inclusion. AB - Nanoscale interfaces can modify the phase transition behaviors of polymeric materials. Here, we report the double glass transition temperature (Tg) behavior of sulfonated polystyrene (sPS) by the inclusion of 14 nm amine-functionalized silica (NH2-SiO2) nanoparticles, which is different from the single Tg behaviors of neat sPS and silica (SiO2)-filled sPS. The inclusion of 20 wt% NH2-SiO2 nanoparticles results in an increase of Tg by 9.3 degrees C as well as revealing a second Tg reduced by 44.7 degrees C compared to the Tg of neat sPS. By contrast, when SiO2 nanoparticles with an identical concentration and size to NH2 SiO2 are dispersed, sPS composites possess a single Tg of 7.3 degrees C higher than that of the neat sPS. While a nanoscale dispersion is observed for SiO2 nanoparticles, as confirmed by microscopic and X-ray scattering analyses, NH2 SiO2 nanoparticles show the coexistence of micron-scale clustering along with a nanoscale dispersion of the individual nanoparticles. The micro-phase separation contributes to the free volume induced Tg reduction by the plasticization effect, whereas the Tg increase originates from the polymer segment mobility constrained by nanoconfinement and the rigid amorphous fractions deriving from strong polymer particle interactions. PMID- 25909459 TI - The Immune Adaptor ADAP Regulates Reciprocal TGF-beta1-Integrin Crosstalk to Protect from Influenza Virus Infection. AB - Highly pathogenic avian influenza virus (HPAI, such as H5N1) infection causes severe cytokine storm and fatal respiratory immunopathogenesis in human and animal. Although TGF-beta1 and the integrin CD103 in CD8+ T cells play protective roles in H5N1 virus infection, it is not fully understood which key signaling proteins control the TGF-beta1-integrin crosstalk in CD8+ T cells to protect from H5N1 virus infection. This study showed that ADAP (Adhesion and Degranulation promoting Adapter Protein) formed a complex with TRAF6 and TAK1 in CD8+ T cells, and activated SMAD3 to increase autocrine TGF-beta1 production. Further, TGF beta1 induced CD103 expression via an ADAP-, TRAF6- and SMAD3-dependent manner. In response to influenza virus infection (i.e. H5N1 or H1N1), lung infiltrating ADAP-/- CD8+ T cells significantly reduced the expression levels of TGF-beta1, CD103 and VLA-1. ADAP-/- mice as well as Rag1-/- mice receiving ADAP-/- T cells enhanced mortality with significant higher levels of inflammatory cytokines and chemokines in lungs. Together, we have demonstrated that ADAP regulates the positive feedback loop of TGF-beta1 production and TGF-beta1-induced CD103 expression in CD8+ T cells via the TbetaRI-TRAF6-TAK1-SMAD3 pathway and protects from influenza virus infection. It is critical to further explore whether the SNP polymorphisms located in human ADAP gene are associated with disease susceptibility in response to influenza virus infection. PMID- 25909462 TI - Quantitative analysis of relationships between irradiation parameters and the reproducibility of cyclotron-produced (99m)Tc yields. AB - Cyclotron production of (99m)Tc through the (100)Mo(p,2n) (99m)Tc reaction channel is actively being investigated as an alternative to reactor-based (99)Mo generation by nuclear fission of (235)U. An exciting aspect of this approach is that it can be implemented using currently-existing cyclotron infrastructure to supplement, or potentially replace, conventional (99m)Tc production methods that are based on aging and increasingly unreliable nuclear reactors. Successful implementation will require consistent production of large quantities of high radionuclidic-purity (99m)Tc. However, variations in proton beam currents and the thickness and isotopic composition of enriched (100)Mo targets, in addition to other irradiation parameters, may degrade reproducibility of both radionuclidic purity and absolute (99m)Tc yields. The purpose of this article is to present a method for quantifying relationships between random variations in production parameters, including (100)Mo target thicknesses and proton beam currents, and reproducibility of absolute (99m)Tc yields (defined as the end of bombardment (EOB) (99m)Tc activity). Using the concepts of linear error propagation and the theory of stochastic point processes, we derive a mathematical expression that quantifies the influence of variations in various irradiation parameters on yield reproducibility, quantified in terms of the coefficient of variation of the EOB (99m)Tc activity. The utility of the developed formalism is demonstrated with an example. We show that achieving less than 20% variability in (99m)Tc yields will require highly-reproducible target thicknesses and proton currents. These results are related to the service rate which is defined as the percentage of (99m)Tc production runs that meet the minimum daily requirement of one (or many) nuclear medicine departments. For example, we show that achieving service rates of 84.0%, 97.5% and 99.9% with 20% variations in target thicknesses requires producing on average 1.2, 1.5 and 1.9 times the minimum daily activity requirement. The irradiation parameters that would be required to achieve these service rates are described. We believe the developed formalism will aid in the development of quality-control criteria required to ensure consistent supply of large quantities of high-radionuclidic-purity cyclotron-produced (99m)Tc. PMID- 25909463 TI - Pharmacists on primary care teams: Effect on antihypertensive medication management in patients with type 2 diabetes. AB - OBJECTIVE: To identify which activities produced a significant improvement in blood pressure control in patients with type 2 diabetes when pharmacists were added to primary care teams. METHODS: This prespecified, secondary analysis evaluated medication management data from a randomized controlled trial. The primary outcome was a change in treatment, defined as addition, dosage increase, or switching of an antihypertensive medication during the 1-year study period. The secondary outcome was a change in antihypertensive medication adherence using the medication possession ratio (MPR). RESULTS: The 200 evaluable trial patients had a mean age of 59 (SD, 11) years, 44% were men, and mean blood pressure was 130 (SD, 16)/74 (SD, 10) mm Hg at baseline. Treatment changes occurred in 45 (42%) of 107 patients in the intervention group and 24 (26%) of 93 patients in the control group (RR, 1.63; 95% CI, 1.08-2.46). Addition of a new medication was the most common type of change, occurring in 34 (32%) patients in the intervention group and 17 (18%) patients in the control group (P = 0.029). Adherence to antihypertensive medication was high at baseline (MPR, 93%). Although medication adherence improved in the intervention group (MPR, 97%) and declined in the control group (MPR, 91%), the difference between groups was not significant (P = 0.21). CONCLUSION: The observed improvement in blood pressure control when pharmacists were added to primary care teams was likely achieved through antihypertensive treatment changes and not through improvements in antihypertensive medication adherence. PMID- 25909464 TI - Transplantation With Livers From Deceased Donors Older Than 75 Years. AB - BACKGROUND: The availability of donor organs limits the number of patients in need who are offered liver transplantation. Measures to expand the donor pool are crucial to prevent on-list mortality. The aim of this study was to evaluate the use of livers from deceased donors who were older than 75 years. METHODS: Fifty four patients who received a first liver transplant (D75 group) from 2001 to 2011 were included. Donor and recipient data were collected from the Nordic Liver Transplant Registry and medical records. The outcome was compared with a control group of 54 patients who received a liver graft from donors aged 20 to 49 years (D20-49 group). Median donor age was 77 years (range, 75-86 years) in the D75 group and 41 years (range, 20-49 years) in the D20-49 group. Median recipient age was 59 years (range, 31-73 years) in the D75 group and 58 years (range, 31-74 years) in the D20-49 group. RESULTS: The 1-, 3-, and 5-year patient/graft survival values were 87/87%, 81/81%, and 71/67% for the D75 group and 88/87%, 75/73%, and 75/73% for the D20-49 group, respectively. Patient (P = 0.89) and graft (P = 0.79) survival did not differ between groups. The frequency of biliary complications was higher in the D75 group (29.6/13%, P = 0.03). CONCLUSIONS: Selected livers from donors over age 75 years should not be excluded based on age, which does not compromise patient or graft survival despite a higher frequency of biliary complications. PMID- 25909465 TI - The effect of an information and communication technology (ICT) on older adults' quality of life: study protocol for a randomized control trial. AB - BACKGROUND: This study investigates the use of an information and communication technology (Elder Tree) designed for older adults and their informal caregivers to improve older adult quality of life and address challenges older adults face in maintaining their independence (for example, loneliness and isolation, falling, managing medications, driving and transportation). METHODS/DESIGN: This study, an unblinded randomized controlled trial, will evaluate the effectiveness and cost of Elder Tree. Older adults who are at risk for losing their independence - along with their informal caregivers, if they name them - are randomized to two groups. The intervention group has access to their usual sources of information and communication as well as to Elder Tree for 18 months while the control group uses only their usual sources of information and communication. The primary outcome of the study is older adult quality of life. Secondary outcomes are cost per Quality-Adjusted Life Year and the impact of the technology on independence, loneliness, falls, medication management, driving and transportation, and caregiver appraisal and mastery. We will also examine the mediating effect of self-determination theory. We will evaluate the effectiveness of Elder Tree by comparing intervention- and control-group participants at baseline and months 6, 12, and 18. We will use mixed-effect models to evaluate the primary and secondary outcomes, where pretest score functions as a covariate, treatment condition is a between-subjects factor, and the multivariate outcome reflects scores for a given assessment at the three time points. Separate analyses will be conducted for each outcome. Cost per Quality-Adjusted Life Year will be compared between the intervention and control groups. Additional analyses will examine the mediating effect of self-determination theory on each outcome. DISCUSSION: Elder Tree is a multifaceted intervention, making it a challenge to assess which services or combinations of services account for outcomes in which subsets of older adults. If Elder Tree can improve quality of life and reduce healthcare costs among older adults, it could suggest a promising way to ease the burden that advancing age can place on older adults, their families, and the healthcare system. TRIAL REGISTRATION: ClinicalTrials.gov NCT02128789 . Registered on 26 March 2014. PMID- 25909467 TI - An evaluation of the finger flexion, Hoffman's and plantar reflexes as markers of cervical spinal cord compression - A comparative clinical study. AB - OBJECTIVES: This study aimed at determining the frequency of abnormal finger flexion, Hoffman's and extensor plantar (Babinski) response in healthy adults and to determine the sensitivity and specificity of these tests as markers of spinal cord compression in symptomatic patients. METHODS: Patients attending the neurosurgery clinic with neck related complaints formed the case group. The control group consisted of consenting patient attenders and volunteers drawn from the students and faculty of our institute. All subjects underwent examination of the finger flexion, Hoffman's and plantar reflexes and an MRI as per standard protocol. The frequency of the reflexes in the control group, sensitivity and specificity of the reflexes to detect cord compression in the case group were computed. RESULTS: The frequency of the reflexes in healthy controls were finger flexion - 1%, Hoffman's - 0.3% and Babinski sign - 0%. None of the controls with positive reflexes had any abnormality on MR imaging. A combination of the three reflexes had a sensitivity of 91.7%, specificity of 87.5%, PPV of 95.7% and NPV of 77.8% in detecting spinal cord compression. CONCLUSIONS: A combination of finger flexion, Hoffman's and plantar reflexes could be used effectively as a marker of spinal cord compression in symptomatic individuals. They cannot, however, be depended on as screening tests in asymptomatic individuals. PMID- 25909468 TI - Effects of agricultural biodiversity and seasonal rain on dietary adequacy and household food security in rural areas of Kenya. AB - BACKGROUND: Kenya has a high prevalence of underweight and stunting in children. It is believed that both agricultural biodiversity and seasonal rainfall influences household food security and dietary intake. In the present study we aimed to study the effects of agricultural biodiversity and seasonal rains on dietary adequacy and household food security of preschool Kenyan children, and to identify significant relationships between these variables. METHODS: Two cross sectional studies were undertaken in resource-poor households in rural Kenya approximately 6 months apart. Interviews were done with mothers/caregivers to collect data from randomly selected households (N = 525). A repeated 24-hour recall was used to calculate dietary intake in each phase while household food security was measured using the Household Food Insecurity Access Scale (HFIAS). A nutrient adequacy ratio (NAR) was calculated for each nutrient as the percent of the nutrient meeting the recommended nutrient intake (RNI) for that nutrient. A mean adequacy ratio (MAR) was calculated as the mean of the NARs. Agricultural biodiversity was calculated for each household by counting the number of different crops and animals eaten either from domestic sources or from the wild. RESULTS: Dietary intake was low with the majority of households not meeting the RNIs for many nutrients. However intake of energy (p < 0.001), protein (p < 0.01), iron (p < 0.01), zinc (p < 0.05), calcium (p < 0.05), and folate (p < 0.01) improved significantly from the dry to the rainy season. Household food security also increased significantly (p < 0.001) from the dry (13.1 SD 6.91) to the rainy season (10.9 SD 7.42). Agricultural biodiversity was low with a total of 26 items; 23 domesticated and 3 from the natural habitat. Agricultural biodiversity was positively and significantly related to all NARs (Spearman, p < 0.05) and MAR (Spearman, p < 0.001) indicating a significant positive relationship between agricultural biodiversity of the household with dietary adequacy of the child's diet. CONCLUSION: Important significant relationships were found in this study: between agricultural biodiversity and dietary adequacy; between agricultural biodiversity and household food security and between dietary adequacy and household food security. Furthermore, the effect of seasonality on household food security and nutrient intake was illustrated. PMID- 25909469 TI - Stepwise Two-Photon-Gated Photochemical Reaction in Photochromic [2.2]Paracyclophane-Bridged Bis(imidazole dimer). AB - Stepwise two-photon processes not only have great potential for efficient light harvesting but also can provide valuable insights into novel photochemical sciences. Here we have designed a [2.2]paracyclophane-bridged bis(imidazole dimer), a molecule that is composed of two photochromic units and absorbs two photons in a stepwise manner. The absorption of the first photon leads to the formation of a short-lived biradical species (half-life = 88 ms at 298 K), while the absorption of the additional photon by the biradical species triggers a subsequent photochromic reaction to afford a long-lived quinoid species. The short-lived biradical species and the long-lived quinoid species display significantly different absorption spectra and rates of the thermal back reaction. The stepwise two-photon excitation process in this photochromic system can be initiated even by incoherent continuous-wave light irradiation, indicating that this two-photon reaction is highly efficient. Our molecule based on the bridged bis(imidazole dimer) unit should be a good candidate for multiphoton gated optical materials. PMID- 25909470 TI - CCTop: An Intuitive, Flexible and Reliable CRISPR/Cas9 Target Prediction Tool. AB - Engineering of the CRISPR/Cas9 system has opened a plethora of new opportunities for site-directed mutagenesis and targeted genome modification. Fundamental to this is a stretch of twenty nucleotides at the 5' end of a guide RNA that provides specificity to the bound Cas9 endonuclease. Since a sequence of twenty nucleotides can occur multiple times in a given genome and some mismatches seem to be accepted by the CRISPR/Cas9 complex, an efficient and reliable in silico selection and evaluation of the targeting site is key prerequisite for the experimental success. Here we present the CRISPR/Cas9 target online predictor (CCTop, http://crispr.cos.uni-heidelberg.de) to overcome limitations of already available tools. CCTop provides an intuitive user interface with reasonable default parameters that can easily be tuned by the user. From a given query sequence, CCTop identifies and ranks all candidate sgRNA target sites according to their off-target quality and displays full documentation. CCTop was experimentally validated for gene inactivation, non-homologous end-joining as well as homology directed repair. Thus, CCTop provides the bench biologist with a tool for the rapid and efficient identification of high quality target sites. PMID- 25909471 TI - Metabolic outcome of female mice exposed to a mixture of low-dose pollutants in a diet-induced obesity model. AB - Pollutants are suspected to contribute to the etiology of obesity and related metabolic disorders. Apart from occupational exposure which concerns a subset of chemicals, humans are mostly exposed to a large variety of chemicals, all life long and at low doses. Food ingestion is a major route of exposure and it is suggested that pollutants have a worsened impact when combined with a high-fat diet. In the experimental studies described herein, we aimed to add further evidence on the metabolic impact of food pollutants using a recently set up model in which mice are life-long fed a high-fat/high-sucrose diet (HFSD) with/without common food pollutants shown to exhibit metabolic disrupting activities. Specifically, this mixture comprised bisphenol A, dioxin, polychlorobiphenyl PCB153, and phthalate and was added in HFSD at doses resulting in mice exposure at the Tolerable Daily Intake dose range for each pollutant. We herein focused on the 7-week-old females which exhibited early signs of obesity upon HFSD feeding. We observed no signs of toxicity and no additional weight gain following exposure to the mixture but alleviated HFSD-induced glucose intolerance in the absence of alteration of gluconeogenesis and steatosis. It suggested that the observed metabolic improvement was more likely due to effects on muscle and/or adipose tissues rather than on the liver. Consistently, female mice exhibited enhanced lean/fat mass ratio and skeletal muscle insulin sensitivity. Moreover, expression levels of inflammatory markers were reduced in adipose tissue at 7 but enhanced at 12 weeks of age in agreement with the inverse alterations of glucose tolerance observed at these ages upon pollutant exposure in the HFSD-fed females. Collectively, these data suggest apparent biphasic effects of pollutants upon HFSD feeding along with obesity development. These effects were not observed in males and may depend on interactions between diet and pollutants. PMID- 25909472 TI - View-Angle Tilting and Slice-Encoding Metal Artifact Correction for Artifact Reduction in MRI: Experimental Sequence Optimization for Orthopaedic Tumor Endoprostheses and Clinical Application. AB - BACKGROUND: MRI plays a major role in follow-up of patients with malignant bone tumors. However, after limb salvage surgery, orthopaedic tumor endoprostheses might cause significant metal-induced susceptibility artifacts. PURPOSES: To evaluate the benefit of view-angle tilting (VAT) and slice-encoding metal artifact correction (SEMAC) for MRI of large-sized orthopaedic tumor endoprostheses in an experimental model and to demonstrate clinical benefits for assessment of periprosthetic soft tissue abnormalities. METHODS: In an experimental setting, tumor endoprostheses (n=4) were scanned at 1.5T with three versions of optimized high-bandwidth turbo-spin-echo pulse sequences: (i) standard, (ii) VAT and (iii) combined VAT and SEMAC (VAT&SEMAC). Pulse sequences included coronal short-tau-inversion-recovery (STIR), coronal T1-weighted (w), transverse T1-w and T2-w TSE sequences. For clinical evaluation, VAT&SEMAC was compared to conventional metal artifact-reducing MR sequences (conventional MR) in n=25 patients with metal implants and clinical suspicion of tumor recurrence or infection. Diameters of artifacts were measured quantitatively. Qualitative parameters were assessed on a five-point scale (1=best, 5=worst): "image distortion", "artificial signal changes at the edges" and "diagnostic confidence". Imaging findings were correlated with pathology. T-tests and Wilcoxon-signed rank tests were used for statistical analyses. RESULTS: The true size of the prostheses was overestimated on MRI (P<0.05). A significant reduction of artifacts was achieved by VAT (P<0.001) and VAT&SEMAC (P=0.003) compared to the standard group. Quantitative scores improved in the VAT and VAT&SEMAC group (P<0.05). On clinical MR images, artifact diameters were significantly reduced in the VAT&SEMAC-group as compared with the conventional-group (P<0.001). Distortion and artificial signal changes were reduced and diagnostic confidence improved (P<0.05). In two cases, tumor-recurrence, in ten cases infection and in thirteen cases other pathologies were diagnosed. CONCLUSIONS: Significant reduction of metallic artifacts was achieved by VAT and SEMAC. Clinical results suggest, that these new techniques will be beneficial for detecting periprosthetic pathologies during postoperative follow-up. PMID- 25909473 TI - Effects of blueberry supplementation on measures of functional mobility in older adults. AB - Limited functional mobility in older adults has been associated with declines in tests of motor, psychomotor, and executive function. Animal studies have demonstrated reversals in indices of motor and psychomotor function via supplementation with polyphenolic-rich foods such as blueberries. The purpose of this study was to examine whether 6 weeks of daily consumption of 2 cups of frozen blueberries affects functional mobility in older adults. Pre- and post intervention assessments of grip strength, simple reaction time, adaptive gait, and executive function were completed for older adults (age >60 years) partially randomly assigned to a blueberry (BB) supplementation or a carrot juice drink control (CAR) group. Paired t tests were used to assess within-group effects for outcome variables in each supplementation group, and a mixed-model analysis of covariance (ANCOVA) was used to determine group (CAR vs. BB) differences. Mixed model analysis indicated that the BB group demonstrated significant improvements relative to the CAR group in performance (i.e., number of step errors) of a challenging dual-task adaptive gait test that were independent of differences in gait speed. Within only the BB group, significant improvements were also seen in 3 other measures (i.e., usual gait speed; number of step errors during single task adaptive gait; and gait speed during dual-task adaptive gait). These preliminary findings support the hypothesis that blueberry supplementation may provide an effective countermeasure to age-related declines in functional mobility and serve as justification for an expansion to larger trials to more fully assess this nonpharmacologic approach to maintaining optimal mobility and independence. PMID- 25909474 TI - Preparation, characterization and antibacterial properties of ZnO/kaoline nanocomposites. AB - This paper describes laboratory preparation, characterization and antibacterial activity testing of ZnO/kaoline composites. ZnO/kaoline composites with 50 wt.% of ZnO were laboratory prepared, dried at 105 degrees C and calcined at 500 degrees C. XRPD analysis revealed that thermal treatment caused the phase transformation of Zn containing precursor into ZnO. Scanning and transmission electron microscopy techniques were used for characterization of morphology of the prepared samples. A standard microdilution test was used for evaluation of antibacterial activity using four common human pathogens (Staphylococcus aureus, Escherichia coli, Enterococcus faecalis and Pseudomonas aeruginosa). Daylight was used for induction photocatalytically based antibacterial activity. Second possible explanation of antibacterial activity of ZnO/kaoline could be the presence of biologically available forms of zinc. During the antibacterial activity assays the ZnO/kaoline composites exhibited antibacterial activity, where differences in an onset of the antibacterial activity and activity against bacterial strains were observed. The highest antibacterial activity was observed against S. aureus, where the lowest value of minimum inhibitory concentration was determined equal to 0.41 mg/ml. PMID- 25909475 TI - Evidence and practice in spine registries. AB - BACKGROUND AND PURPOSE: We performed a systematic review and a survey in order to (1) evaluate the evidence for the impact of spine registries on the quality of spine care, and with that, on patient-related outcomes, and (2) evaluate the methodology used to organize, analyze, and report the "quality of spine care" from spine registries. METHODS: To study the impact, the literature on all spinal disorders was searched. To study methodology, the search was restricted to degenerative spinal disorders. The risk of bias in the studies included was assessed with the Newcastle-Ottawa scale. Additionally, a survey among registry representatives was performed to acquire information about the methodology and practice of existing registries. RESULTS: 4,273 unique references up to May 2014 were identified, and 1,210 were eligible for screening and assessment. No studies on impact were identified, but 34 studies were identified to study the methodology. Half of these studies (17 of the 34) were judged to have a high risk of bias. The survey identified 25 spine registries, representing 14 countries. The organization of these registries, methods used, analytical approaches, and dissemination of results are presented. INTERPRETATION: We found a lack of evidence that registries have had an impact on the quality of spine care, regardless of whether intervention was non-surgical and/or surgical. To improve the quality of evidence published with registry data, we present several recommendations. Application of these recommendations could lead to registries showing trends, monitoring the quality of spine care given, and ultimately improving the value of the care given to patients with degenerative spinal disorders. PMID- 25909476 TI - Hyperparasitism in a Generalist Ectoparasitic Pupal Parasitoid, Pachycrepoideus vindemmiae (Hymenoptera: Pteromalidae), on Its Own Conspecifics: When the Lack of Resource Lead to Cannibalism. AB - Hyperparasitism is a normal behavior of parasitoids, which often happens among species. Conspecific hyperparasitism, such as some kinds of heteronomous hyperparasitic behaviors, has been only reported in some species belonging to Aphelinidae. In this article, the conspecific hyperparasitism of Pachycrepoideus vindemmiae (Pteromalidae) is reported, with Drosophila puparia as hosts. Hosts were exposed to P. vindemmiae females twice to parasitism with nine, twelve, and fifteen day intervals between the two exposures. None of the infested hosts emerged more than one offspring, and emergence of parasitoid offspring occurred in two obvious events, synchronously with the exposure time intervals, which suggested that offspring emerging during the first and second events would come from the primary and secondary parasitoids, respectively, and the inference with the developmental duration of offspring also indicated this. With two P. vindemmiae strains that could be identified by a simple sequence repeat marker, the above speculation of the origin of those offspring emerging during the two events was confirmed. Dissection of hosts exposed twice revealed a cannibalism behavior of larvae from the secondary foundresses on the primary conspecific pupae. Our results suggested a conspecific hyperparasitism behavior of the secondary parasitoids on the primary conspecifics. Measures showed a reduced body size for the adults from the conspecific hyperparasitism. Foundresses from the conspecific hyperparasitism had less fitness variables than those from primary parasitism, with shorter longevity, less life time fecundity, lower values of infestation degree, and lower success rate of parasitism. However, when the parasitoids from the conspecific hyperparasitism met healthy Drosophila puparia, their offspring would recover to normal size. Frequency of the conspecific hyperparasitism behavior enhanced with the decreasing of proportion of healthy hosts in the oviposition patch. The conspecific hyperparasitism of P. vindemmiae on the primary conspecifics would be helpful to last the population when healthy hosts are absent in the oviposition patch. PMID- 25909477 TI - Inhibiting K63 polyubiquitination abolishes no-go type stalled translation surveillance in Saccharomyces cerevisiae. AB - Incidental ribosome stalling during translation elongation is an aberrant phenomenon during protein synthesis and is subjected to quality control by surveillance systems, in which mRNA and a nascent protein are rapidly degraded. Their detailed molecular mechanisms as well as responsible factors for these processes are beginning to be understood. However, the initial processes for detecting stalled translation that result in degradation remain to be determined. Among the factors identified to date, two E3 ubiquitin ligases have been reported to function in distinct manners. Because ubiquitination is one of the most versatile of cellular signals, these distinct functions of E3 ligases suggested diverse ubiquitination pathways during surveillance for stalled translation. In this study, we report experimental evidences for a unique role of non-proteasomal K63 polyubiquitination during quality control for stalled translation. Inhibiting K63 polyubiquitination by expressing a K63R ubiquitin mutation in Saccharomyces cerevisiae cells markedly abolished the quality control responses for stalled translation. More detailed analyses indicated that the effects of K63R mutants were independent of the proteasome and that K63 polyubiquitination is dependent on Hel2, one of the E3 ligases. Moreover, a K63R ubiquitin mutant barely inhibited the quality control pathway for nonstop translation, indicating distinct mechanisms for these highly related quality control pathways. Our results suggest that non-proteasomal K63 polyubiquitination is included in the initial surveillance process of stalled translation and presumably triggers protein degradation steps upon translational stall. These findings provide crucial information regarding the detailed molecular mechanisms for the initial steps involved in quality control systems and their classification. PMID- 25909479 TI - Diastereo-specific conformational properties of neutral, protonated and radical cation forms of (1R,2S)-cis- and (1R,2R)-trans-amino-indanol by gas phase spectroscopy. AB - Chirality effects on the intramolecular interactions strongly depend on the charge and protonation states. Here, the influence of chirality on the structure of the neutral, protonated, and radical cation forms of (1R,2S)-cis- and (1R,2R) trans-1-amino-2-indanol diastereomers, prototypical molecules with two chiral centers, is investigated in a molecular beam by laser spectroscopy coupled with quantum chemical calculations. The neutral systems are structurally characterised by double resonance IR-UV spectroscopy, while IR-induced dissociation spectroscopy is employed for the charged molecules. The sterical constraints due to the cyclic nature of the molecule emphasise the chirality effects, which manifest themselves by the formation of an intramolecular hydrogen bond in neutral or protonated (1R,2S)-cis-amino-indanol. In contrast, this interaction is not possible in (1R,2R)-trans-amino-indanol. In the protonated species, chirality also influences the spectroscopic probes in the NH/OH stretch range by fine tuning subtle effects such as the hyperconjugation between the sigma(OH) orbital and sigma* orbitals localised on the alicyclic ring. The radical cation undergoes opening of the alicyclic ring, which results in an ionisation-induced loss of the chirality effects. PMID- 25909478 TI - Genome sequencing of the Trichoderma reesei QM9136 mutant identifies a truncation of the transcriptional regulator XYR1 as the cause for its cellulase-negative phenotype. AB - BACKGROUND: Trichoderma reesei is the main industrial source of cellulases and hemicellulases required for the hydrolysis of biomass to simple sugars, which can then be used in the production of biofuels and biorefineries. The highly productive strains in use today were generated by classical mutagenesis. As byproducts of this procedure, mutants were generated that turned out to be unable to produce cellulases. In order to identify the mutations responsible for this inability, we sequenced the genome of one of these strains, QM9136, and compared it to that of its progenitor T. reesei QM6a. RESULTS: In QM9136, we detected a surprisingly low number of mutagenic events in the promoter and coding regions of genes, i.e. only eight indels and six single nucleotide variants. One of these indels led to a frame-shift in the Zn2Cys6 transcription factor XYR1, the general regulator of cellulase and xylanase expression, and resulted in its C-terminal truncation by 140 amino acids. Retransformation of strain QM9136 with the wild type xyr1 allele fully recovered the ability to produce cellulases, and is thus the reason for the cellulase-negative phenotype. Introduction of an engineered xyr1 allele containing the truncating point mutation into the moderate producer T. reesei QM9414 rendered this strain also cellulase-negative. The correspondingly truncated XYR1 protein was still able to enter the nucleus, but failed to be expressed over the basal constitutive level. CONCLUSION: The missing 140 C-terminal amino acids of XYR1 are therefore responsible for its previously observed auto-regulation which is essential for cellulases to be expressed. Our data present a working example of the use of genome sequencing leading to a functional explanation of the QM9136 cellulase-negative phenotype. PMID- 25909480 TI - Tissue responses to postoperative laser therapy in diabetic rats submitted to excisional wounds. AB - In a previous study about low-level laser therapy biomodulation on a full thickness burn model we showed that single and fractionated dose regimens increased wound healing and leukocyte influx similarly when compared with untreated control. In order to verify if this finding would be similar in an impaired wound model, we investigated the effect of single and multiple irradiations on wound closure rate, type of inflammatory infiltrate, myofibroblasts, collagen deposition, and optical retardation of collagen in diabetic rats. Female Wistar rats in the same estrous cycle had diabetes induced with streptozotocin and an 8-mm excisional wound performed with a punch. The experimental groups were: control group--untreated ulcer; single-dose group- ulcer submitted to single dose of diode laser therapy (lambda = 660 +/- 2 nm; P = 30 mW; energy density: 4 J/cm2) and fractionated-dose group--ulcer submitted to 1 J/cm2 laser therapy on Days 1, 3, 8, and 10. The ulcers were photographed on the experimental days and after euthanasia tissue samples were routinely processed for histological and immunohistochemistry analyses. Independently of the energy density, laser therapy accelerated wound closure by approximately 40% in the first three days in comparison to the control group. Laser therapy increased acute inflammatory infiltrate until Day 3. Both laser groups exhibited more myofibroblasts and better collagen organization than the control group. The findings demonstrate that low-level laser therapy in the immediate postoperative period can enhance the tissue repair process in a diabetes model. Similar effects were achieved with laser therapy applied a single time with an energy density of 4 J/cm2 and applied four times with an energy density of 1 J/cm2. The application of laser therapy in the inflammatory phase was the most important factor to the enhancement of the tissue repair process. PMID- 25909481 TI - Magic electron affection in preparation process of silicon nanocrystal. AB - It is very interesting that magic electron affection promotes growth of nanocrystals due to nanoscale characteristics of electronic de Broglie wave which produces resonance to transfer energy to atoms. In our experiment, it was observed that silicon nanocrystals rapidly grow with irradiation of electron beam on amorphous silicon film prepared by pulsed laser deposition (PLD), and silicon nanocrystals almost occur in sphere shape on smaller nanocrystals with less irradiation time of electron beam. In the process, it was investigated that condensed structures of silicon nanocrystals are changed with different impurity atoms in silicon film, in which localized states emission was observed. Through electron beam irradiation for 15 min on amorphous Si film doped with oxygen impurity atoms by PLD process, enhanced photoluminescence emission peaks are observed in visible light. And electroluminescence emission is manipulated into the optical communication window on the bigger Si-Yb-Er nanocrystals after irradiation of electron beam for 30 min. PMID- 25909482 TI - Nosocomial Outbreak of New Delhi Metallo-beta-Lactamase-1-Producing Gram-Negative Bacteria in South Africa: A Case-Control Study. AB - OBJECTIVE: New Delhi metallo-beta-lactamase (NDM)-producing Gram-negative bacteria have spread globally and pose a significant public health threat. There is a need to better define risk factors and outcomes of NDM-1 clinical infection. We assessed risk factors for nosocomial infection with NDM-1-producers and associated in-hospital mortality. METHODS: A matched case-control study was conducted during a nosocomial outbreak of NDM-1-producers in an adult intensive care unit (ICU) in South Africa. All patients from whom NDM-1-producers were identified were considered (n=105). Cases included patients admitted during the study period in whom NDM-1 producing Gram-negative bacteria were isolated from clinical specimens collected >=48 hours after admission, and where surveillance definitions for healthcare-associated infections were met. Controls were matched for age, sex, date of hospital admission and intensive-care admission. Conditional logistic regression was used to identify risk factors for NDM-1 clinical infection and associated in-hospital mortality. FINDINGS: 38 cases and 68 controls were included. Klebsiella pneumoniae was the most common NDM-1 producer (28/38, 74%). Cases had longer mean hospital stays (44.0 vs. 13.3 days; P < 0.001) and ICU stays (32.5 vs. 8.3 days; P < 0.001). Adjusting for co-morbid disease, the in-hospital mortality of cases was significantly higher than controls (55.3% vs. 14.7%; AOR, 11.29; P < 0.001). Higher Charlson co-morbidity index score (5.2 vs. 4.1; AOR, 1.59; P = 0.005), mechanical ventilation days (7.47 vs. 0.94 days; AOR, 1.32; P = 0.003) and piperacillin/tazobactam exposure (11.03 vs. 1.05 doses; AOR, 1.08; P = 0.013) were identified as risk factors on multivariate analysis. Cases had a significantly higher likelihood of in-hospital mortality when the NDM-1-producer was Klebsiella pneumoniae (AOR, 16.57; P = 0.007), or when they had a bloodstream infection (AOR, 8.84; P = 0.041). CONCLUSION: NDM-1 infection is associated with significant in-hospital mortality. Risk factors for hospital-associated infection include the presence of co-morbid disease, mechanical ventilation and piperacillin/tazobactam exposure. PMID- 25909483 TI - Matrix metalloproteinase triggered size-shrinkable gelatin-gold fabricated nanoparticles for tumor microenvironment sensitive penetration and diagnosis of glioma. AB - To improve glioma targeting delivery efficiency and to monitor drug delivery and treatment outcome, a novel tumor microenvironment sensitive size-shrinkable theranostic system was constructed and evaluated. The G-AuNPs-DC-RRGD system was constructed by fabricating small sized gold nanoparticles (AuNPs) onto matrix metalloproteinase-2 (MMP-2) degradable gelatin nanoparticles (GNPs), doxorubicin (DOX) and Cy5.5 were decorated onto AuNPs through a hydrazone bond to enable the system with pH triggered cargoes release, and RRGD, a tandem peptide of RGD and octarginine was surface-modified onto the system to enable it with glioma active targeting ability. In vitro, the size of G-AuNPs-DC-RRGD could effectively shrink from 188.2 nm to 55.9 nm after incubation with MMP-2, while DOX and Cy5.5 were released in a pH dependent manner. Cellular uptake demonstrated that G-AuNPs-DC RRGD could be effectively taken up by cells with higher intensity than G-AuNPs-DC PEG. A study of tumor spheroids further demonstrated that the particles with smaller size showed better penetration ability, while RRGD modification could further improve permeability. In vivo, G-AuNPs-DC-RRGD displayed the best glioma targeting and accumulation efficiency, with good colocalization with neovessels. Cy5.5 also was colocalized well with DOX, indicating that Cy5.5 could be used for imaging of DOX delivery. PMID- 25909484 TI - The Epidemiology of HIV and Prevention Needs of Men Who Have Sex with Men in Abidjan, Cote d'Ivoire. AB - To determine HIV prevalence and associated risk factors among men who have sex with men (MSM) in Abidjan, Cote d'Ivoire. We conducted a cross-sectional RDS survey of MSM in Abidjan from October 2011 to February 2012. Eligibility criteria included age >= 18 years and having had oral or anal sex with another man in the last 12 months. Weighted data analysis was conducted with RDSAT and SAS. We enrolled 603 participants, of whom 601 (99.7%) completed the questionnaire and 581 (96.7%) consented to HIV testing. HIV population prevalence was estimated as 18.0% (95% CI: 13.0-23.1); 86.4% (95% CI: 75.1-94.9) of HIV-positive MSM were unaware of their serostatus. In multivariable analysis, adjusting for age, education, and income, HIV infection was associated with unprotected sex at last sex with a woman, more than two male anal sex partners in last 12 months, inconsistent condom use during anal sex with a man, self-perceived risk of HIV, history of forced sex, history of physical abuse due to MSM status, and not receiving last HIV test result prior to study. HIV prevalence among MSM in Abidjan is more than four times as high as that of general population men. MSM engage in high-risk sexual behavior and most HIV-positive MSM are unaware of their serostatus. Greater access to HIV prevention, care, and treatment services targeted to MSM is necessary. PMID- 25909485 TI - Reliance on technical solutions to environmental problems: caution is needed. PMID- 25909487 TI - Quantitative evaluation of noise reduction and vesselness filters for liver vessel segmentation on abdominal CTA images. AB - Liver vessel segmentation in CTA images is a challenging task, especially in the case of noisy images. This paper investigates whether pre-filtering improves liver vessel segmentation in 3D CTA images. We introduce a quantitative evaluation of several well-known filters based on a proposed liver vessel segmentation method on CTA images. We compare the effect of different diffusion techniques i.e. Regularized Perona-Malik, Hybrid Diffusion with Continuous Switch and Vessel Enhancing Diffusion as well as the vesselness approaches proposed by Sato, Frangi and Erdt. Liver vessel segmentation of the pre-processed images is performed using a histogram-based region grown with local maxima as seed points. Quantitative measurements (sensitivity, specificity and accuracy) are determined based on manual landmarks inside and outside the vessels, followed by T-tests for statistic comparisons on 51 clinical CTA images. The evaluation demonstrates that all the filters make liver vessel segmentation have a significantly higher accuracy than without using a filter (p < 0.05); Hybrid Diffusion with Continuous Switch achieves the best performance. Compared to the diffusion filters, vesselness filters have a greater sensitivity but less specificity. In addition, the proposed liver vessel segmentation method with pre-filtering is shown to perform robustly on a clinical dataset having a low contrast-to-noise of up to 3 (dB). The results indicate that the pre-filtering step significantly improves liver vessel segmentation on 3D CTA images. PMID- 25909486 TI - Genetic Analysis Using an Isogenic Mating Pair of Aspergillus fumigatus Identifies Azole Resistance Genes and Lack of MAT Locus's Role in Virulence. AB - Invasive aspergillosis (IA) due to Aspergillus fumigatus is a major cause of mortality in immunocompromised patients. The discovery of highly fertile strains of A. fumigatus opened the possibility to merge classical and contemporary genetics to address key questions about this pathogen. The merger involves sexual recombination, selection of desired traits, and genomics to identify any associated loci. We constructed a highly fertile isogenic pair of A. fumigatus strains with opposite mating types and used them to investigate whether mating type is associated with virulence and to find the genetic loci involved in azole resistance. The pair was made isogenic by 9 successive backcross cycles of the foundational strain AFB62 (MAT1-1) with a highly fertile (MAT1-2) progeny. Genome sequencing showed that the F9 MAT1-2 progeny was essentially identical to the AFB62. The survival curves of animals infected with either strain in three different animal models showed no significant difference, suggesting that virulence in A. fumigatus was not associated with mating type. We then employed a relatively inexpensive, yet highly powerful strategy to identify genomic loci associated with azole resistance. We used traditional in vitro drug selection accompanied by classical sexual crosses of azole-sensitive with resistant isogenic strains. The offspring were plated under varying drug concentrations and pools of resulting colonies were analyzed by whole genome sequencing. We found that variants in 5 genes contributed to azole resistance, including mutations in erg11A (cyp51A), as well as multi-drug transporters, erg25, and in HMG-CoA reductase. The results demonstrated that with minimal investment into the sequencing of three pools from a cross of interest, the variation(s) that contribute any phenotype can be identified with nucleotide resolution. This approach can be applied to multiple areas of interest in A. fumigatus or other heterothallic pathogens, especially for virulence associated traits. PMID- 25909488 TI - Anticholinergic drugs and health-related quality of life in older adults with dementia. AB - OBJECTIVES: To examine the association between the use of anticholinergic drugs and the health-related quality of life (HRQoL) among community-dwelling older adults with dementia. METHODS: This was a retrospective, longitudinal, cohort study of older adults aged 65 years and above diagnosed with dementia using Medical Expenditure Panel Survey data. Anticholinergic drug exposure was measured using the Anticholinergic Drug Scale. The HRQoL measures of interest were Physical Component Score (PCS) and Mental Component Score (MCS). Two separate unweighted multiple linear regression analyses were performed to determine the association of anticholinergic drugs with PCS and MCS, while adjusting for other factors and baseline HRQoL measures. RESULTS: The study included 112 patients with dementia; 15.18% of whom used anticholinergic drugs. The majority of the patients were between the ages of 65 and 79 years (53%), women (57%), and had poor or low family income (65%). After controlling for other factors and baseline HRQoL, anticholinergic drug use was associated with 7.48 unit reductions in PCS (P <0.01), whereas no association was found between anticholinergic drug use and MCS. Baseline HRQoL measures were found to be significant in both models. CONCLUSION: Anticholinergic drugs are associated with reduced PCS of HRQoL in older adults with dementia. The study findings suggest the need for carefully monitoring the health status of elderly patients when prescribing anticholinergic agents in this vulnerable population. PMID- 25909489 TI - A new technique to identify the location of the mucogingival junction on computer tomographic scans before implant placement. AB - A new technique is presented to identify the location of mucogingival junction (MGJ) on CT scans before implant placement. This case report describes the step by-step fabrication of a radiographic template, which when used in conjunction with CT scans enables the clinician to locate the position of MGJ before implant placement and predict the amount of keratinized tissue (KT) that will be present around an implant. Using this technique, the operator can determine whether or not flapless implant surgery may be a treatment option and whether simultaneous soft tissue augmentation will be necessary at the time of implant placement to establish an adequate band of KT. PMID- 25909491 TI - Management of the second phase of labour: perineum protection techniques. AB - The obstetric experience alongside scientific evidences in literature indicate several management techniques during the expulsive period of labour to minimize obstetric complications. Among the various methods that can be used for the protection of the perineum during the expulsive phase, some are performed prepartum (perineum massage), while most are used during childbirth. Among the second group, progressively increasing importance is assumed by the manual techniques to protect the perineum (using the "hands-on" and "hands-off") and by episiotomy. These techniques, when used in accordance to the guidelines, may favour the reduction of adverse outcomes for both the mother and the newborn, both immediately after birth and after a longer time. The midwife should be aware of the evidences in literature so that a critical analysis of the available techniques can be made and put in action during the expulsive phase in order to protect the mother and the foetus from any unfavourable outcomes. Currently, clinical evidence in literature is directing obstetric and medical staff towards a careful analysis of the maternal-foetal parameters, in order to achieve a precise assessment of the risks factors of intrapartum and postpartum outcomes. Increasingly, there is the need for close collaboration between the midwife and medical staff to ensure proper personalized assistance based on the peculiar characteristics of the woman and the fetus. PMID- 25909490 TI - Correlations between sonographically measured and actual incision site thickness of lower uterine segment after repeated caesarean section. AB - AIM: The aim of the present study was to verify how much the sonographically measured thickness of the lower uterine segment caesarean-section (LUS-CS) scar correlates with incision site thickness in a repeated caesarean section after uterotonic administration. METHODS: Sixty-three obstetric patients at term undergoing repeated caesarean section. LUS-CS thickness was measured sonographically before the repeated caesarean. Some seconds after delivery of the fetus and placenta and administration of an institutional, standard uterotonic, LUS was measured on the site of surgical incision (upper side and lower side) using Castroviejo's caliper. Multiple measurements were taken and averaged for improving accuracy. Mean measurements were used for calculations (unilinear correlations and multilinear regression analyses.). RESULTS: Poor correlation was found between sonographically measured scar thickness and lower uterine side incision thickness (r 0.311; C.I. 95% 0.068-0.519; P=0.013) and between sonographically measured scar thickness and uterine scar overall incision thickness (mean of upper side and lower side measurements) (r 0.254; C.I. 95% 0.007-0.472; P=0.045). Sonographically measured scar thickness was smaller in patients with two or more previous caesareans (P=0.045) and greater in patients who had undergone the last of the previous caesarean sections longer than two years earlier (P=0.043). Patients with two or more previous caesareans had smaller upper-side incision thickness (P=0.005); smaller lower-side incision thickness (P=0.038); smaller incision site overall thickness (P=0.006). CONCLUSION: Sonographically measured thickness and incision site thickness of the LUS-CS scar are poorly correlated (about 25%), despite the fact that patients most at risk for uterine rupture have thinner LUS, both sonographically and when measured during surgery. PMID- 25909492 TI - A particular association: aberrant right subclavian artery, persistent left superior vena cava and a dilatation of pulmonary artery in a dysmorphic SGA fetus. PMID- 25909493 TI - Effect of the Polymer Architecture on the Structural and Biophysical Properties of PEG-PLA Nanoparticles. AB - Polymers made of poly(ethylene glycol) chains grafted to poly(lactic acid) chains (PEG-g-PLA) were used to produce stealth drug nanocarriers. A library of comblike PEG-g-PLA polymers with different PEG grafting densities was prepared in order to obtain nanocarriers with dense PEG brushes at their surface, stability in suspension, and resistance to protein adsorption. The structural properties of nanoparticles (NPs) produced from these polymers by a surfactant-free method were assessed by dynamic light scattering, zeta potential, and transmission electron microscopy and found to be controlled by the amount of PEG present in the polymers. A critical transition from a solid NP structure to a soft particle with either a "micellelike" or a "polymer nanoaggregate" structure was observed when the PEG content was between 15 and 25% w/w. This structural transition was found to have a profound impact on the size of the NPs, their surface charge, their stability in suspension in the presence of salts, and the binding of proteins to the surface of the NPs. The arrangement of the PEG-g-PLA chains at the surface of the NPs was investigated by (1)H NMR and X-ray photoelectron spectroscopy (XPS). NMR results confirmed that the PEG chains were mostly segregated at the NP surface. Moreover, XPS and quantitative NMR allowed quantification of the PEG chain coverage density at the surface of the solid NPs. Concordance of the results between the two methods was found to be remarkable. Physical-chemical properties of the NPs such as resistance to aggregation in a saline environment as well as antifouling efficacy were related to the PEG surface density and ultimately to the polymer architecture. Resistance to protein adsorption was assessed by isothermal titration calorimetry using lysozyme. The results indicate a correlation between the PEG surface coverage and level of protein interactions. The results obtained lead us to propose such PEG-g-PLA polymers for nanomedicine development as an alternative to the predominant polyester-PEG diblock polymers. PMID- 25909494 TI - Evolution of the complement system C3 gene in Antarctic teleosts. AB - Notothenioidei are typical Antarctic teleosts evolved to adapt to the very low temperatures of the Antarctic seas. Aim of the present paper is to investigate sequence and structure of C3, the third component of the complement system of the notothenioid Trematomus bernacchii and Chionodraco hamatus. We determined the complete nucleotide sequence of two C3 isoforms of T. bernacchii and a single C3 isoform of C. hamatus. These sequences were aligned against other homologous teleost sequences to check for the presence of diversifying selection. Evidence for positive selection was observed in the evolutionary lineage of Antarctic teleost C3 sequences, especially in that of C. hamatus, the most recently diverged species. Adaptive selection affected numerous amino acid positions including three residues located in the anaphylatoxin domain. In an attempt to evaluate the link between sequence variants and specific structural features, we constructed molecular models of Antarctic teleost C3s, of their proteolytic fragments C3b and C3a, and of the corresponding molecules of the phylogenetically related temperate species Epinephelus coioides, using human crystallographic structures as templates. Subsequently, we compared dynamic features of these models by molecular dynamics simulations and found that the Antarctic C3s models show higher flexibility, which likely allows for more pronounced movements of both the TED domain in C3b and the carboxyl-terminal region of C3a. As such dynamic features are associated to positively selected sites, it appears that Antarctic teleost C3 molecules positively evolved toward an increased flexibility, to cope with low kinetic energy levels of the Antarctic marine environment. PMID- 25909495 TI - Soluble monosodium urate, but not its crystal, induces toll like receptor 4 dependent immune activation in renal mesangial cells. AB - BACKGROUND: Uric acid has emerged as a novel and potential modifiable risk factor for the incidence and progression of kidney diseases, however, the deteriorate effect of uric acid on renal mesangial cells remains unclear. The present study is to examine the immune activation of soluble and crystal forms of uric acid in human mesangial cells. METHODS: We stimulated primary human mesangial cells (HMCs) with increasing concentrations (from 50 to 200 MUg/ml) of soluble monosodium urate (MSU) or MSU crystals. We examined interleukin (IL)-1beta protein expression levels in cell culture by ELISA. The stimulated HMCs were further stimulated with soluble MSU or MSU crystals at 200 MUg/ml with or without the pre-incubation of toll like receptor (TLR) 4 inhibitor TAK242 (1MUM). TLR4, nod-like receptor protein (NLRP3, also known as NALP3), IL-1beta, human leukocyte antigen (HLA)-DR and CD40 were examined by Realtime-PCR, Western blot and ELISA, respectively. RESULTS: We found that both soluble MSU and MSU crystals increased IL-1beta protein expression levels in dose-dependent fashion. Soluble MSU significantly enhanced the expression of TLR4, NLRP3, IL-1beta, HLA-DR and CD40 while MSU crystals only upregulated the expression of TLR4 and IL-1beta. TLR4 inhibitor TAK242 significantly blocked the up-regulation of NLRP3, IL-1beta, HLA DR and CD40 induced by soluble MSU while no TAK242 suppression effect on MSU crystals induced IL-1beta up-regulation was found. CONCLUSIONS: Our results suggested that soluble MSU, but not MSU crystals, induce NLRP3, IL-1beta, HLA-DR and CD40 upregulation in a TLR4-dependent manner. These findings indicate that soluble MSU may play a pathological role in hyperuricemia induced renal mesangial injury. PMID- 25909496 TI - The impact of elder abuse education on young adults. AB - The present study examined the effectiveness of educational interventions in altering tolerance for and behavioral intentions of elder abuse among college student young adults. Participants were 225 undergraduates who were assigned to one of four educational groups: Elder Abuse Education, Aging Education, Family Education, and a Pre- and Posttest only condition. While the Elder Abuse Education group reported less tolerance and intentions for elder abuse compared to the other groups at the immediate posttest, a decrement in such positive changes at 1-month follow-up was observed in such persons. These mixed findings suggest that while specific interventions may reduce elder abuse tolerance, supplemental educational efforts over time may be necessary to maintain intervention-specific gains in intentions and behaviors particular to elder abuse. PMID- 25909497 TI - Electrochemical treatment of perfluorooctanoic acid (PFOA) and perfluorooctane sulfonic acid (PFOS) in groundwater impacted by aqueous film forming foams (AFFFs). AB - Laboratory experiments were performed to evaluate the use of electrochemical treatment for the decomposition of perfluorooctanoic acid (PFOA) and perfluorooctane sulfonic acid (PFOS), as well as other perfluoroalkyl acids (PFAAs), in aqueous film forming foam (AFFF)-impacted groundwater collected from a former firefighter training area and PFAA-spiked synthetic groundwater. Using a commercially-produced Ti/RuO2 anode in a divided electrochemical cell, PFOA and PFOS decomposition was evaluated as a function of current density (0-20 mA/cm(2)). Decomposition of both PFOA and PFOS increased with increasing current density, although the decomposition of PFOS did not increase as the current density was increased above 2.5 mA/cm(2). At a current density of 10 mA/cm(2), the first-order rate constants, normalized for current density and treatment volume, for electrochemical treatment of both PFOA and PFOS were 46 * 10(-5) and 70 * 10(-5) [(min(-1)) (mA/cm(2))(-1) (L)], respectively. Defluorination was confirmed for both PFOA and PFOS, with 58% and 98% recovery as fluoride, respectively (based upon the mass of PFOA and PFOS degraded). Treatment of other PFAAs present in the groundwater also was observed, with shorter chain PFAAs generally being more recalcitrant. Results highlight the potential for electrochemical treatment of PFAAs, particularly PFOA and PFOS, in AFFF-impacted groundwater. PMID- 25909498 TI - Characterization of trichloroethylene adsorption onto waste biocover soil in the presence of landfill gas. AB - Waste biocover soils (WBS) have been demonstrated to have great potential in mitigating trichloroethylene (TCE) emission from landfills, due to the relatively high TCE-degrading capacity. In this study, the characteristics of TCE adsorption on WBS in the presence of the major landfill gas components (i.e., CH4 and CO2) were investigated in soil microcosms. The adsorption isotherm of TCE onto WBS was fitted well with linear model within the TCE concentrations of 7000 ppmv. The adsorption capacity of TCE onto WBS was affected by temperature, soil moisture content and particle size, of which, temperature was the dominant factor. The adsorption capacity of TCE onto the experimental materials increased with the increasing organic matter content. A significantly positive correlation was observed between the adsorption capacity of TCE and the organic matter content of experimental materials that had relatively higher organic content (r = 0.988, P = 0.044). To better understand WBS application in practice, response surface methodology was developed to predict TCE adsorption capacity and emissions through WBS in different landfills in China. These results indicated that WBS had high adsorption capacity of TCE in LFG and temperature should be paid more attention to manipulate WBS to reduce TCE emissions from landfills. PMID- 25909499 TI - Microsecond Deprotonation of Aspartic Acid and Response of the alpha/beta Subdomain Precede C-Terminal Signaling in the Blue Light Sensor Plant Cryptochrome. AB - Plant cryptochromes are photosensory receptors that regulate various central aspects of plant growth and development. These receptors consist of a photolyase homology region (PHR) carrying the oxidized flavin adenine dinucleotide (FAD) cofactor, and a cryptochrome C-terminal extension (CCT), which is essential for signaling. Absorption of blue/UVA light leads to formation of the FAD neutral radical as the likely signaling state, and ultimately activates the CCT. Little is known about the signal transfer from the flavin to the CCT. Here, we investigated the photoreaction of the PHR by time-resolved step-scan FT-IR spectroscopy complemented by UV-vis spectroscopy. The first spectrum at 500 ns shows major contributions from the FAD anion radical, which is demonstrated to then be protonated by aspartic acid 396 to the neutral radical within 3.5 MUs. The analysis revealed the existence of three intermediates characterized by changes in secondary structure. A marked loss of beta-sheet structure is observed in the second intermediate evolving with a time constant of 500 MUs. This change is accompanied by a conversion of a tyrosine residue, which is identified as the formation of a tyrosine radical in the UV-vis. The only beta-sheet in the PHR is located within the alpha/beta subdomain, ~25 A away from the flavin. This subdomain has been previously attributed a role as a putative antenna binding site, but is now suggested to have evolved to a component in the signaling of plant cryptochromes by mediating the interaction with the CCT. PMID- 25909500 TI - Improved outcomes of feeding low birth weight infants with predominantly raw human milk versus donor banked milk and formula. AB - OBJECTIVES: To investigate the benefits of treating low birth weight infants predominantly with mother's own raw milk and early initiation of breastfeeding (raw human milk/breast-fed infants), in comparison to feeding only with donor banked milk (until the third week of life) and afterwards a preterm formula until hospital discharge (donor banked/formula-fed infants). METHODS: One hundred and ninety-two predominantly raw human milk-fed infants (70% of raw and 30% of donor milk) were matched to 192 donor/formula-fed ones (on 1:1 ratio). Aggressive nutrition policy and targeted fortification of human milk were implemented in both groups. RESULTS: The two groups show similar demographic and perinatal characteristics. Predominantly raw milk-fed infants regained earlier their birth weight, suffered less episodes of feeding intolerance and presented a higher body length and head circumference at discharge (p < 0.001). Those treated mainly with their mothers' milk were able to initiate breastfeeding almost 2 weeks earlier compared to those fed with donor milk who achieved to be bottle-fed later on post conceptual age (p < 0.001). Infants being breastfed until the 8th month of life conducted less visits for a viral infection to a pediatrician compared to those in the other group (p < 0.001). CONCLUSIONS: Feeding predominantly with mother's raw milk seems to result in optimal neonatal outcomes. PMID- 25909501 TI - Fas and FasL expression in placentas complicated with intrauterine growth retardation with and without preeclampsia. AB - OBJECTIVE: To compare the level of Fas and FasL immunohistochemical expression in villous trophoblast (VT), extravillous trophoblast (EVT) cells, decidual cells (DC), endothelial cells (EC) of villous blood vessels and spiral arteries between the study groups of intrauterine growth retardation (IUGR) placentas with and without preeclampsia (PE). METHODS: The study included 17 placentas from pregnancies complicated by IUGR + PE and 17 placentas from pregnancies complicated by idiopathic IUGR (I-IUGR). Seventeen placentas from normal pregnancies served as a control group. CD31 was used to detect endothelial cells (EC). Immunohistochemical expression of Fas and FasL was assessed in all examined parts of placenta using the semi-quantitative HSCORE method. RESULTS: FasL expression was significantly higher in all examined parts of placenta in I-IUGR as compared to IUGR + PE and control group. Placentas with IUGR + PE had the significantly lowest expression of FasL in VT and EC of villi vessels. Expression of Fas did not differ significantly between the study groups. CONCLUSION: Different expression of FasL in placentas from I-IUGR and IUGR + PE suggests that FasL probably has a different role in the etiology of these two syndromes. PMID- 25909502 TI - Building school-based cardiovascular health promotion capacity in youth: a mixed methods study. AB - BACKGROUND: Essential to building cardiovascular health promotion capacity in youth, which extends into adulthood, are approaches that seek to empower, educate, and support. The Five Cs model of positive youth development (PYD) guided this study. This model represents the ability of youth to develop competence, confidence, connection, character, and caring when given the appropriate resources. The purpose of this two-year school-based feasibility study was to determine if providing a research intervention in the form of education, empowerment, and support build youth's capacity for cardiovascular health promotion. METHODS: A mixed methods case study design was used to evaluate the process, and outcome of a youth-led cardiovascular health promotion program. Twenty-six youth aged 12-13 years from a Canadian middle school took part in the study. Youth participating in this study planned, implemented, and monitored cardiovascular health promotion activities in four areas: smoking, physical inactivity, nutrition and obesity. Qualitative data was collected from the youth participants using three focus groups and individual reflective journals. Quantitative data was collected with the PYD.2, a self-report questionnaire that assesses positive youth development and consists of 5 subscales: character, competence, caring, connection, and confidence. The participants completed the PYD before and after the program to determine if there were any changes in PYD scores after the intervention. The quantitative data was analyzed using paired samples t-tests, and the qualitative data was analyzed using constant comparative analysis. RESULTS: While the PYD scores showed no significant changes, the qualitative findings confirmed that the youth acquired increased awareness and understanding of cardiovascular health promotion initiatives. Four themes emerged from the qualitative data, (1) doing the right thing, (2) wanting to make a change, but feeling constrained, (3) I get it, and (4) The project has changed me! The intervention was found to be acceptable and feasible for the youth participants and their school. CONCLUSIONS: The contributions of this study were twofold. It generated evidence to support integrating positive youth development strategies into cardiovascular health promotion programs. Secondly, this study determined that the research intervention improved the participants' knowledge and attitudes about cardiovascular health and were suitable for further implementation and testing. PMID- 25909503 TI - A Functional Role of Fibroblast Growth Factor Receptor 1 (FGFR1) in the Suppression of Influenza A Virus Replication. AB - Influenza A virus causes annual epidemics and occasional pandemics in humans. Here, we investigated four members of the fibroblast growth factor receptor (FGFR) family; FGFR1 to 4, and examined their expression patterns in human lung epithelial cells A549 with influenza A virus infection. We identified a functional role of FGFR1 in influenza A/Puerto Rico/8/1934 (PR8) and A/Anhui/01/2005 (H5N1) virus replication. Our results showed that FGFR1 silencing by siRNA interference promoted influenza A/PR8 and H5N1 virus replication in A549 cells, while lentivirus-mediated exogenous FGFR1 expression significantly suppressed influenza A virus replication; however, FGFR4 did not have the same effects. Moreover, FGFR1 phosphorylation levels were downregulated in A549 cells by influenza A virus infection, while the repression of FGFR1 kinase using PD173074, a potent and selective FGFR1 inhibitor, could enhance virus replication. Furthermore, we found that FGFR1 inhibits influenza virus internalization, but not binding, during viral entry. These results suggested that FGFR1 specifically antagonizes influenza A virus replication, probably by blocking viral entry. PMID- 25909504 TI - To Float or Not to Float: How Interactions between Light and Dissolved Inorganic Carbon Species Determine the Buoyancy of Stratiotes aloides. AB - Structural diversity formed by dense, floating Stratiotes aloides stands, generates hotspots of biodiversity of flora and fauna in wetlands. However, only part of the populations become emergent and provide this important facilitation. Since it has been hypothesised that its buoyancy depends on the rates of underwater photosynthesis, we investigated the role of dissolved CO2 availability and PAR on photosynthesis, biomass production and buoyancy in a controlled greenhouse experiment. Photosynthesis and growth were strongly influenced by both PAR and CO2 availability. At low PAR, plants formed less biomass and produced no emergent leaves, even when CO2 was abundant. At low CO2 levels, S. aloides switched to HCO3- use, resulting in a lower photosynthetic O2 production, decreased emergent leaf formation and increased CaCO3 precipitation on its leaves, all of which impaired buoyancy. At high PAR, low CO2 availability resulted in slower colonisation of the water layer, whereas CO2 availability did not influence PAR-limited plants. Our study shows that site conditions, rather than the sole abundance of potentially facilitating species, may strongly determine whether or not they form the structure necessary to act as a facilitator for biodiversity in aquatic environments. PMID- 25909506 TI - beta-Selective C-Arylation of Diisobutylaluminum Hydride Modified 1,6 Anhydroglucose: Synthesis of Canagliflozin without Recourse to Conventional Protecting Groups. AB - The beta-selective phenylation of benzyl and boronate protected 1,6 anhydroglucose and the direct phenylation of unprotected 1,6-anhydroglucose (10), pretreated with i-Bu2AlH, i-Bu3Al, Et3Al, Me3Al, or n-octyl3Al, with triphenylalane or aryl(chloro)alanes is reported. The utility of the unprotected version of the method is demonstrated by the synthesis of the SGLT2 inhibitor, canagliflozin (1a), from commercially available 10 in one C-C bond-forming step. This approach circumvents the need for conventional protecting groups, and therefore no formal protection and deprotection steps are required. PMID- 25909505 TI - A Neutral Thermostable beta-1,4-Glucanase from Humicola insolens Y1 with Potential for Applications in Various Industries. AB - We cloned a new glycoside hydrolase family 6 gene, Hicel6C, from the thermophilic fungus Humicola insolens Y1 and expressed it in Pichia pastoris. Using barley beta-glucan as a substrate, recombinant HiCel6C protein exhibited neutral pH (6.5) and high temperature (70 degrees C) optima. Distinct from most reported acidic fungal endo-beta-1,4-glucanases, HiCel6C was alkali-tolerant, retaining greater than 98.0, 61.2, and 27.6% of peak activity at pH 8.0, 9.0, and 10.0, respectively, and exhibited good stability over a wide pH range (pH 5.0-11.0) and at temperatures up to 60 degrees C. The Km and Vmax values of HiCel6C for barley beta-glucan were 1.29 mg/mL and 752 MUmol/min.mg, respectively. HiCel6C was strictly specific for the beta-1,4-glucoside linkage exhibiting activity toward barley beta-glucan, lichenan, and carboxy methylcellulose sodium salt (CMC-Na), but not toward laminarin (1,3-beta-glucan). HiCel6C cleaved the internal glycosidic linkages of cellooligosaccharides randomly and thus represents an endo cleaving enzyme. The predominant product of polysaccharide hydrolysis by HiCel6C was cellobiose, suggesting that it functions by an endo-processive mechanism. The favorable properties of HiCel6C make it a good candidate for basic research and for applications in the textile and brewing industries. PMID- 25909507 TI - Vibrational control of electron-transfer reactions: a feasibility study for the fast coherent transfer regime. AB - Molecular vibrations and electron-vibrational interactions are central to the control of biomolecular electron and energy-transfer rates. The vibrational control of molecular electron-transfer reactions by infrared pulses may enable the precise probing of electronic-vibrational interactions and of their roles in determining electron-transfer mechanisms. This type of electron-transfer rate control is advantageous because it does not alter the electronic state of the molecular electron-transfer system or irreversibly change its molecular structure. For bridge-mediated electron-transfer reactions, infrared (vibrational) excitation of the bridge linking the electron donor to the electron acceptor was suggested as being capable of influencing the electron-transfer rate by modulating the bridge-mediated donor-to-acceptor electronic coupling. This kind of electron-transfer experiment has been realized, demonstrating that bridge mediated electron-transfer rates can be changed by exciting vibrational modes of the bridge. Here, we use simple models and ab initio computations to explore the physical constraints on one's ability to vibrationally perturb electron-transfer rates using infrared excitation. These constraints stem from the nature of molecular vibrational spectra, the strengths of the electron-vibrational coupling, and the interaction between molecular vibrations and infrared radiation. With these constraints in mind, we suggest parameter regimes and molecular architectures that may enhance the vibrational control of electron transfer for fast coherent electron-transfer reactions. PMID- 25909508 TI - Obtaining self-samples to diagnose curable sexually transmitted infections: a systematic review of patients' experiences. AB - BACKGROUND: Routine screening is key to sexually transmitted infection (STI) prevention and control. Previous studies suggest that clinic-based screening programmes capture only a small proportion of people with STIs. Self-sampling using non- or minimally invasive techniques may be beneficial for those reluctant to actively engage with conventional sampling methods. We systematically reviewed studies of patients' experiences of obtaining self-samples to diagnose curable STIs. METHODS: We conducted an electronic search of MEDLINE, EMBASE, CINAHL, PsychINFO, BNI, and Cochrane Database of Systematic Reviews to identify relevant articles published in English between January 1980 and March 2014. Studies were included if participants self-sampled for the diagnosis of a curable STI and had specifically sought participants' opinions of their experience, acceptability, preferences, or willingness to self-sample. RESULTS: The initial search yielded 558 references. Of these, 45 studies met the inclusion criteria. Thirty-six studies assessed patients' acceptability and experiences of self-sampling. Pooled results from these studies shows that self-sampling is a highly acceptable method with 85% of patients reporting the method to be well received and acceptable. Twenty-eight studies reported on ease of self-sampling; the majority of patients (88%) in these studies found self-sampling an "easy" procedure. Self-sampling was favoured compared to clinician sampling, and home sampling was preferred to clinic-based sampling. Females and older participants were more accepting of self sampling. Only a small minority of participants (13%) reported pain during self sampling. Participants were willing to undergo self-sampling and recommend others. Privacy and safety were the most common concerns. CONCLUSION: Self sampling for diagnostic testing is well accepted with the majority having a positive experience and willingness to use again. Standardization of self sampling procedures and rigorous validation of outcome measurement will lead to better comparability across studies. Future studies need to conduct rigorous economic evaluations of self-sampling to inform policy development for the management of STI. PMID- 25909509 TI - Frequent house invasion of Trypanosoma cruzi-infected triatomines in a suburban area of Brazil. AB - BACKGROUND: The demographic transition of populations from rural areas to large urban centers often results in a disordered occupation of forest remnants and increased economic pressure to develop high-income buildings in these areas. Ecological and socioeconomic factors associated with these urban transitions create conditions for the potential transmission of infectious diseases, which was demonstrated for Chagas disease. METHODOLOGY/PRINCIPAL FINDINGS: We analyzed 930 triatomines, mainly Triatoma tibiamaculata, collected in artificial and sylvatic environments (forests near houses) of a suburban area of the city of Salvador, Bahia State, Brazil between 2007 and 2011. Most triatomines were captured at peridomiciles. Adult bugs predominated in all studied environments, and nymphs were scarce inside houses. Molecular analyses of a randomly selected sub-sample (n=212) of triatomines showed Trypanosoma cruzi infection rates of 65%, 50% and 56% in intradomestic, peridomestic and sylvatic environments, respectively. We detected the T. cruzi lineages I and II and mixed infections. We also showed that T. tibiamaculata fed on blood from birds (50%), marsupials (38%), ruminants (7%) and rodents (5%). The probability of T. cruzi infection was higher in triatomines that fed on marsupial blood (odds ratio (OR) = 1.95, 95% confidence interval (CI) = 1.22-3.11). Moreover, we observed a protective effect against infection in bugs that fed on bird blood (OR = 0.43, 95% CI = 0.30-0.73). CONCLUSIONS/SIGNIFICANCE: The frequent invasion of houses by infected triatomines indicates a potential risk of T. cruzi transmission to inhabitants in this area. Our results reinforce that continuous epidemiological surveillance should be performed in areas where domestic transmission is controlled but enzootic transmission persists. PMID- 25909511 TI - Anisotropic optical properties of oriented silver nanorice and nanocarrots in stretched polymer films. AB - Stretching-induced orientation of both silver nanorice and silver nanocarrots dispersed in or deposited on the surface of poly(vinyl alcohol) (PVA) films was investigated using polarized UV-visible-near-infrared (NIR) spectroscopy and atomic force microscopy (AFM). The results show that the film stretching not only aligns the long axis of individual nanorice or nanocarrots preferentially along the stretching direction, but also induces assembly of these nanostructures into oriented arrays of random lengths in the deformation process. Consequently, the longitudinal surface plasmon resonance peaked at 820 nm for nanorice and 1050 nm for nanocarrots before stretching can be replaced by continuous extinction over the entire 800-1800 nm NIR spectral range after stretching. Stretched PVA films containing either silver nanorice or nanocarrots thus display polarization dependent transmission of NIR light. PMID- 25909510 TI - Cyclophilin A is associated with peripheral artery disease and chronic kidney disease in geriatrics: The Tianliao Old People (TOP) study. AB - Cyclophilin A (CyPA), secreted by vascular smooth muscle cells in response to oxidative stress, is important in the pathogenesis of progressive peripheral arterial occlusion disease (PAOD), which is common among chronic kidney disease. We explored the prevalence of PAOD in Taiwan's elderly (>= 65 years old) population and its association with CyPA and renal function. Residents of Tianliao District, a rural community in southern Taiwan, were surveyed. An ankle brachial index (ABI) < 0.91 was defined as PAOD. Chronic kidney disease (CKD) was defined based on eGFR levels < 60 mL/min/1.73 m(2). Serum CyPA was measured. Of the 473 participants, 68 (14.4%) had PAOD. Multiple logistic regression analysis showed PAOD was significantly associated with lower eGFR, lower BMI, higher glycated hemoglobin and higher pulse pressure. Serum CyPA levels in participants with PAOD were significantly higher than those with normal ABI values (47.3 +/- 0.4 vs. 25.5 +/- 0.2 ng/mL, p < 0.001). Moreover, eGFR inversely correlated with serum CyPA level (p < 0.05) in participants with CKD, but not in participants with normal renal function. In conclusion, with a prevalence of PAOD as high as 14.4% in an elderly community, CyPA might be the link between PAOD and advanced impaired renal function. PMID- 25909512 TI - Cytotoxic Effects during Knock Out of Multiple Porcine Endogenous Retrovirus (PERV) Sequences in the Pig Genome by Zinc Finger Nucleases (ZFN). AB - Xenotransplantation has been proposed as a solution to the shortage of suitable human donors for transplantation and pigs are currently favoured as donor animals. However, xenotransplantation may be associated with the transmission of zoonotic microorganisms. Whereas most porcine microorganisms representing a risk for the human recipient may be eliminated by designated pathogen free breeding, multiple copies of porcine endogenous retroviruses (PERVs) are integrated in the genome of all pigs and cannot be eliminated this way. PERVs are released as infectious particles and infect human cells. The zinc finger nuclease (ZFN) technology allows knocking out specifically cellular genes, however it was not yet used to eliminate multiple integrated proviral sequences with a strong conservation in the target sequence. To reduce the risk of horizontal PERV transmission and to knock out as many as possible proviruses, for the first time the powerful tool of the ZFN technology was used. ZFN were designed to bind specifically to sequences conserved in all known replication-competent proviruses. Expression and transport of the ZFN into the nucleus was shown by Western blot analysis, co-localisation analysis, PLA and FRET. Survival of transfected cells was analysed using fluorescent ZFN and cell counting. After transfection a strong expression of the ZFN proteins and a co-localisation of the expressed ZFN proteins were shown. However, expression of the ZFN was found to be extremely toxic for the transfected cells. The induced cytotoxicity was likely due to the specific cutting of the high copy number of the PERV proviruses, which is also commonly observed when ZFN with low specificity cleave numerous off target sites in a genome. This is the first attempt to knock out multiple, nearly identical, genes in a cellular genome using ZFN. The attempt failed, and other strategies should be used to prevent PERV transmission. PMID- 25909513 TI - Effects of Clozapine and other Atypical Antipsychotics on Infants Development Who Were Exposed to as Fetus: A Post-Hoc Analysis. AB - OBJECTIVE: To investigate the developmental effects of clozapine and other atypical antipsychotics on infants who were exposed to as fetus. METHOD: The developmental progress of 33 infants who were exposed to clozapine as fetus was compared to 30 infants who were exposed to risperidone, olanzapine or quetiapine as fetus by assessing Apgar scoring, birth weight at birth, body weight, height, and the Bayley Scales of Infant and Toddler Development, Third Edition (BSID-III) at months 2, 6 and 12 of age. Five subscale scores of BSID-III including cognitive, language, motor, social-emotional, and adaptive behavior were also compared. Student's t test and Chi-square analysis were used as appropriate. Repeated measurements were evaluated by analysis of covariance. RESULTS: Of the 63 infants, 58 (92.1%) completed a 12-month study period. At the age of 2 and 6 months, mean adaptive behavior scores of BSID-III were significantly lower in clozapine-exposed infants than infants who exposed to other atypical antipsychotic at 2 and 6 months of age. More clozapine-exposed infants had delayed development (defined as the subscale score of <85) for adaptive behavior at 2 and 6 months of age. There was no difference between the two groups for cognitive, language, motor, social and emotional at 2, 6 and 12 months of age. More infants who were exposed to clozapine as fetus (25 of 33, 75.8%) had disturbed sleep and a labile state than those who were exposed to other atypical antipsychotics (8 of 30, 26.7%) during 2 months of age (P<0.001). CONCLUSION: These results suggest that clozapine has more adaptive behavior effects on infants who were exposed to as a fetus than other atypical antipsychotics at 2 and 6 months of age. TRIAL REGISTRATION: ClinicalTrials.gov NCT01479400. PMID- 25909514 TI - Ameliorative effect of chrysin on adenine-induced chronic kidney disease in rats. AB - Chrysin (5, 7- dihydroxyflavone) is a flavonoid with several pharmacological properties that include antioxidant, anti-inflammatory and antiapoptotic activities. in this work, we investigated some effects of three graded oral doses of chrysin (10, 50 and 250 mg/kg) on kidney structure and function in rats with experimental chronic renal disease (CKD) induced by adenine (0.25% w/w in feed for 35 days), which is known to involve inflammation and oxidative stress. Using several indices in plasma, urine and kidney homogenates, adenine was found to impair kidney function as it lowered creatinine clearance and increased plasma concentrations of creatinine, urea, neutrophil gelatinase-associated lipocalin and N-Acetyl-beta-D-glucosaminidase activity. Furthermore, it raised plasma concentrations of the uremic toxin indoxyl sulfate, some inflammatory cytokines and urinary albumin concentration. Renal morphology was severely damaged and histopathological markers of inflammation and fibrosis were especially increased. In renal homogenates, antioxidant indices, including superoxide dismutase and catalase activities, total antioxidant capacity and reduced glutathione were all adversely affected. Most of these adenine - induced actions were moderately and dose -dependently mitigated by chrysin, especially at the highest dose. Chrysin did not cause any overt adverse effect on the treated rats. The results suggest that different doses of chrysin produce variable salutary effects against adenine induced CKD in rats, and that, pending further pharmacological and toxicological studies, its usability as a possible ameliorative agent in human CKD should be considered. PMID- 25909515 TI - A pharmacist's contribution within a patient-centered medical home. AB - OBJECTIVES: To evaluate the impact of a pharmacist embedded in a primary care physician (PCP) group practice to assist in achieving patient-centered medical home (PCMH) accreditation by increasing chronic care measures through the use of angiotensin-converting enzyme inhibitor (ACEI) or angiotensin II receptor blocker (ARB) medications in patients with concomitant diabetes mellitus (DM) and hypertension (HTN). SETTING: PCP practice in Pittsburgh, PA. PRACTICE DESCRIPTION: 16 decentralized PCPs linked by electronic health record system. PRACTICE INNOVATION: An academically based pharmacist provided medication management services to the PCP group for patients with DM and HTN using criteria developed by the quality committee of the practice. INTERVENTIONS: Using the electronic health records and inclusion criteria, a list of patients with concomitant DM and HTN and not currently taking ACEI or ARB medications was obtained. Patients were excluded based on predetermined criteria. Electronic messages were sent to PCPs responsible for the remaining patients. RESULTS: Across the 16 participating office locations, 5,258 patients were diagnosed with DM and HTN. Of these, 4,304 were already being treated with an ACEI or ARB medication (81.9%). Of the remaining 954 patients, the pharmacist determined that 784 met at least one of the exclusion criteria (82.2%). Recommendations were sent for the remaining 170 patients, and the pharmacist received 150 responses (88.2%). Physicians agreed with the recommendation to initiate therapy in 82 patients (54.7%), and therapy was started in 56 of those patients (68.3%). CONCLUSION: This project showed the positive effect of a pharmacist in helping a PCP group address quality projects relating to PCMH accreditation and improvements in care that can affect Medicare star ratings. PMID- 25909517 TI - Growing your knowledge base and practice with specialist referrals. PMID- 25909516 TI - Dose-mass inverse optimization for minimally moving thoracic lesions. AB - In the past decade, several different radiotherapy treatment plan evaluation and optimization schemes have been proposed as viable approaches, aiming for dose escalation or an increase of healthy tissue sparing. In particular, it has been argued that dose-mass plan evaluation and treatment plan optimization might be viable alternatives to the standard of care, which is realized through dose volume evaluation and optimization. The purpose of this investigation is to apply dose-mass optimization to a cohort of lung cancer patients and compare the achievable healthy tissue sparing to that one achievable through dose-volume optimization. Fourteen non-small cell lung cancer (NSCLC) patient plans were studied retrospectively. The range of tumor motion was less than 0.5 cm and motion management in the treatment planning process was not considered. For each case, dose-volume (DV)-based and dose-mass (DM)-based optimization was performed. Nine-field step-and-shoot IMRT was used, with all of the optimization parameters kept the same between DV and DM optimizations. Commonly used dosimetric indices (DIs) such as dose to 1% the spinal cord volume, dose to 50% of the esophageal volume, and doses to 20 and 30% of healthy lung volumes were used for cross comparison. Similarly, mass-based indices (MIs), such as doses to 20 and 30% of healthy lung masses, 1% of spinal cord mass, and 33% of heart mass, were also tallied. Statistical equivalence tests were performed to quantify the findings for the entire patient cohort. Both DV and DM plans for each case were normalized such that 95% of the planning target volume received the prescribed dose. DM optimization resulted in more organs at risk (OAR) sparing than DV optimization. The average sparing of cord, heart, and esophagus was 23, 4, and 6%, respectively. For the majority of the DIs, DM optimization resulted in lower lung doses. On average, the doses to 20 and 30% of healthy lung were lower by approximately 3 and 4%, whereas lung volumes receiving 2000 and 3000 cGy were lower by 3 and 2%, respectively. The behavior of MIs was very similar. The statistical analyses of the results again indicated better healthy anatomical structure sparing with DM optimization. The presented findings indicate that dose mass-based optimization results in statistically significant OAR sparing as compared to dose-volume-based optimization for NSCLC. However, the sparing is case-dependent and it is not observed for all tallied dosimetric endpoints. PMID- 25909518 TI - Unintentional root fragment retention in proximity to dental implants: a series of six human case reports. AB - There has been renewed interest in intentionally placing dental implants in proximity to or in contact with tooth root fragments. In clinical practice, human teeth are usually extracted due to nonrestorable caries, vertical or horizontal root fractures, periodontal disease, or endodontic failure, which is commonly accompanied by inflammation and bacterial contamination. The aim of this case series is to present the adverse effects in humans of clinically undetected root to-implant contact (CURIC), where implants were unintentionally placed in proximity to undetected retained root fragments. The adverse effects of small (3 to 5 mm) root fragments were detectible 6 to 48 months post implant placement. Three out of seven implants in six patients were removed due to severe coronal bone loss. This differs from retrograde peri-implantitis, where only the apical area of the implant is affected and the coronal portion remains integrated. The detrimental effect of root fragment-to-implant contact is described along with its clinical management. Based on the review of currently relevant data, mixed results have been documented regarding the success of dental implants in proximity to tooth-root fragments. Careful evaluation of long-term, postloading results in humans where hopeless teeth have been extracted due to infection and significant bone loss are required before intentional root fragment retention is considered a safe and reliable clinical option for implant placement. PMID- 25909519 TI - Consecutive case series of monolithic and minimally veneered zirconia restorations on teeth and implants: up to 68 months. AB - The aim of this study was to evaluate the performance of monolithic zirconia in function and minimally veneered zirconia (feldspathic ceramic, not in function, on the facial surface to enhance tooth esthetics or replace gingival structures) on both teeth and implants. This open-ended consecutive case series involved 238 patients between the ages of 16 and 92 years, 1,022 restoration units, and 365 cases in all categories of tooth and implant restorations in a private practice clinical environment for up to 68 months. The restoration parameters monitored in the patient base were fracture, cracking, or chipping of the zirconia structure and/or the minimally veneered feldspathic ceramic. There were no observed complications with respect to these parameters associated with any of the restorations included in this study. PMID- 25909520 TI - Tissue engineering for lateral ridge augmentation with recombinant human bone morphogenetic protein 2 combination therapy: a case report. AB - This case report describes a tissue-engineered reconstruction with recombinant human bone morphogenetic protein 2/acellular collagen sponge (rhBMP-2/ ACS) + cancellous allograft and space maintenance via Medpor Contain mesh in the treatment of a patient requiring maxillary and mandibular horizontal ridge augmentation to enable implant placement. The patient underwent a previously unsuccessful corticocancellous bone graft at these sites. Multiple and contiguous sites in the maxilla and in the mandibular anterior, demonstrating advanced lateral ridge deficiencies, were managed using a tissue engineering approach as an alternative to autogenous bone harvesting. Four maxillary and three mandibular implants were placed 9 and 10 months, respectively, after tissue engineering reconstruction, and all were functioning successfully after 24 months of follow up. Histomorphometric analysis of a bone core obtained at the time of the maxillary implant placement demonstrated a mean of 76.1% new vital bone formation, 22.2% marrow/cells, and 1.7% residual graft tissue. Tissue engineering for lateral ridge augmentation with combination therapy requires further research to determine predictability and limitations. PMID- 25909521 TI - Treatment of severe mucogingival defects with a combination of strip gingival grafts and a xenogeneic collagen matrix: a prospective case series study. AB - Large areas of mucogingival alterations may result from advanced regenerative procedures. This prospective case series study was performed to introduce and evaluate a surgical approach that combines the strip gingival graft technique with the use of a xenogeneic collagen matrix. The primary outcome measurement was the increase in keratinized tissue width from baseline to 12 months postprocedure. Twenty patients were enrolled, and they all completed the 12-month evaluation. All treated sites exhibited a significant gain in keratinized tissue at 12 months, with a mean width of 6.33 mm (SD: 2.16), while there was a 43% contraction of the grafted area at 6 months. Tissue dimensions remained stable between 6 and 12 months. The use of the combination graft was well accepted by the patients, with minimal morbidity according to the patients' low self-reported pain and the low utilization of pain medication. PMID- 25909522 TI - Coronally Advanced Flap for Root Coverage: A 2-Year Case Series Follow-up. AB - The coronally advanced flap (CAF) has demonstrated controversial results in the treatment of gingival recession (GRs). The hypothesis of this study was that the CAF can partially reduce GR values over time. Root coverage (RC) in 24 Miller Class I GRs treated with a CAF by one experienced operator is presented with several periodontal parameters and postoperative morbidity. The mean percentage of RC was 80.35% at 3 months and 58.56% at 24 months; these differences were statistically significant. Keratinized gingival width, keratinized papillary gingival height, and gingival thickness were related to RC at 6 months. Postoperative pain was not statistically different over time. The CAF is not a predictable treatment for Miller Class I GRs after a 2-year follow-up period. PMID- 25909523 TI - Tissue preservation strategies for fostering long-term soft and hard tissue stability. AB - As placement of functionally stable dental implants has become routine, concerns have shifted to maintenance of crestal bone and soft tissue stability. This article proposes the development of a tissue preservation philosophy to avoid crestal bone loss and gingival recession and thus foster long-term esthetics around implants. Pillars of this philosophy must include avoidance or minimization of an implant-abutment microgap and micromovement, use of platform switching, appropriate implant positioning relative to the bone crest, and preservation of the papillae when placing both single and multiple implants. PMID- 25909524 TI - An innovative technique to manage sinus membrane perforations: report of two cases. AB - The most frequent intraoperative complication of maxillary sinus elevation procedures is the perforation of the sinus membrane, for which various protocols and grafting materials have been proposed in the literature. This article describes a novel suturing technique to close large sinus mucosa perforations. The technique is demonstrated through two clinical cases in which the sinus perforations occurred (1) in the course of a maxillary sinus elevation procedure and (2) after the removal of a cystic lesion. Bone grafting material and dental implants were placed simultaneously with the sinus repair. No infections occurred, and clinical and radiographic outcomes at 1 year postloading revealed successful implant osseointegration. PMID- 25909525 TI - Histologic characterization of human extraction sockets 3 years after grafting: a case report. AB - There is a need for the evaluation of the long-term response to xenogeneic extraction socket grafting. In this case report, two maxillary incisors were extracted, and the sockets were filled with a xenogeneic bone substitute to counteract postextraction volume loss. Three years after tooth extraction and ridge preservation, there was ample bone volume to insert two implants. Histologic and histomorphometric analysis of trephine drill biopsy specimens provided evidence of new bone formation and biologic integration of the bone substitute. The results confirm the benefit of ridge preservation techniques and give insight into the histologic long-term results after socket filling. PMID- 25909526 TI - A randomized, crossover trial to evaluate the effect of two mouthrinses on plaque regrowth in the absence of brushing. AB - This study assessed the effects on plaque in the absence of brushing of two twice daily mouthrinses, one with an enzymatic-based formulation (Biotene) and one with an antimicrobial chlorhexidine-based formulation (Peridex), and sterile water. Plaque levels were assessed in 23 participants using a 4-day, nonbrushing plaque regrowth model after twice-daily rinsing with sterile water (negative control), the enzyme-based mouthrinse, or the chlorhexidine-based mouthrinse (positive control). Peridex showed significantly greater prevention of plaque regrowth when compared with water and the enzyme-based Biotene mouthrinse. After 4 days, the enzyme-based mouthrinse was associated with a small but nonsignificant reduction in plaque regrowth compared with water. This study confirmed that Peridex is effective at prevention of plaque regrowth. Twice-daily rinsing with a Biotene formula that contained enzymes showed a small but nonsignificant trend toward prevention of plaque regrowth versus rinsing with water. PMID- 25909527 TI - Clinical Case Report on Treatment of Generalized Aggressive Periodontitis: 5-Year Follow-up. AB - Generalized aggressive periodontitis (GAgP) is a distinct type of periodontal disease associated with considerably more rapid periodontal tissue destruction than chronic periodontitis. This study presents the 5-year follow-up of a patient with GAgP. A 29-year-old man reported experiencing increasing gingival recession. He was treated using cause-related therapy, provisional splints, and flap surgery combined with allograft grafting and was followed up for 5 years. This case study shows that elimination of infectious microorganisms and meticulous long-term maintenance provide an effective treatment modality for aggressive periodontitis cases. This treatment modality can restore the masticatory function and provide the GAgP patient with improved quality of life. PMID- 25909528 TI - The effects of scanning electron microscopy desiccation preparation on demineralized dentin surfaces. AB - This study assessed the effect various scanning electron microscopy (SEM) desiccation preparation techniques have on a tufted collagen surface produced using an acid-burnished (rubbed) demineralization application technique. Citric acid- soaked cotton pellets (30%) were burnished on the dentin treatment region, rinsed in water, and then fixed. Four SEM desiccation preparation techniques were employed: (1) air-dried from glutaraldehyde; (2) air-dried from ethanol; (3) critical point dried from liquid carbon dioxide (control); or (4) air-dried from tetramethylsilane. Control specimens all displayed a characteristic tufted fibril surface. In all experimental groups, fibrils collapsed, forming an intact, undulating nondescript surface monolayer. All air-drying SEM desiccation preparation procedures appear to cause artifactual distortion of a tufted dentin collagen surface. PMID- 25909529 TI - Plasma cell gingivitis: treatment with chlorpheniramine maleate. AB - Plasma cell gingivitis is a benign lesion of unknown etiology characterized by massive and diffuse infiltration of plasma cells into the gingival connective tissue. Clinically, it can be seen as a diffuse, erythematous, and edematous swelling involving the marginal gingiva and extending into the attached gingiva. Although usually painless, the lesion can be esthetically unappealing, especially when anterior gingiva is involved. Although the usual line of management is removal of the offending agent, this report describes the treatment of plasma cell gingivitis with the topical application of chlorpheniramine maleate (25 mg) for a period of 10 days. PMID- 25909530 TI - Treatment of Peri-implant Bone Defects with Platelet-Rich Fibrin. AB - The objective of this study was to investigate and compare the clinical effectiveness of the application of platelet-rich fibrin (PRF) and conventional flap surgery for the treatment of peri-implant bone loss. Nineteen patients (8 women, 11 men) with peri-implant bone loss were randomly allocated to two groups, with the PRF group comprising patients who received fibrin scaffold and the control group made up of those who received only the access flap. At 3 and 6 months after surgery, respectively, the PRF group demonstrated higher mean probing depth reductions (2.41 +/- 1.06 and 2.82 +/- 1.03 mm versus 1.65 +/- 1.02 and 2.05 +/- 0.77 mm) and more gains in clinical attachment level (2.89 +/- 1.01 and 3.31 +/- 1.08 mm versus 1.43 +/- 1.08 and 1.84 +/- 0.81 mm) compared with the control group. In addition, the increase in the amount of keratinized mucosa from baseline to 6 months postoperatively was statistically significant for the PRF group (P < .001). Hence, the data from the current study led to the conclusion that PRF application in periimplant bone loss provided better clinical results than conventional flap surgery. PMID- 25909531 TI - Esthetic and functional rehabilitation of a severely compromised central incisor: an interdisciplinary approach. AB - This case report of a patient with a central incisor with rapid destruction of periodontal tissues associated with pathologic tooth migration illustrates the esthetic and functional reconstruction of a severely compromised tooth. An interdisciplinary approach, including resolution of the infection and regenerative periodontal surgery followed by orthodontic tooth movement, transformed a hopeless tooth with high mobility, attachment loss approaching the apex, and a Miller Class IV recession into a clinically healthy tooth. Treatment planning for periodontally involved anterior teeth with pathologic migration should consider a multidisciplinary approach for preservation of the natural dentition. PMID- 25909532 TI - Comparison of ridge expansion and ridge splitting techniques for narrow alveolar ridge in a Swine cadaver model. AB - Ridge splitting and ridge expansion have been used to expand narrow alveolar ridges. Piezosurgical ridge splitting involves separating the atrophic crests with piezosurgical inserts. Ridge expansion with motor-driven expanders was proposed to achieve the cortical dilation. The purpose of this study was to evaluate the efficacy of ridge gain by ridge expansion or ridge splitting. Eighteen (36 ramus) swine cadaver jaws were first divided into two groups- ridge expansion with a motor-driven expander or ridge splitting with the piezosurgical system. Then, either an active-tapping implant or nonactivetapping cylinder-type implant was inserted. The crestal ridge diameter change was measured with a Boley gauge. The area of bony perforation, which includes fenestrations and dehiscences, was measured with a prefabricated reference grid. The results showed that there was no statistically significant difference in crestal width gain between groups. However, the combination of the motor-driven ridge expansion technique and the active-tapping implant could be beneficial in significantly decreasing the bony perforation area. PMID- 25909533 TI - Implant-connected versus tooth-connected implant-supported partial dentures: 2 year clinical and radiographic comparative evaluation. AB - The purpose of this study was to clinically and radiographically compare implant connected and tooth-connected implant-supported fixed-detachable mandibular partial dentures. Twenty partially edentulous patients (age range: 25 to 50 years) with mandibular Kennedy Class II configurations were equally divided into two groups receiving a three-unit, fixed-detachable, screw-retained partial denture. Group 1 comprised patients with unilateral missing mandibular molars and premolars. Two implants were placed at the mandibular first premolar and first molar areas. Group 2 comprised patients with missing mandibular molars and second premolars. An implant was placed at the mandibular first molar area, the first premolar was prepared, and a coping was cemented to the tooth with permanent cement. Each case was evaluated clinically and radiographically at baseline (partial denture insertion) and after 6, 12, and 24 months. Data were collected and statistically analyzed using repeated-measures one-way and two-way analysis of variance tests. There was no statistically significant difference between the two groups (P > .05). The implant-tooth-supported prosthesis provided an equally predictable treatment option compared to the totally implant-supported prosthesis in terms of implant survival and loss of marginal bone. PMID- 25909534 TI - Providing emergency care for patients with ventricular assist devices. AB - Emergency medicine clinicians who care for patients with ventricular assist devices (VADs) must have basic knowledge of the device mechanics, population specific patient assessment techniques, and specific hospital recommendations for care of these patients. This case report illustrates a systematic approach that can be used in the ED for evaluating patients with VADs. PMID- 25909535 TI - Bridging the gap between training and advanced practice provider critical care competency. AB - Given the meteoric rise in physician assistants and nurse practitioners in critical care units across the United States, identifying successful paradigms with which to train these clinicians is critical to help meet current and future demands. We describe an apprenticeship model of training that is deployable in any ICU including curriculum, didactic and procedural training, as well as 3- and 6-month benchmarks that embraces dedicated intensivist mentorship. PMID- 25909537 TI - Perplexing bruises on the forearms. PMID- 25909538 TI - The old is new: Lipid therapy and CKD. AB - On the heels of the 2013 American College of Cardiology/American Heart Association guidelines for lipid therapy, Kidney Disease: Improving Global Outcomes (KDIGO) released updated guidelines for managing hyperlipidemia in patients with chronic kidney disease. This article describes the KDIGO guidelines' focus on individualized cardiovascular risk assessment and treatment. PMID- 25909540 TI - An unusual presentation of compartment syndrome. AB - Compartment syndrome occurs when excessive pressure in an enclosed space in the body compromises perfusion. Without treatment, this condition can cause tissue ischemia and necrosis. Typically, acute compartment syndrome develops acutely after traumatic injury. The article describes a case of delayed compartment syndrome after a fall. PMID- 25909541 TI - Radiofrequency catheter ablation for atrial fibrillation. AB - Antiarrhythmic drugs are the first-line treatment for atrial fibrillation (AF); as a result, catheter ablation usually is not considered until a patient is experiencing symptomatic AF refractory to at least one antiarrhythmic medication or is intolerant to medical therapy. For these patients, catheter ablation is shown to be more effective than medical therapy for controlling AF. This article reviews catheter ablation and its indications. PMID- 25909542 TI - Usability testing of a fall prevention toolkit. AB - OBJECTIVES: This study sought to evaluate a fall prevention toolkit, determine its ease of use and user satisfaction, and determine the preferred venue of distribution. METHODS: Three forms of assessment were used: focus groups, usability testing, and surveys. Focus group participants were recruited from four locations: two rural health clinics and two urban centers. Usability testing participants were recruited from two rural health clinics. Survey questions included self-reported prior falls, current fall prevention habits, reaction to the toolkit, and demographics. RESULTS: Participants reported the toolkit was attractive, well-organized, and easy to use, but may contain too much information. Most participants admitted they would not actively use the toolkit on their own, but prefer having it introduced by a healthcare provider or in a social setting. CONCLUSIONS: Healthcare focuses on customer satisfaction; therefore, providers benefit from knowing patient preferred methods of learning fall prevention strategies. PMID- 25909543 TI - A woman with difficulty walking and multiple falls. PMID- 25909545 TI - [Simultaneous resection of the two tracheal fragments for cicatrical stenosis]. AB - Treatment of multifocal and extended tracheal stenosis is associated with considerable difficulties in comparison with local lesions. Resection with restoration of respiratory lumen by using of direct intertracheal anastomosis substantially entered into common clinical practice. But these interventions in patients with two-level lesion are performed rarely. Among 900 operated patients with cicatrical tracheal stenosis resection of two tracheal segments with forming of anastomoses was performed only in 5 patients. We presented an experience of single-stage resections of different segments of respiratory tract for nonneoplastic cicatrical stenosis. Indications and contraindications are defined. Technical features of resection are discussed. Our data show that such operations are possible and safe. All patients recovered. Their breath was completely restored. Risk of postoperative complications after similar operations is not higher than after one-level resection. But at present time these techniques may be used by specialists and institutions with serious experience in tracheal surgery. PMID- 25909546 TI - [Immediate and remote results of endovascular treatment of patients with postinfarction cardiosclerosis]. AB - Two approaches in treatment of 131 patients with postinfarction cardiosclerosis are compared in the work. Tactics of "total" myocardial revascularization means restoration of coronary blood flow in all arteries with hemodynamically significant lesion while "selective" revascularization provides restoration of coronary blood flow only in those arteries which have a viable myocardium in their pool. It was concluded that restoration of coronary blood flow in patients after myocardial infarction permits to prevent postinfarction heart remodeling, development of heart failure thereby affecting on the prognosis. Evaluation of myocardial viability in the area of suggested surgery increases efficiency of revascularization, reduces number of implantable stents and decreases frequency of unfounded coronary interventions. Elimination of ischemia in the area of hibernation provides a rapid restoration of myocardial contractility in most of left ventricle segments with initially impaired kinetics. It was revealed that terms of contractility restoration of hibernating myocardium depend on duration of hibernation period up to revascularization. PMID- 25909547 TI - [Comparative results of open robot-assisted and laparoscopic distal pancreatic resection]. AB - It was performed a retrospective analysis of the results of distal pancreatic resections (DPR) in 89 patients with different tumors. Conventional open operations were performed in 60 patients, robot-assisted - in 19 patients, laparoscopic - in 10 cases. Absolute indication for open surgery was pancreatic cancer T3-4 stages. Mini-invasive distal resections (robot-assisted and laparoscopic) were performed in cases of pancreatic cancer T1-2 stages, benign tumors and tumors with low potential of malignancy and diameter up to 4-5 cm. Results of robot-assisted and laparoscopic interventions are similar but robot assisted technique provides more precise surgery. It improves quality of lymphadenectomy, decreases probability of intraoperative bleeding. Duration of robot-assisted and open operation did not differ significantly. Blood loss was significantly lower in group of robot-assisted method (mean 470 ml) while in cases of open and laparoscopic techniques this parameter was 1013.8 and 833.3 ml respectively. Postoperative complications in open, laparoscopic and robot assisted groups developed in 45.1, 52.6 and 50% of observations respectively. Pancreatic fistulas were revealed in 58.8, 80 and 58.3% of cases respectively. There were not deaths after laparoscopic and robot-assisted pancreatic resections. 2 patients died after open surgery. PMID- 25909548 TI - [Endoscopic transpapillary interventions in diagnostics and treatment of patients with diseases of the pancreatobiliary area]. AB - It was performed analysis of efficiency of endoscopic retrograde transpapillary interventions in diagnostics and treatment of 1513 patients with diseases of the pancreatobiliary area for the period 2008--2012. About half of patients had choledocholithiasis. There were tumors in 9.5% of patients. Associated diseases confirmed or first identified during transpapillary intervention (stricture + choledocholithiasis, cancer + choledocholithiasis, etc.) were revealed in 6.8% of patients. We used almost all types of endoscopic transpapillary techniques which are applies for biliary hypertension including retrograde cholangiopancreatography, endoscopic papillotomy, endoscopic mechanical lithoextraction and lithotripsy, nasobiliary drainage, bougienage, balloon dilatation, stenting and endoscopic contact electrohydraulic lithotripsy of calculus of common bile duct. Efficiency of endoscopic transpapillary interventions was 96.5%. Complications were observed in 4.3% of patients. Mortality rate was 0.06%. PMID- 25909549 TI - [Biological implant in single-stage reconstruction of mammary gland for cancer]. AB - Brief literature review about features of biological implants application for mammary gland reconstruction is presented in the article. Possible complications after such materials use, first experience of acellular dermal matrix administration for single-stage mammary gland reconstruction in 6 patients with breast cancer are also described. We offered surgical techniques, complications and methods of its treatment. We presented advantages of biological implant use which are consisted in decrease of surgical damage and duration of surgery, opportunity for enlargement of pocket for implant, decrease of pain syndrome. PMID- 25909550 TI - [Spleen-preserving D2-lymphodissection in gastric cancer surgery]. AB - Oncological advisability of spleen removal during surgical treatment of gastric cancer is arguable at present time. It is presented technique of spleen preserving D2-lymphodissection used for gastric body and proximal part cancer which was applied in 155 patients. Control group included 197 patients who underwent gastrectomy with splenectomy. Spleen-preserving D2-lymphodissection increased duration of surgery but decreased frequency of subdiaphragmatic abscess and pancreatic fistulas and duration of hospital stay. 5-years survival (Kaplan Meier) was 59% in main group, in control group - 55% (p>0.05). We consider that spleen-preserving D2-lymphodissection is radical and safe surgical method for locally advanced cancer of gastric body and proximal part. PMID- 25909551 TI - [Damage of reconstructive operations in patients after urgent obstructive resection of colon]. AB - It was performed comparative analysis of results of reconstructive operations in 116 patients with terminal colostomy after urgent obstructive resection of colon. Damage of reconstructive operations which differ by only access was estimated. Midline access was used in 49 patients, parastomal - in 51 cases. Laparoscopic operation was applied in 16 patients. The most traumatic method was middle laparotomy for restoration of colonic integrity. Laparoscopic operations and parastomal access are less invasive. Laparoscopic operations are accompanied by longer duration, greater blood loss and later restoration of intestinal motility pattern in comparison with surgery through parastomal access. It is associated with duration and damage of adhesiotomy stage. PMID- 25909552 TI - [Button gastrostomy in children]. AB - For the period January 2002 to December 2013 it was performed 84 interventions for introduction of gastrostomy tube. The first group included 24 open operations and the second group had 60 laparoscopic operations by using of button devices MIC-KEY (Kimberly-Clark, Roswell, USA) in neonates and infants. Statistically significant difference was not observed during comparison of demographic data of patients. Differences in groups were found in statistical analysis of intra- and postoperative parameters (p<0.05). Mean duration of surgery in the first group was 37.29 min, in the second group - 23.97 min. Time to start of feeding and transition to complete enteral nutrition was less in patients who underwent laparoscopic surgery than after open intervention (10.5 and 19.13 hours, 23.79 and 35.88 hours respectively; p<0.05). It was revealed augmentation of hospital stay in the 1st group in comparison with the 2(nd) group (11.71 and 7.09 days respectively; p<0.05). Frequency of postoperative complications was 18.33% in the 2(nd) group and 24% - in the 1st group (p<0.05). The authors consider that button devices are simply and effective technique of gastrostomy establishment in children. It is associated with minimal surgery duration and allows to start early enteral nutrition in comparison with open techniques. PMID- 25909553 TI - [Rformation of algorithms to determine the severity of endotoxemia in peritonitis]. AB - We have analyzed the results of treatment of 110 patients admitted to a clinic with diagnosed acute peritonitis for the period from 2010 to 2014. Patients were divided into three groups according to the classification of B. Savchuk. The first group included 40 patients who admitted into clinic within 24 hours after the attack. There were 36 patients who admitted in terms from 24 to 48 hours after the first attack in the second group. The third group included 34 patients who admitted in 48 to 72 hours or more after the first attack. After further diagnosis all patients have undergone emergency surgery under endotracheal anesthesia. Peritonitis focus was eliminated and abdominal cavity sanitation was carried out. Depending on the size and nature of exudate abdominal cavity was drained. Based on these data we have created an algorithm reflecting the severity of endotoxemia in peritonitis, which allows to monitor the dynamics of the endotoxemia development. Our suggested algorithm is simple and may be used in all clinics, even in district hospitals. PMID- 25909554 TI - [Use of prolonged corticosteroids and hyaluronic acid salts in treatment of gonarthrosis]. PMID- 25909555 TI - [Surgical treatment of patient with thoracoabdominal aorta rupture and large false aneurysm]. PMID- 25909556 TI - [Difficulties in central vena catheterization due to cardiovascular malformations]. PMID- 25909557 TI - [Epinephros metastasis of colorectal cancer complicated by tumor thrombosis of inferior vena cava]. AB - Metastasis of colorectal cancer (CRC) in an adrenal gland develops in 1.8% of cases (in synchrony or in metachrony) for patients with liver metastatic lesion and aggravates for certain prognosis for long-term survival. There are no data concerning colorectal metastasis in an adrenal gland with tumor thrombosis of inferior vena cava (IVC) in world-wide literature. A patient, 57 years old, on 04.29.11 underwent palliative distal sigmoid colectomy in respect of CRC pT3N2M1 (metastatic lesion of liver right lobe). Process stabilization was noticed after 4 courses of polychemotherapy. On 07.28.11 she underwent right-sided hemihepatectomy. She underwent further 4 courses in accordance with the same scheme. On 12.06.13 case-control USI and multi-layer spiral CT of abdominal cavity detected mass lesion in the right adrenal gland, it was estimated as metastatic lesion with compression of inferior vena cava and thrombosis in its lumen at retroliver segment level. Right-sided adrenalectomy. Thrombectomy of IVC was carried out in the condition of total vascular isolation. Taking into account metastasis respectability in an adrenal gland and small extent of a tumor thrombus we suppose the described surgical practice to be justified. The problem of neoadjuvant chemotherapy prescription is still controversial. PMID- 25909559 TI - [Transplantation of left lateral liver sector to child from mother with liver steatosis]. PMID- 25909558 TI - [Fetus in fetus or teratoma?]. PMID- 25909560 TI - [Lobar emphysema of inferior lobe of left lung]. PMID- 25909561 TI - [Surgical and therapeutic tactics for tuberculosis of multiple sites]. PMID- 25909562 TI - [Acute appendicitis in postoperative hernia]. PMID- 25909563 TI - Surface modification of multipass caliber-rolled Ti alloy with dexamethasone loaded graphene for dental applications. AB - Titanium (Ti) and its alloys with a high mechanical strength and a small diameter can be effectively exploited for minimally invasive dental implantation. Here, we report a multipass caliber-rolled Ti alloy of Ti13Nb13Zr (MPCR-TNZ) with a high mechanical strength and strong fatigue characteristics. For further dental applications, MPCR-TNZ was surface-modified with reduced graphene oxide (RGO) and loaded with osteogenic dexamethasone (Dex) via pi-pi stacking on the graphitic domain of RGO. The Dex-loaded RGO-MPCR-TNZ (Dex/RGO-MPCR-TNZ) resulted in significantly enhanced growth and differentiation of MC3T3-E1 cells into osteoblasts, which was confirmed by Alizarin red staining, alkaline phosphatase activity test, immunocytochemistry, and real-time PCR. Moreover, we could confirm the feasibility of Dex/RGO-MPCR-TNZ from the implantation test of a prototype of a dental implant to an artificial bone block for clinical dental applications. PMID- 25909564 TI - Subsequent Cancer Risk of Women Receiving Hysterosalpingography: A Nationwide Population-Based Retrospective Cohort Study. AB - The objective of this study was to estimate the subsequent cancer risk of women after receiving hysterosalpingography (HSG) by conducting a nationwide retrospective cohort study. We identified a study cohort of 4,371 patients who had had a HSG examination and a comparison cohort of 17,484 women without HSG examination between 1998 and 2005. Both cohorts were followed up with until the end of 2010 to measure the incidence of cancer. The risk of developing cancer for patients with HSG was assessed using the Cox proportional hazard model. In the multivariate analyses, the HSG cohort did not have a significantly greater risk of cancer (Hazard Ratio [HR] = 1.02, 95% CI = 0.79-1.31) than the non-HSG cohort. The HR was highest for genital cancer (HR = 1.32, 95% CI = 0.77-2.25), followed by urinary system cancer (HR = 1.11, 95% CI = 0.23-5.40), and abdominal cancer not involving the GU system (HR = 1.04, 95% CI = 0.53-2.03), all of which were non-significant elevations. The cancer incidence rates, especially that for urinary system cancer, were increased in the HSG cohort, but the increase in cancer incidence was small and not statistically significant. PMID- 25909565 TI - Three new species of spiny throated reed frogs (Anura: Hyperoliidae) from evergreen forests of Tanzania. AB - BACKGROUND: The East African spiny-throated reed frog complex (Hyperolius spinigularis, H. tanneri, and H. minutissimus) is comprised of morphologically similar species with highly fragmented populations across the Eastern Afromontane Region. Recent genetic evidence has supported the distinctiveness of populations suggesting a number of cryptic species. We analyse newly collected morphological data and evaluate the taxonomic distinctiveness of populations. RESULTS: We find three new distinct species on the basis of morphological and molecular evidence. The primary morphological traits distinguishing species within the Hyperolius spinigularis complex include the proportions and degree of spinosity of the gular flap in males and snout-urostyle length in females. Other features allow the three species to be distinguished from each other (genetics). We refine the understanding of H. minutissimus which can be found in both forest and grassland habitats of the Udzungwa Mountains, and provide more details on the call of this species. Further details on ecology are noted for all species where known. CONCLUSIONS: Three new species are described and we narrow the definition and distribution of Hyperolius spinigularis and H. minutissimus in East Africa. The spiny-throated reed frogs have highly restricted distributions across the fragmented mountains of the Eastern Afromontane region. Given the newly defined and substantially narrower distributions of these spiny-throated reed frog species, conservation concerns are outlined. PMID- 25909566 TI - Toward cove-edged low band gap graphene nanoribbons. AB - Graphene nanoribbons (GNRs), defined as nanometer-wide strips of graphene, have attracted increasing attention as promising candidates for next-generation semiconductors. Here, we demonstrate a bottom-up strategy toward novel low band gap GNRs (Eg = 1.70 eV) with a well-defined cove-type periphery both in solution and on a solid substrate surface with chrysene as the key monomer. Corresponding cyclized chrysene-based oligomers consisting of the dimer and tetramer are obtained via an Ullmann coupling followed by oxidative intramolecular cyclodehydrogenation in solution, and much higher GNR homologues via on-surface synthesis. These oligomers adopt nonplanar structures due to the steric repulsion between the two C-H bonds at the inner cove position. Characterizations by single crystal X-ray analysis, UV-vis absorption spectroscopy, NMR spectroscopy, and scanning tunneling microscopy (STM) are described. The interpretation is assisted by density functional theory (DFT) calculations. PMID- 25909567 TI - Comparative effectiveness and safety of image guidance systems in neurosurgery: a preclinical randomized study. AB - OBJECT: Over the last decade, image guidance systems have been widely adopted in neurosurgery. Nonetheless, the evidence supporting the use of these systems in surgery remains limited. The aim of this study was to compare simultaneously the effectiveness and safety of various image guidance systems against that of standard surgery. METHODS: In this preclinical, randomized study, 50 novice surgeons were allocated to one of the following groups: 1) no image guidance, 2) triplanar display, 3) always-on solid overlay, 4) always-on wire mesh overlay, and 5) on-demand inverse realism overlay. Each participant was asked to identify a basilar tip aneurysm in a validated model head. The primary outcomes were time to task completion (in seconds) and tool path length (in mm). The secondary outcomes were recognition of an unexpected finding (i.e., a surgical clip) and subjective depth perception using a Likert scale. RESULTS: The time to task completion and tool path length were significantly lower when using any form of image guidance compared with no image guidance (p < 0.001 and p = 0.003, respectively). The tool path distance was also lower in groups using augmented reality compared with triplanar display (p = 0.010). Always-on solid overlay resulted in the greatest inattentional blindness (20% recognition of unexpected finding). Wire mesh and on-demand overlays mitigated, but did not negate, inattentional blindness and were comparable to triplanar display (40% recognition of unexpected finding in all groups). Wire mesh and inverse realism overlays also resulted in better subjective depth perception than always-on solid overlay (p = 0.031 and p = 0.008, respectively). CONCLUSIONS: New augmented reality platforms may improve performance in less-experienced surgeons. However, all image display modalities, including existing triplanar displays, carry a risk of inattentional blindness. PMID- 25909568 TI - Endoscopic hematoma evacuation for acute and subacute subdural hematoma in elderly patients. AB - OBJECT: Endoscopic surgery was performed for acute or subacute subdural hematoma (SDH), and its effectiveness and safety in elderly patients were evaluated. METHODS: Between September 2007 and November 2013, endoscopic surgery was performed in 11 elderly patients with acute SDH (8 patients) and subacute SDH (3 patients). The criteria for surgery were as follows: 1) the presence of clinical symptoms; 2) age older than 70 years; 3) no brain injury (intracerebral hematoma, brain contusion); 4) absence of an enlarging SDH; and 5) no high risk of bleeding. Hematoma evacuation was performed with a 4-mm rigid endoscope with a 0 degrees lens and a malleable irrigation suction cannula. RESULTS: Endoscopic surgery was performed under local anesthesia. The mean age of the patients was 82.6 years (range 73-91 years). There were 5 female and 6 male patients. The mean preoperative Glasgow Coma Scale score was 12, and 5 patients had been receiving antithrombotic drug therapy. The mean operation time was 85 minutes. Only 1 patient had rebleeding, and reoperation with the same technique was performed uneventfully in this individual. A total of 7 patients had a good recovery (modified Rankin Scale Score 0-2) at discharge. CONCLUSIONS: Endoscopic hematoma evacuation of acute and subacute SDH is a safe and effective method of clot removal that minimizes operative complications. This technique may be a less invasive method for treating elderly patients with acute and subacute SDHs. PMID- 25909569 TI - Enhancing subdural effusions mimicking acute subdural hematomas following angiography and endovascular procedures: report of 2 cases. AB - Hyperdense enhancing subdural effusion due to contrast extravasation has been recently described as a potential mimicker of acute subdural hematoma following a percutaneous coronary procedure. Herein, the authors report on 2 patients who presented with subarachnoid hemorrhage from ruptured cerebral aneurysms and who developed enhancing subdural effusions mimicking acute subdural hematomas after angiography and endovascular coil placement. In 1 case, the subdural effusions completely cleared but recurred after a second angiography. CT attenuation values higher than expected for blood, as well as the evolution of the effusions and density over time, allowed for differentiation of enhancing subdural effusions from acute subdural hematomas. PMID- 25909570 TI - Reversible occlusion of donor vessel caused by mouth opening after superficial temporal artery-middle cerebral artery anastomosis in adult moyamoya patients. AB - OBJECT: The authors experienced an intriguing phenomenon in 2 adult patients with moyamoya disease. Mouth opening caused reversible occlusion of the donor superficial temporal artery (STA), and the patients exhibited transient cerebral ischemic symptoms. The aim of this study was to assess the incidence of such occlusion and the mechanism of this phenomenon. METHODS: Twelve consecutive adult patients with moyamoya disease (15 affected sides) who underwent STA-middle cerebral artery anastomosis were included in this study. Ultrasound examination was performed more than 3 months postoperatively to determine whether mouth opening affected blood flow of the donor STA and led to any ischemic symptoms within 1 minute. Computed tomography angiography was performed during both mouth opening and mouth closing, when blood flow changes of the donor STA were recognized. RESULTS: Under wide mouth opening, steno-occlusion of the donor STA occurred in 5 of 15 sides (33.3%). On 1 side (6.7%), complete occlusion induced ischemic symptoms. Steno-occlusion occurred by at least 2 mechanisms: either the stretched temporalis muscle pushed the donor STA against the edge of the bone window, or the redundant donor STA kinked when the muscle was stretched. CONCLUSIONS: Even with temporary occlusion of the donor STA, ischemic symptoms seem to rarely occur. However, to avoid the "big bite ischemic phenomenon," the authors recommend securing a sufficient distance between the donor STA and the edge of the bone window and avoiding a redundant course of the donor STA within the muscle layer. PMID- 25909571 TI - The combined microscopic-endoscopic technique for radical resection of cerebellopontine angle tumors. AB - OBJECT: The combined microscopic and endoscopic technique has shown significant advantages in the management of various lesions through different approaches. Endoscopic-assisted techniques have frequently been applied to cerebellopontine angle (CPA) surgery in the context of minimally invasive craniotomies. In this paper the authors report on the use of the endoscope in the CPA as a tool to increase the extent of resection, minimize complications, and preserve the function of the delicate CPA structures. They also describe a technique of the simultaneous use of the microscope and endoscope in the CPA and dissection of CPA tumors under tandem endoscopic and microscopic vision to overcome the shortcomings of introducing the endoscope alone in the CPA. The reliability of using the microscope alone in dissecting CPA tumors is evaluated, as is the effectiveness of the combined technique in increasing the resectability of various types of CPA tumors. METHODS: The authors conducted a retrospective analysis of 50 patients who underwent combined microscopic-endoscopic resection of CPA tumors by the senior author over a period of 3 years (February 2011 to February 2014) at Brigham and Women's Hospital, Harvard Medical School. The reliability of the extent of microscopic removal was evaluated with endoscopic exploration. Additional resection was performed with both microscopic and the combined microscopic-endoscopic technique. Endoscopically verified total resection was validated by intraoperative or postoperative MRI. The function of the cranial nerves was evaluated to assess the impact of the combined technique on their function. RESULTS: A tumor remnant was endoscopically identified in 69% of the 26 patients who were believed to have microscopic total resection. The utilization of the endoscopic visualization and dissection increased endoscopically verified total removal to 38 patients, and 82% of these patients had no sign of residual tumor on postoperative imaging. The technique was most effective with epidermoid tumors. There were a total of 17 new cranial nerve deficits in 10 patients. Preoperative fifth cranial nerve deficits improved in 52% and hearing improved in 29% of patients after surgery. CONCLUSIONS: This method provides simultaneous microscopic and endoscopic visualization and dissection techniques through skull-base approaches to CPA tumors. It overcomes some of the shortcomings of endoscopic-assisted surgery, further extends the surgical field, and increases the radicality of tumor resection with good functional outcomes. PMID- 25909572 TI - A quantitative analysis of adverse radiation effects following Gamma Knife radiosurgery for arteriovenous malformations. AB - OBJECT: The authors review outcomes following Gamma Knife radiosurgery (GKRS) of cerebral arteriovenous malformations (AVMs) and their correlation to postradiosurgery adverse radiation effects (AREs). METHODS: From a prospective institutional review board-approved database, the authors identified patients with a minimum of 2 years of follow-up and thin-slice T2-weighted MRI sequences for volumetric analysis. A total of 105 AVM patients were included. The authors analyzed the incidence and quantitative changes in AREs as a function of time after GKRS. Statistical analysis was performed to identify factors related to ARE development and changes in the ARE index. RESULTS: The median clinical follow-up was 53.8 months (range 24-212.4 months), and the median MRI follow-up was 36.8 months (range 24-212.4 months). 47.6% of patients had an AVM with a Spetzler Martin grade >= III. The median administered margin and maximum doses were 22 and 40 Gy, respectively. The overall obliteration rate was 70.5%. Of patients who showed complete obliteration, 74.4% developed AREs within 4-6 months after GKRS. Late-onset AREs (i.e., > 12 months) correlated to a failure to obliterate the nidus. 58.1% of patients who developed appreciable AREs (defined as ARE index > 8) proceeded to have a complete nidus obliteration. Appreciable AREs were found to be influenced by AVM nidus volume > 3 ml, lobar location, number of draining veins and feeding arteries, prior embolization, and higher margin dose. On the other hand, a minimum ARE index > 8 predicted obliteration (p = 0.043). CONCLUSIONS: ARE development after radiosurgery follows a temporal pattern peaking at 7-12 months after stereotactic radiosurgery. The ARE index serves as an important adjunct tool in patient follow-up and outcome prediction. PMID- 25909573 TI - Awake craniotomy to maximize glioma resection: methods and technical nuances over a 27-year period. AB - OBJECT: Awake craniotomy is currently a useful surgical approach to help identify and preserve functional areas during cortical and subcortical tumor resections. Methodologies have evolved over time to maximize patient safety and minimize morbidity using this technique. The goal of this study is to analyze a single surgeon's experience and the evolving methodology of awake language and sensorimotor mapping for glioma surgery. METHODS: The authors retrospectively studied patients undergoing awake brain tumor surgery between 1986 and 2014. Operations for the initial 248 patients (1986-1997) were completed at the University of Washington, and the subsequent surgeries in 611 patients (1997 2014) were completed at the University of California, San Francisco. Perioperative risk factors and complications were assessed using the latter 611 cases. RESULTS: The median patient age was 42 years (range 13-84 years). Sixty percent of patients had Karnofsky Performance Status (KPS) scores of 90-100, and 40% had KPS scores less than 80. Fifty-five percent of patients underwent surgery for high-grade gliomas, 42% for low-grade gliomas, 1% for metastatic lesions, and 2% for other lesions (cortical dysplasia, encephalitis, necrosis, abscess, and hemangioma). The majority of patients were in American Society of Anesthesiologists (ASA) Class 1 or 2 (mild systemic disease); however, patients with severe systemic disease were not excluded from awake brain tumor surgery and represented 15% of study participants. Laryngeal mask airway was used in 8 patients (1%) and was most commonly used for large vascular tumors with more than 2 cm of mass effect. The most common sedation regimen was propofol plus remifentanil (54%); however, 42% of patients required an adjustment to the initial sedation regimen before skin incision due to patient intolerance. Mannitol was used in 54% of cases. Twelve percent of patients were active smokers at the time of surgery, which did not impact completion of the intraoperative mapping procedure. Stimulation-induced seizures occurred in 3% of patients and were rapidly terminated with ice-cold Ringer's solution. Preoperative seizure history and tumor location were associated with an increased incidence of stimulation-induced seizures. Mapping was aborted in 3 cases (0.5%) due to intraoperative seizures (2 cases) and patient emotional intolerance (1 case). The overall perioperative complication rate was 10%. CONCLUSIONS: Based on the current best practice described here and developed from multiple regimens used over a 27-year period, it is concluded that awake brain tumor surgery can be safely performed with extremely low complication and failure rates regardless of ASA classification; body mass index; smoking status; psychiatric or emotional history; seizure frequency and duration; and tumor site, size, and pathology. PMID- 25909575 TI - Anatomy of the subthalamic nucleus, with correlation of deep brain stimulation [RETRACTED]. AB - OBJECT The goal in this study was to examine the cadaveric anatomy of the subthalamic nucleus (STN) and to analyze the implications of the findings for deep brain stimulation (DBS) surgery. METHODS Five formalin-fixed human cerebrums were dissected using the Klingler fiber dissection technique. Digital photographs of the dissections were fused to obtain an anaglyphic image. RESULTS The STN was located posteroinferior to the anterior corticospinal fibers, posterosuperior to the substantia nigra, and anteromedial to the red nucleus, lenticular fasciculus, and thalamic fasciculus. The subthalamic region is ventral to the thalamus, medial to the internal capsule, and lateral and caudal to the hypothalamus. The nuclei found within the subthalamic region include the STN. The relationship between the STN and surrounding structures, which are not delineated sharply, is described. CONCLUSIONS The fiber dissection technique supports the presence of the subthalamic region as an integrative network in humans and offers the potential to aid in understanding the impacts of DBS surgery of the STN in patients with Parkinson disease. Further research is needed to define the exact role of the STN in the integrative process. PMID- 25909574 TI - A comparison of head dynamic response and brain tissue stress and strain using accident reconstructions for concussion, concussion with persistent postconcussive symptoms, and subdural hematoma. AB - OBJECT: Concussions typically resolve within several days, but in a few cases the symptoms last for a month or longer and are termed persistent postconcussive symptoms (PPCS). These persisting symptoms may also be associated with more serious brain trauma similar to subdural hematoma (SDH). The objective of this study was to investigate the head dynamic and brain tissue responses of injury reconstructions resulting in concussion, PPCS, and SDH. METHODS: Reconstruction cases were obtained from sports medicine clinics and hospitals. All subjects received a direct blow to the head resulting in symptoms. Those symptoms that resolved in 9 days or fewer were defined as concussions (n = 3). Those with symptoms lasting longer than 18 months were defined as PPCS (n = 3), and 3 patients presented with SDHs (n = 3). A Hybrid III headform was used in reconstruction to obtain linear and rotational accelerations of the head. These dynamic response data were then input into the University College Dublin Brain Trauma Model to calculate maximum principal strain and von Mises stress. A Kruskal-Wallis test followed by Tukey post hoc tests were used to compare head dynamic and brain tissue responses between injury groups. Statistical significance was set at p < 0.05. RESULTS: A significant difference was identified for peak resultant linear and rotational acceleration between injury groups. Post hoc analyses revealed the SDH group had higher linear and rotational acceleration responses (316 g and 23,181 rad/sec(2), respectively) than the concussion group (149 g and 8111 rad/sec(2), respectively; p < 0.05). No significant differences were found between groups for either brain tissue measures of maximum principal strain or von Mises stress. CONCLUSIONS: The reconstruction of accidents resulting in a concussion with transient symptoms (low severity) and SDHs revealed a positive relationship between an increase in head dynamic response and the risk for more serious brain injury. This type of relationship was not found for brain tissue stress and strain results derived by finite element analysis. Future research should be undertaken using a larger sample size to confirm these initial findings. Understanding the relationship between the head dynamic and brain tissue response and the nature of the injury provides important information for developing strategies for injury prevention. PMID- 25909576 TI - Anatomical considerations of fascial release in ulnar nerve transposition: a concept revisited. AB - OBJECT: Surgical transposition of the ulnar nerve to alleviate entrapment may cause otherwise normal structures to become new sources of nerve compression. Recurrent or persistent neuropathy after anterior transposition is commonly attributable to a new distal compression. The authors sought to clarify the anatomical relationship of the ulnar nerve to the common aponeurosis of the humeral head of the flexor carpi ulnaris (FCU) and flexor digitorum superficialis (FDS) muscles following anterior transposition of the nerve. METHODS: The intermuscular septa of the proximal forearm were explored in 26 fresh cadaveric specimens. The fibrous septa and common aponeurotic insertions of the flexor pronator muscle mass were evaluated in relation to the ulnar nerve, with particular attention to the effect of transposition upon the nerve in this region. RESULTS: An intermuscular aponeurosis associated with the FCU and FDS muscles was present in all specimens. Transposition consistently resulted in angulation of the nerve during elbow flexion when this fascial septum was not released. The proximal site at which the nerve began to traverse this fascial structure was found to be an average of 3.9 cm (SD 0.7 cm) from the medial epicondyle. CONCLUSIONS: The common aponeurosis encountered between the FDS and FCU muscles represents a potential site of posttransposition entrapment, which may account for a subset of failed anterior transpositions. Exploration of this region with release of this structure is recommended to provide an unconstrained distal course for a transposed ulnar nerve. PMID- 25909577 TI - Nonmelanoma cutaneous cancers involving the skull base: outcomes of aggressive multimodal management. AB - OBJECT: A relative paucity of information exists regarding outcomes from craniofacial resection for advanced nonmelanoma skin cancers involving the skull base. In light of advances in surgical technique and adjuvant therapy protocols, the authors reviewed their surgical experience to determine disease control rates, overall survival (OS), morbidity, and mortality. METHODS: A retrospective review of 24 patients with nonmelanoma cutaneous cancers with skull base involvement treated with craniofacial resection at The University of Texas MD Anderson Cancer Center from 1994 to 2012 was performed. Of these patients, 19 (79%) had squamous cell carcinoma (SCC), 4 (17%) had basosquamous carcinoma (BSCC), and 1 patient (4%) had adenocarcinoma. Factors as assessed were prior treatment, TNM staging, tumor involvement, extent of intracranial extension, margin status, postoperative complications, recurrence, disease status at last follow-up, and long-term survival. The majority of tumors were T4 (67%) according to the TNM classification; perineural extension was noted in 58%, cavernous sinus involvement in 25%, and dural involvement in 29%. RESULTS: Postoperative complications occurred in 4 patients (17%) including 1 death. Kaplan-Meier estimates were calculated for OS and progression-free survival (PFS). Median OS was 43.2 months with an 82% 1-year OS and 37% 5-year OS; the median PFS was 91.2 months. Margin status was positively associated with median OS in SCC (91 months [for negative margins] vs 57 months, p = 0.8) and in BSCC (23.7 vs 3.2 months, p < 0.05). Postoperative radiotherapy was associated with improved median OS (43.2 vs 22 months, p = 0.6). Brain involvement was uniformly fatal after 1 year, while cavernous sinus involvement (31 vs 43 months, p = 0.82), perineural disease (31 vs 54 months, p = 0.30), and T4 stage (22 vs 91.2 months, p = 0.09) were associated with worsened OS. Similar associations were found with median PFS. CONCLUSIONS: Aggressive multimodality management with surgery and postoperative radiotherapy can positively impact locoregional control and OS. With improvements in technique and adjuvant therapy protocols, treatment can still be considered in situations of perineural disease and cavernous sinus involvement and as a salvage option for patients in whom prior treatment has failed. As patients with advanced NMSCs often have few options, craniofacial resection, as part of a coordinated multimodal management plan, is justified if it can be performed safely. PMID- 25909578 TI - Performance assessment of a commonly used "accumulation and wash-off" model from long-term continuous road runoff turbidity measurements. AB - The suitability of a commonly used accumulation and wash-off model for continuous modelling of urban runoff contamination was evaluated based on 11-month turbidity and flow-rate records from an urban street. Calibration and uncertainty analysis were performed using a Markov Chain Monte-Carlo sampling method for both suspended solids loads (discharge rates) and concentration modelling. Selected models failed at replicating suspended solids concentration over the complete monitoring period. The studied dataset indeed suggests that the accumulation process is rather unpredictable and cannot be satisfactorily represented with usual accumulation models unless short periods are considered. Regarding suspended solid loads modelling, noticeably better performance was achieved, but similar results could as well be obtained with much simpler constant concentration models. Unless providing very accurate estimates of concentrations in runoff, accounting for their temporal variability during rain events may therefore not always be necessary for pollutant loads modelling, as loads are in fact mostly explained by runoff volumes. PMID- 25909579 TI - Knowledge, attitudes, behaviors, and practices differences regarding HIV in populations living along the Maroni river: particularities of operational interest for Amerindian and Maroon populations. AB - The Maroni basin, an isolated region delineating the border between Suriname and French Guiana has been affected by the human immunodeficiency virus (HIV) epidemic 10 years after coastal French Guiana. However, the rise in HIV prevalence was sharp, exceeding 1% within 10 years. The aim of the present study is to compare, using the first quantitative data from the general population in remote villages, the knowledge, attitudes, and behaviors regarding HIV between Maroon and Amerindian populations, the two most frequent populations living along the Maroni. Data were collected in 2012 using a structured questionnaire among a random sample of 896 individuals residing in the remote villages on the Maroni river. Proportions were compared between the Maroni and the coastal general population, and between Maroon and Amerindian populations. The present study shows significant differences between territories and between communities living on the Maroni river: the multiple sexual partnerships, more common among population living on the Maroni river, were more frequently reported in Maroons than in Amerindians. Condom use was more frequently reported among men on the Maroni river than on the coast, but these findings were reversed for women. Moreover, among people living on the Maroni river, condom use was more frequently reported among Maroons than among Amerindians. Regarding genital factors that may affect transmission, penile implant seemed to have no ethnic boundaries, steam baths seemed specific to Maroon women. The present results should help to improve community-based specific interventions. PMID- 25909580 TI - Auditory working memory predicts individual differences in absolute pitch learning. AB - Absolute pitch (AP) is typically defined as the ability to label an isolated tone as a musical note in the absence of a reference tone. At first glance the acquisition of AP note categories seems like a perceptual learning task, since individuals must assign a category label to a stimulus based on a single perceptual dimension (pitch) while ignoring other perceptual dimensions (e.g., loudness, octave, instrument). AP, however, is rarely discussed in terms of domain-general perceptual learning mechanisms. This is because AP is typically assumed to depend on a critical period of development, in which early exposure to pitches and musical labels is thought to be necessary for the development of AP precluding the possibility of adult acquisition of AP. Despite this view of AP, several previous studies have found evidence that absolute pitch category learning is, to an extent, trainable in a post-critical period adult population, even if the performance typically achieved by this population is below the performance of a "true" AP possessor. The current studies attempt to understand the individual differences in learning to categorize notes using absolute pitch cues by testing a specific prediction regarding cognitive capacity related to categorization - to what extent does an individual's general auditory working memory capacity (WMC) predict the success of absolute pitch category acquisition. Since WMC has been shown to predict performance on a wide variety of other perceptual and category learning tasks, we predict that individuals with higher WMC should be better at learning absolute pitch note categories than individuals with lower WMC. Across two studies, we demonstrate that auditory WMC predicts the efficacy of learning absolute pitch note categories. These results suggest that a higher general auditory WMC might underlie the formation of absolute pitch categories for post-critical period adults. Implications for understanding the mechanisms that underlie the phenomenon of AP are also discussed. PMID- 25909581 TI - Scale invariance of temporal order discrimination using complex, naturalistic events. AB - Recent demonstrations of scale invariance in cognitive domains prompted us to investigate whether a scale-free pattern might exist in retrieving the temporal order of events from episodic memory. We present four experiments using an encoding-retrieval paradigm with naturalistic stimuli (movies or video clips). Our studies show that temporal order judgement retrieval times were negatively correlated with the temporal separation between two events in the movie. This relation held, irrespective of whether temporal distances were on the order of tens of minutes (Exp 1-2) or just a few seconds (Exp 3-4). Using the SIMPLE model, we factored in the retention delays between encoding and retrieval (delays of 24 h, 15 min, 1.5-2.5 s, and 0.5 s for Exp 1-4, respectively) and computed a temporal similarity score for each trial. We found a positive relation between similarity and retrieval times; that is, the more temporally similar two events, the slower the retrieval of their temporal order. Using Bayesian analysis, we confirmed the equivalence of the RT/similarity relation across all experiments, which included a vast range of temporal distances and retention delays. These results provide evidence for scale invariance during the retrieval of temporal order of episodic memories. PMID- 25909584 TI - Functional carbon nanotubes for high-quality charge transfer and moisture regulation through membranes: structural and functional insights. AB - Functional single walled carbon nanotubes (SWCNTs) are assembled onto porous supports by using layer-by-layer (LBL) approaches. Directed nano-assembly of nanotubes is identified as a crucial factor for controlling the combined functions of hybrid-composite membranes, including charge and moisture transport. In both the cases, donor-acceptor interactions are indicated to be responsible for the rearrangement of nanotubes inside the LBL multilayer and their related properties. Aggregation and stratification of the carbon nanotubes along with the availability of selective-site interactions are complementarily investigated by using SEM, Raman and infrared spectroscopy, while high electrical charge and water vapor transfer are achievable, provided that a large number of connections and competitive interactions are allowed. Ohmic behavior is observed for all types of carbon nanotubes, even if better-quality charge transfer pathways are obtained with carboxylated conductive filaments. Likewise, assisted moisture regulation is succeeded when using functional filaments with the capability to establish competitive H-donor-acceptor interactions with water. PMID- 25909582 TI - Semantic facilitation in bilingual first language acquisition. AB - Bilingual first language learners face unique challenges that may influence the rate and order of early word learning relative to monolinguals. A comparison of the productive vocabularies of 435 children between the ages of 6 months and 7 years-181 of which were bilingual English learners-found that monolinguals learned both English words and all-language concepts faster than bilinguals. However, bilinguals showed an enhancement of an effect previously found in monolinguals-the preference for learning words with more associative cues. Though both monolinguals and bilinguals were best fit by a similar model of word learning, semantic network structure and growth indicated that the two groups were learning English words in a different order. Further, in comparison with a model of two-monolinguals-in-one-mind, bilinguals overproduced translational equivalents. Our results support an emergent account of bilingual first language acquisition, where learning a word in one language facilitates its acquisition in a second language. PMID- 25909583 TI - Food insecurity is a barrier to prevention of mother-to-child HIV transmission services in Zimbabwe: a cross-sectional study. AB - BACKGROUND: Food insecurity (FI) is the lack of physical, social, and economic access to sufficient food for dietary needs and food preferences. We examined the association between FI and women's uptake of services to prevent mother-to-child HIV transmission (MTCT) in Zimbabwe. METHODS: We analyzed cross-sectional data collected in 2012 from women living in five of ten provinces. Eligible women were >=16 years old, biological mothers of infants born 9-18 months before the interview, and were randomly selected using multi-stage cluster sampling. Women and infants were tested for HIV and interviewed about health service utilization during pregnancy, delivery, and post-partum. We assessed FI in the past four weeks using a subset of questions from the Household Food Insecurity Access Scale and classified women as living in food secure, moderately food insecure, or severely food insecure households. RESULTS: The weighted population included 8,790 women. Completion of all key steps in the PMTCT cascade was reported by 49%, 45%, and 38% of women in food secure, moderately food insecure, and severely food insecure households, respectively (adjusted prevalence ratio (PRa) = 0.95, 95% confidence interval (CI): 0.90, 1.00 (moderate FI vs. food secure), PRa = 0.86, 95% CI: 0.79, 0.94 (severe FI vs. food secure)). Food insecurity was not associated with maternal or infant receipt of ART/ARV prophylaxis. However, in the unadjusted analysis, among HIV-exposed infants, 13.3% of those born to women who reported severe household food insecurity were HIV-infected compared to 8.2% of infants whose mothers reported food secure households (PR = 1.62, 95% CI: 1.04, 2.52). After adjustment for covariates, this association was attenuated (PRa = 1.42, 95% CI: 0.89, 2.26). There was no association between moderate food insecurity and MTCT in unadjusted or adjusted analyses (PRa = 0.68, 95% CI: 0.43, 1.08). CONCLUSIONS: Among women with a recent birth, food insecurity is inversely associated with service utilization in the PMTCT cascade and severe household food insecurity may be positively associated with MTCT. These preliminary findings support the assessment of FI in antenatal care and integrated food and nutrition programs for pregnant women to improve maternal and child health. PMID- 25909585 TI - Organocatalytic enantioselective Pictet-Spengler approach to biologically relevant 1-benzyl-1,2,3,4-tetrahydroisoquinoline alkaloids. AB - A general procedure for the synthesis of 1-benzyl-1,2,3,4-tetrahydroisoquinolines was developed, based on organocatalytic, regio- and enantioselective Pictet Spengler reactions (86-92% ee) of N-(o-nitrophenylsulfenyl)-2-arylethylamines with arylacetaldehydes. The presence of the o-nitrophenylsulfenyl group, together with the MOM-protection in the catechol part of the tetrahydroisoquinoline ring system, appeared to be a productive combination. To demonstrate the versatility of this approach, 10 biologically and pharmaceutically relevant alkaloids were prepared using (R)-TRIP as the chiral catalyst: (R)-norcoclaurine, (R) coclaurine, (R)-norreticuline, (R)-reticuline, (R)-trimemetoquinol, (R) armepavine, (R)-norprotosinomenine, (R)-protosinomenine, (R)-laudanosine, and (R) 5-methoxylaudanosine. PMID- 25909587 TI - A DFT study of the extractive desulfurization mechanism by [BMIM](+)[AlCl4](-) ionic liquid. AB - In this work, the interaction nature between [BMIM](+)[AlCl4](-) ionic liquid (IL) and aromatic sulfur compounds (thiophene, benzothiophene, and dibenzothiophene) has been studied by means of density functional theory (M06-2X functional) combined with an implicit solvation model. Although [BMIM](+)[AlCl4]( ) is a metal-containing IL, its extractive desulfurization mechanism is different from other metal-containing ILs but similar to non-metal-containing ILs. Important reactions involved in extractive desulfurization (EDS) were systematically studied. Our results have demonstrated that both the cation and the anion play important roles in EDS. On the basis of the structure analysis, reduced density gradient analaysis (RDG), and energy decomposition analysis, [BMIM](+) cation affords a pi-pi interaction while [AlCl4](-) anion provides a hydrogen bonding interaction. Electrostatic potential analysis implies the dominant pi-pi interaction and hydrogen bonding interaction are driven by electrostatic interaction between IL and aromatic sulfur compounds. Interaction energy between [BMIM](+)[AlCl4](-) and thiophene (TH), benzothiophene (BT), and dibenzothiophene (DBT) follows the order TH < BT < DBT. Moreover, Al-containing IL with a high molar ratio of AlCl3 ([BMIMCl]/2[AlCl3]) has also been studied. Results show that [Al2Cl7](-) species will be formed with excess AlCl3. However, the [Al2Cl7](-)-based IL cannot improve the EDS performance. Improvement of EDS performance with a high molar ratio of AlCl3 is credited to the Lewis acidity of AlCl3. Charge analysis reveals that there is no obvious charge transfer during the reaction, which is different from Fe-containing ILs as well as solid sorbents. In addition, CH-pi interaction is not important for the current system. PMID- 25909586 TI - Chloroform-Methanol Residue of Coxiella burnetii Markedly Potentiated the Specific Immunoprotection Elicited by a Recombinant Protein Fragment rOmpB-4 Derived from Outer Membrane Protein B of Rickettsia rickettsii in C3H/HeN Mice. AB - The obligate intracellular bacteria, Rickettsia rickettsii and Coxiella burnetii, are the potential agents of bio-warfare/bio-terrorism. Here C3H/HeN mice were immunized with a recombinant protein fragment rOmp-4 derived from outer membrane protein B, a major protective antigen of R. rickettsii, combined with chloroform methanol residue (CMR) extracted from phase I C. burnetii organisms, a safer Q fever vaccine. These immunized mice had significantly higher levels of IgG1 and IgG2a to rOmpB-4 and interferon-gamma (IFN-gamma) and tumor necrosis factor-alpha (TNF-alpha), two crucial cytokines in resisting intracellular bacterial infection, as well as significantly lower rickettsial loads and slighter pathological lesions in organs after challenge with R. rickettsii, compared with mice immunized with rOmpB-4 or CMR alone. Additionally, after challenge with C. burnetii, the coxiella loads in the organs of these mice were significantly lower than those of mice immunized with rOmpB-4 alone. Our results prove that CMR could markedly potentiate enhance the rOmpB-4-specific immunoprotection by promoting specific and non-specific immunoresponses and the immunization with the protective antigen of R. rickettsii combined with CMR of C. burnetii could confer effective protection against infection of R. rickettsii or C. burnetii. PMID- 25909588 TI - A sensitive label-free amperometric immunosensor for alpha-fetoprotein based on gold nanorods with different aspect ratio. AB - A simple and accurate label-free amperometric immunosensor for alpha-fetoprotein (AFP) detection is developed based on gold nanorods (GNRs) with different aspect ratio and compared with gold particles (GNPs). The positively charged GNRs and GNPs due to the surface immobilized cetyltrimethyl ammonium bromide (CTAB) can adsorb the negatively charged AFP antibody (Ab) directly. The presence of the GNRs not only enhanced the immobilized amount of biomolecules, but also improved the electrochemical properties of the immunosensor. With the aid of GNRs, the electrochemical signal was greatly enhanced in comparison with GNPs. Under optimal conditions, the proposed immunosensor could detect AFP in a linear range from 0.1 to 200 ng/mL with a detection limit of 0.04 ng/mL (signal-to-noise ratio = 3), and it also possessed good reproducibility and storage stability. Moreover, the detection of AFP in five human serum samples also showed satisfactory accuracy. The proposed methodology was potentially attractive for clinical immunoassay. PMID- 25909589 TI - The impact of legal coercion on the therapeutic relationship in adult schizophrenia patients. AB - The quality of the therapeutic relationship between psychiatric patients and their attending physicians plays a key role in treatment success. We hypothesize that mandatory treatment is negatively associated with the quality of the therapeutic relationship. In a cross-sectional study design, data on psychopathological symptom load (as captured with the Brief Psychiatric Rating Scale) and on the quality of the therapeutic relationship (as measured with the Scale to Assess the Therapeutic Relationship) were collected from 113 adult male psychiatric patients and 35 attending physicians. Patients belonged to one of three groups: self-referred or involuntarily admitted patients from general psychiatry wards or patients from medium secure forensic psychiatric units. On average, self-referred patients rated the quality of the therapeutic relationship significantly more positive than did involuntarily admitted patients in general psychiatry wards. Forensic psychiatric patients, on average, gave an intermediate rating of the quality of the therapeutic relationship. There was no association between patients' ratings and physicians' ratings of the quality of the therapeutic relationship. Patients' ratings of the quality of the therapeutic relationship were inversely related to symptom severity in general and hostility in particular. Ratings of the quality of the therapeutic relationship are not associated with patients' legal status but rather with patients' symptoms of hostility. PMID- 25909590 TI - IL-4 Up-Regulates MiR-21 and the MiRNAs Hosted in the CLCN5 Gene in Chronic Lymphocytic Leukemia. AB - Interleukin 4 (IL-4) induces B-cell differentiation and survival of chronic lymphocytic leukemia (CLL) cells. MicroRNAs (miRNAs) regulate mRNA and protein expression, and several miRNAs, deregulated in CLL, might play roles as oncogenes or tumor suppressors. We have studied the miRNA profile of CLL, and its response to IL-4, by oligonucleotide microarrays, resulting in the detection of a set of 129 mature miRNAs consistently expressed in CLL, which included 41 differentially expressed compared to normal B cells (NBC), and 6 significantly underexpressed in ZAP-70 positive patients. IL-4 stimulation brought about up-regulation of the 5p and 3p mature variants of the miR-21 gene, which maps immediately downstream to the VMP1 gene, and of the mature forms generated from the miR-362 (3p and 5p), miR-500a (3p), miR-502 (3p), and miR-532 (3p and 5p) genes, which map within the third intron of the CLCN5 gene. Both genes are in turn regulated by IL-4, suggesting that these miRNAs were regulated by IL-4 as passengers from their carrier genes. Their levels of up-regulation by IL-4 significantly correlated with cytoprotection. MiR-21 has been reported to be leukemogenic, associated to bad prognosis in CLL, and the miRNA more frequently overexpressed in human cancer. Up-regulation by IL-4 of miR-21 and the miRNAs hosted in the CLCN5 locus may contribute to evasion of apoptosis of CLL cells. These findings indicate that the IL-4 pathway and the miRNAs induced by IL-4 are promising targets for the development of novel therapies in CLL. PMID- 25909591 TI - Structural and Biochemical Analysis of Tyrosine Phosphatase Related to Biofilm Formation A (TpbA) from the Opportunistic Pathogen Pseudomonas aeruginosa PAO1. AB - Biofilms are important for cell communication and growth in most bacteria, and are responsible for a number of human clinical infections and diseases. TpbA (PA3885) is a dual specific tyrosine phosphatase (DUSP) that negatively regulates biofilm formation in the opportunistic pathogen Pseudomonas aeruginosa PAO1 by converting extracellular quorum sensing signals into internal gene cascade reactions that result in reduced biofilm formation. We have determined the three dimensional crystal structure of wild-type TpbA from P. aeruginosa PAO1 in the phosphate-bound state and a TpbA (C132S) mutant with phosphotyrosine. Comparison between the phosphate-bound structure and the previously reported ligand-free TpbA structure reveals the extent of conformational changes that occur upon substrate binding. The largest changes occur in the functional loops that define the substrate binding site, including the PTP, general acid and alpha4-alpha5 loops. We further show that TpbA efficiently catalyzes the hydrolysis of two phosphotyrosine peptides derived from the periplasmic domain of TpbB (YfiN, PA1120), with a strong preference for dephosphorylating Tyr48 over Tyr62. This work adds to the small repertoire of DUSP structures in both the ligand-free and ligand-bound states, and provides a starting point for further study of the role of TpbA in biofilm formation. PMID- 25909593 TI - Correction to Spectrophotometric Calibration of pH Electrodes in Seawater Using Purified m-Cresol Purple. PMID- 25909592 TI - Tissue localization and extracellular matrix degradation by PI, PII and PIII snake venom metalloproteinases: clues on the mechanisms of venom-induced hemorrhage. AB - Snake venom hemorrhagic metalloproteinases (SVMPs) of the PI, PII and PIII classes were compared in terms of tissue localization and their ability to hydrolyze basement membrane components in vivo, as well as by a proteomics analysis of exudates collected in tissue injected with these enzymes. Immunohistochemical analyses of co-localization of these SVMPs with type IV collagen revealed that PII and PIII enzymes co-localized with type IV collagen in capillaries, arterioles and post-capillary venules to a higher extent than PI SVMP, which showed a more widespread distribution in the tissue. The patterns of hydrolysis by these three SVMPs of laminin, type VI collagen and nidogen in vivo greatly differ, whereas the three enzymes showed a similar pattern of degradation of type IV collagen, supporting the concept that hydrolysis of this component is critical for the destabilization of microvessel structure leading to hemorrhage. Proteomic analysis of wound exudate revealed similarities and differences between the action of the three SVMPs. Higher extent of proteolysis was observed for the PI enzyme regarding several extracellular matrix components and fibrinogen, whereas exudates from mice injected with PII and PIII SVMPs had higher amounts of some intracellular proteins. Our results provide novel clues for understanding the mechanisms by which SVMPs induce damage to the microvasculature and generate hemorrhage. PMID- 25909594 TI - Bringing Diagnostic Optical Technologies Into the Clinic. PMID- 25909595 TI - Patients' knowledge, attitudes, behaviour and health care experiences on the prevention, detection, management and control of hypertension in Colombia: a qualitative study. AB - Hypertension is a leading cause of premature death worldwide and the most important modifiable risk factor for cardiovascular disease. Effective screening programs, communication with patients, regular monitoring, and adherence to treatment are essential to successful management but may be challenging in health systems facing resource constraints. This qualitative study explored patients' knowledge, attitudes, behaviour and health care seeking experiences in relation to detection, treatment and control of hypertension in Colombia. We conducted in depth interviews and focus group discussions with 26 individuals with hypertension and 4 family members in two regions. Few participants were aware of ways to prevent high blood pressure. Once diagnosed, most reported taking medication but had little information about their condition and had a poor understanding of their treatment regime. The desire for good communication and a trusting relationship with the doctor emerged as key themes in promoting adherence to medication and regular attendance at medical appointments. Barriers to accessing treatment included co-payments for medication; costs of transport to health care facilities; unavailability of drugs; and poor access to specialist care. Some patients overcame these barriers with support from social networks, family members and neighbours. However, those who lacked such support, experienced loneliness and struggled to access health care services. The health insurance scheme was frequently described as administratively confusing and those accessing the state subsidized system believed that the treatment was inferior to that provided under the compulsory contributory system. Measures that should be addressed to improve hypertension management in Colombia include better communication between health care professionals and patients, measures to improve understanding of the importance of adherence to treatment, reduction of co payments and transport costs, and easier access to care, especially in rural areas. PMID- 25909596 TI - Comparison of digital breast tomosynthesis and 2D digital mammography using a hybrid performance test. AB - This paper introduces a hybrid method for performing detection studies in projection image based modalities, based on image acquisitions of target objects and patients. The method was used to compare 2D mammography and digital breast tomosynthesis (DBT) in terms of the detection performance of spherical densities and microcalcifications. The method starts with the acquisition of spheres of different glandular equivalent densities and microcalcifications of different sizes immersed in a homogeneous breast tissue simulating medium. These target objects are then segmented and the subsequent templates are fused in projection images of patients and processed or reconstructed. This results in hybrid images with true mammographic anatomy and clinically relevant target objects, ready for use in observer studies. The detection study of spherical densities used 108 normal and 178 hybrid 2D and DBT images; 156 normal and 321 hybrid images were used for the microcalcifications. Seven observers scored the presence/absence of the spheres/microcalcifications in a square region via a 5-point confidence rating scale. Detection performance in 2D and DBT was compared via ROC analysis with sub-analyses for the density of the spheres, microcalcification size, breast thickness and z-position. The study was performed on a Siemens Inspiration tomosynthesis system using patient acquisitions with an average age of 58 years and an average breast thickness of 53 mm providing mean glandular doses of 1.06 mGy (2D) and 2.39 mGy (DBT). Study results showed that breast tomosynthesis (AUC = 0.973) outperformed 2D (AUC = 0.831) for the detection of spheres (p < 0.0001) and this applied for all spherical densities and breast thicknesses. By way of contrast, DBT was worse than 2D for microcalcification detection (AUC2D = 0.974, AUCDBT = 0.838, p < 0.0001), with significant differences found for all sizes (150-354 um), for breast thicknesses above 40 mm and for heights above the detector of 20 mm and above. In conclusion, the hybrid method was successfully used to produce images for a detection study; results showed breast tomosynthesis outperformed 2D for spherical densities while further optimization of DBT for microcalcifications is suggested. PMID- 25909597 TI - Reliability of pain intensity clamping using response-dependent thermal stimulation in healthy volunteers. AB - BACKGROUND: Pain intensity clamping uses the REsponse-Dependent Stimulation (REDSTIM) methodology to automatically adjust stimulus intensity to maintain a desired pain rating set-point which is continuously monitored from a subject's real-time pain ratings. REDSTIM blinds subjects regarding the pain intensity set point, supporting its use for assessing intervention efficacy. By maintaining the pain intensity at a constant level, a potential decrease in pain sensitivity can be detected by an increase in thermode temperature (unknown to the subject) and not by pain ratings alone. Further, previously described sensitizing and desensitizing trends within REDSTIM provide a novel insight into human pain mechanisms overcoming limitations of conventional testing methods. The purpose of the present study was to assess the test-retest reliability of pain intensity clamping using REDSTIM during three separate sessions. METHODS: We used a method for testing changes in pain sensitivity of human subjects (REDSTIM) where the stimulus temperature is modulated to clamp pain intensity near a desired set point. Temperature serves as the response variable and is used to infer pain sensitivity. Several measures were analyzed for reliability including average temperature and area under the curve (AUC). Intraclass correlation coefficients were calculated for each measure at pain rating set-points of 20/100 and 35/100. RESULTS: Sixteen healthy individuals (mean age = 21.6 +/- 3.9) participated in three experiments two days apart at both pain rating set-points. Most reliability coefficients were in the moderate to substantial range (r's = 0.79 to 0.94) except for the negative AUC (r = 0.52), but only at the 20/100 pain rating set point. CONCLUSIONS: The present study supports the test-retest reliability of pain intensity clamping using the REDSTIM methodology while providing a novel tool to examine human pain modulatory mechanisms and overcoming common shortcomings of conventional quantitative sensory testing methods. PMID- 25909598 TI - Effects of Prebiotic and Synbiotic Supplementation on Inflammatory Markers and Anthropometric Indices After Roux-en-Y Gastric Bypass: A Randomized, Triple blind, Placebo-controlled Pilot Study. AB - BACKGROUND: Studies have shown that prebiotics and synbiotics modulate the intestinal microbiota and may have beneficial effects on the immune response and anthropometric indices; however, the impact of the use of these supplements after bariatric surgery is not yet known. GOALS: This study investigated the effects of prebiotic and synbiotic supplementation on inflammatory markers and anthropometric indices in individuals undergoing open Roux-en-Y gastric bypass (RYGB). STUDY: In this randomized, controlled, and triple-blind trial conducted as a pilot study, individuals undergoing RYGB (n=9) and healthy individuals (n=9) were supplemented with 6 g/d of placebo (maltodextrin), prebiotic (fructo oligosaccharide, FOS), or synbiotic (FOS+Lactobacillus and Bifidobacteria strains) for 15 days. RESULTS: Interleukin-1beta, interleukin-6, tumor necrosis factor-alpha, C-reactive protein, albumin, and the C-reactive protein/albumin ratio showed no significant changes on comparison between groups after supplementation. The reduction in the body weight of patients undergoing RYGB was 53.8% higher in the prebiotic group compared with the placebo group (-0.7 kg, P=0.001), whereas the reduction in the BMI and the increase in the percentage of excess weight loss were higher in the placebo and the prebiotic groups compared with the synbiotic group (P<0.05). CONCLUSIONS: Supplementation of FOS increased weight loss, whereas both prebiotics and synbiotics were not able to promote significant changes in inflammatory markers, although in most analyses, there was a reduction in their absolute values. The use of FOS may represent a potential adjunct in the treatment of obesity. PMID- 25909599 TI - Total Colonic Decompression After Colonoscopy Decreases Postcolonoscopy Abdominal Pain: A Randomized Double-Blind Controlled Trial. AB - GOALS: The purpose of this study was to determine whether total colonic decompression after colonoscopy decreased postcolonoscopy abdominal pain. BACKGROUND: Abdominal pain that occurs after a colonoscopy may cause significant discomfort in some patients, and residual bowel gas is thought to be a key contributor to this abdominal pain. STUDY: Asymptomatic 300 patients who underwent colonoscopy under sedation were randomized to either the decompression group or the control group. Initial colonoscopic procedure was performed uniformly in both the groups. After the colonoscopy examination was completed, the colonoscope was reinserted into the cecum, and the intraluminal air was aspirated during withdrawal in the decompression group. Abdominal pain was assessed before discharge and 24 to 48 hours after colonoscopy using a 10-point visual analogue scale (VAS). RESULTS: The 2 groups were similar with regard to clinical, demographic, and procedural factors. Among 288 patients, the incidence of abdominal pain (VAS>=1) after colonoscopy was 38 (26.6%) of 143 patients in the decompression group and 95 (65.5%) of 145 patients in the control group (VAS 0.68+/-1.35 vs. 2.14+/-2.15, P<0.001). There was an 86.1% reduction rate of abdominal pain by colonic decompression, based on multivariate analysis (odds ratio 0.139 [95% confidence interval, 0.077-0.250], P<0.001). Furthermore, independent factors for abdominal pain included female gender and total duration of procedure >800 seconds. There were no reinsertion-related complications in the decompression group. CONCLUSION: Total colonic decompression after colonoscopy has a beneficial effect and can reduce postcolonoscopy abdominal pain without additional complications. PMID- 25909601 TI - Fast, sensitive, and selective ion-triggered disassembly and release based on tris(bipyridine)ruthenium(II)-functionalized metal-organic frameworks. AB - Metal-organic frameworks (MOFs) are microporous materials assembled from metal ions and organic linkers. Recently, many studies have been focused on the syntheses of MOFs with permanent porosity for various applications. However, no attention has been paid to controllable disassembly of MOFs and related applications. In this work, for the first time we synthesized novel tris(bipyridine)ruthenium(II)-functionalized MOFs (i.e., RuMOFs) that could be ion-responsively disassembled and release massive guest materials loaded in the frameworks. The synthesized RuMOFs exhibited much stability in aqueous solutions containing H(+), and many metal ions, but could be selectively and sensitively disassembled by Hg(2+) ions, resulting in the release of large quantities of Ru(bpy)3(2+). The target-responsive release mechanism was investigated and discussed in detail. On the basis of the ion-responsive disassembly and release, an ultrasensitive electrochemiluminescence sensing method for Hg(2+) has been developed with a very low limit of detection (5.3 * 10(-13) M). It was envisioned that the RuMOFs and similar target-responsive functional MOF materials would have promising applications in ultrasensitive and highly selective chemical sensing and even in accurately controllable drug delivering and releasing. PMID- 25909600 TI - Cell, isoform, and environment factors shape gradients and modulate chemotaxis. AB - Chemokine gradient formation requires multiple processes that include ligand secretion and diffusion, receptor binding and internalization, and immobilization of ligand to surfaces. To understand how these events dynamically shape gradients and influence ensuing cell chemotaxis, we built a multi-scale hybrid agent-based model linking gradient formation, cell responses, and receptor-level information. The CXCL12/CXCR4/CXCR7 signaling axis is highly implicated in metastasis of many cancers. We model CXCL12 gradient formation as it is impacted by CXCR4 and CXCR7, with particular focus on the three most highly expressed isoforms of CXCL12. We trained and validated our model using data from an in vitro microfluidic source sink device. Our simulations demonstrate how isoform differences on the molecular level affect gradient formation and cell responses. We determine that ligand properties specific to CXCL12 isoforms (binding to the migration surface and to CXCR4) significantly impact migration and explain differences in in vitro chemotaxis data. We extend our model to analyze CXCL12 gradient formation in a tumor environment and find that short distance, steep gradients characteristic of the CXCL12-gamma isoform are effective at driving chemotaxis. We highlight the importance of CXCL12-gamma in cancer cell migration: its high effective affinity for both extracellular surface sites and CXCR4 strongly promote CXCR4+ cell migration. CXCL12-gamma is also more difficult to inhibit, and we predict that co inhibition of CXCR4 and CXCR7 is necessary to effectively hinder CXCL12-gamma induced migration. These findings support the growing importance of understanding differences in protein isoforms, and in particular their implications for cancer treatment. PMID- 25909602 TI - Smoking and risk of prosthesis-related complications after total hip arthroplasty: a meta-analysis of cohort studies. AB - OBJECTIVE: Increasing evidence suggests that smoking may increase the incidence of prosthesis-related complications after total hip arthroplasty (THA). We performed a meta-analysis of cohort studies to quantitatively evaluate the association between smoking and the risk of prosthesis-related complications after THA. METHODS: Relevant articles published before August 15, 2014, were identified by searching the PubMed, EMBASE and Cochrane library databases. Pooled risk ratios (RRs) or weighted mean differences (WMDs) with 95% confidence intervals (CIs) were calculated with either a fixed- or random-effects model. RESULTS: Six cohort studies, involving a total of 8181 participants, were included in the meta-analysis. Compared with the patients who never smoked, smokers had a significantly increased risk of aseptic loosening of prosthesis (summary RR=3.05, 95% CI: 1.42-6.58), deep infection (summary RR=3.71, 95% CI: 1.86-7.41) and all-cause revisions (summary RR=2.58, 95% CI: 1.27-5.22). However, no significant difference in the risk of implant dislocation (summary RR= 1.27, 95% CI: 0.77-2.10) or length of hospital stay (WMD=0.03, 95% CI: -0.65-0.72) was found between smokers and nonsmokers. CONCLUSIONS: Smoking is associated with a significantly increased risk of aseptic loosening of prosthesis, deep infection and all-cause revisions after THA, but smoking is not correlated with a risk of implant dislocation or the length of hospital stay after surgery. PMID- 25909604 TI - [Antagonism of lactobacilli, oral streptococci and staphylococci]. AB - From the oral cavity of healthy young people aged 18-22 years there were isolated 26 strains of lactobacilli, 28 streptococci, including the pathogenic and opportunistic strains, and 32 strains of staphylococci, 10 of which were methicillin-resistant S.aureus. Oral lactobacilli possessed by a high probiotic potential, showing high antagonism to methicillin-resistant staphylococci, pathogenic and opportunistic streptococci and enterococci. Oral lactobacilli showed medium and high adhesive activity that determines their high adaptive capacity. Staphylococci and streptococci in 90.3% of cases have not an antagonistic effect on lactobacilli. Isolated lactobacilli can be used as probiotic strains for oral administration. PMID- 25909603 TI - Barriers to Physical Activity Among African American Women: An Integrative Review of the Literature. AB - A key aspect for researchers to consider when developing culturally appropriate physical activity (PA) interventions for African American (AA) women are the specific barriers AA women face that limit their participation in PA. Identification and critical examination of these barriers is the first step in developing comprehensive culturally relevant approaches to promote PA and help resolve PA-related health disparities in this underserved population. We conducted a systematic integrative literature review to identify barriers to PA among AA women. Five electronic databases were searched, and forty-two studies (twenty-seven qualitative, fourteen quantitative, one mixed method) published since 1990 (range 1998-2013) in English language journals met inclusion criteria for review. Barriers were classified as intrapersonal, interpersonal, or environment/community according to their respective level of influence within our social ecological framework. Intrapersonal barriers included lack of time, knowledge, and motivation; physical appearance concerns; health concerns; monetary cost of exercise facilities; and tiredness/fatigue. Interpersonal barriers included family/caregiving responsibilities; lack of social support; and lack of a PA partner. Environmental barriers included safety concerns; lack of facilities; weather concerns; lack of sidewalks; and lack of physically active AA role models. Results provide key leverage points for researchers to consider when developing culturally relevant PA interventions for AA women. PMID- 25909605 TI - [Blood supply topographic features in maxilla and mandible]. AB - Topographic anatomical studies provide data on the characteristics of blood supply to maxilla and mandible. It is established that maxilla is supplied by the large number of major arteries which are commonly anastomosed to each other. Mandible intraosseous blood supply is by one major lower alveolar artery and a large number of small extraosseous arteries that supply blood to the bone, masticatory and facial muscles. PMID- 25909606 TI - [Microbiological monitoring of oral fluid of clinically healthy children]. AB - The article presents qualitative and quantitative parameters of microbiocenosis of oral fluid and feces of clinically healthy children in different age groups. In most of the cases compensated disbiotic changes were found, which were characterized by reduction in the number of indigenous microflora (lactobacilli and bifidobacteria) and increase of representatives of opportunistic pathogens (Staphylococcus, Bacillus and Candida). Microecological changes in different gastrointestinal biotopes are closely interrelated. Saliva may be considered as a specimen of integral fluid of human environment and can be used for complex assessment of the state of gastrointestinal tract microflora. PMID- 25909607 TI - [Clinical and laboratory rationale for galvanophoresis of hydroxide copper calcium by root canals treatment]. AB - Double blind study presents clinical and laboratory estimation of root canal system (RC) cleaning by endodontic treatment of apical periodontitis by means of galvanophoresis of hydroxide copper-calcium (GP HCC). In 60 patients the amount and composition of RC fluid from incisors and canines by GP HCC were estimated within 2 weeks with three different galvano-pair and the efficiency of RC decontamination were compared by standard report irrigation and GP HCC. The intensity of electroosmotic allocation of RC liquid by GP HCC is gradually increased at 4-5 day, and then slowly reduced at 10-12 day. The RC liquid contained proteins and carbohydrates - typical rests of pulp and biofilm. GP HCC suppresses aerobic and anaerobic microflora in RC 65.5% more effectively than standard irrigation and may be seen as an alternative method of endodontic treatment of apical periodontitis. PMID- 25909608 TI - [Placebo controlled study of analgesic activity of analgin, paracetamol and dexalgin by electric pulp sensitivity testing]. AB - The aim of the study was to evaluate the analgesic activity of paracetamol, analgin, dexalgin and placebo using electrical pulp sensitivity testing. Blind randomized study was performed on 112 volunteers, 52 men and 70 women aged 19-28 years. Pain threshold was measured before and 15, 30, 45 and 60 minutes after oral intake of medications using EOM-3 device. Paired t- and chi2-test was used for statistical analysis. Height effect was observed at 30 min: 9.4 mkA for analgin, 8.7 mkA for dexalgin, 6.5 mkA for paracetamol and 5.2 mkA for placebo. Paracetamol showed analgesic efficiency close to placebo effect. PMID- 25909609 TI - [Role of viruses with oncogenic potential and their associations in oncogenesis in maxillofacial area]. AB - The potential role of viruses with oncogenic potential such as human papilloma virus, cytomegalovirus, Epstein-Barr virus, herpes simplex virus type 1 and 2, herpes virus type 6, in the development of benign and pre-cancerous tumors of maxillofacial region was assessed in the study. We examined 26 patients with tumors in maxillofacial region (skin and mucosa) using molecular-genetic and histological studies of surgically removed neoplasms removed. In 53.8% of the examined samples DNA of Epstein-Barr virus, herpes virus type 6, herpes simplex virus type 1, or cytomegalovirus and in 35.7% of them the association of the above mentioned viruses were detected. It may confirm their relation with the development of benign, precancerous and malignant neoplasms in maxillofacial region. PMID- 25909610 TI - [Dental and oncological status of patients with tongue carcinoma]. AB - After the supervision over patients with cancer of mucous membrane of oral cavity (MMOC) admitted for treatment in the Tver Regional Clinical Oncological Hospital (TRCOH), the analysis of 427 primary revealed cases of cancer of mobile part of the tongue MPoT (S 02) was carried out. The study included retrospective analysis of case records of 237 patients treated from 1997 to 2013 with the diagnosis of MPoT and prospective examination of 190 patients treated by authors in specialized departments of TRCOH. On the basis of questioning of 67 III-IV stages tongue carcinoma patients at the age of 50-59 years clinical course features, cancer risk factors and oral care patterns were studied. It was revealed that patients often make decision to see an oncologist to meet relatives wishes, prefer self-treatment, trust hearings and quacks or simply hope for self recovery. Studying of dental status revealed high prevalence and intensity of caries. All males and the majority of sampled women weren't informed about additional methods of oral cavity hygiene (dental floss, mouthwashes, gels) and had unsatisfactory or bad level of Fedorov-Volodkina hygienic index. We revealed a high necessity in treatment of caries and its complications, an average of 3.61 and 2.73 teeth needed filling and 4,43 and 1.77 teeth - extraction in male and female patients, correspondently. The received data identify a great need for dental treatment and patient education in patients with tongue malignancy. PMID- 25909611 TI - [Microbiocenosis of major biotopes of the oral cavity in patients with tongue carcinoma during complex treatment]. AB - The composition of the microflora in three biotopes of the oral cavity was examined in 36 patients with tongue carcinoma before chemotherapy, one - two weeks after two courses of chemotherapy and before gemiglosseklomiya. The oral dysbiosis was revealed in patients before antitumor therapy. The opportunistic and pathogenic bacteria in concentration more than 4 lg CFU/cm2 were dominant in microbiocenosis of oral cavity. Most of the isolated microorganisms were capable of maintaining the inflammatory process by secreting oral enzymes and toxins. The microflora formed normobiocenosis in oral cavity after two courses of chemotherapy. The pathogenic potential of selected microflora in patients after preoperative radiotherapy before surgery was more pronounced than the microflora of healthy people, and also in patients prior to treatment. Dysbiosis of III degree was detected in oral cavity of patients with tongue carcinoma before gemiglosseklomiya. requiring correction for the prevention the postoperative complications. PMID- 25909612 TI - [Use of analgesia and sedation in dental implantology in patients with concomitant hypertension]. AB - Dental implants surgery in patients with hypertension increases the risk of vascular complications. The aim of the study was to examine the effect of analgesia and sedation on blood pressure and postoperative pain in dental implantology. In 76 patients with hypertension implant surgery was performed under local anesthesia only (40 patients) or under local anesthesia with propofol sedation and pre-emptive analgesia with ketorolac (36 patients). Intraoperative systolic blood pressure in the second group was 20% less than in the first group while the intensity of pain in the postoperative period in the second group was three times less than in the first one. Propofol sedation in dental implantology provides hemodynamic stability in patients with concomitant hypertension and preemptive analgesia with ketorolac allows minimizing postoperative pain. PMID- 25909613 TI - [Rational antimicrobial therapy in patients with purulent inflammatory diseases of maxillofacial area]. AB - The aim of the study was to reveal optimal antimicrobial agents in patients with purulent inflammatory diseases of maxillofacial area according to bacteriological study results. One hundred twenty-one culture samples from 32 patients aged from 21 to 68 years admitted to Nurnberg Maxillofacial Surgery Clinic. Pathogenic flora was mostly mixed with 66.9% of anaerobic germs in the majority of cases irresponsible to ampicillin (1.3%) and clindamycin (0.7%). The drugs of choice are ampicillin/sulbactam and amoxicillin/clavulanate. Bacteriological study should be included as a useful tool in treatment protocols of patients with purulent inflammatory diseases of maxillofacial area. PMID- 25909614 TI - [Changes in gingival blood circulation in patients with provisional fixed acrylic dentures]. AB - The adhesion of oral microorganisms to the surface of teeth and dental restorative materials is often the starting point in the developments of caries and periodontal disease. Formation of biofilm on the surface provisional acrylic bridge is especially quickly and can potentially generate decay or periodontal disease on the teeth. Occlusion trauma and occlusion disorders effects on increasing of injure regional periodontal tissues. Using ultrasonic doppler diagnostics oral mucosal blood flow was measured in 79 patients with periodontitis of medium severity with different hygiene conditions before and during orthopedic treatment by provisional fixed dentures was model by different methods. According to the results of this study was stated optimization of oral mucosal blood flow after pre-prosthetic treatments and the supportive hygiene periodontal care during the treatment. Results was used for reduce of functional stress in the in periodontal tissues during the orthopedic alignment by the use of fixed dentures. Specific prosthodontic hygiene protocol and model by individual articulator must be used to treat patients with widespread chronic periodontitis by interim prostheses. PMID- 25909615 TI - [Oral microbiocenosis features of diabetic patients after orthopedic treatment with various types of crowns]. AB - The article gives a detailed analysis of oral cavity microbiocenosis features of 36 patients with type II diabetes for 5 years. These data reflects microbiocenosis features before and after orthopedic treatment with metal-ceramic and pressed crowns. These results indicate that frequency of occurrence and the number of microorganisms of the genus Streptococcus, Staphylococcus (including S. aureus), Peptostreptococcus and Candida is significantly higher in patients after orthopedic treatment with pressed crowns than with metal-ceramic crowns. A high percentage of normal microflora, particularly lactobacilli (60%), was revealed on gingival mucosa in patients after orthopedic treatment with metal-ceramic crowns. PMID- 25909616 TI - [Microbiological aspects of zirconia orthopedic structures]. AB - The article gives a detailed analysis of oral cavity microbiological aspects of 23 patients before and after prosthetic treatment with zirconia structures. Microbiocenoses of oral cavity in patients with defects of the dentition can be described as disbiotic. It was found that the incidence of lactobacilli and bifidobacteria was increased and frequency of occurrence of pathogens, including Staphylococcus aureus, was decreased under the influence of temporary plastic prosthesis as an intermediate step prosthetics. After applying prosthetic zirconia an increase of the normal biotopes number was seen, as well as reduce in the number of Staphylococcus aureus and the yeast fungus Candida to less than 4 lg CFU/ml. Such amounts do not cause inflammation in the oral cavity. PMID- 25909617 TI - [Clinical rationale for interdisciplinary approach to treatment of dental diseases in children with chronic pathology of upper GI tract]. AB - The article presents clinical rationale for interdisciplinary approach to treatment of dental diseases in children with chronic pathology of upper GI tract based on the morphofunctional changes of oral cavity organs. The dental markers of somatic diseases and unfavorable dynamics of the individual health level in the process of ontogenesis were determined. The results of the study allow considering the oral cavity as a target organ in chronic GI pathology. PMID- 25909618 TI - [Dental status in children and adolescents diagnosed with obesity]. AB - Dental status was studied in 168 obese teenagers aged from 12 to 17 years. The study revealed high prevalence in this group of teenagers of oral pathology like caries and fluorosis, inflammatory periodontal disease in 75% of children and poor oral hygiene level. One should consider high need for development of treatment-and-prophylactic measures for improvement of dental status in obese teenagers. PMID- 25909619 TI - [Long-term dental interventions in mentally retarded children under general anesthesia with sevoflurane]. AB - Dental procedures in mentally retarded children is challenging for both dentist and for anesthesiologist. The aim of the study was to evaluate the efficacy and safety of dental care procedures under general anesthesia with sevoflurane by means of laryngeal mask in mentally retarded children. The randomized controlled study included 65 mentally retarded children with ASA 2-3 who underwent dental treatment. All patients had multiple caries. The children were divided into two groups. The first group included 35 children with normal body weigh while the second one - 30 obese children. All patients received a rapid induction with sevoflurane with the subsequent installation of the laryngeal mask. In the second group the signs of hypoventilation recorded an average of 10 +/- 4 minutes after induction of anesthesia, which was manifested in increasing Pso2greater than 50 mm Hg. In the first group, the signs of hypoventilation marked an average of 18 +/- 3.5 minutes from the start of induction of anesthesia. All patients were transferred to the artificial lung ventilation through the LMA. By dental treatment under general anesthesia with sevoflurane and laryngeal mask all mentally retarded children had respiratory depression with increased levels of carbon dioxide greater than 50 mmHg, but obese children developed these signs of hypoventilation twice as fast. Conducting long dental treatment in mentally retarded children require artificial lung ventilation. PMID- 25909620 TI - [Prevalence of dentition defects among pre-school children of Tver region according to epidemiological study]. AB - Epidemiological dental study of 724 pre-school children in Tver region revealed high prevalence of dentition defects due to premature removal of temporary molars. Dependence of pediatric population need for prosthetic dentistry from regional dental care system staff competence is shown. The date proved the need for standard correction of orthodontists number and broad application of pediatric prosthetics in daily practice. PMID- 25909621 TI - [Evaluation of clinical efficiency of various space maintainers in premature loss of deciduous molars]. AB - The paper presents the results of two years observation of clinical application of three variants of space maintainers in early primary molars loss. Sixty-five children aged 6-12 years were included in the study. The most common problems when using fixed space maintainers is a deformation of intermediate part seen in 58.3% of children when applying crown (ring) with bracer. Support elements debonding at stabilizing devise fixed directly to tooth enamel is registered in 49.6% of children. Cementation releasing of support elements is observed by the application of crown (ring) with bracer at 45.8% of children. PMID- 25909622 TI - [Peculiarities of microbiological composition of oral fluid during various stages of orthodontic treatment in children and adolescents]. AB - The article presents the results of analysis of spectrum, the rate of frequency and the amount of microorganisms in oral liquid before the beginning of orthodontic treatment of dental abnormalities and deformations and in its stages (6 and 12 months later). As the result of the study the appearance of pathologic microorganisms Staphylococcus aureus and a great number of conditionally pathogenic fungi of Candida family and Porphyromonas spp. were determined. The obtained results show the need of elaboration of standards for the treatment of orthodontic patients. PMID- 25909623 TI - [Efficiency of the upper molars distalization by means of custom-made appliances]. AB - The paper describes an original design of appliance for distalization of maxillary molars; it's principle of work; comparison with the available conventional appliances for similar purpose. PMID- 25909624 TI - Cancer cell detection and therapeutics using peroxidase-active nanohybrid of gold nanoparticle-loaded mesoporous silica-coated graphene. AB - Development of efficient artificial enzymes is an emerging field in nanobiotechnology, since these artificial enzymes could overcome serious disadvantages of natural enzymes. In this work, a new nanostructured hybrid was developed as a mimetic enzyme for in vitro detection and therapeutic treatment of cancer cells. The hybrid (GSF@AuNPs) was prepared by the immobilization of gold nanoparticles (AuNPs) on mesoporous silica-coated nanosized reduced graphene oxide conjugated with folic acid, a cancer cell-targeting ligand. The GSF@AuNPs hybrid showed unprecedented peroxidase-like activity, monitored by catalytic oxidation of a typical peroxidase substrate, 3,3',5,5'-tetramethylbenzidine (TMB), in the presence of H2O2. On basis of this peroxidase activity, the hybrid was utilized as a selective, quantitative, and fast colorimetric detection probe for cancer cells. Finally, the hybrid as a mimetic enzyme was employed for H2O2- and ascorbic acid (AA)-mediated therapeutics of cancer cells. In vitro experiments using human cervical cancer cells (HeLa cells) exhibited the formation of reactive oxygen species (OH(*) radical) in the presence of peroxidase-mimic GSF@AuNPs with either exogenous H2O2 or endogenous H2O2 generated from AA, leading to an enhanced cytotoxicity to HeLa cells. In the case of normal cells (human embryonic kidney HEK 293 cells), the treatment with the hybrid and H2O2 or AA showed no obvious damage, proving selective killing effect of the hybrid to cancer cells. PMID- 25909625 TI - Discrete stacking of aromatic oligoamide macrocycles. AB - Unlike the precise structural control typical of closed assemblies, curbing the stacking of disc- and ring-shaped molecules is quite challenging. Here we report the discrete stacking of rigid aromatic oligoamide macrocycles 1. With increasing concentration, the aggregation of 1 quickly plateaus, forming a discrete oligomer, as suggested by 1D (1)H, 2D nuclear Overhauser effect, and diffusion ordered NMR spectroscopy. Quantum-chemical calculations indicate that the tetramer of 1 is the most stable among oligomeric stacks. X-ray crystallography revealed a tetrameric stack containing identical molecules adopting two different conformations. With a defined length and an inner pore capable of accommodating distinctly different guests, the tetramers of 1 densely pack into 2D layers. Besides being a rare system of conformation-regulated supramolecular oligomerization, the discrete stacks of 1, along with their higher-order assemblies, may offer new nanotechnological applications. PMID- 25909626 TI - A trend analysis of ergonomic research themes in Taiwan. AB - This paper examines the development of ergonomics in Taiwan by analysing 1404 scientific articles published by 113 permanent members of the Ergonomics Society of Taiwan (EST). Each article was classified by key words and abstract content. Each article was also coded by period of publication (1971-1992 (first period), 1993-1997 (second period), 1998-2002 (third period), 2003-2007 (fourth period), and 2008-2012 (fifth period), and against 13 topic categories. The results show that rate of publication has increased by approximately 100 articles every five years since 1993.The most popular topic was ergonomics assessment and analysis techniques in the first period, force exertion-related research in the second period, product design and evaluation in the third period, occupational safety and health in the fourth period and human-computer interface in the fifth period. Each of these is highly relevant to current contemporary issues around the world. Finally, potential areas for future ergonomics research in Taiwan are discussed. PRACTITIONER SUMMARY: This study investigates the trends in academic papers published by members of the EST. Over time, topics have shifted from ergonomics evaluation methods to occupational safety and health, and human-computer interaction. The findings should be considered as important references for planning the future of ergonomics in Taiwan. PMID- 25909627 TI - Prevalence of Sexual Dysfunction and Associations with Psychiatric Disorders Among Women Aged 50 and Older. AB - OBJECTIVE: This study investigated the prevalence of sexual problems and associated factors, focusing particularly on comorbid psychiatric disorders, among older Korean women. METHODS: A nationally representative sample of women aged 50-74 years (n=3828) responded to in-person interviews using the Korean version of the Composite International Diagnostic Interview to assess psychiatric disorders and four symptoms of sexual dysfunction: (1) lack of sexual interest/sexual aversion, (2) dyspareunia, (3) loss of pleasure, and (4) other organic dysfunction (e.g., inability of sexual arousal). We examined the likelihood of sexual dysfunction by sociodemographic and clinical variables, including specific psychiatric disorders, and compared the characteristics of sexual dysfunction among women with and without a comorbid psychiatric disorder. RESULTS: A total of 334 (8.7%) women reported one or more symptoms of sexual dysfunction during the year preceding the interview: lack of sexual interest/sexual aversion was most prevalent (7.7%), followed by loss of pleasure (4.2%), dyspareunia (2.4%), and other organic dysfunction (0.4%). Having a psychiatric disorder was associated with a 2.7-fold increase in the probability of sexual dysfunction. Among women with sexual dysfunction, having comorbid mental disorder was associated with being unmarried status, a symptom of loss of pleasure, and a history of sexual dysfunction before 50 years of age. CONCLUSIONS: The present study suggests a relatively lower prevalence of sexual dysfunction than previously reported, but supports its strong association with psychiatric disorders among postmenopausal women. We should evaluate comorbid mental disorder with sexual dysfunction, especially among those having some characteristics. PMID- 25909628 TI - Age of onset and progression of hoarding symptoms in older adults with hoarding disorder. AB - OBJECTIVES: We investigated (1) age of onset of hoarding disorder (HD) symptoms and diagnosis, (2) late-onset HD, (3) progression of HD symptoms, and (4) association between demographics and hoarding progression. METHOD: Eighty-two older adults with HD provided retrospective ratings of their hoarding symptoms for each decade of life. Age of onset of symptoms (saving, difficulty discarding, and clutter) was operationalized as the first decade in which the participant reported at least minor symptom severity, and age of onset for possible HD diagnosis was operationalized as the first decade in which the participant reported all three symptoms. We used mixed effects modeling to examine the progression of HD symptoms. RESULTS: The median age of onset for symptoms was between 10 and 20 years, and the median age of onset for possible HD diagnosis was between 20 and 30 years. Twenty-three percent of participants reported onset of possible HD diagnosis after the age of 40. All HD symptoms increased in severity over time. Men reported higher initial clutter and a slower increase in hoarding severity for all symptoms. Increased education was associated with slower increase in saving. Having at least one parent with hoarding tendencies was associated with higher initial hoarding symptoms. CONCLUSION: Generally, symptoms of HD begin relatively early and worsen across the lifespan. However, approximately one fourth of older adults with HD reported a possible onset after the age of 40. PMID- 25909629 TI - Characterization of Burkholderia pseudomallei Strains Using a Murine Intraperitoneal Infection Model and In Vitro Macrophage Assays. AB - Burkholderia pseudomallei, the etiologic agent of melioidosis, is a gram-negative facultative intracellular bacterium. This bacterium is endemic in Southeast Asia and Northern Australia and can infect humans and animals by several routes. It has also been estimated to present a considerable risk as a potential biothreat agent. There are currently no effective vaccines for B. pseudomallei, and antibiotic treatment can be hampered by nonspecific symptomology, the high incidence of naturally occurring antibiotic resistant strains, and disease chronicity. Accordingly, there is a concerted effort to better characterize B. pseudomallei and its associated disease. Before novel vaccines and therapeutics can be tested in vivo, a well characterized animal model is essential. Previous work has indicated that mice may be a useful animal model. In order to develop standardized animal models of melioidosis, different strains of bacteria must be isolated, propagated, and characterized. Using a murine intraperitoneal (IP) infection model, we tested the virulence of 11 B. pseudomallei strains. The IP route offers a reproducible way to rank virulence that can be readily reproduced by other laboratories. This infection route is also useful in distinguishing significant differences in strain virulence that may be masked by the exquisite susceptibility associated with other routes of infection (e.g., inhalational). Additionally, there were several pathologic lesions observed in mice following IP infection. These included varisized abscesses in the spleen, liver, and haired skin. This model indicated that commonly used laboratory strains of B. pseudomallei (i.e., K96243 and 1026b) were significantly less virulent as compared to more recently acquired clinical isolates. Additionally, we characterized in vitro strain-associated differences in virulence for macrophages and described a potential inverse relationship between virulence in the IP mouse model of some strains and in the macrophage phagocytosis assay. Strains which were more virulent for mice (e.g., HBPU10304a) were often less virulent in the macrophage assays, as determined by several parameters such as intracellular bacterial replication and host cell cytotoxicity. PMID- 25909631 TI - Investigation of biophysical mechanisms in gold nanoparticle mediated laser manipulation of cells using a multimodal holographic and fluorescence imaging setup. AB - Laser based cell manipulation has proven to be a versatile tool in biomedical applications. In this context, combining weakly focused laser pulses and nanostructures, e.g. gold nanoparticles, promises to be useful for high throughput cell manipulation, such as transfection and photothermal therapy. Interactions between laser pulses and gold nanoparticles are well understood. However, it is still necessary to study cell behavior in gold nanoparticle mediated laser manipulation. While parameters like cell viability or perforation efficiency are commonly addressed, the influence of the manipulation process on other essential cell parameters is not sufficiently investigated yet. Thus, we set out to study four relevant cell properties: cell volume and area, ion exchange and cytoskeleton structure after gold nanoparticle based laser manipulation. For this, we designed a multimodal imaging and manipulation setup. 200 nm gold nanoparticles were attached unspecifically to canine cells and irradiated by weakly focused 850 ps laser pulses. Volume and area change in the first minute post laser manipulation was monitored using digital holography. Calcium imaging and cells expressing a marker for filamentous actin (F-actin) served to analyze the ion exchange and the cytoskeleton, respectively. High radiant exposures led to cells exhibiting a tendency to shrink in volume and area, possibly due to outflow of cytoplasm. An intracellular raise in calcium was observed and accompanied by an intercellular calcium wave. This multimodal approach enabled for the first time a comprehensive analysis of the cell behavior in gold nanoparticle mediated cell manipulation. Additionally, this work can pave the way for a better understanding and the evaluation of new applications in the context of cell transfection or photothermal therapy. PMID- 25909630 TI - MXS-Chaining: A Highly Efficient Cloning Platform for Imaging and Flow Cytometry Approaches in Mammalian Systems. AB - The continuous improvement of imaging technologies has driven the development of sophisticated reporters to monitor biological processes. Such constructs should ideally be assembled in a flexible enough way to allow for their optimization. Here we describe a highly reliable cloning method to efficiently assemble constructs for imaging or flow cytometry applications in mammalian cell culture systems. We bioinformatically identified a list of restriction enzymes whose sites are rarely found in human and mouse cDNA libraries. From the best candidates, we chose an enzyme combination (MluI, XhoI and SalI: MXS) that enables iterative chaining of individual building blocks. The ligation scar resulting from the compatible XhoI- and SalI-sticky ends can be translated and hence enables easy in-frame cloning of coding sequences. The robustness of the MXS-chaining approach was validated by assembling constructs up to 20 kb long and comprising up to 34 individual building blocks. By assessing the success rate of 400 ligation reactions, we determined cloning efficiency to be 90% on average. Large polycistronic constructs for single-cell imaging or flow cytometry applications were generated to demonstrate the versatility of the MXS-chaining approach. We devised several constructs that fluorescently label subcellular structures, an adapted version of FUCCI (fluorescent, ubiquitination-based cell cycle indicator) optimized to visualize cell cycle progression in mouse embryonic stem cells and an array of artificial promoters enabling dosage of doxycyline inducible transgene expression. We made publicly available through the Addgene repository a comprehensive set of MXS-building blocks comprising custom vectors, a set of fluorescent proteins, constitutive promoters, polyadenylation signals, selection cassettes and tools for inducible gene expression. Finally, detailed guidelines describe how to chain together prebuilt MXS-building blocks and how to generate new customized MXS-building blocks. PMID- 25909632 TI - Factors controlling vegetation fires in protected and non-protected areas of myanmar. AB - Fire is an important disturbance agent in Myanmar impacting several ecosystems. In this study, we quantify the factors impacting vegetation fires in protected and non-protected areas of Myanmar. Satellite datasets in conjunction with biophysical and anthropogenic factors were used in a spatial framework to map the causative factors of fires. Specifically, we used the frequency ratio method to assess the contribution of each causative factor to overall fire susceptibility at a 1km scale. Results suggested the mean fire density in non-protected areas was two times higher than the protected areas. Fire-land cover partition analysis suggested dominant fire occurrences in the savannas (protected areas) and woody savannas (non-protected areas). The five major fire causative factors in protected areas in descending order include population density, land cover, tree cover percent, travel time from nearest city and temperature. In contrast, the causative factors in non-protected areas were population density, tree cover percent, travel time from nearest city, temperature and elevation. The fire susceptibility analysis showed distinct spatial patterns with central Myanmar as a hot spot of vegetation fires. Results from propensity score matching suggested that forests within protected areas have 11% less fires than non-protected areas. Overall, our results identify important causative factors of fire useful to address broad scale fire risk concerns at a landscape scale in Myanmar. PMID- 25909635 TI - Bronsted versus Lewis Acid Type Anion Recognition by Arylboronic Acids. AB - Interactions between arylboronic acids and a series of anions as tetrabutylammonium salts in DMSO and MeCN were studied by (1)H and (11)B NMR as well as spectrophotometrically. Boronic acids act as Bronsted acid type receptors through hydrogen bonding with B(OH)2 hydroxyl groups toward Cl(-), Br(-), HSO4( ), and AcO(-), but they act as Lewis acid type receptors toward F(-) and H2PO4( ), which form tetrahedral adducts with the B(III) center of boronic acids, although there is also evidence for some contribution of hydrogen bonding with these anions. The Hammett plot for the binding constants of AcO(-) with 3- and 4 substituted phenylboronic acids in DMSO is nonlinear, with a small negative slope for electron-donating and weakly electron-accepting substituents and a large positive slope for strongly electron-accepting substituents. 3-Nitrophenylboronic acid recognizes zwitterions of amino acids in DMSO, and its UV absorption maximum undergoes a significant red shift in the presence of acetate anions, providing a means for sensing anions optically. Arylboronic acids as Bronsted acid type receptors show relatively low sensitivity to solvent polarity and are equally or even more efficient than widely employed proton donors such as ureas or dicarboxamides. PMID- 25909633 TI - Bayesian geostatistical model-based estimates of soil-transmitted helminth infection in Nigeria, including annual deworming requirements. AB - BACKGROUND: The acceleration of the control of soil-transmitted helminth (STH) infections in Nigeria, emphasizing preventive chemotherapy, has become imperative in light of the global fight against neglected tropical diseases. Predictive risk maps are an important tool to guide and support control activities. METHODOLOGY: STH infection prevalence data were obtained from surveys carried out in 2011 using standard protocols. Data were geo-referenced and collated in a nationwide, geographic information system database. Bayesian geostatistical models with remotely sensed environmental covariates and variable selection procedures were utilized to predict the spatial distribution of STH infections in Nigeria. PRINCIPAL FINDINGS: We found that hookworm, Ascaris lumbricoides, and Trichuris trichiura infections are endemic in 482 (86.8%), 305 (55.0%), and 55 (9.9%) locations, respectively. Hookworm and A. lumbricoides infection co-exist in 16 states, while the three species are co-endemic in 12 states. Overall, STHs are endemic in 20 of the 36 states of Nigeria, including the Federal Capital Territory of Abuja. The observed prevalence at endemic locations ranged from 1.7% to 51.7% for hookworm, from 1.6% to 77.8% for A. lumbricoides, and from 1.0% to 25.5% for T. trichiura. Model-based predictions ranged from 0.7% to 51.0% for hookworm, from 0.1% to 82.6% for A. lumbricoides, and from 0.0% to 18.5% for T. trichiura. Our models suggest that day land surface temperature and dense vegetation are important predictors of the spatial distribution of STH infection in Nigeria. In 2011, a total of 5.7 million (13.8%) school-aged children were predicted to be infected with STHs in Nigeria. Mass treatment at the local government area level for annual or bi-annual treatment of the school-aged population in Nigeria in 2011, based on World Health Organization prevalence thresholds, were estimated at 10.2 million tablets. CONCLUSIONS/SIGNIFICANCE: The predictive risk maps and estimated deworming needs presented here will be helpful for escalating the control and spatial targeting of interventions against STH infections in Nigeria. PMID- 25909634 TI - Prophylaxis and Treatment of Pneumocystis jiroveci Pneumonia in Lymphoma Patients Subjected to Rituximab-Contained Therapy: A Systemic Review and Meta-Analysis. AB - Pneumocystis jiroveci pneumonia (PCP) is frequently reported in lymphoma patients treated with rituximab-contained regimens. There is a trend toward a difference in PCP risk between bi- and tri-weekly regimens. The aims of this systemic review and meta-analysis were to estimate the risk for PCP in these patients, compare the impact of different regimens on the risk, and evaluate the efficacy of prophylaxis. The cohort studies with incept up to January 2014 were retrieved from the Cochrane Library, Medline, Embase, and Web of Science databases. Studies that compared the incidence of PCP in patients with and without rituximab treatment were conducted. Studies that reported the results of prophylaxis were concentrated to evaluate the efficacy of prophylaxis. Fixed effect Mantel Haenszel model was chosen as the main analysis method. Funnel plots were examined to estimate the potential selection bias. Egger's test and Begg's test were used for the determination of possible small study bias. Eleven cohort studies that met the inclusion criteria were finally included. Results indicated that rituximab was associated with a significantly increased risk for PCP (28/942 vs 5/977; risk ratio: 3.65; 95% confidence interval 1.65 to 8.07; P=0.001), and no heterogeneity existed between different studies (I2=0%). Little significant difference in PCP risk was found between bi-weekly and tri-weekly regimens (risk ratio: 3.11; 95% confidence interval 0.92 to 10.52, P=0.068). PCP risk was inversely associated with prophylaxis in patients treated with rituximab (0/222 vs 26/986; risk ratio: 0.28; 95% confidence interval 0.09 to 0.94; P=0.039). In conclusion, PCP risk was increased significantly in lymphoma patients subjected to rituximab-contained chemotherapies. Difference in PCP risk between bi-weekly and tri-weekly regimens was not significant. Additionally, prophylaxis was dramatically effective in preventing PCP in rituximab-received lymphoma patients, suggesting that rituximab should be recommended for these patients. PMID- 25909636 TI - Re-constructing historical Adelie penguin abundance estimates by retrospectively accounting for detection bias. AB - Seabirds and other land-breeding marine predators are considered to be useful and practical indicators of the state of marine ecosystems because of their dependence on marine prey and the accessibility of their populations at breeding colonies. Historical counts of breeding populations of these higher-order marine predators are one of few data sources available for inferring past change in marine ecosystems. However, historical abundance estimates derived from these population counts may be subject to unrecognised bias and uncertainty because of variable attendance of birds at breeding colonies and variable timing of past population surveys. We retrospectively accounted for detection bias in historical abundance estimates of the colonial, land-breeding Adelie penguin through an analysis of 222 historical abundance estimates from 81 breeding sites in east Antarctica. The published abundance estimates were de-constructed to retrieve the raw count data and then re-constructed by applying contemporary adjustment factors obtained from remotely operating time-lapse cameras. The re-construction process incorporated spatial and temporal variation in phenology and attendance by using data from cameras deployed at multiple sites over multiple years and propagating this uncertainty through to the final revised abundance estimates. Our re-constructed abundance estimates were consistently higher and more uncertain than published estimates. The re-constructed estimates alter the conclusions reached for some sites in east Antarctica in recent assessments of long-term Adelie penguin population change. Our approach is applicable to abundance data for a wide range of colonial, land-breeding marine species including other penguin species, flying seabirds and marine mammals. PMID- 25909637 TI - Structured learning for spatial information extraction from biomedical text: bacteria biotopes. AB - BACKGROUND: We aim to automatically extract species names of bacteria and their locations from webpages. This task is important for exploiting the vast amount of biological knowledge which is expressed in diverse natural language texts and putting this knowledge in databases for easy access by biologists. The task is challenging and the previous results are far below an acceptable level of performance, particularly for extraction of localization relationships. Therefore, we aim to design a new system for such extractions, using the framework of structured machine learning techniques. RESULTS: We design a new model for joint extraction of biomedical entities and the localization relationship. Our model is based on a spatial role labeling (SpRL) model designed for spatial understanding of unrestricted text. We extend SpRL to extract discourse level spatial relations in the biomedical domain and apply it on the BioNLP-ST 2013, BB-shared task. We highlight the main differences between general spatial language understanding and spatial information extraction from the scientific text which is the focus of this work. We exploit the text's structure and discourse level global features. Our model and the designed features substantially improve on the previous systems, achieving an absolute improvement of approximately 57 percent over F1 measure of the best previous system for this task. CONCLUSIONS: Our experimental results indicate that a joint learning model over all entities and relationships in a document outperforms a model which extracts entities and relationships independently. Our global learning model significantly improves the state-of-the-art results on this task and has a high potential to be adopted in other natural language processing (NLP) tasks in the biomedical domain. PMID- 25909638 TI - An Ordovician variation on Burgess Shale-type biotas. AB - The Cambrian Burgess Shale-type biotas form a globally consistent ecosystem, usually dominated by arthropods. Elements of these communities continued into the Early Ordovician at high latitude, but our understanding of ecological changes during the Great Ordovician Biodiversification Event (GOBE) is currently limited by the paucity of Ordovician exceptionally preserved open-marine faunas. Here we clarify the early stages of the GOBE by describing a new open-marine Konservat Lagerstatte from the Early Ordovician of Wales. The Afon Gam Biota includes many lineages typical of the Cambrian Burgess Shale-type biotas, but the most abundant groups were sponges, algae and worms, with non-trilobite arthropods being unexpectedly rare. Labile tissues occur abundantly in the sponges and are also present in other groups, including brachiopods and hyoliths. Taphonomic biases are considered and rejected as explanations for arthropod rarity; the preserved biota is considered to be an approximation to the original community composition. We note that other exceptionally preserved communities in the Welsh Ordovician are also sponge-dominated, suggesting a regional change in benthic ecology during the early stages of the GOBE. PMID- 25909639 TI - Pt-functionalized Fe2O3 photoanodes for solar water splitting: the role of hematite nano-organization and the platinum redox state. AB - Pt/alpha-Fe2O3 nanocomposites were synthesized on fluorine-doped tin oxide (FTO) substrates by a sequential plasma enhanced-chemical vapor deposition (PE CVD)/radio frequency (RF) sputtering approach, tailoring the overall Pt content as a function of sputtering time. The chemico-physical properties of the as prepared systems were extensively investigated by means of complementary techniques, including X-ray diffraction (XRD), X-ray photoelectron spectroscopy (XPS), field emission-scanning electron microscopy (FE-SEM), energy dispersive X ray spectroscopy (EDXS), secondary ion mass spectrometry (SIMS), and optical absorption spectroscopy, and compared to those of the homologous Pt/alpha-Fe2O3 systems annealed in air prior and/or after sputtering. The obtained results evidenced that the material compositional, structural and morphological features, with particular regard to the Pt oxidation state and hematite nano-organization, could be finely tailored as a function of the adopted processing conditions. Pt/alpha-Fe2O3 systems were finally tested as photoanodes in photoelectrochemical (PEC) water splitting experiments, evidencing a remarkable interplay between functional performances and the above-mentioned material properties, as also testified by transient absorption spectroscopy (TAS) results. PMID- 25909641 TI - Evaluation of monoscopic and stereoscopic displays for visual-spatial tasks in medical contexts. AB - In the medical field, digital images are present in diagnosis, pre-operative planning, minimally invasive surgery, instruction, and training. The use of medical digital imaging has afforded new ways to interact with a patient, such as seeing fine details inside a body. This increased usage also raises many basic research questions on human perception and performance when utilizing these images. The work presented here attempts to answer the question: How would adding the stereopsis depth cue affect relative position tasks in a medical context compared to a monoscopic view? By designing and conducting a study to isolate the benefits between monoscopic 3D and stereoscopic 3D displays in a relative position task, the following hypothesis was tested: stereoscopic 3D displays are beneficial over monoscopic 3D displays for relative position judgment tasks in a medical visualization setting. 44 medical students completed a series of relative position judgments tasks. The results show that stereoscopic condition yielded a higher score than the monoscopic condition with regard to the hypothesis. PMID- 25909640 TI - Infection of Female BWF1 Lupus Mice with Malaria Parasite Attenuates B Cell Autoreactivity by Modulating the CXCL12/CXCR4 Axis and Its Downstream Signals PI3K/AKT, NFkappaB and ERK. AB - Systemic lupus erythematosus (SLE) is a prototypic autoimmune disease characterized by abnormal autoreactivity in B cells. Lymphocytes and their soluble mediators contribute to the disease pathogenesis. We recently demonstrated that infecting lupus mice with malaria confers protection against lupus nephritis by attenuating oxidative stress in both liver and kidney tissues. In the current study, we further investigated B cell autoreactivity in female BWF1 lupus mice after infection with either live or gamma-irradiated malaria, using ELISA, flow cytometry and Western blot analysis. The lupus mice exhibited a significant elevation in plasma levels of IL-4, IL-6, IL-7, IL-12, IL-17, IFN alpha, IFN-gamma, TGF-beta, BAFF and APRIL and a marked elevation of IgG2a, IgG3 and ant-dsDNA autoantibodies compared with normal healthy mice. Infecting lupus mice with live but not gamma-irradiated malaria parasite partially and significantly restored the levels of the soluble mediators that contribute to the progression of lupus. Furthermore, the B cells of lupus mice exhibited an increased proliferative capacity; aberrant overexpression of the chemokine receptor CXCR4; and a marked elevation in responsiveness to their cognate ligand (CXCL12) via aberrant activation of the PI3K/AKT, NFkappaB and ERK signaling pathways. Interestingly, infecting lupus mice with live but not gamma-irradiated malaria parasite restored a normal proliferative capacity, surface expression of CXCR4 and B cell response to CXCL-12. Taken together, our data present interesting findings that clarify, for the first time, the molecular mechanisms of how infection of lupus mice with malaria parasite controls B cell autoreactivity and thus confers protection against lupus severity. PMID- 25909642 TI - A human-phantom coupling experiment and a dispersive simulation model for investigating the variation of dielectric properties of biological tissues. AB - Variation of the dielectric properties of tissues could happen due to aging, moisture of the skin, muscle denervation, and variation of blood flow by temperature. Several studies used burst-modulated alternating stimulation to improve activation and comfort by reducing tissue impedance as a possible mechanism to generate muscle activation with less energy. The study of the effect of dielectric properties of biological tissues in nerve activation presents a fundamental problem, which is the difficulty of systematically changing the morphological factors and dielectric properties of the subjects under study. We tackle this problem by using a simulation and an experimental study. The experimental study is a novel method that combines a fat tissue-equivalent phantom, with known and adjustable dielectric properties, with the human thigh. In this way, the dispersion of the tissue under study could be modified to observe its effects systematically in muscle activation. We observed that, to generate a given amount of muscle or nerve activation under conditions of decreased impedance, the magnitude of the current needs to be increased while the magnitude of the voltage needs to be decreased. PMID- 25909643 TI - Optimized selective lactate excitation with a refocused multiple-quantum filter. AB - Selective detection of lactate signals in in vivo MR spectroscopy with spectral editing techniques is necessary in situations where strong lipid or signals from other molecules overlap the desired lactate resonance in the spectrum. Several pulse sequences have been proposed for this task. The double-quantum filter SSel MQC provides very good lipid and water signal suppression in a single scan. As a major drawback, it suffers from significant signal loss due to incomplete refocussing in situations where long evolution periods are required. Here we present a refocused version of the SSel-MQC technique that uses only one additional refocussing pulse and regains the full refocused lactate signal at the end of the sequence. PMID- 25909644 TI - Measuring material susceptibility using NMR. AB - We report on a method of measuring the high-field susceptibilities of paramagnetic and diamagnetic materials using only a standard NMR system equipped with pulsed field gradients. We demonstrate the accuracy and sensitivity of the technique by measuring a series of 99.9% copper wires with diameters between 0.16 mm and 0.79 mm. We measured the volumetric susceptibility of the copper to be chi=-9.5+/-0.2.10(-6), which agrees with the literature value of pure copper, 9.6.10(-6). In addition to making quantitative measurements, this technique can also be used to evaluate the effectiveness of compensation schemes used to produce "zero-susceptibility" materials needed for construction of high resolution NMR probes. PMID- 25909645 TI - Analysis of ligand-protein exchange by Clustering of Ligand Diffusion Coefficient Pairs (CoLD-CoP). AB - NMR spectroscopy is a powerful tool in describing protein structures and protein activity for pharmaceutical and biochemical development. This study describes a method to determine weak binding ligands in biological systems by using hierarchic diffusion coefficient clustering of multidimensional data obtained with a 400 MHz Bruker NMR. Comparison of DOSY spectrums of ligands of the chemical library in the presence and absence of target proteins show translational diffusion rates for small molecules upon interaction with macromolecules. For weak binders such as compounds found in fragment libraries, changes in diffusion rates upon macromolecular binding are on the order of the precision of DOSY diffusion measurements, and identifying such subtle shifts in diffusion requires careful statistical analysis. The "CoLD-CoP" (Clustering of Ligand Diffusion Coefficient Pairs) method presented here uses SAHN clustering to identify protein-binders in a chemical library or even a not fully characterized metabolite mixture. We will show how DOSY NMR and the "CoLD-CoP" method complement each other in identifying the most suitable candidates for lysozyme and wheat germ acid phosphatase. PMID- 25909646 TI - Design of an MR image processing module on an FPGA chip. AB - We describe the design and implementation of an image processing module on a single-chip Field-Programmable Gate Array (FPGA) for real-time image processing. We also demonstrate that through graphical coding the design work can be greatly simplified. The processing module is based on a 2D FFT core. Our design is distinguished from previously reported designs in two respects. No off-chip hardware resources are required, which increases portability of the core. Direct matrix transposition usually required for execution of 2D FFT is completely avoided using our newly-designed address generation unit, which saves considerable on-chip block RAMs and clock cycles. The image processing module was tested by reconstructing multi-slice MR images from both phantom and animal data. The tests on static data show that the processing module is capable of reconstructing 128*128 images at speed of 400 frames/second. The tests on simulated real-time streaming data demonstrate that the module works properly under the timing conditions necessary for MRI experiments. PMID- 25909647 TI - Native fluorescence spectroscopic characterization of DMBA induced carcinogenesis in mice skin for the early detection of tissue transformation. AB - The objective of the study is to characterize the endogenous porphyrin fluorescence in a dimethylbenz(a)anthracene (DMBA) induced mouse skin tumor model using native fluorescence emission and excitation spectroscopy. Two intensity ratio parameters I580/I635 and I420/I515 were selected to represent the key fluorophore of endogenous porphyrins from emission and excitation spectra recorded in vivo from 31 DMBA treated animals and 5 control animals. In the emission spectrum, the endogenous porphyrin was elevated at 635 nm in different transformation lesions such as hyperplasia, papilloma, dysplasia, ESCC and WDSCC. This is corroborated by the endogenous porphyrin elevation at 420, 515, 550 and 588 nm in the WDSCC lesions from the excitation spectra. The elevation of endogenous porphyrin, probably protoporphyrin IX (PpIX), is due to biochemical and metabolic alterations in epithelial cells during tissue transformation. The loss of ferrochelatase activity might be responsible for enhanced PpIX in the transformed tissues. The sensitivity and specificity were determined for different lesion pairs from the scatter plot based on the discrimination value by validation with histopathological results. The emission intensity ratio I580/I635 at 405 nm excitation was selected to discriminate normal from hyperplasia, hyperplasia from papilloma, papilloma from dysplasia, dysplasia from early squamous cell carcinoma (ESCC), and ESCC from well differentiated squamous cell carcinoma (WDSCC) with specificities of 100%, 88%, 100%, 86%, and 100% and sensitivities of 100%, 80%, 100%, 100% and 100% respectively. Similarly, the excitation intensity ratio I420/I515 for 635 nm emission used to discriminate between WDSCC lesions and normal tissue gives 100% specificity and 100% sensitivity. PMID- 25909648 TI - Spectral properties of single gold nanoparticles in close proximity to biological fluorophores excited by 2-photon excitation. AB - Metallic nanoparticles (NPs) are able to modify the excitation and emission rates (plasmonic enhancement) of fluorescent molecules in their close proximity. In this work, we measured the emission spectra of 20 nm Gold Nanoparticles (AuNPs) fixed on a glass surface submerged in a solution of different fluorophores using a spectral camera and 2-photon excitation. While on the glass surface, we observed the presence in the emission at least 3 components: i) second harmonic signal (SHG), ii) a broad emission from AuNPS and iii) fluorescence arising from fluorophores nearby. When on the glass surface, we found that the 3 spectral components have different relative intensities when the incident direction of linear polarization was changed indicating different physical origins for these components. Then we measured by fluctuation correlation spectroscopy (FCS) the scattering and fluorescence signal of the particles alone and in a solution of 100 nM EGFP using the spectral camera or measuring the scattering and fluorescence from the particles. We observed occasional fluorescence bursts when in the suspension we added fluorescent proteins. The spectrum of these burst was devoid of the SHG and of the broad emission in contrast to the signal collected from the gold nanoparticles on the glass surface. Instead we found that the spectrum during the burst corresponded closely to the spectrum of the fluorescent protein. An additional control was obtained by measuring the cross-correlation between the reflection from the particles and the fluorescence arising from EGFP both excited at 488 nm. We found a very weak cross-correlation between the AuNPs and the fluorescence confirming that the burst originate from a few particles with a fluorescence signal. PMID- 25909649 TI - Localization of the Dual Oxidase BLI-3 and Characterization of Its NADPH Oxidase Domain during Infection of Caenorhabditis elegans. AB - Dual oxidases (DUOX) are enzymes that contain an NADPH oxidase domain that produces hydrogen peroxide (H2O2) and a peroxidase domain that can utilize H2O2 to carry out a variety of reactions. The model organism Caenorhabditis elegans produces the DUOX, BLI-3, which has roles in both cuticle development and in protection against infection. In previous work, we demonstrated that while certain peroxidases were protective against the human bacterial pathogen Enterococcus faecalis, the peroxidase domain of BLI-3 was not, leading to the postulate that the NADPH oxidase domain is the basis for BLI-3's protective effects. In this work, we show that a strain carrying a mutation in the NADPH oxidase domain of BLI-3, bli-3(im10), is more susceptible to E. faecalis and the human fungal pathogen Candida albicans. Additionally, less H2O2 is produced in response to pathogen using both an established Amplex Red assay and a strain of C. albicans, WT-OXYellow, which acts as a biosensor of reactive oxygen species (ROS). Finally, a C. elegans line containing a BLI-3::mCherry transgene was generated. Previous work suggested that BLI-3 is produced in the hypodermis and the intestine. Expression of the transgene was observed in both these tissues, and additionally in the pharynx. The amount and pattern of localization of BLI-3 did not change in response to pathogen exposure. PMID- 25909650 TI - In Vivo Multiphoton Microscopy of Basal Cell Carcinoma. AB - IMPORTANCE: Basal cell carcinomas (BCCs) are diagnosed by clinical evaluation, which can include dermoscopic evaluation, biopsy, and histopathologic examination. Recent translation of multiphoton microscopy (MPM) to clinical practice raises the possibility of noninvasive, label-free in vivo imaging of BCCs that could reduce the time from consultation to treatment. OBJECTIVES: To demonstrate the capability of MPM to image in vivo BCC lesions in human skin, and to evaluate if histopathologic criteria can be identified in MPM images. DESIGN, SETTING, AND PARTICIPANTS: Imaging in patients with BCC was performed at the University of California-Irvine Health Beckman Laser Institute & Medical Clinic, Irvine, between September 2012 and April 2014, with a clinical MPM-based tomograph. Ten BCC lesions were imaged in vivo in 9 patients prior to biopsy. The MPM images were compared with histopathologic findings. MAIN OUTCOMES AND MEASURES: MPM imaging identified in vivo and noninvasively the main histopathologic feature of BCC lesions: nests of basaloid cells showing palisading in the peripheral cell layer at the dermoepidermal junction and/or in the dermis. RESULTS: The main MPM feature associated with the BCC lesions involved nests of basaloid cells present in the papillary and reticular dermis. This feature correlated well with histopathologic examination. Other MPM features included elongated tumor cells in the epidermis aligned in 1 direction and parallel collagen and elastin bundles surrounding the tumors. CONCLUSIONS AND RELEVANCE: This study demonstrates, in a limited patient population, that noninvasive in vivo MPM imaging can provide label-free contrast that reveals several characteristic features of BCC lesions. Future studies are needed to validate the technique and correlate MPM performance with histopathologic examination. PMID- 25909652 TI - Inspiratory muscle training in pulmonary arterial hypertension. AB - PURPOSE: The purpose of this study was to investigate the effects of inspiratory muscle training (IMT) on functional capacity, respiratory muscle strength, pulmonary function, quality of life, and fatigue and dyspnea perception in patients with pulmonary arterial hypertension (PAH). METHODS: Twenty-nine clinically stable PAH patients were included in this study. These patients were randomly assigned to a 6-week IMT program (14 patients) or to a sham IMT protocol (15 patients). Before and after the treatment, pulmonary function, respiratory muscle strength, functional capacity, dyspnea and fatigue perception, and quality of life were evaluated. RESULTS: There were significant increases in maximal inspiratory and expiratory pressure, forced expiratory volume in 1 second (% predicted) and 6-minute walk distance in the IMT group compared with the control group (P < .05). There were significant decreases in the Fatigue Severity Scale score, Modified Medical Research Council dyspnea scores, and Nottingham Health Profile emotional reactions subscale in the IMT group compared with the control group (P < .05). CONCLUSIONS: Inspiratory muscle training promotes significant improvements in respiratory muscle strength and functional capacity, thus resulting in a reduction of dyspnea during activities of daily living and less fatigue in PAH patients. Inspiratory muscle training is a clinically practical treatment for PAH without any complications. PMID- 25909651 TI - Effect of sodium nitrite on ischaemia and reperfusion-induced arrhythmias in anaesthetized dogs: is protein S-nitrosylation involved? AB - BACKGROUND AND PURPOSE: To provide evidence for the protective role of inorganic nitrite against acute ischaemia and reperfusion-induced ventricular arrhythmias in a large animal model. EXPERIMENTAL APPROACH: Dogs, anaesthetized with chloralose and urethane, were administered intravenously with sodium nitrite (0.2 umol kg(-1) min(-1)) in two protocols. In protocol 1 nitrite was infused 10 min prior to and during a 25 min occlusion of the left anterior descending (LAD) coronary artery (NaNO2-PO; n = 14), whereas in protocol 2 the infusion was started 10 min prior to reperfusion of the occluded vessel (NaNO2-PR; n = 12). Control dogs (n = 15) were infused with saline and subjected to the same period of ischaemia and reperfusion. Severities of ischaemia and ventricular arrhythmias, as well as changes in plasma nitrate/nitrite (NOx) levels in the coronary sinus blood, were assessed throughout the experiment. Myocardial superoxide and nitrotyrosine (NT) levels were determined during reperfusion. Changes in protein S-nitrosylation (SNO) and S-glutathionylation were also examined. KEY RESULTS: Compared with controls, sodium nitrite administered either pre-occlusion or pre-reperfusion markedly suppressed the number and severity of ventricular arrhythmias during occlusion and increased survival (0% vs. 50 and 92%) upon reperfusion. There were also significant decreases in superoxide and NT levels in the nitrite treated dogs. Compared with controls, increased SNO was found only in NaNO2-PR dogs, whereas S-glutathionylation occurred primarily in NaNO2-PO dogs. CONCLUSIONS: Intravenous infusion of nitrite profoundly reduced the severity of ventricular arrhythmias resulting from acute ischaemia and reperfusion in anaesthetized dogs. This effect, among several others, may result from an NO-mediated reduction in oxidative stress, perhaps through protein SNO and/or S-glutathionylation. PMID- 25909654 TI - Theta, mental flexibility, and post-traumatic stress disorder: connecting in the parietal cortex. AB - Post-traumatic stress disorder (PTSD) is a mental health injury characterised by re-experiencing, avoidance, numbing and hyperarousal. Whilst the aetiology of the disorder is relatively well understood, there is debate about the prevalence of cognitive sequelae that manifest in PTSD. In particular, there are conflicting reports about deficits in executive function and mental flexibility. Even less is known about the neural changes that underlie such deficits. Here, we used magnetoencephalography to study differences in functional connectivity during a mental flexibility task in combat-related PTSD (all males, mean age = 37.4, n = 18) versus a military control (all males, mean age = 33.05, n = 19) group. We observed large-scale increases in theta connectivity in the PTSD group compared to controls. The PTSD group performance was compromised in the more attentionally demanding task and this was characterised by 'late-stage' theta hyperconnectivity, concentrated in network connections involving right parietal cortex. Furthermore, we observed significant correlations with the connectivity strength in this region with a number of cognitive-behavioural outcomes, including measures of attention, depression and anxiety. These findings suggest atypical coordination of neural synchronisation in large scale networks contributes to deficits in mental flexibility for PTSD populations in timed, attentionally-demanding tasks, and this propensity toward network hyperconnectivity may play a more general role in the cognitive sequelae evident in this disorder. PMID- 25909655 TI - Plasmodium falciparum in the southeastern Atlantic forest: a challenge to the bromeliad-malaria paradigm? AB - BACKGROUND: Recently an unexpectedly high prevalence of Plasmodium falciparum was found in asymptomatic blood donors living in the southeastern Brazilian Atlantic forest. The bromeliad-malaria paradigm assumes that transmission of Plasmodium vivax and Plasmodium malariae involves species of the subgenus Kerteszia of Anopheles and only a few cases of P. vivax malaria are reported annually in this region. The expectations of this paradigm are a low prevalence of P. vivax and a null prevalence of P. falciparum. Therefore, the aim of this study was to verify if P. falciparum is actively circulating in the southeastern Brazilian Atlantic forest remains. METHODS: In this study, anophelines were collected with Shannon and CDC-light traps in seven distinct Atlantic forest landscapes over a 4-month period. Field-collected Anopheles mosquitoes were tested by real-time PCR assay in pools of ten, and then each mosquito from every positive pool, separately for P. falciparum and P. vivax. Genomic DNA of P. falciparum or P. vivax from positive anophelines was then amplified by traditional PCR for sequencing of the 18S ribosomal DNA to confirm Plasmodium species. Binomial probabilities were calculated to identify non-random results of the P. falciparum-infected anopheline findings. RESULTS: The overall proportion of anophelines naturally infected with P. falciparum was 4.4% (21/480) and only 0.8% (4/480) with P. vivax. All of the infected mosquitoes were found in intermixed natural and human modified environments and most were Anopheles cruzii (22/25 = 88%, 18 P. falciparum plus 4 P. vivax). Plasmodium falciparum was confirmed by sequencing in 76% (16/21) of positive mosquitoes, whereas P. vivax was confirmed in only 25% (1/4). Binomial probabilities suggest that P. falciparum actively circulates throughout the region and that there may be a threshold of the forested over human-modified environment ratio upon which the proportion of P. falciparum infected anophelines increases significantly. CONCLUSIONS: These results show that P. falciparum actively circulates, in higher proportion than P. vivax, among Anopheles mosquitoes of fragments of the southeastern Brazilian Atlantic forest. This finding challenges the classical bromeliad-malaria paradigm, which considers P. vivax circulation as the driver for the dynamics of residual malaria transmission in this region. PMID- 25909656 TI - Aldehyde Dehydrogenase Gene Superfamily in Populus: Organization and Expression Divergence between Paralogous Gene Pairs. AB - Aldehyde dehydrogenases (ALDHs) constitute a superfamily of NAD(P)+-dependent enzymes that catalyze the irreversible oxidation of a wide range of reactive aldehydes to their corresponding nontoxic carboxylic acids. ALDHs have been studied in many organisms from bacteria to mammals; however, no systematic analyses incorporating genome organization, gene structure, expression profiles, and cis-acting elements have been conducted in the model tree species Populus trichocarpa thus far. In this study, a comprehensive analysis of the Populus ALDH gene superfamily was performed. A total of 26 Populus ALDH genes were found to be distributed across 12 chromosomes. Genomic organization analysis indicated that purifying selection may have played a pivotal role in the retention and maintenance of PtALDH gene families. The exon-intron organizations of PtALDHs were highly conserved within the same family, suggesting that the members of the same family also may have conserved functionalities. Microarray data and qRT-PCR analysis indicated that most PtALDHs had distinct tissue-specific expression patterns. The specificity of cis-acting elements in the promoter regions of the PtALDHs and the divergence of expression patterns between nine paralogous PtALDH gene pairs suggested that gene duplications may have freed the duplicate genes from the functional constraints. The expression levels of some ALDHs were up- or down-regulated by various abiotic stresses, implying that the products of these genes may be involved in the adaptation of Populus to abiotic stresses. Overall, the data obtained from our investigation contribute to a better understanding of the complexity of the Populus ALDH gene superfamily and provide insights into the function and evolution of ALDH gene families in vascular plants. PMID- 25909657 TI - Transcriptome profiling reveals the regulatory mechanism underlying pollination dependent and parthenocarpic fruit set mainly mediated by auxin and gibberellin. AB - BACKGROUND: Fruit set is a key process for crop production in tomato which occurs after successful pollination and fertilization naturally. However, parthenocarpic fruit development can be uncoupled from fertilization triggered by exogenous auxin or gibberellins (GAs). Global transcriptome knowledge during fruit initiation would help to characterize the molecular mechanisms by which these two hormones regulate pollination-dependent and -independent fruit set. PRINCIPAL FINDINGS: In this work, digital gene expression tag profiling (DGE) technology was applied to compare the transcriptomes from pollinated and 2, 4-D/GA3-treated ovaries. Activation of carbohydrate metabolism, cell division and expansion as well as the down-regulation of MADS-box is a comprehensive regulatory pathway during pollination-dependent and parthenocarpic fruit set. The signaling cascades of auxin and GA are significantly modulated. The feedback regulations of Aux/IAAs and DELLA genes which functioned to fine-tune auxin and GA response respectively play fundamental roles in triggering fruit initiation. In addition, auxin regulates GA synthesis via up-regulation of GA20ox1 and down-regulation of KNOX. Accordingly, the effect of auxin on fruit set is mediated by GA via ARF2 and IAA9 down-regulation, suggesting that both pollination-dependent and parthenocarpic fruit set depend on the crosstalk between auxin and GA. SIGNIFICANCE: This study characterizes the transcriptomic features of ovary development and more importantly unravels the integral roles of auxin and GA on pollination-dependent and parthenocarpic fruit set. PMID- 25909658 TI - Is diabetes a risk factor for a severe clinical presentation of dengue?--review and meta-analysis. AB - BACKGROUND: The mean age of acute dengue has undergone a shift towards older ages. This fact points towards the relevance of assessing the influence of age related comorbidities, such as diabetes, on the clinical presentation of dengue episodes. Identification of factors associated with a severe presentation is of high relevance, because timely treatment is the most important intervention to avert complications and death. This review summarizes and evaluates the published evidence on the association between diabetes and the risk of a severe clinical presentation of dengue. METHODOLOGY/FINDINGS: A systematic literature review was conducted using the MEDLINE database to access any relevant association between dengue and diabetes. Five case-control studies (4 hospital-based, 1 population based) compared the prevalence of diabetes (self-reported or abstracted from medical records) of persons with dengue (acute or past; controls) and patients with severe clinical manifestations. All except one study were conducted before 2009 and all studies collected information towards WHO 1997 classification system. The reported odds ratios were formally summarized by random-effects meta analyses. A diagnosis of diabetes was associated with an increased risk for a severe clinical presentation of dengue (OR 1.75; 95% CI: 1.08-2.84, p = 0.022). CONCLUSIONS/SIGNIFICANCE: Large prospective studies that systematically and objectively obtain relevant signs and symptoms of dengue fever episodes as well as of hyperglycemia in the past, and at the time of dengue diagnosis, are needed to properly address the effect of diabetes on the clinical presentation of an acute dengue fever episode. The currently available epidemiological evidence is very limited and only suggestive. The increasing global prevalence of both dengue and diabetes justifies further studies. At this point, confirmation of dengue infection as early as possible in diabetes patients with fever if living in dengue endemic regions seems justified. The presence of this co-morbidity may warrant closer observation for glycemic control and adapted fluid management to diminish the risk for a severe clinical presentation of dengue. PMID- 25909660 TI - Monte Carlo calculated and experimentally determined output correction factors for small field detectors in Leksell Gamma Knife Perfexion beams. AB - The measurement of output factors (OF) for the small photon beams generated by Leksell Gamma Knife(r) (LGK) radiotherapy units is a challenge for the physicist due to the under or over estimation of these factors by a vast majority of the detectors commercially available. Output correction factors, introduced in the international formalism published by Alfonso (2008 Med. Phys. 35 5179-86), standardize the determination of OFs for small photon beams by correcting detector-reading ratios to yield OFs in terms of absorbed-dose ratios. In this work output correction factors for a number of detectors have been determined for LGK PerfexionTM (60)Co gamma-ray beams by Monte Carlo (MC) calculations and measurements. The calculations were made with the MC system PENELOPE, scoring the energy deposited in the active volume of the detectors and in a small volume of water; the detectors simulated were two silicon diodes, one liquid ionization chamber (LIC), alanine and TLD. The calculated LIC output correction factors were within +/- 0.4%, and this was selected as the reference detector for experimental determinations where output correction factors for twelve detectors were measured, normalizing their readings to those of the LIC. The MC-calculated and measured output correction factors for silicon diodes yielded corrections of up to 5% for the smallest LGK collimator size of 4 mm diameter. The air ionization chamber measurements led to extremely large output correction factors, caused by the well-known effect of partial volume averaging. The corrections were up to 7% for the natural diamond detector in the 4 mm collimator, also due to partial volume averaging, and decreased to within about +/- 0.6% for the smaller synthetic diamond detector. The LIC, showing the smallest corrections, was used to investigate machine-to-machine output factor differences by performing measurements in four LGK units with different dose rates. These resulted in OFs within +/- 0.6% and +/- 0.2% for the 4 mm and 8 mm collimators, respectively, providing evidence for the use of generic OFs for these LGK beams. Using the experimentally derived output correction factors, OFs can be measured using a wide range of commercially available detectors. PMID- 25909659 TI - Identification of MicroRNAs and their Targets Associated with Embryo Abortion during Chrysanthemum Cross Breeding via High-Throughput Sequencing. AB - BACKGROUND: MicroRNAs (miRNAs) are important regulators in plant development. They post-transcriptionally regulate gene expression during various biological and metabolic processes by binding to the 3'-untranslated region of target mRNAs to facilitate mRNA degradation or inhibit translation. Chrysanthemum (Chrysanthemum morifolium) is one of the most important ornamental flowers with increasing demand each year. However, embryo abortion is the main reason for chrysanthemum cross breeding failure. To date, there have been no experiments examining the expression of miRNAs associated with chrysanthemum embryo development. Therefore, we sequenced three small RNA libraries to identify miRNAs and their functions. Our results will provide molecular insights into chrysanthemum embryo abortion. RESULTS: Three small RNA libraries were built from normal chrysanthemum ovules at 12 days after pollination (DAP), and normal and abnormal chrysanthemum ovules at 18 DAP. We validated 228 miRNAs with significant changes in expression frequency during embryonic development. Comparative profiling revealed that 69 miRNAs exhibited significant differential expression between normal and abnormal embryos at 18 DAP. In addition, a total of 1037 miRNA target genes were predicted, and their annotations were defined by transcriptome data. Target genes associated with metabolic pathways were most highly represented according to the annotation. Moreover, 52 predicted target genes were identified to be associated with embryonic development, including 31 transcription factors and 21 additional genes. Gene ontology (GO) annotation also revealed that high-ranking miRNA target genes related to cellular processes and metabolic processes were involved in transcription regulation and the embryo developmental process. CONCLUSIONS: The present study generated three miRNA libraries and gained information on miRNAs and their targets in the chrysanthemum embryo. These results enrich the growing database of new miRNAs and lay the foundation for the further understanding of miRNA biological function in the regulation of chrysanthemum embryo abortion. PMID- 25909661 TI - Poly(ethylene oxide) functionalized polyimide-based microporous films to prevent bacterial adhesion. AB - Preventing microbial adhesion onto membranes is a crucial issue that determines the durability of the membrane. In this Research Article, we prepared aromatic polyimides (extensively employed for the elaboration of ultrafiltration membranes) containing PEO branches. Four polyimide-g-PEO copolymers were prepared from 6F dianhydride and a novel aromatic diamine containing PEO-550 side groups. The copolymers were designed to have variable PEO content, and were characterized by their spectroscopic and physical properties. The Breath Figure technique was successfully applied to create an ordered surface topography, where the PEO chains were preferentially located on the surface of the micrometer size holes. These unique features were explored to reduce bacterial adhesion. It was established that surface modified polyimide membranes have a high resistance to biofouling against Staphylococcus aureus. In particular, we observed that an increase of the PEO the content in the copolymer produced a decrease in the bacterial adhesion. PMID- 25909662 TI - Lamellar keratoplasty in rabbits using human and rabbit amniotic membrane grafts: a comparative study. AB - OBJECTIVE: To compare the behavior of human and rabbit amniotic membrane (AM) grafts in surgically induced corneal thinning in rabbits. ANIMALS STUDIED: Thirty two NZWR were randomly assigned to two groups of 16 animals each according to AM type (Human AM: group HAM and Rabbit AM: group RAM). PROCEDURE: All animals were submitted to right keratectomy at a depth of 0.1 mm using a 5 mm trephine. Animals from HAM group had a button of 5 mm of human AM sutured into the corneal bed with a continuous pattern and 10.0 nylon monofilament suture, while animals from the RAM group had a button of 6 mm diameter of rabbit AM. Four animals in each group were euthanized 2, 7, 15, and 30 days postoperatively. Their corneas were harvested, fixed in 2% glutaraldehyde solution, and stained with haematoxylin-eosin, picrosirius red, and alcian blue for evaluation under light optical microscopy. Microscope images were digitalized and inflammatory cells and stromal blood vessels were counted. RESULTS: There were no clinically significant differences between groups, and complete corneal epithelialization was observed in all animals in 30 days. Light optical microscopy revealed AM incorporation and resorption in both groups. However, the number of inflammatory cells and blood vessels was significantly higher in group HAM than in group RAM (P < 0.05, Mann Whitney test). Clinical responses to human or rabbit AM were similar; however, human AM induced greater inflammatory reaction and stromal neovascularization in the rabbit cornea than in rabbit AM. CONCLUSION: These differences may reflect a potential reaction to the xenograft. More studies are needed to further characterize these findings. PMID- 25909663 TI - Exploring the Cervical Cancer Screening Experiences of Black Lesbian, Bisexual, and Queer Women: The Role of Patient-Provider Communication. AB - Few studies have focused on the health and health care of U.S. black lesbian, bisexual, and queer (LBQ) women. To understand the facilitators of and barriers to cervical cancer screening in this population, focus group discussions were conducted in Boston and Cambridge, Massachusetts between November and December 2012. Using purposive sampling methods, the authors enrolled 18 black LBQ women who participated in one of four focus groups. Using thematic analysis, patient provider communication was identified, which consisted of four sub-themes--health care provider communication style and demeanor; heteronormative provider assumptions; heterosexism, racism, and classism; and provider professional and sociodemographic background--as the most salient theme. Participants reported fears and experiences of multiple forms of discrimination and preferred receiving care from providers who were knowledgeable about same-sex sexual health and shared their life experiences at the intersection of gender, race/ethnicity, and sexual orientation. The cervical cancer screening experiences of black LBQ women would be improved by training all health care providers in same-sex sexual health, offering opportunities for clinicians to learn about the effects of various forms of discrimination on women's health care, and increasing the presence of LBQ women of color in health care settings. PMID- 25909664 TI - [The system of prophylaxis in otorhinolaryngology]. AB - This publication is focused on the modern basis behind the system for the prevention of acute and chronic ENT diseases with special reference to the compliance with the principles of primary, secondary, and tertiary prophylaxis. The special emphasis is laid on the role of the otorhinolaryngologist in the formation of the healthy lifestyle, organization of regular medical examination and rehabilitative treatment of the population. A detailed description of the activities of an otorhinolaryngologist in the framework of mass prophylaxis programs is presented. The main drawbacks of the current normative-regulatory documentation are discussed. It is concluded, based on the analysis of ENT morbidity among the Russian population, that the participation of otorhinolaryngologists is indispensable at the first, second, and third stages of regular medical examination. The modern regulations for the prophylaxis of occupational ENT diseases are considered. PMID- 25909665 TI - [Sensorineural hearing impairment in combination with mycoplasma infection]. AB - The objective of the present study was to elucidate the incidence of mycoplasma infection concomitant with sensorineural hearing impairment and its clinical manifestations with special reference to the methods for its diagnostics and treatment. The main method for the detection of mycoplasma infection is PCR in real time and the auxiliary one is the immunoenzymatic assay. The study revealed mycoplasma infection in 15 (13.9%) of the examined patients. The results of our investigations give evidence of the necessity to further study the clinical symptoms of mycoplasma infection associated with sensorineural hearing impairment and to search for the methods of the management of this condition. PMID- 25909666 TI - [The level of beta-endorphin, chronic stress, and depression associated with vestibular pathology]. AB - The objective of the present study was to evaluate the presence and the severity of manifestations of anxiety and depression in the patients presenting with vestibular dysfunction making use of the psychometric scales and taking into consideration variations in the plasma beta-endorphin level as a biochemical marker before and after medicamental and physical rehabilitative treatment. A total of 8 patients presenting with stage I-III Meniere's disease and 8 patients suffering from dyscirculatory encephalopathy concomitant with vestibular ataxic syndrome were available for the observation. We separately analysed the results of examination of two patients with vestibular neuronitis and two others presenting with vestibular migraine. It was shown that the degree of anxiety and depression correlated with the plasma beta-endorphin level whereas its correlation with the severity of vestibular oculomotor and vestibular motor disorders during the inter-bout periods was not documented. It was demonstrated that the plasma beta-endorphin level was many times higher than the normal value of 20 ng/l in the patients with the well apparent vegetative symptoms accompanied by dizziness and the patients suffering from vegetative migraine. PMID- 25909667 TI - [The influence of dead lymphocytes from middle ear secretion on the development of sensorineural hearing impairment associated with acute otitis media]. AB - The objective of the present work was to estimate the number of lymphocytes in the middle ear secretion that had died as a result of apoptosis or necrosis in the patients presenting with acute otitis media and to elucidate the relationship between this phenomenon and the development of sensorineural impairment of hearing. The study included a total of 106 patients suffering from acute middle otitis allocated two groups. Group 1 was comprised of 75 (70.8%) patients with hearing loss of the conductive type alone while group 2 contained 31 (29.2%) patients with the combined type of hearing loss. The contents of the tympanic cavity was obtained by means of tympanic puncture, the lymphocytes isolated from middle ear secretion were studied with the use of a flow cytometer in order to determine the number of dead cells. In the patients of group 1, 15.2+/-0.6% and 10.6+/-0.5% of all lymphocytes underwent apoptosis and necrosis respectively. In the patients of group, lymphocyte apoptosis was observed in 24.7+/-1.% of the cases (p<0.05) and necrosis in 14.0+/-0.5% ones (p<0.05). It was shown that liberation of intracellular proteolytic enzymes and cytokines taking place largely in the course of necrosis activates phagocytosis, stimulates the inflammatory reaction, and thereby promotes resolution of the pathological processes in the middle ear due to the prevention of their extension into the labyrinth. PMID- 25909668 TI - [The ototoxic action of cisplatin on the middle ear]. AB - The objective of the present study was to elucidate the mechanisms underlying the ototoxic action of cisplatin after its single administration using an experimental model (white mice). Short latency acoustically evoked potentials (SAEP) and distortion-product otoacoustic emissions (DPOAE) were recorded for the purpose. The results of the study confirm the possibility of using the proposed model for the estimation of the cisplatin-induced loss of hearing. It was shown that a single cisplatin dose causes hearing impairment in the mice within 7 days after its administration; with the maximum effect becoming apparent on day 30. PMID- 25909669 TI - [Cholesteatoma of the external and middle ear in the childhood]. AB - The objective of the present work was to enhance the effectiveness of diagnostics of cholesteatoma of the external and middle ear in the children. The study included 66 patients presenting with chronic suppurative otitis media and one child having cholesteatoma of the external auditory meatus. All the patients were examined with the use of otoendoscopy and CT of the temporal bones. It was shown that the frequent occurrence of acute suppurative otitis media, exudative suppurative otitis media, and adhesive otitis media is the risk factor of the development of cholesteatoma of the external and middle ear in the children. The following CT features of cholesteatoma of the external ear were revealed: the sclerotic or mixed type of the mastoid process, the presence of pathological contents in the epitympanic space, homogeneous character of pathological contents in the antrum, widened aditus, caries of antrum walls, the presence of soft tissues around the auditory ossicles, destruction of the long process of the anval bone, and a soft-tissue structure in the external auditory meatus. PMID- 25909670 TI - [Pedagogical rehabilitation of deaf pre-school children following cochlear implantation]. AB - This publication was designed to summarize the results of the long-term study with the purpose of developing a scientific and methodological approach to rehabilitation of the children having cochlear implants. The main emphasis is laid on the initial (launching) stage of rehabilitative measures aimed at the reconstruction of the sensory basis of communication and interaction with the surrounding hearing subjects taking into consideration peculiarities of the children who experienced the loss of hearing late in their life and deaf children with different levels of speech development. The main corrective measures are described to be taken at the initial stage of rehabilitation of the young and pre school children unable to speak by the time of prescribed cochlear implantation. The markers of completion of the initial phase of the rehabilitative period are identified indicating transition of a child toward the normal development as a result of cochlear implantation. The author discusses the results of corrective pedagogical measures that can be achieved by their adequate organization and consistent implementation. PMID- 25909671 TI - [The characteristic of middle ear microflora in the patients presenting with chronic otitis media in the Transbaikal Krai]. AB - The objective of the present work was to study the characteristics of middle ear microflora in the patients presenting with chronic suppurative otitis media (CSOM), clarify changes in its species composition over the territory of the Transbaikal Krai during the period from 2000 till 2013, and elucidate its dependence on the treatment prescribed with due regard for sensitivity of microorganisms to medications. The results of 13 year observations of the bacterial contents and resistance of microflora to antibacterial preparations in the middle ear of the patients suffering from CSOM in the Transbaikal Krai are presented. PMID- 25909672 TI - [Tympanometry in premature babies during the first year of life]. AB - The objective of the present work was to study the tympanograms of the premature infants during the first year of their life and to determine the optimal time for performing high-frequency and low-frequency tympanometry in the babies of different gestational age. It was shown that the middle ear as an apparatus of the sound-transmitting system becomes to function stably by the 6th month of life although the mechanisms for regulation of stabilization develop only in the end of the first year. For this reason, tympanometry in the children of the gestational age 29 - 32 , 33 - 37 i 38 - 40 weeks should be performed using two frequencies of the probing tone (226 Hz and 1 kHz) up to the 6 months of life inclusive and from 28 weeks to 1 year.Key words: premature baby, tympanometry, acoustic function. PMID- 25909673 TI - [Papillomatosis as a criteria for the formation of the group at risk of laryngeal cancer]. AB - The objective of the present study was to determine the incidence of dysplastic pre-neoplastic alterations in the patients presenting with papillomatosis. The results of the clinical, endoscopic, and morphological examination of 42 patients presenting with laryngeal papillomas made it possible to diagnose grade II-III laryngeal cancer in 7 (16.7%) patients. Half of them exhibited pre-neoplastic changes in laryngeal mucosa. The following criteria for the formation of laryngeal cancer risk groups, besides grade II-III epithelial dysplasia, were identified: long (over 12 months) history of papillomatosis, human papilloma virus infection, the history of smoking over 20 years, professional contacts with petroleum, oil, and lubrication materials, and the male gender. An algorithm of observation and treatment for each group of patients differing in the degree of dysplastic changes in laryngeal mucosa was proposed. It is concluded that adequate clinical and endoscopic monitoring of the patients at risk of laryngeal cancer makes it possible to increase the frequency of detection of this condition at the early stages of its development. PMID- 25909674 TI - [The electron microscopic study of tumour-like structures on the vocal cords]. AB - We have undertaken the electron microscopic investigation into peculiarities of six tumour-like structures on the vocal cords. The study has demonstrated changes in the number and distribution patterns of intercellular junctions, keratin and tonofilament contents in epithelial cells, basal membrane structure, and composition of the basic substance in lamina propria. All the examined tumour like structures contained bacteria an two of them had viral particles in vacuoles of fibroblasts. Moreover, the bacteria were found on the surface of epithelium, between epithelial cells and in the basic substance in lamina propria. Cytoplasm of epithelial cells and fibroblasts not infrequently contained bacteria in the phase of division. PMID- 25909675 TI - [Variations of clinical and functional characteristics of nasal cavity mucosa in the patients of different age groups presenting with acute rhinosinusitis]. AB - The objective of the present study was to evaluate changes in the functional properties of nasal cavity mucosa during the treatment of the patients of different age groups presenting with acute rhinosinusitis. The following methods were used for the purpose: daily measurement of pH, body temperature, pain sensitivity threshold in the intranasal mucous membrane, mucociliary transport (MCT) time; in addition, joulemetry was performed to examine the patients suffering from acute rhinosinusitis. The study has demonstrated marked differences in the functional conditions of nasal cavity mucosa associated with the treatment. The aged and elderly patients were characterized by lowered mucosal temperature at all stages of therapy, elevated pain sensitivity threshold, and long duration of the recovery of ciliary epithelium activity that reflected non-responsiveness inherent in the patients of this age group. The direct joulemetry technique made possible the most detailed evaluation of dynamics of these pathological changes in nasal cavity mucosa and its age specific features. It is concluded that the clinical manifestations of acute rhinosinusitis are characterized by well apparent age-specific features that should be taken into consideration in diagnostics and treatment of this condition. The comprehensive evaluation of the parameters of the functional state of nasal cavity mucosa associated with this pathology allows the severity of inflammation and the effectiveness of its treatment to be estimated; moreover, it permits to correcte in due time the scope of the prescribed therapy. PMID- 25909676 TI - [The results of a comparative randomized study on the effectiveness of various methods for the correction of the nasal valve: the subjective evaluation]. AB - The objective of the present study was to compare the effectiveness of several extensively used techniques for the correction of the nasal valve in terms of the main clinical manifestations with the application of various scales for subjective evaluation of the outcomes of the treatment. It was demonstrated in the course of this prospective study that the patients described the elimination of nasal valve dysfunction with the help of expanding transplants as the most effective method in terms of the improvement of nasal breathing and the achievement of the acceptable aesthetic results. The plastic correction with the use of local tissues was reported to be less efficacious even if ensuring the stable result. This method did not worsen the shape of the nose but failed to remove its existing cosmetic defect. As far as the aesthetic outcome of the treatment is concerned, the suture correction technique was recognized to be the least efficacious approach because it resulted in the deterioration of the nose shape in more than half of the cases. PMID- 25909677 TI - [The specific features of vegetative disorders in the children presenting with rhinosinusitis]. AB - The authors examined 79 children presenting with rhinosinusitis. The objective of the study was to evaluate the state of the autonomous nervous system in these patients. The vegetative tone was determined with the use of the Wayne tables and questionnaires based on the results of the Preveli and Danielopulo tests. The functional condition of the myocardium was assessed by ECG and echocardiography. It was shown that the acute period of rhinosinusitis was more frequently associated with the development of asthenoneurotic syndrome, emotional lability, and changes of arterial pressure than with other symptoms of vegetative dysfunction. The pathological changes suggesting the functional disorders were recorded on ECG in 63.3% of the patients while the echocardiographic studies revealed alterations in the valvular apparatus in 40.5% of the cases. PMID- 25909678 TI - [The enhancement of the efficacy of early diagnostics of laryngopharyngeal reflux]. AB - The objective of the present study was to improve early diagnostics of extraoesophageal reflux (EGER) disease encountered in the routine otorhinolaryngological practice. The questionnaire for rapid diagnostics of gastroesophageal reflux disease (GERDq), the heartburn severity scoring scale (HBSS), and the reflux symptom index (RSI) were used to estimate the conditions of 91 patients at the age varying from 17 to 72 years meeting the inclusion criteria. The patients were interviewed based on these three scoring systems during the initial consultation and after the test with a proton pipe inhibitor (PPI). The results were used to allocate the patients to two groups one of which was comprised of those with complaints of suffering from heartburn (n=61), the other included the patients free from the heartburn symptoms (n=30). The RSI scores suggested the statistically significant decrease in the symptoms of laryngopharyngeal reflux in the patients of both groups after the test with PPI. The GERD questionnaire was found to be insufficiently informative. It is concluded that the patients complaining of heartburn should be examined first with the help of the heartburn severity scale and then based on RSI. The latter approach should be employed to examine the patients presenting with the clinical symptoms of laryngopharyngeal reflux in the absence of heartburn. The PPI test makes it possible to confirm the presence of laryngopharyngeal reflux and a decrease in its clinical manifestations. PMID- 25909679 TI - [The experience with the reconstruction of the superoposterior wall of the external auditory meatus during stapedoplasty]. AB - The objective of the present study was to improve the effectiveness of stapedoplasty by developing the method for the prevention of the formation of retraction pockets in the tympanic membrane and cicatrical fixation of auditory ossicles. A total of 60 patients presenting with grade I-II otosclerosis and conductive or mixed-type hearing impairment were surgically treated during the period from 2008 to 2014. Twenty four of these patients had undergone stapedoplasty in the preceding period in different clinics that either failed to improve their conditions or resulted in their deterioration. A new method was proposed for the reconstruction of the superoposterior wall of the auditory canal during stapedoplasty that consists of the replacement of the removed fragment by the last 150-200 mcm ultrathin allocartilaginous plate. This plate prevented the subsequent retraction of the superoposterior portions of the tympanic membrane and its fusion with either the long process of the anvil bone or the prosthetic ring. The method of this operation is described. The analysis of long-term results of the treatment confirmed the high effectiveness of the proposed approach. PMID- 25909680 TI - [About the surgical treatment of vestibular window abnormalities]. AB - The objective of the present study was to develop the sparing strategy for the surgical treatment of the patients presenting with malformations of the vestibular window based on the results of the evaluation of synopty of the main clues of the internal and middle ears. This article contains the analysis of the effectiveness of the surgical treatment of 17 patients with malformations of the vestibular window operated during the period from 2008 till 2013. It presents the results of investigations into the topographic relationships between the principal structures of the internal and middle ears of special importance for the assessment of the possibilities for the surgical treatment of such patients with the minimal risk of development of postoperative complications. The results of the surgical treatment were estimated based on the data of audiological studies in the early and late postoperative periods. It was shown that none of the patients developed the symptoms of dizziness, unstable gait or sensorineural impairment of hearing in the immediate postoperative period. Good functional results in the form of the reduced bone-air interval (15.2+/-1.0 dB) were achieved in 13 patients. Nevertheless, the considerable decrease in the sound conductivity in the late postoperative period observed in 64.7% of the patients related to the closure of the vestibular fistula dictates the necessity of developing the novel techniques for its prevention. PMID- 25909681 TI - [The assessment of the clinical effectiveness of fenspiride for the treatment of acute obstruction of the Eustachian tube]. AB - The objective of the present study was to estimate the clinical effectiveness of fenspiride used to correct the obstruction of the Eustachian tube in 80 patients presenting with acute tubootitis and exudative otitis media. The algorithm of the examination included the evaluation of the severity of subjective clinical symptoms based on the relevant analog-visual scale, results of tonal audiometry, and tympanometry. The control group was comprised of 34 patients treated with antibacterial preparations, topical decongestants, and transtubal administration of glucocorticoids. The study group included 46 patients who received fenspiride at a dose of 80 mg thrice daily in addition to the above pharmacotherapy. The severity of clinical symptoms in the patients treated with fenspiride decreased faster than in the control subjects. The frequency analysis of dynamics of the air-bone gaps on the audiometric curves revealed the significantly more intensive recovery of the hearing function in the patients treated by basal pharmacotherapy in the combination with fenspiride. Type A tympanograms predominated on day 7 after the onset of the conservative treatment with the use of fenspiride whereas type C tympanograms continued to predominate in the patients of the control group. It is concluded that the introduction of fenspiride into combined therapy of acute tubootitis and exudative otitis media promotes the normalization of the ventilation and drainage functions and relieves the severity of subjective clinical symptoms. PMID- 25909682 TI - [Diagnostics of neoplasms of the nasal cavity and paranasal sinuses]. AB - The objective of the present work was to address earlier diagnostics of benign and malignant tumours in the nasal cavity and paranasal sinuses with a view to its improvemen. The immunohistochemical study and the analysis of its results made possible not only differential diagnostics of the tumorigenic processes in the nasal cavity and paranasal sinuses but also the estimation of the qualitative potential of each neoplasm. The immunohistochemical study demonstrated that the development of cancer of the nasal cavity and paranasal sinuses was associated with a substantial increase in the proliferative activity of epithelium and the appearance of a large amount of the mutant P53 protein in the atypical cells. The cells of inverted papilloma and unaffected epithelium exhibited only weak proliferative activity, contained cytokeratin-8 in their cytoplasm, and did not express a pathological receptor protein at the cytoplasmic membrane surface. PMID- 25909683 TI - Evaluation of vaccine seroresponse rates and adverse event rates through Bayesian and frequentist methods. AB - In the evaluation of vaccine seroresponse rates and adverse reaction rates, extreme test results often occur, with substantial adverse event rates of 0% and/or seroresponse rates of 100%, which has produced several data challenges. Few studies have used both the Bayesian and frequentist methods on the same sets of data that contain extreme test cases to evaluate vaccine safety and immunogenicity. In this study, Bayesian methods were introduced, and the comparison with frequentist methods was made based on practical cases from randomized controlled vaccine trials and a simulation experiment to examine the rationality of the Bayesian methods. The results demonstrated that the Bayesian non-informative method obtained lower limits (for extreme cases of 100%) and upper limits (for extreme cases of zero), which were similar to the limits that were identified with the frequentist method. The frequentist rate estimates and corresponding confidence intervals (CIs) for extreme cases of 0 or 100% always equaled and included 0 or 100%, respectively, whereas the Bayesian estimations varied depending on the sample size, with none equaling zero or 100%. The Bayesian method obtained more reasonable interval estimates of the rates with extreme data compared with the frequentist method, whereas the frequentist method objectively expressed the outcomes of clinical vaccine trials. The two types of statistical results are complementary, and it is proposed that the Bayesian and frequentist methods should be combined to more comprehensively evaluate clinical vaccine trials. PMID- 25909684 TI - Spot the difference: Operational event sequence diagrams as a formal method for work allocation in the development of single-pilot operations for commercial aircraft. AB - Function Allocation methods are important for the appropriate allocation of tasks between humans and automated systems. It is proposed that Operational Event Sequence Diagrams (OESDs) provide a simple yet rigorous basis upon which allocation of work can be assessed. This is illustrated with respect to a design concept for a passenger aircraft flown by just a single pilot where the objective is to replace or supplement functions normally undertaken by the second pilot with advanced automation. A scenario-based analysis (take off) was used in which there would normally be considerable demands and interactions with the second pilot. The OESD analyses indicate those tasks that would be suitable for allocation to automated assistance on the flight deck and those tasks that are now redundant in this new configuration (something that other formal Function Allocation approaches cannot identify). Furthermore, OESDs are demonstrated to be an easy to apply and flexible approach to the allocation of function in prospective systems. PRACTITIONER SUMMARY: OESDs provide a simple yet rigorous basis upon which allocation of work can be assessed. The technique can deal with the flexible, dynamic allocation of work and the deletion of functions no longer required. This is illustrated using a novel design concept for a single-crew commercial aircraft. PMID- 25909685 TI - Fluorinated carbide-derived carbon: more hydrophilic, yet apparently more hydrophobic. AB - We explore the effect of fluorine doping on hydrophobicity of nanoporous silicon carbide-derived carbon (SiCDC), and investigate the underlying barriers for adsorption and diffusion of water vapor and CO2 in the fluorinated and nonfluorinated structures. We develop atomistic models of fluorine-doped SiCDC at three different levels of fluorination, based on a hybrid reverse Monte Carlo constructed model of SiCDC, and develop a novel first-principles force field for the simulation of adsorption and transport of water and CO2 in the fluorine-doped carbon materials. We demonstrate an apparent dual effect of fluorination, showing that while fluorination generates more hydrophilic carbon surfaces, they actually act as more hydrophobic structures due to enhanced energy barriers in the disordered network of microporous carbon. While an increase in adsorption energy and in water uptake is seen for fluorine-doped carbon, large internal free energy barriers as well as the results of MD simulations demonstrate that the increased adsorption is kinetically limited and not experimentally observable on practical time scales. We show that an increase in apparent hydrophobicity due to fluorination is mediated by larger free energy barriers arising from stronger binding of fluid molecules inside the pore network, as opposed to repulsion or steric hindrance to the diffusion of molecules through narrow pore entries. For carbon dioxide, adsorption enthalpies and activation energy barriers are both decreased on fluorination, indicating weakened solid-fluid binding energies in the fluorinated systems. PMID- 25909686 TI - Droplet-interface-bilayer assays in microfluidic passive networks. AB - Basic biophysical studies and pharmacological processes can be investigated by mimicking the intracellular and extracellular environments across an artificial cell membrane construct. The ability to reproduce in vitro simplified scenarios found in live cell membranes in an automated manner has great potential for a variety of synthetic biology and compound screening applications. Here, we present a fully integrated microfluidic system for the production of artificial lipid bilayers based on the miniaturisation of droplet-interface-bilayer (DIB) techniques. The platform uses a microfluidic design that enables the controlled positioning and storage of phospholipid-stabilized water-in-oil droplets, leading successfully to the scalable and automated formation of arrays of DIBs to mimic cell membrane processes. To ensure robustness of operation, we have investigated how lipid concentration, immiscible phase flow velocities and the device geometrical parameters affect the system performance. Finally, we produced proof of-concept data showing that diffusive transport of molecules and ions across on chip DIBs can be studied and quantified using fluorescence-based assays. PMID- 25909688 TI - Photocurrent generation with two-dimensional van der Waals semiconductors. AB - Two-dimensional (2D) materials have attracted a great deal of interest in recent years. This family of materials allows for the realization of versatile electronic devices and holds promise for next-generation (opto)electronics. Their electronic properties strongly depend on the number of layers, making them interesting from a fundamental standpoint. For electronic applications, semiconducting 2D materials benefit from sizable mobilities and large on/off ratios, due to the large modulation achievable via the gate field-effect. Moreover, being mechanically strong and flexible, these materials can withstand large strain (>10%) before rupture, making them interesting for strain engineering and flexible devices. Even in their single layer form, semiconducting 2D materials have demonstrated efficient light absorption, enabling large responsivity in photodetectors. Therefore, semiconducting layered 2D materials are strong candidates for optoelectronic applications, especially for photodetection. Here, we review the state-of-the-art in photodetectors based on semiconducting 2D materials, focusing on the transition metal dichalcogenides, novel van der Waals materials, black phosphorus, and heterostructures. PMID- 25909687 TI - Association of arsenic with kidney function in adolescents and young adults: Results from the National Health and Nutrition Examination Survey 2009-2012. AB - BACKGROUND: Long-term exposure to arsenic is a major public health concern. Emerging evidence suggests adverse health effects even at low levels of exposure. This study examined the association of arsenic exposure with estimated glomerular filtration rate (eGFR) and compared methods of adjustment for urinary dilution in a representative sample of U.S. adolescents and young adults. METHODS: We performed a cross-sectional study of 1253 participants ages 12-30 years in the 2009-2012 National Health and Nutrition Examination Survey (NHANES) with available urinary arsenic and eGFR measures. Multivariable linear regression was used to model the association of urinary total arsenic and dimethylarsinate (DMA) with eGFR. RESULTS: The median urinary total arsenic and DMA concentrations were 6.3 MUg/L (IQR 3.3-12.7 MUg/L) and 3.3 MUg/L (IQR 1.7-5.7 MUg/L), respectively. Median eGFR was 109 mL/min/1.73 m(2). Adjusting arsenic for urine concentration with urinary creatinine, eGFR was 4.0 mL/min/1.73 m(2) higher (95% confidence interval [CI] 1.0-7.1 mL/min/1.73 m(2)) and 4.3mL/min/1.73 m(2) higher (95% CI 0.5-8.0 mL/min/1.73 m(2)) per log-unit increase in total arsenic and DMA, respectively. When using urine osmolality to adjust for urine concentration, a log-unit increase in total arsenic and DMA was associated with a 0.4 mL/min/1.73 m(2) (95% CI -1.8 to 1.1 mL/min/1.73 m(2)) and 0.01 (95% CI -1.9 to 1.9 mL/min/1.73 m(2)) lower eGFR, respectively. CONCLUSIONS: Discordant associations were observed between arsenic and eGFR levels depending on whether urinary creatinine or osmolality was used to adjust for urine concentration. Further study should be dedicated to validating the best approach to account for urinary dilution in research in toxicants, and this may have implications for all studies which examine urinary biomarkers. PMID- 25909689 TI - Theoretical investigations into the electronic structures and electron transport properties of fluorine and carbonyl end-functionalized quarterthiophenes. AB - In this work, we concentrate on systematic investigation on the fluorination and carbonylation effect on electron transport properties of thiophene-based materials with the aim of seeking and designing electron transport materials. Some relative factors, namely, frontier molecular orbital (FMO), vertical electron affinity (VEA), electron reorganization energy (lambdaele), electron transfer integral (tele), electron drift mobility (MUele) and band structures have been calculated and discussed based on density functional theory. The results show that the introduction of fluorine atoms and carbonyl group especially for the latter could effectively increase EA and reduce lambdaele, which is beneficial to the improvement of electron transport performance. Furthermore, these introductions could also affect the tele by changing molecular packing manner and distribution of FMO. Finally, according to our calculation, the 3d system is considered to be a promising electron transport material with small lambdaele, high electron transport ability and good ambient stability. PMID- 25909690 TI - Diaryl-Substituted (Dihydro)pyrrolo[3,2,1-hi]indoles, a Class of Potent COX-2 Inhibitors with Tricyclic Core Structure. AB - A new compound class of diaryl-substituted heterocycles with tricyclic dihydropyrrolo[3,2,1-hi]indole and pyrrolo[3,2,1-hi]indole core structures has been designed and was synthesized by a modular sequence of Friedel-Crafts acylation, amide formation, and McMurry cyclization. This synthesis route represents a novel and versatile access toward dihydropyrrolo[3,2,1-hi]indoles and is characterized by good chemical yields and high modularity. From a set of 19 derivatives, 11 candidates were selected for determination of their COX inhibition potency and were found to be selective inhibitors with high affinity to COX-2 (IC50 ranging from 20-2500 nM and negligible inhibition of COX-1). The binding mode of the novel inhibitors in the active side of COX-2 was calculated in silico using the protein-ligand docking program GOLD by application of the molecular structures of two compounds derived from X-ray crystallography. Two novel compounds with high affinity to COX-2 (6k = 70 nM, 8e = 60 nM) have a fluoro substituent, making them promising candidates for the development of (18)F radiolabeled COX-2 inhibitors for imaging purposes with positron emission tomography (PET). PMID- 25909691 TI - Numerical study of the most stable contact angle of drops on tilted surfaces. AB - We present results for the most stable contact angle using a numerical implementation of the tilting plate method of Montes et al. (Montes Ruiz-Cabello, F. J.; Rodriguez-Valverde, M. A.; Cabrerizo-Vilchez, M. Soft Matter 2011, 7, 10457-10461). Comparison with the experimental results is made, obtaining a good agreement in most situations. In addition, the evolution of the contact angles of a tilted drop with a fixed circular line is analyzed. This analysis allows one to theoretically predict the most stable contact angle for tilted drops. PMID- 25909692 TI - Fibre intake and blood pressure: more facts, more questions. PMID- 25909693 TI - NT-proBNP and the risk of incident hypertension: is change over time a better predictor than baseline value? PMID- 25909694 TI - Aortic wave speed: two-point and peripheral pressure methods compared with the gold standard. PMID- 25909695 TI - Microvascular function: disturbed by obesity and rescued by angiotensin blockade. PMID- 25909696 TI - Blood pressure-lowering treatment in acute intracerebral haemorrhage. PMID- 25909697 TI - High blood pressure and associated risk factors among women attending antenatal clinics in Tanzania. AB - AIM: Hypertension during pregnancy (HDP) is one of the leading causes of maternal and perinatal mortality worldwide. This study examined prevalence and potential risk factors for HDP among pregnant women in Tanzania. METHODS: We examined 910 pregnant women, aged at least 20 years, mean gestational age 27 weeks, from rural (n = 301) and urban (n = 609) areas, during their usual antenatal clinic visits. Hypertension was defined as clinic SBP at least 140 mmHg or DBP at least 90 mmHg. Dietary assessment included dietary diversity score using 16 food groups. Multiple logistic regression analysis was used to assess the independent association of risk factors associated with prevalence of hypertension. RESULTS: A total of 62 women (6.9%) had HDP, prevalence being higher in urban (8.1%) compared to rural area (4.4%). For the urban area, mother's age [odds ratio (OR) 1.10, 95% confidence interval (CI) 1.03-1.20], gestational age (OR 1.10, 95% CI 1.02-1.20), mid-upper arm circumference (OR 1.13, 95% CI 1.01-1.23), dietary diversity score (OR 1.31, 95% CI 1.20-1.60) and being HIV-positive (OR 2.40, 95% CI 1.10-5.18) were independently associated with HDP. When adjusted for proteinuria, associations with HIV status and mid-upper arm circumference weakened. In the rural area, HDP risk increased with age and gestational age. CONCLUSION: Prevalence of HDP was higher in urban compared to rural area, which points at high risk for preterm delivery, low birth weight and future cardiovascular diseases. The observed risk factors identify risk groups to be screened and targeted for prevention. The role of HIV status needs to be further explored. PMID- 25909699 TI - Suppression of transient receptor potential melastatin 4 expression promotes conversion of endothelial cells into fibroblasts via transforming growth factor/activin receptor-like kinase 5 pathway. AB - OBJECTIVE: To study whether transient receptor potential melastatin 4 (TRPM4) participates in endothelial fibrosis and to investigate the underlying mechanism. METHODS: Primary human endothelial cells were used and pharmacological and short interfering RNA-based approaches were used to test the transforming growth factor beta (TGF-beta)/activin receptor-like kinase 5 (ALK5) pathway participation and contribution of TRPM7 ion channel. RESULTS: Suppression of TRPM4 expression leads to decreased endothelial protein expression and increased expression of fibrotic and extracellular matrix markers. Furthermore, TRPM4 downregulation increases intracellular Ca levels as a potential condition for fibrosis. The underlying mechanism of endothelial fibrosis shows that inhibition of TRPM4 expression induces TGF-beta1 and TGF-beta2 expression, which act through their receptor, ALK5, and the nuclear translocation of the profibrotic transcription factor smad4. CONCLUSION: TRPM4 acts to maintain endothelial features and its loss promotes fibrotic conversion via TGF-beta production. The regulation of TRPM4 levels could be a target for preserving endothelial function during inflammatory diseases. PMID- 25909698 TI - Increasing aminoterminal-pro-B-type natriuretic peptide precedes the development of arterial hypertension: the multiethnic study of atherosclerosis. AB - BACKGROUND: Longitudinal associations between the aminoterminal pro-B-type natriuretic peptide (NT-proBNP) and incident hypertension are lacking. METHODS: We tested associations between baseline NT-proBNP (bNT-proBNP) and change in NT proBNP (DeltaNT-proBNP) (visit 3 NT-proBNP - bNT-proBNP, 3.2 years apart) with incident hypertension (SBP >= 140 and/or DBP >=90 mmHg or taking antihypertensive medications). Incident hypertension was evaluated in 5596 individuals in the Multi-Ethnic Study of Atherosclerosis without hypertension at baseline (53% women, age range 45-84 years without overt cardiovascular disease) and follow-up for 9.5 years and in a subgroup (1550) who had bNT-proBNP less than 100 pg/ml and no hypertension at visit 3. Incident hypertension was regressed (proportional hazards) on quintiles of bNT-proBNP (range) (reference <19.2, 19.3-40.8, 40.9 70.9, 71-135.2, and >135.5) and also on DeltaNT-proBNP categories (reference < 10, -10 to 10, >10 to 50, and >50 pg/ml). Hazard ratios were adjusted for age, race, sex, education, diabetes, obesity, left ventricle mass/height, SBP and DBP, interleukin-6, salt intake, estimated glomerular filtration rate, and exercise. RESULTS: Compared with the reference category, hazard ratios (95% confidence interval) for incident hypertension compared with the first quintile of bNT proBNP were 1.47 (1.13-1.93), 1.57 (1.18-2.09), 1.52 (1.12-2.06), and 2.36 (1.62 3.41). Hazard ratios for incident hypertension by categories of DeltaNT-proBNP from 3.2 to 9.5 years follow-up were 0.98 (0.62-1.56), 1.13 (0.72-1.79), and 1.82 (1.07-3.12). CONCLUSION: The development of hypertension tended to be preceded by elevated levels of bNT-proBNP or a substantial positive DeltaNT-proBNP. PMID- 25909700 TI - The vascular response to vasodilators is related to the membrane content of polyunsaturated fatty acids in hypertensive patients. AB - OBJECTIVE: Abnormal vascular reactivity contributes to the pathophysiology of hypertension and hypertension-related organ damage. As the dietary content of fatty acids may affect the vascular responses, we investigated the relationship of endothelium-independent and endothelium-dependent vasodilation with the fatty acid composition of red blood cell (RBC) membranes in hypertension. METHODS: In 45 uncomplicated hypertensive patients, we measured the content of fatty acids in RBC membrane as a marker of dietary intake of fatty acids, and the vasodilatory response of the brachial artery to both nitrate-donor compound (nitrate-mediated vasodilation, NMD) and postischemic reactive hyperemia (flow-mediated vasodilation, FMD). RESULTS: Baseline diameter of the brachial artery was significantly lower and vasodilatory response to NMD was significantly greater in patients with RBC membrane polyunsaturated-to-saturated fatty acid (PUFA/SFA) ratio above the median of the distribution than in patients with PUFA/SFA ratio below the median, whereas no difference was observed in FMD. n-3 PUFA and n-6 PUFA content, and the PUFA/SFA ratio of RBC membranes were related inversely with brachial artery diameter and directly with maximal NMD, whereas no relationship of fatty acid components of RBC membrane with FMD was observed. Multivariate analysis that included demographic, anthropometric, clinical, and biochemical variables indicated that the RBC membrane PUFA/SFA ratio was an independent determinant of brachial artery diameter and NMD response. CONCLUSION: The endothelium-independent brachial artery vasodilation is independently related to the PUFA content of RBC membranes in patients with hypertension. This suggests the possible benefits of PUFA-enriched diets on the regulation of vascular tone and blood pressure in these patients. PMID- 25909701 TI - Blockade of the renin-angiotensin system in small arteries and anticontractile function of perivascular adipose tissue. AB - BACKGROUND/AIMS: In patients with obesity, there is increased inflammation with attendant oxidative stress in perivascular adipose tissue. This has functional consequences with loss of vasodilator adipokine bioavailability. Part of the inflammatory response is mediated by increased activation of the renin angiotensin-aldosterone axis. Therefore, this study was designed to investigate whether angiotensin-converting enzyme inhibitors or angiotensin receptor blockers can improve the anticontractile function of perivascular adipose tissue. METHODS: Segments of rat mesenteric small artery were dissected and mounted in a wire myograph and contracted to incremental doses of norepinephrine in the presence and absence of perivascular adipose tissue and in conditions of normal oxygenation or after hypoxia and incubated with captopril or telmisartan. RESULTS: Vessels with perivascular adipose tissue contracted significantly less than arteries with perivascular adipose tissue removed under normal oxygenation conditions, indicating that perivascular adipose tissue exerts an anticontractile effect. Hypoxia induced a loss of this anticontractile effect which could be completely prevented with captopril or telmisartan. CONCLUSION: The in-vitro creation of a hypoxic environment can simulate the loss of anticontractile perivascular adipose tissue function seen in vivo in obese patients, and this can be prevented using inhibitors of the renin-angiotensin cascade. PMID- 25909702 TI - Relationship between insulin resistance and tissue blood flow in preeclampsia. AB - OBJECTIVE: Preeclampsia is characterized by generalized endothelial dysfunction and impaired maternal tissue perfusion, and insulin resistance is a prominent feature of this disease. The aim of this study was to test the hypothesis that insulin resistance in preeclampsia is related to the reduced resting tissue blood flow. METHODS: We used venous occlusion plethysmography to compare the resting calf muscle blood flow (measured as QaU) in 20 nulliparous women with preeclampsia and 20 normal pregnant controls matched for maternal age, gestational age, parity and BMI during the third trimester. Fasting blood samples were obtained to measure the plasma concentrations of insulin and glucose, and to calculate the fasting insulin resistance index (FIRI), a measure of insulin resistance in both groups of women. RESULTS: Calf blood flow was significantly reduced in the preeclampsia group (1.93 +/- 0.86 QaU), compared with normal pregnant controls (3.94 +/- 1.1 QaU, P < 0.001). Fasting insulin concentrations and Insulin Resistance Index were significantly higher in preeclampsia compared with normal pregnancy (P < 0.001 for both variables). There were significant inverse correlations between resting calf blood flow and fasting insulin concentrations (r = -0.57, P = 0.008) and FIRI (r = -0.59, P = 0.006) in preeclampsia, but not in normal pregnancy. CONCLUSION: These findings support our hypothesis and raise the possibility that reduced tissue blood flow may a play a role in the increased insulin resistance seen in preeclampsia. PMID- 25909703 TI - Evolution of clinical profile, treatment and blood pressure control in treated hypertensive patients according to the sex from 2002 to 2010 in Spain. AB - OBJECTIVES: To examine the evolution of clinical profile, management of hypertension, and blood pressure (BP) control according to sex in the past decade in Spain. METHODS: Data were taken from three surveys (PRESion arterial en la poblacion espanola en los Centros de Atencion Primaria studies) aimed to determine BP control rates in treated hypertensive patients, who attended the primary care in Spain during 2002, 2006, and 2010, respectively. Adequate BP control was defined as BP lower than 140/90 mmHg for the general hypertensive population in the three surveys. In patients with diabetes, chronic kidney disease, or cardiovascular disease, BP control was established as lower than 130/85 mmHg in the 2002 survey and lower than 130/80 mmHg in the 2006 and 2010 surveys. RESULTS: A total of 12 754 (57.2% women), 10 520 (53.7% women), and 12 961 (51.7% women) patients were included. The proportion of patients with cardiovascular disease increased from 27.1% in men and 21.9% in women in 2002, to 33.0 and 23.9%, respectively, in 2010 (P < 0.0001 in men and women, respectively). In 2002, 36.3% of men and 35.9% of women achieved BP goals (P = NS); 39.7 and 42.9% in 2006 (P < 0.001); and 44.7 and 47.9% in 2010 (P < 0.0001). The proportion of men on combined therapy increased from 44.2% in 2002 to 63.9% in 2010 (P for trend < 0.0001), and in women it increased from 43.9 and 63.2%, respectively (P for trend <0.0001). CONCLUSION: Despite the fact that clinical profile of treated hypertensive patients has worsened in the past years in Spain, BP control rates have improved, particularly in women. This improvement was related with a higher use of combined therapy, regardless of sex. PMID- 25909704 TI - Are two commonly used self-report questionnaires useful for identifying antihypertensive medication nonadherence? AB - OBJECTIVE: Medication nonadherence is a major cause of uncontrolled hypertension, but clinicians are poor at judging adherence, and the gold standard for measuring adherence, electronic monitoring, is rarely available in clinical settings. Self report questionnaires (SRQs), by contrast, are inexpensive, easy to administer, and hence, may be useful for 'diagnosing' nonadherence. In this study, we evaluated the validity of two commonly used medication adherence SRQs among patients with uncontrolled hypertension, using electronic pillbox measurement as the gold standard. METHODS: A total of 149 patients with uncontrolled hypertension had adherence to their antihypertensive medication regimen monitored using a four-compartment electronic pillbox (MedSignals) between two primary care visits (median 50 days). Participants completed the 8-item Morisky Medication Adherence Scale (MMAS-8) and the Visual Analog Scale (VAS) at the second visit. Likelihood ratios were calculated using less than 80% correct dosing adherence by electronic measurement as the gold standard. RESULTS: SRQ scores indicating low adherence (MMAS-8 <6 and VAS <80%, 23 and 9% of participants, respectively) had likelihood ratios of 2.00 [95% confidence interval (CI) 1.10-3.65] and 7.72 (95% CI 1.77-33.6), respectively, for detecting nonadherence compared to electronic measurement. SRQ scores indicating highest adherence (MMAS-8 = 8 and VAS = 100%, 43 and 61% of participants, respectively) had likelihood ratios of 0.55 (95% CI 0.35-0.85) and 0.76 (95% CI 0.57-1.01), respectively, for detecting nonadherence. CONCLUSION: The MMAS-8 and VAS are modestly useful in identifying antihypertensive medication nonadherence. Other tools, including electronic measurement, may be needed to guide titration of antihypertensive medications among patients with uncontrolled hypertension. PMID- 25909705 TI - Comparison of single-pill strategies first line in hypertension: perindopril/amlodipine versus valsartan/amlodipine. PMID- 25909706 TI - Comparison of single-pill strategies first line in hypertension: perindopril/amlodipine versus valsartan/amlodipine. PMID- 25909708 TI - Optimization of irradiance for photodynamic therapy of port-wine stain. AB - Controllable and effective irradiation of lesions is among the key factors that affect the potency of photodynamic therapy (PDT). An optimization method for the irradiance distribution of treatment was proposed which can be used to improve the efficacy of PDT and allow more lesions to receive the desired irradiance level in a single therapy session. With the proposed digital illumination binocular treatment system, the preferred surface normal vectors, irradiation angles, as well as area and weight coefficients of lesions can be achieved and used as characteristic parameters to optimize the irradiation direction. Two port wine stain phantom experiments were performed. The comparison of the illumination area between preoptimization and postoptimization showed that the proposed method can effectively guide the light source control, improve the distribution of light dose, and increase the effective treatment area. PMID- 25909707 TI - In vivo evaluation of battery-operated light-emitting diode-based photodynamic therapy efficacy using tumor volume and biomarker expression as endpoints. AB - In view of the increase in cancer-related mortality rates in low- to middle income countries (LMIC), there is an urgent need to develop economical therapies that can be utilized at minimal infrastructure institutions. Photodynamic therapy (PDT), a photochemistry-based treatment modality, offers such a possibility provided that low-cost light sources and photosensitizers are available. In this proof-of-principle study, we focus on adapting the PDT light source to a low resource setting and compare an inexpensive, portable, battery-powered light emitting diode (LED) light source with a standard, high-cost laser source. The comparison studies were performed in vivo in a xenograft murine model of human squamous cell carcinoma subjected to 5-aminolevulinic acid-induced protoporphyrin IX PDT. We observed virtually identical control of the tumor burden by both the LED source and the standard laser source. Further insights into the biological response were evaluated by biomarker analysis of necrosis, microvessel density, and hypoxia [carbonic anhydrase IX (CAIX) expression] among groups of control, LED-PDT, and laser-PDT treated mice. There is no significant difference in the percent necrotic volume and CAIX expression in tumors that were treated with the two different light sources. These encouraging preliminary results merit further investigations in orthotopic animal models of cancers prevalent in LMICs. PMID- 25909709 TI - Correlation of renal histopathology with renal echogenicity in dogs and cats: an ex-vivo quantitative study. AB - BACKGROUND: Increased cortical or cortical and medullary echogenicity is one of the most common signs of chronic or acute kidney disease in dogs and cats. Subjective evaluation of the echogenicity is reported to be unreliable. Patient and technical-related factors affect in-vivo quantitative evaluation of the echogenicity of parenchymal organs. The aim of the present study is to investigate the relationship between histopathology and ex-vivo renal cortical echogenicity in dogs and cats devoid of any patient and technical-related biases. RESULTS: Kidney samples were collected from 68 dog and 32 cat cadavers donated by the owners to the Veterinary Teaching Hospital of the University of Padua and standardized ultrasonographic images of each sample were collected. The echogenicity of the renal cortex was quantitatively assessed by means of mean gray value (MGV), and then histopathological analysis was performed. Statistical analysis to evaluate the influence of histological lesions on MGV was performed. The differentiation efficiency of MGV to detect pathological changes in the kidneys was calculated for dogs and cats. Statistical analysis revealed that only glomerulosclerosis was an independent determinant of echogenicity in dogs whereas interstitial nephritis, interstitial necrosis and fibrosis were independent determinants of echogenicity in cats. The global influence of histological lesions on renal echogenicity was higher in cats (23%) than in dogs (12%). CONCLUSIONS: Different histopathological lesions influence the echogenicity of the kidneys in dogs and cats. Moreover, MGV is a poor test for distinguishing between normal and pathological kidneys in the dog with a sensitivity of 58.3% and specificity of 59.8%. Instead, it seems to perform globally better in the cat, resulting in a fair test, with a sensitivity of 80.6% and a specificity of 56%. PMID- 25909710 TI - Plasma TNF-alpha and Soluble TNF Receptor Levels after Doxorubicin with or without Co-Administration of Mesna-A Randomized, Cross-Over Clinical Study. AB - PURPOSE: Chemotherapy-induced cognitive impairment (CICI) is a common sequelae of cancer therapy. Recent preclinical observations have suggested that CICI can be mediated by chemotherapy-induced plasma protein oxidation, which triggers TNF alpha mediated CNS damage. This study evaluated sodium-2-mercaptoethane sulfonate (Mesna) co-administration with doxorubicin to reduce doxorubicin-induced plasma protein oxidation and resultant cascade of TNF-alpha, soluble TNF receptor levels and related cytokines. METHODS: Thirty-two evaluable patients were randomized using a crossover design to receive mesna or saline in either the first or second cycle of doxorubicin in the context of a standard chemotherapy regimen for either non-Hodgkin lymphoma or breast cancer. Mesna (360 mg/m2) or saline administration occurred 15 minutes prior and three hours post doxorubicin. Pre-treatment and post-treatment measurements of oxidative stress, TNF-alpha and related cytokines were evaluated during the two experimental cycles of chemotherapy. RESULTS: Co administration of mesna with chemotherapy reduced post-treatment levels of TNF related cytokines and TNF-receptor 1 (TNFR1) and TNF-receptor 2 (TNFR2) (p = 0.05 and p = 0.002, respectively). Patients with the highest pre-treatment levels of each cytokine and its receptors were the most likely to benefit from mesna co administration. CONCLUSIONS: The extracellular anti-oxidant mesna, when co administered during a single cycle of doxorubicin, reduced levels of TNF-alpha and its receptors after that cycle of therapy, demonstrating for the first time a clinical interaction between mesna and doxorubicin, drugs often coincidentally co administered in multi-agent regimens. These findings support further investigation to determine whether rationally-timed mesna co-administration with redox active chemotherapy may prevent or reduce the cascade of events that lead to CICI. TRIAL REGISTRATION: clinicaltrials.gov NCT01205503. PMID- 25909711 TI - Environmental Response and Genomic Regions Correlated with Rice Root Growth and Yield under Drought in the OryzaSNP Panel across Multiple Study Systems. AB - The rapid progress in rice genotyping must be matched by advances in phenotyping. A better understanding of genetic variation in rice for drought response, root traits, and practical methods for studying them are needed. In this study, the OryzaSNP set (20 diverse genotypes that have been genotyped for SNP markers) was phenotyped in a range of field and container studies to study the diversity of rice root growth and response to drought. Of the root traits measured across more than 20 root experiments, root dry weight showed the most stable genotypic performance across studies. The environment (E) component had the strongest effect on yield and root traits. We identified genomic regions correlated with root dry weight, percent deep roots, maximum root depth, and grain yield based on a correlation analysis with the phenotypes and aus, indica, or japonica introgression regions using the SNP data. Two genomic regions were identified as hot spots in which root traits and grain yield were co-located; on chromosome 1 (39.7-40.7 Mb) and on chromosome 8 (20.3-21.9 Mb). Across experiments, the soil type/ growth medium showed more correlations with plant growth than the container dimensions. Although the correlations among studies and genetic co-location of root traits from a range of study systems points to their potential utility to represent responses in field studies, the best correlations were observed when the two setups had some similar properties. Due to the co-location of the identified genomic regions (from introgression block analysis) with QTL for a number of previously reported root and drought traits, these regions are good candidates for detailed characterization to contribute to understanding rice improvement for response to drought. This study also highlights the utility of characterizing a small set of 20 genotypes for root growth, drought response, and related genomic regions. PMID- 25909712 TI - Coverage of the 2011 Q fever vaccination campaign in the Netherlands, using retrospective population-based prevalence estimation of cardiovascular risk conditions for chronic Q fever. AB - BACKGROUND: In 2011, a unique Q fever vaccination campaign targeted people at risk for chronic Q fever in the southeast of the Netherlands. General practitioners referred patients with defined cardiovascular risk-conditions (age >15 years). Prevalence rates of those risk-conditions were lacking, standing in the way of adequate planning and coverage estimation. We aimed to obtain prevalence rates retrospectively in order to estimate coverage of the Q fever vaccination campaign. METHODS: With broad search terms for these predefined risk conditions, we extracted patient-records from a large longitudinal general practice research-database in the Netherlands (IPCI-database). After validation of these records, obtained prevalence rates (stratified for age and sex) extrapolated to the Q fever high-incidence area population, gave an approximation of the size of the targeted patient-group. Coverage calculation addressed people actually screened by a pre-vaccination Q fever skin test and serology (coverage) and patients referred by their general practitioners (adjusted-coverage) in the 2011 campaign. RESULTS: Our prevalence estimate of any risk-condition was 3.1% (lower-upper limits 2.9-3.3%). For heart valve defects, aorta aneurysm/prosthesis, congenital anomalies and endocarditis, prevalence was 2.4%, 0.6%, 0.4% and 0.1%, respectively. Estimated number of eligible people in the Q fever high-incidence area was 11,724 (10,965-12,532). With 1330 people screened for vaccination, coverage of the vaccination campaign was 11%. For referred people, the adjusted coverage was 18%. Coverage was lowest among the very-old and highest for people aged 50-70 years. CONCLUSION: The estimated coverage of the vaccination campaign was limited. This should be interpreted in the light of the complexity of this target-group with much co-morbidity, and of the vaccine that required invasive pre-vaccination screening. Calculation of prevalence rates of risk-conditions based on the IPCI-database was feasible. This procedure proved an efficient tool for future use, when prevalence estimates for policy, implementation or surveillance of subgroup-vaccination or other health-care interventions are needed. PMID- 25909714 TI - Asymmetric activation spreading in the multiplication associative network due to asymmetric overlap between numerosities semantic representations? AB - Simple multiplication facts are thought to be organised in a network structure in which problems and solutions are associated. Converging evidence suggests that the ability for solving symbolic arithmetic problems is based on an approximate number system (ANS). Most theoretical stances concerning the metric underlying the ANS converge on the assumption that the representational overlap between two adjacent numbers increases as the numerical magnitude of the numbers increases. Given a number N, the overlap between N and N+1 is larger than the overlap between N and N-1. Here, we test whether this asymmetric overlap influences the activation spreading within the multiplication associative network (MAN). When verifying simple multiplication problems such as 8*4 participants were slower in rejecting false but related outcomes that were larger than the actual outcome (e.g., 8*4=36) than rejecting smaller related outcomes (e.g., 8*4=28), despite comparable numerical distance from the correct result (here: 4). This effect was absent for outcomes which are not part of either operands table (e.g., 8*4=35). These results suggest that the metric of the ANS influences the activation spreading within the MAN, further substantiating the notion that symbolic arithmetic is grounded in the ANS. PMID- 25909716 TI - Optimized wavelength selection for molecular absorption thermometry. AB - A differential evolution (DE) algorithm is applied to a recently developed spectroscopic objective function to select wavelengths that optimize the temperature precision of water absorption thermometry. DE reliably finds optima even when many-wavelength sets are chosen from large populations of wavelengths (here 120 000 wavelengths from a spectrum with 0.002 cm(-1) resolution calculated by 16 856 transitions). Here, we study sets of fixed wavelengths in the 7280-7520 cm(-1) range. When optimizing the thermometer for performance within a narrow temperature range, the results confirm that the best temperature precision is obtained if all the available measurement time is split judiciously between the two most temperature-sensitive wavelengths. In the wide temperature range case (thermometer must perform throughout 280-2800 K), we find (1) the best four wavelength set outperforms the best two-wavelength set by an average factor of 2, and (2) a complete spectrum (all 120 000 wavelengths from 16 856 transitions) is 4.3 times worse than the best two-wavelength set. Key implications for sensor designers include: (1) from the perspective of spectroscopic temperature sensitivity, it is usually sufficient to monitor two or three wavelengths, depending on the sensor's anticipated operating temperature range; and (2) although there is a temperature precision penalty to monitoring a complete spectrum, that penalty may be small enough, particularly at elevated pressure, to justify the complete-spectrum approach in many applications. PMID- 25909713 TI - Hepatitis B Virus Pre-S2 Mutant Induces Aerobic Glycolysis through Mammalian Target of Rapamycin Signal Cascade. AB - Hepatitis B virus (HBV) pre-S2 mutant can induce hepatocellular carcinoma (HCC) via the induction of endoplasmic reticulum stress to activate mammalian target of rapamycin (MTOR) signaling. The association of metabolic syndrome with HBV related HCC raises the possibility that pre-S2 mutant-induced MTOR activation may drive the development of metabolic disorders to promote tumorigenesis in chronic HBV infection. To address this issue, glucose metabolism and gene expression profiles were analyzed in transgenic mice livers harboring pre-S2 mutant and in an in vitro culture system. The pre-S2 mutant transgenic HCCs showed glycogen depletion. The pre-S2 mutant initiated an MTOR-dependent glycolytic pathway, involving the eukaryotic translation initiation factor 4E binding protein 1 (EIF4EBP1), Yin Yang 1 (YY1), and myelocytomatosis oncogene (MYC) to activate the solute carrier family 2 (facilitated glucose transporter), member 1 (SLC2A1), contributing to aberrant glucose uptake and lactate production at the advanced stage of pre-S2 mutant transgenic tumorigenesis. Such a glycolysis-associated MTOR signal cascade was validated in human HBV-related HCC tissues and shown to mediate the inhibitory effect of a model of combined resveratrol and silymarin product on tumor growth. Our results provide the mechanism of pre-S2 mutant induced MTOR activation in the metabolic switch in HBV tumorigenesis. Chemoprevention can be designed along this line to prevent HCC development in high-risk HBV carriers. PMID- 25909717 TI - Visualization of Water Distribution in the Facial Epidermal Layers of Skin Using High-Sensitivity Near-Infrared (NIR) Imaging. AB - Skin moisturization is an important function of cosmetics in dermatology, and acquisition of two-dimensional information about the water content of facial skin is of great interest. Near-infrared (NIR) imaging using the water OH band centered near 1460 nm has been applied to the evaluation of water in skin. However, detection of small changes in the water content of skin water is difficult using this band because of the low absorption coefficient of water at that wavelength and inadequate optical units. We developed a high-sensitivity water imaging system using strong water bands centered near 1920 nm. This system can be used for the entire face. With the water imaging system, time-dependent changes in the water content of moisturizer-treated skin and hair were visualized with high sensitivity. In this study, we performed a water distribution analysis, with the aim of understanding the water distribution in facial skin under different environmental conditions. The water imaging system combines a diffuse illumination unit and an extended-range indium-gallium arsenide NIR camera with a detection range of 1100-2200 nm. The skin water distributions for multiple subjects with different facial shapes and sizes were compared using averaged NIR image data and a mesh partition analysis using a developed algorithm. Changes in the facial skin water content with season and humidity were visualized by the algorithm. The water content decreased in autumn, especially near the eyes and upper-cheek. Compared to other areas on the face, the water content around the eyes decreased more during an 85 min stay in a room at 10% relative humidity. The proposed method for water distribution analysis provides a powerful tool for facial skin hydration research in dermatological and cosmetics fields. PMID- 25909718 TI - Binding of alkenes and ionic liquids to B-H-functionalized boron nanoparticles: creation of particles with controlled dispersibility and minimal surface oxidation. AB - The interaction of B-H-functionalized boron nanoparticles with alkenes and nitrogen-rich ionic liquids (ILs) is investigated by a combination of X-ray photoelectron spectroscopy, FTIR spectroscopy, dynamic light scattering, thermogravimetric analysis, and helium ion microscopy. Surface B-H bonds are shown to react with terminal alkenes to produce alkyl-functionalized boron particles. The interaction of nitrogen-rich ILs with the particles appears, instead, to be dominated by boron-nitrogen bonding, even for an ILs with terminal alkene functionality. This chemistry provides a convenient approach to producing and capping boron nanoparticles with a protective organic layer, which is shown to protect the particles from oxidation during air exposure. By controlling the capping group, particles with high dispersibility in nonpolar or polar liquids can be produced. For the particles capped with ILs, the effect of particle loading on hypergolic ignition of the ILs is reported. PMID- 25909719 TI - Testing a Conceptual Model of Postpartum Depressive Symptoms in the First Year. AB - Postpartum depressive symptoms (PPDS) are likely to have a multifactorial etiology. The relationships among identified PPDS risk factors, however, remain inconclusive. A vulnerability-stress conceptualization of PPDS was tested with a sample of 144 U.S. mothers aged 18-46 years, who had given birth in the last 12 months. The Edinburgh Postnatal Depression Scale, Dysfunctional Attitude Scale Form A-17, Parenting Sense of Competence Scale, and Quality of Relationships Inventory were completed. The conceptual model and three alternative models were tested using structural equation modeling. A variation of the conceptual model yielded the best fit, chi(2) (98) = 133.541, p = .0099, Standardized Root Mean Residual (SRMR) = 0.071, Root Mean Square Error of Approximation (RMSEA) = 0.050 (90% CI = 0.026-0.070), Tucker Lewis Index (TLI) = 0.953, Comparative Fix Index (CFI) = 0.961. Dependency and partner conflict were positively related to PPDS, while maternal-efficacy was negatively related to PPDS. Dependency moderated the relationship between maternal-efficacy and PPDS, so that this relationship was stronger for mothers with higher dependency than for those with lower dependency. Dependency, partner conflict, and maternal-efficacy should be considered when building interventions that target the wellbeing of mothers in the first year after birth. PMID- 25909720 TI - Wineries wastewater treatment by constructed wetlands: a review. AB - The application of wetland systems for the treatment of wineries wastewater started in the early 1990s in the USA followed a few years later by France, Italy, Germany and Spain. Various studies demonstrated the efficiency of constructed wetlands (CWs) as a low cost, low maintenance and energy-saving technology for the treatment of wineries wastewater. Several of these experiences have also shown lessons to be learnt, such as some limits in the tolerance of the horizontal subsurface flow and vertical subsurface flow classic CWs to the strength of the wineries wastewater, especially in the first stage for the multistage systems. This paper is presenting an overview of all the reported experiences at worldwide level during the last 15 years, giving particular attention and provision of details to those systems that have proven to get reliable and constant performances in the long-term period and that have been designed and realized as optimized solutions for the application of CW technology to this particular kind of wastewater. The organic loading rates (OLRs) applied to the examined 13 CW systems ranged from about 30 up to about 5,000 gCOD/m2 d (COD: chemical oxygen demand), with the 80th percentile of the reported values being below 297 gCOD/m2 d and the median at 164 gCOD/m2 d; the highest OLR values have in all cases been measured during the peak season (vintage) and often have been linked to lower surface removal rates (SRRs) in comparison to the other periods of the year. With such OLRs the SRRs have ranged from a minimum of 15 up to 4,700 gCOD/m2 d, with the 80th percentile of the reported values being below 308 gCOD/m2 d and the median at 112 gCOD/m2 d. PMID- 25909721 TI - The joint acute effect of tetracycline, erythromycin and sulfamethoxazole on acetoclastic methanogens. AB - In this study, we aimed to develop an understanding of the triple effects of sulfamethoxazole-erythromycin-tetracycline (ETS) and the dual effects of sulfamethoxazole-tetracycline (ST), erythromycin-sulfamethoxazole (ES) and erythromycin-tetracycline (ET) on the anaerobic treatment of pharmaceutical industry wastewater throughout a year of operation. Concentrations of the antibiotics in the influent were gradually increased until the metabolic collapse of the anaerobic sequencing batch reactors (SBRs), which corresponded to ETS (40 + 3 + 3 mg/L) and ST (25 + 2.5 mg/L), ET (4 + 4 mg/L) and ES (3 + 40 mg/L). Acetate accumulation in the anaerobic SBRs, acetoclastic activity of the anaerobic sludge taken from different antibiotic feeding stages and also expression of acetyl-coA synthetase from the acetoclastic methanogenic pathway on the mRNA level were assessed. The results indicated that, while acetate accumulation and decrease of acetoclastic activity were observed after stage 3 in the ST and ES reactors, and stage 7 in the ETS and ET reactors, the expression of acetyl-coA synthetase was mostly decreased in the last stages in all SBRs, in which antibiotic mixture feeding was terminated. It might be speculated that acetoclastic methanogens have an important role in acetate degradation by expressing acetyl-coA synthetase. PMID- 25909722 TI - Combined sewer overflow control with LID based on SWMM: an example in Shanghai, China. AB - Although low impact development (LID) has been commonly applied across the developed countries for mitigating the negative impacts of combined sewer overflows (CSOs) on urban hydrological environment, it has not been widely used in developing countries yet. In this paper, a typical combined sewer system in an urbanized area of Shanghai, China was used to demonstrate how to design and choose CSO control solutions with LID using stormwater management model. We constructed and simulated three types of CSO control scenarios. Our findings support the notion that LID measures possess favorable capability on CSO reduction. Nevertheless, the green scenarios which are completely comprised by LID measures fail to achieve the maximal effectiveness on CSO reduction, while the gray-green scenarios (LID measure combined with gray measures) achieve it. The unit cost-effectiveness of each type of scenario sorts as: green scenario > gray-green scenario > gray scenario. Actually, as the storage tank is built in the case catchment, a complete application of green scenario is inaccessible here. Through comprehensive evaluation and comparison, the gray-green scenario F which used the combination of storage tank, bio-retention and rain barrels is considered as the most feasible one in this case. PMID- 25909723 TI - Clofibric acid and gemfibrozil removal in membrane bioreactors. AB - The removal of two blood lipid regulators, clofibric acid (CLA) and gemfibrozil (GFZ), was evaluated using two identical aerobic membrane bioreactors with 6.5 L effective volume each. Polysulfone ultrafiltration hollow fiber membranes were submerged in the reactors. Different operating conditions were tested varying the organic load (F/M), hydraulic residence time (HRT), biomass concentration measured as total suspended solids in the mixed liquor (MLTSS) and the sludge retention time (SRT). Complete GFZ removal was obtained with F/M of 0.21-0.48 kg COD kgTSS-1 d-1, HRT of 4-10 hours, SRT of 10-32 d and MLTSS of 6-10 g L-1. The GFZ removal can be attributed to biodegradation and there was no accumulation of the compound in the biomass. The CLA removals improved with the SRT and HRT increase and F/M decrease. Average removals of 78-79% were obtained with SRT 16 32 d, F/M of 0.21-0.34 kgCOD kgTSS-1 d-1, HRT of 7-10 hours and MLTSS of 6-10 g L 1. Biodegradation was found to be the main removal pathway. PMID- 25909724 TI - Fat, oil and grease waste from municipal wastewater: characterization, activation and sustainable conversion into biofuel. AB - Fat, oil and grease (FOG) recovered by the oil/water separator of a wastewater treatment plant (WWTP) were sampled, characterized, activated and converted into biofuel. Free acids (50-55%) and fatty soaps (26-32%) not only composed the main components, but they were also easily separable from the starting waste. The respective free fatty acid profiles were gas-chromatographically evaluated, interestingly verifying that free acids had a different profile (mainly oleic acid) with respect to the soapy fraction (saturated fatty acids were dominant). The inorganic composition was also determined for soaps, confirming that calcium is the most commonly present metal. The chemical activation of this fatty waste was made possible by converting the starting soaps into the respective free fatty acids by using formic acid as activator, coproducing the relevant formates. The activated fatty matter was then converted into biofuel through direct esterification under very mild conditions (345 K, atmospheric pressure) and obtaining thermodynamic conversion in less than 2 h. The process was easily scaled up, isolating at the end pure biodiesel (purity > 96%) through distillation under vacuum, providing a final product conformed to commercial purposes. PMID- 25909725 TI - Performance of a pilot showcase of different wetland systems in an urban setting in Singapore. AB - The Alexandra Wetlands, part of PUB's Active, Beautiful, Clean Waters (ABC Waters) Programme, showcase a surface flow wetland, an aquatic pond and a sub surface flow wetland on a 200 m deck built over an urban drainage canal. Water from the canal is pumped to a sedimentation basin, before flowing in parallel to the three wetlands. Water quality monitoring was carried out monthly from April 2011 to December 2012. The order of removal efficiency is sub-surface flow (81.3%) >aquatic pond (58.5%) >surface flow (50.7%) for total suspended solids (TSS); sub-surface (44.9%) >surface flow (31.9%) >aquatic pond (22.0%) for total nitrogen (TN); and surface flow (56.7%) >aquatic pond (39.8%) >sub-surface flow (5.4%) for total phosphorus (TP). All three wetlands achieved the Singapore stormwater treatment objectives (STO) for TP removal, but only the sub-surface flow wetland met the STO for TSS, and none met the STO for TN. Challenges in achieving satisfactory performance include inconsistent feed water quality, undesirable behaviour such as fishing, release of pets and feeding of animals in the wetlands, and canal dredging during part of the monitoring period. As a pilot showcase, the Alexandra Wetlands provide useful lessons for implementing multi objective wetlands in an urban setting. PMID- 25909726 TI - Treatment of papermaking tobacco sheet wastewater by electrocoagulation combined with electrochemical oxidation. AB - Attempts were made in this study to examine the efficiency of electrocoagulation (EC) using aluminum (Al) anode and stainless steel net cathode combined with electrochemical oxidation with a beta-PbO2anode or a mixed metal oxide (MMO) anode for treatment of papermaking tobacco sheet wastewater, which has the characteristics of high content of suspended solids (SS), intensive color, and low biodegradability. The wastewater was first subjected to the EC process under 40 mA/cm2 of current density, 2.5 g/L of NaCl, and maintaining the original pH of wastewater. After 6 minutes of EC process, the effluent was further treated by electrochemical oxidation. The results revealed that the removal of SS during the EC process was very beneficial to mass transfer of organics during electrochemical oxidation. After the combined process, 83.9% and 82.8% of chemical oxygen demand (COD) removal could be achieved on the beta-PbO2and MMO anodes, respectively. The main components of the final effluent were biodegradable organic acids, such as acetic acid, propionic acid, butyric acid, valeric acid, and hexahyl carbonic acid; the 5-day biochemical oxygen demand/chemical oxygen demand (BOD5/COD) ratio increased from 0.06 to 0.85 (Al + beta-PbO2) or 0.80 (Al + MMO). Therefore, this integrated process is a promising alternative for pretreatment of papermaking tobacco sheet wastewater prior to biological treatment. PMID- 25909727 TI - Activated sludge optimization using ATP in pulp and paper industry. AB - The activated sludge process is an old technology, but still the most commonly used one for treatment of wastewater. Despite the wide spread usage the technology still suffers from instability (Tandoi et al. 2006) and high operating cost. Activated sludge processes often carry a large solids inventory. Managing the total inventory without interference is the key component of the optimization process described in this paper. Use of nutrients is common in pulp and paper effluent treatment. Feeding enough nutrients to support the biomass growth is a delicate balance. Overfeeding or underfeeding of nutrients can result in higher costs. Detrimental substances and toxic components in effluents entering a biological treatment system can cause severe, long lasting disturbances (Hynninen & Ingman 1998; Bergeron & Pelletier 2004). A LumiKem test kit is used to measure biological activity with adenosine triphosphate (ATP) in a pulp and paper mill. ATP data are integrated with other standardized mill parameters. Measurements of active volatile suspended solids based on ATP can be used to quantify the living biomass in the activated sludge process and to ensure that sufficient biomass is present in order to degrade the wastewater constituents entering the process. Information about active biomass will assist in optimizing sludge inventories and feeding of nutrients allowing the living biomass to re-populate to create optimal efficiency. ATP measurements can also be used to alert operators if any components toxic to bacteria are present in wastewater. The bio stress index represents the stress level experienced by the microbiological population. This parameter is very useful in monitoring toxicity in and around bioreactors. Results from the wastewater process optimization and ATP measurements showed that treatment cost could be reduced by approximately 20-30% with fewer disturbances and sustained biological activity compared to the reference period. This was mainly achieved by the removal of detrimental substances and optimized nutrient dosage. PMID- 25909728 TI - Modelling of moving bed biofilm membrane reactors (MBBMR) for on-site greywater treatment. AB - The study evaluates with a mechanistic model the pilot plant results of a combined moving bed biofilm process and membrane filtration (MBBMR) treating single household greywater. It mainly includes the simulation of reactor hydraulics, degradation of pollutants, development of biomass and settlement of sludge. Iterative calibration was made with steady-state results of a 10-month pilot test. The model shows good predictions of readily biodegradable chemical oxygen demand and ammonium removal, as well as biomass concentration on carriers and in suspension. Also, a sensitivity analysis was made which calculates the relative significance factor of each model coefficient and by this provides comparability with other studies. Simulation data and actually measured parameters show that the suggested process was rather independent of ambient temperatures and short-term load fluctuations. Obtained datasets and model structure could be of use for future designers, as well as sellers and users of this process for on-site greywater reclamation. PMID- 25909729 TI - Adsorption isotherms and kinetics of activated carbons produced from coals of different ranks. AB - Activated carbons (ACs) from six coals, ranging from low-rank lignite brown coal to high-rank stone coal, were utilized as adsorbents to remove basic methylene blue (MB) from an aqueous solution. The surface properties of the obtained ACs were characterized via thermal analysis, N2 isothermal sorption, scanning electron microscopy, Fourier transform infrared spectroscopy, X-ray photoelectron spectroscopy and Boehm titration. As coal rank decreased, an increase in the heterogeneity of the pore structures and abundance of oxygen-containing functional groups increased MB coverage on its surface. The equilibrium data fitted well with the Langmuir model, and adsorption capacity of MB ranged from 51.8 to 344.8 mg g-1. Good correlation coefficients were obtained using the intra particle diffusion model, indicating that the adsorption of MB onto ACs is diffusion controlled. The values of the effective diffusion coefficient ranged from 0.61 * 10-10 to 7.1 * 10-10 m2 s-1, indicating that ACs from lower-rank coals have higher effective diffusivities. Among all the ACs obtained from selected coals, the AC from low-rank lignite brown coal was the most effective in removing MB from an aqueous solution. PMID- 25909730 TI - Treatment of emulsified oils by electrocoagulation: pulsed voltage applications. AB - The effect of pulsed voltage application on energy consumption during electrocoagulation was investigated. Three voltage profiles having the same arithmetic average with respect to time were applied to the electrodes. The specific energy consumption for these profiles were evaluated and analyzed together with oil removal efficiencies. The effects of applied voltages, electrode materials, electrode configurations, and pH on oil removal efficiency were determined. Electrocoagulation experiments were performed by using synthetic and real wastewater samples. The pulsed voltages saved energy during the electrocoagulation process. In continuous operation, energy saving was as high as 48%. Aluminum electrodes used for the treatment of emulsified oils resulted in higher oil removal efficiencies in comparison with stainless steel and iron electrodes. When the electrodes gap was less than 1 cm, higher oil removal efficiencies were obtained. The highest oil removal efficiencies were 95% and 35% for the batch and continuous operating modes, respectively. PMID- 25909731 TI - A probabilistic QMRA of Salmonella in direct agricultural reuse of treated municipal wastewater. AB - Developing reliable quantitative microbial risk assessment (QMRA) procedures aids in setting recommendations on reuse applications of treated wastewater. In this study, a probabilistic QMRA to determine the risk of Salmonella infections resulting from the consumption of edible crops irrigated with treated wastewater was conducted. Quantitative polymerase chain reaction (qPCR) was used to enumerate Salmonella spp. in post-disinfected samples, where they showed concentrations ranging from 90 to 1,600 cells/100 mL. The results were used to construct probabilistic exposure models for the raw consumption of three vegetables (lettuce, cabbage, and cucumber) irrigated with treated wastewater, and to estimate the disease burden using Monte Carlo analysis. The results showed elevated median disease burden, when compared with acceptable disease burden set by the World Health Organization, which is 10-6 disability-adjusted life years per person per year. Of the three vegetables considered, lettuce showed the highest risk of infection in all scenarios considered, while cucumber showed the lowest risk. The results of the Salmonella concentration obtained with qPCR were compared with the results of Escherichia coli concentration for samples taken on the same sampling dates. PMID- 25909732 TI - The heterotrophic-combined-with-autotrophic denitrification process: performance and interaction mechanisms. AB - In this work, the interaction mechanisms between an autotrophic denitrification (AD) and heterotrophic denitrification (HD) process in a heterotrophic autotrophic denitrification (HAD) system were investigated, and the performance of the HAD system under different S/Ac(-) molar ratios was also evaluated. The results demonstrated that the heterotrophic-combined-with-autotrophic denitrification process is a promising technology which can remove chemical oxygen demand (COD), sulfide and nitrate simultaneously. The reduction rate of NO(3)(-) to NO(2)(-) by the HD process was much faster than that of reducing NO(2)(-) to N2, while the reduction rate of NO(3)(-) to NO(2)(-) by the AD process was slower than that of NO(2)(-) to N2. Therefore, the AD process could use the surplus NO(2)(-) produced by the HD process. This could alleviate the NO(2)(-)-N accumulation and increase the denitrification rate. In addition, the inhibition effects of acetate on AD bacteria and sulfide on HD were observed, and the inhibition was compensated by the promotion effects on NO(2)(-). Therefore, the processes of AD and HD seem to react in parallel, without disturbing each other, in our HAD system. PMID- 25909733 TI - French vertical-flow constructed wetlands in mountain areas: how do cold temperatures impact performances? AB - The French version of vertical-flow constructed wetlands (VFCWs) is characterized by treating directly raw wastewater on a first-stage filter. VFCW is a well developed technology with more than 3,500 plants in operation in France. However, VFCW performance may be affected under the low temperatures reached in mountain areas during winter. The effect of cold conditions over 12 plants, ranging from 75 to 1,900 person equivalent and from 680 to 1,500 m above sea level, was studied over 2 years. The plant hydraulic loads, and air and filter temperatures were continuously measured. In addition, 24-h flow proportional sampling, at each stage of treatment, was conducted in summer (as a reference) and winter. Online measurements of ammonium and nitrates were also analyzed to describe the nitrogen removal dynamics. Since no impact on chemical oxygen demand (COD), biochemical oxygen demand (BOD) and suspended solids removal was observed, the effect of cold temperatures on nitrification was further analyzed. Nitrogen removal was relatively unaffected during winter season. Significant effects were confirmed only for the second stage for loads above 10 gTKN/m2/d (TKN: total Kjeldahl nitrogen). Temperature profiles allowed analysis of the filter buffer capacity in terms of freezing. Under minimal air temperature of -19 degrees C, no critical operation was observed, although design and operation recommendations can be provided to ensure suitable plant performances. PMID- 25909734 TI - Biodiesel from wastewater: lipid production in high rate algal pond receiving disinfected effluent. AB - The production of different species of microalgae in consortium with other micro organisms from wastewaters may represent an alternative process, to reduce the costs, for obtaining biofuels. The aim of this study was to evaluate the influence of pre-ultraviolet disinfection (UV) in the production of lipids from biomass produced in high rate ponds. Two high rate algal ponds were evaluated: a pond that received domestic sewage without disinfection and the other receiving domestic sewage previously disinfected by UV radiation (uvHRAP). The UV disinfection did not lead to significant differences in fatty acid profile and total lipid productivities, although it increased algal biomass concentration and productivity as well as lipid content. Moreover, the overall biomass concentrations and productivities decreased with the UV disinfection, mostly as a consequence of a loss in bacterial load. We thus conclude that uvHRAP disinfection may represent a potential strategy to promote the cleaner and safer growth of algal biomass when cultivated in consortium with other micro-organisms. Mainly regarding the use of wastewater as culture medium, together with a cheaper production of lipids for biodiesel, pre-disinfection may represent an advance since extraction costs could be significantly trimmed due to the increase in lipid content. PMID- 25909735 TI - Activated sludge microbial community responses to single-walled carbon nanotubes: community structure does matter. AB - The ecological effects of carbon nanotubes (CNTs) have been a worldwide research focus due to their extensive release and accumulation in environment. Activated sludge acting as an important gathering place will inevitably encounter and interact with CNTs, while the microbial responses have been rarely investigated. Herein, the activated sludges from six wastewater treatment plants were acclimated and treated with single-walled carbon nanotubes (SWCNTs) under identical conditions. Illumina high-throughput sequencing was applied to in-depth analyze microbial changes and results showed SWCNTs differently perturbed the alpha diversity of the six groups (one increase, two decrease, three no change). Furthermore, the microbial community structures were shifted, and specific bacterial performance in each group was different. Since the environmental and operational factors were identical in each group, it could be concluded that microbial responses to SWCNTs were highly depended on the original community structures. PMID- 25909736 TI - Long-term performance of side-stream deammonification in a continuous flow granular-activated sludge process for nitrogen removal from high ammonium wastewater. AB - An innovative granular sludge deammonification system was incorporated into a conventional-activated sludge process. The process incorporated an internal baffle in the bioreactor for continuous separation of granular biomass from flocculent biomass, which allowed for controlling the solids retention time of flocculent sludge. The process was evaluated for ammonium removal from municipal digested sludge dewatering centrate under various operating conditions lasting over 450 days. The process successfully removed, on average, 90% of the ammonium from centrate at various ammonium loading reaching 1.4 kg/m3d at 20 hours hydraulic retention time. Controlling the retention time of the flocculent biomass and maintaining low nitrite concentration were both found to be effective for nitrite oxidizing bacteria management, resulting in a low nitrate concentration (below 50 mg/L) over a wide range of flocculent biomass concentration in the bioreactor. PMID- 25909737 TI - Enhanced photobactericidal activity of ZnO nanorods modified by meso-tetrakis(4 sulfonatophenyl)porphyrin under visible LED lamp irradiation. AB - In this study, zinc oxide (ZnO) nanorods have been synthesized using a simple template-free precipitation technique and deposited on glass substrate. The meso tetrakis(4-sulfonatophenyl)porphyrin (TPPS) has been synthesized and then immobilized on the surface of ZnO nanorods to prepare an organic/inorganic composite. The samples were characterized by various techniques such as X-ray diffraction, diffuse reflectance spectra, Fourier transform-infrared spectroscopy and scanning electron microscopy. In addition, the photobactericidal activity of TPPS/ZnO composite, TPPS and ZnO nanorods was tested against the pathogenic bacterium of Escherichia coli under visible LED lamp irradiation. The results indicate that the photobactericidal activity of TPPS-loaded ZnO nanorods was better than TPPS or ZnO nanorods, separately. PMID- 25909738 TI - Optimization of industrial structure based on water environmental carrying capacity in Tieling City. AB - A system dynamics optimization model of the industrial structure of Tieling City based on water environmental carrying capacity has been established. This system is divided into the following subsystems: water resources, economics, population, contaminants, and agriculture and husbandry. Three schemes were designed to simulate the model from 2011 to 2020, and these schemes were compared to obtain an optimal social and economic development model in Tieling City. Policy recommendations on industrial structure optimization based on the optimal solution provide scientific decision-making advice to develop a strong and sustainable economy in Tieling. PMID- 25909739 TI - Pathogen removal from domestic and swine wastewater by experimental constructed wetlands. AB - This study examined the performance of subsurface flow horizontal wetlands in total coliforms, faecal coliforms, enterococci and Salmonella removal from swine and domestic wastewaters. The effects of organic loading rate, contact time (CT) and the presence of aquatic macrophytes, Typha dominguensis and Typha latifolia, on treatment performance were evaluated. In general, chemical oxygen demand (COD) and total suspended solids (TSS) were reduced by 66 and 72% after 24 h and 75 and 84% after 48 h in domestic wastewaters, and 73 and 71% after 24 h and 72 and 78% after 48 h in swine wastewater. Total coliform and faecal coliform reductions of 70-83% and 65-78% were observed in the vegetated systems after 24 h of CT, while after 48 h, total coliform and faecal coliform reductions of 80-82% and 86-91% were noted. PMID- 25909740 TI - A global optimization approach to multi-polarity sentiment analysis. AB - Following the rapid development of social media, sentiment analysis has become an important social media mining technique. The performance of automatic sentiment analysis primarily depends on feature selection and sentiment classification. While information gain (IG) and support vector machines (SVM) are two important techniques, few studies have optimized both approaches in sentiment analysis. The effectiveness of applying a global optimization approach to sentiment analysis remains unclear. We propose a global optimization-based sentiment analysis (PSOGO Senti) approach to improve sentiment analysis with IG for feature selection and SVM as the learning engine. The PSOGO-Senti approach utilizes a particle swarm optimization algorithm to obtain a global optimal combination of feature dimensions and parameters in the SVM. We evaluate the PSOGO-Senti model on two datasets from different fields. The experimental results showed that the PSOGO Senti model can improve binary and multi-polarity Chinese sentiment analysis. We compared the optimal feature subset selected by PSOGO-Senti with the features in the sentiment dictionary. The results of this comparison indicated that PSOGO Senti can effectively remove redundant and noisy features and can select a domain specific feature subset with a higher-explanatory power for a particular sentiment analysis task. The experimental results showed that the PSOGO-Senti approach is effective and robust for sentiment analysis tasks in different domains. By comparing the improvements of two-polarity, three-polarity and five polarity sentiment analysis results, we found that the five-polarity sentiment analysis delivered the largest improvement. The improvement of the two-polarity sentiment analysis was the smallest. We conclude that the PSOGO-Senti achieves higher improvement for a more complicated sentiment analysis task. We also compared the results of PSOGO-Senti with those of the genetic algorithm (GA) and grid search method. From the results of this comparison, we found that PSOGO Senti is more suitable for improving a difficult multi-polarity sentiment analysis problem. PMID- 25909741 TI - [Stereotactic radiotherapy for spinal meningiomas and neurinomas]. AB - INTRODUCTION: Over the past decades, stereotactic conformal radiotherapy of intracranial meningiomas and schwannomas has been recognized as an effective and safe procedure. Due to the wide use of the CyberKnife system and the procedure of extracranial stereotactic radiotherapy and radiosurgery, the positive experience can be used to treat spinal tumors. This study assessed the effectiveness of stereotactic radiaotherapy of spinal meningiomas and neurinomas using the CyberKnife system. MATERIAL AND METHODS: 46 patients (34 females and 12 males) received treatment between November 2009 and December 2013 (65 tumor nodules). The median age of patients receiving radiotherapy was 49 years (range: 20 to 82 years). Twenty neoplasms were subjected to surgical treatment. In 11 patients, formation of the recurrent tumor foci following treatment was observed along with the systemic disease, neurofibromatosis. Six patients had multiple meningiomas. The median total dose of radiation therapy of neurinomas was 13.6 Gy (12.1-14.1 Gy) per fraction; up to 18.2 Gy (16.0-21.1 Gy) per three fractions; and up to 25.6 Gy (24.8-27.6 Gy) per five fractions. Higher doses were used for meningiomas: 15.9 Gy (14.1-16.2 Gy) per fraction; 20.9 Gy (19.5-21.1 Gy) per three fractions; and 27.5 Gy (25.0-29.9 Gy) per five fractions. The load to 0.15 cm3 of the spinal cord was no higher than the maximum permissible load of 12 Gy per fraction. The mean catamnestic follow-up was 18.1 (4-52) months: 21,1 (4-52) months for neurinomas and 18 (4-31) months for meningiomas. We have not observed complete tumor elimination (i.e., complete response to radiation therapy) in our series. Partial response was observed in 9 (13.8%) cases; stabilization was achieved in 54 (83.1%) cases; and tumor continued to grow in 2 (3.1%) cases. The patients' status was evaluated using the Frankel, the Karnofsky, and the VAS scales. CONCLUSIONS: Our findings clearly demonstrate the short-term benefits of using CyberKnife radiotherapy for benign spinal cord tumors. The catamnestic follow-up needs to be extended to elaborate recommendations for radiation. The progress in this therapy type will considerably improve the quality of medical care provided to this cohort of patients. PMID- 25909742 TI - [The outcomes of stereotactic radiotherapy in patients with cerebral arteriovenous malformations]. AB - INTRODUCTION: Cerebral arteriovenous malformations (AVMs) are the congenital anomalies of development of cerebral vessels during the embryonic period. The conventional therapy for AVMs currently includes endovascular management, microneurosurgical resection, and stereotactic irradiation. MATERIAL AND METHODS: A total of 315 patients with brain AVMs were subjected to stereotactic radiotherapy in 2005-2011. 238 (76%) patients had previous subarachnoid hemorrhage (SAH) within different time (6 months to 5 years) before the therapy; 214 (68%) patients had headaches; 113 (36%) patients had focal neurological symptoms caused by localization; and 82 (26%) patients had seizures. Twenty-three patients were subjected to surgical resection of an intracerebral hematoma prior to radiotherapy and 119 (36%) patients received endovascular treatment including partial embolization of the stroma of AVM. 267 patients received single-fraction radiosurgical irradiation. In patients with large AVMs, we used the hypofractionation technique consisting in target irradiation with several (usually 2-7) fractions; the radiation dose per fraction exceeds 2 Gy. Forty-six patients were irradiated in the hypofractionation mode; two patients had a course of stereotactic radiotherapy in the standard fractionation mode. The marginal dose of radiosurgical irradiation was 13-30 Gy (the average dose was 24 Gy). The main group of patients (38 individuals) with large AVMs was treated using hypofractionation of 35 Gy per 5 fractions. RESULTS: Control angiography was carried out in 225 patients who had been followed up for at least 2 years after therapy showed that complete obliteration was achieved in 83% of cases. The rate of symptomatic radiation reactions was less than 10%. The higher risk of developing obliteration was observed for AVMs less than 2 cm3 in size at marginal doses more than 24 Gy. In the hypofractionation group consisting of 27 patients with complete follow-up data, obliteration was observed in 10 (37%) patients. The rate of symptomatic reactions was less than 35%. CONCLUSIONS: The radiosurgical method is a minimally invasive choice of treatment for patients with brain AVM, which allows one to achieve sufficiently high degree of obliteration with the minimum complication rate. The hypofractionation procedure is the method of choice for treating large AVMs. Stereotactic irradiation using the Novalis linear accelerator makes it possible to treat patients with AVMs of virtually any location and volume. PMID- 25909743 TI - [Intraoperative indocyanine green fluorescence angiography in surgery of brain aneurysms. The first experience with using the technique and literature review]. AB - Intraoperative blood flow assessment after aneurysm clipping has become a standard procedure in vascular neurosurgery worldwide. Intraoperative indacyanine green angiography (ICG) has recently been certified in Russia. Fifteen patients with aneurysms operated with ICG control in Burdenko NSI are described in present publication. ICG advantages and weaknesses are discussed along with alternative flow control techniques available now. PMID- 25909744 TI - [Intraoperative indocyanine green video angiography in cerebrovascular surgery]. PMID- 25909745 TI - [The use of transcallosal ventriculostomy to treat complicated forms of aneurismal intracranial hemorrhages]. AB - The present paper reports two cases of successful use of the anterior interhemispheric transcallosal approach during ultra-early surgery in patients in decompensated condition with severe intraventricular hemorrhage caused by rupture of cerebral aneurysms. PMID- 25909746 TI - [The outcomes of treatment of cauda equina ependymomas in adults]. AB - Ependymoma is a rare tumor that accounts for about 4% of all central nervous system tumors. Ependymomas typically have intramedullary localization; however, sometimes the tumor is located outside of the spinal cord and affects the cauda equina nerve roots. OBJECTIVE: To study the outcomes of treatment in patients diagnosed with extramedullary ependymoma. MATERIAL AND METHODS: Fifty patients (23 males and 27 females) aged 38.7 years (range: 18-76 years) with ependymoma of the cauda equina region were operated on at the 10th Department of the N.N. Burdenko Neurosurgical Institute between January 2009 and December 2013. Thirty six patients were newly diagnosed with tumors. Fourteen patients were admitted to the N.N. Burdenko Neurosurgical Institute with recurrent or continued tumor growth. The patients were subdivided into two groups according to this criterion. The outcomes of treatment were evaluated using the Frankel, the Karnofsky, and the VAS scales. The criteria proposed by Kawabata et al. were used to assess the long-term outcomes of surgical treatment. Tumor growth was monitored by contrast enhanced MRI. RESULTS: Tumors were divided into two subtypes: the encapsulated vs. infiltrative forms. Ependymomas were resected subtotally in 5 patients; continued growth of ependymoma was observed in 3 patients. Positive results were obtained for both groups according to the evaluation performed using the scales. According to the criteria of Kawabata et al., the patients were distributed in a following way: in group 1 patients, the good outcome (class 1) was observed in 26 (72%); the fair outcome (class 2), in 8 (22.5%) patients; while the results were equivocal in 2 (5.5%) patients. A number of patients received radiotherapy as a component of combination treatment. Tumor growth stabilization was achieved. CONCLUSIONS: Microsurgical intervention is obligatory, since it has a positive effect on the outcomes of surgical treatment of extramedullary intradural tumors, including ependymomas of the cauda equina region. Treatment effectiveness decreases for the infiltrative subtype of tumor growth. Radiation therapy should be used if continued tumor growth is detected or degree of tumor resection was subtotal. PMID- 25909747 TI - [The outcomes of arthroplasty in degenerative lesions in the lumbar spine]. AB - STUDY DESIGN: A retrospective study. OBJECTIVE: To investigate the safety and effectiveness of total intervertebral disc replacement with a Maverick prosthesis in patients with discogenic pain in the lower lumbar spine. SUMMARY OF BACKGROUND DATA: Lumbar disc arthroplasty has been developed as an alternative to rigid interbody fusion for patients with pathology in the lower lumbar discs. According to the developers, motion preservation in the operated segment should prevent secondary pathology of the adjacent segments. MATERIAL AND METHODS: From November 2007 to date, 41 patients have been operated on and 42 disc prostheses have been placed. All patients underwent surgery in the same hospital by the same surgeon. The clinical and radiological results of treatment of 35 patients were studied. The patients were examined before surgery, immediately after surgery and then in the intervals of 3-6, 6-12, 12-24, and 36-48 months. The longest follow-up was 61 months. Mean follow-up was 30 months. RESULTS: Patients operated on using total intervertebral disc prosthesis demonstrated a significant improvement compared to their preoperative status. A significant reduction of back and leg pain intensity was observed. The quality of life significantly improved. The intervertebral disc space height, the sagittal balance and the balance in the adjacent levels were restored and preserved after correction. The motion in the implanted segment was preserved. CONCLUSIONS: Total lumbar disc replacement with a Maverick prosthesis has proved to be an effective and safe technique. The clinical and radiological methods showed the significant improvement of the patients' status. PMID- 25909748 TI - [Lateral ventricle diverticulum as a variant of hydrocephalus evolution]. AB - A clinical case of a 12 year-old girl with hydrocephalus complicated by rare condition, lateral ventricular diverticulum, is reported. Progression of the diverticulum was followed up according to MRI. The diverticulum of the lateral ventricular wall has emerged in the interval of 1 year (14 months have passed between the two MRI examinations) and spread towards the quadrigeminal cistern. In addition, compression of cerebellum, aqueductus cerebri Sylvii, and the fourth ventricle of the brain have emerged. A surgical treatment was suggested after the hydrocephalus had been initially revealed (when the diverticulum had not been formed yet); however, the child's parents refused the therapy. One year later, a series of epileptic seizures emerged, and MR scans showed a cystic neoplasm in the postcranial fossa above the cerebellum. The genesis of the cyst and its nature were unclear and additional invasive examination methods were required. MSCT ventriculography confirmed the diverticulum of the right lateral ventricle towards the quadrigeminal cistern. PMID- 25909749 TI - [Recommended protocol for treating complicated and uncomplicated acute spinal injury in adults (Association of Neurosurgeons of Russia). Part 2]. PMID- 25909750 TI - Rapid emergence of multidrug resistant, H58-lineage Salmonella typhi in Blantyre, Malawi. AB - INTRODUCTION: Between 1998 and 2010, S. Typhi was an uncommon cause of bloodstream infection (BSI) in Blantyre, Malawi and it was usually susceptible to first-line antimicrobial therapy. In 2011 an increase in a multidrug resistant (MDR) strain was detected through routine bacteriological surveillance conducted at Queen Elizabeth Central Hospital (QECH). METHODS: Longitudinal trends in culture-confirmed Typhoid admissions at QECH were described between 1998-2014. A retrospective review of patient cases notes was conducted, focusing on clinical presentation, prevalence of HIV and case-fatality. Isolates of S. Typhi were sequenced and the phylogeny of Typhoid in Blantyre was reconstructed and placed in a global context. RESULTS: Between 1998-2010, there were a mean of 14 microbiological diagnoses of Typhoid/year at QECH, of which 6.8% were MDR. This increased to 67 in 2011 and 782 in 2014 at which time 97% were MDR. The disease predominantly affected children and young adults (median age 11 [IQR 6-21] in 2014). The prevalence of HIV in adult patients was 16.7% [8/48], similar to that of the general population (17.8%). Overall, the case fatality rate was 2.5% (3/94). Complications included anaemia, myocarditis, pneumonia and intestinal perforation. 112 isolates were sequenced and the phylogeny demonstrated the introduction and clonal expansion of the H58 lineage of S. Typhi. CONCLUSIONS: Since 2011, there has been a rapid increase in the incidence of multidrug resistant, H58-lineage Typhoid in Blantyre. This is one of a number of reports of the re-emergence of Typhoid in Southern and Eastern Africa. There is an urgent need to understand the reservoirs and transmission of disease and how to arrest this regional increase. PMID- 25909751 TI - Melanin-Like Pigment Synthesis by Soil Bacillus weihenstephanensis Isolates from Northeastern Poland. AB - Although melanin is known for protecting living organisms from harmful physical and chemical factors, its synthesis is rarely observed among endospore-forming Bacillus cereus sensu lato. Here, for the first time, we reported that psychrotolerant Bacillus weihenstephanensis from Northeastern Poland can produce melanin-like pigment. We assessed physicochemical properties of the pigment and the mechanism of its synthesis in relation to B. weihenstephanensis genotypic and phenotypic characteristics. Electron paramagnetic resonance (EPR) spectroscopy displayed a stable free radical signal of the pigment from environmental isolates which are consistent with the commercial melanin. Fourier transform infrared spectroscopy (FT-IR) and physicochemical tests indicated the phenolic character of the pigment. Several biochemical tests showed that melanin-like pigment synthesis by B. weihenstephanensis was associated with laccase activity. The presence of the gene encoding laccase was confirmed by the next generation whole genome sequencing of one B. weihenstephanensis strain. Biochemical (API 20E and 50CHB tests) and genetic (Multi-locus Sequence Typing, 16S rRNA sequencing, and Pulsed-Field Gel Electrophoresis) characterization of the isolates revealed their close relation to the psychrotrophic B. weihenstephanensis DSMZ 11821 reference strain. The ability to synthesize melanin-like pigment by soil B. weihenstephanensis isolates and their psychrotrophic character seemed to be a local adaptation to a specific niche. Detailed genetic and biochemical analyses of melanin-positive environmental B. weihenstephanensis strains shed some light on the evolution and ecological adaptation of these bacteria. Moreover, our study raised new biotechnological possibilities for the use of water-soluble melanin like pigment naturally produced by B. weihenstephanensis as an alternative to commercial non-soluble pigment. PMID- 25909752 TI - Causes of decreased life expectancy over the life span in bipolar disorder. AB - BACKGROUND: Accelerated aging has been proposed as a mechanism explaining the increased prevalence of comorbid general medical illnesses in bipolar disorder. AIMS: To test the hypothesis that lost life years due to natural causes starts in early and mid-adulthood, supporting the hypothesis of accelerated aging. METHODS: Using individual data from nationwide registers of patient with a diagnosis of bipolar disorder we calculated remaining life expectancies before age 90 years for values of age 15, 25, 35...75 years among all individuals alive in year 2000. Further, we estimated the reduction in life expectancy due to natural causes (physical illnesses) and unnatural causes (suicide and accidents) in relation to age. RESULTS: A total of 22,635 patients with bipolar disorder were included in the study in addition to data from the entire Danish general population of 5.4 million people. At age 15 years, remaining life expectancy before age 90 years was decreased 12.7 and 8.9 life years, respectively, for men and women with bipolar disorder. For 15-year old boys with bipolar disorder, natural causes accounted for 58% of all lost life years and for 15-year old girls, natural causes accounted for 67% increasing to 74% and 80% for 45-year old men and women, respectively. LIMITATIONS: Data concern patients who get contact to hospital psychiatry only. CONCLUSIONS: Natural causes of death is the most prevalent reason for lost life years already from adolescence and increases substantially during early and mid-adulthood, in this way supporting the hypothesis of accelerated aging. Early intervention in bipolar disorder should not only focus on improving outcome of the bipolar disorder but also on decreasing the risk of comorbid general medical illnesses. PMID- 25909753 TI - Weighted estimation of the accelerated failure time model in the presence of dependent censoring. AB - Independent censoring is a crucial assumption in survival analysis. However, this is impractical in many medical studies, where the presence of dependent censoring leads to difficulty in analyzing covariate effects on disease outcomes. The semicompeting risks framework offers one approach to handling dependent censoring. There are two representative estimators based on an artificial censoring technique in this data structure. However, neither of these estimators is better than another with respect to efficiency (standard error). In this paper, we propose a new weighted estimator for the accelerated failure time (AFT) model under dependent censoring. One of the advantages in our approach is that these weights are optimal among all the linear combinations of the previously mentioned two estimators. To calculate these weights, a novel resampling-based scheme is employed. Attendant asymptotic statistical results for the estimator are established. In addition, simulation studies, as well as an application to real data, show the gains in efficiency for our estimator. PMID- 25909754 TI - Genetic differentiation in Indian Major Carp, Cirrhinus mrigala (Hamilton, 1822) from Indian Rivers, as revealed by direct sequencing analysis of mitochondrial Cytochrome b region. AB - A 307 bp segment of Cytochrome b gene of mtDNA was sequenced and analyzed for 90 individuals of Cirrhinus mrigala collected across the three rivers, namely Ganges, Narmada and Brahmaputra. Analyses revealed the presence of 14 haplotypes with haplotype diversity (h) ranging from 0.304 to 0.692, and nucleotide diversity (pi) 0.002-0.043. The majority of variation was found within the population (96.21%), and the FST value (0.035) as well as the value of exact test of population differentiation (0.893) were found to be insignificant (p<0.05). Analysis of molecular variance (AMOVA) also indicated insignificant differentiation among sub-populations. Generally, low genetic differences were observed even though those populations were from different geographic locations. The present study suggests a single panmictic population of C. mrigala across the three rivers of India. PMID- 25909755 TI - A generalizable platform for interrogating target- and signal-specific consequences of electrophilic modifications in redox-dependent cell signaling. AB - Despite the known propensity of small-molecule electrophiles to react with numerous cysteine-active proteins, biological actions of individual signal inducers have emerged to be chemotype-specific. To pinpoint and quantify the impacts of modifying one target out of the whole proteome, we develop a target protein-personalized "electrophile toolbox" with which specific intracellular targets can be selectively modified at a precise time by specific reactive signals. This general methodology, T-REX (targetable reactive electrophiles and oxidants), is established by (1) constructing a platform that can deliver a range of electronic and sterically different bioactive lipid-derived signaling electrophiles to specific proteins in cells; (2) probing the kinetics of targeted delivery concept, which revealed that targeting efficiency in cells is largely driven by initial on-rate of alkylation; and (3) evaluating the consequences of protein-target- and small-molecule-signal-specific modifications on the strength of downstream signaling. These data show that T-REX allows quantitative interrogations into the extent to which the Nrf2 transcription factor-dependent antioxidant response element (ARE) signaling is activated by selective electrophilic modifications on Keap1 protein, one of several redox-sensitive regulators of the Nrf2-ARE axis. The results document Keap1 as a promiscuous electrophile-responsive sensor able to respond with similar efficiencies to discrete electrophilic signals, promoting comparable strength of Nrf2-ARE induction. T-REX is also able to elicit cell activation in cases in which whole cell electrophile flooding fails to stimulate ARE induction prior to causing cytotoxicity. The platform presents a previously unavailable opportunity to elucidate the functional consequences of small-molecule-signal- and protein target-specific electrophilic modifications in an otherwise unaffected cellular background. PMID- 25909756 TI - Sociotechnical attributes of safe and unsafe work systems. AB - Theoretical and practical approaches to safety based on sociotechnical systems principles place heavy emphasis on the intersections between social organisational and technical-work process factors. Within this perspective, work system design emphasises factors such as the joint optimisation of social and technical processes, a focus on reliable human-system performance and safety metrics as design and analysis criteria, the maintenance of a realistic and consistent set of safety objectives and policies, and regular access to the expertise and input of workers. We discuss three current approaches to the analysis and design of complex sociotechnical systems: human-systems integration, macroergonomics and safety climate. Each approach emphasises key sociotechnical systems themes, and each prescribes a more holistic perspective on work systems than do traditional theories and methods. We contrast these perspectives with historical precedents such as system safety and traditional human factors and ergonomics, and describe potential future directions for their application in research and practice. PRACTITIONER SUMMARY: The identification of factors that can reliably distinguish between safe and unsafe work systems is an important concern for ergonomists and other safety professionals. This paper presents a variety of sociotechnical systems perspectives on intersections between social- organisational and technology--work process factors as they impact work system analysis, design and operation. PMID- 25909757 TI - Isotopic and Geochemical Tracers for U(VI) Reduction and U Mobility at an in Situ Recovery U Mine. AB - In situ recovery (ISR) uranium (U) mining mobilizes U in its oxidized hexavalent form (U(VI)) by oxidative dissolution of U from the roll-front U deposits. Postmining natural attenuation of residual U(VI) at ISR mines is a potential remediation strategy. Detection and monitoring of naturally occurring reducing subsurface environments are important for successful implementation of this remediation scheme. We used the isotopic tracers (238)U/(235)U (delta(238)U), (234)U/(238)U activity ratio, and (34)S/(32)S (delta(34)S), and geochemical measurements of U ore and groundwater collected from 32 wells located within, upgradient, and downgradient of a roll-front U deposit to detect U(VI) reduction and U mobility at an ISR mining site at Rosita, TX, USA. The delta(238)U in Rosita groundwater varies from +0.610/00 to -2.490/00, with a trend toward lower delta(238)U in downgradient wells. The concurrent decrease in U(VI) concentration and delta(238)U with an epsilon of 0.480/00 +/- 0.080/00 is indicative of naturally occurring reducing environments conducive to U(VI) reduction. Additionally, characteristic (234)U/(238)U activity ratio and delta(34)S values may also be used to trace the mobility of the ore zone groundwater after mining has ended. These results support the use of U isotope-based detection of natural attenuation of U(VI) at Rosita and other similar ISR mining sites. PMID- 25909759 TI - Changes in peptidergic fiber density in the synovium of mice with collagenase induced acute arthritis. AB - The effect of acute osteoarthritis (OA) on peripheral nerve fibers (NFs) in synovial tissue, and their association with histological changes were investigated in collagenase-induced OA mice. Collagenase (10 U in 5 MUL saline) was injected into the right knee, and the same volume of saline was injected into the left knee as the control. Mice were sacrificed 1, 2, 3, and 4 weeks after the collagenase injection. Histopathological changes in the knee joints were evaluated. The numbers of protein gene product (PGP) 9.5-, calcitonin-gene related peptide (CGRP)-, and substance P (SP)-positive NFs in the synovial tissue were determined, and their densities in the tissue were calculated. The densities of PGP 9.5- and CGRP-positive NFs in the synovium were drastically decreased 1 week after the collagenase injection. However, by week 4, the density of PGP 9.5- and CGRP-positive NFs had recovered to 84% and 79% of their normal levels, respectively. Despite the poor correlation between the synovitis score and the density of CGRP- or SP-positive NFs in the synovium, the ossification rate of chondrophytes in chondro/osteophyte lesions correlated strongly with the density of CGRP-positive NFs (R = 0.855). These results suggest that the ossification of chondrophytes occurred in parallel with the increase in CGRP-positive fiber density in the synovium during the acute phase of collagenase-induced OA. PMID- 25909758 TI - Neuroreceptor activation by vibration-assisted tunneling. AB - G protein-coupled receptors (GPCRs) constitute a large family of receptor proteins that sense molecular signals on the exterior of a cell and activate signal transduction pathways within the cell. Modeling how an agonist activates such a receptor is fundamental for an understanding of a wide variety of physiological processes and it is of tremendous value for pharmacology and drug design. Inelastic electron tunneling spectroscopy (IETS) has been proposed as a model for the mechanism by which olfactory GPCRs are activated by a bound agonist. We apply this hyothesis to GPCRs within the mammalian nervous system using quantum chemical modeling. We found that non-endogenous agonists of the serotonin receptor share a particular IET spectral aspect both amongst each other and with the serotonin molecule: a peak whose intensity scales with the known agonist potencies. We propose an experiential validation of this model by utilizing lysergic acid dimethylamide (DAM-57), an ergot derivative, and its deuterated isotopologues; we also provide theoretical predictions for comparison to experiment. If validated our theory may provide new avenues for guided drug design and elevate methods of in silico potency/activity prediction. PMID- 25909760 TI - Hybrid nanostructured C-dot decorated Fe3O4 electrode materials for superior electrochemical energy storage performance. AB - Research on energy storage devices has created a niche owing to the ever increasing demand for alternative energy production and its efficient utilisation. Here, a novel composite of Fe3O4 nanospheres and carbon quantum dots (C-dots) have been synthesized by a two step chemical route. Hybrids of C-dots with metal oxides can contribute to charge storage capacity through the combined effect of Faradaic pseudocapacitance from the Fe3O4 and the excellent electrical properties of the C-dots, which are a promising new member of the carbon family. The structural and morphological properties of the obtained Fe3O4-C hybrid nanocomposite were extensively studied. Detailed electrochemical studies show that the high performance of the magnetically responsive Fe3O4-C hybrid nanocomposite makes it an efficient supercapacitor electrode material. The remarkable improvement in the electrochemical performance of the Fe3O4-C hybrid nanocomposite is attributed to the Faradaic pseudocapacitance of Fe3O4 coupled with the high electrical conductivity of the C-dot which aided in fast transport and ionic motion during the charge-discharge cycles. Cyclic voltammetry and galvanostatic charge-discharge studies of Fe3O4-C hybrid nanocomposite show that the nanosystem delivers a maximum specific capacitance of ~208 F g(-1). These results demonstrate that the novel Fe3O4-C hybrid nanocomposite has great potential as a high performance electrode material for supercapacitors. PMID- 25909762 TI - Associations between neighborhood perceptions and mental well-being among older adults. AB - This study examined whether perceived neighborhood factors were associated with positive well-being in older adults using data from the English Longitudinal Study of Ageing. Neighborhood perceptions were assessed at baseline (2006/2007) and three measures of well-being - hedonic, eudaimonic and evaluative - were assessed at baseline and follow-up (2010/2011) for 6134 participants. In cross sectional and longitudinal analyses, negative neighborhood perceptions were associated with poorer well-being on all three measures. These associations remained significant after adjusting for a range of sociodemographic and health status variables and depressive symptoms. PMID- 25909761 TI - Childhood neighbourhoods as third places: Developing durable skills and preferences that enhance wellbeing in adulthood. AB - Study purpose The social environment is an important new area in neighbourhoods and health research that complements existing research on the built environment and household characteristics. Through a narrative analysis of the life-stories of 16 women we explored the influence of the neighbourhood social environment on social wellbeing. PRINCIPAL RESULTS: In order for adults to capitalise on local health-enhancing social opportunities they require particular social skills and preferences. We found one way the attainment of those skills and preferences comes about is through the experience of the childhood neighbourhood as a third place, with preferences and practices being carried forward to adulthood, influencing wellbeing through different modes of neighbourly engagement. MAJOR CONCLUSIONS: The experience of the childhood neighbourhood as a third place provided the opportunity for establishing a durable, taken-for-granted template of how to do 'neighbourhood'. Without such a template, the benefits to well-being associated with local social connections are difficult to access in adulthood. PMID- 25909763 TI - Fluorinated and Conformationally Fixed Derivatives of L-HomoDMDP: Synthesis and Glycosidase Inhibition. AB - Fluorinated and conformationally fixed derivatives of L-homoDMDP, i.e., 2,5 dideoxy-2,5-imino-DL-glycero-L-manno-heptitol, have been synthesized from d xylose-derived cyclic nitrone 10 with oxazolidinone 19 or 28 and oxazinanone 22 or 32 as key intermediates. An evaluation of glycosidase inhibition showed replacement of the C-6 hydroxyl groups with fluoride in L-homoDMDP and its C-6 epimer did not have a significant influence on alpha-glucosidase inhibition by these iminosugars, while replacement of an amino group with a cyclic carbamate group in most conformationally fixed derivatives led to a sharp decrease in the level of glycosidase inhibition, revealing the importance of the free amino group in interaction of enzymes with these molecules. PMID- 25909764 TI - beta-Cyclodextrin at the Water/1-Bromobutane Interface: Molecular Insight into Reverse Phase Transfer Catalysis. AB - Molecular insight into the role of beta-cyclodextrin (betaCD) as a phase transfer catalyst at the liquid/liquid interface is obtained by molecular dynamics simulations of the structure and dynamics of betaCD adsorbed at the interface between water and 1-bromobutane. In particular, we consider the structure and dynamics of the water and bromobutane molecules inside the betaCD cavity and compare them with the behavior when betaCD is dissolved in bulk water. betaCD is preferentially oriented at the interface, with the cavity opening along the interface normal. While in bulk water the cavity includes 6-8 water molecules that are relatively mobile with short residence time, at the interface the cavity is mostly dehydrated and includes a single bromobutane molecule. This inclusion complex is stable in bulk water. The implication of this behavior for reverse phase transfer catalysis is discussed. PMID- 25909765 TI - Reverse Oblique and Transverse Intertrochanteric Femoral Fractures Treated With the Long Cephalomedullary Nail. AB - OBJECTIVE: To evaluate the healing rate, complications, role of reduction and screw placement, and the 1-year mortality in the treatment of reverse oblique and transverse intertrochanteric femoral fractures treated with the long cephalomedullary nail. DESIGN: Retrospective review. SETTING: Two different Level 1 trauma centers: Geisinger Medical Center and the University of Utah. PATIENTS: One hundred forty-eight patients with intertrochanteric fractures (AO/OTA class 31-A3) eligible for review. All patients had a minimum of 12 months of follow-up and were available for radiologic checks and assessment of outcomes and complications. INTERVENTION: Long cephalomedullary nail. MAIN OUTCOME MEASURES: Medical records were reviewed for reoperation, demographic parameters, length of hospital stay, estimated blood loss, and need for transfusion. Mortality rates at 1 month, 6 months, and 1 year were also recorded. Patients were followed clinically and radiographically at 6 weeks, 3 months, 6 months, 12 months, and yearly as needed. RESULTS: The average age of patients was 69.9 (range, 19-95) years. Average length of follow-up was 53 (range, 12-148) months. The average surgical time was 71.8 (range, 26-229) minutes. Twenty-four patients (16%) required blood transfusions, and the average transfusion required was 205.1 mL (range, 20-800). Five different long nail designs were used to treat the patients. One patient (0.6%) experienced an intraoperative complication. Eighteen patients (12%) sustained postoperative complications. Twelve (8%) patients required reoperations. One-year mortality rates were 10.1%. CONCLUSIONS: Long cephalomedullary nails remain the preferred treatment option for the treatment of 31-A3-type fractures, demonstrating acceptable complication rates, low reoperation rates, and high rates of healing. LEVEL OF EVIDENCE: Therapeutic Level IV. See Instructions for Authors for a complete description of levels of evidence. PMID- 25909766 TI - Automatic and controlled stimulus processing in conflict tasks: Superimposed diffusion processes and delta functions. AB - An elaborated diffusion process model (a Diffusion Model for Conflict Tasks, DMC) is introduced that combines conceptual features of standard diffusion models with the notion of controlled and automatic processes. DMC can account for a variety of distributional properties of reaction time (RT) in conflict tasks (e.g., Eriksen flanker, Simon, Stroop). Specifically, DMC is compatible with all observed shapes of delta functions, including negative-going delta functions that are particularly challenging for the class of standard diffusion models. Basically, DMC assumes that the activations of controlled and automatic processes superimpose to trigger a response. Monte Carlo simulations demonstrate that the unfolding of automatic activation in time largely determines the shape of delta functions. Furthermore, the predictions of DMC are consistent with other phenomena observed in conflict tasks such as error rate patterns. In addition, DMC was successfully fitted to experimental data of the standard Eriksen flanker and the Simon task. Thus, the present paper reconciles the prominent and successful class of diffusion models with the empirical finding of negative-going delta functions. PMID- 25909769 TI - High-Sensitivity Surface-Enhanced Raman Scattering (SERS) Substrate Based on a Gold Colloid Solution with a pH Change for Detection of Trace-Level Polycyclic Aromatic Hydrocarbons in Aqueous Solution. AB - In this study, a gold colloid solution whose parameters were optimized, and without any surfactants, was developed as a surface-enhanced Raman scattering (SERS) substrate for the detection of trace-level polycyclic aromatic hydrocarbons (PAHs). A gold colloid solution with 57 nm gold particles and pH 13 was prepared to be the SERS substrate. It had impressive enhancement that was two orders of magnitude higher than that of a gold colloid solution with 57 nm gold particles and without pH change (pH 6). Even with a compact field-based Raman spectrometer, naphthalene, phenanthrene, anthracene, fluoranthene, and pyrene were detected, with limits of detection at 6.8 nM, 3.4 nM, 1.8 nM, 0.68 nM (680 pM), and 0.44 nM (440 pM), respectively. The significant enhancement was ascribed to an electromagnetic mechanism and a charge-transfer mechanism. Quantitative analyses for these five PAHs in water were also performed. The SERS intensities of PAHs were found to have good linear dependence relations with the concentrations in low concentration. This high-sensitivity, easily prepared substrate offers a promising technology for the quantitative detection of trace level PAHs. PMID- 25909770 TI - Terahertz (6-15 THz) Spectroscopy and Numerical Modeling of Intermolecular Vibrations in Benzoic Acid and Its Derivatives. AB - Terahertz spectroscopy of benzoic acid (BA) and two of its derivatives, 2 hydroxybenzoic acid (2OH-BA) and 3-hydroxybenzoic acid (3OH-BA), has been investigated in the spectral region 200 to 500 cm(-1) (6.06 to 15.15 THz). The spectra show distinct absorption features. There is agreement between some of the absorption lines observed for these compounds, despite a shift in energy, which is attributed to the differences in the molecular structures. Numerical modeling gave corresponding absorption lines, and this helped in the assignment. Temperature dependence studies revealed that most of the absorption lines are composite lines in this frequency region. PMID- 25909771 TI - Optical Characteristics and Chemical Composition of Dissolved Organic Matter (DOM) from Riparian Soil by Using Excitation-Emission Matrix (EEM) Fluorescence Spectroscopy and Mass Spectrometry. AB - Understanding the quantity and quality of soil dissolved organic matter (DOM) in riparian buffer zones is critical for explaining the biogeochemical processes of soil DOM in river ecosystems. Here, we investigated the dissolved organic carbon, fluorescent DOM (FDOM), and DOM molecules from riparian soils on Chongming Island in eastern China. Simultaneously, the soil DOM was extensively characterized in terms of the total aromaticity index (TAI) and several optical indices. The excitation (Ex)-emission (Em) matrix parallel factor analysis results showed that two humic-like components were present (Ex/Em = 283(364)/454 nm; 337/410 nm), a fulvic-like component (Ex/Em = 241/426 nm) and a microbial degradation component (Ex/Em = 295/382 nm). The humic-like and fulvic-like substances were the main components in the riparian soil FDOM, accounting for ~90% of the FDOM. Mass spectrometry provided more detailed information for the soil DOM molecules. Six chemical fractions, amino acids, carbonyl compounds, fatty acids, lipids, proteins and sugars, were identified using liquid chromatography with quadrupole time-of-flight mass spectrometry. Lipids, proteins, and carbonyl compounds were dominant in the soil DOM, accounting for >85% of the detected molecules (m/z < 1000). Significant differences were observed between the quantities of the six soil DOM chemical fractions at the different sampling locations. Discriminant molecules verified the hypothesis that the chemical soil DOM fractions varied with the land use of the adjacent watersheds. The TAI for the soil DOM could provide more reliable information regarding the biogeochemical processes of DOM. The carbonyl compounds and lipid fractions controlled this index. Overall, the optical indices and TAI values can improve our understanding of soil DOM quality; however, the optical indices did not provide quantitative evidence regarding the sources or properties of the soil DOM. The observations from this study provided detailed information regarding the soil DOM quality and the presence of specific molecules and improved our understanding of the biogeochemical processes of DOM. PMID- 25909772 TI - Optical Properties of Sodium Chloride Solution Within the Spectral Range from 300 to 2500 nm at Room Temperature. AB - The optical properties of sodium chloride (NaCl) solution were experimentally determined by double optical pathlength transmission method in the spectral range from 300 to 2500 nm at the NaCl concentration range from 0 to 360 g/L. The results show that the refractive index of NaCl solution increases with NaCl concentrations and correlates nonlinearly with the concentration of NaCl solution. The absorption index of NaCl solution increases with NaCl concentrations in the visible spectral range of 300-700 nm, but varies little in the near-infrared spectral range of 700-2500 nm at room temperature. For the sake of applications, the fitted formulae of the refractive index and absorption index of NaCl solution as a function of wavelength and NaCl concentration are presented. PMID- 25909774 TI - Contemporary perioperative management of adult familial dysautonomia (Riley-Day syndrome). AB - Familial dysautonomia (Riley-Day syndrome) is a rare multisystem disorder associated with an excess risk of perioperative morbidity and mortality. Because life expectancy is limited, few reports consider the perioperative management of familial dysautonomia in adults with advanced disease and end-organ dysfunction. Here, we report on the management of an adult patient with familial dysautonomia, highlighting recent developments in perioperative technology and pharmacology of special relevance to this challenging population. PMID- 25909773 TI - Characterization of Bacterial and Fungal Microbiome in Children with Hirschsprung Disease with and without a History of Enterocolitis: A Multicenter Study. AB - Development of potentially life-threatening enterocolitis is the most frequent complication in children with Hirschsprung disease (HSCR), even after definitive corrective surgery. Intestinal microbiota likely contribute to the etiology of enterocolitis, so the aim of this study was to compare the fecal bacterial and fungal communities of children who developed Hirschsprung-associated enterocolitis (HAEC) with HSCR patients who had never had enterocolitis. Eighteen Hirschsprung patients who had completed definitive surgery were enrolled: 9 had a history of HAEC and 9 did not. Fecal DNA was isolated and 16S and ITS-1 regions sequenced using Next Generation Sequencing and data analysis for species identification. The HAEC group bacterial composition showed a modest reduction in Firmicutes and Verrucomicrobia with increased Bacteroidetes and Proteobacteria compared with the HSCR group. In contrast, the fecal fungi composition of the HAEC group showed marked reduction in diversity with increased Candida sp., and reduced Malassezia and Saccharomyces sp. compared with the HSCR group. The most striking finding within the HAEC group is that the Candida genus segregated into "high burden" patients with 97.8% C. albicans and 2.2% C. tropicalis compared with "low burden" patients 26.8% C. albicans and 73% C. tropicalis. Interestingly even the low burden HAEC group had altered Candida community structure with just two species compared to more diverse Candida populations in the HSCR patients. This is the first study to identify Candida sp. as potentially playing a role in HAEC either as expanded commensal species as a consequence of enterocolitis (or treatment), or possibly as pathobioants contributing to the pathogenesis of HAEC. These findings suggest a dysbiosis in the gut microbial ecosystem of HAEC patients, such that there may be dominance of fungi and bacteria predisposing patients to development of HAEC. PMID- 25909775 TI - Alcohol increases bonding between the tracheal tube and the tracheal tube connector. AB - The tracheal tube (TT) connector needs to be firmly seated in both the TT and the breathing circuit to prevent disconnection during use. However, at times, the connector may loosen from its connection into the TT, increasing the likelihood of disconnection. We report a very simple yet useful technique to circumvent this problem. PMID- 25909776 TI - Emergency cardiopulmonary bypass for massive pulmonary embolism occurring during nephrectomy. AB - We report a case of cardiac arrest secondary to pulmonary tumor embolization occurring in a patient undergoing nephrectomy for renal cell carcinoma with a tumor thrombus invading the inferior vena cava infrahepatically. Tumor embolization in such cases is very rare (1.5%), but if it occurs, mortality is 75%. In our case, resources were rapidly mobilized, and cardiopulmonary bypass was initiated for pulmonary embolectomy within 34 minutes of the cardiac arrest. The patient's trachea was extubated on postoperative day 1, and he was discharged home 9 days later neurologically intact. Excellent preoperative and intraoperative communication among all involved health care providers, as well as rapid mobilization of the available resources, played important roles in the patient's positive outcome. PMID- 25909777 TI - Airway Compromise and Perioperative Management of a Patient with Acquired Factor XIII Inhibitor. AB - Perioral hematomas can lead to acute airway compromise and can present significant challenges in both direct and indirect approaches to airway instrumentation. In patients with normal cell counts and routine coagulation tests, spontaneous hematomas are rare, but when encountered, they elicit a limited differential diagnosis that includes von Willebrand factor deficiency, platelet dysfunction, and the acquired factor XIII (FXIII) deficiency. Although spontaneous hematoma formation resulting from FXIII inhibition has been reported, we describe what may be the first reported case of FXIII inhibitor-related hematoma leading to acute airway compromise. Successful management of this patient required multidisciplinary cooperation among anesthesiologists, intensivists, otolaryngologists, and hematologists. PMID- 25909778 TI - Editorial Comment: Factor XIII: One More Critical Factor for Hemostasis. PMID- 25909779 TI - Function of the Pseudomonas aeruginosa NrdR Transcription Factor: Global Transcriptomic Analysis and Its Role on Ribonucleotide Reductase Gene Expression. AB - Ribonucleotide reductases (RNRs) are a family of sophisticated enzymes responsible for the synthesis of the deoxyribonucleotides (dNTPs), the building blocks for DNA synthesis and repair. Although any living cell must contain one RNR activity to continue living, bacteria have the capacity to encode different RNR classes in the same genome, allowing them to adapt to different environments and growing conditions. Pseudomonas aeruginosa is well known for its adaptability and surprisingly encodes all three known RNR classes (Ia, II and III). There must be a complex transcriptional regulation network behind this RNR activity, dictating which RNR class will be expressed according to specific growing conditions. In this work, we aim to uncover the role of the transcriptional regulator NrdR in P. aeruginosa. We demonstrate that NrdR regulates all three RNR classes, being involved in differential control depending on whether the growth conditions are aerobic or anaerobic. Moreover, we also identify for the first time that NrdR is not only involved in controlling RNR expression but also regulates topoisomerase I (topA) transcription. Finally, to obtain the entire picture of NrdR regulon, we performed a global transcriptomic analysis comparing the transcription profile of wild-type and nrdR mutant strains. The results provide many new data about the regulatory network that controls P. aeruginosa RNR transcription, bringing us a step closer to the understanding of this complex system. PMID- 25909780 TI - A Maltose-Binding Protein Fusion Construct Yields a Robust Crystallography Platform for MCL1. AB - Crystallization of a maltose-binding protein MCL1 fusion has yielded a robust crystallography platform that generated the first apo MCL1 crystal structure, as well as five ligand-bound structures. The ability to obtain fragment-bound structures advances structure-based drug design efforts that, despite considerable effort, had previously been intractable by crystallography. In the ligand-independent crystal form we identify inhibitor binding modes not observed in earlier crystallographic systems. This MBP-MCL1 construct dramatically improves the structural understanding of well-validated MCL1 ligands, and will likely catalyze the structure-based optimization of high affinity MCL1 inhibitors. PMID- 25909782 TI - [New biomarkers and drug targets for diagnosis and therapy of Alzheimer's disease (molecular determinants of zinc-dependent oligomerization of Beta-amyloid)]. AB - In view of the amyloid hypothesis of Alzheimer's disease (AD), the key molecular event is the structural transition of Beta-amyloid from the physiologically normal monomer state to soluble neurotoxic oligomers accumulating in the form of insoluble extracellular aggregates (amyloid plaques) in brain tissues. Zinc ions are known to play a crucial role in the formation of these pathological aggregates. The authors and collaborators have identified that the certain chemical modification and point amino acid substitutions in the metal-binding domain play a critical role in the formation of neurotoxic zinc-dependent oligomers and induce the development of cerebral amyloidosis and other pathological processes characteristic of AD. The results allow to use these forms of Beta-amyloid as potential biomarkers of early diagnosis of AD. Zinc-dependent dimerization and oligomerization of Beta-amyloid can be used as drug target for treatment of AD. PMID- 25909781 TI - The effect of protease inhibitors on the induction of osteoarthritis-related biomarkers in bovine full-depth cartilage explants. AB - OBJECTIVE: The specific degradation of type II collagen and aggrecan by matrix metalloproteinase (MMP)-9, -13 and ADAMTS-4 and -5 (aggrecanase-1 and -2) in the cartilage matrix is a critical step in pathology of osteoarthritis (OA). The aims of this study were: i) To investigate the relative contribution of ADAMTS-4 and ADAMTS-5 to cartilage degradation upon catabolic stimulation; ii) To investigate the effect of regulating the activities of key enzymes by mean of broad-spectrum inhibitors. METHODS: Bovine full-depth cartilage explants stimulated with tumor necrosis factor alpha (TNF-alpha) and Oncostatin M (OSM) were cultured for 21 days with or without a number of inhibitors targeting different types of proteases. Monoclonal antibodies were raised against the active sites of ADAMTS 4, -5, MMP-9 and -13, and 4 ELISAs were developed and technically validated. In addition, the established AGNxI (ADAMTS-degraded aggrecan), AGNxII (MMP-degraded aggrecan), and CTX-II (MMP-derived type II collagen) were quantified in the explants-conditioned media. RESULTS: We found that: i) Active ADAMTS-4, MMP-9, 13 were released in the late stage of TNF-alpha/ OSM stimulation, whereas no significant active ADAMTS-5 was detected in either extracts or supernatants; ii) Active ADAMTS-4 was primarily responsible for E373-374A bond cleavage in aggrecan in this setting; and iii) The compensatory mechanism could be triggered following the blockage of the enzyme caused by inhibitors. CONCLUSIONS: ADAMTS-4 appeared to be the major protease for the generation of 374ARGS aggrecan fragment in the TNF-alpha/OSM stimulated bovine cartilage explants. This study addresses the need to determine the roles of ADAMTS-4 and ADAMTS-5 in human articular degradation in OA and hence identify the attractive target for slowing down human cartilage breakdown. PMID- 25909783 TI - [Adolescent's refusal of school: a psychopathological aspect]. AB - OBJECTIVE: Despite the multiple studies on the school refusal phenomenon, clinical/psychopathological aspects of this problem need further studies. Authors performed a clinical/psychopathological analysis of the school refusal phenomenon in adolescents who are under supervision of a psychiatrist. MATERIAL AND METHODS: It were examined 223 adolescent patients (169 males and 54 females) with different appearances of school refusal. RESULTS: A set of factors predisposing to school refusal (family system dysfunction, heritability, character features, psychological immaturity, demoralization syndrome) was identified. Psychopathological causes of school refusal were divided into school phobia (31.8%), protest reactions in the frames of developing disorders of excitable personality type (4.9%), signs of mood disorders (22.9%), schizophrenic process (14.4%) and symptoms of organic cognitive impairment (26%). The analysis of clinical/dynamic characteristics of school refusal in different clinical variants demonstrated the differences by gender, stereotype of development, cognitive function and the dynamics of the phenomenon per se. CONCLUSION: In accordance to clinical variant of school refusal, we suggest to use differentiated therapeutic and preventive strategies. PMID- 25909784 TI - [Changes in light sensitivity of the visual system with age and in patients with ischemic optic neuropathy]. AB - OBJECTIVE: To evaluate contrast-color sensitivity (CCS) of central vision, contrast-frequency sensitivity (CFS) and dynamic visual acuity (DVA) in healthy people and patients with ischemic optic neuropathy (ION). MATERIAL AND METHODS: The study was performed for 115 eyes with normal static visual acuity (1.0) in 111 healthy people; 25 patients (39 eyes) with acute anterior ION and 26 patients (26 eyes) with chronic ION. Assessment of static visual acuity and refraction as well as ophthalmoscopy of the eye fundus were performed. RESULTS AND CONCLUSION: Based on the data analysis of CFS, DVA and photometry of CCS, the quantitative estimation of age-related changing in light sensitivity and changing sensitivity of ill and healthy eyes of patients with acute and chronic ION has been carried out. The differences between changing of these functional parameters are used for discussion of the role of age-related changes of visual system hemodynamics in decreasing of light sensitivity. The possibility of usig the data of light sensitivity decreasing in the early diagnostics of visual system ischemic impairment is discussed. PMID- 25909785 TI - [Information processing and brain metabolic characteristics in patients at ultra high risk for endogenous psychosis]. AB - OBJECTIVE: Functional and structural brain abnormalities in people at high risk for psychosis is a subject of intensive studies in biological psychiatry over the last decades. We studied correlations between neurophysiological and neuroimaging parameters in ultra-high risk patients. MATERIAL AND METHODS: Fifty-six patients, aged 17-25 years, with nonpsychotic mental disorders were examined. The control group included 30 age- and sex-matched healthy people. Neurophysiological study measured sensory gating. Proton MR-spectroscopy was used to study metabolic processes in the brain (index for glutamate/glutamine, N-acetylaspartate and choline containing compounds in the dorsolateral prefrontal cortex and thalamus of both hemispheres as well as in the genu and splenium of the corpus callosum). RESULTS AND CONCLUSION: We found the abnormality of sensory gating in patients at ultra-high risk for endogenous psychosis that was not correlated with the metabolic parameters. The latter were normal or were normalized during treatment. PMID- 25909786 TI - [Venlafaxine in the treatment of moderate and severe depressions: the ways to increase treatment efficacy]. AB - OBJECTIVE: To find factors influencing the efficacy of venlafaxine in moderate and severe depressions. MATERIAL AND METHODS: An observational study was carried out in real clinical practice. We examined 62 patients with depression, 21 men and 41 women, aged from 19 to 61 years, treated with venlafaxine. The duration of treatment was 84 days (first at the hospital and then at home). The initial dose was 75 mg daily, mean therapeutic dose 225 mg daily. Patient's status was assessed using clinical/psychological methods and psychometric scales (MADRS, Beck scale, CGI, UKU). RESULTS AND CONCLUSION: The high efficacy of the drug in the treatment of severe and moderate depressions was demonstrated. Venlafaxine was mostly effective in the treatment of anxious depression and less effective for hypochondriac depression. The rapid increase in dose of venlafaxine makes it possible to reach treatment effect in shorter time without worsening drug tolerability. PMID- 25909787 TI - [Efficacy of sanatorium treatment to patients with consequences of cerebrovascular disease]. AB - OBJECTIVE: To estimate the efficacy of the introduction of Russian standard of the sanatorium treatment of patients with cerebrovascular diseases. MATERIAL AND METHODS: We examined 480 neurological patients. Efficacy of treatment was estimated according to conclusions of the physician on the basis of dynamic supervision and the scale "The Rehabilitation Profile of Activity" (Rehabilitation Activities Profile). RESULTS AND CONCLUSION: The general for all patients was physiotherapy exercises and diet therapy. The majority of patients received medical shower (62.9+/-2.2%), psychotherapy (83.5+/-1.7%) and used terrainkur (52.1+/-2.3%). Frequencies of separate methods of treatment effects in groups of patients with positive and negative outcomes did not differ. The reliability of distinction was noted only for frequencies of dry-air bathtubs (36 and 16%), local bathtubs (39 and 14%), medical shower (76 and 52%), sinusoidal modulated currents (36 and 18%), reflex therapy (36 and 18%), massage (58 and 38%), psychotherapy (100 and 76%), naftalan therapy (44 and 24%). The significance of the ratio between sensitivity and specificity of treatment methods is emphasized. PMID- 25909788 TI - [The effect of cellex on cognitive and speech impairments in the acute stage of stroke]. AB - OBJECTIVE: To study the effect of cellex on the recovery of cognitive and speech functions in the acute stage of stroke. MATERIAL AND METHODS: A multicenter comparative open clinical study of the efficacy and safety of cellex in treatment of patients with acute stroke was carried out in 6 clinical sites. The study involved 180 patients, including 147 (81.7%) with ischemic stroke and 33 (18.3%) with hemorrhagic stroke. Celex was introduced subcutaneously in dose 0.1 mg once a day during the first 10 days and from 21 to 27th days. RESULTS AND CONCLUSION: The rapid and complete recovery of neurological and cognitive functions was observed. The more marked dynamics was seen in patients with greater initial stroke severity and with large hemisphere lesions. PMID- 25909789 TI - [Application of whole exome sequencing in the diagnosis of hereditary neurological diseases]. AB - Whole Exome Sequencing (WES) is a promising method in human genetics. Because the majority of pathogenic mutations that lead to the development of diseases are localized in exons and splice sites, WES could become a major tool for the diagnosis of diseases with a complex hereditary nature. This tool appears to be particularly useful for hereditary neurological diseases, such as autism spectrum disorders, Charcot-Marie-Tooth disease and others. In our review, we discuss the clinical application of WES, with special emphasis on the diagnosis of hereditary neurological diseases. PMID- 25909790 TI - [Description and validation of a new scale for assessment of autonomy in patients with schizophrenia]. AB - OBJECTIVE: During the last years there is a clear shift of interest from acute to non-acute stages of schizophrenia: psychopathology and quality of remission, social functioning, and quality of life of patients. Authors think that in addition to that, a separate object of research should be the ability of patient to independent existence, or phenomenon of autonomy. For systematic research of autonomy in patients with schizophrenia a specialized assessment scale was constructed. MATERIAL AND METHODS: On the basis of preliminary clinical data, we realized that for description of autonomy it is necessary to consider consistency of patients at least in the following areas of life: to possess sufficient level of physical and psychic power; to be able to form specific and realistic goals at least in the nearest future and structure behavior correspondingly to goal achievement; to be able to use support from the social environment in case of deficit of personal resources; to use efficiently and on regular basis contacts with a doctor and other medical resources; to be able to manage everyday needs from hygiene to self-sufficiency, including ability to support compliance. Scale comprises five items. Each of them is assessed on basis of semi-structured interview and other sources of information: medical records, reports from relatives and/or care-givers, medical stuff. In order to study the validity of the scale 40 patients (13 males and 27 females, age 49.8+/-9, duration of illness 22+/-8.6), who were diagnosed as schizophrenia according to ICD-10. They were assessed with the help of the scale of autonomy and well-known scales GAF, PSP, PANSS, NSA and CGI-S, cognitive functioning was assessed by BACS. RESULTS: Analysis of internal consistency showed high consistency of items - Cronbach's alfa - 0.83. Analysis of convergent validity demonstrated low or moderate correlations of indices with related scales GAF and PSP. Discriminative validity showed low or moderate correlations only with negative subscale of PANSS, CGI-S score, NSA total score, BACS total score. CONCLUSION: Sompliance of the scale of autonomy to major psychodiagnostic requirements showed that the scale is a new reliable and sensitive psychometric instrument. The study demonstrated that the scale measured specifically ability of patients to be autonomous (self-dependent support of culturally adequate existence in presence of chronic disease) and can't be reduced to existing categories - quality of life, personal or social functioning. PMID- 25909791 TI - [Contrast agents in MRI-diagnosis of multiple sclerosis]. AB - Magnetic resonance imaging using contrast agents plays an important role in diagnosis and assessment of treatment efficacy in multiple sclerosis. The development of contrast agents on the basis of gadolinium or iron oxide nanoparticles has potential for diagnosis of pathological foci (tumors, amyloid plaques, inflammation and foci of demyelination or necrosis) in nervous system diseases. Newly developing types of diagnostic substances for visualization of pathological foci in multiple sclerosis are presented in this review. PMID- 25909792 TI - [EEG frequency and regional properties in patients with paranoid schizophrenia: effects of positive and negative symptomatology prevalence]. AB - OBJECTIVE: EEG changes in schizophrenic patients are caused by a multitude of factors related to clinical heterogeneity of the disease, current state of patients, and conducted therapy. EEG spectral analysis remains an actual methodical approach for the investigation of the neurophysiological mechanisms of the disease. The goal of the investigation was the study of frequency and regional EEG correlating with the intensity of productive and negative disorders. MATERIAL AND METHODS: Models of summary prevalence of positive/negative disorders and evidence of concrete clinical indices of the PANSS scale were used. Spectral characteristics of background EEG in the frequency range of 1-60 Hz were studied in 35 patients with paranoid schizophrenia free from psychoactive medication and in 19 healthy volunteers. RESULTS: It was established that the main index of negative symptomatology in summary assessment was diffuse increase of spectral power of gamma and delta ranges. Deficient states with the predominance of volitional disorders were characterized by a lateralized increase of spectral power of beta-gamma ranges in the left hemisphere, and of delta range - in frontal areas of this hemisphere. Positive symptomatology was noticeably less reflected in EEG changes than negative ones. CONCLUSION: An analysis of psychopathological symptom complexes revealed the significance of spatially structured EEG patterns in the beta range: for the delusion disturbances with psychic automatism phenomena - in frontal areas of the left hemisphere, and for the paranoid syndrome with primary interpretative delusion - in cortical areas of the right hemisphere. PMID- 25909793 TI - [No effect of the BDNF Val66Met polymorphism on cognitive deficit in patients with schizophrenia and on the risk of the disease in their relatives]. AB - OBJECTIVE: The brain-derived neurotrophic factor (BDNF) gene is thought to be a candidate gene for schizophrenia. At the same time, many studies failed to find the association between BDNF and the disease though the contribution of the BDNF Val66Met polymorphism to the variance of characteristics of schizophrenia has been confirmed. Authors suggested that this contribution was the consequence of the involvement of this gene in the formation of "cognitive reserve" that had a protective effect on the different aspects of the disease. This protective effect should emerge in relatively intact cognitive function in patients with the protective Val66Met genotype as well as in the accumulation of the protective genotypes in unaffected relatives. MATERIAL AND METHODS: We examined 169 patients with schizophrenia spectrum disorders, 320 their first-degree relatives and control groups using molecular-genetic and experimental psychological methods. RESULTS: No effect of the Val66Met polymorphism on verbal memory, executive functions and total index of cognitive functioning was found. Besides, we did not find any differences in Val66Met genotype frequencies in first-degree relatives of patients with schizophrenia and healthy people without family history of schizophrenia. CONCLUSION: The results do not support our hypothesis that BDNF is a gene of "cognitive reserve". PMID- 25909794 TI - [The effect of long-chain polyunsaturated omega-3 fatty acids on the arterial stiffness parameters in patients with diabetes mellitus type 2 and cardiovascular autonomic neuropathy]. AB - OBJECTIVE: To analyze the effect of long-chain (LC) polyunsaturated w-3 fatty acids (PUFAs) on the daily arterial stiffness parameters in patients with type 2 diabetes (DM2) and cardiovascular autonomic neuropathy (CAN). MATERIAL AND METHODS: The study involved 39 patients with DM2 and verified functional stage of CAN. Patients were divided into 2 groups: therapy group (n=21) and control group (n=18). Patients of the control group received traditional hypoglycemic therapy; patients of the therapy group additionally received 1 capsule/day of the omega-3 PUFAs for three months. RESULTS: The use of the omega-3 PUFAs resulted in a statistically significant decrease in aortic augmentation index (AAI) and pulse wave velocity in the aorta (PWV) during the active period. There was a decrease in AAI in the aorta and the brachial artery and in PWV in the aorta during the night. CONCLUSION: The efficacy of omega-3-PUFAs is a result of a direct effect of the pharmacological agent on the circadian arterial stiffness parameters. PMID- 25909795 TI - [Publishing activity of Russian research institutes in the field of psychiatry and addictology in 2006-2013]. AB - OBJECTIVE: To compare the publication activity of 6 psychiatric institutes based on the data from the Russian Citation Index (RCI). MATERIAL AND METHODS: Weighted average data of the last five years was selected for analysis: number of publications and citations per author, number of citations per publication, impact factor of journals published the papers. The analysis of the dynamics of publication activity and citations for the period of 2006-2013 for 6 institutes has been performed. RESULTS: The analysis shows that the Research Center of Mental Health of the Russian Academy of Medical Sciences (RAMS) is the leader among in publication activity in the field of "psychiatry and addiction medicine". In second place the Moscow Research Institute of Psychiatry and the National Research Center of Addictology. Then, by a large margin, are the Bechterev St.Peterburg Research Psycho-Neurological Institute, the Serbsky National Research Center of Social and Forensic Psychiatry and the Siberian Research Mental Health Institute of RAMS. CONCLUSION: RCI data is an important source of information regarding scientific activity of research institutes although the data should be interpreted with caution. PMID- 25909796 TI - [Characteristics of autonomic-vascular status in patients with hemihypoplasia]. AB - OBJECTIVE: To evaluate characteristics of autonomic-vascular status in patients with hemihypoplasia. MATERIAL AND METHODS: We examined 67 patients with hemihypoplasia, aged from 16 to 43 years. The control group included 35 healthy people. All patients underwent general neurological examination and detailed study of the autonomic nervous system using special probes and acupuncture tests. Arterial ultrasound was used to evaluate the vascular system. RESULTS AND CONCLUSION: The syndrome of autonomic dystonia was identified in 63 (94%) patients. Asympathicotonic variant of the syndrome, along with the decrease in autonomic reactivity and activity maintenance, were most frequent. All diameter sizes of the lumen of the arteries of shortened limbs were within age-adjusted normal limits and did not exceed the values of physiological asymmetry. Asymmetry of resistive index between paired arteries on the right and left sides did not exceed 3%. PMID- 25909797 TI - [Comorbodity of kleptomania and eating disorders]. AB - A case of comorbid anorexia nervosa and kleptomania is reported in a female patient aged 31 years old. Personality pathology and kleptomanic behavior developed since childhood together with dysmorphophobia related to the congenital chest defect. Later on, the distinct association between the severity of dysmorphophobia, affective disorder and appearances of pathological drives was identified. The patient received several ICD-10 diagnoses (F61.0, F50.0, F62.3, F33.1). The patient's condition was improved after pharmacotherapy in the combination with psychotherapy. PMID- 25909798 TI - [Chronic tics and Tourette syndrome in children and adolescents: diagnostic and treatment characteristics]. AB - Chronic tics (CT) are observed in 3-4% population, Tourette syndrome (TS) in 0.1 3.0%. In most cases, tic disorders start at age 2-15 years, but frequently they are diagnosed late. Clinical presentations of tics and comorbid disorders are various and depend on child's age. Difficulties in treatment of CT are associated with their persistence and those for TS with the fluctuating course of tics and probable onset of the disease in the form of behavioral disorders. Treatment of CT and TS is individual. Methods of behavioral and psychotherapy are recommended for a certain period of time if tics do not hamper everyday life. Increase in tick frequency and severity indicate the necessity of using pharmacological treatment. The European recommendations on pharmacotherapy of tic disorders and the drugs available in Russia are considered. Results of the studies on the efficacy of antiepileptic drugs and tenoten children in CT and TS are presented. PMID- 25909799 TI - [Depressive disorders in psychopathological structure of first episode psychosis manifesting in adolescence and young adulthood]. AB - OBJECTIVE: Clinical analysis of affective disorders in the structure of acute transitory psychosis in adolescents and young adulthood. MATERIAL AND METHODS: We examined 40 patients, 12 men and 28 women, mean age 18+/-1.3 years, with acute transitory psychosis (ICD-10 item F23). Psychometric scales PANSS, HAMD-21 and YMRS were used for assessment of patient's mental state. RESULTS AND CONCLUSION: Marked affective disturbances were characteristic of acute psychotic disorders. The inversion of depressive affect was more frequently observed in psychoses with the symptoms of schizophrenia compared to those without schizophrenic symptoms. Mixed mania with the following residual affective symptoms may be considered as a predictor of the repeated psychotic episode. The results obtained in the study allow to classify 25% of the cases as atypical onset of schizophrenia that gives grounds to prescribe supportive therapy after the clinical reduction of the first psychotic episode. PMID- 25909800 TI - [About the comorbidity of affective and conversion disorders in epilepsy]. AB - In this literature review, special attention is drawn to the pathogenesis of conversion disorders in patients with epilepsy, in particular, with psychogenic non-epileptic seizures. Diagnostic issues and pharmacotherapy of affective and conversion disorders in patients with epilepsy is discussed. PMID- 25909801 TI - [Cognitive impairments in depression: neuropsychological and MRI-studies]. AB - OBJECTIVE: A complex neuropsychological and neuroimaging study of deep brain structures in depression with cognitive impairment. MATERIAL AND METHODS: We studied 73 patients with endogenous depression and 86 patients with depressive syndrome in temporal epilepsy. MRI and neuropsychological methods were used to study brain structures. Results and sonclusion. Neurocognitive impairment was more severe in patients with depressive syndrome in the structure of temporal epilepsy. The differences between the patients with endogenous and organic (temporal epilepsy) affective disturbances were determined by the more marked memory and spatial-constructive impairments in patients with organic disorders. Deficit of executive functions, planning functions and cognitive organization were more typical for the patients with endogenous affective disorders. The MRI study revealed the decrease in the left hippocampus due to sclerotic processes in patients with temporal epilepsy and the increase in the right amygdale in patients with endogenous depressive disorders. The results demonstrate the significant similarity between characteristics of the cognitive profile in patients with endo- and exogenous depressions. PMID- 25909802 TI - [Impairments of social cognition and depressions]. AB - Directions in the studies of social cognition in depression are presented. Social cognition should be studied basing on the experience and content of the key psychotherapeutic approaches to depression treatment as well as on the studies of cognitive and motivational characteristics of patients with depression. The authors suggest the directions for further development of the problem: the relationship between impairment of social intelligence and general deficit in abilities to self-regulation of thinking; studies of a role of motivation and social anhedonia in the structure of social cognition impairment. PMID- 25909803 TI - [A comparative study of different types of pharmacotherapy in treatment of depressive phase of bipolar II disorder]. AB - OBJECTIVE: A comparative evaluation of the efficacy and safety of different types of pharmacotherapy: antidepressant monotherapy (agomelatine or sertraline), mood stabilizer monotherapy (valproate) and combination therapy (valproate + sertraline) in bipolar II disorder patients with major depressive episode. MATERIAL AND METHODS: A 6-week open randomized study included 89 inpatients and outpatients. Basic criteria of efficacy were >=50% reduction of HAMD total score and remission (<=7 points) to the end of the study. RESULTS: At the end of the study (day 42), the highest number of patients with 50% reduction of HAMD total score was noted in the sertraline (65%) and combination therapy (60%) groups, in the valproate group it was 57.1%, and the lowest - in agomelatine group (42.9%), but the differences were not statistically significant. Remission was observed in 45% patients in combination therapy group compared with 33.3% in valproate group, 32.1% in agomelatine group and only 20% in group of sertraline, but the differences between the groups also were not significant. CONCLUSION: Antidepressants (agomelatine and sertraline) have demonstrated fast but insufficient influence on the reduction of depression in the patients. Treatment with sertraline rarely led to remission and was frequently associated with high rate of switch into hypomania. Valproate therapy was moderately effective and well-tolerated without risk of switching. Combination of valproic acid with sertraline had the highest efficacy and was fairly well tolerated. PMID- 25909804 TI - [Spectral model of therapy resistant depression]. AB - In the present article, we describe different staging models of therapy resistant depression (TRD). Their advantages and disadvantages are pointed out. Also the possibilities of using various TRD staging models in clinical practice are considered. It is proposed to develop a single spectral model of TRD. PMID- 25909805 TI - [Evidence-based choice and antidepressants treatment in psychiatry]. AB - Depression is a severe and usually recurrent mental disorder which leads to a prominent impairment of physical and social functioning, a reduced quality of life of the patients, implies as well an increased morbidity and mortality. Reducing the social-economic depression burden is possible in the optimization of decision-making process of antidepressant choice (including SSRIs and SNRIs) based on the evidence-based risk/benefit ratio and resource saving potential treatment involving target psychosocial interventions and monitoring of long-term treatment adherence. PMID- 25909806 TI - [Treatment of endogenous depression with venflaxine: clinical action, tolerability and personalized treatment options]. AB - OBJECTIVE: To specify clinical action of venflaxine during the course treatment of patients with different depressive states of endogenous nature. MATERIAL AND METHODS: An open naturalistic study of 32 patients with different nosological forms of endogenous depression (manic-depressive psychosis, cyclothymia, schizophrenia) was carried out. Duration of the course treatment with venflaxine (velaxin) administered in daily dose of 37,5-300 mg was 56 days. Clinical and psychometric methods were used. RESULTS: Venflaxine was a highly effective antidepressant. In the end of treatment, a "good" therapeutic effect with >50% reduction in total scores on the Hamilton scale (HAMD-D) was achieved in 84,4% of patients, a "marked" effect up to complete recovery with >80% reduction in HAMD-D scores was in 78,1% of cases. CONCLUSION: Due to its clinical characteristics, venflaxine may be regarded as a multiprofile antidepressant with the distinct balanced action. In the spectrum of its antidepressant activity, a thymoleptic effect is most pronounced compared to anxiolytic and stimulating effects. This provides a high efficacy of the drug in different types of endogenous depression (anxiety, apatho-adynamic and, in particular, melancholic). PMID- 25909807 TI - [Monoamine-hormonal interactions in the pathogenesis of anxious depression]. AB - Biochemical aspects of the relationship between monoaminergic and hormonal systems in the pathogenesis of anxious depression are analyzed on the basis of literature and own results published earlier. Significant alterations in biogenic monoamine metabolism and changes in the hormonal status, that reflects homeostasis disturbance in whole, are inherent to anxious depression. The biochemical mechanisms of imbalance between serotonergic and noradrenergic systems and a role of cortisol in this process are discussed. PMID- 25909808 TI - [Disturbance of serum albumin conformation in patients with melancholic depression]. AB - OBJECTIVE: Conformational protein changes may be an important component of the disturbance of molecular processes in the development of pathological process in the body. We studied conformations of albumin molecule in the blood of patients with depression using biophysical -nanotechnical approach. MATERIAL AND METHODS: We examined 19 patients with depression and 25 healthy controls. Properties of serum albumin were compared in patients with typical melancholic depression and controls using spectroscopy (subnanosecond range) with K-35 fluorescent probe. RESULTS AND CONCLUSION: The properties of albumin binding sites in patients before and after treatment differed from those in controls. The authors suggest that it points to the changes in albumin molecule conformation that may influence the functional state of the protein. It has been suggested that these changes may be considered as biomarkers of pharmacotherapeutic efficacy. PMID- 25909809 TI - Interfacility Transports Utilizing the 9-1-1 Emergency Medical Services System. AB - BACKGROUND: With the increasing development of regional specialty centers, emergency physicians are often confronted with patients needing definitive care unavailable at their hospital. Interfacility transports (IFTs) may be a useful option to ensure timely, definitive patient care. However, since traditional IFT can be a challenging and time-consuming process, some EMS agencies that have previously limited their service to 9-1-1 emergency responses are now performing emergency IFTs. OBJECTIVE: We sought to determine the frequency and nature of transfers provided by a local fire-based 9-1-1 EMS agency that recently began to provide limited IFT for time-critical emergencies. METHODS: A retrospective review of paramedic reports for all IFTs between April 2007 and March 2014 in the City of Los Angeles, California. All IFTs initiated by 9-1-1 call from an emergency department (ED) and performed by Los Angeles Fire Department paramedics were included. Reason for transfer, patient demographics, and key time metrics were captured. RESULTS: There were 919 IFTs during the study period, out of approximately 1,160,000 total ambulance transports (0.1%). The most frequent reason for IFT request was for transport of patients with ST segment elevation MI (STEMI) to a STEMI receiving center, followed by major trauma to a trauma center, and intracranial hemorrhage to a center with neurosurgical capability. Less common reasons included vascular emergencies, acute stroke, obstetric emergencies, and transfers to pediatric critical care facilities. Median transport time was 8 minutes (IQR 6-13 minutes) and median total time for IFT was 51 minutes (IQR 39-69 minutes). All IFTs involved a potentially life-threatening condition requiring a higher level of care than was available at the referring hospital. CONCLUSIONS: Emergent ED-to-ED interfacility transport can provide access to time critical definitive care. EMS agencies that have limited the scope of their response to community 9-1-1 emergencies should have policies in place to assure timely response for emergent IFT requests. PMID- 25909810 TI - Quantifying error in OSCE standard setting for varying cohort sizes: A resampling approach to measuring assessment quality. AB - BACKGROUND: The use of the borderline regression method (BRM) is a widely accepted standard setting method for OSCEs. However, it is unclear whether this method is appropriate for use with small cohorts (e.g. specialist post-graduate examinations). AIMS AND METHODS: This work uses an innovative application of resampling methods applied to four pre-existing OSCE data sets (number of stations between 17 and 21) from two institutions to investigate how the robustness of the BRM changes as the cohort size varies. Using a variety of metrics, the 'quality' of an OSCE is evaluated for cohorts of approximately n = 300 down to n = 15. Estimates of the standard error in station-level and overall pass marks, R(2) coefficient, and Cronbach's alpha are all calculated as cohort size varies. RESULTS AND CONCLUSION: For larger cohorts (n > 200), the standard error in the overall pass mark is small (less than 0.5%), and for individual stations is of the order of 1-2%. These errors grow as the sample size reduces, with cohorts of less than 50 candidates showing unacceptably large standard error. Alpha and R(2) also become unstable for small cohorts. The resampling methodology is shown to be robust and has the potential to be more widely applied in standard setting and medical assessment quality assurance and research. PMID- 25909811 TI - Determining the Functions of HIV-1 Tat and a Second Magnesium Ion in the CDK9/Cyclin T1 Complex: A Molecular Dynamics Simulation Study. AB - The current paradigm of cyclin-dependent kinase (CDK) regulation based on the well-established CDK2 has been recently expanded. The determination of CDK9 crystal structures suggests the requirement of an additional regulatory protein, such as human immunodeficiency virus type 1 (HIV-1) Tat, to exert its physiological functions. In most kinases, the exact number and roles of the cofactor metal ions remain unappreciated, and the repertoire has thus gained increasing attention recently. Here, molecular dynamics (MD) simulations were implemented on CDK9 to explore the functional roles of HIV-1 Tat and the second Mg2+ ion at site 1 (Mg12+). The simulations unveiled that binding of HIV-1 Tat to CDK9 not only stabilized hydrogen bonds (H-bonds) between ATP and hinge residues Asp104 and Cys106, as well as between ATP and invariant Lys48, but also facilitated the salt bridge network pertaining to the phosphorylated Thr186 at the activation loop. By contrast, these H-bonds cannot be formed in CDK9 owing to the absence of HIV-1 Tat. MD simulations further revealed that the Mg12+ ion, coupled with the Mg22+ ion, anchored to the triphosphate moiety of ATP in its catalytic competent conformation. This observation indicates the requirement of the Mg12+ ion for CDK9 to realize its function. Overall, the introduction of HIV 1 Tat and Mg12+ ion resulted in the active site architectural characteristics of phosphorylated CDK9. These data highlighted the functional roles of HIV-1 Tat and Mg12+ ion in the regulation of CDK9 activity, which contributes an important complementary understanding of CDK molecular underpinnings. PMID- 25909812 TI - Neural substrates of motor and non-motor symptoms in Parkinson's disease: a resting FMRI study. AB - BACKGROUND: Recently, non-motor symptoms of Parkinson's disease (PD) have been considered crucial factors in determining a patient's quality of life and have been proposed as the predominant features of the premotor phase. Researchers have investigated the relationship between non-motor symptoms and the motor laterality; however, this relationship remains disputed. This study investigated the neural connectivity correlates of non-motor and motor symptoms of PD with respect to motor laterality. METHODS: Eight-seven patients with PD were recruited and classified into left-more-affected PD (n = 44) and right-more affected PD (n = 37) based on their MDS-UPDRS (Movement Disorder Society-sponsored revision of the Unified Parkinson's Disease Rating Scale) motor examination scores. The patients underwent MRI scanning, which included resting fMRI. Brain regions were labeled as ipsilateral and contralateral to the more-affected body side. Correlation analysis between the functional connectivity across brain regions and the scores of various symptoms was performed to identify the neural connectivity correlates of each symptom. RESULTS: The resting functional connectivity centered on the ipsilateral inferior orbito-frontal area was negatively correlated with the severity of non-motor symptoms, and the connectivity of the contralateral inferior parietal area was positively correlated with the severity of motor symptoms (p < 0.001, |r| > 0.3). CONCLUSIONS: These results suggest that the inferior orbito-frontal area may play a crucial role in non-motor dysfunctions, and that the connectivity information may be utilized as a neuroimaging biomarker for the early diagnosis of PD. PMID- 25909813 TI - Combined Influence of EGF+61G>A and TGFB+869T>C Functional Polymorphisms in Renal Cell Carcinoma Progression and Overall Survival: The Link to Plasma Circulating MiR-7 and MiR-221/222 Expression. AB - The epidermal growth factor (EGF) is responsible for the activation of intracellular signal transducers that act on cell-cycle progression, cell motility, angiogenesis and inhibition of apoptosis. However, cells can block these effects activating opposite signaling pathways, such as the transforming growth factor beta 1 (TGFbeta1) pathway. Thus changes in expression levels of EGF and TGFB1 in renal cells might modulate the renal cell carcinoma (RCC) development, in consequence of changes in regulatory elements of signaling networks such as the microRNAs (miRNAs). Our purpose was to investigate the synergic role of EGF+61G>A and TGFB1+869T>C polymorphisms in RCC development. Genetic polymorphisms were studied by allelic discrimination using real-time PCR in 133 RCC patients vs. 443 healthy individuals. The circulating EGF/EGFR-MAPK related miR-7, miR-221 and miR-222 expression was analyzed by a quantitative real time PCR in plasma from 22 RCC patients vs. 27 healthy individuals. The intermediate/high genetic proliferation profile patients carriers present a significantly reduced time-to-progression and a higher risk of an early relapse compared with the low genetic proliferation profile carriers (HR = 8.8, P = 0.038) with impact in a lower overall survival (Log rank test, P = 0.047). The RCC patients presented higher circulating expression levels of miR-7 than healthy individuals (6.1-fold increase, P<0.001). Moreover, the intermediate/high genetic proliferation profile carriers present an increase in expression levels of miR-7, miR-221 and miR-222 during the RCC development and this increase is not observed in low genetic proliferation profile (P<0.001, P = 0.004, P<0.001, respectively). The stimulus to angiogenesis, cell-cycle progression and tumoral cells invasion, through activation of EGFR/MAPK signaling pathway in intermediate/high proliferation profile carriers is associated with an early disease progression, resulting in a poor overall survival. We also demonstrated that the intermediate/high proliferation profile is an unfavorable prognostic factor of RCC and miR-7, miR-221 and miR-222 expressions may be useful phenotype biomarkers of EGFR/MAPK activation. PMID- 25909815 TI - Anisotropic encapsulation-induced synthesis of asymmetric single-hole mesoporous nanocages. AB - Asymmetric single-hole mesoporous silica nanocages, which are eccentric hollow structured spheres and consist of mesoporous shell with an open hole on their surface, with uniform particle size (100-240 nm), have successfully been synthesized via a novel anisotropic encapsulation of the mesoporous silica. In this unique nanocarrier, the eccentric hollow cavity and big hole (~25 nm) can serve as a storage space and passage for large guest molecules. Meanwhile, the uniform mesopores (2-10 nm) with a high surface area (~500 m(2)/g) in the silica shells of the nanocages can provide storage space for small guest molecules. The obtained single-hole mesoporous nanocages can be endowed upconversion luminescence. The obtained upconversion nanoparticles functionalized eccentric single-hole nanorattles were used to codeliver bovine serum albumin and doxorubicin dual-sized guests. The release of the dual-sized guests can be well controlled independently by heat and near-infrared (NIR) light with the assistance of NIR to ultraviolet/visible (UV/vis) optical properties of upconversion nanoparticles and heat-sensitive phase change materials. PMID- 25909814 TI - Establishment of a new quality control and vaccine safety test for influenza vaccines and adjuvants using gene expression profiling. AB - We have previously identified 17 biomarker genes which were upregulated by whole virion influenza vaccines, and reported that gene expression profiles of these biomarker genes had a good correlation with conventional animal safety tests checking body weight and leukocyte counts. In this study, we have shown that conventional animal tests showed varied and no dose-dependent results in serially diluted bulk materials of influenza HA vaccines. In contrast, dose dependency was clearly shown in the expression profiles of biomarker genes, demonstrating higher sensitivity of gene expression analysis than the current animal safety tests of influenza vaccines. The introduction of branched DNA based-concurrent expression analysis could simplify the complexity of multiple gene expression approach, and could shorten the test period from 7 days to 3 days. Furthermore, upregulation of 10 genes, Zbp1, Mx2, Irf7, Lgals9, Ifi47, Tapbp, Timp1, Trafd1, Psmb9, and Tap2, was seen upon virosomal-adjuvanted vaccine treatment, indicating that these biomarkers could be useful for the safety control of virosomal-adjuvanted vaccines. In summary, profiling biomarker gene expression could be a useful, rapid, and highly sensitive method of animal safety testing compared with conventional methods, and could be used to evaluate the safety of various types of influenza vaccines, including adjuvanted vaccine. PMID- 25909816 TI - Anaerobic microbial transformation of halogenated aromatics and fate prediction using electron density modeling. AB - Halogenated homo- and heterocyclic aromatics including disinfectants, pesticides and pharmaceuticals raise concern as persistent and toxic contaminants with often unknown fate. Remediation strategies and natural attenuation in anaerobic environments often build on microbial reductive dehalogenation. Here we describe the transformation of halogenated anilines, benzonitriles, phenols, methoxylated, or hydroxylated benzoic acids, pyridines, thiophenes, furoic acids, and benzenes by Dehalococcoides mccartyi strain CBDB1 and environmental fate modeling of the dehalogenation pathways. The compounds were chosen based on structural considerations to investigate the influence of functional groups present in a multitude of commercially used halogenated aromatics. Experimentally obtained growth yields were 0.1 to 5 * 10(14) cells mol(-1) of halogen released (corresponding to 0.3-15.3 g protein mol(-1) halogen), and specific enzyme activities ranged from 4.5 to 87.4 nkat mg(-1) protein. Chlorinated electron-poor pyridines were not dechlorinated in contrast to electron-rich thiophenes. Three different partial charge models demonstrated that the regioselective removal of halogens is governed by the least negative partial charge of the halogen. Microbial reaction pathways combined with computational chemistry and pertinent literature findings on Co(I) chemistry suggest that halide expulsion during reductive dehalogenation is initiated through single electron transfer from B12Co(I) to the apical halogen site. PMID- 25909818 TI - Increasing the delivery of next generation therapeutics from high throughput screening libraries. AB - The pharmaceutical industry has historically relied on high throughput screening as a cornerstone to identify chemical equity for drug discovery projects. However, with pharmaceutical companies moving through a phase of diminished returns and alternative hit identification strategies proving successful, it is more important than ever to understand how this approach can be used more effectively to increase the delivery of next generation therapeutics from high throughput screening libraries. There is a wide literature that describes HTS and fragment based screening approaches which offer clear direction on the process for these two distinct activities. However, few people have considered how best to identify medium to low molecular weight compounds from large diversity screening sets and increase downstream success. PMID- 25909817 TI - MicroRNA transcriptomes of distinct human NK cell populations identify miR-362-5p as an essential regulator of NK cell function. AB - Natural killer (NK) cells are critical effectors in the immune response against malignancy and infection, and microRNAs (miRNAs) play important roles in NK cell biology. Here we examined miRNA profiles of human NK cells from different cell compartments (peripheral blood, cord blood, and uterine deciduas) and of NKT and T cells from peripheral blood, and we identified a novel miRNA, miR-362-5p, that is highly expressed in human peripheral blood NK (pNK) cells. We also demonstrated that CYLD, a negative regulator of NF-kappaB signaling, was a target of miR-362-5p in NK cells. Furthermore, we showed that the over-expression of miR 362-5p enhanced the expression of IFN-gamma, perforin, granzyme-B, and CD107a in human primary NK cells, and we found that silencing CYLD with a small interfering RNA (siRNA) mirrored the effect of miR-362-5p over-expression. In contrast, the inhibition of miR-362-5p had the opposite effect in NK cells, which was abrogated by CYLD siRNA, suggesting that miR-362-5p promotes NK-cell function, at least in part, by the down-regulation of CYLD. These results provide a resource for studying the roles of miRNAs in human NK cell biology and contribute to a better understanding of the physiologic significance of miRNAs in the regulation of NK cell function. PMID- 25909819 TI - Protein oxidation affects proteolysis in a meat model system. AB - The effect of hydrogen peroxide-induced protein oxidation and pH (4.8 and 5.2) on meat proteolysis was investigated in a meat model system for dry fermented sausages. In oxidised samples, increased protein carbonyl contents and decreased thiol concentrations were found. The initial concentration of protein carbonyls was significantly lower in oxidised samples at pH4.8 than in ones at pH5.2, but after ten days comparable levels were reached. The inhibition of proteolysis by the addition of a protease inhibitor cocktail did not influence protein oxidation. Yet, proteolysis was negatively affected by low pH values as well as by oxidation, resulting in a reduced release of amino acids during ripening. PMID- 25909820 TI - Quantification of aortic calcification - how and why should we do it? PMID- 25909821 TI - Acute vascular effects of waterpipe smoking: Importance of physical activity and fitness status. AB - OBJECTIVE: While new forms of tobacco, including waterpipe (WP) smoking, continue to gain popularity, limited literature has examined the vascular health consequences. The purpose of the current study was to examine: (i) the acute WP induced changes in vascular function; (ii) whether acute changes in vascular function are modified by lifestyle behaviors (habitual physical activity, physical fitness). METHODS: Fifty three (22.7 y, 36% F, 23.4 kg/m(2)) otherwise healthy WP smokers were recruited. Strain-gauge plethysmography was used to measure forearm blood flow, vascular resistance, venous capacitance, and venous outflow at rest and following occlusion. Habitual physical activity was determined using the Arabic version of short-form international physical activity questionnaire, while physical fitness was assessed using the 6 min walk test and handgrip strength. Partial correlations were used to examine the relationships between post-smoking vascular function and lifestyle behaviors, controlling for pre-smoking vascular measures. RESULTS: (i) WP had a small effect on forearm post occlusion blood flow (d = -0.19), a moderate effect on venous outflow (d = 0.30), and a moderate effect on post-occlusion vascular resistance (d = 0.32). (ii) Total habitual physical activity strongly correlated with resting blood flow (r = 0.50) and moderately with vascular resistance (r = -0.40). Handgrip strength moderately correlated with venous capacitance (r = 0.30) and post-occlusion blood flow (r = 0.30), while 6 min walked distance moderately correlated with resting venous capacitance (r = 0.30). CONCLUSION: Waterpipe smoking is associated with immediate changes in vascular function, which are exacerbated in individuals with low habitual physical activity and physical fitness levels in young otherwise healthy individuals. PMID- 25909822 TI - Polynuclear Speciation of Trivalent Cations near the Surface of an Electrolyte Solution. AB - Despite long-standing efforts, there is no agreed upon structural model for electrolyte solutions at air-liquid interfaces. We report the simultaneous detection of the near-surface and bulk coordination environments of a trivalent metal cation (europium) in an aqueous solution by use of X-ray absorption spectroscopy. Within the first few nanometers of the liquid surface, the cations exhibit oxygen coordination typical of inner-sphere hydration of an aquated Eu(3+) cation. Beyond that, outer-sphere ion-ion correlations are observed that are otherwise not present in the bulk electrolyte. The combination of near surface and bulk sensitivities to probe metal ion speciation in electrolyte solutions is achieved by detecting electron-yield and X-ray fluorescence signals from an inverted pendant drop. The results provide new knowledge about the near surface chemistry of aqueous solutions of relevance to aerosols and ion transport processes in chemical separations and biological systems. PMID- 25909823 TI - Comprehension of figurative language in Taiwanese children with autism: The role of theory of mind and receptive vocabulary. AB - First-order theory of mind (ToM) is necessary for comprehension of metaphors, and second-order ToM is necessary for comprehension of irony. This study investigated the role of ToM and language ability in comprehending figurative language in 50 Taiwanese children with high-functioning autism spectrum disorders (HFASDs) compared with 50 typically developing children. Results showed that the No-ToM HFASDs group performed worse than the first-order ToM HFASDs group and the second order ToM HFASDs group in comprehension of metaphors, irony, sarcasm and indirect reproach, but not for indirect request. Receptive vocabulary correlated only with metaphor comprehension. The volatility of results seen among studies in terms of the relationship between ToM and figurative language comprehension is discussed. PMID- 25909824 TI - Precarious employment and new-onset severe depressive symptoms: a population based prospective study in South Korea. AB - OBJECTIVES: Considering the effect of sex and head of household responsibilities, this study was designed to evaluate whether precarious employment is associated with the development of new-onset severe depressive symptoms. METHODS: We followed 2214 male and 1276 female waged workers, <=59 years of age and without moderate depressive symptom, from the Korean Welfare Panel Study 2007-2013. Their employment status was classified as full-time permanent, precarious, self employed, or unemployed after baseline. Except for occupation and company size, all variables were treated as time-dependent. Severe depressive symptoms were measured using the 11-item Center for Epidemiologic Studies Depression Scale (CES D-11). A generalized estimating equation was used to evaluate the effect of employment status on the development of new-onset severe depressive symptoms. RESULTS: After adjusting for initial baseline CES-D-11 score, chronic disease, and other socioeconomic covariates, precarious employment was associated with the development of new-onset severe depressive symptoms among male heads of household [odds ratio (OR) 1.52, 95% confidence interval (95% CI) 1.02-2.25] and female heads of household (OR 4.19, 95% CI 1.70-10.32). In addition, the transition from full-time permanent employment to another employment status was associated with the development of new-onset severe depressive symptoms among both sexes, with an especially strong association among females. CONCLUSION: The present study suggests that, depending on head of household status and sex, precarious employment is associated with the development of new-onset severe depressive symptoms. PMID- 25909825 TI - Sustained Improvement in Neonatal Intensive Care Unit Safety Attitudes After Teamwork Training. AB - OBJECTIVES: This study aimed to measure safety attitudes in the neonatal intensive care unit (NICU) before and serially after a compulsory, multidisciplinary teamwork and communication training initiative and novel sustainment program. METHODS: Training was administered to NICU staff and subsequent sustainment efforts were directed at enculturating core principles over the following year. A modified Agency for Healthcare Research and Quality Survey on Patient Safety Culture was administered before as well as 3 and 12 months after training. Longitudinal survey results were compared with the national Agency for Healthcare Research and Quality survey data. RESULTS: Ninety six percent of 350 NICU staff were trained over 2 months. Survey response rates were 84%, 71%, and 83% before, at 3 months, and at 12 months after training, respectively. Items with sustained improvement pertained to staff empowerment and patient hand-offs. The proportion of participants who agreed with the statement, "Staff feel free to question the decisions or actions of those with more authority" increased from 55% to 76% and 83% at 3 and 12 months, respectively (P < 0.0001). The proportion of participants who disagreed with the statement, "Things 'fall between the cracks' when transferring patients from one unit to another" increased from 36% to 48% and 52% at 3 and 12 months, respectively (P < 0.01). The only significant decline was for the statement, "We are actively doing things to improve patient safety." The proportion of respondents who agreed dropped from 93% to 83% at 3 months (P = 0.02). CONCLUSIONS: A novel sustainment program after teamwork and communication training measurably improved most staff safety attitudes over 1 year. PMID- 25909826 TI - Developing a Comprehensive Model of Intensive Care Unit Processes: Concept of Operations. AB - OBJECTIVES: This study aimed to use a systems engineering approach to improve performance and stakeholder engagement in the intensive care unit to reduce several different patient harms. METHODS: We developed a conceptual framework or concept of operations (ConOps) to analyze different types of harm that included 4 steps as follows: risk assessment, appropriate therapies, monitoring and feedback, as well as patient and family communications. This framework used a transdisciplinary approach to inventory the tasks and work flows required to eliminate 7 common types of harm experienced by patients in the intensive care unit. The inventory gathered both implicit and explicit information about how the system works or should work and converted the information into a detailed specification that clinicians could understand and use. PROTOTYPE CONOPS TO ELIMINATE HARM: Using the ConOps document, we created highly detailed work flow models to reduce harm and offer an example of its application to deep venous thrombosis. In the deep venous thrombosis model, we identified tasks that were synergistic across different types of harm. We will use a system of systems approach to integrate the variety of subsystems and coordinate processes across multiple types of harm to reduce the duplication of tasks. Through this process, we expect to improve efficiency and demonstrate synergistic interactions that ultimately can be applied across the spectrum of potential patient harms and patient locations. CONCLUSIONS: Engineering health care to be highly reliable will first require an understanding of the processes and work flows that comprise patient care. The ConOps strategy provided a framework for building complex systems to reduce patient harm. PMID- 25909827 TI - Graphical data representation methods to assess the quality of LC columns. AB - We discuss the most important plot types for the kinetic performance of liquid chromatography columns and elaborate on how these plots should best be constructed and can be made dimensionless. Distinction is made between plots that are most suited for practitioners (column users) versus those most suited for theoreticians and column manufacturers. PMID- 25909828 TI - Improving brain-computer interface classification using adaptive common spatial patterns. AB - Common Spatial Patterns (CSP) is a widely used spatial filtering technique for electroencephalography (EEG)-based brain-computer interface (BCI). It is a two class supervised technique that needs subject-specific training data. Due to EEG nonstationarity, EEG signal may exhibit significant intra- and inter-subject variation. As a result, spatial filters learned from a subject may not perform well for data acquired from the same subject at a different time or from other subjects performing the same task. Studies have been performed to improve CSP's performance by adding regularization terms into the training. Most of them require target subjects' training data with known class labels. In this work, an adaptive CSP (ACSP) method is proposed to analyze single trial EEG data from single and multiple subjects. The method does not estimate target data's class labels during the adaptive learning and updates spatial filters for both classes simultaneously. The proposed method was evaluated based on a comparison study with the classic CSP and several CSP-based adaptive methods using motor imagery EEG data from BCI competitions. Experimental results indicate that the proposed method can improve the classification performance as compared to the other methods. For circumstances where true class labels of target data are not instantly available, it was examined if adding classified target data to training data would improve the ACSP learning. Experimental results show that it would be better to exclude them from the training data. The proposed ACSP method can be performed in real-time and is potentially applicable to various EEG-based BCI applications. PMID- 25909829 TI - Securing opioid substitution treatment access and quality for people who inject drugs. PMID- 25909830 TI - Acute porphyria precipitated by efavirenz. PMID- 25909831 TI - Apparent spontaneous clearance of chronic hepatitis C virus infection in a HIV co infected patient with decompensated cirrhosis: a case report. PMID- 25909832 TI - An unexpected interaction between warfarin and cobicistat-boosted elvitegravir. PMID- 25909833 TI - Lack of evidence for the selection of E138 mutations by first-generation non nucleoside reverse transcriptase inhibitors in patients infected with HIV-1 non-B subtypes. PMID- 25909834 TI - Genetic Incorporation of epsilon-N-2-Hydroxyisobutyryl-lysine into Recombinant Histones. AB - Here, we report the evolution of an orthogonal amber suppressor pyrrolysyl-tRNA synthetase (PylRS)/tRNACUA(Pyl) pair that genetically encodes the post translationally modified amino acid, epsilon-N-2-hydroxyisobutyryl-lysine (HibK), in bacteria and mammalian cells. HibK is a new type of histone mark that is widely distributed in histone proteins. The ability to site-specifically incorporate HibK into proteins provides a useful tool to probe the biological function of this newly identified post-translational modification. PMID- 25909836 TI - Effect of Acid Etching on Long-term Microleakage of Nano Ionomer Restorations in Burand Laser-prepared Cavities in Primary Teeth. AB - PURPOSE: The purpose of this study was to evaluate the effect of etching on marginal sealing of nanofilled resin-modified glass ionomer restorations in Class V cavities in primary teeth prepared with an Er, Cr:YSGG laser compared to bur preparation. METHODS: Standard Class V cavities were prepared on the buccal surfaces of 56 extracted primary canines that were randomly divided into four groups of 14 teeth each, according to laser or bur preparation and whether acid etching was used or not in the cavity. All cavities were restored with Nano primer/Ketac N100. After storage for six months in water and 2,000 thermal cycles, the specimens were placed in a one percent basic fuchsin dye solution. Dye penetration was evaluated with a stereomicroscope. The data were analyzed via nonparametric tests (P<.05). RESULTS: Etching in bur- and laser-prepared cavities significantly reduced enamel microleakage (P=.031 and P=.001, respectively). At the dentin margin, etching significantly increased microleakage in bur-prepared cavities (P=.009) and significantly decreased it in laser-prepared cavities (P=.009). CONCLUSIONS: Etching may improve the sealing ability of Ketac N100 at both margins in laser-prepared cavities and at the enamel margin in bur-prepared cavities. It had an adverse effect on dentinal sealing in aged Ketac N100 restorations in primary teeth. PMID- 25909835 TI - Haematological cancer and quality of life: a systematic literature review. AB - The aim of this study is to examine the impact of haematological cancers on quality of life (QoL). A review of the international literature was conducted from the databases 'PsycInfo' and 'Medline' using the keywords: 'haematological cancer', 'quality of life', 'physical', 'psychological', 'social', 'vocational', 'professional', 'economic', 'cognitive', and 'sexual'. Twenty-one reliable studies were analysed. Among these studies, 12 showed that haematological cancer altered overall QoL, 8 papers found a deterioration of physical dimension, 8 papers reported on functional and role dimensions, 11 papers reported on the psychological component and 9 on the social component. Moreover, one study and two manuscripts, respectively, reported deteriorated sexual and cognitive dimensions. Our review demonstrates that the different dimensions of QoL are deteriorated by haematological malignancies and, probably, by the side effects of treatment. PMID- 25909837 TI - Erosive potential of processed and fresh orange juice on human enamel. AB - PURPOSE: The purpose of this study was to analyze the erosive potential of processed and fresh orange juice on human enamel. METHODS: Sixty enamel slabs, incubated in human saliva to develop acquired pellicle, were exposed to processed and freshly squeezed juice from oranges and lime oranges. Daily erosive cycles were performed by immersing the slabs in the juices for 20 minutes over five days. During the intervals, the samples were immersed in artificial saliva. The pH, titratable acidity (TA), and buffer capacity (beta) of the juices were determined. Analysis of variance and Tukey's tests were used to compare the percentage of surface hardness loss and the amount of wear between groups. RESULTS: The ranges of pH, TA, and beta were 3.66 to 3.75, 3.33 to 110 mmol/L, and 2.98 to 40.97 mmol/L * pH, respectively. A similar erosive potential was found for all groups, except for the lime orange juices (P<.05). CONCLUSION: Both processed and freshly squeezed orange juices were erosive to enamel. However, the lime orange juice was acidless and, therefore, not able to produce any significant changes in enamel. PMID- 25909838 TI - Bond strength of a sealant to enamel after a cariogenic challenge using three bonding protocols: an in vitro study. AB - PURPOSE: The purpose of this study was to evaluate in vitro the tensile bond strength of a resin-based pit and fissure sealant to enamel after a cariogenic challenge using three bonding protocols. METHODS: The demineralized tooth specimens were assigned to three groups of equal size: Group 1 (37 percent phosphoric acid gel), Group 2 (total-etch adhesive system), and Group 3 (one-step self-etch adhesive system). After the surface treatment, a resin-based sealant was applied and cured. The specimens were thermocycled and tensile bond strength was measured using a universal testing machine by an investigator who was blinded to the group distribution. RESULTS: The mean tensile bond strength was highest with the total-etch adhesive system, which was statistically significant (P<.001). A post hoc test revealed a significant difference between Groups 1 and 2 (P<.001) and Groups 2 and 3 (P<.001), but none between Groups 1 and 3 (P=.44). CONCLUSION: The total-etch bonding system resulted in significantly higher tensile bond strength with incipient enamel caries. PMID- 25909839 TI - Contemporary behavior management techniques in clinical pediatric dentistry: out with the old and in with the new? AB - Effective behavior management guides children through the complex social context of dentistry utilizing techniques based on a current understanding of the social, emotional, and cognitive development of children. Behavior management techniques facilitate effective communication and establish social and behavioral guidelines for the dental environment. Contemporary parenting styles, expectations, and attitudes of modern parents and society have influenced the use of behavior management techniques with a prevailing emphasis on communicative techniques and pharmacological management over aversive techniques. PMID- 25909840 TI - Social Conditions and High Levels of Dental Caries in Five-year-old Children in Brazil. AB - PURPOSE: To identify factors associated with dental caries experience in at least four primary teeth in five-year-old Brazilian children. METHODS: This was a case control study, part of a prior investigation of the prevalence of dental caries in the primary dentition of five-year-old children conducted in 2006 in public health services in Recife, Brazil. Study patients had a decayed, missing, and filled teeth [dmft] score >= 4 and controls had a dmft score <= 3. The cutoff point was based on the dmft scores mean value of the study population. Categories of independent variables were sociodemographic, family structure, oral health behavior, and use of oral health services. Crude odds ratios and 95% CI were calculated. Variables associated with dmft greater than or equal to four at a significance level of P<=.20 in univariate analyses were included in multivariate logistic regression models using a backward stepwise variable selection method and permanence criterion in the final model of P<=.10. RESULTS: The study included 479 children (171 study patients and 308 controls). After controlling for confounding variables, factors associated with a dmft score >= 4 were children living in households with at least six people, residence in a poor area, caregiver's low educational level, consumption of sweets between meals, and the reason for and location of oral health care seeking. CONCLUSION: Most factors associated with high levels of dental caries in five-year-old children were related to the social conditions in which they lived. PMID- 25909841 TI - Influence of oral rehabilitation on the oral health-related quality of life of a child with ectodermal dysplasia. AB - Ectodermal dysplasia (ED) is a rare congenital hereditary disorder among a group of syndromes characterized by abnormalities of ectodermic structures. The purpose of this report is to compare the oral health-related quality of life (OHRQoL) before and after complete oral rehabilitation of a five-year-old boy with ED. Delivery of upper and lower dentures resulted in immediate improvement of the child's OHRQoL. Although ED affects patients physically and emotionally, the early oral rehabilitation of young patients is crucial to improve their social interaction and restore their speech and masticatory function. PMID- 25909842 TI - Restorative management of severely ankylosed primary molars. AB - Severe dentoalveolar ankylosis is an etiological factor for malocclusion. When infraocclusion occurs early, it progresses with time, leading to severe consequences in young children because of compensatory supra-eruption of the antagonist tooth and mesialization of adjacent teeth. Early diagnosis allows for interception of the problem and may prevent orthodontic treatment. The purpose of this manuscript is to report two cases of infraocclusion of primary mandibular second molars that were diagnosed early and were treated with composite resin crowns. The use of indirect composite restorations for ankylosed teeth is a good option for primary teeth with a moderate/ severe degree of ankylosis. PMID- 25909843 TI - Resection of Gingival Fibromatosis with High-power Laser. AB - Hereditary gingival fibromatosis (HGF), also known as hereditary gingival hyperplasia, idiopathic gingival fibromatosis, and hereditary gingival overgrowth, is a rare condition but the most common form of gingival hyperplasia. Overgrowth of gingival tissue is usually slow and progressive and may delay or prevent tooth eruption, resulting in cosmetic and functional impairments. Hypertrichosis, epilepsy, and intellectual disability may be associated with HGF, which can occur in isolation or as part of a syndrome. The purpose of this case report is to describe a diode laser resection of gingival hyperplasia in a seven year-old patient with nonsyndromic HGF and hypertrichosis. The diode laser enabled efficient removal of hypertrophic gingival tissue with good healing and minimal postoperative discomfort. PMID- 25909844 TI - Periostitis ossificans managed with endodontic treatment. AB - Periostitis ossificans (PO) is a specific type of chronic osteomyelitis. Radiographically, it is characterized by the presence of lamellae of newly formed periosteal bone outside the cortex, giving the characteristic appearance of "onion skin." The most common cause of PO is periapical infection of the mandibular permanent first molar, which occurs primarily in children and young adults. Treatment in these cases is directed toward eliminating the source of the infection, either by extraction of the offending tooth or endodontic therapy. The purpose of this paper is to present a case of PO involving a permanent mandibular first molar managed with endodontic treatment. PMID- 25909845 TI - Mucoepidermoid carcinoma of the palate in adolescence. AB - Although relatively rare, minor salivary gland tumors are more likely to be malignant in pediatric patients than in adults. Mucoepidermoid carcinoma (MEC) represents the most common malignant tumor of the salivary glands. It is critical to differentiate such tumors from common benign salivary gland lesions. The purposes of this report are to present the case of a 15-year-old female with MEC of the palate, and to discuss the importance of a thorough intraoral examination on all patients regardless of age, as well as the need for timely referral for appropriate diagnosis and treatment. PMID- 25909846 TI - Impact of Anodal and Cathodal Transcranial Direct Current Stimulation over the Left Dorsolateral Prefrontal Cortex during Attention Bias Modification: An Eye Tracking Study. AB - People with anxiety disorders show an attentional bias for threat (AB), and Attention Bias Modification (ABM) procedures have been found to reduce this bias. However, the underlying processes accounting for this effect remain poorly understood. One explanation suggests that ABM requires the modification of attention control, driven by the recruitment of the dorsolateral prefrontal cortex (DLPFC). In the present double-blind study, we examined whether modifying left DLPFC activation influences the effect of ABM on AB. We used transcranial direct current stimulation (tDCS) to directly modulate cortical excitability of the left DLPFC during an ABM procedure designed to reduce AB to threat. Anodal tDCS increases excitability, whereas cathodal tDCS decreases it. We randomly assigned highly trait-anxious individuals to one of three conditions: 1) ABM combined with cathodal tDCS, 2) ABM combined with anodal tDCS, or 3) ABM combined with sham tDCS. We assessed the effects of these manipulations on both reaction times and eye-movements on a task indexing AB. Results indicate that combining ABM and anodal tDCS over the left DLPFC reduces the total duration that participants' gaze remains fixated on threat, as assessed using eye-tracking measurement. However, in contrast to previous studies, there were no changes in AB from baseline to post-training for participants that received ABM without tDCS. As the tendency to maintain attention to threat is known to play an important role in the maintenance of anxiety, the present findings suggest that anodal tDCS over the left DLPFC may be considered as a promising tool to reduce the maintenance of gaze to threat. Implications for future translational research combining ABM and tDCS are discussed. PMID- 25909847 TI - High frequency of resistance, lack of clinical benefit, and poor outcomes in capreomycin treated South African patients with extensively drug-resistant tuberculosis. AB - BACKGROUND: There are limited data about the epidemiology and treatment-related outcomes associated with capreomycin resistance in patients with XDR-TB. Capreomycin achieves high serum concentrations relative to MIC but whether capreomycin has therapeutic benefit despite microbiological resistance remains unclear. METHODS: We reviewed the susceptibility profiles and outcomes associated with capreomycin usage in patients diagnosed with XDR-TB between August 2002 and October 2012 in two provinces of South Africa. Patients whose isolates were genotypically tested for capreomycin resistance were included in the analysis. RESULTS: Of 178 XDR-TB patients 41% were HIV-infected. 87% (154/178) isolates contained a capreomycin resistance-conferring mutation [80% (143/178) rrs A1401G and 6% (11/178) were heteroresistant (containing both the rrs A1401G mutation and wild-type sequences)]. Previous MDR-TB treatment, prior usage of kanamycin, or strain type was not associated with capreomycin resistance. 92% (163/178) of XDR TB patients were empirically treated with capreomycin. Capreomycin resistance decreased the odds of sputum culture conversion. In capreomycin sensitive and resistant persons combined weight at diagnosis was the only independent predictor for survival (p=<0.001). By contrast, HIV status and use of co amoxicillin/clavulanic acid were independent predictors of mortality (p=<0.05). Capreomycin usage was not associated with survival or culture conversion when the analysis was restricted to those whose isolates were resistant to capreomycin. CONCLUSION: In South Africa the frequency of capreomycin conferring mutations was extremely high in XDR-TB isolates. In those with capreomycin resistance there appeared to be no therapeutic benefit of using capreomycin. These data inform susceptibility testing and the design of treatment regimens for XDR-TB in TB endemic settings. PMID- 25909850 TI - EMS Intubation Improves with King Vision Video Laryngoscopy. AB - INTRODUCTION: Intubation success by paramedics has historically been variable. The lack of first-pass success (FPS) has been associated with increased adverse events. Various video laryngoscope (VL) devices have been investigated to improve success among paramedics. Conflicting research exists on VL vs. direct laryngoscopy (DL) by paramedics and on the effects of the specific King Vision device on FPS and overall success (OS) in an emergency medical services (EMS) system with low intubation frequency and historically low success rates. OBJECTIVES: To evaluate the effect of an ongoing training program using the King Vision VL on FPS, OS, and success per attempt when compared with DL in one suburban EMS system with low historical intubation success rates. METHODS: We performed a retrospective analysis of electronic patient care reports in a suburban EMS system. We analyzed three metrics of intubation success before DL and after implementation of ongoing training with VL in both cardiac arrest and in all other indications: success per attempt, overall success, and first-pass success. We also performed an intention to treat analysis of these rates to account for protocol violations. RESULTS: During the study period, intubation was attempted on 514 patients. There was no difference between the DL and VL groups in age, weight, gender, or percentage receiving paralytic medications. There was improvement over DL with VL in each of the outcome measures: overall success (64.9 vs. 91.5%, p < 0.01), first-pass success (43.8% vs. 74.2%, p < 0.01), and success per attempt (44.4 vs. 71.2%, p < 0.01). A subgroup analysis by indication for intubation also showed improvement in all metrics for all indications. There were several protocol violations: 11 of 376 attempts that should have used VL (2.9%) but were done with DL. An intention to treat analysis was therefore done. Again, we saw an improvement in all metrics for all indications. CONCLUSION: In this suburban EMS system with historically low intubation success rates and low frequency of intubation, paramedics were able to improve all measures of intubation success using the King Vision video laryngoscope and an ongoing training program when compared with direct laryngoscopy. PMID- 25909849 TI - Reduced Haemodynamic Response in the Ageing Visual Cortex Measured by Absolute fNIRS. AB - The effect of healthy ageing on visual cortical activation is still to be fully explored. This study aimed to elucidate whether the haemodynamic response (HDR) of the visual cortex altered as a result of ageing. Visually normal (healthy) participants were presented with a simple visual stimulus (reversing checkerboard). Full optometric screening was implemented to identify two age groups: younger adults (n = 12, mean age 21) and older adults (n = 13, mean age 71). Frequency-domain Multi-distance (FD-MD) functional Near-Infrared Spectroscopy (fNIRS) was used to measure absolute changes in oxygenated [HbO] and deoxygenated [HbR] haemoglobin concentrations in the occipital cortices. Utilising a slow event-related design, subjects viewed a full field reversing checkerboard with contrast and check size manipulations (15 and 30 minutes of arc, 50% and 100% contrast). Both groups showed the characteristic response of increased [HbO] and decreased [HbR] during stimulus presentation. However, older adults produced a more varied HDR and often had comparable levels of [HbO] and [HbR] during both stimulus presentation and baseline resting state. Younger adults had significantly greater concentrations of both [HbO] and [HbR] in every investigation regardless of the type of stimulus displayed (p<0.05). The average variance associated with this age-related effect for [HbO] was 88% and [HbR] 91%. Passive viewing of a visual stimulus, without any cognitive input, showed a marked age-related decline in the cortical HDR. Moreover, regardless of stimulus parameters such as check size, the HDR was characterised by age. In concurrence with present neuroimaging literature, we conclude that the visual HDR decreases as healthy ageing proceeds. PMID- 25909851 TI - Twelve tips for enhancing anatomy teaching and learning using radiology. AB - Anatomy is a keystone of many healthcare curricula and its understanding fundamental to patient care. The close relationship between clinical radiology and anatomy is well recognised and expanding. Imaging resources can be effectively integrated alongside traditional methods for learning anatomy in a resource efficient manner in order to enhance anatomy teaching. The following 12 tips have been divided into imaging tips, clinical tips and educational tips and offer practical advice and suggestions for designing and integrating radiological resources across the curriculum. PMID- 25909852 TI - Novel series of coumarinyl substituted-thiazolidin-2,4-dione analogs as anticancer agents: design, synthesis, spectral studies and cytotoxicity evaluation. AB - In this research work, a series of eighteen novel coumarinyl substituted thiazolidin-2,4-dione analogs (4a-4r) have been designed by molecular hybridization approach, synthesized and their structures were established on the basis of FTIR, 1H NMR, 13C NMR and elemental (CHN) analysis. These title compounds were screened for their cytotoxicity using MTT assay methodology against five different mammalian cancer cell lines viz. hormone dependant breast adenocarcinoma (MCF7), cervical carcinoma (HeLa), colorectal carcinoma (HT29), lung cancer (A549) and prostate adeno carcinoma (PC3). The cytotoxicity screening studies revealed that MCF-7, HeLa and A549 cancer cell lines were sensitive to all the tested compounds. Though the compounds showed varying degrees of cytotoxicity in the tested cell lines, most significant effect was observed for compounds 4i (1.06, 2.4 and 3.06 uM) and 4o (0.95, 3.2 and 2.38 MUM) against MCF7, HeLa and A549 cell lines respectively. In conclusion, the anticancer results of these promising leads strongly encouraged us for additional lead optimization with the aim of developing more potential anticancer agents. PMID- 25909848 TI - BMP9 Crosstalk with the Hippo Pathway Regulates Endothelial Cell Matricellular and Chemokine Responses. AB - Endoglin is a type III TGFbeta auxiliary receptor that is upregulated in endothelial cells during angiogenesis and, when mutated in humans, results in the vascular disease hereditary hemorrhagic telangiectasia (HHT). Though endoglin has been implicated in cell adhesion, the underlying molecular mechanisms are still poorly understood. Here we show endoglin expression in endothelial cells regulates subcellular localization of zyxin in focal adhesions in response to BMP9. RNA knockdown of endoglin resulted in mislocalization of zyxin and altered formation of focal adhesions. The mechanotransduction role of focal adhesions and their ability to transmit regulatory signals through binding of the extracellular matrix are altered by endoglin deficiency. BMP/TGFbeta transcription factors, SMADs, and zyxin have recently been implicated in a newly emerging signaling cascade, the Hippo pathway. The Hippo transcription coactivator, YAP1 (yes associated protein 1), has been suggested to play a crucial role in mechanotransduction and cell-cell contact. Identification of BMP9-dependent nuclear localization of YAP1 in response to endoglin expression suggests a mechanism of crosstalk between the two pathways. Suppression of endoglin and YAP1 alters BMP9-dependent expression of YAP1 target genes CCN1 (cysteine-rich 61, CYR61) and CCN2 (connective tissue growth factor, CTGF) as well as the chemokine CCL2 (monocyte chemotactic protein 1, MCP-1). These results suggest a coordinate effect of endoglin deficiency on cell matrix remodeling and local inflammatory responses. Identification of a direct link between the Hippo pathway and endoglin may reveal novel mechanisms in the etiology of HHT. PMID- 25909854 TI - Near-infrared (NIR) emitting Nd/Yb(III) complexes sensitized by MLCT states of Ru(II)/Ir(III) metalloligands in the visible light region. AB - Four Ru(II)/Ir(III) metalloligands have been designed and synthesized from polypyridine and bibenzimidazole (BiBzIm) organic ligands, which show strong visible light absorption via metal-to-ligand charge transfer (MLCT) transitions. Nd/Yb(III) complexes were further assembled from these Ru(II)/Ir(III) metalloligands, and Ln(III)-centered NIR emissions can be efficiently sensitized by (3)MLCT states of the metalloligands in the visible-light region. The energy transfer rates for the complexes are generally in the order Nd > Yb, which is due to the better matching between (3)MLCT states of Ru(II)/Ir(III) metalloligands and densely distributed excited states of Nd(III) ions. Long decayed lifetimes on a MUs scale and high quantum yields up to 1% are obtained in these lanthanide complexes, suggesting that the Ru(II)/Ir(III) metalloligands can serve as a good visible light harvesting antenna to efficiently sensitize Ln(III)-based NIR luminescence. PMID- 25909853 TI - Antiviral Activity of the Human Cathelicidin, LL-37, and Derived Peptides on Seasonal and Pandemic Influenza A Viruses. AB - Human LL-37, a cationic antimicrobial peptide, was recently shown to have antiviral activity against influenza A virus (IAV) strains in vitro and in vivo. In this study we compared the anti-influenza activity of LL-37 with that of several fragments derived from LL-37. We first tested the peptides against a seasonal H3N2 strain and the mouse adapted H1N1 strain, PR-8. The N-terminal fragment, LL-23, had slight neutralizing activity against these strains. In LL 23V9 serine 9 is substituted by valine creating a continuous hydrophobic surface. LL-23V9 has been shown to have increased anti-bacterial activity compared to LL 23 and we now show slightly increased antiviral activity compared to LL-23 as well. The short central fragments, FK-13 and KR-12, which have anti-bacterial activity did not inhibit IAV. In contrast, a longer 20 amino acid central fragment of LL-37 (GI-20) had neutralizing activity similar to LL-37. None of the peptides inhibited viral hemagglutination or neuraminidase activity. We next tested activity of the peptides against a strain of pandemic H1N1 of 2009 (A/California/04/09/H1N1 or "Cal09"). Unexpectedly, LL-37 had markedly reduced activity against Cal09 using several cell types and assays of antiviral activity. A mutant viral strain containing just the hemagglutinin (HA) of 2009 pandemic H1N1 was inhibited by LL-37, suggested that genes other than the HA are involved in the resistance of pH1N1. In contrast, GI-20 did inhibit Cal09. In conclusion, the central helix of LL-37 incorporated in GI-20 appears to be required for optimal antiviral activity. The finding that GI-20 inhibits Cal09 suggests that it may be possible to engineer derivatives of LL-37 with improved antiviral properties. PMID- 25909855 TI - Proteomics and Genetics for Identification of a Bacterial Antimonite Oxidase in Agrobacterium tumefaciens. AB - Antimony (Sb) and its compounds are listed by the United States Environmental Protection Agency (USEPA, 1979) and the European Union (CEC, 1976) as a priority pollutant. Microbial redox transformations are presumed to be an important part of antimony cycling in nature; however, regulation of these processes and the enzymology involved are unknown. In this study, comparative proteomics and reverse transcriptase-PCR analysis of Sb(III)-oxidizing bacterium Agrobacterium tumefaciens GW4 revealed an oxidoreductase (anoA) is widely distributed in microorganisms, including at least some documented to be able to oxidize Sb(III). Deletion of the anoA gene reduced Sb(III) resistance and decreased Sb(III) oxidation by ~27%, whereas the anoA complemented strain was similar to the wild type GW4 and a GW4 anoA overexpressing strain increased Sb(III) oxidation by ~34%. Addition of Sb(III) up-regulated anoA expression and cloning anoA to Escherichia coli demonstrated direct transferability of this activity. A His-tag purified AnoA was found to require NADP(+) as cofactor, and exhibited a K(m) for Sb(III) of 64 +/- 10 MUM and a V(max) of 150 +/- 7 nmol min(-1) mg(-1). This study contributes important initial steps toward a mechanistic understanding of microbe-antimony interactions and enhances our understanding of how microorganisms participate in antimony biogeochemical cycling in nature. PMID- 25909856 TI - Phenotypic and genetic analyses of the varroa sensitive hygienic trait in Russian honey bee (hymenoptera: apidae) colonies. AB - Varroa destructor continues to threaten colonies of European honey bees. General hygiene, and more specific Varroa Sensitive Hygiene (VSH), provide resistance towards the Varroa mite in a number of stocks. In this study, 32 Russian (RHB) and 14 Italian honey bee colonies were assessed for the VSH trait using two different assays. Firstly, colonies were assessed using the standard VSH behavioural assay of the change in infestation of a highly infested donor comb after a one-week exposure. Secondly, the same colonies were assessed using an "actual brood removal assay" that measured the removal of brood in a section created within the donor combs as a potential alternative measure of hygiene towards Varroa-infested brood. All colonies were then analysed for the recently discovered VSH quantitative trait locus (QTL) to determine whether the genetic mechanisms were similar across different stocks. Based on the two assays, RHB colonies were consistently more hygienic toward Varroa-infested brood than Italian honey bee colonies. The actual number of brood cells removed in the defined section was negatively correlated with the Varroa infestations of the colonies (r2 = 0.25). Only two (percentages of brood removed and reproductive foundress Varroa) out of nine phenotypic parameters showed significant associations with genotype distributions. However, the allele associated with each parameter was the opposite of that determined by VSH mapping. In this study, RHB colonies showed high levels of hygienic behaviour towards Varroa -infested brood. The genetic mechanisms are similar to those of the VSH stock, though the opposite allele associates in RHB, indicating a stable recombination event before the selection of the VSH stock. The measurement of brood removal is a simple, reliable alternative method of measuring hygienic behaviour towards Varroa mites, at least in RHB stock. PMID- 25909857 TI - Antagonizing Effects of Aspartic Acid against Ultraviolet A-Induced Downregulation of the Stemness of Human Adipose Tissue-Derived Mesenchymal Stem Cells. AB - Ultraviolet A (UVA) irradiation is responsible for a variety of changes in cell biology. The purpose of this study was to investigate effects of aspartic acid on UVA irradiation-induced damages in the stemness properties of human adipose tissue-derived mesenchymal stem cells (hAMSCs). Furthermore, we elucidated the UVA-antagonizing mechanisms of aspartic acid. The results of this study showed that aspartic acid attenuated the UVA-induced reduction of the proliferative potential and stemness of hAMSCs, as evidenced by increased proliferative activity in the 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay and upregulation of stemness-related genes OCT4, NANOG, and SOX2 in response to the aspartic acid treatment. UVA-induced reduction in the mRNA level of hypoxia-inducible factor (HIF)-1alpha was also significantly recovered by aspartic acid. In addition, the antagonizing effects of aspartic acid against the UVA effects were found to be mediated by reduced production of PGE2 through the inhibition of JNK and p42/44 MAPK. Taken together, these findings show that aspartic acid improves reduced stemness of hAMSCs induced by UVA and its effects are mediated by upregulation of HIF-1alpha via the inhibition of PGE2-cAMP signaling. In addition, aspartic acid may be used as an antagonizing agent to mitigate the effects of UVA. PMID- 25909859 TI - Breaking new ground in the regulation of the early steps of plant isoprenoid biosynthesis. AB - The common metabolic precursors used for the production of all isoprenoid compounds are synthesized by two unrelated pathways in plants. The methylerythritol 4-phosphate (MEP) pathway produces these precursors in the plastid, whereas the biosynthesis of non-plastidial isoprenoids relies on the operation of the mevalonic acid (MVA) pathway. Despite the physical separation of the two pathways, some interaction exists at molecular and metabolic levels. Recent results have provided strong evidence that a high degree of control over each individual pathway takes place at the post-translational level. In particular, new mechanisms regulating the levels and activity of rate-determining enzymes have been unveiled. Current challenges include the study of the subcellular operation of the MEP and MVA pathways and their coordination with upstream and downstream pathways that supply their substrates and consume their products. PMID- 25909860 TI - Some agreement on kin selection and eusociality? AB - The authors of "Relatedness, Conflict, and the Evolution of Eusociality" respond to objections raised by Martin Nowak and Benjamin Allen. PMID- 25909858 TI - The General Amino Acid Permease FfGap1 of Fusarium fujikuroi Is Sorted to the Vacuole in a Nitrogen-Dependent, but Npr1 Kinase-Independent Manner. AB - The rice pathogenic fungus Fusarium fujikuroi is well known for the production of a broad spectrum of secondary metabolites (SMs) such as gibberellic acids (GAs), mycotoxins and pigments. The biosynthesis of most of these SMs strictly depends on nitrogen availability and of the activity of permeases of nitrogen sources, e.g. the ammonium and amino acid permeases. One of the three ammonium permeases, MepB, was recently shown to act not only as a transporter but also as a nitrogen sensor affecting the production of nitrogen-repressed SMs. Here we describe the identification of a general amino acid permease, FfGap1, among the 99 putative amino acid permeases (AAPs) in the genome of F. fujikuroi. FfGap1 is able to fully restore growth of the yeast gap1? mutant on several amino acids including citrulline and tryptophane. In S. cerevisiae, Gap1 activity is regulated by shuttling between the plasma membrane (nitrogen limiting conditions) and the vacuole (nitrogen sufficiency), which we also show for FfGap1. In yeast, the Npr1 serine/threonine kinase stabilizes the Gap1 position at the plasma membrane. Here, we identified and characterized three NPR1-homologous genes, encoding the putative protein kinases FfNpr1-1, FfNpr1-2 and FfNpr1-3 with significant similarity to yeast Npr1. Complementation of the yeast npr1Delta mutant with each of the three F. fujikuroi NPR1 homologues, resulted in partial restoration of ammonium, arginine and proline uptake by FfNPR1-1 while none of the three kinases affect growth on different nitrogen sources and nitrogen-dependent sorting of FfGap1 in F. fujikuroi. However, exchange of the putative ubiquitin-target lysine 9 (K9A) and 15 (K15A) residues of FfGap1 resulted in extended localization to the plasma membrane and increased protein stability independently of nitrogen availability. These data suggest a similar regulation of FfGap1 by nitrogen dependent ubiquitination, but differences regarding the role of Fusarium Npr1 homologues compared to yeast. PMID- 25909862 TI - Sonority vs. independency: A comparison of the sonority hierarchy and phonological make-up in child Japanese. AB - Although awareness of the underlying phonological structure of a language is said to be a prerequisite in learning to read, there is still much debate as to which phonological units are the best predictors. The syllable plays an important role in accounting for various phonological phenomena observed cross-linguistically, and studies have shown its importance in promoting reading abilities. However, in the case of Tokyo Japanese, the role of the syllable is inconspicuous compared to the mora unit. This is due to the fact that in practice, the syllable often overlaps with the mora, exceptions arising from the syllables that contain the so called 'special moras', i.e. the heavy syllables containing two moras. Traditionally, the main focus of attention in Japanese had been laid on different behaviours observed between the plain 'normal' moras and the 'special' moraic phonemes. However, in recent years, studies conducted have been focused on the different phonological patterning observed within the moraic phonemes themselves. In order to better understand the characteristics of these moraic phonemes, we report on our findings based on reversal tasks administered to elementary school students. The result of the experiment suggests that the degree of independency of these moraic phonemes in terms of phonological make-up seems to have an effect on the error patterns observed. PMID- 25909861 TI - Optimization of amine-rich multilayer thin films for the capture and quantification of prostate-specific antigen. AB - It is demonstrated that poly(allylamine hydrochloride)/poly(styrenesulfonate) (PAH/SPS) multilayer films can be successfully tailored for the capture and detection of small biomolecules in dilute concentrations. Based on in vitro results, these films could be potentially applied for rapid and high-throughput diagnosis of dilute biomarkers in serum or tissue. PAH presents functional amino groups that can be further reacted with desired chemistries in order to create customizable and specific surfaces for biomolecule capture. A variety of film assembly characteristics were tested (pH, molecular weight of PAH, and ionic strength) to tune the biotinylation and swelling behavior of these films to maximize detection capabilities. The resultant optimized biotinylated PAH/SPS 9.3/9.3 system was utilized in conjunction with quantum dots (Qdots) to capture and detect a dilute biomarker for prostate cancer, prostate-specific antigen (PSA). Compared to previous work, our system presents a good sensitivity for PSA detection within the clinically relevant range of 0.4-100 ng/mL. PMID- 25909863 TI - 2014 Harry Shwachman award. PMID- 25909864 TI - 2014 NASPGHAN Distinguished Service Award. PMID- 25909865 TI - 2014 AAP Murray Davidson award. PMID- 25909866 TI - Progression to high-risk gastroesophageal varices in children with biliary atresia with low-risk signs at first endoscopy. AB - OBJECTIVES: Biliary atresia carries a risk of bleeding because of portal hypertension. Our goal was to define the factors associated with the emergence of endoscopic signs carrying a high risk of bleeding in children who did not display these signs at the first upper gastrointestinal endoscopy. METHODS: From 1989 to 2013, a total of 225 children with low-risk signs at the first endoscopic examination underwent >=2 upper gastrointestinal endoscopic examinations. The emergence of high-risk gastroesophageal varices was observed in 76 children in the 10 years following the first endoscopic examination. A survival study using the occurrence of high-risk varices as an event was performed to identify factors related to the emergence of these varices and to describe the probability of their emergence in 2 groups of children ages older than 18 months and 18 months or younger at the time of the first endoscopy. RESULTS: High total serum bilirubin concentration, young age, and high number/grade of esophageal varices at the first endoscopy were significantly related to the emergence of high-risk varices. The probability of the emergence of high-risk signs was higher and these signs appeared faster in infants 12 months of age or younger and/or when the first endoscopic examination displayed >1 grade 1 or grade 2 varices. Progression to high-risk varices was also related to bilirubinemia in children older than 18 months at the first endoscopy. CONCLUSIONS: The results allow defining a program of repeat endoscopies to detect high-risk varices and to discuss endoscopic primary prophylaxis of bleeding or hasten liver transplantation when these signs are found. PMID- 25909867 TI - In situ synthesis of silver nanoparticles uniformly distributed on polydopamine coated silk fibers for antibacterial application. AB - Fabrication of silver nanoparticles (AgNPs)-modified silk for antibacterial application is one of the hottest topics in the textile material research. However, the utilization of a polymer as both 3-dimensional matrix and reductant for the in-situ synthesis of AgNPs on silk fibers has not been realized. In this work, a facile, efficient and green approach was developed to in-situ grow AgNPs on the polydopamine (PDA)-functionalized silk. AgNPs with the size of 30-90 nm were uniformly deposited on the silk fiber surface with the PDA coating layer as a reduction reagent. The AgNPs exhibit excellent face-centered cubic crystalline structures. The bacterial growth curve and inhibition zone assays clearly demonstrate the antibacterial properties of the functionalized silk. Both high Ag(+) release level and long-time release profile were observed for the as prepared AgNPs-PDA-coated silk, indicating the high-density loading of AgNPs and the possible long-term antibacterial effects. This work may provide a new method for the preparation of AgNPs-functionalized silk with antibacterial activity for the clothing and textile industry. PMID- 25909868 TI - Partitioning of nitroxides in dispersed systems investigated by ultrafiltration, EPR and NMR spectroscopy. AB - HYPOTHESIS: The partitioning behavior of paramagnetic nitroxides in dispersed systems can be determined by deconvolution of electron paramagnetic resonance (EPR) spectra giving equivalent results with the validated methods of ultrafiltration techniques (UF) and pulsed-field gradient nuclear magnetic resonance spectroscopy (PFG-NMR). EXPERIMENTS: The partitioning behavior of nitroxides with increasing lipophilicity was investigated in anionic, cationic and nonionic micellar systems and 10 wt% o/w emulsions. Apart from EPR spectra deconvolution, the PFG-NMR was used in micellar solutions as a non-destructive approach, while UF based on separation of very small volume of the aqueous phase. FINDINGS: As a function of their substituent and lipophilicity, the proportions of nitroxides that were solubilized in the micellar or emulsion interface increased with increasing nitroxide lipophilicity for all emulsifier used. Comparing the different approaches, EPR deconvolution and UF revealed comparable nitroxide proportions that were solubilized in the interfaces. Those proportions were higher than found with PFG-NMR. For PFG-NMR self-diffusion experiments the reduced nitroxides were used revealing a high dynamic of hydroxylamines and emulsifiers. Deconvolution of EPR spectra turned out to be the preferred method for measuring the partitioning behavior of paramagnetic molecules as it enables distinguishing between several populations at their individual solubilization sites. PMID- 25909869 TI - The role of genetic factors in the pathogenesis of neonatal intraventricular hemorrhage. AB - Intraventricular hemorrhage (IVH) affects 15-20% of babies born before 32 weeks of pregnancy. Besides gestational age (below 32 weeks) there are a number of IVH risk factors. Increasing attention is being paid to genetic factors in the development of IVH. The authors discuss genetic factors (mutations of coagulation factors, gene polymorphisms in pro-inflammatory cytokines, mutation of type IV collagen gene, polymorphisms of genes responsible for the regulation of systemic blood pressure and cerebral blood flows) whose involvement in IVH pathogenesis has been confirmed in the highest number of reports and for which being a carrier plays an important role in their pathophysiology. The role of genetic factors in IVH remains unclear. Further analysis of the role of genetic factors in the pathophysiology of IVH will make it possible to determine the group of newborns who are specifically at risk of developing IVH in the perinatal period. PMID- 25909870 TI - Erk activation as a possible mechanism of transformation of subependymal nodule into subependymal giant cell astrocytoma. AB - INTRODUCTION: Subependymal nodule (SEN) and subependymal giant cell astrocytoma (SEGA) are brain lesions frequently found in tuberous sclerosis (TS). As about 10 15% of SENs enlarge and transform into SEGAs, we examined here the possible mechanism of the phenomenon. MATERIAL AND METHODS: Using Western blot we studied 1 SEN and 3 SEGA samples; SEN and 1 SEGA came from the same TS patient. We evaluated e.g. the activation of the phosphorylated forms of proteins belonging to Akt, Erk and mTOR pathways. RESULTS: Differences in Erk pathway activation between SEN and SEGA were found. There was no upregulation of p-Erk, p-Mek or p RSK1 in the SEN specimen, whilst we found these proteins to be significantly uptriggered in SEGA samples. Also, for the first time, we found p-Akt, p-GSK3? and p-PDK1 upregulated in both SEN and SEGA from the same TS patient. CONCLUSIONS: Our current study shows for the first time the possible mechanism of SEN/SEGA transformation, where Erk pathway hyperactivation seems to be significant. We hypothesize that SEN/SEGA transformation may depend on Erk potentiation. PMID- 25909871 TI - Laminar distribution of beta-amyloid (Abeta) peptide deposits in the frontal lobe in familial and sporadic Alzheimer's disease. AB - To determine whether genetic factors influence frontal lobe degeneration in Alzheimer's disease (AD), the laminar distributions of diffuse, primitive, and classic beta-amyloid (Abeta) peptide deposits were compared in early-onset familial AD (EO-FAD) linked to mutations of the amyloid precursor protein (APP) or presenilin 1 (PSEN1) gene, late-onset familial AD (LO-FAD), and sporadic AD (SAD). The influence of apolipoprotein E (Apo E) genotype on laminar distribution was also studied. In the majority of FAD and SAD cases, maximum density of the diffuse and primitive Abeta?deposits occurred in the upper cortical layers, whereas the distribution of the classic Abeta deposits was more variable, either occurring in the lower layers, or a double-peaked (bimodal) distribution was present, density peaks occurring in upper and lower layers. The cortical layer at which maximum density of Abeta deposits occurred and maximum density were similar in EO-FAD, LO-FAD and SAD. In addition, there were no significant differences in distributions in cases expressing Apo E epsilon4 alleles compared with cases expressing the epsilon2 or epsilon3 alleles. These results suggest that gene expression had relatively little effect on the laminar distribution of Abeta deposits in the frontal lobe of the AD cases studied. Hence, the pattern of frontal lobe degeneration in AD is similar regardless of whether it is associated with APP and PSEN1, mutation, allelic variation in Apo E, or with SAD. PMID- 25909872 TI - Association of the rs1801133 variant in the MTHFR gene and sporadic Parkinson's disease. AB - The MTHFR gene has been reported as a susceptibility locus for sporadic Parkinson's disease (sPD). The functional variant rs1801133 has been linked to hyperhomocysteinemia and dopaminergic cell death. Among different populations, Mexican-Mestizos (most present-day Mexicans) have the highest frequency of this variant. Therefore, we sought to determine a possible association of rs1801133 with SPD. In total, 356 individuals were included: 140 patients with PD, diagnosed according to the Queen Square Brain Bank criteria, and 216 neurologically healthy controls. Genotyping was performed using TaqMan probes for rs1801133 and real-time PCR. Logistic regression analysis with adjustment for smoking and gender was used to test for an association between genotype and SPD. The CC genotype was associated with SPD; exp(?) = 2.06; 95% CI: 1.101-3.873, p = 0.024. No association with age at onset, cognitive impairment or gender was found in our study group. Our data suggest an important role of MTHFR gene variants in SPD. PMID- 25909873 TI - Cabergoline protects dopaminergic neurons against rotenone-induced cell death in primary mesencephalic cell culture. AB - In the present study, primary mesencephalic cell cultures prepared from embryonic mouse mesencephala were used to investigate the neuroprotective effect of cabergoline, an ergoline D2 receptor agonist, against the pesticide and neurotoxin rotenone relevant to Parkinson disease (PD). Treatment of cultures with cabergoline alone significantly increased the number of tyrosine hydroxylase immunoreactive (THir) neurons and reduced the release of lactate dehydrogenase (LDH) into the culture medium compared to untreated controls. Against rotenone toxicity, cabergoline significantly rescued degenerating THir neurons, reduced the release of LDH into the culture medium and improved the morphology of surviving THir neurons. The neuroprotective effects afforded by cabergoline were independent of dopaminergic stimulation as blocking of dopamine receptors by the dopamine receptor antagonist sulpiride did not prevent them. Furthermore, rotenone-induced formation of reactive oxygen species (ROS) was significantly reduced by cabergoline. Although cabergoline increased the glutathione (GSH) content in the culture, the protective effect for dopaminergic neurons seemed not to be predominantly mediated by increasing GSH, as depletion of GSH by L buthionine-(S,R)-sulfoximine (BSO), a GSH biosynthesis inhibitor, did not prevent cabergoline-mediated neuroprotection of THir neurons in rotenone-treated cultures. Moreover, cabergoline significantly increased the ATP/protein ratio in primary mesencephalic cell cultures when added alone or prior to rotenone treatment. These results indicate a neuroprotective effect of cabergoline for dopaminergic neurons against rotenone toxicity. This effect was independent of dopamine receptor stimulation and was at least partially mediated by reducing ROS production and increasing the ATP/protein ratio. PMID- 25909874 TI - Subdural infusion of dexamethasone inhibits leukomyelitis after acute spinal cord injury in a rat model. AB - Trauma in spinal cord injury often results in massive damage to the white matter and in damage to myelin that results in a severe phagocyte-rich infiltration apparently directed at removing immunologically toxic myelin debris. In the epidural balloon crush injury to the rat cranial thoracic spinal cord, the dorsal column was crushed, which at one week post-op resulted in its obliteration by a severe infiltration by a virtually pure population of macrophages that internalized all damaged myelin. A week-long subdural infusion of dexamethasone, a stable synthetic corticosteroid, resulted in remarkable inhibition of the macrophage infiltration of the crush cavity and in the lack of removal of myelin debris by phagocytosis. In this study we demonstrated that spinal cord injury results in a severe inflammatory response directed at massively damaged myelin, and we inhibited this response with a subdural infusion of a powerful anti inflammatory drug, dexamethasone. PMID- 25909875 TI - Prognostic significance of the markers IDH1 and YKL40 related to the subventricular zone. AB - Glioblastoma multiforme (GBM), a highly aggressive brain cancer characterized by uncontrolled proliferation, resistance to cell death, angiogenesis, and vascular edema, remains one of the deadliest types of cancer. The subventricular zone (SVZ) harbors cells with great proliferative potential, and the microenvironment within the SVZ is permissive to growth and proliferation. This neurogenic niche is suspected to be a vulnerable site for the origin of subtypes of GBM. The aim of our study was to determine the immunohistochemical expression of mIDH1 and YKL40 in relationship to the SVZ of GBMs. YKL40, also known as chitinase-like protein 1, is included as a mesenchymal marker and associated with a poor prognosis. The protein is a secreted inflammatory molecule with no chitinolytic activity. However, the mutation of IDH1 (mIDH1) has been found in the cytoplasm and peroxisomes of 70-80% of secondary GBMs. In our study we found that YKL40 positive GBM is significantly linked to SVZ types IV and V (p < 0.0001). Our results show the diversity among GBMs related to the SVZ, which should be considered in the design of future targeted therapies. There was a significant impact of patient age, mIDH1 positivity, SVZ type III, and chemoradiotherapy on overall survival. PMID- 25909876 TI - Hydrocephalus induced via intraventricular kaolin injection in adult rats. AB - Hydrocephalus is a common neurological disease in humans, but a uniform and particularly effective hydrocephalic animal model amenable to proper appraisal and deep study has not yet been established. In this study, we attempted to construct a high-efficiency model of hydrocephalus via intraventricular kaolin injection. Adult male Sprague-Dawley rats were randomly divided into 2 groups: the control group (n = 15) and the experimental group (n = 30). Kaolin was injected into the lateral ventricle of experimental animals. Control rats underwent the same procedure but received sterile saline injection instead of kaolin. All animals with kaolin injection into the lateral ventricle developed hydrocephalus according to magnetic resonance imaging (MRI) results (success rate up to 100%). Also, the Morris water maze (MWM) test demonstrated disturbed spatial learning and memory. Furthermore, there were significant differences between groups with respect to the histological changes in the periventricular tissue. Our results indicate that experimental hydrocephalus induced by lateral ventricle injection of kaolin in adult rats is feasible and may be widely used. PMID- 25909877 TI - Sertraline and curcumin prevent stress-induced morphological changes of dendrites and neurons in the medial prefrontal cortex of rats. AB - Stress induces structural and behavioral impairments. The changes in dendrites and neurons are accompanied by impairments in the tasks mediated by the medial prefrontal cortex (mPFC). The present study was conducted to evaluate the structural changes of the dendrites and neurons of the mPFC after stress using stereological methods. In addition, the effects of a natural and a synthetic substance, i.e., curcumin and sertraline, were evaluated. The rats were divided into 7 groups: stress + distilled water, stress + olive oil, curcumin (100 mg/kg/day), sertraline (10 mg/kg/day), stress + curcumin, stress + sertraline, and control groups. The animals were submitted to chronic variable stress for 56 days. The results showed an average 15% reduction in the length of the dendrites per neuron in the mPFC after stress (p < 0.004). The total spine density was reduced by 50% in the stress (+ olive oil or + distilled water) groups in comparison with the control group (p < 0.01). The main reduction was seen in the thin and mushroom spines, while the stubby spines remained unchanged. Mean volume and surface area of the neurons were decreased by 14% and 10% on average in the stress (+ distilled water or + olive oil) rats in comparison to the control rats, respectively (p < 0.01). The data revealed that treatment of stressed rats with curcumin or sertraline can prevent the loss of spines and reduction of dendrite length, volume and surface area of the neurons. Sertraline and curcumin can prevent structural changes of the neurons and dendrites induced by stress in the mPFC of rats. PMID- 25909878 TI - Atypical teratoid/rhabdoid tumor of the brain in an adult with 22q deletion but no absence of INI1 protein: a case report and review of the literature. AB - We report a case of atypical teratoid/rhabdoid tumor (AT/RT) of the central nervous system (CNS) in an adult and its immunological phenotype and chromosomal DNA imbalance characteristics, as detected by comparative genomic hybridization (CGH). The immunohistochemical characteristics showed that atypical rhabdoid cells were positive for epithelial membrane antigen, vimentin, desmin, and glial fibrillary acidic protein, but there was no absence of INI1 protein. The CGH results identified the imbalances of the case to be the loss of 1p, 5q, 12q, 15q, 19q and 22q and the gain of 9q. Our discovery raises the question whether INI1 is implicated in all cases and whether its deletion is necessary in the pathogenesis of AT/RT, and also whether additional genetic pathways might exist. These data will offer useful information for further research on AT/RTs. PMID- 25909879 TI - Rheology and microstructure of non-Brownian suspensions in the liquid and crystal coexistence region: strain stiffening in large amplitude oscillatory shear. AB - Concentrated hard-sphere suspensions in the liquid and crystal coexistence region show a unique nonlinear behavior under a large amplitude oscillatory shear flow, the so-called strain stiffening, in which the viscosity or modulus suddenly starts to increase near a critical strain amplitude. Even though this phenomenon has been widely reported in experiments, its key mechanism has never been investigated in a systematic way. To have a good understanding of this behavior, a numerical simulation was performed using the lattice Boltzmann method (LBM). Strain stiffening was clearly observed at large strain amplitudes, and the critical strain amplitude showed an angular frequency dependency. The distortion of the shear stress appeared near the critical strain amplitude, and the nonlinear behavior was quantified by the Fourier transformation (FT) and the stress decomposition methods. Above the critical strain amplitude, an increase in the global bond order parameter Psi(6) was observed at the flow reversal. The maximum of Psi(6) and the maximum shear stress occurred at the same strain. These results show how strongly the ordered structure of the particles is related to the stress distortion. The ordered particles maintained a bond number of "two" with alignment with the compressive axis, and they were distributed over a narrow range of angular distribution (110 degrees -130 degrees ). In addition, the ordered structure was formed near the lowest shear rate region (the flow reversal). The characteristics of the ordered structure were remarkably different from those of the hydroclusters which are regarded as the origin of shear thickening. It is clear that strain stiffening and shear thickening originate from different mechanisms. Our results clearly demonstrate how the ordering of the particles induces strain stiffening in the liquid and crystal coexistence region. PMID- 25909881 TI - Regarding a peculiar case of suicide enacted through the ancient Japanese ritual of jigai. PMID- 25909880 TI - Covalent Inhibition of Ubc13 Affects Ubiquitin Signaling and Reveals Active Site Elements Important for Targeting. AB - Ubc13 is an E2 ubiquitin conjugating enzyme that functions in nuclear DNA damage signaling and cytoplasmic NF-kappaB signaling. Here, we present the structures of complexes of Ubc13 with two inhibitors, NSC697923 and BAY 11-7082, which inhibit DNA damage and NF-kappaB signaling in human cells. NSC697923 and BAY 11-7082 both inhibit Ubc13 by covalent adduct formation through a Michael addition at the Ubc13 active site cysteine. The resulting adducts of both compounds exploit a binding groove unique to Ubc13. We developed a Ubc13 mutant which resists NSC697923 inhibition and, using this mutant, we show that the inhibition of cellular DNA damage and NF-kappaB signaling by NSC697923 is largely due to specific Ubc13 inhibition. We propose that unique structural features near the Ubc13 active site could provide a basis for the rational development and design of specific Ubc13 inhibitors. PMID- 25909882 TI - Concurrent isolation of lymphocytes and granulocytes using prefocused free flow acoustophoresis. AB - Microchip-based free flow acoustophoresis (FFA) in combination with two dimensional cell prefocusing enables concurrent multiple target outlet fractionation of leukocytes into subpopulations (lymphocytes, monocytes, and granulocytes); we report on this method here. We also observed significantly increased accuracy in size-based fractionation of microbeads as compared to previously presented FFA multiple outlet systems. Fluorescence microscopy illustrates the importance of two-dimensional prefocusing where a sample mixture of 3, 7, and 10 MUm beads are separated into well-confined particle streams and collected in their respective target outlets. Flow cytometry data for lymphocytes and granulocytes, respectively, in their corresponding outlets verify concurrent isolation of leukocyte subpopulations with high purity (95.2 +/- 0.6% and 98.5 +/ 0.7%) and high recovery (86.5 +/- 10.9% and 68.4 +/- 10.6%). A relatively low purity and high recovery of monocytes (25.2% +/- 5.4% and 83.1 +/- 4.3%) was obtained in the third target outlet. No subpopulation bias was observed. These data demonstrate an unprecedented separation of leukocyte subpopulations at flow rates of ~100 MUL/min and ~1 M cells/mL sample concentrations, not previously reported in acoustofluidic systems. Two-dimensional prefocusing FFA with multiple target outlets is a viable alternative to current methods for particle fractionation and cell isolation, requiring a minimum of sample preparation and lowering analysis time and cost. PMID- 25909883 TI - An exploration of factors affecting the long term psychological impact and deterioration of mental health in flooded households. AB - The long term psychological effect of the distress and trauma caused by the memory of damage and losses associated with flooding of communities remains an under researched impact of flooding. This is particularly important for communities that are likely to be repeatedly flooded where levels of mental health disorder will damage long term resilience to future flooding. There are a variety of factors that affect the prevalence of mental health disorders in the aftermath of flooding including pre-existing mental health, socio-economic factors and flood severity. However previous research has tended to focus on the short term impacts immediately following the flood event and much less focus has been given to the longer terms effects of flooding. Understanding of factors affecting the longer term mental health outcomes for flooded households is critical in order to support communities in improving social resilience. Hence, the aim of this study was to explore the characteristics associated with psychological distress and mental health deterioration over the longer term. The research examined responses from a postal survey of households flooded during the 2007 flood event across England. Descriptive statistics, correlation analysis and binomial logistic regression were applied to data representing household characteristics, flood event characteristics and post-flood stressors and coping strategies. These factors were related to reported measures of stress, anxiety, depression and mental health deterioration. The results showed that household income, depth of flooding; having to move out during reinstatement and mitigating actions are related to the prevalence of psycho-social symptoms in previously flooded households. In particular relocation and household income were the most predictive factors. The practical implication of these findings for recovery after flooding are: to consider the preferences of households in terms of the need to move out during restorative building works and the financial resource constraints that may lead to severe mental hardship. In addition the findings suggest that support with installing mitigation measures may lead to improved mental health outcomes for communities at risk. PMID- 25909884 TI - Hepatocyte-specific Bid depletion reduces tumor development by suppressing inflammation-related compensatory proliferation. AB - Liver cancer is a major health-care concern and its oncogenic mechanisms are still largely unclear. Persistent hepatocyte cell death is a common feature among various chronic liver diseases, the blocking of which presents as logical treatment. Therefore, we aimed at investigating tumor development in mice with hepatocyte-specific Bid depletion--a BH3-only Bcl-2 family member that amplifies apoptotic death signals. Hepatocyte-specific conditional Bid-knockout mice (Bid(Deltahep)) were injected with 25 mg/kg diethylnitrosamine (DEN) at 14 days of age, and liver tumorigenesis was investigated 9 months later. Additionally, different models of acute liver injury were used including: acute high-dose DEN challenge, 3,5-diethoxycarbonyl-1,4-dihydrocollidine (DDC) diet and carbon tetrachloride (CCL4) injection. Bid(Deltahep) mice developed significantly fewer tumors, showed smaller maximal and average tumor size and reduced tumor incidence. In the acute DEN model, 48 h post injection we observed a significant reduction in liver injury in Bid(Deltahep) animals, assessed via serum transaminases and liver histopathology. Furthermore, TNF-alpha, IL-1beta, cJUN and IL-6 mRNA expression was reduced. These findings were accompanied by reduced compensatory hepatocyte proliferation in Bid(Deltahep) mice when compared with controls by immunohistochemistry for Ki67 and proliferating cell nuclear antigen 48 h after DEN injection. In the acute CCL4 model, Bid(Deltahep) mice displayed reductions in liver injury and inflammation when compared with controls. No differences in liver injury and serum bilirubin levels were detected in Bid(Deltahep) and Bid(flo/flo) mice fed with DDC, which induces bile duct injury and a ductular reaction. Our study demonstrates that in DEN-induced hepatocellular carcinoma, the inhibition of hepatocyte death pathways through Bid deletion protects animals from tumorigenesis. These results suggest that reducing hepatocyte cell death, liver inflammation and compensatory proliferation has a stronger beneficial effect than the potential side effect of enhancing tumor cell survival. PMID- 25909885 TI - Pharmacological targeting of guanosine monophosphate synthase suppresses melanoma cell invasion and tumorigenicity. AB - Malignant melanoma possesses one of the highest metastatic potentials among human cancers. Acquisition of invasive phenotypes is a prerequisite for melanoma metastases. Elucidation of the molecular mechanisms underlying melanoma invasion will greatly enhance the design of novel agents for melanoma therapeutic intervention. Here, we report that guanosine monophosphate synthase (GMPS), an enzyme required for the de novo biosynthesis of GMP, has a major role in invasion and tumorigenicity of cells derived from either BRAF(V600E) or NRAS(Q61R) human metastatic melanomas. Moreover, GMPS levels are increased in metastatic human melanoma specimens compared with primary melanomas arguing that GMPS is an attractive candidate for anti-melanoma therapy. Accordingly, for the first time we demonstrate that angustmycin A, a nucleoside-analog inhibitor of GMPS produced by Streptomyces hygroscopius efficiently suppresses melanoma cell invasion in vitro and tumorigenicity in immunocompromised mice. Our data identify GMPS as a powerful driver of melanoma cell invasion and warrant further investigation of angustmycin A as a novel anti-melanoma agent. PMID- 25909886 TI - Tissue-specific targeting of cell fate regulatory genes by E2f factors. AB - Cell cycle proteins are important regulators of diverse cell fate decisions, and in this capacity have pivotal roles in neurogenesis and brain development. The mechanisms by which cell cycle regulation is integrated with cell fate control in the brain and other tissues are poorly understood, and an outstanding question is whether the cell cycle machinery regulates fate decisions directly or instead as a secondary consequence of proliferative control. Identification of the genes targeted by E2 promoter binding factor (E2f) transcription factors, effectors of the pRb/E2f cell cycle pathway, will provide essential insights into these mechanisms. We identified the promoter regions bound by three neurogenic E2f factors in neural precursor cells in a genome-wide manner. Through bioinformatic analyses and integration of published genomic data sets we uncovered hundreds of transcriptionally active E2f-bound promoters corresponding to genes that control cell fate processes, including key transcriptional regulators and members of the Notch, fibroblast growth factor, Wnt and Tgf-beta signaling pathways. We also demonstrate a striking enrichment of the CCCTC binding factor transcription factor (Ctcf) at E2f3-bound nervous system-related genes, suggesting a potential regulatory co-factor for E2f3 in controlling differentiation. Finally, we provide the first demonstration of extensive tissue specificity among E2f target genes in mammalian cells, whereby E2f3 promoter binding is well conserved between neural and muscle precursors at genes associated with cell cycle processes, but is tissue-specific at differentiation-associated genes. Our findings implicate the cell cycle pathway as a widespread regulator of cell fate genes, and suggest that E2f3 proteins control cell type-specific differentiation programs by regulating unique sets of target genes. This work significantly enhances our understanding of how the cell cycle machinery impacts cell fate and differentiation, and will importantly drive further discovery regarding the mechanisms of cell fate control and transcriptional regulation in the brain, as well as in other tissues. PMID- 25909887 TI - Chaperone-like protein p32 regulates ULK1 stability and autophagy. AB - Mitophagy mediates clearance of dysfunctional mitochondria, and represents one type of mitochondrial quality control, which is essential for optimal mitochondrial bioenergetics. p32, a chaperone-like protein, is crucial for maintaining mitochondrial membrane potential and oxidative phosphorylation. However, the relationship between p32 and mitochondrial homeostasis has not been addressed. Here, we identified p32 as a key regulator of ULK1 stability by forming complex with ULK1. p32 depletion potentiated K48-linked but impaired K63 linked polyubiquitination of ULK1, leading to proteasome-mediated degradation of ULK1. As a result, silencing p32 profoundly impaired starvation-induced autophagic flux and the clearance of damaged mitochondria caused by mitochondrial uncoupler. Importantly, restoring ULK1 expression in p32-depleted cells rescued autophagy and mitophagy defects. Our findings highlight a cytoprotective role of p32 under starvation conditions by regulating ULK1 stability, and uncover a crucial role of the p32-ULK1-autophagy axis in coordinating stress response, cell survival and mitochondrial homeostasis. PMID- 25909888 TI - Synaptic dysfunction, memory deficits and hippocampal atrophy due to ablation of mitochondrial fission in adult forebrain neurons. AB - Well-balanced mitochondrial fission and fusion processes are essential for nervous system development. Loss of function of the main mitochondrial fission mediator, dynamin-related protein 1 (Drp1), is lethal early during embryonic development or around birth, but the role of mitochondrial fission in adult neurons remains unclear. Here we show that inducible Drp1 ablation in neurons of the adult mouse forebrain results in progressive, neuronal subtype-specific alterations of mitochondrial morphology in the hippocampus that are marginally responsive to antioxidant treatment. Furthermore, DRP1 loss affects synaptic transmission and memory function. Although these changes culminate in hippocampal atrophy, they are not sufficient to cause neuronal cell death within 10 weeks of genetic Drp1 ablation. Collectively, our in vivo observations clarify the role of mitochondrial fission in neurons, demonstrating that Drp1 ablation in adult forebrain neurons compromises critical neuronal functions without causing overt neurodegeneration. PMID- 25909890 TI - ADAM12-directed ectodomain shedding of E-cadherin potentiates trophoblast fusion. AB - Trophoblasts, placental cells of epithelial lineage, undergo extensive differentiation to form the cellular components of the placenta. Trophoblast progenitor cell differentiation into the multinucleated syncytiotrophoblast is a key developmental process required for placental function, where defects in syncytiotrophoblast formation and turnover associate with placental pathologies and link to poor pregnancy outcomes. The cellular and molecular processes governing syncytiotrophoblast formation are poorly understood, but require the activation of pathways that direct cell fusion. The protease, A Disintegrin and Metalloproteinase 12 (ADAM12), controls cell fusion in myoblasts and is highly expressed in the placenta localizing to multiple trophoblast populations. However, the importance of ADAM12 in regulating trophoblast fusion is unknown. Here, we describe a function for ADAM12 in regulating trophoblast fusion. Using two distinct trophoblast models of cell fusion, we show that ADAM12 is dynamically upregulated and is under the transcriptional control of protein kinase A. siRNA-directed loss of ADAM12 impedes spontaneous fusion of primary cytotrophoblasts, whereas overexpression of the secreted variant, ADAM12S, potentiates cell fusion in the Bewo trophoblast cell line. Mechanistically, both ectopic and endogenous levels of ADAM12 were shown to control trophoblast fusion through E-cadherin ectodomain shedding and remodeling of intercellular boundaries. This study describes a novel role for ADAM12 in placental development, specifically highlighting its importance in controlling the differentiation of villous cytotrophoblasts into multinucleated cellular structures. Moreover, this work identifies E-cadherin as a novel ADAM12 substrate, and highlights the significance that cell adhesion molecule ectodomain shedding has in normal development. PMID- 25909889 TI - Regulators of G protein signaling 12 promotes osteoclastogenesis in bone remodeling and pathological bone loss. AB - Regulators of G protein signaling (Rgs) have pivotal roles in controlling various cellular processes, such as cell differentiation. How Rgs proteins regulate osteoclast (OC) differentiation, function and bone homeostasis is poorly understood. It was previously demonstrated that Rgs12, the largest protein in the Rgs family, is predominantly expressed in OCs and regulates OC differentiation in vitro. To further understand the role and mechanism of Rgs12 in OC differentiation and bone diseases in vivo, we created OC-targeted Rgs12 knockout mice by using inducible Mx1-Cre and CD11b-Cre. Deletion of Rgs12 in hematopoietic cells or specifically in OC precursors resulted in increased bone mass with decreased OC numbers. Loss of Rgs12 impaired OC differentiation and function with impaired Ca(2+) oscillations and reduced nuclear factor of activated T cells (NFAT) 2 expression. The introduction of wild-type osteoblasts did not rescue the defective osteoclastogenesis. Ectopic expression of NFAT2 rescued defective OC differentiation in CD11b;Rgs12(fl/fl) cells and promoted normal OC differentiation. Moreover, deletion of Rgs12 significantly inhibited pathological osteoclastogenesis and bone destruction in Rgs12-deficient mice that were subjected to ovariectomy and lipodysaccharide for bone loss. Thus our findings demonstrate that Rgs12 is an important regulator in OC differentiation and function and identify Rgs12 as a potential therapeutic target for osteoporosis and inflammation-induced bone loss. PMID- 25909891 TI - Astrocyte NMDA receptors' activity sustains neuronal survival through a Cdk5-Nrf2 pathway. AB - Neurotransmission unavoidably increases mitochondrial reactive oxygen species. However, the intrinsic antioxidant defense of neurons is weak and hence the mechanism whereby these cells are physiologically protected against oxidative damage is unknown. Here we found that the antioxidant defense of neurons is repressed owing to the continuous protein destabilization of the master antioxidant transcriptional activator, nuclear factor-erythroid 2-related factor 2 (Nrf2). By contrast, Nrf2 is highly stable in neighbor astrocytes explaining their robust antioxidant defense and resistance against oxidative stress. We also show that subtle and persistent stimulation of N-methyl-d-aspartate receptors (NMDAR) in astrocytes, through a mechanism not requiring extracellular Ca2+ influx, upregulates a signal transduction pathway involving phospholipase C mediated endoplasmic reticulum release of Ca2+ and protein kinase Cdelta activation. Active protein kinase Cdelta promotes, by phosphorylation, the stabilization of p35, a cyclin-dependent kinase-5 (Cdk5) cofactor. Active p35/Cdk5 complex in the cytosol phosphorylates Nrf2 at Thr(395), Ser(433) and Thr(439) that is sufficient to promote Nrf2 translocation to the nucleus and induce the expression of antioxidant genes. Furthermore, this Cdk5-Nrf2 transduction pathway boosts glutathione metabolism in astrocytes efficiently protecting closely spaced neurons against oxidative damage. Thus, intercellular communication through NMDAR couples neurotransmission with neuronal survival. PMID- 25909892 TI - Prehospital Identification of Underlying Coronary Artery Disease by Community Paramedics. AB - There is a lack of definitive evidence that preventative, in-home medical care provided by highly trained community paramedics reduces acute health care utilization and improves the overall well-being of patients suffering from chronic diseases. The Expanding Paramedicine in the Community (EPIC) trial is a randomized controlled trial designed to investigate the use of community paramedics in chronic disease management (ClinicalTrials.gov ID: NCT02034045). This case of a patient randomized to the intervention arm of the EPIC study demonstrates how the added layer of frequent patient contact by community paramedics and real-time electronic medical record (EMR) correspondence between the paramedics, physicians and other involved practitioners prevented possible life-threatening complications. The visiting community paramedic deduced the need for an electrocardiogram, which prompted the primary care physician to order a stress test revealing abnormalities and thus a coronary artery bypass graft was performed without emergency procedures, unnecessary financial expenditure or further health degradation such as a myocardial infarction. PMID- 25909893 TI - Immucillins Impair Leishmania (L.) infantum chagasi and Leishmania (L.) amazonensis Multiplication In Vitro. AB - Chemotherapy against visceral leishmaniasis is associated with high toxicity and drug resistance. Leishmania parasites are purine auxotrophs that obtain their purines from exogenous sources. Nucleoside hydrolases release purines from nucleosides and are drug targets for anti-leishmanial drugs, absent in mammal cells. We investigated the substrate specificity of the Leishmania (L.) donovani recombinant nucleoside hydrolase NH36 and the inhibitory effect of the immucillins IA (ImmA), DIA (DADMe-ImmA), DIH (DADMe-ImmH), SMIH (SerMe-ImmH), IH (ImmH), DIG (DADMe-ImmG), SMIG (SerMe-ImmG) and SMIA (SerME-ImmA) on its enzymatic activity. The inhibitory effects of immucillins on the in vitro multiplication of L. (L.) infantum chagasi and L. (L.) amazonensis promastigotes were determined using 0.05-500 MUM and, when needed, 0.01-50 nM of each drug. The inhibition on multiplication of L. (L.) infantum chagasi intracellular amastigotes in vitro was assayed using 0.5, 1, 5 and 10 MUM of IA, IH and SMIH. The NH36 shows specificity for inosine, guanosine, adenosine, uridine and cytidine with preference for adenosine and inosine. IA, IH, DIH, DIG, SMIH and SMIG immucillins inhibited L. (L.) infantum chagasi and L. (L.) amazonensis promastigote growth in vitro at nanomolar to micromolar concentrations. Promastigote replication was also inhibited in a chemically defined medium without a nucleoside source. Addition of adenosine decreases the immucillin toxicity. IA and IH inhibited the NH36 enzymatic activity (Ki = 0.080 MUM for IA and 0.019 MUM for IH). IA, IH and SMIH at 10 MUM concentration, reduced the in vitro amastigote replication inside mice macrophages by 95% with no apparent effect on macrophage viability. Transmission electron microscopy revealed global alterations and swelling of L. (L.) infantum chagasi promastigotes after treatment with IA and IH while SMIH treatment determined intense cytoplasm vacuolization, enlarged vesicles and altered kinetoplasts. Our results suggest that IA, IH and SMIH may provide new chemotherapy agents for leishmaniasis. PMID- 25909894 TI - Multiband Semimetallic Electronic Structure of Superconducting Ta2PdSe5. AB - We report the electronic structure and related properties of the superconductor Ta2PdSe5 as determined from density functional calculations. The Fermi surface has two disconnected sheets, both derived from bands of primarily chalcogenide p states. These are a corrugated hole cylinder and a heavier complex shaped electron sheet. The sheets contain 0.048 holes and a compensating number of electrons per formula unit, making the material a semimetallic superconductor. The results support the presence of two band superconductivity, although a discrepancy in the specific heat is noted. This discrepancy is discussed as a possible consequence of Pd deficiency in samples. PMID- 25909896 TI - The OSCE progress test--Measuring clinical skill development over residency training. AB - PURPOSE: The purpose of this study was to explore the use of an objective structured clinical examination for Internal Medicine residents (IM-OSCE) as a progress test for clinical skills. METHODS: Data from eight administrations of an IM-OSCE were analyzed retrospectively. Data were scaled to a mean of 500 and standard deviation (SD) of 100. A time-based comparison, treating post-graduate year (PGY) as a repeated-measures factor, was used to determine how residents' performance progressed over time. RESULTS: Residents' total IM-OSCE scores (n = 244) increased over training from a mean of 445 (SD = 84) in PGY-1 to 534 (SD = 71) in PGY-3 (p < 0.001). In an analysis of sub-scores, including only those who participated in the IM OSCE for all three years of training (n = 46), mean structured oral scores increased from 464 (SD = 92) to 533 (SD = 83) (p < 0.001), physical examination scores increased from 464 (SD = 82) to 520 (SD = 75) (p < 0.001), and procedural skills increased from 495 (SD = 99) to 555 (SD = 67) (p = 0.033). There was no significant change in communication scores (p = 0.97). CONCLUSIONS: The IM-OSCE can be used to demonstrate progression of clinical skills throughout residency training. Although most of the clinical skills assessed improved as residents progressed through their training, communication skills did not appear to change. PMID- 25909895 TI - Leucine supplementation improves acquired growth hormone resistance in rats with protein-energy malnutrition. AB - BACKGROUND: Protein-energy malnutrition (PEM) can lead to growth hormone (GH) resistance. Leucine supplementation diets have been shown to increase protein synthesis in muscles. Our study aimed at investigating if long-term leucine supplementation could modulate GH-insulin-like growth factor (IGF)-1 system function and mammalian target of rapamycin (mTOR)-related signal transduction in skeletal muscles in a rat model of severe malnutrition. METHODOLOGY/PRINCIPAL FINDINGS: Male Sprague-Dawley rats (n = 50; weight, 302 +/- 5 g) were divided into 5 treatment groups, including 2 control groups (a normal control group that was fed chow and ad libitum water [CON, n = 10] and a malnourished control group [MC, n = 10] that was fed a 50% chow diet). After undergoing a weight loss stage for 4 weeks, rats received either the chow diet (MC-CON, n = 10), the chow diet supplemented with low-dose leucine (MC-L, n = 10), or the chow diet supplemented with high-dose leucine (MC-H, n = 10) for 2 weeks. The muscle masses of the gastrocnemius, soleus, and extensor digitorum longus were significantly reduced in the MC group. Re-feeding increased muscle mass, especially in the MC-L and MC H groups. In the MC group, serum IGF-1, IGF-binding protein (IGFBP)-3, and hepatic growth hormone receptor (GHR) levels were significantly decreased and phosphorylation of the downstream anabolic signaling effectors protein kinase B (Akt), mTOR, and ribosomal protein S6 kinase 1 (S6K1) were significantly lower than in other groups. However, serum IGF-1 and IGF binding protein (IGFBP)-3 concentrations and hepatic growth hormone receptor (GHR) levels were significantly higher in the MC-L and MC-H groups than in the MC-CON group, and serum IGFBP-1 levels was significantly reduced in the MC-L and MC-H groups. These changes were consistent with those observed for hepatic mRNA expression levels. Phosphorylation of the downstream anabolic signaling effectors Akt, mTOR, and S6K1 were also significantly higher in the MC-L and MC-H groups than in the MC CON group. CONCLUSION/SIGNIFICANCE: Our data are the first to demonstrate that long-term supplementation with leucine improved acquired growth hormone resistance in rats with protein-energy malnutrition. Leucine might promote skeletal muscle protein synthesis by regulating downstream anabolic signaling transduction. PMID- 25909897 TI - Molecular Targets of Omega-3 Fatty Acids for Cancer Therapy. AB - Nowadays, dietary guidelines acknowledge the therapeutic role of omega-3 polyunsaturated fatty acids, as the most important class of fatty acids, against different human diseases. During the last two decades, the average level of consumption of omega-3 polyunsaturated fatty acids has increased from 0.1 to 0.2 g per day. Omega-3 polyunsaturated fatty acids are a group of long-chain polyunsaturated fatty acids which are identified in different foods such as fatty fish, shellfish, and vegetable oils. A growing body of epidemiological and experimental evidence supports the anticancer effects of omega-3 polyunsaturated fatty acids, which led to the identification of their molecular targets in several cancer models. The present review focuses on the basic evidence supporting the potential applications of omega-3 polyunsaturated fatty acids in cancer therapy. PMID- 25909899 TI - Current and Future Environmental Balance of Small-Scale Run-of-River Hydropower. AB - Globally, the hydropower (HP) sector has significant potential to increase its capacity by 2050. This study quantifies the energy and resource demands of small scale HP projects and presents methods to reduce associated environmental impacts based on potential growth in the sector. The environmental burdens of three (50 650 kW) run-of-river HP projects were calculated using life cycle assessment (LCA). The global warming potential (GWP) for the projects to generate electricity ranged from 5.5-8.9 g CO2 eq/kWh, compared with 403 g CO2 eq/kWh for UK marginal grid electricity. A sensitivity analysis accounted for alternative manufacturing processes, transportation, ecodesign considerations, and extended project lifespan. These findings were extrapolated for technically viable HP sites in Europe, with the potential to generate 7.35 TWh and offset over 2.96 Mt of CO2 from grid electricity per annum. Incorporation of ecodesign could provide resource savings for these HP projects: avoiding 800 000 tonnes of concrete, 10 000 tonnes of steel, and 65 million vehicle miles. Small additional material and energy contributions can double a HP system lifespan, providing 39-47% reductions for all environmental impact categories. In a world of finite resources, this paper highlights the importance of HP as a resource-efficient, renewable energy system. PMID- 25909898 TI - Motor Performance Assessment in Parkinson's Disease: Association between Objective In-Clinic, Objective In-Home, and Subjective/Semi-Objective Measures. AB - Advances in wearable technology allow for the objective assessment of motor performance in both in-home and in-clinic environments and were used to explore motor impairments in Parkinson's disease (PD). The aims of this study were to: 1) assess differences between in-clinic and in-home gait speed, and sit-to-stand and stand-to-sit duration in PD patients (in comparison with healthy controls); and 2) determine the objective physical activity measures, including gait, postural balance, instrumented Timed-up-and-go (iTUG), and in-home spontaneous physical activity (SPA), with the highest correlation with subjective/semi-objective measures, including health survey, fall history (fallers vs. non-fallers), fear of falling, pain, Unified Parkinson's Disease Rating Scale, and PD stage (Hoehn and Yahr). Objective assessments of motor performance were made by measuring physical activities in the same sample of PD patients (n = 15, Age: 71.2+/-6.3 years) and age-matched healthy controls (n = 35, Age: 71.9+/-3.8 years). The association between in-clinic and in-home parameters, and between objective parameters and subjective/semi-objective evaluations in the PD group was assessed using linear regression-analysis of variance models and reported as Pearson correlations (R). Both in-home SPA and in-clinic assessments demonstrated strong discriminatory power in detecting impaired motor function in PD. However, mean effect size (0.94+/-0.37) for in-home measures was smaller compared to in-clinic assessments (1.30+/-0.34) for parameters that were significantly different between PD and healthy groups. No significant correlation was observed between identical in-clinic and in-home parameters in the PD group (R = 0.10-0.25; p>0.40), while the healthy showed stronger correlation in gait speed, sit-to stand duration, and stand-to-sit duration (R = 0.36-0.56; p<0.03). This suggests a better correlation between supervised and unsupervised motor function assessments in healthy controls compared to PD group. In the PD group, parameters related to velocity and range-of-motion of lower extremity within gait assessment (R = 0.58-0.84), and turning duration and velocity within iTUG test (R = 0.62 0.77) demonstrated strong correlations with PD stage (p<0.01). PMID- 25909900 TI - Spectroscopic and electrochemical studies of the interaction between oleuropein, the major bio-phenol in olives, and salmon sperm DNA. AB - Interaction of oleuropein, the major bio-phenol in olive leaf and fruit, with salmon sperm double-stranded DNA was investigated by employing electronic absorption titrations, fluorescence quenching spectroscopy, competitive fluorescence spectroscopy, thermal denaturation and voltammetric studies. Titration of oleuropein with the DNA caused a hypochromism accompanied with a red shift indicating an intercalative mode of interaction. Binding constant of 1.4*10(4) M(-1) was obtained for this interaction. From the curves of fluorescence titration of oleuropein with the DNA, binding constant and binding sites were calculated to be 8.61*10(3) M(-1) and 1.05, respectively. Competitive studies with ethidium bromide (a well-known DNA intercalator) showed that the bio phenol could take the place of ethidium bromide in the DNA intercalation sites. The interaction of oleuropein with DNA was also studied electrochemically. In the presence of the DNA, the anodic and cathodic peak currents of oleuropein decreased accompanied with increases in peak-to-peak potential separation and formal potential, indicating the intercalation of oleuropein into the DNA double helix. Moreover, melting temperature of the DNA was found to increase in the presence of oleuropein, indicating the stabilization of the DNA double helix due to an intercalative interaction. PMID- 25909901 TI - Dielectric studies on struvite urinary crystals, a gateway to the new treatment modality for urolithiasis. AB - Struvite or magnesium ammonium phosphate hexahydrate (MAPH) are biological crystals, found in the kidney, which are formed due to the infection caused by urea splitting bacteria in the urinary tract. The struvite crystals observe different morphologies and were developed using single diffusion gel growth technique. The crystalline nature and its composition were studied from different characterization techniques like X-ray Diffraction (XRD) and FTIR. The dielectric behavior of the developed crystal was studied by varying temperature and at different frequencies. The parameters like dielectric constant, dielectric loss, ac conductivity, ac resistivity, impedance and admittance of the struvite crystals were calculated. The studies proved that the dielectric loss or dissipation heat is high in lower frequencies at normal body temperature, which develops a plasma state in the stones and in turn leads to the disintegration of urinary stones. The dielectric nature of the stones leads to the dielectric therapy, which will be a gateway for future treatment modality for urolithiasis. PMID- 25909902 TI - Low-temperature phase transformation studies in the stearic acid: C form. AB - This paper reports the temperature-dependent measurements in the C form of stearic acid. Raman scattering, X-ray diffraction, and differential scanning calorimetry measurements were performed at low temperatures. The polarized Raman spectra were measured for temperatures ranging from 8 to 300 K over the spectral range of 30-3000 cm(-1). The spectral changes observed in both the lattice vibrational modes and the internal vibrational modes regions of the Raman spectrum, allowed to identify a phase transition undergone by the stearic acid crystal occurring between 210 and 170 K and a change in the structure continues to be observed down to 8 K. The anharmonicity of some vibrational modes and the possible space groups presented by the crystal at low temperatures were also discussed. Low-temperature X-ray diffraction measurements were performed from 290 to 80 K and the results showed slight changes in the lattice parameters at ~200 K. Furthermore, the evidence of the phase transformation was provided by the differential scanning calorimetry measurements, which identified an enthalpic anomaly at about 160 K. PMID- 25909903 TI - Microwave, structural, conformational, vibrational studies and ab initio calculations of fluoroacetyl chloride. AB - The infrared and Raman spectra (3200-50 cm(-1)) of the gas, liquid or solution, and solid of fluoroacetyl chloride, FCH2COCl have been recorded. FT-microwave studies have also been carried out and 22 transitions were recorded for the trans conformer. Variable temperature (-50 to -105 degrees C) studies of the infrared and Raman spectra (3200-50 cm(-1)) of xenon solutions have been carried out. From these data, the trans, cis and gauche conformers have been identified and their relative stabilities obtained. The enthalpy difference has been determined to be 159+/-11 cm(-1) (1.90+/-0.14 kJ mol(-1)) with the trans conformer the more stable form than the cis. The energy difference between the cis and gauche form is 222+/ 18 cm(-1) (2.66+/-0.21 kJ/mol) and the energy difference between the trans and gauche forms is 386+/-13 cm(-1) (4.61+/-0.16 kJ/mol). Vibrational assignments have been made for the observed bands for the three conformers with initial predictions by MP2(full)/6-31G(d) ab initio calculations to obtain harmonic force constants, wavenumbers, infrared intensities, and Raman activities for the three conformers. By utilizing the microwave rotational constants of two isotopomers for trans, combined with the structural parameters predicted from MP2(full)/6 311+G(d,p) calculations, adjusted r0 parameters have been obtained for the trans conformer. The results are discussed and compared to the corresponding properties of some related molecules. PMID- 25909904 TI - State-resolved collisional relaxation of highly vibrationally excited CsH by CO2. AB - Quenching of highly vibrationally excited CsH(X(1)Sigma(+), v=15-23) by collisions with CO2 was investigated. A significant fraction of the initial population of highly vibrationally excited CsH(v=22) was relaxed to a low vibrational level (Deltav=-5). The near-resonant 5-1 vibration-to-vibration (V-V) energy was efficiently exchanged. The rate constants for the rotational levels of CO2(00(0)0) [J=36-60] and CO2(00(0)1) [J=5-31] from the collisions with excited CsH were determined. The experiments revealed that the collisions resulting in CO2(00(0)0) were accompanied by substantial excitation in rotation and translation. The vibrationally excited CO2(00(0)1) state exhibited rotational and translational energy distributions near those of the initial state. The total quenching rates relative to the probed state of excited CsH were determined for both CO2 states. The corresponding data indicated that the gains in the rotational and translational energies in CO2 were sensitive to the collisional depletion of excited CsH. PMID- 25909905 TI - Fluorescent probe 7-(prop-2-yn-1-yloxy)-2H-chromen-2-one: Experimental and DFT based approach to photophysical properties. AB - Compound 7-(prop-2-yn-1-yloxy)-2H-chromen-2-one was synthesized by Pechmann condensation reaction and characterized by various spectroscopic techniques. The structure of title compound was confirmed by single crystal X-ray diffraction. The compound crystallized in the orthorhombic system with P 21 21 21 space group and the corresponding lattice parameters were found to be a=4.0138 (11) A, alpha=90 degrees ; b=23.536 (6) A, beta=90 degrees ; c=10.93 (2) A, gamma=90 degrees . The crystal packing of molecule showed that intermolecular hydrogen bonds C3-H3?O3 [D=3.53 A], C-13-H13?O2 [D=3.67 A] and intermolecular short interaction between C1-H1?C1-H1 [2.68 A] forms a dimeric unit which finally stabilizes the crystal packing in three dimensional network in the molecule. Absorption and emission spectra shows that compound is fluorescent with good Stoke shift values ranging between 57 and 62 nm. Thermal analysis further supports by TGA, DTA. The photophysical results show that the compound exhibits change in fluorescence quantum yield with change in solvent polarity. The structural parameters and the vibrational wave numbers obtained from the optimized geometry of the compound from DFT-B3LYP calculations employing 6-311G (d,p) basis set are in good agreement with the experimental data. UV-Vis spectrum calculated by employing time dependent density functional theory (TD-DFT) is also in very good agreement with the experiment for all solvents. PMID- 25909906 TI - Synthesis, photoisomerization properties and thermal bleaching kinetics of pyrazolones containing 3-cyanobenzal. AB - Through the design of molecules and the modification of structures, ten novel pyrazolone derivatives containing 3-cyanobenzal have been synthesized. They are 1 phenyl-3-methyl-4-(3-cyanobenzal)-5-hydroxypyrazole thiosemicarbazone (1)/4 methyl-3-thiosemicarbazone (2)/4-ethyl-3-thiosemicarbazone (3)/4-phenyl-3 thiosemicarbazone (4)/4-phenylsemicarbazone (5) and 1,3-diphenyl-4-(3 cyanobenzal)-5-hydroxypyrazole thiosemicarbazone (6)/4-methyl-3-thiosemicarbazone (7)/4-ethyl-3-thiosemicarbazone (8)/4-phenyl-3-thiosemicarbazone (9)/4 phenylsemicarbazone (10), in which seven compounds (1, 2, 3, 6, 7, 8 and 10) have photoisomerization behaviors. Their structures, photoisomerization properties, and first-order kinetics were investigated. The results show that the compounds 2, 3, 7 and 8 exhibit irreversible photoisomerization behaviors, the other three compounds have reversible photoisomerization behaviors under 365nm light irradiation and heat. But only 1,3-diphenyl-4-(3-cyanobenzal)-5-hydroxypyrazole 4 phenylsemicarbazone (10) exhibits good photochromic properties and fatigue resistance. Moreover, effects of various temperatures on the thermal bleaching reaction for 10 and substituent groups on the photochromic phenomenon are discussed. PMID- 25909907 TI - A novel red emitting phosphor of Eu(3+) doped Sr2La2MgW2O12 for white light emitting diodes. AB - In this paper, we reported a series of Eu(3+) activated Sr2La2MgW2O12 phosphors synthesized by the solid state reaction method. X-ray diffraction analysis revealed that Sr2La2MgW2O12 doped with Eu(3+) was pure phase. Upon the 464 nm light excitation, Sr2La2MgW2O12:Eu(3+) phosphors exhibited a red emission centered at 613 nm, originated from the (5)D0-(7)F2 transition of Eu(3+) ions. The optimum concentration of Eu(3+) for the highest luminescence was found to be 20 mol%, and the critical distance was calculated to be 11.98A. The Commission International de l'Eclairage (CIE) chromaticity coordinate of Sr2La1.8MgW2O12:0.20Eu(3+) was (x=0.626, y=0.374), which was closed to the standard of NTSC (x=0.670, y=0.330). The results indicated that Sr2La2MgW2O12:Eu(3+) could be a potential red phosphor for white light-emitting diodes (WLEDs). PMID- 25909908 TI - Comparative study of novel versus conventional two-wavelength spectrophotometric methods for analysis of spectrally overlapping binary mixture. AB - Smart spectrophotometric methods have been applied and validated for the simultaneous determination of a binary mixture of chloramphenicol (CPL) and prednisolone acetate (PA) without preliminary separation. Two novel methods have been developed; the first method depends upon advanced absorbance subtraction (AAS), while the other method relies on advanced amplitude modulation (AAM); in addition to the well established dual wavelength (DW), ratio difference (RD) and constant center coupled with spectrum subtraction (CC-SS) methods. Accuracy, precision and linearity ranges of these methods were determined. Moreover, selectivity was assessed by analyzing synthetic mixtures of both drugs. The proposed methods were successfully applied to the assay of drugs in their pharmaceutical formulations. No interference was observed from common additives and the validity of the methods was tested. The obtained results have been statistically compared to that of official spectrophotometric methods to give a conclusion that there is no significant difference between the proposed methods and the official ones with respect to accuracy and precision. PMID- 25909909 TI - Associations of maternal retinal vasculature with subsequent fetal growth and birth size. AB - OBJECTIVE: We aimed to study the maternal retinal microvasculature at mid trimester and its relationship with subsequent fetal growth and birth size. METHODS: We recruited 732 pregnant women aged 18-46 years in the first trimester with singleton pregnancies. All had retinal photography and fetal scan performed at 26-28 weeks gestation, and subsequent fetal scan at 32-34 weeks gestation. Infant anthropometric measurements were done at birth. Retinal microvasculature was measured using computer software from the retinal photographs. RESULTS: In multiple linear regression models, each 10 MUm narrowing in maternal retinal arteriolar caliber was associated with decreases of 1.36 mm in fetal head circumference at 32-34 weeks gestation, as well as decreases of 1.50 mm and 2.30 mm in infant head circumference and birth length at delivery, respectively. Each standard deviation decrease in maternal retinal arteriolar fractal dimension was associated with decreases of 1.55 mm in fetal head circumference at 32-34 weeks gestation, as well as decreases of 1.08 mm and 46.42 g in infant head circumference and birth weight at delivery, respectively. CONCLUSIONS: Narrower retinal arteriolar caliber and a sparser retinal vascular network in mothers, reflecting a suboptimal uteroplacental microvasculature during mid-pregnancy, were associated with poorer fetal growth and birth size. PMID- 25909910 TI - Functional marker detection and analysis on a comprehensive transcriptome of large yellow croaker by next generation sequencing. AB - Large yellow croaker (Larimichthys crocea) is an important economic fish in China and Eastern Asia. Because of the exhaustive fishing and overdense aquaculture, the wild population and the mariculture of the species are facing serious challenges on germplasm degeneration and susceptibility to infectious disease agents. However, a comprehensive transcriptome from multi-tissues of the species has not been reported and functional molecular markers have not yet been detected and analyzed. In this work, we applied RNA-seq with the Illumina Hiseq2000 platform for a multi-tissue sample of large yellow croaker and assembled the transcriptome into 88,103 transcripts. Of them, 52,782 transcripts have been successfully annotated by nt/nr, InterPro, GO and KEGG database. Comparing with public fish proteins, we have found that 34,576 protein coding transcripts are shared in large yellow croaker with zebrafish, medaka, pufferfish, and stickleback. For functional markers, we have discovered 1,276 polymorphic SSRs and 261, 000 SNPs. The functional impact analysis of SNPs showed that the majority (~75%) of small variants cause synonymous mutations in proteins, followed by variations in 3' UTR region. The functional enrichment analysis illuminated that transcripts involved in DNA bindings, enzyme activities, and signal pathways prominently exhibit less single-nucleotide variants but genes for the constituent of the muscular tissue, the cytoskeleton, and the immunity system contain more frequent SNP mutations, which may reflect the structural and functional selections of the translated proteins. This is the first work for the high-throughput detection and analysis of functional polymorphic SSR and SNP markers in a comprehensive transcriptome of large yellow croaker. Our study provides valuable transcript sequence and functional marker resources for the quantitative trait locus (QTL) identification and molecular selection of the species in the research community. PMID- 25909912 TI - Ultrastructure of the Interlamellar Membranes of the Nacre of the Bivalve Pteria hirundo, Determined by Immunolabelling. AB - The current model for the ultrastructure of the interlamellar membranes of molluscan nacre imply that they consist of a core of aligned chitin fibers surrounded on both sides by acidic proteins. This model was based on observations taken on previously demineralized shells, where the original structure had disappeared. Despite other earlier claims, no direct observations exist in which the different components can be unequivocally discriminated. We have applied different labeling protocols on non-demineralized nacreous shells of the bivalve Pteria. With this method, we have revealed the disposition and nature of the different fibers of the interlamellar membranes that can be observed on the surface of the nacreous shell of the bivalve Pteria hirundo by high resolution scanning electron microscopy (SEM). The minor chitin component consists of very thin fibers with a high aspect ratio and which are seemingly disoriented. Each fiber has a protein coat, which probably forms a complex with the chitin. The chitin-protein-complex fibers are embedded in an additional proteinaceous matrix. This is the first time in which the sizes, positions and distribution of the chitin fibers have been observed in situ. PMID- 25909911 TI - Diverse Phenotypes and Specific Transcription Patterns in Twenty Mouse Lines with Ablated LincRNAs. AB - In a survey of 20 knockout mouse lines designed to examine the biological functions of large intergenic non-coding RNAs (lincRNAs), we have found a variety of phenotypes, ranging from perinatal lethality to defects associated with premature aging and morphological and functional abnormalities in the lungs, skeleton, and muscle. Each mutant allele carried a lacZ reporter whose expression profile highlighted a wide spectrum of spatiotemporal and tissue-specific transcription patterns in embryos and adults that informed our phenotypic analyses and will serve as a guide for future investigations of these genes. Our study shows that lincRNAs are a new class of encoded molecules that, like proteins, serve essential and important functional roles in embryonic development, physiology, and homeostasis of a broad array of tissues and organs in mammals. PMID- 25909913 TI - Face and body recognition show similar improvement during childhood. AB - Adults are proficient in extracting identity cues from faces. This proficiency develops slowly during childhood, with performance not reaching adult levels until adolescence. Bodies are similar to faces in that they convey identity cues and rely on specialized perceptual mechanisms. However, it is currently unclear whether body recognition mirrors the slow development of face recognition during childhood. Recent evidence suggests that body recognition develops faster than face recognition. Here we measured body and face recognition in 6- and 10-year old children and adults to determine whether these two skills show different amounts of improvement during childhood. We found no evidence that they do. Face and body recognition showed similar improvement with age, and children, like adults, were better at recognizing faces than bodies. These results suggest that the mechanisms of face and body memory mature at a similar rate or that improvement of more general cognitive and perceptual skills underlies improvement of both face and body recognition. PMID- 25909914 TI - Inclusive fitness theorizing invokes phenomena that are not relevant for the evolution of eusociality. AB - In this Formal Comment, the authors challenge the claims of a recent theoretical study that genetic relatedness is important in the evolution of eusociality. PMID- 25909915 TI - Bending elasticity of vesicle membranes studied by Monte Carlo simulations of vesicle thermal shape fluctuations. AB - The membrane bending stiffness of nearly spherical lipid vesicles can be deduced from the analysis of their thermal shape fluctuations. The theoretical basis of this analysis [Milner and Safran, Phys. Rev. A: At., Mol., Opt. Phys., 1987, 36, 4371-4379] uses the mean field approximation. In this work we apply Monte Carlo simulations and estimate the error in the determination of the bending stiffness due to the approximations applied in the theory. It is less than 10%. The method presented in this work can also be used to determine the changes of the bending stiffness of biological membranes due to their chemical and/or structural modifications. PMID- 25909916 TI - An assessment of the usefulness of a coconut as a model of the human skull for forensic identification of a homicide weapon. AB - The authors made an attempt to verify if a coconut can be used as a model of human skull to determine the homicide weapon. During our experiment 27 strike attempts were performed with the use of 9 different tools. Among them there were authentic murder weapons and instruments which had been used in similar experiments conducted on human skulls in 1955. Depending on the size of an area in contact with a coconut, weapons caused dents corresponding to the shape of a weapon, irregular fractures or long linear cracks. Our results have shown that coconut can be used as an inexpensive screening model of human skull, but only to determine fractures made by tools with small striking surface. PMID- 25909917 TI - Analysis of variability of concentrations of valproic acid (VPA) and its selected metabolites in the blood serum of patients treated with VPA and patients hospitalized because of VPA poisoning. AB - AIM OF THE STUDY: To compare the metabolic profile of valproic acid (VPA) in the studied groups of cases through an analysis of variability of concentrations of VPA with its selected metabolites (2-ene-VPA, 4-ene-VPA, 3-keto-VPA). STUDY MATERIAL: Blood serum samples collected from 27 patients treated with VPA drugs in the Psychiatry Unit and in the Neurology and Cerebral Strokes Unit at the Ludwik Rydygier Provincial Specialist Hospital in Krakow, and blood serum samples collected from 26 patients hospitalized because of suspected acute VPA poisoning at the Toxicology Department, Chair of Toxicology and Environmental Diseases, Jagiellonian University Medical College in Krakow. RESULTS AND CONCLUSIONS: The analysis of concentrations of VPA and its selected metabolites has shown that the metabolic profile of VPA determined in cases of acute poisoning is different from cases of VPA therapy. One of VPA's metabolic pathways - the process of desaturation - is unchanged in acute poisoning and prevails over the process of beta-oxidation. The ingestion of toxic VPA doses results in an increased formation of 4-ene-VPA, proportional to an increase in VPA concentration. Acute VPA poisoning involves the saturation of VPA's metabolic transformations at the stage of beta-oxidation. The process of oxidation of 2-ene-VPA to 3-keto-VPA is slowed down after the ingestion of toxic doses. PMID- 25909918 TI - Analysis of the origin and importance of acetone and isopropanol levels in the blood of the deceased for medico-legal testimony. AB - The aim of the study was to analyze the incidence of acetone and isopropanol in the blood of the deceased, and to assess cases in which the compounds have been detected with a focus on their origin and usefulness for medico-legal testimony. MATERIAL AND METHODS: The study material consisted of results of tests detecting ethyl alcohol and reports of autopsies performed at the Department of Forensic Medicine, Medical University of Warsaw, from January 2008 to April 2009 - a total of 2,475 cases. The test group proper (group B) comprised only those cases in which acetone was detected in blood, either with or without isopropanol [n = 202 (8.2%)]. The blood levels of isopropanol varied depending on the cause of death. The need for differentiating the origin of isopropanol in the case of its presence in the blood of the deceased was pointed out. RESULTS: The results of the present study show that the differentiation should be based on the isopropanol and acetone concentration ratio, as isopropanol concentration alone is not sufficient for preparing expert opinions. Even high concentrations of isopropanol, when accompanied by even higher concentrations of acetone, imply that isopropanol could have been formed as a result of acetone transformations. Isopropanol concentrations exceeding acetone levels strongly point to the exogenous origin of isopropanol, particularly when high levels of ethanol are concurrently detected. PMID- 25909919 TI - Case of sudden death following rupture of thoracic aortic aneurysm during "a manual therapy" procedure in the spinal area. AB - The reported case concerns the rupture of an aneurysm located in the descending part of the thoracic aorta during the procedure of the so-called "spinal adjustment" performed by a chiropractor. A 45-year-old patient with no significant medical history of cardiovascular diseases visited, along with his wife, one of "manual therapy" practices because of back pain. During the procedure, the patient suddenly lost consciousness. Despite cardiopulmonary resuscitation and emergency assistance given by an ambulance team, the patient died. An autopsy revealed that the cause of death was increasing cardiorespiratory failure secondary to bleeding into the lumen of the left pleural cavity following the rupture of pathologically altered thoracic aortic wall. PMID- 25909920 TI - Insects feeding on cadavers as an alternative source of human genetic material. AB - In some criminal cases, the use of classical sources of human genetic material is difficult or even impossible. One solution may be the use of insects, especially blowfly larvae which feed on corpses. A recent review of case reports and experimental studies available in biomedical databases has shown that insects can be a valuable source of human mitochondrial and genomic deoxyribonucleic acid (DNA), allowing for an effective analysis of hypervariable region (HVR) sequences and short tandem repeat (STR) profiles, respectively. The optimal source of human DNA is the crop (a part of the gut) of active third-instar blowfly larvae. Pupae and insect faeces can be also used in forensic genetic practice instead of the contents of the alimentary tract. PMID- 25909921 TI - Neurofilaments and traumatic brain injury. AB - Objective determination of the time of brain contusion is of key importance in medicolegal neurotraumatology. Currently, the progress of immunohistochemistry allows the study of structural elements of cells including neurofilaments, i.e. neuronal cytoskeletal proteins possessing properties that could be used for determining the age of brain injury in forensic medicine. The purpose of this study was to review recently published literature with a focus on studies investigating changes which occur in neurofilaments after brain trauma, both in animal models and in human biological material. The review has shown a lack of data on temporal changes in neurofilament expression after human brain trauma which could be used for determining the age of injuries in forensic medicine. PMID- 25909922 TI - Post-mortem diagnostics in cases of sepsis. Part 1. Aetiology, epidemiology and microbiological tests. AB - Clinical practice has an effective methodology of diagnostic procedures to be followed in cases of sepsis. However, there are as yet no corresponding standards of action in post-mortem diagnostics. The scope of examinations is limited to an autopsy and histopathological tests. This situation may lead to errors in medico legal opinions on the cause of death and in the assessment of appropriateness of medical procedures. In cases of suspected sepsis, medico-legal investigations require obtaining detailed information about the circumstances of death (including symptoms and results of intravital examinations) before autopsy is performed, as well as sterile collection of specimens for microbiological tests and interpretation of their results on the basis of knowledge of epidemiology, pathophysiology and clinical progression of sepsis. PMID- 25909923 TI - Platelet Reactivity Unit in Predicting Risk of Bleeding in Patients Undergoing Coronary Artery Bypass Graft Surgery. AB - Bleeding is a common complication of cardiac surgery, accounting for a significant proportion of the total transfusions performed in the United States and Europe. The relationship between platelet reactivity, bleeding, and other adverse events after coronary artery bypass graft surgery (CABGS) has been incompletely characterized. This study investigated the relationship between platelet reactivity and bleeding as a clinical outcome after successful CABGS. A total of 238 patients who underwent CABGS were retrospectively followed for postoperative bleeding. Platelet reactivity unit (PRU) values for all patients were obtained preoperatively to assess the platelet reactivity. The data showed that a range of 180-200 PRU suggests the likelihood of bleeding after CABGS (P = 0.004), with a statistically significant association only for dual antiplatelet therapy with aspirin and clopidogrel. In conclusion, by using PRU values as a method to assess platelet reactivity and antiplatelet responsiveness, our findings suggest that it may be possible to stratify patients undergoing CABGS for the risk of postoperative bleeding particularly patients on dual antiplatelet therapy. PMID- 25909924 TI - Comparison of the Effects of Lobectomy on Immunologic Function Between Video Assisted Thoracoscopic Surgery and Traditional Open Surgery for Non-Small-Cell Lung Cancer. AB - To compare the effects of lobectomy on immunologic function between video assisted thoracoscopic surgery (VATS) and traditional open surgery (TOS) for non small-cell lung cancer (NSCLC). A total of 80 patients with NSCLC were recruited from Liaoning Cancer Hospital & Institute between June 2013 and August 2014. The participators were grouped into VATS and TOS at random. The levels of C-reactive protein, serum amyloid A, interleukin (IL) 6, and IL-2R were detected before operation, 24 hours, and 72 hours after operation. The number of peripheral blood lymphocytes and the proportion of CD4 T lymphocytes, CD8 T lymphocytes, and natural killer in lymphocytes of all patients should be detected before operation, 3 days, and 7 days after operation. The preoperative and postoperative quality of life assessment of patients with NSCLC was evaluated. All data were analyzed using SPSS 17.0 software. The blood loss and transfusion volume during operation in VATS group were obviously less than those in TOS group. The levels of CPR, serum amyloid A, IL-6, and IL-2R after operation were significantly higher as compared with those before operation. The postoperative proportions of CD4 T lymphocytes and natural killer in lymphocytes and the number of lymphocytes were decreased compared with those before operation. The proportion of CD8 T lymphocytes 7 days after operation in TOS group was clearly lower than that in VATS group. The postoperative quality of life was evidently higher compared with that after operation in VATS and TOS groups. In conclusion, when compared with TOS, VATS could decrease perioperative acute-phase reaction, lighten the restrain of immunologic function, and improve quality of life in patients with early-stage NSCLC, suggesting that VATS lobectomy is an appropriate method for patients with early-stage NSCLC as compared with TOS. PMID- 25909925 TI - Severe Hemolysis in a Patient With Erythrocytosis During Coupled Plasma Filtration Adsorption Therapy Was Prevented by Changing From Membrane-Based Technique to a Centrifuge-Based One. AB - Coupled plasma filtration adsorption (CPFA) usually adopts membrane to separate plasma from blood. Here, we reported a case with erythrocytosis experienced severe hemolysis and membrane rupture during CPFA, which was avoided by changing from membrane-based technique to a centrifuge-based one. A 66-year-old man was to receive CPFA for severe hyperbilirubinemia (total bilirubin 922 MUmol/L, direct bilirubin 638 MUmol/L) caused by obstruction of biliary tract. He had erythrocytosis (hemoglobin 230 g/L, hematocrit 0.634) for years because of untreated tetralogy of Fallot. Severe hemolysis and membrane rupture occurred immediately after blood entering into the plasma separator even at a low flow rate (50 mL/min) and persisted after changing a new separator. Finally, centrifugal plasma separation technique was used for CPFA in this patient, and no hemolysis occurred. After 3 sessions of CPFA, total bilirubin level decreased to 199 MUmol/L with an average decline by 35% per session. Thereafter, the patient received endoscopic biliary stent implantation, and total bilirubin level returned to nearly normal. Therefore, centrifugal-based plasma separation can also be used in CPFA and may be superior to a membrane-based one in patients with hyperviscosity. PMID- 25909926 TI - Lack of high-quality studies comparing the effectiveness, and cost-effectiveness, of dental auxiliaries and dentists in performing dental care. AB - DATA SOURCES: Cochrane Effective Practice and Organisation of Care (EPOC) Group's Specialised Register; Cochrane Oral Health Group's Specialised Register; the Cochrane Central Register of Controlled Trials Medline; Embase; CINAHL; Cochrane Database of Systematic Reviews; Database of Abstracts of Reviews of Effectiveness; five other databases and two trial registries. A number of dental journals were hand-searched and a grey literature search preformed. STUDY SELECTION: Randomised controlled trials (RCTs), non-randomised controlled trials (NRCTs), controlled before and after studies (CBAs) and interrupted time series (ITSs) were considered. Selection was conducted independently by two reviewers. DATA EXTRACTION AND SYNTHESIS: Three reviewers extracted data and assessed risk of bias. Meta-analysis was not possible so a narrative summary was presented. RESULTS: Four studies evaluated sealant placement; three found no evidence of a difference in retention rates of those placed by dental auxiliaries and dentists over a range of follow-up periods (six to 24 months). One study found that sealants placed by a dental auxiliary had lower retention rates than ones placed by a dentist after 48 months (9.0% with auxiliary versus 29.1% with dentist); but the net reduction in the number of teeth exhibiting caries was lower for teeth treated by the dental auxiliary than the dentist (three with auxiliary versus 60 with dentist, P value < 0.001). One study showed no evidence of a difference in dental decay after treatment with fissure sealants between groups. One study comparing the effectiveness of dental auxiliaries and dentists performing ART reported no difference in survival rates of the restorations (fillings) after 12 months. CONCLUSIONS: We only identified five studies for inclusion in this review, all of which were at high risk of bias, and four were published more than 20 years ago, highlighting the paucity of high-quality evaluations of the relative effectiveness, cost-effectiveness and safety of dental auxiliaries compared with dentists in performing clinical tasks. No firm conclusions could be drawn from the present review about the relative effectiveness of dental auxiliaries and dentists. PMID- 25909927 TI - Payment methods may influence behaviour of primary care dentists. AB - DATA SOURCES: The Cochrane Effective Practice and Organisation of Care (EPOC) Group Specialised Register; the Cochrane Central Register of Controlled Trials (CENTRAL), Medline, Embase, EconLit the NHS Economic Evaluation Database (EED) and the Health Economic Evaluations Database (HEED). STUDY SELECTION: Randomised controlled trials (RCTs), non-randomised controlled clinical trials (NRCTs), controlled before-after (CBA) studies and interrupted time series (ITS) studies were considered. Study selection was undertaken independently by three reviewers. Fee-for-service payments, fixed salary payments, capitation payments of combinations thereof included. DATA EXTRACTION AND SYNTHESIS: Standard Cochrane methodological procedures were followed. RESULTS: Two cluster-RCTs, with data from 503 dental practices, representing 821 dentists and 4771 patients, met the selection criteria. The risk of bias for the two studies was considered to be high and the overall quality of evidence for the outcomes was low/very low for all outcomes, as assessed using the GRADE approach.One study conducted in the four most deprived areas of Scotland used a factorial design to investigate the impact of fee-for-service and an educational intervention on the placement of fissure sealants. The authors reported a statistically significant increase in clinical activity in the arm that was incentivised with a fee-for-service payment. Measures of health service utilisation or patient outcomes were not reported. The second study used a parallel group design undertaken over a three year period to compare the impact of capitation payments with fee-for-service payments on primary care dentists' clinical activity. The study reported on measures of clinical activity, patient outcomes and healthcare costs. Teeth were restored at a later stage in the disease process in the capitation system and the clinicians tended to see their patients less frequently and tended to carry out fewer fillings and extractions, but also tended to give more preventive advice.There was insufficient information regarding the cost-effectiveness of the different remuneration methods. CONCLUSIONS: Financial incentives within remuneration systems may produce changes to clinical activity undertaken by primary care dentists. However, the number of included studies is limited and the quality of the evidence from the two included studies was low/very low for all outcomes. Further experimental research in this area is highly recommended given the potential impact of financial incentives on clinical activity, and particular attention should be paid to the impact this has on patient outcomes. PMID- 25909928 TI - Training and fairer payments would increase caries prevention in practice. AB - DATA SOURCES: PubMed, Embase, PsycoInfo, Scielo, Scopus, Web of Science, BBO, Lilacs and York databases supplemented by Google scholar. STUDY SELECTION: Qualitative studies with findings derived from individual or group interviews and structured questionnaires reporting factors that drove dentists towards or away from incorporating caries preventive measures were considered. Two reviewers conducted selection independently. DATA EXTRACTION AND SYNTHESIS: Data were abstracted independently by two reviewers and a qualitative metasummary carried out. This involves the extraction, grouping and formatting of findings and the calculation of frequency and intensity effect sizes in order to provide mixed research syntheses and to conduct a posteriori analyses of the relationship between reports and findings. RESULTS: Seven qualitative studies and 41 surveys (36,501 participants) were included. The reports were grouped together into six categories that were judged to be topically similar; education and training, personal beliefs, work conditions, remuneration, gender, place of residence and patients. Biologicism (27%), low remuneration (25%), length of time since graduation (22%) and male dentists (19%) were found to be the highest frequency effect size driving dentists away from using preventive approaches, and team work (21%), post-graduation (12%) and professional understanding of the benefits (12%) were identified as the main reasons for dentists' adherence to preventive measures. CONCLUSIONS: Despite the questionable quality of the included reports the evidence that emerged seems to indicate that further education and training coupled with a fairer pay scheme would be a reasonable approach to change the balance in favour of the provision of dental caries preventive measures by dentists. The results of this review could be of value in the planning and decision-making processes aimed at encouraging changes in professional dental practice that could result in the improvement of the oral health care provided to the population in general. PMID- 25909929 TI - Nano Silver Fluoride for preventing caries. AB - DESIGN: Randomised controlled trial, double blind, in a community setting. INTERVENTION: School children with active caries in primary teeth and no pulpal exposure, fistula or decay in permanent teeth were chosen. Caries and unsupported enamel were left as found and cotton wool rolls were used for isolation. Two drops of NSF or one drop of water were applied to the tooth with a microbrush for two minutes, once in a 12-month period. OUTCOME MEASURE: At one week, five months and 12 months the presence of active caries, as classified using International Caries Detection and Assessment System (ICDAS II) criteria, was measured. If a blunt probe easily penetrated dentine with light force, active caries was recorded and taken to be a failure. RESULTS: One hundred and thirty primary teeth in 60 children with a mean age of 6.31 (+/- 0.60) were randomised. Sixty-three teeth were in the NSF group and 67 in the control group. After one week there were no losses, at the five-month follow up eight teeth were lost from the NSF group due to exfoliation or extraction and five from the control group. At twelve months a further five teeth were lost from the NSF group and 13 from the control group.At the one week follow up there was a 19% failure rate in the NSF group compared to 100% in the control group. At the five month recall this was 27.3% NSF compared to 72.6% water and at the final recall there was a 33.3% NSF failure rate and 65.3% control failure rate. The preventative fraction at this point was 50% and the NNT 3.12. All were statistically significant results (p= <0.05). CONCLUSIONS: The annual application of NSF solution was more effective in hardening and arresting dentine caries in primary teeth than the placebo. The effectiveness of NSF was found to be similar to silver diamine fluoride when applied once a year, but did not stain the dental tissue black and had no metallic taste. The application is simple, does not require a clinical setting and is inexpensive. NSF was demonstrated to be effective in arresting caries in children in poor communities, but further studies are required to investigate alternative protocols and for use in tooth sensitivity and root caries. PMID- 25909930 TI - Topical agents for root caries prevention. AB - DATA SOURCES: PubMed, EMBASE and Cochrane Central Register of Controlled Trials. STUDY SELECTION: Randomised and nonrandomised, controlled, and prospective studies comparing preventive regimes for root caries were considered. Only English or German language studies were considered. DATA EXTRACTION AND SYNTHESIS: Standard data items were extracted. Mean differences (MD) and standard mean differences (SMD) were primary effect measures. Changes were calculated for DMFRS/DFRS (decayed, missing, filled root surfaces), and RCI (root caries index). Random-effects meta-analysis was conducted. Study quality was assessed using the Cochrane risk of bias tool and grading of evidence was performed according to the GRADE. RESULTS: Thirty trials reported in 34 studies involving 10,126 patients were included. Twenty-nine were RCTs, the other a controlled trial. Risk of bias was considered low for only five studies. In all 28 chemical agents were tested. Eleven studies assessed dentifrices; ten rinses; eight varnishes; three fluoride solutions; three gels; two ozone applications; one preventive dental regimen. Meta-analyses revealed that dentifrices containing 5,000 ppm F- (RR = 0.49; 95% CI= 0.42, 0.57; high level of evidence) or 1.5% arginine plus 1,450 ppm F- (RR = 0.79; 95% CI = 0.64, 0.98; very low level) are more effective in inactivating RCLs than dentifrices containing 1,100 to 1,450 ppm F-. Self-applied AmF/SnF2 containing dentifrice and rinse decreased the initiation of RCLs when compared with NaF products (SMD = 0.15; 95% CI = -0.22, 0.52; low level evidence). Mouth rinse containing 225 to 900 ppm F- revealed a significantly reduced DMFRS/DFRS (MD = -0.18; 95% CI = -0.35, -0.01; low level) when compared with a placebo rinse. Significantly reduced RCI was found for Chlorhexidine (MD = -0.67; 95% CI = -1.01, -0.32; very low level evidence) as well as SDF (MD = -0.33; 95% CI = 0.39, -0.28; very low level) when compared with placebo varnish. CONCLUSIONS: Based on meta-analysis, dentifrice containing 5,000 ppm F- and professionally applied CHX or SDF varnish may inactivate existing and/or reduce the initiation of RCLs. However, results should be interpreted with caution due to the low numbers of clinical trials for each agent, the high risk of bias within studies, and the limiting grade of evidence. PMID- 25909931 TI - Fluoride releasing sealants may possess minimal cariostatic effect on adjacent surfaces. AB - DESIGN: Randomised controlled trial. INTERVENTION: Children with at least two sound permanent first molars and the presence of at least one sound distal surface of adjacent second primary molar were eligible. Children were randomised into three groups. In group one first permanent molars were sealed with a high viscosity glass ionomer cement (GIC group; n = 926), group two received a resin based fluoride containing sealant (RBF group; n = 923) and group three a resin based sealant without fluoride (RB group; n = 927). Two examiners blind to group allocation conducted examinations at 30 months. Sealant retention and caries at D1-D3 levels was assessed. Bitewing radiographs were taken. OUTCOME MEASURE: Caries prevalence and incidence rate ratios were calculated. RESULTS: Two thousand seven hundred and seventy-six children were enrolled; the number of dropouts were similar in each group (GIC group; n = 75), (RBF group; n = 67), (RB group; n = 77). The prevalence of affected surfaces was significantly lower in the GIC (p = .03) and FRB groups (p = .04). Fewer new caries developed on the distal surfaces of the second primary molars in the GIC group than in the other two groups. Incidence rate ratios (IRRs) were: 0.70 (95% CI: 0.50, 0.68; p < .01) for GIC vs. RB; 0.89 (95% CI: 0.89, 1.28; p = .10) for GIC vs. FRB and 0.79 (95% CI: 0.53, 1.04; p = .005) for FRB vs RB. Partial sealant loss was higher in the GIC group (76 molars; 2.95%), compared with FRB (52 molars; 1.41%), RB group (50 molars;1.35%). CONCLUSIONS: Fluoride-releasing sealants (high-viscosity GIC and fluoride RB) were demonstrated to provide protection against caries on the distal surface of second primary molars. This preventive strategy might contribute to maintaining the integrity of the mesial surfaces of the first permanent molars. PMID- 25909932 TI - Little difference between triclosan and stannous fluoride dentifrices on gingival inflammation. AB - DATA SOURCES: Medline, the Cochrane Central Register of Controlled Trials and Embase. STUDY SELECTION: Randomised, controlled trials (RCTs) or controlled clinical trials (CCTs) in adults >=17 years of age involving either triclosan or stannous-fluoride-containing dentifrices and self-performed manual brushing with a minimum four' weeks of follow-up were considered. DATA EXTRACTION AND SYNTHESIS: Study quality was assessed by two reviewers and meta-analysis performed where using fixed or random effects models as appropriate. RESULTS: Fifteen RCTs including four unpublished trials from one manufacturer met the criteria.No differences in the gingival index were seen between the two dentifrices [Diff-0.04, 95% confidence interval CI (-0.11; 0.04); P = 0.34]. However the change in the average gingival bleeding score was significantly in favour of SnF [DiffM0.02, 95% CI (0.01; 0.02); P < 0.00001]. Plaque scores demonstrated a statistically significant difference in favour of TCS, according to the Quigley-Hein Plaque Index (Q&H PI; Diff-0.29, 95% CI [-0.45; -0.13]; P = 0.0004), but there was no difference according to Rustogi Modified Navy Plaque Index (RMNPI) [Diff-0.09, 95% CI (-0.01; 0.18); P = 0.07]. CONCLUSIONS: In the context of inconclusive results for the primary outcome variable of gingival health, it can be concluded that there was a minor and most likely clinically insignificant difference between Tcs- and SnF-containing dentifrices. Meta analysis of plaque score reduction was also inconclusive; whereas TCS was more effective when assessed by the Q&H PI, it was not when scored with the RMNPI. PMID- 25909933 TI - Few studies addressing toothbrushing frequency and periodontitis. AB - DATA SOURCES: PubMed and seven other databases. STUDY SELECTION: English-language articles evaluating the association between the frequency of tooth brushing and periodontitis were considered. Two reviewers independently conducted study selection with study quality being assessed using the Health Evidence Bulletin (HEB) Wales checklist. DATA EXTRACTION AND SYNTHESIS: Relevant study characteristics were extracted and where necessary, effect measures and corresponding confidence intervals (CIs) were recalculated from the reported papers. Random and fixed effects meta-analyses were conducted. RESULTS: Fourteen studies were included (12 cross-sectional, two case-controlled). Sample sizes ranged from 44 - 9203. A fixed effects meta-analysis (12 cross sectional studies) found a significant overall odds ratio (OR) 1.41 (95%CI: 1.25-1.58, P <0.0001). A random effects meta-analysis (all 14 studies) found OR =1.44 (95%CI: 1.21-1.71, P < <0.0001) a slight indication for heterogeneity (I(2) = 48%, P = 0.02). CONCLUSIONS: There are relatively few studies evaluating the association between tooth brushing frequency and periodontitis. A clear effect was observed, indicating that infrequent tooth brushing was associated with severe forms of periodontal disease. Further epidemiological studies are needed to precisely estimate the effect of key risk factors for periodontitis and their interaction effects. PMID- 25909934 TI - Little evidence for the use of diode lasers as an adjunct to non-surgical periodontal therapy. AB - DATA SOURCES: Medline, PubMed, the Cochrane Central Register of Controlled Trials (CENTRAL) and Embase databases. STUDY SELECTION: Randomised controlled trials (RCTs) using thermal diode lasers as an adjunct to non-surgical conventional periodontal initial therapy conducted in patients >=18 years old written in English or Dutch were considered. DATA EXTRACTION AND SYNTHESIS: Study assessment data extraction and quality assessment was carried out independently by two reviewers. The main outcome variables were probing pocket depth (PPD) and clinical attachment loss (CAL), but plaque scores (PS), bleeding scores (BS) and the Gingival Index (GI) were also considered. Meta-analysis was carried out using a random effects model. RESULTS: Nine studies involving 247 patients were included. Seven studies were of split mouth design and two were parallel group studies. The study designs showed considerable heterogeneity and follow up ranged from six weeks to six months. Meta-analysis found no significant effect on PPD, CAL and PS. There was however a significant effect for GI and BS favouring adjunctive use of the diode laser. CONCLUSIONS: The collective evidence regarding adjunctive use of the diode laser with SRP indicates that the combined treatment provides an effect comparable to that of SRP alone. With respect to BS the results showed a small but significant effect favouring the diode laser, however, the clinical relevance of this difference remains uncertainStandard . This systematic review questions the adjunctive use of diode laser with traditional mechanical modalities of periodontal therapy in patients with periodontitis. The strength of the recommendation for the adjunctive use of the diode laser is considered to be 'moderate' for changes in PPD and CAL. PMID- 25909935 TI - Insufficient evidence of effect of periodontal treatment on prevention or management of cardiovascular disease. AB - DATA SOURCES: The Cochrane Oral Health Group's Trials Register, the Cochrane Central Register of Controlled Trials (CENTRAL), Medline, Embase, CINAHL, OpenGrey, the Chinese BioMedical Literature Database, the China National Knowledge Infrastructure and the VIP database, the US National Institutes of Health Trials Register, the World Health Organisation (WHO) Clinical Trials Registry Platform and Sciencepaper Online databases were searched with no restrictions on language or date. STUDY SELECTION: Two reviewers independently selected studies and only randomised controlled trials (RCTs) and quasi-RCTs with follow-up times >= one year were considered. DATA EXTRACTION AND SYNTHESIS: Data extraction and risk of bias assessment were carried out independently and in duplicate. Standard Cochrane methodological approaches were used. RESULTS: Only one trial involving 303 patients that compared scaling and root andomiz (SRP) with community care was included. It was considered to be at high risk of bias. No data on deaths (all-cause or CVD-related) were reported. There was insufficient evidence to determine the effect of SRP and community care in reducing the risk of CVD recurrence in patients with chronic periodontitis (risk ratio (RR) 0.72; 95% confidence interval (CI) 0.23 to 2.22; very low quality evidence). The effects of SRP compared with community care on high-sensitivity C reactive protein (hs-CRP) (mean difference (MD) 0.62; -1.45 to 2.69), the number of patients with high hs-CRP (RR 0.77; 95% CI 0.32 to 1.85) and adverse events (RR 9.06; 95% CI 0.49 to 166.82) were also not statistically significant. The study did not assess modifiable cardiovascular risk factors, other blood test results, heart function parameters or revascularisation procedures. CONCLUSIONS: We found very low quality evidence that was insufficient to support or refute whether periodontal therapy can prevent the recurrence of CVD in the long term in patients with chronic periodontitis. No evidence on primary prevention was found. PMID- 25909936 TI - Shortened dental arch concept shown to be cost effective. AB - DESIGN: Randomised controlled trial. INTERVENTION: All patients received treatment to render them dentally fit. Patients were randomly allocated to either the removable dental prostheses (RPD) or the shortened dental arch (SDA) group. Patients in the RDP group were restored to complete arches with RDP using cobalt chromium frameworks according to a standardised protocol. For the SDA group, patients were restored to a shortened arch of ten occluding pairs of natural and replacement teeth using resin-bonded bridgework (RBB). OUTCOME MEASURE: Treatment effect was measured using the change in oral health-related quality of life (OHrQOL). For each patient the costs of delivering treatment were recorded by a research nurse during the intervention period. Laboratory costs were recorded as part of normal hospital policy for all patients. All of the dental materials used were recorded and given a unit price. The cost of professional time per patient was estimated using the highest point of the salary scale for the Community Dental Service in Ireland. RESULTS: One hundred and thirty-two patients were randomised; 65 to the RPD group and 67 to the SDA group. Ninety-two patients (69.7%) completed the study (46 in RPD group; 46in SDA group). There was no difference in the success rates of the two treatments over the period. Five pieces of resin-bonded bridgework (RBB) debonded and were recemented over the 12 month period giving a success rate of 95.5% for the RBB. Four patients discontinued wearing their RPDs; all four RPDS were fitted in the lower arch and included bilateral free end saddles, a success rate of 95.9%. Both RPD and SDA groups demonstrated statistically significant improvements in OHrQoL scores after 12 months.The total cost of achieving the minimally important clinical difference (MID) in OHrQOL for an average patient in the RDP group was [euro ]464.64. For the SDA group, the cost of achieving the MID for an average patient was [euro ]252.00. The cost-effectiveness ratio was therefore 1:1.84 in favour of SDA treatment. CONCLUSIONS: With an increasingly ageing population, many patients will continue to benefit from removable prostheses to replace their missing natural teeth. From a purely economic standpoint, the results from this analysis suggest that the treatment of partially dentate older adults should be focused on functionally orientated treatment because it is simply more cost-effective. PMID- 25909937 TI - Insufficient evidence for sinus lifts over short implants for dental implant rehabilitation. AB - DATA SOURCES: The Cochrane Oral Health Group's Trials Register, Cochrane Central Register of Controlled Trials (CENTRAL), Medline and Embase databases were searched with no language or date restrictions. STUDY SELECTION: Two reviewers independently selected studies. Randomised controlled trials (RCTs) of different techniques and materials for augmenting the maxillary sinus for rehabilitation with dental implants that reported the outcome of implant success or failure at least four months after initial loading were considered. DATA EXTRACTION AND SYNTHESIS: Data were extracted independently by two reviewers and study risk of bias assessed. Results were expressed using fixed-effect models as there were either fewer than four studies or we used Peto odds ratios (ORs) for dichotomous data when there were zero cells in either the treatment or control or both arms and the number of trials was small. RESULTS: Eighteen trials involving 650 patients were included. Five studies were considered to be at low risk of bias, 11 at high risk and two of unclear risk. Four trials (102 patients) evaluated short implants (5 to 8.5 mm long) as an alternative to sinus lift in bone with residual height between 4 and 9 mm. One year after loading there was insufficient evidence to claim differences between the two procedures for prosthesis failure (OR (Peto) 0.37, 95% confidence interval (CI) 0.05 to 2.68; three trials) or implant failure (OR (Peto) 0.44, 95% CI 0.10 to 1.99; four trials). There was however an increase in complications at treated sites when undertaking the sinus lift (OR (Peto) 4.77, 95% CI 1.79 to 12.71, P value = 0.002; four trials).Fourteen trials (548 patients) compared different sinus lift techniques. Only three comparisons included more than one trial. These were bone graft versus no bone graft, autogenous bone versus bone substitute, bone graft with or without platelet-rich plasma (PRP). There was insufficient evidence to claim a benefit for any of these techniques for the primary outcomes of prosthesis and implant failure.The other comparisons with single studies were rotary versus piezosurgery to open a lateral sinus window, two different bone substitutes, use or not of a membrane to seal the lateral window, one- versus two-stage lateral sinus lift, two-stage granular bone versus one-stage autogenous bone blocks and crestal versus lateral sinus lift; two trials compared three different crestal sinus lifting techniques: rotatory versus hand malleting (patients preferred rotatory instruments over hand malleting) and hand versus electric malleting. There was no evidence of a benefit for any sinus lift procedure compared to any other for the primary outcomes prosthesis or implant failure. CONCLUSIONS: There is moderate quality evidence which is insufficient to determine whether sinus lift procedures in bone with residual height between 4 and 9 mm are more or less successful than placing short implants (5 to 8.5 mm) in reducing prosthesis or implant failure up to one year after loading. However, there are more complications at sites treated with sinus lift procedures. Many trials compared different sinus lift procedures and none of these indicated that one procedure reduced prosthetic or implant failures when compared to the other. Based on low quality evidence, patients may prefer rotary instruments over hand malleting for crestal sinus lift. PMID- 25909938 TI - CBCT is valuable for diagnosis of tooth fracture. AB - DATA SOURCES: PubMed, Embase, Web of Science, ProQuest Dissertations & Theses, CNKI and SIGLE databases. STUDY SELECTION: Two reviewers independently selected studies. Studies examining the diagnostic accuracy of CBCT for tooth fractures in vivo were considered. Only studies with a minimum of ten participants using a reference test of surgical exploration or extractions to establish the diagnosis of tooth fractures were included. DATA EXTRACTION AND SYNTHESIS: Data abstraction was carried out independently by two reviewers and study quality assessed using the Quality Assessment of Studies of Diagnostic Accuracy-2 (QUADAS-2) tool. The main study outcomes were sensitivity, specificity, positive likelihood ratio (LR), negative LR and summary receiver operating characteristic (SROC). RESULTS: Twelve studies were included in a meta-analysis. The pooled sensitivity was 0.92 (95% CI=0.89-0.94) and pooled specificity 0.85 (95% CI=0.75-0.92). The pooled positive and negative likelihood ratios were 5.68 (95% CI=3.42-9.45) and 0.13 (95% CI=0.09-0.18) respectively. The summary receiver operating characteristic was 0.94 (95% CI=0.90-0.98). The pooled prevalence of tooth fractures in patients with clinically suspected but periapical-radiography-undetected tooth fractures was 91% (95% CI = 83%-97%). Positive and negative predictive values were 0.98 and 0.43 (subgroup analysis: 0.98 and 0.28 for endodontically treated teeth; 0.99 and 0.77 for non endodontically treated teeth). CONCLUSIONS: We suggest that CBCT has a high diagnostic accuracy for tooth fractures and could be used in clinical settings. We can be very confident with positive test results but should be very cautious with negative test results. For patients with negative results, close follow-ups are recommended. The diagnostic accuracy of CBCT is similar among different types of tooth fractures, which should be interpreted with caution due to unavailability of data for subgroup analysis on horizontal and oblique tooth fractures. PMID- 25909939 TI - Quad-helix appliances may be more successful than removable expansion plates at correcting posterior crossbites. AB - DATA SOURCES: The Cochrane Oral Health Group's Trials Register, the Cochrane Central Register of Controlled Trials (CENTRAL) Medline, Embase, the US National Institutes of Health Trials Register and the World Health Organisation (WHO) Clinical Trials Registry Platform were searched with no restrictions. STUDY SELECTION: Randomised controlled trials (RCTs) of orthodontic treatment for posterior crossbites in children and adults were considered. DATA EXTRACTION AND SYNTHESIS: Study selection, data abstraction and risk of bias assessment were carried out independently by two reviewers. Dichotomous data were summarised with risk ratios (RR) and 95% confidence intervals (CIs) and continuous data with mean differences (MD) with 95% CIs. Meta-analyses were conducted when comparisons and outcomes were sufficiently similar. RESULTS: Fifteen studies were included; seven were at high risk of bias, two at low risk and six at unclear risk. Nine studies compared fixed appliances with mid-palatal expansion but no difference between appliances was reported. Low quality evidence from two studies with 96 participants found that fixed quad-helix appliances may be 20% more likely to correct crossbites than removable expansion plates (RR 1.20; 95% CI 1.04 to 1.37), and quad-helix appliances may achieve 1.15 mm more molar expansion than expansion plates (MD 1.15 mm; 95% CI 0.40 to 1.90;). Very limited evidence showed that both fixed quad-helix appliances and removable expansion plates were superior to composite onlays in terms of crossbite correction, molar and canine expansion. CONCLUSIONS: There is a very small body of low to moderate quality evidence to suggest that the quad-helix appliance may be more successful than removable expansion plates at correcting posterior crossbites and expanding the inter-molar width for children with early mixed dentition (aged eight to 10 years). The remaining evidence we found was of very low quality and was insufficient to allow the conclusion that any one intervention is better than another for any of the outcomes in this review. PMID- 25909940 TI - Salt water mouthwash post extraction reduced post operative complications. AB - DESIGN: Randomised controlled trial. INTERVENTION: Patients aged >=16 years requiring non-surgical extraction were randomised into three groups. Group A (n = 40) were instructed to gargle six times daily with warm saline and group B (n = 40) twice daily; group C (n = 40) were not instructed to gargle with warm saline and served as controls. All patients received the same oral antibiotics and analgesics, and similar postoperative instructions, except regarding saline rinses. Mouth rinsing was to start 24 hours after the procedure and patients were reviewed at 72 hours. OUTCOME MEASURE: The patients were evaluated 72 h post operatively for the presence of alveolar osteitis, acute inflamed socket and acute infected socket by an independent observer who was blinded to the treatment group. RESULTS: One hundred and twenty patients were randomised (40 per group). The overall prevalence of alveolar osteitis was 10.0% and that of acute inflamed socket was 25.0%. No cases of acute infected socket were observed.There was a statistically significant difference between the study groups with respect to the development of alveolar osteitis (x(2) = 15.43, df = 2, P = 0.001), but not for acute inflamed socket, with only 2.5% of the saline groups (2 out of 80) developing alveolar osteitis compared with 25% (10 of 40) in the control group. CONCLUSIONS: The instruction to use warm saline mouth rinse is beneficial in the prevention of alveolar osteitis after dental extractions. There is no significant difference in the efficacy of the twice-daily warm saline mouth rinse regimen compared to the six times daily regimen. The twice-daily saline mouth rinse regimen is more convenient, and patient compliance may be better than with the six times daily rinse routine. PMID- 25909941 TI - Trials needed to identify best management of iatrogenic inferior alveolar and lingual nerve injuries. AB - DATA SOURCES: The Cochrane Oral Health Group's Trials Register, Cochrane Central Register of Controlled Trials (CENTRAL), Medline and Embase databases were searched with no language or date restrictions. STUDY SELECTION: Three reviewers independently selected studies. Randomised controlled trials (RCTs) involving interventions to treat patients with neurosensory defect of the inferior alveolar or lingual nerve or both as a sequela of iatrogenic injury were considered. DATA EXTRACTION AND SYNTHESIS: Standard Cochrane methodological procedures were followed. RESULTS: Two studies considered at high risk of bias, reporting data from 26 analysed patients were included. Both studies investigated the effectiveness of low-level laser treatment compared to placebo laser therapy on inferior alveolar sensory deficit as a result of iatrogenic injury. Two studies assessed as at high risk of bias, reporting data from 26 analysed participants were included in this review. The age range of participants was from 17 to 55 years. Both trials investigated the effectiveness of low-level laser treatment compared to placebo laser therapy on inferior alveolar sensory deficit as a result of iatrogenic injury.Patient-reported altered sensation was partially reported in one study and fully reported in another. Following treatment with laser therapy, there was some evidence of an improvement in the subjective assessment of neurosensory deficit in the lip and chin areas compared to placebo, though the estimates were imprecise: a difference in mean change in neurosensory deficit of the chin of 8.40 cm (95% confidence interval (CI) 3.67 to 13.13) and a difference in mean change in neurosensory deficit of the lip of 21.79 cm (95% CI 5.29 to 38.29). The overall quality of the evidence for this outcome was very low. No studies reported on the effects of the intervention on the remaining primary outcomes of pain, difficulty eating, speaking or taste. No studies reported on quality of life or adverse events. CONCLUSIONS: There is clearly a need for randomised controlled clinical trials to investigate the effectiveness of surgical, medical and psychological interventions for iatrogenic inferior alveolar and lingual nerve injuries. Primary outcomes of this research should include: patient-focused morbidity measures including altered sensation and pain, pain, quantitative sensory testing and the effects of delayed treatment. PMID- 25909944 TI - Effect of concurrent elevation of serum creatinine and C-reactive protein values on the long-term outcome in patients with ST-elevation acute myocardial infarction. PMID- 25909945 TI - Probability of Return of Spontaneous Circulation as a Function of Timing of Vasopressor Administration in Out-of-Hospital Cardiac Arrest. AB - INTRODUCTION: Vasopressors (epinephrine and vasopressin) are associated with return of spontaneous circulation (ROSC). Recent retrospective studies reported a greater likelihood of ROSC when vasopressors were administered within the first 10 minutes of arrest. However, it is unlikely that the relationship between ROSC and the timing of vasopressor administration is a binary function (i.e., <=10 vs. >10 minutes). More likely, this relationship is a function of time measured on a continuum, with diminishing effectiveness even within the first 10 minutes of arrest, and potentially, some lingering benefit beyond 10 minutes. However, this relationship remains undefined. OBJECTIVE: To develop a model describing the likelihood of ROSC as a function of the call receipt to vasopressor interval (CRTVI) measured on a continuum. METHODS: We conducted a retrospective study of cardiac arrest using the North Carolina Prehospital Care Reporting System (PREMIS). Inclusionary criteria were all adult patients suffering a witnessed, nontraumatic arrest during January-June 2012. Chi-square and t-tests were used to analyze the relationships between ROSC and CRTVI; patient age, race, and gender; endotracheal intubation (ETI); automated external defibrillator (AED) use; presenting cardiac rhythm; and bystander cardiopulmonary resuscitation (CPR). A multivariate logistic regression model calculated the odds ratio (OR) of ROSC as a function of CRTVI while controlling for potential confounding variables. RESULTS: Of the 1,122 patients meeting inclusion criteria, 542 (48.3%) experienced ROSC. ROSC was less likely with increasing CRTVI (OR = 0.96, p < 0.01). Compared to patients with shockable rhythms, patients with asystole (OR = 0.42, p < 0.01) and pulseless electrical activity (OR = 0.52, p < 0.01) were less likely to achieve ROSC. Males (OR = 0.64, p = 0.02) and patients receiving bystander CPR (OR = 0.42, p < 0.01) were less likely to attain ROSC, although emergency medical services response times were significantly longer among patients receiving bystander CPR. Race, age, ETI, and AED were not predictors of ROSC. CONCLUSIONS: We found that time to vasopressor administration is significantly associated with ROSC, and the odds of ROSC declines by 4% for every 1-minute delay between call receipt and vasopressor administration. These results support the notion of a time-dependent function of vasopressor effectiveness across the entire range of administration delays rather than just the first 10 minutes. Large, prospective studies are needed to determine the relationship between the timing of vasopressor administration and long-term outcomes. PMID- 25909946 TI - Correction: Ecuador's Mangrove Forest Carbon Stocks: A Spatiotemporal Analysis of Living Carbon Holdings and Their Depletion since the Advent of Commercial Aquaculture. PMID- 25909948 TI - The structure, photoluminescence and influence of temperature on energy transfer in co-doped Ca9La(GeO4)0.75(PO4)6 red-emission phosphors. AB - A novel phosphate Ca9La(GeO4)0.75(PO4)6 was investigated to add to the family of phosphate phosphors and application in LEDs. In this work, the single phase red emission Ce(3+),Mn(2+) co-doped phosphate Ca9La(GeO4)0.75(PO4)6 phosphor was synthesized by the solid-state reaction from both theoretical and practical points of view. The crystal structure was determined by Rietveld refinement and TEM. Its cell parameters are a = b = 10.4077605(2) A, and c = 37.4714968(1) A. The characteristic photoluminescence properties were studied in detail using photoluminescence excitation spectra, emission spectra, decay times and thermal quenching properties. Purple and red broad band emission from Ce(3+) and Mn(2+) was detected under excitation at 313 nm. According to this research, the Ca9La(GeO4)0.75(PO4)6:Ce(3+),Mn(2+) phosphor shows high thermal stability in the red-emission area. With the increase of the temperature, the intensity ratio of Mn(2+) and Ce(3+) emission rises rapidly and the purity of red-emission is improved. In order to reasonably explain this special phenomenon, an implicit mechanism between thermal quenching and energy transfer is proposed based on the configurational coordinate diagram. In addition, the mechanism could be helpful for understanding the thermal properties of multiple activators Ce(3+) and Mn(2+) co-doped phosphors as the reference. PMID- 25909947 TI - Proteome Analysis of Watery Saliva Secreted by Green Rice Leafhopper, Nephotettix cincticeps. AB - The green rice leafhopper, Nephotettix cincticeps, is a vascular bundle feeder that discharges watery and gelling saliva during the feeding process. To understand the potential functions of saliva for successful and safe feeding on host plants, we analyzed the complexity of proteinaceous components in the watery saliva of N. cincticeps. Salivary proteins were collected from a sucrose diet that adult leafhoppers had fed on through a membrane of stretched parafilm. Protein concentrates were separated using SDS-PAGE under reducing and non reducing conditions. Six proteins were identified by a gas-phase protein sequencer and two proteins were identified using LC-MS/MS analysis with reference to expressed sequence tag (EST) databases of this species. Full -length cDNAs encoding these major proteins were obtained by rapid amplification of cDNA ends PCR (RACE-PCR) and degenerate PCR. Furthermore, gel-free proteome analysis that was performed to cover the broad range of salivary proteins with reference to the latest RNA-sequencing data from the salivary gland of N. cincticeps, yielded 63 additional protein species. Out of 71 novel proteins identified from the watery saliva, about 60 % of those were enzymes or other functional proteins, including GH5 cellulase, transferrin, carbonic anhydrases, aminopeptidase, regucalcin, and apolipoprotein. The remaining proteins appeared to be unique and species- specific. This is the first study to identify and characterize the proteins in watery saliva of Auchenorrhyncha species, especially sheath-producing, vascular bundle-feeders. PMID- 25909949 TI - Correlation of a decline in aerobic capacity with development of emphysema in patients with chronic obstructive pulmonary disease: a prospective observational study. AB - In patients with COPD, CT assessment of emphysema and airway disease is known to be associated with lung function and 6-minute walk distance. However, it remains to be determined whether low attenuation area (LAA) on CT is associated with aerobic capacity assessed using cardiopulmonary exercise testing (CPET). In this prospective observational study, we repeatedly conducted high-resolution CT and CPET using a treadmill in 81 COPD patients over a median interval of 3.5 years. Two investigators independently scored LAA on images obtained at the aortic arch level, tracheal bifurcation level, and supradiaphragmatic level. Grades for the images of each lung were added to yield the total LAA score. Total LAA score was negatively correlated with peak aerobic capacity ([Formula: see text]) (p<0.001, r = -0.485). LAA scores of the upper (aortic arch level) and the lower (supradiaphragmatic level) lungs were both significantly associated with peak [Formula: see text]. There was a significant correlation between total LAA score and peak CO2 output ([Formula: see text]) (p<0.001, r = -0.433). Total LAA score was correlated with oxygen saturation at peak exercise (p<0.001, r = -0.634) and the estimated dead space fraction (p<0.001, r = 0.416). The mean annual change in total LAA score was significantly correlated with those in peak [Formula: see text] (p<0.001, r = -0.546) and peak [Formula: see text] (p<0.001, r = -0.488). The extent of emphysema measured by CT was associated with the results of CPET. The time-dependent changes in CPET data were also correlated with that in total LAA score. CT assessment could be a non-invasive tool to predict aerobic capacity in patients with COPD. PMID- 25909950 TI - The effects of a short-term memory task on postural control of stroke patients. AB - BACKGROUND: Many studies have been conducted on the changes in the balance capabilities of stroke patients. However, results regarding the effects of dual task activities on postural control in these patients have been variable. OBJECTIVE: To evaluate the effects of a short-term memory task on the sway characteristics of stroke patients. METHOD: Center of pressure (COP) fluctuations were measured in three levels of postural difficulty (rigid surface with closed and open eyes and foam surface with closed eyes), as well as two levels of cognitive difficulty (easy and difficult). COP parameters included mean velocity, standard deviation of velocity in both medial-lateral (M.L) and anterior posterior (A.P) directions, total phase plane portrait, area. Nineteen stroke patients and 19 gender, age, height, and weight matching healthy volunteers participated in this study. RESULTS: Our findings indicate that mean velocity (F = 14.21, P = 0.001), standard deviation of velocity in both M.L (F = 17.50, P = 0.000) and A.P (F = 11.03, P = 0.002) directions, total phase plane portrait (F = 44.12, P = 0.001), and area (F = 13.95, P = 0.01) of center of pressure of patients were statistically greater than normal subjects, while significant interaction of group * postural difficulty and postural * cognitive difficulty were observed for all parameters of postural sway. CONCLUSIONS: Different measures of postural sway showed complex response to postural and cognitive difficulties between stroke patients and normals. Cognitive error was not affected by the main effects of group and postural difficulty, while greatly increased at more difficult cognitive task (F = 75.73, P = 0.000). PMID- 25909951 TI - Biochar and activated carbon for enhanced trace organic contaminant retention in stormwater infiltration systems. AB - To assess the effectiveness of biochar and activated carbon (AC) for enhanced trace organic contaminant (TOrC) retention in stormwater infiltration systems, an approach combining forward-prediction modeling and laboratory verification experiments was employed. Batch and column tests were conducted using representative TOrCs and synthetic stormwater. Based on batch screening tests, two commercially available biochars (BN-biochar and MCG-biochar) and an AC were investigated. The AC exhibited the strongest sorption, followed by MCG-biochar and BN-biochar. Langmuir isotherms provided better fits to equilibrium data than Freundlich isotherms. Due to superior sorption kinetics, 0.2 wt % MCG-biochar in saturated sand columns retained TOrCs more effectively than 1.0 wt % BN-biochar. A forward-prediction intraparticle diffusion model based on the Langmuir isotherm adequately predicted column results when calibrated using only batch parameters, as indicated by a Monte Carlo uncertainty analysis. Case study simulations estimated that an infiltration basin amended with F300-AC or MCG-biochar could obtain sorption-retarded breakthrough times for atrazine of 54 or 5.8 years, respectively, at a 1 in./h infiltration rate. These results indicate that biochars or ACs with superior sorption capacity and kinetics can enhance TOrC retention in infiltration systems, and performance under various conditions can be predicted using results from batch tests. PMID- 25909952 TI - Association between Inflammation and Cardiac Geometry in Chronic Kidney Disease: Findings from the CRIC Study. AB - BACKGROUND: Left ventricular hypertrophy (LVH) and myocardial contractile dysfunction are independent predictors of mortality in patients with chronic kidney disease (CKD). The association between inflammatory biomarkers and cardiac geometry has not yet been studied in a large cohort of CKD patients with a wide range of kidney function. METHODS: Plasma levels of interleukin (IL)-1beta, IL-1 receptor antagonist (IL-1RA), IL-6, tumor necrosis factor (TNF)-alpha, transforming growth factor (TGF)-beta, high-sensitivity C-Reactive protein (hs CRP), fibrinogen and serum albumin were measured in 3,939 Chronic Renal Insufficiency Cohort study participants. Echocardiography was performed according to the recommendations of the American Society of Echocardiography and interpreted at a centralized core laboratory. RESULTS: LVH, systolic dysfunction and diastolic dysfunction were present in 52.3%, 11.8% and 76.3% of the study subjects, respectively. In logistic regression analysis adjusted for age, sex, race/ethnicity, diabetic status, current smoking status, systolic blood pressure, urinary albumin- creatinine ratio and estimated glomerular filtration rate, hs CRP (OR 1.26 [95% CI 1.16, 1.37], p<0.001), IL-1RA (1.23 [1.13, 1.34], p<0.0001), IL-6 (1.25 [1.14, 1.36], p<0.001) and TNF-alpha (1.14 [1.04, 1.25], p = 0.004) were associated with LVH. The odds for systolic dysfunction were greater for subjects with elevated levels of hs-CRP (1.32 [1.18, 1.48], p<0.001) and IL-6 (1.34 [1.21, 1.49], p<0.001). Only hs-CRP was associated with diastolic dysfunction (1.14 [1.04, 1.26], p = 0.005). CONCLUSION: In patients with CKD, elevated plasma levels of hs-CRP and IL-6 are associated with LVH and systolic dysfunction. PMID- 25909953 TI - On the impact of discreteness and abstractions on modelling noise in gene regulatory networks. AB - In this paper, we explore the impact of different forms of model abstraction and the role of discreteness on the dynamical behaviour of a simple model of gene regulation where a transcriptional repressor negatively regulates its own expression. We first investigate the relation between a minimal set of parameters and the system dynamics in a purely discrete stochastic framework, with the twofold purpose of providing an intuitive explanation of the different behavioural patterns exhibited and of identifying the main sources of noise. Then, we explore the effect of combining hybrid approaches and quasi-steady state approximations on model behaviour (and simulation time), to understand to what extent dynamics and quantitative features such as noise intensity can be preserved. PMID- 25909954 TI - Clinical Neuropathology teaching case 3-2015: female or male brain? Anti ubiquitin visualizes Barr bodies in hippocampal granule cells which allows the determination of gender in human brains. PMID- 25909955 TI - Long-term trends and seasonality of omphalocele during 1996-2010 in China: a retrospective analysis based on the hospital-based birth defects surveillance system. AB - BACKGROUND: Little is known about secular trends and seasonal variation in the birth prevalence of omphalocele in China. This study aimed to explore the long term trends and seasonality of this birth defect, to provide insight into the etiology and prevention of omphalocele. METHODS: A retrospective analysis of all births with omphalocele (1322 cases in 8.8 million births) registered in the hospital-based Chinese Birth Defects Monitoring Network between January 1996 and September 2010. Negative binomial cyclical regression models were used to analyze the long-term trends and seasonal fluctuations of omphalocele occurrence in the southern and northern regions and urban and rural areas of China. RESULTS: The total prevalence of omphalocele was 1.50 cases (95% confidence interval (CI): 1.42-1.58) per 10,000 births. There was no significant secular trend of omphalocele occurrence in China between 1996 and 2010. The observed prevalence of omphalocele in rural areas was 2.03-2.54 cases per 10,000 births between May and August, which was higher than that observed in other months. The highest prevalence of births with omphalocele in rural areas occurred at the end of June; on average, the prevalence of omphalocele at that time point increased by 20% (95% CI: 6-35%) compared with other months. CONCLUSIONS: There were no long-term trends found for occurrence of omphalocele in China between 1996 and 2010; however, seasonality was observed for omphalocele in women living in rural areas. These results may help generate hypotheses for further study of environmental factors that vary by season. PMID- 25909956 TI - Using Visualized Matrix Effects to Develop and Improve LC-MS/MS Bioanalytical Methods, Taking TRAM-34 as an Example. AB - Matrix effects (MEs) continue to be an obstacle in the development of the LC MS/MS method, with phospholipids being the major cause of MEs. Changing the mobile phase has been a common strategy to reduce MEs; however, the underlying mechanism is unclear. "In-source multiple-reaction monitoring" (IS-MRM) for glycerophosphocholines (PCs) has been commonly applied in many bioanalytical methods. "Visualized MEs" is a suitable term to describe the application of IS MRM to visualize the elution pattern of phospholipids. We selected a real case to discuss the relationship of MEs and phospholipids in different mobile phases by quantitative, qualitative, and visualized MEs in LC-MS/MS bioanalysis. The application of visualized MEs not only predicts the ion-suppression zone but also helps in selecting an appropriate (1) mobile phase, (2) column, (3) needle wash solvent for the residue of analyte and phospholipids, and (4) evaluates the clean up efficiency of sample preparation. The TRAM-34 LC-MS/MS method, improved by using visualized MEs, was shown to be a precise and accurate analytical method. All data indicated that the use of visualized MEs indeed provided useful information about the LC-MS/MS method development and improvement. In this study, an integrative approach for the qualitative, quantitative, and visualized MEs was used to decipher the complexity of MEs. PMID- 25909957 TI - Biodistribution and Clearance of TiO2 Nanoparticles in Rats after Intravenous Injection. AB - Titanium dioxide (TiO2) nanoparticles are used in many applications. Due to their small size, easy body penetration and toxicological adverse effects have been suspected. Numerous studies have tried to characterize TiO2 translocation after oral, dermal or respiratory exposure. In this study, we focused on TiO2 nanoparticle biodistribution, clearance and toxicological effects after intravenous injection, considering TiO2 translocation in the blood occurs. Using ICP-OES, transmission electron microscopy, and histological methods, we found TiO2 accumulation in liver, lungs and spleen. We estimated TiO2 nanoparticles' half life in the body to about 10 days. Clinical biomarkers were also quantified for 56 days to identify potential toxicological impact on lungs, blood, liver, spleen and kidneys. Results showed absence of toxicological effects after TiO2 intravenous injection at concentrations of 7.7 to 9.4 mg/kg. PMID- 25909958 TI - Circumstances surrounding stroke onset: symbolic meaning of time factors related to numbers and days of the week. AB - PURPOSE: To explore the circumstances surrounding the onset of stroke, and especially the symbolic meaning of time factors related to numbers and days of the week. METHOD: Phenomenological qualitative study involving individual interviews conducted 5-8 weeks post-stroke. The audiotaped interviews were transcribed, then comprehensively coded by two team members, and summaries of each case were written. Since this was a secondary analysis, special attention was paid to the significance of themes, numbers and days of the week when analyzing the summaries and transcripts. RESULTS: Interviews were conducted with 37 participants (mean age 56.3 +/- 11.9 years, 60% male). Five themes were identified with respect to the meaning attributed to numbers: (1) personal events, (2) historical events, (3) annual events, (4) age, and (5) avoidance. Themes identified as being associated with days of the week were work, leisure activities, household chores and medical tests/appointments. CONCLUSION: The impact of internalised emotions related to these perceptions can be quite significant. This study suggests that health professionals should personalise the secondary prevention of strokes by considering clients holistically and also give clients the opportunity to freely express their feelings about the meaning of time factors to foster awareness of their own perceptions. IMPLICATIONS FOR REHABILITATION: The use of checklists only for stroke secondary prevention does not allow taking into account psychosocial factors as potential precipitating factors. An open dialogue about personal circumstances starting on the date and day the stroke happened enabled the emergence of meaningful themes. As relationships emerged as the overarching essential theme, quality of relationships could be addressed in rehabilitation post-stroke and thus potentially contribute to prevent stroke recurrence. PMID- 25909960 TI - Symptoms of muscle dysmorphia, body dysmorphic disorder, and eating disorders in a nonclinical population of adult male weightlifters in Australia. AB - The current study aimed to (a) determine the rates of symptoms of muscle dysmorphia (MD), body dysmorphic disorder (BDD), and eating disorder; (b) determine the relationships among symptoms of MD, BDD, and eating disorders; and (c) provide a comprehensive comparison of symptoms of MD, BDD, and eating disorders in a nonclinical population of adult male weightlifters in Australia. The participants (N = 648, mean age = 29.5 years, SD = 10.1) participated in an online survey, consisting of Muscle Appearance Satisfaction Scale, the Body Dysmorphic Disorder Questionnaire, and the Eating Attitude Test-26. Results indicated that 110 participants (17%) were at risk of having MD, 69 participants (10.6%) were at risk of having BDD, and 219 participants (33.8%) were at risk of having an eating disorder. Furthermore, 36 participants (5.6%) were found at risk of having both MD and BDD, and 60 participants (9.3%) were at risk of having both MD and an eating disorder. Significant correlations and associations were found between symptoms of MD and BDD, and symptoms of MD and eating disorders. Support was provided for the comorbidity of, and symptomatic similarities between, symptoms of MD and BDD, and symptoms of MD and eating disorders. This may reflect a shared pathogenesis between symptoms of MD, BDD, and eating disorders. Strength and conditioning professionals, exercise scientists, athletic trainers, and personal trainers should be aware that adult males who are working out with weights (i.e., free weights or machines) may be at increased risk of having MD, BDD, and eating disorders. PMID- 25909961 TI - Description and predictive value of a novel method for determining the respiratory compensation point using standard scores. AB - The ability to use data from tests of maximum aerobic capacity to estimate the ventilatory threshold and point of respiratory compensation (RCP) is useful for coaches and practitioners in the development of training schemes. Current methods for determining the RCP generally involve identifying deflections in respiratory variables when examined alongside minute ventilation. This investigation describes a novel mathematical method for determining RCP using standard scores (Z-scores) for minute ventilation (VE) and oxygen consumption (VO2). This method allows for the point where ventilation becomes disproportionate to oxygen consumption to be quantified as an intersection between 2 lines of best fit. This novel Z-score method was compared with a well-described determination of RCP and was found to be highly correlated (r = 0.926, p <= 0.001). The Z-score method was also found to be related to 10-km road race performance using regression analysis (R(2) = 0.824, p <= 0.001) in a group of 18 athletes and recreational runners. Based on the evidence from this study, the Z-score method of RCP determination is highly correlated to previous methods and endurance performance. This method potentially offers further benefits as it is not reliant on visual determination of changes in slope in variables of interest but rather on the mathematical solution to the intersection of 2 regression lines. PMID- 25909959 TI - Phagocytosed Clofazimine Biocrystals Can Modulate Innate Immune Signaling by Inhibiting TNFalpha and Boosting IL-1RA Secretion. AB - Clofazimine (CFZ) is an FDA-approved leprostatic and anti-inflammatory drug that massively accumulates in macrophages, forming insoluble, intracellular crystal like drug inclusions (CLDIs) during long-term oral dosing. Interestingly, when added to cells in vitro, soluble CFZ is cytotoxic because it depolarizes mitochondria and induces apoptosis. Accordingly, we hypothesized that, in vivo, macrophages detoxify CFZ by sequestering it in CLDIs. To test this hypothesis, CLDIs of CFZ-treated mice were biochemically isolated and then incubated with macrophages in vitro. The cell biological effects of phagocytosed CLDIs were compared to those of soluble CFZ. Unlike soluble CFZ, phagocytosis of CLDIs did not lead to mitochondrial destabilization or apoptosis. Rather, CLDIs altered immune signaling response pathways downstream of Toll-like receptor (TLR) ligation, leading to enhanced interleukin-1 receptor antagonist (IL-1RA) production, dampened NF-kappaB activation and tissue necrosis factor alpha (TNFalpha) production, and ultimately decreased TLR expression levels. In aggregate, our results constitute evidence that macrophages detoxify soluble CFZ by sequestering it in a biocompatible, insoluble form. The altered cellular response to TLR ligation suggests that CLDI formation may also underlie CFZ's anti-inflammatory activity. PMID- 25909962 TI - Long-term athletic development, part 2: barriers to success and potential solutions. AB - The first installment of this two-part commentary reviewed existing models of long-term athletic development. However, irrespective of the model that is adopted by practitioners, existing structures within competitive youth sports in addition to the prevalence of physical inactivity in a growing number of modern day youth may serve as potential barriers to the success of any developmental pathway. The second part of this commentary will initially highlight common issues that are likely to impede the success of long-term athletic development programs and then propose solutions that will address the negative impact of such issues. PMID- 25909965 TI - Gemini supra-amphiphiles with finely-controlled self-assemblies. AB - Novel gemini supra-amphiphiles, [Mim-4-Mim][DBS](2) and [Mim-4-Mim][DS](2), were facilely constructed. A slight variation of building blocks can effectively modulate the driving forces for the fabrication of gemini supra-amphiphiles, thus leading to the fine control of subsequent self-assemblies. [Mim-4-Mim][DS](2), constructed via electrostatic attraction, tends to form micelles and hexagonal liquid crystals. Rich lamellar structures, including unilamellar and multilamellar vesicles, planar bilayers, and lamellar liquid crystals can be formed by [Mim-4-Mim][DBS](2), which is constructed through electrostatic and pi pi stacking interactions. With increasing temperatures, [Mim-4-Mim][DBS](2) exhibits interesting phase separation in the L(a) phase, behaving like common nonionic surfactants. The cross-linking between vesicles, where the "bola-type" [Mim-4-Mim](2+) cations act as the bridges, was found to promote the elongation of aggregates until the occurrence of phase separation. PMID- 25909964 TI - Association between an Internet-Based Measure of Area Racism and Black Mortality. AB - Racial disparities in health are well-documented and represent a significant public health concern in the US. Racism-related factors contribute to poorer health and higher mortality rates among Blacks compared to other racial groups. However, methods to measure racism and monitor its associations with health at the population-level have remained elusive. In this study, we investigated the utility of a previously developed Internet search-based proxy of area racism as a predictor of Black mortality rates. Area racism was the proportion of Google searches containing the "N-word" in 196 designated market areas (DMAs). Negative binomial regression models were specified taking into account individual age, sex, year of death, and Census region and adjusted to the 2000 US standard population to examine the association between area racism and Black mortality rates, which were derived from death certificates and mid-year population counts collated by the National Center for Health Statistics (2004-2009). DMAs characterized by a one standard deviation greater level of area racism were associated with an 8.2% increase in the all-cause Black mortality rate, equivalent to over 30,000 deaths annually. The magnitude of this effect was attenuated to 5.7% after adjustment for DMA-level demographic and Black socioeconomic covariates. A model controlling for the White mortality rate was used to further adjust for unmeasured confounders that influence mortality overall in a geographic area, and to examine Black-White disparities in the mortality rate. Area racism remained significantly associated with the all-cause Black mortality rate (mortality rate ratio = 1.036; 95% confidence interval = 1.015, 1.057; p = 0.001). Models further examining cause-specific Black mortality rates revealed significant associations with heart disease, cancer, and stroke. These findings are congruent with studies documenting the deleterious impact of racism on health among Blacks. Our study contributes to evidence that racism shapes patterns in mortality and generates racial disparities in health. PMID- 25909966 TI - [News with clinical relevance from major scientific meetings 2014 - Update Urooncology]. AB - What is new in urooncology in the year 2014? This review gives a brief but comprehensive overview of new developments in diagnosis and treatment of localized as well as advanced prostate, bladder and kidney cancer which have been presented on the occasion of the annual meetings of the European and American urologic and oncological associations in 2014. Attention is particularly directed to those data and results from trials which might be of direct or indirect clinical relevance. PMID- 25909963 TI - Blue cone monochromacy: visual function and efficacy outcome measures for clinical trials. AB - BACKGROUND: Blue Cone Monochromacy (BCM) is an X-linked retinopathy caused by mutations in the OPN1LW / OPN1MW gene cluster, encoding long (L)- and middle (M) wavelength sensitive cone opsins. Recent evidence shows sufficient structural integrity of cone photoreceptors in BCM to warrant consideration of a gene therapy approach to the disease. In the present study, the vision in BCM is examined, specifically seeking clinically-feasible outcomes for a future clinical trial. METHODS: BCM patients (n = 25, ages 5-72) were studied with kinetic and static chromatic perimetry, full-field sensitivity testing, and eye movement recordings. Vision at the fovea and parafovea was probed with chromatic microperimetry. RESULTS: Kinetic fields with a Goldmann size V target were generally full. Short-wavelength (S-) sensitive cone function was normal or near normal in most patients. Light-adapted perimetry results on conventional background lights were abnormally reduced; 600-nm stimuli were seen by rods whereas white stimuli were seen by both rods and S-cones. Under dark-adapted conditions, 500-nm stimuli were seen by rods in both BCM and normals. Spectral sensitivity functions in the superior retina showed retained rod and S-cone functions in BCM under dark-adapted and light-adapted conditions. In the fovea, normal subjects showed L/M-cone mediation using a 650-nm stimulus under dark adapted conditions, whereas BCM patients had reduced sensitivity driven by rod vision. Full-field red stimuli on bright blue backgrounds were seen by L/M-cones in normal subjects whereas BCM patients had abnormally reduced and rod-mediated sensitivities. Fixation location could vary from fovea to parafovea. Chromatic microperimetry demonstrated a large loss of sensitivity to red stimuli presented on a cyan adapting background at the anatomical fovea and surrounding parafovea. CONCLUSIONS: BCM rods continue to signal vision under conditions normally associated with daylight vision. Localized and retina-wide outcome measures were examined to evaluate possible improvement of L/M-cone-based vision in a clinical trial. PMID- 25909967 TI - [In Process Citation]. PMID- 25909968 TI - Identification of bulk oxide defects in an electrochemical environment. AB - We discuss how electronic-structure calculations can be used to identify the dominant point defects that control the growth and dissolution of the oxide barrier layer formed if a metal comes into contact with a corrosive environment. Using the example of the Zn/ZnO/H(2)O interface we develop and apply a theoretical approach that is firmly based on ab initio computed defect formation energies and that unifies concepts of semiconductor defect chemistry with electrochemical concepts. Employing this approach we find that the commonly invoked and chemically intuitive defects such as the doubly negatively charged oxygen vacancy in electrochemically formed ZnO films may not be present. Rather, hitherto not discussed defects such as the oxygen interstitial or unexpected charge states, such as the neutral oxygen vacancy, are found. These new defect types will be shown to critically impact our understanding of fundamental corrosion mechanisms and to provide new insight into strategies to develop alloys with higher corrosion resistance. PMID- 25909969 TI - A Randomized, Double-blinded Trial of a "Rule of Threes" Algorithm versus Continuous Infusion of Oxytocin during Elective Cesarean Delivery. AB - BACKGROUND: The administration of uterotonic agents during cesarean delivery is highly variable. The authors hypothesized a "rule of threes" algorithm, featuring oxytocin 3 IU, timed uterine tone evaluations, and a systematic approach to alternative uterotonic agents, would reduce the oxytocin dose required to obtain adequate uterine tone. METHODS: Sixty women undergoing elective cesarean delivery were randomized to receive a low-dose bolus or continuous infusion of oxytocin. To blind participants, the rule group simultaneously received intravenous oxytocin (3 IU/3 ml) and a "wide-open" infusion of 0.9% normal saline (500 ml); the standard care group received intravenous 0.9% normal saline (3 ml) and a "wide-open" infusion of oxytocin (30 IU in 0.9% normal saline/500 ml). Uterine tone was assessed at 3, 6, 9, and 12 min, and if inadequate, additional uterotonic agents were administered. Uterine tone, total dose and timing of uterotonic agent use, maternal hemodynamics, side effects, and blood loss were recorded. RESULTS: Adequate uterine tone was achieved with lower oxytocin doses in the rule versus standard care group (mean, 4.0 vs. 8.4 IU; point estimate of the difference, 4.4 +/- 1.0 IU; 95% CI, 2.60 to 6.15; P < 0.0001). No additional oxytocin or alternative uterotonic agents were needed in either group after 6 min. No differences in the uterine tone, maternal hemodynamics, side effects, or blood loss were observed. CONCLUSION: A "rule of threes" algorithm using oxytocin 3 IU results in lower oxytocin doses when compared with continuous-infusion oxytocin in women undergoing elective cesarean delivery. PMID- 25909970 TI - Compliance with Surgical Care Improvement Project for Body Temperature Management (SCIP Inf-10) Is Associated with Improved Clinical Outcomes. AB - BACKGROUND: In an effort to measure and improve the quality of perioperative care, the Surgical Care Improvement Project (SCIP) was introduced in 2003. The SCIP guidelines are evidence-based process measures designed to reduce preventable morbidity, but it remains to be determined whether SCIP-measure compliance is associated with improved outcomes. METHODS: The authors retrospectively analyzed the electronic medical record data from 45,304 inpatients at a single institution to assess whether compliance with SCIP Inf-10 (body temperature management) was associated with a reduced incidence of morbidity and mortality. The primary outcomes were hospital-acquired infection and ischemic cardiovascular events. Secondary outcomes were mortality and hospital length of stay. RESULTS: Body temperature on admission to the postoperative care unit was higher in the SCIP-compliant group (36.6 degrees +/- 0.5 degrees C; n = 44,064) compared with the SCIP-noncompliant group (35.5 degrees +/- 0.5 degrees C; n = 1,240) (P < 0.0001). SCIP compliance was associated with improved outcomes in both nonadjusted and risk-adjusted analyses. SCIP compliance was associated with a reduced incidence of hospital-acquired infection (3,312 [7.5%] vs.160 [12.9%] events; risk-adjusted odds ratio [OR], 0.68; 95% CI, 0.54 to 0.85), ischemic cardiovascular events (602 [1.4%] vs. 38 [3.1%] events; risk-adjusted OR, 0.60; 95% CI, 0.41 to 0.92), and mortality (617 [1.4%] vs. 60 [4.8%] events; risk-adjusted OR, 0.41; 95% CI, 0.29 to 0.58). Median (interquartile range) hospital length of stay was also decreased: 4 (2 to 8) versus 5 (2 to 14) days; P < 0.0001. CONCLUSION: Compliance with SCIP Inf-10 body temperature management guidelines during surgery is associated with improved clinical outcomes and can be used as a quality measure. PMID- 25909971 TI - Non-linear Membrane Properties in Entorhinal Cortical Stellate Cells Reduce Modulation of Input-Output Responses by Voltage Fluctuations. AB - The presence of voltage fluctuations arising from synaptic activity is a critical component in models of gain control, neuronal output gating, and spike rate coding. The degree to which individual neuronal input-output functions are modulated by voltage fluctuations, however, is not well established across different cortical areas. Additionally, the extent and mechanisms of input-output modulation through fluctuations have been explored largely in simplified models of spike generation, and with limited consideration for the role of non-linear and voltage-dependent membrane properties. To address these issues, we studied fluctuation-based modulation of input-output responses in medial entorhinal cortical (MEC) stellate cells of rats, which express strong sub-threshold non linear membrane properties. Using in vitro recordings, dynamic clamp and modeling, we show that the modulation of input-output responses by random voltage fluctuations in stellate cells is significantly limited. In stellate cells, a voltage-dependent increase in membrane resistance at sub-threshold voltages mediated by Na+ conductance activation limits the ability of fluctuations to elicit spikes. Similarly, in exponential leaky integrate-and-fire models using a shallow voltage-dependence for the exponential term that matches stellate cell membrane properties, a low degree of fluctuation-based modulation of input-output responses can be attained. These results demonstrate that fluctuation-based modulation of input-output responses is not a universal feature of neurons and can be significantly limited by subthreshold voltage-gated conductances. PMID- 25909972 TI - Enrichment of DNRA bacteria in a continuous culture. AB - Denitrification and dissimilatory nitrate reduction to ammonium (DNRA) are competing microbial nitrate-reduction processes. The occurrence of DNRA has been shown to be effected qualitatively by various parameters in the environment. A more quantitative understanding can be obtained using enrichment cultures in a laboratory reactor, yet no successful DNRA enrichment culture has been described. We showed that a stable DNRA-dominated enrichment culture can be obtained in a chemostat system. The enrichment was based on the hypothesis that nitrate limitation is the dominant factor in selecting for DNRA. First, a conventional denitrifying culture was enriched from activated sludge, with acetate and nitrate as substrates. Next, the acetate concentration in the medium was increased to obtain nitrate-limiting conditions. As a result, conversions shifted from denitrification to DNRA. In this selection of a DNRA culture, two important factors were the nitrate limitation and a relatively low dilution rate (0.026 h( 1)). The culture was a highly enriched population of Deltaproteobacteria most closely related to Geobacter lovleyi, based on 16S rRNA gene sequencing (97% similarity). We established a stable and reproducible cultivation method for the enrichment of DNRA bacteria in a continuously operated reactor system. This enrichment method allows to further investigate the DNRA process and address the factors for competition between DNRA and denitrification, or other N-conversion pathways. PMID- 25909973 TI - Non-symbiotic Bradyrhizobium ecotypes dominate North American forest soils. AB - The genus Bradyrhizobium has served as a model system for studying host-microbe symbiotic interactions and nitrogen fixation due to its importance in agricultural productivity and global nitrogen cycling. In this study, we identify a bacterial group affiliated with this genus that dominates the microbial communities of coniferous forest soils from six distinct ecozones across North America. Representative isolates from this group were obtained and characterized. Using quantitative population genomics, we show that forest soil populations of Bradyrhizobium represent ecotypes incapable of nodulating legume root hairs or fixing atmospheric nitrogen. Instead, these populations appear to be free living and have a greater potential for metabolizing aromatic carbon sources than their close symbiotic relatives. In addition, we identify fine-scaled differentiation between populations inhabiting neighboring soil layers that illustrate how diversity within Bradyrhizobium is structured by habitat similarity. These findings reconcile incongruent observations about this widely studied and important group of bacteria and highlight the value of ecological context to interpretations of microbial diversity and taxonomy. These results further suggest that the influence of this genus likely extends well beyond facilitating agriculture, especially as forest ecosystems are large and integral components of the biosphere. In addition, this study demonstrates how focusing research on economically important microorganisms can bias our understanding of the natural world. PMID- 25909974 TI - Calcite-accumulating large sulfur bacteria of the genus Achromatium in Sippewissett Salt Marsh. AB - Large sulfur bacteria of the genus Achromatium are exceptional among Bacteria and Archaea as they can accumulate high amounts of internal calcite. Although known for more than 100 years, they remain uncultured, and only freshwater populations have been studied so far. Here we investigate a marine population of calcite accumulating bacteria that is primarily found at the sediment surface of tide pools in a salt marsh, where high sulfide concentrations meet oversaturated oxygen concentrations during the day. Dynamic sulfur cycling by phototrophic sulfide-oxidizing and heterotrophic sulfate-reducing bacteria co-occurring in these sediments creates a highly sulfidic environment that we propose induces behavioral differences in the Achromatium population compared with reported migration patterns in a low-sulfide environment. Fluctuating intracellular calcium/sulfur ratios at different depths and times of day indicate a biochemical reaction of the salt marsh Achromatium to diurnal changes in sedimentary redox conditions. We correlate this calcite dynamic with new evidence regarding its formation/mobilization and suggest general implications as well as a possible biological function of calcite accumulation in large bacteria in the sediment environment that is governed by gradients. Finally, we propose a new taxonomic classification of the salt marsh Achromatium based on their adaptation to a significantly different habitat than their freshwater relatives, as indicated by their differential behavior as well as phylogenetic distance on 16S ribosomal RNA gene level. In future studies, whole-genome characterization and additional ecophysiological factors could further support the distinctive position of salt marsh Achromatium. PMID- 25909975 TI - Stability and succession of the rhizosphere microbiota depends upon plant type and soil composition. AB - We examined succession of the rhizosphere microbiota of three model plants (Arabidopsis, Medicago and Brachypodium) in compost and sand and three crops (Brassica, Pisum and Triticum) in compost alone. We used serial inoculation of 24 independent replicate microcosms over three plant generations for each plant/soil combination. Stochastic variation between replicates was surprisingly weak and by the third generation, replicate microcosms for each plant had communities that were very similar to each other but different to those of other plants or unplanted soil. Microbiota diversity remained high in compost, but declined drastically in sand, with bacterial opportunists and putative autotrophs becoming dominant. These dramatic differences indicate that many microbes cannot thrive on plant exudates alone and presumably also require carbon sources and/or nutrients from soil. Arabidopsis had the weakest influence on its microbiota and in compost replicate microcosms converged on three alternative community compositions rather than a single distinctive community. Organisms selected in rhizospheres can have positive or negative effects. Two abundant bacteria are shown to promote plant growth, but in Brassica the pathogen Olpidium brassicae came to dominate the fungal community. So plants exert strong selection on the rhizosphere microbiota but soil composition is critical to its stability. microbial succession/ plant microbe interactions/rhizosphere microbiota/selection. PMID- 25909976 TI - Nitrogenase diversity and activity in the gastrointestinal tract of the wood eating catfish Panaque nigrolineatus. AB - The Amazonian catfish, Panaque nigrolineatus, consume large amounts of wood in their diets. The nitrogen-fixing community within the gastrointestinal (GI) tract of these catfish was found to include nifH phylotypes that are closely related to Clostridium sp., Alpha and Gammaproteobacteria, and sequences associated with GI tracts of lower termites. Fish fed a diet of sterilized palm wood were found to contain nifH messenger RNA within their GI tracts, displaying high sequence similarity to the nitrogen-fixing Bradyrhizobium group. Nitrogenase activity, measured by acetylene reduction assays, could be detected in freshly dissected GI tract material and also from anaerobic enrichment cultures propagated in nitrogen free enrichment media; nifH sequences retrieved from these cultures were dominated by Klebsiella- and Clostridium-like sequences. Microscopic examination using catalyzed reporter deposition-enhanced immunofluorescence revealed high densities of nitrogenase-containing cells colonizing the woody digesta within the GI tract, as well as cells residing within the intestinal mucous layer. Our findings suggest that the P. nigrolineatus GI tract provides a suitable environment for nitrogen fixation that may facilitate production of reduced nitrogen by the resident microbial population under nitrogen limiting conditions. Whether this community is providing reduced nitrogen to the host in an active or passive manner and whether it is present in a permanent or transient relationship remains to be determined. The intake of a cellulose rich diet and the presence of a suitable environment for nitrogen fixation suggest that the GI tract microbial community may allow a unique trophic niche for P. nigrolineatus among fish. PMID- 25909977 TI - Dietary input of microbes and host genetic variation shape among-population differences in stickleback gut microbiota. AB - To explain differences in gut microbial communities we must determine how processes regulating microbial community assembly (colonization, persistence) differ among hosts and affect microbiota composition. We surveyed the gut microbiota of threespine stickleback (Gasterosteus aculeatus) from 10 geographically clustered populations and sequenced environmental samples to track potential colonizing microbes and quantify the effects of host environment and genotype. Gut microbiota composition and diversity varied among populations. These among-population differences were associated with multiple covarying ecological variables: habitat type (lake, stream, estuary), lake geomorphology and food- (but not water-) associated microbiota. Fish genotype also covaried with gut microbiota composition; more genetically divergent populations exhibited more divergent gut microbiota. Our results suggest that population level differences in stickleback gut microbiota may depend more on internal sorting processes (host genotype) than on colonization processes (transient environmental effects). PMID- 25909978 TI - Forest harvesting reduces the soil metagenomic potential for biomass decomposition. AB - Soil is the key resource that must be managed to ensure sustainable forest productivity. Soil microbial communities mediate numerous essential ecosystem functions, and recent studies show that forest harvesting alters soil community composition. From a long-term soil productivity study site in a temperate coniferous forest in British Columbia, 21 forest soil shotgun metagenomes were generated, totaling 187 Gb. A method to analyze unassembled metagenome reads from the complex community was optimized and validated. The subsequent metagenome analysis revealed that, 12 years after forest harvesting, there were 16% and 8% reductions in relative abundances of biomass decomposition genes in the organic and mineral soil layers, respectively. Organic and mineral soil layers differed markedly in genetic potential for biomass degradation, with the organic layer having greater potential and being more strongly affected by harvesting. Gene families were disproportionately affected, and we identified 41 gene families consistently affected by harvesting, including families involved in lignin, cellulose, hemicellulose and pectin degradation. The results strongly suggest that harvesting profoundly altered below-ground cycling of carbon and other nutrients at this site, with potentially important consequences for forest regeneration. Thus, it is important to determine whether these changes foreshadow long-term changes in forest productivity or resilience and whether these changes are broadly characteristic of harvested forests. PMID- 25909979 TI - WITHDRAWN: Traditional acupuncture and myocardial ischemia. AB - The Publisher regrets that this article is an accidental duplication of an article that has already been published in Int. J. Cardiol. 189 (2015) 281, http://dx.doi.org/10.1016/j.ijcard.2014.11.202. The duplicate article has therefore been withdrawn.The full Elsevier Policy on Article Withdrawal can be found at http://www.elsevier.com/locate/withdrawalpolicy. PMID- 25909980 TI - Could myocardial inflammation in Takotsubo syndrome be secondary to the mechanical disruption, rather than a primary feature, of the illness? PMID- 25909981 TI - Giant left coronary artery aneurysms: Review of the literature and report of a rare case diagnosed by transthoracic echocardiography. PMID- 25909982 TI - Performance of currently available risk models in a cohort of mechanically supported high-risk percutaneous coronary intervention--From the PROTECT II randomized trial. AB - BACKGROUND: Procedural risk scores facilitate clinical decision making by using individual patient characteristics to estimate the risk of adverse events. The performance of PCI-based risk scores is not well-described among patients undergoing hemodynamically supported high risk PCI. METHODS AND RESULTS: A total of 427 patients with unprotected left main disease, last remaining vessel or three-vessel disease with severely reduced left ventricular function underwent supported high-risk PCI with an intra-aortic balloon pump (IABP, N = 211) or a left ventricular assist device (Impella 2.5, N = 216) as part of the PROTECT II trial. We examined the performance of the additive Euroscore, logistic Euroscore, STS mortality score, STS morbidity and mortality score, Mayo Clinic risk score and New York state PCI risk score on the endpoint of 90-day mortality in this unique high-risk population. Mean age was 67.2 +/- 10.9 years; 65.8% of patients were in NYHA class III/IV, and mean LVEF was 24%. All-cause 90-day mortality was 10.4%. The scores were generally correlated (p < 0.0001 for all comparisons), with R(2) values ranging from 0.28 (STS morbidity/mortality and Mayo Clinic) to 0.68 (logistic Euroscore and STS mortality). However, receiver-operator curves for 90-day all-cause mortality for all risk scores demonstrated poor discriminatory performance with c-statistics of 0.542-0.616. Calibration of the risk scores was not poor, but varied according to the specific score examined. CONCLUSION: The discriminatory capacity of currently available risk models is suboptimal when applied to a cohort of mechanically supported complex high-risk PCI. A risk score designed specifically for this population could help to further refine risk assessment. PMID- 25909983 TI - Coronary artery disease/Takotsubo syndrome vs. acute coronary syndromes/Takotsubo syndrome, and their physical/emotional triggers. PMID- 25909985 TI - Copper mediated decyano decarboxylative coupling of cyanoacetate ligands: Pesci versus Lewis acid mechanism. AB - A combination of gas-phase ion trap multistage mass spectrometry (MS(n)) experiments and density functional theory (DFT) calculations have been used to examine the mechanisms of the sequential decomposition reactions of copper cyanoacetate anions, [(NCCH2CO2)2Cu](-), introduced into the gas-phase via electrospray ionization. Gas phase IR spectroscopy, used to probe the coordination mode of the cyanoacetate ligands, revealed that the initial precursor ions are bound to the Cu via the carboxylate, [NCCH2CO2CuO2CCH2CN], 1. Multistage collision-induced dissociation (CID) of 1 gave sequential losses of CO2 and ethene. DFT calculations suggest that the lowest energy pathways for sequential decarboxylation involve Lewis acid mechanisms in which the binding of the cyanoacetate ligand sequentially rearranges from O to N: [NCCH2CO2CuO2CCH2CN](-) -> [NCCH2CO2CuNCCH2CO2](-) -> [NCCH2CO2CuNCCH2](-) + CO2 and [NCCH2CO2CuNCCH2](-) -> [O2CCH2CNCuNCCH2](-) -> [CH2CNCuNCCH2](-) + CO2. Loss of ethene involves sequential rearrangement of the binding of the cyanomethyl carbanion ligands from N to C: [CH2CNCuNCCH2](-) -> [NCCH2CuNCCH2](-) -> [NCCH2CuCH2CN](-). CH2=CH2 loss then proceeds via a 1,2-dyotropic rearrangement to form [NCCuCH2CH2CN](-) followed by beta-cyanide transfer. This study highlights the rich mechanistic possibilities for metal mediated decarboxylation reactions involving ambidentate carboxylate ligands. PMID- 25909984 TI - A Comparison of Invasive Airway Management and Rates of Pneumonia in Prehospital and Hospital Settings. AB - INTRODUCTION: Infection is a major cause of morbidity and mortality in trauma. Infection in trauma is poorly understood. The impact of prehospital invasive airway management (IAM) on the incidence of pneumonia and health services utilization is unknown. We hypothesized that trauma patients exposed to prehospital IAM will suffer higher rates of pneumonia compared to no IAM or exposure to IAM performed in the hospital. We hypothesized that patients who develop pneumonia subsequent to prehospital IAM will have longer intensive care unit (ICU) and hospital length of stay (LOS) compared to patients who acquired pneumonia after IAM performed in the hospital. METHODS: This is an observational cohort study of data previously collected for the Resuscitation Outcomes Consortium hypertonic resuscitation randomized trial. Patients were included if traumatic injury resulted in shock, traumatic brain injury, or both. Patients were excluded if they died 24 hours after injury, or pneumonia data were missing. Adjusted and unadjusted logistic regression was used to calculate the odds ratio of pneumonia if exposed in the prehospital setting compared to no exposure or exposure in the hospital. RESULTS: Of 2,222 patients enrolled in the hypertonic resuscitation trial, 1,676 patients met enrollment criteria for this study. Four and a half percent of patients suffered pneumonia. IAM in the prehospital setting resulted in 6.8-fold increase (C.I. 2.0, 23.0, p = 0.003) in the adjusted odds of developing pneumonia compared to not being intubated, while in-hospital intubation resulted in 4.8-fold increase (C.I. 1.4, 16.6, p = 0.01), which was not statistically significantly different to the odds ratio of prehospital IAM. There were no statistically significant increases in health services utilization resulting from pneumonia incurred after IAM. CONCLUSION: Exposure to IAM in prehospital and hospital settings results in an increase in pneumonia, but there does not appear to be a link between the source of pneumonia and an increase in ICU or hospital LOS. PMID- 25909986 TI - A salient and task-irrelevant collinear structure hurts visual search. AB - Salient distractors draw our attention spontaneously, even when we intentionally want to ignore them. When this occurs, the real targets close to or overlapping with the distractors benefit from attention capture and thus are detected and discriminated more quickly. However, a puzzling opposite effect was observed in a search display with a column of vertical collinear bars presented as a task irrelevant distractor [6]. In this case, it was harder to discriminate the targets overlapping with the salient distractor. Here we examined whether this effect originated from factors known to modulate attentional capture: (a) low probability-the probability occurrence of target location at the collinear column was much less (14%) than the rest of the display (86%), and observers might strategically direct their attention away from the collinear distractor; (b) attentional control setting-the distractor and target task interfered with each other because they shared the same continuity set in attentional task; and/or (c) lack of time to establish the optional strategy. We tested these hypotheses by (a) increasing to 60% the trials in which targets overlapped with the same collinear distractor columns, (b) replacing the target task to be connectivity irrelevant (i.e., luminance discrimination), and (c) having our observers practice the same search task for 10 days. Our results speak against all these hypotheses and lead us to conclude that a collinear distractor impairs search at a level that is unaffected by probabilistic information, attentional setting, and learning. PMID- 25909987 TI - Origin and alteration of organic matter in termite mounds from different feeding guilds of the Amazon rainforests. AB - The impact of termites on nutrient cycling and tropical soil formation depends on their feeding habits and related material transformation. The identification of food sources, however, is difficult, because they are variable and changed by termite activity and nest construction. Here, we related the sources and alteration of organic matter in nests from seven different termite genera and feeding habits in the Terra Firme rainforests to the properties of potential food sources soil, wood, and microepiphytes. Chemical analyses comprised isotopic composition of C and N, cellulosic (CPS), non-cellulosic (NCPS), and N-containing saccharides, and molecular composition screening using pyrolysis-field ionization mass spectrometry (Py-FIMS). The isotopic analysis revealed higher soil delta13C (-27.40/00) and delta15N (6.60/00) values in nests of wood feeding Nasutitermes and Cornitermes than in wood samples (delta13C = -29.10/00, delta15N = 3.40/00), reflecting stable-isotope enrichment with organic matter alterations during or after nest construction. This result was confirmed by elevated NCPS:CPS ratios, indicating a preferential cellulose decomposition in the nests. High portions of muramic acid (MurAc) pointed to the participation of bacteria in the transformation processes. Non-metric multidimensional scaling (MDS) revealed increasing geophagy in the sequence Termes < Embiratermes < Anoplotermes and increasing xylophagy for Cornitermes < Nasutitermes., and that the nest material of Constrictotermes was similar to the microepiphytes sample, confirming the report that Constrictotermes belongs to the microepiphyte-feeders. We therewith document that nest chemistry of rainforest termites shows variations and evidence of modification by microbial processes, but nevertheless it primarily reflects the trophic niches of the constructors. PMID- 25909988 TI - Microbial Synthesis of Myrcene by Metabolically Engineered Escherichia coli. AB - Myrcene, a monoterpene (C10), has gathered attention as a starting material for high-value compounds, such as geraniol/linalool and (-)-menthol. Metabolic engineering has been successfully applied to produce monoterpenes, such as pinene and limonene, at high levels in microbial hosts. However, microbial synthesis of myrcene has not yet been reported. Thus, we metabolically engineered Escherichia coli for production of myrcene by introducing a heterologous mevalonate pathway and overexpressing tailoring enzymes, such as geranyl diphosphate synthase (GPPS) and myrcene synthase (MS). Although MSs have broad ranges of functionality for producing various monoterpenes, our engineered E. coli strains harboring MS from Quercus ilex L. produced only myrcene (1.67 +/- 0.029 mg/L). Subsequent engineering resulted in higher production of myrcene by optimizing the levels of GPPS in amino-acid-enriched (EZ-rich) defined medium, where glycerol as a carbon source was used. The production level of myrcene (58.19 +/- 12.13 mg/L) was enhanced by 34-fold using in situ two-phase extraction to eliminate cellular toxicity and the evaporation of myrcene. PMID- 25909989 TI - Increased plasma clot permeability and susceptibility to lysis are associated with heavy menstrual bleeding of unknown cause: a case-control study. AB - BACKGROUND: Formation of compact and poorly lysable clots has been reported in thromboembolic disorders. Little is known about clot properties in bleeding disorders. OBJECTIVES: We hypothesized that more permeable and lysis-sensitive fibrin clots can be detected in women with heavy menstrual bleeding (HMB). METHODS: We studied 52 women with HMB of unknown cause and 52 age-matched control women. Plasma clot permeability (Ks), turbidity and efficiency of fibrinolysis, together with coagulation factors, fibrinolysis proteins, and platelet aggregation were measured. RESULTS: Women with HMB formed looser plasma fibrin clots (+16% [95%CI 7-18%] Ks) that displayed lower maximum absorbancy (-7% [95%CI -9 - -1%] DeltaAbsmax), and shorter clot lysis time (-17% [95%CI -23 - -11%] CLT). The HMB patients and controls did not differ with regard to coagulation factors, fibrinogen, von Willebrand antigen, thrombin generation markers and the proportion of subjects with defective platelet aggregation. The patients had lower platelet count (-12% [95%CI -19 - -2%]), tissue plasminogen activator antigen (-39% [95%CI -41 - -29%] tPA:Ag), and plasminogen activator inhibitor-1 antigen (-28% [95%CI -38 - -18%] PAI-1:Ag) compared with the controls. Multiple regression analysis upon adjustment for age, body mass index, glucose, and fibrinogen showed that decreased tPA:Ag and shortened CLT were the independent predictors of HMB. CONCLUSIONS: Increased clot permeability and susceptibility to fibrinolysis are associated with HMB, suggesting that altered plasma fibrin clot properties might contribute to bleeding disorders of unknown origin. PMID- 25909990 TI - Casque infection, resolution, and subsequent repneumatization in a trumpeter hornbill (Bycanistes buccinator). PMID- 25909992 TI - Quantifying the degradation of TNT and RDX in a saline environment with and without UV-exposure. AB - Terrorist attacks in a maritime setting, such as the bombing of the USS Cole in 2000, or the detection of underwater mines, require the development of proper protocols to collect and analyse explosive material from a marine environment. In addition to proper analysis of the explosive material, protocols must also consider the exposure of the material to potentially deleterious elements, such as UV light and salinity, time spent in the environment, and time between storage and analysis. To understand how traditional explosives would be affected by such conditions, saline solutions of explosives were exposed to natural and artificial sunlight. Degradation of the explosives over time was then quantified using negative chemical ionization gas chromatography mass spectrometry (GC/NCI-MS). Two explosives, trinitrotoluene (TNT) and cyclotrimethylenetrinitramine (RDX), were exposed to different aqueous environments and light exposures with salinities ranging from freshwater to twice the salinity of ocean water. Solutions were then aged for up to 6 months to simulate different conditions the explosives may be recovered from. Salinity was found to have a negligible impact on the degradation of both RDX and TNT. RDX was stable in solutions of all salinities while TNT solutions degraded regardless of salinity. Solutions of varying salinities were also exposed to UV light, where accelerated degradation was seen for both explosives. Potential degradation products of TNT were identified using electrospray ionization mass spectrometry (ESI-MS), and correspond to proposed degradation products discussed in previously published works [1]. PMID- 25909993 TI - Donepezil distribution in postmortem cases and potential for redistribution. AB - Donepezil (DPZ) is an acetylcholine-esterase inhibitor currently used as the frontline drug to treat Alzheimer's disease. The aim of this study was to investigate the possibility of postmortem redistribution (PMR) of DPZ, which could complicate the determination of cause of death in medico-legal cases. Additionally, metabolic enzyme DNA polymorphism, drug-drug interaction and the presence of lesions in metabolic and egestion organs were examined to eliminate the possibility of a high antemortem DPZ concentration. Subsequently, the average DPZ concentration of four sites of peripheral blood (right and left femoral artery and vein) was compared with central blood and liver DPZ concentrations in seven postmortem cases. DPZ concentrations ranged from 0.02 to 0.45MUg/mL in the peripheral blood, 0.09-0.4MUg/mL in central blood, and from 1.2 to 6.7MUg/kg in the liver. In most specimens, the concentrations were higher than the therapeutic range (approximately 0.030-0.075MUg/mL). DPZ central blood to peripheral blood (C/P) ratios averaged 1.73+/-1.02 (+/-standard deviation) while liver to peripheral blood (L/P) ratios were higher and averaged 17.5+/-7.25. It is documented that a C/P ratio of less than (or about) 1.0 and an L/P ratio less than 5 are not indicative of PMR, whereas a C/P ratio exceeding 2 and L/P ratio exceeding 20 highlight a propensity for significant PMR. Our data suggest that DPZ exhibits a moderate degree of PMR. Additionally, a lowered pH was found in all blood specimens (<6-6.75 in the peripheral blood and <6-6.66 in the central blood). This postmortem reduction in blood pH may increase the ionic forms of DPZ, resulting in a high blood DPZ concentration. PMID- 25909991 TI - Activation of the Liver X Receptor by Agonist TO901317 Improves Hepatic Insulin Resistance via Suppressing Reactive Oxygen Species and JNK Pathway. AB - Activation of Liver X receptors (LXRs), key transcriptional regulators of glucose metabolism, normalizes glycemia and improves insulin sensitivity in rodent models with insulin resistance. However, the molecular mechanism is unclear. This study is aimed to elucidate the mechanism of LXRs-mediated liver glucose metabolic regulation in vitro and in vivo. Db/db mice were used as an in vivo model of diabetes; palmitate (PA)-stimulated HepG2 cells were used as an in vitro cell model with impairment of insulin signaling. TO901317 (TO) was chosen as the LXRs agonist. We demonstrated that TO treatment for 14 days potently improved the hepatic glucose metabolism in db/db mice, including fasting blood glucose, fasting insulin level, and HOMA-IR. TO had no effect on the glucose metabolism in normal WT mice. TO-mediated activation of hepatic LXRs led to strong inhibition of ROS production accompanied by inactivation of JNK pathway and re-activation of Akt pathway. TO also suppressed the expression of gluconeogenic genes such as PEPCK and G-6-pase in db/db mice, but not in WT mice. In HepG2 cells, TO almost completely restored PA-induced Akt inactivation, and suppressed PA-stimulated ROS production and JNK activation. Interestingly, basal level of ROS was also inhibited by TO in HepG2 cells. TO significantly inhibited PA-stimulated expressions of gluconeogenic genes. Finally, we found that anti-oxidative genes, such as Nrf2, were up-regulated after LXRs activation by TO. These results strongly support the notion that activation of LXRs is critical in suppression of liver gluconeogenesis and improvement of insulin sensitivity in diabetic individuals. At molecular levels, the mode of action appears to be as fellows: under diabetic condition, ROS production is increased, JNK is activated, and Akt activity is inhibited; TO-mediated LXR activation potently inhibits ROS production, increases anti-oxidative gene expressions, suppresses JNK activation, and restores Akt activity. Our data provide new evidence to support LXRs as promising therapeutic targets for anti-diabetic drug development. PMID- 25909994 TI - Isotope ratio mass spectrometry as a tool for source inference in forensic science: A critical review. AB - Isotope ratio mass spectrometry (IRMS) has been used in numerous fields of forensic science in a source inference perspective. This review compiles the studies published on the application of isotope ratio mass spectrometry (IRMS) to the traditional fields of forensic science so far. It completes the review of Benson et al. [1] and synthesises the extent of knowledge already gathered in the following fields: illicit drugs, flammable liquids, human provenancing, microtraces, explosives and other specific materials (packaging tapes, safety matches, plastics, etc.). For each field, a discussion assesses the state of science and highlights the relevance of the information in a forensic context. Through the different discussions which mark out the review, the potential and limitations of IRMS, as well as the needs and challenges of future studies are emphasized. The paper elicits the various dimensions of the source which can be obtained from the isotope information and demonstrates the transversal nature of IRMS as a tool for source inference. PMID- 25909995 TI - Critical review of forensic trace evidence analysis and the need for a new approach. AB - The historical development, contributions and limitations of the two traditional approaches to trace evidence analysis are reviewed. The first approach was as generalist practitioner, looking broadly at an assemblage of many different particle types. The second was that of specialist practitioner, with attention focused on one specific particle type. Four factors have significantly impacted the effectiveness of these approaches: (1) increasing technological capabilities, (2) increasing complexity in the character of manufactured materials, (3) changes in forensic laboratory management, and (4) changing scientific and legal expectations. The effectiveness of each approach is assessed within the context of these changes. More recently, new technologies have been applied to some trace evidence problems, intended to address one or more limitations. This has led to a third approach founded on discrete, highly technical methods addressing specific analytical problems. After evaluating the contributions and limitations of this third approach, we consider the different ways that technologies could be developed to address unmet needs in forensic trace evidence analysis. The route toward effective use of new technologies is contrasted with how forensic science laboratories are currently choosing and employing them. The conclusion is that although new technologies are contributing, we are not on a path that will result in their most effective and appropriate use. A new approach is required. Based on an analysis of the contributions of each of the three exisiting approaches, seven characteristics of an effective trace evidence analysis capability were determined: (1) particle traces should be a major problem-solving tool, (2) there should be readily available, straightforward methods to enable their use, (3) all available and potentially useful particle types should be considered, (4) decisions to use them should be made in the context of each case, guided by what they can contribute to the case and how efficiently they can do so, (5) analyses should be conducted using appropriate technologies, (6) findings should be timely and directly integrated with case-specific problems, and (7) new technologies should be used to improve the overall effectiveness of the capability. Clearly new technologies have the potential to revolutionize forensic trace evidence, but just as clearly some of the traditional capabilities have been rendered ineffective, or lost entirely, by the way we have come to approach the problem. Having critically defined the current limitations of and the desired outcomes, the next focus should be consideration of alternative approaches that might achieve such a result. PMID- 25909996 TI - Toward Ferroelectric Control of Monolayer MoS2. AB - The chemical vapor deposition (CVD) of molybdenum disulfide (MoS2) single-layer films onto periodically poled lithium niobate is possible while maintaining the substrate polarization pattern. The MoS2 growth exhibits a preference for the ferroelectric domains polarized "up" with respect to the surface so that the MoS2 film may be templated by the substrate ferroelectric polarization pattern without the need for further lithography. MoS2 monolayers preserve the surface polarization of the "up" domains, while slightly quenching the surface polarization on the "down" domains as revealed by piezoresponse force microscopy. Electrical transport measurements suggest changes in the dominant carrier for CVD MoS2 under application of an external voltage, depending on the domain orientation of the ferroelectric substrate. Such sensitivity to ferroelectric substrate polarization opens the possibility for ferroelectric nonvolatile gating of transition metal dichalcogenides in scalable devices fabricated free of exfoliation and transfer. PMID- 25909997 TI - BRCA1 and CtIP Are Both Required to Recruit Dna2 at Double-Strand Breaks in Homologous Recombination. AB - Homologous recombination plays a key role in the repair of double-strand breaks (DSBs), and thereby significantly contributes to cellular tolerance to radiotherapy and some chemotherapy. DSB repair by homologous recombination is initiated by 5' to 3' strand resection (DSB resection), with nucleases generating the 3' single-strand DNA (3'ssDNA) at DSB sites. Genetic studies of Saccharomyces cerevisiae demonstrate a two-step DSB resection, wherein CtIP and Mre11 nucleases carry out short-range DSB resection followed by long-range DSB resection done by Dna2 and Exo1 nucleases. Recent studies indicate that CtIP contributes to DSB resection through its non-catalytic role but not as a nuclease. However, it remains elusive how CtIP contributes to DSB resection. To explore the non catalytic role, we examined the dynamics of Dna2 by developing an immuno cytochemical method to detect ionizing-radiation (IR)-induced Dna2-subnuclear focus formation at DSB sites in chicken DT40 and human cell lines. Ionizing radiation induced Dna2 foci only in wild-type cells, but not in Dna2 depleted cells, with the number of foci reaching its maximum at 30 minutes and being hardly detectable at 120 minutes after IR. Induced foci were detectable in cells in the G2 phase but not in the G1 phase. These observations suggest that Dna2 foci represent the recruitment of Dna2 to DSB sites for DSB resection. Importantly, the depletion of CtIP inhibited the recruitment of Dna2 to DSB sites in both human cells and chicken DT40 cells. Likewise, a defect in breast cancer 1 (BRCA1), which physically interacts with CtIP and contributes to DSB resection, also inhibited the recruitment of Dna2. Moreover, CtIP physically associates with Dna2, and the association is enhanced by IR. We conclude that BRCA1 and CtIP contribute to DSB resection by recruiting Dna2 to damage sites, thus ensuring the robust DSB resection necessary for efficient homologous recombination. PMID- 25909999 TI - A Smart Capsule With GI-Tract-Location-Specific Payload Release. AB - In this paper, we present a smart capsule for location-specific drug release in the gastrointestinal tract. Once activated through a magnetic proximity fuse, the capsule opens up and releases its powdered payload in a location specified by an implanted miniature magnetic marker or an externally worn larger magnet. The capsule (9 mm * 26 mm) comprises of two compartments: one contains a charged capacitor and a reed switch, while the second one houses the drug reservoir capped by a taut nylon thread intertwined with a nichrome wire. The nichrome wire is connected to the capacitor through the reed switch. The capacitor is charged to 2.7 V before ingestion and once within the proximity of the permanent magnet; the reed switch closes, discharging the capacitor through the nichrome wire, melting the nylon thread, detaching the cap, and emptying the drug reservoir. PMID- 25910000 TI - Global and Local Panoramic Views for Gastroscopy: An Assisted Method of Gastroscopic Lesion Surveillance. AB - Gastroscopy plays an important role in the diagnosis of gastric disease. In this paper, we develop an image panoramic system to assist endoscopists in improving lesion surveillance and reducing many of the tedious operations associated with gastroscopy. The constructed panoramic view has two categories: 1) the local view broadens the endoscopist's field of view in real time. Combining with the original gastroscopic video, this mosaicking view enables the endoscopist to diagnose the lesion comprehensively; 2) the global view constructs a large-area panoramic scene of the internal gastric surface, which can be used for intraoperative surgical navigation and postoperative scene review. Due to the irregular texture and inconsistent reflection of the gastric internal surface, common registration methods cannot accurately stitch this surface. Thereby, a six degree of freedom position tracking endoscope is devised to accommodate for the accumulated mosaicking error and provide efficient mosaicking results. For the global view, a dual-cube constraint model and a Bundle Adjustment algorithm are incorporated to deal with the mosaicking error caused by the irregular inflation and nonrigid deformation of the stomach. Moreover, texture blending and frame selection schemes are developed to make the mosaicking results feasible in real clinical applications. The experimental results demonstrate that our system performs with a speed of 7.12 frames/s in a standard computer environment, and the mosaicking mean error is 0.43 mm for local panoramic view and 3.71 mm for global panoramic view. PMID- 25909998 TI - The novel analogue of hirsutine as an anti-hypertension and vasodilatary agent both in vitro and in vivo. AB - In this paper, an analogue of hirsutine (compound 1) has been synthesized and evaluated as an anti-hypertension agent, which exhibits extraordinary effects on the contractile response of thoracic aorta rings from male SD rats in vitro (IC50 = 1.129*10(-9)+/-0.5025) and the abilities of reducing the systolic blood pressure (SBP) and heart rate (HR) of SHR in vivo. The mechanism investigation reveals that the vasodilatation induced by compound 1 is mediated by both endothelium-dependent and -independent manners. The relaxation in endothelium intact aortic rings induced by compound 1 can be inhibited by L-NAME (1*10(-6) mol*L(-1)) and ODQ (1*10(-6) mol*L(-1)). Moreover, compound 1 can also block Ca2+ influx through L-type Ca2+ channels and inhibit intracellular Ca2+ release while no effect on K+ channel has been observed. All these data demonstrated that the NO/cyclic GMP pathway can be involved in endothelium-dependent manner induced by compound 1. Meanwhile the mechanism on the vasodilatation of compound 1 probably also related to blockade of Ca2+ influx through L-type Ca2+ channels and inhibition of intracellular Ca2+ release may have no relationship with K+ channels. PMID- 25910002 TI - Stochastic dynamic causal modelling of FMRI data with multiple-model Kalman filters. AB - INTRODUCTION: This article is part of the Focus Theme of Methods of Information in Medicine on "Biosignal Interpretation: Advanced Methods for Neural Signals and Images". BACKGROUND: Dynamic Causal Modelling (DCM) is a generic formalism to study effective brain connectivity based on neuroimaging data, particularly functional Magnetic Resonance Imaging (fMRI). Recently, there have been attempts at modifying this model to allow for stochastic disturbances in the states of the model. OBJECTIVES: This paper proposes the Multiple-Model Kalman Filtering (MMKF) technique as a stochastic identification model discriminating among different hypothetical connectivity structures in the DCM framework; moreover, the performance compared to a similar deterministic identification model is assessed. METHODS: The integration of the stochastic DCM equations is first presented, and a MMKF algorithm is then developed to perform model selection based on these equations. Monte Carlo simulations are performed in order to investigate the ability of MMKF to distinguish between different connectivity structures and to estimate hidden states under both deterministic and stochastic DCM. RESULTS: The simulations show that the proposed MMKF algorithm was able to successfully select the correct connectivity model structure from a set of pre-specified plausible alternatives. Moreover, the stochastic approach by MMKF was more effective compared to its deterministic counterpart, both in the selection of the correct connectivity structure and in the estimation of the hidden states. CONCLUSIONS: These results demonstrate the applicability of a MMKF approach to the study of effective brain connectivity using DCM, particularly when a stochastic formulation is desirable. PMID- 25910001 TI - Electric Field Model of Transcranial Electric Stimulation in Nonhuman Primates: Correspondence to Individual Motor Threshold. AB - OBJECTIVE: To develop a pipeline for realistic head models of nonhuman primates (NHPs) for simulations of noninvasive brain stimulation, and use these models together with empirical threshold measurements to demonstrate that the models capture individual anatomical variability. METHODS: Based on structural MRI data, we created models of the electric field (E-field) induced by right unilateral (RUL) electroconvulsive therapy (ECT) in four rhesus macaques. Individual motor threshold (MT) was measured with transcranial electric stimulation (TES) administered through the RUL electrodes in the same subjects. RESULTS: The interindividual anatomical differences resulted in 57% variation in median E field strength in the brain at fixed stimulus current amplitude. Individualization of the stimulus current by MT reduced the E-field variation in the target motor area by 27%. There was significant correlation between the measured MT and the ratio of simulated electrode current and E-field strength (r(2) = 0.95, p = 0.026). Exploratory analysis revealed significant correlations of this ratio with anatomical parameters including of the superior electrode-to cortex distance, vertex-to-cortex distance, and brain volume (r(2) > 0.96, p < 0.02). The neural activation threshold was estimated to be 0.45 +/-0.07 V/cm for 0.2-ms stimulus pulse width. CONCLUSION: These results suggest that our individual-specific NHP E-field models appropriately capture individual anatomical variability relevant to the dosing of TES/ECT. These findings are exploratory due to the small number of subjects. SIGNIFICANCE: This study can contribute insight in NHP studies of ECT and other brain stimulation interventions, help link the results to clinical studies, and ultimately lead to more rational brain stimulation dosing paradigms. PMID- 25910003 TI - Anterior chamber depth and refractive change in late postoperative capsular bag distension syndrome: a retrospective analysis. AB - PURPOSE: To assess the characteristic findings and effects of laser capsulotomy in patients with late postoperative capsular bag distension syndrome (CBDS). METHODS: Twenty patients diagnosed with late postoperative CBDS between July 2010 and August 2013 were retrospectively reviewed. Before and 1 week after capsulotomy, changes in the anterior chamber depth (ACD) were assessed using ultrasound biomicroscopy. Changes in the refractive status and uncorrected visual acuity (UCVA) were also measured 1 week and 1 month after capsulotomy. For patients who received bilateral cataract surgery, preoperative ACD and axial length measured by IOLMaster were compared between the two eyes. RESULTS: Twenty two eyes from 20 patients who had undergone laser capsulotomy showed a mean UCVA improvement of 0.27 +/- 0.24 logMAR (range, 0.00-0.90). ACD was increased by an average of +0.04 mm (95% confidence interval, +0.01 to +0.06 mm, p = 0.034), equivalent to predicted refractive change of +0.10 D. The discrepancy between actual (+1.33 D) and predicted refractive change after capsulotomy suggests that refractive change may not be generated from IOL displacement in late postoperative CBDS. Preoperative ACD was deeper in the eye with late postoperative CBDS in all bilaterally pseudophakic patients (mean, 3.68 mm vs. 3.44 mm in the fellow eye, p = 0.068). CONCLUSIONS: Late postoperative CBDS showed refractive changes that were resolved successfully after laser capsulotomy. The convex lens effects of opalescent material in the distended capsular bag may play a major role in myopic shift. A larger preoperative ACD is possibly associated with the development of late postoperative CBDS. PMID- 25910004 TI - Optimal intensity and biomass density for biofuel production in a thin-light-path photobioreactor. AB - Production of competitive microalgal biofuels requires development of high volumetric productivity photobioreactors (PBRs) capable of supporting high density cultures. Maximal biomass density supported by the current PBRs is limited by nonuniform distribution of light as a result of self-shading effects. We recently developed a thin-light-path stacked photobioreactor with integrated slab waveguides that distributed light uniformly across the volume of the PBR. Here, we enhance the performance of the stacked waveguide photobioreactor (SW PBR) by determining the optimal wavelength and intensity regime of the incident light. This enabled the SW-PBR to support high-density cultures, achieving a carrying capacity of OD730 20. Using a genetically modified algal strain capable of secreting ethylene, we improved ethylene production rates to 937 MUg L(-1) h( 1). This represents a 4-fold improvement over a conventional flat-plate PBR. These results demonstrate the advantages of the SW-PBR design and provide the optimal operational parameters to maximize volumetric production. PMID- 25910006 TI - Somatostatin: still a pharmaceutical defense weapon against post-ERCP pancreatitis? A 30-year story. PMID- 25910005 TI - Substrate recognition and modification by the nosiheptide resistance methyltransferase. AB - BACKGROUND: The proliferation of antibiotic resistant pathogens is an increasing threat to the general public. Resistance may be conferred by a number of mechanisms including covalent or mutational modification of the antibiotic binding site, covalent modification of the drug, or the over-expression of efflux pumps. The nosiheptide resistance methyltransferase (NHR) confers resistance to the thiazole antibiotic nosiheptide in the nosiheptide producer organism Streptomyces actuosus through 2'O-methylation of 23S rRNA at the nucleotide A1067. Although the crystal structures of NHR and the closely related thiostrepton-resistance methyltransferase (TSR) in complex with the cofactor S Adenosyl-L-methionine (SAM) are available, the principles behind NHR substrate recognition and catalysis remain unclear. METHODOLOGY/PRINCIPAL FINDINGS: We have analyzed the binding interactions between NHR and model 58 and 29 nucleotide substrate RNAs by gel electrophoresis mobility shift assays (EMSA) and fluorescence anisotropy. We show that the enzyme binds to RNA as a dimer. By constructing a hetero-dimer complex composed of one wild-type subunit and one inactive mutant NHR-R135A subunit, we show that only one functional subunit of the NHR homodimer is required for its enzymatic activity. Mutational analysis suggests that the interactions between neighbouring bases (G1068 and U1066) and A1067 have an important role in methyltransfer activity, such that the substitution of a deoxy sugar spacer (5') to the target nucleotide achieved near wild-type levels of methylation. A series of atomic substitutions at specific positions on the substrate adenine show that local base-base interactions between neighbouring bases are important for methylation. CONCLUSION/SIGNIFICANCE: Taken together these data suggest that local base-base interactions play an important role in aligning the substrate 2' hydroxyl group of A1067 for methyl group transfer. Methylation of nucleic acids is playing an increasingly important role in fundamental biological processes and we anticipate that the approach outlined in this manuscript may be useful for investigating other classes of nucleic acid methyltransferases. PMID- 25910007 TI - More adenomas - less cancer? Advanced imaging in colonoscopy. PMID- 25910008 TI - Is the double-guidewire technique used to facilitate selective bile duct cannulation or to prevent post-ERCP pancreatitis? PMID- 25910009 TI - Small-caliber rescue pancreatic stenting for severe post-ERCP pancreatitis: a useful tool to pull the pancreas out of the fire. PMID- 25910010 TI - The role of salvage ERCP for the treatment of post-ERCP pancreatitis. PMID- 25910011 TI - Further studies are needed on urgent ERCP with pancreatic stent placement or replacement for salvage of post-ERCP pancreatitis. PMID- 25910012 TI - Reply to three letters: Dubravcsik et al, Murion et al and Fan et al The horse must come before the cart .... PMID- 25910015 TI - [In Process Citation]. PMID- 25910016 TI - [In Process Citation]. PMID- 25910017 TI - Video Comment on Christine Kestens et al., pages 409-414. PMID- 25910018 TI - Video Comment on Yu Bai et al., pages 415-420. PMID- 25910019 TI - Video Comment on Gian Eugenio Tontini et al., pages 437-443. PMID- 25910020 TI - Atmospheric pitting corrosion of 304L stainless steel: the role of highly concentrated chloride solutions. AB - The morphology of atmospheric pitting corrosion in 304L stainless steel plate was analysed using MgCl(2) droplets in relation to changes in relative humidity (RH) and chloride deposition density (CDD). It was found that highly reproducible morphologies occur that are distinct at different RH. Pitting at higher concentrations, i.e. lower RH, resulted in satellite pits forming around the perimeter of wide shallow dish regions. At higher RH, these satellite pits did not form and instead spiral attack into the shallow region was observed. Increasing CDD at saturation resulted in a very broad-mouthed pitting attack within the shallow dish region. Large data sets were used to find trends in pit size and morphology in what is essentially a heterogeneous alloy. Electrochemical experiments on 304 stainless steel wires in highly saturated solutions showed that the passive current density increased significantly above 3 M MgCl(2) and the breakdown pitting potential dropped as the concentration increased. It is proposed that the shallow dish regions grow via enhanced dissolution of the passive film, whereas satellite pits and a spiral attack take place with active dissolution of bare metal surfaces. PMID- 25910021 TI - Cation binding to halorhodopsin. AB - A member of the retinal protein family, halorhodopsin, acts as an inward light driven Cl(-) pump. It was recently demonstrated that the Natronomonas pharaonis halorhodopsin-overproducing mutant strain KM-1 contains, in addition to the retinal chromophore, a lipid soluble chromophore, bacterioruberin, which binds to crevices between adjacent protein subunits. It is established that halorhodopsin has several chloride binding sites, with binding site I, located in the retinal protonated Schiff base vicinity, affecting retinal absorption. However, it remained unclear whether cations also bind to this protein. Our electron paramagnetic resonance spectroscopy examination of cation binding to the halorhodopsin mutant KM-1 reveals that divalent cations like Mn(2+) and Ca(2+) bind to the protein. Halorhodopsin has a high affinity for Mn(2+) ions, which bind initially to several strong binding sites and then to binding sites that exhibit positive cooperativity. The binding behavior is pH-dependent, and its strength is influenced by the nature of counterions. Furthermore, the binding strength of Mn(2+) ions decreases upon removal of the retinal chromophore from the protein or following bacterioruberin oxidation. Our results also indicate that Mn(2+) ions, as well as Cl(-) ions, first occupy binding sites other than site I. The observed synergetic effect between cation and anion binding suggests that while Cl(-) anions bind to halorhodopsin at low concentrations, the occupancy of site I requires a high concentration. PMID- 25910022 TI - Research Guidelines Endorsed by Annals of Plastic Surgery to Improve the Quality of Published Articles. PMID- 25910023 TI - Use of Intraoperative Fluorescent Indocyanine Green Angiography for Real-Time Vascular Evaluation of Pericranial Flaps. AB - BACKGROUND: Pericranial flaps (PCFs) have been widely used for skull base reconstruction. The key to successful skull base reconstruction using PCF depends on flap vascularity, but there have been no reports describing the real-time vascularity of PCF. In this study, we performed intraoperative fluorescent indocyanine green angiography to evaluate the real-time vascularity and viability of PCF and to estimate the reliability of this flap. METHODS: Eleven anteriorly based PCF (with a bilateral pedicle, ipsilateral pedicle, and random-pattern flap) and 11 laterally based PCF (with and without temporal muscle) were included in this study. The flap vascularity of each flap type considering the patients' background was evaluated using indocyanine green angiography intraoperatively. RESULTS: Anteriorly based PCF had significantly better vascularity compared to laterally based PCF. In anteriorly based PCF, there was no significant difference in vascularity between PCF with bilateral pedicles and an ipsilateral pedicle. In laterally based PCF, PCF without temporal muscle showed a wider vascular area compared to PCF with temporal muscle. As for the patient background, those older than 45 years, body mass index more than 25, and who were smokers tended to have lower vascularity. Preoperative radiation therapy did not show any significant differences in terms of flap vascularity. CONCLUSIONS: Anteriorly based PCF had significantly better vascularity compared to laterally based PCF and seemed safer to harvest regardless of flap pedicle type. Also, the feasibility of harvesting muscle sparing laterally based PCF was indicated. Finally, being older than 45 years, a body mass index more than 25, or being a smoker might increase the risk of reducing flap vascularity. PMID- 25910024 TI - The Deep Inferior Epigastric Perforator Learning Curve in the Current Era. AB - BACKGROUND: Over the last 2 decades, the deep inferior epigastric perforator (DIEP) flap has gained significant popularity in breast reconstruction. However, for some, the increased technical difficulties associated with DIEP breast reconstruction can be a discouraging factor in adopting this technique. There has been a trend in the literature to acknowledge an acute learning curve in the adoption of DIEP breast reconstruction but little evidence to support its ongoing relevance to surgeons who gain significant exposure in training. METHODS: We test the learning curve concept on the senior author's series of 214 DIEP and superficial inferior epigastric artery flaps in a single-surgeon, retrospective study analyzing chronological trends in complication rates both major (total and partial flap loss, reexploration) and minor (fat necrosis, donor site hernia and bulge). RESULTS: The total complication rate was 7.9%, including 1 (0.5%) partial and 1 (0.5%) total flap failure. A comparison of complication rates in the initial 30 flaps in comparison to the remainder of the series revealed no significant difference in major complications (3.3% vs 3.3%, P = 1.00) or minor complications (6.7% vs 4.3%, P = 0.635). Linear-by-linear analysis performed on chronologically ordered groups of 30 flaps revealed no statistically significant trends over the series. CONCLUSIONS: The learning curve associated with the DIEP is complex and likely relates to competency gained in both technical and decision making aspects of breast reconstruction. This series has demonstrated that with adequate training and an algorithmic approach to DIEP breast reconstruction, eliminating the early learning curve and improving early outcomes are possible. PMID- 25910025 TI - Neonatal Compartment Syndrome Associated With Disseminated Intravascular Coagulation. AB - Neonatal compartment syndrome is a rare, but devastating limb-threatening condition that requires early recognition and timely surgical intervention. We discuss the clinical presentation and management challenges of a neonate with forearm compartment syndrome and disseminated intravascular coagulation. PMID- 25910027 TI - Paramuscular perforators in DIEAP flap for breast reconstruction: an important variation in perforator flap nomenclature. PMID- 25910028 TI - Rational Treatment of the Basal Cell Carcinoma or Confessions of A "Part-Time Dermatologist". PMID- 25910026 TI - Remodeling Characteristics and Collagen Distributions of Biologic Scaffold Materials Biopsied From Postmastectomy Breast Reconstruction Sites. AB - OBJECTIVE: The study purpose was to evaluate the associations between patient characteristics and the histologic remodeling scores of acellular dermal matrices (ADMs) biopsied from breast reconstruction sites in the first attempt to generate a multivariable risk prediction model of nonconstructive remodeling. It was hypothesized that host characteristics and surgical site assessments predict the degree of graft remodeling for ADMs used during breast reconstruction. METHODS: The ADMs were biopsied from the breast reconstruction sites of n = 62 patients during a subsequent breast procedure, stained with hematoxylin-eosin, and evaluated according to a semi-quantitative scoring system for remodeling characteristics (cell types, cell infiltration, extracellular matrix deposition, scaffold degradation, fibrous encapsulation, and neovascularization) and a mean composite score. Biopsies were stained with Sirius Red and Fast Green, and analyzed to determine the collagen I:III ratio. Based on univariate analyses between subject clinical characteristics and the histologic remodeling scores, cohort variables were selected for multivariable regression models using a P value of 0.20 or less. RESULTS: The composite score model yielded 3 variables: pack-year history, corticosteroid use, and radiation timing (r pseudo = 0.81). The model for collagen I yielded 2 variables: corticosteroid use and reason for reoperation (r pseudo = 0.78). The model for collagen III yielded 1 variable: reason for reoperation (r pseudo = 0.35). CONCLUSIONS: These preliminary results constitute the first steps in generating a risk prediction model that predicts the patients and clinical circumstances most likely to experience nonconstructive remodeling of biologic grafts used to reconstruct the breast. PMID- 25910029 TI - PLCG1 Gene Mutations Are Uncommon in Cutaneous T-Cell Lymphomas. PMID- 25910031 TI - Phytase-producing capacity of yeasts isolated from traditional African fermented food products and PHYPk gene expression of Pichia kudriavzevii strains. AB - Phytate is known as a strong chelate of minerals causing their reduced uptake by the human intestine. Ninety-three yeast isolates from traditional African fermented food products, belonging to nine species (Pichia kudriavzevii, Saccharomyces cerevisiae, Clavispora lusitaniae, Kluyveromyces marxianus, Millerozyma farinosa, Candida glabrata, Wickerhamomyces anomalus, Hanseniaspora guilliermondii and Debaryomyces nepalensis) were screened for phytase production on solid and liquid media. 95% were able to grow in the presence of phytate as sole phosphate source, P. kudriavzevii being the best growing species. A phytase coding gene of P. kudriavzevii (PHYPk) was identified and its expression was studied during growth by RT-qPCR. The expression level of PHYPk was significantly higher in phytate-medium, compared to phosphate-medium. In phytate-medium expression was seen in the lag phase. Significant differences in gene expression were detected among the strains as well as between the media. A correlation was found between the PHYPk expression and phytase extracellular activity. PMID- 25910030 TI - Epigenetic Silencing of SPINT2 Promotes Cancer Cell Motility via HGF-MET Pathway Activation in Melanoma. AB - Aberrant HGF-MET (hepatocyte growth factor-met proto-oncogene) signaling activation via interactions with surrounding stromal cells in tumor microenvironment has significant roles in malignant tumor progression. However, extracellular proteolytic regulation of HGF activation, which is influenced by the tumor microenvironment, and its consequential effects on melanoma malignancy remain uncharacterized. In this study, we identified SPINT2 (serine peptidase inhibitor Kunitz type 2), a proteolytic inhibitor of hepatocyte growth factor activator (HGFA), which has a significant role in the suppression of the HGF-MET pathway and malignant melanoma progression. SPINT2 expression is significantly lower in metastatic melanoma tissues compared with those in early-stage primary melanomas, which also corresponded with DNA methylation levels isolated from tissue samples. Treatment with the DNA-hypomethylating agent decitabine in cultured melanoma cells induced transcriptional reactivation of SPINT2, suggesting that this gene is epigenetically silenced in malignant melanomas. Furthermore, we show that ectopically expressed SPINT2 in melanoma cells inhibits the HGF-induced MET-AKT (v-Akt murine thymoma viral oncogene) signaling pathway and decreases malignant phenotype potential such as cell motility and invasive growth of melanoma cells. These results suggest that SPINT2 is associated with tumor-suppressive functions in melanoma by inhibiting an extracellular signal regulator of HGF, which is typically activated by tumor-stromal interactions. These findings indicate that epigenetic impairment of the tightly regulated cytokine-receptor communications in tumor microenvironment may contribute to malignant tumor progression. PMID- 25910033 TI - Frontobiparietal remodeling with or without a widening bridge for sagittal synostosis: comparison of 2 cohorts for aesthetic and functional outcome. AB - OBJECT Various techniques to correct sagittal synostosis have been described. The authors of this study assess the results of 2 techniques for late complete cranial remodeling and test the hypothesis that adding a widening bridge would improve outcome. METHODS In this retrospective study, the authors evaluated patients with nonsyndromic sagittal synostosis-those who underwent frontobiparietal remodeling (FBR) and those who underwent modified FBR (MFBR) involving the introduction of a bony bridge to increase the width of the skull. Outcomes for both groups are described in terms of the aesthetic results assessed on photographs and any changes in the cranial index (CI) and head circumference over time, the presence of papilledema, and complaints of headache. The effect of the surgical technique on CI and head circumference over time was assessed using linear regression analysis, with adjustment for preoperative CI and head circumference. RESULTS Sixty-nine patients with isolated sagittal synostosis were included in this study: 35 underwent MFBR and 34 underwent the original technique of FBR. The mean follow-up period was 7 years. In the 1st year after surgery, mean CI improved by 9% in the FBR group and by 12% in the MFBR group. One year after surgery, CI in the MFBR group was on average 4.7% higher than that in the FBR group (p < 0.001). During follow-up, CI decreased in both groups; however, at all time points CI was significantly higher in the MFBR group than in the FBR group. The impact of surgical technique on CI was less important than the impact of preoperative CI (R(2)= 0.26 vs 0.54), and this applied at all time points during follow-up. Head circumference declined during follow-up in both groups. It was influenced by preoperative head circumference, but not by surgical technique. Aesthetic outcome, prevalence of headache (42%), and papilledema (7%) were comparable in both groups. CONCLUSIONS Adding a widening bridge to late complete remodeling significantly improved CI and helped to prevent CI from decreasing in the long term. This addition did not affect the head circumference growth curve. Despite a mean head circumference remaining at +1 SD, patients continued to develop papilledema postoperatively (7%). PMID- 25910032 TI - Automated Processing of Imaging Data through Multi-tiered Classification of Biological Structures Illustrated Using Caenorhabditis elegans. AB - Quantitative imaging has become a vital technique in biological discovery and clinical diagnostics; a plethora of tools have recently been developed to enable new and accelerated forms of biological investigation. Increasingly, the capacity for high-throughput experimentation provided by new imaging modalities, contrast techniques, microscopy tools, microfluidics and computer controlled systems shifts the experimental bottleneck from the level of physical manipulation and raw data collection to automated recognition and data processing. Yet, despite their broad importance, image analysis solutions to address these needs have been narrowly tailored. Here, we present a generalizable formulation for autonomous identification of specific biological structures that is applicable for many problems. The process flow architecture we present here utilizes standard image processing techniques and the multi-tiered application of classification models such as support vector machines (SVM). These low-level functions are readily available in a large array of image processing software packages and programming languages. Our framework is thus both easy to implement at the modular level and provides specific high-level architecture to guide the solution of more complicated image-processing problems. We demonstrate the utility of the classification routine by developing two specific classifiers as a toolset for automation and cell identification in the model organism Caenorhabditis elegans. To serve a common need for automated high-resolution imaging and behavior applications in the C. elegans research community, we contribute a ready-to-use classifier for the identification of the head of the animal under bright field imaging. Furthermore, we extend our framework to address the pervasive problem of cell-specific identification under fluorescent imaging, which is critical for biological investigation in multicellular organisms or tissues. Using these examples as a guide, we envision the broad utility of the framework for diverse problems across different length scales and imaging methods. PMID- 25910034 TI - The role of percutaneous embolization techniques in the management of dural sinus malformations with atypical angioarchitecture in neonates: report of 2 cases. AB - Dural sinus malformations (DSMs) are rare congenital malformations that can be midline or lateral in location. Midline DSMs have been reported to have a worse prognosis than lateral DSMs and have traditionally been more difficult to manage. The authors report 2 unusual manifestations of midline DSMs and their management with percutaneous transfontanelle embolization. The first patient (Case 1) presented at 21 days of life with a large midline DSM and multiple highflow dural and pial arteriovenous shunts. The child developed congestive cardiac failure and venous congestion with intracranial hemorrhage and seizures within a few weeks. The second patient (Case 2) presented with a large midline DSM found on prenatal imaging that was determined to be a purely venous malformation on postnatal evaluation. This large malformation resulted in consumptive coagulopathy and apneic episodes from brainstem compression. The patient in Case 1 was treated initially with endovascular embolization and eventually with curative percutaneous-transfontanelle embolization. The patient in Case 2 was treated with percutaneous transfontanelle embolization in combination with posterior fossa decompression and cranial expansion surgery. PMID- 25910035 TI - Repeat resective surgery in complex pediatric refractory epilepsy: lessons learned. AB - OBJECT Resection can sometimes offer the best chance of meaningful seizure reduction in children with medically intractable epilepsy. However, when surgery fails to achieve the desired outcome, reoperation may be an option. The authors sought to investigate outcomes following resective reoperation in pediatric patients with refractory epilepsy, excluding tumoral epilepsies. Differences in preoperative workup between surgeries are analyzed to identify factors influencing outcomes and complications in this complex group. METHODS Medical records were reviewed for all pediatric patients undergoing a repeat resective surgery for refractory epilepsy at the authors' institution between 2005 and 2012. Tumor and vascular etiologies were excluded. Preoperative evaluation and outcomes were analyzed for each surgery and compared. RESULTS Ten patients met all inclusion criteria. The median age at seizure onset was 4.5 months. Preoperative MRI revealed no lesion in 30%. Nonspecific gliosis and cortical dysplasia were the most common pathologies. The majority of preoperative workups included MRI, video-electroencephalography (EEG), and SISCOM. Intracranial EEG was performed for 60% for the first presurgical evaluation and 70% for the second evaluation. The goal of surgery was palliative in 4 patients with widespread cortical dysplasia. The final Engel outcome was Class I in 50%. The rate of favorable outcome (Engel Class I-II) was 70%. The complication rate for the initial surgery was 10%. However, the rate increased to 50% with the second surgery, and 3 of these 5 complications were pseudomeningoceles requiring shunt placement (2 of the 3 patients underwent hemispherotomy). CONCLUSIONS Resective reoperation for pediatric refractory epilepsy has a high rate of favorable outcome and should be considered in appropriate candidates, even as a palliative measure. Intracranial EEG monitoring should be considered on initial workup in cases where the results of imaging or EEG studies are ambiguous or conflicting. Epilepsy secondary to cortical dysplasia, especially if the dysplasia is not seen clearly on MRI, can be difficult to cure surgically. Therefore, in these cases, as large a resection as can be safely accomplished should be done, particularly when the goal is palliative. The rate of complications, particularly pseudomeningocele ultimately requiring shunt placement, is much higher following reoperation, and patients should be counseled accordingly. PMID- 25910036 TI - Endoscopic monoportal removal of a choroid plexus papilloma in the posterior third ventricle in a child. AB - Currently, only a few reports describe the minimally invasive removal of choroid plexus papillomas (CPPs) and, to the best of the authors' knowledge, no reports detail the resection of such a papilloma through an endoscopic approach in infants. The authors here describe the endoscopic removal of a third ventricle CPP in a child. A 5-month-old male infant presented with progressive macrocephaly, vomiting, and convulsions. A lesion in the posterior third ventricle was detected on brain MRI. Because of the patient's very young age, neuroendoscopy was used as the least invasive technique. The tumor was completely resected through a monoportal neuroendoscopic approach. Histologically, the tumor was classified as a WHO Grade I CPP. After surgery, the patient's condition improved, with no complications during his recovery. Ten-month follow-up neuroimaging revealed no evidence of tumor recurrence or progressive hydrocephaly. In view of the successful neuroendoscopic excision of this posterior third ventricle CPP, the authors believe that this method seems promising in the treatment of young children with intraventricular lesions. PMID- 25910037 TI - N-Alkylfluorenyl-substituted N-heterocyclic carbenes as bimodal pincers. AB - Two N-heterocyclic carbene precursors having their nitrogen atoms substituted by the expanded 9-ethyl-9-fluorenyl group, namely imidazolinium chloride 6 and imidazolium chloride 7, have been synthesized in high yields from fluorenone (1). The key intermediate of their syntheses is the new primary amine 9-ethyl-9 fluorenylamine (3), which was prepared in 75% yield. Both salts were readily converted into the corresponding PEPPSI-type palladium complexes, 8 and 9 (PEPPSI: pyridine-enhanced precatalyst preparation stabilisation and initiation). Despite rotational freedom of the ethylfluorenyl moieties about the N C(fluorenyl) bond in their cationic precursors, the carbene ligands of the Pd(II) complexes 8 and 9 both behave as bimodal pincers in solution and in the solid state, the resulting confinement being essentially due to (weak) attractive anagostic interactions between the CH2(fluorenyl) groups and the metal centre. Unlike in 8 and 9, there was no indication for similar anagostic interactions in the imidazolylidene chlorosilver complex 11, which could be obtained from 7. In the solid state, however, 11 adopts a remarkable "open sandwich" structure, with the two alkylfluorenilidene planes eta2-bonded to the silver, this constituting a further bimodal pincer-type bonding mode of this ligand class. Complexes 8 and 9 were assessed in Suzuki-Miyaura cross-coupling reactions. The imidazolylidene complex 9 displayed high activity towards unencumbered aryl chlorides. Its activity is comparable to that of the previously reported, highly efficient benzimidazolylidene analogue 10. PMID- 25910038 TI - Influence of coffee genotype on bioactive compounds and the in vitro capacity to scavenge reactive oxygen and nitrogen species. AB - The influence of green coffee genotype on the bioactive compounds and the in vitro antioxidant capacity against the principal reactive oxygen (ROO(*), H2O2, HO(*), and HOCl) and nitrogen (NO(*) and ONOO(-)) species of biological relevance was investigated. This is the first report on the capacity of green coffee to scavenge H2O2, HOCl, and NO(*). Variations in the contents of total chlorogenic acids (22.9-37.9 g/100 g), cinnamoyl-amino acid conjugates (0.03-1.12 g/100 g), trigonelline (3.1-6.7 g/100 g), and caffeine (3.9-11.8 g/100 g) were found. Hydrophilic extracts of Coffea canephora and Coffea kapakata were the most potent scavengers of ROO(*), H2O2, HO(*), NO(*), and ONOO(-) due to their chlorogenic acid contents, which were, on average, 30% higher than those found in Coffea arabica and Coffea racemosa. The results showed that genotype is a determinant characteristic in the bioactive compound contents and consequently in the antioxidant capacity of green coffee. PMID- 25910040 TI - Robust modeling of differential gene expression data using normal/independent distributions: a Bayesian approach. AB - In this paper, the problem of identifying differentially expressed genes under different conditions using gene expression microarray data, in the presence of outliers, is discussed. For this purpose, the robust modeling of gene expression data using some powerful distributions known as normal/independent distributions is considered. These distributions include the Student's t and normal distributions which have been used previously, but also include extensions such as the slash, the contaminated normal and the Laplace distributions. The purpose of this paper is to identify differentially expressed genes by considering these distributional assumptions instead of the normal distribution. A Bayesian approach using the Markov Chain Monte Carlo method is adopted for parameter estimation. Two publicly available gene expression data sets are analyzed using the proposed approach. The use of the robust models for detecting differentially expressed genes is investigated. This investigation shows that the choice of model for differentiating gene expression data is very important. This is due to the small number of replicates for each gene and the existence of outlying data. Comparison of the performance of these models is made using different statistical criteria and the ROC curve. The method is illustrated using some simulation studies. We demonstrate the flexibility of these robust models in identifying differentially expressed genes. PMID- 25910039 TI - Differential Gene Expression Profile in the Rat Caudal Vestibular Nucleus is Associated with Individual Differences in Motion Sickness Susceptibility. AB - OBJECTIVE: To identify differentially expressed genes associated with motion sickness (MS) susceptibility in the rat caudal vestibular nucleus. METHODS: We identified MS susceptible (MSS) and insusceptible (inMSS) rats by quantifying rotation-induced MS symptoms: defecation and spontaneous locomotion activity. Microarray analysis was used to screen differentially expressed genes in the caudal vestibular nucleus (CVN) after rotation. Plasma stress hormones were identified by radioimmunoassay. Candidate genes were selected by bioinformatics analysis and the microarray results were verified by real-time quantitative-PCR (RT-qPCR) methods. By using Elvax implantation, receptor antagonists or recombinant adenovirus targeting the candidate genes were applied to the CVN to evaluate their contribution to MS susceptibility variability. Validity of gene expression manipulation was verified by RT-qPCR and western blot analysis. RESULTS: A total of 304 transcripts were differentially expressed in the MSS group compared with the inMSS group. RT-qPCR analysis verified the expression pattern of candidate genes, including nicotinic cholinergic receptor (nAchR) alpha3 subunit, 5-hydroxytryptamine receptor 4 (5-HT4R), tachykinin neurokinin-1 (NK1R), gamma-aminobutyric acid A receptor (GABAAR) alpha6 subunit, olfactory receptor 81 (Olr81) and homology 2 domain-containing transforming protein 1 (Shc1). In MSS animals, the nAchR antagonist mecamylamine significantly alleviated rotation-induced MS symptoms and the plasma beta-endorphin response. The NK1R antagonist CP99994 and Olr81 knock-down were effective for the defecation response, while the 5-HT4R antagonist RS39604 and Shc1 over-expression showed no therapeutic effect. In inMSS animals, rotation-induced changes in spontaneous locomotion activity and the plasma beta-endorphin level occurred in the presence of the GABAAR antagonist gabazine. CONCLUSION: Our findings suggested that the variability of the CVN gene expression profile after motion stimulation might be a putative molecular basis for individual differences in MS susceptibility and provide information for the development of new therapeutic strategies for MSS individuals. PMID- 25910042 TI - Development of montelukast sodium loaded niosomal carriers by film hydration technique. AB - The aim of this study was to develop and characterize montelukast sodium loaded niosomal drug carrier systems. The vesicles were prepared by film hydration technique using different surfactants. The optimized formulation was selected on the basis of results obtained from drug entrapment, morphology and in vitro drug release studies, and further evaluated for possible drug-excipient interaction, thermal behavior and drug physical state, before and after formulation using Fourier transform infrared spectroscopy, differential scanning calorimetry and X ray diffraction analysis methods, respectively. The morphological characterization of vesicles was done using Transmission electron microscopy. Energy-dispersive X-ray spectroscopy system was used for elemental and dimensional analysis of developed vesicles. The vesicle surface charge was determined using zeta potential measurements. The results suggested that the optimized formulation had small size (103+/-6.01 nm) and high drug entrapment (72.20+/-2.10%). No chemical interaction was observed between the drug and excipients. The study revealed that Span 60 is a good nonionic surfactant for vesicle formulation. After 3 months storage at 2-8 degrees C, the optimized formulation preserved stability in terms of formulation colour, drug amount and percent drug release. After 3 months, flocculation occured and hard cake was not formed on the settlement of vesicles. The preliminary results of this study suggest that the designed vesicles could enhance drug entrapment, reduce the initial burst release of drug and modulate the drug release. PMID- 25910041 TI - Carbapenem non-susceptible enterobacteriaceae in Quebec, Canada: results of a laboratory surveillance program (2010-2012). AB - The emergence and spread of carbapenemase-producing Enterobacteriaceae (CPE) represent a major public health concern because these bacteria are usually extensively resistant to most antibiotics. In order to evaluate their dissemination in Quebec, a surveillance program was introduced in 2010. We report the molecular and epidemiological profiles of CPE isolates collected. Between August 2010 and December 2012, a total of 742 non-duplicate isolates non susceptible to carbapenems were analysed. AmpC beta-lactamase and metallo-beta lactamase production were detected by Etest and carbapenemase production by the modified Hodge test (MHT). Antibiotic susceptibility profiles were determined using broth microdilution or Etest. Clonality of Klebsiella pneumoniae carbapenemase (KPC) strains was analyzed by pulsed-field gel electrophoresis (PFGE). The presence of genes encoding carbapenemases as well as other beta lactamases was detected using PCR. Of the 742 isolates tested, 169 (22.8%) were CPE. Of these 169 isolates, 151 (89.3%) harboured a blaKPC gene while the remaining isolates carried blaSME (n = 9), blaOXA-48 (n = 5), blaNDM (n = 3), and blaNMC (n = 1) genes. Among the 93 KPC strains presenting with a unique pattern (unique PFGE pattern and/or unique antibiotics susceptibility profile), 99% were resistant to ertapenem, 95% to imipenem, 87% to meropenem, 97% to aztreonam, 31% to colistin and 2% to tigecycline. In 19 patients, 2 to 5 KPC strains from different species or with a different PFGE pattern were isolated. CPE strains were present in the province of Quebec with the majority of strains harbouring KPC. Alternately, SME, OXA-48 and NMC containing strains were rarely found. PMID- 25910043 TI - A Longitudinal Investigation of the Relationship between Posttraumatic Stress Symptoms and Posttraumatic Growth in a Cohort of Israeli Jews and Palestinians during Ongoing Violence. AB - OBJECTIVES: Meta-analytic evidence based on cross-sectional investigations between posttraumatic growth (PTG) and posttraumatic stress disorder (PTSD) demonstrates that the two concepts are positively related and that ethnic minorities report greater PTG. Few longitudinal studies have quantified this relationship so the evidence is limited regarding the potential benefit PTG may have on post-traumatic adjustment and whether differences between ethnic groups exist. METHODS: The current study attempts to fill a substantial gap in the literature by exploring the relationship between PTG and PTSD symptom clusters longitudinally using a nationally representative cohort of 1613 Israelis and Palestinian Citizens of Israel (PCI) interviewed via telephone on three measurement occasions during one year. Latent cross-lagged structural models estimated the relationship between PTG and each PTSD symptom cluster, derived from confirmatory factor analysis, representing latent and statistically invariant PTSD symptom factors, best representing PTSD for both ethnic groups. RESULTS: PTG was not associated with less PTSD symptom severity in any of the four PTSD clusters, for Jews and PCI. In contrast, PTSD symptom severity assessed earlier was related to later reported PTG in both groups. CONCLUSIONS: This study demonstrates that PTSD symptoms contribute to greater reported PTG, but that PTG does not provide a salutatory benefit by reducing symptoms of PTSD. PMID- 25910044 TI - Intake of Vitamin C, beta-Carotene, and Polyphenolic Compounds by Children and Adolescents from Orphanages. AB - OBJECTIVE: The objective of this study was analytical assessment of the concentration of selected antioxidants as well as total antioxidant capacity of daily diets of children and adolescents from orphanages in Krakow (Poland). METHODS: Daily diets of children and adolescents were collected in 4 seasons of the year from 7 orphanages located in Krakow. The concentrations of vitamin C, beta-carotene, polyphenolic compounds, and antioxidant capacity were measured. RESULTS: The lowest content of vitamin C in diets of children and adolescents was measured in diets collected in autumn. The estimated average requirement (EAR) was in the range 49.0%-76.4%. In winter the content of this compound was significantly higher in daily diets (113.9%-192.0% coverage of EAR) compared to the level of this nutrient in daily diets from other seasons. The content of beta carotene, lower than 50% of EAR value, calculated as the vitamin A equivalent, has been demonstrated in 4 orphanages in summer and in one in spring and autumn. The highest mean content of this antioxidant in daily diets was found in winter, when beta-carotene intake met recommendations in the range 131%-368%. The mean concentration of polyphenolic compounds per year was in the range 301.5-537.5 mg/person/day. It has been observed that diets during the winter and autumn generally provide higher amounts of polyphenols than in other seasons. The highest antioxidant activity was measured in diets collected during the winter season. CONCLUSIONS: The results indicate that the diets of children and adolescents should contain more fresh vegetables and fruits, which are good source of natural antioxidants. PMID- 25910045 TI - Simultaneous determination of doxorubicin and curcumin in rat plasma by LC-MS/MS and its application to pharmacokinetic study. AB - A specific, sensitive and rapid liquid chromatography tandem mass spectrometry (LC-MS/MS) method has been developed and validated for simultaneous quantification of doxorubicin and curcumin in rat plasma after intravenous administration. The analytes of doxorubicin and curcumin were extracted with methanol precipitation using glibenclamide as internal standard (IS). The chromatographic separation was performed on a C18 column with acetonitrile and 0.1% formic acid water as mobile phase and with gradient elution at a flow rate of 0.2 mL/min. Calibration curves were linear over the ranges of 2-8000 ng/mL for doxorubicin and 5-2000 ng/mL for curcumin (r > 0.99). The lower limit of quantification (LLOQ) was 2 ng/mL for DOX and 5 ng/mL for Cur. Finally, this developed method was successfully applied in the pharmacokinetic study of doxorubicin and curcumin in rats and evaluated the effects of curcumin on the absorption of doxorubicin after intravenous administration. PMID- 25910046 TI - Catechin inhibition of influenza neuraminidase and its molecular basis with mass spectrometry. AB - The molecular basis for the antiviral inhibitory properties of three catechins epigallocatechin gallate, epicatechin gallate and catechin-5-gallate derived from green tea was assessed in terms of their ability to interact with influenza neuraminidase. This was investigated using a molecular based MALDI mass spectrometry approach in conjunction with companion inhibition assays employing confocal microscopy. Together with computational molecular docking, all three catechins were found to bind to influenza neuraminidase in the vicinity of a structurally conserved cavity adjacent to residue 430 that has been suggested to be a secondary sialic acid binding site. In doing so, they were effective inhibitors of the enzyme preventing the release of progeny viruses from host cells at inhibitor concentrations (IC50 values) of between 100 and 173 MUM. Importantly, their different binding profiles avoid the limitations of existing neuraminidase inhibitors manifested by the evolution of antiviral resistance strains. PMID- 25910047 TI - HPLC-UV/DAD and ESI-MS(n) analysis of flavonoids and antioxidant activity of an Algerian medicinal plant: Paronychia argentea Lam. AB - Paronychia argentea Lam., belonging to the Caryophyllaceae family, is a perennial plant widely distributed in Algeria. Even though this plant is used in the Algerian popular medicine, its phytochemical characterization is incomplete. In this study, the flavonoid profile and the in vitro antioxidant activity of the ethanolic extract, decoction and infusion of P. argentea aerial parts are reported. Flavonoids were analyzed by means of high-performance liquid chromatography coupled with diode array detection and electrospray ionization mass spectrometry. Eleven compounds were identified and six of them, including isorhamnetin-3-O-dihexoside, quercetin-3-O-glucoside, quercetinmethylether-O hexoside, quercetin, jaceosidin and isorhamnetin, were described in this plant for the first time. The ethanol extract showed the highest flavonoid content, followed by the decoction and the infusion (25.4 +/- 0.8 mg/g of DM, 8.4 +/- 0.5 mg/g of DM, 0.2 mg/g of DM, respectively), while the best antioxidant activity was shown by the decoction (RC0.5 = 178 MUg/mL for reducing power, 72.4% of inhibition of lipid peroxidation, IC50 = 27.38MU g/mL for DPPH radical scavenging activity and 59.7% of inhibition of NO radical). These results showed that P. argentea decoction could be considered as a valuable source of flavonoids and antioxidants that might contribute to the valorization of the phytotherapeutic potential of this plant. PMID- 25910048 TI - Preparation, characterization and application of molecularly imprinted monolithic column for hesperetin. AB - The molecularly imprinted solid-phase extraction (MISPE) monolithic column coupled with high-performance liquid chromatography (HPLC) was firstly developed for the extraction of hesperetin in the flesh of Citrus reticulata cv. Chachiensis, which is a traditional Chinese medicine (TCM). The molecularly imprinted polymers (MIPs) have been prepared by a thermal polymerization method using hesperetin as the template, acrylamide (AM) as functional monomer and ethylene glycol dimethacrylamide (EGDMA) as cross-linker in the mixed porogen of methanol, toluene and dodecanol. The prepared MIPs were characterized in detail by SEM and FTIR. The results confirmed the uniform and open structure of network skeleton with large flow-through pores. The influence of synthesis conditions on the specific recognition properties of hesperetin MIPs were also investigated systematically. The results showed that high adsorption capacity and good selectivity of MIPs were achieved when using non-imprinted polymer monolith (NIP) and structure similarly compound rutin as references. Furthermore, several parameters of the MISPE method have been optimized, and then it was successfully applied to the extraction of hesperetin from the flesh of Citrus reticulata cv. Chachiensis. Good gathering and impurity removing ability of prepared MIP were demonstrated. The MISPE method was proven to be a potentially competitive technique for separation and cleanup of hesperetin in complex TCM with satisfied recovery (90.8 +/- 3.2%) and good precision (RSD = 6.48%). PMID- 25910049 TI - Insulin-Like Growth Factor-Independent Effects of Growth Hormone on Growth Plate Chondrogenesis and Longitudinal Bone Growth. AB - GH stimulates growth plate chondrogenesis and longitudinal bone growth directly at the growth plate. However, it is not clear yet whether these effects are entirely mediated by the local expression and action of IGF-1 and IGF-2. To determine whether GH has any IGF-independent growth-promoting effects, we generated (TamCart)Igf1r(flox/flox) mice. The systemic injection of tamoxifen in these mice postnatally resulted in the excision of the IGF-1 receptor (Igf1r) gene exclusively in the growth plate. (TamCart)Igf1r(flox/flox) tamoxifen-treated mice [knockout (KO) mice] and their Igf1r(flox/flox) control littermates (C mice) were injected for 4 weeks with GH. At the end of the 4-week period, the tibial growth and growth plate height of GH-treated KO mice were greater than those of untreated C or untreated KO mice. The systemic injection of GH increased the phosphorylation of Janus kinase 2 and signal transducer and activator of transcription 5B in the tibial growth plate of the C and KO mice. In addition, GH increased the mRNA expression of bone morphogenetic protein-2 and the mRNA expression and protein phosphorylation of nuclear factor-kappaB p65 in both C and KO mice. In cultured chondrocytes transfected with Igf1r small interfering RNA, the addition of GH in the culture medium significantly induced thymidine incorporation and collagen X mRNA expression. In conclusion, our findings demonstrate that GH can promote growth plate chondrogenesis and longitudinal bone growth directly at the growth plate, even when the local effects of IGF-1 and IGF 2 are prevented. Further studies are warranted to elucidate the intracellular molecular mechanisms mediating the IGF-independent, growth-promoting GH effects. PMID- 25910050 TI - A Nonradioactive Uptake Assay for Rapid Analysis of Thyroid Hormone Transporter Function. AB - Thyroid hormones (TH) are actively taken up into target cells via TH transmembrane transporters (THTT). Their activity and expression patterns define a layer of endocrine regulation that is poorly understood. Therefore, THTT are potential targets for interfering agents (endocrine disruptors) as well as for pharmacological interventions. Inactivating mutations have been identified as the underlying cause of heritable diseases (monocarboxylate transporter 8-associated Allan-Herndon-Dudley syndrome) and might also define a class of subclinical TH insensitivity. As a basic tool to solve questions regarding THTT substrate specificity, activation or inactivation by compounds and functional changes from mutations, uptake assays with radiolabeled tracers are standard. Due to the need for radioactive isotopes, this technique is limited to screening of labelled substrates and disadvantageous regarding handling, setup, and regulatory issues. To overcome these hurdles, we developed an uptake assay protocol using nonradioactive ligands. In brief, uptake of nonradioactive iodine-containing substrate molecules was monitored via Sandell-Kolthoff reaction. The novel assay was designed to the common microtiter plate layout. As a prove-of-principle, we measured TH uptake by monocarboxylate transporter 8-transfected MDCK1 cells. Titrations with bromosulphthalein as an example for inhibitor screening setups and a side-by-side comparison with the radioactive method prove this assay to be reliable, sensitive, and convenient. Furthermore, the method was applicable on primary murine astrocytes, which enables high-throughput screening studies on in vitro model systems with physiological transporter regulation. Due to its design, it is applicable for high-throughput screening of modulatory compounds, but it is also a safe, inexpensive and an easily accessible method for functional testing of THTT in basic science. PMID- 25910051 TI - Criterion Validity of Competing Accelerometry-Based Activity Monitoring Devices. AB - PURPOSE: The purpose of this study was to examine the comparative and criterion validity of the three activity monitors in relation to a portable metabolic analyzer (Oxycon Mobile (OM)) in adults. METHODS: A total of 52 adults age 18-40 yr each performed a series of 15 activities for 5 min each, with 1-min resting intervals between different activities. Participants completed the trials while wearing the three activity monitors and while being measured with the OM. Estimates of energy expenditure (EE) were obtained from the ActiGraph (one based on the vertical axis and the other from vector magnitude) as well as from the activPAL (AP) and the Core Armband (CA). The EE estimates were converted into MET(RMR) values by standardizing EE values with each person's resting metabolic rate and then temporarily matched to facilitate minute-by-minute comparisons. Equivalence testing and mean absolute percent errors (MAPE) were used to evaluate the agreement. RESULTS: MET(RMR) values from the CA were significantly equivalent to those from the OM for the overall group comparison (90% confidence interval (CI), 3.65 and 3.85 MET(RMR)) and vigorous intensity (90% CI, 8.27 and 10.10 MET(RMR)). The CA had the smallest MAPE for moderate (20.7%) and vigorous (14.5%) intensity, but the AP had smaller MAPE for sedentary activities (27.4%) and light (24.7%) intensity activities. CONCLUSIONS: The CA showed good agreement relative to the OM for the overall group comparison and for moderate and vigorous activities. The AP, in contrast, was the most accurate for sedentary and light activities. The combined use of the CA and AP may yield more accurate estimates of EE than using a single monitor. PMID- 25910052 TI - Optimizing Cold Water Immersion for Exercise-Induced Hyperthermia: A Meta analysis. AB - PURPOSE: Cold water immersion (CWI) provides rapid cooling in events of exertional heat stroke. Optimal procedures for CWI in the field are not well established. This meta-analysis aimed to provide structured analysis of the effectiveness of CWI on the cooling rate in healthy adults subjected to exercise induced hyperthermia. METHODS: An electronic search (December 2014) was conducted using the PubMed and Web of Science. The mean difference of the cooling rate between CWI and passive recovery was calculated. Pooled analyses were based on a random-effects model. Sources of heterogeneity were identified through a mixed effects model Q statistic. Inferential statistics aggregated the CWI cooling rate for extrapolation. RESULTS: Nineteen studies qualified for inclusion. Results demonstrate CWI elicited a significant effect: mean difference, 0.03 degrees C.min(-1); 95% confidence interval, 0.03-0.04 degrees C.min(-1). A conservative, observed estimate of the CWI cooling rate was 0.08 degrees C.min(-1) across various conditions. CWI cooled individuals twice as fast as passive recovery. Subgroup analyses revealed that cooling was more effective (Q test P < 0.10) when preimmersion core temperature >=38.6 degrees C, immersion water temperature <=10 degrees C, ambient temperature >=20 degrees C, immersion duration <=10 min, and using torso plus limbs immersion. There is insufficient evidence of effect using forearms/hands CWI for rapid cooling: mean difference, 0.01 degrees C.min(-1); 95% confidence interval, -0.01 degrees C.min(-1) to 0.04 degrees C.min(-1). A combined data summary, pertaining to 607 subjects from 29 relevant studies, was presented for referencing the weighted cooling rate and recovery time, aiming for practitioners to better plan emergency procedures. CONCLUSIONS: An optimal procedure for yielding high cooling rates is proposed. Using prompt vigorous CWI should be encouraged for treating exercise-induced hyperthermia whenever possible, using cold water temperature (approximately 10 degrees C) and maximizing body surface contact (whole-body immersion). PMID- 25910053 TI - Ligand-Controlled Regioselective Copper-Catalyzed Trifluoromethylation To Generate (Trifluoromethyl)allenes. AB - "Cu-CF3" species have been used historically for a broad spectrum of nucleophilic trifluoromethylation reactions. Although recent advancements have employed ligands to stabilize and harness the reactivity of this key organometallic intermediate, the ability of a ligand to differentiate a regiochemical outcome of a Cu-CF3-mediated or -catalyzed reaction has not been previously reported. Herein, we report the first example of a Cu-catalyzed trifluoromethylation reaction in which a ligand controls the regiochemical outcome. More specifically, we demonstrate the ability of bipyridyl-derived ligands to control the regioselectivity of the Cu-catalyzed nucleophilic trifluoromethylation reactions of propargyl electrophiles to generate (trifluoromethyl)allenes. This method provides a variety of di-, tri-, and tetrasubstituted (trifluoromethyl)allenes, which can be further modified to generate complex fluorinated substructures. PMID- 25910056 TI - Description and characterization of a novel method for partial volume simulation in software breast phantoms. AB - A modification to our previous simulation of breast anatomy is proposed to improve the quality of simulated x-ray projections images. The image quality is affected by the voxel size of the simulation. Large voxels can cause notable spatial quantization artifacts; small voxels extend the generation time and increase the memory requirements. An improvement in image quality is achievable without reducing voxel size by the simulation of partial volume averaging in which voxels containing more than one simulated tissue type are allowed. The linear x-ray attenuation coefficient of voxels is, thus, the sum of the linear attenuation coefficients weighted by the voxel subvolume occupied by each tissue type. A local planar approximation of the boundary surface is employed. In the two-material case, the partial volume in each voxel is computed by decomposition into up to four simple geometric shapes. In the three-material case, by application of the Gauss-Ostrogradsky theorem, the 3D partial volume problem is converted into one of a few simpler 2D surface area problems. We illustrate the benefits of the proposed methodology on simulated x-ray projections. An efficient encoding scheme is proposed for the type and proportion of simulated tissues in each voxel. Monte Carlo simulation was used to evaluate the quantitative error of our approximation algorithms. PMID- 25910055 TI - Probable nature of higher-dimensional symmetries underlying mammalian grid-cell activity patterns. AB - Lattices abound in nature-from the crystal structure of minerals to the honey comb organization of ommatidia in the compound eye of insects. These arrangements provide solutions for optimal packings, efficient resource distribution, and cryptographic protocols. Do lattices also play a role in how the brain represents information? We focus on higher-dimensional stimulus domains, with particular emphasis on neural representations of physical space, and derive which neuronal lattice codes maximize spatial resolution. For mammals navigating on a surface, we show that the hexagonal activity patterns of grid cells are optimal. For species that move freely in three dimensions, a face-centered cubic lattice is best. This prediction could be tested experimentally in flying bats, arboreal monkeys, or marine mammals. More generally, our theory suggests that the brain encodes higher-dimensional sensory or cognitive variables with populations of grid-cell-like neurons whose activity patterns exhibit lattice structures at multiple, nested scales. PMID- 25910057 TI - Multiple LREK active contours for knee meniscus ultrasound image segmentation. AB - Quantification of knee meniscus degeneration and displacement in an ultrasound image requires simultaneous segmentation of femoral condyle, meniscus, and tibial plateau in order to determine the area and the position of the meniscus. In this paper, we present an active contour for image segmentation that uses scalable local regional information on expandable kernel (LREK). It includes using a strategy to adapt the size of a local window in order to avoid being confined locally in a homogeneous region during the segmentation process. We also provide a multiple active contours framework called multiple LREK (MLREK) to deal with multiple object segmentation without merging and overlapping between the neighboring contours in the shared boundaries of separate regions. We compare its performance to other existing active contour models and show an improvement offered by our model. We then investigate the choice of various parameters in the proposed framework in response to the segmentation outcome. Dice coefficient and Hausdorff distance measures over a set of real knee meniscus ultrasound images indicate a potential application of MLREK for assessment of knee meniscus degeneration and displacement. PMID- 25910054 TI - C-terminal threonines and serines play distinct roles in the desensitization of rhodopsin, a G protein-coupled receptor. AB - Rod photoreceptors generate measurable responses to single-photon activation of individual molecules of the G protein-coupled receptor (GPCR), rhodopsin. Timely rhodopsin desensitization depends on phosphorylation and arrestin binding, which quenches G protein activation. Rhodopsin phosphorylation has been measured biochemically at C-terminal serine residues, suggesting that these residues are critical for producing fast, low-noise responses. The role of native threonine residues is unclear. We compared single-photon responses from rhodopsin lacking native serine or threonine phosphorylation sites. Contrary to expectation, serine only rhodopsin generated prolonged step-like single-photon responses that terminated abruptly and randomly, whereas threonine-only rhodopsin generated responses that were only modestly slower than normal. We show that the step-like responses of serine-only rhodopsin reflect slow and stochastic arrestin binding. Thus, threonine sites play a privileged role in promoting timely arrestin binding and rhodopsin desensitization. Similar coordination of phosphorylation and arrestin binding may more generally permit tight control of the duration of GPCR activity. PMID- 25910058 TI - A higher-order tensor vessel tractography for segmentation of vascular structures. AB - A new vascular structure segmentation method, which is based on a cylindrical flux-based higher order tensor (HOT), is presented. On a vessel structure, the HOT naturally models branching points, which create challenges for vessel segmentation algorithms. In a general linear HOT model embedded in 3D, one has to work with an even order tensor due to an enforced antipodal-symmetry on the unit sphere. However, in scenarios such as in a bifurcation, the antipodally-symmetric tensor embedded in 3D will not be useful. In order to overcome that limitation, we embed the tensor in 4D and obtain a structure that can model asymmetric junction scenarios. During construction of a higher order tensor (e.g. third or fourth order) in 4D, the orientation vectors lie on the unit 3-sphere, in contrast to the unit 2-sphere in 3D tensor modeling. This 4D tensor is exploited in a seed-based vessel segmentation algorithm, where the principal directions of the 4D HOT is obtained by decomposition, and used in a HOT tractography approach. We demonstrate quantitative validation of the proposed algorithm on both synthetic complex tubular structures as well as real cerebral vasculature in Magnetic Resonance Angiography (MRA) datasets and coronary arteries from Computed Tomography Angiography (CTA) volumes. PMID- 25910060 TI - Life Cycle Thinking, Measurement and Management for Food System Sustainability. AB - Food systems critically contribute to our collective sustainability outcomes. Improving food system sustainability requires life cycle thinking, measurement and management strategies. This article reviews the status quo and future prospects for bringing life cycle approaches to food system sustainability to the fore. PMID- 25910059 TI - The Development and Evaluation of a Loop-Mediated Isothermal Amplification Method for the Rapid Detection of Salmonella enterica serovar Typhi. AB - Typhoid fever remains a public health threat in many countries. A positive result in traditional culture is a gold-standard for typhoid diagnosis, but this method is time consuming and not sensitive enough for detection of samples containing a low copy number of the target organism. The availability of the loop-mediated isothermal amplification (LAMP) assay, which offers high speed and simplicity in detection of specific targets, has vastly improved the diagnosis of numerous infectious diseases. However, little research efforts have been made on utilizing this approach for diagnosis of Salmonella enterica serovar Typhi by targeting a single and specific gene. In this study, a LAMP assay for rapid detection of S. Typhi based on a novel marker gene, termed STY2879-LAMP, was established and evaluated with real-time PCR (RT-PCR). The specificity tests showed that STY2879 could be amplified in all S. Typhi strains isolated in different years and regions in China, whereas no amplification was observable in non-typhoidal strains covering 34 Salmonella serotypes and other pathogens causing febrile illness. The detection limit of STY2879-LAMP for S. Typhi was 15 copies/reaction in reference plasmids, 200 CFU/g with simple heat-treatment of DNA extracted from simulated stool samples and 20 CFU/ml with DNA extracted from simulated blood samples, which was 10 fold more sensitive than the parallel RT-PCR control experiment. Furthermore, the sensitivity of STY2879-LAMP and RT-PCR combining the traditional culture enrichment method for simulated stool and blood spiked with lower S. Typhi count during the 10 h enrichment time was also determined. In comparison with LAMP, the positive reaction time for RT-PCR required additional 2 3 h enrichment time for either simulated stool or blood specimens. Therefore, STY2879-LAMP is of practical value in the clinical settings and has a good potential for application in developing regions due to its easy-to-use protocol. PMID- 25910062 TI - Development of a novel endoscopic manipulation system: the Endoscopic Operation Robot ver.3. AB - BACKGROUND AND AIMS: The next generation of flexible endoscopy platforms such as The Master and Slave Transluminal Endoscopic Robot (MASTER) is primarily for remote control manipulation of forceps, but manipulation of the flexible endoscope itself still depends on conventional techniques. We have developed the Endoscopic Operation Robot (EOR) ver.3, which incorporates haptic feedback to provide complete remote control flexible-endoscope manipulation. The present study aimed to evaluate the performance of the EOR ver.3. METHOD: A colonoscopy training model was used with scope insertion to the cecum. Force during insertion and insertion time (seconds) to the cecum were evaluated. The data were compared by colon zone and experience level (trainee or expert). RESULTS: The mean insertion time into the cecum was 118.54 +/- 89.42 seconds. Stronger force and torque were required for deeper insertion of the scope. Expert and trainee endoscopists differed in the insertion time to the cecum, maximum counterclockwise torque, mean clockwise torque, and mean counterclockwise torque. CONCLUSION: The EOR ver.3 has operability with which endoscopists can easily familiarize themselves. PMID- 25910061 TI - Ensemble Empirical Mode Decomposition Analysis of EEG Data Collected during a Contour Integration Task. AB - We discuss a data-driven analysis of EEG data recorded during a combined EEG/fMRI study of visual processing during a contour integration task. The analysis is based on an ensemble empirical mode decomposition (EEMD) and discusses characteristic features of event related modes (ERMs) resulting from the decomposition. We identify clear differences in certain ERMs in response to contour vs noncontour Gabor stimuli mainly for response amplitudes peaking around 100 [ms] (called P100) and 200 [ms] (called N200) after stimulus onset, respectively. We observe early P100 and N200 responses at electrodes located in the occipital area of the brain, while late P100 and N200 responses appear at electrodes located in frontal brain areas. Signals at electrodes in central brain areas show bimodal early/late response signatures in certain ERMs. Head topographies clearly localize statistically significant response differences to both stimulus conditions. Our findings provide an independent proof of recent models which suggest that contour integration depends on distributed network activity within the brain. PMID- 25910063 TI - ERCP-guided cholangioscopy using a single-use system: nationwide register-based study of its use in clinical practice. AB - BACKGROUND AND STUDY AIMS: Single-operator peroral cholangioscopy enables direct visualization of duct lesions, biopsy, and therapeutic interventions in the biliary and pancreatic ductal systems. The aim of this study was to address the use and outcome of this technology in wider clinical practice. PATIENTS AND METHODS: A nationwide study of endoscopic retrograde cholangiopancreatography (ERCP) procedures, with or without cholangioscopy, was conducted. Procedures that were registered in the Swedish Registry for Gallstone Surgery and ERCP (GallRiks), between 2007 and 2012 were included. The primary outcome was ERCP specific adverse events. RESULTS: Data from 36 352 ERCP procedures were analyzed, including 408 cholangioscopy procedures. Postprocedural adverse events were more prevalent when cholangioscopy was used (19.1 % vs. 14.0 %). Pancreatitis (7.4 % vs. 3.9 %) and cholangitis (4.4 % vs. 2.7 %) were ERCP-specific adverse events that were elevated in the cholangioscopy group. However, in multivariate analysis, the risks of intraprocedural and postprocedural adverse events were significantly increased in the cholangioscopy group whereas the risks of pancreatitis and cholangitis, when adjusted for confounders, were not. CONCLUSION: The single-operator peroral cholangioscopy technique is an advanced technique for intraluminal visual inspection, and for therapeutic intervention of the biliary and pancreatic ducts. However, there is a significantly increased risk of intra- and postprocedural adverse events. Thus, this method should preferably be performed at tertiary referral centers in carefully selected patients. PMID- 25910064 TI - Split dosing with a low-volume preparation is not inferior to split dosing with a high-volume preparation for bowel cleansing in patients with a history of colorectal resection: a randomized trial. AB - BACKGROUND AND STUDY AIM: The study compared the efficacy of bowel cleansing using a low-volume mixed preparation (15 mg bisacodyl plus 2 L polyethylene glycol [PEG] solution) versus a standard high-volume preparation (4 L PEG) in patients with previous colorectal resection. PATIENTS AND METHODS: A total of 120 patients with prior colorectal resection for cancer undergoing surveillance colonoscopy were randomized to receive either a split-dose low-volume (n = 60) or high-volume (n = 60) preparation for bowel cleansing. The quality of bowel preparation, rated according to a modified Ottawa Bowel Preparation scale (mOBPS), represented the primary outcome measure. Tolerability, safety, and lesion detection rates were secondary outcomes. RESULTS: No significant difference was observed between the low-volume and high-volume preparations in achievement of adequate cleansing (i. e. mOBPS <= 4; low-volume vs. high-volume group, 85.0 % vs. 81.7 %, P = 0.624). The low-volume preparation showed a higher success rate for cleansing of the right colon (P = 0.025); better tolerability in terms of intake of the whole amount of the preparation (P < 0.001) was also observed. According to the logistic regression analysis, the only predictors of unsuccessful cleansing were previous left colectomy (P = 0.012) and a longer elapsed time since the intervention (P = 0.034). Lesion detection rates were comparable between the groups. No serious adverse events were reported. CONCLUSION: A low-volume preparation is not inferior to a high-volume preparation for adequate bowel cleansing in patients with prior colorectal resection for cancer. If larger, multicenter, prospective studies confirm our findings, a low volume preparation will represent a more tolerable option for such patients. TRIAL REGISTRATION NUMBER: ClinicalTrial.gov identifier NCT01887158. PMID- 25910065 TI - Clinical outcomes in patients with a diagnosis of "indefinite for dysplasia" in Barrett's esophagus: a multicenter cohort study. AB - BACKGROUND AND STUDY AIM: Data are limited on the natural history of patients with Barrett's esophagus with a diagnosis of "indefinite for dysplasia" (IND). The aims of this study were to: (i) determine rates of progression to high grade dysplasia (HGD) or esophageal adenocarcinoma, and compare these with rates for low grade dysplasia (LGD); and (ii) determine the proportion of patients whose histological IND diagnosis changed on follow-up endoscopy. PATIENTS AND METHODS: Demographic, endoscopic, and histologic information of patients with diagnoses of IND and LGD and at least 12 months of follow-up were extracted from the database of a multicenter Barrett's esophagus study. Rates and times for progression to HGD and esophageal adenocarcinoma and regression to nondysplastic epithelium were calculated. Proportions of diagnoses upgraded to HGD/esophageal adenocarcinoma or downgraded to nondysplastic epithelium at first follow-up endoscopy were evaluated. RESULTS: Amongst 2264 patients, 83 with a diagnosis of IND (mean age 60 years, 95 % men, 95 % white; mean follow-up 5.6 years) and 79 with diagnosis of LGD were identified. In the IND group, annual incidences of esophageal adenocarcinoma and HGD were 0.21 % and 0.64 %, respectively, representing a combined incidence of 0.8 %. Mean time to progression was 4.72 years. Within the IND group 55 % patients showed regression to nondysplastic epithelium at first follow-up endoscopy and the overall regression rate was 80 %. Corresponding rates in LGD patients were similar. CONCLUSIONS: Lesions diagnosed as IND and LGD show similar biological behavior and can be treated as a single category with respect to surveillance and follow-up. PMID- 25910066 TI - Vitamin D Receptor Polymorphisms Are Associated with Reduced Esophageal Vitamin D Receptor Expression and Reduced Esophageal Adenocarcinoma Risk. AB - Epidemiological studies indicate that vitamin D exerts a protective effect on the development of various solid cancers. However, concerns have been raised regarding the potential deleterious role of high vitamin D levels in the development of esophageal adenocarcinoma (EAC). This study investigated genetic variation in the vitamin D receptor (VDR) in relation to its expression and risk of Barrett esophagus (BE) and EAC. VDR gene regulation was investigated by immunohistochemistry, reverse transcriptase-polymerase chain reaction (RT-PCR) and gel shift assays. Fifteen haplotype tagging single-nucleotide polymorphisms (SNPs) of the VDR gene were analyzed in 858 patients with reflux esophagitis (RE), BE or EAC and 202 healthy controls. VDR mRNA expression was higher in BE compared with squamous epithelium. VDR protein was located in the nucleus in BE. An rs1989969T/rs2238135G haplotype was identified in the 5' regulatory region of the VDR gene. It was associated with an approximately two-fold reduced risk of RE, BE and EAC. Analysis of a replication cohort was done for BE that confirmed this. The rs1989969T allele causes a GATA-1 transcription factor binding site to appear. The signaling of GATA-1, which is regarded as a negative transcriptional regulator, could explain the findings for rs1989969. The rs2238135G allele was associated with a significantly reduced VDR expression in BE; for the rs1989969T allele, a trend in reduced VDR expression was observed. We identified a VDR haplotype associated with reduced esophageal VDR expression and a reduced incidence of RE, BE and EAC. This VDR haplotype could be useful in identifying individuals who benefit most from vitamin D chemoprevention. PMID- 25910067 TI - A Genotypic-Oriented View of CFTR Genetics Highlights Specific Mutational Patterns Underlying Clinical Macrocategories of Cystic Fibrosis. AB - Cystic fibrosis (CF) is a monogenic disease caused by mutations of the cystic fibrosis transmembrane conductance regulator (CFTR) gene. The genotype-phenotype relationship in this disease is still unclear, and diagnostic, prognostic and therapeutic challenges persist. We enrolled 610 patients with different forms of CF and studied them from a clinical, biochemical, microbiological and genetic point of view. Overall, there were 125 different mutated alleles (11 with novel mutations and 10 with complex mutations) and 225 genotypes. A strong correlation between mutational patterns at the genotypic level and phenotypic macrocategories emerged. This specificity appears to largely depend on rare and individual mutations, as well as on the varying prevalence of common alleles in different clinical macrocategories. However, 19 genotypes appeared to underlie different clinical forms of the disease. The dissection of the pathway from the CFTR mutated genotype to the clinical phenotype allowed to identify at least two components of the variability usually found in the genotype-phenotype relationship. One component seems to depend on the genetic variation of CFTR, the other component on the cumulative effect of variations in other genes and cellular pathways independent from CFTR. The experimental dissection of the overall biological CFTR pathway appears to be a powerful approach for a better comprehension of the genotype-phenotype relationship. However, a change from an allele-oriented to a genotypic-oriented view of CFTR genetics is mandatory, as well as a better assessment of sources of variability within the CFTR pathway. PMID- 25910069 TI - Controlling factors in localised corrosion morphologies observed for magnesium immersed in chloride containing electrolyte. AB - The early stages of localised corrosion affecting magnesium (Mg) surfaces when immersed in aqueous sodium chloride (NaCl) solutions involves the propagation of dark regions, within which both anodic metal dissolution and cathodic hydrogen evolution occur. For nominally "pure" Mg, these dark areas can either take the form of discs which expand radially with time, or filiform-like tracks which lengthen with time. For Mg surfaces which display disc-form corrosion features in concentrated NaCl electrolyte, a transition to filiform corrosion (FFC) is observed as the concentration is decreased, indicating ohmic constraints on radial propagation. A similar effect is observed when Mg specimens of different iron impurity are immersed in a fixed, high concentration NaCl solution, where disc-form corrosion is observed on samples having >=280 ppm Fe, but FFC predominates at <=80 ppm Fe. An in situ scanning vibrating electrode technique (SVET) is used to determine current density distributions within the propagating corrosion features. Cathodic current density values of between -100 and -150 A m( 2) measured in central areas of disc-like features are sufficient to sustain the radial growth of a local anode at the perimeter of the discs. However, for high purity Mg specimens (<=80 ppm Fe), cathodic current densities of -10 A m(-2) or less are measured over FFC affected regions, indicating that linear propagation arises when there is insufficient cathodic current produced on the corroded surface to sustain radial growth. The results are consistent with surface control of localised corrosion propagation in concentrated electrolyte, but ohmic control in dilute, lower conductivity NaCl solution. PMID- 25910068 TI - Cathepsin L Mediates the Degradation of Novel APP C-Terminal Fragments. AB - Alzheimer's disease (AD) is characterized by the deposition of amyloid beta (Abeta), a peptide generated from proteolytic processing of its precursor, amyloid precursor protein (APP). Canonical APP proteolysis occurs via alpha-, beta-, and gamma-secretases. APP is also actively degraded by protein degradation systems. By pharmacologically inhibiting protein degradation with ALLN, we observed an accumulation of several novel APP C-terminal fragments (CTFs). The two major novel CTFs migrated around 15 and 25 kDa and can be observed across multiple cell types. The process was independent of cytotoxicity or protein synthesis. We further determine that the accumulation of the novel CTFs is not mediated by proteasome or calpain inhibition, but by cathepsin L inhibition. Moreover, these novel CTFs are not generated by an increased amount of BACE. Here, we name the CTF of 25 kDa as eta-CTF (eta-CTF). Our data suggest that under physiological conditions, a subset of APP undergoes alternative processing and the intermediate products, the 15 kDa CTFs, and the eta-CTFs aret rapidly degraded and/or processed via the protein degradation machinery, specifically, cathepsin L. PMID- 25910070 TI - Correction: Assessment of Chronic Sublethal Effects of Imidacloprid on Honey Bee Colony Health. PMID- 25910071 TI - Dielectrical Properties of CeO2 Nanoparticles at Different Temperatures. AB - A template-free precipitation method was used as a simple and low cost method for preparation of CeO2 nanoparticles. The structure and morphology of the prepared nanoparticle samples were studied in detail using X-ray diffraction, Raman spectroscopy and Scanning Electron Microscopy (SEM) measurements. The whole powder pattern modelling (WPPM) method was applied on XRD data to accurately measure the crystalline domain size and their size distribution. The average crystalline domain diameter was found to be 5.2 nm, with a very narrow size distribution. UV-visible absorbance spectrum was used to calculate the optical energy band gap of the prepared CeO2 nanoparticles. The FT-IR spectrum of prepared CeO2 nanoparticles showed absorption bands at 400 cm(-1) to 450 cm(-1) regime, which correspond to CeO2 stretching vibration. The dielectric constant (epsilonr) and dielectric loss (tan delta) values of sintered CeO2 compact consolidated from prepared nanoparticles were measured at different temperatures in the range from 298 K (room temperature) to 623 K, and at different frequencies from 1 kHz to 1 MHz. PMID- 25910073 TI - Ready-to-eat street-vended food as a potential vehicle of bacterial pathogens and antimicrobial resistance: An exploratory study in Porto region, Portugal. AB - The ready-to-eat street vending commerce, as street mobile food vendors, has grown exponentially worldwide, representing in some countries a significant proportion of food consumed by the urban population. However, the microbiological food safety hazards of mobile vending units in industrialized countries are scarcely evaluated. To assess the microbiological quality and safety of this type of food and try to achieve the connection of its contamination with hygienic conditions of food-handlers, we analyzed hotdogs (n = 10), hamburgers (n = 10) and hands (n = 9) from ten street-vending trailers in the Porto region. Food and food-handler samples were tested for Enterobacteriaceae and coliform counts, Escherichia coli and coagulase-positive staphylococci counts/detection and presence of Salmonella. Aerobic mesophilic counts and detection of Listeria monocytogenes (Pulsed Field Gel Electrophoresis-PFGE and serotyping) were also tested in food samples. E. coli isolates were confirmed by MALDI-TOF and characterized for clonality (phylogenetic groups-PhG, PFGE and Multilocus Sequence Typing), antibiotic resistance (disk diffusion, PCR/sequencing) and intestinal pathogenic virulence factors (PCR/sequencing). All food samples presented poor microbiological quality (100% Enterobacteriaceae and coliforms; 20% E. coli (4 hamburgers, 4 trailers) and 20% (2 hamburgers/2 hotdogs, 3 trailers) were positive for L. monocytogenes (2 PFGE-types belonging to serotype 1/2a and 4b). Salmonella and coagulase-positive staphylococci were not detected. Food-handlers carried Enterobacteriaceae and coliforms (100%), E. coli (11%) and/or coagulase-positive staphylococci (44%). E. coli was detected in 12 samples (n = 30-food/food-handlers; phylogenetic groups A0/A1/B1) with 33% resistant to one or more antibiotics. Two multidrug resistant atypical E. coli pathotype strains (astA-ST165(CC165)/food-handler, eaeA-ST327/food) were detected. Three out of eight E. coli clonal lineages [ST409/ST976(CC10)/ST297] and the two L. monocytogenes clones were spread in different samples/trailers, suggesting cross contamination or a common source of contamination. This exploratory study, in Porto region, showed ready-to-eat street foods from vending trailers as potential vehicles of clinically relevant L. monocytogenes serotypes and/or E. coli carrying clinically relevant virulence/antibiotic resistance features, and food handlers as a critical risk factor in this expanding food sector. PMID- 25910072 TI - From 2D to 3D: novel nanostructured scaffolds to investigate signalling in reconstructed neuronal networks. AB - To recreate in vitro 3D neuronal circuits will ultimately increase the relevance of results from cultured to whole-brain networks and will promote enabling technologies for neuro-engineering applications. Here we fabricate novel elastomeric scaffolds able to instruct 3D growth of living primary neurons. Such systems allow investigating the emerging activity, in terms of calcium signals, of small clusters of neurons as a function of the interplay between the 2D or 3D architectures and network dynamics. We report the ability of 3D geometry to improve functional organization and synchronization in small neuronal assemblies. We propose a mathematical modelling of network dynamics that supports such a result. Entrapping carbon nanotubes in the scaffolds remarkably boosted synaptic activity, thus allowing for the first time to exploit nanomaterial/cell interfacing in 3D growth support. Our 3D system represents a simple and reliable construct, able to improve the complexity of current tissue culture models. PMID- 25910074 TI - Focusing on the role of platelets in immune defence against invading pathogens. PMID- 25910076 TI - Inhibition of SlMPK1, SlMPK2, and SlMPK3 Disrupts Defense Signaling Pathways and Enhances Tomato Fruit Susceptibility to Botrytis cinerea. AB - Mitogen-activated protein kinases (MAPKs) are major components of defense signaling pathways that transduce extracellular stimuli into intracellular responses in plants. Our previous study indicated that SlMPK1/2/3 were associated with nitric oxide-induced defense response in tomato fruit. In this study, we determine whether SlMPK1/2/3 influence the tomato fruit's innate immunity and whether plant hormones and reactive oxygen species (ROS) are involved in SlMPK1/2/3 defense signaling pathways. Treatment with 10 MUM U0126 significantly inhibited the relative expression of SlMPK1, SlMPK2, and SlMPK3 (P < 0.05). U0126 treated fruit showed higher concentrations of auxin indole acetic acid (IAA), abscisic acid (ABA), and gibberellic acid (GA), but a lower concentration of methyl jasmonate (MeJA). The activities of defense enzymes, including beta-1,3 glucanases (GLU), chitinase (CHI), phenylalanine ammonia lyase (PAL), and polyphenol oxidase (PPO), decreased after U0126 treatment. Meanwhile, H2O2 content increased, and catalase (CAT), ascorbate peroxidase (APX), and peroxidase (POD) activities decreased after U0126 treatment. U0126 treatment enhanced the susceptibility of tomato fruit to Botrytis cinerea and resulted in more severe gray mold rot. These results demonstrate that inhibition of SlMPK1/2/3 disrupts tomato fruit defense signaling pathways and enhances the susceptibility to B. cinerea and also that plant hormones and ROS are associated with SlMPK1/2/3 defense signaling pathways. PMID- 25910075 TI - Bud-Localization of CLB2 mRNA Can Constitute a Growth Rate Dependent Daughter Sizer. AB - Maintenance of cellular size is a fundamental systems level process that requires balancing of cell growth with proliferation. This is achieved via the cell division cycle, which is driven by the sequential accumulation and destruction of cyclins. The regulatory network around these cyclins, particularly in G1, has been interpreted as a size control network in budding yeast, and cell size as being decisive for the START transition. However, it is not clear why disruptions in the G1 network may lead to altered size rather than loss of size control, or why the S-G2-M duration also depends on nutrients. With a mathematical population model comprised of individually growing cells, we show that cyclin translation would suffice to explain the observed growth rate dependence of cell volume at START. Moreover, we assess the impact of the observed bud-localisation of the G2 cyclin CLB2 mRNA, and find that localised cyclin translation could provide an efficient mechanism for measuring the biosynthetic capacity in specific compartments: The mother in G1, and the growing bud in G2. Hence, iteration of the same principle can ensure that the mother cell is strong enough to grow a bud, and that the bud is strong enough for independent life. Cell sizes emerge in the model, which predicts that a single CDK-cyclin pair per growth phase suffices for size control in budding yeast, despite the necessity of the cell cycle network around the cyclins to integrate other cues. Size control seems to be exerted twice, where the G2/M control affects bud size through bud-localized translation of CLB2 mRNA, explaining the dependence of the S-G2-M duration on nutrients. Taken together, our findings suggest that cell size is an emergent rather than a regulatory property of the network linking growth and proliferation. PMID- 25910077 TI - Enhanced bi-stability in a ruthenium alkynyl spiropyran complex. AB - The inclusion of a ligated ruthenium moiety to ethynyl spiropyran, 5'-ethynyl 1',3',3'-trimethyl-6-nitrospiro[chromene-2,2'-indoline], has been shown to increase the lifetime of the ring-opened merocyanine form twentyfold. Calculations suggest that the higher barrier to thermal reversion of the merocyanine form of the metal alkynyl complex arises from the capacity for greater delocalisation of charge consequent of the presence of the ruthenium moiety. The complex may provide a different switching mechanism to the 5,5' dithienylperfluorocyclopentene electrode decoupling seen previously. PMID- 25910079 TI - A new extraction method of loess shoulder-line based on Marr-Hildreth operator and terrain mask. AB - Loess shoulder-lines are significant structural lines which divide the complicated loess landform into loess interfluves and gully-slope lands. Existing extraction algorithms for shoulder-lines mainly are based on local maximum of terrain features. These algorithms are sensitive to noise for complicated loess surface and the extraction parameters are difficult to be determined, making the extraction results usually inaccurate. This paper presents a new extraction approach for loess shoulder-lines, in which Marr-Hildreth edge operator is employed to construct initial shoulder-lines. Then the terrain mask for confining the boundary of shoulder-lines is proposed based on slope degree classification and morphology methods, avoiding interference from non-valley area and modify the initial loess shoulder-lines. A case study is conducted in Yijun located in the northern Shanxi Loess Plateau of China. The Digital Elevation Models with a grid size of 5 m is applied as original data. To obtain optimal scale parameters, the Euclidean Distance Offset Percentages between shoulder-lines is calculated by the Marr-Hildreth operator and the manual delineations. The experimental results show that the new method could achieve the highest extraction accuracy when sigma = 5 in Gaussian smoothing. According to the accuracy assessment, the average extraction accuracy is about 88.5%, which indicates that the proposed method is applicable for the extraction of loess shoulder-lines in the loess hilly and gully areas. PMID- 25910078 TI - R-spondin 1/dickkopf-1/beta-catenin machinery is involved in testicular embryonic angiogenesis. AB - Testicular vasculogenesis is one of the key processes regulating male gonad morphogenesis. The knowledge of the molecular cues underlining this phenomenon is one of today's most challenging issues and could represent a major contribution toward a better understanding of the onset of testicular morphogenetic disorders. R-spondin 1 has been clearly established as a candidate for mammalian ovary determination. Conversely, very little information is available on the expression and role of R-spondin 1 during testicular morphogenesis. This study aims to clarify the distribution pattern of R-spondin 1 and other partners of its machinery during the entire period of testicular morphogenesis and to indicate the role of this system in testicular development. Our whole mount immunofluorescence results clearly demonstrate that R-spondin 1 is always detectable in the testicular coelomic partition, where testicular vasculature is organized, while Dickkopf-1 is never detectable in this area. Moreover, organ culture experiments of embryonic male UGRs demonstrated that Dickkopf-1 acted as an inhibitor of testis vasculature formation. Consistent with this observation, real-time PCR analyses demonstrated that DKK1 is able to slightly but significantly decrease the expression level of the endothelial marker Pecam1. The latter experiments allowed us to observe that DKK1 administration also perturbs the expression level of the Pdgf-b chain, which is consistent with some authors' observations relating this factor with prenatal testicular patterning and angiogenesis. Interestingly, the DKK1 induced inhibition of testicular angiogenesis was rescued by the co-administration of R-spondin 1. In addition, R spondin 1 alone was sufficient to enhance, in culture, testicular angiogenesis. PMID- 25910080 TI - Assessment of the potential diagnostic role of anaplastic lymphoma kinase for inflammatory myofibroblastic tumours: a meta-analysis. AB - OBJECTIVE: To assess the value of anaplastic lymphoma kinase for the diagnosis of inflammatory myofibroblastic tumours using a comprehensive meta-analysis. METHODS: We searched the related literature using electronic databases and manual searches. Approximately 454 cases from several countries were included in this analysis. The quality of studies included was assessed by QUADAS (quality assessment of studies of diagnostic accuracy). The diagnostic odds ratio (DOR), positive likelihood ratio (PLR), negative likelihood ratio (NLR), sensitivity and specificity were calculated to assess the role of anaplastic lymphoma kinase in the diagnosis of inflammatory myofibroblastic tumours. The overall test performance was summarised by an SROC (summary receiver operating characteristic curve). The heterogeneity and publication bias were analysed using Meta regression and Deeks' test. All data were analysed by Stata 12.0 software. RESULTS: Eight studies were included according to our inclusion criteria. The overall results for the specificity, sensitivity, PLR, NLR, DOR and area under the curve (AUC) were 0.99 (95% CI 0.82-1.00), 0.67 (95% CI 0.46-0.83), 0.67 (95% CI 0.46-0.83), 60.6 (95% CI 3.3-1112.4), 0.33 (95% CI 0.19-0.60), 181 (95% CI 9 3684) and 0.95 (95% CI 0.93-0.97), respectively, while the specificity, sensitivity, PLR, NLR, DOR and AUC for bladder IMTs were 0.99 (95% CI 0.67-1.00), 0.86 (95% CI 0.58-0.96), 95.6 (95% CI 2.0-4616.2), 0.14 (95% CI 0.04-0.50), 671 (95% CI 16-28913) and 0.99 (95% CI 0.97-0.99), respectively. CONCLUSION: The present meta-analysis indicated that anaplastic lymphoma kinase plays a significant role in the differential diagnosis of inflammatory myofibroblastic tumours, particularly for inflammatory myofibroblastic tumours of the urinary bladder. PMID- 25910081 TI - Dietary and Behavioral Factors Associated with Diet Quality among Low-income Overweight and Obese African American Women. AB - OBJECTIVES: The goal of this research was to assess the roles of demographic and home food environment characteristics on diet quality measured with the U.S. Department of Agriculture's Healthy Eating Index (HEI) in a population of low income overweight and obese African American women. DESIGN: Cross-sectional analysis of baseline data. SETTING: A community-based study of low-income overweight and obese African American women. SUBJECTS: Participants enrolled in the Healthy Homes/Healthy Families study including a home environment survey (e.g., food availability, food practices and social support) and 24-hour recall dietary data collected on one weekday and one weekend day (n = 198). RESULTS: In multivariate regression analyses, demographic characteristics were not significantly associated with diet quality; however, several home food environment characteristics were significantly associated with higher quality diets, including healthy shopping (e.g., regularly purchasing fresh fruits and vegetables), selecting healthy beverages (e.g., without added sugar), healthy food preparation, and serving behaviors. Eating while watching television was associated with lower quality diets. Nearly 33% (p < 0.001) of the variance in HEI total score was explained by the home food environment factors, far surpassing that explained by demographic characteristics (3.5%, p = 0.21). CONCLUSIONS: Interventions targeting the home food environment may improve overall diet quality in low-income overweight African American populations. PMID- 25910083 TI - Serum C-reactive protein distribution in minimally invasive total knee arthroplasty do not differ with distribution in conventional total knee arthroplasty. AB - Minimally invasive total knee arthroplasty (MITKA) has been developed to reduce surgical trauma and facilitate rehabilitation after arthroplasty. A plausible hypothesis is that this reduced trauma results in lower concentrations of circulating inflammatory biomarkers, such as C-reactive protein (CRP). In this study, we compared CRP concentrations in patients undergoing MITKA to those undergoing conventional TKA (CTKA). Eight hundred and seven patients undergoing MITKA were prospectively recruited. CRP was measured before operation and on days 2, 4, 21, and 42 after operation. Two hundred and forty-seven patients who had CTKA were collected retrospectively, with the same inclusion and exclusion criteria as those who had MITKA. We found in both groups, that CRP values rose abruptly after operation, with peak values reached on day 2 or 4. Values then declined so that by days 21 and 42 they were only modestly above baseline values. Throughout the entire study period, mean CRP in MITKA patients did not differ significantly from those in CTKA patients. However, a significantly higher proportion of CTKA patients than of MITKA patients had peak CRP values at day 4 rather than at day 2 (76.8% vs 42.5%), a difference that was more pronounced in women. Also, by day 42, CRP values were still above baseline in 18.5% of MITKA patients and 28.8% of CTKA patients without known complications. In conclusion, CRP distribution pattern was similar in patients who received MITKA or CTKA,. CRP values remained slightly elevated in both MITKA and CTKA patients for as long 42 days after operation. These findings suggest that MITKA is no less traumatic than CTKA, as determined by CRP values, and the patterns of postoperative CRP may be useful in the management of TKA patients. PMID- 25910084 TI - Nano Clinoptilolite: Highly Efficient Catalyst for the Synthesis of Chromene Derivatives Under Solvent-Free Conditions. AB - An efficient and selective synthesis of substituted chromene derivatives via three-component reaction of 4-hydroxycoumarin or 1,3-dicarbonyl compounds, activated acetylenic compounds and N-nucleophiles is described. The reaction was conducted under solvent-free conditions at 70 degrees C using potassium fluoride impregnated on natural zeolite as a cheap and available solid base. The procedure has several advantages involving selectivity, excellent yields and a convenient work-up method. PMID- 25910082 TI - Next-generation sequencing reveals novel differentially regulated mRNAs, lncRNAs, miRNAs, sdRNAs and a piRNA in pancreatic cancer. AB - BACKGROUND: Previous studies identified microRNAs (miRNAs) and messenger RNAs with significantly different expression between normal pancreas and pancreatic cancer (PDAC) tissues. Due to technological limitations of microarrays and real time PCR systems these studies focused on a fixed set of targets. Expression of other RNA classes such as long intergenic non-coding RNAs or sno-derived RNAs has rarely been examined in pancreatic cancer. Here, we analysed the coding and non coding transcriptome of six PDAC and five control tissues using next-generation sequencing. RESULTS: Besides the confirmation of several deregulated mRNAs and miRNAs, miRNAs without previous implication in PDAC were detected: miR-802, miR 2114 or miR-561. SnoRNA-derived RNAs (e.g. sno-HBII-296B) and piR-017061, a piwi interacting RNA, were found to be differentially expressed between PDAC and control tissues. In silico target analysis of miR-802 revealed potential binding sites in the 3' UTR of TCF4, encoding a transcription factor that controls Wnt signalling genes. Overexpression of miR-802 in MiaPaCa pancreatic cancer cells reduced TCF4 protein levels. Using Massive Analysis of cDNA Ends (MACE) we identified differential expression of 43 lincRNAs, long intergenic non-coding RNAs, e.g. LINC00261 and LINC00152 as well as several natural antisense transcripts like HNF1A-AS1 and AFAP1-AS1. Differential expression was confirmed by qPCR on the mRNA/miRNA/lincRNA level and by immunohistochemistry on the protein level. CONCLUSIONS: Here, we report a novel lncRNA, sncRNA and mRNA signature of PDAC. In silico prediction of ncRNA targets allowed for assigning potential functions to differentially regulated RNAs. PMID- 25910085 TI - Patient-Specific Factors Associated With Dissatisfaction After Elective Surgery for Degenerative Spine Diseases. AB - BACKGROUND: Patient satisfaction metrics are emerging as determinants of quality of care and reimbursement after spine surgery. Identifying modifiable factors that improve satisfaction is of utmost importance. OBJECTIVE: To evaluate whether patient-related factors or patient-reported outcomes could predict dissatisfaction after spine surgery. METHODS: Patients undergoing elective surgery for degenerative lumbar and cervical disease over a period of 2 years were enrolled in a prospective longitudinal registry. Patient-reported outcome, the Oswestry Disability Index (ODI)/Neck Disability Index (NDI), and numeric rating scale for back/neck (BP/NP) and leg/arm pain (LP/AP), were recorded at baseline and the 12-month follow-up. Previously published values of minimal clinically important differences of 14.9% for ODI, 17.3% for NDI, 2.1/2.6 for BP/NP, and 2.8/4.1 for LP/AP were used. Patient satisfaction was assessed with the North American Spine Society Satisfaction Questionnaire. RESULTS: A total of 1645 patients underwent elective spine surgery (811 male patients; age, 57 +/- 13 years). Eighty-three percent of patients (1362) reported satisfaction with outcome 12 months after surgery. In a multivariable analysis, after controlling for an array of patient-specific factors, the inability to achieve minimal clinically important difference for ODI/NDI (P < .001; odds ratio [OR] = 4.215; 95% confidence interval [CI], 2.7-6.5), BP/NP pain (P < .001; OR = 3.1; 95% CI, 2.188-4.43), and LP/NP (P < .001; OR = 2.6, 95% CI, 1.8-3.6); Medicaid/uninsured payer status (P = .04; OR = 1.39; 95% CI, 1.01-1.93); and higher baseline ODI/NDI (P = .002; OR = 1.11; 95% CI, 1.04-1.19) and BP/NP scores (P = .002; OR = 1.03; 95% CI, 1.01-1.06) were the independent predictors of patient dissatisfaction at 12 months after surgery. CONCLUSION: Patient satisfaction with outcome may accurately represent the effectiveness of surgical spine care in terms of 1-year improvement in pain and disability. However, healthcare stakeholders relying on satisfaction as a proxy of overall quality or effectiveness of care need to account for Medicaid/uninsured payer status and worse baseline pain and disability scores as confounders. PMID- 25910088 TI - 2D Segmentation Using a Robust Active Shape Model With the EM Algorithm. AB - Statistical shape models have been extensively used in a wide range of applications due to their effectiveness in providing prior shape information for object segmentation problems. The most popular method is the Active Shape Model (ASM). However, accurately fitting the shape model to an object boundary under a cluttered environment is a challenging task. Under such assumptions, the model is often attracted towards invalid observations (outliers), leading to meaningless estimates of the object boundary. In this paper, we propose a novel algorithm that improves the robustness of ASM in the presence of outliers. The proposed framework assumes that both type of observations (valid observations and outliers) are detected in the image. A new strategy is devised for treating the data in different ways, depending on the observations being considered as valid or invalid. The proposed algorithm assigns a different weight to each observation. The shape parameters are recursively updated using the Expectation Maximization method, allowing a correct and robust fit of the shape model to the object boundary in the image. Two estimation criteria are considered: 1) the maximum likelihood criterion; and 2) the maximum a posteriori criterion that uses priors for the unknown parameters. The methods are tested with synthetic and real images, comprising medical images of the heart and image sequences of the lips. The results are promising and show that this approach is robust in the presence of outliers, leading to a significant improvement over the standard ASM and other state of the art methods. PMID- 25910086 TI - Complications and Resource Use Associated With Surgery for Chiari Malformation Type 1 in Adults: A Population Perspective. AB - BACKGROUND: Outcomes research on Chiari malformation type 1 (CM-1) is impeded by a reliance on small, single-center cohorts. OBJECTIVE: To study the complications and resource use associated with adult CM-1 surgery using administrative data. METHODS: We used a recently validated International Classification of Diseases, Ninth Revision, Clinical Modification code algorithm to retrospectively study adult CM-1 surgeries from 2004 to 2010 in California, Florida, and New York using State Inpatient Databases. Outcomes included complications and resource use within 30 and 90 days of treatment. We used multivariable logistic regression to identify risk factors for morbidity and negative binomial models to determine risk-adjusted costs. RESULTS: We identified 1947 CM-1 operations. Surgical complications were more common than medical complications at both 30 days (14.3% vs 4.4%) and 90 days (18.7% vs 5.0%) postoperatively. Certain comorbidities were associated with increased morbidity; for example, hydrocephalus increased the risk for surgical (odds ratio [OR] = 4.51) and medical (OR = 3.98) complications. Medical but not surgical complications were also more common in older patients (OR = 5.57 for oldest vs youngest age category) and male patients (OR = 3.19). Risk-adjusted hospital costs were $22530 at 30 days and $24852 at 90 days postoperatively. Risk-adjusted 90-day costs were more than twice as high for patients experiencing surgical ($46264) or medical ($65679) complications than for patients without complications ($18880). CONCLUSION: Complications after CM-1 surgery are common, and surgical complications are more frequent than medical complications. Certain comorbidities and demographic characteristics are associated with increased risk for complications. Beyond harming patients, complications are also associated with substantially higher hospital costs. These results may help guide patient management and inform decision making for patients considering surgery. PMID- 25910089 TI - Exploring sparseness and self-similarity for action recognition. AB - We propose that the dynamics of an action in video data forms a sparse self similar manifold in the space-time volume, which can be fully characterized by a linear rank decomposition. Inspired by the recurrence plot theory, we introduce the concept of Joint Self-Similarity Volume (Joint-SSV) to model this sparse action manifold, and hence propose a new optimized rank-1 tensor approximation of the Joint-SSV to obtain compact low-dimensional descriptors that very accurately characterize an action in a video sequence. We show that these descriptor vectors make it possible to recognize actions without explicitly aligning the videos in time in order to compensate for speed of execution or differences in video frame rates. Moreover, we show that the proposed method is generic, in the sense that it can be applied using different low-level features, such as silhouettes, tracked points, histogram of oriented gradients, and so forth. Therefore, our method does not necessarily require explicit tracking of features in the space time volume. Our experimental results on five public data sets demonstrate that our method produces promising results and outperforms many baseline methods. PMID- 25910087 TI - Indole-based hydrazide-hydrazones and 4-thiazolidinones: synthesis and evaluation as antitubercular and anticancer agents. AB - A new series of indolylhydrazones (6) and indole-based 4-thiazolidinones (7, 8) have been designed, synthesized and screened for in vitro antitubercular activity against Mycobacterium tuberculosis H37Rv. 4-Thiazolidinone derivatives 7g-7j, 8g, 8h and 8j displayed notable antituberculosis (anti-TB) activity showing 99% inhibition at MIC values ranging from 6.25 to 25.0 ug/ml. Compounds 7g, 7h, 7i, 8h and 8j demonstrated anti-TB activity at concentrations 10-fold lower than those cytotoxic for the mammalian cell lines. The indolylhydrazone derivative 6b has also been evaluated for antiproliferative activity against human cancer cell lines at the National Cancer Institute (USA). Compound 6b showed an interesting anticancer profile against different human tumor-derived cell lines at sub micromolar concentrations with obvious selectivity toward colon cancer cell line COLO 205. PMID- 25910090 TI - Boundary detection using double-opponency and spatial sparseness constraint. AB - Brightness and color are two basic visual features integrated by the human visual system (HVS) to gain a better understanding of color natural scenes. Aiming to combine these two cues to maximize the reliability of boundary detection in natural scenes, we propose a new framework based on the color-opponent mechanisms of a certain type of color-sensitive double-opponent (DO) cells in the primary visual cortex (V1) of HVS. This type of DO cells has oriented receptive field with both chromatically and spatially opponent structure. The proposed framework is a feedforward hierarchical model, which has direct counterpart to the color opponent mechanisms involved in from the retina to V1. In addition, we employ the spatial sparseness constraint (SSC) of neural responses to further suppress the unwanted edges of texture elements. Experimental results show that the DO cells we modeled can flexibly capture both the structured chromatic and achromatic boundaries of salient objects in complex scenes when the cone inputs to DO cells are unbalanced. Meanwhile, the SSC operator further improves the performance by suppressing redundant texture edges. With competitive contour detection accuracy, the proposed model has the additional advantage of quite simple implementation with low computational cost. PMID- 25910091 TI - A very fast algorithm for simultaneously performing connected-component labeling and euler number computing. AB - Labeling connected components and calculating the Euler number in a binary image are two fundamental processes for computer vision and pattern recognition. This paper presents an ingenious method for identifying a hole in a binary image in the first scan of connected-component labeling. Our algorithm can perform connected component labeling and Euler number computing simultaneously, and it can also calculate the connected component (object) number and the hole number efficiently. The additional cost for calculating the hole number is only O(H) , where H is the hole number in the image. Our algorithm can be implemented almost in the same way as a conventional equivalent-label-set-based connected-component labeling algorithm. We prove the correctness of our algorithm and use experimental results for various kinds of images to demonstrate the power of our algorithm. PMID- 25910092 TI - Spatiotemporal saliency detection for video sequences based on random walk with restart. AB - A novel saliency detection algorithm for video sequences based on the random walk with restart (RWR) is proposed in this paper. We adopt RWR to detect spatially and temporally salient regions. More specifically, we first find a temporal saliency distribution using the features of motion distinctiveness, temporal consistency, and abrupt change. Among them, the motion distinctiveness is derived by comparing the motion profiles of image patches. Then, we employ the temporal saliency distribution as a restarting distribution of the random walker. In addition, we design the transition probability matrix for the walker using the spatial features of intensity, color, and compactness. Finally, we estimate the spatiotemporal saliency distribution by finding the steady-state distribution of the walker. The proposed algorithm detects foreground salient objects faithfully, while suppressing cluttered backgrounds effectively, by incorporating the spatial transition matrix and the temporal restarting distribution systematically. Experimental results on various video sequences demonstrate that the proposed algorithm outperforms conventional saliency detection algorithms qualitatively and quantitatively. PMID- 25910093 TI - Learning a Nonnegative Sparse Graph for Linear Regression. AB - Previous graph-based semisupervised learning (G-SSL) methods have the following drawbacks: 1) they usually predefine the graph structure and then use it to perform label prediction, which cannot guarantee an overall optimum and 2) they only focus on the label prediction or the graph structure construction but are not competent in handling new samples. To this end, a novel nonnegative sparse graph (NNSG) learning method was first proposed. Then, both the label prediction and projection learning were integrated into linear regression. Finally, the linear regression and graph structure learning were unified within the same framework to overcome these two drawbacks. Therefore, a novel method, named learning a NNSG for linear regression was presented, in which the linear regression and graph learning were simultaneously performed to guarantee an overall optimum. In the learning process, the label information can be accurately propagated via the graph structure so that the linear regression can learn a discriminative projection to better fit sample labels and accurately classify new samples. An effective algorithm was designed to solve the corresponding optimization problem with fast convergence. Furthermore, NNSG provides a unified perceptiveness for a number of graph-based learning methods and linear regression methods. The experimental results showed that NNSG can obtain very high classification accuracy and greatly outperforms conventional G-SSL methods, especially some conventional graph construction methods. PMID- 25910094 TI - Many-body localization in periodically driven systems. AB - We consider disordered many-body systems with periodic time-dependent Hamiltonians in one spatial dimension. By studying the properties of the Floquet eigenstates, we identify two distinct phases: (i) a many-body localized (MBL) phase, in which almost all eigenstates have area-law entanglement entropy, and the eigenstate thermalization hypothesis (ETH) is violated, and (ii) a delocalized phase, in which eigenstates have volume-law entanglement and obey the ETH. The MBL phase exhibits logarithmic in time growth of entanglement entropy when the system is initially prepared in a product state, which distinguishes it from the delocalized phase. We propose an effective model of the MBL phase in terms of an extensive number of emergent local integrals of motion, which naturally explains the spectral and dynamical properties of this phase. Numerical data, obtained by exact diagonalization and time-evolving block decimation methods, suggest a direct transition between the two phases. PMID- 25910095 TI - Monogamy equalities for qubit entanglement from Lorentz invariance. AB - A striking result from nonrelativistic quantum mechanics is the monogamy of entanglement, which states that a particle can be maximally entangled only with one other party, not with several ones. While there is the exact quantitative relation for three qubits and also several inequalities describing monogamy properties, it is not clear to what extent exact monogamy relations are a general feature of quantum mechanics. We prove that in all many-qubit systems there exist strict monogamy laws for quantum correlations. They come about through the curious relationship between the nonrelativistic quantum mechanics of qubits and Minkowski space. We elucidate the origin of entanglement monogamy from this symmetry perspective and provide recipes to construct new families of such equalities. PMID- 25910096 TI - Unifying framework for relaxations of the causal assumptions in Bell's theorem. AB - Bell's theorem shows that quantum mechanical correlations can violate the constraints that the causal structure of certain experiments impose on any classical explanation. It is thus natural to ask to which degree the causal assumptions-e.g., locality or measurement independence-have to be relaxed in order to allow for a classical description of such experiments. Here we develop a conceptual and computational framework for treating this problem. We employ the language of Bayesian networks to systematically construct alternative causal structures and bound the degree of relaxation using quantitative measures that originate from the mathematical theory of causality. The main technical insight is that the resulting problems can often be expressed as computationally tractable linear programs. We demonstrate the versatility of the framework by applying it to a variety of scenarios, ranging from relaxations of the measurement independence, locality, and bilocality assumptions, to a novel causal interpretation of Clauser-Horne-Shimony-Holt inequality violations. PMID- 25910097 TI - Atom interferometer gyroscope with spin-dependent phase shifts induced by light near a tune-out wavelength. AB - Tune-out wavelengths measured with an atom interferometer are sensitive to laboratory rotation rates because of the Sagnac effect, vector polarizability, and dispersion compensation. We observed shifts in measured tune-out wavelengths as large as 213 pm with a potassium atom beam interferometer, and we explore how these shifts can be used for an atom interferometer gyroscope. PMID- 25910098 TI - Universal adiabatic quantum computation via the space-time circuit-to-Hamiltonian construction. AB - We show how to perform universal adiabatic quantum computation using a Hamiltonian which describes a set of particles with local interactions on a two dimensional grid. A single parameter in the Hamiltonian is adiabatically changed as a function of time to simulate the quantum circuit. We bound the eigenvalue gap above the unique ground state by mapping our model onto the ferromagnetic XXZ chain with kink boundary conditions; the gap of this spin chain was computed exactly by Koma and Nachtergaele using its q-deformed version of SU(2) symmetry. We also discuss a related time-independent Hamiltonian which was shown by Janzing to be capable of universal computation. We observe that in the limit of large system size, the time evolution is equivalent to the exactly solvable quantum walk on Young's lattice. PMID- 25910099 TI - Experimental quantum-walk revival with a time-dependent coin. AB - We demonstrate a quantum walk with time-dependent coin bias. With this technique we realize an experimental single-photon one-dimensional quantum walk with a linearly ramped time-dependent coin flip operation and thereby demonstrate two periodic revivals of the walker distribution. In our beam-displacer interferometer, the walk corresponds to movement between discretely separated transverse modes of the field serving as lattice sites, and the time-dependent coin flip is effected by implementing a different angle between the optical axis of half-wave plate and the light propagation at each step. Each of the quantum walk steps required to realize a revival comprises two sequential orthogonal coin flip operators, with one coin having constant bias and the other coin having a time-dependent ramped coin bias, followed by a conditional translation of the walker. PMID- 25910100 TI - Quantum benchmark via an uncertainty product of canonical variables. AB - We present an uncertainty-relation-type quantum benchmark for continuous-variable (CV) quantum channels that works with an input ensemble of Gaussian-distributed coherent states and homodyne measurements. It determines an optimal trade-off relation between canonical quadrature noises that is unbeatable by entanglement breaking channels and refines the notion of two quantum duties introduced in the original papers of CV quantum teleportation. This benchmark can verify the quantum-domain performance for all one-mode Gaussian channels. We also address the case of stochastic channels and the effect of asymmetric gains. PMID- 25910101 TI - Experimental realization of a quantum support vector machine. AB - The fundamental principle of artificial intelligence is the ability of machines to learn from previous experience and do future work accordingly. In the age of big data, classical learning machines often require huge computational resources in many practical cases. Quantum machine learning algorithms, on the other hand, could be exponentially faster than their classical counterparts by utilizing quantum parallelism. Here, we demonstrate a quantum machine learning algorithm to implement handwriting recognition on a four-qubit NMR test bench. The quantum machine learns standard character fonts and then recognizes handwritten characters from a set with two candidates. Because of the wide spread importance of artificial intelligence and its tremendous consumption of computational resources, quantum speedup would be extremely attractive against the challenges of big data. PMID- 25910102 TI - Experimental estimation of average fidelity of a Clifford gate on a 7-qubit quantum processor. AB - One of the major experimental achievements in the past decades is the ability to control quantum systems to high levels of precision. To quantify the level of control we need to characterize the dynamical evolution. Full characterization via quantum process tomography is impractical and often unnecessary. For most practical purposes, it is enough to estimate more general quantities such as the average fidelity. Here we use a unitary 2-design and twirling protocol for efficiently estimating the average fidelity of Clifford gates, to certify a 7 qubit entangling gate in a nuclear magnetic resonance quantum processor. Compared with more than 10^{8} experiments required by full process tomography, we conducted 1656 experiments to satisfy a statistical confidence level of 99%. The average fidelity of this Clifford gate in experiment is 55.1%, and rises to at least 87.5% if the signal's decay due to decoherence is taken into account. The entire protocol of certifying Clifford gates is efficient and scalable, and can easily be extended to any general quantum information processor with minor modifications. PMID- 25910103 TI - Identifying local and quasilocal conserved quantities in integrable systems. AB - We outline a procedure for counting and identifying a complete set of local and quasilocal conserved operators in integrable lattice systems. The method yields a systematic generation of all independent, conserved quasilocal operators related to the time average of local operators with a support on up to M consecutive sites. As an example, we study the anisotropic Heisenberg spin-1/2 chain and show that the number of independent conserved operators grows linearly with M. In addition to the known local operators, there exist novel quasilocal conserved quantities in all the parity sectors. The existence of quasilocal conserved operators is shown also for the isotropic Heisenberg model. Implications for the anomalous relaxation of quenched systems are discussed as well. PMID- 25910104 TI - Flip-flopping binary black holes. AB - We study binary spinning black holes to display the long term individual spin dynamics. We perform a full numerical simulation starting at an initial proper separation of d~25M between equal mass holes and evolve them down to merger for nearly 48 orbits, 3 precession cycles, and half of a flip-flop cycle. The simulation lasts for t=20 000M and displays a total change in the orientation of the spin of one of the black holes from an initial alignment with the orbital angular momentum to a complete antialignment after half of a flip-flop cycle. We compare this evolution with an integration of the 3.5 post-Newtonian equations of motion and spin evolution to show that this process continuously flip flops the spin during the lifetime of the binary until merger. We also provide lower order analytic expressions for the maximum flip-flop angle and frequency. We discuss the effects this dynamics may have on spin growth in accreting binaries and on the observational consequences for galactic and supermassive binary black holes. PMID- 25910105 TI - Local invariants vanishing on stationary horizons: a diagnostic for locating black holes. AB - Inspired by the example of Abdelqader and Lake for the Kerr metric, we construct local scalar polynomial curvature invariants that vanish on the horizon of any stationary black hole: the squared norms of the wedge products of n linearly independent gradients of scalar polynomial curvature invariants, where n is the local cohomogeneity of the spacetime. PMID- 25910106 TI - Violation of the strong Huygen's principle and timelike signals from the early universe. AB - We analyze the implications of the violations of the strong Huygen's principle in the transmission of information from the early Universe to the current era via massless fields. We show that much more information reaches us through timelike channels (not mediated by real photons) than is carried by rays of light, which are usually regarded as the only carriers of information. PMID- 25910108 TI - Unity of cosmological inflation attractors. AB - Recently, several broad classes of inflationary models have been discovered whose cosmological predictions, in excellent agreement with Planck, are stable with respect to significant modifications of the inflaton potential. Some classes of models are based on a nonminimal coupling to gravity. These models, which we call xi attractors, describe universal cosmological attractors (including Higgs inflation) and induced inflation models. Another class describes conformal attractors (including Starobinsky inflation and T models) and their generalization to alpha attractors. The aim of this Letter is to elucidate the common denominator of these attractors: their robust predictions stem from a joint pole of order 2 in the kinetic term of the inflaton field in the Einstein frame formulation prior to switching to the canonical variables. Model-dependent differences only arise at subleading level in the kinetic term. As a final step towards the unification of the different attractors, we introduce a special class of xi attractors which is fully equivalent to alpha attractors with the identification alpha=1+(1/6xi). While r is generically predicted to be of the order 1/N^{2}, there is no theoretical lower bound on r in this class of models. PMID- 25910109 TI - Anomalous solutions to the strong CP problem. AB - We present a new mechanism for solving the strong CP problem using a Z_{2} discrete symmetry and an anomalous U(1) symmetry. A Z_{2} symmetry is used so that two gauge groups have the same theta angle. An anomalous U(1) symmetry makes the difference between the two theta angles physical and the sum unphysical. Two models are presented where the anomalous symmetry manifests itself in the IR in different ways. In the first model, there are massless bifundamental quarks, a solution reminiscent of the massless up quark solution. In the IR of this model, the eta^{'} boson relaxes the QCD theta angle to the difference between the two theta angles-in this case zero. In the second model, the anomalous U(1) symmetry is realized in the IR as a dynamically generated mass term that has exactly the phase needed to cancel the theta angle. Both of these models make the extremely concrete prediction that there exist new colored particles at the TeV scale. PMID- 25910107 TI - Search for neutrinos from annihilation of captured low-mass dark matter particles in the sun by super-kamiokande. AB - Super-Kamiokande (SK) can search for weakly interacting massive particles (WIMPs) by detecting neutrinos produced from WIMP annihilations occurring inside the Sun. In this analysis, we include neutrino events with interaction vertices in the detector in addition to upward-going muons produced in the surrounding rock. Compared to the previous result, which used the upward-going muons only, the signal acceptances for light (few-GeV/c^{2}-200-GeV/c^{2}) WIMPs are significantly increased. We fit 3903 days of SK data to search for the contribution of neutrinos from WIMP annihilation in the Sun. We found no significant excess over expected atmospheric-neutrino background and the result is interpreted in terms of upper limits on WIMP-nucleon elastic scattering cross sections under different assumptions about the annihilation channel. We set the current best limits on the spin-dependent WIMP-proton cross section for WIMP masses below 200 GeV/c^{2} (at 10 GeV/c^{2}, 1.49*10^{-39} cm^{2} for chichi >bb[over -] and 1.31*10^{-40} cm^{2} for chichi->tau^{+}tau^{-} annihilation channels), also ruling out some fraction of WIMP candidates with spin-independent coupling in the few-GeV/c^{2} mass range. PMID- 25910113 TI - Indications for a critical end point in the phase diagram for hot and dense nuclear matter. AB - Excitation functions for the Gaussian emission source radii difference (R_{out}^{2}-R_{side}^{2}) obtained from two-pion interferometry measurements in Au+Au (sqrt[s_{NN}]=7.7-200 GeV) and Pb+Pb (sqrt[s_{NN}]=2.76 TeV) collisions are studied for a broad range of collision centralities. The observed nonmonotonic excitation functions validate the finite-size scaling patterns expected for the deconfinement phase transition and the critical end point (CEP), in the temperature versus baryon chemical potential (T,MU_{B}) plane of the nuclear matter phase diagram. A finite-size scaling (FSS) analysis of these data suggests a second order phase transition with the estimates T^{cep}~165 MeV and MU_{B}^{cep}~95 MeV for the location of the critical end point. The critical exponents (nu~0.66 and gamma~1.2) extracted via the same FSS analysis place this CEP in the 3D Ising model universality class. PMID- 25910112 TI - Quark mass relations to four-loop order in perturbative QCD. AB - We present results for the relation between a heavy quark mass defined in the on shell and minimal subtraction (MS[over -]) scheme to four-loop order. The method to compute the four-loop on-shell integral is briefly described and the new results are used to establish relations between various short-distance masses and the MS[over -] quark mass to next-to-next-to-next-to-leading order accuracy. These relations play an important role in the accurate determination of the MS[over -] heavy quark masses. PMID- 25910114 TI - Particle-vibration coupling effect on the beta decay of magic nuclei. AB - Nuclear beta decay in magic nuclei is investigated, taking into account the coupling between particles and collective vibrations, on top of self-consistent random phase approximation calculations based on Skyrme density functionals. The low-lying Gamow-Teller strength is shifted downwards and at times becomes fragmented; as a consequence, the beta-decay half-lives are reduced due to the increase of the phase space available for the decay. In some cases, this leads to a very good agreement between theoretical and experimental lifetimes: this happens, in particular, in the case of the Skyrme force SkM* that can also reproduce the line shape of the high-energy Gamow-Teller resonance as was previously shown. PMID- 25910115 TI - Streaking temporal double-slit interference by an orthogonal two-color laser field. AB - We investigate electron momentum distributions from single ionization of Ar by two orthogonally polarized laser pulses of different color. The two-color scheme is used to experimentally control the interference between electron wave packets released at different times within one laser cycle. This intracycle interference pattern is typically hard to resolve in an experiment. With the two-color control scheme, these features become the dominant contribution to the electron momentum distribution. Furthermore, the second color can be used for streaking of the otherwise interfering wave packets establishing a which-way marker. Our investigation shows that the visibility of the interference fringes depends on the degree of the which-way information determined by the controllable phase between the two pulses. PMID- 25910118 TI - Matter wave lensing to picokelvin temperatures. AB - Using a matter wave lens and a long time of flight, we cool an ensemble of ^{87}Rb atoms in two dimensions to an effective temperature of less than 50_{ 30}^{+50} pK. A short pulse of red-detuned light generates an optical dipole force that collimates the ensemble. We also report a three-dimensional magnetic lens that substantially reduces the chemical potential of evaporatively cooled ensembles with a high atom number. By observing such low temperatures, we set limits on proposed modifications to quantum mechanics in the macroscopic regime. These cooling techniques yield bright, collimated sources for precision atom interferometry. PMID- 25910116 TI - Beyond the single-atom response in absorption line shapes: probing a dense, laser dressed helium gas with attosecond pulse trains. AB - We investigate the absorption line shapes of laser-dressed atoms beyond the single-atom response, by using extreme ultraviolet (XUV) attosecond pulse trains to probe an optically thick helium target under the influence of a strong infrared (IR) field. We study the interplay between the IR-induced phase shift of the microscopic time-dependent dipole moment and the resonant-propagation-induced reshaping of the macroscopic XUV pulse. Our experimental and theoretical results show that as the optical depth increases, this interplay leads initially to a broadening of the IR-modified line shape, and subsequently, to the appearance of new, narrow features in the absorption line. PMID- 25910117 TI - Storing keV negative ions for an hour: the lifetime of the metastable ^(2)P((1/2)^(o)) level in ^(32)S^(-). AB - We use a novel electrostatic ion storage ring to measure the radiative lifetime of the upper level in the 3p^{5} ^{2}P_{1/2}^{o}->3p^{5} ^{2}P_{3/2}^{o} spontaneous radiative decay in ^{32}S^{-} to be 503+/-54 sec. This is by orders of magnitude the longest lifetime ever measured in a negatively charged ion. Cryogenic cooling of the storage ring gives a residual-gas pressure of a few times 10^{-14} mbar at 13 K and storage of 10 keV sulfur anions for more than an hour. Our experimental results differ by 1.3sigma from the only available theoretical prediction [P. Andersson et al., Phys. Rev. A 73, 032705 (2006)]. PMID- 25910110 TI - Constraints on models of the Higgs boson with exotic spin and parity using decays to bottom-antibottom quarks in the full CDF data set. AB - A search for particles with the same mass and couplings as those of the standard model Higgs boson but different spin and parity quantum numbers is presented. We test two specific alternative Higgs boson hypotheses: a pseudoscalar Higgs boson with spin-parity J^{P}=0^{-} and a gravitonlike Higgs boson with J^{P}=2^{+}, assuming for both a mass of 125 GeV/c^{2}. We search for these exotic states produced in association with a vector boson and decaying into a bottom-antibottom quark pair. The vector boson is reconstructed through its decay into an electron or muon pair, or an electron or muon and a neutrino, or it is inferred from an imbalance in total transverse momentum. We use expected kinematic differences between events containing exotic Higgs bosons and those containing standard model Higgs bosons. The data were collected by the CDF experiment at the Tevatron proton-antiproton collider, operating at a center-of-mass energy of sqrt[s]=1.96 TeV, and correspond to an integrated luminosity of 9.45 fb^{-1}. We exclude deviations from the predictions of the standard model with a Higgs boson of mass 125 GeV/c^{2} at the level of 5 standard deviations, assuming signal strengths for exotic boson production equal to the prediction for the standard model Higgs boson, and set upper limits of approximately 30% relative to the standard model rate on the possible rate of production of each exotic state. PMID- 25910119 TI - Transient impulsive electronic Raman redistribution. AB - Resonant Raman excitation by ultrafast vacuum ultraviolet laser pulses is a powerful means to study electron dynamics in molecules, but experiments must contend with linear background ionization: frequencies high enough to reach resonant core-valence transitions will usually ionize all occupied orbitals as well, and the ionization cross sections are usually dominant. Here we show that attosecond pulses can induce a process, transient impulsive stimulated Raman scattering, which can overwhelm valence ionization. Calculations are performed for atomic sodium, but the principal is valid for many molecular systems. This approach opens the path for high-fidelity multidimensional spectroscopy with attosecond pulses. PMID- 25910120 TI - High-energy recollision processes of laser-generated electron-positron pairs. AB - Two oppositely charged particles created within a microscopic space-time region can be separated, accelerated over a much larger distance, and brought to a recollision by a laser field. Consequently, new reactions become feasible, where the energy absorbed by the particles is efficiently released. By investigating the laser-dressed polarization operator, we identify a new contribution describing high-energy recollisions experienced by an electron-positron pair generated by pure light when a gamma photon impinges on an intense, linearly polarized laser pulse. The energy absorbed in the recollision process over the macroscopic laser wavelength corresponds to a large number of laser photons and can be exploited to prime high-energy reactions. Thus, the recollision contribution to the polarization operator differs qualitatively and quantitatively from the well-known one, describing the annihilation of an electron-positron pair within the microscopic formation region. PMID- 25910121 TI - Dicke simulators with emergent collective quantum computational abilities. AB - Using an approach inspired from spin glasses, we show that the multimode disordered Dicke model is equivalent to a quantum Hopfield network. We propose variational ground states for the system at zero temperature, which we conjecture to be exact in the thermodynamic limit. These ground states contain the information on the disordered qubit-photon couplings. These results lead to two intriguing physical implications. First, once the qubit-photon couplings can be engineered, it should be possible to build scalable pattern-storing systems whose dynamics is governed by quantum laws. Second, we argue with an example of how such Dicke quantum simulators might be used as a solver of "hard" combinatorial optimization problems. PMID- 25910122 TI - Strong single-photon coupling in superconducting quantum magnetomechanics. AB - We show that the inductive coupling between the quantum mechanical motion of a superconducting microcantilever and a flux-dependent microwave quantum circuit can attain the strong single-photon nanomechanical coupling regime with feasible experimental parameters. We propose to use a superconducting strip, which is in the Meissner state, at the tip of a cantilever. A pickup coil collects the flux generated by the sheet currents induced by an external quadrupole magnetic field centered at the strip location. The position-dependent magnetic response of the superconducting strip, enhanced by both diamagnetism and demagnetizing effects, leads to a strong magnetomechanical coupling to quantum circuits. PMID- 25910123 TI - Vacuum Rabi spectra of a single quantum emitter. AB - We report the observation of the vacuum Rabi splitting of a single quantum emitter by measuring its direct spontaneous emission into free space. We use a semiconductor quantum dot inside a photonic crystal nanocavity, in conjunction with an appropriate cavity design and filtering with a polarizer and an aperture, enabling the extraction of the inherently weak emitter's signal. The emitter's vacuum Rabi spectra exhibit clear differences from those measured by detecting the cavity photon leakage. Moreover, we observe an asymmetric vacuum Rabi spectrum induced by interference between the emitter and cavity detection channels. Our observations lay the groundwork for accessing various cavity quantum electrodynamics phenomena that manifest themselves only in the emitter's direct spontaneous emission. PMID- 25910124 TI - Fabrication of a material assembly of silver nanoparticles using the phase gradients of optical tweezers. AB - Optical matter can be created using the intensity gradient and electrodynamic (e.g., optical binding) forces that nano- and microparticles experience in focused optical beams. Here we show that the force associated with phase gradient is also important. In fact, in optical line traps the phase gradient force is crucial in determining the structure and stability of optical matter arrays consisting of Ag nanoparticles (NPs). NP lattices can be repeatedly assembled and disassembled simply by changing the sign of the phase gradient. The phase gradient creates a compressive force (and thus a stress) in the optically bound Ag NP lattices, causing structural transitions (a stress response) from 1D "chains" to 2D lattices, and even to amorphous structures. The structural transitions and dynamics of driven transport are well described by electrodynamics simulations and modeling using a drift-diffusion Langevin equation. PMID- 25910125 TI - Carrier-wave Rabi-flopping signatures in high-order harmonic generation for alkali atoms. AB - We present a theoretical investigation of carrier-wave Rabi flopping in real atoms by employing numerical simulations of high-order harmonic generation (HHG) in alkali species. Given the short HHG cutoff, related to the low saturation intensity, we concentrate on the features of the third harmonic of sodium (Na) and potassium (K) atoms. For pulse areas of 2pi and Na atoms, a characteristic unique peak appears, which, after analyzing the ground state population, we correlate with the conventional Rabi flopping. On the other hand, for larger pulse areas, carrier-wave Rabi flopping occurs, and is associated with a more complex structure in the third harmonic. These characteristics observed in K atoms indicate the breakdown of the area theorem, as was already demonstrated under similar circumstances in narrow band gap semiconductors. PMID- 25910126 TI - Optical rogue waves in integrable turbulence. AB - We report optical experiments allowing us to investigate integrable turbulence in the focusing regime of the one-dimensional nonlinear Schrodinger equation (1D NLSE). In analogy with broad spectrum excitation of a one-dimensional water tank, we launch random initial waves in a single mode optical fiber. Using an original optical sampling setup, we measure precisely the probability density function of optical power of the partially coherent waves rapidly fluctuating with time. The probability density function is found to evolve from the normal law to a strong heavy-tailed distribution, thus revealing the formation of rogue waves in integrable turbulence. Numerical simulations of 1D NLSE with stochastic initial conditions quantitatively reproduce the experiments. Our numerical investigations suggest that the statistical features experimentally observed rely on the stochastic generation of coherent analytic solutions of 1D NLSE. PMID- 25910127 TI - Nonlocal resonances in weak turbulence of gravity-capillary waves. AB - We report a laboratory investigation of weak turbulence of water surface waves in the gravity-capillary crossover. By using time-space-resolved profilometry and a bicoherence analysis, we observe that the nonlinear processes involve three-wave resonant interactions. By studying the solutions of the resonance conditions, we show that the nonlinear interaction is dominantly one dimensional and involves collinear wave vectors. Furthermore, taking into account the spectral widening due to weak nonlinearity explains why nonlocal interactions are possible between a gravity wave and high-frequency capillary ones. We observe also that nonlinear three-wave coupling is possible among gravity waves, and we raise the question of the relevance of this mechanism for oceanic waves. PMID- 25910128 TI - Nonlinear force propagation during granular impact. AB - We experimentally study nonlinear force propagation into granular material during impact from an intruder, and we explain our observations in terms of the nonlinear grain-scale force relation. Using high-speed video and photoelastic particles, we determine the speed and spatial structure of the force response just after impact. We show that these quantities depend on a dimensionless parameter, M^{'}=t_{c}v_{0}/d, where v_{0} is the intruder speed at impact, d is the particle diameter, and t_{c} is the collision time for a pair of grains impacting at relative speed v_{0}. The experiments access a large range of M^{'} by using particles of three different materials. When M^{'}?1, force propagation is chainlike with a speed, v_{f}, satisfying v_{f}?d/t_{c}. For larger M^{'}, the force response becomes spatially dense and the force propagation speed departs from v_{f}?d/t_{c}, corresponding to collective stiffening of a strongly compressed packing of grains. PMID- 25910129 TI - Instability, turbulence, and 3D magnetic reconnection in a line-tied, zero net current screw pinch. AB - This Letter reports the first experimental investigation into a line-tied plasma with a reversed current profile. Discrete current sources create a cylindrical plasma equilibrium with an axial field and zero net current. Detailed magnetic measurements show that an internal m=1 mode with no external character grows exponentially. The nonlinear evolution of the mode drives 3D reconnection events that reorganize the plasma equilibrium. The plasma is turbulent and exhibits reconnection events on a range of scales. These data are consistent with recent simulations of coronal loops and the nanoflare coronal heating mechanism. PMID- 25910130 TI - From phase locking to phase slips: a mechanism for a quiescent H mode. AB - We demonstrate that E*B shear, V_{E*B}^{'}, governs the dynamics of the cross phase of the peeling-ballooning-(PB-)mode-driven heat flux, and so determines the evolution from the edge-localized (ELMy) H mode to the quiescent (Q) H mode. A physics-based scaling of the critical E*B shearing rate (V_{E*B,cr}^{'}) for accessing the QH mode is predicted. The ELMy H mode to the QH-mode evolution is shown to follow from the conversion from a phase locked state to a phase slip state. In the phase locked state, PB modes are pumped continuously, so bursts occur. In the slip state, the PB activity is a coherent oscillation. Stronger E*B shearing implies a higher phase slip frequency. This finding predicts a new state of cross phase dynamics and shows a new way to understand the physics mechanism for ELMy to the QH-mode evolution. PMID- 25910131 TI - Plasma undulator based on laser excitation of wakefields in a plasma channel. AB - An undulator is proposed based on the plasma wakefields excited by a laser pulse in a plasma channel. Generation of the undulator fields is achieved by inducing centroid oscillations of the laser pulse in the channel. The period of such an undulator is proportional to the Rayleigh length of the laser pulse and can be submillimeter, while preserving high undulator strength. The electron trajectories in the undulator are examined, expressions for the undulator strength are presented, and the spontaneous radiation is calculated. Multimode and multicolor laser pulses are considered for greater tunability of the undulator period and strength. PMID- 25910133 TI - Three-dimensional drift kinetic response of high-beta plasmas in the DIII-D tokamak. AB - A quantitative interpretation of the experimentally measured high-pressure plasma response to externally applied three-dimensional (3D) magnetic field perturbations, across the no-wall Troyon beta limit, is achieved. The self consistent inclusion of the drift kinetic effects in magnetohydrodynamic (MHD) modeling [Y. Q. Liu et al., Phys. Plasmas 15, 112503 (2008)] successfully resolves an outstanding issue of the ideal MHD model, which significantly overpredicts the plasma-induced field amplification near the no-wall limit, as compared to experiments. The model leads to quantitative agreement not only for the measured field amplitude and toroidal phase but also for the measured internal 3D displacement of the plasma. The results can be important to the prediction of the reliable plasma behavior in advanced fusion devices, such as ITER [K. Ikeda, Nucl. Fusion 47, S1 (2007)]. PMID- 25910132 TI - Thin shell, high velocity inertial confinement fusion implosions on the national ignition facility. AB - Experiments have recently been conducted at the National Ignition Facility utilizing inertial confinement fusion capsule ablators that are 175 and 165 MUm in thickness, 10% and 15% thinner, respectively, than the nominal thickness capsule used throughout the high foot and most of the National Ignition Campaign. These three-shock, high-adiabat, high-foot implosions have demonstrated good performance, with higher velocity and better symmetry control at lower laser powers and energies than their nominal thickness ablator counterparts. Little to no hydrodynamic mix into the DT hot spot has been observed despite the higher velocities and reduced depth for possible instability feedthrough. Early results have shown good repeatability, with up to 1/2 the neutron yield coming from alpha particle self-heating. PMID- 25910134 TI - Quantum critical spin-2 chain with emergent SU(3) symmetry. AB - We study the quantum critical phase of an SU(2) symmetric spin-2 chain obtained from spin-2 bosons in a one-dimensional lattice. We obtain the scaling of the finite-size energies and entanglement entropy by exact diagonalization and density-matrix renormalization group methods. From the numerical results of the energy spectra, central charge, and scaling dimension we identify the conformal field theory describing the whole critical phase to be the SU(3)_{1} Wess-Zumino Witten model. We find that, while the Hamiltonian is only SU(2) invariant, in this critical phase there is an emergent SU(3) symmetry in the thermodynamic limit. PMID- 25910135 TI - Ultracompact interference phonon nanocapacitor for storage and lasing of coherent terahertz lattice waves. AB - We introduce a novel ultracompact nanocapacitor of coherent phonons formed by high-finesse interference mirrors based on atomic-scale semiconductor metamaterials. Our molecular dynamics simulations show that the nanocapacitor stores coherent monochromatic terahertz lattice waves, which can be used for phonon lasing-the emission of coherent phonons. Either one- or two-color phonon emission can be realized depending on the geometry of the nanodevice. The two color regime of the interference phonon nanocapacitor originates from the different incidence-angle dependence of the transmission of longitudinal and transverse phonons at the respective interference antiresonances. Coherent phonon storage can be achieved by an adiabatic cooling the nanocapacitor initially thermalized at room temperature or by the pump-probe optical technique. The linewidth narrowing and the computed relative phonon participation number confirm strong phonon confinement in the ultracompact interference nanocavity by an extremely small amount of resonance defects. The emission of coherent terahertz acoustic beams from the nanocapacitor can be realized by applying a tunable reversible stress, which shifts the frequencies of the interference antiresonances. PMID- 25910136 TI - Phonon-induced population dynamics and intersystem crossing in nitrogen-vacancy centers. AB - We report direct measurement of population dynamics in the excited state manifold of a nitrogen-vacancy (NV) center in diamond. We quantify the phonon-induced mixing rate and demonstrate that it can be completely suppressed at low temperatures. Further, we measure the intersystem crossing (ISC) rate for different excited states and develop a theoretical model that unifies the phonon induced mixing and ISC mechanisms. We find that our model is in excellent agreement with experiment and that it can be used to predict unknown elements of the NV center's electronic structure. We discuss the model's implications for enhancing the NV center's performance as a room-temperature sensor. PMID- 25910137 TI - Force field analysis suggests a lowering of diffusion barriers in atomic manipulation due to presence of STM tip. AB - We study the physics of atomic manipulation of CO on a Cu(111) surface by combined scanning tunneling microscopy and atomic force microscopy at liquid helium temperatures. In atomic manipulation, an adsorbed atom or molecule is arranged on the surface using the interaction of the adsorbate with substrate and tip. While previous experiments are consistent with a linear superposition model of tip and substrate forces, we find that the force threshold depends on the force field of the tip. Here, we use carbon monoxide front atom identification (COFI) to characterize the tip's force field. Tips that show COFI profiles with an attractive center can manipulate CO in any direction while tips with a repulsive center can only manipulate in certain directions. The force thresholds are independent of bias voltage in a range from 1 to 10 mV and independent of temperature in a range of 4.5 to 7.5 K. PMID- 25910138 TI - Dynamics of atomic stick-slip friction examined with atomic force microscopy and atomistic simulations at overlapping speeds. AB - Atomic force microscopy (AFM) and atomistic simulations of atomic friction with silicon oxide tips sliding on Au(111) are conducted at overlapping speeds. Experimental data unambiguously reveal a stick-slip friction plateau above a critical scanning speed, in agreement with the thermally activated Prandtl Tomlinson (PTT) model. However, friction in experiments is larger than in simulations. PTT energetic parameters for the two are comparable, with minor differences attributable to the contact area's influence on the barrier to slip. Recognizing that the attempt frequency may be determined by thermal vibrations of the larger AFM tip mass or instrument noise fully resolves the discrepancy. Thus, atomic stick-slip is well described by the PTT model if sources of slip-assisting energy are accounted for. PMID- 25910139 TI - Charge-density wave in Ca-intercalated bilayer graphene induced by commensurate lattice matching. AB - We report the emergence of a charge-density wave (CDW) in Ca-intercalated bilayer graphene (C_{6}CaC_{6}), the thinnest limit of superconducting C_{6}Ca, observed by low-temperature, high-magnetic-field scanning tunneling microscopy or spectroscopy, and angle-resolved photoemission spectroscopy. While the possible superconductivity was not observed in epitaxially grown C_{6}CaC_{6} on a SiC substrate, a CDW order different from that observed on the surface of bulk C_{6}Ca was observed. It is inferred that the CDW state is induced by the potential modulation due to the commensurate lattice matching between the C_{6}CaC_{6} film and the SiC substrate. PMID- 25910140 TI - Differences between thermal and laser-induced diffusion. AB - A combination of femtosecond laser excitation with a low-temperature scanning tunneling microscope is used to study long-range interaction during diffusion of CO on Cu(111). Both thermal and laser-driven diffusion show an oscillatory energy dependence on the distance to neighboring molecules. Surprisingly, the phase is inverted; i.e., at distances at which thermal diffusion is most difficult, it is easiest for laser-driven diffusion and vice versa. We explain this unexpected behavior by a transient stabilization of the negative ion during diffusion as corroborated by ab initio calculations. PMID- 25910141 TI - Thermocapillary phenomena and performance limitations of a wickless heat pipe in microgravity. AB - A counterintuitive, thermocapillary-induced limit to heat- pipe performance was observed that is not predicted by current thermal-fluid models. Heat pipes operate under a number of physical constraints including the capillary, boiling, sonic, and entrainment limits that fundamentally affect their performance. Temperature gradients near the heated end may be high enough to generate significant Marangoni forces that oppose the return flow of liquid from the cold end. These forces are believed to exacerbate dry out conditions and force the capillary limit to be reached prematurely. Using a combination of image and thermal data from experiments conducted on the International Space Station with a transparent heat pipe, we show that in the presence of significant Marangoni forces, dry out is not the initial mechanism limiting performance, but that the physical cause is exactly the opposite behavior: flooding of the hot end with liquid. The observed effect is a consequence of the competition between capillary and Marangoni-induced forces. The temperature signature of flooding is virtually identical to dry out, making diagnosis difficult without direct visual observation of the vapor-liquid interface. PMID- 25910142 TI - Mobility of Holstein polaron at finite temperature: an unbiased approach. AB - We present the first unbiased results for the mobility MU of a one-dimensional Holstein polaron obtained by numerical analytic continuation combined with diagrammatic and worldline Monte Carlo methods in the thermodynamic limit. We have identified for the first time several distinct regimes in the lambda-T plane including a band conduction region, incoherent metallic region, an activated hopping region, and a high-temperature saturation region. We observe that although mobilities and mean free paths at different values of lambda differ by many orders of magnitude at small temperatures, their values at T larger than the bandwidth become very close to each other. PMID- 25910143 TI - Estimating excitonic effects in the absorption spectra of solids: problems and insight from a guided iteration scheme. AB - A major obstacle for computing optical spectra of solids is the lack of reliable approximations for capturing excitonic effects within time-dependent density functional theory. We show that the accurate prediction of strongly bound electron-hole pairs within this framework using simple approximations is still a challenge and that available promising results have to be revisited. Deriving a set of analytical formulas we analyze and explain the difficulties. We deduce an alternative approximation from an iterative scheme guided by previously available knowledge, significantly improving the description of exciton binding energies. Finally, we show how one can "read" exciton binding energies from spectra determined in the random phase approximation, without any further calculation. PMID- 25910144 TI - Reemergent superconductivity and avoided quantum criticality in Cd-doped CeIrIn(5) under pressure. AB - We investigated the electrical resistivity and heat capacity of 1% Cd-doped CeIrIn_{5} under hydrostatic pressure up to 2.7 GPa, near where long-range antiferromagnetic order is suppressed and bulk superconductivity suddenly reemerges. The pressure-induced T_{c} is close to that of pristine CeIrIn_{5} at 2.7 GPa, and no signatures of a quantum critical point under pressure support a local origin of the antiferromagnetic moments in Cd-CeIrIn_{5} at ambient pressure. Similarities between superconductors CeIrIn_{5} and CeCoIn_{5} in response to Cd substitutions suggest a common magnetic mechanism. PMID- 25910145 TI - Band structures of plasmonic polarons. AB - Using state-of-the-art many-body calculations based on the "GW plus cumulant" approach, we show that electron-plasmon interactions lead to the emergence of plasmonic polaron bands in the band structures of common semiconductors. Using silicon and group IV transition-metal dichalcogenide monolayers (AX_{2} with A=Mo,W and X=S, Se) as prototypical examples, we demonstrate that these new bands are a general feature of systems characterized by well-defined plasmon resonances. We find that the energy versus momentum dispersion relations of these plasmonic structures closely follow the standard valence bands, although they appear broadened and blueshifted by the plasmon energy. Based on our results, we identify general criteria for observing plasmonic polaron bands in the angle resolved photoelectron spectra of solids. PMID- 25910146 TI - Nearest neighbor tight binding models with an exact mobility edge in one dimension. AB - We investigate localization properties in a family of deterministic (i.e., no disorder) nearest neighbor tight binding models with quasiperiodic on site modulation. We prove that this family is self-dual under a generalized duality transformation. The self-dual condition for this general model turns out to be a simple closed form function of the model parameters and energy. We introduce the typical density of states as an order parameter for localization in quasiperiodic systems. By direct calculations of the inverse participation ratio and the typical density of states we numerically verify that this self-dual line indeed defines a mobility edge in energy separating localized and extended states. Our model is a first example of a nearest neighbor tight binding model manifesting a mobility edge protected by a duality symmetry. We propose a realistic experimental scheme to realize our results in atomic optical lattices and photonic waveguides. PMID- 25910147 TI - Chiral thermoelectrics with quantum Hall edge states. AB - The thermoelectric properties of a three-terminal quantum Hall conductor are investigated. We identify a contribution to the thermoelectric response that relies on the chirality of the carrier motion rather than on spatial asymmetries. The Onsager matrix becomes maximally asymmetric with configurations where either the Seebeck or the Peltier coefficients are zero while the other one remains finite. Reversing the magnetic field direction exchanges these effects, which originate from the chiral nature of the quantum Hall edge states. The possibility to generate spin-polarized currents in quantum spin Hall samples is discussed. PMID- 25910148 TI - Experimental verification of the van Vleck nature of long-range ferromagnetic order in the vanadium-doped three-dimensional topological insulator Sb(2)Te(3). AB - We demonstrate by high resolution low temperature electron energy loss spectroscopy (EELS) measurements that the long range ferromagnetic (FM) order in the vanadium- (V-)doped topological insulator Sb_{2}Te_{3} has the nature of van Vleck-type ferromagnetism. The positions and the relative amplitudes of two core level peaks (L_{3} and L_{2}) of the V EELS spectrum show unambiguous change when the sample is cooled from room temperature to T=10 K. Magnetotransport and comparison of the measured and simulated EELS spectra confirm that these changes originate from the onset of FM order. Crystal field analysis indicates that in V doped Sb_{2}Te_{3}, partially filled core states contribute to the FM order. Since van Vleck magnetism is a result of summing over all states, this magnetization of core level verifies the van Vleck-type ferromagnetism in a direct manner. PMID- 25910149 TI - Charge and spin transport in edge channels of a nu=0 quantum Hall system on the surface of topological insulators. AB - Three-dimensional topological insulators of finite thickness can show the quantum Hall effect (QHE) at the filling factor nu=0 under an external magnetic field if there is a finite potential difference between the top and bottom surfaces. We calculate energy spectra of surface Weyl fermions in the nu=0 QHE and find that gapped edge states with helical spin structure are formed from Weyl fermions on the side surfaces under certain conditions. These edge channels account for the nonlocal charge transport in the nu=0 QHE which is observed in a recent experiment on (Bi_{1-x}Sb_{x})_{2}Te_{3} films. The edge channels also support spin transport due to the spin-momentum locking. We propose an experimental setup to observe various spintronics functions such as spin transport and spin conversion. PMID- 25910150 TI - Local density of states at metal-semiconductor interfaces: an atomic scale study. AB - We investigate low temperature grown, abrupt, epitaxial, nonintermixed, defect free n-type and p-type Fe/GaAs(110) interfaces by cross-sectional scanning tunneling microscopy and spectroscopy with atomic resolution. The probed local density of states shows that a model of the ideal metal-semiconductor interface requires a combination of metal-induced gap states and bond polarization at the interface which is nicely corroborated by density functional calculations. A three-dimensional finite element model of the space charge region yields a precise value for the Schottky barrier height. PMID- 25910151 TI - Voltage fluctuation to current converter with Coulomb-coupled quantum dots. AB - We study the rectification of voltage fluctuations in a system consisting of two Coulomb-coupled quantum dots. The first quantum dot is connected to a reservoir where voltage fluctuations are supplied and the second one is attached to two separate leads via asymmetric and energy-dependent transport barriers. We observe a rectified output current through the second quantum dot depending quadratically on the noise amplitude supplied to the other Coulomb-coupled quantum dot. The current magnitude and direction can be switched by external gates, and maximum output currents are found in the nA region. The rectification delivers output powers in the pW region. Future devices derived from our sample may be applied for energy harvesting on the nanoscale beneficial for autonomous and energy efficient electronic applications. PMID- 25910152 TI - Collapse of the normal-state pseudogap at a Lifshitz transition in the Bi(2)Sr(2)CaCu(2)O(8+delta) cuprate superconductor. AB - We report a fine tuned doping study of strongly overdoped Bi_{2}Sr_{2}CaCu_{2}O_{8+delta} single crystals using electronic Raman scattering. Combined with theoretical calculations, we show that the doping, at which the normal-state pseudogap closes, coincides with a Lifshitz quantum phase transition where the active holelike Fermi surface becomes electronlike. This conclusion suggests that the microscopic cause of the pseudogap is sensitive to the Fermi surface topology. Furthermore, we find that the superconducting transition temperature is unaffected by this transition, demonstrating that their origins are different on the overdoped side. PMID- 25910153 TI - Field-orientation dependence of low-energy quasiparticle excitations in the heavy electron superconductor UBe(13). AB - Low-energy quasiparticle excitations in the superconducting (SC) state of UBe_{13} were studied by means of specific-heat (C) measurements in a rotating field. Quite unexpectedly, the magnetic-field dependence of C(H) is linear in H with no angular dependence at low fields in the SC state, implying that the gap is fully open over the Fermi surfaces, in stark contrast to previous expectations. In addition, a characteristic cubic anisotropy of C(H) was observed above 2 T with a maximum (minimum) for H?[001] ([111]) within the (11[over -]0) plane, in the normal as well as in the SC states. This oscillation possibly originates from the anisotropic response of the heavy quasiparticle bands, and might be a key to understand the unusual properties of UBe_{13}. PMID- 25910154 TI - Emergent loop-nodal s(+/-)-wave superconductivity in CeCu(2)Si(2): similarities to the iron-based superconductors. AB - Heavy-fermion superconductors are prime candidates for novel electron-pairing states due to the spin-orbital coupled degrees of freedom and electron correlations. Superconductivity in CeCu_{2}Si_{2} discovered in 1979, which is a prototype of unconventional (non-BCS) superconductors in strongly correlated electron systems, still remains unsolved. Here we provide the first report of superconductivity based on the advanced first-principles theoretical approach. We find that the promising candidate is an s_{+/-}-wave state with loop-shaped nodes on the Fermi surface, different from the widely expected line-nodal d-wave state. The dominant pairing glue is magnetic but high-rank octupole fluctuations. This system shares the importance of multiorbital degrees of freedom with the iron based superconductors. Our findings reveal not only the long-standing puzzle in this material, but also urge us to reconsider the pairing states and mechanisms in all heavy-fermion superconductors. PMID- 25910155 TI - NMR investigation of the quasi-one-dimensional superconductor K(2)Cr(3)As(3). AB - We report ^{75}As NMR measurements on the new quasi-one-dimensional superconductor K_{2}Cr_{3}As_{3} (T_{c}~6.1 K) [J. K. Bao et al., Phys. Rev. X 5, 011013 (2015)]. We found evidence for strong enhancement of Cr spin fluctuations above T_{c} in the [Cr_{3}As_{3}]_{infinity} double-walled subnanotubes based on the nuclear spin-lattice relaxation rate 1/T_{1}. The power law temperature dependence, 1/T_{1}T~T^{-gamma} (gamma~0.25), is consistent with the Tomonaga-Luttinger liquid. Moreover, absence of the Hebel-Slichter coherence peak of 1/T_{1} just below T_{c} suggests an unconventional nature of superconductivity. PMID- 25910156 TI - Scattering continuum and possible fractionalized excitations in alpha-RuCl(3). AB - The combination of electronic correlation and spin-orbit coupling is thought to precipitate a variety of highly unusual electronic phases in solids, including topological and quantum spin liquid states. We report a Raman scattering study that provides evidence for unconventional excitations in alpha-RuCl_{3}, a spin orbit coupled Mott insulator on the honeycomb lattice. In particular, our measurements reveal unusual magnetic scattering, typified by a broad continuum. The temperature dependence of this continuum is evident over a large scale compared to the magnetic ordering temperature, suggestive of frustrated magnetic interactions. This is confirmed through an analysis of the phonon linewidths, which show a related anomaly due to spin-phonon coupling. These observations are in line with theoretical expectations for the Heisenberg-Kitaev model and suggest that alpha-RuCl_{3} may be close to a quantum spin liquid ground state. PMID- 25910158 TI - Quantum versus classical annealing: insights from scaling theory and results for spin glasses on 3-regular graphs. AB - We discuss an Ising spin glass where each S=1/2 spin is coupled antiferromagnetically to three other spins (3-regular graphs). Inducing quantum fluctuations by a time-dependent transverse field, we use out-of-equilibrium quantum Monte Carlo simulations to study dynamic scaling at the quantum glass transition. Comparing the dynamic exponent and other critical exponents with those of the classical (temperature-driven) transition, we conclude that quantum annealing is less efficient than classical simulated annealing in bringing the system into the glass phase. Quantum computing based on the quantum annealing paradigm is therefore inferior to classical simulated annealing for this class of problems. We also comment on previous simulations where a parameter is changed with the simulation time, which is very different from the true Hamiltonian dynamics simulated here. PMID- 25910157 TI - Ferromagnetism and nonmetallic transport of thin-film alpha-FeSi(2): a stabilized metastable material. AB - A metastable phase alpha-FeSi_{2} was epitaxially stabilized on a silicon substrate using pulsed laser deposition. Nonmetallic and ferromagnetic behaviors are tailored on alpha-FeSi_{2} (111) thin films, while the bulk material of alpha FeSi_{2} is metallic and nonmagnetic. The transport property of the films renders two different conducting states with a strong crossover at 50 K, which is accompanied by the onset of a ferromagnetic transition as well as a substantial magnetoresistance. These experimental results are discussed in terms of the unusual electronic structure of alpha-FeSi_{2} obtained within density functional calculations and Boltzmann transport calculations with and without strain. Our finding sheds light on achieving ferromagnetic semiconductors through both their structure and doping tailoring, and provides an example of a tailored material with rich functionalities for both basic research and practical applications. PMID- 25910159 TI - Predicting a ferrimagnetic phase of Zn(2)FeOsO(6) with strong magnetoelectric coupling. AB - Multiferroic materials, in which ferroelectric and magnetic ordering coexist, are of practical interest for the development of novel memory devices that allow for electrical writing and nondestructive magnetic readout operation. The great challenge is to create room temperature multiferroic materials with strongly coupled ferroelectric and ferromagnetic (or ferrimagnetic) orderings. BiFeO_{3} is the most heavily investigated single-phase multiferroic to date due to the coexistence of its magnetic order and ferroelectric order at room temperature. However, there is no net magnetic moment in the cycloidal (antiferromagneticlike) magnetic state of bulk BiFeO_{3}, which severely limits its realistic applications in electric field controlled memory devices. Here, we predict that LiNbO_{3}-type Zn_{2}FeOsO_{6} is a new multiferroic with properties superior to BiFeO_{3}. First, there are strong ferroelectricity and strong ferrimagnetism at room temperature in Zn_{2}FeOsO_{6}. Second, the easy plane of the spontaneous magnetization can be switched by an external electric field, evidencing the strong magnetoelectric coupling existing in this system. Our results suggest that ferrimagnetic 3d-5d LiNbO_{3}-type material may therefore be used to achieve voltage control of magnetism in future memory devices. PMID- 25910160 TI - All-in-all-out magnetic domains: x-ray diffraction imaging and magnetic field control. AB - Long-range noncollinear all-in-all-out magnetic order has been directly observed for the first time in real space in the pyrochlore Cd_{2}Os_{2}O_{7} using resonant magnetic microdiffraction at the Os L_{3} edge. Two different antiferromagnetic domains related by time-reversal symmetry could be distinguished and have been mapped within the same single crystal. The two types of domains are akin to magnetic twins and were expected-yet unobserved so far-in the all-in-all-out model. Even though the magnetic domains are antiferromagnetic, we show that their distribution can be controlled using a magnetic field-cooling procedure. PMID- 25910161 TI - Proposed parameter-free model for interpreting the measured positron annihilation spectra of materials using a generalized gradient approximation. AB - Positron annihilation spectroscopy is often used to analyze the local electronic structure of materials of technological interest. Reliable theoretical tools are crucial to interpret the measured spectra. Here, we propose a parameter-free gradient correction scheme for a local-density approximation obtained from high quality quantum Monte Carlo data. The results of our calculations compare favorably with positron affinity and lifetime measurements, opening new avenues for highly precise and advanced positron characterization of materials. PMID- 25910162 TI - Spin precession mapping at ferromagnetic resonance via nuclear resonant scattering of synchrotron radiation. AB - We probe the spin dynamics in a thin magnetic film at ferromagnetic resonance by nuclear resonant scattering of synchrotron radiation at the 14.4 keV resonance of ^{57}Fe. The precession of the magnetization leads to an apparent reduction of the magnetic hyperfine field acting at the ^{57}Fe nuclei. The spin dynamics is described in a stochastic relaxation model adapted to the ferromagnetic resonance theory by Smit and Beljers to model the decay of the excited nuclear state. From the fits of the measured data, the shape of the precession cone of the spins is determined. Our results open a new perspective to determine magnetization dynamics in layered structures with very high depth resolution by employing ultrathin isotopic probe layers. PMID- 25910163 TI - Electromagnetic radiation under explicit symmetry breaking. AB - We report our observation that radiation from a system of accelerating charges is possible only when there is explicit breaking of symmetry in the electric field in space within the spatial configuration of the radiating system. Under symmetry breaking, current within an enclosed area around the radiating structure is not conserved at a certain instant of time resulting in radiation in free space. Electromagnetic radiation from dielectric and piezoelectric material based resonators are discussed in this context. Finally, it is argued that symmetry of a resonator of any form can be explicitly broken to create a radiating antenna. PMID- 25910164 TI - Why microtubules run in circles: mechanical hysteresis of the tubulin lattice. AB - The fate of every eukaryotic cell subtly relies on the exceptional mechanical properties of microtubules. Despite significant efforts, understanding their unusual mechanics remains elusive. One persistent, unresolved mystery is the formation of long-lived arcs and rings, e.g., in kinesin-driven gliding assays. To elucidate their physical origin we develop a model of the inner workings of the microtubule's lattice, based on recent experimental evidence for a conformational switch of the tubulin dimer. We show that the microtubule lattice itself coexists in discrete polymorphic states. Metastable curved states can be induced via a mechanical hysteresis involving torques and forces typical of few molecular motors acting in unison, in agreement with the observations. PMID- 25910165 TI - Hyperuniform density fluctuations and diverging dynamic correlations in periodically driven colloidal suspensions. AB - The emergence of particle irreversibility in periodically driven colloidal suspensions has been interpreted as resulting either from a nonequilibrium phase transition to an absorbing state or from the chaotic nature of particle trajectories. Using a simple model of a driven suspension, we show that a nonequilibrium phase transition is accompanied by hyperuniform static density fluctuations in the vicinity of the transition, where we also observe strong dynamic heterogeneities reminiscent of dynamics in glassy materials. We find that single particle dynamics becomes intermittent and strongly non-Fickian, and that collective dynamics becomes spatially correlated over diverging length scales. Our results suggest that the two theoretical scenarii can be experimentally discriminated using particle-resolved measurements of standard static and dynamic observables. PMID- 25910166 TI - Uncertainty loops in travel-time tomography from nonlinear wave physics. AB - Estimating image uncertainty is fundamental to guiding the interpretation of geoscientific tomographic maps. We reveal novel uncertainty topologies (loops) which indicate that while the speeds of both low- and high-velocity anomalies may be well constrained, their locations tend to remain uncertain. The effect is widespread: loops dominate around a third of United Kingdom Love wave tomographic uncertainties, changing the nature of interpretation of the observed anomalies. Loops exist due to 2nd and higher order aspects of wave physics; hence, although such structures must exist in many tomographic studies in the physical sciences and medicine, they are unobservable using standard linearized methods. Higher order methods might fruitfully be adopted. PMID- 25910167 TI - Comment on "origin of surface canting within Fe(3)O(4) nanoparticles". PMID- 25910168 TI - Krycka et al. reply. PMID- 25910169 TI - A model-based assessment of the cost-utility of strategies to identify Lynch syndrome in early-onset colorectal cancer patients. AB - BACKGROUND: Lynch syndrome is an autosomal dominant cancer predisposition syndrome caused by mutations in the DNA mismatch repair genes MLH1, MSH2, MSH6 and PMS2. Individuals with Lynch syndrome have an increased risk of colorectal cancer, endometrial cancer, ovarian and other cancers. Lynch syndrome remains underdiagnosed in the UK. Reflex testing for Lynch syndrome in early-onset colorectal cancer patients is proposed as a method to identify more families affected by Lynch syndrome and offer surveillance to reduce cancer risks, although cost-effectiveness is viewed as a barrier to implementation. The objective of this project was to estimate the cost-utility of strategies to identify Lynch syndrome in individuals with early-onset colorectal cancer in the NHS. METHODS: A decision analytic model was developed which simulated diagnostic and long-term outcomes over a lifetime horizon for colorectal cancer patients with and without Lynch syndrome and for relatives of those patients. Nine diagnostic strategies were modelled which included microsatellite instability (MSI) testing, immunohistochemistry (IHC), BRAF mutation testing (methylation testing in a scenario analysis), diagnostic mutation testing and Amsterdam II criteria. Biennial colonoscopic surveillance was included for individuals diagnosed with Lynch syndrome and accepting surveillance. Prophylactic hysterectomy with bilateral salpingo-oophorectomy (H-BSO) was similarly included for women diagnosed with Lynch syndrome. Costs from NHS and Personal Social Services perspective and quality-adjusted life years (QALYs) were estimated and discounted at 3.5% per annum. RESULTS: All strategies included for the identification of Lynch syndrome were cost-effective versus no testing. The strategy with the greatest net health benefit was MSI followed by BRAF followed by diagnostic genetic testing, costing L5,491 per QALY gained over no testing. The effect of prophylactic H-BSO on health-related quality of life (HRQoL) is uncertain and could outweigh the health benefits of testing, resulting in overall QALY loss. CONCLUSIONS: Reflex testing for Lynch syndrome in early-onset colorectal cancer patients is predicted to be a cost-effective use of limited financial resources in England and Wales. Research is recommended into the cost effectiveness of reflex testing for Lynch syndrome in other associated cancers and into the impact of prophylactic H-BSO on HRQoL. PMID- 25910170 TI - Automatic supporting system for regionalization of ventricular tachycardia exit site in implantable defibrillators. AB - Electrograms stored in Implantable Cardioverter Defibrillators (ICD-EGM) have been proven to convey useful information for roughly determining the anatomical location of the Left Ventricular Tachycardia exit site (LVTES). Our aim here was to evaluate the possibilities from a machine learning system intended to provide an estimation of the LVTES anatomical region with the use of ICD-EGM in the situation where 12-lead electrocardiogram of ventricular tachycardia are not available. Several machine learning techniques were specifically designed and benchmarked, both from classification (such as Neural Networks (NN), and Support Vector Machines (SVM)) and regression (Kernel Ridge Regression) problem statements. Classifiers were evaluated by using accuracy rates for LVTES identification in a controlled number of anatomical regions, and the regression approach quality was studied in terms of the spatial resolution. We analyzed the ICD-EGM of 23 patients (18+/-10 EGM per patient) during left ventricular pacing and simultaneous recording of the spatial coordinates of the pacing electrode with a navigation system. Several feature sets extracted from ICD-EGM (consisting of times and voltages) were shown to convey more discriminative information than the raw waveform. Among classifiers, the SVM performed slightly better than NN. In accordance with previous clinical works, the average spatial resolution for the LVTES was about 3 cm, as in our system, which allows it to support the faster determination of the LVTES in ablation procedures. The proposed approach also provides with a framework suitable for driving the design of improved performance future systems. PMID- 25910171 TI - Clinical and economic consequences of failure of initial antibiotic therapy for patients with community-onset complicated intra-abdominal infections. AB - OBJECTIVES: Complicated intra-abdominal infection (cIAI) is infection that extends beyond the hollow viscus of origin into the peritoneal space, and is associated with either abscess formation or peritonitis. There are few studies that have assessed the actual costs and outcomes associated with failure of initial antibiotic therapy for cIAI. The aims of this study were to evaluate risk factors and impact on costs and outcomes of failure of initial antibiotic therapy for community-onset cIAI. METHODS: A retrospective study was performed at eleven tertiary-care hospitals. Hospitalized adults with community-onset cIAI who underwent an appropriate source control procedure between August 2008 and September 2011 were included. Failure of initial antibiotic therapy was defined as a change of antibiotics due to a lack of improvement of the clinical symptoms and signs associated with cIAI in the first week. RESULTS: A total of 514 patients hospitalized for community-onset cIAI were included in the analysis. The mean age of the patients was 53.3 +/- 17.6 years, 72 patients (14%) had health care-associated infection, and 48 (9%) experienced failure of initial antibiotic therapy. Failure of initial antibiotic therapy was associated with increased costs and morbidity. After adjustment for covariates, patients with unsuccessful initial therapy received an additional 2.9 days of parenteral antibiotic therapy, were hospitalized for an additional 5.3 days, and incurred $3,287 in additional inpatient charges. Independent risk factors for failure of initial antibiotic therapy were health care-associated infection, solid cancer, and APACHE II >=13. CONCLUSIONS: To improve outcomes and costs in patients with community-onset cIAI, rapid assessment of health care-associated risk factors and severity of disease, selection of an appropriate antibiotic regimen accordingly, and early infection source control should be performed. PMID- 25910172 TI - Growth of the tropical zoanthid Palythoa caribaeorum (Cnidaria: Anthozoa) on reefs in northeastern Brazil. AB - In Brazilian reefs, zoanthids, especially Palythoa caribaeorum are fundamental for structuring the local benthic community. The objective of this study was to determine the growth rate of P. caribaeorum, and to assess the influence of the site (different beaches), season (dry and wet), location (intertidal or infralittoral zones), and human pressure associated with tourism. For one year we monitored the cover of P. caribaeorum in transects and focused on 20 colonies. We cut off a square (100 cm2) from the central part of the colony and monitored the bare area for four months in each season. The average growth rates varied from 0.015 and 0.021 cm.day(-1). The rate was homogeneous in all localities, and there was no influence from colony site, location, or touristic visitation, showing that the growth velocity may be an intrinsic characteristic of the species, with a strong genetic component. The growth rate of P. caribaeorum differed among months, and peaked in the first month after injury. The average cover varied from 6.2 to 22.9% and was lower on the reef visited by tourists. The present study corroborates the hypothesis that P. caribaeorum is important for coastal reef dynamics due to its fast and continuous growth. PMID- 25910173 TI - Saturniidae and Sphingidae (Lepidoptera, Bombycoidea) assemblage in Vossoroca, Tijucas do Sul, Parana, Brazil. AB - The richness and abundance of the assemblage of species in a community are a way to understand the patterns of diversity found around the world. This study describes the assemblages of Saturniidae and Sphingidae in an area of Montana Mixed Ombrophilous Forest, Tijucas do Sul, Parana, Brazil, 880m, 25o50'8.93"S, 49o 02'55.20"W. Samples were collected between November 2010 and September 2011 during two nights at the twelve new moons periods with a light trap equipped with black light lamp (ultraviolet) of 46 watts between two mercury mixed-light lamps HWL 250 watts from 6:00 p.m to 06:00 a.m. The sampling effort totaled 288 hours. This sampling effort was responsible for the capture of 1235 specimens, distributed in 124 species: 858 specimens and 86 species of Saturniidae, and 377 specimens and 38 species of Sphingidae. It is noteworthy the sampling of 10 new species: one of Automerella Michener, 1949, two of Hylesia Hubner, [1820], one of Lonomia Walker, 1855 and six of Periga Walker, 1855, that will be described. PMID- 25910174 TI - Diurnal versus nocturnal pollination success in Billbergia horrida Regel (Bromeliaceae) and the first record of chiropterophily for the genus. AB - Billbergia horrida is endemic of the Atlantic Forest fragments in southeastern Brazil and characterized by flowers with typical traits for pollination by nocturnal animals. Although the majority of Billbergia species rely on diurnal pollination by hummingbirds, B. horrida is also visited by bats and this study evidences for the first time the occurrence of chiropterophily within the genus. The role of different groups of pollinators on the reproductive success of B. horrida was evaluated, as well as the correlation of nectar features in sustaining these animals during different periods of the day. Bats contributed to 82.1% of fruit set of B. horrida. Hummingbirds, in turn, contributed to only 10% of fruit set, and were poorly related to the reproductive success of this species. Amounts of nectar production and sugar concentration were similar to those of other chiropterophilous bromeliads and only the nectar volume changed significantly throughout the period of flower availability. Recurring visits by hummingbirds were probably because the flowers of B. horrida were open for 24h, offering energetic rewards for daytime visitors and due to the presence of other attractive bromeliad species growing at the same phorophyte and flowering at the same time. PMID- 25910175 TI - Neurotrophins, cytokines, oxidative parameters and funcionality in Progressive Muscular Dystrophies. AB - We investigated the levels of brain derived-neurotrophic factor (BDNF), cytokines and oxidative parameters in serum and tried to correlate them with the age and functionality of patients with Progressive Muscle Dystrophies (PMD). The patients were separated into six groups (case and controls pared by age and gender), as follows: Duchenne Muscular Dystrophy (DMD); Steinert Myotonic Dystrophy (SMD); and Limb-girdle Muscular Dystrophy type-2A (LGMD2A). DMD patients (+/- 17.9 years old) had a decrease of functionality, an increase in the IL-1beta and TNF-alpha levels and a decrease of IL-10 levels and superoxide dismutase activity in serum. SMD patients (+/- 25.8 years old) had a decrease of BDNF and IL-10 levels and superoxide dismutase activity and an increase of IL-1beta levels in serum. LGMD2A patients (+/- 27.7 years old) had an decrease only in serum levels of IL-10. This research showed the first evidence of BDNF involvement in the SMD patients and a possible unbalance between pro-inflammatory and anti-inflammatory cytokine levels, along with decreased superoxide dismutase activity in serum of DMD and SMD patients. PMID- 25910176 TI - Glands on the foliar surfaces of tribe Cercideae (Caesapiniodeae, Leguminosae): distribution and taxonomic significance. AB - Large elongated glands occur on Cercideae leaf surfaces. Leaves of Bauhinia (55 taxa, 53 species), Cercis (1 species), Phanera (1 species), Piliostigma (2 species), Schnella (19 species) and Tylosema (1 species) were observed to determine location and relative number of glands. They were only observed on the abaxial leaf surface of 42 Bauhinia taxa. The glands were analyzed by light stereomicroscope and scanning electron microscopy. They are large (up to 270 um long and 115 um wide) and multicellular, containing lipophilic substances, probably volatile oils. Presence or absence and density of the glands in species of Bauhinia may be useful to determine species delimitation or distinction among infraspecific taxa. Higher density of glands is more common in species from "cerrado" (a savanna ecosystem) and "caatinga" (a semiarid ecosystem from northeast Brazil) areas. Bauhinia species devoid of foliar glands are frequently from humid forests. PMID- 25910177 TI - Pushing the Limits: 3D Layer-by-Layer-Assembled Composites for Cathodes with 160 C Discharge Rates. AB - Deficiencies of cathode materials severely limit cycling performance and discharge rates of Li batteries. The key problem is that cathode materials must combine multiple properties: high lithium ion intercalation capacity, electrical/ionic conductivity, porosity, and mechanical toughness. Some materials revealed promising characteristics in a subset of these properties, but attaining the entire set of often contrarian characteristics requires new methods of materials engineering. In this paper, we report high surface area 3D composite from reduced graphene oxide loaded with LiFePO4 (LFP) nanoparticles made by layer by-layer assembly (LBL). High electrical conductivity of the LBL composite is combined with high ionic conductivity, toughness, and low impedance. As a result of such materials properties, reversible lithium storage capacity and Coulombic efficiency were as high as 148 mA h g(-1) and 99%, respectively, after 100 cycles at 1 C. Moreover, these composites enabled unusually high reversible charge discharge rates up to 160 C with a storage capacity of 56 mA h g(-1), exceeding those of known LFP-based cathodes, some of them by several times while retaining high content of active cathode material. The study demonstrates that LBL assembled composites enable resolution of difficult materials engineering tasks. PMID- 25910178 TI - Unusual Example of Chelate Ring Opening upon Coordination of the 9-Ethylguanine Nucleobase to [Pt(di-(6-methyl-2-picolyl)amine)Cl]Cl. AB - Anticancer-active monofunctional Pt(II) complexes have bulky carrier ligands and bind to G residues in DNA, causing structural distortions. To gain fundamental chemical information on such monofunctional adducts, we assessed the 9 ethylguanine (9-EtG) adducts formed by [Pt(N(H)6,6'-Me2dpa)Cl]Cl (N(H)6,6'-Me2dpa = di-(6-methyl-2-picolyl)amine). 9-EtG added to [Pt(N(H)6,6'-Me2dpa)Cl]Cl to form not only the expected [Pt(N(H)6,6'-Me2dpa)(9-EtG)](2+) monoadduct having syn and anti conformers but also a [Pt(N(H)6,6'-Me2dpa)(9-EtG)2](2+) bisadduct consisting of LambdaHT and DeltaHT conformers (HT = head-to-tail). For both adducts, the two conformers exist as a dynamic equilibrium mixture. Concomitant with formation of the bisadduct, the binding mode of the N(H)6,6'-Me2dpa ligand converts from tridentate to bidentate. A Pt(II)-bound 6-methyl-2-picolyl chain and the secondary amine constitute the bidentate chelate ring. The other 6-methyl-2 picolyl chain is dangling. The secondary nitrogen is an asymmetric center, and each conformer exists as a racemic mixture of two enantiomers. For a given configuration at the secondary amine of the [Pt(N(H)6,6'-Me2dpa)(9-EtG)2](2+) adduct, the more abundant HT conformer can form a hydrogen bond between the NH of the bidentate ligand and the cis 9-EtG O6. [Pt(N(H)6,6'-Me2dpa)Cl]Cl forms the monoadduct in ~1/20 the time for its parent, [Pt(N(H)dpa)Cl]Cl (N(H)dpa = di(2 picolyl)amine), which exhibited typical behavior in forming only a monoadduct. We attribute the unusual new findings for [Pt(N(H)6,6'-Me2dpa)Cl]Cl to Pt-N bond weakening induced by the steric bulk of 6/6'-Me groups. We hypothesize that undetectable intermediates with a dangling 6-methyl-2-picolyl chain facilitate both rapid monoadduct formation and also bisadduct formation. Consistent with the intermediacy of such species with a dangling chain, addition of HCl to a [Pt(N(H)6,6'-Me2dpa)Cl]Cl solution readily produced a dichloro complex with the N(H)6,6'-Me2dpa chelate ligand in the bidentate mode, whereas HCl addition had no effect on [Pt(N(H)dpa)Cl]Cl. PMID- 25910179 TI - Surgical Site Infections after Free Flap Breast Reconstruction: An Analysis of 2,899 Patients from the ACS-NSQIP Datasets. AB - BACKGROUND: Surgical site infections (SSIs) are a costly complication, resulting in lower patient satisfaction and higher health care expenditures. Incidence varies widely in the literature by surgery type, yet few studies focus exclusively on autologous breast reconstruction, an increasingly common surgery. The aim of this study is to identify risk factors for SSIs in free flap breast reconstruction using the National Surgical Quality Improvement Program Database (NSQIP). METHODS: Patients undergoing breast reconstruction with any flap type were identified by Current Procedural Terminology codes in the NSQIP database. Patients with superficial or deep SSIs within 30 days of surgery were compared with controls by univariate analysis and multivariate logistic regression across various characteristics. RESULTS: Overall, 2,899 patients undergoing autologous reconstruction were identified. Of these, 143 (4.9%) patients developed SSIs. Those who developed wound complications were more likely smokers (18.2 vs. 8.4%, p < 0.001) and diabetics (9.8 vs. 3.4%, p < 0.001) with hypertension (38.2 vs. 25.4%, p < 0.001) and pulmonary (4.5 vs. 1.3%, p = 0.01) history. SSIs occurred in patients with higher American Society of Anesthesiologists (p = 0.003) and the World Health Organization obesity (p < 0.001) classes. On multivariate regression, SSIs were significantly associated with smoking (odds ratio [OR] = 3.59, p < 0.001) and hypertension (OR = 1.86, p = 0.03). CONCLUSIONS: This study demonstrates that patients who are active smokers or have hypertension are at the highest risk for SSIs. Preoperative identification and tailored postoperative management of these patients may decrease the incidence of this complication. PMID- 25910180 TI - Pressure-dependent optical behaviors of colloidal CdSe nanoplatelets. AB - Two-dimensional (2D) colloidal anisotropic CdSe nanoplatelets (NPLs) have attracted a great deal of attraction within recent years. Their strong thickness dependent absorption and emission spectra exhibit significant differences from those of other shaped CdSe nanocrystals (NCs) due to a unique atomically flat morphology. Based on their dielectric confinement effect and the large confinement energy, the 2D CdSe NPLs exhibit the best characteristics of optical and electronic properties as compared to the other CdSe nanocrystallite ensembles. Here, we systematically investigate the in situ high-pressure photoluminescence (PL), absorption, and time-resolved PL spectroscopy of CdSe NPLs with different thicknesses. The pressure-dependent optical behaviors of these NPLs exhibit several remarkable differences compared with those of other shaped CdSe NCs such as a higher phase transition pressure, irreversible PL and absorption spectra after the release of pressure, a narrower tunable range of absorption and PL peak energies, and minor changes in the ranges of PL decay time with increasing pressure. These phenomena and results are attributed to their unique geometric shape and distinctive soft ligand bonding on the surface. PMID- 25910181 TI - Binding of Substrate Locks the Electrochemistry of CRY-DASH into DNA Repair. AB - VcCry1, a member of the CRY-DASH family, may serve two diverse roles in vivo, including blue-light signaling and repair of UV-damaged DNA. We have discovered that the electrochemistry of the flavin adenine dinucleotide cofactor of VcCry1 is locked to cycle only between the hydroquinone and neutral semiquinone states when UV-damaged DNA is present. Other potential substrates, including undamaged DNA and ATP, have no discernible effect on the electrochemistry, and the kinetics of the reduction is unaffected by damaged DNA. Binding of the damaged DNA substrate determines the role of the protein and prevents the presumed photochemistry required for blue-light signaling. PMID- 25910182 TI - Circulating levels of interleukin 6 soluble receptor and its natural antagonist, sgp130, and the risk of myocardial infarction. AB - OBJECTIVE: To investigate the association between circulating levels of the soluble interleukin 6 receptor (sIL6R) and the soluble gp130 (sgp130) with myocardial infarction (MI) and to explore the potential interaction between sIL6R and sgp130 in this association. METHODS: Study population is the Stockholm Heart Epidemiology Program (SHEEP), a population-based case-control study. SIL6R (ng/mL) and sgp130 (ng/mL) levels were measured in serum samples from 682 and 664 MI cases and 1103 and 1062 controls, respectively. Odds ratios (with 95% CIs) for MI were calculated using unconditional logistic regression. We adjusted for age, sex, hospital catchment area (crude) and for hypertension, diabetes, hypercholesterolemia, body mass index and smoking (adjusted model). Synergy index (S) and attributable proportion (AP) were estimated as measures of biological interaction. RESULTS: Elevated concentrations of sIL6R (>75th percentile value) were associated with an increased occurrence of MI (compared to <=75th percentile), with an adjusted OR of 1.4 (95% CI, 1.1-1.8). Very high (>90th percentile value) levels of sgp130 were associated with a reduced occurrence of MI [OR 0.7 (95% CI, 0.5-0.9)] (adjusted). There was an indication of a possible interaction between high sIL6R and low sgp130 (adjusted S score 1.7, 95% CI = 0.5 6.1; AP 0.19, 95% CI = -0.2-0.5), suggesting that low sgp130 levels may synergize with high sIL6R levels to increase risk of MI. CONCLUSIONS: sIL6R and sgp130 had opposing associations with MI. Indeed, circulating sgp130 levels may modify the association of elevated sIL6R levels with MI. PMID- 25910183 TI - Metal halide solid-state surface treatment for high efficiency PbS and PbSe QD solar cells. AB - We developed a layer-by-layer method of preparing PbE (E = S or Se) quantum dot (QD) solar cells using metal halide (PbI2, PbCl2, CdI2, or CdCl2) salts dissolved in dimethylformamide to displace oleate surface ligands and form conductive QD solids. The resulting QD solids have a significant reduction in the carbon content compared to films treated with thiols and organic halides. We find that the PbI2 treatment is the most successful in removing alkyl surface ligands and also replaces most surface bound Cl(-) with I(-). The treatment protocol results in PbS QD films exhibiting a deeper work function and band positions than other ligand exchanges reported previously. The method developed here produces solar cells that perform well even at film thicknesses approaching a micron, indicating improved carrier transport in the QD films. We demonstrate QD solar cells based on PbI2 with power conversion efficiencies above 7%. PMID- 25910184 TI - Correction: A Genome-Wide Association Study for Diabetic Retinopathy in a Japanese Population: Potential Association with a Long Intergenic Non-Coding RNA. PMID- 25910185 TI - Cystic Fibrosis below the Diaphragm: Abdominal Findings in Adult Patients. AB - Cystic fibrosis (CF) is the most common lethal autosomal recessive disease in the white population. Mutation of the CF transmembrane conductance regulator gene on chromosome 7 results in production of abnormally viscous mucus and secretions in the lungs of patients with CF. A similar pathologic process occurs in the gastrointestinal tract, pancreas, and hepatobiliary system. Inspissated mucus causes luminal obstruction and resultant clinical and radiologic complications associated with the disease process. Pancreatic involvement can result in exocrine and endocrine insufficiency, pancreatic atrophy, fatty replacement, or lipomatous pseudohypertrophy. Acute and chronic pancreatitis, pancreatic calcification, cysts, and cystosis also occur. Hepatic manifestations include hepatic steatosis, focal biliary and multilobular cirrhosis, and portal hypertension. Biliary complications include cholelithiasis, microgallbladder, and sclerosing cholangitis. The entire digestive tract can be involved. Distal ileal obstruction syndrome, intussusception, appendicitis, chronic constipation, colonic wall thickening, fibrosing colonopathy, pneumatosis intestinalis, gastroesophageal reflux, and peptic ulcer disease have been described. Renal manifestations include nephrolithiasis and secondary amyloidosis. The educational objectives of this review are to reveal the abdominal manifestations of CF to facilitate focused analysis of cross-sectional imaging in adult patients. Life expectancy in patients with CF continues to improve because of a combination of aggressive antibiotic treatment, improved emphasis on nutrition and physiotherapy, and development of promising new CF transmembrane conductance regulator modulators. As lung function and survival improve, extrapulmonary conditions, including hepatic and gastrointestinal malignancy, will be an increasing cause of morbidity and mortality. Awareness of the expected abdominal manifestations of CF may assist radiologists in identifying acute inflammatory or neoplastic conditions. ((c))RSNA, 2015. PMID- 25910187 TI - In Vitro Production of Fumonisins by Fusarium verticillioides under Oxidative Stress Induced by H2O2. AB - The effects of oxidative stress induced by H2O2 were tested in liquid cultures in the fumonisin-producing fungus Fusarium verticillioides. The quantitative analysis of fumonisins B1, B2, B3, and B4 was achieved by means of liquid chromatography coupled to high-resolution mass spectrometry. Two effects in F. verticillioides, consisting of different abilities to produce fumonisins in response to oxidative stress, were identified. Following H2O2 addition, two F. verticillioides strains produced significantly more fumonisin (>300%) while three other strains produced significantly less (<20%) in comparison to control cultures. Transcriptional studies with seven biosynthetic genes showed a significant increase in transcript levels in the strain that made more fumonisin and either no or minimal changes in the strain that made less fumonisin. Our data indicate the important role of oxidative stress toward the modulation of the fumonisin biosynthesis and suggest the necessity to verify the presence of such divergent behavior in F. verticillioides populations under natural conditions. PMID- 25910188 TI - One-pot synthesis of CuInS2 nanocrystals using different anions to engineer their morphology and crystal phase. AB - A simple one-pot colloidal method has been described to engineer ternary CuInS2 nanocrystals with different crystal phases and morphologies, in which dodecanethiol is chosen as the sulfur source and the capping ligands. By a careful choice of the anions in the metal precursors and manipulation of the reaction conditions including the reactant molar ratios and the reaction temperature, CuInS2 nanocrystals with chalcopyrite, zincblende and wurtzite phases have been successfully synthesized. The type of anion in the metal precursors has been found to be essential for determining the crystal phase and morphology of the as-obtained CuInS2 nanocrystals. In particular, the presence of Cl(-) ions plays an important role in the formation of CuInS2 nanoplates with a wurtzite-zincblende polytypism structure. In addition, the molar ratios of Cu to In precursors have a significant effect on the crystal phase and morphology, and the intermediate Cu2S-CuInS2 heteronanostructures are formed which are critical for the anisotropic growth of CuInS2 nanocrystals. Furthermore, the optical absorption results of the as-obtained CuInS2 nanocrystals exhibit a strong dependence on the crystal phase and size. PMID- 25910186 TI - Faecalibacterium prausnitzii Strain HTF-F and Its Extracellular Polymeric Matrix Attenuate Clinical Parameters in DSS-Induced Colitis. AB - A decrease in the abundance and biodiversity of intestinal bacteria within the Firmicutes phylum has been associated with inflammatory bowel disease (IBD). In particular, the anti-inflammatory bacterium Faecalibacterium prausnitzii, member of the Firmicutes phylum and one of the most abundant species in healthy human colon, is underrepresented in the microbiota of IBD patients. The aim of this study was to investigate the immunomodulatory properties of F. prausnitzii strain A2-165, the biofilm forming strain HTF-F and the extracellular polymeric matrix (EPM) isolated from strain HTF-F. For this purpose, the immunomodulatory properties of the F. prausnitzii strains and the EPM were studied in vitro using human monocyte-derived dendritic cells. Then, the capacity of the F. prausnitzii strains and the EPM of HTF-F to suppress inflammation was assessed in vivo in the mouse dextran sodium sulphate (DSS) colitis model. The F. prausnitzii strains and the EPM had anti-inflammatory effects on the clinical parameters measured in the DSS model but with different efficacy. The immunomodulatory effects of the EPM were mediated through the TLR2-dependent modulation of IL-12 and IL-10 cytokine production in antigen presenting cells, suggesting that it contributes to the anti-inflammatory potency of F. prausnitzii HTF-F. The results show that F. prausnitzii HTF-F and its EPM may have a therapeutic use in IBD. PMID- 25910189 TI - Mixed signal learning by spike correlation propagation in feedback inhibitory circuits. AB - The brain can learn and detect mixed input signals masked by various types of noise, and spike-timing-dependent plasticity (STDP) is the candidate synaptic level mechanism. Because sensory inputs typically have spike correlation, and local circuits have dense feedback connections, input spikes cause the propagation of spike correlation in lateral circuits; however, it is largely unknown how this secondary correlation generated by lateral circuits influences learning processes through STDP, or whether it is beneficial to achieve efficient spike-based learning from uncertain stimuli. To explore the answers to these questions, we construct models of feedforward networks with lateral inhibitory circuits and study how propagated correlation influences STDP learning, and what kind of learning algorithm such circuits achieve. We derive analytical conditions at which neurons detect minor signals with STDP, and show that depending on the origin of the noise, different correlation timescales are useful for learning. In particular, we show that non-precise spike correlation is beneficial for learning in the presence of cross-talk noise. We also show that by considering excitatory and inhibitory STDP at lateral connections, the circuit can acquire a lateral structure optimal for signal detection. In addition, we demonstrate that the model performs blind source separation in a manner similar to the sequential sampling approximation of the Bayesian independent component analysis algorithm. Our results provide a basic understanding of STDP learning in feedback circuits by integrating analyses from both dynamical systems and information theory. PMID- 25910190 TI - Longitudinal analysis of osteogenic and angiogenic signaling factors in healing models mimicking atrophic and hypertrophic non-unions in rats. AB - Impaired bone healing can have devastating consequences for the patient. Clinically relevant animal models are necessary to understand the pathology of impaired bone healing. In this study, two impaired healing models, a hypertrophic and an atrophic non-union, were compared to physiological bone healing in rats. The aim was to provide detailed information about differences in gene expression, vascularization and histology during the healing process. The change from a closed fracture (healing control group) to an open osteotomy (hypertrophy group) led to prolonged healing with reduced mineralized bridging after 42 days. RT-PCR data revealed higher gene expression of most tested osteogenic and angiogenic factors in the hypertrophy group at day 14. After 42 days a significant reduction of gene expression was seen for Bmp4 and Bambi in this group. The inhibition of angiogenesis by Fumagillin (atrophy group) decreased the formation of new blood vessels and led to a non-healing situation with diminished chondrogenesis. RT-PCR results showed an attempt towards overcoming the early perturbance by significant up regulation of the angiogenic regulators Vegfa, Angiopoietin 2 and Fgf1 at day 7 and a further continuous increase of Fgf1, -2 and Angiopoietin 2 over time. However uCT angiograms showed incomplete recovery after 42 days. Furthermore, lower expression values were detected for the Bmps at day 14 and 21. The Bmp antagonists Dan and Twsg1 tended to be higher expressed in the atrophy group at day 42. In conclusion, the investigated animal models are suitable models to mimic human fracture healing complications and can be used for longitudinal studies. Analyzing osteogenic and angiogenic signaling patterns, clear changes in expression were identified between these three healing models, revealing the importance of a coordinated interplay of different factors to allow successful bone healing. PMID- 25910191 TI - Building social networks for maternal and newborn health in poor urban settlements: a cross-sectional study in Bangladesh. AB - BACKGROUND: The beneficial influence of social networks on health and wellbeing is well-established. In poor urban settlements in Bangladesh, BRAC's Manoshi programme trains community health workers (CHWs) to support women through pregnancy, delivery and postpartum periods. This paper test the hypothesis that the introduction of CHWs as weak ties into the social networks of Manoshi members mediates improvements in maternal and neonatal health (MNH) best practices by providing support, facilitating ideational change, connecting mother to resources, and strengthening or countering the influence of strong ties. METHODS: 1000 women who had given birth in the last three months were identified and interviewed as part of ongoing monitoring of 5 poor urban settlements in Dhaka, Bangladesh. A social networks questionnaire was administered which elicited women's perceived networks around pregnancy, delivery and post-partum periods. Mediation analysis was performed to test the hypothesis that penetration of Manoshi CHWs into women's perceived networks has a beneficial effect on MNH best practises. RESULTS: The presence and influence of Manoshi CHWs in women's networks significantly mediated the effect of Manoshi membership on MNH best practices. Respondents who were Manoshi members and who listed Manoshi CHWs as part of their support networks were significantly more likely to deliver with a trained birth attendant (OR 3.61; 95%CI 2.36-5.51), to use postnatal care (OR 3.09; 95%CI 1.83-5.22), and to give colostrum to their newborn (OR 7.51; 95%CI 3.51-16.05). CONCLUSION: Manoshi has succeeded in penetrating the perceived pregnancy, delivery and post-partum networks of poor urban women through the introduction of trained CHWs. Study findings demonstrate the benefits of moving beyond urban health care delivery models that concentrate on the provision of clinical services by medical providers, to an approach that nurtures the power of social networks as a means to support the poorest and most marginalized in changing behaviour and effectively accessing appropriate maternal services. PMID- 25910192 TI - Vascular Impact of Metabolic Syndrome in Subjects with Normal Weight, Overweight, or Obesity: Is Normal Weight Sufficient for Vascular Health? AB - OBJECTIVE: Obesity appears to be one of the major risk factors for metabolic complications. However, no direct relationship between body weight and metabolic abnormalities exists. The present study was designed to investigate the impact of body mass index (BMI) and the presence of metabolic syndrome (MS) on early vascular atherosclerotic changes, as determined by augmentation index (AI) and pulse wave velocity (PWV). DESIGN AND METHODS: The 285 study participants were divided into four groups according to BMI and the presence of MS. Subjects without MS were defined as metabolically normal, while subjects with MS were defined as metabolically obese. Group 1 included 71 metabolically normal, normal weight subjects (MNNW), Group 2 included 69 metabolically obese, normal-weight subjects (MONW), Group 3 included 66 metabolically obese, overweight subjects (MOOW), and Group 4 included 79 metabolically obese, obese subjects (MOOB). RESULTS: AI and PWV differed significantly between groups, such that they increased from Group 1 to Group 4 in a continuous fashion. AI was significantly lower in normal-weight subjects without MS than in normal-weight subjects with MS (p < 0.001). In univariate general linear model (GLM) analysis, significant by group differences in AI persisted even after adjustment for age, sex, and blood pressure. CONCLUSIONS: AI was significantly higher in normal-weight subjects with MS than in normal-weight metabolically benign individuals. Thus, even in patients with normal weight (BMI <= 25), presence of metabolic syndrome was associated with significant deterioration in terms of arterial stiffness. PMID- 25910193 TI - The Use of Maleic Hydrazide for Effective Hybridization of Setaria viridis. AB - An efficient method for crossing green foxtail (Setaria viridis) is currently lacking. S. viridis is considered to be the new model plant for the study of C4 system in monocots and so an effective crossing protocol is urgently needed. S. viridis is a small grass with C4-NADP (ME) type of photosynthesis and has the advantage of having small genome of about 515 Mb, small plant stature, short life cycle, multiple tillers, and profuse seed set, and hence is an ideal model species for research. The objectives of this project were to develop efficient methods of emasculation and pollination, and to speed up generation advancement. We assessed the response of S. viridis flowers to hot water treatment (48 degrees C) and to different concentrations of gibberellic acid, abscisic acid, maleic hydrazide (MH), and kinetin. We found that 500 MUM of MH was effective in the emasculation of S. viridis, whilst still retaining the receptivity of the stigma to pollination. We also report effective ways to accelerate the breeding cycle of S. viridis for research through the germination of mature as well as immature seeds in optimized culture media. We believe these findings will be of great interest to researchers using Setaria. PMID- 25910194 TI - Monitoring Neuro-Motor Recovery From Stroke With High-Resolution EEG, Robotics and Virtual Reality: A Proof of Concept. AB - A novel system for the neuro-motor rehabilitation of upper limbs was validated in three sub-acute post-stroke patients. The system permits synchronized cortical and kinematic measures by integrating high-resolution EEG, passive robotic device and Virtual Reality. The brain functional re-organization was monitored in association with motor patterns replicating activities of daily living (ADL). Patients underwent 13 rehabilitation sessions. At sessions 1, 7 and 13, clinical tests were administered to assess the level of motor impairment, and EEG was recorded during rehabilitation task execution. For each session and rehabilitation task, four kinematic indices of motor performance were calculated and compared with the outcome of clinical tests. Functional source maps were obtained from EEG data and projected on the real patients' anatomy (MRI data). Laterality indices were calculated for hemispheric dominance assessment. All patients showed increased participation in the rehabilitation process. Cortical activation changes during recovery were detected in relation to different motor patterns, hence verifying the system's suitability to add quantitative measures of motor performance and neural recovery to classical tests. We conclude that this system seems a promising tool for novel robot-based rehabilitation paradigms tailored to individual needs and neuro-motor responses of the patients. PMID- 25910196 TI - Operative Treatment of Terrible Triad of the Elbow via Posterolateral and Anteromedial Approaches. AB - The aim of the study was to explore the clinical outcome of posterolateral and anteromedial approaches in treatment of terrible triad of the elbow. The study involved 12 patients with closed terrible triad of the elbow treated by posterolateral and anteromedial approaches between January 2010 and June 2012. The mechanism of injury included fall from height in 9 patients and traffic accident in 3. According to O'Driscoll classification for fractures of the ulnar coronoid, there were 11 patients with type I and 1 with type II fractures. According to Mason classification for fractures of the radial head, there were 3 patients with type I, 7 with type II and 2 with type III fractures. All patients were followed up for 12-27 months (average 15.5 months), which showed no pain or severe pain in all patients except for 2 patients with mild pain. At the last follow-up, the mean flexion was for 125 degrees (range, 90 degrees -140 degrees ), the mean extension loss for 20 degrees (range, 0 degrees -70 degrees ), the mean pronation for 66 degrees (range, 20 degrees -85 degrees ) and the mean supination for 60 degrees (range, 30 degrees -85 degrees ). The bony union time was 8-14 weeks (average 11 weeks) and the elbows were stable in flexion-extension and varus-valgus in all patients. The elbows maintained a concentric reduction of both the ulnotrochlear and the radiocapitellar articulation. Mild heterotopic ossification of the elbow occurred in 3 patients at 6 months after operation and mild degenerative change in 1 patient at 18 months after operation. The Broberg and Morrey elbow performance score was 82 points (range, 58-98 points). The results were excellent in 6 patients, good in 4, fair in 1 and poor in 1, with excellence rate of 83.3%. The results showed that the combined posterolateral and anteromedial approaches can facilitate the reduction and fixation of terrible triad of the elbow. Repair of radial head, coronoid, medial and lateral collateral ligaments can sufficiently restore the elbow stability, allow early postoperative motion and enhance the functional recovery. PMID- 25910197 TI - Five years of molecular radiotherapy growth in the UK: survey results from 2007 to 2012. PMID- 25910195 TI - Characterization of Aldh2 (-/-) mice as an age-related model of cognitive impairment and Alzheimer's disease. AB - BACKGROUND: The study of late-onset/age-related Alzheimer's disease (AD)(sporadic AD, 95% of AD cases) has been hampered by a paucity of animal models. Oxidative stress is considered a causative factor in late onset/age-related AD, and aldehyde dehydrogenase 2 (ALDH2) is important for the catabolism of toxic aldehydes associated with oxidative stress. One such toxic aldehyde, the lipid peroxidation product 4-hydroxynonenal (HNE), accumulates in AD brain and is associated with AD pathology. Given this linkage, we hypothesized that in mice lacking ALDH2, there would be increases in HNE and the appearance of AD-like pathological changes. RESULTS: Changes in relevant AD markers in Aldh2 (-/-) mice and their wildtype littermates were assessed over a 1 year period. Marked increases in HNE adducts arise in hippocampi from Aldh2 (-/-) mice, as well as age-related increases in amyloid-beta, p-tau, and activated caspases. Also observed were age-related decreases in pGSK3beta, PSD95, synaptophysin, CREB and pCREB. Age-related memory deficits in the novel object recognition and Y maze tasks begin at 3.5-4 months and are maximal at 6.5-7 months. There was decreased performance in the Morris Water Maze task in 6 month old Aldh2 (-/-) mice. These mice exhibited endothelial dysfunction, increased amyloid-beta in cerebral microvessels, decreases in carbachol-induced pCREB and pERK formation in hippocampal slices, and brain atrophy. These AD-associated pathological changes are rarely observed as a constellation in current AD animal models. CONCLUSIONS: We believe that this new model of age-related cognitive impairment will provide new insight into the pathogenesis and molecular/cellular mechanisms driving neurodegenerative diseases of aging such as AD, and will prove useful for assessing the efficacy of therapeutic agents for improving memory and for slowing, preventing, or reversing AD progression. PMID- 25910198 TI - Measuring Working Memory With Digit Span and the Letter-Number Sequencing Subtests From the WAIS-IV: Too Low Manipulation Load and Risk for Underestimating Modality Effects. AB - The Wechsler Adult Intelligence Scale (WAIS) is one of the most frequently used tests among psychologists. In the fourth edition of the test (WAIS-IV), the subtests Digit Span and Letter-Number Sequencing are expanded for better measurement of working memory (WM). However, it is not clear whether the new extended tasks contribute sufficient complexity to be sensitive measures of manipulation WM, nor do we know to what degree WM capacity differs between the visual and the auditory modality because the WAIS-IV only tests the auditory modality. Performance by a mixed sample of 226 patients referred for neuropsychological examination on the Digit Span and Letter-Number Sequencing subtests from the WAIS-IV and on Spatial Span from the Wechsler Memory Scale Third Edition was analyzed in two confirmatory factor analyses to investigate whether a unitary WM model or divisions based on modality or level/complexity best fit the data. The modality model showed the best fit when analyzing summed scores for each task as well as scores for the longest span. The clinician is advised to apply tests with higher manipulation load and to consider testing visual span as well before drawing conclusions about impaired WM from the WAIS IV. PMID- 25910199 TI - Natural evolution of broadly neutralizing antibodies. AB - Wu et al. couple next-generation sequencing with structural analysis to illuminate the key processes that enable the natural evolution and selection of broadly neutralizing antibodies to HIV-1, providing a potential roadmap for the development of HIV-1 vaccine strategies to accelerate the induction of protective antibodies. PMID- 25910200 TI - Single-Molecule Visualization of MCM2-7 DNA Loading: Seeing Is Believing. AB - The first event in the initiation of eukaryotic DNA replication is the recruitment of the MCM2-7 ATPase, the core of the replicative DNA helicase, to origins. Ticau et al. use single-molecule imaging to reveal how ORC, Cdc6, and Cdt1 cooperate to load MCM2-7 onto DNA, enabling bidirectional replication. PMID- 25910201 TI - Gradients are shaping up. AB - In animal embryos, morphogen gradients determine tissue patterning and morphogenesis. Shyer et al. provide evidence that, during vertebrate gut formation, tissue folding generates graded activity of signals required for subsequent steps of gut growth and differentiation, thereby revealing an intriguing link between tissue morphogenesis and morphogen gradient formation. PMID- 25910202 TI - Membrane nanoclusters-tails of the unexpected. AB - The existence, nature, and role of highly ordered membrane domains, often referred to as lipid rafts, have been highly debated by cell biologists for many years. In this issue, Raghupathy et al. describe molecular mechanisms leading to the formation of ordered lipid-protein clusters. PMID- 25910203 TI - A genetic clog in the vitamin A transport machinery. AB - Chou et al. discover a new mode of maternal inheritance by analyzing human mutations in plasma retinol binding protein (RBP). Mechanistically, these mutations simultaneously lower RBP's affinity for vitamin A and greatly increase its affinity for its cell-surface receptor, thus dominantly blocking the transmembrane transport of vitamin A. PMID- 25910204 TI - A primer to single-particle cryo-electron microscopy. AB - Cryo-electron microscopy (cryo-EM) of single-particle specimens is used to determine the structure of proteins and macromolecular complexes without the need for crystals. Recent advances in detector technology and software algorithms now allow images of unprecedented quality to be recorded and structures to be determined at near-atomic resolution. However, compared with X-ray crystallography, cryo-EM is a young technique with distinct challenges. This primer explains the different steps and considerations involved in structure determination by single-particle cryo-EM to provide an overview for scientists wishing to understand more about this technique and the interpretation of data obtained with it, as well as a starting guide for new practitioners. PMID- 25910205 TI - Single-Particle Cryo-EM at Crystallographic Resolution. AB - Until only a few years ago, single-particle electron cryo-microscopy (cryo-EM) was usually not the first choice for many structural biologists due to its limited resolution in the range of nanometer to subnanometer. Now, this method rivals X-ray crystallography in terms of resolution and can be used to determine atomic structures of macromolecules that are either refractory to crystallization or difficult to crystallize in specific functional states. In this review, I discuss the recent breakthroughs in both hardware and software that transformed cryo-microscopy, enabling understanding of complex biomolecules and their functions at atomic level. PMID- 25910206 TI - Selective elimination of mitochondrial mutations in the germline by genome editing. AB - Mitochondrial diseases include a group of maternally inherited genetic disorders caused by mutations in mtDNA. In most of these patients, mutated mtDNA coexists with wild-type mtDNA, a situation known as mtDNA heteroplasmy. Here, we report on a strategy toward preventing germline transmission of mitochondrial diseases by inducing mtDNA heteroplasmy shift through the selective elimination of mutated mtDNA. As a proof of concept, we took advantage of NZB/BALB heteroplasmic mice, which contain two mtDNA haplotypes, BALB and NZB, and selectively prevented their germline transmission using either mitochondria-targeted restriction endonucleases or TALENs. In addition, we successfully reduced human mutated mtDNA levels responsible for Leber's hereditary optic neuropathy (LHOND), and neurogenic muscle weakness, ataxia, and retinitis pigmentosa (NARP), in mammalian oocytes using mitochondria-targeted TALEN (mito-TALENs). Our approaches represent a potential therapeutic avenue for preventing the transgenerational transmission of human mitochondrial diseases caused by mutations in mtDNA. PAPERCLIP. PMID- 25910207 TI - Mammalian NET-Seq Reveals Genome-wide Nascent Transcription Coupled to RNA Processing. AB - Transcription is a highly dynamic process. Consequently, we have developed native elongating transcript sequencing technology for mammalian chromatin (mNET-seq), which generates single-nucleotide resolution, nascent transcription profiles. Nascent RNA was detected in the active site of RNA polymerase II (Pol II) along with associated RNA processing intermediates. In particular, we detected 5'splice site cleavage by the spliceosome, showing that cleaved upstream exon transcripts are associated with Pol II CTD phosphorylated on the serine 5 position (S5P), which is accumulated over downstream exons. Also, depletion of termination factors substantially reduces Pol II pausing at gene ends, leading to termination defects. Notably, termination factors play an additional promoter role by restricting non-productive RNA synthesis in a Pol II CTD S2P-specific manner. Our results suggest that CTD phosphorylation patterns established for yeast transcription are significantly different in mammals. Taken together, mNET-seq provides dynamic and detailed snapshots of the complex events underlying transcription in mammals. PMID- 25910209 TI - Transbilayer lipid interactions mediate nanoclustering of lipid-anchored proteins. AB - Understanding how functional lipid domains in live cell membranes are generated has posed a challenge. Here, we show that transbilayer interactions are necessary for the generation of cholesterol-dependent nanoclusters of GPI-anchored proteins mediated by membrane-adjacent dynamic actin filaments. We find that long saturated acyl-chains are required for forming GPI-anchor nanoclusters. Simultaneously, at the inner leaflet, long acyl-chain-containing phosphatidylserine (PS) is necessary for transbilayer coupling. All-atom molecular dynamics simulations of asymmetric multicomponent-membrane bilayers in a mixed phase provide evidence that immobilization of long saturated acyl-chain lipids at either leaflet stabilizes cholesterol-dependent transbilayer interactions forming local domains with characteristics similar to a liquid ordered (lo) phase. This is verified by experiments wherein immobilization of long acyl-chain lipids at one leaflet effects transbilayer interactions of corresponding lipids at the opposite leaflet. This suggests a general mechanism for the generation and stabilization of nanoscale cholesterol-dependent and actin mediated lipid clusters in live cell membranes. PMID- 25910210 TI - The cellular mechanisms of neuronal swelling underlying cytotoxic edema. AB - Cytotoxic brain edema triggered by neuronal swelling is the chief cause of mortality following brain trauma and cerebral infarct. Using fluorescence lifetime imaging to analyze contributions of intracellular ionic changes in brain slices, we find that intense Na(+) entry triggers a secondary increase in intracellular Cl(-) that is required for neuronal swelling and death. Pharmacological and siRNA-mediated knockdown screening identified the ion exchanger SLC26A11 unexpectedly acting as a voltage-gated Cl(-) channel that is activated upon neuronal depolarization to membrane potentials lower than -20 mV. Blockade of SLC26A11 activity attenuates both neuronal swelling and cell death. Therefore cytotoxic neuronal edema occurs when sufficient Na(+) influx and depolarization is followed by Cl(-) entry via SLC26A11. The resultant NaCl accumulation causes subsequent neuronal swelling leading to neuronal death. These findings shed light on unique elements of volume control in excitable cells and lay the ground for the development of specific treatments for brain edema. PMID- 25910208 TI - Native elongating transcript sequencing reveals human transcriptional activity at nucleotide resolution. AB - Major features of transcription by human RNA polymerase II (Pol II) remain poorly defined due to a lack of quantitative approaches for visualizing Pol II progress at nucleotide resolution. We developed a simple and powerful approach for performing native elongating transcript sequencing (NET-seq) in human cells that globally maps strand-specific Pol II density at nucleotide resolution. NET-seq exposes a mode of antisense transcription that originates downstream and converges on transcription from the canonical promoter. Convergent transcription is associated with a distinctive chromatin configuration and is characteristic of lower-expressed genes. Integration of NET-seq with genomic footprinting data reveals stereotypic Pol II pausing coincident with transcription factor occupancy. Finally, exons retained in mature transcripts display Pol II pausing signatures that differ markedly from skipped exons, indicating an intrinsic capacity for Pol II to recognize exons with different processing fates. Together, human NET-seq exposes the topography and regulatory complexity of human gene expression. PMID- 25910211 TI - Biochemical Basis for Dominant Inheritance, Variable Penetrance, and Maternal Effects in RBP4 Congenital Eye Disease. AB - Gestational vitamin A (retinol) deficiency poses a risk for ocular birth defects and blindness. We identified missense mutations in RBP4, encoding serum retinol binding protein, in three families with eye malformations of differing severity, including bilateral anophthalmia. The mutant phenotypes exhibit dominant inheritance, but incomplete penetrance. Maternal transmission significantly increases the probability of phenotypic expression. RBP normally delivers retinol from hepatic stores to peripheral tissues, including the placenta and fetal eye. The disease mutations greatly reduce retinol binding to RBP, yet paradoxically increase the affinity of RBP for its cell surface receptor, STRA6. By occupying STRA6 nonproductively, the dominant-negative proteins disrupt vitamin A delivery from wild-type proteins within the fetus, but also, in the case of maternal transmission, at the placenta. These findings establish a previously uncharacterized mode of maternal inheritance, distinct from imprinting and oocyte derived mRNA, and define a group of hereditary disorders plausibly modulated by dietary vitamin A. PMID- 25910213 TI - Human gene-centered transcription factor networks for enhancers and disease variants. AB - Gene regulatory networks (GRNs) comprising interactions between transcription factors (TFs) and regulatory loci control development and physiology. Numerous disease-associated mutations have been identified, the vast majority residing in non-coding regions of the genome. As current GRN mapping methods test one TF at a time and require the use of cells harboring the mutation(s) of interest, they are not suitable to identify TFs that bind to wild-type and mutant loci. Here, we use gene-centered yeast one-hybrid (eY1H) assays to interrogate binding of 1,086 human TFs to 246 enhancers, as well as to 109 non-coding disease mutations. We detect both loss and gain of TF interactions with mutant loci that are concordant with target gene expression changes. This work establishes eY1H assays as a powerful addition to the toolkit of mapping human GRNs and for the high throughput characterization of genomic variants that are rapidly being identified by genome-wide association studies. PMID- 25910214 TI - Efficient intracellular delivery of native proteins. AB - Modulation of protein function is used to intervene in cellular processes but is often done indirectly by means of introducing DNA or mRNA encoding the effector protein. Thus far, direct intracellular delivery of proteins has remained challenging. We developed a method termed iTOP, for induced transduction by osmocytosis and propanebetaine, in which a combination of NaCl hypertonicity induced macropinocytosis and a transduction compound (propanebetaine) induces the highly efficient transduction of proteins into a wide variety of primary cells. We demonstrate that iTOP is a useful tool in systems in which transient cell manipulation drives permanent cellular changes. As an example, we demonstrate that iTOP can mediate the delivery of recombinant Cas9 protein and short guide RNA, driving efficient gene targeting in a non-integrative manner. PMID- 25910212 TI - Widespread macromolecular interaction perturbations in human genetic disorders. AB - How disease-associated mutations impair protein activities in the context of biological networks remains mostly undetermined. Although a few renowned alleles are well characterized, functional information is missing for over 100,000 disease-associated variants. Here we functionally profile several thousand missense mutations across a spectrum of Mendelian disorders using various interaction assays. The majority of disease-associated alleles exhibit wild-type chaperone binding profiles, suggesting they preserve protein folding or stability. While common variants from healthy individuals rarely affect interactions, two-thirds of disease-associated alleles perturb protein-protein interactions, with half corresponding to "edgetic" alleles affecting only a subset of interactions while leaving most other interactions unperturbed. With transcription factors, many alleles that leave protein-protein interactions intact affect DNA binding. Different mutations in the same gene leading to different interaction profiles often result in distinct disease phenotypes. Thus disease-associated alleles that perturb distinct protein activities rather than grossly affecting folding and stability are relatively widespread. PMID- 25910215 TI - SnapShot: Sensing and Signaling by Cilia. AB - Primary cilia are cellular appendages that coordinate diverse sensory and signaling activities. They are important for proper mammalian development, adult tissue homeostasis, and vision and odorant detection, and their dysfunction contributes to disease pathology and developmental defects. PMID- 25910216 TI - Development of an In-House Multiplex Nested RT-PCR Method for Detecting Acute HIV 1 Infection in High Risk Populations. AB - BACKGROUND: The detection of acute HIV infection (AHI) among high risk populations can help reduce secondary transmission of HIV. The nucleic acid testing (NAT) can shorten the test window period by up to 7-12 days. In this study, we describe an in-house NAT based on the multiplex nested RT-PCR method to detect the HIV RNA. We also evaluated it in a high risk cohort in Beijing. METHODS: Four primer pairs were designed and evaluated for the detection of different HIV-1 subtypes in group M. Multiplex RT-PCR and nested PCR were performed. The sensitivity, specialty, primers compatibility among HIV subtypes were evaluated simultaneously. In an MSM cohort in Beijing during a 3-year period, a total of 11,808 blood samples that were negative by ELISA or indeterminate by Western blot were analyzed by this multiplex nested RT-PCR with pooling strategy. RESULTS: The multiplex nested RT-PCR was successfully applied for the detection of at least six HIV-1 subtypes. The sensitivity was 40 copies/ml and the specificity was 100%. A total of 29 people were tested HIV-1 positive with acute infection in a MSM cohort of Beijing during a 3 years period. CONCLUSION: This multiplex nested RT-PCR provides a useful tool for the rapid detection of acute HIV-1 infection. When used in combination with the 3(rd) generation ELISA, it can improve the detection rate of HIV infection, especially in the source limited regions. PMID- 25910217 TI - In Silico analysis of perturbed steroidogenesis and gonad growth in fathead minnows (P. promelas) exposed to 17alpha-ethynylestradiol. AB - The multi-factorial nature of adverse reproductive effects mediated by endocrine disrupting compounds (or EDCs) makes understanding the mechanistic basis of reproductive dysfunction a highly pertinent area of research. As a consequence, a main motivator for continued research is to integrate 'multi-leveled' complexity (i.e., from genes to phenotype) using mathematical methods capable of encapsulating properties of physiological relevance. In this study, an in silico stoichiometric model of piscine steroidogenesis was augmented with a 'biomass' reaction associating the underlying stoichiometry of steroidogenesis with a reaction representative of gonad growth. The ability of the in silico model to predict perturbed steroidogenesis and subsequent effects on gonad growth was tested by exposing reproductively active male and female fathead minnows (Pimephales promelas) to 88 ng/L of the synthetic estrogen, 17alpha ethynylestradiol (EE2). The in silico model was parameterized (or constrained) with experimentally quantified concentrations of selected steroid hormones (using mass spectrometry) and fold changes in gene expression (using RT-qPCR) for selected steroidogenic enzyme genes, in gonads of male and female fish. Once constrained, the optimization framework of flux balance analysis (FBA) was used to calculate an optimal flux through the biomass reaction (analogous to gonad growth) and associated steroidogenic flux distributions required to generate biomass. FBA successfully predicted effects of EE2 exposure on fathead minnow gonad growth (%gonadosomatic index or %GSI) and perturbed production of steroid hormones. Specifically, FBA accurately predicted no effects of exposure on male %GSI and a significant reduction for female %GSI. Furthermore, in silico simulations accurately identified disrupted reaction fluxes catalyzing productions of androgens (in male fish) and progestogens (in female fish), an observation which agreed with in vivo experimentation. The analyses presented is the first-ever to successfully associate underlying flux properties of the steroidogenic network with gonad growth in fish, an approach which can incorporate in silico predictions with toxicological risk assessments. PMID- 25910218 TI - Polynuclear Hydroxido-Bridged Complexes of Platinum(IV) with Terminal Nitrato Ligands. AB - For the first time the polynuclear hydroxido-bridged platinum(IV) nitrato complexes with nuclearity higher than two were isolated from nitric acid solutions of [Pt(H2O)2(OH)4] and crystallized as supramolecular compounds of macrocyclic cavitands cucurbit[n]uril (CB[n], n = 6,8) and 18-crown-6 ether: [Pt4(MU3-OH)2(MU2-OH)4(NO3)10].CB[6].25H2O (I), [Pt6(MU3-OH)4(MU2 OH)6(NO3)12](NO3)2.CB[8].50H2O (II), and [H3O?18-crown-6]2[Pt2(MU2 OH)2(NO3)8][Pt4(MU3-OH)2(MU2-OH)4(NO3)10] (III). The isolation of the compounds in the single crystalline state allows the determination of the structure of the tetranuclear and hexanuclear complexes [Pt4(MU3-OH)2(MU2-OH)4(NO3)10] and [Pt6(MU3-OH)4(MU2-OH)6(NO3)12](2+), which have been previously unknown in the solid state. Stability of Ptx(OH)y cores of the polynuclear nitrato complexes toward alkaline hydrolysis was verified by (195)Pt NMR spectroscopy. Analysis of (195)Pt NMR spectra of the compound III reveals that addition of every Pt(MU OH)2Pt ring results in ~260 ppm downfield shift relative to the mononuclear form, which allows the prediction of signal positions for complexes of higher nuclearity. PMID- 25910220 TI - Symptoms of Sternal Nonunion Late after Cardiac Surgery. AB - Background A cohort of patients having symptoms of sternal nonunion late after sternotomy was studied to find out whether the complaints were related to true sternal nonunion or decreased bone density. Methods A survey was mailed to 2,053 cardiac surgical patients operated in our institution between July 2007 and June 2010. The patients were requested about symptoms referring to sternal instability. A group of symptomatic individuals as well as 1:1 age- and time matched asymptomatic controls were examined with sternal palpation, ultrasound during standardized sternal pressure provocation, and computed tomography (CT). Results The number of patients replied in the survey was 1,918 (93.4%); 2.3% (44 patients) reported sensation of movement or clicking in sternum during body movements and during coughing. Symptomatic patients living within 200 km to the hospital (21) and their asymptomatic controls (21) were selected for further clinical and imaging studies. Mean period between the initial operation and the examinations was 36 (22-56) months. Sternal palpation pain was significantly associated with reported symptoms suggestive of sternal nonunion (odds ratio [OR] 22.0; 95% confidence interval [CI] 2.5-195); however, none of the patients had clinically unstable sternum or nonunion in the sternal imaging. The symptoms of sternal instability were more frequent in patients whose bone mineralization rate (as measured with T-scores) was higher. Conclusion Symptoms suggestive of sternal nonunion were experienced by 2.3%. However, their symptoms did not correlate with CT scans or provocation ultrasound although palpation pain was evident. Thus the pain is derived from nonmechanical etiologies. Higher bone mineralization rate correlated with abnormal symptoms of sternal wound. PMID- 25910219 TI - Fibril Core of Transforming Growth Factor Beta-Induced Protein (TGFBIp) Facilitates Aggregation of Corneal TGFBIp. AB - Mutations in the transforming growth factor beta-induced (TGFBI) gene result in a group of hereditary diseases of the cornea that are collectively known as TGFBI corneal dystrophies. These mutations translate into amino acid substitutions mainly within the fourth fasciclin 1 domain (FAS1-4) of the transforming growth factor beta-induced protein (TGFBIp) and cause either amyloid or nonamyloid protein aggregates in the anterior and central parts of the cornea, depending on the mutation. The A546T substitution in TGFBIp causes lattice corneal dystrophy (LCD), which manifests as amyloid-type aggregates in the corneal stroma. We previously showed that the A546T substitution renders TGFBIp and the FAS1-4 domain thermodynamically less stable compared with the wild-type (WT) protein, and the mutant FAS1-4 is prone to amyloid formation in vitro. In the present study, we identified the core of A546T FAS1-4 amyloid fibrils. Significantly, we identified the Y571-R588 region of TGFBIp, which we previously found to be enriched in amyloid deposits in LCD patients. We further found that the Y571-R588 peptide seeded fibrillation of A546T FAS1-4, and, more importantly, we demonstrated that native TGFBIp aggregates in the presence of fibrils formed by the core peptide. Collectively, these data suggest an involvement of the Y571 R588 peptide in LCD pathophysiology. PMID- 25910221 TI - Risk and Prognosis of Bloodstream Infections among Patients on Chronic Hemodialysis: A Population-Based Cohort Study. AB - BACKGROUND AND OBJECTIVES: Infections are common complications among patients on chronic hemodialysis. This population-based cohort study aims to estimate risk and case fatality of bloodstream infection among chronic hemodialysis patients. METHODS: In this population-based cohort study we identified residents with end stage renal disease in Central and North Jutland, Denmark who had hemodialysis as first renal replacement therapy (hemodialysis patients) during 1995-2010. For each hemodialysis patient, we sampled 19 persons from the general population matched on age, gender, and municipality. Information on positive blood cultures was obtained from regional microbiology databases. All persons were observed from cohort entry until first episode of bloodstream infection, emigration, death, or end of hemodialysis treatment, whichever came first. Incidence-rates and incidence-rate ratios were computed and risk factors for bloodstream infection assessed by Poisson regression. Case fatality was compared by Cox regression. RESULTS: Among 1792 hemodialysis patients and 33 618 matched population controls, we identified 461 and 1126 first episodes of bloodstream infection, respectively. Incidence rates of first episode of bloodstream infection were 13.7 (95% confidence interval (CI), 12.5-15.0) per 100 person-years among hemodialysis patients and 0.53 (95% CI, 0.50-0.56) per 100 person-years among population controls. In hemodialysis patients, the most common causative microorganisms were Staphylococcus aureus (43.8%) and Escherichia coli (12.6%). The 30-day case fatality was similar among hemodialysis patients and population controls 16% (95% CI, 13%-20%) vs. 18% (95% CI, 15%-20%). CONCLUSIONS: Hemodialysis patients have extraordinary high risk of bloodstream infection while short-term case fatality following is similar to that of population controls. PMID- 25910223 TI - Facile preparation of ferric giniite hollow microspheres and their enhanced Fenton-like catalytic performance under visible-light irradiation. AB - Ferric giniite hollow spheres with diameters of about 1.2-1.4 MUm were successfully fabricated with a one-pot hydrothermal process. All chemicals used were low-cost compounds and environmentally benign. The obtained products were characterized by field emission scanning electron microscope (FESEM), high resolution transmission electron microscopy (HRTEM), X-ray diffraction (XRD), nitrogen adsorption-desorption isotherms, Fourier-transform IR spectroscopy (FTIR) and X-ray photoelectron spectroscopy (XPS). It was found that as-prepared ferric giniite hollow spheres exhibited much enhanced photocatalytic activity (99.5%) for the degradation of methylene blue in the presence of visible light irradiation and H2O2. Experimental results indicate that the existence of the carbonaceous shells enhances the photocatalytic activity of ferric giniite hollow spheres via the synergistic effect between carbon and ferric giniite, such as improving the adsorption, absorbing more light and exhibiting high activity to produce hydroxyl radicals through catalytic decomposition of H2O2. PMID- 25910222 TI - CD4-Positive T Cells and M2 Macrophages Dominate the Peritoneal Infiltrate of Patients with Encapsulating Peritoneal Sclerosis. AB - BACKGROUND: Encapsulating peritoneal sclerosis (EPS) is a severe complication of peritoneal dialysis (PD). Previously, it has been shown that infiltrating CD4 positive T cells and M2 macrophages are associated with several fibrotic conditions. Therefore, the characteristics of the peritoneal cell infiltrate in EPS may be of interest to understand EPS pathogenesis. In this study, we aim to elucidate the composition of the peritoneal cell infiltrate in EPS patients and relate the findings to clinical outcome. STUDY DESIGN, SETTING, AND PARTICIPANTS: We studied peritoneal membrane biopsies of 23 EPS patients and compared them to biopsies of 15 PD patients without EPS. The cellular infiltrate was characterized by immunohistochemistry to detect T cells (CD3-positive), CD4-positive (CD4+) and CD8-positive T cell subsets, B cells (CD20-positive), granulocytes (CD15 positive), macrophages (CD68-positive), M1 (CD80-positive), and M2 (CD163 positive) macrophages. Tissues were analysed using digital image analysis. Kaplan Meier survival analysis was performed to investigate the survival in the different staining groups. RESULTS: The cellular infiltrate in EPS biopsies was dominated by mononuclear cells. For both CD3 and CD68, the median percentage of area stained was higher in biopsies of EPS as opposed to non-EPS patients (p<0.001). EPS biopsies showed a higher percentage of area stained for CD4 (1.29% (0.61-3.20)) compared to CD8 (0.71% (0.46-1.01), p = 0.04), while in the non-EPS group these cells were almost equally represented (respectively 0.28% (0.05-0.83) versus 0.22% (0.17-0.43), p = 0.97). The percentage of area stained for both CD80 and CD163 was higher in EPS than in non-EPS biopsies (p<0.001), with CD163+ cells being the most abundant phenotype. Virtually no CD20-positive and CD15-positive cells were present in biopsies of a subgroup of EPS patients. No relation was found between the composition of the mononuclear cell infiltrate and clinical outcome. CONCLUSIONS: A characteristic mononuclear cell infiltrate consisting of CD4+ and CD163+ cells dominates the peritoneum of EPS patients. These findings suggest a role for both CD4+ T cells and M2 macrophages in the pathogenesis of EPS. PMID- 25910224 TI - Interfacial bonding in a CdS/PVA nanocomposite: A Raman scattering study. AB - Raman spectroscopy is employed to characterize the bonding between CdS nanoparticles (NPs) and a polyvinyl alcohol (PVA) as well as structural changes in the polymeric matrix caused by incorporation of NPs. It is shown that after the formation of CdS NPs the vibrations of carbonyl groups in acetate residuals of PVA and of C-O groups at the macromolecules ends disappear. Formation of NPs also leads to an increased degree of hydrogen bonding and crystallinity of the hybrid material as compared with the unloaded polymer. The observed changes are ascribed to the formation of coordinative bonds and hydrogen between the CdS nanoparticles and polymeric macromolecules. The scheme of this interfacial bonding is also proposed. PMID- 25910226 TI - Histogram Analysis of Amide Proton Transfer Imaging to Identify Contrast enhancing Low-Grade Brain Tumor That Mimics High-Grade Tumor: Increased Accuracy of MR Perfusion. AB - PURPOSE: To determine whether histogram analysis of amide proton transfer (APT) imaging provides increased accuracy of magnetic resonance (MR) perfusion imaging for the identification of contrast material-enhancing low-grade tumor (World Health Organization grades 1 and 2) that mimics high-grade tumor (World Health Organization grades 3 and 4). MATERIALS AND METHODS: This retrospective study was approved by the institutional review board. Forty-five patients with pathologically proven, solitary, contrast-enhancing tumors were enrolled in this study. APT-derived signal intensity from the calculated APT asymmetry at the offset frequency of 3.5 ppm and normalized cerebral blood volume (nCBV) were measured on solid portions of the tumor by using a 90% histogram cutoff (denoted as APT90 and nCBV90, respectively). The diagnostic performance of the imaging parameters was determined with leave-one-out cross validation. Interobserver agreement was assessed by using the intraclass correlation coefficient. RESULTS: APT90 demonstrated a significant difference between contrast-enhancing low-grade and high-grade tumors for both readers (P < .001 for both readers). Compared with nCBV90, adding APT90 significantly improved the area under the receiver operating characteristic curve (AUC) for the identification of contrast-enhancing low-grade tumor from 0.80 to 0.97 for reader 1 (P = .023) and from 0.82 to 0.97 for reader 2 (P = .035), respectively. By using leave-one-out cross-validation, the cross validated AUC of the combination of nCBV90 and APT90 was 0.95 for reader 1 and 0.96 for reader 2. The intraclass correlation coefficient for the APT90 calculations was 0.89. CONCLUSION: Histogram analysis of APT imaging provided increased accuracy of MR perfusion imaging for the identification of contrast enhancing low-grade tumor that mimics high-grade tumor. PMID- 25910225 TI - Loss of PTPRM associates with the pathogenic development of colorectal adenoma carcinoma sequence. AB - Identification and functional analysis of genes from genetically altered chromosomal regions would suggest new molecular targets for cancer diagnosis and treatment. Here we performed a genome-wide analysis of chromosomal copy number alterations (CNAs) in matching sets of colon mucosa-adenoma-carcinoma samples using high-throughput oligonucleotide microarray analysis. In silico analysis of NCBI GEO and TCGA datasets allowed us to uncover the significantly altered genes (p <= 0.001) associated with the identified CNAs. We performed quantitative PCR analysis of the genomic and complementary DNA derived from primary mucosa, adenoma, and carcinoma samples, and confirmed the recurrent loss and down regulation of PTPRM in colon adenomas and carcinomas. Functional characterization demonstrated that PTPRM negatively regulates cell growth and colony formation, whereas loss of PTPRM promotes oncogenic cell growth. We further showed that, in accordance to Knudson's two-hit hypothesis, inactivation of PTPRM in colon cancer was mainly attributed to loss of heterozygosity and promoter hypermethylation. Taken together, this study demonstrates a putative tumor suppressive role for PTPRM and that genetic and epigenetic alterations of PTPRM may contribute to early step of colorectal tumorigenesis. PMID- 25910227 TI - Synbiotics reduce ethanol-induced hepatic steatosis and inflammation by improving intestinal permeability and microbiota in rats. AB - Clinical and animal experiments indicated that gut-derived endotoxin and imbalanced intestinal microbiota contribute to the pathogenesis of alcoholic liver disease (ALD). In this study, we investigated whether synbiotic supplementation could improve ALD in rats by altering the intestinal microbial composition and improving the intestinal integrity. Male Wistar rats were divided into four groups according to plasma aspartate aminotransferase (AST) and alanine aminotransferase (ALT) activities and subjected to either a normal liquid diet (C), a normal liquid diet with synbiotic supplementation (C + S), an ethanol liquid diet (E), or an ethanol liquid diet with synbiotic supplementation (E + S) for 12 weeks. Results revealed that the ethanol-fed group showed increases in plasma AST and ALT activities, the endotoxin level, the hepatic triglyceride (TG) level, and hepatic tumor necrosis factor (TNF)-alpha, interleukin (IL)-1beta and IL-6 levels, and a decrease in the hepatic IL-10 level. Ethanol-feeding also contributed to increased intestinal permeability and decreased fecal bifidobacteria and lactobacilli amounts. However, synbiotic supplementation effectively attenuated the plasma endotoxin, hepatic TG and TNF-alpha levels, and increased the hepatic IL-10 level. Furthermore, synbiotic supplementation protected the rats against ethanol-induced hyperpermeability of the intestine, and significantly increased amounts of bifidobacteria and lactobacilli in the feces. This study demonstrated that synbiotics possess a novel hepatoprotective function by improving the intestinal permeability and microbiota in rats with ethanol-induced liver injury. PMID- 25910228 TI - Correction: Multigene Assessment of the Species Boundaries and Sexual Status of the Basidiomycetous Yeasts Cryptococcus flavescens and C. terrestris (Tremellales). PMID- 25910229 TI - Detection of Angiostrongylus cantonensis in the Blood and Peripheral Tissues of Wild Hawaiian Rats (Rattus rattus) by a Quantitative PCR (qPCR) Assay. AB - The nematode Angiostrongylus cantonensis is a rat lungworm, a zoonotic pathogen that causes human eosinophilic meningitis and ocular angiostrongyliasis characteristic of rat lungworm (RLW) disease. Definitive diagnosis is made by finding and identifying A. cantonensis larvae in the cerebral spinal fluid or by using a custom immunological or molecular test. This study was conducted to determine if genomic DNA from A. cantonensis is detectable by qPCR in the blood or tissues of experimentally infected rats. F1 offspring from wild rats were subjected to experimental infection with RLW larvae isolated from slugs, then blood or tissue samples were collected over multiple time points. Blood samples were collected from 21 rats throughout the course of two trials (15 rats in Trial I, and 6 rats in Trial II). In addition to a control group, each trial had two treatment groups: the rats in the low dose (LD) group were infected by approximately 10 larvae and the rats in the high dose (HD) group were infected with approximately 50 larvae. In Trial I, parasite DNA was detected in cardiac bleed samples from five of five LD rats and five of five HD rats at six weeks post-infection (PI), and three of five LD rats and five of five HD rats from tail tissue. In Trial II, parasite DNA was detected in peripheral blood samples from one of two HD rats at 53 minutes PI, one of two LD rats at 1.5 hours PI, one of two HD rats at 18 hours PI, one of two LD rats at five weeks PI and two of two at six weeks PI, and two of two HD rats at weeks five and six PI. These data demonstrate that parasite DNA can be detected in peripheral blood at various time points throughout RLW infection in rats. PMID- 25910230 TI - Existence and control of Go/No-Go decision transition threshold in the striatum. AB - A typical Go/No-Go decision is suggested to be implemented in the brain via the activation of the direct or indirect pathway in the basal ganglia. Medium spiny neurons (MSNs) in the striatum, receiving input from cortex and projecting to the direct and indirect pathways express D1 and D2 type dopamine receptors, respectively. Recently, it has become clear that the two types of MSNs markedly differ in their mutual and recurrent connectivities as well as feedforward inhibition from FSIs. Therefore, to understand striatal function in action selection, it is of key importance to identify the role of the distinct connectivities within and between the two types of MSNs on the balance of their activity. Here, we used both a reduced firing rate model and numerical simulations of a spiking network model of the striatum to analyze the dynamic balance of spiking activities in D1 and D2 MSNs. We show that the asymmetric connectivity of the two types of MSNs renders the striatum into a threshold device, indicating the state of cortical input rates and correlations by the relative activity rates of D1 and D2 MSNs. Next, we describe how this striatal threshold can be effectively modulated by the activity of fast spiking interneurons, by the dopamine level, and by the activity of the GPe via pallidostriatal backprojections. We show that multiple mechanisms exist in the basal ganglia for biasing striatal output in favour of either the 'Go' or the 'No Go' pathway. This new understanding of striatal network dynamics provides novel insights into the putative role of the striatum in various behavioral deficits in patients with Parkinson's disease, including increased reaction times, L-Dopa induced dyskinesia, and deep brain stimulation-induced impulsivity. PMID- 25910231 TI - Curcumin induces apoptosis of upper aerodigestive tract cancer cells by targeting multiple pathways. AB - Curcumin, a natural compound isolated from the Indian spice "Haldi" or "curry powder", has been used for centuries as a traditional remedy for many ailments. Recently, the potential use of curcumin in cancer prevention and therapy urges studies to uncover the molecular mechanisms associated with its anti-tumor effects. In the current manuscript, we investigated the mechanism of curcumin induced apoptosis in upper aerodigestive tract cancer cell lines and showed that curcumin-induced apoptosis is mediated by the modulation of multiple pathways such as induction of p73, and inhibition of p-AKT and Bcl-2. Treatment of cells with curcumin induced both p53 and the related protein p73 in head and neck and lung cancer cell lines. Inactivation of p73 by dominant negative p73 significantly protected cells from curcumin-induced apoptosis, whereas ablation of p53 by shRNA had no effect. Curcumin treatment also strongly inhibited p-AKT and Bcl-2 and overexpression of constitutively active AKT or Bcl-2 significantly inhibited curcumin-induced apoptosis. Taken together, our findings suggest that curcumin-induced apoptosis is mediated via activating tumor suppressor p73 and inhibiting p-AKT and Bcl-2. PMID- 25910233 TI - Purification of recombinant virus-like particles of porcine circovirus type 2 capsid protein using ion-exchange monolith chromatography. AB - Diseases associated with porcine circovirus type 2 (PCV2) infection are having a severe economic impact on swine-producing countries. The PCV2 capsid (Cap) protein expressed in eukaryotic systems self-assemble into virus-like particles (VLPs) which can serve as antigens for diagnostics or/and as vaccine candidates. In this work, conventional adsorbents as well as a monolithic support with large pore sizes were examined for the chromatographic purification of PCV2 Cap VLPs from clarified yeast lysate. Q Sepharose XL was used for the initial separation of VLPs from residual host nucleic acids and some host cell proteins. For the further purification of PCV2 Cap VLPs, SP Sepharose XL, Heparin Sepharose CL-6B and CIMmultus SO3 monolith were tested. VLPs were not retained on SP Sepharose XL. The purity of VLPs after chromatography on Heparin Sepharose CL-6B was only 4 7% and the recovery of VLPs was 5-7%. Using ion-exchange chromatography on the CIMmultus SO3 monolith, PCV2 Cap VLPs with the purity of about 40% were obtained. The recovery of VLPs after chromatography on the CIMmultus SO3 monolith was 15 18%. The self-assembly of purified PCV2 Cap protein into VLPs was confirmed by electron microscopy. Two-step chromatographic purification procedure of PCV2 Cap VLPs from yeast lysate was developed using Q Sepharose XL and cation-exchange CIMmultus SO3 monolith. PMID- 25910232 TI - Recommendation for a Standardised Method of Broth Microdilution Susceptibility Testing for Porcine Bordetella bronchiseptica. AB - The objective was to establish and standardise a broth microdilution susceptibility testing method for porcine Bordetella (B.) bronchiseptica. B. bronchiseptica isolates from different geographical regions and farms were genotyped by macrorestriction analysis and subsequent pulsed-field gel electrophoresis. One reference and one type strain plus two field isolates of B. bronchiseptica were chosen to analyse growth curves in four different media: cation-adjusted Mueller-Hinton broth (CAMHB) with and without 2% lysed horse blood, Brain-Heart-Infusion (BHI), and Caso broth. The growth rate of each test strain in each medium was determined by culture enumeration and the suitability of CAMHB was confirmed by comparative statistical analysis. Thereafter, reference and type strain and eight epidemiologically unrelated field isolates of B. bronchiseptica were used to test the suitability of a broth microdilution susceptibility testing method following CLSI-approved performance standards given in document VET01-A4. Susceptibility tests, using 20 antimicrobial agents, were performed in five replicates, and data were collected after 20 and 24 hours incubation and statistically analysed. Due to the low growth rate of B. bronchiseptica, an incubation time of 24 hours resulted in significantly more homogeneous minimum inhibitory concentrations after five replications compared to a 20-hour incubation. An interlaboratory comparison trial including susceptibility testing of 24 antimicrobial agents revealed a high mean level of reproducibility (97.9%) of the modified method. Hence, in a harmonization for broth microdilution susceptibility testing of B. bronchiseptica, an incubation time of 24 hours in CAMHB medium with an incubation temperature of 35 degrees C and an inoculum concentration of approximately 5 x 10(5) cfu/ml was proposed. PMID- 25910234 TI - A simple U-HPLC-MS/MS method for the determination of liensinine and isoliensinine in rat plasma. AB - An ultra-high performance liquid chromatography tandem mass spectrometry (U-HPLC MS/MS) method was developed and validated to determine liensinine and isoliensinine in rat plasma simultaneously. Plasma samples were prepared using protein precipitation with acetonitrile. The two analytes and the internal standard pirfenidone were separated on an Acquity U-HPLC BEH C18 column with the mobile phase of acetonitrile and 1% formic acid in water with gradient elution at a flow rate of 0.40mL/min. Both liensinine and isoliensinine were eluted at 0.63 and 0.82min, respectively. The detection was performed on a triple quadrupole tandem mass spectrometer equipped with positive-ion electrospray ionization (ESI) by multiple reactions monitoring (MRM) of the transitions at m/z 611.6 -> 206.2 for liensinine and m/z 611.4 -> 192.2 for isoliensinine. The linearity of this method was found to be within the concentration range of 5-700ng/mL for liensinine and isoliensinine in rat plasma. The lower limits of quantification (LLOQ) were all 5ng/mL for liensinine and isoliensinine. The relative standard deviations (RSD) of intra and inter precision were less than 10% for both liensinine and isoliensinine. The method was also successfully applied to the pharmacokinetic study of liensinine and isoliensinine in rats. PMID- 25910235 TI - Development and validation of LC-MS/MS assay for the determination of the prodrug Midodrine and its active metabolite Desglymidodrine in plasma of ascitic patients: Application to individualized therapy and comparative pharmacokinetics. AB - Midodrine (MD) is a prodrug that is converted after oral administration to Desglymidodrine (DMD). In this study, an LC-MS/MS assay was developed and validated for investigation of the pharmacokinetics of MD and DMD in non azotemic patients with liver cirrhosis and tense ascites. Results were compared to those noted with healthy volunteers following the adminstration of a single oral dose of MD. Sample preparation was performed by liquid-liquid extraction using t-butyl methyl ether. HPLC separation was carried out using RP C18 column (4.6mm*50mm, 5MUm). Isocratic elution was performed using methanol:0.2% formic acid (70:30, v/v) as the mobile phase, at a flow rate of 0.7mL/min. Tandem mass spectrometric detection was employed at positive electrospray ionization in MRM mode for the determination of MD and DMD. Analysis was carried out within 1.0min over a concentration range of 0.50-40.00ng/mL for the prodrug and its active metabolite. The assay was validated according to FDA guidelines for bioanalytical method validation and satisfactory results were obtained. The applicability of the assay for the determination of the pharmacokinetic parameters of MD and DMD and personalized therapy was demonstrated in healthy volunteers and ascitic patients. Results revealed significant differences in pharmacokinetic parameters among the studied groups. Such differences were explained on the basis of the medical condition and co-adminstered medications exerting possible drug-drug interaction. Results confirmed the need for implementation of reliable analysis tools for therapeutic dose adjustment. PMID- 25910236 TI - Sodium-dependent phosphate transporters in osteoclast differentiation and function. AB - Osteoclasts are multinucleated bone degrading cells. Phosphate is an important constituent of mineralized bone and released in significant quantities during bone resorption. Molecular contributors to phosphate transport during the resorptive activity of osteoclasts have been controversially discussed. This study aimed at deciphering the role of sodium-dependent phosphate transporters during osteoclast differentiation and bone resorption. Our studies reveal RANKL induced differential expression of sodium-dependent phosphate transport protein IIa (NaPi-IIa) transcript and protein during osteoclast development, but no expression of the closely related NaPi-IIb and NaPi-IIc SLC34 family isoforms. In vitro studies employing NaPi-IIa-deficient osteoclast precursors and mature osteoclasts reveal that NaPi-IIa is dispensable for bone resorption and osteoclast differentiation. These results are supported by the analysis of structural bone parameters by high-resolution microcomputed tomography that yielded no differences between adult NaPi-IIa WT and KO mice. By contrast, both type III sodium-dependent phosphate transporters Pit-1 and Pit-2 were abundantly expressed throughout osteoclast differentiation, indicating that they are the relevant sodium-dependent phosphate transporters in osteoclasts and osteoclast precursors. We conclude that phosphate transporters of the SLC34 family have no role in osteoclast differentiation and function and propose that Pit-dependent phosphate transport could be pivotal for bone resorption and should be addressed in further studies. PMID- 25910237 TI - Tackling oxidative stress by a direct route: a new job for HDAC inhibitors? AB - Olson et al. (2015) propose that some hydroxamic acid-based small molecules, already in clinical use as histone deacetylase inhibitors, may protect against oxidative stress through a direct chemical reaction of dismutation of hydrogen peroxide into water. PMID- 25910238 TI - Macrophage activation: on par with LPS. AB - The inflammatory response is a critical component of the immune system that is activated by stimuli such as cytokines, foreign DNA, RNA, or other harmful substances. Krukenberg et al. (2015) identify poly(ADP-ribose) as a new signaling molecule that activates inflammation, thus providing yet another mechanism by which PARPs are involved in cellular stress responses. PMID- 25910239 TI - Chemical proteomics of host-pathogen interaction. AB - In less than two decades, activity-based protein profiling (ABPP) has expanded to become the de facto tool for the study of small molecule-protein interactions in a proteomic environment. In this issue, Na et al. (2015) present another ABPP method, which they called reactive probe-based chemical proteomics, to study host pathogen interaction and subsequently identify the protein PheA as a potential key effector during the pathogen infection process. PMID- 25910240 TI - From worms to targeting virulence factors. AB - Rising antibiotic resistance means that alternative antibacterial strategies are sorely needed. In this issue, Zhu et al. (2015) report the use of a Caenorhabditis elegans model to validate the Pseudomonas aeruginosa virulence factor LasB as a potential therapeutic target and to identify a LasB inhibitor with in vivo efficacy. PMID- 25910241 TI - Tuberculosis terpene targets. AB - In this issue, Young, Moody, and colleagues report the discovery of an isomer of the Mycobacterium tuberculosis (Mtb) virulence factor 1-tuberculosinyl adenosine, N(6)-tuberculosinyl adenosine, in mice infected with tuberculosis. These Mtb derived terpene compounds may serve as sensitive and specific biomarkers of infection. PMID- 25910242 TI - The structure of the PanD/PanZ protein complex reveals negative feedback regulation of pantothenate biosynthesis by coenzyme A. AB - Coenzyme A (CoA) is an ubiquitous and essential cofactor, synthesized from the precursor pantothenate. Vitamin biosynthetic pathways are normally tightly regulated, including the pathway from pantothenate to CoA. However, no regulation of pantothenate biosynthesis has been identified. We have recently described an additional component in the pantothenate biosynthetic pathway, PanZ, which promotes the activation of the zymogen, PanD, to form aspartate alpha decarboxylase (ADC) in a CoA-dependent manner. Here we report the structure of PanZ in complex with PanD, which reveals the structural basis for the CoA dependence of this interaction and activation. In addition, we show that PanZ acts as a CoA-dependent inhibitor of ADC catalysis. This inhibitory effect can effectively regulate the biosynthetic pathway to pantothenate, and thereby also regulate CoA biosynthesis. This represents a previously unobserved mode of metabolic regulation whereby a cofactor-utilizing protein negatively regulates the biosynthesis of the same cofactor. PMID- 25910243 TI - In vivo biosynthesis of terpene nucleosides provides unique chemical markers of Mycobacterium tuberculosis infection. AB - Although small molecules shed from pathogens are widely used to diagnose infection, such tests have not been widely implemented for tuberculosis. Here we show that the recently identified compound, 1-tuberculosinyladenosine (1-TbAd), accumulates to comprise >1% of all Mycobacterium tuberculosis lipid. In vitro and in vivo, two isomers of TbAd were detected that might serve as infection markers. Using mass spectrometry and nuclear magnetic resonance, we established the structure of the previously unknown molecule, N(6)-tuberculosinyladenosine (N(6) TbAd). Its biosynthesis involves enzymatic production of 1-TbAd by Rv3378c followed by conversion to N(6)-TbAd via the Dimroth rearrangement. Intact biosynthetic genes are observed only within M. tuberculosis complex bacteria, and TbAd was not detected among other medically important pathogens, environmental bacteria, and vaccine strains. With no substantially similar known molecules in nature, the discovery and in vivo detection of two abundant terpene nucleosides support their development as specific diagnostic markers of tuberculosis. PMID- 25910244 TI - Small molecule fluoride toxicity agonists. AB - Fluoride is a ubiquitous anion that inhibits a wide variety of metabolic processes. Here, we report the identification of a series of compounds that enhance fluoride toxicity in Escherichia coli and Streptococcus mutans. These molecules were isolated by using a high-throughput screen (HTS) for compounds that increase intracellular fluoride levels as determined via a fluoride riboswitch reporter fusion construct. A series of derivatives were synthesized to examine structure-activity relationships, leading to the identification of compounds with improved activity. Thus, we demonstrate that small molecule fluoride toxicity agonists can be identified by HTS from existing chemical libraries by exploiting a natural fluoride riboswitch. In addition, our findings suggest that some molecules might be further optimized to function as binary antibacterial agents when combined with fluoride. PMID- 25910245 TI - Toward the rational design of carbapenem uptake in Pseudomonas aeruginosa. AB - Understanding how compound penetration occurs across the complex cell walls of Gram-negative bacteria is one of the greatest challenges in discovering new drugs to treat the infections they cause. A combination of next-generation transposon sequencing, computational metadynamics simulations (CMDS), and medicinal chemistry was used to define genetic and structural elements involved in facilitated carbapenem entry into Pseudomonas aeruginosa. Here we show for the first time that these compounds are taken up not only by the major outer membrane channel OccD1 (also called OprD or PA0958) but also by a closely related channel OccD3 (OpdP or PA4501). Transport-mediating molecular interactions predicted by CMDS for these channels were first confirmed genetically, then used to guide the design of carbapenem analogs with altered uptake properties. These results bring us closer to the rational design of channel transmissibility and may ultimately lead to improved permeability of compounds across bacterial outer membranes. PMID- 25910246 TI - Glucocorticoids Distinctively Modulate the CFTR Channel with Possible Implications in Lung Development and Transition into Extrauterine Life. AB - During fetal development, the lung is filled with fluid that is secreted by an active Cl- transport promoting lung growth. The basolateral Na+,K+,2Cl- cotransporter (NKCC1) participates in Cl- secretion. The apical Cl- channels responsible for secretion are unknown but studies suggest an involvement of the cystic fibrosis transmembrane conductance regulator (CFTR). CFTR is developmentally regulated with a high expression in early fetal development and a decline in late gestation. Perinatal lung transition is triggered by hormones that stimulate alveolar Na+ channels resulting in fluid absorption. Little is known on how hormones affect pulmonary Cl- channels. Since the rise of fetal cortisol levels correlates with the decrease in fetal CFTR expression, a causal relation may be assumed. The aim of this study was to analyze the influence of glucocorticoids on pulmonary Cl- channels. Alveolar cells from fetal and adult rats, A549 cells, bronchial Calu-3 and 16HBE14o- cells, and primary rat airway cells were studied with real-time quantitative PCR and Ussing chambers. In fetal and adult alveolar cells, glucocorticoids strongly reduced Cftr expression and channel activity, which was prevented by mifepristone. In bronchial and primary airway cells CFTR mRNA expression was also reduced, whereas channel activity was increased which was prevented by LY-294002 in Calu-3 cells. Therefore, glucocorticoids strongly reduce CFTR expression while their effect on CFTR activity depends on the physiological function of the cells. Another apical Cl- channel, anoctamin 1 showed a glucocorticoid-induced reduction of mRNA expression in alveolar cells and an increase in bronchial cells. Furthermore, voltage-gated chloride channel 5 and anoctamine 6 mRNA expression were increased in alveolar cells. NKCC1 expression was reduced by glucocorticoids in alveolar and bronchial cells alike. The results demonstrate that glucocorticoids differentially modulate pulmonary Cl- channels and are likely causing the decline of CFTR during late gestation in preparation for perinatal lung transition. PMID- 25910247 TI - Clostridium perfringens Alpha-Toxin Induces Gm1a Clustering and Trka Phosphorylation in the Host Cell Membrane. AB - Clostridium perfringens alpha-toxin elicits various immune responses such as the release of cytokines, chemokines, and superoxide via the GM1a/TrkA complex. Alpha toxin possesses phospholipase C (PLC) hydrolytic activity that contributes to signal transduction in the pathogenesis of gas gangrene. Little is known about the relationship between lipid metabolism and TrkA activation by alpha-toxin. Using live-cell fluorescence microscopy, we monitored transbilayer movement of diacylglycerol (DAG) with the yellow fluorescent protein-tagged C1AB domain of protein kinase C-gamma (EYFP-C1AB). DAG accumulated at the marginal region of the plasma membrane in alpha toxin-treated A549 cells, which also exhibited GM1a clustering and TrkA phosphorylation. Annexin V binding assays showed that alpha toxin induced the exposure of phosphatidylserine on the outer leaflet of the plasma membrane. However, H148G, a variant toxin which binds cell membrane and has no enzymatic activity, did not induce DAG translocation, GM1a clustering, or TrkA phosphorylation. Alpha-toxin also specifically activated endogenous phospholipase Cgamma-1 (PLCgamma-1), a TrkA adaptor protein, via phosphorylation. U73122, an endogenous PLC inhibitor, and siRNA for PLCgamma-1 inhibited the formation of DAG and release of IL-8. GM1a accumulation and TrkA phosphorylation in A549 cells treated with alpha-toxin were also inhibited by U73122. These results suggest that the flip-flop motion of hydrophobic lipids such as DAG leads to the accumulation of GM1a and TrkA. We conclude that the formation of DAG by alpha-toxin itself (first step) and activation of endogenous PLCgamma-1 (second step) leads to alterations in membrane dynamics, followed by strong phosphorylation of TrkA. PMID- 25910248 TI - Successful Splenectomy for Hypersplenism in Wilson's Disease: A Single Center Experience from China. AB - Splenomegaly and pancytopenia are common in Wilson's disease (WD) and splenectomy is one of the conventional treatments for splenomegaly and the associated pancytopenia. However, splenectomy remained controversial for hypersplenism in WD as it was reported that splenectomy leaded to serious emotional and neurological deterioration in WD patients with hypersplenism. In the current study, we present our experiences in 70 WD patients with hypersplenism who had undergone splenectomy, outlining the safety and efficacy of splenectomy in WD. The clinical database of 70 WD patients with hypersplenism who had undergone splenectomy in our hospital between 2009 and 2013 were reviewed and followed-up regularly. Before splenectomy, all the patients accepted a short period of anti-copper treatment with intravenous sodium 2, 3-dimercapto-1-propane sulfonate (DMPS). All the patients demonstrated a marked improvement in platelet and leucocyte counts after splenectomy. No severe postoperative complication was observed. In particular, none of the 37 patients with mixed neurologic and hepatic presentations experienced neurological deterioration after splenectomy, and none of the patients with only hepatic presentations newly developed neurological symptoms. During the one year follow-up period, no patient presented hepatic failure or hepatic encephalopathy, no hepatic patient newly developed neurological presentations, and only 3 patients with mixed neurologic and hepatic presentations suffered neurological deterioration and these 3 patients had poor compliance of anti-copper treatment. Quantative analysis of the neurological symptoms in the 37 patients using the Unified Wilson's Disease Rating Scale (UWDRS) showed that the neurological symptoms were not changed in a short-term of one week after splenectomy but significantly improved in a long-term of one year after splenectomy. Additionally, compared to that before splenectomy, the esophageal gastric varices in most patients significantly improved one year after splenectomy. Thus, we may conclude that splenectomy is a safe and effective therapeutic measure for hypersplenism in WD patients who had been preoperatively treated with DMPS for powerful anti-copper therapy. PMID- 25910250 TI - Correction: Attenuated Age-Impact on Systemic Inflammatory Markers in the Presence of a Metabolic Burden. PMID- 25910249 TI - Physical activity in non-frail and frail older adults. AB - INTRODUCTION: Physical activity (PA) is important for healthy ageing. Better insight into objectively measured PA levels in older adults is needed, since most previous studies employed self-report measures for PA assessment, which are associated with overestimation of PA. AIM: This study aimed to provide insight in objectively measured indoor and outdoor PA of older adults, and in PA differences by frailty levels. METHODS: Data were collected among non-frail (N = 74) and frail (N = 10) subjects, aged 65 to 89 years. PA, measured for seven days with accelerometers and GPS-devices, was categorized into three levels of intensity (sedentary, light, and moderate-to-vigorous PA). RESULTS: Older adults spent most time in sedentary and light PA. Subjects spent 84.7%, 15.1% and 0.2% per day in sedentary, light and moderate-to-vigorous PA respectively. On average, older adults spent 9.8 (SD 23.7) minutes per week in moderate-to-vigorous activity, and 747.0 (SD 389.6) minutes per week in light activity. None of the subjects met the WHO recommendations of 150 weekly minutes of moderate-to-vigorous PA. Age-, sex- and health status-adjusted results revealed no differences in PA between non frail and frail older adults. Subjects spent significantly more sedentary time at home, than not at home. Non-frail subjects spent significantly more time not at home during moderate-to-vigorous activities, than at home. CONCLUSIONS: Objective assessment of PA in older adults revealed that most PA was of light intensity, and time spent in moderate-to-vigorous PA was very low. None of the older adults met the World Health Organization recommendations for PA. These levels of MVPA are much lower than generally reported based on self-reported PA. Future studies should employ objective methods, and age specific thresholds for healthy PA levels in older adults are needed. These results emphasize the need for effective strategies for healthy PA levels for the growing proportion of older adults. PMID- 25910251 TI - An Integrated Wireless Power Management and Data Telemetry IC for High-Compliance Voltage Electrical Stimulation Applications. AB - This paper describes a 13.56-MHz wireless power recovery system with bidirectional data link for high-compliance-voltage neural/muscle stimulator. The power recovery circuit includes a 2-stage rectifier, 2 LDOs and a high voltage charge pump to provide 3 DC outputs: 1.8 V, 3.3 V and 20 V for the stimulator. A 2-stage time division based rectifier is proposed to provide 3 DC outputs simultaneously. It improves the power efficiency without introducing any impact on the forward data recovery. The 20 V output is generated by a modified low ripple charge pump that reduces the ripple voltage by 40%. The power management system shows 49% peak power efficiency. The data link includes a clock and data recovery (CDR) circuit and a load shift keying (LSK) modulator for bidirectional data telemetry. The forward and backward data rates of the data telemetry are 61.5 kbps and 33.3 kbps, respectively. In addition, a power monitor circuit for closed-loop power control is implemented. The whole system has been fabricated in a 24 V HV LDMOS option 1.8 MU m CMOS process, occupying a core area of around 3.5 mm (2). PMID- 25910252 TI - Turn Down That Noise: Synaptic Encoding of Afferent SNR in a Single Spiking Neuron. AB - We have added a simplified neuromorphic model of Spike Time Dependent Plasticity (STDP) to the previously described Synapto-dendritic Kernel Adapting Neuron (SKAN), a hardware efficient neuron model capable of learning spatio-temporal spike patterns. The resulting neuron model is the first to perform synaptic encoding of afferent signal-to-noise ratio in addition to the unsupervised learning of spatio-temporal spike patterns. The neuron model is particularly suitable for implementation in digital neuromorphic hardware as it does not use any complex mathematical operations and uses a novel shift-based normalization approach to achieve synaptic homeostasis. The neuron's noise compensation properties are characterized and tested on random spatio-temporal spike patterns as well as a noise corrupted subset of the zero images of the MNIST handwritten digit dataset. Results show the simultaneously learning common patterns in its input data while dynamically weighing individual afferents based on their signal to noise ratio. Despite its simplicity the interesting behaviors of the neuron model and the resulting computational power may also offer insights into biological systems. PMID- 25910254 TI - QoS Differential Scheduling in Cognitive-Radio-Based Smart Grid Networks: An Adaptive Dynamic Programming Approach. AB - As the next-generation power grid, smart grid will be integrated with a variety of novel communication technologies to support the explosive data traffic and the diverse requirements of quality of service (QoS). Cognitive radio (CR), which has the favorable ability to improve the spectrum utilization, provides an efficient and reliable solution for smart grid communications networks. In this paper, we study the QoS differential scheduling problem in the CR-based smart grid communications networks. The scheduler is responsible for managing the spectrum resources and arranging the data transmissions of smart grid users (SGUs). To guarantee the differential QoS, the SGUs are assigned to have different priorities according to their roles and their current situations in the smart grid. Based on the QoS-aware priority policy, the scheduler adjusts the channels allocation to minimize the transmission delay of SGUs. The entire transmission scheduling problem is formulated as a semi-Markov decision process and solved by the methodology of adaptive dynamic programming. A heuristic dynamic programming (HDP) architecture is established for the scheduling problem. By the online network training, the HDP can learn from the activities of primary users and SGUs, and adjust the scheduling decision to achieve the purpose of transmission delay minimization. Simulation results illustrate that the proposed priority policy ensures the low transmission delay of high priority SGUs. In addition, the emergency data transmission delay is also reduced to a significantly low level, guaranteeing the differential QoS in smart grid. PMID- 25910255 TI - Generating Highly Accurate Predictions for Missing QoS Data via Aggregating Nonnegative Latent Factor Models. AB - Automatic Web-service selection is an important research topic in the domain of service computing. During this process, reliable predictions for quality of service (QoS) based on historical service invocations are vital to users. This work aims at making highly accurate predictions for missing QoS data via building an ensemble of nonnegative latent factor (NLF) models. Its motivations are: 1) the fulfillment of nonnegativity constraints can better represent the positive value nature of QoS data, thereby boosting the prediction accuracy and 2) since QoS prediction is a learning task, it is promising to further improve the prediction accuracy with a carefully designed ensemble model. To achieve this, we first implement an NLF model for QoS prediction. This model is then diversified through feature sampling and randomness injection to form a diversified NLF model, based on which an ensemble is built. Comparison results between the proposed ensemble and several widely employed and state-of-the-art QoS predictors on two large, real data sets demonstrate that the former can outperform the latter well in terms of prediction accuracy. PMID- 25910256 TI - DC Proximal Newton for Nonconvex Optimization Problems. AB - We introduce a novel algorithm for solving learning problems where both the loss function and the regularizer are nonconvex but belong to the class of difference of convex (DC) functions. Our contribution is a new general purpose proximal Newton algorithm that is able to deal with such a situation. The algorithm consists in obtaining a descent direction from an approximation of the loss function and then in performing a line search to ensure a sufficient descent. A theoretical analysis is provided showing that the iterates of the proposed algorithm admit as limit points stationary points of the DC objective function. Numerical experiments show that our approach is more efficient than the current state of the art for a problem with a convex loss function and a nonconvex regularizer. We have also illustrated the benefit of our algorithm in high dimensional transductive learning problem where both the loss function and regularizers are nonconvex. PMID- 25910253 TI - Identifying stride-to-stride control strategies in human treadmill walking. AB - Variability is ubiquitous in human movement, arising from internal and external noise, inherent biological redundancy, and from the neurophysiological control actions that help regulate movement fluctuations. Increased walking variability can lead to increased energetic cost and/or increased fall risk. Conversely, biological noise may be beneficial, even necessary, to enhance motor performance. Indeed, encouraging more variability actually facilitates greater improvements in some forms of locomotor rehabilitation. Thus, it is critical to identify the fundamental principles humans use to regulate stride-to-stride fluctuations in walking. This study sought to determine how humans regulate stride-to-stride fluctuations in stepping movements during treadmill walking. We developed computational models based on pre-defined goal functions to compare if subjects, from each stride to the next, tried to maintain the same speed as the treadmill, or instead stay in the same position on the treadmill. Both strategies predicted average behaviors empirically indistinguishable from each other and from that of humans. These strategies, however, predicted very different stride-to-stride fluctuation dynamics. Comparisons to experimental data showed that human stepping movements were generally well-predicted by the speed-control model, but not by the position-control model. Human subjects also exhibited no indications they corrected deviations in absolute position only intermittently: i.e., closer to the boundaries of the treadmill. Thus, humans clearly do not adopt a control strategy whose primary goal is to maintain some constant absolute position on the treadmill. Instead, humans appear to regulate their stepping movements in a way most consistent with a strategy whose primary goal is to try to maintain the same speed as the treadmill at each consecutive stride. These findings have important implications both for understanding how biological systems regulate walking in general and for being able to harness these mechanisms to develop more effective rehabilitation interventions to improve locomotor performance. PMID- 25910257 TI - Two Machine Learning Approaches for Short-Term Wind Speed Time-Series Prediction. AB - The increasing liberalization of European electricity markets, the growing proportion of intermittent renewable energy being fed into the energy grids, and also new challenges in the patterns of energy consumption (such as electric mobility) require flexible and intelligent power grids capable of providing efficient, reliable, economical, and sustainable energy production and distribution. From the supplier side, particularly, the integration of renewable energy sources (e.g., wind and solar) into the grid imposes an engineering and economic challenge because of the limited ability to control and dispatch these energy sources due to their intermittent characteristics. Time-series prediction of wind speed for wind power production is a particularly important and challenging task, wherein prediction intervals (PIs) are preferable results of the prediction, rather than point estimates, because they provide information on the confidence in the prediction. In this paper, two different machine learning approaches to assess PIs of time-series predictions are considered and compared: 1) multilayer perceptron neural networks trained with a multiobjective genetic algorithm and 2) extreme learning machines combined with the nearest neighbors approach. The proposed approaches are applied for short-term wind speed prediction from a real data set of hourly wind speed measurements for the region of Regina in Saskatchewan, Canada. Both approaches demonstrate good prediction precision and provide complementary advantages with respect to different evaluation criteria. PMID- 25910258 TI - Relevance Vector Machine for Survival Analysis. AB - An accelerated failure time (AFT) model has been widely used for the analysis of censored survival or failure time data. However, the AFT imposes the restrictive log-linear relation between the survival time and the explanatory variables. In this paper, we introduce a relevance vector machine survival (RVMS) model based on Weibull AFT model that enables the use of kernel framework to automatically learn the possible nonlinear effects of the input explanatory variables on target survival times. We take advantage of the Bayesian inference technique in order to estimate the model parameters. We also introduce two approaches to accelerate the RVMS training. In the first approach, an efficient smooth prior is employed that improves the degree of sparsity. In the second approach, a fast marginal likelihood maximization procedure is used for obtaining a sparse solution of survival analysis task by sequential addition and deletion of candidate basis functions. These two approaches, denoted by smooth RVMS and fast RVMS, typically use fewer basis functions than RVMS and improve the RVMS training time; however, they cause a slight degradation in the RVMS performance. We compare the RVMS and the two accelerated approaches with the previous sparse kernel survival analysis method on a synthetic data set as well as six real-world data sets. The proposed kernel survival analysis models have been discovered to be more accurate in prediction, although they benefit from extra sparsity. The main advantages of our proposed models are: 1) extra sparsity that leads to a better generalization and avoids overfitting; 2) automatic relevance sample determination based on data that provide more accuracy, in particular for highly censored survival data; and 3) flexibility to utilize arbitrary number and types of kernel functions (e.g., non-Mercer kernels and multikernel learning). PMID- 25910260 TI - A Multidimensional Time-Series Similarity Measure With Applications to Eldercare Monitoring. AB - In the last decade, data mining techniques have been applied to sensor data in a wide range of application domains, such as healthcare monitoring systems, manufacturing processes, intrusion detection, database management, and others. Many data mining techniques are based on computing the similarity between two sensor data patterns. A variety of representations and similarity measures for multiattribute time series have been proposed in the literature. In this paper, we describe a novel method for computing the similarity of two multiattribute time series based on a temporal version of Smith-Waterman (SW), a well-known bioinformatics algorithm. We then apply our method to sensor data from an eldercare application for early illness detection. Our method mitigates difficulties related to data uncertainty and aggregation that often arise when processing sensor data. The experiments take place at an aging-in-place facility, TigerPlace, located in Columbia, MO, USA. To validate our method, we used data from nonwearable sensor networks placed in TigerPlace apartments, combined with information from an electronic health record. We provide a set of experiments that investigate temporal version of SW properties, together with experiments on TigerPlace datasets. On a pilot sensor dataset from nine residents, with a total of 1902 days and around 2.1 million sensor hits of collected data, we obtained an average abnormal events prediction F-measure of 0.75. PMID- 25910259 TI - Health and economic impacts of eight different dietary salt reduction interventions. AB - BACKGROUND: Given the high importance of dietary sodium (salt) as a global disease risk factor, our objective was to compare the impact of eight sodium reduction interventions, including feasible and more theoretical ones, to assist prioritisation. METHODS: Epidemiological modelling and cost-utility analysis were performed using a Markov macro-simulation model. The setting was New Zealand (NZ) (2.3 million citizens, aged 35+ years) which has detailed individual-level administrative cost data. RESULTS: Of the most feasible interventions, the largest health gains were from (in descending order): (i) mandatory 25% reduction in sodium levels in all processed foods; (ii) the package of interventions performed in the United Kingdom (UK); (iii) mandatory 25% reduction in sodium levels in bread, processed meats and sauces; (iv) media campaign (as per a previous UK one); (v) voluntary food labelling as currently used in NZ; (vi) dietary counselling as currently used in NZ. Even larger health gains came from the more theoretical options of a "sinking lid" on the amount of food salt released to the national market to achieve an average adult intake of 2300 mg sodium/day (211,000 QALYs gained, 95% uncertainty interval: 170,000-255,000), and from a salt tax. All the interventions produced net cost savings (except counseling--albeit still cost-effective). Cost savings were especially large with the sinking lid (NZ$ 1.1 billion, US$ 0.7 billion). Also the salt tax would raise revenue (up to NZ$ 452 million/year). Health gain per person was greater for Maori (indigenous population) men and women compared to non-Maori. CONCLUSIONS: This study substantially expands on the range of previously modelled salt reduction interventions and suggests that some of these might achieve major health gains and major cost savings (particularly the regulatory interventions). They could also reduce ethnic inequalities in health. PMID- 25910261 TI - Enabling wireless powering and telemetry for peripheral nerve implants. AB - Wireless power delivery and telemetry have enabled completely implantable neural devices. Current day implants are controlled, monitored, and powered wirelessly, eliminating the need for batteries and prolonging the lifetime. A brief overview of wireless platforms for such implantable devices is presented in this paper alongside an in-depth discussion of wireless platform for peripheral nerve implants covering design requirements, link design, and safety. Initial acute studies on the performance of the wireless power and data links in rodents are also presented. PMID- 25910262 TI - Standard Plane Localization in Fetal Ultrasound via Domain Transferred Deep Neural Networks. AB - Automatic localization of the standard plane containing complicated anatomical structures in ultrasound (US) videos remains a challenging problem. In this paper, we present a learning-based approach to locate the fetal abdominal standard plane (FASP) in US videos by constructing a domain transferred deep convolutional neural network (CNN). Compared with previous works based on low level features, our approach is able to represent the complicated appearance of the FASP and hence achieve better classification performance. More importantly, in order to reduce the overfitting problem caused by the small amount of training samples, we propose a transfer learning strategy, which transfers the knowledge in the low layers of a base CNN trained from a large database of natural images to our task-specific CNN. Extensive experiments demonstrate that our approach outperforms the state-of-the-art method for the FASP localization as well as the CNN only trained on the limited US training samples. The proposed approach can be easily extended to other similar medical image computing problems, which often suffer from the insufficient training samples when exploiting the deep CNN to represent high-level features. PMID- 25910263 TI - Automatic UPDRS Evaluation in the Sit-to-Stand Task of Parkinsonians: Kinematic Analysis and Comparative Outlook on the Leg Agility Task. AB - In this study, we first characterize the sit-to-stand (S2S) task, which contributes to the evaluation of the degree of severity of the Parkinson's disease (PD), through kinematic features, which are then linked to the Unified Parkinson's disease rating scale (UPDRS) scores. We propose to use a single body worn wireless inertial node placed on the chest of a patient. The experimental investigation is carried out considering 24 PD patients, comparing the obtained results directly with the kinematic characterization of the leg agility (LA) task performed by the same set of patients. We show that i) the S2S and LA tasks are rather unrelated and ii) the UPDRS distributions (for both S2S and LA tasks) across the patients have a direct impact on the observed system performance. PMID- 25910264 TI - PSF: A Unified Patient Similarity Evaluation Framework Through Metric Learning With Weak Supervision. AB - Patient similarity is an important analytic operation in healthcare applications. At the core, patient similarity takes an index patient as the input and retrieves a ranked list of similar patients that are relevant in a specific clinical context. It takes patient information such as their electronic health records as input and computes the distance between a pair of patients based on those information. To construct a clinically valid similarity measure, physician input often needs to be incorporated. However, obtaining physicians' input is difficult and expensive. As a result, typically only limited physician feedbacks can be obtained on a small portion of patients. How to leverage all unlabeled patient data and limited supervision information from physicians to construct a clinically meaningful distance metric? In this paper, we present a patient similarity framework (PSF) that unifies and significantly extends existing supervised patient similarity metric learning methods. PSF is a general framework that can learn an appropriate distance metric through supervised and unsupervised information. Within PSF framework, we propose a novel patient similarity algorithm that uses local spline regression to capture the unsupervised information. To speedup the incorporation of physician feedback or newly available clinical information, we introduce a general online update algorithm for an existing PSF distance metric. PMID- 25910267 TI - Compact Structure Hashing via Sparse and Similarity Preserving Embedding. AB - Over the past few years, fast approximate nearest neighbor (ANN) search is desirable or essential, e.g., in huge databases, and therefore many hashing-based ANN techniques have been presented to return the nearest neighbors of a given query from huge databases. Hashing-based ANN techniques have become popular due to its low memory cost and good computational complexity. Recently, most of hashing methods have realized the importance of the relationship of the data and exploited the different structure of data to improve retrieval performance. However, a limitation of the aforementioned methods is that the sparse reconstructive relationship of the data is neglected. In this case, few methods can find the discriminating power and own the local properties of the data for learning compact and effective hash codes. To take this crucial issue into account, this paper proposes a method named special structure-based hashing (SSBH). SSBH can preserve the underlying geometric information among the data, and exploit the prior information that there exists sparse reconstructive relationship of the data, for learning compact and effective hash codes. Upon extensive experimental results, SSBH is demonstrated to be more robust and more effective than state-of-the-art hashing methods. PMID- 25910266 TI - Voluntary Alcohol Intake following Blast Exposure in a Rat Model of Mild Traumatic Brain Injury. AB - Alcoholism is a frequent comorbidity following mild traumatic brain injury (mTBI), even in patients without a previous history of alcohol dependence. Despite this correlational relationship, the extent to which the neurological effects of mTBI contribute to the development of alcoholism is unknown. In this study, we used a rodent blast exposure model to investigate the relationship between mTBI and voluntary alcohol drinking in alcohol naive rats. We have previously demonstrated in Sprague Dawley rats that blast exposure leads to microstructural abnormalities in the medial prefrontal cortex (mPFC) and other brain regions that progress from four to thirty days. The mPFC is a brain region implicated in alcoholism and drug addiction, although the impact of mTBI on drug reward and addiction using controlled models remains largely unexplored. Alcohol naive Sprague Dawley rats were subjected to a blast model of mTBI (or sham conditions) and then tested in several common measures of voluntary alcohol intake. In a seven-week intermittent two-bottle choice alcohol drinking test, sham and blast exposed rats had comparable levels of alcohol intake. In a short access test session at the conclusion of the two-bottle test, blast rats fell into a bimodal distribution, and among high intake rats, blast treated animals had significantly elevated intake compared to shams. We found no effect of blast when rats were tested for an alcohol deprivation effect or compulsive drinking in a quinine adulteration test. Throughout the experiment, alcohol drinking was modest in both groups, consistent with other studies using Sprague Dawley rats. In conclusion, blast exposure had a minimal impact on overall alcohol intake in Sprague Dawley rats, although intake was increased in a subpopulation of blast animals in a short access session following intermittent access exposure. PMID- 25910268 TI - Adversarial Feature Selection Against Evasion Attacks. AB - Pattern recognition and machine learning techniques have been increasingly adopted in adversarial settings such as spam, intrusion, and malware detection, although their security against well-crafted attacks that aim to evade detection by manipulating data at test time has not yet been thoroughly assessed. While previous work has been mainly focused on devising adversary-aware classification algorithms to counter evasion attempts, only few authors have considered the impact of using reduced feature sets on classifier security against the same attacks. An interesting, preliminary result is that classifier security to evasion may be even worsened by the application of feature selection. In this paper, we provide a more detailed investigation of this aspect, shedding some light on the security properties of feature selection against evasion attacks. Inspired by previous work on adversary-aware classifiers, we propose a novel adversary-aware feature selection model that can improve classifier security against evasion attacks, by incorporating specific assumptions on the adversary's data manipulation strategy. We focus on an efficient, wrapper-based implementation of our approach, and experimentally validate its soundness on different application examples, including spam and malware detection. PMID- 25910269 TI - Time-Delay Neural Network for Continuous Emotional Dimension Prediction From Facial Expression Sequences. AB - Automatic continuous affective state prediction from naturalistic facial expression is a very challenging research topic but very important in human computer interaction. One of the main challenges is modeling the dynamics that characterize naturalistic expressions. In this paper, a novel two-stage automatic system is proposed to continuously predict affective dimension values from facial expression videos. In the first stage, traditional regression methods are used to classify each individual video frame, while in the second stage, a time-delay neural network (TDNN) is proposed to model the temporal relationships between consecutive predictions. The two-stage approach separates the emotional state dynamics modeling from an individual emotional state prediction step based on input features. In doing so, the temporal information used by the TDNN is not biased by the high variability between features of consecutive frames and allows the network to more easily exploit the slow changing dynamics between emotional states. The system was fully tested and evaluated on three different facial expression video datasets. Our experimental results demonstrate that the use of a two-stage approach combined with the TDNN to take into account previously classified frames significantly improves the overall performance of continuous emotional state estimation in naturalistic facial expressions. The proposed approach has won the affect recognition sub-challenge of the Third International Audio/Visual Emotion Recognition Challenge. PMID- 25910265 TI - Novel cancer chemotherapy hits by molecular topology: dual Akt and Beta-catenin inhibitors. AB - BACKGROUND AND PURPOSE: Colorectal and prostate cancers are two of the most common types and cause of a high rate of deaths worldwide. Therefore, any strategy to stop or at least slacken the development and progression of malignant cells is an important therapeutic choice. The aim of the present work is the identification of novel cancer chemotherapy agents. Nowadays, many different drug discovery approaches are available, but this paper focuses on Molecular Topology, which has already demonstrated its extraordinary efficacy in this field, particularly in the identification of new hit and lead compounds against cancer. This methodology uses the graph theoretical formalism to numerically characterize molecular structures through the so called topological indices. Once obtained a specific framework, it allows the construction of complex mathematical models that can be used to predict physical, chemical or biological properties of compounds. In addition, Molecular Topology is highly efficient in selecting and designing new hit and lead drugs. According to the aforementioned, Molecular Topology has been applied here for the construction of specific Akt/mTOR and beta catenin inhibition mathematical models in order to identify and select novel antitumor agents. EXPERIMENTAL APPROACH: Based on the results obtained by the selected mathematical models, six novel potential inhibitors of the Akt/mTOR and beta-catenin pathways were identified. These compounds were then tested in vitro to confirm their biological activity. CONCLUSION AND IMPLICATIONS: Five of the selected compounds, CAS n degrees 256378-54-8 (Inhibitor n degrees 1), 663203-38 1 (Inhibitor n degrees 2), 247079-73-8 (Inhibitor n degrees 3), 689769-86-6 (Inhibitor n degrees 4) and 431925-096 (Inhibitor n degrees 6) gave positive responses and resulted to be active for Akt/mTOR and/or beta-catenin inhibition. This study confirms once again the Molecular Topology's reliability and efficacy to find out novel drugs in the field of cancer. PMID- 25910270 TI - Stability of Solutions to Classes of Traveling Salesman Problems. AB - By performing stability analysis on an optimal tour for problems belonging to classes of the traveling salesman problem (TSP), this paper derives margins of optimality for a solution with respect to disturbances in the problem data. Specifically, we consider the asymmetric sequence-dependent TSP, where the sequence dependence is driven by the dynamics of a stack. This is a generalization of the symmetric non sequence-dependent version of the TSP. Furthermore, we also consider the symmetric sequence-dependent variant and the asymmetric non sequence-dependent variant. Amongst others these problems have applications in logistics and unmanned aircraft mission planning. Changing external conditions such as traffic or weather may alter task costs, which can render an initially optimal itinerary suboptimal. Instead of optimizing the itinerary every time task costs change, stability criteria allow for fast evaluation of whether itineraries remain optimal. This paper develops a method to compute stability regions for the best tour in a set of tours for the symmetric TSP and extends the results to the asymmetric problem as well as their sequence dependent counterparts. As the TSP is NP-hard, heuristic methods are frequently used to solve it. The presented approach is also applicable to analyze stability regions for a tour obtained through application of the k -opt heuristic with respect to the k -neighborhood. A dimensionless criticality metric for edges is proposed, such that a high criticality of an edge indicates that the optimal tour is more susceptible to cost changes in that edge. Multiple examples demonstrate the application of the developed stability computation method as well as the edge criticality measure that facilitates an intuitive assessment of instances of the TSP. PMID- 25910271 TI - Improved Memetic Algorithm Based on Route Distance Grouping for Multiobjective Large Scale Capacitated Arc Routing Problems. AB - The capacitated arc routing problem (CARP) has attracted considerable attention from researchers due to its broad potential for social applications. This paper builds on, and develops beyond, the cooperative coevolutionary algorithm based on route distance grouping (RDG-MAENS), recently proposed by Mei et al. Although Mei's method has proved superior to previous algorithms, we discuss several remaining drawbacks and propose solutions to overcome them. First, although RDG is used in searching for potential better solutions, the solution generated from the decomposed problem at each generation is not the best one, and the best solution found so far is not used for solving the current generation. Second, to determine which sub-population the individual belongs to simply according to the distance can lead to an imbalance in the number of the individuals among different sub-populations and the allocation of resources. Third, the method of Mei et al. was only used to solve single-objective CARP. To overcome the above issues, this paper proposes improving RDG-MAENS by updating the solutions immediately and applying them to solve the current solution through areas shared, and then according to the magnitude of the vector of the route direction, and a fast and simple allocation scheme is proposed to determine which decomposed problem the route belongs to. Finally, we combine the improved algorithm with an improved decomposition-based memetic algorithm to solve the multiobjective large scale CARP (LSCARP). Experimental results suggest that the proposed improved algorithm can achieve better results on both single-objective LSCARP and multiobjective LSCARP. PMID- 25910272 TI - Total Variation Regularized RPCA for Irregularly Moving Object Detection Under Dynamic Background. AB - Moving object detection is one of the most fundamental tasks in computer vision. Many classic and contemporary algorithms work well under the assumption that backgrounds are stationary and movements are continuous, but degrade sharply when they are used in a real detection system, mainly due to: 1) the dynamic background (e.g., swaying trees, water ripples and fountains in real scenarios, as well as raindrops and snowflakes in bad weather) and 2) the irregular object movement (like lingering objects). This paper presents a unified framework for addressing the difficulties mentioned above, especially the one caused by irregular object movement. This framework separates dynamic background from moving objects using the spatial continuity of foreground, and detects lingering objects using the temporal continuity of foreground. The proposed framework assumes that the dynamic background is sparser than the moving foreground that has smooth boundary and trajectory. We regard the observed video as being made up of the sum of a low-rank static background, a sparse and smooth foreground, and a sparser dynamic background. To deal with this decomposition, i.e., a constrained minimization problem, the augmented Lagrangian multiplier method is employed with the help of the alternating direction minimizing strategy. Extensive experiments on both simulated and real data demonstrate that our method significantly outperforms the state-of-the-art approaches, especially for the cases with dynamic backgrounds and discontinuous movements. PMID- 25910273 TI - A Clustering-Based Approach to Enriching Code Foraging Environment. AB - Developers often spend valuable time navigating and seeking relevant code in software maintenance. Currently, there is a lack of theoretical foundations to guide tool design and evaluation to best shape the code base to developers. This paper contributes a unified code navigation theory in light of the optimal food foraging principles. We further develop a novel framework for automatically assessing the foraging mechanisms in the context of program investigation. We use the framework to examine to what extent the clustering of software entities affects code foraging. Our quantitative analysis of long-lived open-source projects suggests that clustering enriches the software environment and improves foraging efficiency. Our qualitative inquiry reveals concrete insights into real developer's behavior. Our research opens the avenue toward building a new set of ecologically valid code navigation tools. PMID- 25910111 TI - Measurement of spin correlation in top-antitop quark events and search for top squark pair production in pp collisions at ?s=8 TeV using the ATLAS detector. AB - A measurement of spin correlation in tt[over -] production is presented using data collected with the ATLAS detector at the Large Hadron Collider in proton proton collisions at a center-of-mass energy of 8 TeV, corresponding to an integrated luminosity of 20.3 fb^{-1}. The correlation between the top and antitop quark spins is extracted from dilepton tt[over -] events by using the difference in the azimuthal angle between the two charged leptons in the laboratory frame. In the helicity basis the measured degree of correlation corresponds to A_{helicity}=0.38+/-0.04, in agreement with the standard model prediction. A search is performed for pair production of top squarks with masses close to the top quark mass decaying to predominantly right-handed top quarks and a light neutralino, the lightest supersymmetric particle. Top squarks with masses between the top quark mass and 191 GeV are excluded at the 95% confidence level. PMID- 25910274 TI - Optimal Group Size for Software Change Tasks: A Social Information Foraging Perspective. AB - Group size is a key factor in collaborative software development and many other cybernetic applications where task assignments are important. While methods exist to estimate its value for proprietary projects, little is known about how group size affects distributed and decentralized cybernetic applications and in particular open source software (OSS) development. This paper presents a novel approach in which we frame developers' collective resolution of OSS change tasks as a social information foraging problem. This new perspective enables us to predict the optimal group size and quantify group size's effect on individual performance. We test the theory with data mined from two projects: 1) Firefox and 2) Mylyn. This paper not only uncovers the mismatch of optimal and actual group sizes, but also reveals the association of optimality with improved productivity. In addition, the social-level productivity gain is observed as project evolves. We show this paper's impact by extending the frontiers of knowledge in two areas: 1) social coding and 2) recommendation systems. PMID- 25910278 TI - Correction: Wood-Inhabiting Beetles in Low Stumps,High Stumps and Logs on Boreal Clear-Cuts: Implications for Dead Wood Management. PMID- 25910277 TI - Functional validation of a constitutive autonomous silencer element. AB - Sequences of the genome that are capable of silencing gene expression are thought to play a key role in gene regulation. However, very few silencer elements capable of functioning in mammalian cells have been described, and only a fraction of these have been tested for the ability to function in an autonomous fashion. We report here the characterization and functional validation of a constitutive autonomous silencer element from the human genome called T39, and the comparison of T39 to three other putative silencer elements previously described by others. Functional analysis included one assay for enhancer-blocking insulator activity and two independent assays for silencer activity, all based on stable transfection and comparison to a neutral spacer control. In erythroid K562 cells, T39 exhibited potent silencer activity, the previously described element PRE2-S5 exhibited modest silencer activity, and the two other previously described elements exhibited no silencer activity. T39 was further found to be capable of silencing three disparate promoters, of silencing gene expression in three disparate cell lines, and of functioning as a single copy in a topology independent manner. Of the four elements analyzed, only T39 exhibits a constitutive pattern of DNase hypersensitivity and binding by CTCF. In its native location the T39 element also exhibits a unique interaction profile with a subset of distal putative regulatory elements. Taken together, these studies validate T39 as a constitutive autonomous silencer, identify T39 as a defined control for future studies of other regulatory elements such as insulators, and provide a basic chromatin profile for one highly potent silencer element. PMID- 25910275 TI - Temporal and Molecular Analyses of Cardiac Extracellular Matrix Remodeling following Pressure Overload in Adiponectin Deficient Mice. AB - Adiponectin, circulating levels of which are reduced in obesity and diabetes, mediates cardiac extracellular matrix (ECM) remodeling in response to pressure overload (PO). Here, we performed a detailed temporal analysis of progressive cardiac ECM remodelling in adiponectin knockout (AdKO) and wild-type (WT) mice at 3 days and 1, 2, 3 and 4 weeks following the induction of mild PO via minimally invasive transverse aortic banding. We first observed that myocardial adiponectin gene expression was reduced after 4 weeks of PO, whereas increased adiponectin levels were detected in cardiac homogenates at this time despite decreased circulating levels of adiponectin. Scanning electron microscopy and Masson's trichrome staining showed collagen accumulation increased in response to 2 and 4 weeks of PO in WT mice, while fibrosis in AdKO mice was notably absent after 2 weeks but highly apparent after 4 weeks of PO. Time and intensity of fibroblast appearance after PO was not significantly different between AdKO and WT animals. Gene array analysis indicated that MMP2, TIMP2, collagen 1alpha1 and collagen 1alpha3 were induced after 2 weeks of PO in WT but not AdKO mice. After 4 weeks MMP8 was induced in both genotypes, MMP9 only in WT mice and MMP1alpha only in AdKO mice. Direct stimulation of primary cardiac fibroblasts with adiponectin induced a transient increase in total collagen detected by picrosirius red staining and collagen III levels synthesis, as well as enhanced MMP2 activity detected via gelatin zymography. Adiponectin also enhanced fibroblast migration and attenuated angiotensin-II induced differentiation to a myofibroblast phenotype. In conclusion, these data indicate that increased myocardial bioavailability of adiponectin mediates ECM remodeling following PO and that adiponectin deficiency delays these effects. PMID- 25910279 TI - Satellite-Based Estimates of Long-Term Exposure to Fine Particles and Association with Mortality in Elderly Hong Kong Residents. AB - BACKGROUND: A limited number of studies on long-term effects of particulate matter with aerodynamic diameter < 2.5 MUm (PM2.5) on health suggest it can be an important cause of morbidity and mortality. In Asia where air quality is poor and deteriorating, local data on long-term effects of PM2.5 to support policy on air quality management are scarce. OBJECTIVES: We assessed long-term effects of PM2.5 on the mortality in a single Asian city. METHODS: For 10-13 years, we followed up a cohort of 66,820 participants >= 65 years of age who were enrolled and interviewed in all 18 Elderly Health Centres of the Department of Health, Hong Kong, in 1998-2001. Their residential addresses were geocoded into x- and y coordinates, and their proxy exposures to PM2.5 at their addresses in 1 * 1 km grids were estimated from the U.S. National Aeronautics and Space Administration (NASA) satellite data. We used Cox regression models to calculate hazard ratios (HRs) of mortality associated with PM2.5. RESULTS: Mortality HRs per 10-MUg/m3 increase in PM2.5 were 1.14 (95% CI: 1.07, 1.22) for all natural causes, 1.22 (95% CI: 1.08, 1.39) for cardiovascular causes, 1.42 (95% CI: 1.16, 1.73) for ischemic heart disease, 1.24 (95% CI: 1.00, 1.53) for cerebrovascular disease, and 1.05 (95% CI: 0.90, 1.22) for respiratory causes. CONCLUSIONS: Our methods in using NASA satellite data provide a readily accessible and affordable approach to estimation of a sufficient range of individual PM2.5 exposures in a single city. This approach can expand the capacity to conduct environmental accountability studies in areas with few measurements of fine particles. CITATION: Wong CM, Lai HK, Tsang H, Thach TQ, Thomas GN, Lam KB, Chan KP, Yang L, Lau AK, Ayres JG, Lee SY, Chan WM, Hedley AJ, Lam TH. 2015. Satellite-based estimates of long-term exposure to fine particles and association with mortality in elderly Hong Kong residents. Environ Health Perspect 123:1167-1172; http://dx.doi.org/10.1289/ehp.1408264. PMID- 25910276 TI - Alkaline phosphatase protects lipopolysaccharide-induced early pregnancy defects in mice. AB - Excessive cytokine inflammatory response due to chronic or superphysiological level of microbial infection during pregnancy leads to pregnancy complications such as early pregnancy defects/loss and preterm birth. Bacterial toxin lipopolysaccharide (LPS), long recognized as a potent proinflammatory mediator, has been identified as a risk factor for pregnancy complications. Alkaline phosphatase (AP) isozymes have been shown to detoxify LPS by dephosphorylation. In this study, we examined the role of alkaline phosphatase (AP) in mitigating LPS-induced early pregnancy complications in mice. We found that 1) the uterus prior to implantation and implantation sites following embryo implantation produce LPS recognition and dephosphorylation molecules TLR4 and tissue non specific AP (TNAP) isozyme, respectively; 2) uterine TNAP isozyme dephosphorylates LPS at its sites of production; 3) while LPS administration following embryo implantation elicits proinflammatory cytokine mRNA levels at the embryo implantation sites (EISs) and causes early pregnancy loss, dephosphorylated LPS neither triggers proinflammatory cytokine mRNA levels at the EISs nor induces pregnancy complications; 4) AP isozyme supplementation to accelerate LPS detoxification attenuates LPS-induced pregnancy complications following embryo implantation. These findings suggest that a LPS dephosphorylation strategy using AP isozyme may have a unique therapeutic potential to mitigate LPS- or Gram-negative bacteria-induced pregnancy complications in at-risk women. PMID- 25910280 TI - Exposure to Elemental Carbon, Organic Carbon, Nitrate, and Sulfate Fractions of Fine Particulate Matter and Risk of Preterm Birth in New Jersey, Ohio, and Pennsylvania (2000-2005). AB - BACKGROUND: Particulate matter <= 2.5 MUm in aerodynamic diameter (PM2.5) has been consistently associated with preterm birth (PTB) to varying degrees, but roles of PM2.5 species have been less studied. OBJECTIVE: We estimated risk differences (RD) of PTB (reported per 106 pregnancies) associated with change in ambient concentrations of elemental carbon (EC), organic carbon (OC), nitrates (NO3), and sulfates (SO4). METHODS: From live birth certificates from three states, we constructed a cohort of singleton pregnancies at or beyond 20 weeks of gestation from 2000 through 2005 (n = 1,771,225; 8% PTB). We estimated mean species exposures for each week of gestation from monitor-corrected Community Multi-Scale Air Quality modeling data. RDs and 95% confidence intervals (CIs) for four PTB categories were estimated for each exposure using linear regression, adjusted for maternal race/ethnicity, marital status, education, age, smoking, maximum temperature, ozone, and season of conception. We also adjusted for other species in multi-species models. RESULTS: RDs varied by exposure window and outcome period. EC was positively associated with PTB after 27 and before 35 weeks of gestation. For example, for a 0.25-MUg/m(3) increase in EC exposure during gestational week 9, RD = 96 (95% CI: -20, 213) and RD = 145 (95% CI: -50, 341) for PTB during weeks 28-31 and 32-34, respectively. Associations with OCs were null or negative. RDs for NO3 were elevated with exposure in early weeks of gestation, and null in later weeks. RDs for SO4 exposure were positively associated with PTB, though magnitude varied across gestational weeks. We observed effect measure modification for associations between EC and PTB by race/ethnicity and smoking status. CONCLUSION: EC and SO4 may contribute to associations between PM2.5 and PTB. Associations varied according to the timing of exposure and the timing of PTB. PMID- 25910281 TI - Association of Prenatal Exposure to Persistent Organic Pollutants with Obesity and Cardiometabolic Traits in Early Childhood: The Rhea Mother-Child Cohort (Crete, Greece). AB - BACKGROUND: Prenatal exposure to endocrine-disrupting chemicals such as persistent organic pollutants (POPs) may increase risk of obesity later in life. OBJECTIVE: We examined the relation of in utero POPs exposure to offspring obesity and cardiometabolic risk factors at 4 years of age in the Rhea mother child cohort in Crete, Greece (n = 689). METHODS: We determined concentrations of polychlorinated biphenyls (PCBs), dichlorodiphenyldichloroethylene (DDE), and hexachlorobenzene (HCB) in first-trimester maternal serum. We measured child weight, height, waist circumference, skinfold thicknesses, blood pressure (BP), blood levels of lipids, C-reactive protein, and adipokines at 4 years of age. Childhood obesity was defined using age- and sex-specific cut points for body mass index (BMI) as recommended by the International Obesity Task Force. RESULTS: On multivariable regression analyses, a 10-fold increase in HCB was associated with a higher BMI z-score (adjusted beta = 0.49; 95% CI: 0.12, 0.86), obesity [relative risk (RR) = 8.14; 95% CI: 1.85, 35.81], abdominal obesity (RR = 3.49; 95% CI: 1.08, 11.28), greater sum of skinfold thickness (beta = 7.71 mm; 95% CI: 2.04, 13.39), and higher systolic BP (beta = 4.34 mmHg; 95% CI: 0.63, 8.05) at 4 years of age. Prenatal DDE exposure was associated with higher BMI z-score (beta = 0.27; 95% CI: 0.04, 0.5), abdominal obesity (RR = 3.76; 95% CI: 1.70, 8.30), and higher diastolic BP (beta = 1.79 mmHg; 95% CI: 0.13, 3.46). PCBs were not significantly associated with offspring obesity or cardiometabolic risk factors. CONCLUSIONS: Prenatal exposure to DDE and HCB was associated with excess adiposity and higher blood pressure levels in early childhood. PMID- 25910282 TI - Interweaving Knowledge Resources to Address Complex Environmental Health Challenges. AB - BACKGROUND: Complex problems do not respect academic disciplinary boundaries. Environmental health research is complex and often moves beyond these boundaries, integrating diverse knowledge resources to solve such challenges. Here we describe an evolving paradigm for interweaving approaches that integrates widely diverse resources outside of traditional academic environments in full partnerships of mutual respect and understanding. We demonstrate that scientists, social scientists, and engineers can work with government agencies, industry, and communities to interweave their expertise into metaphorical knowledge fabrics to share understanding, resources, and enthusiasm. OBJECTIVE: Our goal is to acknowledge and validate how interweaving research approaches can contribute to research-driven, solution-oriented problem solving in environmental health, and to inspire more members of the environmental health community to consider this approach. DISCUSSION: The National Institutes of Health's National Institute of Environmental Health Sciences Superfund Research Program (SRP), as mandated by Congress, has evolved to become a program that reaches across a wide range of knowledge resources. SRP fosters interweaving multiple knowledge resources to develop innovative multidirectional partnerships for research and training. Here we describe examples of how motivation, ideas, knowledge, and expertise from different people, institutions, and agencies can integrate to tackle challenges that can be as complex as the resources they bring to bear on it. CONCLUSIONS: By providing structure for interweaving science with its stakeholders, we are better able to leverage resources, increase potential for innovation, and proactively ensure a more fully developed spectrum of beneficial outcomes of research investments. CITATION: Anderson BE, Naujokas MF, Suk WA. 2015. Interweaving knowledge resources to address complex environmental health challenges. Environ Health Perspect 123:1095-1099; http://dx.doi.org/10.1289/ehp.1409525. PMID- 25910283 TI - More on SUPPORT: the controversy continues. AB - The article by Sunita VS Bandewar in the January-March issue does an excellent job of describing the controversy over informed consent in the SUPPORT clinical trial. As one of the authors of the duelling articles Bandewar cites, I commend the author's conclusions calling for disclosure not only of randomisation in so called "standard of care" clinical trials, but also the comprehensive disclosure of risks in this type of research (also known as "comparative effectiveness research [CER]"). Bandewar surmises that the disclosure of randomisation could result in a "much higher chance of patients declining to participate in a randomised trial"; and that this may be one of the motives of those who argue for non-disclosure of randomisation. In fact, at least some supporters of limited disclosure of the risks in CER trials have expressly acknowledged their concerns about the recruitment of participants if all the risks of "standard of care" treatments are mentioned in the consent forms. PMID- 25910284 TI - Diffusion-weighted imaging in the head and neck region: usefulness of apparent diffusion coefficient values for characterization of lesions. AB - PURPOSE: We aimed to evaluate the role of apparent diffusion coefficient (ADC) values calculated from diffusion-weighted imaging for head and neck lesion characterization in daily routine, in comparison with histopathological results. METHODS: Ninety consecutive patients who underwent magnetic resonance imaging (MRI) at a university hospital for diagnosis of neck lesions were included in this prospective study. Diffusion-weighted echo-planar MRI was performed on a 1.5 T unit with b factor of 0 and 1000 s/mm2 and ADC maps were generated. ADC values were measured for benign and malignant whole lesions seen in daily practice. RESULTS: The median ADC value of the malignant tumors and benign lesions were 0.72*10-3 mm2/s, (range, 0.39-1.51*10-3 mm2/s) and 1.17*10-3 mm2/s, (range, 0.52 2.38*10-3 mm2/s), respectively, with a significant difference between them (P < 0.001). A cutoff ADC value of 0.98*10-3 mm2/s was used to distinguish between benign and malignant lesions, yielding 85.3% sensitivity and 78.6% specificity. The median ADC value of lymphomas (0.44*10-3 mm2/s; range, 0.39-0.58*10-3 mm2/s) was significantly smaller (P < 0.001) than that of squamous cell carcinomas (median ADC value 0.72*10-3 mm2/s; range, 0.65-1.06*10-3 mm2/s). There was no significant difference between median ADC values of inflammatory (1.13*10-3 mm2/s; range, 0.85-2.38*10-3 mm2/s) and noninflammatory benign lesions (1.26*10-3 mm2/s; range, 0.52-2.33*10-3 mm2/s). CONCLUSION: Diffusion-weighted imaging and the ADC values can be used to differentiate and characterize benign and malignant head and neck lesions. PMID- 25910285 TI - Defecation patterns of the infants mainly breastfed from birth till the 12th month: Prospective cohort study. AB - BACKGROUND/AIMS: Studies about defecation patterns have been mostly conducted on infants who were breastfed in a short term but were fed predominantly with formula. In this study, defecation patterns of 125 infants, most of them being breastfed during 12th month were evaluated. MATERIALS AND METHODS: Frequency, consistency and color of the stool were analyzed in relation to the feeding pattern at the 15th day and at the 1st, 2nd, 3rd, 4th, 5th, 6th and 12th months. RESULTS: Frequency of defecation was highest in 15th day with a median of 6/day. It decreased with age (p=0.0001), being 4/day and 3/day in 1st and 2nd months respectively, and 2/day between 3rd-12th months. During first 5 months, the stool frequency was higher in infants who were exclusively breastfed compared to those being fed with breastfed and formula (p<0.05). The effect of the feeding pattern on stool frequency disappeared in the following months (p>0.05). Stool frequency decreased by half at the 2nd month when the rate of less than once/day attained its highest value (24.8%). In those who had a rate of less than once/day, stool frequency stayed low until the 6th month and exclusively breastfed rate was also found lower (p<0.05). CONCLUSION: Besides the age, exclusive breastfeeding was also effective on stool frequency. It points out that infants who are fed with formula in addition to breastfeeding may defecate less than once per day hence should not be diagnosed as having constipation depending solely on defecation frequency and should not receive unneccesary treatments. PMID- 25910286 TI - Anatomic variations of the celiac trunk and hepatic arterial system with digital subtraction angiography. AB - BACKGROUND/AIMS: Anatomical variation of the abdominal arteries is important. Historic and modern anatomists, radiologists, as well as surgeons have reported and accumulated anatomical variations with a morphological and clinical interest. During graft procurement and reconstruction, accidental injury of the hepatic artery is more likely in the presence of hepatic arterial variation, which can be a common clinical entity. During cadaveric dissection and diagnostic radiological imaging, various types of vascular anomalies are frequently found in human abdominal viscera, especially the celiac trunk. The aim of the present study is to determine anatomical variations in the celiac trunk and hepatic arterial system. MATERIALS AND METHODS: Digital subtraction angiography data were collected from 152 consecutive donor patients (103 males and 49 females, aged between 6 and 77 years) who underwent orthotopic liver transplantation. RESULTS: We examined the anatomy of the celiac trunk in a total of 152 consecutive patients. In total, 62.5% (95/152) of patients showed the classical trifurcation of the celiac trunk. Variant right hepatic arteries arising from the superior mesenteric artery were observed in 17.8% (27/152), the hepatic arteries arising from the left gastric artery were found in 13.1% (20/152), and common hepatic arteries arising from the superior mesenteric artery were observed in 6.6% (10/152) of patients. CONCLUSION: These data are useful for planning and performing surgical and radiological procedures of the upper abdomen. PMID- 25910288 TI - Copper excess in liver HepG2 cells interferes with apoptosis and lipid metabolic signaling at the protein level. AB - BACKGROUND/AIMS: Copper is an essential trace element that serves as an important catalytic cofactor for cuproenzymes, carrying out major biological functions in growth and development. Although Wilson's disease (WD) is unquestionably caused by mutations in the ATP7B gene and subsequent copper overload, the precise role of copper in inducing pathological changes remains poorly understood. MATERIALS AND METHODS: Our study aimed to explore, in HepG2 cells exposed to copper, the cell viability and apoptotic cells was tested by MTT and Hoechst 33342 stainning respectively, and the signaling pathways involved in oxidative stress response, apoptosis and lipid metabolism were determined by real time RT-PCR and Western blot analysis. RESULTS: The results demonstrate dose- and time-dependent cell viability and apoptosis in HepG2 cells following treatment with 10 MUM, 200 MUM and 500 MUM of copper sulfate for 8 and 24 h. Copper overload significantly induced the expression of HSPA1A (heat shock 70 kDa protein 1A), an oxidative stress-responsive signal gene, and BAG3 (BCL2 associated athanogene3), an anti apoptotic gene, while expression of HMGCR (3-hydroxy-3-methylglutaryl-CoA reductase), a lipid biosynthesis and lipid metabolism gene, was inhibited. CONCLUSION: These findings provide new insights into possible mechanisms accounting for the development of liver apoptosis and steatosis in the early stages of Wilson's disease. PMID- 25910287 TI - Clinical outcomes of nonvariceal upper gastrointestinal bleeding in Kosova. AB - BACKGROUND/AIMS: The aim was to determine the sociodemographic and etiologic factors, endoscopic accuracy, treatment efficiency and clinical outcome of patients with nonvariceal upper gastrointestinal system bleeding in Kosova. MATERIALS AND METHODS: We retrospectively evaluated patients who had applied to our Gastroenterology Department between January 2006 and December 2010. RESULTS: There were 460 eligible cases with mean age 56.85+16.18 years, while male /female ratio was 2.71/1. The greatest occurrence was at age group of 60-69 years (27.1 %). The most common clinical symptom was melena (62.6%). Comorbid diseases were present in 57, 6% of the patients. The percentage of patients using acetylsalicylic acid and /or other non-steroidal anti-inflammatory drugs was 43.7%. Five point two percent were using anticoagulants. Peptic ulcer was the main cause of bleeding (82.2%) and most of them were Forrest III (41.6%). Endoscopic treatment was performed in 90 patients, primary hemostasis was achieved in 96.7% while rebleeding developed in 10% of these patients. The average length of hospital stay was 9.29+5.58 (1-35) days. Rebleeding was reported in 4.1% of all patients while the overall mortality rate was 5.7%. CONCLUSION: Age over 60 years, previous history of gastrointestinal bleeding, treatment with anticoagulants, low hemoglobin values at presentation (<7 g/dL), hematemesis, Forrest class, localization of lesion of bleeding, comorbidities, tachycardia, transfusion requirement>2 unit, type of treatment and time of endoscopy were predictors of poor outcome in study present. PMID- 25910289 TI - NOD2/CARD15 gene influences disease behaviour but not IBD susceptibility in a Moroccan population. AB - BACKGROUND/AIMS: IBD (Crohn's disease and Ulcerative Colitis) is chronic and multifactorial disease of the gastrointestinal tract. Till now, his pathogenesis remains unclear. It involves innate immunity, environmental component and genetic predisposition. Polymorphisms in NOD2/CARD15 have been implicated in Crohn's disease in several ethnic groups. The purpose of our study was to assess the frequency of the three major variants of this gene (Leu1007fsinsC, R702W, and G908R) in Moroccan IBD patients and to determine a possible effect of these variants on Disease's phenotype and clinical course. MATERIALS AND METHODS: A total of 96 Moroccan unrelated IBD patients and 114 healthy controls were genotyped (PCR-RFLP method) for the three main polymorphisms. RESULTS: In this study, no correlation was found between NOD2/CARD15 polymorphisms and ulcerative colitis or Crohn's disease in our population. Nevertheless, 3020insC (Leu1007fsinsC) variant was associated to a structuring behaviour on CD patients. CONCLUSION: These findings suggest that NOD2/CARD15 influences disease behaviour but not susceptibility to crohn's disease in Moroccan IBD patients. PMID- 25910290 TI - Characterization of de novo colonic stricture due to Crohn's disease. AB - BACKGROUND/AIMS: The development of colonic stenosis is a rare complication of Crohn's disease (CD) without a surgical anastomosis history. So, the management and long-term follow-up results of colonic stricture due to CD have not been clearly defined. In this study, we aimed to characterize de novo colonic stricture due to CD. MATERIALS AND METHODS: We evaluated 702 patients with CD to investigate colonic stricture. Colonic stricture was considered to exist when passage of a standard colonoscope was not possible and was diagnosed radiologically and endoscopically in this study. RESULTS: Of the 702 patients, 14 had colonic stricture according to the definition above. Of the 14, 8 were male. The interval between diagnosis of disease and recognition of the stricture varied from 0 to 13 years. Localization of the strictures differed from the rectum to cecum. Of the 14, 3 patients had more than 1 stricture. Pathological examination of the stricture(s) did not show dysplasia or malignancy initially or during the follow-up. CONCLUSION: De novo colonic stricture due to CD is a rare condition according to the presented study's results. Distribution of the stricture(s) varied from the rectum to cecum without increased colonic cancer risk. We observed the antifibrotic role of thiopurines and biologic agents in this study. PMID- 25910291 TI - Evaluation of concentrations of pro/anti-inflammatory cytokines after complication-free ECRP in cholangiocarcinoma. AB - BACKGROUND/AIMS: Variations in pro and anti-inflammatory cytokine levels occur commonly after ERCP procedure complications, such as in post-ERCP pancreatitis. Besides, the relationship between increased cytokine levels and multidrug resistance has been shown in cholangiocarcinoma patients. Our aim was to investigate the impact of cytokine level changes on treatment strategy after uncomplicated ERCP procedures in cholangiocarcinoma patients. MATERIALS AND METHODS: Of 75 patients enrolled in this study, 25 were cholangiocarcinoma, and 50 were choledocholithiasis patients. Levels of serum IL-1beta, IL-6, IL-8, IL 10, and TNF-alpha were evaluated 2 hours before and 12 hours after complication free ERCP, and statistical analysis of the results was obtained; if p value<0.05, it was accepted as statistically significant. RESULTS: There was no statistically significant difference in the distribution of age (23-87 years; range: 59.8+/ 16.6), gender (37 males vs 38 females), and levels of pre- and post-ERCP serum IL 1beta, IL-6, IL-8, IL-10, and TNF-alpha in both patient groups, despite the presence of some change in test means (p:0.179, 0.445, 0.522, 0.937, and 0.065, respectively). However, significantly decreased levels of TNF-alpha were observed in the benign group, when comparing pre- and post-ERCP period (p<0.05). CONCLUSION: Serum concentrations of IL-1beta, IL-6, IL-8, IL-10, and TNF-alpha evaluated after complication-free ERCP performed in patients with cholangiocarcinoma do not cause any change in treatment planning that would affect multidrug resistance. PMID- 25910292 TI - Fatty liver disease might increase the risk of abdominal operation in patients with fatty liver and the prevalence of cancer in first-degree relatives. AB - BACKGROUND/AIMS: We investigated the risk of abdominal operation in patients with fatty liver and the risk of any cancer in first-degree relatives of patients with fatty liver. MATERIALS AND METHODS: We evaluated 105 patients with nonalcoholic fatty liver disease (NAFLD), 121 patients with biopsy-proven hepatitis C (61 patients with fatty liver and 60 patients without fatty liver), 50 patients with inflammatory bowel disease (IBD), and 109 patients with dyspepsia. RESULTS: There was no difference in sex, mean age, and marital status among the groups except that patients with IBD were younger than the others (p<0.001). The frequency of cancer among family members was 18% in IBD, 9% in dyspepsia, 28% in hepatitis C with steatosis, 21.5% in hepatitis C without steatosis, and 27% in NAFLD (p=0.006). Then, we divided the study group into two groups as follows: group 1: (IBD+dyspepsia+hepatitis C without steatosis) and group 2: (hepatitis C with steatosis+NAFLD). We found that the frequency of cancer was 16% in group 1 versus 24.4 % in group 2 (p=0.037). We also investigated the risk of abdominal operation in patients with fatty liver. The results were as follows: 33% in group without fatty liver versus 43% in group with fatty liver (p=0.043). CONCLUSION: Understanding the underlying causes of fatty liver forms might decrease the cancer frequency in the population and number of operations in patients with fatty liver. PMID- 25910293 TI - Relation between serum quantitative HBsAg, ALT and HBV DNA levels in HBeAg negative chronic HBV infection. AB - BACKGROUND/AIMS: In this study, we aimed to investigate whether quantitative HBsAg and alanine aminotransferase (ALT) levels correlated with Hepatitis B Virus (HBV) DNA levels in patients with HBeAg negative chronic HBV infection. MATERIALS AND METHODS: Ninetynine patients were divided into two groups; inactive HBsAg carriers (IC) and active carriers (AC) with HBV DNA>2000 IU/mL. These two groups were compared in terms of ALT and HBsAg levels. Quantitative HBsAg measurements were performed with Elecsys HBsAg II Quant assay (Roche Diagnostic). RESULTS: Mean age of patients was 43.11+/-14.79 years. HBsAg and ALT values of IC and AC patients were 2.47+/-1.35 log10 IU/mL, 3.59+/-0.97 log10 IU/mL (p=0.0001), and 25.94+/-13.06 IU/mL, 55.54+/-82.38 IU/mL (p=0.015), respectively and the difference was significant. When ROC analysis was performed to determine the most appropriate quantitative HBsAg value to define inactive carrier patients, the area under the ROC curve for HBsAg was 0.738 (95% CI:0.637-0.840). A cut-off of 2147 IU/mL revealed sensitivity of 76% and specificity of 70% for diagnosing the IC. Also, a significant correlation was also found between levels of HBV DNA (log) and HBsAg (log) (r: 0.503, p=0.0001). CONCLUSION: It has been concluded that quantitative measurements of HBsAg could be used to differentiate between IC and AC patients. PMID- 25910294 TI - Serum peptidome patterns of hepatocellular carcinoma based on magnetic bead separation and mass spectrometry analysis. AB - BACKGROUND/AIMS: The only hope for a cure from hepatocellular carcinoma (HCC) rests on early diagnosis. The present study aims to determine serum peptidome patterns for early diagnosis of HCC. MATERIALS AND METHODS: To identify novel peptidome patterns for diagnosing HCC, serum from31 healthy volunteers and 32 HCC patients were subjected to a comparative proteomic analysis using a ClinProt Kit combined with mass spectrometry (MS). This approach allows the determination of peptidome patterns that are able to differentiate the HCC from healthy volunteers. For further validation, the diagnostic and differential diagnostic capabilities of the peptidome patterns were verified blindly by an independent group of sera consisted of 31 HCC, 23 liver fibrosis and 33 healthy volunteers. RESULTS: A Quick Classifier Algorithm was used to construct the peptidome patterns for the identification of HCC from the control samples. One of the identified peaks at m/z 7771 was used to construct the peptidome patterns with almost 100% accuracy. Furthermore, the peptidome patterns could also differentiate the validation group with high accuracy. CONCLUSION: These results suggest that the ClinProt Kit combined with MS achieves significantly high accuracy for HCC diagnosis and differential diagnosis. PMID- 25910295 TI - Neutropenia and viral load decline during treatment of hepatitis C virus genotype 4. AB - BACKGROUND/AIMS: Neutrophil count and magnitude of decrease from baseline are not correlated with infection rate in recipients of interferon-based therapy for hepatitis C (HCV). The association of neutropenia with viral response raises the potential dilemma of trying to maintain patients on therapy despite adverse events. We studied the relationship between early viral clearance in response to treatment, and neutrophil count and fall in neutrophils in HCV-genotype 4 patients. MATERIALS AND METHODS: Two-hundred and one patients with HCV-genotype 4 were enrolled. RESULTS: Rapid and early virological responses (RVR and EVR) were achieved in 33.3% and 61.5% respectively. None of the patients developed symptomatic infection regardless of the degree of neutrophil decline. Neutrophil decline at week 2 significantly correlated with viral load at week 12 (r=0.40, p=0.042), and neutrophil decline at week 4 significantly correlated with viral load decline at week 12 (r=0.21, p=0.006). Using logistic regression, pretreatment neutrophil count significantly predicted RVR and EVR, such that individuals who achieved RVR and EVR had higher pretreatment neutrophils compared to non-responders (X2= 4.94, p=0.026; X2=7.67, p=0.005 respectively). Adjusting for age, sex, grade, fibrosis, and pretreatment neutropenia; decline in neutrophil count was significantly associated with lower viral load over time (t= 2.27, p=0.027) and higher viral load decline over time (t=2.73, p=0.009) and achieving EVR (t=2.04, p=0.044). CONCLUSION: In genotype 4 patients, neutropenia can be a predictor of response. Neutropenia may reflect disappearance of genomic hepatitis C viral RNA from mononuclear cells. The relationship between neutropenia and response is confined to the first 12 weeks of therapy. PMID- 25910296 TI - Endoscopic diagnosis and treatment of calcifying fibrous tumors. AB - BACKGROUND/AIMS: The calcifying fibrous tumor (CFT) is classified as a benign fibrous lesion, and it is a rare pathologic entity. We evaluated the feasibility, efficacy and safety of endoscopy treatment for CFT. MATERIALS AND METHODS: We retrospectively analyzed a total of 4 gastric CFTs that were treated with ESD or EFR at the endoscopic center of Zhongshan Hospital, Fudan University, in Shanghai, between Jan 2007 and Sept 2011. We used endoscopic ultrasound (EUS) to assess whether endoscopy treatment was suitable. Tumor characteristics, complications, the en bloc resection rate, and the local recurrence rate were evaluated. RESULTS: Of the 4 patients, the median age was 55.5 years old. The mean maximum size of the lesions was 1.95+/-0.67 (range: 1.0-2.5). The EUS features of the lesions included a mass in the muscularis propria of the gastric wall and a heterogeneous hypoechoic (1/4) or homogeneous (3/4) hypoechoic pattern. All of the endoscopic treatments were completed successfully. The en bloc resection rate was 100%. Confirmed diagnoses were made by pathologic results. No local recurrence or complications were observed during the follow-up period (ranging from 15 to 28 months). CONCLUSION: Endoscopic treatment, especially ESD/EFR, appears to be a feasible and safe procedure for CFT with relatively few complications and low mortality. PMID- 25910297 TI - Diagnosis and treatment of Helicobacter pylori for peptic ulcer bleeding in clinical practice - factors associated with non-diagnosis and non-treatment, and diagnostic yield in various settings. AB - BACKGROUND/AIMS: To study the practice of clinicians in the diagnosis and treatment of H. pylori for peptic ulcer bleeding, and the diagnostic yield of H. pylori tests in various situations. MATERIALS AND METHODS: All consecutive patients aged >=18 years who underwent esophagogastroduodenoscopy for the indications of coffee-grounds vomitus, hematemesis or melena with endoscopically diagnosed peptic ulcers were included. RESULTS: 374 patients were included. H. pylori testing was performed during acute bleeding for 296 patients. 80% of patients who tested negative for H. pylori during the acute episode were planned for repeat H. pylori testing. 11/88 patients who tested negative for H. pylori during the acute episode were positive for H. pylori during repeat testing (diagnostic yield 12.5%). Prior proton-pump inhibitor and antibiotic ingestion within 4 weeks of presentation was associated with lower diagnostic yield for H. pylori. On multivariate analysis, patient's age, systolic blood pressure, heart rate, activated partial thromboplastin time, and need for endoscopic treatment were associated with failure to take biopsies for H. pylori testing during acute episode. 100/106 patients tested positive for H. pylori during the acute episode of gastrointestinal bleeding had H. pylori treatment. CONCLUSION: Repeat H. pylori testing after index negative H. pylori testing during acute episodes gave a diagnostic yield of 12.5%, reinforcing the importance of repeat testing. PMID- 25910298 TI - Laparoscopic distal pancreatectomy for benign or borderline malignant pancreatic tumors. AB - BACKGROUND/AIMS: Laparoscopic distal pancreatectomy (LDP) for benign conditions is increasingly performed. But, there are few limited studies about the outcomes of the laparoscopic surgery compared with open surgery. The aim of this study was to evaluate the clinical outcomes of LDP and compare it to that of open distal pancreatectomy (ODP). MATERIALS AND METHODS: From July 2007 to February 2012, 60 consecutive patients (41 LDP patients and 19 ODP patients) who underwent elective distal pancreatectomy with an apparent diagnosis of benign or borderline malignant tumor were recruited into the current study. RESULTS: There were no significant differences in operation time, transfusion, intravenous patient controlled analgesia (IV-PCA) duration, pancreatic fistula, mortality, and recurrence between the two groups. Compared to ODP, LDP had lower blood loss (272.7+/-134.8 vs. 476.9+/-140.8 ml; p=0.002), shorter time to first flatus (2.4+/-0.5 vs. 4.0+/-1.5 days; p=0.003), earlier time to oral intake (3.4+/-1.6 vs. 5.4+/-1.9 days; p=0.013), and shorter postoperative hospital stay (9.4+/-6.9 vs. 17.0+/-6.7 days; p=0.043). CONCLUSION: LDP is a safe procedure and should be considered as a standard treatment option for benign or borderline malignant pancreatic tumors. PMID- 25910299 TI - A comparison of the effects of infliximab, adalimumab, and pentoxifylline on rats with non-alcoholic steatohepatitis. AB - BACKGROUND/AIMS: Non-alcoholic steatohepatitis (NASH) lacks effective medical treatment. Since tumor necrosis factor alpha (TNF-alpha) plays an important role in NASH pathogenesis, we aimed to investigate drugs affecting TNF-alpha as possible treatment options during the development of NASH. MATERIALS AND METHODS: A total of 35 rats were divided into five groups and evaluated over a 6 week period. One group received a normal diet alone or in combination with the administration of infliximab, adalimumab or pentoxifylline. RESULTS: NASH was successfully established in the MCD diet group. Levels of TNF-alpha were effectively suppressed in the three groups that received anti-TNF agents. No statistically significant differences were observed between the three agents in terms of the histological NASH score. CONCLUSION: Our study showed that the anti TNF agents infliximab, adalimumab, and pentoxifylline effectively suppress TNF alpha. Although these drugs did not prevent the development of NASH, they were able to slightly reverse the NASH histopathology score and positively affect liver function tests. PMID- 25910300 TI - Relationship between HER-2, COX-2, p53 and clinicopathologic features in gastric adenocarcinoma. Do these biomarkers have any prognostic significance? AB - BACKGROUND/AIMS: The aim of this study was to examine the expression of HER-2, p53 and COX-2 in gastric adenocarcinoma and to investigate whether these markers were useful in predicting the clinicopathologic features. MATERIALS AND METHODS: Primary gastric adenocarcinoma specimens were obtained from 56 patients who underwent total/subtotal gastrectomy with extended lymphadenectomy between December 2011 - December 2012. We investigated the association between the expression of these markers and clinicopathologic factors by immunohistochemistry. RESULTS: COX-2 positive cases were detected in 28 (50%) of the 56 patients and COX-2 expression was significantly correlated with presence of perineural invasion (p=0,032). 37 cases (66.1%) were defined positive for p53. The expression of p53 was significantly correlated with increasing age (p=0,003), but there was no correlation with other clinicopathological variables. Among the 56 primary gastric cancers, 9 (16.1%) cases showed intermediate (2+) positive expression and 7 (12.5%) cases showed (3+) positive expression for HER-2. No significant correlations were determined between HER-2 and the other variables. CONCLUSION: Although, this study failed to show any relationship between HER-2 and clinicopathological factors, but our results demondtrated that COX-2 expression might serve as a powerful indicator for estimating perineural invasion, which is an independent worse prognostic factor for survival in gastric adenocarcinoma. Additionally, detecting the expression of p53 can assist with the treatment options for elderly patients with gastric adenocarcinoma. A better understanding of HER-2, COX-2 and p53 expression in gastric adenocarcinoma may improve the staging strategies and influence new treatment modalities. PMID- 25910301 TI - A retrospective study on endoscopic missing diagnosis of colorectal polyp and its related factors. AB - BACKGROUND/AIMS: To investigate missing diagnosis of the polyp by colonoscopy, and to reveal the endoscopic, pathological features of missed polyps and related factors inducing missing diagnosis. MATERIALS AND METHODS: We reviewed the data of the patients who received colonoscopy twice within 180 days. The missing rate of the colorectal polyps ware calculated and the endoscopic and pathological features of the missed polyps were summarized. Possible related factors inducing the missing diagnosis were analyzed. RESULTS: The missing rate of colorectal polyps in this study was 27.7%, with as high as 11.5% missing rate of advanced polyps. Most missed polyps were those of <5 mm in diameter (55.2%) or flat ones (75.9%). Most of missed polyps are located in the rectum (21.8%), sigmoid (41.4%) and transverse colon (17.2%). No significant correlation was observed between the missing rate and colonoscopic manners (p>0.05), neither between the missing rate and operators (p>0.05). But number of basal polyps was proved to be significantly correlative with number of missed polyps (r=0.694, p<0.001). CONCLUSION: Polyps of <5 mm in diameter or flat polyps are more likely to be missed in the endoscopy. Most of missed polyps are located in rectum, sigmoid and transverse colon. More basal polyps usually accompany with more polyps missed. PMID- 25910302 TI - Complete biliary obstruction without jaundice due to an anatomic variation. AB - An aberrant right posterior hepatic duct is present in 4.8-8.4% of the population. It is one of the causes of bile duct injury during laparascopic cholecystectomy. Herein we present a patient with complete transection of the common hepatic duct during laparascopic cholecystectomy (Stewart-Way class 3). Interestingly, the patient had an intact aberrant right posterior duct draining into the common hepatic duct distal to the obstruction site that prevented early diagnosis of the biliary injury because of drainage of the liver sufficient to prevent the development of jaundice. PMID- 25910303 TI - Limited form of Wegener's granulomatosis in a patient with Crohn's disease. A case report. AB - Wegener's granulomatosis (WG) is a multisystemic disease of unknown etiology characterized by necrotizing vasculitis and granulomatous inflammation. Although, the gastrointestinal tract can be involved in this vasculitis, the association between WG and Crohn's disease (CD) exists and was previously described. We report the case of a 29 year-old Tunisian white patient previously diagnosed with CD, presenting 3 years later with a perforated nasal septum, mucosal ulcers and sinusitis. He had also a skin ulcerative eruption of the trunk. There was no evidence of a flare of his CD. A computed tomography scan of the head showed nasal septal perforation, and maxillary pansinusitis. A biopsy from the nasal septum demonstrated nasal mucosa with extensive necrotizing granulomatous reaction associated with vasculitis. The patient was diagnosed as having limited form of Wegener's granulomatosis. He was treated with prednisone 60 mg/day and methotrexate 15 mg weekly. After Two months of treatment, he had no complaints, skin eruption and orofacial lesions were improved. Although, the gastrointestinal tract can be involved in patients with WG, the association with a CD exists and was previously described. The distinction between the two conditions and their possible coexistence is very important and requires histological examination of involved tissue. PMID- 25910304 TI - An ileal duplication cyst manifested as an ileocolic intussusception in an adult. AB - An enteric duplication cyst presenting as enterocolic intussusception is an exceptional clinical entity. We herein report a rare case of an ileal duplication cyst that manifested as an ileocolic intussusception. A 19-year-old woman was hospitalized due to right upper quadrant pain. Colonoscopy revealed a polypoid mass protruding into the colonic lumen. Ultrasonography demonstrated intussusception with a teardrop-shaped cystic mass at the tip. Computed tomography also showed ileocolic intussusception with a 2.5 cm-sized round cystic mass at the tip of intussusceptum. Microscopically, the cystic wall consisted of a well-defined smooth muscle coat and heterotopic gastric mucosa, consistent with an enteric duplication cyst. This case highlights an ileal duplication cyst as an uncommon cause of adult ileocolic intussusception. To the best of our knowledge, this is the first case of enteric duplication cyst identified as a pathological lead point for enterocolic intussusception in an adult. Enteric duplication cysts should be included in the differential diagnosis of cystic-leading lesions for adult intussusceptions. PMID- 25910305 TI - An unusual cause of recurrent pancreatitis: A gastric duplication cyst with an accessory pancreatic lobe. AB - Congenital anomalies of pancreas and its ductal drainage are uncommon but in general surgically correctable causes of recurrent pancreatitis. A gastric duplication cyst communicated with an accessory pancreatic lobe is an extremely rare cause of recurrent pancreatitis, but an early and accurate diagnosis of this anomaly is important because suitable surgical treatment may lead to a satisfactory outcome. Herein, we presented multidetector computed tomography and magnetic resonance imaging findings of a gastric duplication cyst communicating with an accessory pancreatic lobe via an aberrant duct in a 29-year-old woman with recurrent acute pancreatitis and also reviewed other similar cases reported in the literature. PMID- 25910306 TI - Evaluation of increased subclinical atherosclerosis risk with carotid intima media thickness and pulse wave velocity in inflamatory bowel disease. AB - BACKGROUND/AIMS: A significant increase in accelerated atherosclerosis risk have determined in chronic inflammatory diseases. Recent studies have suggested a pathophysiological link between inflamatory bowel disease (IBD) and atherosclerosis; for which carotid intima-media thickness (CIMT) and pulse wave velocity (PWV) has been considered as an early marker. The aim of this study was to determine the presence of early atherosclerosis in IBD patients without clinically diagnosed cardiovascular disease and any coincident risk factors for atherosclerosis. MATERIALS AND METHODS: 40 IBD patients who are in remission and without known atherosclerosis and also without any risk factors for atherosclerosis (17 Crohn's disease and 23 ulcerative colitis ) and 40 healthy subjects for control group involved in the study. The measurement of bilateral CIMT and carotis-femoral PWV have done in patients and control groups. RESULTS: Significant differences existed between control subjects and patients with IBD in the values of PWV (5.97+/-0.54 vs. 7.17+/-0.92 m/sn; p<0.001), maximum CIMT (0.76+/-0.06 vs. 0.86+/-0.11 mm; p<0.001) and mean CIMT (0.66+/-0.06 vs 0.74+/ 0.09 mm; p<0.001). In the correlation analysis, a positive correlation has determined between PWV and maximum CIMT and mean CIMT ( p<0.001, r=0.75 / p<0.001, r=0.74 respectively ). CONCLUSION: IBD patients have an increased risk of subclinical atherosclerosis than healty controls as showed by greater values of CIMT and PWV. PMID- 25910307 TI - Retraction of the main papilla toward the biliary system in patients with primary sclerosing cholangitis. AB - BACKGROUND/AIMS: Retraction of the main papilla toward the biliary system was observed in 70% of patients with primary sclerosing cholangitis (PSC). However, this observation was confounded by the fact that all of the patients with this finding had a prior history of sphincterotomy. The aim of the present study was to observe whether main papillary retraction can be seen in patients with naive papillae and accompanies the progression of the disease. MATERIALS AND METHODS: The study was conducted in a single tertiary reference center and included 4 patients with PSC. RESULTS: Main papillary retraction was seen to emerge with progression of PSC after an initial presentation with intra and extrahepatic involvement in 2 patients and after progression from intrahepatic to extrahepatic bile ducts in 1 patient. Main papillary retraction was seen in 2 patients with naive papillae and could be detected by magnetic resonance cholangiography in 1 patient. CONCLUSION: Retraction of the main papilla can be seen in patients with PSC regardless of prior sphincterotomy history. PMID- 25910308 TI - A case of entecavir resistance which is developed after complete viral suppression during entecavir treatment for nucleoside-naive chronic hepatitis B. AB - Entecavir (ETV) is a potent nucleoside analogue against hepatitis B virus (HBV), and the emergence of drug resistance is rare in nucleoside-naive patients because development of ETV resistance (ETVr) requires at least three amino acid substitutions in HBV reverse transcriptase. We observed a case of genotypic ETVr with viral and biochemical breakthrough during ETV treatment of nucleoside-naive patients with chronic hepatitis B (CHB). A 57-years-old HBeAg-positive man received ETV 0.5 mg/day for 145 weeks. HBV DNA was 7.7 log10 copies/ml at baseline, decreased to below 2 at week 48, declined to a nadir of 0 (negative) at week 72, and rebounded to 2.2 log10 copies/ ml at week 90 and remained this level until 109 weeks and increased to 6.8 log10 copies/ml at week 145. Alanine aminotransferase (ALT) level increased to 440 IU/L at week 145. The ETVr-related substitution (rtS202P) and lamivudine resistance-related substitutions (rtL180M+rtM204V) were detected by DNA sequencing analysis at week 145. The patient discontinued ETV therapy at week 145, and then received 245 mg of tenofovir disoproxil fumarate (TDF). Afterwards, HBV DNA level dropped to below 2.6 log10 copies/ml and ALT level was normalized after 19 weeks of TDF dosing. The three substitutions associated with ETV and lamivudine resistance developed after complete viral suppression in a nucleoside-naive CHB patient during ETV treatment. In spite of the extremely rare chance of viral mutation during ETV treatment, nucleoside-naive patients should be carefully monitored for resistance even if complete suppression is present. PMID- 25910310 TI - A rare cause of gastrointestinal bleeding, "GANT". AB - Acute gastrointestinal hemorrhage is frequently seen in emergency surgical conditions. Benign pathologies are generally responsible in etiologic factors. Our case is a GANT. GANT is a mesenchymal tumor originated from Cajal cells or precursors of them. Cajal cells are pacemaker cells in the intestinal wall. Because GANT is a very rare tumor, we would like to report our case to the medical literature. We think very rare cases and treatments of its as like our case create view point states in etiology of acute gastrointestinal hemorrhage. PMID- 25910309 TI - Iliac arteriovenous fistula presenting with ascites. AB - Arteriovenous fistula presents rarely with ascites. Diagnosis, with an elusive clinical presentation, is often incidental or delayed. A 35-year-old woman presented with ascites and cardiac decompensation. Contrast enhanced computed tomography revealed arteriovenous fistula between the left common iliac artery aneurysm and the left common iliac vein. The patient underwent endovascular treatment with arterial access was performed, with implantation of a stent graft in the iliac artery to cover the fistulous communication. At follow-up 1 month later, she was asymptomatic without ascites. Arteriovenous fistula should be considered in the differential diagnosis of patients with ascites and cardiac decompensation. The endovascular treatment of the arteriovenous fistula should be considered as a first line option. PMID- 25910311 TI - A very rare cause of acute pancreatitis: Berardinelli-Seip congenital lipodystrophy. AB - Pancreatitis is among rare diseases in pediatrics clinics. It is usually presented with a sign of underlying systemic disease. Berardinelli-Seip congenital lipodystrophy (BSCL) is a very rare disease characterized by near absence of adipose tissue resulting in apparent muscle hypertrophy from birth or early infancy associated with severe insulin resistance. Common clinical features are hypertriglyceridemia, acanthosis nigricans, hepatomegaly with or without splenomegaly and high stature. Acromegaloid features, cardiomyopathy and mental retardation can also be present. We describe a 7-year-old Turkish boy with these clinical features of BSCL and presented with acute pancreatitis. PMID- 25910312 TI - Hemosuccus pancreaticus following Parathyroidectomy for Primary parathyroid adenoma. AB - Hemosuccus pancreaticus is defined as intermittent bleeding from the pancreatic duct into the GI tract, usually caused by the rupture of an pseudoaneurysm, which is usually associated with pancreatitis, abdominal surgery, and can result in life-threatening hemorrhage. Hyperparathyroidism is a rare cause of pancreatitis, it should be suspected in all patients with a history of primary hyperpara!t hyroidism, When these diseases coexist, the course of pancreatitis can be rather severe and often complicated. This report detail a case of Hemosuccus pancreaticus due to hyperparathyroidism associated pancreatitis and its successful emergency conservative management by Embolization Techniques. PMID- 25910313 TI - Liver abscesses with venous extension - rare complication of a common problem. AB - Considering the high incidence of amoebic and pyogenic liver abscess in the developing world, occurrence of inferior vena cava thrombosis secondary to liver abscess is a rare but life threatening complication. We report 4 such complicated cases of liver abscess(s). The first case involved a large caudate lobe abscess extending across middle hepatic vein into suprahepatic inferior vena cava (IVC). Development of a left hepatic artery pseudoaneurysm following attempted percutaneous aspiration highlights the difficulties encountered in percutaneous interventional management of caudate lobe abscesses. The second case involved multiple liver abscesses with large thrombus in the right ventricular cavity & right ventricular outflow tract. The patient developed cardiorespiratory arrest limiting any aggressive management options for the complex nature of illness. The third case had a large caudate lobe abscess with direct extension into Intrahepatic IVC while the fourth showed a segment 4 abscess with thrombosis of adjacent left hepatic vein. These cases highlight the fact that diagnosis of such life threatening complications of liver abscesses as hepatic vein & IVC thrombosis requires high clinical suspicion followed by targeted imaging. Image guided interventional therapy is a useful tool for management in cases of liver abscess. But, abscesses in precarious locations like caudate lobe are associated with higher risk of complications including pseudoaneurysm formation asking for a cautious approach to interventional therapy in such circumstances. PMID- 25910314 TI - Gastric cancer with bone marrow invasion presenting as severe thrombocytopenia. PMID- 25910315 TI - Plaster ingestion for suicidal attempt: A rare cause of gastric bezoar. PMID- 25910316 TI - Acute colitis presenting with hematochezia in a patient with chronic myeloid leukemia during dasatinib therapy. PMID- 25910317 TI - Pyloric gland type adenoma including intramucosal carcinoma focus of gallbladder. PMID- 25910318 TI - Hepatic portal venous gas associated with hemorrhagic gastroduodenal ulcers. PMID- 25910319 TI - Perianal basal cell carcinoma: An uncommon localization. PMID- 25910321 TI - Wide spectrum of neuroendocrine differentiation in identical appearing colon polyps: A report of 2 mixed endocrine-glandular polyps. PMID- 25910320 TI - Percutaneus endoscopic gastrostomy in a patient with hemophilia A. PMID- 25910322 TI - Synchronous squamous cell carcinoma in the esophagus and stomach: A case report. PMID- 25910323 TI - A rare case report of A solitary gastric Peutz-Jeghers type polyp. PMID- 25910324 TI - Aneurysm of the dorsal pancreatic artery associated with celiac artery occlusion. PMID- 25910325 TI - An unusual cause of esophageal ulcer; sertraline hydrochloride. PMID- 25910326 TI - Selective internal radiotherapy for hepatic epithelioid hemangioendothelioma. PMID- 25910327 TI - Embryonal rhabdomyosarcoma of the common bile duct and porta hepatis in an infant: A rare presentation. PMID- 25910328 TI - Synchronous occurance of adenocarcinoma and gastrointestinal stromal tumor of the stomach. PMID- 25910329 TI - Portal hypertension and intrahepatic cholestasis in primary amyloidosis. PMID- 25910330 TI - Evaluation of immunity status to routine vaccination in pediatric liver transplant candidates. AB - BACKGROUND/AIMS: Generally, prevention of infections by vaccination is the least invasive and most cost-effective approach to reduce the incidence of infections and the morbidity and mortality in transplant recipients. Genetic diversity and different liver disease among patients contributes to variability in immune responses to vaccines and pathogens. The aim of this study was to evaluate immunity status to different vaccinated organisms in pediatric liver-transplant candidates. MATERIALS AND METHODS: The vaccination charts of 90 patients who were referred to Organ Transplant Center of Shiraz University of Medical Sciences were reviewed and compare with National Immunization Program recommendation, after that 10 mL blood was drawn from these patients for serologic studies by ELISA. RESULTS: Eighty percent of the patients had protective antibody titers for poliomyelitis, 65.6% for rubella, 62.3% for diphtheria, 60% for tetanus, 57.7% for pertussis, 55.5% for measles, 42.2% for hepatitis B and 36.7% for mumps. CONCLUSION: Overall seroconversion rates were not satisfactory for many infections that may be due to lower rate of vaccination or even the underlying liver disease that interfere with optimal immunogenecity of vaccination. Therefore, vaccination charts should be periodically reviewed and updated, also repeated measurements of serum antibodies and appropriate revaccination if titers decline is recommended to prevent the vaccine-preventable disease in liver transplant candidates after transplant. PMID- 25910331 TI - A case of tuberculous colitis mimicking Crohn's disease. PMID- 25910332 TI - A metastatic melanoma of the small intestine diagnosed by single-balloon enteroscopy. PMID- 25910333 TI - Parsonage-Turner syndrome and inflammatory bowel disease: A possible physiopathological relationship. PMID- 25910334 TI - Acute cholecystitis complicated by pylephlebitis. PMID- 25910335 TI - A rare cause of massive lower gastrointestinal bleeding; jejunal Dieulafoy's lesion. PMID- 25910336 TI - Rectal bleeding from seeds impaction. PMID- 25910337 TI - Hepatitis B surface antigen seroconversion in HBeAg negative chronic hepatitis B patient during entecavir treatment. PMID- 25910338 TI - Esophageal squamous papilloma in a child. PMID- 25910339 TI - Clinicopathological dissociation in isolated esophageal eosinophilia. PMID- 25910340 TI - Steroid treatment of protracted cholestatic hepatitis A in a child with beta thalassemia. PMID- 25910341 TI - Esophageal gastrointestinal autonomic nerve tumor. PMID- 25910342 TI - Neuroendocrine/squamous gastric collision tumor: A rare entity. PMID- 25910343 TI - Osteoblastic metastasis from signet ring cell gastric cancer in a young male. AB - Bone metastasis is common in patients with lung, prostate, and breast cancers but it isn't common in stomach cancer. Gastric carcinoma infrequently metastasizes to the bone and rarely in an osteoblastic form. Herein we presented a rare case of signet ring cell gastric adenocarcinoma in early stage with osteoblastic metastasis. To our knowledge our case was the youngest signet cell gastric cancer patient with osteoblastic bone metastasis reported in literature. PMID- 25910344 TI - Malignant duodenocolic fistula diagnosed by endoscopy. PMID- 25910345 TI - Ischemic gastritis. PMID- 25910346 TI - A juxtapapillary windsock diverticulum connected with the third portion of the duodenum via a natural orifice. PMID- 25910347 TI - Different treatment choice for first-line treatment of Helicobacter pylori in an area with a high antibiotic resistance. PMID- 25910348 TI - Malignant melanoma of the stomach in an elderly patient. PMID- 25910349 TI - Uncurable duodenal bulb ulcer-may be duodenal bulb cancer. PMID- 25910350 TI - An unusual presentation of unresectable gastric cancer in a young woman, treated with palliative endoscopic treatment with triple metal stents. PMID- 25910351 TI - Submucosal hematoma of the esophagus due to fish bone ingestion. PMID- 25910352 TI - Endoscopic foreign body retrieval using laparoscopic shears after gastrostomy. PMID- 25910353 TI - Phlebosclerotic colitis with fecal bezoar. PMID- 25910354 TI - Villous adenoma in gallbladder volvulus: A rare coincidence. PMID- 25910355 TI - A subcutaneous hydatid cyst. PMID- 25910356 TI - A rare cause of bile duct obstruction in adolescence: Neuroendocrine tumor. AB - Extrahepatic bile duct is one of the rare places for neuroendocrine tumors which comprise 0.2-2% off all neuroendocrine tumors of gastrointestinal tract. The aim of this paper is to report a case of a 16-year-old boy with a neuroendocrine tumor of extra hepatic bile duct. Laboratory and imaging findings is supported obstructive jaundice. After a pre-operative detailed evaluation, the common bile and common hepatic duct with gallbladder were resected and Roux-en-Y hepaticojejunostomy was performed. After a 36 months follow up, no locoregional recurrence or metastatic disease was observed. Pre-operative diagnosis of neuroendocrine tumors are extremely difficult and often confused with cholangiocarcinoma. Treatment modality of this rare entity depends on the location of the tumor and aggressive surgery is still the best chocie of treatment. It should be kept in mind that disease-free survival for patients with neuroendocrine tumor depends on success of surgery. PMID- 25910357 TI - Late dysphagia due to cervical plate. PMID- 25910358 TI - An uncommon presentation of invasive lobular carcinoma of breast: An incidental finding after Cholecsytectomy. PMID- 25910359 TI - Sclerosing mesenteritis (panniculitis) mimicking peritoneal tuberculosis. PMID- 25910360 TI - Coincidence of celiac disease with sarcina infection. PMID- 25910361 TI - Air cholangiogram is not sufficent to detect common bile duct stones during ERCP. PMID- 25910363 TI - Aortoesophageal fistula (AEF): Fatal upper gastrointesinal haemorrhage. PMID- 25910362 TI - Advanced oxidation protein products, total thiol levels and total oxidant/antioxidant status in patients with nash. AB - BACKGROUND/AIMS: In this study we aim to evaluate the relationship of advanced oxidation protein products (AOPP), total thiol, total antioxidant status (TAS), total oxidant status (TOS) levels and oxidative stress index (OSI) in patients with nonalcoholic steatohepatitis (NASH). MATERIALS AND METHODS: A total of 28 patients with NASH and 19 age-and-gender-matched healthy subjects were enrolled in the study as control group. Plasma AOPP and thiol levels were determined by spectrophotometric methods. Plasma TAS and TOS levels were measured using commercially available kits and OSI was calculated. RESULTS: Plasma AOPP (256.7 vs. 125.8 MUmol/L) and TOS levels (8.9 vs. 5.9 MUmol H2O2 equiv/L) were higher in patients with NASH than the controls (p<0.019 and p<0.041 respectively). Plasma total thiol levels (235.0 vs. 291.6 MUmol/L) were lower in patients with NASH than the controls (p<0.001). TAS levels (1.14 vs. 1.14 mmol Trolox equiv/L) were not significantly different in patients with NASH than the controls (p>0.900). OSI values (8.0 vs. 5.5) were higher in patients with NASH than the controls (p<0.039). CONCLUSION: Our findings indicate that oxidative stress increases in patients with NASH as shown by increases in TOS level. We think effective antioxidant therapy to inhibit protein oxidation and also to increase of TAS and total thiol levels may be a therapeutic option in patients with NASH who have under increased oxidative stress. PMID- 25910364 TI - Endoscopic removal of fractured basket traction wire. PMID- 25910365 TI - Role of argon plasma coagulation in management of bleeding GI tumors: evaluating outcomes and survival. AB - BACKGROUND/AIMS: Tumor related gastrointestinal (GI) bleeding is a challenging clinical problem in cancer patients. Argon plasma coagulation (APC) is preferred for the management of bleeding arterio-venous malformations. Our objective was to assess the role of APC in the management of bleeding GI tumors. MATERIALS AND METHODS: This is a retrospective review of endoscopies performed at the UT MD Anderson Cancer Center over 3 consecutive years (2009-2011). This study involved patients with primary or metastatic gastrointestinal cancer with suspected GI bleeding and interventions included were endoscopies with APC. Our main outcome measurements were immediate hemostasis rate, change in transfusion requirements, re-bleeding rate, and 30-day mortality. RESULTS: Immediate hemostasis was achieved in all 10 (100%) patients, with either APC performed alone (8 patients) or with adjuvant epinephrine (2 patients). There were no procedure related complications. The pooled transfusion requirements for all 10 patients 48 hours prior to the procedure were 26 packed red blood cells units, 11 platelet units and 6 fresh frozen plasma units, while the overall requirements in the 48 hours after the procedure were 5 packed red blood cells units, 6 platelet units and no fresh frozen plasma units. Re-bleeding occurred in 3 (30%) patients during follow up. Thirty day mortality rate was 0%. Total of 7 (70%) of patients were able to continue cancer specific therapy of either chemotherapy, radiation or both. CONCLUSION: APC is feasible and safe in routine practice to manage bleeding GI tumors. It is very effective in achieving initial hemostasis (100%) and allows majority of the patients (70%) to undergo cancer specific therapy. PMID- 25910366 TI - Effects of N-acetylcysteine on liver remote injury after skeletal muscle ischemia reperfusion in rats. AB - BACKGROUND/AIMS: This study evaluated the effects of N-acetylcysteine as a scavenger of radical oxygen species on liver injury as a remote organ after skeletal muscle ischemia reperfusion. MATERIALS AND METHODS: Twenty male Wistar rats were allocated randomly into two experimental groups: ischemia reperfusion (I/R) and ischemia reperfusion + N-acetylcysteine (I/R+NAC). All animals were undergone 2h of ischemia by occlusion femoral artery and 24h of reperfusion. Rats that were treated with N-acetylcysteine given intravenously at a dose of 150 mg/kg, immediately before reperfusion. Serum levels of aspartate aminotransferase (AST), and alanine aminotransferase (ALT) were measured. Livers were harvested for histopathological and biochemical studies. Liver tissue malondialdehyde (MDA), glutathione (GSH) and myeloperoxidase (MPO) activity were assayed. RESULTS: The ALT and AST values were significantly lower in I/R+NAC group. Hepatic MDA level and MPO activity were significantly increased in I/R group. The levels of GSH in liver tissue were significantly depressed by ischemia reperfusion. Liver histopathologic study in I/R group showed enlarged sinusoids, sinusoidal congestion, cytoplasmic vacuolation, cellular degenerative changes and necrosis. Histopathologically, there was a significant difference between two groups. CONCLUSION: Histopatological and biochemical results have shown that N acetylcysteine was able to protect liver from skeletal muscle ischemia reperfusion injury. PMID- 25910367 TI - Is gastroesophageal reflux contribute to the development chronic cough by triggering pulmonary fibrosis. AB - BACKGROUND/AIMS: Previous studies have shown that the prevalence of abnormal acid reflux in fibrotic lung disease patients is high, and in particular, patients with secondary pulmonary fibrosis show higher esophageal acid exposure than normal controls. There are also some findings that, in patients with pathological reflux, pulmonary fibrosis may develop. The aim of this study is to investigate if pulmonary fibrosis is involved in the pathogenesis of chronic cough due to Gastroesophageal Reflux. MATERIALS AND METHODS: A prospective study was performed in twenty-one patients with chronic cough due to gastroesophageal reflux who was diagnosed as reflux esophagitis by upper gastrointestinal endoscopy, histology, and in ten healthy controls without GER or any lung disease. All participitants underwent laryngoscopic examination and gastroesophageal scintigraphy with late lung imaging. Bronchoalveolar lavage fluid total and differential cell counts, T and B cell subsets, and the concentrations of IL- 1beta and TNF-alpha were measured. RESULTS: Reflux extending into the proximal esophagus was noted in 52.5%, and posterior laryngitis was present in 90.5% of the patients. No evidence of pulmonary aspiration was noted in the patients with reflux on scintigraphic examination. No significant difference was found between the GER and control groups in terms of cellular content, IL-1beta and TNF-alpha levels or mean T cell subsets and B cell counts in bronchoalveolar lavage fluid. Forced expiratory volume in one second, forced vital capacity FEV1/FVC, total lung capacity, and carbon monoxide diffusion capacity values were within normal limits in the gastroesophageal reflux group. CONCLUSION: Our findings do not support the hypothesis that gastroesophageal reflux leads to chronic cough by triggering alveolar epithelial injury and subsequent pulmonary fibrosis. PMID- 25910368 TI - The therapeutic results after laparoscopic hellers' myotomy and partial fundoplication for achalasia. AB - BACKGROUND/AIMS: The aim of this prospectively designed study was to postoperatively assess the subjective complaints or relief of symptoms of achalasia patients' who underwent Laparoscopic Hellers' myotomy and partial fundoplication in our clinic. MATERIALS AND METHODS: 40 patients were enrolled in the study that underwent Laparoscopic Hellers' myotomy and partial fundoplication (toupet or dor) for idiopathic achalasia in our clinic between years 2002 and 2012. Postoperative follow-up was conducted at 1st, 3rd. and 6th months in each patient for symptoms and a follow-up questionnaire was completed which is classified according to Vantrappen and Hellemans' modified classification. RESULTS: 34 patients underwent Laparoscopic Heller myotomy with Toupet fundoplication whereas 6 patients underwent Laparoscopic Heller myotomy with Dor fundoplication. After 3 months, 2 patients' complaints of dysphagia were detected (5%). In the 6 month follow-up, one of these two patient dysphagia symptoms got worsened and a balloon dilatation was performed (2.5%). In the other one no clinical reason was found for dysphagia and medical therapy was initiated. In the 6 th month only three patients (7.5%) were presented with gastroesophageal reflux which successful medical treatment was initiated. CONCLUSION: Laparoscopic myotomy with fundoplication seems to be the most effective surgical technique that provides both short and long term symptomatic relief with released hospitalization time and less complication rate. PMID- 25910369 TI - QT interval changes and reversibility of QT dispersion in patients with acute pancreatitis. AB - BACKGROUND/AIMS: QT dispersion is a sign of heterogeneity of ventricular myocardial wall and is associated with cardiac mortality and morbidity. Data regarding with the persistence of QT interval changes in cases with acute pancreatitis (AP) that required clinical follow-up, are insufficient. Therefore, in this study, we aimed to evaluate the QT interval changes during attack and after remission of the disease, in cases with AP. MATERIALS AND METHODS: The cases admitted to the Gastroenterohepatology Clinic with the diagnosis of AP were included into the study. Ranson's score parameters, electrocardiography and echocardiography of all patients included into the study were evaluated. Electrocardiographic changes were evaluated two times, during attack and after remission of the disease. RESULTS: A total of 134 subjects (F/M:54/80, 41/59%) diagnosed as AP were included into the study. Seventy two (54%) of the AP cases included into the study were biliary, 32 (24%) were alcohol dependant, 19 (14%) were idiopathic, 9 (7%) were hyperlipidemic and 2 (1%) were ERCP related cases. Mean age of the patents was 57.7+/-15 years old (range: 19-82 years old) and mean Ranson's score was 3.8+/-1.9 (range: 1-7), according to the numerical scoring system. We compared QT interval changes during the attack and after the remission of AP and found significant increase in QT dispersion levels during acute attack of AP (p<0,001). CONCLUSION: The most common electrocardiographic changes in AP patients are QT interval changes including QT dispersion. QT dispersion which was emerged during the attack recovered after the remission of the disease. PMID- 25910370 TI - Epidemiological shift of hepatitis A in central Adana, Turkey. AB - BACKGROUND/AIMS: The aim of the study was to determine the epidemiological shift that may have occurred in the last 11 years of Hepatitis A virus (HAV) seroprevalence. MATERIALS AND METHODS: In 1998, we reported the anti-HAV seroprevalence in 711 children aged between 2 and 16 years children in Adana city center. Eleven years later we repeated the same study at the same locations in a similar population with the same method. RESULTS: From 1998 to 2009 anti-HAV seroprevalence declined from 33.9% to 22.2%, 29.5% to 25.3% (p>0,05), 52.2% to 30.8%, 69.7% to 35.2%, 66.9% to 37.7% and 71.4% to 47.3% (p<0,0001) in the age groups of 48-71, 72-95, 96-119, 120-143, 144-167 and 168-198 months respectively. CONCLUSION: Our study showed that anti-HAV seroprevalence has decreased statistically significantly during the last 11 years in school-aged children. Results showed that anti-HAV seroprevalence has shifted to further ages. Since adolescents and young adults are at risk of symptomatic HAV infection, routine hepatitis A vaccination of children will be initiated in 2012 in Turkey. PMID- 25910371 TI - The relationship between insulin resistance, metabolic syndrome and nonalcoholic fatty liver disease in non-obese non-diabetic Turkish individuals: A pilot study. AB - BACKGROUND/AIMS: Nonalcoholic fatty liver disease is related to obesity, metabolic syndrome, and insulin resistance. Nonalcoholic fatty liver disease and metabolic syndrome may also be encountered in non-obese, non-diabetic individuals, and there are no published data about the prevalence of these conditions in non-obese, non-diabetic Turkish subjects. We aimed to determine the difference between non-obese, non-diabetic nonalcoholic fatty liver disease patients and healthy controls in terms of insulin resistance and metabolic syndrome in Turkish subjects. MATERIALS AND METHODS: Non-obese, non-diabetic individuals (n=219) were enrolled. The cohort was divided into two groups according to presence of steatosis in ultrasonography: nonalcoholic fatty liver disease group (n=143) and healthy control group (n=76). Insulin resistance and metabolic syndrome were analyzed and compared between the two groups. RESULTS: The prevalences of metabolic syndrome (32.2% vs. 5.3%, respectively; p<0.001) and insulin resistance (46.2% vs. 9.2%, respectively; p<0.001) were significantly higher in the nonalcoholic fatty liver disease group. According to multiple logistic regression analysis, age (odds ratio 1.534; p=0.0032), insulin resistance (odds ratio 1.074; p<0.001), and serum ALT levels (odds ratio 1.102; p<0.001) were independently associated with nonalcoholic fatty liver disease. CONCLUSION: Insulin resistance and metabolic syndrome are not rare in non-obese, non-diabetic Turkish subjects with nonalcoholic fatty liver disease. Ultrasonographically detected fatty liver was independently associated with insulin resistance, irrespective of the presence of metabolic syndrome. PMID- 25910372 TI - Temporary placement of a paclitaxel or rapamycin-eluting stent is effective to reduce stenting induced inflammatory reaction and scaring in benign cardia stricture models. AB - BACKGROUND/AIMS: To investigate whether temporary placement of a paclitaxel or rapamycin eluting stent is more effective to reduce stenting induced inflammatory reaction and scaring than a bared stent in benign cardia stricture models. MATERIALS AND METHODS: Eighty dog models of stricture were randomly divided into a control group (CG, n=20, no stent insertion), a bare stent group (BSG, n=20), a paclitaxel eluting (Pacl-ESG, n=20) and a rapamycin eluting stent group (Rapa ESG, n=20), with one-week stent retention. Lower-oesophageal-sphincter pressure (LOSP), 5-minute barium height (5-mBH) and cardia diameter were assessed before, immediately after the procedure, and regularly for 6 months. Five dogs in each group were euthanized for histological examination at each follow-up assessment. RESULTS: Stent insertion was well tolerated, with similar migration rates in three groups. At 6 months, LOSP and 5-mBH improved in Pacl-ESG and Rapa-ESG compared to BSG (p<0.05), with no difference between Pacl-ESG and Rapa-ESG (p>0.05). Cardia kept more patency in the Pacl-ESG and Rapa-ESG than in BSG (p<0.05). Reduced peak inflammatory reactions and scarring occurred in the Pacl ESG and Rapa-ESG compared to BSG (p<0.05), with a similar outcome in the Pacl-ESG and Rapa-ESG (p>0.05). CONCLUSION: Paclitaxel or rapamycin-eluting stents insertion led to better outcomes than bare stents in benign cardia stricture models. PMID- 25910373 TI - Comparison of FISH, RFLP and agar dilution methods for testing clarithromycin resistance of Helicobacter pylori. AB - BACKGROUND/AIMS: Clarithromycin resistance is an important factor of Helicobacter pylori (H. pylori) eradication failure in adults and children. There are some tests to determine resistance such as restriction fragment length polimorphism (RFLP), fluorescence in situ hibridisation (FISH), PCR and (culture) agar dilution. Clarithromycin resistance is reported between 16.8%-48.2% in Turkey using PCR, 18% in Japan using RFLP. The aim of the study is to compare the efficacy of FISH, RFLP and culture. MATERIALS AND METHODS: Patients with gastric complaint underwent endoscopic examination. H. pylori status of all patients was tested with urea breath test. Gastric biopsy samples obtained from adult patients and children were studied. Each tissue was analised with FISH, PCR-RFLP anda gar dilution. RESULTS: A total 100 patients were positive by UBT and histology for H. pylori. Tissues from 89 adults and 11 children were evaluated. According to FISH and RFLP clarithromycin resistance was 26% and 16% respectively. Among 100 patients H. pylori was cultured in 52 tissue samples, among these samples 7 were resistant to clarithromycin. There was strong correlation between the results of FISH and RFLP; RFLP and culture; and FISH and culture. CONCLUSION: There is a high ratio of clarithromycin resistance in the studied population. All 3 tests are valuable, but FISH seems to be more sensitive among these tests. We suggest FISH should be used for detecting clarithromycin resistance among H. pylori infected patients before eradication therapy. PMID- 25910375 TI - Effect of 3-aminobenzamide on perforation an experimental colitis model. AB - BACKGROUND/AIMS: The anti-inflammatory activity of 3-aminobenzamide (3-AB) has been shown via histopathology and immunohistochemistry in various colitis models. We aimed to study the effects of 3-AB on tissue mechanical endurance and, associatively, preventing perforation in colitis. MATERIALS AND METHODS: Thirty male Wistar albino rats were randomly divided into three groups. Rectal saline was administered to Group 1 (sham+saline). Rectal trinitrobenzensulphonic acid was applied to induce colitis in Group 2 (colitis+saline) and Group 3 (colitis+3 AB). Groups 1 and 2 were treated intraperitoneally with saline (1 ml every 12 hours) and Group 3 was treated with 3-AB (10 mg/kg every 12 hours). After seven days, rats were sacrificed and colon lipid peroxidation levels, the serum tumor necrosis factor alpha (TNF-alpha) level, bowel bursting pressures, and bowel wall tensions were measured. RESULTS: Bowel bursting pressure in Group 2 was significantly lower than in Groups 1 and 3 (p<0.001 for both groups). Bowel wall tension in Group 2 was significantly lower than in Groups 1 and 3 (p<0.001 for both groups). There were no significant differences between groups for serum TNF alpha levels. For lipid peroxidation, malondialdehyde (MDA) levels were increased in Groups 2 and 3 compared to Group 1. CONCLUSION: 3-AB may aid prevention of perforations that develop in inflammatory bowel disease, requiring surgical treatment. PMID- 25910374 TI - The role of interleukin-1 gene polymorphisms and Helicobacter pylori in gastroesophageal reflux disease. AB - BACKGROUND/AIMS: Our aim is to assess the relationship between interleukin 1beta (IL-1 beta), (-511,-31 alleles), interleukin 1RN (IL-RN), Helicobacter pylori (HP) status and gastroesophageal reflux disease (GERD) diagnosed by pH monitoring in the Turkish population. MATERIALS AND METHODS: A Total of 100 consecutive patients with GERD were enrolled in the study. Genotypes of IL-1beta (-511,-31), IL-1RN gene polymorphisms and HP status of the patients were analyzed. RESULTS: While thirty-two patients were diagnosed as esophagitis with varying severity the remaining patients had no esophagitis. Seventy six participants were positive for HP and the remaining patients were negative. The difference between erosive and non-erosive groups was statistically significant when we compared IL-1beta (-511) but no difference regarding IL-1beta (-31) and IL-1RN variations. We also analyzed T/T, C/T and C/C alleles and the difference was significant statistically in T/T allele between patients with and without erosive GERD 1 (3.1%) vs. 12 (17.9%), respectively with a p value<0.05. But C/C, C/T alleles of (-511), (-31) and IL-1RN polymorphisms were not statistically significant between the groups. CONCLUSION: IL-1beta genetic polymorphisms may take part in the pathophysiology of gastroesophageal reflux disease. PMID- 25910376 TI - Investigation of right lobe hepatic vein variations of donor using 64-detector computed tomography before living donor liver transplantation. AB - BACKGROUND/AIMS: To investigate the anatomy and variations of right lobe accessory veins and segment 5-8 veins draining into middle hepatic vein with 64 slice multidetector computed tomography (CT). MATERIALS AND METHODS: 100 consecutive living donor candidates underwent 64 slice CT angiography. Image interpretation was performed based on source axial images, multiplanar reformats, and three-dimensional postprocessing images by the same radiologist. RESULTS: Segment 5 and 8 veins with larger diameters were frequently found to be the proximal ones. Accessory hepatic veins were present in the great majority of cases (83%). Most of them were the inferior right hepatic veins (55%). All cases were classified according to the number of segment 5-8 veins and the presence or absence of a right accessory hepatic vein. Most of the donors had more than one segment 5-8 vein and right lobe accessory veins (57%). CONCLUSION: Multidetector CT is a valuable technique for investigating the venous anatomy of the liver in living donor candidates. Anatomy and variations of the hepatic veins can easily be evaluated by using multiplanar images. PMID- 25910377 TI - Carotid intima-media thickness and flow-mediated dilation in obese children with non-alcoholic fatty liver disease. AB - BACKGROUND/AIMS: This study aimed to understand the role of non-alcoholic fatty liver disease (NAFLD) in increasing the risk of atherosclerosis in obese pediatric patients. MATERIALS AND METHODS: The study included 109 obese children (age, 9-15 years) and a control group comprising 44 healthy age- and gender matched children with normal weight. NAFLD was diagnosed using conventional ultrasound (US) examination. Both right carotid intima-media thickness (CIMT) and flow-mediated dilation (FMD) were assessed in addition to anthropometric measures and serum biochemical parameters, including lipid profile and fasting glucose and insulin levels. Homeostatic model assessment of insulin resistance (HOMA-IR) was calculated as a measure of insulin resistance. RESULTS: Mean age and gender distributions were similar in the obese children and control group (p=0.168 and p=0.705, respectively). Median body mass index standard deviation scores of obese children with grade II-III NAFLD were significantly higher than those of obese children without hepatosteatosis (p<0.001). Median total cholesterol levels were similar in all the groups (p=0.263). Low-density lipoprotein cholesterol and triglyceride levels increased and high-density lipoprotein cholesterol levels decreased significantly as the grade of steatosis increased (p<0.001, p<0.05, and p=0.05, respectively). Median alanine aminotransaminase (ALT) and HOMA-IR levels of obese children with grade II-III NAFLD were significantly higher than those of obese children without NAFLD (p=0.01) and obese children with grade I NAFLD (p=0.001). CIMT was significantly correlated with the grade of steatosis (p<0.001) and level of ALT (p=0.005). Linear regression analysis showed that the grade of hepatosteatosis had a significant effect on CIMT. FMD decreased as the grade of hepatosteatosis increased, but it did not reach a significant level. CONCLUSION: The obese children with hepatosteatosis showed increased CIMT, as indicated by the grade of steatosis, compared with healthy controls and obese children without hepatosteatosis. FMD was not superior to CIMT in predicting the risk of early atherosclerosis. PMID- 25910378 TI - Comparison of standard and standard plus vitamin E therapy for Helicobacter pylori eradications in children. AB - BACKGROUND/AIMS: Although various drugs can be used in adults for Helicobacter pylori eradication in adults, treatment options are limited in children. The aim of this study was to compare the effects of the standard lansoprazole, amoxicillin, and clarithromycin (LAC) protocol to those of LAC+vitamin E (LACE) combination for H. pylori eradication. MATERIALS AND METHODS: The study included 90 children (age range: 10-17 years) who were admitted to four pediatric gastroenterology centers between March 2011 and November 2012 with dyspeptic symptoms and who had tested positive for H. pylori by 14C-urea breath tests. The patients were randomized into two groups. The LAC group [45 patients (pts)] was treated with a standard regimen consisting of lansoprazole (1 mg/kg/day), amoxicillin (50 mg/kg/day), and clarithromycin (14 mg/kg/day), each of which was given in two equally divided doses every 12 h for 14 days; the LACE group (45 pts) was given the standard regimen and vitamin E at 200 IU/day for 14 days. H. pylori eradication was assessed using the 14C-UBT in the 6th week after the cessation of treatment. RESULTS: H. pylori was eradicated in 21 (46.6%) pts in the LAC group, while it was eradicated in 29 (64.4%) pts in the LACE group. There was no statistical difference between the two groups (p=0.13). CONCLUSION: The eradication rate of H. pylori in children while using the LAC regimen has decreased in the last years. The LACE regimen has been associated with an increased eradication rate but can reach to statistically significance. Further studies with larger cohorts are needed to examine the success of the LACE regimen for H. pylori eradication. PMID- 25910379 TI - When does familiarity promote versus undermine interpersonal attraction? A proposed integrative model from erstwhile adversaries. AB - This article began as an adversarial collaboration between two groups of researchers with competing views on a longstanding question: Does familiarity promote or undermine interpersonal attraction? As we explored our respective positions, it became clear that the limitations of our conceptualizations of the familiarity-attraction link, as well as the limitations of prior research, were masking a set of higher order principles capable of integrating these diverse conceptualizations. This realization led us to adopt a broader perspective, which focuses on three distinct relationship stages-awareness, surface contact, and mutuality-and suggests that the influence of familiarity on attraction depends on both the nature and the stage of the relationship between perceivers and targets. This article introduces the framework that emerged from our discussions and suggests directions for research to investigate its validity. PMID- 25910380 TI - Pair-bonding, romantic love, and evolution: the curious case of Homo sapiens. AB - This article evaluates a thesis containing three interconnected propositions. First, romantic love is a "commitment device" for motivating pair-bonding in humans. Second, pair-bonding facilitated the idiosyncratic life history of hominins, helping to provide the massive investment required to rear children. Third, managing long-term pair bonds (along with family relationships) facilitated the evolution of social intelligence and cooperative skills. We evaluate this thesis by integrating evidence from a broad range of scientific disciplines. First, consistent with the claim that romantic love is an evolved commitment device, our review suggests that it is universal; suppresses mate search mechanisms; has specific behavioral, hormonal, and neuropsychological signatures; and is linked to better health and survival. Second, we consider challenges to this thesis posed by the existence of arranged marriage, polygyny, divorce, and infidelity. Third, we show how the intimate relationship mind seems to be built to regulate and monitor relationships. Fourth, we review comparative evidence concerning links among mating systems, reproductive biology, and brain size. Finally, we discuss evidence regarding the evolutionary timing of shifts to pair-bonding in hominins. We conclude there is interdisciplinary support for the claim that romantic love and pair-bonding, along with alloparenting, played critical roles in the evolution of Homo sapiens. PMID- 25910381 TI - Building a more mobile America--one income quintile at a time. AB - A core tenet of the American ethos is that there is considerable economic mobility. Americans seem willing to accept vast financial inequalities as long as they believe that everyone has the opportunity to succeed. We examined whether people's beliefs about the amount of economic mobility in the contemporary United States conform to reality. We found that (a) people believe there is more upward mobility than downward mobility; (b) people overestimate the amount of upward mobility and underestimate the amount of downward mobility; (c) poorer individuals believe there is more mobility than richer individuals; and (d) political affiliation influences perceptions of economic mobility, with conservatives believing that the economic system is more dynamic-with more people moving both up and down the income distribution-than liberals do. We discuss how these findings can shed light on the intensity and nature of political debate in the United States on economic inequality and opportunity. PMID- 25910382 TI - A person-centered approach to moral judgment. AB - Both normative theories of ethics in philosophy and contemporary models of moral judgment in psychology have focused almost exclusively on the permissibility of acts, in particular whether acts should be judged on the basis of their material outcomes (consequentialist ethics) or on the basis of rules, duties, and obligations (deontological ethics). However, a longstanding third perspective on morality, virtue ethics, may offer a richer descriptive account of a wide range of lay moral judgments. Building on this ethical tradition, we offer a person centered account of moral judgment, which focuses on individuals as the unit of analysis for moral evaluations rather than on acts. Because social perceivers are fundamentally motivated to acquire information about the moral character of others, features of an act that seem most informative of character often hold more weight than either the consequences of the act or whether a moral rule has been broken. This approach, we argue, can account for numerous empirical findings that are either not predicted by current theories of moral psychology or are simply categorized as biases or irrational quirks in the way individuals make moral judgments. PMID- 25910383 TI - A resource-control account of sustained attention: evidence from mind-wandering and vigilance paradigms. AB - Staying attentive is challenging enough when carrying out everyday tasks, such as reading or sitting through a lecture, and failures to do so can be frustrating and inconvenient. However, such lapses may even be life threatening, for example, if a pilot fails to monitor an oil-pressure gauge or if a long-haul truck driver fails to notice a car in his or her blind spot. Here, we explore two explanations of sustained-attention lapses. By one account, task monotony leads to an increasing preoccupation with internal thought (i.e., mind wandering). By another, task demands result in the depletion of information-processing resources that are needed to perform the task. A review of the sustained-attention literature suggests that neither theory, on its own, adequately explains the full range of findings. We propose a novel framework to explain why attention lapses as a function of time-on-task by combining aspects of two different theories of mind wandering: attentional resource (Smallwood & Schooler, 2006) and control failure (McVay & Kane, 2010). We then use our "resource-control" theory to explain performance decrements in sustained-attention tasks. We end by making some explicit predictions regarding mind wandering in general and sustained attention performance in particular. PMID- 25910385 TI - Editorial from the incoming editor: should I submit my article to Perspectives on Psychological Science? PMID- 25910386 TI - Perceiving political polarization in the United States: party identity strength and attitude extremity exacerbate the perceived partisan divide. AB - An important component of political polarization in the United States is the degree to which ordinary people perceive political polarization. We used over 30 years of national survey data from the American National Election Study to examine how the public perceives political polarization between the Democratic and Republican parties and between Democratic and Republican presidential candidates. People in the United States consistently overestimate polarization between the attitudes of Democrats and Republicans. People who perceive the greatest political polarization are most likely to report having been politically active, including voting, trying to sway others' political beliefs, and making campaign contributions. We present a 3-factor framework to understand ordinary people's perceptions of political polarization. We suggest that people perceive greater political polarization when they (a) estimate the attitudes of those categorized as being in the "opposing group"; (b) identify strongly as either Democrat or Republican; and (c) hold relatively extreme partisan attitudes particularly when those partisan attitudes align with their own partisan political identity. These patterns of polarization perception occur among both Democrats and Republicans. PMID- 25910387 TI - Beyond good and evil: what motivations underlie children's prosocial behavior? AB - Researchers have proposed different accounts of the development of prosocial behavior in children. Some have argued that behaviors like helping and sharing must be learned and reinforced; others propose that children have an initially indiscriminate prosocial drive that declines and becomes more selective with age; and yet others contend that even children's earliest prosocial behaviors share some strategic motivations with the prosociality of adults (e.g., reputation enhancement, social affiliation). We review empirical and observational research on children's helping and sharing behaviors in the first 5 years of life, focusing on factors that have been found to influence these behaviors and on what these findings suggest about children's prosocial motivations. We use the adult prosociality literature to highlight parallels and gaps in the literature on the development of prosocial behavior. We address how the evidence reviewed bears on central questions in the developmental psychology literature and propose that children's prosocial behaviors may be driven by multiple motivations not easily captured by the idea of intrinsic or extrinsic motivation and may be selective quite early in life. PMID- 25910388 TI - Learning versus performance: an integrative review. AB - The primary goal of instruction should be to facilitate long-term learning-that is, to create relatively permanent changes in comprehension, understanding, and skills of the types that will support long-term retention and transfer. During the instruction or training process, however, what we can observe and measure is performance, which is often an unreliable index of whether the relatively long term changes that constitute learning have taken place. The time-honored distinction between learning and performance dates back decades, spurred by early animal and motor-skills research that revealed that learning can occur even when no discernible changes in performance are observed. More recently, the converse has also been shown-specifically, that improvements in performance can fail to yield significant learning-and, in fact, that certain manipulations can have opposite effects on learning and performance. We review the extant literature in the motor- and verbal-learning domains that necessitates the distinction between learning and performance. In addition, we examine research in metacognition that suggests that people often mistakenly interpret their performance during acquisition as a reliable guide to long-term learning. These and other considerations suggest that the learning-performance distinction is critical and has vast practical and theoretical implications. PMID- 25910389 TI - Taking stock of loneliness: introduction to the special section. PMID- 25910390 TI - Loneliness across phylogeny and a call for comparative studies and animal models. AB - Loneliness typically refers to the feelings of distress and dysphoria resulting from a discrepancy between a person's desired and achieved levels of social relations, and there is now considerable evidence that loneliness is a risk factor for poor psychological and physical health. Loneliness has traditionally been conceptualized as a uniquely human phenomenon. However, over millions of years of evolution, efficient and manifold neural, hormonal, and molecular mechanisms have evolved for promoting companionship and mutual protection/assistance and for organizing adaptive responses when there is a significant discrepancy between the preferred and realized levels of social connection. We review evidence suggesting that loneliness is not a uniquely human phenomenon, but, instead, as a scientific construct, it represents a generally adaptive predisposition that can be found across phylogeny. Central to this argument is the premise that the brain is the key organ of social connections and processes. Comparative studies and animal models, particularly when integrated with human studies, have much to contribute to the understanding of loneliness and its underlying principles, mechanisms, consequences, and potential treatments. PMID- 25910391 TI - The genetics of loneliness: linking evolutionary theory to genome-wide genetics, epigenetics, and social science. AB - As a complex trait, loneliness is likely to be influenced by the interplay of numerous genetic and environmental factors. Studies in behavioral genetics indicate that loneliness has a sizable degree of heritability. Candidate-gene and gene-expression studies have pointed to several genes related to neurotransmitters and the immune system. The notion that these genes are related to loneliness is compatible with the basic tenets of the evolutionary theory of loneliness. Research on gene-environment interactions indicates that social environmental factors (e.g., low social support) may have a more pronounced effect and lead to higher levels of loneliness if individuals carry the sensitive variant of these candidate genes. Currently, there is no extant research on loneliness based on genome-wide association studies, gene-environment-interaction studies, or studies in epigenetics. Such studies would allow researchers to identify networks of genes that contribute to loneliness. The contribution of genetics to loneliness research will become stronger when genome-wide genetics and epigenetics are integrated and used along with well-established methods in psychology to analyze the complex process of gene-environment interplay. PMID- 25910392 TI - Loneliness and social isolation as risk factors for mortality: a meta-analytic review. AB - Actual and perceived social isolation are both associated with increased risk for early mortality. In this meta-analytic review, our objective is to establish the overall and relative magnitude of social isolation and loneliness and to examine possible moderators. We conducted a literature search of studies (January 1980 to February 2014) using MEDLINE, CINAHL, PsycINFO, Social Work Abstracts, and Google Scholar. The included studies provided quantitative data on mortality as affected by loneliness, social isolation, or living alone. Across studies in which several possible confounds were statistically controlled for, the weighted average effect sizes were as follows: social isolation odds ratio (OR) = 1.29, loneliness OR = 1.26, and living alone OR = 1.32, corresponding to an average of 29%, 26%, and 32% increased likelihood of mortality, respectively. We found no differences between measures of objective and subjective social isolation. Results remain consistent across gender, length of follow-up, and world region, but initial health status has an influence on the findings. Results also differ across participant age, with social deficits being more predictive of death in samples with an average age younger than 65 years. Overall, the influence of both objective and subjective social isolation on risk for mortality is comparable with well-established risk factors for mortality. PMID- 25910393 TI - Loneliness across the life span. AB - Most people have experienced loneliness and have been able to overcome it to reconnect with other people. In the current review, we provide a life-span perspective on one component of the evolutionary theory of loneliness-a component we refer to as the reaffiliation motive (RAM). The RAM represents the motivation to reconnect with others that is triggered by perceived social isolation. Loneliness is often a transient experience because the RAM leads to reconnection, but sometimes this motivation can fail, leading to prolonged loneliness. We review evidence of how aspects of the RAM change across development and how these aspects can fail for different reasons across the life span. We conclude with a discussion of age-appropriate interventions that may help to alleviate prolonged loneliness. PMID- 25910394 TI - The role of temperament in traumatic hearing loss: a single case study of a cochlear-implanted patient. AB - INTRODUCTION: The majority of existing research regarding cochlear-implanted patients focuses on acoustic perception and language skills in children and adolescents, or on the postoperative quality of life in adults. PURPOSE: We hypothesized that a patient's psychological reaction to a cochlear implant (CI) may be influenced by the temperament of the implanted subject. This case study aims to assess whether temperament plays a role in the adaptation to CIs and if certain temperamental and character traits may be risk or protective factors for surgery and rehabilitation outcomes. METHOD: We evaluated a 21-year-old male patient presenting a history of traumatic hearing loss. The Temperament and Character Inventory (TCI) was employed to obtain a psychological evaluation. RESULTS: The findings suggest a connection between the scores obtained on the TCI questionnaire and the patient's behavior toward the CI. The effects of the operation may be mediated by some temperamental and character traits. CONCLUSION: In the field of clinical psychology and hearing rehabilitation, psychological evaluation may contribute a more profound understanding of the personality dynamics that influence the patient's reaction toward traumatic hearing loss, compliance, and CI surgery outcomes. PMID- 25910395 TI - Characteristics of health-promoting schools from Iranian adolescents' point of view. AB - AIM: Although characteristics of health-promoting schools are mentioned in the World Health Organization guidelines, different countries need to design more details of indicators for assessing these schools according to their social and cultural context. The aim of this study was to investigate characteristics of health-promoting schools from Iranian adolescent girls' point of view. MATERIALS AND METHODS: In this cross-sectional study, 2010 middle school and high school female adolescents were selected from randomly selected schools in Mazandaran province, Iran. They completed a self-completion questionnaire around their views about characteristics of health- promoting schools. Data were analyzed using descriptive statistics and an independent t-test. RESULTS: It is revealed that from Iranian adolescents' point of view the most important feature of health promoting schools was the schools with no stressful exams and where notices are kindly given to students for their mistakes. CONCLUSION: The results suggest that there is a need for more measurable standards of health-promoting schools based on the socio-cultural context of both developing and developed countries. PMID- 25910396 TI - Hepatitis C: is it still around? PMID- 25910397 TI - Smoking: do you really know the risk? PMID- 25910398 TI - Traumatic brain injury: some good news. PMID- 25910399 TI - The glucocorticoid receptor in inflammatory processes: transrepression is not enough. AB - Glucocorticoids (GCs) are the most commonly used anti-inflammatory agents to treat inflammatory and immune diseases. However, steroid therapies are accompanied by severe side-effects during long-term treatment. The dogma that transrepression of genes, by tethering of the glucocorticoid receptor (GR) to DNA bound pro-inflammatory transcription factors, is the main anti-inflammatory mechanism, is now challenged. Recent discoveries using conditional GR mutant mice and genomic approaches reveal that transactivation of anti-inflammatory acting genes is essential to suppress many inflammatory disease models. This novel view radically changes the concept to design selective acting GR ligands with a reduced side-effect profile. PMID- 25910400 TI - Highlight: molecular medicine of sphingolipids. PMID- 25910401 TI - Elucidation of RNA binding regions of gonadotropin-regulated testicular RNA helicase (GRTH/DDX25) to transcripts of a chromatin remodeling protein essential for spermatogenesis. AB - BACKGROUND: Gonadotropin-regulated testicular RNA helicase (GRTH) is a testis specific member of the DEAD-box family of RNA helicases present in Leydig and germ cells. It is a transport protein of mRNAs from nucleus to cytoplasmic sites and is essential for posttranscriptional regulation and completion of spermatogenesis. Transition protein 2 (Tp2), which associates with GRTH and is required for spermatid elongation, failed to express in GRTH null mice with impaired mRNA nuclear export. The present study determines GRTH binding motifs/regions that associate with Tp2 mRNA transcripts. MATERIALS AND METHODS: RNA-protein interaction was analyzed using biotin-labeled electrophoretic mobility gel shift assays (EMSA). 3'-biotin-labeled RNA (Tp2) was incubated with mGRTH protein (full length/sequential deletion of specific and conserved RNA helicase motifs of GRTH) expressed from in vitro TNT coupled reticulocyte lysate system. Binding specificity was further elucidated by mutagenesis and antibody supershift analysis. RESULTS: RNA-EMSA revealed that the 3' UTR of Tp2 RNA (127 nt from TGA) was retarded in presence of full length GRTH. Nucleotide sequences downstream of TGA of the Tp2 transcript (1-47 and 78-127 nt) are important for binding to GRTH. Sequential deletions/point mutations in GRTH revealed region(s) of conserved binding motifs of RNA helicases (Ia and V) essential for GRTH binding to Tp2 mRNA. CONCLUSIONS: Our studies provide insights into the association of Tp2 expression via binding to the conserved RNA binding motifs of GRTH protein and the basis for understanding GRTH in the regulation of the genes essential for germ cell elongation and completion of spermatogenesis. PMID- 25910402 TI - Quinazoline derivatives as anticancer drugs: a patent review (2011 - present). AB - INTRODUCTION: Quinazoline is one of the most studied moieties in medicinal chemistry due to the wide range of biological properties such as the anticancer, antibacterial, anti-inflammatory, antimalarial and antihypertensive activities. During the past decades, several patents and articles have been published in international peer-reviewed literature regarding the discovery and development of original and promising quinazoline derivatives for cancer treatment. Although quinazolines are well known to inhibit EGFR, there is also a large panel of other therapeutic protein targets. AREAS COVERED: This review summarized the new patents and articles published about quinazoline derivatives as anticancer drugs since 2011. EXPERT OPINION: Since 2011, a lot of quinazoline compounds have shown EGFR inhibition. Unlike the first-generation EGFR inhibitors, they inhibit both wild-type and mutated EGFR. In recent years, a number of studies on quinazoline synthesis have been reported and used by several medicinal chemistry groups for better and easier development of new derivatives. Therefore, several patents have been approved for the use of quinazoline compounds as inhibitors of other kinases, histone deacetylase, Nox and some metabolic pathways. Because of the large number of proteins targeted, some high structural diversity is observed in patented quinazoline compounds. Due to the vast applications of quinazoline derivatives, development of novel quinazoline compounds as anticancer drugs remains a promising field. PMID- 25910403 TI - Alopecia and hirsutism in a postmenopausal woman as the presenting complaint of ovarian hilus (Leydig) cell tumor. PMID- 25910404 TI - The assessment of lesions of the Achilles tendon by ultrasound imaging in inflammatory arthritis: A systematic review and meta-analysis. AB - OBJECTIVE: Ultrasound (US) is a highly sensitive, reliable and non-invasive tool, which allows for the assessment of lesions of tendons and entheseal sites. The aim of this systematic review and meta-analysis is to identify differences in US lesions of the Achilles tendon (AT) between people with inflammatory arthritis (IA) and healthy controls. METHODS: An electronic literature search was performed on Medline, CINAHL, SportDiscus and The Cochrane Library. Methodological quality was assessed using a modified Quality Index. Odds ratios with 95% confidence intervals (CI) were determined. Meta-analysis was conducted on those studies that were considered to be homogenous. RESULTS: A total of 13 high-to-medium quality studies met the inclusion criteria. The majority of studies reported US lesions in spondyloarthropathy (SpA), with limited evidence for other forms of IA. US lesions were not consistently defined with regard to Outcome Measures in Rheumatology Clinical Trials (OMERACT) definitions, and numerous scoring systems were used across the majority of studies. The mean AT thickness at the enthesis in people with SpA was 0.54mm thicker (95% CI: 0.10-0.97mm) with more frequent erosions in people with SpA (odds ratio = 7.43, 95% CI: 1.99-27.77, P = 0.003) and rheumatoid arthritis (RA) (odds ratio = 9.60, 95% CI: 1.23-74.94, P = 0.03), compared to controls. There was no significant difference in the frequency of enthesophyte formation in people with SpA compared to the controls (odds ratio = 2.48, 95% CI: 0.64-9.70, P = 0.19). CONCLUSIONS: The systematic review identified that a majority of studies reporting US lesions were in SpA, but limited evidence relating to other forms of IA. Consistent application of the OMERACT US definitions and scoring of US lesions is required in future studies of AT disease in IA. Further work is also required to distinguish between US lesions reflective of inflammation and structural damage. PMID- 25910405 TI - Primary tumors of the facial nerve. AB - This article describes the pathophysiology, diagnosis, treatment, and outcomes of primary tumors of the facial nerve. These tumors include facial nerve schwannomas, geniculate ganglion hemangiomas, glomus facialis, and granular cell tumors. Although these tumors are rare, collected data help to form a consensus with regard to optimal treatment methods. PMID- 25910406 TI - Tumors of the ear and lateral skull base: part 2. PMID- 25910408 TI - Reduction in the desaturation capacity of the liver in mice subjected to high fat diet: Relation to LCPUFA depletion in liver and extrahepatic tissues. AB - alpha-Linolenic (ALA) and linoleic (LA) acids are precursors of long chain polyunsaturated fatty acids (LCPUFAs), FAs with important biochemical and physiological functions. In this process, desaturation reactions catalyzed by Delta5- and Delta6-desaturase play a major role, enzymes that are subjected to hormonal and dietary regulation. The aim of this study was to assess the influence of a high fat diet (HFD) on activity of liver Delta5 and Delta6 desaturases, in relation to LCPUFA composition in liver and extrahepatic tissues. Male C57BL/6J mice received control diet (CD) (10% fat, 20% protein and 70% carbohydrate) or high fat diet (HFD) (60% fat, 20% protein, and 20% carbohydrate) for 12 weeks. After this time, blood and liver samples were taken for metabolic, morphologic, inflammatory, oxidative stress and desaturase activity assessment, besides FA phospholipid analysis in erythrocytes, heart, adipose tissue and brain. HFD significantly increased hepatic total fat, triacylglycerides and free FA content with macrovesicular steatosis and oxidative stress enhancement, concomitantly with higher fasting serum glucose and insulin levels, HOMA, and serum cholesterol, triacylglycerols, TNF-alpha, and IL-6. Diminution in liver Delta5- and Delta6-desaturase activities and LCPUFA depletion were induced by HFD, the later finding being also observed in extrahepatic tissues. In conclusion, HFD-induced reduction in the bioavailability of liver LCPUFA is associated with defective desaturation of ALA and LA, with Delta5- and Delta6 desaturase activities being correlated with insulin resistance development. Data analyzed point to the liver as a major organ responsible for extrahepatic LCPUFA homeostasis, which is markedly deranged by HFD. PMID- 25910409 TI - In reference to paper "Prevalence of renal stones in Andalusian population: Results of PreLiRenA study". PMID- 25910407 TI - Somatic mosaicism: implications for disease and transmission genetics. AB - Nearly all of the genetic material among cells within an organism is identical. However, single-nucleotide variants (SNVs), small insertions/deletions (indels), copy-number variants (CNVs), and other structural variants (SVs) continually accumulate as cells divide during development. This process results in an organism composed of countless cells, each with its own unique personal genome. Thus, every human is undoubtedly mosaic. Mosaic mutations can go unnoticed, underlie genetic disease or normal human variation, and may be transmitted to the next generation as constitutional variants. We review the influence of the developmental timing of mutations, the mechanisms by which they arise, methods for detecting mosaic variants, and the risk of passing these mutations on to the next generation. PMID- 25910410 TI - The relationship between semaphorin 3C and microvessel density in the progression of breast and oral neoplasia. AB - This study aimed to identify the expression of semaphorin 3C (SEMA3C) in the normal-metastatic spectrum of breast and oral cancers, and correlate expression with microvessel density (MVD, CD31), a surrogate marker of angiogenesis. Histological analysis revealed that SEMA3C expression was reduced in the development of oral cancer from normal oral tissue (P<0.0001) and expression was inversely correlated with MVD (r=-0.394, P=0.05). In contrast, SEMA3C expression increased in the transition from normal to invasive breast disease in epithelial/tumour cells (P=0.001) and endothelial cells (P=0.006), with both correlating weakly with MVD (r=0.35, p=0.03 and r=0.243, p=0.041 respectively). Furthermore, histological analysis of a breast cancer tissue microarray revealed a weak positive correlation with tumour grade (r=0.305, P=<0.001) and biological phenotype (r=0.237, p=0.004) with tumour cell expression of SEMA3C highest in triple negative and ER-, PR-, HER2+ subtypes. These data suggest that SEMA3C expression is differentially regulated in the development and progression of breast versus oral neoplasia, and that increased expression of SEMA3C may be modulating breast cancer progression and angiogenesis, and could represent a biomarker of metastatic disease. PMID- 25910411 TI - The association of RBBP6 variant 3 expressions with apoptosis in human immunodeficiency virus-associated nephropathy (HIVAN). AB - South Africa has one of the highest HIV infection rates in the world. One of the complications of HIV infection is the development of HIV-associated nephropathy (HIVAN), which is characterized by deregulation in tubular epithelial apoptosis. The pathways that HIV-1 promotes in the pathogenesis of HIVAN remain less understood. There are many genes that have not been characterized in the pathogenesis of HIVAN. On the other hand, RBBP6 has been shown to play a role in both promoting and inhibiting apoptosis in human cancers. This study was aimed at determining an association between RBBP6 isoform 3 expression and the levels of apoptosis in HIVAN cases. HIVAN biopsy tissues from Johannesburg patients in South Africa were used in this study. These tissues were stained for RBBP6 expression and apoptosis levels using immunohistochemistry staining and TUNEL method respectively. Image analysis was used for quantitative analysis and GraphPad Version 4 was used for statistical analysis. High expression levels of RBBP6 were found in HIVAN cases (n=30) relative to the normal tissues (n=10). High apoptosis levels were also obtained in the HIVAN tissues. This direct association between RBBP6 expression and apoptosis levels suggests that RBBP6 may play a role in HIVAN pathogenesis. RBBP6 may then be targeted for both diagnostic and therapeutic strategies in HIVAN. PMID- 25910412 TI - P16INK4A and survivin: Diagnostic and prognostic markers in cervical intraepithelial neoplasia and cervical squamous cell carcinoma. AB - OBJECTIVE: To explore the the correlations of p16INK4A (p16) and survivin expressions with cervical intraepithelial neoplasia (CIN) and cervical squamous cell carcinoma. METHODS: The p16 and survivin expressions were detected in 50 cervical squamous cell carcinoma tissues, 150 various grades of CIN tissues and 30 normal cervical tissues using immunohistochemistry. All data were analyzed applying SPSS 17.0 software. RESULTS: The p16 and survivin expressions showed the presence of statistical significance in cervical cancer, CINI, CINII, CINIII and normal cervical tissues (P<0.05), and the comparison also revealed statistical significance among groups (all P<0.05); the p16 and survivin expressions were positively correlated with the grade of cervical diseases (both P<0.05). Moreover, p16 protein was associated with CIN grade and lymph node metastases in cervical cancer (all P<0.05); survivin protein was also related with clinical stages, CIN grade and lymph node metastases (all P<0.05); the p16 and survivin expressions were positively correlated with cervical cancer (r=0.854, P<0.001), and associated with poor prognosis of cervical cancer. CONCLUSION: Briefly, p16 and survivin expression may be correlated with the clinico-pathological and prognosis of cervical cancer. PMID- 25910413 TI - Association of mutations in the mitochondrial genome with the subclinical carotid atherosclerosis in women. AB - The importance of the study of an association of mitochondrial DNA mutations with asymptomatic atherosclerosis in women is undeniable. In the present study, a series of PCR with primers for mutation region and further amplificate pyrosequencing were carried out to identify point substitutions or microdeletions of the mitochondrial genome. The results obtained were processed using the original method of estimating the level of heteroplasmy. Five mutations in the mitochondrial genome, namely C3256T, G14709A, G12315A, G13513A and G14846A, in which the heteroplasmy level was associated with the degree of preclinical atherosclerosis in women, were identified. The data obtained in the study showed that C3256T, G14709A and G12315A mutations have a positive correlation with atherosclerosis while G13513A and G14846A mutations have a negative correlation with atherosclerotic lesions. Total mutational load of the mitochondrial genome for C3256T, G14709A, G12315A, G13513A and G14846A mutations explains 68% of the variability of thickness of the carotid intima-medial layer, while the complex of traditional risk factors for cardiovascular diseases explains only 8% of the IMT variability. Data on the correlation between heteroplasmy levels of C3256T, G14709A, G12315A, G13513A and G14846A mutations prompt a suggestion that these mutations may be present on the same haplotypes of mitochondrial genome, associated with atherosclerosis. PMID- 25910415 TI - Development of a liposome formulation for improved biodistribution and tumor accumulation of pentamidine for oncology applications. AB - Pentamidine isethionate, widely used for the treatment of parasitic infections, has shown strong anticancer activity in cancer cells and models of melanoma and lung cancer. Systemic administration of pentamidine is associated with serious toxicities, particularly renal, affecting as many as 95% of patients (O'Brien et al., 1997). This work presents the development of a liposome pentamidine formulation for greater tumor accumulation and lower drug exposure to vulnerable tissues. Liposomes formulated with saturated/unsaturated phospholipids of different chain lengths, varying cholesterol content, and surface PEG were explored to understand the effects of such variations on drug release, encapsulation efficiency, stability and in vivo performance. Saturated phospholipids with longer chain lengths, higher cholesterol content and PEG resulted in greater stability. The optimal formulation obtained showed significantly lower clearance rate (3.6 +/- 1.2 mL/h/Kg) and higher AUC0-inf (348 +/- 31 MUmol/L * h) in vivo when compared to free drug (414 +/- 138 mL/h/Kg and 2.58 +/- 0.74 MUmol/L * h, respectively). In tumor-bearing mice, liposomal delivery decreased kidney drug levels by up to 5-fold at 6 and 24h post administration. Tumor drug exposure was up to 12.7-fold greater with liposomal administration compared to free drug. Overall, the liposomal pentamidine formulation developed has significant potential for the treatment of solid tumors. PMID- 25910414 TI - Doxorubicin liposomes as an investigative model to study the skin permeation of nanocarriers. AB - The objectives of this study were to develop an innovative investigative model using doxorubicin as a fluorophore to evaluate the skin permeation of nanocarriers and the impact of size and surface characteristics on their permeability. Different doxorubicin-loaded liposomes with mean particle size <130 nm and different surface chemistry were prepared by ammonium acetate gradient method using DPPC, DOPE, Cholesterol, DSPE-PEG 2000 and 1,1-Di-((Z)-octadec-9-en 1-yl) pyrrolidin-1-ium chloride (CY5)/DOTAP/1,2-dioleoyl-sn-glycero-3-phosphate (DOPA) as the charge modifier. There was minimal release of doxorubicin from the liposomes up to 8h; indicating that fluorescence observed within the skin layers was due to the intact liposomes. Liposomes with particle sizes >600 nm were restricted within the stratum corneum. DOTAP (p<0.01) and CY5 (p<0.05) liposomes demonstrated significant permeation into the skin than DOPA and PEG liposomes. Tape stripping significantly (p<0.01) enhanced the skin permeation of doxorubicin liposomes but TAT-decorated doxorubicin liposomes permeated better (p<0.005). Blockage of the hair follicles resulted in significant reduction in the extent and intensity of fluorescence observed within the skin layers. Overall, doxorubicin liposomes proved to be an ideal fluorophore-based model. The hair follicles were the major route utilized by the liposomes to permeate skin. Surface charge and particle size played vital roles in the extent of permeation. PMID- 25910416 TI - The effect of modality and narration style on recall of online health information: results from a Web-based experiment. AB - BACKGROUND: Older adults are increasingly using the Internet for health information; however, they are often not able to correctly recall Web-based information (eHealth information). Recall of information is crucial for optimal health outcomes, such as adequate disease management and adherence to medical regimes. Combining effective message strategies may help to improve recall of eHealth information among older adults. Presenting information in an audiovisual format using conversational narration style is expected to optimize recall of information compared to other combinations of modality and narration style. OBJECTIVE: The aim of this paper is to investigate the effect of modality and narration style on recall of health information, and whether there are differences between younger and older adults. METHODS: We conducted a Web-based experiment using a 2 (modality: written vs audiovisual information) by 2 (narration style: formal vs conversational style) between-subjects design (N=440). Age was assessed in the questionnaire and included as a factor: younger (<65 years) versus older (>=65 years) age. Participants were randomly assigned to one of four experimental webpages where information about lung cancer treatment was presented. A Web-based questionnaire assessed recall of eHealth information. RESULTS: Audiovisual modality (vs written modality) was found to increase recall of information in both younger and older adults (P=.04). Although conversational narration style (vs formal narration style) did not increase recall of information (P=.17), a synergistic effect between modality and narration style was revealed: combining audiovisual information with conversational style outperformed combining written information with formal style (P=.01), as well as written information with conversational style (P=.045). This finding suggests that conversational style especially increases recall of information when presented audiovisually. This combination of modality and narration style improved recall of information among both younger and older adults. CONCLUSIONS: We conclude that combining audiovisual information with conversational style is the best way to present eHealth information to younger and older adults. Even though older adults did not proportionally recall more when audiovisual information was combined with conversational style than younger adults, this study reveals interesting implications for improving eHealth information that is effective for both younger and older adults. PMID- 25910417 TI - N-Heterocyclic Carbene-Catalyzed delta-Carbon LUMO Activation of Unsaturated Aldehydes. AB - An N-heterocyclic carbene (NHC) catalyzed domino reaction triggered by a delta LUMO activation of alpha,beta-gamma,delta-diunsaturated enal has been developed for the formal [4 + 2] construction of multisubstituted arenes and 3 ylidenephthalide. These two products, formed in a highly chemo- and regioselective manner, were obtained via different catalytic pathways due to a simple change of the substrate. The activation of the remote delta-carbon of unsaturated aldehydes expands the synthetic potentials of NHC organocatalysis. PMID- 25910418 TI - Chronic neglect and aggression/delinquency: A longitudinal examination. AB - Neglect is the most common form of maltreatment in the United States, yet its impact on development remains understudied, especially for chronic neglect. Chronic neglect is also one of the most costly burdens on child welfare systems. This study examines the effects of chronic neglect, including two subtypes (Failure to Provide and Lack of Supervision) on adolescent aggression and delinquency using a diverse longitudinal sample of youth. Chronic neglect and chronic failure to provide (ages 0-12) predicted aggression/delinquency (age 14) even after controlling for the effects of other maltreatment (ages 0-12). Chronic lack of supervision, however, did not. Gender significantly moderated these effects, suggesting that males are more likely to respond to neglect by becoming aggressive/delinquent. Finally, social problems (age 12) partially mediated for boys, and fully mediated for girls, the connections between chronic neglect and aggression/delinquency, bolstering theorizing that neglect impairs social functioning broadly. Implications include the need for further research on chronic neglect, especially in providing guidance for child welfare systems. Interventions for chronically neglected youth should include social skill development. PMID- 25910419 TI - Verbal fluency, clustering, and switching in patients with psychosis following traumatic brain injury (PFTBI). AB - Verbal fluency in patients with psychosis following traumatic brain injury (PFTBI) has been reported as comparable to healthy participants. This finding is counterintuitive given the prominent fluency impairments demonstrated post traumatic brain injury (TBI) and in psychotic disorders, e.g. schizophrenia. We investigated phonemic (executive) fluency (3 letters: 'F' 'A' and 'S'), and semantic fluency (1 category: fruits and/or vegetables) in four matched groups; PFTBI (N=10), TBI (N=10), schizophrenia (N=23), and healthy controls (N=23). Words produced (minus perseverations and errors), and clustering and switching scores were compared for the two fluency types across the groups. The results confirmed that PFTBI patients do show impaired fluency, aligned with existing evidence in TBI and schizophrenia. PFTBI patients produced the least amount of words on the phonemic fluency ('A') trial and total score, and demonstrated reduced switching on both phonemic and semantic tasks. No significant differences in clustering performance were found. Importantly, the pattern of results suggested that PFTBI patients share deficits with their brain-injured (primarily executive), and psychotic (executive and semantic), counterparts, and that these are exacerbated by their dual-diagnosis. These findings add to a very limited literature by providing novel evidence of the nature of fluency impairments in dually-diagnosed PFTBI. PMID- 25910420 TI - Electroconvulsive therapy improves clinical manifestations of treatment-resistant depression without changing serum BDNF levels. AB - Electroconvulsive therapy (ECT) is effective in treatment-resistant depression (TRD). It may act through intracellular process modulation, but its exact mechanism is still unknown. Animal research supports a neurotrophic effect for ECT. We aimed to investigate the association between changes in serum brain derived neurotrophic factor (sBDNF) levels and clinical improvement following ECT in patients with TRD. Twenty-one patients with TRD (2 men, 19 women; mean age, 63.5 years; S.D., 11.9) were assessed through the Hamilton Depression Rating Scale (HDRS), the Brief Psychiatric Rating Scale (BPRS), and the Clinical Global Impressions scale, Severity (CGIs) before and after a complete ECT cycle. At the same time-points, patients underwent blood withdrawal for measuring sBDNF levels. ECT significantly reduced HDRS, BPRS, and CGIS scores, but not sBDNF levels. No significant correlation was found between sBDNF changes, and each of HDRS, BPRS, and CGIs score changes. sBDNF levels in TRD patients were low both at baseline and post-ECT. Our results do not support that improvements in TRD following ECT are mediated through increases in sBDNF levels. PMID- 25910421 TI - Inhibition of FAAH reduces nitroglycerin-induced migraine-like pain and trigeminal neuronal hyperactivity in mice. AB - There is evidence to suggest that a dysregulation of endocannabinoid signaling may contribute to the etiology and pathophysiology of migraine. Thus, patients suffering from chronic migraine or medication overuse headache showed alterations in the activity of the arachidonoylethanolamide (AEA) degrading enzyme fatty acid amide hydrolase (FAAH) and a specific AEA membrane transporter, alongside with changes in AEA levels. The precise role of different endocannabinoid system components is, however, not clear. We have therefore investigated mice with a genetic deletion of the two main cannabinoid receptors CB1 and CB2, or the main endocannabinoid degrading enzymes, FAAH and monoacylglycerol lipase (MAGL), which degrades 2-arachidonoylglycerol (2-AG), in a nitroglycerine-induced animal model of migraine. We found that nitroglycerin-induced mechanical allodynia and neuronal activation of the trigeminal nucleus were completely abolished in FAAH deficient mice. To validate these results, we used two structurally different FAAH inhibitors, URB597 and PF3945. Both inhibitors also dose-dependently blocked nitroglycerin-induced hyperalgesia and the activation of trigeminal neurons. The effects of the genetic deletion of pharmacological blockade of FAAH are mediated by CB1 receptors, because they were completely disrupted with the CB1 antagonist rimonabant. These results identify FAAH as a target for migraine pharmacotherapy. PMID- 25910422 TI - Coupling in the cortico-basal ganglia circuit is aberrant in the ketamine model of schizophrenia. AB - Recent studies have suggested the implication of the basal ganglia in the pathogenesis of schizophrenia. To investigate this hypothesis, here we have used the ketamine model of schizophrenia to determine the oscillatory abnormalities induced in the rat motor circuit of the basal ganglia. The activity of free moving rats was recorded in different structures of the cortico-basal ganglia circuit before and after an injection of a subanesthesic dose of ketamine (10mg/kg). Spectral estimates of the oscillatory activity, phase-amplitude cross frequency coupling interactions (CFC) and imaginary event-related coherence together with animals' behavior were analyzed. Oscillatory patterns in the cortico-basal ganglia circuit were highly altered by the effect of ketamine. CFC between the phases of low-frequency activities (delta, 1-4; theta 4-8Hz) and the amplitude of high-gamma (~80Hz) and high-frequency oscillations (HFO) (~150Hz) increased dramatically and correlated with the movement increment shown by the animals. Between-structure analyses revealed that ketamine had also a massive effect in the low-frequency mediated synchronization of the HFO's across the whole circuit. Our findings suggest that ketamine administration results in an aberrant hypersynchronization of the whole cortico-basal circuit where the tandem theta/HFO seems to act as the main actor in the hyperlocomotion shown by the animals. Here we stress the importance of the basal ganglia circuitry in the ketamine model of schizophrenia and leave the door open to further investigations devoted to elucidate to what extent these abnormalities also reflect the prominent neurophysiological deficits observed in schizophrenic patients. PMID- 25910424 TI - Mutation of Gly717Phe in human topoisomerase 1B has an effect on enzymatic function, reactivity to the camptothecin anticancer drug and on the linker domain orientation. AB - Human topoisomerase 1B controls the topological state of supercoiled DNA allowing the progression of fundamental cellular processes. The enzyme, which is the unique molecular target of the natural anticancer compound camptothecin, acts by cleaving one DNA strand and forming a transient protein-DNA covalent adduct. In this work the role of the Gly717 residue, located in a alpha-helix structure bridging the active site and the linker domain, has been investigated mutating it in Phe. The mutation gives rise to drug resistance in vivo as observed through a viability assay of yeast cells. In vitro activity assays show that the mutant is characterized by a fast religation rate, only partially reduced by the presence of the drug. Comparative molecular dynamics simulations of the native and mutant proteins indicate that the mutation of Gly717 affects the motion orientation of the linker domain, changing its interaction with the DNA substrate, likely affecting the strand rotation and religation rate. The mutation also causes a slight rearrangement of the active site and of the drug binding site, providing an additional explanation for the lowered effect of camptothecin toward the mutant. PMID- 25910423 TI - Electrophysiological endophenotypes in rodent models of schizophrenia and psychosis. AB - Schizophrenia is caused by a diverse array of risk factors and results in a similarly diverse set of symptoms. Electrophysiological endophenotypes lie between risks and symptoms and have the potential to link the two. Electrophysiological studies in rodent models, described here, demonstrate that widely differing risk factors result in a similar set of core electrophysiological endophenotypes, suggesting the possibility of a shared neurobiological substrate. PMID- 25910425 TI - Subcellular quantitative proteomic analysis reveals host proteins involved in human cytomegalovirus infection. AB - Viral replication requires host cell macromolecules and energy, although host cells can alter their protein expression to restrict viral replication. To study the host cell response to human cytomegalovirus (HCMV) infection, a stable isotope labeling by amino acids in cell culture (SILAC)-based subcellular quantitative proteomic study of HCMV-infected human embryo lung fibroblast (HEL) cells was performed, and a total of 247 host proteins were identified as differentially regulated by HCMV. Western blotting and immunofluorescence confocal microscopy were performed to validate the data sets. Gene Ontology analysis indicated that cellular processes involving the metabolism, localization and immune system were regulated as a result of HCMV infection. Functional analysis of selected regulated proteins revealed that knockdown of HNRPD, PHB2 and UB2V2 can increase HCMV replication, while knockdown of A4 and KSRP resulted in decreased HCMV replication. Our study may improve our understanding of the dynamic interactions between HCMV and its host and provide multiple potential targets for anti-HCMV agent research. PMID- 25910427 TI - C2 Nerve Field Stimulation for the Treatment of Fibromyalgia: A Prospective, Double-blind, Randomized, Controlled Cross-over Study. AB - BACKGROUND: Fibromyalgia is a condition characterized by widespread chronic pain. Due to the high prevalence and high costs, it has a substantial burden on society. Treatment results are diverse and only help a small subset of patients. C2 nerve field stimulation, aka occipital nerve stimulation, is helpful and a minimally invasive treatment for primary headache syndromes. Small C2 pilot studies seem to be beneficial in fibromyalgia. METHODS: Forty patients were implanted with a subcutaneous electrode in the C2 dermatoma as part of a prospective, double-blind, randomized, controlled cross-over study followed by an open label follow up period of 6 months. The patients underwent 2 week periods of different doses of stimulation consisting of minimal (.1 mA), subthreshold, and suprathreshold (for paresthesias) in a randomized order. Twenty seven patients received a permanent implant and 25 completed the 6 month open label follow up period. RESULTS: During the 6 week trial phase of the study, patients had an overall decrease of 36% on the fibromyalgia impact questionnaire (FIQ), a decrease of 33% fibromyalgia pain and improvement of 42% on the impact on daily life activities and quality. These results imply an overall improvement in the disease burden, maintained at 6 months follow up, as well as an improvement in life quality of 50%. Seventy six percent of patients were satisfied or very satisfied with their treatment. There seems to be a dose-response curve, with increasing amplitudes leading to better clinical outcomes. CONCLUSION: Subcutaneous C2 nerve field stimulation seems to offer a safe and effective treatment option for selected medically intractable patients with fibromyalgia. PMID- 25910428 TI - Ultramicroscopic examination of mature massulae of Habenaria arinaria (Orchidaceae). AB - The mature massula of H. arinaria was examined by means of transmission electron microscopy, with the aim to understand the nature of cohesion between grains, the accumulation of pollen storage reserves, and the behavior of the nucleus of the vegetative cell in this composite type of pollen. The massula was a union of a large number of polygonal pollen grains that were tightly linked together. The exine within the massula were highly simplified, consisting of a single layer of nexine-2, lacking tectum, bacula, and nexine-1, while all the four layers comprised the exine on the massula surface. The two layers of nexine-2 of adjacent grains fused into a seamless whole. Undoubtedly the fusion of the nexine 2 was the mechanism by which the grains of the massula were linked together. No starch grains, lipid bodies, or storage proteins were present in the mature massula, and so the composite pollen of this species belonged to a novel type with regard to storage reserves. The vegetative nucleus was not lobed and revealed a huge amount of highly condensed chromatin, indicating a quiescent status. The condensed status of the vegetative nuclei in this composite type of pollen system is in striking contrast to the highly decondensed status reported in the free type of pollen grains. PMID- 25910429 TI - Structural investigation of Ru/Pt nanocomposite films prepared by plasma-enhanced atomic layer depositions. AB - We have fabricated Ru and Pt nanocomposite films using plasma-enhanced atomic layer deposition (PE-ALD), and characterized their structure by means of analytical electron microscopy. Pt and Ru were deposited in Ar/O(2) plasma using trimethyl(methylcyclopentadienyl) platinum(IV) and bis(cyclopentadienyl)Ru(II) or bis(ethylcyclopentadienyl)Ru(II) as precursors, respectively. The resistivity of a Pt film deposited on a Si substrate at 300 degrees C was 16.2MUOmegacm, and that of a Ru film was as low as 11MUOmegacm, showing the film to be metallic and not oxidized. It was revealed that the film prepared by successive PE-ALDs of Pt and Ru on a thin amorphous carbon substrate for electron microscopy analysis is a nanocomposite of Ru ribbons and PtRu (7:3) alloy ribbons with 2-3 nm in width. The Ru ribbon comprised small particles with poor crystallinity of the hcp A3 structure and the PtRu ribbon comprised crystallites with good crystallinity of the fcc Al structure. The atomic layer deposition would be one of potential techniques to produce Ru/Pt nanocomposites for fuel cell catalysts. PMID- 25910426 TI - Maternally responsive neurons in the bed nucleus of the stria terminalis and medial preoptic area: Putative circuits for regulating anxiety and reward. AB - Postpartum neuropsychiatric disorders are a major source of morbidity and mortality and affect at least 10% of childbearing women. Affective dysregulation within this context has been identified in association with changes in reproductive steroids. Steroids promote maternal actions and modulate affect, but can also destabilize mood in some but not all women. Potential brain regions that mediate these effects include the medial preoptic area (mPOA) and ventral bed nucleus of the stria terminalis (vBNST). Herein, we review the regulation of neural activity in the mPOA/vBNST by environmental and hormonal concomitants in puerperal females. Such activity may influence maternal anxiety and motivation and have significant implications for postpartum affective disorders. Future directions for research are also explored, including physiological circuit-level approaches to gain insight into the functional connectivity of hormone-responsive maternal circuits that modulate affect. PMID- 25910430 TI - DAD in nonresolving ARDS provides support for prolonged glucocorticoid treatment: a rebuttal. PMID- 25910431 TI - Paroxysmal Kinesigenic Dyskinesia: Seeing Is Believing. PMID- 25910433 TI - Increased antimicrobial susceptibility rates for Pseudomonas aeruginosa bloodstream isolates across the Veterans Affairs Healthcare System. AB - This study sought to characterize the trends in antimicrobial susceptibility rates for Pseudomonas aeruginosa causing bacteremias across the US Veterans Healthcare Administration from 2007 through 2013 utilizing a national clinical database. Data were gathered from 107 Veterans Affairs medical centers involving 4418 patients with 4826 blood cultures with positive growth of P. aeruginosa. Susceptibility rates of beta-lactam antimicrobials, carbapenems, fluoroquinolones, and aminoglycosides all significantly increased throughout the 7-year period, closely corresponding to a significant decline in the incidence of P. aeruginosa blood cultures of nosocomial origin. Several statistically significant increases in susceptibility rates were found for antimicrobial agents across different geographic regions of the United States. There were no statistically significant decreases in susceptibility rates for any antimicrobial agents for any region. Levels of multidrug resistance significantly declined throughout the study period in 2 regions and increased in 1. Additional efforts should evaluate variables associated with these improvements. PMID- 25910432 TI - The assessment of anterior and posterior ocular structures in hyperopic anisometropic amblyopia. AB - BACKGROUND: The aim of this study was to examine the relationship or differences in ocular structures of amblyopic eyes compared to fellow eyes in children and young adults with hyperopic anisometropic amblyopia. MATERIAL/METHODS: Hyperopic participants with anisometropic amblyopia, defined as the presence of best corrected visual acuity differences of at least 2 Snellen lines and 1.5 diopters between amblyopic and fellow eyes, were studied. Using the IOL Master, Pentacam Scheimpflug imaging and Spectralis optical coherence tomography, the axial length, corneal curvature, and anterior chamber depth (ACD), as well as the thickness of the cornea, peripapillary retinal nerve fiber layer (RNFL), and macula, were compared between children and young adults and between their amblyopic and fellow eyes. RESULTS: In 53 participants with hyperopic anisometropic amblyopia, there were significant differences in the anterior corneal curvature, ACD and axial length between the amblyopic and fellow eyes of all the patients. The mean central macular thickness in the amblyopic eyes was significantly thicker (P=.001) in the group aged 5 to 12 years; however, this was not the case in the group aged 13 to 42 years. There was no significant difference in average RNFL thickness in either group. CONCLUSIONS: We found significantly greater mean central macular thickness in anisometropic amblyopic eyes among participants aged 5 to 12 years, but not among those who were older. Similarly, the interocular differences in axial length parameters seemed to be related to the central macular thickness differences between the amblyopic and fellow eyes in the younger group. PMID- 25910434 TI - Expression of both CuZnSOD and APX in chloroplasts enhances tolerance to sulfur dioxide in transgenic sweet potato plants. AB - We have previously reported that transgenic sweet potato (Ipomoea batatas) plants overexpressing both CuZn superoxide dismutase (CuZnSOD) and ascorbate peroxidase (APX) under the control of a stress-inducible SWPA2 promoter in chloroplasts (referred to as SSA plants) showed increased resistance to methyl viologen mediated oxidative stress and chilling. To investigate whether SSA plants show enhanced tolerance to air pollutants, they were exposed to 500ppb of sulfur dioxide (SO2). SO2 caused visible damage to the leaves of sweet potato, but damage in the leaves of non-transgenic (NT) plants was more severe than in those of SSA plants. The photosynthetic activity (Fv/Fm) of the SSA plants decreased by only 7% on the 5th day after the treatment, whereas that of NT plants severely decreased by 63% after 5days of recovery. Moreover, the chlorophyll content in the oldest leaf of NT plants decreased by 69%, whereas that of SSA plants remained at a high level. APX activity in NT plants increased about three times under an SO2 stress, and in SSA plants about five times compared to the case with no stress conditions. These results suggest that the overexpression of both CuZnSOD and APX in chloroplasts reduces the oxidative stress derived from SO2. PMID- 25910435 TI - Evaluation of the 5alpha-reductase inhibitor finasteride on reproduction and gonadal development in medaka, Oryzias latipes. AB - 5-alpha reductase (5alphaR) inhibitors have an anti-androgenic effect in mammals because they inhibit the conversion of testosterone to the potent androgen, dihydrotestosterone. Finasteride is a type-2 5alphaR inhibitor that is used as a human pharmaceutical for the treatment of prostate cancer, benign prostate hyperplasia and male pattern baldness. This study evaluated the impacts of finasteride (50, 500 and 5000MUg/L) on the development and reproduction of medaka (Oryzias latipes) exposed continuously over multiple generations (F0, F1 and F2). The exposure was initiated with reproductively mature fish (F0 generation) and continued until the hatching of the F2 generation. There were no significant effects on survival, fecundity or fertility in the F0 (50, 500, 5000MUg/L) and F1 (50, 500MUg/L) generations. The F1 generation exposed to 5000MUg/L exhibited significant mortality. Histopathology of the gonads demonstrated that medaka and pre-clinical species respond similarly to finasteride exposure. Intersex condition and maldeveloped gonads were observed in F0 generation males exposed to 5000MUg/L and F1 generation males exposed to 500MUg/L. F1 generation males exposed to 500MUg/L displayed reduced gonadosomatic index with an increased incidence of testicular degeneration. Males in both generations exhibited an increased incidence of Leydig cell hyperplasia at concentrations ?500MUg/L. F0 generation females exposed to 5000MUg/L exhibited increased gonadosomatic index. An increased prevalence of accelerated post-ovulatory follicle involution was observed in females at concentrations ?500MUg/L in both generations. The gonadal changes induced by finasteride support the idea that 5-alpha reductase inhibition impacts androgen signaling in fish. Results from this study are discussed in the context of differential expression of the androgen receptor between species of fish. PMID- 25910437 TI - Stein's neuronal model with pooled renewal input. AB - The input of Stein's model of a single neuron is usually described by using a Poisson process, which is assumed to represent the behaviour of spikes pooled from a large number of presynaptic spike trains. However, such a description of the input is not always appropriate as the variability cannot be separated from the intensity. Therefore, we create and study Stein's model with a more general input, a sum of equilibrium renewal processes. The mean and variance of the membrane potential are derived for this model. Using these formulas and numerical simulations, the model is analyzed to study the influence of the input variability on the properties of the membrane potential and the output spike trains. The generalized Stein's model is compared with the original Stein's model with Poissonian input using the relative difference of variances of membrane potential at steady state and the integral square error of output interspike intervals. Both of the criteria show large differences between the models for input with high variability. PMID- 25910436 TI - Matrix metalloproteinase inhibition influences aspects of photoperiod stimulated ovarian recrudescence in Siberian hamsters. AB - Blocking matrix metalloproteinase (MMP) activity in vivo with inhibitor GM6001 impedes photostimulated ovarian recrudescence in photoregressed Siberian hamsters. Since direct and indirect effects of MMPs influence a myriad of ovarian functions, we investigated the effect of in vivo MMP inhibition during recrudescence on ovarian mRNA expression of steroidogenic acute regulatory protein (StAR), 3beta-hydroxysteroid dehydrogenase (3beta-HSD), Cyp19a1 aromatase, epidermal growth factor receptor (EGFR), amphiregulin (Areg), estrogen receptors (Esr1 and Esr2), tissue inhibitors of MMPs (TIMP-1,-2,-3), proliferating cell nuclear antigen (PCNA), vascular endothelial growth factor A (VEGFA), its receptor VEGFR-2, and angiopoietin-2 (Ang-2). Female Siberian hamsters were randomly assigned to one of four photoperiod groups: stimulatory long (LD) or inhibitory short (SD) photoperiods, or transferred from SD to LD for 2 weeks (post-transfer, PT). Half of the PT hamsters were injected (ip) daily with GM6001 (PTG). SD exposure reduced ovarian StAR, 3beta-HSD, Cyp19a1, Esr1, Esr2, TIMPs 2-3, PCNA, VEGFR-2 and Ang-2 mRNA expression (p<0.05), and 2 weeks of photostimulation restored mRNA expression of 3beta-HSD and PCNA and increased Areg and VEGFA mRNA expression in the PT group. GM6001 treatment during photostimulation (PTG) increased TIMP-1, -2 and -3 and PCNA mRNA, but inhibited Areg mRNA expression compared to PT. Neither photoperiod nor GM6001 altered EGFR expression. Results of this study suggest that in vivo inhibition of MMP activity by GM6001 may impede ovarian recrudescence, particularly follicular growth, in two ways: (1) directly by partially inhibiting the release of EGFR ligands like Areg, thereby potentially affecting EGFR activation and its downstream pathway, and (2) indirectly by its effect on TIMPs which themselves can affect proliferation, angiogenesis and follicular growth. PMID- 25910438 TI - Electrospun polycaprolactone nanofibers as a potential oromucosal delivery system for poorly water-soluble drugs. AB - The number of poorly water-soluble drug candidates is rapidly increasing; this represents a major challenge for the pharmaceutical industry. As a consequence, novel formulation approaches are required. Furthermore, if such a drug candidate is intended for the therapy of a specific group of the population, such as geriatric or pediatric, the formulation challenge is even greater, with the need to produce a dosage form that is acceptable for specific patients. Therefore, the goal of our study was to explore electrospun polycaprolactone (PCL) nanofibers as a novel nanodelivery system adopted for the oromucosal administration of poorly water-soluble drugs. The nanofibers were evaluated in comparison with polymer films loaded with ibuprofen or carvedilol as the model drugs. Scanning electron microscopy revealed that the amount of incorporated drug affects the diameter and the morphology of the nanofibers. The average fiber diameter increased with a higher drug loading, whereas the morphology of the nanofibers was noticeably changed in the case of nanofibers with 50% and 60% ibuprofen. The incorporation of drugs into the electrospun PCL nanofibers was observed to reduce their crystallinity. Based on the morphology of the nanofibers and the films, and the differential scanning calorimetry results obtained in this study, it can be assumed that the drugs incorporated into the nanofibers were partially molecularly dispersed in the PCL matrix and partially in the form of dispersed nanocrystals. The incorporation of both model drugs into the PCL nanofibers significantly improved their dissolution rates. The PCL nanofibers released almost 100% of the incorporated ibuprofen in 4h, whereas only up to 77% of the incorporated carvedilol was released during the same time period, indicating the influence of the drug's properties, such as molecular weight and solubility, on its release from the PCL matrix. The obtained results clearly demonstrated the advantages of the new nanodelivery system compared to the drug-loaded polymer films that were used as the reference formulation. As a result, electrospinning was shown to be a very promising nanotechnology-based approach to the formulation of poorly water-soluble drugs in order to enhance their dissolution. In addition, the great potential of the produced drug-loaded PCL nanofiber mats for subsequent formulation as oromucosal drug delivery systems for children and the elderly was confirmed. PMID- 25910439 TI - Rosemary tea consumption results to anxiolytic- and anti-depressant-like behavior of adult male mice and inhibits all cerebral area and liver cholinesterase activity; phytochemical investigation and in silico studies. AB - Our aim was to investigate the possible effects of regular drinking of Rosmarinus officinalis L. leaf infusion on behavior and on AChE activity of mice. Rosemary tea (2% w/w) phytochemical profile was investigated through LC/DAD/ESI-MS(n). Adult male mice were randomly divided into two groups: "Rosemary-treated" that received orally the rosemary tea for 4weeks and "control" that received drinking water. The effects of regular drinking of rosemary tea on behavioral parameters were assessed by passive avoidance, elevated plus maze and forced swimming tests. Moreover, its effects on cerebral and liver cholinesterase (ChE) isoforms activity were examined colorimetricaly. Phytochemical analysis revealed the presence of diterpenes, flavonoids and hydroxycinnamic derivatives in rosemary tea; the major compounds were quantitatively determined. Its consumption rigorously affected anxiety/fear and depression-like behavior of mice, though memory/learning was unaffected. ChE isoforms activity was significantly decreased in brain and liver of "rosemary treated" mice. In order to explain the tissue ChE inhibition, principal component analysis, pharmacophore alignment and molecular docking were used to explore a possible relationship between main identified compounds of rosemary tea, i.e. rosmarinic acid, luteolin-7-O-glucuronide, caffeic acid and known AChE inhibitors. Results revealed potential common pharmacophores of the phenolic components with the inhibitors. Our findings suggest that rosemary tea administration exerts anxiolytic and antidepressant effects on mice and inhibits ChE activity; its main phytochemicals may function in a similar way as inhibitors. PMID- 25910440 TI - Arsenic fractionation in agricultural soil using an automated three-step sequential extraction method coupled to hydride generation-atomic fluorescence spectrometry. AB - A fully automated modified three-step BCR flow-through sequential extraction method was developed for the fractionation of the arsenic (As) content from agricultural soil based on a multi-syringe flow injection analysis (MSFIA) system coupled to hydride generation-atomic fluorescence spectrometry (HG-AFS). Critical parameters that affect the performance of the automated system were optimized by exploiting a multivariate approach using a Doehlert design. The validation of the flow-based modified-BCR method was carried out by comparison with the conventional BCR method. Thus, the total As content was determined in the following three fractions: fraction 1 (F1), the acid-soluble or interchangeable fraction; fraction 2 (F2), the reducible fraction; and fraction 3 (F3), the oxidizable fraction. The limits of detection (LOD) were 4.0, 3.4, and 23.6 MUg L( 1) for F1, F2, and F3, respectively. A wide working concentration range was obtained for the analysis of each fraction, i.e., 0.013-0.800, 0.011-0.900 and 0.079-1.400 mg L(-1) for F1, F2, and F3, respectively. The precision of the automated MSFIA-HG-AFS system, expressed as the relative standard deviation (RSD), was evaluated for a 200 MUg L(-1) As standard solution, and RSD values between 5 and 8% were achieved for the three BCR fractions. The new modified three-step BCR flow-based sequential extraction method was satisfactorily applied for arsenic fractionation in real agricultural soil samples from an arsenic contaminated mining zone to evaluate its extractability. The frequency of analysis of the proposed method was eight times higher than that of the conventional BCR method (6 vs 48 h), and the kinetics of lixiviation were established for each fraction. PMID- 25910441 TI - Determination and identification of synthetic cannabinoids and their metabolites in different matrices by modern analytical techniques - a review. AB - Synthetic cannabinoids have gained popularity due to their easy accessibility and psychoactive effects. Furthermore, they cannot be detected in urine by routine drug monitoring. The wide range of active ingredients in analyzed matrices hinders the development of a standard analytical method for their determination. Moreover, their possible side effects are not well known which increases the danger. This review is focused on the sample preparation and the determination of synthetic cannabinoids in different matrices (serum, urine, herbal blends, oral fluid, hair) published since 2004. The review includes separation and identification techniques, such as thin layer chromatography, gas and liquid chromatography and capillary electrophoresis, mostly coupled with mass spectrometry. The review also includes results by spectral methods like infrared spectroscopy, nuclear magnetic resonance or direct-injection mass spectrometry. PMID- 25910442 TI - Potentiometric analytical microsystem based on the integration of a gas-diffusion step for on-line ammonium determination in water recycling processes in manned space missions. AB - The design, construction and evaluation of a versatile cyclic olefin copolymer (COC)-based continuous flow potentiometric microanalyzer to monitor the presence of ammonium ion in recycling water processes for future manned space missions is presented. The microsystem integrates microfluidics, a gas-diffusion module and a detection system in a single substrate. The gas-diffusion module was integrated by a hydrophobic polyvinylidene fluoride (PVDF) membrane. The potentiometric detection system is based on an all-solid state ammonium selective electrode and a screen-printed Ag/AgCl reference electrode. The analytical features provided by the analytical microsystem after the optimization process were a linear range from 0.15 to 500 mg L(-1) and a detection limit of 0.07 +/- 0.01 mg L(-1). Nevertheless, the operational features can be easily adapted to other applications through the modification of the hydrodynamic variables of the microfluidic platform. PMID- 25910443 TI - Fabrication of a totally renewable off-channel amperometric platform for microchip electrophoresis. AB - In this approach, a novel method to fabricate an integrated amperometric platform used in off-channel electrophoresis has been introduced. A simple screen printed protocol combining a wet etching procedure was used to define the pattern on a glass substrate, and whole electrodes were constructed by filling the conductive carbon ink into the etched cavities. A simple Teflon tape was used to align this platform with the micro-channel, and the variation of reassembling of this device can be down to 2.2% without the assistance of microscope. This device was characterized by dopamine (DA) and catechol (CA), and the width of half peak is around 4s, even a 100 MUm double T shape injection design and a 550 MUm working electrode were used in this work. Under the optimum condition, this device possesses a low background with a noise level of 1.4 pA (peak to peak). The linear range for DA and CA are 0.1-100 MUM (R = 0.998) and 0.2-200 MUM (R = 0.996) with a theoretical plate number of 1.57 * 10(4) and 3.46 * 10(4) (plate/m), respectively. PMID- 25910444 TI - Sensitive electrochemical sensor using a graphene-polyaniline nanocomposite for simultaneous detection of Zn(II), Cd(II), and Pb(II). AB - This work describes the development of an electrochemical sensor for simultaneous detection of Zn(II), Cd(II), and Pb(II) using a graphene-polyaniline (G/PANI) nanocomposite electrode prepared by reverse-phase polymerization in the presence of polyvinylpyrrolidone (PVP). Two substrate materials (plastic film and filter paper) and two nanocomposite deposition methods (drop-casting and electrospraying) were investigated. Square-wave anodic stripping voltammetry currents were higher for plastic vs. paper substrates. Performance of the G/PANI nanocomposites was characterized by scanning electron microscopy (SEM) and cyclic voltammetry. The G/PANI-modified electrode exhibited high electrochemical conductivity, producing a three-fold increase in anodic peak current (vs. the unmodified electrode). The G/PANI-modified electrode also showed evidence of increased surface area under SEM. Square-wave anodic stripping voltammetry was used to measure Zn(II), Cd(II), and Pb(II) in the presence of Bi(III). A linear working range of 1-300 MUg L(-1) was established between anodic current and metal ion concentration with detection limits (S/N=3) of 1.0 MUg L(-1) for Zn(II), and 0.1 MUg L(-1) for both Cd(II) and Pb(II). The G/PANI-modified electrode allowed selective determination of the target metals in the presence of common metal interferences including Mn(II), Cu(II), Fe(III), Fe(II), Co(III), and Ni(II). Repeat assays on the same device demonstrated good reproducibility (%RSD<11) over 10 serial runs. Finally, this system was utilized for determining Zn(II), Cd(II), and Pb(II) in human serum using the standard addition method. PMID- 25910445 TI - Quantitative surface-enhanced Raman measurements with embedded internal reference. AB - Analytical applications of SERS are often more associated with qualitative than quantitative analysis, because of the difficulty in obtaining quantitative SERS results. In this paper we introduce a new strategy to quantitatively measure the SERS signals of analytes based on Au-core/Ag-shell nanoparticles with embedded 4 aminothiophenol as the internal reference. Successful detections of two analytes, Toluidine Blue O in aqueous solution (detection limit of 0.1 MUM) and melamine in milk (detection limit of ~5 MUM), are demonstrated. The improvement in the linear fitting illustrates that the use of internal reference significantly improves the accuracy of the quantitative SERS measurements. The successful detection of melamine in milk illustrates the versatility of this detection scheme for a wide variety of analytes. PMID- 25910446 TI - A miniature chemiresistor sensor for carbon dioxide. AB - A carpet-like nanostructure of polyaniline (PANI) nanothin film functionalized with poly(ethyleneimine), PEI, was used as a miniature chemiresistor sensor for detection of CO2 at room temperature. Good sensing performance was observed upon exposing the PEI-PANI device to 50-5000 ppm CO2 in presence of humidity with negligible interference from ammonia, carbon monoxide, methane and nitrogen dioxide. The sensing mechanism relied on acid-base reaction, CO2 dissolution and amine-catalyzed hydration that yielded carbamates and carbonic acid for a subsequent pH detection. The sensing device showed reliable results in detecting an unknown concentration of CO2 in air. PMID- 25910447 TI - Surface plasmon resonance biosensor for highly sensitive detection of microRNA based on DNA super-sandwich assemblies and streptavidin signal amplification. AB - MicroRNAs (miRNAs) play an important regulatory role in cells and dysregulation of miRNA has been associated with a variety of diseases, making them a promising biomarker. In this work, a novel biosensing strategy has been developed for label free detection of miRNA using surface plasmon resonance (SPR) coupled with DNA super-sandwich assemblies and biotin-strepavidin based amplification. The target miRNA is selectively captured by surface-bound DNA probes. After hybridization, streptavidin is employed for signal amplification via binding with biotin on the long DNA super-sandwich assemblies, resulting in a large increase of the SPR signal. The method shows very high sensitivity, capable of detecting miRNA at the concentration down to 9 pM with a wide dynamic range of 6 orders of magnitude (from 1 * 10(-11) M to 1 * 10(-6) M) in 30 min, and excellent specificity with discriminating a single base mismatched miRNA sequence. This biosensor exhibits good reproducibility and precision, and has been successfully applied to the detection of miRNA in total RNA samples extracted from human breast adenocarcinoma MCF-7 cells. It, therefore, offers a highly effective alternative approach for miRNA detection in biomedical research and clinical diagnosis. PMID- 25910448 TI - A novel antibody-antigen based impedimetric immunosensor for low level detection of HER2 in serum samples of breast cancer patients via modification of a gold nanoparticles decorated multiwall carbon nanotube-ionic liquid electrode. AB - A highly sensitive impedimetric immunosensor based on a gold nanoparticles/multiwall carbon nanotube-ionic liquid electrode (AuNPs/MW-CILE) was developed for the determination of human epidermal growth factor receptor 2 (HER2). Gold nanoparticles were used to enhance the extent of immobilization and to retain the immunoactivity of the antibody Herceptin on the electrode. Cyclic voltammetry and electrochemical impedance spectroscopy were employed for characterization of various layers coated onto the AuNPs/MW-CILE. The impedance measurements at different steps were based on the charge transfer kinetics of the [Fe(CN)6](3-/4-) redox pair. The immobilization of antibody and the corresponding antigen-antibody interaction at the electrode surface altered the interfacial electron transfer. The interactions of antibody with various concentrations of antigen were also monitored via the change of impedance response. The results showed that the charge transfer resistance increases linearly with increasing concentrations of HER2 antigen. The linear range and limit of detection were found as 10-110 ng mL(-1) and 7.4 ng mL(-1), respectively. The sensitivity and specificity of the immunosensor were validated. The results showed that the prepared immunosensor is a useful tool for screening of trace amounts of HER2 in serum samples of breast cancer patients. PMID- 25910449 TI - Sensitive CE-MS analysis of potentially genotoxic alkylation compounds using derivatization and electrokinetic injection. AB - A CE-MS method has been developed to detect trace levels of potentially genotoxic alkyl halides. After derivatization of the target components with 4 dimethylaminopyridine (DMAP) or butyl 1-(pyridinyl-4yl) piperidine 4-carboxylate (BPPC), the natively positively charged derivatives are pre-concentrated by applying electrokinetic injection and separated by a highly efficient CZE method using a background electrolyte (BGE) consisting of 100mM of TRIS adjusted to pH 2.5 with phosphoric acid. Using a sheath liquid interface, subsequent MS detection allows highly specific and sensitive analysis of alkyl halides. Conditions for electrokinetic injection were optimized to allow selective and effective injection. Injection of samples with low water content at 10 kV for 150 s using a high concentration of buffer in the BGE resulted in optimum sample stacking during injection and a highly efficient CE separation. At the sample pH applied, neutral and negatively charged components are shown to be selectively discarded, resulting in injection of positively charged ions only. The sample matrix influences the efficiency of the injection, but when using an internal standard, reproducibilities better than 10% RSD are obtained. Relative recoveries of the derivatives spiked to different types of model API between 85 and 115% demonstrate that the method can be applied for quantitative analysis. Detection limits of lower than 1 mg kg(-1) for the tested alkyl halides obtained in CE-MS at least equal the sensitivity obtained in LC-MS. The CE-MS method is a valuable alternative for the LC-MS method used for analysis of alkylation compounds. PMID- 25910450 TI - Development and validation of ultra-high performance supercritical fluid chromatography method for determination of illegal dyes and comparison to ultra high performance liquid chromatography method. AB - A novel simple, fast and efficient ultra-high performance supercritical fluid chromatography (UHPSFC) method was developed and validated for the separation and quantitative determination of eleven illegal dyes in chili-containing spices. The method involved a simple ultrasound-assisted liquid extraction of illegal compounds with tetrahydrofuran. The separation was performed using a supercritical fluid chromatography system and CSH Fluoro-Phenyl stationary phase at 70 degrees C. The mobile phase was carbon dioxide and the mixture of methanol:acetonitrile (1:1, v/v) with 2.5% formic acid as an additive at the flow rate 2.0 mL min(-1). The UV-vis detection was accomplished at 500 nm for seven compounds and at 420 nm for Sudan Orange G, Butter Yellow, Fast Garnet GBC and Methyl Red due to their maximum of absorbance. All eleven compounds were separated in less than 5 min. The method was successfully validated and applied using three commercial samples of chili-containing spices - Chili sauce (Indonesia), Feferony sauce (Slovakia) and Mojo sauce (Spain). The linearity range of proposed method was 0.50-9.09 mg kg(-1) (r >= 0.995). The detection limits were determined as signal to noise ratio of 3 and were ranged from 0.15 mg kg(-1) to 0.60 mg kg(-1) (1.80 mg kg(-1) for Fast Garnet) for standard solution and from 0.25 mg kg(-1) to 1.00 mg kg(-1) (2.50 mg kg(-1) for Fast Garnet, 1.50 mg kg(-1) for Sudan Red 7B) for chili-containing samples. The recovery values were in the range of 73.5-107.2% and relative standard deviation ranging from 0.1% to 8.2% for within-day precision and from 0.5% to 8.8% for between-day precision. The method showed potential for being used to monitor forbidden dyes in food constituents. The developed UHPSFC method was compared to the UHPLC-UV method. The orthogonality of Sudan dyes separation by these two methods was demonstrated. Benefits and drawbacks were discussed showing the reliability of both methods for monitoring of studied illegal dyes in real food constituents. PMID- 25910451 TI - Applicability of Euglena gracilis for biorefineries demonstrated by the production of alpha-tocopherol and paramylon followed by anaerobic digestion. AB - In this study the use of Euglena gracilis biomass for alpha-tocopherol, paramylon and biogas production in a value-added chain was investigated. Therefore, we analyzed the dry cell weight and product concentrations at different growth phases during heterotrophic, photoheterotrophic and photoautotrophic cultivation in a low-cost minimal medium. Furthermore, the specific biogas yields for differently derived biomass with and without product recovery were investigated. We demonstrate that growth phase and cultivation mode not only have a significant impact on product formation, but also influence the yield of biogas obtained from anaerobic digestion of Euglena gracilis biomass. The maximum dry cell weight concentration ranged from 12.3+/-0.14gL(-1) for heterotrophically to 3.4+/ 0.02gL(-1) for photoautotrophically grown Euglena gracilis cells. The heterotrophically grown biomass accumulated product concentrations of 5.3+/ 0.12mgL(-1) of alpha-tocopherol and 9.3+/-0.1gL(-1) of paramylon or 805+/-10.9mL of biogasgvs(-1) (per gram volatile solids). The results for photoautotrophically grown cells were 8.6+/-0.22mgL(-1) of alpha-tocopherol and 0.78+/-0.01gL(-1) of paramylon or 648+/-7.2mL of biogasgvs(-1). For an energy-saving downstream procedure the extracting agent methanol does not have to be removed strictly. Samples with residual methanol showed a significantly increased biogas yield, because the solvent can be used as an additional substrate for methane production by archaebacteria. PMID- 25910452 TI - Unisexual reproduction in Huntiella moniliformis. AB - Sexual reproduction in fungi is controlled by genes present at the mating type (MAT) locus, which typically harbors transcription factors that influence the expression of many sex-related genes. The MAT locus exists as two alternative idiomorphs in ascomycetous fungi and sexual reproduction is initiated when genes from both idiomorphs are expressed. Thus, the gene content of this locus determines whether a fungus is heterothallic (self-sterile) or homothallic (self fertile). Recently, a unique sub-class of homothallism has been described in fungi, where individuals possessing a single MAT idiomorph can reproduce sexually in the absence of a partner. Using various mycological, molecular and bioinformatic techniques, we investigated the sexual strategies and characterized the MAT loci in two tree wound-infecting fungi, Huntiella moniliformis and Huntiella omanensis. H. omanensis was shown to exhibit a typically heterothallic sexual reproductive cycle, with isolates possessing either the MAT1-1 or MAT1-2 idiomorph. This was in contrast to the homothallism via unisexual reproduction that was shown in H. moniliformis, where only the MAT1-2-1 gene was present in sexually reproducing cultures. While the evolutionary benefit and mechanisms underpinning a unisexual mating strategy remain unknown, it could have evolved to minimize the costs, while retaining the benefits, of normal sexual reproduction. PMID- 25910453 TI - Sex differences in unilateral landing mechanics from absolute and relative heights. AB - BACKGROUND: The prevalence of anterior cruciate ligament injuries in athletic populations and the sex disparity in injury rates are well documented. It is also recognized that landing from a jump is a common noncontact injury mechanism. Yet, most studies utilize absolute landing heights, and few have utilized landing heights equal to participants' maximal jumping ability. The purpose of this study was to examine unilateral landing mechanics from relative and absolute heights. METHODS: Twenty-one female and twenty male participants completed a series of landings from absolute heights of 30, 40, and 50cm, as well as a height equal to their maximum jumping ability. Right leg three-dimensional kinematics, kinetics, and energetics were calculated from initial contact to maximum knee flexion. RESULTS: Females landed with greater peak posterior ground reaction force compared to males. Additionally, both female and male participants utilized the knee as the primary energy absorber, but females appear to emphasize greater ankle energy absorption compared to males. Females also displayed increased peak knee adduction moment, while males displayed decreased peak hip abduction moment as landing height increased. CONCLUSIONS: It appears that females and males respond to increasing landing heights differently. However, landings from 40 and 50cm may have represented an unrealistic mechanical demand for females, and influence subsequent inferences regarding ACL injury risk. Therefore, we suggest that comparisons between studies utilizing different landing heights be made with caution, and participants jumping ability be taken into account whenever possible. CLINICAL RELEVANCE: The findings of this study offer novel insights with regard to landing height and lower extremity mechanics with the potential to inform anterior cruciate ligament injury intervention programs. PMID- 25910454 TI - Lymph Node Harvest During Esophagectomy Is Not Influenced by Use of Neoadjuvant Therapy or Clinical Disease Stage. AB - INTRODUCTION: The purpose of this study was to evaluate the effects of neoadjuvant therapy on lymph node harvest (LNH), lymph node ratio (LNR), and overall survival rates after esophagectomy. METHODS: A retrospective analysis of 111 patients who underwent esophagectomy for esophageal adenocarcinoma from 2001 to 2010 was performed. Patients were divided into two groups: neoadjuvant chemoradiotherapy prior to surgery (NEOSURG) versus surgery alone (SURG). RESULTS: There were 83 patients (75%) in the NEOSURG group and 28 (25%) in the SURG group with a mean age of 66 and 67 years, respectively. The median LNH in the NEOSURG group and SURG group was 16.0 and 15.5, respectively (p = 0.57). Within the NEOSURG group, the median LNH was 16 for complete responders, 14 for partial responders, 16 for nonresponders, and 18 in those who were pathologically upstaged (p = 0.434). The median LNR was 0, 0, 0.1, and 0.2, respectively (p < 0.001). Complete response after neoadjuvant therapy demonstrated a trend toward improved survival (p = 0.056). CONCLUSION: The LNH was not significantly influenced by neoadjuvant treatment or pathologic response. The LNR was inversely related to pathologic response after neoadjuvant therapy. Complete pathologic response to neoadjuvant therapy trends to improve survival rates. PMID- 25910455 TI - Comparison of two fluid solutions for resuscitation in a rabbit model of crush syndrome. AB - BACKGROUND: Crush syndrome is a common injury, the main characteristics of which include acute kidney injury. However, there is still lack of reliable animal model of crush syndrome, and it also remains controversial as to which type of fluid should be chosen as a more appropriate treatment option for prevention and treatment of acute kidney injury. METHODS: The rabbits were crushed at the lower limbs for 6 h with 36 times the body weight, which means the pressure of each leg was also 36 times the body weight. Fluid resuscitation was performed from 1 h prior to the end of the crush treatment until 24 h after the reperfusion. Tissue, blood and urine samples were collected at predetermined time points before and after reperfusion. Twelve rabbits in each group were taken for survival observation for 72 h. RESULTS: The model group showed elevated serum creatine kinase, aspartate aminotransferase, alanine aminotransferase, and K(+) level, reduced serum Ca(2+) level and Na(+) level, and increased serum creatinine and blood urea nitrogen levels, neutrophil gelatinase-associated lipocalin, and kidney injury molecule-1 (p < 0.05). The 0.9 % normal saline (SAL) group and SAL plus 6 % hydroxyethyl starch 130/0.4 SAL/HES group showed reduced serum creatinine and blood urea nitrogen levels (p < 0.05). The SAL/HES group also showed reduced serum IL-6 and IL-10 levels (p < 0.05). The 72 h survival rate of the SAL/HES group was higher than that of the model group (p < 0.05). CONCLUSION: The rabbit model of crush syndrome showed clinical features consistent with those of crush syndrome. There was no significant difference in the ability of preventing AKI after a crush injury between the two fluid solutions, while SAL/HES can improve the survival rate. PMID- 25910456 TI - Evaluation of genotoxic effects caused by extracts of chlorinated drinking water using a combination of three different bioassays. AB - Potential genotoxic effects of chlorinated drinking water now are of a great concern. In this study, raw water, finished water, and tap water from a water plant in Wuhan, China were collected in two different sampling times of the year (January and July). Genotoxic effects of water extracts were evaluated using a combination of three different bioassays: SOS/umu test, HGPRT gene mutation assay, and micronucleus assay, which were separately used to detect DNA damage, gene mutation, and chromosome aberration. The results of three different bioassays showed that all water samples in January and July induced at least one types of genotoxic effects, of which the DNA-damage effects were all detectable. The levels of DNA-damage effects and gene-mutation effects of finished water and tap water in January were higher than those in July. Chlorination could increase the DNA-damage effects of drinking water in January and the gene-mutation effects of drinking water in both January and July, but did not increase the chromosome aberration effects of drinking water in both January and July. Our results highlighted the importance of using a combination of different bioassays to evaluate the genotoxicity of water samples in different seasons. PMID- 25910457 TI - Fate of Escherichia coli O157: H7 in agricultural soils amended with different organic fertilizers. AB - Five organic fertilizers (vermicompost, pig manure, chicken manure, peat and oil residue) were applied to agricultural soils to study their effects on the survival of Escherichia coli O157:H7 (E. coli O157:H7). Results showed that E. coli O157:H7 survival changed greatly after organic fertilizers application, with shorter td values (survival time needed to reach the detection limit of 100 CFU g(-1)) (12.57+/-6.57 days) in soils amended with chicken manure and the longest (25.65+/-7.12 days) in soils amended with pig manure. Soil pH, EC and free Fe/Al (hydro) oxides were significant explanatory factors for E. coli O157:H7 survival in the original soils. Soil constituents (minerals and organic matter) and changes in their surface charges with pH increased the effect of soil pH on E. coli O157:H7 survival. However, electrical conductivity played a more important role in regulating E. coli O157:H7 survival in fertilizer-amended soils. This study highlighted the importance of choosing appropriate organic fertilizers in the preharvest environment to reduce food-borne bacterial contamination. PMID- 25910458 TI - The mechanism for degrading Orange II based on adsorption and reduction by ion based nanoparticles synthesized by grape leaf extract. AB - Biomolecules taken from plant extracts have often been used in the single-step synthesis of iron-based nanoparticles (Fe NPs) due to their low cost, environmental safety and sustainable properties. However, the composition of Fe NPs and the degradation mechanism of organic contaminants by them are limited because these are linked to the reactivity of Fe NPs. In this study, Fe NPs synthesized by grape leaf extract served to remove Orange II. Batch experiments showed that more than 92% of Orange II was removed by Fe NPs at high temperature based on adsorption and reduction and confirmed by kinetic studies. To understand the role of Fe NPs in the removal process of azo dye, surface analysis via X-ray photoelectron spectroscopy (XPS) and transmission electron microscopy (TEM) were employed, showing that the Fe NPs were composed of biomolecules, hydrous iron oxides and Fe(0), thus providing evidence for the adsorption of Orange II onto hydrous iron oxides and its reduction by Fe(0). Degraded products such as 2 naphthol were identified using LC-MS analysis. A degradation mechanism based on asymmetrical azo bond cleavage for the removal of Orange II was proposed. PMID- 25910459 TI - Evaluating drug delivery with salt formation: Drug disproportionation studied in situ by ATR-FTIR imaging and Raman mapping. AB - Two different vibrational spectroscopic approaches, ATR-FTIR spectroscopic imaging and Raman mapping, were used to investigate the components within a tablet containing an ionised drug during dissolution experiments. Delivering certain drugs in their salt form is a method that can be used to improve the bioavailability and dissolution of the poorly aqueous soluble materials. However, these ionised species have a propensity to covert back to their thermodynamically favourable free acid or base forms. Dissolution experiments of the ionised drug in different aqueous media resulted in conversion to the more poorly soluble free acid form, which is detrimental for controlled drug release. This study investigates the chemical changes occurring to formulations containing a development ionised drug (37% by weight), in different aqueous pH environments. Firstly, dissolution in a neutral medium was studied, showing that there was clear release of ionised monosodium form of the drug from the tablet as it swelled in the aqueous medium. There was no presence of any drug in the monohydrate free acid form detected in these experiments. Dissolution in an acidic (0.1M HCl) solution showed disproportionation forming the free acid form. Disproportionation occurred rapidly upon contact with the acidic solution, initially resulting in a shell of the monohydrate free acid form around the tablet edges. This slowed ingress of the solution into the tablet before full conversion of the ionised form to the free acid form was characterised in the spectroscopic data. PMID- 25910460 TI - Cardioprotective effect of linseed oil against isoproterenol-induced myocardial infarction in Wistar rats: a biochemical and electrocardiographic study. AB - The present study was designed to evaluate the cardioprotective effect of Tunisian flaxseed oil (Linum usitatissimum) against isoproterenol-induced myocardial infarction in rats by studying hypertensive and cardiac damage markers especially electrocardiographic changes and troponin T serum level. In vitro, the extracted oil showed an important inhibition of angiotensin converting enzyme (ACE) with an IC50 = 85.96 MUg/ml. According to chemical analysis, this extract is composed essentially of alpha linolenic acid (ALA), an n-3 polyunsaturated fatty acid (58.59 %). Male rats were randomly divided into three groups, namely control (C), isoproterenol (ISO), and isoproterenol-treated group with flaxseed oil (FO + ISO). Isoproterenol injection showed changes in ECG pattern, including ST-segment elevation (diagnostic of myocardial infarction), increase in the serum levels of Troponin T and cardiac injury markers (creatine kinase-MB (CK-MB), lactate dehydrogenase (LDH), alkaline phosphatase (ALP), aspartate transaminase (AST), and alanine transaminase (ALT)). However, Linum oil pre-co-treatment prevented almost all the parameters isoproterenol-induced myocardial infarction in rats. Results of the present study proved that flaxseed oil has a significant effect by heart protection against isoproterenol-induced myocardial infarction through beneficial effect of the important fraction of ALA. PMID- 25910461 TI - A dominance shift from the zebra mussel to the invasive quagga mussel may alter the trophic transfer of metals. AB - Bioinvasions are a major cause of biodiversity and ecosystem changes. The rapid range expansion of the invasive quagga mussel (Dreissena rostriformis bugensis) causing a dominance shift from zebra mussels (Dreissena polymorpha) to quagga mussels, may alter the risk of secondary poisoning to predators. Mussel samples were collected from various water bodies in the Netherlands, divided into size classes, and analysed for metal concentrations. Concentrations of nickel and copper in quagga mussels were significantly lower than in zebra mussels overall. In lakes, quagga mussels contained significantly higher concentrations of aluminium, iron and lead yet significantly lower concentrations of zinc66, cadmium111, copper, nickel, cobalt and molybdenum than zebra mussels. In the river water type quagga mussel soft tissues contained significantly lower concentrations of zinc66. Our results suggest that a dominance shift from zebra to quagga mussels may reduce metal exposure of predator species. PMID- 25910462 TI - Short-term soil bioassays may not reveal the full toxicity potential for nanomaterials; bioavailability and toxicity of silver ions (AgNO3) and silver nanoparticles to earthworm Eisenia fetida in long-term aged soils. AB - This study investigated if standard risk assessment hazard tests are long enough to adequately provide the worst case exposure for nanomaterials. This study therefore determined the comparative effects of the aging on the bioavailability and toxicity to earthworms of soils dosed with silver ions and silver nanoparticles (Ag NP) for 1, 9, 30 & 52 weeks, and related this to the total Ag in the soil, Ag in soil pore water and earthworm tissue Ag concentrations. For ionic Ag, a classical pattern of reduced bioavailability and toxicity with time aged in the soil was observed. For the Ag NP, toxicity increased with time apparently driven by Ag ion dissolution from the added Ag NPs. Internal Ag in the earthworms did not always explain toxicity and suggested the presence of an internalised, low-toxicity Ag fraction (as intact or transformed NPs) after shorter aging times. Our results indicate that short-term exposures, without long term soil aging, are not able to properly assess the environmental risk of Ag NPs and that ultimately, with aging time, Ag ion and Ag NP effect will merge to a common value. PMID- 25910463 TI - Analysis of age, refractive error and gender related changes of the cornea and the anterior segment of the eye with Scheimpflug imaging. AB - PURPOSE: To assess age, refractive error and gender related changes occurring in the cornea and the anterior segment of the eye using a Scheimpflug system. METHODS: The study included 666 healthy eyed subjects with a mean age of 39.3+/ 19.7 years (range: 3-85 years). All analyses were based on the right eyes of the patients as all measured parameters correlated well between the right and left eyes. Each parameter was correlated with age and the right eye's spherical equivalent (SE) using Pearson correlations. Univariate linear regression models were constructed for analyses of parameters. RESULTS: The anterior corneal surface asphericity showed significant positive correlations whereas posterior corneal surface asphericity showed significant negative correlations with age. Anterior chamber depth (ACD), volume (ACV) and angle (ACA) showed significant negative correlations with age and SE. Age explained 25% of the variance in anterior corneal surface asphericity, 22% of variance in posterior corneal surface asphericity, 26% of variance in ACV, 27% of variance in ACD, and 19% of variance in ACA. In the SE model SE was identified to account for 25% of variance in ACV, 22% of variance in ACD, each, and 17% of variance in ACA. Significant differences were detected in anterior and posterior keratometry values, ACV, ACD and ACA among gender groups (p<0.01). CONCLUSIONS: The cornea shows a tendency for a decrease in anterior corneal surface asphericity and an increase in posterior corneal surface asphericity with advancing age. Men have flatter corneas and women have shallower anterior chambers and narrower anterior chamber angles. PMID- 25910464 TI - Contact lens management of irregular corneas after traumatic aphakia: A pediatric case series. AB - PURPOSE: Pediatric patients account for 35% of all cases that present after ocular trauma and 20.9% of those result in a ruptured globe. When repairing the globe, the removal of the natural lens results in a significant change in refractive error and loss of accommodation. In addition, the eye can have scarring, irregular astigmatism, and changes to the ocular surface. Treatment and vision rehabilitation should be aggressive and done quickly to prevent amblyopia. Advanced lens designs are often needed to treat both the irregular ocular surface and the aphakia. Treatment options are often confounded with the usual issues of contact lens compliance, intolerance, and complications. CASE REPORT: This case series follows three aphakic pediatric patients through the contact lens fitting process after sustaining a ruptured globe that left them aphakic with residual irregular astigmatism and corneal scarring. Patient 1 is a 3-year-old Hispanic male fit with a bitoric gas permeable contact lens with irregular astigmatism and an elevated central corneal scarring. Patient 2 is a 12-year-old Caucasian male with minimal residual astigmatism fit in a multifocal soft contact lens. Patient 3 is an 8-year-old African American male fit with a hybrid contact lens that was needed to vault the irregular astigmatism and central corneal scarring. CONCLUSIONS: Treating patients with irregular corneas or aphakia can be challenging in their own right, but in combination are some of the most advanced specialty contact lens fittings. This case series followed three pediatric patients through the fitting process and demonstrated the options and challenges when fitting this unique patient population. PMID- 25910465 TI - Improving the environment for weaned piglets using polypropylene fabrics above the animals in cold periods. AB - This study aimed at evaluating the use of polypropylene fabrics in weaned pig facilities (5-10 weeks of age) during the winter period to improve thermal environment and energy saving for heating. Two experiments were conducted to validate the effects of fabrics (F) compared to control (C) in three 2-week periods using natural ventilation (assay 1, 2013) and forced ventilation (assay 2, 2014). Air temperature was greater in F than in C compartments in both years, particularly during the first 2-week periods (2 degrees C of mean difference). Natural ventilation was not enough to maintain relative humidity levels below 70 % at the end of the postweaning period (9-10 weeks of age) in both groups (F and C), whereas forced ventilation allowed controlling daily mean relative humidity levels <60 %. About 12-26 % of the radiant heat was transmitted through the fabrics cover, depending on the wavelength. There were no differences on growth performance of piglets in the two compartments in both years. The use of polypropylene fabrics was associated with a significant electric energy saving for heating during the first (data available only in 2014) and second 2-week period in both years. In conclusion, polypropylene fabrics may be an interesting tool to provide optimal environmental conditions for weaned piglets in winter, especially during the two first weeks after weaning. Their transmittance properties allow trapping infrared emission produced by the piglets and heating, avoiding heat losses through the roof, and therefore saving heating energy. PMID- 25910466 TI - Raising trophy kids: The role of mothers' contingent self-esteem in maternal promotion of extrinsic goals. AB - This study examined the role of mothers' child-invested contingent self-esteem, that is, their tendency to hinge their self-worth on their child's achievements, in maternal promotion of extrinsic goals, as perceived by adolescents. It was also examined whether maternal promotion of extrinsic goals would, in turn, relate to adolescents' Social Dominance Orientation (SDO). Participants were 184 mothers and their adolescent children (66% female). Maternal child-invested contingent self-esteem predicted adolescent-perceived maternal promotion of extrinsic goals, even when taking into account the variance shared between the promotion of extrinsic goals and mothers' use of a controlling parenting style. Maternal child-invested contingent self-esteem also moderated associations between mothers' personal pursuit of extrinsic goals and their promotion of those goals, such that the association between mothers' own extrinsic goals and their promotion of those goals was significant only among mothers high on child invested contingent self-esteem. Maternal promotion of extrinsic goals was, in turn, related to adolescent SDO, suggesting that the dynamics examined in this study ultimately relate to adolescents' social and ideological development. PMID- 25910467 TI - Sedentary behavior, depressed affect, and indicators of mental well-being in adolescence: Does the screen only matter for girls? AB - The study investigated the effects of sedentary behavior (SB) on mental well being and examined differences between screen-based (sSB) and non-screen-based sedentary behaviors (nSB) separately by gender. In a total sample of 1296 students (609 girls) aged 12-17 (m = 13.7, SD = 0.67), SB, depressed affect, self esteem, physical self-concept, general self-efficacy and physical activity were assessed through self-administered questionnaires. Among girls, lower scores in self-esteem, physical self-concept as well as general self-efficacy were associated with higher sSB but not nSB. Among boys higher levels of sSB related to higher self-esteem, nSB but not sSB predicted higher scores in depressed affect, and there was a u-shaped association between sSB and general self efficacy. Results replicate the inverse association between SB and mental well being, and suggest a distinction between nSB and sSB especially among girls. Additional studies will be necessary to replicate, and further examine mediating mechanisms. PMID- 25910468 TI - Adolescents' beliefs about the fairness of exclusion of peers with mental health problems. AB - Stigma research suggests that exclusion of peers with mental health problems is acceptable, however, no research has explored young people's beliefs about the fairness of exclusion. Group interviews with 148 adolescents explored judgements about the fairness of excluding peers with ADHD or depression from dyads and groups. Young people evaluated exclusion of peers with ADHD or depression from dyads and groups, with the exception of group exclusion of the peer with ADHD, as mostly unfair. Beliefs about the fairness of exclusion were influenced by the attributions that they applied to the target peer's behaviour, social obligations and loyalty within friendships and concerns about the adverse psychological effects of exclusion. Furthermore, their evaluations were influenced by personal beliefs about the social and personal costs of including the target peer. Evaluations of exclusion highlight novel avenues for to develop knowledge on the stigma of mental health problems. PMID- 25910469 TI - Kidney retransplantation for BK virus nephropathy with active viremia without allograft nephrectomy. AB - BK virus nephropathy is an important cause of kidney allograft failure. Retransplantation has been successfully performed for patients with previous allograft loss due to BK virus nephropathy; however, whether allograft nephrectomy and viral clearance are required prior to retransplantation is controversial. Some recent studies have suggested that retransplantion can be successfully achieved without allograft nephrectomy if viremia is cleared prior to retransplant. The only published experience of successful retransplantation in the presence of active viremia occurred in the presence of concomitant allograft nephrectomy of the failing kidney. In this report, we describe a case of successful repeat kidney transplant in a patient with high-grade BK viremia and fulminant hepatic failure without concomitant allograft nephrectomy performed under the setting of a simultaneous liver-kidney transplant. PMID- 25910470 TI - Management of stroke prevention in Bulgarian patients with non-valvular atrial fibrillation (BUL-AF Survey). PMID- 25910471 TI - Diastolic dysfunction in controlled hypertensive patients with mild-moderate obstructive sleep apnea. AB - BACKGROUND: Hypertension and severe obstructive sleep apnea (OSA) may independently contribute to left ventricular diastolic dysfunction. However, scanty data is available on this issue in hypertensives with mild-moderate OSA. METHODS AND RESULTS: We performed polysomnography, echocardiography and 24h ambulatory blood pressure monitoring in 115 treated essential hypertensives with suspicion of OSA. After exclusion of severe/treated OSA and/or cardiovascular disease patients, mild-moderate OSA (5 <= apnoea/hypopnoea index<30 events.h(-1)) was diagnosed in 47.3% of the remaining 91 patients, while 52.7% were free of OSA. Transmitral early (E) and late (A) peak flow velocities were assessed in 69 patients, and mitral annular velocity (E') in 53. Compared to non-OSA, mild moderate OSA heart rate was higher (p=0.031) while E/A was lower (p<0.001) without differences in 24h mean systolic and diastolic blood pressures (125.36 +/ 12.46/76.46 +/- 6.97 vs 128.63 +/- 11.50/77.70 +/- 7.72 mmHg, respectively, NS). Patients with E'< 10 cm/s and E/A<0.8 showed a lower mean SpO2 than subjects with normal diastolic function (p=0.004; p<0.001). In a logistic regression model age, mean SpO2, daytime heart rate and nocturnal diastolic blood pressure fall were associated with altered relaxation pattern, independently from BMI and gender. CONCLUSIONS: In controlled hypertensives mild-moderate OSA may be associated with early diastolic dysfunction, independently from age, gender and mean blood pressure and in the absence of concentric left ventricular hypertrophy. Moreover nocturnal hypoxia may be a key factor in determining early diastolic dysfunction, under the synergic effects of hypertension and mild-moderate OSA. PMID- 25910473 TI - Comparative Usability Study of a Novel Auto-Injector and an Intranasal System for Naloxone Delivery. AB - INTRODUCTION: The standard of care for reversal of opioid-induced respiratory depression associated with opioid overdose is injectable naloxone. This study compared the usability of two naloxone delivery devices, a naloxone auto-injector (NAI) and a naloxone intranasal delivery system (NXN), in the administration of naloxone during a simulated opioid overdose emergency. NAI (EVZIO ((r)) ; kaleo, Inc., Richmond, VA, USA) is a Food and Drug Administration approved single-use pre-filled auto-injector containing 0.4 mg of naloxone. METHODS: Study participants were randomly assigned to administer naloxone using NAI and NXN, sequentially. The primary endpoint was successful administration of a simulated dose of naloxone into a mannequin during a simulated opioid emergency, both before and after receiving training. Secondary endpoints included using the NAI or NXN in accordance with the instructions-for-use and the comparative measurement of successful completion time of administration for both NAI and NXN. RESULTS: A total of 42 healthy participants aged 18-65 years were enrolled in the study. The proportion of participants able to successfully administer a simulated dose of naloxone was significantly greater for NAI compared to NXN both before (90.5% vs. 0.0%, respectively, P < 0.0001) and after (100% vs. 57.1%, respectively, P < 0.0001) participant training. The proportion of participants able to administer a simulated dose of naloxone in accordance with the instructions-for-use was also significantly greater for NAI compared to NXN before (85.7% vs. 0.0%, respectively, P < 0.0001) and after (100% vs. 0.0%, respectively, P < 0.0001) participant training. The average time to task completion for administration attempt before training was 0.9 +/- 0.25 min for NAI versus 6.0 +/- 4.76 min for NXN and after training was 0.5 +/- 0.15 min for NAI versus 2.0 +/- 2.15 min for NXN. CONCLUSION: Laypersons experienced substantially greater success administering a simulated dose of naloxone, both before and after training, using NAI versus NXN during a simulated opioid overdose emergency. No participants correctly used NXN without training. PMID- 25910472 TI - Clinical outcomes of zirconia-based implant- and tooth-supported single crowns. AB - OBJECTIVES: Zirconia-based restorations have been increasingly used on implant and teeth abutments, but the evidence about clinical outcomes of these restorations is limited. The aim of this study was to assess up to 7-year clinical outcomes of implant- and tooth-supported zirconia-based single crowns. MATERIALS AND METHODS: In this retrospective study, 261 patients with 556 single crowns supported by either teeth (324) or implants (232) were examined during 3- to 7-year follow-up (mean observation of 60.70 months for tooth and 59.20 months for implant-supported crowns). California Dental Association (CDA) quality evaluation system was used to evaluate the restorations. Soft tissue status was assessed using plaque and gingival index scores, bleeding on probing, and pocket depth. Patient and professional satisfaction were evaluated by visual analog scale (VAS). RESULTS: The 5-year Kaplan-Meier survival probability was 98.3 and 97.3 for implant- and tooth-supported crowns, respectively. In regard to CDA rating, most of the crowns were ranked as either excellent or acceptable (99.5 %). The recorded failures were replacement of the crown due to porcelain chipping (3), implant failure (1), and teeth extraction (5). Soft tissue parameters were not affected by the restorations compare to control teeth. The VAS was high for both patients and clinicians. CONCLUSIONS: Zirconia-based single crowns on both tooth and implant abutments showed promising clinical performance in this up to 7 year follow-up. CLINICAL RELEVANCE: The zirconia-based single crowns can be used clinically for tooth- and implant-supported restorations. PMID- 25910474 TI - Comparative analysis of cytokine release from epithelial cell cultures of the upper airway. AB - INTRODUCTION: Upper airway epithelial cells show a multi-potential ability to produce a variety of cytokines/chemokines in the steady-state and under external stimuli. OBJECTIVE: To compare various cytokines/chemokines released from primary cultures of human nasal epithelial cells (HNECs) derived from healthy controls and subjects with allergic rhinitis (AR), chronic rhinosinusitis with nasal polyps (CRSwNPs) in non- stimulated and IL-17A-stimulated conditions. METHODS: The supernatants derived from HNECs of healthy control, AR, CRSwNPs were used to measure 20 of cytokines/chemo- kines in the non-stimulated and IL-17A-stimulated conditions. RESULTS: AR and CRSwNPs showed significant up-regulation in the release of IL-6, IL-33, and thymic stromal lymphopoietin (TSLP), and the release of IL-6, TSLP, granulocyte macrophage colony-stimulating factor (GM-CSF), and tumor necrosis factor alpha (TNFalpha) in comparison with normal controls, respectively. Secretion of GM-CSF and TNFalpha were enhanced in patients with nasal polyps as compared with AR. Stimulation with IL-17A enhanced the secretion of IL-8 and granulocyte-colony stimulating factor (G-CSF) in the normal control, IL-6 and IL-8 in AR, and IL-6, TSLP, G-CSF, GM-CSF and TNFalpha in nasal polyps. CONCLUSION: Epithelial cells derived from AR and CRSwNPs showed up-regulation of secretion of several cytokines/chemokines both in the steady state and after IL 17A stimulation, which may contribute to the inflammatory responses of AR and CRSwNPs. PMID- 25910475 TI - Electrophysiological function of the retina and optic nerve in patients with atrial fibrillation. AB - PURPOSE: To evaluate the effects of atrial fibrillation (AF) and ablation procedures on electrophysiological function in the retina and optic nerve. METHODS: Thirty two eyes of 17 patients with AF were analyzed. The full-field electroretinogram (ERG), pattern electroretinogram (PERG) and pattern visual evoked potential (PVEP) were performed. The results were compared to age-matched healthy controls (n = 30). In 12 eyes, electrophysiological tests were performed before and 3 months after ablation treatment. RESULTS: Statistically significant differences between AF patients and healthy controls were detected. In the full field ERG, a reduction in the oscillatory potentials wave index (OPs WI; p = 0.012) and scotopic (0 dB) a-wave amplitude (p = 0.009) was observed. The amplitude of b-waves, scotopic (24 dB; p = 0.011), photopic single flash (p = 0.008) and photopic flicker (p = 0.009), was decreased. The photopic flicker b wave peak time was increased (p = 0.005). Other parameters of ERG/PERG/PVEP did not differ significantly from controls. After the ablation procedure, the only statistically significant change was an increase in the OPs WI (p = 0.002). CONCLUSIONS: In the analyzed series of AF patients, retinal dysfunction was detected in the ERG test. The AF ablation may improve the retinal function as indicated by an increase in the OPs WI. The OPs WI has a potential value in the estimation of the effectiveness of AF ablation. PMID- 25910476 TI - Is vaginal mucosal graft the excellent substitute material for urethral reconstruction in female-to-male transsexuals? AB - PURPOSE: Construction of a neourethra is always considered to be a difficult part in phalloplasty, especially for the female-to-male (FTM) transsexual patients. We report our experience with prefabricated pars pendulans urethrae using vaginal mucosal graft for phalloplasty in FTM transsexuals. MATERIALS AND METHODS: We retrospectively reviewed notes on the 22 FTM patients treated with pedicled-flap phalloplasty with prefabricated pars pendulans urethrae using vaginal mucosal graft between January 2008 and December 2012. Surgical outcome, urological function, and complications were recorded. Histological difference between normal mucosa and skin, and pathological changes of vaginal mucosal graft were also observed. RESULTS: All the reconstructive penis survived, and patients could void in a standing position finally at a median follow-up of 25.4 +/- 6.0 months. Urethral fistula and urethral stricture rates were 31.8 % (7/22 patients) and 4.5 % (1/22 patients), respectively. The occurrence of the urethral stricture was remarkably low compared with previous reports. Our histological results also showed a pronounced similarity between vaginal and buccal mucosa. Morphologically, they resembled urethral epithelium more closely than the forearm skin. Following the free transfer, the vaginal mucosal graft also showed a good revascularization and the inflammatory reaction and the extent of fibrosis of the mucosa decreased to the normal level after a 6-month prefabrication. CONCLUSION: With prefabrication of vaginal mucosal graft, we reconstruct a competent phallic neourethra in these FTM transsexuals. According to its histological similarities and source character, the vaginal mucosa is the excellent substitute material for promising urethral reconstruction in FTM transsexuals. PMID- 25910477 TI - An evaluation of the timing of surgical complications following nephrectomy: data from the American College of Surgeons National Surgical Quality Improvement Program (ACS-NSQIP). AB - PURPOSE: The rates of complications following radical/partial nephrectomy (RN/PN) are well known; however, the data regarding timing are opaque. Accordingly, we sought to assess the median time-to-event for 19 principal postoperative complications within 30 days following surgery. METHODS: Patients undergoing RN/PN were identified within the American College of Surgeons National Surgical Quality Improvement Program database (2005-2011). Primary endpoint was time-to complication. Secondary endpoints included length-of-stay (LOS), re-intervention, re-admission and 30-day mortality. Multivariable regression models assessed the predictors for pre-/post-discharge complications and the effect of time-to complication on secondary outcomes. RESULTS: Overall, 3820 patients underwent nephrectomy (RN = 63.6 %). The overall complication rate was 16.8 %, and the median LOS was 4 days. The majority of major complications (88.1 %), including bleeding/transfusion, renal, septic, deep venous thrombosis or pulmonary embolism, pulmonary, cardiac and neurologic, occurred prior to discharge. Conversely, the relatively minor complications, including wound and urinary tract infections, occurred predominantly post-discharge (70.7 %). The median time to major complications was 3 versus 13 days for minor complications. In multivariable analyses, age [odds ratio (OR) 1.02, p < 0.001], American Society of Anesthesiologists score >= 2 (p < 0.01) and PN (p < 0.001) were predictors of pre-discharge complications, while female gender (OR 1.67, p < 0.001), hypertension (OR 1.28, p = 0.007) and diabetes (OR 1.48, p < 0.001) were predictors of post-discharge complications. Creatinine >= 1.2 mg/dl and hematocrit < 30 increased (p < 0.01), whereas a minimally invasive approach decreased the odds (p < 0.05) for both pre-/post-discharge complications. For a given complication, time-to-complication did not affect the odds for mortality (p = 0.343) or re-intervention (p = 0.872). CONCLUSIONS: Approximately one in six patients suffers a complication following RN/PN; major complications tend to occur early with the majority occurring pre-discharge. Knowledge regarding the timing and risk factors for complications may facilitate improved patient physician communication, both at admission and at discharge. PMID- 25910479 TI - Critical appraisal of clinical practice guidelines in pediatric infectious diseases. AB - BACKGROUND: There is a need to critically appraise clinical practice guidelines in order to ensure safe and effective practices are being implemented to optimize patient care. Appraising guidelines within one therapeutic area enable recommendations for improvement during guideline creation and dissemination. OBJECTIVES: Study objectives were to systematically appraise selected published guidelines used in the treatment of pediatric infectious diseases and to make recommendations for improvement throughout the development and dissemination processes. SETTING: The study occurred between collaborative academic and practice-based institutions located in Canada and Qatar. METHODS: A literature search identified guidelines for management of pediatric infectious diseases from 1997 to 2013. Each guideline was appraised by four independent assessors, according to the appraisal of guidelines for research and evaluation II (AGREE II) instrument. Standardized domain scores were calculated for each guideline and pooled. Final endorsements for use in clinical practice were also determined. Inter-rater reliability was assessed using intraclass correlation coefficients. MAIN OUTCOME MEASURE: Standardized domain scores according to the AGREE II instrument. RESULTS: Twenty guidelines met inclusion criteria and were appraised. Pooled domain scores were: scope and purpose (69.9), stakeholder involvement (40.1), rigour of development (47.1), clarity of presentation (73.4), applicability (23.7), editorial independence (46.7), and overall assessment (55.8). Two (10%) guidelines were recommended for use without revision, 13 (65%) guidelines were recommended with modifications, and 5 (25%) guidelines were not recommended for implementation into practice. Inter-rater reliability was moderate to good with intra-class correlations of 0.65-0.93 per guideline. CONCLUSION: The majority of appraised guidelines were moderately rated, with a 25% of guidelines not recommended for use. Strategies for improvement require the involvement of all key stakeholders (caregivers, patients, and allied health professionals), and consideration of facilitators, barriers and resource implications during implementation. Additionally, critical appraisal of guidelines should become standard practice prior to adoption into clinical settings. PMID- 25910478 TI - En bloc resection of urothelium carcinoma of the bladder (EBRUC): a European multicenter study to compare safety, efficacy, and outcome of laser and electrical en bloc transurethral resection of bladder tumor. AB - PURPOSE: En bloc resection of bladder tumors (ERBT) may improve staging quality and perioperative morbidity and influence tumor recurrence. This study was designed to evaluate the safety, efficacy, and recurrence rates of electrical versus laser en bloc resection of bladder tumors. METHODS: This European multicenter study included 221 patients at six academic hospitals. Transurethral ERBT was performed with monopolar/bipolar current or holmium/thulium laser energy. Staging quality measured by detrusor muscle involvement, various perioperative parameters, and 12-month follow-up data was analyzed. RESULTS: Electrical and laser ERBT were used to treat 156 and 65 patients, respectively. Median tumor size was 2.1 cm; largest tumor was 5 cm. Detrusor muscle was present in 97.3 %. A switch to conventional TURBT was significantly more frequent in the electrical ERBT group (26.3 vs. 1.5 %, p < 0.001). Median operation duration (25 min), postoperative irrigation (1 day), catheterization time (2 days), and hospitalization (3 days) were similar. Overall complication rate was low (Clavien >= 3, n = 6 [2.7 %]). Hemoglobin was significantly lower after electrical ERBT (p = 0.0013); however, overall hemoglobin loss was not clinically relevant (0.38 g/dl). Patients (n = 148) were followed for 12 months; 33 (22.3 %) had recurrences. In total, 63.6 % recurrences occurred outside the ERBT resection field. No difference was noted between ERBT groups. CONCLUSIONS: ERBT is safe and reliable regardless of the energy source and provides high-quality resections of tumors >1 cm. Recurrence rates did not differ between groups, and the majority of recurrences occurred outside the ERBT resection field. PMID- 25910480 TI - Efficiency of adalimumab, etanercept and infliximab in ankylosing spondylitis in clinical practice. AB - BACKGROUND: Information on the use of ankylosing spondylitis (AS) therapies in clinical practice is a key factor in decision making, as more efficient treatments may involve substantial savings while maintaining the clinical benefits for the patient. OBJECTIVE: To assess the mean annual doses and associated costs of the three main anti-tumour necrosis factor agents used in Spanish daily clinical practice in ankylosing spondylitis patients and to correlate these costs with disease activity. SETTING: This retrospective, observational study included adult ankylosing spondylitis patients over a 4-year period that had been treated for at least 6 months with adalimumab, etanercept or infliximab at two University Hospitals in Spain. METHODS: Disease activity was estimated with Bath Ankylosing Spondylitis Disease Activity Index (BASDAI) scores at the start of anti-tumour necrosis factor (anti-TNF) therapy and in the last visit or whenever the drug was switched. Mean costs were estimated for a 52-week horizon from the delivered doses registered by pharmacy records. Outcomes were the doses and costs of anti TNFs administered to each patient, and the BASDAI score. RESULTS: A total of 119 patients (137 cases) were included (28 cases treated with adalimumab, 48 cases with etanercept and 61 with infliximab). Mean doses of adalimumab and etanercept were 92.8 and 88.8% of the initially prescribed doses, respectively, while the mean dose of infliximab administered was 102%. There were no statistical differences among treatments in terms of clinical effectiveness. Associated mean patient-year costs were significantly higher in the infliximab group (?14,235), compared to the other treatments [adalimumab ?11,934; etanercept ?10,516; (P < 0.05)]. CONCLUSION: In certain ankylosing spondylitis patients, doses and associated costs of biological therapies can be reduced while controlling disease activity. Mean doses used in our clinical practice vary from the recommended doses and are significantly lower for adalimumab and etanercept than for infliximab. These differences impact directly on associated patient-year costs, and, thus, on treatment efficiency. PMID- 25910481 TI - Polyomavirus interaction with the DNA damage response. AB - Viruses are obligate intracellular parasites that subvert cellular metabolism and pathways to mediate their own replication-normally at the expense of the host cell. Polyomaviruses are a group of small DNA viruses, which have long been studied as a model for eukaryotic DNA replication. Polyomaviruses manipulate host replication proteins, as well as proteins involved in DNA maintenance and repair, to serve as essential cofactors for productive infection. Moreover, evidence suggests that polyomavirus infection poses a unique genotoxic threat to the host cell. In response to any source of DNA damage, cells must initiate an effective DNA damage response (DDR) to maintain genomic integrity, wherein two protein kinases, ataxia telangiectasia mutated (ATM) and ATM- and Rad3-related (ATR), are major regulators of DNA damage recognition and repair. Recent investigation suggests that these essential DDR proteins are required for productive polyomavirus infection. This review will focus on polyomaviruses and their interaction with ATM- and ATR-mediated DNA damage responses and the effect of this interaction on host genomic stability. PMID- 25910482 TI - Recent advances in the study of HPV-associated carcinogenesis. AB - Human papillomaviruses (HPVs) cause virtually all cervical cancers, the second leading cause of death by cancer among women, as well as other anogenital cancers and a subset of head and neck cancers. Approximately half of women, who develop cervical cancer die from it. Despite the optimism that has accompanied the introduction of prophylactic vaccines to prevent some HPV infections, the relatively modest uptake of the vaccine, especially in the developing world, and the very high fraction of men and women who are already infected, means that HPV associated disease will remain as a significant public health problem for decades. In this review, we summarize some recent findings on HPV-associated carcinogenesis, such as miRNAs in HPV-associated cancers, implication of stem cells in the biology and therapy of HPV-positive cancers, HPV vaccines, targeted therapy of cervical cancer, and drug treatment for HPV-induced intraepithelial neoplasias. PMID- 25910484 TI - Rural-Urban Differences in Colorectal Cancer Screening Barriers in Nebraska. AB - Nebraska ranks 36th nationally in colorectal cancer screening. Despite recent increases in CRC screening rates, rural areas in Nebraska have consistently shown lower rates of CRC screening uptake, compared to urban areas. The objective of this study was to investigate reasons for lower CRC screening rates among Nebraska residents, especially among rural residents. We developed a questionnaire based on Health Belief Model (HBM) constructs to identify factors associated with the use of CRC screening. The questionnaire was mailed in 2014 to adults aged 50-75 years in an urban community in the east and a rural community in the west regions of the state. Multiple logistic regression models were created to assess the effects of HBM constructs, rural residence, and demographic factors on CRC screening use. Of the 1200 surveys mailed, 393 were returned (rural n = 200, urban n = 193). Rural respondents were more likely to perceive screening cost as a barrier. Rural residents were also more likely to report that CRC cannot be prevented and it would change their whole life. In multiple regression models, rural residence, perceived embarrassment, and perceived unpleasantness about screening were significantly associated with reduced odds of receiving colonoscopy. Older age (62 years and older), having a personal doctor, and perceived risk of getting CRC were significantly associated with increased odds of receiving colonoscopy. Interventions to increase uptake of colorectal cancer screening in rural residents should be tailored to acknowledge unique perceptions of screening methods and barriers to screening. PMID- 25910483 TI - The role of Epstein-Barr virus infection in the pathogenesis of nasopharyngeal carcinoma. AB - Nasopharyngeal carcinoma (NPC) is closely associated with Epstein-Barr virus (EBV) infection. EBV episomes are detected in almost all NPC cells. The role of EBV in NPC pathogenesis has long been postulated but remains enigmatic. In contrast to infection of B lymphocytes, EBV infection does not directly transform nasopharyngeal epithelial cells into proliferative clones with malignant potential. EBV infection of normal pharyngeal epithelial cells is predominantly lytic in nature. Genetic alterations in premalignant nasopharyngeal epithelium, in combination with inflammatory stimulation in the nasopharyngeal mucosa, presumably play essential roles in the establishment of a latent EBV infection in infected nasopharyngeal epithelial cells during the early development of NPC. Establishment of latent EBV infection in premalignant nasopharyngeal epithelial cells and expression of latent viral genes, including the BART transcripts and BART-encoded microRNAs, are crucial features of NPC. Expression of EBV genes may drive further malignant transformation of premalignant nasopharyngeal epithelial cells into cancer cells. The difficulties involved in the establishment of NPC cell lines and the progressive loss of EBV epsiomes in NPC cells propagated in culture strongly implicate the contribution of host stromal components to the growth of NPC cells in vivo and maintenance of EBV in infected NPC cells. Defining the growth advantages of EBV-infected NPC cells in vivo will lead to a better understanding of the contribution of EBV infection in NPC pathogenesis, and may lead to the identification of novel therapeutic targets for NPC treatment. PMID- 25910485 TI - Corner Store Purchases in a Low-Income Urban Community in NYC. AB - We assessed purchases made, motivations for shopping, and frequency of shopping at four New York City corner stores (bodegas). Surveys and purchase inventories (n = 779) were collected from consumers at four bodegas in Bronx, NY. We use Chi square tests to compare types of consumers, items purchased and characteristics of purchases based on how frequently the consumer shops at the specific store and the time of day the purchase was made. Most consumers shopped at the bodega because it was close to their home (52 %). The majority (68 %) reported shopping at the bodega at least once per day. The five most commonly purchased items were sugary beverages, (29.27 %), sugary snacks (22.34 %), coffee, (13.99 %), sandwiches, (13.09 %) and non-baked potato chips (12.2 %). Nearly 60 % of bodega customers reported their purchase to be healthy. Most of the participants shopped at the bodega frequently, valued its convenient location, and purchased unhealthy items. Work is needed to discover ways to encourage healthier choices at these stores. PMID- 25910486 TI - Dubious findings concerning the prevalence of late-life depression. PMID- 25910487 TI - MSF launches lifesaving mission in Mediterranean because Europe "is not willing". PMID- 25910488 TI - Clenbuterol Distribution and Residues in Goat Tissues After the Repeated Administration of a Growth-Promoting Dose. AB - This study was conducted to investigate the deposition and depletion process of clenbuterol (CL) in goat tissues, plasma and urine after the repeated administration of a growth-promoting dose. The experiment was conducted in 24 goats (21 treated and 3 controls). Treated animals were administered orally in a dose of 16 ug/kg body mass once daily for 21 consecutive days and randomly sacrificed on days 0.25, 1, 3, 7, 14, 21 and 28 of the withdrawal period. CL in goat tissues was extracted with organic solvents and determined using liquid chromatography tandem mass spectrometry. The depletion rates of tissue differed significantly. The highest concentrations of CL in all tissues are detected on day 0.25 of treatment discontinuation. After administration had been discontinued for 28 days, CL still residues in all tissues, especially, in whole eye, where the concentrations reach 363.29 +/- 31.60 MUg/kg. These findings confirmed that the whole eye, which are rich in pigment, showed a much higher concentration than any other studied tissue during the withdrawal period. PMID- 25910489 TI - Current status and outcomes of patients developing PSA recurrence after prostatectomy who were treated with salvage radiotherapy: a JROSG surveillance study. AB - The conditions and outcomes of Japanese patients with prostate cancer who developed PSA failure after radical prostatectomy (RP), and who were treated via salvage radiotherapy (S-RT), were surveyed. Clinical data on S-RT were gathered in questionnaires completed by facilities participating in the Japanese Radiation Oncology Study Group. S-RT was defined as external-beam radiotherapy delivered to the prostate beds of patients with prostate cancer who had eventually developed PSA failure, although their PSA values had at one stage attained levels <0.2 ng/ml following RP. Hormonal therapy was combined with S-RT in ~40% of cases. Outcomes were evaluated in 186 cases treated via S-RT alone. The nadir PSA level after RP, and the level upon initiation of S-RT, were 0.0135 ng/ml and 0.292 ng/ml, respectively. The median period between RP and S-RT was 18.6 months. The median follow-up period was 58 months. The 5-year PSA recurrence-free survival (PRFS) and clinical failure-free survival (CFFS) rates were 50.1% (95% CI: 42.8 57.9%) and 90.1% (95% CI: 86.4-95.7%), respectively. PRFS was significantly superior in patients with PSA values <=0.3 ng/ml upon initiation of S-RT than in those with PSA values >0.3 ng/ml (57.5% vs 40.5%, P = 0.027). In Japan, hormonal therapy is combined with S-RT in ~40% of cases. The 5-year PRFS and CFFS rates of cases treated via S-RT alone were 50.1% and 90.1%, respectively. A PSA value of 0.3 ng/ml served as a significant cut-off for prediction of PRFS. PMID- 25910491 TI - Outlook for aptamers after twenty five years. AB - Twenty-five years after the emergence of powerful molecular recognition elements known as aptamers, these synthetic receptors are finding applications in therapeutics, imaging, diagnostics and biosensors. Comparisons have been drawn between aptamers and antibodies since their earliest days. This review will highlight how some of the most promising and successful aptamer-based applications have exploited the advantages aptamers have over their antibody counterparts and will point to future applications of this enabling technology. PMID- 25910490 TI - A pooling-based approach to mapping genetic variants associated with DNA methylation. AB - DNA methylation is an epigenetic modification that plays a key role in gene regulation. Previous studies have investigated its genetic basis by mapping genetic variants that are associated with DNA methylation at specific sites, but these have been limited to microarrays that cover <2% of the genome and cannot account for allele-specific methylation (ASM). Other studies have performed whole genome bisulfite sequencing on a few individuals, but these lack statistical power to identify variants associated with DNA methylation. We present a novel approach in which bisulfite-treated DNA from many individuals is sequenced together in a single pool, resulting in a truly genome-wide map of DNA methylation. Compared to methods that do not account for ASM, our approach increases statistical power to detect associations while sharply reducing cost, effort, and experimental variability. As a proof of concept, we generated deep sequencing data from a pool of 60 human cell lines; we evaluated almost twice as many CpGs as the largest microarray studies and identified more than 2000 genetic variants associated with DNA methylation. We found that these variants are highly enriched for associations with chromatin accessibility and CTCF binding but are less likely to be associated with traits indirectly linked to DNA, such as gene expression and disease phenotypes. In summary, our approach allows genome-wide mapping of genetic variants associated with DNA methylation in any tissue of any species, without the need for individual-level genotype or methylation data. PMID- 25910492 TI - On Corporate Accountability: Lead, Asbestos, and Fossil Fuel Lawsuits. AB - This paper examines the use of lawsuits against three industries that were eventually found to be selling products damaging to human heath and the environment: lead paint, asbestos, and fossil fuels. These industries are similar in that some companies tried to hide or distort information showing their products were harmful. Common law claims were eventually filed to hold the corporations accountable and compensate the injured. This paper considers the important role the lawsuits played in helping establish some accountability for the industries while also noting the limitations of the lawsuits. It will be argued that the lawsuits helped create pressure for government regulation of the industries' products but were less successful at securing compensation for the injured. Thus, the common law claims strengthened and supported administrative regulation and the adoption of industry alternatives more than they provided a means of legal redress. PMID- 25910493 TI - Time to benefit for colorectal cancer screening: survival meta-analysis of flexible sigmoidoscopy trials. PMID- 25910494 TI - A new mobile phone-based tool for assessing energy and certain food intakes in young children: a validation study. AB - BACKGROUND: Childhood obesity is an increasing health problem globally. Obesity may be established already at pre-school age. Further research in this area requires accurate and easy-to-use methods for assessing the intake of energy and foods. Traditional methods have limited accuracy, and place large demands on the study participants and researchers. Mobile phones offer possibilities for methodological advancements in this area since they are readily available, enable instant digitalization of collected data, and also contain a camera to photograph pre- and post-meal food items. We have recently developed a new tool for assessing energy and food intake in children using mobile phones called the Tool for Energy Balance in Children (TECH). OBJECTIVE: The main aims of our study are to (1) compare energy intake by means of TECH with total energy expenditure (TEE) measured using a criterion method, the doubly labeled water (DLW) method, and (2) to compare intakes of fruits and berries, vegetables, juice, and sweetened beverages assessed by means of TECH with intakes obtained using a Web-based food frequency questionnaire (KidMeal-Q) in 3 year olds. METHODS: In this study, 30 Swedish 3 year olds were included. Energy intake using TECH was compared to TEE measured using the DLW method. Intakes of vegetables, fruits and berries, juice, as well as sweetened beverages were assessed using TECH and compared to the corresponding intakes assessed using KidMeal-Q. Wilcoxon matched pairs test, Spearman rank order correlations, and the Bland-Altman procedure were applied. RESULTS: The mean energy intake, assessed by TECH, was 5400 kJ/24h (SD 1500). This value was not significantly different (P=.23) from TEE (5070 kJ/24h, SD 600). However, the limits of agreement (2 standard deviations) in the Bland Altman plot for energy intake estimated using TECH compared to TEE were wide (2990 kJ/24h), and TECH overestimated high and underestimated low energy intakes. The Bland-Altman plots for foods showed similar patterns. The mean intakes of vegetables, fruits and berries, juice, and sweetened beverages estimated using TECH were not significantly different from the corresponding intakes estimated using KidMeal-Q. Moderate but statistically significant correlations (rho=.42 .46, P=.01-.02) between TECH and KidMeal-Q were observed for intakes of vegetables, fruits and berries, and juice, but not for sweetened beverages. CONCLUSION: We found that one day of recordings using TECH was not able to accurately estimate intakes of energy or certain foods in 3 year old children. PMID- 25910496 TI - Muscle wasting in end-stage renal disease promulgates premature death: established, emerging and potential novel treatment strategies. AB - Muscle wasting (or sarcopenia) is a common feature of the uremic phenotype and predisposes this vulnerable patient population to increased risk of comorbid complications, poor quality of life, frailty and premature death. The old age of dialysis patients is in addition a likely contributor to loss of muscle mass. As recent evidence suggests that assessment of muscle strength (i.e. function) is a better predictor of outcome and comorbidities than muscle mass, this opens new screening, assessment and therapeutic opportunities. Among established treatment strategies, the benefit of resistance exercise and endurance training are increasingly recognized among nephrologists as being effective and should be promoted in sedentary chronic kidney disease patients. Testosterone and growth hormone replacement appear as the most promising among emerging treatments strategies for muscle wasting. As treatment of muscle wasting is difficult and seldom successful in this often old, frail, sedentary and exercise-hesitant patient group, novel treatment strategies are urgently needed. In this review, we summarize recent studies on stimulation of mitochondrial biogenesis, myogenic stem (satellite) cells and manipulation of transforming growth factor family members, all of which hold promise for more effective therapies to target muscle mass loss and function in the future. PMID- 25910495 TI - Phosphate, fibroblast growth factor 23 and retinopathy in chronic kidney disease: the Chronic Renal Insufficiency Cohort Study. AB - BACKGROUND: Elevated circulating concentrations of phosphate and fibroblast growth factor 23 (FGF23) contribute to the pathogenesis of cardiovascular disease in chronic kidney disease (CKD). Retinopathy is a common manifestation of microvascular disease in CKD, but its associations with phosphate and FGF23 have not been studied. We tested the hypothesis that higher serum phosphate is associated with more severe retinopathy in individuals with CKD, independent of FGF23 and known risk factors for retinopathy. METHODS: We tested the associations of serum phosphate and plasma FGF23 with retinopathy in a cross-sectional analysis of 1800 participants in the Chronic Renal Insufficiency Cohort Study who underwent fundus photography. Retinopathy severity was graded according to the Early Treatment of Diabetic Retinopathy Severity score, and retinal venous and arterial diameters were measured. RESULTS: Mean estimated glomerular filtration rate (eGFR) was 46.5 +/- 15.4 mL/min/1.73 m(2), mean serum phosphate was 3.7 +/- 0.6 mg/dl and median plasma C-terminal FGF23 was 133 RU/mL (interquartile range 87.2, 217.8 RU/mL). In multivariable ordinal logistic regression models, higher serum phosphate was associated with greater retinopathy severity independent of hypertension, diabetes, CKD severity and FGF23 [adjusted odds ratio of being in one higher category of retinopathy severity: 1.19 per 1 standard deviation increase; 95% confidence interval (CI) 1.05, 1.36; P = 0.007]. Presence of diabetes or hypertension did not modify the results. Higher serum phosphate was also independently associated with greater retinal venous diameter (multivariable adjusted 1.70 um increase per 1 standard deviation increase in phosphate; 95% CI 0.46, 2.93; P = 0.007). FGF23 levels were not independently associated with retinopathy severity or retinal venous diameter, and neither FGF23 nor phosphate was associated with retinal arterial diameter. CONCLUSIONS: Among individuals with moderate-to-severe CKD, higher serum phosphate but not FGF23 was independently associated with more severe retinopathy and microvascular retinal venous dilatation. PMID- 25910497 TI - Preparing to take the USMLE Step 1: a survey on medical students' self-reported study habits. AB - BACKGROUND: The USA Medical Licensing Examination Step 1 is a computerised multiple-choice examination that tests the basic biomedical sciences. It is administered after the second year in a traditional four-year MD programme. Most Step 1 scores fall between 140 and 260, with a mean (SD) of 227 (22). Step 1 scores are an important selection criterion for residency choice. Little is known about which study habits are associated with a higher score. OBJECTIVE: To identify which self-reported study habits correlate with a higher Step 1 score. METHODS: A survey regarding Step 1 study habits was sent to third year medical students at Tulane University School of Medicine every year between 2009 and 2011. The survey was sent approximately 3 months after the examination. RESULTS: 256 out of 475 students (54%) responded. The mean (SD) Step 1 score was 229.5 (22.1). Students who estimated studying more than 8-11 h per day had higher scores (p<0.05), but there was no added benefit with additional study time. Those who reported studying <40 days achieved higher scores (p<0.05). Those who estimated completing >2000 practice questions also obtained higher scores (p<0.01). Students who reported studying in a group, spending the majority of study time on practice questions or taking >40 preparation days did not achieve higher scores. CONCLUSIONS: Certain self-reported study habits may correlate with a higher Step 1 score compared with others. Given the importance of achieving a high Step 1 score on residency choice, it is important to further identify which characteristics may lead to a higher score. PMID- 25910498 TI - Reverse Tako-tsubo cardiomyopathy: a clinical entity mimicking acute coronary syndrome. PMID- 25910500 TI - Correction. PMID- 25910499 TI - Reversed oxygen sensing using colloidal quantum wells towards highly emissive photoresponsive varnishes. AB - Colloidal quantum wells combine the advantages of size-tunable electronic properties with vast reactive surfaces that could allow one to realize highly emissive luminescent-sensing varnishes capable of detecting chemical agents through their reversible emission response, with great potential impact on life sciences, environmental monitoring, defence and aerospace engineering. Here we combine spectroelectrochemical measurements and spectroscopic studies in a controlled atmosphere to demonstrate the 'reversed oxygen-sensing' capability of CdSe colloidal quantum wells, that is, the exposure to oxygen reversibly increases their luminescence efficiency. Spectroelectrochemical experiments allow us to directly relate the sensing response to the occupancy of surface states. Magneto-optical measurements demonstrate that, under vacuum, heterostructured CdSe/CdS colloidal quantum wells stabilize in their negative trion state. The high starting emission efficiency provides a possible means to enhance the oxygen sensitivity by partially de-passivating the particle surfaces, thereby enhancing the density of unsaturated sites with a minimal cost in term of luminescence losses. PMID- 25910501 TI - Clinical impact of gastrointestinal bleeding in patients undergoing percutaneous coronary interventions. AB - BACKGROUND: The risk factors and clinical sequelae of gastrointestinal bleeding (GIB) in the current era of drug-eluting stents, prolonged dual antiplatelet therapy, and potent P2Y12 inhibitors are not well established. We determined the frequency, predictors, and clinical impact of GIB after percutaneous coronary interventions (PCIs) in a contemporary cohort of consecutive patients treated with unrestricted use of drug-eluting stents. METHODS AND RESULTS: Between 2009 and 2012, all consecutive patients undergoing PCI were prospectively included in the Bern PCI Registry. Bleeding Academic Research Consortium (BARC) GIB and cardiovascular outcomes were recorded within 1 year of follow-up. Among 6212 patients, 84.1% received new-generation drug-eluting stents and 19.5% received prasugrel. At 1 year, GIB had occurred in 65 patients (1.04%); 70.8% of all events and 84.4% of BARC >= 3B events were recorded > 30 days after PCI. The majority of events (64.4%) were related to upper GIB with a more delayed time course compared with lower GIB. Increasing age, previous GIB, history of malignancy, smoking, and triple antithrombotic therapy (ie, oral anticoagulation plus dual antiplatelet therapy) were independent predictors of GIB in multivariable analysis. GIB was associated with increased all-cause mortality (adjusted hazard ratio, 3.40; 95% confidence interval, 1.67-6.92; P = 0.001) and the composite of death, myocardial infarction, or stroke (adjusted hazard ratio, 3.75; 95% confidence interval, 1.99-7.07; P < 0.001) and was an independent predictor of all-cause mortality during 1 year. CONCLUSIONS: Among unselected patients undergoing PCI, GIB has a profound effect on prognosis. Triple antithrombotic therapy emerged as the single drug-related predictor of GIB in addition to patient-related risk factors within 1 year of PCI. CLINICAL TRIAL REGISTRATION: URL: http://www.clinicaltrials.gov. Unique identifier: NCT02241291. PMID- 25910502 TI - Reperfusion Times for Radial Versus Femoral Access in Patients With ST-Elevation Myocardial Infarction Undergoing Primary Percutaneous Coronary Intervention: Observations From the Cardiac Care Network Provincial Primary PCI Registry. AB - BACKGROUND: Radial access is associated with less bleeding and vascular complications. However, it may delay reperfusion during primary percutaneous coronary intervention for ST-segment-elevation myocardial infarction. METHODS AND RESULTS: A provincial database prospectively collected clinical and procedural characteristics for all urgent percutaneous coronary intervention procedures performed between June 2010 and September 2011 in Ontario for ST-segment elevation myocardial infarction, including time of arrival in the catheterization laboratory and time of first balloon inflation. After excluding patients with cardiogenic shock, with previous bypass surgery, or who received fibrinolysis, 2947 patients were included in the analysis. Propensity score matching was used to minimize difference in clinical characteristics between radial and femoral access procedures. Predictors of radial access included younger age and male sex. After propensity score matching, the median time from arrival in the cardiac catheterization laboratory to first balloon was 27 minutes (25th%-75th%, 21-34) for the femoral group and 30 minutes (25th%-75th %, 24-39) for the radial group (P<0.001). When hospitals were stratified based on the proportion of primary percutaneous coronary intervention cases that were performed using radial access, there was no difference in treatment times between radial and femoral access in the tercile of hospitals that used radial access most frequently. There were no significant differences in the rates of death or myocardial infarction at 30 days. CONCLUSIONS: This contemporary multicenter registry demonstrates that the time to first balloon inflation is slightly longer with radial access than with femoral access, although the 3 minute difference is unlikely to be clinically relevant. There is no difference in treatment times at hospitals that frequently use radial access for primary percutaneous coronary intervention. Short-term mortality and reinfarction rates are similar with radial and femoral access. PMID- 25910504 TI - Native and Non-native Speech Perception by Hearing-Impaired Listeners in Noise- and Speech Maskers. AB - This study evaluated how hearing-impaired listeners perceive native (Swedish) and nonnative (English) speech in the presence of noise- and speech maskers. Speech reception thresholds were measured for four different masker types for each target language. The maskers consisted of stationary and fluctuating noise and two-talker babble in Swedish and English. Twenty-three hearing-impaired native Swedish listeners participated, aged between 28 and 65 years. The participants also performed cognitive tests of working memory capacity in Swedish and English, nonverbal reasoning, and an English proficiency test. Results indicated that the speech maskers were more interfering than the noise maskers in both target languages. The larger need for phonetic and semantic cues in a nonnative language makes a stationary masker relatively more challenging than a fluctuating-noise masker. Better hearing acuity (pure tone average) was associated with better perception of the target speech in Swedish, and better English proficiency was associated with better speech perception in English. Larger working memory and better pure tone averages were related to the better perception of speech masked with fluctuating noise in the nonnative language. This suggests that both are relevant in highly taxing conditions. A large variance in performance between the listeners was observed, especially for speech perception in the nonnative language. PMID- 25910503 TI - How hearing impairment affects sentence comprehension: using eye fixations to investigate the duration of speech processing. AB - The main objective of this study was to investigate the extent to which hearing impairment influences the duration of sentence processing. An eye-tracking paradigm is introduced that provides an online measure of how hearing impairment prolongs processing of linguistically complex sentences; this measure uses eye fixations recorded while the participant listens to a sentence. Eye fixations toward a target picture (which matches the aurally presented sentence) were measured in the presence of a competitor picture. Based on the recorded eye fixations, the single target detection amplitude, which reflects the tendency of the participant to fixate the target picture, was used as a metric to estimate the duration of sentence processing. The single target detection amplitude was calculated for sentence structures with different levels of linguistic complexity and for different listening conditions: in quiet and in two different noise conditions. Participants with hearing impairment spent more time processing sentences, even at high levels of speech intelligibility. In addition, the relationship between the proposed online measure and listener-specific factors, such as hearing aid use and cognitive abilities, was investigated. Longer processing durations were measured for participants with hearing impairment who were not accustomed to using a hearing aid. Moreover, significant correlations were found between sentence processing duration and individual cognitive abilities (such as working memory capacity or susceptibility to interference). These findings are discussed with respect to audiological applications. PMID- 25910505 TI - Toward a Global Consensus on Outcome Measures for Clinical Trials in Tinnitus: Report From the First International Meeting of the COMiT Initiative, November 14, 2014, Amsterdam, The Netherlands. AB - In Europe alone, over 70 million people experience tinnitus; for seven million people, it creates a debilitating condition. Despite its enormous socioeconomic relevance, progress in successfully treating the condition is somewhat limited. The European Union has approved funding to create a pan-European tinnitus research collaboration network (2014-2018). The goal of one working group is to establish an international standard for outcome measurements in clinical trials of tinnitus. Importantly, this would enhance tinnitus research by informing sample-size calculations, enabling meta-analyses, and facilitating the identification of tinnitus subtypes, ultimately leading to improved treatments. The first meeting followed a workshop on "Agreed Standards for Measurement: An International Perspective" with invited talks on clinimetrics and existing international initiatives to define core sets for outcome measurements in hearing loss (International classification of functioning, disability, and health core sets for hearing loss) and eczema (Harmonizing outcome measures for eczema). Both initiatives have taken an approach that clearly distinguishes the specification of what to measure from that of how to measure it. Meeting delegates agreed on taking a step-wise roadmap for which the first output would be a consensus on what outcome domains are essential for all trials. The working group seeks to embrace inclusivity and brings together clinicians, tinnitus researchers, experts on clinical research methodology, statisticians, and representatives of the health industry. People who experience tinnitus are another important participant group. This meeting report is a call to those stakeholders across the globe to actively participate in the initiative. PMID- 25910507 TI - The Gene Network Underlying Hypodontia. AB - Mammalian tooth development is a precise and complicated procedure. Several signaling pathways, such as nuclear factor (NF)-kappaB and WNT, are key regulators of tooth development. Any disturbance of these signaling pathways can potentially affect or block normal tooth development, and presently, there are more than 150 syndromes and 80 genes known to be related to tooth agenesis. Clarifying the interaction and crosstalk among these genes will provide important information regarding the mechanisms underlying missing teeth. In the current review, we summarize recently published findings on genes related to isolated and syndromic tooth agenesis; most of these genes function as positive regulators of cell proliferation or negative regulators of cell differentiation and apoptosis. Furthermore, we explore the corresponding networks involving these genes in addition to their implications for the clinical management of tooth agenesis. We conclude that this requires further study to improve patients' quality of life in the future. PMID- 25910506 TI - Candidate Gene Analyses of Skeletal Variation in Malocclusion. AB - This study evaluated associations between craniofacial candidate genes and skeletal variation in patients with malocclusion. Lateral cephalometric radiographs of 269 untreated adults with skeletal classes I, II, and III malocclusion were digitized with 14 landmarks. Two-dimensional coordinates were analyzed using Procrustes fit and principal component (PC) analysis to generate continuous malocclusion phenotypes. Skeletal class classifications (I, II, or III) were used as a categorical phenotype. Individuals were genotyped for 198 single-nucleotide polymorphisms (SNPs) in 71 craniofacial genes and loci. Phenotype-genotype associations were tested via multivariate linear regression for continuous phenotypes and multinomial logistic regression for skeletal malocclusion class. PC analysis resulted in 4 principal components (PCs) explaining 69% of the total skeletal facial variation. PC1 explained 32.7% of the variation and depicted vertical discrepancies ranging from skeletal deep to open bites. PC1 was associated with a SNP near PAX5 (P = 0.01). PC2 explained 21.7% and captured horizontal maxillomandibular discrepancies. PC2 was associated with SNPs upstream of SNAI3 (P = 0.0002) and MYO1H (P = 0.006). PC3 explained 8.2% and captured variation in ramus height, body length, and anterior cranial base orientation. PC3 was associated with TWIST1 (P = 0.000076). Finally, PC4 explained 6.6% and detected variation in condylar inclination as well as symphysis projection. PC4 was associated with PAX7 (P = 0.007). Furthermore, skeletal class II risk increased relative to class I with the minor alleles of SNPs in FGFR2 (odds ratio [OR] = 2.1, P = 0.004) and declined with SNPs in EDN1 (OR = 0.5, P = 0.007). Conversely, skeletal class III risk increased versus class I with SNPs in FGFR2 (OR 2.2, P = 0.005) and COL1A1 (OR = 2.1, P = 0.008) and declined with SNPs in TBX5 (OR = 0.5, P = 0.014). PAX5, SNAI3, MYO1H, TWIST1, and PAX7 are associated with craniofacial skeletal variation among patients with malocclusion, while FGFR2, EDN1, TBX5, and COL1A1 are associated with type of skeletal malocclusion. PMID- 25910508 TI - Corrigendum. PMID- 25910509 TI - Selective Formation of Heterometallic Ru-Ag Supramolecules via Stoichiometric Control of Multiple Different Tectons. AB - Stoichiometric control of Ru, Ag, and tetrazolyl ligands resulted in the formation of different heterometallic Ru-Ag supramolecular architectures. Although the reaction of Ru and 5-(2-hydroxyphenyl)-1H-tetrazolyl (LH2) in a molar ratio of 2:1 or 6:4 resulted in the formation of dimeric or hexameric Ru complexes, Ag metal ions caused the Ru complexes to form three-dimensional cylindrical Ru6Ag6L6 and double-cone-shaped Ru6Ag8L6 complexes by occupying vacant coordination sites. PMID- 25910510 TI - Ebola virus: current and future perspectives. AB - The present outbreak associated with Ebola disease in Western countries of the African continent which is believed to be one of the massive eruptions caused by the Ebola viral infections. In the present scenario ebola has been transmitted to the European and American regions through the travelers from wide spread countries like Guinea, Liberia, Sierra Leone and Nigeria. The viral disease is spreading through the contact in any form by the infected persons or patients and creating huge risks to the mortals. The symptoms related to ebola virus are often highly pathogenic; about 70-80% of death cases are reported due to critical hemorrhagic fever. Early in infection, ebola virus infects macrophages and endothelial cells. It mainly produces a Viral Protein 24 (eVP24) which prevents interferon-based signals which are important for destruction of viruses. How ebola virus manipulates the function of the immune system is still unclear. Due to lack of this knowledge, no approved treatment is available. In this review, we have tried to compile the epidemiology, pathogenesis and treatment of ebola virus infection. The promising ligands against ebola virus have been also discussed which will be helpful for researchers to design drugs for the treatment of ebola virus disease. PMID- 25910511 TI - Substituent and solvent effects on the UV-vis absorption spectrum of the photoactive yellow protein chromophore. AB - Solvent effects on the UV-vis absorption spectra and molecular properties of four models of the photoactive yellow protein (PYP) chromophore have been studied with ASEP/MD, a sequential quantum mechanics/molecular mechanics method. The anionic trans-p-coumaric acid (pCA(-)), thioacid (pCTA(-)), methyl ester (pCMe(-)), and methyl thioester (pCTMe(-)) derivatives have been studied in gas phase and in water solution. We analyze the modifications introduced by the substitution of sulfur by oxygen atoms and hydrogen by methyl in the coumaryl tail. We have found some differences in the absorption spectra of oxy and thio derivatives that could shed light on the different photoisomerization paths followed by these compounds. In solution, the spectrum substantially changes with respect to that obtained in the gas phase. The n -> pi1* state is destabilized by a polar solvent like water, and it becomes the third excited state in solution displaying an important blue shift. Now, the pi -> pi1* and pi -> pi2* states mix, and we find contributions from both transitions in S1 and S2. The presence of the sulfur atom modulates the solvent effect and the first two excited states become practically degenerate for pCA(-) and pCMe(-) but moderately well-separated for pCTA(-) and pCTMe(-). PMID- 25910512 TI - Novel therapeutic targets and predictive markers for hepatocellular carcinoma. AB - INTRODUCTION: Following the approval of sorafenib as the first systemic agent for treatment of advanced hepatocellular carcinoma (HCC), there have been an increasing number of targeted treatments under testing for the cancer. However, most of the recently published drug trials in HCC failed to produce remarkable results. The researchers are actively pursuing novel therapeutic targets as well as predictive biomarker for treatment of HCC. AREAS COVERED: This review discusses a number of potential novel targets for drug development of HCC. Focus is put on the underlying rationale for therapeutic development of the target and the possibility of using a predictive biomarker to select patients for drug testing. EXPERT OPINION: Future direction of drug development will be discussed. Notably, a clinical trial on drug testing in HCC should be shifted from all comers approach to selected populations based on underlying viral etiology and molecular targets. A study to evaluate predictive biomarker is crucial to the development of targeted agents for HCC. Design of clinical trials on HCC should introduce measures to encourage acquisition of tumor and plasma samples for biomarker development. PMID- 25910513 TI - Screening Mammography in a Public Hospital Serving Predominantly African-American Women: A Stage-Survival-Cost Model. AB - BACKGROUND: Ethnic and socioeconomic disparities pervade breast cancer patterns and outcomes. Mammography guidelines reflect the difficulty in optimizing mortality reduction and cost-effectiveness, with controversy still surrounding the 2009 U.S. Preventive Services Task Force (USPSTF) recommendations. This study simulates USPSTF and American Cancer Society (ACS) guidelines' effects on stage, survival, and cost of treatment in an urban public hospital. METHODS: Charts of 274 women diagnosed with stage I, II, or III breast cancer (2008-2010) were reviewed. Published tumor doubling times were used to predict size at diagnosis under simulated screening guidelines. Stage distributions under ACS and USPSTF guidelines were compared with those observed. Cohort survival for observed and hypothetical scenarios was estimated using national statistics. Treatment costs by stage, calculated from Georgia Medicaid claims data, were similarly applied. RESULTS: Mean age at diagnosis was 56 years. African Americans predominated (82.5%), with 96% publically insured or uninsured. Simulated stages at diagnosis significantly favored ACS guidelines (43.1% stage 1/38.3% stage 2/9.9% stage 3 vs. USPSTF 23.0%/53.3 %/15.0%), as did 5-year survival and cost of treatment relative to both observed and USPSTF-predicted schema (p<.0001). Following USPSTF guidelines predicted lower survival and additional costs. CONCLUSIONS: Following ACS guidelines seems to lead to earlier diagnosis for low-income African-American women and increase 5-year survival with lower overall and breast-specific costs. The data suggest that adjusting screening practices for lower socioeconomic status, ethnic minority women may prove essential in addressing cancer disparities. PMID- 25910515 TI - Stakeholder opinions on the practicality of management interventions to control bovine tuberculosis. AB - Livestock disease control strategies are usually determined at national and international levels, yet their successful implementation is determined by stakeholders operating at local scales. Such stakeholders may also have detailed knowledge that would contribute to the development of disease control options suited to the socio-cultural and environmental conditions where management is undertaken. The aim of this study was to evaluate stakeholders' opinions of a list of potential bovine tuberculosis (TB) management interventions for South Central Spain. This area has high TB prevalence in wildlife and livestock, so veterinarians, livestock farmers and hunters are all key stakeholders in TB management. A literature review identified possible management activities. The effectiveness of each intervention was ranked by local experts, and practicality was ranked by hunters, cattle farmers and veterinarians, using a best-worst scaling exercise as part of a questionnaire. The most effective intervention, the banning of supplemental feeding of game species, was not considered practical by stakeholders. The most effective and practical interventions were the separation of wildlife and livestock access to waterholes, testing cattle every 3 months on farms with a recent positive TB case and removing gut-piles from the land after hunting events. Although all three of these options were well supported, each stakeholder group supported different approaches more strongly, suggesting that it might be effective to promote different disease management contributions in different stakeholder communities. This integrated approach contributes to the identification of the optimum combination of management tools that can be delivered effectively. PMID- 25910514 TI - Airway clearance techniques used by people with cystic fibrosis in the UK. AB - OBJECTIVES: To describe the current use of airway clearance techniques among people with cystic fibrosis (CF) in the UK, and the baseline characteristics for users of different airway clearance techniques. DESIGN: Analysis of the UK CF Registry 2011 data. SETTING AND PARTICIPANTS: All people with CF in the UK aged >=11 years (n=6372). RESULTS: Of the 6372 people on the UK CF registry in 2011, 89% used airway clearance techniques. The most commonly used primary techniques were forced expiratory techniques (28%) and oscillating positive expiratory pressure (PEP) (23%). Postural drainage and high-frequency chest wall oscillation were used by 4% and 1% of people with CF, respectively. The male:female ratio of individuals who used exercise as their primary airway clearance technique was 2:1, compared with 1:1 for other techniques. Individuals with more severe lung disease tended to use devices such as non-invasive ventilation or high-frequency chest wall oscillation. CONCLUSIONS: Forced expiratory techniques and oscillating PEP are the most common airway clearance techniques used by people with CF in the UK, and postural drainage and high-frequency chest wall oscillation are the least common techniques. This is significant in terms of planning airway clearance technique trials, where postural drainage has been used traditionally as the comparator. The use of airway clearance techniques varies between countries, but the reasons for these differences are unknown. PMID- 25910516 TI - Initial evaluation of a canine stifle arthrotomy post-operative pain model. AB - Most models of acute post-operative orthopedic pain involve the injection of a clinically irrelevant pro-inflammatory agent. The ideal model should, however, be clinically relevant and allow full functional recovery of enrolled animals after research is completed. This study explored the validity of a model employing arthrotomy and objectively measured limb use. Six purpose-bred Beagles underwent arthrotomies on each stifle with a washout period in between. Using a randomized crossover design, each dog received placebo and an extended-release buprenorphine (ER-Bup) preparation. Static and dynamic ground reaction forces (GRFs) were measured prior to and for 72 h following surgery using a pressure sensitive walkway (PSW). GRFs for each hind limb were compared using difference (delta), and symmetry indices (SI). The effects of surgery and of treatment were analyzed using repeated measures ANCOVA. The results indicated significantly decreased limb use compared to baseline for placebo, and significantly increased limb use in the ER-Bup group over placebo at all times for % bodyweight distribution (%BWdistrib), peak vertical force (PVF) and vertical impulse (VI). There was a significant treatment by time interaction for velocity (P = 0.03) and %BWdistrib (P = 0.01, 0.003). Overall, the data show that reduced limb use was present for at least 72 h following arthrotomy. In addition, the use of the ER-Bup analgesic decreased lameness, confirming the validity of this approach as a model of post operative pain. Subjective assessments did not detect the pain-inducing effects of arthrotomy or pain-alleviating effects of treatment, and subjective measures of procedural pain in research dogs need to be developed. PMID- 25910517 TI - Puzzling questions on antithrombin: Diagnostic limitations and real incidence in venous and arterial thrombosis. PMID- 25910518 TI - Platelet Function: the Janus face of haemostasis in cirrhosis. PMID- 25910519 TI - Oxidative Stress and Potential Renal Damage in Neonates. PMID- 25910520 TI - Computer-based assessment for facioscapulohumeral dystrophy diagnosis. AB - The paper presents a computer-based assessment for facioscapulohumeral dystrophy (FSHD) diagnosis through characterisation of the fat and oedema percentages in the muscle region. A novel multi-slice method for the muscle-region segmentation in the T1-weighted magnetic resonance images is proposed using principles of the live-wire technique to find the path representing the muscle-region border. For this purpose, an exponential cost function is used that incorporates the edge information obtained after applying the edge-enhancement algorithm formerly designed for the fingerprint enhancement. The difference between the automatic segmentation and manual segmentation performed by a medical specialists is characterised using the Zijdenbos similarity index, indicating a high accuracy of the proposed method. Finally, the fat and oedema are quantified from the muscle region in the T1-weighted and T2-STIR magnetic resonance images, respectively, using the fuzzy c-mean clustering approach for 10 FSHD patients. PMID- 25910521 TI - [Diffuse cutaneous lesions]. PMID- 25910522 TI - [An abdominal mass]. PMID- 25910523 TI - Comparison of Short- and Long-Term Cardiac Mortality in Early Versus Late Stent Thrombosis (from Pooled PROTECT Trials). AB - Studies have indicated varying mortality risks with timing of stent thrombosis (ST), but few have been adequately powered with prospective late follow-up. PROTECT randomized 8,709 subjects to either Endeavor zotarolimus-eluting or Cypher sirolimus-eluting stents. PROTECT Continued Access enrolled 1,018 patients treated with Endeavor zotarolimus-eluting stents. Subjects completed at least 4 and 3 years of follow-up, respectively. ARC-defined definite and probable ST events were stratified by time from index procedure: early (<=30 days), late (>30 and <=360 days), and very late (>360 days). Rates of death and myocardial infarction were analyzed by ST timing. Median follow-up was 4.1 years. There were 184 ST events (1.9%): 61 early, 27 late, and 96 very late. Patient and procedural characteristics were similar between timing groups. There was no difference in dual-antiplatelet therapy use at discharge (97%) or 1 year (84%). Cardiac death in patients with ST at 4 years occurred in 32.1% compared with 2.5% in patients without ST (p <0.001). Combined rates of cardiac death and myocardial infarction did not differ according to ST timing, yet early ST was more commonly associated with cardiac death at 4 years than later ST (50.8% for early vs 18.5% for late vs 24.0% for very late; p <0.001). The relation between ST timing and outcomes did not differ between stent types. In conclusion, in prospective data, cardiac death was more common after early ST than later ST. Although ST remains infrequent, continued efforts to determine how to reduce ST, particularly within the first 30 days, are warranted. (The PROTECT trial is registered with ClinicalTrials.gov, number NCT00476957.). PMID- 25910524 TI - Emotional, neurohormonal, and hemodynamic responses to mental stress in Tako Tsubo cardiomyopathy. AB - Tako-Tsubo cardiomyopathy (TTC) is characterized by apical ballooning of the left ventricle and symptoms and signs mimicking acute myocardial infarction. The high catecholamine levels in the acute phase of TTC and common emotional triggers suggest a dysregulated stress response system. This study examined whether patients with TTC show exaggerated emotional, neurohormonal, and hemodynamic responses to mental stress. Patients with TTC (n = 18; mean age 68.3 +/- 11.7, 78% women) and 2 comparison groups (healthy controls, n = 19; mean age 60.0 +/- 7.6, 68% women; chronic heart failure, n = 19; mean age 68.8 +/- 10.1, 68% women) performed a structured mental stress task (anger recall and mental arithmetic) and low-grade exercise with repeated assessments of negative emotions, neurohormones (catecholamines: norepinephrine, epinephrine, dopamine, hypothalamic-pituitary-adrenal axis hormones: adrenocorticotropic hormone [ACTH], cortisol), echocardiography, blood pressure, and heart rate. TTC was associated with higher norepinephrine (520.7 +/- 125.5 vs 407.9 +/- 155.3 pg/ml, p = 0.021) and dopamine (16.2 +/- 10.3 vs 10.3 +/- 3.9 pg/ml, p = 0.027) levels during mental stress and relatively low emotional arousal (p <0.05) compared with healthy controls. During exercise, norepinephrine (511.3 +/- 167.1 vs 394.4 +/- 124.3 pg/ml, p = 0.037) and dopamine (17.3 +/- 10.0 vs 10.8 +/- 4.1 pg/ml, p = 0.017) levels were also significantly higher in patients with TTC compared with healthy controls. In conclusion, catecholamine levels during mental stress and exercise were elevated in TTC compared with healthy controls. No evidence was found for a dysregulated hypothalamic-pituitary-adrenal axis or hemodynamic responses. Patients with TTC showed blunted emotional arousal to mental stress. This study suggests that catecholamine hyper-reactivity and not emotional hyper reactivity to stress is likely to play a role in myocardial vulnerability in TTC. PMID- 25910525 TI - Orbital Atherectomy for Treating De Novo Severely Calcified Coronary Narrowing (1 Year Results from the Pivotal ORBIT II Trial). AB - Percutaneous coronary intervention of severely calcified lesions has historically been associated with major adverse cardiac event (MACE) rates as high as 30%. In the ORBIT II (Evaluate the Safety and Efficacy of OAS in Treating Severely Calcified Coronary Lesions) trial, treatment of de novo severely calcified lesions with the Diamondback 360 degrees Coronary Orbital Atherectomy System (OAS) resulted in low rates of procedural and 30-day adverse ischemic events. The long-term results from this trial have not been reported. We sought to determine the 1-year outcomes after orbital atherectomy of severely calcified coronary lesions. ORBIT II was a single-arm trial enrolling 443 subjects at 49 US sites with severely calcified lesions usually excluded from randomized trials. OAS utilizes a centrifugal differential sanding mechanism of action for plaque modification prior to stent implantation. After OAS drug-eluting stents were implanted in 88.2% of the patients. The primary safety end point was 30-day MACE, the composite of cardiac death, myocardial infarction, or target vessel revascularization [TVR]. The present analysis reports the 1-year follow-up results from ORBIT II. One-year data were available in 433 of 443 patients (97.7%), with median follow-up time of 16.7 months. The 1-year MACE rate was 16.4%, including cardiac death (3.0%), myocardial infarction (9.7%), and target vessel revascularization (5.9%). The 1-year target lesion revascularization rate was 4.7%, and stent thrombosis occurred in 1 patient (0.2%). Independent predictors of 1-year MACE and target vessel revascularization were diameter stenosis at baseline and the use of bare-metal stents. In patients with severely calcified lesions who underwent percutaneous coronary intervention, the use of OAS was associated with low rates of 1-year adverse ischemic events compared with historical controls. This finding has important clinical implications for the selection of optimum treatment strategies for patients with severely calcified lesions. PMID- 25910526 TI - Reply: To PMID 25465934. PMID- 25910527 TI - Usefulness of vascular stenting with and without transvenous pacing leads for vena caval obstruction among children and adults with repaired congenital heart disease. AB - Vena caval obstruction (VCO) is a common complication after vascular manipulation for congenital heart disease. Long-term efficacy of stent therapy for relief of VCO and long-term stent patency with and without intrastent transvenous pacing leads (TPLs) is not well described. This was a retrospective review of patients treated for VCO, including those who received intrastent TPLs, between 1995 and 2012. Patient demographics, diagnoses, vascular pressure gradients, and vessel diameters were analyzed. Forty-one patients (mean age 23.5 +/- 10.3 years) with and without congenital heart disease underwent stent implantation, 26 of whom also received intrastent TPLs. Short-term stent implantation success in relieving obstructions was 93%. Poststent vascular pressure gradients and percentage vascular narrowing significantly improved (from 6.2 +/- 4.5 to 1.1 +/- 1.6 mm Hg and from 63.1 +/- 19.5% to 18.0 +/- 17.1%, respectively, p <0.05). On follow-up in 38 of 41 patients from 0.2 to 18 years (median 6.0), all survived; 6 (14%) required stent reintervention. Freedom from reintervention was 87% at 15 years. Patients with short-term procedural failure were at higher risk for stent reintervention. Among 27 patients with intrastent TPLs, freedom from reintervention was 96%. In 26 patients with follow-up catheterization, intrastent intimal proliferation was not significantly associated with TPL but was higher in the superior vena cava-innominate vein junction compared with other stent locations (p <0.05). In conclusion, stent therapy for VCO can be successfully and safely performed with good long-term results. Pre-pacing lead stent placement for VCO is effective in allowing TPL placement with encouraging long-term patency. PMID- 25910528 TI - Comparison of clinical efficacy and cost of a cardiac imaging strategy versus a traditional exercise test strategy for the investigation of patients with suspected stable coronary artery disease. AB - We evaluated the clinical efficacy and cost of a cardiac imaging strategy versus a traditional exercise tolerance test (ETT) strategy for the investigation of suspected stable coronary artery disease (CAD). We retrospectively collected data of consecutive patients seen in rapid access chest pain clinics at 2 UK hospitals for a period of 12 months. Hospital A investigated patients by performing ETT. Hospital B investigated patients using cardiac imaging test; 483 patients from hospital A and 295 from hospital B were included. In hospital A, 209 patients (43.3%) had contraindication to ETT. Of those who had ETT, 151 (55.1%) had negative ETT, 68 (24.8%) had equivocal ETT, and 55 (20.1%) had positive ETT, of which 53 (96.4%) had invasive coronary angiography (ICA), and of these 23 (43.4%) had obstructive CAD. In hospital B, 26 patients (8.8%) with low pretest probability had calcium score and 3 (11.5%) were positive leading to computed tomography coronary angiography; 98 patients (33.2%) with intermediate pretest probability had computed tomography coronary angiography and 5 (5.1%) were positive; 77 patients (26.1%) had stress echocardiogram and 6 (7.8%) were positive; and 57 patients (19.3%) had myocardial perfusion scintigraphy and 11 (19.3%) were positive. Hospital A performed 127 ICA (26.3% of population) and 52 (40.9%) had obstructive CAD. Hospital B performed 63 ICA (21.4% of population) and 32 (50.8%) had obstructive CAD. The average cost per patient in hospital A was L566.6 +/- 490.0 ($875 +/- 758) and in hospital B was L487.9 +/- 469.6 ($750 +/- 725) (p <0.001). In conclusion, our results suggest that a cardiac imaging pathway leads to fewer ICA and a higher yield of obstructive CAD at lower cost per patient. PMID- 25910529 TI - The incidence of coring and fragmentation of medication vial rubber stoppers. PMID- 25910530 TI - Internal jugular veins must be measured before catheterisation. PMID- 25910531 TI - Sugammadex usage in a patient with dermatomyositis. PMID- 25910533 TI - Endocarditic sinus of valsalva fistulae to right ventricular outflow tract in adult ventricular septal defects. AB - Surgical repair of congenital ventricular septal defects (VSDs) in adults is quite rare. Most congenital VSDs are repaired in children. Of those adult patients diagnosed as having VSDs, many are not repaired due to irreversible pulmonary vascular disease. Repair in a patient with a VSD and fistula is even more uncommon. From a review of the literature, we found no other case reports with our unique combination of echocardiographic and surgical findings: a supracristal VSD, right and left sinus of Valsalva fistulas into the right ventricular outflow tract, and a pulmonary artery to pulmonary vein fistula in the context of an aseptic endocarditis lesion. We review the important aspects of anesthetic management in an adult with an intracardiac shunt. An adult patient with unrepaired congenital VSD may develop multiple fistulas as a consequence of endocarditis. This patient refused surgery until the progressive dyspnea was worsened by the endocarditis and the fistulas. At the time of surgery, his ventricular ejection fraction measured 47%, the ventricular chambers were enlarged, and the pulmonary to systemic flow ratio measured 2:1. He did well clinically after the VSD and fistulae repair. PMID- 25910532 TI - Evaluation of the effect of ketamine on remifentanil-induced hyperalgesia: a double-blind, randomized study. AB - STUDY OBJECTIVE: Opioids are associated with hyperalgesia that can reduce their analgesic effect. The aim of this study was to determine whether the addition of ketamine reduces remifentanil-induced hyperalgesia; improves its analgesic effect; and alters interleukin 6 (IL-6), IL-8, and IL-10 levels. DESIGN: This is a prospective, randomized, double-blind study. SETTING: The setting is in a operating room and ward in a university hospital. PATIENTS: There are 56 patients, aged >=18 years, American Society of Anesthesiologists I or II, who underwent laparoscopic cholecystectomy. INTERVENTIONS: Anesthesia was induced with remifentanil, 50% oxygen, and isoflurane. Patients randomized to group 1 received remifentanil (0.4 MUg/kg per minute) and ketamine (5 MUg/kg per minute), and patients randomized to group 2 received remifentanil (0.4 MUg/kg per minute) and saline solution. Postoperative analgesia was achieved using morphine via patient-controlled analgesia. MEASUREMENTS: The measurements were postoperative pain intensity during 24 hours; morphine consumption; time to first morphine supplementation; hyperalgesia (using monofilaments and an algometer) and allodynia (using a soft brush) in the thenar eminence of the nondominant hand and in the periumbilical region 24 hours after surgery; extent of hyperalgesia using a 300-g monofilament near the periumbilical region 24 hours after surgery; and serum levels of IL-6, IL-8, and IL-10. MAIN RESULTS: Groups were similar for baseline characteristics. There were no differences in pain intensity, time to first request of morphine, and total 24 hours dose of morphine between groups. There was a difference in hyperalgesia using monofilaments 24 hours after the surgery in the thenar eminence of the nondominant hand, with a better profile for the experimental group. However, there were no differences in hyperalgesia using an algometer, in allodynia using a soft brush; in extent of hyperalgesia; or in levels of IL-6, IL-8, and IL-10. CONCLUSIONS: It was not possible to demonstrate that the addition of ketamine (5 MUg/kg per minute) is effective in preventing or reducing remifentanil-induced postoperative hyperalgesia in laparoscopic cholecystectomy. PMID- 25910534 TI - An in vivo and in vitro assessment of the anti-inflammatory, antinociceptive, and immunomodulatory activities of Clematis terniflora DC. extract, participation of aurantiamide acetate. AB - AIM: Clematis terniflora DC. has been widely used as a traditional Chinese medicine for the treatment of tonsillitis, rheumatoid arthritis, and prostatitis. Despite its widespread use in China, there are currently no studies systematically examined its therapeutic effects and mechanism of action. As such, the present study was conducted to evaluate the anti-inflammatory, antinociceptive, and immunomodulatory effects of C. terniflora DC. using rodent and cellular models. METHODS: The anti-inflammatory properties of the 70% ethanol eluted fraction of the 70% ethanol extract of C. terniflora DC. (EECTD) were evaluated using the xylene-induced ear swelling test, the carrageenan-induced edema model, and the cotton pellet granuloma method. Its antinociceptive activities were determined using both the acetic acid-induced writhing test and the hot plate assay. In parallel, we conducted an in vitro assay in LPS-induced RAW264.7 cells to examine the anti-inflammatory effects of EECTD and its purified form, aurantiamide acetate (AA) on inhibition of nitric oxide (NO) and prostaglandin E2 (PGE2) release. RESULTS: EECTD (300mg/kg) significantly reduced the number of writhing, extended the pain response latency, and suppressed xylene induced ear swelling. Each EECTD treatment group also had significant inhibition of cotton granulation formation in addition to reduced carrageenan-induced paw edema. EECTD was also shown to alleviate signs of inflammation in histopathological paw sections. However, it had a less noticeable effect on mouse ear swelling in the delayed type hypersensitivity test. A purified compound was isolated from EECTD and its structure was identified as AA. In vitro experimental results showed that both EECTD and AA were able to significantly inhibit the release of pro-inflammatory cytokines NO and PGE2 on LPS-induced RAW264.7 cells. CONCLUSION: These results suggest that EECTD has significant anti-inflammatory and antinociceptive activities, partially related to one of the active substances identified as AA. We hypothesize that these effects are related to its ability to inhibit the production of cytokines NO and PGE2. However, further work will be needed to determine its exact mechanism of action. PMID- 25910535 TI - UPLC-MS/MS determination and gender-related pharmacokinetic study of five active ingredients in rat plasma after oral administration of Eucommia cortex extract. AB - ETHNOPHARMACOLOGICAL RELEVANCE: Eucommiae cortex (EC), the bark of Eucommia ulmoides Oliv., has been traditionally used to treat many diseases in China for more than 2000 years. The pharmacological effects are primarily attributed to the presence of lignans, iridoids and phenolics, which are main active ingredients in EC. AIM OF THE STUDY: First, to investigate the active ingredients that can be absorbed into the rat plasma according to which ingredients exhibit significant correlation of drug concentration-time curve. Second, to establish an efficient ultra-performance liquid chromatography/tandem mass spectrometry (UPLC-MS/MS) method for simultaneous determination of ingredients absorbed in rat plasma. Finally, to investigate gender effect on the pharmacokinetics of the ingredients absorbed in male and female rats plasma after oral administration with EC extract. MATERIALS AND METHODS: 18 ingredients from EC were detected by UPLC MS/MS, 9 out of 18 ingredients were absorbed into rat plasma. And 5 ingredients exhibit significant correlation of drug concentration-time curve. They were pinoresinol di-O-beta-d-glucopyranoside (PDG), geniposide (GE), geniposidic acid (GA), aucubin (AN) and chlorogenic acid (CA). The analytes were extracted from rat plasma via a simple protein precipitation procedure and osalmid was used as the internal standard. Chromatographic separation was achieved on a Waters ACQUITY HSS T3 column (2.1mm*100mm, 1.8MUm) using a gradient elution program with acetonitrile and 0.1% formic acid water as the mobile phase, with a flow rate of 0.3mLmin(-1). The detection was performed on a triple-quadrupole tandem mass spectrometer by multiple reactions monitoring (MRM) mode in a positive ion mode via electrospray ionization (ESI). The transition monitored were /z 683.00[M+H](+)->235.10 for PDG, / z 389.00[M+H](+)->208.80 for GE, m/z 375.00[M+H](+)->194.79 for GA, m/z 364.00[M+NH4](+)->148.81 for AN, m/z 355.10[M+H](+)->162.84 for CA and m/z 230.03[M+H](+)->120.77 for internal standard. RESULTS: The developed method showed good linearity over a wide concentration range, the lower limits of quantification and higher accuracy and precision for determination of the 5 analytes. Then the method was applied to study the pharmacokinetics in rats, and the results indicated that there were significant differences in pharmacokinetic parameters of the analytes between the male and female rats, and absorptions of these analytes in male group were all significantly higher than those in female group. CONCLUSION: This study established an efficient, sensitive and selective UPLC-MS/MS method for simultaneous determination of the five ingredients in rat plasma, and it could be successfully applied to the comparative pharmacokinetic studies in male and female rats after oral administration with EC extract. PMID- 25910536 TI - Biochemistry of storage lesions of red cell and platelet concentrates: A continuous fight implying oxidative/nitrosative/phosphorylative stress and signaling. AB - The mechanisms responsible for the reduced lifespan of transfused red blood cells (RBCs) and platelets (PLTs) are still under investigation, however one explanation refers to the detrimental biochemical changes occurring during ex vivo storage of these blood products. A myriad of historical and more recent studies has contributed to advance our understanding of storage lesion. Without any doubts, proteomics had great impact on transfusion medicine by profiling the storage-dependent changes in the total detectable protein pool of both RBCs and PLTs. This review article focuses on the role of oxidative/nitrosative stress in developing RBC and PLT storage lesions, with a special glance at its biochemistry and cross-talk with phosphorylative signal transduction. In this sense, we enlighten the potential contribution of new branches of proteomics in identifying novel points of intervention for the improvement of blood product quality. PMID- 25910537 TI - A randomized double blind control trial comparing filgrastim and pegfilgrastim in cyclophosphamide peripheral blood hematopoietic stem cell mobilization. AB - There are few randomized trials comparing filgrastim and pegfilgrastim in peripheral blood stem cell mobilization (PBSCM). None of the trials studied the effects of the timing of pegfilgrastim administration on the outcomes of mobilization. We conducted a randomized triple blind control trial comparing the outcomes of filgrastim 5 ug/kg daily from day 3 onwards, 'early' pegfilgrastim 6 mg on day 3 and 'delayed' pegfilgrastim 6 mg on day 7 in cyclophosphamide PBSCM in patients with no previous history of mobilization. Peripheral blood (PB) CD34+ cell count was checked on day 8 and day 11 onward. Apheresis was started when PB CD34+ >= 10/ul from day 11 onward. The primary outcome was the successful mobilization rate, defined as cumulative collection of >= 2 * 10(6)/kg CD34+ cells in three or less apheresis. The secondary outcomes were the day of neutrophil and platelet engraftment post transplantation. There were 156 patients randomized and 134 patients' data analyzed. Pegfilgrastim 6 mg day 7 produced highest percentage of successful mobilization, 34 out of 48 (70.8%) analyzed patients, followed by daily filgrastim, 28 out of 44 (63.6%) and day 3 pegfilgrastim, 20 out of 42 (47.6%) (p = 0.075). Pegfilgrastim day 7 and daily filgrastim reported 1.48 (p = 0.014) and 1.49 (p = 0.013) times higher successful mobilization rate respectively as compared to pegfilgrastim day 3 after adjusting for disease, gender and exposure to myelotoxic agent. Multiple myeloma patients were three times more likely to achieve successful mobilization as compared to acute leukemia or lymphoma patients. Pegfilgrastim avoided the overshoot of white cells compared to filgrastim. There was no difference in the duration of both white cells and platelet recovery post transplantation between the three interventional arms. PMID- 25910538 TI - A concise review on extracorporeal photochemotherapy: Where we began and where we are now and where are we going! AB - Currently, more than 1080 peer-reviewed papers are displayed on PubMed when initiating a search for therapeutic indications and mechanisms of action of extracorporeal photochemotherapy (ECP). This concise review focuses mainly on some prevalent and traditional treatment-resistant disorders with an emphasis on immunologic complications emerging from stem cell and solid organ transplantation. PMID- 25910539 TI - Systemic impact molds mesenchymal stromal/stem cell aging. AB - Aging is associated with an accruing emergence of non-functional tissues. Mesenchymal stem cells (MSC) bring forth progenitors with multi-lineage differentiation potential, yet, they also exhibit anti-inflammatory and tissue protective properties. Due to aging, altered tissue microenvironments constrict controlled stem cell proliferation and progenitor differentiation, thus diminishing the fitness of MSC. Therefore, deepening our understanding of metabolic, molecular and environmental factors impacting on MSC during human aging as well as providing new vistas on their role in promoting healthy aging and preventing age-associated disease is pivot. It is anticipated that integrative quantification of systemic parameters dominantly impacting on MSC will also enable effective personalized prognosis and provision of effective early medical interventions. Working along this line, it can be envisaged that standards in medical therapies can be individually adjusted by accounting not solely for the patient's chronological age or other physical parameters rather than specific physiological parameters which are believed to functionally shape stem cell niches within the bone marrow. PMID- 25910540 TI - Big Data Technologies: New Opportunities for Diabetes Management. AB - The so-called big data revolution provides substantial opportunities to diabetes management. At least 3 important directions are currently of great interest. First, the integration of different sources of information, from primary and secondary care to administrative information, may allow depicting a novel view of patient's care processes and of single patient's behaviors, taking into account the multifaceted nature of chronic care. Second, the availability of novel diabetes technologies, able to gather large amounts of real-time data, requires the implementation of distributed platforms for data analysis and decision support. Finally, the inclusion of geographical and environmental information into such complex IT systems may further increase the capability of interpreting the data gathered and extract new knowledge from them. This article reviews the main concepts and definitions related to big data, it presents some efforts in health care, and discusses the potential role of big data in diabetes care. Finally, as an example, it describes the research efforts carried on in the MOSAIC project, funded by the European Commission. PMID- 25910541 TI - Youth-Perceived Burden of Type 1 Diabetes: Problem Areas in Diabetes Survey Pediatric Version (PAID-Peds). AB - BACKGROUND: Management of type 1 diabetes in childhood can be challenging and overwhelming. Despite availability of advanced treatments and new technologies, the burden has not decreased as current approaches to intensive therapy are not without need for patient involvement. This study aimed to design and validate a measure of youth-reported burden related to type 1 diabetes management. METHOD: A multidisciplinary pediatric diabetes team designed the survey, based on a previously validated parent measure of diabetes-related burden (PAID-PR); survey revisions and pilot testing followed. The 20-item PAID-Peds assesses burden over the past month. Youth with type 1 diabetes (N = 126, ages 8-17, intensively treated with insulin pump therapy or multiple daily injections) completed the new survey, along with other surveys; parents completed companion measures. Electronic medical records and blood glucose meter download provided other salient data. RESULTS: The PAID-Peds displayed excellent internal consistency (alpha = .94) and acceptable test-retest reliability (intraclass correlation .66, P < .0001). The PAID-Peds correlated significantly with both youth and parent reports of diabetes-specific family conflict, negative affect around blood glucose monitoring, depressive symptomatology, trait anxiety, and quality of life. It was not correlated with demographic or clinical characteristics of the youth. CONCLUSIONS: This new measure, the PAID-Peds, of youth-reported burden related to type 1 diabetes may have clinical and research utility, particularly in the current era of emerging diabetes technologies that require ongoing patient input. PMID- 25910543 TI - Adiponectin in Diabetic Subjects Without Any Micro- or Macrovascular Complications: A Review. PMID- 25910542 TI - The Effect of a Global, Subject, and Device-Specific Model on a Noninvasive Glucose Monitoring Multisensor System. AB - BACKGROUND: We study here the influence of different patients and the influence of different devices with the same patients on the signals and modeling of data from measurements from a noninvasive Multisensor glucose monitoring system in patients with type 1 diabetes. The Multisensor includes several sensors for biophysical monitoring of skin and underlying tissue integrated on a single substrate. METHOD: Two Multisensors were worn simultaneously, 1 on the upper left and 1 on the upper right arm by 4 patients during 16 study visits. Glucose was administered orally to induce 2 consecutive hyperglycemic excursions. For the analysis, global (valid for a population of patients), personal (tailored to a specific patient), and device-specific multiple linear regression models were derived. RESULTS: We find that adjustments of the model to the patients improves the performance of the glucose estimation with an MARD of 17.8% for personalized model versus a MARD of 21.1% for the global model. At the same time the effect of the measurement side is negligible. The device can equally well measure on the left or right arm. We also see that devices are equal in the linear modeling. Thus hardware calibration of the sensors is seen to be sufficient to eliminate interdevice differences in the measured signals. CONCLUSIONS: We demonstrate that the hardware of the 2 devices worn on the left and right arms are consistent yielding similar measured signals and thus glucose estimation results with a global model. The 2 devices also return similar values of glucose errors. These errors are mainly due to nonstationarities in the measured signals that are not solved by the linear model, thus suggesting for more sophisticated modeling approaches. PMID- 25910544 TI - Use of Pectus Bars in the Reconstruction of Complex Anterior Chest Wall Defects. PMID- 25910545 TI - Incidence and Triggers of Asthma Exacerbations Attended in the Emergency Department as a Level of Care Indicator (ASMAB III, 2005 and ASMAB IV, 2011). AB - INTRODUCTION: The identification of asthma exacerbations (AE) seen in emergency departments and in the home is proposed as a parameter of asthma control and for monitoring environmental triggers. PATIENTS AND METHODS: All AEs seen in 2005 and 2011 in the reference hospital of the region and in the patients' homes by the Emergency Medical Services were identified. RESULTS: The incidence of AE was 1.93/10(6)inhabitants/day during 2005, and 2/10(6)inhabitants/day in 2011. The most common triggers were slow onset common cold of more than 24h duration in 104/219 (47%) AEs in 2005 and 107/220 (49%) in 2011; prior bronchial symptoms with cough, expectoration and fever were recorded in 41/219 (19%) in 2005 and in 57/220 (26%) AEs in 2011. In total, 49% (2005) and 74% (2011) of the AEs had onset more than 24h before admission. CONCLUSIONS: No significant differences were observed in the rate of attendance in the emergency department due to AE between 2005 and 2011. The most common triggers were common cold and bronchial symptoms with expectoration and fever. AE had begun more than 24h previously in at least half of cases. These findings appear to suggest that there may be a scope for improvement in the outpatient care of the asthmatic patient. PMID- 25910546 TI - Double or Dual Bronchodilation: Defining the Correct Term. PMID- 25910547 TI - Cortico-dependent Asthma: Our Clinical Experience. PMID- 25910548 TI - Defining Patient and Caregivers' Experience of Home Oxygen Therapy. AB - INTRODUCTION: Home oxygen therapy has a great impact on the lives of patients and their families. The aim of this study is to define the opinions, perceptions and attitudes of patients and their caregivers regarding home oxygen. METHOD: Qualitative, phenomenological study of a sample of 57 subjects, consisting of 18 family members and/or caregivers and 39 patients receiving home oxygen in urban centers. Five focus groups were formed between March and July 2014 in hospitals in Barcelona, Madrid and Alicante. Prior informed consent was obtained from patients and families. The study material consisted of audio recordings of all focus group interviews, transcription of selected materials and field notes. Data analysis was performed using constant comparison method, establishing 2 levels of analysis. RESULTS: Data from the focus groups were analyzed on 2 levels. A first level of analysis gave 21 categories. In a second level of analysis, these were integrated into 6 meta-categories: care provided by health professionals, psychological impact, care provided by commercial companies, impact on daily life, problems and satisfaction. CONCLUSIONS: Home oxygen has a major psychological impact on the daily lives of both patients and their families, and can cause social isolation. Although the results show that healthcare professionals are highly appreciated, better coordination is needed between different levels of care and companies supplying oxygen in order to provide patients and families with consistent information and useful strategies. PMID- 25910549 TI - BODE Index: A Good Quality of Life Marker in Chronic Obstructive Pulmonary Disease Patients. PMID- 25910550 TI - Provision of care by medical residents and the impact on quality. AB - The quality of care received by patients is a basic element of modern medicine. Medical residents or interns are essential within the healthcare system, but their lack of experience can raise concerns about the quality of care given. A registrar or specialist has greater knowledge and skills, while a resident has greater motivation and enthusiasm. The aim of training programs is to prepare residents to provide high quality care. This requires close supervision that seems to be lacking, with the consequent impact on both healthcare quality and academic results. The so-called "July effect" refers to the diminished quality of care during the summer months when resident physicians switch over. The results of studies analysing this effect vary widely, but the loss of efficacy during these months does seem to be real. Pulmonology is one of medical specialties that generates the least demand for internships and residencies, but it is impossible to determine if this affects the quality of care. The high prevalence of respiratory diseases and the latest diagnostic and therapeutic advances may mean that this situation will change in coming years. PMID- 25910551 TI - 14N Quadrupole Resonance line broadening due to the earth magnetic field, occuring only in the case of an axially symmetric electric field gradient tensor. AB - As demonstrated before, the application of a weak static B0 magnetic field (less than 10 G) may produce definite effects on the 14N Quadrupole Resonance line when the electric field gradient tensor at the nitrogen nucleus level is of axial symmetry. Here, we address more precisely the problem of the relative orientation of the two magnetic fields (the static field and the radio-frequency field of the pure NQR experiment). For a field of 6G, the evolution of the signal intensity, as a function of this relative orientation, is in very good agreement with the theoretical predictions. There is in particular an intensity loss by a factor of three when going from the parallel configuration to the perpendicular configuration. By contrast, when dealing with a very weak magnetic field (as the earth field, around 0.5 G), this effect drops to ca. 1.5 in the case Hexamethylenetetramine (HMT).This is explained by the fact that the Zeeman shift (due to the very weak magnetic field) becomes comparable to the natural line width. The latter can therefore be determined by accounting for this competition. Still in the case of HMT, the estimated natural line-width is half the observed line-width. The extra broadening is thus attributed to earth magnetic field. The latter constitutes therefore the main cause of the difference between the natural transverse relaxation time (T2) and the transverse relaxation time derived from the observed line-width (T2(*)). PMID- 25910552 TI - Photodynamic efficiency of hypericin compared with chlorin and hematoporphyrin derivatives in HEp-2 and Vero epithelial cell lines. AB - Hypericin (HY) is a photoactive aromatic dianthraquinone that is considered a potent photodynamic agent. In this study, hypericin and two other photosensitizers, a hematoporphyrin derivative (Photogem((r)); PG) and a chlorin derivative (Photodithazine((r)); PZ), were compared in terms of their phototoxicity toward two cell lines, HEp-2 and Vero. The median inhibitory concentration (IC(50)) of each of the photosensitizers was obtained after a 16.2J cm(-2) dose of irradiation at 630 +/- 10 nm. The IC(50) values were 0.07 +/- 0.01 (HY), 1.0 +/- 0.2 (PZ), and 9 +/- 1 MUgmL(-1) (PG) in HEp-2 cells and 0.3 +/- 0.1 (HY), 1.6 +/- 0.2 (PZ) and 11 +/- 1 MUgmL(-1) (PG) in Vero cells, showing that HY is more phototoxic than the others when irradiated at 630 nm. If these results are analyzed, simultaneously, with the first-order constant for BSA tryptophan photooxidation, obtained by fluorescence decay (lambda(excitation)=280 nm), which are 11*10(-3) min(-1)+/-1. 10(-3) min(-1) (HY), 10 * 10(-3) min(-1)+/-1 * 10(-3) min(-1) (PZ), and 6 * 10(-3)min(-1) +/- 1*10(-3)min(-1) (PG), it is possible to infer that the photodynamic efficiency alone is not sufficient to explain the higher HY phototoxicity. The lipophilicity is also an important factor for an efficient target cell accumulation and was assessed for all sensitizers through the octanol-water partition coefficient (log P): 1.20 +/- 0.02 (HY), -0.62 +/- 0.03 (PZ), and -0.9 +/- 0.2 (PG). The higher value for HY correlates well with its observed superior efficiency to promote damage at low concentrations and doses. As HY is used for the long-term treatment of mild depression, it is considered safe for humans. This fact and the present results reinforce the great potential of this photosensitizer to replace porphyrin derivatives, with the advantages that mean it could be used as photosensitizer in clinical photodynamic therapy. PMID- 25910553 TI - State adoption of Medicaid 1915(c) waivers for children and youth with Autism Spectrum Disorder. AB - BACKGROUND: The prevalence of Autism Spectrum Disorder (ASD) has increased dramatically, with one in every 68 children in the U.S. currently diagnosed with ASD. Medicaid is the primary public funder of health care services for individuals with ASD. One mechanism state Medicaid agencies can use to craft ASD specific services is a 1915(c) waiver. OBJECTIVE: This study investigated what state policy makers perceived to be primary success factors and barriers to adopting an ASD specific 1915(c) waiver, as well as what services and supports are available in each state for children and transition-age youth with ASD. METHODS: Data were collected by contacting state Medicaid directors via email with an electronic survey, with an 84% response rate. RESULTS: Support from state legislators and parents and family members were the primary success factors in adopting an ASD specific waiver. The primary barrier was insufficient funding. States not adopting an ASD specific waiver also perceived that children and youth with ASD were served sufficiently well through other Medicaid benefits. Analysis of specific services indicated that the majority of states provide their services to children and transition age youth with ASD through a 1915(c) waiver for individuals with intellectual or developmental disabilities, often coupled with an ASD specific waiver for children, another 1915(c) waiver for children, and/or a another 1915(c) waiver, most often for children with serious emotional disturbance. CONCLUSION: Further research is needed to determine which approach(es) is most effective in enhancing access and improving outcomes for children and youth with ASD. PMID- 25910554 TI - Factors associated with parental ratings of condition severity for children with autism spectrum disorder. AB - BACKGROUND: There is currently little consensus on how the severity of a child's autism spectrum disorder (ASD) should be measured, and yet despite the lack of a standardized definition, parents were readily able to answer a question asking them to describe the severity of his/her child's ASD in a national survey. OBJECTIVE: The current study examined factors associated with a parent's judgment of ASD severity, by identifying child and household characteristics that were associated with a parent's severity rating of his/her child's ASD, including child ASD symptomatology, child impact, and family impact. METHODS: Data came from the 2011 Survey of Pathways to Diagnosis and Services ("Pathways"). A total of 967 parents in households with a child diagnosed with ASD between the ages of 6-17 were eligible for the current study. A measurement model was used to create latent factors of child symptoms, child impact, and family impact; multivariate logistic regression models examined the relationship between these latent factors and the parent's severity rating of their child's ASD. RESULTS: Children with higher family impact factor scores were more likely to have parents who rated their child's ASD as the most severe. Surprisingly, symptomatology and impact on the child were less predictive of severe ratings. CONCLUSIONS: A parent's conceptualization of their child's ASD severity may vary more as a function of the impact of the child's condition on the family and less as a function of the symptoms exhibited by the child or the impact directly felt by the child. PMID- 25910555 TI - The epidemiology of self-defense gun use: evidence from the National Crime Victimization Surveys 2007-2011. AB - OBJECTIVES: To describe the epidemiology of self-defense gun use (SDGU) and the relative effectiveness of SDGU in preventing injury and property loss. METHODS: Data come from the National Crime Victimization Survey for 2007-2011, focusing on personal contact crimes. For property loss, we examined incidents where the intent was to steal property. Multivariate analyses controlled for age, gender of offender and victim, if offender had a gun, urbanicity, and thirteen types of self-protective action. RESULTS: Of over 14,000 incidents in which the victim was present, 127 (0.9%) involved a SDGU. SDGU was more common among males, in rural areas, away from home, against male offenders and against offenders with a gun. After any protective action, 4.2% of victims were injured; after SDGU, 4.1% of victims were injured. In property crimes, 55.9% of victims who took protective action lost property, 38.5 of SDGU victims lost property, and 34.9% of victims who used a weapon other than a gun lost property. CONCLUSIONS: Compared to other protective actions, the National Crime Victimization Surveys provide little evidence that SDGU is uniquely beneficial in reducing the likelihood of injury or property loss. PMID- 25910556 TI - Advances in upper airway cough syndrome. AB - Upper airway cough syndrome (UACS), previously referred to as postnasal drip syndrome, is one of the most common causes of chronic cough. However, the pathogenesis of UACS/postnasal drip syndrome remains unclear, and physicians in countries throughout the world have different definitions and ways of treating this disease. The various proposed pathogeneses of UACS include the early postnasal drip theory, subsequent chronic airway inflammation theory, and a recent sensory neural hypersensitivity theory. Additionally, some researchers suggest that UACS is a clinical phenotype of cough hypersensitivity syndrome. While the general principles involved in treating UACS are similar throughout the world, the specific details of treatment differ. This review summarizes the various definitions, pathogenic mechanisms, treatments, and other aspects of UACS, to aid clinicians in expanding their knowledge of how to diagnose and treat this syndrome. PMID- 25910557 TI - Clinically acceptable colchicine concentrations have potential for the palliative treatment of human cholangiocarcinoma. AB - Microtubules are an ideal target for anticancer drugs because of their essential role in mitosis. Colchicine is a microtubule destabilizer. Whether the clinically acceptable colchicine concentrations had anticancer effects on human cholangiocarcinoma cells was investigated. Two human cholangiocarcinoma cell lines (C14/KMUH, C51/KMUH) were investigated using clinically acceptable plasma colchicine concentrations (2 ng/mL and 6 ng/mL for the in vitro experiment, 0.07 mg colchicine/kg/d * 14 days for the nude mouse experiment). Our results showed that colchicine caused significantly dose-dependent antiproliferative effects on both cell lines (all p < 0.0001). Nude mouse (BALB/c-nu) experiments showed that the increased tumor volume ratios in colchicine-treated mice were significantly lower than control mice started from the 11th day of treatment (p = 0.0167). The tumor growth rates in colchicine-treated mice after 14 days of treatment were significantly lower than in control mice (0.147 +/- 0.004/d vs. 0.274 +/- 0.003/d, p = 0.0015). In addition to the well-known direct colchicine-tubulin interaction as a common anticancer mechanism of colchicine, microarray and quantitative reverse transcriptase-polymerase chain reaction showed that the antiproliferative effects of both 2 ng/mL and 6 ng/mL colchicine on C14/KMUH cells could be partially explained by downregulations of both HSD11B2 and MT-COI. There was no effect of colchicine on MT-COI expression in C51/KMUH cells, however, 6 ng/mL colchicine also downregulated HSD11B2 in this cell line. In conclusion, clinically acceptable colchicine concentrations can inhibit the proliferation of human cholangiocarcinoma cells. This drug has good potential for the palliative treatment of cholangiocarcinoma due to its low cost and our long standing prescription experience. PMID- 25910558 TI - Vitamin D decreases the secretion of matrix metalloproteinase-2 and matrix metalloproteinase-9 in fibroblasts derived from Taiwanese patients with chronic rhinosinusitis with nasal polyposis. AB - Vitamin D and its derivatives have modulatory effects in immunological and inflammatory responses. Such properties suggest that they might have an impact on chronic inflammatory airway diseases, including nasal polyposis. The aim of this study was to understand the role of vitamin D in chronic rhinosinusitis with nasal polyps (CRSwNP) by investigating its effect on the secretion of matrix metalloproteinase-2 (MMP-2) and MMP-9 in nasal polyp-derived fibroblasts. Two primary fibroblast cultures were established from nasal polyp tissues obtained during surgery. The nasal polyp-derived fibroblasts were stimulated with tumor necrosis factor-alpha (TNF-alpha; 10 ng/mL) for 24 hours, followed by replacement with media alone or with vitamin D derivatives (calcitriol or tacalcitol; 10MUM) and incubated for another 24 hours. After the treatments, the levels of MMP-2 and MMP-9 secreted were evaluated by both enzyme-linked immunosorbent assay (ELISA) and Western blot analysis. ELISA results revealed that TNF-alpha could substantially stimulate the secretion of MMP-2 (p < 0.01) and MMP-9 (p < 0.001) in nasal polyp-derived fibroblasts. More importantly, such stimulatory effect was significantly suppressed by adding calcitriol (p <= 0.01 for MMP-2 and p < 0.001 for MMP-9) or tacalcitol (p < 0.005 for both MMP-2 and MMP-9). The ELISA results were also confirmed by Western blot analysis. The inhibitory effect of vitamin D derivatives on MMP-2 and MMP-9 secretion could potentiate their application in pharmacotherapy of Taiwanese CRSwNP patients. PMID- 25910559 TI - Buffered l-ascorbic acid, alone or bound to KMUP-1 or sildenafil, reduces vascular endothelium growth factor and restores endothelium nitric oxide synthase in hypoxic pulmonary artery. AB - Ascorbic acid bound to KMUP-1 and sildenafil were examined for their antioxidant effects on vascular endothelium growth factor (VEGF) and endothelium nitric oxide synthase (eNOS) in hypoxic pulmonary artery (PA). Inhaled KMUP-1 and oral sildenafil released NO from eNOS. The effect of buffered l-ascorbic acid, alone and bound to KMUP-1 or sildenafil, for treating pulmonary arterial hypertension (PAH) is unclear. In this study, the antioxidant capacity of ascorbic acid increased the beneficial effects of KMUP-1 on PAH. KMUP-1A and sildenafil-A (5 mg/kg/d) were administered to hypoxic PAH rats. Pulmonary artery blood pressure, and VEGF, Rho kinase II (ROCK II), eNOS, soluble guanylate cyclase (sGC-alpha), and protein kinase G expression in lung tissues were measured to link PAH and right ventricular hypertrophy. Hypoxic rats had higher pulmonary artery blood pressure, greater PA medial wall thickness and cardiac weight, and a higher right ventricle/left ventricle + septum [RV/(LV+S)] ratio than normoxic rats. Oral KMUP 1A or sildenafil-A for 21 days in hypoxia prevented the rarefaction of eNOS in immunohistochemistry (IHC), reduced the IHC of VEGF in PAs, restored eNOS/protein kinase G/phosphodiesterase 5A; unaffected sGC-alpha and inactivated ROCK II expression were also found in lung tissues. In normoxic PA, KMUP-1A/Y27632 (10MUM) increased eNOS and reduced ROCK II. ROCK II/reactive oxidative species was increased and eNOS was reduced after long-term hypoxia for 21 days. KMUP-1A or Y27632 blunted ROCK II in short-term hypoxic PA at 24 hours. l-Ascorbic acid + l-sodium ascorbate (40, 80MUM) buffer alone directly inhibited the IHC of VEGF in hypoxic PA. Finally, KMUP-1A or sildenafil-A reduced PAH and associated right ventricular hypertrophy. PMID- 25910560 TI - Genetic polymorphisms of CYP2C19 and IL1B have no influence on esomeprazole treatment for mild erosive esophagitis. AB - Interleukin (IL)-1beta is a potent inhibitor of gastric acid secretion and its genetic polymorphism is linked to the severity of reflux esophagitis. Proton-pump inhibitor (PPI) metabolized by P450 2C19 (CYP2C19) is the chief medication in reflux esophagitis treatment. The CYP2C19 genotype may influence the therapeutic effect of PPI for reflux esophagitis. From November 2009 to June 2012, 184 patients were enrolled in this study with endoscopy examination, 8 weeks of esomeprazole treatment, and 20 weeks of follow-up with questionnaire. These patients also received endoscopy examination after 20 weeks. Blood was collected for genetic polymorphism analysis with polymerase chain reaction. After 8 weeks of treatment with esomeprazole, all of these 184 patients had achieved complete symptom relief. However, in the following 12 weeks, 58.70% (108/184) complained of symptom relapse, 45.65% (84/184) patients had persistent esophageal erosion verified by endoscopy, and in total, 76.09% (140/184) patients had treatment failure at the end of 20 weeks. There were no influences between the genetic polymorphisms of CYP2C19 and IL1B to treatment failure (p = 0.896). Therefore, prolonging PPI treatment and further lifestyle modification might be warranted for symptomatic mild esophagitis. There were no relationships between IL-1beta and CYP2C19 in the treatment effect in mild reflux esophagitis. PMID- 25910561 TI - Risk factors and treatment responses in patients with vitiligo in Japan--A retrospective large-scale study. AB - Vitiligo is a refractory skin disease. To investigate the risk factors and treatment responses of patients with vitiligo in Japan, we recorded and analyzed the details of 713 vitiligo patients (comorbidity, treatment responses, family history, age, and sex) who visited the dermatology clinic of the Nagoya City University Hospital, Nagoya, Japan between January 2004 and August 2010 (mean age, 35.2 years; 302 men, 411 women) using logistic regression analysis. The results are expressed as odds ratios (OR) with 95% confidence interval (CI). Patients were diagnosed with vitiligo [n = 644; 338 generalized type (47.4%), 170 segmental type (23.8%), and 136 localized type (19.1%)], nevus depigmentosus (n = 53, 7.4%), halo nevus (n = 14, 2.0%), and hypomelanosis of Ito (n = 2, 0.3%). For generalized and localized types, none of the analyzed factors were statistically significant. For the segmental type, antinuclear antibody (OR = 1.005; 95% CI, 1.00-1.01; p < 0.05) and onset age < 14 years were the significant factors in patients between 15 years and 29 years (OR = 0.246; 95% CI, 0.113-0.538; p < 0.001), 30-54 years (OR = 0.0419; 95% CI, 0.0133-0.132; p < 0.001), and >55 years (OR = 0.0171; 95% CI, 0.00333-0.0879; p < 0.001). The treatment response rates for narrow-band UV-B, topical vitamin D3, and punch graft (1 mm minigraft) were, respectively, as follows: (1) generalized type: 46.3%, 21.1%, and 38.9%; (2) segmental type: 20.3%, 29.0%, and 77.3%; and (3) localized type: 29.2%, 54.8%, and 73.3%. We report the comorbidities and efficacy rates of these treatments. The response data for these treatments, in particular, would be of assistance to the previous explanations, because there were only a few reports on the response data for these treatments. The appropriate treatment should be selected depending on the type of vitiligo. PMID- 25910562 TI - Palatal bone thickness and associated factors in adult miniscrew placements: A cone-beam computed tomography study. AB - Palatal bone thickness measurements obtained by cone-beam computed tomography (CBCT) in 30 men and 28 women were evaluated for associated factors. Palatal bone thickness was measured at 20 locations unilateral to the midpalatal suture and posterior to the incisive foramen. Tongue position, presence of posterior crossbite, and palatal morphology were recorded. Lateral cephalograms acquired from CBCT data were used to calculate Frankfort-mandibular plane angles (FMA). At almost all sites, bone thickness was greater in males than in females, but the difference was statistically significant at only seven sites. Bone thickness showed no associations with tongue position, palatal morphology, or presence of posterior crossbite. In women, FMA significantly correlated with bone thickness at 12 locations. In conclusion, palatal bone thickness is unassociated with tongue position, posterior crossbite, or palatal morphology. In hyperdivergent women, however, available bone may be smaller than normal in the middle and posterior palatal areas; in such cases, a shorter than normal miniscrew may be needed to avoid penetrating the nasal cavity. PMID- 25910563 TI - Host and virological characteristics of patients with hepatitis C virus mixed genotype 1 and 2 infection. AB - The prevalence and characteristics of patients with hepatitis C virus mixed genotype 1 and 2 infection (HCV-1/2) remains unclear. For each HCV-1/2 patient with histological data available, two age- and sex-matched HCV-1 and HCV-2 infected patients were selected for comparison, respectively. Of the 2776 patients, 261 (9.4%) patients were identified as having mixed HCV-1/2 infection. The histological severity did not differ among HCV-1/2 patients and controls. The proportion of patients with the interleukin-28B (IL-28B) rs8099917 TT genotype did not differ between patients with mixed-1/2 and HCV-1 infection (82.6% vs. 86.5%, p = 0.38). However, HCV-2 infected patients had a significantly higher proportion of the rs8099917 TT genotype compared to patients with mixed HCV-1/2 infections (91.6% vs. 82.6%, p = 0.03). The HCV RNA levels were similar in patients with HCV-1/2 and HCV-1 infections (5.5 +/- 0.8 log IU/mL vs. 5.5 +/- 0.9 log IU/L, p = 0.73), which were both significantly higher than that of HCV-2 infection (5.1 +/- 0.9 log IU/mL, both p < 0.001). Linear regression analysis revealed that the factors of HCV-1/2 infection [beta: 0.204; 95% confidence interval (CI): 0.183-0.598, p < 0.001], body weight (beta: 0.150; CI: 0.003 0.021, p = 0.008), and age (beta: -0.139; CI: -0.020 to -0.002, p = 0.01) were independently correlated with HCV RNA levels in patients with HCV-2 and mixed HCV 1/2 infection. We concluded that the host genetic and viral presentations of patients with mixed HCV-1/2 infection were more similar to those of patients with HCV-1 infection than patients with HCV-2 infection. PMID- 25910564 TI - Perils and promise in big data. PMID- 25910565 TI - Effectiveness and feasibility of hysteroscopic sterilization techniques: a systematic review and meta-analysis. AB - OBJECTIVE: To assess whether hysteroscopic sterilization is feasible and effective in preventing pregnancy. Secondarily, to identify risk factors for failure of hysteroscopic sterilization. DESIGN: A systematic review and meta analysis. SETTING: Not applicable. PATIENT(S): Women undergoing hysteroscopic sterilization. INTERVENTION(S): Hysteroscopic sterilization with a commercially available system (Ovabloc Intra Tubal Device, Essure system, or Adiana permanent contraception system). MAIN OUTCOME MEASURE(S): Successful placement at first attempt, confirmed correct placement, complications, incidence of pregnancy, and risk factors for placement failure in hysteroscopic sterilization. RESULT(S): Of the 429 citations identified, 45 articles were eligible for analyses. No randomized controlled trials (RCTs) were identified, just cohort studies. Six articles concerned Ovabloc, 37 Essure, and two Adiana sterilization. The probabilities for successful bilateral placement in a first attempt for Ovabloc, Essure, and Adiana, were, respectively, in the ranges 78%-84%, 81%-98%, and 94%. The probabilities of successful bilateral placement could not be pooled because of substantial heterogeneity. The 36 months' cumulative pregnancy rate of Adiana was 16 of 1,000. Reliable pregnancy rates after sterilization with Ovabloc or Essure method could not be calculated. For all three hysteroscopic techniques, the incidence of complications and their severity has not been studied adequately and remains unclear. We also found too little evidence to identify risk factors for placement failure. CONCLUSION(S): Sterilization by hysteroscopy seems feasible, but the effectiveness and risk factors for failure of sterilization remain unclear owing to the poor-quality evidence. Both currently applied hysteroscopic sterilization techniques and the coming new techniques must be evaluated properly for feasibility and effectiveness. Appropriate RCTs and observational studies with sufficient power and complete and long-term (>10 years) follow-up data on unintended pregnancies and complications are needed. PMID- 25910567 TI - Pregnancy-related complications and adverse pregnancy outcomes in multiple pregnancies resulting from assisted reproductive technology: a meta-analysis of cohort studies. AB - OBJECTIVE: To provide an up-to-date comparison of pregnancy-related complications and adverse pregnancy outcomes of multiple pregnancies generated with assisted reproductive technology (ART) vs. spontaneous conception. DESIGN: Meta-analysis. SETTING: University-affiliated teaching hospital. PATIENT(S): Multiple pregnancies conceived by ART or naturally. INTERVENTION(S): Searches through October 2014 were conducted on PubMed, Google Scholar, Cochrane Libraries, China Biology Medicine disc, Chinese Scientific Journals Fulltext Database, China National Knowledge Infrastructure, and Wanfang Data, to identify studies that met prestated inclusion criteria. Either a fixed- or a random-effects model was used to calculate the overall combined risk estimates. Subgroup analysis was performed to explore potential heterogeneity moderators. MAIN OUTCOME MEASURE(S): Pregnancy related complications and adverse pregnancy outcomes. RESULT(S): Thirty-nine cohort studies involving 146,008 multiple births were included in the meta analysis. Multiple pregnancies from ART were associated with a higher risk of premature rupture of membranes (relative risk [RR] = 1.20, 95% confidence interval [CI]: 1.05-1.37; I(2) = 15%); pregnancy-induced hypertension (RR = 1.11, 95% CI: 1.04-1.19; I(2) = 6%); gestational diabetes mellitus (RR = 1.78, 95% CI: 1.25-2.55; I(2) = 42%); preterm birth (RR = 1.08, 95% CI: 1.03-1.14; I(2) = 83%); very preterm birth (RR = 1.18, 95% CI: 1.04-1.34; I(2) = 79%); low birth weight (RR = 1.04, 95% CI: 1.01-1.07; I(2) = 47%); very low birth weight (RR = 1.13, 95% CI: 1.01-1.25; I(2) = 62%); and congenital malformation (RR = 1.11, 95% CI: 1.02 1.22; I(2) = 30%). The relevant heterogeneity moderators have been identified by subgroup analysis. Sensitivity analysis yielded similar results. No evidence of publication bias was observed. CONCLUSION(S): Although the role of potential bias and evidence of heterogeneity should be carefully evaluated, the present study suggests that multiple pregnancies generated via ART, vs. spontaneous conception, are associated with higher risks of pregnancy-related complications and adverse pregnancy outcomes. Further research is needed to determine which aspect of ART poses the most risk and how this risk can be minimized. PMID- 25910568 TI - Poor ovarian response in women undergoing in vitro fertilization is associated with altered microRNA expression in cumulus cells. AB - OBJECTIVE: To analyze the association of micro-ribonucleic acid (miRNA) expression with the number of oocytes retrieved, in women undergoing in vitro fertilization (IVF). DESIGN: Experimental study. SETTING: Academic medical center. PATIENT(S): A total of 189 women undergoing IVF-intracytoplasmic sperm injection (ICSI). INTERVENTION(S): Pooled cumulus cells were collected. MAIN OUTCOME MEASURE(S): Poor responders were identified as patients who produced fewer oocytes than the 25th percentile of their respective age group. MicroRNAs were extracted from cumulus cells, and an miRNA microarray was performed, comparing poor responders (n = 3) to non-poor responders (n = 3). Expression of miR-21-5p (active strand of miR-21) and miR-21-3p was tested in poor responders (n = 21) and non-poor responders (n = 29), using reverse transcription real-time polymerase chain reaction (qRT-PCR). Regulation of miR-21-5p and miR-21-3p, in human granulosa-like tumor (KGN) cells, by estradiol (E2), was tested in vitro. RESULT(S): MicroRNA microarray analysis showed up-regulation of 16 miRNAs and down-regulation of 88 miRNAs in poor responders. Notably, miR-21 was significantly up-regulated 5-fold in poor-responder samples. Analysis using qRT PCR confirmed that miR-21-5p expression was significantly up-regulated in poor responders, whereas miR-21-3p expression was significantly lower, suggesting that elevated miR-21-5p expression in cumulus cells is not regulated at the pre-miR-21 level in poor responders. Both miR-21-5p and miR-21-3p were increased in KGN cells in response to higher doses of E2; their expression was not affected at lower E2 concentrations. CONCLUSION(S): We found that poor response to IVF is associated with altered miRNA expression in cumulus cells, specifically with elevated expression of miR-21-5p, and that this elevated expression is independent of lower serum E2 levels in poor responders. PMID- 25910570 TI - Gestational hypothyroidism: development of mild hypothyroidism in early pregnancy in previously euthyroid women. AB - OBJECTIVE: To determine the proportion of euthyroid women attending a fertility practice who develop hypothyroidism in very early pregnancy (gestational hypothyroidism [GHT]), and to examine the association of GHT with exogenous gonadotropin treatment. DESIGN: Retrospective cohort study. SETTING: A private reproductive medicine practice. PATIENT(S): All healthy women (N = 94) with infertility or recurrent pregnancy loss, TSH level <2.5 mIU/L, negative thyroid peroxidase antibodies at initial evaluation, and not taking thyroid medication, who conceived during an 18-month period. INTERVENTION(S): Usual fertility care; 30 women who had received exogenous gonadotropins. MAIN OUTCOME MEASURE(S): Serum TSH level at the time of pregnancy detection. RESULT(S): Gestational hypothyroidism (TSH >= 2.5 mIU/L) developed in 23 of 94 women (24%). The mean increase in serum TSH level from initial evaluation to early pregnancy was 0.45 +/- 0.08 [SE] mIU/L. There was a trend toward the association of GHT with use of exogenous gonadotropins. Gestational hypothyroidism was positively associated with initial prepregnancy TSH level. CONCLUSION(S): Euthyroid women may develop mild hypothyroidism in early pregnancy, especially after exogenous gonadotropin treatment. Appropriate vigilance will allow for timely levothyroxine treatment. PMID- 25910569 TI - Histone methylation and acetylation in ejaculated human sperm: effects of swim-up and smoking. AB - OBJECTIVE: To assess global methylation and acetylation level before and after swim-up in ejaculated human sperm. DESIGN: Prospective experimental study. SETTING: University-based hospital. PATIENT(S): Semen samples were obtained from 50 healthy volunteers (single sample per person) between December 2012 and May 2014. INTERVENTION(S): The semen samples were processed by the swim-up method. MAIN OUTCOME MEASURE(S): Sperm motility, strict morphology, DNA fragmentation index (DFI) by TUNEL, abnormal chromatin structure by toluidine blue staining, immunostaining of 8-hydroxy-2'-deoxyguanosine (8-OHdG) as an oxidative stress marker, immunostaining of 5-methyl-cytosine (5-mC) as a measurement of methylation level and immunostaining of six acetylation markers (H3K9ac, H3K14ac, H4K5ac, H4K8ac, H4K12ac, and H4K16ac) before and after swim-up. RESULT(S): After swim-up, motility and the percentage of normal form was significantly elevated. In the swim-up fraction, DFI and the percentage of abnormal chromatin structure were significantly lower and 8-OHdG levels were significantly higher. The 5-mC levels were significantly lower in the swim-up fraction, whereas no changes were observed in the positivity of six acetylation markers. Elevated percentage of normal form and decreased DFI and 5-mC levels were observed only in nonsmokers; 8 OHdG level was significantly higher in the swim-up fraction only from smokers. After swim-up, 5-mC levels were positively correlated with DFI. CONCLUSION(S): This is the first study demonstrating decreased methylation and unchanged acetylation patterns in human sperm after swim-up preparation. PMID- 25910571 TI - Predictive value of maternal serum human chorionic gonadotropin levels in pregnancies achieved by in vitro fertilization with single cleavage and single blastocyst embryo transfers. AB - OBJECTIVE: To compare serum hCG levels after transfer of a single fresh cleavage embryo and of a single fresh blastocyst embryo and to determine the predictive value of serum hCG levels for pregnancy outcomes. DESIGN: A single center retrospective cohort study. SETTING: Tertiary university health center. PATIENT(S): All fresh single ETs between December 2008 and December 2013. INTERVENTION(S): None. MAIN OUTCOME MEASURE(S): Mean serum hCG levels on day 16 after oocyte collection, after the transfer of a fresh single cleavage embryo and a fresh single blastocyst embryo were compared. Multivariable regression analysis was performed to determine the association of potential factors on hCG value and a clinical pregnancy. RESULT(S): One thousand twenty-six fresh single ETs were analyzed, 801 (638 pregnancies) from a single blastocyst transfer and 225 (167 pregnancies) from a single cleavage ET. The mean hCG levels resulting from a single fresh blastocyst transfer (299 +/- 204 IU/L) were significantly higher than those from a cleavage transfer (245 +/- 204 IU/L). This difference remained after adjusting for confounding variables. The threshold value predicting a clinical pregnancy for a cleavage embryo was 100 IU/L, and for a blastocyst transfer, 133 IU/L. CONCLUSION(S): Our study suggests that initial serum hCG values are higher after the transfer of a single fresh blastocyst embryo compared with after a single fresh cleavage ET, even after adjusting for confounding variables. PMID- 25910573 TI - Combination of transarterial chemoembolisation (TACE) plus antivirals for the management of hepatitis B-related hepatocellular carcinoma: A systematic review of the literature. AB - BACKGROUND: Hepatocellular carcinoma (HCC) is the most frequently occurring liver neoplasm and the fifth most common cancer worldwide. Intermediate-stage HCC is a distinct disease entity that is traditionally treated with transarterial chemoembolisation (TACE). However, the risk of viral reactivation and subsequent hepatic decompensation is considerable. Therefore, in this systematic review, we explore the evidence surrounding the benefits of using TACE/antiviral combination in this subset of HCC. METHODS: PubMed, Medline, the Cochrane Library, Trip Database, and Google Scholar were searched using the terms "Hepatocellular carcinoma" OR "Hepatoma" or "Liver cancer" AND "Transarterial chemoembolisation" OR "Chemoembolisation" AND "Antivirals" and specifying only English literature. The outcomes of interest included progression-free survival and overall survival (PFS and OS), tumour response, and toxicities. RESULTS: A total of six potentially relevant trials were identified, from which one study was excluded. Hence, five trials involving 818 patients were included, encompassing three phase II studies and two retrospective studies. The median PFS was reported in one out of the five studies, which was 23 months in the combination arm versus 20 months in the TACE-only arm. The median OS was reported in one out of the four studies: 29 months in the combination arm versus 26 months in the TACE-only arm. The hepatic toxicity parameters showed consistent benefit for the combination arm versus the TACE-only arm in the five studies included. CONCLUSIONS: An antiviral/TACE combination shows promise as an effective and tolerable treatment strategy for intermediate-stage HCC. The reported efficacy and toxicity of the antiviral/TACE combination appears to compare favorably with TACE monotherapy, the most commonly implemented strategy for intermediate-stage HCC. Further clinical studies are warranted to accurately determine which patients are expected to benefit most from such combination strategies. PMID- 25910572 TI - Menopausal hot flashes and the default mode network. AB - OBJECTIVE: To test whether more physiologically assessed hot flashes were associated with more connectivity in the default mode network (DMN), the network of brain regions active during rest. We particularly focus on DMN networks supporting the hippocampus as this region is rich in estrogen (E) receptors (ER) and has previously been linked to hot flashes. DESIGN: Women underwent 24 hours of physiologic and diary hot flash monitoring, functional magnetic resonance imaging (MRI), 72 hours of sleep actigraphy monitoring, a blood draw, questionnaires, and physical measures. SETTING: University medical center. PATIENT(S): Twenty midlife women aged 40-60 years who had their uterus and both ovaries and were not taking hormone therapy (HT). INTERVENTION(S): None. MAIN OUTCOME MEASURE(S): The DMN functional connectivity. RESULT(S): Controlling for age, race, and education, more physiologically-monitored hot flashes were associated with greater DMN connectivity (beta, B [SE] = 0.004 [0.002]), particularly hippocampal DMN connectivity (B [SE] = 0.005 [0.002]). Findings were most pronounced for sleep physiologic hot flashes (with hippocampal DMN, B [SE] = 0.02 [0.007]). Associations also persisted controlling for sleep, depressive symptoms, and serum E2 concentrations. CONCLUSION(S): More physiologically monitored hot flashes were associated with more DMN connectivity, particularly networks supporting the hippocampus. Findings were most pronounced for sleep hot flashes. Findings underscore the importance of continued investigation of the central nervous system in efforts to understand this classic menopausal phenomenon. PMID- 25910574 TI - An unusual cause of duodenal obstruction in adults. AB - BACKGROUND: Intestinal malrotation refers to a spectrum of anomalies of midgut rotation and fixation at various stages during early embryonic development. In adults, malrotation manifests itself mainly in chronic non-specific abdominal complaints and may therefore be easily misdiagnosed beyond infancy. CASE PRESENTATION: We present a case of an 82-year-old Caucasian man with vomiting and abdominal pain owing to malrotation complicated by duodenal obstruction and intestinal ischaemia confirmed by radiologic evaluation and autopsy report. CONCLUSION: Although intestinal malrotation is generally discovered near birth, our case demonstrates that physicians should consider this diagnosis at advanced age as well. In addition, particularly radiologic findings are supportive in diagnosing malrotation. PMID- 25910575 TI - Transient receptor potential-canonical 3 modulates sperm motility and capacitation-associated protein tyrosine phosphorylation via [Ca2+]i mobilization. AB - Ca(2+) signaling is pivotal for sperm maturation, including the processes of motility, capacitation, and the acrosome reaction. As a Ca(2+) conductor, transient receptor potential-canonical 3 (TRPC3) plays an important role in somatic cells. However, the function of TRPC3 in sperm is not well understood. Here, a pharmacological approach was used to investigate the role and mechanism of TPRC3 in sperm function. The TRPC3 antagonist Pyr3 could inhibit sperm motility and accelerate capacitation-associated protein tyrosine phosphorylation in a time- and dose-dependent manner, regardless of the presence or absence of Ca(2+) in the incubation medium. Further investigation revealed that sperm [Ca(2+)]i fell immediately once Pyr3 was added to Ca(2+)-free medium, and then gradually increased and returned to baseline levels. Moreover, the [Ca(2+)]i levels markedly elevated when sperm were incubated for 30 min in the presence of Pyr3; this change was subsequently accompanied by a significant reduction in sperm mitochondrial membrane potential. This study suggested that TRPC3 can modulate sperm function via mobilization of sperm [Ca(2+)]i. PMID- 25910576 TI - Exendin-4 regulates redox homeostasis in rats fed with high-fat diet. AB - Non-alcoholic fatty liver disease (NAFLD) is associated with increased plasma homocysteine level, which is caused by down-regulation of hepatic cystathionine beta-synthase (CBS) activity. CBS catalyzes the first step in the transsulfuration of homocysteine to cysteine, which contributes ~50% of the cysteine required for hepatic biosynthesis of glutathione (GSH), the most abundant antioxidant in cells. As the glucagon-like peptide-1 (GLP-1) receptor agonists (e.g. exendin-4) effectively reverse hepatic steatosis, the effect of exendin-4 on both homocysteine and redox status was investigated in the livers of rats fed with high-fat diet (HFD). It was found that HFD down-regulated CBS protein expression, which was probably due to induction of rno-miR-376c expression in the liver. The level of GSH was markedly reduced, whereas the level of malonydialdehyde, an indicator of lipid peroxidation, was significantly increased in the livers of rats fed with HFD. Exendin-4 treatment increased hepatic CBS protein and GSH levels, and reduced malonydialdehyde level in hyperlipidemic rats. Our findings suggest that GLP-1 receptor agonists have beneficial effects on redox homeostasis in NAFLD. PMID- 25910577 TI - Are age and sex differences in brain oxytocin receptors related to maternal and infanticidal behavior in naive mice? AB - This article is part of a Special Issue "Parental Care". There is significant variability in the behavioral responses displayed by naive young and adult mice when first exposed to pups. This variability has been associated with differences in the expression of oxytocin receptors (OXTRs) in the brain in several species. Experiment I investigated the behavioral responses of juvenile, adolescent, and adult CB57BL/6 males and females when first exposed to pups. We found an age increase in maternal females (11% of juveniles, 20% of adolescents, and 50% of young adults), and infanticidal males (0% of juveniles, 30% of adolescents, 44.5% of young adults, and 100% of older adults). Experiment II investigated OXTR density in the brain of juvenile and adult mice. Our results revealed an age decline in the density of OXTR in several brain regions, including the lateral septum, cingulated and posterior paraventricular thalamic nucleus in both males and females. Adult females had higher OXTR density in the ventromedial nucleus/postero-ventral hypothalamus (VMH) and the accessory olfactory bulb (AOB), but lower density in the ventral region of the lateral septum (LSv) than juveniles. Males had lower OXTR density in the anterior olfactory area (AOA) compared to juveniles. No age or sex differences were found in the medial preoptic area, and amygdaloid nuclei, among other brain regions. This study suggests that 1) maturation of parental and infanticidal behavioral responses is not reached until adulthood; 2) the pattern of development of OXTR in the mouse brain is unique, region specific, and differs from that observed in other rodents; 3) either up or down regulation of OXTR in a few brain regions (VMH/AOB/LSv/AOA) might contribute to age or sex differences in parental or infanticidal behavior. PMID- 25910578 TI - A doxycycline-loaded polymer-lipid encapsulation matrix coating for the prevention of implant-related osteomyelitis due to doxycycline-resistant methicillin-resistant Staphylococcus aureus. AB - Implant-associated bone infections caused by antibiotic-resistant pathogens pose significant clinical challenges to treating physicians. Prophylactic strategies that act against resistant organisms, such as methicillin-resistant Staphylococcus aureus (MRSA), are urgently required. In the present study, we investigated the efficacy of a biodegradable Polymer-Lipid Encapsulation MatriX (PLEX) loaded with the antibiotic doxycycline as a local prophylactic strategy against implant-associated osteomyelitis. Activity was tested against both a doxycycline-susceptible (doxy(S)) methicillin-susceptible S. aureus (MSSA) as well as a doxycycline-resistant (doxy(R)) methicillin-resistant S. aureus (MRSA). In vitro elution studies revealed that 25% of the doxycycline was released from the PLEX-coated implants within the first day, followed by a 3% release per day up to day 28. The released doxycycline was highly effective against doxy(S) MSSA for at least 14days in vitro. A bolus injection of doxycycline mimicking a one day release from the PLEX-coating reduced, but did not eliminate, mouse subcutaneous implant-associated infection (doxy(S) MSSA). In a rabbit intramedullary nail-related infection model, all rabbits receiving a PLEX doxycycline-coated nail were culture negative in the doxy(S) MSSA-group and the surrounding bone displayed a normal physiological appearance in both histological sections and radiographs. In the doxy(R) MRSA inoculated rabbits, a statistically significant reduction in the number of culture-positive samples was observed for the PLEX-doxycycline-coated group when compared to the animals that had received an uncoated nail, although the reduction in bacterial burden did not reach statistical significance. In conclusion, the PLEX-doxycycline coating on titanium alloy implants provided complete protection against implant-associated MSSA osteomyelitis, and resulted in a significant reduction in the number of culture positive samples when challenged with a doxycycline-resistant MRSA. PMID- 25910579 TI - Sustained BMP-2 delivery and injectable bone regeneration using thermosensitive polymeric nanoparticle hydrogel bearing dual interactions with BMP-2. AB - Localized and continuous osteogenic stimulation to defected sites is required for effective bone regeneration. Here, we suggest an injectable and sustained bone morphogenetic protein-2 (BMP-2) release system using thermosensitive polymeric nanoparticles bearing dual interacting forces with BMP-2. For sustained BMP-2 release, hydrophobic and ionic interactions were introduced to thermosensitive poly(phosphazene). Hydrophobic isoleucine ethyl ester and hydrophilic poly ethylene glycol were mainly substituted to the poly(phosphazene) back bone for amphiphilicity and hydrophobic interaction with BMP-2. Carboxylic acid moiety was additionally substituted to the back bone for ionic interaction with BMP-2. These dual interacting polymeric nanoparticles (D-NPs) formed compact nanocomplexes with BMP-2. The aqueous solution of BMP-2/D-NP nanocomplexes was transformed to hydrogel when the temperature of the solution increased. Loaded BMP-2 was sustain released for three weeks from the BMP-2/D-NP nanocomplex hydrogel. The extended BMP-2 exposure caused higher osteocalcin secretion in C2C12 cells. Significant bone generations were observed at the target site by single injection of BMP-2/D NP nanocomplexes in vivo. PMID- 25910581 TI - Red blood cell distribution width and mean platelet volume: Surrogate markers for, or treatment targets in, dyslipidemia? PMID- 25910580 TI - Theranostic applications of carbon nanomaterials in cancer: Focus on imaging and cargo delivery. AB - Carbon based nanomaterials have attracted significant attention over the past decades due to their unique physical properties, versatile functionalization chemistry, and biological compatibility. In this review, we will summarize the current state-of-the-art applications of carbon nanomaterials in cancer imaging and drug delivery/therapy. The carbon nanomaterials will be categorized into fullerenes, nanotubes, nanohorns, nanodiamonds, nanodots and graphene derivatives based on their morphologies. The chemical conjugation/functionalization strategies of each category will be introduced before focusing on their applications in cancer imaging (fluorescence/bioluminescence, magnetic resonance (MR), positron emission tomography (PET), single-photon emission computed tomography (SPECT), photoacoustic, Raman imaging, etc.) and cargo (chemo/gene/therapy) delivery. The advantages and limitations of each category and the potential clinical utilization of these carbon nanomaterials will be discussed. Multifunctional carbon nanoplatforms have the potential to serve as optimal candidates for image-guided delivery vectors for cancer. PMID- 25910582 TI - Cholesterol homeostasis in cardiovascular disease and recent advances in measuring cholesterol signatures. AB - Despite the biochemical importance of cholesterol, its abnormal metabolism has serious cellular consequences that lead to endocrine disorders such as cardiovascular disease (CVD). Nevertheless, the impact of blood cholesterol as a CVD risk factor is still debated, and treatment with cholesterol-lowering drugs remains controversial, particularly in older patients. Although, the prevalence of CVD increases with age, the underlying mechanisms for this phenomenon are not well understood, and metabolic changes have not been confirmed as predisposing factors of atherogenesis. The quantification of circulating biomarkers for cholesterol homeostasis is therefore warranted, and reference values for cholesterol absorption and synthesis should be determined in order to establish CVD risk factors. The traditional lipid profile is often derived rather than directly measured and lacks a universal standard to interpret the results. In contrast, mass spectrometry-based cholesterol profiling can accurately measure free cholesterol as a biologically active component. This approach allows to detect alterations in various metabolic pathways that control cholesterol homeostasis, by quantitative analysis of cholesterol and its precursors/metabolites as well as dietary sterols. An overview of the mechanism of cholesterol homeostasis under different physiological conditions may help to identify predictive biomarkers of concomitant atherosclerosis and conventional CVD risk factors. PMID- 25910583 TI - The relationship between plasma and salivary NOx. AB - Several studies have shown that fasting plasma nitrite (NO2(-)) is an indicator of endothelial nitric oxide synthase (NOS) activity while plasma nitrate (NO3(-)) or the sum of NO2(-) and NO3(-) (NOx) does not reflect NOS function. Plasma NO2( ) can also be elevated through dietary NO3(-) where the NO3(-) is partially reduced to NO2(-) by oral bacteria and enters the plasma through the digestive system. NO3(-) is taken up from plasma by salivary glands and the cycle repeats itself. Thus, one may propose that salivary NO2(-) is an indicator of plasma NO2( ) and consequently of NO production. Many brands of nitric oxide (NO) saliva test strips have been developed that suggest that their product is indicative of circulatory NO availability. However, data supporting a relationship between salivary and plasma NO2(-) or NO bioavailability are lacking. Here we have measured basal salivary and plasma NO2(-) and NO3(-) to determine if any correlation exists between these in 13 adult volunteers. We found no significant correlation between basal salivary and plasma NO2(-). Also no correlation exists between salivary NO3(-) and plasma NO2(-). However, we did see a correlation between salivary NO3(-) and plasma NO3(-), and between salivary NO2(-) and plasma NO3(-). In a separate study, we compared the efficiency of salivary NO3(-) reduction with the efficacy of increasing plasma NO3(-) and NO2(-) after drinking beet juice, a high NO3(-)-containing beverage, in 10 adult volunteers. No significant correlation was observed between the ex vivo salivary reduction of NO3(-) to NO2(-) and plasma increases in NO3(-) or NO2(-). These results suggest that measures of salivary NO3(-), NO2(-) or NOx are not good indicators of endothelial function. In addition, the efficiency of saliva to reduce NO3(-) to NO2(-)ex-vivo does not demonstrate one's ability to increase plasma NO2(-) following consumption of dietary NO3(-). PMID- 25910584 TI - 1-Benzyl-4-phenyl-1H-1,2,3-triazoles improve the transcriptional functions of estrogen-related receptor gamma and promote the browning of white adipose. AB - The estrogen-related receptor gamma (ERRgamma) is a potential molecular target for the development of small molecules to stimulate the adipose browning process, which may represent a novel attractive strategy to treat obesity related disorders. The receptor possesses a very small ligand binding cavity and therefore identification of small molecule ERRgamma modulators is a considerable challenge. We have successfully designed and synthesized a series of 1-benzyl-4 phenyl-1H-1,2,3-triazoles and demonstrated that they improve the transcriptional functions of ERRgamma, potently elevating both the mRNA levels and the protein levels of ERRgamma downstream targets. One of the most promising compounds, 4-(1 (4-iso-propylbenzyl)-1H-1,2,3-triazol-4-yl)benzene-1,2-diol (2e) was further shown to directly bind with the ERRgamma ligand binding domain (ERRgamma-LBD) in an isothermal calorimetric (ITC) assay and to thermally stabilize ERRgamma-LBD protein by increasing its melting temperature (Tm) as demonstrated by circular dichroism (CD) spectroscopy. Furthermore, 2e potently stimulates the adipocyte browning process and induces mitochondrial biogenesis both in vitro and in vivo, suggesting the considerable therapeutic potential of this compound for the treatment of obesity and related disorders. PMID- 25910585 TI - Protonography, a powerful tool for analyzing the activity and the oligomeric state of the gamma-carbonic anhydrase identified in the genome of Porphyromonas gingivalis. AB - Carbonic anhydrases (CAs, EC 4.2.1.1) are metalloenzymes, mostly containing zinc within their active site, which catalyze a simple but physiologically relevant reaction in all life kingdoms, carbon dioxide hydration to bicarbonate and protons. Six CA classes (alpha, beta, gamma, delta, zeta and eta) and multiple CA isoforms evolved in organisms all over the phylogenetic tree, for facing the need to efficiently convert high amounts of CO2 to its hydration products. These enzymes are thus involved in many physiologic processes, such as photosynthesis, respiration, CO2 transport, electrolyte secretion in many tissues/organs; biosynthetic reactions (gluconeogenesis, lipogenesis, ureagenesis), etc. Recently, our group reported a new technique to assay CA activity on SDS-PAGE gels, named 'protonography' due to its similarity to zymography. By using protonography, the conversion of CO2 into protons can be visualized as a yellow band on a polyacrylamide gel. By using this technique we demonstrated the possibility to detect activity of the alpha-CA from Vibrio cholerae as well as the beta- and gamma-CAs present in Escherichia coli extracts. Furthermore, the activity of the newly discovered eta-class enzyme from Plasmodium falciparum has also been evidenced with protonography, illustrating its wide use. Here we show that protonography can be also useful to reveal the oligomeric state of the gamma CA identified in the genome of the bacterial parasite colonizing the oral cavity, Porphyromonas gingivalis, possibly allowing for a simple and efficient diagnostic method. PMID- 25910586 TI - Structure-activity relationship studies on acremomannolipin A, the potent calcium signal modulator with a novel glycolipid structure 3: role of the length of alditol side chain. AB - Five homologs of a novel glycolipid acremomannolipin A (1a), the potential Ca(2+) signal modulator isolated from Acremonium strictum, bearing alditols of different length (1g-1k) were synthesized by a stereoselective beta-mannosylation of appropriately protected mannosyl sulfoxide (2) with five alditols (1g: C2, 1h: C3, 1i: C4, 1j: C5 and 1k: C7 units), and their potential in modulating Ca(2+) signaling were evaluated. Homologs with alditols of more than 4 carbons (1i, 1j and 1k) were equally or more potent than the parent compound (1a) regardless of the length of the alditol chain. Whereas activities of two homologs with shorter chains (1g and 1h) decreased to a considerable extent. The results indicated that the length of the alditol side chain was a crucial determinant for the potent calcium signal modulating activity. PMID- 25910587 TI - Inhibitory effects of hydroxylated cinnamoyl esters on lipid absorption and accumulation. AB - Obesity is a risk factor associated with several lifestyle-related diseases, for example, diabetes, high blood pressure, hyperlipidemia and cancer. Caffeic acid 2 phenylethyl ester (CAPE, 1), a naturally-occurring compound found in various plants and propolis, which exhibits anti-inflammatory, immunomodulatory and cytotoxic activities and inhibits 3T3-L1 differentiation to adipocytes. As part of our efforts to moderate lifestyle-related diseases, we synthesized analogs of 1 and studied their effects on pancreatic lipase activities, lipid absorption, and 3T3-L1 differentiation. We found that catechols 1-4 show inhibitory activities against pancreatic lipase in a dose-dependent manner in vitro. Compounds 1-3 proved to be more potent inhibitors of pancreatic lipase than 5, 6, 8, and 9, which have one hydroxyl group, respectively. Compound 7 has three aromatic hydroxyl groups and restrains greater lipase inhibitory activity than the other compounds. In addition, 7 and 3 significantly suppress a rise in blood triglyceride (TG) levels in mice given corn oil orally. Furthermore, 2 and 3 are more potent at preventing 3T3-L1 differentiation (lipid accumulation) than 1, while 7 is more potent than 3, 8, and 9 in these assays. Compounds 2, 3, and 7 inhibit lipid absorption and accumulation, with new compound 7 being the most potent. These results indicate that 7 may have potential benefits as a health agent with anti-obesity properties. PMID- 25910588 TI - Polarization of tumor-associated macrophages and Gas6/Axl signaling in oral squamous cell carcinoma. AB - BACKGROUND: This study investigated the potential involvement of Axl signaling in polarization of tumor-associated macrophages (TAMs) in oral squamous cell carcinoma (OSCC). METHODS: Condition medium (CM) from OSCC cells (OEC-M1 and YD38) were collected and their effects on macrophage (THP-1) polarization were examined. Modulation of Axl, PI3/Akt, and NF-kappaB were performed to investigate their potential involvement in TAM polarization. Expression of pAxl and CD206 were analyzed by immunohistochemistry in OSCC tissues. RESULTS: THP-1 polarized to M2 phenotype with increasing expression of interleukins, vascular endothelial growth factor, matrix metalloproteinase and CD206 upon treatment with CM of OSCC. Activated Axl signaling in OSCC enhanced M2 induction ability. Suppression of Axl signaling and inhibition of PI3/Akt and NF-kappaB diminished M2 induction. pAxl expression was significantly associated with distribution of CD206 positive cells in OSCC tissues. CONCLUSION: Axl signaling of OSCC involved in polarizing TAMs toward M2 phenotype. Induction of M2 phenotype macrophage polarization by OSCC cells might involve the Axl/PI3/Akt/NF-kappaB pathway. PMID- 25910589 TI - Noninfectious subcutaneous emphysema of the upper extremity. PMID- 25910590 TI - Modalities for Complex Regional Pain Syndrome. PMID- 25910591 TI - Reduction of fifth metacarpal neck fractures with a Kirschner wire. AB - This article reports on a percutaneous joystick technique for reduction of fifth metacarpal neck fractures. The technique was performed in 76 hands. Reduction was achieved in all cases. The technique is a useful reduction maneuver in the treatment of fifth metacarpal neck fractures. PMID- 25910592 TI - Drug-coated balloon angioplasty for coronary chronic total occlusions. An OCT analysis for a "new" intriguing strategy. PMID- 25910593 TI - Transcatheter aortic valve implantation in patients with bicuspid aortic valve: A patient level multi-center analysis. AB - OBJECTIVE: We sought to evaluate the safety and efficacy of transcatheter aortic valve implantation (TAVI) in patients with bicuspid aortic valve (BiAV). BACKGROUND: BiAV remains a relative contraindication to TAVI resulting in exclusion from TAVI trials and thus limiting data on the clinical performance of transcatheter valves in these patients. METHODOLOGY: We conducted an international patient level multicenter analysis on outcomes in patients with BiAV undergoing TAVI. The primary outcome of the study was the combined early safety endpoint--a composite of 30 day mortality, stroke, life-threatening bleeding, acute kidney injury, coronary artery obstruction, major vascular complication and valve related dysfunction. Secondary endpoints included the individual components of the primary endpoint as well as post-TAVI paravalvular leak (PVL), rehospitalization, new pacemaker insertion and device success rates at 30 days and 1 year. RESULTS: A total of 108 patients with BiAV were identified in 21 centers in Canada, Spain, Italy, Poland and Singapore who underwent TAVI between January 2005 and March 2014. The composite primary outcome occurred in one quarter of patients (26.9%)--mainly driven by re-intervention for valve malposition (9.3%). The 30-day and 1 year mortality rates were 8.3% and 16.9% respectively with AR >= 3+ occurring in 9.6% of patients. Device success was achieved in 85.2% of cases with pacemaker insertion in 19.4%. While PVL was not associated with an increased risk of 30 day or 1 year mortality--Type I BiAV anatomy with left and right cusp fusion had significantly better outcomes than other valve variants. CONCLUSION: In selected patients with BiAV and severe aortic stenosis, TAVI appears both safe and feasible with acceptable clinical outcomes. Clinical studies of TAVI in this patient population are warranted. PMID- 25910594 TI - Present and future contraception: does discovery of targets lead to new contraceptives? AB - Although many highly effective methods of reversible contraception are available, high rates of unintended pregnancy and abortion provide evidence that current methods do not meet the needs of all couples. In recent years, a number of highly specific targets have been identified in key pathways that regulate the development of male and female gametes. Support for development of novel approaches has moved from industry to governmental and foundation funders. Continued public funding will be needed to move promising leads into clinical trials. PMID- 25910595 TI - Predictors of late initiation for prenatal care in a metropolitan region in Belgium. A cohort study. AB - OBJECTIVES: Timely initiation of prenatal care (PNC) in the first pregnancy trimester allows prevention, identification and treatment of risk factors. However, not all women initiate PNC timely, especially women in a deprived situation. The aim of this study was to measure the prevalence of late initiation, defined as initiation after 14 weeks of gestational age. Secondly the authors wanted to identify predictors for late PNC onset. STUDY DESIGN: Observational cohort study. METHODS: Pregnant women (n = 1750) were recruited in all four hospitals in Ghent (Belgium), a metropolitan region. A socio-economic deprivation ranking was measured by using a General Deprivation Index (GDI), which consists of six criteria to assess a socio-economic situation as deprived. A univariate analysis and a forward conditional multivariate logistic regression model were used analysing the association between deprivation and the likelihood to initiate PNC late. RESULTS: 1115 women were included of whom 6.1% (n = 68) initiated PNC late. A foreign maternal country of birth (OR 2.10; 95% CI 1.15 3.83) and a total GDI >=3 (OR 4.40; 95% CI 2.36-8.21) were good predictors for late initiation. More specifically, the GDI criteria education (OR 4.02; 95% CI 2.00-8.08) and unemployment (OR 2.40; 95% CI 1.17-4.90) were significantly associated with higher likelihood for late initiation. CONCLUSIONS: A small group of women initiates PNC late. Vulnerable groups, at risk for late initiation can be identified through assessing their deprivation status. Priority for additional support should be given to women with low educational attainment or women in uncertain employment situations. PMID- 25910596 TI - Metabolic syndrome among psychiatric inpatients with schizophrenia in Indonesia. AB - Despite the fact that antipsychotic medication increases the risk of metabolic syndrome (MetS), the rate of MetS among psychiatric patients in Indonesia is rarely reported. This study aimed to investigate the prevalence of MetS among inpatients with schizophrenia in Indonesia. Eighty-six hospitalised psychiatric patients with schizophrenia were randomly recruited, and underwent physical examination including a blood test. MetS was assessed based on the International Diabetes Federation (IDF) criteria for South Asia. Among the sample, only eight patients (9.3%) met the IDF criteria for MetS. Women have a higher rate of MetS than men (23.8% vs 4.6%; p=0.02). Reduced high-density lipoprotein (HDL) cholesterol was the most frequent (81.4%) metabolic abnormality among them, followed by central obesity (29.1%), raised triglycerides (23.3%), raised fasting plasma glucose (12.8%), and raised blood pressure (10.5%). Among the various antipsychotics, no differences in MetS prevalence were observed in this population. The rate of MetS among the psychiatric inpatients in this study is lower compared both to the previously reported rate in the general population and to the findings among psychiatric patients with schizophrenia in developed countries. Several factors related to the reduced rate of MetS in this psychiatric inpatient population will be discussed. PMID- 25910597 TI - Insight into the Ebola virus nucleocapsid assembly mechanism: crystal structure of Ebola virus nucleoprotein core domain at 1.8 A resolution. AB - Ebola virus (EBOV) is a key member of Filoviridae family and causes severe human infectious diseases with high morbidity and mortality. As a typical negative sense single-stranded RNA (-ssRNA) viruses, EBOV possess a nucleocapsid protein (NP) to facilitate genomic RNA encapsidation to form viral ribonucleoprotein complex (RNP) together with genome RNA and polymerase, which plays the most essential role in virus proliferation cycle. However, the mechanism of EBOV RNP formation remains unclear. In this work, we solved the high resolution structure of core domain of EBOV NP. The polypeptide of EBOV NP core domain (NP(core)) possesses an N-lobe and C-lobe to clamp a RNA binding groove, presenting similarities with the structures of the other reported viral NPs encoded by the members from Mononegavirales order. Most strikingly, a hydrophobic pocket at the surface of the C-lobe is occupied by an alpha-helix of EBOV NP(core) itself, which is highly conserved among filoviridae family. Combined with other biochemical and biophysical evidences, our results provides great potential for understanding the mechanism underlying EBOV RNP formation via the mobility of EBOV NP element and enables the development of antiviral therapies targeting EBOV RNP formation. PMID- 25910598 TI - Calm down when the heart is stressed: Inhibiting calmodulin-dependent protein kinase II for antiarrhythmias. AB - Ca(2+)/calmodulin-dependent protein kinase II (CaMKII) plays a pivotal role in many regulatory processes of cellular functions ranging from membrane potentials and electric-contraction (E-C) coupling to mitochondrial integrity and survival of cardiomyocytes. The review article by Hund and Mohler in this issue of Trends in Cardiovascular Medicine highlights the importance of the elevated CaMKII signaling pathways under stressed conditions such as myocardial hypertrophy and ischemia in the detrimental remodeling of ion channels and in the genesis of cardiac arrhythmias. Down-regulation of the elevated CaMKII is now emerging as a powerful therapeutic strategy for the treatment of cardiac arrhythmias and other forms of heart disease such as hypertrophic and ischemic heart failure. The development of new specific and effective CaMKII inhibitors as therapeutic agents for cardiac arrhythmias is challenged by the tremendous complexity of CaMKII expression and distribution of multi isoforms, as well as the multitude of downstream targets in the CaMKII signaling pathways and regulatory processes. A systematic understanding of the structure and regulation of the CaMKII signaling and functional network under the scope of genome and phenome may improve and extend our knowledge about the role of CaMKII in cardiac health and disease and accelerate the discovery of new CaMKII inhibitors that target not only the ATP binding site but also the regulation sites in the CaMKII signaling and functional network. PMID- 25910599 TI - Depression in cardiovascular disease: From awareness to action. PMID- 25910600 TI - Management and diagnosis of gallbladder polyps: a systematic review. AB - PURPOSE: Recommendation for management of gallbladder polyps (GBPs) >1 cm is cholecystectomy. No consensus exists on management of GBPs <1 cm. This systematic review examines current evidence on management of GBPs. METHODS: MEDLINE, EMBASE and Cochrane library databases were searched from January 1991 to June 2013 using specified terms. A predefined protocol for data extraction was used to retrieve specified end points. RESULTS: Literature search yielded 43 manuscripts with a dataset of 11,685 patients with GBPs. M:F ratio was 1.3:1. Average age (range) was 49 years (32-83). Patients with malignant GBPs had an average (range) age of 58 (50-66) years with M:F ratio of 0.78:1. Cholesterol polyps constituted 60.5% of GBPs followed by adenomas (15.2%) and cancer (11.6%). Malignant GBPs >=1 cm, <1 cm and <5 mm constituted 8.5, 1.2 and 0% of GBPs, respectively. Majority of patients requiring surgical intervention had laparoscopic cholecystectomy. CONCLUSIONS: Presently employed policy of cholecystectomy for GBPs >1 cm is appropriate. For GBPs <1 cm, the authors propose (accepting existence of differing proposals) the following: 1. Surveillance may not be needed for GBPs <5 mm. 2. For GBPs between 5 and 10 mm, two scans at six monthly intervals is suggested and after that, tailor surveillance to age, growth and ethnicity. In the non-Asian population, if GBP remains the same size or number, discontinuation of surveillance may be considered. In the Asian population, if GBPs remain the same, yearly surveillance is continued for a suggested period of 3 years. 3. Discontinue surveillance if GBPs is/are smaller/ disappeared. Cholecystectomy is advised where size increases to >10 mm. PMID- 25910601 TI - Reducing Burnout in Primary Care: A Step Toward Solutions. PMID- 25910602 TI - Seasonal Patterns in Microbial Community Composition in Denitrifying Bioreactors Treating Subsurface Agricultural Drainage. AB - Denitrifying bioreactors, consisting of water flow control structures and a woodchip-filled trench, are a promising approach for removing nitrate from agricultural subsurface or tile drainage systems. To better understand the seasonal dynamics and the ecological drivers of the microbial communities responsible for denitrification in these bioreactors, we employed microbial community "fingerprinting" techniques in a time-series examination of three denitrifying bioreactors over 2 years, looking at bacteria, fungi, and the denitrifier functional group responsible for the final step of complete denitrification. Our analysis revealed that microbial community composition responds to depth and seasonal variation in moisture content and inundation of the bioreactor media, as well as temperature. Using a geostatistical analysis approach, we observed recurring temporal patterns in bacterial and denitrifying bacterial community composition in these bioreactors, consistent with annual cycling. The fungal communities were more stable, having longer temporal autocorrelations, and did not show significant annual cycling. These results suggest a recurring seasonal cycle in the denitrifying bioreactor microbial community, likely due to seasonal variation in moisture content. PMID- 25910603 TI - Deciphering Cyanide-Degrading Potential of Bacterial Community Associated with the Coking Wastewater Treatment Plant with a Novel Draft Genome. AB - Biotreatment processes fed with coking wastewater often encounter insufficient removal of pollutants, such as ammonia, phenols, and polycyclic aromatic hydrocarbons (PAHs), especially for cyanides. However, only a limited number of bacterial species in pure cultures have been confirmed to metabolize cyanides, which hinders the improvement of these processes. In this study, a microbial community of activated sludge enriched in a coking wastewater treatment plant was analyzed using 454 pyrosequencing and Illumina sequencing to characterize the potential cyanide-degrading bacteria. According to the classification of these pyro-tags, targeting V3/V4 regions of 16S rRNA gene, half of them were assigned to the family Xanthomonadaceae, implying that Xanthomonadaceae bacteria are well adapted to coking wastewater. A nearly complete draft genome of the dominant bacterium was reconstructed from metagenome of this community to explore cyanide metabolism based on analysis of the genome. The assembled 16S rRNA gene from this draft genome showed that this bacterium was a novel species of Thermomonas within Xanthomonadaceae, which was further verified by comparative genomics. The annotation using KEGG and Pfam identified genes related to cyanide metabolism, including genes responsible for the iron-harvesting system, cyanide-insensitive terminal oxidase, cyanide hydrolase/nitrilase, and thiosulfate:cyanide transferase. Phylogenetic analysis showed that these genes had homologs in previously identified genomes of bacteria within Xanthomonadaceae and even presented similar gene cassettes, thus implying an inherent cyanide-decomposing potential. The findings of this study expand our knowledge about the bacterial degradation of cyanide compounds and will be helpful in the remediation of cyanides contamination. PMID- 25910604 TI - [Loss of weight and diabetes]. PMID- 25910605 TI - [Therapeutic inertia in the management of type 2 diabetic patients in Primary Health Care]. AB - OBJECTIVE: To assess therapeutic inertia (TI) in the management of type 2 diabetic patients (DM2), as regards glycemic and lipid control. MATERIALS AND METHODS: Two groups of patients were studied. Group 1: All the patients were older than 14 years, diagnosed with DM2 up to 28th February 2013, and their last determination of HbA1c was >= 8.5%. Group 2: All patients, under 60 years old, diagnosed with DM2 between the 1st January 2011 and the 31st December 2012, with no chronic complications and their last determination of HbA1c was >= 6.5%. RESULTS: Group 1: 253 patients were included (13% of DM2 diagnosed). TI was 43% for DM2, 83% for LDL cholesterol, and 80% for triglycerides. TI was lower (P=.037) in patients with HbA1c >= 10%. There was no difference in TI as regards the management of lipid profile depending on the HbA1c levels. Group 2: All DM2 patients (n=53) who met inclusion criteria were assessed (2.7% of DM2 diagnosed). Percentage of visits of those patients that had TI: 55% for DM2, 63% for LDL cholesterol and 64% for triglycerides. A more intense therapy was observed in patients with HbA1c>7.5% in 3 of the 5 visits made. CONCLUSIONS: TI in both groups was high and there is a lack of recording the reasons for this. It is important to improve the attitude of the professionals who care for the diabetic population. PMID- 25910606 TI - Comment on: Incidence and Risk of Hypertension with Ramucirumab in Cancer Patients: A Meta-Analysis of Published Studies. PMID- 25910607 TI - The Effect of Ear Canal Orientation on Tympanic Membrane Motion and the Sound Field Near the Tympanic Membrane. AB - The contribution of human ear canal orientation to tympanic membrane (TM) surface motion and sound pressure distribution near the TM surface is investigated by using an artificial ear canal (aEC) similar in dimensions to the natural human ear canal. The aEC replaced the bony ear canal of cadaveric human temporal bones. The radial orientation of the aEC relative to the manubrium of the TM was varied. Tones of 0.2 to 18.4 kHz delivered through the aEC induced surface motions of the TM that were quantified using stroboscopic holography; the distribution of sound in the plane of the tympanic ring P TR was measured with a probe tube microphone. The results suggest that the ear canal orientation has no substantial effect on TM surface motions, but P TR at frequencies above 10 kHz is influenced by the ear canal orientation. The complex TM surface motion patterns observed at frequencies above a few kilohertz are not correlated with simpler variations in P TR distribution at the same frequencies, suggesting that the complex sound-induced TM motions are more related to the TM mechanical properties, shape, and boundary conditions rather than to spatial variations in the acoustic stimulus. PMID- 25910608 TI - Demonstration of an adaptive response to preconditioning Frankliniella occidentalis (Pergande) to sublethal doses of spinosad: a hormetic-dose response. AB - Sublethal doses of some insecticides have been reported to either stimulate or reduce the survival and fecundity of insects. Many sublethal-effect studies have been conducted after exposure of only one generation to sublethal insecticides, and there is little information about the sublethal effects on insects after long term exposure to sublethal insecticides. In this study, changes in biological characteristics were investigated in spinosad-susceptible (Spin-S) and sublethal spinosad-treated (Spin-Sub) strains of Frankliniella occidentalis (Pergande) after exposure to their corresponding sublethal concentrations of spinosad. The results showed that for the Spin-S strain, the LC10 concentration of spinosad slightly affected the biotic fitness both in parents and offspring of F. occidentalis. The LC25 concentration of spinosad prolonged the development time, reduced the fecundity, and significantly reduced the intrinsic rate of increase, the net reproductive rate and the finite rate of increase in the Spin-S strain. However, the negative effects were not as pronounced in the offspring (F1 generation) as in the parent generation. For the Spin-Sub strain, the LC10 and LC25 concentrations of spinosad had little negative effect on the development and fecundity, and no significant difference was found between the effects of the LC10 and LC25 treatments on the Spin-Sub strain. The Spin-Sub strain exhibited a shorter developmental time, and larger intrinsic rates of increase and net reproductive rates, compared with the corresponding treatments of the Spin-S strain. These findings combined with our previous studies suggest that the biotic fitness increased in the Spin-Sub strain and the strain became more adaptable to sublethal doses of spinosad, compared with the Spin-S strain. Physiological and biochemical adaptation may contribute to these changes after long treatment times at sublethal doses. PMID- 25910609 TI - Pleomorphic leiomyosarcoma with a dedifferentiation-like appearance in the kidney: case report and literature review. AB - Although primary leiomyosarcoma of the kidney is extremely rare, it is the most common sarcoma of the kidney. Leiomyosarcoma with a large pleomorphic component is designated as pleomorphic leiomyosarcoma. The pleomorphic component is usually similar to undifferentiated high-grade pleomorphic sarcoma, although it variably expresses smooth muscle markers on immunohistochemistry. In the few reported cases of pleomorphic leiomyosarcoma of the kidney, cases with the pleomorphic component showing distinct nodularity similar to dedifferentiated leiomyosarcoma have not been described, to the best of our knowledge. Herein, we present a case of a 49-year-old woman with pleomorphic leiomyosarcoma in the kidney showing distinct nodularity of smooth muscle marker-expressing pleomorphic cells within a background of classic leiomyosarcoma. Along with the classification as a pleomorphic leiomyosarcoma, suggesting aggressive clinical behavior, the renal origin itself might also be a predictor of poor prognosis, as shown in a previous study. This case also involved concomitant distant metastases, already present during the initial detection of the renal tumor. PMID- 25910610 TI - High uterosacral vault suspension vs Sacrocolpopexy for treating apical defects: a randomized controlled trial with twelve months follow-up. AB - INTRODUCTION AND HYPOTHESIS: The high uterosacral vault suspension (HUVS) is a vaginal approach for treating apical prolapse that provides shorter operative and recovery times and is associated with lower morbidity rates. Success rates reported for this technique are comparable with the abdominal sacrocolpopexy (SCP); however, to date, there are no prospective randomized studies comparing HUVS to SCP. The aim of the study was to compare the anatomical objective cure rates for the apical compartment in patients undergoing either HUVS or SCP at 12 months' follow-up. METHODS: We performed a single-center parallel randomized controlled trial in patients with severe apical defect defined as Pelvic Organ Prolapse Quantification (POP-Q) point C >= stage 3. Based on the center's previous experience, a sample size of 124 patients was required to show a 20% cure rate difference between both techniques with 80% power and using a two tailed 5% level of significance. One hundred and ten patients were available for analysis; 54 were allocated to abdominal SCP and 56 to HUVS. The primary outcome was to evaluate surgical objective success defined as POP-Q point C stage<2. The Pelvic Floor Distress Inventory (PFDI-20), the Perceived Quality of Life Scale (P QOL), and the Pelvic Organ Prolapse/Urinary Incontinence Sexual Function Questionnaire (PISQ-12) questionnaires were used for subjective assessment. RESULTS: The objective success rate for apical suspension at 12 months' follow-up was 100% for abdominal SCP and 82.5% for HUVS (log-rank p 0.033). Both techniques showed a significant improvement with regards to prolapse symptoms, quality of life (QOL), and sexual function. The significant improvement in postoperative questionnaires was comparable between both surgeries at 12 months' follow-up. CONCLUSIONS: Abdominal SCP has statistically significant better anatomical results when compared with HUVS for correcting apical defects at 12 months. PMID- 25910611 TI - Recognition and treatment of endometriosis involving the sacral nerve roots. AB - INTRODUCTION AND HYPOTHESIS: Endometriosis involving the sacral plexus is still poorly understood or neglected by many surgeons. Looking at that scenario, we have designed this educational video to explain and describe the symptoms suggestive of endometriotic involvement of the sacral plexus in addition to the technique for the laparoscopic treatment of this condition. METHODS: Retrospective analysis of 13 consecutive cases of endometriotic entrapment of nerves of the lumbosacral plexus. RESULTS: Paired t test revealed a statistically significant (p < 0.0000001) reduction in pain VAS score, from preoperative average 9.1 (+/-1.98) to postoperative 1.46 (+/-1.66). Twelve out of 13 patients (92.3%) experienced a reduction of 50% or more in VAS score and 6 (46.15%) became completely pain-free. CONCLUSION: The signs suggestive of intrapelvic nerve involvement include perineal pain or pain irradiating to the lower limbs, lower urinary tract symptoms, tenesmus or dyschezia associated with gluteal pain. Whenever deeply infiltrating lesions are present, the patient must be asked about those symptoms and specific MRI sequences for the sacral plexus must be taken, so that the equipment and team can be arranged and proper treatment performed. PMID- 25910613 TI - Effect of long-term pulsed electromagnetic field exposure on hepatic and immunologic functions of rats. AB - BACKGROUND: In this report, the effects of long-term pulsed electromagnetic field (PEMF) exposure on hepatic and immunologic functions were examined. METHODS: Male rats were randomly divided into four groups: a control group and three experimental groups exposed to a 50-Hz PEMF at 5, 10, or 20 mT for 10 weeks. RESULTS: Compared with the control group, activities of serum alanine aminotransferase and aspartate aminotransferase and concentrations of serum, liver, and spleen Metabolism of lipid peroxidation (MDA) in the 10- and 20-mT PEMF groups were significantly increased. The activities of Glutathione peroxidase (GSH-Px) and Superoxide Dismutase (SOD) in the serum, liver, and spleen and concentrations of serum immunoglobulins were significantly decreased. CONCLUSION: These results demonstrate that long-term exposure to PEMF can lead to oxidative damage of the liver and spleen. PMID- 25910614 TI - Impact of top end anastomosis design on patency and flow stability in coronary artery bypass grafting. AB - For coronary artery bypass grafting (CABG), free grafts such as a saphenous vein or radial artery are often used for grafts to the lateral and posterior walls. However, the relationship between top-end anastomosis design and long-term patency remains unknown. Because coronary artery blood flow is dominant during diastole, top-end anastomosis may work better if the graft is directed towards the apex, whereas the shortest graft pathway appears to be most efficient. Using computational fluid dynamic models, we evaluated the hemodynamic variables that were affected by the angle of the top-end anastomosis. We created three dimensional geometries of the aortic root with coronary arteries that involved 75 % stenosis in the obtuse marginal and postero-lateral branches. Two bypass models under vasodilator administration were created: in a"Model A", the top-end anastomosis is parallel to the long axis of the ascending aorta and the graft passed over the conus directed towards the apex; in a "Model B", the top-end anastomosis is directed toward the shortest pathway, and form near the right angles to the long axis of the ascending aorta. Wall shear stress (WSS) and its fluctuation, an oscillatory shear index (OSI) were evaluated to predict fibrosis progression at the anastomosis site and graft flow. Graft flow was 197.3 ml/min and 207.3 ml/min in the "Model A" and "Model B", respectively. The minimal WSS value inside the graft with the "Model A" and "Model B" was 0.53 Pa and 4.09 Pa, respectively, and the OSI value was 0.46 and 0.04, respectively. The top-end anastomosis of a free graft should be directed vertically towards the aorta to achieve the shortest graft pathway to maintain a high graft flow rate and to avoid the risks of endothelial fibrosis and plaque progression over the long-term after CABG. PMID- 25910615 TI - Epidemiology of Multiple System Atrophy in Hokkaido, the Northernmost Island of Japan. AB - Multiple system atrophy (MSA) is an intractable neurodegenerative disorder that is characterized by various combinations of autonomic failure, cerebellar ataxia, and parkinsonism. We conducted an epidemiological study of MSA using the combined data of a national registry system and a postal survey in Hokkaido, Japan. A postal survey was conducted in 2013 based on national registry data from 2006 to 2011. This survey contained the current status of each patient with MSA that had been collected from attending physicians and recorded into a national registry. Survey items included date, outcomes, primary symptoms, and activities of daily living at the last medical examination. Confirmation data of the diagnosis by a board-certified neurologist was also collected. Based on the national registry data, 1,092 patients with MSA were selected as our target population. The response rate of the postal survey was 81% (885/1,092). After excluding inappropriate responses, 839 patients with MSA were analyzed. Forty-nine percent of the patients were male, and the mean onset age was 62.1 +/- 10.4 years. A Kaplan-Meier survival curve revealed that patients with onset symptoms of cerebellar ataxia had a better prognosis than those with onset of parkinsonism or autonomic failure (p < 0.01). Additionally, we found that a higher onset age was associated with poor prognosis. We found that patients with cerebellar ataxia at onset had a better survival prognosis than those with parkinsonism or autonomic failure at onset and that patients with an older age at onset had a worse survival prognosis. PMID- 25910616 TI - MicroRNAs Promote Granule Cell Expansion in the Cerebellum Through Gli2. AB - MicroRNAs (miRNAs) are important regulators of cerebellar function and homeostasis. Their deregulation results in cerebellar neuronal degeneration and spinocerebellar ataxia type 1 and contributes to medulloblastoma. Canonical miRNA processing involves Dicer, which cleaves precursor miRNAs into mature double stranded RNA duplexes. In order to address the role of miRNAs in cerebellar granule cell precursor development, loxP-flanked exons of Dicer1 were conditionally inactivated using the granule cell precursor-specific Atoh1-Cre recombinase. A reduction of 87% in Dicer1 transcript was achieved in this conditional Dicer knockdown model. Although knockdown resulted in normal survival, mice had disruptions to the cortical layering of the anterior cerebellum, which resulted from the premature differentiation of granule cell precursors in this region during neonatal development. This defect manifested as a thinner external granular layer with ectopic mature granule cells, and a depleted internal granular layer. We found that expression of the activator components of the Hedgehog-Patched pathway, the Gli family of transcription factors, was perturbed in conditional Dicer knockdown mice. We propose that loss of Gli2 mRNA mediated the anterior-restricted defect in conditional Dicer knockdown mice and, as proof of principle, were able to show that miR-106b positively regulated Gli2 mRNA expression. These findings confirm the importance of miRNAs as positive mediators of Hedgehog-Patched signalling during granule cell precursor development. PMID- 25910617 TI - Using white blood cell counts to predict metabolic syndrome in the elderly: A combined cross-sectional and longitudinal study. AB - BACKGROUND: Metabolic syndrome (MetS) has an important implication from a preventive medicine perspective as early recognition and intervention will reduce associated mortality and morbidity. To better identify patients at risk for developing MetS and cardiovascular disease, we conduct a combined cross-sectional and longitudinal study to shed light on the elevated white blood cell (WBC) level in elderly. METHODS: A total of 10,463 subjects were eligible for analysis. In the first stage of study, subjects were enrolled in the cross-sectional study to find out not only the correlation between WBC and MetS but also the optimal cut off value of WBC with higher chances to have MetS. In the second stage of current study, subjects with MetS at baseline were excluded from the same study group, and performed a median 6.8-year longitudinal study to validate the optimal cut off value of WBC predicting MetS. RESULTS: WBC is significantly higher in the group with than without MetS in both genders. All MetS components were associated with WBC in multivariate analysis except diastolic blood pressure and fasting plasma glucose. In the longitudinal study, WBC showed to be a good predictor of MetS in both genders. CONCLUSION: WBC is a good marker to identify the high risk subjects having MetS in the current status or in the future. Elderly with a higher WBC and without any underlying chronic diseases should receive more attention on the potential to develop MetS. PMID- 25910618 TI - Anterior perineal fistulectomy in repairing H-type rectovestibular fistula with a normal anus in female children. AB - The purpose of this study was to review a 7-year operative experience of anterior perineal fistulectomy in repairing H-type rectovestibular fistula with a normal anus in female children. From January 2007 to December 2013, 105 female children with H-type rectovestibular fistula and a normal anus underwent anterior perineal fistulectomy in the Department of General Surgery, Beijing Children's Hospital, Capital Medical University. Clinical data were retrospectively analyzed. Patients' age ranged from 6 months to 13 years 10 months, with an average age 5 years 2 months. The clinical feature of this disease was a definite history of vestibular infection at about 30 days after birth and leakage of gas or loose stool through vestibular fistular orifice after the infection was controlled. All patients had a normal anus. Follow-up through telephone or outpatient visits from 6 months to 7 years (median, 5.2 years), showed that all the patients were continent and had regular bowel movements. Among the 105 patients, 97 (92.4%) gained primary healing with a satisfactory appearance; 8 (7.6%) patients relapsed, among which 5 healed after hip bathing treatment within 3 weeks, 2 required another anterior perineal fistulectomy 7 months later and were cured, and the last one had another anterior perineal fistulectomy 1 year 10 months later but relapsed again, which healed after hip bathing treatment within 3weeks after the second surgery. Anterior perineal fistulectomy is a simple, safe and reliable surgical method to treat H-type rectovestibular fistula with a normal anus. PMID- 25910619 TI - Translation of the Diabetes Prevention Program to Ethnic Communities in the United States. AB - The Diabetes Prevention Program (DPP), an evidenced-based lifestyle intervention for type 2 diabetes (T2D), has been translated for use with ethnic minority communities throughout the United States that are disproportionately at-risk for T2D. The present paper sought to critically review ethnic translation studies of the DPP with respect to translation methods utilized, the success of these methods, and alternative or supplemental methodologies for future translation efforts. Manuscripts reviewed were found by searching PubMed and PsycINFO, using the terms: "diabetes prevention program" AND ["translation" or "ethnic"]. Of 89 papers found, only 6 described ethnic translations of the DPP in the United States, and were included in this review. Translations of the DPP to African American, Hispanic/Latino, Native Hawaiian and Other Pacific Islander, Arab American, and American Indian and Native Alaskan communities were identified and reviewed. The most common translation strategies included group-based delivery and use of bilingual study personnel. Generally, these factors appeared to increase acceptability of the intervention within the ethnic communities reviewed, and should be considered in future efforts to implement and translate the DPP to ethnic communities in the United States. PMID- 25910620 TI - Role of Social Support in Examining Acculturative Stress and Psychological Distress Among Asian American Immigrants and Three Sub-groups: Results from NLAAS. AB - This study examined the impact of acculturative stress and social support (family and friend) on psychological distress among Asian American immigrants and three Asian sub-groups (Vietnamese, Filipino and Chinese) immigrants. The National Latino and Asian American Study 2002-2003 dataset was used. The study findings were: (1) among all Asian American immigrants high language barrier and discrimination stress were associated with increased level of psychological distress, but similar association was not present for legal stress; (2) among all Asian American immigrants high family social support decreased the levels of psychological distress, and in addition, friend social support buffered the relationship of discrimination and psychological distress; and (3) among Vietnamese, Filipino, and Chinese, differential association of social support and acculturative stress to psychological distress were observed. These findings highlight the importance of social support among Asian American immigrants, while also paying attention to the variation that may exist between different sub groups. PMID- 25910621 TI - The effect of aging on mitochondrial and cytosolic hepatic intrinsic death pathway and apoptosis associated proteins in Fischer 344 rats. AB - Apoptosis is increased in the liver in old age and is a common pathological feature of liver disease. The mitochondria play a key role in regulating apoptosis via the intrinsic death pathway. As the effect of aging on this pathway is unclear, we aimed to characterize the impact of aging on the hepatic intrinsic death pathway and apoptosis. Livers from young adult (6.6 +/- 0.3 months, n = 9) and old (25.4 +/- 0.7 months, n = 9) male Fischer 344 rats were extracted for cellular fractionation and immunobloting. In old age there were lower mitochondrial protein levels of pro-apoptotic BAK, BID, tBID and VDAC1 (p < 0.05) and of anti-apoptotic Bcl-2. Compared to young, old rats had lower cytosolic protein levels of pro-apoptotic BAX, BAK, BID, tBID and anti-apoptotic Bcl-xL (p < 0.05). BAK, Bcl-2 and Bcl-xL were found in the cytosol. Furthermore with old age, cytosolic protein levels of cytochrome C, AIF and cleaved caspase-9 did not change but activation of caspase-3, -6 and -7 increased (p < 0.05) and DNA fragmentation trended to increase. Our results suggest an age-related decline in the levels of a number of proteins involved in the intrinsic death pathway, an uncoupling of intermediate apoptosis signaling and increased cellular apoptosis in the liver in old age. PMID- 25910622 TI - Exercise training increases anabolic and attenuates catabolic and apoptotic processes in aged skeletal muscle of male rats. AB - Aging results in significant loss of mass and function of the skeletal muscle, which negatively impacts the quality of life. In this study we investigated whether aerobic exercise training has the potential to alter anabolic and catabolic pathways in the skeletal muscle. Five and twenty eight month old rats were used in the study. Aging resulted in decreased levels of follistatin/mTOR/Akt/Erk activation and increased myostatin/Murf1/2, proteasome subunits, and protein ubiquitination levels. In addition, TNF-alpha, reactive oxygen species (ROS), p53, and Bax levels were increased while Bcl-2 levels were decreased in the skeletal muscle of aged rats. Six weeks of exercise training at 60% of VO2max reversed the age-associated activation of catabolic and apoptotic pathways and increased anabolic signaling. The results suggest that the age associated loss of muscle mass and cachexia could be due to the orchestrated down regulation of anabolic and up-regulation of catabolic and pro-apoptotic processes. These metabolic changes can be attenuated by exercise training. PMID- 25910623 TI - Field evaluation of a rapid diagnostic test to detect antibodies in human toxocariasis. AB - Human toxocariasis which is caused mainly by the larvae of Toxocara canis and Toxocara cati, is a worldwide zoonotic disease that can be a potentially serious human infection. The enzyme-linked immunosorbent assay (ELISA) using T. canis excretory-secretory (TES) antigens harvested from T. canis larvae is currently the serological test for confirming toxocariasis. An alternative to producing large amounts of Toxocara TES and improved diagnosis for toxocariasis is through the development of highly specific recombinant antigens such as the T. canis second stage larva excretory-secretory 30 kDa protein (recTES-30). The aim of this study was to evaluate the sensitivity and specificity of a rapid diagnostic kit (RDT, named as iToxocara kit) in comparison to recTES-30 ELISA in Serendah Orang Asli village in Selangor, Malaysia. A total of 133 subjects were included in the study. The overall prevalence rates by ELISA and RDT were 29.3% and 33.1%, respectively, with more positive cases detected in males than females. However, no association was found between toxocariasis and gender or age. The percentage sensitivity, specificity, positive predictive value and negative predictive value of RDT were 85.7%, 90.1%, 80% and 93.2%, respectively. The prevalence for toxocariasis in this population using both ELISA and RDT was 27.1% (36/133) and the K-concordance test suggested good agreement of the two tests with a Cohen's kappa of 0.722, P<0.01. In addition, the followed-up Spearman rank correlation showed a moderately high correlation at R=0.704 and P<0.01. In conclusion, the RDT kit was faster and easier to use than an ELISA and is useful for the laboratory diagnosis of hospitalized cases of toxocariasis. PMID- 25910624 TI - Draft genome of neurotropic nematode parasite Angiostrongylus cantonensis, causative agent of human eosinophilic meningitis. AB - Angiostrongylus cantonensis is a bursate nematode parasite that causes eosinophilic meningitis (or meningoencephalitis) in humans in many parts of the world. The genomic data from A. cantonensis will form a useful resource for comparative genomic and chemogenomic studies to aid the development of diagnostics and therapeutics. We have sequenced, assembled and annotated the genome of A. cantonensis. The genome size is estimated to be ~260 Mb, with 17,280 genomic scaffolds, 91X coverage, 81.45% for complete and 93.95% for partial score based on CEGMA analysis of genome completeness. The number of predicted genes of >=300 bp was 17,482. A total of 7737 predicted protein-coding genes of >=50 amino acids were identified in the assembled genome. Among the proteins of known function, kinases are the most abundant followed by transferases. The draft genome contains 34 excretory-secretory proteins (ES), a minimum of 44 Nematode Astacin (NAS) metalloproteases, 12 Homeobox (HOX) genes, and 30 neurotransmitters. The assembled genome size (260 Mb) is larger than those of Pristionchus pacificus, Caenorhabditis elegans, Necator americanus, Caenorhabditis briggsae, Trichinella spiralis, Brugia malayi and Loa loa, but smaller than Haemonchus contortus and Ascaris suum. The repeat content (25%) is similar to H. contortus. The GC content (41.17%) is lower compared to P. pacificus (42.7%) and H. contortus (43.1%) but higher compared to C. briggsae (37.69%), A. suum (37.9%) and N. americanus (40.2%) while the scaffold N50 is 42,191. This draft genome will facilitate the understanding of many unresolved issues on the parasite and the disorder it causes. PMID- 25910625 TI - Development of a recombinant OppA-based indirect hemagglutination test for the detection of antibodies against Haemophilus parasuis. AB - An indirect hemagglutination (IHA) test that could detect antibodies against Haemophilus parasuis was developed. The full-length cDNA sequence of the oligopeptide permease ABC transporter membrane protein (OppA) gene was cloned, and inserted into the prokaryotic expression vector pET-30a(+) to construct recombinant plasmid pET-30a-OppA. The recombinant OppA protein was expressed partly in soluble form in Escherichia coli BL21 (DE3) and then purified by Ni(2+) column. Furthermore, the recombinant OppA protein was used as an antigen to develop an IHA assay for detecting antibodies against H. parasuis. Results showed that this IHA test could detect species-specific antibodies against H. parasuis. Compared with currently available ELISA, the IHA test had a sensitivity of 85.0% and a specificity of 95.0%. The overall agreement between these two methods was 90.0%. The developed IHA test was used to evaluate the seroprevalence of H. parasuis in Hubei Province, China. The H. parasuis seroprevalence rate ranged from 5.5% to 26.2% in 325 tested clinical serum samples that were collected from three different pig farms in Hubei Province, China. The IHA test developed in this study will greatly contribute to the epidemiological surveys and immunization surveillance of H. parasuis. PMID- 25910626 TI - How genomics is contributing to the fight against artemisinin-resistant malaria parasites. AB - Plasmodium falciparum, the malignant malaria parasite, has developed resistance to artemisinin, the most important and widely used antimalarial drug at present. Currently confined to Southeast Asia, the spread of resistant parasites to Africa would constitute a public health catastrophe. In this review we highlight the recent contributions of genomics to our understanding how the parasite develops resistance to artemisinin and its derivatives, and how resistant parasites may be monitored and tracked in real-time, using molecular approaches. PMID- 25910627 TI - Squamasnema amazonica n. gen. n. sp. (Heligmonellinae): A new parasite of Proechimys roberti (Rodentia: Echimyidae) in the Brazilian Amazon. AB - A new species of nematode, Squamasnema amazonica n. gen. n. sp., is described based on specimens found parasitizing the small intestine of Proechimys roberti (Rodentia: Echimyidae) collected during a survey of the fauna of Tapirape-Aquiri National Forest (Brazil, Eastern Brazilian Amazon). The nematodes were fixed and processed for light microscopy and scanning electron microscopy (SEM). These nematodes were classified under the family Heligmonellidae and the subfamily Heligmonellinae. Although several species in the family Heligmonellidae exhibit discontinuous ridges, Squamasnema n. gen. and Trichotravassosia are the only genera with columns of scales along their entire body, as an apomorphy of the synlophe. Squamasnema n. gen. has columns of cuticular cells along its body, except for on the left flank, and exhibits a synlophe with no size gradient or inclination and does not present chitinized structures supporting the synlophe. Therefore, due to these morphological differences of Squamasnema n. gen., the creation of a new genus was necessary. PMID- 25910628 TI - Mitochondrial dynamics in the mouse liver infected by Schistosoma mansoni. AB - Mitochondrial dynamics is crucial for regulation of cell homeostasis. Schistosoma mansoni is one of the most common parasites known to cause liver disease. Mice infected by S. mansoni show acute symptoms of schistosomiasis after 8 weeks. Hence, in this study, we attempted to assess the direct effects of S. mansoni infection on mice liver, and to explore the expression of mitochondrial morphology, dynamics, and function. Our recent findings show that S. mansoni infection changes mitochondrial morphology and affects mitochondrial functions, which attenuates mitochondrial membrane potential and ATP generation. S. mansoni infected mice increases mitochondrial numbers by upregulating of genes involved in mitochondrial biogenesis, including peroxisome proliferator-activated receptor c co-activator 1alpha (PGC1alpha) and mitochondrial transcription factor A (Tfam). This may promote mitochondria generation for accelerating the recovery of mitochondrial functions. Moreover, S. mansoni would disrupt mitochondrial dynamics including induced mitochondrial fission and promoted mitochondrial fragmentation in mice liver. More importantly, S. mansoni further stimulated upregulation both extrinsic and intrinsic apoptosis pathway in infected mice liver. The intrinsic pathway was triggered by cytochrome c release. Additionally, NFkappaB (nuclear factor-kappa B, p65) could play a protective role to inhibit apoptosis through reducing active caspase-3 expression. Therefore, our results confirmed the liver damage mechanism of experimental schistosomiasis in mice model. PMID- 25910629 TI - Apical Organelle Secretion by Toxoplasma Controls Innate and Adaptive Immunity and Mediates Long-Term Protection. AB - Apicomplexan parasites have unique apical rhoptry and microneme secretory organelles that are crucial for host infection, although their role in protection against Toxoplasma gondii infection is not thoroughly understood. Here, we report a novel function of the endolysosomal T. gondii sortilin-like receptor (TgSORTLR), which mediates trafficking to functional apical organelles and their subsequent secretion of virulence factors that are critical to the induction of sterile immunity against parasite reinfection. We further demonstrate that the T. gondii armadillo repeats-only protein (TgARO) mutant, which is deficient only in apical secretion of rhoptries, is also critical in mounting protective immunity. The lack of TgSORTLR and TgARO proteins completely inhibited T-helper 1-dependent adaptive immunity and compromised the function of natural killer T-cell-mediated innate immunity. Our findings reveal an essential role for apical secretion in promoting sterile protection against T. gondii and provide strong evidence for rhoptry-regulated discharge of antigens as a key effector for inducing protective immunity. PMID- 25910631 TI - Where Do We Go From Here? PMID- 25910630 TI - A Single Mutation in K13 Predominates in Southern China and Is Associated With Delayed Clearance of Plasmodium falciparum Following Artemisinin Treatment. AB - BACKGROUND: Artemisinin resistance in Plasmodium falciparum has emerged in Southeast Asia and poses a threat to malaria control and elimination. Mutations in a P. falciparum gene encoding a kelch protein on chromosome 13 have been associated with delayed parasite clearance following artemisinin treatment elsewhere in the region, but not yet in China. METHODS: Therapeutic efficacy studies of artesunate and dihydroartemisinin-piperaquine were conducted from 2009 to 2012 in the Yunnan Province of China near the border with Myanmar. K13 mutations were genotyped by capillary sequencing of DNA extracted from dried blood spots collected in these clinical trials and in routine surveillance. Associations between K13 mutations and delayed parasite clearance were tested using regression models. RESULTS: Parasite clearance half-lives were prolonged after artemisinin treatment, with 44% of infections having half-lives >5 hours (n = 109). Fourteen mutations in K13 were observed, with an overall prevalence of 47.7% (n = 329). A single mutation, F446I, predominated, with a prevalence of 36.5%. Infections with F446I were significantly associated with parasitemia on day 3 following artemisinin treatment and with longer clearance half-lives. CONCLUSIONS: Plasmodium falciparum infections in southern China displayed markedly delayed clearance following artemisinin treatment. F446I was the predominant K13 mutation and was associated with delayed parasite clearance. PMID- 25910633 TI - Using concurrent think-aloud and protocol analysis to explore student nurses' social learning information communication technology knowledge and skill development. AB - Observations obtained through concurrent think-aloud and protocol analysis offer new understanding about the influence of social learning on student nurses' acquisition of Information and Communication Technology (ICT) knowledge and skills. The software used provides a permanent record of the underpinning study method, events and analyses. The emerging themes reflect the dimensions of social engagement, and the characteristics of positive and negative reactions to ICT. The evidence shows that given the right conditions, stronger learners will support and guide their peers. AIMS: To explore the use of concurrent think-aloud and protocol analysis as a method to examine how student nurses approach ICT. To identify the benefits and challenges of using observational technology to capture learning behaviours. To show the influence of small group arrangement and student interactions on their ICT knowledge and skills development. BACKGROUND: Previous studies examining social interaction between students show how they work together and respond to interactive problem solving. Social interaction has been shown to enhance skills in both ICT and collaborative decision making. DESIGN: Structured observational analysis using concurrent think-aloud and protocol analysis. RESULTS: Students displayed varying degrees of pastoral support and emotional need, leadership, reflection, suggestion and experimentation skills. CONCLUSION: Encouraging student nurses to work in small mixed ability groups can be conducive for social and ICT skill and knowledge development. Observational software gives a permanent record of the proceedings. PMID- 25910632 TI - Serum Procalcitonin Measurement and Viral Testing to Guide Antibiotic Use for Respiratory Infections in Hospitalized Adults: A Randomized Controlled Trial. AB - BACKGROUND: Viral lower respiratory tract illness (LRTI) frequently causes adult hospitalization and is linked to antibiotic overuse. European studies suggest that the serum procalcitonin (PCT) level may be used to guide antibiotic therapy. We conducted a trial assessing the feasibility of using PCT algorithms with viral testing to guide antibiotic use in a US hospital. METHODS: Three hundred patients hospitalized with nonpneumonic LRTI during October 2013-April 2014 were randomly assigned at a ratio of 1:1 to receive standard care or PCT-guided care and viral PCR testing. The primary outcome was antibiotic exposure, and safety was assessed at 1 and 3 months. RESULTS: Among the 151 patients in the intervention group, viruses were identified in 42% (63), and 83% (126) had PCT values of <0.25 ug/mL. There were no significant differences in antibiotic use or adverse events between intervention patients and those in the nonintervention group. Subgroup analyses revealed fewer subjects with positive results of viral testing and low PCT values who were discharged receiving antibiotics (20% vs 45%; P = .002) and shorter antibiotic durations among algorithm-adherent intervention patients versus nonintervention patients (2.0 vs 4.0 days; P = .004). Compared with historical controls (from 2008-2011), antibiotic duration in nonintervention patients decreased by 2 days (6.0 vs 4.0 days; P < .001), suggesting a study effect. CONCLUSIONS: Although antibiotic use was similar in the 2 arms, subgroup analyses of intervention patients suggest that physicians responded to viral and biomarker data. These data can inform the design of future US studies. CLINICAL TRIALS REGISTRATION: NCT01907659. PMID- 25910634 TI - Gene expression in Listeria monocytogenes exposed to sublethal concentration of benzalkonium chloride. AB - In this study, tolerance at sublethal concentration of benzalkonium chloride and transcription levels of mdrL, ladR, lde, sigB and bcrABC genes in Listeria monocytogenes strains were evaluated. Viable cells reduction occurred in 45% of strains and clinical isolates showed lower sensitivity than isolates from foods. An increased transcription of an efflux system encoding gene was found in 60% of strains, and simultaneous mdrL overexpression and ladR underexpression occurred in 30% of isolates. A significant association between reduced benzalkonium chloride activity and both mdrL and sigB overexpression was observed; sigB expression also correlated with both mdrL and ladR genes. The bcrABC gene was only found in six strains, all isolated from foods and sensitive to benzalkonium chloride, and in four strains an underexpression was observed. Disinfection at sublethal concentration was less effective in clinical isolates, and mdrL and sigB expression was significantly affected by disinfection. Further insights are needed to understand the adaptation to benzalkonium chloride and to evaluate whether changes in gene expression could affect the L. monocytogenes virulence traits and persistence in the environment. PMID- 25910635 TI - Effect of negatively charged cellulose nanofibers on the dispersion of hydroxyapatite nanoparticles for scaffolds in bone tissue engineering. AB - Nanofibrous 2,2,6,6-tetramethylpiperidine-1-oxyl(TEMPO)-oxidized bacterial cellulose (TOBC) was used as a dispersant of hydroxyapatite (HA) nanoparticles in aqueous solution. The surfaces of TOBC nanofibers were negatively charged after the reaction with the TEMPO/NaBr/NaClO system at pH 10 and room temperature. HA nanoparticles were simply adsorbed on the TOBC nanofibers (HA-TOBC) and dispersed well in DI water. The well-dispersed HA-TOBC colloidal solution formed a hydrogel after the addition of gelatin, followed by crosslinking with glutaraldehyde (HA TOBC-Gel). The chemical modification of the fiber surfaces and the colloidal stability of the dispersion solution confirmed TOBC as a promising HA dispersant. Both the Young's modulus and maximum tensile stress increased as the amount of gelatin increased due to the increased crosslinking of gelatin. In addition, the well-dispersed HA produced a denser scaffold structure resulting in the increase of the Young's modulus and maximum tensile stress. The well-developed porous structures of the HA-TOBC-Gel composites were incubated with Calvarial osteoblasts. The HA-TOBC-Gel significantly improved cell proliferation as well as cell differentiation confirming the material as a potential candidate for use in bone tissue engineering scaffolds. PMID- 25910636 TI - Mechanistic studies on the reversible photophysical properties of carbon nanodots at different pH. AB - The pH-dependent photoluminescence (PL) behavior of carbon nanodots (C-dots) and its mechanism has been exhaustively studied in this work. The PL and UV-vis absorption spectra are reversible in the pH between 3 and 13. We speculate that two kinds of reactions (fast and slow) occurring at the surface of C-dots may contribute to this pH-dependent PL behavior. When C-dots solutions are switched to acidic conditions, they will quickly self-assembled aggregate into larger particles and surface oxygen-related groups of C-dots would be slowly oxidized at room temperature. Moreover, it should be noted that this is the first direct observation of self-assembled aggregation of C-dots under acidic conditions. In addition, the optimal PL spectra of C-dots blue-shift while their sizes increase, so-called 'inverse PL shift' phenomenon is also observed. Meanwhile, as the solution is adjusted to alkaline conditions, a structural tautomerization of C dots rapidly takes place and hydrogenation/deoxygenation reaction proceeds in a much slower rate. Furthermore, through distinct decay dynamics as well as the characterizations of C-dots at different pHs, the PL properties are proposed to be mainly related to the surface states of C-dots. PMID- 25910637 TI - Long-term sequelae after Ebola virus disease in Bundibugyo, Uganda: a retrospective cohort study. AB - BACKGROUND: The limited data available for long-term Ebola virus disease health outcomes suggest that sequelae persist for longer than 1 year after infection. The magnitude of the present outbreak in west Africa necessitates a more complete understanding of the health effects and future medical needs of these patients. METHODS: We invited adult survivors of the 2007 Bundibugyo Ebola virus outbreak in Uganda and their contacts to take part in an observational study roughly 29 months after the outbreak. We collected information about health status, functional limitations, and demographics. We collected blood samples for clinical chemistry, haematology, and filovirus antibodies using ELISA. Analyses were restricted to probable and confirmed survivors and their seronegative contacts. FINDINGS: We recruited 70 survivors of the 2007 Bundibugyo Ebola virus and 223 contacts. We did analyses for 49 probable and confirmed survivors and 157 seronegative contacts. Survivors of the Bundibugyo Ebola virus were at significantly increased risk of ocular deficits (retro-orbital pain [RR 4.3, 95% CI 1.9-9.6; p<0.0001], blurred vision [1.9, 1.1-3.2; p=0.018]), hearing loss (2.3, 1.2-4.5; p=0.010), difficulty swallowing (2.1, 1.1-3.9; p=0.017), difficulty sleeping (1.9, 1.3-2.8; p=0.001), arthralgias (2.0, 1.1-3.6; p=0.020), and various constitutional symptoms controlling for age and sex. Chronic health problems (prevalence ratio [PR] 2.1, 95% CI 1.2-3.6; p=0.008) and limitations due to memory loss or confusion (PR 5.8, 1.5-22.4; p=0.010) were also reported more frequently by survivors of Bundibugyo Ebola virus. INTERPRETATION: Long-term sequelae persist for more than 2 years after Ebola virus disease. Definition of health consequences related to Ebola virus disease could improve patient care for survivors and contribute to understanding of disease pathogenesis. FUNDING: Chemical Biological Technologies Directorate, Defense Threat Reduction Agency. PMID- 25910638 TI - Sequelae after Ebola virus disease: even when it's over it's not over. PMID- 25910640 TI - Stimulation of osteogenesis and angiogenesis of hBMSCs by delivering Si ions and functional drug from mesoporous silica nanospheres. AB - Multifunctional bioactive materials with the ability to stimulate osteogenesis and angiogenesis of stem cells play an important role in the regeneration of bone defects. However, how to develop such biomaterials remains a significant challenge. In this study, we prepared mesoporous silica nanospheres (MSNs) with uniform sphere size (~90 nm) and mesopores (~2.7 nm), which could release silicon ions (Si) to stimulate the osteogenic differentiation of human bone marrow stromal cells (hBMSCs) via activating their ALP activity, bone-related gene and protein (OCN, RUNX2 and OPN) expression. Hypoxia-inducing therapeutic drug, dimethyloxaloylglycine (DMOG), was effectively loaded in the mesopores of MSNs (D MSNs). The sustained release of DMOG from D-MSNs could stabilize HIF-1alpha and further stimulated the angiogenic differentiation of hBMSCs as indicated by the enhanced VEGF secretion and protein expression. Our study revealed that D-MSNs could combine the stimulatory effect on both osteogenic and angiogenic activity of hBMSCs. The potential mechanism of D-MSN-stimulated osteogenesis and angiogenesis was further elucidated by the supplementation of cell culture medium with pure Si ions and DMOG. Considering the easy handling characteristics of nanospheres, the prepared D-MSNs may be applied in the forms of injectable spheres for minimally invasive surgery, or MSNs/polymer composite scaffolds for bone defect repair. The concept of delivering both stimulatory ions and functional drugs may offer a new strategy to construct a multifunctional biomaterial system for bone tissue regeneration. PMID- 25910639 TI - Functional-segregated coumarin-containing telodendrimer nanocarriers for efficient delivery of SN-38 for colon cancer treatment. AB - Four coumarin-containing telodendrimers (denoted as P-I, P-II, P-III and P-IV) were designed and synthesized to self-assemble into the corresponding nanoparticles. Of those, two nanoparticles (P-II and P-IV micelles) were screened and selected for targeted drug delivery of 7-ethyl-10-hydroxy camptothecin (SN 38), a prominent and efficacious anticancer agent, for the treatment of colon cancers. The nanoparticle encapsulation significantly increased the solubility of SN-38 in aqueous solution. Dynamic light scattering (DLS) showed the size of these SN-38 nanoparticles to be around 50 nm, and rod-shaped micelles were observed using transmission electron microscopy (TEM). These two novel nanoformulations of SN-38/P-II and SN-38/P-IV were found to exhibit similar in vitro cytotoxic activity against colon cancer cells as the free drug (SN-38 in DMSO) and were 500-fold more potent than irinotecan (a prodrug of SN-38). In addition, near infrared fluorescent (NIRF) optical imaging was utilized to monitor the tumor targeted delivery of SN-38/NPs via co-loading a NIRF dye. It was demonstrated that these NPs preferentially accumulated in tumors when compared to healthy tissue. A pharmacokinetics study showed that SN-38 micelle formulations had a longer circulating time in blood than irinotecan. Furthermore, SN-38 loaded nanoformulations exhibit superior anti-tumor efficacy when compared with irinotecan at equivalent SN-38 dose in HT-29 human colon cancer xenograft models. PMID- 25910641 TI - On the effect of serum on the transport of reactive oxygen species across phospholipid membranes. AB - The transport of plasma generated reactive oxygen species (ROS) across a simple phospholipid membrane mimic of a (real) cell was investigated. Experiments were performed in cell culture media (Dulbecco's modified Eagle's medium, DMEM), with and without 10% serum. A (broad spectrum) ROS reporter dye, 2,7 dichlorodihydrofluorescein (DCFH), was used to detect the generation of ROS by a helium (He) plasma jet in DMEM using free DCFH and with DCFH encapsulated inside phospholipid membrane vesicles dispersed in DMEM. The authors focus on the concentration and on the relative rates (arbitrary units) for oxidation of DCFH [or the appearance of the oxidized product 2,7-dichlorofluorescein (DCF)] both in solution and within vesicles. In the first 1 h following plasma exposure, the concentration of free DCF in DMEM was ~15* greater in the presence of serum (cf. to the serum-free DMEM control). The DCF in vesicles was ~2* greater in DMEM containing serum compared to the serum-free DMEM control. These data show that serum enhances plasma ROS generation in DMEM. As expected, the role of the phospholipid membrane was to reduce the rate of oxidation of the encapsulated DCFH (with and without serum). And the efficiency of ROS transport into vesicles was lower in DMEM containing serum (at 4% efficiency) when compared to serum-free DMEM (at 32% efficiency). After 1 h, the rate of DCFH oxidation was found to have significantly reduced. Based upon a synthesis of these data with results from the open literature, the authors speculate on how the components of biological fluid and cellular membranes might affect the kinetics of consumption of plasma generated ROS. PMID- 25910642 TI - CD4(+) CD44(v.low) cells are unique peripheral precursors that are distinct from recent thymic emigrants and stem cell-like memory cells. AB - CD4(+) CD44(v.low) cells are peripheral precursor T cells that inhibit lymphopenia by generating a large CD4(+) T cell pool containing balanced numbers of naive, memory, and regulatory Foxp3(+) cells with a diverse TCR repertoire. Recent thymic emigrants (RTE) and stem cell-like memory T cells (T(SCM)) can also replenish a T cell pool. In this study we formally test whether CD44(v.low) cells are the same population as RTE and T(SCM). Our data show that, in contrast to RTE, CD44(v.low) cells express high levels of CD45RB and low levels of CD24. Moreover, CD44(v.low) cells isolated from mice devoid of RTE retain their capacity to repopulate lymphopenic mice with naive and memory cells and Foxp3(+) Tregs. In addition, CD44(v.low) cells do not express IL-2Rbeta, Sca-1, and CXCR3, the phenotypic hallmarks of T(SCM). Overall, these data demonstrate that CD44(v.low) cells are neither RTE nor T(SCM). PMID- 25910643 TI - Handwriting and pre-frailty in the Lausanne cohort 65+ (Lc65+) study. AB - BACKGROUND: Frailty is detected by weight loss, weakness, slow walking velocity, reduced physical activity or poor endurance/exhaustion. Handwriting has not been examined in the context of frailty, despite its functional importance. OBJECTIVE: Our goal was to examine quantitative handwriting measures in people meeting 0, 1, and 2 or more (2+) frailty criteria. We also examined if handwriting parameters were associated with gait performance, weakness, poor endurance/exhaustion and cognitive impairment. METHODS: From the population-based Lc65+, 72 subjects meeting 2+ frailty criteria with complete handwriting samples were identified. Gender-matched controls meeting 1 criterion or no criteria were identified. Cognitive impairment was defined by a Mini-Mental State Examination score of 25 or less or the lowest 20th percentile of Trail Making Test Part B. Handwriting was recorded using a writing tablet and measures of velocity, pauses, and pressure were extracted. RESULTS: Subjects with 2+ criteria were older, had more health problems and need for assistance but had higher education. No handwriting parameter differed between frailty groups (age and education adjusted). Writing velocity was not significantly slower among participants from the slowest 20th percentile of gait velocity but writing pressure was significantly lower among those from the lowest 20th percentile of grip strength. Poor endurance/exhaustion was not associated with handwriting measures. Low cognitive performance was related to longer pauses. CONCLUSIONS: Handwriting parameters might be associated with specific aspects of the frailty phenotype, but not reliably with global definitions of frailty at its earliest stages among subjects able to perform handwriting tests. PMID- 25910644 TI - Fabrication of porous chitin with continuous substructure by regeneration from gel with CaBr2.2H2O/methanol. AB - In this study, we investigated the fabrication of porous chitins with continuous channel substructure by regeneration from gels with CaBr2.2H2O/methanol solution. After rapidly removing methanol from the gels, the products were immersed in methanol, followed by washing out CaBr2 with water and lyophilization to obtain regenerated chitins with inter-connected continuous pore morphology. Scanning electron microscopic results supported that the materials were consisted of continuous substructures of porous channels. The materials were further characterized by SEM-EDX and XRD measurements. The mechanical property and water absorbability were also evaluated. The plausible mechanism for the formation of the inter-connected pore morphology during the regeneration procedure was discussed. PMID- 25910645 TI - Rheology of mixed alginate-hyaluronan aqueous solutions. AB - The present manuscript addresses the description of binary systems of hyaluronan (HA) and alginate (Alg) in semi-concentrated solution. The two polysaccharides were completely miscible in the entire range of relative weight fraction explored at a total polymer concentration of up to 3% (w/V). The rheological study encompassed steady flow and mechanical spectra for HA/Alg systems at different weight fractions with hyaluronan at different molecular weights. These extensive analyses allowed us to propose a model for the molecular arrangement in solution that envisages a mutual exclusion between the two polysaccharides even though a clear phase separation does not occur. This result may have profound implications when combinations of alginate and hyaluronan are proposed in the field of biomedical materials. PMID- 25910646 TI - Dendrobium huoshanense polysaccharide prevents ethanol-induced liver injury in mice by metabolomic analysis. AB - The prevalence of alcohol consumption has increased in modern dietary life and alcoholic liver injury can follow. Dendrobium huoshanense polysaccharide (DHP) is a homogeneous polysaccharide isolated from Dendrobium huoshanense, which possesses hepatoprotection function. In this study, we investigated the metabolic profiles of serum and liver tissues extracts from control, ethanol-treated and DHP?ethanol-treated mice using a UHPLC/LTQ Orbitrap XL MS-based metabolomics approach. Our results indicated that DHP alleviated early steatosis and inflammation in liver histology and the metabolomic analysis of serum and hepatic tissue revealed that first, ethanol treatment mainly altered phosphatidylcholines (PCs) including PC (13:0) and phosphocholine, arachidonic acid metabolites including 20-ethyl PGF2alpha and amino acids including L-Proline; Second, DHP supplementation ameliorated the altered metabolic levels particularly involved in phosphocholine and L-Proline. These data suggested that DHP might restore the perturbed metabolism pathways by ethanol exposure to prevent the progression of alcoholic liver injury. PMID- 25910647 TI - Human urinary renalase lacks the N-terminal signal peptide crucial for accommodation of its FAD cofactor. AB - Renalase is a recently discovered secretory protein involved in the regulation of blood pressure. Cells synthesize all known isoforms of human renalase (1 and 2) as flavoproteins. Accommodation of FAD in the renalase protein requires the presence of its N-terminal peptide. However, in secretory proteins, such peptides are usually cleaved during their export from the cell. In the present study, we have isolated human renalase from urinary samples of healthy volunteers and human recombinant renalases 1 and 2 expressed in Escherichia coli cells. In these proteins, we investigated the presence of the renalase N-terminal peptide and the FAD cofactor and performed computer-aided molecular analysis of the renalase crystal structure to evaluate possible consequences of removal of the N-terminal peptide. In contrast to human recombinant renalase isoforms 1 and 2 containing non-covalently bound FAD and clearly detectable N-terminal peptide, renalase purified from human urine lacks both the N-terminal signal peptide and FAD. The computer-aided analysis indicates that the removal of this peptide results in inability of the truncated renalase to bind the FAD cofactor. Thus, our results indicate that human renalase secreted in urine lacks its N-terminal peptide, and therefore catalytic activities of urinary renalase reported in the literature cannot be attributed to FAD-dependent mechanisms. We suggest that FAD-dependent catalytic functions are intrinsic properties of intracellular renalases, whereas extracellular renalases act in FAD- and possibly catalytic-independent manner. PMID- 25910648 TI - Chitin extraction from crab shells by Bacillus bacteria. Biological activities of fermented crab supernatants. AB - Crab shells waste were fermented using six protease-producing Bacillus species (Bacillus subtilis A26, Bacillus mojavensis A21, Bacillus pumilus A1, Bacillus amyloliquefaciens An6, Bacillus licheniformis NH1 and Bacillus cereus BG1) for the production of chitin and fermented-crab supernatants (FCSs). In medium containing only crab shells, the highest demineralization DM was obtained with B. licheniformis NH1 (83+/-0.5%) and B. pumilus A1 (80+/-0.6%), while the highest deproteinization (DP) was achieved with A1 (94+/-1%) followed by NH1 (90+/-1.5%) strains. Cultures conducted in medium containing crab shells waste supplemented with 5% (w/v) glucose, were found to remarkably promote demineralization efficiency, and enhance slightly deproteinization rates. FTIR spectra of chitins showed the characteristics bands of alpha-chitin. FCSs showed varying degrees of antioxidant activities which were in a dose-dependent manner (p<0.01). In fact, FCS produced by B. amyloliquefaciens An6 exhibited the highest DPPH free radical scavenging activity (92% at 4 mg/ml), while the lowest hydroxyl radical scavenging activity (60% at 4 mg/ml) was obtained with B. subtilis A26 hydrolysates. However, the highest reducing power (OD700nm=2 at 0.5 mg/ml) was obtained by B.amyloliquefaciens An6 hydrolysates. These results suggest that crab hydrolysates are good sources of natural antioxidants. Further, FCSs were found to exhibit antibacterial activity against Gram-positive and Gram-negative bacteria. PMID- 25910649 TI - Constitutive over-expression of rice chymotrypsin protease inhibitor gene OCPI2 results in enhanced growth, salinity and osmotic stress tolerance of the transgenic Arabidopsis plants. AB - Protease inhibitors are involved primarily in defense against pathogens. In recent years, these proteins have also been widely implicated in response of plants to diverse abiotic stresses. Rice chymotrypsin protease inhibitor gene OCPI2 is highly induced under salt and osmotic stresses. The construct containing the complete coding sequence of OCPI2 cloned downstream to CaMV35S promoter was transformed in Arabidopsis and single copy, homozygous transgenic lines were produced. The transgenic plants exhibited significantly enhanced tolerance to NaCl, PEG and mannitol stress as compared to wild type plants. Importantly, the vegetative and reproductive growth of transgenic plants under unstressed, control conditions was also enhanced: transgenic plants were more vigorous than wild type, resulting into higher yield in terms of silique number. The RWC values and membrane stability index of transgenic in comparison to wild type plants was higher. Higher proline content was observed in the AtOCPI2 lines, which was associated with higher transcript expression of pyrroline-5-carboxylate synthase and lowered levels of proline dehydrogenase genes. The chymotrypsin protease activities were lower in the transgenic as against wild type plants, under both unstressed, control as well as stressed conditions. It thus appears that rice chymotrypsin protease inhibitor gene OCPI2 is a useful candidate gene for genetic improvement of plants against salt and osmotic stress. PMID- 25910650 TI - Isolation and characterization of a phosphatidylglycerophosphate phosphatase1, PGPP1, in Chlamydomonas reinhardtii. AB - Phosphatidylglycerol (PG) is the exclusive phospholipid synthesized in chloroplasts and plays important roles in photosynthesis. However, phosphatidylglycerophosphate phosphatase (PGPP), which catalyzes the final step of PG biosynthesis, is a missing piece in photosynthetic eukaryotes. Here, we isolated a previously uncharacterized haloacid dehalogenase-like phosphatase, designated CrPGPP1, as a putative PGPP in Chlamydomonas reinhardtii. CrPGPP1 complemented growth and lipid compositional defects in Deltagep4, a yeast mutant of PGPP, which indicates that CrPGPP1 is a functional PGPP. Two aspartic acid residues, which are both essential for the yeast PGPP (Gep4p) activity, are also conserved in the putative catalytic motif of CrPGPP1. Site-specific mutagenesis showed that the first but not the second aspartic acid residue was required for CrPGPP1 to complement the growth defect of Deltagep4 mutant, which highlights the distinct molecular features of CrPGPP1. Our results suggest that CrPGPP1 is a functional PGPP in C. reinhardtii, for the first PGPP in photosynthetic eukaryotes. PMID- 25910651 TI - Mitochondrial Dysfunction and Its Relation to Translocator Protein, Oxidative Stress, mTOR Signaling, and Synaptic Protein. PMID- 25910652 TI - Mitochondrial Dysfunction and Its Relationship with mTOR Signaling and Oxidative Damage in Autism Spectrum Disorders. AB - Mitochondria are organelles that play a central role in processes related to cellular viability, such as energy production, cell growth, cell death via apoptosis, and metabolism of reactive oxygen species (ROS). We can observe behavioral abnormalities relevant to autism spectrum disorders (ASDs) and their recovery mediated by the mTOR inhibitor rapamycin in mouse models. In Tsc2(+/-) mice, the transcription of multiple genes involved in mTOR signaling is enhanced, suggesting a crucial role of dysregulated mTOR signaling in the ASD model. This review proposes that the mTOR inhibitor may be useful for the pharmacological treatment of ASD. This review offers novel insights into mitochondrial dysfunction and the related impaired glutathione synthesis and lower detoxification capacity. Firstly, children with ASD and concomitant mitochondrial dysfunction have been reported to manifest clinical symptoms similar to those of mitochondrial disorders, and it therefore shows that the clinical manifestations of ASD with a concomitant diagnosis of mitochondrial dysfunction are likely due to these mitochondrial disorders. Secondly, the adenosine triphosphate (ATP) production/oxygen consumption pathway may be a potential candidate for preventing mitochondrial dysfunction due to oxidative stress, and disruption of ATP synthesis alone may be related to impaired glutathione synthesis. Finally, a decrease in total antioxidant capacity may account for ASD children who show core social and behavioral impairments without neurological and somatic symptoms. PMID- 25910653 TI - Mitochondrial carnitine/acylcarnitine translocase: insights in structure/ function relationships. Basis for drug therapy and side effects prediction. AB - The mitochondrial carnitine/acylcarnitine translocase has been identified, purified and reconstituted in liposomes in 1990. Since that time it has been object of studies aimed to characterize its function and to define the molecular determinants of the translocation pathway. Thanks to these tenacious studies the molecular map of the amino acids involved in the catalysis has been constructed and the roles of critical residues in the translocation pathway have been elucidated. This has been possible through the combination of transport assay in reconstituted liposomes, site-directed mutagenesis, chemical labeling and bioinformatics. Recently some molecules which modulate CACT activity have been identified, such as glutathione and hydrogen peroxide, constituting some of the few cases of control mechanisms of mitochondrial carriers. The vast knowledge on the carnitine/acylcarnitine translocase is essential both as a progress in basic science and as instrument to foresee therapeutic or toxic effects of xenobiotics and drugs. Such studies have been already started pointing out the inhibitory action of drugs such as K(+)/H(+)-ATPase inhibitors (omeprazole) or antibiotics (beta-lactams) on the carnitine/acylcarnitine translocase, which can explain some of their adverse effects. PMID- 25910654 TI - Synthesis and Biological Activities of Organotin(IV) Complexes as Antitumoral and Antimicrobial Agents. A Review. AB - Advances in the use of organotin(IV) compounds have gained relevant interest in both the chemical and pharmaceutical industry. Tin(IV) form stable complexes with a unique structure and physicochemical properties that are used in organic synthesis as heat stabilizers and catalysts, in drug development as biologically active agents, and in other areas. This review focuses on recent progress in the classical and convenient synthesis procedure, on their mechanism of action, and biological activities as antitumoral and antimicrobial agents. PMID- 25910655 TI - The reproducibility of liquid chromatography separation technology and its potential impact on large scale plant metabolomics experiments. AB - Unraveling the constituents of biological samples using HPLC is a central core technology in metabolomics experiments. Consistency in retention time across many samples is a critical criterion for judging the quality of a data set, which must be met before further analysis are possible. Here, the performance of two ultra high-performance liquid chromatography (UHPLC) systems has been compared using an established separation protocol optimized for phenylpropanoids, a class of secondary compounds found in plants displaying intermediate polarity. The two systems differed markedly with respect to their reproducibility and pressure stability. The standard deviation of the retention time of representative peaks differs up to 30-folds between the systems. Adjustments made to the gradient profiles succeeded in equalizing their level of performance. However, the modifications made to the separation protocol reduced the quality of the separation, particularly of the more rapidly eluting components, and lengthened the run time. PMID- 25910656 TI - Editorial. PMID- 25910657 TI - The inhibitors of apoptosis (IAPs): Over 20 years of research into life and death. PMID- 25910658 TI - EUS-guided alcohol injection of pancreatic neuroendocrine tumor. PMID- 25910659 TI - Value of EGD in patients referred for cholecystectomy: a systematic review and meta-analysis. AB - BACKGROUND: As many as 33% of patients with symptomatic cholelithiasis report persisting abdominal pain after cholecystectomy, suggesting alternative causes of these symptoms. EGD may serve as a tool to identify additional symptomatic abdominal disorders beforehand to avoid unnecessary gallbladder surgery. There is controversy as to whether routine EGD before cholecystectomy is appropriate. OBJECTIVE: To perform a systematic review and meta-analysis to assess the value of EGD before cholecystectomy. DESIGN: A systematic literature search was conducted to identify studies that reported the proportion of patients who were referred for cholecystectomy, but in whom initial surgery could be avoided after treatment of abnormalities detected with EGD. Pooled estimates with 95% confidence intervals (CIs) were calculated by using random-effects models. SETTING: Meta-analysis of 12 cohort studies. PATIENTS: A total of 6317 patients with cholelithiasis underwent EGD. RESULTS: The pooled estimate of abnormalities detected with EGD was 36.3% (95% CI, 28.0-45.0). In a total of 3.8% (95% CI, 1.4 7.6) of patients referred for cholecystectomy who underwent previous EGD, gallbladder surgery was avoided. LIMITATIONS: Lack of information regarding characteristics of patients referred for cholecystectomy, criteria for performing EGD, algorithms for the treatment of identified pathologies, and response criteria for the decision to avoid cholecystectomy in included studies. CONCLUSIONS: Our study indicates that, despite the high diagnostic yield of EGD, its value as a tool to prevent gallbladder surgery is limited. EGD should only be considered selectively in patients with cholelithiasis referred for cholecystectomy. PMID- 25910660 TI - Endoscopic management of esophago-mediastinal fistula secondary to mediastinal tuberculosis infection. PMID- 25910661 TI - Position change during colonoscope withdrawal increases polyp and adenoma detection in the right but not in the left side of the colon: results of a randomized controlled trial. AB - BACKGROUND: It has been suggested that changing patient position during colonoscope withdrawal increases adenoma detection. The results of previous studies have been conflicting. OBJECTIVE: To evaluate whether routine position change during colonoscope withdrawal improves polyp detection. DESIGN: Randomized, 2-way, crossover study. SETTING: Teaching hospital. PATIENTS: A total of 130 patients attending for diagnostic colonoscopy. INTERVENTIONS: Patients undergoing colonoscopy had each colon segment examined twice: the right side of the colon (cecum to hepatic flexure) in the supine and left lateral position and the left side of the colon (splenic flexure and descending colon) in the supine and right lateral position. The transverse colon was examined twice in the supine position. MAIN OUTCOME MEASUREMENTS: The primary outcome measure was the polyp detection rate (>=1 polyp) per colon segment. Secondary outcome measures included the number and proportion of patients with >=1 adenoma in each segment and adequacy of luminal distension (1 = total collapse and 5 = no collapse). RESULTS: Examination of the right side of the colon in the left lateral position significantly improved polyp detection (26.2% vs 17.7%; P = .01) and luminal distension (mean = 4.0 vs 3.5; P < .0001). Position change did not improve polyp detection in the left side of the colon (5.4% vs 4.6%; P = .99). There was no significant correlation between luminal distension and polyp detection in the right side of the colon (r = .03). LIMITATIONS: Single center and open study design. CONCLUSION: Examining the right side of the colon in the left lateral position increased polyp detection compared with examination in the supine position. Polyp detection in the left side of the colon was similar in the right lateral and supine positions. ( CLINICAL TRIAL REGISTRATION NUMBER: NCT01554098.). PMID- 25910662 TI - EUS-guided pseudocyst drainage: prospective evaluation of early removal of fully covered self-expandable metal stents with pancreatic ductal stenting in selected patients. AB - BACKGROUND: EUS-guided pseudocyst drainage with fully covered self-expandable metal stents (FCSEMSs) was recently described. The appropriate period for stent removal is not known. OBJECTIVE: To assess the safety and efficacy of EUS-guided FCSEMS placement for 3 weeks, along with pancreatic ductal stenting in selected patients. STUDY DESIGN: Prospective, single-center evaluation. SETTING: Tertiary referral center. PATIENTS: Symptomatic pseudocysts in the body and tail region of the pancreas. INTERVENTIONS: EUS-guided transgastric placement of FCSEMS. MRCP was performed after 3 weeks. Patients with a suspected pancreatic duct leak underwent ERCP and plastic stent placement. The FCSEMSs were removed at 3 weeks. MAIN OUTCOME MEASUREMENTS: Success of FCSEMS placement, adverse events, and recurrence rate. RESULTS: Forty-seven patients met the eligibility criteria. Technical and functional success was achieved in 43 patients (intention to treat, 91.48% and 95.34% patients [per protocol, 41/43, respectively]). Adverse events occurred in 2 patients (cyst infections, 4.6%). Follow-up of 42 patients at 3 weeks was performed. MRCP detected a ductal leak in 3 patients (7.1%) and a disconnected duct in 2 patients (4.7%). ERCP and stenting were successful in all 3 patients with a ductal leak. During a median follow-up of 306 days in 42 patients, 2 recurrences (4.7%) were detected, both in patients with disconnected duct. Multivariate analysis showed that pancreatic ductal leak or disconnection was an independent factor affecting pseudocyst resolution at 3 weeks (P = .0001). LIMITATIONS: Single-center study. CONCLUSION: Short-term placement of FCSEMSs with pancreatic ductal stenting in selected patients appears safe and effective for the treatment of pseudocysts. PMID- 25910663 TI - Patient preferences of a resect and discard paradigm. AB - BACKGROUND: Resect and discard is a new paradigm for management of diminutive polyps. It is unknown whether patients will embrace this new paradigm in which small polyps would not be sent for histopathologic review. OBJECTIVE: To determine whether patients would be willing to pay for pathology costs with their own money and which factors influence patients' decisions to pay or not pay for pathology costs with their own money. DESIGN: Single-center, prospective, survey study. SETTING: Hospital outpatient endoscopy center. PATIENTS: Adults undergoing colonoscopy for screening or routine polyp surveillance. INTERVENTIONS: Patient survey. MAIN OUTCOME MEASUREMENTS: Willingness to pay out-of-pocket for pathology costs when a diminutive polyp is found and factors that influence patients' decisions to pay or not pay for pathology costs with their own money. RESULTS: A total of 500 participants completed the survey. A total of 360 respondents (71.9%) indicated a hypothetical willingness to pay out-of-pocket for histopathologic polyp analysis if this interpretation was not covered by insurance. Patient factors significantly associated with willingness to pay for polyp analysis included higher income and education and female sex. LIMITATIONS: Single center, hypothetical situation. CONCLUSION: Over two-thirds of patients were willing to pay to have their diminutive polyp sent for pathologic evaluation if their insurance carrier would not pay the cost. Factors associated with willingness to pay included higher income, higher education, and female sex. Patients who were unwilling to pay raised concerns about cost and are less concerned about cancer risk compared with those willing to pay. ( CLINICAL TRIAL REGISTRATION NUMBER: NCT02305251.). PMID- 25910664 TI - Polidocanol injection decreases the bleeding rate after colon polypectomy: a propensity score analysis. AB - BACKGROUND: EMR is the standard of care for the resection of large polyps. OBJECTIVE: To compare the efficacy and safety profile of submucosal polidocanol injection with epinephrine-saline solution injection for colon polypectomy with a diathermic snare. DESIGN: After 1-to-1 propensity score caliper matching, comparison of submucosal epinephrine injection was performed with polidocanol injection. SETTING: Endoscopic suite at the University of Foggia between 2005 and 2014. PATIENTS: Of 711 patients who underwent endoscopic resection of colon sessile polyps 20 mm or larger, 612 were analyzed after matching. INTERVENTIONS: Submucosal epinephrine injection in 306 patients and polidocanol injection in 306 patients. MAIN OUTCOME MEASUREMENTS: Univariate and multivariate logistic regression models aimed at identifying independent predictors of postpolypectomy bleeding (PPB). RESULTS: The 2 groups presented similar baseline clinical parameters and lesion characteristics. All patients had a single polyp 20 mm or larger; the median size was 32 mm (interquartile range [IQR], 25-38) in the polidocanol group and 32 (IQR, 24-38) in the epinephrine group (P=.7). Polidocanol was more effective in preventing both immediate and delayed PPB (P<.001 and P=.003, respectively), and its efficacy was confirmed in almost all of the subgroups, regardless of polyp size and histology. Postprocedure perforation was observed in 2 patients (0.3%), both in the epinephrine group (P=.49). The 2 groups did not differ in the number of snare resections of lesions or the procedure duration (P=.24 and .6, respectively). LIMITATIONS: Absence of randomization. CONCLUSION: The submucosal injection of polidocanol for colon EMR is effective and significantly lowers the PPB rate. PMID- 25910666 TI - Characterization and significance of protrusions in the mucosal defect after cold snare polypectomy. AB - BACKGROUND: Cold snare polypectomy (CSP) is widely practiced; however, the endoscopic features of the CSP mucosal defect have not been studied. In particular, protrusions within the cold snare defect (CSDPs) may create concern for residual polyp. The frequency and constituents of this phenomenon are unknown. OBJECTIVE: To describe the frequency, predictors, and histologic constituents of CSDPs. DESIGN: Prospective observational study. SETTING: Tertiary care hospital endoscopy unit. PATIENTS: Eighty-eight consecutive patients undergoing CSP for a polyp <= 10 mm in size. INTERVENTION: Inspection of the cold snare mucosal defect with high-definition white light and biopsy sampling of CSDPs for separate histologic assessment, when present. MAIN OUTCOME MEASUREMENT: Frequency and constituents of CSDPs. RESULTS: Two hundred fifty-seven consecutive polyps <= 10 mm in size were removed in 88 patients (50 men [57%], mean age 63 years). Polyps were predominately adenomatous (162, 63%), located in the proximal colon (159, 62%) and flat (200, 78%). Mean lesion size was 5.5 mm (range, 2-10 mm). High-grade dysplasia was present in a single polyp for which the defect was bland. CSDPs occurred in 36 polypectomies (14%). CSDPs were associated with polyp size >= 6 mm (odds ratio, 3.7; P < .001 multivariable analysis) but not age, sex, lesion, histopathology, morphology, or location. Histopathologic examination of CSDPs revealed submucosa in 34 (94%) and muscularis mucosa in 29 (80%). No residual adenomatous or serrated polyp tissue was detected. LIMITATIONS: Single center study. Small number of polyps with high-grade dysplasia. CONCLUSION: Protrusions are common within the CSP mucosal defect and are associated with polyp size >= 6 mm. CSDPs do not represent vascular structures, do not contain residual polyp, and are not associated with adverse outcomes in short-term follow up. However, CSDPs represent incomplete mucosal layer resection. PMID- 25910665 TI - Natural language processing as an alternative to manual reporting of colonoscopy quality metrics. AB - BACKGROUND AND AIMS: The adenoma detection rate (ADR) is a quality metric tied to interval colon cancer occurrence. However, manual extraction of data to calculate and track the ADR in clinical practice is labor-intensive. To overcome this difficulty, we developed a natural language processing (NLP) method to identify adenomas and sessile serrated adenomas (SSAs) in patients undergoing their first screening colonoscopy. We compared the NLP-generated results with that of manual data extraction to test the accuracy of NLP and report on colonoscopy quality metrics using NLP. METHODS: Identification of screening colonoscopies using NLP was compared with that using the manual method for 12,748 patients who underwent colonoscopies from July 2010 to February 2013. Also, identification of adenomas and SSAs using NLP was compared with that using the manual method with 2259 matched patient records. Colonoscopy ADRs using these methods were generated for each physician. RESULTS: NLP correctly identified 91.3% of the screening examinations, whereas the manual method identified 87.8% of them. Both the manual method and NLP correctly identified examinations of patients with adenomas and SSAs in the matched records almost perfectly. Both NLP and the manual method produced comparable values for ADRs for each endoscopist and for the group as a whole. CONCLUSIONS: NLP can correctly identify screening colonoscopies, accurately identify adenomas and SSAs in a pathology database, and provide real time quality metrics for colonoscopy. PMID- 25910667 TI - Radiographic staging practices of newly diagnosed colorectal cancer vary according to medical specialty. AB - BACKGROUND: Since 2008, multiple guidelines have endorsed incorporation of chest CT in the radiographic staging assessment of newly diagnosed colorectal cancer (CRC). Radiographic staging practices performed after CRC is detected have not been studied. OBJECTIVE: To evaluate radiographic staging practices for newly diagnosed CRC between gastroenterologists versus non-gastroenterologists. DESIGN: Observational cohort study. SETTING: Single, tertiary-care referral center. PATIENTS: Patients newly diagnosed with a T1 or higher stage CRC at time of colonoscopy between 2008 and 2013. INTERVENTIONS: Radiographic staging. MAIN OUTCOME MEASUREMENTS: Radiographic preoperative staging examinations ordered by gastroenterologists in comparison to those ordered by non-gastroenterology specialists. RESULTS: This study included 277 patients with CRC newly diagnosed by colonoscopy. There were 141 total ordering physicians (68 gastroenterologists and 73 non-gastroenterologists). The majority of preoperative radiographic staging was performed by gastroenterologists (59.2% of patients, n = 164). Colorectal surgeons managed staging in 28.7% of patients (n = 47). Gastroenterologists were more likely to omit a staging chest CT than were non gastroenterologists (64.6% vs 46.9%; P < .001). Physician practice setting, rectal location of tumor, and advanced endoscopic appearance of tumors were predictors of chest CT inclusion. LIMITATIONS: Single center, moderate sample size of both providers and patients. CONCLUSION: Gastroenterologists more frequently ordered the initial radiographic staging studies in newly diagnosed CRC patients. However, gastroenterologists were less likely to include chest CT in the initial staging of CRC despite current guideline recommendations to do so. If confirmed with further studies, educational efforts to improve compliance and standardization may be needed. PMID- 25910668 TI - The effect of interhospital transfers, emergency medical services, and distance on ischemic time in a rural ST-elevation myocardial infarction system of care. AB - BACKGROUND: Regional myocardial infarction systems of care have been shown to improve timely access to primary percutaneous coronary intervention (PCI). However, there is a relatively sparse research on rural "frontier" regions. Arrival mode, high rates of interhospital transfers, long transport times, low population density, and mostly volunteer emergency medical services (EMS) distinguish this region from metropolitan systems of care. We sought to assess the effect of interhospital transfers, distance, and arrival mode on total ischemic times for patients with ST-elevation myocardial infarctions undergoing primary PCI. METHODS: We assessed patient data from our observational cohort of 395 patients with ST-elevation myocardial infarction with PCI as their primary treatment strategy. Data came from the 10 PCI hospitals participating in the Wyoming Mission: Lifeline program from January 2013 to September 2014. We performed both regression and tests of differences. RESULTS: Median total ischemic time was nearly 2.7 times greater in transferred patients than those presenting directly (379 vs 140 minutes). Distance in miles traveled between patient's home and PCI facility was 2.5 times larger in transfer patients (51 vs 20 miles). Emergency medical services arrival was associated with 23% shorter total ischemic times than self-arrival. CONCLUSIONS: Transfer patients from referral hospitals had significantly greater total ischemic time, and use of EMS was associated with significantly lower times. Transport distance was mixed in its effect. These findings suggest a continued focus on improving transitions between referral and receiving centers and enhancing coordination in rural systems of care to reduce the multiplier effect of transfers on total ischemic time. PMID- 25910669 TI - Salvage ECMO deployment for fatal aluminum phosphide poisoning. PMID- 25910670 TI - Some tricks in iatrogenic pneumothorax. PMID- 25910671 TI - An artificial pneumoperitoneum created by injection of oxygen may prevent acute mountain sickness. PMID- 25910672 TI - Comparison of surgical fixation and nonsurgical management of flail chest and pulmonary contusion. AB - OBJECTIVE: The objective of this study is to compare the clinical efficacy of surgical fixation and nonsurgical management of flail chest and pulmonary contusion (FC-PC) and to compare the diverse timings of surgery to discuss case management in FC-PC. METHODS: The data of 39 patients diagnosed with FC-PC were obtained from the intensive care unit of Shanghai First People's Hospital and analyzed retrospectively from July 2010 to Dec 2013. The patients required ventilator support and were divided into a surgical group and a nonsurgical group, according to the treatment method. The clinical data, such as mortality, the duration of mechanical ventilation (DMV), intensive care unit length of stay, hospital length of stay (HLOS), days of antibiotic use, transfusion volume, medical expense as well as the incidence of tracheotomy, pleural effusion, and incidence of ventilator associated pneumonia, were collected for all subjects. The surgical group was further divided into 2 groups according to the surgery timing. Surgery within 7 days of admission was defined as early surgery, and all other times were defined as late surgery. The clinical data and incidence of incision infection were collected and compared. RESULTS: The patients in the surgical group had a slightly shorter HLOS. No differences were noted in mortality and the other clinical data between the groups. The early surgical group had a shorter DMV and less incidence of tracheotomy. The other parameters had no differences. CONCLUSIONS: Surgery for FC-PC could reduce the HLOS, and early surgery could decrease the DMV and the need for tracheotomy. PMID- 25910674 TI - A quantitative proteomic analysis of the tegumental proteins from Schistosoma mansoni schistosomula reveals novel potential therapeutic targets. AB - The tegument of Schistosoma mansoni plays an integral role in host-parasite interactions, particularly during the transition from the free-living cercariae to the intra-mammalian schistosomula stages. This developmental period is characterised by the transition from a trilaminate surface to a heptalaminate tegument that plays key roles in immune evasion, nutrition and excretion. Proteins exposed at the surface membranes of newly transformed schistosomula are therefore thought to be prime targets for the development of new vaccines and drugs for schistosomiasis. Using a combination of tegumental labelling and high throughput quantitative proteomics, more than 450 proteins were identified on the apical membrane of S. mansoni schistosomula, of which 200 had significantly regulated expression profiles at different stages of schistosomula development in vitro, including glucose transporters, sterols, heat shock proteins, antioxidant enzymes and peptidases. Current vaccine antigens were identified on the apical membrane (Sm-TSP-1, calpain) or sub-tegumental (Sm-TSP-2, Sm29) fractions of the schistosomula, displaying localisation patterns that, in some cases, differ from that in the adult stage fluke. This work provides the first known in-depth proteomic analysis of the surface-exposed proteins in the schistosomula tegument, and some of the proteins identified are clear targets for the generation of new vaccines and drugs against schistosomiasis. PMID- 25910675 TI - Implications of dose-dependent target tissue absorption for linear and non linear/threshold approaches in development of a cancer-based oral toxicity factor for hexavalent chromium. AB - Dose-dependent changes in target tissue absorption have important implications for determining the most defensible approach for developing a cancer-based oral toxicity factor for hexavalent chromium (CrVI). For example, mouse target tissue absorption per unit dose is an estimated 10-fold lower at the CrVI dose corresponding to the federal maximum contaminant level (MCL) than at the USEPA draft oral slope factor (SFo) point of departure dose. This decreasing target tissue absorption as doses decrease to lower, more environmentally-relevant doses is inconsistent with linear low-dose extrapolation. The shape of the dose response curve accounting for this toxicokinetic phenomenon would clearly be non linear. Furthermore, these dose-dependent differences in absorption indicate that the magnitude of risk overestimation by a linear low-dose extrapolation approach (e.g., SFo) increases and is likely to span one or perhaps more orders of magnitude as it is used to predict risk at progressively lower, more environmentally-relevant doses. An additional apparent implication is that no single SFo can reliably predict risk across potential environmental doses (e.g., doses corresponding to water concentrations?the federal MCL). A non-linear approach, consistent with available mode of action data, is most scientifically defensible for derivation of an oral toxicity factor for CrVI-induced carcinogenesis. PMID- 25910676 TI - A strategy for safety assessment of chemicals with data gaps for developmental and/or reproductive toxicity. AB - Alternative methods for full replacement of in vivo tests for systemic endpoints are not yet available. Read across methods provide a means of maximizing utilization of existing data. A limitation for the use of read across methods is that they require analogs with test data. Repeat dose data are more frequently available than are developmental and/or reproductive toxicity (DART) studies. There is historical precedent for using repeat dose data in combination with a database uncertainty factor (UF) to account for missing DART data. We propose that use of the DART decision tree (Wu et al., 2013), in combination with a database UF, provides a path forward for DART data gap filling that better utilizes all of the data. Our hypothesis was that chemical structures identified by the DART tree as being related to structures with known DART toxicity would potentially have lower DART NOAELs compared to their respective repeat dose NOAELs than structures that lacked this association. Our analysis supports this hypothesis and as a result also supports that the DART decision tree can be used as part of weight of evidence in the selection of an appropriate DART database UF factor. PMID- 25910677 TI - Oxidation-reduction processes in ice swimmers after ice-cold water bath and aerobic exercise. AB - The effect of an ice-cold water (ICW) bath as a recovery intervention from aerobic exercise on the oxidant-antioxidant balance in healthy ice swimmers was determined. Twenty ice swimmers aged 31.2 +/- 6.3 years performed a 30-min cycloergometer exercise test at room temperature (20 degrees C, RT), followed by recovery at RT or in a pool of ice-cold water (ICW bath, 3 degrees C, 5 min). Blood for laboratory assays was collected from the basilic vein two times: before the exercise (baseline) and 40 min after the RT or ICW recovery. The concentrations of plasma and erythrocytic thiobarbituric acid reactive substances (plTBARS and erTBARS, respectively), serum concentrations of 8-iso-prostaglandin F2alpha, 4-hydroxynonenal and malondialdehyde, along with the erythrocytic activities of catalase (CAT) and superoxide dismutase (SOD), as well as the serum level of total antioxidant capacity, were assessed. No statistically significant changes were observed. However, a statistically significant negative linear correlation between the erTBARS concentration and the SOD activity was found 40 min after the combination of exercise/RT recovery (r=-0.571, P<0.01). The baseline CAT and SOD activities were also linearly correlated (r=0.469, P<0.05). Both the 5-min ICW bath and the 30-min aerobic exercise have practically no impact on the oxidant-antioxidant balance in healthy ice swimmers. PMID- 25910678 TI - Enolase1 (ENO1) and glucose-6-phosphate isomerase (GPI) are good markers to predict human sperm freezability. AB - Sperm cryopreservation is a method to preserve sperm samples for a long period. However, the fertility of sperm decreases markedly after freezing and thawing in a certain amount of samples. The aim of the present study was to find useful and reliable predictive biomarkers of the capacity to withstand the freeze-thawing process in human ejaculates. Previous researches have shown that enolase1 (ENO1) and glucose-6-phosphate isomerase (GPI) are closely related to spermatozoa quality. We chose the two proteins as probable markers of sperm freezing capacity. Ejaculate samples were separated into good freezability ejaculates (GFE) and poor freezability ejaculates (PFE) according to progressive motility of the sperm after thawing. Before starting cryopreservation protocols, the two proteins from each group were compared using western blot analysis and immunofluorescence. Results showed that normalized content of ENO1 (P<0.05) and GPI (P<0.01) were both significantly higher in GFE than in PFE. The association of ENO1 and GPI with postthaw sperm viability and motility was confirmed using Pearson's linear correlation. In conclusion, ENO1 and GPI can be used as markers of human sperm freezability before starting the cryopreservation procedure. PMID- 25910679 TI - Chitin is a component of the Rhodnius prolixus midgut. AB - Chitin is an essential component of the peritrophic matrix (PM), which is a structure that lines the insect's gut and protects against mechanical damage and pathogens. Rhodnius prolixus (Hemiptera: Reduviidae) does not have a PM, but it has an analogous structure, the perimicrovillar membrane (PMM); chitin has not been described in this structure. Here, we show that chitin is present in the R. prolixus midgut using several techniques. The FTIR spectrum of the KOH-resistant putative chitin-material extracted from the midgut bolus showed peaks characteristic of the chitin molecule at 3500, 1675 and 1085 cm(1). Both the midgut bolus material and the standard chitin NMR spectra showed a peak at 1.88 ppm, which is certainly due to methyl protons in the acetamide a group. The percentages of radioactive N-acetylglucosamine (CPM) incorporated were 2 and 4% for the entire intestine and bolus, respectively. The KOH-resistant putative chitin-material was also extracted and purified from the N-acetylglucosamine radioactive bolus, and the radioactivity was estimated through liquid scintillation. The intestinal CHS cDNA translated sequence was the same as previously described for the R. prolixus cuticle and ovaries. Phenotypic alterations were observed in the midgut of females with a silenced CHS gene after a blood meal, such as retarded blood meal digestion; the presence of fresh blood that remained red nine days after the blood meal; and reduced trachea and hemozoin content compared with the control. Wheat germ agglutinin (a specific probe that detects chitin) labeling proximal to the intestine (crop and midgut) was much lower in females with a silenced CHS gene, especially in the midgut region, where almost no fluorescence signal was detected compared with the control groups. Midguts from females with a CHS gene silenced by dsRNA-CHS and control midguts pre-treated with chitinase showed that the chitin-derived fluorescence signal decreased in the region around the epithelium, the region facing the midgut and projections towards the intestinal lumen when evaluated microscopically. The relative reduction in CHS transcripts by approximately 80% using an RNAi assay supports the phenotypical alterations in the midgut observed using fluorescence microscopy assays. These data show that chitin is present in the R. prolixus midgut epithelium and in its surface projections facing the lumen. The CHS gene expression and the presence of chitin in the R. prolixus midgut may suggest a target for controlling Chagas disease vectors and addressing this public health problem. PMID- 25910680 TI - Genome-wide analysis of homeobox genes from Mesobuthus martensii reveals Hox gene duplication in scorpions. AB - Homeobox genes belong to a large gene group, which encodes the famous DNA-binding homeodomain that plays a key role in development and cellular differentiation during embryogenesis in animals. Here, one hundred forty-nine homeobox genes were identified from the Asian scorpion, Mesobuthus martensii (Chelicerata: Arachnida: Scorpiones: Buthidae) based on our newly assembled genome sequence with approximately 248 * coverage. The identified homeobox genes were categorized into eight classes including 82 families: 67 ANTP class genes, 33 PRD genes, 11 LIM genes, five POU genes, six SINE genes, 14 TALE genes, five CUT genes, two ZF genes and six unclassified genes. Transcriptome data confirmed that more than half of the genes were expressed in adults. The homeobox gene diversity of the eight classes is similar to the previously analyzed Mandibulata arthropods. Interestingly, it is hypothesized that the scorpion M. martensii may have two Hox clusters. The first complete genome-wide analysis of homeobox genes in Chelicerata not only reveals the repertoire of scorpion, arachnid and chelicerate homeobox genes, but also shows some insights into the evolution of arthropod homeobox genes. PMID- 25910681 TI - Prostacyclin protects vascular integrity via PPAR/14-3-3 pathway. AB - Vascular integrity is protected by the lining endothelial cells (ECs) through structural and molecular protective mechanisms. In response to external stresses, ECs are dynamic in producing protective molecules such as prostacyclin (PGI2). PGI2 is known to inhibit platelet aggregation and controls smooth muscle cell contraction via IP receptors. Recent studies indicate that PGI2 defends endothelial survival and protects vascular smooth muscle cell from apoptosis via peroxisome-proliferator activated receptors (PPAR). PPAR activation results in 14 3-3 upregulation. Increase in cytosolic 14-3-3E or 14-3-3beta enhances binding and sequestration of Akt-mediated phosphorylated Bad and reduces Bad-mediated apoptosis via the mitochondrial pathway. Experimental data indicate that administration of PGI2 analogs or augmentation of PGI2 production by gene transfer attenuates endothelial damage and organ infarction caused by ischemia reperfusion injury. The protective effect of PGI2 is attributed in part to preserving endothelial integrity. PMID- 25910682 TI - Bring your paper into the 'Fast Lane' of the editorial process and increase your changes for final acceptance in Micron, The International Research and Review Journal for Microscopy. AB - In the past few years Micron has revised the scope of the journal, bringing it back to its original core values when it was founded in 1969. Micron's aim is to be the leading international microscopy and microanalysis journal, covering the latest advances in the fields of biological and physical science. In order to achieve this, the editorial team carefully revised the guidelines to authors in 2011. As a team we now find it timely to report on the outcomes of this policy change. PMID- 25910683 TI - Super-resolved enhancing and edge deghosting (SEED) for spatiotemporally encoded single-shot MRI. AB - Spatiotemporally encoded (SPEN) single-shot MRI is an ultrafast MRI technique proposed recently, which utilizes quadratic rather than linear phase profile to extract the spatial information. Compared to the echo planar imaging (EPI), this technique has great advantages in resisting field inhomogeneity and chemical shift effects. Super-resolved (SR) reconstruction is adopted to compensate the inherent low resolution of SPEN images. Due to insufficient sampling rate, the SR image is challenged by aliasing artifacts and edge ghosts. The existing SR algorithms always compromise in spatial resolution to suppress these undesirable artifacts. In this paper, we proposed a novel SR algorithm termed super-resolved enhancing and edge deghosting (SEED). Different from artifacts suppression methods, our algorithm aims at exploiting the relationship between aliasing artifacts and real signal. Based on this relationship, the aliasing artifacts can be eliminated without spatial resolution loss. According to the trait of edge ghosts, finite differences and high-pass filter are employed to extract the prior knowledge of edge ghosts. By combining the prior knowledge with compressed sensing, our algorithm can efficiently reduce the edge ghosts. The robustness of SEED is demonstrated by experiments under various situations. The results indicate that the SEED can provide better spatial resolution compared to state-of the-art SR reconstruction algorithms in SPEN MRI. Theoretical analysis and experimental results also show that the SR images reconstructed by SEED have better spatial resolution than the images obtained with conventional k-space encoding methods under similar experimental condition. PMID- 25910684 TI - Skuller: A volumetric shape registration algorithm for modeling skull deformities. AB - We present an algorithm for volumetric registration of 3D solid shapes. In comparison to previous work on image based registration, our technique achieves higher efficiency by leveraging a template tetrahedral mesh. In contrast to point and surface-based registration techniques, our method better captures volumetric nature of the data, such as bone thickness. We apply our algorithm to study pathological skull deformities caused by a particular condition, i.e., craniosynostosis. The input to our system is a pair of volumetric 3D shapes: a tetrahedral mesh and a voxelized object represented by a set of voxel cells segmented from computed tomography (CT) scans. Our general framework first performs a global registration and then launches a novel elastic registration process that uses as much volumetric information as possible while deforming the generic template tetrahedral mesh of a healthy human skull towards the underlying geometry of the voxel cells. Both data are high-resolution and differ by large non-rigid deformations. Our fully-automatic solution is fast and accurate, as compared with the state of the arts from the reconstruction and medical image registration fields. We use the resulting registration to match the ground-truth surfaces extracted from the medical data as well as to quantify the severity of the anatomical deformity. PMID- 25910686 TI - Molecular characterization of piebaldism in a Tunisian family. AB - OBJECTIVE: The present study is aimed at performing the molecular characterization of a Tunisian family with piebaldism. METHODS: As the proband and her mother showed a severe phenotype, we first chose to screen exons 10, 11, 12, 13, 16, 17 and 18 of the KIT proto-oncogene by direct sequencing. RESULTS: Direct sequencing analysis showed a C to T substitution at 1939 in exon 13 (c.1939C>T) in heterozygous state in the patient and her mother. The mutation was not found in their unaffected family members or normal controls. CONCLUSION: Our results provide additional support that mutations in the tyrosine kinase domain of the KIT gene are responsible for the severe form of piebaldism. PMID- 25910685 TI - Impact of electronic health record technology on the work and workflow of physicians in the intensive care unit. AB - OBJECTIVE: To assess the impact of EHR technology on the work and workflow of ICU physicians and compare time spent by ICU resident and attending physicians on various tasks before and after EHR implementation. DESIGN: EHR technology with electronic order management (CPOE, medication administration and pharmacy system) and physician documentation was implemented in October 2007. MEASUREMENT: We collected a total of 289 h of observation pre- and post-EHR implementation. We directly observed the work of residents in three ICUs (adult medical/surgical ICU, pediatric ICU and neonatal ICU) and attending physicians in one ICU (adult medical/surgical ICU). RESULTS: EHR implementation had an impact on the time distribution of tasks as well as the temporal patterns of tasks. After EHR implementation, both residents and attending physicians spent more of their time on clinical review and documentation (40% and 55% increases, respectively). EHR implementation also affected the frequency of switching between tasks, which increased for residents (from 117 to 154 tasks per hour) but decreased for attendings (from 138 to 106 tasks per hour), and the temporal flow of tasks, in particular around what tasks occurred before and after clinical review and documentation. No changes in the time spent in conversational tasks or the physical care of the patient were observed. CONCLUSIONS: The use of EHR technology has a major impact on ICU physician work (e.g., increased time spent on clinical review and documentation) and workflow (e.g., clinical review and documentation becoming the focal point of many other tasks). Further studies should evaluate the impact of changes in physician work on the quality of care provided. PMID- 25910687 TI - A novel biomarker for marine environmental pollution of pi-class glutathione S transferase from Mytilus coruscus. AB - Glutathione S-transferases (GSTs) are the superfamily of phase II detoxification enzymes that play crucial roles in innate immunity. In this study, a pi-class GST homolog was identified from Mytilus coruscus (named as McGST1, KC525103). The full-length cDNA sequence of McGST1 was 621bp with a 5' untranslated region (UTR) of 70bp and a 3'-UTR of 201bp. The deduced amino acid sequence was 206 residues in length with theoretical pI/MW of 5.60/23.72kDa, containing the conserved G site and diversiform H-site. BLASTn analysis and phylogenetic relationship strongly suggested that this cDNA sequence was a member of pi class GST family. The prediction of secondary structure displayed a preserved N-terminal and a C terminal comprised with alpha-helixes. Quantitative real time RT-PCR showed that constitutive expression of McGST1 was occurred, with increasing order in mantle, muscle, gill, hemocyte, gonad and hepatopancreas. The stimulation of bacterial infection, heavy metals and 180CST could up-regulate McGST1 mRNA expression in hepatopancreas with time-dependent manners. The maximum expression appeared at 6h after pathogenic bacteria injected, with 10-fold in Vibrio alginolyticus and 16 fold in Vibrio harveyi higher than that of the control. The highest point of McGST1 mRNA appeared at different time for exposure to copper (10-fold at day 15), cadmium (9-fold at day10) and 180 CST (10-fold at day 15). These results suggested that McGST1 played a significant role in antioxidation and might potentially be used as indicators and biomarkers for detection of marine environmental pollution. PMID- 25910688 TI - Reducing arsenic accumulation in rice grain through iron oxide amendment. AB - Effects of soil-arsenic (As), phosphorus and iron oxide on As accumulation in rice grain were investigated. Cultivars that have significantly different sensitivity to As, straighthead-resistant Zhe 733 and straighthead-susceptible Cocodrie, were used to represent different cultivar varieties. The grain accumulation of other elements of concern, selenium (Se), molybdenum (Mo), and cadmium (Cd) was also monitored. Results demonstrated that high soil-As not only resulted in high grain-As, but could also result in high grain-Se, and Zhe 733 had significantly less grain-As than Cocodrie did. However, soil-As did not impact grain-Mo and Cd. Among all elements monitored, iron oxide amendment significantly reduced grain-As for both cultivars, while the phosphate application only reduced grain-Se for Zhe 733. Results also indicated that cultivar type significantly impacted grain accumulation of all monitored trace elements. Therefore, applying iron oxide to As-contaminated land, in addition to choosing appropriate rice cultivar, can effectively reduce the grain accumulation of As. PMID- 25910689 TI - Biomarker responses in the earthworm, Dichogaster curgensis exposed to fly ash polluted soils. AB - Earthworms are globally accepted as a model organism in terrestrial ecotoxicology for assessment of environmental pollution. This study evaluated and compared effects of fly ash polluted soils collected from two geographically different thermal power plants on biomarker responses in the earthworm, Dichogaster curgensis. To evaluate relationship between distance sampling and biomarker responses in the earthworm D. curgensis, soil samples at 0.5, 1 and 3km from thermal plant were analyzed for physico-chemical properties and metal concentrations. Biochemical alterations, lysosomal membrane stability, genotoxic effects, and histological changes were examined on 1, 7, and 14 d of exposure to fly ash contaminated soils collected from different thermal power plants. The activities of superoxide dismutase (SOD), glutathione peroxidase (GPx), and malondialdehyde (MDA) levels were significantly increased, while glutathione reductase (GR) activity was found to be decreased in treated animals. Catalase (CAT) and glutathione-S- transferase (GST) activities were found to be increased initially up to 7d exposure and further decreased on 14d exposure. D. curgensis exposed to fly ash contaminated soils showed significant lysosomal membrane destabilization and DNA damage. Extensive histopathological changes were observed in the tissues of the body wall and intestinal tract of the exposed D. curgensis along with accumulation of heavy metals. These results demonstrate that soil pollution around thermal power plants has adverse biological effects of on the indicator organism D. curgensis and no correlation was found between distance and extent of biological biochemical responses. PMID- 25910690 TI - How do health insurer market concentration and bargaining power with hospitals affect health insurance premiums? AB - The US health insurance industry is highly concentrated, and health insurance premiums are high and rising rapidly. Policymakers have focused on the possible link between the two, leading to ACA provisions to increase insurer competition. However, while market power may enable insurers to include higher profit margins in their premiums, it may also result in stronger bargaining leverage with hospitals to negotiate lower payment rates to partially offset these higher premiums. We empirically examine the relationship between employer-sponsored fully-insured health insurance premiums and the level of concentration in local insurer and hospital markets using the nationally-representative 2006-2011 KFF/HRET Employer Health Benefits Survey. We exploit a unique feature of employer sponsored insurance, in which self-insured employers purchase only administrative services from managed care organizations, to disentangle these different effects on insurer concentration by constructing one concentration measure representing fully-insured plans' transactions with employers and the other concentration measure representing insurers' bargaining with hospitals. As expected, we find that premiums are indeed higher for plans sold in markets with higher levels of concentration relevant to insurer transactions with employers, lower for plans in markets with higher levels of insurer concentration relevant to insurer bargaining with hospitals, and higher for plans in markets with higher levels of hospital market concentration. PMID- 25910691 TI - Reference intervals for thromboelastometry with the ROTEM delta in cats. AB - This study aimed to assess precision of viscoelastic measurements of feline blood using the ROTEM delta analyser and to establish reference intervals. Intra-assay variability was evaluated by analysing samples of two cats in quadruplicate. Reference intervals were established based on 55 clinically healthy European shorthair cats including different sexes and age groups. Analyses were performed without activation and after activation with different reagents (kaolin, in-tem, ex-tem). For the majority of parameters, coefficient of variation was <10%. The activating reagent containing tissue factor (ex-tem) produced the shortest clotting times (reference interval: 44.0-98.7 s) and highest maximum lyses. Reference values of many parameters revealed a wide inter-individual variation. Only sporadically, differences between the individual age groups were found. In conclusion, analysis of feline blood using the ROTEM analyser showed acceptable reproducibility. The established reference intervals may be a useful orientation for measurements of feline blood using the ROTEM delta analyser. PMID- 25910692 TI - Evaluation of traction stirrup distraction technique to increase the joint space of the shoulder joint in the dog: A cadaveric study. AB - The objective of this study was to evaluate technical feasibility and efficacy of a joint distraction technique by traction stirrup to facilitate shoulder arthroscopy and assess potential soft tissue damage. Twenty shoulders were evaluated radiographically before distraction. Distraction was applied with loads from 40 N up to 200 N, in 40 N increments, and the joint space was recorded at each step by radiographic images. The effects of joint flexion and intra articular air injection at maximum load were evaluated. Radiographic evaluation was performed after distraction to evaluate ensuing joint laxity. Joint distraction by traction stirrup technique produces a significant increase in the joint space; an increase in joint laxity could not be inferred by standard and stress radiographs. However, further clinical studies are required to evaluate potential neurovascular complications. A wider joint space may be useful to facilitate arthroscopy, reducing the likelihood for iatrogenic damage to intra articular structures. PMID- 25910693 TI - Construction of scFv that bind both fibronectin-binding protein A and clumping factor A of Stapylococcus aureus. AB - Bovine mastitis (BM) causes significant losses to the dairy industry. Vaccines against the causative agent of BM, Staphylococcus aureus, do not confer adequate protection. Because passive immunization with antibodies permits disease prevention, we constructed a recombinant single-chain antibody (scFv) against fibronectin-binding protein A (FnBPA) and clumping factor A (ClfA), two important virulence factors in S. aureus infection. The DNA coding sequences of the variable heavy (VH) and variable light (VL) domains of antibodies produced in the peripheral blood lymphocytes of cows with S. aureus-induced mastitis were obtained using reverse transcription and polymerase chain reaction, and the VH and VL cDNAs were assembled in-tandem using a DNA sequence encoding a (Gly4Ser)3 peptide linker. The scFv cDNAs were cloned into the pOPE101 plasmid for the expression of soluble scFv protein in Escherichia coli. The binding of the scFvs to both FnBPA and ClfA was confirmed using an indirect ELISA and Western blotting. The DNA sequences of the framework regions of the VH and VL domains were highly conserved, and the complementarity-determining regions displayed significant diversity, especially in CDR3 of the VH domain. These novel bovine antibody fragments may be useful as a therapeutic candidate for the prevention and treatment of S. aureus-induced bovine mastitis. PMID- 25910694 TI - ms-data-core-api: an open-source, metadata-oriented library for computational proteomics. AB - The ms-data-core-api is a free, open-source library for developing computational proteomics tools and pipelines. The Application Programming Interface, written in Java, enables rapid tool creation by providing a robust, pluggable programming interface and common data model. The data model is based on controlled vocabularies/ontologies and captures the whole range of data types included in common proteomics experimental workflows, going from spectra to peptide/protein identifications to quantitative results. The library contains readers for three of the most used Proteomics Standards Initiative standard file formats: mzML, mzIdentML, and mzTab. In addition to mzML, it also supports other common mass spectra data formats: dta, ms2, mgf, pkl, apl (text-based), mzXML and mzData (XML based). Also, it can be used to read PRIDE XML, the original format used by the PRIDE database, one of the world-leading proteomics resources. Finally, we present a set of algorithms and tools whose implementation illustrates the simplicity of developing applications using the library. AVAILABILITY AND IMPLEMENTATION: The software is freely available at https://github.com/PRIDE Utilities/ms-data-core-api. SUPPLEMENTARY INFORMATION: Supplementary data are available at Bioinformatics online CONTACT: juan@ebi.ac.uk. PMID- 25910695 TI - Inferring data-specific micro-RNA function through the joint ranking of micro-RNA and pathways from matched micro-RNA and gene expression data. AB - MOTIVATION: In practice, identifying and interpreting the functional impacts of the regulatory relationships between micro-RNA and messenger-RNA is non-trivial. The sheer scale of possible micro-RNA and messenger-RNA interactions can make the interpretation of results difficult. RESULTS: We propose a supervised framework, pMim, built upon concepts of significance combination, for jointly ranking regulatory micro-RNA and their potential functional impacts with respect to a condition of interest. Here, pMim directly tests if a micro-RNA is differentially expressed and if its predicted targets, which lie in a common biological pathway, have changed in the opposite direction. We leverage the information within existing micro-RNA target and pathway databases to stabilize the estimation and annotation of micro-RNA regulation making our approach suitable for datasets with small sample sizes. In addition to outputting meaningful and interpretable results, we demonstrate in a variety of datasets that the micro-RNA identified by pMim, in comparison to simpler existing approaches, are also more concordant with what is described in the literature. AVAILABILITY AND IMPLEMENTATION: This framework is implemented as an R function, pMim, in the package sydSeq available from http://www.ellispatrick.com/r-packages. CONTACT: jean.yang@sydney.edu.au SUPPLEMENTARY INFORMATION: Supplementary data are available at Bioinformatics online. PMID- 25910696 TI - Data-dependent bucketing improves reference-free compression of sequencing reads. AB - MOTIVATION: The storage and transmission of high-throughput sequencing data consumes significant resources. As our capacity to produce such data continues to increase, this burden will only grow. One approach to reduce storage and transmission requirements is to compress this sequencing data. RESULTS: We present a novel technique to boost the compression of sequencing that is based on the concept of bucketing similar reads so that they appear nearby in the file. We demonstrate that, by adopting a data-dependent bucketing scheme and employing a number of encoding ideas, we can achieve substantially better compression ratios than existing de novo sequence compression tools, including other bucketing and reordering schemes. Our method, Mince, achieves up to a 45% reduction in file sizes (28% on average) compared with existing state-of-the-art de novo compression schemes. AVAILABILITY AND IMPLEMENTATION: Mince is written in C++11, is open source and has been made available under the GPLv3 license. It is available at http://www.cs.cmu.edu/~ckingsf/software/mince. CONTACT: carlk@cs.cmu.edu SUPPLEMENTARY INFORMATION: Supplementary data are available at Bioinformatics online. PMID- 25910697 TI - Addressing false discoveries in network inference. AB - MOTIVATION: Experimentally determined gene regulatory networks can be enriched by computational inference from high-throughput expression profiles. However, the prediction of regulatory interactions is severely impaired by indirect and spurious effects, particularly for eukaryotes. Recently, published methods report improved predictions by exploiting the a priori known targets of a regulator (its local topology) in addition to expression profiles. RESULTS: We find that methods exploiting known targets show an unexpectedly high rate of false discoveries. This leads to inflated performance estimates and the prediction of an excessive number of new interactions for regulators with many known targets. These issues are hidden from common evaluation and cross-validation setups, which is due to Simpson's paradox. We suggest a confidence score recalibration method (CoRe) that reduces the false discovery rate and enables a reliable performance estimation. CONCLUSIONS: CoRe considerably improves the results of network inference methods that exploit known targets. Predictions then display the biological process specificity of regulators more correctly and enable the inference of accurate genome-wide regulatory networks in eukaryotes. For yeast, we propose a network with more than 22 000 confident interactions. We point out that machine learning approaches outside of the area of network inference may be affected as well. AVAILABILITY AND IMPLEMENTATION: Results, executable code and networks are available via our website http://www.bio.ifi.lmu.de/forschung/CoRe. CONTACT: robert.kueffner@helmholtz-muenchen.de SUPPLEMENTARY INFORMATION: Supplementary data are available at Bioinformatics online. PMID- 25910698 TI - PDBest: a user-friendly platform for manipulating and enhancing protein structures. AB - PDBest (PDB Enhanced Structures Toolkit) is a user-friendly, freely available platform for acquiring, manipulating and normalizing protein structures in a high throughput and seamless fashion. With an intuitive graphical interface it allows users with no programming background to download and manipulate their files. The platform also exports protocols, enabling users to easily share PDB searching and filtering criteria, enhancing analysis reproducibility. AVAILABILITY AND IMPLEMENTATION: PDBest installation packages are freely available for several platforms at http://www.pdbest.dcc.ufmg.br CONTACT: wellisson@dcc.ufmg.br, dpires@dcc.ufmg.br, raquelcm@dcc.ufmg.br SUPPLEMENTARY INFORMATION: Supplementary data are available at Bioinformatics online. PMID- 25910699 TI - CiVi: circular genome visualization with unique features to analyze sequence elements. AB - We have developed CiVi, a user-friendly web-based tool to create custom circular maps to aid the analysis of microbial genomes and sequence elements. Sequence related data such as gene-name, COG class, PFAM domain, GC%, and subcellular location can be comprehensively viewed. Quantitative gene-related data (e.g. expression ratios or read counts) as well as predicted sequence elements (e.g. regulatory sequences) can be uploaded and visualized. CiVi accommodates the analysis of genomic elements by allowing a visual interpretation in the context of: (i) their genome-wide distribution, (ii) provided experimental data and (iii) the local orientation and location with respect to neighboring genes. CiVi thus enables both experts and non-experts to conveniently integrate public genome data with the results of genome analyses in circular genome maps suitable for publication. CONTACT: L.Overmars@gmail.com SUPPLEMENTARY INFORMATION: Supplementary data are available at Bioinformatics online. AVAILABILITY AND IMPLEMENTATION: CiVi is freely available at http://civi.cmbi.ru.nl. PMID- 25910700 TI - iFoldRNA v2: folding RNA with constraints. AB - A key to understanding RNA function is to uncover its complex 3D structure. Experimental methods used for determining RNA 3D structures are technologically challenging and laborious, which makes the development of computational prediction methods of substantial interest. Previously, we developed the iFoldRNA server that allows accurate prediction of short (<50 nt) tertiary RNA structures starting from primary sequences. Here, we present a new version of the iFoldRNA server that permits the prediction of tertiary structure of RNAs as long as a few hundred nucleotides. This substantial increase in the server capacity is achieved by utilization of experimental information such as base-pairing and hydroxyl radical probing. We demonstrate a significant benefit provided by integration of experimental data and computational methods. AVAILABILITY AND IMPLEMENTATION: http://ifoldrna.dokhlab.org CONTACT: dokh@unc.eu. PMID- 25910701 TI - Tokuhashi score and other prognostic factors in 260 patients with surgery for vertebral metastases. AB - BACKGROUND: Metastatic disease of the spine is an increasingly common public health problem. Surgery should be an integral component of the overall cancer treatment plan and, importantly, must neither delay not jeopardize any of the other components. The prognosis governs the choice of the surgical strategy. Tokuhashi et al. developed a prognostic score in 1990, then revised it in 2000 and 2005. Here, our objective was to evaluate the performance of the Tokuhashi score in a cohort of 260 patients and to look for other variables that might improve preoperative outcome prediction. MATERIAL AND METHOD: We retrospectively established a single-centre cohort of 260 patients who underwent spinal metastasis surgery between 1998 and 2008. For each patient, the following data were collected prospectively: socio-demographic features, history of the malignancy, variables needed to determine the Tokuhashi score, and treatments used. SAS 9.0 software was chosen for the statistical analysis. Variables were described as mean +/- SD, overall survival was estimated using the Kaplan-Meier method, and survivals in subgroups were compared by the log-rank test. To assess agreement between survival predicted by the Tokuhashi score and observed survival, we computed Cohen's kappa and interpreted the results according to Landis and Koch. RESULTS: There were 143 females and 117 males with a mean age of 59 years and overall median survival of 10 months. Median observed survivals in the three Tokuhashi score categories (< 6, 6-12, and > 12 months predicted survival) were 5, 10, and 36 months, respectively. These survival times differed significantly (P < 0.0001). Cohen's kappa indicated moderate agreement between predicted and observed survivals. Other factors associated with significant survival differences were time from cancer diagnosis to metastasis diagnosis (synchronous, < 2 years, 2-5 years, or > 5 years; P < 0.0001) and age (< 70 years or >= 70 years, P = 0.0053). CONCLUSION: Our cohort study supports the validity and reproducibility of the Tokuhashi score. Our finding that shorter time to metastasis diagnosis and age >= 70 years were also significantly associated with survival in our population invites further efforts to improve and update the Tokuhashi score. PMID- 25910702 TI - Elbow arthroscopy: An alternative to anteromedial portals. AB - BACKGROUND: Elbow arthroscopy is considered to be a difficult procedure with a high complication rate. These two disadvantages are due to the proximity of neurovascular structures. HYPOTHESIS: The aim of our study was to evaluate the efficacy and complication rate of a new elbow arthroscopy technique without anteromedial portals. This approach was taken because of the high rate of ulnar nerve damage using the medial portal, and the difficulty of performing triangulation of opposite portals in a patient in the lateral decubitus position. MATERIAL AND METHODS: Fifteen patients were operated on by the same surgeon between 2010 and 2012. Range of motion and the "MEPS" elbow score were calculated preoperatively and at the final postoperative follow-up. The average age of patients was 38.3 years. The follow-up was 11.1 months. Personal portals (high anterolateral and intermediate anterolateral portals) were used instead of the anteromedial portals. RESULTS: Elbow flexion increased from 113 degrees preoperatively to 129 degrees at the final follow-up (P=0.009). Extension increased from -33 degrees to -10 degrees (P<0.0001). The preoperative and final postoperative "MEPS" scores were 56.3 and 94 respectively (P<0.0001). Two patients (13.3%) had radial nerve palsy with complete recovery 6 and 9 months after surgery. DISCUSSION: The rate of nerve complications following elbow arthroscopy varies from 0 to 14%. The rate in our series (13.3%) is comparable to the results of the literature. This rate should be placed in perspective (since one patient had multiple open surgery elbow operations before arthroscopy). All complications were transient. Improved elbow range of motion in our study is consistent with the results in literature. PMID- 25910703 TI - Ultrasound-guided diagnosis of fractures of the distal forearm in children. AB - PURPOSE: Distal radius and forearm fractures are injuries that are frequently seen in trauma surgery outpatient clinics. Usually, the wrist is X-rayed in 2 planes as standard diagnostic procedure. In contrast, we evaluate in our study the accuracy of ultrasonography (US) in diagnosing these fractures. METHODS: This prospective study includes the patients who presented at two trauma surgery clinics with a presumptive diagnosis of distal radius or forearm fracture between January and December 2012. After a clinical examination, US imaging of the distal forearm was first carried out on 6 standardized planes followed by radiographs of the wrist made in two planes. The age limit was set at the end of 11 years. RESULTS: In total, 201 patients between 4 and 11 years of age were recruited with an average age of 9.5 years at the time of the trauma. There were 104 (51.7%) fractures distributed as follows: 89 (85.9%) injuries of the distal radius, 9 (8.7%) injuries of the distal ulna, and 6 (5.8%) combined injuries (radius and ulna). Sixty-five greenstick fractures were detected. Surgery was necessary in 34 cases. Specificity and sensitivity of ultrasound diagnosis were 99.5%. CONCLUSION: Ultrasound imaging is suitable to demonstrate fractures of the distal forearm. It is a highly sensitive procedure in detecting distal forearm fractures. In our opinion, a negative result in ultrasound may reduce the need for further radiographs in children with distal forearm lesions. But in any doubtful situation the need for conventional radiographs remains. PMID- 25910704 TI - Antimicrobial agents from selected medicinal plants in Libya. AB - OBJECTIVE: To test the in vitro antimicrobial efficacy of water and methanol extracts of 23 plant species that are commonly used in Libyan folk medicine. METHODS: The antimicrobial activity was determined using the well-diffusion method. Four test microorganisms were used namely, Escherichia coli, Salmonella species, Staphylococcus aureus and Bacillus subtilis. The minimum inhibitory concentration (MIC) was determined for the high biologically active crude plant extracts. RESULTS: Among 23 medicinal plants used in the study, only 5 methanolic extracts [Rosmarinus offcinalis L., Carduus marianium L., Lantana camara L., Rhus tripartite (ueria) Grande, and Thymus capitatus (L.) Hoffm (link)] showed the highest antimicrobial activity against Staphylococcus aureus, Bacillus subtilis and Salmonella species, while 22 methanolic and aqueous extracts showed moderate to weak antimicrobial activity on all tested organisms. However 19 of the extracts showed no activity at all against Gram-ve and Gram +ve microorganisms. MIC was found to be 1.25 mg/mL (Thymus capitatus), 3 mg/mL (Rhus tripartite), 4 mg/mL (Carduus marianium), 5 mg/mL (Rosamarinus officinalis) and 5 mg/mL (Lantana camara), respectively. CONCLUSIONS: The present results revealed that, crude methanolic extracts of the investigated Libyan folk medicinal plants exhibited mild to high in vitro antibacterial activities against Gram-positive and Gram negative microorganisms. PMID- 25910705 TI - The expression of CDK1 is associated with proliferation and can be a prognostic factor in epithelial ovarian cancer. AB - Overexpression of cyclin-dependent kinase 1 (CDK1) has been noted to correlation with several human cancers. However, the effects of CDK1 on ovarian cancer development remain unclear. The aim of this study was to examine the effect of CDK1 and related mechanism in the proliferation and resistance to chemotherapeutic drugs of epithelial ovarian cancer (EOC). Immunohistochemical analysis was performed in 119 human ovarian cancer samples, and the data were correlated with clinicopathologic features. Furthermore, Western blot analysis was performed for CDK1 in EOC samples and cell lines to evaluate their protein levels and molecular interaction. Kaplan-Meier survival analysis showed that strong expression of CDK1 exhibited a significant correlation with poor prognosis in human EOC (P = 0.02). Meanwhile, we found that knockdown CDK1 by shCDK1 promoted the apoptosis rate and increased the sensitivity to chemotherapy drugs. Thus, CDK1 might serve as a prognostic marker, and it might be of great value for experimental therapies in EOC. PMID- 25910706 TI - Lysosome-associated protein transmembrane-4beta-35 is a novel independent prognostic factor in small cell lung cancer. AB - The lysosome-associated protein transmembrane-4beta-35 (LAPTM4B-35) protein has been indicated to be involved in solid tumors, while its role in small cell lung cancer (SCLC) remains unknown. The aim of this study is to investigate the LAPTM4B-35 protein expression and its clinical and prognostic role in SCLC patients. A total of 88 SCLC patients who underwent radical surgery between 2002 and 2010 were enrolled in the study. The level of messenger RNA (mRNA) and protein was detected from the fresh paired tumor specimens and adjacent normal tissues. The clinicopathological and survival data were collected. And the relationship between LAPTM4B-35 and clinicopathological features was analyzed. The prognostic value of LAPTM4B-35 for SCLC was investigated by univariate and multivariate analyses. The LAPTM4B-35 was overexpressed significantly in SCLC cancer tissues. The elevated protein expression was correlated strongly with clinical stage (p = 0.012) and tumor recurrence (p = 0.023). The 5-year overall survival and disease-free survival (DFS) were significantly worse in the patients with high LAPTM4B-35 level. Multivariate Cox analysis indicated that high LAPTM4B 35 expression was an independent prognostic factor for overall survival (OS) and DFS (p = 0.017 vs p = 0.011). LAPTM4B-35 overexpression was an independent factor in SCLC prognosis, which may be considered a potential useful marker in defining the SCLC prognosis. PMID- 25910707 TI - Differential expression of inflammasomes in lung cancer cell lines and tissues. AB - As pivotal elements involved in inflammation, inflammasomes represent a group of multiprotein complexes triggering the maturation of proinflammatory cytokine interleukin (IL)-1beta and IL-18. Although the importance of the inflammasomes in inflammatory diseases is well appreciated, a precise characterization of their expressions in lung cancer remains obscure. This study aimed to determine the expressions of inflammasomes in various lung cancer cell lines and tissues to understand their potential roles in lung cancer. Our findings showed that inflammasome components were markedly upregulated in lung cancer and elicited the maturation of IL-1beta and IL-18. In addition, enormous variations in subtypes and levels of inflammasomes were detected in lung cancers depending on their histological type and grading, invasion ability, as well as chemoresistance. Generally, AIM2 inflammasome was overexpressed in nonsmall cell lung cancer (NSCLC), while NLRP3 inflammasome was upregulated in lung adenocarcinoma (ADC) and small cell lung cancer (SCLC). The high-metastatic or cisplatin-sensitive NSCLC cells expressed more inflammasome components and products than their counterpart low-metastatic or cisplatin-resistant NSCLC cells, respectively. In resected lung cancer tissues, high-grade ADC expressed more inflammasome components and products than low-grade ADC. Together, these findings suggest that inflammasomes may be crucial biomarkers for lung cancer as well as potential modulators of the biological behaviors of lung cancer. Further, pharmacotherapeutics targeting inflammasomes might be novel adjuvant therapy strategies for lung cancer. PMID- 25910709 TI - Clinical long-term outcome, technical success, and cost analysis of radiofrequency ablation for the treatment of osteoblastomas and spinal osteoid osteomas in comparison to open surgical resection. AB - OBJECTIVE: To assess the clinical success and costs of computed tomography (CT) guided radiofrequency ablation (RFA) of osteoblastoma (OB) and spinal osteoid osteoma (OO). MATERIALS AND METHODS: Nineteen patients with OB and eight patients with spinal OO were treated with CT-guided RFA. The OBs were localized in the extremities (n = 10), the vertebral column (n = 2), and (juxta-)articular (n = 7). Dedicated procedural techniques included three-dimensional CT-guided access planning in all cases, overlapping RFA needle positions (median, two positions; range, 1-6 RF-electrode positions) within the OB nidus (multiple ablation technique, n = 15), and thermal protection in case of adjacent neural structure in four spinal OO. The data of eight operated OB and ten operated spinal OO patients were used for comparison. Long-term success was assessed by clinical examination and using a questionnaire sent to all operated and RFA-treated patients including visual analogue scales (VAS) regarding the effect of RFA on severity of pain and limitations of daily activities (0-10, with 0 = no pain/limitation up to 10 = maximum or most imaginable pain/limitation). RESULTS: All patients had a clear and persistent pain reduction until the end of follow up. The mean VAS score for all spinal OO patients and all OB patients treated either with RFA or with surgical excision significantly decreased for severity of pain at night, severity of pain during the day, and both for limitations of daily and of sports activities. CONCLUSIONS: RFA is an efficient method for treating OB and spinal OO and should be regarded as the first-line therapy after interdisciplinary individual case discussion. PMID- 25910708 TI - Overexpression of the ?Np73 isoform is associated with centrosome amplification in brain tumor cell lines. AB - The p73 protein is a member of the p53 family, and this protein is known to be essential for the maintenance of genomic stability, DNA repair, and apoptosis regulation. Transcription from two promoters leads to two main N-terminal isoforms: the TAp73 isoform is reported to have tumor suppressor function, whereas the DeltaNp73 isoform likely has oncogenic potential. The present study is focused on the investigation of a possible role of both these p73 N-terminal isoforms in the process of centrosome amplification. HGG-02 and GM7 glioblastoma cell lines and the Daoy medulloblastoma cell line were used in this study. The cells were analyzed using indirect immunofluorescence to determine TAp73 and DeltaNp73 expression patterns and possible co-localization with the BubR1 protein, as well as the number of centrosomes. A transiently transfected GM7 cell line was used to verify the results concerning the N-terminal isoforms in relation to centrosome amplification. We found that increased immunoreactivity for the DeltaNp73 isoform is associated with the occurrence of an abnormal number of centrosomes in particular cells. Using the transiently transfected GM7 cell line, we confirmed that centrosome amplification is present in cells with overexpression of the DeltaNp73 isoform. In contrast, the immunoreactivity for the TAp73 isoform was weak or medium in most of the cells with an aberrant number of centrosomes. To determine the putative counterpart of the p73 N-terminal isoforms among spindle assembly checkpoint (SAC) proteins, we also evaluated possible interactions between the N-terminal isoforms and BubR1 protein, but no co-localization of these proteins was observed. PMID- 25910710 TI - Investigating a Multimodal Intervention for Children With Limited Expressive Vocabularies Associated With Autism. AB - PURPOSE: This study investigated a new intervention package aimed at increasing expressive word learning by school-age children with autism who have limited expressive vocabularies. This pilot investigation was intended to show proof of concept. METHOD: Ten children between the ages of 6 and 10 years participated, with educational diagnoses of autism and limited expressive vocabularies at the outset of the study. A multimodal intervention composed of speech sound practice and augmentative and alternative communication was used to teach individualized vocabulary words that were selected on the basis of initial speech sound repertoires and principles of phonotactic probability and neighborhood density. A multiple-probe design was used to evaluate learning outcomes. RESULTS: Five children showed gains in spoken-word learning across successive word sets (high responders). Five children did not meet learning criteria (low responders). Comparisons of behaviors measured prior to intervention indicated that high responders had relatively higher skills in receptive language, prelinguistic communication, vocal/verbal imitation, adaptive behavior, and consonant productions. CONCLUSIONS: The intervention package holds promise for improving spoken word productions for some children with autism who have limited expressive vocabularies. Further research is needed to better describe who may most benefit from this approach as well as investigate generalized benefits to untaught contexts and targets. PMID- 25910711 TI - [Indoor fungal exposure: What impact on clinical and biological status regarding Aspergillus during cystic fibrosis]. AB - The sources of exposure during diseases due to Aspergillus fungi in cystic fibrosis patients are still poorly explored. We assessed home fungal exposure in patients suffering from cystic fibrosis and analysed its impact on the presence of Aspergillus biological markers, the colonisation of airways, as well as the sensitization and Aspergillus serology. Between March 2012 and August 2012, 34 patients benefited from a visit performed by a home environment medical adviser including sampling for mycological analysis. The number of colonies of Aspergillus was not significantly different in the various sampling sites (P=0.251), but the number of non-Aspergillus colonies was much higher in the kitchen (P=0.0045). Subsequently, home fungal exposure was compared between the groups "absence of Aspergillus-related markers" and "presence of Aspergillus related markers". Home exposure to Aspergillus (P=0.453) and non-Aspergillus (P=0.972) flora was not significant between the 2 groups. Within this series of 34 patients that should be expanded, we note an absence of clear relationship between home exposure and the Aspergillus-linked markers in patients suffering from cystic fibrosis. This result should be taken into account regarding too restrictive hygiene advices provided to families, given the fact that fungal exposure can also results from activities performed away from home. PMID- 25910712 TI - Characterization of the three-dimensional kinematic behavior of axons in central nervous system white matter. AB - Traumatic injury to axons in white matter of the brain and spinal cord occurs primarily via tensile stretch. During injury, the stress and strain experienced at the tissue level is transferred to the microscopic axons. How this transfer occurs, and the primary constituents dictating this transfer must be better understood to develop more accurate multi-scale models of injury. Previous studies have characterized axon tortuosity and kinematic behavior in 2-dimensions (2-D), where axons have been modeled to exhibit non-affine (discrete), affine (composite-like), or switching behavior. In this study, we characterize axon tortuosity and model axon kinematic behavior in 3-dimensions (3-D). Embryonic chick spinal cords at different development stages were excised and stretched. Cords were then fixed, transversely sectioned, stained, and imaged. 3-D axon tortuosity was measured from confocal images using a custom-built MATLAB script. 2-D kinematic models previously described in Bain et al. (J Biomech Eng 125(6):798, 2003) were extended, re-derived, and validated for the 3-D case. Results showed that 3-D tortuosity decreased with stretch, exhibiting similar trends with changes in development as observed in the 2-D studies. Kinematic parameters also displayed similar general trends. Axons demonstrated more affine behavior with increasing stretch and development. In comparison with 2-D results, a smaller percentage of the populations of 3-D axons were predicted to follow pure non-affine behavior. The data and kinematic models presented herein can be incorporated into multi-scale CNS injury models, which can advance the accuracy of the models and improve the potential to identify axonal injury thresholds. PMID- 25910713 TI - SPH simulations of WBC adhesion to the endothelium: the role of haemodynamics and endothelial binding kinetics. AB - A multiscale Lagrangian particle solver introduced in our previous work is extended to model physiologically realistic near-wall cell dynamics. Three dimensional simulation of particle trajectories is combined with realistic receptor-ligand adhesion behaviour to cover full cell interactions in the vicinity of the endothelium. The selected stochastic adhesion model, which is based on a Monte Carlo acceptance-rejection method, fits in our Lagrangian framework and does not compromise performance. Additionally, appropriate inflow/outflow boundary conditions are implemented for our SPH solver to enable realistic pulsatile flow simulation. The model is tested against in-vitro data from a 3D geometry with a stenosis and sudden expansion. In both steady and pulsatile flow conditions, results show close agreement with the experimental ones. Furthermore we demonstrate, in agreement with experimental observations, that haemodynamics alone does not account for adhesion of white blood cells, in this case U937 monocytic human cells. Our findings suggest that the current framework is fully capable of modelling cell dynamics in large arteries in a realistic and efficient manner. PMID- 25910714 TI - Vanin-1 expression and methylation discriminate pediatric asthma corticosteroid treatment response. AB - BACKGROUND: There is considerable heterogeneity in asthma treatment response. OBJECTIVE: We sought to identify biomarkers of corticosteroid treatment response in children with asthma and evaluate the utility and mechanistic basis of these biomarkers. METHODS: Children (5-18 years) presenting to the emergency department with an acute asthma exacerbation were recruited and followed during hospitalization. Nasal epithelial cells were collected on presentation to the emergency department (T0) and 18 to 24 hours later (T1), and T1/T0 gene expression ratios were analyzed to identify genes associated with good and poor corticosteroid treatment response phenotypes. The utility of these genes in discriminating between systemic corticosteroid treatment response groups was then tested prospectively in a new cohort of patients. A gene candidate (vanin-1 [VNN1]) that consistently distinguished good versus poor response phenotypes was further studied in an experimental asthma model, and VNN1 promoter methylation was measured by means of bisulfite pyrosequencing in patients. RESULTS: VNN1 mRNA expression changes were associated with systemic corticosteroid treatment response in children with acute asthma, and VNN1 was required for optimal response to corticosteroid treatment in an experimental asthma model. A CpG site within the VNN1 promoter was differentially methylated between good versus poor treatment response groups, and methylation at this site correlated with VNN1 mRNA expression. CONCLUSIONS: We have identified a biological basis for poor corticosteroid treatment response that can be used to distinguish a subgroup of asthmatic children who respond poorly to systemic corticosteroid treatment. VNN1 contributes to corticosteroid responsiveness, and changes in VNN1 nasal epithelial mRNA expression and VNN1 promoter methylation might be clinically useful biomarkers of treatment response in asthmatic children. PMID- 25910715 TI - Promiscuous T-cell responses to drugs and drug-haptens. PMID- 25910716 TI - Association between respiratory infections in early life and later asthma is independent of virus type. AB - BACKGROUND: Lower respiratory tract infections in the first years of life are associated with later asthma, and this observation has led to a focus on the potential causal role of specific respiratory viruses, such as rhinoviruses and respiratory syncytial virus, in asthma development. However, many respiratory viruses and bacteria trigger similar respiratory symptoms and it is possible that the important risk factors for asthma are the underlying susceptibility to infection and the exaggerated reaction to such triggers rather than the particular triggering agent. OBJECTIVE: We sought to study the association between specific infections in early life and development of asthma later in childhood. METHODS: Three hundred thirteen children were followed prospectively in the Copenhagen Prospective Studies of Asthma in Childhood2000 high-risk birth cohort. Nine respiratory virus types (respiratory syncytial virus, rhinoviruses, other picornaviruses, coronaviruses 229E and OC43, parainfluenza viruses 1-3, influenza viruses AH1, AH3, and B, human metapneumovirus, adenoviruses, and bocavirus) and 3 pathogenic airway bacteria (Streptococcus pneumoniae, Haemophilus influenzae, and Moraxella catarrhalis) were identified in airway secretions sampled during episodes of troublesome lung symptoms in the first 3 years of life. Asthma was determined by age 7 years. RESULTS: In unadjusted analyses, all viruses and pathogenic bacteria identified during episodes of troublesome lung symptoms were associated with increased risk of asthma by age 7 years with similar odds ratios for all viruses and pathogenic bacteria. After adjustment for the frequency of respiratory episodes, the particular triggers were no longer associated with asthma. CONCLUSION: The number of respiratory episodes in the first years of life, but not the particular viral trigger, was associated with later asthma development. This suggests that future research should focus on the susceptibility and exaggerated response to lower respiratory tract infections in general rather than on the specific triggering agent. PMID- 25910717 TI - Functional Long Non-coding RNAs in Vascular Smooth Muscle Cells. AB - Increasing evidence shows that long non-coding RNAs (lncRNAs) are not "transcriptional noise" but function in a myriad of biological processes. As such, this rapidly growing class of RNAs is important in both development and disease. Vascular smooth muscle cells are integral cells of the blood vessel wall. They are responsible for relaxation and contraction of the blood vessel and respond to hemodynamic as well as environmental signals to regulate blood pressure. Pathophysiological changes to these cells such as hyperproliferation, hypertrophy, migration, and inflammation contribute to cardiovascular diseases (CVDs) such as restenosis, hypertension, and atherosclerosis. Understanding the molecular mechanisms involved in these pathophysiological changes to VSMCs is paramount to developing therapeutic treatments for various cardiovascular disorders. Recent studies have shown that lncRNAs are key players in the regulation of VSMC functions and phenotype and, perhaps also, in the development of VSMC-related diseases. This chapter describes our current understanding of the functions of lncRNAs in VSMCs. It highlights the emerging role of lncRNAs in VSMC proliferation and apoptosis, their role in contractile and migratory phenotype of VSMCs, and their potential role in VSMC disease states. PMID- 25910718 TI - Land cover mapping based on random forest classification of multitemporal spectral and thermal images. AB - Thematic mapping of complex landscapes, with various phenological patterns from satellite imagery, is a particularly challenging task. However, supplementary information, such as multitemporal data and/or land surface temperature (LST), has the potential to improve the land cover classification accuracy and efficiency. In this paper, in order to map land covers, we evaluated the potential of multitemporal Landsat 8's spectral and thermal imageries using a random forest (RF) classifier. We used a grid search approach based on the out-of bag (OOB) estimate of error to optimize the RF parameters. Four different scenarios were considered in this research: (1) RF classification of multitemporal spectral images, (2) RF classification of multitemporal LST images, (3) RF classification of all multitemporal LST and spectral images, and (4) RF classification of selected important or optimum features. The study area in this research was Naghadeh city and its surrounding region, located in West Azerbaijan Province, northwest of Iran. The overall accuracies of first, second, third, and fourth scenarios were equal to 86.48, 82.26, 90.63, and 91.82%, respectively. The quantitative assessments of the results demonstrated that the most important or optimum features increase the class separability, while the spectral and thermal features produced a more moderate increase in the land cover mapping accuracy. In addition, the contribution of the multitemporal thermal information led to a considerable increase in the user and producer accuracies of classes with a rapid temporal change behavior, such as crops and vegetation. PMID- 25910719 TI - A new P. putida instrumental toxicity bioassay. AB - Here, we present a new toxicity bioassay (CO2-TOX), able to detect toxic or inhibitory compounds in water samples, based on the quantification of Pseudomonas putida KT2440 CO2 production. The metabolically produced CO2 was measured continuously and directly in the liquid assay media, with a potentiometric gas electrode. The optimization studies were performed using as a model toxicant 3,5 DCP (3,5-dichlorophenol); later, heavy metals (Pb(2+), Cu(2+), or Zn(2+)) and a metalloid (As(5+)) were assayed. The response to toxics was evident after 15 min of incubation and at relatively low concentrations (e.g., 1.1 mg/L of 3,5-DCP), showing that the CO2-TOX bioassay is fast and sensitive. The EC50 values obtained were 4.93, 0.12, 6.05, 32.17, and 37.81 mg/L for 3,5-DCP, Cu(2+), Zn(2+), As(5+), and Pb(2+), respectively, at neutral pH. Additionally, the effect of the pH of the sample and the use of lyophilized bacteria were also analyzed showing that the bioassay can be implemented in different conditions. Moreover, highly turbid samples and samples with very low oxygen levels were measured successfully with the new instrumental bioassay described here. Finally, simulated samples containing 3,5-DCP or a heavy metal mixture were tested using the proposed bioassay and a standard ISO bioassay, showing that our test is more sensible to the phenol but less sensible to the metal mixtures. Therefore, we propose CO2-TOX as a rapid, sensitive, low-cost, and robust instrumental bioassay that could perform as an industrial wastewater-process monitor among other applications. PMID- 25910720 TI - Effects of selective withdrawal on hydrodynamics and water quality of a thermally stratified reservoir in the southern side of the Mediterranean Sea: a simulation approach. AB - This study uses a multidisciplinary approach to simulate the spatial and temporal patterns of hydrodynamics and water quality in a thermally stratified reservoir in the southern side of the Mediterranean Sea in response to water withdrawal elevation using the 2D water quality and laterally averaged hydrodynamic model CE QUAL-W2. The withdrawal elevation controls largely the transfer of heat and constituents in the dam in particular during thermal stratification. Fifteen scenarios of withdrawal elevation are possible. To identify the most effective scenarios, a hierarchical clustering technique was performed and only four scenarios were clustered. Deep withdrawals deepen the hypoxia, increase the thickness of the metalimnion, and weaken the stratification stability, which facilitate the vertical transfer of heat and dissolved oxygen mainly. Surface withdrawals, however, shrink the metalimnion and tend to strengthen the stratification, resulting in less transfer of matter from the epilimnion to the hypolimnion. Most of the bottom sediment is overlaid by the hypolimnion. The oxygen depletes significantly and waters become anoxic at a few meters depth. For all scenarios, the reservoir experiences a summer hypolimnetic anoxia, which lasts from 42 to 80 days and seems to decrease as withdrawal elevation increases. At the end of stratification, waters below the withdrawal elevation showed a noticeable release of iron, nutrients, and suspended sediments that increases with depth and near-bottom turbulence. Attention should be drawn to shallower withdrawals because they accumulate nutrients and silts continuously in the reservoir, which may deteriorate water quality. Based on these results, a withdrawal elevation rule is presented. This rule may be adjusted to optimize water withdrawal elevation for dams in the region with similar geometry. PMID- 25910721 TI - Modelling of lindane transport in groundwater of metropolitan city Vadodara, Gujarat, India. AB - Migration pattern of organochloro pesticide lindane has been studied in groundwater of metropolitan city Vadodara. Groundwater flow was simulated using the groundwater flow model constructed up to a depth of 60 m considering a three layer structure with grid size of 40 * 40 * 40 m(3). The general groundwater flow direction is from northeast to south and southwest. The river Vishwamitri and river Jambua form natural hydrologic boundary. The constant head in the north and south end of the study area is taken as another boundary condition in the model. The hydraulic head distribution in the multilayer aquifer has been computed from the visual MODFLOW groundwater flow model. TDS has been computed though MT3D mass transport model starting with a background concentration of 500 mg/l and using a porosity value of 0.3. Simulated TDS values from the model matches well with the observed data. Model MT3D was run for lindane pesticide with a background concentration of 0.5 MUg/l. The predictions of the mass transport model for next 50 years indicate that advancement of containment of plume size in the aquifer system both spatially and depth wise as a result of increasing level of pesticide in river Vishwamitri. The restoration of the aquifer system may take a very long time as seen from slow improvement in the groundwater quality from the predicted scenarios, thereby, indicating alarming situation of groundwater quality deterioration in different layers. It is recommended that all the industries operating in the region should install efficient effluent treatment plants to abate the pollution problem. PMID- 25910723 TI - Isolation of Intact Mitochondria from the Model Plant Species Arabidopsis thaliana and Oryza sativa. AB - The study of mitochondrial composition, biogenesis, and metabolism requires the isolation of intact functional mitochondria, often in relatively large quantities sufficient for downstream biochemical and proteomic analysis. Here we describe techniques optimized for the isolation of functional mitochondria from a variety of tissues from the model monocot and dicot species Arabidopsis (Arabidopsis thaliana) and rice (Oryza sativa). PMID- 25910722 TI - Distribution, bioavailability, and potential ecological risk of Cu, Pb, and Zn in soil in a potential groundwater source area. AB - In this study, we examined three horizontal and vertical soil profiles along a sewage drainage ditch in order to determine the spatial distribution of Cu, Pb, and Zn in soils and to assess the bioavailability and potential ecological risks associated with these metals in a potential groundwater source area. Results showed that the concentrations of Cu, Pb, and Zn were approximately at background level, suggesting that human activities (industrial and agricultural pollution) had a negligible influence on these metals in soil, and that the concentrations reflected the natural background levels in the study area. Cu, Pb, and Zn concentrations were slightly higher in topsoil (0-20 cm) than deeper in the soil profile. Using a modified BCR sequential extraction method to evaluate the mobility and bioavailability of metals showed that the potential bioavailability sequence of Cu, Pb, and Zn at three depths in the soil profile was in the order Cu ~ Pb < Zn. The potential ecological risk from the metals was evaluated using risk assessment code, and the results suggest that Cu and Zn pose no or low risk, while there is a low or medium risk from Pb. Results from groundwater monitoring showed that the groundwater was not polluted by leaching from soil. PMID- 25910724 TI - Determining mitochondrial transcript termini for the study of transcription start sites and transcript 5' end maturation. AB - Mitochondrial gene expression in plants is considerably more complex than in animals or fungi. In plants, mitochondrial transcripts are generated from transcription initiation at numerous, poorly conserved promoters located throughout the mitochondrial genome. Most genes have more than one transcription start site. Posttranscriptional RNA 5' end maturation contributes to the diversity of transcripts produced from each mitochondrial gene. Understanding transcriptional mechanisms and transcript maturation requires knowledge on transcription start sites and processing sites. This chapter describes two different, complementary experimental approaches for determining these sites in mitochondrial genomes through mapping of transcript 5' ends. In order to distinguish 5' ends deriving from transcription initiation, both strategies exploit the presence of triphosphates at these specific 5' termini. PMID- 25910725 TI - Mitochondrial run-on transcription assay using biotin labeling. AB - RNA synthesis and different posttranscriptional processes shape the transcriptome of plant mitochondria. It is believed that mitochondrial transcription in plants is not stringently controlled, and that RNA degradation has a major impact on mitochondrial steady-state transcript levels. Nevertheless, the presence of two RNA polymerases with different gene specificities in mitochondria of dicotyledonous species indicates that transcriptional mechanisms may provide a means to control mitochondrial steady-state RNA pools and gene expression. To experimentally assess transcriptional activities in mitochondria, run-on transcription assays have been developed. These assays measure elongation rates for endogenous transcripts in freshly prepared mitochondrial extracts. The mitochondrial run-on transcription protocol described here has been optimized for the model plant Arabidopsis (Arabidopsis thaliana). It uses mitochondria prepared from soil-grown Arabidopsis plants and employs nonradioactive labeling for the subsequent detection of run-on transcripts. PMID- 25910726 TI - In vitro RNA uptake studies in plant mitochondria. AB - During evolution, most of the ancestral genes from the endosymbiotic alpha proteobacteria at the origin of mitochondria have been either lost or transferred to the nuclear genome. To allow the comeback of proteins and RNAs [in particular transfer RNA (tRNAs)] into the organelle, macromolecule import systems were universally established. While protein import processes have been studied into details, much less is known about tRNA mitochondrial import. In plants, part of the knowledge on the tRNA import process into mitochondria has been acquired thanks to in vitro import assays. Furthermore, the development of in vitro RNA import strategies allowed the study of plant mitochondrial gene expression. The purpose of this chapter is to provide detailed protocols to perform in vitro RNA uptake into potato (Solanum tuberosum) or Arabidopsis (Arabidopsis thaliana) mitochondria as well as approaches to analyze them. PMID- 25910727 TI - In vitro and in vivo protein uptake studies in plant mitochondria. AB - The study of protein uptake into mitochondria is an important tool for investigating the subcellular distribution of proteins and the molecular mechanisms that determine location. Here we describe five techniques that allow the quantitative or qualitative monitoring of protein uptake into mitochondria using both in vitro and in vivo approaches. PMID- 25910728 TI - Plant mitochondrial proteomics. AB - Mitochondrial proteomics has significantly developed since the first plant mitochondrial proteomes were published in 2001. Many studies have added to our knowledge of the protein components that make up plant mitochondria in a wide range of species. Here we present two common and one emerging quantitative proteomic techniques that can be used to study the abundance of mitochondrial proteins. For this publication, we have described the methods as an approach to determine the amount of contamination in a mitochondrial isolation to contrast historical approaches that involved the use of use of antibodies to specific marker proteins or the measurement of activity of marker enzymes. However, these approaches could easily be adapted to carry out control versus treatment studies. PMID- 25910729 TI - Identification of lysine-acetylated mitochondrial proteins and their acetylation sites. AB - The (epsilon)N-acetylation of lysine side chains is a highly conserved posttranslational modification of both prokaryotic and eukaryotic proteins. Lysine acetylation not only occurs on histones in the nucleus but also on many mitochondrial proteins in plants and animals. As the transfer of the acetyl group to lysine eliminates its positive charge, lysine acetylation can affect the biological function of proteins. This chapter describes two methods for the identification of lysine-acetylated proteins in plant mitochondria using an anti acetyllysine antibody. We describe the Western blot analysis of a two-dimensional blue native-polyacrylamide gel electrophoresis with an anti-acetyllysine antibody as well as the immuno-enrichment of lysine-acetylated peptides followed by liquid chromatography-tandem mass spectrometry data acquisition and analysis. PMID- 25910730 TI - A flowchart to analyze protease activity in plant mitochondria. AB - Proteases are one of the most abundant classes of enzymes and are involved in a plethora of biological processes in many cellular compartments, including the mitochondria. To understand the role of proteases is essential to determine their substrate repertoire, preferably in an in vivo setting. In this chapter we describe general guidelines to analyze protease activity using several strategies, from in-gel analysis to mass spectrometry mapping of the cleavage site(s) and fluorogenic probes that can easily be used in vivo. To exemplify this flowchart, we used the recently characterized organellar oligopeptidase of Arabidopsis (Arabidopsis thaliana), an enzyme that takes part in degradation of short peptides within mitochondria and chloroplasts. PMID- 25910731 TI - Activity measurements of mitochondrial enzymes in native gels. AB - In-gel activity assays are useful tools to identify and characterize enzymes within gels. Prerequisite are electrophoretic protein separations that are carried out under conditions compatible with enzyme activity. While blue native polyacrylamide gel electrophoresis (BN-PAGE) is widely used for activity assays of the five enzyme complexes of the oxidative phosphorylation system, the blue background of this electrophoretic system is not compatible with activity assays for some other mitochondrial enzymes. As an alternative system, clear native (CN) PAGE can be used for visualizing activities of mitochondrial enzymes. Here, we describe enzyme activity assays for mitochondrial enzymes in BN and CN gels. PMID- 25910732 TI - Activity assay for plant mitochondrial enzymes. AB - Mitochondria are sites for respiration to produce chemical energy via oxidative phosphorylation. Their primary role has been viewed as the oxidation of organic acids via the tricarboxylic acid (TCA) cycle and the synthesis of ATP coupled to the transfer of electrons to O2. TCA cycle enzymes are essential for plant carbon metabolism and provide the reductant for the electron transport chain (ETC) enzymes that in turn drives ATP synthesis. The activity of individual enzymes will determine the flux of metabolism and thus the downstream consequences for respiration rate. Measurements of activities of mitochondrial enzymes, such as components of TCA cycle and the ETC, can provide insight into regulation of mitochondrial function. The activities of these enzymes vary between developmental stages, in different tissues, and in response to environmental conditions. In this chapter, methods for enzymatic assay of TCA cycle enzymes and a number of the ETC complex enzymes are described in detail. PMID- 25910733 TI - Analysis of Type II NAD(P)H Dehydrogenases. AB - Plant mitochondria contain at least four type II NAD(P)H dehydrogenases that link NAD(P)H oxidation to the inner membrane electron transport chain and bypass proton pumping at Complex I, hence ATP synthesis. These activities have been found in mitochondria isolated from all plant species analyzed to date. In this chapter, methods are presented to analyze the expression of genes encoding these dehydrogenases and to detect protein levels in mitochondria isolated from Arabidopsis (Arabidopsis thaliana). In addition, methods and assay conditions are presented to detect the activity of each of these four type II NAD(P)H dehydrogenases in isolated plant mitochondria. PMID- 25910734 TI - Assessment of respiration in isolated plant mitochondria using Clark-type electrodes. AB - Mitochondrial respiration involves two key gas exchanges, the consumption of oxygen and the release of carbon dioxide. The ability to measure the consumption of oxygen via Clark-type electrodes has been one of the key techniques for advancing our knowledge of mitochondrial function in whole organisms, tissue samples, cells, and isolated subcellular fractions. In plants, oxygen electrode analyses provided the first evidence for some of the unique respiratory properties of plant mitochondria. This chapter briefs the principles of respiration and oxidative phosphorylation, how oxygen consumption measurements can be used to assess the quality of isolated mitochondrial preparations, and how these measurements can answer important questions in plant biochemistry and physiology. Finally, it presents instructions on assembling the oxygen electrode apparatus and how to conduct various assays. PMID- 25910735 TI - Micro-respiratory measurements in plants. AB - Respiratory measurement in plants is one of the commonly used techniques to assess metabolic activity and in vivo redox state of plant mitochondria. However, respiration rate monitoring of Arabidopsis (Arabidopsis thaliana) remains a challenge for researchers due to the small size of its organs. In this chapter we introduce adaptations to micro-respiratory technologies to study three tissues of special interest to plant biologists: leaf sections, root tips, and seeds in this model plant species. This assay opens up new possibilities to screen and study mutants and to identify differences in ecotypes or populations of plants. PMID- 25910736 TI - Improvements to define mitochondrial metabolomics using nonaqueous fractionation. AB - Defining metabolite abundance and resulting fractional isotope enrichments, within and between cellular compartments, still remain a major challenge in modern plant biochemistry. Optimized protocols for rapid isolation of mitochondria (e.g., silicone oil centrifugation or membrane filters) or visualization of metabolites/metabolic states (e.g., fluorescence resonance energy transfer (FRET) or redox-sensitive fluorescent markers (roGFP)) have significantly improved and expanded our knowledge regarding mitochondrial metabolism. However, the application of nonaqueous fractionation (NAQF) to separate and quantify metabolites across subcellular compartments remains popular as a nontargeted, validated approach towards studying metabolism, and provides a top-down overview of metabolite distribution across the majority of the subcellular compartments in a single preparation. Unfortunately, of all the organelles resolved using this method, the mitochondrion still remains the most poorly defined. Here, the development and suggested improvements to resolve the mitochondrial metabolome are described. PMID- 25910737 TI - Mitochondrial Markers of Programmed Cell Death in Arabidopsis thaliana. AB - In plants, apoptosis-like programmed cell death (AL-PCD) is readily distinguished from other forms of programmed cell death (PCD) through a distinct morphology. Detection of cytochrome c release from mitochondria and changes in mitochondrial morphology are the earliest markers for detection of this form of PCD in plants. In this chapter we provide detailed technical methods for the visualization of both of these mitochondrial markers of AL-PCD in Arabidopsis. PMID- 25910738 TI - Imaging and analysis of mitochondrial dynamics in living cells. AB - One of the most striking features of plant mitochondria when visualized in living tissue is their dynamism. The beauty of cytoplasmic streaming, driving, and being driven by the motility of mitochondria and other small organelles belies the complexity of the process. Equally, capturing that dynamism and investigating the genes, proteins, and mechanisms underpinning the processes using molecular cell biology and bioimaging is a complex process. It requires the generation of fluorescent protein constructs, stable transgenic plants sometimes expressing multiple fusions, and generation of mutants, even before one is ready for analytical experimentation. Here, we describe some of the key tools and methods necessary to investigate plant mitochondrial dynamics. PMID- 25910739 TI - Analysis of plant mitochondrial function using fluorescent protein sensors. AB - Mitochondrial physiology sets the basis for function of the organelle and vice versa. While a limited range of in vivo parameters, such as oxygen consumption, has been classically accessible for measurement, a growing collection of fluorescent protein sensors can now give insights into the physiology of plant mitochondria. Nevertheless, the meaningful application of these sensors in mitochondria is technically challenging and requires rigorous experimental standards. Here we exemplify the application of three genetically encoded sensors to monitor glutathione redox potential, pH, and calcium in the matrix of mitochondria in intact plants. We describe current methods for quantitative imaging and analysis in living root tips by confocal microscopy and discuss methodological limitations. PMID- 25910740 TI - In planta analysis of leaf mitochondrial superoxide and nitric oxide. AB - Superoxide (O2(-)) and nitric oxide (NO) are produced within plant mitochondria and may have signaling functions within the cell. Here we describe semiquantitative fluorescence imaging-based approaches to estimate the mitochondrial amount of these reactive and short-lived species within intact leaf tissue. We also outline a biochemical method using oxyhemoglobin to measure NO within a whole leaf tissue extract. This quantitative method, while not specifically evaluating mitochondrial localized NO, does nonetheless provide another independent measure of NO that can be useful. PMID- 25910741 TI - Databases and informatics resources for analysis of plant mitochondria. AB - As more omics data is generated from various plant species, it is becoming increasingly possible to carry out a range of in silico analyses to gain insight into mitochondrial function in plants. From the use of software tools for DNA motif analyses and transcript expression visualization to proteomic and subcellular localization resources, it is possible to carry out significant in silico analyses that are highly informative to researchers and can help to guide experimental design for further mitochondrial study. Databases specific to plant mitochondrial analyses have been developed in recent years, revealing mitochondria-specific information. This chapter outlines the databases and informatics resources that are useful for plant mitochondrial studies, with specific examples presented to indicate how these resources can be used to gain insight into plant mitochondrial function(s). PMID- 25910742 TI - Expression and crystallization of the plant alternative oxidase. AB - The alternative oxidase (AOX) is an integral monotopic membrane protein located on the inner surface of the inner mitochondrial membrane. Branching from the traditional respiratory chain at the quinone pool, AOX is responsible for cyanide resistant respiration in plants and fungi, heat generation in thermogenic plants, and survival of parasites, such as Trypanosoma brucei, in the human host. A recently solved AOX structure provides insight into its active site, thereby facilitating rational phytopathogenic and antiparasitic drug design. Here, we describe expression of recombinant AOX using two different expression systems. Purification protocols for the production of highly pure and stable AOX protein in sufficient quantities to facilitate further kinetic, biophysical, and structural analyses are also described. PMID- 25910743 TI - [Laser Blended Vision for presbyopia: Results after 3 years]. AB - PURPOSE: Retrospective study of the first 173 patients with presbyopia who underwent LASIK with a non-linear aspheric ablation profile and micro-monovision for the correction of presbyopia with myopia, astigmatism, hyperopia or emmetropia: Laser Blended Vision((r)) Program by Carl Zeiss Meditec((r)) (Jena, Germany). METHODS: We retrospectively studied the first consecutive 173 patients with presbyopia who underwent LASIK with the wavefront-guided Laser Blended Vision((r)) Program by Zeiss((r)) in our Excimer Laser Zeiss Mel-80 by Carl Zeiss Meditec((r)) (Jena, Germany) over the last three years in our clinic (Optima Laser Clinic, Valence, Spain). The program has a non-linear aspheric ablation profile that increases the spherical aberration in both eyes. A slight myopia of 1.5 diopters (D) in the non-dominant eye is also programmed. We analysed the results and patient satisfaction. The patients were separated into two groups: less than 50 years old and 50 years or more. Follow-up was from 1 to 28 months. We also separated two groups: follow-up under 12 months and follow-up of 12 months or more. We analysed the efficacy, safety and predictability of the procedure. RESULTS: Seventy-nine male and 94 female patients between 42 and 69 years old were studied, for a total of 337 eyes. Only eight patients (4.62%) were between 42 and 44; 55 (31.79%) were between 45 and 49; 110 patients (63.58%) were 50 years or more. Nine patients underwent the surgery in the non-dominant eye only. Twelve (6.94%) patients were emmetropic (0.5 or less spherical equivalent), 42 (24.28%) were myopic or myopic astigmatic, and 119 (68.79%) were hyperopic or hyperopic astigmatic. One hundred and thirty-six patients (78.61%) had pre operative near vision between J4 and J10. One hundred and seventy-one patients (98.84%) had post-operative near vision between J1 and J3; 150 (86.7%) had J1 (efficacy). Post-operative visual acuity without correction for distance was 20/20 or better in 159 patients (91.91%) (binocular). The predictability within 0.5 D was 87.86%. Safety 99.7% (336/337 eyes): one eye of a diabetic patient lost two lines BCVA. A total of 93.64% were satisfied with the procedure, 2.89% used eye-glasses for certain activities, 1.73% reported dry eye, 0.58% reported a nonspecific lack of adaptation, and there were no serious complications; 3.47% did not achieve their expectations. Twenty-four patients (13.87%) needed an enhancement, 18 of them (75.5%) for only one eye, with 88.89% of these being the non-dominant eye. Forty-nine patients (28.32%) had over 12 months follow-up, with 95.92% still satisfied. CONCLUSIONS: Laser Blended Vision((r)) is an excellent option, well tolerated, stable and effective for patients with presbyopia and myopia, astigmatism, hyperopia or emmetropia, also avoiding an intraocular procedure. PMID- 25910744 TI - Association of polymorphisms in the beta-2 adrenergic receptor gene with fracture risk and bone mineral density. AB - Signaling through the beta-2 adrenergic receptor (B2AR) on the osteoblast influences bone remodeling in rodents. In the B2AR gene, three polymorphisms influence receptor function. We show that these polymorphisms are not associated with fracture risk or bone mineral density in the UCP, Rotterdam Study, and GEFOS cohorts. INTRODUCTION: Signaling through the beta-2 adrenergic receptor (B2AR) on the osteoblast influences bone remodeling in rodents. In the B2AR gene, three polymorphisms are known to influence receptor function in vitro and in vivo (rs1042713, rs1042714, and rs1800888). We examined the role of these polymorphisms in the B2AR gene on human bone metabolism. METHODS: We performed nested case-control studies to determine the association of these polymorphisms with fracture risk in the Utrecht Cardiovascular Pharmacogenetics (UCP) cohort and in three cohorts of the Rotterdam Study. We also determined the association of these polymorphisms with bone mineral density (BMD) in the GEFOS Consortium. UCP contains drug-dispensing histories from community pharmacies linked to national registrations of hospital discharges in the Netherlands. The Rotterdam Study is a prospective cohort study investigating demographics and risk factors of chronic diseases. GEFOS is a large international collaboration studying the genetics of osteoporosis. Fractures were defined by ICD-9 codes 800-829 in the UCP cohort (158 cases and 2617 unmatched controls) and by regular X-ray examinations, general practitioner, and hospital records in the Rotterdam Study (2209 cases and 8559 unmatched controls). BMD was measured at the femoral neck and lumbar spine using dual-energy X-ray absorptiometry in GEFOS (N = 32,961). RESULTS: Meta-analysis of the two nested case-control studies showed pooled odds ratios of 0.98 (0.91-1.05, p = 0.52), 1.04 (0.97-1.12, p = 0.28), and 1.16 (0.83 1.62, p = 0.38) for the associations between rs1042713, rs1042714, and rs1800888 per minor allele and fractures, respectively. There were no significant associations of the polymorphisms and BMD in GEFOS. CONCLUSION: In conclusion, polymorphisms in the beta-2 adrenergic receptor gene are not associated with fracture risk or BMD. PMID- 25910745 TI - Excess mortality associated with second hip fracture. AB - Hip fracture increases death risk. Ten percent of survivors have second hip fracture. It is not known if second hip fracture further increases death risk. Here, we report that second hip fracture increases death risk beyond that expected for an increase in age. Secondary prevention after hip fracture could save lives. INTRODUCTION: The purpose of this study is to determine if second hip fracture is associated with an increased death rate. METHODS: We retrieved 42,435 hospitalization records of patients aged 60 years or older, who were discharged after admission for hip fracture surgery between 1990 and 2005 in British Columbia, Canada. The outcome variable was the time to death. RESULTS: During follow-up, the average monthly death rate was 16.2 (95 % CI 16.0-16.4) per 1000 patient-months for those without second hip fracture and 21.1 (95 % CI 20.2-22.1) per 1000 patient-months for those with second hip fracture. The hazard of death was 55 % higher for patients with second hip fracture compared to those without second hip fracture (HR = 1.55, 95 % CI 1.47-1.63). The hazard of death was 58 % higher for men with second hip fracture than in men without second hip fracture (HR = 1.58, 95 % CI 1.42-1.75). The hazard of death was 54 % higher for women with second hip fracture compared to women without second hip fracture (HR = 1.54, 95 % CI 1.46-1.63). These sex-specific HRs were not statistically different (p = 0.70). CONCLUSION: Our results are the first to show that second hip fracture increases the risk of death above that anticipated for an increase in age for both men and women. Effective secondary prevention strategies could not only reduce morbidity after hip fracture but could also save lives. PMID- 25910747 TI - Serum sclerostin: the missing link in the bone-vessel cross-talk in hemodialysis patients? AB - We found for the first time that in maintenance hemodialysis patients, higher sclerostin serum level was associated with severe abdominal aortic calcification (AAC). In addition, cortical bone microarchitecture (density and thickness) assessed by high-resolution peripheral quantitative computed tomography (HR-pQCT) at tibia was also independently associated with severe AAC. These results suggest that sclerostin may be involved in the association of mineral and bone disorder with vascular calcification in hemodialysis patients. INTRODUCTION: Severe abdominal aortic calcifications are predictive of high cardiovascular mortality in maintenance hemodialysis (MHD) patients. In patients with end-stage renal disease, a high aortic calcification score was associated with lower bone turnover on bone biopsies. Thus, we hypothesized that sclerostin, a Wnt pathway inhibitor mainly secreted by osteocytes and acting on osteoblasts to reduce bone formation, may be associated with vascular calcifications in MHD patients. METHODS: Fifty-three MHD patients, aged 53 years [35-63] (median [Q1-Q3]) were included. Serum was sampled before the MHD session to assay sclerostin. Framingham score was computed and the abdominal aortic calcification (AAC) score was assessed according to Kauppila method on lateral spine imaging using DEXA. Tibia bone status was evaluated by high-resolution peripheral quantitative computed tomography (HR-pQCT). Patients were distributed into two groups according to their AAC score: patients with mild or without AAC (score below 6) versus patients with severe AAC (score of 6 and above). RESULTS: In multivariate analysis, after adjustment on age, dialysis duration and diabetes, serum sclerostin and cortical thickness were independently associated with severe AAC (odds ratio (OR) = 1.43 for each 0.1 ng/mL increase [95 % confidence interval (CI) 1.10-1.83]; p = 0.006 and 0.16 for 1 SD increase [0.03-0.73]; p = 0.018, respectively). A second cardiovascular model adjusted on Framingham score and the above mentioned confounders showed similar results. CONCLUSIONS: Elevated sclerostin serum level and poorer tibia cortical bone structure by HR-pQCT were positively and independently associated with higher odds of severe AAC in MHD patients. Serum sclerostin may become a biomarker of mineral and bone disorder and vascular risk in MHD patients. PMID- 25910746 TI - Oral anti-diabetic drugs and fracture risk, cut to the bone: safe or dangerous? A narrative review. AB - Fracture risk is higher in older adults with type 2 diabetes and may be influenced by treatments for diabetes. Oral anti-diabetic drugs have different effects on bone metabolism. The purpose of this review is to describe the effects of these drugs on bone metabolism and fracture risk. Osteoporosis is a progressive skeletal disorder that is characterized by compromised bone strength and increased risk of fracture. This condition has become an important global health problem, affecting approximately 200 million people worldwide. Another chronic and highly prevalent condition is diabetes mellitus, which affects more than 380 million people; both type 1 and type 2 diabetes are risk factors for fracture. Type 2 diabetes, in particular, is associated with impaired bone strength, although it is characterized by normal or elevated bone mineral density. Several therapeutic strategies are available to achieve the best outcomes in the management of diabetes mellitus but these have different effects on bone metabolism. The purpose of this narrative review is to describe the effects of oral hypoglycemic agents (metformin, sulfonylureas, thiazolidinediones, meglitinides, dipeptidyl peptidase-4 inhibitors, glucagon like peptide-1 receptor agonists and sodium-dependent glucose transporter 2 inhibitors) on bone metabolism and on the risk of developing fragility fractures in patients with type 2 diabetes. Both diabetes and osteoporosis represent a significant burden in terms of healthcare costs and quality of life. It is very important to choose therapies for diabetes that ensure good metabolic control whilst preserving skeletal health. PMID- 25910748 TI - Serum 25-hydroxyvitamin D level and risk of falls in Japanese community-dwelling elderly women: a 1-year follow-up study. AB - The present prospective follow-up study among 1,393 community-dwelling elderly women aged 75 years or older was conducted to clarify the association between serum 25-hydroxyvitamin D (25(OH)D) level and risk of falls. Lower serum 25(OH)D, particularly level <20 ng/mL, was significantly associated with an increased risk of falls. INTRODUCTION: Serum 25(OH)D level has been revealed to be important factor not only for skeletal health but also for fall prevention among the elderly. Our previous cross-sectional study indicated that low serum 25(OH)D level is associated with inferior physical performance and falls among elderly Japanese women. The present prospective study was designed to clarify the association between serum 25(OH)D level and risk of falls before and after 1 year of follow-up. METHODS: The community-dwelling elderly women aged 75 years or older (N = 1,393) who participated in a mass health examination were followed 1 year later by a mailed self-administered questionnaire. RESULTS: Responses were obtained from 1,285 subjects (response rate = 92.2%). The incidence of falls at baseline and at 1-year follow-up was 18.8 and 24.4%, respectively. The baseline prevalence of serum 25(OH)D <20 ng/mL was 35.2%. Odds ratios (95% confidence intervals) in the lowest tertile of serum 25(OH)D (<20 ng/mL) compared with those in the highest tertile (>=25 ng/mL) were 1.40 (1.01-1.94) for any falls and 1.47 (0.93-2.32) for recurrent falls vs. no falls adjusted for potential risk factors. CONCLUSIONS: Among elderly Japanese women, the lower serum 25(OH)D, particularly level <20 ng/mL, was significantly associated with an increased risk of falls. PMID- 25910749 TI - Bone micro-architecture of elite alpine skiers is not reflected by bone mineral density. AB - Bone quality is affected by muscle forces and external forces. We investigated how micro-architecture is influenced in elite alpine skiers who have received high loading levels throughout their adolescent bone development. Bone strength was higher in skiers, likely due to external forces, but muscle forces may also be a significant contributor. INTRODUCTION: Impact loading and muscle forces affect bone quality, but little is known about how they influence 3 dimensional aspects of bone structure. This study investigated bone quality in female and male elite alpine skiers using high-resolution peripheral quantitative computed tomography (HR-pQCT). METHODS: HR-pQCT at the distal radius and tibia, whole-body lean mass, and muscle strength were assessed in 10 female (22.7 +/- 3.9 years) and 12 male (25.5 +/- 3.3 years) Canadian national alpine team athletes and compared to recreationally active female (N = 10, 23.8 +/- 3.2 years) and male (N = 12; 23.7 +/- 3.6 years) control subjects. HR-pQCT standard parameters and customized cortical and finite element (FE) analyses were performed and analyzed using one-way ANOVA and Pearson's correlation. RESULTS: Male and female skiers had stronger bones than controls at radius (38-49 %, p < 0.001) and tibia (24-28 %, p < 0.001). This result was not consistently reflected by total bone mineral density (BMD) because higher trabecular BMD occurred in parallel with lower cortical BMD, which was due to a redistribution of mineral leading to a shift of the endocortical margin toward a thicker cortex. The endocortical regional adaptation was likely responsible for the greater strength of the athletes' bones. Lean mass and muscle strength was 29 to 90 % greater (p < 0.001) in athletes compared to controls. Good associations between muscle strength and FE estimated bone strength were found (r = 0.63 to 0.80; p < 0.001), although micro architecture was more strongly associated with muscle outcomes in females than males. CONCLUSIONS: Higher bone strength in elite alpine skiers is achieved through micro-architectural adaptation that is not apparent by BMD measurements alone. The improved micro-architecture at radius and tibia suggests that muscle forces may play an important role in bone adaptation. PMID- 25910750 TI - Predicting distress among people who care for patients living longer with high grade malignant glioma. AB - PURPOSE: Caregivers of patients living longer with high-grade malignant glioma (HGG) have the unique challenge of caring for a person who may have cognitive impairment, along with cancer-related issues over a prolonged period of time. This study aims to detail the psychosocial profile of long-term caregivers, to describe their perceptions of the patient's quality of life and to examine predictors of their psychological distress. METHODS: Sixty-nine caregivers (48%) of eligible patients with HGG surviving over 2 years were recruited from two Australian metropolitan tertiary hospitals. Caregivers completed cross-sectional measures of psychological distress (GHQ-12), caregiver impact (FACQ-PC) and patient functional well-being (FACT-Br TOI). Correlational analyses identified factors related to caregiver psychological distress. Those of significance (p <= .01) were examined using multiple regression models to determine their predictive value. RESULTS: Caregivers were mostly female (73%), spouses (67%), cohabiting (78%) and were caring for patients surviving a median of 5.9 years since diagnosis. Whilst caregivers overall reported minimal psychological distress, 28% endorsed moderate to severe psychological distress, warranting clinical attention. Caregiver strain and low patient functional well-being both significantly predicted caregiver psychological distress (adjusted R(2) = .35, F(4, 60) = 17.7, p < .001), accounting for a moderate amount (35%) of variance. Other typical factors such as duration of caregiving, performance status, symptom burden and disease or demographic related factors were not predictive. CONCLUSIONS: Psychological distress affects a significant proportion of caregivers of patients living longer with HGG. The presence of caregiver strain and low patient functional well-being are the most important predictors of psychological distress among this cohort of caregivers. PMID- 25910751 TI - Catheter-associated bloodstream infections and thrombotic risk in hematologic patients with peripherally inserted central catheters (PICC). AB - PURPOSE: The use of peripherally inserted central catheters (PICC) as an alternative to other central venous access devices (CVAD) is becoming very frequent in cancer patients. To evaluate the impact of complications associated to these devices in patients with hematologic malignancies, we revised the catheter-related bloodstream infections (CRBSI) and the catheter-related thrombotic complications (CRTC) observed at our institute between January 2009 and December 2012. METHODS: A total of 612 PICCs were inserted into 483 patients at diagnosis or in subsequent phases of their hematologic disease. PICCs were successfully inserted in all cases. The median duration of in situ PICC placement was 101 days (interquartile range, 48-184 days). RESULTS: A CRBSI occurred in 47 cases (7.7 %), with a rate of 0.59 per 1000 PICC days. A CRTC was recorded in 16 cases (2.6 %), with a rate of 0.20 per 1000 PICC days. No serious complication was associated to these events. Cox regression analyses of variables associated to CRBSIs and to CRTCs showed that only the type of disease (acute leukemia compared to other diseases) was significantly associated to a higher incidence of CRBSIs, while no feature was predictive for a higher risk of CRTCs. CONCLUSIONS: PICCs represent a useful and safe alternative to conventional CVAD for the management of patients with hematologic malignancies. PMID- 25910752 TI - Reduction in retinal nerve fiber layer thickness in tuberous sclerosis complex. AB - PURPOSE: The aim of our study was to non-invasively investigate central nervous system axonal integrity in patients with tuberous sclerosis complex (TSC). Diffuse microstructural white matter abnormalities reflecting axonal disorganization, reduced/altered myelination, or gliosis have been described in individuals with TSC. Optical coherence tomography (OCT) is a fast, easy-to perform, non-invasive, and cost-efficient method to assess retinal morphology in vivo and to measure the thickness of the retinal nerve fiber layer (RNFL). METHODS: In order to assess central nervous system axonal integrity, eight subjects with TSC have been investigated by OCT to evaluate RNFL and they have been compared with matched healthy controls. RESULTS: When comparing mean overall RNFL thicknesses of the TSC group with those of the control group, the TSC group presented with significantly lower RNFL values, compared to the control group, in the temporal quadrant (62.5 +/- 6.9 vs. 76.9 +/- 5.4; t = 14.438; p < 0.0001). CONCLUSIONS: Since a reduced RNFL thickness might be seen as an indicator of chronic axonal degeneration or lack of appropriate neuronal development, our results support the presence of axonal alterations in TSC and also that white matter disorganization could be much more diffuse than originally thought. Since axonal alterations directly derive from mammalian target of rapamycin (mTOR) overactivation, which occurs early during fetus development, the RNFL thinning we observed could represent one of the facets of such early neurodevelopmental abnormalities. PMID- 25910753 TI - REVEILLE1 promotes NADPH: protochlorophyllide oxidoreductase A expression and seedling greening in Arabidopsis. AB - Chlorophyll biosynthesis plays a crucial role in the greening process and survival of etiolated seedlings and yet the mechanism underlying the regulation of this process is poorly understood. Upon light stimulation, NADPH: protochlorophyllide oxidoreductase (POR) catalyzes the reduction of protochlorophyllide (Pchlide) to chlorophyllide. Whereas this represents a key step in the chlorophyll biosynthetic pathway, the regulation of POR remains largely unknown. Three POR isoforms exist in Arabidopsis thaliana, i.e., PORA, PORB, and PORC. In this study, we identified a transcription factor, REVEILLE1 (RVE1), that binds directly to the PORA promoter through the EE-box cis regulatory element. Analysis of PORA expression in RVE1 loss-of-function (rve1) and overexpression (RVE1-OX) Arabidopsis plants showed that RVE1 positively regulates the transcription of PORA. We found that Pchlide levels were reduced in RVE1-OX seedlings. Furthermore, rve1 etiolated seedlings had lower greening rates than the wild type when exposed to light, whereas RVE1-OX seedlings had higher greening rates. In addition, when etiolated seedlings were exposed to light, RVE1 OX plants had less reactive oxygen species (ROS) accumulation and cell death than the wild type, and had reduced levels of ROS-responsive gene expression. Taken together, our study reveals an important role for RVE1 in regulating chlorophyll biosynthesis and promoting seedling greening during early plant growth and development. PMID- 25910754 TI - Phospho-DeltaNp63alpha-responsive microRNAs contribute to the regulation of necroptosis in squamous cell carcinoma upon cisplatin exposure. AB - This study shows that specific microRNAs differentially regulated by DeltaNp63alpha in cisplatin-sensitive and resistant squamous cell carcinoma (SSC) cells of larynx and tongue affect the expression of members of the necroptotic pathway CYLD, RIPK1, and MLKL. Different degrees of protein interaction between necroptotic signaling intermediates were also observed in SCC cells sensitive or resistant to cisplatin. Modulation of RIPK1 with miR-101-3p mimic or inhibitor, as well as with siRNA, or chemical inhibitors was shown to affect sensitivity of SCC cells to cisplatin. This is the first report showing the modulatory effect of DeltaNp63alpha-responsive microRNAs on the specific members of necroptotic pathway in SCC tumor cells variably responding to platinum chemotherapy. PMID- 25910755 TI - FDG PET/CT in cardiac electronic devices infection: Now is the time to target guidelines implementation. PMID- 25910757 TI - Idiopathic Subglottic and Tracheal Stenosis: A Survey of the Patient Experience. AB - OBJECTIVES: To report and compare patients' experiences with acquired subglottic stenosis (AS) versus idiopathic subglottic and tracheal stenosis (ISTS). METHODS: A survey was made available to patients with AS and ISTS. Results were analyzed for inter- and intragroup differences using a 2-tailed t test. RESULTS: The study included 160 survey participants (AS n = 28; ISTS n = 132), with a predominance of female participants (82% AS, 98% ISTS). Acid reflux was the most prevalent comorbidity across groups (42%-43%). A significant difference in time to diagnosis was found between groups, with 32% of AS patients diagnosed within 3 months of symptom onset, compared to 2% with ISTS. A diagnosis delay greater than 18 months occurred for 58% of ISTS patients. There was no difference in treatment approach, with the most common treatment being balloon dilation, followed by laser dilation. Tracheal resection was performed in 36% of patients in both groups. Patient satisfaction with surgical outcomes was significantly higher after tracheal resection (76%) compared to other treatment modalities (39%). CONCLUSIONS: ISTS remains a diagnostic challenge as highlighted by the delay in diagnosis compared to AS. There appears to be no historical or symptomatic factors specific to ISTS. Additionally, patients report increased satisfaction and symptom resolution after tracheal resection. PMID- 25910760 TI - Elderly man with syncope. Aortoenteric fistula. PMID- 25910761 TI - Commentary. PMID- 25910758 TI - MicroRNA as tools and therapeutics in lung cancer. AB - Lung cancer is the number one cause of cancer related deaths. The lack of specific and accurate tools for early diagnosis and minimal targeted therapeutics both contribute to poor outcomes. The recent discovery of microRNAs (miRNAs) revealed a novel mechanism for post-transcriptional regulation in cancer and has created new opportunities for the development of diagnostics, prognostics and targeted therapeutics. In lung cancer, miRNA expression profiles distinguish histological subtypes, predict chemotherapeutic response and are associated with prognosis, metastasis and survival. Furthermore, miRNAs circulate in body fluids and hence may serve as important biomarkers for early diagnosis or stratify patients for personalized therapeutic strategies. Here, we provide an overview of the miRNAs implicated in lung cancer, with an emphasis on their clinical utility. PMID- 25910759 TI - Proteomic Analysis of ABCA1-Null Macrophages Reveals a Role for Stomatin-Like Protein-2 in Raft Composition and Toll-Like Receptor Signaling. AB - Lipid raft membrane microdomains organize signaling by many prototypical receptors, including the Toll-like receptors (TLRs) of the innate immune system. Raft-localization of proteins is widely thought to be regulated by raft cholesterol levels, but this is largely on the basis of studies that have manipulated cell cholesterol using crude and poorly specific chemical tools, such as beta-cyclodextrins. To date, there has been no proteome-scale investigation of whether endogenous regulators of intracellular cholesterol trafficking, such as the ATP binding cassette (ABC)A1 lipid efflux transporter, regulate targeting of proteins to rafts. Abca1(-/-) macrophages have cholesterol-laden rafts that have been reported to contain increased levels of select proteins, including TLR4, the lipopolysaccharide receptor. Here, using quantitative proteomic profiling, we identified 383 proteins in raft isolates from Abca1(+/+) and Abca1(-/-) macrophages. ABCA1 deletion induced wide-ranging changes to the raft proteome. Remarkably, many of these changes were similar to those seen in Abca1(+/+) macrophages after lipopolysaccharide exposure. Stomatin-like protein (SLP)-2, a member of the stomatin-prohibitin-flotillin-HflK/C family of membrane scaffolding proteins, was robustly and specifically increased in Abca1(-/-) rafts. Pursuing SLP-2 function, we found that rafts of SLP-2-silenced macrophages had markedly abnormal composition. SLP-2 silencing did not compromise ABCA1-dependent cholesterol efflux but reduced macrophage responsiveness to multiple TLR ligands. This was associated with reduced raft levels of the TLR co-receptor, CD14, and defective lipopolysaccharide-induced recruitment of the common TLR adaptor, MyD88, to rafts. Taken together, we show that the lipid transporter ABCA1 regulates the protein repertoire of rafts and identify SLP-2 as an ABCA1 dependent regulator of raft composition and of the innate immune response. PMID- 25910762 TI - American Board of Emergency Medicine report on residency training information (2014-2015). AB - The American Board of Emergency Medicine (ABEM) gathers extensive background information on emergency medicine residency programs and the residents in those programs. We present the 2015 annual report on the status of US emergency medicine training programs. PMID- 25910763 TI - Generosity. PMID- 25910764 TI - It Is Not Just Touchy-Feely: Understanding How Rigorous Qualitative Methodology Can Lead to Effective Implementation of Community Interventions. May 2015 Annals of Emergency Medicine Journal Club. PMID- 25910765 TI - Elderly woman with headache. Giant cell arteritis/temporal arteritis. PMID- 25910766 TI - Giant cell arteritis: read the fine print! PMID- 25910767 TI - Ultrasonographically Guided Puncture of the Radial Artery for Blood Gas Analysis: A Prospective, Randomized Controlled Trial. PMID- 25910768 TI - One more reason to ban "medical clearance" for psychiatric evaluation? PMID- 25910769 TI - In reply. PMID- 25910770 TI - Uncertainty With D-dimer Use and the ADJUST-PE Study. PMID- 25910771 TI - Drug firms must cut price of pneumonia vaccine, says MSF. PMID- 25910772 TI - Moderation of Harsh Parenting on Genetic and Environmental Contributions to Child and Adolescent Deviant Peer Affiliation: A Longitudinal Twin Study. AB - Affiliation with deviant peers is associated with biologically influenced personal attributes, and is itself a major contributor to growth in antisocial behavior over childhood and adolescence. Several studies have shown that variance in child and adolescent deviant peer affiliation includes genetic and non-genetic influences, but none have examined longitudinal genetic and environmental stability or change within the context of harsh parenting. To address this gap, we tested the moderating role of harsh parenting on genetic and environmental stability or change of deviant peer affiliation in a longitudinal (spanning one and a half years) study of Chinese child and adolescent twin pairs (N = 993, 52.0% female). Using multiple informants (child- and parent-reports) and measurement methods to minimize rater bias, we found that individual differences in deviant peer affiliation at each assessment were similarly explained by moderate genetic and nonshared environmental variance. The longitudinal stability and change of deviant peer affiliation were explained by genetic and nonshared environmental factors. The results also revealed that the genetic variance for deviant peer affiliation is higher in the families with harsher parenting. This amplified genetic risk underscores the role of harsh parenting in the selection and socialization process of deviant peer relationships. PMID- 25910773 TI - Obituary: A Remembrance of Henry Phil Gross MD (1930-2014). PMID- 25910774 TI - CORR Insights(r): Developmental Dislocation of the Hip Successfully Treated by Preoperative Traction and Medial Open Reduction: A 22-year Mean Followup. PMID- 25910775 TI - Scapular Bracing is Effective in Some Patients but Symptoms Persist in Many Despite Bracing. AB - BACKGROUND: A scapular-protecting brace is one option for treating patients with a winging scapula in isolated serratus palsy. However, outcomes after brace treatment have been reported in only a few studies, and to our knowledge, none has results reported at long-term beyond 10 years. QUESTIONS/PURPOSE: We asked: (1) What was the average length of time patients wore the brace? (2) Did scapular winging and ROM improve with brace treatment? (3) Was pain decreased? (4) Did the duration of symptoms before brace treatment influence the outcome? PATIENTS AND METHODS: Between 1980 and 1999, we treated 110 patients with a scapular protecting brace. General indications for this treatment included electroneuromyography-verified isolated serratus palsy, 3 cm or greater scapular winging, and limited ROM. For patients with scapular winging less than 3 cm we used observation and avoidance of all heavy work or lifting. Of the patients treated with a brace, 55 (50%) were available at a minimum followup of 10 years (mean, 22 years; range, 10-28 years). Mean patient age was 30 years at the onset of symptoms (range, 15-52 years). Brace use was based on patient self-report, and we determined the degree of scapular winging and ROM clinically and level of pain by chart review before and after treatment. RESULTS: The brace was applied a mean 6 months (median, 5 months) after onset of symptoms. Mean duration of brace use was 10 months for 12 hours per day. Winging of the scapula, measured in 90 degrees flexion without resistance, disappeared in 35 patients (64%) with brace use. Flexion averaged 153 degrees and abduction 168 degrees . Ten patients (18%) were pain-free during exertion and 18 (33%) at rest. Pain at rest was present in 37 patients (67%); of those, it was present only seldom in 15 (27%), sometimes present in 21 (38%), and one patient (2%) experienced continuous pain at rest despite brace treatment. With the number of patients available, there were no differences between patients who started brace treatment early (within 6 months of onset of symptoms) and those who started later (more than 6 months after symptom onset) in terms of improvement of scapular winging in flexion at 90 degrees with resistance (mean, 1.2+/-2.0 cm vs 1.7+/-2.3 cm; p=0.415; 95% CI, 1.6 to 0.7), better flexion (mean, 156 degrees +/-17 degrees flexion vs 149 degrees +/-28 degrees flexion; p<0.253; 95% CI, -5 to 19), or improvement in other parameters that we measured. CONCLUSIONS: Compliance was high for scapular protecting brace treatment in patients with serratus palsy but recovery was incomplete for many patients, most of whom still had some pain and a large proportion still had some degree of scapular winging. We continue to use scapular bracing for treating patients who have 3 cm or more scapular winging and limited ROM, and whose work or hobbies demand motions causing winging, although we counsel our patients that recovery is likely to be incomplete. LEVEL OF EVIDENCE: Level IV, therapeutic study. PMID- 25910776 TI - Editorial Comment: Symposium: 2014 Musculoskeletal Infection Society. PMID- 25910777 TI - Surgical Treatment of Hip Instability in Patients With Lower Lumbar Level Myelomeningocele: Is Muscle Transfer Required? AB - BACKGROUND: Treatment of hip instability in patients with lower lumbar level myelomeningocele is clinically challenging. Muscle transfer procedures, release of contractures, and intertrochanteric varus-rotation osteotomies have been described to restore weak or absent abductor strength as well as relocation of the hip. However, controlled trials evaluating hip instability in lower lumbar myelomeningocele are limited in the current literature. QUESTIONS/PURPOSES: The purposes of this study were to compare the (1) radiographic evidence for joint stability; (2) clinical outcomes (including abductor strength, ambulatory ability, and residual use of orthoses); and (3) complications between patients undergoing combined periarticular contracture releases and bony procedures with and without external oblique abdominal muscle transfers. METHODS: Between 2004 and 2013, 14 pediatric patients (16 hips) were treated for hip instability secondary to myelomeningocele using releases with or without muscle transfer. From those, 13 patients (15 hips) with a mean age of 6 years who had L3 to L5 level involvement were evaluated retrospectively. The patients were separated into two groups. Nine hips (in eight patients) were treated by performing a combination of external oblique abdominal muscle transfer to the greater trochanter, periarticular release of contractures, and bony procedures. These were compared with six hips (five patients) treated by performing a combination of periarticular release of contractures and bony procedures without external oblique abdominal muscle transfer. This study compared the results between two surgeons, one of whom always performed these muscle transfers in this setting and the other who never performed muscle transfer during the study period. The patients were clinically followed up at a mean of 41 months (range, 14-122 months); none of the patients was lost to followup. Radiographic evaluation criteria included Reimer's migration index, acetabular index, femoral neck-shaft angle, pelvic obliquity, and the presence of scoliosis. Clinical evaluation included muscle strength examination, periarticular contractures, necessity for using orthoses as walking aids, and Hoffer criteria of mobility. All complications were also noted from a chart review. RESULTS: There were no differences between the two groups regarding postoperative femoral head localization, reflecting the presence or absence of residual subluxation, according to Reimer's index (Reimer's index = 32%; range, 10%-40%, in the muscle transfer group compared with 27%; range, 15%-43%, in the no-transfer group at latest followup; p = 0.723). Postoperatively, abductor strength improved in the group treated with external oblique transfer compared with the group treated without muscle transfer (median improvement of 2 versus 0, p = 0.02), but this improvement neither resulted in a clinically important difference in Hoffer criteria of mobility (no change was detected in either group) nor decreased the need for use of an orthosis (no change was detected in either group). With the numbers available, there was no difference with respect to complications between the two groups (two complications versus one). CONCLUSIONS: External oblique abdominal muscle transfer did not provide a clinically important improvement in functional recovery when compared with patients with L3 to L5 myelomeningocele and hip instability who were treated without it. We therefore do not recommend a routine muscle transfer procedure during the operative management of hip instability in patients with lower lumbar level myelomeningocele. LEVEL OF EVIDENCE: Level III, therapeutic study. PMID- 25910778 TI - Editor's Spotlight/Take 5: Addition of Vancomycin to Cefazolin Prophylaxis Is Associated With Acute Kidney Injury After Primary Joint Arthroplasty. PMID- 25910779 TI - Acetate templating on digital images is more accurate than computer-based templating for total hip arthroplasty. AB - BACKGROUND: Templating is an important aspect of preoperative planning for total hip arthroplasty and can help determine the size and positioning of the prosthesis. Historically, templating has been performed using acetate templates over printed radiographs. As a result of the increasing use of digital imaging, surgeons now either obtain additional printed radiographs solely for templating purposes or use specialized digital templating software, both of which carry additional cost. QUESTIONS/PURPOSES: The purposes of this study was to compare acetate templating of digitally calibrated images on an LCD monitor to digital templating in terms of (1) accuracy; (2) reproducibility; and (3) time efficiency. METHODS: Acetate onlay templating was performed directly over digital radiographs on an LCD monitor and was compared with digital templating. Five separate observers participated in this study templating on 52 total hip arthroplasties. For the acetate templating, the digital images were magnified to the scaled reference on the templates provided by the manufacturer (ratio 1.2:1) before templating using a 25-mm marker as a reference. Both the acetate and digital templating results were then compared with the actual implanted components to determine accuracy. Interobserver and intraobserver variability was determined by an intraclass correlation coefficient. Observers recorded time to complete templating from the time of complete upload of patients' imaging onto the system to completion of templating. RESULTS: Both acetate and digital templates demonstrated moderate accuracy in predicting within one size of the eventual implanted acetabular cup (77% [199 of 260]; 70% [181 of 260], respectively; p = 0.050; 95% confidence interval [CI], 0.058-0.32), whereas acetate templating was better at predicting the femoral stem compared to digital templating (75% [195 of 260]; 60% [155 of 260], respectively; p < 0.001; 95% CI, 0.084-0.32). Acetate templating showed moderate to substantial interobserver agreement (cup intraclass correlation coefficient [ICC] = 0.55; 95% CI, 0.14 0.86; femoral ICC = 0.75; 95% CI, 0.39-0.95) and both methods showed almost perfect intraobserver agreement in reproducibility (acetate cup ICC = 0.82; 95% CI, 0.66-0.97; acetate femoral ICC = 0.86; 95% CI, 0.74-0.97; digital cup ICC = 0.82; 95% CI, 0.68-0.97; digital femoral ICC = 0.88; 95% CI, 0.77-1.0). Acetate templating could be performed more quickly (acetate mean 119 seconds; range, 37 220 seconds versus 154 seconds; range, 73-343 seconds; p < 0.001). CONCLUSIONS: Acetate onlay templating on digitally calibrated images can be a reliable substitute for digital templating using specialized software. It is quicker to perform and much less expensive. Hospitals and practices need not purchase expensive software, particularly at lower volume centers. LEVEL OF EVIDENCE: Level III, diagnostic study. PMID- 25910780 TI - Deltoid Tuberosity Index: A Simple Radiographic Tool to Assess Local Bone Quality in Proximal Humerus Fractures. AB - BACKGROUND: Osteoporosis may complicate surgical fixation and healing of proximal humerus fractures and should be assessed preoperatively. Peripheral quantitative CT (pQCT) and the Tingart measurement are helpful methods, but both have limitations in clinical use because of limited availability (pQCT) or fracture lines crossing the area of interest (Tingart measurement). The aim of our study was to introduce and validate a simple cortical index to assess the quality of bone in proximal humerus fractures using AP radiographs. QUESTIONS/PURPOSES: We asked: (1) How do the deltoid tuberosity index and Tingart measurement correlate with each other, with patient age, and local bone mineral density (BMD) of the humeral head, measured by pQCT? (2) Which threshold values for the deltoid tuberosity index and Tingart measurement optimally discriminate poor local bone quality of the proximal humerus? (3) Are the deltoid tuberosity index and Tingart measurement clinically applicable and reproducible in patients with proximal humerus fractures? METHODS: The deltoid tuberosity index was measured immediately above the upper end of the deltoid tuberosity. At this position, where the outer cortical borders become parallel, the deltoid tuberosity index equals the ratio between the outer cortical and inner endosteal diameter. In the first part of our study, we retrospectively measured the deltoid tuberosity index on 31 patients (16 women, 15 men; mean age, 65 years; range, 22-83 years) who were scheduled for elective surgery other than fracture repair. Inclusion criteria were available native pQCT scans, AP shoulder radiographs taken in internal rotation, and no previous shoulder surgery. The deltoid tuberosity index and the Tingart measurement were measured on the preoperative internal rotation AP radiograph. The second part of our study was performed by reviewing 40 radiographs of patients with proximal humerus fractures (31 women, nine men; median age, 65 years; range, 22-88 years). Interrater (two surgeons) and intrarater (two readings) reliabilities, applicability, and diagnostic accuracy were assessed. RESULTS: The correlations between radiograph measurements and local BMD (pQCT) were strong for the deltoid tuberosity index (r = 0.80; 95% CI, 0.63-0.90; p < 0.001) and moderate for the Tingart measurement (r = 0.67; 95% CI, 0.42-0.83; p < 0.001). There was moderate correlation between patient age and the deltoid tuberosity index (r = 0.65; p < 0.001), patient age and the Tingart measurement (r = 0.69; p < 0.001), and patient age and pQCT (r = 0.73; p < 0.001). The correlation between the deltoid tuberosity index and the Tingart measurement was strong (r = 0.84; p < 0.001). We determined the cutoff value for the deltoid tuberosity index to be 1.44, with the area under the curve = 0.87 (95% CI, 0.74 0.99). This provided a sensitivity of 0.88 and specificity of 0.80. For the Tingart measurement, we determined the cutoff value to be 5.3 mm, with the area under the curve = 0.83 (95% CI, 0.67-0.98), which resulted in a sensitivity of 0.81 and specificity of 0.85. The intraobserver reliability was high and not different between the Tingart measurement (intraclass correlation coefficients [ICC] = 0.75 and 0.88) and deltoid tuberosity index (ICC = 0.88 and 0.82). However, interobserver reliability was higher for the deltoid tuberosity index (ICC = 0.96; 95% CI, 0.93-0.98) than for the Tingart measurement (ICC = 0.85; 95% CI, 0.69-0.93).The clinical applicability on AP radiographs of fractures was better for the deltoid tuberosity index (p = 0.025) because it was measureable on more of the radiographs (77/80; 96%) than the Tingart measurement (69/80; 86%). CONCLUSIONS: The deltoid tuberosity index correlated strongly with local BMD measured on pQCT and our study evidence shows that it is a reliable, simple, and applicable tool to assess local bone quality in the proximal humerus. We found that deltoid tuberosity index values consistently lower than 1.4 indicated low local BMD of the proximal humerus. Furthermore, the use of the deltoid tuberosity index has important advantages over the Tingart measurement regarding clinical applicability in patients with proximal humerus fractures, when fracture lines obscure the Tingart measurement landmarks. However, further studies are needed to assess the effect of the deltoid tuberosity index measurement and osteoporosis on treatment and outcome in patients with proximal humerus fractures. LEVEL OF EVIDENCE: Level IV, diagnostic study. PMID- 25910781 TI - Approach to Investigating Congenital Skeletal Abnormalities in Livestock. AB - Congenital skeletal abnormalities may be genetic, teratogenic, or nutritional in origin; distinguishing among these different causes is essential in the management of the disease but may be challenging. In some cases, teratogenic or nutritional causes of skeletal abnormalities may appear very similar to genetic causes. For example, chondrodysplasia associated with intrauterine zinc or manganese deficiency and mild forms of hereditary chondrodysplasia have very similar clinical features and histologic lesions. Therefore, historical data are essential in any attempt to distinguish genetic and acquired causes of skeletal lesions; as many animals as possible should be examined; and samples should be collected for future analysis, such as genetic testing. Acquired causes of defects often show substantial variation in presentation and may improve with time, while genetic causes frequently have a consistent presentation. If a disease is determined to be of genetic origin, a number of approaches may be used to detect mutations, each with advantages and disadvantages. These approaches include sequencing candidate genes, single-nucleotide polymorphism array with genomewide association studies, and exome or whole genome sequencing. Despite advances in technology and increased cost-effectiveness of these techniques, a good clinical history and description of the pathology and a reliable diagnosis are still key components of any investigation. PMID- 25910783 TI - Aerobic fitness is associated with inhibitory control in persons with multiple sclerosis. AB - Cognitive impairment is highly prevalent, disabling, and poorly managed in persons with multiple sclerosis (MS). Aerobic fitness might be a target of exercise training interventions for improving cognition in this population. It is unknown if the well-established pattern of associations between higher aerobic fitness and better inhibitory control in the general population exists among persons with MS. The current cross-sectional study examined the effects of aerobic fitness (VO2peak) on inhibitory control, using a modified flanker task, in 28 persons with MS and 28 healthy controls matched by age, sex, and body mass index. This involved performing bivariate correlations and hierarchical linear regression analyses on measures of aerobic fitness and inhibitory control. Persons with MS demonstrated lower VO2peak (d = -0.45), slower (d = 0.62-0.84), and less accurate (d = -0.60 to 0.71) performance on the flanker task than controls. VO2peak was similarly associated with reaction time measures of inhibitory control in the MS and control samples (rho = -0.40 to 0.54). VO2peak (p < .01), but not group (p >= .08) (MS vs. control), predicted reaction time on the flanker task, irrespective of age, sex, and education. This supports the development of aerobic exercise interventions for improving reaction time on tasks of inhibitory control in persons with MS, much like what has been successfully undertaken in the general population. PMID- 25910782 TI - Targeting breast to brain metastatic tumours with death receptor ligand expressing therapeutic stem cells. AB - Characterizing clinically relevant brain metastasis models and assessing the therapeutic efficacy in such models are fundamental for the development of novel therapies for metastatic brain cancers. In this study, we have developed an in vivo imageable breast-to-brain metastasis mouse model. Using real time in vivo imaging and subsequent composite fluorescence imaging, we show a widespread distribution of micro- and macro-metastasis in different stages of metastatic progression. We also show extravasation of tumour cells and the close association of tumour cells with blood vessels in the brain thus mimicking the multi-foci metastases observed in the clinics. Next, we explored the ability of engineered adult stem cells to track metastatic deposits in this model and show that engineered stem cells either implanted or injected via circulation efficiently home to metastatic tumour deposits in the brain. Based on the recent findings that metastatic tumour cells adopt unique mechanisms of evading apoptosis to successfully colonize in the brain, we reasoned that TNF receptor superfamily member 10A/10B apoptosis-inducing ligand (TRAIL) based pro-apoptotic therapies that induce death receptor signalling within the metastatic tumour cells might be a favourable therapeutic approach. We engineered stem cells to express a tumour selective, potent and secretable variant of a TRAIL, S-TRAIL, and show that these cells significantly suppressed metastatic tumour growth and prolonged the survival of mice bearing metastatic breast tumours. Furthermore, the incorporation of pro-drug converting enzyme, herpes simplex virus thymidine kinase, into therapeutic S-TRAIL secreting stem cells allowed their eradication post-tumour treatment. These studies are the first of their kind that provide insight into targeting brain metastasis with stem-cell mediated delivery of pro apoptotic ligands and have important clinical implications. PMID- 25910784 TI - Radiographic Outcomes of a Mobile-Bearing Total Ankle Replacement. AB - BACKGROUND: Contemporary total ankle prostheses embody design changes intended to address weaknesses in first-generation implants. Due to these changes, outcomes of the newer designs are of particular interest. We have previously published self-reported patient outcomes for the STAR (Scandinavian Total Ankle Replacement) prosthesis. The present study documents radiographic outcome measurements for the STAR prosthesis at intermediate to long-term follow-up. METHODS: Of 89 consecutive ankle replacements performed between July 1998 and April 2007, 79 had a minimum follow-up of 2 years and were followed prospectively. Serial radiographs were measured by 2 of the authors, including varus, valgus, alpha, beta, and gamma angles, as well as point contact ratio. Inter- and intrarater reliability was calculated and reported. A "severe" subgroup of patients with preoperative coronal plane deformity exceeding 10 degrees was assessed separately. Preoperative and immediate postoperative measurements were compared and maintenance of correction evaluated on subsequent radiographs. Heterotopic ossification and pericomponent lucency were documented and followed, and subsequent procedures were recorded to follow survivorship. The mean follow-up was 8.0 years. RESULTS: Of the 79 ankles, 25 underwent a secondary surgery (31.6%). Coronal correction averaged 5.1 degrees (P < .001), and this was maintained to final follow-up. The severe subgroup (n = 21), with a mean preoperative coronal angulation of 16.1 degrees, was corrected to 4.6 degrees at final follow-up (P < .001). The severe subgroup had a higher secondary surgery rate at 33.3%, with metallic component revision or failure occurring in 3 cases (14.3%) compared to 8 (10.1%) in the entire cohort. The heterotopic ossification rate was 100%, slightly higher than prior reports. CONCLUSIONS: STAR prosthesis survivorship was similar to that documented in prior studies of second-generation implants in European patient cohorts. Statistically significant correction in coronal alignment was achieved immediately after surgery and maintained until a final mean follow-up of 8 years, even in patients with preoperative deformity greater than 10 degrees. LEVEL OF EVIDENCE: Level III, retrospective cohort study. PMID- 25910785 TI - Phlegmasia Cerulea Dolens: A Rare Clinical Presentation. PMID- 25910786 TI - Outcomes of acute myocardial infarction in patients with hypertrophic cardiomyopathy. AB - BACKGROUND: Acute myocardial infarction is a recognized complication in patients with hypertrophic cardiomyopathy. However, limited data are available on outcomes of patients with hypertrophic cardiomyopathy and acute myocardial infarction. METHODS: We analyzed the 2003-2011 Nationwide Inpatient Sample databases to identify all patients aged >=18 years with a principal diagnosis of acute myocardial infarction. Patients with a concomitant diagnosis of hypertrophic cardiomyopathy were then identified and analyzed as a separate cohort. Multivariate logistic regression was used to compare outcomes in patients with acute myocardial infarction with and without hypertrophic cardiomyopathy. RESULTS: Of 5,901,827 patients with acute myocardial infarction, 5688 (0.1%) had a diagnosis of hypertrophic cardiomyopathy. Patients with hypertrophic cardiomyopathy were older, more likely to be female, and less likely to have traditional cardiovascular risk factors. Compared with patients without hypertrophic cardiomyopathy, patients with hypertrophic cardiomyopathy were less likely to present with ST-elevation myocardial infarction and more likely to present with non-ST-elevation myocardial infarction. Patients with hypertrophic cardiomyopathy with ST-elevation myocardial infarction or non-ST-elevation myocardial infarction were less likely to receive revascularization. In the overall population with acute myocardial infarction, there was no difference in risk-adjusted in-hospital mortality between patients with and without hypertrophic cardiomyopathy (odds ratio [OR], 0.96; 95% confidence interval [CI], 0.84-1.11; P = .59). In the population with ST-elevation myocardial infarction, patients with hypertrophic cardiomyopathy had lower risk-adjusted in-hospital mortality than those without hypertrophic cardiomyopathy (OR, 0.75; 95% CI, 0.63 0.91; P = .003), whereas in the population with non-ST-elevation myocardial infarction, there was no difference in risk-adjusted in-hospital mortality between patients with and without hypertrophic cardiomyopathy (OR, 0.97; 95% CI, 0.84-1.11; P = .63). CONCLUSIONS: Patients with hypertrophic cardiomyopathy represent a small proportion of patients with acute myocardial infarction and are less likely to receive revascularization. Compared with patients without hypertrophic cardiomyopathy, patients with hypertrophic cardiomyopathy with ST elevation myocardial infarction have lower risk-adjusted in-hospital mortality. PMID- 25910787 TI - Visualization of Coronary Artery Calcification: Influence on Risk Modification. AB - OBJECTIVES: Direct health provider to patient presentation of coronary computed tomography angiography findings may increase adherence to preventive therapy and risk modification. The purpose of this study was to assess the influence of visualization of coronary artery calcification and lifestyle recommendations on cholesterol concentrations and other risk variables in symptomatic patients with nonobstructive coronary artery disease and hyperlipidemia. METHODS: We performed a prospective 2-center randomized controlled trial. Patients were randomized 1:1 to intervention or standard follow-up in general practice. The primary end point was change in plasma total cholesterol concentration at 6 months follow-up. RESULTS: We included 189 patients (mean [+/- standard deviation] age 61 [12] years, 57% were male). Median (range) Agatston score was 166 (70-2054). The reduction in plasma total cholesterol concentrations tended to be higher in the intervention group than in the control group, 51.04 mg/dL versus 45.63 mg/dL (P = .181). In a subgroup including patients continuing statin therapy during follow up (n = 147), the reduction in plasma total cholesterol concentrations was more pronounced in the intervention group than in the control group, 66.13 mg/dL versus 55.68 mg/dL (P = .027). In the intervention group, there was a higher degree of statin adherence and a higher proportion of patients who stopped smoking and commenced healthier dietary behavior than in the control group. CONCLUSIONS: Visualization of coronary artery calcification and brief recommendations about risk modification after coronary computed tomography angiography in symptomatic patients with nonobstructive coronary artery disease and hyperlipidemia may have a favorable influence on plasma total cholesterol concentration, adherence to statin therapy, and risk behavior. Further investigations are needed. PMID- 25910788 TI - Pinch Purpura: A Cutaneous Manifestation of Systemic Amyloidosis. PMID- 25910789 TI - Fever and Back Pain with Abdominal Aorta Tenderness: Takayasu Arteritis. PMID- 25910790 TI - Net Clinical Benefit of Non-vitamin K Antagonist Oral Anticoagulants Versus Warfarin in Phase III Atrial Fibrillation Trials. AB - OBJECTIVES: The evaluation of the "net clinical benefit" allows an integrated assessment of both the anti-ischemic and the prohemorrhagic effects of non vitamin K antagonist oral anticoagulants compared with warfarin, and-in the absence of direct comparisons-may inform clinical decisions. We estimated the net clinical benefit of non-vitamin K antagonist oral anticoagulants versus warfarin across the 4 phase III clinical trials performed in patients with atrial fibrillation. METHODS: We considered various composites of the main ischemic and hemorrhagic events, estimating the rate ratio of all treatment groups versus warfarin for each composite outcome. Because the clinical relevance of the various ischemic or hemorrhagic events is not identical, we then attributed to each of them a weight, according to its impact on death, as derived from previous studies. We evaluated a weighed net clinical benefit of each non-vitamin K antagonist oral anticoagulant compared with warfarin in the 4 trials. RESULTS: The composite outcome of ischemic + hemorrhagic stroke was reduced by dabigatran 150 mg and apixaban. The composite of disabling stroke + life-threatening bleeding was reduced by all non-vitamin K antagonist oral anticoagulants. The composite of ischemic stroke + systemic embolism + myocardial infarction + hemorrhagic stroke + major bleeding was reduced by apixaban and edoxaban at both doses. By attributing weights to these events according to their impact on mortality, all non-vitamin K antagonist oral anticoagulants featured a favorable net clinical benefit compared with warfarin, albeit to a quantitatively different extent. CONCLUSIONS: The choice of the proper antithrombotic treatment in patients with atrial fibrillation has to consider the net clinical benefit of each drug. However, all non-vitamin K antagonist oral anticoagulants have a better efficacy/safety profile than warfarin in patients with atrial fibrillation. PMID- 25910791 TI - Medically unexplained neurologic symptoms: a primer for physicians who make the initial encounter. AB - Medically unexplained symptoms are ubiquitous in clinical practice. Medical use costs of medically unexplained symptoms are projected at approximately $256 billion per year. When initially seen, these symptoms are often baffling, not only to the patients but also to the physicians who encounter them. Because of this, properly diagnosing them is seen generally as difficult at best, leading to massive overuse of unnecessary testing. Subsequently, their management can be cumbersome. All this burdens the patients with unnecessary costs, financially and emotionally. This primer discusses historical perspectives of these and the changing nomenclature, and outlines how to think about these complex symptoms and neurologic findings that will enable a positive diagnosis rather than a diagnosis of exclusion. We also offer useful heuristic principles of their management so that physician-patient relationships can be better maintained and the quality of life of these patients can be improved by way of some simple, economic approaches. PMID- 25910792 TI - Fatal water intoxication and cardiac arrest in runners during marathons: prevention and treatment based on validated clinical paradigms. AB - Cerebral edema due to exercise-associated hyponatremia and cardiac arrest due to atherosclerotic heart disease cause rare marathon-related fatalities in young female and middle-aged male runners, respectively. Studies in asymptomatic middle aged male physician-runners during races identified inflammation due to skeletal muscle injury after glycogen depletion as the shared underlying cause. Nonosmotic secretion of arginine vasopressin as a neuroendocrine stress response to rhabdomyolysis mediates hyponatremia as a variant of the syndrome of inappropriate antidiuretic hormone secretion. Fatal hyponatremic encephalopathy in young female runners was curtailed using emergent infusion of intravenous hypertonic (3%) saline to reverse cerebral edema on the basis of this paradigm. This treatment was arrived at through a consensus process within the medical community. An increasing frequency of cardiac arrest and sudden death has been identified in middle-aged male runners in 2 studies since the year 2000. Same aged asymptomatic male physician-runners showed post-race elevations in interleukin-6 and C-reactive protein, biomarkers that predict acute cardiac events in healthy persons. Hypercoagulability with in vivo platelet activation and release of cardiac troponin and N-terminal pro-brain natriuretic peptide were also observed post-race in these same subjects. High short-term risk for atherothrombosis during races as shown by stratification of biomarkers in asymptomatic men may render nonobstructive coronary atherosclerotic plaques vulnerable to rupture. Pre-race aspirin use in this high-risk subgroup is prudent according to conclusive evidence for preventing first acute myocardial infarctions in same-aged healthy male physicians. On the basis of validated clinical paradigms, taking a low-dose aspirin before a marathon and drinking to thirst during the race may avert preventable deaths in susceptible runners. PMID- 25910794 TI - Quantitative analysis of post-translational modifications in human serum transthyretin associated with familial amyloidotic polyneuropathy by targeted LC MS and intact protein MS. AB - Transthyretin (TTR) is an amyloidogenic tetrameric protein, present in human plasma, associated with several familial amyloidoses. Variability of TTR is not only due to point mutations in the encoding gene but also to post-translational modifications (PTMs) at Cys10, being the most common PTMs the S-sulfonation, S glycinylcysteinylation, S-cysteinylation and S-glutathionylation. It is thought that PTMs at Cys10 may play an important biological role in the onset and pathological process of the amyloidosis. We report here the development of a methodology for quantification of PTMs in serum samples, as well as for the determination of serum TTR levels, from healthy (wt) and TTR-amyloidotic (V30M mutation) individuals. It involves an enrichment step by immunoprecipitation followed by mass spectrometry analysis of (i) the intact TTR protein and (ii) targeted LC-MS analysis of peptides carrying the PTMs of interest. Analysis of serum samples by the combination of the two methods affords complementary information on the relative and absolute amounts of the selected TTR PTM forms. It is shown that methods based on intact protein are biased for specific PTMs since they assume constant response factors, whereas the novel targeted LC-MS method provides absolute quantification of PTMs and total TTR variants. BIOLOGICAL SIGNIFICANCE: The study of TTR has a high clinical relevance since it is responsible for diverse familial polyneuropathies. In particular, more than 80 point mutations have been described through genetic studies. However, genetic heterogeneity alone fails to explain the diverse onset and pathological process of the TTR related amyloidosis. The use of proteomic characterization is required to gather information about the PTMs variants present in serum, which have been suggested to be relevant for the amyloidotic pathology. This article is part of a Special Issue entitled: HUPO 2014. PMID- 25910793 TI - [Item 167 - UE 6 Skin ectoparasitosis: scabies and pediculosis]. PMID- 25910795 TI - Ultrasound classification of solitary renal cysts in children. AB - INTRODUCTION: Solitary renal cysts are typically incidentally found in children who have undergone renal ultrasound (US). The main concern is a cystic tumor. There is no US-based grading system for children to guide management. OBJECTIVE: To evaluate a US-based, modified Bosniak grading system in order to differentiate between simple (grade I or II) and complex (grade II or IV) renal cysts and guide management in children. STUDY DESIGN: This was a retrospective (2003-2011) study of 212 children (114 females), age range one day to 17 years (mean 8.4 years), with solitary renal cysts diagnosed by US. Two radiologists, who were independent and blinded to clinical information, graded the cysts using the modified Bosniak classification system. In children with more than one year of follow-up US, the change (>10%) in cyst diameter was evaluated. Inter-observer variability (Kappa) was calculated. RESULTS: Radiologists one and two saw simple renal cysts in 96.2 96.6% (204-205/212) of the children. Ten children had complex renal cysts, as rated by either of the radiologists. There was good inter-observer agreement (kappa = 0.65) for simple versus complex cysts. In 20.2% (18/89) of the children, the cysts increased in size. A definitive diagnosis was obtained in 8.5% (18/212) of the children. A cystic tumor (multilocular cystic nephroma) was found in one child (Figure) with a complex cyst (graded III by both radiologists). DISCUSSION: The use of a modified Bosniak classification system to grade renal cysts was found to have good inter-observer variability (kappa = 0.65) in differentiating between simple and complex renal cysts. Using this classification, few (<4%) renal cysts were classified as complex. Cystic tumors are rare and the only cystic tumor (multilocular cystic nephroma) was classified as complex renal cysts by the two radiologists. Growth of simple, solitary renal cyst is common (20.2%) and, therefore, if not associated with other imaging findings, is not an indication for a cystic tumor. There were limitations inherent in the retrospective nature of the study and because only one child had a cystic tumor. CONCLUSION: The modified Bosniak classification system demonstrated good inter observer agreement, and identified the single tumor as a complex cyst. The vast majority of solitary renal cysts in children are simple and if asymptomatic, they require no other imaging evaluation. Complex renal cysts are uncommon and should be evaluated with a pre-intravenous and postintravenous contrast CT scan to exclude a tumor. PMID- 25910796 TI - Accuracy of orchidometry in boys with varicocele. AB - INTRODUCTION: Orchidometric evaluation of the testis has been proposed as a cost effective alternative to measurement of the testis with high-frequency linear ultrasound, which may be costly in terms of hospital resources and patient time. It is known from animal experiments, autopsy series, and small clinical studies that, under ideal conditions, orchidometry may approximate ultrasound measurement. However, little is known of the effectiveness of orchidometry in the clinical setting in a large sample of adolescents with varicocele. OBJECTIVE: We sought to analyze the performance characteristics of Rochester orchidometry and its agreement with ultrasound testis volumes in boys with varicocele. STUDY DESIGN: Our institutional varicocele database was analyzed from March 2000 to May 2013, including all boys with Rochester orchidometric measurement and ultrasound based volume measurement performed on the same day. The Lambert formula (L*W*H*0.71) was used to calculate ultrasound volumes. Seven-hundred and twenty measurements were included: 360 of the left testis, and 360 of the right testis. Each subject was included once; in the event of serial measurements the earliest measurement was analyzed. Bland-Altman plots with 95% limits of agreement were used to compare orchidometry and ultrasound measurements. Analysis was performed with JMP, v11 Pro. RESULTS: Age at exam ranged from 11.2 to 18.5 years (median 15.8). With respect to varicocele grade, 183 (50.8%) were grade III, 113 (31.4%) were grade II, 42 (11.7%) were grade I, 12 (0.3%) were bilateral, and 10 (0.3%) were ungraded. Mean ultrasound left testis volume was 13.6 cc (SD 6.6) and mean right testis volume was 15.1 cc (SD 6.9). Eleven surgeons performed the orchidometric measurements; one surgeon performed 71% of the exams. Mean overestimation on the right was 2.0 cc (SD 4.2) and on the left was 1.9 cc (SD 4.1); each was highly statistically significant (p < 0.0001, paired t test). Error was correlated with testis size, implying a greater degree of overestimation with increasing volume (p < 0.01, Pearson's correlation 0.09). Amount of volume overestimation and variability was not significantly different for right and left testis. Sensitivity and specificity of Rochester orchidometry to detect a testis volume differential (TVD) of 20% were 33% (95% CI 23-42%) and 96% (95% CI 92-97%), respectively. Testis size, varicocele grade, or examining surgeon had no effect on sensitivity or specificity. DISCUSSION: We have shown in a large series of boys with adolescent varicocele that in clinical practice there is a modest degree of overestimation of testis volume on average (1.9-2.0 cc), although there is a large range of volume estimation, such that the 95% confidence interval ranges are quite wide, from approximately 6 cc lower than the true volume to 10 cc greater than the true volume. Furthermore, the low sensitivity (33%) of orchidometry for 20% testis volume differential renders this a suboptimal screening tool for this clinical parameter, which has been shown to be associated with semen analysis outcomes. Knowledge of the performance characteristics of orchidometry is similarly important for research, as factors such as the prevalence of testis volume differential are then dependent on the modality of measurement. Lastly, that this was conducted over a long time course with several surgeons involved suggests that these data reflect real-world application of orchidometry. CONCLUSIONS: Appropriate caution should be exercised when relying solely on orchidometric evaluation of the testis. Rochester orchidometry in general appears to overestimate testis size, and there is wide variability in the estimation. In clinical practice, the sensitivity of Rochester orchidometry is modest in detecting a 20% testis volume differential; this difference would be missed in approximately two out of three of boys screened with orchidometry alone. PMID- 25910797 TI - Sutureless circumcision using 2-Octyl cyanoacrylate results in more rapid and less painful procedures with excellent cosmetic satisfaction. AB - INTRODUCTION: Circumcision is the most common surgical procedure in male children in the world and is performed because of cultural, religious or medical reasons. Traditionally, interrupted sutures are used to close the wound, but 2-Octyl cyanoacrylate (2-OCA) tissue glue can be used as an alternative method to close the circumcision wound. OBJECTIVES: To compare the use of 2-OCA with absorbable sutures in circumcision wound closure in prepubescent patients in terms of operative time, complication rate, postoperative pain and cosmetic results. STUDY DESIGN: We retrospectively evaluated 662 circumcision procedures using sutures and 609 procedures using 2-OCA for wound closure in prepubescent boys. All circumcision procedures were performed by 2 surgeons in a single centre. Operative time was collected from the hospital surgical software system. 62% of the patients in the suture group and 59% of the patients in the 2-OCA group presented for a postoperative check-up 6 weeks after the circumcision. Data regarding postoperative pain, need for analgesia, cosmetic satisfaction and the ease of wound care were collected through questionnaires completed by 25% of the boy's parents in the suture group and 53% of the parents in the 2-OCA group. RESULTS: Mean operative time was significantly shorter in the 2-OCA group (13 min) than in the suture group (17 min). Complications were comparable and mostly minor. Reintervention was only required in 3 cases. According to the parents, the degree of postoperative pain and the postoperative need for analgesics was significantly lower in the 2-OCA group. Wounds closed with 2-OCA were easier to care for. The cosmetic results after 1 day, after 1 week and after 1 month in the 2-OCA group were significantly superior than in the suture group, according to the parents' evaluation. DISCUSSION: The use of 2-OCA in circumcision wound closure has been reported before. Previous studies with mainly limited patient numbers report less pain, shorter procedure times and a higher surgeon satisfaction in terms of cosmetic results. This study is the largest study comparing the use of 2-OCA and interrupted sutures in circumcision wound closure. The retrospective character of the study, the lack of a validated questionnaire tool for the cosmetic evaluation and the use of the parent's evaluation are the limitations of this study. CONCLUSION: The use of 2-OCA in circumcision wound closure results in a shorter operative time, in less postoperative pain, in easy postoperative wound care and in excellent cosmesis when compared to interrupted absorbable sutures. 2-OCA is our current technique of choice in circumcision wound closure. PMID- 25910798 TI - Advances in phage display technology for drug discovery. AB - INTRODUCTION: Over the past decade, several library-based methods have been developed to discover ligands with strong binding affinities for their targets. These methods mimic the natural evolution for screening and identifying ligand target interactions with specific functional properties. Phage display technology is a well-established method that has been applied to many technological challenges including novel drug discovery. AREAS COVERED: This review describes the recent advances in the use of phage display technology for discovering novel bioactive compounds. Furthermore, it discusses the application of this technology to produce proteins and peptides as well as minimize the use of antibodies, such as antigen-binding fragment, single-chain fragment variable or single-domain antibody fragments like VHHs. EXPERT OPINION: Advances in screening, manufacturing and humanization technologies demonstrate that phage display derived products can play a significant role in the diagnosis and treatment of disease. The effects of this technology are inevitable in the development pipeline for bringing therapeutics into the market, and this number is expected to rise significantly in the future as new advances continue to take place in display methods. Furthermore, a widespread application of this methodology is predicted in different medical technological areas, including biosensing, monitoring, molecular imaging, gene therapy, vaccine development and nanotechnology. PMID- 25910799 TI - Endothelial Dimethylarginine Dimethylaminohydrolase 1 Is an Important Regulator of Angiogenesis but Does Not Regulate Vascular Reactivity or Hemodynamic Homeostasis. AB - BACKGROUND: Asymmetrical dimethylarginine (ADMA) is an endogenous inhibitor of nitric oxide synthesis and a risk factor for cardiovascular disease. Dimethylarginine dimethylaminohydrolase (DDAH) enzymes are responsible for ADMA breakdown. It has been reported that endothelial DDAH1 accounts for the majority of ADMA metabolism. However, we and others have shown strong DDAH1 expression in a range of nonendothelial cell types, suggesting that the endothelium is not the only site of metabolism. We have developed a new endothelium-specific DDAH1 knockout mouse (DDAH1(En-/-)) to investigate the significance of endothelial ADMA in cardiovascular homeostasis. METHODS AND RESULTS: DDAH1 deletion in the DDAH1(En-/-) mouse was mediated by Tie-2 driven Cre expression. DDAH1 deletion was confirmed through immunocytochemistry, whereas Western blotting showed that DDAH1 remained in the kidney and liver, confirming expression in nonendothelial cells. Plasma ADMA was unchanged in DDAH1(En-/-) mice, and cultured aortas released amounts of ADMA to similar to controls. Consistent with these observations, vasoreactivity ex vivo and hemodynamics in vivo were unaltered in DDAH1(En-/-) mice. In contrast, we observed significantly impaired angiogenic responses both ex vivo and in vivo. CONCLUSIONS: We demonstrate that endothelial DDAH1 is not a critical determinant of plasma ADMA, vascular reactivity, or hemodynamic homeostasis. DDAH1 is widely expressed in a range of vascular and nonvascular cell types; therefore, the additive effect of DDAH1 expression in multiple organ systems determines plasma ADMA concentrations. Endothelial deletion of DDAH1 profoundly impairs the angiogenic capacity of endothelial cells, indicating that intracellular ADMA is a critical determinant of endothelial cell response. PMID- 25910800 TI - Mass Screening for Untreated Atrial Fibrillation: The STROKESTOP Study. AB - BACKGROUND: The aims of the present study were to define the prevalence of untreated atrial fibrillation (AF) in a systematic screening program using intermittent ECG recordings among 75- to 76-year-old individuals and to study the feasibility of initiating protective oral anticoagulant (OAC) treatment. METHODS AND RESULTS: Half of the 75- to 76-year-old population in 2 Swedish regions were invited to a screening program for AF. Participants without a previous diagnosis of AF underwent intermittent ECG recordings over 2 weeks. If AF was detected, participants were offered OAC. During the 28-month inclusion period, 13 331 inhabitants were invited. Of these, 7173 (53.8%) participated. Of the participants, 218 (3.0%; 95% confidence interval [CI], 2.7-3.5) were found to have previously unknown AF, and of these, AF was found in 37 (0.5% of the screened population) on their first ECG. The use of intermittent ECGs increased new AF detection 4-fold. A previous diagnosis of AF was known in 9.3% (n=666; 95% CI, 8.6-10.0). Total AF prevalence in the screened population was 12.3%. Of participants with known AF, 149 (2.1%; 95% CI, 1.8-2.4) had no OAC treatment. In total, 5.1% (95% CI, 4.6-5.7) of the screened population had untreated AF; screening resulted in initiation of OAC treatment in 3.7% (95% CI, 3.3-4.2) of the screened population. More than 90% of the participants with previously undiagnosed AF accepted initiation of OAC treatment. CONCLUSIONS: Mass screening for AF in a 75- to 76-year-old population identifies a significant proportion of participants with untreated AF. Initiation of stroke prophylactic treatment was highly successful in individuals with newly diagnosed AF. CLINICAL TRIAL REGISTRATION: URL: http://www.clinicaltrials.gov. Unique identifier: NCT01593553. PMID- 25910801 TI - Sub-millimeter spine position monitoring for stereotactic body radiotherapy using offline digital tomosynthesis. AB - PURPOSE: Spine stereotactic radiotherapy (SBRT) requires intrafraction motion <1 2mm. We evaluated the accuracy and precision of digital tomosynthesis (DTS) in combination with triangulation for spine position tracking. MATERIALS/METHODS: Single-slice DTS images were generated from kV cone beam CT (CBCT) projection images. They were registered to reference DTS images reconstructed from the planning CT-scan to determine 2D shifts between actual patient position and treatment plan position. 3D spine position was obtained by triangulation of each registration with a previous registration, for every 1 degrees of data. For 7 patients who underwent spine SBRT, the standard deviation (SD) of DTS+triangulation over one entire dataset was evaluated for different DTS angles (2-16 degrees ) and triangulation angles (1-46 degrees ). For 32 CBCT datasets, acquired before or after treatment of the 7 patients, using 4 degrees DTS and 18 degrees triangulation angle, SDs were determined and average positions were compared to clinically performed CBCT registrations. RESULTS: Mean SDs were 0.29+/-0.10mm for lateral (range 0.1-0.55mm), 0.14+/-0.08 for longitudinal (0.05 0.39) and 0.24+/-0.10 for the vertical direction (0.10-0.57). Lateral and vertical SDs for thoracic spine were higher than for lumbar spine. Differences between clinical CBCT registration and DTS+triangulation were 0.1+/-0.26, 0.02+/ 0.33 and -0.07+/-0.21mm. CONCLUSION: The combination of DTS and triangulation allows for monitoring spine position with sub-mm accuracy and precision. PMID- 25910802 TI - Pyruvate modifies metabolic flux and nutrient sensing during extracorporeal membrane oxygenation in an immature swine model. AB - Extracorporeal membrane oxygenation (ECMO) provides mechanical circulatory support for infants and children with postoperative cardiopulmonary failure. Nutritional support is mandatory during ECMO although specific actions for substrates on the heart have not been delineated. Prior work shows that enhancing pyruvate oxidation promotes successful weaning from ECMO. Accordingly, we tested the hypothesis that prolonged systemic pyruvate supplementation activates pyruvate oxidation in an immature swine model in vivo. Twelve male mixed-breed Yorkshire piglets (age 30-49 days) received systemic infusion of either normal saline (group C) or pyruvate (group P) during the final 6 h of 8 h of ECMO. Over the final hour, piglets received [2-(13)C] pyruvate, as a reference substrate for oxidation, and [(13)C6]-l-leucine, as an indicator for amino acid oxidation and protein synthesis. A significant increase in lactate and pyruvate concentrations occurred, along with an increase in the absolute concentration of the citric acid cycle intermediates. An increase in anaplerotic flux through pyruvate carboxylation in group P occurred compared with no change in pyruvate oxidation. Additionally, pyruvate promoted an increase in the phosphorylation state of several nutrient-sensitive enzymes, like AMP-activated protein kinase and acetyl CoA carboxylase, suggesting activation for fatty acid oxidation. Pyruvate also promoted O-GlcNAcylation through the hexosamine biosynthetic pathway. In conclusion, although prolonged pyruvate supplementation did not alter pyruvate oxidation, it did elicit changes in nutrient- and energy-sensitive pathways. Therefore, the observed results support the further study of pyruvate and its downstream effect on cardiac function. PMID- 25910803 TI - OPC-28326, a selective peripheral vasodilator with angiogenic activity, mitigates postinfarction cardiac remodeling. AB - Although OPC-28326, 4-(N-methyl-2-phenylethylamino)-1-(3,5-dimethyl-4-propionyl aminobenzoyl) piperidine hydrochloride monohydrate, was developed as a selective peripheral vasodilator with alpha2-adrenergic antagonist properties, it also reportedly exhibits angiogenic activity in an ischemic leg model. The purpose of this study was to examine the effect of OPC-28326 on the architectural dynamics and function of the infarcted left ventricle during the chronic stage of myocardial infarction. Myocardial infarction was induced in male C3H/He mice, after which the mice were randomly assigned into two groups: a control group receiving a normal diet and an OPC group whose diet contained 0.05% OPC-28326. The survival rate among the mice (n = 18 in each group) 4 wk postinfarction was significantly greater in the OPC than control group (83 vs. 44%; P < 0.05), and left ventricular remodeling and dysfunction were significantly mitigated. Histologically, infarct wall thickness was significantly greater in the OPC group, due in part to an abundance of nonmyocyte components, including blood vessels and myofibroblasts. Five days postinfarction, Ki-67-positive proliferating cells were more abundant in the granulation tissue in the OPC group, and there were fewer apoptotic cells. These effects were accompanied by activation of myocardial Akt and endothelial nitric oxide synthase. Hypoxia within the infarct issue, assessed using pimonidazole staining, was markedly attenuated in the OPC group. In summary, OPC-28326 increased the nonmyocyte population in infarct tissue by increasing proliferation and reducing apoptosis, thereby altering the tissue dynamics such that wall stress was reduced, which might have contributed to a mitigation of postinfarction cardiac remodeling and dysfunction. PMID- 25910804 TI - Therapeutic potential of sustained-release sodium nitrite for critical limb ischemia in the setting of metabolic syndrome. AB - Nitrite is a storage reservoir of nitric oxide that is readily reduced to nitric oxide under pathological conditions. Previous studies have demonstrated that nitrite levels are significantly reduced in cardiovascular disease states, including peripheral vascular disease. We investigated the cytoprotective and proangiogenic actions of a novel, sustained-release formulation of nitrite (SR nitrite) in a clinically relevant in vivo swine model of critical limb ischemia (CLI) involving central obesity and metabolic syndrome. CLI was induced in obese Ossabaw swine (n = 18) by unilateral external iliac artery deployment of a full cross-sectional vessel occlusion device positioned within an endovascular expanded polytetrafluoroethylene-lined nitinol stent-graft. At post-CLI day 14, pigs were randomized to placebo (n = 9) or SR-nitrite (80 mg, n = 9) twice daily by mouth for 21 days. SR-nitrite therapy increased nitrite, nitrate, and S nitrosothiol in plasma and ischemic skeletal muscle. Oxidative stress was reduced in ischemic limb tissue of SR-nitrite- compared with placebo-treated pigs. Ischemic limb tissue levels of proangiogenic growth factors were increased following SR-nitrite therapy compared with placebo. Despite the increases in cytoprotective and angiogenic signals with SR-nitrite therapy, new arterial vessel formation and enhancement of blood flow to the ischemic limb were not different from placebo. Our data clearly demonstrate cytoprotective and proangiogenic signaling in ischemic tissues following SR-nitrite therapy in a very severe model of CLI. Further studies evaluating longer-duration nitrite therapy and/or additional nitrite dosing strategies are warranted to more fully evaluate the therapeutic potential of nitrite therapy in peripheral vascular disease. PMID- 25910805 TI - Regulation of myogenic tone and structure of parenchymal arterioles by hypertension and the mineralocorticoid receptor. AB - Proper perfusion is vital for maintenance of neuronal homeostasis and brain function. Changes in the function and structure of cerebral parenchymal arterioles (PAs) could impair blood flow regulation and increase the risk of cerebrovascular diseases, including dementia and stroke. Hypertension alters the structure and function of large cerebral arteries, but its effects on PAs remain unknown. We hypothesized that hypertension increases myogenic tone and induces inward remodeling in PAs; we further proposed that antihypertensive therapy or mineralocorticoid receptor (MR) blockade would reverse the effects of hypertension. PAs from 18-wk-old stroke-prone spontaneously hypertensive rats (SHRSP) were isolated and cannulated in a pressure myograph. At 50-mmHg intraluminal pressure, PAs from SHRSP showed higher myogenic tone (%tone: 39.1 +/ 1.9 vs. 28.7 +/- 2.5%, P < 0.01) and smaller resting luminal diameter (34.7 +/- 1.9 vs. 46.2 +/- 2.4 MUm, P < 0.01) than those from normotensive Wistar-Kyoto rats, through a mechanism that seems to require Ca(2+) influx through L-type voltage-gated Ca(2+) channels. PAs from SHRSP showed inward remodeling (luminal diameter at 60 mmHg: 55.2 +/- 1.4 vs. 75.7 +/- 5.1 MUm, P < 0.01) and a paradoxical increase in distensibility and compliance. Treatment of SHRSP for 6 wk with antihypertensive therapy reduced PAs' myogenic tone, increased their resting luminal diameter, and prevented inward remodeling. In contrast, treatment of SHRSP for 6 wk with an MR antagonist did not reduce blood pressure or myogenic tone, but prevented inward remodeling. Thus, while hypertensive remodeling of PAs may involve the MR, myogenic tone seems to be independent of MR activity. PMID- 25910806 TI - Role played by interleukin-6 in evoking the exercise pressor reflex in decerebrate rats: effect of femoral artery ligation. AB - IL-6 signaling via the soluble IL-6 receptor (sIL-6r) has been shown to increase primary afferent responsiveness to noxious stimuli. This finding prompted us to test the hypothesis that IL-6 and sIL-6r would increase the exercise pressor reflex in decerebrate rats with freely perfused femoral arteries. We also tested the hypothesis that soluble glycoprotein (sgp)130, an inhibitor of IL-6/sIL-6r signaling, would decrease the exaggerated exercise pressor reflex that is found in decerebrate rats with ligated femoral arteries. In rats with freely perfused femoral arteries, coinjection of 50 ng of IL-6 and sIL-6r into the arterial supply of the hindlimb significantly increased the peak pressor response to static (control: 14 +/- 3 mmHg and IL-6/sIL-6r: 17 +/- 2 mmHg, P = 0.03) and intermittent isometric (control: 10 +/- 2 mmHg and IL-6/sIL-6r: 15 +/- 4 mmHg, P = 0.03) hindlimb muscle contraction. In rats with ligated femoral arteries, injection of 50 ng of sgp130 into the arterial supply of the hindlimb reduced the peak pressor response to static (control: 24 +/- 2 mmHg and sgp130: 16 +/- 3 mmHg, P = 0.01) and intermittent isometric (control: 16 +/- 2 mmHg and sgp130: 13 +/- 2 mmHg, P = 0.04) hindlimb muscle contraction, whereas there was no effect of sgp130 on the exercise pressor reflex in rats with freely perfused femoral arteries. We conclude that coinjection of exogenous IL-6 and sIL-6r increased the exercise pressor reflex in rats with freely perfused femoral arteries. More importantly, we also conclude that IL-6 and sIL-6r play an endogenous role in evoking the exercise pressor reflex in rats with ligated femoral arteries but not in rats with freely perfused femoral arteries. PMID- 25910807 TI - Impaired coronary collateral growth: miR-shaken neutrophils caught in the act. PMID- 25910808 TI - Partial deletion of ROCK2 protects mice from high-fat diet-induced cardiac insulin resistance and contractile dysfunction. AB - Obesity is associated with cardiac insulin resistance and contractile dysfunction, which contribute to the development of heart failure. The RhoA-Rho kinase (ROCK) pathway has been reported to modulate insulin resistance, but whether it is implicated in obesity-induced cardiac dysfunction is not known. To test this, wild-type (WT) and ROCK2(+/-) mice were fed normal chow or a high-fat diet (HFD) for 17 wk. Whole body insulin resistance, determined by an insulin tolerance test, was observed in HFD-WT, but not HFD-ROCK2(+/-), mice. The echocardiographically determined myocardial performance index, a measure of global systolic and diastolic function, was significantly increased in HFD-WT mice, indicating a deterioration of cardiac function. However, no change in myocardial performance index was found in hearts from HFD-ROCK2(+/-) mice. Speckle-tracking-based strain echocardiography also revealed regional impairment in left ventricular wall motion in hearts from HFD-WT, but not HFD-ROCK2(+/-), mice. Activity of ROCK1 and ROCK2 was significantly increased in hearts from HFD WT mice, and GLUT4 expression was significantly reduced. Insulin-induced phosphorylation of insulin receptor substrate (IRS) Tyr(612), Akt, and AS160 was also impaired in these hearts, while Ser(307) phosphorylation of IRS was increased. In contrast, the increase in ROCK2, but not ROCK1, activity was prevented in hearts from HFD-ROCK2(+/-) mice, and cardiac levels of TNFalpha were reduced. This was associated with normalization of IRS phosphorylation, downstream insulin signaling, and GLUT4 expression. These data suggest that increased activation of ROCK2 contributes to obesity-induced cardiac dysfunction and insulin resistance and that inhibition of ROCK2 may constitute a novel approach to treat this condition. PMID- 25910809 TI - Dynamics of AV coupling during human atrial fibrillation: role of atrial rate. AB - The causal relationship between atrial and ventricular activities during human atrial fibrillation (AF) is poorly understood. This study analyzed the effects of an increase in atrial rate on the link between atrial and ventricular activities during AF. Atrial and ventricular time series were determined in 14 patients during the spontaneous acceleration of the atrial rhythm at AF onset. The dynamic relationship between atrial and ventricular activities was quantified in terms of atrioventricular (AV) coupling by AV synchrogram analysis. The technique identified n:m coupling patterns (n atrial beats in m ventricular cycles), quantifying their percentage, maximal length, and conduction ratio (= m/n). Simulations with a difference-equation AV model were performed to correlate the observed dynamics to specific atrial/nodal properties. The atrial rate increase significantly affected AV coupling and ventricular response during AF. The shortening of atrial intervals from 185 +/- 32 to 165 +/- 24 ms (P < 0.001) determined transitions toward AV patterns with progressively decreasing m/n ratios (from conduction ratio = 0.34 +/- 0.09 to 0.29 +/- 0.08, P < 0.01), lower occurrence (from percentage of coupled beats = 27.1 +/- 8.0 to 21.8 +/- 6.9%, P < 0.05), and higher instability (from maximal length = 3.9 +/- 1.5 to 2.8 +/- 0.7 s, P < 0.01). Advanced levels of AV block and coupling instability at higher atrial rates were associated with increased ventricular interval variability (from 123 +/- 52 to 133 +/- 55 ms, P < 0.05). AV pattern transitions and coupling instability in patients were predicted, assuming the filtering of high-rate irregular atrial beats by the slow recovery of nodal excitability. These results support the role of atrial rate in determining AV coupling and ventricular response and may have implications for rate control in AF. PMID- 25910810 TI - Increased activity of mitochondrial uncoupling protein 2 improves stress resistance in cultured endothelial cells exposed in vitro to high glucose levels. AB - The endothelium is relatively independent of the mitochondrial energy supply, but mitochondria-derived ROS may play an important role in the development of many cardiovascular diseases. Energy-dissipating uncoupling proteins (UCPs) mediate free fatty acid-activated, purine nucleotide-inhibited proton conductance (uncoupling) in the inner mitochondrial membrane. We have described a functional characteristic and an antioxidative role for UCP2 in endothelial cells and isolated mitochondria and how this function is altered by long-term growth in high concentrations of glucose. Human umbilical vein endothelial cells (EA.hy926 line) were grown in media with either high (25 mM) or normal (5.5 mM) glucose concentrations. Under nonphosphorylating and phosphorylating conditions, UCP activity was significantly higher in mitochondria isolated from high glucose treated cells. More pronounced control of the respiratory rate, membrane potential, and ROS by UCP2 was observed in these mitochondria. A greater UCP2 mediated decrease in ROS generation indicates an improved antioxidative role for UCP2 under high glucose conditions. Mitochondrial and nonmitochondrial ROS generations were significantly higher in high glucose-treated cells independent of UCP2 expression. UCP2 gene silencing led to elevated mitochondrial ROS formation and ICAM1 expression, especially in high glucose-cultured cells. UCP2 influenced endothelial cell viability and resistance to oxidative stress. Endothelial cells exposed to high glucose concentrations were significantly more resistant to peroxide. In these cells, the increased activity of UCP2 led to improved stress resistance and protection against acute oxidative stress. Our results indicate that endothelial UCP2 may function as a sensor and negative regulator of mitochondrial ROS production in response to hyperglycemia. PMID- 25910811 TI - Effect of docosahexaenoic acid monoacylglyceride on systemic hypertension and cardiovascular dysfunction. AB - omega-3 Fatty acid supplementation has been associated with lower blood pressure. Cardiovascular diseases are also known to be linked directly to an increase in omega-6 and a reduction in omega-3 fatty acid levels in blood circulation and tissues. To determine the effect of docosahexaenoic acid monoglycerides (MAG-DHA) on blood pressure, lipid profiles, and vascular remodeling in rats fed a high fat/high-carbohydrate (HFHC) diet. Studies were performed in male rats subjected to 8 wk of HFHC diet supplemented or not with 3 g/day MAG-DHA. After 8 wk of daily MAG-DHA treatment, rats in the HFHC + MAG-DHA group had lower arterial blood pressure and heart rate compared with the HFHC group. Moreover, MAG-DHA prevented the increase aortic wall thickness, whereas lipid analysis of aortic tissues revealed an increase in DHA/AA ratio correlated with the production of resolvin D2 and D3 metabolites. Histological analysis revealed that MAG-DHA prevented the development of LVH in the HFHC group. Serum lipid profile analysis further showed a decrease in total cholesterol (TC) and LDL, including very low density lipoprotein (VLDL) and triglyceride (TG) levels, together with an increase in HDL levels after 8 wk of MAG-DHA treatment compared with the HFHC group. Furthermore, daily MAG-DHA treatment resulted in reduced proinflammatory marker levels such as CRP, IL-6, TNFalpha, and IL-1beta. Altogether, these findings revealed that per os administration of MAG-DHA prevents HFHC-diet induced hypertension and LVH in rats. PMID- 25910813 TI - Means yield to ends in weight loss: focusing on "how" vs "why" aspects of losing weight can lead to poorer regulation of dietary practices. PMID- 25910812 TI - NTS adenosine A2a receptors inhibit the cardiopulmonary chemoreflex control of regional sympathetic outputs via a GABAergic mechanism. AB - Adenosine is a powerful central neuromodulator acting via opposing A1 (inhibitor) and A2a (activator) receptors. However, in the nucleus of the solitary tract (NTS), both adenosine receptor subtypes attenuate cardiopulmonary chemoreflex (CCR) sympathoinhibition of renal, adrenal, and lumbar sympathetic nerve activity and attenuate reflex decreases in arterial pressure and heart rate. Adenosine A1 receptors inhibit glutamatergic transmission in the CCR pathway, whereas adenosine A2a receptors most likely facilitate release of an unknown inhibitory neurotransmitter, which, in turn, inhibits the CCR. We hypothesized that adenosine A2a receptors inhibit the CCR via facilitation of GABA release in the NTS. In urethane-chloralose-anesthetized rats (n = 51), we compared regional sympathetic responses evoked by stimulation of the CCR with right atrial injections of the 5-HT3 receptor agonist phenylbiguanide (1-8 MUg/kg) before and after selective stimulation of NTS adenosine A2a receptors [microinjections into the NTS of CGS-21680 (20 pmol/50 nl)] preceded by blockade of GABAA or GABAB receptors in the NTS [bicuculline (10 pmol/100 nl) or SCH-50911 (1 nmol/100 nl)]. Blockade of GABAA receptors virtually abolished adenosine A2a receptor-mediated inhibition of the CCR. GABAB receptors had much weaker but significant effects. These effects were similar for the different sympathetic outputs. We conclude that stimulation of NTS adenosine A2a receptors inhibits CCR-evoked hemodynamic and regional sympathetic reflex responses via a GABA-ergic mechanism. PMID- 25910814 TI - Repertoire and evolution of TNF superfamily in Crassostrea gigas: implications for expansion and diversification of this superfamily in Mollusca. AB - Tumor necrosis factor superfamily (TNFSF) members represent a group of cytokines participating in diverse immunological, pathological and developmental pathways. However, compared with deuterostomia and cnidaia, the composition and evolution of TNF homologous in protostomia are still not well understood. In the present study, a total of 81 TNF superfamily (TNFSF) genes from 15 mollusk species, including 23 TNFSF genes from Crassostrea gigas, were surveyed by genome-wide bioinformatics analysis. The phylogenetic analysis showed that 14 out of 23 C. gigas TNFSF genes in five clades exhibited orthologous relationships with Pinctada fucata TNFSF genes. Moreover, there were 15 C. gigas TNFSF genes located in oyster-specific clusters, which were contributed by small-scaled tandem and/or segmental duplication events in oyster. By comparing the sequences of duplicated TNFSF pairs, exon loss and variant in exon/intron length were revealed as the major modes of divergence in gene structure. Most of the duplicated C. gigas TNFSF pairs were evolved under purifying selection with consistent tissue expression patterns, implying functional constraint shaped diversification. This study demonstrated the expansion and early divergence of TNF superfamily in C. gigas, which provides potential insight into revealing the evolution and function of this superfamily in mollusk. PMID- 25910815 TI - Recurrent intimal sarcoma mimicking pulmonary embolism. PMID- 25910816 TI - Deregulation of EGFR/PI3K and activation of PTEN by photodynamic therapy combined with carboplatin in human anaplastic thyroid cancer cells and xenograft tumors in nude mice. AB - Phosphatidylinositol-3-kinase (PI3K) is one of the major activated pathways involved in the progression of anaplastic thyroid cancer. The activated PI3K pathway starts from the overexpression of epidermal growth-factor receptor (EGFR) which plays a key role in cancer development and metastasis. However, a protein, PTEN negatively regulates the PI3K pathway. Here we studied the possibility of using a combination of conventional chemotherapy and photodynamic therapy to inhibit the growth of human anaplastic thyroid cancer in vitro and in vivo. Carboplatin (CBDCA) and radachlorin-photodynamic therapy (PDT) were used for the combination treatment of human anaplastic thyroid cancer cells FRO and tumor xenograft in athymic mice. Confocal microscopic and flow cytometric observations showed that cell death was mainly through an enhanced apoptosis with the combination of CBDCA and PDT. Generation of reactive oxygen species and dysfunction of mitochondrial membranes suggested that the enhanced apoptosis was achieved through the mitochondrial cell death pathway. This was confirmed by Western blot analysis of caspase 3, 9 expressions. Further analysis showed that the combination of CBDCA and PDT inhibited the expression of EGFR and PI3K with higher efficacy. PTEN also was activated more in this combination group. This suggests a combination of CBDCA and PDT modulates EGFR and PI3K as well as activates PTEN to inhibit tumor growth and induce apoptosis with an enhanced efficacy in anaplastic thyroid cancer. PMID- 25910817 TI - Wnt Signaling Cascades and the Roles of Syndecan Proteoglycans. AB - Wnt signaling comprises a group of pathways emanating from the extracellular environment through cell-surface receptors into the intracellular milieu. Wnt signaling cascades can be divided into two main branches, the canonical/beta catenin pathway and the non-canonical pathways containing the Wnt/planar cell polarity and Wnt/calcium signaling. Syndecans are type I transmembrane proteoglycans with a long evolutionary history, being expressed in all Bilateria and in almost all cell types. Both Wnt pathways have been extensively studied over the past 30 years and shown to have roles during development and in a multitude of diseases. Although the first evidence for interactions between syndecans and Wnts dates back to 1997, the number of studies connecting these pathways is low, and many open questions remained unanswered. In this review, syndecan's involvement in Wnt signaling pathways as well as some of the pathologies resulting from dysregulation of the components of these pathways are summarized. PMID- 25910818 TI - Mechanical and biological properties of the micro-/nano-grain functionally graded hydroxyapatite bioceramics for bone tissue engineering. AB - Functionally graded materials (FGM) open the promising approach for bone tissue repair. In this study, a novel functionally graded hydroxyapatite (HA) bioceramic with micrograin and nanograin structure was fabricated. Its mechanical properties were tailored by composition of micrograin and nanograin. The dynamic mechanical analysis (DMA) indicated that the graded HA ceramics had similar mechanical property compared to natural bones. Their cytocompatibility was evaluated via fluorescent microscopy and MTT colorimetric assay. The viability and proliferation of rabbit bone marrow mesenchymal stem cells (BMSCs) on ceramics indicated that this functionally graded HA ceramic had better cytocompatibility than conventional HA ceramic. This study demonstrated that functionally graded HA ceramics create suitable structures to satisfy both the mechanical and biological requirements of bone tissues. PMID- 25910819 TI - Symptomatic venous thromboembolism following circular frame treatment for tibial fractures. AB - INTRODUCTION: Venous thromboembolism (VTE) is a significant cause of morbidity and mortality following tibial fractures. The risk is as high as 77% without prophylaxis and around 10% with prophylaxis. Within the current literature there are no figures reported specifically for those individuals treated with circular frames. Our aim was to evaluate the VTE incidence within a single surgeon series and to evaluate potential risk factors. METHODS: We retrospectively reviewed our consecutive single surgeon series of 177 patients admitted to a major trauma unit with tibial fractures. All patients received standardised care, including chemical thromboprophylaxis within 24h of injury until independent mobility was achieved. We comprehensively reviewed our prospective database and medical records looking at demographics and potential risk factors. RESULTS: Seven patients (4.0% +/- 2.87%) developed symptomatic VTE during the course of frame treatment; three deep vein thrombosis (DVTs) and four pulmonary embolisms (PEs). Those with a VTE event had significantly increased body mass index (BMI) (p = 0.01) when compared to those without symptomatic VTE. No differences (p > 0.05) were observed between the groups in age, gender, smoking status, fracture type (anatomical allocation or open/closed), delay to frame treatment, weight bearing status post-frame, inpatient stay or total duration of frame treatment. CONCLUSION: This study suggests that increased BMI is a statistically significant risk factor for VTE, as reported in current literature. In addition, we calculated the true risk of VTE following circular frame treatment for tibial fracture in our series is from 1.13% to 6.87%, which is at least comparable to other forms of treatment. PMID- 25910820 TI - Do split paediatric forearm POP casts need to be completed? A biomechanical study. AB - INTRODUCTION: Displaced paediatric forearm fractures are most often treated by manipulation under anaesthetic, followed by the application of a circumferential Plaster of Paris (POP) splint. Some surgeons choose to split the cast in order to facilitate immediate "spreading" with minimal distress to the patient, should the distal limb become compromised. Usually however, this does not occur, and the cast is completed at a later visit to the plaster room. Time, money and inconvenience could be saved if this modification was not necessary, and the final plaster would be lighter. OBJECTIVE: To establish whether the mechanical properties of a split POP are sufficient to stabilise a forearm fracture, and protect the patient from further injury. MATERIALS AND METHODS: The repeatability of all tests was established on control samples before undertaking the trial. 42 standardised 8 layer POP cylinders of appropriate dimensions were fabricated, of which 21 were split longitudinally. The splints were subjected to non-destructive tests in 4-point bending (Bending), 3-Point Kinking (kinking) and torsion modes, and the load at clinically relevant end-points was recorded. These simulated the deformity at which the splint no longer provided adequate stability and alignment, or at which the wearer was no longer protected. The splints were then loaded to destruction to establish the mode of ultimate failure. RESULTS: The mean loads at the clinical end points for split POP splints were: 1375N in Bending, 544N in Kinking and 12 Nm in Torsion (equalling 67.3%, 70.4% and 47.4% of the equivalent values for a circumferential splints). Loads were in excess of body weight for most paediatric patients. After ultimate failure, the proportion of casts that became unstable was similar (44% of full casts and 50% of split casts). CONCLUSION: Split POP splints which have not been spread, provide adequate stabilisation and protection of paediatric forearm fractures, and do not routinely require completion. PMID- 25910821 TI - The influence of the Chinese zodiac on the male-to-female ratio at birth in Hong Kong. AB - BACKGROUND: Secular trends have been found in the male-female ratio at birth (M/F: male births divided by total births) in various countries, and this ratio is anticipated to approximate 0.515. Births in Dragon years are considered auspicious. Fertility is known to have increased in Dragon years in Hong Kong. This study analyzed M/F with reference to Dragon years. METHODS: Annual national data for male and female live births in Hong Kong were obtained from the World Health Organization and analyzed with contingency Tables. RESULTS: There were 3,827,347 live births (1960-2009). Births declined steadily, then increased from 2004 in association with M/F. M/F was stable prior to this time, with spikes in 1975-1976, 1988, and 2000, associated with increases in births for these same years. CONCLUSION: M/F follows a U-shaped regression on cycle day of insemination. Families attempting to conceive children during Dragon years may have increased coital rates, inadvertently skewing M/F in favor of a male excess. PMID- 25910822 TI - Identification of Superior Mesenteric Artery Syndrome from Vascular Angle Measurements. PMID- 25910823 TI - Neck Pain One Week after Pacemaker Generator Replacement. AB - BACKGROUND: The incidence of cardiac pacemaker implantation has risen markedly in the past three decades, making awareness of possible postprocedural complications critical to the emergency physician. This case is the first documented instance of internal jugular (IJ) deep vein thrombosis (DVT) from an uncomplicated pacemaker generator replacement. CASE REPORT: A patient presented to an Emergency Department with a 2-day history of mild left temporal headache migrating to his left neck. The patient did not volunteer this information, but review of systems revealed a temporary transvenous pacemaker inserted through the right IJ vein 1 week previously during a routine exchange of a left-sided cardiac pacemaker generator. Manipulation of the existing pacemaker wires entering the left subclavian vein was minimal. Computed tomographic angiography of the neck demonstrated near-complete thrombotic occlusion of the entire length of his left IJ vein. This required hospital admission for observation and treatment with anticoagulation. WHY SHOULD AN EMERGENCY PHYSICIAN BE AWARE OF THIS?: DVT, with thrombotic extension into adjacent vessels anywhere along the course of pacemaker wires, should be considered by the emergency provider in the evaluation of head, neck, or upper extremity symptoms after recent or remote implantation or manipulation of a transvenous cardiac pacemaker, including generator replacement. Failure to identify and treat appropriately could result in significant morbidity and mortality from airway edema, septic thrombophlebitis, superior vena cava syndrome, superior sagittal sinus thrombosis, or pulmonary embolism. PMID- 25910824 TI - Age-Related Emergency Department Reliance in Patients with Sickle Cell Disease. AB - BACKGROUND: Emergency Department Reliance (EDR: total emergency department [ED] visits/total ambulatory [outpatient + ED] visits) differentiates acute episodic ED users from those who may not have adequate access to outpatient care. OBJECTIVE: This study's aim was to investigate age-related patterns of EDR and associated health-care costs in pediatric patients with sickle cell disease (SCD) and those transitioning from pediatric to adult care. METHODS: State Medicaid data were used for this study. Patients with two or more SCD diagnoses and one or more blood transfusion were included. Quarterly rates of ED visits, EDR, SCD complications associated with ED visits, and ED visits resulting in hospitalization were evaluated. Risk factors associated with high EDR and the association between high EDR and health-care costs were explored through regression analyses. RESULTS: A total of 3208 patients were included. The most common SCD complications associated with ED visits were pain, infection, and pneumonia. Beginning at the age of 15 years, EDR rose from 0.17 to 0.29 visits per quarter at age 22 years, and remained high throughout adulthood. Regression analyses indicated that patients were most likely to have high EDR during the post-transition period and when experiencing an SCD complication. Patients with high EDR incurred statistically significantly higher inpatient and ED costs, resulting in significantly higher total health-care costs. CONCLUSIONS: Compared to children, patients transitioning to adulthood relied more on the ED for their care. In addition, patients with high EDR incurred more days in the hospital and significantly higher health-care costs, highlighting the need to improve transition-related support, including better access to primary care and increased engagement with patients with SCD. PMID- 25910825 TI - Crowned Dens Syndrome: Report of Three Cases and a Review of the Literature. AB - BACKGROUND: Patients with crowned dens syndrome (CDS), which is pseudogout of the atlantoaxial junction induced by "crown-like" calcifications around the dens, present with symptoms of severe neck pain, rigidity, and high fever. CDS patients are often misdiagnosed as having meningitis or polymyalgia rheumatica, leading to potentially unnecessary invasive procedures for diagnosis and treatment. CASE REPORT: We report 3 patients with CDS who had characteristic findings on computed tomography (CT), all of whom quickly recovered with nonsteroidal antiinflammatory drug (NSAID) administration. In addition, we reviewed 72 published cases, including our patients. CDS typically occurs in elderly people (mean age 71.4 years). Common symptoms include neck pain (100%), neck rigidity (98%), and fever (80.4%), and most show elevated inflammatory markers (88.3%) on serum laboratory tests. Neck pain on rotation is a characteristic and helpful symptom in the diagnosis. The most useful modality is CT (97.1%), showing linear calcium deposits around the dens, mostly in the transverse ligament of atlas (TLA). CT number is especially helpful to distinguish a normal TLA (35-110 HU) from a calcified one (202-258 HU) in our cases. The most effective treatment is NSAID administration (85%), which usually leads to marked resolution of symptoms within days or weeks. WHY SHOULD AN EMERGENCY PHYSICIAN BE AWARE OF THIS?: Due to acute and severe symptoms, CDS patients often present to an emergency department. To avoid unnecessary invasive procedures for diagnosis and treatment, CDS should be considered in the differential diagnosis of febrile neck pain. PMID- 25910826 TI - Noninfectious Funiculitis. PMID- 25910827 TI - Perineal Rash and Perianal Pain. PMID- 25910828 TI - Response to Cantrell and Villano. PMID- 25910830 TI - Young Injury in an Older Ankle. PMID- 25910829 TI - Risk Factors Associated with Urologic Intervention in Emergency Department Patients with Suspected Renal Colic. AB - BACKGROUND: Whereas most patients with urolithiasis pass their stones spontaneously and require only symptomatic management, a minority will require urologic intervention. OBJECTIVE: Our primary objective was to confirm previously reported risk factors and to identify additional predictors of urologic intervention within 90 days, for emergency department (ED) patients with suspected renal colic. METHODS: We conducted a prospective cohort study of adult patients presenting to one of two tertiary care EDs with suspected renal colic over a 20-month period. Multivariate logistic regression models determined predictor variables independently associated with urologic intervention. RESULTS: Of the 565 patients included in the analysis, 220 (38.9%) patients had a ureteric stone visualized on diagnostic imaging. Eighty-four patients (14.9%) had urologic intervention within 90 days of their initial ED visit. Urinary nitrites (odds ratio [OR] 4.2, 95% confidence interval [CI] 1.3-13.6), stone size >= 5 mm (OR 4.2, 95% CI 2.4-7.4), proximal ureteric stone (OR 3.1, 95% CI 1.5-6.4), age >= 50 years (OR 2.8, 95% CI 1.5-5.0), tachycardia at triage (OR 2.5, 95% CI 1.1-5.4), urinary leukocyte esterase (OR 2.3, 95% CI 1.2-4.5), abnormal serum white blood cells (OR 2.0, 95% CI 1.2-3.3), and history of renal colic (OR 1.8, 95% CI 1.1 3.1) were factors independently associated with urologic intervention within 90 days. CONCLUSIONS: Our study reports eight risk factors associated with urologic intervention within 90 days in patients presenting to the ED with renal colic. These risk factors should be considered when making management, prognostic, and disposition decisions for patients with suspected urolithiasis. PMID- 25910831 TI - Blast-Induced Compartment Syndrome. PMID- 25910832 TI - Validation of Single Radial Haemolysis assay: A reliable method to measure antibodies against influenza viruses. AB - The Single Radial Haemolysis (SRH) assay is a serological method widely used for measuring antibodies against influenza viruses. Despite the broad application and recommendation by licensing authorities, the SRH assay has not been standardized. The aim of this study is to demonstrate how the SRH assay satisfies validation parameters of regulatory agencies in terms of specificity, precision, repeatability, intermediate precision, linearity, accuracy and robustness. This study shows that the SRH is a rapid, simple, reliable and reproducible assay, which requires only small volumes of serum samples and can be easily standardized. PMID- 25910833 TI - Efficient generation of human IgA monoclonal antibodies. AB - Immunoglobulin A (IgA) is the most abundant antibody isotype produced in humans. IgA antibodies primarily ensure immune protection of mucosal surfaces against invading pathogens, but also circulate and are present in large quantities in blood. IgAs are heterogeneous at a molecular level, with two IgA subtypes and the capacity to form multimers by interacting with the joining (J) chain. Here, we have developed an efficient strategy to rapidly generate human IgA1 and IgA2 monoclonal antibodies in their monomeric and dimeric forms. Recombinant monomeric and dimeric IgA1/IgA2 counterparts of a prototypical IgG1 monoclonal antibody, 10 1074, targeting the HIV-1 envelope protein, were produced in large amounts after expression cloning and transient transfection of 293-F cells. 10-1074 IgAs were FPLC-purified using a novel affinity-based resin engrafted with anti-IgA chimeric Fabs, followed by a monomers/multimers separation using size exclusion-based FPLC. ELISA binding experiments confirmed that the artificial IgA class switching of 10-1074 did not alter its antigen recognition. In summary, our technical approach allows the very efficient production of various forms of purified recombinant human IgA molecules, which are precious tools in dissecting IgA B cell responses in physiological and pathophysiological conditions, and studying the biology, function and therapeutic potential of IgAs. PMID- 25910834 TI - Safety assessment of [3S, 3'S]-astaxanthin--Subchronic toxicity study in rats. AB - Astaxanthin, a naturally occurring xanthophyll, is commercially used as a coloring agent in salmon feed, but also marketed as a dietary supplement. The objective of this study was to investigate the subchronic toxicity of synthetic [3S, 3'S]-Astaxanthin in rats. A powder formulation containing approximately 20% [3S, 3'S]-Astaxanthin was administered via the diet to groups of 10 male and 10 female Wistar rats at concentrations of 5000, 15,000 and 50,000 ppm for a period of 13 weeks. A formulation of comparable composition but without [3S, 3'S] Astaxanthin served as a placebo control. There were no effects observed on survival, clinical examinations, clinical pathology, estrous cycle as well as on sperm parameters. At terminal necropsy, a macroscopically visible brown-blue discoloration of the gastrointestinal contents was noted which was considered to be secondary to the violet-brown color of the test material. No other significant or dose-related abnormalities were found in the tissues collected at termination. Our observations support that ingestion of [3S, 3'S]-Astaxanthin of up to 700-920 mg/kg bw/day in rats in a gelatin/carbohydrate formulation is without adverse effects. PMID- 25910835 TI - Vetiver oil (Java) attenuates cisplatin-induced oxidative stress, nephrotoxicity and myelosuppression in Swiss albino mice. AB - Clinical efficacy of the widely used anticancer drug cisplatin is limited due to its adverse side effects in normal tissues mediated by oxidative stress. This study was aimed to investigate the protective effects of vetiver acetate oil, Java (VO) against cisplatin-induced toxicity in Swiss albino mice. The ameliorating potential was evaluated by orally priming the animals with VO at doses 5, 10 or 20 mg/kg bw for 7 days prior to cisplatin treatment. Acute toxicity in mice was induced by injecting cisplatin (3 mg/kg bw) intraperitoneally for 5 consecutive days. Significant attenuation of renal toxicity was confirmed by histopathological examination, lowered levels of serum blood urea nitrogen, creatinine and reduced DNA damage. VO also compensated deficits in the renal antioxidant system. VO intervention significantly inhibited DNA damage, clastogenic effects, and cell cycle arrest in the bone marrow cells of mice. Hematological parameters indicated attenuation of cisplatin-induced myelosuppression. Overall, this study provides for the first time that VO has a protective role in the abatement of cisplatin-induced toxicity in mice which may be attributed to its antioxidant activity. PMID- 25910836 TI - AVE protein expression and visceral endoderm cell behavior during anterior posterior axis formation in mouse embryos: Asymmetry in OTX2 and DKK1 expression. AB - The initial landmark of anterior-posterior (A-P) axis formation in mouse embryos is the distal visceral endoderm, DVE, which expresses a series of anterior genes at embryonic day 5.5 (E5.5). Subsequently, DVE cells move to the future anterior region, generating anterior visceral endoderm (AVE). Questions remain regarding how the DVE is formed and how the direction of the movement is determined. This study compares the detailed expression patterns of OTX2, HHEX, CER1, LEFTY1 and DKK1 by immunohistology and live imaging at E4.5-E6.5. At E6.5, the AVE is subdivided into four domains: most anterior (OTX2, HHEX, CER1-low/DKK1-high), anterior (OTX2, HHEX, CER1-high/DKK1-low), main (OTX2, HHEX, CER1, LEFTY1-high) and antero-lateral and posterior (OTX2, HHEX-low). The study demonstrates how this pattern is established. AVE protein expression in the DVE occurs de novo at E5.25-E5.5. Neither HHEX, LEFTY1 nor CER1 expression is asymmetric. In contrast, OTX2 expression is tilted on the future posterior side with the DKK1 expression at its proximal domain; the DVE cells move in the opposite direction of the tilt. PMID- 25910837 TI - Extracorporeal membrane oxygenation in acute massive pulmonary embolism: a systematic review. AB - Massive pulmonary embolism (PE) can present with extreme physiological dysfunction, characterised by acute right ventricular failure, hypoxaemia unresponsive to conventional therapy and cardiac arrest. Consensus regarding the management of patients with persistent shock following thrombolysis is lacking. Our primary objective was to describe the application of extracorporeal membrane oxygenation (ECMO) in the treatment of acute massive PE. We were unable to identify any randomised controlled trials (RCTs) comparing ECMO with other support systems in the setting of massive PE. We reviewed case reports and case series published in the past 20 years to evaluate the mortality rate and any poor prognostic factors. Overall survival was 70.1% and none of the definitive treatment modalities was associated with a higher mortality (thrombolysis - OR - 0.99, P - 0.9, catheter embolectomy - OR - 1.01, P - 0.99, surgical embolectomy - OR - 0.44, P - 0.20). Patients who had ECMO instituted whilst in cardiorespiratory arrest had a higher risk of death. (OR - 16.71, P - 0.0004). When compared with other causes of cardiac arrest, patients who survived a massive PE presented a good neurological outcome (cerebral performance category 1 or 2). PMID- 25910838 TI - Miniaturized versus conventional cardiopulmonary bypass and acute kidney injury after cardiac surgery. AB - INTRODUCTION: Acute kidney injury (AKI) is a serious complication after coronary artery bypass grafting (CABG). There are conflicting reports whether a miniaturized cardiopulmonary bypass (MCPB) system is associated with a lower AKI incidence compared with conventional cardiopulmonary bypass (CCPB). It is unknown if AKI risk factors differ between the two groups. We assessed if MCPB decreases AKI after CABG and compared the risk factors between both groups. METHODS: Sixty eight Asian patients presenting for elective CABG at a tertiary heart centre were enrolled. They were randomly assigned to MCPB (n=34) or CCPB group (n=34) and followed up in a single-blinded, prospective, randomized, controlled trial. The primary outcome was Acute Kidney Injury Network stage 1 AKI. RESULTS: The AKI incidence was 21.5% and was not significantly different between patients undergoing MCPB versus CCPB (21.9% versus 21.2%, p=0.948). The first CPB haematocrit was independently associated with AKI in the MCPB group (Relative Risk [RR]=0.484, 95% Confidence Interval [CI]=0.268-0.876, p=0.016); post operative blood loss and inflammation were independently associated with AKI in the CCPB group (RR=1.005, 95%CI=1.003-1.007, p<0.001; RR=1.018, 95%CI=1.010 1.028, p<0.001). CONCLUSION: The MCPB system is not associated with a lower incidence of AKI in Asian patients undergoing CABG. Risk factors for AKI differed between patients using the MCPB and CCPB systems. PMID- 25910839 TI - Use of pulmonary arteriovenous extracorporeal membrane oxygenation in conjunction with the total artificial heart. PMID- 25910840 TI - The MGMT promoter SNP rs16906252 is a risk factor for MGMT methylation in glioblastoma and is predictive of response to temozolomide. AB - BACKGROUND: Promoter methylation of O(6)-methylguanine-DNA methyltransferase (MGMT) is an important predictive biomarker in glioblastoma. The T variant of the MGMT promoter-enhancer single nucleotide polymorphism (SNP; rs16906252) has been associated with the presence of MGMT promoter methylation in other cancers. We examined the association of the T allele of rs16906252 with glioblastoma development, tumor MGMT methylation, MGMT protein expression, and survival outcomes. METHODS: Two independent temozolomide-treated glioblastoma cohorts-one Australian (Australian Genomics and Clinical Outcomes of Glioma, n = 163) and the other American (University of California Los Angeles/Kaiser Permanente Los Angeles, n = 159)-were studied. Allelic bisulphite sequencing was used to determine if methylation was specific to the T allele. Additionally, we compared the incidence of the T allele between glioblastoma cases and matched controls to assess whether it was a risk factor for developing MGMT methylated glioblastoma. RESULTS: Carriage of the T allele of the rs16906252 SNP was associated with both MGMT methylation and low MGMT protein expression and predicted significantly longer survival in temozolomide-treated patients with both MGMT methylated and nonmethylated glioblastoma. Methylation was linked to the T allele, inferring that the T variant plays a key role in the acquisition of MGMT methylation. Carriage of the T allele was associated with a significantly elevated risk of developing glioblastoma (adjusted odds ratio, 1.96; P = .013), increasing further when glioblastoma was classified by the presence of MGMT methylation (adjusted odds ratio, 2.86; P = .001). CONCLUSIONS: The T allele of the rs16906252 SNP is a key determinant in the acquisition of MGMT methylation in glioblastoma. Temozolomide-treated patients with the rs16906252 T genotype have better survival, irrespective of tumor methylation status. PMID- 25910842 TI - Predictive imaging marker of bevacizumab efficacy: perfusion MRI. PMID- 25910841 TI - Does lung cancer mutation status and targeted therapy predict for outcomes and local control in the setting of brain metastases treated with radiation? AB - BACKGROUND: We investigated effects of genetic alterations in epidermal growth factor receptor (EGFR), anaplastic lymphoma kinase (ALK), and Kirsten rat sarcoma viral oncogene homolog (KRAS) on overall survival (OS) and local control after stereotactic radiosurgery for brain metastases in non-small cell lung cancer (NSCLC). METHODS: A cohort of 89 out of 262 NSCLC patients (2003-2013) treated with gamma knife radiosurgery for brain metastases had genotyping available and were selected as our study population. RESULTS: Median follow-up was 12 months. Median OS rates for the EGFR, KRAS, echinoderm microtubule-associated protein like 4 (EML4)-ALK mutated, and wild-type cohorts were 17, 7, 27, and 12 months, respectively (P = .019), and for targeted versus nontargeted therapy 21 and 11 months, respectively (P = .071). Targeted therapy was a strong predictor of increased OS on univariate (P = .037) and multivariate (P = .022) analysis. Gender, primary tumor controlled status, recursive partitioning analysis class, and graded prognostic assessment score were associated with OS (P < .05). On multivariate analysis, positive EGFR mutational status was a highly significant predictor for decreased survival (hazard ratio: 8.2; 95% CI: 2.0-33.7; P = .003). However, when we recategorized EGFR-mutant cases based on whether they received tyrosine kinase inhibitor, OS was no longer significantly shorter (hazard ratio: 1.5; P = .471). Median OS for patients with and without local failure was 17 and 12 months, respectively (P = .577). Local failure rates for EGFR, KRAS, EML4-ALK mutated, and wild-type cohorts by lesion were 8.7%, 5.4%, 4.3%, and 5.1%, respectively. CONCLUSIONS: This study suggests that EGFR tyrosine kinase mutation and ALK translocation results in improved survival to targeted therapies and that mutation status itself does not predict survival and local control in patients with brain metastases from NSCLC. PMID- 25910843 TI - MicroRNA Therapeutics. PMID- 25910844 TI - Varying Associations Between Body Mass Index and Physical and Cognitive Function in Three Samples of Older Adults Living in Different Settings. AB - BACKGROUND: The study investigates variations in the associations between body mass index (BMI) and (a) physical and (b) cognitive function across three samples of older adults living in different settings, and moreover determines if the association between BMI and physical function is confounded by cognitive abilities. METHODS: One hundred ninety-five patients of a geriatric day hospital, 322 persons receiving home care (HC), and 183 nursing home (NH) residents were examined regarding BMI, cognitive (Mini-Mental State Examination), and physical function (Barthel Index for activities of daily living). Differences in Mini Mental State Examination and activities of daily living scores between BMI groups (<22, 22-<25, 25-<30, 30-<35, >=35kg/m(2)) were tested by analysis of covariance considering relevant confounders. RESULTS: Activities of daily living and Mini Mental State Examination impairments increased from the geriatric day hospital over the HC to the NH sample, whereas prevalence rates of obesity and severe obesity (35%, 33%, 25%) decreased. In geriatric day hospital patients cognitive and physical function did not differ between BMI groups. In the HC and NH samples, cognitive abilities were highest in obese and severely obese subjects. Unadjusted mean activities of daily living scores differed between BMI groups in HC receivers (51.6+/-32.2, 61.8+/-26.1, 67.5+/-28.3, 72.0+/-23.4, 66.2+/-24.2, p = .002) and NH residents (35.6+/-28.6, 48.1+/-25.7, 39.9+/-28.7, 50.8+/-24.0, 57.1+/-28.2, p = .029). In both samples significance was lost after adjustment indicating cognitive function as dominant confounder. CONCLUSIONS: In older adults the associations between BMI and physical and cognitive function were dependent on the health and care status corresponding to the setting. In the HC and the NH samples, cognitive status, as measured by the Mini-Mental State Examination, emerged as an important confounder within the association between BMI and physical function. PMID- 25910846 TI - Dietary Fatty Acids and Temperature Modulate Mitochondrial Function and Longevity in Drosophila. AB - Fluctuations in temperature and resource availability are conditions many organisms contend with in nature. Specific dietary nutrients such as fatty acids play an essential role in reproduction, cold adaptation, and metabolism in a variety of organisms. The present study characterizes how temperature and diet interact to modulate Drosophila physiology and life span. Flies were raised on media containing specific saturated, monounsaturated, or polyunsaturated fatty acids supplements at low concentrations and were placed in varied thermal environments. We found that dietary long-chain polyunsaturated fatty acids improve chill coma recovery and modulate mitochondrial function. Additionally, monounsaturated and polyunsaturated fatty acid food supplements were detrimental to life span regardless of temperature, and antioxidants were able to partially rescue this effect. This study provides insight into environmental modulation of Drosophila physiology and life span. PMID- 25910847 TI - High-throughput transcriptome analysis of ISAV-infected Atlantic salmon Salmo salar unravels divergent immune responses associated to head-kidney, liver and gills tissues. AB - Infectious salmon anaemia virus (ISAV) is an orthomyxovirus causing high mortality in farmed Atlantic salmon (Salmo salar). The collective data from the Atlantic salmon-ISAV interactions, performed "in vitro" using various salmon cell lines and "in vivo" fish infected with different ISAV isolates, have shown a strong regulation of immune related transcripts during the infection. Despite this strong defence response, the majority of fish succumb to infections with ISAV. The deficient protection of the host against ISAV is in part due to virulence factors of the virus, which allow evade the host-defence machinery. As such, the viral replication is uninhibited and viral loads quickly spread to several tissues causing massive cellular damage before the host can develop an effective cell-mediated and humoral outcome. To interrogate the correlation of the viral replication with the host defence response, we used fish that have been infected by cohabitation with ISAV-injected salmons. Whole gene expression patterns were measured with RNA-seq using RNA extracted from Head-kidney, Liver and Gills. The results show divergent mRNA abundance of functional modules related to interferon pathway, adaptive/innate immune response and cellular proliferation/differentiation. Furthermore, gene regulation in distinct tissues during the infection process was independently controlled within the each tissue and the observed mRNA expression suggests high modulation of the ISAV-segment transcription. Importantly this is the first time that strong correlations between functional modules containing significant immune process with protein protein affinities and viral-segment transcription have been made between different tissues of ISAV-infected fish. PMID- 25910845 TI - Comparative Approaches to Understanding the Relation Between Aging and Physical Function. AB - Despite dedicated efforts to identify interventions to delay aging, most promising interventions yielding dramatic life-span extension in animal models of aging are often ineffective when translated to clinical trials. This may be due to differences in primary outcomes between species and difficulties in determining the optimal clinical trial paradigms for translation. Measures of physical function, including brief standardized testing batteries, are currently being proposed as biomarkers of aging in humans, are predictive of adverse health events, disability, and mortality, and are commonly used as functional outcomes for clinical trials. Motor outcomes are now being incorporated into preclinical testing, a positive step toward enhancing our ability to translate aging interventions to clinical trials. To further these efforts, we begin a discussion of physical function and disability assessment across species, with special emphasis on mice, rats, monkeys, and man. By understanding how physical function is assessed in humans, we can tailor measurements in animals to better model those outcomes to establish effective, standardized translational functional assessments with aging. PMID- 25910848 TI - MiR-200 modulates coelomocytes antibacterial activities and LPS priming via targeting Tollip in Apostichopus japonicus. AB - In order to explore the potential roles of microRNAs (miRNAs) in regulating Toll like receptor (TLR) pathways, we identified Toll interacting protein as a putative target of miR-200 in Apostichopus japonicus coelomocytes by RNA-seq screening (denoted as AjTollip). The positive expression profiles of miR-200 and AjTollip were detected in both LPS exposure primary coelomocytes and Vibrio splendidus challenge sea cucumber. Co-infection miR-200 mimics significantly elevated the expression of AjTollip and its down-stream molecules. In contrast, miR-200 inhibitor significantly repressed the expression of these TLR-pathway members. More importantly, miR-200 displayed not only to enhance coelomocytes antibacterial activities, but to suppress LPS priming in vitro. Overall, all these results will enhance our understanding on miR-200 regulatory roles in anti bacterial process in sea cucumber. PMID- 25910849 TI - Characterization of MMP-9 gene from a normalized cDNA library of kidney tissue of yellow catfish (Pelteobagrus fulvidraco). AB - Matrix metalloproteinase-9 (MMP-9), one of members of the MMP family, is important for the cleaving of structural extracellular matrix (ECM) molecules and involved in inflammatory processes. In this study, MMP-9 cDNA was isolated and characterized from a normalized cDNA library of kidney tissue of yellow catfish (designated as YcMMP-9). The complete sequence of YcMMP-9 cDNA consisted of 2561 nucleotides. The open reading frame potentially encoded a protein of 685 amino acids with a calculated molecular mass of approximately 77.182 kDa. Amino acid sequence of YcMMP-9 have typical characteristics of MMP-9 family and showed highest identity (85.3%) to channel catfish MMP-9. The YcMMP-9 genomic DNA contains 13 exons and 12 introns. Quantitative RT-PCR (qRT-PCR) analysis showed that YcMMP-9 mRNA was constitutively expressed in all examined tissues in normal fish with high expression in head kidney, trunk kidney, blood, and spleen. However, expression of YcMMP-9 mRNA was induced by Aeromonas hydrophila stimulation, especially in these four tissues mentioned above. It indicated that YcMMP-9 was involved in innate immune responses against bacterial infection. PMID- 25910850 TI - The introduction of a potentially abuse deterrent oxycodone formulation: Early findings from the Australian National Opioid Medications Abuse Deterrence (NOMAD) study. AB - BACKGROUND: There is increasing concern about tampering of pharmaceutical opioids. We describe early findings from an Australian study examining the potential impact of the April 2014 introduction of an abuse-deterrent sustained release oxycodone formulation (Reformulated OxyContin((r))). METHODS: Data on pharmaceutical opioid sales; drug use by people who inject drugs regularly (PWID); client visits to the Sydney Medically Supervised Injecting Centre (MSIC); and last drug injected by clients of inner-Sydney needle-syringe programmes (NSPs) were obtained, 2009-2014. A cohort of n=606 people tampering with pharmaceutical opioids was formed pre-April 2014, and followed up May-August 2014. RESULTS: There were declines in pharmacy sales of 80mg OxyContin((r)) post introduction of the reformulated product, the dose most commonly diverted and injected by PWID. Reformulated OxyContin((r)) was among the least commonly used and injected drugs among PWID. This was supported by Sydney NSP data. There was a dramatic reduction in MSIC visits for injection of OxyContin((r)) post introduction of the new formulation (from 62% of monthly visits pre-introduction to 5% of visits, August 2014). The NOMAD cohort confirmed a reduction in OxyContin((r)) use/injection post-introduction. Reformulated OxyContin((r)) was cheaper and less attractive for tampering than Original OxyContin((r)). CONCLUSIONS: These data suggest that, in the short term, introduction of an abuse deterrent formulation of OxyContin((r)) in Australia was associated with a reduction in injection of OxyContin((r)), with no clear switch to other drugs. Reformulated OxyContin((r)), in this short follow-up, does not appear to be considered as attractive for tampering. PMID- 25910851 TI - A comparative study of the effects of pulse parameters for intracranial direct electrical stimulation in epilepsy. AB - OBJECTIVES: Intracranial direct electrical stimulation (iDES) uses different parameters for mapping the epileptogenic and functional areas in patients with drug-resistant epilepsy. We aim at finding the common factor driving the electrographic responses to various iDES protocols reported in the literature. METHODS: We recorded early responses to single-pulse iDES in 11 subjects undergoing stereoelectroencephalographic presurgical evaluation. We systematically explored the role of several pulse parameters in evoking responses: monophasic versus biphasic pulses, current intensity, and pulse duration. We performed a correlation and regression analysis between responses to different protocols by amplitude, duration, and charge per phase. RESULTS: Regression analysis revealed that the responses were similar for the same charge per phase, regardless of their pulse duration and amplitude. Over eighty percent (82.8%) of the responses to variable pulse duration biphasic stimulation and between 58.6% and 81.9% of the responses to monophasic stimulation, depending on pulse polarity, were correlated to the responses evoked by the variable amplitude biphasic protocol, when expressing stimulus strength in terms of charge per phase. CONCLUSIONS: Regardless of the combination of different stimulation currents, it is the underlying charge per phase parameter that determines the magnitude of the responses to single-pulse electrical stimulation. SIGNIFICANCE: Our results provide a unifying method for comparing iDES protocols. PMID- 25910852 TI - Spectral and source structural development of mu and alpha rhythms from infancy through adulthood. AB - OBJECTIVE: To assess the developmental trajectory of spectral, topographic, and source structural properties of functional mu desynchronization (characterized during voluntary reaching/grasping movement), and investigate its spectral/topographic relation to spontaneous EEG in the developing alpha band. METHODS: Event related desynchronization (ERD) and power spectral density spectra/topography are analyzed in 12 month-old infants, 4 year-old children, and adults. Age-matched head models derived from structural MRI are used to obtain current density reconstructions of mu desynchronization across the cortical surface. RESULTS: Infant/child EEG contains spectral peaks evident in both the upper and lower developing alpha band, and spectral/topographic properties of functionally identified mu rhythm strongly reflect those of upper alpha in all subject groups. Source reconstructions show distributed frontoparietal patterns of cortical mu desynchronization concentrated in specific central and parietal regions which are consistent across age groups. CONCLUSIONS: Peak frequencies of mu desynchronization and spontaneous alpha band EEG increase with age, and characteristic mu topography/source-structure is evident in development at least as early as 12 months. SIGNIFICANCE: Results provide evidence for a cortically distributed functional mu network, with spontaneous activity measurable in the upper alpha band throughout development. PMID- 25910853 TI - Sewage workers with low antibody responses may be colonized successively by several Tropheryma whipplei strains. AB - OBJECTIVES: Asymptomatic faecal carriage of Tropheryma whipplei, the agent of Whipple's disease, is reported among sewage workers. However, the potential development of such carriage is unknown. A 7-year follow-up of T. whipplei carrying sewage workers is reported. METHODS: Nineteen sewage workers previously detected as faecal carriers of T. whipplei were followed to ascertain the chronicity of their carriage. Faeces were tested by molecular assays using quantitative real-time PCR specifically targeting T. whipplei. Serological anti T. whipplei Western blotting was also performed. RESULTS: Seventy-nine percent (15/19) of workers exhibited a strong immune response against T. whipplei. Among these, five were followed for more than 1 year. Four maintained a strong response, with three carrying the same strain and one becoming negative. The fifth exhibited a decreased immune response, a negative faeces result, and subsequent carriage of another strain. Three individuals with low immune responses were also followed. Two never developed a response, with one carrying the same strain and one becoming negative and then positive with another strain; the third developed a strong response and became negative. CONCLUSIONS: Chronic T. whipplei carriers appear to be protected against reinfection, but those with low or decreasing antibody levels may be re-colonized by another strain. PMID- 25910856 TI - Virtual reality video games to promote movement recovery in stroke rehabilitation: a guide for clinicians. PMID- 25910855 TI - The microbial epidemiology of breast implant infections in a regional referral centre for plastic and reconstructive surgery in the south of France. AB - BACKGROUND: Breast implant infections are usually caused by Staphylococcus aureus and coagulase-negative staphylococci. Gram-negative bacilli are rarely reported to be involved in breast implant infections. METHODS: Thirty-seven cases of microbiologically confirmed breast implant infection managed from January 2008 to June 2012 in the study centre were reviewed, including 10 cases from the study centre itself and 27 cases from private clinics in the region. RESULTS: The prevalence of breast implant infection in the study centre was 0.74% of breast implantation, i.e., 3.23% in breast reconstruction for breast cancer and 0.27% in aesthetic breast augmentation (p=0.0002). Of the 37 cases, 30% had undergone radiotherapy and 11% had undergone a lymph node dissection. S. aureus was identified in 18 cases, Gram-negative bacilli in 10 cases, coagulase-negative staphylococci in eight cases, anaerobic bacteria in eight cases, and streptococci in three cases. Pseudomonas aeruginosa was the second most commonly identified pathogen. Staphylococcus epidermidis was the most frequent coagulase-negative Staphylococcus species. In addition to Propionibacterium acnes and Actinomyces neuii, other facultative and strict anaerobic bacteria have not been reported before, e.g., Bacteroides thetaiotaomicron, Corynebacterium simulans, Dermabacter hominis, Finegoldia magna, and Peptoniphilus harei. Seventy-percent of cases were treated by immediate implant removal. All cases treated only with antibiotics were treated with surgery at the second visit. CONCLUSIONS: The microbiological epidemiology was noted by an increasing the proportion of Gram-negative bacteria and anaerobic bacteria detected with the advent of MALDI-TOF MS and molecular identification for diagnosis. PMID- 25910854 TI - Age, sex, and nutritional status modify the CD4+ T-cell recovery rate in HIV tuberculosis co-infected patients on combination antiretroviral therapy. AB - BACKGROUND: Baseline age and combination antiretroviral therapy (cART) were examined as determinants of CD4+ T-cell recovery during 6 months of tuberculosis (TB) therapy with/without cART. It was determined whether this association was modified by patient sex and nutritional status. METHODS: This longitudinal analysis included 208 immune-competent, non-pregnant, ART-naive HIV-positive patients from Uganda with a first episode of pulmonary TB. CD4+ T-cell counts were measured using flow cytometry. Age was defined as <=24, 25-29, 30-34, and 35 39 vs. >=40 years. Nutritional status was defined as normal (>18.5kg/m(2)) vs. underweight (<=18.5kg/m(2)) using the body mass index (BMI). Multivariate random effects linear mixed models were fitted to estimate differences in CD4+ T-cell recovery in relation to specified determinants. RESULTS: cART was associated with a monthly rise of 15.7 cells/MUl (p<0.001). Overall, age was not associated with CD4+ T-cell recovery during TB therapy (p = 0.655). However, among patients on cART, the age-associated CD4+ T-cell recovery rate varied by sex and nutritional status, such that age <40 vs. >=40 years predicted superior absolute CD4+ T-cell recovery among females (p=0.006) and among patients with a BMI >=18.5kg/m(2) (p<0.001). CONCLUSIONS: TB-infected HIV-positive patients aged >=40 years have a slower rate of immune restoration given cART, particularly if BMI is >18.5kg/m(2) or they are female. These patients may benefit from increased monitoring and nutritional support during cART. PMID- 25910857 TI - Brain uptake of a non-radioactive pseudo-carrier and its effect on the biodistribution of [(18)F]AV-133 in mouse brain. AB - INTRODUCTION: 9-[(18)F]Fluoropropyl-(+)-dihydrotetrabenazine ([(18)F]AV-133) is a new PET imaging agent targeting vesicular monoamine transporter type II (VMAT2). To shorten the preparation of [(18)F]AV-133 and to make it more widely available, a simple and rapid purification method using solid-phase extraction (SPE) instead of high-pressure liquid chromatography (HPLC) was developed. The SPE method produced doses containing the non-radioactive pseudo-carrier 9-hydroxypropyl-(+) dihydrotetrabenazine (AV-149). The objectives of this study were to evaluate the brain uptake of AV-149 by UPLC-MS/MS and its effect on the biodistribution of [(18)F]AV-133 in the brains of mice. METHODS: The mice were injected with a bolus including [(18)F]AV-133 and different doses of AV-149. Brain tissue and blood samples were harvested. The effect of different amounts of AV-149 on [(18)F]AV 133 was evaluated by quantifying the brain distribution of radiolabelled tracer [(18)F]AV-133. The concentrations of AV-149 in the brain and plasma were analyzed using a UPLC-MS/MS method. RESULTS: The concentrations of AV-149 in the brain and plasma exhibited a good linear relationship with the doses. The receptor occupancy curve was fit, and the calculated ED50 value was 8.165mg/kg. The brain biodistribution and regional selectivity of [(18)F]AV-133 had no obvious differences at AV-149 doses lower than 0.1mg/kg. With increasing doses of AV-149, the brain biodistribution of [(18)F]AV-133 changed significantly. CONCLUSION: The results are important to further support that the improved radiolabelling procedure of [(18)F]AV-133 using an SPE method may be suitable for routine clinical application. PMID- 25910858 TI - Nonalcoholic fatty liver disease induced by 13-week oral administration of 1,3 dichloro-2-propanol in C57BL/6J mice. AB - 1,3-Dichloro-2-propanol (1,3-DCP) is a food born chloropropanol contaminant that has been detected during the production process of a wide range of foods. In this study, we investigated the effect of 1,3-DCP on lipid metabolism of mice after 13 week subchronic exposure. The data showed that 1,3-DCP (0.05-0.5mg/kg/day) could induce nonalcoholic fatty liver disease (NAFLD) in C57BL/6J mice and the NOAEL was 0.01mg/kg/day. In addition, we studied the signaling pathway to see how 1,3 DCP worked. The data showed that NAFLD induced by 1,3-DCP was due to the dysregulation of AMPK signaling pathway. As far as we are aware, this is the first study to use 13-week subchronic toxicology to investigate the effect of 1,3 DCP on the development of NAFLD in mice. Our study provided evidence for diet contaminants in the development of NAFLD and furthered the safety evaluation of 1,3-DCP through subchronic exposure. PMID- 25910859 TI - Intestinal colonization with phylogenetic group B2 Escherichia coli related to inflammatory bowel disease: a systematic review and meta-analysis. AB - BACKGROUND AND OBJECTIVES: Increased numbers of Escherichia coli and, furthermore, specific subtypes of E. coli, such as E. coli of the phylogenetic groups B2 and D have been found in the intestine of patients with inflammatory bowel disease (IBD). In this review, we wanted to evaluate the relationship between B2 and D E. coli intestinal colonization and IBD. METHODS: A systematic review with meta-analyses. We included studies comparing colonization with B2 and D E. coli in IBD patients and in controls. Random-effects and fixed-effect meta analyses were performed. RESULTS: We included 7 studies on 163 patients with IBD and 89 controls. Among IBD patients, 57 patients had ulcerative colitis (UC) and 95 Crohn's disease (CD). Random-effects meta-analysis showed that IBD patients were more likely to have B2 E. coli intestinal colonization compared with controls (odds ratio [OR]: 2.28; 95% confidence interval [CI]: 1.25-4.16). There was little between-study heterogeneity (I(2) = 0). The result was confirmed in subgroup analyses of patients with UC (OR: 3.58; 95% CI: 1.62-7.90), but not CD (OR: 1.94; 95% CI: 0.98-3.82). Intestinal colonization with phylogenetic group D E. coli was not found to be related to IBD, UC or CD. CONCLUSIONS: Our study reveals that intestinal colonization with phylogenetic group B2 E. coli is associated with UC. Due to the design, we are unable to determine if the colonization with B2 E. coli leads to the development of the disease or the disease increases the risk of colonization with B2 E. coli. PMID- 25910860 TI - Global occurrence of anti-infectives in contaminated surface waters: Impact of income inequality between countries. AB - The presence anti-infectives in environmental waters is of interest because of their potential role in the dissemination of anti-infective resistance in bacteria and other harmful effects on non-target species such as algae and shellfish. Since no information on global trends regarding the contamination caused by these bioactive substances is yet available, we decided to investigate the impact of income inequality between countries on the occurrence of anti infectives in surface waters. In order to perform such study, we gathered concentration values reported in the peer-reviewed literature between 1998 and 2014 and built a database. To fill the gap of knowledge on occurrence of anti infectives in African countries, we also collected 61 surface water samples from Ghana, Kenya, Mozambique and South Africa, and measured concentrations of 19 anti infectives. A mixed one-way analysis of covariance (ANCOVA) model, followed by Turkey-Kramer post hoc tests was used to identify potential differences in anti infective occurrence between countries grouped by income level (high, upper middle and lower-middle and low income) according to the classification by the World Bank. Comparison of occurrence of anti-infectives according to income level revealed that concentrations of these substances in contaminated surface waters were significantly higher in low and lower-middle income countries (p=0.0001) but not in upper-middle income countries (p=0.0515) compared to high-income countries. We explained these results as the consequence of the absence of or limited sewage treatment performed in lower income countries. Furthermore, comparison of concentrations of low cost anti-infectives (sulfonamides and trimethoprim) and the more expensive macrolides between income groups suggest that the cost of these substances may have an impact on their environmental occurrence in lower income countries. Since wastewaters are the most important source of contamination of anti-infectives and other contaminants of emerging concern in the environment, it is expected that deleterious effects to the aquatic biota caused by these substances will be more pronounced in countries with inadequate wastewater and collection infrastructure. With the information currently available, we could not evaluate either the role of the receiving environment or the importance of regulatory frameworks on the occurrence of anti infectives in surface waters. Future studies should focus on these two factors in order to better evaluate risks to aquatic ecosystems in LM&LICs. We propose that CECs such as anti-infectives could be used as a new class of environmental degradation indicators that could be helpful to assess the state of development of wastewater collection and treatment infrastructure around the world. PMID- 25910861 TI - Explicit analytic equations for multimolecular thermal melting curves. AB - The analysis of thermal melting curves requires the knowledge of equations for the temperature dependence of the relative fraction of folded and unfolded components. To implement these equations as standard tools for curve fitting, they should be as explicit as possible. From the van't Hoff formalism it is known that the equilibrium constant and hence the folded fraction is a function of the absolute temperature, the van't Hoff transition enthalpy, and the melting temperature. The work presented here is devoted to the mathematically self contained derivation and the listing of explicit equations for the folded fraction as a function of the thermodynamic parameters in the case of arbitrary molecularities. Part of the results are known, others are new. It is in particular shown for the first time that the folded fraction is the composition of a universal function which depends solely on the molecularity and a dimensionless function which is governed by the concrete thermodynamic regime but is independent of the molecularity. The results will prove useful for extracting the thermodynamic parameters from experimental data on the basis of regression analysis. As supporting information, open-source Matlab scripts for the computer implementation of the equations are provided. PMID- 25910862 TI - Effects of heel base size, walking speed, and slope angle on center of pressure trajectory and plantar pressure when wearing high-heeled shoes. AB - High-heeled shoes are associated with instability and a high risk of fall, fracture, and ankle sprain. This study investigated the effects of heel base size (HBS) on walking stability under different walking speeds and slope angles. The trajectory of the center of pressure (COP), maximal peak pressure, pressure time integral, contact area, and perceived stability were analyzed. The results revealed that a small HBS increased the COP deviations, shifting the COP more medially at the beginning of the gait cycle. The slope angle mainly affected the COP in the anteroposterior direction. An increased slope angle shifted the COP posterior and caused greater pressure and a larger contact area in the midfoot and rearfoot regions, which can provide more support. Subjective measures on perceived stability were consistent with objective measures. The results suggested that high-heeled shoes with a small HBS did not provide stable plantar support, particularly on a small slope angle. The changes in the COP and pressure pattern caused by a small HBS might increase joint torque and muscle activity and induce lower limb problems. PMID- 25910863 TI - [Carotid endarterectomy: review of 10 years of practice of general and locoregional anesthesia in a tertiary care hospital in Portugal]. AB - BACKGROUND: Retrospective and prospective randomized studies have compared general and locoregional anesthesia for carotid endarterectomy, but without definitive results. OBJECTIVES: Evaluate the incidence of complications (medical, surgical, neurological, and hospital mortality) in a tertiary center in Portugal and review the literature. METHODS: Retrospective analysis of patients undergoing endarterectomy between 2000 and 2011, using a software for hospital consultation. RESULTS: A total of 750 patients were identified, and locoregional anesthesia had to be converted to general anesthesia in 13 patients. Thus, a total of 737 patients were included in this analysis: 74% underwent locoregianal anesthesia and 26% underwent general anesthesia. There was no statistically significant difference between the two groups regarding perioperative variables. The use of shunt was more common in patients undergoing general anesthesia, a statistically significant difference. The difference between groups of strokes and mortality was not statistically significant. The average length of stay was shorter in patients undergoing locoregional anesthesia with a statistically significant difference. CONCLUSIONS: We found that our data are overlaid with the literature data. After reviewing the literature, we found that the number of studies comparing locoregional and general anesthesia and its impact on delirium, cognitive impairment, and decreased quality of life after surgery is still very small and can provide important data to compare the two techniques. Thus, some questions remain open, which indicates the need for randomized studies with larger number of patients and in new centers. PMID- 25910864 TI - Diabetes mellitus: Possible risk and promoting factors of cholangiocarcinoma: Association of diabetes mellitus and cholangiocarcinoma. AB - The highest incidence of Cholangiocarcinoma (CCA), a malignancy of bile duct epithelia, is in the Northeast of Thailand. The liver fluke, Opisthorchis viverrini, is the known risk factor for CCA development in this region. Approximately 1% of O. viverrini infected individuals develop CCA. There could be other factors that influence the cholangiocarcinogenesis particularly in the O. viverrini infected individuals. The global epidemiological studies of risk factors for CCA in non-O. viverrini related patients indicated diabetes mellitus (DM) as a risk factor of CCA. The molecular studies in many cancers indicated that high levels of glucose, insulin and an obese condition directly and indirectly enhanced growth of cancers. For O. viverrini associated CCA, there is limited information related to DM and CCA development. High mortality rates of CCA and DM, however, were reported in the same geographical areas of northeastern Thailand. Whether DM is a factor that enhances CCA development in O. viverrini infected individuals or promotes CCA progression are discussed in a perspective of epidemiological and molecular studies. PMID- 25910865 TI - Participation, yield, and interval carcinomas in three rounds of biennial FIT based colorectal cancer screening. AB - BACKGROUND: The effectiveness of colorectal cancer screening programs based on the fecal immunochemical test (FIT) is influenced by program adherence during consecutive screening rounds. We aimed to evaluate the participation rate, yield, and interval cancers in a third round of biennial CRC screening using FIT and to compare those with the first and the second screening round. METHODS: A total of 3566 average-risk individuals aged 50-75 years were invited to participate in a third round of biennial FIT-based CRC screening. All FIT positives were recommended to undergo colonoscopy. We merged our data with the national cancer registry in the Netherlands to identify all non-screen-detected cancers in our cohort. RESULTS: Of the invitees, 2142 (60%) returned the FIT in this third screening round, compared to 56% in the second round and 57% in the first round. Overall, 153 of the third-round participants (7.1%) had a positive FIT result, versus 7.9% in the second round and 8.1% in the first round (P=0.05). Of all FIT positives, 123 (80%) underwent colonoscopy. Within this group, 33 persons had advanced neoplasia. The predictive value of FIT positivity for advanced neoplasia was 27% (33/123), compared to 42% in the second round and 54% in the first round a significant decline (P<0.01). CONCLUSION: In an FIT-based screening program, participation rates remained stable over consecutive biennial screening rounds, while the FIT positivity rate and positive predictive value for advanced neoplasia gradually declined. Cancers in non-participants are significantly more advanced in staging than cancers in participants in the first round of screening. PMID- 25910866 TI - Osteoporosis management and fractures in the Metis of Ontario, Canada. AB - Half of Metis citizens, compared to less than 10 % of the general population of Ontario, reside in northern regions, with little access to bone mineral density (BMD) testing. Metis citizens had lower sex-specific and age-standardized rates of BMD testing, yet similar rates of fracture (both sexes) and pharmacotherapy (women only). PURPOSE: To examine osteoporosis management and common osteoporosis related fractures among Metis citizens compared to the general population of older adults residing in Ontario. METHODS: We linked healthcare (medical and pharmacy) utilization and administrative (demographic) databases with the Metis Nation of Ontario citizenship registry to estimate osteoporosis management (bone mineral density [BMD] testing, pharmacotherapy) and fractures (hip, humerus, radius/ulna) among adults aged >=50 years, from April 1, 2006 to March 31, 2011. Pharmacotherapy data were limited to residents aged >=65 years. Sex-specific and age-standardized rates were compared between the Metis and the general population. Multivariable logistic regression was used to compare rates of BMD testing after controlling for differences in age and region of residence between the Metis and the general population. RESULTS: We studied 4219 Metis citizens (55 % men), and 140 (3 %) experienced a fracture. Half of Metis citizens, compared to less than 10 % of the general population of Ontario, resided in northern regions. We identified significantly lower sex-specific and age-standardized rates of BMD testing among Metis compared to the general population, yet found little difference in fracture rates (both sexes) or pharmacotherapy (women only). Differences in BMD testing disappeared after adjusting for region of residence among women yet remained significant among men. CONCLUSIONS: Despite finding significantly lower rates of osteoporosis management among men, Metis men and women were found to have similar age-standardized fracture rates to the general population. PMID- 25910867 TI - Carpal and scaphoid fracture incidence in south-eastern Australia: an epidemiologic study. AB - Carpal fractures were identified by the Geelong Osteoporosis Study Fracture Grid for 2006-2007. Incidence rates were higher in males than females. Males had a lower median age of fracture than females. Females had more fractures on the left side than males. Most fractures were the result of a fall. PURPOSE: In this study, we report the incidence of carpal bone fractures (scaphoid and non scaphoid) amongst residents from the Barwon Statistical Division over 2 years. METHODS: X-ray reports from imaging centres in the region were used to identify incident fractures during 2006 and 2007. Data were collected as part of the Geelong Osteoporosis Study Fracture Grid. RESULTS: During 2006 and 2007, there were 171 and 41 carpal fractures in males and females, respectively. Of these, 131 males and 29 females had fractured the scaphoid bone. Females had a higher proportion of left-sided fractures (>70 %) than males (~40 %). Most fractures were the result of an accidental fall (>87 %). Patterns of incidence for males showed one major peak around 20-29 years. For females, peaks occurred around age 10-19 years and 70-79 years. Incidence rates for males (per 100,000 persons per year) were 54.6 (95 % confidence interval (CI) 53.6, 55.7) and 15.9 (95 % CI 15.4, 16.5) for scaphoid and non-scaphoid fractures, respectively. In females, the corresponding rates were 10.6 (95 % CI 10.2, 11.1) and 4.5 (95 % CI 4.2, 4.8). CONCLUSION: Almost all fractures were the result of a fall. In males, carpal fractures were sustained mainly during early adulthood and in females during adolescence and after menopause. Incidence rates for males were higher than those in females for both scaphoid and non-scaphoid fractures. PMID- 25910868 TI - Publication outcomes of the abstracts presented at the 2011 European Congress on Osteoporosis, Osteoarthritis and Musculo-Skeletal Diseases (ECCEO-IOF11): A position paper of the European Society for Clinical and Economical Aspects of Osteoporosis, Osteoarthritis and Musculo-Skeletal Diseases (ESCEO) and the International Osteoporosis and Other Skeletal Diseases Foundation (IOF). AB - The publication outcomes of the abstracts presented during the ECCEO-IOF 2011 reflect a high research productivity, support the robustness of the selection process conducted by the Scientific Advisory Committee and suggest that IOF-ESCEO WCO is successful in its mission to promote and disseminate research. BACKGROUND AND OBJECTIVE: The European (now World) Congress on Osteoporosis, Osteoarthritis and Musculo-Skeletal Diseases (IOF-ESCEO WCO, formerly ECCEO-IOF) is the largest worldwide event fully dedicated to the clinical, epidemiological, translational and economic aspects of bone, joint and muscle diseases. The role of the Scientific Advisory Committee is to select abstracts for oral communication or poster presentation based on a short summary of the research. The aim of the present survey was to determine the publication rate in international peer reviewed journals of abstracts accepted at the IOF-ESCEO WCO 2011 Meeting (formerly ECCEO-IOF11), the relationship, if any, between the presentation format of the abstract and its subsequent full publication and the impact factor of the journal in which research was published. RESULTS: Of 619 abstracts accepted at the 2011 ECCEO-IOF11 annual meeting, 45 were accepted for oral communication and 574 accepted for poster presentation. In the subsequent 3 years (2011-2014), 191 abstracts were published as a full-length manuscript (30.9 %). The publication rate was significantly higher for oral communications (75.6 %) than for poster presentations (27.4 %; p < 0.0001). Publications derived from oral communications were published in journals with a higher impact factor (8.3 +/- 10.1) than those arising from poster presentations (4.0 +/- 2.3; p < 0.0001), but there was no difference in the time to publication (OC 16.3 [IQR 8.4-23.3] months vs PP 11.3 [IQR 5.3-21.4]; p = 0.14). CONCLUSION: These results indicate a high research productivity and an appropriate selection of oral communication by the Scientific Advisory Committee of ESCEO-IOF. PMID- 25910869 TI - Consolidating the State of Knowledge: A Synoptical Review of Wind Energy's Wildlife Effects. AB - Wind energy development contributes substantially to achieve climate protection goals. Unintended side effects, especially on wildlife, have long been discussed and substantial research has evolved over the last decade. At this stage, it is important to identify what we have learnt so far, as well as which predominant uncertainties and gaps remain. This review article aims to consolidate the state of knowledge, providing a qualitative analysis of the main effects of wind energy development on- and offshore, focusing on frequently studied species groups (bats, breeding and resting birds, raptors, migratory birds, marine mammals). We reviewed over 220 publications from which we identified predominant hypotheses that were summarized and displayed in tables. Journal publications, conference contributions, and further studies have been considered. We found that research focusing on offshore wind energy within the last couple of years has increased significantly as well, catching up with the vast amount of onshore studies. Some hypotheses have been verified by numerous publications and a consensus has been reached (e.g., correlation between bat activity and weather factors), while others are still being debated more (e.g., determination of migratory corridors) or remain unknown (e.g., effect on population level). Factors influencing potential effects were mainly related to species characteristics (morphology, phenology, abundance, behavior, and response to turbines) or site characteristics (landscape features, weather, and habitat quality). Consolidating the state of research provides the groundwork for the identification of mitigation measures and advanced planning approaches. However, the quantification of effects remains challenging and uncertainties will always persist. PMID- 25910870 TI - Assessment Approach for Identifying Compatibility of Restoration Projects with Geomorphic and Flooding Processes in Gravel Bed Rivers. AB - A critical requirement for a successful river restoration project in a dynamic gravel bed river is that it be compatible with natural hydraulic and sediment transport processes operating at the reach scale. The potential for failure is greater at locations where the influence of natural processes is inconsistent with intended project function and performance. We present an approach using practical GIS, hydrologic, hydraulic, and sediment transport analyses to identify locations where specific restoration project types have the greatest likelihood of working as intended because their function and design are matched with flooding and morphologic processes. The key premise is to identify whether a specific river analysis segment (length ~1-10 bankfull widths) within a longer reach is geomorphically active or inactive in the context of vertical and lateral stabilities, and hydrologically active for floodplain connectivity. Analyses involve empirical channel geometry relations, aerial photographic time series, LiDAR data, HEC-RAS hydraulic modeling, and a time-integrated sediment transport budget to evaluate trapping efficiency within each segment. The analysis segments are defined by HEC-RAS model cross sections. The results have been used effectively to identify feasible projects in a variety of alluvial gravel bed river reaches with lengths between 11 and 80 km and 2-year flood magnitudes between ~350 and 1330 m(3)/s. Projects constructed based on the results have all performed as planned. In addition, the results provide key criteria for formulating erosion and flood management plans. PMID- 25910871 TI - The Relationship Between Perceptions of Wilderness Character and Attitudes Toward Management Intervention to Adapt Biophysical Resources to a Changing Climate and Nature Restoration at Sequoia and Kings Canyon National Parks. AB - In a recent national survey of federal wilderness managers, respondents identified the high priority need for scientific information about public attitudes toward biophysical intervention to adapt to climate change and attitudes of the public toward restoration of natural conditions. In a survey of visitors to one National Park wilderness in California, visitors revealed that they largely do not support biophysical intervention in wilderness to mitigate the effects of climate change, but broad support for activities that restore natural conditions exists. In an attempt to understand how these attitudes vary among visitors, it was found that those visitors who most value naturalness aspects of wilderness character also most positively support restoration and are most negative toward climate change intervention practices. More information about visitor-defined wilderness character attributes is needed and strategic planning to guide intervention decisions and restoration should be a priority. In this study, it was found that wilderness character is largely defined by visitors based on its wildness attributes, which include natural sounds, low density of people, pure water, clean air, and the presence of humans substantially unnoticeable. PMID- 25910872 TI - Head Position in the Early Phase of Acute Ischemic Stroke: An International Survey of Current Practice. AB - BACKGROUND: Evidence to recommend a specific head position for patients in the early phase of acute ischemic stroke (AIS) is scarce. The aim of this study was to assess current head position practice for AIS patients among physicians from hospitals in different countries. METHODS: A cross-sectional survey research design was used; physicians who are part of a stroke research network were invited to participate by e-mail. Descriptive statistics were used. RESULTS: An invitation to participate was delivered to 298 doctors from 16 countries and 42.9% completed all survey questions. Participant responses were evenly divided in sitting up and lying flat position as the most usual at their hospital: 52.8% (95% confidence interval [CI], 43.7-61.0) of respondents preferred sitting up, whereas 47.2% (95% CI, 38.2-55.5) preferred lying flat; 53.9% (95% CI, 45.3-62.5) of participants answered that no written protocol specifying the indicated head position for stroke patients was available at their hospital or department, and 71% (95% CI, 63.2-78.9) recognized being uncertain about the best position for AIS patients. CONCLUSIONS: Common practice differs between physicians, and there is a lack of consensus about the best strategy regarding head position for AIS patients in many countries. An opportunity exists for a randomized trial to resolve this uncertainty and develop evidence-based consensus protocols to improve patient management and outcomes. PMID- 25910873 TI - High Incidence of Dementia Conversion than Stroke Recurrence in Poststroke Patients of Late Elder Society. AB - BACKGROUND: This study investigated the incidence of current poststroke dementia (PSD), the annual conversion ratio into PSD, and the risk factors for conversion. METHODS: In a 4.8-year follow-up period, 112 poststroke patients (ischemic stroke and intracerebral hemorrhage) were retrospectively investigated in cognitive examinations. They were categorized into 3 subgroups: converters into PSD, nonconverters who maintained their normal cognitive functions, and reverters who recovered to the normal mentality range. The clinical and demographic characteristics of these 3 subgroups were analyzed. RESULTS: Among all 112 poststroke patients (61.6% male, 73.6 +/- 10.4 years old), 16.1% had PSD. During the follow-up period, a part of the normal baseline mentality group (83.9% of 112 original patients) newly developed PSD (subdivided into converters) with an annual conversion rate of 7.6%. The reversion rate from the baseline PSD group was 11.3%. There were significant differences in age (P < .05), baseline mini mental state examination scores (P < .05), body mass index (P < .05), and periventricular and deep white matter hyperintensity grades (P < .05 and P = .01, respectively) between converters and nonconverters. The annual rate of stroke recurrence was only 2.2% in all stroke subtypes. CONCLUSIONS: In comparison with stroke recurrence (2.2%), 7.6% of the annual PSD conversion rate was very high. Therefore, prevention of direct conversion into PSD without stroke recurrence may be another important aspect of poststroke clinics, especially in late elder society. PMID- 25910874 TI - Haplotypic diversity of porcine LEP and LEPR genes involved in growth and fatness regulation. AB - The analysis of structural genetic variability in candidate genes can make it possible to analyse the selection footprint and deepen the understanding of the genetic basis of complex traits. The leptin (LEP) and its receptor (LEPR) porcine genes are involved in food intake and energy homeostasis, and polymorphisms associated to growth and fatness traits have been detected in both genes. The main objective of this study was to explore the genetic variability of the most polymorphic regions of both genes in a variety of pig populations and wild boars from diverse European and Asian origins. In total, 54 animals were included in the analyses, with a remarkable sampling of Spanish wild boars and Iberian pigs. The sequencing allowed the identification of 69 and 26 polymorphisms in LEP and LEPR genes, respectively. Neighbour-joining trees built for the 69 haplotypes identified in the LEP and the 24 haplotypes detected in the LEPR showed the known genetic divergence between European and Asian pig breeds. A high variability of the LEP was detected in the different analysed populations providing new data for the existence of two domestication centres in Asia. In comparison to the LEP gene, the LEPR showed a lower variability, especially in the Iberian breed that showed no variability. Moreover, results of the Hudson-Kreitman-Aguade neutrality test support a possible selection event of the LEPR gene region in this breed, potentially related with its leptin resistance pattern and good adaptation to a traditional extensive production system with strong seasonal changes of feeding resources. PMID- 25910875 TI - MicroRNAs and the functional beta cell mass: For better or worse. AB - Insulin secretion from pancreatic beta cells plays a central role in the control of blood glucose levels. The amount of insulin released by beta cells is precisely adjusted to match organism requirements. A number of conditions that arise during life, including pregnancy and obesity, can result in a decreased sensitivity of insulin target tissues and a consequent rise in insulin needs. To preserve glucose homoeostasis, the augmented insulin demand requires a compensatory expansion of the pancreatic beta cell mass and an increase in its secretory activity. This compensatory process is accompanied by modifications in beta cell gene expression, although the molecular mechanisms underlying the phenomenon are still poorly understood. Emerging evidence indicates that at least part of these compensatory events may be orchestrated by changes in the level of a novel class of gene regulators, the microRNAs. Indeed, several of these small, non-coding RNAs have either positive or negative impacts on beta cell proliferation and survival. The studies reviewed here suggest that the balance between the actions of these two groups of microRNAs, which have opposing functional effects, can determine whether beta cells expand sufficiently to maintain blood glucose levels in the normal range or fail to meet insulin demand and thus lead, as a consequence, towards diabetes manifestation. A better understanding of the mechanisms governing changes in the microRNA profile will open the way for the development of new strategies to prevent and/or treat both type 2 and gestational diabetes. PMID- 25910876 TI - Real life narratives enhance learning about the 'art and science' of midwifery practice. AB - Health professional educators have long grappled with how to teach the more elusive art of practice alongside the science (a term that encompasses the sort of professional knowledge that can be directly passed on). A competent practitioner is one who knows when, how and for whom to apply knowledge and skills, thereby making the links between theory and practice. They combine art and science in such a way that integrates knowledge with insight. This participatory hermeneutic study explored the experience of teachers and students of implementing a narrative-centred curriculum in undergraduate midwifery education. It revealed that when real life narratives were central to the learning environment, students' learning about the art of midwifery practice was enhanced as they learned about midwifery decisions, reflected on their own values and beliefs and felt an emotional connection with the narrator. Further, art and science became melded together in the context specific wisdom of practice (phronesis). PMID- 25910877 TI - Relationships among nitric oxide metabolites and pulses of a PGF2alpha metabolite during and after luteolysis in mares. AB - Hourly circulating concentrations of a PGF2alpha metabolite (PGFM), progesterone (P4), and LH were obtained from a reported project, and concentrations of nitric oxide (NO) metabolites (NOMs; nitrates and nitrites) were determined in eight mares. Unlike the reported project, hormone concentrations were normalized to the peak of the first PGFM pulse of luteolysis (early luteolysis), second PGFM pulse (late luteolysis), and a pulse after luteolysis. The duration of luteolysis was 23.1 +/- 1.0 hours, and the peak of the first and second PGFM pulses occurred 6.5 +/- 0.9 and 14.8 +/- 0.8 hours after the beginning of luteolysis. Concentration of P4 decreased progressively within and between the PGFM pulses Changes were not detected in LH concentration in association with the PGFM pulses. Concentration of NOMs was greater (P < 0.05) at the peak of the PGFM pulse during early luteolysis (88.8 +/- 15.0 MUg/mL) than during late luteolysis (58.8 +/- 9.0 MUg/mL). Concentration of NOMs began to decrease (P < 0.05) 4 hours before the peak of the PGFM pulse of early luteolysis. Concentration began to increase (P < 0.05) an hour after the peak of the PGFM pulse of late luteolysis. An NOM decrease and increase was not detected during the PGFM pulse after luteolysis. On a temporal basis, results indicated that NO either is not required for luteolysis in mares or has a role in or responds only during late luteolysis. A caveat is that the relative contribution of the CL versus other body tissues to circulating concentrations of NOMs in mares has not been determined. PMID- 25910878 TI - The Pharmacogenetics of Tramadol. AB - BACKGROUND AND OBJECTIVE: Tramadol hydrochloride is used worldwide as an analgesic drug with a unique dual function. The metabolic enzymes cytochrome P450 (CYP) 3A4, CYP2B6, and CYP2D6 and the various transporters [adenosine triphosphate-binding cassette B1/multidrug resistance 1/P-glycoprotein, organic cation transporter 1, serotonin transporter (SERT), norepinephrine transporter (NET)] and receptor genes (opioid receptor MU 1 gene) give possible genetic differences that might affect the pharmacokinetics and/or pharmacodynamics of tramadol. Therefore, the aim of this review is to present a systematic walkthrough of all possible genetic factors involved in the pharmacology of tramadol. METHOD: A systematic literature search was conducted in PubMed and EMBASE involving all metabolic enzymes, drug transporters and receptors, as well as SERT and NET that are involved in the pharmacokinetics and pharmacodynamics of tramadol. An additional search on population pharmacokinetics with genetic factors as covariates was performed separately. RESULTS: A total of 56 studies (45 cohort and case-control studies, three case reports, six in vitro studies, and two animal studies) were included. CONCLUSION: In this systematic review, the current knowledge on all possible genetic factors that might influence the metabolism or clinical efficacy of tramadol has been collected and summarized. Only the effect of CYP2D6 polymorphisms on the metabolism of tramadol and the consequent effect on pain relief has been thoroughly studied and sufficiently established as clinically relevant. PMID- 25910879 TI - Investigation of Saliva as an Alternative to Plasma Monitoring of Voriconazole. AB - BACKGROUND AND OBJECTIVES: Therapeutic drug monitoring (TDM) of voriconazole is increasingly being implemented in clinical practice. However, as blood sampling can be difficult in paediatric and ambulatory patients, a non-invasive technique for TDM is desirable. The aim of this study was to compare the pharmacokinetics of voriconazole in saliva with the pharmacokinetics of unbound and total voriconazole in plasma in order to clinically validate saliva as an alternative to plasma in voriconazole TDM. METHODS: In this pharmacokinetic study, paired plasma and saliva samples were taken at steady state in adult haematology and pneumology patients treated with voriconazole. Unbound and bound plasma voriconazole concentrations were separated using high-throughput equilibrium dialysis. Voriconazole concentrations were determined with liquid chromatography tandem mass spectrometry. Pharmacokinetic parameters were calculated using log linear regression. RESULTS: Sixty-three paired samples were obtained from ten patients (seven haematology and three pneumology patients). Pearson's correlation coefficients (R values) for saliva versus unbound and total plasma voriconazole concentrations showed a very strong correlation, with values of 0.970 (p < 0.001) and 0.891 (p < 0.001), respectively. Linear mixed modelling revealed strong agreement between voriconazole concentrations in saliva and unbound plasma voriconazole concentrations, with a mean bias of -0.03 (95 % confidence interval 0.14 to 0.09; p = 0.60). For total concentrations below 10 mg/L, the mean ratio of saliva to total plasma voriconazole concentrations was 0.51 +/- 0.08 (n = 63), which did not differ significantly (p = 0.76) from the unbound fraction of voriconazole in plasma of 0.49 +/- 0.03 (n = 36). CONCLUSIONS: Saliva can serve as a reliable alternative to plasma in voriconazole TDM, and it can easily be implemented in clinical practice. PMID- 25910880 TI - Molecular stacking character and charge transport properties of tetrabenzoheptacenes derivatives: the effects of nitrogen doping and phenyl substitution. AB - The nitrogen doping and phenyl substitution effects on the geometries, molecular stacking character, electronic, and charge transport properties of tetrabenzoheptacene (TTBH) have been investigated by means of density functional theory (DFT) calculation and incoherent charge hopping model. Our results indicate that the nitrogen doping (TTH) at the 6,8,15,17 positions improves its stability in air and the ability of electron injection and in the meantime slightly changes the molecular stacking due to the C-H...N interaction. For both TTBH and TTH, large hole transport mobility (MUh) and electron transport mobility (MUe), which are on the same order of magnitude, are given rise by their dense displaced pi-stacking in crystal. Comparatively, the phenyl substitution (Ph TTBH) at the 6,8,15,17 positions adopts a non-planar conformation, adverse to close packing and therefore leads to smaller electron/hole transport mobility (MU) than those of TTBH and TTH. The calculations suggest TTBH and TTH are promising candidates for excellent ambipolar OFET materials. PMID- 25910881 TI - Stimuli-responsive materials in analytical separation. AB - This review focuses on the fundamentals of stimuli-responsive materials and their applications to three common separation techniques, namely extraction, chromatography, and electrophoresis. Although still little investigated, materials that switch their affinity for the analyte on and off as a function of tiny changes in physical and biochemical variables offer relevant advantages for analyte extraction, concentration, and separation. Temperature and/or pH responsive polymers in the form of chains or networks, which are dispersed in the sample as free entities or after being grafted onto beads (which may incorporate magnetic cores), enable quantitative capture and/or elution of the analyte under mild conditions and without needing organic solvents. Regarding liquid chromatography separation, responsive stationary phases enable the implementation of "all-in-water" procedures in which retention times are modulated by means of temperature or pH gradients. Other stimuli that can be externally applied, for example light or magnetic fields, can also be used for efficient extraction or separation of the target substance without altering the composition of the sample matrix. Moreover, stimuli-responsiveness enables straightforward recycling of solid and/or stationary phases for a prolonged lifetime. Improved understanding of the phase transitions of stimuli-responsive materials and design of suitable formats for analytical applications should enable wider and more successful application of stimuli-responsive materials in analytical separations. PMID- 25910882 TI - GC * GC-TOFMS and supervised multivariate approaches to study human cadaveric decomposition olfactive signatures. AB - In forensic thanato-chemistry, the understanding of the process of soft tissue decomposition is still limited. A better understanding of the decomposition process and the characterization of the associated volatile organic compounds (VOC) can help to improve the training of victim recovery (VR) canines, which are used to search for trapped victims in natural disasters or to locate corpses during criminal investigations. The complexity of matrices and the dynamic nature of this process require the use of comprehensive analytical methods for investigation. Moreover, the variability of the environment and between individuals creates additional difficulties in terms of normalization. The resolution of the complex mixture of VOCs emitted by a decaying corpse can be improved using comprehensive two-dimensional gas chromatography (GC * GC), compared to classical single-dimensional gas chromatography (1DGC). This study combines the analytical advantages of GC * GC coupled to time-of-flight mass spectrometry (TOFMS) with the data handling robustness of supervised multivariate statistics to investigate the VOC profile of human remains during early stages of decomposition. Various supervised multivariate approaches are compared to interpret the large data set. Moreover, early decomposition stages of pig carcasses (typically used as human surrogates in field studies) are also monitored to obtain a direct comparison of the two VOC profiles and estimate the robustness of this human decomposition analog model. In this research, we demonstrate that pig and human decomposition processes can be described by the same trends for the major compounds produced during the early stages of soft tissue decomposition. PMID- 25910883 TI - Study of vortex-assisted MSPD and LC-MS/MS using alternative solid supports for pharmaceutical extraction from marketed fish. AB - A procedure based on vortex-assisted matrix solid-phase dispersion (MSPD) for the extraction of 15 pharmaceuticals from fish samples with determination by liquid chromatography-tandem mass spectrometry (LC-MS/MS) was validated. Florisil, C18, diatomaceous earth, chitin, and chitosan were evaluated as solid supports. Best results were obtained with 0.5 g of diatomaceous earth, 0.5 g of sodium sulfate, and 5 mL of methanol. Analytical recoveries ranged from 58 to 128 % with relative standard deviation (RSD) lower than 15 %. Limit of quantification (LOQ) values for the 15 compounds ranged from 5 to 1000 ng g(-1). The method under investigation has shown to be a simple and fast extraction tool with minimum instrumentation and low amount of reagent, resulting in method low cost. Besides, alternative materials, such as chitin and chitosan, which were applied to the dispersion step for the first time, were found to be interesting alternatives. PMID- 25910884 TI - Anti-idiotypic nanobody as citrinin mimotope from a naive alpaca heavy chain single domain antibody library. AB - Compared with peptide-based mimotope, anti-idiotypic antibodies (AIds) are considered as promising biosynthetic surrogate antigen because these antibodies display stable protein conformation. Nevertheless, conventional AIds are generated by immunizing animals with heterologous idiotypic antibody in vivo; isolated AIds commonly exhibit a higher affinity to primary antibodies than target analytes because AIds undergo an affinity-matured process during immune responses, resulting in low sensitivity in competitive immunoassay. In the present study, an anti-citrinin monoclonal antibody (anti-CIT McAb) was designed as primary antibody; one beta-type AI alpaca heavy chain single domain antibody (beta-AI VHH) was selected as a citrinin (CIT) surrogate from a naive phage displayed VHH library. The affinity constant (K D) of obtained beta-AI VHH to anti-CIT McAb (160 nM) is 2.35 times lower than that of CIT and ovalbumin conjugates (CIT-OVA) to anti-CIT McAb (68 nM). The developed VHH-based enzyme linked immunosorbent assay (V-ELISA) can be used to perform dynamic linear detection of CIT in 10% (v/v) methanol/PBS from 5.0 to 300.0 ng/mL, with a median inhibitory concentration (IC50) of 44.6 ng/mL (n = 3); this result was twice as good as that of indirect competitive ELISA (ic-ELISA, IC50 = 96.2 ng/mL) with CIT OVA as a coating antigen. Moreover, the precision of V-ELISA was evaluated by analyzing average recoveries and coefficient of variations of CIT-spiked cereal sample; the reliability of V-ELISA was also validated with a conventional ic ELISA. In summary, the proposed strategy has a great potential for panning other beta-AI VHH toward small organic molecules from a naive VHH library. PMID- 25910885 TI - Smoking as dominant risk factor for anastomotic leak after left colon resection. AB - BACKGROUND: Some risk factors for anastomotic leak have been identified, but the effect of smoking is unknown. METHODS: This study aimed to evaluate the effect of smoking on clinical leak after left-sided anastomoses. Adult patients who underwent elective left colectomy between January 1, 2008 and December 31, 2012 were included. Those with stomas and inflammatory bowel diseases were excluded. Primary outcome was anastomotic leak requiring percutaneous drainage or operative intervention within 30 days. RESULTS: There were 246 patients included; 56% were female. Most had a diagnosis of diverticular disease (53%) or cancer (37%). Anastomotic leak rate was 6.5% (n = 16). The rate in smokers was 17% versus 5% in nonsmokers (P = .01). Smokers had over 4 times greater chance of leak (odds ratio 4.2, 95% confidence interval 1.3 to 13.5, P = .02). CONCLUSION: Smoking is a risk factor for leak after left colectomy. Consideration should be given to delaying elective left colectomy until smoking cessation is achieved. PMID- 25910886 TI - Comparison of short-term surgical results of single-port and multi-port laparoscopic rectal resection for rectal cancer. AB - BACKGROUND: Single-port surgery is a recent advancement in minimally invasive techniques for colon disease. However, single-port laparoscopic rectal resection (SPLR) is rare. The aim of this study was to compare the short-term results of SPLR with those of multi-port laparoscopic rectal resection (MPLR) for rectal cancer. METHODS: Patients who underwent SPLR (n = 50) or MPLR (n = 50) for rectal cancer from July 2010 to March 2014 were analyzed. Patients with tumor diameter less than 40 mm and body mass index less than 30 kg/m(2) were matched for age, sex, tumor location, and preoperative evaluation. Operative parameters and outcomes were compared between groups. Patients with lower rectal cancer were excluded. RESULTS: SPLR was successful in 98.0% of cases. Operative procedure, operative time, blood loss, field of lymph node dissection, and rate of postoperative complications did not differ significantly. Length of hospital stay was shorter with SPLR than with MPLR (8 vs 10 days, respectively; P = .018). Oncological outcomes did not differ significantly between the 2 groups. CONCLUSION: SPLR is safe and feasible in selected patients with rectal cancer. PMID- 25910887 TI - Geriatric surgery--evolution of a clinical community. AB - BACKGROUND: We reviewed the current scientific data and opinions from thought leaders in the field of surgery in the elderly population and queried whether a new society should be formed. METHODS: The science of geriatric surgery (GS) was reviewed, including topics scientific sessions focused on GS. A town hall meeting was held, which included geriatric surgical scholars. A survey was created to define the interest in GS as a specialty society was sent to surgical scholars. RESULTS: As the volume of GS scholarly work has increased, the focus of geriatric science has migrated toward clinical studies on frailty and geriatric syndromes. Our town hall meeting outlined the need for a multidisciplinary GS team. Our survey documented more interest in multidisciplinary sessions at national meetings rather than a new, unique society. CONCLUSIONS: GS as a discipline is a multidisciplinary practice. Our data suggest that this unique characteristic speaks to the development of a clinical community rather than an independent society. PMID- 25910888 TI - Current status of anesthesia residency in Taiwan: a questionnaire survey. AB - PURPOSE: There are 26 teaching hospitals in Taiwan that provide anesthesia residency training programs (one program per hospital), and only an average of 40 medical graduates are accepted for residency training per year. The aim of this study is to understand how this situation affects the learning and working conditions of anesthesia residents in Taiwan. METHODS: A self-structured survey was mailed to all 178 anesthesia residents receiving training in Taiwan in April 20, 2012. Survey questions included resident characteristics, working and learning conditions, satisfaction with resident training programs, and reasons for choosing anesthesiology as a career. In addition to descriptive statistics, linear regression was used to test correlation between working conditions and satisfaction with training programs. RESULTS: The survey was completed by 136 residents. Although the residents' expected optimal working time was 54.1 +/- 12.2 h per week, their actual working time was an average of 64.0 +/- 15.7 h per week. In addition, the workload included managing 4.2 +/- 1.3 operating rooms simultaneously. The ratio of working vs. learning time was 2.2 +/- 1.1. Less than 40 % of the residents were satisfied with their training in critical care and pain management. Anesthesia residents with heavier workloads and higher ratios of work vs. learning time had significantly lower satisfaction with their training programs, especially with training environments (R (2) = 0.169). General interest in anesthesiology and related work (66.1 %) was the main factor in choosing anesthesia as their career. CONCLUSIONS: Anesthesia residents in Taiwan are treated as an integral part of hospital manpower. This may limit the effectiveness of their learning and cause dissatisfaction with their training environment. To improve the current status, anesthesia residents should perform anesthesia in one operating room at a time and some of the anesthesia training hospitals should be suggested for removal. PMID- 25910889 TI - Laryngoscopy facilitates successful i-gel insertion by novice doctors: a prospective randomized controlled trial. AB - BACKGROUND: This study investigated the hypothesis that the efficacy of insertion of the supraglottic device i-gel((r)) (i-gel) can be improved by laryngoscopy and can provide better sealing pressure in anesthetized patients by novice doctors. METHODS: Eighty-four adult patients were assigned to the laryngoscopy group (L group, 42 patients) or control group (i.e., conventional blind insertion; C group, 42 patients). Anesthesia was induced with propofol and remifentanil, and rocuronium 0.6-0.9 mg/kg was administered. The number of attempts until successful insertion, sealing pressure, vital sign changes upon insertion, and subjective difficulty of insertion by novice doctors were compared between the groups. RESULTS: The total number of insertion attempts was one (L group 36 cases, C group 23 cases), two (L group 6 cases, C group 18 cases), and three (L group 0 case, C group 1 case), with significant differences between groups (P = 0.007). The sealing pressure was significantly higher in the L group than in the C group (L group 22.3 +/- 2.6 cmH2O, C group 19.5 +/- 2.7 cmH2O, P < 0.001). Vital sign changes (heart rate and blood pressure) did not differ between the two groups. The subjective difficulty of insertion was significantly lower in the L group than in the C group (L group 26.8 +/- 11.8 mm, C group 47.0 +/- 15.1 mm, P < 0.001). The incidence of postoperative pharyngeal pain was significantly lower in the L group than in the C group (P < 0.001), while the incidence of hoarseness did not differ between the two groups (P = 1.00). CONCLUSION: Our results suggest that laryngoscopy facilitates i-gel insertion by novice doctors, as reflected in the rate of successful insertions, higher sealing pressure, and lower subjective difficulty of insertion in anesthetized patients. PMID- 25910890 TI - Contrast medium at the site of the anastomosis is crucial in detecting anastomotic leakage with CT imaging after colorectal surgery. AB - PURPOSE: The use of computed tomography (CT) to detect anastomotic leakage (AL) is becoming the standard of care. Accurate detection of AL is crucial. The aim of this study was to define CT criteria that are most predictive for AL. METHODS: From January 2006 to December 2012, all consecutive patients who had undergone CT imaging because of clinical suspicion of anastomotic leakage after colorectal surgery were analysed. All CT scans were re-evaluated by two independent abdominal radiologists blinded for clinical outcome. The images were scored with a set of criteria and a conclusion whether or not AL was present was drawn. Each separate criterion was analysed for its value in predicting AL by uni- and multivariable logistic regression RESULTS: Of 668 patients with colorectal surgery, 108 had undergone CT imaging within 16 days postoperatively. According to our standard of reference, 34 (31%) of the patients had AL. Univariable analysis showed that "fluid near anastomosis" (radiologist 1 (rad 1), p < 0.001; radiologist 2 (rad 2), p < 0.001) and "air near anastomosis" (rad 1, p < 0.001; rad 2, p < 0.001), "air intra-abdominally" (rad 1, p = 0.019; rad 2, p = 0.004) and "contrast leakage" (rad 1, p < 0.001; rad 2, p < 0.001) were associated with AL. Contrast leakage was the only independent predictor for AL in multivariable analysis for both radiologists (rad 1, OR 5.43 (95% CI 1.18-25.02); rad 2, OR 8.51 (95% CI 2.21-32.83)). CONCLUSION: The only independent variable predicting AL is leakage of contrast medium. To improve the accuracy of CT imaging, optimal contrast administration near the anastomosis appears to be crucial. PMID- 25910891 TI - Management strategies for acute coronary occlusion associated with CoreValve transcatheter aortic valve replacement. PMID- 25910893 TI - [Using the RAND-36 among community-dwelling older adults can lead to an underestimation of self-reported health]. AB - The overall health status of the population is often measured by RAND-36 item Health Survey. In 2012, Fontys and partners started a longitudinal field study in the Netherlands. This study is aimed at identifying factors that influence the use of technology by elderly individuals in order to increase independent living. A total of 50 participants aged 70 years or older, are interviewed every eight months, for a total of four years. In addition, participants are asked to fill in several questionnaires. One questionnaire that is (partly) included is the Dutch version of the RAND-36, which includes the statement; "I am as healthy as anybody I know". Some participants who find themselves healthier than other people they know (want to) fill in an answer that indicates that they find themselves less healthy than others (e.g. "I am not as healthy as anybody, I am healthier so I answer 'definitely false'"). Hence, the Dutch version of this RAND-36 statement can lead to an underestimation of the overall health status of Dutch elderly individuals. PMID- 25910892 TI - Highly porous non-precious bimetallic electrocatalysts for efficient hydrogen evolution. AB - A robust and efficient non-precious metal catalyst for hydrogen evolution reaction is one of the key components for carbon dioxide-free hydrogen production. Here we report that a hierarchical nanoporous copper-titanium bimetallic electrocatalyst is able to produce hydrogen from water under a mild overpotential at more than twice the rate of state-of-the-art carbon-supported platinum catalyst. Although both copper and titanium are known to be poor hydrogen evolution catalysts, the combination of these two elements creates unique copper-copper-titanium hollow sites, which have a hydrogen-binding energy very similar to that of platinum, resulting in an exceptional hydrogen evolution activity. In addition, the hierarchical porosity of the nanoporous copper titanium catalyst also contributes to its high hydrogen evolution activity, because it provides a large-surface area for electrocatalytic hydrogen evolution, and improves the mass transport properties. Moreover, the catalyst is self supported, eliminating the overpotential associated with the catalyst/support interface. PMID- 25910894 TI - The Frits Huyse Award for Outstanding Contribution to the Development of Consultation-Liaison Psychiatry in Europe: An interview with Professor Frits Huyse and Professor Antonio Lobo. PMID- 25910895 TI - Endogenous conversion of n-6 to n-3 polyunsaturated fatty acids attenuates K/BxN serum-transfer arthritis in fat-1 mice. AB - It is suggested that n-3 polyunsaturated fatty acids (PUFAs) can be used in the preventive or therapeutic management of rheumatoid arthritis (RA); however, controversial results have been reported. Here, we examined the effects of a decrease in the n-6/n-3 PUFA ratio on RA using fat-1 transgenic mice. First, we tested whether fat-1 expression modulated signaling pathways in fibroblast-like synoviocytes (FLSs) stimulated with tumor necrosis factor alpha (TNF-alpha). TNF alpha activated p38 mitogen-activated protein kinase and increased phosphorylation of the signal transducer and activator of transcription 3 in wild type (WT) FLSs but not in fat-1 FLSs. Arthritis was induced by injection of K/BxN serum. Based on clinical scores, ankle thickness and pathological severity, we showed that WT mice developed clinically overt arthritis, whereas fat-1 mice showed attenuated arthritis. Moreover, fat-1 mice exhibited down-regulated local and systemic levels of inflammatory cytokines. Lastly, bone marrow-derived macrophages (BMMs) of WT mice differentiated into tartrate-resistant acid phosphatase-positive multinucleated osteoclasts, whereas the osteoclastogenenic process was suppressed in BMMs of fat-1 mice. The endogenous conversion of n-6 to n-3 PUFAs via fat-1 plays a key role in attenuation of RA; therefore, dietary supplementation of n-3 PUFAs may have therapeutic potential for the management of RA. PMID- 25910896 TI - MiR-34a promotes Fas-mediated cartilage endplate chondrocyte apoptosis by targeting Bcl-2. AB - Apoptosis of cartilage endplate (CEP) chondrocytes is associated with the pathogenesis of intervertebral disk degeneration (IDD). Recent studies have shown that miR-34a is crucially involved in chondrocyte apoptosis during osteoarthritic cartilage. Here, we investigated the involvement of miR-34a in CEP chondrocyte apoptosis in IDD. In human degenerated CEP chondrocytes, miRNA (miR)-34a was markedly elevated in association with increased apoptosis. Bioinformatics target prediction identified Bcl-2 as a putative target of miR-34a. Furthermore, miR-34a inhibited Bcl-2 expression by directly targeting their 3'-untranslated regions, and this inhibition was abolished by mutation of the miR-34a binding sites. In vitro, knockdown of miR-34a in human endplate chondrocytes resulted in overexpression of Bcl-2, whereas upregulation of miR-34a led to repression of Bcl 2. Fas-mediated apoptosis was decreased when antagonizing miR-34a with locked nucleotide analog-miR-34a in human endplate chondrocytes. Taken together, our results demonstrate that upregulated miR-34a potentiates Fas-mediated endplate chondrocyte apoptosis, which is associated with IDD. PMID- 25910897 TI - Hair Selenium Levels of School Children in Kashin-Beck Disease Endemic Areas in Tibet, China. AB - Previous studies have shown that the selenium (Se) deficiency is an important factor for the etiology of Kashin-Beck disease (KBD). Although KBD is presently controlled in most regions of China, it is still active in the Tibetan Plateau. The present study aimed to assess the nutritional status of selenium in school children by using the Se level in hair as a biomarker in KBD endemic areas of Lhasa in Tibet, China. Hair samples of 155 school children aged 6-15 years were collected in both KBD areas and non-KBD areas of Lhasa in 2013. The Se level in the hair samples was determined by inductive coupled plasma mass spectrometry (ICP-MS). The average concentration of Se in children's hair was 0.232 MUg/g in KBD areas of Lhasa, which was significantly higher than the data reported decades ago. A significant difference in hair Se was observed between the boys (0.255 MUg/g) and the girls (0.222 MUg/g) in the studied KBD areas (P < 0.01, Mann Whitney U test), but hair Se did not vary by age or region. School children in KBD endemic areas in Lhasa likely have improved Se status as a result of high Se content staple food substitution with the enforcement of Free Education Policy and Nutrition Improvement Plan in Tibet. Nevertheless, there were still 20.3 % of students with low Se status (hair Se <0.20 MUg/g), which showed that Se status of school children was also partly affected by low Se environment in KBD endemic areas of Lhasa. PMID- 25910898 TI - Decreased Zn(2+) Influx Underlies the Protective Role of Hypoxia in Rat Nucleus Pulposus Cells. AB - Zn(2+) is an essential component of metalloproteinases, and is required for their activity in cartilage; however, the effect of Zn(2+) on nucleus pulposus (NP) cells has not been widely investigated. The aim of this paper was to investigate the effect of intracellular Zn(2+) concentration ([Zn(2+)]i) in hypoxia-induced regulation of metalloproteinases (MMPs) and extracellular matrix (ECM) production in NP cells. NP cells from Sprague-Dawley (SD) rats were cultured as monolayers or in alginate beads. [Zn(2+)]i was assayed by FluoZin-3 AM staining. Alcian Blue staining, immunochemistry, 1,9-dimethylmethylene blue (DMMB) assay, and real-time PCR were used to assay collagen II, proteoglycan, and COL2A1, MMP-13, and ADAMTS 5 mRNA expression. ZIP8, a main Zn(2+) transporter in chondrocytes, was assayed by immunochemistry and in Western blotting. Interleukin (IL)-1beta- and ZnCl2 induced increases of [Zn(2+)]i were significantly inhibited by hypoxia. Hypoxia did not reverse a decline of ECM expression caused by IL-1beta and ZnCl2 in monolayer cultures, but did significantly attenuate the decreases of proteoglycan, glycosaminoglycan (GAG), and COL2A1 mRNA expression following IL 1beta and ZnCl2 treatment in alginate bead cultures. However, ZnCl2 inhibited the protective effect of hypoxia. Both an intracellular Zn(2+) chelator and hypoxia prevented the increase in MMP-13 mRNA expression. IL-1beta and ZnCl2 treatment increased ZIP8 expression in NP cells, and hypoxia inhibited ZIP8 expression. In conclusion, decrease of Zn(2+) influx mediates the protective role of hypoxia on ECM and MMP-13 expression. Consequently, changes in intracellular Zn(2+) concentration maybe involved in intervertebral disc degeneration. PMID- 25910899 TI - Effect of Zinc Source on Hematological, Metabolic Parameters and Mineral Balance in Lambs. AB - This experiment was conducted to study the effects of different sources of zinc (Zn) on blood metabolites and balances of some minerals in lambs. In the first part, 20 6-7-month-old lambs were randomly allotted to four treatments including (1) basal diet containing 22.47 mg Zn/kg DM without supplementary Zn (control), (2) basal diet + 40 mg Zn/kg DM as ZnSO4 (ZnSO4 40), (3) basal diet + 20 mg Zn/kg DM as Zn-proteinate (Zn-Pro 20), and (4) basal diet + 40 mg Zn/kg DM as Zn proteinate (Zn-Pro 40). Blood samples were taken on days 0, 28, and 65 before morning feeding. In the second part, four lambs from each treatment were randomly transferred to metabolic cages to evaluate the effects of different sources of Zn on N, Zn, Fe, and Cu retentions. This trial consisted of 18 days, with the first 12 days as the adaptation period followed by 6 days of sample collection. The results of this study showed that the source of Zinc had no significant effect on the analyzed parameters. Average daily gain and feed efficiency were improved by Zn supplementation (P < 0.05). Daily feed intake, plasma glucose, Fe and Cu concentrations, serum total antioxidant capacity, red blood cell count, packed cell volume, and hemoglobin concentration did not differ significantly between treatments (P > 0.05). Plasma Zn concentration, alkaline phosphatase (ALP) and bone-specific alkaline phosphatase (BALP) activity, and white blood cell and lymphocyte count differed significantly between control and Zn-supplemented groups (P < 0.05) as Zn supplementation improved these parameters. Nitrogen, Fe, and Cu retentions did not differ between treatments (P > 0.05). Zinc retention showed a significant difference between control and Zn-supplemented groups (P < 0.05), but there were no significant differences among the Zn-supplemented groups. The results of this study show that Zn supplementation improved performance and zinc retention in lambs. However, there were no significant differences between zinc sources used in this study. PMID- 25910900 TI - Trivalent Chromium has no Effect on Delaying Azoxymethane-Induced Colorectal Cancer in FVB/NJ Mice. AB - As Cr(III) compounds have been shown to increase insulin sensitivity and decrease plasma cholesterol and triglycerides in rodent models of diabetes and insulin resistance and as colorectal cancer risk has been associated with insulin resistance and diabetes, the effects of the Cr(III) compound Cr3 ([Cr3O(O2CCH2CH3)6(H2O)3](+)) were investigated in male and female FVB/NJ mice with azoxymethane-induced colorectal cancer. In contrast to a previous study on the effects of Cr3 on 1,2-dimethylhydrazine-induced colorectal cancer in Sprague Dawley rats, no effects of Cr3 at daily doses of 1 and 10 mg Cr/kg body mass were observed, leaving in question whether administration of Cr(III) compounds can delay or prevent the onset of colorectal cancer. PMID- 25910901 TI - Experimental pathology of T-2 toxicosis and mycoplasma infection on performance and hepatic functions of broiler chickens. AB - This experiment was conducted using 192 day-old Ross 308 chicks, divided into 4 groups of 4 replicate consisting 48 birds. Group I was fed a control diet, Group II was fed control diet supplemented with 0.5 ppm T-2 toxin for 5 weeks, Group III was fed control diet supplemented with 8 * 10(8) cfu/mL of Mycoplasma gallisepticum, and group IV was fed control diet supplemented by T-2 toxin and Mycoplasma gallisepticum. Body weight and feed conversation ratio (FCR), relative organ weights, clinical signs, biochemical characteristics, and gross and histopathological lesions were recorded in the experimental groups at the end of the second and fifth weeks of age. Body weight and relative weights of bursa of Fabricius, thymus, and spleen decreased and FCR increased significantly (P <= 0.05), but the relative weights of liver and kidney showed no significant decrease (P <= 0.05) in the serum total proteins, albumin, and increase in aspartate aminotransferase and alanine transaminase were observed in T-2 toxin and T-2 accompanied with Mycoplasma fed birds when compared to the control group. Liver was enlarged, friable, and yellowish discoloration with distended gall bladder was noticed. Lymphoid organs such as bursa of Fabricius, thymus, and spleen were atrophied in group II and group IV throughout the study. Microscopically, liver showed vacuolar degeneration of hepatocytes, with increased Kupffer cell activity, bile duct epithelial hyperplasia, and infiltration of inflammatory cells. Kidney showed vacuolar degeneration of tubular epithelium along with pyknotic nuclei. Lymphoid organs showed lymphocytolysis and depletion with prominent reticuloepithelial cells. Proventriculus revealed desquamation of villous epithelial cells and lymphoid infiltration in submucosa. Heart showed mild hemorrhage with infiltration of inflammatory cells. Lung showed edema and inflammatory cells in the bronchioles. Trachea showed desquamation and erosions of mucosa. Proliferation of mucosal glands with increased mucous secretion was obvious. Air sacs showed thickening with presence of inflammatory cells and edema. PMID- 25910902 TI - Contribution of intestinal- and cereal-derived phytase activity on phytate degradation in young broilers. AB - There is little consensus as to the capability of poultry to utilize dietary phytate without supplemental phytase. Therefore, an experiment was conducted to examine the extent to which endogenous phytase of intestinal and cereal origin contributes to phytate degradation in birds aged 0 to 14 d posthatch. Ross 308 broilers (n = 720) were fed one of 4 experimental diets with differing dietary ingredient combinations and approximate total phytate levels of 10 g/kg, dietary phytase activity analyzed at 460 U/kg, dietary calcium (Ca) levels of 11 g/kg, and nonphytate-phosphorus (P) levels of 4 g/kg. Broiler performance, gizzard, duodenum, jejunum and ileum pH, Ca and P digestibility and solubility, amount of dietary phytate hydrolyzed in the gizzard, jejunum, and ileal digesta phytase activity were analyzed at d 4, 6, 8, 10, 12, and 14 posthatch. Intestinal endogenous phytase activity increased significantly (P < 0.001) between d 4 and 6, resulting in increased phytate hydrolysis in the gizzard (P = 0.003), jejunum (P < 0.001), and ileum (P < 0.001). Phytase activity and phytate hydrolysis continued to increase with age, with a greater phytase activity and associated increase in phytate hydrolysis and mineral utilization between d 10 and 12. Gizzard and jejunum Ca and P solubility and ileal Ca and P digestibility increased significantly (P < 0.001), and gastrointestinal pH decreased significantly (P < 0.001) between d 4 and 6. By d 14, phytase activity recovered in the ileum was approximately 45 U/kg. There were strong correlations between phytase activity measured in the ileum and phytate hydrolyzed in the gizzard (r = 0.905, P < 0.001), jejunum (r = 0.901, P = 0.023), and ileum (r = 0.938, P = 0.042). This study shows intestinal- and dietary-derived endogenous phytase activity is responsible for phytate-P hydrolysis in broilers. PMID- 25910903 TI - Persistence of fecal shedding of Salmonella Enteritidis by experimentally infected laying hens housed in conventional or enriched cages. AB - Salmonella Enteritidis can be deposited inside eggs laid by infected hens, so the prevalence of this pathogen in commercial egg-producing flocks is an important risk factor for human illness. Opportunities for the introduction, transmission, and persistence of salmonellae in poultry are potentially influenced by flock housing and management systems. Animal welfare concerns have spurred the development of alternatives to traditional cage-based housing. However, the consequences of poultry housing systems for food safety have not been fully resolved by prior research. The present study assessed the effects of two different housing systems (conventional cages and colony cages enriched with perching and nesting areas) on the persistence of fecal shedding of Salmonella Enteritidis by groups of experimentally infected laying hens. In each of two trials, 136 hens were distributed among cages of both housing systems and orally inoculated with doses of 10(8) cfu of Salmonella Enteritidis (phage type 13a in one trial and phage type 4 in the other). At weekly intervals, samples of voided feces were collected from beneath each cage and cultured to detect Salmonella Enteritidis. Fecal shedding of Salmonella Enteritidis was detected for up to 8 wk post-inoculation by hens housed in enriched colony cages and 10 wk by hens housed in conventional cages. For both trials combined, the frequency of positive fecal cultures was significantly (P < 0.05) greater for conventional cages than for enriched colony cages at 1 wk (84.7 vs. 71.5%), 2 wk (54.2 vs. 31.3%), 3 wk (21.5 vs. 7.6%), and 4 wk (9.7 vs. 2.8%) post-inoculation. These results demonstrate that the susceptibility of hens to intestinal colonization by Salmonella Enteritidis can differ between conventional and enriched cage-based production systems, although this effect does not necessarily translate into a corresponding difference in the longer-term persistence of fecal shedding. PMID- 25910904 TI - Effects of acute and chronic heat stress on plasma metabolites, hormones and oxidant status in restrictedly fed broiler breeders. AB - Heat tolerance can be improved by feed restriction in broiler chickens. It is unknown whether the same is true for broiler breeders, which are restrictedly fed. Therefore, the current study was conducted to study the effects of heat stress on plasma metabolites, hormones, and oxidative status of restricted fed broiler breeders with special emphases on the temperature and latency of heat exposure. In trial 1, 12 broiler breeders were kept either in a thermoneutral chamber (21 degrees C, control, n = 6) or in a chamber with a step-wise increased environmental temperature from 21 to 33 degrees C (21, 25, 29, 33 degrees C, heat stressed, n = 6). Changes in plasma total cholesterol, glucose, and triiodothyronine (T3) were closely related to the environmental temperature. When the temperature reached 29 degrees C, plasma T3 (P < 0.05) was significantly decreased in acute heat-stressed birds, whereas plasma glucose (P < 0.001) and cholesterol (P = 0.002) increased only when the temperature reached 33 degrees C. Plasma triglyceride (P = 0.026) and creatine kinase (CK, P = 0.018) were lower in heat-stressed birds than controls regardless of the temperatures applied. In Trial 2, 24 broiler breeders were divided into 2 groups and raised under 21 degrees C and 32 degrees C for 8 weeks, respectively. Total cholesterol was increased in chronic heat-stressed broiler breeders after 4 weeks. Plasma lactate dehydrogenase (LDH, P = 0.047) and glutamic-oxaloacetic transaminase (GOT, P = 0.036) was up-regulated after 6 weeks of thermal treatment, whereas plasma CK (P = 0.009) was increased at the end of thermal treatment. Plasma malonaldehyde, protein carbonyl content, activity of total superoxide dismutase (SOD), and corticosterone content were not altered after acute and prolonged heat challenges. Taken together, acute heat stress primarily resulted in disturbance of plasma metabolites, whereas chronic heat stress caused tissue damage reflected by increased plasma LDA, GOT, and CK. During acute heat stress, plasma metabolites were minimally disturbed in broiler breeders until the environmental temperature reached 33 degrees C. PMID- 25910905 TI - Early intestinal growth and development in poultry. AB - While there are many accepted "facts" within the field of poultry science that are in truth still open for discussion, there is little debate with respect to the tremendous genetic progress that has been made with commercial broilers and turkeys (Havenstein et al., 2003, 2007). When one considers the changes in carcass development in poultry meat strains, these genetic "improvements" have not always been accompanied by correlated changes in other physiological systems and this can predispose some birds to developmental anomalies (i.e. ascites; Pavlidis et al., 2007; Wideman et al., 2013). Over the last decade, there has been increased interest in intestinal growth/health as poultry nutritionists have attempted to adopt new approaches to deal with the broader changes in the overall nutrition landscape. This landscape includes not only the aforementioned genetic changes but also a raft of governmental policies that have focused attention on the environment (phosphorus and nitrogen excretion), consumer pressure on the use of antibiotics, and renewable biofuels with its consequent effects on ingredient costs. Intestinal morphology has become a common research tool for assessing nutritional effects on the intestine but it is only one metric among many that can be used and histological results can often be interpreted in a variety of ways. This study will address the broader body of research on intestinal growth and development in commercial poultry and will attempt to integrate the topics of the intestinal: microbial interface and the role of the intestine as an immune tissue under the broad umbrella of intestinal physiology. PMID- 25910906 TI - High natural antibody titers of indigenous chickens are related with increased hazard in confinement. AB - Natural antibody (NAb) levels and survival rates were evaluated in 4 breeds of laying hens in Ethiopia: indigenous, improved indigenous, exotic layer, and crossbred. Titers of NAb isotypes IgG and IgM binding keyhole limpet hemocyanin (KLH) in serum were measured at 20, 26, 35, and 45 wk age. Repeated-measure ANOVA showed that IgG and IgM levels vary with time within each breed (P < 0.05). Indigenous chickens had significantly (P < 0.05) higher NAb levels at all ages. The Cox proportional hazard analysis showed increased hazard with increased levels of NAbs in the exotic layers (P < 0.05). However, the reduced hazards with increased levels of NAbs were not significant in the improved indigenous and crossbred chickens. Indigenous chickens showed increased hazard with increasing levels of NAb (P > 0.05). We concluded that not only the NAb levels but also the effect of Nabs on survival vary between indigenous and improved breeds. The results indicate that NAb levels are associated with survival in elite (improved) breeds, but are associated with increased hazard in indigenous chickens. PMID- 25910908 TI - Making decisions about decision-making: conscience, regulation, and the law. AB - The exercise of conscience can have far reaching effects. Poor behaviour can be fatal, as it has occurred in various medical scandals over the years. This article takes a wide definition of conscience as its starting point, and argues that the decision-making processes open to society--legal regulation and professional regulation--can serve to limit the options available to an individual and thus her ability to exercise her conscience. The article charts the law's changing attitude to legal intervention, which now seeks to limit the use of conscience by individuals, and addresses concerns that this may serve to 'de-moralise' medicine. It also examines the reasons for this legal change of approach. PMID- 25910909 TI - The ethics of cluster-randomized trials requires further evaluation: a refinement of the Ottawa Statement. AB - OBJECTIVES: The Ottawa Statement is the first guidance document for the ethical and scientific conduct of cluster-randomized trials (CRTs). However, not all recommendations are straightforward to implement. In this paper we will reflect in particular on the recommendation on identifying human research subjects and the issue to what extent the randomization process should be disclosed if there is a risk of contamination. STUDY DESIGN AND SETTING: The Ottawa Statement was thoroughly evaluated within a multidisciplinary research team, consisting amongst others of epidemiologists and ethicists. RESULTS: Patients in a CRT may also be considered as research subjects if they are indirectly affected by the studied interventions in a CRT. Second, health care workers are research subjects in CRTs but have a different moral status compared with ordinary research participants. This different status has implications for withdrawal and the choice of the primary objective. Third, modified informed consent for CRTs may be obtained when researchers can demonstrate that disclosure of the randomization process would affect the validity of a CRT. CONCLUSION: Recommendations of the Ottawa Statement on identifying the research subject and providing informed consent can and should be refined. PMID- 25910910 TI - A reliable and valid index was developed to measure appropriate psychotropic drug use in dementia. AB - OBJECTIVES: The aim of this study was to develop an index derived from the Medication Appropriateness Index (MAI) items that is suited for clinical studies evaluating appropriateness of psychotropic drug use (PDU) for neuropsychiatric symptoms (NPS) in patients with dementia in nursing homes and to test its reliability and validity. STUDY DESIGN AND SETTING: An expert panel reviewed the MAI items to develop items for appropriateness of PDU; a second, independent, expert panel determined content validity of the items. An interrater reliability study was conducted (N = 54), and a summated index score, based on weighted item scores, was developed to enhance the use in clinical studies. Construct validity was explored using a representative sample of 560 medical records. RESULTS: Five existing MAI items were used, the MAI item "indication" was adjusted, a new item "evaluation" was added, and scoring rules were based on guideline recommendations, to create the Appropriate Psychotropic drugs use In Dementia (APID) index. The second expert panel concluded that all items contributed to the construct "appropriateness." All items and the summated index score had moderate to almost perfect interrater reliability (intraclass correlation coefficient for agreement, 0.577-1). The summated index score showed promising construct validity, for example, no multicollinearity issues were found. CONCLUSION: The results of this study show that the APID index is reliable and valid for measuring appropriateness of PDU for NPS in dementia in nursing homes in clinical studies. PMID- 25910911 TI - Basic study design influences the results of orthodontic clinical investigations. AB - OBJECTIVES: Meta-analysis is the gold standard for synthesizing evidence on the effectiveness of health care interventions. However, its validity is dependent on the quality of included studies. Here, we investigated whether basic study design (i.e., randomization and timing of data collection) in orthodontic research influences the results of clinical trials. STUDY DESIGN AND SETTING: This meta epidemiologic study used unrestricted electronic and manual searching for meta analyses in orthodontics. Differences in standardized mean differences (DeltaSMD) between interventions and their 95% confidence intervals (CIs) were calculated according to study design through random-effects meta-regression. Effects were then pooled with random-effects meta-analyses. RESULTS: No difference was found between randomized and nonrandomized trials (25 meta-analyses; DeltaSMD = 0.07; 95% CI = -0.21, 0.34; P = 0.630). However, retrospective nonrandomized trials reported inflated treatment effects compared with prospective (40 meta-analyses; DeltaSMD = -0.30; 95% CI = -0.53, -0.06; P = 0.018). No difference was found between randomized trials with adequate and those with unclear/inadequate generation (25 meta-analyses; DeltaSMD = 0.01; 95% CI = -0.25, 0.26; P = 0.957). Finally, subgroup analyses indicated that the results of randomized and nonrandomized trials differed significantly according to scope of the trial (effectiveness or adverse effects; P = 0.005). CONCLUSION: Caution is warranted when interpreting systematic reviews investigating clinical orthodontic interventions when nonrandomized and especially retrospective nonrandomized studies are included in the meta-analysis. PMID- 25910912 TI - Associations between neighborhood effects and physical activity, obesity, and diabetes: The Jamaica Health and Lifestyle Survey 2008. AB - OBJECTIVE: To examine the impact of neighborhood disorder, perceived neighborhood safety, and availability of recreational facilities on prevalence of physical activity (PA), obesity, and diabetes mellitus (DM). STUDY DESIGN AND SETTING: Multilevel analyses were conducted among 2,848 respondents from the 2007-08 Jamaica Health and Lifestyle Survey. Neighborhood effects were based on aggregated interviewer responses to systematic social observation questions. Mixed-effect logistic regression models were created to assess the relationship between neighborhood indicators and DM and the modifiable risk factors PA and overweight/obesity. RESULTS: There was significant clustering in PA levels of 20 minutes at least once per week (intraclass correlation coefficient [ICC] = 10.7%), low/no PA (ICC = 7.22%), diabetes (ICC = 5.44%), and obesity (ICC = 3.33%) across neighborhoods. Greater levels of neighborhood disorder, home disorder, and counterintuitively recreational space availability were associated with higher levels of low/no PA among women. There was significant interaction by sex between neighborhood infrastructure and overweight/obesity with a significant association in men (odds ratio [OR] = 1.16; 95% confidence interval [CI] = 1.05, 1.28) but not women (OR = 1.01; 95% CI = 0.95, 1.07). CONCLUSION: Differences in PA and obesity-related outcomes among Jamaicans may be partially explained by characteristics of the neighborhood environment and differ by sex. Future studies must be conducted to determine the mechanistic pathways through which the neighborhood environment may impact such outcomes to better inform prevention efforts. PMID- 25910914 TI - Tl+ induces the permeability transition pore in Ca2+-loaded rat liver mitochondria energized by glutamate and malate. AB - It is known that Ca2+ and heavy metals more actively induce MPTP opening in mitochondria, energized by the I complex substrates. Thus, a rise in a Tl+ induced MPTP was proposed in experiments on isolated rat liver mitochondria energized by the complex I substrate (glutamate and malate). Expose of the mitochondria to Ca2+ into a medium containing TlNO3, glutamate, and malate as well as sucrose or KNO3 resulted in a decrease in state 3, state 4, or DNP stimulated respiration as well as an increase of both mitochondrial swelling and DeltaPsimito dissipation. The MPTP inhibitors, CsA and ADP, almost completely eliminated the effect of Ca2+, which was more pronounced in the presence of the complex I substrates than the complex II substrate (succinate) and rotenone (Korotkov and Saris, 2011). The present study concludes that Tl+-induced MPTP opening is more appreciable in mitochondria energized by glutamate and malate but not succinate in the presence of rotenone. We assume that the Tl+-induced MPTP opening along with followed swelling and possible structural deformations of the complex I in Ca2+-loaded mitochondria may be a part of the thallium toxicity mechanism on mitochondria in living organisms. At the same time, oxidation of Tl+ to Tl3+ by mitochondrial oxygen reactive species is proposed for the mechanism. PMID- 25910913 TI - High Diagnostic Yield of Whole Exome Sequencing in Participants With Retinal Dystrophies in a Clinical Ophthalmology Setting. AB - PURPOSE: To assess the diagnostic yield and the practicality of implementing whole exome sequencing within a clinical ophthalmology setting. DESIGN: Evaluation of a diagnostic protocol. METHODS: setting: Patient participants were enrolled during clinical appointments in a university-based ophthalmic genetics clinic. PATIENT POPULATION: Twenty-six patients with a variety of presumed hereditary retinal dystrophies. INTERVENTION: Participants were offered whole exome sequencing in addition to clinically available sequencing gene panels between July 2012 and January 2013 to determine the molecular etiology of their retinal dystrophy. MAIN OUTCOME MEASURES: Diagnostic yield and acceptability of whole exome sequencing in patients with retinal disorders. RESULTS: Twenty-six of 29 eligible patients (~90%) who were approached opted to undergo molecular testing. Each participant chose whole exome sequencing in addition to, or in lieu of, clinically available sequencing gene panels. Time to obtain informed consent was manageable in the clinical context. Whole exome sequencing successfully identified known pathogenic mutations or suspected deleterious variants in 57.7% of participants. Additionally, 1 participant had 2 autosomal dominant medically actionable incidental findings (unrelated to retinopathy) that were reported to enable the participant to take preventive action and reduce risk for future disease. CONCLUSIONS: In this study, we identified the molecular etiology for more than half of all participants. Additionally, we found that participants were widely accepting of whole exome sequencing and the possibility of being informed about medically actionable incidental findings. PMID- 25910915 TI - Testosterone-induced micronuclei and increased nuclear division rate in L929 cell line expressing the androgen receptor. AB - Data on the possible genotoxic effects of testosterone are limited: in particular, the potential clastogenic and/or aneugenic effects have not yet been properly investigated. An in vitro micronucleus (MN) assay was performed on L929 cells exposed to testosterone at doses of 10, 15, 20, 30, and 40 MUg/mL. Significantly increased MN frequencies were detected at doses of 20, 30, and 40 MUg/mL after 24 h and 48 h of incubation. The nuclear division index was higher after 48 h than 24 h of incubation. A benchmark dose (BMD) calculation was used to estimate the 1% extra risk level for MN and increased tetranucleated cells. The calculated 1% extra risk level for MN at 24 h was 12.01 MUg/mL, with a 95% lower confidence limit (BMDL) at 8.98 MUg/mL; the corresponding BMD and BMDL at 48 h were 17.35 MUg/mL and 10.69 MUg/mL, respectively. The BMD for tetranucleated cells at 24 h was 14.86 MUg/mL, with a BMDL of 7.75 MUg/mL; the corresponding values at 48 h were 0.50 MUg/mL for BMD and 0.87MUg/mL for BMD. These findings suggest that the intensity of the mitogenic effect of testosterone increases upon prolonged exposure. The results of our study show that testosterone acts both as a mitogenic and genotoxic agent in L929 cells. PMID- 25910916 TI - In vitro study of the neuropathic potential of the organophosphorus compounds fenamiphos and profenofos: Comparison with mipafox and paraoxon. AB - Organophosphorus-induced delayed neuropathy (OPIDN) is a central-peripheral distal axonopathy that develops 8-14 days after poisoning by a neuropathic organophosphorus compound (OP). Several OPs that caused OPIDN were withdrawn from the agricultural market due to induction of serious delayed effects. Therefore, the development of in vitro screenings able to differentiate neuropathic from non neuropathic OPs is of crucial importance. Thus, the aim of this study was to evaluate the differences in the neurotoxic effects of mipafox (neuropathic OP) and paraoxon (non-neuropathic OP) in SH-SY5Y human neuroblastoma cells, using the inhibition and aging of neuropathy target esterase (NTE), inhibition of acetylcholinesterase (AChE), activation of calpain, neurite outgrowth, cytotoxicity and intracellular calcium as indicators. Additionally, the potential of fenamiphos and profenofos to cause acute and/or delayed effects was also evaluated. Mipafox had the lowest IC50 and induced the highest percentage of aging of NTE among the OPs evaluated. Only mipafox was able to cause calpain activation after 24 h of incubation. Concentrations of mipafox and fenamiphos which inhibited at least 70% of NTE were also able to reduce neurite outgrowth. Cytotoxicity was higher in non-neuropathic than in neuropathic OPs while the intracellular calcium levels were higher in neuropathic than in non-neuropathic OPs. In conclusion, the SH-SY5Y cellular model was selective to differentiate neuropathic from non-neuropathic OPs; fenamiphos, but not profenofos presented results compatible with the induction of OPIDN. PMID- 25910917 TI - In vitro antiproliferative and antioxidant effects of urolithin A, the colonic metabolite of ellagic acid, on hepatocellular carcinomas HepG2 cells. AB - The intestinal metabolites of ellagic acid (EA), urolithins are known to effectively inhibit cancer cell proliferation. This study investigates antiproliferative and antioxidant effects of urolithin A (UA) on cell survival of the HepG2 hepatic carcinomas cell line. The antiproliferative effects of UA (0 500 MUM) on HepG2 cells were determined using a CCK assay following 12-36 h exposure. Effects on beta-catenin and other factors of expression were assessed by using real-time PCR and Western blot. We found that UA showed potent antiproliferative activity on HepG2 cells. When cell death was induced by UA, it was found that the expression of beta-catenin, c-Myc and Cyclin D1 were decreased and TCF/LEF transcriptional activation was notably down-regulated. UA also increased protein expression of p53, p38-MAPK and caspase-3, but suppressed expression of NF-kappaB p65 and other inflammatory mediators. Furthermore, the antioxidant assay afforded by UA and EA treatments was associated with decreases in intracellular ROS levels, and increases in intracellular SOD and GSH-Px activity. These results suggested that UA could inhibit cell proliferation and reduce oxidative stress status in liver cancer, thus acting as a viably effective constituent for HCC prevention and treatment. PMID- 25910918 TI - Evaluation and management of symptomatic isolated spontaneous celiac trunk dissection. AB - The purpose of this study is to describe 10 cases of symptomatic isolated spontaneous celiac trunk dissection (ISCTD) in order to evaluate the initial clinical presentation, diagnosis, treatment modalities and outcomes. A retrospective search was performed from 2009 to 2014 and 10 patients with ISCTD were included in the study. Patients with associated aortic and/or other visceral artery dissection were excluded. The following information was collected from each case: sex, age, associated risk factors, symptoms, diagnostic method, anatomic dissection pattern, treatment modality and outcome. Most patients were male (90%), with an average age of 44.8 years, and the most common symptom was abdominal pain (100%). Hypertension and vasculitis (polyarteritis nodosa) were the most frequent risk factors (40% and 30%, respectively). Diagnosis was made in all patients with computed tomography. Dissection was limited to the celiac trunk in three patients and extended to celiac branches in the other seven. Initial conservative treatment was attempted in every case and was successful in nine patients. In one case, initial conservative treatment was unsuccessful and arterial stenting with coil embolization of the false lumen was performed. After successful initial treatment, late progression of the dissection to aneurysmal dilatation was observed in two patients and it was decided to perform endovascular treatment. Mean follow-up was 19 months, ranging from 2 to 59 months. In conclusion, initial conservative treatment seems adequate for most patients with ISCTD. Long-term follow-up is mandatory, owing to the risk of later progression to aneurysm. PMID- 25910919 TI - Immunogenicity and safety of an AS03-adjuvanted H5N1 pandemic influenza vaccine in Korean adults: a phase IV, randomized, open-label, controlled study. AB - BACKGROUND: AS03-adjuvanted H5N1 pandemic influenza vaccines have been assessed in an extensive clinical development program conducted in North America, Europe, and Asia including children from 6 months of age, adults, and elderly adults. We evaluated AS03-H5N1 in Korean adults 18 through 60 years of age. METHODS: This Phase IV, randomized, study was conducted to assess the immunogenicity, reactogenicity, and safety of two doses (3.75MUg of hemagglutinin antigen) of A/Indonesia/5/2005 (H5N1) adjuvanted with AS03 given 21 days apart in Korean adults. Antibody responses were assessed using hemagglutination-inhibition (HI) assays against the vaccine strain and a vaccine-heterologous strain (A/Vietnam/1194/2004) 21 days after the second dose. A control group (safety) received a licensed seasonal inactivated trivalent influenza vaccine (TIV). Reactogenicity was assessed for 7 days after each vaccination, and unsolicited adverse events were assessed for 182 days following vaccination in both study groups (NCT01730378). RESULTS: AS03-H5N1 was immunogenic and elicited robust HI antibody responses with seroconversion rates of 100% for the vaccine strain and 69.1% for the heterologous strain (N=81). HI antibody responses fulfilled the European licensure criteria for immunogenicity (primary endpoint). The incidence of local and systemic solicited adverse events (reactogenicity) was higher with AS03-H5N1 than TIV. There was no apparent difference in the rate of unsolicited adverse events in the AS03-H5N1 and TIV groups. CONCLUSION: The results indicate that AS03-H5N1 vaccine is immunogenic with reactogenicity and safety findings that are consistent with the established profile of AS03-H5N1 vaccine. PMID- 25910920 TI - Age-dependent immune responses and immune protection after avian coronavirus vaccination. AB - Infectious bronchitis virus (IBV) is an endemic disease of chickens and a major contributor to economic losses for the poultry industry despite vaccination. Recent observations indicated that chicks may have an immature immune system immediately after hatching when vaccinated for IBV. Therefore we hypothesized that early IBV vaccination will generate an immature, poorly protective IBV specific immune response contributing to immune escape and persistence of IBV. To test this hypothesis the IBV-specific immune response and immune protection were measured in chicks vaccinated at different ages. This demonstrated a delayed production of IgG and IgA plasma antibodies in the 1, 7 and 14-day-old vaccination groups and also lower IgA antibody levels were observed in plasma of the 1-day-old group. Similar observations were made for antibodies in tears. In addition, IgG antibodies from the 1-day-old group had lower avidity indices than day 28 vaccinated birds. The delayed and/or lower antibody response combined with lower IgG avidity indices coincided with increased tracheal inflammation and depletion of tracheal epithelia cells and goblet cells upon IBV field strain challenge. The lack of vaccine-mediated protection was most pronounced in the 1 day-old vaccination group and to a lesser extent the 7-day-old group, while the 14-day-old and older chickens were protected. These data strongly support IBV vaccination after day 7 post hatch. PMID- 25910921 TI - Building the case for wider use of typhoid vaccines. AB - Efficacious typhoid fever vaccines have been available for decades. Typhoid fever burden of disease estimates indicate a substantial burden of illness and death in low-resource areas. The World Health Organization has recommended that countries consider the use of typhoid vaccines for high-risk groups and populations, and for outbreak control. Despite this, typhoid vaccines are not widely used in endemic areas. By examining strategies to improve burden of disease data, use of transmission dynamic models, economic evaluations, vaccine strategies, and experiences with typhoid vaccine pilot projects, the papers in this supplement help to plot the path toward rational and wider use of typhoid vaccines. PMID- 25910922 TI - Development of broadly reactive H5N1 vaccine against different Egyptian H5N1 viruses. AB - The H5N1 highly pathogenic avian influenza (HPAI) virus was isolated for the first time in Egypt in 2006, since then, the virus has become endemic causing a significant threat to the poultry industry and humans. H5N1 HPAI outbreaks continue to occur despite extensive vaccination programs that have been implemented nationwide in different poultry species. Several studies showed that the co-circulating H5N1 viruses in Egypt are genetically and antigenically distant raising a question on the cross protective efficacy of commercial vaccines. In this study, we introduced mutations at the antigenic sites of the hemagglutinin (HA) to broaden reactivity of the Egyptian H5N1 virus. A reverse genetically created variant H5N1 virus (A/chicken/Egypt/1063/2010) with five amino acid mutations (G140R, Y144F, I190L, K192Q, D43N) in the HA gene showed enhanced cross reactivity. This virus showed up to 16 fold increase in reactivity to the classic-lineageH5N1viruses measured by hemagglutination inhibition (HI) assay while maintaining similar level of reactivity with the variant-lineage viruses compared to wild-type virus. In addition, a single amino acid substitution (N165H), which removes potential glycosylation site at the HA globular head of two classic strains (A/chicken/Egypt/527/2012 and A/chicken/Egypt/102d/2010) broadened the reactivity to antisera generated against H5N1 viruses from different clusters. The broadened reactivity of the mutant viruses were also confirmed by testing reactivity of antisera prepared from the mutant viruses against reference viruses from both classic and variant clades. The virus neutralization test using selected antisera and viruses further confirmed the cross HI results. This study highlights that targeted mutation in the HA may be effectively used as a tool to develop broadly reactive influenza vaccines to cope with the continuous antigenic evolution of viruses. PMID- 25910924 TI - Grafted Activated Schwann Cells Support Survival of Injured Rat Spinal Cord White Matter. AB - BACKGROUND AND OBJECTIVE: The influence of cultured Schwann cells on injured spinal cord in rats is examined. METHODS: Focal injury of spinal cord white matter at the T10 level was produced using our original non-laminectomy method with a high-pressure air stream. Schwann cells from 7-day predegenerated rat sciatic nerves were cultured, transducted with green fluorescent protein and injected into the cisterna magna (experimental group) 3 times: immediately after spinal cord injury and 3 and 7 days later. Neurons in the brainstem and motor cortex were labeled with FluoroGold (FG) delivered caudally from the injury site a week before the end of the experiment. The functional outcome and morphologic features of neuronal survival were analyzed during a 12-week follow-up. The lesions were visualized and analyzed using magnetic resonance imaging. The maximal distance of expansion of implanted cells in the spinal cord was measured and the number of FG-positive neurons in the brain was counted. RESULTS: Rats treated with Schwann cells presented significant improvement of locomotor performance and spinal cord morphology compared with the control group. The distance covered by Schwann cells was 7 mm from the epicenter of the injury. The number of brainstem and motor cortex FG-positive neurons in the experimental group was significantly higher than in the control group. CONCLUSIONS: The data show that activated Schwann cells are able to induce the repair of injured spinal cord white matter. The route of application of cells via the cisterna magna seemed to be useful for their delivery in spinal cord injury therapy. PMID- 25910925 TI - Data-Based Decision Making in Professional Learning for School Speech-Language Pathologists. AB - PURPOSE: School-based speech-language pathologists (SLPs) are often asked to adopt new policies or practices at the school, district, or state level. Professional learning (PL) opportunities usually accompany these changes but are often delivered in a one-size-fits-all workshop format. The authors challenge school-based SLPs and district leadership to consider PL in a new light, guided by data-based decision making to ultimately improve student outcomes. METHOD: This article discusses the research supporting the assessment and delivery of high-quality PL for school professionals, including SLPs, and a specific model for measuring change: the concerns-based adoption model (CBAM; Hall & Hord, 2015). An example of how CBAM was used to examine the adoption process with school-based SLPs in a large school district is provided. CONCLUSION: Based on the review of the literature, the current approach to PL experienced by most SLPs is problematic. High-quality PL should target improvement in student outcomes and should be focused, ongoing, supported, and evaluated. PMID- 25910926 TI - Accumulation of plutonium in mammalian wildlife tissues following dispersal by accidental-release tests. AB - We examined the distribution of plutonium (Pu) in the tissues of mammalian wildlife inhabiting the relatively undisturbed, semi-arid former Taranaki weapons test site, Maralinga, Australia. The accumulation of absorbed Pu was highest in the skeleton (83% +/- 6%), followed by muscle (10% +/- 9%), liver (6% +/- 6%), kidneys (0.6% +/- 0.4%), and blood (0.2%). Pu activity concentrations in lung tissues were elevated relative to the body average. Foetal transfer was higher in the wildlife data than in previous laboratory studies. The amount of Pu in the gastrointestinal tract was highly elevated relative to that absorbed within the body, potentially increasing transfer of Pu to wildlife and human consumers that may ingest gastrointestinal tract organs. The Pu distribution in the Maralinga mammalian wildlife generally aligns with previous studies related to environmental exposure (e.g. Pu in humans from worldwide fallout), but contrasts with the partitioning models that have traditionally been used for human worker protection purposes (approximately equal deposition in bone and liver) which appear to under-predict the skeletal accumulation in environmental exposure conditions. PMID- 25910923 TI - Longitudinal study on Streptococcus pneumoniae, Haemophilus influenzae and Staphylococcus aureus nasopharyngeal colonization in HIV-infected and -uninfected infants vaccinated with pneumococcal conjugate vaccine. AB - BACKGROUND: Streptococcus pneumoniae, Haemophilus influenzae and Staphylococcus aureus are all potentially pathogenic, which frequently colonize the nasopharynx (NP) prior to causing disease. We studied bacterial NP-colonization in 321 HIV infected and 243 HIV-uninfected children vaccinated with 7-valent pneumococcal conjugate vaccine (PCV7) at 6, 10 and 14 weeks of age. METHODS: HIV-uninfected infants included those born to HIV-uninfected (HUU) and HIV-infected women (HEU); HIV-infected children with CD4+ lymphocyte >=25% were randomized to initiate antiretroviral therapy immediately (ART-Immed) or when clinically indicated (ART Def). Nasopharyngeal swabs for bacterial culture were taken prior to each PCV7 dose (Visits 1-3) and at 20, 39, 47 and 67 weeks of age (Visits 4-7). Swabs were cultured by standard methods and pneumococcal serotyping done by the Quellung method. RESULTS: Colonization patterns for pneumococcus, H. influenzae and S. aureus did not differ between HUU and HEU children; and were also generally similar between ART-Def and ART-Immed children. Prevalence of PCV7-serotype colonization was similar between HIV-infected and HIV-uninfected children, however, overall pneumococcal and specifically non-vaccine serotype colonization tended to be lower in HIV-infected children. HIV-infected children also had a 44% lower prevalence of S. aureus colonization at Visit-1 (p=0.010); and H. influenzae colonization was also lower among HIV-infected than HIV-uninfected children at Visit-2, Visit-3, Visit-6 and Visit-7. CONCLUSION: Vaccine-serotype colonization is similar in PCV-immunized HIV-infected and HIV-uninfected children. We, however, identified a lower prevalence of overall-pneumococcal and H. influenzae colonization in HIV-infected children post-PCV vaccination, the clinical-relevance of which warrants further study. PMID- 25910927 TI - A descriptive and follow-up study of 40 parricidal patients hospitalized in a French secure unit over a 15-year period. AB - Parricide is rare and represents 3% of all homicides in France, and 4% of resolved homicides in North America. Consequently, related international literature is sparse, especially concerning the evolution of offenders, and most studies concern small samples or anecdotal cases. We wished to identify the main characteristics of parricidal subjects and their victims, and to assess the socioclinical evolution of the offenders after the assault. To this end, we first studied the sociodemographic, clinical and forensic characteristics of all parricidal patients admitted to France's Henri Colin secure unit between 1996 and 2010 (40 patients). We also assessed the evolution of the 36 patients who had left the secure unit, using questionnaires sent to the psychiatric hospitals where the patients were transferred. We found most offenders to be men (97.5%), with a mean age of 28 years, who were mostly single, unemployed, living with the victim prior to the assault (77.5%), and with a history of psychiatric disorder (72.5%). The population of offenders also displayed an overrepresentation of schizophrenia (87.5%), significant toxic exposure and criminal or violent history. Some patients had attempted suicide before or right after the offense. The assault was mostly committed in the parent's house with an edged weapon, and was characterized by brutality and lack of premeditation. Precipitating factors included substance use and cessation of psychotropic medication. Matricide was more frequent than patricide. At the time of this study, half of the parricidal patients were working or attending therapeutic activities, and most were actively keeping in contact with their family, living as compliant outpatients with no signs of violent behavior. The results of our study on 40 parricidal patients are consistent with data in the literature. With regard to sample evolution, family and community reintegration was relatively effective considering the seriousness of the offense. Several biases in our study disallow the generalization of these findings, and further studies are needed. PMID- 25910928 TI - Comparative risk of gastrointestinal bleeding with dabigatran, rivaroxaban, and warfarin: population based cohort study. AB - OBJECTIVE: To determine the real world risk of gastrointestinal bleeding associated with the use of the novel oral anticoagulants dabigatran and rivaroxaban compared with warfarin. DESIGN: Retrospective, propensity matched cohort study. SETTING: Optum Labs Data Warehouse, a large database including administrative claims data on privately insured and Medicare Advantage enrollees. PARTICIPANTS: New users of dabigatran, rivaroxaban, and warfarin from 1 November 2010 to 30 September 2013. MAIN OUTCOME MEASURES: Incidence rates (events/100 patient years) and propensity score matched Cox proportional hazards models were used to estimate rates of total gastrointestinal bleeds, upper gastrointestinal bleeds, and lower gastrointestinal bleeds for the novel oral anticoagulants compared with warfarin in patients with and without atrial fibrillation. Heterogeneity of treatment effect related to age was examined using a marginal effects model. RESULTS: The incidence of gastrointestinal bleeding associated with dabigatran was 2.29 (95% confidence interval 1.88 to 2.79) per 100 patient years and that associated with warfarin was 2.87 (2.41 to 3.41) per 100 patient years in patients with atrial fibrillation. In non-atrial fibrillation patients, the incidence of gastrointestinal bleeding was 4.10 (2.47 to 6.80) per 100 patient years with dabigatran and 3.71 (2.16 to 6.40) per 100 patient years with warfarin. With rivaroxaban, 2.84 (2.30 to 3.52) gastrointestinal bleeding events per 100 patient years occurred in atrial fibrillation patients (warfarin 3.06 (2.49 to 3.77)/100 patient years) and 1.66 (1.23 to 2.24) per 100 patient years in non-atrial fibrillation patients (warfarin 1.57 (1.25 to 1.99)/100 patient years). In propensity score matched models, the risk of gastrointestinal bleeding with novel oral anticoagulants was similar to that with warfarin in atrial fibrillation patients (dabigatran v warfarin, hazard ratio 0.79 (0.61 to 1.03); rivaroxaban v warfarin, 0.93 (0.69 to 1.25)) and in non-AF patients (dabigatran v warfarin, hazard ratio 1.14 (0.54 to 2.39); rivaroxaban v warfarin, 0.89 (0.60 to 1.32)). The risk of gastrointestinal bleeding increased after age 65, such that by age 76 the risk exceeded that with warfarin among atrial fibrillation patients taking dabigatran (hazard ratio 2.49 (1.61 to 3.83)) and patients with and without atrial fibrillation taking rivaroxaban (2.91 (1.65 to 4.81) and 4.58 (2.40 to 8.72), respectively). CONCLUSIONS: The risk of gastrointestinal bleeding related to novel oral anticoagulants was similar to that for warfarin. Caution should be used when prescribing novel oral anticoagulants to older people, particularly those over 75 years of age. PMID- 25910929 TI - Low-Income Individuals' Perceptions About Fruit and Vegetable Access Programs: A Qualitative Study. AB - OBJECTIVE: To examine how fruit and vegetable (FV) programs address barriers to FV access and consumption as perceived by low-income individuals. DESIGN: From 2011 to 2012, the researchers used 13 focus groups to better understand low income individuals' perceptions about FV programs. SETTING: Five North Carolina counties at community-serving organizations. PARTICIPANTS: Low-income participants aged >= 18 years were included in the study. A majority were African American women with a high school education or less, and received government assistance. PHENOMENON OF INTEREST: Low-income individuals' perceptions about how FV access programs can reduce barriers and increase consumption. ANALYSIS: A socio-ecological framework guided data analysis, and 2 trained researchers coded transcripts, identified major themes, and summarized findings. RESULTS: A total of 105 participants discussed how mobile markets could overcome barriers such as availability, convenience, transportation, and quality/variety. Some were worried about safety in higher-crime communities. Participants' opinions about how successful food assistance programs were at overcoming cost barriers were mixed. Participants agreed that community gardens could increase access to affordable, conveniently located produce but worried about feasibility and implementation issues. IMPLICATIONS FOR RESEARCH AND PRACTICE: Addressing access barriers through FV programs could improve consumption. Programs have the potential to be successful if they address multiple access barriers. PMID- 25910930 TI - Single-blinded, randomised preliminary study evaluating the effects of 2 Hz electroacupuncture for postoperative pain in patients with total knee arthroplasty. AB - OBJECTIVE: To explore the point-specific clinical effect of 2 Hz electroacupuncture (EA) in treating postoperative pain in patients undergoing total knee arthroplasty (TKA), METHODS: In a randomised, partially single-blinded preliminary study, 47patients with TKA were randomly divided into three groups: control group (CG, n=17) using only patient-controlled analgesia (PCA); EA group (EAG, n=16) with 2 Hz EA applied at ST36 (Zusanli) and GB34 (Yanglingquan) contralateral to the operated leg for 30 min on the first two postoperative days, also receiving PCA; and non-point group (NPG, n=14), with EA identical to the EAG except given 1 cm lateral to both ST36 and GB34. The Mann-Whitney test was used to show the difference between two groups and the Kruskal-Wallis test to show the difference between the three groups. RESULTS: The time until patients first required PCA in the CG was 34.1+/-22.0 min, which was significantly shorter than the 92.0+/-82.7 min in the EAG (p<0.001) and 90.7+/-94.8 min in the NPG (p<0.001); there was no difference between the EAG and NPG groups (p>0.05). The total dosage of PCA solution given was 4.6+/-0.9 mL/kg body weight in the CG, 4.2+/-1.0 mL/kg in the EAG and 4.5+/-1.0 mL/kg in the NPG; there were no significant differences (p>0.05) among the three groups. CONCLUSIONS: In this small preliminary study, EA retarded the first demand for PCA in comparison with no EA. No effect was seen on the total dosage of PCA required and no point specific effect was seen. PMID- 25910931 TI - Risk factors and derived formosa score for intravenous immunoglobulin unresponsiveness in Taiwanese children with Kawasaki disease. AB - BACKGROUND/PURPOSE: Kawasaki disease (KD) is the most common pediatric vasculitis. The study aimed to identify the risk factors of intravenous immunoglobulin (IVIG) unresponsiveness from the initial clinical parameters of the Taiwanese KD patients. METHODS: We enrolled 248 KD (development dataset: 181, validation: 67) patients who received IVIG within 10 days after fever onset. IVIG unresponsiveness was defined by persistent fever beyond 24 hours after IVIG or recrudescent fever with KD symptoms. RESULTS: From the development dataset (181 patients), IVIG unresponsiveness was noted in 22 patients (12.1%). The preIVIG levels of albumin, percentage of neutrophils, and positive lymphadenopathy were identified with highest risk for IVIG unresponsiveness. These three variables were used to construct a three-variable logistic regression model, which yielded an area under the receiver-operating-characteristics curve of 0.87. These three variables were further used to generate a composite scoring model (Formosa score) which yielded a sensitivity of 90.9% and specificity of 81.3% for a cut-off point of three or more. Validation in an independent cohort (67 KD patients) yielded sensitivity and specificity of 71.4% and 81.0%, respectively. CONCLUSION: We have established a simple three-variable Formosa score for KD patients to identify early those at risk of IVIG unresponsiveness for timely aggressive immunomodulation initially. PMID- 25910932 TI - Accessing external innovation in drug discovery and development. AB - INTRODUCTION: A decline in the productivity of the pharmaceutical industry research and development (R&D) pipeline has highlighted the need to reconsider the classical strategies of drug discovery and development, which are based on internal resources, and to identify new means to improve the drug discovery process. Accepting that the combination of internal and external ideas can improve innovation, ways to access external innovation, that is, opening projects to external contributions, have recently been sought. AREAS COVERED: In this review, the authors look at a number of external innovation opportunities. These include increased interactions with academia via academic centers of excellence/innovation centers, better communication on projects using crowdsourcing or social media and new models centered on external providers such as built-to-buy startups or virtual pharmaceutical companies. EXPERT OPINION: The buzz for accessing external innovation relies on the pharmaceutical industry's major challenge to improve R&D productivity, a conjuncture favorable to increase interactions with academia and new business models supporting access to external innovation. So far, access to external innovation has mostly been considered during early stages of drug development, and there is room for enhancement. First outcomes suggest that external innovation should become part of drug development in the long term. However, the balance between internal and external developments in drug discovery can vary largely depending on the company strategies. PMID- 25910933 TI - [3D mandibular distraction planification in a case of severe temporomandibular ankylosis]. AB - INTRODUCTION: When occurring in childhood, temporomandibular ankylosis joint is responsible for complex maxillofacial deformities, including mandibular growth deficiency. We present a case of temporomandibular joint ankylosis associated with severe mandibular asymmetry treated by mandibular bone distraction performed under computer assistance. OBSERVATION: A 27-year-old patient presented with a severe facial asymmetry consisting in hypoplasia of the left hemi-mandible and maxilla. Mouth opening was non-existent. The CT-scan showed a left temporomandibular ankylosis. A left mandibular distraction was decided. The distraction characteristics (choice and positioning of the distractor, axis and amount of distraction) were determined preoperatively on the 3D CT-scan. The planning has been transferred to a navigation console (Kolibri(r), Brainlab(r)). A combined intraoral and cutaneous was performed. Navigation allowed for an appropriate placement of the osteotomy line and fixation of the distractor. Distraction was started at the 5th postoperative day at the rate of 1mm per day and lasted 25 days without complication. DISCUSSION: 3D planning allows for better indication setting, better preparation of the procedure, reducing complications and operative time. It may help as an educational tool for young surgeons and for a better understanding from the patient. Navigation is an accurate method for the transfer of the planning in the operation room. PMID- 25910935 TI - Deadly tricks to combat atherosclerosis. PMID- 25910934 TI - Sphingosine-1-phosphate receptor 1 agonism attenuates lung ischemia-reperfusion injury. AB - Outcomes for lung transplantation are the worst of any solid organ, and ischemia reperfusion injury (IRI) limits both short- and long-term outcomes. Presently no therapeutic agents are available to prevent IRI. Sphingosine 1-phosphate (S1P) modulates immune function through binding to a set of G protein-coupled receptors (S1PR1-5). Although S1P has been shown to attenuate lung IRI, the S1P receptors responsible for protection have not been defined. The present study tests the hypothesis that protection from lung IRI is primarily mediated through S1PR1 activation. Mice were treated with either vehicle, FTY720 (a nonselective S1P receptor agonist), or VPC01091 (a selective S1PR1 agonist and S1PR3 antagonist) before left lung IR. Function, vascular permeability, cytokine expression, neutrophil infiltration, and myeloperoxidase levels were measured in lungs. After IR, both FTY720 and VPC01091 significantly improved lung function (reduced pulmonary artery pressure and increased pulmonary compliance) vs. vehicle control. In addition, FTY720 and VPC01091 significantly reduced vascular permeability, expression of proinflammatory cytokines (IL-6, IL-17, IL-12/IL-23 p40, CC chemokine ligand-2, and TNF-alpha), myeloperoxidase levels, and neutrophil infiltration compared with control. No significant differences were observed between VPC01091 and FTY720 treatment groups. VPC01091 did not significantly affect elevated invariant natural killer T cell infiltration after IR, and administration of an S1PR1 antagonist reversed VPC01091-mediated protection after IR. In conclusion, VPC01091 and FTY720 provide comparable protection from lung injury and dysfunction after IR. These findings suggest that S1P-mediated protection from IRI is mediated by S1PR1 activation, independent of S1PR3, and that selective S1PR1 agonists may provide a novel therapeutic strategy to prevent lung IRI. PMID- 25910936 TI - Circulating mitochondrial DNA and Toll-like receptor 9 are associated with vascular dysfunction in spontaneously hypertensive rats. AB - AIMS: Immune system activation is a common feature of hypertension pathogenesis. However, the mechanisms that initiate this activation are not well understood. Innate immune system recognition and response to danger are becoming apparent in many cardiovascular diseases. Danger signals can arise from not only pathogens, but also damage-associated molecular patterns (DAMPs). Our first hypothesis was that the DAMP, mitochondrial DNA (mtDNA), which is recognized by Toll-like receptor 9 (TLR9), is elevated in the circulation of spontaneously hypertensive rats (SHR), and that the deoxyribonuclease enzymes responsible for its degradation have decreased activity in SHR. Based on these novel SHR phenotypes, we further hypothesized that (i) treatment of SHR with an inhibitory oligodinucleotide for TLR9 (ODN2088) would lower blood pressure and that (ii) treatment of normotensive rats with a TLR9-specific CpG oligonucleotide (ODN2395) would cause endothelial dysfunction and increase blood pressure. METHODS AND RESULTS: We observed that SHR have elevated circulating mtDNA and diminished deoxyribonuclease I and II activity. Additionally, treatment of SHR with ODN2088 lowered systolic blood pressure. On the other hand, treatment of normotensive rats with ODN2395 increased systolic blood pressure and rendered their arteries less sensitive to acetylcholine-induced relaxation and more sensitive to norepinephrine-induced contraction. This dysfunctional vasoreactivity was due to increased cyclooxygenase and p38 mitogen-activated protein kinase activation, increased reactive oxygen species generation, and reduced nitric oxide bioavailability. CONCLUSION: Circulating mtDNA and impaired deoxyribonuclease activity may lead to the activation of the innate immune system, via TLR9, and contribute to elevated arterial pressure and vascular dysfunction in SHR. PMID- 25910937 TI - VEGF-A isoform-specific regulation of calcium ion flux, transcriptional activation and endothelial cell migration. AB - Vascular endothelial growth factor A (VEGF-A) regulates many aspects of vascular physiology such as cell migration, proliferation, tubulogenesis and cell-cell interactions. Numerous isoforms of VEGF-A exist but their physiological significance is unclear. Here we evaluated two different VEGF-A isoforms and discovered differential regulation of cytosolic calcium ion flux, transcription factor localisation and endothelial cell response. Analysis of VEGF-A isoform specific stimulation of VEGFR2-dependent signal transduction revealed differential capabilities for isoform activation of multiple signal transduction pathways. VEGF-A165 treatment promoted increased phospholipase Cgamma1 phosphorylation, which was proportional to the subsequent rise in cytosolic calcium ions, in comparison to cells treated with VEGF-A121. A major consequence of this VEGF-A isoform-specific calcium ion flux in endothelial cells is differential dephosphorylation and subsequent nuclear translocation of the transcription factor NFATc2. Using reverse genetics, we discovered that NFATc2 is functionally required for VEGF-A-stimulated endothelial cell migration but not tubulogenesis. This work presents a new mechanism for understanding how VEGF-A isoforms program complex cellular outputs by converting signal transduction pathways into transcription factor redistribution to the nucleus, as well as defining a novel role for NFATc2 in regulating the endothelial cell response. PMID- 25910938 TI - Planar polarization of Vangl2 in the vertebrate neural plate is controlled by Wnt and Myosin II signaling. AB - The vertebrate neural tube forms as a result of complex morphogenetic movements, which require the functions of several core planar cell polarity (PCP) proteins, including Vangl2 and Prickle. Despite the importance of these proteins for neurulation, their subcellular localization and the mode of action have remained largely unknown. Here we describe the anteroposterior planar cell polarity (AP PCP) of the cells in the Xenopus neural plate. At the neural midline, the Vangl2 protein is enriched at anterior cell edges and that this localization is directed by Prickle, a Vangl2-interacting protein. Our further analysis is consistent with the model, in which Vangl2 AP-PCP is established in the neural plate as a consequence of Wnt-dependent phosphorylation. Additionally, we uncover feedback regulation of Vangl2 polarity by Myosin II, reiterating a role for mechanical forces in PCP. These observations indicate that both Wnt signaling and Myosin II activity regulate cell polarity and cell behaviors during vertebrate neurulation. PMID- 25910939 TI - Pex11mediates peroxisomal proliferation by promoting deformation of the lipid membrane. AB - Pex11p family proteins are key players in peroxisomal fission, but their molecular mechanisms remains mostly unknown. In the present study, overexpression of Pex11pbeta caused substantial vesiculation of peroxisomes in mammalian cells. This vesicle formation was dependent on dynamin-like protein 1 (DLP1) and mitochondrial fission factor (Mff), as knockdown of these proteins diminished peroxisomal fission after Pex11pbeta overexpression. The fission-deficient peroxisomes exhibited an elongated morphology, and peroxisomal marker proteins, such as Pex14p or matrix proteins harboring peroxisomal targeting signal 1, were discernible in a segmented staining pattern, like beads on a string. Endogenous Pex11pbeta was also distributed a striped pattern, but which was not coincide with Pex14p and PTS1 matrix proteins. Altered morphology of the lipid membrane was observed when recombinant Pex11p proteins were introduced into proteo liposomes. Constriction of proteo-liposomes was observed under confocal microscopy and electron microscopy, and the reconstituted Pex11pbeta protein localized to the membrane constriction site. Introducing point mutations into the N-terminal amphiphathic helix of Pex11pbeta strongly reduced peroxisomal fission, and decreased the oligomer formation. These results suggest that Pex11p contributes to the morphogenesis of the peroxisomal membrane, which is required for subsequent fission by DLP1. PMID- 25910940 TI - Trade-offs between performance and variability in the escape responses of bluegill sunfish (Lepomis macrochirus). AB - Successful predator evasion is essential to the fitness of many animals. Variation in escape behaviour may be adaptive as it reduces predictability, enhancing escape success. High escape velocities and accelerations also increase escape success, but biomechanical factors likely constrain the behavioural range over which performance can be maximized. There may therefore be a trade-off between variation and performance during escape responses. We have used bluegill sunfish (Lepomis macrochirus) escape responses to examine this potential trade off, determining the full repertoire of escape behaviour for individual bluegill sunfish and linking this to performance as indicated by escape velocity and acceleration. Fish escapes involve an initial C-bend of the body axis, followed by variable steering movements. These generate thrust and establish the escape direction. Directional changes during the initial C-bend were less variable than the final escape angle, and the most frequent directions were associated with high escape velocity. Significant inter-individual differences in escape angles magnified the overall variation, maintaining unpredictability from a predator perspective. Steering in the latter stages of the escape to establish the final escape trajectory also affected performance, with turns away from the stimulus associated with reduced velocity. This suggests that modulation of escape behaviour by steering may also have an associated performance cost. This has important implications for understanding the scope and control of intra- and inter-individual variation in escape behaviour and the associated costs and benefits. PMID- 25910942 TI - Using high-level construal and perceptions of changeability to promote self change over self-protection motives in response to negative feedback. AB - Diagnostic negative information presents people with a motivational dilemma. Although negative feedback can provide useful information with which to guide future self-improvement efforts, it also presents short-term affective costs. We propose that construal level, jointly with the perceived changeability of the feedback domain, determines whether people choose to accept or dismiss such information. Whereas low-level construal promotes short-term self-protection motivation (promoting dismissal), high-level construal promotes long-term self change motivation (promoting acceptance)--to the extent that change is perceived as possible. Four studies support this hypothesis and examine underlying cognitive and motivational mechanisms. The present work may provide an integrative theoretical framework for understanding when people will be open to and accept negative diagnostic information, and has important practical implications for promoting self-change efforts. PMID- 25910941 TI - Excessive centrifugal fields damage high density lipoprotein. AB - HDL is typically isolated ultracentrifugally at 40,000 rpm or greater, however, such high centrifugal forces are responsible for altering the recovered HDL particle. We demonstrate that this damage to HDL begins at approximately 30,000 rpm and the magnitude of loss increases in a rotor speed-dependent manner. The HDL is affected by elevated ultracentrifugal fields resulting in a lower particle density due to the shedding of associated proteins. To circumvent the alteration of the recovered HDL, we utilize a KBr-containing density gradient and a lowered rotor speed of 15,000 rpm to separate the lipoproteins using a single 96 h centrifugation step. This recovers the HDL at two density ranges; the bulk of the material has a density of about 1.115 g/ml, while lessor amounts of material are recovered at >1.2 g/ml. Thus, demonstrating the isolation of intact HDL is possible utilizing lower centrifuge rotor speeds. PMID- 25910943 TI - Clinical outcomes of patients with acute minor stroke receiving rescue IA therapy following early neurological deterioration. AB - BACKGROUND: Patients presenting with minor ischemic stroke frequently have early neurological deterioration (END) and poor final outcome. The optimal management of patients with END has not been determined. OBJECTIVE: To investigate rescue IA therapy (IAT) when patients with acute minor ischemic stroke develop END. METHODS: This was a retrospective study of consecutively registered patients with acute minor stroke and END. 'END' was defined as an increase in National Institutes of Health Stroke Scale (NIHSS) scores by 1 or more points (or development of new neurological symptoms) and 'DeltaEND-NIHSS' was defined as numerical difference between NIHSS scores at the time of END and before END. Rescue IAT following END was adjusted for the covariates to evaluate the association between IAT and favorable outcome at 3 months. RESULTS: Among 982 patients with acute minor ischemic stroke, END occurred in 232 (23.6%). Of the 209 patients with END with full data available, 87 (41.6%) had favorable outcomes at 3 months. Rescue IAT following END was performed in 28 (13.4%). Favorable 3 month outcomes were seen in 50% of patients undergoing rescue IAT, including 8/19 (42.1%) undergoing rescue IAT beyond 8 h. By multivariate logistic regression analysis, rescue IAT following END was independently associated with favorable outcome at 3 months (OR=10.9; 95% CI 3.06 to 38.84; p<0.001). CONCLUSIONS: The results suggest that rescue IAT may be safe and effective when END occurs in selected patients with acute minor ischemic stroke. Further prospective and randomized studies are needed to confirm our results. PMID- 25910944 TI - High Prevalence of Obesity and Female Gender Among Patients With Concomitant Tibialis Posterior Tendonitis and Plantar Fasciitis. AB - The link between increased body weight and hindfoot complaints is largely based on correlation to single foot pathology. We retrospectively reviewed 6879 patients with tibialis posterior tendonitis (TPT), plantar fasciitis (PF), or both. Among patients with either TPT or PF, 1 in 11 (9%) had both. We then compared age, gender, and body mass index among these groups. Patients with both diagnoses were neither statistically older nor more obese than patients with single diagnoses. However, they were statistically more female. Given the overall high prevalence of obesity in the study population, we feel these data support the link between obesity and multiple foot pathology. LEVELS OF EVIDENCE: Prognostic, Level IV: Case series. PMID- 25910945 TI - Synovial Chondromatosis Surrounding the First Metatarsophalangeal Joint: A Case Report. AB - Synovial chondromatosis is a benign synovial tumor that rarely occurs in the foot. We present a case of a 36-year-old male who underwent surgical excision of primary synovial chondromatosis of the first metatarsophalangeal joint. This report also presents a review of the literature related to synovial chondromatosis of the foot. Currently in the literature, this pathology has been described as occurring in multiple locations in the foot and ankle. Synovial chondromatosis can occur primarily or secondarily in diseased joints. Treatment is based on the phase of disease, with a goal to decrease pain and arthritis, and increase mobility. Surgical techniques used for foot and ankle synovial chondromatosis have been adapted from larger joints where the condition is more prevalent. Further case studies are needed to formulate a treatment protocol for foot and ankle synovial chondromatosis, but successful surgical excision was found in this case report. LEVELS OF EVIDENCE: Therapeutic, Level IV: Case study. PMID- 25910946 TI - The Biomechanical Evaluation of Revision First Metatarsophalangeal Arthrodesis: A Cadaveric Study. AB - BACKGROUND: First metatarsophalangeal (MP) arthrodesis in the setting of bone loss is a difficult problem. Bone loss may compromise stability of implant fixation. Union rates may be adversely affected by these circumstances. The primary goals of this cadaveric, biomechanical study were to (1) investigate stiffness of a dual mini-plate construct versus a standard MP arthrodesis plate in the setting of severe bone loss and (2) evaluate arthrodesis interface motion when an interpositional graft is used. METHODS: Twelve matched cadaveric samples were used in this study. In a given pair, both dual mini-plate fixation and standard MP arthrodesis plate were used. Interpositional graft was used in 6 of the specimen pairs. After implantation, soft tissues were dissected away and specimens were placed into a cantilever bending setup. A cantilever load was applied at a rate of 6 mm/min until catastrophic failure of the test construct or 5-mm plantar gapping of either bone block interface. RESULTS: Based on load to failure data, there were no differences between the various constructs in terms of stiffness. There was a high degree of calculated plantar gapping with the placement of a bone block, irrespective of the fixation type. CONCLUSIONS: Although no construct differences were observed in terms of stiffness, the dual mini-plate is an alternative option for fixation when asymmetric bone loss is either seen on the phalangeal or metatarsal head side. The high degree of plantar gapping of the proximal interface with the placement of the bone block may have implications for healing potential across the arthrodesis site. CLINICAL RELEVANCE: This is the first biomechanical study investigating the stiffness of multiple constructs for MP arthrodesis in the setting of severe bone loss. Furthermore, this is the first study to introduce a biomechanical rationale for difficulties in healing for this particular clinical scenario. LEVELS OF EVIDENCE: Level V: Bench testing. PMID- 25910948 TI - The A to Z of A/C plasmids. AB - Plasmids belonging to incompatibility groups A and C (now A/C) were among the earliest to be associated with antibiotic resistance in Gram-negative bacteria. A/C plasmids are large, conjugative plasmids with a broad host range. The prevalence of A/C plasmids in collections of clinical isolates has revealed their importance in the dissemination of extended-spectrum beta-lactamases and carbapenemases. They also mobilize SGI1-type resistance islands. Revived interest in the family has yielded many complete A/C plasmid sequences, revealing that RA1, designated A/C1, is different from the remainder, designated A/C2. There are two distinct A/C2 lineages. Backbones of 128-130 kb include over 120 genes or ORFs encoding proteins of at least 100 amino acids, but very few have been characterized. Genes potentially required for replication, stability and transfer have been identified, but only the replication system of RA1 and the regulation of transfer have been studied. There is enormous variety in the antibiotic resistance genes carried by A/C2 plasmids but they are usually clustered in larger regions at various locations in the backbone. The ARI-A and ARI-B resistance islands are always at a specific location but have variable content. ARI-A is only found in type 1 A/C2 plasmids, which disseminate blaCMY-2 and blaNDM-1 genes, whereas ARI-B, carrying the sul2 gene, is found in both type 1 and type 2. This review summarizes current knowledge of A/C plasmids, and highlights areas of research to be considered in the future. PMID- 25910947 TI - First step in using molecular data for microbial food safety risk assessment; hazard identification of Escherichia coli O157:H7 by coupling genomic data with in vitro adherence to human epithelial cells. AB - The potential for using whole genome sequencing (WGS) data in microbiological risk assessment (MRA) has been discussed on several occasions since the beginning of this century. Still, the proposed heuristic approaches have never been applied in a practical framework. This is due to the non-trivial problem of mapping microbial information consisting of thousands of loci onto a probabilistic scale for risks. The paradigm change for MRA involves translation of multidimensional microbial genotypic information to much reduced (integrated) phenotypic information and onwards to a single measure of human risk (i.e. probability of illness). In this paper a first approach in methodology development is described for the application of WGS data in MRA; this is supported by a practical example. That is, combining genetic data (single nucleotide polymorphisms; SNPs) for Shiga toxin-producing Escherichia coli (STEC) O157 with phenotypic data (in vitro adherence to epithelial cells as a proxy for virulence) leads to hazard identification in a Genome Wide Association Study (GWAS). This application revealed practical implications when using SNP data for MRA. These can be summarized by considering the following main issues: optimum sample size for valid inference on population level, correction for population structure, quantification and calibration of results, reproducibility of the analysis, links with epidemiological data, anchoring and integration of results into a systems biology approach for the translation of molecular studies to human health risk. Future developments in genetic data analysis for MRA should aim at resolving the mapping problem of processing genetic sequences to come to a quantitative description of risk. The development of a clustering scheme focusing on biologically relevant information of the microbe involved would be a useful approach in molecular data reduction for risk assessment. PMID- 25910949 TI - Population data for 15 autosomal STR loci in the Bouyei ethnic minority from Guizhou Province, Southwest China. PMID- 25910950 TI - A Multicenter, Phase II, Randomized, Noncomparative Clinical Trial of Radiation and Temozolomide with or without Vandetanib in Newly Diagnosed Glioblastoma Patients. AB - PURPOSE: Vandetanib, a tyrosine kinase inhibitor of KDR (VEGFR2), EGFR, and RET, may enhance sensitivity to chemotherapy and radiation. We conducted a randomized, noncomparative, phase II study of radiation (RT) and temozolomide with or without vandetanib in patients with newly diagnosed glioblastoma (GBM). EXPERIMENTAL DESIGN: We planned to randomize a total of 114 newly diagnosed GBM patients in a ratio of 2:1 to standard RT and temozolomide with (76 patients) or without (38 patients) vandetanib 100 mg daily. Patients with age >= 18 years, Karnofsky performance status (KPS) >= 60, and not on enzyme-inducing antiepileptics were eligible. Primary endpoint was median overall survival (OS) from the date of randomization. Secondary endpoints included median progression-free survival (PFS), 12-month PFS, and safety. Correlative studies included pharmacokinetics as well as tissue and serum biomarker analysis. RESULTS: The study was terminated early for futility based on the results of an interim analysis. We enrolled 106 patients (36 in the RT/temozolomide arm and 70 in the vandetanib/RT/temozolomide arm). Median OS was 15.9 months [95% confidence interval (CI), 11.0-22.5 months] in the RT/temozolomide arm and 16.6 months (95% CI, 14.9-20.1 months) in the vandetanib/RT/temozolomide (log-rank P = 0.75). CONCLUSIONS: The addition of vandetanib at a dose of 100 mg daily to standard chemoradiation in patients with newly diagnosed GBM or gliosarcoma was associated with potential pharmacodynamic biomarker changes and was reasonably well tolerated. However, the regimen did not significantly prolong OS compared with the parallel control arm, leading to early termination of the study. PMID- 25910951 TI - A Hypoxia-Induced Vascular Endothelial-to-Mesenchymal Transition in Development of Radiation-Induced Pulmonary Fibrosis. AB - PURPOSE: Radiation-induced pulmonary fibrosis (RIPF) is a late side effect of thoracic radiotherapy. The purpose of our study was to gain further insight into the development of RIPF. EXPERIMENTAL DESIGN/RESULTS: Here, we observed that irradiation of mouse lungs induced collagen deposition, particularly around blood vessels, in the early phase of RIPF. Such deposition subsequently became evident throughout the irradiated tissues. Accompanied by the collagen deposition, vascular EndMT (endothelial-to-mesenchymal transition) began to develop in the early phase of RIPF, before the appearance of EMT (epithelial-to-mesenchymal transition) of alveolar epithelial (AE) II cells in the substantive fibrotic phase. Concomitant with the EndMT, we detected vascular endothelial cell (EC) specific hypoxic damage in the irradiated lung tissues. In human pulmonary artery endothelial cells (HPAEC), the radiation-induced EndMT via activation of TGFbeta R1/Smad signaling was dependent on HIF1alpha expression. A novel HIF1alpha inhibitor, 2-methoxyestradiol (2-ME), inhibited the irradiation-induced EndMT via downregulation of HIF1alpha-dependent Smad signaling. In vivo, 2-ME inhibited the vascular EndMT, and decreased the collagen deposition associated with RIPF. Furthermore, HIF1alpha-related EndMT was observed also in human RIPF tissues. CONCLUSIONS: We provide the first evidence that an EndMT occurs in RIPF development and that the EndMT may be effectively inhibited by modulating vascular EC-specific hypoxic damage. PMID- 25910953 TI - Venous claudication in Behcet's disease. AB - OBJECTIVE: We have previously shown that venous claudication is significantly more common among patients with Behcet's disease (BD) and had proposed that this was a "venous claudication" because it was specifically more common among men with lower extremity venous thrombosis (LEVT). With this study, we reassessed the presence of claudication prospectively by a questionnaire and a treadmill exercise. METHODS: We studied all men: 61 BD patients with LEVT, 40 BD patients without vascular involvement, and 56 healthy controls. Venous claudication was assessed by a standardized questionnaire. In addition, patients were asked to walk on a treadmill for 10 minutes. Patients who experienced symptoms consistent with venous claudication but still able to walk and those who had to give up the treadmill exercise were noted. Ankle-brachial pressure indices measured before and after the treadmill test did not indicate any peripheral arterial disease. RESULTS: Twenty-one BD patients with LEVT (34%), two BD patients without vascular involvement (5%), and none of the healthy controls described venous claudication when assessed with the questionnaire (P < .001). There were significantly more patients who described claudication during the treadmill exercise among patients with LEVT (21%) compared with those with no vascular disease (8%) and healthy controls (2%) (P = .002). Finally, only those with LEVT (6 of 61) had to stop the treadmill challenge because of claudication. CONCLUSIONS: Venous claudication is a severe and frequent symptom, being present in up to one third of BD patients with LEVT. It impairs walking capacity in 10% of these patients. PMID- 25910955 TI - 12 h shifts and rates of error among nurses: A systematic review. AB - OBJECTIVE: To determine the effect of working 12 h or more on a single shift in an acute care hospital setting compared with working less than 12 h on rates of error among nurses. DESIGN: Systematic review. METHOD: A three-step search strategy was utilised. An initial search of Cochrane, the Joanna Briggs Institute (JBI), MEDLINE and CINAHL was undertaken. A second search using all identified keywords and index terms was then undertaken across all included databases (Embase, Current contents, Proquest Nursing and Allied Health Source, Proquest Theses and Dissertations, Dissertation Abstracts International). Thirdly, reference lists of identified reports and articles were searched for additional studies. Studies published in English before August 2014 were included. FINDINGS: Following review of title and abstract of 5429 publications, 26 studies were identified as meeting the inclusion criteria and selected for full retrieval and assessment for methodological quality. Of these, 13 were of sufficient quality to be included for review. Six studies reported higher rates of error for nurses working greater than 12 h on a single shift, four reported higher rates of error on shifts of up to 8 h, and three reported no difference. The six studies reporting significant rises in error rates among nurses working 12 h or more on a single shift comprised 89% of the total sample size (N=60,780 with the total sample size N=67,967). CONCLUSION: The risk of making an error appears higher among nurses working 12 h or longer on a single shift in acute care hospitals. Hospitals and units currently operating 12 h shift systems should review this scheduling practice due to the potential negative impact on patient outcomes. Further research is required to consider factors that may mitigate the risk of error where 12 h shifts are scheduled and this cannot be changed. PMID- 25910952 TI - Regulator of Chromosome Condensation 2 Identifies High-Risk Patients within Both Major Phenotypes of Colorectal Cancer. AB - PURPOSE: Colorectal cancer has high incidence and mortality worldwide. Patients with microsatellite instable (MSI) tumors have significantly better prognosis than patients with microsatellite stable (MSS) tumors. Considerable variation in disease outcome remains a challenge within each subgroup, and our purpose was to identify biomarkers that improve prediction of colorectal cancer prognosis. EXPERIMENTAL DESIGN: Mutation analyses of 42 MSI target genes were performed in two independent MSI tumor series (n = 209). Markers that were significantly associated with prognosis in the test series were assessed in the validation series, followed by functional and genetic explorations. The clinical potential was further investigated by immunohistochemistry in a population-based colorectal cancer series (n = 903). RESULTS: We identified the cell-cycle gene regulator of chromosome condensation 2 (RCC2) as a cancer biomarker. We found a mutation in the 5' UTR region of RCC2 that in univariate and multivariate analyses was significantly associated with improved outcome in the MSI group. This mutation caused reduction of protein expression in dual luciferase gene reporter assays. siRNA knockdown in MSI colon cancer cells (HCT15) caused reduced cell proliferation, cell-cycle arrest, and increased apoptosis. Massive parallel sequencing revealed few RCC2 mutations in MSS tumors. However, weak RCC2 protein expression was significantly associated with poor prognosis, independent of clinical high-risk parameters, and stratifies clinically important patient subgroups with MSS tumors, including elderly patients (>75 years), stage II patients, and those with rectal cancer. CONCLUSIONS: Impaired RCC2 affects functional and clinical endpoints of colorectal cancer. High-risk patients with either MSI or MSS tumors can be identified with cost-effective routine RCC2 assays. PMID- 25910956 TI - Event-related EEG responses to anticipation and delivery of monetary and social reward. AB - Monetary and a social incentive delay tasks were used to characterize reward anticipation and delivery with electroencephalography. During reward anticipation, N1, P2 and P3 components were modulated by both prospective reward value and incentive type (monetary or social), suggesting distinctive allocation of attentional and motivational resources depending not only on whether rewards or non-rewards were cued, but also on the monetary and social nature of the prospective outcomes. In the delivery phase, P2, FRN and P3 components were also modulated by levels of reward value and incentive type, illustrating how distinctive affective and cognitive processes were attached to the different outcomes. Our findings imply that neural processing of both reward anticipation and delivery can be specific to incentive type, which might have implications for basic as well as translational research. These results are discussed in the light of previous electrophysiological and neuroimaging work using similar tasks. PMID- 25910957 TI - Effects of injustice sensitivity and sex on the P3 amplitude during deception. AB - In deception tasks, personality traits like the sensitivity to injustice (SI) modulate the P3 amplitude, which is an indicator of stimulus salience. Based on findings that demonstrated women to be more injustice sensitive than men, we expected sex to modulate effects of SI in deception tasks. We analyzed the P3 amplitudes of 57 participants in a deception task that comprised probe, target, and irrelevant pictures. Larger P3 amplitudes occurred for probes (known pictures that required deceptive responses) than for irrelevant pictures (unknown pictures that required truthful responses). Women with higher SI scores demonstrated larger P3 differences between probes and irrelevant stimuli. The findings suggest that women and men have different ways to process ethically-salient information and that SI modulates stimulus salience during deception. The effects of sex and personality have implications for the linkage between forensic psychophysiology and psychological assessment, because assessment is often based on individual differences. PMID- 25910958 TI - Automatic generation of computable implementation guides from clinical information models. AB - Clinical information models are increasingly used to describe the contents of Electronic Health Records. Implementation guides are a common specification mechanism used to define such models. They contain, among other reference materials, all the constraints and rules that clinical information must obey. However, these implementation guides typically are oriented to human-readability, and thus cannot be processed by computers. As a consequence, they must be reinterpreted and transformed manually into an executable language such as Schematron or Object Constraint Language (OCL). This task can be difficult and error prone due to the big gap between both representations. The challenge is to develop a methodology for the specification of implementation guides in such a way that humans can read and understand easily and at the same time can be processed by computers. In this paper, we propose and describe a novel methodology that uses archetypes as basis for generation of implementation guides. We use archetypes to generate formal rules expressed in Natural Rule Language (NRL) and other reference materials usually included in implementation guides such as sample XML instances. We also generate Schematron rules from NRL rules to be used for the validation of data instances. We have implemented these methods in LinkEHR, an archetype editing platform, and exemplify our approach by generating NRL rules and implementation guides from EN ISO 13606, openEHR, and HL7 CDA archetypes. PMID- 25910959 TI - CRTAM is negatively regulated by ZEB1 in T cells. AB - T cell activation leads to the induction of genes that are required for appropriate immune responses. This includes CRTAM (Class-I MHC-restricted T cell associated molecule), a protein that plays a key role in T cell development, proliferation, and generating cell polarity during activation. We previously characterized the CRTAM promoter and described how AP-1 family members are important for inducing CRTAM expression upon antigenic activation. Here, we show that CRTAM is a molecular target for ZEB1 (zinc finger E-box-binding protein), a homeodomain/Zn finger transcription factor. Overexpression of ZEB1 repressed CRTAM promoter activity, as well as endogenous CRTAM levels in human T cells. ZEB1-mediated transcriptional repression was abolished when E-box-like elements in the CRTAM promoter are mutated. In summary, ZEB1 functions as a transcriptional repressor for the CRTAM gene in both non-stimulated and stimulated T cells, thereby modulating adaptive immune responses. PMID- 25910960 TI - Comparison of genetic structures and biochemical properties of tandem cutinase type polyesterases from Thermobifida alba AHK119. AB - This study described the genetic map of tandem genes (est1 and est119) encoding cutinase-type polyesterases in Thermobifida alba AHK119 and comparison of wild type and mutant enzymes of Est1 and Est119. Two genes were independently and constitutively expressed. The activity of Est1 was higher by approximately 1.6 1.7-fold than that of Est119 towards p-nitrophenyl butyrate, although both enzymes shared 95% sequence identity and 98% similarity and possessed similar 3D structures except that several amino acids in the probable substrate-docking loops were different from each other. Calcium ion enhanced the activity and the thermostability of both enzymes. Based on conserved sequences among Thermobifida cutinases, valine, proline and lysine were introduced into Est1 at Ala68, Thr253 and Met256, respectively. Among wild and mutant enzymes of Est119 and Est1, Est1 (A68V/T253P) possessed three prolines in the substrate-docking loops and displayed the highest thermostability that spotlighted the important effect of proline numbers in the loops. Est1 (A68V/T253P) was stable for 1 h below 60 degrees C and even at 65 degrees C, more than 70% and 50% activities were maintained after 30 and 60 min, respectively. Est1 (A68V/T253P) degraded various aliphatic and aliphatic-co-aromatic polyesters and hydrophilized an amorphous PET film. The enzyme hydrolyzed a PET trimer model compound, indicating its specificity towards an ester bond between terephthalic acid and ethylene glycol. PMID- 25910961 TI - Heterotrophic nitrogen removal by Acinetobacter sp. Y1 isolated from coke plant wastewater. AB - A strain of Acinetobacter sp. Y1, which exhibited an amazing ability to remove ammonium, nitrite and nitrate, was isolated from the activated sludge of a coking wastewater treatment plant. The aim of this work was to study the ability, influence factors and possible pathway of nitrogen removal by Acinetobacter sp. Y1. Results showed that maximum removal rate of NH4(+)-N by the strain was 10.28 mg-N/L/h. Carbon source had significant influence on the growth and ammonium removal efficiencies of strain Y1. Pyruvate, citrate and acetate were favourable carbon sources for the strain. Temperature, pH value and shaking speed could affect the growth and nitrogen removal ability. Nitrate or nitrite could be used as a sole nitrogen source for the growth and removed efficiently by the strain. N2 levels increased to 53.74%, 50.21% and 55.13% within 36 h when 100 mg/L NH4(+) N, NO2(-)-N or NO3(-) -N was used as sole nitrogen source in the gas detection experiment. The activities of hydroxylamine oxidoreductase (HAO), nitrate reductase (NR) and nitrite reductase (NiR), which are key enzymes in heterotrophic nitrification and aerobic denitrification, were all detectable in the strain. Consequently, a possible pathway for ammonium removal by the strain was also suggested. PMID- 25910962 TI - The starvation tolerance of anammox bacteria culture at 35 degrees C. AB - Anammox is an environmental-friendly and cost-effective technology for nitrogen removal. This study provides the nitrogen removal profiles, physiological traits of anammox bacteria culture under the substrate deficiency conditions at the optimal cultivation temperature 35 degrees C. The determined period of starvation tolerance was 4 weeks in the absence of nitrite, 5 weeks in the absence of ammonium, as well as 7 weeks for the absence of these two substrates at 36 degrees C, pH 7-8 and anaerobic conditions. The physiological traits of bacteria consortium were identified through flow cytometry (FCM) analysis, and the ordinal change of increased RNA synthesizing amounts, phosphatidylserine exposure and bacteria death occurred under starvation stress. In addition, the starvation induced the increased protein content in extracellular polymeric substances and the poorer bacteria settling capacity. This study helps to develop a better understanding of anammox process in engineering environment. PMID- 25910963 TI - Optimal fusion of antibody binding domains resulted in higher affinity and wider specificity. AB - Antibody is a very important protein in biotechnological and biomedical fields because of its high affinity and specificity to various antigens. Due to the rise of human antibody therapeutics, its cost-effective purification is an urgent issue for bio-industry. In this study, we made novel fusion proteins PAxPG with a flexible (DDAKK)n linker between the two Ig binding domains derived from Staphylococcus protein A and Streptococcus protein G. The fusion proteins bound human and mouse IgGs and their fragments with up to 58-times higher affinity and wider specificity than the parental binding domains. Interestingly, the optimal linker for human Fab fragment was n = 4, which was close to the modeled distance between the termini of domains bound to heavy chain, implying increased avidity as a possible mechanism. For binding to Fc, the longest n=6 linker gave the highest affinity, implying longer interchain distance between the two binding sites. The novel fusion protein with optimized interdomain linker length will be a useful tool for the purification and detection of various IgGs including mouse IgG1 that binds only weakly to natural protein A. PMID- 25910964 TI - miR-203 downregulates Yes-1 and suppresses oncogenic activity in human oral cancer cells. AB - The purpose of this study was to elucidate the molecular mechanisms of microRNA 203 (miR-203) as a tumor suppressor in KB human oral cancer cells. MicroRNA microarray results showed that the expression of miR-203 was significantly down regulated in KB cells compared with normal human oral keratinocytes. The viability of KB cells was decreased by miR-203 in the time- and dose-dependent manners. In addition, over-expressed miR-203 not only increased the nuclear condensation but also significantly increased the apoptotic population of KB cells. These results indicated that the over-expression of miR-203 induced apoptosis of KB cells. Furthermore, the target gene array analyses revealed that the expression of Yes-1, a member of the Src family kinases (SFKs), was significantly down-regulated by miR-203 in KB cells. Moreover, both the mRNA and protein levels of Yes-1 were strongly reduced in KB cells transfected with miR 203. Therefore, these results indicated that Yes-1 is predicted to be a potential target gene of miR-203. Through a luciferase activity assay, miR-203 was confirmed to directly targets the Yes-1 3' untranslated region (UTR) to suppress gene expression. Therefore, our findings indicate that miR-203 induces the apoptosis of KB cells by directly targeting Yes-1, suggesting its application in anti-cancer therapeutics. PMID- 25910965 TI - Improvement of acquisition and analysis methods in multi-electrode array experiments with iPS cell-derived cardiomyocytes. AB - INTRODUCTION: Multi-electrode array (MEA) systems and human induced pluripotent stem (iPS) cell-derived cardiomyocytes are frequently used to characterize the electrophysiological effects of drug candidates for the prediction of QT prolongation and proarrhythmic potential. However, the optimal experimental conditions for obtaining reliable experimental data, such as high-pass filter (HPF) frequency and cell plating density, remain to be determined. METHODS: Extracellular field potentials (FPs) were recorded from iPS cell-derived cardiomyocyte sheets by using the MED64 and MEA2100 multi-electrode array systems. Effects of HPF frequency (0.1 or 1Hz) on FP duration (FPD) were assessed in the presence and absence of moxifloxacin, terfenadine, and aspirin. The influence of cell density on FP characteristics recorded through a 0.1-Hz HPF was examined. The relationship between FP and action potential (AP) was elucidated by simultaneous recording of FP and AP using a membrane potential dye. RESULTS: Many of the FP waveforms recorded through a 1-Hz HPF were markedly deformed and appeared differentiated compared with those recorded through a 0.1-Hz HPF. The concentration-response curves for FPD in the presence of terfenadine reached a steady state at concentrations of 0.1 and 0.3MUM when a 0.1-Hz HPF was used. In contrast, FPD decreased at a concentration of 0.3MUM with a characteristic bell shaped concentration-response curve when a 1-Hz HPF was used. The amplitude of the first and second peaks in the FP waveform increased with increasing cell plating density. The second peak of the FP waveform roughly coincided with AP signal at 50% repolarization, and the negative deflection at the second peak of the FP waveform in the presence of E-4031 corresponded to early afterdepolarization and triggered activity. DISCUSSION: FP can be used to assess the QT prolongation and proarrhythmic potential of drug candidates; however, experimental conditions such as HPF frequency are important for obtaining reliable data. PMID- 25910966 TI - A wide spectrum of EGFR mutations in glioblastoma is detected by a single clinical oncology targeted next-generation sequencing panel. AB - With the advent of large-scale genomic analysis, the genetic landscape of glioblastoma (GBM) has become more clear, including characteristic genetic alterations in EGFR. In routine clinical practice, genetic alterations in GBMs are identified using several disparate techniques that consume already limited amounts of tissue and add to overall testing costs. In this study, we sought to determine if the full spectrum of EGFR mutations in GBMs could be detected using a single next generation sequencing (NGS) based oncology assay in 34 consecutive cases. Using a battery of informatics tools to identify single nucleotide variants, insertions and deletions, and amplification (including variants EGFRvIII and EGFRvV), twenty-one of the 34 (62%) individuals had at least one alteration in EGFR by sequencing, consistent with published datasets. Mutations detected include several single nucleotide variants, amplification (confirmed by fluorescence in situ hybridization), and the variants EGFRvIII and EGFRvV (confirmed by multiplex ligation-dependent probe amplification). Here we show that a single NGS assay can identify the full spectrum of relevant EGFR mutations. Overall, sequencing based diagnostics have the potential to maximize the amount of genetic information obtained from GBMs and simultaneously reduce the total time, required specimen material, and costs associated with current multimodality studies. PMID- 25910967 TI - Mistletoe Plant Extract in Patients with Nonmuscle Invasive Bladder Cancer: Results of a Phase Ib/IIa Single Group Dose Escalation Study. AB - PURPOSE: We determined the maximum tolerated dose, safety and effectiveness of intravesical instillation of mistletoe extract after transurethral resection of nonmuscle invasive bladder cancer. MATERIALS AND METHODS: In this single group dose escalation study patients with nonmuscle invasive bladder cancer were treated with weekly instillations of mistletoe extract for 6 weeks. Four weeks before instillation therapy all patients underwent transurethral resection of bladder tumors. During this procedure a marker tumor was left. At 12 weeks after the start of instillation therapy transurethral resection of the marker tumor or biopsy of the former marker tumor location was done so that patients were tumor free when entering followup until week 48. During the followup clinical assessment laboratory tests for safety and cystoscopy were done every 12 weeks. RESULTS: A total of 36 patients were treated with increasing doses of mistletoe extract. We found no dose limiting toxicity up to a dose of 675 mg of plant extract. Besides local reactions we saw hints that pyrexia may develop. All adverse events were well manageable. At 12 weeks a marker tumor remission rate of 55.6% (95% CI 38.1 to 72.1) was achieved. At 1 year a recurrence rate of 26.3% (95% CI 9.1 to 51.2) was observed. CONCLUSIONS: In this study intravesical instillation of mistletoe extract as treatment in patients with nonmuscle invasive bladder cancer was shown to be safe and well tolerated. Promising data on efficacy were observed and will be further investigated in a phase III study. PMID- 25910968 TI - Mechanical Removal of Migrated Onyx Due to Microcatheter Rupture During AVM Embolization: A Technical Case Report. AB - We report a case where migrated Onyx could be removed safely with a mechanical thrombectomy device after withdrawal of the damaged microcatheter. A microcatheter was retained in the superior cerebellar artery with attached Onyx fragments on its tip during embolization of a bled cerebellar AVM. During retrieval maneuvers microcatheter shaft was ruptured and Onyx fragments were released into the vertebrobasilar system causing occlusion. Finally, Onyx fragment on tip of the microcatheter could be detached with dimethyl sulfoxide injection and the microcatheter could be withdrawn. A Merci retriever device (Concentric Medical, Mountain View, CA, USA) was successfully used to retrieve most of the dislodged Onyx material and recanalize the vertebrobasilar circulation. PMID- 25910969 TI - Angiographic Endpoint Using "Artificial Flow" on Uterine Artery Embolization for Leiomyomas in the Circumstance with no Free Flow in Uterine Artery. PMID- 25910970 TI - Curved Needles in CT-Guided Fine Needle Biopsies of Abdominal and Retroperitoneal Small Lesions. AB - PURPOSE: To demonstrate the advantages of using curved needles in fine needle aspiration (FNA) with CT-guided, for analyzing abdominal and/or retroperitoneal small lesions which are impossible to reach with conventional non-surgical biopsy techniques, particularly in cases in which the cytology sample was not possible to obtain by means of US or CT guide with axial images. MATERIALS AND METHODS: An authorization for CT-guided FNA in patients with neoplasms is not required by the institutional review board of our Institute. From April 2012 to November 2014, the study included retrospectively 25 patients (16 M, 9 F) who underwent CT guided FNA of abdominal and/or retroperitoneal small lesions (<30 mm), in which the ultrasound and axial CT scans were not reliable guides for the biopsy procedure because of the interposition of anatomical obstacles. Patients with suspected lymphomas or sarcomas, pediatric patients and patients with bleeding diathesis were excluded. Cytology reports were used for evaluating suitability. RESULTS: The biological material was considered to be suitable for cytological study, with a diagnostic value in all 25 cases, finding in particular: out of 23 neoplastic lesions (85%), 21 were malignant (90.2%) and 2 were benign (8%). 2 out 25 were non-neoplastic benign lesions (8%). No procedural complications arose in any of the cases (0%). CONCLUSION: Using curved needles, there is an effective improvement in CT-guided FNA of abdominal and retroperitoneal small lesions which are difficult to achieve with conventional CT or ultrasound guide. PMID- 25910971 TI - EX-PRESS glaucoma filtration device: Review of clinical experience and comparison with trabeculectomy. AB - Glaucoma filtration surgery is performed to reduce intraocular pressure (IOP) in patients for whom maximal tolerable pharmacologic IOP-lowering therapy and/or laser surgery fail to lower IOP sufficiently and/or fail to prevent optic nerve damage or visual field deterioration. For decades, the most widely utilized procedure for glaucoma filtration surgery has been trabeculectomy. Although this approach reliably provides long-term IOP reduction in many patients, the postoperative complication rate is high. This has driven the development of alternative approaches to reduce IOP surgically. The EX-PRESS glaucoma filtration device was developed to mimic IOP control by trabeculectomy and to have a better safety profile. This non-valved, medical-grade stainless steel device diverts aqueous humor from the anterior chamber to an intrascleral space. Despite the widespread use of the EX-PRESS device, only a few studies compare its efficacy and safety with that of trabeculectomy. We analyze available data regarding the safety and efficacy of the EX-PRESS device, particularly in comparison with trabeculectomy. PMID- 25910972 TI - Assessing positive body image: Contemporary approaches and future directions. AB - Empirical and clinical interest in positive body image has burgeoned in recent years. This focused attention is generating various measures and methods for researchers and psychotherapists to assess an array of positive body image constructs in populations of interest. No resource to date has integrated the available measures and methods for easy accessibility and comparison. Therefore, this article reviews contemporary scales for the following positive body image constructs: body appreciation, positive rational acceptance, body image flexibility, body functionality, attunement (body responsiveness, mindful self care), positive/self-accepting body talk, body pride, body sanctification, broad conceptualization of beauty, and self-perceived body acceptance by others. Guidelines for the qualitative assessment of positive body image and recommendations for integrating positive body image assessment within psychotherapy and applied research settings are also offered. The article concludes with articulating broad future directions for positive body image assessment, including ideas for expanding its available measures, methods, and dynamic expressions. PMID- 25910973 TI - CO2 adsorption on diatomaceous earth modified with cetyltrimethylammonium bromide and functionalized with tetraethylenepentamine: Optimization and kinetics. AB - The carbon dioxide (CO2) adsorbent diatomaceous earth (DE) was modified with cetyltrimethylammonium bromide (CTAB) and functionalized with varying levels of tetraethylenepentamine (TEPA). The CO2 absorption at atmospheric pressure was optimized by varying the TEPA-loading level (0-40% (w/w)), operating temperature (40-80 degrees C) and water vapor concentration (0-16% (v/v)) in a 10% (v/v) CO2 feed stream in helium balance using a full 2(3) factorial design. The TEPA/CTAB DE adsorbents were characterized by X-ray diffractometry, Fourier transform infrared spectrometry and thermogravimetric analyses. The CO2 adsorption capacity increased as each of these three factors increased. The TEPA loading level-water concentration interaction had a positive influence on the CO2 adsorption while the operating temperature-water concentration interaction was antagonistic. The optimal condition for CO2 adsorption on 40%TEPA/CTAB-DE, evaluated via a factorial design response surface method (RSM), was a temperature of 58-68 degrees C and a water vapor concentration of 9.5-14% (v/v), with a maximum CO2 adsorption capacity of 149.4 mg g(-1) at 63.5 degrees C and 12% (v/v) water vapor concentration in the feed. Validation and sensitivity tests revealed that the estimated CO2 adsorption capacity was within +/-4% of the experimental values, suggesting that the RSM model was satisfied and acceptable. From three kinetic models (pseudo-first-order, pseudo-second-order model and Avrami's equation), assessed using an error function (Err) and the coefficient of determination (R(2)), Avrami's equation was the most appropriate to describe the kinetics of CO2 adsorption on the 40%TEPA/CTAB-DE adsorbent and suggested that more than one reaction pathway occurred in the CO2 adsorption. PMID- 25910974 TI - Removal of naphthalene from aqueous systems by poly(divinylbenzene) and poly(methyl methacrylate-divinylbenzene) resins. AB - Treatment of the oily wastewater from crude oil extraction is a growing challenge due to rising concern for the environment. Polyaromatic hydrocarbons (PAHs) deserve special attention because of their high toxicity. There is a need to develop processes able to minimize the discharge of these compounds and analytic techniques to monitor the levels of PAHs in aqueous media. In this study poly(methyl methacrylate-divinylbenzene) (MMA-DVB) and poly(divinylbenzene) (DVB) were assessed with respect to their capacity to retain naphthalene (NAF) in continuous flow and batch processes (adsorption equilibrium and kinetics). The analytic techniques applied were gas chromatography and spectrofluorimetry, which was adapted for quantification of NAF. The batch adsorption studies showed that DVB is more efficient in adsorption than MMA-DVB, and the Freundlich model and pseudo-second-order model better fitted the equilibrium data and adsorption kinetics, respectively. The elution results showed that both resins are highly efficient in removing NAF, with DVB outperforming MMA-DVB. However, MMA is cheaper raw material, making MMA-DVB more competitive for treatment of oily wastewater. The resins were regenerated by eluting about 7.2 and 2.5 L of methanol:water (70:30 v/v), respectively for DVB and MMA-DVB. Regarding to the useful life after regeneration, the resins presented a reduction about 30%, relating to zero concentration of NAF. PMID- 25910975 TI - Use of Bacillus thuringiensis supernatant from a fermentation process to improve bioremediation of chlorpyrifos in contaminated soils. AB - The aim of this research was to investigate the potential of a nutrient-rich organic waste, namely the cell-free supernatant of Bacillus thuringiensis (BtS) gathered from fermentation, as a biostimulating agent to improve and sustain microbial populations and their enzymatic activities, thereby assisting in the bioremediation of chlorpyrifos-contaminated soil at a high dose (70 mg kg(-1)). Experiments were performed for up to 80 d. Chlorpyrifos degradation and its major metabolic product, 3,5,6-trichloro-2-pyridinol (TCP), were quantified by high performance liquid chromatography (HPLC); total microbial populations were enumerated by direct counts in specific medium; and fluorescein diacetate (FDA) hydrolysis was measured as an index of soil microbial activity. Throughout the experiment, there was higher chlorpyrifos degradation in soil supplemented with BtS (83.1%) as compared to non-supplemented soil. TCP formation and degradation occurred in all soils, but the greatest degradation (30.34%) was observed in soil supplemented with BtS. The total microbial populations were significantly improved by supplementation with BtS. The application of chlorpyrifos to soil inhibited the enzymatic activity; however, this negative effect was counteracted by BtS, inducing an increase of approximately 16% in FDA hydrolysis. These results demonstrate the potential of B. thuringiensis supernatant as a suitable biostimulation agent for enhancing chlorpyrifos and TCP biodegradation in chlorpyrifos-contaminated soils. PMID- 25910976 TI - An overview of food waste management in developing countries: Current status and future perspective. AB - Food waste (FW) related issues in developing countries is currently considered to be a major threatening factor for sustainable development and FW management systems. Due to incomplete FW management systems, many developing countries are facing challenges, such as environmental and sanitary problems that are caused by FW. The difference in FW generation trends between developing countries and developed countries was reviewed in this work, which demonstrated that the effects of income level, population growth, and public participation in FW management are very important. Thus, this work aimed to provide an overview of recycling activities, related regulations, and current FW treatment technology in developing countries by following some case studies. Taiwan, has been suggested as being a successful case in terms of FW management, and is therefore a typical model for developing countries to follow. Finally, an integrative management system as a suitable model for FW management has been suggested for developing countries. PMID- 25910977 TI - Mobility of coated and uncoated TiO2 nanomaterials in soil columns--Applicability of the tests methods of OECD TG 312 and 106 for nanomaterials. AB - Nanomaterials are commonly used in everyday life products and during their life cycle they can be released into the environment. Soils and sediments are estimated as significant sinks for those nanomaterials. To investigate and assess the behaviour of nanomaterials in soils and sediments standardized test methods are needed. In this study the applicability of two existing international standardized test guidelines for the testing of nanomaterials, OECD TG 106 "Adsorption/Desorption using a Bath Equilibrium Method" and the OECD TG 312 "Leaching in Soil Columns", were investigated. For the study one coated and two uncoated TiO2 nanomaterials were used, respectively. The results indicate that the OECD TG 106 is not applicable for nanomaterials. However, the test method according to OECD TG 312 was found to be applicable if nano-specific adaptations are applied. The mobility investigations of the OECD TG 312 indicated a material dependent mobility of the nanomaterials, which in some cases may lead to an accumulation in the upper soil layers. Whereas no significant transport was observed for the uncoated materials for the double-coated material (coating with dimethicone and aluminiumoxide) a significant transport was detected and attributed to the coating. PMID- 25910978 TI - Implementing REDD+ at the local level: Assessing the key enablers for credible mitigation and sustainable livelihood outcomes. AB - Achieving cost-effective mitigation and sustainable livelihoods through reducing emissions from deforestation and forest degradation (REDD+) depends heavily on the local context within which REDD+ projects are implemented. Studies have focused on how REDD+ can benefit or harm local people, with little attention paid to how people, their assets and institutions can promote or impede REDD+. This paper examines the key local assets necessary for REDD+ to protect forests and support local livelihoods based on evidence from a globally-linked REDD+ project in Kenya. Household interviews (n = 100), focus group discussions (n = 6) and in depth interviews with government (n = 8) and project stakeholders (n = 14) were undertaken to rank and explain how local assets interact with the project's efforts to protect forests, and the role of State institutions in shaping project asset interactions. Locally, pro-poor assets such as land tenure and water access had most influence on the project's ability to protect forests. Inclusion of communal forests as part of the REDD+ project entitled local poor peasant farmers to participate in and benefit from the project and so dissuaded them from using protected forests for charcoal production. Water access determined agricultural productivity and intensity of forest use for livelihoods and coping. Even though carbon revenues were distributed equally between social groups and support directed to pro-poor livelihood initiatives, efforts were impeded by State decisions on land that interfered with communal approaches to forest conservation, by strict carbon standards that limited trade-offs between livelihoods and forest protection and by fluctuating carbon prices and buyers that limited funds needed for project operations and local livelihoods. Equitable and pro-poor benefit sharing are necessary but not sufficient for effective REDD+ implementation unless national institutions are reformed and global carbon pricing harmonized with local livelihood needs. PMID- 25910979 TI - Plasma oxytocin and personality traits in psychiatric outpatients. AB - The oxytocin system is regarded as being of relevance for social interaction. In spite of this, very few studies have investigated the relationship between oxytocin and personality traits in clinical psychiatric populations. We assessed the relationship between personality traits and plasma oxytocin levels in a population of 101 medication-free psychiatric outpatients (men = 37, women = 64). We used the Karolinska Scale of Personality (KSP) and diagnostic and symptomatic testing. Plasma oxytocin levels were analysed with a specific radioimmunoassay at inclusion and after one month for testing of stability. Plasma oxytocin levels were stable over time and did not differ between patients with or without personality disorders, nor were they related to severity of depressive or anxiety symptoms. The KSP factors Impulsiveness and Negative Emotionality were significant independent predictors of plasma oxytocin. A subscale analysis of these personality factors showed significant positive correlations between baseline plasma oxytocin and the KSP subscales monotony avoidance and psychic anxiety. The significant association between the KSP factor Impulsiveness and oxytocin levels observed at baseline was observed also one month later in men. These findings suggest that personality traits such as Impulsiveness and Negative emotionality which are linked to social functioning in several psychiatric disorders seem to be associated with endogenous plasma oxytocin levels. These variations in oxytocin levels might have an impact on social sensitivity or social motivation with possible gender differences. PMID- 25910980 TI - Olfactory and Gustatory Function After Bariatric Surgery. AB - BACKGROUND: Neither hormone levels nor malabsorption alone fully explains the distinct weight loss after bariatric surgery in morbidly obese patients. Postoperatively, patients regularly report a change in the sense of taste and the development of food aversions. Hedonic and sensory components like olfactory and gustatory stimuli significantly affect appetite and flavour. METHODS: We prospectively analysed the orthonasal olfactory and gustatory function with psychophysical testing in 44 patients undergoing laparoscopic Roux-en-Y gastric bypass (RYGB), sleeve gastrectomy (SG) or adjustable gastric banding (AGB) and in 23 healthy controls. RESULTS: About 22.7 % of morbidly obese patients were hyposmic, showing significantly lower threshold-discrimination-identification (TDI) scores (p = 0.009) with decreased discrimination and identification ability. In addition, 22.7 % of patients were tested to be limited in gustatory function, with significantly lower taste strip test (TST) scores (p = 0.003). Six months after surgery, olfactory and gustatory function was not different when compared to healthy controls. CONCLUSIONS: Due to obesity, patients frequently show impaired olfactory and gustatory function. Six months after laparoscopic bariatric surgery, both chemosensory functions improve. The TDI test is an appropriate tool to measure olfactory function in obese patients. PMID- 25910981 TI - Optimization of Vitamin D Status After Roux-en-Y Gastric Bypass Surgery in Obese Patients Living in Northern Climate. AB - BACKGROUND: Patients who undergo bariatric surgery are at risk for micronutrient deficiencies. The aims of this study were to determine the prevalence and predictors of vitamin D deficiency in obese patients residing in the northern climate, and to evaluate the effectiveness of a daily maintenance dose of vitamin D 2000 IU in preventing hypovitaminosis D within 1 year after bariatric surgery. METHODS: A cohort study involving adult patients undergoing RYGB was conducted. Longitudinal changes in serum vitamin D concentrations and clinical parameters were measured and collected. RESULTS: Data from 134 recipients of RYGB were analyzed. Hypovitaminosis D was identified in 86 patients (64 %), and was significantly affected by seasonal change and the number of comorbidities. Follow up data were available in 60 patients. Vitamin D sufficiency was achieved in 62.5 % of those patients with baseline vitamin D insufficiency. A dose-response relationship of vitamin D intake was observed, with the most significant increase in 25(OH)D associated with daily vitamin D intakes >= 2000 IU. CONCLUSIONS: The prevalence of hypovitaminosis D before RYGB was comparable to patients living in the non-northern climate. Daily vitamin D intake meeting at least 2000 IU is associated with greater improvement in serum vitamin D concentration. PMID- 25910982 TI - Surgical Elimination of the Gastric Digestion by Roux-en-Y Gastric Bypass Impacts on Food Sensitisation-a Pilot Study. AB - BACKGROUND: Impairment of gastric digestion due to pH elevation increases the risk for food allergy induction. As patients after Roux-en-Y gastric bypass (RYGB) surgery have lower gastric acidity and less gastric gland secretion, we aimed to analyse in a prospective study the effect of limiting gastric digestion capacity by surgical intervention on the immune response towards allergens. METHODS: Nine patients undergoing RYGB surgery for morbid obesity and one control patient having undergone surgery for treatment of an incisional hernia were enrolled in the study. Before and 1, 3, 6, 9 and 12 months after surgery, blood was collected for analysis of specific IgE antibodies, and patients were subjected to skin prick testing with 16 food and 18 aeroallergens. RESULTS: Skin prick test results revealed an increase of positive reactions indicating sensitisations towards the tested food and aeroallergens in 77.8 and 88.9 % of the patients, respectively, after surgical elimination of gastric digestion. These results were in line with elevated titers of food- and aeroallergen specific IgE antibodies in 7 out of 9 (7/9) and 5/9 patients, respectively, after RYGB surgery. Serum cytokine levels revealed a mixed response for IFN-gamma and were mostly beneath detection limit for IL-4. CONCLUSION: A change of IgE reactivity pattern occurred after impairment of gastric digestion due to surgical elimination underlining the important gastric gatekeeping function during oral sensitisation. Even though this study indicates an increased allergy risk for gastric bypass patients, further studies are needed to investigate in-depth the immunological changes associated with RYGB surgery. PMID- 25910983 TI - Physical Activity in the Immediate Postoperative Phase in Patients Undergoing Roux-en-Y Gastric Bypass-a Randomized Controlled Trial. AB - BACKGROUND: The purpose of this study is to register the number of steps taken during the first postoperative week by patients who underwent laparoscopic Roux en-Y gastric bypass surgery (LRYGB) and evaluate whether goals for steps taken per day could affect the patients' physical activity level, time to first flatus and stool, days at hospital, and recovery. METHODS: Fifty-five patients undergoing LRYGB surgery carried a step counter on the first postoperative week and recorded the number of steps taken. They also registered hours spent sitting, lying down and sleeping, assessed their level of recovery, and noted the first day of flatus and defecation. The intervention group was informed to try to reach a daily goal regarding the number of steps to be taken. RESULTS: The patients took 2000-3000 steps/day on the first postoperative days. There were significant differences between the groups in numbers of steps taken in favor of the intervention group on four of the postoperative days. The patients in the intervention group found that the goals were set at the right level, except for the second day, where they thought 1300 steps were too few. There were no significant differences between the groups in the mean time spent sitting or lying. Neither were there any differences in time for first flatus, stool, days at hospital, nor degree of recovery. CONCLUSIONS: Goals set for steps taken per day increase the amount of steps walked in patients undergoing gastric bypass surgery. Step counters and predefined goals can be used to facilitate mobilization after obesity surgery. PMID- 25910984 TI - Role of Intraoperative Real-Time Three-Dimensional Transesophageal Echocardiography During Cone Procedure for Ebstein's Anomaly. PMID- 25910985 TI - Effect of Preload Alterations on Left Ventricular Systolic Parameters Including Speckle-Tracking Echocardiography Radial Strain During General Anesthesia. AB - OBJECTIVES: Frequently used parameters for evaluation of left ventricular systolic function are load-sensitive. However, the impact of preload alterations on speckle-tracking echocardiographic parameters during anesthesia has not been validated. Therefore, two-dimensional (2D) speckle-tracking echocardiography radial strain (RS) was assessed during general anesthesia, simulating 3 different preload conditions. DESIGN: Single-center prospective observational study. SETTING: University hospital. PARTICIPANTS: Thirty-three patients with normal left ventricular systolic function undergoing major surgery. INTERVENTIONS: Transgastric views of the midpapillary level of the left ventricle were acquired at 3 different positions. MEASUREMENTS AND MAIN RESULTS: Fractional shortening (FS), fractional area change (FAC), and 2D speckle-tracking echocardiography RS were analyzed in the transgastric midpapillary view. Considerable correlation above 0.5 was found for FAC and FS in the zero and Trendelenburg positions (r = 0.629, r = 0.587), and for RS and FAC in the anti-Trendelenburg position (r = 0.518). In the repeated-measures analysis, significant differences among the values measured at the 3 positions were found for FAC and FS. For FAC, there were differences up to 2.8 percentage points between the anti-Trendelenburg position and the other 2 positions. For FS, only the difference between position zero and anti-Trendelenburg was significant, with an observed change of 1.66. Two dimensional RS was not significantly different at all positions, with observed changes below 1 percentage point. CONCLUSIONS: Alterations in preload did not result in clinically relevant changes of RS, FS, or FAC. Observed changes for RS were smallest; however, the variation of RS was larger than that of FS or FAC. PMID- 25910986 TI - Transition of Care in the Cardiothoracic Intensive Care Unit: A Review of Handoffs in Perioperative Cardiothoracic and Vascular Practice. PMID- 25910987 TI - Patient-reported outcomes in randomised controlled trials of colorectal cancer: an analysis determining the availability of robust data to inform clinical decision-making. AB - PURPOSE: Randomised controlled trials (RCTs) are the most robust study design measuring outcomes of colorectal cancer (CRC) treatments, but to influence clinical practice trial design and reporting of patient-reported outcomes (PROs) must be of high quality. Objectives of this study were as follows: to examine the quality of PRO reporting in RCTs of CRC treatment; to assess the availability of robust data to inform clinical decision-making; and to investigate whether quality of reporting improved over time. METHODS: A systematic review from January 2004-February 2012 identified RCTs of CRC treatment describing PROs. Relevant abstracts were screened and manuscripts obtained. Methodological quality was assessed using International Society for Quality of Life Research-patient reported outcome reporting standards. Changes in reporting quality over time were established by comparison with previous data, and risk of bias was assessed with the Cochrane risk of bias tool. RESULTS: Sixty-six RCTs were identified, seven studies (10 %) reported survival benefit favouring the experimental treatment, 35 trials (53 %) identified differences in PROs between treatment groups, and the clinical significance of these differences was discussed in 19 studies (29 %). The most commonly reported treatment type was chemotherapy (n = 45; 68 %). Improvements over time in key methodological issues including the documentation of missing data and the discussion of the clinical significance of PROs were found. Thirteen trials (20 %) had high-quality reporting. CONCLUSIONS: Whilst improvements in PRO quality reporting over time were found, several recent studies still fail to robustly inform clinical practice. Quality of PRO reporting must continue to improve to maximise the clinical impact of PRO findings. PMID- 25910989 TI - Toxic Shock Syndrome detected at 21 weeks' gestation complicating acute chorioamnionitis with intact sac. PMID- 25910988 TI - Radiation-induced fibrosis: mechanisms and implications for therapy. AB - PURPOSE: Radiation-induced fibrosis (RIF) is a long-term side effect of external beam radiation therapy for the treatment of cancer. It results in a multitude of symptoms that significantly impact quality of life. Understanding the mechanisms of RIF-induced changes is essential to developing effective strategies to prevent long-term disability and discomfort following radiation therapy. In this review, we describe the current understanding of the etiology, clinical presentation, pathogenesis, treatment, and directions of future therapy for this condition. METHODS: A literature review of publications describing mechanisms or treatments of RIF was performed. Specific databases utilized included PubMed and clinicaltrials.gov, using keywords "Radiation-Induced Fibrosis," "Radiotherapy Complications," "Fibrosis Therapy," and other closely related terms. RESULTS: RIF is the result of a misguided wound healing response. In addition to causing direct DNA damage, ionizing radiation generates reactive oxygen and nitrogen species that lead to localized inflammation. This inflammatory process ultimately evolves into a fibrotic one characterized by increased collagen deposition, poor vascularity, and scarring. Tumor growth factor beta serves as the primary mediator in this response along with a host of other cytokines and growth factors. Current therapies have largely been directed toward these molecular targets and their associated signaling pathways. CONCLUSION: Although RIF is widely prevalent among patients undergoing radiation therapy and significantly impacts quality of life, there is still much to learn about its pathogenesis and mechanisms. Current treatments have stemmed from this understanding, and it is anticipated that further elucidation will be essential for the development of more effective therapies. PMID- 25910990 TI - Intracellular uptake and toxicity of three different Titanium particles. AB - INTRODUCTION: Titanium (Ti) and its alloys are used for implants and other dental materials. In this study, cytotoxicity, DNA damage, cellular uptake and size of three kinds of Ti particles were measured. METHODS: Cytotoxicity for Ti microparticles (Ti-MPs, <44 MUm), NiTi microparticles (NiTi-MPs, <44 MUm), and Ti nanoparticles (Ti-NPs, <100 nm) in periodontal ligament (PDL)-hTERT cells was measured with XTT test. DNA damage was determined with comet assay. Particle size was measured with scanning electron microscope, intracellular uptake was determined with laser scanning confocal microscopy and transmission electron microscopy. RESULTS: The EC50 values of investigated particles were: 2.8 mg/ml (Ti-NPs), 41.8 mg/ml (NiTi-MPs) and >999 mg/ml (Ti-MPs). The Olive Tail Moment (OTM) values at 1/10 EC50 were: 3.2 (Ti-NPs) and 2.2 (NiTi-MPs). An OTM of 2.2 for Ti-MPs was detected at the concentration of 6666 MUg/ml. Determined sizes of investigated particles were 20-250 nm (Ti-NPs), 0.7-90 MUm (NiTi-MPs) and 0.3-43 MUm (Ti-MPs). The highest cellular uptake efficiency was observed with Ti-NPs, followed by Ti-MPs and NiTi-MPs. Only Ti-NPs were found in the nucleus. CONCLUSION: Compared to Ti-MPs and NiTi-MPs, Ti-NPs induced higher cellular uptake efficiency and higher toxic potential in PDL-hTERT cells. Ni in the alloy NiTi induced an increase in the toxic potential compared to Ti-MPs. PMID- 25910991 TI - Seasonal variation in the populations of Polyphagotarsonemus latus and Tetranychus bastosi in physic nut (Jatropha curcas) plantations. AB - Studies on the seasonal variation of agricultural pest species are important for the establishment of integrated pest control programs. The seasonality of pest attacks on crops is affected by biotic and abiotic factors, for example, climate and natural enemies. Besides that, characteristics of the host plant, crop management, location and the pests' bioecology also affect this seasonality. The mites Polyphagotarsonemus latus (Prostigmata: Tarsonemidae) and Tetranychus bastosi (Prostigmata: Tetranychidae) are the most important pests in the cultivation of physic nut, Jatropha curcas (Euphorbiaceae). All parts of J. curcas can be used for a wide range of purposes. In addition many researchers have studied its potential for use as neat oil, as transesterified oil (biodiesel), or as a blend with diesel. However studies about physic nut pests have been little known. The objective of this study was to assess the seasonal variation of P. latus and T. bastosi in physic nut. This study was conducted at three sites in the state of Tocantins, Brazil. We monitored climatic elements and the densities of the two mite species and of their natural enemies for a period of 2 years. Attack by P. latus occurred during rainy seasons, when the photoperiod was short and the physic nut had new leaves. In contrast, attack by T. bastosi occurred during warmer seasons with longer photoperiods and stronger winds. Populations of both mites and their natural enemies were greater in sites with greater plant diversity adjacent to the plantations. The predators found in association with P. latus and T. bastosi were Euseius concordis (Acari: Phytoseiidae), spiders, Stethorus sp. (Coleoptera: Coccinellidae) and Chrysoperla sp. (Neuroptera: Chrysopidae). PMID- 25910992 TI - Comparative morphology and ultrastructure of the prosomal salivary glands in the unfed larvae Leptotrombidium orientale (Acariformes, Trombiculidae), a possible vector of tsutsugamushi disease agent. AB - The prosomal salivary glands of the unfed larvae Leptotrombidium orientale (Schluger) were investigated using transmission electron microscopy. In total, four pairs of the prosomal glands were identified--three pairs, the lateral, the medial and the anterior, belong to the podocephalic system, and one pair, the posterior, is separate having an own excretory duct. All glands are simple alveolar/acinous with prismatic cells arranged around a relatively small intra alveolar lumen with the duct base. The cells of all glands besides the lateral ones contain practically mature electron-dense secretory granules ready to be discharged from the cells. The secretory granules in the lateral glands undergo formation and maturation due to the Golgi body activity. The cells of all gland types contain a large basally located nucleus and variously expressed rough endoplasmic reticulum. Specialized duct-forming cells filled with numerous freely scattered microtubules are situated in the middle zone of each gland's acinus and form the intra-alveolar lumen and the duct base. Both the acinar (secretory) and the duct-forming cells contact each other via gap junctions and septate desmosomes. Axons of nerve cells come close to the basal extensions of the duct forming cells where they form the bulb-shaped synaptic terminations. The process of secretion is under the control of the nerve system that provides contraction of the duct-forming cells and discharge of secretion from the secretory cells into the intra-alveolar lumen and further to the exterior. Unfed larvae of L. orientale, the potential vector of tsutsugamushi disease agents, contain the most simply organized salivary secretory granules among known trombiculid larvae, and this secretion, besides the lateral glands, does not undergo significant additional maturation. Thus, the larvae are apparently ready to feed on the appropriate host just nearly after hatching. PMID- 25910993 TI - Is the internal connection more efficient than external connection in mechanical, biological, and esthetical point of views? A systematic review. AB - PURPOSE: This systematic review aimed to evaluate if the internal connection is more efficient than the external connection and its associated influencing factors. METHODS: A specific question was formulated according to the Population, Intervention, Control, and Outcome (PICO): Is internal connection more efficient than external connection in mechanical, biological, and esthetical point of views? An electronic search of the MEDLINE and the Web of Knowledge databases was performed for relevant studies published in English up to November 2013 by two independent reviewers. The keywords used in the search included a combination of "dental implant" and "internal connection" or "Morse connection" or "external connection." Selected studies were randomized clinical trials, prospective or retrospective studies, and in vitro studies with a clear aim of investigating the internal and/or external implant connection use. RESULTS: From an initial screening yield of 674 articles, 64 potentially relevant articles were selected after an evaluation of their titles and abstracts. Full texts of these articles were obtained with 29 articles fulfilling the inclusion criteria. Morse taper connection has the best sealing ability. Concerning crestal bone loss, internal connections presented better results than external connections. The limitation of the present study was the absence of randomized clinical trials that investigated if the internal connection was more efficient than the external connection. CONCLUSIONS: The external and internal connections have different mechanical, biological, and esthetical characteristics. Besides all systems that show proper success rates and effectiveness, crestal bone level maintenance is more important around internal connections than external connections. The Morse taper connection seems to be more efficient concerning biological aspects, allowing lower bacterial leakage and bone loss in single implants, including aesthetic regions. Additionally, this connection type can be successfully indicated for fixed partial prostheses and overdenture planning, since it exhibits high mechanical stability. PMID- 25910994 TI - Does the use of an acellular dermal graft in abdominal closure after rectus flap harvest impact the occurrence of post-operative hernia? AB - IMPORTANCE: Patients with rectus free flap harvest extending below the arcuate line are predisposed to postoperative hernia formation. As such, many authors have advocated the use of closure adjuncts to increase the integrity of the closure and prevent hernia or abdominal wall bulging. SETTING: Busy level 1 public trauma center in metropolitan Fort Worth, Texas INTERVENTIONS: Following harvest of the rectus free flap, 48 patients underwent primary closure; 24 of these patients had defects extending below the arcuate line. Forty patients were closed with an acellular dermal graft; 22 of these patients had defects extending below the arcuate line. MAIN OUTCOME MEASURE: Postoperative hernia formation and local infection rate were examined in a minimum follow-up period of 1 year. RESULTS: Regardless of closure method, no hernias were observed in the postoperative period. Using an unpaired t test and an alpha value of 0.05, there was no statistically significant difference in the infection rate between the two groups. CONCLUSION: Following rectus abdominis myocutaneous free flap harvest, the use of an acellular dermal graft in abdominal wall closure may not be of any further advantage in the prevention of hernia. LEVEL OF EVIDENCE: Retrospective (Level III). PMID- 25910996 TI - The calcium-sensing receptor: And its involvement in parathyroid pathology. PMID- 25910995 TI - Competition between frontal lobe functions and implicit sequence learning: evidence from the long-term effects of alcohol. AB - Implicit sequence learning is a fundamental mechanism that underlies the acquisition of motor, cognitive and social skills. The relationship between implicit learning and executive functions is still debated due to the overlapping fronto-striatal networks. According to the framework of competitive neurocognitive networks, disrupting specific frontal lobe functions, such as executive functions, increases performance on implicit learning tasks. The aim of our study was to explore the nature of such a relationship by investigating the effect of long-term regular alcohol intake on implicit sequence learning. Since alcohol dependency impairs executive functions, we expected intact or even better implicit learning in patient group compared to the healthy controls based on the competitive relationship between these neurocognitive networks. To our knowledge, this is the first study to examine the long-term effects of alcohol dependency both on implicit learning and on executive functions requiring different but partly overlapping neurocognitive networks. Here, we show weaker executive functions but intact implicit learning in the alcohol-dependent group compared to the controls. Moreover, we found negative correlation between these functions in both groups. Our results confirm the competitive relationship between the fronto striatal networks underlying implicit sequence learning and executive functions and suggest that the functional integrity of this relationship is unaltered in the alcohol-dependent group despite the weaker frontal lobe functions. PMID- 25910997 TI - Parathyroid carcinoma: Challenges in diagnosis and treatment. AB - Parathyroid carcinoma is a malignant neoplasm affecting 0.5 to 5.0% of all patients suffering from primary hyperparathyroidism. This cancer continues to cause challenges for diagnosis and treatment because of its rarity, overlapping features with benign parathyroid disease, and lack of distinct characteristics. The third/second generation PTH assay ratio provides valuable information to distinguish between benign parathyroid disease and parathyroid carcinoma. An abnormal ratio (>1) could indicate a high suspicion regarding carcinoma and metastatic disease. Early en bloc surgical resection of the primary tumour with clear margins remains the best curative treatment. Although prolonged survival is possible with recurrent or metastatic disease, cure is rarely achievable. The efficacy of classical adjuvant therapies, such as radiotherapy and chemotherapy, in management of persistent, recurrent, or metastatic disease has been disappointing. In metastatic disease the goal of therapeutic support is to control the PTH-driven hypercalcemia that represents the primary cause of mortality. Calcimimetics, which are allosteric modulators of the calcium sensing receptor, have a sustained effect in lowering serum calcium levels. Bone anti resorptive therapy, like intravenous bisphosphonates (pamidronate and zolendronate), or more recently denosumab (fully human monoclonal antibody with high affinity to bind RANK ligand) might be temporarily useful. In a small number of cases treated with anti-PTH immunotherapy, inducing anti-PTH antibodies, promising results have been seen with clinical improvements and decrease of calcemia. In one case metastasis shrinkage has been observed. PMID- 25910998 TI - Pseudohypoparathyroidism type Ib in 2015. AB - The term pseudohypoparathryoidism (PHP) refers to a group of rare genetic and epigenetic disorders characterized by resistance to the action of parathyroid hormone (PTH) that activates cAMP signaling in target cells. Together with pseudohypoparathyroidism, Albright hereditary osteodystrophy (AHO) and progressive osseous heteroplasia (POH) represent rare, related and deeply impairing disorders encompassing heterogeneous features, such as brachydactyly, ectopic ossifications, short stature, mental retardation and endocrine deficiencies due to resistance to the action of different hormones. The two main subtypes, PHP-Ia and PHP-Ib, are caused by mutations in GNAS exons 1-13 and methylation defects in the imprinted GNAS cluster respectively, while mutations in the PRKAR1A and PDE4D genes (also involved in mediating cAMP signalling) have been demonstrated in patients with acrodysostosis, a disease of bone formation with characteristics similar to AHO. The molecular overlap among these disorders indicates the need for different classification models and seriously alters our understanding of the mechanisms through which GNAS defects, together with the new recently described defects involving other components of the cAMP signalling cascade, cause AHO-related disorders. PMID- 25910999 TI - Treatment with rhPTH in children. PMID- 25911000 TI - Primary hyperparathyroidism and nephrolithiasis. AB - Calcifications in the kidneys may occur in the parenchyma (nephrocalcinosis), pelvis renis (nephrolithiasis) or ureters (ureterolithiasis). Several factors may protect against stone formation or promote precipitation of stones. Most stones contain calcium, and the hypercalciuria seen in primary hyperparathyroidism is a contributing factor to stone formation in the kidneys and urinary tract. In early case series, renal stone formation was frequent, whereas the proportion of patients with symptomatic renal stones has declined in recent years. However, a substantial proportion of patients presents with asymptomatic nephrocalcinosis or nephrolithiasis. Before diagnosis and treatment of primary hyperparathyroidism, renal stone events are more frequent than in the general population. However, even after surgical cure, an increased rate of renal stone events may be seen. This may to some extent be the result of stones or calcifications already present at the time of diagnosis or sequelae to prior stones such as infections or ureter strictures. PMID- 25911001 TI - The parathyroid glands: An object of universal fascination. PMID- 25911002 TI - Effect of bisphosphonates treatment on cytokine imbalance between TH17 and Treg in osteoporosis. AB - Imbalance of T-helper-cell (TH) subsets (TH1/TH2/TH17) and regulatory T cells (Tregs) is suggested to contribute to the pathogenesis of osteoporosis. Broken TH17/Treg balance has been reported contributing to several inflammatory diseases. Although bisphosphonates are well-recognized inhibitors of osteoclastic activity, there is no serious examination of their effect on T cell subset (TH1/TH2/TH17/Treg) balances. Patients were categorized into 20 osteopenic and 20 osteoporotic patients treated with bisphosphonates for 1 year. We studied plasma levels of interleukins 4 (IL-4), IL-6, IL-10, IL-12, IL-17, IL-23, and interferon gamma (IFN-gamma), and transforming growth factor-beta (TGF-beta) and their interrelations and correlation with osteoporosis treatment were evaluated. Treated osteoporotic patients have a significant reduction of plasma IL-6 (p < 0.05), IL-17 (p < 0.05), IL-23 (p < 0.05), and IFN-gamma (p < 0.05), a significant increase in IL-4 (p < 0.05), IL-10 (p < 0.05), and TGF-beta (p < 0.001), and comparable IL-12 levels as compared to controls. In conclusion, the significant reduction of Th17 cell cytokine cascade (IL-6, IL-17, and IL-23) and elevation of Treg cytokine cascade (IL-10 and TGF-beta) might be considered as a very important observation about the effect of bisphosphonates on TH17/Treg imbalance in osteoporosis. PMID- 25911004 TI - Effect of FecB status on the allometric measurements and reproductive performance of Garole * Malpura ewes under hot semi-arid environment. AB - The study was conducted with the primary objective to establish the influence of FecB gene mutation on the growth and reproductive performance of Garole * Malpura ewes. The duration of the study was for 5 months involving 97 adult Garole * Malpura (GM) ewes. These 97 animals were segregated based on FecB genotype and the animals were divided into three groups as group I (FecB(BB) ; n = 13), group II (FecB(B+); n = 65), and group III (FecB(++); n = 19). All the animals were kept under semi-intensive management system by subjecting the animals to grazing during day time and housing them in the night. Apart from grazing, ewes were provided with concentrate mixture at the rate of 150 g/day/ewe. The ewes in estrus after 12 h of onset of estrus were hand mated twice at 12-h intervals with a ram of proven fertility in the morning and evening. The pregnancy was confirmed by real time B-mode transabdominal ultrasonography. The experiment was continued until lambing. Under the treatments of different FecB genotype, the ewe's growth and reproductive parameters were assessed. FecB genotype significantly (P < 0.05) influenced body weight, heart girth, pin shoulder length, height at wither, lambing percentage, litter size, twinning percentage, and birth weight of lambs. From this study, it can be concluded that breeding Galore and Malpura breed shall help insure an economically viable production system. PMID- 25911003 TI - Medium-chain triglyceride ameliorates insulin resistance and inflammation in high fat diet-induced obese mice. AB - PURPOSE: The aim of the present study was to investigate the in vivo effects of dietary medium-chain triglyceride (MCT) on inflammation and insulin resistance as well as the underlying potential molecular mechanisms in high fat diet-induced obese mice. METHODS: Male C57BL/6J mice (n = 24) were fed one of the following three diets for a period of 12 weeks: (1) a modified AIN-76 diet with 5 % corn oil (normal diet); (2) a high-fat control diet (17 % w/w lard and 3 % w/w corn oil, HFC); (3) an isocaloric high-fat diet supplemented with MCT (17 % w/w MCT and 3 % w/w corn oil, HF-MCT). Glucose metabolism was evaluated by fasting blood glucose levels and intraperitoneal glucose tolerance test. Insulin sensitivity was evaluated by fasting serum insulin levels and the index of homeostasis model assessment-insulin resistance. The levels of serum interleukin-6 (IL-6), interleukin-10 (IL-10), and tumor necrosis factor-alpha were measured by ELISA, and hepatic activation of nuclear factor kappaB (NF-kappaB) and mitogen-activated protein kinase (MAPK) pathways was determined using western blot analysis. RESULTS: Compared to HFC diet, consumption of HF-MCT did not induce body weight gain and white adipose tissue accumulation in mice. HFC-induced increases in serum fasting glucose and insulin levels as well as glucose intolerance were prevented by HF-MCT diet. Meanwhile, HF-MCT resulted in significantly lower serum IL-6 level and higher IL-10 level, and lower expression levels of inducible nitric oxide synthase and cyclooxygenase-2 protein in liver tissues when compared to HFC. In addition, HF-MCT attenuated HFC-triggered hepatic activation of NF kappaB and p38 MAPK. CONCLUSIONS: Our study demonstrated that MCT was efficacious in suppressing body fat accumulation, insulin resistance, inflammatory response, and NF-kappaB and p38 MAPK activation in high fat diet-fed mice. These data suggest that MCT may exert beneficial effects against high fat diet-induced insulin resistance and inflammation. PMID- 25911005 TI - Retrospective analysis of the prevalence of Brucella antibodies in sheep in the Karas Region of Namibia. AB - In this retrospective study, complete Brucella serology data from the annual national brucellosis testing program and disease investigation for the years 2008 2010 was collated and analyzed to estimate the prevalence of brucellosis in sheep in the Karas Region of Namibia. A total of 22,994 serological results from 762 flocks screened using the Rose Bengal test (RBT) and confirmed using the complement fixation test (CFT) were analyzed. An overall prevalence of 0.14% was recorded over the 3 years. Yearly prevalence was 0.19% (2008), 0.05% (2009), and 0.18% (2010). At district level, brucellosis prevalence was estimated to be between 0 and 0.49%. On positive farms (n = 32), prevalence was between 2.25 and 30%. True prevalence was zero at district level and in all the three study years. We concluded that the prevalence of Brucella antibodies in sheep was low taking into account that some farmers may have vaccinated against the disease. The low prevalence confirms the effectiveness of existing brucellosis control measures implemented by the official veterinary services. PMID- 25911006 TI - Sauna bathing: a warm heart proves beneficial. PMID- 25911007 TI - Ischaemic heart disease during pregnancy or post-partum: systematic review and case series. AB - The risk of manifestations of ischaemic heart disease (IHD) in fertile women is elevated during pregnancy and the post-partum period. With increasing maternal age and a higher prevalence of cardiac risk factors, the incidence of IHD during pregnancy is rising. However, information in the literature is scarce. We therefore performed a retrospective cohort study and systematically reviewed the overall (1975-2013) and contemporary (2005-2013) literature concerning IHD presenting during pregnancy or in the post-partum period. We report two cases of IHD with atypical presentation during pregnancy or post-partum. In our review, we describe 146 pregnancies, including 57 contemporary cases (2005-2013). Risk factors for IHD were present in 80 %. Of the cases of IHD, 71 % manifested in the third trimester or the post-partum period, and 95 % presented with chest pain. The main cause was coronary dissection (35 %), or thrombus/emboli (35 %) in the more contemporary group. Maternal mortality was 8 % (6 % in the contemporary group), and the main cardiac complication was ventricular tachycardia (n = 17). Premature delivery rate was 56 %, and caesarean section was performed in 57 %. Perinatal mortality was 4 %. In conclusion, IHD during pregnancy or in the post partum period has high maternal mortality and morbidity rates. Also, premature delivery and perinatal mortality rates are high. PMID- 25911008 TI - Significant narrowing of the circumflex artery leads to worse outcomes than right coronary artery narrowing in patients with anterior myocardial infarction treated invasively. AB - BACKGROUND: Occlusion of the circumflex artery (Cx) often does not present signs in the ECG. It can lead to delayed angiography during ST-elevation myocardial infarction (STEMI). The aim of this analysis was to determine if Cx narrowing is related to diverse outcomes in comparison with right coronary artery (RCA) stenosis in patients with STEMI, treated with percutaneous coronary intervention (PCI) of the left descending artery (LAD). METHODS AND RESULTS: Inclusion criteria were as follows: first STEMI treated with PCI of the LAD and additional significant (>= 70 %) Cx or RCA narrowing-two-vessel disease. A total of 234 consecutive patients with STEMI were included. Total mortality was estimated during long-term follow-up, at mean 639 (+/- 224) days after STEMI. Patients with Cx narrowing constituted 46 % (N = 108) of the study population, and patients with RCA narrowing amounted to 54 % (N = 126). Patients with narrowing of the Cx had worse long-term outcomes in terms of mortality than patients with RCA narrowing (22 vs. 11 %, p < 0.05, respectively). Multiple regression analysis showed independent risk factors for death during long-term follow-up such as: age, ejection fraction and Cx narrowing. CONCLUSION: Significant Cx narrowing leads to worse outcomes than RCA narrowing in patients with STEMI treated with PCI of the LAD. PMID- 25911009 TI - Male baldness; association with coronary artery disease? PMID- 25911010 TI - Association of male pattern baldness with angiographic coronary artery disease severity and collateral development. AB - OBJECTIVE: We aimed to investigate whether there is an association between male pattern baldness and angiographic coronary artery disease (CAD) severity and collateral development, which has not been reported previously. METHODS: Coronary arteriograms, CAD risk factors, lipid parameters and presence and severity of baldness in 511 male patients were prospectively evaluated. Baldness was classified into five groups. Severity of CAD was evaluated with the Gensini scoring system and collateral development with Rentrop scores. RESULTS: Although subjects with a higher Gensini score had more frequent and severe baldness, they were older than the group with lower Gensini scores. Bald patients had a higher Gensini score when compared with their non-bald counterparts. In univariate analysis, age more than 60, body mass index more than 30, smoking and baldness were predictors of high Gensini scores. In multivariate analysis, only age more than 60, body mass index more than 30 and smoking were independent predictors of a high Gensini score. There were no differences in terms of presence and severity of baldness in subjects with and without adequate collateral development. CONCLUSIONS: There was no relation between presence, severity and age of occurrence of male pattern baldness and Gensini and Rentrop scores, which are important measures of presence and severity of CAD. PMID- 25911011 TI - Quality of life in pulmonary arterial hypertension. PMID- 25911012 TI - Decrease in quality of life predicts mortality in adult patients with pulmonary arterial hypertension due to congenital heart disease. AB - BACKGROUND: Decrease in quality of life (QoL) in left-sided heart failure precedes poor survival, which can be reversed with exercise training. We investigated whether QoL is associated with mortality in pulmonary arterial hypertension due to congenital heart disease (PAH-CHD) patients. METHODS: In this observational study, PAH-CHD adults referred for PAH-specific therapy were included. QoL surveys (SF36) were recorded during 2 years of therapy. Based on shift in SF36 scores during this period, patients had either decreased or non decreased QoL. Subsequently, the patients were followed for mortality. RESULTS: Thirty-nine PAH-CHD patients (mean age 42, 44 % male, 49 % Down's syndrome) were analysed. Following PAH-specific therapy, SF36 physical component summary (PCS) decreased in 13 (35-31 points, p = 0.001) and showed no decrease in 26 patients (34-43 points, mean values, p < 0.001). Post-initiation phase, median follow-up was 4.5 years, during which 12 deaths occurred (31 %), 10 (56 %) in the decreased and 2 (10 %) in the non-decreased group (p = 0.002). Cox regression showed a decrease in SF36 PCS predicted mortality (HR 3.4, 95 % CI 1.03-11, p = 0.045). CONCLUSIONS: In PAH-CHD patients, decrease in SF36 PCS following initiation of PAH-specific therapy is a determinant of mortality. PMID- 25911013 TI - Broad, broader, broadest. PMID- 25911014 TI - Neoatherosclerosis causing edge in-stent restenosis: optical coherence tomography findings. AB - A patient presenting with 'edge' in-stent restenosis 12 years after the implantation of a bare-metal stent in the mid-left anterior descending coronary artery is described. Optical coherence tomography disclosed the presence of ruptured neoatherosclerosis at the stent edge. The value of this imaging technique to unravel this unique underlying anatomic substrate is discussed. The therapy of choice for patients presenting with edge in-stent restenosis (ISR) is reviewed. PMID- 25911015 TI - Broad, broader, broadest. PMID- 25911016 TI - A Dutch perspective on the ESC/EACTS guidelines on myocardial revascularisation. PMID- 25911017 TI - Exhaustion or fatigability may not only be cardiac but also myopathic. PMID- 25911018 TI - Reply to the letter from Finsterer and Stollberger "Exhaustion or fatigability may not only be cardiac but also myopathic". PMID- 25911019 TI - Reply to the editorial comment from Van der Wall concerning 'The right ventricle: always normal in normal subjects?'. PMID- 25911020 TI - Direct observation during surgery shows preservation of cerebral microcirculation in patients with traumatic brain injury. AB - OBJECTIVE: To describe the alterations of the cortical microcirculation of the brain (blood flow and vessel density) in TBI patients who and compare them with a control group. METHODS: Prospective and observational study in a third-level university hospital. Cortical microcirculation in the brain was directly observed using sidestream dark-field (SDF) imaging in 14 patients who underwent surgery: 5 subdural hematomas (SDH) and 9 parenchymal lesions (contusions/hematomas). In this last set of patients, images were recorded in the "pericontusional" areas and in the "surrounding" brain (areas that were as far from the lesion as the craniotomy allowed). These patients were compared to five patients who underwent craniotomy for a disease that did not affect the cortex. RESULTS: There were fewer "pericontusional" images that could be analyzed due to the presence of subarachnoid hemorrhage. The proportion or perfused vessels was similar in all groups: control 99.5% +/- 1.3%; SDH 98.6% +/- 2.4%; "pericontusional" area 98.2% +/- 2.4%; "surrounding" area 98.4% +/- 2.5% (p = 0.145). The perfused vessel density index was smaller in the "pericontusional" area: control 6.5 +/- 1.6 l/mm; SDH 6.5 +/- 2.5 l/mm; "pericontusional" area 5.4 +/- 2.6 l/mm; "surrounding" 6.6 +/- 2.1 l/mm (p = 0.07). CONCLUSIONS: Although the analysis of pericontusional zone was difficult, there were fewer vessels than in the controls and there was no change in the flow. In the surrounding zone and in patients with SDH, we did not document alterations in the microcirculation. Direct imaging of cerebral microcirculation in TBI patients showed that despite serious brain injury the cerebral microcirculation was remarkably well preserved. PMID- 25911021 TI - Gaze palsy and exotropia in internuclear ophthalmoplegia. AB - BACKGROUND AND PURPOSE: Unilateral gaze palsy associated with internuclear ophthalmoplegia (INO), i.e., one-and-a-half syndrome, is well known. Exotropia can also be associated with INO, but it has been reported only rarely. We sought to determine the frequencies and courses of gaze palsy and exotropia in INO. METHODS: Patients hospitalized with acute-onset INO during the period January 2009 through December 2013 were identified from our clinical registry. Associated gaze palsy and exotropia were evaluated in the identified patients. RESULTS: Twenty-five patients with unilateral INO and 7 patients with bilateral INO were included in this study. Of the 25 patients with unilateral INO, 4 (16.0.0%) had ipsilateral gaze palsy (one-and-a-half syndrome), 8 (32.0%) had exotropia (non paralytic pontine exotropia), and 6 (24.0%) had both ipsilateral gaze palsy and exotropia (paralytic pontine exotropia). Six (85.7%) of the 7 patients with bilateral INO had exotropia. The gaze palsy persisted more than 1 week in 40.0% of patients, whereas the exotropia disappeared within 1 week in 92.9% of patients when the INO was unilateral. CONCLUSION: Exotropia is not uncommon in the acute stage of INO. However, it is often overlooked because of its short duration. PMID- 25911022 TI - Gastrointestinal symptoms in late-onset Pompe disease: Early response to enzyme replacement therapy. PMID- 25911023 TI - A case of papilloedema associated with Chiari I malformation. PMID- 25911024 TI - Acupuncture as a Treatment Option in Treating Posttraumatic Stress Disorder Related Tinnitus in War Veterans: A Case Presentation. AB - Although close associations between tinnitus and posttraumatic stress disorder (PTSD) among war veterans has been documented, there is limited research that explores evidence-based, efficacious interventions to treat the condition in this particular population. This article presents a case of three war veterans with PTSD symptoms who received a series of acupuncture treatments for tinnitus with positive outcomes. Even though the article presents cases of only three veterans and was based on self-reports, there were very clear trends on how veterans with tinnitus symptoms responded to acupuncture treatments. Information generated from this case presentation is a good starting place in exploring evidence-based approaches in treating tinnitus symptoms in war veterans with PTSD. PMID- 25911025 TI - Mutual Needs and Wishes of Cancer Patients and Their family Caregivers During the Last Week of Life: A Descriptive Phenomenological Study. AB - The last week of life represents an important time for people dying of cancer and their families. To explore the needs and wishes of patients and their caregivers during the last week of life at home, a descriptive phenomenological study was undertaken in a home care facility located in the northeast of Italy. A purposeful sample of participants affected by advanced cancer was included. For each included patient, a family member assuming the role of principal caregiver was also included. A total of 11 dyads (22 people) were selected and interviewed on a weekly basis. A series of qualitative, semistructured interviews was conducted. Each conversation was intended to provide researchers with an overview of the patient's and family caregiver's needs and wishes. The last interview conducted before the patient died was selected and considered for the analysis performed by researchers independently, who then worked closely together for theme triangulations. Needs and wishes in the last week of life were focused on four main themes: (a) Remaining attached to my life ("I wish I was doing things like I used to"); (b) Detaching myself from life, immediately ("I wish this Calvary were over"); (c) Dealing with the dying process ("Waiting in fear"); and (d) Starting to think of life without each other ("Unshared worries"). In order to improve personalized care in the last week of life, nurses are encouraged to assess both patient and caregiver needs and wishes, as well as their reciprocal influence and correspondence, to identify each patient-caregiver unit's unique holistic care priorities. PMID- 25911026 TI - A Proactive Innovation for Health Care Transformation: Health and Wellness Nurse Coaching. AB - A cohort of holistic nurses, recognizing opportunities inherent in health care transformation, organized and worked together from 2009 to 2012. The goal was to hold space for holistic nursing by developing a health and wellness coaching role and certification program for holistic nurses. The intent was to ensure that holistic nurses could work to the fullest of their ability within the evolving health care system, and others could discover the merit of holistic nursing as they explored the possibilities of nurse coaching. Challenges emerged that required the cohort plan strategies that would hold the space for nursing while also moving toward the intended goal. As they worked, this cohort demonstrated leadership skills, knowledge, values, and attitudes of holistic nursing that provide an example for others who follow in the wake of health care transformation. The American Holistic Credentialing Corporation's perspective of the events that unfolded and of the related decisions made by the coalition provides a record of the evolution of holistic nursing. PMID- 25911028 TI - Peace in the Clinic: Rethinking "Global Health Diplomacy" in the Somali Region of Ethiopia. AB - Drawing on ethnographic research with Somalis, within aid organizations, and within health care facilities in the Somali Region of Ethiopia, this article argues that what is called "global health diplomacy," despite its origins and articulations in interstate politics, is fundamentally local and interpersonal. As evidence, I outline two very different health programs in the Somali Region of Ethiopia, and how, in each, existing animosities and political grievances were either reinforced or undermined. I argue that the provision of health care in politically insecure and post-conflict settings like the Somali Region of Ethiopia is precarious but pivotal: medical encounters have the potential to either worsen the conditions in which conflicts and crises recur, or build new interpersonal and governmental relations of trust. Effective global health diplomacy, therefore, cannot be limited to building clinics and donating medicine, but must also explicitly include building positive relationships of trust between oppositional groups within clinical spaces. PMID- 25911027 TI - Responsible and controlled use: Older cannabis users and harm reduction. AB - BACKGROUND: Cannabis use is becoming more accepted in mainstream society. In this paper, we use Zinberg's classic theoretical framework of drug, set, and setting to elucidate how older adult cannabis users managed health, social and legal risks in a context of normalized cannabis use. METHODS: We present selected findings from our qualitative study of Baby Boomer (born 1946-1964) cannabis users in the San Francisco Bay Area. Data collection consisted of a recorded, in depth life history interview followed by a questionnaire and health survey. Qualitative interviews were analyzed to discover the factors of cannabis harm reduction from the users' perspectives. RESULTS: Interviewees made harm reduction choices based on preferred cannabis derivatives and routes of administration, as well as why, when, where, and with whom to use. Most interviewees minimized cannabis-related harms so they could maintain social functioning in their everyday lives. Responsible and controlled use was described as moderation of quantity and frequency of cannabis used, using in appropriate settings, and respect for non-users. Users contributed to the normalization of cannabis use through normification. CONCLUSION: Participants followed rituals or cultural practices, characterized by sanctions that helped define "normal" or "acceptable" cannabis use. Users contributed to cannabis normalization through their harm reduction methods. These cultural practices may prove to be more effective than formal legal prohibitions in reducing cannabis-related harms. Findings also suggest that users with access to a regulated market (medical cannabis dispensaries) were better equipped to practice harm reduction. More research is needed on both cannabis culture and alternative routes of administration as harm reduction methods. PMID- 25911029 TI - Signet Ring Cell Carcinoma of the Ampulla of Vater with Early Development of Bone Metastasis: Case Report and Review of the Rare Malignancy. PMID- 25911030 TI - Clear Cell Cancer of the Liver Presenting with Pathological Humeral Fracture: a Case Report. PMID- 25911031 TI - Adherence of Candida sp. to host tissues and cells as one of its pathogenicity features. AB - The ability of Candida sp. cells to adhere to the mucosal surfaces of various host organs as well as synthetic materials is an important pathogenicity feature of those fungi which contributes to the development of infection. This property varies depending on the species of the fungus and is the greatest for C. albicans. The process of adhesion depends on plenty of factors related to the fungal and host cells as well as environmental conditions. The main adhesins present on the fungal cell wall are: Als, Epa, Hwp1, but also Eap1, Sun41, Csh1 and probably Hyr1; for adhesion significant are also secreted aspartyl proteases Sap. Various researchers specify a range of genes which contribute to adhesion, such as: CZF1, EFG1, TUP1, TPK1, TPK2, HGC1, RAS1, RIM101, VPS11, ECM1, CKA2, BCR1, BUD2, RSR1, IRS4, CHS2, SCS7, UBI4, UME6, TEC1 and GAT2. Influence for adherence have also heat shock proteins Hsp70, Mediator Middle domain subunit Med31 and morphological transition. Among factors affecting adhesion related to host cells it is necessary to mention fibronectins and integrins (receptors for Candida sp. adhesins), type of epithelial cells, their morphology and differentiation phase. To a lesser degree influence on adhesion have non-specific factors and environmental conditions. PMID- 25911032 TI - The efficacy of topical and oral ivermectin in the treatment of human scabies. AB - Scabies is an itchy skin condition caused by the microscopic mite Sarcoptes scabei. The itching is caused by an allergic reaction to the mites. The treatment of choice is still controversial. It is commonly treated with topical insecticides. The aim of this study was to assess the efficacy of topical and oral ivermectin in the treatment of human scabies. We searched electronic databases (Cochrane Occupational Safety and Health Review Group Specialised Register, CENTRAL (The Cochrane Library), MEDLINE (Ovid), Pubmed, EMBASE, LILACS, CINAHL, Open Grey and WHO ICTRP) up to September 2014. Randomized controlled trials (RCTs) or cluster RCTs which compared the efficacy of ivermectin with other medications in the treatment of scabies. Interventions could be compared to each other, or to placebo or to no treatment. The author intended to extract dichotomous data (developed infection or did not develop infection) for the effects of interventions. We intended to report any adverse outcomes similarly. It has been sated that ivermectin was as effective as permethrin in the treatment of scabies. In comparison to other medications such as lindane, benzyl benzoate, crotamiton and malathion, ivermectin was more effective in the treatment of scabies. Ivermectin is an effective and cost-comparable alternative to topical agents in the treatment of scabies infection. PMID- 25911033 TI - The occurrence of Mansonella perstans among residents of Calabar metropolis in Cross River State of Nigeria. AB - The occurrence of Mansonella perstans was studied among people who had resided in Calabar metropolis for at least one year prior to the time of this study, which lasted from February to August, 2011. One thousand residents, comprising 530 males and 470 females, with an age range of 4 to 59 years, participated in the study, after an informed consent. Two millilitres of venous blood were collected at day time into EDTA bottles. The blood samples were processed by diluting 1ml of blood in 9 mls of 1% formalin and centrifuging the preparation at 3,000 revolutions per minute for 5 minutes. Deposits were left as blood smears on clean slides and after air-drying, were stained with 3% Giemsa solution for microscopy. Overall, the prevalence of Mansonella perstans was 2% (20 vs 1,000). The prevalence of the parasite among the females was 2.1% (10 vs 470) and males 1.9% (10 vs 530). Microfilaraemia only occurred among subjects aged between 25 and 45 years. The results of this study suggest that loiasis, which earned Calabar an unenviable mention in early medical literature, is no longer very prevalent in the area. Instead, a low prevalence of mansonelliasis occurs, in tandem with the existence of sparse farmlands of banana and plantain. Old stems of these crops provide suitable habitats for Culicoides species, which transmit Mansonella perstans. PMID- 25911034 TI - Composition of fatty acids in the Varroa destructor mites and their hosts, Apis mellifera drone-prepupae. AB - The fatty acid (FA) profile of lipids extracted from the Varroa destructor parasitic mite and its host, drone-prepupae of Apis mellifera, was determined by gas chromatography (GC). The percentages of saturated fatty acids (SFAs), monounsaturated fatty acids (MUFAs) and polyunsaturated fatty acids (PUFAs) were generally similar in parasites and their hosts. Fatty acids were arranged in the following descending order based on their content: MUFAs (ca. 52-55%), SFAs (ca. 41%) and PUFAs (ca. 3%). The predominant fatty acids were oleic acid (46% in mites, 44% in prepupae) and palmitic acid (23% and 30%, respectively). Varroa parasites differed from their hosts in the quantity of individual FAs and in their FA profiles. Three PUFAs noted in the host were not observed in parasitic mites, whereas the presence of C21:0, C24:0 and C22:1 FAs was reported in mites, but not in drones. PMID- 25911035 TI - Basic morphofunctional features of pharmaceutic leech (Hirudo verbana Carena, 1820) tissues in various forms of response after hirudotherapeutic procedures. AB - It is analyzed morphofunctional features of Hirudo verbana tissues on histological sections in order to determine the possible causes of their partial death after hirudotherapeutic procedure. In the study was taken 4 groups of leeches: hungry (control), healthy well-fed, well-fed that vomited blood and well fed dead. Morphofunctional changes in midgut of healthy well-fed H. verbana compared to the hungry are the changes of epithelium height through stretching eaten blood. In well-fed that vomited blood and well-fed dead leeches in the intestinal epithelium were observed degenerative processes that are accompanied by a decrease in the height of the epithelium, its partial desquamation. Botryoidal tissue of hungry leeches is in an inactive state, in healthy well-fed ones it responds with an increased physiological vascularization, activation of some botryoidal granulocytes with an increase in their average size, on receipt of the products of digestion. Activation of some botryoidal granulocytes, without a significant increase in their sizes, in well-fed leeches that vomited eaten blood and well-fed dead leeches, with increased infiltration of the adjacent connective tissue lymphocyte- and macrophage-like cells, amebocytes and granulocytes indicates the development of pathological processes, which are resulting in immunological conflict between eaten human blood and leeches' tissue microenvironment. PMID- 25911036 TI - New data on occurrence of Demodex flagellurus (Acari, Demodecidae) - rarely recorded parasite from the house mouse Mus musculus (Rodentia, Muridae). AB - Demodex flagellurus Bukva, 1985 is one of two known demodecid mites of the house mouse Mus musculus Linnaeus, 1758, in which it is observed in genital area. Skin fragments of 30 house mice from various regions of Poland (residential buildings in Gdynia and Gdansk, rural region in Wielkopolska-Kujawska Lowland) were examined. The mites were noted in 25.0% of the mice, with mean intensity of 48.0 and intensity range of 2-103. D. flagellurus demonstrated the differentiated occurrence in host populations. PMID- 25911037 TI - Revision of the species complex Amidostomum acutum (Lundahl, 1848) (Nematoda: Amidostomatidae) by use of molecular techniques. AB - The aim of the work is to confirm the species differentiation of the nematodes of the Amidostomatidae family: Amidostomoides acutum (Lundahl, 1848) Lomakin, 1991; Amidostomoides monodon (Linstow, 1882) Lomakin, 1991, and Amidostomoides petrovi (Shakhtahtinskaya, 1956) Lomakin, 1991, which still are used in the parasitological literature as synonyms of Amidostomum acutum (Lundahl, 1848). The research material consisted of nematodes isolated from gizzards of dabbling ducks from the north-west of Poland. To confirm the species differentiation, DNA from the nematodes was isolated and approximately 630bp of the 28S rRNA gene were sequenced. The obtained DNA sequences were tabulated and then phylogenetic analysis were conducted using the UPGMA method. The results of the research distinctly diversify the nematodes of the genus Amidostomoides at the DNA level, which together with morphological and ecological differences among them (hosts from different systematic groups) enables to classify them into the separate species. PMID- 25911038 TI - Parasite infections in red deer Cervus elaphus from Krakow area, southern Poland. AB - The study describes the parasitofauna of red deer Cervus elaphus from Krakow area (southern Poland). The study was done in years 2011-2012 and included altogether 6 animals. Five deer originated from the forest areas (hunted) and one came from the urban site (it died in a road accident). In addition to post-mortem examination, coproscopic analyses with sporulation were performed to define Eimeria species diversity. The deer were infected with four species of nematodes: Ashworthius sidemi, Spiculopteragia spiculoptera, Oesophagostomum venulosum and O. sikae, and two species of coccidia: E. elaphi and E. austriaca. The level of parasitie infections was low, but the results indicate the important role of deer as possible transmitter of A. sidemi to other ungulates in examined area. PMID- 25911039 TI - Helminthofauna of Ohrid gudgeon (Gobio ohridanus Karaman, 1924) from the Lake Ohrid, Macedonia. AB - Total, 94 specimens of gudgeon (Gobio ohridanus Karaman, 1924) from the Macedonian part of the Lake Ohrid were examined and 61 fishes (64.89%) were infected with parasites. The presence of 4 parasite species was established: Dactylogyrus cryptomeres f. typica (Monogenea), Cystidicoloides tenuissima and Philometra ovata (Nematoda), and Pomphorhynchus laevis (Acanthocephala). The highest prevalence and intensity of infection was with Dactylogyrus cryptomeres f. typica (59.57%; mean intensity 6.07). The lowest one was with Cystidicoloides tenuissima and Philometra ovata (2.13%; 1.0). Dactylogyrus cryptomeres f. typica is recorded for the first time in the ichthyoparasitofauna of Lake Ohrid and Macedonia. PMID- 25911040 TI - Isolated cystic echinococcosis of kidney burlesquing as renal cell carcinoma: a diagnostic pitfall. AB - Echinococcus granulosus infection affects worldwide population, including countries of South and Central America, Middle East, sub-Saharan region, Russia and China. In cystic echinococcosis diagnosis is related to the presence of single or multiple well-delineated spherical primary cyst, commonly seen involving liver followed by lungs. Renal hydatid cyst is rare, comprising of about 2-3% of all locations, isolated renal involvement is even rarer. We present a case of hydatid disease in a 45 year male patient who presented with the history of vague flank pain, mild fever and hematuria. IVU showed a filling defect while USG and CT scan displayed multiloculated cyst in the upper pole of right kidney, correlating the clinical and radiological findings a differential diagnosis of cystic renal cell carcinoma and cystic nephroma was derived. Total nephrectomy was done but the histopathological examination of the lesion revealed hydatid cysts and final diagnosis of renal cystic echinococcosis was made. PMID- 25911041 TI - Capillaria hepatica infection: a rare differential for peripheral eosinophilia and an imaging dilemma for abdominal lymphadenopathy. AB - Capillaria hepatica which accidentally infects humans is a zoonotic parasite of mammalian liver, primarily rodents and causes hepatic capillariasis. The diagnosis is difficult because of the non-specific nature of clinical symptoms, leading to misdiagnosis and can be confirmed only through liver biopsy or on autopsy results. This paper is written with an objective to report a new case of hepatic capillariasis as a rare differential for peripheral eosinophilia and an imaging dilemma for abdominal lymphadenopathy. PMID- 25911042 TI - Simultaneous electrochemical detection of multiple biomarkers using gold nanoparticles decorated multiwall carbon nanotubes as signal enhancers. AB - In this work, a novel sandwich-type electrochemical immunosensor has been developed for simultaneous detection of carcinoembryonic antigen (CEA) and alpha fetoprotein (AFP) based on metal ion labels. Gold nanoparticles decorated multiwall carbon nanotubes (AuNPs@MWCNTs) were used as carriers to immobilize secondary antibodies and distinguishable electrochemical tags of Pb(2+) and Cd(2+) to amplify the signals. Due to the intrinsic property of high surface-to volume ratio, the AuNPs@MWCNTs could load numerous secondary antibodies and labels. Therefore, the multiplexed immunoassay exhibited good sensitivity and selectivity. Experimental results revealed that this sandwich-type immunoassay displayed an excellent linear response, with a linear range of 0.01 to 60 ng mL( 1) for both analytes and detection limits of 3.0 pg mL(-1) for CEA and 4.5 pg mL( 1) for AFP (at a signal-to-noise ratio of 3). The method was successfully applied for the determination of AFP and CEA levels in clinical serum samples. PMID- 25911044 TI - Alkaline hydrolysis of hexahydro-1,3,5-trinitro-1,3,5-triazine: M06-2X investigation. AB - Alkaline hydrolysis mechanism of possible environmental contaminant RDX (hexahydro-1,3,5-trinitro-1,3,5-triazine) was investigated computationally at the PCM(Pauling)/M06-2X/6-311++G(d,p) level of theory. Results obtained show that the initial deprotonation of RDX by hydroxide leads to nitrite elimination and formation of a denitrated cyclohexene intermediate. Further nucleophilic attack by hydroxide onto cyclic CN double bond results in ring opening. It was shown that the presence of hydroxide is crucial for this stage of the reaction. The dominant decomposition pathway leading to a ring-opened intermediate was found to be formation of 4-nitro-2,4-diazabutanal. Hydrolytic transformation of its byproduct (methylene nitramine) leads to end products such as formaldehyde and nitrous oxide. Computational results are in a good agreement with experimental data on hydrolysis of RDX, suggesting that 4-nitro-2,4-diazabutanal, nitrite, formaldehyde, and nitrous oxide are main products for early stages of RDX decomposition under alkaline conditions. PMID- 25911043 TI - Regulation of bitter taste responses by tumor necrosis factor. AB - Inflammatory cytokines are important regulators of metabolism and food intake. Over production of inflammatory cytokines during bacterial and viral infections leads to anorexia and reduced food intake. However, it remains unclear whether any inflammatory cytokines are involved in the regulation of taste reception, the sensory mechanism governing food intake. Previously, we showed that tumor necrosis factor (TNF), a potent proinflammatory cytokine, is preferentially expressed in a subset of taste bud cells. The level of TNF in taste cells can be further induced by inflammatory stimuli. To investigate whether TNF plays a role in regulating taste responses, in this study, we performed taste behavioral tests and gustatory nerve recordings in TNF knockout mice. Behavioral tests showed that TNF-deficient mice are significantly less sensitive to the bitter compound quinine than wild-type mice, while their responses to sweet, umami, salty, and sour compounds are comparable to those of wild-type controls. Furthermore, nerve recording experiments showed that the chorda tympani nerve in TNF knockout mice is much less responsive to bitter compounds than that in wild-type mice. Chorda tympani nerve responses to sweet, umami, salty, and sour compounds are similar between TNF knockout and wild-type mice, consistent with the results from behavioral tests. We further showed that taste bud cells express the two known TNF receptors TNFR1 and TNFR2 and, therefore, are potential targets of TNF. Together, our results suggest that TNF signaling preferentially modulates bitter taste responses. This mechanism may contribute to taste dysfunction, particularly taste distortion, associated with infections and some chronic inflammatory diseases. PMID- 25911045 TI - Accumulation of polycyclic aromatic hydrocarbons by lichen transplants: Comparison with gas-phase passive air samplers. AB - This study compared the accumulation of 16 polycyclic aromatic hydrocarbons (PAHs) in samples of the lichen Evernia prunastri exposed for 3 months in and around an industrial area of S Italy with that in co-located passive gas-phase air samplers. The results showed a strong linear correlations (R=0.96, P<0.05) between total PAHs in lichens and in passive samplers, clearly indicating that lichen transplants may provide direct quantitative information on the atmospheric load by total PAHs, allowing translation of lichen values into atmospheric concentrations. To the best of our knowledge this is the first study reporting such a correlation with gas-phase passive air samplers. PMID- 25911046 TI - Geochemistry of mercury in tropical swamps impacted by gold mining. AB - Artisanal and small-scale gold mining (ASGM) poses a serious threat to the local environment. Colombia has very active ASGM activities, where mercury (Hg) ends in piles of mining waste, soils, and waterways. In this study, we assessed Hg speciation and bioavailability in sediments of two tropical swamps, impacted by ASGM. In Ayapel swamp, total Hg (T-Hg) concentrations in sediments ranged between 145 and 313 ng g(-1) dry weight (dw) (mean: 235 +/- 49 ng g(-1) dw), whereas Grande Achi swamp levels are 3-fold higher (range: 543-1021 ng g(-1) dw; mean: 722 +/- 145 ng g(-1) dw). Even though lower levels of Hg were found in Ayapel, methylation was found to be significantly higher than in Grande Achi, and it is significantly higher in the dry than in the rainy season for both swamps. This increased methylation is linked to the statistically significant correlation between T-Hg, MeHg and organic matter in the Ayapel swamp. In fact, Hg content in both swamps is mainly associated to the organic fraction (Hg-o), with a higher statistically significant difference in Ayapel (43 +/- 5%) compared to Grande Achi (33 +/- 5%). On the other hand, a significant percentage (30 +/- 6%) of elemental Hg fraction (Hg-e) was found in Grande Achi, directly related with Hg released during the gold recovery process from upstream ASGM sites. The percentage of the bioavailable fraction (Hg-w and Hg-h) is elevated (up to 15%), indicating a potential risk to the aquatic environment and human health because these labile Hg species could enter the water column and bioaccumulate in biota. PMID- 25911047 TI - Particulate matter, gaseous and particulate polycyclic aromatic hydrocarbons (PAHs) in an urban traffic tunnel of China: Emission from on-road vehicles and gas-particle partitioning. AB - Traffic vehicles are a main source of polycyclic aromatic hydrocarbon (PAH) emission in urban area. It is vital to understand PAH gas-particle partitioning in real traffic environment and assess PAH vehicular emission factors in developing China. Concentrations of particulate matter, carbonaceous products, gaseous and particulate PAHs were measured during 2011-2012 in a road tunnel of Shanghai, China. Time variation of them reflected basic traffic operation of the tunnel. PAHs approached equilibrium between gas and particle phases and the partitioning was predicted better by a dual sorption model combining absorption into organic matter and adsorption onto black carbon. The influence of black carbon adsorption on the partitioning behavior of PAHs was important. The difference in isomer ratios of gaseous and particulate PAHs was attributed to PAH contributions from different traffic-related PAHs sources. Real-world vehicle emission factors of gaseous and particulate PAHs were quantified based on fuel burned model and vehicle kilometer traveled model. PMID- 25911048 TI - The sea urchin Paracentrotus lividus immunological response to chemical pollution exposure: The case of lindane. AB - In the marine environment organochlorine insecticides can be broadly detected in water, sediments, and biota. These pollutants may have major ecological consequences since they may affect marine organisms and endanger organismal growth, reproduction or survival. In this study we investigated the modification of some sea urchin immunological parameters in response to subchronic lindane (gamma-HCH) exposure. Adult specimens of the sea urchin Paracentrotus lividus were exposed to two different concentrations (0.1 and 0.5 mg L(-1)) of lindane. After 24 and 48h of treatment, we examined the lindane influence on coelomocytes vitality and enumeration as well on some humoral parameters. Our results showed that the presence of the pesticide affected both cellular and humoral components of the immune system. In particular, P. lividus coelomocytes vitality did not change but a decrease of the total cell number and an increase of the red cells was recorded. Haemolytic and lysozyme-like activities as well as antibacterial activity on Vibrio alginolyticus of treated animals decreased. Sea urchin immunological competence modifications might represent a tool for monitoring disease susceptibility thus providing biological criteria for the implementation of water quality standards to protect marine organisms. PMID- 25911049 TI - Source identification of eight heavy metals in grassland soils by multivariate analysis from the Baicheng-Songyuan area, Jilin Province, Northeast China. AB - The characterization of the concentration, chemical speciation and source of heavy metals in soils is an imperative for pollution monitoring and the potential risk assessment of the metals to animal and human health. A total of 154 surface horizons and 53 underlying horizons of grassland soil were collected from the Baicheng-Songyuan area in Jilin Province, Northeast China, in which the concentrations and chemical fractionations of As, Cd, Cr, Cu, Hg, Ni, Pb, and Zn were investigated. The mean concentrations of heavy metals in grassland topsoil were 7.2, 0.072, 35, 16.7, 0.014, 15.2, 18.3 and 35 mg kg(-)(1) for As, Cd, Cr, Cu, Hg, Ni, Pb and Zn, respectively, and those averaged contents were lower than their China Environmental Quality Standard values for the Soils, implying that heavy metal concentrations in the studied soils were of the safety levels. The mobility sequence of the heavy metals based on the sum of the soluble, exchangeable, carbonate-bound and humic acid-bound fractions among the seven fractions decreased in the order of Cd 50.4%)>Hg (39.8%)>Cu (26.5%)>As (19.9%)>Zn (19.1%)>Ni (15.9%)>Pb (14.1%)>Cr (4.3%), suggesting Cd and Hg may pose more potential risk of soil contamination than other metals. Multivariate statistical analysis suggested that As, Cr, Cu, Ni, Pb, Zn, Cd and Hg had the similar lithogenic sources, however, Cd and Hg were more relevant to organic matter than other heavy metals, which was confirmed by the chemical speciation analysis of the metals. The study provides a base for local authority in the studied area to monitor the long term accession of heavy metals into grassland soil. PMID- 25911050 TI - Effectiveness of prolonged clopidogrel-based dual antiplatelet therapy after drug eluting stent implantation: Evidence-based meta-analysis. AB - The use of drug-eluting stents (DESs) for patients with coronary artery disease is widespread. DESs have been associated with a lower rate of repeat revascularization, death, and myocardial infarction compared with bare metal stents. However, DESs can lead to a prothrombotic environment in the coronary arteries, resulting in a higher rate of thrombotic events. To counteract this, dual-antiplatelet therapy (DAPT) consisting of aspirin and clopidogrel is recommended. Currently, there are no clear guidelines on the duration of DAPT. We therefore conducted a meta-analysis to assess the effectiveness of prolonged DAPT after DES implantation. PMID- 25911051 TI - Role of cathepsin D activation in major adverse cardiovascular events and new onset heart failure after STEMI. AB - AIM: Increased serum levels of the activated aspartic lysosomal endopeptidase cathepsin D (CatD) have been found in patients with acute myocardial infarction (AMI). However, to date there have been no analyses of clinical follow-up data measuring the enzyme course and its role in the development of post-MI heart failure. This study aimed to evaluate the role of serum CatD activity in the development of heart failure in patients with ST-segment elevation acute myocardial infarction (STEMI). PATIENTS AND METHODS: Eighty-eight consecutive patients (79.5 % men, mean age 57.4 +/- 10.2 years) with STEMI were included in this study. Serum CatD activity was measured directly after primary percutaneous coronary intervention (PCI), before discharge, and at the 6-month follow-up. Patients were monitored for major adverse cardiovascular events (MACE), defined as hospitalization due to cardiovascular causes, recurrent nonfatal myocardial infarction, unplanned PCI, new-onset heart failure, and cardiovascular mortality. RESULTS: Serum CatD activity was significantly higher in patients with AMI after PCI and during follow-up (FU) than that in age-matched controls (16.2 +/- 7.5 and 29.8 +/- 8.9 vs. 8.5 +/- 4.2 RFU; p < 0.001 for each time point). At the 6-month follow-up, serum CatD activity in these patients was inversely related to new onset cardiac dysfunction compared with patients with preserved and improved LVEF after treatment (23.1 +/- 3.2 vs. 28.8 +/- 7.0 and 29.7 +/- 5.0 RFU respectively, p < 0.01). Patients suffering from MACE during a follow-up period of 6 months had lower serum levels of activated CatD than those without any MACE (23.8 +/- 4.6 vs 29.6 +/- 6.9 RFU; p < 0.001). CONCLUSIONS: Serum CatD activity as a marker of healthy endogenous phagocytosis and remodeling was impaired in patients with new onset cardiac dysfunction, and lower levels of serum CatD were associated with MACE at the 6-month post-MI follow-up. PMID- 25911053 TI - Malignant cutaneous adnexal tumours of the head and neck: an update on management. AB - Adnexal tumours form a heterogeneous group of relatively rare neoplasms. Many of them have a poor prognosis and treatment can sometimes be difficult and controversial. We summarise the latest publications relating to malignant cutaneous adnexal tumours of the head and neck, and give an update on their management. We discuss Merkel cell carcinoma and other rare malignant adnexal tumours including dermatofibrosarcoma protuberans and atypical fibroxanthoma. PMID- 25911052 TI - The association of hospital prevention processes and patient risk factors with the risk of Clostridium difficile infection: a population-based cohort study. AB - BACKGROUND: Clostridium difficile is the most common cause of healthcare-acquired infection; the real-world impacts of some proposed C. difficile prevention processes are unknown. METHODS: We conducted a population-based retrospective cohort study of all patients admitted to acute care hospitals between April 2011 and March 2012 in Ontario, Canada. Hospital prevention practices were determined by survey of infection control programmes; responses were linked to patient-level risk factors and C. difficile outcomes in Ontario administrative databases. Multivariable generalised estimating equation (GEE) regression models were used to assess the impact of selected understudied hospital prevention processes on the patient-level risk of C. difficile infection, accounting for patient risk factors, baseline C. difficile rates and structural hospital characteristics. RESULTS: C. difficile infections complicated 2341 of 653 896 admissions (3.6 per 1000 admissions). Implementation of the selected C. difficile prevention practices was variable across the 159 hospitals with isolation of all patients at onset of diarrhoea reported by 43 (27%), auditing of antibiotic stewardship compliance by 26 (16%), auditing of cleaning practices by 115 (72%), on-site diagnostic testing by 74 (47%), vancomycin as first-line treatment by 24 (15%) and reporting rates to senior leadership by 52 (33%). None of these processes were associated with a significantly reduced risk of C. difficile after adjustment for baseline C. difficile rates, structural hospital characteristics and patient-level factors. Patient-level factors were strongly associated with C. difficile risk, including age, comorbidities, non-elective and medical admissions. CONCLUSIONS: In the largest study to date, selected hospital prevention strategies were not associated with a statistically significant reduction in patients' risk of C. difficile infection. These prevention strategies have either limited effectiveness or were ineffectively implemented during the study period. PMID- 25911054 TI - Surgically facilitated experimental movement of teeth: systematic review. AB - Several surgical techniques based on corticotomy and dental distraction have been developed to improve the movement of teeth and reduce the duration of orthodontic treatment. In this systematic review we have critically assessed published studies on the experimental movement of teeth to find out whether operations such as corticotomy and dental distraction osteogenesis increase the rate of movement, and to find out which biological mechanisms are engaged during surgically facilitated orthodontics, and which complications may be seen. We searched PubMed and Embase for publications until January 2014 and screened the titles and abstracts. Articles that met the inclusion criteria were retrieved in full and assessed independently by 2 of the authors. A total of 22 studies were included, and corticotomy and distraction techniques were the main surgical methods. Generally, all studies reported that movement of teeth was faster after operation than with conventional orthodontics. The peak velocity was always at an early postoperative stage regardless of the surgical technique used. Immunohistological data showed simultaneous regional increases in catabolic and anabolic activity. Histomorphometric data showed more direct resorption of bone and less hyalinisation after operation, and a reduced bone volume density around the surgical site. When present, complications such as root resorption or periodontal problems were minimal. Current experimental animal studies show that procedures such as corticotomy and dental distraction can accelerate the movement of teeth without severe complications because of the regional increase in catabolic and anabolic remodelling. PMID- 25911055 TI - Resident and Fellow Glaucoma Surgical Experience Following the Tube Versus Trabeculectomy Study. PMID- 25911056 TI - Making It Happen: Training health-care providers in emergency obstetric and newborn care. AB - An estimated 289,000 maternal deaths, 2.6 million stillbirths and 2.4 million newborn deaths occur globally each year, with the majority occurring around the time of childbirth. The medical and surgical interventions to prevent this loss of life are known, and most maternal and newborn deaths are in principle preventable. There is a need to build the capacity of health-care providers to recognize and manage complications during pregnancy, childbirth and the post partum period. Skills-and-drills competency-based training in skilled birth attendance, emergency obstetric care and early newborn care (EmONC) is an approach that is successful in improving knowledge and skills. There is emerging evidence of this resulting in improved availability and quality of care. To evaluate the effectiveness of EmONC training, operational research using an adapted Kirkpatrick framework and a theory of change approach is needed. The Making It Happen programme is an example of this. PMID- 25911057 TI - [Pediatric management by mobile intensive care units in the northern French Alps emergency network]. AB - INTRODUCTION: The northern French Alps emergency network (RENAU) manages emergent care and patient treatment pathways in a three-county area in the French Alps. The aim of the study was to describe the pediatric activity in mobile intensive care units (MICUs). METHOD: This retrospective observational study was conducted from 1 January to 31 December 2012. Data were obtained from patients' medical records in seven representative MICUs of the RENAU. Consecutive patients between 1 month and 18 years of age were enrolled. RESULTS: During the study period, MICUs carried out 11,951 primary transports and 3087 secondary transfers. A total of 1325 patients were enrolled: 1087 primary transports and 238 secondary transfers. In primary interventions, 531 (48.9%) patients were managed for a trauma, 118 (11%) children were discharged and stayed home, 427 (39.9%) underwent an intravenous cannulation and 27 (2.5%) on-scene intubation. A pediatrician was in charge of 64 (26.9%) secondary transfers. Among 1649 (18%) mountain rescues, 296 (18.7%) involved a child. CONCLUSION: Emergency physicians in MICUs are involved with children's prehospital care and need dedicated materiel and special training. PMID- 25911058 TI - Ecthyma gangrenosum: A manifestation of community-acquired Pseudomonas aeruginosa septicemia in three infants. AB - OBJECTIVES: Pseudomonas aeruginosa sepsis usually carries a high mortality rate in immunocompromised children. Ecthyma gangrenosum is a known cutaneous manifestation due mainly to Pseudomonas infection with or without septicemia. We describe clinical, biological, and therapeutic data. PATIENTS AND METHODS: Of those children admitted to the pediatric intensive care unit, three pediatric cases of community-acquired P. aeruginosa septicemia associated with ecthyma gangrenosum were retrospectively reviewed. RESULTS: The three patients were aged 5 months, 9 months, and 1 year. Underlying hypogammaglobulinemia was detected in the oldest patient. Pseudomonas aeruginosa was isolated in all patients in blood and once in cultures of skin lesions and endotracheal aspirate. Two deaths occurred due to septic shock and multisystem organ failure despite numerous aggressive resuscitation attempts. CONCLUSIONS: P. aeruginosa sepsis should be treated as early as possible. Recognition of ecthyma gangrenosum allows early diagnosis and prescription of adequate antibiotic therapy without awaiting blood culture reports. PMID- 25911059 TI - Dictyostelium acetoacetyl-CoA thiolase is a dual-localizing enzyme that localizes to peroxisomes, mitochondria and the cytosol. AB - Acetoacetyl-CoA thiolase is an enzyme that catalyses both the CoA-dependent thiolytic cleavage of acetoacetyl-CoA and the reverse condensation reaction. In Dictyostelium discoideum, acetoacetyl-CoA thiolase (DdAcat) is encoded by a single acat gene. The aim of this study was to assess the localization of DdAcat and to determine the mechanism of its cellular localization. Subcellular localization of DdAcat was investigated using a fusion protein with GFP, and it was found to be localized to peroxisomes. The findings showed that the targeting signal of DdAcat to peroxisomes is a unique nonapeptide sequence (15RMYTTAKNL23) similar to the conserved peroxisomal targeting signal-2 (PTS-2). Cell fractionation experiments revealed that DdAcat also exists in the cytosol. Distribution to the cytosol was caused by translational initiation from the second Met codon at position 16. The first 18 N-terminal residues also exhibited function as a mitochondrial targeting signal (MTS). These results indicate that DdAcat is a dual-localizing enzyme that localizes to peroxisomes, mitochondria and the cytosol using both PTS-2 and MTS signals, which overlap each other near the N-terminus, and the alternative utilization of start codons. PMID- 25911060 TI - Investigational therapies for the treatment of spinal muscular atrophy. AB - INTRODUCTION: Currently, there is no cure available for the hereditary neurodegenerative disease proximal spinal muscular atrophy (SMA), which is the number one genetic killer in early childhood. However, growing knowledge of SMA pathophysiology has opened new avenues for potential therapeutic interventions. AREAS COVERED: This review summarizes a variety of investigational therapeutic approaches for SMA. Focusing on the current state-of-the-art applications, the authors discuss the outcome of the first clinical interventions and compare the first results from the newest strategies. The achievements of the investigational drugs highlighted in this article were deduced from original articles, pharmaceutical company press releases and clinical trial results. EXPERT OPINION: Nearly two decades after the discovery of the disease causing gene survival motor neuron 1, many therapeutic options for SMA have been developed, some of which made it to clinical trials but could not prove their promising experimental results. Recently, big research efforts from academia, government and the pharmaceutical industry have led to the development of highly promising compounds that are currently in clinical trials, and which could lead to feasible treatment options in the future. PMID- 25911062 TI - [Radioembolization with (90)Y-microspheres for liver tumors]. PMID- 25911064 TI - Migraine headaches. PMID- 25911063 TI - Headache in the elderly. PMID- 25911061 TI - A Literature Review of Renal Surgical Anatomy and Surgical Strategies for Partial Nephrectomy. AB - CONTEXT: A detailed understanding of renal surgical anatomy is necessary to optimize preoperative planning and operative technique and provide a basis for improved outcomes. OBJECTIVE: To evaluate the literature regarding pertinent surgical anatomy of the kidney and related structures, nephrometry scoring systems, and current surgical strategies for partial nephrectomy (PN). EVIDENCE ACQUISITION: A literature review was conducted. EVIDENCE SYNTHESIS: Surgical renal anatomy fundamentally impacts PN surgery. The renal artery divides into anterior and posterior divisions, from which approximately five segmental terminal arteries originate. The renal veins are not terminal. Variations in the vascular and lymphatic channels are common; thus, concurrent lymphadenectomy is not routinely indicated during PN for cT1 renal masses in the setting of clinically negative lymph nodes. Renal-protocol contrast-enhanced computed tomography or magnetic resonance imaging is used for standard imaging. Anatomy based nephrometry scoring systems allow standardized academic reporting of tumor characteristics and predict PN outcomes (complications, remnant function, possibly histology). Anatomy-based novel surgical approaches may reduce ischemic time during PN; these include early unclamping, segmental clamping, tumor specific clamping (zero ischemia), and unclamped PN. Cancer cure after PN relies on complete resection, which can be achieved by thin margins. Post-PN renal function is impacted by kidney quality, remnant quantity, and ischemia type and duration. CONCLUSIONS: Surgical renal anatomy underpins imaging, nephrometry scoring systems, and vascular control techniques that reduce global renal ischemia and may impact post-PN function. A contemporary ideal PN excises the tumor with a thin negative margin, delicately secures the tumor bed to maximize vascularized remnant parenchyma, and minimizes global ischemia to the renal remnant with minimal complications. PATIENT SUMMARY: In this report we review renal surgical anatomy. Renal mass imaging allows detailed delineation of the anatomy and vasculature and permits nephrometry scoring, and thus precise, patient-specific surgical planning. Novel off-clamp techniques have been developed that may lead to improved outcomes. PMID- 25911065 TI - Study on detecting leachate leakage of municipal solid waste landfill site. AB - The article studies the detection of the leakage passage of leachate in a waste landfill dam. The leachate of waste landfill has its own features, like high conductivity, high chroma and an increasing temperature, also, the horizontal flow velocity of groundwater on the leakage site increases. This article proposes a comprehensive tracing method to identify the leakage site of an impermeable membrane by using these features. This method has been applied to determine two leakage sites of the Yahu municipal solid waste landfill site in Pingshan District, Shenzhen, China, which shows that there are two leachate leakage passages in the waste landfill dam A between NZK-2 and NZK-3, and between NZK-6 and NZK-7. PMID- 25911066 TI - Private hospitals are told to treat acid attack victims free of charge. PMID- 25911067 TI - Genetic animal models of malformations of cortical development and epilepsy. AB - Malformations of cortical development constitute a variety of pathological brain abnormalities that commonly cause severe, medically-refractory epilepsy, including focal lesions, such as focal cortical dysplasia, heterotopias, and tubers of tuberous sclerosis complex, and diffuse malformations, such as lissencephaly. Although some cortical malformations result from environmental insults during cortical development in utero, genetic factors are increasingly recognized as primary pathogenic factors across the entire spectrum of malformations. Genes implicated in causing different cortical malformations are involved in a variety of physiological functions, but many are focused on regulation of cell proliferation, differentiation, and neuronal migration. Advances in molecular genetic methods have allowed the engineering of increasingly sophisticated animal models of cortical malformations and associated epilepsy. These animal models have identified some common mechanistic themes shared by a number of different cortical malformations, but also revealed the diversity and complexity of cellular and molecular mechanisms that lead to the development of the pathological lesions and resulting epileptogenesis. PMID- 25911068 TI - Long-term imaging of circadian locomotor rhythms of a freely crawling C. elegans population. AB - BACKGROUND: Locomotor activity is used extensively as a behavioral output to study the underpinnings of circadian rhythms. Recent studies have required a populational approach for the study of circadian rhythmicity in Caenorhabditis elegans locomotion. NEW METHOD: We describe an imaging system for long-term automated recording and analysis of locomotion data of multiple free-crawling C. elegans animals on the surface of an agar plate. We devised image analysis tools for measuring specific features related to movement and shape to identify circadian patterns. RESULTS: We demonstrate the utility of our system by quantifying circadian locomotor rhythms in wild-type and mutant animals induced by temperature cycles. We show that 13 degrees C:18 degrees C (12:12h) cycles are sufficient to entrain locomotor activity of wild-type animals, which persist but are rapidly damped during 13 degrees C free-running conditions. Animals with mutations in tax-2, a cyclic nucleotide-gated (CNG) ion channel, significantly reduce locomotor activity during entrainment and free-running. COMPARISON WITH EXISTING METHOD(S): Current methods for measuring circadian locomotor activity is generally restricted to recording individual swimming animals of C. elegans, which is a distinct form of locomotion from crawling behavior generally observed in the laboratory. Our system works well with up to 20 crawling adult animals, and allows for a detailed analysis of locomotor activity over long periods of time. CONCLUSIONS: Our population-based approach provides a powerful tool for quantification of circadian rhythmicity of C. elegans locomotion, and could allow for a screening system of candidate circadian genes in this model organism. PMID- 25911069 TI - Comparison of culture-negative and culture-positive microbial keratitis: cause of culture negativity, clinical features and final outcome. AB - PURPOSE: To determine the causes of culture negativity and compare clinical outcomes in patients with culture-negative (CN) keratitis versus culture-positive (CP) keratitis. METHODS: Medical and microbiology records of 60 patients, who presented at the L V Prasad Eye Institute, Bhubaneswar, between January 2009 and December 2010, and who were clinically diagnosed to have microbial keratitis were retrospectively reviewed. Detailed ocular examination was performed before corneal scraping was sent for microbiological workup. The data collected from each record included age, gender, predisposing factors (ocular and systemic), clinical presentation, management and outcome of treatment. RESULTS: The duration of symptoms and prior use of topical medication was significantly higher in the CN group (p=0.005, p=0.007, respectively). Infiltrate size (p=0.42) and history of ocular trauma (p=0.14) had no association. While patients in the CP group underwent 9 (30%) minor major surgical procedures and 14 (46.7%) major surgical procedures, patients in the CN group underwent 11 (36.7%) minor surgical procedures and 1 (3.3%) major surgical procedure. Success in treatment was achieved in 27 (90%) and 25 (83.3%) patients in CP and CN groups, respectively. The mean visual acuity (logMAR) at presentation in the CP group was 2.53 which improved to 1.83 at the last follow-up (p=0.0001). Similarly, the mean visual acuity (logMAR) at presentation in the CN group was 2.57 which marginally improved to 2.34 at the last follow-up (p=0.03). CONCLUSIONS: CN keratitis is associated with long duration of topical medication. The number of major surgical interventions in CN keratitis is significantly less compared with CP keratitis. However, the final outcome of treatment is similar in both CP and CN keratitis. PMID- 25911070 TI - From the editor: managing your manuscripts. PMID- 25911071 TI - JCL Roundtable: is inflammation a future target in preventing arteriosclerotic cardiovascular disease. AB - It has been a long developing concept that inflammatory infiltration by white blood cells from the blood plasma is an important part of the atherosclerotic process. However, we have thought of this as a secondary phenomenon resulting from the causative insults of high concentrations of apolipoprotein B (apoB) containing lipoproteins, toxins such as those from cigarette smoke, high blood pressure, and high blood glucose. Much research has provided evidence as to how the invading cells interact with the basic components of the arterial structure to produce the damage observed throughout the vessel wall. We have focused our preventive efforts on the clinical risk factors with significant but partial success in patients with active disease. It is a relatively new concept that suppressing the inflammation itself, as an adjunct to risk factor modification, could help reduce the clinical manifestations of atherosclerosis. This concept is now being tested in randomized clinical trials. Our discussants in this Roundtable are Dr Alan Remaley, a Senior Investigator in the Lipoprotein Metabolism Section of the National Heart Lung and Blood Institute and Dr Paul Ridker, a cardiologist at the Brigham and Women's Hospital and a Professor at the Harvard Medical School. Both have made very significant contributions to our understanding of the signaling process that drives this inflammatory aspect of the disease. PMID- 25911072 TI - National lipid association recommendations for patient-centered management of dyslipidemia: part 1--full report. AB - The leadership of the National Lipid Association convened an Expert Panel to develop a consensus set of recommendations for patient-centered management of dyslipidemia in clinical medicine. An Executive Summary of those recommendations was previously published. This document provides support for the recommendations outlined in the Executive Summary. The major conclusions include (1) an elevated level of cholesterol carried by circulating apolipoprotein B-containing lipoproteins (non-high-density lipoprotein cholesterol and low-density lipoprotein cholesterol [LDL-C], termed atherogenic cholesterol) is a root cause of atherosclerosis, the key underlying process contributing to most clinical atherosclerotic cardiovascular disease (ASCVD) events; (2) reducing elevated levels of atherogenic cholesterol will lower ASCVD risk in proportion to the extent that atherogenic cholesterol is reduced. This benefit is presumed to result from atherogenic cholesterol lowering through multiple modalities, including lifestyle and drug therapies; (3) the intensity of risk-reduction therapy should generally be adjusted to the patient's absolute risk for an ASCVD event; (4) atherosclerosis is a process that often begins early in life and progresses for decades before resulting a clinical ASCVD event. Therefore, both intermediate-term and long-term or lifetime risk should be considered when assessing the potential benefits and hazards of risk-reduction therapies; (5) for patients in whom lipid-lowering drug therapy is indicated, statin treatment is the primary modality for reducing ASCVD risk; (6) nonlipid ASCVD risk factors should also be managed appropriately, particularly high blood pressure, cigarette smoking, and diabetes mellitus; and (7) the measurement and monitoring of atherogenic cholesterol levels remain an important part of a comprehensive ASCVD prevention strategy. PMID- 25911073 TI - Understanding PCSK9 and anti-PCSK9 therapies. AB - Inhibitors of proprotein convertase subtilisin kexin type 9 (PCSK9) represent a new therapeutic category of drugs for the treatment of dyslipidemia and atherosclerotic cardiovascular disease. To appreciate the efficacy of these agents and interpret research results, it is important to understand the dynamic relationship between PCSK9, low-density lipoprotein-receptors, intrahepatic cholesterol synthesis, and blood cholesterol levels. Drugs which negate the action of PCSK9 can produce substantial reductions in atherogenic lipoprotein cholesterol-carrying particles and thereby hold the potential for further reducing events associated with atherosclerotic cardiovascular disease. This article will describe and discuss PCSK9 interactive mechanisms and apply them to the interpretation of clinical trial results, which involve PCSK9 monoclonal antibodies. PMID- 25911074 TI - Familial hypercholesterolemia mutations in the Middle Eastern and North African region: a need for a national registry. AB - BACKGROUND: Familial hypercholesterolemia (FH) is a well-understood Mendelian disorder that increases the risk of cardiovascular disease (CVD), a leading cause of mortality in Middle Eastern and North African (MENA) countries. OBJECTIVE: Review the reporting status of FH mutations across MENA and propose a systemic and strategic method for building a MENA FH registry. METHODS: Systematic literature search for statistics pertaining to CVD and comparison of number of FH mutations reported in MENA countries and countries with established FH registries. RESULTS: Only 57 mutations were reported in 17 MENA countries, whereas more than 500 mutations reported in 3 Western countries. Mortality rates due to CVD were significantly higher in MENA countries compared with Western countries. CONCLUSIONS: The relatively low reporting of FH mutations in the consanguineous MENA communities with higher prevalence of CVD indicates poor awareness of CVD genetic risk and warrants a registry to prevent premature CVD due to FH. This registry will help in identifying novel and reported FH mutations, all of which will have clinical and research benefits in MENA countries. PMID- 25911075 TI - Total cholesterol-to-high-density lipoprotein cholesterol ratio predicts high sensitivity C-reactive protein levels in Turkish children. AB - BACKGROUND: High-sensitivity C-reactive protein (hs-CRP) is a biomarker of continued long-term systemic inflammation and cardiovascular (CV) risk. OBJECTIVE: To analyze the association of hs-CRP levels with CV risk factors in healthy school children. METHODS: The study sample was derived from a survey on the prevalence of CV risk factors (dyslipidemia, obesity, high blood pressure, and insulin resistance in school children. Along with anthropometry, hs-CRP levels, lipids, glucose levels, and insulin levels were measured. RESULTS: Ninety one male (12.5 +/- 3.4 years) and 77 female students (12.7 +/- 3.4; P = .624) were included. Median (interquartile range) hs-CRP levels were similar among boys and girls (0.4 [1.2] vs 0.5 [0.7]; P = .928). Risk factors such as obesity (16%), high triglycerides (20%), low high-density lipoprotein cholesterol (HDL-C, 16%), and elevated blood pressure (25%) were commonly observed in study participants. Gender-stratified analysis displayed that insulin resistance (18 [19.8%] vs 3 [3.9%]; P = .002) and high triglycerides (26 [28.6%] vs 8 [10.4%]; P = .003) were more commonly observed among boys compared with girls. hs-CRP levels correlated positively with cardiometabolic risk factors such as waist circumference (boys) and total cholesterol (TC)-to-HDL-C ratio. Linear regression analysis displayed that among the covariates of age, body mass index, and glucose, TC-to-HDL-C ratio was the most significant determinant of hs-CRP levels (P = .004). CONCLUSION: Cardiometabolic risk factors such as TC-to-HDL-C ratio correlate with hs-CRP levels in children and adolescents. Long-term prospective studies are needed to confirm the association between hs-CRP and cardiometabolic risk in children. PMID- 25911076 TI - Mipomersen preferentially reduces small low-density lipoprotein particle number in patients with hypercholesterolemia. AB - BACKGROUND: Because of variability in lipoprotein cholesterol content, low density lipoprotein (LDL) cholesterol frequently underrepresents or overrepresents the number of LDL particles. Mipomersen is an antisense oligonucleotide that reduces hepatic production of apolipoprotein B-100, the sole apolipoprotein of LDL. OBJECTIVE: To characterize the effects of mipomersen on lipoprotein particle numbers as well as subclass distribution using nuclear magnetic resonance (NMR) spectroscopy. METHODS: We compared the tertiary results for the direct measurement of LDL particle numbers by NMR among 4 placebo controlled, phase 3 studies of mipomersen that had similar study designs but different patient populations: homozygous familial hypercholesterolemia (HoFH), severe hypercholesterolemia, heterozygous familial hypercholesterolemia with established coronary artery disease, or hypercholesterolemia with high risk for coronary heart disease (HC-CHD). RESULTS: HoFH patients had the highest median total LDL particles at baseline compared with HC-CHD patients, who had the lowest. At baseline, the HoFH population uniquely had a greater mean percentage of large LDL particles (placebo, 60.2%; mipomersen, 54.9%) compared with small LDL particles (placebo, 33.1%; mipomersen, 38.9%). In all 4 studies, mipomersen was associated with greater reductions from baseline in the concentrations of small LDL particles compared with those of large LDL particles, and both total LDL particles and small LDL particles were statistically significantly reduced. CONCLUSIONS: Mipomersen consistently reduced all LDL particle numbers and preferentially reduced the concentration of small LDL particles in all 4 phase 3 studies. PMID- 25911077 TI - Changes in ultracentrifugally separated plasma lipoprotein subfractions in patients with polygenic hypercholesterolemia, familial combined hyperlipoproteinemia, and familial hypercholesterolemia after treatment with atorvastatin. AB - BACKGROUND: Plasma levels of low-density lipoproteins (LDLs) are decreased through stimulation of their hepatic uptake by statins via an LDL receptor. However, it is unclear whether statins equally stimulate the hepatic uptake of all LDL subfractions. OBJECTIVE: We compared the effects of atorvastatin on 3 LDL subfractions, and their associations with LDL-receptor activities, in Japanese patients with polygenic hypercholesterolemia (PHC), familial combined hyperlipoproteinemia (FCHL), and familial hypercholesterolemia (FH). MATERIALS AND METHODS: Atorvastatin was administered to patients with PHC (n = 11), FCHL (n = 16), and FH (n = 13). We measured plasma levels of lipids, remnant-like particle cholesterol, apoproteins, and cholesterol in lipoprotein fractions. Sequential ultracentrifugation was performed to subfractionate the plasma lipoproteins, and lymphocyte LDL-receptor activities were estimated using flow cytometry. RESULTS: The average daily dosage of atorvastatin was 10, 27, and 40 mg in patients with PHC, FCHL, and FH, respectively; after 12 months of atorvastatin treatment, LDL cholesterol (LDL-C) plasma levels decreased by 44%, 50%, and 53%, respectively (all, P < .0001). Atorvastatin reduced low-density LDL C plasma levels in patients with PHC (48% reduction), FCHL (53%), and FH (46%) (all, P < .0001). Plasma levels of medium-density and high-density LDL-C were also significantly reduced in the 3 patient groups (all, P <= .0147). LDL receptor activity was negatively correlated with baseline levels of medium density LDL-C and with the decreases in plasma md-LDL-C levels. CONCLUSION: Atorvastatin decreased the levels of the 3 LDL fractions. The md-LDL decrease appeared to be mainly because of stimulation of LDL-receptor activity. PMID- 25911078 TI - Efficacy and safety of mipomersen in treatment of dyslipidemia: a meta-analysis of randomized controlled trials. AB - BACKGROUND: Low-density lipoprotein cholesterol (LDL-C) is the primary target of lipid-lowering therapy in people at risk for cardiovascular diseases. Mipomersen inhibits apolipoprotein B-100 (apoB) synthesis and causes reduction in LDL-C by reducing apoB. OBJECTIVE: We aimed to perform a meta-analysis of all published randomized controlled trials comparing safety and efficacy of mipomersen with placebo in adults with dyslipidemia. METHODS: We searched PUBMED, CENTRAL, and EMBASE from inception through March 2014 and used random-effects model to compute the effect size. RESULTS: We identified 8 randomized controlled trials (n = 462). Mipomersen compared with placebo significantly reduced LDL-C by 32.37% (95% confidence interval, 25.55-39.18; P < .00001), total cholesterol by 24.18% (18.54 29.83; P < .00001), very low-density lipoprotein cholesterol by 21.59% (9.16 34.02; P = .0007), non-high-density lipoprotein cholesterol (HDL-C) by 30.83% (23.92-37.74; P < .00001), and triglycerides by 36.26% (22-50.54; P < .00001). It also significantly reduced apoB, lipoprotein(a), and apolipoprotein A1. However, mipomersen did not significantly change HDL-C levels. In safety analysis, mipomersen compared with placebo increased the risks of injection-site reaction (risk ratio, 2.05; 95% confidence interval, 1.39-3.04; P = .0003), flu-like symptoms (1.63; 1.22-2.17; P = .0008), alanine aminotransferase >=3X upper limit of normal (4.44; 1.67-11.86; P = .003), and hepatic steatosis (3.85, 1.39-10.67; P = .01). The risks of alanine aminotransferase >=10X upper limit of normal did not reach statistical significance (1.57; 0.32-7.6, P = .58). CONCLUSION: Mipomersen resulted in a significant improvement in lipid parameters except for HDL-C and increased the risks of injection-site reactions, flu-like symptoms, and hepatic steatosis compared with placebo. PMID- 25911079 TI - Gender-related lipid and/or lipoprotein responses to statins in subjects in primary and secondary prevention. AB - BACKGROUND: Cardiovascular risk in men rises around the fourth decade of life, whereas women appear to be protected by sex hormones until menopause. This, in turn, tends to negatively affect the lipid profile. Since the 1980s, the incidence of cardiovascular diseases has been reported to progressively decline in men, but it has persisted almost unchanged in women. Major clinical trials on statins have been mostly conducted in men and have fostered the introduction of these agents into clinical practice worldwide. However, only few reports have examined a possible differential activity of statins in the 2 genders, providing in some cases opposite findings. OBJECTIVE: To evaluate gender-related differences in statin responses. METHODS: Variations of lipid profile after 1 year of treatment with different statins in 337 dyslipidemic patients (171 men and 166 women). RESULTS: In this series of patients, a significantly attenuated reduction of total cholesterol and low-density lipoprotein cholesterol in women vs men on drug treatment was noted after adjustment for dose and statin power (low-density lipoprotein cholesterol: -28.5 +/- 11.8% in men vs -22.7 +/- 11.8% in women; P < .001). CONCLUSIONS: The present study indicates that statin treatment has a reduced effectiveness in improving the plasma lipid profile in dyslipidemic women vs men. Whether such gender-related differences may have an impact on clinical outcomes remains to be elucidated. PMID- 25911080 TI - Clinical observations and treatment of pediatric homozygous familial hypercholesterolemia due to a low-density lipoprotein receptor defect. AB - BACKGROUND: Clinical observation and treatment of children with homozygous familial hypercholesterolemia (HoFH) has rarely been reported. We report clinical observations and treatment of 10 ethnic Chinese children with HoFH due to low density lipoprotein receptor (LDLR) defect. OBJECTIVES: In children with HoFH, we evaluated the response to conventional cholesterol-lowering drug therapy and performed LDLR gene analysis. METHODS: A retrospective review of lipid profile changes in pediatric patients diagnosed with HoFH seen in our pediatric endocrinology outpatient clinic was performed. HoFH was diagnosed by molecular study of these patients and their parents. RESULTS: One novel (c.64del G) and 12 known mutations were found in the LDLR gene. Mutation of p.C308Y was the most common and was found in 26% of the studied alleles.Seven patients had fair responses to conventional drug therapy (high-dose statin with ezetimibe) with a reduction of 50% or more of the total cholesterol levels. The low-density lipoprotein-cholesterol levels of three patients decreased to lower than 160 mg/dL. One who had a good response to conventional drug therapy developed significant atheromatous plaques (largest plaque: 7.4 * 2.7 cm) in the extracranial carotid arteries and myocardial ischemia changes at 11 years old. CONCLUSION: The results suggest that despite aggressive therapy, many patients are not well controlled; atherosclerosis may progress, and novel therapies are required. PMID- 25911081 TI - Disparities in lipid control and statin drug use among diabetics with noncoronary atherosclerotic vascular disease vs those with coronary artery disease. AB - BACKGROUND: Diabetes mellitus (DM), coronary artery disease (CAD), and noncoronary atherosclerotic vascular diseases (NCVDs) have similar risks of cardiovascular events and similar recommendations for lipid control. There are limited data regarding lipid control in diabetic patients with NCVD in current clinical practice. OBJECTIVE: To assess current day practice of lipid control in patients with DM with NCVD vs those with CAD. METHODS: We retrospectively identified 3336 patients with DM and known atherosclerotic vascular disease between January 2009 and March 2012. We compared demographic variables, lipid levels, and statin use in diabetics with CAD alone vs diabetics without CAD but with one or more NCVD. RESULTS: There were 234 patients in DM with NCVD group and 3102 patients in DM with CAD group. The DM with NCVD group had a higher mean total cholesterol (152 +/- 40 vs 146 +/- 42 mg/dL; P = .019) and mean low-density lipoprotein (LDL; 86 +/- 35 vs 80 +/- 34 mg/dL; P = .04) with only 70% of patients achieving LDL of <100 mg/dL (compared with 80% in the DM with CAD group; P < .001). Statin use was 100% in CAD vs 75% in NCVD group (P < .001). In addition to limited use of more potent statins in the NCVD group, there was also a significantly lower dose of statins used overall. CONCLUSION: Our study demonstrates lower use and less aggressive application of statins among diabetics with NCVD compared with diabetics with CAD, resulting in higher mean LDL and total cholesterol in the NCVD group. PMID- 25911082 TI - Discordance between apolipoprotein B and low-density lipoprotein particle number is associated with insulin resistance in clinical practice. AB - BACKGROUND: Discordance between measures of atherogenic lipoprotein particle number (apolipoprotein B [ApoB] and low-density lipoprotein [LDL] particle number by nuclear magnetic resonance spectroscopy [LDL-PNMR]) is not well understood. Appropriate treatment considerations in such cases are unclear. OBJECTIVES: To assess discordance between apoB determined by immunoassay and LDL-PNMR in routine clinical practice, and to characterize biomarker profiles and other clinical characteristics of patients identified as discordant. METHODS: Two retrospective cohorts were evaluated. First, 412,013 patients with laboratory testing performed by Health Diagnostic Laboratory, Inc., as part of routine care; and second, 1411 consecutive patients presenting for risk assessment/reduction at 6 US outpatient clinics. Discordance was quantified as a percentile difference (LDL-PNMR percentile - apoB percentile) and attainment of percentile cutpoints (LDL-PNMR >= 1073 nmol/L or apoB >= 69 mg/dL). A wide range of cardiovascular risk factors were compared. RESULTS: ApoB and LDL-PNMR values were highly correlated (R(2) = 0.79), although substantial discordance was observed. Similar numbers of patients were identified as at-risk by LDL-PNMR when apoB levels were < 69 mg/dL (5%-6%) and by apoB values when LDL-PNMR was < 1073 nmol/L (6%-7%). Discordance (LDL-PNMR > apoB) was associated with insulin resistance, smaller LDL particle size, increased systemic inflammation, and low circulating levels of "traditional" lipids, whereas discordance (apoB > LDL-PNMR) was associated with larger LDL particle size, and elevated levels of lipoprotein(a) and lipoprotein-associated phospholipase A2 (Lp-PLA2). CONCLUSION: Discordance between apoB and LDL-PNMR in routine clinical practice is more widespread than currently recognized and may be associated with insulin resistance. PMID- 25911083 TI - Use of lipid-lowering medications in myasthenia gravis: a case report and literature review. AB - We present a patient with myasthenia gravis (MG) who developed worsening of his condition after starting ezetimibe. We review the literature concerning lipid modifying medications and MG. The use of bile acid sequestrant agents may have a place in the lipid management of MG patients because they did not seem to cause muscle-related side effects or worsening of MG. PMID- 25911084 TI - Extreme hypercholesterolemia presenting with pseudohyponatremia - a case report and review of the literature. AB - Pseudohyponatremia has been reported in association with severe hypertriglyceridemia and hyperparaproteinemia, but its association with severe hypercholesterolemia is not well-known. We report a 43-year-old woman with refractory primary biliary cirrhosis who presented with asymptomatic hyponatremia (121 mmol/L; normal range: 135-145 mmol/L). She was ultimately found to have a total serum cholesterol level of 2415 mg/dL (normal range: 120-199 mg/dL) - secondary to accumulation of lipoprotein-X-causing pseudohyponatremia. The diagnosis was confirmed by measurement of serum osmolality (296 mOsm/kg H2O; normal range: 270-300 mOsm/kg H2O) and serum sodium by direct potentiometry (141 mmol/L). Furthermore, following 16 sessions of plasmapheresis over a 4-month period, there was marked lowering of serum cholesterol to 200 mg/dL and normalization of serum sodium (139 mmol/L) as measured by indirect potentiometry. This case shows that extreme hypercholesterolemia from elevation of lipoprotein-X particles in cholestasis can be a rare cause of pseudohyponatremia. It highlights the need to measure serum sodium with direct potentiometry in the setting of extreme hypercholesterolemia and consider this possibility before initiating treatment of hyponatremia. PMID- 25911085 TI - A 3-day-old neonate with severe hypertriglyceridemia from novel mutations of the GPIHBP1 gene. AB - BACKGROUND: Familial chylomicronemia is a genetic defect of the intravascular lipolysis of triglyceride (TG)-rich lipoproteins. Intravascular lipolysis involves the TG-hydrolase lipoprotein lipase (LPL) as well as other factors such as apolipoprotein CII and apolipoprotein AV (activators of LPL), GPIHBP1 (the molecular platform required for LPL activity on endothelial surface), and LMF1 (a factor required for intracellular formation of active LPL). METHODS: We sequenced the familial chylomicronemia candidate genes in a neonate with chylomicronemia. RESULTS: A 3-day-old newborn was found to have chylomicronemia (plasma TG 18.8 mmol/L, 1.667 mg/dL). The discontinuation of breastfeeding for 24 hours reduced plasma TG to 2.3 mmol/L (201 mg/dL), whereas its resumption induced a sharp TG increase (7.9 mmol/L, 690 mg/dL). The child was switched to a low-fat diet, which was effective in maintaining TG level below 3.5 mmol/L (294 mg/dL) during the first months of life. The child was found to be a compound heterozygous for 2 novel mutations in GPIHBP1 gene. The first mutation was a 9-bp deletion and 4-bp insertion in exon 2, causing a frameshift that abolished the canonical termination codon TGA. The predicted translation product of the mutant messenger RNA is a peptide that contains 51 amino acids of the N-terminal end of the wild type protein followed by 252 novel amino acids. The second mutation was a nucleotide change (c.319T>C), causing an amino acid substitution p.(Ser107Pro) predicted in silico to be damaging. CONCLUSIONS: GPIHBP1 mutations should be considered in neonates with chylomicronemia negative for mutations in LPL gene. PMID- 25911086 TI - A germline mutation in PBRM1 predisposes to renal cell carcinoma. AB - BACKGROUND: Many cases of familial renal cell carcinoma (RCC) remain unexplained by mutations in the known predisposing genes or shared environmental factors. There are therefore additional, still unidentified genes involved in familial RCC. PBRM1 is a tumour suppressor gene and somatic mutations are found in 30-45% of sporadic clear cell (cc) RCC. METHODS: We selected 35 unrelated patients with unexplained personal history of ccRCC and at least one affected first-degree relative, and sequenced the PBRM1 gene. RESULTS: A germline frameshift mutation (c.3998_4005del [p.Asp1333Glyfs]) was found in one patient. The patient's mother, his sister and one niece also had ccRCC. The mutation co-segregated with the disease as the three affected relatives were carriers, while an unaffected sister was not, according with autosomal-dominant transmission. Somatic studies supported these findings, as we observed both loss of heterozygosity for the mutation and loss of protein expression in renal tumours. CONCLUSIONS: We show for the first time that an inherited mutation in PBRM1 predisposes to RCC. International studies are necessary to estimate the contribution of PBRM1 to RCC susceptibility, estimate penetrance and then integrate the gene into routine clinical practice. PMID- 25911088 TI - Changing the face of fever of unknown origin in Egypt: a single hospital study. PMID- 25911087 TI - Detection of E. coli O157:H7 and Shigella dysenteriae toxins in clinical samples by PCR-ELISA. AB - Shiga toxin producing bacteria are potential causes of serious human disease such as hemorrhagic colitis, severe inflammations of ileocolonic regions of gastrointestinal tract, thrombocytopenia, septicemia, malignant disorders in urinary ducts, hemolytic uremic syndrome (HUS). Shiga toxin 1 (stx1), shiga toxin 2 (stx2), or a combination of both are responsible for most clinical symptoms of these diseases. A lot of methods have been developed so far to detect shiga toxins such as cell culture, ELISA, and RFPLA, but due to high costs and labor time in addition to low sensitivity, they have not received much attention. In this study, PCR-ELISA method was used to detect genes encoding shiga toxins1 and 2 (stx1 and stx2). To detect stx1 and stx2 genes, two primer pairs were designed for Multiplex-PCR then PCR-ELISA. PCR products (490 and 275, respectively) were subsequently verified by sequencing. Sensitivity and specificity of PCR-ELISA method were determined by using genome serial dilution and Enterobacteria strains. PCR-ELISA method used in this study proved to be a rapid and precise approach to detect different types of shiga toxins and can be used to detect bacterial genes encoding shiga toxins. PMID- 25911089 TI - Factors associated with vaccination against hepatitis B in adolescents and young adults from an urban settlement. PMID- 25911090 TI - Effects of endothelin and nitric oxide on cardiac muscle functions in experimental septic shock model. AB - We aimed to investigate the possible roles of nitric oxide (NO) and endothelin on the changes of cardiac muscle function in both hyper- and hypodynamic septic shock periods. Cecal ligation and puncture was performed in 50 Wistar albino rats to induce septic shock. Changes in atrium and right ventricle papillary muscle contractions, atrium beat rate, adrenergic and cholinergic responses in these tissues were evaluated in vitro. Atrium beat rate increased in hypodynamic period (p < 0.001) that was reversed by bosentan (p < 0.001) and N(G)-nitro-L-arginine methylester (L-NAME; p < 0.05). Atrium contractions decreased in both hyper- and hypodynamic periods (p < 0.001) that were partially ameliorated by bosentan in both periods (p < 0.01) and only in hypodynamic period by L-NAME (p < 0.001). L NAME increased papillary muscle contractions in both periods (p < 0.01), but bosentan increased it only in hyperdynamic period (p < 0.01). Bosentan and L-NAME increased potency of isoproterenol on atrium beat rate in both periods and increased carbachol potency on atrium beat rate and atrium contraction amplitude only in hypodynamic period. Bosentan increased atrium contraction response to isoproterenol in hypodynamic period (p < 0.05). Papillary muscle contraction response to isoproterenol increased in hypodynamic period (p < 0.05). L-NAME increased papillary muscle contraction response to carbachol in both periods (p < 0.01, p < 0.05, respectively). These results show that NO and endothelin may play a role in positive inotropic and negative chronotropic effects for atrium in septic shock. Bosentan and L-NAME may change potency and efficacy of isoproterenol and carbachol via upregulation of adrenergic and cholinergic receptors and/or through post receptor factors. PMID- 25911091 TI - The health status of adults on the autism spectrum. AB - Compared to the general pediatric population, children with autism have higher rates of co-occurring medical and psychiatric illnesses, yet very little is known about the general health status of adults with autism. The objective of this study was to describe the frequency of psychiatric and medical conditions among a large, diverse, insured population of adults with autism in the United States. Participants were adult members of Kaiser Permanente Northern California enrolled from 2008 to 2012. Autism spectrum disorder cases (N = 1507) were adults with autism spectrum disorder diagnoses (International Classification of Diseases-9 Clinical Modification codes 299.0, 299.8, 299.9) recorded in medical records on at least two separate occasions. Controls (N = 15,070) were adults without any autism spectrum disorder diagnoses sampled at a 10:1 ratio and frequency matched to cases on sex and age. Adults with autism had significantly increased rates of all major psychiatric disorders including depression, anxiety, bipolar disorder, obsessive-compulsive disorder, schizophrenia, and suicide attempts. Nearly all medical conditions were significantly more common in adults with autism, including immune conditions, gastrointestinal and sleep disorders, seizure, obesity, dyslipidemia, hypertension, and diabetes. Rarer conditions, such as stroke and Parkinson's disease, were also significantly more common among adults with autism. Future research is needed to understand the social, healthcare access, and biological factors underlying these observations. PMID- 25911092 TI - Child characteristics associated with outcome for children with autism in a school-based behavioral intervention. AB - This study examined the extent to which clinical and demographic characteristics predicted outcome for children with autism spectrum disorder. Participants included 152 students with autism spectrum disorder in 53 kindergarten-through second-grade autism support classrooms in a large urban public school district. Associations between child characteristics (including age, language ability, autism severity, social skills, adaptive behavior, co-occurring psychological symptoms, and restrictive and repetitive behavior) and outcome, as measured by changes in cognitive ability following one academic year of an intervention standardized across the sample were evaluated using linear regression with random effects for classroom. While several scales and subscales had statistically significant bivariate associations with outcome, in adjusted analysis, only age and the presence of symptoms associated with social anxiety, such as social avoidance and social fearfulness, as measured through the Child Symptom Inventory 4, were associated with differences in outcome. The findings regarding the role of social anxiety are new and have important implications for treatment. Disentangling the construct of social anxiety to differentiate between social fearfulness and social motivation has important implications for shifting the focus of early treatment for children with autism spectrum disorder. PMID- 25911093 TI - Support for learning goes beyond academic support: Voices of students with Asperger's disorder and attention deficit hyperactivity disorder. AB - The purpose of this study was to describe and explore the experiences of support at school among young adults with Asperger's disorder and attention deficit hyperactivity disorder and also to examine what support they, in retrospect, described as influencing learning. Purposive sampling was used to enroll participants. Data were collected through semi-structured interviews with 13 young adults aged between 20 and 29 years. A qualitative analysis, based on interpreting people's experiences, was conducted by grouping and searching for patterns in data. The findings indicate that the participants experienced difficulties at school that included academic, social, and emotional conditions, all of which could influence learning. Support for learning included small groups, individualized teaching methods, teachers who cared, and practical and emotional support. These clusters together confirm the overall understanding that support for learning aligns academic and psychosocial support. In conclusion, academic support combined with psychosocial support at school seems to be crucial for learning among students with Asperger's disorder and attention deficit hyperactivity disorder. PMID- 25911094 TI - Odontogenic Ameloblast-associated Protein (ODAM) Mediates Junctional Epithelium Attachment to Teeth via Integrin-ODAM-Rho Guanine Nucleotide Exchange Factor 5 (ARHGEF5)-RhoA Signaling. AB - Adhesion of the junctional epithelium (JE) to the tooth surface is crucial for maintaining periodontal health. Although odontogenic ameloblast-associated protein (ODAM) is expressed in the JE, its molecular functions remain unknown. We investigated ODAM function during JE development and regeneration and its functional significance in the initiation and progression of periodontitis and peri-implantitis. ODAM was expressed in the normal JE of healthy teeth but absent in the pathologic pocket epithelium of diseased periodontium. In periodontitis and peri-implantitis, ODAM was extruded from the JE following onset with JE attachment loss and detected in gingival crevicular fluid. ODAM induced RhoA activity and the expression of downstream factors, including ROCK (Rho-associated kinase), by interacting with Rho guanine nucleotide exchange factor 5 (ARHGEF5). ODAM-mediated RhoA signaling resulted in actin filament rearrangement. Reduced ODAM and RhoA expression in integrin beta3- and beta6-knockout mice revealed that cytoskeleton reorganization in the JE occurred via integrin-ODAM-ARHGEF5-RhoA signaling. Fibronectin and laminin activated RhoA signaling via the integrin-ODAM pathway. Finally, ODAM was re-expressed with RhoA in regenerating JE after gingivectomy in vivo. These results suggest that ODAM expression in the JE reflects a healthy periodontium and that JE adhesion to the tooth surface is regulated via fibronectin/laminin-integrin-ODAM-ARHGEF5-RhoA signaling. We also propose that ODAM could be used as a biomarker of periodontitis and peri implantitis. PMID- 25911095 TI - Islet Endothelial Cells Induce Glycosylation and Increase Cell-surface Expression of Integrin beta1 in beta Cells. AB - The co-culturing of insulinoma and islet-derived endothelial cell (iEC) lines results in the spontaneous formation of free-floating pseudoislets (PIs). We previously showed that iEC-induced PIs display improved insulin expression and secretion in response to glucose stimulation. This improvement was associated with a de novo deposition of extracellular matrix (ECM) proteins by iECs in and around the PIs. Here, iEC-induced PIs were used to study the expression and posttranslational modification of the ECM receptor integrin beta1. A wide array of integrin beta subunits was detected in betaTC3 and NIT-1 insulinomas as well as in primary islets, with integrin beta1 mRNA and protein detected in all three cell types. Interestingly, the formation of iEC-induced PIs altered the glycosylation patterns of integrin beta1, resulting in a higher molecular weight form of the receptor. This form was found in native pancreas but was completely absent in monolayer beta-cells. Fluorescence-activated cell sorting analysis of monolayers and PIs revealed a higher expression of integrin beta1 in PIs. Antibody-mediated blocking of integrin beta1 led to alterations in beta-cell morphology, reduced insulin gene expression, and enhanced glucose secretion under baseline conditions. These results suggest that iEC-induced PI formation may alter integrin beta1 expression and posttranslational modification by enhancing glycosylation, thereby providing a more physiological culture system for studying integrin-ECM interactions in beta cells. PMID- 25911096 TI - Strain Differences in Presynaptic Function: PROTEOMICS, ULTRASTRUCTURE, AND PHYSIOLOGY OF HIPPOCAMPAL SYNAPSES IN DBA/2J AND C57Bl/6J MICE. AB - The inbred strains C57BL/6J and DBA/2J (DBA) display striking differences in a number of behavioral tasks depending on hippocampal function, such as contextual memory. Historically, this has been explained through differences in postsynaptic protein expression underlying synaptic transmission and plasticity. We measured the synaptic hippocampal protein content (iTRAQ (Isobaric Tags for Relative and Absolute Quantitation) and mass spectrometry), CA1 synapse ultrastructural morphology, and synaptic functioning in adult C57BL/6J and DBA mice. DBA mice showed a prominent decrease in the Ras-GAP calcium-sensing protein RASAL1. Furthermore, expression of several presynaptic markers involved in exocytosis, such as syntaxin (Stx1b), Ras-related proteins (Rab3a/c), and rabphilin (Rph3a), was reduced. Ultrastructural analysis of CA1 hippocampal synapses showed a significantly lower number of synaptic vesicles and presynaptic cluster size in DBA mice, without changes in postsynaptic density or active zone. In line with this compromised presynaptic morphological and molecular phenotype in DBA mice, we found significantly lower paired-pulse facilitation and enhanced short term depression of glutamatergic synapses, indicating a difference in transmitter release and/or refilling mechanisms. Taken together, our data suggest that in addition to strain-specific postsynaptic differences, the change in dynamic properties of presynaptic transmitter release may underlie compromised synaptic processing related to cognitive functioning in DBA mice. PMID- 25911097 TI - Gemin5 Binds to the Survival Motor Neuron mRNA to Regulate SMN Expression. AB - Reduced expression of SMN causes spinal muscular atrophy, a severe neurodegenerative disease. Despite the importance of maintaining SMN levels, relatively little is known about the mechanisms by which SMN levels are regulated. We show here that Gemin5, the snRNA-binding protein of the SMN complex, binds directly to the SMN mRNA and regulates SMN expression. Gemin5 binds with high specificity, both in vitro and in vivo, to sequence and structural elements in the SMN mRNA 3'-untranslated region that are reminiscent of the snRNP code to which Gemin5 binds on snRNAs. Reduction of Gemin5 redistributes the SMN mRNA from heavy polysomes to lighter polysomes and monosomes, suggesting that Gemin5 functions as an activator of SMN translation. SMN protein is not stoichiometrically present on the SMN mRNA with Gemin5, but the mRNA-binding activity of Gemin5 is dependent on SMN levels, providing a feedback mechanism for SMN to regulate its own expression via Gemin5. This work both reveals a new autoregulatory pathway governing SMN expression, and identifies a new mechanism through which SMN can modulate specific mRNA expression via Gemin5. PMID- 25911098 TI - [Ca2+]i Oscillations and IL-6 Release Induced by alpha-Hemolysin from Escherichia coli Require P2 Receptor Activation in Renal Epithelia. AB - Urinary tract infections are commonly caused by alpha-hemolysin (HlyA)-producing Escherichia coli. In erythrocytes, the cytotoxic effect of HlyA is strongly amplified by P2X receptors, which are activated by extracellular ATP released from the cytosol of the erythrocytes. In renal epithelia, HlyA causes reversible [Ca(2+)]i oscillations, which trigger interleukin-6 (IL-6) and IL-8 release. We speculate that this effect is caused by HlyA-induced ATP release from the epithelial cells and successive P2 receptor activation. Here, we demonstrate that HlyA-induced [Ca(2+)]i oscillations in renal epithelia were completely prevented by scavenging extracellular ATP. In accordance, HlyA was unable to inflict any [Ca(2+)]i oscillations in 132-1N1 cells, which lack P2R completely. After transfecting these cells with the hP2Y2 receptor, HlyA readily triggered [Ca(2+)]i oscillations, which were abolished by P2 receptor antagonists. Moreover, HlyA-induced [Ca(2+)]i oscillations were markedly reduced in medullary thick ascending limbs isolated from P2Y2 receptor-deficient mice compared with wild type. Interestingly, the following HlyA-induced IL-6 release was absent in P2Y2 receptor-deficient mice. This suggests that HlyA induces ATP release from renal epithelia, which via P2Y2 receptors is the main mediator of HlyA-induced [Ca(2+)]i oscillations and IL-6 release. This supports the notion that ATP signaling occurs early during bacterial infection and is a key player in the further inflammatory response. PMID- 25911099 TI - Role of a Novel Human Leukocyte Antigen-DQA1*01:02;DRB1*15:01 Mixed Isotype Heterodimer in the Pathogenesis of "Humanized" Multiple Sclerosis-like Disease. AB - Gene-wide association and candidate gene studies indicate that the greatest effect on multiple sclerosis (MS) risk is driven by the HLA-DRB1*15:01 allele within the HLA-DR15 haplotype (HLA-DRB1*15:01-DQA1*01:02-DQB1*0602-DRB5*01:01). Nevertheless, linkage disequilibrium makes it difficult to define, without functional studies, whether the functionally relevant effect derives from DRB1*15:01 only, from its neighboring DQA1*01:02-DQB1*06:02 or DRB5*01:01 genes of HLA-DR15 haplotype, or from their combinations or epistatic interactions. Here, we analyzed the impact of the different HLA-DR15 haplotype alleles on disease susceptibility in a new "humanized" model of MS induced in HLA-transgenic (Tg) mice by human oligodendrocyte-specific protein (OSP)/claudin-11 (hOSP), one of the bona fide potential primary target antigens in MS. We show that the hOSP associated MS-like disease is dominated by the DRB1*15:01 allele not only as the DRA1*01:01;DRB1*15:01 isotypic heterodimer but also, unexpectedly, as a functional DQA1*01:02;DRB1*15:01 mixed isotype heterodimer. The contribution of HLA-DQA1/DRB1 mixed isotype heterodimer to OSP pathogenesis was revealed in (DRB1*1501xDQB1*0602)F1 double-Tg mice immunized with hOSP(142-161) peptide, where the encephalitogenic potential of prevalent DRB1*1501/hOSP(142-161) reactive Th1/Th17 cells is hindered due to a single amino acid difference in the OSP(142-161) region between humans and mice; this impedes binding of DRB1*1501 to the mouse OSP(142-161) epitope in the mouse CNS while exposing functional binding of mouse OSP(142-161) to DQA1*01:02;DRB1*15:01 mixed isotype heterodimer. This study, which shows for the first time a functional HLA-DQA1/DRB1 mixed isotype heterodimer and its potential association with disease susceptibility, provides a rationale for a potential effect on MS risk from DQA1*01:02 through functional DQA1*01:02;DRB1*15:01 antigen presentation. Furthermore, it highlights a potential contribution to MS risk also from interisotypic combination between products of neighboring HLA-DR15 haplotype alleles, in this case the DQA1/DRB1 combination. PMID- 25911100 TI - Genome Protection by the 9-1-1 Complex Subunit HUS1 Requires Clamp Formation, DNA Contacts, and ATR Signaling-independent Effector Functions. AB - The RAD9A-HUS1-RAD1 (9-1-1) complex is a heterotrimeric clamp that promotes checkpoint signaling and repair at DNA damage sites. In this study, we elucidated HUS1 functional residues that drive clamp assembly, DNA interactions, and downstream effector functions. First, we mapped a HUS1-RAD9A interface residue that was critical for 9-1-1 assembly and DNA loading. Next, we identified multiple positively charged residues in the inner ring of HUS1 that were crucial for genotoxin-induced 9-1-1 chromatin localization and ATR signaling. Finally, we found two hydrophobic pockets on the HUS1 outer surface that were important for cell survival after DNA damage. Interestingly, these pockets were not required for 9-1-1 chromatin localization or ATR-mediated CHK1 activation but were necessary for interactions between HUS1 and its binding partner MYH, suggesting that they serve as interaction domains for the recruitment and coordination of downstream effectors at damage sites. Together, these results indicate that, once properly loaded onto damaged DNA, the 9-1-1 complex executes multiple, separable functions that promote genome maintenance. PMID- 25911101 TI - Tubulin-tyrosine Ligase (TTL)-mediated Increase in Tyrosinated alpha-Tubulin in Injured Axons Is Required for Retrograde Injury Signaling and Axon Regeneration. AB - Injured peripheral neurons successfully activate a pro-regenerative program to enable axon regeneration and functional recovery. The microtubule-dependent retrograde transport of injury signals from the lesion site in the axon back to the cell soma stimulates the increased growth capacity of injured neurons. However, the mechanisms initiating this retrograde transport remain poorly understood. Here we show that tubulin-tyrosine ligase (TTL) is required to increase the levels of tyrosinated alpha-tubulin at the axon injury site and plays an important role in injury signaling. Preventing the injury-induced increase in tyrosinated alpha-tubulin by knocking down TTL impairs retrograde organelle transport and delays activation of the pro-regenerative transcription factor c-Jun. In the absence of TTL, axon regeneration is reduced severely. We propose a model in which TTL increases the levels of tyrosinated alpha-tubulin locally at the injury site to facilitate the retrograde transport of injury signals that are required to activate a pro-regenerative program. PMID- 25911102 TI - Structural and Biochemical Basis for the Inhibitory Effect of Liprin-alpha3 on Mouse Diaphanous 1 (mDia1) Function. AB - Diaphanous-related formins are eukaryotic actin nucleation factors regulated by an autoinhibitory interaction between the N-terminal RhoGTPase-binding domain (mDiaN) and the C-terminal Diaphanous-autoregulatory domain (DAD). Although the activation of formins by Rho proteins is well characterized, its inactivation is only marginally understood. Recently, liprin-alpha3 was shown to interact with mDia1. Overexpression of liprin-alpha3 resulted in a reduction of the cellular actin filament content. The molecular mechanisms of how liprin-alpha3 exerts this effect and counteracts mDia1 activation by RhoA are unknown. Here, we functionally and structurally define a minimal liprin-alpha3 core region, sufficient to recapitulate the liprin-alpha3 determined mDia1-respective cellular functions. We show that liprin-alpha3 alters the interaction kinetics and thermodynamics of mDiaN with RhoA.GTP and DAD. RhoA displaces liprin-alpha3 allosterically, whereas DAD competes with liprin-alpha3 for a highly overlapping binding site on mDiaN. Liprin-alpha3 regulates actin polymerization by lowering the regulatory potency of RhoA and DAD on mDiaN. We present a model of a mechanistically unexplored and new aspect of mDiaN regulation by liprin-alpha3. PMID- 25911103 TI - The V4 and V5 Variable Loops of HIV-1 Envelope Glycoprotein Are Tolerant to Insertion of Green Fluorescent Protein and Are Useful Targets for Labeling. AB - The mature human immunodeficiency virus type 1 (HIV-1) envelope glycoprotein (Env) comprises the non-covalently associated gp120 and gp41 subunits generated from the gp160 precursor. Recent structural analyses have provided quaternary structural models for gp120/gp41 trimers, including the variable loops (V1-V5) of gp120. In these models, the V3 loop is located under V1/V2 at the apical center of the Env trimer, and the V4 and V5 loops project outward from the trimeric protomers. In addition, the V4 and V5 loops are predicted to have less movement upon receptor binding during membrane fusion events. We performed insertional mutagenesis using a GFP variant, GFPOPT, placed into the variable loops of HXB2 gp120. This allowed us to evaluate the current structural models and to simultaneously generate a GFP-tagged HIV-1 Env, which was useful for image analyses. All GFP-inserted mutants showed similar levels of whole-cell expression, although certain mutants, particularly V3 mutants, showed lower levels of cell surface expression. Functional evaluation of their fusogenicities in cell-cell and virus-like particle-cell fusion assays revealed that V3 was the most sensitive to the insertion and that the V1/V2 loops were less sensitive than V3. The V4 and V5 loops were the most tolerant to insertion, and certain tag proteins other than GFPOPT could also be inserted without functional consequences. Our results support the current structural models and provide a GFPOPT-tagged Env construct for imaging studies. PMID- 25911104 TI - Tumor-suppressive p53 Signaling Empowers Metastatic Inhibitor KLF17-dependent Transcription to Overcome Tumorigenesis in Non-small Cell Lung Cancer. AB - Metastasis, which is controlled by concerted action of multiple genes, is a complex process and is an important cause of cancer death. Kruppel-like factor 17 (KLF17) is a negative regulator of metastasis and epithelial-mesenchymal transition (EMT) during cancer progression. However, the underlying molecular mechanism and biological relevance of KLF17 in cancer cells are poorly understood. Here, we show that tumor suppressor protein p53 plays an integral role to induce KLF17 expression in non-small cell lung cancer (NSCLC). p53 is recruited to the KLF17 promoter and results in the formation of p53-DNA complex. p53 enhances binding of p300 and favors histone acetylation on the KLF17 promoter. Mechanistically, p53 physically interacts with KLF17 and thereby enhances the anti-metastatic function of KLF17. p53 empowers KLF17-mediated EMT genes transcription via enhancing physical association of KLF17 with target gene promoters. Nutlin-3 recruits KLF17 to EMT target gene promoters and results in the formation of KLF17-DNA complex via a p53-dependent pathway. p53 depletion abrogates DNA binding affinity of KLF17 to EMT target gene promoters. KLF17 is critical for p53 cellular activities in NSCLC. Importantly, KLF17 enhances p53 transcription to generate a novel positive feedback loop. KLF17 depletion accelerates lung cancer cell growth in response to chemotherapy. Mechanistically, we found that KLF17 increases the expression of tumor suppressor genes p53, p21, and pRB. Functionally, KLF17 required p53 to suppress cancer cell invasion and migration in NSCLC. In conclusion, our study highlights a novel insight into the anti-EMT effect of KLF17 via a p53-dependent pathway in NSCLC, and KLF17 may be a new therapeutic target in NSCLC with p53 status. PMID- 25911105 TI - Aryl Hydrocarbon Receptor Interacting Protein Targets IRF7 to Suppress Antiviral Signaling and the Induction of Type I Interferon. AB - The transcription factor IRF7 (interferon regulatory factor 7) is a key regulator of type I interferon and plays essential roles in restricting virus infection and spread. IRF7 activation is tightly regulated to prevent excessive inflammation and autoimmunity; however, how IRF7 is suppressed by negative regulators remains poorly understood. Here, we have identified AIP (aryl hydrocarbon receptor interacting protein) as a new binding partner of IRF7. The interaction between AIP and IRF7 is enhanced upon virus infection, and AIP potently inhibits IRF7 induced type I IFN (IFNalpha/beta) production. Overexpression of AIP blocks virus induced activation of IFN, whereas knockdown of AIP by siRNA potentiates virally activated IFN production. Consistently, AIP-deficient murine embryonic fibroblasts are highly resistant to virus infection because of increased production of IFNalpha/beta. AIP inhibits IRF7 function by antagonizing the nuclear localization of IRF7. Together, our study identifies AIP as a novel inhibitor of IRF7 and a negative regulator of innate antiviral signaling. PMID- 25911106 TI - Redox Control of Protein Arginine Methyltransferase 1 (PRMT1) Activity. AB - Elevated levels of asymmetric dimethylarginine (ADMA) correlate with risk factors for cardiovascular disease. ADMA is generated by the catabolism of proteins methylated on arginine residues by protein arginine methyltransferases (PRMTs) and is degraded by dimethylarginine dimethylaminohydrolase. Reports have shown that dimethylarginine dimethylaminohydrolase activity is down-regulated and PRMT1 protein expression is up-regulated under oxidative stress conditions, leading many to conclude that ADMA accumulation occurs via increased synthesis by PRMTs and decreased degradation. However, we now report that the methyltransferase activity of PRMT1, the major PRMT isoform in humans, is impaired under oxidative conditions. Oxidized PRMT1 displays decreased activity, which can be rescued by reduction. This oxidation event involves one or more cysteine residues that become oxidized to sulfenic acid (-SOH). We demonstrate a hydrogen peroxide concentration-dependent inhibition of PRMT1 activity that is readily reversed under physiological H2O2 concentrations. Our results challenge the unilateral view that increased PRMT1 expression necessarily results in increased ADMA synthesis and demonstrate that enzymatic activity can be regulated in a redox sensitive manner. PMID- 25911107 TI - Histone Deacetylase 3 (HDAC3)-dependent Reversible Lysine Acetylation of Cardiac Myosin Heavy Chain Isoforms Modulates Their Enzymatic and Motor Activity. AB - Reversible lysine acetylation is a widespread post-translational modification controlling the activity of proteins in different subcellular compartments. We previously demonstrated that a class II histone deacetylase (HDAC), HDAC4, and a histone acetyltransferase, p300/CREB-binding protein-associated factor, associate with cardiac sarcomeres and that a class I and II HDAC inhibitor, trichostatin A, enhances contractile activity of myofilaments. In this study we show that a class I HDAC, HDAC3, is also present at cardiac sarcomeres. By immunohistochemical and electron microscopic analyses, we found that HDAC3 was localized to A-band of sarcomeres and capable of deacetylating myosin heavy chain (MHC) isoforms. The motor domains of both cardiac alpha- and beta-MHC isoforms were found to be reversibly acetylated. Biomechanical studies revealed that lysine acetylation significantly decreased the Km for the actin-activated ATPase activity of MHC isoforms. By in vitro motility assay, we found that lysine acetylation increased the actin-sliding velocity of alpha-myosin by 20% and beta-myosin by 36% compared with their respective non-acetylated isoforms. Moreover, myosin acetylation was found to be sensitive to cardiac stress. During induction of hypertrophy, myosin isoform acetylation increased progressively with duration of stress stimuli independently of isoform shift, suggesting that lysine acetylation of myosin could be an early response of myofilaments to increase contractile performance of the heart. These studies provide the first evidence for localization of HDAC3 at myofilaments and uncover a novel mechanism modulating the motor activity of cardiac MHC isoforms. PMID- 25911108 TI - The cost of multiple sclerosis drugs in the US and the pharmaceutical industry: Too big to fail? AB - OBJECTIVE: To examine the pricing trajectories in the United States of disease modifying therapies (DMT) for multiple sclerosis (MS) over the last 20 years and assess the influences on rising prices. METHODS: We estimated the trend in annual drug costs for 9 DMTs using published drug pricing data from 1993 to 2013. We compared changes in DMT costs to general and prescription drug inflation during the same period. We also compared the cost trajectories for first-generation MS DMTs interferon (IFN)-beta-1b, IFN-beta-1a IM, and glatiramer acetate with contemporaneously approved biologic tumor necrosis factor (TNF) inhibitors. RESULTS: First-generation DMTs, originally costing $8,000 to $11,000, now cost about $60,000 per year. Costs for these agents have increased annually at rates 5 to 7 times higher than prescription drug inflation. Newer DMTs commonly entered the market with a cost 25%-60% higher than existing DMTs. Significant increases in the cost trajectory of the first-generation DMTs occurred following the Food and Drug Administration approvals of IFN-beta-1a SC (2002) and natalizumab (reintroduced 2006) and remained high following introduction of fingolimod (2010). Similar changes did not occur with TNF inhibitor biologics during these time intervals. DMT costs in the United States currently are 2 to 3 times higher than in other comparable countries. CONCLUSIONS: MS DMT costs have accelerated at rates well beyond inflation and substantially above rates observed for drugs in a similar biologic class. There is an urgent need for clinicians, payers, and manufacturers in the United States to confront the soaring costs of DMTs. PMID- 25911109 TI - Escalating MS drug costs in the US: Puzzling, troubling, and suspicious. PMID- 25911110 TI - Postoperative chemotherapy in patients with rectal cancer receiving preoperative radio(chemo)therapy: A meta-analysis of randomized trials comparing surgery +/- a fluoropyrimidine and surgery + a fluoropyrimidine +/- oxaliplatin. AB - BACKGROUND: There is no consensus on the role of postoperative chemotherapy in patients with rectal cancer who have received preoperative radio(chemo)therapy. MATERIALS AND METHODS: A systematic review and meta-analysis were performed of trials that used preoperative radio(chemo)therapy and randomized patients either between postoperative chemotherapy and observation or between a fluoropyrimidine only (FU-only) and a fluoropyrimidine with oxaliplatin (FU-OXA) as postoperative chemotherapy. RESULTS: Five randomized studies compared postoperative chemotherapy with observation in a total of 2398 patients. None of these trials demonstrated a statistically significant benefit of chemotherapy for OS and DFS. The pooled differences in OS and DFS did not differ statistically significantly between the chemotherapy group and the observation group. The hazard ratios (HRs) and 95% confidence intervals (CIs) were 0.95 (CI: 0.82-1.10), P = 0.49 and 0.92 (CI: 0.80-1.04), P = 0.19, respectively. In the subgroup of trials in which randomization was performed after surgery (n = 753), a statistically significant positive pooled chemotherapy effect was observed for DFS (HR = 0.79, 95% CI: 0.62 1.00, P = 0.047), but not for OS (P = 0.39). Four randomized trials compared adjuvant FU-OXA with adjuvant FU-only in 2710 patients. In two trials, the difference in DFS between groups was statistically significant in favour of FU OXA, and in the other two trials, the difference was not significant. The pooled difference in DFS between the FU-OXA group and the FU-only group was not statistically significant: HR = 0.84 (CI: 0.66-1.06), P = 0.15. CONCLUSION: The use of postoperative chemotherapy in patients with rectal cancer receiving preoperative radio(chemo)therapy is not based on strong scientific evidence. PMID- 25911111 TI - Surgical strategies for duodenal GISTs: Benefits and limitations of minimal resections. PMID- 25911112 TI - Vitamin D-binding protein is required for the protective effects of vitamin D in renal fibroblasts and is phosphorylated in diabetic rats. AB - Serum vitamin D is bound to vitamin D-binding protein (DBP). We studied the roles of DBP in streptozotocin-diabetic rats and high glucose (HG)-cultured cells. In diabetic rat sera, there was one upregulated (with a lower isoelectric point [pI], phosphorylated at S268, S270, S464 and T269) and one downregulated (with a higher pI, phosphorylated at S454 and S457) DBP. DBP levels with lower pI were increased in diabetic rat kidney and liver. HG (30 mM) increased DBP protein expression in NRK-49F cells and Clone-9 hepatocytes. HG decreased pI of DBP in Clone-9 hepatocytes. Moreover, DBP short hairpin ribonucleic acid attenuated 1,25 (OH)2D3-induced attenuation of HG-induced renin (but not collagen IV and fibronectin) protein expression in NRK-49F cells. Thus, DBP level is increased whereas DBP is phosphorylated in diabetic rat serum. HG increased DBP protein expression in renal fibroblasts and hepatocytes. Moreover, DBP is required for vitamin D-induced attenuation of HG-induced renin in NRK-49F cells. PMID- 25911114 TI - Apoptosis induction and release of inflammatory cytokines in the oviduct of egg laying hens experimentally infected with H9N2 avian influenza virus. AB - The H9N2 subtype avian influenza virus (AIV) can cause serious damage to the reproductive tract of egg-laying hens, leading to severe egg-drop and poor egg shell quality. However, previous studies in relation to the oviductal-dysfunction resulted from this agent have not clearly been elucidated. In this study, apoptosis and pathologic changes in the oviducts of egg-laying hens caused by H9N2 AIV were evaluated. To understand the immune response in the pathogenic processes, 30-week old specific pathogen free (SPF) egg-laying hens inoculated with H9N2 subtype of AIV through combined intra-ocular and intra-nasal routes. H9N2 AIV infection resulted in oviductal lesions, triggered apoptosis and expression of immune related genes accompanied with infiltration of CD3(+)CD4(+) and CD3(+)CD8alpha(+) cells. Significant tissue damage and apoptosis were observed in the five oviductal parts (infundibulum, magnum, isthmus, uterus and vagina) at 5 days post-inoculation (dpi). Furthermore, immune-related genes, including chicken TLR3 (7, 21), MDA5, IL-2, IFN-beta, CXCLi1, CXCLi2, XCL1, XCR1 and CCR5 showed variation in the egg-laying hens infected with H9N2 AIV. Notably, mRNA expression of IFN-alpha was suppressed during the infection. These results show distinct expression patterns of inflammatory cytokines and chemokines amongst segments of the oviduct. Differential gene expression of inflammatory cytokines and lymphocytes aggregation occurring in oviducts may initiate the infected tissue in response to virus replication which may eventually lead to excessive cellular apoptosis and tissue damage. PMID- 25911113 TI - Multiple exportins influence thyroid hormone receptor localization. AB - The thyroid hormone receptor (TR) undergoes nucleocytoplasmic shuttling and regulates target genes involved in metabolism and development. Previously, we showed that TR follows a CRM1/calreticulin-mediated nuclear export pathway. However, two lines of evidence suggest TR also follows another pathway: export is only partially blocked by leptomycin B (LMB), a CRM1-specific inhibitor; and we identified nuclear export signals in TR that are LMB-resistant. To determine whether other exportins are involved in TR shuttling, we used RNA interference and fluorescence recovery after photobleaching shuttling assays in transfected cells. Knockdown of exportins 4, 5, and 7 altered TR shuttling dynamics, and when exportins 5 and 7 were overexpressed, TR distribution shifted toward the cytosol. To further assess the effects of exportin overexpression, we examined transactivation of a TR-responsive reporter gene. Our data indicate that multiple exportins influence TR localization, highlighting a fine balance of nuclear import, retention, and export that modulates TR function. PMID- 25911115 TI - Variable underlying morphology of culprit plaques associated with ST-elevation myocardial infarction: an optical coherence tomography analysis from the SMART trial. AB - AIMS: The objective was to assess in vivo culprit lesion morphologies that caused ST-segment elevation myocardial infarction (STEMI) using optical coherence tomography (OCT). METHODS AND RESULTS: Culprit lesions in 80 patients presenting within 6 h of STEMI onset from the CompariSon of Manual Aspiration with Rheolytic Thrombectomy in patients undergoing primary PCI (SMART) trial were evaluated. Underlying morphology of 64 culprit lesions was identifiable by OCT and included 37 lesions with plaque rupture, 25 lesions without plaque rupture, and 2 lesions with calcified nodules. Patients with plaque rupture tended to be younger (64 +/- 12 versus 70 +/- 10 years, P = 0.08) and less often female (11 versus 40%, P = 0.007) compared with patients without plaque rupture. More thin-cap fibroatheromas were identified (60 versus 20%, P = 0.002); and residual thrombus was greater in the rupture than in the non-rupture group. OCT at 6 months showed more stent malapposition (65 versus 33%, P = 0.04) in the rupture compared with the non-rupture group. CONCLUSION: OCT analysis showed two dominant culprit lesion morphologies in STEMI: (i) lesions with plaque rupture with a large amount of thrombus or (ii) lesions without plaque rupture and a lesser amount of thrombus. PMID- 25911116 TI - Comparison of optical coherence tomography and intravascular ultrasound for evaluation of coronary lipid-rich atherosclerotic plaque progression and regression. AB - AIMS: Compared with intravascular ultrasound (IVUS), optical coherence tomography (OCT) has relative merits and demerits for detecting plaque characteristics. It remains unknown whether the IVUS and OCT evaluations of plaque progression/regression are consistent. We sought to analyse the correlations between IVUS and OCT evaluations of plaques at single time points, and compare temporal changes in the IVUS and OCT data. METHODS AND RESULTS: Eighty-eight lipid-rich plaques from 65 patients with coronary artery disease were analysed with IVUS and OCT at baseline and 12-month follow-up. Fibrous cap thickness on OCT was negatively correlated with total atheroma volume on IVUS (r = -0.28, P = 0.009), but not with percent atheroma volume (P = 0.84). Changes on OCT were not significantly correlated with changes on IVUS. Plaques that showed progression, regression, or no change on IVUS showed no differences in terms of changes in the OCT parameters fibrous cap thickness (P = 0.199), maximum lipid core arc (P = 0.755), mean lipid core arc (P = 0.936), and lipid index (P = 0.91). The incidence of thin-cap fibroatheroma (TCFA) was similar among the above three plaque groups at baseline (P = 0.79) and follow-up (P = 0.609). CONCLUSION: Although fibrous cap thickness on OCT was negatively correlated with plaque size on IVUS at single time points, changes in OCT parameters were not correlated with changes in IVUS measures over time. Lesion progression/regression on IVUS was not associated with changes in OCT parameters (fibrous cap thickness, lipid core arc, lipid index, and TCFA). PMID- 25911117 TI - Ultra-low-dose CT for left atrium and pulmonary veins imaging using new model based iterative reconstruction algorithm. AB - AIMS: To evaluate the feasibility of ultra-low-dose CT for left atrium and pulmonary veins using new model-based iterative reconstruction (MBIR) algorithm. METHODS AND RESULTS: Two hundred patients scheduled for catheter ablation were randomized into two groups: Group 1 (100 patients, Multidetector row CT (MDCT) with MBIR, no ECG triggering, tube voltage and tube current of 100 kV and 60 mA, respectively) and Group 2 [100 patients, MDCT with adaptive statistical iterative reconstruction algorithm (ASIR), no ECG triggering, and kV and mA tailored on patient BMI]. Image quality, CT attenuation, image noise, signal-to-noise ratio (SNR), contrast-to-noise ratio (CNR) of left atrium (LA) and pulmonary veins, and effective dose (ED) were evaluated for each exam and compared between two groups.No significant differences between groups in terms of population characteristics, cardiovascular risk factors, anatomical features, prevalence of persistent atrial fibrillation and image quality score. Statistically significant differences were found between Group 1 and Group 2 in mean attenuation, SNR, and CNR of LA. Significantly, lower values of noise were found in Group 1 versus Group 2. Group 1 showed a significantly lower mean ED in comparison with Group 2 (0.41 +/- 0.04 versus 4.17 +/- 2.7 mSv). CONCLUSION: The CT for LA and pulmonary veins imaging using MBIR is feasible and allows examinations with very low radiation exposure without loss of image quality. PMID- 25911118 TI - Factors That Affect Disease Progression After First Attack of Acute Pancreatitis. AB - BACKGROUND & AIMS: Little is known about recurrence of pancreatitis after an initial episode, and little is known about how the disease progresses or what factors affect progression. We performed a population-based study of patients with acute pancreatitis (AP) to determine their outcomes and associated factors. METHODS: We performed a retrospective study of patients with first-time AP from 2003 through 2012 in a well-defined area of Sweden. Data were collected from medical records on disease etiology, severity (according to the Atlanta classification), recurrence of AP, subsequent chronic pancreatitis, and mortality. Patients were followed up for a median time of 4.6 years, until death or the end of 2013. RESULTS: We identified 1457 patients with first-time AP (48% biliary disease, 17% alcohol-associated, 9.9% severe); 23% of patients had 1 or more recurrences. Risk for recurrence was significantly higher among smokers (hazard ratio [HR], 1.42; 95% confidence interval [CI], 1.03-1.95; P = .03), patients with alcohol-associated AP (HR, 1.58; 95% CI, 1.25-2.23; P < .01), after organ failure (HR, 1.46; 95% CI 1.05-2.03; P = .02), and in patients with systemic complications (HR, 1.88; 95% CI, 1.27-2.79; P < .01) or local complications (HR, 1.66; 95% CI, 1.22-2.27; P < .01). AP of all etiologies progressed to chronic pancreatitis, although alcohol-associated AP progressed most frequently (2.8/100 patient-years). Patients with recurrent AP were at the highest risk for chronic pancreatitis (HR, 6.74; 95% CI, 4.02-11.3; P < .01), followed by alcohol-associated AP (HR, 3.10; 95% CI, 2.05-5.87; P < .01), smoking (HR, 2.26; 95% CI, 1.12-4.58; P = .02), systemic complications (HR, 1.37; 95% CI, 1.06-4.62; P = .03), and peripancreatic necrosis (HR, 2.74; 95% CI, 1.7-4.43; P < .01). In-hospital mortality was 2.8%, and independently associated only with organ failure (odds ratio, 71.17; 95% CI, 21.14-239.60; P < .01). Fifty-three percent of patients who died during disease recurrence had biliary AP; a higher percentage of these patients died upon first recurrence (5.9%) than upon first attack of AP (2%; P = .01). CONCLUSIONS: The severity of first-time AP, smoking, and alcohol abuse are related to recurrence and subsequent chronic pancreatitis. Recurrence increases the risk for progression to chronic pancreatitis. Most patients who die upon disease recurrence have biliary AP. PMID- 25911119 TI - Features and Outcomes of Patients With Ischemia Isolated to the Right Side of the Colon When Accompanied or Followed by Acute Mesenteric Ischemia. AB - BACKGROUND & AIMS: Patients with ischemia isolated to the right side of the colon (IRCI) frequently have poor outcomes. IRCI and acute mesenteric ischemia (AMI) are caused by reductions in blood supply from the superior mesenteric artery and its branches. We investigated a group of patients with IRCI associated with AMI that developed initially or shortly thereafter, and compared outcomes of patients with IRCI and AMI vs those with only IRCI. METHODS: We performed a retrospective study of data collected from 313 consecutive patients with colonic ischemia who were hospitalized at Montefiore Medical Center in New York from 1998 through 2009. Based on colonoscopy, biopsy analyses, and surgery reports, we identified patients with IRCI with concurrent or proximately developing AMI (IRCI+AMI) and those with only IRCI. Demographics, evaluation, disease distribution, and outcome data were compared between groups. RESULTS: Of 313 patients with colonic ischemia, 20.8% had IRCI; of these, 84.6% had only IRCI and 15.4% had IRCI+AMI. Chronic obstructive pulmonary disease was found more frequently in patients with IRCI+AMI (40.0%) than in patients with IRCI alone (12.7%; P < .05). At the time of IRCI diagnosis, mean levels of blood urea nitrogen were significantly higher in patients with IRCI+AMI than with IRCI alone (37.9 +/- 14.4 mEq/L vs 26.4 +/- 18.8 mEq/L; P < .05), as were mean white blood cell counts (20.3 +/- 12.1 vs 12.7 +/- 6.8 * 10(3)/MUL; P < .01). A higher proportion of patients with IRCI+AMI underwent surgery than patients with only IRCI (100.0% vs 43.1%; P = .001), and 30-day mortality was higher among patients with IRCI+AMI (70.0% vs 14.5% for patients with only IRCI; P < .001). CONCLUSIONS: Based on an analysis of 313 patients with colonic ischemia, patients with IRCI+AMI have even more severe disease than those with IRCI alone. Chronic obstructive pulmonary disease was observed more frequently in patients with IRCI+AMI. Patients with IRCI+AMI had increased levels of blood urea nitrogen and/or white blood cell counts. Patients with IRCI should undergo vascular imaging analyses immediately to detect AMI; patients without AMI should be monitored closely for its subsequent development. PMID- 25911120 TI - Concomitant Use of Immunomodulators Affects the Durability of Infliximab Therapy in Children With Crohn's Disease. AB - BACKGROUND & AIMS: It is important to determine the effects of immunomodulators on the ability of children to remain on infliximab therapy for Crohn's disease (durability of therapy), given the potential benefits and risks of concomitant therapy-especially with thiopurines in male patients. We investigated how immunomodulatory treatment affects the durability of infliximab therapy. METHODS: We collected data from the Pediatric Inflammatory Bowel Disease Collaborative Research Group Registry, from January 2002 through August 2014, on 502 children with Crohn's disease who participated in a prospective multicenter study. Data were collected from patients who received at least a 3-dose induction regimen of infliximab, and their concomitant use of immunomodulators: no thiopurine or methotrexate treatment, treatment for 6 months or less during infliximab therapy, or treatment for more than 6 months during infliximab therapy. RESULTS: The probabilities (+/- standard error) that children remained on infliximab therapy for 1 year, 3 years, and 5 years after the treatment began were 0.84 +/- 0.02, 0.69 +/- 0.03, and 0.60 +/- 0.03, respectively. Age, sex, and disease extent or location did not affect the durability of infliximab therapy. Greater length of concomitant use of immunomodulators was associated with increased time of infliximab therapy. The probability that patients with more than 6 months of immunomodulator use remained on infliximab therapy for 5 years was 0.70 +/- 0.04, compared with 0.48 +/- 0.08 for patients who did not receive immunomodulators and 0.55 +/- 0.06 for patients who received immunomodulators for 6 months or less (P < .001). In boys who received immunomodulators for 6 months or more after starting infliximab, the overall durability of infliximab therapy was greater among patients receiving methotrexate than thiopurine (P < .01); the probabilities that they remained on infliximab therapy for 5 years were 0.97 +/- 0.03 vs 0.58 +/- 0.08, respectively. CONCLUSIONS: In children with Crohn's disease, concomitant treatment with an immunomodulator for more than 6 months after starting infliximab therapy increases the chances that patients will remain on infliximab. In boys, methotrexate appears to increase the durability of infliximab therapy compared with thiopurine. PMID- 25911121 TI - Conservative treatment of a mandibular condyle fracture: Comparing intermaxillary fixation with screws or arch bar. A randomised clinical trial. AB - INTRODUCTION: A mandibular condyle fracture can be treated conservatively by intermaxillary fixation (IMF) or by open reposition and internal fixation (ORIF). Many IMF-modalities can be chosen, including IMF-screws (IMFS). This prospective multi-centre randomised clinical trial compared the use of IMFS with the use of arch bars in the treatment of mandibular condyle fractures. RESULTS: The study population consisted of 50 patients (mean age: 31.8 years). Twenty-four (48%) patients were allocated in the IMFS group. Twenty-six (52%) patients were assigned to the arch bars group. In total 188 IMF-screws were used (5-12 screws per patient, mean 7.83 screws per patient). All pain scores were lower in the IMFS group. Three patients developed a malocclusion (IFMS-group: one patient, arch bars-group: two patients). Mean surgical time was significantly shorter in the IMFS group (59 vs. 126 min; p<0.001). There were no needlestick injuries (0%) in the IMFS group and eight (30.7%) in the arch bars group (p=0.003). One IMF screw fractured on insertion (0.53%), one (0.53%) screw was inserted into a root. Six (3.2%) screws loosened spontaneously in four patients. Mucosal disturbances were seen in 22 patients, equally divided over both groups. CONCLUSION: Considering the advantages and the disadvantages of IMFS, and observing the results of this study, the authors conclude that IMFS provide a superior method for IMF. IMFS are safer for the patients and surgeons. PMID- 25911122 TI - Accuracy of fibula reconstruction using patient-specific CAD/CAM reconstruction plates and dental implants: A new modality for functional reconstruction of mandibular defects. AB - BACKGROUND: The purpose of this study was to analyze the accuracy of mandibular reconstruction using patient-specific computer-aided designed and computer-aided manufactured (CAD/CAM) reconstruction plates as a guide to place fibula grafts and dental implants in a one-stage procedure using pre-operative 3D virtual planning. METHODS: Seven consecutive patients were analyzed retrospectively, the 3D accuracy of placement of the fibula grafts and dental implants was compared to the virtual plan. RESULTS: Six out of seven flaps survived for an average follow up time of 9.4 months. The outcome was compared to the virtual plan, superimposed on the mandible. For the fibula segments, the mean deviation (SD) was 3.0 (1.8) mm and the mean angulation (SD) was 4.2 degrees (3.2 degrees ). For the implants, the mean deviation (SD) was 3.3 (1.3) mm and the mean angulation (SD) was 13.0 degrees (6.7 degrees ). The mean (SD) mandibular resection plane deviation was 1.8 (0.9) mm. CONCLUSIONS: A patient-specific reconstruction plate is a valuable tool in the reconstruction of mandibular defects with fibula grafts and dental implants. Implant angulation showed a greater deviation from the virtual plans in patients with a sharp ventral fibula rim, where the guide is removed after pilot drilling of the implants. PMID- 25911123 TI - Folk explanations of behavior: a specialized use of a domain-general mechanism. AB - People typically explain others' behaviors by attributing them to the beliefs and motives of an unobservable mind. Although such attributional inferences are critical for understanding the social world, it is unclear whether they rely on processes distinct from those used to understand the nonsocial world. In the present study, we used functional MRI to identify brain regions associated with making attributions about social and nonsocial situations. Attributions in both domains activated a common set of brain regions, and individual differences in the domain-specific recruitment of one of these regions--the dorsomedial prefrontal cortex (DMPFC)--correlated with attributional accuracy in each domain. Overall, however, the DMPFC showed greater activation for attributions about social than about nonsocial situations, and this selective response to the social domain was greatest in participants who reported the highest levels of social expertise. We conclude that folk explanations of behavior are an expert use of a domain-general cognitive ability. PMID- 25911124 TI - Money earlier or later? Simple heuristics explain intertemporal choices better than delay discounting does. AB - Heuristic models have been proposed for many domains involving choice. We conducted an out-of-sample, cross-validated comparison of heuristic models of intertemporal choice (which can account for many of the known intertemporal choice anomalies) and discounting models. Heuristic models outperformed traditional utility-discounting models, including models of exponential and hyperbolic discounting. The best-performing models predicted choices by using a weighted average of absolute differences and relative percentage differences of the attributes of the goods in a choice set. We concluded that heuristic models explain time-money trade-off choices in experiments better than do utility discounting models. PMID- 25911125 TI - Physical experience enhances science learning. AB - Three laboratory experiments involving students' behavior and brain imaging and one randomized field experiment in a college physics class explored the importance of physical experience in science learning. We reasoned that students' understanding of science concepts such as torque and angular momentum is aided by activation of sensorimotor brain systems that add kinetic detail and meaning to students' thinking. We tested whether physical experience with angular momentum increases involvement of sensorimotor brain systems during students' subsequent reasoning and whether this involvement aids their understanding. The physical experience, a brief exposure to forces associated with angular momentum, significantly improved quiz scores. Moreover, improved performance was explained by activation of sensorimotor brain regions when students later reasoned about angular momentum. This finding specifies a mechanism underlying the value of physical experience in science education and leads the way for classroom practices in which experience with the physical world is an integral part of learning. PMID- 25911127 TI - ERP evidence for the influence of scene context on the recognition of ambiguous and unambiguous objects. AB - We are used to seeing objects in specific settings, and in association with other related objects. This contextual information allows for fast and efficient object recognition and influences brain-related processes. The influence of scene context has been studied using event-related potentials (ERPs) in order to further our understanding of the underlying brain mechanisms. Current ERP studies have focused on effects related to the incongruity between unambiguous objects and their scenes, rather than the specific influence of a congruent scene. The present study sought to examine ERPs associated with the beneficial influence of scene context on object recognition. This influence was examined using ambiguous objects that required a congruent scene in order to be recognized, as well as unambiguous objects, to determine whether scene processing occurs even when it is unnecessary for recognizing the object. Twenty healthy subjects were instructed to indicate whether they recognized, had a vague idea, or did not recognize target objects that appeared within congruent and neutral scenes. ERPs from 250 to 1000 ms, including the N300 and N400, were more positive at anterior sites and more negative at posterior sites, when objects appeared in congruent scenes as opposed to when they appeared in neutral scenes, with a larger effect seen for ambiguous objects. Upon further examination, the results showed that the ERPs to ambiguous objects became similar to those of unambiguous objects when they appeared in congruent contexts. These findings indicated that a congruent context exerted its influence by reducing the ambiguity of objects. PMID- 25911126 TI - Cardiac resynchronization therapy induces adaptive metabolic transitions in the metabolomic profile of heart failure. AB - BACKGROUND: Heart failure (HF) is associated with ventricular dyssynchrony and energetic inefficiency, which can be alleviated by cardiac resynchronization therapy (CRT). The aim of this study was to determine the metabolomic signature in HF and its prognostic value regarding the response to CRT. METHODS AND RESULTS: This prospective study consisted of 24 patients undergoing CRT for advanced HF and 10 control patients who underwent catheter ablation for supraventricular arrhythmia but not CRT. Blood samples were collected before and 3 months after CRT. Metabolomic profiling of plasma samples was performed with the use of gas chromatography-mass spectrometry and nuclear magnetic resonance. The plasma metabolomic profile was altered in the HF patients, with a distinct panel of metabolites, including Krebs cycle and lipid, amino acid, and nucleotide metabolism. CRT improved the metabolomic profile. The succinate-glutamate ratio, an index of Krebs cycle activity, improved from 0.58 +/- 0.13 to 2.84 +/- 0.60 (P < .05). The glucose-palmitate ratio, an indicator of the balance between glycolytic and fatty acid metabolism, increased from 0.96 +/- 0.05 to 1.54 +/- 0.09 (P < .01). Compared with nonresponders to CRT, responders had a distinct baseline plasma metabolomic profile, including higher isoleucine, phenylalanine, leucine, glucose, and valine levels and lower glutamate levels at baseline (P < .05). CONCLUSIONS: CRT improves the plasma metabolomic profile of HF patients, indicating harmonization of myocardial energy substrate metabolism. CRT responders may have a favorable metabolomic profile as a potential biomarker for predicting CRT outcome. PMID- 25911128 TI - Testing the inter-hemispheric competition account of visual extinction with combined TMS/fMRI. AB - Theoretical models of visual neglect and extinction entail claims about the normal functioning of attention and parietal cortex in the healthy brain: (1) 'pseudoneglect', a commonly observed attentional bias towards left space, reflects the greater dominance of parietal cortex activity of the right versus left hemisphere; (2) the capacity to distribute attention bilaterally depends causally on the relative balance of parietal activity between the hemispheres; (3) disruption of the dominant right parietal cortex shifts this inter hemispheric balance leftward, causing a rightward shift in attentional bias. We tested these claims using low-frequency offline transcranial magnetic stimulation (TMS) to transiently inhibit activity in the right angular gyrus/intra-parietal sulcus, followed by a visual detection task to assess changes in attentional bias, and functional magnetic resonance imaging (fMRI) to test for the predicted leftward shift in brain activity. The task required participants to covertly monitor both hemifields to detect and report the location of upcoming transient visual targets that appeared on the left, right or bilaterally. In the behavioural experiment, participants exhibited a leftward attentional bias ('pseudoneglect') at baseline, which was abolished by TMS. In the fMRI experiment, participants activated an expected network of visual, parietal and frontal cortex bilaterally during the period of covert bilateral attention. TMS shifted the relative hemispheric balance of parietal activity from right to left. The consistent direction of TMS-induced behavioural and functional change indicates a causal role for parietal inter-hemispheric balance in distributing visual attention across space. PMID- 25911129 TI - Malignancy of bladder cancer cells is enhanced by tumor-associated fibroblasts through a multifaceted cytokine-chemokine loop. AB - The microenvironment of tumor cells is critically involved in tumor development and progression. Tumor-associated fibroblasts (TAFs) represent a major constituent of the tumor stroma. Tumor cells are operative in the activation of TAFs, whereas TAFs in turn contribute to tumor cell malignancy. This report describes mechanisms of communication between fibroblasts and urinary bladder cancer (UBC) cells. Migration of bladder cancer cell lines RT112 and Cal-29, representing two different grades of dedifferentiation, was enhanced by cocultivation with TAFs. Conditioned medium from tumor cells induced the release of interleukin (IL)-8, hepatocyte growth factor (HGF), matrix metalloproteinase 2, granulocyte macrophage colony-stimulating factor, and monocyte chemotactic protein (MCP)-1 by TAFs. Tumor cell-derived IL-1alpha was identified as a major mediator of these stimulatory effects. Fibroblasts, on the other hand, exerted a migration and invasion stimulating influence on UBC cells. MCP-1 and HGF were shown to promote cell migration of both bladder cancer cell lines. PMID- 25911130 TI - The utility of a classificatory decision tree approach to assist clinical differentiation of melancholic and non-melancholic depression. AB - BACKGROUND: Studies suggest that differentiating melancholic from non-melancholic depressive disorders is advanced by use of illness course as well as symptom variables but, in practice, potentially differentiating variables are generally positioned as having equal value. Judging that differentiating features are more likely to vary in their signal intensity, we sought to determine the number of features required to effect differentiation and their hierarchical order. METHODS: The 24-item clinician-rated Sydney Melancholia Prototype Index (SMPI-CR) was completed for 364 unipolar depressed patients. The sample was divided into two cohorts according to the recruitment period. An RPART classification tree analysis identified the most discriminating SMPI items in the development sample of 197 patients, and examined the sensitivity and specificity of the diagnostic decisions, then sought to replicate findings in a validation sample of 169 patients. RESULTS: Independent analyses of putative SMPI items identified only seven items as required to discriminate those with clinically-diagnosed melancholic or non-melancholic depression when the conditions were examined separately. An RPART analysis considering differentiation of melancholic and non melancholic depression in the total samples retained five of those items in the classification tree, three of which were non-symptom items, and with 92% sensitivity and 80% specificity in the development sample. This reduced item set showed 93% sensitivity and 82% specificity in the validation sample. LIMITATIONS: Our clinical judgment of melancholic or non-melancholic depression may not correspond with the clinical logic employed by other clinicians. CONCLUSION: Only five SMPI items were required to derive a succinct and efficient decision tree, comprising high sensitivity and specificity in differentiating melancholic and non-melancholic depression. Current study findings provide an empirical model that could enrich clinicians' approach to differentiating melancholic and non melancholic depression. PMID- 25911131 TI - Very low birth-weight as a risk factor for postpartum depression four to six weeks postbirth in mothers and fathers: Cross-sectional results from a controlled multicentre cohort study. AB - BACKGROUND: Preterm birth and survival rates of very low birth-weight (VLBW: <1.500g) infants have increased. Although new parents are frequently affected by depressive symptoms, little is known about prevalence, risk, and predictors of parental postpartum depression (PPD) following VLBW birth. Furthermore, most studies assessing PPD in parents of preterm children relied on self-report only. METHODS: As part of the HaFEn cohort-study, data from the index groups of parents with VLBW infants and the control group of parents with term infants were cross sectionally analysed. Families were recruited at the three largest centres of perinatal medical care in Hamburg, Germany. PPD was evaluated one month postpartum using standardized questionnaires and clinical interviews. Socioeconomic status, social support, risks during pregnancy, and psychiatric lifetime diagnoses were also assessed. A multiple random coefficient model was used to examine predictors of PPD in both parents simultaneously. RESULTS: 230 mothers and 173 fathers were included. Depending on the measure, the risk of being postnatally depressed was 4 to 18 times higher in mothers and 3 to 9 times higher in fathers from the index group. The most relevant risk factor for PPD was the birth of a VLBW infant, followed by female sex, lifetime psychiatric disorder, and low social support. LIMITATIONS: Results presented here, are based on cross sectional data. Therefore no temporal relationships can be established. CONCLUSIONS: Our findings highlight the importance of early screening for PPD in both parents of VLBW infants. Factors contributing to developing depression should also be considered in neonatal care. PMID- 25911132 TI - Dose equivalents of antidepressants: Evidence-based recommendations from randomized controlled trials. AB - BACKGROUND: Dose equivalence of antidepressants is critically important for clinical practice and for research. There are several methods to define and calculate dose equivalence but for antidepressants, only daily defined dose and consensus methods have been applied to date. The purpose of the present study is to examine dose equivalence of antidepressants by a less arbitrary and more systematic method. METHODS: We used data from all randomized, double-blind, flexible-dose trials comparing fluoxetine or paroxetine as standard drugs with any other active antidepressants as monotherapy in the acute phase treatment of unipolar depression. We calculated the ratio of the mean doses for each study and weighted it by the total sample size to find the weighted mean ratio for each drug, which was then used to define the drug's dosage equivalent to fluoxetine 40mg/d. RESULTS: We included 83 studies (14 131 participants). In the primary analysis, fluoxetine 40mg/day was equivalent to paroxetine dosage of 34.0mg/day, agomelatine 53.2mg/day, amitriptyline, 122.3mg/day, bupropion 348.5mg/day, clomipramine 116.1mg/day, desipramine 196.3mg/day, dothiepin 154.8mg/day, doxepin 140.1mg/day, escitalopram 18.0mg/day, fluvoxamine 143.3mg/day, imipramine 137.2mg/day, lofepramine 250.2mg/day, maprotiline 118.0mg/day, mianserin, 101.1mg/day, mirtazapine 50.9mg/day, moclobemide 575.2mg/day, nefazodone 535.2mg/day, nortriptyline 100.9mg/day, reboxetine 11.5mg/day, sertraline 98.5mg/day, trazodone 401.4mg/day, and venlafaxine 149.4mg/day. Sensitivity analyses corroborated the results except for doxepin. LIMITATIONS: The number of studies for some drugs was small. The current method assumes dose response relationship of antidepressants. CONCLUSIONS: Our findings can be useful for clinicians when they switch antidepressants and for researchers when they compare various antidepressants in their research. PMID- 25911133 TI - Obsessional Disorders in al-Balkhi's 9th century treatise: Sustenance of the Body and Soul. AB - Some argue that the earliest case of Obsessive-Compulsive Disorder (OCD) was reported by Robert Burton in his compendium The Anatomy of Melancholy (1621) and that only in the 19th century did modern concepts of OCD evolve, differentiating it from other types of mental illness. In this paper, we aim to reveal an even earlier presentation of the malady we now call OCD based on the 9th century work, Sustenance of the Body and Soul, written by Abu Zayd al-Balkhi during the Islamic Golden Era. Discovery of this manuscript reveals that Abu Zayd al-Balkhi should be credited with differentiating OCD from other forms of mental illnesses nearly a millennium earlier than is currently claimed by anthologies documenting the history of mental illness. Particular attention is paid to al-Balkhi's classifications, symptom descriptions, predisposing factors, and the treatment modalities for obsessional disorders. Analysis of this manuscript in light of the DSM-5 and modern scientific discoveries reveals transcultural diagnostic consistency of OCD across many centuries. Theoretical and clinical implications of these findings are also discussed. PMID- 25911134 TI - Maternal and fetal outcomes in pregnant women with acute promyelocytic leukemia. AB - The management of pregnant women with acute promyelocytic leukemia (APL) is a challenge with limited evidence-based information available. We are reporting a series of 14 consecutive pregnant women with APL who were registered in the PETHEMA Data Centre between 1996 and 2012. APL was diagnosed during early pregnancy in five women, late pregnancy in seven, and two additional patients after delivery in an extremely poor clinical condition (pulmonary and cerebral hemorrhage). Eleven of the 12 patients eligible for induction therapy with all trans retinoic acid and idarubicin achieved complete remission (CR 92 %) and are still in the first CR. All early pregnancies ended in abortion (four induced and one spontaneous), with four of them achieving CR. Eight of nine women in late pregnancy delivered a healthy infant (six cesarean section and two vaginal delivery). All eight babies developed normally. Our results confirm a high cure rate for pregnant women with APL who received all-trans retinoic acid and idarubicin for induction therapy, and an excellent outcome for babies when the disease is diagnosed during late pregnancy. PMID- 25911135 TI - Erratum to: A novel ELISA for diagnosis of Glanzmann's thrombasthenia and the heterozygote carriers. AB - Erratum to: Annals of Hematology 91(6): 917-921. DOI 10.1007/s00277-011-1390-1 . The authors inadvertently omitted 2 fellow authors from the author list: Dr. Diego Butera should be listed as the fourth author. His affiliation is Lowy Cancer Research Centre and Prince of Wales Clinical School, University of New South Wales, Sydney, NSW, Australia. His contributions are as follows: Designed, synthesized and produced EcAPv. He has no competing interests to declare. Dr. Geraldo S. Magalhaes should be listed as the fifth author. His affiliation is Laboratory of Immunopathology, Butantan Institute, Sao Paulo, SP, Brazil. His contributions are as follows: Produced more EcAPv when requested in October 2009. He has no competing interests to declare. PMID- 25911136 TI - Characteristics and catheter ablation of focal atrial tachycardia originating from the interatrial septum. AB - BACKGROUND: Ablation of focal atrial tachycardia (AT) originating from the interatrial septum (IAS) is challenging because of its complex anatomy. METHODS: We studied the electrocardiographic and electrophysiologic characteristics of focal, septal AT in seven patients who underwent successful ablation. RESULTS: The site of successful ablation was at the site of earliest activation on the right side of the IAS in three patients and on the left side in four patients, >1cm away from the centre of the fossa ovalis in the septum secundum. A negative or +/- versus a positive or -/+ P wave in lead V1 during AT accurately predicted a right- versus left-sided origin of the AT, respectively. In the four left septal AT cases, right atrial activation mapping opposite the site of successful ablation revealed the presence of a small, low-frequency potential followed by a larger, high-frequency potential. In contrast, a high-frequency potential was not preceded by a low-frequency potential in the three right septal AT cases. CONCLUSIONS: Septal AT may originate from either side of the septum secundum. The P wave polarity in lead V1 accurately predicted the side of the IAS that the AT originated from. Left septal AT is characterised by the recording of double potentials reflecting far-field activation of the left-sided IAS, followed by near-field activation of the right-sided IAS, when recording from its right side, opposite the AT origin. These observations are particularly relevant when mapping an apparent right septal AT. PMID- 25911137 TI - Different needs or treated differently? Understanding ethnic inequalities in coronary revascularisation rates. AB - BACKGROUND: Several studies have reported major ethnic inequalities in cardiac revascularisation. This paper attempts to explain why in New Zealand, Maori and Pacific patients may be less likely to receive cardiac revascularisation interventions than Europeans. METHODS: Angiograms of 55 Maori, 45 Pacific and 100 age-sex matched European patients with ST elevation myocardial infarction were reviewed by two cardiologists blinded to the patients' ethnicity to determine ethnic differences in actual and recommended revascularisation likelihood. RESULTS: Maori and Pacific patients were 18% (95% C.I. 6%-29%) less likely to receive cardiac revascularisation procedures compared to European patients. If intervention had been based on the recommendation from blinded angiogram review they would have been 14% (2%-24%) less likely to receive revascularisation. Maori and Pacific were significantly more likely to be recommended for CABG (RR=2.9; C.I. 1.4-5.8) and less likely for PCI (RR=0.60; 0.48-0.75). Maori and Pacific were at significantly higher risk of under-treatment overall (RR=5.0; 1.1-22.8) and for CABG (RR=8.0; 1.0-64.0), but not for PCI (RR=2.0; 0.2-22.1). However these relative risks became non-significant when cases not eligible for surgery due to comorbidities were excluded. CONCLUSIONS: Maori and especially Pacific STEMI patients present with a pattern of ischaemic heart disease that is less amenable to PCI, even after allowing for differences in the number of diseased vessels and diabetes prevalence. The lower likelihood of Maori and Pacific patients receiving recommended CABG is largely explained by higher comorbidity prevalence. PMID- 25911138 TI - Computed Tomography in Prosthetic Aortic Graft Infections. PMID- 25911139 TI - Response to Letter to the Editor: Essential Service Standards for Equitable National Cardiovascular Care for Aboriginal and Torres Strait Islander people. PMID- 25911140 TI - Accuracy of transthoracic ultrasound for the prediction of chest wall infiltration by lung cancer and of lung infiltration by chest wall tumours. AB - BACKGROUND: We wanted to determine the accuracy of transthoracic ultrasound in the prediction of chest wall infiltration by lung cancer or lung infiltration by chest wall tumours. METHODS: Patients having preoperative CT-scan suspect for lung/chest wall infiltration were prospectively enrolled. Inclusion criteria for lung cancer were: obliteration of extrapleural fat, obtuse angle between tumour and chest wall, associated pleural thickening. The criteria for chest wall tumours were: rib destruction and intercostal muscles infiltration with extrapleural fat obliteration and intrathoracic extension. Lung cancer patients with evident chest wall infiltration were excluded. Transthoracic ultrasound was preoperatively performed. Predictions were checked during surgical intervention. RESULTS: Twenty-three patients were preoperatively examined. Sensitivity, specificity, positive and negative predictive values of transthoracic ultrasound were 88.89%, 100%, 100% and 93.3%, respectively. Youden index was used to determine the best cut-off for tumour size in predicting lung/chest wall infiltration: 4.5cm. At univariate logistic regression, tumour size (<4.5 vs >= 4.5cm) (p=0.0072) was significantly associated with infiltration. CONCLUSIONS: Transthoracic ultrasound is a useful instrument for predicting neoplastic lung or chest wall infiltration in cases of suspect CT-scans and could be used as part of the preoperative workup to assess tumour staging and to plan the best surgical approach. PMID- 25911141 TI - Adenosine-Sensitive Ventricular Tachycardia arising from the Middle Cardiac Vein. PMID- 25911142 TI - Heart involvement in children and adults with cystic fibrosis: correlation with pulmonary indexes and inflammation markers. AB - BACKGROUND: Cardiovascular involvement in Cystic Fibrosis (CF) is a not rare condition, although the prevalence of subclinical pulmonary hypertension (PH) and cardiac dysfunction is not known in the early stages of CF progression. The aim of our study was to assess cardiac involvement in children and adults affected by cystic fibrosis compared with healthy subjects of same age using echocardiography. METHODS: Fifty-five patients, 25 adults and 30 children completed the study. We assessed FEV1 (Forced Expiratory Volume in one second), and carried out colour Doppler-echocardiography evaluating ejection fraction (EF) measurement of left ventricle, tricuspid annular plane systolic excursion (TAPSE) of right ventricle and pulmonary artery pressure (PAP). We compared the auxological, respiratory and cardiologic data with those of 16 adults and 34 children of the same age. RESULTS: We discovered significantly different values of PAP between patients and controls in both children (p = 0.0001, r=- 0.62) and adults (p=0.0001, r=- 0.63), whereas the EF and TAPSE showed significantly different values in only adults (p=0.0023 and p=0.0194 respectively). We found in both children and adults with CF an inverse correlation between PAP and FEV1 (p=0.000, p=0.001), Erythrocyte Sedimentation Rate (ESR) and FEV 1 (p=0.015, r=- 0.43; p=0.009, r=- 0.51), and highly sensitive C-reactive protein (hs-CRP) and FEV 1 (p=0.007, r=- 0.48; p=0.001, r=- 0.60). In adults we also detected direct correlation between PAP and hs-CRP (p=0.008, r=0.51) and PAP and ESR (p=0.009, r=0.51). CONCLUSIONS: In paediatric-aged CF patients there are already early signs of potential heart impairment, represented by an increase of pulmonary blood pressure, and in adult age the systolic function of right ventricle may be impaired. We hypothesise that such cardiac impairments may gradually arise due to preceding chronic inflammation related to prior degeneration of lung function and thus it is very important to keep patients clinically stable and address chronic inflammation as early as possible in the progression of CF. PMID- 25911143 TI - Ebstein's anomaly in those surviving to adult life - a single centre experience. AB - BACKGROUND: Ebstein's anomaly (EA) occurs in about one to five per 200 000 live births. Long-term follow-up data of adults with EA is scarce due to the relatively low frequency of the disease and the variation of its anatomic and haemodynamic severity. METHODS: Since 1995, in our adult congenital heart disease (ACHD) centre, we have practised a uniform approach to management of adults with EA, with surgery reserved for those with refractory arrhythmia (failed medical and/or catheter-based treatment) or worsening symptoms of breathlessness. A retrospective review of medical records of all such patients with EA and normal cardiac connections was performed. RESULTS: Fifty-one EA patients (17 males) were identified. Mean age at diagnosis was 21+/-21 years and mean follow-up time at our centre was 21+/-14 years. During this time, 18 patients (35%) had documented supraventricular arrhythmia. Sixteen patients (30%) underwent ablation therapy with long-term relief from arrhythmia in nine (56%). Nine patients (18%) underwent tricuspid valve (TV) surgery (four repair and five replacement), with seven patients having undergone a tricuspid valve surgery prior to referral to our unit. Three patients died, one of cardiogenic shock after redo surgery (58 years), one of progressive heart failure (45 years) and one with malignancy. Overall survival was 100% to age 40 years, 95% to age 50 years and 81% to age 60 years. CONCLUSIONS: Ebstein's Anomaly in adulthood often has severe morphological abnormalities but is compatible with good medium-term survival, with a generally symptom driven approach to the indications for interventions. PMID- 25911144 TI - Supermoon-like Thrombus at the Mitral Valve: Struggle between the Bad and the Worse. PMID- 25911145 TI - Should We Recommend Exercise after the Fontan Procedure? AB - BACKGROUND: The Fontan procedure, the last of a series of operations performed in patients with congenital heart defects, offers improved exercise capacity compared to baseline function but is still reduced compared to healthy peers. Exercise training may improve exercise tolerance but there is no consensus on the safety of this practice or the optimal training regimen. We performed a systematic literature review on the effects of exercise training in patients with a Fontan circulation. METHODS: Medline and Embase databases were systematically searched for articles regarding Fontan Procedure and cardiac rehabilitation. RESULTS: A total of 23 articles met all inclusion criteria; in total, 201 Fontan subjects were included. Characteristics of the exercise training programs varied significantly. There were no adverse effects related to training programs reported in the literature. Most studies reported benefit across various exercise parameters related to exercise tolerance. CONCLUSIONS: Exercise training is safe and beneficial in patients with a Fontan circulation. Exercise training should become a standard of care within this population. Physiological adaptation following exercise training needs to be investigated more extensively. PMID- 25911146 TI - Percutaneous Coronary Intervention of an Anomalous Left Main Coronary Artery Arising from the Right Sinus of Valsalva. AB - Anomalous origination of a coronary artery from the opposite sinus of Valsalva is an uncommon congenital anomaly. Intervention for concurrent coronary artery disease is challenging due to the location of the ostia, the takeoff of the vessel as well as the course of the artery in question. It is also important, where possible, to exclude a "malignant" course as the most common adverse outcome from this anomaly is that of sudden cardiac death. Here we present a case of percutaneous coronary intervention in a patient with anomalous left main origination from the right coronary sinus of Valsalva and a brief discussion on the subject. PMID- 25911147 TI - An attempt to bridge muscle architecture dynamics and its instantaneous rate of force development using ultrasonography. AB - Muscle force output is an essential index in rehabilitation assessment or physical exams, and could provide considerable insights for various applications such as load monitoring and muscle assessment in sports science or rehabilitation therapy. Besides direct measurement of force output using a dynamometer, electromyography has earlier been used in several studies to quantify muscle force as an indirect means. However, its spatial resolution is easily compromised as a summation of the action potentials from neighboring motor units of electrode site. To explore an alternative method to indirectly estimate the muscle force output, and with better muscle specificity, we started with an investigation on the relationship between architecture dynamics and force output of triceps surae. The muscular architecture dynamics is captured in ultrasonography sequences and estimated using a previously reported motion estimation method. Then an indicator named as the dorsoventrally averaged motion profile (DAMP) is employed. The performance of force output is represented by an instantaneous version of the rate of force development (RFD), namely I-RFD. From experimental results on ten normal subjects, there were significant correlations between the I-RFD and DAMP for triceps surae, both normalized between 0 and 1, with the sum of squares error at 0.0516+/-0.0224, R-square at 0.7929+/-0.0931 and root mean squared error at 0.0159+/-0.0033. The statistical significance results were less than 0.01. The present study suggested that muscle architecture dynamics extracted from ultrasonography during contraction is well correlated to the I-RFD and it can be a promising option for indirect estimation of muscle force output. PMID- 25911148 TI - Analysis of second-harmonic generation by primary ultrasonic guided wave propagation in a piezoelectric plate. AB - The effect of second-harmonic generation (SHG) by primary ultrasonic guided wave propagation is analyzed, where the nonlinear elastic, piezoelectric, and dielectric properties of the piezoelectric plate material are considered simultaneously. The formal solution of the corresponding second-harmonic displacement field is presented. Theoretical and numerical investigations clearly show that the SHG effect of primary guided wave propagation is highly sensitive to the electrical boundary conditions of the piezoelectric plate. The results obtained may provide a means through which the SHG efficiency of ultrasonic guided wave propagation can effectively be regulated by changing the electrical boundary conditions of the piezoelectric plate. PMID- 25911149 TI - Trial registration is required for any human intervention study. PMID- 25911151 TI - Phenotype, genotype, and antibiotic susceptibility of Swedish and Thai oral isolates of Staphylococcus aureus. AB - OBJECTIVE: The present study investigated phenotypes, virulence genotypes, and antibiotic susceptibility of oral Staphylococcus aureus strains in order to get more information on whether oral infections with this bacterium are associated with certain subtypes or related to an over-growth of the S. aureus variants normally found in the oral cavity of healthy carriers. MATERIALS AND METHODS: A total number of 157 S. aureus strains were investigated. Sixty-two strains were isolated from Swedish adults with oral infections, 25 strains were from saliva of healthy Swedish dental students, and 45 strains were from tongue scrapings of HIV positive subjects in Thailand, and 25 Thai strains from non-HIV controls. The isolates were tested for coagulase, nitrate, arginine, and hemolysin, and for the presence of the virulence genes: hlg, clfA, can, sdrC, sdrD, sdrE, map/eap (adhesins) and sea, seb, sec, tst, eta, etb, pvl (toxins). MIC90 and MIC50 were determined by E-test against penicillin V, oxacillin, amoxicillin, clindamycin, vancomycin, fusidic acid, and cefoxitin. RESULTS: While the hemolytic phenotype was significantly (p<0.001) more common among the Thai strains compared to Swedish strains, the virulence genes were found in a similar frequency in the S. aureus strains isolated from all four subject groups. The Panton-Valentine leukocidin (PVL) genotype was found in 73-100% of the strains. More than 10% of the strains from Swedish oral infections and from Thai HIV-positives showed low antibiotic susceptibility, most commonly for clindamycin. Only three methicillin resistant S. aureus (MRSA) strains were identified, two from oral infections and one from a Thai HIV patient. CONCLUSIONS: S. aureus is occasionally occurring in the oral cavity in both health and disease in Sweden and Thailand. It is therefore most likely that S. aureus in opportunistic oral infections originate from the oral microbiota. S. aureus should be considered in case of oral infections and complaints and the antibiotic susceptibility (including MRSA) should regularly be checked. The frequent presence of S. aureus, although in low numbers among students and staff, emphasizes the importance of standard infection control precautions and of using diagnostic test in the dental clinic. PMID- 25911150 TI - Survivorship care plan preferences of cancer survivors and health care providers: a systematic review and quality appraisal of the evidence. AB - PURPOSE: The purpose of this systematic review was to describe and examine the current use of treatment summaries and survivorship care plans (TSs/SCPs) for cancer survivors, as well as to summarize and critically assess relevant literature regarding their preferences and usefulness. There is a knowledge gap regarding the preferences of stakeholders as to what is useful on a treatment summary or survivorship care plan. METHODS: A systematic review of eligible manuscripts was conducted using preferred reporting items for systematic reviews and meta-analyses (PRISMA) guidelines. Relevant studies were identified via PubMed, CINAHL Plus, and the Cochrane Library from 2005 through 2013. Eligible studies were critically appraised with qualitative and quantitative appraisal tools. RESULTS: There were 29 studies included in this review; 19 were quantitative. Survivors and primary care physicians preferred a printable format delivered 0 to 6 months posttreatment and highlighting signs and symptoms of recurrence, late, and long-term effects, and recommendations for healthy living. Oncology providers supported the concept of treatment summary and survivorship care plan but reported significant barriers to their provision. No studies incorporated caregiver perspectives of treatment summary and survivorship care plan. CONCLUSION: This systematic review did not reveal conclusive evidence regarding the needs of survivors or providers regarding treatment summaries and survivorship care plans. A lack of rigorous studies contributed to this. IMPLICATIONS FOR CANCER SURVIVORS: Treatment summaries and survivorship care plans are useful for cancer survivors; however, future rigorous studies should be conducted to identify and prioritize the preferences of survivors regarding these. PMID- 25911152 TI - PEIMAN 1.0: Post-translational modification Enrichment, Integration and Matching ANalysis. AB - Conventional proteomics has discovered a wide gap between protein sequences and biological functions. The third generation of proteomics was provoked to bridge this gap. Targeted and untargeted post-translational modification (PTM) studies are the most important parts of today's proteomics. Considering the expensive and time-consuming nature of experimental methods, computational methods are developed to study, analyze, predict, count and compute the PTM annotations on proteins. The enrichment analysis softwares are among the common computational biology and bioinformatic software packages. The focus of such softwares is to find the probability of occurrence of the desired biological features in any arbitrary list of genes/proteins. We introduce Post-translational modification Enrichment Integration and Matching Analysis (PEIMAN) software to explore more probable and enriched PTMs on proteins. Here, we also represent the statistics of detected PTM terms used in enrichment analysis in PEIMAN software based on the latest released version of UniProtKB/Swiss-Prot. These results, in addition to giving insight to any given list of proteins, could be useful to design targeted PTM studies for identification and characterization of special chemical groups. Database URL: http://bs.ipm.ir/softwares/PEIMAN/ PMID- 25911153 TI - ProtoBug: functional families from the complete proteomes of insects. AB - ProtoBug (http://www.protobug.cs.huji.ac.il) is a database and resource of protein families in Arthropod genomes. ProtoBug platform presents the relatedness of complete proteomes from 17 insects as well as a proteome of the crustacean, Daphnia pulex. The represented proteomes from insects include louse, bee, beetle, ants, flies and mosquitoes. Based on an unsupervised clustering method, protein sequences were clustered into a hierarchical tree, called ProtoBug. ProtoBug covers about 300,000 sequences that are partitioned to families. At the default setting, all sequences are partitioned to ~20,000 families (excluding singletons). From the species perspective, each of the 18 analysed proteomes is composed of 5000-8000 families. In the regime of the advanced operational mode, the ProtoBug provides rich navigation capabilities for touring the hierarchy of the families at any selected resolution. A proteome viewer shows the composition of sequences from any of the 18 analysed proteomes. Using functional annotation from an expert system (Pfam) we assigned domains, families and repeats by 4400 keywords that cover 73% of the sequences. A strict inference protocol is applied for expanding the functional knowledge. Consequently, secured annotations were associated with 81% of the proteins, and with 70% of the families (>=10 proteins each). ProtoBug is a database and webtool with rich visualization and navigation tools. The properties of each family in relation to other families in the ProtoBug tree, and in view of the taxonomy composition are reported. Furthermore, the user can paste its own sequences to find relatedness to any of the ProtoBug families. The database and the navigation tools are the basis for functional discoveries that span 350 million years of evolution of Arthropods. ProtoBug is available with no restriction at: www.protobug.cs.huji.ac.il. Database URL: www.protobug.cs.huji.ac.il PMID- 25911154 TI - Working memory capacity and the scope and control of attention. AB - Complex span and visual arrays are two common measures of working memory capacity that are respectively treated as measures of attention control and storage capacity. A recent analysis of these tasks concluded that (1) complex span performance has a relatively stronger relationship to fluid intelligence and (2) this is due to the requirement that people engage control processes while performing this task. The present study examines the validity of these conclusions by examining two large data sets that include a more diverse set of visual arrays tasks and several measures of attention control. We conclude that complex span and visual arrays account for similar amounts of variance in fluid intelligence. The disparity relative to the earlier analysis is attributed to the present study involving a more complete measure of the latent ability underlying the performance of visual arrays. Moreover, we find that both types of working memory task have strong relationships to attention control. This indicates that the ability to engage attention in a controlled manner is a critical aspect of working memory capacity, regardless of the type of task that is used to measure this construct. PMID- 25911155 TI - Tonal priming is resistant to changes in pitch height. AB - Research on tonal priming has consistently shown that tonally expected events are processed more efficiently and has confirmed that the locus of the effect is cognitive rather than sensory. However, it is also important to investigate the role of pitch height, because models of tonal priming collapse across octaves, yet it is possible that pitch height may modulate the effectiveness of tonal priming. We systematically tested this issue by varying the pitch heights of a related (tonic) or a less-related (subdominant) target chord following a tonal context. Musically untrained participants (N = 30) made speeded consonant/dissonant judgments of the final chord of an eight-chord sequence. The effects of tonal priming emerged in accuracy and reaction time measures for all octaves, except for a ceiling effect on accuracy in the matching (original pitch height) condition. In a second experiment, we increased the shift to two octaves and compressed the chords to eliminate overlap between the target and context chords; again, tonal priming emerged. These findings have implications for the behavioral study of tonal priming and support the assumption of octave equivalence in computational models. PMID- 25911156 TI - Sleep after practice reduces the attentional blink. AB - The attentional blink (AB) is an impairment in detecting the second of two targets that appear in close temporal succession. We investigated the effect of practice and a nap on the magnitude of the AB deficit. We found evidence that sleep boosts practice-dependent reduction of the AB. Participants reported two target letters embedded in a rapid serial visual presentation display. After two morning sessions, half the participants took a polysomnographically recorded nap, while the others remained awake. Comparing two afternoon sessions to the two morning sessions, we observed a decreased AB only within the group who napped. The improvement was due to increased efficacy of the attentional selection of T2 (the probability of reporting a T2-relevant item). There was no change in selection's latency or temporal precision. The magnitude of improvement was positively associated with the duration of N2 sleep and the number of N2 sleep spindles. Our results suggest that sleep, particularly N2 sleep and sleep spindles, improves attentional selection in time. PMID- 25911157 TI - Extraction optimization and nanoencapsulation of jujube pulp and seed for enhancing antioxidant activity. AB - The aim of this study was to optimize extraction conditions for jujube pulp and seed in order to obtain maximum active ingredient yield and antioxidant activity, as well as to prepare chitosan nanoparticles loaded with jujube pulp and seed extracts for enhancing stability. The extraction conditions, i.e. temperature, time, and ethanol concentration, were optimized at the following respective values: 61.2 degrees C, 38 h, and 60.4% for pulp, and 58 degrees C, 34 h, and 59.2% for seed. The jujube nanoparticle size significantly increased with a higher chitosan/sodium tripolyphosphate ratio and extract concentration. Entrapment efficiency was greater than 80% regardless of preparation conditions. The stabilities of jujube pulp and seed extract in terms of total phenolic content and antioxidant activity were effectively enhanced by nanoencapsulation. In conclusion, jujube pulp and seed extracts prepared using optimal conditions could be useful as a natural functional food ingredient with antioxidant activity, and nanoencapsulation can be used to improve the stability of jujube extract. Therefore, these results could be used to promote the utilization of not only jujube pulp but also seed, by product. PMID- 25911158 TI - Influence of gamma ray irradiation and annealing temperature on the optical constants and spectral dispersion parameters of metal-free and zinc tetraphenylporphyrin thin films: A comparative study. AB - In this work, we report on the effect of gamma-ray irradiation and annealing temperature on the optical properties of metal-free tetraphenylporphyrin, H2TPP, and zinc tetraphenylporphyrin, ZnTPP, thin films. Thin films of H2TPP and ZnTPP were successfully prepared by the thermal evaporation technique. The optical properties of H2TPP and ZnTPP films were investigated using spectrophotometric measurements of the transmittance and reflectance at normal incidence of light in the wavelength range from 200 to 2500 nm. The absorption spectra of H2TPP showed four absorption bands, namely the Q, B, N and M bands. The effect of inserting Zn atom into the cavity of porphyrin macrocycle in ZnTPP molecule distorted the Q and B bands, reduced the width of absorption region and influenced the optical constants and dispersion parameters. In all conditions, the type of electron transition is indirect allowed transition. Anomalous dispersion is observed in the absorption region but normal dispersion occurs in the transparent region of spectra. We adopted multi-oscillator model and the single oscillator model to interpret the anomalous and normal dispersion, respectively. We have found that the annealing temperature has mostly the opposite effect of gamma-ray irradiation on absorption and dispersion characteristics of these films. PMID- 25911159 TI - A dansyl based fluorescence chemosensor for Hg(2+) and its application in the complicated environment samples. AB - We have developed a novel fluorescent chemosensor (DAM) based on dansyl and morpholine units for the detection of mercury ion with excellent selectivity and sensitivity. In the presence of Hg(2+) in a mixture solution of HEPES buffer (pH 7.5, 20 mM) and MeCN (2/8, v/v) at room temperature, the fluorescence of DAM was almost completely quenched from green to colorless with fast response time. Moreover, DAM also showed its excellent anti-interference capability even in the presence of large amount of interfering ions. It is worth noting that DAM could be used to detect Hg(2+) specifically in the Yellow River samples, which significantly implied the potential applications of DAM in the complicated environment samples. PMID- 25911160 TI - Spectrophotometric determination of pico-molar level of hydrazine by using Alizarin red in water and urine samples. AB - In this paper, very simple and rapid sensor has been developed for the spectrophotometric determination of pico-molar level of hydrazine using Alizarin red. There was a decrease of optical intensity of the probe in the presence of hydrazine. The LOD is calculated from the linear graph between 5-100 pM as 0.66 pM of hydrazine which is well below the risk level proposed by Agency for Toxic Substance and Disease Registry. The probe selectivity for the detection of hydrazine was tested in the presence of commonly encountered metal ions and anions. The calibration curves showed good linearity for working ranges from 5 100 pM and 0.5-40 mM respectively, with R(2)=0.9911 and 0.9744, indicate the validity of the Beer-Lambert law. The binding constant and the free energy change values are determined by the Benesi-Hildebrand method. Determination of hydrazine in environmental water and human urine samples are successfully performed by the proposed method with the recovery of 100%. PMID- 25911161 TI - Smoking Initiation Among Mexican Heritage Youth and the Roles of Family Cohesion and Conflict. AB - PURPOSE: High levels of family conflict increase the risk for early smoking initiation and smoking escalation among adolescents, whereas high levels of warmth and cohesion in the family are protective against smoking initiation. However, little is known about the associations between changes in family function during adolescence on subsequent smoking initiation among Mexican heritage adolescents. METHODS: In 2005-2006, 1,328 Mexican heritage adolescents aged 11-14 years enrolled in a cohort study to examine nongenetic and genetic factors associated with cigarette experimentation. In 2008-2009, 1,154 participants completed a follow-up. Multivariate logistic regression models were computed to prospectively examine associations between smoking behavior assessed in 2008-2009 and changes in family cohesion and family conflict assessed in both 2005-2006 and 2008-2009, controlling for gender, age, and linguistic acculturation, positive outcome expectations associated with smoking, as well as friends and family smoking behavior. RESULTS: Overall 21% had tried cigarettes by 2008-2009. Consistently low levels of family cohesion (odds ratio [OR] = 3.06; 95% confidence interval [CI], 1.38-6.73) and decreases in family cohesion (OR = 2.36; 95% CI, 1.37-4.07), as well as consistently high levels of family conflict (OR = 1.74; 95% CI, 1.08-2.79) and increases in conflict (OR = 1.87; 95% CI, 1.19 2.94) were independent risk factors for smoking initiation among Mexican heritage youth. CONCLUSIONS: Our findings suggest that family cohesion protects against adolescent smoking, whereas family conflict increases the risk for smoking. Therefore, intervention programs for adolescents and parents could focus on enhancing family bonding and closeness, which is protective against smoking initiation. PMID- 25911162 TI - The Impact of Early Bedtimes on Adolescent Caloric Intake Varies by Chronotype. AB - PURPOSE: Adolescent sleep restriction is common and can lead to overeating. Here, we test whether lengthening sleep via early bedtimes affects dietary intake differently for adolescents accustomed to a later sleep phase ("night owls") versus an earlier sleep phase ("morning larks"). METHODS: Using a randomized cross-over design, 67 adolescents changed bedtimes to create five-night periods of sleep restriction (6.5 hours in bed) versus healthy sleep (10 hours in bed). Caloric intake was measured via validated interviews. Phase preference was based on participants' premanipulation sleep. RESULTS: Actigraphy verified that the manipulation altered sleep regardless of phase preference. Phase preference moderated the effect of the manipulation on cumulative caloric intake (p = .01 .03). Night owls showed little effect, but morning larks reduced their evening intake during healthy sleep. CONCLUSIONS: An "early to bed" approach confers little dietary benefit for night owls but may have a protective effect for adolescents who gravitate toward earlier bedtimes. PMID- 25911163 TI - Ivermectin treatment of free-ranging endangered Australian sea lion (Neophoca cinerea) pups: effect on hookworm and lice infection status, haematological parameters, growth, and survival. AB - A placebo-controlled study was used to investigate the effectiveness of ivermectin to treat hookworm (Uncinaria sanguinis) and lice (Antarctophthirus microchir) infections in free-ranging Australian sea lion (Neophoca cinerea) pups and to test the hypotheses that these parasitic infections cause anaemia, systemic inflammatory responses, and reduced growth, and contribute towards decreased pup survival. Ivermectin was identified as an effective and safe anthelmintic in this species. Pups administered ivermectin had significantly higher erythrocyte counts and significantly lower eosinophil counts compared to controls at 1-2 months post-treatment, confirming that U. sanguinis and/or A. microchir are causatively associated with disease and demonstrating the positive effect of ivermectin treatment on clinical health parameters. Higher growth rates were not seen in ivermectin-treated pups and, unexpectedly, relatively older pups treated with ivermectin demonstrated significantly reduced growth rates when compared to matched saline-control pups. Differences in survival were not identified between treatment groups; however, this was attributed to the unexpectedly low mortality rate of recruited pups, likely due to the unintended recruitment bias towards pups >1-2 months of age for which mortality due to hookworm infection is less likely. This finding highlights the logistical and practical challenges associated with treating pups of this species shortly after birth at a remote colony. This study informs the assessment of the use of anthelmintics as a tool for the conservation management of free-ranging wildlife and outlines essential steps to further the development of strategies to ensure the effective conservation of the Australian sea lion and its parasitic fauna. PMID- 25911164 TI - Mucoadhesive polymeric platform for drug delivery; a comprehensive review. AB - Mucoadhesion can be defined as adhesion in biological setting. Process of mucoadhesion takes place in 3 stages- the first stage being that of wetting or swelling of mucoadhesive polymer. Second stage involves interpenetration of the chains of mucoadhesive polymer and the third stage involves formation of chemical bonds between entangled chains. Several polymer related factors like molecular weight, chain length, degree of cross-linking, hydration, functional groups, charge, polymer concentration and several environmental and physiological factors like contact time, mucin turnover rate and mucus viscosity affect the degree of mucoadhesion. Formulation scientists have structured and engineered several mucoadhesive polymers for their usefulness in enhancement of bioavailability, controlled and targeted drug delivery. Mucoadhesive polymers can be classified as non-specific first generation polymers and novel second generation polymers based on the mechanism of mucoadhesion. Mucoadhesive drug delivery systems have been applied to buccal cavity, oesophagus, gastrointestinal tract, eye, nasal cavity, vagina and rectal cavity. Several in vitro/ex vivo and in vivo evaluation techniques have evolved for the evaluation of mucoadhesive strength of these polymers. This review provides historical perspective on mucoadhesive polymers and an understanding of the phenomenon of mucoadhesion, factors affecting mucoadhesion, types of mucoadhesive polymers, their practical applications and the various evaluation techniques for determination of mucoadhesive strength. PMID- 25911165 TI - Self-emulsifying lipid formulation: an overview. AB - An important step in oral drug development is to identify drug candidates that show sufficient aqueous solubility and could resist or bypass first-pass metabolism in order to overcome bioavailability problems. Aqueous solubility is characteristically low for Biopharmaceutical Classification System (BCS) class II and class IV drug candidates. Several formulation approaches are being identified to overcome the low solubility aspect of a drug candidate such as particle size manipulation, solid dispersions, inclusion complexes and several of nanoparticle based options. However, the formulation for drug candidates that in addition to low aqueous solubility shows high intestinal and first-pass metabolism is challenging. The self-emulsifying lipid formulations (SELF) provide a mean for sidestepping these factors and improve the bioavailability of lipophilic and highly first- pass metabolised drugs. Nevertheless, formulation of a successful SELF requires an exhaustive understanding of the component used to formulate them, the behaviour of the formulation within the gastrointestinal (GI) milieu and the mechanism by which the drug is released and absorbed. This review gives a brief description of the formulation aspects of SELF and their potential role to mitigate the bioavailability problem related to lipophilic and highly first- pass metabolised drugs. PMID- 25911166 TI - Optimization of ultrasonic-assisted extraction of total carotenoids from peach palm fruit (Bactris gasipaes) by-products with sunflower oil using response surface methodology. AB - The present study reports on the extraction of total carotenoids from peach palm fruit by-products with sunflower oil. Response surface methodology (RSM) was used to investigate the effect of process variables on the ultrasound-assisted extraction (UAE). Three independent variables including ultrasonic intensity (764 1528, W/m(2)), temperature (25-45 degrees C), and the extraction time (10-30 min). According to the results, the optimal UAE condition was obtained with an ultrasonic intensity of 1528 W/m(2), extraction temperature of 35 degrees C and extraction time of 30 min. At these conditions, extraction maximum extraction of total carotenoids as 163.47 mg/100 g dried peel. The experimental values under optimal condition were in good consistent with the predicted values. PMID- 25911167 TI - Biomarkers in acute heart failure. AB - The care of patients with acutely decompensated heart failure is being reshaped by the availability and understanding of several novel and emerging heart failure biomarkers. The gold standard biomarkers in heart failure are B-type natriuretic peptide and N-terminal pro-B-type natriuretic peptide, which play an important role in the diagnosis, prognosis, and management of acute decompensated heart failure. Novel biomarkers that are increasingly involved in the processes of myocardial injury, neurohormonal activation, and ventricular remodeling are showing promise in improving diagnosis and prognosis among patients with acute decompensated heart failure. These include midregional proatrial natriuretic peptide, soluble ST2, galectin-3, highly-sensitive troponin, and midregional proadrenomedullin. There has also been an emergence of biomarkers for evaluation of acute decompensated heart failure that assist in the differential diagnosis of dyspnea, such as procalcitonin (for identification of acute pneumonia), as well as markers that predict complications of acute decompensated heart failure, such as renal injury markers. In this article, we will review the pathophysiology and usefulness of established and emerging biomarkers for the clinical diagnosis, prognosis, and management of acute decompensated heart failure. PMID- 25911168 TI - Predictors of Luminal Loss in Pulmonary Veins After Radiofrequency Ablation. AB - INTRODUCTION AND OBJECTIVES: The reported incidences of stenosis after radiofrequency ablation of pulmonary veins are highly variable. Moreover, most studies have focused on severe stenosis and have overlooked mild stenosis. Our aims were to study postablation morphological changes in the pulmonary veins and to evaluate preablation magnetic resonance imaging predictors for stenosis. METHODS: Eighty consecutive patients with atrial fibrillation underwent cardiac magnetic resonance imaging before undergoing radiofrequency ablation. Magnetic resonance imaging was repeated a median of 95 days after ablation. Ostium area/ellipticity and atrial volume were blindly assessed. We evaluated the presence of stenosis and classified it as mild (< 50% area reduction), moderate (50%-70%), and severe (> 70%). RESULTS: Postablation stenosis was identified in 78 of 322 veins (24.2%). The stenosis was mild in 66 (84.6%), moderate in 11 (14.1%), and severe in 1 (1.3%). All of them were asymptomatic. The left inferior pulmonary vein showed the highest frequency of stenosis, which was detected in 26% of them (P < .001). A multiple regression analysis revealed that left inferior pulmonary vein (odds ratio = 3.089; P = .02) and a greater preablation ostium area (odds ratio = 1.009; P < .001) were independent predictors for postablation stenosis. Age (odds ratio = 1.033) showed a strong trend to statistical significance (P = .06). CONCLUSIONS: After ablation, vein ostia size is reduced and stenosis is detected in less than one third of patients. Most cases are mild, and severe stenosis is rare. Postablation stenosis is more likely to develop in older patients, those with larger vein ostia, and in the left inferior pulmonary veins. PMID- 25911170 TI - Law's power to safeguard global health: a Lancet-O'Neill Institute, Georgetown University Commission on Global Health and the Law. PMID- 25911169 TI - Involvement of NADPH oxidase in A2A adenosine receptor-mediated increase in coronary flow in isolated mouse hearts. AB - Adenosine increases coronary flow mainly through the activation of A2A and A2B adenosine receptors (ARs). However, the mechanisms for the regulation of coronary flow are not fully understood. We previously demonstrated that adenosine-induced increase in coronary flow is in part through NADPH oxidase (Nox) activation, which is independent of activation of either A1 or A3ARs. In this study, we hypothesize that adenosine-mediated increase in coronary flow through Nox activation depends on A2A but not A2BARs. Functional studies were conducted using isolated Langendorff-perfused mouse hearts. Hydrogen peroxide (H2O2) production was measured in isolated coronary arteries from WT, A2AAR knockout (KO), and A2BAR KO mice using dichlorofluorescein immunofluorescence. Adenosine-induced concentration-dependent increase in coronary flow was attenuated by the specific Nox2 inhibitor gp91 ds-tat or reactive oxygen species (ROS) scavenger EUK134 in both WT and A2B but not A2AAR KO isolated hearts. Similarly, the A2AAR selective agonist CGS-21680-induced increase in coronary flow was significantly blunted by Nox2 inhibition in both WT and A2BAR KO, while the A2BAR selective agonist BAY 60 6583-induced increase in coronary flow was not affected by Nox2 inhibition in WT. In intact isolated coronary arteries, adenosine-induced (10 MUM) increase in H2O2 formation in both WT and A2BAR KO mice was attenuated by Nox2 inhibition, whereas adenosine failed to increase H2O2 production in A2AAR KO mice. In conclusion, adenosine-induced increase in coronary flow is partially mediated by Nox2-derived H2O2, which critically depends upon the presence of A2AAR. PMID- 25911171 TI - Bladder catheterisation after female genital fistula repair. PMID- 25911173 TI - What is the maximum safe tourniquet time in elective upper limb surgery? PMID- 25911172 TI - Breakdown of simple female genital fistula repair after 7 day versus 14 day postoperative bladder catheterisation: a randomised, controlled, open-label, non inferiority trial. AB - BACKGROUND: Duration of bladder catheterisation after female genital fistula repair varies widely. We aimed to establish whether 7 day bladder catheterisation was non-inferior to 14 days in terms of incidence of fistula repair breakdown in women with simple fistula. METHODS: In this randomised, controlled, open-label, non-inferiority trial, we enrolled patients at eight hospitals in the Democratic Republic of the Congo, Ethiopia, Guinea, Kenya, Niger, Nigeria, Sierra Leone, and Uganda. Consenting patients were eligible if they had a simple fistula that was closed after surgery and remained closed 7 days after surgery, understood study procedures and requirements, and agreed to return for follow-up 3 months after surgery. We excluded women if their fistula was not simple or was radiation induced, associated with cancer, or due to lymphogranuloma venereum; if they were pregnant; or if they had multiple fistula. A research assistant at each site randomly allocated participants 1:1 (randomly varying block sizes of 4-6; stratified by country) to 7 day or 14 day bladder catheterisation (via a random allocation sequence computer generated centrally by WHO). Outcome assessors were not masked to treatment assignment. The primary outcome was fistula repair breakdown, on the basis of dye test results, any time between 8 days after catheter removal and 3 months after surgery. The non-inferiority margin was 10%, assessed in the per-protocol population. This trial is registered with ClinicalTrials.gov, number NCT01428830. FINDINGS: We randomly allocated 524 participants between March 7, 2012, and May 6, 2013; 261 in the 7 day group and 263 in the 14 day group. In the per-protocol analysis, ten (4%) of 250 patients had repair breakdown in the 7 day group (95% CI 2-8) compared with eight (3%) of 251 (2-6) in the 14 day group (risk difference 0.8% [95% CI -2.8 to 4.5]), meeting the criteria for non-inferiority. INTERPRETATION: 7 day bladder catheterisation after repair of simple fistula is non-inferior to 14 day catheterisation and could be used for management of women after repair of simple fistula with no evidence of a significantly increased risk of repair breakdown, urinary retention, or residual incontinence up to 3 months after surgery. FUNDING: US Agency for International Development. PMID- 25911174 TI - Airway management strategies in patients with halo vest fixation devices. PMID- 25911175 TI - In reply: Airway management strategies in patients with halo vest fixation devices. PMID- 25911176 TI - Increased expression of IL-28RA mRNA in peripheral blood mononuclear cells from patients with systemic lupus erythematosus. AB - Systemic lupus erythematosus (SLE) is a systemic autoimmune and inflammatory disease with a strong genetic contribution and characterized by kinds of immune reactions. Our previous genome-wide association studies have identified IL-28RA as a susceptibility gene for SLE. In this study, we performed a quantitative reverse transcription polymerase chain reaction (RT-PCR) in 62 patients with SLE and 69 controls to investigate the different expression levels of IL-28RA in peripheral blood mononuclear cells (PBMCs) from SLE patients and healthy controls and the association between IL-28RA expression and systemic lupus erythematosus disease activity index (SLEDAI) or the variant of the single-nucleotide polymorphism (SNP) rs4649203. The expression levels of IL-28RA messenger RNA (mRNA) in SLE patients were significantly increased compared with those of healthy controls. In addition, there were also significant differences in the expression levels of IL-28RA between active (SLEDAI >= 6) or inactive (SLEDAI < 6) SLE groups and healthy controls. However, no correlation was observed between IL-28RA mRNA expression level and SLEDAI. There was no association between the variant of the SNP rs4649203 and IL-28RA mRNA expression levels neither. These results indicated that expression of IL-28RA mRNA may be correlated with the pathogenesis of SLE. PMID- 25911177 TI - The Defecation Index as a Measure of Emotionality: Questions Raised by HPA Axis and Prolactin Response to Stress in the Maudsley Model. AB - The Maudsley Reactive and Maudsley Non-Reactive strains have been selectively bred for differences in open-field defecation (OFD), a putative index of stress. We investigated whether variations in the hypothalamic-pituitary-adrenal (HPA) axis are correlated with strain differences in OFD in the Maudsley model. Exposure to the open-field test did not result in increases in ACTH in male rats of either strain and there were no strain differences in the large increases in ACTH and corticosteroid that occurred in response to intermittent footshock. Parallel studies of prolactin showed that Maudsley Reactive rats had greater response to the open-field and to footshock than Maudsley Non-Reactive rats. The lack of correlation between strain differences in OFD and reactivity of the HPA axis is consistent with the idea that HPA response to stress and OFD reflect the output of different neural systems and that individual differences in emotionality, as indexed by OFD do not influence other measures of stress reactivity in a simple manner, if at all. The reactivity of the prolactin system to the open-field test and lack of response of ACTH to the same situation is consistent with the idea that the prolactin system is sensitive to lower levels of stress than the HPA axis, a finding at variance with the presumed extreme sensitivity of the latter system. Earlier comparisons of the HPA axis in these strains implicate local factors such as neuropeptide-Y peptide in the adrenal in attenuating the response of the adrenal cortex to ACTH and hints at the complexity of regulation of the HPA axis. PMID- 25911178 TI - St Jude Medical Trifecta aortic prosthesis: Considerations for implantation. PMID- 25911179 TI - Differential toll-like receptor activation in lung ischemia reperfusion injury. AB - OBJECTIVE: The requirement for toll-like receptors (TLRs) in lung ischemia reperfusion injury (LIRI) has been demonstrated but not fully characterized. Previously, we reported that TLR-4 is required by alveolar macrophages but not pulmonary endothelial or epithelial cells for development of LIRI. Additionally, we demonstrated differential patterns of mitogen-activated protein kinase (MAPK) activation and cytokine release in these cell types during LIRI. Here, we sought to determine whether these differences in activation responses are related to cell-specific TLR activation requirements. METHODS: Primary cultures of alveolar macrophages, pulmonary endothelial, and immortalized epithelial cells were pretreated with TLR-2 or TLR-4 short interference RNA (ribonucleic acid) before hypoxia and reoxygenation. Cell lysates and media were analyzed for receptor knockdown, MAPK activation, and cytokine production. Rats were pretreated with TLR-2 or TLR-4 short interference RNA before lung ischemia reperfusion and changes in lung vascular permeability were assessed. RESULTS: Knockdown of TLR-2 in alveolar macrophages did not affect MAPK phosphorylation or cytokine secretion. Conversely, TLR-2 knockdown in pulmonary endothelial and epithelial cells demonstrated significant reductions in extracellular signal-regulated kinase 1/2 activation and cytokine secretion. The lung permeability index in LIRI was decreased by TLR-4 but not TLR-2. CONCLUSIONS: Differential TLR signaling and MAPK activation in response to LIRI seem to be cell specific. Short interference RNA provides an outstanding tool for examination of the underlying mechanism. PMID- 25911180 TI - Cryptic recurrent mitral valve excrescences: A rare cause of stroke. PMID- 25911181 TI - Lies, damned lies, and statistics. PMID- 25911182 TI - Adenocarcinoma arising from cervical esophageal gastric inlet patch. PMID- 25911183 TI - Better seeing is more believing: Angioscopy in aortic valve repair. PMID- 25911184 TI - Antisense approach to inflammatory bowel disease: prospects and challenges. AB - Despite the great success of anti-tumour necrosis factor-based therapies, the treatment of Crohn's disease (CD) and ulcerative colitis (UC) still remains a challenge for clinicians, as these drugs are not effective in all patients, their efficacy may wane with time, and their use can increase the risk of adverse events and be associated with the development of new immune-mediated diseases. Therefore, new therapeutic targets are currently being investigated both in pre clinical studies and in clinical trials. Among the technologies used to build new therapeutic compounds, the antisense oligonucleotide (ASO) approach is slowly gaining space in the field of inflammatory bowel diseases (IBDs), and three ASOs have been investigated in clinical trials. Systemic administration of alicaforsen targeting intercellular adhesion molecule-1, a protein involved in the recruitment of leukocytes to inflamed intestine, was not effective in CD, even though the same compound was of benefit when given as an enema to UC patients. DIMS0150, targeting nuclear factor (NF) kappaB-p65, a transcription factor that promotes pro-inflammatory responses, was very promising in pre-clinical studies and is currently being tested in clinical trials. Oral mongersen, targeting Smad7, an intracellular protein that inhibits transforming growth factor (TGF) beta1 activity, was safe and well tolerated by CD patients, and the results of a phase II clinical trial showed the efficacy of the drug in inducing clinical remission in patients with active disease. In this leading article, we review the rationale and the clinical data available regarding these three agents, and we discuss the challenge of using ASOs in IBD. PMID- 25911185 TI - The expanding role of somatostatin analogs in gastroenteropancreatic and lung neuroendocrine tumors. AB - Somatostatin analogs (SSAs) were initially developed as antisecretory agents used for the control of hormonal syndromes associated with neuroendocrine tumors (NETs). In recent years, accumulating evidence has also supported their role as antiproliferative agents in well or moderately differentiated NETs. The phase III PROMID trial demonstrated that octreotide long-acting repeatable (LAR) can significantly prolong time to progression among patients with metastatic midgut NETs. More recently, the randomized CLARINET trial reported a significant improvement in progression-free survival in a heterogeneous population of patients with gastroenteropancreatic (GEP)-NETs treated with depot lanreotide. Octreotide and lanreotide target somatostatin receptor subtypes in a similar fashion, and appear to be clinically interchangeable; however, comparative noninferiority trials have not been performed. Further studies are needed to evaluate the efficacy of novel SSAs such as pasireotide in the refractory setting, and the role of high-dose SSAs for symptom and tumor control. PMID- 25911186 TI - Ibandronate increases sclerostin levels and bone strength in male patients with idiopathic osteoporosis. AB - The pathomechanism of male idiopathic osteoporosis (MIO) differs from postmenopausal osteoporosis with regard to alterations in osteoblast activity. We evaluated intravenous ibandronate (IBN) in 25 MIO patients with fragility fractures in a prospective, monocentric, single-arm, and open-label study for 24 months. The impact and changes of sclerostin (Scl), Dickkopf-1 (DKK-1), CTX, and PINP were examined. Additionally, volumetric cortical, trabecular and areal bone mineral density (BMD), trabecular bone score (TBS), and finite element analyses (FEA) were evaluated. Compared to baseline, median Scl levels were increased after 1 month (Delta 121%, p < 0.0001) and remained elevated for 12 months. DKK-1 decreased (p < 0.001) to a lesser extent until month 9 with values comparable to baseline at study endpoint. Early changes (baseline-month 1) of Scl negatively correlated with early changes of DKK-1 (-0.72), CTX (-0.82), and PINP (-0.55; p < 0.005 for all). The overall changes over the 24 months study period of Scl negatively correlated with decreased CTX (-0.32) and DKK-1 levels (-0.57, p < 0.0001 for both); CTX and PINP changes positively correlated at each time point (p < 0.001). Volumetric hip BMD increased by 12 and 18%, respectively (p < 0.0001 for both). Cross-sectional moment of inertia and section modulus for total hip significantly improved (p < 0.05 for all). Areal BMD at total hip, spine, and TBS increased. FEA displayed an increase in bone strength both in the hip (17%) and vertebrae (13%, all p < 0.0001) at anatomical sites susceptible for fragility fracture. IBN increases Scl and improves cortical and trabecular bone strength with early and ongoing vigorous suppression of bone resorption. PMID- 25911187 TI - Three-times-weekly administration of teriparatide improves vertebral and peripheral bone density, microarchitecture, and mechanical properties without accelerating bone resorption in ovariectomized rats. AB - Daily and weekly administration of teriparatide (PTH1-34) reduces the risk of osteoporotic bone fractures. However, their effects on markers of bone formation and bone resorption differ. These results indicate that the dosing frequency of teriparatide may affect bone metabolism and bone structure, with different effects on bone strength. In the present study, to evaluate the dose-related effects of a low administration frequency of teriparatide on bone status, we investigated the effects of three-times-weekly administration of teriparatide (1.1, 5.6, or 28.2 ug/kg) for 12 months on bone parameters, including bone metabolism markers, bone mineral density (BMD), micro-computed tomography, and bone strength, using 6-month-old ovariectomized (OVX) rats. Three-times-weekly administration of teriparatide dose-dependently increased the BMD of the lumbar vertebra and femur in OVX rats, and increased serum osteocalcin (a marker of bone formation), but not type I collagen C-telopeptide (a marker of bone resorption). The trabecular number and thickness increased in the vertebrae and femur, as in prior reports of daily teriparatide administration in OVX rats. Cortical thickness increased only toward the endocortical side of the femur, unlike with daily administration. Bone strength of the vertebrae and proximal and shaft of the femur was correlated with the changes in BMD and bone structure. These results demonstrate the effects of low frequency, intermittent administration of teriparatide on the biomechanical, and microstructural properties of bone in OVX rats. PMID- 25911188 TI - Characterization of a naturally occurring truncated Dicer. AB - Dicer is central to small RNA silencing pathways, thus playing an important role in physiological and pathological states. Recently, a number of mutations in dicer gene have been identified in diverse types of cancer, implicating Dicer in oncogenic cooperation. Here we report on the properties of a rare splice variant of the human dicer gene, occurring in neuroblastoma cells, and not detectable in normal tissues. Due to the skipping of one exon, the alternatively spliced transcript encodes a putative truncated protein, t-Dicer, lacking the dsRNA binding domain and bearing altered one of the two RNase III catalytic centers. The ability of the exon-depleted t-dicer transcript to be translated in vitro was first investigated by the expression of flagged t-Dicer in human cells. We found that t-dicer transcript could be translated in vitro, albeit not as efficiently as full-length dicer transcript. Then, the possible enzymatic activity of t-Dicer was analyzed by an in vitro dicing assay able to distinguish the enzymatic activity of the individual RNase III domains. We showed that t-Dicer preserved partial dicing activity. Overall, the results indicate that t-dicer transcript could produce a protein still able to bind the substrate and to cleave only one of the two pre-miRNA strands. Given the increasing number of mutations reported for dicer gene in tumours, our experimental approach could be useful to characterize the activity of these mutants, which may dictate changes in selected classes of small RNAs and/or lead to their aberrant maturation. PMID- 25911189 TI - Inhibition of mammalian target of rapamycin protects against reperfusion injury in diabetic heart through STAT3 signaling. AB - Diabetic patients suffer augmented severity of myocardial infarction. Excessive activation of the mammalian target of rapamycin (mTOR) and decreased activation of STAT3 are implicated in diabetic complications. Considering the potent cardioprotective effect of mTOR inhibitor, rapamycin, we hypothesized that reperfusion therapy with rapamycin would reduce infarct size in the diabetic hearts through STAT3 signaling. Hearts from adult male db/db or wild type (WT) C57 mice were isolated and subjected to 30 min of normothermic global ischemia and 60 min of reperfusion in Langendorff mode. Rapamycin (100 nM) was infused at the onset of reperfusion. Myocardial infarct size (IS) was significantly reduced in rapamycin-treated mice (13.3 +/- 2.4 %) compared to DMSO vehicle control (35.9 +/- 0.9 %) or WT mice (27.7 +/- 1.1 %). Rapamycin treatment restored phosphorylation of STAT3 and enhanced AKT phosphorylation (target of mTORC2), but significantly reduced ribosomal protein S6 phosphorylation (target of mTORC1) in the diabetic heart. To determine the cause and effect relationship of STAT3 in cardioprotection, inducible cardiac-specific STAT3-deficient (MCM TG:STAT3(flox/flox)) and WT mice (MCM TG:STAT3(flox/flox)) were made diabetic by feeding high fat diet (HFD). Rapamycin given at reperfusion reduced IS in WT mice but not in STAT3-deficient mice following I/R. Moreover, cardiomyocytes isolated from HFD-fed WT mice showed resistance against necrosis (trypan blue staining) and apoptosis (TUNEL assay) when treated with rapamycin during reoxygenation following simulated ischemia. Such protection was absent in cardiomyocytes from HFD-fed STAT3-deficient mice. STAT3 signaling plays critical role in reducing IS and attenuates cardiomyocyte death following reperfusion therapy with rapamycin in diabetic heart. PMID- 25911190 TI - Risk factors for postoperative complications after gastrectomy in gastric cancer patients with comorbidities. AB - PURPOSE: We conducted this retrospective cohort study to evaluate which preoperative comorbidities and their combinations are most strongly associated with postoperative complications after gastrectomy. METHODS: We collected data on 214 consecutive patients who underwent gastrectomy for gastric cancer. Preoperative comorbidities were placed into one of ten categories: cardiac, pulmonary, liver, renal, central nervous system, hypertension, diabetes, endocrine/metabolic, vascular, and immune/hematological. The relationship between the number of comorbidities and the incidence of postoperative complications was evaluated. RESULTS: Among 120 patients (56.1 %) with comorbidities, 48 had a single comorbidity and 72 had multiple (>=2) comorbidities. The incidence of postoperative complications was 45.8 % (33/72) for patients with multiple comorbidities and 23.9 % (34/142) for those with 0 or 1 comorbidity (P = 0.001). Among the ten types of comorbidities, only pulmonary (P = 0.019) and vascular diseases (P = 0.007) were significantly associated with the occurrence of postoperative complications. CONCLUSION: Patients with multiple comorbidities had a significantly higher incidence of postoperative complications after gastrectomy. Among the comorbidities studied, pulmonary and vascular diseases had the strongest association with postoperative complications. PMID- 25911191 TI - The effect of metal ions as co-catalysts on acidic ionic liquid catalyzed single step saccharification of corn stover in water. AB - The effects of adding Cr(3+), Mn(2+), Fe(3+), Co(2+) Ni(2+), Cu(2+), Zn(2+) and La(3+) chlorides as co-catalysts to 1-(1-propylsulfonic)-3-methylimidazolium chloride acidic ionic liquid catalyzed saccharification of corn stover in aqueous medium was studied at 140-170 degrees C, by measuring the total reducing sugar (TRS) and glucose yields. The samples with Mn(2+), Fe(3+), Co(2+) as co-catalysts produced higher TRS yields compared to the sample without the metal ions. The Mn(2+) produced the highest catalytic effect enhancements and produced TRS yields of 68.0%, 72.9%, 90.2% and 87.9% at 140, 150, 160 and 170 degrees C respectively; whereas the corn stover samples without the Mn(2+) produced TRS yields of 42.9%, 52.3%, 54.4% and 53.5% at the same four temperatures. At higher temperatures of 160 and 170 degrees C, all metal ions studied produced significant enhancements in glucose yields, except Cr(3+). The addition of La(3+) as a co-catalyst produced the highest glucose yield improvement. PMID- 25911192 TI - Increased anaerobic production of methane by co-digestion of sludge with microalgal biomass and food waste leachate. AB - The co-digestion of multiple substrates is a promising method to increase methane production during anaerobic digestion. However, limited reliable data are available on the anaerobic co-digestion of food waste leachate with microalgal biomass. This report evaluated methane production by the anaerobic co-digestion of different mixtures of food waste leachate, algal biomass, and raw sludge. Co digestion of substrate mixture containing equal amounts of three substrates had higher methane production than anaerobic digestion of individual substrates. This was possibly due to a proliferation of methanogens over the entire digestion period induced by multistage digestion of different substrates with different degrees of degradability. Thus, the co-digestion of food waste, microalgal biomass, and raw sludge appears to be a feasible and efficient method for energy conversion from waste resources. PMID- 25911193 TI - A comprehensive study on algal-bacterial communities shift during thiocyanate degradation in a microalga-mediated process. AB - Changes in algal and bacterial communities during thiocyanate (SCN(-)) decomposition in a microalga-mediated process were studied. Pyrosequencing indicated that Thiobacillus bacteria and Micractinium algae predominated during SCN(-) hydrolysis, even after its complete degradation. Principal components analysis and evenness profiles (based on the Pareto-Lorenz curve) suggested that the changes in the bacterial communities were driven by nitrogen and sulfur oxidation, pH changes, and photoautotrophic conditions. The populations of predominant microalgae remained relatively stable during SCN(-) hydrolysis, but the proportion of bacteria - especially nitrifying bacteria - fluctuated. Thus, the initial microalgal population may be crucial in determining which microorganisms dominate when the preferred nitrogen source becomes limited. The results also demonstrated that microalgae and SCN(-)-hydrolyzing bacteria can coexist, that microalgae can be effectively used with these bacteria to completely treat SCN(-), and that the structure of the algal-bacterial community is more stable than the community of nitrifying bacteria alone during SCN(-) degradation. PMID- 25911194 TI - Moderate Childhood Stress Buffers Against Depressive Response to Proximal Stressors: A Multi-Wave Prospective Study of Early Adolescents. AB - Although the majority of research in the field has focused on childhood stressors as a risk factor for psychopathology, a burgeoning body of literature has focused on the possible steeling effect of moderate types of stressful events. The current study investigated the effects of proximal life stressors on prospective changes in depressive symptoms, and whether a history of moderate childhood adversity would moderate this relationship in a multi-wave study of a diverse community sample of early adolescents (N = 163, 52 % female, 51 % Caucasian). Hierarchical linear modeling was run with four waves of data. Adolescents with greater moderately severe early life events evinced a blunted depressive symptom response to changes in proximal stressful events in the previous 9 months, compared to those with fewer early moderately severe experiences of adversity. These results held after controlling for between-subject factors such as race, gender, severe early life stress, and average stress over the four waves of data. Findings indicate that greater exposure to moderate childhood stressors may buffer against the negative effects of subsequent stressors, suggesting the importance of a nuanced developmental approach to studying the effects of early life stress. PMID- 25911195 TI - Peer Victimization Mediates the Impact of Maternal Depression on Risk for Suicidal Ideation in Girls but not Boys: A Prospective Study. AB - Although children of depressed mothers are at an increased risk for suicidal thinking, little is known about the potential mechanisms by which this occurs. The present study is the first to our knowledge to utilize a prospective design with the goal of examining whether the impact of maternal depression on children's risk for suicidal ideation is mediated by children's levels of overt and relational peer victimization. Participants were 203 mother-child pairs recruited from the community. The age range of the children was 8 to 14 years old (50.2 % girls). Mothers either met criteria for a major depressive disorder (MDD) during their child's lifetime (n = 96) or had no lifetime diagnosis of any DSM-IV mood disorder and no current Axis I diagnosis (n = 107). At the baseline assessment, diagnostic interviews were used to assess mothers' and children's histories of MDD and children completed a self-report measure of peer victimization. Follow-up assessments were conducted at 6, 12, 18, and 24 months after the initial assessment during which time interviewers assessed for the occurrence of suicidal ideation in the children. Utilizing a mediated moderation model, we found significant indirect pathways from maternal depression to children's suicidal ideation through both relational and overt forms of peer victimization among girls, but not among boys. The current study suggests that peer victimization may constitute one of the potential mechanisms by which daughters of depressed mothers are at increased risk for suicidal thinking. PMID- 25911196 TI - Nonenzymatic lipid mediators, neuroprostanes, exert the antiarrhythmic properties of docosahexaenoic acid. AB - Neuroprostanes are lipid mediators produced by nonenzymatic free radical peroxidation of docosahexaenoic acid (DHA). DHA is associated with a lower atherosclerosis risk, suggesting a beneficial role in cardiovascular diseases. The aim of this study was to investigate the influence of DHA peroxidation on its potentially antiarrhythmic properties (AAP) in isolated ventricular cardiomyocytes and in vivo in post-myocardial infarcted mice. Calcium imaging and biochemical experiments indicate that cardiac arrhythmias induced by isoproterenol are associated with Ca(2+) leak from the sarcoplasmic reticulum after oxidation and phosphorylation of the type 2 ryanodine receptor (RyR2) leading to dissociation of the FKBP12.6/RyR2 complex. Both oxidized DHA and 4(RS) 4-F4t-NeuroP prevented cellular arrhythmias and posttranslational modifications of the RyR2 leading to a stabilized FKBP12.6/RyR2 complex. DHA per se did not have AAP. The AAP of 4(RS)-4-F4t-NeuroP was also observed in vivo. In this study, we challenged the paradigm that spontaneously formed oxygenated metabolites of lipids are undesirable as they are unconditionally toxic. This study reveals that the lipid mediator 4(RS)-4-F4t-neuroprostane derived from nonenzymatic peroxidation of docosahexaenoic acid can counteract such deleterious effects through cardiac antiarrhythmic properties. Our findings demonstrate 4(RS)-4-F4t NeuroP as a mediator of the cardioprotective AAP of DHA. This discovery opens new perspectives for products of nonenzymatic oxidized omega3 polyunsaturated fatty acids as potent mediators in diseases that involve ryanodine complex destabilization such as ischemic events. PMID- 25911197 TI - Docetaxel-induced Haemorrhagic Interstitial Pneumonitis - An Acute Life threatening Adverse Effect. PMID- 25911198 TI - Association Between PARP1 Single Nucleotide Polymorphism and Brain Tumors. AB - To systematically evaluate the association between poly(ADP-ribose) polymerase 1 (PARP1) rs1136410 T>C and brain tumor risk, a meta-analysis has been carried out. We performed a meta-analysis of 2004 brain tumor patients and 2944 controls by use of STATA version 12.0 to determine whether the risk of brain tumors was associated with the genotypes or alleles of rs1136410 T>C. We found a significantly decreased risk (ranging from 0.18- to 0.16-fold) in the dominant model (OR = 0.84, 95% CI = 0.75-0.95), the C vs. T model (OR = 0.82, 95% CI = 0.74-0.91), and the CT vs. TT model (OR = 0.86, 95% CI = 0.76-0.98). The same genetic models demonstrated noteworthy associations when analysis was restrained to glioma (OR = 0.85, 95% CI = 0.75-0.96; OR = 0.83, 95% CI = 0.74-0.92; OR = 0.87, 95% CI = 0.76-0.99, respectively). This meta-analysis suggests that PARP1 rs1136410 T>C may play a significant role in the protection against the development of brain tumors and glioma. PMID- 25911199 TI - Neurovascular Invasion and Histological Grade Serve as the Risk Factors of Cervical Lymph Node Metastases in Early Tongue Squamous Cell Carcinoma. AB - The objectives of this study were to analyze the regional characteristics of the cervical lymph node metastasis and to investigate the factors associated with the risk of lymph node involvement. One hundred seventy-one patients suffering from early primary squamous cell carcinoma (SCC) of the tongue (cT1-2N0) were enrolled. Gender, age, growth site, T stage, histological grade, and neurovascular invasion were statistically analyzed by K-M survival analysis and Cox multivariate analysis to evaluate the relationship between the factors and the neck lymph node metastasis. Of the 171 cases divided into the neck dissection group and observation group, 40 ended up with lymph node metastasis, of which 17 were metastasized to level I, 27 to level II, 10 to level III, 2 to level IV, and 1 to level V. Histological grade and neurovascular invasion were significantly associated with lymph node involvement in univariate and multivariate analyses. Age distribution was found to be significantly associated with the lymph node metastasis in multivariate analysis. The metastasis of early tongue SCC has a certain regularity at different sites. Age was not a critical risk factor for cervical lymph node metastasis after surgery. Tumor size was suspected to exert a negative effect on metastasis by influencing tumor invasion. Histological grade and neurovascular invasion were significantly associated with the risk of cervical lymph node metastasis of early tongue SCC. PMID- 25911201 TI - Central T cell tolerance: Identification of tissue-restricted autoantigens in the thymus HLA-DR peptidome. AB - Promiscuous gene expression (pGE) of tissue-restricted self-antigens (TRA) in medullary thymic epithelial cells (mTECs) is in part driven by the Autoimmune Regulator gene (AIRE) and essential for self-tolerance. The link between AIRE functional mutations and multi-organ autoimmunity in human and mouse supports the role of pGE. Deep sequencing of the transcriptome revealed that mouse mTECs potentially transcribe an unprecedented range of >90% of all genes. Yet, it remains unclear to which extent these low-level transcripts are actually translated into proteins, processed and presented by thymic APCs to induce tolerance. To address this, we analyzed the HLA-DR-associated thymus peptidome. Within a large panel of peptides from abundant proteins, two TRA peptides were identified: prostate-specific semenogelin-1 (an autoantigen in autoimmune chronic prostatitis/chronic pelvic pain syndrome) and central nervous system-specific contactin-2 (an autoantigen in multiple sclerosis). Thymus expression of both genes was restricted to mTECs. SEMG1 expression was confined to mature HLA-DR(hi) mTECs of male and female donors and was AIRE-dependent, whereas CNTN2 was apparently AIRE-independent and was expressed by both populations of mTECs. Our findings establish a link between pGE, MHC-II peptide presentation and autoimmunity for bona fide human TRAs. PMID- 25911202 TI - [Tropical medicine/tropical dermatology training in Tanzania and Ghana: Personal experience and selected case reports]. AB - As a consultant for dermatology with special interested in tropical diseases, I accepted my employers offer (German Armed Forces) to start my training in tropical medicine and tropical dermatology in Africa. The dermatological part of the training was completed at the Regional Dermatology Training Centre (RDTC) in Moshi, Tanzania. This was followed by tropical medicine training at the Presbyterian Hospital in Agogo, Ghana. In this article, I report on my experiences in Africa and present selected case reports. PMID- 25911200 TI - TNF-like weak inducer of apoptosis promotes blood brain barrier disruption and increases neuronal cell death in MRL/lpr mice. AB - Neuropsychiatric disease is one of the most common manifestations of human systemic lupus erythematosus, but the mechanisms remain poorly understood. In human brain microvascular endothelial cells in vitro, TNF-like weak inducer of apoptosis (TWEAK) decreases tight junction ZO-1 expression and increases the permeability of monolayer cell cultures. Furthermore, knockout (KO) of the TWEAK receptor, Fn14, in the MRL/lpr lupus mouse strain markedly attenuates neuropsychiatric disease, as demonstrated by significant reductions in depressive like behavior and improved cognitive function. The purpose of the present study was to determine the mechanisms by which TWEAK signaling is instrumental in the pathogenesis of neuropsychiatric lupus (NPSLE). Evaluating brain sections of MRL/lpr Fn14WT and Fn14KO mice, we found that Fn14KO mice displayed significantly decreased cellular infiltrates in the choroid plexus. To evaluate the integrity of the blood brain barrier (BBB) in MRL/lpr mice, Western blot for fibronectin, qPCR for iNOS, and immunohistochemical staining for VCAM-1/ICAM-1 were performed. We found preserved BBB permeability in MRL/lpr Fn14KO mice, attributable to reduced brain expression of VCAM-1/ICAM-1 and iNOS. Additionally, administration of Fc-TWEAK intravenously directly increased the leakage of a tracer (dextran FITC) into brain tissue. Furthermore, MRL/lpr Fn14KO mice displayed reduced antibody (IgG) and complement (C3, C6, and C4a) deposition in the brain. Finally, we found that MRL/lpr Fn14KO mice manifested reduced neuron degeneration and hippocampal gliosis. Our studies indicate that TWEAK/Fn14 interactions play an important role in the pathogenesis of NPSLE by increasing the accumulation of inflammatory cells in the choroid plexus, disrupting BBB integrity, and increasing neuronal damage, suggesting a novel target for therapy in this disease. PMID- 25911203 TI - [Dermatology in the tropics and in medical missions: Consequences for the training of dermatologists and for continuing medical education]. AB - Dermatologists from Germany are increasingly involved in international missions under tropical conditions. While civilian operations take place primarily in the context of international development cooperation, non-governmental organizations and private initiatives, dermatologists of the German Armed Forces have been engaged in numerous military missions and international disaster relief missions abroad. The specific requirements of these missions require a specialist qualification; however, the specialist training in "Skin and Venereal Diseases" under the conditions for medical care in Germany is frequently not sufficient. For an optimal preparation for dermatological missions in tropical regions, an additional qualification in tropical medicine is to be recommended. Since this additional training is time-consuming and can often not be put into practice, especially in the civilian sector, the acquisition of the certificate "Tropical and Travel Dermatology (DDA)" of the International Society for Dermatology in the Tropics in cooperation with the German Dermatological Academy (DDA) can be recommended. In the future, training in tropical dermatology should be incorporated into the main curriculum of dermatology for those specialists planning to work on dermatological missions in the tropics. PMID- 25911204 TI - Gait parameters database for young children: The influences of age and walking speed. AB - BACKGROUND: Reference databases are mandatory in orthopaedics because they enable the detection of gait abnormalities in patients. Such databases rarely include data on children under seven years of age. In young children, gait is principally influenced by age and walking speed. The influence of the age-speed interaction has not been well established. Therefore, the objective of the present study is to propose normative values for biomechanical gait parameters in children taking into account age, walking speed, and the age-speed interaction. METHODS: Gait analyses were performed on 106 healthy children over a large age range (between one and seven years of age) during gait trials at a self-selected speed. From these gait cycles, biomechanical parameters, such as the joint angles and joint power of the lower limbs, were computed. Specific peak values and the times of occurrence of each biomechanical gait parameter were identified. Linear regressions are proposed for studying the influence of age, walking speed and the age-speed interaction. FINDINGS: Most of the regressions achieved good accuracy in fitting the curve peaks and times of occurrence, and the normal reference targets of biomechanical parameters could be deduced from these regressions. The biomechanical gait parameters of a pathological case were plotted against the normal reference targets to illustrate the relevance of the proposed targeting method. INTERPRETATION: The normal reference targets for biomechanical gait parameters based on age-speed regressions in a large database might help clinicians detect gait abnormalities in children from one to seven years of age. PMID- 25911205 TI - Assessing the clinical utility of combined movement examination in symptomatic degenerative lumbar spondylosis. AB - OBJECTIVES: The aim of this study is to report the development and validation of a low back computer-aided combined movement examination protocol in normal individuals and record treatment outcomes of cases with symptomatic degenerative lumbar spondylosis. DESIGN: Test-retest, following intervention. BACKGROUND: Self report assessments and combined movement examination were used to record composite spinal motion, before and following neurosurgical and pain medicine interventions. METHODS: 151 normal individuals aged from 20 years to 69 years were assessed using combined movement examination between L1 and S1 spinal levels to establish a reference range. Cases with degenerative low back pain and sciatica were assessed before and after therapeutic interventions with combined movement examination and a battery of self-report pain and disability questionnaires. Change scores for combined movement examination and all outcome measures were derived. FINDINGS: Computer-aided combined movement examination validation and intraclass correlation coefficient with 95% confidence interval and least significant change scores indicated acceptable reliability of combined movement examination when recording lumbar movement in normal subjects. In both clinical cases lumbar spine movement restrictions corresponded with self-report scores for pain and disability. Post-intervention outcomes all showed significant improvement, particularly in the most restricted combined movement examination direction. INTERPRETATION: This study provides normative reference data for combined movement examination that may inform future clinical studies of the technique as a convenient objective surrogate for important clinical outcomes in lumbar degenerative spondylosis. It can be used with good reliability, may be well tolerated by individuals in pain and appears to change in concert with validated measures of lumbar spinal pain, functional limitation and quality of life. PMID- 25911206 TI - Treating posttransplantation diabetes mellitus. AB - INTRODUCTION: Transplant physicians have tried to avoid graft rejection and early graft loss for many years. However, physicians are now aware about improving long term kidney and patient survival, a challenge that needs to focus on cardiovascular risk management. One major contributor of this risk is the development of posttransplant diabetes mellitus (PTDM). AREAS COVERED: We performed a literature search based on PubMed, covering prevalence, risk factors, prevention and treatment of PTDM. EXPERT OPINION: We need good quality clinical trials on PTDM prevention and management. In addition, basic and translational targeted studies should be encouraged, as high-quality molecular and mechanistic analyses are not frequent in this area. Hard end points such as patient and graft survival, cardiovascular and other microvascular complications in patients with PTDM are very difficult to reach, so we need good surrogate end points. The currently used ones are extrapolations from the general population. The target glucose or HbA1c levels to achieve are largely unknown. We need strategies to delay or prevent PTDM, and tailoring immunosuppression and antidiabetic management including early insulin and oral agents from the early transplant surgery could be essential. Treatment of established PTDM with the new families of oral hypoglycemic agents--secretagogues and incretins--needs higher levels of evidence to prove their short- and long-term safety and efficacy, even at early PTDM stages. PMID- 25911207 TI - Transport, resealing, and re-poration dynamics of two-pulse electroporation mediated molecular delivery. AB - Electroporation is of interest for many drug-delivery and gene-therapy applications. Prior studies have shown that a two-pulse-electroporation protocol consisting of a short-duration, high-voltage first pulse followed by a longer, low-voltage second pulse can increase delivery efficiency and preserve viability. In this work the effects of the field strength of the first and second pulses and the inter-pulse delay time on the delivery of two different-sized Fluorescein Dextran (FD) conjugates are investigated. A series of two-pulse-electroporation experiments were performed on 3T3-mouse fibroblast cells, with an alternating current first pulse to permeabilize the cell, followed by a direct-current second pulse. The protocols were rationally designed to best separate the mechanisms of permeabilization and electrophoretic transport. The results showed that the delivery of FD varied strongly with the strength of the first pulse and the size of the target molecule. The delivered FD concentration also decreased linearly with the logarithm of the inter-pulse delay. The data indicate that membrane resealing after electropermeabilization occurs rapidly, but that a non-negligible fraction of the pores can be reopened by the second pulse for delay times on the order of hundreds of seconds. The role of the second pulse is hypothesized to be more than just electrophoresis, with a minimum threshold field strength required to reopen nano-sized pores or defects remaining from the first pulse. These results suggest that membrane electroporation, sealing, and re-poration is a complex process that has both short-term and long-term components, which may in part explain the wide variation in membrane-resealing times reported in the literature. PMID- 25911208 TI - A comparative calorimetric and spectroscopic study of the effects of cholesterol and of the plant sterols beta-sitosterol and stigmasterol on the thermotropic phase behavior and organization of dipalmitoylphosphatidylcholine bilayer membranes. AB - We performed comparative DSC and FTIR spectroscopic measurements of the effects of beta-sitosterol (Sito) and stigmasterol (Stig) on the thermotropic phase behavior and organization of DPPC bilayers. Sito and Stig are the major sterols in the biological membranes of higher plants, whereas cholesterol (Chol) is the major sterol in mammalian membranes. Sito differs in structure from Chol in having an ethyl group at C24 of the alkyl side-chain, and Stig in having both the C24 ethyl group and trans-double bond at C22. Our DSC studies indicate that the progressive incorporation of Sito and Stig decrease the temperature and cooperativity of the pretransition of DPPC to a slightly lesser and greater extent than Chol, respectively, but the pretransition persists to 10 mol % sterol concentration in all cases. All three sterols produce essentially identical effects on the thermodynamic parameters of the sharp component of the DPPC main phase transition. However, the ability to increase the temperature and decrease the cooperativity and enthalpy of the broad component decreases in the order Chol>Sito>Stig. Nevertheless, at higher Sito/Stig concentrations, there is no evidence of sterol crystallites. Our FTIR spectroscopic studies demonstrate that Sito and especially Stig incorporation produces a smaller ordering of the hydrocarbon chains of fluid DPPC bilayers than does Chol. In general, the presence of a C24 ethyl group in the alkyl side-chain reduces the characteristic effects of Chol on the thermotropic phase behavior and organization of DPPC bilayer membranes, and a trans-double bond at C22 magnifies this effect. PMID- 25911209 TI - Antiepileptic drug prescribing patterns in Iraq and Afghanistan war veterans with epilepsy. AB - OBJECTIVE: We examined patterns of antiepileptic drug (AED) use in a cohort of Iraq/Afghanistan war veterans (IAVs) who were previously identified as having epilepsy. We hypothesized that clinicians would be more likely to prescribe newer AEDs and would select specific AEDs to treat seizures based on patient characteristics including gender and comorbidities. METHODS: From the cohort of IAVs previously identified with epilepsy between fiscal years 2009 and 2010, we selected those who received AEDs from the Veterans Health Administration in FY2010. Regimens were classified as monotherapy or polytherapy, and specific AED use was examine overall and by gender. Multivariable logistic regression examined associations of age; gender; race/ethnicity; medical, psychiatric, and neurological comorbidities; and receipt of neurology specialty care associated with the six most commonly used AEDs. RESULTS: Among 256,284 IAVs, 2123 met inclusion criteria (mean age: 33years; 89% men). Seventy-two percent (n=1526) received monotherapy, most commonly valproate (N=425) and levetiracetam (n=347). Sixty-one percent of those on monotherapy received a newer AED (levetiracetam, topiramate, lamotrigine, zonisamide, oxcarbazepine). Although fewer women than men received valproate, nearly 90% (N=45) were of reproductive age (<=45years). Antiepileptic drug prescribing patterns were associated with posttraumatic stress disorder, bipolar disorder, cerebrovascular disease, dementia/cognitive impairment, headache, and receipt of neurological specialty care (all p<0.01). SIGNIFICANCE: In this cohort of veterans with epilepsy, most received AED monotherapy and newer AEDs. Prescribing patterns were different for men and women. The patterns observed between AEDs and neurological/psychiatric comorbidities suggest that clinicians are practicing rational prescribing. PMID- 25911210 TI - Preliminary results of recurrent cubital tunnel syndrome treated with neurolysis and porcine extracellular matrix nerve wrap. AB - PURPOSE: To evaluate the clinical results of revision neurolysis and wrapping with porcine extracellular matrix (AxoGuard Nerve Protector, AxoGen Inc., Alachua, FL) for cubital tunnel syndrome after one previous surgical decompression. METHODS: Twelve patients with recurrent cubital tunnel syndrome were treated with decompression, porcine extracellular matrix nerve wrap, and minimal medial epicondylectomy (if not previously performed). The average follow up period was 41 months (range, 24-61 mo). All patients had recurrent symptoms after having previously undergone one surgical decompression. The mean patient age was 45 years (range, 30-58 y). All patients were evaluated subjectively and objectively (pain, satisfaction, static 2-point discrimination, grip strength, and pinch strength). RESULTS: A significant improvement was demonstrated in postoperative pain levels (from 8.5 to 1.7), grip strength (from 41% to 86% of the unaffected side), and pinch strength (from 64% to 83% of the unaffected side). Static 2-point discrimination improved from an average 10.4 mm preoperatively to 7.6 mm postoperatively. Eleven of 12 patients demonstrated 2 mm or more improvement in 2-point discrimination postoperatively. There were no complications related to the use of the porcine extracellular matrix for nerve wrapping. CONCLUSIONS: This study found that secondary decompression combined with porcine extracellular matrix nerve wrapping was an effective and safe treatment for patients with recurrent cubital tunnel syndrome. TYPE OF STUDY/LEVEL OF EVIDENCE: Therapeutic IV. PMID- 25911211 TI - Perioperative management of diabetic patients undergoing hand surgery. PMID- 25911212 TI - Educational video recording and editing for the hand surgeon. AB - Digital video recordings are increasingly used across various medical and surgical disciplines including hand surgery for documentation of patient care, resident education, scientific presentations, and publications. In recent years, the introduction of sophisticated computer hardware and software technology has simplified the process of digital video production and improved means of disseminating large digital data files. However, the creation of high-quality surgical video footage requires a basic understanding of key technical considerations, together with creativity and sound aesthetic judgment of the videographer. In this article we outline the practical steps involved in equipment preparation, video recording, editing, and archiving, as well as guidance for the choice of suitable hardware and software equipment. PMID- 25911213 TI - Ultrasonography can be used to assess phalanx fractures. PMID- 25911214 TI - Letter regarding "conservative treatment of thumb base osteoarthritis: a systematic review". PMID- 25911215 TI - In reply. PMID- 25911216 TI - Is Computed Tomography an Adequate Imaging Modality for the Evaluation of Juvenile Ossifying Fibroma? A Comparison of 2 Imaging Modalities (Computed Tomography and Magnetic Resonance Imaging). AB - PURPOSE: Given the problems of overuse of medical technology and the current burden of health care cost in the United States, it is important to establish clear imaging guidelines to diagnose conditions such as juvenile ossifying fibroma (JOF). This study compared the efficacy of computed tomography (CT) and magnetic resonance imaging (MRI) in the evaluation of JOF and thus could aid establishing such guidelines. MATERIALS AND METHODS: Radiologic criteria were established by 2 radiologists to compare the efficacy of CT and MRI in the evaluation of JOF. The following parameters were compared: presence of a well defined corticated border, presence of a well-delineated internal calcified component, fluid-to-fluid levels, and anatomic extent of the lesion. Six patients diagnosed with JOF of the craniofacial bones from 2002 to 2013 had preoperative CT and MRI studies available for review. RESULTS: After review of CT and MRI images, fluid-to-fluid levels and anatomic extent of the lesions were comparable on CT and MRI. However, the corticated borders and the internal calcified component were better defined on CT images, which also enabled for distinction between the 2 subtypes of JOF. No MRI characteristics were identified that allowed for this distinction. CONCLUSION: Based on these findings, CT is an adequate and preferable imaging modality in the evaluation of JOF. PMID- 25911217 TI - Selective nuclei accumulation of ruthenium(II) complex enantiomers that target G quadruplex DNA. AB - Different enantiomers exhibit large differences in their biological activity and/or toxicity, but they rarely involve the relationship of the agents for molecular and cellular imaging with the chiral structure of ruthenium complexes. Here, we report that an enantiomer of a polypyridyl ruthenium complex can selectively accumulate in the nucleus of HepG2 cells. Confocal laser scanning microscopy studies show that this phenomenon occurs via a non-endocytotic, but temperature-dependent, mechanism of cellular uptake in HepG2 cells. DNA oligonucleotides with repetitive tracts of guanine bases that can form G quadruplex structures have aroused interest as therapeutic agents and as targets for anticancer drug design. Various biophysical techniques show that the Lambda enantiomer of ruthenium complexes can selectively stabilize human telomeric G quadruplex DNA and has a strong preference for G-quadruplex over duplex DNA. Judged from the NMR results, we speculate that at higher 4:1 ligand/G-quadruplex stoichiometry, complex Lambda-Ru is likely to bind with each groove of the tetraplex in a dimeric form or intercalate with the G-tetrad in the 3' terminal face and coexist with other modes. The molecular modeling analysis is in agreement with the NMR titrations performed in this investigation indicating that ruthenium complexes are actually characterized by a mixed binding mode. The results provide many opportunities for the development of novel agents for living cell-related studies. PMID- 25911218 TI - Potential cytotoxicity of water-soluble fraction of dust and particulate matters and relation to metal(loid)s based on three human cell lines. AB - Hepatocellular liver carcinoma (HepG2), human skin derived keratinocyte (KERTr,) and lung epithelial carcinoma (A549) were employed in MTT assay to evaluate the cytotoxicity of water-soluble fraction of road dust, air-conditioning (AC) filter dust and PM2.5 via ingestion, dermal contact and inhalation. Their effects on cell growth were dependent on exposure time and concentration. The LC20s of PM2.5 for A549 cell were approximately one order of magnitude lower than those of road dust and AC filter dust for KERTr cell and HepG2 cell. The LC20s of aqueous extracts were negatively correlated to the water-soluble metal(loid)s contained in dust coarse particles (KERTr: p=0.004; HepG2: p<0.001). However, no significant correlation between soluble metal(loid)s and LC20s of PM2.5 was observed for A549 cell (p>0.05). Other water-soluble components in dust and PM might cause the cell hazards synergistically or additively with metal(loid)s. PMID- 25911219 TI - Postpartum glucose testing for women with gestational diabetes mellitus: Improving regional recall rates. AB - Our aim was to evaluate attendance for postpartum glucose testing among women attending five antenatal centres with a diagnosis of GDM in the preceding pregnancy. A central, regional coordinator who made verbal and written contact with each individual facilitated a favourable recall rate of 75%. PMID- 25911220 TI - Npas4 deficiency increases vulnerability to juvenile stress in mice. AB - During specific windows of postnatal brain development, individuals are particularly susceptible to developing mental illnesses in adulthood. Adolescence is such a window during which environmental stress can have long-lasting consequences on social and cognitive functions. In individuals, highly vulnerable to stress, a relatively mild stressful situation can trigger the onset of psychiatric conditions. The genetic factors and mechanisms underlying vulnerability to stress are not well understood. Here, we show that variations in expression of the brain-specific transcription factor Npas4 contributes to the long-term consequences of juvenile stress on cognitive abilities. We observed that transgenic Npas4-deficient mice exposed to chronic mild stress during adolescence (but not during adulthood) develop prefrontal cortex-dependent cognitive deficits in adulthood, while the same stress did not affect Npas4 wild type mice. These cognitive deficits were accompanied by fewer neuroblasts in the subventricular zone, and reduced ability of these immature neuronal cells to migrate away from this neurogenic zone toward cortical regions. These findings suggest for the first time that the transcription factor Npas4 could play a significant role in coping with juvenile stress. They also suggest that Npas4 could modulate resilience or vulnerability to stress by mediating the effects of stress on neurogenesis. PMID- 25911221 TI - The current crisis in the NHS: are we missing the point? An essay by Jan Filochowski. PMID- 25911222 TI - Increased risk of mycobacterial infections associated with anti-rheumatic medications. AB - RATIONALE: Anti-tumour necrosis factor (TNF) agents and other anti-rheumatic medications increase the risk of TB in rheumatoid arthritis (RA). Whether they increase the risk of infections with nontuberculous mycobacteria (NTM) is uncertain. OBJECTIVES: To determine the effect of anti-TNF therapy and other anti rheumatic drugs on the risk of NTM disease and TB in older patients with RA. METHODS: Population-based nested case-control study among Ontario seniors aged >=67 years with RA who were prescribed at least one anti-rheumatic medication between 2001 and 2011. We identified cases of TB and NTM disease microbiologically and identified drug exposures using linked prescription drug claims. We estimated ORs using conditional logistic regression, controlling for several potential confounders. MEASUREMENTS AND MAIN RESULTS: Among 56 269 older adults with RA, we identified 37 cases of TB and 211 cases of NTM disease; each case was matched to up to 10 controls. Individuals with TB or NTM disease were both more likely to be using anti-TNF therapy (compared with non-use); adjusted ORs (95% CIs) were 5.04 (1.27 to 20.0) and 2.19 (1.10 to 4.37), respectively. Exposure to leflunomide and other anti-rheumatic drugs with high immunosuppressing potential also were associated with both TB and NTM disease, while oral corticosteroids and hydroxychloroquine were associated with NTM disease. CONCLUSIONS: Anti-TNF use is associated with increased risk of both TB and NTM disease, but appears to be a relatively greater risk for TB. Several other anti-rheumatic drugs were also associated with mycobacterial infections. PMID- 25911223 TI - Short-term and long-term response to pulmonary exacerbation treatment in cystic fibrosis. AB - BACKGROUND: Treatment of pulmonary exacerbations (PEx) in cystic fibrosis (CF) varies widely with no consensus on management practices or best indicators of therapeutic success. To design trials evaluating PEx treatment factors, we characterise the heterogeneity of PEx care in adults and paediatrics, and correlate it with measures of clinical response including short-term and long term lung function changes, change in symptom severity score and time to next intravenous antibiotic therapy. METHODS: Data were used from a prospective observational study of patients with CF >=10 years of age enrolled at six sites between 2007 and 2010. All were started on intravenous antibiotics for a clinically diagnosed PEx. Analysis of variance, logistic and Cox regression were used to examine the association of treatment factors with short-term and long term clinical response. RESULTS: Of 123 patients with CF (60% women, aged 23.1+/ 10.2 years), 33% experienced <10% relative improvement in FEV1 during treatment, which was associated with failing to recover baseline lung function 3 months after treatment (OR=7.8, 95% CI 1.9 to 31.6, p=0.004) and a longer time to next intravenous antibiotic (HR=0.48, 95% CI 0.27 to 0.85, p=0.011). Symptom improvement was observed but was not associated with subsequent lung function or time to next antibiotic therapy, which had a median recurrence time of 143 days. CONCLUSIONS: Immediate symptomatic or respiratory response to PEx treatment did not have a clear relationship with subsequent outcomes such as lung function or intravenous antibiotic-free interval. These results can inform future research of treatment regimens for PEx in terms of interventions and outcome measures. TRIAL REGISTRATION: NCT00788359 (www.clinicaltrials.gov). PMID- 25911224 TI - Longitudinal Associations among Discordant Sexual Orientation Dimensions and Hazardous Drinking in a Cohort of Sexual Minority Women. AB - We examined differences between sexual minority women's (SMW's) sexual identity and sexual behavior or sexual attraction as potential contributors to hazardous drinking across a 10-year period. Data are from a longitudinal study examining drinking and drinking-related problems in a diverse, community-based sample of self-identified SMW (Wave 1: n = 447; Wave 2: n = 384; Wave 3: n = 354). Longitudinal cross-lagged models showed that SMW who report higher levels of identity-behavior or identity-attraction discordance may be at greater risk of concurrent and subsequent hazardous drinking. Results of multigroup models suggest that sexual orientation discordance is a more potent risk factor for risky drinking outcomes among SMW in older adulthood than in younger adulthood. Findings support that discordance between sexual orientation dimensions may contribute to hazardous drinking among SMW and provide evidence that cognitive behavioral consistency is important for individuals expressing diverse and fluid sexual identities, attraction, and behavior. PMID- 25911225 TI - The Aspergillus fumigatus sitA Phosphatase Homologue Is Important for Adhesion, Cell Wall Integrity, Biofilm Formation, and Virulence. AB - Aspergillus fumigatus is an opportunistic pathogenic fungus able to infect immunocompromised patients, eventually causing disseminated infections that are difficult to control and lead to high mortality rates. It is important to understand how the signaling pathways that regulate these factors involved in virulence are orchestrated. Protein phosphatases are central to numerous signal transduction pathways. Here, we characterize the A. fumigatus protein phosphatase 2A SitA, the Saccharomyces cerevisiae Sit4p homologue. The sitA gene is not an essential gene, and we were able to construct an A. fumigatus null mutant. The DeltasitA strain had decreased MpkA phosphorylation levels, was more sensitive to cell wall-damaging agents, had increased beta-(1,3)-glucan and chitin, was impaired in biofilm formation, and had decreased protein kinase C activity. The DeltasitA strain is more sensitive to several metals and ions, such as MnCl2, CaCl2, and LiCl, but it is more resistant to ZnSO4. The DeltasitA strain was avirulent in a murine model of invasive pulmonary aspergillosis and induces an augmented tumor necrosis factor alpha (TNF-alpha) response in mouse macrophages. These results stress the importance of A. fumigatus SitA as a possible modulator of PkcA/MpkA activity and its involvement in the cell wall integrity pathway. PMID- 25911226 TI - Multiple Conserved Heteroplasmic Sites in tRNA Genes in the Mitochondrial Genomes of Terrestrial Isopods (Oniscidea). AB - Mitochondrial genome structure and organization are relatively conserved among metazoans. However, in many isopods, especially the terrestrial isopods (Oniscidea), the mitochondrial genome consists of both ~14-kb linear monomers and ~28-kb circular dimers. This unusual organization is associated with an ancient and conserved constitutive heteroplasmic site. This heteroplasmy affects the anticodon of a tRNA gene, allowing this single locus to function as a "dual" tRNA gene for two different amino acids. Here, we further explore the evolution of these unusual mitochondrial genomes by assembling complete mitochondrial sequences for two additional Oniscidean species, Trachelipus rathkei and Cylisticus convexus. Strikingly, we find evidence of two additional heteroplasmic sites that also alter tRNA anticodons, creating additional dual tRNA genes, and that are conserved across both species. These results suggest that the unique linear/circular organization of isopods' mitochondrial genomes may facilitate the evolution of stable mitochondrial heteroplasmies, and, conversely, once such heteroplasmies have evolved, they constrain the multimeric structure of the mitochondrial genome in these species. Finally, we outline some possible future research directions to identify the factors influencing mitochondrial genome evolution in this group. PMID- 25911228 TI - Two Routes to Genetic Suppression of RNA Trimethylguanosine Cap Deficiency via C Terminal Truncation of U1 snRNP Subunit Snp1 or Overexpression of RNA Polymerase Subunit Rpo26. AB - The trimethylguanosine (TMG) caps of small nuclear (sn) RNAs are synthesized by the enzyme Tgs1 via sequential methyl additions to the N2 atom of the m(7)G cap. Whereas TMG caps are inessential for Saccharomyces cerevisiae vegetative growth at 25 degrees to 37 degrees , tgs1? cells that lack TMG caps fail to thrive at 18 degrees . The cold-sensitive defect correlates with ectopic stoichiometric association of nuclear cap-binding complex (CBC) with the residual m(7)G cap of the U1 snRNA and is suppressed fully by Cbc2 mutations that weaken cap binding. Here, we show that normal growth of tgs1? cells at 18 degrees is also restored by a C-terminal deletion of 77 amino acids from the Snp1 subunit of yeast U1 snRNP. These results underscore the U1 snRNP as a focal point for TMG cap function in vivo. Casting a broader net, we conducted a dosage suppressor screen for genes that allowed survival of tgs1? cells at 18 degrees . We thereby recovered RPO26 (encoding a shared subunit of all three nuclear RNA polymerases) and RPO31 (encoding the largest subunit of RNA polymerase III) as moderate and weak suppressors of tgs1? cold sensitivity, respectively. A structure-guided mutagenesis of Rpo26, using rpo26? complementation and tgs1? suppression as activity readouts, defined Rpo26-(78-155) as a minimized functional domain. Alanine scanning identified Glu89, Glu124, Arg135, and Arg136 as essential for rpo26? complementation. The E124A and R135A alleles retained tgs1? suppressor activity, thereby establishing a separation-of-function. These results illuminate the structure activity profile of an essential RNA polymerase component. PMID- 25911229 TI - Maximum-Likelihood Tree Estimation Using Codon Substitution Models with Multiple Partitions. AB - Many protein sequences have distinct domains that evolve with different rates, different selective pressures, or may differ in codon bias. Instead of modeling these differences by more and more complex models of molecular evolution, we present a multipartition approach that allows maximum-likelihood phylogeny inference using different codon models at predefined partitions in the data. Partition models can, but do not have to, share free parameters in the estimation process. We test this approach with simulated data as well as in a phylogenetic study of the origin of the leucin-rich repeat regions in the type III effector proteins of the pythopathogenic bacteria Ralstonia solanacearum. Our study does not only show that a simple two-partition model resolves the phylogeny better than a one-partition model but also gives more evidence supporting the hypothesis of lateral gene transfer events between the bacterial pathogens and its eukaryotic hosts. PMID- 25911227 TI - Transcriptional Response to Acute Thermal Exposure in Juvenile Chinook Salmon Determined by RNAseq. AB - Thermal exposure is a serious and growing challenge facing fish species worldwide. Chinook salmon (Oncorhynchus tshawytscha) living in the southern portion of their native range are particularly likely to encounter warmer water due to a confluence of factors. River alterations have increased the likelihood that juveniles will be exposed to warm water temperatures during their freshwater life stage, which can negatively impact survival, growth, and development and pose a threat to dwindling salmon populations. To better understand how acute thermal exposure affects the biology of salmon, we performed a transcriptional analysis of gill tissue from Chinook salmon juveniles reared at 12 degrees and exposed acutely to water temperatures ranging from ideal to potentially lethal (12 degrees to 25 degrees ). Reverse-transcribed RNA libraries were sequenced on the Illumina HiSeq2000 platform and a de novo reference transcriptome was created. Differentially expressed transcripts were annotated using Blast2GO and relevant gene clusters were identified. In addition to a high degree of downregulation of a wide range of genes, we found upregulation of genes involved in protein folding/rescue, protein degradation, cell death, oxidative stress, metabolism, inflammation/immunity, transcription/translation, ion transport, cell cycle/growth, cell signaling, cellular trafficking, and structure/cytoskeleton. These results demonstrate the complex multi-modal cellular response to thermal stress in juvenile salmon. PMID- 25911230 TI - Tracing the Evolutionary History of Inositol, 1, 4, 5-Trisphosphate Receptor: Insights from Analyses of Capsaspora owczarzaki Ca2+ Release Channel Orthologs. AB - Cellular Ca(2+) homeostasis is tightly regulated and is pivotal to life. Inositol 1,4,5-trisphosphate receptors (IP3Rs) and ryanodine receptors (RyRs) are the major ion channels that regulate Ca(2+) release from intracellular stores. Although these channels have been extensively investigated in multicellular organisms, an appreciation of their evolution and the biology of orthologs in unicellular organisms is largely lacking. Extensive phylogenetic analyses reveal that the IP3R gene superfamily is ancient and diverged into two subfamilies, IP3R A and IP3R-B/RyR, at the dawn of Opisthokonta. IP3R-B/RyR further diversified into IP3R-B and RyR at the stem of Filozoa. Subsequent evolution and speciation of Holozoa is associated with duplication of IP3R-A and RyR genes, and loss of IP3R-B in the vertebrate lineages. To gain insight into the properties of IP3R important for the challenges of multicellularity, the IP3R-A and IP3R-B family orthologs were cloned from Capsaspora owczarzaki, a close unicellular relative to Metazoa (designated as CO.IP3R-A and CO.IP3R-B). Both proteins were targeted to the endoplasmic reticulum. However, CO.IP3R-A, but strikingly not CO.IP3R-B, bound IP3, exhibited robust Ca(2+) release activity and associated with mammalian IP3Rs. These data indicate strongly that CO.IP3R-A as an exemplar of ancestral IP3R-A orthologs forms bona fide IP3-gated channels. Notably, however, CO.IP3R-A appears not to be regulated by Ca(2+), ATP or Protein kinase A-phosphorylation. Collectively, our findings explore the origin, conservation, and diversification of IP3R gene families and provide insight into the functionality of ancestral IP3Rs and the added specialization of these proteins in Metazoa. PMID- 25911232 TI - Microbiota regulation of the Mammalian gut-brain axis. AB - The realization that the microbiota-gut-brain axis plays a critical role in health and disease has emerged over the past decade. The brain-gut axis is a bidirectional communication system between the central nervous system (CNS) and the gastrointestinal tract. Regulation of the microbiota-brain-gut axis is essential for maintaining homeostasis, including that of the CNS. The routes of this communication are not fully elucidated but include neural, humoral, immune, and metabolic pathways. A number of approaches have been used to interrogate this axis including the use of germ-free animals, probiotic agents, antibiotics, or animals exposed to pathogenic bacterial infections. Together, it is clear that the gut microbiota can be a key regulator of mood, cognition, pain, and obesity. Understanding microbiota-brain interactions is an exciting area of research which may contribute new insights into individual variations in cognition, personality, mood, sleep, and eating behavior, and how they contribute to a range of neuropsychiatric diseases ranging from affective disorders to autism and schizophrenia. Finally, the concept of psychobiotics, bacterial-based interventions with mental health benefit, is also emerging. PMID- 25911231 TI - A Coevolutionary Arms Race between Hosts and Viruses Drives Polymorphism and Polygenicity of NK Cell Receptors. AB - Natural killer cell receptors (NKRs) monitor the expression of major histocompatibility class I (MHC-I) and stress molecules to detect unhealthy tissue, such as infected or tumor cells. The NKR gene family shows a remarkable genetic diversity, containing several genes encoding receptors with activating and inhibiting signaling, and varying in gene content and allelic polymorphism. The expansion of the NKR genes is species-specific, with different species evolving alternative expanded NKR genes, which encode structurally different proteins, yet perform comparable functions. So far, the biological function of this expansion within the NKR cluster has remained poorly understood. To study the evolution of NKRs, we have developed an agent-based model implementing a coevolutionary scenario between hosts and herpes-like viruses that are able to evade the immune response by downregulating the expression of MHC-I on the cell surface. We show that hosts evolve specific inhibitory NKRs, specialized to particular MHC-I alleles in the population. Viruses in our simulations readily evolve proteins mimicking the MHC molecules of their host, even in the absence of MHC-I downregulation. As a result, the NKR locus becomes polygenic and polymorphic, encoding both specific inhibiting and activating receptors to optimally protect the hosts from coevolving viruses. PMID- 25911233 TI - Aromatic metabolism of filamentous fungi in relation to the presence of aromatic compounds in plant biomass. AB - The biological conversion of plant lignocellulose plays an essential role not only in carbon cycling in terrestrial ecosystems but also is an important part of the production of second generation biofuels and biochemicals. The presence of the recalcitrant aromatic polymer lignin is one of the major obstacles in the biofuel/biochemical production process and therefore microbial degradation of lignin is receiving a great deal of attention. Fungi are the main degraders of plant biomass, and in particular the basidiomycete white rot fungi are of major importance in converting plant aromatics due to their ability to degrade lignin. However, the aromatic monomers that are released from lignin and other aromatic compounds of plant biomass are toxic for most fungi already at low levels, and therefore conversion of these compounds to less toxic metabolites is essential for fungi. Although the release of aromatic compounds from plant biomass by fungi has been studied extensively, relatively little attention has been given to the metabolic pathways that convert the resulting aromatic monomers. In this review we provide an overview of the aromatic components of plant biomass, and their release and conversion by fungi. Finally, we will summarize the applications of fungal systems related to plant aromatics. PMID- 25911234 TI - Candida survival strategies. AB - Only few Candida species, e.g., Candida albicans, Candida glabrata, Candida dubliniensis, and Candida parapsilosis, are successful colonizers of a human host. Under certain circumstances these species can cause infections ranging from superficial to life-threatening disseminated candidiasis. The success of C. albicans, the most prevalent and best studied Candida species, as both commensal and human pathogen depends on its genetic, biochemical, and morphological flexibility which facilitates adaptation to a wide range of host niches. In addition, formation of biofilms provides additional protection from adverse environmental conditions. Furthermore, in many host niches Candida cells coexist with members of the human microbiome. The resulting fungal-bacterial interactions have a major influence on the success of C. albicans as commensal and also influence disease development and outcome. In this chapter, we review the current knowledge of important survival strategies of Candida spp., focusing on fundamental fitness and virulence traits of C. albicans. PMID- 25911235 TI - Tailoring specialized metabolite production in streptomyces. AB - Streptomycetes are prolific producers of a plethora of medically useful metabolites. These compounds are made by complex secondary (specialized) metabolic pathways, which utilize primary metabolic intermediates as building blocks. In this review we discuss the evolution of specialized metabolites and how expansion of gene families in primary metabolism has lead to the evolution of diversity in these specialized metabolic pathways and how developing a better understanding of expanded primary metabolic pathways can help enhance synthetic biology approaches to industrial pathway engineering. PMID- 25911236 TI - Serum Levels of Biomarkers of Immune Activation and Associations With Neurological Impairment in Relapsing-Remitting Multiple Sclerosis Patients During Remission. AB - INTRODUCTION: Although much is known about cytokines and adhesion molecules during an active course of multiple sclerosis (MS), there is limited information about their serum levels during remission. OBJECTIVE: This study aimed to (1) compare peripheral levels of tumor necrosis factor-alpha (TNF-alpha), soluble interleukin-2 receptor alpha (sIL-2Ralpha), soluble intercellular adhesion molecule-1 (sICAM-1), and soluble E-selectin (sE-selectin) in MS patients during clinical remission with those of healthy controls and (2) explore possible relationships between the levels of these cytokines and adhesion molecules and neurological impairment. METHODS: Initially, 92 patients with relapsing-remitting multiple sclerosis (RRMS) who were in clinical remission and 30 healthy controls were recruited for this study. The severity of neurological impairment was assessed with the Expanded Disability Status Scale (EDSS). Serum concentrations of TNF-alpha, sIL-2Ralpha, sICAM-1, and sE-selectin were determined using the sandwich enzyme-linked immunosorbent (ELISA) technique and compared between patients and controls. In a subset of RRMS patients (n = 67), the levels of these cytokines and adhesion molecules were compared between subgroups of patients based on scores on the EDSS subscales, which measure disability level for specific neurological functions. RESULTS: The MS patients' TNF-alpha, sICAM-1, and sE-selectin levels were markedly lower than those of the controls, while their sIL-2Ralpha level was higher. The serum sICAM-1 concentration was positively associated with EDSS total score (rho = .291, p = .017) as well as with the EDSS pyramidal (rho = .267, p = .029) and cerebellar subscores (rho = .303, p = .013). In the patients with cerebellar deficits and severe brain stem dysfunction, sICAM-1 levels were upregulated. CONCLUSION: Although a decreased sICAM-1 concentration was observed in RRMS patients in remission as compared to healthy controls, sICAM-1 seemed to reflect neurological impairment and clinical disability. These data suggest that increasing serum sICAM-1 levels may be associated with progression of cerebellar or brain stem perturbations. However, further studies are required to confirm these findings in a larger population of RRMS patients. PMID- 25911238 TI - Sample conditions determine the ability of thrombin generation parameters to identify bleeding phenotype in FXI deficiency. AB - Individuals with Factor XI (FXI) deficiency have a variable bleeding tendency that does not correlate with FXI:C levels or genotype. Comparing a range of sample conditions, we tested whether the thrombin generation assay (TGA) could discriminate between control subjects (n = 50) and FXI-deficient individuals (n = 97), and between those with bleeding tendency (n = 50) and without (n = 24). The comparison used platelet-rich plasma (PRP) and platelet-poor plasma (PPP), either with or without corn trypsin inhibitor (CTI) to prevent contact activation, over a range of tissue factor (TF) concentrations. When contact activation was inhibited and platelets were absent, FXI:C levels did not correlate with thrombin generation parameters, and control and FXI-deficient individuals were not distinguished. In all other sample types, the best discrimination was obtained using TF 0.5 pM and assay measures: endogenous thrombin potential (ETP) and peak height. We showed that although a number of conditions could distinguish differences between the groups tested, TGA measured in PRP with CTI best differentiated between bleeders and nonbleeders. These measures provided high sensitivity and specificity (peak height receiver operating characteristic [ROC] area under the curve [AUC] = 0.9362; P < .0001) (ETP ROC AUC = 0.9362; P < .0001). We conclude that by using sample conditions directed to test specific pathways of FXI activation, the TGA can identify bleeding phenotype in FXI deficiency. PMID- 25911237 TI - RUNX1 represses the erythroid gene expression program during megakaryocytic differentiation. AB - The activity of antagonizing transcription factors represents a mechanistic paradigm of bidirectional lineage-fate control during hematopoiesis. At the megakaryocytic/erythroid bifurcation, the cross-antagonism of krueppel-like factor 1 (KLF1) and friend leukemia integration 1 (FLI1) has such a decisive role. However, how this antagonism is resolved during lineage specification is poorly understood. We found that runt-related transcription factor 1 (RUNX1) inhibits erythroid differentiation of murine megakaryocytic/erythroid progenitors and primary human CD34(+) progenitor cells. We show that RUNX1 represses the erythroid gene expression program during megakaryocytic differentiation by epigenetic repression of the erythroid master regulator KLF1. RUNX1 binding to the KLF1 locus is increased during megakaryocytic differentiation and counterbalances the activating role of T-cell acute lymphocytic leukemia 1 (TAL1). We found that corepressor recruitment by RUNX1 contributes to a block of the KLF1-dependent erythroid gene expression program. Our data indicate that the repressive function of RUNX1 influences the balance between erythroid and megakaryocytic differentiation by shifting the balance between KLF1 and FLI1 in the direction of FLI1. Taken together, we show that RUNX1 is a key player within a network of transcription factors that represses the erythroid gene expression program. PMID- 25911239 TI - Radiation triggering immune response and inflammation. AB - Radiation therapy (RT) is a well-established but still under optimization branch of Cancer Therapy (CT). RT uses electromagnetic waves or charged particles in order to kill malignant cells, by accumulating the energy onto these cells. The issue at stake for RT, as well as for any other Cancer Therapy technique, is always to kill only cancer cells, without affecting the surrounding healthy ones. This perspective of CT is usually described under the terms "specificity" and "selectivity". Specificity and selectivity are the ideal goal, but the ideal is never entirely achieved. Thus, in addition to killing healthy cells, changes and effects are observed in the immune system after irradiation. In this review, we mainly focus on the effects of ionizing radiation on the immune system and its components like bone marrow. Additionally, we are interested in the effects and benefits of low-dose ionizing radiation on the hematopoiesis and immune response. Low dose radiation has been shown to induce biological responses like inflammatory responses, innate immune system activation and DNA repair (adaptive response). This review reveals the fact that there are many unanswered questions regarding the role of radiation as either an immune-activating (low dose) or immunosuppressive (high dose) agent. PMID- 25911240 TI - The regulation of radiosensitivity by p53 and its acetylation. AB - The p53 signaling pathway plays critical roles in determining the radio sensitivity of normal tissues but is frequently inactivated in cancer. In various cancer cells, p53 has different effects on radio-sensitivity through complex mechanisms. Acetylation of p53 is an important means of post-translational modifications and is indispensable for its activation that is a reversible enzymatic process. Both acetylation and deacetylation of p53 are involved in the fine regulation of cellular responses to DNA damage and genotoxic stress, such as radiation. Targeting the acetylation of p53 may enable the modulation of radio sensitivity of cancer cells. PMID- 25911241 TI - A unique presentation of a renal clear cell carcinoma with atypical metastases. AB - INTRODUCTION: Renal cancer is a relatively common neoplasia with renal clear cell carcinoma being the most frequent histological type. This tumor has a strong tendency to metastasize virtually to all organs. Today, new diagnostic tools allow physicians to distinguish between those patients with "incidental findings" and those with advanced metastatic disease. PRESENTATION OF CASE: A 70-year-old male with multiple indolent subcutaneous masses underwent colonoscopy after a positive fecal screening test for colorectal carcinoma. A rectal lesion was discovered but biopsy was negative. CT scan revealed advanced renal cancer involving the peritoneal cavity, retroperitoneum and lung. Biopsy of subcutaneous masses confirmed the suspected metastases. The patient underwent surgery (an open left nephrectomy with rectosigmoid resection and metastases debulking) because of a high risk of bowel obstruction and increasing anemia. After three years of multi-targeted therapy and follow-up, the patient is still asymptomatic and in good general condition. DISCUSSION: Treatment of metastatic renal cancer is still controversial even if more than 30% of patients have metastasis at the time of diagnosis. Recently introduced targeted therapies are encouraging but still present problems with side effects and an unlimited period of efficacy. Although there is no consensus, several studies and guidelines consider metastasectomy to be a valid option. CONCLUSION: Recent series highlight surgery as a key-point in the management of advanced renal clear cell carcinoma. Our case demonstrates the validity of a surgical strategy supported by a multidisciplinary approach. PMID- 25911242 TI - TLR9-deficiency reduces TLR1, TLR2 and TLR3 expressions in Leishmania major infected macrophages. AB - The parasite Leishmania major counteractively modulates TLR2 and TLR9 expression and their functions. Although TLR1, TLR3, TLR4, and TLR7 are also implicated in Leishmania infection, whether their expression was altered in TLR2 or TLR9 deficiency remained unknown. Therefore, we examined TLR1, TLR3, TLR4 and TLR7 expression in L. major infection in TLR2-deficient or TLR9-deficient macrophages. We observed that TLR9-deficiency reduced TLR1, TLR2 and TLR3 but not TLR7 expression in the macrophages treated with live or killed L. major promastigotes. TLR2-deficiency had little effects by comparison. TLR9-deficient macrophages had reduced CD40 expression and less IL-12 and TNF-alpha expression. Thus, we report that TLR9 modulates TLR1, TLR2 and TLR3, but not TLR7, expression in L. major infected macrophages. PMID- 25911243 TI - In-vitro sensitivity of Pakistani Leishmania tropica field isolate against buparvaquone in comparison to standard anti-leishmanial drugs. AB - In this study, in vitro anti-leishmanial activity of buparvaquone was evaluated against promastigotes and intracellular amastigotes of Pakistani Leishmania tropica isolate KWH23 in relation to the current standard chemotherapy for leishmaniasis (sodium stibogluconate, sodium stibogluconate, amphotericin B and miltefosine). For buparvaquone, mean % inhibition in intracellular amastigotes at four different concentrations (1.35 uM, 0.51 uM, 0.17 uM and 0.057 uM) was 78%, 44%, 20% and 14% respectively, whereas, against promastigotes it was 89%, 77%, 45% and 35% respectively. IC50 values calculated to estimate the anti-leishmanial activity of buparvaquone against intra-cellular amastigotes and promastigotes was 0.53 uM (95% C.I. = 0.32-0.89) and 0.15 uM (95% C.I. = 0.01-1.84) respectively. Amphotericin B was the most potent in-vitro drug tested, with an IC50 of 0.075 uM (95% C.I. = 0.006-0.907) against promastigotes, and 0.065 uM (95% C.I. = 0.048 0.089) against intra-cellular amastigotes. Amphotericin B was more cytotoxic against THP1 cells, with an IC50 of 0.15 uM (95% C.I. = 0.01-0.95) and an apparent in-vitro therapeutic index of 2.0, than was buparvaquone, with an IC50 of 12.03 uM (95% C.I. = 5.36-26.96) against THP1 cells and a therapeutic index of 80.2. The study proposes that buparvaquone may be further investigated as a candidate drug for treatment of cutaneous leishmaniasis. PMID- 25911244 TI - Impact of age-related socio-economic and clinical determinants of quality of life among long-term breast cancer survivors. AB - OBJECTIVES: The main purpose of this study was to identify age-related socioeconomic and clinical determinants of quality of life among breast cancer survivors five years after the diagnosis. The secondary objective was to describe quality of life in the studied population according to age. STUDY DESIGN: A cross sectional survey in five-year breast cancer survivors was conducted in women diagnosed with breast cancer in 2007 and 2008 in Cote d'Or. MAIN OUTCOME MEASURES: Quality of life was assessed with the SF-12, the EORTC-QLQ-C30 and the EORTC-QLQ-BR23 questionnaires. Socio-economic deprivation was assessed by the EPICES questionnaire. Social support was assessed by the Sarason questionnaire and clinical features were collected through the Cote d'Or breast cancer registry. Age-related determinants of quality of life were identified using multivariate mixed model analysis for each SF-12 dimension. RESULTS: Overall 396 women completed the questionnaires. Women aged <65 years had a better quality of life and a greater availability of social support than did women aged >=65 years. Body mass index, relapse and EPICES were found to be determinants of quality of life in younger women (p<0.006). For older women, comorbidities and EPICES deprivation scores were predictors of low quality of life scores (p<0.006). CONCLUSIONS: Five years after breast cancer diagnosis, disease severity did not affect quality of life. The major determinants of quality of life in younger women were disease relapse and EPICES deprivation scores while those in older women were comorbidities and EPICES deprivation scores. PMID- 25911245 TI - Identifying prediabetes - Is it beneficial in the long run? AB - The rates of long-term diabetes related complications have declined substantially over the past decade. On the contrary, the growth in the incidence of prediabetes is note-worthy - especially in the population 60 years and above. As a result, the focus is now shifting toward early identification and prevention of diabetes. Prediabetes is a high risk state in the continuum of glycemic progression and beta cell dysfunction toward the development of diabetes mellitus. Observational studies have shown association of prediabetes with increased incidence of vascular complications. Long-term prospective randomized clinical trials across the globe have demonstrated a reduction in progression of prediabetes when lifestyle modifications are adopted and these effects can last up to 20 years beyond the period of intervention. While there has been recent interest in using pharmacotherapy for diabetes prevention, they have not been shown to be superior to lifestyle changes. This review hopes to provide a concise summary for the interested reader. PMID- 25911246 TI - Predicting rectal cancer T stage using circumferential tumor extent determined by computed tomography colonography. AB - BACKGROUND AND AIM: Patients with stage T3 or T4 rectal cancer are candidates for neoadjuvant chemoradiation therapy. The aim of this study is to clarify the usefulness of circumferential tumor extent determined by computed tomography (CT) colonography in differentiating T3 or T4 from T1 or T2 rectal cancer. METHODS: Seventy consecutive rectal cancer patients who underwent curative-intent surgery were enrolled in this study. All patients underwent colonoscopy and CT colonography on the same day. The circumferential tumor extent was estimated in 10% increments. The pathological T stage was used as the reference. RESULTS: The median circumferential tumor extent evaluated by colonoscopy for T1 (n = 6), T2 (n = 21), and T3/T4 (n = 43) were 10%, 30%, and 80%, respectively (T1/T2 vs. T3/T4, p < 0.0001). The median circumferential tumor extent evaluated by CT colonography for T1, T2, and T3/T4 is 10%, 30%, and 70%, respectively (T1/T2 vs. T3/T4, p < 0.0001). The correlation coefficient between colonoscopy and CT colonography was very high (0.94). By defining a circumferential tumor extent >= 50% by CT colonography as the criterion for stage T3 or T4, the sensitivity, specificity, positive predictive value and accuracy were 72%, 88%, 91%, and 79%, respectively. CONCLUSION: Circumferential tumor extent >= 50% determined by CT colonography is a simple and potentially useful marker to identify candidates for neoadjuvant chemoradiation therapy. PMID- 25911247 TI - Role of sleep for encoding of emotional memory. AB - Total sleep deprivation (TSD) has been consistently found to impair encoding of information during ensuing wakefulness, probably through suppressing NonREM (non rapid eye movement) sleep. However, a possible contribution of missing REM sleep to this encoding impairment after TSD has so far not been systematically examined in humans, although such contribution might be suspected in particular for emotional information. Here, in two separate experiments in young healthy men, we compared effects of TSD and of selective REM sleep deprivation (REMD), relative to respective control conditions of undisturbed sleep, on the subsequent encoding of neutral and emotional pictures. The pictures were presented in conjunction with colored frames to also assess related source memory. REMD was achieved by tones presented contingently upon initial signs of REM sleep. Encoding capabilities were examined in the evening (18:00h) after the experimental nights, by a picture recognition test right after encoding. TSD significantly decreased both the rate of correctly recognized pictures and of recalled frames associated with the pictures. The TSD effect was robust and translated into an impaired long term memory formation, as it was likewise observed on a second recognition testing one week after the encoding phase. Contrary to our expectation, REMD did not affect encoding in general, or particularly of emotional pictures. Also, REMD did not affect valence ratings of the encoded pictures. However, like TSD, REMD distinctly impaired vigilance at the time of encoding. Altogether, these findings indicate an importance of NonREM rather than REM sleep for the encoding of information that is independent of the emotionality of the materials. PMID- 25911248 TI - The role of stress during memory reactivation on intrusive memories. AB - Intrusive memories are unwanted recollections that maintain distress in psychological disorders. Increasing evidence suggests that memories that are reactivated through retrieval become temporarily vulnerable to environmental or pharmacological manipulation, including changes in levels of circulating stress hormones. This study investigated the influence of stress during memory reactivation of an emotionally arousing trauma film on subsequent intrusive memories. Three groups of participants (N=63) viewed a trauma film depicting a serious car accident at baseline. Two days later (Time 2), one group received a reactivation induction following a socially evaluated cold pressor test (SECPT; Stress/Reactivation condition), whilst the second group reactivated the memory after a control procedure (Reactivation condition). A third group underwent the SECPT but was not asked to reactivate memory of the trauma film (Stress condition). Two days later (Time 3), all participants received a surprise cued memory recall test and intrusions questionnaire which they completed online. Results showed that those in the Stress/Reactivation group had higher intrusions scores than the other two groups, suggesting that acute stress promotes intrusive memories only when the memory trace is reactivated shortly afterwards. Increased cortisol predicted enhanced intrusive experiences in the Stress/Reactivation condition but not in the other conditions. This pattern of results suggests that acute stress during the reactivation of emotional material impacts on involuntary emotional memories. These findings suggest a possible explanation for the mechanism underlying the maintenance of intrusive memories in clinical disorders. PMID- 25911249 TI - Viscous flow past a collapsible channel as a model for self-excited oscillation of blood vessels. AB - Motivated by collapse of blood vessels for both healthy and diseased situations under various circumstances in human body, we have performed computational studies on an incompressible viscous fluid past a rigid channel with part of its upper wall being replaced by a deformable beam. The Navier-Stokes equations governing the fluid flow are solved by a multi-block lattice Boltzmann method and the structural equation governing the elastic beam motion by a finite difference method. The mutual coupling of the fluid and solid is realized by the momentum exchange scheme. The present study focuses on the influences of the dimensionless parameters controlling the fluid-structure system on the collapse and self excited oscillation of the beam and fluid dynamics downstream. The major conclusions obtained in this study are described as follows. The self-excited oscillation can be intrigued by application of an external pressure on the elastic portion of the channel and the part of the beam having the largest deformation tends to occur always towards the end portion of the deformable wall. The blood pressure and wall shear stress undergo significant variations near the portion of the greatest oscillation. The stretching motion has the most contribution to the total potential elastic energy of the oscillating beam. PMID- 25911250 TI - Hemodynamic insight into overlapping bare-metal stents strategy in the treatment of aortic aneurysm. AB - Clinical trials have shown overlapping bare-metal stents provoke effective thrombus clot within the aneurysm sac and shrinkage of the aneurysm by directly regulating the hemodynamics. To gain insight into the hemodynamic mechanism of the technique, three cases of simplified thoracic aortic aneurysm models (with no stent, a single stent and two overlapped stents deployed within the aneurysm sac) were studied and compared in terms of time-varying velocity and shear rate, time averaged wall shear stress (TAWSS), oscillating shear index (OSI) and relative residence time (RRT). The results demonstrated that the overlapping stents' strategy was more effective in reducing the velocity of blood flow within the aneurysm, especially for the area near the aneurysm wall. Stenting induced a dramatic change trend of shear rate during the cardiac cycle, in which a very high shear rate (>10,000 s(-1)) during the systole and a quite low shear rate (<1000 s(-1)) during the diastole were observed, respectively. Moreover, reduced TAWSS and OSI and elevated RRT values were observed on the aneurysm wall after stent placement. The effects of stenting on the shear rate, TAWSS, OSI and RRT in the aneurysm would be significantly enhanced by two overlapped stents. The present findings therefore indicated that, the overlapping bare-metal stents can isolate the aneurysm effectively and may create a favorable hemodynamic environment provoking platelets activation and aggregation within the aneurysm, which may promote thrombus formation/growth there, hence contribute to degradation of the aneurysm. PMID- 25911251 TI - Characterization of the elastic and viscoelastic properties of dentin by a nanoindentation creep test. AB - Dentin is the main supporting structure of teeth, but its mechanical properties may be adversely affected by pathological demineralization. The purposes of this study were to develop a quantitative approach to characterize the viscoelastic properties of dentin after de- and re-mineralization, and to examine the elastic properties using a nanoindentation creep test. Dentin specimens were prepared to receive both micro- and nano-indentation tests at wet and dry states. These tests were repeatedly performed after demineralization (1% citric acid for 3 days) and remineralization (artificial saliva immersion for 28 days). The nanoindentation test was executed in a creep mode, and the resulting displacement-time responses were disintegrated into primary (transient) and secondary (viscous) creep. The structural changes and mineral densities of dentin were also examined under SEM and microCT, respectively. The results showed that demineralization removed superficial minerals of dentin to the depth of 400 MUm, and affected its micro- and nano-hardness, especially in the hydrate state. Remineralization only repaired the minerals at the surface layer, and partially recovered the nanohardness. Both the primary the secondary creep increased in the demineralized dentin, while the hydration further enhanced creep deformation of untreated and remineralized dentin. Remineralization reduced the primary creep of dentin, but did not effectively increase the viscosity. In conclusion, water plasticization increases the transient and viscous creep strains of demineralized dentin and reduces load sustainability. The nanoindentation creep test is capable of analyzing the elastic and viscoelastic properties of dentin, and reveals crucial information about creep responses. PMID- 25911252 TI - Characterization of the toughness and elastic properties of fresh and cryopreserved arteries. AB - Surgical interventions are used to manage severe complications of heart valve diseases and to prevent the eventual rupture of an aortic aneurysm. Soft-tissue allografts, xenografts, and prosthetic grafts are used in these interventions; however, there are pre-surgical difficulties and post-surgical complications in using these grafts. One of these is the rupture potential of cryopreserved allografts at the time of transplantation and/or after the thawing process for the cryopreserved tissue. Moreover, a number of clinical observations report the patency of prosthetic grafts and aneurysm of cryopreserved allografts after the transplantation. This work aims to study the effect of cryopreservation on the resistance of arterial tissue to crack growth and propagation; we examined the biomechanical parameters which could be used in designing more efficient prosthetic grafts. Investigation of the toughness properties can also be helpful to understand the failure mechanisms of pathological arterial tissues. The toughness and biaxial tensile properties of the post-cryopreserved and fresh arteries have been examined. PMID- 25911253 TI - Meniscus mechanics and mechanobiology. PMID- 25911254 TI - The hippocampus is an integral part of the temporal limbic system during emotional processing: Comment on "The quartet theory of human emotions: An integrative and neurofunctional model" by S. Koelsch et al. PMID- 25911255 TI - The Quartet does not play alone: Comment on "The quartet theory of human emotions: An integrative and neurofunctional model" by S. Koelsch et al. PMID- 25911256 TI - Variability and situatedness of human emotions: Comment on "The quartet theory of human emotions: An integrative and neurofunctional model" by S. Koelsch et al. PMID- 25911257 TI - Evolutionary perspectives on emotions and their link to intentions, dispositions and behavior: Comment on "The quartet theory of human emotions: An integrative and neurofunctional model" by S. Koelsch et al. PMID- 25911258 TI - Searching for the one and many emotional brains: Comment on "The quartet theory of human emotions: An integrative and neurofunctional model" by S. Koelsch et al. PMID- 25911259 TI - Aesthetic emotions goals: Comment on "The quartet theory of human emotions: An integrative and neurofunctional model" by S. Koelsch et al. PMID- 25911260 TI - Predictive coding links perception, action, and learning to emotions in music: Comment on "The quartet theory of human emotions: An integrative and neurofunctional model" by S. Koelsch et al. PMID- 25911261 TI - Evolutionary considerations on complex emotions and music-induced emotions: Comment on "The quartet theory of human emotions: An integrative and neurofunctional model" by S. Koelsch et al. PMID- 25911262 TI - Smooth muscle and adenoma-like renal tumor: a previously unreported variant of mixed epithelial stromal tumor or a distinctive renal neoplasm? AB - We describe 6 cases of a biphasic renal neoplasm, which we designate smooth muscle and adenoma-like renal tumor, which do not cleanly fit any category as currently defined. There were 4 females and 2 males (age, 27-70 years); neither male had a history of hormone exposure. All 5 neoplasms with available history were discovered incidentally on imaging studies with sizes ranging from 4 to 20 cm. The stroma was composed of smooth muscle fascicles alternating with looser, edematous areas; none of the cases contained ovarian-like stroma. The complex but cytologically benign epithelial component consisted of tubulopapillary nodules, branching tubules, clefts, and large cysts. The stroma of all of the cases labeled diffusely for desmin. Estrogen receptor labeling was absent in 4 cases with only minimal (<10%) weak labeling in the remaining 2. The epithelial component of each case labeled diffusely for cytokeratin 7 and was patchy for alpha-methyl-CoA racemase (P504S). Carbonic anhydrase IX, HMB45, WT-1, and inhibin were negative. None of the 5 cases tested demonstrated trisomies of chromosome 7 or 17 by fluorescence in situ hybridization. Two patients with significant follow-up are disease free at 18.5 and 2.5 years. Smooth muscle and adenoma-like renal tumor could potentially represent a variant of mixed epithelial stromal tumor, which would expand its reported spectrum. However, the absence of clinical history of hormone exposure, predominance of smooth muscle with lack of ovarian-like stroma, prominence of epithelial nodules, and typical absence of estrogen receptor labeling suggest that it may represent a distinct entity. PMID- 25911264 TI - External eating mediates the relationship between impulsivity and unhealthy food intake. AB - Recent evidence from the eating domain shows a link between impulsivity and unhealthy food intake. However, the mechanism underlying this relationship remains unclear. One possibility is an external eating style, which has been linked to both impulsivity and food intake. The current study investigated the potential mediating role of external eating in the relationship between impulsivity and food intake. Participants were 146 undergraduate women who completed measures of impulsivity and external eating, and took part in a laboratory taste test as a behavioural index of unhealthy snack food intake. It was found that attentional and motor impulsivity interacted in predicting sweet food intake, but only motor impulsivity predicted both external eating and sweet food intake. Furthermore, the relationship between motor impulsivity and food intake was mediated by external eating. These findings support the development of interventions aimed at targeting specific aspects of impulsivity in order to reduce unhealthy eating behaviour. PMID- 25911263 TI - Intragastric fat self-administration is impaired in GPR40/120 double knockout mice. AB - Mice acquire strong preferences for flavors paired with intragastric (IG) fat infusions. This IG fat conditioning is attenuated in double knockout (DoKO) mice missing GPR40 and GPR120 fatty acid receptors. Here we determined if GPR40/120 DoKO mice are also impaired in IG fat self-administration in an operant lick task. In daily 1-h sessions the mice were trained with a sipper spout that contained dry food pellets; licks on the spout triggered infusions of IG fat (Intralipid). The training sessions were followed by test sessions with an empty spout. GPR40/120 DoKO mice self-infused more 20% fat than wild type (WT) C57BL/6 mice in training with a food-baited spout (2.4 vs. 2.0kcal/h) but self-infused less 20% fat than WT mice in empty spout tests (1.2 vs. 1.7kcal/h). The DoKO mice also self-infused less 5% fat than WT mice (0.6 vs. 1.3kcal/h) although both groups emitted more licks for 5% fat than 20% fat. The DoKO and WT mice did not differ, however, in their self-infusion of 12.5% glucose (1.5 vs. 1.6kcal/h), which is isocaloric to 5% fat. A second 5% IL test showed that the DoKO mice reverted to a reduced self-infusion compared to WT mice. When the infusion was shifted to water, WT mice reduced licking in the first extinction session, whereas DoKO mice were less sensitive to the absence of infused fat. Our results indicate that post-oral GPR40/120 signaling is not required to process IG fat infusions in food-baited spout training sessions but contributes to post-oral fat reinforcement in empty spout tests and flavor conditioning tests. PMID- 25911265 TI - Defensive coping and renovascular disease risk - Adrenal fatigue in a cohort of Africans and Caucasians: The SABPA study. AB - BACKGROUND: Defensive coping is an established cardiovascular risk factor in Africans. Additionally, chronic, excessive or inadequate hypothalamic-pituitary adrenal axis (HPAA) stress responses could either increase or decrease cortisol responses, which may relate to renal impairment. We scrutinised the relationship between urinary cortisol levels and renovascular disease risk in Africans and Caucasians utilising defensive coping. METHODS: Africans (n=168) and Caucasians (n=207) from the SABPA (Sympathetic activity and Ambulatory Blood Pressure in Africans) study were included in our analyses, excluding HIV positive, diabetic, renal impairment, and cortisone users. The Coping Strategy Indicator questionnaire assessed preferred coping responses. Ambulatory blood pressure was recorded together with 8h fasting blood and urine sampling. Renovascular disease risk markers included the albumin-to-creatinine ratio (ACR) and estimated glomerular filtration rate (eGFR). RESULTS: The main findings revealed that Caucasians with high cortisol showed augmented renovascular disease risk. Conversely, Africans revealed low cortisol levels whilst 21.84% reported experience of severe stress, possibly depicting HPAA hypoactivity. Additionally, these Africans with low cortisol revealed increased ACR and decreased eGFR, which was further enhanced by defensive coping. CONCLUSIONS: Defensive coping enhanced renovascular risk in Africans, especially in those with lower cortisol, which may be due to HPAA dysfunction and/or adrenal fatigue. PMID- 25911266 TI - Role of cerebrospinal fluid-contacting nucleus in sodium sensing and sodium appetite. AB - The brainstem plays an important role in controlling sodium and water homeostasis. It is a major regulatory site for autonomic and motor functions. Moreover, it integrates cerebrospinal fluid (CSF) signals with neuronal and hormonal signals. Evidence suggests that the CSF-contacting nucleus (CSF-CN) transmits and integrates CSF signals, but, the definitive role of CSF-CN in sodium homeostasis is poorly understood. In this study, we used c-Fos as a marker of neuronal activity and causing colocalization of Nax channel and 5-HT. This proved that CSF-CN played a role in sensing the increase of CSF sodium level. Then, we determined the role of the CSF-contacting nucleus in increasing the sodium appetite of rats. So, we performed targeted lesion of the CSF-contacting nucleus in the brainstem using the cholera toxin subunit B-saporin (CB-SAP), a cytotoxin coupled to cholera toxin subunit B. The lesion of the CSF-CN showed decreased and degenerative neurons, while sodium appetite have increased and Fos immunocytochemistry detected neuronal activity in the lateral parabrachial nucleus (LPBN), but not in the subfornical organ (SFO) and organum vasculosum of the lamina terminalis (OVLT). These results indicate that the CSF-CN plays an important role in sensing CSF sodium level and satiating sodium appetite by influencing the LPBN but not SFO and OVLT. The Nax channel and 5-HT might be the molecular mechanisms through which contribute to sodium homeostasis. PMID- 25911267 TI - Psychosocial predator-based animal model of PTSD produces physiological and behavioral sequelae and a traumatic memory four months following stress onset. AB - We have a well-established animal model of PTSD composed of predator exposure administered in conjunction with social instability that produces PTSD-like behavioral and physiological abnormalities one month after stress initiation. Here, we assessed whether the PTSD-like effects would persist for at least 4months after the initiation of the psychosocial stress regimen. Adult male Sprague-Dawley rats were exposed to either 2 or 3 predator-based fear conditioning sessions. During each session, rats were placed in a chamber for a 3 min period that terminated with a 30-s tone, followed by 1h of immobilization of the rats during cat exposure (Day 1). All rats in the stress groups received a second fear conditioning session 10days later (Day 11). Half of the stress rats received a third fear conditioning session 3weeks later (Day 32). The two cat exposed groups were also exposed to daily unstable housing conditions for the entire duration of the psychosocial stress regimen. The control group received stable (conventional) housing conditions and an equivalent amount of chamber exposure on Days 1, 11 and 32, without cat exposure. Behavioral testing commenced for all groups on Day 116. The stress groups demonstrated increased anxiety on the elevated plus maze, impaired object recognition memory and robust contextual and cued fear conditioned memory 3months after the last conditioning session. Combined data from the two stress groups revealed lower post-stress corticosterone levels and greater diastolic blood pressure relative to the control group. These findings indicate that predator-based psychosocial stress produces persistent PTSD-like physiological and behavioral abnormalities that may provide insight into the neurobiological and endocrine sequelae in traumatized people with PTSD. PMID- 25911268 TI - Late effects and quality of life after chemo-radiation for the treatment of anal cancer. AB - PURPOSE: The aim of this study was to evaluate the late effects and quality of life of patients following chemo-radiation treatment for anal cancer. METHODS: All surviving anal cancer patients treated within NHS Lothian between 1990 and 2007 were invited to participate. Data were collected using the EORTC QLQ-C30, the EORTC QLQ-CR38 and the Memorial Sloan-Kettering Cancer Centre Bowel Function Instrument (MSKCC). RESULTS: Overall response rate was 46% (n = 42); mean age 54.7 years and with a median time interval of 63.8 months between treatment and completion of the questionnaires. Thirty-five percent of the participants were 'rarely' or 'never' able to wait 15 min to get to the toilet; 50% were 'rarely' or 'never' able to control the passage of gas; 35% limited the types of solid foods they eat; 22% had leakage of stool during the day; 39% required to use a protective pad and 29% altered their daily activities because of bowel function 'always' or 'most of the time'. Seventeen percent of patients reported financial difficulties ('quite a bit' and 'very much'). Both men and women reported high symptomology for sexual problems with a median score of 83.3 (50.0. 100.0). CONCLUSION: This study has shown that in a sub-set of patients treated with chemo radiation for anal cancer, persistent treatment related issues are reported at a medium time interval of 5.3 years. Further work is now required to understand the impact of symptoms on day-to-day life and the challenges that people face in managing these inter-related and complex problems. PMID- 25911269 TI - Early-phase differences in health-related quality of life, psychological status, and physical function between human leucocyte antigen-haploidentical and other allogeneic haematopoietic stem cell transplantation recipients. AB - PURPOSE: This study investigated the differences between allogeneic haematopoietic stem cell transplantation (allo-HSCT) patients receiving HSC from human leucocyte antigen (HLA)-haploidentical donors (HID) and other donors that included HLA-matched sibling, matched unrelated, and unrelated umbilical cord blood donors in the 6 weeks after HSCT with respect to quality of life (QOL), psychological status, and physical function. METHODS: The study included 126 patients (HID group, n = 100; other donor group, n = 26) who underwent allo-HSCT between July 2007 and December 2012. Patients were evaluated for health-related QOL using the Medical Outcome Study 36-item Short Form Health Survey. Psychological status was measured by Hospital Anxiety and Depression Scale. Physical function was assessed using tests for handgrip strength, knee extensor strength, and the 6-min walk test. RESULTS: After HSCT, the HID group showed significantly greater improvements in the general health subscale and Mental Component Summary (MCS) of QOL than the other donor group (P < 0.01). Multivariate analysis confirmed that complete remission and age were associated with changes in the general health subscale before and after HSCT (P < 0.05). With regard to physical function, the HID group showed significantly more decline than the other donor group with respect to handgrip strength and knee extensor muscle strength after HSCT (P < 0.05). Total corticosteroid dose was associated with decreased handgrip strength before and after HSCT (P < 0.05). CONCLUSIONS: The donor type affects QOL, psychological status, and physical function in allo HSCT recipients; these findings may provide insights for customised rehabilitation strategies for HSCT recipients. PMID- 25911270 TI - Neighborhood Environments and Socioeconomic Inequalities in Mental Well-Being. AB - INTRODUCTION: It has been suggested that socioeconomic inequalities in health might be reduced among populations with good access to green space. However, the potential for other neighborhood characteristics to reduce socioeconomic health inequalities, or to confound the effects of green space, has not been well explored. Therefore, this study investigates which, if any, neighborhood characteristics are associated with narrower socioeconomic inequalities in mental well-being in a large, international sample of urban residents. METHODS: The 2012 European Quality of Life Survey provided data on 21,294 urban residents from 34 European nations. Associations between mental well-being (captured by the WHO-5 scale) and level of financial strain were assessed for interaction with five different neighborhood characteristics, including reported access to recreational/green areas, financial services, transport, and cultural facilities. Multilevel regression models allowed for clustering of individuals within region and country in this cross-sectional, observational study. Data were analyzed in 2014. RESULTS: Socioeconomic inequality in mental well-being was 40% (8.1 WHO-5 points) narrower among respondents reporting good access to green/recreational areas, compared with those with poorer access. None of the other neighborhood characteristics or services were associated with narrower inequality. CONCLUSIONS: If societies cannot, or will not, narrow socioeconomic inequality, research should explore the so-called equigenic environments-those that can disrupt the usual conversion of socioeconomic inequality to health inequality. This large, international, observational study suggests that access to recreational/green areas may offer such a disruption. PMID- 25911271 TI - Success and Complications of Salpingectomy at the Time of Vaginal Hysterectomy. AB - STUDY OBJECTIVES: To document the success rates and complications of salpingectomy performed at the time of vaginal hysterectomy to possibly reduce ovarian cancer rates. DESIGN: Retrospective cohort study (Canadian Task Force Classification II-2). SETTING: Community-based hospital with university affiliation in Calgary, Canada. INTERVENTION: All women undergoing hysterectomy for benign conditions were offered preferentially a vaginal approach with prophylactic salpingectomy. MEASUREMENTS AND MAIN RESULTS: During the study period (October 2011 to January 2014), a total of 425 vaginal hysterectomies were performed. The overall success rate of salpingectomy was 88%. Pelvic adhesions significantly predicted the ability to perform salpingectomies (odds ratio, 6.3; 95% confidence interval, 2.8-14.3; p < .001). Age also was predictive of outcomes (p = .007), with increasing age predicting decrease success. The overall postoperative complication rate was 15%, with 3.8% possibly attributable to salpingectomy (i.e., intrapelvic complications). No associated factors were found on regression analysis. CONCLUSION: Salpingectomy at the time of vaginal hysterectomy is a feasible procedure. Complication rates are low. Only pelvic adhesions are associated with failure to complete a salpingectomy. PMID- 25911272 TI - Resisting anchoring effects: The roles of metric and mapping knowledge. AB - The biasing influence of anchors on numerical estimates is well established, but the relationship between knowledge level and the susceptibility to anchoring effects is less clear. In two studies, we addressed the potential mitigating effects of having knowledge in a domain on vulnerability to anchoring effects in that domain. Of critical interest was a distinction between two forms of knowledge-metric and mapping knowledge. In Study 1, participants who had studied question-relevant information-that is, high-knowledge participants-were less influenced by anchors than were participants who had studied irrelevant information. The results from knowledge measures suggested that the reduction in anchoring was tied to increases in metric rather than mapping knowledge. In Study 2, participants studied information specifically designed to influence different types of knowledge. As we predicted, increases in metric knowledge-and not mapping knowledge-led to reduced anchoring effects. Implications for debiasing anchoring effects are discussed. PMID- 25911273 TI - Patterns of glucose lowering drugs utilization in Portugal and in the Netherlands. Trends over time. AB - AIMS: To compare the temporal trends in the consumption patterns of glucose lowering drugs (GLD) between Portugal and the Netherlands from 2004 to 2013 and to examine possible reasons behind the cross-national variation found. METHODS: All GLD (ATC pharmacological subgroup A10B) were selected for analysis. Consumption data were obtained for the 10-year period. Portuguese and Dutch drug estimates were obtained from nationwide databases. RESULTS: The consumption of GLD increased in Portugal from 52.9 defined daily dose per 1000 inhabitants per day (DHD) in 2004 to 70.0 DHD in 2013 and in the Netherlands from 44.9 DHD in 2004 to 50.7 DHD in 2013. In Portugal, the use of fixed-dose combinations, especially with dipeptidyl peptidase-4 inhibitors (DPP-4) increased remarkably and in 2013 represented almost a quarter of total GLD consumption. In the Netherlands, the use of combinations was residual. CONCLUSIONS: The consumption of GLD rose over the 10-year period in both countries. However, Portuguese overall consumption and costs of GLD were higher. The differentially rapid uptake of DPP-4 inhibitors in Portugal was the main driver of the cost difference. PMID- 25911274 TI - Biodiversity conservation across taxa and landscapes requires many small as well as single large habitat fragments. AB - Agricultural intensification has been shown to reduce biodiversity through processes such as habitat degradation and fragmentation. We tested whether several small or single large habitat fragments (re-visiting the 'single large or several small' debate) support more species across a wide range of taxonomic groups (plants, leafhoppers, true bugs, snails). Our study comprised 14 small (<1 ha) and 14 large (1.5-8 ha) fragments of calcareous grassland in Central Germany along orthogonal gradients of landscape complexity and habitat connectivity. Each taxon was sampled on six plots per fragment. Across taxa, species richness did not differ between large and small fragments, whereas species-area accumulation curves showed that both overall and specialist species richness was much higher on several small fragments of calcareous grassland than on few large fragments. On average, 85% of the overall species richness was recorded on all small fragments taken together (4.6 ha), whereas the two largest ones (15.1 ha) only accounted for 37% of the species. This could be due to the greater geographic extent covered by many small fragments. However, community composition differed strongly between large and small fragments, and some of the rarest specialist species appeared to be confined to large fragments. The surrounding landscape did not show any consistent effects on species richness and community composition. Our results show that both single large and many small fragments are needed to promote landscape-wide biodiversity across taxa. We therefore question the focus on large fragments only and call for a new diversified habitat fragmentation strategy for biodiversity conservation. PMID- 25911275 TI - The effects of orthographic transparency and familiarity on reading Hebrew words in adults with and without dyslexia. AB - The current study examined the effects of transparency and familiarity on word recognition in adult Hebrew dyslexic readers with a phonological processing deficit as compared to typical readers. We measured oral reading response time and accuracy of single nouns in several conditions: diacritics that provide transparent but less familiar information and vowel letters that increase orthographic transparency without compromise familiarity. In line with former studies with adult dyslexics, Hebrew-speaking adults with dyslexia were significantly slower than controls. However, both dyslexic and typical readers read unpointed words faster when vowel letters were present, indicating that they may benefit from increase in orthographic transparency, when the graphemic representations are familiar. Only dyslexics read pointed words slower than unpointed words and were more sensitive to word frequency. In unpointed words, only typical readers benefitted from the reduced competition of orthographic neighbors of longer words. Results indicate that both orthographic transparency and familiarity play an important role in word recognition. Dyslexics are impaired in decoding of smaller units and are more sensitive to reduction in the familiarity of words. PMID- 25911276 TI - Reading and coherent motion perception in school age children. AB - This study includes an evaluation, according to age, of the reading and global motion perception developmental trajectories of 2027 school age children in typical stages of development. Reading is assessed using the reading rate score test, for which all of the student participants, regardless of age, received the same passage of text of a medium difficulty reading level. The coherent motion perception threshold is determined according to the adaptive psychophysical protocol based on a four-alternative, forced-choice procedure. Three different dot velocities: 2, 5, and 8 deg/s were used for both assemblies of coherent or randomly moving dots. Reading rate score test results exhibit a wide dispersion across all age groups, so much so that the outlier data overlap, for both the 8 and 18-year-old student-participant age groups. Latvian children's reading fluency developmental trajectories reach maturation at 12-13 years of age. After the age of 13, reading rate scores increase slowly; however, the linear regression slope is different from zero and positive: F(1, 827) = 45.3; p < 0.0001. One hundred eighty-one student-participants having results below the 10th percentile were classified as weak readers in our study group. The reading fluency developmental trajectory of this particular group of student-participants does not exhibit any statistically significant saturation until the age of 18 years old. Coherent motion detection thresholds decrease with age and do not reach saturation. Tests with slower moving dots (2 deg/s) yield results that exhibit significant differences between strong and weak readers. PMID- 25911277 TI - Should they team up to make your brain clock? AB - Large-conductance calcium-activated potassium channels (BK channels) are important regulators of neuronal excitability in the mammalian nervous system. BK channels are activated by changes in membrane electrical potential and intracellular calcium concentration and play a key role in shaping neuronal action potential. Indeed, under typical physiological conditions, opening of BK channels allows potassium ions to flow outside of the cell leading to membrane repolarization and fast afterhyperpolarization, thus controlling cellular excitability. These aspects are of direct relevance to a new study by Farajnia et al., 2015, reported in this issue of Neurobiology of Aging, on the role of BK channels in aging circadian clock neurons. PMID- 25911278 TI - Endogenous murine Abeta increases amyloid deposition in APP23 but not in APPPS1 transgenic mice. AB - Endogenous murine amyloid-beta peptide (Abeta) is expressed in most Abeta precursor protein (APP) transgenic mouse models of Alzheimer's disease but its contribution to beta-amyloidosis remains unclear. We demonstrate ~ 35% increased cerebral Abeta load in APP23 transgenic mice compared with age-matched APP23 mice on an App-null background. No such difference was found for the much faster Abeta depositing APPPS1 transgenic mouse model between animals with or without the murine App gene. Nevertheless, both APP23 and APPPS1 mice codeposited murine Abeta, and immunoelectron microscopy revealed a tight association of murine Abeta with human Abeta fibrils. Deposition of murine Abeta was considerably less efficient compared with the deposition of human Abeta indicating a lower amyloidogenic potential of murine Abeta in vivo. The amyloid dyes Pittsburgh Compound-B and pentamer formyl thiophene acetic acid did not differentiate between amyloid deposits consisting of human Abeta and deposits of mixed human murine Abeta. Our data demonstrate a differential effect of murine Abeta on human Abeta deposition in different APP transgenic mice. The mechanistically complex interaction of human and mouse Abeta may affect pathogenesis of the models and should be considered when models are used for translational preclinical studies. PMID- 25911279 TI - Contribution of adiponectin and its type 1 receptor to age-related hearing impairment. AB - Age-related hearing impairment (ARHI) is a complex neurodegenerative disorder caused by a combination of environmental and genetic factors. We have reported previously that obesity increases the risk for ARHI, and that plasma levels of adiponectin are associated with ARHI. In the present study, we further explored the role of adiponectin in the pathophysiology of ARHI by investigating the genotypes of ADIPOQ and ADIPOR1, the genes of adiponectin and its type 1 receptor, respectively. A total of 1682 volunteers were enrolled, and their audiological phenotypes were determined according to the z scores converted from their original frequency-specific hearing thresholds. A total of 9 tag-single nucleotide polymorphisms (tagSNPs) in ADIPOQ and 4 tagSNPs in ADIPOR1 were genotyped, and the genotypes were correlated to the audiological phenotypes under the assumption of various inheritance models. Significant associations were identified between certain ADIPOQ tagSNPs and z scores under dominant, codominant, or additive models, whereas no association was identified between ADIPOR1 tagSNPs and z scores. The associations between ADIPOQ tagSNPs and z scores appear to exist only in subjects with specific ADIPOR1 genotypes, indicating an interaction between adiponectin and AdipoR1. Measurement of plasma adiponectin in 736 subjects revealed that ADIPOQ genotypes might exert their effects on hearing levels via modulation of plasma adiponectin levels. Subsequently, we confirmed the expression of AdipoR1 in the inner ear of mice, and demonstrated antiapoptotic effects of adiponectin in cochlear explant cultures. These results provide insights into the physiological function and potential clinical implications of adiponectin against ARHI. PMID- 25911280 TI - Efficacy of chess training for the treatment of ADHD: A prospective, open label study. AB - OBJECTIVE: To examine the effectiveness of playing chess as a treatment option for children with ADHD. METHODS: Parents of 44 children ages 6 to 17 with a primary diagnosis of ADHD consented to take part in the study. Parents completed the Spanish version of the Swanson, Nolan and Pelham Scale for parents (SNAP-IV) and the Abbreviated Conner's Rating Scales for parents (CPRS-HI) prior to an 11 week chess-training program. We used a paired t-test to compare pre- and post intervention outcomes, and Cohen-d calculations to measure the magnitude of the effect. The statistical significance was set at P<.05. RESULTS: Children with ADHD improved in both the SNAP-IV (t=6.23; degrees of freedom (df)=41; P<.001) and the CPRS-HI (t=5.39; df=33; P<.001). Our results suggest a large effect in decreasing the severity of ADHD as measured by the SNAP-IV (d=0.85) and the CPRS HI (d=0.85). Furthermore, we found a correlation between intelligence quotient and SNAP-IV improvement (P<.05). CONCLUSIONS: The results of our pilot study should be interpreted with caution. This pilot project highlights the importance of carrying out larger studies with a case-control design. If our results are replicated in better designed studies, playing chess could be included within the multimodal treatment of ADHD. PMID- 25911281 TI - In the wake of a possible mistake: Security motivation, checking behavior, and OCD. AB - BACKGROUND AND OBJECTIVES: In previous experiments, OCD washers did not differ significantly from controls in their initial level of activation in response to the potential threat of contamination; however, they were less able to reduce their activation by engaging in hand-washing, suggesting that the key problem in OCD is a faulty stopping mechanism. The main objectives of the present experiments were to develop a similar experimental paradigm for investigating checking behavior, and to use it to test the hypothesis that a faulty stopping mechanism also underlies OCD checking. METHODS: Participants sorted pills under the guise of beta testing a new medication system and then were given suggestions of the possibility of having made mistakes with potentially serious consequences. Later, participants engaged in a 90-s checking period and an unlimited period of checking. At baseline and three other times during the experiment, security motivation was measured with respiratory sinus arrhythmia (RSA) and subjective ratings of confidence. Experiment 1 established the parameters of the paradigm in non-patient participants, and Experiment 2 contrasted OCD checkers with OCD washers and non-patients. RESULTS: Results for both subjective and physiological measures of security motivation closely replicated previous findings for washing behavior. Groups did not differ significantly in initial activation, but the OCD checkers were unable to reduce their activation by engaging in period of checking that was ample for returning controls to baseline. LIMITATIONS: The sample size for the patient groups was modest. CONCLUSIONS: These results lend further support to the security-motivation theory of OCD. PMID- 25911283 TI - Effective management of sewage sludge. PMID- 25911282 TI - What are the implications of implementation science for medical education? AB - BACKGROUND: Derived from multiple disciplines and established in industries outside of medicine, Implementation Science (IS) seeks to move evidence-based approaches into widespread use to enable improved outcomes to be realized as quickly as possible by as many as possible. METHODS: This review highlights selected IS theories and models, chosen based on the experience of the authors, that could be used to plan and deliver medical education activities to help learners better implement and sustain new knowledge and skills in their work settings. RESULTS: IS models, theories and approaches can help medical educators promote and determine their success in achieving desired learner outcomes. We discuss the importance of incorporating IS into the training of individuals, teams, and organizations, and employing IS across the medical education continuum. Challenges and specific strategies for the application of IS in educational settings are also discussed. CONCLUSIONS: Utilizing IS in medical education can help us better achieve changes in competence, performance, and patient outcomes. IS should be incorporated into curricula across disciplines and across the continuum of medical education to facilitate implementation of learning. Educators should start by selecting, applying, and evaluating the teaching and patient care impact one or two IS strategies in their work. PMID- 25911284 TI - Arsenic immobilization in the contaminated soil using poorly crystalline Fe oxyhydroxy sulfate. AB - A low crystalline Fe-oxyhydroxy sulfate (FeOS) was used to immobilize arsenic (As) in soils in this study. The effects of FeOS amount, treatment time and soil moisture on As immobilization were investigated. The results showed that water soluble and NaHCO3-extractable As were immobilized by 53.4-99.8 and 13.8-73.3% respectively, with 1-10% of FeOS addition. The highest immobilization of water soluble (98.5%) and NaHCO3-extractable arsenic (47.2%) was achieved under condition of 4% of FeOS and 80% of soil moisture. Further, more amounts of FeOS addition resulted in less time requirement for As immobilization. Sequential chemical extraction experiment revealed that easily mobile arsenic phase was transferred to less mobile phase. The FeOS-bonded As may play a significant role in arsenic immobilization. Under leaching with simulated acid rain at 60 times pore volumes, accumulation amount of As release from untreated soil and soil amended with FeOS were 98.4 and 1.2 mg, respectively, which correspond to 7.69 and 0.09% of total As amounts in soil. The result showed that the low crystalline FeOS can be used as a suitable additive for arsenic immobilization in soils. PMID- 25911285 TI - Immobilization of Cd(II) in acid soil amended with different biochars with a long term of incubation. AB - Biochars derived from bamboo, coconut shell, pine wood shavings, and sugarcane bagasse were applied into Ultisol to investigate their effects on Cd(II) immobilization. After 360 days of incubation, the physical/chemical properties of the Ultisol were improved by the addition of different biochars. As a result, the maximum adsorption capacities of soil for Cd(II) were increased from 8.02 to 9.07 11.51 mmol/kg, and bamboo biochar showed the highest effect on Cd(II) immobilization. The Langmuir model (R(2) > 0.983) fitted the data better than the Freundlich model (R (2) were 0.902-0.937). Column leaching experiments suggested that biochar can also increase the immobilization of Cd(II) under leaching conditions. Biochar mainly increased the weak/unstable binding force of Cd(II) by soil, such as ion exchange, electrostatic attraction, physical adsorption, and carbonate precipitation. In addition, a significant enhancement of surface complexation was also observed. PMID- 25911286 TI - Bacterial communities of Beijing surface waters as revealed by 454 pyrosequencing of the 16S rRNA gene. AB - As a better understanding of Beijing surface water ecosystems can provide clues for environmental management and public health, here, we report a study of the bacterial communities of five Beijing surface waters conducted using 454 pyrosequencing of 16S ribosomal RNA (rRNA) genes. We expected to observe a core bacterial community among the surface waters and differences in bacterial community abundance over the different locations of sampling. In this study, we obtained a total of 60,810 trimmed reads from the five samples after the removal of unqualified reads. Bacterial sequences from the five samples were classified into taxonomic classes using the default settings of the mothur platform. Our results provided insight into the bacterial community composition of surface waters and revealed that there was a core microbial community in the microbial populations of surface samples at different geographic locations, with 13 phyla and 40 genera in common. Our findings also revealed the differences in bacterial communities among five surface water samples obtained at different locations. PMID- 25911287 TI - Formation and removal of dissolved organic nitrogen (DON) in membrane bioreactor and conventional activated sludge processes. AB - Dissolved organic nitrogen (DON) has become a growing concern due to its contribution to eutrophication and nitrogenous disinfection byproducts (N-DBPs) formation. However, information of DON in membrane bioreactors (MBRs) is very limited. In this study, occurrence, transformation and fate of DON in an MBR system were systematically investigated. MBR sludge showed a larger hydrolysis rate of particle organic nitrogen (PON) and also a higher transformation rate of DON to nitrate compared to conventional activated sludge (CAS). For long-term experiments, MBR achieved higher DON removal efficiency at low temperature than CAS; however, at high temperature, the effluent DON concentrations were almost the same in both systems. Batch tests on DON biodegradability showed that DON concentration increased and large molecular weight DON accumulated after 3-h aeration at low temperature, while DON concentration continuously decreased with the increase of aeration time at high temperature. The obtained results provide insights in DON removal in MBRs for meeting increasingly stringent regulations in terms of nitrogen removal. PMID- 25911288 TI - Modeling of trihalomethanes (THMs) in drinking water supplies: a case study of eastern part of India. AB - This study aimed at developing a model for predicting the formation of trihalomethanes (THMs) in drinking water supplies. Monitoring of THMs in five major water treatment plants situated in the Eastern part of India revealed high concentration of THMs (231-484 MUg l(-1)). Chloroform was predominant, contributing 87-98.9% to total THMs. Seasonal variation in THMs levels dictated that the concentration were higher in autumn than other seasons. Linear regression analysis of data indicated that TOC is the major organic precursors for THMs formation followed by DOC and UV254. Linear and non-linear predictive models were developed using SPSS software version 16.0. Validation results indicated that there is no significant difference in the predictive and observed values of THMs. Linear model performed better than non-linear one in terms of percentage prediction errors. The model developed were site specific and the predictive capabilities in the distribution systems vary with different environmental conditions. PMID- 25911289 TI - A review of the characterization and revegetation of bauxite residues (Red mud). AB - Bauxite residue (Red mud) is produced in alumina plants by the Bayer process in which Al-containing minerals are dissolved in hot NaOH. The global residue inventory reached an estimated 3.5 billion tons in 2014, increasing by approximately 120 million tons per annum. The appropriate management of bauxite residue is becoming a global environmental concern following increased awareness of the need for environmental protection. Establishment of a vegetation cover is the most promising way forward for the management of bauxite residue, although its physical and chemical properties can limit plant growth due to high alkalinity and salinity, low hydraulic conductivity, trace element toxicity (Al and Fe), and deficiencies in organic matter and nutrition concentrations. This paper discusses the various revegetation and rehabilitation strategies. Studies of the rehabilitation of bauxite residues have mainly focused on two approaches, amelioration of the surface layer and screening of tolerant plants and soil microorganisms. Amendment with gypsum can reduce the high alkalinity and salinity, promote soil aggregation, and increase the hydraulic conductivity of bauxite residues. Organic matter can provide a source of plant nutrients, form stable complexes with metal cations, promote hydraulic conductivity, stabilize soil structure, and provide an energy source for soil organisms. Tolerant plants and microorganisms such as halophytes and alkaliphilic microbes show the greatest potential to ameliorate bauxite residues. However, during restoration or as a result of natural vegetation establishment, soil formation becomes a critical issue and an improved understanding of the various pedogenic processes are required, and future direction should focus on this area. PMID- 25911290 TI - Chronic villitis of unknown etiology and massive chronic intervillositis have similar immune cell composition. AB - INTRODUCTION: Chronic villitis of unknown etiology (CVUE) and massive chronic intervillositis (MCI) are placental lesions associated with infiltration of mononuclear cells in the chorionic villi and the intervillous spaces, respectively. It is not well known whether immune cells in CVUE and MCI have similar phenotypic characteristics. METHODS: A cross-sectional study of third trimester placentas was conducted to identify immune cell subpopulations in CVUE and MCI (n = 17/group). CVUE was diagnosed with H&E staining and antibody to CD3 in serial sections; and MCI, by the presence of massive infiltration of mononuclear cells in the intervillous spaces. Immune cells, ICAM-1 expression and nuclear factor kappaB (NF-kappaB) activation were determined immunohistochemically. RESULTS: CVUE and MCI showed similar infiltrates, mainly CD68+ and CD3+ cells. Most cells (>80%) were CD45RB+, and one third were CD45RO+ in both lesions. There were slightly more CD8+ than CD4+ cells in both CVUE and MCI. More than 90% of cells in CVUE and MCI were ICAM-1+ with NFkappaB nuclear localization. Syncytiotrophoblast ICAM-1 expression was significantly (p < 0.001) higher in MCI (mean of 81.0; range of 71.6-86.0) than in CVUE (52.4; 36.4-59.4) or normal placentas (0.2; 0.0-0.6). Both, failure of physiologic transformation of spiral arteries and placental atherosclerosis-like lesions of atherosis were significantly more frequent in MCI than in CVUE or normal placentas (p = 0.044 and p = 0.007, respectively). DISCUSSION: These finding suggest that MCI and CVUE have very similar infiltration of immune cells although MCI has more severe placental lesions. PMID- 25911291 TI - Reduced serum vitamin D levels in neuromyelitis optica. PMID- 25911293 TI - Salidroside-Mediated Neuroprotection is Associated with Induction of Early Growth Response Genes (Egrs) Across a Wide Therapeutic Window. AB - Salidroside exhibits anti-inflammatory, anti-oxidative, and anti-apoptotic properties. To identify whether salidroside might be a candidate for treating ischemic stroke, we investigated the effects of salidroside or vehicle, given daily for 6 days, after middle cerebral artery occlusion (MCAO) for 2 h and reperfusion for either 1 or 48 h in rats. Salidroside reduced cerebral infarct volume and significantly improved neurological scores whether started after 1 or 48 h of reperfusion. Microarray analysis showed that 20 % (133/678) of the genes down-regulated by ischemia and 1 h of reperfusion were up-regulated by salidroside, whereas 13 % (105/829) of the genes induced by ischemia-reperfusion were inhibited by salidroside, suggesting that salidroside can reverse effects of ischemia-reperfusion on gene expression. The main enriched functional categories induced by salidroside were genes related to synaptic plasticity, whereas salidroside inhibited genes related to inflammation. Induction of Egr1, Egr2, Egr4, and Arc by salidroside was confirmed by qRT-PCR and western blotting in ischemic brains treated after either 1 or 48 h of reperfusion. The potential protective role of Egr4 in salidroside-mediated neuroprotection was subsequently investigated in CoCl2-treated PC12 cells. Egr4 was dose-dependently induced by salidroside in PC12 cells, and depleting Egr4 with target-specific siRNA increased caspase-3 activity and Bax, but decreased Bcl-xl, which were reversed by salidroside. Finally, we confirmed that salidroside inhibited the Bax/Bcl-xl related apoptosis after MCAO with reperfusion. In conclusion, salidroside is highly neuroprotective with a wide therapeutic time window after ischemia reperfusion injury in the rat, and this partially involves induction of Egrs, leading to inhibition of Bax/Bcl-xl-related apoptosis. PMID- 25911294 TI - Central Precocious Puberty: Update on Diagnosis and Treatment. AB - Central precocious puberty (CPP) is characterized by the same biochemical and physical features as normally timed puberty but occurs at an abnormally early age. Most cases of CPP are seen in girls, in whom it is usually idiopathic. In contrast, ~50% of boys with CPP have an identifiable cause. The diagnosis of CPP relies on clinical, biochemical, and radiographic features. Untreated, CPP has the potential to result in early epiphyseal fusion and a significant compromise in adult height. Thus, the main goal of therapy is preservation of height potential. The gold-standard treatment for CPP is gonadotropin-releasing hormone (GnRH) analogs (GnRHa). Numerous preparations with a range of delivery systems and durations of action are commercially available. While the outcomes of patients treated for CPP have generally been favorable, more research about the psychological aspects, optimal monitoring, and long-term effects of all forms of GnRHa treatment is needed. Several potential therapeutic alternatives to GnRHa exist and await additional investigation. PMID- 25911295 TI - Stereotactic radiosurgery in combination with up-front high-dose methotrexate as a first-line treatment for newly diagnosed primary central nervous system lymphoma. AB - The efficacy of stereotactic radiosurgery (SRS) instead of whole brain radiotherapy (WBRT) following high-dose methotrexate (HD-MTX) for primary central nervous system lymphoma (PCNSL) is unclear. To clarify whether SRS in combination with up-front HD-MTX supplements the effect of HD-MTX in remaining or refractory lesions after initial HD-MTX treatment. The authors conducted a retrospective review for newly diagnosed PCNSL patients who underwent SRS after HD-MTX as a first-line treatment. The local control (LC), the progression-free survival (PFS), the recurrence patterns, the salvage treatments, the overall survival (OS), the Karnofsky Performance Status (KPS), the activities of daily living (ADL) were analyzed as well as radiosurgical parameters. Twenty patients underwent SRS for 51 lesions with the median volume of 0.45 cm(3). The median age at SRS was 67 (range 37-82). The median KPS at SRS was 90. The LC rate at 2 years was 86.0 %, the median PFS after SRS was 17 months, necessitating additional SRS and chemotherapy. The median OS was 52 months. No significant side effects related to SRS were observed. During follow-up period, the good ADL preservation was achieved for 13 months from SRS. Patients with KPS >= 90 at SRS demonstrated longer ADL preservation (32 months from SRS). SRS following up-front HD-MTX without WBRT provided excellent LC, acceptable OS and the long ADL preservation period. These benefits may be more emphasized especially in patients with good KPS, but should be validated in a large patient population. PMID- 25911297 TI - The supraorbital keyhole approach: how I do it. AB - BACKGROUND: Improvements in image guidance, endoscopy, and instruments, have significantly advanced "keyhole" neurosurgery. We describe the concept and technique of the supraorbital keyhole approach. METHODS: The supraorbital keyhole approach is performed through an eyebrow skin incision. Image guidance may be used to define the optimal surgical trajectory. A limited supraorbital craniotomy is fashioned. The frontal lobe is mobilized and the central skull base approached, without the need for brain retractors. Endoscopy is used to enhance visualization, and tube-shaft instruments to improve manipulation through the narrow surgical corridor. CONCLUSIONS: The supraorbital keyhole approach provides a safe method to access selected skull base lesions. PMID- 25911296 TI - Tumor bed radiosurgery: an emerging treatment for brain metastases. AB - While typically used for treating small intact brain metastases, an increasing body of literature examining tumor bed directed stereotactic radiosurgery (SRS) is emerging. There are now over 1000 published cases treated with this approach, and the first prospective trial was recently published. The ideal sequencing of tumor bed SRS is unclear. Current approaches include, a neoadjuvant treatment before resection, alone as an adjuvant after resection, and following surgery combined with whole brain radiotherapy either as an adjuvant or salvage treatment. Based on available evidence, adjuvant stereotactic radiosurgery improves local control following surgery, reduces the number of patients who require whole brain radiotherapy, and is well tolerated. While results from published series vary, heterogeneity in both patient populations and methods of reporting results make comparisons difficult. Additional prospective data, including randomized trials are needed to confirm equivalent outcomes to the current standard of care. We review the current literature, identify areas of ongoing contention, and highlight ongoing studies. PMID- 25911298 TI - Intradural communication between dorsal rootlets of spinal nerves: their clinical significance. AB - BACKGROUND: Anatomical and surgical textbooks give almost no attention to the intradural communications between dorsal rootlets of adjacent spinal nerves. These communications can be of significance in various neurosurgical procedures and clinical conditions of the region. METHODS: The spinal cord of six formaldehyde-fixed cadavers was dissected from C1-S5. The dorsal rootlets of the spinal nerves were exposed via a posterior approach and communications between adjacent spinal nerves were documented. RESULTS: The frequency of communication between adjacent dorsal rootlets of the spinal nerves showed variations among spinal levels. Thirty-eight dorsal rootlet communications were observed in six cadavers (12 sides) and 20 (52.6%) were at cervical levels, 14 (36.8%) at thoracic levels, and four (10.5%) at lumbar levels. The majority of communications were observed on the left side (65.8%). Communications were most frequently observed at cervical (C4-C5, C5-C6) and upper thoracic (T1-T2) levels and seen least frequently at lower thoracic and lumbar levels. No communications were observed at sacral levels. Five types of communication were observed: I. oblique ascending, II. oblique descending III. short Y, IV. long Y and V shaped. None of the communication extended beyond one segment at any spinal level. The occurrence of such dorsal rootlet communications ranged from 3 to 7 for each cadaver and the mean was 4.8 +/- 1.3. Histological sections from various levels of the dorsal rootlet communications showed that all consisted of myelinated fibers of varying diameters. CONCLUSIONS: Such communications may lead to misinterpretation of the pathology on the basis of clinical signs and symptoms and also should be considered in rhizotomy. PMID- 25911299 TI - A Technique for Bronchoscopic Intubation During High-Flow Nasal Cannula Oxygen Therapy. AB - Despite preoxygenation, critical hypoxemia can occur during intubation. We describe a technique of high-flow nasal cannula oxygen support during bronchoscopic intubation. PMID- 25911300 TI - Structure activity relationship of substituted 1,5-naphthyridine analogs of oxabicyclooctane-linked novel bacterial topoisomerase inhibitors as broad spectrum antibacterial agents (Part-4). AB - Bacterial resistance is rapidly growing, necessitating the need to discover new agents. Novel bacterial topoisomerase inhibitors (NBTIs) are new class of broad spectrum antibacterial agents targeting bacterial DNA gyrase and topoisomerase IV. This class of inhibitors binds to an alternative binding site relative to fluoroquinolones and shows no cross-resistance to quinolones. NBTIs consist of three structural motifs. A structure activity relationship of the left hand motif 1,5-naphthyridine of oxabicyclooctane-linked NBTIs is described. Fifty five compounds were evaluated against a panel of key Gram-positive and Gram-negative strains of bacteria, as well as for hERG activity and five compounds were tested for in vivo efficacy in murine model of Staphylococcus aureus infection. These studies suggest that only a narrow range (activating and deactivating) of substitutions at C-2 and C-7 are tolerated for optimal antibacterial activity and spectrum. An alkoxy (methoxy) and CN at C-2, and a halogen and hydroxyl at C-7, appeared to be preferred in this series. Substitutions on the other three carbons generally have detrimental effect on the activity. No clear hERG activity SAR emerged from these substitutions. PMID- 25911301 TI - Current kinase inhibitors cover a tiny fraction of fragment space. AB - We analyze the chemical space coverage of kinase inhibitors in the public domain from a fragment point of view. A set of 26,668 kinase inhibitors from the ChEMBL database of bioactive molecules were decomposed automatically by fragmentation at rotatable bonds. Remarkably, about half of the resulting 10,302 fragments originate from inaccessible libraries, as they are not present in commercially available compounds. By mapping to the established kinase pharmacophore models, privileged fragments in sub-pockets are identified, for example, the 5681 ring containing fragments capable of forming bi-dentate hydrogen bonds with the hinge region in the ATP binding site. Surprisingly, hinge-binding fragments in current kinase inhibitors cover only 1% of the potential hinge-binders obtained by decomposing a library of nearly 7.5 million commercially available compounds, which indicates that a large fraction of chemical space is unexplored. PMID- 25911292 TI - "Boomerang Neuropathology" of Late-Onset Alzheimer's Disease is Shrouded in Harmful "BDDS": Breathing, Diet, Drinking, and Sleep During Aging. AB - Brain damage begins years before substantial neurodegeneration and Alzheimer's dementia. Crucial fundamental activities of life are breathing, eating, drinking, and sleeping. When these pivotal functions are maligned over a prolonged period, they impart escalating dyshomeostasis. The latter may lead to disastrous consequences including cognitive dysfunction and Alzheimer's disease (AD). The current theme here is that multiple pathophysiological derangements are promoted over a prolonged period by the very fundamental activities of life-when "rendered unhealthy." They may converge on several regulating/modulating factors (e.g., mitochondrial energy production, oxidative stress, innate immunity, and vascular function) and promote insidious neuropathology that culminates in cognitive decline in the aged. This is of course associated with the accumulation of amyloid beta and phosphorylated tau in the brain. Epidemiological, biomarker, and neuroimaging studies have provided significant copious evidence on the presence of indolent prodromal AD neuropathology many years prior to symptomatic onset. Progressive oxidative damage to specific gene promoters may result in gene silencing. A mechanistic link may possibly exist between epigenomic state, DNA damage, and chronically unhealthy/dysfunctional body systems. This paper, therefore, addresses and delineates the deleterious pathophysiological impact triggered by dysfunctional breathing, harmful diet, excess of alcohol consumption, and sleep deprivation; indeed, their impact may alter epigenetic state. It is mandatory, therefore, to abrogate cognitive decline and attenuate AD pathology through adoption of a healthy lifestyle, in conjunction with combination therapy with known moderators of cognitive decline. This strategy may thwart multiple concurrent and synergistic pathologies, including epigenetic dysfunction. A multi-factorial therapeutic intervention is required to overcome wide ranging neuropathology and multi-faceted disease process. Such an approach may attenuate neuropathology and ameliorate memory dysfunction. PMID- 25911302 TI - Highly positive-charged zinc(II) phthalocyanine as non-aggregated and efficient antifungal photosensitizer. AB - A new tetra-alpha-substituted zinc(II) phthalocyanine containing dodeca-amino groups (compound 4) and its quaternized analogue (compound 5) have been prepared and evaluated for their photoactivities against Candida albicans. Compared with the dodeca-amino phthalocyanine 4, the dodeca-cationic phthalocyanine 5 exhibits a higher photodynamic inactivation against C. albicans with an IC90 value down to 1.46 MUM, which can be attributed to its non-aggregated nature in aqueous environments and more efficient cellular uptake. More interestingly, 5 shows a higher photodynamic inactivation on C. albicans due to its stronger affinity to C. albicans cells than mammalian cells. These results suggest that the highly positive-charged phthalocyanine 5 is a potential non-aggregated antifungal photosensitizer, which shows some selectivity toward the fungus. PMID- 25911304 TI - Video-Based Intervention in Teaching Fraction Problem-Solving to Students with Autism Spectrum Disorder. AB - The purpose of this study was to determine the effectiveness of a point-of-view video modeling intervention to teach mathematics problem-solving when working on word problems involving subtracting mixed fractions with uncommon denominators. Using a multiple-probe across students design of single-case methodology, three high school students with ASD completed the study. All three students demonstrated greater accuracy in solving fraction word problems and maintained accuracy levels at a 1-week follow-up. PMID- 25911303 TI - The Empathy and Systemizing Quotient: The Psychometric Properties of the Dutch Version and a Review of the Cross-Cultural Stability. AB - The 'Empathy Quotient' (EQ) and 'Systemizing Quotient' (SQ) are used worldwide to measure people's empathizing and systemizing cognitive styles. This study investigates the psychometric properties of the Dutch EQ and SQ in healthy participants (n = 685), and high functioning males with autism spectrum disorder (n = 42). Factor analysis provided support for three subscales of the abridged 28 item EQ: Cognitive Empathy, Emotional Empathy and Social Skills. Overall, the Dutch EQ and SQ appeared reliable and valid tools to assess empathizing and systemizing cognitive style in healthy adults and high functioning adults with autism. The literature showed good cross-cultural stability of the SQ and EQ in Western countries, but in Asian countries EQ is less stable and less sensitive to sex differences. PMID- 25911305 TI - Dismantling the Active Ingredients of an Intervention for Children with Autism. AB - This study evaluated the association of fidelity to each of the components of the Strategies for Teaching based on Autism Research (STAR) program, a comprehensive treatment package for children with autism that includes discrete trial training, pivotal response training, and teaching in functional routines, on outcomes for 191 students ages 5-8 years in a large public school district. Fidelity to all components was relatively low, despite considerable training and support, suggesting the need to develop new implementation strategies. Fidelity to pivotal response training, but not discrete trial training or functional routines, was positively associated with gains in cognitive ability despite low levels of fidelity, and may be an effective intervention choice in under-resourced settings. PMID- 25911306 TI - Poverty and the Growth of Emotional and Conduct Problems in Children with Autism With and Without Comorbid ADHD. AB - We investigated the longitudinal relationship between socio-economic disadvantage (SED) and trajectories of emotional and conduct problems among children with autism spectrum disorder (ASD) who had comorbid attention deficit/hyperactivity disorder (ADHD; ASD + ADHD) or not (ASD - ADHD). The sample was 209 children with ASD who took part in the UK's Millennium Cohort Study. Trajectories of problems across ages 3, 5 and 7 years were analyzed using growth curve models. The ASD - ADHD group decreased in conduct problems over time but the ASD + ADHD group continued on a high trajectory. Although SED was not a risk factor for ASD + ADHD, it was associated with elevated emotional problems among children with ASD + ADHD. This effect of SED on emotional problems was not attenuated by parenting or peer problems. PMID- 25911307 TI - Psychological Well-Being of Mothers and Siblings in Families of Girls and Women with Rett Syndrome. AB - Few published studies have reported on the psychological well-being of family members of individuals with Rett syndrome (RTT). Eighty-seven mothers of girls and women with RTT completed a questionnaire survey about their daughters' behavioral phenotype, current health, and behavior problems, and their own and a sibling's well-being. Mothers reported increased anxiety but similar levels of depression when compared to a normative sample. Across all problem domains on the Strengths and Difficulties Questionnaire, child and adolescent siblings (n = 39) were reported by mothers to have fewer difficulties than a normative sample. The severity of their daughters' RTT behavioral phenotype predicted increased anxiety and stress for mothers. Increased RTT daughters' current health problems predicted more maternal perceptions of positive gain. PMID- 25911308 TI - Introducing a new histologic scoring system for iron deposition in liver of thalassemic patients, compared with atomic absorption spectrometry. AB - Iron deposition in liver is a major finding in thalassemic patients and because of direct iron toxicity to liver it is associated with several consequences for example liver fibrosis. Liver biopsies from 63 patients were evaluated, 40 (63.5%) were male and 20 (36.5%) were female. The mean age of the patients was 8.01 +/- 3.7 and the age range was from 1.8 to 15 years. Histologic grading and staging was performed for each case according to modified HAI (Hepatitis Activity Index) system. Iron scoring was performed according to Sindram & Marx and MTK1-3 scoring systems. The mean (SD) dry weight (dw) of liver specimens was 1.34 (0.11) mg (range 0.20 to 3.80 mg). The mean (SD) of hepatic iron concentration was 230.9 (121.2)MUmol/g dry weight. The relationship between the variables HIC, HII (hepatic iron index) and all histological gradings of iron (S&M and MTK1-3) was very strong. The relationship between the HIC and staging by HAI method was good. Significant differences were identified between the mean HIC in scores 1&2 of all histological iron scorings (S&M and MTK1-3), but no significant differences identified between mean HIC in other adjacent scores in all histological iron scorings (S&M and MTK1, 2 and 3). New scoring system introduced by us in this study which considered size and density of iron granules as well as zone of iron deposition was very much the same as simple Sindram and Marx classification. PMID- 25911309 TI - Repeated exposure to 5-bromo-2'-deoxyuridine causes decreased proliferation and low-grade inflammation in the lungs of mice. AB - Incorporation of 5-bromo-2'-deoxyuridine (BrdU) into proliferating cells has been used to label dividing cells in many tissues. Although BrdU has been shown to be genotoxic, teratogenic and mutagenic, such adverse effects have largely been ignored by researchers. We determined whether long-term BrdU exposure causes any histopathological changes in the lungs of mice. Eight-week-old male C57/BL6J mice were administered BrdU by intraperitoneal injection on 3 consecutive days of each week for 14 weeks. While no obvious structural changes such as tissue damage, fibrosis, emphysema, airway remodeling, vascular thickening or tumorigenesis were noted, a moderate degree of macrophage infiltration was observed in the airways and lung parenchyma in the lungs of the mice exposed repeatedly to BrdU (BrdU exposed mice). The proliferative activities of the airway and alveolar epithelial and mesenchymal cells were reduced in the BrdU-exposed mice, although the numbers of these cells in the lungs were maintained. Double immunofluorescence study of the lungs of the BrdU-exposed mice showed overexpression of IL-6 in the airway epithelial and alveolar wall cells, some of which were also double-positive for BrdU. These results indicate that long-term exposure to BrdU inhibits cell proliferation and induces low-grade inflammation in the lungs of mice. Our findings underscore the need for caution in the interpretation of studies that involve long-term exposure to BrdU. PMID- 25911310 TI - Trazodone treatment protects neuronal-like cells from inflammatory insult by inhibiting NF-kappaB, p38 and JNK. AB - Growing evidence suggests that alterations of the inflammatory/immune system contribute to the pathogenesis of major depression and that inflammatory processes may influence the antidepressant treatment response. Depressed patients exhibit increased levels of inflammatory markers in both the periphery and brain, and high co-morbidity exists between depression and diseases associated with inflammatory alterations. Trazodone (TDZ) is a triazolopyridine derivative that belongs to the class of serotonin receptor antagonists and reuptake inhibitors. Although the trophic and protective properties of classic antidepressants have extensively been exploited, the effects of TDZ remain to be fully elucidated. In this study, the pharmacological activities of TDZ on human neuronal-like cells were investigated under both physiological and inflammatory conditions. An in vitro inflammatory model was established using lipopolysaccharide (LPS) and tumour necrosis factor-alpha (TNF-alpha), which efficiently mimic the stress related changes in neurotrophic and pro-inflammatory genes. Our results showed that TDZ significantly increased the mRNA expression of both brain-derived nerve factor (BDNF) and cAMP response element-binding protein (CREB) and decreased the cellular release of the pro-inflammatory cytokine interferon gamma (IFN-gamma) in neuronal-like cells. In contrast, neuronal cell treatment with LPS and TNF-alpha decreased the expression of CREB and BDNF and increased the expression of nuclear factor kappa B (NF-kappaB), a primary transcription factor that functions in inflammatory response initiation. Moreover, the two agents induced the release of pro-inflammatory cytokines (i.e., interleukin-6 and IFN-gamma) and decreased the production of the anti-inflammatory cytokine interleukin-10. TDZ pre-treatment completely reversed the decrease in cell viability and counteracted the decrease in BDNF and CREB expression mediated by LPS-TNF-alpha. In addition, the production of inflammatory mediators was inhibited, and the release of interleukin-10 was restored to control levels. Furthermore, the intracellular signalling mechanism regulating TDZ-elicited effects was specifically investigated. TDZ induced extracellular signal-regulated kinase (ERK) phosphorylation and inhibited constitutive p38 activation. Moreover, TDZ counteracted the activation of p38 and c-Jun NH2-terminal kinase (JNK) elicited by LPS-TNF-alpha, suggesting that the neuro-protective role of TDZ could be mediated by p38 and JNK. Overall, our results demonstrated that the protective effects of TDZ under inflammation in neuronal-like cells function by decreasing pro-inflammatory signalling and by enhancing anti-inflammatory signalling. PMID- 25911311 TI - Comparison of field-of-view (FOV) optimized and constrained undistorted single shot (FOCUS) with conventional DWI for the evaluation of prostate cancer. AB - OBJECTIVES: Qualitative and quantitative comparison of the application value of diffusion-weighted imaging (DWI) magnetic resonance imaging based on field-of view (FOV) optimized and constrained undistorted single shot (FOCUS) with the standard single-shot echo-planar imaging (ss-EPI) in patients with prostate cancer. METHODS: A total of 28 patients with 33 prostate cancers underwent ss-EPI and FOCUS DWI. Two independent readers assessed image studies. RESULTS: Image qualities of FOCUS were rated superior to ss-EPI (P<.001). The mean apparent diffusion coefficient value of 33 cancers was 974.030*10(-6)mm(2)/s and 941.727*10(-6)mm(2)/s, respectively, and the difference was statistically significant (t=2.579, P=.015). CONCLUSIONS: FOCUS as a high-resolution DWI technique has potential clinical utility. PMID- 25911312 TI - (99m)Tc-3PRGD 2 SPECT/CT predicts the outcome of advanced nonsquamous non-small cell lung cancer receiving chemoradiotherapy plus bevacizumab. AB - BACKGROUND: Functional imaging can help clinicians assess the individual response of advanced nonsquamous non-small cell lung cancer (NSCLC) to chemoradiation therapy plus bevacizumab. Our purpose is to investigate the ability of (99m)Tc 3PRGD2 single photon emission computed tomography/computed tomography (SPECT/CT) in predicting the early response to treatment. METHODS: Patients with advanced nonsquamous NSCLC diagnosed by histological or cytological examination were imaged with (99m)Tc-3PRGD2 SPECT/CT at 3 time points: 1-3 days before the start of treatment (SPECT1), 40 Gy radiotherapy with 2 cycles of chemotherapy plus bevacizumab (SPECT2) and 4 weeks after chemoradiotherapy plus bevacizumab (SPECT3). The images were evaluated semiquantitatively by measuring the tumor to non-tumor ratio (T/N) and calculating the percentage change in T/N ratio. Short term outcome was assessed by the treatment response evaluation according to the Response Evaluation Criteria in Solid Tumors criteria as: complete response (CR), partial response (PR), stable disease (SD) and progressive disease (PD). Patients were divided two groups: responders (CR and PR) and nonresponders (SD and PD). To determine a threshold for percent reduction in T/N ratios, receiver-operating characteristic (ROC) curve analysis was used. Patients were grouped again based on the threshold of P1 (the change percentage from SPECT1 to SPECT2) and P2 (the change percentage from SPECT1 to SPECT3): P1 responders and P1 nonresponders; P2 responders and P2 nonresponders. Patients were followed up starting 4 weeks after completion of therapy and then every 3 months for the first 2 years and every 6 months after 2 years. OS of P1 responders, P1 nonresponders, P2 responders and P2 nonresponders was estimated and graphically illustrated using the Kaplan-Meier method and the log-rank test was used to test the null hypotheses of equal OS in subgroups of patients. RESULTS: A total of 28 patients completed all imaging and treatment. All primary lung tumors were well visualized on SPECT1. The mean T/N ratio of SPECT1 in responders and nonresponders was not statistically different (2.73 +/- 0.59 vs. 2.59 +/- 0.52, p > 0.05). At SPECT2 and SPECT3, the mean T/N ratios were both lower in the responders compared with the nonresponders and had statistical significance (p < 0.05). P1 and P2 in the responders was larger than the nonresponders with significant difference (P1: 34.18 +/- 21.55 % vs. 9.02 +/- 14.02 %, p < 0.05; P2: 53.02 +/- 15.50 % vs. 7.74 +/- 37.95 %, p < 0.05). The optimal threshold of P1 that can discriminate between P1 responders and P1 nonresponders was greater than 25.9 % reduction, and that of P2 that can discriminate between P2 responders and P2 nonresponders was 34.0 % reduction. The area under the ROC curve (AUC) of P1 and P2 for determining residual disease was 0.856 and 0.909, respectively; but there was no statistical significance between them (p > 0.05). There was a significant difference for OS between P1 responders and P1 nonresponders (p < 0.05), and also for OS between P2 responders and P2 nonresponders (p < 0.05). But there was no difference between the P1 responders and P2 responders (p > 0.05), or between the P1 nonresponders and P2 nonresponders (p > 0.05). CONCLUSION: A (99m)Tc-3PRGD2 SPECT/CT after two cycles of chemoradiotherapy plus bevacizumab can predict patients who will have a better response to treatment and survival. PMID- 25911314 TI - Transplant immunology and immunosuppression: core curriculum 2015. PMID- 25911313 TI - Prenatal exposure to aflatoxin B1: developmental, behavioral, and reproductive alterations in male rats. AB - Previous studies have shown that aflatoxin B1 (AfB1) inhibits androgen biosynthesis as a result of its ability to form a high-affinity complex with the steroidogenic acute regulatory protein. The results of the present study demonstrate the postnatal effects of in utero exposure to AfB1 in the rat. Pregnant Wistar rats were given 10, 20, or 50 MUg AfB1/kg body weight daily from gestation day (GD) 12 to GD 19. At parturition, newborns were observed for clinical signs and survival. All animals were born alive and initially appeared to be active. Male pups from control and AfB1-exposed animals were weaned and maintained up to postnatal day (PD) 100. Litter size, birth weight, sex ratio, survival rate, and crown-rump length of the pups were significantly decreased in AfB1-exposed rats when compared to controls. Elapsed time (days) for testes to descend into the scrotal sac was significantly delayed in experimental pups when compared to control pups. Behavioral observations such as cliff avoidance, negative geotaxis, surface rightening activity, ascending wire mesh, open field behavior, and exploratory and locomotory activities were significantly impaired in experimental pups. Body weights and the indices of testis, cauda epididymis, prostate, seminal vesicles, and liver were significantly reduced on PD 100 in male rats exposed to AfB1 during embryonic development when compared with controls. Significant reduction in the testicular daily sperm production, epididymal sperm count, and number of viable, motile, and hypo-osmotic tail coiled sperm was observed in experimental rats. The levels of serum testosterone and activity levels of testicular hydroxysteroid dehydrogenases were significantly decreased in a dose-dependent manner with a significant increase in the serum follicle-stimulating hormone and luteinizing hormone in experimental rats. Deterioration in the testicular and cauda epididymal architecture was observed in experimental rats. The results of fertility studies revealed a significant decrease in the mating index in experimental rats with an increase in the pre- and post-implantation losses in rats mated with prenatal AfB1-exposed males, indicating poor male reproductive performance. These results indicate that in utero exposure to AfB1 severely compromised postnatal development of neonatal rats, and caused a delay in testes descent and reduction in steroidogenesis and spermatogenesis that were accomplished by suppressed reproduction at adulthood. PMID- 25911315 TI - The US pediatric nephrology workforce: a report commissioned by the American Academy of Pediatrics. AB - The US pediatric nephrology workforce is poorly characterized. This report describes clinical and nonclinical activities, motivations and disincentives to a career in pediatric nephrology, future workforce needs, trainee recruitment, and possible explanations for personnel shortages. An e-mail survey was sent in 2013 to all identified US-trained or -practicing pediatric nephrologists. Of 504 respondents, 51% are men, 66% are US graduates, and 73% work in an academic setting. About 20% of trained pediatric nephrologists no longer practice pediatric nephrology. Among the 384 respondents practicing pediatric nephrology full or part-time in the United States, the mean work week was 56.1+/-14.3 hours, with time divided between patient care (59%), administration (13%), teaching (10%), clinical research (9%), basic research (6%), and other medical activities (3%). Most (>85%) care for dialysis and transplantation patients. The median number of weeks annually on call is 16, and 29% work with one or no partner. One third of US pediatric nephrologists (n=126) plan to reduce or stop clinical nephrology practice in the next 5 years, and 53% plan to fully or partially retire. Almost half the division chiefs (47%) report inadequate physician staffing. Ongoing efforts to monitor and address pediatric nephrology workforce issues are needed. PMID- 25911317 TI - Pharmacotherapy options for cluster headache. AB - INTRODUCTION: Cluster headache (CH) is a primary headache disorder and the most common trigeminal autonomic cephalalgia. Patients suffer from very severe unilateral headache attacks accompanied by ipsilateral trigeminal autonomic symptoms. Previous studies described a high burden of disease due to its impact on social life as well as an increased suicide ideation rate. The mean time to diagnosis in western industrialized countries is estimated at 4 years. AREAS COVERED: Many treatment options for CH exist, but due to the rarity of the disease, controlled randomized clinical studies remain difficult to perform. This review summarizes the current knowledge about the treatment of CH including internationally accepted treatment guidelines, and an additional MEDLINE search (1 February 2015). EXPERT OPINION: International treatment recommendations and official guidelines give reassurance about specific pharmacotherapy options for CH, but only few of these are backed by sufficient scientific evidence. The limited therapeutic efficacy in some patients leads to the use of alternative, complementary, but also illicit drugs to better cope with the disease. Many single cases, case series and uncontrolled studies were performed with different substances in an attempt to find a better way to treat or prevent the excruciatingly painful attacks associated with CH. Large-scale, randomized controlled clinical trials are desperately needed in order to further increase the quality of patient care for this outstanding but terrifying disease. PMID- 25911316 TI - Subcutaneous implantable cardioverter defibrillator for dialysis patients: a strategy to reduce central vein stenoses and infections. AB - Central venous stenosis is a common complication of the transvenous leads associated with an implantable cardioverter defibrillator (ICD). Although epicardial leads have been reported to bypass this complication, their placement is much more invasive than the subcutaneous ICDs (SICDs) and requires the services of a cardiothoracic surgeon. Recent data have demonstrated successful defibrillation using an SICD. In this report, we present 4 long-term hemodialysis patients treated successfully with an SICD. 3 patients received the device for primary prevention of sudden cardiac death (cardiomyopathy with low ejection fraction). The patient in the fourth case had a prolonged QT interval and received the device for secondary prevention. 3 patients had an arteriovenous fistula, whereas 1 patient was dialyzing with a tunneled dialysis catheter. Insertion of an SICD is a minimally invasive procedure. By virtue of leaving the venous system untouched, this approach might offer the advantage of reduced risk of central venous stenosis and infection over an endocardial ICD with transvenous leads. SICD is not experimental; it has been approved by the US Food and Drug Administration and is currently being used in the United States and Europe. PMID- 25911318 TI - Phospholipase Cbeta1b directly binds the SH3 domain of Shank3 for targeting and activation in cardiomyocytes. AB - Phospholipase Cbeta1b (PLCbeta1b) is an atypical splice variant of PLCbeta1 that has a C-terminal proline-rich sequence instead of the PDZ-interacting motif common to other PLCbeta subtypes. PLCbeta1b targets to the cardiomyocyte sarcolemma through an undefined association with the scaffolding protein Shank3. The C-terminal splice variant specific sequence of PLCbeta1b bound to deletion mutants of Shank3 that included the SH3 domain, but not to constructs lacking this domain. Mutating proline residues in the extreme C-terminal region of PLCbeta1b prevented the interaction between PLCbeta1b and Shank3 resulting in reduced sarcolemmal localization and downstream signalling responses. We conclude that PLCbeta1b activation and downstream signalling require the association of a previously unidentified C-terminal proline-rich motif with the SH3 domain of Shank3. PLCbeta1b is the first confirmed protein ligand for the SH3 domain of Shank3. PMID- 25911319 TI - Vitamin D deficiency independent of hypocalcemia elevates blood pressure in rats. AB - Essential hypertension is a polygenic disorder with a complex and multifactorial nature. Although no single gene is responsible, multiple genes provide incremental contributions to this disorder. Vitamin D is a primary regulator of calcium homeostasis. Epidemiological and clinical studies appear to point to a role for vitamin D in hypertension but direct experimental evidence is lacking. Sprague-Dawley rats were made vitamin D deficient by feeding a purified vitamin D deficient diet and eliminating all sources of ultraviolet light. Vitamin D deficiency was confirmed by very low serum calcium levels. Blood pressure was measured in conscious rats non-invasively with a volume pressure recording system. Vitamin D deficiency results in elevated blood pressures independent of serum calcium concentration. The administration of 1alpha,25-dihydroxyvitamin D3 (1,25-(OH)2D3) and a less calcemic analog, 2-methylene-19-nor-20(S)-1alpha hydroxyl-bishomopregnacalciferol (2MbisP) significantly reduced blood pressure in these rats. Thus, vitamin D status is one of the determining factors regulating blood pressure. PMID- 25911320 TI - Adipose-derived stromal cell cluster with light therapy enhance angiogenesis and skin wound healing in mice. AB - Human adipose-derived mesenchymal stem cells (hASCs) are attractive cell source for skin tissue engineering. The aim of this study was to investigate the effects of low-level light therapy (LLLT) on transplanted cluster hASC in a skin wound animal model. The hASCs were cultured in monolayer or clusters. The LLLT, hASCs, hASC clusters, and hASC clusters transplantation with LLLT (cluster + LLLT) were applied to the wound bed in athymic mice. Wound healing was assessed by gross evaluation and by hematoxylin and eosin staining, and elastin van gieson histochemistry. The survival, differentiation, and secretion of vascular endothelial growth factor (VEGF), basic fibroblast growth factor (FGF), and hepatocyte growth factor (HGF) of the cluster ASC were evaluated by immunohistochemistry and Western blotting. The cluster + LLLT group enhanced the wound healing, including neovascularization and regeneration of skin appendages, compared with the cluster group. The secretion of growth factors was stimulated in the cluster + LLLT group compared with the ASCs and cluster group. These data suggest that LLLT is an effective biostimulator of cluster hASCs in wound healing that enhances the survival of hASCs and stimulates the secretion of growth factors in the wound bed. PMID- 25911321 TI - Micropillar displacements by cell traction forces are mechanically correlated with nuclear dynamics. AB - Cells sense physical cues at the level of focal adhesions and transduce them to the nucleus by biochemical and mechanical pathways. While the molecular intermediates in the mechanical links have been well studied, their dynamic coupling is poorly understood. In this study, fibroblast cells were adhered to micropillar arrays to probe correlations in the physical coupling between focal adhesions and nucleus. For this, we used novel imaging setup to simultaneously visualize micropillar deflections and EGFP labeled chromatin structure at high spatial and temporal resolution. We observed that micropillar deflections, depending on their relative positions, were positively or negatively correlated to nuclear and heterochromatin movements. Our results measuring the time scales between micropillar deflections and nucleus centroid displacement are suggestive of a strong elastic coupling that mediates differential force transmission to the nucleus. PMID- 25911322 TI - Oxidative stress, the term and the concept. AB - The 30th birthday of a central concept in biomedicine, such as oxidative stress (OS) is a good time for re-evaluation of its contribution to science and particularly to the field of redox biology. In his recent communication, Sies described the history of the concept as well as the benefits and pitfalls of the term OS. In this mini-review, we discuss the problems associated with the still common perception of "bad OS, good antioxidants". Specifically, the term OS is an intuitively understood term originally used to describe an imbalance between pro oxidative factors and anti-oxidative factors. It has no units, its level is dependent on the way it is measured and there is no correlation between various criteria of OS, which indicates that there are sub-classes (types) of OS (other than the classifications presented by Sies). In spite of these limitations, it is commonly regarded a measure of a person's probability to suffer from oxidative damages and is being held responsible for many diseases and antioxidants are predicted to be good to us. In fact, a "Basal OS" is vital and antioxidants may interfere with the mechanisms responsible for maintaining the oxidative status. We also discuss the linkage of OS to the outcome of antioxidant supplementation and comment on the importance of kinetic studies in evaluation of OS and on the ranking of antioxidants. PMID- 25911323 TI - WEHI-3 cells inhibit adipocyte differentiation in 3T3-L1 cells. AB - By investigating the anti-adipogenic effects of WEHI-3 cells - a murine acute myelomonocytic leukemia cell line - we sought to improve the efficiency of hematopoietic stem cell transplantation (HSCT). Analysis of Oil Red O staining and the expression of adipogenic genes, including PPARgamma, C/EBPalpha, FAS and LPL, indicated that WEHI-3 cells significantly inhibited 3T3-L1 mouse preadipocyte cells from differentiating into adipocytes. In vivo, fat vacuoles in mice injected with WEHI-3 cells were also remarkably reduced in the murine bone marrow pimelosis model. Moreover, the key gene in the Rho signaling pathway, ROCKII, and the key gene in the Wnt signaling pathway, beta-catenin, were both upregulated compared with the control group. siRNA-mediated knockdown of ROCKII and beta-catenin reversed these WEHI-3-mediated anti-adipogenic effects. Taken together, these data suggest that WEHI-3 cells exert anti-adipogenic effects and that both ROCKII and beta-catenin are involved in this process. PMID- 25911324 TI - OCT4 mediates FSH-induced epithelial-mesenchymal transition and invasion through the ERK1/2 signaling pathway in epithelial ovarian cancer. AB - Our previous study showed that Octamer-binding transcription factor 4 (OCT4) expression was upregulated and significantly associated with histological grade through the analysis of OCT4 expression in 159 ovarian cancer tissue samples, and OCT4 mediated follicle-stimulating hormone (FSH)-induced anti-apoptosis in epithelial ovarian cancer. Nevertheless, whether OCT4 participates in FSH-induced invasion in ovarian cancer is still unknown. Therefore, the present study aimed to define whether FSH-induced ovarian cancer invasion is mediated by OCT4. In present study, we showed that FSH induced not only the epithelial-mesenchymal transition (EMT) and invasive phenotype but also the upregulation of OCT4 expression in a dose- and time-dependent manner in epithelial ovarian cancer cells. In addition, the expression of FSH receptor (FSHR) was upregulated by FSH induction, and knockdown of FSHR inhibited FSH-stimulated OCT4 expression. ERK1/2 signaling pathway participated in the enhanced expression of OCT4 and Snail induced by FSH. We further showed that the activated expression of Snail and N cadherin, the suppressed expression of E-cadherin and the morphological change of the cells stimulated by FSH were blocked by OCT4-specific small interfering RNA. Moreover, our results showed that OCT4 mediated the increase in invasive capacity induced by FSH in ovarian cancer cells. Taken together, our work reveals that OCT4 is an essential mediator in FSH-induced EMT and invasion in epithelial ovarian cancer and may act as a potential therapeutic target. PMID- 25911325 TI - The effect of mitochondrial calcium uniporter on mitochondrial fission in hippocampus cells ischemia/reperfusion injury. AB - The mitochondrial calcium uniporter (MCU) transports free Ca(2+) into the mitochondrial matrix, maintaining Ca(2+) homeostasis, thus regulates the mitochondrial morphology. Previous studies have indicated that there was closely crosstalk between MCU and mitochondrial fission during the process of ischemia/reperfusion injury. This study constructed a hypoxia reoxygenation model using primary hippocampus neurons to mimic the cerebral ischemia/reperfusion injury and aims to explore the exactly effect of MCU on the mitochondrial fission during the process of ischemia/reperfusion injury and so as the mechanisms. Our results found that the inhibitor of the MCU, Ru360, decreased mitochondrial Ca(2+) concentration, suppressed the expression of mitochondrial fission protein Drp1, MIEF1 and Fis1, and thus improved mitochondrial morphology significantly. Whereas spermine, the agonist of the MCU, had no significant impact compared to the I/R group. This study demonstrated that the MCU regulates the process of mitochondrial fission by controlling the Ca(2+) transport, directly upregulating mitochondrial fission proteins Drp1, Fis1 and indirectly reversing the MIEF1 induced mitochondrial fusion. It also provides new targets for brain protection during ischemia/reperfusion injury. PMID- 25911326 TI - Further policy changes are needed to improve depression care. PMID- 25911327 TI - Escitalopram in treatment of antiandrogen-related mood disturbance in a patient with chronic schizophrenia and adenocarcinoma of the prostate. PMID- 25911328 TI - Non conventional biological treatment based on Trametes versicolor for the elimination of recalcitrant anticancer drugs in hospital wastewater. AB - This work presents a study about the elimination of anticancer drugs, a group of pollutants considered recalcitrant during conventional activated sludge wastewater treatment, using a biological treatment based on the fungus Trametes versicolor. A 10-L fluidized bed bioreactor inoculated with this fungus was set up in order to evaluate the removal of 10 selected anticancer drugs in real hospital wastewater. Almost all the tested anticancer drugs were completely removed from the wastewater at the end of the batch experiment (8 days) with the exception of Ifosfamide and Tamoxifen. These two recalcitrant compounds, together with Cyclophosphamide, were selected for further studies to test their degradability by T. versicolor under optimal growth conditions. Cyclophosphamide and Ifosfamide were inalterable during batch experiments both at high and low concentration, whereas Tamoxifen exhibited a decrease in its concentration along the treatment. Two positional isomers of a hydroxylated form of Tamoxifen were identified during this experiment using a high resolution mass spectrometry based on ultra-high performance chromatography coupled to an Orbitrap detector (LTQ Velos Orbitrap). Finally the identified transformation products of Tamoxifen were monitored in the bioreactor run with real hospital wastewater. PMID- 25911329 TI - Adsorption characteristics of diclofenac and sulfamethoxazole to graphene oxide in aqueous solution. AB - The adsorptive properties of graphene oxide (GO) were characterized, and the binding energies of diclofenac (DCF) and sulfamethoxazole (SMX) on GO adsorption were predicted using molecular modeling. The adsorption behaviors of DCF and SMX were investigated in terms of GO dosage, contact time, and pH. Additionally, the effects of sonication on GO adsorption were examined. GO adsorption involves "oxygen-containing functional groups" (OCFGs) such as COOH, which exhibit negative charges over a wide range of pH values (pH 3-11). DCF (-18.8 kcal mol( 1)) had a more favorable binding energy on the GO surface than SMX (-15.9 kcal mol(-1)). Both DCF and SMX were removed from solution (adsorbed to GO), up to 35% and 12%, respectively, within 6h, and an increase in GO dosage enhanced the removal of DCF. Electrostatic repulsion occurred between dissociated DCF/SMX and the more negatively charged GO at basic pH (>pKa). The sonication of GO significantly improved the removal of DCF (75%) and SMX (30%) due to dispersion of exfoliated GO particles and the reduction of OCFGs on the GO surface. Both DCF and SMX in the adsorption isotherm were explained well by the Freundlich model. The results of this study can be used to maximize the adsorption capacities of micropollutants using GO in water treatment processes. PMID- 25911330 TI - The Clinical Use of Genomic Profiling to Distinguish Intrapulmonary Metastases From Synchronous Primaries in Non-Small-Cell Lung Cancer: A Mini-Review. AB - The ability to reliably distinguish synchronous primary non-small-cell lung cancer (NSCLC) from intrapulmonary metastatic spread affects staging and treatment decisions in resected NSCLC. Adjuvant therapy for early-stage NSCLC is complicated and recommendations are primarily based on older data from trials that used now-outdated staging systems. Patients found to have 2 tumors with similar morphology in the same lobe are currently staged as pathologic T3 (pT3) but such cases represent a minority of patients in adjuvant lung cancer trials. Potentially more precise than tumor morphology alone, comprehensive genomic profiling technologies have the power to discriminate whether tumors in the same lobe represent 2 separate primary lesions or localized spread of a single lesion. In addition to lineage insights, tumor profiling simultaneously provides information on actionable genomic alterations. In this review we discuss the data that support the ability of molecular technologies to distinguish synchronous primary tumors from intrapulmonary metastases and discuss the use of molecular assays as an adjunct to current staging systems. Two cases are presented to highlight the potential immediate clinical implications of comprehensive genomic profiling. PMID- 25911331 TI - Construction of joint confidence regions for the optimal true class fractions of Receiver Operating Characteristic (ROC) surfaces and manifolds. AB - The three-class approach is used for progressive disorders when clinicians and researchers want to diagnose or classify subjects as members of one of three ordered categories based on a continuous diagnostic marker. The decision thresholds or optimal cut-off points required for this classification are often chosen to maximize the generalized Youden index (Nakas et al., Stat Med 2013; 32: 995-1003). The effectiveness of these chosen cut-off points can be evaluated by estimating their corresponding true class fractions and their associated confidence regions. Recently, in the two-class case, parametric and non parametric methods were investigated for the construction of confidence regions for the pair of the Youden-index-based optimal sensitivity and specificity fractions that can take into account the correlation introduced between sensitivity and specificity when the optimal cut-off point is estimated from the data (Bantis et al., Biomet 2014; 70: 212-223). A parametric approach based on the Box-Cox transformation to normality often works well while for markers having more complex distributions a non-parametric procedure using logspline density estimation can be used instead. The true class fractions that correspond to the optimal cut-off points estimated by the generalized Youden index are correlated similarly to the two-class case. In this article, we generalize these methods to the three- and to the general k-class case which involves the classification of subjects into three or more ordered categories, where ROC surface or ROC manifold methodology, respectively, is typically employed for the evaluation of the discriminatory capacity of a diagnostic marker. We obtain three- and multi dimensional joint confidence regions for the optimal true class fractions. We illustrate this with an application to the Trail Making Test Part A that has been used to characterize cognitive impairment in patients with Parkinson's disease. PMID- 25911332 TI - The effect of heterogeneous variance on efficiency and power of cluster randomized trials with a balanced 2 * 2 factorial design. AB - Sample size calculation for cluster randomized trials (CRTs) with a [Formula: see text] factorial design is complicated due to the combination of nesting (of individuals within clusters) with crossing (of two treatments). Typically, clusters and individuals are allocated across treatment conditions in a balanced fashion, which is optimal under homogeneity of variance. However, the variance is likely to be heterogeneous if there is a treatment effect. An unbalanced allocation is then more efficient, but impractical because the optimal allocation depends on the unknown variances. Focusing on CRTs with a [Formula: see text] design, this paper addresses two questions: How much efficiency is lost by having a balanced design when the outcome variance is heterogeneous? How large must the sample size be for a balanced allocation to have sufficient power under heterogeneity of variance? We consider different scenarios of heterogeneous variance. Within each scenario, we determine the relative efficiency of a balanced design, as a function of the level (cluster, individual, both) and amount of heterogeneity of the variance. We then provide a simple correction of the sample size for the loss of power due to heterogeneity of variance when a balanced allocation is used. The theory is illustrated with an example of a published 2 x2 CRT. PMID- 25911333 TI - A permutation test to analyse systematic bias and random measurement errors of medical devices via boosting location and scale models. AB - Measurement errors of medico-technical devices can be separated into systematic bias and random error. We propose a new method to address both simultaneously via generalized additive models for location, scale and shape (GAMLSS) in combination with permutation tests. More precisely, we extend a recently proposed boosting algorithm for GAMLSS to provide a test procedure to analyse potential device effects on the measurements. We carried out a large-scale simulation study to provide empirical evidence that our method is able to identify possible sources of systematic bias as well as random error under different conditions. Finally, we apply our approach to compare measurements of skin pigmentation from two different devices in an epidemiological study. PMID- 25911334 TI - First evidence-based guidelines for the diagnosis and management of hepatic encephalopathy: A welcome development. PMID- 25911335 TI - EASL-ALEH Clinical Practice Guidelines: Non-invasive tests for evaluation of liver disease severity and prognosis. PMID- 25911336 TI - EASL Recommendations on Treatment of Hepatitis C 2015. PMID- 25911337 TI - MyPro: A seamless pipeline for automated prokaryotic genome assembly and annotation. AB - MyPro is a software pipeline for high-quality prokaryotic genome assembly and annotation. It was validated on 18 oral streptococcal strains to produce submission-ready, annotated draft genomes. MyPro installed as a virtual machine and supported by updated databases will enable biologists to perform quality prokaryotic genome assembly and annotation with ease. PMID- 25911338 TI - The role of sponsorship in achieving our mission. PMID- 25911339 TI - Laying the foundation for expanding the Dietary Guidelines for Americans to address children from birth to 24 months and women who are pregnant. PMID- 25911340 TI - Global food practices, cultural competency, and dietetics: part 3. PMID- 25911341 TI - New menu labeling requirements: Academy advocacy expands opportunities. PMID- 25911342 TI - Position of the academy of nutrition and dietetics: vegetarian diets. AB - It is the position of the Academy of Nutrition and Dietetics that vegetarian diets can provide health benefits in the prevention and treatment of certain health conditions, including atherosclerosis, type 2 diabetes, hypertension, and obesity. Well-designed vegetarian diets that may include fortified foods or supplements meet current nutrient recommendations and are appropriate for all stages of the life cycle, including pregnancy, lactation, infancy, childhood, and adolescence. Vegetarians must use special care to ensure adequate intake of vitamin B-12. Vegetarian diets are primarily plant-based, comprised of grains, legumes, nuts, seeds, vegetables, and fruit; do not include flesh foods (beef, pork, poultry and fowl, wild game, and fish); and may or may not include some animal products, such as dairy (milk and milk products), eggs, and processed foods that contain casein or whey. Although vegetarians may have a higher deficiency risk for some nutrients (eg, vitamin B-12) compared to nonvegetarians, nutritional deficiencies are not the main causes of mortality or morbidity in Western societies. Vegetarian diets are associated with a lower risk of ischemic heart disease, hypertension, type 2 diabetes, obesity, and some types of cancer; low-fat vegetarian diets, in combination with other healthy lifestyle factors, have been shown to be effective in the treatment of these diseases. Vegetarians have lower low-density lipoprotein, better serum glucose control, and lower oxidative stress. Low intake of foods containing saturated fat and cholesterol, and high intake of vegetables, fruits, whole grains, legumes, nuts and seeds, and soy products that are rich in fiber and phytochemicals are components of a vegetarian diet that contribute to reduction of chronic disease. PMID- 25911343 TI - Registered dietitian nutritionists and nutrition and dietetics technicians, registered, are ethically obligated to maintain personal competence in practice. PMID- 25911344 TI - 2014 Lenna Francis Cooper Memorial Lecture: Inside Out: How Retail RDNs Transform Food Culture. PMID- 25911345 TI - What nutritional contribution do edible flowers make? PMID- 25911346 TI - Surgeon is struck off for punching patient in the face to try to repair fracture. PMID- 25911347 TI - An evaluation of the Parents Plus-Parenting When Separated programme. AB - This study evaluated the Parents Plus-Parenting when Separated Programme, an intervention specifically designed to address the needs of separated parents in an Irish context. In a randomized control trial, 82 separated parents with young children were assigned to the Parents Plus-Parenting when Separated Programme treatment group and 79 to a waiting-list control group. They were assessed on measures of client goals, parenting satisfaction, child and parental adjustment and interparental conflict at baseline (Time 1) and 6 weeks later (Time 2), after the treatment group completed the Parents Plus-Parenting when Separated Programme. From Time 1 to 2, significant goal attainment, increases in parenting satisfaction and decreases in child behaviour problems, parental adjustment problems and interparental conflict occurred in the Parents Plus-Parenting when Separated Programme group, but not in the control group. These results supported the effectiveness of Parents Plus-Parenting when Separated Programme, which should be made more widely available to separated parents. PMID- 25911348 TI - Ovary removal is linked to lower breast cancer mortality in BRCA1 carriers. PMID- 25911350 TI - Possible late diagnosis of the Brugada syndrome in a patient presenting with a primary cardiac arrest. PMID- 25911349 TI - Insights into new-onset atrial fibrillation following open heart surgery and implications for type II atrial flutter. AB - AIMS: Postoperative atrial fibrillation (POAF), new-onset AF after open heart surgery (OHS), is thought to be related to pericarditis. Based on AF studies in the canine sterile pericarditis model, we hypothesized that POAF in patients after OHS may be associated with a rapid, regular rhythm in the left atrium (LA), suggestive of an LA driver maintaining AF. The aim of this study was to test the hypothesis that in patients with POAF, atrial electrograms (AEGs) recorded from at least one of the two carefully selected LA sites would manifest a rapid, regular rhythm with AEGs of short cycle length (CL) and constant morphology, but a selected right atrial (RA) site would manifest AEGs with irregular CLs and variable morphology. METHODS AND RESULTS: In 44 patients undergoing OHS, AEGs recorded from the epicardial surface of the RA, the LA portion of Bachmann's bundle, and the posterior LA during sustained AF were analysed for regularity of CL and morphology. Sustained AF occurred in 15 of 44 patients. Atrial electrograms were recorded in 11 of 15 patients; 8 of 11 had rapid, regular activation with constant morphology recorded from at least one LA site; no regular AEG sites were present in 3 of 11 patients. CONCLUSIONS: Atrial electrograms recorded during sustained POAF frequently demonstrated rapid, regular activation in at least one LA site, consistent with a driver maintaining AF. PMID- 25911351 TI - A rare cause of severe lactic acidosis. AB - Sarcoidosis is a multisystem disease of unknown aetiology with a classic histology of non-caseating granulomas. It most often occurs in those below the age of 50 years, and has a female preponderance. The main targets, often symptomless, are the lung and hilar lymph nodes, although liver involvement is not uncommon. Hepatic sarcoidosis encompasses a broad spectrum of presentations, from asymptomatic hepatic granulomas with slight liver function test derangement to severe liver involvement with cholestasis, advanced liver cirrhosis or chronic liver failure. Mortality due to acute liver failure is far less common than lung and heart involvement. We describe a case of fulminant liver failure with multiorgan failure presenting initially with chronic non-specific symptoms, in addition to minimal abnormal investigations such as mild anaemia, neutrophil leucocytosis and mild obstructive liver dysfunction. Presenting features included confusion, hypotension, oliguria and rapidly deteriorating liver function with severe lactic acidosis. Postmortem examination confirmed extensive systemic sarcoidosis. PMID- 25911352 TI - Intra-operative acidosis during 5-aminolevulinic acid assisted glioma resection. AB - A 47-year-old man underwent 5-aminolevulinic acid assisted resection of high grade glioma. Intraoperatively, he developed a compensated lactic acidosis that was managed medically and did not cause long term complications. PMID- 25911353 TI - A chest wall pulsating mass. AB - A 34-year-old HIV-positive man with intravenous drug addiction presented with a 2 week history of fever and a pulsatile presternal mass; 2 weeks prior he had suffered a traumatic sternal fracture. The CT scan showed a bulky abscess with presternal and retrosternal extension that contacted the heart (which explained its pulsatile effect) and pulmonary necrotising lesions. Drainage of the thoracic wall abscess was performed, and antibiotics (flucloxacillin plus gentamicin) were started on the presumption of staphylococcal bacteraemia given the patient's intravenous drug habit. Blood cultures and culture of the aspirated pus confirmed growth of methicillin-sensitive Staphylococcus aureus; transoesophageal echocardiography showed endocarditis of the tricuspid valve. We therefore assumed pulmonary septic embolisation from right-sided endocarditis and acute sternal osteomyelitis, and the patient was treated for 6 weeks with clinical resolution. PMID- 25911354 TI - Syndrome of inappropriate antidiuretic hormone secretion: a story of duloxetine induced hyponatraemia. AB - Hyponatraemia is the most commonly encountered electrolyte abnormality in clinical practice. Syndrome of inappropriate antidiuretic hormone secretion (SIADH) accounts for nearly 60% of all hyponatraemias. Selective serotonin reuptake inhibitors (SSRIs) are well known to have side effects of SIADH. There have been few reported cases of serotonin norepinephrine reuptake inhibitors (SNRIs) causing SIADH-induced hyponatraemia. Duloxetine is one type of SNRI used to treat several conditions, including depression and diabetic neuropathy. We present a case of a 76-year-old woman with a history of fibromyalgia who had recently been prescribed duloxetine for her condition. On admission to the hospital, her sodium decreased to a low of 118 mmol/L. Evaluation for other causes of hyponatraemia yielded negative results. Duloxetine was discontinued and after 3 days the patient's sodium increased to 130 mmol/L. The purpose of this case report is to highlight the importance of having suspicion for rare but real side effects of medications such as duloxetine. PMID- 25911355 TI - Severe pelvic abscess formation following caesarean section. AB - We report a case of a 24-year-old woman with severe pelvic abscess formation 2 weeks after secondary caesarean section. The isolated pathogens were a mixture of Gardnerella vaginalis, Mycoplasma hominis and Ureaplasma urealyticum. After initial resistance to systemic antibiotic treatment, she underwent radiologically guided drainage of the abscesses, whereon she had a continuous recovery. PMID- 25911356 TI - Tuberculous lymphadenitis and syndrome of inappropriate antidiuresis, improbable partners. AB - A patient with acute respiratory infection and severe hyponatraemia was admitted to our department. The hyponatraemia study was compatible with syndrome of inappropriate antidiuresis (SIAD) and an association with the respiratory problem was initially assumed. The recurrence of hyponatraemia after resolution of the pulmonary infection led to further investigation and to the diagnosis of tuberculous lymphadenitis. After treatment of this condition, discontinuation of SIAD treatment was possible, making this association presumable. We would like to highlight the importance of considering alternative conditions in the approach to SIAD. PMID- 25911357 TI - Oncocytic adrenocortical carcinoma--a rare pathological variant. AB - Oncocytic adrenocortical carcinoma is a rare histopathological variant of adrenocortical carcinoma with very few instances reported in the literature to date. With progressive research, new insights have emerged in the molecular profiling of these tumours. This advancement has led to more clarity in reporting of this tumour. We report a case of oncocytic adrenocortical carcinoma with its attending clinical presentation, immunohistochemical profiling and characteristic electron microscopy findings. PMID- 25911358 TI - Primary osteosarcoma of the clavicle and the perils of bone biopsy. AB - We present a rare case of delayed diagnosis of osteosarcoma of the medial clavicle in a young man. He presented following a pathological fracture with a falsely reassuring core and fine-needle aspiration biopsy. The initial biopsy was suggestive of an aneurysmal bone cyst and was therefore treated conservatively without further follow-up. The rapid increase in size over the next 8 months triggered a repeat presentation and subsequent repeat biopsy. The open biopsy confirmed high-grade osteosarcoma and the patient underwent claviculectomy with neoadjuvant chemotherapy. PMID- 25911359 TI - Metastatic basal cell carcinoma: a frequent disease with rare clinical evolution. AB - Basal cell carcinoma (BCC) is the most common malignancy worldwide. BCC has a benign evaluation, despite the high rate of local recurrence. Conversely, metastatic BCC (mBCC) is extremely rare. In this article, we present a case of an 86-year-old woman with a history of forearm mBCC, excised in 2009. In 2011, she experienced a left axilla enlargement and the evaluation revealed metastasis of mBCC. The patient began chemotherapy but had regional progression. After she had undergone radiotherapy, initiation of a clinical phase II trial was proposed, which she refused. The patient died in March 2013, 17 months after metastases diagnosis. mBCC poses a significant management challenge and current treatment options are limited. The gold standard treatment is surgical excision. Given the rarity of metastatic spread of cancer and the limited effectiveness of cytostatic agents, it has been a challenge to treat these types of patients. PMID- 25911360 TI - Renal infarction caused by medium vessel vasculitis. AB - A 44-year-old Italian man presented to the emergency department on three occasions over 4 days with severe left flank pain. Initial investigations including a renal tract ultrasound were normal and he was discharged with analgaesia. On his third presentation, a CT angiogram was performed due to persisting pain, which demonstrated infarction of his left kidney as well as thickening of the anterior branch of left renal artery and complete occlusion with focal intimal dissection of the coeliac artery. His antineutrophil cytoplasmic antibody was negative. A medium vessel vasculitis was suspected and confirmed on positron emission tomography-CT, which revealed increased metabolic activity involving the right internal mammary artery and coeliac artery. Treatment with pulse methylprednisolone was started followed by a tapering prednisolone regimen, with a rapid reduction in his inflammatory indices. Twenty four months later his renal function remains normal off all immunosuppression. PMID- 25911361 TI - The truth is in the water: metastatic prostate cancer presenting as an intermittent facial nerve palsy. AB - An elderly man presented to the acute ear, nose and throat (ENT) services with a history of intermittent, self-limiting facial nerve palsy. Full ENT examination was normal, with all cranial nerves and peripheral neurology intact. Multiple imaging modalities suggested an aggressive bony lesion, secondary to locally advanced prostate malignancy with extensive metastatic infiltration. Prostate cancer is known to preferentially metastasise to bone and has been known to cause multiple cranial nerve palsies and ophthalmoplegia. This is the first case described in the literature of metastatic prostate cancer presenting with intermittent facial nerve palsy. PMID- 25911362 TI - When myopathy breaks the rules: a late-onset distal presentation. AB - Myopathies typically present with proximal or generalised muscle weakness, but it is important for clinicians to recognise they may also have other distributions. This paper describes a case of distal myopathy that was confirmed genetically as ZASP (Z-band alternatively spliced PDZ motif-containing protein) myofibrillar myopathy (MFM). MFMs are particularly topical because the genetic basis of several have recently been established, enabling diagnosis of conditions previously labelled 'idiopathic myopathy', and shedding new light on their pathophysiology. This paper describes a purely distal lower limb phenotype of ZASP MFM, the pathophysiology of ZASP and other MFMs, and the differential diagnosis of late-onset distal symmetrical weakness. The case includes several learning points: ZASP MFM is a new diagnosis; it should be included in differential diagnoses for late-onset myopathy, especially if there is a distal pattern or autosomal dominant inheritance; testing for cardiomyopathy is recommended, and a genetic test is now available. PMID- 25911363 TI - Appendiceal faecolith: a radiological finding not to be missed. PMID- 25911364 TI - Recent developments in malaria vaccinology. AB - The development of a highly effective malaria vaccine remains a key goal to aid in the control and eventual eradication of this devastating parasitic disease. The field has made huge strides in recent years, with the first-generation vaccine RTS,S showing modest efficacy in a Phase III clinical trial. The updated 2030 Malaria Vaccine Technology Roadmap calls for a second generation vaccine to achieve 75% efficacy over two years for both Plasmodium falciparum and Plasmodium vivax, and for a vaccine that can prevent malaria transmission. Whole-parasite immunisation approaches and combinations of pre-erythrocytic subunit vaccines are now reporting high-level efficacy, whilst exciting new approaches to the development of blood-stage and transmission-blocking vaccine subunit components are entering clinical development. The development of a highly effective multi component multi-stage subunit vaccine now appears to be a realistic ambition. This review will cover these recent developments in malaria vaccinology. PMID- 25911365 TI - PfEMP1 - A Parasite Protein Family of Key Importance in Plasmodium falciparum Malaria Immunity and Pathogenesis. AB - Plasmodium falciparum causes the most severe form of malaria and is responsible for essentially all malaria-related deaths. The accumulation in various tissues of erythrocytes infected by mature P. falciparum parasites can lead to circulatory disturbances and inflammation, and is thought to be a central element in the pathogenesis of the disease. It is mediated by the interaction of parasite ligands on the erythrocyte surface and a range of host receptor molecules in many organs and tissues. Among several proteins and protein families implicated in this process, the P. falciparum erythrocyte membrane protein 1 (PfEMP1) family of high-molecular weight and highly variable antigens appears to be the most prominent. In this chapter, we aim to provide a systematic overview of the current knowledge about these proteins, their structure, their function, how they are presented on the erythrocyte surface, and how the var genes encoding them are regulated. The role of PfEMP1 in the pathogenesis of malaria, PfEMP1-specific immune responses, and the prospect of PfEMP1-specific vaccination against malaria are also covered briefly. PMID- 25911366 TI - Prospects for Vector-Based Gene Silencing to Explore Immunobiological Features of Schistosoma mansoni. AB - Schistosomiasis is a prevalent, socioeconomically important disease of humans caused by parasites of the genus Schistosoma (schistosomes or blood flukes). Currently, more than 200 million people worldwide are infected with schistosomes. Despite major research efforts, there is only one drug routinely used for effective treatment, and no vaccine is available to combat schistosomiasis. The purpose of the present article is to (1) provide a background on the parasites and different forms of disease; (2) describe key immunomolecular aspects of disease induced in the host; and (3) critically appraise functional genomic methods employed to explore parasite biology, parasite-host interactions and disease at the molecular level. Importantly, the article also describes the features and advantages of lentiviral delivery of artificial microRNAs to silence genes. It also discusses the first successful application of such an approach in schistosomes, in order to explore the immunobiological role of selected target proteins known to be involved in egg-induced disease. The lentiviral transduction system provides exciting prospects for future, fundamental investigations of schistosomes, and is likely to have broad applicability to other eukaryotic pathogens and infectious diseases. The ability to achieve effective and stable gene perturbation in parasites has major biotechnological implications, and might facilitate the development of radically new methods for the treatment and control of parasitic diseases. PMID- 25911367 TI - Chronobiology of trematode cercarial emergence: from data recovery to epidemiological, ecological and evolutionary implications. AB - One major challenge for parasites with complex cycles consists to succeed in the transmission from one host to the next host. To maximize the probability of encountering the right host, numerous trematode species have selected various emergence rhythms occurring during the escape of the short-lived cercariae from the mollusc host. Cercarial shedding patterns are beautiful examples of adaptation of the parasite for a successful rendezvous with its subsequent host. In this review, after an analysis of the technical and statistical aspects specific to such studies, we compile the knowledge and unresolved issues we have about the synchronization of these rhythms, their genetic support and the role of the host physiology or activity. We are also interested on how cercarial rhythmicity influences cercarial densities in waters of transmission sites and then the risk of host infection in case of schistosomiasis. Ecological significance of the inter- and intra-specific diversity of these rhythms is emphasized as well as the evolutionary implication of new chronotypes resulting from the capture of new host species and promoting reproductive isolation and alloxenic speciation. Currently, genome sequence data now available for some trematodes such as the schistosomes provide an unprecedented resource for new research approaches that should contribute identification of the genes and mechanisms involved in determining the cercarial shedding rhythms observed. PMID- 25911368 TI - Strongyloidiasis with emphasis on human infections and its different clinical forms. AB - Strongyloidiasis (caused by Strongyloides stercoralis, and to a lesser extent by Strongyloides fuelleborni) is one of the most neglected tropical diseases with endemic areas and affecting more than 100 million people worldwide. Chronic infections in endemic areas can be maintained for decades through the autoinfective cycle with the L3 filariform larvae. In these endemic areas, misdiagnosis, inadequate treatment and the facilitation of the hyperinfection syndrome by immunosuppression are frequent and contribute to a high mortality rate. Despite the serious health impact of strongyloidiasis, it is a neglected disease and very little is known about this parasite and the disease when compared to other helminth infections. Control of the disease is difficult because of the many gaps in our knowledge of strongyloidiasis. We examine the recent literature on different aspects of strongyloidiasis with emphasis in those aspects that need further research. PMID- 25911369 TI - A perspective on Cryptosporidium and Giardia, with an emphasis on bovines and recent epidemiological findings. AB - Cryptosporidium and Giardia are two common aetiological agents of infectious enteritis in humans and animals worldwide. These parasitic protists are usually transmitted by the faecal-oral route, following the ingestion of infective stages (oocysts or cysts). An essential component of the control of these parasitic infections, from a public health perspective, is an understanding of the sources and routes of transmission in different geographical regions. Bovines are considered potential sources of infection for humans, because species and genotypes of Cryptosporidium and Giardia infecting humans have also been isolated from cattle in molecular parasitological studies. However, species and genotypes of Cryptosporidium and Giardia of bovids, and the extent of zoonotic transmission in different geographical regions in the world, are still relatively poorly understood. The purpose of this article is to (1) provide a brief background on Cryptosporidium and Giardia, (2) review some key aspects of the molecular epidemiology of cryptosporidiosis and giardiasis in animals, with an emphasis on bovines, (3) summarize research of Cryptosporidium and Giardia from cattle and water buffaloes in parts of Australasia and Sri Lanka, considering public health aspects and (4) provide a perspective on future avenues of study. Recent studies reinforce that bovines harbour Cryptosporidium and Giardia that likely pose a human health risk and highlight the need for future investigations of the biology, population genetics and transmission dynamics of Cryptosporidium and Giardia in cattle, water buffaloes and other ruminants in different geographical regions, the fate and transport of infective stages following their release into the environment, as well as for improved strategies for the control and prevention of cryptosporidiosis and giardiasis, guided by molecular epidemiological studies. PMID- 25911370 TI - eComment. A bicycle inner tube in a glass of water! Video-assisted thoracoscopic surgery for spontaneous pneumothorax and the submersion test. PMID- 25911371 TI - eComment. Innovation for minimally invasive surgical treatment of pneumothorax. PMID- 25911372 TI - eComment. The combined use of clinical pretest probability and brain natriuretic peptide in predicting the risk of atrial fibrillation. PMID- 25911373 TI - eComment. "Practice makes the master" Patrick Rothfuss--The Name of the Wind. PMID- 25911374 TI - eComment. Possible risk factors and mechanisms of metalloptysis. PMID- 25911375 TI - eReply. Patient features versus surgeon experience: the clash of the titans. PMID- 25911376 TI - eComment. The role of local recurrence in the development of post-resectional bronchopleural fistula. PMID- 25911377 TI - eComment. Preoperative computed tomography scan for the proper planning of surgery for heart valve endocarditis. PMID- 25911378 TI - eReply. Re: Preoperative computed tomography scan for the proper planning of surgery for heart valve endocarditis. PMID- 25911379 TI - Treatment solution by the readers: Endovascular treatment of aortic arch aneurysms following aortic debranching. PMID- 25911380 TI - The seventh zinc finger motif of A20 is required for the suppression of TNF-alpha induced apoptosis. AB - The ubiquitin-editing enzyme A20 suppresses nuclear factor-kappaB (NF-kappaB) activation and tumor necrosis factor-alpha (TNF-alpha)-induced apoptosis in a deubiquitinating and ubiquitin ligase activity-dependent manner. Although recent studies revealed that A20 regulates NF-kappaB independently of its enzymatic activity through its seventh zinc finger motif (ZnF7), the involvement of ZnF7 in TNF-alpha-induced apoptosis is not clear. In this study, ZnF7 was found to be important for A20-mediated suppression of TNF-alpha-induced apoptosis. We also found that the ubiquitin ligases cIAP1/2 are required for A20 to suppress TNF alpha-induced apoptosis. Because A20 binds to cIAP1/2 through ZnF7, these results suggest that A20 may control cIAP1/2 when suppressing TNF-alpha-induced apoptosis. PMID- 25911381 TI - Comments on "Characterization of four new designer drugs, 5-chloro-NNEI, NNEI indazole analog, alpha-PHPP and alpha-POP, with 11 newly distributed designer drugs in illegal products". PMID- 25911382 TI - The effects of salinity changes on the Polychaete Diopatra neapolitana: Impacts on regenerative capacity and biochemical markers. AB - Polychaetes have been identified by several authors as a group of marine invertebrates that respond rapidly to anthropogenic stressors. However, studies investigating alterations in Polychaetes affected by climate changes are scarce. Thus, the present study aimed to assess the impact of salinity changes (14, 21, 28, 35, 42g/L) on the physiological and biochemical performance of the Polychaete Diopatra neapolitana, evaluating the species regenerative ability and biochemical alterations. The results obtained demonstrated that organisms exposed to extreme salinity conditions (14, 21 and 42g/L) presented higher mortality rates, needed more days to completely regenerate the missing body region and also regenerated less chaetigers, when compared to organisms exposed to salinities 28 and 35g/L. The present study further demonstrated that D. neapolitana presented significantly lower glycogen and protein content at salinities 21 and 42g/L, which can be explained by higher energy expenditure in the physiological and biochemical processes. A marked impairment of the glutathione redox status was also recorded at salinities 21 and 42g/L. Increased antioxidant enzyme activities were observed at salinity 21g/L while LPO levels were increased at salinity 42g/L. Overall the present study demonstrated that the regenerative capacity of D. neapolitana can be used as a tool to assess environmental changes, namely salinity shifts. Moreover, stress related biomarkers revealed to be useful to evaluate the alterations in Polychaetes due to salinity changes. D. neapolitana revealed to be a good bioindicator to salinity alterations. PMID- 25911383 TI - The resolution of inflammation: Principles and challenges. AB - The concept that chemokines, cytokines and pro-inflammatory mediators act in a co ordinated fashion to drive the initiation of the inflammatory reaction is well understood. The significance of such networks acting during the resolution of inflammation however is poorly appreciated. In recent years, specific pro resolving mediators were discovered which activate resolution pathways to return tissues to homeostasis. These mediators are diverse in nature, and include specialized lipid mediators (lipoxins, resolvins, protectins and maresins) proteins (annexin A1, galectins) and peptides, gaseous mediators including hydrogen sulphide, a purine (adenosine), as well as neuromodulator release under the control of the vagus nerve. Functionally, they can act to limit further leukocyte recruitment, induce neutrophil apoptosis and enhance efferocytosis by macrophages. They can also switch macrophages from classical to alternatively activated cells, promote the return of non-apoptotic cells to the lymphatics and help initiate tissue repair mechanisms and healing. Within this review we highlight the essential cellular aspects required for successful tissue resolution, briefly discuss the pro-resolution mediators that drive these processes and consider potential challenges faced by researchers in the quest to discover how inflammation resolves and why chronic inflammation persists. PMID- 25911384 TI - PRR-signaling pathways: Learning from microbial tactics. AB - Recognition of bacterial pathogens by the mammalian host relies on the induction of early innate immune responses initiated by the activation of pattern recognition receptors (PRRs) upon sensing of their cognate microbe-associated patterns (MAMPs). Successful pathogens have evolved to intercept PRR activation and signaling at multiple steps. The molecular dissection of the underlying mechanisms revealed many of the basic mechanisms used by the immune system. Here we provide an overview of the different strategies used by bacterial pathogens and commensals to subvert and reprogram PPR-mediated innate immune responses. A particular attention is given to recent discoveries highlighting novel molecular details of the host inflammatory response in mammalian cells and current advances in our understanding of the interaction of commensals with PRR-mediated responses. PMID- 25911385 TI - Insight into the retention mechanism on immobilized artificial membrane chromatography using two stationary phases. AB - The retention behavior of sixty structurally diverse drugs on two immobilized artificial membrane (IAM) columns, IAM.PC.MG and IAM.PC.DD2 types, at two pH values, 7.4 and 5.5, was established. Extrapolated to pure aqueous phase retention factors, logkw(IAM), were determined and the role of acetonitrile as organic modifier was explored, considering the relationships with the slopes, S, of the extrapolation procedure. Good interrelations between retention factors on the two IAM stationary phases were observed, although logkw(IAM.PC.DD2) values are generally higher than logkw(IAM.PC.MG). In order to investigate the underlying retention mechanism, relationships between IAM retention factors and lipophilicity, expressed as logP or logD at pH 7.4 were established. Electrostatic interactions were considered by introducing the positively and negatively charged molecular fractions as additional parameters in the logkw(IAM)/logD relationships. The positive contribution of these fractions supported the involvement of the electrostatic interactions in the retention mechanism. Special attention was given to the retention behavior of zwitterionic compounds and for compounds with special structural characteristics. PMID- 25911386 TI - Influence of binding pH and protein solubility on the dynamic binding capacity in hydrophobic interaction chromatography. AB - Hydrophobic interaction chromatography (HIC) is one of the most frequently used purification methods in biopharmaceutical industry. A major drawback of HIC, however, is the rather low dynamic binding capacity (DBC) obtained when compared to e.g. ion exchange chromatography (IEX). The typical purification procedure for HIC includes binding at neutral pH, independently of the proteins nature and isoelectric point. Most approaches to process intensification are based on resin and salt screenings. In this paper a combination of protein solubility data and varying binding pH leads to a clear enhancement of dynamic binding capacity. This is shown for three proteins of acidic, neutral, and alkaline isoelectric points. High-throughput solubility screenings as well as miniaturized and parallelized breakthrough curves on Media Scout RoboColumns (Atoll, Germany) were conducted at pH 3-10 on a fully automated robotic workstation. The screening results show a correlation between the DBC and the operational pH, the protein's isoelectric point and the overall solubility. Also, an inverse relationship of DBC in HIC and the binding kinetics was observed. By changing the operational pH, the DBC could be increased up to 30% compared to the standard purification procedure performed at neutral pH. As structural changes of the protein are reported during HIC processes, the applied samples and the elution fractions were proven not to be irreversibly unfolded. PMID- 25911387 TI - Effect of Initial Graft Tension on Knee Stability and Graft Tension Pattern in Double-Bundle Anterior Cruciate Ligament Reconstruction. AB - PURPOSE: To determine the initial minimal tension for restoring knee stability during double-bundle anterior cruciate ligament (ACL) reconstruction in vivo. METHODS: Patients who underwent primary double-bundle ACL reconstruction with an autologous semitendinosus tendon during 2012 were included. The bundles were fixed to a graft-tensioning system during surgery. Initial graft tensions were set to the following tensions per 6 mm in graft diameter: (1) 30 N, (2) 25 N, and (3) 20 N. Bundle tension was recorded during knee flexion-extension and in response to anterior or rotatory loads. In addition, anterior knee laxity was measured with the KT-1000 arthrometer (MEDmetric, San Diego, CA), and the pivot shift test was evaluated. RESULTS: Sixty patients were evaluated. The tension curves of both bundles among different initial tension settings were significantly different (P < .0001), with the tension in the 30-N setting being highest and that in the 20-N setting being lowest. The tension in both bundles showed reciprocal pattern during flexion-extension (P = .019). The tension of the posterolateral bundle graft was significantly lower than that of the anteromedial bundle graft in response to the anterior load at all settings (P = .0017, P = .0019, and P = .0021 at 30 degrees in the 30-N, 25-N, and 20-N settings, respectively, and P < .0001 at 90 degrees at all settings), whereas the tensions in both bundles in response to rotatory loads were equivalent. Two cases showed a grade 1 pivot shift in the 20-N setting, whereas no case showed a positive pivot shift in the other settings. KT measurements in the 30-N and 25-N settings showed no difference. CONCLUSIONS: In double-bundle ACL reconstruction, initial tension could be set as low as 25 N; however, initial tension of 20 N is not recommended because it might result in residual pivot shift in some cases, although the pivot shift difference was not significant. LEVEL OF EVIDENCE: Level IV, therapeutic case series. PMID- 25911388 TI - Correlation Between American Shoulder and Elbow Surgeons and Single Assessment Numerical Evaluation Score After Rotator Cuff or SLAP Repair. AB - PURPOSE: To compare the American Shoulder and Elbow Surgeons (ASES) and the Single Assessment Numerical Evaluation (SANE) scores after rotator cuff repair, rotator cuff revision, and SLAP repair. METHODS: This study was a retrospective review of a prospectively filled database of 262 patients who underwent arthroscopic surgery for rotator cuff tears or SLAP lesions between 1999 and 2007. All patients were operated on by the same surgeon, with a minimum follow-up of 2 years. The patient database included preoperative and outcome measures, such as pain, range of motion, and notably postoperative ASES and SANE scores. Any patient with incomplete data was removed from the study. RESULTS: Three groups were identified: primary rotator cuff repair (n = 135), rotator cuff revision (n = 73), and SLAP repair (n = 54). The overall mean ASES and SANE scores after surgery were 82.7 (+/- 20.2) and 83.3 (+/- 19.6), respectively. The Pearson correlation coefficient (r) between both scores was 0.8 (P < .001), demonstrating a very good correlation. In subgroup analysis, the correlation was highest in the cuff revision group (r = 0.88; P < .001) followed by the SLAP group (r = 0.78; P < .001) and primary cuff group (r = 0.75; P < .001). CONCLUSIONS: This study shows that there is a significant correlation between postoperative SANE and ASES rating methods in rotator cuff and SLAP repairs. We recommend the SANE score as a reliable outcome indicator for iterative follow-up, which can then be combined with a more clinically informative score such as the ASES or other process-based scores for preoperative and final workup. LEVEL OF EVIDENCE: Level III, retrospective comparative study. PMID- 25911389 TI - Local Application of Gelatin Hydrogel Sheets Impregnated With Platelet-Derived Growth Factor BB Promotes Tendon-to-Bone Healing After Rotator Cuff Repair in Rats. AB - PURPOSE: To determine whether the local application of platelet-derived growth factor BB (PDGF-BB) in hydrogel sheets would promote healing and improve histologic characteristics and biomechanical strength after rotator cuff (RC) repair in rats. METHODS: To assess the effect of PDGF-BB on tendon-to-bone healing we divided 36 adult male Sprague-Dawley rats treated with bilateral surgery to repair the supraspinatus tendon at its insertion site into 3 groups: group 1 = suture-only group; group 2 = suture and gelatin hydrogel sheets impregnated with phosphate-buffered saline (PBS); and group 3 = suture and gelatin hydrogel sheets impregnated with PDGF-BB (0.5 MUg). Semiquantitative histologic evaluation was carried out 2, 6, and 12 weeks later; cell proliferation was assessed 2 and 6 weeks postoperatively by immunostaining for proliferating cell nuclear antigen (PCNA), and biomechanical testing, including ultimate load to failure, stiffness, and ultimate stress to failure, was performed 12 weeks after the operation. RESULTS: At 2 weeks, the average percentage of PCNA-positive cells at the insertion site was significantly higher in group 3 (40.5% +/- 2.4%) than in group 1 (32.1% +/- 6.9%; P = .03) and group 2 (31.9% +/- 3.7%; P = .02). At 2 and 6 weeks, the histologic scores were similar among the 3 groups. At 12 weeks, the histologic score was significantly higher in group 3 (10.3 +/- 0.8) than in group 1 (8.5 +/- 0.5; P = .002) or group 2 (8.8 +/ 0.8; P = .009), whereas ultimate load to failure, stiffness, and ultimate load to stress (normal control population, 44.73 +/- 9.75 N, 27.59 +/- 4.32 N/mm, and 21.33 +/- 4.65 N/mm(2), respectively) were significantly higher in group 3 (28.28 +/- 6.28 N, 11.05 +/- 2.37 N/mm, and 7.99 +/- 2.13 N/mm(2), respectively) than in group 1 (10.44 +/- 1.98 N, 4.74 +/- 1.31 N/mm, and 3.28 +/- 1.27 N/mm(2), respectively; all P < .001) or group 2 (11.85 +/- 2.89 N, 5.86 +/- 1.75 N/mm, and 3.31 +/- 0.80 N/mm(2), respectively; all P < .001). CONCLUSIONS: The placement of a PDGF-BB-impregnated hydrogel sheet just lateral to a transected and acutely reattached supraspinatus tendon produced significantly more PCNA-positive cells at 2 weeks and greater collagen fiber orientation, ultimate failure loads, stiffness, and stress to failure at 12 weeks than did a PBS-impregnated hydrogel sheet. No differences in vascularity or cellularity were observed. CLINICAL RELEVANCE: The local application of PDGF-BB-impregnated gelatin hydrogel may help to promote tendon-to-bone healing after RC repair in humans. PMID- 25911390 TI - Arthroscopic Suture Anchor Fixation of Bony Bankart Lesions: Clinical Outcome, Magnetic Resonance Imaging Results, and Return to Sports. AB - PURPOSE: The purpose of this study was to evaluate the outcome, return to sporting activity, and postoperative articular cartilage and bony morphology of shoulders that underwent arthroscopic suture anchor repair of bony Bankart lesions. METHODS: The inclusion criteria for this retrospective study were anterior glenoid rim fractures after traumatic shoulder instability that were treated with arthroscopic suture anchor repair. Patients were surveyed by a questionnaire including sport-specific outcome, Rowe score, Western Ontario Shoulder Instability Index, and Oxford Instability Score. Three-tesla magnetic resonance imaging could be performed in 30 patients to assess osseous integration, glenoid reconstruction, and signs of osteoarthritis. RESULTS: From November 1999 to April 2010, 81 patients underwent an anterior bony Bankart repair in our department (50 arthroscopic suture anchor repairs, 5 arthroscopic screw fixations, and 26 open repairs). The 55 arthroscopic repairs comprised a consecutive cohort of patients treated by a single surgeon. Of the 50 patients in the suture anchor group, 45 (90%) were available for evaluation. At 82 +/- 31 months postoperatively, the mean Rowe score was 85.9 +/- 20.5 points, the mean Western Ontario Shoulder Instability Index score was 89.4% +/- 14.7%, and the mean Oxford Instability Score was 13.6 +/- 5.4 points. Compared with the contralateral shoulder, all scores showed a significantly reduced outcome (P < .001, P < .001, and P < .001, respectively). A redislocation occurred in 3 patients (6.6%). Regarding satisfaction, 35 patients (78%) were very satisfied, 9 (20%) were satisfied, and 1 was partly satisfied. Overall, 95% of patients returned to any sporting activity after surgery. The number of sports disciplines (P < .001), duration (P = .005), level (P = .02), and risk category (P = .013) showed a significant reduction compared with the pretrauma condition. However, only 19% of patients reported that shoulder complaints were the reason for the reduction in activity. Nonunion occurred in 16.6%, with a higher frequency in patients with chronic lesions (P = .031). Anatomic reduction was achieved in 72%, the medial step-off in patients with nonanatomic reduction averaged 1.8 +/- 0.9 mm, and the remaining glenoid defect size averaged 6.8% +/- 7.3%. Full-thickness cartilage defects of the anterior glenoid were detected in 70% of patients. CONCLUSIONS: Arthroscopic suture anchor repair may enable an anatomic reduction of bony Bankart lesions with no or only minimal articular steps and provides successful midterm outcomes concerning clinical scores, recurrence, and patient satisfaction. The return to activity is limited for various, mostly non-shoulder related causes. Chronic lesions may have an inferior healing potential; therefore early surgical stabilization of acute Bankart fragments is suggested to avoid possible nonunion. LEVEL OF EVIDENCE: Level IV, therapeutic case series. PMID- 25911391 TI - Worldwide Research Productivity in the Field of Arthroscopy: A Bibliometric Analysis. AB - PURPOSE: This study aimed to evaluate the quantity and quality of articles from different countries involving arthroscopy to investigate the characteristics of worldwide research productivity. METHODS: Web of Science was searched for arthroscopy articles published between 1999 and 2013. The numbers of articles and citations were analyzed to assess the contributions of different countries. Publication activity was adjusted by country population and gross domestic product (GDP). RESULTS: A total of 12,553 articles were published worldwide. The time trend for the number of articles showed an increase of 2.27-fold between 1999 and 2013. North America, Western Europe, and Eastern Asia were the most productive areas. High-income countries published 90.86% of the articles; middle income countries, 9.11%; and lower-income countries, only 0.02%. The United States published the most articles (35.40%), followed by Germany (9.53%), the United Kingdom (6.80%), the Republic of Korea (5.45%), and Japan (4.76%), and had the highest total citations (78,161). However, Sweden had the highest mean citations (35.56), followed by Switzerland (23.39) and the Netherlands (18.90). There were positive correlations between the number of publications and population/GDP (P < .01). When normalized to population, Switzerland ranked the highest, followed by Finland and Sweden. When adjusted by GDP, the Republic of Korea ranked first, followed by Finland and Turkey. CONCLUSIONS: The number of publications on arthroscopy increased significantly from 1999 to 2013, with a more than 2-fold increase in volume. The United States was the most productive country as measured by total publications, but when adjusted for population, Switzerland published the highest number of articles, followed by Finland and Sweden. When publications were adjusted for GDP, the Republic of Korea ranked first, with Finland second and Turkey third. CLINICAL RELEVANCE: Bibliometric analysis allows us to understand contributions of different world regions in scientific research in the field of arthroscopy and gives insight into the quantity and quality of articles related to arthroscopy. PMID- 25911392 TI - The Shoulder Objective Practical Assessment Tool: Evaluation of a New Tool Assessing Residents Learning in Diagnostic Shoulder Arthroscopy. AB - PURPOSE: To design and validate an objective practical assessment tool for diagnostic shoulder arthroscopy that would provide residents with a method to evaluate their progression in this field of surgery and to identify specific learning needs. METHODS: We designed and evaluated the shoulder Objective Practical Assessment Tool (OPAT). The shoulder OPAT was designed by us, and scoring domains were created using a Delphi process. The shoulder OPAT was trialed by members of the British Elbow & Shoulder Society Education Committee for internal consistency and ease of use before being offered to other trainers and residents. Inter-rater reliability and intrarater reliability were calculated. One hundred forty orthopaedic residents, of varying seniority, within 5 training regions in the United Kingdom, were questioned regarding the tool. A pilot study of 6 residents was undertaken. RESULTS: Internal consistency was 0.77 (standardized Cronbach alpha). Inter-rater reliability was 0.60, and intrarater reliability was 0.82. The Spearman correlation coefficient (r) between the global summary score for the shoulder OPAT and the current assessment tool used in postgraduate training for orthopaedic residents undertaking diagnostic shoulder arthroscopy equaled 0.74. Of the residents, 82% agreed or strongly agreed when asked if the shoulder OPAT would be a useful tool in monitoring progression and 72% agreed or strongly agreed with the introduction of the shoulder OPAT within the orthopaedic domain. CONCLUSIONS: This study shows that the shoulder OPAT fulfills several aspects of reliability and validity when tested. Despite the inter-rater reliability being 0.60, we believe that the shoulder OPAT has the potential to play a role alongside the current assessment tool in the training of orthopaedic residents. CLINICAL RELEVANCE: The shoulder OPAT can be used to assess residents during shoulder arthroscopy and has the potential for use in medical education, as well as arthroscopic skills training in the operating theater. PMID- 25911393 TI - Acetabular Labral Base Repair Versus Circumferential Suture Repair: A Matched Paired Comparison of Clinical Outcomes. AB - PURPOSE: To determine whether an acetabular labral repair technique would be superior to another repair technique based on clinical outcomes measured by patient-reported outcome (PRO) scores. METHODS: We identified 465 patients who underwent labral base repair or circumferential suture repair from February 2008 to February 2012. The type of repair performed was based on labral size and tear type. The 2 groups were pair matched for age within 5 years, sex, crossover sign within 15%, coxa profunda, Workers' Compensation status, and microfracture (femur, acetabulum, or none). Data were prospectively collected and retrospectively reviewed. PROs included a visual analog scale score and the modified Harris Hip Score, Non-Arthritic Hip Score, Hip Outcome Score-Activities of Daily Living, and Hip Outcome Score-Sports-Specific Subscale. RESULTS: One hundred ten patients met the inclusion criteria for labral base repair and were pair matched on a 1:1 basis with 110 patients who underwent circumferential suture repair. The mean follow-up period was 30 months for both groups, with a range of 19.2 to 60 months for the labral base repair group and 19.2 to 67 months for the circumferential suture repair group. Radiographic data were similar between groups with respect to the lateral center-edge angle (P = .906), acetabular inclination (P = .329), anterior center-edge angle (P = .208), alpha angle (P = .387), and joint space width (P = .388). All preoperative PRO scores were statistically similar. Both groups showed significant improvements in all PROs. There were no statistical differences in postoperative PRO scores at latest follow-up (modified Harris Hip Score, P = .215; Hip Outcome Score-Activities of Daily Living, P = .839; Hip Outcome Score-Sports-Specific Subscale, P = .561; Non Arthritic Hip Score, P = .333; visual analog scale score, P = .373; and satisfaction, P = .483). There were similar rates of revision (n = 10 for both groups) and conversion to arthroplasty (n = 2 for both groups). CONCLUSIONS: On the basis of PRO scores at 2 years' follow-up, there is no difference in outcomes based on the type of labral repair performed. LEVEL OF EVIDENCE: Level III, retrospective comparative study. PMID- 25911394 TI - Cortical Suspensory Button Versus Aperture Interference Screw Fixation for Knee Anterior Cruciate Ligament Soft-Tissue Allograft: A Prospective, Randomized Controlled Trial. AB - PURPOSE: To compare anterior cruciate ligament (ACL) soft-tissue allograft reconstruction using suspensory versus aperture fixation. METHODS: After we performed prospective power analysis and obtained institutional review board approval, as well as patient consent, 64 patients were block randomized among 3 study sites to the aperture fixation group or suspensory fixation group. All patients underwent all-inside ACL reconstruction with soft-tissue allograft using either (1) femoral and tibial joint-line fixation with a femoral cannulated interference screw and a tibial cannulated interference retrograde screw (aperture) or (2) femoral and tibial cortical buttons (suspensory). Our primary outcome measure was knee anteroposterior (AP) stability measured using the KT 1000 device (MEDmetric, San Diego, CA). Secondary outcome measures included change in pain score on a visual analog scale versus preoperatively, narcotic consumption, International Knee Documentation Committee knee examination rating, International Knee Documentation Committee subjective evaluation score, Knee Society Scores, Short Form 12 scores, and radiographic analysis for socket widening. RESULTS: Ultimately, 6 included patients (9%) were not treated (cancelled surgery), and at 2 years' follow-up, 43 treated patients (74%) completed clinical evaluation. The primary outcome measure, instrumented knee AP stability at 25 degrees of knee flexion, showed no difference between groups (P = .61) at 24 months' follow-up. In addition, no statistically significant difference between groups was observed for secondary measures. CONCLUSIONS: Our results show no significant differences in knee AP stability or other outcomes comparing all-inside ACL allograft reconstruction using aperture fixation and all inside ACL allograft reconstruction using suspensory fixation. LEVEL OF EVIDENCE: Level II, lesser-quality randomized controlled trial with follow-up of less than 80% at 2 years. PMID- 25911395 TI - Femoral Tunnel Drilling Angles for Posteromedial Corner Reconstructions of the Knee. AB - PURPOSE: To determine the best angle to drill the femoral tunnels of the superficial medial collateral ligament (sMCL) and posterior oblique ligament (POL) with concomitant posterior cruciate ligament (PCL) reconstruction to avoid either short tunnels or tunnel collisions. METHODS: Eight cadaveric knees were studied. Double-bundle PCL femoral tunnels were arthroscopically drilled. Drilling of the sMCL and POL tunnels was performed in 4 different combinations of 0 degrees and 30 degrees axial (anteriorly directed) and coronal (proximally directed) angulations. Specimens were scanned with computed tomography to document the relations of the sMCL and POL tunnels to the intercondylar notch and PCL tunnels. A minimum tunnel length of 25 mm was required. RESULTS: When the sMCL femoral tunnel was drilled at 0 degrees axial and 30 degrees coronal (proximally directed) angulations or 30 degrees axial (anteriorly directed) and 0 degrees coronal angulations, the risk of tunnel collision with the PCL tunnels increased in comparison with the remaining evaluated angulations (P < .001). No POL tunnels collided with either PCL tunnel bundle with the exception of tunnels drilled at 0 degrees axial and 30 degrees coronal (proximally directed) angulations, which did so in 3 of 8 cases (P < .001). The minimum required tunnel length was obtained in all the sMCL and POL tunnels (P < .001 and P = .02, respectively). However, some of those angled at 0 degrees on the axial plane violated the intercondylar notch. CONCLUSIONS: When one is performing posteromedial reconstructions with concomitant PCL procedures, the sMCL and POL femoral tunnels should be drilled anteriorly and proximally at both 30 degrees axial and 30 degrees coronal angulations. The POL femoral tunnel may also be angled 0 degrees in the coronal plane. Tunnels at 0 degrees axial angulations showed a shorter distance to the intercondylar notch and a higher risk of collision with the PCL tunnels. CLINICAL RELEVANCE: Specific drilling angles are necessary to avoid short tunnels or collisions between the drilled tunnels when sMCL and POL femoral tunnels are placed with concomitant PCL reconstruction. PMID- 25911396 TI - A Simple Weighing Method for Spherical Cells. AB - This article presents a simple weighing method for spherical cells to avoid the high cost of correlated devices in traditional cell-weighing methods. In this method, the constant falling speeds of the spherical objects in liquid are derived to estimate their masses online. Using this method, the detected density of one type of microbead is highly in accordance with the known value. This method is proved to be capable of detecting tiny variations of the cell mass (at least within 1% of the cell mass). Finally, the proposed method is applied in nuclear transplantation operations, and, for the first time, the proper amount of the removed cytoplasm in porcine enucleation is estimated. The proposed method is able to weigh cells with a success rate of 92% at an average speed of 22 s/cell, and it can be performed on traditional microoperation systems, which makes it easily applicable in biological applications. PMID- 25911397 TI - The immune microenvironment of the colorectal tumor: Involvement of immunity genes and microRNAs belonging to the TH17 pathway. AB - Colorectal cancer is a complex and multifactorial disease. Various factors such as genetic, immunological, epigenetic and environmental constitute minor risk factors with their additive effects contributing to the advent of colorectal cancer. In order to evaluate the role of innate and adaptive immunity in the susceptibility, the presentation and the development of colorectal cancer, we considered an immunogenetic approach on polymorphisms in the TLR4 gene and NOD2/CARD15 gene (receptors of innate immunity) as well as in cytokine genes of the TH17 pathway IL17A, IL17F and cytokine receptor IL23R. Then, we evaluated the expression of microRNAs regulated by TLR4 and NOD2/CARD15 or targeting TLR4, IL17 and proinflammatory cytokines (IL-6, TNF) induced by IL17. Through a case-control study, we showed that the polymorphism of IL17A is associated with its susceptibility to colorectal cancer. Considering the tumor location, we found that the mutated alleles of IL17A, IL17F and IL23R are rather associated with colon cancer and not with rectum cancer. This result confirms that the colon and rectum are two different physiological entities. This study shows that TLR4, IL17A/F and IL23R polymorphisms are involved in the presentation of the disease with regard to tumor architecture, histology, and differentiation, advanced stage of the disease and lymph node and metastasis. Overall, these polymorphisms are associated with a poor prognosis of the disease. Furthermore, in order to evaluate the involvement of epigenetic mechanisms in the occurrence of colorectal cancer, we aimed at analyzing the tumor compared to a normal adjacent tissue and the expression of miRNAs (miR21, miR146a, miR135a, miR147b and miR155) that regulate immunity genes especially the cytokines of the TH17 pathway. This research has shown that microRNAs 21, 135a and 146a are associated with colorectal cancer. Indeed, these three miRs are overexpressed in cancer tissue compared to healthy tissue. These results clearly confirm the involvement of epigenetics in colorectal cancer. In other words, this study reveals the importance of immunity and specifically the TH17 pathway in the development and presentation of colorectal cancer. These results suggest that TLR4, IL17A, IL17F and IL23R polymorphisms as well as the expression of microRNAs that regulate inflammation and the TH17 pathway are associated with the evolution and progression of the colorectal tumor that could be considered as biomarkers in colorectal cancer. PMID- 25911402 TI - Synthesis, biological and electrochemical evaluation of novel nitroaromatics as potential anticancerous drugs. AB - Nitroaromatics i.e. 1-nitro-4-phenoxybenzene (1), 4-(4-nitrophenyloxy) biphenyl (2), 1-(4-nitrophenoxy) naphthalene (3) and 2-(4-nitrophenoxy) naphthalene (4) were synthesized by Williamson etherification and characterized by elemental analysis, FTIR, NMR ((1)H, (13)C), UV-visible spectroscopy, mass spectrometry and single crystal X-ray diffraction analysis. Their brine shrimp cytotoxicity resulted in LD50 values <1 MUg/mL indicating significant antitumor activity with IC50 values ranging from 29.0 to 8.4 MUg/mL. They are highly active in protecting DNA against hydroxyl free radicals in a concentration dependent manner. Voltammetric studies showed one electron reversible reduction at a platinum electrode with diffusion coefficient (Do) values of the order ~10(-6)-10(-7) cm(2)s(-1). Strong interaction with the human blood DNA through intercalative mode was contemplated through electrochemical and UV-visible spectroscopic studies which are in agreement with the conclusions drawn from biological analysis, unravelling the potential anticancerous nature of the synthesized compounds. PMID- 25911403 TI - A TPS kernel for calculating survival vs. depth: distributions in a carbon radiotherapy beam, based on Katz's cellular Track Structure Theory. AB - An algorithm was developed of a treatment planning system (TPS) kernel for carbon radiotherapy in which Katz's Track Structure Theory of cellular survival (TST) is applied as its radiobiology component. The physical beam model is based on available tabularised data, prepared by Monte Carlo simulations of a set of pristine carbon beams of different input energies. An optimisation tool developed for this purpose is used to find the composition of pristine carbon beams of input energies and fluences which delivers a pre-selected depth-dose distribution profile over the spread-out Bragg peak (SOBP) region. Using an extrapolation algorithm, energy-fluence spectra of the primary carbon ions and of all their secondary fragments are obtained over regular steps of beam depths. To obtain survival vs. depth distributions, the TST calculation is applied to the energy fluence spectra of the mixed field of primary ions and of their secondary products at the given beam depths. Katz's TST offers a unique analytical and quantitative prediction of cell survival in such mixed ion fields. By optimising the pristine beam composition to a published depth-dose profile over the SOBP region of a carbon beam and using TST model parameters representing the survival of CHO (Chinese Hamster Ovary) cells in vitro, it was possible to satisfactorily reproduce a published data set of CHO cell survival vs. depth measurements after carbon ion irradiation. The authors also show by a TST calculation that 'biological dose' is neither linear nor additive. PMID- 25911404 TI - Thermomechanical effects caused by heavy ions propagating in tissue. AB - The thermomechanical effects caused by ions propagating in tissue are discussed. Large energy densities in small regions surrounding ion paths cause shock waves propagating in tissue. The strength of the shock waves depends on the linear energy transfer. Molecular dynamics simulations help in determining the necessary strength of shock waves in order for the stresses caused by them to directly produce DNA strand breaks. At much smaller values of linear energy transfer, the shock waves may be instrumental in propagating reactive species formed close to the ion's path to large distances, successfully competing with diffusion. PMID- 25911405 TI - Measuring scatter radiation in diagnostic X rays for radiation protection purposes. AB - During the last decades, radiation protection and dosimetry in medical X-ray imaging practice has been extensively studied. The purpose of this study was to measure secondary radiation in a conventional radiographic room, in terms of ambient dose rate equivalent H*(10) and its dependence on the radiographic exposure parameters such as X-ray tube voltage, tube current and distance. With some exceptions, the results indicated that the scattered radiation was uniform in the space around the water cylindrical phantom. The results also showed that the tube voltage and filtration affect the dose rate due to the scatter radiation. Finally, the scattered X-ray energy distribution was experimentally calculated. PMID- 25911406 TI - Advances in microbeam technologies and applications to radiation biology. AB - Charged-particle microbeams (CPMs) allow the targeting of sub-cellular compartments with a counted number of energetic ions. While initially developed in the late 1990s to overcome the statistical fluctuation on the number of traversals per cell inevitably associated with broad beam irradiations, CPMs have generated a growing interest and are now used in a wide range of radiation biology studies. Besides the study of the low-dose cellular response that has prevailed in the applications of these facilities for many years, several new topics have appeared recently. By combining their ability to generate highly clustered damages in a micrometric volume with immunostaining or live-cell GFP labelling, a huge potential for monitoring radiation-induced DNA damage and repair has been introduced. This type of studies has pushed end-stations towards advanced fluorescence microscopy techniques, and several microbeam lines are currently equipped with the state-of-the-art time-lapse fluorescence imaging microscopes. In addition, CPMs are nowadays also used to irradiate multicellular models in a highly controlled way. This review presents the latest developments and applications of charged-particle microbeams to radiation biology. PMID- 25911407 TI - Advanced proton imaging in computed tomography. AB - In recent years the use of hadrons for cancer radiation treatment has grown in importance, and many facilities are currently operational or under construction worldwide. To fully exploit the therapeutic advantages offered by hadron therapy, precise body imaging for accurate beam delivery is decisive. Proton computed tomography (pCT) scanners, currently in their R&D phase, provide the ultimate 3D imaging for hadrons treatment guidance. A key component of a pCT scanner is the detector used to track the protons, which has great impact on the scanner performances and ultimately limits its maximum speed. In this article, a novel proton-tracking detector was presented that would have higher scanning speed, better spatial resolution and lower material budget with respect to present state of-the-art detectors, leading to enhanced performances. This advancement in performances is achieved by employing the very latest development in monolithic active pixel detectors (to build high granularity, low material budget, large area silicon detectors) and a completely new proprietary architecture (to effectively compress the data). PMID- 25911408 TI - Development of a primary thoron activity standard for the calibration of thoron measurement instruments. AB - The LNHB and IRSN are working on a reference atmosphere for thoron ((220)Rn) instrument calibration. The LNHB, as the national metrology institute for activity measurement in France, has to create a new thoron reference standard in order to estimate with accuracy the thoron concentration of a reference atmosphere. The measurement system presented in this paper is based on a reference volume using an alpha detector, which is able to measure thoron and its decay products to define the thoron concentration of a thoron reference atmosphere. This paper presents the first results with this new system using a well-known radon ((222)Rn) atmosphere and a thoron ((220)Rn) atmosphere. PMID- 25911409 TI - Microdosimetric spread for cell-sized targets exposed to 60Co, 192Ir and 125I sources. AB - The magnitude of the spread in specific energy deposition per cell may be a confounding factor in dose-response analysis motivating derivation of explicit data for the most common brachytherapy isotopes (125)I and (192)Ir, and for (60)Co radiation frequently used as reference in RBE studies. The aim of this study is to analyse the microdosimetric spread as given by the frequency distribution of specific energy for a range of doses imparted by (125)I, (192)Ir and (60)Co sources. An upgraded version of the Monte Carlo code PENELOPE was used for scoring energy deposition distributions in liquid water for each of the radiation qualities. Frequency distributions of specific energy were calculated according to the formalism of Kellerer and Chmelevsky. Results indicate that the magnitude of the microdosimetric spread increases with decreasing target size and decreasing energy of the radiation quality. Within the clinical relevant dose range (1 to 100 Gy), the spread does not exceed 4 % for (60)Co, 5 % for (192)Ir and 6 % for (125)I. The frequency distributions can be accurately approximated with symmetrical normal distributions at doses down to 0.2 Gy for (60)Co, 0.1 Gy for (192)Ir and 0.08 Gy for (125)I. PMID- 25911410 TI - 214Bi/214Pb radioactivity ratio in rainwater for residence time estimation of cloud droplets and raindrops. AB - Continuous observation of radioactivity ratio of (214)Bi to (214)Pb as tracers in rainwater was carried out with 15-min cyclic measurement at Nagoya, Japan, from August 2011 to July 2012 to characterise wet deposition. The ratio ranged from 0.55 to 3.82. Based on the observation and a simplified time evolution model of (214)Pb and (214)Bi radioactivities during rainwater formation, the 'age' of raindrops ranged from sub-10 to several 100 min. The age would have negative correlation to rainfall intensity, but its variation for lower rainfall intensities was quite large. Secular equilibrium of (214)Pb and (214)Bi radioactivities in cloud water with airborne radon did not hold for some rainfall events. PMID- 25911411 TI - Radon mapping strategies in Austria. AB - According to current European and international recommendations (e.g. by IAEA, WHO and European Union), countries shall identify high radon areas. In Austria, this task was initiated already in the early 1990s, which yielded the first Austrian Radon Potential Map. This map is still in use, updated with recent indoor radon data in 2012. The map is based on radon gas measurements in randomly selected dwellings, normalised to a standard situation. To meet the current (legal) requirements, uncertainties in the existing Austrian radon map should be reduced. A new indoor radon survey with a different sampling strategy was started, and possible mapping methods are studied and tested. In this paper, the methodology for the existing map as well as the planned strategies to improve this map is discussed. PMID- 25911412 TI - Modulation of NF-kappaB in rescued irradiated cells. AB - Studies by different groups on the rescue effect, where unirradiated bystander cells mitigated the damages in the irradiated cells, since its discovery by the authors' group in 2011 were first reviewed. The properties of the rescue effect were then examined using a novel experimental set-up to physically separate the rescue signals from the bystander signals. The authors' results showed that the rescue effect was mediated through activation of the nuclear factor-kappaB (NF kappaB) response pathway in the irradiated cells, and that the NF-kappaB activation inhibitor BAY-11-7082 did not affect the activation of this response pathway in the irradiated cells induced by direct irradiation. PMID- 25911413 TI - The history, development and the present status of the radon measurement programme in the United States of America. AB - The US radon measurement programme began in the late 1950s by the US Public Health Service in Colorado, New Mexico and Utah during the uranium frenzy. After the 1967 Congressional Hearings on the working conditions in uranium mines, the US Atomic Energy Commission (AEC) was asked to conduct studies in active uranium mines to assess the exposure of the miners on the Colorado Plateau and in New Mexico. From 1967 to 1972, the Health and Safety Laboratory of the US AEC in New York investigated more than 20 uranium mines for radon and radon decay product concentrations and particle size in 4 large uranium mines in New Mexico. In 1970, the US Environmental Protection Agency (EPA) was established and took over some of the AEC radon measurement activities. Between 1975 and 1978, the Environmental Measurements Laboratory of the US Department of Energy conducted the first detailed indoor radon survey in the USA. Later in 1984, the very high concentrations of radon found in Pennsylvania homes set the wheels in motion and gave birth to the US Radon Industry. The US EPA expanded its involvement in radon issues and assumed an active role by establishing the National Radon Proficiency Program to evaluate the effectiveness of radon measurement and mitigation methods. In 1998, due to limited resources EPA privatised the radon programme. This paper presents a personal perspective of past events and current status of the US radon programme. It will present an update on radon health effects, the incidence rate of lung cancer in the USA and the number of radon measurements made from 1988 to 2013 using short-term test methods. More than 23 million measurements were made in the last 25 y and as a result more than 1.24 million homes were mitigated successfully. It is estimated that <2 % of the radon measurements performed in the USA are made using long-term testing devices. The number of homes above the US action level of 148 Bq m(-3) (4 pCi l(-1)) may be ~8.5 million because ~50 million homes were added since 1990 to the home inventory. This paper will discuss the current instruments and methods used to measure radon in the USA, and what is the effectiveness of radon resistant new construction, the current status of mitigation standards and the proposed testing protocols in schools and large buildings. PMID- 25911414 TI - How Europe keeps migrants out of its health system. PMID- 25911415 TI - Damage to the Ventromedial Prefrontal Cortex Impairs Learning from Observed Outcomes. AB - Individuals learn both from the outcomes of their own internally generated actions ("experiential learning") and from the observation of the consequences of externally generated actions ("observational learning"). While neuroscience research has focused principally on the neural mechanisms by which brain structures such as the ventromedial prefrontal cortex (vmPFC) support experiential learning, relatively less is known regarding how learning proceeds through passive observation. We explored the necessity of the vmPFC for observational learning by testing a group of patients with damage to the vmPFC as well as demographically matched normal comparison and brain-damaged comparison groups--and a single patient with bilateral dorsal prefrontal damage--using several value-learning tasks that required learning from direct experience, observational learning, or both. We found a specific impairment in observational learning in patients with vmPFC damage manifest in the reduced influence of previously observed rewards on current choices, despite a relatively intact capacity for experiential learning. The current study provides evidence that the vmPFC plays a critical role in observational learning, suggests that there are dissociable neural circuits for experiential and observational learning, and offers an important new extension of how the vmPFC contributes to learning and memory. PMID- 25911416 TI - Mechanistic studies of anticancer aptamer AS1411 reveal a novel role for nucleolin in regulating Rac1 activation. AB - AS1411 is a G-rich quadruplex-forming oligodeoxynucleotide that binds specifically to nucleolin, a protein found on the surface and in the cytoplasm of most malignant cells but absent from the surface/cytoplasm of most normal cells. AS1411 has shown promising clinical activity and is being widely used as a tumor targeting agent, but its mechanism of action is not fully understood. Previously, we showed that AS1411 is taken up in cancer cells by macropinocytosis (fluid phase endocytosis) and subsequently stimulates further macropinocytosis by a nucleolin-dependent mechanism. In the current study, we have investigated the significance and molecular mechanisms of AS1411-induced macropinocytosis. Our results indicate that the antiproliferative activity of AS1411 in various cell lines correlated with its capacity to stimulate macropinocytosis. In DU145 prostate cancer cells, AS1411 induced activation of EGFR, Akt, p38, and Rac1. Activation of Akt and p38 were not critical for AS1411 activity because Akt activation was not observed in all AS1411-responsive cell lines and knockdown of p38 had no effect on AS1411's ability to inhibit proliferation. On the other hand, activation of EGFR and Rac1 appeared to play a role in AS1411 activity in all cancer cell lines examined (DU145, MDA-MB-468, A549, LNCaP) and their inhibition significantly reduced AS1411-mediated macropinocytosis and AS1411 antiproliferative activity. Interestingly, downregulation of nucleolin expression by siRNA also produced a substantial increase in activated Rac1, revealing a previously unknown role for nucleolin as a negative regulator of Rac1 activation. Our results are consistent with a model whereby AS1411 binding to nucleolin leads to sustained activation of Rac1 and causes methuosis, a novel type of nonapoptotic cell death characterized by hyperstimulation of macropinocytosis. We speculate that methuosis is a tumor/metastasis suppressor mechanism that opposes the malignant functions of Rac1 and that cancer cells may overexpress nucleolin to surmount this barrier. PMID- 25911417 TI - Intramedullary Tibial Nailing Reduces the Attachment Area and Ultimate Load of the Anterior Medial Meniscal Root: A Potential Explanation for Anterior Knee Pain in Female Patients and Smaller Patients. AB - BACKGROUND: Intramedullary (IM) nailing is the treatment of choice among orthopaedic surgeons for tibial shaft fractures. However, because of the close proximity of the nail's insertion site to the anterior medial (AM) meniscal root on the tibial plateau, there is increased risk of iatrogenic injury to the meniscal root during nailing. PURPOSE: To quantify the area of the AM meniscal root footprint damaged by IM tibial reaming and determine its subsequent effects on the ultimate failure load in female versus male knees. STUDY DESIGN: Controlled laboratory study. METHODS: Twelve matched pairs (6 male and 6 female pairs; average age, 50.2 years) of human cadaveric knees were randomly assigned to native and reamed groups. In the reamed group, knees were reamed within the "safe zone" according to current guidelines for IM tibial nail insertion (3 mm lateral to the center of the tibial tubercle and adjacent to the anterior margin of the tibial plateau). The attachment areas and ultimate failure load were quantified and compared with paired knees in the native group. RESULTS: Intra articular reaming within the "safe zone" for IM tibial nail insertion did not significantly decrease the AM root attachment area or ultimate failure load in male specimens, as only 2 of the 6 knees were damaged by reaming. In contrast, all 6 of the AM roots in the female knees were damaged by reaming, and on average, reaming decreased the female AM root attachment area by 19% and significantly decreased ultimate failure load by 37% (P = .028). There was a strong negative correlation (R(2) = 0.77) between reamed tunnel-AM root overlap area and medial-lateral width in female but not in male knees. CONCLUSION: Standard reaming for an IM tibial nail induced significant damage to the AM meniscal root in smaller, female specimens, whereas larger, male specimens were not affected. CLINICAL RELEVANCE: These findings may suggest that improvements in current guidelines and surgical techniques are warranted to prevent iatrogenic injury to the AM meniscal root during intramedullary reaming for tibial shaft fractures in females and in smaller patients. PMID- 25911418 TI - In our own image? Emotional and neural processing differences when observing human-human vs human-robot interactions. AB - Notwithstanding the significant role that human-robot interactions (HRI) will play in the near future, limited research has explored the neural correlates of feeling eerie in response to social robots. To address this empirical lacuna, the current investigation examined brain activity using functional magnetic resonance imaging while a group of participants (n = 26) viewed a series of human-human interactions (HHI) and HRI. Although brain sites constituting the mentalizing network were found to respond to both types of interactions, systematic neural variation across sites signaled diverging social-cognitive strategies during HHI and HRI processing. Specifically, HHI elicited increased activity in the left temporal-parietal junction indicative of situation-specific mental state attributions, whereas HRI recruited the precuneus and the ventromedial prefrontal cortex (VMPFC) suggestive of script-based social reasoning. Activity in the VMPFC also tracked feelings of eeriness towards HRI in a parametric manner, revealing a potential neural correlate for a phenomenon known as the uncanny valley. By demonstrating how understanding social interactions depends on the kind of agents involved, this study highlights pivotal sub-routes of impression formation and identifies prominent challenges in the use of humanoid robots. PMID- 25911419 TI - Diel growth dynamics in tree stems: linking anatomy and ecophysiology. AB - Impacts of climate on stem growth in trees are studied in anatomical, ecophysiological, and ecological disciplines, but an integrative framework to assess those impacts remains lacking. In this opinion article, we argue that three research efforts are required to provide that integration. First, we need to identify the missing links in diel patterns in stem diameter and stem growth and relate those patterns to the underlying mechanisms that control water and carbon balance. Second, we should focus on the understudied mechanisms responsible for seasonal impacts on such diel patterns. Third, information on stem anatomy and ecophysiology should be integrated in the same experiments and mechanistic plant growth models to capture both diel and seasonal scales. PMID- 25911420 TI - Newborn baby is UK's youngest ever organ donor. PMID- 25911421 TI - Olfactory processing: detection of rapid changes. AB - Changes in the olfactory environment have a rather poor chance of being detected. Aim of the present study was to determine, whether the same (cued) or different (uncued) odors can generally be detected at short inter stimulus intervals (ISI) below 2.5 s. Furthermore we investigated, whether inhibition of return, an attentional phenomenon facilitating the detection of new stimuli at longer ISI, is present in the domain of olfaction. Thirteen normosmic people (3 men, 10 women; age range 19-27 years; mean age 23 years) participated. Stimulation was performed using air-dilution olfactometry with 2 odors: phenylethylalcohol and hydrogen disulfide. Reaction time to target stimuli was assessed in cued and uncued conditions at ISIs of 1, 1.5, 2, and 2.5 s. There was a significant main effect of ISI, indicating that odors presented only 1 s apart are missed frequently. Uncued presentation facilitated detection at short ISIs, implying that changes of the olfactory environment are detected better than presentation of the same odor again. Effects in relation to "olfactory inhibition of return," on the other hand, are not supported by our results. This suggests that attention works different for the olfactory system compared with the visual and auditory systems. PMID- 25911422 TI - Bench scale synthesis of p-hydroxybenzoic acid using whole-cell nitrilase of Gordonia terrae mutant E9. AB - Mutants of Gordonia terrae were generated using chemical mutagens for better activity, stability and higher substrate/product tolerance of its nitrilase enzyme. Mutant E9 showed two-time increase in activity and tolerated p hydroxybenzonitrile (p-HBN) up to 50 mM. Response surface methodology and inducer mediation approach further enhanced the production of enzyme to 2.5-fold. The bench scale production of p-hydroxybenzoic acid (p-HBA) was carried out in a fed batch reaction (500-mL scale) using whole-cell nitrilase of mutant E9 in 0.1 M potassium phosphate buffer (pH 8.0) at 40 degrees C. Total six feedings each at an interval of 45 min resulted in accumulation of 360 mM (21.6 g) of p-HBA with a purity of 99%. The catalytic and volumetric productivity of bioprocess using mutant G. terrae was improved to 1.8 g h(-1) g DCW (-1) and 43.2 g L(-1), respectively, from 0.78 g h(-1) g DCW (-1) and 28.8 g L(-1) using resting cells of wild strain. K m and V max of purified nitrilase from mutant E9 were 55 U mg( 1) and 1.8 mM for p-HBN with a higher turnover number of 36 s(-1) * 10(-3). PMID- 25911423 TI - Towards unravelling the kinetics of an acute myeloid leukaemia model system under oxidative and starvation stress: a comparison between two- and three-dimensional cultures. AB - A great challenge when conducting ex vivo studies of leukaemia is the construction of an appropriate experimental platform that would recapitulate the bone marrow (BM) environment. Such a 3D scaffold system has been previously developed in our group [1]. Additionally to the BM architectural characteristics, parameters such as oxygen and glucose concentration are crucial as their value could differ between patients as well as within the same patient at different stages of treatment, consequently affecting the resistance of leukaemia to chemotherapy. The effect of oxidative and glucose stress-at levels close to human physiologic ones-on the proliferation and metabolic evolution of an AML model system (K-562 cell line) in conventional 2D cultures as well as in 3D scaffolds were studied. We observed that the K-562 cell line can proliferate and remain alive for 2 weeks in medium with glucose close to physiological levels both in 20 and 5% O2. We report interesting differences on the cellular response to the environmental, i.e., oxidative and/or nutritional stress stimuli in 2D and 3D. Higher adaptation to oxidative stress under non-starving conditions is observed in the 3D system. The glucose level in the medium has more impact on the cellular proliferation in the 3D compared to the 2D system. These differences can be of significant importance both when applying chemotherapy in vitro and also when constructing mathematical tools for optimisation of disease treatment. PMID- 25911424 TI - Optimization of liquid-liquid extraction of biosurfactants from corn steep liquor. AB - In this work, the optimization of the operational conditions for the chloroform based extraction of surface-active compounds from corn steep liquor (CSL) was carried out and the nutritional properties of the remnant aqueous phase (CSL-less biosurfactant) was evaluated as microbial fermentation medium. The optimal conditions to obtain biosurfactants from CSL were as follows: chloroform/CSL ratio 2 (v/v), 56 degrees C at extraction times >30 min. At the optima conditions, 100 % of biosurfactant extract can be obtained from CSL, obtaining 12.0 +/- 0.5 g of biosurfactant extract/Kg of CSL. The critical micelle concentration (CMC) of the biosurfactant extract was 399.4 mg L(-1). This value is similar to the CMC of cetrimonium bromide (CTAB), a cationic surfactant used in the formulation of nanoparticles. The extraction of biosurfactant can be also carried out at room temperature although in this case, the extraction yield decreased about 15 %. The extraction of surface-active compounds from agroindustrial streams can suppose important advances for the bio-based surfactants industry. Biosurfactants obtained in this work are not only more eco friendly than chemical detergents but also can be cost competitive with its chemical counterparts. Furthermore, after the extraction of surface-active compounds, CSL-less biosurfactant was found to be suitable as nutritional supplement for lactic acid bacteria, maintaining its nutritional properties in comparison with regular CSL. PMID- 25911425 TI - Identification in residue analysis based on liquid chromatography with tandem mass spectrometry: Experimental evidence to update performance criteria. AB - Liquid chromatography-tandem mass spectrometry (LC-MS/MS) is one of the most widely used techniques for identification (and quantification) of residues and contaminants across a number of different chemical domains. Although the same analytical technique is used, the parameters and criteria for identification vary depending on where in the world the analysis is performed and for what purpose (e.g. determination of pesticides, veterinary drugs, forensic toxicology, sports doping). The rationale for these differences is not clear and in most cases the criteria are essentially based on expert opinions rather than underpinned by experimental data. In the current study, the variability of the two key identification parameters, retention time and ion ratio, was assessed and compared against requirements set out in different legal and guidance documents. The study involved the analysis of 120 pesticides, representing various chemical classes, polarities, molecular weights, and detector response factors, in 21 different fruit and vegetable matrices of varying degrees of complexity. The samples were analysed non-fortified, and fortified at 10, 50 and 200 MUg kg(-1), in five laboratories using different LC-MS/MS instruments and conditions. In total, over 135,000 extracted-ion chromatograms were manually verified to provide an extensive data set for the assessment. The experimental data do not support relative tolerances for retention time, or different tolerances for ion ratios depending on relative abundance of the two product ions measured. Retention times in today's chromatographic systems are sufficiently stable to justify an absolute tolerance of +/-0.1 min. Ion ratios are stable as long as sufficient response is obtained for both product ions. Ion ratio deviations are typically within +/-20% (relative), and within +/-45% (relative) in case the response of product ions are close to the limit of detection. Ion ratio tolerances up to 50% did not result in false positives and reduced the false negative rate for pesticides with product ions in the low S/N range to <5%. Without ion ratio criterion, two false positives were obtained in 105 non-fortified samples. Although the study has been conducted for pesticides residues in fruits and vegetables, the impact of these findings is believed to extend towards other application areas and possibly support adjustment or consolidation of criteria across other analytical domains. PMID- 25911426 TI - Sample preparation with solid phase microextraction and exhaustive extraction approaches: Comparison for challenging cases. AB - In chemical analysis, sample preparation is frequently considered the bottleneck of the entire analytical method. The success of the final method strongly depends on understanding the entire process of analysis of a particular type of analyte in a sample, namely: the physicochemical properties of the analytes (solubility, volatility, polarity etc.), the environmental conditions, and the matrix components of the sample. Various sample preparation strategies have been developed based on exhaustive or non-exhaustive extraction of analytes from matrices. Undoubtedly, amongst all sample preparation approaches, liquid extraction, including liquid-liquid (LLE) and solid phase extraction (SPE), are the most well-known, widely used, and commonly accepted methods by many international organizations and accredited laboratories. Both methods are well documented and there are many well defined procedures, which make them, at first sight, the methods of choice. However, many challenging tasks, such as complex matrix applications, on-site and in vivo applications, and determination of matrix-bound and free concentrations of analytes, are not easily attainable with these classical approaches for sample preparation. In the last two decades, the introduction of solid phase microextraction (SPME) has brought significant progress in the sample preparation area by facilitating on-site and in vivo applications, time weighted average (TWA) and instantaneous concentration determinations. Recently introduced matrix compatible coatings for SPME facilitate direct extraction from complex matrices and fill the gap in direct sampling from challenging matrices. Following introduction of SPME, numerous other microextraction approaches evolved to address limitations of the above mentioned techniques. There is not a single method that can be considered as a universal solution for sample preparation. This review aims to show the main advantages and limitations of the above mentioned sample preparation approaches and the applicability and capability of each technique for challenging cases such as complex matrices, on-site applications and automation. PMID- 25911427 TI - Polydimethylsiloxane composites containing 1,2-naphtoquinone 4-sulphonate as unique dispositive for estimation of casein in effluents from dairy industries. AB - A unique dispositive to determine casein which is the most abundant protein in dairy sewages has been proposed. In this sensing technology, the derivatization reagent 1,2-naphtoquininone 4-sulphonate (NQS) is embedded into a polydimethylsiloxane-tetraethylortosilicate-SiO2 nanoparticles composite (PDMS TEOS-SiO2NPs). When the composite is immersed into the samples, casein is extracted from the solution and derivatized inside the PDMS matrix after 10 min at 100 degrees C. The sensing support changes its color from yellow to orange depending on the casein concentration. Quantitative analysis can be carried out by measuring the absorbance with a reflection probe or by image-processing tool (GIMP). This sensor provides good sensitivity and precision (RSD% <12%). The method validation has been done by applying the biocinchoninic acid method (BCA). Moreover, semiquatitative analysis of casein can be performed by visual observation. Taking into account the advantages of small size, rapidity, simplicity, good stability and high compatibility in aqueous solution, this sensor is expected to have potential practical applications for in-situ determination of casein. Finally the method has been applied to analyze effluents from dairy industries. PMID- 25911428 TI - Quantification of benzene, toluene, ethylbenzene and o-xylene in internal combustion engine exhaust with time-weighted average solid phase microextraction and gas chromatography mass spectrometry. AB - A new and simple method for benzene, toluene, ethylbenzene and o-xylene (BTEX) quantification in vehicle exhaust was developed based on diffusion-controlled extraction onto a retracted solid-phase microextraction (SPME) fiber coating. The rationale was to develop a method based on existing and proven SPME technology that is feasible for field adaptation in developing countries. Passive sampling with SPME fiber retracted into the needle extracted nearly two orders of magnitude less mass (n) compared with exposed fiber (outside of needle) and sampling was in a time weighted-averaging (TWA) mode. Both the sampling time (t) and fiber retraction depth (Z) were adjusted to quantify a wider range of Cgas. Extraction and quantification is conducted in a non-equilibrium mode. Effects of Cgas, t, Z and T were tested. In addition, contribution of n extracted by metallic surfaces of needle assembly without SPME coating was studied. Effects of sample storage time on n loss was studied. Retracted TWA-SPME extractions followed the theoretical model. Extracted n of BTEX was proportional to Cgas, t, Dg, T and inversely proportional to Z. Method detection limits were 1.8, 2.7, 2.1 and 5.2 mg m(-3) (0.51, 0.83, 0.66 and 1.62 ppm) for BTEX, respectively. The contribution of extraction onto metallic surfaces was reproducible and influenced by Cgas and t and less so by T and by the Z. The new method was applied to measure BTEX in the exhaust gas of a Ford Crown Victoria 1995 and compared with a whole gas and direct injection method. PMID- 25911429 TI - Magnetic N-doped carbon nanotubes: A versatile and efficient material for the determination of polycyclic aromatic hydrocarbons in environmental water samples. AB - This paper describes a new, efficient and versatile method for the sampling and preconcentration of PAH in environmental water matrices using special hybrid magnetic carbon nanotubes. These N-doped amphiphilic CNT can be easily dispersed in any aqueous matrix due to the N containing hydrophilic part and at the same time show high efficiency for the adsorption of different PAH contaminants due to the very hydrophobic surface. After adsorption, the CNT can be easily removed from the medium by a simple magnetic separation. GC/MS analyses showed that the CNT method is more efficient than the use of polydimethylsiloxane (PDMS) with much lower solvent consumption, technical simplicity and time, showing good linearity (range 0.18-80.00 MUg L(-1)) and determination coefficient (R(2) > 0.9810). The limit of detection ranged from 0.05 to 0.42 MUg L(-1) with limit of quantification from 0.18 to 1.40 MUg L(-1). Recovery (n=9) ranged from 80.50 +/- 10 to 105.40 +/- 12%. Intraday precision (RSD, n=9) ranged from 1.91 to 9.01%, whereas inter day precision (RSD, n=9) ranged from 7.02 to 17.94%. The method was applied to the analyses of PAH in four lake water samples collected in Belo Horizonte City, Brazil. PMID- 25911430 TI - Preparation of C18 composite solid-phase microextraction fiber and its application to the determination of organochlorine pesticides in water samples. AB - In this work, a C18 composite solid-phase microextraction (SPME) fiber was prepared with a new method and applied to the analysis of organochlorine pesticides (OCPs) in water sample. A stainless steel wire (o.d. 127 MUm) was used as the substrate, and a mixture of the C18 particle (3.5 MUm) and the 184 silicone was used as the coating material. During the process of fiber preparation, a section of capillary column was used to fix the mixture onto the stainless steel wire and to ensure the constant of coating thickness. The prepared fiber showed excellent thermal stability and solvent resistance. By coupling with gas chromatography-mass spectrometry (GC-MS), the fiber exhibited wide linearity (2-500 ng L(-1)) and good sensitivity for the determination of six OCPs in water samples, the OCPs tested included hexachlorobezene, trans chlordane, cis-chlordane, o,p-DDT, p,p-DDT and mirex. Not only the extraction performance of the newly prepared fiber was more than seven times higher than those of commercial fibers, the limits of detections (LODs) (0.059-0.151 ng L( 1)) for OCPs achieved under optimized conditions were also lower than those of reported SPME methods. The fiber was successfully applied to the determination of OCPs in real water samples by using developed SPME-GC-MS method. PMID- 25911431 TI - Affinity of aptamers binding 33-mer gliadin peptide and gluten proteins: Influence of immobilization and labeling tags. AB - Aptamers are starting to increase the reagents tool box to develop more sensitive and reliable methods for food allergens. In most of these assays, aptamers have to be modified for detection and/or immobilization purposes. To take full advantage of their affinity, which decisively influence the detectability, these modifications must be faced rationally. In this work, a recently developed aptamer for an immunotoxic peptide of gliadin associated to celiac disease is used in different configurations and modified with various markers and anchored groups to evaluate the influence of such modifications on the real affinity. The interaction in solution with the peptide is strong for a relatively small molecule (Kd = 45 +/- 10 nM, 17 degrees C) and slightly stronger than that for the immobilized intact protein due to a cooperative binding effect. Comparatively, while only minor differences were found when the peptide or the aptamer were immobilized, labeling with a biotin resulted preferable over fluorescein (Kd = 102 +/- 11 vs 208 +/- 54 nM, 25 degrees C). These findings are of prime importance for the design of an aptamer-based analytical method for gluten quantification. PMID- 25911432 TI - Plasmon waveguide resonance for sensing glycan-lectin interactions. AB - Carbohydrate-modified interfaces have been shown to be valuable tools for the study of protein-glycan recognition events. Label-free approache such as plasmonic based techniques are particularly attractive. This paper describes a new analytical platform for the sensitive and selective screening of carbohydrate lectin interactions using plasmon waveguide resonance. Planar optical waveguides (POW), consisting of glass prisms coated with silver (50 nm) and silica (460 nm) layers were derivatized with mannose or lactose moieties. The specific association of the resulting interface with selected lectins was assessed by following the changes in its plasmonic response. The immobilization strategy investigated in this work is based on the formation of a covalent bond between propargyl-functionalized glycans and surface-linked azide groups via a Cu(I) "click" chemistry. Optimization of the surface architecture through the introduction of an oligo(ethylene glycol) spacer between the plasmonic surface and the glycan ligands provided an interface which allowed screening of glycan lectin interactions in a highly selective manner. The limit of detection (LOD) of this method for this particular application was found to be in the subnanomolar range (0.5 nM), showing it to constitute a promising analytical platform for future development and use in a pharmaceutical or biomedical setting. PMID- 25911433 TI - Coumarine-imino-C2-glucosyl conjugate as receptor for Cu(2+) in blood serum milieu, on silica gel sheet and in Hep G2 cells and the characterization of the species of recognition. AB - A coumarine-imino-C2-glucosyl conjugate (L) was synthesized and characterized. The conjugate L is found to recognize Cu(2+) in aqueous HEPES buffer by exhibiting a 95% fluorescence quenching in pH range 7-10 even in the presence of several biologically and ecologically relevant metal ions. Fluorescence on-off behavior has been clearly demonstrated on the basis of the binding variability of Cu(2+) to L. The binding has been elicited through the changes observed in fluorescence, absorption, ESI-MS and (1)H NMR titrations. All the other thirteen metal ions studied did not show any change in the fluorescence emission. These ions do not interfere with the recognition of Cu(2+) by L. The structural features of [CuL]2 complex in both the isomeric forms were established by DFT computational calculations. The utility of L has been demonstrated by showing its sensitivity toward Cu(2+) on a thin layer of silica gel. The L gives sensitive fluorescence signals for Cu(2+) even in blood serum and exhibits appropriate fluorescence responses in living cells. PMID- 25911434 TI - Fluorescent peptide-based sensors for the ratiometric detection of nanomolar concentration of heparin in aqueous solutions and in serum. AB - New fluorescent peptide-based sensors (1-3) for monitoring heparin in serum sample were synthesized using short peptides (1~3mer) as a receptor. The peptide based sensors (2 and 3) showed a sensitive ratiometric response to heparin both in aqueous buffered solution (10 mM HEPES, pH 7.4) and in 2% human serum sample by increase of excimer emission of pyrene at 480 nm and concomitant decrease of monomer emission of pyrene at 376 nm, whereas the peptide-based sensor 1 showed a turn off response only by decrease of monomer emission at 376 nm. 2 and 3 exhibited excellent selectivity toward heparin among various anions and competitors of heparin including chondroitin 4-sulfate (ChS) and hyaluronic acid (HA). Peptide-based sensor 3 showed a more sensitive response to heparin than 2. The detection limit of 3 was determined as 36 pM (R(2) = 0.998) for heparin in aqueous solution and 204 pM (R(2) = 0.999) for heparin in aqueous solutions containing 2% human serum. The peptide-based sensors, 2 and 3 provided a practical and potential tool for the detection and quantification of heparin in real biological samples. PMID- 25911435 TI - Cell-based assay of nongenomic actions of progestins revealed inhibitory G protein coupling to membrane progestin receptor alpha (mPRalpha). AB - Previously, we established cell lines stably producing goldfish membrane progestin receptor alpha (goldfish mPRalpha) proteins, which mediate steroidal nongenomic actions. In this study, we transfected these cell lines (MDA-MD-231) with cDNAs encoding a recombinant luciferase gene (GloSensor). These cells can be used for monitoring the effects of ligands that bind to mPR by means of luminescence, the intensity of which reflects intracellular cyclic adenosine monophosphate (cAMP) levels. Luminescence intensity of the cells increased significantly when cells were treated with forskolin, strong activator of adenylyl cyclase. Then, we established a strategy to measure changes in luminescence that correlated with the actions of the ligands. The actions of ligands were measurable by the prevention of stimulation caused by forskolin after ligand stimulation. The studies using these cell lines indicated that cAMP concentrations were decreased specifically by the mPR ligands 17alpha,20beta dihydroxy-4-pregnen-3-one, diethylstilbestrol and progesterone. Furthermore, pertussis toxin inhibited the decrease in cAMP levels caused by mPR ligands. These results support evidence from previous results that mPRalpha is coupled to an inhibitory G protein. PMID- 25911436 TI - Identification of seven novel CYP11B1 gene mutations in Chinese patients with 11beta-hydroxylase deficiency. AB - Steroid 11beta-hydroxylase deficiency (11beta-OHD), one of common cause of congenital adrenal hyperplasia (CAH), is an autosomal recessive disorder characterized by virilization, precocious pseudo-puberty, and hypertension. It is caused by CYP11B1 gene mutation. We performed molecular genetic analysis of the CYP11B1 gene in six patients with preliminary clinical diagnosis of 11beta-OHD and four patients identified as potential 11beta-OHD from a CAH cohort in which CYP21A2 gene mutations consecutively screened. Seven novel CYP11B1 mutations, including p.R454H, p.Q472P, p.Q155X, p.K173X, IVS2-1G>A, R454A fs 573X, and g.2704_g.3154del, and six previously described mutations (p.P94L, p.G267S, p.G379V, p.R448H, p.R454C and p.R141X) were identified. These mutations mainly clustered in exons 3 and 8. Eight of twenty alleles carried mutations occurring at the Arg454 position, which is a mutational hot spot for Han Chinese. The pathogenic nature of novel p.R454H mutation was predicted by protein sequence alignment and in silico analysis. All the identified mutations were responsible for the clinical features observed in these ten unrelated Chinese patients. This study expands the CYP11B1 mutation spectrum and provides evidence for prenatal diagnosis and genetic counseling. Genetic analysis is an alternative approach to help clinicians confirm uncertain 11beta-OHD diagnosis, facilitating reasonable steroid replacement. PMID- 25911437 TI - Annual Cost of U.S. Hospital Visits for Pediatric Abusive Head Trauma. AB - We estimated the frequency and direct medical cost from the provider perspective of U.S. hospital visits for pediatric abusive head trauma (AHT). We identified treat-and-release hospital emergency department (ED) visits and admissions for AHT among patients aged 0-4 years in the Nationwide Emergency Department Sample and Nationwide Inpatient Sample (NIS), 2006-2011. We applied cost-to-charge ratios and estimated professional fee ratios from Truven Health MarketScan((r)) to estimate per-visit and total population costs of AHT ED visits and admissions. Regression models assessed cost differences associated with selected patient and hospital characteristics. AHT was diagnosed during 6,827 (95% confidence interval [CI] [6,072, 7,582]) ED visits and 12,533 (95% CI [10,395, 14,671]) admissions (28% originating in the same hospital's ED) nationwide over the study period. The average medical cost per ED visit and admission were US$2,612 (error bound: 1,644 3,581) and US$31,901 (error bound: 29,266-34,536), respectively (2012 USD). The average total annual nationwide medical cost of AHT hospital visits was US$69.6 million (error bound: 56.9-82.3 million) over the study period. Factors associated with higher per-visit costs included patient age <1 year, males, coexisting chronic conditions, discharge to another facility, death, higher household income, public insurance payer, hospital trauma level, and teaching hospitals in urban locations. Study findings emphasize the importance of focused interventions to reduce this type of high-cost child abuse. PMID- 25911438 TI - Analgesic use before and after oral anticoagulant initiation--a population-based study in Finland. AB - PURPOSE: Due to potential drug-drug interactions and subsequent bleeding risk, analgesic use should be reviewed when an oral anticoagulant is initiated. The aim of this study was to compare use of non-steroidal anti-inflammatory drugs (NSAIDs) and other analgesics before and after oral anticoagulant initiation. METHODS: All individuals who initiated warfarin, dabigatran, or rivaroxaban between January 2012 and September 2013 were identified from the Finnish Prescription Register. Prevalence of analgesic use during 3 months after oral anticoagulant initiation was compared to analgesic use during 4 months before initiation. Analgesics included were NSAIDs, paracetamol, paracetamol in doses >= 2 g/day, tramadol, and other opioids. Conditional logistic regression was used to calculate odds ratios (OR) with 95% confidence intervals (CI). RESULTS: In total, 54,025 initiated warfarin, 16,894 rivaroxaban, and 1569 dabigatran. The odds of NSAID use decreased among warfarin initiators (odds ratio (OR) 0.10; 95% confidence interval (CI) 0.09-0.10); 2.6% used NSAID after initiation. In contrast, the odds of NSAID use increased among rivaroxaban (OR 3.56; 95% CI 3.37 3.75) and dabigatran initiators (OR 1.44; 95% CI 1.16-1.78). The proportions using NSAIDs after the initiation were 69 and 32%, respectively. However, NSAID use decreased among dabigatran initiators with confirmed atrial fibrillation (OR 0.46; 95% CI 0.23-0.92) and among rivaroxaban initiators with a daily dose of >= 15 mg (OR 0.28; 95% CI 0.19-0.40). CONCLUSIONS: The use of NSAIDs decreases extensively among warfarin initiators which is encouraging. However, the use of NSAIDs increases among rivaroxaban and dabigatran initiators. This is a concern as the bleeding risk may increase due to potential pharmacodynamic interactions. PMID- 25911439 TI - Excessive polypharmacy and survival in polypathological patients. AB - PURPOSE: The purpose of this study was to determine whether excessive polypharmacy is associated with a higher survival rate in polypathological patients. PATIENTS AND METHODS: An observational, prospective, and multicenter study was carried out on those polypathological patients admitted to the internal medicine and acute geriatrics departments between March 1 and June 30, 2011. For each patient, data concerning age, sex, comorbidity, Barthel and Lawton-Brody indexes, Pfeiffer's questionnaire, socio-familial Gijon scale, delirium, number of drugs, and number of admissions during the previous year were gathered, and the PROFUND index was calculated. Polypharmacy was defined as the use of >= 5 drugs and excessive polypharmacy as the use of >= 10. A 1-year long follow-up was carried out. A logistic regression model was performed to analyze the association of variables with excessive polypharmacy and a Cox proportional hazard model to determine the association between polypharmacy and survival. RESULTS: We included 457 polypathological patients. Mean age was 81.0 (8.8) years and 54.5% were women. The mean number of drugs used was 8.2 (3.4). Excessive polypharmacy was directly associated with heart disease [hazard ratio (HR) 2.33 95% CI 1.40-3.87; p =0.001], respiratory disease [HR 1.87 95% CI 1.13-3.09; p = 0.01], peripheral artery disease/diabetes with retinopathy and/or neuropathy [HR 2.02 95% CI 1.17 3.50; p = 0.01], and the number of admissions during the previous year [HR 1.21 96%CI 1.01-1.44; p = 0.04]. It was inversely associated with delirium [HR 0.48 95% CI 0.25-0.91; p = 0.02]. There were no statistical differences regarding the probability of 1-year survival between patients with no polypharmacy, with simple polypharmacy, and with excessive polypharmacy (0.66, 0.60, and 0.57, respectively, p = 0.12). CONCLUSIONS: A greater use of drugs may not be harmful but is also not associated with a higher probability of survival in polypathological patients. PMID- 25911440 TI - Genetic characterization of Chikungunya virus in the Central African Republic. AB - Chikungunya virus (CHIKV) is an alphavirus transmitted by the bite of mosquito vectors. Over the past 10 years, the virus has gained mutations that enhance its transmissibility by the Aedes albopictus vector, resulting in massive outbreaks in the Indian Ocean, Asia and Central Africa. Recent introduction of competent A. albopictus vectors into the Central African Republic (CAR) pose a threat of a Chikungunya fever (CHIKF) epidemic in this region. We undertook this study to assess the genetic diversity and background of CHIKV strains isolated in the CAR between 1975 and 1984 and also to estimate the ability of local strains to adapt to A. albopictus. Our results suggest that, local CHIKV strains have a genetic background compatible with quick adaptation to A. albopictus, as previously observed in other Central African countries. Intense surveillance of the human and vector populations is necessary to prevent or anticipate the emergence of a massive CHIKF epidemic in the CAR. PMID- 25911441 TI - Achieving safe femoral arterial access. AB - Percutaneous coronary intervention can lead to vascular access complications that prolong patient hospital stay and costs as well as increase patient morbidity and mortality. Given its ease of use and familiarity, transfemoral access is still the preferred method of approach by many operators. The transfemoral approach is used when large bore access is required or if transradial access is not feasible due to variations in the anatomy of the upper extremity artery. The use of fluoroscopy, ultrasonography, and femoral angiography can help the operator obtain proper arteriotomy of the common femoral artery. Measures to decrease vascular access complications include proper technique, optimal pharmacotherapy, and avoiding the use of arterial sheaths >6 Fr. Optimal pharmacotherapy includes the use of bivalirudin and weight-based unfractionated heparin to avoid supratherapeutic activated clotting times, and to avoid glycoprotein IIb/IIIa inhibitors. When used appropriately, vascular closure devices can decrease the risk of bleeding complications. Randomized trials are needed to confirm these recommendations. PMID- 25911442 TI - Stress echocardiography: what is new and how does it compare with myocardial perfusion imaging and other modalities? AB - Cardiovascular disease is a leading cause of morbidity and mortality, and noninvasive strategies to diagnose and risk stratify patients remain paramount in the evaluative process. Stress echocardiography is a well-established, versatile, real-time imaging modality with advantages including lack of radiation exposure, portability, and affordability. Innovative techniques in stress echocardiography include myocardial contrast echocardiography, deformation imaging, three dimensional (3D) echocardiography, and assessment of coronary flow reserve. Myocardial perfusion imaging with single-photon emission computed tomography (SPECT) or positron emission tomography (PET) are imaging alternatives, and stress cardiac magnetic resonance imaging and coronary computed tomography (CT) angiography, including CT perfusion imaging, are emerging as newer approaches. This review will discuss recent and upcoming developments in the field of stress testing, with an emphasis on stress echocardiography while highlighting comparisons with other modalities. PMID- 25911443 TI - Entrainment and task co-representation effects for discrete and continuous action sequences. AB - A large body of work has established an influence of other people's actions on our own actions. For example, actors entrain to the movements of others, in studies that typically employ continuous movements. Likewise, studies on co representation have shown that people automatically co-represent a co-actor's task, in studies that typically employ discrete actions. Here we examined entrainment and co-representation within a single task paradigm. Participants sat next to a confederate while simultaneously moving their right hand back and forth between two targets. We crossed whether or not the participant and the confederate moved over an obstacle and manipulated whether participants generated discrete or continuous movement sequences, while varying the space between the actors and whether the actors could see each other's movements. Participants moved higher when the confederate cleared an obstacle than when he did not. For continuous movements, this effect depended on the availability of visual information, as would be expected on the basis of entrainment. In contrast, the co-actor's task modulated the height of discrete movements, regardless of the availability of visual information, which is consistent with co-representation. Space did not have an effect. These results provide new insights into the interplay between co-representation and entrainment for discrete- and continuous action tasks. PMID- 25911444 TI - Dynamic memory searches: Selective output interference for the memory of facts. AB - The benefits of testing on later memory performance are well documented; however, the manner in which testing harms memory performance is less well understood. This research is concerned with the finding that accuracy decreases over the course of testing, a phenomena termed "output interference" (OI). OI has primarily been investigated with episodic memory, but there is limited research investigating OI in measures of semantic memory (i.e., knowledge). In the current study, participants were twice tested for their knowledge of factual questions; they received corrective feedback during the first test. No OI was observed during the first test, when participants presumably searched semantic memory to answer the general-knowledge questions. During the second test, OI was observed. Conditional analyses of Test 2 performance revealed that OI was largely isolated to questions answered incorrectly during Test 1. These were questions for which participants needed to rely on recent experience (i.e., the feedback in episodic memory) to respond correctly. One possible explanation is that episodic memory is more susceptible to the sort of interference generated during testing (e.g., gradual changes in context, encoding/updating of items) relative to semantic memory. Alternative explanations are considered. PMID- 25911445 TI - Evaluation of composition and individual variability of rumen microbiota in yaks by 16S rRNA high-throughput sequencing technology. AB - The Yak (Bos grunniens) is a unique species of ruminant animals that is important to agriculture of the Tibetan plateau, and has a complex intestinal microbial community. The objective of the present study was to characterize the composition and individual variability of microbiota in the rumen of yaks using 16S rRNA gene high-throughput sequencing technique. Rumen samples used in the present study were obtained from grazing adult male yaks (n = 6) in a commercial farm in Ganzi Autonomous Prefecture of Sichuan Province, China. Universal prokaryote primers were used to target the V4-V5 hypervariable region of 16S rRNA gene. A total of 7200 operational taxonomic units (OTUs) were obtained after sequence filtering and chimera removal. Within these OTUs, 0.56% belonged to Archaea (40 OTUs), 7.19% to unassigned species (518 OTUs), and the remaining OTUs (6642) in all samples were of bacterial origin. When examining the community structure of bacteria, we identified 23 phyla within 159 families after taxonomic summarization. Bacteroidetes and Firmicutes were the predominant phyla accounting for 39.68% (SD = 0.05) and 45.90% (SD = 0.06), respectively. Moreover, 3764 OTUs were identified as shared OTUs (i.e. represented in all yaks) and belonged to 35 genera, exhibiting highly variable abundance across individual samples. Phylogenetic placement of these genera across individual samples was examined. In addition, we evaluated the distance among the 6 rumen samples by adding taxon phylogeny using UniFrac, representing 24.1% of average distance. In summary, the current study reveals a shared rumen microbiome and phylogenetic lineage and presents novel information on composition and individual variability of the bacterial community in the rumen of yaks. PMID- 25911446 TI - Quantitative comparison of hemodynamics in simulated and 3D angiography models of cerebral aneurysms by use of computational fluid dynamics. AB - In this study, we evaluated hemodynamics using simulated models and determined how cerebral aneurysms develop in simulated and patient-specific models based on medical images. Computational fluid dynamics (CFD) was analyzed by use of OpenFOAM software. Flow velocity, stream line, and wall shear stress (WSS) were evaluated in a simulated model aneurysm with known geometry and in a three dimensional angiographic model. The ratio of WSS at the aneurysm compared with that at the basilar artery was 1:10 in simulated model aneurysms with a diameter of 10 mm and 1:18 in the angiographic model, indicating similar tendencies. Vortex flow occurred in both model aneurysms, and the WSS decreased in larger model aneurysms. The angiographic model provided accurate CFD information, and the tendencies of simulated and angiographic models were similar. These findings indicate that hemodynamic effects are involved in the development of aneurysms. PMID- 25911447 TI - A sandwich-hybridization assay for simultaneous determination of HIV and tuberculosis DNA targets based on signal amplification by quantum dots PowerVisionTM polymer coding nanotracers. AB - A novel sandwich-hybridization assay for simultaneous electrochemical detection of multiple DNA targets related to human immune deficiency virus (HIV) and tuberculosis (TB) was developed based on the different quantum dots PowerVision(TM) polymer nanotracers. The polymer nanotracers were respectively fabricated by immobilizing SH-labeled oligonucleotides (s-HIV or s-TB), which can partially hybrid with virus DNA (HIV or TB), on gold nanoparticles (Au NPs) and then modified with PowerVision(TM) (PV) polymer-encapsulated quantum dots (CdS or PbS) as signal tags. PV is a dendrimer enzyme linked polymer, which can immobilize abundant QDs to amplify the stripping voltammetry signals from the metal ions (Pb or Cd). The capture probes were prepared through the immobilization of SH-labeled oligonucleotides, which can complementary with HIV and TB DNA, on the magnetic Fe3O4@Au (GMPs) beads. After sandwich-hybridization, the polymer nanotracers together with HIV and TB DNA targets were simultaneously introduced onto the surface of GMPs. Then the two encoding metal ions (Cd(2+) and Pb(2+)) were used to differentiate two viruses DNA due to the different subsequent anodic stripping voltammetric peaks at -0.84 V (Cd) and -0.61 V (Pb). Because of the excellent signal amplification of the polymer nanotracers and the great specificity of DNA targets, this assay could detect targets DNA as low as 0.2 femtomolar and exhibited excellent selectivity with the dynamitic range from 0.5 fM to 500 pM. Those results demonstrated that this electrochemical coding assay has great potential in applications for screening more viruses DNA while changing the probes. PMID- 25911448 TI - Electrochemical detection of Bisphenol A with high sensitivity and selectivity using recombinant protein-immobilized graphene electrodes. AB - A novel Bisphenol A (4,4'-isopropylidenediphenol, BPA) sensor was developed harnessing an electrochemical platform comprising a layer-by-layer assembled reduced graphene oxide (rGO) electrode and a designer probe specifically recognizing BPA. The BPA detection probe, a recombinant protein (LacI-BPA), was constructed by fusing a disulfide-constrained high affinity BPA binding peptide (CKSLENSYC) to the C-terminus of Lac repressor (LacI). Following expression and purification, the LacI-BPA was heat-denatured on-purpose to facilitate its direct adhesion on the rGO electrode surface via pi-stacking interaction. When the performance of the fabricated BPA sensor (LacI-BPA/rGO) was assessed by electrochemical impedance spectroscopy (EIS), it showed a wide linear dynamic range of BPA detection spanning from 100 fM to 10nM. Moreover, our BPA sensor exhibited negligible cross reactivity to BPA analogs such as Bisphenol S (BPS) and Bisphenol F (BPF) and almost complete spike recovery of BPA from plastic extracts containing various potential interferents. With these merits, the BPA sensor developed in the present study is expected to find practical application in selective and sensitive detection of BPA from diverse sample solutions. PMID- 25911449 TI - Malaria vaccine is partly effective in young children, study shows. PMID- 25911450 TI - Alternative providers of GP services perform worse than traditional practices. PMID- 25911451 TI - Determination of Sucrose in Honey with Derivatization/Solid-Phase Microextraction and Gas-Chromatography/Mass Spectrometry. AB - A new method for the determination of sucrose in honey with derivatization solid phase microextraction and gas chromatography/mass spectrometry (D-SPME-GC/MS) was developed. The method incorporates a sample derivatization with acetic anhydride using N-methylimidazole as the catalyst and the subsequent enrichment of the analyte in a Polyacrylate-SPME fiber. Results show that 100 uL N-methylimidazole and 800 uL acetic anhydride were sufficient to complete the acetylation for sucrose in 100 uL aqueous sample at room temperature. For SPME, an enrichment time of 30 min was sufficient. SPME was performed by immersing the fiber into the solution with additional vibration. Then, the analyte was desorbed for 5 min at 280 degrees C in the GC/MS injection port with splitless mode. The present method exhibits good linearity at a concentration range of 0.3-8% of sucrose in honey with excellent regression (R = 0.9993). The method has been successfully applied to the control of sucrose adulteration in honey. PMID- 25911452 TI - Erratum to: Potential of Plant Growth Promoting Traits by Bacteria Isolated from Heavy Metal Contaminated Soils. PMID- 25911453 TI - Pericyte NF-kappaB activation enhances endothelial cell proliferation and proangiogenic cytokine secretion in vitro. AB - Pericytes are skeletal muscle resident, multipotent stem cells that are localized to the microvasculature. In vivo, studies have shown that they respond to damage through activation of nuclear-factor kappa-B (NF-kappaB), but the downstream effects of NF-kappaB activation on endothelial cell proliferation and cell-cell signaling during repair remain unknown. The purpose of this study was to examine pericyte NF-kappaB activation in a model of skeletal muscle damage; and use genetic manipulation to study the effects of changes in pericyte NF-kappaB activation on endothelial cell proliferation and cytokine secretion. We utilized scratch injury to C2C12 cells in coculture with human primary pericytes to assess NF-kappaB activation and monocyte chemoattractant protein-1 (MCP-1) secretion from pericytes and C2C12 cells. We also cocultured endothelial cells with pericytes that expressed genetically altered NF-kappaB activation levels, and then quantified endothelial cell proliferation and screened the conditioned media for secreted cytokines. Pericytes trended toward greater NF-kappaB activation in injured compared to control cocultures (P = 0.085) and in comparison to C2C12 cells (P = 0.079). Second, increased NF-kappaB activation in pericytes enhanced the proliferation of cocultured endothelial cells (1.3-fold, P = 0.002). Finally, we identified inflammatory signaling molecules, including MCP-1 and interleukin 8 (IL-8) that may mediate the crosstalk between pericytes and endothelial cells. The results of this study show that pericyte NF-kappaB activation may be an important mechanism in skeletal muscle repair with implications for the development of therapies for musculoskeletal and vascular diseases, including peripheral artery disease. PMID- 25911454 TI - Assessment of the water chemical quality improvement based on human health risk indexes: Application to a drinking water treatment plant incorporating membrane technologies. AB - A methodology has been developed in order to evaluate the potential risk of drinking water for the health of the consumers. The methodology used for the assessment considered systemic and carcinogenic effects caused by oral ingestion of water based on the reference data developed by the World Health Organisation (WHO) and the Risk Assessment Information System (RAIS) for chemical contaminants. The exposure includes a hypothetical dose received by drinking this water according to the analysed contaminants. An assessment of the chemical quality improvement of produced water in the Drinking Water Treatment Plant (DWTP) after integration of membrane technologies was performed. Series of concentration values covering up to 261 chemical parameters over 5 years (2008 2012) of raw and treated water in the Sant Joan Despi DWTP, at the lower part of the Llobregat River basin (NE Spain), were used. After the application of the methodology, the resulting global indexes were located below the thresholds except for carcinogenic risk in the output of DWTP, where the index was slightly above the threshold during 2008 and 2009 before the upgrade of the treatment works including membrane technologies was executed. The annual evolution of global indexes showed a reduction in the global values for all situations: HQ systemic index based on RAIS dropped from 0.64 to 0.42 for surface water and from 0.61 to 0.31 for drinking water; the R carcinogenic index based on RAIS was negligible for input water and varied between 4.2*10(-05) and 7.4*10(-06) for drinking water; the W systemic index based on the WHO data varied between 0.41 and 0.16 for surface water and between 0.61 and 0.31 for drinking water. A specific analysis for the indexes associated with trihalomethanes (THMs) showed the same pattern. PMID- 25911455 TI - Clinical Outcomes in a Primary Care Practice Within a Center for Health Equity. AB - OBJECTIVE: A Center for Health Equity that included a primary care practice was built in a neighborhood affected by long-term disparities related to race and class in order to promote health equity within the population. Changes in blood pressure and HbA1c (glycated hemoglobin) over 2 years were examined to assess the impact of providing culturally appropriate and patient-centered care. METHODS: Data from June 1, 2012, to June 30, 2014 were obtained. Patients with high blood pressure or elevated HbA1c levels were treated according to evidence based guidelines. Blood pressure and HbA1c values at the first and last visit were compared using paired t tests. RESULTS: Of the 390 patients seen with a systolic pressure >=140 mm Hg, 358 came back for at least 1 visit (92%). By the time of the last visit, 70% had values <140 mm Hg. Mean decreases for systolic and diastolic pressure between the first and last visit were statistically significant (both P < .001). Of the 88 patients seen with HbA1c values >=7%, 68 came back for at least 1 visit (77%). By the last visit, 31% had values <7%. The change in mean HbA1c levels between the first and last visits was statistically significant (P = .001). CONCLUSION: Data from this report demonstrate statistically significant improved clinical outcomes among members of this community who sought and received care from physicians within this Center for Health Equity. PMID- 25911456 TI - The diagnostic accuracy of the squeeze test to identify arthritis: a cross sectional cohort study. AB - OBJECTIVES: In daily practice, the squeeze test is used to screen for arthritis in metacarpophalangeal (MCP) and metatarsophalangeal (MTP) joints. This cross sectional cohort study determined the diagnostic accuracy of this test. METHODS: Patients referred with arthralgia of recent onset that had either a clinical suspicion for progression to arthritis or clinically apparent arthritis were studied. The main outcome was swelling at physical examination of >=1 MCP or MTP joint. Joint inflammation detected at extremity MRI was the secondary outcome. RESULTS: Both at MCP and MTP joints, a positive squeeze test associated with swollen joints (p<0.005). The sensitivity of the test at the MCP joints was 53%, specificity 82%, positive likelihood ratio (LR+) 3.0, negative likelihood ratio (LR-) 0.6 and area under the receiver operator characteristic curve (AUC) 0.68. At the MTP joints, the sensitivity was 54%, specificity 74%, LR+ 2.1, LR- 0.6 and AUC 0.64. With MRI-detected inflammation as outcome, the sensitivity and specificity were 39% and 86% and 31% and 69% for the test at the MCP and MTP joints, respectively. CONCLUSIONS: A positive squeeze test is associated with local joint inflammation but the sensitivity is low, indicating a high percentage of swollen joints with a negative squeeze test. When the test is used on its own, it is insufficient to detect early arthritis. PMID- 25911457 TI - Impact of point-of-care ultrasound training on surgical residents' confidence. AB - OBJECTIVE: Point-of-care ultrasound (POCUS) is a vital tool for diagnosis and management of critically ill patients, particularly in resource-limited settings where access to diagnostic imaging may be constrained. We aimed to develop a novel POCUS training curriculum for surgical practice in the United States and in resource-limited settings in low- and middle-income countries and to determine its effect on surgical resident self-assessments of efficacy and confidence. DESIGN: We conducted an observational cohort study evaluating a POCUS training course that comprised 7 sessions of 2 hours each with didactics and proctored skills stations covering ultrasound applications for trauma (Focused Assessement with Sonography for Trauma (FAST) examination), obstetrics, vascular, soft tissue, regional anesthesia, focused echocardiography, and ultrasound guidance for procedures. Surveys on attitudes, prior experience, and confidence in point of-care ultrasound applications were conducted before and after the course. SETTING: General Surgery Training Program in Seattle, Washington. PARTICIPANTS: A total of 16 residents participated in the course; 15 and 10 residents completed the precourse and postcourse surveys, respectively. RESULTS: The mean composite confidence score from pretest compared with posttest improved from 23.3 (+/-10.2) to 37.8 (+/-6.7). Median confidence scores (1-6 scale) improved from 1.5 to 5.0 in performance of FAST (p < 0.001). Residents reported greater confidence in their ability to identify pericardial (2 to 4, p = 0.009) and peritoneal fluid (2 to 4.5, p < 0.001), to use ultrasound to guide procedures (3.5 to 4.0, p = 0.008), and to estimate ejection fraction (1 to 4, p = 0.004). Both before and after training, surgical residents overwhelmingly agreed with statements that ultrasound would improve their US-based practice, make them a better surgical resident, and improve their practice in resource-limited settings. CONCLUSIONS: After a POCUS course designed specifically for surgeons, surgical residents had improved self-efficacy and confidence levels across a broad range of skills. PMID- 25911458 TI - Training surgical residents for a career in academic global surgery: a novel training model. AB - Academic global surgery is a nascent field focused on improving surgical care in resource-poor settings through a broad-based scholarship agenda. Although there is increasing momentum to expand training opportunities in low-resource settings among academic surgical programs, most focus solely on establishing short-term elective rotations rather than fostering research or career development. Given the complex nature of surgical care delivery and programmatic capacity building in the resource-poor settings, many challenges remain before global surgery is accepted as an academic discipline and an established career path. Brigham and Women's Hospital has established a specialized global surgery track within the general surgery residency program to develop academic leaders in this growing area of need and opportunity. Here we describe our experience with the design and development of the program followed by practical applications and lessons learned from our early experiences. PMID- 25911459 TI - Stratification of Expert vs Novice Laparoscopists Using the Basic Laparoscopic Urologic Surgery (BLUS) Curriculum at a Single Institution. AB - PURPOSE: To assess determinants of performance applying the tasks of the Basic Laparoscopic Urologic Surgery (BLUS) skills curriculum administered at a single institution. METHODS: After obtaining institutional review board approval, fourth year medical students, urology residents (postgraduate year 1-5), and staff attending surgeons from an academic institution were recruited. Participants were grouped by level of experience and evaluated on 4 different BLUS modules testing fundamental laparoscopic techniques from September 2012 to September 2013. Task completion time (TCT) and missed objectives were compared with previous laparoscopic experience, amount of endourological training, and scores obtained through the EDGE simulator. RESULTS: TCTs among the participants were slower and accrued greater errors in the novice group (n = 10) than in the intermediate level (n = 9) and expert-level (n = 9) groups. Completion times on the peg transfer were 213.4, 128.1, and 108.7 seconds (p < 0.05); on the circle cutting were 182.4, 128.3, and 97.2 seconds (p < 0.05); on the clip application were 44.4, 43.2, and 38.1 seconds (p = 0.08); and on the suturing were 286.1, 177.3, and 123.6 seconds (p < 0.05) for novice, intermediate, and expert groups, respectively. When past laparoscopic numbers of participants were compared with TCTs, a positive correlation of R(2) = 0.39 was seen, signifying a relationship between number of laparoscopic cases and TCT outcomes. CONCLUSION: Performance on the EDGE simulator device during the BLUS modules significantly correlated with the amount of laparoscopic experience. Increase in the years of experience and number of laparoscopic cases led to faster and more accurate TCTs. PMID- 25911460 TI - Simulation Improves Nontechnical Skills Performance of Residents During the Perioperative and Intraoperative Phases of Surgery. AB - OBJECTIVE: Failures in nontechnical skills (NTS) rather than technical expertise are frequently at the root of medical errors in the operating room (OR). NTS are the cognitive (decision making and situation awareness) and interpersonal (communication and teamwork) skills that are recognized but are not formally addressed in surgical training. The purpose of the study was to examine the effect of simulation-based training (SBT) on NTS performance of surgical residents during simulated laparoscopic cholecystectomy (LC). SETTING: The study was performed in a simulated OR at the Center for Medical Education and Innovation at Riverside Methodist Hospital, Columbus, OH. The simulated OR was arranged with standard equipment for LC, a high-fidelity patient simulator, and a real OR team. DESIGN: General surgical residents completed 2 identical SBT sessions. For each session, residents were briefed on the LC case, completed the case in the simulated OR, and debriefed their videotaped simulation performance with a content expert. The video recordings were reviewed and the residents' NTS were scored using a perioperative time-out checklist and an intraoperative checklist for LC by 4 raters who were blinded to both the residents' postgraduate year level and the order of the videotaped simulation sessions. RESULTS: Residents showed a significant improvement in completeness of the perioperative time-out checklist from session 1 (mean score = 1.27 +/- 1.00) to session 2 (mean score = 5.00 +/- 1.28), p < 0.001. Residents' scores on the intraoperative checklist also improved from session 1 to session 2, p < 0.05. Overall, residents felt that the simulation was a valuable teaching and training tool and recommend that it be incorporated into residency training. CONCLUSION: SBT appears to be an effective technique for improving NTS of surgical residents during the perioperative and intraoperative phases of surgery. As surgical proficiency is 75% nontechnical and 25% technical, it could be reasonably argued that improved NTS of surgeons could improve surgical outcomes. PMID- 25911461 TI - Changing with the times. PMID- 25911462 TI - Training the 21st Century Immunologist. AB - Immunology, along with other fields of biology, is undergoing a revolution. Here we discuss the challenges and opportunities presented by considering the dynamical systems properties of the immune system, and harnessing the power of data-rich technologies. We present specific recommendations for changing graduate programs to incorporate training that will enable students to actively participate in the analyses of complex data and their biological system, and urge that we move from viewing quantitative and computational biology as interdisciplinary, to recognizing these as intrinsic to the discipline of immunology going forward. PMID- 25911463 TI - Portal hypertension and celiac disease: a true association? PMID- 25911464 TI - High-resolution manometry is comparable to timed barium esophagogram for assessing response to pneumatic dilation in patients with achalasia. AB - BACKGROUND: Reduction in height of barium column in timed barium esophagogram (TBE) and lower esophageal sphincter (LES) pressure on manometry has been used to assess efficacy of pneumatic dilation (PD) in patients with achalasia; data comparing these two methods to assess efficacy of PD are scanty. METHODS: Sixty two patients with achalasia undergoing PD were evaluated clinically (Eckardt's score), high-resolution manometry (HRM), and TBE (films at 1 and 5 min) before and 4 weeks after PD using 30 and 35 mm Rigiflex balloon (Microvasive, Milliford, MA, USA) in female and male patients, respectively. Response was defined clinically as Eckardt's score <3, by manometry as LES pressure <22.5 mmHg, and by TBE as adequate esophageal emptying (reduction in height of barium column by more than 50 % of pretreatment value in 5-min radiograph). RESULTS: Forty-three out of sixty-two (69 %) patients [age 34 +/- 12 years, 36 (58 %) male] responded, and 19 (31 %) did not respond to the first session of PD as assessed by post-PD Eckardt's score. Thirty-eight out of 43 (88 %) responders had adequate esophageal emptying of barium in TBE, while 31/43 (72 %) had LES pressure below 22.5 mmHg on HRM (p = ns). Eight out of 19 (42 %) nonresponders showed failure in esophageal emptying (defined by lack of reduction in height of barium column by 50 %) in TBE, and 11/19 (58 %) had LES pressure >22.5 mmHg (p = ns). Kaplan-Meier analysis showed that response on TBE and HRM at 1 month predicted clinical response well during 6 months follow up. CONCLUSION: TBE and esophageal HRM were comparable in assessing efficacy of PD in treatment of achalasia. PMID- 25911466 TI - Retraction Note to: Anti-Inflammatory Effects of Chronic Aspirin on Brain Arachidonic Acid Metabolites. Neurochem Res (2011) 36:139-45. PMID- 25911465 TI - Placental mesenchymal stromal cells rescue ambulation in ovine myelomeningocele. AB - Myelomeningocele (MMC)-commonly known as spina bifida-is a congenital birth defect that causes lifelong paralysis, incontinence, musculoskeletal deformities, and severe cognitive disabilities. The recent landmark Management of Myelomeningocele Study (MOMS) demonstrated for the first time in humans that in utero surgical repair of the MMC defect improves lower limb motor function, suggesting a capacity for improved neurologic outcomes in this disorder. However, functional recovery was incomplete, and 58% of the treated children were unable to walk independently at 30 months of age. In the present study, we demonstrate that using early gestation human placenta-derived mesenchymal stromal cells (PMSCs) to augment in utero repair of MMC results in significant and consistent improvement in neurologic function at birth in the rigorous fetal ovine model of MMC. In vitro, human PMSCs express characteristic MSC markers and trilineage differentiation potential. Protein array assays and enzyme-linked immunosorbent assay show that PMSCs secrete a variety of immunomodulatory and angiogenic cytokines. Compared with adult bone marrow MSCs, PMSCs secrete significantly higher levels of brain-derived neurotrophic factor and hepatocyte growth factor, both of which have known neuroprotective capabilities. In vivo, functional and histopathologic analysis demonstrated that human PMSCs mediate a significant, clinically relevant improvement in motor function in MMC lambs and increase the preservation of large neurons within the spinal cord. These preclinical results in the well-established fetal ovine model of MMC provide promising early support for translating in utero stem cell therapy for MMC into clinical application for patients. SIGNIFICANCE: This study presents placenta-derived mesenchymal stromal cell (PMSC) treatment as a potential therapy for myelomeningocele (MMC). Application of PMSCs can augment current in utero surgical repair in the well established and rigorously applied fetal lamb model of MMC. Treatment with human PMSCs significantly and dramatically improved neurologic function and preserved spinal cord neuron density in experimental animals. Sixty-seven percent of the PMSC-treated lambs were able to ambulate independently, with two exhibiting no motor deficits whatsoever. In contrast, none of the lambs treated with the vehicle alone were capable of ambulation. The locomotor rescue demonstrated in PMSC-treated lambs indicates great promise for future clinical trials to improve paralysis in children afflicted with MMC. PMID- 25911467 TI - Intermittent Hypoxia-Induced Parvalbumin-Immunoreactive Interneurons Loss and Neurobehavioral Impairment is Mediated by NADPH-Oxidase-2. AB - Obstructive sleep apnea usually contribute to psychiatric diseases and cognitive impairments in adults. Loss of parvalbumin (PV)-immunoreactive interneurons (PV IN) in the brain cortex is an important feature of psychiatric diseases, such as schizophrenia. Here we investigate the causal contribution of oxidative stress in the brain cortex to neuropathological alterations in a mouse model of sleep apnea. Wild-type (WT) and the NADPH-oxidase-2 (gp91-phox/NOX2) knock-out adult male C57BL/6J mice were exposed to intermittent hypoxia (IH) or standard room air in the same chamber. In vivo we determined the impact (1) of IH exposures on NOX2 expression, (2) of genetic gp91-phox/NOX2 knock-out and (3) of pharmacological NOX2 inhibition on IH-induced neuropathological alterations in adult mice. Endpoints were oxidative stress, PV-IN and neurobehavioral alterations. The results showed IH exposures increased NOX2 expression in the prefrontal cortex of WT mice, which was accompanied with elevations of indirect markers of oxidative stress (HNE, HIF-1alpha, 8-OHDG). WT mice showed loss of PV-IN in the prefrontal cortex and increased locomotion activity and anxiety levels after exposed to IH, while no change emerged in NOX2 knock-out mice. Treatment of WT mice with the antioxidant/NOX inhibitor apocynin prevented the neuropathological and neurobehavioral alterations induced by IH exposures. Our data suggest that NOX2 derived oxidative stress is involved in the loss of PV-IN in the prefrontal cortex and development of neurobehavioral alterations for adult mice exposed to IH. These results provide a molecular mechanism for the coupling between sleep apnea and brain oxidative stress as well as potential new therapeutic avenues. PMID- 25911468 TI - A preliminary candidate approach identifies the combination of chemerin, fetuin A, and fibroblast growth factors 19 and 21 as a potential biomarker panel of successful aging. AB - Although the number of centenarians is growing worldwide, the potential factors influencing the aging process remain only partially elucidated. Researchers are increasingly focusing toward biomarkers as tools to shed more light on the pathophysiology of complex phenotypes, including the ability to reach successful aging, i.e., free of major chronic diseases. We therefore conducted a case control study examining the potential associations of multiple candidate biomarkers in healthy centenarians and sex-matched healthy elderly controls. Using a case-control study of 81 centenarians (aged >= 100 years) selected based on the fact that they were disease-free and 46 healthy elderly controls (aged 70 80 years), serum levels of 15 different candidate biomarkers involved in the regulation of metabolism, angiogenesis, inflammation, and bone formation were measured. Of the 15 biomarkers tested, four molecules (chemerin, fetuin-A, and fibroblast growth factors [FGF] 19 and 21) were found to be independently associated with successful aging regardless of sex. Logistic regression analysis confirmed that chemerin, fetuin-A, FGF19, and FGF21 were independently associated with successful aging [predicted probability (PP) = 1 / [1 + 1 / exp (11.832 - 0.027 * (chemerin) - 0.009 * (fetuin-A) + 0.014 * (FGF19) - 0.007 * (FGF21)]. The area under the curve (AUC) of predicted probability values for the four-biomarker panel revealed that it can discriminate between centenarians and elderly controls with excellent accuracy (AUC > 0.94, P < 0.001). Although preliminary in essence and limited by the low sample size and lack of replication in other independent cohorts, our data suggest an independent association between successful aging and serum chemerin, fetuin-A, FGF19, and FGF21, which may provide novel information on the mechanisms behind the human aging process. Whether the four-biomarker panel may predict successful aging deserves further scrutiny. PMID- 25911469 TI - Medium-intensity, high-volume "hypertrophic" resistance training did not induce improvements in rapid force production in healthy older men. AB - The aim of the study was to determine whether it is possible to improve both maximum and rapid force production using resistance training that is typically used to induce muscle hypertrophy in previously untrained older men. Subjects (60 72 years) performed 20 weeks of "hypertrophic" resistance training twice weekly (n = 27) or control (n = 11). Maximum dynamic and isometric leg press, as well as isometric force over 0-100 ms, and maximum concentric power tests were performed pre- and post-intervention. Muscle activity was assessed during these tests by surface electromyogram of the vastus lateralis and medialis muscles. Muscle hypertrophy was assessed by panoramic ultrasound of the vastus lateralis. The intervention group increased their maximum isometric (from 2268 +/- 544 to 2538 +/- 701 N) and dynamic force production (from 137 +/- 24 to 165 +/- 29 kg), and these changes were significantly different to control (isometric 12 +/- 16 vs. 1 +/- 9 %; dynamic 21 +/- 12 vs. 2 +/- 4 %). No within- or between-group differences were observed in rapid isometric force or concentric power. Relative increases in vastus lateralis cross-sectional area trended to be statistically greater in the intervention group (10 +/- 8 vs. 3 +/- 6 %, P = 0.061). It is recommendable that resistance training programs for older individuals integrate protocols emphasizing maximum force/muscle hypertrophy and rapid force production in order to induce comprehensive health-related and functionally important improvements in this population. PMID- 25911470 TI - Comparative Genotypic and Phenotypic Analysis of Cronobacter Species Cultured from Four Powdered Infant Formula Production Facilities: Indication of Pathoadaptation along the Food Chain. AB - Cronobacter species are opportunistic pathogens commonly found in the environment. Among the seven Cronobacter species, Cronobacter sakazakii sequence type 4 (ST-4) is predominantly associated with recorded cases of infantile meningitis. This study reports on a 26-month powdered infant formula (PIF) surveillance program in four production facilities located in distinct geographic regions. The objective was to identify the ST(s) in PIF production environments and to investigate the phenotypic features that support their survival. Of all 168 Cronobacter isolates, 133 were recovered from a PIF production environment, 31 were of clinical origin, and 4 were laboratory type strains. Sequence type 1 (n = 84 isolates; 63.9%) was the dominant type in PIF production environments. The majority of these isolates clustered with an indistinguishable pulsotype and persisted for at least an 18-month period. Moreover, DNA microarray results identified two phylogenetic lineages among ST-4 strains tested. Thereafter, the ST-1 and -4 isolates were phenotypically compared. Differences were noted based on the phenotypes expressed by these isolates. The ST-1 PIF isolates produced stronger biofilms at both 28 degrees C and 37 degrees C, while the ST-4 clinical isolates exhibited greater swimming activity and increased binding to Congo red dye. Given the fact that PIF is a low-moisture environment and that the clinical environment provides for an interaction between the pathogen and its host, these differences may be consistent with a form of pathoadaptation. These findings help to extend our current understanding of the epidemiology and ecology of Cronobacter species in PIF production environments. PMID- 25911471 TI - Photoautotrophic Polyhydroxybutyrate Granule Formation Is Regulated by Cyanobacterial Phasin PhaP in Synechocystis sp. Strain PCC 6803. AB - Cyanobacteria are photoautotrophic microorganisms which fix atmospheric carbon dioxide via the Calvin-Benson cycle to produce carbon backbones for primary metabolism. Fixed carbon can also be stored as intracellular glycogen, and in some cyanobacterial species like Synechocystis sp. strain PCC 6803, polyhydroxybutyrate (PHB) accumulates when major nutrients like phosphorus or nitrogen are absent. So far only three enzymes which participate in PHB metabolism have been identified in this organism, namely, PhaA, PhaB, and the heterodimeric PHB synthase PhaEC. In this work, we describe the cyanobacterial PHA surface-coating protein (phasin), which we term PhaP, encoded by ssl2501. Translational fusion of Ssl2501 with enhanced green fluorescent protein (eGFP) showed a clear colocalization to PHB granules. A deletion of ssl2501 reduced the number of PHB granules per cell, whereas the mean PHB granule size increased as expected for a typical phasin. Although deletion of ssl2501 had almost no effect on the amount of PHB, the biosynthetic activity of PHB synthase was negatively affected. Secondary-structure prediction and circular dichroism (CD) spectroscopy of PhaP revealed that the protein consists of two alpha-helices, both of them associating with PHB granules. Purified PhaP forms oligomeric structures in solution, and both alpha-helices of PhaP contribute to oligomerization. Together, these results support the idea that Ssl2501 encodes a cyanobacterial phasin, PhaP, which regulates the surface-to-volume ratio of PHB granules. PMID- 25911472 TI - Patterns and determinants of halophilic archaea (class halobacteria) diversity in tunisian endorheic salt lakes and sebkhet systems. AB - We examined the diversity and community structure of members of the halophilic Archaea (class Halobacteria) in samples from central and southern Tunisian endorheic salt lakes and sebkhet (also known as sebkha) systems using targeted 16S rRNA gene diversity survey and quantitative PCR (qPCR) approaches. Twenty three different samples from four distinct locations exhibiting a wide range of salinities (2% to 37%) and physical characteristics (water, salt crust, sediment, and biofilm) were examined. A total of 4,759 operational taxonomic units at the 0.03 (species-level) cutoff (OTU0.03s) belonging to 45 currently recognized genera were identified, with 8 to 43 genera (average, 30) identified per sample. In spite of the large number of genera detected per sample, only a limited number (i.e., 2 to 16) usually constituted the majority (>=80%) of encountered sequences. Halobacteria diversity showed a strong negative correlation to salinity (Pearson correlation coefficient = -0.92), and community structure analysis identified salinity, rather than the location or physical characteristics of the sample, as the most important factor shaping the Halobacteria community structure. The relative abundance of genera capable of biosynthesis of the compatible solute(s) trehalose or 2-sulfotrehalose decreased with increasing salinities (Pearson correlation coefficient = -0.80). Indeed, qPCR analysis demonstrated that the Halobacteria otsB (trehalose-6 phosphatase)/16S rRNA gene ratio decreases with increasing salinities (Pearson correlation coefficient = -0.87). The results highlight patterns and determinants of Halobacteria diversity at a previously unexplored ecosystem and indicate that genera lacking trehalose biosynthetic capabilities are more adapted to growth in and colonization of hypersaline (>25% salt) ecosystems than trehalose producers. PMID- 25911473 TI - Combining Lactic Acid Spray with Near-Infrared Radiation Heating To Inactivate Salmonella enterica Serovar Enteritidis on Almond and Pine Nut Kernels. AB - The aim of this study was to investigate the efficacy of near-infrared radiation (NIR) heating combined with lactic acid (LA) sprays for inactivating Salmonella enterica serovar Enteritidis on almond and pine nut kernels and to elucidate the mechanisms of the lethal effect of the NIR-LA combined treatment. Also, the effect of the combination treatment on product quality was determined. Separately prepared S. Enteritidis phage type (PT) 30 and non-PT 30 S. Enteritidis cocktails were inoculated onto almond and pine nut kernels, respectively, followed by treatments with NIR or 2% LA spray alone, NIR with distilled water spray (NIR DW), and NIR with 2% LA spray (NIR-LA). Although surface temperatures of nuts treated with NIR were higher than those subjected to NIR-DW or NIR-LA treatment, more S. Enteritidis survived after NIR treatment alone. The effectiveness of NIR DW and NIR-LA was similar, but significantly more sublethally injured cells were recovered from NIR-DW-treated samples. We confirmed that the enhanced bactericidal effect of the NIR-LA combination may not be attributable to cell membrane damage per se. NIR heat treatment might allow S. Enteritidis cells to become permeable to applied LA solution. The NIR-LA treatment (5 min) did not significantly (P > 0.05) cause changes in the lipid peroxidation parameters, total phenolic contents, color values, moisture contents, and sensory attributes of nut kernels. Given the results of the present study, NIR-LA treatment may be a potential intervention for controlling food-borne pathogens on nut kernel products. PMID- 25911474 TI - Vibriophages Differentially Influence Biofilm Formation by Vibrio anguillarum Strains. AB - Vibrio anguillarum is an important pathogen in marine aquaculture, responsible for vibriosis. Bacteriophages can potentially be used to control bacterial pathogens; however, successful application of phages requires a detailed understanding of phage-host interactions under both free-living and surface associated growth conditions. In this study, we explored in vitro phage-host interactions in two different strains of V. anguillarum (BA35 and PF430-3) during growth in microcolonies, biofilms, and free-living cells. Two vibriophages, PhiH20 (Siphoviridae) and KVP40 (Myoviridae), had completely different effects on the biofilm development. Addition of phage PhiH20 to strain BA35 showed efficient control of biofilm formation and density of free-living cells. The interactions between BA35 and PhiH20 were thus characterized by a strong phage control of the phage-sensitive population and subsequent selection for phage-resistant mutants. Addition of phage KVP40 to strain PF430-3 resulted in increased biofilm development, especially during the early stage. Subsequent experiments in liquid cultures showed that addition of phage KVP40 stimulated the aggregation of host cells, which protected the cells against phage infection. By the formation of biofilms, strain PF430-3 created spatial refuges that protected the host from phage infection and allowed coexistence between phage-sensitive cells and lytic phage KVP40. Together, the results demonstrate highly variable phage protection mechanisms in two closely related V. anguillarum strains, thus emphasizing the challenges of using phages to control vibriosis in aquaculture and adding to the complex roles of phages as drivers of prokaryotic diversity and population dynamics. PMID- 25911475 TI - Rich Medium Composition Affects Escherichia coli Survival, Glycation, and Mutation Frequency during Long-Term Batch Culture. AB - Bacteria such as Escherichia coli are frequently grown to high density to produce biomolecules for study in the laboratory. To achieve this, cells can be incubated in extremely rich media that increase overall cell yield. In these various media, bacteria may have different metabolic profiles, leading to changes in the amounts of toxic metabolites produced. We have previously shown that stresses experienced during short-term growth can affect the survival of cells during the long-term stationary phase (LTSP). Here, we incubated cells in LB, 2* yeast extract tryptone (YT), Terrific Broth, or Super Broth medium and monitored survival during the LTSP, as well as other reporters of genetic and physiological change. We observe differential cell yield and survival in all media studied. We propose that differences in long-term survival are the result of changes in the metabolism of components of the media that may lead to increased levels of protein and/or DNA damage. We also show that culture pH and levels of protein glycation, a covalent modification that causes protein damage, affect long-term survival. Further, we measured mutation frequency after overnight incubation and observed a correlation between high mutation frequencies at the end of the log phase and loss of viability after 4 days of LTSP incubation, indicating that mutation frequency is potentially predictive of long-term survival. Since glycation and mutation can be caused by oxidative stress, we measured expression of the oxyR oxidative stress regulator during log-phase growth and found that higher levels of oxyR expression during the log phase are consistent with high mutation frequency and lower cell density during the LTSP. Since these complex rich media are often used when producing large quantities of biomolecules in the laboratory, the observed increase in damage resulting in glycation or mutation may lead to production of a heterogeneous population of plasmids or proteins, which could affect the quality of the end products yielded in some laboratory experiments. PMID- 25911476 TI - Distribution and Characterization of Salmonella enterica Isolates from Irrigation Ponds in the Southeastern United States. AB - Irrigation water has been implicated as a likely source of produce contamination by Salmonella enterica. Therefore, the distribution of S. enterica was surveyed monthly in irrigation ponds (n = 10) located within a prime agricultural region in southern Georgia and northern Florida. All ponds and 28.2% of all samples (n = 635) were positive for Salmonella, with an overall geometric mean concentration (0.26 most probable number [MPN]/liter) that was relatively low compared to prior reports for rivers in this region. Salmonella peaks were seasonal; the levels correlated with increased temperature and rainfall (P < 0.05). The numbers and occurrence were significantly higher in water (0.32 MPN/liter and 37% of samples) than in sediment (0.22 MPN/liter and 17% of samples) but did not vary with depth. Representative isolates (n = 185) from different ponds, sample types, and seasons were examined for resistance to 15 different antibiotics; most strains were resistant to streptomycin (98.9%), while 20% were multidrug resistant (MDR) for 2 to 6 antibiotics. DiversiLab repetitive extragenic palindromic-element sequence based PCR (rep-PCR) revealed genetic diversity and showed 43 genotypes among 191 isolates, as defined by >95% similarity. The genotypes did not partition by pond, season, or sample type. Genetic similarity to known serotypes indicated Hadar, Montevideo, and Newport as the most prevalent. All ponds achieved the current safety standards for generic Escherichia coli in agricultural water, and regression modeling showed that the E. coli level was a significant predictor for the probability of Salmonella occurrence. However, persistent populations of Salmonella were widely distributed in irrigation ponds, and the associated risks for produce contamination and subsequent human exposure are unknown, supporting continued surveillance of this pathogen in agricultural settings. PMID- 25911477 TI - Effects of Colonization of the Roots of Domestic Rice (Oryza sativa L. cv. Amaroo) by Burkholderia pseudomallei. AB - Burkholderia pseudomallei is a saprophytic bacterium that causes melioidosis and is often isolated from rice fields in Southeast Asia, where the infection incidence is high among rice field workers. The aim of this study was to investigate the relationship between this bacterium and rice through growth experiments where the effect of colonization of domestic rice (Oryza sativa L. cv Amaroo) roots by B. pseudomallei could be observed. When B. pseudomallei was exposed to surface-sterilized seeds, the growth of both the root and the aerosphere was retarded compared to that in controls. The organism was found to localize in the root hairs and endodermis of the plant. A biofilm formed around the root and root structures that were colonized. Growth experiments with a wild rice species (Oryza meridionalis) produced similar retardation of growth, while another domestic cultivar (O. sativa L. cv Koshihikari) did not show retarded growth. Here we report B. pseudomallei infection and inhibition of O. sativa L. cv Amaroo, which might provide insights into plant interactions with this important human pathogen. PMID- 25911478 TI - Dynamics of Escherichia coli Virulence Factors in Dairy Herds and Farm Environments in a Longitudinal Study in the United States. AB - Pathogenic Escherichia coli or its associated virulence factors have been frequently detected in dairy cow manure, milk, and dairy farm environments. However, it is unclear what the long-term dynamics of E. coli virulence factors are and which farm compartments act as reservoirs. This study assessed the occurrence and dynamics of four E. coli virulence factors (eae, stx1, stx2, and the gamma allele of the tir gene [gamma-tir]) on three U.S. dairy farms. Fecal, manure, water, feed, milk, and milk filter samples were collected from 2004 to 2012. Virulence factors were measured by postenrichment quantitative PCR (qPCR). All factors were detected in most compartments on all farms. Fecal and manure samples showed the highest prevalence, up to 53% for stx and 21% for gamma-tir in fecal samples and up to 84% for stx and 44% for gamma-tir in manure. Prevalence was low in milk (up to 1.9% for stx and 0.7% for gamma-tir). However, 35% of milk filters were positive for stx and 20% were positive for gamma-tir. All factors were detected in feed and water. Factor prevalence and levels, expressed as qPCR cycle threshold categories, fluctuated significantly over time, with no clear seasonal signal independent from year-to-year variability. Levels were correlated between fecal and manure samples, and in some cases autocorrelated, but not between manure and milk filters. Shiga toxins were nearly ubiquitous, and 10 to 18% of the lactating cows were potential shedders of E. coli O157 at least once during their time in the herds. E. coli virulence factors appear to persist in many areas of the farms and therefore contribute to transmission dynamics. PMID- 25911479 TI - Aerobic Hydrogen Production via Nitrogenase in Azotobacter vinelandii CA6. AB - The diazotroph Azotobacter vinelandii possesses three distinct nitrogenase isoenzymes, all of which produce molecular hydrogen as a by-product. In batch cultures, A. vinelandii strain CA6, a mutant of strain CA, displays multiple phenotypes distinct from its parent: tolerance to tungstate, impaired growth and molybdate transport, and increased hydrogen evolution. Determining and comparing the genomic sequences of strains CA and CA6 revealed a large deletion in CA6's genome, encompassing genes related to molybdate and iron transport and hydrogen reoxidation. A series of iron uptake analyses and chemostat culture experiments confirmed iron transport impairment and showed that the addition of fixed nitrogen (ammonia) resulted in cessation of hydrogen production. Additional chemostat experiments compared the hydrogen-producing parameters of different strains: in iron-sufficient, tungstate-free conditions, strain CA6's yields were identical to those of a strain lacking only a single hydrogenase gene. However, in the presence of tungstate, CA6 produced several times more hydrogen. A. vinelandii may hold promise for developing a novel strategy for production of hydrogen as an energy compound. PMID- 25911480 TI - Recent Emergence of Escherichia coli with Cephalosporin Resistance Conferred by blaCTX-M on Washington State Dairy Farms. AB - Enterobacteriaceae-associated blaCTX-M genes have become globally widespread within the past 30 years. Among isolates from Washington State cattle, Escherichia coli strains carrying blaCTX-M (CTX-M E. coli strains) were absent from a set of 2008 isolates but present in a set of isolates from 2011. On 30 Washington State dairy farms sampled in 2012, CTX-M E. coli prevalence was significantly higher on eastern than on northwestern Washington farms, on farms with more than 3,000 adult cows, and on farms that recently received new animals. The addition of fresh bedding to calf hutches at least weekly and use of residual fly sprays were associated with lower prevalence of CTX-M E. coli. In Washington State, the occurrence of human pathogens carrying blaCTX-M genes preceded the emergence of blaCTX-M-associated E. coli in cattle, indicating that these resistance determinants and/or their bacterial hosts may have emerged in human populations prior to their dissemination to cattle populations. PMID- 25911481 TI - The Xanthomonas oryzae pv. oryzae PilZ Domain Proteins Function Differentially in Cyclic di-GMP Binding and Regulation of Virulence and Motility. AB - The PilZ domain proteins have been demonstrated to be one of the major types of receptors mediating cyclic di-GMP (c-di-GMP) signaling pathways in several pathogenic bacteria. However, little is known about the function of PilZ domain proteins in c-di-GMP regulation of virulence in the bacterial blight pathogen of rice Xanthomonas oryzae pv. oryzae. Here, the roles of PilZ domain proteins PXO_00049 and PXO_02374 in c-di-GMP binding, regulation of virulence and motility, and subcellular localization were characterized in comparison with PXO_02715, identified previously as an interactor with the c-di-GMP receptor Filp to regulate virulence. The c-di-GMP binding motifs in the PilZ domains were conserved in PXO_00049 and PXO_02374 but were less well conserved in PXO_02715. PXO_00049 and PXO_02374 but not PXO_02715 proteins bound to c-di-GMP with high affinity in vitro, and the R(141) and R(10) residues in the PilZ domains of PXO_00049 and PXO_02374, respectively, were crucial for c-di-GMP binding. Gene deletion of PXO_00049 and PXO_02374 resulted in significant increases in virulence and hrp gene transcription, indicating their negative regulation of virulence via type III secretion system expression. All mutants showed significant changes in sliding motility but not exopolysaccharide production and biofilm formation. In trans expression of the full-length open reading frame (ORF) of each gene in the relevant mutants led to restoration of the phenotype to wild-type levels. Moreover, PXO_00049 and PXO_02374 displayed mainly multisite subcellular localizations, whereas PXO_02715 showed nonpolar distributions in the X. oryzae pv. oryzae cells. Therefore, this study demonstrated the different functions of the PilZ domain proteins in mediation of c-di-GMP regulation of virulence and motility in X. oryzae pv. oryzae. PMID- 25911482 TI - Thermophilic Coenzyme B12-Dependent Acyl Coenzyme A (CoA) Mutase from Kyrpidia tusciae DSM 2912 Preferentially Catalyzes Isomerization of (R)-3-Hydroxybutyryl CoA and 2-Hydroxyisobutyryl-CoA. AB - The recent discovery of a coenzyme B12-dependent acyl-coenzyme A (acyl-CoA) mutase isomerizing 3-hydroxybutyryl- and 2-hydroxyisobutyryl-CoA in the mesophilic bacterium Aquincola tertiaricarbonis L108 (N. Yaneva, J. Schuster, F. Schafer, V. Lede, D. Przybylski, T. Paproth, H. Harms, R. H. Muller, and T. Rohwerder, J Biol Chem 287:15502-15511, 2012, http://dx.doi.org/10.1074/jbc.M111.314690) could pave the way for a complete biosynthesis route to the building block chemical 2-hydroxyisobutyric acid from renewable carbon. However, the enzyme catalyzes only the conversion of the stereoisomer (S)-3-hydroxybutyryl-CoA at reasonable rates, which seriously hampers an efficient combination of mutase and well-established bacterial poly (R)-3-hydroxybutyrate (PHB) overflow metabolism. Here, we characterize a new 2 hydroxyisobutyryl-CoA mutase found in the thermophilic knallgas bacterium Kyrpidia tusciae DSM 2912. Reconstituted mutase subunits revealed highest activity at 55 degrees C. Surprisingly, already at 30 degrees C, isomerization of (R)-3-hydroxybutyryl-CoA was about 7,000 times more efficient than with the mutase from strain L108. The most striking structural difference between the two mutases, likely determining stereospecificity, is a replacement of active-site residue Asp found in strain L108 at position 117 with Val in the enzyme from strain DSM 2912, resulting in a reversed polarity at this binding site. Overall sequence comparison indicates that both enzymes descended from different prokaryotic thermophilic methylmalonyl-CoA mutases. Concomitant expression of PHB enzymes delivering (R)-3-hydroxybutyryl-CoA (beta-ketothiolase PhaA and acetoacetyl-CoA reductase PhaB from Cupriavidus necator) with the new mutase in Escherichia coli JM109 and BL21 strains incubated on gluconic acid at 37 degrees C led to the production of 2-hydroxyisobutyric acid at maximal titers of 0.7 mM. Measures to improve production in E. coli, such as coexpression of the chaperone MeaH and repression of thioesterase II, are discussed. PMID- 25911483 TI - Efficient Genome Editing in Clostridium cellulolyticum via CRISPR-Cas9 Nickase. AB - The CRISPR-Cas9 system is a powerful and revolutionary genome-editing tool for eukaryotic genomes, but its use in bacterial genomes is very limited. Here, we investigated the use of the Streptococcus pyogenes CRISPR-Cas9 system in editing the genome of Clostridium cellulolyticum, a model microorganism for bioenergy research. Wild-type Cas9-induced double-strand breaks were lethal to C. cellulolyticum due to the minimal expression of nonhomologous end joining (NHEJ) components in this strain. To circumvent this lethality, Cas9 nickase was applied to develop a single-nick-triggered homologous recombination strategy, which allows precise one-step editing at intended genomic loci by transforming a single vector. This strategy has a high editing efficiency (>95%) even using short homologous arms (0.2 kb), is able to deliver foreign genes into the genome in a single step without a marker, enables precise editing even at two very similar target sites differing by two bases preceding the seed region, and has a very high target site density (median interval distance of 9 bp and 95.7% gene coverage in C. cellulolyticum). Together, these results establish a simple and robust methodology for genome editing in NHEJ-ineffective prokaryotes. PMID- 25911484 TI - Evaluation of the Ion Torrent Personal Genome Machine for Gene-Targeted Studies Using Amplicons of the Nitrogenase Gene nifH. AB - The sequencing chips and kits of the Ion Torrent Personal Genome Machine (PGM), which employs semiconductor technology to measure pH changes in polymerization events, have recently been upgraded. The quality of PGM sequences has not been reassessed, and results have not been compared in the context of a gene-targeted microbial ecology study. To address this, we compared sequence profiles across available PGM chips and chemistries and with 454 pyrosequencing data by determining error types and rates and diazotrophic community structures. The PGM was then used to assess differences in nifH-harboring bacterial community structure among four corn-based cropping systems. Using our suggested filters from mock community analyses, the overall error rates were 0.62, 0.36, and 0.39% per base for chips 318 and 314 with the 400-bp kit and chip 318 with the Hi-Q chemistry, respectively. Compared with the 400-bp kit, the Hi-Q kit reduced indel rates by 28 to 59% and produced one to seven times more reads acceptable for downstream analyses. The PGM produced higher frameshift rates than pyrosequencing that were corrected by the RDP FrameBot tool. Significant differences among platforms were identified, although the diversity indices and overall site-based conclusions remained similar. For the cropping system analyses, a total of 6,182 unique NifH operational taxonomic units at 5% amino acid dissimilarity were obtained. The current crop type, as well as the crop rotation history, significantly influenced the composition of the soil diazotrophic community detected. PMID- 25911485 TI - VirR-Mediated Resistance of Listeria monocytogenes against Food Antimicrobials and Cross-Protection Induced by Exposure to Organic Acid Salts. AB - Formulations of ready-to-eat (RTE) foods with antimicrobial compounds constitute an important safety measure against foodborne pathogens such as Listeria monocytogenes. While the efficacy of many commercially available antimicrobial compounds has been demonstrated in a variety of foods, the current understanding of the resistance mechanisms employed by L. monocytogenes to counteract these stresses is limited. In this study, we screened in-frame deletion mutants of two component system response regulators associated with the cell envelope stress response for increased sensitivity to commercially available antimicrobial compounds (nisin, lauric arginate, epsilon-polylysine, and chitosan). A virR deletion mutant showed increased sensitivity to all antimicrobials and significantly greater loss of membrane integrity when exposed to nisin, lauric arginate, or epsilon-polylysine (P < 0.05). The VirR-regulated operon, dltABCD, was shown to be the key contributor to resistance against these antimicrobial compounds, whereas another VirR-regulated gene, mprF, displayed an antimicrobial specific contribution to resistance. An experiment with a beta-glucuronidase (GUS) reporter fusion with the dlt promoter indicated that nisin does not specifically induce VirR-dependent upregulation of dltABCD. Lastly, prior exposure of L. monocytogenes parent strain H7858 and the DeltavirR mutant to 2% potassium lactate enhanced subsequent resistance against nisin and epsilon polylysine (P < 0.05). These data demonstrate that VirRS-mediated regulation of dltABCD is the major resistance mechanism used by L. monocytogenes against cell envelope-damaging food antimicrobials. Further, the potential for cross protection induced by other food-related stresses (e.g., organic acids) needs to be considered when applying these novel food antimicrobials as a hurdle strategy for RTE foods. PMID- 25911486 TI - PilZ Domain Proteins of the Plant Pathogen Xanthomonas oryzae pv. oryzae Function Differentially in Virulence. PMID- 25911487 TI - Highly Active and Specific Tyrosine Ammonia-Lyases from Diverse Origins Enable Enhanced Production of Aromatic Compounds in Bacteria and Saccharomyces cerevisiae. AB - Phenylalanine and tyrosine ammonia-lyases form cinnamic acid and p-coumaric acid, which are precursors of a wide range of aromatic compounds of biotechnological interest. Lack of highly active and specific tyrosine ammonia-lyases has previously been a limitation in metabolic engineering approaches. We therefore identified 22 sequences in silico using synteny information and aiming for sequence divergence. We performed a comparative in vivo study, expressing the genes intracellularly in bacteria and yeast. When produced heterologously, some enzymes resulted in significantly higher production of p-coumaric acid in several different industrially important production organisms. Three novel enzymes were found to have activity exclusively for phenylalanine, including an enzyme from the low-GC Gram-positive bacterium Brevibacillus laterosporus, a bacterial-type enzyme from the amoeba Dictyostelium discoideum, and a phenylalanine ammonia lyase from the moss Physcomitrella patens (producing 230 MUM cinnamic acid per unit of optical density at 600 nm [OD600]) in the medium using Escherichia coli as the heterologous host). Novel tyrosine ammonia-lyases having higher reported substrate specificity than previously characterized enzymes were also identified. Enzymes from Herpetosiphon aurantiacus and Flavobacterium johnsoniae resulted in high production of p-coumaric acid in Escherichia coli (producing 440 MUM p coumaric acid OD600 unit(-1) in the medium) and in Lactococcus lactis. The enzymes were also efficient in Saccharomyces cerevisiae, where p-coumaric acid accumulation was improved 5-fold over that in strains expressing previously characterized tyrosine ammonia-lyases. PMID- 25911488 TI - Extraintestinal Pathogenic and Antimicrobial-Resistant Escherichia coli Contamination of 56 Public Restrooms in the Greater Minneapolis-St. Paul Metropolitan Area. AB - How extraintestinal pathogenic Escherichia coli (ExPEC) and antimicrobial resistant E. coli disseminate through the population is undefined. We studied public restrooms for contamination with E. coli and ExPEC in relation to source and extensively characterized the E. coli isolates. For this, we cultured 1,120 environmental samples from 56 public restrooms in 33 establishments (obtained from 10 cities in the greater Minneapolis-St. Paul, MN, metropolitan area in 2003) for E. coli and compared ecological data with culture results. Isolates underwent virulence genotyping, phylotyping, clonal typing, pulsed-field gel electrophoresis (PFGE), and disk diffusion antimicrobial susceptibility testing. Overall, 168 samples (15% from 89% of restrooms) fluoresced, indicating presumptive E. coli: 25 samples (2.2% from 32% of restrooms) yielded E. coli isolates, and 10 samples (0.9% from 16% of restrooms) contained ExPEC. Restroom category and cleanliness level significantly predicted only fluorescence, gender predicted fluorescence and E. coli, and feces-like material and toilet-associated sites predicted all three endpoints. Of the 25 E. coli isolates, 7 (28%) were from phylogenetic group B2(virulence-associated), and 8 (32%) were ExPEC. ExPEC isolates more commonly represented group B2 (50% versus 18%) and had significantly higher virulence gene scores than non-ExPEC isolates. Six isolates (24%) exhibited >=3-class antibiotic resistance, 10 (40%) represented classic human-associated sequence types, and one closely resembled reference human clinical isolates by pulsed-field gel electrophoresis. Thus, E. coli, ExPEC, and antimicrobial-resistant E. coli sporadically contaminate public restrooms, in ways corresponding with restroom characteristics and within-restroom sites. Such restroom-source E. coli strains likely reflect human fecal contamination, may pose a health threat, and may contribute to population-wide dissemination of such strains. PMID- 25911489 TI - Heat Shock-Enhanced Conjugation Efficiency in Standard Campylobacter jejuni Strains. AB - Campylobacter jejuni, the leading bacterial cause of human gastroenteritis in the United States, displays significant strain diversity due to horizontal gene transfer. Conjugation is an important horizontal gene transfer mechanism contributing to the evolution of bacterial pathogenesis and antimicrobial resistance. It has been observed that heat shock could increase transformation efficiency in some bacteria. In this study, the effect of heat shock on C. jejuni conjugation efficiency and the underlying mechanisms were examined. With a modified Escherichia coli donor strain, different C. jejuni recipient strains displayed significant variation in conjugation efficiency ranging from 6.2 * 10( 8) to 6.0 * 10(-3) CFU per recipient cell. Despite reduced viability, heat shock of standard C. jejuni NCTC 11168 and 81-176 strains (e.g., 48 to 54 degrees C for 30 to 60 min) could dramatically enhance C. jejuni conjugation efficiency up to 1,000-fold. The phenotype of the heat shock-enhanced conjugation in C. jejuni recipient cells could be sustained for at least 9 h. Filtered supernatant from the heat shock-treated C. jejuni cells could not enhance conjugation efficiency, which suggests that the enhanced conjugation efficiency is independent of secreted substances. Mutagenesis analysis indicated that the clustered regularly interspaced short palindromic repeats system and the selected restriction modification systems (Cj0030/Cj0031, Cj0139/Cj0140, Cj0690c, and HsdR) were dispensable for heat shock-enhanced conjugation in C. jejuni. Taking all results together, this study demonstrated a heat shock-enhanced conjugation efficiency in standard C. jejuni strains, leading to an optimized conjugation protocol for molecular manipulation of this organism. The findings from this study also represent a significant step toward elucidation of the molecular mechanism of conjugative gene transfer in C. jejuni. PMID- 25911490 TI - Leaf-cutter ant fungus gardens are biphasic mixed microbial bioreactors that convert plant biomass to polyols with biotechnological applications. AB - Leaf-cutter ants use plant matter to culture the obligate mutualistic basidiomycete Leucoagaricus gongylophorus. This fungus mediates ant nutrition on plant resources. Furthermore, other microbes living in the fungus garden might also contribute to plant digestion. The fungus garden comprises a young sector with recently incorporated leaf fragments and an old sector with partially digested plant matter. Here, we show that the young and old sectors of the grass cutter Atta bisphaerica fungus garden operate as a biphasic solid-state mixed fermenting system. An initial plant digestion phase occurred in the young sector in the fungus garden periphery, with prevailing hemicellulose and starch degradation into arabinose, mannose, xylose, and glucose. These products support fast microbial growth but were mostly converted into four polyols. Three polyols, mannitol, arabitol, and inositol, were secreted by L. gongylophorus, and a fourth polyol, sorbitol, was likely secreted by another, unidentified, microbe. A second plant digestion phase occurred in the old sector, located in the fungus garden core, comprising stocks of microbial biomass growing slowly on monosaccharides and polyols. This biphasic operation was efficient in mediating symbiotic nutrition on plant matter: the microbes, accounting for 4% of the fungus garden biomass, converted plant matter biomass into monosaccharides and polyols, which were completely consumed by the resident ants and microbes. However, when consumption was inhibited through laboratory manipulation, most of the plant polysaccharides were degraded, products rapidly accumulated, and yields could be preferentially switched between polyols and monosaccharides. This feature might be useful in biotechnology. PMID- 25911491 TI - Systematic Analysis of White Pox Disease in Acropora palmata of the Florida Keys and Role of Serratia marcescens. AB - White pox disease (WPD) affects the threatened elkhorn coral, Acropora palmata. Owing in part to the lack of a rapid and simple diagnostic test, there have been few systematic assessments of the prevalence of acroporid serratiosis (caused specifically by Serratia marcescens) versus general WPD signs. Six reefs in the Florida Keys were surveyed between 2011 and 2013 to determine the disease status of A. palmata and the prevalence of S. marcescens. WPD was noted at four of the six reefs, with WPD lesions found on 8 to 40% of the colonies surveyed. S. marcescens was detected in 26.9% (7/26) of the WPD lesions and in mucus from apparently healthy colonies both during and outside of disease events (9%; 18/201). S. marcescens was detected with greater frequency in A. palmata than in the overlying water column, regardless of disease status (P = 0.0177). S. marcescens could not be cultured from A. palmata but was isolated from healthy colonies of other coral species and was identified as pathogenic pulsed-field gel electrophoresis type PDR60. WPD lesions were frequently observed on the reef, but unlike in prior outbreaks, no whole-colony death was observed. Pathogenic S. marcescens was circulating on the reef but did not appear to be the primary pathogen in these recent WPD episodes, suggesting that other pathogens or stressors may contribute to signs of WPD. Results highlight the critical importance of diagnostics in coral disease investigations, especially given that field manifestation of disease may be similar, regardless of the etiological agent. PMID- 25911492 TI - Arrhythmia care co-ordinators: Their impact on anxiety and depression, readmissions and health service costs. AB - BACKGROUND: In 2005, the UK Department of Health recommended that a new role, the arrhythmia care coordinator (ACC), be created to guide patients through the diagnosis and treatment for arrhythmia. The belief was that this would improve the efficiency of care and improve their quality of life. The British Heart Foundation provided funding for 32 such posts, all of which were filled by arrhythmia specialist nurses, and commissioned an evaluation of the new service to assess its impact on patients. AIMS: This paper focuses on the impact of the ACCs on their patients' levels of anxiety and depression, hospital readmissions and costs to the National Health Service (NHS). METHODS: From 2008 to 2010, using questionnaires, we conducted a longitudinal audit of the psychological status of the patients referred to the ACCs; we also assessed the ACCs' impact on readmissions and cost benefits to the NHS using UK Hospital Episode Statistics. RESULTS: We found high levels of anxiety and depression amongst patients. Nearly one-third were at the 'borderline' or 'clinically anxious' and 18% were at the 'borderline' or 'clinically depressed' level at their first assessment with small changes at follow-up. In arrhythmia specialist nurse sites, readmission rates were reduced by half. After deducting the cost of the ACCs and their support, the estimated annual saving was L29,357 per ACC. CONCLUSION: This evaluation has shown that the NHS saves L29,357 per year over and above the costs of employing a British Heart Foundation ACC and that all arrhythmia centres should be encouraged to employ an appropriate number of such specialists. PMID- 25911493 TI - Protective Role of tert-Butylhydroquinone Against Sodium Fluoride-Induced Oxidative Stress and Apoptosis in PC12 Cells. AB - The neurotoxicity of fluoride is associated with oxidative stress due to imbalance between production and removal of reactive oxygen species (ROS). In contrast, induction of detoxifying and antioxidant genes through activation of NF E2-related factor 2 (Nrf2) has been implicated in preventing oxidative stress and apoptosis in neurodegenerative diseases. The present study aimed to investigate the possible neuroprotective role of tert-butylhydroquinone (tBHQ), a general Nrf2 activator, on sodium fluoride (NaF)-induced oxidation damage and apoptosis in neuron-like rat pheochromocytoma (PC12) cells. Pretreatment with tBHQ protected PC12 cells against NaF-induced cytotoxicity as measured by MTT assay and apoptosis detection, simultaneously, inhibited NaF-induced overproduction of intracellular ROS and reduction of total glutathione content. Furthermore, NaF or tBHQ induced the stabilization of Nrf2, and enhanced expression of heme oxygenase 1 (HO-1) and gamma-glutamylcysteine synthetase (gamma-GCS) as a consequence of Nrf2 inducing. These findings indicated that tBHQ pretreatment conferred protective effect on PC12 cells against NaF-induced apoptotic cell death and oxidation-redox imbalance through stabilization of Nrf2 and elevation of downstream HO-1 and gamma-GCS expressions. PMID- 25911494 TI - Role of adrenomedullin in the cerebrospinal fluid-contacting nucleus in the modulation of immobilization stress. AB - The contribution of the cerebrospinal fluid-contacting nucleus (CSF-contacting nucleus) and adrenomedullin (ADM) to the developmental modulation of stressful events remains controversial. This study explored the effects of endogenous ADM in the CSF-contacting nucleus on immobilization of stress-induced physiological parameter disorders and glucocorticoid hormone releasing hormone (CRH), rat plasma corticosterone expression, and verification of such effects by artificially lowering ADM expression in the CSF-contacting nucleus by targeted ablation of the nucleus. Immunohistochemical experiments showed that ADM-like immunoreactivity and the calcitonin receptor-like receptor (CRLR) marker were localized in the CSF-contacting nucleus. After 7 continuous days of chronic immobilization stress (CIS), animals exhibited anxiety-like behavior. Also, an increase in serum corticosterone, and enhanced expression of ADM in the CSF contacting nucleus were observed, following activation by CIS. The intracerebroventricular (i.c.v.) administration of the ADM receptor antagonist AM22-52 significantly reduced ADM in the CSF-contacting nucleus, additionally, blocked the effects of ADM, meaning the expression of CRH in the hypothalamic paraventricular nucleus (Pa) and serum corticosterone level were increased, and the physiological parameters of the rats became correspondingly deteriorated. Additionally, the i.c.v. administration of cholera toxin subunit B-saporin (CB SAP), a cytotoxin coupled to a cholera toxin subunit, completely eliminated the CSF-contacting nucleus, worsening the reaction of the body to CIS. The collective results demonstrated that ADM acted as a stress-related peptide in the CSF contacting nucleus, and its lower expression and blocked effects in the nucleus contributed to the deterioration of stress-induced physiologic parameter disorders as well as the excessive expressions of stress-related hormones which were part of the hypothalamic-pituitary-adrenal (HPA) axis. PMID- 25911495 TI - HemoVision: An automated and virtual approach to bloodstain pattern analysis. AB - Bloodstain pattern analysis (BPA) is a subspecialty of forensic sciences, dealing with the analysis and interpretation of bloodstain patterns in crime scenes. The aim of BPA is uncovering new information about the actions that took place in a crime scene, potentially leading to a confirmation or refutation of a suspect's statement. A typical goal of BPA is to estimate the flight paths for a set of stains, followed by a directional analysis in order to estimate the area of origin for the stains. The traditional approach, referred to as stringing, consists of attaching a piece of string to each stain, and letting the string represent an approximation of the stain's flight path. Even though stringing has been used extensively, many (practical) downsides exist. We propose an automated and virtual approach, employing fiducial markers and digital images. By automatically reconstructing a single coordinate frame from several images, limited user input is required. Synthetic crime scenes were created and analysed in order to evaluate the approach. Results demonstrate the correct operation and practical advantages, suggesting that the proposed approach may become a valuable asset for practically analysing bloodstain spatter patterns. Accompanying software called HemoVision is currently provided as a demonstrator and will be further developed for practical use in forensic investigations. PMID- 25911496 TI - Simple protocol for extracting diatoms from lung tissues of suspected drowning cases within 3h: First practical application. AB - Conventional acid digestion of tissues for analyzing diatoms obtained from suspected drowning cases is time-consuming, laborious and potentially dangerous. We propose a new protocol for solubilizing lung tissue using only Qiagen Proteinase K, Qiagen Buffer ATL, and 5N hydrochloric acid that can accelerate and simplify diatom extraction from suspected drowning cases. The lower lobe of the right lung (1g, inner region) and the upper lobe of the left lung (1g, peripheral region) of ten immersed victims were digested in 15-mL conical centrifuge tubes containing 9mL of Buffer ATL and 1mL of 20mg/mL Proteinase K solution at 56 degrees C for 15-60min. The digest was washed with ultrapure water and then heated at 70 degrees C for 15min in 5N hydrochloric acid. The acid residue was washed with ultrapure water followed by ethanol. The identification of 60-23,000 valves in 20 lung samples from the ten victims suggested that they had aspirated water before death. The proposed digestive protocol required only a low-speed centrifuge and a block incubator (or water bath) and diatoms could usually be extracted from lung samples within about 3h. Informative results of lung diatom tests were very helpful to confirm drowning as a cause of death. Therefore, the proposed protocol can be useful as a simple minimal test to support or challenge a diagnosis of death by drowning when characteristic autopsy findings of drowning are obvious and the probability of drowning is very high, when characteristic autopsy findings of drowning are absent and the probability of drowning is very low, and when conventional diatom testing is not performed due to logistic, personnel or budgetary limitations. PMID- 25911497 TI - Comparison of effectiveness of different surgical treatments for meralgia paresthetica: Results of a prospective observational study and protocol for a randomized controlled trial. AB - INTRODUCTION: Various surgical procedures can be applied in the treatment of meralgia paresthetica. The two main ones are neurolysis and neurectomy of the lateral femoral cutaneous nerve. To date, no prospective or randomized controlled trial has compared the effectiveness of these procedures with standardized outcome measures. In this study we present our results for two prospectively followed cohorts and we present the protocol for a double blind randomized controlled trial (RCT). METHODS AND ANALYSIS: All patients that had an indication for surgical treatment of idiopathic meralgia paresthetica between August 2012 and April 2014 were included in the study. The patient decided on the type of treatment (neurolysis or neurectomy) after informed consent had been given. Primary outcome was measured using the Likert scale obtained 6 weeks after the surgery. Successful pain reduction was defined as Likert 1 or 2. Secondary outcome measures were the Numeric Rating Scale (NRS) and Bothersomeness Index (BSI). In case of neurectomy the BSI for numbness was also obtained. RESULTS: A total of 22 consecutive patients were included: neurolysis was performed in 8 patients and neurectomy in 14 patients (one bilateral case). Successful pain reduction was observed more frequently after neurectomy (93.3%) than after neurolysis (37.5%, P<0.05). Secondary outcome scores (NRS and BSI pain) were also better after neurectomy, although not significantly (respectively P=0.07 and 0.05). Paired analysis of the scores before and after the surgery showed an improvement in both the NRS and BSI after the neurectomy procedure (both P<0.001), while scores were not significantly different before and after the neurolysis procedure. Patient's scores for the BSI numbness after the neurectomy procedure were low (mean 1.4, SD+/-1.0, range 0-3). DISCUSSION: The results of our prospective study confirm results previous studies reported in the literature in that the percentage pain relief was better after neurectomy than after neurolysis. A RCT is needed to further investigate potential differences in effectiveness. The protocol for such a trial is presented in this article. PMID- 25911498 TI - Hydrogen bond donation to the heme distal ligand of Staphylococcus aureus IsdG tunes the electronic structure. AB - Staphylococcus aureus IsdG catalyzes the final step of staphylococcal iron acquisition from host hemoglobin, whereby host-derived heme is converted to iron and organic products. The Asn7 distal pocket residue is known to be critical for enzyme activity, but the influence of this residue on the substrate electronic structure was unknown prior to this work. Here, an optical spectroscopic and density functional theory characterization of azide- and cyanide-inhibited wild type and N7A IsdG is presented. Magnetic circular dichroism data demonstrate that Asn7 perturbs the electronic structure of azide-inhibited, but not cyanide inhibited, IsdG. As the iron-ligating alpha-atom of azide, but not cyanide, can act as a hydrogen bond acceptor, these data indicate that the terminal amide of Asn7 is a hydrogen bond donor to the alpha-atom of a distal ligand to heme in IsdG. Circular dichroism characterization of azide- and cyanide-inhibited forms of WT and N7A IsdG strongly suggests that the Asn7...N3 hydrogen bond influences the orientation of a distal azide ligand with respect to the heme substrate. Specifically, density functional theory calculations suggest that Asn7...N3 hydrogen bond donation causes the azide ligand to rotate about an axis perpendicular to the porphyrin plane and weakens the pi-donor strength of the azide ligand. This lowers the energies of the Fe 3d xz and 3d yz orbitals, mixes Fe 3d xy and porphyrin a 2u character into the singly-occupied molecular orbital, and results in spin delocalization onto the heme meso carbons. These discoveries have important implications for the mechanism of heme oxygenation catalyzed by IsdG. PMID- 25911499 TI - Impact of acupressure on onset of labour and labour duration: A systematic review. AB - BACKGROUND: There is worldwide concern with increasing rates of pharmacologically induced labour and operative birth. Many women would like to avoid medical or surgical interventions in childbirth; a desire that may contribute towards the popularity of complementary and alternative medicine/therapies. METHOD: This systematic review examines the effects of acupressure on labour onset and duration of labour. We searched MEDLINE, CINAHL, AMED, Cochrane Collaboration, and Science Direct from 1999 to 2013 for published randomised controlled trials and controlled trials comparing acupressure with placebo and no treatment. Studies recruited primiparous and/or multiparous women with either spontaneous or induced onset of labour. The outcome measures were labour onset and duration of all stages of labour. FINDINGS: Seven trials with data reporting on 748 women using different acupressure points and methods of administration were included in the review. One study examined the initiation of labour and six studies examined labour duration and/or pain levels. The two most studied acupoints were Sanyinjiao/Spleen 6 and Hegu/Large Intestine 4. Results suggest acupressure may reduce the length of labour particularly in the first stage. CONCLUSION: Further research is required on whether acupressure can shorten labour duration, augment prolonged labour or initiate onset of labour by stimulating uterine contractions. Clinical trials should report the basis for acupressure treatment described in the STRICTA (minus needling) and CONSORT non-pharmaceutical guidelines. PMID- 25911500 TI - Treatment of Popliteal Aneurysm by Open and Endovascular Surgery: A Contemporary Study of 592 Procedures in Sweden. AB - BACKGROUND: Popliteal aneurysm (PA) is traditionally treated by open repair (OR). Endovascular repair (ER) has become more common. The aim was to describe time trends and compare results (OR/ER). METHODS: The Swedish vascular registry, Swedvasc, has a specific PA module. Data were collected (2008-2012) and supplemented with a specific protocol (response rate 99.1%). Data were compared with previously published data (1994-2002) from the same database. RESULTS: The number of operations for PA was 15.7/million person-years (8.3 during 1994-2001). Of 592 interventions for PA (499 patients), 174 (29.4%) were treated for acute ischaemia, 13 (2.2%) for rupture, 105 (17.7%) for other symptoms, and 300 (50.7%) were asymptomatic (31.5% were treated for acute ischaemia, 1994-2002, p = .58). There were no differences in background characteristics between OR and ER in the acute ischaemia group. The symptomatic and asymptomatic groups treated with ER were older (p = .006, p < .001). ER increased 3.6 fold (4.7% 1994-2002, 16.7% 2008-2012, p = .0001). Of those treated for acute ischaemia, a stent graft was used in 27 (16.4%). Secondary patency after ER was 70.4% at 30 days and 47.6% at 1 year, versus 93.1% and 86.8% after OR (p = .001, <.001). The amputation rate at 30 days was 14.8% after ER, 3.7% after OR (p = .022), and 17.4% and 6.8% at 1 year (p = .098). A stent graft was used in 18.3% for asymptomatic PA. Secondary patency after ER was 94.5% at 30 days and 83.7% at 1 year, compared with 98.8% and 93.5% after OR (p = .043 and 0.026). OR was performed with vein graft in 87.6% (395/451), with better primary and secondary patency at 1 year than prosthetic grafts (p = .002 and <.001), and with a posterior approach in 20.8% (121/581). CONCLUSIONS: The number of operations for PA doubled while the indications remained similar. ER patency was inferior to OR, especially after treatment for acute ischaemia, and the amputation risk tended to be higher, despite similar pre-operative characteristics. PMID- 25911501 TI - Safety of instrumentation and fusion at the time of surgical debridement for spinal infection. AB - The present study aims to assess the results of single-stage instrumentation and fusion at the time of surgical debridement of spinal infections; vertebral osteomyelitis or epidural abscess. Nine patients with spinal infection were treated with instrumentation and fusion after radical debridement in a single stage operation. Predisposing factors and comorbidities, pain, American Spinal Injury Association motor scores, primary pathologies, microbiology and perioperative markers were recorded. Seven patients with pyogenic and two with tuberculous spinal infection were encountered; the most common pathogen was Staphylococcus aureus. Five patients were predisposed to infection because of diabetes mellitus. Duration of antibiotic therapy lasted up to 12 months. Six patients had thoracic infection, two lumbar and one cervical. No post-operative complications were encountered. There was a significant reduction in pain scores compared to pre-operatively. All patients with neurological deficits improved post-operatively. Despite introduction of hardware, no patients had a recurrence of their infection in the 12 month follow up period. Single-stage debridement and instrumentation appeared to be a safe and effective method of managing spinal infections. The combination of debridement and fusion has the dual benefit of removing a focus of infection and stabilising the spine. The current series confirms that placing titanium cages into an infected space is safe in a majority of patients. Stabilisation and correction of spinal deformity reduces pain, aids neurologic recovery and improves quality of life. The small patient population and retrospective nature limit the present study. PMID- 25911502 TI - Decreased dopaminergic treatment of hospitalized Parkinson's disease patients during infectious diseases is associated with poor outcomes. AB - A retrospective analysis of consecutive Parkinson's disease (PD) patients hospitalized in internal medicine wards during the years 2008 to 2013 due to infectious disease was performed. PD patients are prone to infections, often leading to hospitalization in internal medicine wards. We observed that during these hospitalizations, chronic anti-Parkinson's medications are frequently overlooked and withdrawn, their reintroduction is delayed and dosages are decreased. Only patients on chronic therapy with at least one anti-Parkinson's medication were included in this study. Multivariate analyses established the association between medication dose reductions on short-term clinical outcomes, including in-hospital mortality and change in discharge destination. Medical records from 528 PD patients were analyzed and 430 were excluded. Of the 98 included, 53 had pneumonia and 58 had urinary tract infections. The overall in hospital mortality rate was 11.2%. 56.1% of patients' dopaminergic medications were decreased in dose upon admission (22.5% mean decrease in levodopa equivalent daily dose [LEDD]; p<0.001). Both absolute and relative LEDD reductions were associated with significantly increased in-hospital mortality (mean reduction of 394.5 mg versus 188.4 mg; p=0.035 by analysis of variance adjusted to age, sex and renal function) and was also associated with worse discharge destination relative to original place of arrival (mean reduction of 377.8 mg versus 150.7 mg; p=0.014). Decreased dopaminergic medication dosing upon admission of PD patients due to infection is widespread and potentially associated with worse clinical outcomes. PMID- 25911503 TI - Paradoxical topiramate-induced hyperphagia successfully treated with phentermine in a woman with migraine. AB - We report a 49-year-old female migraineur who experienced paradoxical hyperphagia and concurrent intrusive food thoughts leading to rapid weight gain and a substantial increase in waist circumference. A significant reduction in migraine frequency was also observed during topiramate treatment, a widely used migraine prophylactic agent which is generally associated with weight loss. Withdrawal of topiramate saw appetite return to baseline levels, however, migraine frequency was again increased. Topiramate was reinitiated in combination with phentermine, a drug indicated for weight management, without reoccurrence of adverse effects. Migraine control was maintained and progressive weight loss ensued. Combination treatment with phentermine may be a useful strategy should other patients experience this adverse reaction while gaining therapeutic anti-migraine benefit from topiramate. PMID- 25911504 TI - Living with joint hypermobility syndrome: patient experiences of diagnosis, referral and self-care. AB - BACKGROUND: Musculoskeletal problems are common reasons for seeking primary health care. It has been suggested that many people with 'everyday' non inflammatory musculoskeletal problems may have undiagnosed joint hypermobility syndrome (JHS), a complex multi-systemic condition. JHS is characterized by joint laxity, pain, fatigue and a wide range of other symptoms. Physiotherapy is usually the preferred treatment option for JHS, although diagnosis can be difficult. The lived experience of those with JHS requires investigation. OBJECTIVE: The aim of the study was to examine patients' lived experience of JHS, their views and experiences of JHS diagnosis and management. METHODS: Focus groups in four locations in the UK were convened, involving 25 participants with a prior diagnosis of JHS. The focus groups were audio recorded, fully transcribed and analysed using the constant comparative method to inductively derive a thematic account of the data. RESULTS: Pain, fatigue, proprioception difficulties and repeated cycles of injury were among the most challenging features of living with JHS. Participants perceived a lack of awareness of JHS from health professionals and more widely in society and described how diagnosis and access to appropriate health-care services was often slow and convoluted. Education for patients and health professionals was considered to be essential. CONCLUSIONS: Timely diagnosis, raising awareness and access to health professionals who understand JHS may be particularly instrumental in helping to ameliorate symptoms and help patients to self-manage their condition. Physiotherapists and other health professionals should receive training to provide biopsychosocial support for people with this condition. PMID- 25911505 TI - Inappropriate antibiotic prescription for respiratory tract indications: most prominent in adult patients. AB - BACKGROUND: Numerous studies suggest overprescribing of antibiotics for respiratory tract indications (RTIs), without really authenticating inappropriate prescription; the strict criteria of guideline recommendations were not taken into account as information on specific diagnoses, patient characteristics and disease severity was not available. OBJECTIVE: The aim of this study is to quantify and qualify inappropriate antibiotic prescribing for RTIs. METHODS: This is an observational study of the (antibiotic) management of patients with RTIs, using a detailed registration of RTI consultations by general practitioners (GPs). Consultations of which all necessary information was available were benchmarked to the prescribing guidelines for acute otitis media (AOM), acute sore throat, rhinosinusitis or acute cough. Levels of overprescribing for these indications and factors associated with overprescribing were determined. RESULTS: The overall antibiotic prescribing rate was 38%. Of these prescriptions, 46% were not indicated by the guidelines. Relative overprescribing was highest for throat (including tonsillitis) and lowest for ear consultations (including AOM). Absolute overprescribing was highest for lower RTIs (including bronchitis). Overprescribing was highest for patients between 18 and 65 years of age, when GPs felt patients' pressure for an antibiotic treatment, for patients presenting with fever and with complaints longer than 1 week. Underprescribing was observed in <4% of the consultations without a prescription. CONCLUSION: Awareness of indications and patient groups provoking antibiotic overprescribing can help in the development of targeted strategies to improve GPs' prescribing routines for RTIs. PMID- 25911506 TI - Psychosocial, musculoskeletal and somatoform comorbidity in patients with chronic low back pain: original results from the Dutch Transition Project. AB - BACKGROUND: Better insight into frequent comorbidities in patients with chronic (>= 3 months) low back pain (LBP) may help general practitioners when planning comprehensive care for these patients. OBJECTIVE: To prospectively study the prevalence of psychological, social, musculoskeletal and somatoform disorders in patients presenting with chronic non-specific LBP to general practitioners, in comparison to a contrast group of patients consulting in the same setting. METHODS: This case-control study is embedded in a historical cohort, based on a primary care practice-based research network. All the health problems presented by the patients were prospectively coded according to the international classification of primary care between 1996 and 2013. The prevalence of psychological, social, musculoskeletal and somatoform disorders presented by the adult patients from 1 year before the onset of chronic LBP to 2 years after onset was compared to that of matched patients consulting without LBP, using conditional logistic regressions. RESULTS: The 1511 patients with chronic LBP more often presented musculoskeletal disorders than the contrast group during the year before the onset of LBP and during the second year after it, with odds ratios (95%confidence intervals) of 1.39 (1.20-1.61) and 1.56 (1.35-1.81), respectively. They did not more often present psychological, social or non musculoskeletal somatoform disorders. CONCLUSIONS: General practitioners should consider all the musculoskeletal symptoms when caring for patients with chronic LBP. Rather than systematically screening for specific psychological, social or somatoform disorders, they should consider with the patient how LBP and any type of potential comorbidity interfere with his/her daily functioning. PMID- 25911507 TI - An abyssal mobilome: viruses, plasmids and vesicles from deep-sea hydrothermal vents. AB - Mobile genetic elements (MGEs) such as viruses, plasmids, vesicles, gene transfer agents (GTAs), transposons and transpovirions, which collectively represent the mobilome, interact with cellular organisms from all three domains of life, including those thriving in the most extreme environments. While efforts have been made to better understand deep-sea vent microbial ecology, our knowledge of the mobilome associated with prokaryotes inhabiting deep-sea hydrothermal vents remains limited. Here we focus on the abyssal mobilome by reviewing accumulating data on viruses, plasmids and vesicles associated with thermophilic and hyperthermophilic Bacteria and Archaea present in deep-sea hydrothermal vents. PMID- 25911508 TI - Expanding MYCN's reach in oncogenic transcription. PMID- 25911509 TI - The beginning of the end: vaccine prevention of HPV-driven cancers. PMID- 25911510 TI - Trends in Adenoma Detection Rates During the First 10 Years of the German Screening Colonoscopy Program. AB - BACKGROUND & AIMS: The adenoma detection rate (ADR) is an important quality indicator of screening colonoscopy; it is inversely associated with risk of interval cancers and colorectal cancer mortality. We assessed trends in the ADR in the first 10 years of the German screening colonoscopy program. METHODS: We calculated age-adjusted and age-specific detection rates of nonadvanced adenomas and advanced adenomas for each calendar year based on 4.4 million screening colonoscopies conducted from 2003 through 2012 and reported to the German screening colonoscopy registry. RESULTS: We observed a steady and strong increase in rate of detection of nonadvanced adenomas in both sexes and all age groups. Age-adjusted rates of detection of nonadvanced adenomas increased from 13.3% to 22.3% among men and from 8.4% to 14.9% among women. This increase was mostly due to an increase in detection rates of adenomas <0.5 cm, and it is partly explained by an innovation effect (higher ADRs among incoming colonoscopists than among leaving colonoscopists, and relatively stable ADRs among continuing colonoscopists). Only modest increases were observed in detection rates of advanced adenomas (from 7.4% to 9.0% among men, and from 4.4% to 5.2% among women) and colorectal cancer. In 2012, overall ADR reached 31.3% and 20.1% in men and women, respectively. CONCLUSIONS: We observed a strong increase in ADRs from 2003 through 2012 in Germany. Although we cannot exclude the effects of secular trends in colorectal neoplasm prevalence, the observed increase was mainly the result of a steady increase in detection of nonadvanced adenomas (especially adenomas <0.5 cm). Further research should address potential implications for defining screening and surveillance intervals. PMID- 25911512 TI - Response to the Letter from Robert A. Zorowitz, "Intravenous and subcutaneous infusions in nursing homes". PMID- 25911511 TI - Quantification and Potential Functions of Endogenous Agonists of Transient Receptor Potential Channels in Patients With Irritable Bowel Syndrome. AB - BACKGROUND & AIMS: In mice, activation of the transient receptor potential cation channels (TRP) TRPV1, TRPV4, and TRPA1 causes visceral hypersensitivity. These receptors and their agonists might be involved in development of irritable bowel syndrome (IBS). We investigated whether polyunsaturated fatty acid (PUFA) metabolites, which activate TRPs, are present in colon tissues from patients with IBS and act as endogenous agonists to induce hypersensitivity. METHODS: We analyzed colon biopsy samples from 40 patients with IBS (IBS biopsies) and 11 healthy individuals undergoing colorectal cancer screening (controls), collected during colonoscopy at the University of Bologna, Italy. Levels of the PUFA metabolites that activate TRPV1 (12-hydroperoxyeicosatetraenoic acid, 15 hydroxyeicosatetraenoic acid, 5-hydroxyeicosatetraenoic acid, and leukotriene B4), TRPV4 (5,6-epoxyeicosatrienoic acid [EET] and 8,9-EET), and TRPA1 (PGA1, 8 iso-prostaglandin A2, and 15-deoxy-Delta-prostaglandin J2) were measured in biopsies and their supernatants using liquid chromatography and tandem mass spectrometry; we also measured levels of the PUFA metabolites prostaglandin E2 (PGE2) and resolvins. C57Bl6 mice were given intrathecal injections of small interfering RNAs to reduce levels of TRPV4, or control small interfering RNAs, along with colonic injections of biopsy supernatants; visceral hypersensitivity was measured based on response to colorectal distension. Mouse sensory neurons were cultured and incubated with biopsy supernatants and lipids extracted from biopsies or colons of mice. Immunohistochemistry was used to detect TRPV4 in human dorsal root ganglia samples (from the National Disease Research Interchange). RESULTS: Levels of the TRPV4 agonist 5,6-EET, but not levels of TRPV1 or TRPA1 agonists, were increased in IBS biopsies compared with controls; increases correlated with pain and bloating scores. Supernatants from IBS biopsies, but not from controls, induced visceral hypersensitivity in mice. Small interfering RNA knockdown of TRPV4 in mouse primary afferent neurons inhibited the hypersensitivity caused by supernatants from IBS biopsies. Levels of 5,6-EET and 15-HETE were increased in colons of mice with, but not without, visceral hypersensitivity. PUFA metabolites extracted from IBS biopsies or colons of mice with visceral hypersensitivity activated mouse sensory neurons in vitro, by activating TRPV4. Mouse sensory neurons exposed to supernatants from IBS biopsies produced 5,6-EET via a mechanism that involved the proteinase-activated receptor 2 and cytochrome epoxygenase. In human dorsal root ganglia, TPV4 was expressed by 35% of neurons. CONCLUSIONS: Colon tissues from patients with IBS have increased levels of specific PUFA metabolites. These stimulate sensory neurons from mice and generate visceral hypersensitivity via activation of TRPV4. PMID- 25911513 TI - Aarskog-Scott syndrome presenting with psychosis: A case study. PMID- 25911514 TI - Retaining Hispanic Dietetic Undergraduate Students through Mentoring and Professional Development. PMID- 25911515 TI - Global food practices, cultural competency, and dietetics. PMID- 25911517 TI - Global food practices, cultural competency, and dietetics: part 3. PMID- 25911516 TI - Global food practices, cultural competency, and dietetics: part 2. PMID- 25911518 TI - Role of Registered Dietitian Nutritionists in the Research and Promotion of Native and Cultural Foods. PMID- 25911519 TI - Maternal Attitudes and Behaviors Regarding Feeding Practices in Elementary School Aged Latino Children: A Pilot Qualitative Study on the Impact of the Cultural Role of Mothers in the US-Mexican Border Region of San Diego, California. AB - This study aimed to explore the attitudes and behaviors of Latino mothers around feeding their children. Using qualitative methods, we conducted four focus groups in Spanish with 41 Latino mothers of elementary school-age children in San Diego County, CA. Latino mothers' mean age was 41 years; 90% were foreign-born; and 74% had a high school education or less. We explored cultural viewpoints around feeding and cooking and feeding strategies used. Focus groups were analyzed based on a priori and emergent themes. The following themes around feeding emerged: feeding attitudes central to the maternal responsibility of having well-fed children and feeding behaviors that centered on cooking methods, supportive behaviors, and reinforcement strategies for "eating well." These findings increase our understanding of the Latino maternal role to feed children and can help to inform more culturally appropriate research to effectively address nutritional issues and obesity prevention in Latino children. PMID- 25911520 TI - !Cocinar Para Su Salud!: Randomized Controlled Trial of a Culturally Based Dietary Intervention among Hispanic Breast Cancer Survivors. AB - BACKGROUND: There is a need for culturally relevant nutrition programs targeted to underserved cancer survivors. OBJECTIVE: Our aim was to examine the effect of a culturally based approach to dietary change on increasing fruit/vegetable (F/V) intake and decreasing fat intake among Hispanic breast cancer survivors. DESIGN: Participants were randomized to Intervention and Control groups. Diet recalls, detailed interviews, fasting blood, and anthropometric measures were collected at baseline, 3, 6, and 12 months. PARTICIPANTS/SETTING: Hispanic women (n=70) with stage 0 to III breast cancer who completed adjuvant treatment and lived in New York City were randomized between April 2011 and March 2012. INTERVENTION: The Intervention group (n=34) participated in !Cocinar Para Su Salud!, a culturally based nine-session (24 hours over 12 weeks) intervention including nutrition education, cooking classes, and food-shopping field trips. The Control group (n=36) received written dietary recommendations for breast cancer survivors. MAIN OUTCOME MEASURES: Change at 6 months in daily F/V servings and percent calories from total fat were the main outcome measures. STATISTICAL ANALYSES: Linear regression models adjusted for stratification factors and estimated marginal means were used to compare changes in diet from baseline to 3 and 6 months. RESULTS: Baseline characteristics were the following: mean age 56.6 years (standard deviation 9.7 years), mean time since diagnosis 3.4 years (standard deviation 2.7 years), mean body mass index (calculated as kg/m(2)) 30.9 (standard deviation 6.0), 62.9% with annual household income <=$15,000, mean daily servings of all F/V was 5.3 (targeted F/V 3.7 servings excluding legumes/juices/starchy vegetables/fried foods), and 27.7% of daily calories from fat. More than 60% in the Intervention group attended seven or more of nine classes, with overall study retention of 87% retention at 6 months. At month 6, the Intervention group compared with Control group reported an increase in mean servings of F/V from baseline (all F/V: +2.0 vs -0.1; P=0.005; targeted F/V: +2.7 vs +0.5; P=0.002) and a nonsignificant decrease in percent calories from fat (-7.5% vs -4.4%; P=0.23) and weight (-2.5 kg vs +3.8 kg; P=0.22). CONCLUSIONS: !Cocinar Para Su Salud! was effective at increasing short-term F/V intake in a diverse population of Hispanic breast cancer survivors. PMID- 25911521 TI - Think globally, practice locally: culturally competent dietetics. PMID- 25911522 TI - Perspectives of cultural competency from an international service learning project. PMID- 25911523 TI - A comparison of remote therapy, face to face therapy and an attention control intervention for people with aphasia: a quasi-randomised controlled feasibility study. AB - OBJECTIVE: To test the feasibility of a randomised controlled trial comparing face to face and remotely delivered word finding therapy for people with aphasia. DESIGN: A quasi-randomised controlled feasibility study comparing remote therapy delivered from a University lab, remote therapy delivered from a clinical site, face to face therapy and an attention control condition. SETTING: A University lab and NHS outpatient service. PARTICIPANTS: Twenty-one people with aphasia following left hemisphere stroke. INTERVENTIONS: Eight sessions of word finding therapy, delivered either face to face or remotely, were compared to an attention control condition comprising eight sessions of remotely delivered supported conversation. The remote conditions used mainstream video conferencing technology. OUTCOME MEASURES: Feasibility was assessed by recruitment and attrition rates, participant observations and interviews, and treatment fidelity checking. Effects of therapy on word retrieval were assessed by tests of picture naming and naming in conversation. RESULTS: Twenty-one participants were recruited over 17 months, with one lost at baseline. Compliance and satisfaction with the intervention was good. Treatment fidelity was high for both remote and face to face delivery (1251/1421 therapist behaviours were compliant with the protocol). Participants who received therapy improved on picture naming significantly more than controls (mean numerical gains: 20.2 (remote from University); 41 (remote from clinical site); 30.8 (face to face); 5.8 (attention control); P <.001). There were no significant differences between groups in the assessment of conversation. CONCLUSIONS: Word finding therapy can be delivered via mainstream internet video conferencing. Therapy improved picture naming, but not naming in conversation. PMID- 25911524 TI - Evaluation of 3D cognitive fatigue using heart-brain synchronization. AB - The purpose of this study was to identify an evaluation method for 3D cognitive fatigue based on a heart-brain synchronization phenomenon known as the heartbeat evoked potential (HEP). Thirty undergraduate students (15 females) watched a video in both 2D and 3D for an hour. Because visual fatigue is related to cognitive load, the HEP was used as an indicator of communication between the heart and the brain and therefore of cognitive function; responses were compared after 2D and 3D viewing. At the standard EEG sites F3 and F4, the alpha activity of the first and second HEP components was significantly increased after 3D video viewing relative to 2D. This increase likely indicates that sensory input from 3D video requires heavy computation by the brain, stimulating heart activity. The conclusion is that the first and second HEP components are significant parameters that can quantitatively evaluate 3D visual fatigue. Further work is needed to uncover the cause of 3D visual fatigue. PMID- 25911525 TI - Will targeting oropharyngeal gonorrhoea delay the further emergence of drug resistant Neisseria gonorrhoeae strains? AB - Gonorrhoea is an important sexually transmitted infection associated with serious complications and enhanced HIV transmission. Oropharyngeal infections are often asymptomatic and will only be detected by screening. Gonococcal culture has low sensitivity (<50%) for detecting oropharyngeal gonorrhoea, and, although not yet approved commercially, nucleic acid amplification tests (NAAT) are the assay of choice. Screening for oropharyngeal gonorrhoea should be performed in high-risk populations, such as men-who-have-sex-with-men(MSM). NAATs have a poor positive predictive value when used in low-prevalence populations. Gonococci have repeatedly thwarted gonorrhoea control efforts since the first antimicrobial agents were introduced. The oropharyngeal niche provides an enabling environment for horizontal transfer of genetic material from commensal Neisseria and other bacterial species to Neisseria gonorrhoeae. This has been the mechanism responsible for the generation of mosaic penA genes, which are responsible for most of the observed cases of resistance to extended-spectrum cephalosporins (ESC). As antimicrobial-resistant gonorrhoea is now an urgent public health threat, requiring improved antibiotic stewardship, laboratory-guided recycling of older antibiotics may help reduce ESC use. Future trials of antimicrobial agents for gonorrhoea should be powered to test their efficacy at the oropharynx as this is the anatomical site where treatment failure is most likely to occur. It remains to be determined whether a combination of frequent screening of high-risk individuals and/or laboratory-directed fluoroquinolone therapy of oropharyngeal gonorrhoea will delay the further emergence of drug-resistant N. gonorrhoeae strains. PMID- 25911527 TI - Safety of new oral anticoagulants. PMID- 25911526 TI - Risk of gastrointestinal bleeding associated with oral anticoagulants: population based retrospective cohort study. AB - OBJECTIVES: To determine the real world safety of dabigatran or rivaroxaban compared with warfarin in terms of gastrointestinal bleeding. DESIGN: Retrospective cohort study. SETTING: Large administrative database of commercially insured people in United States from 1 October 2010 through 31 March 2012. PARTICIPANTS: Enrollees with a prescription of warfarin, dabigatran, or rivaroxaban between 1 October 2010 and 31 March 2012, who were aged 18 years or older, had continuous enrollment and no oral anticoagulant use during the six months before the entry date, with known age and sex, and with no gastrointestinal bleeding for at least six months before the cohort entry date. The final study sample of 46,163 patients included 4907 using dabigatran, 1649 using rivaroxaban, and 39,607 using warfarin. MAIN OUTCOME MEASURE: Time to gastrointestinal bleeding. Hazard ratios were derived from Cox proportional hazard models with propensity score weighting and robust estimates of errors. RESULTS: Dabigatran users tended to be older (dabigatran v rivaroxaban v warfarin: 62.0 v 57.6 v 57.4 years) and more likely to be male (69% v 49% v 53%). The rate of gastrointestinal bleeding was highest among dabigatran users and lowest among rivaroxaban users (dabigatran v rivaroxaban v warfarin: 9.01 v 3.41 v 7.02 cases per 100 person years). After adjustment for potentially confounding covariates, there was no evidence of a statistically significant difference in the risk of gastrointestinal bleeding between dabigatran and warfarin users (adjusted hazard ratio 1.21, 95% confidence interval 0.96 to 1.53) or between rivaroxaban and warfarin users (0.98, 0.36 to 2.69). CONCLUSIONS: Although rates of gastrointestinal bleeding seem to be similar in this commercially insured sample of adults in the United States, we cannot rule out as much as a 50% increase in the risk of gastrointestinal bleeding with dabigatran compared with warfarin or a more than twofold higher risk of bleeding with rivaroxaban compared with warfarin. PMID- 25911528 TI - Workers' health protection still poor two years after factory collapse in Bangladesh. PMID- 25911529 TI - Environmental control of branching in petunia. AB - Plants alter their development in response to changes in their environment. This responsiveness has proven to be a successful evolutionary trait. Here, we tested the hypothesis that two key environmental factors, light and nutrition, are integrated within the axillary bud to promote or suppress the growth of the bud into a branch. Using petunia (Petunia hybrida) as a model for vegetative branching, we manipulated both light quality (as crowding and the red-to-far-red light ratio) and phosphate availability, such that the axillary bud at node 7 varied from deeply dormant to rapidly growing. In conjunction with the phenotypic characterization, we also monitored the state of the strigolactone (SL) pathway by quantifying SL-related gene transcripts. Mutants in the SL pathway inhibit but do not abolish the branching response to these environmental signals, and neither signal is dominant over the other, suggesting that the regulation of branching in response to the environment is complex. We have isolated three new putatively SL related TCP (for Teosinte branched1, Cycloidia, and Proliferating cell factor) genes from petunia, and have identified that these TCP-type transcription factors may have roles in the SL signaling pathway both before and after the reception of the SL signal at the bud. We show that the abundance of the receptor transcript is regulated by light quality, such that axillary buds growing in added far-red light have greatly increased receptor transcript abundance. This suggests a mechanism whereby the impact of any SL signal reaching an axillary bud is modulated by the responsiveness of these cells to the signal. PMID- 25911531 TI - Renal involvement in the immunodysregulation, polyendocrinopathy, enteropathy, X linked (IPEX) disorder. AB - BACKGROUND: Immunodysregulation, polyendocrinopathy, enteropathy, X-linked (IPEX) disorder is an autoimmune disease caused by loss-of-function mutations in the gene encoding the forkhead box P3 (FOXP3) transcription factor. These mutations affect the normal function of circulating regulatory T cells. IPEX is characterized by profound immune dysregulation leading to dermatitis, enteropathy, multiple endocrinopathies and failure to thrive. Different forms of renal injury have also been noted in these patients but these have been described to a very limited extent. CASE-DIAGNOSIS: Three patients with IPEX with characteristic renal findings and mutations in FOXP3, including one novel mutation, are described. Case presentations are followed by a review of the renal manifestations noted in IPEX and the range of therapeutic options for this disorder. CONCLUSIONS: We recommend that IPEX be considered in the differential diagnosis of young children who present with signs of immune dysregulation with a concomitant renal biopsy demonstrating immune complex deposition in a membranous like pattern and/or interstitial nephritis. PMID- 25911530 TI - Posttranslational Modifications of Chloroplast Proteins: An Emerging Field. AB - Posttranslational modifications of proteins are key effectors of enzyme activity, protein interactions, targeting, and turnover rate, but despite their importance, they are still poorly understood in plants. Although numerous reports have revealed the regulatory role of protein phosphorylation in photosynthesis, various other protein modifications have been identified in chloroplasts only recently. It is known that posttranslational N(alpha)-acetylation occurs in both nuclear- and plastid-encoded chloroplast proteins, but the physiological significance of this acetylation is not yet understood. Lysine acetylation affects the localization and activity of key metabolic enzymes, and it may work antagonistically or cooperatively with lysine methylation, which also occurs in chloroplasts. In addition, tyrosine nitration may help regulate the repair cycle of photosystem II, while N-glycosylation determines enzyme activity of chloroplastic carbonic anhydrase. This review summarizes the progress in the research field of posttranslational modifications of chloroplast proteins and points out the importance of these modifications in the regulation of chloroplast metabolism. PMID- 25911532 TI - Interest and limits of endoscopic approaches for pineal region tumours. AB - Endoscopy of pineal region tumours has been developed since the year 2000 either via a transventricular or extracerebral approach. The initial purpose of applying neuroendoscopy in the management of pineal region tumours was to resolve the obstructive hydrocephalus, and identify the pathological characteristics of the tumour. Based on this approach, a piecemeal resection of the tumour can be performed. The approaches, derived from the microsurgical pathway using an endoscope to expose the operative field, have been proposed either via an infratentorial supracerebellar approach or posterior transtentorial interhemispheric approach. Neuroendoscopic procedures can be considered as a therapeutic alternative to the microsurgical approach when CSF markers are negative. This procedure is considered mini-invasive for the approach along the surgical corridor access but extensive and in depth at the interface between the tumour and the surrounding neurological parenchyma. The limitations and complications are related to the type of procedure (mono- or bimanual) as well as the tumoral characteristics. Different approaches are presented in detail in order to avoid the occurrence of any surgical complications. PMID- 25911533 TI - A novel subgroup 16SrVII-D phytoplasma identified in association with Erigeron witches' broom. AB - Erigeron sp. plants showing symptoms of witches' broom and stunting were found near orchards of passion fruit in Sao Paulo state, Brazil. These symptoms were indicative of infection by phytoplasmas. Thus, the aim of this study was to detect and identify possible phytoplasmas associated with diseased plants. Total DNA was extracted from symptomatic and asymptomatic plants and used in nested PCR conducted with the primer pairs P1/Tint and R16F2n/16R2. Amplification of genomic fragments of 1.2 kb from the 16S rRNA gene confirmed the presence of phytoplasma in all symptomatic samples. The sequence identity scores between the 16S rRNA gene of the phytoplasma strain identified in the current study and those of previously reported 'Candidatus Phytoplasma fraxini'-related strains ranged from 98% to 99% indicating the phytoplasma to be a strain affiliated with 'Candidatus Phytoplasma fraxini'. The results from a phylogenetic analysis and virtual RFLP analysis of the 16S rRNA gene sequence with 17 restriction enzymes revealed that the phytoplasma strain belongs to the ash yellows phytoplasma group (16SrVII); the similarity coefficient of RFLP patterns further suggested that the phytoplasma represents a novel subgroup, designated 16SrVII-D. The representative of this new subgroup was named EboWB phytoplasma (Erigeron bonariensis Witches' Broom). PMID- 25911534 TI - Isaria takamizusanensis is the anamorph of Cordyceps ryogamimontana, warranting a new combination, Purpureocillium takamizusanense comb. nov. AB - The entomogenous anamorphic fungus Isaria takamizusanensis has not been resolved clearly in its teleomorphic state. We succeeded in inducing ascostroma formation by incubating conidiomata of I. takamizusanensis on cicada adults in a moist chamber. We observed the ascostroma and conducted a phylogenetic analysis based on ITS rDNA and EF-1alpha genes. The morphology of the ascostroma was identical to that of Cordyceps ryogamimontana. In the phylogenetic tree inferred from EF 1alpha, the isolate from the partspores grouped with nine strains derived from conidia of I. takamizusanensis, which was distinct from a clade including Purpureocillium lilacinum. Moreover, a conidial structure identical to that of I. takamizusanensis was rediscovered on the holotype specimen of C. ryogamimontana. As a result, we propose a new name, Purpureocillium takamizusanense, which is a combination of the teleomorph-anamorph connection of C. ryogamimontana-I. takamizusanensis, in accordance with the 'one fungus, one name' concept of the International Code of Nomenclature for Algae, Fungi, and Plants (ICN). PMID- 25911535 TI - Erythrobacter luteus sp. nov., isolated from mangrove sediment. AB - A Gram-staining-negative, orange-pigmented, aerobic bacterial strain, designated KA37T, was isolated from a mangrove sediment sample collected from Yunxiao mangrove National Nature Reserve, Fujian Province, China. Growth was observed at 4-37 degrees C, 0-3% (w/v) NaCl and pH 5-10. Mg2+ ions were required for growth. Phylogenetic analysis based on 16S rRNA gene sequencing revealed that the isolate was a member of the genus Erythrobacter, which belongs to the family Erythrobacteraceae. Strain KA37T was most closely related to Erythrobacter gangjinensis KCTC 22330T (96.9% sequence similarity), followed by Erythrobacter marinus KCTC 23554T (96.8%); similarity to other members of the genus was below 96.6%. The major fatty acids were C17 : 1omega6c, summed feature 3 (C16 : 1omega7c and/or C16 : 1omega6c) and summed feature 8 (C18 : 1omega7c and/or C18 : 1omega6c). Strain KA37T did not produce bacteriochlorophyll a. The predominant respiratory quinone was ubiquinone 10 (Q-10). The polar lipids of strain KA37T were sphingoglycolipid, phosphatidylglycerol, diphosphatidylglycerol, phosphatidylethanolamine, phosphatidylcholine, five unknown lipids and one unidentified phospholipid. According to its morphology, physiology, fatty acid composition and 16S rRNA sequence, the novel strain most appropriately belongs to the genus Erythrobacter, but can be distinguished readily from species of the genus Erythrobacter with validly published names. The name Erythrobacter luteus sp. nov. is proposed, with strain KA37T ( = MCCC 1F01227T = KCTC 42179T) as the type strain. PMID- 25911536 TI - Bullera vrieseae sp. nov., a tremellaceous yeast species isolated from bromeliads. AB - Two independent surveys of yeasts associated with different bromeliads in different Brazilian regions led to the proposal of a novel yeast species, Bullera vrieseae sp. nov., belonging to the Tremellales clade (Agaricomycotina, Basidiomycota). Analysis of the sequences in the internal transcribed spacer (ITS) region and D1/D2 domain of the LSU rRNA gene suggested affinity to a phylogenetic lineage that includes Bullera miyagiana and Bullera sakaeratica. Six isolates of the novel species were obtained from different bromeliads and regions in Brazil. Sequence analysis of the D1/D2 domains of the large subunit of the rRNA gene showed that the novel species differs from B. miyagiana and B. sakaeratica by 85 and 64 nt substitutions, respectively and by more than 75 nt substitutions in the ITS region. Phenotypically, Bullera vrieseae sp. nov. can be distinguished from both species based on the assimilation of meso-erythritol, which was negative for B. vrieseae sp. nov. but positive for the others, assimilation of d-glucosamine, which was positive for B. vrieseae sp. nov. but negative for B. miyagiana and of l-sorbose, which was negative for B. vrieseae sp. nov. but positive for B. sakaeratica. The novel species Bullera vrieseae sp. nov. is proposed to accommodate these isolates. The type strain of Bullera vrieseae sp. nov. is UFMG-CM-Y379T (BRO443T; ex-type CBS 13870T). PMID- 25911537 TI - Exploring the Use of Cost-Benefit Analysis to Compare Pharmaceutical Treatments for Menorrhagia. AB - BACKGROUND: The extra-welfarist theoretical framework tends to focus on health related quality of life, whilst the welfarist framework captures a wider notion of well-being. EQ-5D and SF-6D are commonly used to value outcomes in chronic conditions with episodic symptoms, such as heavy menstrual bleeding (clinically termed menorrhagia). Because of their narrow-health focus and the condition's periodic nature these measures may be unsuitable. A viable alternative measure is willingness to pay (WTP) from the welfarist framework. OBJECTIVE: We explore the use of WTP in a preliminary cost-benefit analysis comparing pharmaceutical treatments for menorrhagia. METHODS: A cost-benefit analysis was carried out based on an outcome of WTP. The analysis is based in the UK primary care setting over a 24-month time period, with a partial societal perspective. Ninety-nine women completed a WTP exercise from the ex-ante (pre-treatment/condition) perspective. Maximum average WTP values were elicited for two pharmaceutical treatments, levonorgestrel-releasing intrauterine system (LNG-IUS) and oral treatment. Cost data were offset against WTP and the net present value derived for treatment. Qualitative information explaining the WTP values was also collected. RESULTS: Oral treatment was indicated to be the most cost-beneficial intervention costing L107 less than LNG-IUS and generating L7 more benefits. The mean incremental net present value for oral treatment compared with LNG-IUS was L113. The use of the WTP approach was acceptable as very few protests and non responses were observed. CONCLUSION: The preliminary cost-benefit analysis results recommend oral treatment as the first-line treatment for menorrhagia. The WTP approach is a feasible alternative to the conventional EQ-5D/SF-6D approaches and offers advantages by capturing benefits beyond health, which is particularly relevant in menorrhagia. PMID- 25911538 TI - Contemporary Concepts in Treating Pre-Arthritic Hip Disease. PMID- 25911539 TI - Systematic review of EASY-care needs assessment for community-dwelling older people. AB - BACKGROUND: undertaking comprehensive geriatric assessments (CGAs) combined with long-term health and social care management can improve the quality of life of older people [ 1]. The EASY-Care tool is a CGA instrument designed for assessing the physical, mental and social functioning and unmet health and social needs of older people in community settings or primary care. It has also been used as a frailty assessment tool and for gathering population-level data. OBJECTIVE: to review the evidence of reliability, validity and acceptability of EASY-Care and its appropriateness for assessing the needs of community-dwelling older people. METHODS: systematic search of literature databases using pre-defined search terms (January 1994-May 2014) for English language articles reporting on the reliability, validity, acceptability and implementation of EASY-Care in primary care and community settings. Eligible articles were critically reviewed. Discussion papers mapping professionals' use of the tool were also included as these could be considered an aspect of validity. RESULTS: twenty-nine papers met the inclusion criteria and underwent data extraction. A narrative synthesis was performed, because there was a variety of quantitative and qualitative outcomes and characteristics. Reliability evidence for EASY-Care is minimal. Evidence for validity is good, and it has received numerous positive endorsements of acceptability in international settings from older people and practitioners. CONCLUSION: evidence supports the use of EASY-Care for individual needs assessment; further research is needed for other uses. Of the papers that made statements about who should administer EASY-Care, the majority indicated that nurses were preferable to self-completion. PMID- 25911540 TI - Insights into the cellular responses to hypoxia in filamentous fungi. AB - Most eukaryotes require molecular oxygen for growth. In general, oxygen is the terminal electron acceptor of the respiratory chain and represents an important substrate for the biosynthesis of cellular compounds. However, in their natural environment, such as soil, and also during the infection, filamentous fungi are confronted with low levels of atmospheric oxygen. Transcriptome and proteome studies on the hypoxic response of filamentous fungi revealed significant alteration of the gene expression and protein synthesis upon hypoxia. These analyses discovered not only common but also species-specific responses to hypoxia with regard to NAD(+) regeneration systems and other metabolic pathways. A surprising outcome was that the induction of oxidative and nitrosative stress defenses during oxygen limitation represents a general trait of adaptation to hypoxia in many fungi. The interplay of these different stress responses is poorly understood, but recent studies have shown that adaptation to hypoxia contributes to virulence of pathogenic fungi. In this review, results on metabolic changes of filamentous fungi during adaptation to hypoxia are summarized and discussed. PMID- 25911542 TI - The hip adductor muscle group in caviomorph rodents: anatomy and homology. AB - Anatomical comparative studies including myological data of caviomorph rodents are relatively scarce, leading to a lack of use of muscular features in cladistic and morphofunctional analyses. In rodents, the hip adductor muscles constitute an important group of the hindlimb musculature, having an important function during the beginning of the stance phase. These muscles are subdivided in several distinct ways in the different clades of rodents, making the identification of their homologies hard to establish. In this contribution we provide a detailed description of the anatomical variation of the hip adductor muscle group of different genera of caviomorph rodents and identify the homologies of these muscles in the context of Rodentia. On this basis, we identify the characteristic pattern of the hip adductor muscles in Caviomorpha. Our results indicate that caviomorphs present a singular pattern of the hip adductor musculature that distinguishes them from other groups of rodents. They are characterized by having a single m. adductor brevis that includes solely its genicular part. This muscle, together with the m. gracilis, composes a muscular sheet that is medial to all other muscles of the hip adductor group. Both muscles probably have a synergistic action during locomotion, where the m. adductor brevis reinforces the multiple functions of the m. gracilis in caviomorphs. Mapping of analyzed myological characters in the context of Rodentia indicates that several features are recovered as potential synapomorphies of caviomorphs. Thus, analysis of the myological data described here adds to the current knowledge of caviomorph rodents from anatomical and functional points of view, indicating that this group has features that clearly differentiate them from other rodents. PMID- 25911541 TI - Quantitative single dilution liquid phase blocking ELISA for sero-monitoring of foot-and-mouth disease in India. AB - Three of the seven serotypes of foot-and-mouth disease (FMD) virus are prevailing in India. A massive vaccination campaign is on to control and eradicate the disease from the country. However, FMD vaccines provide short term immunity, hence regular assessment of antibody level in the vaccinated herds is indispensible for the success of the control programme. The antibodies are quantitatively estimated, either by virus neutralization test or by end-point dilution liquid-phase-blocking ELISA (LPBE). Millions of cattle and buffalo in the country are now systematically vaccinated, and thousands of serum samples are routinely screened in the country for estimation of herd immunity against FMDV serotypes O, A and Asia1. Testing such a large number of serum samples within limited a period of time by the conventional end point dilution method of LPBE requires lots of man power, and biological reagents. A more economical high throughput single dilution LPBE (SdLPBE) assay was optimized and validated for quantitative estimation of antibody levels against the three FMD virus serotypes. The assay was thoroughly validated against LPBE method before adopting it for country-wide use. The biological reagents used in the assay were prepared in thermo-stable form to enable transportation to the field level FMD diagnostic laboratories. PMID- 25911543 TI - Health impact and monetary cost of exposure to particulate matter emitted from biomass burning in large cities. AB - The study deals with the assessment of health impact and the respective economic cost attributed to particulate matter (PM) emitted into the atmosphere from biomass burning for space heating, focusing on the differences between the warm and cold seasons in 2011-2012 and 2012-2013 in Thessaloniki (Greece). Health impact was assessed based on estimated exposure levels and the use of established WHO concentration-response functions (CRFs) for all-cause mortality, infant mortality, new chronic bronchitis cases, respiratory and cardiac hospital admissions. Monetary cost was based on the valuation of the willingness-to pay/accept (WTP/WTA), to avoid or compensate for the loss of welfare associated with illness. Results showed that long term mortality during the 2012-2013 winter increased by 200 excess deaths in a city of almost 900,000 inhabitants or 3540 years of life lost, corresponding to an economic cost of almost 200-250m?. New chronic bronchitis cases dominate morbidity estimates (490 additional new cases corresponding to a monetary cost of 30m?). Estimated health and monetary impacts are more severe during the cold season, despite its smaller duration (4 months). Considering that the increased ambient air concentrations (and the integral of outdoor/indoor exposure) are explained by shifting from oil to biomass for domestic heating purposes, several alternative scenarios were evaluated. Policy scenario analysis revealed that significant public health and monetary benefits (up to 2b? in avoided mortality and 130m? in avoided illness) might be obtained by limiting the biomass share in the domestic heat energy mix. Fiscal policy affecting fuels/technologies used for domestic heating needs to be reconsidered urgently, since the net tax loss from avoided oil taxation due to reduced consumption was further compounded by the public health cost of increased mid term morbidity and mortality. PMID- 25911544 TI - Seven years of observational atmospheric CO2 at a maritime site in northernmost Japan and its implications. AB - Surface atmospheric CO2 mixing ratio reflects both natural fluctuation of the carbon cycle and the effect of anthropogenic activities. Long-term observation of atmospheric CO2 forms the basis for model simulations of the carbon cycle both in the straightforward and the inversion ways. Atmospheric CO2 has been measured on Rishiri Island (45.1 degrees N, 141.2 degrees E) in the western North Pacific since May 2006. We report the first 7-year temporal CO2 variations from diurnal to inter-annual scales and the implications on the vegetation phenology. Diurnally, an obvious cycle appeared as a minimum in the afternoon and maximum at midnight in the summer months, caused by local vegetation. Seasonally, the maximum CO2 concentration appeared around the beginning of April, while the minimum appeared around the middle of August. This seasonal variation implied the natural cycle of terrestrial biological activities of the boreal forest, mostly in the east Eurasia. A mean growing season length of ~126 days was estimated. In the period from 2007 to 2012, the peak-to-peak amplitude increased until 2009 and decreased thereafter, with a mean value of 19.7 ppm. Inter-annually, atmospheric CO2 is increasing by a mean growth rate of 2.1 ppm year(-1). The study provides invaluable dataset and useful information to better understand the carbon cycle and its interaction with climate change. PMID- 25911546 TI - Early versus late misoprostol administration after mifepristone for medical abortion. AB - PURPOSE: To evaluate the successful medical termination of pregnancy comparing two regimens: misoprostol 2 or 48 h after mifepristone administration. DESIGN: Prospective randomized study. SETTING: Department of Obstetrics and Gynecology. SAMPLE: One hundred pregnant women admitted for medical termination of pregnancy were enrolled; no pregnancies were over 55 days gestational age. METHODS: All subjects were randomly assigned for misoprostol administration either 2 or 48 h after mifepristone. All participants underwent transvaginal ultrasound examination for uterine contents 48 h and 3 weeks after mifepristone. MAIN OUTCOME MEASURE: Procedure failure, defined as the presence of fetal heart activity, presence of a gestational sac, or a need for uterine curettage after misoprostol administration. RESULTS: Each group consisted of 50 women. Fetal heart activity was significantly more frequent after 48 h in the 2-h interval group (10/50) than in the 48-h interval group (0/50) (p = 0.002). Three weeks after misoprostol administration, fetal heart activity was present in 4/50 (8 %) in the 2-h interval group (p = 0.118) and none of the 48-h interval group. At 48 h residual tissue was present in 13/50 (26 %) and 5/50 (10 %) in the 2 and 48-h interval groups, respectively (p = 0.031); this was reduced to 12/50 (24 %) compared to 5/50 (10 %) in the two groups, respectively (p = 0.054) after 3 weeks. CONCLUSIONS: Successful medical termination of pregnancy can be achieved using misoprostol administration 2 h after mifepristone in 76 % of cases. However, this regimen is not recommended as it is significantly inferior to the traditional 48-h interval regimen. PMID- 25911545 TI - Humidification during laparoscopic surgery: overview of the clinical benefits of using humidified gas during laparoscopic surgery. AB - PURPOSE: The peritoneum is the serous membrane that covers the abdominal cavity and most of the intra-abdominal organs. It is a very delicate layer highly susceptible to damage and it is not designed to cope with variable conditions such as the dry and cold carbon dioxide (CO2) during laparoscopic surgery. The aim of this review was to evaluate the effects caused by insufflating dry and cold gas into the abdominal cavity after laparoscopic surgery. METHODS: A literature search using the Pubmed was carried out. Articles identified focused on the key issues of laparoscopy, peritoneum, morphology, pneumoperitoneum, humidity, body temperature, pain, recovery time, post-operative adhesions and lens fogging. RESULTS: Insufflating dry and cold CO2 into the abdomen causes peritoneal damage, post-operative pain, hypothermia and post-operative adhesions. Using humidified and warm gas prevents pain after surgery. With regard to hypothermia due to desiccation, it can be fully prevented using humidified and warm gas. Results relating to the patient recovery are still controversial. CONCLUSIONS: The use of humidified and warm insufflation gas offers a significant clinical benefit to the patient, creating a more physiologic peritoneal environment and reducing the post-operative pain and hypothermia. In animal models, although humidified and warm gas reduces post-operative adhesions, humidified gas at 32 degrees C reduced them even more. It is clear that humidified gas should be used during laparoscopic surgery; however, a question remains unanswered: to achieve even greater clinical benefit to the patient, at what temperature should the humidified gas be when insufflated into the abdomen? More clinical trials should be performed to resolve this query. PMID- 25911547 TI - Effect of Progesterone, Its Hydroxylated and Methylated Derivatives, and Dydrogesterone on Lipid Bilayer Membranes. AB - The interaction of progesterone (PG), 17-hydroxyprogesterone (17-OHPG), 21 hydroxyprogesterone (21-OHPG), medroxyprogesterone (MP), medroxyprogesterone acetate (MPA), and dydrogesterone (DYG), with zwitterionic dipalmitoyl phosphatidylcholine (DPPC) multilamellar liposome, was investigated as a function of drug concentration using Fourier transform infrared spectroscopy and differential scanning calorimetry. The results reveal that progesterone and its derivatives changed the physical properties of the DPPC bilayers by decreasing the main phase-transition temperature (T m) and enthalpy (DeltaH m), abolishing the pre-transition and disordering the membrane. From the thermodynamic parameters analysis, we concluded that PG, 21-OHPG, and MPA are localized inside the membrane. Whereas, the insertion of 17-OHPG in the lipid bilayers cannot be excluded in view of the significant decrease in the transition enthalpy at two molar ratios. MP and DYG are rather localized near the polar heads of phospholipids at the interface water-lipid bilayer. PG derivatives increase the membrane fluidity in the order: PG ~ 21-OHPG ~ MPA > 17-OHPG > MP ~ DYG. The distinct effects produced by steroids are discussed in terms of hydrophobicity and chemical structure. PMID- 25911548 TI - A Simple Fluorescence Quenching Method for the Determination of Vanillin Using TGA-capped CdTe/ZnS Nanoparticles as Probes. AB - Based on the quenching of the fluorescence intensity of thioglycolic acid (TGA) capped core-shell CdTe/ZnS nanoparticles (NPs) by vanillin, a novel, simple and rapid method for the determination of vanillin was proposed. In aqueous medium, the functionalized core-shell CdTe/ZnS NPs were successfully synthesized with TGA as the capping ligand. TGA-capped core-shell CdTe/ZnS NPs were characterized by using X-ray diffraction (XRD), transmission electron microscopy (TEM) and Fourier transform infrared (FTIR) spectroscopy. Factors affecting the vanillin detection were investigated, and the optimum conditions were also determined. Under the optimum conditions, the relative fluorescence intensity of CdTe/ZnS NPs was linearly proportional to vanillin over a concentration range from 9.4 * 10(-7) to 5.2 * 10(-4) M with a correlation coefficient of 0.998 and a detection limit of 2.6 * 10(-7) M. The proposed method was also employed to detect trace vanillin in cookies with satisfactory results. PMID- 25911549 TI - Flow cytometric detection of MPL (CD110) as a diagnostic tool for differentiation of congenital thrombocytopenias. PMID- 25911550 TI - B-cell receptor usage correlates with the sensitivity to CD40 stimulation and the occurrence of CD4+ T-cell clonality in chronic lymphocytic leukemia. PMID- 25911551 TI - Pbx3 and Meis1 cooperate through multiple mechanisms to support Hox-induced murine leukemia. AB - Hox homeobox transcription factors drive leukemogenesis efficiently only in the presence of Meis or Pbx proteins. Here we show that Pbx3 and Meis1 need to dimerize to support Hox-induced leukemia and we analyze the molecular details of this cooperation. In the absence of Pbx3, Meis1 was highly unstable. As shown by a deletion analysis Meis1 degradation was contingent on a motif coinciding with the Pbx-binding domain. Either deletion of this sequence or binding to Pbx3 prolonged the half-life of Meis1 by preventing its ubiquitination. Meis1 break down could also be blocked by inhibition of the ubiquitin proteasome system, indicating tight post-transcriptional control. In addition, Meis1 and Pbx3 cooperated genetically as overexpression of Pbx3 induced endogenous Meis1 transcription. These functional interactions translated into in vivo activity. Blocking Meis1/Pbx3 dimerization abrogated the ability to enhance proliferation and colony-forming cell numbers in primary cells transformed by Hoxa9. Furthermore, expression of Meis1 target genes Flt3 and Trib2 was dependent on Pbx3/Meis1 dimerization. This correlated with the requirement of Meis1 to bind Pbx3 in order to form high affinity DNA/Hoxa9/Meis1/Pbx3 complexes in vitro. Finally, kinetics and severity of disease in transplantation assays indicated that Pbx3/Meis1 dimers are rate-limiting factors for Hoxa9-induced leukemia. PMID- 25911552 TI - Erythropoiesis is not equally suppressed in transfused males and females with beta-thalassemia major: are there clinical implications? PMID- 25911553 TI - Rituximab maintenance for patients with aggressive B-cell lymphoma in first remission: results of the randomized NHL13 trial. AB - We investigated rituximab maintenance therapy in patients with diffuse large B cell lymphoma (n=662) or follicular lymphoma grade 3b (n=21) in first complete remission. Patients were randomized to rituximab maintenance (n=338) or observation (n=345). At a median follow-up of 45 months, the event-free survival rate (the primary endpoint) at 3 years was 80.1% for rituximab maintenance versus 76.5% for observation. This difference was not statistically significant for the intent-to-treat population (likelihood ratio P=0.0670). The hazard ratio by treatment arm was 0.79 (95% confidence interval 0.57-1.08; P=0.1433). The secondary endpoint, progression-free survival was also not met for the whole statistical model (likelihood ratio P=0.3646). Of note, rituximab maintenance was superior to observation when treatment arms only were compared (hazard ratio: 0.62; 95% confidence interval 0.43-0.90; P=0.0120). Overall survival remained unchanged (92.0 versus 90.3%). In subgroup analysis male patients benefited from rituximab maintenance with regards to both event-free survival (84.1% versus 74.4%) (hazard ratio: 0.58; 95% confidence interval 0.36-0.94; P=0.0267) and progression-free survival (89.0% versus 77.6%) (hazard ratio: 0.45; 95% confidence interval 0.25-0.79; P=0.0058). Women had more grade 3/4 adverse events (P=0.0297) and infections (P=0.0341). Men with a low International Prognostic Index treated with rituximab had the best outcome. In summary, rituximab maintenance in first remission after R-CHOP-like treatment did not prolong event free, progression-free or overall survival of patients with aggressive B-non Hodgkin lymphoma. The significantly better outcome of men warrants further studies prior to the routine use of rituximab maintenance in men with low International Prognostic Index. This trial is registered under EUDRACT #2005 005187-90 and www.clinicaltrials.gov as #NCT00400478. PMID- 25911554 TI - Bendamustine, bortezomib and prednisone for the treatment of patients with newly diagnosed multiple myeloma: results of a prospective phase 2 Spanish/PETHEMA trial. AB - Bendamustine is a bifunctional alkylating agent with proven activity in myeloma. In this study 60 newly diagnosed myeloma patients were given bendamustine plus bortezomib and prednisone in a regimen consisting of one cycle of bortezomib twice weekly for 6 weeks (1.3 mg/m(2) on days 1, 4, 8, 11, 22, 25, 29, and 32), plus bendamustine (90 mg/m(2) on days 1 and 4) and prednisone. The following cycles included bortezomib once weekly. Patients who were transplant candidates proceeded to stem cell collection after four cycles and the transplant was performed after six cycles. Patients who were not candidates for transplantation received up to nine cycles. Forty-two patients were transplant candidates and after six cycles, 50% achieved at least a very good partial response, with 24% having complete responses; 35 proceeded to a transplant, and the complete response rate was 54%. Seventeen patients continued up to nine cycles, and 57% achieved at least a very good partial response, including 26% with complete responses. The 2-year progression-free survival and overall survival rates were 62% and 86%, respectively. The safety profile was manageable, but stem cell mobilization was compromised in 35% of patients. In summary, this combination is effective in untreated patients, with an acceptable toxicity profile, but given the introduction of second-generation novel agents and monoclonal antibodies, the combination will probably be better reserved for relapsing patients, in whom stem cell collection is not needed, while cost-effective combinations with non-cross resistant drugs continue to represent a medical need. This trial was registered with ClinicalTrials.gov, number NCT01376401. PMID- 25911555 TI - Extrahepatic sources of factor VIII potentially contribute to the coagulation cascade correcting the bleeding phenotype of mice with hemophilia A. AB - A large fraction of factor VIII in blood originates from liver sinusoidal endothelial cells although extrahepatic sources also contribute to plasma factor VIII levels. Identification of cell-types other than endothelial cells with the capacity to synthesize and release factor VIII will be helpful for therapeutic approaches in hemophilia A. Recent cell therapy and bone marrow transplantation studies indicated that Kupffer cells, monocytes and mesenchymal stromal cells could synthesize factor VIII in sufficient amount to ameliorate the bleeding phenotype in hemophilic mice. To further establish the role of blood cells in expressing factor VIII, we studied various types of mouse and human hematopoietic cells. We identified factor VIII in cells isolated from peripheral and cord blood, as well as bone marrow. Co-staining for cell type-specific markers verified that factor VIII was expressed in monocytes, macrophages and megakaryocytes. We additionally verified that factor VIII was expressed in liver sinusoidal endothelial cells and endothelial cells elsewhere, e.g., in the spleen, lungs and kidneys. Factor VIII was well expressed in sinusoidal endothelial cells and Kupffer cells isolated from human liver, whereas by comparison isolated human hepatocytes expressed factor VIII at very low levels. After transplantation of CD34(+) human cord blood cells into NOD/SCIDgammaNull hemophilia A mice, fluorescence activated cell sorting of peripheral blood showed >40% donor cells engrafted in the majority of mice. In these animals, plasma factor VIII activity 12 weeks after cell transplantation was up to 5% and nine of 12 mice survived after a tail clip-assay. In conclusion, hematopoietic cells, in addition to endothelial cells, express and secrete factor VIII: this information should offer further opportunities for understanding mechanisms of factor VIII synthesis and replenishment. PMID- 25911557 TI - Persistent reduced oxygen requirement following blood transfusion during recovery from hemorrhagic shock. AB - Our study intended to determine the effects on oxygen uptake (VO2) of restoring a normal rate of O2 delivery following blood transfusion (BT) after a severe hemorrhage (H). Spontaneously breathing urethane anesthetized rats were bled by removing 20 ml/kg of blood over 30 min. Rats were then infused with their own shed blood 15 min after the end of H. At mid-perfusion, half of the rats received a unique infusion of the decoupling agent 2,4-dinitrophenol (DNP, 6 mg/kg). VO2 and arterial blood pressure (ABP) were continuously measured throughout the study, along with serial determination of blood lactate concentration [La]. Animals were euthanized 45 min after the end of reperfusion; liver and lungs were further analyzed for early expression of oxidative stress gene using RT-PCR. Our bleeding protocol induced a significant decrease in ABP and increase in [La], while VO2 dropped by half. The O2 deficit progressively accumulated during the period of bleeding reached -114 +/- 53 ml/kg, just before blood transfusion. Despite the transfusion of blood, a significant O2 deficit persisted (-82 +/- 59 ml/kg) 45 min after reperfusion. This slow recovery of VO2 was sped up by DNP injection, leading to a fast recovery of O2 deficit after reperfusion, becoming positive (+460 +/- 132 ml/kg) by the end of the protocol, supporting the view that O2 supply is not the main controller of VO2 dynamics after BT. Of note is that DNP also enhanced oxidative stress gene expression (up-regulation of NADPH oxidase 4 in the lung for instance). The mechanism of slow recovery of O2 requirement/demand following BT and the resulting effects on tissues exposed to relatively high O2 partial pressure are discussed. PMID- 25911556 TI - A central theory of biology. AB - The history of physiologic cellular-molecular interrelationships can be traced all the way back to the unicellular state by following the pathway formed by lipids ubiquitously accommodating calcium homeostasis, and its consequent adaptive effects on oxygen uptake by cells, tissues and organs. As a result, a cohesive, mechanistically integrated view of physiology can be formulated by recognizing the continuum comprising conception, development, physiologic homeostasis and death mediated by soluble growth factor signaling. Seeing such seemingly disparate processes as embryogenesis, chronic disease and dying as the gain and subsequent loss of cell-cell signaling provides a novel perspective for physiology and medicine. It is emblematic of the self-organizing, self referential nature of life, starting from its origins. Such organizing principles obviate the pitfalls of teleologic evolution, conversely providing a way of resolving such seeming dichotomies as holism and reductionism, genotype and phenotype, emergence and contingence, proximate and ultimate causation in evolution, cells and organisms. The proposed approach is scale-free and predictive, offering a Central Theory of Biology. PMID- 25911558 TI - Type III-IV muscle afferents are not required for steady-state exercise hyperpnea in healthy subjects and patients with COPD or heart failure. AB - Blockade of group III-IV muscle afferents by intrathecal injection of the MU opioid agonist fentanyl (IF) in humans has been variously reported to depress exercise hyperpnea in some studies but not others. A key unanswered question is whether such an effect is transient or persists in the steady state. Here we show that in healthy subjects undergoing constant-load cycling exercise IF significantly slows the transient exercise ventilatory kinetics but has no discernible effect on the ventilatory response when exercise is sufficiently prolonged. Thus, the ventilatory response to group III-IV muscle afferents input in healthy subjects is not a simple reflex but acts like a high-pass filter with maximum sensitivity during early-phase exercise and is reset in the late phase. In patients with chronic heart failure (CHF) IF causes sustained CO2 retention not only during exercise but also in the resting state, where muscle afferents feedback is minimal. In patients with chronic obstructive pulmonary disease (COPD), IF also elicits sustained decreases in the exercise ventilatory response but with little or no resultant CO2 retention due to concomitant decreases in physiological VD/VT (dead space-to-ventilation ratio). These results support the proposition that optimal long-term regulation of exercise hyperpnea in health and in disease is determined centrally by the respiratory controller through the continuing adaptation of an internal model which dynamically tracks the metabolic CO2 load and the ventilatory inefficiency 1/1-VD/VT that must be overcome for the maintenance of arterial PCO2 homeostasis, rather than being reflexively driven by group III-IV muscle afferents feedback per se. PMID- 25911559 TI - Hypercapnic thresholds for embryonic acid-base metabolic compensation and hematological regulation during CO2 challenges in layer and broiler chicken strains. AB - Time specific acid-base metabolic compensation and responses of hematological respiratory variables were measured in day 15 layer (Hyline) and broiler (Cornish Rock) chicken embryos during acute hypercapnic challenges (3, 6, 10 and 20% CO2). Control acid-base status and hematology differed between two strains. Broiler embryos were relatively respiratory acidotic and had higher hematocrit (Hct) and hemoglobin concentration. The partial metabolic compensation for respiratory acidosis produced by <= 10% CO2 exposures occurred in proportion to CO2 concentrations in both strains, but metabolic compensation for 20% CO2 respiratory acidosis was depressed at 2, 6 and 24h, particularly in broiler embryos. Exposure to <= 10% CO2 induced the same hematological responses across CO2 concentrations; i.e., Hct and mean corpuscular volume (MCV) increased while RBC concentration remained unchanged. In response to 20% CO2 exposure, Hct and MCV increased dramatically in both stains. Consequently, altered acid-base and hematology responses to 20% CO2 exposure compared to <= 10% CO2 suggest that the hypercapnic threshold to compensation for acidosis and regulation of hematology is >10% CO2. PMID- 25911560 TI - Molecular cloning, characterisation and mRNA expression analysis of the sheep myosin light chain 1 gene. AB - The complete cDNA sequence of the sheep MYL1 (Myosin light chain 1) gene was cloned using RT-PCR, 5' RACE and 3' RACE. We obtained two alternatively spliced isoforms of the MYL1 gene, MYL1a and MYL1b, which are 849 and 1046bp in length and encode proteins composed of 150 and 192 amino acid residues, respectively. And the GenBank accession numbers of MYL1a and MYL1b full-length cDNA sequences that we cloned are KJ700419 and KJ710701, respectively. Neither protein was predicted to have a signal peptide, but both were predicted to have several N glycosylation and phosphorylation sites. More than half of the secondary structure of these proteins was predicted to be alpha-helical. The human MYL2 protein (1m8q.1.C) is the most similar in tertiary structure. Sequence alignment showed that the sheep MYL1a protein shares more than 92% amino acid sequence similar with Mus musculus, Homo sapiens, Rattus norvegicus, Sus scrofa and Gallus gallus and that the MYL1b protein shares more than 93% amino acid sequence similar with M. musculus, H. sapiens, R. norvegicus, Bos taurus and Oryctolagus cuniculus. Transcription profile analyses of various tissues indicated that the sheep MYL1a and MYL1b mRNAs were highly but differentially expressed in the longissimus dorsi. Moreover, the expression levels of these genes in the longissimus dorsi differed between Dorper and Small-tailed Han sheep. These results serve as a foundation for further investigations of the function of the sheep MYL1 gene. PMID- 25911561 TI - Trunk kinematics and muscle activities during arm elevation. AB - BACKGROUND: While trunk movement accompanies arm elevation, trunk muscle activities during arm elevation at different speeds are unclear. The purpose of this study was to examine the trunk muscle activities at various speeds of arm elevation and then to evaluate their roles in trunk kinematics. METHODS: Twenty two healthy subjects participated. The participants performed right shoulder flexion at three different speeds. Surface electromyography was used to measure the activities of bilateral external oblique muscles (EO), internal oblique muscles (IO), rectus abdominis muscles (RA) and lumber erector spinae muscles (ES). A three-dimensional motion analyzer was used to measure arm and trunk movements. RESULTS: In natural and slow movements, the muscle activities of left ES, right EO and left IO were significantly augmented compared with those of the contralateral muscles, in the relatively late phase. In fast movement, the muscle activities of both ES were significantly augmented during the early phase compared with later in the action. The muscle activities of the left ES and the right EO were significantly augmented compared with those of the contralateral muscles. There was a consistent pattern of trunk extension, lateral flexion and rotation during arm elevation, irrespective of the speed. CONCLUSIONS: Bilateral ES activity may be required for back-extension torques, especially for the early phase of rapid elevating motion. The anterior muscles' activity may contribute to the production of anterior force against the backward movement of the center of mass of the upper limb in the late phase. Trunk rotation, controlled by the trunk muscles in harmony, may assist the scapular movement to align the scapular plane in the arm elevating plane. PMID- 25911562 TI - Loxoprofen sodium and celecoxib for postoperative pain in patients after spinal surgery: a randomized comparative study. AB - BACKGROUND: Nonsteroidal anti-inflammatory drugs (NSAIDs) are often used to treat inflammation, pain, and fever, but no criterion standard exists for the management of postoperative pain following spinal surgery. In the present study, we compared the analgesic efficacy of loxoprofen sodium (loxoprofen) and celecoxib for the management of postoperative pain following spinal surgery. METHODS: One-hundred forty-one patients (mean age 62.2 years) were randomly assigned to two groups before spinal surgery: a loxoprofen group (n = 73, 180 mg/day) and a celecoxib group (n = 68, 200 mg/day). The drugs were administered from 1 day until 7 days after surgery. A numeric rating scale (NRS) was used to evaluate pain at nine predefined times every day and the findings were compared between the two groups. Laboratory data and adverse events were also recorded. RESULTS: There was no significant difference in the maximum and mean NRS scores on each day between loxoprofen and celecoxib, suggesting a comparable analgesic effect for these two NSAIDs. Greater improvement in the NRS score between preadministration (baseline) and 30 min or 2 h after administration was obtained for loxoprofen. This tendency was shown for both slight (NRS score <5 at baseline) and severe pain (NRS score >= 5 at baseline). Loxoprofen was discontinued in one patient on day 4 because of renal dysfunction. Celecoxib was discontinued in one patient on day 2 at the patient's request. CONCLUSIONS: Both loxoprofen sodium and celecoxib were well tolerated for the relief of acute postoperative pain after spinal surgery. A single administration of loxoprofen showed superior and rapid effectiveness compared with celecoxib for both slight and severe postoperative pain. PMID- 25911563 TI - Revisiting Lipomatous Meningioma: A Case Report and Review of an Unusual Entity. AB - Lipomatous meningioma is a very rare subtype of metaplastic meningioma. It is defined by the presence of adipocytic-like cells, which are thought to result from lipid accumulation in meningothelial cells or true metaplastic change. We report a case of a lipomatous meningioma arising in a female patient complaining of recent seizures. Imaging studies revealed a 4-cm dural-based mass, with severe perilesional edema. Histologically, the tumor was composed of meningothelial whorls intermixed with adipocytic-like cells. No atypical criteria or brain invasion were found. The 2 components have differences in progesterone receptor expression and Ki-67 labeling, which may suggest that adipocytic-like cells may represent some quiescent form of meningothelial neoplastic cells, characterized by metabolic abnormalities, leading to lipid accumulation and very low proliferative activity. Lipomatous meningioma should also be kept in mind when considering the differential diagnosis of dural lesions with vasogenic edema in the absence of brain invasion. PMID- 25911564 TI - Tumor Budding Is Independently Predictive for Lymph Node Involvement in Early Gastric Cancer. AB - BACKGROUND: The most important prognostic factor for early gastric cancer (EGC) is the lymph node status. It is important to predict early lesions without lymph node metastasis (LNM) before proceeding to radical surgery in locally excised lesions. Tumor budding is a feature known to be related to aggressive tumor behavior in several solid tumors. We aimed to assess the predictive value of tumor budding for LNM in pT1a and pT1b gastric cancer. METHODS: We retrospectively investigated radical gastrectomy specimens for of 126 EGC patients and assess the possible relation between the clinicopathologic features, including age, gender, tumor location, tumor size, macroscopic tumor type, histologic differentiation, depth and width of submucosal invasion, lymphovascular invasion, and tumor budding with lymph node involvement. RESULTS: Among the 126 EGCs, 38 were stages as pT1a and 88 as pT1b. LNM rate in pT1a tumors was 13% whereas it was 33% in pT1b tumors. Tumor budding was the only factor significantly and independently related to LNM in pT1a patients. Female gender and tumor budding were found to be independent risk factors in pT1b group. Other clinicopathologic features were not related to LNM. CONCLUSION: Based on these results, we suggest that budding is a promising parameter to assess for prediction of LNM in EGC removed by endoscopic surgery, and to decide on the appropriate surgical approach. PMID- 25911565 TI - Malignant Peripheral Nerve Sheath Tumor With Rhabdomyosarcomatous and Glandular Elements: Rare Epithelial Differentiation in a Triton Tumor. AB - Divergent differentiation occurs in a subset of malignant peripheral nerve sheath tumors (MPNST), but differentiation toward epithelial elements is unusual. MPNST with both heterologous rhabdomyosarcomatous differentiation (malignant Triton tumor), and glandular epithelial differentiation is exceedingly rare, with only 11 cases reported since 1973, and only 1 with histologically proven metastasis. We describe a case occurring in the mediastinum (between the ascending aorta and the main pulmonary artery) of a 40-year-old man with neurofibromatosis type-1. Despite treatment, the tumor metastasized to the right frontal lobe 16 months after diagnosis. Histologically, the primary neoplasm comprised cellular fascicles of atypical spindle cells, with discrete foci of well-formed or more primitive glandular epithelial structures, while the metastases comprised spindle cell sarcoma, including rhabdomyosarcoma, without epithelial elements. We review and discuss the literature on these little characterized neoplasms, including histology and clinical features, adding to the spectrum of documented cases of divergent epithelial differentiation in Triton tumor. PMID- 25911566 TI - Jejunal Metastasis Colliding With a Borderline Tumor in the Ovary: A Hitherto Unreported Eventuality. AB - Metastatic adenocarcinomas to the ovary can show morphologically innocuous areas simulating primary benign lesions or borderline tumors. Ruling out a metastasis can be a difficult issue for pathologists, especially when facing with cystic tumors. Because of the important clinical implications of differentiating metastatic adenocarcinomas from primary ovarian tumors, the integration of clinical, pathological, and immunohistochemical features is warranted, primarily in case of mucinous adenocarcinomas. Vice versa, the synchronous presence of a metastasis and a primary in the same ovary is virtually excluded as a very unlikely eventuality. Here, we describe a case of metastatic adenocarcinoma from the jejunum colliding with a seromucinous borderline tumor in the same ovary, an unreported eventuality so far. PMID- 25911567 TI - Significance of Vascular Endothelial Growth Factor (VEGF)-C and VEGF-D in the Progression of Cutaneous Melanoma. AB - INTRODUCTION: Induction of tumor lymphangiogenesis by vascular endothelial growth factor (VEGF)-C and VEGF-D promotes metastasis in many human cancers. AIM: The aim of this study was to examine the role of VEGF-C and VEGF-D in lymphangiogenesis and lymph node metastasis in patients with cutaneous melanoma. MATERIALS AND METHODS: Fifty-four melanoma specimens (18 with lymph node metastasis, 36 nonmetastatic) were investigated by immunostaining for VEGF-C, VEGF-D, and for lymphatic endothelial marker D2-40. VEGF-C and VEGF-D expression was assessed as a percentage and intensity of stained tumor cells, tumor associated macrophages and fibroblasts. The quantification of lymphangiogenesis was conducted by computer-assisted morphometric analysis. RESULTS: The expressions of both VEGF-C and VEGF-D in tumor cells were significantly higher in lymph node metastatic melanomas compared with nonmetastatic melanomas (P = .015 VEGF-C; P = .005 VEGF-D). There was no statistically significant difference between metastatic and nonmetastatic melanomas regarding the expression of VEGF-C and VEGF-D in macrophages and fibroblasts. Metastatic melanomas showed a significantly higher intratumoral and peritumoral lymphatic vessel density (LVD) compared with nonmetastatic melanomas (P = .000 intratumoral, P = .000 peritumoral). Melanomas with VEGF-C positive tumor cells showed a significantly higher intratumoral and peritumoral LVD compared with VEGF-C negative tumor cells group of melanomas (P = .006 intratumoral, P = .010 peritumoral). VEGF-C expression in macrophages, fibroblasts, as well as VEGF-D expression in tumor cells, macrophages, and fibroblasts, showed no correlation with the intratumoral and peritumoral LVD. CONCLUSIONS: Our findings show the significance of VEGF-C in tumor cells in the induction of intratumoral and peritumoral lymphangiogenesis. This study suggests that both VEGF-C and VEGF-D in tumor cells promote lymph node metastasis, and that the immunohistochemical analysis of expression can be a useful tool for predicting clinical behavior of cutaneous melanoma. PMID- 25911568 TI - Gunpowder or Mycetoma? PMID- 25911569 TI - Malignant Transformation of Pelvic Endometriosis: Case Series and Review of the Literature. AB - Endometriosis affects 4% to 13% of all women of reproductive age although its true incidence is unknown. The ability of endometriosis to transform into malignancy, first described by Sampson in 1925, is a rare occurrence affecting 1% of lesions with ovary being the primary site in 79%. The authors describe 3 premenopausal women without risk factors for malignancy presenting with ovarian and/or extraovarian endometrioid adenocarcinoma. All of them demonstrated features of pre-/coexisting endometriosis but malignancy was preoperatively suspected in only 1 instance. Postsurgical follow-up of the cases did not document any recurrence. The propensity for malignant conversion occurring in women 10 to 20 years younger vis-a-vis those affected by de novo ovarian cancer, destruction of the endometriotic foci, and underreporting vindicate close follow up and scrutiny of women with endometriosis and ovarian endometriomas. PMID- 25911570 TI - Twenty-seven cases of pineal parenchymal tumours of intermediate differentiation: mitotic count, Ki-67 labelling index and extent of resection predict prognosis. AB - OBJECTIVE: Optimal grading and treatment of pineal parenchymal tumours of intermediate differentiation (PPTID) have not been established due to their rarity. After careful review of more than 500 pineal region tumours treated in our centre, 27 patients with PPTID were identified. METHODS: Diagnoses were confirmed according to WHO classification and graded as suggested by Jouvet et al. The relationship between the WHO grade, histopathological characters, management and outcome was analysed. RESULTS: The WHO grade did not demonstrate significant correlation with outcome. Mitotic count and Ki-67 labelling index (LI) were detected as prognostic factors. Stratification of patients by mitotic count and Ki-67 LI correlated significantly with overall survival and progression free survival. All the patients underwent resection. Gross total resection (GTR) was achieved in 16/27 (59.3%) patients, subtotal resection in 6/27 (22.2%) patients and partial resection in 5/27 (18.5%) patients. Log rank test confirmed GTR correlated with significantly better survival. Adjuvant therapy had a tendency to correlate significantly with progression-free survival. Among the high-risk patients, 6/9 patients with residual tumour received radiotherapy and 50% (3/6) were free of local tumour recurrence. In the other three high-risk patients with residual tumour who did not receive adjuvant therapy, recurrence occurred early and Ki-67 LI predicted prognosis. CONCLUSIONS: Risk evaluation combining mitotic count and Ki-67 LI predicts prognosis. Surgery is the most efficient management. GTR is related to better prognosis. If GTR is not achieved, adjuvant therapy might delay tumour progression or recurrence, especially in high risk patients. PMID- 25911571 TI - Gentle blood aspiration and tube cushioning reduce pneumatic tube system interference in lactate dehydrogenase assays. AB - BACKGROUND: Use of a hospital pneumatic tube system may be associated with measurement errors. METHODS: A venous blood sample was collected from 79 patients into a pair of lithium heparin tubes; one tube was sent to the laboratory by porter and the other was sent via the pneumatic tube system. Plasma lactate dehydrogenase concentrations were then assayed. RESULTS: Lactate dehydrogenase concentrations were overestimated (median bias: 18.8%) when evacuated vacuum lithium heparin tubes were sent by pneumatic tube system. This bias was reduced by bubble-wrapping the standard lithium heparin tube or using Monovette lithium heparin tubes in aspiration mode (median bias: +8.7% and -0.3%, respectively). CONCLUSIONS: Cushioning and aspiration-mode sampling may limit pneumatic tube system-associated overestimation of lactate dehydrogenase concentrations. PMID- 25911572 TI - Development of phenotype algorithms using electronic medical records and incorporating natural language processing. PMID- 25911573 TI - Conditional net survival: Relevant prognostic information for colorectal cancer survivors. A French population-based study. AB - BACKGROUND: Traditionally, survival estimates have been reported as survival from the time of diagnosis. A patient's probability of survival changes according to time elapsed since the diagnosis and this is known as conditional survival. The aim was to estimate 5-year net conditional survival in patients with colorectal cancer in a well-defined French population at yearly intervals up to 5 years. METHODS: Our study included 18,300 colorectal cancers diagnosed between 1976 and 2008 and registered in the population-based digestive cancer registry of Burgundy (France). We calculated conditional 5-year net survival, using the Pohar Perme estimator, for every additional year survived after diagnosis from 1 to 5 years. RESULTS: The initial 5-year net survival estimates varied between 89% for stage I and 9% for advanced stage cancer. The corresponding 5-year net survival for patients alive after 5 years was 95% and 75%. Stage II and III patients who survived 5 years had a similar probability of surviving 5 more years, respectively 87% and 84%. For survivors after the first year following diagnosis, five-year conditional net survival was similar regardless of age class and period of diagnosis. CONCLUSIONS: For colorectal cancer survivors, conditional net survival provides relevant and complementary prognostic information for patients and clinicians. PMID- 25911574 TI - Visually complex foveal words increase the amount of parafoveal information acquired. AB - This study investigates the effect of foveal load (i.e., processing difficulty of currently fixated words) on parafoveal information processing. Contrary to the commonly accepted view that high foveal load leads to reduced parafoveal processing efficiency, results of the present study showed that increasing foveal visual (but not linguistic) processing load actually increased the amount of parafoveal information acquired, presumably due to the fact that longer fixation duration on the pretarget word provided more time for parafoveal processing of the target word. It is therefore proposed in the present study that foveal linguistic processing load is not the only factor that determines parafoveal processing; preview time (afforded by foveal word visual processing load) may jointly influence parafoveal processing. PMID- 25911575 TI - Time-averaged copper concentrations from continuous exposures predicts pulsed exposure toxicity to the marine diatom, Phaeodactylum tricornutum: Importance of uptake and elimination. AB - Intermittent, fluctuating and pulsed contaminant discharges result in organisms receiving highly variable contaminant exposures. Current water quality guidelines are predominantly derived using data from continuous exposure toxicity tests, and most frequently applied by regulators with the assumption that concentrations from a single sampling event will provide a meaningful approach to assessing potential effects. This study investigated the effect of single and multiple (daily) dissolved copper pulses on the marine diatom, Phaeodactylum tricornutum, including measurements of copper uptake and elimination to investigate the toxic mechanism. Copper pulses of between 0.5 and 24h and continuous exposures with equivalent 72-h time-averaged concentrations (TACs) resulted in similar biomass inhibition of P. tricornutum, with continuous exposures often being marginally more toxic. Rates of cell division generally recovered to control levels within 24h of the copper pulse removal. Upon resuspension in clean seawater, the extracellular copper per cell decreased rapidly, whereas the intracellular copper per cell decreased slowly. Negligible loss of copper from the total algal biomass indicated that P. tricornutum did not have an effective mechanism for eliminating copper from cells, rather the intracellular copper decreased as a result of dilution by cellular division as the algal growth rate recovered. The measurement of copper uptake after 72-h exposure and kinetics of elimination thereafter suggest that continuous exposures are marginally more toxic to P. tricornutum than pulsed copper exposures with equivalent TACs because slow internalization and saturation of algal membrane transport sites results in less copper uptake into pulse-exposed cells than continuously-exposed cells coupled with dilution of internalized copper via cellular division in the post-exposure period. In the case of P. tricornutum, the results indicate that water quality guidelines for copper based on continuous exposure will be conservative when applied to short term discharges. PMID- 25911576 TI - Effects of the anti-androgen cyproterone acetate (CPA) on oocyte meiotic maturation in rainbow trout (Oncorhynchus mykiss). AB - In the present study, we aimed at characterizing the effect of cyproterone acetate (CPA), an anti-androgenic compound, on oocyte meiotic maturation in a freshwater teleost fish species, the rainbow trout (Oncorhynchus mykiss). Fully grown post-vitellogenic ovarian follicles were incubated in vitro with CPA, luteinizing hormone (Lh) or a combination of CPA and Lh. Incubations were also performed using a combination of Lh and testosterone (T). The occurrence of oocyte maturation (i.e., resumption of the meiotic process) was assessed by monitoring germinal vesicle breakdown (GVBD) after a 72h in vitro incubation. The effect of CPA on the production of 17,20beta-dihydroxy-4-pregnen-3-one (17,20betaP), the natural maturation-inducing steroid (MIS), was quantified by radioimmunoassay. Our results show that CPA dramatically inhibits Lh-induced oocyte maturation and MIS synthesis. We also observed a synergistic effect of Lh and T on oocyte maturation in highly competent oocytes (i.e., able to resume meiosis after stimulation by low doses of Lh). Our results also show that a combination of CPA and Lh inhibits phosphorylation of extracellular signal regulated kinase (Erk), kinases that are associated with oocyte maturation in many species. As a whole, our results indicate that CPA has a potential to alter meiotic maturation in rainbow trout. Further analyses are, however, needed to determine the mechanisms by which this anti-androgen interferes with the meiotic process. Furthermore, the present study provides a framework for better understanding of the ecological consequences of exposure to anti-androgens and resulting meiotic maturation abnormalities observed in trout. PMID- 25911577 TI - Mixture effects between different azoles and beta-naphthoflavone on the CYP1A biomarker in a fish cell line. AB - The cytochrome P450 1A (CYP1A) biomarker response was studied in the Poeciliopsis lucida hepatocellular carcinoma (PLHC-1) cell line, which represents a good model for studies on aryl hydrocarbon receptor (AhR) - CYP1A signaling. The PLHC-1 cells were exposed to the prototypical CYP1A inducer and AhR agonist beta naphthoflavone (BNF) in combination with different azoles. Two imidazoles (clotrimazole and prochloraz) and two benzimidazoles (nocodazole and omeprazole) were used. Exposure to clotrimazole, prochloraz and nocodazole resulted in 2-4 fold induction of the CYP1A-mediated ethoxyresorufin-O-deethylase (EROD) activities at 24 and 48h, whereas exposure to the omeprazole for 48h had no effect on the EROD activity. Clotrimazole, nocodazole and prochloraz also acted as inhibitors of EROD activities in situ in PLHC-1 cells (IC50=1.3-7.7MUM), whereas omeprazole had no effect on this activity (IC50=72MUM). Exposure to 10MUM prochloraz resulted in 3-fold induction of CYP1A mRNA and exposure to 10MUM nocodazole resulted in 16-fold induction of CYP1A mRNA levels at 24h compared to controls. In the mixture experiments, more-than-additive mixture effects between BNF and the azoles clotrimazole, prochloraz and nocodazole on EROD activities were evident, with nocodazole showing the strongest mixture effect. The presence of nocodazole increased the response to BNF up to 200-fold on CYP1A mRNA and up to 16-fold on EROD activities and prolonged the effect of BNF exposure on EROD activities by 24h or longer. This suggests that azoles that are inhibitors and/or competing substrates for the CYP1A enzymes can cause increased sensitivity to exposures to chemicals that depend on CYP1A metabolism for their elimination in situations of mixed chemical exposures. The results also suggest that the EROD biomarker response can be significantly affected in azole-contaminated areas. The responsiveness of the EROD biomarker to BNF exposure was studied in PLHC-1 that had been pre-treated with nocodazole for 5 or 24h at concentrations that are known to disassemble microtubules at 24h in these cells. Pre-treatment of PLHC-1 cells with nocodazole for either 5 or 24h had no effect on the responsiveness to BNF exposure, which implies that the EROD activity can be induced in cells with disassembled microtubules. PMID- 25911578 TI - A Research Note on Time With Children in Different- and Same-Sex Two-Parent Families. AB - Public debate on same-sex marriage often focuses on the disadvantages that children raised by same-sex couples may face. On one hand, little evidence suggests any difference in the outcomes of children raised by same-sex parents and different-sex parents. On the other hand, most studies are limited by problems of sample selection and size, and few directly measure the parenting practices thought to influence child development. This research note demonstrates how the 2003-2013 American Time Use Survey (n=44,188) may help to address these limitations. Two-tier Cragg's Tobit alternative models estimated the amount of time that parents in different-sex and same-sex couples engaged in child-focused time. Women in same-sex couples were more likely than either women or men in different-sex couples to spend such time with children. Overall, women (regardless of the gender of their partners) and men coupled with other men spent significantly more time with children than men coupled with women, conditional on spending any child-focused time. These results support prior research that different-sex couples do not invest in children at appreciably different levels than same-sex couples. We highlight the potential for existing nationally representative data sets to provide preliminary insights into the developmental experiences of children in nontraditional families. PMID- 25911579 TI - Hematopoietic Stem Cell Transplantation in Multiple Myeloma: A Retrospective Study of the Societe Francaise de Greffe de Moelle et de Therapie Cellulaire (SFGM-TC). AB - Because the indication of allograft (allogeneic stem cell transplantation [alloSCT]) for multiple myeloma (MM) has widened in recent years, thanks to the development of reduced-intensity conditionings (RIC), it is still unclear if myeloablative conditioning (MAC) remains appropriate. This study compares retrospectively outcomes of patients undergoing either RIC or MAC regimens for MM. Based on the SFGM-TC registry, we included 446 MM patients receiving alloSCT between 1999 and 2009 for whom a minimal data set was available. Median follow-up for the entire cohort was 33.6 months (range, 0 to 164.5). RIC and MAC populations were different regarding age (53.5 versus 47.1 years, respectively), number of prior autologous (auto)SCTs (93.2% versus 79.6% had at least 2 autoSCTs), and stem cell source (90.2% versus 61.2% received peripheral blood). For RIC and MAC populations the nonrelapse mortality at 2 years was 24.6% and 22.4%, respectively, progression-free survival 35.5% and 51.1%, and overall survival 59.5% and 66.7% (not significant). These outcomes were not affected by conditioning intensity either on univariate or multivariate analysis. Despite some limitations in the study design, these results indicate that MAC should remain a valuable option in alloSCT for MM, especially for young and less-treated patient with no comorbidity. The constant progress in induction treatments of MM and supportive care after alloSCT could improve these results in the near future. PMID- 25911581 TI - Optogenetic excitation of LDTg axons in the VTA reinforces operant responding in rats. AB - The laterodorsal tegmental nucleus (LDTg) importantly contributes to regulating firing activity of midbrain dopamine neurons and forebrain dopamine levels. Whether excitation of LDTg afferents to the ventral tegmental area (VTA) can reinforce operant behavior in rats is not known. Rats received adeno-associated viral vectors encoding channelrhodopsin2 (ChR2) and EYFP or EYFP only into the LDTg and were implanted with bilateral optic probes aimed at the VTA. LDTg ChR2 infected rats, but not LDTg EYFP-infected rats acquired lever pressing to obtain photostimulation into the VTA. During reversal testing, where contingencies between response levers were reversed, LDTg ChR2-infected rats learned to press the alternate, now reinforced, lever within one session. Following pretreatment with the broad-spectrum dopamine receptor blocker flupenthixol LDTg ChR2-infected rats initiated lever-pressing with normal latencies and lever-pressed normally for the first ten minutes of the session. Lever-pressing rates were strongly reduced thereafter. These results provide further support for an important role of LDTg inputs to the VTA in appetitively motivated behaviors. PMID- 25911580 TI - Glucose administration after traumatic brain injury exerts some benefits and no adverse effects on behavioral and histological outcomes. AB - The impact of hyperglycemia after traumatic brain injury (TBI), and even the administration of glucose-containing solutions to head injured patients, remains controversial. In the current study adult male Sprague-Dawley rats were tested on behavioral tasks and then underwent surgery to induce sham injury or unilateral controlled cortical impact (CCI) injury followed by injections (i.p.) with either a 50% glucose solution (Glc; 2g/kg) or an equivalent volume of either 0.9% or 8% saline (Sal) at 0, 1, 3 and 6h post-injury. The type of saline treatment did not significantly affect any outcome measures, so these data were combined. Rats with CCI had significant deficits in beam-walking traversal time and rating scores (p's < 0.001 versus sham) that recovered over test sessions from 1 to 13 days post-injury (p's < 0.001), but these beam-walking deficits were not affected by Glc versus Sal treatments. Persistent post-CCI deficits in forelimb contraflexion scores and forelimb tactile placing ability were also not differentially affected by Glc or Sal treatments. However, deficits in latency to retract the right hind limb after limb extension were significantly attenuated in the CCI-Glc group (p < 0.05 versus CCI-Sal). Both CCI groups were significantly impaired in a plus maze test of spatial working memory on days 4, 9 and 14 post-surgery (p < 0.001 versus sham), and there was no effect of Glc versus Sal on this cognitive outcome measure. At 15 days post-surgery the loss of cortical tissue volume (p < 0.001 versus sham) was significantly less in the CCI-Glc group (30.0%; p < 0.05) compared to the CCI-Sal group (35.7%). Counts of surviving hippocampal hilar neurons revealed a significant (~40%) loss ipsilateral to CCI (p < 0.001 versus sham), but neuronal loss in the hippocampus was not different in the CCI-Sal and CCI-Glc groups. Taken together, these results indicate that an early elevation of blood glucose may improve some neurological outcomes and, importantly, the induction of hyperglycemia after isolated TBI did not adversely affect any sensorimotor, cognitive or histological outcomes. PMID- 25911582 TI - Enhanced visuo-haptic integration for the non-dominant hand. AB - Visuo-haptic integration contributes essentially to object shape recognition. Although there has been a considerable advance in elucidating the neural underpinnings of multisensory perception, it is still unclear whether seeing an object and exploring it with the dominant hand elicits the same brain response as compared to the non-dominant hand. Using fMRI to measure brain activation in right-handed participants, we found that for both left- and right-hand stimulation the left lateral occipital complex (LOC) and anterior cerebellum (aCER) were involved in visuo-haptic integration of familiar objects. These two brain regions were then further investigated in another study, where unfamiliar, novel objects were presented to a different group of right-handers. Here the left LOC and aCER were more strongly activated by bimodal than unimodal stimuli only when the left but not the right hand was used. A direct comparison indicated that the multisensory gain of the fMRI activation was significantly higher for the left than the right hand. These findings are in line with the principle of "inverse effectiveness", implying that processing of bimodally presented stimuli is particularly enhanced when the unimodal stimuli are weak. This applies also when right-handed subjects see and simultaneously touch unfamiliar objects with their non-dominant left hand. Thus, the fMRI signal in the left LOC and aCER induced by visuo-haptic stimulation is dependent on which hand was employed for haptic exploration. PMID- 25911583 TI - Primary afferent neurons express functional delta opioid receptors in inflamed skin. AB - Peripherally-restricted opiate compounds attenuate hyperalgesia in experimental models of inflammatory pain, but have little discernable effect on nociceptive behavior in normal animals. This suggests that activation of opioid receptors on peripheral sensory axons contributes to decreased afferent activity after injury. Previously, we reported that direct application of morphine to cutaneous receptive fields decreased mechanical and heat-evoked responses in a population of C-fiber nociceptors in inflamed skin. Consistent with reported behavioral studies, direct application of morphine had no effect on fiber activity in control skin. The aim of the present study was to determine whether mechanical responsiveness of nociceptors innervating inflamed skin was attenuated by direct activation of delta opioid receptors (DORs) on peripheral terminals. An ex vivo preparation of rat plantar skin and tibial nerve was used to examine effects of a selective DOR agonist, deltorphin II, on responsiveness of single fibers innervating inflamed skin. Electrical recordings were made eighteen hours after injection of complete Freund's adjuvant into the hindpaw. Deltorphin II produced an inhibition of the mechanical responsiveness of single fibers innervating inflamed skin; an effect blocked by the DOR-selective antagonist, naltrindole. The population of units responsive to deltorphin II was identified as consisting of C fiber mechanical nociceptors. PMID- 25911584 TI - Cerebral processing of umami: A pilot study on the effects of familiarity. AB - AIM: The identification of umami taste among people is extremely variable. Based on functional magnetic resonance imaging (fMRI) the aim of this study was to investigate changes of brain activation in participants before and after they were familiarized with this peculiar taste. MATERIAL AND METHOD: A total of 10 healthy, right-handed subjects (7 women, mean age 25 years) participated in this study. A computer-controlled gustometer was used to deliver the umami stimuli at supra-threshold concentrations. After the first session of fMRI experiments, participants went through two weeks of controlled exposure to umami taste, before the second session of fMRI experimentation. RESULTS: Results from psychophysical assessment showed that umami became more familiar (p < 0.001) among the participants after the gustatory exposure. No significant differences for pleasantness and intensity were observed before and after umami training. FMRI data showed that a broader central-nervous network was activated before "umami training" as compared to imaging after "umami training". Significant activation was found in the primary and high level sensory specific gustatory area (insula and anterior cingulate cortex) before training, whereas, significant activation was observed in memory retrieval areas (parahippocampal gyrus) after training. CONCLUSION: The main finding of the present study suggests that repeated exposure to umami taste over a relatively short period of time does not produce an increased response at the level of taste primary and secondary areas, but that increased familiarity with umami leads to an increased activation of the parahippocampal gyrus. PMID- 25911585 TI - High resolution ECG-aided early prognostic model for comatose survivors of out of hospital cardiac arrest. AB - Out of hospital cardiac arrest (OHCA) has a high mortality despite modern treatment. Reliable early prognosis in OHCA could significantly improve clinical decision making. We explored prognostic utility of advanced ECG parameters, obtained from high-resolution ECG, in combination with clinical and OHCA-related parameters during treatment with mild induced hypothermia (MIH) and after rewarming in unconscious survivors of OHCA. Ninety-two patients during MIH and 66 after rewarming were included. During MIH, a score based on initial rhythm, QRS upslope and systolic pressure resulted in an area under curve (AUC) of 0.82 and accuracy of 80% for survival. After rewarming, a score based on admission rhythm, sum of 12 lead QRS voltages, and mean lateral ST segment level in leads I and V6 resulted in an AUC of 0.88 and accuracy of 85% for survival. ECG can assist with early prognostication in unconscious survivors of OHCA during MIH and after rewarming. PMID- 25911586 TI - Soluble Syndecan-1: Does This Biomarker Address a Seemingly Insoluble Problem in Inflammatory Bowel Disease? PMID- 25911587 TI - Randomized controlled clinical trial evaluating multiplex polymerase chain reaction for pathogen identification and therapy adaptation in critical care patients with pulmonary or abdominal sepsis. AB - OBJECTIVE: To determine whether a multiplex polymerase chain reaction (PCR)-based test could reduce the time required for initial pathogen identification in patients in an intensive care unit (ICU) setting. METHODS: This double-blind, parallel-group randomized controlled trial** enrolled adults with suspected pulmonary or abdominal sepsis caused by an unknown pathogen. Both the intervention and control groups underwent the standard blood culture (BC) testing, but additional pathogen identification, based on the results of a LightCycler(r) SeptiFast PCR test, were provided in the intervention group. RESULTS: The study enrolled 37 patients in the control group and 41 in the intervention group. Baseline clinical and demographic characteristics were similar in both groups. The PCR-based test identified a pathogen in 10 out of 41 (24.4%) patients in the intervention group, with a mean duration from sampling to providing the information to the ICU of 15.9 h. In the control group, BC results were available after a significantly longer period (38.1 h). CONCLUSION: The LightCycler(r) SeptiFast PCR test demonstrated a significant reduction in the time required for initial pathogen identification, compared with standard BC. PMID- 25911589 TI - Selective serotonin reuptake inhibitors and venlafaxine in early pregnancy and risk of birth defects: population based cohort study and sibling design. PMID- 25911590 TI - A Model for Interstitial Drainage Through a Sliding Lymphatic Valve. AB - This study investigates fluid flow and elastic deformation in tissues that are drained by the primary lymphatic system. A model is formulated based on the Rossi hypothesis that states that the primary lymphatic valves, which are formed by overlapping endothelial cells around the circumferential lining of lymphatic capillaries, open in response to swelling of the surrounding tissue. Tissue deformation and interstitial fluid flow through the tissue are treated using the Biot equations of poroelasticity and, the fluid flux (into the interstitium) across the walls of the blood capillaries, is assumed to be linearly related to the pressure difference across the walls via a constant of proportionality (the vascular permeability). The resulting model is solved in a periodic domain containing one blood capillary and one lymphatic capillary starting from a configuration in which the tissue is undeformed. On imposition of a constant pressure difference between blood and lymphatic capillaries, the solutions are found to settle to a steady state. Given that the magnitude of pressure fluctuations in the lymphatic system is much smaller than this pressure difference between blood and lymph, it is postulated that the resulting steady state solution gives a good representation of the state of the tissue under physiological conditions. The effects of changes to the Young's modulus of the tissue, the blood-lymphatic pressure difference, vascular permeability and valve dimensions on the steady state are investigated and discussed in terms of their effects on oedema in the context of age- and pregnancy-related changes to the body. PMID- 25911588 TI - Maternal Sick Leave Due to Psychiatric Disorders Following the Birth of a Child With Special Health Care Needs. AB - OBJECTIVE: Child-related stress following the birth of a child with special health care needs (SHCN) can take a toll on parental health. This study examined how the risk of sick leave due to psychiatric disorders (PD) among mothers of children with SHCN compares with that of mothers of children without SHCN during early motherhood. METHODS: Responses from 58,532 mothers participating in the Norwegian Mother and Child Cohort Study were linked to national registries and monitored for physician-certified sick leave from the month of their child's first birthday until the month of their child's fourth birthday. RESULTS: As compared with mothers of children without SHCN, mothers of children with mild and moderate/severe care needs were at substantial risk of a long-term sick leave due to PD in general and due to depression more specifically. CONCLUSIONS: Extensive childhood care needs are strongly associated with impaired mental health in maternal caregivers during early motherhood. PMID- 25911591 TI - A Simple Protein Synthesis Model for the PURE System Operation. AB - The encapsulation of transcription-translation (TX-TL) cell-free machinery inside lipid vesicles (liposomes) is a key element in synthetic cell technology. The PURE system is a TX-TL kit composed of well-characterized parts, whose concentrations are fine tunable, which works according to a modular architecture. For these reasons, the PURE system perfectly fulfils the requirements of synthetic biology and is widely used for constructing synthetic cells. In this work, we present a simplified mathematical model to simulate the PURE system operations. Based on Michaelis-Menten kinetics and differential equations, the model describes protein synthesis dynamics by using 9 chemical species, 6 reactions and 16 kinetic parameters. The model correctly predicts the time course for messenger RNA and protein production and allows quantitative predictions. By means of this model, it is possible to foresee how the PURE system species affect the mechanism of proteins synthesis and therefore help in understanding scenarios where the concentration of the PURE system components has been modified purposely or as a result of stochastic fluctuations (for example after random encapsulation inside vesicles). The model also makes the determination of response coefficients for all species involved in the TX-TL mechanism possible and allows for scrutiny on how chemical energy is consumed by the three PURE system modules (transcription, translation and aminoacylation). PMID- 25911592 TI - Anaerobic co-digestion of cheese whey and the screened liquid fraction of dairy manure in a single continuously stirred tank reactor process: Limits in co substrate ratios and organic loading rate. AB - Mesophilic anaerobic co-digestion of cheese whey and the screened liquid fraction of dairy manure was investigated with the aim of determining the treatment limits in terms of the cheese whey fraction in feed and the organic loading rate. The results of a continuous stirred tank reactor that was operated with a hydraulic retention time of 15.6 days showed that the co-digestion process was possible with a cheese whey fraction as high as 85% in the feed. The efficiency of the process was similar within the range of the 15-85% cheese whey fraction. To study the effect of the increasing loading rate, the HRT was progressively shortened with the 65% cheese whey fraction in the feed. The reactor efficiency dropped as the HRT decreased but enabled a stable operation over 8.7 days of HRT. At these operating conditions, a volumetric methane production rate of 1.37 m(3) CH4 m(-3) d(-1) was achieved. PMID- 25911593 TI - Effect of microalgae supplementation on the silage quality and anaerobic digestion performance of Manyflower silvergrass. AB - The silage quality of Manyflower silvergrass with microalgae supplementation was investigated, and the variation in bacterial communities during ensilage period was analyzed by high-throughput sequencing technology. In addition, the specific methane yields of the silages were also evaluated. Results showed that the samples with microalgae supplementation have lower pH value and higher lactic acid concentration (8.0 mg/g FM). Meanwhile, higher NH3-N concentration was observed since microalgae were N-rich material. Microalgae additions also influenced the bacterial community structure. For the samples without microalgae, the major genus was Enterococcus from day 1 to day 3, and then Lactobacillus became the dominant genus. While the prevalent genus represented in the samples with microalgae supplementation was Lactobacillus. The specific methane yields of all samples were within the range of 153 +/- 1 mL/g VS to 178 +/- 11 mL/g VS and no significant difference was observed. PMID- 25911594 TI - Salinity induced oxidative stress enhanced biofuel production potential of microalgae Scenedesmus sp. CCNM 1077. AB - Microalgal biomass is considered as potential feedstock for biofuel production. Enhancement of biomass, lipid and carbohydrate contents in microalgae is important for the commercialization of microalgal biofuels. In the present study, salinity stress induced physiological and biochemical changes in microalgae Scenedesmus sp. CCNM 1077 were studied. During single stage cultivation, 33.13% lipid and 35.91% carbohydrate content was found in 400 mM NaCl grown culture. During two stage cultivation, salinity stress of 400 mM for 3 days resulted in 24.77% lipid (containing 74.87% neutral lipid) along with higher biomass compared to single stage, making it an efficient strategy to enhance biofuel production potential of Scenedesmus sp. CCNM 1077. Apart from biochemical content, stress biomarkers like hydrogen peroxide, lipid peroxidation, ascorbate peroxidase, proline and mineral contents were also studied to understand the role of reactive oxygen species (ROS) mediated lipid accumulation in microalgae Scenedesmus sp. CCNM 1077. PMID- 25911595 TI - Retrograde approach via left internal mammary artery using a 5 Fr guiding catheter. AB - A 64-year-old female, who had undergone CABG previously, was admitted to our hospital because of non-ST elevation myocardial infarction with acute heart failure. The SVG-RCA was judged the culprit vessel because of the angiographical thrombus. However, primary percutaneous coronary intervention (PCI) in the SVG RCA had a high risk of distal embolism and might have had caused critical slow flow. Primary PCI to the native right coronary artery (RCA) with retrograde approach using the septal channel from left anterior descending artery bypassed by LIMA was successfully performed. A 5 Fr JR-4.0 guiding catheter was deeply engaged to the mid part of LIMA following the microcatheter, and the wire finally reached the distal part of RCA. PMID- 25911596 TI - Biomimicking Robust Hydrogel for the Mesenchymal Stem Cell Carrier. AB - PURPOSE: This study was aimed to develop a hydrogel-nanofiber as an advanced carrier for adipose derived human mesenchymal stem cells (AD-MSCs) and evaluate its potential for immunomodulatory therapies applicable to surface coating of drug eluting stent (DES) against coronary artery diseases (CAD). METHODS: A mixture of dispersing-nanofibers (dNFs) and poly (ethylene glycol)-diacrylate (PEGDA) were blended with sodium alginate to achieve robust mechanical strength. The effects of stem cell niche on cell viability and proliferation rates were evaluated using LDH assay and alamar blue assay, respectively. The amount of Nile red microparticles (NR-MPs) remained in the hydrogel scaffolds was examined as an index for the physical strength of hydrogels. To evaluate the immunomodulatory activity of AD-MSCs as well as their influence by ROS, the level of L-Kynurenine was determined as tryptophan replacement compounds in parallel with IDO secreted from AD-MSCs using a colorimetric assay of L-amino acid. RESULTS: Both SA-cys-PEG and SA-cys-dNF-PEG upon being coated on stents using electrophoretic deposition technique displayed superior mechanical properties against the perfused flow. d NFs had a significant impact on the stability of SA-cys-dNF-PEG, as evidenced by the substantial amount of NR-MPs remained in them. An enhanced subcellular level of ROS by spheroidal cluster yielded the high concentrations of L-Kynurenine (1.67 +/- 0.6 MUM without H2O2, 5.2 +/- 1.14 MUM with 50 MUM of H2O2 and 8.8 +/- 0.51 MUM with 100 MUM of H2O2), supporting the IDO-mediated tryptophan replacement process. CONCLUSION: The "mud-and-straw" hydrogels are robust in mechanical property and can serve as an ideal niche for AD-MSCs with immunomodulatory effects. PMID- 25911597 TI - The value of HCG serum concentrations after trigger in predicting pregnancy and live birth rates in IVF-ICSI. AB - The aim of this study was to determine if an association existed between serum human chorionic gonadotrophin (HCG) level at 12 h after trigger and IVF and intracytoplasmic sperm (ICSI) treatment outcomes. Women undergoing initial IVF ICSI and embryo transfer treatment using the long luteal phase gonadotrophin releasing hormone agonist protocol between April 2012 and March 2013 for tubal factor were included (n = 699). In the clinical pregnancy group, HCG after trigger was significantly elevated (276.0 +/- 5.1 versus 198.5 +/- 6.1 mIU/mL; P < 0.001). The optimal cut-off value proposed by the receiver operating characteristic analysis (area under curve = 0.730) for HCG was 201.2 mIU/ml. Compared with the lower HCG group, the clinical pregnancy rate in the higher HCG group was increased in obese and non-obese patients (77.8% versus 57.3%, P < 0.05; 85.6% versus 53.0%, P < 0.01, respectively). Adjusted for age and body mass index, an increase of HCG was associated with a better IVF-ICSI treatment outcome (OR 4.39, 95% CI 2.99 to 6.45). Clinical pregnancy rate was significantly higher across increasing quartiles of HCG. An elevated level of serum HCG at 12 h after trigger was associated with a better IVF-ICSI outcome. PMID- 25911599 TI - Altered amphiregulin expression induced by diverse luteinizing hormone receptor reactivity in granulosa cells affects IVF outcomes. AB - The expression of specific genes (LHR, AREG, EREG, EGFR, NPPC and NPR2) involved in peri-ovulatory signalling pathways induced by LH surge in granulosa cells was investigated, and their relationships with IVF outcomes analysed. mRNA levels of the genes of 147 infertile women undergoing IVF and intracytoplasmic sperm injection (ICSI) with embryo transfer were evaluated. Compared with non-pregnant women, amphiregulin (AREG) mRNA levels in mural and cumulus graunulosa cells were significantly higher (P < 0.05) in pregnant women, and were positively correlated with number of oocytes retrieved and good-quality embryos. No significant differences were found between the two groups in the remaining detected genes. To investigate the reason for the differences in AREG expression, mural granulosa cells were cultured and stimulated with human chorionic gonadotrophin (HCG) for 2 24 h. At 4 h after HCG stimulation, AREG and epiregulin mRNA expression peaked, with much greater increases in the pregnant group. The fold-change of AREG expression was positively correlated with number of good-quality embryos. No obvious correlation, however, was found between NPPC/Npr2 expression levels in granulosa cells and IVF outcomes. Altered AREG expression induced by diverse luteinizing hormone receptor reactivity in granulosa cells may provide a useful marker for oocyte developmental competency. PMID- 25911598 TI - Impact of whole systems traditional Chinese medicine on in-vitro fertilization outcomes. AB - Patients undergoing IVF may receive either acupuncture or whole-systems traditional Chinese medicine (WS-TCM) as an adjuvant IVF treatment. WS-TCM is a complex intervention that can include acupuncture, Chinese herbal medicine, dietary, lifestyle recommendations. In this retrospective cohort study, 1231 IVF patient records were reviewed to assess the effect of adjuvant WS-TCM on IVF outcomes compared among three groups: IVF with no additional treatment; IVF and elective acupuncture on day of embryo transfer; or IVF and elective WS-TCM. The primary outcome was live birth. Of 1069 non-donor cycles, WS-TCM was associated with greater odds of live birth compared with IVF alone (adjusted odds ratio [AOR] 2.09; 95% confidence interval [CI] 1.36 to 3.21), or embryo transfer with acupuncture only (AOR 1.62; 95% CI 1.04 to 2.52). Of 162 donor cycles, WS-TCM was associated with increased live births compared with all groups (odds Ratio [OR] 3.72; 95% CI 1.05 to 13.24, unadjusted) or embryo transfer with acupuncture only (OR 4.09; 95% CI: 1.02 to 16.38, unadjusted). Overall, IVF with adjuvant WS-TCM was associated with greater odds of live birth in donor and non-donor cycles. These results should be taken cautiously as more rigorous research is needed. PMID- 25911600 TI - An Efficient Estimator for the Expected Value of Sample Information. AB - BACKGROUND: Conventional estimators for the expected value of sample information (EVSI) are computationally expensive or limited to specific analytic scenarios. I describe a novel approach that allows efficient EVSI computation for a wide range of study designs and is applicable to models of arbitrary complexity. METHODS: The posterior parameter distribution produced by a hypothetical study is estimated by reweighting existing draws from the prior distribution. EVSI can then be estimated using a conventional probabilistic sensitivity analysis, with no further model evaluations and with a simple sequence of calculations (Algorithm 1). A refinement to this approach (Algorithm 2) uses smoothing techniques to improve accuracy. Algorithm performance was compared with the conventional EVSI estimator (2-level Monte Carlo integration) and an alternative developed by Brennan and Kharroubi (BK), in a cost-effectiveness case study. RESULTS: Compared with the conventional estimator, Algorithm 2 exhibited a root mean square error (RMSE) 8%-17% lower, with far fewer model evaluations (3-4 orders of magnitude). Algorithm 1 produced results similar to those of the conventional estimator when study evidence was weak but underestimated EVSI when study evidence was strong. Compared with the BK estimator, the proposed algorithms reduced RSME by 18%-38% in most analytic scenarios, with 40 times fewer model evaluations. Algorithm 1 performed poorly in the context of strong study evidence. All methods were sensitive to the number of samples in the outer loop of the simulation. CONCLUSIONS: The proposed algorithms remove two major challenges for estimating EVSI--the difficulty of estimating the posterior parameter distribution given hypothetical study data and the need for many model evaluations to obtain stable and unbiased results. These approaches make EVSI estimation feasible for a wide range of analytic scenarios. PMID- 25911601 TI - Using Dual Beta Distributions to Create "Proper" ROC Curves Based on Rating Category Data. AB - BACKGROUND: Receiver operating characteristic (ROC) analysis helps investigators quantify and describe how well a diagnostic system discriminates between 2 mutually exclusive conditions. The conventional binormal (CvB) curve-fitting model usually produces ROCs that are improper in that they do not have the ever decreasing slope required by signal detection theory. When data sets evaluated under the CvB model have hooks, the resulting ROCs can contain misleading information about the diagnostic performance of the method at low and high false positive rates. OBJECTIVE: To present and evaluate a dual beta (DB) ROC model that assumes diagnostic data arise from 2 beta distributions. The DB model's parameter constraints assure that the resulting ROC curve has a positive, monotonically decreasing slope. DESIGN/METHOD: Computer simulation study comparing results from CvB, DB, and weighted power function (WPF) models. RESULTS: The DB model produces results that are as good as or better than those from the WPF model, and less biased and closer to the true values than curves obtained using the CvB model. CONCLUSIONS: The DB ROC model expresses the relationship between the false positive rate and true positive rate in closed form and allows for quick ROC area calculations using spreadsheet functions. Because it posits simple relationships among the decision axis, operating points, and model parameters, the DB model offers investigators a flexible, easy-to-grasp ROC form that is simpler to implement than other proper ROC models. PMID- 25911602 TI - Choosing a Specialist: Will Patients Vote with Their Feet (and Wallets) for Person-Centered Care? PMID- 25911603 TI - [Bone defect adjusted strategy in revision arthroplasty of the hip : Wich implant in wich situation? Innovations and approved methods]. AB - BACKGROUND: Revision total hip arthroplasty is of rising importance, with 35,000 procedures a year in Germany. OBJECTIVES: Primary stability of the revision implant, reconstruction of the anatomical hip center, reconstruction of bone stock, and permanent secondary integration are the main priorities. METHODS: Current literature and examples from our own experience are presented. RESULTS AND CONCLUSIONS: Novel developments from basic research and industrial partners extend the possibilities for treating affected patients. For an integrated therapy concept in implant selection criteria, such as situation and structure of the defect, combination with any remaining implants, causes of loosening and failure, implant allergy, and patient-specific parameters should be taken into consideration. PMID- 25911604 TI - Is there any effect of first-day usage of a totally implantable venous access device on complications? AB - BACKGROUND: Our aim was to evaluate whether it is safe to use a totally implantable venous access device (TIVAD) on the day of implantation. METHODS: We investigated data from 1315 cancer patients divided into two groups according to the time interval between TIVAD placement and the first use of the TIVAD to adminster chemotherapy: patients whose devices were used during the first 24 h after placement were enrolled into group 1 and patients whose devices were first used more than 24 h after device placement were enrolled into group 2. RESULTS: Early complications were all related to device insertion and occurred before chemotherapy administration. Infection and venous thrombosis were the most frequent complications during the first 6 months after TIVAD insertion in both groups. However, the frequency of late complications was statistically the same for the two groups. CONCLUSIONS: The early use of TIVADs appears safe. Usage of the catheter for chemotherapy administration during the first 24 h after insertion has no effect on the rate of complications. PMID- 25911605 TI - Accumulation of metabolic cardiovascular risk factors in black and white young adults over 20 years. AB - BACKGROUND: Cross-sectional clustering of metabolic risk factors for cardiovascular disease in middle-aged adults is well described, but less is known regarding the order in which risk factors develop through young adulthood and their relation to subclinical atherosclerosis. METHOD AND RESULTS: A total of 3178 black and white women and men in the Coronary Artery Risk Development in Young Adults study were assessed to identify the order in which cardiovascular disease risk factors including diabetes, hypertension, dyslipidemia (low high density lipoprotein cholesterol or high triglyceride levels), hypercholesterolemia (high total or low-density lipoprotein cholesterol), and obesity develop. Observed patterns of risk factor development were compared with those expected if risk factors accumulated randomly, given their overall distribution in the population. Over the 20 years of follow-up, 80% of participants developed at least 1 risk factor. The first factor to occur was dyslipidemia in 39% of participants, obesity in 20%, hypercholesterolemia in 11%, hypertension in 7%, and diabetes in 1%. Dyslipidemia was the only risk factor both to occur first and to be followed by additional risk factors more often than expected (P<0.001 for both). Order of risk factor accrual did not affect subclinical atherosclerosis at year 20. Results were similar by sex, race, and smoking status. CONCLUSIONS: Multiple patterns of cardiovascular risk factor development were observed from young adulthood to middle age. Dyslipidemia, a potentially modifiable condition, often preceded the development of other risk factors and may be a useful target for intervention and monitoring. PMID- 25911607 TI - A comorbidity prognostic effect on post-hospitalization outcome in a geriatric rehabilitation setting: the pivotal role of functionality, assessed by mediation model, and association with the Brass index. AB - BACKGROUND: Discharge planning is a critical feature of hospital's care in geriatric rehabilitation centers. The aim of this study was to evaluate the effects of comorbidity and functionality in identifying patients who are at risk of discharge problems. We also evaluate the association between Blaylock Risk Assessment Screening Score, BRASS index (BI), and post-hospitalization outcome (PHO). METHODS: Eighty patients (58 women and 22 men, with mean age equal to 83.28 +/- 6.77 years) at geriatric rehabilitation division admission were screened with Geriatric Multidimensional Assessment (GMA). Then, BI and PHO were evaluated (mean follow-up time was 205.1 +/- 95.8 days). By Structural Equation Model, we evaluated the existing causal relationships between comorbidity, functionality and PHO, elements of GMA, and the association between PHO and BI. RESULTS: Comorbidity acted on PHO through functionality with indirect effect only (+0.703, P = 0.019). So, the functionality assumes a pivotal role of the causal relationship comorbidity to PHO. BI is positively associated with PHO: correlation returned was equal to +0.313 (P = 0.019). CONCLUSIONS: The comorbidity has a role in getting worse PHO, but its effect is possible only through the mediation of functional status. The study also demonstrated the positive association between BI and PHO. PMID- 25911608 TI - Reduction of falls in older people by improving balance with vestibular rehabilitation (ReFOVeRe study): design and methods. AB - MAIN OBJECTIVE: Evaluate the effectiveness of vestibular rehabilitation (VR) to improve the balance in older people, assessed immediately afterwards. SECONDARY OBJECTIVES: (a) To verify the maintenance of improvement of the balance achieved in the medium term (6-12 months). (b) To consider whether this improvement results in a reduction in the number of falls. (c) To compare among themselves the effectiveness of three different methods of VR in improving balance and to explore whether there are differences to achieve a reduction in the number of falls. METHODOLOGY: DESIGN: Experimental study, single-centre, open, randomised (balanced blocks of patients) in four branches in parallel, in 220 elderly patients (over 64 years) with high risk of falls and a follow-up period of 12 months. SETTING: Department of Otolaryngology of the University Hospital of Santiago. PARTICIPANTS: People over 64 years, fulfilling one of the following requirements: (a) At least one fall in the last year. (b) Take at least 16 s or require some support in perform the test "timed up and go". (c) A percentage of average balance in the sensory organisation test (SOT) in the dynamic posturography (CDP) <68%. (d) At least one fall in any of the conditions in the SOT of CDP. INTERVENTION: Three different protocols of VR. MAIN OUTCOME MEASURE: The percentage of average balance in the SOT in CDP. Secondary measures: time and supports in the test of "timed up and go", scores of the dynamic posturography and SwayStar system, and rate of falls. PMID- 25911606 TI - hERG potassium channel blockade by the HCN channel inhibitor bradycardic agent ivabradine. AB - BACKGROUND: Ivabradine is a specific bradycardic agent used in coronary artery disease and heart failure, lowering heart rate through inhibition of sinoatrial nodal HCN-channels. This study investigated the propensity of ivabradine to interact with KCNH2-encoded human Ether-a-go-go-Related Gene (hERG) potassium channels, which strongly influence ventricular repolarization and susceptibility to torsades de pointes arrhythmia. METHODS AND RESULTS: Patch clamp recordings of hERG current (IhERG) were made from hERG expressing cells at 37 degrees C. Ih ERG was inhibited with an IC50 of 2.07 MUmol/L for the hERG 1a isoform and 3.31 MUmol/L for coexpressed hERG 1a/1b. The voltage and time-dependent characteristics of Ih ERG block were consistent with preferential gated-state dependent channel block. Inhibition was partially attenuated by the N588K inactivation-mutant and the S624A pore-helix mutant and was strongly reduced by the Y652A and F656A S6 helix mutants. In docking simulations to a MthK-based homology model of hERG, the 2 aromatic rings of the drug could form multiple pi pi interactions with the aromatic side chains of both Y652 and F656. In monophasic action potential (MAP) recordings from guinea-pig Langendorff-perfused hearts, ivabradine delayed ventricular repolarization and produced a steepening of the MAPD90 restitution curve. CONCLUSIONS: Ivabradine prolongs ventricular repolarization and alters electrical restitution properties at concentrations relevant to the upper therapeutic range. In absolute terms ivabradine does not discriminate between hERG and HCN channels: it inhibits Ih ERG with similar potency to that reported for native If and HCN channels, with S6 binding determinants resembling those observed for HCN4. These findings may have important implications both clinically and for future bradycardic drug design. PMID- 25911609 TI - High prevalence of undiagnosed vertebral fractures in patients suffering from hip fracture at their hospital admission: weak concordance among observers. AB - BACKGROUND: Vertebral fracture is often underdiagnosed. Patients with hip fracture may suffer from vertebral fracture without knowing it. The diagnosis of vertebral fracture is sometimes difficult because there is no consensus regarding the definition of osteoporotic vertebral fracture, and several indexes may be used to diagnose it and the concordance between several observers may not be optimal. OBJECTIVE: To study the concordance in the diagnosis of vertebral fracture done by three different doctors: an orthopedic surgeon, a radiologist, and a bone mineral metabolism expert. METHODS: A lateral thoracic-lumbar spine X Ray was performed in 177 patients suffering from hip fracture to assess the presence or absence of vertebral fractures. Three different observers applied Genant's criteria for it. Concordance between observers was measured using Cohen's kappa coefficient. RESULTS: Patients suffering from hip fractures have undiagnosed vertebral fractures in a range that varies from 41.8 to 47.5% depending on the observer. The concordance in the diagnosis of vertebral fractures is quite low, ranging a Cohen's kappa coefficient from 0.43 to 0.55 and a percentage of concordance varying from 64 to 72%. The best concordance was found between observers 1 and 3. DISCUSSION: Depending on the observer who made the diagnosis, the prevalence of previously undiagnosed vertebral fractures in patients with HF varied widely. We selected three different observers to assess the possible differences in the diagnosis of vertebral fractures among these patients and using the same method (Genant's semi-quantitative assessment), surprisingly, there was little concordance among the three of them. CONCLUSION: Patients with hip fracture have high prevalence of undiagnosed vertebral fractures. The diagnosis of these fractures varies widely depending on the observers and the Cohen's kappa coefficient and percentage of concordance is rather low. PMID- 25911610 TI - Sphingosine 1-phosphate counteracts insulin signaling in pancreatic beta-cells via the sphingosine 1-phosphate receptor subtype 2. AB - Glucolipotoxic stress has been identified as a key player in the progression of pancreatic beta-cell dysfunction contributing to insulin resistance and the development of type 2 diabetes mellitus (T2D). It has been suggested that bioactive lipid intermediates, formed under lipotoxic conditions, are involved in these processes. Here, we show that sphingosine 1-phosphate (S1P) levels are not only increased in palmitate-stimulated pancreatic beta-cells but also regulate beta-cell homeostasis in a divergent manner. Although S1P possesses a prosurvival effect in beta-cells, an enhanced level of the sphingolipid antagonizes insulin mediated cell growth and survival via the sphingosine 1-phosphate receptor subtype 2 (S1P2) followed by an inhibition of Akt-signaling. In an attempt to investigate the role of the S1P/S1P2 axis in vivo, the New Zealand obese (NZO) diabetic mouse model, characterized by beta-cell loss under high-fat diet (HFD) conditions, was used. The occurrence of T2D was accompanied by an increase of plasma S1P levels. To examine whether S1P contributes to the morphologic changes of islets via S1P2, the receptor antagonist JTE-013 was administered. Most interestingly, JTE-013 rescued beta-cell damage clearly indicating an important role of the S1P2 in beta-cell homeostasis. Therefore, the present study provides a new therapeutic strategy to diminish beta-cell dysfunction and the development of T2D. PMID- 25911611 TI - Junctional adhesion molecule B interferes with angiogenic VEGF/VEGFR2 signaling. AB - De novo formation of blood vessels is a pivotal mechanism during cancer development. During the past few years, antiangiogenic drugs have been developed to target tumor vasculature. However, because of limitations and adverse effects observed with current therapies, there is a strong need for alternative antiangiogenic strategies. Using specific anti-junctional adhesion molecule (JAM) B antibodies and Jam-b-deficient mice, we studied the role in antiangiogenesis of JAM-B. We found that antibodies against murine JAM-B, an endothelium-specific adhesion molecule, inhibited microvessel outgrowth from ex vivo aortic rings and in vitro endothelial network formation. In addition, anti-JAM-B antibodies blocked VEGF signaling, an essential pathway for angiogenesis. Moreover, increased aortic ring branching was observed in aortas isolated from Jam-b deficient animals, suggesting that JAM-B negatively regulates proangiogenic pathways. In mice, JAM-B expression was detected in de novo-formed blood vessels of tumors, but anti-JAM-B antibodies unexpectedly did not reduce tumor growth. Accordingly, JAM-B deficiency in vivo had no impact on blood vessel formation, suggesting that targeting JAM-B in vivo may be offset by other proangiogenic mechanisms. In conclusion, despite the promising effects observed in vitro, targeting JAM-B during tumor progression seems to be inefficient as a stand-alone antiangiogenesis therapy. PMID- 25911612 TI - Submembrane ATP and Ca2+ kinetics in alpha-cells: unexpected signaling for glucagon secretion. AB - Cytoplasmic ATP and Ca(2+) are implicated in current models of glucose's control of glucagon and insulin secretion from pancreatic alpha- and beta-cells, respectively, but little is known about ATP and its relation to Ca(2+) in alpha cells. We therefore expressed the fluorescent ATP biosensor Perceval in mouse pancreatic islets and loaded them with a Ca(2+) indicator. With total internal reflection fluorescence microscopy, we recorded subplasma membrane concentrations of Ca(2+) and ATP ([Ca(2+)]pm; [ATP]pm) in superficial alpha- and beta-cells of intact islets and related signaling to glucagon and insulin secretion by immunoassay. Consistent with ATP's controlling glucagon and insulin secretion during hypo- and hyperglycemia, respectively, the dose-response relationship for glucose-induced [ATP]pm generation was left shifted in alpha-cells compared to beta-cells. Both cell types showed [Ca(2+)]pm and [ATP]pm oscillations in opposite phase, probably reflecting energy-consuming Ca(2+) transport. Although pulsatile insulin and glucagon release are in opposite phase, [Ca(2+)]pm synchronized in the same phase between alpha- and beta-cells. This paradox can be explained by the overriding of Ca(2+) stimulation by paracrine inhibition, because somatostatin receptor blockade potently stimulated glucagon release with little effect on Ca(2+). The data indicate that an alpha-cell-intrinsic mechanism controls glucagon in hypoglycemia and that paracrine factors shape pulsatile secretion in hyperglycemia. PMID- 25911613 TI - Novel role for retinol-binding protein 4 in the regulation of blood pressure. AB - Elevated levels of serum retinol-binding protein 4 (RBP4) contribute to insulin resistance and correlate with increased prevalence of hypertension and myocardial infarction. We sought to determine whether lowering RBP4 would improve blood pressure (BP) and protect against obesity- or angiotensin (Ang)-II-induced hypertension. Systolic and diastolic BP were lower in the RBP4-knockout (RBP4-KO) mice and higher in the RBP4-overexpressing (RBP4-Tg) mice compared with BP in the wild-type (WT) littermates. Carbachol-induced vasodilatation was increased in arteries from the RBP4-KO compared with the WT mice and was impaired in the RBP4 Tg mice. Aortic eNOS(Ser1177) phosphorylation was enhanced ~50% in the RBP4-KO mice, with no change in total eNOS protein. Feeding a high-fat diet increased BP in the RBP4-KO mice only to the level in the WT mice fed chow and had no effect on aortic eNOS(Ser1177) phosphorylation. Ang-II infusion resulted in 22 mmHg lower systolic BP in the RBP4-KO than in the WT mice, although the relative BP increase over saline infusion was ~30% in both. Ang-II treatment decreased aortic eNOS(Ser1177) phosphorylation in the WT and RBP4-KO mice, but phosphorylation remained higher in the RBP4-KO mice. Cardiac hypertrophy with Ang-II treatment was diminished by 56% in the RBP4-KO mice. Thus, elevated serum RBP4 raises BP and lack of RBP4 reduces it, with commensurate changes in aortic eNOS(Ser1177) phosphorylation. Lowering RBP4 may reduce BP through enhanced eNOS-mediated vasodilatation and may be a novel therapeutic approach for hypertension. PMID- 25911614 TI - Crucial role of nicotinic alpha5 subunit variants for Ca2+ fluxes in ventral midbrain neurons. AB - Neuronal nicotinic acetylcholine receptors (nAChRs) containing the alpha5 subunit modulate nicotine consumption, and the human CHRNA5 rs16969968 polymorphism, causing the replacement of the aspartic acid residue at position 398 with an asparagine (alpha5DN), has recently been associated with increased use of tobacco and higher incidence of lung cancer. We show that in ventral midbrain neurons, the alpha5 subunit is essential for heteromeric nAChR-induced intracellular-free Ca(2+) concentration elevations and that in alpha5(-/-) mice, a class of large amplitude nicotine-evoked currents is lost. Furthermore, the expression of the alpha5DN subunit is not able to restore nicotinic responses, indicating a loss of function by this subunit in native neurons. To understand how alpha5DN impairs heteromeric nAChR functions, we coexpressed alpha4, alpha5, or alpha5DN subunits with a dimeric concatemer (beta2alpha4) in a heterologous system, to obtain nAChRs with fixed stoichiometry. Both alpha5(beta2alpha4)2 and alpha5DN(beta2alpha4)2 nAChRs yielded similar levels of functional expression and Ca(2+) permeability, measured as fractional Ca(2+) currents (8.2 +/- 0.7% and 8.0 +/- 1.9%, respectively), 2-fold higher than alpha4(beta2alpha4)2. Our results indicate that the loss of function of nicotinic responses observed in alpha5DN expressing ventral midbrain neurons is neither due to an intrinsic inability of this subunit to form functional nAChRs nor to an altered Ca(2+) permeability but likely to intracellular modulation. PMID- 25911615 TI - Early induction of a prechondrogenic population allows efficient generation of stable chondrocytes from human induced pluripotent stem cells. AB - Regeneration of human cartilage is inherently inefficient; an abundant autologous source, such as human induced pluripotent stem cells (hiPSCs), is therefore attractive for engineering cartilage. We report a growth factor-based protocol for differentiating hiPSCs into articular-like chondrocytes (hiChondrocytes) within 2 weeks, with an overall efficiency >90%. The hiChondrocytes are stable and comparable to adult articular chondrocytes in global gene expression, extracellular matrix production, and ability to generate cartilage tissue in vitro and in immune-deficient mice. Molecular characterization identified an early SRY (sex-determining region Y) box (Sox)9(low) cluster of differentiation (CD)44(low)CD140(low) prechondrogenic population during hiPSC differentiation. In addition, 2 distinct Sox9-regulated gene networks were identified in the Sox9(low) and Sox9(high) populations providing novel molecular insights into chondrogenic fate commitment and differentiation. Our findings present a favorable method for generating hiPSC-derived articular-like chondrocytes. The hiChondrocytes are an attractive cell source for cartilage engineering because of their abundance, autologous nature, and potential to generate articular-like cartilage rather than fibrocartilage. In addition, hiChondrocytes can be excellent tools for modeling human musculoskeletal diseases in a dish and for rapid drug screening. PMID- 25911616 TI - Human AAT gene transfer to pig liver improved by using a perfusion isolated organ endovascular procedure. AB - OBJECTIVE: The efficiency of endovascular liver gene transfer in pigs is evaluated by comparing two models of retrograde catheterization: single lobe catheterization with portal inflow (open procedure) versus whole liver isolation with portal and inferior vena cava blockage (close procedure). METHODS: Percutaneous endovascular catheterization was performed in pigs. Open procedure (n = 3): 8Fr balloon catheter placement in a suprahepatic branch through the jugular vein. Closed procedure (n = 3): simultaneous catheterization of the intrahepatic portal vein (transhepatic catheterization, 10Fr balloon catheter), the supra- and infrahepatic cava veins (8Fr balloon catheters through the jugular and femoral veins). In both models, 200 ml of hAAT DNA solution (20 MUg/ml) were retrogradely injected at 20 ml/s. Tissue samples (8 per liver) were obtained 14 days later and the exogenous DNA, RNA and protein per cell were quantified. Blood samples were collected periodically for transaminase determination in all the animals. RESULTS: The open procedure achieved lower (approx. 1000-fold) DNA delivery, resulting in a significantly lower (p < 0.001) gene transcription (> 100-fold). The closed model also achieved a higher translation index, although differences were smaller (p < 0.001). CONCLUSIONS: Portal inflow blockage increased the delivery, transcription and translation indexes, significantly improving the final procedure efficacy when compared with an open procedure. KEY POINTS: Endovascular hydrodynamic pig liver gene transfer: open procedure versus closed procedure. Open procedure resulted in much lower DNA delivery than closed model. Open procedure reached significantly lower gene transcription index. Translation index with closed model was higher than with the open. PMID- 25911617 TI - Development and psychometric assessment of the healthcare provider cultural competence instrument. AB - This study presents the measurement properties of 5 scales used in the Healthcare Provider Cultural Competence Instrument (HPCCI). The HPCCI measures a health care provider's cultural competence along 5 primary dimensions: (1) awareness/sensitivity, (2) behaviors, (3) patient-centered communication, (4) practice orientation, and (5) self-assessment. Exploratory factor analysis demonstrated that the 5 scales were distinct, and within each scale items loaded as expected. Reliability statistics indicated a high level of internal consistency within each scale. The results indicate that the HPCCI effectively measures the cultural competence of health care providers and can provide useful professional feedback for practitioners and organizations seeking to increase a practitioner's cultural competence. PMID- 25911618 TI - Gillick, bone marrow and teenagers. AB - The Human Tissue Authority can authorise a bone marrow harvest on a child of any age if a person with parental responsibility consents to the procedure. Older children have the legal capacity to consent to medical procedures under Gillick, but it is unclear if Gillick can be applied to non-therapeutic medical procedures. The relevant donation guidelines state that the High Court shall be consulted in the event of a disagreement, but what is in the best interests of the teenage donor under s.1 of the Children Act 1989? There are no legal authorities on child bone marrow harvests in the United Kingdom. This article considers the best interests of the older saviour sibling and questions whether, for the purposes of welfare, the speculative benefits could outweigh the physical burdens. PMID- 25911619 TI - Psychosocial work exposures among European employees: explanations for occupational inequalities in mental health. AB - BACKGROUND: Social inequalities in mental health have been demonstrated but understanding the mechanisms remains unclear. This study aims at exploring the role of psychosocial work factors in explaining occupational inequalities in mental health among European employees. METHODS: The study sample covered 33,443 employees coming from the European Working Conditions Survey 2010. Mental health was measured by the WHO-5 well-being index and socioeconomic position by occupation. Twenty-five psychosocial work factors were constructed including job demands, job influence and development, role stressors, social support, quality of leadership, discrimination, violence at work, working hours, job promotion, job insecurity and work-life imbalance. Multilevel linear regressions and bootstrap analyses were performed. RESULTS: Occupational differences were observed for poor mental health and almost all psychosocial work factors. Factors related to job demands, influence and development at work, social relationships and leadership, working hours and other factors contributed to explain the occupational inequalities in mental health. In particular, factors related to influence and development contributed substantially. Among men, workplace violences were found to contribute little whereas among women these factors did not play a role. CONCLUSIONS: Future prevention interventions should have a broad and comprehensive focus in order to reduce social inequalities in mental health. PMID- 25911620 TI - Validation of a simple tool to assess risk of waterpipe tobacco smoking among sixth and seventh graders in Lebanon. AB - BACKGROUND: Waterpipe tobacco smoking (WTS) is highly prevalent in the Eastern Mediterranean region. While studies have identified socio-demographic factors differentiating smokers from non-smokers, validated tools predicting WTS are lacking. METHODS: Over 1000 (n = 1164) sixth and seventh grade students in Lebanon were randomly assigned to a prediction model group and validation model group. In the prediction model group, backward stepwise logistic regression enabled the identification of socio-demographic and psychosocial factors associated with ever and current WTS. This formed risk scores which were tested on the validation model group. RESULTS: The risk score for current WTS was out of four and included reduced religiosity, cigarette use and the perception that WTS was associated with a good time. The risk score for ever WTS was out of seven and included an additional two variables: increased age and the belief that WTS did not cause oral cancer. In the validation model group, the model displayed moderate discrimination [area under the curve: 0.77 (current), 0.68 (ever)], excellent goodness-of-fit (P > 0.05 for both) and optimal sensitivity and specificity of 80.1 and 58.4% (current), and 39.5 and 94.4%, (ever), respectively. CONCLUSIONS: WTS use can be predicted using simple validated tools. These can direct health promotion and legislative interventions. PMID- 25911621 TI - Feasibility of an Assessment Tool for Children's Competence to Consent to Predictive Genetic Testing: a Pilot Study. AB - Knowledge on children's capacities to consent to medical treatment is limited. Also, age limits for asking children's consent vary considerably between countries. Decision-making on predictive genetic testing (PGT) is especially complicated, considering the ongoing ethical debate. In order to examine just age limits for alleged competence to consent in children, we evaluated feasibility of a standardized assessment tool, and investigated cutoff ages for children's competence to consent to PGT. We performed a pilot study, including 17 pediatric outpatients between 6 and 18 years at risk for an autosomal dominantly inherited cardiac disease, eligible for predictive genetic testing. The reference standard for competence was established by experts trained in the relevant criteria for competent decision-making. The MacArthur Competence Assessment Tool for Treatment (MacCAT-T) served as index test. Data analysis included raw agreement between competence classifications, difference in mean ages between children judged competent and judged incompetent, and estimation of cutoff ages for judgments of competence. Twelve (71 %) children were considered competent by the reference standard, and 16 (94 %) by the MacCAT-T, with an overall agreement of 76 %. The expert judgments disagreed in most cases, while the MacCAT-T judgments agreed in 65 %. Mean age of children judged incompetent was 9.3 years and of children judged competent 12.1 years (p = .035). With 90 % sensitivity, children younger than 10.0 years were judged incompetent, with 90 % specificity children older than 11.8 years were judged competent. Feasibility of the MacCAT-T in children is confirmed. Initial findings on age cutoffs are indicative for children between the age of 12 and 18 to be judged competent for involvement in the informed consent process. Future research on appropriate age-limits for children's alleged competence to consent is needed. PMID- 25911622 TI - "Not Tied Up Neatly with a Bow": Professionals' Challenging Cases in Informed Consent for Genomic Sequencing. AB - As the use of genomic technology has expanded in research and clinical settings, issues surrounding informed consent for genome and exome sequencing have surfaced. Despite the importance of informed consent, little is known about the specific challenges that professionals encounter when consenting patients or research participants for genomic sequencing. We interviewed 29 genetic counselors and research coordinators with considerable experience obtaining informed consent for genomic sequencing to understand their experiences and perspectives. As part of this interview, 24 interviewees discussed an informed consent case they found particularly memorable or challenging. We analyzed these case examples to determine the primary issue or challenge represented by each case. Challenges fell into two domains: participant understanding, and facilitating decisions about testing or research participation. Challenges related to participant understanding included varying levels of general and genomic literacy, difficulty managing participant expectations, and contextual factors that impeded participant understanding. Challenges related to facilitating decision-making included complicated family dynamics such as disagreement or coercion, situations in which it was unclear whether sequencing research would be a good use of participant time or resources, and situations in which the professional experienced disagreement or discomfort with participant decisions. The issues highlighted in these case examples are instructive in preparing genetics professionals to obtain informed consent for genomic sequencing. PMID- 25911623 TI - Lead bioaccessibility in 12 contaminated soils from China: Correlation to lead relative bioavailability and lead in different fractions. AB - This study investigated the relationship between Pb relative bioavailability (RBA) and bioaccessibility, and their relationships with Pb in different pools in soils. Twelve Pb-contaminated soils representing different contamination sources from China were analyzed for Pb bioaccessibility using four in vitro methods (UBM, SBRC, IVG, and PBET), Pb-RBA using a mouse blood model, and Pb fractionation using sequential extraction. Lead bioaccessibility in the gastric phase (GP) and Pb-RBA was generally lower in mining soils (0.46-29% and 7.0-26%) than smelting (19-92% and 31-84%) and farming soils (13-99% and 51-61%), with more Pb in the residual fraction in mining soils. Lead bioaccessibility varied with assays, with SBRC (3.0-99%) producing significantly higher bioaccessible Pb than other assays (0.46-84%) in the gastric phase. However, Pb bioaccessibility in the intestinal phase (IP) of all assays sharply decreased to 0.01-20% possibly due to Pb sorption to solid phase at higher pH. Lead bioaccessibility by UBM-GP assay was best correlated with Pb-RBA (r(2) = 0.67), followed by IVG-GP (r(2) = 0.55). Among different Pb fractions, strong correlation was found between Pb bioaccessibility/Pb-RBA and the sum of exchangeable and carbonate fractions. Our study suggested that UBM-GP assay has potential to determine Pb bioaccessibility in contaminated soils in China. PMID- 25911624 TI - Design, synthesis and structure-activity relationship of oxazolidinone derivatives containing novel S4 ligand as FXa inhibitors. AB - A novel series of potent and efficacious factor Xa inhibitors which possesses pyrrole/indole/thiazole moieties as S4 binding element was identified. Compound 7b showed strong human factor Xa inhibitory activity (IC50 = 2.01 nM) and anticoagulant activities in both human (PTCT2 = 0.15 MUM, APPTCT2 = 0.30 MUM) and rabbit plasma (PTCT2 = 0.46 MUM, APPTCT2 = 0.75 MUM). The SARs analyses indicated that the size and water solubility of different alkylamino group at the position of S4 ligand were responsible for the anticoagulant activity. PMID- 25911625 TI - Synthesis and antitumor activities evaluation of m-(4-morpholinoquinazolin-2 yl)benzamides in vitro and in vivo. AB - In the present study, a series of m-(4-morpholinoquinazolin-2-yl)benzamides were designed, synthesized and characterized. The antiproliferative activities of the synthesized compounds were evaluated against two human cell lines (HCT-116 and MCF-7). Compounds with IC50 values below 4 MUM were further evaluated against U 87 MG and A549 cell lines. Among these evaluated compounds, compound T10 displayed a remarkable antiproliferative effect in vitro. The hoechst staining assay showed that compound T10 caused morphological changes. The cell cycle and apoptosis assay further indicated that compound T10 can arrest HCT-116 cells in G2/M and G0/G1 phase and induce apoptosis. PI3K enzyme assays indicated that compounds T7 and T10 selectively inhibit PI3Kalpha. A Western bolt assay further suggested that compound T10 can block the PI3K/Akt/mTOR pathway. Moreover, compound T10 inhibited tumor growth on a mice S180 homograft model. These findings directly identify m-(4-morpholinoquinazolin-2-yl)benzamide derivatives as novel anticancer agents. PMID- 25911626 TI - Nipple-Sparing Mastectomy via an Inframammary Fold Incision with Implant-Based Reconstruction in Patients with Prior Cosmetic Breast Surgery. AB - BACKGROUND: Nipple-sparing mastectomy through an inframammary fold incision (NSM IMF) with implant-based reconstruction (IBR) is a cosmetically preferable approach to breast cancer treatment in appropriate candidates. However, patients who have undergone prior cosmetic breast surgery (CBS) may be at increased risk for postoperative complications secondary to existing surgical scars. OBJECTIVE: To assess whether prior CBS increases the risk of complications following NSM-IMF with IBR. METHODS: A retrospective chart review was conducted for 398 NSM-IMFs with IBR performed between July 2006 and December 2013. CBS cases were identified. Outcomes were reviewed. RESULTS: Of 398 NSM-IMF cases, 41 had prior CBS: 24 augmentations, 12 reductions, three mastopexies, and two augmentation mastopexies. NSM-IMF was performed an average of 8 years following CBS. CBS cases had lower BMIs (P = .040), more breast tissue resected (P = .021), wider breast bases (P = .0002), more single-stage reconstructions (P < .0001), more ADM use (P < .0001), and larger permanent implants (P = .0051) than those without CBS. Postoperatively, CBS cases had higher rates of mastectomy flap ischemia (P = .0392) and hematoma (P = .0335). Among CBS cases, single-stage reconstruction was associated with increased full-thickness flap ischemia (P = .0066). Compared to prior augmentation cases, prior reduction/mastopexy cases had higher rates of capsular contracture (P = .0409) and seroma (P = .0226). CONCLUSIONS: This series is the largest to date to evaluate the success of NSM-IMF with IBR in CBS patients. These women should be cautiously considered for IBR, particularly in the setting of single-stage reconstruction. LEVEL OF EVIDENCE: 4 Therapeutic. PMID- 25911627 TI - Safety of Cosmetic Procedures in Elderly and Octogenarian Patients. AB - BACKGROUND: The proportion of elderly patients in North America is increasing. This has resulted in an increased number of elderly patients undergoing cosmetic procedures. OBJECTIVES: The purpose of this study was to determine the incidence of postoperative complications in elderly patients (age >=65) undergoing elective aesthetic plastic surgical procedures compared with younger patients. METHODS: A total of 183,914 cosmetic surgical procedures were reviewed using the prospectively enrolled cohort of patients in the CosmetAssure database. Comorbidities and postoperative complications in elderly and younger patient groups were recorded and compared. A separate analysis of postoperative complications was performed in the octogenarian subgroup (age >=80). RESULTS: A total of 6786 elderly patients who underwent cosmetic procedures were included in the study. Mean ages (+/-standard deviation) in elderly and younger patients were 69.1 +/- 4.1 and 39.2 +/- 12.5 years, respectively. The elderly patient population had more men, a higher mean body mass index (BMI), a higher prevalence of diabetes mellitus (DM), and fewer smokers compared with the younger patients. The overall postoperative complication rate was not significantly different between elderly and younger patients. When stratified by type of cosmetic procedure, only abdominoplasty was associated with a higher postoperative complication rate in elderly compared with younger patients. The most common postoperative complications in elderly patients were hematoma and infection. The overall postoperative complication rate in octogenarians was 2.2%, which was not significantly different from the younger population. CONCLUSIONS: Cosmetic procedures in elderly patients, including octogenarians, remain safe with an acceptable complication rate compared to younger patients. PMID- 25911628 TI - The Effect of Hering's Law on Different Ptosis Repair Methods. AB - BACKGROUND: The Hering's law effect has significant importance in surgical planning and outcomes of eyelid surgery. OBJECTIVES: The current study examined the preoperative and intraoperative effect of Hering's law in Mullerectomy and levator aponeurosis advancement. METHODS: A retrospective analysis was conducted of 52 patients with unilateral ptosis who underwent surgical repair from January 2011 through June 2013. Patients underwent levator aponeurosis advancement or Mullerectomy with or without tarsectomy. Preoperative and postoperative clinical documentation and photographs were evaluated. Preoperative Hering's dependency and postoperative changes in positioning of the non-operated eyelid were measured. The decision to operate on the ptotic eye alone or on both eyelids was based on preoperative Hering's dependence and intraoperative changes in the contralateral eyelid. RESULTS: Fifty-two patients with unilateral ptosis were included. Average age was 63.3 +/- 20.1 years (range, 22-88 years; median, 61 years); 34 (65.4%) were female. The 14 cases that were not aponeurotic (either congenital, secondary to trauma, or due to postoperative ptosis) did not need contralateral repair (p = .000). In 4 (19%) cases of Mullerectomy and in 9 (52.9%) cases of levator advancement, both eyelids required surgery (p = .029). Hering's law effect was significantly more apparent in the levator advancement approach than in Mullerectomy. CONCLUSIONS: Levator surgery resulted in a higher incidence of combined intraoperative and postoperative Hering's law effect than did Mullerectomy. Cases with poor levator function or congenital ptosis can be repaired unilaterally with no need for contralateral surgery. The fibrotic levator palpebrae muscle and its special innervations probably explain this phenomenon. This should be considered in surgical planning. PMID- 25911629 TI - Superficial Enhanced Fluid Fat Injection (SEFFI) to Correct Volume Defects and Skin Aging of the Face and Periocular Region. AB - BACKGROUND: Although recent research on micro fat has shown the potential advantages of superficial implantation and high stem cell content, clinical applications thus far have been limited. OBJECTIVES: The authors report their experience with superficial enhanced fluid fat injection (SEFFI) for the correction of volume loss and skin aging of the face in general and in the periocular region. METHODS: The finer SEFFI preparation (0.5 mL) was injected into the orbicularis in the periorbital and perioral areas, and the 0.8-mL preparation was injected subdermally elsewhere in the face. RESULTS: The records of 98 consecutive patients were reviewed. Average follow-up time was 6 months, and average volume of implanted fat was 20 mL and 51.4 mL for the 0.5-mL and 0.8 mL preparations, respectively. Good or excellent results were achieved for volume restoration and skin improvement in all patients. Complications were minor and included an oil cyst in 3 patients. The smaller SEFFI quantity (0.5 mL) was well suited to correct volume loss in the eyelids, especially the deep upper sulcus and tear trough, whereas the larger SEFFI content was effective for larger volume deficits in other areas of the face, including the brow, temporal fossa, zygomatic-malar region, nasolabial folds, marionette lines, chin, and lips. CONCLUSIONS: The fat administered by SEFFI is easily harvested via small side port cannulae, yielding micro fat that is rich in viable adipocytes and stem cells. Both volumes of fat (0.5 mL and 0.8 mL) were effective for treating age related lipoatrophy, reducing facial rhytids, and improving skin quality. LEVEL OF EVIDENCE: 4 Therapeutic. PMID- 25911630 TI - Augmentation Mammaplasty After Breast Enhancement With Hyaluronic Acid. AB - BACKGROUND: Macrolane is a stabilized, hyaluronic acid-based gel that has been available since 2007 as a minimally invasive, nonpermanent option for breast enhancement. However, numerous controversies pertaining to its side effects have highlighted the need for studies involving larger groups of patients. OBJECTIVES: The authors sought to determine complications of Macrolane injections for breast enhancement and performed surgical evacuation of cysts comprising collections of hyaluronic acid in patients who previously received Macrolane treatment and presented for augmentation mammaplasty. METHODS: The authors reviewed a case series of 20 patients who were treated elsewhere with intramammary injection of Macrolane for cosmetic purposes and who presented at the authors' medical studio with multiple intramammary and intramuscular cysts. All patients underwent surgical evacuation of the hyaluronic acid-based cysts in association with augmentation mammaplasty. RESULTS: Good aesthetic results were achieved in all patients. Three months after surgery, 15 of 20 (75%) patients rated themselves as very much improved; 4 patients (20%) rated themselves as moderately improved, and 1 patient (5%) rated herself as somewhat improved. CONCLUSIONS: The authors suggest that Macrolane cannot be considered a valid alternative for breast augmentation at this time. LEVEL OF EVIDENCE: 4 Therapeutic. PMID- 25911631 TI - Relationship between muscle water and glycogen recovery after prolonged exercise in the heat in humans. AB - PURPOSE: It is usually stated that glycogen is stored in human muscle bound to water in a proportion of 1:3 g. We investigated this proportion in biopsy samples during recovery from prolonged exercise. METHODS: On two occasions, nine aerobically trained subjects ([Formula: see text] = 54.4 +/- 1.05 mL kg(-1) min( 1); mean +/- SD) dehydrated 4.6 +/- 0.2 % by cycling 150 min at 65 % [Formula: see text] in a hot-dry environment (33 +/- 4 degrees C). One hour after exercise subjects ingested 250 g of carbohydrates in 400 mL of water (REHLOW) or the same syrup plus water to match fluid losses (i.e., 3170 +/- 190 mL; REHFULL). Muscle biopsies were obtained before, 1 and 4 h after exercise. RESULTS: In both trials muscle water decreased from pre-exercise similarly by 13 +/- 6 % and muscle glycogen by 44 +/- 10 % (P < 0.05). After recovery, glycogen levels were similar in both trials (79 +/- 15 and 87 +/- 18 g kg(-1) dry muscle; P = 0.20) while muscle water content was higher in REHFULL than in REHLOW (3814 +/- 222 vs. 3459 +/- 324 g kg(-1) dm, respectively; P < 0.05; ES = 1.06). Despite the insufficient water provided during REHLOW, per each gram of glycogen, 3 g of water was stored in muscle (recovery ratio 1:3) while during REHFULL this ratio was higher (1:17). CONCLUSIONS: Our findings agree with the long held notion that each gram of glycogen is stored in human muscle with at least 3 g of water. Higher ratios are possible (e.g., during REHFULL) likely due to water storage not bound to glycogen. PMID- 25911632 TI - Intensity-dependent effect of ageing on fatigue during intermittent contractions of the human calf muscle in males and females. AB - Ageing reduces fatigue during submaximal intermittent contractions, but the influence of intensity on this ageing effect in males and females is not clear. Younger males (n = 8; 23 +/- 2 years), younger females (n = 8; 22 +/- 1 years), older males (n = 8; 67 +/- 5 years) and older females (n = 10; 64 +/- 7 years) completed intermittent calf contractions at four submaximal intensities (30-70 %MVC) for up to 20 min. MVC was assessed during exercise at 30-60 s intervals and its linear rate of decline represented fatigue. Individual relationships between intensity and fatigue (%MVC min(-1)) were fitted to a biphasic function consisting of a linear and nonlinear component. There was no age * sex * intensity interaction for fatigue (3-way ANOVA, P = 0.46). However, there were significant interactive effects of age and sex on endurance at 70 %MVC, fatigue at 70 %MVC and the linear component of the intensity-fatigue relationship. Endurance was lower and fatigue and its linear component were greater (P < 0.05) in younger males compared with other groups, but not different between younger and older females. This suggests that there is an intensity-dependent effect of human ageing on fatigue during submaximal exercise that is specific to males. PMID- 25911633 TI - Correction for tissue optical properties enables quantitative skin fluorescence measurements using multi-diameter single fiber reflectance spectroscopy. AB - BACKGROUND AND OBJECTIVE: Fluorescence measurements in the skin are very much affected by absorption and scattering but existing methods to correct for this are not applicable to superficial skin measurements. STUDY DESIGN/MATERIALS AND METHODS: The first use of multiple-diameter single fiber reflectance (MDSFR) and single fiber fluorescence (SFF) spectroscopy in human skin was investigated. MDSFR spectroscopy allows a quantification of the full optical properties in superficial skin (MUa, MUs' and gamma), which can next be used to retrieve the corrected - intrinsic - fluorescence of a fluorophore QMUa,x(f). Our goal was to investigate the importance of such correction for individual patients. We studied this in 22 patients undergoing photodynamic therapy (PDT) for actinic keratosis. RESULTS: The magnitude of correction of fluorescence was around 4 (for both autofluorescence and protoporphyrin IX). Moreover, it was variable between patients, but also within patients over the course of fractionated aminolevulinic acid PDT (range 2.7-7.5). Patients also varied in the amount of protoporphyrin IX synthesis, photobleaching percentages and resynthesis (>100* difference between the lowest and highest PpIX synthesis). The autofluorescence was lower in actinic keratosis than contralateral normal skin (0.0032 versus 0.0052; P<0.0005). CONCLUSIONS: Our results clearly demonstrate the importance of correcting the measured fluorescence for optical properties, because these vary considerably between individual patients and also during PDT. Protoporphyrin IX synthesis and photobleaching kinetics allow monitoring clinical PDT which facilitates individual-based PDT dosing and improvement of clinical treatment protocols. Furthermore, the skin autofluorescence can be relevant for diagnostic use in the skin, but it may also be interesting because of its association with several internal diseases. PMID- 25911635 TI - Targeting Human Long Noncoding Transcripts by Endoribonuclease-Prepared siRNAs. AB - Broad sequencing enterprises such as the FANTOM or ENCODE projects have substantially extended our knowledge of the human transcriptome. They have revealed that a large portion of genomic DNA is actively transcribed and have identified a plethora of novel transcripts. Many newly identified transcripts belong to the class of long noncoding RNAs (lncRNAs), which range from a few hundred bases to multiple kilobases in length and harbor no protein-coding potential. Although the biological activity of some lncRNAs is understood, the functions of most lncRNAs remain elusive. Tools that allow rapid and cost effective access to functional data of lncRNAs are therefore essential. Here, we describe the construction and validation of an endoribonuclease-prepared siRNA (esiRNA) library designed to target 1779 individual human lncRNAs by RNA interference. We present a compendium of lncRNA expression data for 11 human cancer cell lines. Furthermore, we show that the resource is suitable for combined knockdown and localization analysis. We discuss challenges in sequence annotation of lncRNAs with respect to their often low and cell type-specific expression and specify esiRNAs that are suitable for targeting lncRNAs in commonly used human cell lines. PMID- 25911636 TI - Sensing of molecules using quantum dynamics. AB - We design sensors where information is transferred between the sensing event and the actuator via quantum relaxation processes, through distances of a few nanometers. We thus explore the possibility of sensing using intrinsically quantum mechanical phenomena that are also at play in photobiology, bioenergetics, and information processing. Specifically, we analyze schemes for sensing based on charge transfer and polarization (electronic relaxation) processes. These devices can have surprising properties. Their sensitivity can increase with increasing separation between the sites of sensing (the receptor) and the actuator (often a solid-state substrate). This counterintuitive response and other quantum features give these devices favorable characteristics, such as enhanced sensitivity and selectivity. Using coherent phenomena at the core of molecular sensing presents technical challenges but also suggests appealing schemes for molecular sensing and information transfer in supramolecular structures. PMID- 25911637 TI - Reply to Zefferman et al.: Cultural institutions can provide adaptive benefits for costly cooperation. PMID- 25911638 TI - Solving the puzzle of human warfare requires an explanation of battle raids and cultural institutions. PMID- 25911640 TI - Intramyocellular and Extramyocellular Lipids Are Associated With Arterial Stiffness. AB - BACKGROUND: Obese and overweight patients are at increased risk of arterial stiffness, and visceral, epicardial and hepatic fat accumulation is associated with cardiovascular disease risk. In general, muscular lipids are stored either in interstitial adipose tissue (extramyocellular lipid (EMCL)) or in lipid droplets within muscle cells (intramyocellular lipid (IMCL)). However, the association between IMCL or EMCL content and arterial stiffness remains unclear. This cross-sectional study aimed to clarify this association. METHODS: A total of 237 subjects (18-81 years) were enrolled in this study. The IMCL and EMCL contents of the right vastus lateralis muscle were evaluated by proton magnetic resonance spectroscopy. Arterial stiffness was estimated using brachial-ankle pulse wave velocity (baPWV). RESULTS: There were significant correlations between baPWV and the contents of both IMCL (R = -0.23, P < 0.001) and EMCL (R = 0.53, P < 0.001) in all subjects. The baPWV negatively correlated with IMCL content (R = 0.45, P < 0.001) in females only. In contrast, significant positive correlations were observed between baPWV and EMCL content in both males (R = 0.59, P < 0.001) and females (R = 0.55, P < 0.001). IMCL and EMCL contents contributed independently to baPWV variation after adjustment for age, sex, body mass index, visceral and subcutaneous abdominal fat, upper and lower limb fat, blood pressure, heart rate, and lipid profiles. CONCLUSION: These results suggest that IMCL and EMCL contents may be a risk factor for arterial stiffness, and this association differed with gender and age. PMID- 25911639 TI - State of the Art Review: Depression, Stress, Anxiety, and Cardiovascular Disease. AB - The notion that psychological states can influence physical health is hardly new, and perhaps nowhere has the mind-body connection been better studied than in cardiovascular disease (CVD). Recently, large prospective epidemiologic studies and smaller basic science studies have firmly established a connection between CVD and several psychological conditions, including depression, chronic psychological stress, posttraumatic stress disorder (PTSD), and anxiety. In addition, numerous clinical trials have been conducted to attempt to prevent or lessen the impact of these conditions on cardiovascular health. In this article, we review studies connecting depression, stress/PTSD, and anxiety to CVD, focusing on findings from the last 5 years. For each mental health condition, we first examine the epidemiologic evidence establishing a link with CVD. We then describe studies of potential underlying mechanisms and finally discuss treatment trials and directions for future research. PMID- 25911641 TI - Comparing the evolutionary conservation between human essential genes, human orthologs of mouse essential genes and human housekeeping genes. AB - Human housekeeping genes are often confused with essential human genes, and several studies regard both types of genes as having the same level of evolutionary conservation. However, this is not necessarily the case. To clarify this, we compared the differences between human housekeeping genes and essential human genes with respect to four aspects: the evolutionary rate (dN/dS), protein sequence identity, single-nucleotide polymorphism (SNP) density and level of linkage disequilibrium (LD). The results showed that housekeeping genes had lower evolutionary rates, higher sequence identities, lower SNP densities and higher levels of LD compared with essential genes. Together, these findings indicate that housekeeping and essential genes are two distinct types of genes, and that housekeeping genes have a higher level of evolutionary conservation. Therefore, we suggest that researchers should pay careful attention to the distinctions between housekeeping genes and essential genes. Moreover, it is still controversial whether we should substitute human orthologs of mouse essential genes for human essential genes. Therefore, we compared the evolutionary features between human orthologs of mouse essential genes and human housekeeping genes and we got inconsistent results in long-term and short-term evolutionary characteristics implying the irrationality of simply replacing human essential genes with human orthologs of mouse essential genes. PMID- 25911642 TI - Sim K et al (Clin Infect Dis 2015; 60:389-97). PMID- 25911643 TI - Less evidence for an important role of food-producing animals as source of antibiotic resistance in humans. PMID- 25911644 TI - Reply to Bonten and Mevius. PMID- 25911645 TI - Evaluation of the Electroporation Efficiency of a Grid Electrode for Electrochemotherapy: From Numerical Model to In Vitro Tests. AB - Electrochemotherapy (ECT) is a local anticancer treatment based on the combination of chemotherapy and short, tumor-permeabilizing, voltage pulses delivered using needle electrodes or plate electrodes. The application of ECT to large skin surface tumors is time consuming due to technical limitations of currently available voltage applicators. The availability of large pulse applicators with few and more spaced needle electrodes could be useful in the clinic, since they could allow managing large and spread tumors while limiting the duration and the invasiveness of the procedure. In this article, a grid electrode with 2-cm spaced needles has been studied by means of numerical models. The electroporation efficiency has been assessed on human osteosarcoma cell line MG63 cultured in monolayer. The computational results show the distribution of the electric field in a model of the treated tissue. These results are helpful to evaluate the effect of the needle distance on the electric field distribution. Furthermore, the in vitro tests showed that the grid electrode proposed is suitable to electropore, by a single application, a cell culture covering an area of 55 cm(2). In conclusion, our data might represent substantial improvement in ECT in order to achieve a more homogeneous and time-saving treatment, with benefits for patients with cancer. PMID- 25911646 TI - Comparison of Effects Between Central and Peripheral Stage I Lung Cancer Using Image-Guided Stereotactic Body Radiotherapy via Helical Tomotherapy. AB - Lung cancer is a common malignant tumor with high morbidity and mortality. Here we compared the effects and outcome between central and peripheral stage I lung cancer using image-guided stereotactic body radiotherapy. From June 2011 to July 2013, a total of 33 patients with stage I lung cancer were enrolled. A total of 50 Gy in 10 fractions or 60 Gy in 10 fractions was delivered in the central arm (n = 18), while 50 Gy in 5 fractions in the peripheral arm (n = 15). Statistical analyses were performed using logistic regression analysis and Kaplan-Meier method. The mean follow-up time was 38.1 months. Three-month, 1-, 2-, and 3-year overall response rates were 66.7%, 83.3%, 61.1%, and 72.2% and 66.7%, 80%, 80%, and 80% in the central and peripheral arms, respectively. Three-year local control rates (94.4% vs 93.3%, P = .854), regional control rates (94.4% vs 86.7%, P = .412), and distant control rates (64.2% vs 61.7%, P = .509) had no differences between the central and the peripheral arms. Grade 2 radiation pneumonitis was observed in 6 of 18 patients in the central arm and in 1 of 15 patients in the peripheral arm (P = .92). Grade 2 radiation esophagitis was 5.7% in the central arm, while none occurred in the peripheral arm (P = .008). Five (15.1%) of all patients felt slight fatigue during radiotherapy. Other major complications were not observed. In conclusion, helical image-guided stereotactic body radiotherapy for central stage I lung cancer is safe and effective compared to peripheral stage I lung cancer. PMID- 25911647 TI - A case of multiple coronary atresias: a rarity even within the family of coronary anomalies. PMID- 25911648 TI - Cardiac endothelium-myocyte interaction: clinical opportunities for new heart failure therapies regardless of ejection fraction. AB - Heart failure (HF) is an important global health problem with great socioeconomic burden. Outcomes remain sub-optimal. Endothelium-cardiomyocyte interactions play essential roles in cardiovascular homeostasis, and deranged endothelium-related signalling pathways have been implicated in the pathophysiology of HF. In particular, disturbances in nitric oxide (NO)-mediated pathway and neuregulin mediated pathway have been shown to contribute to the development of HF. These signalling pathways hold the potential as pathophysiological targets for new HF therapies, and may aid in patient selection for future HF trials. PMID- 25911649 TI - Cardiovascular dysfunction in children conceived by assisted reproductive technologies. AB - Epidemiological studies demonstrate a relationship between pathological events during foetal development and future cardiovascular risk and the term 'foetal programming of cardiovascular disease' has been coined to describe this phenomenon. The use of assisted reproductive technologies (ARTs) is growing exponentially and 2-5% of children are now born by this procedure. Emerging evidence indicates that ART represents a novel important example of foetal programming. Assisted reproductive technology may modify the cardiovascular phenotype in two ways: (i) ART involves manipulation of the early embryo which is exquisitely sensitive to environmental insults. In line with this concern, ART alters vascular and cardiac function in children and studies in mice show that ART alters the cardiovascular phenotype by epigenetic alterations related to suboptimal culture conditions. (ii) Assisted reproductive technology markedly increases the risk of foetal insults that augment cardiovascular risk in naturally conceived individuals and are expected to have similar consequences in the ART population. Given the young age of the ART population, it will take another 20-30 years before data on cardiovascular endpoints will be available. What is clear already, however, is that ART emerges as an important cardiovascular risk factor. This insight requires us to revise notions on ART's long-term safety and to engage on a debate on its future. There is an urgent need to better understand the mechanisms underpinning ART-induced alteration of the cardiovascular phenotype, improve the procedure and its long-term safety, and, while awaiting this aim, not to abandon medicine's fundamental principle of doing no harm (to future children) and use ART parsimoniously. PMID- 25911650 TI - The Influence of Known Genetic Variants on Subclinical Cardiovascular Outcomes in Childhood: Generation R Study. AB - BACKGROUND: Genome-wide association studies have identified single-nucleotide polymorphisms (SNPs) for subclinical cardiovascular outcomes in adults. We examined the influence of these variants on the same outcomes in childhood. METHODS AND RESULTS: In a population-based prospective cohort study among 4137 children, we examined the associations of SNPs, individually and incorporated in genetic risk scores, which were identified in adults for cardiac (2 SNPs for left ventricular end-diastolic diameter and 5 SNPs for aortic root diameter) and blood pressure outcomes (29 SNPs for systolic and diastolic blood pressure, 22 SNPs for mean arterial pressure, and 10 SNPs for pulse pressure) with the same outcomes in children (median age of 6.0 years [95% range, 4.5-8.7]). Weighted and unweighted risk scores for aortic root diameter were associated with childhood aortic root diameter (difference per additional average risk allele 0.09 mm [95% CI: 0.05, 0.13]). Weighted and unweighted risk scores for pulse pressure were associated with childhood pulse pressure (difference per additional average risk allele 0.22 mm Hg [95% CI: 0.08, 0.35] and 0.18 mm Hg [95% CI: 0.05, 0.31], respectively), but not with childhood systolic or diastolic blood pressure or mean arterial pressure. The risk scores for blood pressure and mean arterial pressure were not associated with any of the childhood blood pressure outcomes. CONCLUSIONS: Genetic risk scores based on SNPs for aortic root diameter and pulse pressure in adults are associated with the same outcomes in children. SNPs related to cardiovascular outcomes in adulthood at least partly influence cardiovascular development from early life onwards. PMID- 25911651 TI - Improving clinician-carer communication for safer hospital care: a study of the 'TOP 5' strategy in patients with dementia. AB - OBJECTIVE: To examine the impact of implementing a clinician-carer communication tool for hospitalized patients with dementia. DESIGN: Surveys were conducted with clinicians and carers about perceptions and experiences. Implementation process and costs were explored through surveys of local staff. Time series analysis was conducted on incident-reported falls, usage of non-regular anti-psychotics and one-to-one nursing. SETTING: Twenty-one hospitals in Australia. PARTICIPANTS: Surveys were returned by 798 clinicians, 240 carers and 21 local liaison staff involved in implementation. INTERVENTION: Implementation of a communication tool over 12 months. MAIN OUTCOME MEASURES: The process of implementation was documented. Outcome measures included clinician and carer perceptions, safety indicators (incident-reported falls and usage of non-regular anti-psychotics), resource use and costs. RESULTS: Clinicians and carers reported high levels of acceptability and perceived benefits for patients. Clinicians rated confidence in caring for patients with dementia as being significantly higher after the introduction of TOP 5, (M = 2.93, SD = 0.65), than prior to TOP 5 (M = 2.74, SD = 0.75); F(1,712) = 11.21, P < 0.05. When analysed together, there was no change in incident-reported falls across all hospitals. At one hospital with a matched control ward, an average of 6.85 fewer falls incidents per month occurred in the intervention ward compared with the matched control ward (B = -6.85, P < 0.05). CONCLUSIONS: Our findings indicate that the use of a simple, low-cost communication strategy for patient care is associated with improvements in clinician and carer experience with potential implications for patient safety. Minimally, TOP 5 represents 'good practice' with a low risk of harm for patients. PMID- 25911652 TI - Clinical accuracy of a low cost portable blood pressure device in pregnancy and pre-eclampsia: the Nissei DS-400. AB - Hypertensive disorders of pregnancy cause significant maternal morbidity and mortality worldwide, particularly in developing countries. This study evaluated the accuracy of the Nissei DS-400, a low cost blood pressure (BP) device, in pregnancy according to the British Hypertension Society protocol. Forty-five pregnant women (15 with pre-eclampsia), were recruited from a large teaching hospital. Nine sequential same-arm BP measurements were taken from each woman by trained observers, alternating between mercury sphygmomanometry and the device. The Nissei DS-400 achieved the highest accuracy grade (A/A) in all subjects (n = 45) and in pregnancy alone (n = 30). The mean difference +/- standard deviation between the standard and the device in pregnancy were -1.0 +/- 5.1 mmHg and -1.1 +/- 5.0 mmHg for systolic and diastolic BP, respectively, and -2.6 +/- 5.9 mmHg and -3.4 +/- 5.8 mmHg in all subjects. The Nissei-DS 400 can be recommended for clinical use in pregnancy and has potential as a good screening tool for pre eclampsia in low resource settings. PMID- 25911653 TI - Trying to overcome the 'chicken or egg' impasse in bicuspid aortopathy research. PMID- 25911655 TI - Young investigators in toxicology: is there a crisis? PMID- 25911657 TI - Corrigendum: Ovarian xenobiotic biotransformation enzymes are altered during phosphoramide mustard-induced ovotoxicity. PMID- 25911656 TI - Polycyclic aromatic hydrocarbons: from metabolism to lung cancer. AB - Excessive exposure to polycyclic aromatic hydrocarbons (PAHs) often results in lung cancer, a disease with the highest cancer mortality in the United States. After entry into the lung, PAHs induce phase I metabolic enzymes such as cytochrome P450 (CYP) monooxygenases, i.e. CYP1A1/2 and 1B1, and phase II enzymes such as glutathione S-transferases, UDP glucuronyl transferases, NADPH quinone oxidoreductases (NQOs), aldo-keto reductases (AKRs), and epoxide hydrolases (EHs), via the aryl hydrocarbon receptor (AhR)-dependent and independent pathways. Humans can also be exposed to PAHs through diet, via consumption of charcoal broiled foods. Metabolism of PAHs through the CYP1A1/1B1/EH pathway, CYP peroxidase pathway, and AKR pathway leads to the formation of the active carcinogens diol-epoxides, radical cations, and o-quinones. These reactive metabolites produce DNA adducts, resulting in DNA mutations, alteration of gene expression profiles, and tumorigenesis. Mutations in xenobiotic metabolic enzymes, as well as polymorphisms of tumor suppressor genes (e.g. p53) and/or genes involved in gene expression (e.g. X-ray repair cross-complementing proteins), are associated with lung cancer susceptibility in human populations from different ethnicities, gender, and age groups. Although various metabolic activation/inactivation pathways, AhR signaling, and genetic susceptibilities contribute to lung cancer, the precise points at which PAHs induce tumor initiation remain unknown. The goal of this review is to provide a current state of-the-science of the mechanisms of human lung carcinogenesis mediated by PAHs, the experimental approaches used to study this complex class of compounds, and future directions for research of these compounds. PMID- 25911658 TI - A Composite-Likelihood Method for Detecting Incomplete Selective Sweep from Population Genomic Data. AB - Adaptive evolution occurs as beneficial mutations arise and then increase in frequency by positive natural selection. How, when, and where in the genome such evolutionary events occur is a fundamental question in evolutionary biology. It is possible to detect ongoing positive selection or an incomplete selective sweep in species with sexual reproduction because, when a beneficial mutation is on the way to fixation, homologous chromosomes in the population are divided into two groups: one carrying the beneficial allele with very low polymorphism at nearby linked loci and the other carrying the ancestral allele with a normal pattern of sequence variation. Previous studies developed long-range haplotype tests to capture this difference between two groups as the signal of an incomplete selective sweep. In this study, we propose a composite-likelihood-ratio (CLR) test for detecting incomplete selective sweeps based on the joint sampling probabilities for allele frequencies of two groups as a function of strength of selection and recombination rate. Tested against simulated data, this method yielded statistical power and accuracy in parameter estimation that are higher than the iHS test and comparable to the more recently developed nSL test. This procedure was also applied to African Drosophila melanogaster population genomic data to detect candidate genes under ongoing positive selection. Upon visual inspection of sequence polymorphism, candidates detected by our CLR method exhibited clear haplotype structures predicted under incomplete selective sweeps. Our results suggest that different methods capture different aspects of genetic information regarding incomplete sweeps and thus are partially complementary to each other. PMID- 25911660 TI - The opioid epidemic: impact on orthopaedic surgery. AB - The past few decades have seen an alarming rise in opioid use in the United States, and the negative consequences from diversion of opioids for nontherapeutic use are dramatically increasing. A significant number of orthopaedic patients are at risk for repercussions from both therapeutic and nontherapeutic opioid use. Orthopaedic surgeons are the third highest prescribers of opioid prescriptions among physicians in the United States. Thus, it is important for orthopaedic surgeons to understand the detrimental effects of opioid abuse on individuals and society and to recognize objective measures to identify patients at risk for nontherapeutic opioid use. These measures include elements of the patient history, recognition of aberrant behaviors, prescription drug monitoring programs, and opioid risk-assessment tools. PMID- 25911659 TI - Adaptation, Clonal Interference, and Frequency-Dependent Interactions in a Long Term Evolution Experiment with Escherichia coli. AB - Twelve replicate populations of Escherichia coli have been evolving in the laboratory for >25 years and 60,000 generations. We analyzed bacteria from whole population samples frozen every 500 generations through 20,000 generations for one well-studied population, called Ara-1. By tracking 42 known mutations in these samples, we reconstructed the history of this population's genotypic evolution over this period. The evolutionary dynamics of Ara-1 show strong evidence of selective sweeps as well as clonal interference between competing lineages bearing different beneficial mutations. In some cases, sets of several mutations approached fixation simultaneously, often conveying no information about their order of origination; we present several possible explanations for the existence of these mutational cohorts. Against a backdrop of rapid selective sweeps both earlier and later, two genetically diverged clades coexisted for >6000 generations before one went extinct. In that time, many additional mutations arose in the clade that eventually prevailed. We show that the clades evolved a frequency-dependent interaction, which prevented the immediate competitive exclusion of either clade, but which collapsed as beneficial mutations accumulated in the clade that prevailed. Clonal interference and frequency dependence can occur even in the simplest microbial populations. Furthermore, frequency dependence may generate dynamics that extend the period of coexistence that would otherwise be sustained by clonal interference alone. PMID- 25911661 TI - Return to play following anterior cruciate ligament reconstruction. AB - In athletes, significant advances in anterior cruciate ligament reconstruction techniques and rehabilitation have led to improved surgical outcomes and increased expectations for return to play. Although an expeditious return to sport has become an achievable and often realistic goal, the factors that most influence safe, timely, and successful return to play remain unknown. The literature offers mainly anecdotal evidence to guide the team physician in the decision-making process, with a paucity of criteria and consensus guidelines available to help determine return to sport. Attempts have been made to introduce criteria-based progression in the rehabilitation process, but validation of subjective and objective criteria has been difficult. Nevertheless, several pertinent factors in the preoperative, intraoperative, and postoperative periods may affect return to play following anterior cruciate ligament reconstruction. Further research is warranted to validate reliable, consensus guidelines with objective criteria to facilitate the return to play process. PMID- 25911662 TI - Management of complex elbow dislocations: a mechanistic approach. AB - Complex elbow dislocations (ie, fracture-dislocations) are challenging injuries to treat and may result in significant patient morbidity. Chronic instability, posttraumatic arthrosis, and poor functional outcomes are frequent. Orthopaedic surgeons should strive to optimize elbow function through restoration of articular congruity and stability coupled with early rehabilitation. Although most of these injuries require surgical management, not all complex elbow dislocations are equivalent. Understanding elbow biomechanics and the injury mechanism provides valuable insight into the variations of pathology that may be observed. Identifying the particular fracture pattern, such as an axial loading, valgus posterolateral rotatory, or varus posteromedial rotatory injury mechanism, helps guide appropriate treatment. PMID- 25911663 TI - Skin cancer of the hand: current concepts. AB - Skin cancer accounts for most hand cancers. Prompt recognition of lesions with malignant potential can lead to early treatment and decreased disease burden. Understanding the appropriate diagnostic algorithm for a given lesion facilitates accurate staging, which guides therapy. A multidisciplinary approach that includes hand surgeons, dermatologists, oncologists, and radiation oncologists is often necessary to manage advanced disease. For most invasive tumors, the primary treatment modality remains surgical excision; however, several effective nonsurgical treatments exist for management of unresectable or low-grade cancers. PMID- 25911665 TI - Let's keep running... exercise, basic science and the knowledge gaps. PMID- 25911666 TI - Marfan syndrome, inherited aortopathies and exercise: what is the right answer? AB - Exercise recommendations for those who have Marfan syndrome or other genetic predisposition for thoracic aortic disease remain controversial and at times ambiguous. There are no outcomes studies to help guide recommendations. In this review, we examine the guidelines regarding exercise and inherited aortic conditions, the theoretical reasoning and circumstantial evidence that support the guidelines, as well as the knowledge gaps that continue to exist. PMID- 25911667 TI - Basic science behind the cardiovascular benefits of exercise. AB - Cardiorespiratory fitness is a strong predictor of cardiovascular (CV) disease and all-cause mortality, with increases in cardiorespiratory fitness associated with corresponding decreases in CV disease risk. The effects of exercise upon the myocardium and vascular system are dependent upon the frequency, intensity and duration of the exercise itself. Following a prolonged period (>=6 months) of regular intensive exercise in previously untrained individuals, resting and submaximal exercising heart rates are typically 5-20 beats lower, with an increase in stroke volume of ~20% and enhanced myocardial contractility. Structurally, all four heart chambers increase in volume with mild increases in wall thickness, resulting in greater cardiac mass due to increased myocardial cell size. With this in mind, the present paper aims to review the basic science behind the CV benefits of exercise. Attention will be paid to understanding (1) the relationship between exercise and cardiac remodelling; (2) the cardiac cellular and molecular adaptations in response to exercise, including the examination of molecular mechanisms of physiological cardiac growth and applying these mechanisms to identify new therapeutic targets to prevent or reverse pathological remodelling and heart failure; and (3) vascular adaptations in response to exercise. Finally, this review will briefly examine how to optimise the CV benefits of exercise by considering how much and how intense exercise should be. PMID- 25911673 TI - Tailoring of alerts substantially reduces the alert burden in computerized clinical decision support for drugs that should be avoided in patients with renal disease. AB - OBJECTIVE: Electronic alerts are often ignored by physicians, which is partly due to the large number of unspecific alerts generated by decision support systems. The aim of the present study was to analyze critical drug prescriptions in a university-based nephrology clinic and to evaluate the effect of different alerting strategies on the alert burden. METHODS: In a prospective observational study, two advanced strategies to automatically generate alerts were applied when medication regimens were entered for discharge letters, outpatient clinic letters, and written prescriptions and compared to two basic reference strategies. Strategy A generated alerts whenever drug-specific information was available, whereas strategy B generated alerts only when the estimated glomerular filtration rate of a patient was below a drug-specific value. Strategies C and D included further patient characteristics and drug-specific information to generate even more specific alerts. RESULTS: Overall, 1012 medication regimens were entered during the observation period. The average number of alerts per drug preparation in medication regimens entered for letters was 0.28, 0.080, 0.019, and 0.011, when using strategy A, B, C, or D (P<0.001, for comparison between the strategies), leading to at least one alert in 87.5%, 39.3%, 13.5%, or 7.81 % of the regimens. Similar average numbers of alerts were observed for medication regimens entered for written prescriptions. CONCLUSIONS: The prescription of potentially hazardous drugs is common in patients with renal impairment. Alerting strategies including patient and drug-specific information to generate more specific alerts have the potential to reduce the alert burden by more than 90 %. PMID- 25911668 TI - Pulmonary Inflammation Impacts on CYP1A1-Mediated Respiratory Tract DNA Damage Induced by the Carcinogenic Air Pollutant Benzo[a]pyrene. AB - Pulmonary inflammation can contribute to the development of lung cancer in humans. We investigated whether pulmonary inflammation alters the genotoxicity of polycyclic aromatic hydrocarbons (PAHs) in the lungs of mice and what mechanisms are involved. To model nonallergic acute inflammation, mice were exposed intranasally to lipopolysaccharide (LPS; 20 ug/mouse) and then instilled intratracheally with benzo[a]pyrene (BaP; 0.5 mg/mouse). BaP-DNA adduct levels, measured by (32)P-postlabeling analysis, were approximately 3-fold higher in the lungs of LPS/BaP-treated mice than in mice treated with BaP alone. Pulmonary Cyp1a1 enzyme activity was decreased in LPS/BaP-treated mice relative to BaP treated mice suggesting that pulmonary inflammation impacted on BaP-induced Cyp1a1 activity in the lung. Our results showed that Cyp1a1 appears to be important for BaP detoxification in vivo and that the decrease of pulmonary Cyp1a1 activity in LPS/BaP-treated mice results in a decrease of pulmonary BaP detoxification, thereby enhancing BaP genotoxicity (ie, DNA adduct formation) in the lung. Because less BaP was detoxified by Cyp1a1 in the lungs of LPS/BaP treated mice, more BaP circulated via the blood to extrapulmonary tissues relative to mice treated with BaP only. Indeed, we observed higher BaP-DNA adduct levels in livers of LPS/BaP-treated mice compared with BaP-treated mice. Our results indicate that pulmonary inflammation could be a critical determinant in the induction of genotoxicity in the lung by PAHs like BaP. Cyp1a1 appears to be involved in both BaP bioactivation and detoxification although the contribution of other enzymes to BaP-DNA adduct formation in lung and liver under inflammatory conditions remains to be explored. PMID- 25911674 TI - R-U policy frontiers for health data de-identification. AB - OBJECTIVE: The Health Insurance Portability and Accountability Act Privacy Rule enables healthcare organizations to share de-identified data via two routes. They can either 1) show re-identification risk is small (e.g., via a formal model, such as k-anonymity) with respect to an anticipated recipient or 2) apply a rule based policy (i.e., Safe Harbor) that enumerates attributes to be altered (e.g., dates to years). The latter is often invoked because it is interpretable, but it fails to tailor protections to the capabilities of the recipient. The paper shows rule-based policies can be mapped to a utility (U) and re-identification risk (R) space, which can be searched for a collection, or frontier, of policies that systematically trade off between these goals. METHODS: We extend an algorithm to efficiently compose an R-U frontier using a lattice of policy options. Risk is proportional to the number of patients to which a record corresponds, while utility is proportional to similarity of the original and de-identified distribution. We allow our method to search 20 000 rule-based policies (out of 2(700)) and compare the resulting frontier with k-anonymous solutions and Safe Harbor using the demographics of 10 U.S. states. RESULTS: The results demonstrate the rule-based frontier 1) consists, on average, of 5000 policies, 2% of which enable better utility with less risk than Safe Harbor and 2) the policies cover a broader spectrum of utility and risk than k-anonymity frontiers. CONCLUSIONS: R-U frontiers of de-identification policies can be discovered efficiently, allowing healthcare organizations to tailor protections to anticipated needs and trustworthiness of recipients. PMID- 25911675 TI - FGF8, c-Abl and p300 participate in a pathway that controls stability and function of the DeltaNp63alpha protein. AB - The p63 transcription factor, homolog to the p53 tumor suppressor gene, plays a crucial role in epidermal and limb development, as its mutations are associated to human congenital syndromes characterized by skin, craniofacial and limb defects. While limb and skin-specific p63 transcriptional targets are being discovered, little is known of the post-translation modifications controlling DeltaNp63alpha functions. Here we show that the p300 acetyl-transferase physically interacts in vivo with DeltaNp63alpha and catalyzes its acetylation on lysine 193 (K193) inducing DeltaNp63alpha stabilization and activating specific transcriptional functions. Furthermore we show that Fibroblast Growth Factor-8 (FGF8), a morphogenetic signaling molecule essential for embryonic limb development, increases the binding of DeltaNp63alpha to the tyrosine kinase c-Abl as well as the levels of DeltaNp63alpha acetylation. Notably, the natural mutant DeltaNp63alpha-K193E, associated to the Split-Hand/Foot Malformation-IV syndrome, cannot be acetylated by this pathway. This mutant DeltaNp63alpha protein displays promoter-specific loss of DNA binding activity and consequent altered expression of development-associated DeltaNp63alpha target genes. Our results link FGF8, c Abl and p300 in a regulatory pathway that controls DeltaNp63alpha protein stability and transcriptional activity. Hence, limb malformation-causing p63 mutations, such as the K193E mutation, are likely to result in aberrant limb development via the combined action of altered protein stability and altered promoter occupancy. PMID- 25911676 TI - Astrocytes influence the severity of spinal muscular atrophy. AB - Systemically low levels of survival motor neuron-1 (SMN1) protein cause spinal muscular atrophy (SMA). alpha-Motor neurons of the spinal cord are considered particularly vulnerable in this genetic disorder and their dysfunction and loss cause progressive muscle weakness, paralysis and eventually premature death of afflicted individuals. Historically, SMA was therefore considered a motor neuron autonomous disease. However, depletion of SMN in motor neurons of normal mice elicited only a very mild phenotype. Conversely, restoration of SMN to motor neurons in an SMA mouse model had only modest effects on the SMA phenotype and survival. Collectively, these results suggested that additional cell types contribute to the pathogenesis of SMA, and understanding the non-autonomous requirements is crucial for developing effective therapies. Astrocytes are critical for regulating synapse formation and function as well as metabolic support for neurons. We hypothesized that astrocyte functions are disrupted in SMA, exacerbating disease progression. Using viral-based restoration of SMN specifically to astrocytes, survival in severe and intermediate SMA mice was observed. In addition, neuromuscular circuitry was improved. Astrogliosis was prominent in end-stage SMA mice and in post-mortem patient spinal cords. Increased expression of proinflammatory cytokines was partially normalized in treated mice, suggesting that astrocytes contribute to the pathogenesis of SMA. PMID- 25911678 TI - A retrospective comparative study of minimally invasive extracorporeal circulation versus conventional extracorporeal circulation in emergency coronary artery bypass surgery patients: a single surgeon analysis. AB - OBJECTIVES: At the moment, the main application of minimally invasive extracorporeal circulation (MiECC) is reserved for elective cardiac operations such as coronary artery bypass grafting (CABG) and/or aortic valve replacement. The purpose of this study was to compare the outcome of emergency CABG operations using either MiECC or conventional extracorporeal circulation (CECC) in patients requiring emergency CABG with regard to the perioperative course and the occurrence of major adverse cardiac and cerebral events (MACCE). METHODS: We analysed the emergency CABG operations performed by a single surgeon, between January 2007 and July 2013, in order to exclude the differences in surgical technique. During this period, 187 emergency CABG patients (113 MiECC vs 74 CECC) were investigated retrospectively with respect to the following parameters: in hospital mortality, MACCE, postoperative hospital stay and perioperative transfusion rate. RESULTS: The mean logistic European System for Cardiac Operative Risk Evaluation was higher in the CECC group (MiECC 12.1 +/- 16 vs CECC 15.0 +/- 20.8, P = 0.15) and the number of bypass grafts per patient was similar in both groups (MiECC 2.94 vs CECC 2.93). There was no significant difference in the postoperative hospital stay or in major postoperative complications. The in hospital mortality was higher in the CECC group 6.8% versus MiECC 4.4% (P = 0.48). The perioperative transfusion rate was lower with MiECC compared with CECC (MiECC 2.6 +/- 3.2 vs CECC 3.8 +/- 4.2, P = 0.025 units of blood per patient). CONCLUSIONS: In our opinion, the use of MiECC in urgent CABG procedures is safe, feasible and shows no disadvantages compared with the use of CECC. Emergency operations using the MiECC system showed a significantly lower blood transfusion rate and better results concerning the unadjusted in-hospital mortality. PMID- 25911677 TI - An N-terminal formyl methionine on COX 1 is required for the assembly of cytochrome c oxidase. AB - Protein synthesis in mitochondria is initiated by formylmethionyl-tRNA(Met) (fMet tRNA(Met)), which requires the activity of the enzyme MTFMT to formylate the methionyl group. We investigated the molecular consequences of mutations in MTFMT in patients with Leigh syndrome or cardiomyopathy. All patients studied were compound heterozygotes. Levels of MTFMT in patient fibroblasts were almost undetectable by immunoblot analysis, and BN-PAGE analysis showed a combined oxidative phosphorylation (OXPHOS) assembly defect involving complexes I, IV and V. The synthesis of only a subset of mitochondrial polypeptides (ND5, ND4, ND1, COXII) was decreased, whereas all others were translated at normal or even increased rates. Expression of the wild-type cDNA rescued the biochemical phenotype when MTFMT was expressed near control levels, but overexpression produced a dominant-negative phenotype, completely abrogating assembly of the OXPHOS complexes, suggesting that MTFMT activity must be tightly regulated. fMet tRNA(Met) was almost undetectable in control cells and absent in patient cells by high-resolution northern blot analysis, but accumulated in cells overexpressing MTFMT. Newly synthesized COXI was under-represented in complex IV immunoprecipitates from patient fibroblasts, and two-dimensional BN-PAGE analysis of newly synthesized mitochondrial translation products showed an accumulation of free COXI. Quantitative mass spectrophotometry of an N-terminal COXI peptide showed that the ratio of formylated to unmodified N-termini in the assembled complex IV was ~350:1 in controls and 4:1 in patient cells. These results show that mitochondrial protein synthesis can occur with inefficient formylation of methionyl-tRNA(Met), but that assembly of complex IV is impaired if the COXI N terminus is not formylated. PMID- 25911679 TI - Preoperative frontal QRS-T angle is an independent correlate of hospital length of stay and predictor of haemodynamic support requirement following off-pump coronary artery bypass graft surgery. AB - OBJECTIVES: With the adoption of novel operative techniques and aggressive care protocols that facilitate earlier extubation and mobilization of patients, postoperative length of stay (LOS) following coronary artery bypass graft surgery (CABG) has declined. However, there is paucity of information regarding preoperative electrocardiographic predictors of LOS following CABG. In this study, we investigated whether frontal QRS-T angle, which is an abnormal repolarization marker in prediction of various cardiovascular events, was an independent correlate of postoperative hospital LOS for off-pump CABG. Furthermore, we evaluated independent predictors of vasopressor agent/intra aortic balloon pump (IABP) support requirement following off-pump CABG. METHODS: In this observational study, 78 patients with stable angina, who were scheduled for elective coronary artery bypass surgery following diagnosis of obstructive coronary artery disease by conventional angiography, were enrolled. RESULTS: Left ventricular ejection fraction (LVEF) was significantly lower and vasopressor agent/IABP support requirement and incidence of sustained atrial or ventricular arrhythmias was higher in patients with wide QRS-T angle (P < 0.05). Postoperative hospital LOS was also longer in this group. From the preoperative characteristics, wide frontal QRS-T angle was found to be an independent correlate of postoperative hospital LOS (B +/- SD: 11.97 +/- 0.62, P <= 0.01). Wide frontal QRS-T angle was also found to be an independent predictor of vasopressor agent/IABP support requirement postoperatively (OR: 7.87, P <= 0.01). CONCLUSIONS: Prediction of the hospital LOS and patient outcome following CABG is of great importance. Being easily obtainable via standard 12-lead electrocardiogram and its low cost may make frontal QRS-T angle a beneficial marker for reducing both patient-based morbidity and economic burden. PMID- 25911680 TI - Efficacy of adjuvant chemotherapy for lung adenocarcinoma patients with positive pleural lavage cytology findings. AB - OBJECTIVES: Positive pleural lavage cytology (PLC) findings are considered to be predictive of a poor prognosis in patients with non-small-cell lung cancer (NSCLC). We investigated the clinical benefit of adjuvant chemotherapy for lung adenocarcinoma patients with positive PLC findings. METHODS: We retrospectively reviewed the medical records of lung adenocarcinoma patients who underwent tumour resection and had positive PLC findings between January 2000 and December 2009. RESULTS: Fifty-three patients (4.8%) of 1114 patients with lung adenocarcinoma had positive PLC findings. The median follow-up period was 33.6 months. Adjuvant chemotherapy was administered to 24 patients (adjuvant chemotherapy group); 7, 8 and 9 patients had pathological Stage I, II and III, respectively . The surgery alone group comprised 29 patients; 12, 8 and 9 patients had pathological Stage I, II and III, respectively. The 5-year recurrence-free survival (RFS) rates were 34.6 and 15.7% (P < 0.01) in adjuvant chemotherapy and surgery-alone groups, respectively. The rate of distant recurrence was significantly reduced in the adjuvant chemotherapy group (25.0 and 58.6%; P = 0.01). Even for Stage I cases, adjuvant chemotherapy tended to improve the 5-year RFS rate compared with surgery alone (60.1 and 29%; P = 0.11). Multivariate analysis for RFS revealed that adjuvant chemotherapy [hazard ratio (HR), 0.45; P = 0.03], tumour size >30 mm (HR, 2.23; P = 0.02) and lymph node metastasis (HR, 2.67; P < 0.01) were significant independent prognostic factors for recurrence. CONCLUSIONS: Adjuvant chemotherapy for lung adenocarcinoma patients with positive PLC findings significantly improved recurrence-free survival. PMID- 25911681 TI - Determinants of exercise intolerance in patients with heart failure and reduced or preserved ejection fraction. AB - This mini-review summarizes the literature regarding the mechanisms of exercise intolerance in patients with heart failure and reduced or preserved ejection fraction (HFREF and HFPEF, respectively). Evidence to date suggests that the reduced peak pulmonary oxygen uptake (pulm Vo2) in patients with HFREF compared with healthy controls is due to both central (reduced convective O2 transport) and peripheral factors (impaired skeletal muscle blood flow, decreased diffusive O2 transport coupled with abnormal skeletal morphology, and metabolism). Although central and peripheral impairments also limit peak pulm Vo2 in HFPEF patients compared with healthy controls, emerging data suggest that the latter may play a relatively greater role in limiting exercise performance in these patients. Unlike HFREF, currently there is limited evidence-based therapies that improve exercise capacity in HFPEF patients, therefore future studies are required to determine whether interventions targeted to improve peripheral vascular and skeletal muscle function result in favorable improvements in peak pulm and leg Vo2 and their determinants in HFPEF patients. PMID- 25911682 TI - Invited Editorial on "Skeletal Muscle Signature of a Champion Sprint Runner". PMID- 25911683 TI - Exceptional case studies. PMID- 25911684 TI - Statistics for studies when N = 1. PMID- 25911685 TI - Duration of action of hypertonic saline on mucociliary clearance in the normal lung. AB - Inhalation of hypertonic saline (HS) acutely enhances mucociliary clearance (MC) in both health and disease. In patients with cystic fibrosis (CF), repeated use of HS causes a sustained improvement in MC as well as clinical benefit. The pharmacodynamic duration of activity on MC may be an important determinant of its therapeutic potential in other airways diseases. Before moving toward testing the clinical benefits of HS for non-CF indications, we sought to assess the duration of pharmacodynamic effects of HS in healthy subjects by performing radiotracer clearance studies at baseline, 30-min post-HS administration, and 4-h post-HS administration. Indeed, acceleration of MC was observed when measured 30 min after HS inhalation. This acceleration was most pronounced in the first 30 min after inhaling the radiotracer in the central lung region (mean Ave30Clr = 15.5 vs. 8.6% for 30-min post-HS treatment vs. mean baseline, respectively, P < 0.005), suggesting that acute HS effects were greatest in the larger bronchial airways. In contrast, when MC was measured 4 h after HS administration, all indices of central lung region MC were slower than at baseline: Ave30Clr = 5.9% vs. 8.6% (P = 0.10); Ave90Clr = 12.4% vs. 16.8% (P < 0.05); clearance through 3 h = 29.4 vs. 43.7% (P < 0.002); and clearance through 6 h = 39.4 vs. 50.2% (P < 0.02). This apparent slowing of MC in healthy subjects 4-h post-HS administration may reflect depletion of airway mucus following acute HS administration. PMID- 25911686 TI - Lungs at high-altitude: genomic insights into hypoxic responses. AB - Hypobaric hypoxia at high altitude (HA) results in reduced blood arterial oxygen saturation, perfusion of organs with hypoxemic blood, and direct hypoxia of lung tissues. The pulmonary complications in the cells of the pulmonary arterioles due to hypobaric hypoxia are the basis of the pathophysiological mechanisms of high altitude pulmonary edema (HAPE). Some populations that have dwelled at HA for thousands of years have evolutionarily adapted to this environmental stress; unadapted populations may react with excessive physiological responses that impair health. Individual variations in response to hypoxia and the mechanisms of HA adaptation provide insight into physiological responses. Adaptive and maladaptive responses include alterations in pathways such as oxygen sensing, hypoxia signaling, K(+)- and Ca(2+)-gated channels, redox balance, and the renin angiotensin-aldosterone system. Physiological imbalances are linked with genetic susceptibilities, and nonhomeostatic responses in gene regulation that occur by small RNAs, histone modification, and DNA methylation predispose susceptible humans to these HA illnesses. Elucidation of the interaction of these factors will lead to a more comprehensive understanding of HA adaptations and maladaptations and will lead to new therapeutics for HA disorders related to hypoxic lungs. PMID- 25911687 TI - Cell- and molecular-level mechanisms contributing to diastolic dysfunction in HFpEF. AB - Heart failure with preserved ejection fraction (HFpEF) is the default diagnosis for patients who have symptoms of heart failure, an ejection fraction >0.5, and evidence of diastolic dysfunction. The clinical condition, which was largely unrecognized 30 years ago, is now a major health problem and currently accounts for 50% of all patients with heart failure. Clinical studies show that patients with HFpEF exhibit increased passive stiffness of the ventricles and a slower rate of pressure decline during diastole. This review discusses some of the cell- and molecular-level mechanisms that contribute to these effects and focuses on data obtained using human samples. Collagen cross linking, modulation of protein kinase G-related pathways, Ca(2+) handling, and strain-dependent detachment of cross bridges are highlighted as potential factors that could be modulated to improve ventricular function in patients with HFpEF. PMID- 25911688 TI - Enhanced Targeting of the EGFR Network with MM-151, an Oligoclonal Anti-EGFR Antibody Therapeutic. AB - Although EGFR is a validated therapeutic target across multiple cancer indications, the often modest clinical responses to current anti-EGFR agents suggest the need for improved therapeutics. Here, we demonstrate that signal amplification driven by high-affinity EGFR ligands limits the capacity of monoclonal anti-EGFR antibodies to block pathway signaling and cell proliferation and that these ligands are commonly coexpressed with low-affinity EGFR ligands in epithelial tumors. To develop an improved antibody therapeutic capable of overcoming high-affinity ligand-mediated signal amplification, we used a network biology approach comprised of signaling studies and computational modeling of receptor-antagonist interactions. Model simulations suggested that an oligoclonal antibody combination may overcome signal amplification within the EGFR:ERK pathway driven by all EGFR ligands. Based on this, we designed MM-151, a combination of three fully human IgG1 monoclonal antibodies that can simultaneously engage distinct, nonoverlapping epitopes on EGFR with subnanomolar affinities. In signaling studies, MM-151 antagonized high-affinity EGFR ligands more effectively than cetuximab, leading to an approximately 65-fold greater decrease in signal amplification to ERK. In cell viability studies, MM-151 demonstrated antiproliferative activity against high-affinity EGFR ligands, either singly or in combination, while cetuximab activity was largely abrogated under these conditions. We confirmed this finding both in vitro and in vivo in a cell line model of autocrine high-affinity ligand expression. Together, these preclinical studies provide rationale for the clinical study of MM-151 and suggest that high-affinity EGFR ligand expression may be a predictive response marker that distinguishes MM-151 from other anti-EGFR therapeutics. PMID- 25911690 TI - XBP1S associates with RUNX2 and regulates chondrocyte hypertrophy. PMID- 25911689 TI - Three-Dimensional Cell Culture-Based Screening Identifies the Anthelmintic Drug Nitazoxanide as a Candidate for Treatment of Colorectal Cancer. AB - Because dormant cancer cells in hypoxic and nutrient-deprived regions of solid tumors provide a major obstacle to treatment, compounds targeting those cells might have clinical benefits. Here, we describe a high-throughput drug screening approach, using glucose-deprived multicellular tumor spheroids (MCTS) with inner hypoxia, to identify compounds that specifically target this cell population. We used a concept of drug repositioning-using known molecules for new indications. This is a promising strategy to identify molecules for rapid clinical advancement. By screening 1,600 compounds with documented clinical history, we aimed to identify candidates with unforeseen potential for repositioning as anticancer drugs. Our screen identified five molecules with pronounced MCTS selective activity: nitazoxanide, niclosamide, closantel, pyrvinium pamoate, and salinomycin. Herein, we show that all five compounds inhibit mitochondrial respiration. This suggests that cancer cells in low glucose concentrations depend on oxidative phosphorylation rather than solely glycolysis. Importantly, continuous exposure to the compounds was required to achieve effective treatment. Nitazoxanide, an FDA-approved antiprotozoal drug with excellent pharmacokinetic and safety profile, is the only molecule among the screening hits that reaches high plasma concentrations persisting for up to a few hours after single oral dose. Nitazoxanide activated the AMPK pathway and downregulated c-Myc, mTOR, and Wnt signaling at clinically achievable concentrations. Nitazoxanide combined with the cytotoxic drug irinotecan showed anticancer activity in vivo. We here report that the FDA-approved anthelmintic drug nitazoxanide could be a potential candidate for advancement into cancer clinical trials. PMID- 25911691 TI - Molecular basis distinguishing the DNA binding profile of Nrf2-Maf heterodimer from that of Maf homodimer. PMID- 25911692 TI - Domain characterization of Bacillus subtilis GabR, a pyridoxal 5'-phosphate dependent transcriptional regulator. AB - Bacillus subtilis GabR is a transcriptional regulator consisting of a helix-turn helix N-terminal DNA-binding domain, a pyridoxal 5'-phosphate (PLP)-binding C terminal domain that has a structure homologous to aminotransferases, and a linker of 29 amino acid residues. In the presence of gamma-aminobutyrate (GABA), GabR activates the transcription of gabT and gabD, which encode GABA aminotransferase and succinate semialdehyde dehydrogenase, respectively. We expressed N-terminal and C-terminal domain fragments (named N'-GabR and C'-GabR) in Escherichia coli cells, and obtained N'-GabR as a soluble monomer and C'-GabR as a soluble dimer. Spectroscopic studies suggested that C'-GabR contains PLP and binds to d-Ala, beta-Ala, d-Asn and d-Gln, as well as GABA, although the intact GabR binds only to GABA. N'-GabR does not bind to the DNA fragment containing the GabR-binding sequence regardless of the presence or absence of C'-GabR. A fusion protein consisting of N'-GabR and 2-aminoadipate aminotransferase of Thermus thermophilus bound to the DNA fragment. These results suggested that each domain of GabR could be an independent folding unit. The C-terminal domain provides the N-terminal domain with DNA-binding ability via dimerization. The N-terminal domain controls the ligand specificity of the C-terminal domain. Connection by the linker is indispensable for the mutual interaction of the domains. PMID- 25911694 TI - A new family and four new genera in Rhizophydiales (Chytridiomycota). AB - Many chytrid phylogenies contain lineages representing a lone taxon or a few organisms. One such lineage in recent molecular phylogenies of Rhizophydiales contained two marine chytrids, Rhizophydium littoreum and Rhizophydium aestuarii. To better understand the relationship between these organisms, we increased sampling such that the R. littoreum/R. aestuarii lineage included 10 strains of interest. To place this lineage in Rhizophydiales, we constructed a molecular phylogeny from partial nuc 28S rDNA D1-D3 domains (28S) of these and 80 additional strains in Rhizophydiales and examined thallus morphology and zoospore ultrastructure of our strains of interest. We also analyzed sequences of the nuc rDNA region encompassing the internal transcribed spacers 1 and 2, along with the 5.8S rDNA (ITS) of our 10 strains of interest to assess sequence similarity and phylogenetic placement of strains within the lineage. The 10 strains grouped together in three well supported clades: (i) Rhizophydium littoreum+Phlyctochytrium mangrovei, (ii) three strains of Rhizophydium aestuarii and (iii) five previously unidentified strains. Light microscopic observations revealed four distinct thallus morphologies, and zoospore ultrastructural analyses revealed four distinct constellations of ultrastructural features. On the bases of morphological, ultrastructural and molecular evidence we place these strains in the new family Halomycetaceae and four new genera (Halomyces, Paludomyces, Ulkenomyces, Paranamyces) in Rhizophydiales. PMID- 25911693 TI - Mother's education and the risk of preterm and small for gestational age birth: a DRIVERS meta-analysis of 12 European cohorts. AB - BACKGROUND: A healthy start to life is a major priority in efforts to reduce health inequalities across Europe, with important implications for the health of future generations. There is limited combined evidence on inequalities in health among newborns across a range of European countries. METHODS: Prospective cohort data of 75 296 newborns from 12 European countries were used. Maternal education, preterm and small for gestational age births were determined at baseline along with covariate data. Regression models were estimated within each cohort and meta analyses were conducted to compare and measure heterogeneity between cohorts. RESULTS: Mother's education was linked to an appreciable risk of preterm and small for gestational age (SGA) births across 12 European countries. The excess risk of preterm births associated with low maternal education was 1.48 (1.29 to 1.69) and 1.84 (0.99 to 2.69) in relative and absolute terms (Relative/Slope Index of Inequality, RII/SII) for all cohorts combined. Similar effects were found for SGA births, but absolute inequalities were greater, with an SII score of 3.64 (1.74 to 5.54). Inequalities at birth were strong in the Netherlands, the UK, Sweden and Spain and marginal in other countries studied. CONCLUSIONS: This study highlights the value of comparative cohort analysis to better understand the relationship between maternal education and markers of fetal growth in different settings across Europe. PMID- 25911695 TI - A phylogenetic assessment and taxonomic revision of the thermotolerant hyphomycete genera Acrophialophora and Taifanglania. AB - We assessed the phylogenetic relationships of 19 isolates belonging to Acrophialophora and Taifanglania based on internal transcribed spacer (ITS), nuclear 18S subunit (nuc 18S) rDNA and beta-tubulin sequences. Phylogenetic data showed that Acrophialophora and Taifanglania comprise a monophyletic clade, but did not support the distinction of two genera. Being the older and more frequently used name, Acrophialophora is adopted as the generic name and Taifanglania is treated as a synonym. The generic concept of Acrophialophora is emended to include the morphological characters formerly used to distinguish Taifanglania. Three new thermotolerant species isolated from soil samples in China are described and illustrated, (i) A. ellipsoidea, with solitary phialides tapering into thin necks and long chains of ellipsoidal to fusiform conidia, (ii) A. angustiphialis with single phialides terminal or lateral on hyphae, and long chains of ellipsoidal or fusiform conidia and, (iii) A. acuticonidiata with single phialides and fusiform conidia with acute ends. Phylogenetic analyses show that A. acuticonidiata, A. angustiphialis and A. ellipsoidea are most closely related to A. curticatenata, A. hechuanensis and A. major, respectively. Growth tests showed that the three new species are thermotolerant, with optimal growth temperatures of 37-40 C, and maximum growth temperatures near 50 C. A key to the accepted species of Acrophialophora is provided. PMID- 25911696 TI - Cytology and molecular phylogenetics of Monoblepharidomycetes provide evidence for multiple independent origins of the hyphal habit in the Fungi. AB - The evolution of filamentous hyphae underlies an astounding diversity of fungal form and function. We studied the cellular structure and evolutionary origins of the filamentous form in the Monoblepharidomycetes (Chytridiomycota), an early diverging fungal lineage that displays an exceptional range of body types, from crescent-shaped single cells to sprawling hyphae. To do so, we combined light and transmission electron microscopic analyses of hyphal cytoplasm with molecular phylogenetic reconstructions. Hyphae of Monoblepharidomycetes lack a complex aggregation of secretory vesicles at the hyphal apex (i.e. Spitzenkorper), have centrosomes as primary microtubule organizing centers and have stacked Golgi cisternae instead of tubular/fenestrated Golgi equivalents. The cytoplasmic distribution of actin in Monoblepharidomycetes is comparable to the arrangement observed previously in other filamentous fungi. To discern the origins of Monoblepharidomycetes hyphae, we inferred a phylogeny of the fungi based on 18S and 28S ribosomal DNA sequence data with maximum likelihood and Bayesian inference methods. We focused sampling on Monoblepharidomycetes to infer intergeneric relationships within the class and determined 78 new sequences. Analyses showed class Monoblepharidomycetes to be monophyletic and nested within Chytridiomycota. Hyphal Monoblepharidomycetes formed a clade sister to the genera without hyphae, Harpochytrium and Oedogoniomyces. A likelihood ancestral state reconstruction indicated that hyphae arose independently within the Monoblepharidomycetes lineage and in at least two other lineages. Cytological differences among monoblepharidalean and other fungal hyphae are consistent with these convergent origins. PMID- 25911697 TI - Two distinct Epichloe species symbiotic with Achnatherum inebrians, drunken horse grass. AB - Achnatherum inebrians, colloquially known as drunken horse grass, is associated with livestock toxicity in northern China. Epichloe gansuensis (Eg) was described from endophyte isolates from A. inebrians in Sunan County, Gansu Province, whereas a morphologically distinct variety, E. gansuensis var. inebrians (Ei), was described based on two isolates from A. inebrians seeds collected in Urumqi County, Xinjiang Province. Genome sequencing and alkaloid analyses also distinguish these taxa; the Ei isolates produce neurotropic lysergic acid amides (ergot alkaloids), and an Eg isolate produces paxilline (an indole-diterpene alkaloid). To better elucidate the taxonomic diversity of Epichloe spp. symbiotic with A. inebrians, we surveyed eight populations in Xinjiang, Gansu and Inner Mongolia provinces of China and analyzed their genotypes by multiplex PCR for alkaloid biosynthesis genes and mating-type genes. Genotypes consistent with Ei were present in all eight populations, of which they dominated seven. The Ei isolates were all mating type A and tested positive for the ergot alkaloid gene, dmaW. In contrast Eg isolates were all mating type B and had the indole-diterpene gene, idtG. The genome was sequenced from an Ei isolate from seeds collected in Xiahe County, Gansu, and compared to that of the varietal ex type isolate from Urumqi. Alkaloid genes and four different housekeeping genes were nearly identical between the two sequenced Ei isolates and were distinct from a sequenced Eg isolate. Phylogenetic analysis placed Ei, Eg and Epichloe sibirica into respective subclades of a clade that emanated from the base of the Epichloe phylogeny. Given its chemotypic, genotypic, morphological and phylogenetic distinctiveness, its widespread occurrence in rangelands of northern China, and its importance in livestock toxicity, we propose raising Ei to species rank as Epichloe inebrians. PMID- 25911698 TI - Determination of amatoxins and phallotoxins in Amanita phalloides mushrooms from northeastern Portugal by HPLC-DAD-MS. AB - Amanita phalloides is a toxic mushroom responsible for the majority of deaths occurring after mushrooms ingestion, mainly due to amatoxins. In the present study the contents and distribution of the major amatoxins and phallotoxins in different tissues of A. phalloides from two different sites of Portugal were analyzed by liquid chromatography (LC) coupled to diode array (DAD) and mass spectrometry (MS) detection. The main toxins were separated by LC and its chemical structures confirmed by MS. alpha-Amanitin contents in caps, stipe and volva tissues were quantified by RP-HPLC. The results show that caps have the highest content of amatoxins, whereas the volva was richest in phallotoxins. Moreover variability in the toxins composition from different geographic sites was also observed. This study provides for the first time the content of toxins in A. phalloides from Portugal. PMID- 25911699 TI - Mitospore stages of Disciotis, Gyromitra and Morchella in the inland Pacific Northwest USA. AB - Colonies of Costantinella species growing on soil, moss and woody debris in the autumn in the inland Pacific Northwest USA were established in culture. Five different mitospore taxa were distinguished based on colony color, presence or absence of setae and internal transcribed spacer region (ITS) rDNA amplicon size. Sequence data from the largest and second largest subunits of RNA polymerase II, translation elongation factor 1-alpha, D1 and D2 domains of nuclear large subunit rDNA and ITS were used to connect each of the distinct mitospore taxa to corresponding vernal-fruiting Pezizales, including Disciotis cf. venosa, Gyromitra cf. esculenta and three species of Morchella. Both meiospore and mitospore stages of Morchella brunnea and M. populiphila collected in spring and autumn within a meter of each other at two urban sites had identical multilocus haplotypes, providing evidence connecting the two stages of the life cycle. Among other Morchella mitospore stages collected, some had identical haplotypes to previously sampled meiospore stages, while others were distinct, possibly representing undescribed species. Mitospore isolates with sequences assigning them to Disciotis or Gyromitra had different haplotypes from meiospore stages occurring in the same area. Meiospore stages of Disciotis and Gyromitra sampled as part of the study were also genetically distinct from European collections of D. venosa and G. esculenta, indicating more diversity is present in these taxa than is reflected in the current taxonomy. The widespread occurrence of mitospore stages of these fungi suggests that the life cycles of morels, false morels and allied taxa are more complex than previously recognized. PMID- 25911700 TI - The phylogenetic position of poroid Hymenochaetaceae (Hymenochaetales, Basidiomycota) from Patagonia, Argentina. AB - Six poroid Hymenochaetaceae from Patagonia, Argentina, were studied phylogenetically with nuc rDNA internal transcribed spacer (ITS) and partial 28S rDNA sequences, together with morphological data. Two new genera and a new species are introduced as well as two new combinations proposed. Arambarria destruens gen. et sp. nov. is proposed for a taxon fruiting on fallen or standing, dead Diostea juncea and Lomatia hirsuta and previously recorded erroneously as Inocutis jamaicensis; it is distinguished by annual, effused to effused-reflexed basidiomes forming pilei, a monomitic hyphal system, thick walled and yellowish basidiospores (brownish chestnut in potassium hydroxide solution), lack of a granular core in the context and lack of setoid elements. Nothophellinus gen. nov. is proposed to accommodate Phellinus andinopatagonicus, the main white wood-rotting polypore of standing Nothofagus pumilio and also an important wood-decayer of other Nothofagus species from southern Argentina and Chile. It is morphologically similar to Phellopilus (type species P. nigrolimitatus) but differs by lacking setae. The new combinations Pseudoinonotus crustosus and Phellinopsis andina are proposed for Inonotus crustosus and Phellinus andinus, respectively. Phellinus livescens, which decays the sapwood of several standing Nothofagus species, is closely related to Phellinus uncisetus, a Neotropical species related to Fomitiporia; for the time being P. livescens is retained in Phellinus sensu lato. An unidentified taxon responsible for a white heart-rot in living Austrocedrus chilensis grouped with Phellinus caryophyllii and Fulvifomes inermis, but its generic affinities remain ambiguous. Transmission electron microscopy studies confirm this unidentified taxon has an imperforate parenthesome, which is typical of the Hymenochaetaceae. PMID- 25911701 TI - Exploring the phylogenetic affiliations and the trophic mode of Sedecula pulvinata (Sedeculaceae). AB - Sedecula is a monotypic genus of hypogeous fungi that is rare and endemic to dry conifer forests of the western United States. The only known species, Sedecula pulvinata, was described in 1941 and its taxonomic placement and trophic status have remained uncertain ever since. Here we employ isotopic and molecular phylogenetic analyses to determine its nutritional mode and placement on the fungal tree of life. Phylogenetic analysis indicates that S. pulvinata is closely related to the genus Coniophora, in Coniophoraceae (Boletales). Stable isotope comparisons with known ectomycorrhizal and saprotrophic fungi together with phylogenetic evidence also suggest that S. pulvinata is saprotrophic. We conclude that Sedecula likely represents a unique morphological transition between a resupinate basidiocarp morphology (in Coniophora and relatives) and a hypogeous, sequestrate basidiocarp morphology (in Sedecula). Spore dimensions are amended from the original description. PMID- 25911702 TI - Rupestriomyces and Spissiomyces, two new genera of rock-inhabiting fungi from China. AB - Bare rocks in arid and semi-arid climates may harbor a bewildering biodiversity of fungi that are overlooked in China. During a survey of rock-inhibiting fungi in China, more than 1000 were isolated and 14 belonging to Dothideomycetes (Ascomycota) were selected for detailed study. Phylogenetic trees based on combined sequence datasets of mt 16S rDNA, partial nuc rDNA 18S and 28S indicated that these strains clustered in two distinct, well supported and previously unknown lineages within the class Dothideomycetes. Therefore two new genera were established corresponding to those two clades. Spissiomyces gen. nov. is characterized by thick-walled, yellowish brown hyphae and globose or subglobose conidia, if present. Rupestriomyces gen. nov. is characterized by globose, barrel shaped, ampulliform or ovoidal conidia formed from acropetal, catenate hyphae. Further phylogenetic analyses using combined sequence datasets of the rDNA internal transcribed spacer (ITS) region and 16S rDNA, part of genes of RPB2, TUB2, nuc rDNA 18S and 28S revealed that those strains represented five new species (i.e. Spissiomyces aggregatus, S. ramosus, Rupestriomyces sinensis, R. ampulliformis, R. torulosus). They were described, illustrated and compared with similar taxa based on morphological characteristics and phylogenetic relationships. The results of this paper provides insight into the richness and diversity of rock-inhibiting fungi in nature. PMID- 25911703 TI - Long-distance dispersal and speciation of Australasian and American species of Cortinarius sect. Cortinarius. AB - We present a multigene phylogeny (partial nuc rDNA and RPB2) of Cortinarius sect. Cortinarius (i.e. the C. violaceus group), which reveals eight species distributed in Europe, Australasia, South America, Central America and North America. Relaxed molecular clock analyses suggested that diversification began during the Miocene, thus rejecting more ancient Gondwanan origin scenarios among the taxa currently occurring in the northern and southern hemispheres. There was strong support for an Australasian origin of the C. violaceus group with initial dispersal to the Neotropics, followed by migration into North America and Europe. A dispersal-extinction cladogenesis model that includes a parameter for founder effects was the most highly supported biogeographic model in the program BioGeoBEARS. A maximum likelihood analysis showed the most recent common ancestor of sect. Cortinarius was an angiosperm ectomycorrhizal associate. Ancestral associations at the plant family level, however, were ambiguous. Of eight recovered species-level lineages, C. violaceus is the only one that associates with Pinaceae and the only species to associate with both Pinaceae and angiosperms. This analysis showed that long-distance dispersal and founder event speciation have been important factors during evolution of the C. violaceus group. PMID- 25911704 TI - Contrast-enhanced ultrasound evaluation of residual blood flow to hepatocellular carcinoma after treatment with transarterial chemoembolization using drug-eluting beads: a prospective study. AB - OBJECTIVES: To evaluate the accuracy and change over time of contrast-enhanced ultrasound (US) imaging for assessing residual blood flow after transarterial chemoembolization of hepatocellular carcinoma with drug-eluting beads at 2 different follow-up intervals. METHODS: Data from 16 tumors treated by transarterial chemoembolization with drug-eluting beads were successfully obtained. As part of the study, patients provided consent to undergo contrast enhanced US examinations the morning before embolization, 1 to 2 weeks after embolization, and the morning before follow-up contrast-enhanced magnetic resonance imaging (MRI) or computed tomography (CT) (1 month after embolization). Blinded review of contrast-enhanced US and MRI/CT studies were performed by 2 radiologists who evaluated residual flow as no change, partial change, or no residual flow. Inter- and intra-reader variability rates were calculated before discordant individual reads were settled by consensus. RESULTS: The only adverse event reported during the contrast-enhanced US examinations was a single episode of transient back pain. Contrast-enhanced US at 1 to 2 weeks after embolization (n = 14) resulted in 100% sensitivity, specificity, positive predictive value, negative predictive value, and accuracy. Contrast-enhanced US 1 month after embolization (n = 15) resulted in 75% sensitivity, 100% specificity, 100% positive predictive value, 92% negative predictive value, and 93% accuracy. Inter reader agreement was 86% for contrast-enhanced US at 1 to 2 weeks, 93% for contrast-enhanced US at 1 month, and 100% for contrast-enhanced MRI/CT at 1 month, whereas intra-reader agreement was 71% for contrast-enhanced US at 1 to 2 weeks, 87% for contrast-enhanced US at 1 month, and 91% for MRI/CT. CONCLUSIONS: Contrast-enhanced US imaging at 1 to 2 weeks after the procedure may be a viable alternative to MRI/CT for evaluating residual blood flow after transarterial chemoembolization with drug-eluting beads, albeit with a higher degree of reader variability. PMID- 25911705 TI - Quantification of kidney fibrosis using ultrasonic shear wave elastography: experimental study with a rabbit model. AB - OBJECTIVES: The purpose of this study was to evaluate the feasibility of ultrasonic shear wave elastography for quantification of renal fibrosis in an experimental rabbit model. METHODS: Thirty-eight kidneys of 19 rabbits were studied and categorized into 3 groups: group I, ureter obstruction (n = 9); group II, renal vein occlusion (n = 10); and group III, normal control (n = 19). Before surgery, we measured stiffness at the renal cortex using shear wave elastography and evaluated the sonographic findings, including size, echogenicity, and resistive index. We repeated the same sonographic examinations weekly until the fourth week. The degree of histologically quantified fibrosis and the measured stiffness values were statistically compared. RESULTS: There was no significant difference in the mean stiffness values for the renal cortex in the 3 groups before surgery (8.95 kPa in group I, 9.06 kPa in group II, and 9.74 kPa in group III; P > .05). However, the mean stiffness in each group on the last sonographic examination was significantly different (10.91 kPa in group I, 13.92 kPa in group II, and 9.77 kPa in group III; P = .003). Pathologically, the degree of fibrosis was also significantly different (3.62% in group I, 11.70% in group II, and 0.70% in group III; P< .001). The fibrosis degree and stiffness were positively correlated (rho = 0.568; P = 0.01). CONCLUSIONS: Tissue stiffness measured by ultrasonic shear wave elastography was positively correlated with histopathologic renal fibrosis. Ultrasonic shear wave elastography may be used as a noninvasive tool for predicting renal fibrosis. PMID- 25911706 TI - Does adding diffuse optical tomography to sonography improve differentiation between benign and malignant breast lesions? Observer performance study. AB - OBJECTIVES: The purpose of this study was to investigate the added value of diffuse optical tomographic categories combined with conventional sonography for differentiating between benign and malignant breast lesions. METHODS: In this retrospective database review, we included 145 breast lesions (116 benign and 29 malignant) from 145 women (mean age, 46 years; range, 16-86 years). Five radiologists independently reviewed sonograms with and without a diffuse optical tomographic category. Each lesion was scored on a scale of 0% to 100% for suspicion of malignancy and rated according to the American College of Radiology Breast Imaging Reporting and Data System classification. Diagnostic performance was analyzed by comparing area under receiver operating characteristic curve values. Reader agreement was assessed by intraclass correlation coefficients. RESULTS: In the multireader multicase receiver operating characteristic analysis, adding a diffuse optical tomographic category to sonography improved the diagnostic accuracy of sonography (mean areas under the curve, 0.923 for sonography alone and 0.969 for sonography with diffuse optical tomography; P = .039). The interobserver correlation was also improved (0.798 for sonography alone and 0.904 for sonography with diffuse optical tomography). The specificity increased for 4 reviewers from a mean of 19.5% to 45.8% (P < .001 for reviewers 1 4; P = .238 for reviewer 5) with no significant change in the sensitivity. When the diffuse optical tomographic category was applied strictly, the specificity increased for all reviewers from a mean of 19.5% to 68.3% (P < .001 for all reviewers) with no significant change in the sensitivity. CONCLUSIONS: The addition of diffuse optical tomographic categories to sonography may improve diagnostic performance and markedly decrease false-positive biopsy recommendations. PMID- 25911707 TI - Value of sonographic bidirectional arterial flow combined with elastography for diagnosis of breast imaging reporting and data system category 4 breast masses. AB - OBJECTIVES: The purpose of this study was to evaluate the role of bidirectional arterial flow combined with ultrasound elastography for differentiation of American College of Radiology Breast Imaging Reporting and Data System (BI-RADS) category 4 masses. METHODS: A total of 116 BI-RADS category 4 breast masses were evaluated with color Doppler sonography, spectral analysis, and elastography. The sensitivity, specificity, accuracy, positive and negative predictive values, and receiver operator characteristic curve were used to estimate the diagnostic performance for each modality and the combination method. RESULTS: The combination method had the best sensitivity (81.1%) but less specificity (94.9%) and the best accuracy (90.5%). The discriminating power of the combined method (area under the curve [AUC], 0.880; 95% confidence interval [CI], 80.0%-96.0%) was significantly higher than that of bidirectional arterial flow (AUC, 0.818; 95% CI, 72.0%-91.6%; P< .01) and elastography (AUC, 0.765; 95% CI, 65.9%-87.0%; P< .01). CONCLUSIONS: Bidirectional arterial flow evaluation, when combined with elastography, could potentially improve diagnostic accuracy for BI-RADS category 4 breast masses. PMID- 25911708 TI - Atypia of undetermined significance and follicular lesions of undetermined significance: sonographic assessment for prediction of the final diagnosis. AB - OBJECTIVES: To determine whether radiologic assessment of thyroid nodules can potentially help guide clinical management after a cytologic diagnosis of atypia of undetermined significance or a follicular lesion of undetermined significance. METHODS: We identified 41 patients with 41 thyroid nodules initially diagnosed as atypia or follicular lesions of undetermined significance on fine-needle aspiration that were subsequently definitively diagnosed by either surgical resection or repeated fine-needle aspiration. All sonograms of nodules were reviewed by 2 blinded board-certifiedradiologists. Lesions were assessed in 3 ways: (1) Mayo pattern classification as benign, indeterminate, or worrisome for malignancy (Ultrasound Q 2005; 21:157-165); (2) thyroid imaging reporting and data system scores (scale of 1-5) based on 2 different previously published scoring criteria (Park et al [Thyroid 2009; 19:1257-1264] and Kwak et al [Radiology 2011; 260:892-899]); and (3) binary classification as benign or malignant. RESULTS: Of the 41 nodules, 25 had benign histologic findings, and 16 were malignant. Mayo pattern classification was 100% accurate for the benign score. Lesions with a Mayo score of indeterminate were malignant in 21% of cases (6 of 28) and benign in 79% (22 of 28). Lesions with a Mayo score of malignant were malignant in 91% of cases (10 of 11) and benign in 9% (1 of 11). Thyroid imaging reporting and data system scores had area under the receiver operating characteristic curve values of 0.827 for Park scores and 0.822 for Kwak scores. Radiologist binary classification of thyroid nodules showed 88% overall accuracy. CONCLUSIONS: Radiologist assessment of thyroid nodules in cases of atypia of undetermined significance or follicular lesions of undetermined significance is highly predictive of the final diagnosis and can help guide management of thyroid nodules of these pathologic types. PMID- 25911709 TI - A new insight for evaluation of the inferior turbinate with ultrasound elastography. AB - OBJECTIVES: There are diseases that affect the stroma of the inferior turbinate and many surgical interventions that alter it. However, an objective method that can evaluate the turbinate's stromal structure in detail has not been defined yet. The primary aim of this study was to investigate the effectiveness and reliability of ultrasound elastography for objective evaluation of the inferior turbinate stroma and define the most suitable elastographic technique. METHODS: Twenty inferior turbinates in 10 healthy participants were included. Five of the participants (50%) were male, and 5 (50%) were female, with a mean age +/- SD of 28.3 +/- 3.2 years (range, 26-35) years. To obtain reliable and reproducible results, elastography was performed twice, 3 days apart, with and without a topical decongestant to evaluate the effects of the nasal cycle and mucosal edema. Two previously described valid elastographic outcome measures were reevaluated for the inferior turbinate. The tissue strain ratio and sound wave propagation speed were calculated for each measurement. RESULTS: Median propagation speeds without and with the decongestant for the first and second measurements were 2.125 (interquartile range [IQR], 0.85), 2.175 (IQR, 0.53), 2.520 (IQR, 0.79), and 2.555 (IQR, 0.53) m/s, respectively. Median turbinate stroma-to-subcutaneous tissue strain ratios without and with the decongestant for the first and second measurements were 1.402 (IQR, 0.96), 0.942 (IQR, 0.24), 1.035 (IQR, 0.98), and 1.427 (IQR, 1.68). CONCLUSIONS: We suggest that elastography is a reliable and reproducible method that is not substantially affected by mucosal edema. It is a novel technique that can evaluate the inferior turbinate stroma and might be used in concordance with other objective functional techniques such as acoustic rhinometry. Therefore, it can be used in further studies regarding diagnosis of turbinate diseases and objective evaluation of previous surgical treatments. PMID- 25911710 TI - Sonographic evaluation of the treatment response in patients with immunoglobulin G4-related disease of the submandibular glands. AB - OBJECTIVES: To evaluate the usefulness of sonography for monitoring the response to glucocorticoid treatment in patients with immunoglobulin G4 (IgG4)-related disease. METHODS: We conducted a retrospective study using sonography in 12 patients with bilateral swollen submandibular glands who had a diagnosis of IgG4 related disease based on an elevated serum IgG4 level (>135 mg/dL) and histopathologic findings between January 2010 and December 2012. Among these patients, 6 were treated with prednisolone, and the other 6 were placed under observation. B-mode sonographic examinations of the submandibular glands were performed with or without color Doppler imaging at the initial examination and 6 months later. Findings were compared between the groups (treated and untreated), and their relationship with the treatment response of the primarily involved organs was investigated. RESULTS: In the treated group, the submandibular glands of all 6 patients decreased in both size and volume after treatment (average volume +/- SD, 27,449.7 +/- 24,227.6 to 4609.7 +/- 1911.4 mm(3); P = .004). The internal echo texture, characterized by multiple hypoechoic foci scattered against a heterogeneous hyperechoic background of submandibular tissue with demarcated hyperechoic lines, with or without hypoechoic tumor formation, disappeared or was obscured in all cases. In addition, the blood flow signals were reduced in all 3 patients who underwent color Doppler sonography, and the response observed on sonography was found to correlate with the IgG4 level and recovery of specific organ involvement. In contrast, in the untreated group, the submandibular glands showed a tendency to increase in both size and volume (average volume, 9326.3 +/- 3054.8 to 12,217.4 +/- 4605.5 mm(3); P= .2) without a decrease in the blood flow signals. CONCLUSIONS: Sonography is considered useful for evaluating the response to glucocorticoid therapy in patients with IgG4 related disease of the submandibular glands. PMID- 25911711 TI - Sonographically based diagnosis of contralateral malignancy in preoperative patients with papillary thyroid microcarcinoma. AB - OBJECTIVES: We aimed to assess the usefulness of sonographically based diagnosis to predict whether contralaterally located dominant thyroid nodules are malignant or benign in patients with known papillary thyroid microcarcinoma. METHODS: We studied 143 patients with primary papillary thyroid microcarcinoma who underwent preoperative thyroid sonography. Each dominant thyroid nodule was prospectively classified into 1 of 5 diagnostic categories by a single radiologist: benign, probably benign, borderline, possibly malignant, and malignant. We calculated the efficacy of sonographic diagnosis for contralateral malignancy by using histopathologic or long-term sonographic follow-up results as reference standards. RESULTS: Of the 143 primary papillary thyroid microcarcinomas, 17 showed satellite carcinomas; hence, the bilaterality rate in all patients was 11.9% (17 of 143). Real-time sonography of the contralateral thyroid yielded no thyroid nodules (n = 55) and benign (n = 52), probably benign (n = 10), borderline (n = 13), possibly malignant (n = 4), and malignant (n = 9) nodules. When the borderline sonographic class was excluded, the sensitivity, specificity, positive and negative predictive values, and accuracy of sonographic diagnosis for detecting contralateral malignancy were 86.7%, 100%, 100%, 98.3%, and 98.5%, respectively. Within individual sonographic classes for the dominant thyroid nodules, the diagnostic accuracy rates for classes IV and V (possibly malignant and malignant) were higher than those for other classes. CONCLUSIONS: Sonographically based diagnosis may be helpful for detection of contralateral malignancy in preoperative patients with papillary thyroid microcarcinoma. PMID- 25911712 TI - Age-related differences in the quantitative echo texture of the median nerve. AB - OBJECTIVES: Currently, there are no quantitative data on the echo texture of a peripheral nerve. This study was designed to objectively compare the differences in the echo texture of the median nerve in the young and the elderly. METHODS: The median nerves of 10 healthy young volunteers (<30 years old; group Y) and 10 elderly patients undergoing lower limb surgery (>60 years old; group E) were scanned at the mid forearm by a standardized protocol. The echo texture of a normalized median nerve image was analyzed for the echo intensity and spatial distribution of pixels. Noise in the image was reduced by using a median filter, and thresholding was performed thereafter. In the resultant binary image, the cross-sectional area, echo intensity, white area index, and black area index of the median nerve were determined by computerized texture analysis. RESULTS: The mean cross-sectional area of the median nerve in group E was significantly smaller than that in group Y (P = .002). The mean echo intensity and white area index in group E were significantly higher than those in group Y (P= .002 and .012). The mean black area index in group E was correspondingly significantly lower than that in group Y (P = .012). In group Y, the mean white area index was significantly lower than the black area index (P = .006) but not in group E (P = .213). CONCLUSIONS: There are significant differences in the echo texture of the median nerve between the young and the elderly. These differences may be due to age-related changes in the relative proportion of neural fascicles and connective tissue within the nerve. PMID- 25911713 TI - Sonography of traumatic quadriceps tendon tears with surgical correlation. AB - OBJECTIVES: Using surgical correlation as the reference standard, the purpose of this study was to assess the ability of sonography to detect quadriceps tendon tears that require surgical treatment (high-grade partial tears and complete ruptures). METHODS: Two hundred thirty-nine consecutive sonographic reports of the knee (May 2001 to October 2008) with subsequent surgical correlation were retrospectively reviewed for surgical intervention on the quadriceps tendon. All sonograms were blindly and retrospectively reviewed. Surgical findings were compared with results from the consensus review. Results from the original sonographic reports (nonretrospective interpretation) were also compared with the surgical findings. RESULTS: On the retrospective consensus review, the sensitivity (23 of 23), specificity (16 of 16), and accuracy (39 of 39) were 100% for identifying high-grade partial tears or complete ruptures versus a normal quadriceps tendon. For the original, nonretrospective sonographic reports, 22 of 23 high-grade partial tears or complete ruptures (96%) were correctly diagnosed. CONCLUSIONS: Sonography is an effective tool for identifying quadriceps tendon tears that require surgical treatment (high-grade partial tears and complete ruptures). PMID- 25911714 TI - Differences in liver fibrosis between patients with chronic hepatitis B and C: evaluation by acoustic radiation force impulse measurements at 2 locations. AB - OBJECTIVES: The purpose of this study was to evaluate liver fibrosis by acoustic radiation force impulse (ARFI) measurements at 2 locations in patients with chronic hepatitis B and C. METHODS: A total of 204 consecutive patients (146 male and 58 female) with chronic hepatitis B (n = 121) and C (n = 83) who underwent liver biopsy were enrolled. All patients received ARFI measurements at 2 locations in the right intercostal space on the same day as biopsy. RESULTS: There was no difference in median ARFI values between detection locations. However, a significant difference was found for low and high values between locations (median +/- SD, 1.38 +/- 0.43 versus 1.56 +/- 0.55 m/s; P < .001). By receiver operating characteristic (ROC) curve analysis for a METAVIR fibrosis score of F4 (cirrhosis), the lower value of 2 measurements had the highest area under the ROC curve (0.750), followed by the mean value (0.744) and the higher value (0.730). Patients with hepatitis C had a higher area under the ROC curve than patients with hepatitis B (0.824 versus 0.707) for predicting liver cirrhosis. By logistic regression analysis, ARFI was the best modality for predicting liver cirrhosis in hepatitis C, and conventional sonography was the best modality in hepatitis B (P < .001). The ARFI value in patients with hepatitis B was significantly influenced by liver inflammation (P = .019). CONCLUSIONS: Acoustic radiation force impulse imaging is the modality of choice for predicting liver cirrhosis in chronic hepatitis C, whereas conventional sonography is still the modality of choice in chronic hepatitis B. PMID- 25911715 TI - Implementation and assessment of a curriculum for bedside ultrasound training. AB - OBJECTIVES: This study assessed a curriculum for bedside ultrasound (US) and compared outcomes from 2 common training pathways. METHODS: The program consisted of e-learning paired with expert-led hands-on training administered to pulmonary/critical care and cardiology fellows with no prior formal training in bedside US. This "simulation-based learner" group completed a survey of attitudes and confidence before and after training, and knowledge and skills were assessed after training. The surveys and scores of the simulation-based learners were compared to the scores of "experts," who were US-trained emergency physicians, and "apprentice learners," who were intensivist physicians informally trained in bedside US on the job during fellowships. RESULTS: There was a significant difference in the self-reported level of prior training between the groups (simulation-based learners, 2.8; apprentice learners, 3.7; experts, 4.1, on a scale of 1-5 [P= .02]) but no difference in the interest level or perceived importance of bedside US. The study curriculum was successful, as shown by scores that exceeded the comparison groups in the cardiac and pulmonary courses (cardiac: simulation-based learners, 80%; apprentice learners, 73%; experts, 62% [P= .001]; pulmonary: 84%, 75%, and 72%, respectively [P =.02]). The simulation based learners gained confidence in skills, whereas the comparison groups lost confidence after testing (P < .005); however, the simulation-based learners gained confidence in US subject areas that were not taught (abdomen [P <.002] and miscellaneous [P =.005]). CONCLUSIONS: The simulation-based learner curriculum resulted in comparable or greater knowledge and confidence in each area of US versus the comparison groups. Findings of overgeneralization of confidence highlight the importance of quality assurance and supervision in bedside US training programs. PMID- 25911716 TI - Impact of accreditation training for residents on sonographic quality in gynecologic emergencies. AB - OBJECTIVES: To assess the impact of an educational intervention based on an original accreditation training program on the quality of emergency sonography performed by obstetrics and gynecology (Ob/Gyn) residents. METHODS: We conducted a prospective before-after study on residents who performed bedside standardized sonographic examinations as first-line investigations in patients seen at our gynecologic emergency department. In both periods, the residents followed a 1 hour class taught by a board-certified Ob/Gyn sonography expert (opinion leader) and received a written standardized imaging protocol. An accreditation training process was implemented for the new residents at the beginning of the second period: 5 complete sonographic examinations were required for each resident, and facilitated feedback from the opinion leader was performed using a dedicated sonographic quality score. During both periods, all consecutive sonograms were collected and stored. The primary outcome was the sonographic quality score. A mixed model for repeated measures was used to compare scores in both periods from 20 consecutive sonographic examinations performed by 5 residents who were different in each period. RESULTS: The mixed model analysis showed an increase in quality scores in the post-accreditation training compared to the pre accreditation training period (estimated coefficient +/- SD, 4.13 +/- 0.51; t = 8.16). The sonographic examination order also had a significant effect in both periods (estimated coefficient +/- SD, 0.11 +/- 0.03; t = 3.99). CONCLUSIONS: An accreditation training process including facilitated feedback from a local opinion leader improved the quality of sonographic examinations performed by Ob/Gyn residents in women presenting to a gynecologic emergency department. PMID- 25911717 TI - Estimation of the growth rate in fetuses with an abnormal cerebroplacental ratio compared to those with suspected growth restriction without evidence of centralization of blood flow. AB - OBJECTIVES: To evaluate the growth rate in fetuses with suspected growth restriction according to their Doppler characteristics. METHODS: A retrospective cohort of fetuses with suspected growth restriction was identified. We reviewed umbilical artery and middle cerebral Doppler pulsatility indices and calculated the cerebroplacental ratio. Three study groups were determined: (1) normal umbilical artery Doppler findings; (2) abnormal umbilical artery findings with a normal cerebroplacental ratio; and (3) abnormal umbilical artery findings with an abnormal cerebroplacental ratio. The primary outcome was the growth rate as estimated by fetal biometry from serial sonographic evaluations. Analysis of the mean growth rate in each study group was performed by analysis of variance. In addition, linear regression analysis comparing the cerebroplacental ratio to the growth rate was performed. RESULTS: Fetal growth restriction was suspected in 416 patients; 176 patients were included in this analysis: 113, 38, and 25 in groups 1, 2, and 3 respectively. The estimated mean (SD) growth rate in group 3 was significantly lower than in groups 1 and 2: 8.3 (4.4) versus 19.6 (6.0) and 18.6 (7.7) g/d, respectively (P < .001). Linear regression analysis revealed a strong correlation between the growth rate and cerebroplacental ratio (r = 0.76; R(2) = 0.58) as well as the birth weight and cerebroplacental ratio (r = 0.78; R(2) = 0.61). CONCLUSIONS: In fetuses with suspected growth restriction and abnormal umbilical artery Doppler findings, an abnormal cerebroplacental ratio is strongly associated with reduced fetal growth. In contrast, if the cerebroplacental ratio is normal, even in the setting of abnormal umbilical artery Doppler findings, fetuses grow similarly to those with normal umbilical artery findings. PMID- 25911718 TI - Abnormal umbilical artery Doppler findings in the recipient twin before laser surgery for twin-twin transfusion syndrome. AB - OBJECTIVES: In twin-twin transfusion syndrome (TTTS), persistent absent or reversed end-diastolic flow in the umbilical artery is a rare finding in the recipient twin, and the clinical implications of this finding are not well characterized. We sought to study the clinical importance of abnormal umbilical artery Doppler waveforms in recipient twins and determine the perinatal survival of these twins after laser surgery. METHODS: A retrospective study of patients with TTTS treated with laser surgery between 2006 and 2012 was conducted. Recipient twins with absent or reversed umbilical artery end-diastolic flow on preoperative sonography were identified, and clinical and perinatal outcomes were compared to the remaining cohort. Statistical analyses were performed with Fisher exact and chi(2) tests. RESULTS: Of 369 consecutive TTTS cases, 14 (3.8%) had absent or reversed umbilical artery end-diastolic flow in the recipient twin. The rate of hydrops was higher in this group compared to those without absent or reversed flow (35.7% [5 of 14] versus 10.1% [36 of 355]; P = .0125). The rate of recipient twin growth restriction was also higher in the absent or reversed flow group (28.6% [4 of 14] versus 3.9% [14 of 355]; P = .0029). There was an increased rate of recipient fetal demise within 24 hours after surgery in those with absent or reversed flow (21.4% [3 of 14] versus 2.5% [9 of 355]; P = .0078), although there was no statistical difference in 30-day survival between the groups (78.6% [11 of 14] versus 89.9% [319 of 355]; P = .1751). CONCLUSIONS: Doppler findings of absent or reversed umbilical artery end-diastolic flow are rare in recipient twins. Although immediate post-laser surgery survival is relatively decreased in this group, overall perinatal survival rates appear to be favorable. PMID- 25911719 TI - Fetal thymus volume estimation by virtual organ computer-aided analysis in normal pregnancies. AB - OBJECTIVES: The thymus has a pyramidal shape, which is best shown in coronal planes. The aim of this study was to evaluate the potential of virtual organ computer-aided analysis to estimate fetal thymus volume in normal pregnancies. METHODS: Three-dimensional volume data sets from the axial upper mediastinal section were acquired from 37 normal pregnancies between 12 and 35 weeks' gestation. Thymus volume was calculated by virtual organ computer-aided analysis by 2 separate examiners. In 12 cases, volumes were also acquired with 4 dimensional sonography and spatiotemporal image correlation software to assess the variability in thymus size between the systolic and diastolic periods of fetal heart motion. Linear regression analysis was used to assess the relationship between the fetal thymus volume and gestational age. Paired Student t tests were used to evaluate both the level of agreement for interobserver and intraobserver variability and the difference between diastolic and systolic thymus volumes. RESULTS: Identification of the borders of the thymus and calculation of its volume were successful in 28 patients (77.7%). Statistically significant linear growth of the thymus during pregnancy, from 12 to 35 weeks, was found. The growth coefficient for each gestational age was 0.43 (95% confidence interval, 0.355 to 0.504; P < .001). The difference in thymus size between systole and diastole was minor (0.0798 cm(3); 95% confidence interval, 0.044 to 0.203 cm(3)). Interobserver and intraobserver variability was not statistically significant. CONCLUSIONS: Although the thymus has a complex shape, it was possible to determine its borders and to calculate its volume by virtual organ computer-aided analysis in 77.7% of cases. Linear growth during pregnancy was found, and the minor changes during systole and diastole could be explained by condensation of the soft tissue of the thymus secondary to cardiac activity. PMID- 25911720 TI - The thy-box for sonographic assessment of the fetal thymus: nomogram and review of the literature. AB - OBJECTIVES: To assess the feasibility and reproducibility of fetal thy-box visualization and to set normative data for the fetal thymus using this technique. METHODS: We performed a cross-sectional observational study in pregnant women in their second trimester of pregnancy who attended the fetal medicine unit of the Hospital Gregorio Maranon from March 2011 to March 2013. Using thy-box sonography, which sets boundaries within the thymus, we assessed the feasibility of the thy-box and analyzed the factors related to its visualization. Measurements of the thy-box anteroposterior and transverse diameters were performed in healthy fetuses. Interobserver agreement was studied for both items. We set normative data for the thy-box diameters in singleton and twin pregnancies. RESULTS: A total of 337 patients from 15 to 37 weeks were recruited after exclusion criteria. Thy-box feasibility was 74.2% (250 of 337). Nonfeasible cases were related to the fetal anterior spine and advanced gestational age. Assessment of the thy-box anteroposterior and transverse diameters was achievable in 250 fetuses. Interobserver agreement was good for feasibility and measurements (kappa = 0.80). Linear growth of the thy-box in both diameters was observed in relation to gestational age during the second half of pregnancy. Thy-box diameters did not show significant differences according to the type of gestation, fetal sex, or chorionicity. CONCLUSIONS: Thy-box diameters are achievable and reproducible by sonography in normal singleton and twin pregnancies during the second trimester; however, although feasible, the thy-box transverse diameter measurement is not reliable beyond 28 weeks. Further studies are needed to evaluate thy-box diameters in pathologic cases, especially conotruncal anomalies. PMID- 25911721 TI - Importance of an adequately performed Valsalva maneuver for detecting a right-to left shunt indicating foramen ovale reopening. AB - OBJECTIVES: The purpose of this study was to investigate the importance of an adequately performed Valsalva maneuver for detecting a right-to-left shunt indicating reopening of the functional closure of the foramen ovale. METHODS: We prospectively analyzed 260 patients (102 women and 158 men; mean age +/- SD, 41 +/- 19 years; range, 13-83 years) who underwent transesophageal echocardiography and agitated saline injection. Two-dimensional echocardiography, color Doppler imaging, and microbubbles were used to detect right-to-left shunts, and the Valsalva maneuver was performed to determine whether the functional closure of the foramen ovale had reopened. RESULTS: Transesophageal echocardiography with color Doppler imaging identified a patent foramen ovale in 20 patients: 18 patients with a patent foramen ovale had left-to-right shunts, and 2 patients with atrial septal defects had bidirectional shunts. Both patients with atrial septal defects showed right-to-left shunt microbubbles without and with the Valsalva maneuver, whereas all 18 patients with a patent foramen ovale showed right-to-left shunt microbubbles only after the Valsalva maneuver. Foramen ovale reopening was identified by transesophageal echocardiography in an additional 40 patients with no shunt during rest on agitated saline injection and in whom the right-to-left shunt appeared only after the Valsalva maneuver. The Valsalva maneuver could cause an atrial septal swing, and its sensitivity and specificity were 100%. CONCLUSIONS: An adequately performed Valsalva maneuver is important for detecting a right-to-left shunt indicating reopening of the functional closure of the foramen ovale. PMID- 25911722 TI - Intraoperative sonography during carotid endarterectomy: normal appearance and spectrum of complications. AB - Carotid endarterectomy is a commonly performed procedure for prevention of stroke related to carotid stenosis. Intraoperative sonography is used to identify potentially correctable technical defects during carotid endarterectomy. The main risk of endarterectomy is perioperative stroke, and great effort has been put into trying to reduce this risk through various surgical techniques and evaluation of the surgical bed. Postoperative carotid thrombosis, or thombo embolization from the arterectomy site, remains a common cause of perioperative stroke and is often related to technical defects in the arterial reconstruction procedure. Re-exploration and repair of any imperfections have the potential to improve outcomes. Intraoperative imaging can identify potentially occult lesions, provide the option for correction, and thus reduce chance of stroke. Familiarity with the spectrum of intraoperative sonographic findings helps correctly identify residual intimal dissection flaps, plaque, thrombi, and stenosis, which may require immediate surgical revision. Our objective is to illustrate the spectrum of intraoperative findings and their importance. PMID- 25911723 TI - Radiologic features of hydatid disease: the importance of sonography. AB - Hydatid disease is commonly encountered in specific geographic areas of the world. Hydatidosis affects multiple organs and has diverse radiologic presentations. Sonography remains an important modality for diagnosing this condition, as it optimally detects cystic structures, floating membranes, and debris. Sonography forms the crux of radiologic diagnosis of hydatid disease. It not only helps diagnose the disease but also aids in guiding therapeutic interventions. The main objective of this article is to describe the imaging features of hydatid disease in its various stages. This article gives an overview of the spectrum of sonographic manifestations of hydatid disease in various locations, along with common differential diagnoses. A brief description of therapeutic management is also presented. PMID- 25911724 TI - Contrast-enhanced sonographically guided thermal ablation for treatment of solid organ hemorrhage: preliminary clinical results. AB - The purpose of this series was to preliminarily evaluate the use of contrast enhanced sonographically guided percutaneous thermal ablation in the evaluation and treatment of solid-organ bleeding by retrospectively analyzing 6 cases observed in clinical practice. Six patients who underwent contrast-enhanced sonographically guided thermal ablation for treatment of solid-organ bleeding (5 in liver and 1 in spleen) from December 2005 to August 2012 were included in this series. Clinical information, contrast-enhanced sonograms before and after ablation, and the ablation method were retrospectively collected and analyzed. In 5 of the 6 patients, the location of the bleeding lesion was clearly seen. Hemostasis was successfully achieved in 4 of these 5 patients: 1 by radiofrequency ablation and 3 by microwave ablation. Ablation failed to achieve hemostasis in 1 patient who had postbiopsy splenic arterial bleeding because the bleeding vessel was a thick branch of the splenic artery. In the sixth remaining patient, who had bleeding after liver biopsy, hemostasis failed because contrast enhanced sonography did not precisely locate the bleeding lesion; hence, the ablation zone did not cover the whole lesion. Contrast-enhanced sonographically guided ablation can be an alternative choice for treating solid-organ bleeding because of its effectiveness and minimal invasiveness. However, it should be carefully investigated for those in whom the bleeding lesion cannot be located by contrast-enhanced sonography and in those who have bleeding in a large vessel. PMID- 25911725 TI - Sonographic findings in an isolated widened fetal subarachnoid space. AB - The purpose of this series was to describe sonographic features of an isolated widened fetal subarachnoid space with a thin cerebral mantle and possible associations. Between January 2004 and December 2013, fetuses with a prenatal diagnosis of a widened subarachnoid space were prospectively recruited and followed. Histories of medical and familial diseases, as well as other demographic data such as drug exposure and lifestyles, were assessed and prospectively recorded. The women were investigated for possible associated factors. Ten pregnant women were recruited. Their fetuses showed various degrees of a widened subarachnoid space, ranging from 5 to 20 mm. Nearly all were diagnosed in the second half of pregnancy. Four cases had normal brain structures documented at midpregnancy anomaly screening. Only 1 case had a prenatal diagnosis of a widened subarachnoid space at 20 weeks' gestation. Two fetuses had exposure to alcohol in utero; 2 were proven to have cytomegalovirus infection; 1 had subarachnoid hemorrhage secondary to maternal use of warfarin; and 1 had a diagnosis of lissencephaly. Only 1 case in this series had normal postnatal development. A prenatal series of fetal widened subarachnoid spaces with possible associated factors is described. Although such relationships were not fully proven, they should be index cases for future studies. PMID- 25911726 TI - Complex fetal ovarian cyst. PMID- 25911727 TI - Subclavian steal following left subclavian artery occlusion during thoracic endovascular aortic repair: Doppler findings and literature review. PMID- 25911728 TI - Erratum. PMID- 25911729 TI - Transcranial Doppler sonography in patients with severe brain injury. PMID- 25911731 TI - Recurrent positive selection and heterogeneous codon usage bias events leading to coexistence of divergent pigeon circoviruses. AB - The capsid genes from 14 pigeon circovirus (PiCV) sequences, collected from Taiwan between 2009 and 2010, were sequenced and compared with 14 PiCV capsid gene sequences from GenBank. Based on pairwise comparison, PiCV strains from Taiwan shared 73.9-100% nucleotide identity and 72-100% amino acid identity with those of the 14 reported PiCV sequences. Phylogenetic analyses revealed that Taiwanese PiCV isolates can be grouped into two clades: clade 1 comprising isolates from Belgium, Australia, USA, Italy and China, and clade 2 showing close relation to isolates from Germany and France. Recurrent positive selection was detected in clade 1 PiCV lineages, which may contribute to the diversification of predominant PiCV sequences in Taiwan. Further observations suggest that synonymous codon usage variations between PiCV clade 1 and clade 2 may reflect the adaptive divergence on translation efficiency of capsid genes in infectious hosts. Variation in selective pressures acting on the evolutionary divergence and codon usage bias of both clades explains the regional coexistence of virus sequences congeners prevented from competitive exclusion within an island such as Taiwan. Our genotyping results also provide insight into the aetiological agents of PiCV outbreak in Taiwan and we present a comparative analysis of the central coding region of PiCV genome. From the sequence comparison results of 28 PiCVs which differs in regard to the geographical origin and columbid species, we identified conserved regions within the capsid gene that are likely to be suitable for primer selection and vaccine development. PMID- 25911732 TI - A meta-analysis of in vivo vertebrate cardiac performance: implications for cardiovascular support in the evolution of endothermy. AB - Endothermy in birds and mammals is associated with high body temperatures, and high rates of metabolism that are aerobically supported by elevated rates of cardiovascular O2 transport. The purpose of this meta-analysis was to examine cardiovascular data from ectothermic and endothermic vertebrates, at rest and during exercise, with the goal of identifying key variables that may have contributed to the role of the cardiovascular system in supporting high rates of O2 transport associated with endothermy. Vascular conductance, cardiac power and stroke work were summarized and calculated from a variety of studies at rest and during exercise for five classes of vertebrates where data were available. Conductance and cardiac power were linearly related to cardiac output from rest to exercise and also interspecifically. Exercise cardiac power and stroke work were greater in the endothermic species, owing to increased flow resulting from increased heart rate and increased pressure. Increased relative ventricle mass (RVM) was related to increased stroke volume in both groups. However, the increased RVM of endotherms was related to the increased pressure, as stroke work per gram of ventricle during exercise was equivalent between the groups. Cardiac power was linearly related to aerobic metabolic power, with 158 mW aerobic power output achieved per mW of cardiac power input. This analysis indicates that the greatly increased heart rate and cardiac stroke work leading to increased blood flow rate and blood pressure was necessary to support the metabolic requirements of endothermy. PMID- 25911730 TI - The human papillomavirus type 16 L1 protein directly interacts with E2 and enhances E2-dependent replication and transcription activation. AB - The human papillomavirus (HPV) E2 protein is a multifunctional protein essential for the control of virus gene expression, genome replication and persistence. E2 is expressed throughout the differentiation-dependent virus life cycle and is functionally regulated by association with multiple viral and cellular proteins. Here, we show for the first time to our knowledge that HPV16 E2 directly associates with the major capsid protein L1, independently of other viral or cellular proteins. We have mapped the L1 binding region within E2 and show that the alpha-2 helices within the E2 DNA-binding domain mediate L1 interaction. Using cell-based assays, we show that co-expression of L1 and E2 results in enhanced transcription and virus origin-dependent DNA replication. Upon co expression in keratinocytes, L1 reduces nucleolar association of E2 protein, and when co-expressed with E1 and E2, L1 is partially recruited to viral replication factories. Furthermore, co-distribution of E2 and L1 was detected in the nuclei of upper suprabasal cells in stratified epithelia of HPV16 genome-containing primary human keratinocytes. Taken together, our findings suggest that the interaction between E2 and L1 is important for the regulation of E2 function during the late events of the HPV life cycle. PMID- 25911733 TI - The cost of digestion in the fish-eating myotis (Myotis vivesi). AB - Flying vertebrates, such as bats, face special challenges with regards to the throughput and digestion of food. On the one hand, as potentially energy-limited organisms, bats must ingest and assimilate energy efficiently in order to satisfy high resting and active metabolic demands. On the other hand, the assimilation of nutrients must be accomplished using a digestive tract that is, compared with that of similarly sized non-flying vertebrates, significantly shorter. Despite these competing demands, and the relative breadth of dietary diversity among bats, little work has been done describing the cost of digestion, termed 'specific dynamic action' (SDA). Here, we provide the first systematic assessment of the SDA response in a bat, the fish-eating myotis (Myotis vivesi). Given the shorter digestive tract and the relatively higher resting and active metabolic rates of bats in general, and based on anecdotal published evidence, we hypothesized that the SDA response in fish-eating myotis would be dependent on meal size and both significantly more brief and intense than in small, non-flying mammals. In agreement with our hypothesis, we found that the peak metabolic rate during digestion, relative to rest, was significantly higher in these bats compared with any other mammals or vertebrates, except for some infrequently eating reptiles and amphibians. Additionally, we found that the magnitude and duration of the SDA response were related to meal size. However, we found that the duration of the SDA response, while generally similar to reported gut transit times in other small bats, was not substantially shorter than in similarly sized non-flying mammals. PMID- 25911734 TI - Western and Clark's grebes use novel strategies for running on water. AB - Few vertebrates run on water. The largest animals to accomplish this feat are western and Clark's grebes (Aechmophorus occidentalis and Aechmophorus clarkii). These birds use water running to secure a mate during a display called rushing. Grebes weigh an order of magnitude more than the next largest water runners, basilisk lizards (Basilicus basiliscus), and therefore face a greater challenge to support their body weight. How do these birds produce the hydrodynamic forces necessary to overcome gravity and sustain rushing? We present the first quantitative study of water running by grebes. High-speed video recordings elucidate the hindlimb movements of grebes rushing in the wild. We complement these findings with laboratory experiments using physical models and a preserved grebe foot to estimate how slapping the water surface contributes to weight support. Our results indicate that grebes use three novel tactics to successfully run on water. First, rushing grebes use exceptionally high stride rates, reaching 10 Hz. Second, grebe foot size and high water impact speed allow grebes to generate up to 30-55% of the required weight support through water slap alone. Finally, flattened foot bones reduce downward drag, permitting grebes to retract each foot from the water laterally. Together, these mechanisms outline a water running strategy qualitatively different from that of the only previously studied water runner, the basilisk lizard. The hydrodynamic specializations of rushing grebes could inform the design of biomimetic appendages. Furthermore, the mechanisms underlying this impressive display demonstrate that evolution can dramatically alter performance under sexual selection. PMID- 25911735 TI - Cambered profile of a California sea lion's body. PMID- 25911736 TI - Estimation of shape of the sea lion for hydrodynamic analysis. Response to 'Cambered profile of a California sea lion's body'. PMID- 25911737 TI - Evolution beyond neo-Darwinism: a new conceptual framework. PMID- 25911738 TI - Insights into plant cell wall structure, architecture, and integrity using glycome profiling of native and AFEXTM-pre-treated biomass. AB - Cell walls, which constitute the bulk of plant biomass, vary considerably in their structure, composition, and architecture. Studies on plant cell walls can be conducted on both native and pre-treated plant biomass samples, allowing an enhanced understanding of these structural and compositional variations. Here glycome profiling was employed to determine the relative abundance of matrix polysaccharides in several phylogenetically distinct native and pre-treated plant biomasses. Eight distinct biomass types belonging to four different subgroups (i.e. monocot grasses, woody dicots, herbaceous dicots, and softwoods) were subjected to various regimes of AFEXTM (ammonia fiber expansion) pre-treatment [AFEX is a trademark of MBI, Lansing (http://www.mbi.org]. This approach allowed detailed analysis of close to 200 cell wall glycan epitopes and their relative extractability using a high-throughput platform. In general, irrespective of the phylogenetic origin, AFEXTM pre-treatment appeared to cause loosening and improved accessibility of various xylan epitope subclasses in most plant biomass materials studied. For most biomass types analysed, such loosening was also evident for other major non-cellulosic components including subclasses of pectin and xyloglucan epitopes. The studies also demonstrate that AFEXTM pre-treatment significantly reduced cell wall recalcitrance among diverse phylogenies (except softwoods) by inducing structural modifications to polysaccharides that were not detectable by conventional gross composition analyses. It was found that monitoring changes in cell wall glycan compositions and their relative extractability for untreated and pre-treated plant biomass can provide an improved understanding of variations in structure and composition of plant cell walls and delineate the role(s) of matrix polysaccharides in cell wall recalcitrance. PMID- 25911740 TI - Interactions between cytokinin signalling and abiotic stress responses. AB - Plants have evolved elaborate mechanisms for sensing and responding to sub optimal environmental conditions. Abiotic stresses caused by these conditions trigger a wide range of local and long-distance signals which must be co ordinated and integrated into whole-plant processes, such as development, in order for the plant to respond properly and survive. Several hormones function as key regulators of stress tolerance, connecting local stimuli to systemic responses. Cytokinin is a hormone well known for its role in numerous aspects of growth and development, although abundant evidence also indicates that cytokinin functions in stress responses as well. At present, a full understanding of the effects of cytokinin on plant resistance to stress is lacking, possibly as a result of the complex interactions between cytokinin and stress signalling. Current knowledge of the physiological relationship between cytokinin and abiotic stress, based on measurements of cytokinin levels under stress conditions and the effects of cytokinin treatment on stress tolerance, has been examined here. A pattern of transcriptional regulation of stress-related genes by cytokinin in different plant species has also been identified. In addition, research regarding the role of specific cytokinin signalling components in a variety of stress responses is presented. We discuss what this body of research collectively implies with regard to cross-talk between cytokinin and abiotic stress tolerance. PMID- 25911739 TI - Nitrate sensing by the maize root apex transition zone: a merged transcriptomic and proteomic survey. AB - Nitrate is an essential nutrient for plants, and crops depend on its availability for growth and development, but its presence in agricultural soils is far from stable. In order to overcome nitrate fluctuations in soil, plants have developed adaptive mechanisms allowing them to grow despite changes in external nitrate availability. Nitrate can act as both nutrient and signal, regulating global gene expression in plants, and the root tip has been proposed as the sensory organ. A set of genome-wide studies has demonstrated several nitrate-regulated genes in the roots of many plants, although only a few studies have been carried out on distinct root zones. To unravel new details of the transcriptomic and proteomic responses to nitrate availability in a major food crop, a double untargeted approach was conducted on a transition zone-enriched root portion of maize seedlings subjected to differing nitrate supplies. The results highlighted a complex transcriptomic and proteomic reprogramming that occurs in response to nitrate, emphasizing the role of this root zone in sensing and transducing nitrate signal. Our findings indicated a relationship of nitrate with biosynthesis and signalling of several phytohormones, such as auxin, strigolactones, and brassinosteroids. Moreover, the already hypothesized involvement of nitric oxide in the early response to nitrate was confirmed with the use of nitric oxide inhibitors. Our results also suggested that cytoskeleton activation and cell wall modification occurred in response to nitrate provision in the transition zone. PMID- 25911742 TI - Interplay of HD-Zip II and III transcription factors in auxin-regulated plant development. AB - The homeodomain-leucine zipper (HD-Zip) class of transcription factors is unique to plants. HD-Zip proteins bind to DNA exclusively as dimers recognizing dyad symmetric sequences and act as positive or negative regulators of gene expression. On the basis of sequence homology in the HD-Zip DNA-binding domain, HD-Zip proteins have been grouped into four families (HD-Zip I-IV). Each HD-Zip family can be further divided into subfamilies containing paralogous genes that have arisen through genome duplication. Remarkably, all the members of the HD-Zip IIgamma and -delta clades are regulated by light quality changes that induce in the majority of the angiosperms the shade-avoidance response, a process regulated at multiple levels by auxin. Intriguingly, it has recently emerged that, apart from their function in shade avoidance, the HD-Zip IIgamma and -delta transcription factors control several auxin-regulated developmental processes, including apical embryo patterning, lateral organ polarity, and gynoecium development, in a white-light environment. This review presents recent advances in our understanding of HD-Zip II protein function in plant development, with particular emphasis on the impact of loss-of-function HD-Zip II mutations on auxin distribution and response. The review also describes evidence demonstrating that HD-Zip IIgamma and -delta genes are directly and positively regulated by HD Zip III transcription factors, primary determinants of apical shoot development, known to control the expression of several auxin biosynthesis, transport, and response genes. Finally, the interplay between HD-Zip II and III transcription factors in embryo apical patterning and organ polarity is discussed. PMID- 25911741 TI - Characterization of the cis elements in the proximal promoter regions of the anthocyanin pathway genes reveals a common regulatory logic that governs pathway regulation. AB - Cellular activities such as compound synthesis often require the transcriptional activation of an entire pathway; however, the molecular mechanisms underlying pathway activation have rarely been explained. Here, the cis regulatory architecture of the anthocyanin pathway genes targeted by the transcription factor (TF) complex including MYB, bHLH, and WDR was systematically analysed in one species and the findings extended to others. In Ipomoea purpurea, the IpMYB1 IpbHLH2-IpWDR1 (IpMBW) complex was found to be orthologous to the PAP1-GL3-TTG1 (AtPGT) complex of Arabidopsis thaliana, and interacted with a 7-bp MYB recognizing element (MRE) and a 6-bp bHLH-recognizing element (BRE) at the proximal promoter region of the pathway genes. There was little transcription of the gene in the absence of the MRE or BRE. The cis elements identified experimentally converged on two syntaxes, ANCNNCC for MREs and CACN(A/C/T)(G/T) for BREs, and our bioinformatic analysis showed that these were present within anthocyanin gene promoters in at least 35 species, including both gymnosperms and angiosperms. For the anthocyanin pathway, IpMBW and AtPGT recognized the interspecific promoters of both early and later genes. In A. thaliana, the seed specific TF complex (TT2, TT8, and TTG1) may regulate all the anthocyanin pathway genes, in addition to the proanthocyanidin-specific BAN. When multiple TF complexes in the anthocyanin pathway were compared, the cis architecture played a role larger than the TF complex in determining the variation in promoter activity. Collectively, a cis logic common to the pathway gene promoters was found, and this logic is essential for the trans factors to regulate the pathway. PMID- 25911743 TI - Small molecules unravel complex interplay between auxin biology and endomembrane trafficking. AB - The establishment and maintenance of controlled auxin gradients within plant tissues are essential for a multitude of developmental processes. Auxin gradient formation is co-ordinated via local biosynthesis and transport. Cell to cell auxin transport is facilitated and precisely regulated by complex endomembrane trafficking mechanisms that target auxin carrier proteins to their final destinations. In turn, auxin and cross-talk with other phytohormones regulate the endomembrane trafficking of auxin carriers. Dissecting such rapid and complicated processes is challenging for classical genetic experiments due to trafficking pathway diversity, gene functional redundancy, and lethality in loss-of-function mutants. Many of these difficulties can be bypassed via the use of small molecules to modify or disrupt the function or localization of proteins. Here, we will review examples of the knowledge acquired by the use of such chemical tools in this field, outlining the advantages afforded by chemical biology approaches. PMID- 25911744 TI - Quo vadis, Pep? Plant elicitor peptides at the crossroads of immunity, stress, and development. AB - The first line of inducible plant defence, pattern-triggered immunity (PTI), is activated by the recognition of exogenous as well as endogenous elicitors. Exogenous elicitors, also called microbe-associated molecular patterns, signal the presence of microbes. In contrast, endogenous elicitors seem to be generated and recognized under more diverse circumstances, making the evaluation of their biological relevance much more complex. Plant elicitor peptides (Peps) are one class of such endogenous elicitors, which contribute to immunity against attack by bacteria, fungi, as well as herbivores. Recent studies indicate that the Pep triggered signalling pathways also operate during the response to a more diverse set of stresses including starvation stress. In addition, in silico data point to an involvement in the regulation of plant development, and a study on Pep mediated inhibition of root growth supports this indication. Importantly, Peps are neither limited to the model plant Arabidopsis nor to a specific plant family like the previously intensively studied systemin peptides. On the contrary, they are present and active in angiosperms all across the phylogenetic tree, including many important crop plants. Here we summarize the progress made in research on Peps from their discovery in 2006 until now. We discuss the two main models which describe their likely function in plant immunity, highlight the studies supporting additional roles of Pep-triggered signalling and identify urgent research tasks to further uncover their biological relevance. PMID- 25911745 TI - LATERAL ROOT PRIMORDIA 1 of maize acts as a transcriptional activator in auxin signalling downstream of the Aux/IAA gene rootless with undetectable meristem 1. AB - Only little is known about target genes of auxin signalling downstream of the Aux/IAA-ARF module. In the present study, it has been demonstrated that maize lateral root primordia 1 (lrp1) encodes a transcriptional activator that is directly regulated by the Aux/IAA protein ROOTLESS WITH UNDETECTABLE MERISTEM 1 (RUM1). Expression of lrp1 is confined to early root primordia and meristems and is auxin-inducible. Based on its primary protein structure, LRP1 is predicted to be a transcription factor. This notion is supported by exclusive LRP1 localization in the nucleus and its ability to activate downstream gene activity. Based on the observation that lrp1 transcription is completely repressed in the semi-dominant gain of function mutant rum1, it was demonstrated that the lrp1 promoter is a direct target of RUM1 proteins. Subsequently, promoter activation assays indicated that RUM1 represses the expression of a GFP reporter fused to the native promoter of lrp1. Constitutive repression of lrp1 in rum1 mutants is a consequence of the stability of mutated rum1 proteins which cannot be degraded by the proteasome and thus constitutively bind to the lrp1 promoter and repress transcription. Taken together, the repression of the transcriptional activator lrp1 by direct binding of RUM1 to its promoter, together with specific expression of lrp1 in root meristems, suggests a function in maize root development via the RUM1-dependent auxin signalling pathway. PMID- 25911746 TI - Functionally different PIN proteins control auxin flux during bulbil development in Agave tequilana. AB - In Agave tequilana, reproductive failure or inadequate flower development stimulates the formation of vegetative bulbils at the bracteoles, ensuring survival in a hostile environment. Little is known about the signals that trigger this probably unique phenomenon in agave species. Here we report that auxin plays a central role in bulbil development and show that the localization of PIN1 related proteins is consistent with altered auxin transport during this process. Analysis of agave transcriptome data led to the identification of the A. tequilana orthologue of PIN1 (denoted AtqPIN1) and a second closely related gene from a distinct clade reported as 'Sister of PIN1' (denoted AtqSoPIN1). Quantitative real-time reverse transcription-PCR (RT-qPCR) analysis showed different patterns of expression for each gene during bulbil formation, and heterologous expression of the A. tequilana PIN1 and SoPIN1 genes in Arabidopsis thaliana confirmed functional differences between these genes. Although no free auxin was detected in induced pedicel samples, changes in the levels of auxin precursors were observed. Taken as a whole, the data support the model that AtqPIN1 and AtqSoPIN1 have co-ordinated but distinct functions in relation to auxin transport during the initial stages of bulbil formation. PMID- 25911747 TI - B7H6-Specific Bispecific T Cell Engagers Lead to Tumor Elimination and Host Antitumor Immunity. AB - Substantial evidence showed that T cells are the key effectors in immune-mediated tumor eradication; however, most T cells do not exhibit antitumor specificity. In this study, a bispecific T cell engager (BiTE) approach was used to direct T cells to recognize B7H6(+) tumor cells. B7H6 is a specific ligand for the NK cell activating receptor NKp30. B7H6 is expressed on various types of primary human tumors, including leukemia, lymphoma, and gastrointestinal stromal tumors, but it is not constitutively expressed on normal tissues. Data from this study showed that B7H6-specific BiTEs direct T cells to mediate cellular cytotoxicity and IFN gamma secretion upon coculturing with B7H6(+) tumors. Furthermore, B7H6-specific BiTE exhibited no self-reactivity to proinflammatory monocytes. In vivo, B7H6 specific BiTE greatly enhanced the survival benefit of RMA/B7H6 lymphoma-bearing mice through perforin and IFN-gamma effector mechanisms. In addition, long-term survivor mice were protected against an RMA lymphoma tumor rechallenge. The B7H6 specific BiTE therapy also decreased tumor burden in murine melanoma and ovarian cancer models. In conclusion, B7H6-specific BiTE activates host T cells and has the potential to treat various B7H6(+) hematological and solid tumors. PMID- 25911748 TI - Viremic HIV Controllers Exhibit High Plasmacytoid Dendritic Cell-Reactive Opsonophagocytic IgG Antibody Responses against HIV-1 p24 Associated with Greater Antibody Isotype Diversification. AB - Identifying the mechanisms of natural control of HIV-1 infection could lead to novel approaches to prevent or cure HIV infection. Several studies have associated natural control of HIV-1 infection with IgG Abs against HIV-1 Gag proteins (e.g., p24) and/or production of IgG2 Abs against HIV-1 proteins. These Abs likely exert their effect by activating antiviral effector cell responses rather than virus neutralization. We hypothesized that an opsonophagocytic IgG Ab response against HIV-1 p24 that activates plasmacytoid dendritic cells (pDCs) through FcgammaRIIa would be associated with control of HIV and that this would be enhanced by Ab isotype diversification. Using the Gen2.2 pDC cell line, we demonstrated that pDC-reactive opsonophagocytic IgG Ab responses against HIV-1 p24 were higher in HIV controllers (HIV RNA < 2000 copies/ml) than noncontrollers (HIV RNA > 10,000 copies/ml), particularly in controllers with low but detectable viremia (HIV RNA 75-2000 copies/ml). Opsonophagocytic Ab responses correlated with plasma levels of IgG1 and IgG2 anti-HIV-1 p24 and, notably, correlated inversely with plasma HIV RNA levels in viremic HIV patients. Phagocytosis of these Abs was mediated via FcgammaRIIa. Isotype diversification (toward IgG2) was greatest in HIV controllers, and depletion of IgG2 from Ig preparations indicated that IgG2 Abs to HIV-1 p24 do not enhance phagocytosis, suggesting that they enhance other aspects of Ab function, such as Ag opsonization. Our findings emulate those for pDC-reactive opsonophagocytic Ab responses against coxsackie, picorna, and influenza viruses and demonstrate a previously undefined immune correlate of HIV-1 control that may be relevant to HIV vaccine development. PMID- 25911749 TI - The Free Radical Scavenger NecroX-7 Attenuates Acute Graft-versus-Host Disease via Reciprocal Regulation of Th1/Regulatory T Cells and Inhibition of HMGB1 Release. AB - Graft-versus-host disease (GVHD) is a major complication associated with allogeneic hematopoietic stem cell transplantation. Despite the prominent role of the adaptive immune system, the importance of controlling the innate immune system in the pathogenesis of GVHD has recently been rediscovered. High-mobility group box 1 (HMGB1) is a crucial damage-associated molecular pattern signal that functions as a potent innate immune mediator in GVHD. In the present study, we investigated treatment of experimental GVHD through HMGB1 blockade using the compound cyclopentylamino carboxymethylthiazolylindole (NecroX)-7. Treated animals significantly attenuated GVHD-related mortality and inhibited severe tissue damage. These protective effects correlated with the decrease in HMGB1 expression and lower levels of reactive oxidative stress. Additionally, NecroX-7 inhibited the HMGB1-induced release of TNF and IL-6, as well as the expression of TLR-4 and receptor for advanced glycation end products. We also observed increased regulatory T cell numbers, which may be associated with regulation of differentiation signals independent of HMGB1. Taken together, these data indicate that NecroX-7 protects mice against lethal GVHD by reciprocal regulation of regulatory T/Th1 cells, attenuating systemic HMGB1 accumulation and inhibiting HMGB1-mediated inflammatory response. Our results indicate the possibility of a new use for a clinical drug that is effective for the treatment of GVHD. PMID- 25911750 TI - The Thrombin-Derived Host Defense Peptide GKY25 Inhibits Endotoxin-Induced Responses through Interactions with Lipopolysaccharide and Macrophages/Monocytes. AB - Host defense peptides have recently gained much interest as novel anti-infectives owing to their ability to kill bacteria and simultaneously modulate host cell responses. The cationic host defense peptide GKY25 (GKYGFYTHVFRLKKWIQKVIDQFGE), derived from the C terminus of human thrombin, inhibits proinflammatory responses in vitro and in vivo, but the mode of action is unclear. In this study, we show that GKY25, apart from binding bacterial LPS, also interacts directly with monocytes and macrophages in vitro, ex vivo, and in vivo. Moreover, GKY25 inhibits TLR4- and TLR2-induced NF-kappaB activation in response to several microbe-derived agonists. Furthermore, GKY25 reduces LPS-induced phosphorylation of MAPKs p38alpha and JNK1/2/3. FACS and electron microscopy analyses showed that GKY25 interferes with TLR4/myeloid differentiation protein-2 dimerization. The results demonstrate a previously undisclosed activity of the host defense peptide GKY25, based on combined LPS and cell interactions leading to inhibition of TLR4 dimerization and subsequent reduction of NF-kappaB activity and proinflammatory cytokine production in monocytes and macrophages. PMID- 25911751 TI - Altered connexin 43 expression underlies age-dependent decrease of regulatory T cell suppressor function in nonobese diabetic mice. AB - Type 1 diabetes is one of the most extensively studied autoimmune diseases, but the cellular and molecular mechanisms leading to T cell-mediated destruction of insulin-producing beta cells are still not well understood. In this study, we show that regulatory T cells (T(regs)) in NOD mice undergo age-dependent loss of suppressor functions exacerbated by the decreased ability of activated effector T cells to upregulate Foxp3 and generate T(regs) in the peripheral organs. This age dependent loss is associated with reduced intercellular communication mediated by gap junctions, which is caused by impaired upregulation and decreased expression of connexin 43. Regulatory functions can be corrected, even in T cells isolated from aged, diabetic mice, by a synergistic activity of retinoic acid, TGF-beta, and IL-2, which enhance connexin 43 and Foxp3 expression in T(regs) and restore the ability of conventional CD4(+) T cells to upregulate Foxp3 and generate peripherally derived T(regs). Moreover, we demonstrate that suppression mediated by T(regs) from diabetic mice is enhanced by a novel reagent, which facilitates gap junction aggregation. In summary, our report identifies gap junction-mediated intercellular communication as an important component of the T(reg) suppression mechanism compromised in NOD mice and suggests how T(reg) mediated immune regulation can be improved. PMID- 25911752 TI - CD14++CD16+ Monocytes Are Enriched by Glucocorticoid Treatment and Are Functionally Attenuated in Driving Effector T Cell Responses. AB - Human peripheral monocytes have been categorized into three subsets based on differential expression levels of CD14 and CD16. However, the factors that influence the distribution of monocyte subsets and the roles that each subset plays in autoimmunity are not well studied. In this study, we show that circulating monocytes from patients with autoimmune uveitis exhibit a skewed phenotype toward intermediate CD14(++)CD16(+) cells, and that this is associated with glucocorticoid therapy. We further demonstrate that CD14(++)CD16(+) monocytes from patients and healthy control donors share a similar cell-surface marker and gene expression profile. Comparison of the effects of intermediate CD14(++)CD16(+) monocytes with classical CD14(++)CD16(-) and nonclassical CD14(+)CD16(++) monocytes revealed that the intermediate CD14(++)CD16(+) subset had an attenuated capacity to promote both naive CD4(+) T cell proliferation and polarization into a Th1 phenotype, and memory CD4(+) T cell proliferation and IL 17 expression. Furthermore, CD14(++)CD16(+) cells inhibit CD4(+) T cell proliferation induced by other monocyte subsets and enhance CD4(+) T regulatory cell IL-10 expression. These data demonstrate the impact of glucocorticoids on monocyte phenotype in the context of autoimmune disease and the differential effects of monocyte subsets on effector T cell responses. PMID- 25911753 TI - miR-155 Deficiency Ameliorates Autoimmune Inflammation of Systemic Lupus Erythematosus by Targeting S1pr1 in Faslpr/lpr Mice. AB - MicroRNA-155 (miR-155) was previously found involved in the development of systemic lupus erythematosus (SLE) and other autoimmune diseases and the inflammatory response; however, the detailed mechanism of miR-155 in SLE is not fully understood. To explore the in vivo role of miR-155 in the pathogenesis of SLE, miR-155-deficient Fas(lpr/lpr) (miR-155(-/-)Fas(lpr/lpr)) mice were obtained by crossing miR-155(-/-) and Fas(lpr/lpr) mice. Clinical SLE features such as glomerulonephritis, autoantibody levels, and immune system cell populations were compared between miR-155(-/-)Fas(lpr/lpr) and Fas(lpr/lpr) mice. Microarray analysis, RT-PCR, Western blot, and luciferase reporter gene assay were used to identify the target gene of miR-155. miR-155(-/-)Fas(lpr/lpr) mice showed milder SLE clinical features than did Fas(lpr/lpr)mice. As compared with Fas(lpr/lpr) mice, miR-155(-/-)Fas(lpr/lpr) mice showed less deposition of total IgA, IgM, and IgG and less infiltration of inflammatory cells in the kidney. Moreover, the serum levels of IL-4 and IL-17a, secreted by Th2 and Th17 cells, were lower in miR-155(-/-)Fas(lpr/lpr) than Fas(lpr/lpr) mice; the CD4(+)/CD8(+) T cell ratio was restored in miR-155(-/-)Fas(lpr/lpr) mice as well. Sphingosine-1-phosphate receptor 1 (S1PR1) was found as a new target gene of miR-155 by in vitro and in vivo studies; its expression was decreased in SLE patients and Fas(lpr/lpr) mice. miR-155(-/-)Fas(lpr/lpr) mice are resistant to the development of SLE by the regulation of the target gene S1pr1. miR-155 might be a new target for therapeutic intervention in SLE. PMID- 25911756 TI - Involvement of CD300a Phosphatidylserine Immunoreceptor in Aluminum Salt Adjuvant Induced Th2 Responses. AB - Aluminum salt (alum) has been widely used for vaccinations as an adjuvant. Alum not only enhances immunogenicity but also induces Th2 cell immune responses. However, the mechanisms of how alum enhances Th2 cell immune responses have been controversial. In an experimental allergic airway inflammation model, in which alum in conjunction with OVA Ag was i.p. injected for immunization, we found that apoptotic cells and inflammatory dendritic cells (iDC) expressing CD300a, an inhibitory immunoreceptor for phosphatidylserine (PS), significantly increased in number in the peritoneal cavity after the immunization. In contrast, apoptotic cells and iDCs were scarcely observed in the peritoneal cavity after injection of OVA alone. In CD300a-deficient mice, eosinophil infiltration in bronchoalveolar lavage fluid, serum IgE levels, and airway hyperreactivity were significantly decreased after immunization with alum plus OVA compared with wild-type mice. In vitro, iDCs purified from CD300a-deficient mice after the immunization induced significantly less IL-4 production from OT-II naive CD4(+) T cells after coculture with OVA Ag. CD300a expressed on iDCs bound PS on apoptotic cells in the peritoneal cavity after injection of OVA plus alum. Blocking CD300a interaction with PS by injection of a neutralizing anti-CD300a Ab resulted in inhibition of the development of allergic airway inflammation. These results suggest that CD300a is involved in alum-induced Th2 skewing. PMID- 25911754 TI - CD8+ TCR Bias and Immunodominance in HIV-1 Infection. AB - Immunodominance describes a phenomenon whereby the immune system consistently targets only a fraction of the available Ag pool derived from a given pathogen. In the case of CD8(+) T cells, these constrained epitope-targeting patterns are linked to HLA class I expression and determine disease progression. Despite the biological importance of these predetermined response hierarchies, little is known about the factors that control immunodominance in vivo. In this study, we conducted an extensive analysis of CD8(+) T cell responses restricted by a single HLA class I molecule to evaluate the mechanisms that contribute to epitope targeting frequency and antiviral efficacy in HIV-1 infection. A clear immunodominance hierarchy was observed across 20 epitopes restricted by HLA B*42:01, which is highly prevalent in populations of African origin. Moreover, in line with previous studies, Gag-specific responses and targeting breadth were associated with lower viral load set-points. However, peptide-HLA-B*42:01 binding affinity and stability were not significantly linked with targeting frequencies. Instead, immunodominance correlated with epitope-specific usage of public TCRs, defined as amino acid residue-identical TRB sequences that occur in multiple individuals. Collectively, these results provide important insights into a potential link between shared TCR recruitment, immunodominance, and antiviral efficacy in a major human infection. PMID- 25911755 TI - Dual Inhibition of TNFR1 and IFNAR1 in Imiquimod-Induced Psoriasiform Skin Inflammation in Mice. AB - Psoriasis is a chronic inflammatory skin disease affecting 2-3% of the world population and is mainly characterized by epidermal hyperplasia, scaling, and erythema. A prominent role for TNF in the pathogenesis of psoriasis has been shown, and consequently various types of TNF antagonists such as etanercept and infliximab have been used successfully. Recently, increasing amounts of data suggest that type I IFNs are also crucial mediators of psoriasis. To investigate whether blocking their respective receptors would be useful, TNFR1- and IFNAR1 deficient mice were challenged with Aldara, which contains imiquimod, and is used as an experimental model to induce psoriasis-like skin lesions in mice. Both transgenic mice showed partial protection toward Aldara-induced inflammation compared with control groups. Additionally, TNFR1 knockout mice showed sustained type I IFN production in response to Aldara. Double knockout mice lacking both receptors showed superior protection to Aldara in comparison with the single knockout mice and displayed reduced levels of IL-12p40, IL-17F, and S100A8, indicating that the TNF and type I IFN pathways contribute significantly to inflammation upon treatment with Aldara. Our findings reveal that dual inhibition of TNFR1 and IFNAR1 may represent a potential novel strategic treatment of psoriasis. PMID- 25911757 TI - Proinflammatory Proteins S100A8/S100A9 Activate NK Cells via Interaction with RAGE. AB - S100A8/A9, a proinflammatory protein, is upregulated in inflammatory diseases, and also has a tumor-promoting activity by the recruitment of myeloid cells and tumor cell invasion. However, whether the expression of S100A8/A9 in tumors predicts a good or poor prognosis is controversial in the clinical setting. In this study, to clarify the in vivo role of S100A8/A9 in the tumor microenvironment, we s.c. inoculated Pan02 cells stably expressing S100A8 and S100A9 proteins (Pan02-S100A8/A9) in syngeneic C57BL/6 mice. Unexpectedly, after small tumor nodules were once established, they rapidly disappeared. Flow cytometry showed that the number of NK cells in the tumors was increased, and an administration of anti-asialoGM1 Ab for NK cell depletion promoted the growth of Pan02-S100A8/A9 s.c. tumors. Although the S100A8/A9 proteins alone did not change the IFN-gamma expression of NK cells in vitro, a coculture with Pan02 cells, which express Rae-1, induced IFN-gamma production, and Pan02-S100A8/A9 cells further increased the number of IFN-gamma(+) NK cells, suggesting that S100A8/A9 enhanced the NK group 2D ligand-mediated intracellular activation pathway in NK cells. We then examined whether NK cell activation by S100A8/A9 was via their binding to receptor of advanced glycation end product (RAGE) by using the inhibitors. RAGE antagonistic peptide and anti-RAGE Ab inhibited the IFN-gamma production of NK cells induced by S100A8/A9 proteins, and an administration of FPS-ZM1, a RAGE inhibitor, significantly enhanced the in vivo growth of Pan02 S100A8/A9 tumors. We thus found a novel activation mechanism of NK cells via S100A8/A9-RAGE signaling, which may open a novel perspective on the in vivo interaction between inflammation and innate immunity. PMID- 25911758 TI - The lung is protected from spontaneous inflammation by autophagy in myeloid cells. AB - The lung is constantly exposed to the outer environment; thus, it must maintain a state of immune ignorance or tolerance not to overrespond to harmless environmental stimuli. How cells in the lung control immune responses under nonpathogenic condition is not fully understood. In this study, we found that autophagy plays a critical role in the lung-specific immune regulation that prevents spontaneous inflammation. Autophagy in pulmonary myeloid cells plays a role in maintaining low burdens of environmental microbes in the lung, as well as in lowering mitochondrial reactive oxygen species production and preventing overresponse to TLR4 ligands in alveolar macrophages. Based on these mechanisms, we also found that intranasal instillation of antibiotics or an inhibitor of reactive oxygen species was efficient in preventing spontaneous pulmonary inflammation. Thus, autophagy in myeloid cells, particularly alveolar macrophages, is critical for inhibiting spontaneous pulmonary inflammation, and pulmonary inflammation caused by dysfunctional autophagy is pharmacologically prevented. PMID- 25911760 TI - Structural Basis for the Function of Complement Component C4 within the Classical and Lectin Pathways of Complement. AB - Complement component C4 is a central protein in the classical and lectin pathways within the complement system. During activation of complement, its major fragment C4b becomes covalently attached to the surface of pathogens and altered self tissue, where it acts as an opsonin marking the surface for removal. Moreover, C4b provides a platform for assembly of the proteolytically active convertases that mediate downstream complement activation by cleavage of C3 and C5. In this article, we present the crystal and solution structures of the 195-kDa C4b. Our results provide the molecular details of the rearrangement accompanying C4 cleavage and suggest intramolecular flexibility of C4b. The conformations of C4b and its paralogue C3b are shown to be remarkably conserved, suggesting that the convertases from the classical and alternative pathways are likely to share their overall architecture and mode of substrate recognition. We propose an overall molecular model for the classical pathway C5 convertase in complex with C5, suggesting that C3b increases the affinity for the substrate by inducing conformational changes in C4b rather than a direct interaction with C5. C4b specific features revealed by our structural studies are probably involved in the assembly of the classical pathway C3/C5 convertases and C4b binding to regulators. PMID- 25911759 TI - Early effector cells survive the contraction phase in malaria infection and generate both central and effector memory T cells. AB - CD4 T cells orchestrate immunity against blood-stage malaria. However, a major challenge in designing vaccines to the disease is poor understanding of the requirements for the generation of protective memory T cells (Tmem) from responding effector T cells (Teff) in chronic parasite infection. In this study, we use a transgenic mouse model with T cells specific for the merozoite surface protein (MSP)-1 of Plasmodium chabaudi to show that activated T cells generate three distinct Teff subsets with progressive activation phenotypes. The earliest observed Teff subsets (CD127(-)CD62L(hi)CD27(+)) are less divided than CD62L(lo) Teff and express memory genes. Intermediate (CD62L(lo)CD27(+)) effector subsets include the most multicytokine-producing T cells, whereas fully activated (CD62L(lo)CD27(-)) late effector cells have a terminal Teff phenotype (PD-1(+), Fas(hi), AnnexinV(+)). We show that although IL-2 promotes expansion, it actually slows terminal effector differentiation. Using adoptive transfer, we show that only early Teff survive the contraction phase and generate the terminal late Teff subsets, whereas in uninfected recipients, they become both central and effector Tmem. Furthermore, we show that progression toward full Teff activation is promoted by increased duration of infection, which in the long-term promotes Tem differentiation. Therefore, we have defined markers of progressive activation of CD4 Teff at the peak of malaria infection, including a subset that survives the contraction phase to make Tmem, and show that Ag and cytokine levels during CD4 T cell expansion influence the proportion of activated cells that can survive contraction and generate memory in malaria infection. PMID- 25911761 TI - Pulmonary alveolar macrophages contribute to the premetastatic niche by suppressing antitumor T cell responses in the lungs. AB - In contrast to tumor-associated macrophages, myeloid-derived suppressor cells, or inflammatory monocytes, functions of tissue resident macrophages, including alveolar macrophages (AM), in cancer were not well studied. Using a mouse model of breast cancer, we show that AM promote cancer metastasis to the lungs by suppressing antitumor T cells in this organ. AM accumulated in the premetastatic lungs through complement C5a receptor-mediated proliferation but not through recruitment from the circulation. AM preconditioned by breast tumors inhibited Th1 and favored generation of Th2 cells that had lower tumoricidal activity than Th1 cells. In addition, AM reduced the number and maturation of lung dendritic cells by regulating TGF-beta in the lung environment. Depletion of AM reversed immunosuppression imposed by these cells and strengthened local Th1 responses, which significantly reduced lung metastatic burden. C5a receptor deficiency, which also lessens myeloid-derived suppressor cells in the premetastatic niche, synergized with the depletion of AM in preventing metastasis, leading to protection of mice from lung metastases. This study identifies AM as a new component of the premetastatic niche, which is harnessed by tumors to impose immunosuppression, and as a new target for cancer immunotherapies to eliminate or reduce metastasis. Because the lungs are the most common target for hematogenous metastasis, this research offers a plausible explanation for susceptibility of the lungs to cancer metastasis. PMID- 25911762 TI - [Orthogonal design method to optimize rehabilitation prescription of pulsed electric field at Jiaji (EX-B 2) points for spinal cord injury]. AB - OBJECTIVE: By using orthogonal design method to optimnize prescription of pulsed electric field at Jiaji (EX- B 2) points for spinal cord injury (SCI). METHODS: Fifty six patients of SCI were selected, in which 36 cases were divided into orthogonal design trial and 20 cases were into clinical verification. With 36 patients who received orthogonal design trial, Frankel grading scale was used as observation index to screen optimal prescription of pulsed electric field. Pulse frequency (factor A) included low frequency (factor A(I), 10(2) Hz). moderate frequency (factor A(II), 10(4) Hz) and high frequency (factor A(III), 10(3) Hz); pulse amplitude (factor B) included 0-30 V (factor B ), 0-60 V (factor B(II)) and 0-90 V (factor B(III)); pulse width (factor C) included 0.1 ms (factor C(I)). 0.6 ms (factor C(II)) and 0.9 ms (factor C(III)); acupuncture time (factor D) included one month (DI), three months (D(II)) and five months (D(III)). Twenty patients were used for clinical efficacy observation and the effects of screened optimal pre scription of pulsed electric field at Jiaji (EX-B 2) points combined with regular rehabilitation training on spasm se- verity, score of sensory and motor functions, Barthel index and Frankel score were observed. RESULTS: (1) As results of orthogonal design trial, the optimal prescription was A(III) B(III), C(I), D(III), which were high frequency (10(3) Hz), 0-90 V of pulse amplitude, 0.4 ms of pulse width and 5 months of treatment time. (2) As results of 20 patient clinical verification, Ashworth score, tendon reflex and clonus were all significantly improved (P<0.001, P<0.01), the scores of sensory and motor functions were evidently improvedtl (P<0.001, P<0.05), and Barthel in dex and Frankel score were also enhanced (P<0.001, P<0.05). CONCLUSION: The optimal prescription of pulsed electric field at Jiaji (EX-B 2) points for spinal cord injury is high frequency (10& Hz), 0-90 V of pulse amplitude, 0.4 ms of pulse width and 5 months of treatment time. The optimal prescription of pulsed electric field at Jiaji (EX-B 2) points combined with regular rehabilitation could obviously improve spasm severity, enhance senso- ry and motor functions, and ameliorate activity of daily life and Frankel score. PMID- 25911763 TI - Polio surveillance: tracking progress towards eradication worldwide, 2013-2014. PMID- 25911764 TI - Performance of acute flaccid paralysis (AFP) surveillance and incidence of poliomyelitis, 2015. PMID- 25911765 TI - Preface: Innate immune sensors in joint diseases. PMID- 25911766 TI - Challenging the exclusion of gambling disorder as a disability under the Americans with Disabilities Act. AB - The Americans with Disabilities Act explicitly excludes "compulsive gambling" from its definition of disability, thus denying gambling addicts protection from employer discrimination based on their disorder. Since the enactment of the ADA, however, scientific understandings of gambling disorder have evolved to view the condition as an addiction, rather than as a compulsion or impulse-control disorder. This move is mirrored in the DSM-5's reclassification of gambling disorder under the category of "substance-related and other addictive disorders." This Note contends that gambling disorder would qualify as a "disability" under the ADA, were it not for the disorder's current statutory exclusion. This Note therefore recommends that the ADA be amended to bring gambling disorder within its coverage. Such a change would not only reflect recent developments in the field of addiction psychology, but would also further the ADA's underlying purpose--to protect individuals with disabilities from workplace discrimination. PMID- 25911767 TI - The impact of the early introduction of palliative care on patient's functioning. AB - (1) After controlling for other factors that could explain patient functioning, the researchers found that each additional palliative care visit during the first month of follow-up increases patient functioning. (2) Patient functioning, as measured at the initial visit, is a far stronger predictor of subsequent functioning than are additional palliative care visits. (3) While palliative care may increase patient functioning, initial patient functioning likely limits what may be achieved in an absolute sense. PMID- 25911768 TI - The time is now: tackling racial and ethnic disparities in mental and behavioral health services in Massachusetts. AB - Massachusetts is in the midst of a demographic shift that will leave the state with unprecedented ethnic, racial and cultural diversity. In light of this change, health care services in the Commonwealth need to respond to and serve an increasingly multicultural population. The time is now for bold initiatives to reduce behavioral health and health service disparities by building collaborations between policymakers, insurers/payers, provider organizations, training institutions, and community groups. In the same way collaboration among diverse stakeholders enabled the Commonwealth to lead the nation in achieving near universal access to health insurance, a new collaboration can pave the way for the elimination of behavioral health and health care disparities. This brief compiles current information on racial and ethnic disparities in mental health and substance use disorders and treatment disparities in Massachusetts. It concludes with state level policy recommendations. The Brief does not recommend policies already in motion, such as moving to universal insurance coverage, enforcement of parity laws, policies to expand coverage of drug treatment services or greater inclusion of consumers in the development and configuration of behavioral health services. Recommendations offered are based on best practices and evidence-based research. Most research, however, studies incremental changes. To transform rather than reform the system, we integrate consideration of experience and research from other policy areas. The ultimate goal is to generate an action plan that motivates policymakers to address persistent racial and ethnic disparities in the availability and quality of behavioral health services in the Commonwealth. PMID- 25911769 TI - A private right of action for informed consent in research. PMID- 25911770 TI - In this issue: developing and amplifying the effectiveness of the primary care workforce. PMID- 25911771 TI - Are you prepared for the job of your dreams? PMID- 25911772 TI - Exceptional frontline nurses practice at the bedside and beyond. PMID- 25911773 TI - How has the nurse navigator role changed care for patients with cancer? PMID- 25911774 TI - Advanced practice nurses evolve healthcare solutions. PMID- 25911775 TI - How have you combined a clinical and research nursing role? PMID- 25911776 TI - Online programs offer busy nurses additional educational options. PMID- 25911777 TI - What should nurses consider when seeking a BSN or MSN education online? PMID- 25911778 TI - The case of the suicidal statements. PMID- 25911779 TI - Choose an online oncology nursing degree program that's right for you. PMID- 25911780 TI - 10 things every patient with cancer should know about chemotherapy. PMID- 25911781 TI - Should hospitals mandate nurses having a BSN? PMID- 25911782 TI - What do the new cancer center QOPI and certification mean for oncology nurses? PMID- 25911783 TI - Consensus model delineates and guides APRN practice. PMID- 25911784 TI - What are the differences in education and practice of APRN roles? PMID- 25911785 TI - Colonic biofilms are associated with right-sided colorectal cancer. PMID- 25911786 TI - [Construction of biopharmaceutics classification system of Chinese materia medica]. AB - Based on the characteristics of multicomponent of traditional Chinese medicine and drawing lessons from the concepts, methods and techniques of biopharmaceutics classification system (BCS) in chemical field, this study comes up with the science framework of biopharmaceutics classification system of Chinese materia medica (CMMBCS). Using the different comparison method of multicomponent level and the CMMBCS method of overall traditional Chinese medicine, the study constructs the method process while setting forth academic thoughts and analyzing theory. The basic role of this system is clear to reveal the interaction and the related absorption mechanism of multicomponent in traditional Chinese medicine. It also provides new ideas and methods for improving the quality of Chinese materia medica and the development of new drug research. PMID- 25911787 TI - [Design and analyze mathematical algorithms of intestinal absorption and metabolism of multicomponent drug]. AB - Evaluation of the permeability mainly focuses on intestinal absorption in biopharmaceutics classification system (BCS). It is more complicated that the absorption and metabolism under multicomponent environment in biopharmaceutics classification system of Chinese materia medica (CMMBCS) compared with single component environment, which needs suitable mathematical models to be described. Therefore, with full consideration of existing single component mathematical algorithm combining with the characteristics of intestinal absorption and metabolism, we explored and designed a new mathematical algorithm of intestinal absorption and metabolism of multicomponent drug. Then we put forward a new coefficient, P (influence), the relative change rate of the single component's intestinal absorption and metabolism under multicomponent environment compared with single component environment, which described the influences of intestinal absorption and metabolism of the component under multicomponent environment. Moreover, P (influence) highlights the distinctive characteristics of multicomponent drug's intestinal absorption and metabolism, and lays the foundation for the construction of CMMBCS. PMID- 25911788 TI - [Study of attribution of multicomponent original medicinal materials in gegen qinlian decoction with intestinal permeability]. AB - The complex level of constructing biopharmaceutics classification system of Chinese materia medica CMMBCS) was the study of traditional Chinese compound, on the premise of insisting that the multicomponent simultaneous determination, when carrying out the study of intestinal permeability, the primary task was to define the source of the components that was absorbed through the intestinal wall, namely, which medicinal material the components belonged to in traditional Chinese compound. The technology of chemical fingerprint and in vitro everted gut sac model were used in this research to make multicomponent an intuitive source attribution which permeated the intestine in the classic formula Gegen Qinlian decoction, and to lay the foundation for the further qualitative and quantitative research of intestinal permeability. PMID- 25911789 TI - [Application of multicomponent dissolution evaluation method of biopharmaceutics classification system of Chinese materia medica in gegen qinlian tablets]. AB - The study is a paticular embodiment of Chinese patent medicine based on biopharmaceutics classification system of Chinese materia medica (CMMBCS) , focusing on assessment of synchronization issues of dissolution that may affect the timing of the multicomponent absorption. The accumulative dissolution percentages of nine components in Gengen Qinlian tablets in different dissolution solvents and times were determined by HPLC. The dissolution curve was drew and its similarity was evaluated by similarity factors (f2) and cluster method. Results in this experiment showed that the components that peak 7 and peak 8 (baicalin) represented had poor similarity with the reference peak 2 (puerarin). Their similarity factors were both 43 in water dissolution media and 31 and 45 in pH 7.4 dissolution media, respectively. Components that peaks represented had better similarity with the reference peak 2 (puerarin) in other medium. It illustrated that components that peak 3,4,5,6 (berberine) represented had fully synchronous dissolution characteristics with the reference peak 2 (puerarin), components peak 1 and 9 represented had nearly fully synchronous dissolution characteristics with the reference peak 2 (puerarin), while components that peak 7 and 8 (baicalin) represented had no synchronous dissolution characteristics with the reference peak 2 (puerarin). PMID- 25911790 TI - [Impacts of multicomponent environment on solubility of puerarin in biopharmaceutics classification system of Chinese materia medica]. AB - To illustrate the solubility involved in biopharmaceutics classification system of Chinese materia medica (CMMBCS) , the influences of artificial multicomponent environment on solubility were investigated in this study. Mathematical model was built to describe the variation trend of their influence on the solubility of puerarin. Carried out with progressive levels, single component environment: baicalin, berberine and glycyrrhizic acid; double-component environment: baicalin and glycyrrhizic acid, baicalin and berberine and glycyrrhizic acid and berberine; and treble-component environment: baicalin, berberin, glycyrrhizic acid were used to describe the variation tendency of their influences on the solubility of puerarin, respectively. And then, the mathematical regression equation model was established to characterize the solubility of puerarin under multicomponent environment. PMID- 25911791 TI - [Effect of multicomponent environment on intestinal permeability of puerarin in biopharmaceutics classification system of Chinese materia medica]. AB - The evaluation of permeability in biopharmaceutics classification system of Chinese materia medica (CMMBCS) requires multicomponent as a whole in order to conduct research, even in the study of a specific component, should also be put in the multicomponent environment. Based on this principle, the high content components in Gegen Qinlian decoction were used as multicomponent environmental impact factors in the experiment, and the relevant parameters of intestinal permeability about puerarin were measured with using in situ single-pass intestinal perfusion model, to investigate and evaluate the intestinal permeability of puerarin with other high content components. The experimental results showed that different proportions of baicalin, glycyrrhizic acid and berberine had certain influence on intestinal permeability of puerarin, and glycyrrhizic acid could significantly inhibit the intestinal absorption of puerarin, moreover, high concentration of berberine could promote the absorption of puerarin. The research results indicated that the important research ideas of permeability evaluation in biopharmaceutics classification system of Chinese materia medica with fully considering the effects of other ingredients in multicomponent environment. PMID- 25911792 TI - [Ginkgo preparations of Chinese medicine and treatment of diabetes: mechanisms and clinical applications]. AB - Ginkgo is one of the most successful cases of botanical drugs developed by modern science and technology during the past fifty years all over the world. At present ginkgo has been applied to the prevention and treatment of cardiovascular disease widely, and has good clinical efficacy. Type 2 diabetes has been proved to be the risk equivalents of cardiovascular disease, therefore it has an important scientific significance for looking for more effective drugs of prevention and control of diabetes. To seek more efficient and safe drug from the plant medicine which has the function of regulate blood sugar and improve insulin resistance becomes a hotspot at home and abroad. Basic and clinical studies have shown the ginkgo preparations of Chinese medicine have certain regulation effect on blood sugar and insulin resistance. In this paper, we review the mechanisms and clinical applications of ginkgo preparations on diabetes and its applications during the past 10 years. PMID- 25911793 TI - [Advance in studies of Panax notoginseng saponins on pharmacological mechanism of nervous system disease]. AB - The pharmacological mechaisms of Panax notoginseng saponins on nervous system diseases (Alzheimer's disease, Parkinson's disease, ischermic cerebral apoplexy and depressive disorder) , including panax notoginseng saponins, protoparaxotriol saponins, panasadiol saponins, ginsenoside Rg1, ginsenoside Rb1, ginsenoside Re and notoginsenoside R1 were summarized to analyze the study hotspots and potential advantages (such as estrogen-like effect) of notoginsenoside's pharmacological actions, provide reference for further pharmacological studies and new ideas for clinical treatment of nervous system diseases and drug studies and development. PMID- 25911794 TI - [Research progress on musk secretion mechanism of forest musk deer]. AB - Forest musk deer (Moschus berezovskii), a rare wild medicinal animal, is listed under the category of the state key protected wildlife list of China. Musk, secreted by the musk glands, is with high economic and medicinal value and used as precious traditional medicine in China. In order to meet the needs of musk in Chinese traditional medicine, forest musk deer farming was conducted in 1950s, but the research progress on musk secretion mechanism was slow. Therefore, by reviewing the histological and anatomical structure of forest musk deer musk gland, the relationship between sex hormones and the musk secretion process, and the molecular mechanism of the musk secretion, the existing problems in investigating the musk secretion mechanism were analyzed and the development trends in this field were also discussed, in order to provide a reference for further studies on the musk secretion mechanism and improve musk production of forest musk deer. PMID- 25911795 TI - [Research progress of phytoestrogens-like chemical constituents in natural medicines]. AB - Phytoestrogens, which can bind with estrogen receptor and produce estrogen-like effects, are a kind of nonsteroidal compound in plant. Phytoestrogens chemically include isoflavones, coumarins, lignans and other compounds. Phytoestrogens are selective estrogen receptor modulator, and have therapeutical effects on breast cancer, prostate cancer, cardiovascular disease, menopausal symptoms, osteoporosis and other disease, however, do not produce stimulatory hyperplasia effects on uterus, mammary glands and other tissues and organs with positive estrogen receptor. Long-term exposure or excessive use of phytoestrogens maybe affects male reproductive system and hematopoietic function of fetus. Some questions need to be further studied, such as evaluation criteria on biological activity, adverse effects, and action mechanism of phytoestrogen. This review covers plant sources, chemical structure, pharmacological activity and safety of phytoestrogens. It will provide a useful reference for intensive research and rational utilization the phytoestrogens. PMID- 25911796 TI - [Pharmaceutical research progress of rhynchophylla based on chemical stability]. AB - Rhynchophylla is a Chinese herb commonly used in clinical practice. It's also the primary herb of some famous Chinese herbal compound such as Tianma Gouteng decoction, and Lingyang Gouteng decoction. According the record from many previous materia medica literatures, rhynchophylla should be added later during decoction. Pharmaceutical research showed that rhynchophylla alkaloids were not stable. Which has resulted in many problems in the research and its application. For example, there was not a quantitative determination method in "Chinese Pharmacopoeia" of past and present versions, which seriously impacted its quality control and product application. Firstly, records from previous materia medica literatures and "Chinese Pharmacopoeia" were systematically sorted based on the chemical stability of rhynchophylla. Secondly, pharmaceutical research including chemical compositions and their stability, pharmacological effects, extraction process and quality analysis, was reviewed after reference of literatures published at home and abroad in recent decades. Positive reference and evidence for further research and development of rhynchophylla will be provided in the article. PMID- 25911797 TI - [Overexpression and RNAi vectors built for key secondary metabolic pathway genes PAL, HMGR, PGT of Arnebia euchroma]. AB - Arnebia euchroma is the main source for medicinal herb Zicao. and its most important component shikonin compounds have high medicinal and industrial value. This research is aimed to build overexpression vectors and RNAi vectors for key secondary metabolism genes of A. euchroma, and bulid platform for constructions of related transgenic lines using GATEWAY technology. To build genetic material based genetic research platform is to provide a great convenience for digging and functional verification of the genes on secondary metabolic pathway, and also to fill the gaps in transgenic research of A. euchroma. This study is also important for the cultivation of shikonin high-yielding strains of A. euchroma. PMID- 25911798 TI - [Identification of chemical signals and haustorium induced of Thesium chinense]. AB - To separate and identify chemical signals which induce Thesium chinense haustorium formation, the components of T. chinense roots secretion collected with XAD-4 resin were detected by GC-MS. The effect of DMBQ as exogenous signals to induce haustorium formation in T. chinense was studied. Fifty-three compounds of 9 types had been detected, including hydrocarbons, esters, organic acids, ketones, alcohols, nitrogen containing compounds, phenolic acids, aldehyde and quinine. It is worth noting that the 2, 5-di-tert-butyl-1,4-benzoquinone has the core structure of 1,4-benzoquinone, which may play an important role in the parasitic relationship of Prunella vulgaris and T. chinense: DMBQ worked effectively on inducing haustoria, but induction effects vary widely in different concentrations. DMBQ with the concentration of 1 MUmol x L(-1) showed the best effect of the inducing ability with a ratio of 110.52 when treated to induce haustoria. PMID- 25911799 TI - [Investigation of ethnic medicinal plants Orobanche, Cistanche and Boschniakia]. AB - In this paper the species of ethnic medicinal plants Orobanche, Cistanche and Boschniakia, and their ethnopharmaceutical uses were comprehensively summarized by field investigation, systematical data analysis and comparison of relevant specimen and references. The results showed that six plants belonging to Orobanche were used as seven kinds of ethnic medicinal plants, two plants attributing Boschniakia were used as ten kinds of ethnic medicinal plants, two plants of Cistanche were used as three ethnic medicinal plants. The same plant was often used as different ethnic medicine in varied ethnic minorities. The effects of the ethnic medicines included yang-tonifying, hemostasis and analgesic activities. Hence, it is necessary to develop the rich plant resource of Orobanche for alleviation of Cistanche resources shortage. PMID- 25911800 TI - [Study on relieving effects of exogenous SNP, Spd on Belamcanda chinensis under salt-alkalline stress]. AB - The study is aimed to provide the theoretical basis for exploiting and utilization of salt-alkaline soil and cultivating Belamcanda chinensis. In this study, we exerted exogenous substances SNP, Spd to relieve the damage of the mixing salt-alkaline stress on B. chinensis seedling which is NaCl, Na2SO4, NaHCO3 and Na2CO3 four kinds of salt molar ratio of 9: 1: 9: 1, salt concentration of 100 mmol x L(-1). The result illustrated that high pH stress is a major factor caused the salt-alkaline stress, the interaction between time and the concentration of each, treatment was observed, what is more, there are synergies between the salt and alkali stress. The content of B. chinensis seedling leaves' membrane peroxidation index (MDA, O2-*) and metabolites (soluble protein, soluble sugars, organic acids) are showing an upward trend in varying degrees under 100 mmol x L(-1) salt-alkaline stress. It is effective to reduce the content of MDA and O2-*. and improve the levels of metabolites, in which the SNP (0.05 mmol x L(-1)) and Spd (0.5 mmol x L(-1)) to alleviate damage effects is the best. Therefore we can hold the conclusion that SNP and Spd can effectively mitigate the damage of B. chinensis seedling on salt-alkaline stress, improve the resistance ability of B. chinensis seedling which can provide the scientific basis for the utilization of salt-alkaline soil, and the cultivation of B. chinensis. PMID- 25911801 TI - [Genetic diversity analysis of Andrographis paniculata in China based on SRAP and SNP]. AB - In order to reveal genetic diversity of domestic Andrographis paniculata and its impact on quality, genetic backgrounds of 103 samples from 7 provinces in China were analyzed using SRAP marker and SNP marker. Genetic structures of the A. paniculata populations were estimated with Powermarker V 3.25 and Mega 6.0 software, and polymorphic SNPs were identified with CodonCode Aligner software. The results showed that the genetic distances of domestic A. paniculata germplasm ranged from 0. 01 to 0.09, and no polymorphic SNPs were discovered in coding sequence fragments of ent-copalyl diphosphate synthase. A. paniculata germplasm from various regions in China had poor genetic diversity. This phenomenon was closely related to strict self-fertilization and earlier introduction from the same origin. Therefore, genetic background had little impact on variable qualities of A. paniculata in domestic market. Mutation breeding, polyploid breeding and molecular breeding were proposed as promising strategies in germplasm innovation. PMID- 25911802 TI - [Research on topographic factors of ecology suitability regionalization of Atractylodis macrocephala]. AB - Through study on the correlation between Atractylodis macrocephala lactones ingredient content and topographic factors, we researched regionalization from topography of five main producing provinces of the country, in order to provide a scientific basis for A. macrocephala reasonable cultivation. By sampling from 40 origins of five main producing provinces of the country, the variation of A. macrocephala lactones ingredient content in different conditions of topographic factors and the effect of altitude, slope and aspect was analyzed by SPSS. Then according to the relationship between A. macrocephala lactones ingredient content and topographic factors, the ecological suitability regionalization was conducted by using ArcGIS based on topographic factors. It is suitable for growth of A. macrocephala in the hilly and mountainous areas of southern whose A. macrocephala lactones ingredient content is in high levels. It is unsuitable for growth of A. macrocephala in Northern plain areas, but we can cultivate A. macrocephala in the hilly and mountainous areas of Northern. The most suitable topographic condition for cultivation of A. macrocephala : altitude 200 meters above, slope 3.00-4.99 degrees. PMID- 25911803 TI - [Genetic relationship and parent selection of some Sarcandra glabra resources based on ISSR]. AB - The study is aimed to assess the genetic diversity and genetic relationship of 18 Sarcandra glabra resources from different populations,and guide parent selection of cross breeding between these resources. The molecular marker technique ISSR was used to investigate the genetic diversity of the 18 resources. Data was analyzed by POPGEN 32, and a cluster diagram was presented by UPGMA. One hundred and ninety-eight amplified fragments were obtained using 23 ISSR primers. One hundred and eighty-four polymorphic loci were identified. Nei's genetic diversity index (h) was 0.32, Shannon diversity index (I) was 0.485 4. The genetic similarity coefficient among the resources ranged from 0.383 8 to 0.878 8 in an average of 0.661 2. The genetic distance between sample S2 and sample S18 was the farthest, so as between sample S3 and sample S18 both Nei's genetic distance was 0.957 5, The genetic distance between sample S4 and sample S5 was the closest, the Nei's genetic distance was 0.129 2,and the sample S1, S2, S3, S7, S10 were significantly different from the others based on the clustering analysis, the three groups S2 vs S3, S2 vs S6, S2 vs S18 were the best parent group selection. There was a middle level of genetic differentiation in the resources. The genetic distance between resources gives useful information to guide parent selection of cross breeding. PMID- 25911804 TI - [Dendrobium officinale stereoscopic cultivation method]. AB - The study is aimed to make the most of available space of Dendrobium officinale cultivation facility, reveal the yield and functional components variation of stereoscopic cultivated D. officinale, and improve quality, yield and efficiency. The agronomic traits and yield variation of stereoscopic cultivated D. officinale were studied by operating field experiment. The content of polysaccharide and extractum were determined by using phenol-sulfuric acid method and 2010 edition of "Chinese Pharmacopoeia" Appendix X A. The results showed that the land utilization of stereoscopic cultivated D. officinale increased 2.74 times, the stems, leaves and their total fresh or dry weight in unit area of stereoscopic cultivated D. officinale were all heavier than those of the ground cultivated ones. There was no significant difference in polysaccharide content between stereoscopic cultivation and ground cultivation. But the extractum content and total content of polysaccharide and extractum were significantly higher than those of the ground cultivated ones. In additional, the polysaccharide content and total content of polysaccharide and extractum from the top two levels of stereoscopic culture matrix were significantly higher than that of the ones from the other levels and ground cultivation. Steroscopic cultivation can effectively improves the utilization of space and yield, while the total content of polysaccharides and extractum were significantly higher than that of the ground cultivated ones. The significant difference in Dendrobium polysaccharides among the plants from different height of stereo- scopic culture matrix may be associated with light factor. PMID- 25911805 TI - [Study on morphology and anatomy of Akebia trifoliate seeds]. AB - Akebia trifoliate has been reported to have many pharmacological activities and the roots, petioles and seeds are used to different symptoms. However, the structure and anatomy of its seeds was almost not reported until now. In the present study, we investigated the morphological characters of the fruit and seed, and the anatomical characters of the testa, micropyle, embryo and endosperm, which could provide evidences for the study on classification, identification and application of A. trifoliate. Our results showed that the testa of A. trifoliate consisted of an epidermic cell layer, the sclerenchyma cells layer, the parenchyma cells layer and an innermost pigment layer. At the micropylar region, the outermost epidermal cells were specialized the white caruncle-like structure and the testa included a lot of lignified tissues. Endosperm comprises two layer cells. Outermost yellowish-brown layer cells contains lots of fat droplets, and innermost white layer cells contains lots of aleurone grains and crystalloids. PMID- 25911806 TI - [In vitro and in vivo study of fluorescent probe PLGA particles prepared by premix membrane emulsification method]. AB - Relatively uniform-sized nanoparticles made of poly (lactic-co-glycolic acid) (PLGA) were prepared by premix membrane emulsification method. After the drug loading property was completed, the dynamic tissue distribution of nanoparticles was recorded. With the average particle size and span as indexes, membrane pore size, number of passing membrane times, membrane pressure, volume ratio of oil water phase and the concentration of poly(vinyl alcohol) (PVA) in external water phase were investigated by single factor test, the optimum preparation technology of blank PLGA nanlparticles was as following: pore size of SPG membrane was 1 MUm, membrane pressure was 1. 15 MPa, the number of passing membrane time was 3, the mass fraction of PVA of 2%, volume ratio of oil-water phase of 1 : 5. Prepared nanoparticles were round with smooth surface, the mean diameter was 332.6 nm, span was 0.010, the confocal laser scanning microscope (CLSM) concluded that fluorescent substance is uniform composizion in PLGA nanoparticle, and the in vivo imaging technology in mice include that the nanoparticles show good liver and spleen targeting property. PMID- 25911807 TI - [Research about improving flowability of powder of Chinese herbs extracts by surface modification technology]. AB - In this study, modification technology by surface coating was used to improve the flowability of powder of Chinese herbs extracts. Seven kinds of powder of Chinese herbs extracts were coated with 1% silica nanoparticles using an under-driven Comil. The powder characteristics tester was used to evaluate the flowability of uncoated and coated powders. Surface morphology and particle size distribution of powders were compared by scanning electron microscope (SEM) and optical microscope. The powder hygroscopicity was also investigated. The results showed that, after modification, angle of repose, angle of spatula, compressibility and adhesiveness extremely decreased, and flowability index substantially increased, the powder flowability was significantly improved, especially Gegen and Dahuang extracts powders. Scanning electron microscopy images showed the distribution of silica nanoparticles on the host drug particle surfaces. There were no remarkable changes in the particle size distribution and hygroscopicity of all powders after coating. Therefore, Comilling for surface coating modification technology was an effective method to improve the flowability of Chinese herbs extracts and suggested a possible way forward to enhance the quality of Chinese drugs pharmaceutics in their study and manufacture. PMID- 25911808 TI - [Preparation, in vitro and in vivo evaluation of cataplasm of white mustard seed varnish to prevent asthma]. AB - The aim of the manuscript was to optimize formulations and preparation technologies of cataplasm of white mustard seed varnish, and to evaluate its anti asthma effect on rats. The single factor experiments included spreading thickness, types of crosslinking agents, dihydroxyaluminum aminoacetate amount, sodium polyacrylate amount, types of adhesive agents with human sense as the evaluation index. Blank cataplasm matrix was optimized by the orthogonal experiment with the amount of glycerine, citric acid, and sodium carboxymethylcellulose as the major influential factors. Initial adhesive force, peeling strength and human sense were as the evaluation index. The optimized formulation of blank cataplasm were as followings: glycerine-water-ethanol-PEG400 dihydroxyaluminum aminoacetate-citric acid-sodium carboxymethylcellulose-sodium carboxymethylcellulose 2 : 8 : 0.8 : 0.4 : 0.07: 0.15 : 0.1 : 0.5. The active ingredients of white mustard seed, corydalis, and gansui root were extracted by alcohol extraction method. Asiasarum volatile oil was extracted by oil extractor. The optimized drug loading amount was 11% with initial adhesive force, peeling strength and human sense as the evaluation index. Asthma rats model were established by sensitized with ovalbumin and nose-scratching time as the evaluation index. High dose (17%) group of drug-loaded cataplasm had the obvious inhibition effect on nose-scratching time of rats (P = 0.037 < 0.05). In comparison, middle dose (11%), low dose (4%) and positive-control groups had no obvious inhibitive effect on rats. White mustard seed cataplasm supplied a novel choice for anti-asthma therapy. And the overall pharmacodynamics assessment will be carried out on molecular level in near future. PMID- 25911809 TI - [Rapid identification of crude and sweated dipsaci radix based on near-infrared spectroscopy combined with principal component analysis-mahalanobis distance]. AB - In order to discriminate the crude and sweated Dipsaci Radix correctly and rapidly, the crude and sweated Dipsaci Radix were scanned by the NIR spectrometer, and an identifying model was developed by near infrared spectroscopy combined with principal component-Mahalanobis distance pattern recognition method. The pretreated spectra data of 129 crude samples and 86 sweated ones were analyzed through principal component analysis (PCA). The identifying model was developed by choosing the spectrum for 9 881.46-4 119.20 cm(-1) and "SNV + spectrum + S-G" to the original spectral preprocessing with 14 principal components, and then was verified by prediction set, identifying with 100% accuracy. The rapid identification model of the crude and sweated Dipsaci Radix by NIR is feasible and efficient, and could be used as an assistant means for identifying the crude and sweated Dipsaci Radix. PMID- 25911810 TI - [Near infrared spectroscopy on-line and real-time monitoring of alcohol precipitation process of reduning injection]. AB - Near infrared (NIR) spectroscopy as a kind of rapid process analysis technology has been successfully applied in Chinese medicine pharmaceutical process. In this research, the technology was adopted to establish the rapid quantitative analysis models of main indicators from the Lonicera japonica and Artemisia annua alcohol precipitation process of Reduning injection. On-line NIR spectra of 142 samples from alcohol precipitation process were collected and the content of main indicators for each sample were detected through off-line HPLC. With eliminating outliers, determination of spectra pretreatment method and selecting optimal band, the NIR quantitative calibration model for each indicator was established using partial least squares (PLS). These models were used to predict the unknown samples from precipitation process of Reduning injection to achieve the goal of rapid detection. The results showed that the models were ideal. The correlation coefficients of models for neochlorogenic acid, chlorogenic acid, 4-O caffeoylquinic acid and secoxyloganin were 0.973 872, 0.985 449, 0.975 509 and 0.979 790, respectively and their relative standard errors of prediction (RSEP) were 2.922 49%, 2.341 37%, 2.930 40% and 2.184 60%, respectively. This study indicated that the NIR quantitative calibration model showed good stability and precision, and it can be used in rapid quantitative detection of main indicators of efficacy in order to on-line monitor the alcohol precipitation process of Reduning injection. PMID- 25911811 TI - [Reliability of sulfur dioxide determination method documented in Chinese pharmacopoeia for evaluating Paeoniae Radix Alba]. AB - The content of SO2 in Paeoniae Radix Alba (RPA) was determined by the method documented in Chinese Pharmacopoeia (CP) 2010 edition to validate the repeatability of the method for evaluating RPA, and the contents of paeoniflorin sulfonate in both the residual material and distilled solution of RPA were determined by HPLC to study the transformation of paeoniflorin sulfonate to SO2 by HCl. It was found that the repeatability of the method in CP for evaluating RPA is unacceptable, and paeoniflorin sulfonate was detectable in both the residual material and distilled solution of RPA even at "the end point" of SO2 determination, merely about 50% of paeoniflorin sulfonate was transformed to SO2 by HCl, indicating that the current SO2 determination method in CP is not able to accurately quantify SO2 in RPA. It is recommended that more special method for determining SO2 content in RPA should be developed regarding the chemical characteristics of sulfur-fumigated RPA. PMID- 25911812 TI - [Determination of beta-sitosterol and total sterols content and antioxidant activity of oil in acai (Euterpe oleracea)]. AB - In order to establish a method for the determination of the sterols of the oil in the freeze-dried acai (Euterpe oleracea Mart.) and to evaluate its antioxidant activities, a saponification/extraction procedure and high performance liquid chromatography (HPLC) analysis method were developed and validated for the analysis of phytosterols in PEE (Petroleum ether extract). Separation was achieved on a Purosper STAR LP C18 column with a binary, gradient solvent system of acetonitrile and isopropanol. Evaporative light scattering detection (ELSD) was used to quantify beta-sitosterol and the total sterols. Peak identification was verified by retention times and spikes with external standards. Standard curves were constructed (r = 0.999 2) to allow for sample quantification. Recovery of the saponification and extraction was demonstrated via analysis of spiked samples. The highest content of total sterols is beta-sitosterol. The antioxidant activities of the extracts were evaluated using the total oxyradical scavenging capacity assay (TOSC assay). The result showed that the PEE exhibited significant antioxidant properties, sample concentration and the antioxidant capacity had a certain relevance. PMID- 25911813 TI - [HPLC fingerprint of liuwei dihuang soft capsule]. AB - In order to establish HPLC fingerprint of Liuwei Dihuang soft capsule, and to provide certain reference for an quality control of it, the HPLC method was performed on an Agilent C18 (4.6 mm x 250 mm, 5 MUm) column with acetonitrile 0.02% trifluoroacetic acid as mobile phase, gradient elution volume flow of 1.0 mL x min(-1), column temperature was 30 degrees C, detection wavelength: 0-60 min, 238 nm, 60-70 min, 210 nm. The software for chromatographic fingerprint was applied to analysis different batches of Liuwei Dihuang soft capsule samples. Sixteen mutual peaks were selected as the fingerprint peaks in 12 samples with loganin as the reference peak, and all of the detected peaks were separated effectively. Cluster analysis (HCA) and similarity analysis (SA) were done based on data of 12 samples clustering analysis of 12 batches of samples were divided into 2 categories. Including 7 for the first class, the rest was second, similarities calculated by SA were all above 0.92, indicating a good similarity between the reference and twelve batches of samples, also, the analysis results of HCA and SA basically the same. This method is simple with good precision, repeatability and stability, and provides the basis for Liuwei Dihuang soft capsule quality control. PMID- 25911814 TI - [Triterpenoids from Stauntonia obovatifoliola Hayata subsp. intermedia stems]. AB - In the current study, a total of nineteen triterpenoids (1-19) from 60% EtOH extracts of Stauntonia obovatifoliola Hayata subsp. intermedia stems were separated and purified by solvent extraction and chromatographic methods including silica gel, ODS as well as preparative HPLC. According to the results of chemical reactions and spectral data, compounds were identified as: lupeol (1), betulinonic acid (2), betulinic acid (3), 3-epi-betulinic acid (4), quinatic acid (5), 24-O-acetyl quinatic acid (6), 3-O-alpha- L-arabinopyranosyl-30-nor hederagenin-28-O-alpha-L-rhamnopyranosyl-(1 --> 4) -beta-D-glucopyranosyl-(1 --> 6) -beta-D-glucopyranosyl ester (7), Stauntoside A (8), kalopanax saponin A (9), kalopanax saponin J (10), Kizuta saponin K10 (11), 3-O-alpha-L-rhamnopyranosyl (1 -> 2) -alpha-L-arabinopyranosyl-hederagenin-28-O-beta-D-xylopyranosyl-(1 --> 6) beta-D-glucopyranosyl ester (12), kalopanax saponin B (13), 3-O-alpha-L rhamnopyranosyl-(1 --> 2) -alpha-L-arabinopyranosyl-hederagenin-28-O-beta-D glucopyranosyl-(1 --> 6) -beta-D-glucopyranosyl ester (14), sieboldianoside A (15), septemoside A (16), kalopanax saponin K (17), septemloside I (18), and 3-O alpha-L-arabinopyranosyl (1 --> 2)-beta-D-glucuronopyranosyl- hederagenin (19). Among them, compounds 4, 6, 10, 12, 14, and 16-19 were isolated from the Stauntonia genus for the first time, and compound 6 was a new natural product. PMID- 25911815 TI - [Triterpene constituents from Rosa cymosa Tratt]. AB - The constituents in 95% ethanol extract of the root of Rosa cymosa Tratt were purified by column chromatography techniques, leading to isolation of eleven triterpenes. Their structures were elucidated by spectroscopic data as pomolic acid (1), fupenzic acid (2), ursolic acid (3), euscaphic acid (4), arjunic acid (5), tomentic acid (6), 3beta-E-feruloyl corosolic acid (7), 1beta hydroxyeuscaphic acid (8), myrianthic acid (9), cecropiacic acid (10), and ilexoside B (11). Among them, compounds 3, 6-8, 10 and 11 were obtained from this plant for the first time, and compounds 7 and 10 were obtained from this genus for the first time. PMID- 25911816 TI - [Identification of main chemical constituents of diterpene lactone effective fraction of Andrographis panniculata by HPLC-DAD/ESI-MS and their preliminary pharmacodynamics research]. AB - OBJECTIVE: To establish an HPLC-DAD/ESI-MS method for quickly identifying chemical constituents in diterpene lactone effective fraction of Andrographis panniculata and to study its pharmacodynamics. METHOD: The separation was performed on an Agilent SB-C18 column (2.1 mm x 150 mm, 5 MUm) with a mobile phase of acetonitrile (A) and water (B). The flow rate was maintained at 0.4 mL x min(-1) and detection wavelength was set at 205 nm. The samples were analyzed in positive ion mode, and mass scan range was m/z 50-1 000. Using two kinds of tumor cell lines made living animal models, and studied preliminary pharmacodynamics on anti-tumor aspect. RESULT: Five diterpene lactones in the diterpene lactone effective fraction of A. panniculata could be separated in one run. Pharmacodynamic experiments showed that the effectve fraction had an inhibitory effect on the growth of tumor. CONCLUSION: A rapid and efficient HPLC-ESI-MS method to determine the chemical constituents in diterpene lactone effective fraction of A. panniculata has been established, and the preliminary pharmacodynamics research has been done, which could be used for the quality control and further studies of diterpene lactone effective fraction of A. panniculata in vivo. PMID- 25911817 TI - [Determination of lignans in schisandrae sphenantherae fructus from different regions]. AB - With an objective to provide an experimental basis for scientific officinal of Schisandrae Sphenantherae Fructus, this research uses UPLC-TQ/MS method to analyze 7 different kinds of lignan in 70 batches of Schisandra sphenantherae Fructus samples from 9 regions. The results showed that in the area south of Qinling mountains, Schisandrae sphenantherae Fructus from Zhashui county and Shanyang county of Shangluo mainly contained schisantherin A and deoxyschizandrin. However, Schisandrae sphenantherae Fructus from Mei county of Baoji, Shiquan county and Ningshan county of Ankang, and Lueyang county of Hanzhong, mainly contained anwuligan. Samples from Ningshan county also consists relatively high level of deoxyschizandrin. In the central area of Qinling mountains and the Daba mountains, Schisandrae Sphenantherae Fructus from Nanzheng county of Hanzhong mainly contained schisanhenol and deoxyschizandrin. In conclusion, the kinds and level of lignan differ significantly in Schisandrae sphenantherae Fructus produced in different regions. In practical application, Schisandrae Sphenantherae Fructus produced in different regions should be distinguished and differently applied based on their main effective components corresponding to different diseases, which can lead to the best clinical use. PMID- 25911818 TI - [Discovery of potential nicotinic acid receptor agonists from Chinese herbal medicines based on molecular simulation]. AB - Nicotinic acid could increase high density lipoprotein and reduce serum total cholesterol, low density lipoprotein cholesterol and triglycerides in human bodies, thus is frequently applied in treating low high-density lipoprotein cholesterol and hypertriglyceridemia in clinic. However, according to the findings, nicotinic acid could also cause adverse effects, such as skin flush, beside its curative effects. In this study, bioisosterism, fragment-based search and Lipinski's Rule of Five were used to preliminarily screen out potential TCM ingredients that may have similar pharmacological effects with nicotinic acid from Traditional Chinese medicine database (TCMD). Afterwards, homology modeling and flexible docking were used to further screen out potential nicotinic acid receptor agonists. As a result, eleven candidate compounds were derived from eight commonly used traditional Chinese medicines. Specifically, all of the candidate compounds' interaction with nicotinic acid receptor was similar to nicotinic acid, and their docking scores were all higher than that of nicotinic acid, but their druggability remained to be further studied. Some of the eight source traditional Chinese medicines were used to lower lipid according to literature studies, implying that they may show effect through above means. In summary, this study provides basis and reference for extracting new nicotinic acid receptor agonists from traditional Chinese medicines and improving the medication status of hyperlipidemia. PMID- 25911819 TI - [Research on building method of spleen kidney Yang deficiency diarrhea rats model]. AB - Spleen kidney Yang deficiency (SKYD) diarrhea is a common syndrome in tranditional Chinese medicine (TCM). Until now, there is not an ideal SKYD diarrhea rat model for the research. In this study, we compared single factor way (method I, injecting hydrocortisone and gavaging Sennae Folium) with compound factors way(method II, gavaging adenine, improper diet, exhaustion, and gavaging Sennae Folium) on establishing SKYD diarrhea rat model. After modelling, diarrhea index, D-xylose excretory rate, NOS/cGMP signal transduction system, organ index and histopathology examination were used to evaluate the two ways. The results showed that, compared with health group, all the assessment criterias of method I and method II had significant differences (P < 0.01, 0.05). In addition, the index such as diarrhea index, NOS/cGMP signal transduction system, organ index (kidney, testis and thymus) and histopathology examination had significant differences (P < 0.01, 0.05) between method I and method II. In conclusion, the compound factors modelling method better conforms to the symptom of diarrhoea model caused by SKYD. This new modelling method provides a basis for studying on TCM astringents warming and tonifying the spleen and kidney, relieving diarrhea. PMID- 25911820 TI - [Pulchinenoside control MeCP2 expression in FLS from RA model rats]. AB - The role of pulchinenoside (PULC) in the regulation of MeCP2 expression was investigated in RA model rats. Adjuvant arthritis rats were used as RA model rats, and fibroblast-like synoviocytes (FLS) from the RA model rats were cultured. The effect of 100 mg x kg(-1) PULC gavage treatment on the MeCP2 expression and the effect of MeCP2 siRNA on the expression of SFRP2 and beta catenin were detected by real time qPCR and Western blotting. The role of PULC in the FLS proliferation was detected by MTT. The results showed that the MeCP2 expression was down-regulated, the SFRP2 expression was up-regulated and the FLS proliferation was inhibited in FLS after therapy. MeCP2 siRNA significantly inhibited the MeCP2 expression, up-regulated the SFRP2 expression and inhibited the beta-catenin expression in FLS from RA model rats. PULC may increase the SFRP2 expression, inhibit the Wnt signaling and inhibit the FLS proliferation in FLS from the RA model rats by inhibiting the MeCP2 expression. PMID- 25911821 TI - [Studies on effects of calycosin-7-O-beta-D-glucoside on prim-O-glucosylcimifugin and cimifugin in vivo pharmacokinetics]. AB - Study on the effects of Astragali Radix main active flavone calycosin-7-O-beta-D glucoside on Saposhnikoviae Radix main active ingredients prim-O glucosylcimifugin and cimifugin, a UPLC-MS/MS method for simultaneous determination of prim-O-glucosylcimifugin and cimifugin in rat plasma was established, and the comparative pharmacokinetics of prim-O-glucosylcimifugin and cimifugin after oral administration of prim-O-glucosylcimifugin and calycosin-7-O beta-D-glucoside-prim-O-glucosylcimifugin to rats were carried out, which might be conductive in exploring the rationality of Astragali Radix - Saposhnikoviae Radix herb couple. Twelve male SD rats were divided into two groups. Prim-O glucosylcimifugin and cimifugin in rat plasma of different time points after oral administration of prim-O-glucosylcimifugin and calycosin-7-O-beta-D-glucoside - prim-O-glucosylcimifugin to rats were determinated. And the main pharmacokinetic parameters were investigated using DAS 3. 2. 4. The established method was rapid, accurate and sensitive for simultaneous determination of prim-O-glucosylcimifugin and cimifugin in rat plasma. The analysis was performed on a Waters Acquity BEH C18 column (2.1 mm x 100 mm, 1.7 MUm) with the mixture of acetonitrile and 0.1% formic acid/water as mobile phase, and the gradient elution at a flow rate of 0.3 mL x min(-1). The analytes were detected by tandem mass spectrometry with the electrospray ionization (ESI) source and in the multiple reaction monitoring (MRM) mode. Compared with prim-O-glucosylcimifugin group, the AUC(0-t)., and AUC(0-infinity) of p-O-glucosylcimifugin as well as the C(max) of cimifugin significantly increased (P < 0.05) in calycosin-7-O-beta-D-glucoside-prim-O glucosylcimifugin group. Calycosin-7-O-beta-D-glucoside could enhance the absorption of prim-O-glucosylcimifugin and cimifugin and improve the bioavailability, explaining preliminarily the rationality of Astragali Radix Saposhnikoviae Radix herb couple. PMID- 25911822 TI - [Urine metabonomic study on long-term use of total ginsenosides in rats]. AB - Due to its effect of systems regulation and promotion on body, Ginseng is always referred to be long-term used as a dietary supplement. But it was still unclear about its target of the tonic effects and also the side-effects long-term use may bring. Urine metabolomic method is suitable for long-term studies of pharmaco dynamics, pharmacology and toxicology of traditional Chinese medicine because of its characteristics of non-invasive and monitoring the whole-body metabolism. This study was designed to detect the dynamic variation of rat urine metabolome along with a long-term administration of total ginsenosides using GC-TOF based metabolomic technology. Our result showed that either short-term or chronic administration of ginsenosides did not impact the rat urine metabolome significantly (as the PCA subgroup was not successful). By comparison, the short term (1-3 w) dose of ginsenosides had the biggest metabolic influence including TCA cycle, catecholamines and neurotransmitter amino acids. Medium-term (6-10 w) dose had a gradually lower effect and long-term (27 w) dose almost had no effect. Our study indicates that both short and long-term administration of ginsenosides showed almost no obvious side-effect on the experimental animals. PMID- 25911823 TI - [Effects of modified Ganmai Dazao decoction on neuroendocrine system in patients with climacteric depression]. AB - Clinical study of modified Ganmai Dazao decoction in the treatment of yang deficiency climacteric depression and observe the effects of modified Ganmai Dazao decoction on neuroendocrine system in patients with yang deficiency climacteric depression. 86 cases were randomly divided into treatment group treated with modified Ganmai Dazao decoction and control group treated with Deanxit. The curative effect was evaluated with Hamilton's depressive scale (HAMD) and pittsburgh sleep quality scale (PSQI) before and at the end of the two and four weeks of the treatment, the serum levels of serotonin (5-HT), norepinephrine (NE), estradiol (E2), follicle stimulating hormone (FSH), luteotropic hormone (LH) were detected before and after the four weeks of the treatment The results showed that the total effective power of treatment group was 88.4% and the total effective power of control group was 81.4% after four weeks interference, with insignificant difference between the two groups. After two and four weeks of the treatment, the score of HAMD decreased remarkably in both groups (P < 0.01), with insignificant difference between the two groups in same phase. After two and four weeks of the treatment, the total score of PSQI decreased remarkably in both groups (P < 0.05), with significant difference between the two groups after four weeks (P < 0.01). After four weeks of treatment, the serum levels of 5-HT and NE increased (P < 0.01), with insignificant difference between the groups. After four weeks of treatment, the serum levels of E2 increased obviously (P < 0.05), the levels of FSH decreased obviously (P < 0.05), the levels of LH decreased insignificant, with insignificant difference between two groups. This study indicates that modified Ganmai Dazao decoction has obvious therapeutic effects in the treatment of climacteric depression, and showed equivalent efficacy with Deanxit, and modified Ganmai Dazao decoction has better effect on improving the sleep quality in patients than Deanxit, the effect of improved clinical symptoms may be through adjusted levels of 5-HT, NE, E2, FSH and LH of climacteric depression. PMID- 25911824 TI - [Change of peripheral blood appetite regulation factor of anorexia children and infect of child anorexia granule]. AB - Study the infect of child anorexia granule on serum ghrelin and leptin of anorexia children and its clinical efficacy. Selected 81 cases of anorexia children aged 1-6 years old into treatment group (42 cases) and control group (39 cases), in addition, 30 case healthy children as healthy control group. The control group children were treated with domperidone suspension 0.3 mg x kg(-1) x d(-1), tid, orally 30 minutes before meals. Treatment group were treated with child anorexia granule, 1-3 years 1 package, bid; 4-6 years 1 package, tid; po, 4 weeks as a course of treatment. Study the change of serum ghrelin and leptin before and after therapy. The study demonstrates that before treatment, the serum ghrelin level of disease group was lower than healthy group (P < 0.01), and the serum leptin level was higher than healthy group (P < 0.01). After treatment, the serum ghrelin level both increase, and the serum leptin decline. And the change of treatment group was significantly different with control group (P < 0.01). And the clinical effective rate are 95.23% and 74.35% (P < 0.01). After 6 months of follow-up visit, the children weight significantly increase in treatment group (P < 0.01). Results indicate that child anorexia granule can facilitate secretion of ghrelin, and inhibit secretion of leptin, so as to work up an appetite. And the molecular mechanism is its infect on serum ghrelin, leptin. PMID- 25911825 TI - In person. PMID- 25911826 TI - Adhesive luting of new CAD/CAM materials. AB - OBJECTIVE: To evaluate the adhesive bonding performance of recently introduced tooth-colored CAD/CAM materials after different pretreatment protocols and using different luting materials. MATERIALS AND METHODS: The CAD/CAM materials under investigation were e.max CAD (lithium disilicate glass ceramic; Ivoclar Vivadent, Schaan, Liechtenstein), Celtra Duo (zirconia-reinforced lithium disilicate ceramic; Dentsply DeTrey, Konstanz, Germany), Lava Ultimate (resin nano ceramic; 3M ESPE, Neuss, Germany), and Enamic (resin infiltrated ceramic; Vita, Bad Sackingen, Germany). A total of 240 blocks (n = 5) received various pretreatments (no pretreatment, silane, sandblasting, sandblasting + silane, hydrofluoric acid, hydrofluoric acid + silane), and then different classes of adhesive luting composites were applied (adhesive: Prime&Bond XP + SCA + Calibra; Dentsply DeTrey; self adhesive: RelyX Unicem; 3M ESPE). After 24 h water storage and 10,000 thermocycles (5 degrees C/55 degrees C), specimens were cut into beams and microtensile bond strengths were recorded. RESULTS: Bonding performance of recent CAD/CAM materials was clearly influenced by the pretreatment method (P < 0.05). In general, significantly higher MU-TBS values were recorded for the ceramic materials compared to the hybrid materials (P < 0.05). Among the hybrid materials, Enamic exhibited higher bond strengths than Lava Ultimate (P < 0.05). However, despite the differences found, all materials showed a high level of bonding performance, being sufficient to withstand intraoral chewing forces during mastication. CONCLUSION: When pretreated as recommended by the manufacturers, recent tooth-colored CAD/CAM materials show an encouraging bonding performance for adhesive luting. PMID- 25911827 TI - Understanding dental CAD/CAM for restorations--the digital workflow from a mechanical engineering viewpoint. AB - As digital technology infiltrates every area of daily life, including the field of medicine, so it is increasingly being introduced into dental practice. Apart from chairside practice, computer-aided design/computer-aided manufacturing (CAD/CAM) solutions are available for creating inlays, crowns, fixed partial dentures (FPDs), implant abutments, and other dental prostheses. CAD/CAM dental solutions can be considered a chain of digital devices and software for the almost automatic design and creation of dental restorations. However, dentists who want to use the technology often do not have the time or knowledge to understand it. A basic knowledge of the CAD/CAM digital workflow for dental restorations can help dentists to grasp the technology and purchase a CAM/CAM system that meets the needs of their office. This article provides a computer science and mechanical-engineering approach to the CAD/CAM digital workflow to help dentists understand the technology. PMID- 25911828 TI - Electronic transfer of sensitive patient data. AB - The purpose of this study was to develop decision-making aids and recommendations for dental practitioners regarding the utilization and sharing of sensitive digital patient data. In the current environment of growing digitization, healthcare professionals need detailed knowledge of secure data management to maximize confidentiality and minimize the risks involved in both archiving patient data and sharing it through electronic channels. Despite well-defined legal requirements, an all-inclusive technological solution does not currently exist. The need for a preliminary review and critical appraisal of common practices of data transfer prompted a search of the literature and the Web to identify viable methods of secure data exchange and to develop a flowchart. A strong focus was placed on the transmission of datasets both smaller than and larger than 10 MB, and on secure communication by smartphone. Although encryption of patient-related data should be routine, it is often difficult to implement. Pretty Good Privacy (PGP) and Secure/Multipurpose Internet Mail Extensions (S/MIME) are viable standards for secure e-mail encryption. Sharing of high volume data should be accomplished with the help of file encryption. Careful handling of sensitive patient data is mandatory, and it is the end-user's responsibility to meet any requirements for encryption, preferably by using free, open-source (and hence transparent) software. PMID- 25911829 TI - Cerec software goes 4.4. PMID- 25911830 TI - Planning and predictability of clinical outcomes in esthetic rehabilitation. AB - In esthetic rehabilitation, it is a challenge to meet the needs of patients with growing expectations. Creating predictable results is the key to success. This can be accomplished by performing a comprehensive esthetic diagnosis, elaborating treatment proposals that satisfy today's esthetic standards, and using modern computer-assisted methods. The diagnostic wax-up and mock-up are effective tools that allow patients to visualize treatment proposals without invasive procedures. Once the patient has approved the proposals, they provide the basis for the fabrication of the final restoration. The use of modern ceramic materials makes it possible to achieve a good esthetic outcome, even in restorations with extremely thin layer thicknesses. Esthetic cementation is the final step of restorative treatment. PMID- 25911831 TI - Dietary inclusion of protease producing novel Pontibacter spp. and Bacillus megaterium as a probiotic enhances immune responses in Labeo rohita. AB - Abstract: This study stresses the key role which can be played by Tannery Fleshing (TF) hydrolyzing probiotic Pontibacter spp. in aqua feed formulation and identifies the probiotic strains in the fish gut capable of enhancing the overall growth and immune responses. Probiotics included are Pontibacter species (Pb) and Bacillus megaterium (BM) wherein Lactobacillus (LB) served as control. Experimental diets includes tannery fleshing (TF1), TF+LB strain (TF2), TF+BM strain (TF3), TF+Pb strain (TF4), Fishmeal+BM(TF5), Fishmeal+Pb and Control fish meal based diet (TF6). Compared with control, total weight gain (TWG), Specific Growth Rate (SGR), Feed Conversion Ratio (FCR) and Protein Efficiency Ratio (PER) in fish fed with diets supplemented with probiotics were significantly increased (p < 0.05). NBT, lysozyme activity, total protein and globulin content were highest in TF4 diet. After challenge with Aeromonas hydrophila, TF4 recorded highest survival and TF1 lowest survival in comparison with the control. Growth and related parameters reveals the effective utilization potential of tannery fleshing probiotic as a feed source. Comparative studies with standard fish meal diets reveals that the fish fed with Pontibacter spp. and Bacillus megaterium included feeds enhanced both assimilating capacity and immunological responses in Labeo rohita. PMID- 25911832 TI - Cost effectiveness of cryoprotective agents and modified De-man Rogosa Sharpe medium on growth of Lactobacillus acidophilus. AB - The effect of cryoprotective agents (namely, sodium chloride, sucrose, dextran, sorbitol, monosodium glutamate, glycerol, skim milk and skim milk with malt extract) and modified De-Man Rogosa Sharpe (MRS) medium, on the viability and stability of L. acidophilus ATCC 4962, was investigated. The modified MRS medium was not only economical, but it gave a relatively higher yield of L. acidophilus ATCC 4962 than the commercial MRS. Monosodium glutamate, skim milk and skim milk with malt extract provided significantly higher viable counts, with optimum concentration at 0.3%. Nevertheless, at concentration above 0.5%, there was a reduction in cell viability, which could be attributed to cell shrinkage associated with osmotic pressure changes inside the cells. It was also found that L. acidophilus ATCC 4962 was stable at 28 degrees C for eight weeks. Skim milk demonstrated a significant growth of probiotics. Skim milk was the preferred cryoprotective agent, as it is of low cost, easily available and demonstrated a significant growth of probiotics. In conclusion, modified MRS medium with skim milk is suggested for the remarkable growth and yield of L. acidophilus. PMID- 25911833 TI - Plant genetic transformation efficiency of selected Malaysian rice based on selectable marker gene (hptII). AB - Rice is one of the most important cereal crops with great potential for biotechnology progress. In transformation method, antibiotic resistance genes are routinely used as powerful markers for selecting transformed cells from surrounding non-transformed cells. In this study, the toxicity level of hygromycin was optimized for two selected mutant rice lines, MR219 line 4 and line 9. The mature embryos were isolated and cultured on an MS medium with different hygromycin concentrations (0, 20, 40, 60, 80 and 100 mg L(-1)). Evidently, above 60 mg L(-1) was effective for callus formation and observed completely dead. Further there were tested for specific concentration (0-60). Although, 21.28% calli survived on the medium containing 45 mg L(-1) hygromycin, it seemed suitable for the identification of putative transformants. These findings indicated that a system for rice transformation in a relatively high frequency and the transgenes are stably expressed in the transgenic plants. Green shoots were regenerated from the explant under hygromycin stress. RT-PCR using hptII and gus sequence specific primer and Southern blot analysis were used to confirm the presence of the transgene and to determine the transformation efficiency for their stable integration in regenerated plants. This study demonstrated that the hygromycin resistance can be used as an effective marker for rice transformation. PMID- 25911834 TI - Taxonomy and pollen morphology of Ankyropetalum Fenzl (Caryophyllaceae) species in Turkiye. AB - There are 4 species belong to Ankyropetalum Fenzl (Caryophyllaceae) genus and three of them (A. reuteri Boiss. and Hausskn, A. arsusianum Kotschy ex Boiss. and A. gypsophiloides Fenzl) are distributed in Turkey. There are doubts about taxonomical studies depending on only morphological characteristics. This study has been made to put forth that palinological studies also contribute taxonomical studies. Pollen morphology of the three species belong to Ankyropetalum Fenzl (Caryophyllaceae) genus distributed in Turkey examined with ray microscope and electron microscope in this study. Results evaluated according to Duncan's multiple range test using SPSS statistic program. Pollen's polar and ecvatoral seeming photographs were taken in preparates. Morphology of pollens examined with 50 repetition for each taxon and morphological assessments were made. The common trait of pollens can be summarized as they are circular, oblate and prolate spheroidal, periporate (pore numbers ranged between 20-33), operculum is granulated, annulus is distinct, the form of pollens are tectat. Definition of pollens are given for each taxon, diagnostic specifications recognized as important are used for making diagnosis key. The difference between species are as below: A. arsusianum's pollen shape is oblate-spheroidal, type of pollen is periporate, pore numbers are between 23-33, form of pollen is tectat, ornamentation is perforate. A. reuteri's pollen shape is prolate-spheroidal, type of pollen is periporate, pore numbers are between 20-33, form of pollen is tectat, ornamentation is from perforate to eureticulate A. gypsophiloides pollen shape is oblate-spheroidal, type of pollen is periporate, pore numbers are between 21-30, form of pollen is tectat, ornamentation is perforate. PMID- 25911835 TI - Chromosomal studies and quantitative karyotypic analysis of Rohu, Labeo rohita. AB - Chromosomal and karyotypic studies are required for genetic improvement of any organisms. This study was performed to identify individual chromosomes on morphological basis and to characterize a standard karyotype using the fish, Rohu (Labeo rohita, Hamilton, 1822). Colchicine (0.05%) treated (2, 2.5 and 3 h) tissues of two day-old larvae were used for slide preparations and selected plates were photomicrographed under high resolution research microscope. Slide preparations were done following hydrolysis (10% HCl), mordanting (2% iron alum) and staining with haematoxylin. Colchicine treatment for 2 h gave satisfactory results in respect of degree of contraction of the chromosomes. Chromosome number 2n = 50 was counted at metaphase stage. Measurements of the chromosomes were taken from the selected plates based on morphologically distinct condition. Standard haploid karyotype was formulated following the combined scatter diagram technique. Six individually identifiable and 19 not individually identifiable chromosomes consisted of the haploid complement. The six individually identifiable ones consisted of 2 m+3 sm+1st and not individually identifiable ones consisted of 16 m+3 sm chromosomes. This study report may provide complete report on chromosomal and karyotype knowledge in L. rohita and suggest the genetic purity of L. rohita may contributes to sustainable aquaculture production. PMID- 25911836 TI - Effects of nitrogen application method and weed control on corn yield and yield components. AB - The effects of nitrogen fertilizer application and different methods for weed control on yield and yield components of corn was evaluated in Khorramabad in 2011. The experiment was conducted as a split plot based on randomized complete block design in 3 replications. Nitrogen application was as main plot in 4 levels (no nitrogen, broadcasting nitrogen, banding nitrogen and sprayed nitrogen) and methods of weed control were in 4 levels (non-control weeds, application Equip herbicide, once hand control of weeds and application Equip herbicide+once time weeding) was as subplots. Result illustrated that effects of nitrogen fertilizer application were significant on grain and forage yield, 100 seeds weight, harvest index, grain number per row and cob weight per plant. Grain yield increased by 91.4 and 3.9% in application banding and broadcasting for nitrogen fertilizer, respectively, compared to the no fertilizer treatment. The results show improved efficiency of nitrogen utilization by banding application. Grain yield, harvest index, seed rows per cob, seeds per row and cob weight were increased by weed control. In the application of Equip herbicide+ hand weeding treatment corn grain yield was increased 126% in comparison to weedy control. It represents of the intense affects of weed competition with corn. The highest corn grain yield (6758 kg h(-1)) was related to the application banding of nitrogen fertilizer and Equip herbicide+once hand weeding. PMID- 25911837 TI - Effects of aqueous extract of Withania somnifera on some liver biochemical and histopathological parameters in male guinea pigs. AB - Organophosphorus (OP) insecticides constitute one of the most widely used classes of pesticides being employed for both agricultural and landscape pest control. The purpose of this study was to investigate the effect of dimethoate (DM), an organophosphorus insecticide, on some biochemical and histopathological parameters in liver of adult male guinea pigs as well as the possible role of Withania somnifera extract in attenuation of DM-induced hepatotoxicity. The animals were divided randomly into 5 groups and kept at 5 animals per group in an environmentally controlled condition with free access to food and water ad libitum. The first group was served as a control group and administered with olive oil orally; the group II received aqueous extract of W. somnifera (100 mg kg(-1) b.wt.) orally, group III, IV and V was administered with DM (14 mg kg(-1); 1/25LD50) for 21 days orally. Group IV and V received 100 mg kg(-1) of W. somnifera extract and silymarin, respectively half hour before DM administration for 21 days. DM caused a statistically significant increase in the serum level of liver enzymes (AST, ALT, ALP) when compared to control animals, whereas, W. somnifera and silymarin pre-treatment to the DM-intoxicated animals resulted in a significant normalization of the enzymes activities. On the other hand W. somnifera extract reduced the incidence of histopathological changes such as cytoplasmic vacuolization and degeneration in nuclei, rupture of epithelia lining the central vein, widened sinusoidal space and lymphocyte infiltration induced by DM treatment in guinea pigs. In conclusion, the results of this study suggest that W. somnifera aqueous extract could protect the liver against DM-induced oxidative damage. PMID- 25911838 TI - Yield loss assessment due to Alternaria blight and its management in linseed. AB - Field experiments were conducted during 2010-11 and 2011-12 to assess the yield losses due to Alternaria blight disease caused by Alternaria lini and A. linicola in recently released cultivars and their management with the integration of Trichoderma viride, fungicides and plant extract. Disease severity on leaves varied from 41.07% (Parvati) to 65.01% (Chambal) while bud damage per cent ranged between 23.56% (Shekhar) to 46.12% (T-397), respectively in different cultivars. Maximum yield loss of 58.44% was recorded in cultivar Neelum followed by Parvati (55.56%), Meera (55.56%) and Chambal (51.72%), respectively while minimum loss was recorded in Kiran (19.99%) and Jeevan (22.22%). Minimum mean disease severity (19.47%) with maximum disease control (69.74%) was recorded with the treatment: seed treatment (ST) with vitavax power (2 g kg(-1) seed) + 2 foliar sprays (FS) of Saaf (a mixture of carbendazim+mancozeb) 0.2% followed by ST with Trichoderma viride (4g kg(-1) seed) + 2 FS of Saaf (0.2%). Minimum bud damage (13.75%) with maximum control (60.94%) was recorded with treatment of ST with vitavax power+2 FS of propiconazole (0.2%). Maximum mean seed yield (1440 kg ha(-1)) with maximum net return (Rs. 15352/ha) and benefit cost ratio (1:11.04) was obtained with treatment ST with vitavax power + 2 FS of Neem leaf extract followed by treatment ST with vitavax power+2 FS of Saaf (1378 kg ha(-1)). PMID- 25911840 TI - Effects of fenugreek seeds on adipogenesis and lipolysis in normal and diabetic rats. AB - Several studies support hypolipidemic effect of fenugreek in normal and diabetic subjects. However, very little is known about the possible direct action of fenugreek on adipose tissue. The present study was designed to investigate the effects of fenugreek seeds on adipogenesis and lipolysis. Preadipocytes were isolated from adipose tissue of normal rats and differentiated to adipocyte in the presence of ethanolic extract of fenugreek seeds. The effect of this extract on lipolysis was also evaluated in fat tissue isolated from diabetic rats. Fenugreek led to a significant reduction in lipid droplet accumulation as evaluated with Oil Red O staining. Incubation of preadipocytes with the extract for 24 h resulted in significant decrease in cell viability. The extract, even at high concentrations (up to 1000 MUg mL(-1)), had virtually no significant effect on lipolysis. The present data demonstrated that fenugreek seed inhibits formation of new differentiated adipocytes from precursor cells through an anti proliferative effect on preadipocytes. PMID- 25911839 TI - Protective effects of ethanolic extract of Nigella sativa seed in paracetamol induced acute hepatotoxicity in vivo. AB - Paracetamol overdose causes serious liver necrosis. Hepatoprotective activity of ethanolic extract of Nigella sativa in Paracetamol induced acute hepatotoxicity was investigated in rats. Fasted male Wistar rats were orally treated with Nigella sativa extract in graded doses for 5 days followed by Nigella sativa extract and paracetamol 3 g kg(-1) on 6 and 7th day. Circulatory liver markers and reduced glutathione (GSH) levels were estimated and histopathological study of liver performed. Paracetamol caused a significant increase in serum alkaline phosphatase, glutamic oxaloacetic transaminase, glutamic pyruvic transaminase and total Bilirubin and a significant decrease in GSH compared to control. Nigella sativa pretreatment significantly prevented the increase in liver enzymes and total bilirubin and decrease in GSH level as compared to paracetamol group. Liver histopathology showed marked reduction in sinusoidal dilatation, midzonal necrosis, portal triaditis and occasional apoptosis in Nigella sativa extract treated groups as compared to group receiving only paracetamol. Nigella sativa extract possesses hepatoprotective action against paracetamol induced acute hepatoxicity. Further research is needed to advocate its prophylactic use for drug induced hepatotoxicity. PMID- 25911841 TI - Production, optimization and characterization of fibrinolytic enzyme by Bacillus subtilis RJAS19. AB - The present study aimed at the production, purification and characterization of fibrinolytic nattokinase enzyme from the bacteria isolated from natto food. For the purpose, a fibrinolytic bacterium was isolated and identified as Bacillus subtilis based on 16S rDNA sequence analysis. The strain was employed for the production and optimization of fibrinolytic enzyme. The strain showed better enzyme production during 72nd h of incubation time with 50 degrees C at the pH 9. The lactose and peptone were found to be increasing the enzyme production rate. The enzyme produced was purified and also characterized with the help of SDS-PAGE analysis. The activity and stability profile of the purified enzyme was tested against different temperature and pH. The observations suggesting that the potential of fibrinolytic enzyme produced by Bacillus subtilis RJAS 19 for its applications in preventive medicines. PMID- 25911842 TI - Nodulation study of natural forage legume in semiarid region, Turkey. AB - In this study, we investigated the natural nodulation of legume forage crops were widely grown in the natural pastures in Sanliurfa, Turkey. This legume forage crops are Vicia sativa L. subsp. sativa L., Vicia narbonensis L. var. narbonensis L., Vicia palaestina Boiss., Vicia hybrida L., Vicia lutea L. var. lutea Boiss. ET Ball., Pisum sativum L. subsp. sativum L. var. sativum L, Cicer echinospermum P.H. Davis, Trifolium tomentosum L., Trifolium retusum L., Trifolium campestre SCHREB., Medicago truncatula GAERTN. var. truncatula Schultz Bip., Trigonella mesopotamica Hub.-Mor., Lens culinaris Medik., Onobrychis crista-galli, Lathyrus cassius Boiss., Melilotus officinalis (L.) DESR., Coronilla scorpioides (L.) W.D.J. Koch. Nodulation, nodule colors and shapes were examined at the blooming period of forage legumes. In this study, the colour of the interior of nodules are pink-red colour and may be related to high rates of nitrogen fixation in legume crops. PMID- 25911843 TI - Multidrug resistant pathogenic Escherichia coli status in water sources and Yamuna River in and around Mathura, India. AB - The present study was taken to understand the status of water resources in the holy city of Mathura, India. As it is a tourist place and pilgrims come from all around the world, there are more chances of spread of pathogens through them. The pathogens which are particularly excreted through urine and feces are most commonly excreted out. E. coli is one of them which causes many severe diseases particularly in neonatal calves or neonates of human. As the city has its limitation of accommodation and river Yamuna is also shrinking, the pressure of millions of pilgrims has enormous, drastic and stipulated effect on water resources particularly river Yamuna. The samples collected showed the presence of pathogenic E. coli. Out of total 100 samples 40 were found positive for E. coli. The 60 samples of different water resources showed the presence of E. coli in 26 samples while 14 were found positive out of 40 samples of Yamuna water. The total coliforms count ranged between 1.08 log10 CFU m L(-1) to 6.34 log10 CFU m L(-1) in drinking water sources and waste water, respectively. The high percentage of positive samples and coliforms count may be because of the method and place of sample collection. When these isolates were analyzed for antibiotic sensitivity pattern against some commonly used antibiotics. They showed a variable effectiveness against them. The number of resistant isolate is significant enough to make an alert at the earliest to protect the water resources and also to secure better and brighter future of human population. PMID- 25911844 TI - Comparative effects of petrol and diesel on enzyme activity in Tympanotonus fuscatus after sublethal exposure. AB - Pollution of the aquatic environment by petroleum and its products is common the world over. This study is aimed at examining sublethal effects of petrol and diesel on enzymes in Tympanotonus fuscatus namely: Aspartate Transaminase (AST) (E.C. 2.6.1.1), Alanine Transaminase (ALT) (E.C. 2.6.2.2) and Alkaline Phosphatase (ALP) (E.C. 3.1.3.1) activity after exposure. The periwinkles were exposed to 10.40, 15.60, 21.00, 26.00 ml L(-1) and a control. The organs were removed on the sixth day and were prepared for enzymatic analysis. Enzyme activities were compared to the control value and between the toxicants. The effects of the toxicants on AST activity in the muscle and viscera were significantly different (p > 0.05) from the control value (137.50 +/- 15.10 IU L( 1)). AST activity were raised more in petrol concentrations than the diesel concentrations in the muscle. The reverse was the case in the viscera at 15.60 ml L(-1) (227.50 +/- 24.75 IU L(-1)). ALT activity in the muscle were not significant (p > 0.05) between the toxicant media. In the viscera, significant differences (p > 0.05) were observed in some of the concentrations with petrol showing higher activity. ALP activity in the muscle were not significant (p > 0.05) in both media, but were more elicited in the diesel concentrations. In the viscera, the activities of ALP were more pronounced in the petrol concentrations and were significant (p > 0.05) at the higher diesel concentrations. The exposure of Tympanotonus fuscatus to petrol and diesel concentrations caused changes in the enzymatic activities in the organism with those of petrol more pronounced than those of the diesel. PMID- 25911845 TI - Investigation of the relationship between carrying school bags (handbags and backpacks) and the prevalence of musculoskeletal pains among 12-15 year old students in Shiraz. AB - Inappropriate school bags put students at risk of musculoskeletal problems and early fatigue. Heavy bags can change the body posture and the musculoskeletal system must react appropriately in order to compensate for this stress. It is recommended that the weight of a school bag must not be more than 10% of the student's body weight and the weight must be placed on both shoulders. The present study aimed to identify the risk factors associated with musculoskeletal disorders by comparing the prevalence of musculoskeletal pains among the students. The present descriptive, cross-sectional study was conducted in different educational districts of Shiraz. The study samples were selected using cluster sampling method. In this study, 800 students marked their painful areas on body maps and the SPSS statistical software (v. 11.5) was used to analyze the data. The results showed that among the students who used backpacks, 48.9% carried the weight on both shoulders, 40.4% carried the weight on their right shoulders, and 10.6% used their left shoulders. Besides, 68.02% of the students carrying handbags often used their right shoulders, while 31.98% used their left shoulders. The study results showed that similar to other countries, Iranian students also mostly made use of backpacks. Moreover, the musculoskeletal pains were most prevalent in the shoulders, which is in line with many other studies conducted on the issue. PMID- 25911846 TI - Sedative activity of methanolic extract of Glochidion multiloculare (Rottler ex Willd) Voigt leaves. AB - Bangladesh is a good repository of medicinal plants. Traditional healers utilize them for treating many pathological states. Unfortunately, very few of them have been scientifically evaluated to know about the deep inside. The current study here is designed to evaluate the in vivo sedative activity of the leaves of Glochidion multiloculare (Rottler ex Willd) Voigt. With this purpose, the plant leaves were collected and powdered for extraction with methanol. Initially, the plant extract was subjected to brine shrimp lethality bioassay to monitor the presence of bioactive molecules. Later on, different neuropharmacological studies including hole cross, open field, thiopental-sodium induced sleeping time and Elevated-Plus Maze (EPM) tests were conducted to investigate sedative action. In the brine shrimp lethality bioassay, the LC50 value of the extract was found 37.19 MUg mL(-1), whereas the standard vincristine sulphate showed the LC50 10.50 MUg mL(-1). The moderate toxicity of the extract on brine shrimp indicated the existence of bioactive secondary metabolites in this extract. Besides, the extract decreased the locomotor activity of mice in hole cross, open field and EPM test indicating the CNS depression capability of the plant. Moreover, the extract was very much effective for prolonging the sleeping time (103 min) with quick onset of action (22 min) in comparison to the control group. The efficacy of the plant extract was found closer to the common sedative drug diazepam. Further investigations are required to explore the underlying mechanism of the sedative action and isolate bioactive principles. PMID- 25911847 TI - Morinda citrifolia L. leaf extract as antibacterial Salmonella typhimurium to increase productivity of quail (Coturnix coturnix japonica). AB - The objective of this study was to apply effect of Morinda citrifolia L. citrifolia L. leaf extract as antibacterial of Salmonella typhimurium on mortality of Day Old Quail (DOQ), egg production and Hen day, hatchability of layer quail. This research was conducted at Laboratory of microbiology and laboratory of poultry nutrition, faculty of animal science, bogor agricultural university and slamet quail farms cilangkap, sukabumi, west java, Indonesia on March-July 2012. Two hundred and forty heads of quail were randomly assigned to four dietary treatments (sixty heads of quail/treatment). Experimental design used was Completely Randomized Design (CRD). The treatments consist of level of biscuit Morinda citrifolia L. Citrifolia L. leaf extract i.e R1 = 0%, R2 = 5%, R3 = 10%, R4 = 15%. The results indicated the treatments had significant effect (p < 0.05) on mortality of Day Old Quail (DOQ). The average mortality of Day Old Quail (DOQ) was given extract Morinda citrifolia L. leaf were R1 (4.00%), R2 (1.00%), R3 (1.33%), R4 (0.67%). The average mortality of Day Old Quail (DOQ) was given 15% extract Morinda citrifolia L. leaf (R4) was lowest than control treatment (R1). The results of the analysis indicated that Morinda citrifolia L. leaf of quail drink had not significant effect (p > 0.05) on egg production, hen day and hatchability. It was concluded that the Morinda citrifolia L. leaf extract 15% can reduce mortality of Day Old Quail (DOQ) and can increase its egg production, hen day and hatchability. PMID- 25911848 TI - High frequency of BRAF proto-oncogene hot spot mutation V600E in cohort of colorectal cancer patients from Ahvaz City, southwest Iran. AB - Colorectal cancer (CRC) is one of the most common forms of cancer around the world. Sporadic CRCs are caused by accumulation of mutations in essential genes regulating normal proliferation and differentiation of cells. The proto-oncogene BRAF encoded by the BRAF gene is involved in the RAS/RAF/MAPK pathway of signal transduction during cell growth. Acquired mutations in BRAF have been found at high frequencies in adult patients with papillary thyroid carcinoma and sporadic CRC. One of the predominant hot spot point mutations is T1799A (V600E) mutation among a cohort of CRC patients from Ahvaz city, southwest Iran. The aim of this study was to estimate the frequency of V600E mutation in CRC patients from Ahvaz city, southwest Iran. We analyzed exon 15 of the BRAF gene in isolated DNA from 80 Formalin Fixed Paraffin-embedded (FFPE) CRC tumor tissues using PCR-RFLP method. Data were analyzed using SPSS statistical program. According to our results 37 out of 80 cases (46.25%) were heterozygous for the mutation while the remaining 43 cases (53.75%) had normal homozygous genotype. No homozygous mutant genotype was found. Based on our findings, the frequency of V600E mutation appears to be significantly increased among CRC patients of the studied population but there was no significant relationship between genotypes and age and sex. In conclusion, these findings might prove the effect of V600E mutation on CRC pathogenesis. However, the exact effect of the mutation in CRC progression requires further work. PMID- 25911849 TI - Correlation between total lymphocyte count, hemoglobin, hematocrit and CD4 count in HIV patients in Nigeria. AB - The expensive and technology limited setting of CD4 count testing is a major setback to the initiation of HAART in a resource limited country like Nigeria. Simple and inexpensive tools such as Hemoglobin (Hb) measurement and Total Lymphocyte Count (TLC) are recommended as substitute marker. In order to assess the correlations of these parameters with CD4 count, 100 "apparently healthy" male volunteers tested HIV positive aged >= 20 years but <= 40 years were recruited and from whom Hb, Hct, TLC and CD4 count were obtained. The correlation coefficients, R, the Nash-Sutcliffe Coefficient of Efficiency (CoE) and the p values of the ANOVA model of Hb, Hct and TLC with CD4 count were assessed. The assessments show that there is no significant relationship of any of these parameters with CD4 count and the correlation coefficients are very weak. This study shows that Hb, Hct and TLC cannot be substitute for CD4 count as this might lead to certain individuals' deprivation of required treatment. PMID- 25911850 TI - Analysis of oxidative stress status through MN test and serum MDA levels in PCOS women. AB - Polycystic Ovary Syndrome (PCOS) is a multifactorial reproductive healthcare problem affecting 4-12% of women and a leading cause of female infertility worldwide. The potential genetic contributors of PCOS are unclear. However, over the past decade emerging evidence has shown that increased Oxidative Stress (OS) and decreased antioxidant status were often linked with PCOS. The present case control study was aimed to assess the reactive oxygen species induced OS in women from South India. A total of 164 individuals comprising of 89 patients and 75 controls were enrolled in the present study. For all the subjects, the frequency of micronucleated cells (MNC) in epithelial samples and serum Malondialdehyde (MDA) levels were estimated to assess genomic instability and cytotoxicity respectively. A statistically significant difference between the groups were identified with respect to Body Mass Index, Waist to Hip Ratio, luteinizing hormone and prolactin levels (< 0.05), however the mean follicle stimulating hormone was not different between the groups (p = 0.055). The frequency of MN cells (5.89 +/- 4.86 vs. 2.24 +/- 2.01) and mean serum MDA (360.84 +/- 87.08 vs. 301.70 +/- 82.82) levels were considerably higher in patients than controls (p = < 0.0001), furthermore, a positive correlation was observed between MNC and MDA levels in patients (r = 0.349, p = 0.0008) and not in controls (r = 0.104, p = 0.37), suggest high OS in PCOS women. Therefore, MN assay and serum MDA levels may serve together or individually as biomarkers of OS in PCOS women. PMID- 25911851 TI - Evaluation of Gastrothylax crumenifer antigenic preparation in serodiagnosis of paramphistomiasis in sheep. AB - An evaluation of Gastrothylax crumenifer crude antigen preparation viz., Somatic Antigen (SAg), Excretory Secretory Antigen (ESAg) and Egg Antigen (EAg) in serodiagnosis of disease was undertaken. Test sera samples were obtained from 30 Paramphistomiasis Positive and 30 Gastrothylax free sheep slaughtered at Hazratbal Kashmir. The referral antigenic preparation were evaluated against Paramphistomiasis positive sera, via., control negative sera, using double immunodiffusion test (DID), (IEP) Immunoelectrophoretic assay and ELISA. The performance of referral antigens, as assessed from percent sensitivity and specificity, revealed an increasing trend from DID (Double immunodiffusion-An immunological technique used in the detection, identification and quantification of antibodies and antigens) to IEP (immunoelectrophoresis-A general name for a number of biochemical methods for separation and characterization of proteins based on electrophoresis and reaction with antibodies), followed by ELISA, detecting higher number of sheep positive for paramphistomiasis. In ELISA the ESAg and SAg were evaluated as most reactive antigens with no significant difference and EAg was the least antigenic. In IEP, EAg had the higher sensitivity (60%) and analogous specificity of SAg and ESAg. The formation of the preceptin lines in the proximity to EAg containing wells (cathode end) in IEP was suggestive of higher molecular weight of G. crumenifer specific protein molecules with slower rate of migration. Purification and characterization of G. crumenifer and identification of specific antigenic molecules, particularly in EAg has been suggested for qualitative improvement of diagnostic value of the antigens in the tests used here in. PMID- 25911852 TI - Assessing validity of serum cystatin C for predicting metabolic syndrome. AB - Serum concentration of cystatin C a marker of glomerular filtration has been associated with Cardiovascular Disease (CVD). The aim of this study was to evaluate cystatin C as a marker of diabetic kidney disease in normoalbuminuric diabetic patients without Chronic Kidney Disease (CKD). The study population consisted of 65 subjects with metabolic syndrome and 32 subjects free of metabolic syndrome (control group). HDL-C, LDL-C, blood urea, triglycerides, glucose, HbA1c, serum cystatin C and serum creatinine were measured in both groups. GFR was calculated in both groups using Cockrofta Gault equation. Metabolic syndrome presented higher cystatin C levels than normal samples (0.98 8 0.26 1.24 8 0.24 p < 0.05). In the binary logistic regression, the presence of diabetes and metabolic syndrome was significantly associated with elevated cystatin C levels. Diabetic patients also presented a slightly greater creatinine (1.11 8 0.09 1.04 0.15 p < 0.05). The results suggest that cystatin C may be a marker for metabolic syndrome and may identify a certain degree of renal dysfunction even when serum creatinine does not exceed normal level. PMID- 25911853 TI - Changes in oxalate and some mineral concentrations of Setaria sphacelata under cutting and uncutting conditions. AB - Oxalate concentration in forage plants is important, because it results mineral deficiency in ruminants. Data on oxalate concentration in forage plants in conjunction with cutting and uncutting conditions throughout the growing period are limited. This study was aimed to investigate the changes in oxalate and some mineral concentrations of setaria (Setaria sphacelata). The plants were harvested at different stages (vegetative, boot, pre-flowering, flowering and seed) of maturity and at about 50 cm in length of regrowth (second to sixth cuttings) for evaluation of soluble oxalate, insoluble oxalate and some mineral concentrations. Soluble oxalate and total oxalate concentrations, as well as mineral concentrations, decreased with advancing maturity. Both oxalate concentrations (soluble or insoluble) were higher in leaf compared to stem. Soluble oxalate and total oxalate concentrations of regrowth were the highest at third cutting and lowest at sixth cutting. Insoluble oxalate concentration of regrowth was almost similar in all cuttings, except for the sixth cutting. The highest concentrations of potassium, sodium and magnesium of regrowth were observed at third cutting, while the highest concentration of calcium was observed at sixth cutting. A relationship between oxalate and mineral concentrations was partially observed. Results suggest that cutting materials of setaria from June to October could achieve oxalate levels that are toxic to ruminants. PMID- 25911854 TI - Phytochemical comparison between Pet ether and ethanolic extracts of Bacopa monnieri, Evolvulus alsinoides and Tinospora cordifolia. AB - Bacopa monnieri, Evolvulus alsinoides and Tinospora cordifolia are established ayurvedic herbs having neuropharmacological effect. In present study is aimed to Phytochemical Comparison between Pet ether and Ethanolic extracts of Bacopa monnieri (BME), Evolvulus alsinoides (EAE) and Tinospora cordifolia (TCE). To identify the presence (+) or absence (-) of different phytoconstituents in Pet ether and Ethanolic extracts of BME, EAE and TCE by using various phytochemical testing methods. Phytochemical investigation showed the presence of various phytochemical constituents in Pet ether and Ethanolic extracts of BME, EAE and TCE. When comparison between Pet ether and Ethanolic extracts of BME, EAE and TCE; Ethanolic extracts of these plants showed more phytoconstituents as compared to Pet ether extracts of these plants. From present investigation, it can be concluded that phytochemical comparison is subsequently momentous and useful in finding chemical constituents in the plant substances that may lead to their quantitative evaluation and also pharmacologically active chemical compounds. PMID- 25911855 TI - Effect of phytohormones on seed germination and seedling growth of Coriandrum sativum L. AB - Coriander commonly known as Dhania or Chinese parsley is generally grown for its use in soups, salads, dressing vegetables, seasoning and chutney. Effect of two phytohormones viz. GA3 and 2,4-D on seed germination, seedling growth and various physiological and biochemical parameters were studied. The hormones were applied individually in different concentrations (10, 50 and 100 MUM concentrations). Both the hormones enhanced the germination percentage, seedling growth (root and shoot length), leaf area, chlorophyll and carotenoid content. The application of these hormones also decreased the germination time. Maximum germination, shoot length, leaf area and carotenoid content was observed in 100 MUm concentration of GA3. Root length, chl. a and chl. b was maximum in 50 MUM of 2,4-D and 100 MUm GA3, respectively. The application of two hormones exhibited a marked increase on all the parameters studied as compared to the control. PMID- 25911856 TI - Micropropagation of Dalbergia sissoo Roxb. through tissue culture technique. AB - Multiple shoots of Dalbergia sissoo Roxb. (Sissoo) were incited from seeds through indirect somatic embryogenesis method. Seeds were inoculated in Murashige and Skoog's medium without any growth hormone. Than cotyledonary leaves were struck and used for callus induction on MS medium amplified with 2, 4 dichlorophenoxyacetic acid (0.5 to 4 mg mL(-1)). After 3 to 4 weeks the embryogenic callus clumps was transferred to medium supplemented with cytokinin (BAP 1 to 5 mg L(-1), kinetin 1-5.0 mg L(-1)) for embryo maturation and germination. The high-frequency shoot proliferation (82%) and maximum number of shoots per explants were recorded in MS medium containing NAA (0.5)+BAP (0.5). The findings of recent investigations have shown that, it is possible to induce indirect somatic embryogenesis in Dalbergia sissoo and plant regeneration from callus cultures derived from cotyledonary leaves as explants. PMID- 25911857 TI - Long-term outcomes after extrahepatic excision of congenital choladocal cysts: 30 years of experience at a single center. AB - BACKGROUND/AIMS: Congenital choladocal cysts are generally treated by resection of the dilated extrahepatic biliary duct followed by hepaticojejunostomy, but it is associated with postoperative complications, including postoperative cholangitis, intrahepatic calculi, pancreatitis, and carcinogenesis, in the remnant bile duct. We investigated the most common long-term complications and identified the factors implicated in their development. METHODOLOGY: We conducted a retrospective review and analysis of the long-term complications of 65 patients surgically treated for congenital choledochal cysts between 1978 and 2008 at one institute. The risk factors for intrahepatic calculi were identified based on the odds ratios of the implicated variables. RESULTS: Cholangitis with high fever or abdominal pain was reported in 14 patients (21.5%), intrahepatic calculi in 12 (18.5%), pancreatitis in 3 (4.6%), and cholangiocarcinoma in 3 (4.6%). Diagnosis with type IVa choledochal cysts was the most significant risk factor, followed by age >=30 years at the time of treatment, and the presence of preoperative intrahepatic calculi. CONCLUSIONS: While precise and thorough surgical treatment is necessary to prevent the long-term development of complications after surgical excision of congenital choledochal cysts, it must be accompanied by long-term postoperative follow-up, especially of elderly patients and those with type IVa cysts. PMID- 25911858 TI - Long term outcomes of choledochoduodenostomy for common bile duct stones in the era of laparoscopy and endoscopy. AB - BACKGROUND/AIMS: Choledochoduodenostomy (CDD) has been reported as an effective treatment of Common bile duct stones (CBDS). This study was designed to analyze short term and long term outcomes of CDD for CBDS. METHODOLOGY: Demographic data, preoperative, intraoperative and postoperative variables were collected. The long term assessment was done in a prospective manner included clinical examination, liver function, abdominal ultrasound, MRCP, upper GIT endoscopy and assessment of quality of life using Gastrointestinal Quality of Life Index (GIQLI). RESULTS: A total of 388 consecutive patients underwent CDD, the mean age was 57.92+/-13.25 years. The mean CBD diameter was 18.22+/-4.01 mm. The mean operative time was 81.21+/-20.23 minutes. Two patients had recurrent stone (0.06%) and managed successfully by endoscope. Gastritis was observed in 16.9% patients. No patient developed sump syndrome, deterioration in liver function or cholangiocarcinoma. Total and subgroup scores on the GIQLI before and after CDD differed significantly at follow-up (P=0.0001). CONCLUSION: CDD is a safe and effective method of drainage of CBD after clearance of CBDS. Long term outcomes are acceptable with good quality of life. Sump syndrome is extremely rare; CDD may be associated with mild to moderate gastritis. CDD doesn't lead to development of cholangiocarcioma. PMID- 25911859 TI - Induction dosing of peginterferon alfa-2a (40 KD) and/or high-dose ribavirin in genotype 1 CHC patients with difficult-to-treat characteristics: pharmacokinetic and viral kinetic (PK/VK) assessment from PROGRESS. AB - BACKGROUND/AIMS: PROGRESS randomized chronic hepatitis C genotype 1 patients with a baseline viral load >=400,000 IU/mL weighing >=85 kg to regimens of 180 MUg/week for 48 weeks or 360 MUg/week for 12 weeks followed by 180 MUg/week for 36 weeks peginterferon alfa-2a plus ribavirin. This analysis explored pharmacokinetics and early viral kinetics (VK) and evaluates differences between groups. METHODOLOGY: Blood samples for pharmacokinetic and VK analyses were collected from 51 patients enrolled in the PROGRESS study. RESULTS: Mean peginterferon alfa-2a trough concentration at week 12 was 11.7+/-4.3 ng/mL for 180 MUg and 23.4+/-11.3 ng/mL for 360 MUg. Early VK profiles suggested a trend towards an enhanced viral decline in the 360 MUg groups with a mean decrease in HCV RNA at 48 hours post first dose of 1.04 log10 (IU/mL) compared with 0.76 log10 (IU/mL) in the 180 MUg groups. Mean beta slope increased with dose, ranging from 0.38+/-0.26 log10 IU/week at 180 MUg to 0.52+/-0.32 log10 IU/week at 360 MUg. CONCLUSIONS: Early viral de clines may be enhanced with the 360 MUg dose. These data may suggest the utility of high-dose peginterfer on alfa-2a plus direct-acting antivirals (DAA) in select difficult-to-treat populations. PMID- 25911860 TI - K-Ras mutation and prognosis of colorectal cancer: a meta-analysis. AB - BACKGROUND/AIMS: Colorectal cancer (CRC) is one of the most common malignant tumors worldwide. Kirsten ras (K-ras) gene is considered to participate in the progression from adenoma to carcinoma of colorectal neoplasms. The correlation between K-ras mutation and the prognosis of CRC is sill controversial. This study aimed at quantitatively summarizing the evidence for such a relationship. METHODOLOGY: The literature search was based on Pub Med. Population-based and hospital-based case-control studies concerning K-ras mutation and prognosis were eligible for analysis. RESULTS: 13 literatures were included in the meta analysis, with 1 multicenter study and 12 case control studies. Totally, 3771 patients were enrolled in the analysis, 1202 of which had K-ras mutation. There were significant difference between the survival of patients with normal and mutated K-ras gene, but no statistic differences were found between either Condon 12 or Condon 13 mutations and prognosis. CONCLUSION: Current available evidences demonstrated the K-ras mutation is a predictive molecular mark of colorectal cancer patients' survivals, further studies are needed to investigate the race difference and the relationship between certain K-ras mutation and prognosis. PMID- 25911861 TI - Clinicopathological risk factors of early carcinoma in colorectal neoplasias according to Japanese and Western criteria. AB - BACKGROUND AND AIMS: There are discrepancies in the classification of early carcinoma in colorectal neoplasia between Japanese and Western criteria. However, no studies have investigated the clinicopathological risk factors associated with early carcinoma according to these criteria. METHODOLOGY: We compared the clinicopathological risk factors of early carcinoma with those of dysplasia, and used multivariate analysis to elucidate the independent risk factors associated with early carcinoma. Lesions with severe cytologic or architectural changes confined to the mucosa are classified as carcinoma in Japanese criteria and as high grade dysplasia (HGD) in Western criteria. RESULTS: Pathologically, 625 total patients were diagnosed with low grade dysplasia (n=321), HGD (n=244), intramucosal carcinoma (n=35) or submucosal carcinoma (n=25). In multivariate analysis, age, large lesion size, and non-polypoid appearance were associated with carcinoma in Japanese criteria; however, only large lesion size was associated with carcinoma in Western criteria. The clinicopathological characteristics of intramucosal carcinoma were similar to those of submucosal carcinoma rather than HGD. CONCLUSIONS: The clinicopathological characteristics for early carcinoma were not identical between Japanese and Western criteria. Japanese criteria classifying intramucosal carcinoma as carcinoma rather than HGD may be supported by our findings. PMID- 25911862 TI - Nutritional management of anastomotic leakage after colorectal cancer surgery using elemental diet jelly. AB - BACKGROUND/AIMS: Anastomotic leakage is major complication of colorectal surgery. Total parenteral nutrition (TPN) and fasting are conservative treatments for leakage in the absence of peritonitis in Japan. Elemental diet (ED) jelly is a completely digested formula and is easily absorbed without secretion of digestive juices. The purpose of this study was to assess the safety of ED jelly in management of anastomotic leakage. METHODOLOGY: Six hundred and two patients who underwent elective surgery for left side colorectal cancer from January 2008 to December 2011 were included in the study. Pelvic drainage was performed for all patients. Sixty-three (10.5%) patients were diagnosed with an anastomotic leakage, and of these, 31 (5.2%) without diverting stoma were enrolled in this study. RESULTS: Sixteen patients received TPN (TPN group) and 15 patients received ED jelly (ED group). The duration of intravenous infusion was significantly shorter in the ED group than in the TPN group (15 days versus 25 days, P= 0.008). In the TPN group, catheter infection was occurred in 2 patients who required re-insertion of the catheter. CONCLUSION: Conservative management of anastomotic leakage after colorectal surgery with ED jelly appears to be a safe and useful approach. PMID- 25911863 TI - Comparison of short- and long-term outcomes of an early experience with robotic and laparoscopic-assisted resection for rectal cancer. AB - BACKGROUND/AIMS: Robotic surgery is increasingly used for rectal cancer. We compared the short- and long-term outcomes between robotic- and laparoscopic assisted resection for rectal cancer. METHODOLOGY: A retrospective chart review was performed between 2006 and 2010. RESULTS: Seventeen robotic and 61 laparoscopic surgeries were performed consecutively. Median follow-up time was 58.2 months. No operation was converted to open surgery. No difference was observed between the groups for types of operations, diverting ileostomy rate, operation time, blood loss, and postoperative hospital stay, tumor diameter, distal margin, circumferential margin, tumor stage, differentiation, lymphovascular, or perineural invasion. However, the number of harvested lymph nodes was higher in the robot than that in the laparoscopy group (p = 0.017). Overall morbidity and reoperation rates were similar between the groups. The 5-yr overall and disease-free survival rates of all patients were 82.5% and 81.3%, respectively. The 5-yr overall and disease-free survival rates of the robotic and the laparoscopy groups were 94.1% and 79.7% (p = 0.241), and 94.1% and 77.9% (p = 0.159), respectively. CONCLUSIONS: Robot-assisted resection for rectal cancer resulted in harvesting more lymph nodes without increasing morbidity and showed a comparable survival rate, compared with those of laparoscopy. PMID- 25911864 TI - Epidermal growth factor receptor in CRC patients in the era of the RAS. AB - The aim of this study was to investigate EGFR expression patterns and the effect of EGFR expression on stage, prognosis and response to conventional chemotherapy agents other than monoclonal antibodies in CRC patients. This study included 59 metastatic CRC patients. The expression of EGFR was quantified by immunochemistry in biopsy specimens that were obtained before treatment was initiated. The cases were considered to be positive for EGFR if >1% of the tumor cells had complete circumferential membranous staining. The median age of the patients was 54.6 years, and 59% of the patients were male. Twenty-six patients presented with stage IV disease, and the remaining patients developed distant metastasis during follow-up. Fifty-one patients were treated with regimens containing irinotecan. The numbers of patients with EGFR expression in the primary tumors, the metastatic lymph nodes and the normal colonic tissue were 34 (65.4%), 10 (76.9%) and 34 (65.4%) respectively. The initial disease stage and lymph node stage were correlated with EGFR expression (p<0.05). Additionally, EGFR positivity was correlated with a statistically significant reduction in the response rate to chemotherapy, the overall survival (21 vs. 28 months) and the progression-free survival (15 vs. 22 months) in metastatic patiens treated with chemotherapy other than targeted therapies. In conclusion, EGFR expression in correlated with stage in all CRC patients and response to chemotherapy and survival in metastatic CRC patients. PMID- 25911865 TI - The value of single-incision laparoscopic surgery for colorectal cancer: a systematic literature review. AB - BACKGROUND/AIMS: Recently, single-incision laparoscopic colectomy (SILC) for colorectal malignancy is rapidly becoming the central issue for explorers of minimally invasive surgery worldwide. The aim of this systematic review was to establish the safety and efficacy of SILC for colorectal malignancy when implemented by experienced surgeons. METHODOLOGY: PubMed, WHO international trial register and Embase were searched for publications concerning SILC and MLC from 2000 to 2013, with the last search on September 10, 2013. Only pure single incision laparoscopic colonic surgery for malignant disease was included. Primary outcomes were the early postoperative complication profiles of SILC. Secondary outcomes were duration of operation time, blood loss, lymph node yields, conversion rate, distal margin of the resected tumor, and duration of hospital stay. RESULTS: Eight studies involving 547 patients met the inclusion criteria. Compared with multiport laparoscopic colectomy (MLC), SILC has less postoperative complication and bleeding. The conversion, the median lymph node retrieval, proximal margin of the resected tumor and distal margin of the resected tumor for malignant disease achieved with SILC was acceptable. There was no significant reduction in length of hospital stay with SILC. CONCLUSION: SILC is a technically reliable and realistic approach with short-term results similar to those obtained with the MLC procedure. PMID- 25911866 TI - Totally laparoscopic right colectomy: technique description. AB - BACKGROUND/AIMS: Total laparoscopic right colectomy (TLRC) with intracorporeal anastomosis is not widely performed as it requires adequate skills and competence in the use of mechanical linear staplers. Here we describe the technique of TLRC for resection for right colon cancer. METHODOLOGY: We have performed TLRC in a patient for right colon cancer. Technique description of TLRC as well as short term outcomes is reported. RESULTS: A TLRC for the right colon adenocarcinoma has been successfully performed in a male patient. The specimen included 11 lymph nodes, all of which were free of metastasis. CONCLUSIONS: TLRC for right colon cancer was safe and feasible. PMID- 25911867 TI - Mesh erosion causes small bowel obstruction: a rare complication of laparoscopic inguinal hernia repair: case description and review of literature. AB - Transabdominal preperitoneal (TAPP) and total extraperitoneal (TEP) are the two types of laparoscopic repair of the inguinal hernia. The main advantages of laparoscopic repair, as compared to open repair, are a shorter hospital stay and a quicker recovery to normal activities. However, we cannot be overlooked or neglected the complication of laparoscopic inguinal hernia repair although it brings us lots of benefits. We report a case of small bowel obstruction caused by a displaced mesh used for the laparoscopic inguinal hernia repair and review of literature. PMID- 25911868 TI - Is perineural invasion (PN) a determinant of disease free survival in early stage colorectal cancer? AB - BACKGROUND/AIMS: The prognostic importance of perineural invasion (PN) in colorectal cancer (CRC) is unclear. The aim of this study to find out whether the PN was an independent stratification factor of postoperative relapse in curatively resected high-risk stage II & III CRC patients who were treated with adjuvant therapy. METHODOLOGY: Data of patients with high risk stage II & all stage III CRCs treated with adjuvant chemotherapy were retrospectively analyzed. Pathological features of final surgical specimen were noted. Disease-free survival was determined by Kaplan-Meier estimator, with differences determined by multivariate analysis using the Cox multiple hazards model. Results were compared using the log-rank test. RESULTS: PN was found to be positive in 26% in the files of 593 eligible patients. In 21% of the reports PN status was not reported. Presence of PN in the resected primary tumors did not have independent effect on DFS. Further analyses for importance of PN on DFS of colon or rectal cancers did not show any effect. CONCLUSIONS: This study had failed to demonstrate any prognostic effect of PN for DFS in surgically resected stage II and III CRC patients who received adjuvant treatments. PMID- 25911869 TI - Endoscopic excavation for the treatment of small esophageal subepithelial tumors originating from the muscularis propria. AB - BACKGROUND/AIMS: This study was designed to evaluate the safety and efficacy of endoscopic excavation for esophageal subepithelial tumors originating from the muscularis propria. METHODOLOGY: Forty-five patients with esophageal subepithelial tumors originating from the muscularis propria were treated with endoscopic excavation between January 2010 and June 2012. The key steps were: (1) making several dots around the tumor; (2) incising the mucosa along with the marker dots, and then seperating the tumor from the muscularis propria by using a hook knife or an insulated-tip knife; (3) closing the artificial ulcer with clips after the tumor was removed. RESULTS: The mean tumor diameter was 1.1 +/- 0.6 cm. Endoscopic excavation was successfully performed in 43 out of 45 cases (95.6%), the other 2 cases were ligated with nylon rope. During the procedure perforation occurred in 4 (8.9%) patients, who recovered after conservative treatment. No massive bleeding or delayed bleeding occurred. Histologic diagnosis was obtained from 43 (95.6%) patients. Pathological diagnoses of these tumors were leiomyomas (38/43) and gastrointestinal stromal tumors (5/43). CONCLUSIONS: Endoscopic excavation is a safe and effective method for the treatment of small esophageal subepithelial tumors originating from the muscularis propria. PMID- 25911870 TI - Thoracoscopic esophagectomy in prone position: advantages of five ports over four ports. AB - BACKGROUND/AIMS: Thoracoscopic esophagectomy in the prone position (ThE-PP) is usually performed with four ports, which makes the operation almost solo surgery. We now perform ThE-PP with five ports, with the advantage of having the assistant able to provide additional help. The aim of this study was to elucidate the benefits of ThE with five ports over ThE with four ports. METHODOLOGY: We retrospectively reviewed the clinical charts of 47 patients with esophageal cancer who underwent ThE-PP. A total of 14 patients underwent ThE-PP with four ports and 33 with five ports. We compared the number of dissected lymph nodes (LNs)--total; upper left, middle, and lower mediastinum--between the four-port and five-port groups. RESULTS: The number of LNs dissected, including the total, the upper left and middle mediastinum, were not significantly different between the two operations. The number of LNs dissected from the lower mediastinum, however, was significantly higher in the five-port group (median number and interquartile range: 5 and 2-7, respectively) than in the four-port group (0.5 and 0-3, respectively) (P < 0.01). CONCLUSIONS: ThE-PP performed with five ports has an advantage over the same operation done with four ports in terms of lymphadenectomy in the lower mediastinum. PMID- 25911871 TI - Analysis of the characteristics and factors influencing lymph node metastasis in thoracic esophageal carcinoma and cancer of the gastric cardia. AB - BACKGROUND/AIMS: To analyze the metastatic characteristics of lymph nodes in thoracic esophageal carcinoma and cancer of the gastric cardia, and to explore the factors influencing lymph node metastasis. METHODOLOGY: A retrospective analysis of the treatment of 37 patients who received surgical treatment for thoracic esophageal and gastric cardia cancers from January 2010 to January 2012 was carried out, RESULTS: Lymph node metastasis in patients with thoracic esophageal carcinoma was frequently found on the superior mediastinum, hilum of the lung, and inferior extremity of the carina. Metastasis in patients with cancer of the gastric cardia occurred mainly in the abdominal cavity and peripheral gastric cardia. A single factor analysis showed that a tumor infiltrating full-thickness, > 5 cm in length, and with a low degree of cell differentiation affected lymph node metastasis (P < 0.05). The degree of differentiation, length, and infiltrating depth of the tumor were independent factors affecting lymph node metastasis (P < 0.05). CONCLUSIONS: Lymph node metastasis in patients with cancers of the esophagus and gastric cardia exhibits special characteristics. The cleaning scope should be assessed according to the actual situation, including the degree of tumor differentiation, lesion length, and infiltration depth. PMID- 25911873 TI - Peroral endoscopic myotomy plus balloon shaping for achalasia: a preliminary study. AB - BACKGROUND/AIMS: To determine the efficacy and safety of circular muscle myotomy plus balloon shaping for achalasia patients. METHODOLOGY: Peroral endoscopic myotomy plus balloon shaping was performed in 34 patients prospectively. Treatment success, changes in manometry outcomes and in body weight before and after myotomy, complications related to the procedure and reflux symptoms after procedure were analyzed. RESULTS: Treatment success was achieved in 97% (33/34) of cases at three months after treatment (mean score pre- vs. post-treatment 7.68 vs 0.82; P<0.001) and treatment success rate at 6 and 12 months was 94% (31/33) and 95% (19/20) respectively. Mean lower esophageal sphincter residual pressure was 25.14 mmHg pre-treatment and 10.72 mmHg post-treatment (P<0.001), with 88% (22/25) of patients' postoperative lower esophageal sphincter pressure restored to normal. The post-treatment average body weight of 34 patients was significantly higher than before (64.56 kg vs 60.04 kg, P<0.001). The overall rate of complications related to the procedure was 14.71%. 26.47% of patients developed symptoms of gastroesophageal reflux after procedure. CONCLUSIONS: Peroral endoscopic myotomy plus balloon shaping is an effective treatment for achalasia resulting in sustained treatment success of about 95% during a mean follow-up period of 13.3 months. PMID- 25911872 TI - Treatment of massive esophageal variceal bleeding by Sengstaken-Blackmore tube compression and intensive endoscopic detachable mini- loop ligation: a retrospective study in 83 patients. AB - BACKGROUND/AIMS: To evaluate the effectiveness of improved sengstaken-blackmore tube combined with intensive endoscopic detachable mini-loop ligation for the treatment of massive esophageal variceal bleeding (EVB). METHODOLOGY: Eighty three patients diagnosed with massive EVB and admitted from January 2005 to July 2011 were retrospectively evaluated. Upon admission, all patients received 12 h balloon tamponade with sengstaken-blackmore tube in addition to conventional therapy (blood volume resuscitation, prophylactic antibiotics and somatostatin). Within 24 h after admission, all patients further received endoscopic variceal ligation (EVL) with intensive endoscopic detachable nylon ring (mini-loop). RESULTS: No severe complications were observed after the patients received the 12 h consistent compression with sengstaken-blackmore tube. Eighty-two patients (98.8%) showed effective hemostasis, among which seventy-eight showed complete hemostasis. After receiving the subsequent EVL therapy with intensive endoscopic detachable mini-loop in 24 h after admission, patients did not show active bleeding in 24 h after EVL. Rehaemorrhagia appeared only in one patient within the 7 days of observation period, which was controlled by a second EVL. Each patient was ligated with 10 to 15 loops. CONCLUSIONS: EVB can be effectively treated with improved sengstaken-blackmore tube followed by EVL therapy with intensive endoscopic detachable mini-loop. PMID- 25911874 TI - Surgery of upper GI gastrointestinal stromal tumors: our experience, prognostic analysis. AB - BACKGROUND/AIMS: To review our treatment experience of gastrointestinal stromal tumors (GISTs) of the upper gastrointestinal tract and identify the prognostic factors that influence tumor recurrence. METHODOLOGY: Data of 46 consecutive patients with upper GI GISTs who underwent surgery from 1988 to 2011 were reviewed. The overall and disease-free survival rates and influence of clinicopathologic variables on disease-free survival rate were evaluated. RESULTS: The median age was 64 years (range, 20-86 years). R0 resections were performed in 43 (93.5%) patients. With a median follow-up time of 33 months (1 275 months), there were 5 (10.9%) recurrences and 2 mortalities in the high-risk group. The overall survival and recurrence-free survival rates at 5 years were 92.1% and 84.6%, respectively. Male gender, tumor size of >10 cm, high numbers of mitotic figures, R1 resection, high risk according to the Joensuu criteria, and a Ki-67 index of >10% were associated with a poor prognosis. CONCLUSIONS: Surgical resection of low- and intermediate-risk GISTs has excellent results. High counts of mitotic figures, male gender, incomplete resection, large tumor size, and a high Ki-67 index are associated with a poor prognosis. PMID- 25911875 TI - Living donor right lobe liver transplantation as a treatment for hepatic alveolar echinococcosis: report of three cases. AB - Echinococcus alveolaris is a parasite from tenia family which causes tumor-like lesions in the livers of infected people. If it is not diagnosed in the early stage of the disease, it frequently causes multiple cysts in the liver. The clinical importance of the disease is rapid progression, infiltration into different tissues like a malignant tumor and capacity of creating metastatic masses. The disease could be treated either by surgical resection or liver transplantation. The resection of the cystic disease is the preferred treatment method. In cases where resection is not possible, liver transplantation is the choice of treatment. Here we present three cases which were admitted to the hospital with unresectable hepatic alveolar echinococcosis and treated by liver transplantation successfully. Patients for whom surgical resection is not possible, we recommend liver transplantation as the treatment method. PMID- 25911876 TI - Importance of thrombocytes for the hypertrophy response after portal vein embolization. AB - BACKGROUND/AIMS: Thrombocytes have proved to be important for liver regeneration after liver resection in the experimental setting. The aim of our study is to examine the effects of thrombocytes on liver hypertrophy after portal vein embolization (PVE). METHODOLOGY: This retrospective cohort study comprised 75 patients with liver metastases from colorectal cancer subjected to PVE in preparation for major liver resection. Patients were divided into 2 groups depending on if chemotherapy was given within 6 weeks before PVE or not. RESULTS: The chemotherapy group showed lower levels of thrombocytes (p=0.003) and lower degree of hypertrophy (p=0.030) as compared to the group without chemotherapy. No correlation within groups between level of thrombocytes and degree of hypertrophy was found. However, in the chemotherapy group, a positive linear correlation between the degree of hypertrophy and the difference in thrombocytes between the time points of PVE and 2 months preceding PVE was found (p=0.0006). DISCUSSION: Preprocedural chemotherapy results in decreased hypertrophy of the liver after PVE and lower levels of thrombocytes at the time for PVE. The absolute number of thrombocytes does not influence liver regeneration after PVE. For patients receiving preprocedural chemotherapy, PVE performed at a time when thrombocytes are decreasing is associated with a reduced regeneration. PMID- 25911878 TI - Fate of necrotic volume after microwave ablation of multiple liver metastases. AB - BACKGROUND/AIMS: The aim of this study was to find the rate of shrinkage of necrosis and time of peak ablation volume after multiple microwave ablations in the treatment of multiple liver metastases of colorectal cancer. These factors are not known and are important in evaluation of treatment and identification of local recurrence, as microwave treatment is becoming more used thanks to improved technology in diagnostics and interventional therapy. METHODOLOGY: A retrospective analysis of non-cirrhotic patients with multiple liver only metastases of colorectal cancer, not suited for resection for this reason. Patients were selected for palliative microwave treatment at a liver multidisciplinary team conference. 68 ablations were made in six patients. Ablation volume was analysed with repeated imaging and computer analyses. RESULTS: The ablation volume peeks after 5-7 days where after reduction of the necrosis in the liver occurs logarithmically with a 60% reduction of ablation volume after 100 days and 80% after a year. DISCUSSION: Liver regeneration after microwave ablations occurs at a constant logarithmic rate after an initial expansion of the ablation volume during the first five days. Evaluation of ablation volume in comparison to tumour volume must take this into account so that follow-up imaging is properly timed. PMID- 25911877 TI - External beam radiation therapy with or without concurrent chemotherapy for patients with unresectable locally advanced hilar cholangiocarcinoma. AB - BACKGROUND/AIMS: To evaluate the efficacy of concurrent chemoradiotherapy (CCRT) compared to radiotherapy (RT) for unresectable, locally advanced hilar cholangiocarcinoma (HCCA). METHODOLOGY: Between 2001 and 2010, 34 patients with unresectable locally advanced HCCA at our institute were reviewed. Eighteen patients received RT and 16 patients received CCRT. Survivals and multivariate analyses were performed to explore potential variables affecting survivals. RESULTS: There were 18 males and 16 females, with a median age of 72 years and median follow-up time 9.4 months. The median overall survival (OS) was 10.4 months (95% CI, 6.7-13.5) with the 1-year survival rates of 41%. The median OS and progression-free survival (PFS) were 13.5 months and 8.8 months for patients receiving CCRT as compared to 6.7 months and 4.4 months for patients receiving RT alone (p = 0.003 and p = 0.005, respectively). On multivariate analysis demonstrated that Karnofsky performance status (KPS) >= 80 (p = 0.001), pretreatment carbohydrate antigen 19-9 (CA 19-9) 200 U/ml (p = 0.045) and CCRT were prognostic factors for OS and PFS. CONCLUSIONS: As compared with RT, CCRT provides longer OS and PFS for patients with unresectable HCCA. The efficacy of adding novel chemotherapeutic to RT needs to be further investigated. PMID- 25911879 TI - A new strategy with a grading system for liver metastases from colorectal cancer. AB - BACKGROUND/AIMS: The optimal indications, including timing, for resection of liver metastases from colorectal cancer (CRCLM) remain controversial. The Japanese Society of Cancer of the Colon and Rectum has proposed "H classification" based on the maximum size and number of CRCLM, and has advocated the "CRCLM-grade system", which involves adding the presence of primary lymph node metastasis status to H-classification. We evaluated clinicopathological factors in order to elucidate the optimal indications for and timing of hepatectomy. METHODOLOGY: Ninety-six patients who underwent initial hepatectomy for CRCLM between August 1995 and May 2009 were retrospectively analyzed with respect to characteristics of primary colorectal metastatic hepatic tumors, operation details and prognosis. RESULTS: Multivariate analysis identified depth of invasion in primary colorectal cancer (within sub-serosal (non-se) vs. beyond serosal (se)) and CRCLM-grade as independent risk factors. We then performed analyses using the combination of non-se/se and CRCLM-grade. Kaplan-Meier analysis identified significant differences between non-se+gradeA and se+gradeA, between non-se+gradeB and se+gradeB, and between non-se+gradeC and se+gradeC groups. CONCLUSIONS: We could retrospectively predict survival in CRCLM patients by adopting this new simple classification. This method may allow more precise assessment of operative indications and timing for both operations and perioperative adjuvant treatment. PMID- 25911880 TI - Incidence and mortality of liver cancer in mainland China: changes in first decade of 21st century. AB - BACKGROUND/AIMS: To longitudinally analyze changes of primary liver cancer incidence and mortality in mainland China during the first decade of 21st century. METHODOLOGY: Available data of crude incidence and mortality of primary liver cancer from annual reports of the National Central Cancer Registry in mainland China were retrieved and analyzed. RESULTS: Either the incidence or mortality of primary liver cancer in mainland China kept increasing and didn't reach peaks during the first decade of the 21st century, particularly among the female population with great incremental rates of incidence (8.76%) and mortality (11.99%) at 2007-2008 and 2009-2010, respectively. The crude incidence increased from 26.18/100,000 persons at 2004 to 29.00/100,000 persons at 2010, while the crude mortality from 25.08/100,000 persons to 28.10/100,000 persons (r=0.857, p=0.014). The incidence and mortality in males kept 2.5-2.9 folds to those in females. The incidence and mortality in rural region were always higher than those in urban regions, but among males both tended to decline in rural region, while in contrast increased in urban region. CONCLUSIONS: Liver cancer still has high incidence and mortality in mainland China, and further effort is required to prevent and control liver cancer, particularly for male and rural population. PMID- 25911881 TI - Prophylactic hepatic artery infusion chemotherapy improved survival after curative resection in patients with hepatocellular carcinoma. AB - BACKGROUND/AIMS: To explore the effect of prophylactic hepatic artery infusion chemotherapy (HAIC) on survival probability after curative resection in patients with hepatocellular carcinoma (HCC). METHODOLOGY: 85 patients with HCC were randomly assigned to HAIC group (42 cases) and control group (43 patients), all the database of two groups had no significant difference. Patients in HAIC groups underwent hepatic artery infusion chemotherapy (5-FU 1000 mg/m2 on day 1, Oxaliplatin 85 mg/m2 on day 1 and Gemcitabine 1000 mg/m2 on day 1 and 8) starting 3 weeks after operation with intervals of 4 weeks. All patients were followed up for 3 years and intrahepatic recurrence-free survival, disease-free survival rate and overall survival rate were recorded. RESULTS: Intrahepatic recurrence rate of HAIC group and the control group was respectively 19.05% and 39.53%, P < 0.05. Disease-free survival rate was respectively 57.14% and 44.19%, P < 0.05. Overall survival rate was 66.67% and 46.51%, P < 0.05. All patients in HAIC group tolerated the therapy. No adverse effect above grade 3 was reported in HAIC group. CONCLUSION: HAIC effectively and safely prevents intrahepatic recurrence and improves the prognosis of patients with HCC after curative resection. PMID- 25911882 TI - Experimental study on the safety of percutaneous transhepatic portal vein ablation. AB - BACKGROUND/AIMS: Portal vein tumor thrombus (PVTT) is a common complication of hepatocellular carcinoma (HCC) with poor prognosis. Radiofrequency ablation (RFA) has been used for PVTT, however, its safety remains unclear. In this study, we have evaluated the safety of percutaneous transhepatic RFA of pigs' normal portal vein (PV). METHODOLOGY: RFA was conducted in miniature pigs either by local direct ablation (group A, n=6), or after occlusion by balloon or by thrombus (group B, n=4). The MRI imaging and pathological changes of PV were recorded after operation. RESULTS: RFA was successful in 4 of 6 pigs in group A and 3 of 4 pigs in group B. One pig (P4) died one day after RFA in group A. P1 showed a significantly increased thrombus in peritoneal cavity in contrast to another survived pig (P2) with inflammatory edema, but no obvious abnormalities were observed in the other two pigs (P1 and P3) in Group A. But in Group B, the range of PV lesion was larger than that in Group A with thrombus in lumens, and even inflammatory edema range increased significantly 3 weeks later. CONCLUSION: The percutaneous intravascular RFA using an endovascular bipolar RF device is technically feasible but the safety needs further investigation. PMID- 25911883 TI - Interferon-alpha combined with lamivudine versus lamivudine monotherapy for the emergence of YMDD mutations in chronic hepatitis B infection: a meta-analysis of randomized controlled trials. AB - BACKGROUND/AIMS: Tyrosine-methionine-aspartate-aspartate (YMDD) mutations were the main limitation of lamivudine (LAM) for treating chronic hepatitis B (CHB). The aim of this study was to evaluate whether LAM combined with IFN-alpha offer advantage over lamivudine monotherapy for the occurrence of YMDD mutations in CHB using a meta-analysis. METHODOLOGY: We searched electronic databases and calculated the odds ratios (OR) with their 95% confidence intervals (CI) and pooled the results. RESULTS: Our meta-analysis indicated that the difference of YMDD mutation rates between the combination therapy of IFN-alpha2b, IFN-alpha2a and Peg-IFN-alpha2a respectively plus LAM and LAM monotherapy (95% CI, 3.25-9.70, 95% CI, 5.77-17.51, 95% CI, 6.79-26.13, respectively). The rate of YMDD mutations in LAM monotherapy was increased when compared with combination and sequential combination group (95% CI, 6.79-22.16, and 95% CI, 2.69-7.75, respectively). The YMDD mutation rate in combination therapy was lower than that of LAM monotherapy in HBeAg positive patients (95% CI, 4.98-13.23). CONCLUSIONS: Our present meta analysis suggests that different types of IFN-a in combination with LAM can significantly reduce the rate of YMDD mutation compared to LAM monotherapy. PMID- 25911884 TI - High intensity focused ultrasound ablation for patients with inoperable liver cancer. AB - BACKGROUND/AIMS: To analyses the feasibility and efficacy of high intensity focused ultrasound (HIFU) treatment in patients with inoperable liver cancer. METHODOLOGY: 187 patients were treated with HIFU, of all these patients 116 cases were Primary Liver Cancer (PLC) and 71 cases were Metastatic Liver Cancer (MLC). According to some parameters, such as clinical symptoms, the basis of main organs functional tests, imaging examinations, and progression-free survival (PFS) time to assess the safety and efficacy of HIFU in the treatment of liver cancer. RESULTS: 55 patients (29.4%) achieved CR and 73 patients (39.0%) achieved PR, 32 patients (17.1%) had responses of SD, and 27 patients (14.4%) were PD, respectively. Response rates were 90.5% (32 CR + 6 PR/42) in left lobe cancer and 64.1% (22 CR + 62 PR/131) in right lobe cancer. The median PFS for those CR case was 7 months, of PLC was 8 months, of MLC was 5 months. CONCLUSIONS: HIFU is effective and feasible in the treatment of liver cancer. It offer a significant noninvasive therapy for local treatment of liver cancer. For those right lobe liver cancers or with poor ultrasonic window, increasing treatment time or repeated treatment may improve the efficiency of HIFU ablation. PMID- 25911885 TI - Comparison of effects of devascularization versus shunt on patients with portal hypertension: a meta-analysis. AB - BACKGROUND/AIMS: To systematically evaluate the effectiveness of devascularization and shunt on patients with portal hypertension. METHODOLOGY: Relevant studies compared devascularization and shunt for the treatment of portal hypertension were identified searching the PubMed, Embase, Elsevier, CNKI (China National Knowledge Infrastructure) database and Cochrane Trial Register searches until December 2013. Data of interest for devascularization and shunt including postoperative recurrent bleeding, postoperative hepatic encephalopathy, ascites, operative mortality rate, and long term survival rate were subjected to meta analysis. RESULTS: Eleven studies were included in the study, the results of the meta-analysis showed that all eleven clinical studies demonstrated a significantly higher postoperative recurrent bleeding rate with devascularization group than with shunt group, the rate of hepatic encephalopathy in the devascularization group was significantly lower compared with the shunt group. CONCLUSION: Devascularization and shunt have different advantages and disadvantages respectively which reflected in postoperative complications and long term survival rate. PMID- 25911886 TI - A correlation between the graft volume evaluation and the prognosis in consideration of hepatic "compliance" in living donor liver transplantation. AB - BACKGROUND/AIMS: The aim is to clarify the correlation between the hepatic compliance and prognosis of the patients who underwent LDLT. METHODOLOGY: Volumetry was performed using a 3D volume analyzer. The hepatic compliance was evaluated based on the difference between the estimated total liver volume in the arterial phase and venous phase (n=66). The correlations among the hepatic compliance, donor background factors and the recipient's prognosis were evaluated. RESULTS: Fourteen cases (21%) presented with a more than 5% increase in volume during the venous phase than in the arterial phase, and 12 of these recipients were still alive. There was a significant increase in death among recipients from donors age 60 years old and older (5/7, 71.4%, p<0.01). In these cases, the hepatic compliance was significantly different between the deceased cases and the surviving cases; while there was no hepatic compliance in the five deceased cases, favorable hepatic compliance was observed in two of the surviving cases (p<0.01). CONCLUSIONS: Hepatic compliance appears to exist. The poor prognosis of liver grafts in recipients from elderly donors may be attributable to hepatic compliance, and assessing the hepatic compliance may be useful for preoperative liver graft evaluation. PMID- 25911887 TI - Surgical treatment of huge hepatocarcinoma with invasion or severe adhesion of diaphragm using the technique of orthotopic liver resection. AB - BACKGROUND/AIMS: To explore the clinical application and significance of the technique of orthotopic liver resection. METHODOLOGY: From January 2004 to December 2011, five patients with huge hepatocellular carcinoma with invasion or severe adhesion of diaphragm were undergone right semi-liver resection using the technique of orthotopic liver resection. The right hemi-liver was isolated from the first liver portal, second liver portal and third liver portal, then isolated from the normal liver, finally the tumor and the invaded diaphragm were resected or removed from the severe adhesion. The approach to hepatic resection involved routine use of Peng's multifunctional operative dissector, selective control of in and out-flow of liver, control of inferior vena cava (IVC) and liver hanging maneuver, anterior approach, etc. RESULTS: The operations were successfully performed in 5 patients. Operative time was 120, 180, 150, 150 and 160 min, respectively. The amount of blood loss were 350, 350, 400, 450, 600 ml, respectively. Postoperative complications were pleural effusion in 3 cases, and other 2 cases recovered without complications. CONCLUSIONS: Although the technique of orthotopic liver resection has a high technical requirement for surgeons, it provides a surgical method and operative opportunity for the patients whose tumor has invaded diaphragm or has been severe adhesion with diaphragm and conventional liver resection cannot be performed. PMID- 25911888 TI - Effect of sustained virological response to interferon therapy for hepatitis C to the hepatectomy for primary hepatocellular carcinoma. AB - BACKGROUND/AIMS: Interferon (IFN) therapy improves the prognosis of the patients with HCV-related hepatocellular carcinoma (HCC). However, the effects of IFN therapy for hepatectomy (Hx) for primary HCC have not been established. Several published reports investigating the effects of IFN therapy on survival and tumor recurrence after curative resection of HCC have been inconclusive. METHODOLOGY: Subjects included 470 patients who underwent Hx for HCV related primary HCC. One hundred and fifty nine patients received IFN therapy past or postoperatively of the first Hx. Seventy-four of those patients attained a sustained viral response (SVR group). The other 396 patients, including 85 were no responders (NR) and 311 patients who had not received IFN therapy (non-IFN) were classified as the control group. RESULTS: Overall survival (SVR group vs. control group: 5-yr, 93.2 vs. 61.9%; p<0.0001) and disease-free survival (SVR group vs. control group: 5 yr, 56.0 vs. 27.4%; p<0.0001) rates were significantly different. By multivariate analysis, NR/non-IFN was the independent risk factor for overall survival (p=0.0002) and disease-free survival (p=0.0053) after Hx. CONCLUSIONS: SVR achieved past or postoperatively to the Hx of HCV-related HCC significantly inhibits recurrence and consequently improves patient survival after Hx for HCC. PMID- 25911889 TI - Predictors of poor prognosis by recurrence patterns after curative hepatectomy for hepatocellular carcinoma in Child-Pugh classification A. AB - BACKGROUND/AIMS: The prevention of recurrence is important for improving long term outcome for HCC. To identify candidates for postoperative adjuvant therapy after curative hepatectomy for HCC in Child-Pugh classification A (Child A). METHODOLOGY: Of 157 patients who underwent initial hepatectomy for Child A HCC, 93 had recurrence and were divided into 2 groups: group A, <=2 tumors, each <3 cm in size at the time of intrahepatic recurrence; group B, >=3 tumors or tumor >=3 cm in size at the time of intrahepatic recurrence and/or extrahepatic recurrence. Clinicopathological and survival data were analyzed retrospectively in each group to identify poor prognostic factors. RESULTS: The 1-year recurrence rate was 50%, and the time to recurrence was shorter in group B (10 months) than in group A (20 months) Overall 1-, 3-, and 5-year survival rates were poorer in group B (83%, 52%, and 35% respectively; p < 0.001) than in group A (100%, 96%, and 71% respectively) Cancer spread (vascular invasion and/or intrahepatic metastasis) was significantly affecting the recurrence pattern of Group B (p=0.0238) on multivariate analysis. CONCLUSIONS: Systemic adjuvant chemotherapy af ter curative hepatectomy for HCC in Child A should be given to patients with microscopic vascular invasion and/or intrahepatic metastasis. PMID- 25911890 TI - Adjuvant S-1 chemotherapy after surgical resection for pancreatic adenocarcinoma. AB - BACKGROUND/AIMS: The aim of this study was determine the effectiveness of adjuvant S-1 chemotherapy for patients with resected pancreatic cancer. METHODOLOGY: Patients with pancreatic carcinoma who underwent pancreatic resection without adjuvant S-1 chemotherapy (n = 11) or with adjuvant S-1 chemotherapy (n = 10) were included. S-1 was administered orally at a dose of 40 mg/m2 twice daily for 28 consecutive days followed by a 14-day pause. The cycle was repeated 4 times. Overall and disease-free survival curves were generated using the Kaplan-Meier method, and statistical differences between groups were analyzed using the log-rank test. RESULTS: The disease-free survival and overall survival were longer among recipients of adjuvant S-1 chemotherapy than among those who received surgery alone (P < 0.05; 5-year disease-free survival rate, 30% versus 0%; 5-year overall survival rate, 65% vs 0%). Although dose reduction was needed in 2 patients because of grade 2 anorexia, only 1 patient with grade 2 hypoalbuminemia discontinued adjuvant chemotherapy because of long-term hospitalization. CONCLUSIONS: S-1 administered as a single agent showed promise as an adjuvant chemotherapy for resected pancreatic cancer. PMID- 25911891 TI - Pancreaticoduodenectomy for choledochal cyst. AB - BACKGROUND/AIMS: Choledochal cyst (CDC) is a rare congenital cystic dilatation of the biliary system that can affect children and adults. Standard treatment for CDC includes surgical excision of the cystic bile duct with restoration of bilioenteric continuity by Roux-en-Y hepaticojejunostomy. In rare situations, however, surgical excision of a CDC may require pancreaticoduodenectomy (PD). The goal of this study was to identify instances where a PD may be deemed necessary. METHODOLOGY: We retrospectively reviewed the medical records of all patients treated for CDC at our institution from January 1988 through December 2011. From this cohort, patients who underwent PD were reviewed in detail. Data on preoperative parameters, operative details, cyst type, pathologic diagnosis, and postoperative course were collected. RESULTS: During the 24-year period, 59 patients with CDC were identified and four (7%) underwent formal PD. Final pathology revealed that none of the resected specimens harbored malignancy and all patients are well at follow-up. CONCLUSION: While the standard surgical care for CDC remains complete cyst excision with Roux-en-Y hepaticojejunostomy, there may be particular instances where PD appears more appropriate. While the need for PD in cases of CDC is rare, it is important to consider this possibility when contemplating surgery for CDC. PMID- 25911892 TI - Clinical characteristics and prognostic factors of gastroenteropancreatic neuroendocrine tumors: a single center experience in China. AB - BACKGROUND/AIMS: Gastroenteropancreatic neuroendocrine tumors (GEP-NETs) are a unique subgroup of tumors in the digestive system but with great clinical heterogeneity. The information on clinical characteristics and prognostic factors of Chinese patients is rather limited. METHODOLOGY: We retrospectively analyzed the clinical features, prognostic factors of this disease in a consecutive cohort (N=294) between January 2007 and December 2012. RESULTS: Functioning tumors accounted for 9.2%. Rectum was the most predominant GEP-NETs locations. Abdominal pain occurred in 46.5% patients which was the most common initial symptom. G1, G2 and G3 tumors accounted for 41.5%, 34.7% and 23.8%, respectively. Endoscopy provided the highest detection rate of 95.7%. Consistence between endoscopic ultrasound guided fine needle aspiration biopsy (EUS-FNAB) and surgically obtained histological Ki-67 index was 36.4%. Serum CgA test showed a 80.0% consistence with the tissue biopsy. The median follow up duration was 2.8 years (0.02-5.90 years), the median survival was 4.8 years, overall 5-year survival rate was 69.6%. We found colonic localization, tumor size larger than 20 mm, G3 tumor and metastasis were associated with worse outcome (p<0.05). CONCLUSION: We found both consistence and differences in GEP-NETs characteristics between our study and previous reports. PMID- 25911893 TI - A simple, secure and universal two-layer continuous running suture pancreaticojejunostomy following pancreaticoduodenectomy. AB - Pancreatic fistula is a leading cause of morbidity and mortality after pancreaticoduodenectomy. We introduce here a simple, secure and universal technique for pancreaticojejunostomy with a two-layer continuous running suture. We also report on the preliminary results for grades of pancreatic fistulas among patients who underwent this new technique. 51 consecutive cases were successfully performed using this new technique during pancreaticoduodenectomy. The overall morbidity was 29.4%. Only 3 (5.9%) grade B pancreatic fistulas were observed postoperatively, and were successfully treated with conservative management. The time taken to create the pancreatic anastomosis was less than 15 minutes in all cases. In conclusion, this novel pancreatic anastomosis technique is easy and quick to perform, universally applicable, and appears to be a secure technique that reduces pancreatic fistula rates after pancreaticoduodenectomy. PMID- 25911894 TI - Preventive effect of omental flap in pancreaticoduodenectomy against postoperative complications: a meta-analysis. AB - BACKGROUND/AIMS: To systematically determine the effect of omental flap in pancreaticoduodenectomy against postoperative complication through metaanalysis of published studies. METHODOLOGY: Thorough literature search in Ovid-MEDLINE and EMBASE databases was conducted to identify studies whether the use of Omental Flap to prevent postoperative complications. Review of 14 article candidates, identified 4 eligible articles with a total of 2971 patients for meta-analysis. Dichotomous data regarding distinction between omental roll-up and nonmental roll up were pooled using random effects model to obtain the diagnostic odds ratios and their 95% confidence intervals (CIs). RESULTS: 1129 patients in omental roll up group, 1842 patients in nonomental group. Omental roll-up during pancreaticoduodenectomy could not prevent postoperative pancreatic fistula (OR=0.81, 95%CI 0.40-1.63, P=0.56). it also could not prevent postoperative intra abdominal bleeding (OR=0.67, 95%CI 0.28-1.59, P=0.37). We use the sensitivity analysis which found The pancreatic fistula was lower in the nonomental roll-up group than in the omental roll-up group (OR=1.24, 95%CI 1.03-1.50, P=0.02). CONCLUSIONS: The use of omental roll-up could not decrease the risk of pancreatic fistula after pancreaticoduodenectomy. Further randomized controlled trials are needed to identify the effect of omental roll-up technique for pancreaticoduodenectomy. PMID- 25911895 TI - Remnant pancreas reconstruction with duct-to-duct anastomosis after middle pancreatectomy: a report of two cases. AB - Reconstruction of a remnant pancreas after middle pancreatectomy has generally been performed with a pancreaticoenterostomy. We report here two cases in which physiological reconstructive procedures were performed. The reconstructive procedures included pancreatic duct-to-duct anastomosis and parenchymal sutures with absorbable monofilament interrupted stitches. A pancreatic tube was inserted for decompression at the anastomotic site in both cases. The patients comprised one with pancreatic metastasis from renal cell carcinoma and another with a non malignant insulinoma. The tumors were located in the pancreatic body. Although an International Study Group on Pancreatic Fistula classification grade B-pancreatic fistula was observed in each patient, they both resolved with conservative therapy. The pancreatic duct at the anastomosis site was patent in both cases, and no atrophic changes developed in the remnant pancreas in either patient. These outcomes confirmed that, in selected cases, this reconstructive procedure is safe and feasible for physiological reconstruction without involvement of the digestive tract. PMID- 25911896 TI - Conservative treatment and percutaneous catheter drainage improve outcome of necrotizing pancreatitis. AB - BACKGROUND/AIMS: To investigate the clinical effects of the maximum conservative treatment algorithm with percutaneous catheter drainage (PCD) as the first choice for necrotizing pancreatitis (NP). METHODOLOGY: Retrospectively analyzed NP patients who had fine needle aspiration (FNA) for proven infection of necrosis which was considered an indication for surgery (n=22, group 1) compared to patients subjected to maximum conservative treatment with PCD in NP patients (n=30, group 2). RESULTS: On admission, most baseline data did not show any statistical difference between the two groups, In group 2, all patients were implemented maximum conservative treatment, 25 of 30 patients were cured by PCD (83.3%), open necrosectomy were needed for 3 patients (10.0%) and 2 dead during hospitalization (6.7%). Whereas, in group 1, surgical operation rate was 45.6% and hospital mortality 31.8%, both of the ratios differed significantly compared with group 2 (45.6% vs. 10%, P=0.004; 31.8% vs. 6.7%, P=0.046 respectively). Furthemore, Hospital stay were significantly higher in group 1 compared with group 2 (90+/-18.5 vs. 39+/-13.4; P=0.033). CONCLUSIONS: A conservative approach with PCD as the first choice to treatment NP might decrease the rate of surgical operation and mortality, and improve the outcome of NP. PMID- 25911897 TI - Clinical implication of peritoneal cytology in the pancreatic cancer patients who underwent curative resection followed by adjuvant gemcitabine or S-1 chemotherapy. AB - BACKGROUND/AIMS: The clinical implications of peritoneal lavage cytology (CY) status in the patients who received curative resection and adjuvant chemotherapy have not been established. METHODOLOGY: We retrospectively analyzed clinical data from 143 consecutive patients who underwent macroscopically curative resection and received adjuvant gemcitabine or S-1 chemotherapy for pancreatic cancer from 2005 to 2014 in our institution. Correlations between CY status and survival and clinicopathological features were investigated. RESULTS: Of the 143 patients, 21 patients were peritoneal washing cytology positive (CY+) (14.7%). Although significant difference was observed in the tumor size, no other correlation between cytology status and clinicopathological parameter existed. The recurrence free survival (RFS) rates at 3 and 5 years after surgery were 5.1% and 0% in CY+ patients, respectively, and were 21.5% and 16.1% in peritoneal washing cytology negative (CY-) patients, respectively, which were significantly different (p=0.001). The OS rates at 3 and 5 years after surgery were 17.1% and 8.6% in CY+ patients, respectively, and were 26.1% and 16.1% in CY- patients, respectively, which were trend to worse in the CY+ patients (p=0.254). CONCLUSION: The patients with CY+ are likely to experience recurrence, even after they received curative resection and adjuvant Gemcitabine or S-1 adjuvant chemotherapy. PMID- 25911898 TI - A preliminary study on pre-operative tumor volumetry measured by three dimensional computer tomography in gastric cancer. AB - BACKGROUND/AIMS: The aim of the present study was to evaluate the clinical significance of tumor volumetry measured by three-dimensional (3-D) multidetector row computed tomography (MD-CT). METHODOLOGY: A total of 50 patients with gastric cancer who had undergone pre-operative tumor volumetry using 3D-MD-CT followed by subsequent laparotomy (11 women, 39 men; mean age 63.9 years) were examined. Tumor volume and conventional clinicopathological factors were studied and then analyzed with respect to survival. RESULTS: Tumor volume was distributed widely and ranged from 0.16 cm3 to 363.5 cm3 with a mean of 43.6 cm3 (<10 cm3, 21 tumors; >=10 cm3, 29 tu- mors). Significant differences in survival were found for volume (<10.0 cm3 vs. >=10.0 cm3; p=0.0414), and depth of invasion (T1-2 vs. T3-4; p=0.0475), but not for diameter (<50 mm vs. >=50 mm; p=0.2142), location (proximal third vs. middle or distal third; p=0.3254), macroscopic type (localized vs. invasive; p=0.3619), or microscopic type (differentiated vs. undifferentiated; p=0.1230). CONCLUSIONS: The present findings suggest that tumor volume measured by pre-operative 3D-MD-CT offers an alternative indicator for determining the prognosis in gastric cancer. PMID- 25911899 TI - The effect of short-term proton pump inhibitor plus anti-ulcer drug on the healing of endoscopic submucosal dissection-derived artificial ulcer: a randomized controlled trial. AB - BACKGROUND/AIMS: Artificial ulcers remain a major complication after Endoscopic submucosal dissection (ESD). The development of more effective treatment regimen for this ulcer is required than the use of proton pump inhibitor (PPI) alone. METHODOLOGY: Patients with ESD-derived artificial ulcers were randomly assigned to two groups: a group of patients who received rabeprazole 20 mg daily for 8 weeks (PPI group) and a group of patients who received a combination of rebamipide 300 mg daily for 8 weeks and rabeprazole 20 mg dairy for the first 4 weeks (reb+PPI group). The area reduction ratio and healing status of ulcers were evaluated endoscopically on postoperative 7, 28 and 56 days. RESULTS: The overall ulcer area reduction ratio was higher in the reb+PPI group than in the PPI group, especially at an early stage. The ratio of progression to the H1 stage in the reb+PPI group was significantly higher than that in the PPI group, especially at an early stage. CONCLUSIONS: Treatment with 8 weeks of rebamipide plus the first 4 weeks of PPI demonstrated a reduction ratio of artificial ulcers superior to that with 8 weeks of PPI mono-therapy. This combination treatment is, therefore, one of the candidate treatment strategies against ESD-derived artificial ulcers. PMID- 25911900 TI - Clinico-pathological features and prognostic analysis of gastric cancer patients in different age groups. AB - BACKGROUND/AIMS: The prognostic value of age on patients with gastric cancer is not well defined. The aim of this retrospective study is to analyze the impact of age on survival in patients with gastric cancer. METHODOLOGY: A total of 1800 patients with gastric carcinoma, who had undergone gastrectomy between 1997-2007 years were included. They were divided into six different age groups (21-30, 31 40, 41-50, 51- 60, 61-70 and 71-80 years). We reviewed patient's clinico pathological characteristics and the prognosis with special reference to their ages. RESULTS: Among the six age groups, the younger patients have more female dominated patients and poorly differentiated carcinoma, whereas the older patients have a higher incidence of large tumors (>=5 cm) and more patients with stage T3. Moreover, there were more liver metastases in the older age groups. Univariate analysis showed that there were significant differences in 5-year survival rates among the six age groups. Multivariate analysis confirmed age, tumor size, pT stage, pN stage and curability were independent prognostic factors. CONCLUSION: There are several distinctive properties related to age of patients with gastric cancer, the older patients have more aggressive features and poorer prognosis than the younger patients. PMID- 25911901 TI - HER2 expression variability between primary gastric cancers and corresponding lymph node metastases. AB - BACKGROUND/AIMS: The efficacy of anti-HER2 therapy is mainly dependent on HER2 overexpression in the metastatic lesions. It is essential to decipher the heterogeneity of gene profiles between primary tumor and matched metastases in gastric cancer. METHODOLOGY: The frequency of HER2 expression in 100 gastric cancers of both primary tumors and corresponding multiple lymph node metastases were determined immunohistochemically. A modified HER2-scoring criteria by Hofmann et al recommended for gastric cancer were followed in our study, which considers basolateral, so-called "U-shape", HER2-expression as positive. RESULTS: HER2 overexpression (2+, 3+) was seen in 33.0% of primary gastric cancers and 39.4% of the corresponding metastatic lymph nodes. For the first time, we compare HER2 expression heterogeneity among different lymph node metastases in the same patient, for the cases with 2 or more metastatic lymph nodes, HER2 expression discordance among the nodes was observed in 25.3% of the cases. CONCLUSIONS: HER2 overexpression was seen in one-third of primary gastric cancers with lymph node metastases. As the receptor expression may lose or gain in the metastases at a probability of approximately 30%, assessment of the receptor status in metastatic lesions is encouraged. PMID- 25911902 TI - Laparoscopic gastrectomy for gastric cancer in China: an overview. AB - Since its introduction in China in 2000, laparoscopic gastrectomy has shown classical advantages of minimally invasive surgery over open counterpart. Like all the pioneers of the technique, Chinese gastrointestinal surgeons claim that laparoscopic gastrectomy led to faster recovery, shorter hospital stay and more rapid return to daily activities respect to open gastrectomy while offering the same functional and oncological results. There has been booming interest in laparoscopic gastrectomy since 2006 in China. The last decade has witnessed national growth in the application of laparoscopic gastrectomy and yielded a significant amount of scientific data to support its clinical merits and advantages. However, few prospective randomized controlled trials have investigated the benefits of laparoscopic gastrectomy in China. In this article, we make an overview of the current data and state of the art of laparoscopic gastrectomy for gastric cancer in China. PMID- 25911903 TI - Effectiveness of using low-dose computed tomography to assess patency in gastrointestinal tracts with a patency capsule. AB - BACKGROUND/AIMS: A patency capsule (PC) is used to safely perform capsule endoscopy. When the PC is not excreted within the defined time frame, radiography often cannot localize the PC. Computed tomography (CT) localizes a PC more definitively than radiography. We evaluated the localization of PCs using low dose (LD)-CT. METHODOLOGY: Forty-nine patients received a PC and 33 did not excrete the PC within the defined time frame and underwent radiography and LDCT with a 90% exposure reduction. RESULTS: LDCT localized the PC in 31 patients (93.9%), whereas radiography localized it in 7 (21.2%), indicating a significantly higher detection rate with LDCT (P<0.0001). PC retention in the small intestine was confirmed by LDCT in 4 patients. Retention was not observed during capsule endoscopy in the patients with confirmed patency of the gastrointestinal tract. In 21 patients who underwent LDCT with the conventional photographing area, the effective radiographic exposure dose associated with LDCT was 1.43+/-1.08 mSv. Conversely, in the 12 patients who underwent LDCT with a reduced photographing area, the effective dose was reduced to 0.62+/-0.27 mSv (P<0.05). CONCLUSION: LDCT with a reduced exposure dose can definitively localize a PC. Therefore, this method may allow capsule endoscopy to be performed for more diseases. PMID- 25911904 TI - Glycemic changes after gastrectomy in non-morbidly obese patients with gastric cancer and diabetes. AB - BACKGROUND/AIMS: To evaluate the glycemic changes after gastrectomy in non morbidly obese patients with gastric cancer (GC) and type 2 diabetes mellitus (T2DM). METHODOLOGY: Between December 2011 and June 2014, we included 46 patients with gastric cancer and T2DM of a body mass index (BMI) < 30 kg/m2, who underwent gastrectomy in our center. The comparisons of FPGs in specific periods were performed according to age, extent of gastrectomy, reconstruction type, preoperative triglyceride (TG) level and so on. RESULTS: The non-morbidly obese patients experienced an improvement of glycemic control. T2DM resolution happened 3 weeks after surgery. FPG decreased significantly after postoperative day 21 compared to preoperative FPG. 32 patients experienced DM improvement after postoperative day 21. The age and relatively lower preoperative TG patients, who underwent total gastrectomy (P<0.001) or duodenal bypass reconstruction (Billroth II, Roux-en-Y gastrojejunostomy, or Roux-en-Y esophagojejunostomy, P=0.009) appeared to have a better glycemic control. CONCLUSIONS: Our finding observed through this simulation model suggested that non-morbidly obese patients may also benefit from metabolic surgery for glycemic control, associated with age, extent of gastrectomy, reconstruction type, and preoperative triglyceride level. PMID- 25911905 TI - [New aspects of pharmacological effects of ursodeoxycholic acid]. AB - The paper reviews the use of hepatoprotective agents in chronic liver diseases (CLD) and biliary disorders. A variety of clinical studies have shown the beneficial effect of ursodeoxycholic acid (UDCA) in liver disease worldwide. Besides the well-known mechanisms of action of UDCA we could show its prebiotic effect. Several studies have demonstrated that UDCA serves as a potential therapeutic agent for a number non-hepatobiliary disorders including cardiovascular disease, immune disorders, organ transplantation and other. PMID- 25911906 TI - [Biliary dysfunction in obese children]. AB - To examine the state of the biliary system, a study of properties of bile "case control") 100 children and adolescents aged 8 to 18 years, held checkup in consultative and diagnostic center for chronic gastroduodenitis. BMI children were divided into 2 groups: group 1-60 children with obesity (BMI of 30 to 40) and group 2-40 children with normal anthropometric indices. Survey methods included clinical examination pediatrician, endocrinologist, biochemical parameters (ALT, AST, alkaline phosphatase level, total protein, bilirubin, lipidogram, glucose, insulin, HOMA-index), ultrasound of the abdomen and retroperitoneum, EGD with aspiration of gallbladder bile. Crystallography bile produced by crystallization of biological substrates micromethods modification Prima AV, 1992. Obese children with chronic gastroduodenita more likely than children of normal weight, had complaints and objective laboratory and instrumental evidence of insulin resistance and motor disorders of the upper gastrointestinal and biliary tract, liver enlargement and biliary "sludge". Biochemical parameters of obese children indicate initial metabolic changes in carbohydrate and fat metabolism and cholestasis, as compared to control children. Colloidal properties of bile in obese children with chronic gastroduodenita reduced, as indicated by the nature of the crystallographic pattern. Conclusions: Obese children with chronic gastroduodenitis often identified enlarged liver, cholestasis and biliary dysfunction, including with the presence of sludge in the gallbladder; most often--hypertonic bile dysfunction. Biochemical features of carbohydrate and fat metabolism reflect the features of the metabolic profile of obese children. Crystallography bile in obese children reveals the instability of the colloidal structure of bile, predisposing children to biliary sludge, which is a risk factor for gallstones. PMID- 25911907 TI - [Hepatic steatosis and fatty pancreas--2 targets of metabolic syndrom in children]. AB - OBJECTIVES: This study aimed to assess frequency of association between hepatic steatosis and pancreatic steatosis in obese children and find out common chains of pathogenesis. METHODS: This study was conducted among 100 children aged 12-17 years, consisted 2 groups: 60 overweight children (BMI from 30,1 to 42,87-1st group) and 40 children with normal BMI (2nd group). Diagnosis of the hepatic steatosis and pancreatic steatosis was based on sonographic findings. Were investigated peculiarities of carbohydrates and lipid metabolism and pancreatic exocrine function. RESULTS: Sonographic findings compatible with pancreatic steatosis in obese children were found with frequency- 70%, whereas sonographic findings compatible with hepatic steatosis were found with frequency- 46.6%. These findings were associated with BMI, parameters of metabolic syndrome: waist circumference, insulinresistancy, disturbances of the carbohydrates and lipid metabolism. Was found decreasing level of the elastase-1 in children with obesity. CONCLUSION: In 70% obese children was found pancreatic steatosis. The presence of fatty pancreas represents a meaningful manifestation of metabolic syndrome together with obesity and hepatic steatosis. PMID- 25911908 TI - [Adipokines and liver function in patients with nonalcoholic fatty liver disease, type 2 diabetes mellitus and its combination]. AB - The aim of the study was to assess the links between leptin, resistin and tumor necrosis factor-alpha (TNF-alpha) and indexes of the functional liver condition in patients with non-alcoholic fatty liver disease (NAFLD), type 2 diabetes mellitus (DM 2) and with its combination. MATERIALS AND METHODS: It were examined 110 patients: 20 of them were with NAFLD, 20 patients with DM 2 and 70 patients with combined disorders (NAFLD+ DM 2), which were divided into 2 subgroups -20 patients with normal body weight and 50 patients with obesity (body mass index >= 30 kg/m2). The control group included 20 healthy individuals. It was a complex clinical, laboratory (with definition of indexes of protein, pigment, enzyme and carbohydrate metabolism, levels of adipokines) and instrumental (ultrasound of the liver and liver biopsy (for 8 patients)) investigation. RESULTS: It was shown a significant increase of plasma levels of leptin, resistin, TNF-alpha in patients with this combined pathology. It was established the significant correlations between leptin, resistin, TNF-alpha and indexes of functional liver condition in these patients. CONCLUSION: In patients with NAFLD, DM 2 and with its combination, particularly with concomitant obesity, there is an imbalance of the products of adipose tissue, which sign is increasing of leptin, resistin and TNF-alpha. Relationships between leptin, resistin, TNF-alpha and indexes of the functional liver condition mainly in subgroup 3-b would give a reason to believe that obesity is activated and compounded te hormone-metabolic disorders that affect liver function. PMID- 25911909 TI - [Role of leptin and leptin resistance in non-alcoholic fatty liver disease development in persons with obesity and overweight]. AB - AIM: To study the impact of leptin and leptinresistance on formation of non alcoholic fatty liver disease (NAFLD) of people with obesity and overweight. METHODS: 105 patients with obesity and overweight were examined, among them 19 men and 86 women, median age 58 (50-63) years. Risk factors development NAFLD, anthropometric indices, biochemical analysis of blood, abdominal ultrasonic studies, levels leptin and its soluble receptor were estimated. examined people with NAFLD were included into 2 groups: main group (patients NAFLD, n = 77) and comparison group (n = 28). RESULTS: Waist volume, body mass index, blood glucose were higher in group of patients with NAFLD (p < 0.0001, p < 0.003, p < 0.00002, level) and had positive connection with the change in liver development (rs = (0.376), p < 0.00008, rs = (0.293), p < 0.002, rs = (0.417), p < 0.00001, level). Leptin has direct dependence (rs = (0.291), p < 0.027), while level of soluble receptors to leptin was of reverse dependence (rs = (-0.456), p < 0.0003) on the degree of body weight. Between these indicators in the group with obesity and overweight negative correlation of moderate strength (rs = (-0.370), p < 0.004) was revealed. There were tendencies to a higher level leptin and lower level receptor to leptin in group with NAFLD (median level leptin 29.20 (12.63-44.98) in main group against 27.49 (12.05-54.79), median receptor to leptin 18.25 (14.69 24.26) against 22.05 (14.57-32.04), respectively). However these indicators in the main group also had a negative correlation bond of moderate strength (rs = ( 0.384), p < 0.007). CONCLUSION: Development of NAFLD are associated with obesity and excess body weight, phenomenon of leptinresistance arises to patients with obesity and can be considered as predictor of the development and progression of NAFLD among this category of patients. PMID- 25911910 TI - [Approaches to the treatment of patients with climacteric disorders complicated with menopausal metabolic syndrome with cholestasis]. AB - RESEARCH OBJECTIVE: Development of the individual comprehensive program of follow treatment of patients with climacteric disorders complicated MMS (menopausal metabolic syndrome) with cholestasis; on the basis of application of low-dose hormone replacement therapy in combination with ursodeoxycholic acid, to improve the quality of life. MATERIALS AND METHODS: We observed 101 woman with climacteric syndrome, obesity and cholestasis; conducted a comprehensive clinical and laboratory examination, ultrasound of the hepatobiliary system, measurement modified menopausal index (MMI), the measurement of the quality of life on questionnaire SF-36 before treatment and after 6 and 12 months. THE RESULTS: Positive and statistically significant changes in lipid spectrum, the activity of transaminases, bilirubin and its fractions, improvement of MMI and quality of life, the indices of coagulation remained virtually unchanged. CONCLUSION: Low dose hormone replacement therapies in combination with ursodeoxycholic acid are highly effective drugs for the treatment of menopausal syndrome, which normalize lipid profile of patients and the performance of the hepatobiliary system. PMID- 25911911 TI - [Hepatic parenchimatous damage and perfusion disturbance in the progression of nonalcoholic fatty liver disease]. AB - AIM: To detect early diagnostic criterions of hepatocellular inflammation and portal hypertension for revealing the progressive course of nonalcoholic fatty liver disease (NAFLD). MATERIALS AND METHODS: We have studied 58 patients with NAFLD: 6 with steatosis, 47 with steatohepatitis (SH), 5 with class A liver cirrhosis (LG). Liver biopsy was performed in 24 (41.4%) patients with estimation of histological activity index (HAI) and fibrosis by Brunt method. Abdominal sonography and dopplerography of portal and spleen venous bloodflow with estimation of portal vein congestive index (CI) were performed in all patients. RESULTS: Among conventional laboratory markers of parenchimatous damage gammaglutamiltransferase (GGTF) was increased more frequently--in 77.6% of patients, then alaninaminotransferase (ALAT)--in 62.0% and aspartataminotransferase (ASAT)--in 51.7% of patients. GGTF correlated more closely with HAI: with fatty cellular degeneratic r = 0.82 (p < 0.01), bottled cellular degeneration--r = 0.65 (p < 0.05), lobular inflammation--0.58 (p < 0.05), fibrosis r = 0.67 (p < 0.05), than ALAT--0.51 (p < 0.05), 0.48 (p < 0.05), 0.42 (p < 0.05), 0.51 (p < 0.05) accordingly. Liver venous perfusion worsening was revealed already in moderate SH, when clinical symptoms of portal hypertension were absent. CI in portal vein correlated closely with HAI r = 0.78 (p < 0.05) and fibrosis r = 0.69 (p < 0.05) in NAFLD, that confirmed its diagnostic role in detection of parenchimatous and vascular liver architectonics deterioration and portal hypertension development. CONCLUSION: GGTF is more sensitive parenchimatous damage marker in NAFLD than ALAT and ASAT. Liver venous perfusion study with estimation portal vein congestive index permits to reveal the portal hypertension long before clinical symptoms of this syndrome appearance. Liver parenchimatous damage and its perfusion disturbance confirm the NAFLD progressive course. PMID- 25911912 TI - [Characteristics of the gastrointestinal myoelectrical activity in patients with nonalcoholic fatty liver disease associated with metabolic syndrome]. AB - PURPOSE: Electrogastroenterography (EGEG) is a method of measuring action potentials of the digestive tract. The aim of the study was to evaluate the main features of the gastrointestinal myoelectrical activity (GI MEA) in patients with nonalcoholic fatty liver disease (NAFLD) associated with metabolic syndrome (MS). MATERIALS AND METHODS: GI motility function in fasting and postprandial periods by the peripheral EGEG (EGEG system "Gastroenterological GEM-01") were recorded in 33 patients with NAFLD associated with MS, 26 patients with mixed type of Irritable Bowel Syndrome (IBS) and 10 healthy volunteers aged from 18 to 70 years. RESULTS: Total fasting GI MEA data of patients with NAFLD associated with MS (Me = 40,99 MB) dominated over the same in patients with IBS (Me = 23.84 mV) and healthy volunteers (Me = 11.26 mV), the differences between EGEG parameters was not significant but critical (H = 5.997, p = 0.050). This trend was observed in postprandial period (H = 0.891, p = 0.640). In postprandial period total GI MEA in patients with NAFLD associated with MS was increased in 36.4% patients (95% CI: 24.7-56.3%) only while in IBS patients and healthy volunteers total GI MEA tract were increased in 76.9% patients (95% CI: 58.0-89.0%) and in 90.0% (95% CI: 59.6-98.2%) correspondently (chi2 = 14.12, p = 0.001). Postprandial ratio (PPR) (ratio between total GI MEA in postprandial and fasting periods) of GI MEA were less than 1.0 in patients with NAFLD associated with MS (Me = 0.65) and less then PPRs in patients with IBS and healthy volunteers (H = 10.378, p = 0.006). PPR in patients with IBS was less then this ratio in healthy volunteers (Me = 1.48 vs Me = 1.66) CONCLUSION: The increased total GI MEA is observed in patients with NAFLD associated with MS. Patients with NAFLD associated with MS have abnormal GI MEA in response on food stimulation. This fact may be important in the development of NAFLD and MS. PMID- 25911913 TI - [Fatty liver in elderly patients with atherosclerotic coronary artery disease (according to autopsy data)]. AB - In article it is a question of morphological research of fragments of tissue of a liver at 143 elderly and old patients with atherosclerosis of the coronary arteries which have died on offices of the S-Petersburg hospital for veterans of wars in 2006-2010. Average age of the died patients was defined in the range from 61 till 98 years and made 82.3 +/- 1.3 years. It is established that at geriatric patients with atherosclerotic defeat of coronary arteries fatty regeneration of a liver was observed in 25.9 +/- 7.3%; more than at 2?3 geriatric patients with atherosclerosis of coronary arteries it was noted cteatogpatit with the minimum degree of the activity, thus specified degree of activity came to light at the surveyed patients with fatty regeneration of a liver (77.8 +/- 8.0% against 60.7 +/- 6.1% in group without fatty regeneration of a liver) more often. Cardiovascular diseases caused death of patients with atherosclerosis of coronary arteries and fatty regeneration of a liver, than in group of patients without a fatty degeneration of a liver (91.7 +/- 4.8% of cases and 73.8 +/- 4.9% of cases respectively) more often. Patients of senile age with atherosclerosis of coronary arteries and fatty regeneration of a liver died because of cardiovascular diseases, than their contemporaries in group without fatty regeneration of a liver (89.7 +/- 6.1% and 71.3 +/- 5.7% respectively) more often. PMID- 25911914 TI - [Clinical immunological diagnostics of overlap syndrome during autoimmune hepatic disorders]. AB - The complex determination of serum autoantibodies to hepatic antigens using enzyme immunoassay and immunoblot allows to increase the frequency of overlap syndrome identification during autoimmune hepatic disorders and its early diagnostics, that has a big clinical, diagnostic and prognostic importance. The levels of overlap autoantibodies combine with biochemical index and with disease activity and intensity of autoimmune processes during overlap syndrome of primary biliary cirrhosis/autoimmune hepatitis (PBC/AIH). PMID- 25911915 TI - [Chronic hepatitis C--clinical and autonomic characteristics]. AB - The article presents the results of a survey of 62 patients with chronic hepatitis C and 103 patients with liver cirrhosis of viral etiology. Besides clinical parameters studied autonomic features by analysis of heart rate variability at rest and active orthostasis. Indicators of frequency and spectral analysis of heart rate in study patients with chronic hepatitis C and cirrhosis of viral etiology confirmed increase in sympathetic activity and weakening of parasympathetic activity in all respects, with the sympathetic influence of enhanced active orthostasis. Indices of regulatory systems of the autonomic nervous system (stress index and the index of autonomic regulation) also indicated a statistically significant predominance sympathicotonia at rest and active orthostasis, indicating serious violations of adaptation in the examinees. PMID- 25911916 TI - [The chronobiological peculiarities of the hepatobiliary system function in chronic cholecystitis with dysfunction of the gallbladder]. AB - Study of biological cycles in chronic cholecystitis with dysfunction of gallbladder has a great practical importance. The results of chronoanalysis testify a dominance of 24-hours cycle in structure of cycles of functional activity of organs of hepatobiliary system. The comparative analysis of trust intervals reveals the intensification of internal connections, expressed intensification of synchronization of cycles of functional activity of system and a breach of synchronism of central regulation and self-regulation, testifying overstrain of proper adaptive possibilities and unconcordance in system of regulation. This manifestations of desynchronization provokes development and progress of dysfunction of gallbladder and dysbalance of vegetative nervous system, that make worse the present disturbances. PMID- 25911917 TI - [Assessment of the effectiveness of laser reflexotherapy in combined treatment of patients with chronic acalculous cholecystitis]. AB - AIM: To study effects of laserpuncture in combined treatment of chronic non calculous cholecystitis on motor function gallbladder, clinical symptoms. MATERIALS AND METHODS: 73 patients of chronic non-calculous cholecystitis were divided in to groups: 35 patients were received treated only by the means of standard therapy (the control group), 38 patients were received a course laserpuncture as part of complex treatment (the study group). RESULTS: Influence laser radiation on acupuncture points was found to induce positive therapeutic effect, such as: decrease the durations of clinical symptoms, correction of motor function gallbladder. CONCLUSION: Laserpuncture is an effective method of non calculous cholecystitis treatment and can be included in relevant combined schemes. PMID- 25911918 TI - [Cholestasis and pancreatic insufficiency: how to start treatment?]. AB - The article presents a detailed analysis of pathogenesis and clinical manifestation of secondary pancreatic excretory insufficiency due to disorders of bile production and choleresis. Pathogenesis of hepatogenic (chologenic) pancreatic insufficiency considered in view of impairment of bile acids' different functions in cholestasis. Authors review pathology of liver and bile ducts resulted in steatorrhea. It was conducted pathogenetic substantiation treatment tactics of patients, which have a combination of cholestasis and secondary pancreatic insufficiency. PMID- 25911919 TI - [Clinical questions of extremal processing of Mirizzi syndrome]. AB - In this article two clinical cases of Mirizzi syndrome is presented. In the observation examined reactive processing of Mirizzi syndrome I with severe overall system reaction to endogenous infection. The data characterizing the current version of Mirizzi syndrome V b is considered in the second observation. Timely diagnosis of Mirizzi syndrome and determination of the most appropriate method of treatment can reduce the risk of intraoperative injury. PMID- 25911920 TI - [Activity of the marker liver enzymes under the conditions of toxic hepatitis and alimentary deprivation of protein]. AB - The activity of the sorbitoldehydrogenase (SDH), alanine aminotransferase (ALT) and alkaline phosphatase (ALP) in the blood serum of rats with acetaminophen induced hepatitis under the conditions of alimentary deprivation of protein was studied. The animals were divided into 3 groups: 1--rats with acute acetaminophen induced hepatitis, maintained on the full ration; 2--rats with acute acetaminophen-induced hepatitis, maintained under the conditions of alimentary deprivation of protein; 3--control. The activity of the sorbitol dehydrogenase in blood serum was determined by the kinetic method, activity of the alanine aminotransferase and alkaline phosphatase - photometrically. It is shown, that in animals with the model hepatitis the activity of sorbitol dehydrogenase in blood serum increases 20-fold, wherein statistical significance between animals with hepatitis maintained under the conditions of full ration and those of low-protein diet is not established. In the group of animals with acetaminophen-induced hepatitis the preservation on the control level of the alkaline phosphatase activity on the base of the increase of alanine aminotransferase by 2.2 times and ratio ALT/ALP>5 testifies about hepatocellular liver injury. In the group of animals with drug-induced hepatitis and alimentary deprivation of protein, the increase of the alkaline phosphatase and alanine aminotransferase activity is observed, herewith the ratio ALT/ALP ranges from 2 to 5 and testifies about mixed liver injury. The conclusion was made, that alimentary deprivation of protein is the critical factor for the development of the disturbances of functional and structural liver integrity, and the therapeutic approaches to the correction of the drug-induced liver injury should be different depending on the value of protein ration in the anamnesis, taking into account the different types of liver injury. PMID- 25911921 TI - [Niemann-Pick disease--a rare disease in children's hepatology (a clinical case)]. AB - The aim is to acquaint medical society with literature data and specific details of clinical incidents of Niemann-Pick disease among 14 year old children. The article gives a brief review of literature on the problem of diagnostics, symptoms and treatment of Niemann-Pick disease in children. A clinical case of a forteen-year-old girl with type C Niemann-Pick disease is presented, the peculiarity of which is a combination of symptoms typical of the disease with a low level of ceruloplasmin in serum. PMID- 25911922 TI - [Case of primary biliary cirrhosis combined with GERD and complicated by peptic strictures of the esophagus]. AB - The clinical case of the two diseases combination such as primary biliary cirrhosis and peptic stricture of the esophagus (complicated GERD) in one patient is presented in the article. PMID- 25911923 TI - [Prevention of malignant neoplasm of digestive organs]. AB - Along with the growth of the overall disease incidence, the cancer incidence is constantly growing as well. Malignancies are diseases that lead to high mortality. This work covers one of the most important provisions of internal diseases--gastroenterology. It is known that the main work of healthcare professionals, therapists, is the diagnosis and treatment, and the second part of their work is prevention (primary, secondary and tertiary) of diseases and on this basis--prevention of malignant diseases. The search of precancerous diseases is always complicated, so it is advisable to create risk groups, which are observed in the dynamics. The Article helps to make the program not only of rational control, but also to designate a circle of the activities continuously replacing oncologic transformation of the observed pathology. The psychological condition of the patient in terms of impact of oncological process is included into the examination, as well as the role of health care professionals- therapist, oncologist and psychologist on the stabilization of the process of recovery and cancer patients. PMID- 25911924 TI - [The method for early diagnosis of the gastric cancer based metabolomics research]. AB - This paper deals with the questions of the usage of metabolomics research results in the diagnosis of gastric cancer. The central idea metabolomics is to identify the specific biomarkers in a biological sample used in a diagnostics this disease. The volatile organic compounds--metabolites isolated from the urine samples from patients are considered as biomarkers. The paper also describes main methods of separation and identification of volatile organic compounds (gas chromatography, mass spectrometry) applied in metabolomics. The paper presents some results of laboratory research aimed at the detection of biomarkers of gastric cancer. The presented material will be of some help in solving the problems of early diagnosis of this disease. PMID- 25911925 TI - [Serpins in hyperplastic colon tissue]. AB - The purpose of the study was to define alpha-2-macroglobulin (alpha-2M) and alpha 1-proteinase inhibitor (alpha-1PI) in tissues of malignant tumors and polyps of the lower parts of the colon. 28 patients had malignant tumors of the sigmoid colon or rectum (T3N0-1M0-2), 29 had polyps of the same location. Content of alpha-2M and alpha-1PI was studied in cytosols of the central, peripheral and conditionally healthy tissues (of resection line) of the mentioned hyperplasias by the ELISA method using standard test kits. Suppression of a-2M and increase of alpha-1PI (perifocal zone) were found in malignant tumor tissue, as well as alpha 1PI maintenance in tumorous focus. Increase of alpha-2M and decrease of alpha-1PI were detected in polyp tissue. Changes in physiological balance of serpins were assessed by alpha-1PI/alpha-2M ratio in comparison with the resection line. The risk of distortion of proliferation and differentiation processes increases in polyps in ineffective inhibition of proteolysis under the influence of released factors of malignancy. Endogenous or medicamentous restoration of balance of interaction of trypsin-like proteases and kallikrein with inhibitors will probably play the crucial role. PMID- 25911926 TI - [Fecal neutrophil gelatinase-associated lipocalin is a surrogate marker of inflammation in inflammatory bowel disease]. AB - AIM: To evaluate the fecal level of neutrophil gelatinase-associated lipocalin (NGAL) in different behavior of inflammatory bowel disease (IBD). MATERIALS AND METHODS: We prospectively included 41 people into the study--30 patients with active IBD and 11 healthy volunteers. The concentration of NGAL in faeces was determined by enzyme immunoassay method. RESULTS: Fecal NGAL level was increased in both UC and CD: in CD--5924.27 +/- 2067.6 ng/ml (p < 0.05), in UC--5826.09 +/- 891.8 ng/ml (p < 0.05) NGAL levels were higher than in the control group (658.8 +/- 237.7 ng/ml). Maximal changes were seen in colonic involvement. NGAL levels increased with the increasing extension of lesion in UC (p < 0.05), while in CD concentration was higher in colitis than in ileitis and ileocolitis (p > 0.05) . NGAL level increased with severity of CD (p < 0.05), in patients with UC difference was not significant. In UC NGAL level was increased with increasing extension of lesions (p < 0.05), in CD this pattern was not marked. Correlation NGAL level with some clinical and laboratory indicators in CD was established. Sensitivity of test in evaluation of exacerbation of IBD was 80%, specificity- 90.9%, area under the ROC curve (AUC)--0.9, positive predictive value--96%, negative predictive value--62.5%; positive likelihood ratio--8.8 and negative likelihood ratio--0.22. CONCLUSIONS: The fecal concentration of NGAL significantly increased during IBD. With increasing severity and activity of disease level ofNGAL was increased in CD (p < 0.05). Lipocalin-2 values was higher with the increasing extension of lesions in UC (p < 0.05). There has been established the high diagnostic value of the detection of fecal NGAL as a marker of the active phase of IBD. PMID- 25911927 TI - [Essential phospholipids in the treatment of alcohol-related liver disease: clinical and experimental study]. AB - Conducted clinical and experimental study showed the effectiveness of the use of essential phospholipids as hepatoprotector alcohol-related liver diseases. The application of essential phospholipids reduces the morphological severity of inflammatory and degenerative changes in the liver, improves the clinical picture and laboratory status of patients. PMID- 25911928 TI - [Endosonography in diagnosis of choledocholithiasis]. AB - BACKGROUND AND STUDY AIMS: In 38-80% patients with suspicion to choledocholithiasis were no stones in common bile duct (CBD) after endoscopic retrograde cholangiopancreatography (ERCP). ERCP is not safe procedure and has a risk of complications ranging 4-15%. The aim of our study was to estimate the diagnostic value and safety of endoscopic ultrasound (EUS) in CBD stones diagnosis. PATIENTS AND METHODS: In patients with medium probability of CBD stones (i.e. CBD <= 10 mm and/or bilirubin <= 2 times upper normal) was performed BUS with Pentax EG-3870UTK and Hitachi EUB-7000HV. From September 2012 till December 2013 it were done 72 investigations in patients with suspicion of CBD stones. RESULTS: After EUS suspicion for CBD stones were in 21 patients. Average size of hyperechoic defects was 5.6 +/- 3.3 (2-12) mm. ERCP was performed in 20 of them. Stones were confirmed and removed in 18 patients, in 2 patients without stones it was found a stricture of terminal part of CBD. In 9 patients absence of stones was confirmed during laparoscopic cholecystectomy with IOC. Patients without indications to cholecystectomy were followed for six months and there were no additional investigations. It were no complications after EUS. EUS sensitivity was 100%, specificity--96.2%, PPV--90%, NPV--100%. CONCLUSION: EUS is effective tool for diagnosis of CBD stones in patients with medium probability of choledocholithiasis. It could be recommended as a first diagnostic step in these patients because the risk of complications is negligible. PMID- 25911929 TI - [Dynamics of growth factors in the spleen and liver of rats at different stages of metastatic hepatic reconstitution]. AB - The aim--to study the dynamics of IGF-I, IGS-II, TGF-beta1 in liver and spleen tissues from rats at different stages of liver metastases. MATERIALS AND METHODS: We have designed a model of liver metastases in male rats. The content of growth factors was examined by ELISA at 1, 2 and 5 weeks of carcinogenesis in tissue of liver and tumors of spleen. RESULTS: The content of growth factors increased in liver tissue at different stages of metastasis. The concentration of TGF-beta, increased from the first to the fifth week of carcinogenesis. The level of IGF-I increased after 2 weeks of carcinogenesis. CONCLUSION. Pathogenetic moments of metastasis to the liver are the change of growth factors levels, indicating intensification of metastasis from 2 weeks of carcinogenesis and proliferation from 1 to 5 weeks. PMID- 25911930 TI - [New polymer materials for endoscopic equipment preventing biofilms formation]. AB - Aim to study: The study of antimicrobial activity, hidrofobisity and physicochemical properties of nanostructured barrier layers on the surface of polyethyleneterephtalate and polytetrafluorethylene, formed by different methods of ion-plasma technique. PMID- 25911931 TI - [Lymphocyte apoptosis enhancement by the synthetic peptide of human alpha fetoprotein (AFP 14-20) in experimental ulcer]. AB - The influence of regulatory peptide type of AFP on the course of experimental ulcers was investigated. It has been shown that activation of apoptosis by AFP enhance local necrotic inflammatory reaction, on the one hand, and enables the development of adhesions with the other. PMID- 25911932 TI - [Interelement correlations in the lungs and the liver in alimentary obesity]. AB - Using a high-fat diet in experiment on rats received model alimentary obesity (AO). Adding zinc to the diet did not affect the severity of the AO. The concentration of K, Ca, Mn, Fe, Cu, Zn, Se, Br, Rb, Sr in the liver and lungs of rats with obesity in both groups did not differ from that of healthy animals. As in the liver and lungs in rats of both groups with obesity has been a redistribution of interelement correlation (COP) and during physiological hunger and soon after consumption of pork fat. Redistribution of interelement COP in a state of physiological hunger reflects the strong changes of metabolic processes of the body. The nature of rearrangements of the COP in the liver and lungs were significantly different in each group of rats. Soon after intake of fatty foods in control rats and rats AO not receiving zinc, found an increase in the total number interelement COP in the lungs and major decline in the liver, which indirectly indicates the active participation of the lungs in the metabolism of dietary fat, over-expressed in control animals. In rats receiving more zinc, the increase in the total number of correlations after eating found in both bodies. PMID- 25911933 TI - [The choleretic and hepatoprotective effect of Hypecoum erectum extract]. AB - The choleretic and hepatoprotective effect of Hypecoum erectum L. dry extract on toxic hepatitis was studied. Experimental hepatitis was caused by the introduction of D-galactosamine to Wistar white rats in the dose of 500 mg/kg of the animal weight once a day for 3 days. The H. erectum extract was administered per os in the dose of 50 mg/kg for 7 days. It has been established that H. erectum extract has a marked hepatoprotective effect in the case of D galactosamine hepatitis in white rats that is characterized by inhibition of the disturbances in cholate-synthetic functions of the liver, increase of bile secretion rate, preservation of cholate concentration in the bile. The tested remedy diminishes dystrophic and necrotic processes, decreases the intensity of inflammatory infiltration in the liver and stimulates regeneration of liver cells in D-galactosamine hepatitis. PMID- 25911934 TI - [Applying of recombinant interleukin-1beta to treat chronic hepatitis C for patients non-response to the previous antiviral therapy]. AB - The search for rational treatment of CHC patients, non-response to the primary antiviral therapy especially with unfavorable genotypes for interleukin-28B, remains valid. PURPOSE: To evaluate the efficacy and safety of recombinant IL 1beta (Betaleukin) in combined antiviral therapy in patients with chronic hepatitis C who did not respond to previous treatment. The study included 26 patients with HCV-1. Patients were divided into 2 groups depending on retreatment scheme: group 1 (n = 10) was treated with recombinant IFN-a2b ("Interal"-P) 5 million IU daily subcutaneously for 12 weeks then every other day until the end of treatment; ribavirin, depending on body weight (800-1200 mg/day) and "Betaleukin" subcutaneously 0.005 mcg/kg every other day for 12 weeks (45 injections); group 2 (n = 16)--recombinant IFN-a2b ("Interal"-P) 3 million IU every other day subcutaneously for 48 weeks; ribavirin--1000 mg/day (for a body weight < 75 kg), 1200 mg/day (for a body weight > 75 kg) and "Betaleukin" subcutaneously 0.005 mcg/kg every other day, five courses for 3 weeks (50 injections). RESULTS: Combined antiviral therapy (alpha-IFN2b and RIB) with IL 1beta (Betaleukin) in patients who had not responded to previous therapy, with a predominance of unfavorable genetic background for IL-28B typing helped to improve SVR (44%) with more efficient 45-day administration of the medications in the first 12 weeks in combination with inductive alpha-IFN therapy and achieve biochemical response at week 24 of treatment. Adverse effects of the IL-1beta mainly limited with fever, moderate local reactions and do not require discontinuation of treatment. PMID- 25911935 TI - [Genetic aspects of pancreatic cancer]. AB - The purpose of the review--to analyze the basic data on modifiable and genetic risk factors of pancreatic cancer (PC). PC is the most fatal disease that kills about 95% of patients. Among the known risk factors for PC only for smoking, obesity, and family history a positive association with the PC risk in meta analyzes confirmed. The PC etiology remains unclear, more than 90% of patients acquire it sporadically. Currently, the most significant genes for PC include KRAS2, p16/CDKN2, TP53, SMAD4/DPC4. Mutations in the KRAS noted in 90% of cases of pancreatic ducts adenocarcinoma. p16/CDKN2A mutation is accompanied by a 38 fold increased risk of PC compared with the general population. TP53 mutations are associated not only with carcinogenesis but also PC metastasis, as well as SMAD4/DPC4 mutations. Study of the role of genetic aspects in the PC development is necessary both to identify individuals with high PC risk, as well as for the development of gene-specific treatments, such as inhibitors of proteins, histone deacetylase, and histone acetyltransferase (vorinostat, belinostat, entinostat, panobinostat, curcumin) are in clinical trials. PMID- 25911936 TI - [Angiogenesis and vascular endothelial growth factor, role in the pathology of the gastrointestinal tract]. AB - A review of the literature, the authors present information about angiogenesis, as the process of formation of new blood vessels in the organ or tissue from pre existing vasculature by migration and proliferation of endothelial cells, as well as on the processes of regulation. Presents key regulatory system angiogenesis. The main attention is paid Vascular endothelial growth factor (VEGF). Specially structured data on the role of Vascular endothelial growth factor in human pathology, including diseases of gastrointestinal tract, inflammatory and neoplastic nature. PMID- 25911937 TI - [Eyes' symptoms of the digestive diseases]. AB - Substantial part of the eye disease manifestations constitute general or systemic diseases. Accordingly, the dosage systemic therapy of these diseases can affect the condition of the eye. Changes of the vision and the appropriate advice ophthalmologist can help the gastroenterologist in the diagnosis and adequate treatment of the patient. The article discusses the possible changes in the organ of vision in diseases of the digestive system and a number of infectious diseases, as well as changes occurring under the influence of drug therapy of these diseases. PMID- 25911938 TI - [Modern endoscopic diagnosis of precancerous lesions and early cancers of the stomach and colon using computer decision support systems]. AB - Modern endoscopic techniques allow a precise diagnosis of superficial epithelial lesions of the stomach and colon and predict their histological structure. Currently, there are a variety of endoscopic classifications based on the use of magnifying endoscopy and NBI for superficial epithelial lesions according to their morphology. For differential diagnosis of benign lesions, mild neoplasia and early cancer in the colon we commonly use the pit-pattern classification of the surface epithelium created by S. Kudo and mucosal capillary pattern classification created by Y. Sano, which have proven effectiveness in prospective studies. For the stomach to date there is no universally accepted comfortable reliable classification for differentiation benign and neoplastic gastric lesions. However, VS-classification, created by K. Yao, is the most prevalent and effective classification today. It is based on regularity of the vascular and surface (V&S) patterns of the gastric mucosa and presence of the demarcation line on the border with the surrounding mucosa. To increase the efficiency of endoscopic diagnosis with using of these classifications, to identify new diagnostic criteria, to train young specialists and to help skilled doctors computer decision support systems for a physician are successfully developed now. PMID- 25911939 TI - Current opinion on the management of iron deficiency anaemia in gastrointestinal diseases. AB - Iron deficiency is the most common cause of anaemia in the world. Despite frequently weak and masked clinical presentation of iron deficiency anaemia (IDA), this disease is very serious with complications leading to early mortality. In the developed countries IDA is predominantly diagnosed as the complication of another disease or as the result of major bleeding events. Diagnosis of IDA should be based on laboratory findings i.e. haemoglobin, mean corpuscular hemoglobin concentration and ferritin. Latter is the most sensitive marker for iron deficiency. Anaemia of chronic disease should be taken into an account as a potential differential diagnosis or coexisting state. For women in fertility age with IDA, gynaecological disorders should be ruled out first. Males and postmenopausal women with IDA should undergo upper, lower and in certain cases capsule endoscopy and/or enteroscopy to find a plausible cause of IDA. The ultimate goal of therapy is to find out and treat the primary cause of IDA. Iron body stores should be restored using either oral or parenteral iron preparations. The use of parenteral iron preparations in patients with gastrointestinal pathologies is often clinically substantiated for the treatment of IDA. Red blood cell transfusion should be administered in emergency cases only. PMID- 25911940 TI - Eponyms in biliary tree. AB - Eponyms are very commonly used in medicine. Eponyms serve the goal of honoring scientists who have made important contribution to medicine. The article describes widespread and seldom used eponyms found in biliary structures. Priority of discovery of the "Heister's valve", "Luschka's ducts", "sphincter of Odd", "Vater's papilla" was established. An author provides biographical sketches of physicians in whose honor some anatomic entities were named. PMID- 25911941 TI - [Report of Scientific Conference European Helicobacter Study Group XXVIIth International Workshop on Helicobacter & Microbiota in Inflammation & Cancer]. PMID- 25911942 TI - [Secondary cancers: Incidence, risk factors and recommendations]. AB - Cure rates for most childhood cancers and adolescents have made remarkable progress over the last thirty to forty years. The development of secondary malignancies has become an important question for these patients. The frequency is low, but the risk is significantly higher (between 3 and 10 times) and it is the leading cause of long-term mortality off relapse. In this literature review, we discuss the epidemiological aspect and the risk factors contributing to this increased risk, and conclude with a summary of current recommendations for screening and surveillance. We also discuss briefly the constitutional predisposing genetic contributions to other cancers. PMID- 25911944 TI - Antcin K, an Active Triterpenoid from the Fruiting Bodies of Basswood-Cultivated Antrodia cinnamomea, Inhibits Metastasis via Suppression of Integrin-Mediated Adhesion, Migration, and Invasion in Human Hepatoma Cells. AB - Previous research demonstrated that the ethyl acetate extract from Antrodia cinnamomea suppresses the invasive potential of human breast and hepatoma cells, but the effective compounds are not identified. The main bioactive compounds of A. cinnamomea are ergostane-type triterpenoids, and the content of antcin K is the highest. The objective of this study was to evaluate the antimetastatic activity and mechanisms of antcin K purified from the fruiting body of basswood cultivated A. cinnamomea on human liver cancer Hep 3B cells. The results showed that adhesion, migration, and invasion of Hep 3B cells were effectively inhibited by antcin K within 24 h of treatment. Antcin K not only reduced the protein expression and activity of MMP-2 and MMP-9 but also down-regulated vimentin and up-regulated E-cadherin in Hep 3B cells. In depth investigation for the molecular mechanism revealed that antcin K could reduce the protein expression of integrin beta1, beta3, alpha5, and alphav and suppress phosphorylation of FAK, Src, PI3K, AKT, MEK, ERK, and JNK. These results suggested that antcin K was able to inhibit the metastasis of human hepatoma cells through suppression of integrin-mediated adhesion, migration, and invasion. Coupled with these findings, antcin K has a good potential to reduce the risk of liver cancer metastasis. PMID- 25911946 TI - Thermophiles in the genomic era: Biodiversity, science, and applications. AB - Thermophiles and hyperthermophiles are present in various regions of the Earth, including volcanic environments, hot springs, mud pots, fumaroles, geysers, coastal thermal springs, and even deep-sea hydrothermal vents. They are also found in man-made environments, such as heated compost facilities, reactors, and spray dryers. Thermophiles, hyperthermophiles, and their bioproducts facilitate various industrial, agricultural, and medicinal applications and offer potential solutions to environmental damages and the demand for biofuels. Intensified efforts to sequence the entire genome of hyperthermophiles and thermophiles are increasing rapidly, as evidenced by the fact that over 120 complete genome sequences of the hyperthermophiles Aquificae, Thermotogae, Crenarchaeota, and Euryarchaeota are now available. In this review, we summarise the major current applications of thermophiles and thermozymes. In addition, emphasis is placed on recent progress in understanding the biodiversity, genomes, transcriptomes, metagenomes, and single-cell sequencing of thermophiles in the genomic era. PMID- 25911947 TI - Observations of probe dependence of the solvation dynamics in ionic liquids. AB - Solvation and rotational dynamics of 4-aminophthalimide (4AP) in four ionic liquids (ILs) are measured using a combination of fluorescence upconversion spectroscopy and time-correlated single photon counting. These data are compared with previously reported data for coumarin 153 (C153) to investigate the probe dependence of solvation dynamics. No fast component (<15 ps) in the fluorescence anisotropy is observed with 4AP. The differences between the solvation response functions of 4AP and C153 are significant in all four ILs, but these differences can be reduced by applying a correction for solute rotation using measured emission anisotropies. Response functions of other probes available in the literature are used to further examine the validity of this correction. The corrected data are also compared to predictions of dielectric continuum models of solvation. By replacing the measured static conductivity of the ILs with an estimated value, such predictions show good agreement with the observed spectral response functions, especially when the anion size is small. PMID- 25911945 TI - Form and function of the mammalian inner ear. AB - The inner ear of mammals consists of the cochlea, which is involved with the sense of hearing, and the vestibule and three semicircular canals, which are involved with the sense of balance. Although different regions of the inner ear contribute to different functions, the bony chambers and membranous ducts are morphologically continuous. The gross anatomy of the cochlea that has been related to auditory physiologies includes overall size of the structure, including volume and total spiral length, development of internal cochlear structures, including the primary and secondary bony laminae, morphology of the spiral nerve ganglion, and the nature of cochlear coiling, including total number of turns completed by the cochlear canal and the relative diameters of the basal and apical turns. The overall sizes, shapes, and orientations of the semicircular canals are related to sensitivity to head rotations and possibly locomotor behaviors. Intraspecific variation, primarily in the shape and orientation of the semicircular canals, may provide additional clues to help us better understand form and function of the inner ear. PMID- 25911943 TI - Mechanisms of action of therapeutic antibodies for cancer. AB - The therapeutic utility of antibodies and their derivatives is achieved by various means. The FDA has approved several targeted antibodies that disrupt signaling of various growth factor receptors for the treatment of a number of cancers. Rituximab, and other anti-CD20 monoclonal antibodies are active in B cell malignancies. As more experience has been gained with anti-CD20 monoclonal antibodies, the multifactorial nature of their anti-tumor mechanisms has emerged. Other targeted antibodies function to dampen inhibitory checkpoints. These checkpoint inhibitors have recently achieved dramatic results in several cancers, including melanoma. These and related antibodies continue to be investigated in the clinical and pre-clinical settings. Novel antibody structures that target two or more antigens have also made their way into clinical use. Tumor targeted antibodies can also be conjugated to chemo- or radiotherapeutic agents, or catalytic toxins, as a means to deliver toxic payloads to cancer cells. Here we provide a review of these mechanisms and a discussion of their relevance to current and future clinical applications. PMID- 25911948 TI - Acquisition of diagnostic and surgical skills in otorhinolaryngology: a comparison of France and Germany. AB - With the coalescing of the European countries, among many others, official initiatives have been launched to propose minimum requirements for Otolaryngology, Head and Neck surgery (ORL) specialty training by creating an European log book. This study was initiated to assess and compare the acquisition of basic medical key diagnostic and surgical skills by residents and recent ORL specialists in France (FRA) and Germany (GER) and to determine whether gender specific differences exist. For this, an anonymous questionnaire with questions to basic medical, diagnostic and surgical procedures specific to ORL was developed. 120 FRA and 125 GER questionnaires were returned from participants with a median training experience of 4 years. The female to male ratio was 1.3:1 and 78% of respondents were residents and 22% recent specialists. Concerning diagnostic procedures, there was no significant overall difference. Germans performed better in basic medical skills, while study participants from FRA had performed surgical procedures significantly more often in a more independent manner than German respondents in the areas of otology, rhinology and head and neck. Only in septoplasty, as part of rhinology, the Germans had a light advantage compared to the French. No difference was found for trauma surgery. No gender-specific difference became apparent. Taken together, in FRA, ORL training is far more surgically orientated than in GER. It remains unclear at what time, the Germans may catch up with their skills. Initiatives should be taken in GER to secure an adequate acquisition of surgical skill and experience to maintain a high level of ORL-specific competence. PMID- 25911949 TI - Diagnosis and management with botulinum toxin in 11 cases of laryngeal synkinesis. AB - Laryngeal synkinesis is a vocal fold movement disorder produced by a misdirected reinnervation after a recurrent laryngeal nerve injury. Its symptoms differ greatly between patients, requiring diverse therapeutical approaches. We aim to describe our experience in the diagnosis and treatment of different laryngeal synkinesis presentations. 11 patients diagnosed between 2011 and 2014 in a tertiary referral center with laryngeal synkinesis confirmed by laryngeal electromyography were included in our study. All medical records and laryngoscopic and electromyographic data were reviewed retrospectively. Four patients had previous unilateral vocal fold palsy and seven had a bilateral palsy with different degrees of clinical involvement. All of them showed paradoxical movements during inhalation in videofibrolaryngoscopic examination. Laryngeal electromyography confirmed the diagnosis of laryngeal synkinesis. Dyspnea was the main presentation symptom. Three patients with mild symptoms were not treated. Patients with unilateral vocal fold immobility were successfully treated with periodic botulinum toxin injections. Patients with bilateral immobility had a good initial response to botulinum toxin, although in some of them, a posterior cordectomy had to be finally performed. In conclusion, laryngeal synkinesis is a heterogeneous clinic entity that appears in patients with unilateral or bilateral vocal fold paralysis. Videofibrolaryngoscopy and laryngeal electromyography are essential to a correct diagnosis. Botulinum toxin injections are the main treatment for symptomatic cases, even if in bilateral palsy cases more aggressive treatments are often required. PMID- 25911950 TI - Current perioperative outcomes for patients with disseminated cancer. AB - BACKGROUND: Surgical morbidity and mortality (M&M) for patients with disseminated malignancy (DMa) is high, and some have questioned the role of surgery. Therefore, we sought to characterize temporal trends in M&M among DMa patients, hypothesizing that surgical intervention would remain prevalent. METHODS: We queried the American College of Surgeons National Surgical Quality Improvement Program from 2006-2010. Excluding patients undergoing a primary hepatic operation, we identified 21,755 patients with DMa. Parametric and/or nonparametric statistics and logistic regression were used to evaluate temporal trends and predictors of M&M. RESULTS: The prevalence of surgical intervention for DMa declined slightly over the time period, from 1.9%-1.6% of all procedures (P < 0.01). Among DMa patients, the most frequent operations performed were bowel resection, other gastrointestinal procedures, and multivisceral resections, these all showed small statistically significant decreases over time (P < 0.01). The rate of emergency operations also decreased (P < 0.01). In contrast, the rate of preoperative independent functional status rose, whereas the rate of preoperative weight loss and sepsis decreased (P < 0.01). Rates of 30-d morbidity (33.7 versus 26.6%), serious morbidity (19.8 versus 14.2%), and mortality (10.4 versus 9.3%) all decreased over the study period (P < 0.05). Multivariate analysis identified standard predictors (e.g., impaired functional status, preoperative weight loss, preoperative sepsis, and hypoalbuminemia) of worse 30-d M&M. CONCLUSIONS: Thirty day morbidity, serious morbidity, and mortality have decreased incrementally for patients with DMa undergoing surgical intervention, but surgical intervention remains prevalent. These data further highlight the importance of careful patient selection and goal-directed therapy in patients with incurable malignancy. PMID- 25911951 TI - Tanshinone IIA ameliorates bleomycin-induced pulmonary fibrosis and inhibits transforming growth factor-beta-beta-dependent epithelial to mesenchymal transition. AB - BACKGROUND: Epithelial to mesenchymal transition (EMT) of alveolar epithelial cells occurs in lung fibrotic diseases. Tanshinone IIA (Tan IIA) has been reported to exert anti-inflammatory effects in pulmonary fibrosis. Nonetheless, whether Tan IIA affects lung fibrosis-related EMT remains unknown and requires for further investigations. MATERIALS AND METHODS: A single intratracheal instillation of saline containing bleomycin (BLM; 5 mg/kg body weight) was performed to induce pulmonary fibrosis in Sprague-Dawley rats. Rats receiving an instillation of equivoluminal normal saline served as controls. Then, these rats were given a daily intraperitoneal administration of Tan IIA (15 mg/kg body weight) for 28 d before sacrifice. In vitro, recombinant transforming growth factor-beta 1 (TGF-beta1; 10 ng/mL) was used to treat human alveolar epithelial A549 cells for 48 h. Tan IIA (10 MUM) or control DMSO was used to pretreat cells for 2 h before TGF-beta1 stimulation. Rat lung tissue samples and A549 cells were then subjected to further assessments. RESULTS: Tan IIA was noted to alleviate BLM-induced pulmonary collagen deposition and macrophage infiltration in rats. Epithelial-cadherin expression was decreased after BLM stimulation, whereas alpha smooth muscle actin, fibronectin, and vimentin were increased. These expression alterations were partially reversed by Tan IIA. Moreover, Tan IIA suppressed BLM induced increases in TGF-beta1, phosphorylated Smad-2, and -3 in rats. Additionally, pretreatment of Tan IIA inhibited TGF-beta1-triggered EMT, reduced collagen I production, and blocked TGF-beta signal transduction in A549 cells. CONCLUSIONS: Our research suggests that Tan IIA mitigates BLM-induced pulmonary fibrosis and suppresses TGF-beta-dependent EMT of lung alveolar epithelial cells. PMID- 25911952 TI - Communicating biliary hydatid cyst with cholangitis: multimodal management. PMID- 25911953 TI - Auditory cortical and hippocampal local-field potentials to frequency deviant tones in urethane-anesthetized rats: An unexpected role of the sound frequencies themselves. AB - The human brain can automatically detect auditory changes, as indexed by the mismatch negativity of event-related potentials. The mechanisms that underlie this response are poorly understood. We recorded primary auditory cortical and hippocampal (dentate gyrus, CA1) local-field potentials to serial tones in urethane-anesthetized rats. In an oddball condition, a rare (deviant) tone (p=0.11) randomly replaced a repeated (standard) tone. The deviant tone was either lower (2200, 2700, 3200, 3700Hz) or higher (4300, 4800, 5300, 5800Hz) in frequency than the standard tone (4000Hz). In an equiprobability control condition, all nine tones were presented at random (p=0.11). Differential responses to deviant tones relative to the standard tone were found in the auditory cortex and the dentate gyrus but not in CA1. Only in the dentate gyrus, the responses were found to be standard- (i.e., oddball condition-) specific. In the auditory cortex, the sound frequencies themselves sufficed to explain their generation. These findings tentatively suggest dissociation among non-contextual afferent, contextual afferent and auditory change detection processes. Most importantly, they remind us about the importance of strict control of physical sound features in mismatch negativity studies in animals. PMID- 25911954 TI - Aldose reductase inhibitors for diabetic complications: Receptor induced atom based 3D-QSAR analysis, synthesis and biological evaluation. AB - Herein, atom-based 3D-QSAR analysis was performed using receptor-guided alignment of 46 flavonoid inhibitors of aldose reductase (ALR2) enzyme. 3D-QSAR models were generated in PHASE programme, and the best model corresponding to PLS factor four (QSAR4), was selected based on different statistical parameters (i.e., Rtrain(2), 0.96; Qtest(2) 0.81; SD, 0.26). The contour plots of different structural properties generated from the selected model were utilized for the designing of five new congener molecules. These designed molecules were duly synthesized, and evaluated for their in vitro ALR2 inhibitory activity that resulted in the micromolar (IC50<22MUM) activity of all molecules. Thus, the newly designed molecules having ALR inhibitory potential could be employed for the management of diabetic complications. PMID- 25911955 TI - The role of Ir4 cluster in enhancing the adsorption of CO2 on selected zeolites - GCMC simulations. AB - We have investigated the adsorption of CO2 molecules inside the EMT, SAO, SBS, SBT and IWS zeolites with respect to the influence of the Ir4 clusters on the adsorption capabilities of these materials. We have determined that the capabilities of CO2 adsorption depend on the combined effect of the framework topology and the position of the Ir4 cluster. Adsorption intensifies despite the fact that a fraction of the pore volume is occupied by the Ir4 cluster, and thus, the adsorption is more intense than that on empty zeolite. The pore topology however is also playing a crucial role in the effect, as in certain cases it allows the CO2 molecules to order in such a way they fill the most pore space. PMID- 25911956 TI - Prophylactic vaccinations in chronic kidney disease: Current status. AB - In this review, recent data on results concerning prophylactic vaccinations against hepatitis B virus, influenza viruses, and pneumococci are presented. Effects of active immunization in chronic kidney disease depend on category of glomerular filtration rate (GFR). The lower GFR category the better results of response to vaccination. Abnormalities in toll-like receptors and down-regulation of B-cell activating factor receptor in transitional B cells were recently included into uremia-associated deficits in immunocompetence. Development of novel, more potent vaccines containing toll-like receptor agonists as adjuvants may help to achieve more effective immunization against hepatitis B virus in immunocompromised patients. Experimental studies announce further vaccine adjuvants. A vaccine against hepatitis C virus is not available yet, but promising results were already obtained in the experimental and preliminary clinical studies. Prophylactic vaccinations against influenza viruses and pneumococci become increasingly popular in dialysis facilities due to their proved benefits. PMID- 25911957 TI - First report of the characterization of the pathophysiological mechanisms caused by the freshwater catfish Pimelodus maculatus (order: Siluriformes). AB - Injuries caused by aquatic animals in Brazil in most cases are provoked by marine and freshwater catfish. Pimelodus maculatus is a freshwater catfish very common in Brazilian basins that causes frequent accidents mainly amongst fishermen, and whose venom characteristics and pathological mechanisms of the venom are poorly known. In the present study for the first time, we have characterized the main pathophysiological mechanisms associated with the clinical manifestation (pain, local inflammation and edema) of the envenomations caused by P. maculatus crude venom. It was estimated that the crude venom of one P. maculatus stinger contains approximately 100 MUg of protein, likely the quantity involved in the envenomation. P. maculatus crude venom induced marked nociceptive and edematogenic effects and caused vascular permeability alterations at doses from 30 to 100 MUg/animal. Additionally, P. maculatus crude venom caused a decrease in the contraction force in in situ frog heart, did not cause hemorrhage or alterations in clotting times (prothrombin time and activated partial thromboplastin time), but induced significant changes in the levels of CK and its isoenzyme CK-MB in mice. In the present work, we present a correlation between the effects obtained experimentally and the main symptoms observed in the human accidents provoked by P. maculatus. PMID- 25911958 TI - Variability in venom volume, flow rate and duration in defensive stings of five scorpion species. AB - Scorpions have been shown to control their venom usage in defensive encounters, depending on the perceived threat. Potentially, the venom amount that is injected could be controlled by reducing the flow speed, the flow duration, or both. We here investigated these variables by allowing scorpions to sting into an oil filled chamber, and recording the accreting venom droplets with high-speed video. The size of the spherical droplets on the video can then be used to calculate their volume. We recorded defensive stings of 20 specimens representing 5 species. Significant differences in the flow rate and total expelled volume were found between species. These differences are likely due to differences in overall size between the species. Large variation in both venom flow speed and duration are described between stinging events of single individuals. Both venom flow rate and flow duration correlate highly with the total expelled volume, indicating that scorpions may control both variables in order to achieve a desired end volume of venom during a sting. PMID- 25911959 TI - Thioredoxin reductase inhibitor auranofin prevents membrane transport of diphtheria toxin into the cytosol and protects human cells from intoxication. AB - During cellular uptake, diphtheria toxin delivers its catalytic domain DTA from acidified endosomes into the cytosol, which requires reduction of the disulfide linking DTA to the transport domain. In vitro, thioredoxin reduces this disulfide and thioredoxin reductase (TrxR) is part of a cytosolic complex facilitating DTA translocation. We found that the TrxR-specific inhibitor auranofin prevented DTA delivery into the cytosol and intoxication of HeLa cells with diphtheria toxin, offering perspectives for novel pharmacological strategies against diphtheria. PMID- 25911960 TI - Production level of tetrodotoxin in Aeromonas is associated with the copy number of a plasmid. AB - Tetrodotoxin (TTX) has been identified from taxonomically diverse organisms. Artificial synthesis of TTX has been reported, but the biosynthetic pathway of TTX remains elusive. In this study, we found TTX producing ability was associated with the copy number of plasmid pNe-1 in Aeromonas strain Ne-1 during fermentation, suggesting that at least one gene encoding a TTX-synthesis enzyme is located on this plasmid. Compared with bacterial genomes, plasmids are small and easier to screen for genes associated with TTX biosynthesis. The approximately 100 kb genome of pNe-1 was sequenced. The plasmid contains 60 complete open reading frames (orfs) of which 32 (53.3%) encode hypothetical proteins. Seven genes are related to the type IV secretion system (T4SS) and 2 genes are related to transposons, indicating that the TTX-producing bacterium Aeromonas might have the ability to transfer the TTX biosynthesis gene via the conjugation and contagion of plasmid pNe-1. In addition, we unexpectedly found that Aeromonas Ne-1 contains unknown TTX-degrading materials, indicating there is a homeostatic mechanism to maintain a stable amount of TTX in the bacterium. These results will help us to better understand TTX biosynthesis, the bacterial origin of TTX, and TTX degradation. PMID- 25911961 TI - Reducing error in feline platelet enumeration by addition of Iloprost to blood specimens: comparison to prostaglandin E1 and EDTA. AB - BACKGROUND: Prostaglandin E1 (PGE1) and Iloprost inhibit platelet aggregation and should prevent or minimize preanalytic error with feline platelet enumeration. OBJECTIVES: The objective was to compare the relative effectiveness in reducing errors in platelet enumeration by adding Iloprost to feline EDTA blood specimens in comparison to adding PGE1 or EDTA alone. In addition, a grading system for platelet aggregation in blood smears was evaluated for effectiveness in predicting prominent errors and compared to ADVIA's PLT-CLM flag. Finally, the use of plateletcrit in feline blood with platelet aggregation was evaluated. METHODS: Blood specimens from 35 cats were included. Blood was collected into EDTA tubes with or without Iloprost or PGE1, and was rapidly mixed. Platelet count (PLT), plateletcrit (PCT), mean platelet volume (MPV), and platelet flags were determined with an ADVIA 2120. Manual PLT was performed with a Leucoplate stain. PLT was determined by an IDEXX VetAutoread hematology analyzer (QBC). RESULTS: Neither addition of Iloprost nor PGE1 to EDTA blood specimens completely prevented platelet aggregation. Iloprost-treated specimens had the least severe aggregation. PGE1 was better than EDTA alone. Significant errors in PLT results were consistently identified by the grading system. ADVIA's PLT-CL flag usually predicted significant errors in PLT. QBC PLT results showed high imprecision. Manual PLT error was smaller than ADVIA PLT in EDTA specimens with aggregation. CONCLUSIONS: Adding Iloprost to feline blood specimens improved platelet enumeration accuracy. A grading system for severity of platelet aggregation and usually the ADVIA's PLT-CL alarm predicted specimens with significant errors in platelet enumeration. PMID- 25911962 TI - Microtensile Bond Strength and Micromorphology of Bur-cut Enamel Using Five Adhesive Systems. AB - PURPOSE: This study compared the microtensile bond strengths (MUTBS) of two etch and-rinse (ER) (OptiBond FL [OBFL]; Prime & Bond NT [PBNT]) and three self etching (SE) (Clearfil SE Bond [CSEB]; Xeno III [XIII]; Xeno V+ [XV+]) adhesives systems to bur-prepared human enamel considering active (AA) and passive (PA) application of the self-etching systems. MATERIALS AND METHODS: Ninety-six enamel surfaces were prepared with a medium-grit diamond bur and randomly allocated into 8 groups to receive adhesive restorations: G1: OBFL; G2: PBNT; G3: CSEB/PA; G4: CSEB/ AA; G5: XIII/PA; G6: XIII/AA; G7: XV+/PA; G8: XV+/AA. After composite buildup, samples were sectioned to obtain a total of 279 bonded sticks (1 mm2) that were submitted to microtensile testing (MUTBS; 0.5 mm/min) after 24-h water storage (37 degrees C). Etching patterns and adhesive interfacial ultramorphology were also evaluated with confocal laser scanning (CLSM) and scanning electron microscopy (SEM). Data was analyzed with one-way ANOVA (alpha = 0.05). Weibull probabilistic distribution was also determined. RESULTS: Regarding MUTBS, both adhesive system and application mode yielded statistically significant differences (p < 0.05) among groups. ER adhesive systems together with CSEB/AA and XIII/PA recorded the highest and statistically similar bond strength results. XV+ presented very low bond strength values, regardless of the application mode. Among self-etching adhesives, CSEB produced significantly higher MUTBS values when applied actively. Qualitative evaluation by SEM and CLSM revealed substantial differences between groups both in adhesive interfaces and enamel conditioning patterns. CONCLUSIONS: ER and SE adhesive systems presented distinctive bond strengths to bur-cut enamel. The application mode effect was adhesive dependent. Active application improved etching patterns and resin interfaces micromorphology. PMID- 25911963 TI - Difficulties in hematopoietic progenitor cell collection from a patient with TEMPI syndrome and severe iatrogenic iron deficiency. AB - BACKGROUND: Collection of hematopoietic progenitor cells by apheresis (HPC-A) requires separation of cells by density. Previous studies highlighted the challenges of HPC-A collection from patients with abnormal red blood cells (RBCs). TEMPI syndrome is a recently described condition defined by teleangiectasias, elevated erythropoietin and erythrocytosis, monoclonal gammopathy, perinephric fluid collections, and intrapulmonary shunting. Patients with TEMPI syndrome have responded to therapies used to treat plasma cell dyscrasias and may benefit from autologous HPC transplantation. We report HPC-A collection from a patient with TEMPI syndrome that was complicated by severe iron deficiency. STUDY DESIGN AND METHODS: The patient received granulocyte-colony stimulating factor (G-CSF) and plerixafor for HPC mobilization and underwent 3 days of HPC-A collection. RESULTS: The patient presented for collection with a microcytic erythrocytosis. Over 3 days, approximately 50 L of whole blood was processed, and 2 * 10(8) CD34+ cells were collected (2.8 * 10(6) CD34+ cells/kg). The mean collection efficiency (CE), percentage of mononuclear cells, hematocrit (Hct), and RBC count were 18%, 90%, 14%, and 9 * 10(11) , respectively. Altering collection variables to avoid RBC contamination reduced CE. Ficoll preparations of the products after freeze-thaw showed RBC contamination and hemolysis. Postthaw viability exceeded 95%. The products were not RBC reduced or washed. There were no adverse reactions during or after infusion. CONCLUSIONS: HPC-A collection from a patient with TEMPI syndrome was complicated by microcytic erythrocytosis, leading to RBC contamination and hemolysis in the product. Adequate HPCs were collected and the patient tolerated infusion without RBC depletion or washing. Our report highlights difficulties of HPC-A collection from iron-deficient patients. PMID- 25911965 TI - Investigation of a Quantitative Method for the Analysis of Chiral Monoterpenes in White Wine by HS-SPME-MDGC-MS of Different Wine Matrices. AB - A valid quantitative method for the analysis of chiral monoterpenes in white wine using head-space solid phase micro-extraction-MDGC-MS (HS-SPME-MDGC-MS) with stable isotope dilution analysis was established. Fifteen compounds: (S)-(-) limonene, (R)-(+)-limonene, (+)-(2R,4S)-cis-rose oxide, (-)-(2S,4R)-cis-rose oxide, (-)-(2R,4R)-trans-rose oxide, (+)-(2S,4S)-cis-rose oxide, furanoid (+) trans-linalool oxide, furanoid (-)-cis-linalool oxide, furanoid (-)-trans linalool oxide, furanoid (+)-cis-linalool oxide, (-)-linalool, (+)-linalool, (-) alpha-terpineol, (+)-alpha-terpineol and (R)-(+)-beta-citronellol were quantified. Two calibration curves were plotted for different wine bases, with varying residual sugar content, and three calibration curves for each wine base were investigated during a single fiber's lifetime. This was needed as both sugar content and fiber life impacted the quantification of the chiral terpenes. The chiral monoterpene content of six Pinot Gris wines and six Riesling wines was then analyzed using the verified method. ANOVA with Tukey multiple comparisons showed significant differences for each of the detected chiral compounds in all 12 wines. PCA score plots showed a clear separation between the Riesling and Pinot Gris wines. Riesling wines had greater number of chiral terpenes in comparison to Pinot Gris wines. Beyond total terpene content it is possible that the differences in chiral terpene content may be driving the aromatic differences in white wines. PMID- 25911964 TI - Antibacterial Activity of Essential Oils and Their Isolated Constituents against Cariogenic Bacteria: A Systematic Review. AB - Dental caries remains the most prevalent and costly oral infectious disease worldwide. Several methods have been employed to prevent this biofilm-dependent disease, including the use of essential oils (EOs). In this systematic review, we discuss the antibacterial activity of EOs and their isolated constituents in view of a potential applicability in novel dental formulations. Seven databases were systematically searched for clinical trials, in situ, in vivo and in vitro studies addressing the topic published up to date. Most of the knowledge in the literature is based on in vitro studies assessing the effects of EOs on caries related streptococci (mainly Streptococcus mutans) and lactobacilli, and on a limited number of clinical trials. The most promising species with antibacterial potential against cariogenic bacteria are: Achillea ligustica, Baccharis dracunculifolia, Croton cajucara, Cryptomeria japonica, Coriandrum sativum, Eugenia caryophyllata, Lippia sidoides, Ocimum americanum, and Rosmarinus officinalis. In some cases, the major phytochemical compounds determine the biological properties of EOs. Menthol and eugenol were considered outstanding compounds demonstrating an antibacterial potential. Only L. sidoides mouthwash (1%) has shown clinical antimicrobial effects against oral pathogens thus far. This review suggests avenues for further non-clinical and clinical studies with the most promising EOs and their isolated constituents bioprospected worldwide. PMID- 25911966 TI - Copper(I) complexes of mesoionic carbene: structural characterization and catalytic hydrosilylation reactions. AB - Two series of different Cu(I)-complexes of "click" derived mesoionic carbenes are reported. Halide complexes of the type (MIC)CuI (with MIC = 1,4-(2,6-diisopropyl) phenyl-3-methyl-1,2,3-triazol-5-ylidene (for 1b), 1-benzyl-3-methyl-4-phenyl 1,2,3-triazol-5-ylidene (for 1c)) and cationic complexes of the general formula [Cu(MIC)2]X (with MIC =1,4-dimesityl-3-methyl-1,2,3-triazol-5-ylidene, X = CuI2- (for 2a), 1,4-dimesityl-3-methyl-1,2,3-triazol-5-ylidene, X = BF4- (for 2a), 1,4 (2,6-diisopropyl)phenyl-3-methyl-1,2,3-triazol-5-ylidene, X = BF4- (for 2b), 1 benzyl-3-methyl-4-phenyl-1,2,3-triazol-5-ylidene, X = BF4- (for 2c)) have been prepared from CuI or [Cu(CH3CN)4](BF4) and the corresponding ligands, respectively. All complexes were characterized by elemental analysis and standard spectroscopic methods. Complexes 2a and 1b were studied by single-crystal X-ray diffraction analysis. Structural analysis revealed 2a to adopt a cationic form as [Cu(MIC)2](CuI2) and comparison of the NMR spectra of 2a and 2a confirmed this conformation in solution. In contrast, after crystallization complex 1b was found to adopt the desired neutral form. All complexes were tested for the reduction of cyclohexanone under hydrosilylation condition at elevated temperatures. These complexes were found to be efficient catalysts for this reaction. 2c was also found to catalyze this reaction at room temperature. Mechanistic studies have been carried out as well. PMID- 25911968 TI - Longitudinal evaluation of the impact of dental caries treatment on oral health related quality of life among schoolchildren. AB - This study aimed to evaluate the impact of dental caries treatment on oral health related quality of life (OHRQoL) among schoolchildren and the responsiveness of the Child Perceptions Questionnaire (CPQ8-10 ) instrument. Brazilian schoolchildren, 8-10 yr of age, were randomly selected and assigned to two groups -dental caries treatment (DCT) and caries-free (CF)--according to their caries experience [decayed, missing, or filled primary teeth (dmft) and decayed, missing or filled secondary teeth (DMFT) values of >= 0]. The CPQ8-10 instrument was administered at baseline and at 4 wk of follow-up (i.e. 4 wk after completion of dental treatment). In the DCT group, increases in CPQ8-10 scores were observed between the baseline and follow-up results. However, longitudinal evaluation of the CF group demonstrated no statistically significant difference in CPQ8-10 scores. Responsiveness of the CPQ8-10 instrument (magnitude of change in CPQ8-10 scores) in the DCT group was greater (effect size >0.7) than in the CF group. The findings of this study show that dental caries treatment has an important impact on OHRQoL of children. The CPQ8-10 was considered an acceptable instrument for longitudinal measurement of changes in OHRQoL. PMID- 25911970 TI - DWI lesions reversal in posterior circulation stroke after reperfusion: Two illustrative cases and review of the literature. PMID- 25911971 TI - Neuro opinion: reforming the academic system is a joint responsibility. PMID- 25911969 TI - Ofatumumab capacity to deplete B cells from chronic lymphocytic leukaemia is affected by C4 complement exhaustion. AB - The management of patients with chronic lymphocytic leukaemia (CLL) has improved with the utilisation of ofatumumab as a novel anti-CD20 monoclonal antibody. However, as half of the patients fail to respond to the treatment, the aim of this study was to evaluate circulating CLL cell depletion and clinical response according to the context of complement activation and FcgammaRIIIA polymorphism in ten CLL patients with relapsed/refractory disease. At the end of the treatment, results indicated that circulating CD5(+) CD19(+) CLL cell depletion was major (<0.01 * 10(9) /L) in 4 of 10 patients, partial (>50% decrease) in 4 of 10 patients and ineffective for the two other patients. No clinical modifications were observed following ofatumumab introduction. Ofatumumab administration leads to a rapid and important exhaustion of complement C4 levels in patients with initial lymphocytosis. C4 exhaustion was accelerated in a non-responder patient, and incomplete in two patients with partial circulating depletion. Moreover, delaying weekly to monthly ofatumumab injections improved CLL cell depletion in two patients. FcgammaRIIIA 158 polymorphism (FF n = 6 and VF n = 4) was not associated with major and/or partial circulating CLL cell depletion. In conclusion, ofatumumab induces an important C4 exhaustion that needs to be taken into account when treating CLL patients with ofatumumab. PMID- 25911967 TI - Phytomelatonin: assisting plants to survive and thrive. AB - This review summarizes the advances that have been made in terms of the identified functions of melatonin in plants. Melatonin is an endogenously produced molecule in all plant species that have been investigated. Its concentration in plant organs varies in different tissues, e.g., roots versus leaves, and with their developmental stage. As in animals, the pathway of melatonin synthesis in plants utilizes tryptophan as an essential precursor molecule. Melatonin synthesis is inducible in plants when they are exposed to abiotic stresses (extremes of temperature, toxins, increased soil salinity, drought, etc.) as well as to biotic stresses (fungal infection). Melatonin aids plants in terms of root growth, leaf morphology, chlorophyll preservation and fruit development. There is also evidence that exogenously-applied melatonin improves seed germination, plant growth and crop yield and its application to plant products post-harvest shows that melatonin advances fruit ripening and may improve food quality. Since melatonin was only discovered in plants two decades ago, there is still a great deal to learn about the functional significance of melatonin in plants. It is the hope of the authors that the current review will serve as a stimulus for scientists to join the endeavor of clarifying the function of this phylogenetically-ancient molecule in plants and particularly in reference to the mechanisms by which melatonin mediates its multiple actions. PMID- 25911972 TI - How low can we go? Recognizing infants at high risk of cerebral palsy earlier. PMID- 25911973 TI - Mental health impacts of racial discrimination in Australian culturally and linguistically diverse communities: a cross-sectional survey. AB - BACKGROUND: Racial discrimination denies those from racial and ethnic minority backgrounds access to rights such as the ability to participate equally and freely in community and public life, equitable service provision and freedom from violence. Our study was designed to examine how people from racial and ethnic minority backgrounds in four Australian localities experience and respond to racial discrimination, as well as associated health impacts. METHODS: Data were collected from 1,139 Australians regarding types of racial discrimination experienced, settings for these incidents, response mechanisms and psychological distress as measured by the Kessler 6 (K6) Psychological Distress Scale. RESULTS: Age, education, religion, gender, visibility and rurality were all significantly associated with differences in the frequency of experiencing racial discrimination. Experiencing racial discrimination was associated with worse mental health. Mental health impacts were not associated with the type of discriminatory experience, but experiencing racial discrimination in shops and in employment and government settings was associated with being above the threshold for high or very high psychological distress. One out of twelve response mechanisms was found to be associated with lower stress following a discriminatory incident. CONCLUSIONS: Study results indicate that poorer mental health was associated with the volume of discrimination experienced, rather than the type of experience. However, the impact of experiencing discrimination in some settings was shown to be particularly associated with high or very high psychological distress. Our findings suggest that interventions designed to prevent the occurrence of racism have more potential to increase mental health in racial and ethnic minority communities than interventions that work with individuals in response to experiencing racism. PMID- 25911974 TI - [Incidence and predictive factors of iron deficiency anemia after acute non variceal upper gastrointestinal bleeding without portal hypertension]. AB - INTRODUCTION: There are few studies on iron deficiency anemia (IDA) after non variceal acute upper gastrointestinal bleeding (UGIB) in patients without portal hypertension. OBJECTIVES: To define the incidence of IDA after UGIB, to characterize the predictive factors for IDA and to design algorithms that could help physicians identify those patients who could benefit from iron therapy. MATERIAL AND METHOD: We registered 391 patients with UGIB between April 2007 and May 2009. Patients with portal hypertension and those with clinical or/and biological conditions that could affect the ferrokinetic pattern were excluded. Blood analyses were performed, including ferric parameters upon admission, on the 5th day, and on the 30th day after the hemorrhage episode. We used a multiple logistic regression model and a classification and regression tree model. RESULTS: A total of 124 patients were included, of which 76 (61.3%) developed IDA 30 days after UGIB. The predictive variables were age >75 years (P=.037; OR 3.9; 95% CI: 1.3-11.6), initial urea level >80mg/dL (P=.027; OR 2.9; 95% CI: 1.1-7.6), initial ferritin level <=65ng/dL (P=.002; OR 7.6; 95% CI: 2.9-18.5), initial hemoglobin level <=100g/L (P=.003; OR 3.2; 95% CI: 1.3-8.0), hemoglobin level on the 5th day <=100g/L (P<.001; OR 14.9; 95% CI: 3.6-61.1) and the value of the transferrin saturation index on the 5th day <10% (p<0.001; OR 7.2; 95% CI: 2.6 20.3). CONCLUSIONS: Most patients with UGIB developed IDA 30 days after the episode. Identification of the predictive factors for IDA may help to establish guidelines for the administration of iron therapy. PMID- 25911975 TI - The "Stroop Walking Task": An innovative dual-task for the early detection of executive function impairment. AB - AIMS OF THE STUDY: To evaluate a dual-task named the "Stroop Walking Task", which is similar to the task of making a decision of whether to cross a street based on a pedestrian traffic light. PATIENTS AND METHODS: Fifty-one subjects (15 young adults, 21 subjectively healthy old subjects and 15 old subjects with mild cognitive impairment) had to respond to a visual signal (pictogram) with an appropriate motor response (walk or stop). We used an electronic walkway system to record the gait parameters and performed a cluster analysis on the obtained data. RESULTS: This dual-task enables the early detection of executive function impairment with 89% sensitivity and 87% specificity. CONCLUSION: The use of a dual-task that is inspired by an everyday event as an evaluation tool seems to facilitate the detection of ageing subjects' cognitive impairment, which is not detectable with traditional psychometric tests. PMID- 25911976 TI - Ant sperm storage organs do not have phenoloxidase constitutive immune activity. AB - The prophenoloxidase system (proPO-AS) is a primordial constituent of insect innate immunity. Its broad action spectrum, rapid response time, and cytotoxic by products induced by phenoloxidase (PO) production contribute to the effective clearing of invading pathogens. However, such immune reactions may not be optimal for insect organs that evolved to have mutualistic interactions with non-self cells. Ant queens are long-lived, but only mate early in adult life and store the sperm in a specialized organ, the spermatheca. They never re-mate so their life time reproductive success is ultimately sperm-limited, which maintains strong selection for high sperm viability before and after storage. The proPO-AS may therefore be inappropriate for the selective clearing of sexually transmitted infections, as it might also target sperm cells that cannot be replaced. We measured PO enzymatic activity in the sperm storage organs of three ant species before and after mating. Our data show that no PO is produced in the sperm storage organs, relative to other somatic tissues as controls, and that these negative results are not due to non-detection in small volumes as non-immune relevant catalase activity in single spermatheca fluid samples of both virgin and mated queens was significant. The lack of PO activity in sperm storage organs across three different ant species may represent an evolutionarily conserved adaptation to life-long sperm storage by ant queens. We expect that PO activity will be similarly suppressed in queen spermathecae of other eusocial Hymenoptera (bees and wasps) and, more generally, of insect females that store sperm for long periods. PMID- 25911977 TI - Pivotal Response Treatment Parent Training for Autism: Findings from a 3-Month Follow-Up Evaluation. AB - This study's objective was to assess maintenance of treatment effects 3 months after completion of a 12-week Pivotal Response Treatment (PRT) parent education group. Families who completed the active treatment (N = 23) were followed for an additional 12 weeks to measure changes in language and cognitive skills. Results indicated a significant improvement in frequency of functional utterances, with maintenance at 3-month follow-up [F(2, 21): 5.9, p = .009]. Children also made significant gains on the Vineland Communication Domain Standard Score [F(2, 12):11.74, p = .001] and the Mullen Scales of Early Learning Composite score [F(1, 20) = 5.43, p = .03]. These results suggest that a brief PRT parent group intervention can lead to improvements in language and cognitive functioning that are maintained 12 weeks post treatment. PMID- 25911978 TI - Screening for Autism in Iranian Preschoolers: Contrasting M-CHAT and a Scale Developed in Iran. AB - Suitable screening instruments for the early diagnosis of autism are not readily available for use with preschoolers in non-Western countries. This study evaluated two tools: M-CHAT which is widely used internationally and one developed in Iran called Hiva. A population sample was recruited of nearly 3000 preschoolers in one Iranian city. Parents self-completed the two tools and children who screened positive were invited for a follow-up interview followed by a diagnostic assessment. The Hiva scale proved to be more efficacious in identifying children with ASD and the resulting prevalence rate was higher than that previously reported for Iranian 5 year olds. The study confirms the need to attune screening tools to the cultural contexts in which they are used. PMID- 25911979 TI - Peripherally applied opioids for postoperative pain: evidence of an analgesic effect? A systematic review and meta-analysis. AB - BACKGROUND: Opioids applied peripherally at the site of surgery may produce postoperative analgesia with few side effects. We performed this systematic review to evaluate the analgesic effect of peripherally applied opioids for acute postoperative pain. METHODS: We searched PubMed (1966 to June 2013), Embase (1980 to June 2013), and the Cochrane Central Register of Controlled Trials (The Cochrane Library 2013, Issue 6). Randomized controlled trials investigating the postoperative analgesic effect of peripherally applied opioids vs. systemic opioids or placebo, measured by pain intensity scores, consumption of supplemental analgesics and time to first analgesic were included. Trials with sample sizes of fewer than 10 patients per treatment group or trials with opioids administered intra-articularly or as peripheral nerve blocks were excluded. RESULTS: Data from 26 studies, including 1531 patients and 13 different surgical interventions were included. Clinical heterogeneity of the studies was substantial. Meta-analysis indicated statistically significant, but not clinically relevant, reductions in VAS score at 6-8 h (mean difference -4 mm, 95% CI: -6 to -2) and 12 h postoperatively (mean difference -5 mm, 95% CI: -7 to -3) for peripherally applied opioids vs. placebo and statistically significant increased time to first analgesic (mean difference 153 min, 95% CI: 41-265). When preoperative inflammation was reported (five studies), peripherally applied opioids significantly improved postoperative analgesia. CONCLUSION: Evidence of a clinically relevant analgesic effect of peripherally applied opioids for acute postoperative pain is lacking. The analgesic effect of peripherally applied opioids may depend on the presence of preoperative inflammation. PMID- 25911982 TI - Palladium(ii) complexes with electron-poor, 4,5-disubstituted diimidazol-2 ylidene ligands: synthesis, characterization and catalytic activity. AB - Diimidazolium salts featuring different bridges between the imidazolium groups, as well as electron-withdrawing groups (chloride, cyanide) at the 4- and 5 position of the heterocyclic rings, have been successfully prepared. The diimidazolium salts serve as convenient precursors of di(N-heterocyclic carbene) ligands, which coordinate in a chelating fashion to palladium(ii) centres. The effect of the newly introduced electron-withdrawing groups on the spectroscopic and structural characteristics of the resulting complexes as well as on their reactivity as catalysts in a model alkyne hydroarylation reaction has been investigated and is discussed herein. PMID- 25911981 TI - Cancer incidence, mortality, and survival in Eastern Libya: updated report from the Benghazi Cancer Registry. AB - PURPOSE: Despite the increasing burden of cancer occurred over recent years in the African continent, epidemiologic data from Northern Africa area have been so far sparse or absent. We present most recently available data from the Benghazi Cancer Registry concerning cancer incidence and mortality as well as the most comprehensive survival data set so far generated for cases diagnosed during 2003 to 2005 in Eastern Libya. METHODS: We collected and analyzed data on cancer incidence, mortality and survival that were obtained over a 3-year study period from January 1st 2003 to December 31st 2005 from the Benghazi Cancer Registry. RESULTS: A total of 3307 cancer patients were registered among residents during the study period. The world age-standardized incidence rate for all sites was 135.4 and 107.1 per 100,000 for males and females, respectively. The most common malignancies in men were cancers of lung (18.9%), colorectum (10.4%), bladder (10.1%), and prostate (9.4%); among women, they were breast (23.2%), colorectum (11.2%), corpus uteri (6.7%), and leukemia (5.1%). A total of 1367 deaths for cancer were recorded from 2003 to 2005; the leading causes of cancer death were cancers of the lung (29.3%), colorectum (8.2%), and brain (7.3%) in males and cancers of breast (14.8%), colorectum (10.6%), and liver (7%) in females. The 5 year relative survival for all cancer combined was 22.3%; survival was lower in men (19.8%) than in women (28.2%). CONCLUSIONS: This study provides an updated report on cancer incidence, mortality, and survival, in Eastern Libya which may represent a useful tool for planning future interventions toward a better cancer control. PMID- 25911980 TI - Explaining racial disparities in HIV incidence in black and white men who have sex with men in Atlanta, GA: a prospective observational cohort study. AB - PURPOSE: To describe factors associated with racial disparities in HIV (human immunodeficiency virus) incidence among men who have sex with men (MSM) in the United States. METHODS: In a longitudinal cohort of black and white HIV-negative MSM in Atlanta, HIV incidence rates were compared by race. Incidence hazard ratios (HRs) between black and white MSM were estimated with an age-scaled Cox proportional hazards model. A change-in-estimate approach was used to understand mediating time-independent and -dependent factors that accounted for the elevated HR. RESULTS: Thirty-two incident HIV infections occurred among 260 black and 302 white MSM during 843 person-years (PY) of follow-up. HIV incidence was higher among black MSM (6.5/100 PY; 95% confidence interval [CI]: 4.2-9.7) than white MSM (1.7/100 PY; CI: 0.7-3.3) and highest among young (18-24 years) black MSM (10.9/100 PY; CI: 6.2-17.6). The unadjusted hazard of HIV infection for black MSM was 2.9 (CI: 1.3-6.4) times that of white MSM; adjustment for health insurance status and partner race explained effectively all of the racial disparity. CONCLUSIONS: Relative to white MSM in Atlanta, black MSM, particularly young black MSM, experienced higher HIV incidence that was not attributable to individual risk behaviors. In a setting where partner pool risk is a driver of disparities, it is also important to maximize care and treatment for HIV-positive MSM. PMID- 25911983 TI - Combined experimental and computational investigation of the absorption spectra of E- and Z-cinnamic acids in solution: The peculiarity of Z-cinnamics. AB - Cinnamic acids are present in all kinds of plant tissues and hence in herbs and derived medicines, cosmetics and foods. The interest in their role in plants and their therapeutic applications has grown exponentially. Because of their molecular structure they can exist in E- and Z-forms, which are both found in plants. However, since only the E-forms are commercially available, very few in vitro and in vivo studies of the Z-form have been reported. In this work the physico-chemical properties of Z-cinnamic acids in solution have been examined by means of UV-absorption spectroscopy and high-level quantum mechanical computations. For each isomer similar absorption spectra were obtained in methanol and acetonitrile. However, distinct trends were found for Z- and E forms of cinnamic acids in water, where a higher hypsochromic shift of the Z-isomer relative to the E-form was observed. In general the wavelength of maximal absorption of the Z-form is dramatically blue shifted (-30 to -40 nm) to lambda<280 nm, while a slightly blue shift of the absorption maxima for the corresponding E-form (+3 to -4 nm) was observed. This difference is associated with the non-planar, largely distorted, Z-structure and to the almost complete flat structure of the E-form. The results provide a basis for the study of functional and biotechnological roles of cinnamic acids and for the analysis of samples containing mixture of both geometric isomers. PMID- 25911984 TI - 24 hour forecast of the surface UV for the antipsoriatic heliotherapy in Poland. AB - Analyses of the spectral and broad-band UV data collected at Belsk (20.79 degrees E, 51.84 degrees N), Poland, show that standard broad-band instrument, Solar Light (SL) 501A, could be used for measurements of both erythemal and antipsoriatic irradiance. A prognostic model is proposed for the next-day duration of outdoor exposure required to receive a dose, the so-called minimum antipsoriatic dose (MAD), equivalent to that received by standard antipsoriatic daily treatment in the phototherapy cabinet containing TL-01 fluorescent tubes. The model uses the 24 h forecast of the column amount of ozone (to predict next day clear sky UV irradiance), and low- and mid-level cloudiness (to estimate a reduction of the clear-sky UV irradiation due to clouds). The predicted duration of sunbathing required to receive a dose of 1 MAD matches the observed value, i.e. the correlation coefficients is 0.68. If the model predicts the antipsoriatic exposure over 1 MAD threshold the observed dose will be also above this threshold in 91% of cases. Thus, the model could be used for planning the next-day outdoor exposure to clear psoriasis. Hourly resolved maps, starting from 6 am up to 1 pm (GMT), showing the duration of antipsoriatic exposure over Poland are made public. The model provides a tool for a psoriatic patient to find the sunbathing starting time and its duration, which has the same healing potential as a single indoor phototherapy session. PMID- 25911985 TI - A rapid injection NMR study of the reaction of organolithium reagents with esters, amides, and ketones. AB - Unexpectedly high rates of reaction between alkyllithium reagents and amides, compared to esters and ketones, were observed by Rapid Inject NMR and competition experiments. Spectroscopic investigations with 4-fluorophenyllithium (ArLi, mixture of monomer and dimer in THF) and a benzoate ester identified two reactive intermediates, a homodimer of the tetrahedral intermediate, stable below -100 degrees C, and a mixed dimer with ArLi. Direct formation of dimers suggested that the ArLi dimer may be the reactive aggregate rather than the usually more reactive monomer. In contrast, RINMR experiments with ketones demonstrated that the ArLi monomer was the reactive species. PMID- 25911986 TI - Whole Exome Sequencing in Monogenic Dyslipidemias. PMID- 25911987 TI - The influence of end of day silicone hydrogel daily disposable contact lens fit on ocular comfort, physiology and lens wettability. AB - PURPOSE: To quantify the end-of-day silicone-hydrogel daily disposable contact lens fit and its influence of on ocular comfort, physiology and lens wettability. METHODS: Thirty-nine subjects (22.1+/-3.5 years) were randomised to wear each of 3 silicone-hydrogel daily-disposable contact lenses (narafilcon A, delefilcon A and filcon II 3), bilaterally, for one week. Lens fit was assessed objectively using a digital video slit-lamp at 8, 12 and 16h after lens insertion. Hyperaemia, non-invasive tear break-up time, tear meniscus height and comfort were also evaluated at these timepoints, while corneal and conjunctival staining were assessed on lens removal. RESULTS: Lens fit assessments were not different between brands (P>0.05), with the exception of the movement at blink where narafilcon A was more mobile. Overall, lag reduced but push-up speed increased from 8 to 12h (P<0.05), but remained stable from 12 to 16h (P>0.05). Movement-on blink was unaffected by wear-time (F=0.403, P=0.670). A more mobile lens fit with one brand did not indicate that person would have a more mobile fit with another brand (r=-0.06 to 0.63). Lens fit was not correlated with comfort, ocular physiology or lens wettability (P>0.01). CONCLUSIONS: Among the lenses tested, objective lens fit changed between 8h and 12h of lens wear. The weak correlation in individual lens fit between brands indicates that fit is dependent on more than ocular shape. Consequently, substitution of a different lens brand with similar parameters will not necessarily provide comparable lens fit. PMID- 25911988 TI - [Acute pericardial syndromes in the intensive care unit]. PMID- 25911989 TI - Comparative study of analytical techniques for determining protein charge. AB - As interest in high-concentration protein formulations has increased, it has become apparent that routine, accurate protein charge measurements are necessary. There are several techniques for charge measurement, and a comparison of the methods is needed. The electrophoretic mobility, effective charge, and Debye Huckel-Henry charge have been determined for bovine serum albumin, and human serum albumin. Three different electrophoretic methods were used to measure the electrophoretic mobility: capillary electrophoresis, electrophoretic light scattering, and membrane confined electrophoresis. In addition, the effective charge was measured directly using steady-state electrophoresis. Measurements made at different NaCl concentrations, pH, and temperatures allow comparison with previous charge estimates based on electrophoresis, Donnan equilibrium, and pH titration. Similar charge estimates are obtained by all of the methods. The strengths and limitations of each technique are discussed, as are some general considerations about protein charge and charge determination. PMID- 25911990 TI - The neglected zoonoses--the case for integrated control and advocacy. AB - The neglected zoonotic diseases (NZDs) have been all but eradicated in wealthier countries, but remain major causes of ill-health and mortality across Africa, Asia, and Latin America. This neglect is, in part, a consequence of under reporting, resulting in an underestimation of their global burden that downgrades their relevance to policy-makers and funding agencies. Increasing awareness about the causes of NZDs and how they can be prevented could reduce the incidence of many endemic zoonoses. Addressing NZDs by targeting the animal reservoir can deliver a double benefit, as enhanced animal health means a reduced risk of infection for humans, as well as improved livelihoods through increased animal productivity. Advocacy for NZD control is increasing, but with it comes a growing awareness that NZD control demands activities both in the short term and over a long period of time. Moreover, despite the promise of cheap, effective vaccines or other control tools, these endemic diseases will not be sustainably controlled in the near future without long-term financial commitment, particularly as disease incidence decreases and other health priorities take hold. NZD intervention costs can seem high when compared with the public health benefits alone, but these costs are easily outweighed when a full cross-sector analysis is carried out and monetary/non-monetary benefits--particularly regarding the livestock sector--are taken into account. Public-private partnerships have recently provided advocacy for human disease control, and could prove equally effective in addressing endemic zoonoses through harnessing social impact investments. Evidence of the disease burdens imposed on communities by the NZDs and demonstration of the cost-effectiveness of integrated control can strengthen the case for a One Health approach to endemic zoonotic disease control. PMID- 25911991 TI - KPC-producing Klebsiella pneumoniae rectal colonization is a risk factor for mortality in patients with diabetic foot infections. AB - To evaluate the relationship between carbapenemase-producing Klebsiella pneumoniae (KPC-Kp) gut colonization and mortality in diabetic patients with a foot infection (DFI) we performed a single-centre, retrospective, matched case control study. In the study period, we identified 21 patients with DFI who had KPC-Kp gut colonization and 21 controls. The 90-day mortality rate was significantly higher in patients with colonized guts (47%) than the controls (4%) (p 0.013). A multivariate analysis demonstrated that gut colonization with KPC-Kp was the only independent predictor of mortality: odds ratio 13.33, 95% CI 1.90 272.80, p 0.024. In patients with DFI, KPC-Kp gut colonization appears to be an important risk factor for mortality. PMID- 25911992 TI - Transcriptomic analysis of colistin-susceptible and colistin-resistant isolates identifies genes associated with colistin resistance in Acinetobacter baumannii. AB - The emergence of colistin-resistant Acinetobacter baumannii is concerning, as colistin is often regarded as the last option for treating multidrug-resistant (MDR) A. baumannii infections. Using mRNA sequencing, we compared whole transcriptomes of colistin-susceptible and colistin-resistant A. baumannii strains, with the aim of identifying genes involved in colistin resistance. A clinical colistin-susceptible strain (06AC-179) and a colistin-resistant strain (07AC-052) were analysed in this study. In addition, a colistin-resistant mutant (06AC-179-R1) derived from 06AC-179 was also included in this study. High throughput mRNA sequencing was performed with an Illumina HiSeq TM 2000. In total, six genes were identified as associated with colistin resistance in A. baumannii. These six genes encode PmrAB two-component regulatory enzymes, PmrC (a lipid A phosphoethanolamine transferase), a glycosyltransferase, a poly-beta-1,6 N-acetylglucosamine deacetylase, and a putative membrane protein. Matrix-assisted laser desorption/ionization time of flight mass spectrometry revealed that all three colistin-resistant strains used in this study had modified lipid A structure by addition of phosphoethanolamine. As genes found in our results are all associated with either lipopolysaccharide biosynthesis or electrostatic changes in the bacterial cell membrane, lipopolysaccharide modification might be one of the principal modes of acquisition of colistin resistance in some A. baumannii strains. PMID- 25911993 TI - New diagnostic tools in clinical parasitology. PMID- 25911994 TI - Combination therapy improves prostate cancer survival for patients with potentially lethal prostate cancer: The impact of Gleason pattern 5. AB - PURPOSE: To investigate the impact of Gleason pattern 5 (GP5) prostate cancer after either external beam radiotherapy (EBRT) or the combination of EBRT with low-dose rate brachytherapy boost (combo). METHODS AND MATERIALS: Between 1998 and 2008, 467 patients with National Comprehensive Cancer Network high-risk prostate cancer were treated with EBRT (n = 326) or combo (low-dose rate to 90 108 Gy using I-125 followed by EBRT) (n = 141). Freedom from biochemical failure, freedom from metastasis (FFM), cancer-specific survival (CSS), and overall survival were evaluated. RESULTS: Combo patients were younger (66 vs. 72 years, p < 0.001) and had fewer comorbidities (Charlson comorbidity index 3.7 vs. 4.4, p < 0.001). EBRT patients had higher tumor stages (T3-4: 30% vs. 21%, p = 0.03) and lower Gleason scores (8-10: 61% vs. 75%, p = 0.01). Androgen deprivation therapy use was similar between cohorts (85% vs. 87%, p = 0.5), but EBRT patients had longer androgen deprivation therapy use (median 14 vs. 12 months, p = 0.05). GP5 predicted worse FFM (p < 0.001, hazard ratio [HR] 3.3, 95% confidence interval [CI]1.8-6.2]) and CSS (p < 0.001, HR 5.9, 95% CI 2.7-12.9) for the EBRT group, but not for the combo group (p = 0.86, HR 0.48, 95% CI 0.1-2.4 for metastasis and p = 0.5, HR 1.6, 95% CI 0.33-8.0 for CSS). In those with GP5 (n = 143), combo was associated with improved outcomes in all endpoints. On univariate analysis, 5 year outcomes for combo vs. EBRT were as follows: freedom from biochemical failure 89% vs. 65%, FFM 89% vs. 67%, CSS 93% vs. 78%, and overall survival 88% vs. 67% (p < 0.05 for all). CONCLUSION: Combo was associated with improved outcomes for men with GP5 prostate cancer. This highlights the importance of local therapy, especially in patients with the highest pathologic grade disease. PMID- 25911995 TI - Adjuvant radiotherapy in Stage II endometrial carcinoma: Is brachytherapy alone sufficient for local control? AB - OBJECTIVE: To evaluate recurrence patterns and overall survival in patients treated with adjuvant radiation after surgical staging for Stage II endometrial carcinoma. Secondary goals include identification of prognostic factors for recurrence and toxicity assessment. METHODS/MATERIALS: The medical records of 41 patients treated with adjuvant radiotherapy at Washington University School of Medicine after surgical staging for endometrial cancer (total abdominal hysterectomy and bilateral salpingo-oophorectomy, peritoneal cytology, lymph node dissection) were reviewed. Nineteen were treated with a combination of external beam radiotherapy and vaginal brachytherapy (VB), and 22 patients were treated with postoperative VB alone. Median followup for all patients was 41 months. RESULTS: Median patient age was 59 years (range, 42-87 years). All tumors were of endometrioid histology. There were 20 Grade 1 tumors, 13 Grade 2 tumors, and 8 Grade 3 tumors. For all patients, the 5-year overall survival was 69.8%, and the 5-year recurrence-free survival was 89.0%. There was no statistically significant difference in overall survival (p = 0.510) or freedom from vaginal (p = 0.840), distant (p = 0.133), or any recurrence (p = 0.275) with respect to modality of treatment (external beam radiotherapy and VB vs. VB alone). There were no pelvic lymph node recurrences. In the univariate analysis, there were no risk factors influencing overall survival or recurrences. One patient experienced a toxicity requiring hospital admission. She was treated with pelvic external beam radiation plus brachytherapy. CONCLUSIONS: VB alone results in excellent local control for patients with Stage II endometrial cancer after surgical staging. Long-term toxicities are rare and more common in the group of patients who were treated with pelvic external beam plus brachytherapy. PMID- 25911996 TI - Comprehensive transcriptomic analysis of molecularly targeted drugs in cancer for target pathway evaluation. AB - Targeted therapy is a rational and promising strategy for the treatment of advanced cancer. For the development of clinical agents targeting oncogenic signaling pathways, it is important to define the specificity of compounds to the target molecular pathway. Genome-wide transcriptomic analysis is an unbiased approach to evaluate the compound mode of action, but it is still unknown whether the analysis could be widely applicable to classify molecularly targeted anticancer agents. We comprehensively obtained and analyzed 129 transcriptomic datasets of cancer cells treated with 83 anticancer drugs or related agents, covering most clinically used, molecularly targeted drugs alongside promising inhibitors of molecular cancer targets. Hierarchical clustering and principal component analysis revealed that compounds targeting similar target molecules or pathways were clustered together. These results confirmed that the gene signatures of these drugs reflected their modes of action. Of note, inhibitors of oncogenic kinase pathways formed a large unique cluster, showing that these agents affect a shared molecular pathway distinct from classical antitumor agents and other classes of agents. The gene signature analysis further classified kinome-targeting agents depending on their target signaling pathways, and we identified target pathway-selective signature gene sets. The gene expression analysis was also valuable in uncovering unexpected target pathways of some anticancer agents. These results indicate that comprehensive transcriptomic analysis with our database (http://scads.jfcr.or.jp/db/cs/) is a powerful strategy to validate and re-evaluate the target pathways of anticancer compounds. PMID- 25911997 TI - Interference of phosphatidylcholines with in-vitro cell proliferation - no flock without black sheep. AB - According to early experiments with natural extracts, phosphatidylcholines (PCs) are widely considered essentially non-toxic. In addition to these physiological mixed-chain PCs, many different synthetic diacyl-PCs are currently available, but they have never been systematically evaluated for any interference with cell proliferation. We thus investigated the cell proliferation of several cell lines in the presence of various liposomes consisting of a single PC component and cholesterol. Most of the PCs investigated did not interfere with cell proliferation, supporting the notion that most PCs are safe excipients. Significant IC50 values below 0.5mM were detected for PC(12:0/12:0), PC(14:1/14:1)trans and all diacyl-PCs containing two polyunsaturated fatty acids (PUFAs). The omega-3 PC(22:6/22:6) was the most toxic PC assessed, revealing IC50 values below 100 MUM, but no rule concerning omega-3/6 configuration or acyl chain length could be observed. Physiological mixed-chain PCs containing PUFAs were much less toxic than respective non-physiological diacyl-PCs. All trans fatty acids in diacyl-PCs interfered more with proliferation than their respective cis-configured counterparts. Depending on the concentration, those diacyl-PCs not only inhibited proliferation but also induced cell death. Unlike the non-toxic PCs usually used for liposomal drug delivery, the elucidated diacyl PCs may be worthy of further examination to eventually construct a toxic shell for toxic drugs, thereby enhancing anticancer drug delivery via lipid particles. PMID- 25912000 TI - Evaluation of Neurodevelopment Using Bayley-III in Children with Cyanotic or Hemodynamically Impaired Congenital Heart Disease. AB - OBJECTIVE: The purpose of this study was to compare neurological development of children with cyanotic or hemodynamically impaired congenital heart disease (CHD) and healthy controls by using "Bayley Scales of Infant and Toddler Development Screening Test, Third Edition" (Bayley-III). PATIENTS: Children with CHD (n = 37) and healthy controls (n = 24) aged between 1 and 41 months who were admitted to the Department of Pediatric Cardiology at our university hospital were included. The participants were assessed using Bayley-III test. All patients had cyanotic or hemodynamically impaired CHD. Weight, height, body mass index (BMI), mid-arm circumference (MAC), triceps skinfold thickness (TSF), and head circumference (HC) were measured and standard deviation scores (SDSs) were determined. RESULTS: SDS values of weight, height, BMI, MAC, and TSF of the patients as well as HC values were significantly lower than the control group (P < .001). Compared with controls, the patients had significantly lower mean scores in all Bayley-III subscales (P < .001). We observed similar results in Bayley-III scores including the mean values of cognitive, language, and global motor scores for the CHD patients with and without cardiac surgery (P > .05). CONCLUSION: This study demonstrated that children with cyanotic or hemodynamically impaired CHD have delayed neurodevelopmental outcomes compared with healthy children as assessed using Bayley-III. PMID- 25911999 TI - Functional mu opioid receptor polymorphism (OPRM1 A(118) G) associated with heroin use outcomes in Caucasian males: A pilot study. AB - BACKGROUND: Heroin's analgesic, euphoric and dependence-producing effects are primarily mediated by the mu opioid receptor (MOR). A single gene, OPRM1, encodes the MOR. The functional polymorphism A(118)G, located in exon 1 of the OPRM1 gene, results in anatomically-specific reductions in MOR expression, which may alter an individual's response to heroin. In prior studies 118G (rare allele) carriers demonstrated significantly greater opioid tolerance, overdose vulnerability, and pain sensitivity than 118AA homozygotes. Those findings suggest OPRM1 genotype may impact characteristics of heroin use. METHODS: The present pilot study characterized the impact of OPRM1 genotype (rs1799971, 118G allele carriers vs. 118AA homozygotes) on heroin-use phenotypes associated with heroin dependence severity in a sample of male, Caucasian chronic heroin users (n = 86). RESULTS: Results indicate that 118G allele carriers reported significantly more heroin use-related consequences and heroin-quit attempts, and were more likely to have sought treatment for their heroin use than 118AA homozygotes. CONCLUSIONS: These preliminary findings, consistent with extant data, illustrate a role for OPRM1 allelic variation on heroin use characteristics, and provide support for considering genotype in heroin treatment and relapse prevention. PMID- 25911998 TI - A potential role for endogenous proteins as sacrificial sunscreens and antioxidants in human tissues. AB - Excessive ultraviolet radiation (UVR) exposure of the skin is associated with adverse clinical outcomes. Although both exogenous sunscreens and endogenous tissue components (including melanins and tryptophan-derived compounds) reduce UVR penetration, the role of endogenous proteins in absorbing environmental UV wavelengths is poorly defined. Having previously demonstrated that proteins which are rich in UVR-absorbing amino acid residues are readily degraded by broadband UVB-radiation (containing UVA, UVB and UVC wavelengths) here we hypothesised that UV chromophore (Cys, Trp and Tyr) content can predict the susceptibility of structural proteins in skin and the eye to damage by physiologically relevant doses (up to 15.4 J/cm(2)) of solar UVR (95% UVA, 5% UVB). We show that: i) purified suspensions of UV-chromophore-rich fibronectin dimers, fibrillin microfibrils and beta- and gamma-lens crystallins undergo solar simulated radiation (SSR)-induced aggregation and/or decomposition and ii) exposure to identical doses of SSR has minimal effect on the size or ultrastructure of UV chromophore-poor tropoelastin, collagen I, collagen VI microfibrils and alpha crystallin. If UV chromophore content is a factor in determining protein stability in vivo, we would expect that the tissue distribution of Cys, Trp and Tyr-rich proteins would correlate with regional UVR exposure. From bioinformatic analysis of 244 key structural proteins we identified several biochemically distinct, yet UV chromophore-rich, protein families. The majority of these putative UV-absorbing proteins (including the late cornified envelope proteins, keratin associated proteins, elastic fibre-associated components and beta- and gamma-crystallins) are localised and/or particularly abundant in tissues that are exposed to the highest doses of environmental UVR, specifically the stratum corneum, hair, papillary dermis and lens. We therefore propose that UV chromophore-rich proteins are localised in regions of high UVR exposure as a consequence of an evolutionary pressure to express sacrificial protein sunscreens which reduce UVR penetration and hence mitigate tissue damage. PMID- 25912001 TI - Significantly higher prevalence of circulating bullous pemphigoid-specific IgG autoantibodies in elderly patients with a nonbullous skin disorder. PMID- 25912003 TI - Letter to the editor. PMID- 25912002 TI - Assessing subjective quality of life domains after multiple sclerosis diagnosis disclosure. AB - BACKGROUND AND OBJECTIVE: An investigation of the domains Italian patients with multiple sclerosis (MS) named as constituting their quality of life over time. DESIGN: We assessed, in 68 patients, QoL domains using the Schedule for the Evaluation of Individual QoL: (a) before MS diagnosis disclosure, (b) thirty days after disclosure, and (c) after one and (d) four years' follow-up. RESULTS: The life domains most frequently named by patients were as follows: Family, Work and Finance, Hobbies, Health, Relationship with Friends and Job Effectiveness. Only Health and Job Effectiveness domains varied with time. The Health domain became a critical dimension when MS diagnosis was revealed. In addition, patients tended to be more satisfied with their health after disclosure compared to pre diagnosis. Job Effectiveness seemed to be an important aspect until 1 year after diagnosis disclosure, but it tended to become less crucial over time. Family seems to be the most important domain over time, and psychological adaptation to MS seems to be characterized by a reconceptualization of aspects that revolve around oneself, such as professional success, rather than relational or affective factors. CONCLUSIONS: Evaluating the most relevant life domains for patients and their alteration over time may provide practitioners with an important tool in making health-related decisions, thus improving health outcomes and QoL. PMID- 25912005 TI - Evaluation of the response chemotherapy for penile metastasis of bladder cancer using 18F-fluorodeoxyglucose-PET/CT. AB - BACKGROUND: Metachronous penile metastasis of bladder cancer occurs very rarely. The clinical management of the disease involves complex problems, and the disease is associated with a poor prognosis. The common mode of spread to the penis is by the retrograde venous route. PATIENTS AND METHODS: A 68-year-old patient who was diagnosed with invasive bladder cancer underwent (18)F-fluorodeoxyglucose (FDG) positron-emission tomography/computed tomography (PET/CT) for staging purposes. An 18mm intracavernosal metastatic lesion was detected in the penis with a SUVmax of 12.9. RESULTS: After the administration of gemcitabine+cisplatin-based chemotherapy, remission was observed in the metastatic penile lesion according to EORTC criteria (12mm, SUVmax: 9), and second line chemotherapy program was planned. CONCLUSION: Penile metastasis from bladder cancer is an indicator of poor prognosis. The patients with penile metastasis poorly respond to therapy, despite the use of effective systemic chemotherapy. The researchers of the current study achieved a partial response to chemotherapy in the current case of penile metastasis. The disease-specific life expectancy is less than one year in these patients. Radical ablative surgery does not contribute to survival; however, it offers an alternative method in symptomatic patients. PMID- 25912004 TI - Central nervous system prophylaxis in non-Hodgkin lymphoma: who, what, and when? AB - Secondary central nervous system (CNS) progression in patients with non-Hodgkin lymphoma (NHL) is associated with a particularly poor prognosis. In this review, we summarize and critically evaluate the current literature to guide the practicing clinician in estimating CNS relapse risk in order to select individual patients who may benefit from CNS prophylaxis, covering histologic subtype, anatomic location, and molecular and clinical factors. We summarize the data regarding different prophylaxis strategies used and provide our recommendation regarding who should receive it, what they should receive, and when it should be administered. PMID- 25912006 TI - Squamous cell carcinoma arising from an epidermal cyst in the thumb. AB - INTRODUCTION: Squamous cell carcinoma arising from an epidermal cyst is rare, and the most frequently affected region is the head and neck. PRESENTATION OF CASE: A 41-year-old man noticed swelling and a small ulceration in the thumb pulp. A lesion with a 2-cm diameter was simply resected based on a diagnosis of infected epidermal cyst. Pathological diagnosis of the resected material was squamous cell carcinoma arising from an epidermal cyst. Consequent amputation was performed. DISCUSSION AND CONCLUSION: The clinical symptoms of squamous cell carcinoma arising from an epidermal cyst can mimic those of an infected epidermal cyst. The current report facilitates awareness of such disease. PMID- 25912007 TI - A rare case of extracranial meningioma in parapharyngeal space presented as a neck mass. AB - BACKGROUND: Meningiomas are the most common intracranial tumor, but rarely, they can develop extracranially, usually in the neck. There are very few cases of parapharyngeal meningioma reported in literature and little is known about their biological behavior and operative management. We present a patient with a primary parapharyngeal meningioma that presented as an anterior neck mass. CASE PRESENTATION: The patient is a 55-year-old female who presented with neck mass. A CT scan and MRI revealed a large, well defined, mildly enhancing soft tissue mass located in the right carotid sheath extended from the level of the thyroid gland into the skull base jugular foramen superiorly. Cervical exploration with partial excision of the mass was performed. Histological examination revealed meningiothelial cells with intranuclear inclusions, arranged in a syncytial pattern. Mutiple psamoma bodies these findings are consistent with the diagnosis of meningioma. CONCLUSION: Extracranial meningiomas are quite rare. The diagnosis of these types of tumors is challenging due to the non specific nature of the symptoms. The anatomic complexity of the region of parapharyngeal space also makes their detection difficult. Imaging modalities can aid in the diagnosis, but pathological examinations are essential in confirming a definite diagnosis. PMID- 25912008 TI - A rare reason of the elevated serum Ca 19-9 and Ca 125 levels in neonatal period: Hydrometrocolpos due to distal vaginal atresia. PMID- 25912013 TI - Cutaneous Penicillium marneffei infection in a patient with idiopathic CD4(+) lymphocytopenia. AB - We describe a case of cutaneous Penicillium marneffei infection in a non-HIV infected male patient with idiopathic CD4(+) T lymphocytopenia (ICL). The cutaneous lesions were cured after the treatment of itraconazole combined with interleukin-2. PMID- 25912014 TI - Organ-Specific Cancer Metabolism and Its Potential for Therapy. AB - Targeting cancer metabolism has the potential to lead to major advances in tumor therapy. Numerous promising metabolic drug targets have been identified. Yet, it has emerged that there is no singular metabolism that defines the oncogenic state of the cell. Rather, the metabolism of cancer cells is a function of the requirements of a tumor. Hence, the tissue of origin, the (epi)genetic drivers, the aberrant signaling, and the microenvironment all together define these metabolic requirements. In this chapter we discuss in light of (epi)genetic, signaling, and environmental factors the diversity in cancer metabolism based on triple-negative and estrogen receptor-positive breast cancer, early- and late stage prostate cancer, and liver cancer. These types of cancer all display distinct and partially opposing metabolic behaviors (e.g., Warburg versus reverse Warburg metabolism). Yet, for each of the cancers, their distinct metabolism supports the oncogenic phenotype. Finally, we will assess the therapeutic potential of metabolism based on the concepts of metabolic normalization and metabolic depletion. PMID- 25912015 TI - Adipose Tissue Stem Cells. PMID- 25912016 TI - Behavioural correlates of combinatorial versus temporal features of odour codes. AB - Most sensory stimuli evoke spiking responses that are distributed across neurons and are temporally structured. Whether the temporal structure of ensemble activity is modulated to facilitate different neural computations is not known. Here, we investigated this issue in the insect olfactory system. We found that an odourant can generate synchronous or asynchronous spiking activity across a neural ensemble in the antennal lobe circuit depending on its relative novelty with respect to a preceding stimulus. Regardless of variations in temporal spiking patterns, the activated combinations of neurons robustly represented stimulus identity. Consistent with this interpretation, locusts reliably recognized both solitary and sequential introductions of trained odourants in a quantitative behavioural assay. However, predictable behavioural responses across locusts were observed only to novel stimuli that evoked synchronized spiking patterns across neural ensembles. Hence, our results indicate that the combinatorial ensemble response encodes for stimulus identity, whereas the temporal structure of the ensemble response selectively emphasizes novel stimuli. PMID- 25912018 TI - Drug discovery in academia. AB - Participation of academic centers in aspects of drug discovery and development beyond target identification and clinical trials is rapidly increasing. Yet many academic drug discovery projects continue to stall at the level of chemical probes, and they infrequently progress to drugs suitable for clinical trials. This gap poses a major hurdle for academic groups engaged in drug discovery. A number of approaches have been pursued to overcome this gap, including stopping at the production of high-quality chemical probes, establishing the resources in house to advance select projects toward clinical trials, partnering with not-for profit groups to bring the necessary resources and expertise to develop probes into drugs, and drug repurposing, whereby known drugs are advanced into clinical trials for new indications. In this review, we consider the role of academia in anticancer drug discovery and development, as well as the strategies used by academic groups to overcome barriers in this process. PMID- 25912017 TI - Possible Role of GADD45gamma Methylation in Diffuse Large B-Cell Lymphoma: Does It Affect the Progression and Tissue Involvement? AB - OBJECTIVE: Diffuse large B-cell lymphoma (DLBCL) is the most common type of non Hodgkin lymphoma among adults and is characterized by heterogeneous clinical, immunophenotypic, and genetic features. Different mechanisms deregulating cell cycle and apoptosis play a role in the pathogenesis of DLBCL. Growth arrest DNA damage-inducible 45 (GADD45gamma) is an important gene family involved in these mechanisms. The aims of this study are to determine the frequency of GADD45gamma methylation, to evaluate the correlation between GADD45gamma methylation and protein expression, and to investigate the relation between methylation status and clinicopathologic parameters in DLBCL tissues and reactive lymphoid node tissues from patients with reactive lymphoid hyperplasia. MATERIALS AND METHODS: Thirty-six tissue samples of DLBCL and 40 nonmalignant reactive lymphoid node tissues were analyzed in this study. Methylation-sensitive high-resolution melting analysis was used for the determination of GADD45gamma methylation status. The GADD45gamma protein expression was determined by immunohistochemistry. RESULTS: GADD45gamma methylation was frequent (50.0%) in DLBCL. It was also significantly higher in advanced-stage tumors compared with early-stage (p=0.041). In contrast, unmethylated GADD45gamma was associated with nodal involvement as the primary anatomical site (p=0.040). CONCLUSION: The results of this study show that, in contrast to solid tumors, the frequency of GADD45gamma methylation is higher and this epigenetic alteration of GADD45gamma may be associated with progression in DLBCL. In addition, nodal involvement is more likely to be present in patients with unmethylated GADD45gamma. PMID- 25912019 TI - Limited efficacy of BMS-911543 in a murine model of Janus kinase 2 V617F myeloproliferative neoplasm. AB - Activation of Janus kinase 2 (JAK2), frequently as a result of the JAK2(V617F) mutation, is a characteristic feature of the classical myeloproliferative neoplasms (MPNs) polycythemia vera, essential thrombocythemia, and myelofibrosis, and it is thought to be responsible for the constitutional symptoms associated with these diseases. BMS-911543 is a JAK2-selective inhibitor that induces apoptosis in JAK2-dependent cell lines and inhibits the growth of CD34(+) progenitor cells from patients with JAK2(V617F)-positive MPN. To explore the clinical potential of this inhibitor, we tested BMS-911543 in a murine retroviral transduction-transplantation model of JAK2(V617F) MPN. Treatment was initiated at two dose levels (3 mg/kg and 10 mg/kg) when the hematocrit exceeded 70%. Following the first week, white blood cell counts were reduced to normal in the high-dose group and were maintained well below the levels in vehicle-treated mice throughout the study. However, BMS-911543 had no effect on red blood cell parameters. After 42 days of treatment, the proportion of JAK2(V617F)-positive cells in hematopoietic tissues was identical or slightly increased compared with controls. Plasma concentrations of interleukin 6, interleukin 15, and tumor necrosis factor alpha were elevated in MPN mice and reduced in the high-dose treatment group, whereas other cytokines were unchanged. Inhibitor activity after dosing was confirmed in a cell culture assay using the plasma of dosed mice and phosphorylated signal transducer and activator of transcription 5 flow cytometry. Collectively, these results show that BMS-911543 has limited activity in this murine model of JAK2(V617F)-driven MPN and suggest that targeting JAK2 alone may be insufficient to achieve effective disease control. PMID- 25912020 TI - Bacterial biogeography in the coastal waters of northern Zhejiang, East China Sea is highly controlled by spatially structured environmental gradients. AB - The underlying mechanisms of microbial community assembly in connective coastal environments are unclear. The coastal water area of northern Zhejiang, East China Sea, is a complex marine ecosystem with multiple environmental gradients, where the distributions and determinants of bacterioplankton communities remain unclear. We collected surface water samples from 95 sites across eight zones in this area for investigating bacterial community with 16S rRNA gene high throughput sequencing. Bacterial alpha-diversity exhibits strong associations with water chemical parameters and latitude, with 75.5% of variation explained by suspended particle. The composition of dominant phyla can group the sampling sites into four bacterial provinces, and most key discriminant phyla and families/genera of each province strongly associate with specific environmental features, suggesting that local environmental conditions shape the biogeographic provincialism of bacterial taxa. At a broader and finer phylogenetic scale, bacterial beta-diversity is dominantly explained by the shared variation of environmental and spatial factors (63.3%); meanwhile, the environmental determinants of bacterial beta-diversity generally exhibit spatially structured patterns, suggesting that bacterial assembly in surface water is highly controlled by spatially structured environmental gradients in this area. This study provides evidence for the unique biogeographic pattern of bacterioplankton communities at an entire scale of this marine ecosystem. PMID- 25912021 TI - High prevalence of methicillin-resistant Staphylococcus aureus (MRSA) carrying the mecC gene in a semi-extensive red deer (Cervus elaphus hispanicus) farm in Southern Spain. AB - The objective was to determine the prevalence of Staphylococcus aureus nasal carriage in red deer of a semi-extensive farm and in humans in contact with the estate animals, and to characterize obtained isolates. Nasal swabs of 65 deer and 15 humans were seeded on mannitol-salt-agar and oxacillin-resistance-screening agar-base. Isolates were identified by microbiological and molecular methods. Antimicrobial susceptibility profile was determined for 16 antibiotics by disk diffusion and the presence of eight antibiotic resistance genes, seven virulence genes and genes of immune-evasion-cluster (IEC) was analyzed by PCR. S. aureus was typed by PFGE-SmaI, spa, agr, SCCmec and MLST. Isolates were detected in 16 deer (24.6%). Eleven S. aureus isolates were methicillin-resistant (MRSA), and five were methicillin-susceptible (MSSA). All MRSA harbored mecC gene and were agr-III/SCCmecXI/ST1945 (four spa-t843 and seven spa-t1535). All mecC-MRSA carried blaZ-SCCmecXI and etd2, were IEC-type-E, and belonged to the same PFGE pattern. The five MSSA were typed as spa-t2420/agr-I/ST133. Regarding humans, S. aureus was recovered from six samples (40%). The isolates were MSSA and were typed as spa-t002/agr-II, spa-t012/agr-III or spa-t822/agr-III and showed different IEC types (A, B, D and F). blaZ and erm(A) genes were detected, as well as cna and tst genes. As conclusion, red deer analyzed in this study are frequent carriers of mecC-MRSA CC130 (16.9%), they are characterized by few resistance and virulence determinants, and by the presence of IEC type-E. Deer could be a source of mecC-MRSA which could potentially be transmitted to other animals, or even to humans. PMID- 25912022 TI - PRRS virus receptors and their role for pathogenesis. AB - Porcine reproductive and respiratory syndrome virus (PRRSV) is endemic in most pig producing countries worldwide and causes enormous economic losses to the swine industry. Specifically differentiated porcine alveolar macrophages are the primary target for PRRSV infection in pigs. At least six cellular molecules have been described so far as putative receptors for PRRSV, and they include heparan sulfate, vimentin, CD151, sialoadhesin (CD169; siglec-1), dendritic cell-specific intercellular adhesion melecule-3-grabbing non-integrin (DC-SIGN; CD209), and CD163 (SRCR, cysteine-rich scavenger receptor). Progress has been made to shed light on the interactions between cells and PRRSV, and this review describes the advances and current understanding of the entry of PRRSV to cells with a particular focus on the role of CD163 and sialoadhesin for infection and PRRSV pathogenesis. CD163 is most likely the primary and core receptor for PRRSV and determines the susceptibility of cells to the virus. Sialoadhesin is either unnecessary for infection or may function as an accessory protein. Sialoadhesin has been mostly studied for genotype I PRRSV whereas the utilization of CD163 has been mostly studied using genotype II PRRSV, and whether each genotype indeed utilizes a different receptor is unclear. PMID- 25912023 TI - Establishment of a novel and highly permissive cell line for the efficient replication of cyprinid herpesvirus 2 (CyHV-2). AB - Haematopoietic necrosis of gibel carp (Carassius auratus gibelio) is caused by cyprinid herpesvirus 2 (CyHV-2) and has caused huge economic losses in aquaculture worldwide. Currently the isolation and propagation of CyHV-2 in vitro is very difficult due to the lack of permissive cell lines. Studies on the pathogenesis of CyHV-2 have been hampered because the virus has not been extensively characterized. In this study, a novel cell line from the brain of gibel carp, denoted GiCB, has been established and characterized. Sustainable propagation of CyHV-2 in the GiCB cell line has been confirmed by virus infection and titration, PCR, transmission electron microscopy, immunofluorescence assay and fluorescence in situ hybridization. The GiCB cells showed typical cytopathic effect by day 6 post-infection with CyHV-2 including cell shrinkage, rounding, and cell fusion with cytoplasmic vacuolization. The virus titer reached 10(7.5 +/ 0.37)TCID50/ml and has been successfully passaged over 50 times in the GiCB cell line. Electron microscopy analysis revealed the complete replication of CyHV-2 in GiCB cells. CyHV-2-infected GiCB cells reacted strongly with polyclonal antibodies against CyHV-2 and CyHV-2 RNA in cells hybridized specifically with the virus RNA probes. Additionally, an experimental infection demonstrated that CyHV-2 produced in GiCB cells caused 100% mortality in gibel carp. All the results provide solid evidence that the GiCB cell line is highly permissive for the isolation and propagation of CyHV-2. This is a significant advancement that will promote additional research on CyHV-2 infection in fish in the future. PMID- 25912024 TI - Susceptibility of farmed juvenile giant grouper Epinephelus lanceolatus to a newly isolated grouper iridovirus (genus Ranavirus). AB - A ranavirus was isolated from the diseased farmed groupers (Grouper iridovirus in genus Ranavirus, GIV-R), Epinephelus hybrids (blotchy rock cod, Epinephelus fuscoguttatus ?*giant grouper, Epinephelus lanceolatus ?), in Sanya, Hainan, in July 2013. In this study, susceptibility of farmed juvenile giant grouper E. lanceolatus to GIV-R was determined by intraperitoneally injection. The cumulative mortality reached to 81% at 5 day post infection. Histologically, severe degeneration with massive pycnotic nuclei in spleen and kidney tissues was observed, and some small-size inclusion body-bearing cells (IBCs) existed in spleen. Hemorrhage and infiltration of inflammatory cells were presented in gill, liver and heart along with tissue degeneration and necrosis of varying severity. The results of immunohistochemistry analysis showed that the strongest immunolabellings were obtained from the kidney and spleen tissues, while intermediate intensity signals were observed in the heart, stomach, gill and liver tissues, and the weakest signals were obtained from the intestine and brain, but no signal was obtained in eyes. Electron microscopy revealed that spleen of moribund fish contained many viral particles in cytoplasm. Interestingly, in surviving fish, abnormal hypertrophic cells were observed in both splenic corpuscle and renal corpuscle, while no hypertrophic cell was observed in the other parts of spleen and kidney tissues. Moreover, immunolabellings only stained the hypertrophic cells in splenic corpuscle and renal corpuscle. This indicated that splenic corpuscle and renal corpuscle play an important role in GIV-R infection and replication. PMID- 25912025 TI - Mequindox resistance and in vitro efficacy in animal-derived Escherichia coli strains. AB - This study investigated the in vitro efficacy of mequindox against enteropathogenic Escherichia coli (EPEC), and characterized the oqxAB genes as the main mequindox resistance determinant in E. coli strains of animal origin. A total of 1123 E. coli isolates were collected from domestic animals in China from the 1970s to 2013, and mequindox susceptibility was tested by broth microdilution. The percentage of E. coli isolates with increased mequindox MICs of >= 64 MUg/ml showed a rising trend each year throughout the study period. Mequindox showed good bactericidal activity in vitro towards 20 EPEC strains, although it had a wide mutant selection window. All 1123 E. coli isolates were tested for the presence of the oqxAB genes, and the operon was detected in 322 isolates, which accounted for 94.4% (322/341) of isolates with increased MICs to mequindox (MIC >= 64 MUg/ml). Of the isolates with mequindox MIC <= 32 MUg/ml, 98.8% (773/782) were oqxAB negative. Polymerase chain reaction-based stability testing revealed that the IS26-oqxAB circular intermediate was present in 93.4% (309/331) of the oqxAB-positive strains, indicating that this IS26-flanked Tn6010 element was unstable and prone to excision via IS26-mediated recombination. Functional analysis of the oqxAB genes confirmed that this operon alone is sufficient to confer resistance or increased MICs to multiple antimicrobials, including mequindox. This is the first study to investigate the relationship between mequindox susceptibility and oqxAB genotype, and may provide the basis for establishing the resistance breakpoint for mequindox against E. coli. PMID- 25912026 TI - Isolation and bioactivity of diterpenoids from the roots of Salvia grandifolia. AB - A phytochemical investigation of root extracts of Salvia grandifolia led to isolation of six previously unreported diterpenoids, grandifolias A-F, along with eight known compounds. The structures of grandifolias A-F were primarily established by extensive 1D and 2D NMR spectroscopic analyses, as well as HRESIMS data. Their absolute configurations were assigned by their calculated and experimental electronic circular dichroism spectra or by X-ray diffraction analysis. All of the diterpenoids were evaluated for their vasorelaxant effects. Grandifolia B and isograndifoliol both exhibited dose-dependent vasorelaxant effects on rat aortic rings, preconstricted by KCl or norepinephrine, with EC50 values of 36.36-74.51MUg/mL. PMID- 25912027 TI - Three-dimensional zinc incorporated borosilicate bioactive glass scaffolds for rodent critical-sized calvarial defects repair and regeneration. AB - The biomaterials with high osteogenic ability are being intensively investigated. In this study, we evaluated the bioactivity and osteogenesis of BG-Zn scaffolds in vitro and in vivo with a rodent calvarial defects model. Zinc containing borosilicate bioactive glass was prepared by doping glass with 1.5, 5 and 10 wt.% ZnO (denoted as BG-1.5Zn, BG-5Zn and BG-10Zn, respectively). When immersed in simulated body fluid, dopant ZnO retarded the degradation process, but did not affect the formation of hydroxyapatite (HA) after long-period soaking. BG-Zn scaffolds showed controlled release of Zn ions into the medium for over 8 weeks. Human bone marrow derived stem cells (hBMSCs) attached well on the BG-1.5Zn and BG-5Zn scaffolds, which exhibited no cytotoxicity to hBMSCs. In addition, the alkaline phosphatase activity of the hBMSCs increased with increasing dopant amount in the glass, while the BG-10Zn group showed over-dose of Zn. Furthermore, when implanted in rat calvarial defects for 8 weeks, the BG-5Zn scaffolds showed a significantly better capacity to regenerate bone tissue compared to the non doping scaffolds. Generally, these results showed the BG-Zn scaffolds with high osteogenic capacity will be promising candidates using in bone tissue repair and regeneration. PMID- 25912028 TI - Athrombogenic hydrogel coatings for medical devices--Examination of biological properties. AB - In the article the authors present hydrogel coatings prepared from polyvinylpyrrolidone (PVP) macromolecules, which are chemically bonded to polyurethane (PU) substrate. The coating is designed to improve the surface hemocompatibility of blood-contacting medical devices. The coating was characterized in terms of physical properties (swelling ratio, hydrogel density, surface morphology, coating thickness, coating durability). In order to examine surface hemocompatibility, the materials were contacted with whole human blood under arterial flow simulated conditions followed by calculation of platelet consumption and the number of platelet aggregates. Samples were also contacted with platelet-poor plasma; the number of surface-adsorbed fibrinogen molecules was measured using ELISA assay. Finally, the inflammatory reaction after implantation was assessed, using New Zealand rabbits. The designed coating is characterized by high water content and excellent durability in aqueous environment - over a 35-day period, no significant changes in coating thickness were observed. Experiments with blood proved twice the reduction in adsorption of serum-derived fibrinogen together with a moderate reduction in the number of platelet aggregates formed during the contact of the material with blood. The analysis of an inflammatory reaction after the implantation confirmed high biocompatibility of the fabricated materials - studies have shown no toxic effects of the implanted material on the surrounding animal tissues. PMID- 25912029 TI - The East Jakarta Project: surveillance for highly pathogenic avian influenza A(H5N1) and seasonal influenza viruses in patients seeking care for respiratory disease, Jakarta, Indonesia, October 2011-September 2012. AB - Indonesia has reported the most human infections with highly pathogenic avian influenza (HPAI) A(H5N1) virus worldwide. We implemented enhanced surveillance in four outpatient clinics and six hospitals for HPAI H5N1 and seasonal influenza viruses in East Jakarta district to assess the public health impact of influenza in Indonesia. Epidemiological and clinical data were collected from outpatients with influenza-like illness (ILI) and hospitalized patients with severe acute respiratory infection (SARI); respiratory specimens were obtained for influenza testing by real-time reverse transcription-polymerase chain reaction. During October 2011-September 2012, 1131/3278 specimens from ILI cases (34.5%) and 276/1787 specimens from SARI cases (15.4%) tested positive for seasonal influenza viruses. The prevalence of influenza virus infections was highest during December May and the proportion testing positive was 76% for ILI and 36% for SARI during their respective weeks of peak activity. No HPAI H5N1 virus infections were identified, including hundreds of ILI and SARI patients with recent poultry exposures, whereas seasonal influenza was an important contributor to acute respiratory disease in East Jakarta. Overall, 668 (47%) of influenza viruses were influenza B, 384 (27%) were A(H1N1)pdm09, and 359 (25%) were H3. While additional data over multiple years are needed, our findings suggest that seasonal influenza prevention efforts, including influenza vaccination, should target the months preceding the rainy season. PMID- 25912031 TI - Targets to increase food production: One Health implications. AB - The increasing world population means that there is a requirement to expand global food production. Looking at the Republic of Ireland as an example, the risks and opportunities associated with the expansion of food production are outlined, particularly in relation to zoonoses transmission. A One Health approach to sustainable food production is required to avert a potential public health problem associated with increased agricultural expansion. PMID- 25912030 TI - A transmembrane C-terminal fragment of syndecan-1 is generated by the metalloproteinase ADAM17 and promotes lung epithelial tumor cell migration and lung metastasis formation. AB - Syndecan-1 is a heparan sulfate proteoglycan expressed by endothelial and epithelial cells and involved in wound healing and tumor growth. Surface expressed syndecan-1 undergoes proteolytic shedding leading to the release of the soluble N-terminal ectodomain from a transmembrane C-terminal fragment (tCTF). We show that the disintegrin and metalloproteinase (ADAM) 17 generates a syndecan-1 tCTF, which can then undergo further intra-membrane proteolysis by gamma secretase. Scratch-induced wound closure of cultured lung epithelial A549 tumor cells associates with increased syndecan-1 cleavage as evidenced by the release of shed syndecan-1 ectodomain and enhanced generation of the tCTF. Both wound closure and the associated syndecan-1 shedding can be suppressed by inhibition of ADAM family proteases. Cell proliferation, migration and invasion into matrigel as well as several signaling pathways implicated in these responses are suppressed by silencing of syndecan-1. These defects of syndecan-1 deficient cells can be overcome by overexpression of syndecan-1 tCTF or a corresponding tCTF of syndecan-4 but not by overexpression of a tCTF lacking the transmembrane domain. Finally, lung metastasis formation of A549 cells in SCID mice was found to be dependent on syndecan-1, and the presence of syndecan-1 tCTF was sufficient for this activity. Thus, the syndecan-1 tCTF by itself is capable of mediating critical syndecan-1-dependent functions in cell proliferation, migration, invasion and metastasis formation and therefore can replace full length syndecan 1 in the situation of increased syndecan-1 shedding during cell migration and tumor formation. PMID- 25912033 TI - MicroRNA-30 Protects Against Carbon Tetrachloride-induced Liver Fibrosis by Attenuating Transforming Growth Factor Beta Signaling in Hepatic Stellate Cells. AB - Transforming growth factor beta (TGF-beta) is crucial for transdifferentiation of hepatic stellate cells (HSCs) and the blunting of TGF-beta signaling in HSCs can effectively prevent liver fibrosis. Kruppel-like factor 11 (KLF11) is an early response transcription factor that potentiates TGF-beta/Smad signaling by suppressing the transcription of inhibitory Smad7. Using a mouse model of carbon tetrachloride (CCl4)-induced liver fibrosis, we observed significant upregulation of KLF11 in the activated HSCs during liver fibrogenesis. Meanwhile, the downregulation of miR-30 was observed in the HSCs isolated from fibrotic liver. Adenovirus-mediated ectopic expression of miR-30 was under the control of smooth muscle alpha-actin promoter, showing that the increase in miR-30 in HSC greatly reduced CCl4-induced liver fibrosis. Subsequent investigations showed that miR-30 suppressed KLF11 expression in HSC and led to a significant upregulation of Smad7 in vivo. Mechanistic studies further confirmed that KLF11 was the direct target of miR-30, and revealed that miR-30 blunted the profibrogenic TGF-beta signaling in HSC by suppressing KLF11 expression and thus enhanced the negative feedback loop of TGF-beta signaling imposed by Smad7. Finally, we demonstrated that miR-30 facilitated the reversal of activated HSC to a quiescent state as indicated by the inhibition of proliferation and migration, the loss of activation markers, and the gain of quiescent HSC markers. In conclusion, our results define miR-30 as a crucial suppressor of TGF-beta signaling in HSCs activation and provide useful insights into the mechanisms underlying liver fibrosis. PMID- 25912032 TI - Developmental Deltamethrin Exposure Causes Persistent Changes in Dopaminergic Gene Expression, Neurochemistry, and Locomotor Activity in Zebrafish. AB - Pyrethroids are commonly used insecticides that are considered to pose little risk to human health. However, there is an increasing concern that children are more susceptible to the adverse effects of pesticides. We used the zebrafish model to test the hypothesis that developmental exposure to low doses of the pyrethroid deltamethrin results in persistent alterations in dopaminergic gene expression, neurochemistry, and locomotor activity. Zebrafish embryos were treated with deltamethrin (0.25-0.50 MUg/l), at concentrations below the LOAEL, during the embryonic period [3-72 h postfertilization (hpf)], after which transferred to fresh water until the larval stage (2-weeks postfertilization). Deltamethrin exposure resulted in decreased transcript levels of the D1 dopamine (DA) receptor (drd1) and increased levels of tyrosine hydroxylase at 72 hpf. The reduction in drd1 transcripts persisted to the larval stage and was associated with decreased D2 dopamine receptor transcripts. Larval fish, exposed developmentally to deltamethrin, had increased levels of homovanillic acid, a DA metabolite. Since the DA system is involved in locomotor activity, we measured the swim activity of larval fish following a transition to darkness. Developmental exposure to deltamethrin significantly increased larval swim activity which was attenuated by concomitant knockdown of the DA transporter. Acute exposure to methylphenidate, a DA transporter inhibitor, increased swim activity in control larva, while reducing swim activity in larva developmentally exposed to deltamethrin. Developmental exposure to deltamethrin causes locomotor deficits in larval zebrafish, which is likely mediated by dopaminergic dysfunction. This highlights the need to understand the persistent effects of low dose neurotoxicant exposure during development. PMID- 25912034 TI - Conjugation of the mycotoxins alternariol and alternariol monomethyl ether in tobacco suspension cells. AB - The mycotoxins alternariol (AOH) and alternariol-9-O-methyl ether (AME) carry three and two phenolic hydroxyl groups, respectively, which makes them candidates for the formation of conjugated metabolites in plants. Such conjugates may escape routine methods of analysis and have therefore been termed masked or, more recently, modified mycotoxins. We report now that AOH and AME are extensively conjugated in suspension cultures of tobacco BY-2 cells. Five conjugates of AOH were identified by MS and NMR spectroscopy as beta-D-glucopyranosides (attached in AOH 3- or 9-position) as well as their 6'-malonyl derivatives, and as a gentiobiose conjugate. For AME, conjugation resulted in the d-glucopyranoside (mostly attached in the AME 3-position) and its 6'- and 4'-malonyl derivatives. Pronounced differences were noted for the quantitative pattern of AOH and AME conjugates as well as for their phytotoxicity. Our in vitro study demonstrates for the first time that masked mycotoxins of AOH and AME can be formed in plant cells. PMID- 25912035 TI - A high-fat diet containing lard accelerates prostate cancer progression and reduces survival rate in mice: possible contribution of adipose tissue-derived cytokines. AB - To examine the effects of high-fat diet (HFD) containing lard on prostate cancer development and progression and its underlying mechanisms, transgenic adenocarcinoma mouse prostate (TRAMP) and TRAMP-C2 allograft models, as well as in vitro culture models, were employed. In TRAMP mice, HFD feeding increased the incidence of poorly differentiated carcinoma and decreased that of prostatic intraepithelial neoplasia in the dorsolateral lobes of the prostate, which was accompanied by increased expression of proteins associated with proliferation and angiogenesis. HFD feeding also led to increased metastasis and decreased survival rate in TRAMP mice. In the allograft model, HFD increased solid tumor growth, the expression of proteins related to proliferation/angiogenesis, the number of lipid vacuoles in tumor tissues, and levels of several cytokines in serum and adipose tissue. In vitro results revealed that adipose tissue-conditioned media from HFD fed mice stimulated the proliferation and migration of prostate cancer cells and angiogenesis compared to those from control-diet-fed mice. These results indicate that the increase of adipose tissue-derived soluble factors by HFD feeding plays a role in the growth and metastasis of prostate cancer via endocrine and paracrine mechanisms. These results provide evidence that a HFD containing lard increases prostate cancer development and progression, thereby reducing the survival rate. PMID- 25912036 TI - Serum phosphorus levels in premature infants receiving a donor human milk derived fortifier. AB - An elevated serum phosphorus (P) has been anecdotally described in premature infants receiving human milk fortified with donor human milk-derived fortifier (HMDF). No studies have prospectively investigated serum P in premature infants receiving this fortification strategy. In this single center prospective observational cohort study, extremely premature infants <= 1250 grams (g) birth weight (BW) were fed an exclusive human milk-based diet receiving HMDF and serum P levels were obtained. We evaluated 93 infants with a mean gestational age of 27.5 +/- 2.0 weeks (Mean +/- SD) and BW of 904 +/- 178 g. Seventeen infants (18.3%) had at least one high serum P level with a mean serum P of 9.2 +/- 1.1 mg/dL occurring at 19 +/- 11 days of life. For all infants, the highest serum P was inversely correlated to the day of life of the infant (p < 0.001, R2 = 0.175) and positively correlated with energy density of HMDF (p = 0.035). Serum P was not significantly related to gender, BW, gestational age, or days to full feeds. We conclude that the incidence of hyperphosphatemia was mild and transient in this population. The risk decreased with infant age and was unrelated to gender, BW, or ethnicity. PMID- 25912037 TI - Enhanced human neutrophil vitamin C status, chemotaxis and oxidant generation following dietary supplementation with vitamin C-rich SunGold kiwifruit. AB - Neutrophils are the body's primary defenders against invading pathogens. These cells migrate to loci of infection where they engulf micro-organisms and subject them to an array of reactive oxygen species and antimicrobial proteins to effect killing. Spent neutrophils subsequently undergo apoptosis and are cleared by macrophages, thereby resolving the inflammatory episode. Neutrophils contain high concentrations of vitamin C (ascorbate) and this is thought to be essential for their function. This may be one mechanism whereby vitamin C enhances immune function. The aim of our study was to assess the effect of dietary supplementation with vitamin C-rich SunGold kiwifruit on four important functions of neutrophils: chemotaxis, oxidant generation, extracellular trap formation, and apoptosis. Fourteen young men (aged 18-30 years) with suboptimal plasma vitamin C status (<50 MUmol/L) were supplemented for four weeks with two SunGold kiwifruit/day. Plasma vitamin C status was monitored weekly and neutrophil vitamin C levels were assessed at baseline and post-intervention. Neutrophil function assays were carried out on cells isolated at baseline and post intervention. Plasma vitamin C levels increased to >70 MUmol/L (p < 0.001) within one week of supplementation and there was a significant increase in neutrophil vitamin C status following four weeks' intervention (p = 0.016). We observed a significant 20% increase in neutrophil chemotaxis post-intervention (p = 0.041) and also a comparable increase in oxidant generation (p = 0.031). Supplementation did not affect neutrophil extracellular trap formation or spontaneous apoptosis. Our data indicate that supplementation with vitamin C-rich kiwifruit is associated with improvement of important neutrophil functions, which would be expected to translate into enhanced immunity. PMID- 25912038 TI - Dried pomegranate potentiates anti-osteoporotic and anti-obesity activities of red clover dry extracts in ovariectomized rats. AB - Red clover (RC) shows potential activity against menopausal symptoms and pomegranates have antioxidative and beneficial effects on postmenopausal symptoms; thus, we investigated whether the anti-climacteric activity of RC could be enhanced by the addition of dried pomegranate concentrate powder (PCP) extracts in ovariectomized (OVX) rats. Regarding the anti-osteoporotic effects, bone mineral density increased significantly in OVX induced rats treated with 60 and 120 mg/kg of an RC:PCP 2:1 mixture, respectively, compared with OVX control rats. Additionally, femoral, tibia, and L4 bone resorption was decreased in OVX induced control rats treated with the RC:PCP 2:1 mixture (60 and 120 mg/kg), respectively, compared with OVX control rats. Regarding anti-obesity effects, the OVX induced rats treated with 60 and 120 mg/kg of the RC:PCP 2:1 mixture showed a decrease in total fat pad thickness, the mean diameters of adipocytes and the body weights gain compared with OVX induced control rats. The estradiol and bone specific alkaline phosphatase levels were significantly increased in OVX induced rats treated with the RC:PCP 2:1 mixture (120 mg/kg) compared with OVX induced control rats, also, the uterine atrophy was significantly inhibited in 60 and 120 mg/kg of the RC:PCP 2:1 mixture treatment compared with OVX control rats. In conclusion, our results indicate that PCP enhanced the anti-climacteric effects of RC in OVX rats. The RC:PCP 2:1 mixture used in this study may be a promising new potent and protective agent for relieving climacteric symptoms. PMID- 25912040 TI - Soy protein-based infant formulas with supplemental fructooligosaccharides: gastrointestinal tolerance and hydration status in newborn infants. AB - Unlike milk-based infant formulas, soy-based infant formulas containing supplemental fructooligosaccharides (FOS) have not been clinically evaluated. A randomized, double-blind, 28 day parallel feeding trial compared gastrointestinal (GI) tolerance and hydration in healthy term newborn infants fed either a commercialized soy formula (with history of safe use) containing sucrose as 20% of total carbohydrate, no supplemental short-chain FOS (scFOS) and no mixed carotenoids (lutein, lycopene, beta-carotene) as a control (CF, n = 62 infants) or one of two experimental soy-based formulas, EF1 (n = 64) and EF2 (n = 62) containing scFOS (2.5 g/L) and mixed carotenoids. EF1 differed from EF2 by containing sucrose. Results indicated no significant study group differences (p > 0.05) in study completion rates (CF = 81, EF1 = 86, & EF2 = 87%), growth, mean rank stool consistency, stool frequency, formula intake, spit-up/vomit, and safety measures (urine specific gravity, USG; hydration status and adverse events). Mean USGs for study groups were normal (<1.03). The EF1 > CF group in percent yellow stools (p < 0.01 at age 14 days). In conclusion, the study suggested that term infants fed soy-based formulas supplemented with scFOS and mixed carotenoids, with or without sucrose in the 1st 35 days of infancy demonstrated good tolerance and hydration comparable to the control soy-based formula with history of safe use. PMID- 25912039 TI - Vitamin D and 1,25(OH)2D regulation of T cells. AB - Vitamin D is a direct and indirect regulator of T cells. The mechanisms by which vitamin D directly regulates T cells are reviewed and new primary data on the effects of 1,25 dihydroxyvitamin D (1,25(OH)2D) on human invariant natural killer (iNK)T cells is presented. The in vivo effects of vitamin D on murine T cells include inhibition of T cell proliferation, inhibition of IFN-gamma, IL-17 and induction of IL-4. Experiments in mice demonstrate that the effectiveness of 1,25(OH)2D requires NKT cells, IL-10, the IL-10R and IL-4. Comparisons of mouse and human T cells show that 1,25(OH)2D inhibits IL-17 and IFN-gamma, and induces T regulatory cells and IL-4. IL-4 was induced by 1,25(OH)2D in mouse and human iNKT cells. Activation for 72 h was required for optimal expression of the vitamin D receptor (VDR) in human and mouse T and iNKT cells. In addition, T cells are potential autocrine sources of 1,25(OH)2D but again only 48-72 h after activation. Together the data support the late effects of vitamin D on diseases like inflammatory bowel disease and multiple sclerosis where reducing IL-17 and IFN-gamma, while inducing IL-4 and IL-10, would be beneficial. PMID- 25912041 TI - Ginseng berry extract supplementation improves age-related decline of insulin signaling in mice. AB - The aim of this study was to evaluate the effects of ginseng berry extract on insulin sensitivity and associated molecular mechanisms in aged mice. C57BL/6 mice (15 months old) were maintained on a regular diet (CON) or a regular diet supplemented with 0.05% ginseng berry extract (GBD) for 24 or 32 weeks. GBD-fed mice showed significantly lower serum insulin levels (p = 0.016) and insulin resistance scores (HOMA-IR) (p = 0.012), suggesting that GBD improved insulin sensitivity. Pancreatic islet hypertrophy was also ameliorated in GBD-fed mice (p = 0.007). Protein levels of tyrosine phosphorylated insulin receptor substrate (IRS)-1 (p = 0.047), and protein kinase B (AKT) (p = 0.037), were up-regulated in the muscle of insulin-injected GBD-fed mice compared with CON-fed mice. The expressions of forkhead box protein O1 (FOXO1) (p = 0.036) and peroxisome proliferator-activated receptor gamma (PPARgamma) (p = 0.032), which are known as aging- and insulin resistance-related genes, were also increased in the muscle of GBD-fed mice. We conclude that ginseng berry extract consumption might increase activation of IRS-1 and AKT, contributing to the improvement of insulin sensitivity in aged mice. PMID- 25912042 TI - Interactions between obesity-related copy number variants and dietary behaviors in childhood obesity. AB - Copy number variants (CNVs) have been implicated as an important genetic marker of obesity, and gene-environment interaction has been found to modulate risk of obesity. To evaluate the associations between CNVs and childhood obesity, as well as the interactions between CNVs and dietary behaviors, we recruited 534 obese children and 508 controls from six cities in China and six candidate CNVs were screened through published genome-wide studies (GWAS) on childhood obesity. We found three loci (10q11.22, 4q25 and 11q11) to be significantly associated with obesity after false discovery rate (FDR) correction (all the p <= 0.05). Cumulative effect of the three positive loci was measured by the genetic risk score (GRS), showing a significant relationship with the risk of obesity (Ptrend < 0.001). The OR of obesity increased to 21.38 (95% CI = 21.19-21.55) among the 10q11.22 deletion carriers who had meat-based diets, indicating prominent multiplicative interaction (MI) between deletions of 10q11.22 and preference for a meat-based diet. Simultaneous deletions of 5q13.2 and duplications of 6q14.1 had significant MI with a preference for salty foods. Our results suggested that CNVs may contribute to the genetic susceptibility of childhood obesity, and the CNV-diet interactions modulate the risk of obesity. PMID- 25912043 TI - Expanding Duplication of Free Fatty Acid Receptor-2 (GPR43) Genes in the Chicken Genome. AB - Free fatty acid receptors (FFAR) belong to a family of five G-protein coupled receptors that are involved in the regulation of lipid metabolism, so that their loss of function increases the risk of obesity. The aim of this study was to determine the expansion of genes encoding paralogs of FFAR2 in the chicken, considered as a model organism for developmental biology and biomedical research. By estimating the gene copy number using quantitative polymerase chain reaction, genomic DNA resequencing, and RNA sequencing data, we showed the existence of 23 +/- 1.5 genes encoding FFAR2 paralogs in the chicken genome. The FFAR2 paralogs shared an identity from 87.2% up to 99%. Extensive gene conversion was responsible for this high degree of sequence similarities between these genes, and this concerned especially the four amino acids known to be critical for ligand binding. Moreover, elevated nonsynonymous/synonymous substitution ratios on some amino acids within or in close-vicinity of the ligand-binding groove suggest that positive selection may have reduced the effective rate of gene conversion in this region, thus contributing to diversify the function of some FFAR2 paralogs. All the FFAR2 paralogs were located on a microchromosome in a same linkage group. FFAR2 genes were expressed in different tissues and cells such as spleen, peripheral blood mononuclear cells, abdominal adipose tissue, intestine, and lung, with the highest rate of expression in testis. Further investigations are needed to determine whether these chicken-specific events along evolution are the consequence of domestication and may play a role in regulating lipid metabolism in this species. PMID- 25912044 TI - The dominance effect of the adaptive transposable element insertion Bari-Jheh depends on the genetic background. AB - Although adaptive mutations are often considered to be dominant, it has been recently shown that a substantial proportion of adaptive mutations should display heterozygote advantage. In this work, we take advantage of a recently characterized transposable element insertion mediating oxidative stress response in Drosophila melanogaster to test the dominance effect of an adaptive mutation. The comparison of the survival curves of heterozygous and the two corresponding homozygous flies indicated that the dominance effect of Bari-Jheh depends on the genetic background. Both in homozygous and in heterozygous flies, Bari-Jheh was associated with upregulation of Jheh1 (Juvenile Hormone Epoxyde Hydrolase 1) and/or Jheh2 genes. Our results add to the limited number of studies in which the dominance effect of adaptive mutations has been empirically estimated and highlights the complexity of their inheritance. PMID- 25912045 TI - Evolution of gene expression after gene amplification. AB - We took a rather unique approach to investigate the conservation of gene expression of prolamin storage protein genes across two different subfamilies of the Poaceae. We took advantage of oat plants carrying single maize chromosomes in different cultivars, called oat-maize addition (OMA) lines, which permitted us to determine whether regulation of gene expression was conserved between the two species. We found that gamma-zeins are expressed in OMA7.06, which carries maize chromosome 7 even in the absence of the trans-acting maize prolamin-box-binding factor (PBF), which regulates their expression. This is likely because oat PBF can substitute for the function of maize PBF as shown in our transient expression data, using a gamma-zein promoter fused to green fluorescent protein (GFP). Despite this conservation, the younger, recently amplified prolamin genes in maize, absent in oat, are not expressed in the corresponding OMAs. However, maize can express the oldest prolamin gene, the wheat high-molecular weight glutenin Dx5 gene, even when maize Pbf is knocked down (through PbfRNAi), and/or another maize transcription factor, Opaque-2 (O2) is knocked out (in maize o2 mutant). Therefore, older genes are conserved in their regulation, whereas younger ones diverged during evolution and eventually acquired a new repertoire of suitable transcriptional activators. PMID- 25912046 TI - The Magellania venosa Biomineralizing Proteome: A Window into Brachiopod Shell Evolution. AB - Brachiopods are a lineage of invertebrates well known for the breadth and depth of their fossil record. Although the quality of this fossil record attracts the attention of paleontologists, geochemists, and paleoclimatologists, modern day brachiopods are also of interest to evolutionary biologists due to their potential to address a variety of questions ranging from developmental biology to biomineralization. The brachiopod shell is a composite material primarily composed of either calcite or calcium phosphate in close association with proteins and polysaccharides which give these composite structures their material properties. The information content of these biomolecules, sequestered within the shell during its construction, has the potential to inform hypotheses focused on describing how brachiopod shell formation evolved. Here, using high throughput proteomic approaches and next generation sequencing, we have surveyed and characterized the first shell-proteome and shell-forming transcriptome of any brachiopod, the South American Magellania venosa (Rhynchonelliformea: Terebratulida). We find that the seven most abundant proteins present in the shell are unique to M. venosa, but that these proteins display biochemical features found in other metazoan biomineralization proteins. We can also detect some M. venosa proteins that display significant sequence similarity to other metazoan biomineralization proteins, suggesting that some elements of the brachiopod shell-forming proteome are deeply evolutionarily conserved. We also employed a variety of preparation methods to isolate shell proteins and find that in comparison to the shells of other spiralian invertebrates (such as mollusks) the shell ultrastructure of M. venosa may explain the effects these preparation strategies have on our results. PMID- 25912047 TI - Phenotypes of severe asthma among children and adolescents in Brazil: a prospective study. AB - BACKGROUND: The morbidity associated with severe uncontrolled asthma is disproportionately higher in low- and middle-income countries than in high-income countries. The aim of this study was to describe the phenotypic characteristics of difficult-to-treat severe asthma and treatment-resistant severe asthma in a sample of children and adolescents in Brazil. METHODS: This was a prospective study, conducted between 2010 and 2014, following 61 patients (6-18 years of age) who had been diagnosed with severe uncontrolled asthma. The patients were classified and managed in accordance with the World Health Organization asthma follow-up protocol, which calls for re-evaluations of the diagnosis, level of control (functional and clinical), comorbidities, inhaler technique, and environmental factors, together with adjustment of the treatment to achieve a target level of control. We assessed pulmonary function, measured fractional exhaled nitric oxide, and performed sputum cytology. After the target rate of >= 80% adherence to inhaled corticosteroid treatment had been reached and all of the re-evaluations had been performed, the patients incorrectly diagnosed with severe uncontrolled asthma were excluded and the remaining patients were classified as having treatment-resistant or difficult-to-treat severe asthma. RESULTS: We found that, of the 61 patients evaluated, 10 had been misdiagnosed (i.e., they did not have asthma), 15 had moderate asthma, and 36 had severe uncontrolled asthma. Among those 36 patients, the asthma was classified as treatment-resistant in 20 (55.6%) and as difficult-to-treat in 16 (44.4%). In comparison with the patients with difficult-to-treat severe asthma, those with treatment-resistant severe asthma showed a higher median level of fractional exhaled nitric oxide (40 ppb vs. 12 ppb; P < 0.037) and a lower median forced expiratory volume in one second (61% vs. 87%; P < 0.001). CONCLUSIONS: Although patients with treatment-resistant severe asthma cannot always be distinguished from those with difficult-to-treat severe asthma on the basis of baseline clinical characteristics, reduced airflow and elevated fractional exhaled nitric oxide are factors that could distinguish the two groups. Patients diagnosed with severe uncontrolled asthma should be re evaluated on a regular basis, in order to exclude other diagnoses, to reduce exacerbations, and to identify patients with persistent airflow limitation. PMID- 25912048 TI - Augmenting mirror visual feedback-induced performance improvements in older adults. AB - Previous studies have indicated that age-related behavioral alterations are not irreversible but are subject to amelioration through specific training interventions. Both training paradigms and non-invasive brain stimulation (NIBS) can be used to modulate age-related brain alterations and thereby influence behavior. It has been shown that mirror visual feedback (MVF) during motor skill training improves performance of the trained and untrained hands in young adults. The question remains of whether MVF also improves motor performance in older adults and how performance improvements can be optimised via NIBS. Here, we sought to determine whether anodal transcranial direct current stimulation (a tDCS) can be used to augment MVF-induced performance improvements in manual dexterity. We found that older adults receiving a-tDCS over the right primary motor cortex (M1) during MVF showed superior performance improvements of the (left) untrained hand relative to sham stimulation. An additional control experiment in participants receiving a-tDCS over the right M1 only (without MVF/motor training of the right hand) revealed no significant behavioral gains in the left (untrained) hand. On the basis of these findings, we propose that combining a-tDCS with MVF might be relevant for future clinical studies that aim to optimise the outcome of neurorehabilitation. PMID- 25912049 TI - Prediction of survival in patients suspected of disseminated intravascular coagulation. AB - BACKGROUND: Although antithrombin (AT), protein C (PC), and antiplasmin (AP) are consumed during disseminated intravascular coagulation (DIC), their association with mortality in patients initially suspected of acute DIC is unknown. We examined how these proteins associate with mortality in consecutive patients initially suspected of DIC, fulfilling or not fulfilling overt DIC criteria. METHODS: All consecutive patients clinically suspected of acute DIC during 5 years at a tertiary referral hospital were scored according to overt International Society of Thrombosis and Haemostasis (ISTH) DIC criteria. The influence of ISTH DIC score and measurements of AT, PC, and AP measured in all on mortality was assessed. RESULTS: During 1825 occurrences in 1814 patients, 91 fulfilled ISTH criteria for overt DIC (score >= 5). Both 28-day and 1-year mortality increased progressively as AT and in particular PC decreased. AT and PC correlated inversely with ISTH score (AT: R(2 ) = 0.14, P < 0.001, PC: R(2 ) = 0.21, P < 0.001). AP decreased when ISTH score of > 3 was reached. The 28-day mortality was 3%, 11%, 16%, 23%, 35%, and 52% and 1-year mortality 5%, 18%, 24%, 36%, 54%, and 63%, respectively for patients with an ISTH score of 0, 1, 2, 3, 4, and >=5 (P < 0.001 for all). CONCLUSIONS: Lowered AT and in particular PC activity was predictive of mortality risk upfront in critically ill patients suspected of acute DIC. Mortality in patients suspected of acute DIC increased progressively across the spectrum of the overt ISTH score and not only in those fulfilling overt DIC criteria. PMID- 25912050 TI - Mucostomy closure using the endoloop/clips technique in a purse-string manner after an unsuccessful closure during peroral endoscopic myotomy. PMID- 25912051 TI - Intravenous carbamazepine as short-term replacement therapy for oral carbamazepine in adults with epilepsy: Pooled tolerability results from two open label trials. AB - OBJECTIVE: To report tolerability findings and maintenance of seizure control from a pooled analysis of phase I open-label trial OV-1015 (NCT01079351) and phase III study 13181A (NCT01128959). METHODS: Patients receiving a stable oral dosage of carbamazepine were switched to an intravenous (IV) carbamazepine formulation solubilized in a cyclodextrin matrix (at a 70% dosage conversion) for either a 15- or a 30-min infusion every 6 h for up to 7 days and then switched back. A subset of patients who tolerated 15-min infusions also received 2- to 5 min (rapid) infusions. Assessments included physical and laboratory evaluations, electrocardiography (ECG) studies, as well as adverse event (AE) monitoring for tolerability. Convulsion/seizure AE terms and data from seizure diaries were used as proxies for the assessment of consistency of seizure control between formulations. RESULTS: Of the 203 patients exposed to IV carbamazepine (30 min, n = 43; 15 min, n = 160), 113 received 149 rapid infusions. During infusion, the most commonly reported AEs (>= 5%) were dizziness (19%), somnolence (6%), headache (6%), and blurred vision (5%). IV carbamazepine was not associated with clinically relevant cardiac AEs. The tolerability profile appeared similar between patients who received <1,600 mg/day (n = 174) and >= 1,600 mg/day (n = 29) carbamazepine. Cyclodextrin exposure was not associated with clinically relevant changes in AEs or renal biomarkers. Seizure control was maintained as patients transitioned between oral and IV carbamazepine. SIGNIFICANCE: IV carbamazepine administered as multiple 30- or 15-min infusions every 6 h, and as a single rapid infusion, was well tolerated as a short-term replacement in adults with epilepsy receiving stable dosages of oral carbamazepine. Infusion site reactions, which were generally mild, were the only unique AEs identified; seizure control was generally unchanged when patients were switching between formulations. PMID- 25912052 TI - Mild chronic graft-versus-host disease may alleviate poor prognosis associated with FLT3 internal tandem duplication for adult acute myeloid leukemia following allogeneic stem cell transplantation with myeloablative conditioning in first complete remission: a retrospective study. AB - Internal tandem duplication (ITD) of the FLT3 gene (Fms-like tyrosine kinase 3) is the most commonly found mutation in acute myeloid leukemia (AML). The significance of FLT3-ITD at diagnosis was retrospectively estimated for allo-HSCT (allogeneic hematopoietic stem cell transplantation) outcomes in 140 patients, median age of 38, undergoing allo-HSCT after myeloablative conditioning in first complete remission of AML. FLT3-ITD was detected at AML diagnosis in 42/140 (30%) of included into this study patients. At 3 years, relapse incidence (RI) following allo-HSCT in AML patients with intermediate or normal karyotype was significantly higher in those FLT3-ITD positive than FLT3-ITD negative [52.9 vs. 20.4%, P = 0.002]. Additionally, patients with mild chronic graft-versus-host disease (cGvHD) had significantly lower RI compared to patients with moderate or severe grade cGvHD or those not experiencing cGvHD, respectively, 4.8 vs. 36.0 vs. 27.8%, P = 0.032. FLT3-ITD was harboring a poor prognosis in AML with intermediate or normal karyotype and significantly increased risk of relapse following allo-HSCT. It appears that allo-HSCT does not cure patients with FLT3 ITD, unless they develop symptoms of mild cGvHD and graft versus leukemia, which may decrease RI. PMID- 25912053 TI - Medical constructions of long-term exhaustion, past and present. AB - Culture and history affect the ways in which medical knowledge is shaped, sustained and changed. The less knowledge we have, the larger the space for the cultural imprint becomes. Based on these assumptions, we ask: how have medical constructions of long-term exhaustion changed over time, and how are changing constructions related to societal change? To discuss these questions we conducted a comparative study of medical texts from two historical periods: 1860-1930 and 1970-2013. Our data are limited to two diagnoses: neurasthenia and encephalomyelitis. After comparing the two periods by identifying diverging and converging aspects, we interpreted observed continuities and interruptions in relation to historical developments. We found that in the medical literature, long-term exhaustion became transformed from a somatic ailment bred by modern civilisation to a self-inflicted psychiatric ailment. At the same time, it changed from being a male-connoted high-status condition to a female-connoted low status condition. We interpret these changes as contingent upon culturally available modes of interpretations. Medical knowledge thereby becomes infused with cultural norms and values which give them a distinct cultural bias. The historical controversies surrounding this medically contested condition neatly display the socially contingent factors that govern the social construction of medical knowledge. PMID- 25912055 TI - Tuning radical reactivity using iodine in oxidative C(sp(3))-H/C(sp)-H cross coupling: an easy way toward the synthesis of furans and indolizines. AB - Molecular iodine was found to be an effective redox catalyst for the oxidative cross-coupling of carbonyl compounds with terminal alkynes. In this work, we demonstrated that iodine could tune radical reactivity through reversible C-I bond formation for controlling the reaction selectivity. This iodine catalysis protocol provided an easy way for the synthesis of various furans and indolizines. PMID- 25912054 TI - Effects of nitric oxide and its congeners on sickle red blood cell deformability. AB - BACKGROUND: Sickle cell disease (SCD) is characterized by hemoglobin polymerization upon deoxygenation. Polymerization causes the sickle cells to become rigid and misshapen (sickling). Red blood cell (RBC) dehydration greatly increases polymerization. Cycles of sickling and unsickling cause an influx of calcium that leads to loss of potassium via the calcium-activated Gardos channel, which dehydrates the cells leading to increased polymerization. In this study the effects of nitric oxide (NO) and its congeners on RBC deformability were examined, focusing on sickle RBCs (sRBCs). STUDY DESIGN AND METHODS: RBCs from patients with SCD and from nonpatients were exposed to various compounds that release NO or its congeners. Intracellular calcium was increased using a calcium ionophore or cycling of oxygen tension for sRBCs. Deformability was measured by laser-assisted osmotic gradient ektacytometry. RESULTS: Consistent with a previous report, sodium nitroprusside (SNP) was found to protect against calcium induced loss of deformability in normal RBCs, but (contrary to some previous reports) no effect of any NO donors was observed when calcium influx was not induced. Importantly, in studies of deoxygenation-induced dehydration of sRBCs, SNP resulted in substantial improvements in deformability (p = 0.036) and hydration (p = 0.024). Sodium nitrite showed similar trends. SNP was shown to have no effect on calcium influx, but reduced potassium efflux. CONCLUSION: These data suggest that SNP and perhaps certain nitrogen oxides (like nitrite) inhibit the Gardos channel and may be able to protect sickle cells from dehydration and thereby improve outcome in the disease. PMID- 25912056 TI - Multiwalled carbon nanotube coated polyester fabric as textile based flexible counter electrode for dye sensitized solar cell. AB - Textile wearable electronics offers the combined advantages of both electronics and textile characteristics. The essential properties of these flexible electronics such as lightweight, stretchable, and wearable power sources are in strong demand. Here, we have developed a facile route to fabricate multi walled carbon nanotube (MWCNT) coated polyester fabric as a flexible counter electrode (CE) for dye sensitized solar cells (DSSCs). A variety of MWCNT and enzymes with different structures were used to generate individual enzyme-dispersed MWCNT (E MWCNT) suspensions by non-covalent functionalization. A highly concentrated colloidal suspension of E-MWCNT was deposited on polyester fabric via a simple tape casting method using an air drying technique. In view of the E-MWCNT coating, the surface structure is represented by topologically randomly assembled tubular graphene units. This surface morphology has a high density of colloidal edge states and oxygen-containing surface groups which execute multiple catalytic sites for iodide reduction. A highly conductive E-MWCNT coated fabric electrode with a surface resistance of 15 Omega sq(-1) demonstrated 5.69% power conversion efficiency (PCE) when used as a flexible CE for DSSCs. High photo voltaic performance of our suggested system of E-MWCNT fabric-based DSSCs is associated with high sheet conductivity, low charge transfer resistance (RCT), and excellent electro catalytic activity (ECA). Such a conductive fabric demonstrated stable conductivity against bending cycles and strong mechanical adhesion of E-MWCNT on polyester fabric. Moreover, the polyester fabric is hydrophobic and, therefore, has good sealing capacity and retains the polymer gel electrolyte without seepage. This facile E-MWCNT fabric CE configuration provides a concrete fundamental background towards the development of textile-integrated solar cells. PMID- 25912071 TI - Large-scale delamination of multi-layers transition metal carbides and carbonitrides "MXenes". AB - Herein we report on a general approach to delaminate multi-layered MXenes using an organic base to induce swelling that in turn weakens the bonds between the MX layers. Simple agitation or mild sonication of the swollen MXene in water resulted in the large-scale delamination of the MXene layers. The delamination method is demonstrated for vanadium carbide and titanium carbonitride MXenes. PMID- 25912072 TI - Do graft diameter or patient age influence the results of ACL reconstruction? AB - PURPOSE: Hamstring tendons are commonly used as a graft source for ACL reconstruction. This study seeks to determine whether either the diameter of the tendon graft or the age of the patient influences the outcome of the ACL reconstruction when measured using a standard, previously validated laxity measurement device. METHODS: This is a retrospective study of 88 patients who underwent ACL reconstruction with a short, quadrupled tendon technique, using the semitendinosus +/- gracilis tendons. Patients included in this study were sequential, unilateral, complete ACL ruptures. The patients were followed for a minimum of 1 year postoperatively, with a mean follow-up of 26 months. Patients were divided into three groups according to the diameter (O) of the graft: group 1 (32 patients): 8 mm <= O <= 9 mm; group 2 (28 patients): 9 mm < O <= 10 mm; and group 3 (28 patients): O > 10 mm. Three groups with differential laxity at 134 N (Delta134 = healthy side vs. operated side) measured with the laximeter GNRB((r)) were compared. The risk of residual laxity (OR) between the three groups taking age, gender, BMI and meniscus status into account was calculated. A side-to-side laxity >3 mm was considered as a residual laxity. RESULTS: The mean patient age at the time of reconstruction was 29.4 years. The three groups were comparable. Postoperative Delta134 was 1.50 +/- 1.3, 1.59 +/- 1.5 and 2 +/- 1.7 mm for groups 1 through 3, respectively. Delta134 > 3 mm was observed in three patients in group 1, four patients in group 2 and nine patients in group 3. As compared to group 1, OR was 1.46 (95 % CI 0.35-6.05) and 3.31 (95 % CI 0.89-12.34) in groups 2 and 3, respectively. Adjustment for age, gender, BMI and meniscus did not change the estimates [OR 1.44 (95 % CI 0.34-6.16) and 3.92 (95 % CI 1-15.37)] in groups 2 and 3, respectively. Patients younger than 20 had a significantly higher average postoperative laximetry (2.4 +/- 1.5 mm) compared to those aged 20 years and over (1.5 +/- 1.5 mm) (p = 0.03), regardless of the diameter of the graft. CONCLUSION: The diameter of the graft between 8 and 10 mm does not affect the laximetric results of an ACL reconstruction. Therefore, there does not appear to be a benefit to harvesting and adding further tissue to increase the diameter of the graft above 10 mm. Patients younger than 20 represent a population at risk of graft elongation. In these patients at risk, postoperative management needs to be modified (delayed weight bearing, articulated splinting, slower rehabilitation) in the first months. LEVEL OF EVIDENCE: Retrospective case series, Level IV. PMID- 25912073 TI - Anatomic anterior cruciate ligament reconstruction: reducing anterior tibial subluxation. AB - PURPOSE: To measure and compare the amount of anterior tibial subluxation (ATS) after anatomic ACL reconstruction for both acute and chronic ACL-deficient patients. METHODS: Fifty-two patients were clinically and radiographically evaluated after primary, unilateral, anatomic ACL reconstruction. Post-operative true lateral radiographs were obtained of both knees with the patient in supine position and knees in full passive extension with heels on a standardized bolster. ATS was measured on the radiographs by two independent and blinded observers. ATS was calculated as the side-to-side difference in tibial position relative to the femur. An independent t test was used to compare ATS between those undergoing anatomic reconstruction for an acute versus chronic ACL injury. Chronic ACL deficiency was defined as more than 12 weeks from injury to surgery. RESULTS: Patients averaged 26.4 +/- 11.5 years (mean +/- SD) of age, 43.6 % were female, and 48.1 % suffered an injury of the left knee. There were 30 and 22 patients in the acute and chronic groups, respectively. The median duration from injury to reconstruction for the acute group was 5 versus 31 weeks for the chronic group. After anatomic ACL reconstruction, the mean ATS was 1.0 +/- 2.1 mm. There was no statistical difference in ATS between the acute and chronic groups (1.2 +/- 2.0 vs. 0.6 +/- 2.3 mm, n.s.). Assessment of inter-tester reliability for radiographic evaluation of ATS revealed an excellent intraclass correlation coefficient of 0.894. CONCLUSIONS: Anatomic ACL reconstruction reduces ATS with a mean difference of 1.0 mm from the healthy contralateral limb. This study did not find a statistical difference in ATS between patients after anatomic ACL reconstruction in the acute or chronic phase. These observations suggest that anatomic ACL reconstruction, performed in either the acute or the chronic phase, approaches the normal AP relationship of the tibiofemoral joint. LEVEL OF EVIDENCE: IV. PMID- 25912074 TI - A study of the provision of hospital based dental general anaesthetic services for children in the northwest of England: part 1--a comparison of service delivery between six hospitals. AB - BACKGROUND: Extensive caries in children can result in a referral for tooth extraction under General Anaesthesia (GA). While there are guidelines for the use of GA within paediatric dentistry this process is ultimately dependent upon the decision making of the treating dentist. This decision can be influenced locally by the availability of services and their waiting list. GA services for paediatric extractions (DGA) have developed from different historical positions, including community dental services, maxillofacial services and paediatric led specialist services. METHODS: This article explores the differences between DGA services provided by 6 randomly selected hospitals across the North West of England. 456 patients who attended a routine DGA appointment in each hospital over a period of two months from 2012 to 2013 gave consent to allow access to their clinical notes and completed a questionnaire (93% consent rate). Data were entered onto SPSS and appropriate statistical tests undertaken. RESULTS: Differences between hospitals included the clinic structure, patient characteristics and the treatment provided. There was a significant difference in the number of previous child DGAs experienced within the family, ranging from 33% to 59% across hospitals. Hospital 1 attendees differed in a number of ways to other areas but notably in the stability of life time residency with 20% of patients having previously lived in another area and with just 58% of parents stating their child regularly attended the dentist (compared to an average of 9% and 81% respectively across other hospitals). CONCLUSION: Findings suggest services throughout the region face different obstacles in providing support and treatment for young children referred for DGA. There are, however common practices such as preventative treatment, which could impact on caries experience and subsequent DGA referral, a particular issue given the high DGA repeat rate observed. For many children a DGA may be their first dental experience. It is therefore vital to engage with both child and family at this stage, attempt to initiate a pattern of dental attendance and to ensure this experience does not create an on-going cycle of poor dental behaviour and health. PMID- 25912075 TI - Recombinant factor VIII Fc fusion protein for the prevention and treatment of bleeding in children with severe hemophilia A. AB - BACKGROUND: Prophylactic factor replacement, which prevents hemarthroses and thereby reduces the musculoskeletal disease burden in children with hemophilia A, requires frequent intravenous infusions (three to four times weekly). OBJECTIVE: Kids A-LONG was a phase 3 open-label study evaluating the safety, efficacy and pharmacokinetics of a longer-acting factor, recombinant factor VIII Fc fusion protein (rFVIIIFc), in previously treated children with severe hemophilia A (endogenous FVIII level of < 1 IU dL(-1) [< 1%]). METHODS: The study enrolled 71 subjects. The starting rFVIIIFc regimen was twice-weekly prophylaxis (Day 1, 25 IU kg(-1) ; Day 4, 50 IU kg(-1) ); dose (<= 80 IU kg(-1) ) and dosing interval (>= 2 days) were adjusted as needed. A subset of subjects had sequential pharmacokinetic evaluations of FVIII and rFVIIIFc. The primary endpoint was development of inhibitors (neutralizing antibodies). Secondary endpoints included pharmacokinetics, annualized bleeding rate (ABR), and number of infusions required to control a bleed. RESULTS: No subject developed an inhibitor to rFVIIIFc. Adverse events were typical of a pediatric hemophilic population. The rFVIIIFc half-life was prolonged relative to that of FVIII, consistent with observations in adults and adolescents. The median ABR was 1.96 overall, and 0.00 for spontaneous bleeds; 46.4% of subjects reported no bleeding episodes on study. Ninety-three per cent of bleeding episodes were controlled with one to two infusions. The median average weekly rFVIIIFc prophylactic dose was 88.11 IU kg( 1) . At study end, 62 of 69 subjects (90%) were infusing twice weekly. Among subjects who had been previously receiving FVIII prophylaxis, 74% reduced their dosing frequency with rFVIIIFc. CONCLUSION: Twice-weekly infusions with rFVIIIFc were well tolerated and yielded low bleeding rates in children with severe hemophilia A. PMID- 25912076 TI - Phase I study of OPB-51602, an oral inhibitor of signal transducer and activator of transcription 3, in patients with relapsed/refractory hematological malignancies. AB - We carried out a multicenter dose-escalation phase I study of oral OPB-51602, a signal transducer and activator of transcription 3 phosphorylation inhibitor, in patients with relapsed or refractory hematological malignancies to evaluate the safety, maximum tolerated dose (MTD), pharmacokinetics, and preliminary antitumor activity. Twenty patients were treated with OPB-51602 at doses of 1, 2, 3, 4, and 6 mg in the "3 + 3" dose escalation design. The most common treatment-related adverse events included nausea (55%), peripheral sensory neuropathy (45%), and diarrhea (40%). The most frequently observed grade 3 or 4 drug-related adverse events were neutropenia (20%), leukopenia (15%), lymphopenia (10%), and thrombocytopenia (10%). The MTD was 6 mg, with dose-limiting toxicities of grade 3 lactic acidosis and increased blood lactic acid levels observed in one of three patients and grade 1-2 peripheral neuropathy in three of three patients. The recommended dose was determined to be 4 mg. OPB-51602 was rapidly absorbed, and exposure tended to increase in a dose-dependent manner. Accumulation of OPB-51602 was seen with 4 weeks of multiple treatments. No clear therapeutic response was observed. Durable stable disease was observed in two patients with acute myeloid leukemia and one with myeloma. In conclusion, the MTD of OPB-51602 was 6 mg. OPB 51602 was safe and well tolerated in a dose range of 1-4 mg. However, long-term administration at higher doses was difficult with the daily dosing schedule, and no response was seen. Therefore, further clinical development of OPB-51602 for hematological malignancies with a daily dosing schedule was terminated. PMID- 25912077 TI - Electrophysiologic and cellular characteristics of cardiomyocytes after X-ray irradiation. AB - The aim of this study was to investigate possible effects of ionizing irradiation on the electrophysiological functionality of cardiac myocytes in vitro. Primary chicken cardiomyocytes with spontaneous beating activity were irradiated with X rays (dose range of 0.5-7 Gy). Functional alterations of cardiac cell cultures were evaluated up to 7 days after irradiation using microelectrode arrays. As examined endpoints, cell proliferation, apoptosis, reactive oxygen species (ROS) and DNA damage were evaluated. The beat rate of the cardiac networks increased in a dose-dependent manner over one week. The duration of single action potentials was slightly shortened. Additionally, we observed lower numbers of mitotic and S phase cells at certain time points after irradiation. Also, the number of cells with gammaH2AX foci increased as a function of the dose. No significant changes in the level of ROS were detected. Induction of apoptosis was generally negligibly low. This is the first report to directly show alterations in cardiac electrophysiology caused by ionizing radiation, which were detectable up to one week after irradiation. PMID- 25912078 TI - Functional interaction between hMYH and hTRADD in the TNF-alpha-mediated survival and death pathways of HeLa cells. AB - The tumor necrosis factor (TNF) signaling pathway is a classical immune system pathway that plays a key role in regulating cell survival and apoptosis. The TNF receptor-associated death domain (TRADD) protein is recruited to the death domain of TNF receptor 1 (TNFR1), where it interacts with TNF receptor-associated factor 2 (TRAF2) and receptor-interacting protein (RIP) for the induction of apoptosis, necrosis, nuclear factor kappa-light-chain-enhancer of activated B cells (NFkappaB), and mitogen-activated protein (MAP) kinase activation. In this study, we found that the human MutY homolog (hMYH) interacted with human TRADD (hTRADD) via the C-terminal domain of hMYH. Moreover, under conditions promoting TNF-alpha induced cell death or survival in HeLa cells, this interaction was weakened or enhanced, respectively. The interaction between hMYH and hTRADD was important for signaling pathways mediated by TNF-alpha. Our results also suggested that the hTRADD-hMYH association was involved in the nuclear translocation of NFkappaB and formation of the TNFR1-TRADD complex. Thus, this study identified a novel mechanism through which the hMYH-hTRADD interaction may affect the TNF-alpha signaling pathway. IMPLICATIONS: In HeLa cells, the hTRADD-hMYH interaction functioned in both cell survival and apoptosis pathways following TNF-alpha stimulation. PMID- 25912079 TI - Methods for comparing mutation rates using fluctuation assay data. AB - Comparing microbial mutation rates via the fluctuation assay protocol is an important routine task in the laboratory. However, methods for the comparison of mutation rates are still scarce and not well understood. This paper proposes new methods to address this situation. First, it provides a likelihood ratio test. Second, it explores the use of confidence intervals that can be readily computed. Third, it uses simulations to assess the new and existing methods. Both the likelihood ratio test and the use of confidence intervals were found to be superior to the general-purpose Mann-Whitney test, while the t-test was found to be unsuitable for fluctuation assay data. In addition, the method based on confidence intervals is suitable for comparison of experiments in which the terminal cell population sizes differ. PMID- 25912080 TI - [Starvation ketosis in a breastfeeding woman]. AB - INTRODUCTION: Bovine ketosis is a rare cause of metabolic acidosis. It is a starvation ketosis that appears in lactating woman. CASE REPORT: A 29-year-old woman had a previous gastric surgery one month ago while breastfeeding her 6 month child. She presented to emergency with dyspnea, fatigue, weight loss and anorexia. The explorations revealed a serious metabolic acidosis with a high anion gap, for which all other causes have been eliminated. CONCLUSION: A restrictive diet in lactating patients is a major risk of ketosis or bovine ketosis. Medico-surgical treatment of obesity during lactation seems unreasonable. Breastfeeding should be systematically sought before a medical and surgical management of obesity. With the spread of bariatric surgery, starvation ketosis is a cause of metabolic acidosis not to ignore. PMID- 25912082 TI - Do we over treat mild hypertension? AB - The important question whether 'mild' hypertension should or should not be treated by drugs is difficult to answer, because the only randomized controlled trials (RCTs) investigating this question were conducted when the definition of 'mild' hypertension was based on diastolic blood pressure only, whereas the present definition of grade 1 hypertension includes both systolic and diastolic values (SBP/DBP), and the concept of 'mild' hypertension also includes that of low-moderate cardiovascular risk (< 5% cardiovascular death rate in 5 years). Due to the lack of evidence from specific RCTs, guidelines recommend drug treatment of mild hypertension only on the basis of expert opinion. However, recent meta analyses have provided some support to drug treatment intervention in low moderate risk grade 1 hypertensives and have shown that, when treatment is deferred until organ damage or cardiovascular disease occur, absolute residual risk (events occurring despite treatment) markedly increases. Although evidence favoring therapeutic intervention in mild hypertension is nowadays stronger than expert opinion, meta-analyses are not substitutes for specific RCTs, and the wide BP spans defining grade 1 hypertension as well as the span defining low-moderate risk leave a wide space for individualized or personalized decisions. PMID- 25912081 TI - The fused in sarcoma protein forms cytoplasmic aggregates in motor neurons derived from integration-free induced pluripotent stem cells generated from a patient with familial amyotrophic lateral sclerosis carrying the FUS-P525L mutation. AB - Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease that primarily affects motor neurons (MNs) and has no effective treatment. Mutations in the fused in sarcoma (FUS) gene and abnormal aggregation of FUS protein have been reported in ALS. However, the mechanisms involved in ALS are poorly understood. Clinical drug trails have failed due to a lack of appropriate disease models, including a lack of access to MNs from ALS patients. Induced pluripotent stem (iPS) cells derived from patients with ALS provide an indispensable resource for in vitro mechanistic studies and for future patient-specific cell-based therapies. Previous reports demonstrated that viral-based ALS-iPS cells generated from fibroblasts harvested from Caucasian populations are ideal for basic research; however, ALS-iPS cells are precluded from cell-based therapeutic applications because of the risks associated with the integration of viral sequences into the genome and inconvenience associated with dermal biopsies. To establish a model for use in clinical applications, using episomal vectors, we generated an integration-free iPS cell line from peripheral blood mononuclear cells (PBMCs) harvested from a familial ALS (FALS) patient carrying the FUS-P525L mutation and a healthy control. Furthermore, we successfully differentiated ALS patient-specific iPS cells into MNs and subsequently detected cytoplasmic mislocalization and formation of FUS protein aggregates in MNs due to the FUS P525L mutation. Our findings offer a cell-based disease model for use in further elucidating ALS pathogenesis and provide a tool for exploring gene repair coupled with cell replacement therapy. PMID- 25912083 TI - Di-rhamnolipid is a mosquito pupicidal metabolite from Pseudomonas fluorescens (VCRC B426). AB - Pseudomonas fluorescens Migula (VCRC B426) produces a secondary metabolite, which was found to be active against pupae of vector mosquitoes namely Culex quinquefasciatus, Anopheles stephensi and Aedes aegypti. The mosquito pupicidal metabolite from P. fluoescens was mass produced and separated by ethyl acetate extraction and purified further by silica gel column chromatography, FPLC, HPLC and TLC. The purified metabolite was characterized by NMR, FT-IR, LC-MS and MALDI TOF. The FT-IR, (1)H and (13)C NMR results showed that it is a rhamnolipid (di rhamnolipid). The matrix assisted laser desorption and ionization-time-of-flight spectrum of the sample showed predominant pupicidal component produced by P. fluorescens was the molecule mass of 673.40 Da. Owing to its high toxicity to mosquito pupae, especially Anopheles sp., and Aedes sp., the di-rhamnolipd has potential in the control of the vectors of dengue, chikungunya, yellow fever and malaria. This is the first report of mosquito pupicidal di-rhamnolipid from P. fluorescens. PMID- 25912084 TI - An improved method for the isolation and culture of retinal pigment epithelial cells from adult rats. AB - PURPOSE: Since adult rats are used in pre-clinical studies, and due to the necessity of investigating the side-effects of drugs on RPE cells in vitro, there is a great need for primary RPE cells from these animals. The aim of this study was to develop a reproducible and quantifiable method of isolation, culture, and maintenance of adult rat RPE cells. Moreover, potential differences between RPE cells from albino versus pigmented rats were also investigated. METHODS: A total of 180 pigmented rats and 340 albino rats aged 6-14 weeks were used. RPE cells were isolated and cultured for several weeks by using three different methods: 1) growing directly on flat mounts, 2) after enzymatic isolation, and 3) after they spontaneously detached from the flat mounts and continued to grow on the plastic. Yield, cell survival, and morphological characteristics were investigated using light and electron microscopy as well as immunohistochemistry. RESULTS: After 0 weeks, the yield of the first method was 30,000 cells/eye; after 2 weeks 18,000 cells/eye; and after 4 weeks 11,000 cells/eye. The yield of RPE cells was very low after enzymatic isolation in method 2 (0 weeks, 13.000 cells/eye; 2 weeks, 30,000 cells/eye; 4 weeks 38,000 cells/eye), whereas it was higher when the RPE cells spontaneously detached from the flat mounts and then continued to grow on the plastic in method three. (0 weeks, 30,000 cells/eye; 2 weeks, 314,000 cells/eye; 4 weeks, 659,000 cells/eye). The second method often showed contamination with fibroblasts, whereas the two other methods showed pure RPE cultures. The RPE cells were able to proliferate when using the second and the third method, but not when they were cultivated directly on the flat mounts (first method). CONCLUSION: The qualitative and quantitative best method for isolating adult rat RPE cells is the culture of RPE cells which spontaneously detach from flat mounts. No differences were observed between albino and pigmented RPE cells. PMID- 25912085 TI - iStent inject in phakic open angle glaucoma. AB - BACKGROUND: The effectiveness and complication profile of the iStent inject implantation among different open angle glaucoma subgroups were analyzed. METHODS: In this retrospective cohort outcome study, 35 consecutive patients suffering from glaucoma (primary open angle glaucoma (POAG) N = 17, pseudoexfoliation glaucoma (PEX) N = 15, and pigmentary glaucoma (PG) N = 3) were treated with the iStent inject. The intraocular pressure (IOP) and the number of antiglaucoma medications before and after surgery were evaluated. RESULTS: In POAG, the mean IOP at 6 months measured 14.19 +/- 1.38 mmHg with an average decrease of 33 % from preoperative IOP (p < 0.001), and 15.33 +/- 1.07 mmHg with an average decrease of 35 % in PEX (p < 0.001), respectively. The number of antiglaucoma medications significantly decreased from 2.19 +/- 0.91 to 0.88 +/- 0.62 in POAG (p < 0.001) and from 2.33 +/- 1.23 to 1.04 +/- 0.30 in PEX (p < 0.001) after 6 months. In PG, IOP before surgery was 28.31 +/- 3.21 mmHg and the number of antiglaucoma medications was 3.66 +/- 0.57. One day after surgery, IOP decreased significantly to 12.33 mmHg +/- 4.93 (p < 0.001). Within four weeks after surgery, IOP was raised above 30 mmHg in every patient. To exclude a steroid response, topical steroids were stopped, but IOP did not decrease. To exclude blockage, Nd:YAG - laser treatment of the visible opening of the iStents was performed. Since the IOP stayed high and escalation of antiglaucoma medication was insufficient to control IOP, trabeculectomy was performed. CONCLUSIONS: In conclusion, implantation of the iStent inject has the ability to lower the postoperative IOP significantly in POAG and PEX after a short follow-up of 6 months with a favorable risk profile. However, limitation of this surgical procedure in phakic PG may exist and need to be investigated in further studies. PMID- 25912087 TI - The use of glial data in human health assessments of environmental contaminants. AB - Central nervous system (CNS) glia (i.e., astrocytes, microglia, and oligodendrocytes) are essential for maintaining neuronal homeostasis, and they orchestrate an organized cellular response to CNS injury. In addition to their beneficial roles, studies have demonstrated that disrupted glial function can have disastrous consequences on neuronal health. While effects on neuron supportive glia are important to consider when evaluating neurotoxicity risk, interpreting glial changes is not always straightforward, particularly when attempting to discern pro-neurotoxic phenotypes from homeostatic processes or adaptive responses. To better understand how glia have been characterized and used in human health assessments of environmental contaminants (e.g., chemicals), an evaluation of all finalized assessments conducted by the U.S. Environmental Protection Agency's influential Integrated Risk Information System (IRIS) program between 1987 and 2013 was performed. Human health assessments to date have placed a clear emphasis on the neuronal cell response to potential toxicants, although more recent assessments increasingly include descriptions of glial changes. However, these descriptions are generally brief and non-specific, and they primarily consist of documenting gliosis following overt neuronal injury. As research interest in this topic continues to increase, methods for evaluating changes in glia continue to be expanded and refined, and assessors' confidence in the reliability of these data is likely to rise. Thus, glial data are anticipated to have an increasingly influential impact on the interpretation of neurotoxicity risk and underlying mechanisms. As our understanding of the complex roles these cells play grows, this knowledge is expected to support the inclusion of more extensive and specific descriptions of glial changes, including informed interpretations of the potential impact on CNS health, in future human health assessments. PMID- 25912088 TI - Assessing gene expression during pathogenesis: Use of qRT-PCR to follow toxin production in the entomopathogenic fungus Beauveria bassiana during infection and immune response of the insect host Triatoma infestans. AB - Entomopathogenic fungi secrete toxic secondary metabolites during the invasion of the insect hemocoel as part of the infection process. Although these compounds have been frequently mentioned as virulence factors, the roles of many of them remain poorly understood, including the question of whether they are expressed during the infection process. A major hurdle to this issue remains the low sensitivity of biochemical detection techniques (e.g., HPLC) within the complex samples that may contain trace quantities of fungal molecules inside the insect. In this study, quantitative reverse transcription real-time PCR (qRT-PCR) was used to measure the transcript levels within the insect fungal pathogen Beauveria bassiana, that encode for the synthetase enzymes of the secondary metabolites tenellin (BbtenS), beauvericin (BbbeaS) and bassianolide (BbbslS) during the infection of Triatoma infestans, a Chagas disease insect vector. Absolute quantification was performed at different time periods after insect treatment with various concentrations of propagules, either by immersing the insects in conidial suspensions or by injecting them with blastospores. Both BbtenS and BbbeaS were highly expressed in conidia-treated insects at days 3 and 12 post treatment. In blastospore-injected insects, BbtenS and BbbeaS expression peaked at 24h post-injection and were also highly expressed in insect cadavers. The levels of BbbslS transcripts were much lower in all conditions tested. The expression patterns of insect genes encoding proteins that belong to the T. infestans humoral immune system were also evaluated with the same technique. This qPCR-based methodology can contribute to decifering the dynamics of entomopathogenic fungal infection at the molecular level. PMID- 25912086 TI - Barriers to shared decision making in mental health care: qualitative study of the Joint Crisis Plan for psychosis. AB - BACKGROUND: Despite increasing calls for shared decision making (SDM), the precise mechanisms for its attainment are unclear. Sharing decisions in mental health care may be especially complex. Fluctuations in service user capacity and significant power differences are particular barriers. OBJECTIVE AND DESIGN: We trialled a form of facilitated SDM that aimed to generate patients' treatment preferences in advance of a possible relapse. The 'Joint Crisis Plan' (JCP) intervention was trialled in four mental health trusts in England between 2008 and 2011. This qualitative study used grounded theory methods to analyse focus group and interview data to understand how stakeholders perceived the intervention and the barriers to SDM in the form of a JCP. RESULTS: Fifty service users with psychotic disorders and 45 clinicians participated in focus groups or interviews between February 2010 and November 2011. Results suggested four barriers to clinician engagement in the JCP: (i) ambivalence about care planning; (ii) perceptions that they were 'already doing SDM'; (iii) concerns regarding the clinical 'appropriateness of service users' choices'; and (iv) limited 'availability of service users' choices'. Service users reported barriers to SDM in routine practice, most of which were addressed by the JCP process. Barriers identified by clinicians led to their lack of constructive engagement in the process, undermining the service users' experience. CONCLUSIONS: Future work requires interventions targeted at the engagement of clinicians addressing their concerns about SDM. Particular strategies include organizational investment in implementation of service users' choices and directly training clinicians in SDM communication processes. PMID- 25912089 TI - Transcriptome analysis of the brain of the silkworm Bombyx mori infected with Bombyx mori nucleopolyhedrovirus: A new insight into the molecular mechanism of enhanced locomotor activity induced by viral infection. AB - Baculoviruses have been known to induce hyperactive behavior in their lepidopteran hosts for over a century. As a typical lepidopteran insect, the silkworm Bombyx mori displays enhanced locomotor activity (ELA) following infection with B. mori nucleopolyhedrovirus (BmNPV). Some investigations have focused on the molecular mechanisms underlying this abnormal hyperactive wandering behavior due to the virus; however, there are currently no reports about B. mori. Based on previous studies that have revealed that behavior is controlled by the central nervous system, the transcriptome profiles of the brains of BmNPV-infected and non-infected silkworm larvae were analyzed with the RNA-Seq technique to reveal the changes in the BmNPV-infected brain on the transcriptional level and to provide new clues regarding the molecular mechanisms that underlies BmNPV-induced ELA. Compared with the controls, a total of 742 differentially expressed genes (DEGs), including 218 up-regulated and 524 down regulated candidates, were identified, of which 499, 117 and 144 DEGs could be classified into GO categories, KEGG pathways and COG annotations by GO, KEGG and COG analyses, respectively. We focused our attention on the DEGs that are involved in circadian rhythms, synaptic transmission and the serotonin receptor signaling pathway of B. mori. Our analyses suggested that these genes were related to the locomotor activity of B. mori via their essential roles in the regulations of a variety of behaviors and the down-regulation of their expressions following BmNPV infection. These results provide new insight into the molecular mechanisms of BmNPV-induced ELA. PMID- 25912090 TI - Combining various types of classifiers and features extracted from magnetic resonance imaging data in schizophrenia recognition. AB - We investigated a combination of three classification algorithms, namely the modified maximum uncertainty linear discriminant analysis (mMLDA), the centroid method, and the average linkage, with three types of features extracted from three-dimensional T1-weighted magnetic resonance (MR) brain images, specifically MR intensities, grey matter densities, and local deformations for distinguishing 49 first episode schizophrenia male patients from 49 healthy male subjects. The feature sets were reduced using intersubject principal component analysis before classification. By combining the classifiers, we were able to obtain slightly improved results when compared with single classifiers. The best classification performance (81.6% accuracy, 75.5% sensitivity, and 87.8% specificity) was significantly better than classification by chance. We also showed that classifiers based on features calculated using more computation-intensive image preprocessing perform better; mMLDA with classification boundary calculated as weighted mean discriminative scores of the groups had improved sensitivity but similar accuracy compared to the original MLDA; reducing a number of eigenvectors during data reduction did not always lead to higher classification accuracy, since noise as well as the signal important for classification were removed. Our findings provide important information for schizophrenia research and may improve accuracy of computer-aided diagnostics of neuropsychiatric diseases. PMID- 25912091 TI - Accumulation of Glycoconjugates of 3-Methyl-4-hydroxyoctanoic Acid in Fruits, Leaves, and Shoots of Vitis vinifera cv. Monastrell following Foliar Applications of Oak Extract or Oak Lactone. AB - Grapevines are capable of absorbing volatile compounds present in the vineyard during the growing season, and in some cases, volatiles have been found to accumulate in fruits or leaves in glycoconjugate forms, that is, with one or more sugar moieties attached. The presence of oak lactone in wine is usually attributable to oak maturation, but oak lactone has been detected in wines made with fruit from grapevines treated with oak extract or oak lactone. This study investigated the accumulation of glycoconjugates of 3-methyl-4-hydroxyoctanoic acid (i.e., the ring-opened form of oak lactone) in the fruits, leaves, and shoots of Monastrell grapevines following foliar application of either oak extract or oak lactone at approximately 7 days postveraison. Fruits, leaves, and shoots were collected at three different time points, including at maturity. The oak lactone content of fruit was determined by gas chromatography-mass spectrometry, with declining concentrations observed in fruit from grapevines treated with oak lactone with ripening. The concentrations of a beta-d glucopyranoside of 3-methyl-4-hydroxyoctanoic acid in fruits, leaves, and shoots was determined by liquid chromatography-tandem mass spectrometry, with the highest oak lactone glucoside levels observed in leaves of grapevines treated with oak lactone. A glucose-glucose disaccharide was also tentatively identified. These results demonstrate both ring-opening and glycosylation of oak lactone occurred after experimental treatments were imposed. PMID- 25912092 TI - Identification of the extent of cortical spreading depression propagation by Npas4 mRNA expression. AB - Cortical spreading depression (CSD) is a phenomenon associated with a propagating large shift in direct current (DC) potential followed by suppression of electrophysiological activity. For temporal analysis of CSD propagation, electrophysiological recording is the most reliable tool. However, it is difficult to completely identify the spatial area of the brain influenced by CSD, because recording sites are technically limited. Histological post hoc identification of activated neurons by labeling the induction of an immediate early gene (IEG) could determine areas of CSD propagation. We found that cortical application of potassium chloride induced expression of Npas4 IEG mRNA in the ipsilateral dorsal cortex. Interestingly, induction of Npas4 was never observed in the ipsilateral hippocampus and there was a clear boundary to the area of Npas4 expression. To determine whether the boundary of the area of Npas4 mRNA expression was the limit of CSD propagation, we recorded local field potentials from multiple sites that crossed the boundary of Npas4 expression. We found that the area of Npas4 mRNA expression coincided with the area of DC-potential shift propagation. We propose that induction of Npas4 identifies the area influenced by CSD propagation. PMID- 25912094 TI - [Antimicrobial photodynamic therapy in dermatology. Part II: Viral and parasitic infections; perspectives]. PMID- 25912093 TI - [Item 158 - UE 6 Sexually transmitted infections]. PMID- 25912095 TI - Is a single infant priming dose of meningococcal serogroup C conjugate vaccine in the United Kingdom sufficient? AB - In 1999, the UK introduced meningococcal serogroup C conjugate (MCC) vaccination at 2, 3, 4 months of age with a single dose for children 1-18 y In 2006, the schedule was refined to a 2 dose priming schedule with a booster in the second year of life. In 2013, the number of priming doses was reduced to a single priming dose, the booster maintained at 12 months of age and an adolescent booster dose introduced. The paper presents the evidence supporting the reduction in the number of priming doses. A UK study provided evidence for reducing the priming doses of MCC-TT together with the positive correlation of lower quantity of antigen and serum bactericidal antibody (SBA) levels post-primary but a higher magnitude of the booster response. Another UK study, demonstrated one dose of MCC TT or MCC-CRM197 at 3 months gave comparable responses to 2 doses (SBA titres >=8) both post-primary vaccination and post-booster Hib/MCC-TT at 12 months. However, the magnitude of the SBA GMT was higher in the MCC-TT primed post booster. A single priming dose of MCC-TT (at 4 or 6 months) compared to 2 doses (2 and 4 months) gave higher SBA titres in all groups, post-primary and post booster at 12-13 months, with the highest SBA responses observed in the 4 month single dose group. A study in Malta, comparing one dose of MCC-TT or MCC-CRM197 at (3 months) versus 2 doses of MCC-CRM197 (3 and 4 months), showed a high proportion (>84.72%) of subjects achieving SBA titres >=8 following a single dose. These studies show that a single-dose priming MCC vaccination in infancy is sufficient. PMID- 25912096 TI - Interaction of Sleep Duration and Sleep Quality on Hypertension Prevalence in Adult Chinese Males. AB - BACKGROUND: Previous studies demonstrated conflicting results about the association of sleep duration and hypertension. Given the potential relationship between sleep quality and hypertension, this study aimed to investigate the interaction of self-reported sleep duration and sleep quality on hypertension prevalence in adult Chinese males. METHODS: We undertook a cross-sectional analysis of 4144 male subjects. Sleep duration were measured by self-reported average sleep time during the past month. Sleep quality was evaluated using the standard Pittsburgh Sleep Quality Index. Hypertension was defined as blood pressure level >=140/90 mm Hg or current antihypertensive treatment. The association between hypertension prevalence, sleep duration, and sleep quality was analyzed using logistic regression after adjusting for basic cardiovascular characteristics. RESULTS: Sleep duration shorter than 8 hours was found to be associated with increased hypertension, with odds ratios and 95% confidence intervals (CIs) of 1.25 (95% CI, 1.03-1.52) for 7 hours, 1.41 (95% CI, 1.14-1.73) for 6 hours, and 2.38 (95% CI, 1.81-3.11) for <6 hours. Using very good sleep quality as the reference, good, poor, and very poor sleep quality were associated with hypertension, with odds ratios of 1.20 (95% CI, 1.01-1.42), 1.67 (95% CI, 1.32-2.11), and 2.32 (95% CI, 1.67-3.21), respectively. More importantly, further investigation of the association of different combinations of sleep duration and quality in relation to hypertension indicated an additive interaction. CONCLUSIONS: There is an additive interaction of poor sleep quality and short sleep duration on hypertension prevalence. More comprehensive measurement of sleep should be performed in future studies. PMID- 25912097 TI - Temporal Trends in Characteristics of Newly Diagnosed Nontraumatic Osteonecrosis of the Femoral Head From 1997 to 2011: A Hospital-Based Sentinel Monitoring System in Japan. AB - BACKGROUND: Nontraumatic osteonecrosis of the femoral head (ONFH) is a rare disorder caused by ischemic necrosis of unknown etiology. A few studies have demonstrated trends in the number of patients with ONFH. However, there are no data on temporal trends in characteristics such as age, gender, and causative factors. To investigate this, we examined data from a multicenter hospital-based sentinel monitoring system in Japan. METHODS: A total of 3041 newly-diagnosed ONFH patients from 34 participating hospitals who were reported to the system from 1997-2011 were analyzed. We examined age at diagnosis, potential causative factors, and underlying diseases for which patients received systemic steroid administration. Their temporal trends were assessed according to date of diagnosis in 5-year intervals (1997-2001, 2002-2006, and 2007-2011). RESULTS: The gender ratio and distribution of potential causative factors did not change. Regarding underlying diseases requiring steroid administration, the proportion of patients with systemic lupus erythematosus decreased in males (10% to 6.4%) and in females (37% to 29%). Proportion of patients with renal transplantation fell consistently across the study period in both males (3.8% to 1.2%) and females (3.2% to 0.8%). In contrast, the proportion of patients receiving steroids for pulmonary disease (except asthma) significantly increased in both males (0.5% to 5.5%) and females (0.5% to 3.6%). CONCLUSIONS: This large descriptive study is the first to investigate temporal trends in the characteristics of ONFH, which provide useful information for future studies. PMID- 25912098 TI - The Japan Environment and Children's Study (JECS): A Preliminary Report on Selected Characteristics of Approximately 10 000 Pregnant Women Recruited During the First Year of the Study. AB - BACKGROUND: The Japan Environment and Children's Study (JECS) is an ongoing nationwide birth cohort study launched in January 2011. In this progress report, we present data collected in the first year to summarize selected maternal and infant characteristics. METHODS: In the 15 Regional Centers located throughout Japan, the expectant mothers were recruited in early pregnancy at obstetric facilities and/or at local government offices issuing pregnancy journals. Self administered questionnaires were distributed to the women during their first trimester and then again during the second or third trimester to obtain information on demographic factors, physical and mental health, lifestyle, occupation, environmental exposure, dwelling conditions, and socioeconomic status. Information was obtained from medical records in the first trimester and after delivery on medical history, including gravidity and related complications, parity, maternal anthropometry, and infant physical examinations. RESULTS: We collected data on a total of 9819 expectant mothers (mean age = 31.0 years) who gave birth during 2011. There were 9635 live births. The selected infant characteristics (singleton births, gestational age at birth, sex, birth weight) in the JECS population were similar to those in national survey data on the Japanese general population. CONCLUSIONS: Our final birth data will eventually be used to evaluate the national representativeness of the JECS population. We hope the JECS will provide valuable information on the impact of the environment in which our children live on their health and development. PMID- 25912099 TI - Assessing dangerous driving behavior during driving inattention: Psychometric adaptation and validation of the Attention-Related Driving Errors Scale in China. AB - Driver inattention is a significant cause of motor vehicle collisions and incidents. The purpose of this study was to translate the Attention-Related Driving Error Scale (ARDES) into Chinese and to verify its reliability and validity. A total of 317 drivers completed the Chinese version of the ARDES, the Dula Dangerous Driving Index (DDDI), the Attention-Related Cognitive Errors Scale (ARCES) and the Mindful Attention Awareness Scale (MAAS) questionnaires. Specific sociodemographic variables and traffic violations were also measured. Psychometric results confirm that the ARDES-China has adequate psychometric properties (Cronbach's alpha=0.88) to be a useful tool for evaluating proneness to attentional errors in the Chinese driving population. First, ARDES-China scores were positively correlated with both DDDI scores and number of accidents in the prior year; in addition, ARDES-China scores were a significant predictor of dangerous driving behavior as measured by DDDI. Second, we found that ARDES China scores were strongly correlated with ARCES scores and negatively correlated with MAAS scores. Finally, different demographic groups exhibited significant differences in ARDES scores; in particular, ARDES scores varied with years of driving experience. PMID- 25912100 TI - Rear seat safety: Variation in protection by occupant, crash and vehicle characteristics. AB - OBJECTIVES: Current information on the safety of rear row occupants of all ages is needed to inform further advances in rear seat restraint system design and testing. The objectives of this study were to describe characteristics of occupants in the front and rear rows of model year 2000 and newer vehicles involved in crashes and determine the risk of serious injury for restrained crash involved rear row occupants and the relative risk of fatal injury for restrained rear row vs. front passenger seat occupants by age group, impact direction, and vehicle model year. METHOD: Data from the National Automotive Sampling System Crashworthiness Data System (NASS-CDS) and Fatality Analysis Reporting System (FARS) were queried for all crashes during 2007-2012 involving model year 2000 and newer passenger vehicles. Data from NASS-CDS were used to describe characteristics of occupants in the front and rear rows and to determine the risk of serious injury (AIS 3+) for restrained rear row occupants by occupant age, vehicle model year, and impact direction. Using a combined data set containing data on fatalities from FARS and estimates of the total population of occupants in crashes from NASS-CDS, logistic regression modeling was used to compute the relative risk (RR) of death for restrained occupants in the rear vs. front passenger seat by occupant age, impact direction, and vehicle model year. RESULTS: Among all vehicle occupants in tow-away crashes during 2007-2012, 12.3% were in the rear row where the overall risk of serious injury was 1.3%. Among restrained rear row occupants, the risk of serious injury varied by occupant age, with older adults at the highest risk of serious injury (2.9%); by impact direction, with rollover crashes associated with the highest risk (1.5%); and by vehicle model year, with model year 2007 and newer vehicles having the lowest risk of serious injury (0.3%). Relative risk of death was lower for restrained children up to age 8 in the rear compared with passengers in the right front seat (RR=0.27, 95% CI 0.12-0.58 for 0-3 years, RR=0.55, 95% CI 0.30-0.98 for 4-8 years) but was higher for restrained 9-12-year-old children (RR=1.83, 95% CI 1.18 2.84). There was no evidence for a difference in risk of death in the rear vs. front seat for occupants ages 13-54, but there was some evidence for an increased relative risk of death for adults age 55 and older in the rear vs. passengers in the right front seat (RR=1.41, 95% CI 0.94-2.13), though we could not exclude the possibility of no difference. After controlling for occupant age and gender, the relative risk of death for restrained rear row occupants was significantly higher than that of front seat occupants in model year 2007 and newer vehicles and significantly higher in rear and right side impact crashes. CONCLUSIONS: Results of this study extend prior research on the relative safety of the rear seat compared with the front by examining a more contemporary fleet of vehicles. The rear row is primarily occupied by children and adolescents, but the variable relative risk of death in the rear compared with the front seat for occupants of different age groups highlights the challenges in providing optimal protection to a wide range of rear seat occupants. Findings of an elevated risk of death for rear row occupants, as compared with front row passengers, in the newest model year vehicles provides further evidence that rear seat safety is not keeping pace with advances in the front seat. PMID- 25912101 TI - Burden of road traffic injuries: Disability-adjusted life years in relation to hospitalization and the maximum abbreviated injury scale. AB - BACKGROUND: The consequences of non-fatal road traffic injuries (RTI) are increasingly adopted by policy makers as an indicator of traffic safety. However, it is not agreed upon which level of severity should be used as cut-off point for assessing road safety performance. Internationally, within road safety, injury severity is assessed by means of the maximum abbreviated injury scale (MAIS). The choice for a severity cut-off point highly influences the measured disease burden of RTI. This paper assesses the burden of RTI in terms of disability adjusted life years (DALYs) by hospitalization status and MAIS cut-off point in the Netherlands. METHODS: Hospital discharge register (HDR) and emergency department (ED) data for RTI in the Netherlands were selected for the years 2007-2009, as well as mortality data. The incidence, years lived with disability (YLD), years of life lost (YLL) owing to premature death, and DALYs were calculated. YLD for admitted patients was subdivided by MAIS severity levels. RESULTS: RTI resulted in 48,500 YLD and 27,900 YLL respectively, amounting to 76,400 DALYs per year in the Netherlands. The largest proportion of DALYs is related to fatalities (37%), followed by admitted MAIS 2 injuries (25%), ED treated injuries (16%) and admitted MAIS 3+ injuries (18%). Admitted MAIS 1 injuries only account for a small fraction of DALYs (4%). In the Netherlands, the diseases burden of RTI is highest among cyclists with 39% of total DALYs. One half of all bicycle related DALYs are attributable to admitted MAIS 2+ injuries, but ED treated injuries also account for a large proportion of DALYs in this group (28%). Car occupants are responsible for 26% of all DALYs, primarily caused by fatalities (66%), followed by admitted MAIS 2+ injuries (25%). ED treated injuries only account for 5% of DALYs in this group. CONCLUSIONS: When using admitted MAIS 3+ or admitted MAIS 2+ as severity cut-off point, 54% and 80% of all DALYs are captured respectively. Assessing the influence of different severity cut-off points by MAIS on the proportion and number of DALYs captured gives valuable information for guiding choices on the definition of serious RTI. PMID- 25912102 TI - Induced autoprocessing of the cytopathic Makes caterpillars floppy-like effector domain of the Vibrio vulnificus MARTX toxin. AB - The multifunctional-autoprocessing repeats-in-toxin (MARTX(Vv)) toxin that harbours a varied repertoire of effector domains is the primary virulence factor of Vibrio vulnificus. Although ubiquitously present among Biotype I toxin variants, the 'Makes caterpillars floppy-like' effector domain (MCF(Vv)) is previously unstudied. Using transient expression and protein delivery, MCF(Vv) and MCF(Ah) from the Aeromonas hydrophila MARTX(Ah)) toxin are shown for the first time to induce cell rounding. Alanine mutagenesis across the C-terminal subdomain of MCF(Vv) identified an Arg-Cys-Asp (RCD) tripeptide motif shown to comprise a cysteine protease catalytic site essential for autoprocessing of MCF(Vv). The autoprocessing could be recapitulated in vitro by the addition of host cell lysate to recombinant MCF(Vv), indicating induced autoprocessing by cellular factors. The RCD motif is also essential for cytopathicity, suggesting autoprocessing is essential first to activate the toxin and then to process a cellular target protein resulting in cell rounding. Sequence homology places MCF(Vv) within the C58 cysteine protease family that includes the type III secretion effectors YopT from Yersinia spp. and AvrPphB from Pseudomonas syringae. However, the catalytic site RCD motif is unique compared with other C58 peptidases and is here proposed to represent a new subgroup of autopeptidase found within a number of putative large bacterial toxins. PMID- 25912103 TI - Eyedrop-shaped, modified Limberg transposition flap in the treatment of pilonidal sinus disease. AB - BACKGROUND: Pilonidal sinus disease is an inflammatory disease seen in the intergluteal region, which is a commonly encountered problem in surgical practice that mostly affects young people. The aim of this study is to assess the effectiveness of the modified Limberg flap technique with eyedrop excision in the treatment of pilonidal sinus disease. PATIENTS: The study population consisted of 91 patients with pilonidal disease in the sacrococcygeal region who underwent operation between June 2010 and December 2012. All cases underwent eyedrop-shaped excision and modified Limberg flap reconstruction. RESULTS: The mean operative time was 41.2 +/- 6.7 minutes. All patients were followed up for >8 months, and the mean follow-up period was 13.1 +/- 3.7 months. There were three wound dehiscences because of fecal contamination and riding cycle on postoperative Day 5. Seroma and flap echimosis were observed in two and four cases, respectively. Five patients experienced recurrence in this series (4.5%). CONCLUSION: The results of the present study suggest that use of the eyedrop-shaped modified Limberg flap is associated with a lower maceration and recurrence rate when compared with the available data on the use of the Limberg flap. Flap necrosis and wound healing was better, and the routine use of drains did not affect the wound-related complications and recurrence rates. PMID- 25912104 TI - Needlescopic-assisted laparoendoscopic single-site adrenalectomy. AB - OBJECTIVE: Our objective was to compare the perioperative parameters of needle assisted and conventional laparoendoscopic single-site adrenalectomy (LESS-A). METHODS: We compared 23 patients undergoing needle-assisted LESS-A with 29 patients undergoing conventional LESS-A at Hiroshima University Hospital between November 2009 and February 2014. Needle-assisted LESS-A was performed using a MiniLap instrument (Stryker, San Jose, CA, USA). We used this instrument to protectively retract the liver at the right side of the tumor and the spleen at the left side by grasping with a Securea endoscopic surgical spacer (Hogy Medical Co., Ltd., Tokyo, Japan). Various parameters including insufflation time, estimated blood loss, pain scale, resumption of oral intake, transfusion rate, and complications were analyzed using the Mann-Whitney U test. RESULTS: In all cases, LESS-A was completed successfully with no major intraoperative complications. Patients in both treatment groups had similar age, body mass index, sex, and laterality. Significantly, needle-assisted LESS-A was performed using the transumbilical approach rather than the subcostal approach. The insufflation time of the needle-assisted LESS-A was shorter than that of the conventional LESS-A (p = 0.0335). No patients required intraoperative or postoperative blood transfusions. Retrospective design and the small sample size are main limitations of this study. CONCLUSION: Needle-assisted LESS-A was performed safely and in a manner that mitigated many of the difficulties of LESS surgery. PMID- 25912105 TI - Takayasu arteritis involving the left main coronary artery treated with a bioresorbable vascular scaffold. PMID- 25912106 TI - Comparative effectiveness of bisoprolol and metoprolol succinate in patients with heart failure. PMID- 25912107 TI - Letter regarding "Hybrid ABSORB bioresorbable vascular scaffold and drug eluting stent or hybrid BVS-DES percutaneous coronary intervention: Method and rationale for hybrid overlapping PCI". PMID- 25912108 TI - Unilateral low-level transcutaneous electrical vagus nerve stimulation: A novel noninvasive treatment for myocardial infarction. PMID- 25912109 TI - Testosterone regulates cardiac calcium homeostasis with enhanced ryanodine receptor 2 expression through activation of TGF-beta. PMID- 25912110 TI - Beta-blockers can improve survival in medically-treated patients with severe symptomatic aortic stenosis. PMID- 25912111 TI - Ascending aortic aneurysm and acute type A aortic dissection in a patient with congenital severe coarctation of the aorta. PMID- 25912112 TI - Simvastatin-ezetimibe combination therapy is associated with a lower rate of major adverse cardiac events in type 2 diabetics than high potency statins alone: A population-based dynamic cohort study. AB - BACKGROUND: Recent trials have shown a reduction in the risk of major adverse cardiac events (MACE) with simvastatin-ezetimibe therapy in patients with acute coronary syndrome. The potential benefits of simvastatin-ezetimibe for patients at a lower risk of MACE are unclear. This study aimed to investigate the differences of MACE risk between patients with type 2 diabetes mellitus (DM) using simvastatin-ezetimibe or high potency statins. METHODS: This population based dynamic cohort study used data from the Taiwan National Health Insurance Database. The study subjects were patients with type 2 DM, aged between 40 and 75 years. The simvastatin-ezetimibe group took simvastatin-ezetimibe only, and the statin group took atorvastatin or rosuvastatin but not simvastatin or ezetimibe. The two groups were matched for age, gender, medication date, DM diagnosis date, hypertension, and cardiovascular complications. The outcome variable was new onset MACE. Univariate and multivariate survival analyses were performed. RESULTS: A total of 20,485 patients (53% male; 4099 in the simvastatin-ezetimibe group and 16,396 in the statin group) were included, with a mean age of 59.1 years. In a total of 37,388 person-years, 1100 patients developed new-onset MACE. The annual incidence rate of new-onset MACE was lower in the simvastatin ezetimibe group (2.61%) than that in the statin group (3.02%) (p=0.0476). After Cox regression analysis, simvastatin-ezetimibe use was independently associated with a lower risk of MACE (HR, 0.77; 95% confidence interval 0.66-0.90). CONCLUSIONS: Compared to high potency statins alone, simvastatin-ezetimibe therapy was associated with a lower incidence of MACE in patients with type 2 DM. PMID- 25912113 TI - Hypertrophic cardiomyopathy and left ventricular non-compaction: Different manifestations of the same cardiomyopathy spectrum? PMID- 25912114 TI - Acute effect of renal sympathetic denervation on blood pressure in refractory hypertensive patients with chronic kidney disease. PMID- 25912115 TI - Exclude pregnancy, vigorous exercise and myopathy before diagnosing noncompaction in healthy subjects. PMID- 25912116 TI - Prognostic significance of low QRS voltage on the admission electrocardiogram in acute coronary syndromes. AB - PURPOSE: To examine the prognostic significance of low QRS voltage in a large contemporary cohort of patients with a broad spectrum of acute coronary syndromes (ACS). METHODS: 12409 patients with STEMI or NSTE-ACS from the Global Registry of Acute Coronary Events (GRACE) and Canadian ACS I registries were stratified based on the presence of low QRS voltage (<0.5 mV in all limb leads and <1.0 mV in all precordial leads) on the admission ECG. We performed multivariable logistic regression to assess the independent association between low voltage and in hospital and 6-month mortality, and tested for its interaction with ST-segment deviation for these outcomes. RESULTS: Patients with low voltage (3.2%) had higher GRACE risk scores, rates of prior myocardial infarction, and pathological Q waves, with less prevalent ST-segment deviation and ST-segment depression. They had worse left ventricular function and higher unadjusted rates of in-hospital and 6-month mortality. After adjustment for established prognosticators in the GRACE risk models in multivariable analysis, low voltage was independently associated with higher in-hospital mortality (adjusted OR 1.77, 95% CI 1.13-2.78, P=0.013) and mortality/re-infarction (adjusted OR 1.42, 95% CI 1.05-1.93, P=0.023), but not 6-month mortality (adjusted OR 1.25, 95% CI 0.85-1.84, P=0.27). There was no significant interaction between low voltage and ST-segment deviation for any endpoint (interaction P>0.10 for all endpoints). CONCLUSIONS: Low QRS voltage was associated with previous myocardial infarction and adverse hemodynamic variables at presentation. After adjusting for other prognosticators, low voltage independently predicted higher in-hospital mortality. This increased risk was not modulated by concomitant ST-segment deviation. PMID- 25912117 TI - Ruptured tricuspid septal leaflet aneurysm in a patient with aortic and mitral valve replacement. PMID- 25912118 TI - Life expectancy after implantation of a first cardiac permanent pacemaker (1995 2008): A population-based study. AB - INTRODUCTION: Research suggests that survival among the recipients of a cardiac permanent pacemaker (PPM) matches the age- and sex-matched general population in the absence of cardiovascular disease. We used linked administrative data to examine life expectancy-based outcomes for adults requiring a cardiac PPM. METHODS: Population-level hospital admissions data were used to identify all recipients of an initial PPM during 1995-2008. Expected years of additional life remaining at the time of implantation were calculated for each patient from population life tables. Observed years were calculated using linked mortality data to end 2011. Cox regression was used to determine demographic and clinical predictors of survival. RESULTS: In 8757 patients age-adjusted risk of death to 5 years was associated with male sex, higher Charlson Comorbidity Index score (excluding cardiac disease), a history of heart failure, cardiomyopathy or atrial fibrillation and emergency admission. Coronary revascularisation surgery reduced long-term risk. The observed/expected ratio of additional years of life was 0.80 for men and 0.84 for women overall, varying from 0.92 for women without significant comorbidity to 0.40 for patients with the highest Charlson score and cardiomyopathy. The oldest patients (80-99 years) did relatively well, probably reflecting patient selection. Heart disease was the most frequent cause of death. CONCLUSIONS: Life expectancy among PPM recipients without significant comorbidity approached that of the general population. Greater non-cardiac comorbidity, heart failure, atrial fibrillation and, in particular, cardiomyopathy, contributed most to the loss of expected years of life in all age groups. The oldest patients and women did relatively well. PMID- 25912119 TI - Right ventricular lead perforation complicating late pacemaker infection. PMID- 25912120 TI - Uses of clopidogrel, rosuvastatin and digoxin on risk of acute pancreatitis. PMID- 25912121 TI - Introducing bioresorbable scaffolds into the show. A potential adjunct to resuscitate Ross procedure. PMID- 25912122 TI - Influence factors might elevate blood red cell distribution width levels in postoperative atrial fibrillation patients. PMID- 25912123 TI - Magnetic fields in noninvasive heart stimulation: A novel approach for anti atrial fibrillation. PMID- 25912124 TI - The role of insulin resistance and metabolic risk factors on culprit coronary plaque. AB - BACKGROUND: Detailed relationships between insulin resistance (IR) and vulnerable plaque are not clear, therefore, we sought the role of IR and metabolic risk factors on culprit coronary plaque. METHODS: Plaque components at a region of interest (ROI, 10mm) were analyzed by virtual histology intravascular ultrasound. IR was defined as quantitative insulin sensitivity check index (QUICKI) <= 0.33. Seven metabolic risk factors (5 risk factors for metabolic syndrome defined by ATP III, history of smoking, and hsCRP) for IR were determined. RESULTS: The data for 150 (males 104) patients were analyzed. Patients with IR (n = 69) had greater necrotic core (NC) at the ROI (21.2 +/- 15.8mm(3) vs 15.7 +/- 11.9 mm(3), p = 0.02) than in patients without IR (n = 81). The NC at the ROI was correlated with QUICKI (r = -0.16, p = 0.05), HbA1c (r = 0.24, p < 0.01), body mass index (r = 0.17, p = 0.04), presence of diabetes mellitus (r = 0.29, p < 0.001), hsCRP (r = 0.17, p = 0.04) and the numbers of risk factors for IR (r = 0.41, p < 0.001). The multivariate analysis revealed that the numbers of risk factors for IR was an independent factor for the NC at the ROI (beta coefficient = 0.44, p = 0.003), but QUICKI was not (beta coefficient = -0.01, p = 0.94). CONCLUSIONS: Instead of a single measurement of IR index or each metabolic risk factor, clustering of risk factors for IR plays an important role on plaque vulnerability. CONDENSED ABSTRACT: We investigated the role of insulin resistance (IR) on culprit coronary plaque. Patients with IR had a greater amount of necrotic core in culprit coronary lesions than in patients without IR. Rather than a single measurement of IR index or each metabolic risk factor, clustering of metabolic risk factors for IR plays an important role in plaque vulnerability in patients with coronary artery disease. Our study demonstrates the role of IR on culprit coronary plaque and highlights the importance of the clustering of metabolic risk factors for IR in vulnerable plaque pathogenesis. PMID- 25912125 TI - Uninterrupted dabigatran versus warfarin in the treatment of intracardiac thrombus in patients with non-valvular atrial fibrillation. PMID- 25912126 TI - Reply: Health status, geriatric syndromes and prescription of oral anticoagulant therapy in elderly medical in-patients with atrial fibrillation: A prospective observational study. PMID- 25912127 TI - Is H63D a 'minor' HFE polymorphism? PMID- 25912128 TI - Meta-analysis reveals no significant correlation between breast cancer survival and ErbB3 expression. AB - Prognostic value of ErbB3 in human breast cancer is still controversial. However, the roles of ErbB3 receptors in drug resistance are recently emerging. The objective of this study was to evaluate the relationship between ErbB3 expression and survival of breast cancer via meta-analysis. A systematic literature search was conducted and 32 potentially relevant studies were included in the meta analysis. Outcomes presented in searched literatures can be classified as disease free survival (DFS), overall survival (OS), and progress free survival (PFS) values. Meta-analysis was performed for each group. Results showed no statistically significant difference in survival. The overall hazard ratio of PFS, DFS, and OS of ErbB3 expression was 1.40 [95% confidence interval/CI (0.51, 3.83)], 1.07 [95% CI (0.82, 1.40)], and 1.15 [95% CI (0.91, 1.44)], respectively. Subgroup analysis according to ErbB2 receptor status, ErbB3 assessment methods (immunohistochemistry/IHC vs non-IHC), and analysis type (multivariate and univariate analysis) were performed. No significant association was found. Using various assessment methods and patient populations, our results revealed that there was no significant correlation between ErbB3 expression and breast cancer survival. Further studies on heterodimers of ErbB3 and other molecular markers involved in ErbB3 related pathway are merited. PMID- 25912129 TI - Oxidized high-density lipoprotein accelerates atherosclerosis progression by inducing the imbalance between treg and teff in LDLR knockout mice. AB - High density lipoprotein (HDL) dysfunction has been widely reported in clinic, and oxidation of HDL (ox-HDL) was shown to be one of the most common modifications in vivo and participate in the progression of atherosclerosis. But the behind mechanisms are still elusive. In this study, we firstly analyzed and found strong relationship between serum ox-HDL levels and risk factors of coronary artery diseases in clinic, then the effects of ox-HDL in initiation and progression of atherosclerosis in LDLR knockout mice were investigated by infusion of ox-HDL dissolved in chitosan hydrogel before the formation of lesions in vivo. Several new evidence were shown: (i) the serum levels of ox-HDL peaked early before the formation of lesions in LDLR mice fed with high fat diet similar to oxidative low density lipoprotein, (ii) the formation of atherosclerotic lesions could be accelerated by infusion of ox-HDL, (iii) the pro-atherosclerotic effects of ox-HDL were accompanied by imbalanced levels of effector and regulatory T cells and relative gene expressions, which implied that imbalance of teff and treg might contribute to the pro-atherosclerosis effects of ox-HDL. PMID- 25912130 TI - Functional polymorphisms in CD86 gene are associated with susceptibility to pneumonia-induced sepsis. AB - Sepsis is an illness in which the body has a severe response to bacteria or other germs. A bacterial infection in the body such as lungs may set off the response that leads to the disease. CD86 (B7-2) is expressed on various immune cells and plays critical roles in immune responses. Genetic polymorphisms in CD86 gene may affect the development of several diseases. Here, we evaluated the association between two CD86 polymorphisms (rs1915087C/T and rs2332096T/G) and susceptibility to pneumonia-induced sepsis. CD86 rs1915087C/T and rs2332096T/G were identified in 186 pneumonia-induced septic patients and 196 healthy controls in the Chinese population. Results revealed that subjects with rs1915087CT and TT genotypes had significantly lower risk of pneumonia-induced sepsis than those with CC genotype [odds ratio (OR) = 0.58, 95% confidence interval (CI), 0.37-0.91, p = 0.017, and OR = 0.40, 95%CI, 0.21-0.76, p = 0.005]. However, prevalence of rs2332096GG genotype and G allele were significantly increased in patients than in healthy controls (OR = 2.75, 95%CI, 1.46-5.16, p = 0.001, and OR = 1.65, 95%CI, 1.21 2.24, p = 0.001]. We further investigated functions of these two polymorphisms by assessing gene expression in peripheral blood mononuclear cells and in monocytes. Data showed subjects carrying rs2332096GG genotype had significantly decreased level of CD86 in monocytes than those carrying rs2332096TT genotype. These results indicate that CD86 polymorphisms are associated with susceptibility to pneumonia-induced sepsis and may affect gene expression in monocytes. PMID- 25912131 TI - Toll-like receptors 3, 7, and 9 in Juvenile nasopharyngeal angiofibroma. AB - Juvenile nasopharyngeal angiofibroma (JNA) is a rare, benign tumor affecting adolescent males. The etiology of JNA as well as the causes determining the variable growth patterns of individual tumors remains unknown. Toll-like receptors (TLRs) are part of the innate immune response to microbes; by recognition of distinct features, they link to induction of pro-inflammatory signaling pathways. We immunostained TLR 3, 7, and 9 in 27 JNA specimens of patients treated at the Helsinki University Central Hospital, Helsinki, Finland, during the years 1970-2009. RESULTS: TLR 3, 7, and 9 expressions were found in stromal and endothelial cells of JNA, and their expression levels varied from negative to very strong positive. TLR 3 expression was found to have a significant correlation with the clinical stage of JNA. CONCLUSIONS: The present results propose a putative role of TLRs in the growth process of JNA. PMID- 25912132 TI - Mast cell infiltrates in vulvodynia represent secondary and idiopathic mast cell hyperplasias. AB - Mast cell infiltrates in tissues of vulvodynia are common, but they have not been characterized for criteria of neoplastic mast cell disease or correlated with patient's concomitant diseases associated with increased mast cells. Formalin fixed specimens of 35 patients with vulvodynia were evaluated immunohistochemically with antibodies to CD 3,4,8,20,117c and human mast cell tryptase, and for WHO-criteria of neoplastic mastocytosis (>25% spindled mast cell, CD25 expression, point mutations of the c-kit gene (D816V), and chronically elevated serum tryptase levels). Only 20/35 specimens showed a T-lymphocyte dominant inflammatory infiltrate on HE-stained sections, but all showed mast cells. 4/35 biopsies showed <10 mast cells/mm(2) , 15/35 specimens 40-60 mast cells/mm(2) and 16/35 specimens >60 mast cells/mm(2) (average 80/mm(2) ). Control tissue contained typically <10 mast cells/mm(2) . Spindling, CD25-expression, c kit gene mutations, or increased serum tryptase levels were not detected. 26/35 (74%) patients had concomitant autoimmune diseases, psoriasis, atopy, various allergies, preceding infections. Independent of the subtype of vulvodynia, the majority of mast cell rich biopsies with >40 mast cells/mm(2) were classified as a secondary mast cell disorder reflecting an activated immune system in 75% of vulvodynia patients. Patients with increased mast cells may benefit from medical therapy targeting mast cells. PMID- 25912133 TI - Mosaicism of an ELANE mutation in an asymptomatic mother in a familial case of cyclic neutropenia. AB - PURPOSE: To confirm and characterize mosaicism of the cyclic neutropenia (CyN) related mutation in the ELANE gene identified in the asymptomatic mother of patients with CyN. METHODS: We identified sibling cases with CyN due to a novel heterozygous splicing site mutation, IVS4 +5SD G>T, in the ELANE gene, resulting in an internal in-frame deletion of 30 nucleotides (corresponding to a ten amino acid deletion, V161-F170). The mutated allele was also detected in their asymptomatic mother but at low frequency. We measured the frequency of the mutant allele from peripheral blood leukocytes (PBLs) by subcloning, and confirmed the allelic frequency of mosaicism in various cell types by massively parallel DNA sequencing (MPS) analysis. RESULTS: In the subcloning analysis, the mutant allele was identified in 21.36 % of PBLs from the asymptomatic mother, compared with 54.72 % of PBLs from the CyN patient. In the MPS analysis, the mutant allele was observed in approximately 30 % of mononuclear cells, CD3(+) T cells, CD14(+) monocytes and the buccal mucosa. Conversely, it was detected in low frequency in polymorphonuclear leukocytes (PLMLs) (3-4 %) and CD16(+) granulocytes (2-3 %). CONCLUSIONS: Mosaicism of the ELANE mutation has only previously been identified in one confirmed and one unconfirmed case of SCN. This is the first report of mosaicism of the ELANE mutation in a case of CyN. The MPS results suggest that this de novo mutation occurred during the two-cell stage of embryogenesis. PLMLs expressing the ELANE mutation were found to be actively undergoing apoptosis. PMID- 25912134 TI - Infection, systemic inflammation, and Alzheimer's disease. AB - Alzheimer's disease (AD) is a leading cause of dementia among elderly. Yet, its etiology remains largely unclear. In this review, we summarize studies that associate systemic infection and neuroinflammation with AD, while highlighting that early-life or life-long exposure to infectious agents predisposes one to develop AD at a later age. PMID- 25912135 TI - Selenium utilization in thioredoxin and catalytic advantage provided by selenocysteine. AB - Thioredoxin (Trx) is a major thiol-disulfide reductase that plays a role in many biological processes, including DNA replication and redox signaling. Although selenocysteine (Sec)-containing Trxs have been identified in certain bacteria, their enzymatic properties have not been characterized. In this study, we expressed a selenoprotein Trx from Treponema denticola, an oral spirochete, in Escherichia coli and characterized this selenoenzyme and its natural cysteine (Cys) homologue using E. coli Trx1 as a positive control. (75)Se metabolic labeling and mutation analyses showed that the SECIS (Sec insertion sequence) of T. denticola selenoprotein Trx is functional in the E. coli Sec insertion system with specific selenium incorporation into the Sec residue. The selenoprotein Trx exhibited approximately 10-fold higher catalytic activity than the Sec-to-Cys version and natural Cys homologue and E. coli Trx1, suggesting that Sec confers higher catalytic activity on this thiol-disulfide reductase. Kinetic analysis also showed that the selenoprotein Trx had a 30-fold higher Km than Cys containing homologues, suggesting that this selenoenzyme is adapted to work efficiently with high concentrations of substrate. Collectively, the results of this study support the hypothesis that selenium utilization in oxidoreductase systems is primarily due to the catalytic advantage provided by the rare amino acid, Sec. PMID- 25912136 TI - p13 overexpression in pancreatic beta-cells ameliorates type 2 diabetes in high fat-fed mice. AB - We examined the pancreatic function of p13 encoded by 1110001J03Rik, whose expression is decreased in pancreatic islets in high-fat-fed diabetic mice, by generating transgenic mice overexpressing p13 (p13-Tg) in pancreatic beta-cells. p13-Tg mice showed normal basal glucose metabolism; however, under high-fat feeding, these animals showed augmented glucose-induced first-phase and total insulin secretion, improved glucose disposal, greater islet area and increased mitotic insulin-positive cells. In addition, high-fat diet-induced 4 hydroxynonenal immunoreactivity, a reliable marker and causative agent of lipid peroxidative stress, was significantly decreased in p13-Tg mouse islets. These results indicate that p13 is a novel pancreatic factor exerting multiple beneficial effects against type 2 diabetes. PMID- 25912137 TI - Two conserved amino acids of juxtaposed domains of a ribosomal maturation protein CgtA sustain its optimal GTPase activity. AB - CgtA is a highly conserved ribosome binding protein involved in ribosome biogenesis and associated with stringent response. It is a 55 KDa GTPase protein consisting of GTPase, Obg and C-terminal domains. The function of the latter two domains was not clear and despite the importance, the mode of action of CgtA is still largely unknown. Knocking out of CgtA gene is lethal and mutations lead to growth, sporulation and developmental defects in bacteria. It was found that a growth defect and pinhole size colony morphology of Bacillus subtilis was associated with a Gly92Asp point mutation on the Obg domain of its CgtA protein, instead of its GTPase domain. CgtA is an important and essential protein of the deadly diarrhea causing bacteria Vibrio cholerae and in order to investigate the mode of action of the V. cholerae CgtA we have utilized this information. We measured the GTPase activity of V. cholerae CgtA (CgtAvc) protein in the presence of purified ribosome. Our results showed 5-fold increased GTP hydrolysis activity compared to its intrinsic activity. Then we explored the GTPase activity of the mutated CgtAvc (Gly98Asp) located at the Obg domain, which reduced the GTP hydrolysis rate to half. The double point mutations (Gly98Asp, and Tyr194Gly) encompassing another conserved residue, Tyr194, located at the diagonally opposite position in the GTPase domain largely restored (about 82%) the reduced GTPase activity, revealing a fine-tuned inter-domain movement readily associated with the GTPase activity of CgtA and thus maintaining the proper functioning of the CgtA protein. PMID- 25912138 TI - Differential regulation of HIF-1alpha and HIF-2alpha in neuroblastoma: Estrogen related receptor alpha (ERRalpha) regulates HIF2A transcription and correlates to poor outcome. AB - Hypoxia-inducible factors (HIFs) are differentially regulated in tumor cells. While the current paradigm supports post-translational regulation of the HIF alpha subunits, we recently showed that hypoxic HIF-2alpha is also transcriptionally regulated via insulin-like growth factor (IGF)-II in the childhood tumor neuroblastoma. Here, we demonstrate that transcriptional regulation of HIF-2alpha seems to be restricted to neural cell-derived tumors, while HIF-1alpha is canonically regulated at the post-translational level uniformly across different tumor forms. Enhanced expression of HIF2A mRNA at hypoxia is due to de novo transcription rather than increased mRNA stability, and chemical stabilization of the HIF-alpha proteins at oxygen-rich conditions unexpectedly leads to increased HIF2A transcription. The enhanced HIF2A levels do not seem to be dependent on active HIF-1. Using a transcriptome array approach, we identified members of the Peroxisome proliferator-activated receptor gamma coactivator (PGC)/Estrogen-related receptor (ERR) complex families as potential regulators of HIF2A. Knockdown or inhibition of one of the members, ERRalpha, leads to decreased expression of HIF2A, and high expression of the ERRalpha gene ESRRA correlates with poor overall and progression-free survival in a clinical neuroblastoma material consisting of 88 tumors. Thus, targeting of ERRalpha and pathways regulating transcriptional HIF-2alpha are promising therapeutic avenues in neuroblastoma. PMID- 25912139 TI - Transduction of PEP-1-heme oxygenase-1 into insulin-producing INS-1 cells protects them against cytokine-induced cell death. AB - Pro-inflammatory cytokines play a crucial role in the destruction of pancreatic beta-cells, thereby triggering the development of autoimmune diabetes mellitus. We recently developed a cell-permeable fusion protein, PEP-1-heme oxygenase-1 (PEP-1-HO-1) and investigated the anti-inflammatory effects in macrophage cells. In this study, we transduced PEP-1-HO-1 into INS-1 insulinoma cells and examined its protective effect against cytokine-induced cell death. PEP-1-HO-1 was successfully delivered into INS-1 cells in time- and dose-dependent manner and was maintained within the cells for at least 48 h. Pre-treatment with PEP-1-HO-1 increased the survival of INS-1 cells exposed to cytokine mixture (IL-1beta, IFN gamma, and TNF-alpha) in a dose-dependent manner. PEP-1-HO-1 markedly decreased cytokine-induced production of reactive oxygen species (ROS), nitric oxide (NO), and malondialdehyde (MDA). These protective effects of PEP-1-HO-1 against cytokines were correlated with the changes in the levels of signaling mediators of inflammation (iNOS and COX-2) and cell apoptosis/survival (Bcl-2, Bax, caspase 3, PARP, JNK, and Akt). These results showed that the transduced PEP-1-HO-1 efficiently prevented cytokine-induced cell death of INS-1 cells by alleviating oxidative/nitrosative stresses and inflammation. Further, these results suggested that PEP-1-mediated HO-1 transduction may be a potential therapeutic strategy to prevent beta-cell destruction in patients with autoimmune diabetes mellitus. PMID- 25912140 TI - Both Rbx1 and Rbx2 exhibit a functional role in the HIV-1 Vif-Cullin5 E3 ligase complex in vitro. AB - Rbx1 and Rbx2 are essential components of Cullin-RING E3 Ligases. Vif is generally believed to preferentially recruit the Cul5-Rbx2 module to induce proteasomal degradation of antiretroviral enzyme APOBEC3G, although some investigators have found that the Cul5-Rbx1 module is recruited. Here, to investigate the function of the two Rbx proteins in the Vif-Cul5 complex, we analyzed the performance of Cul5-Rbx1/Cul5-Rbx2 module in the activity of Vif E3 ligase and evaluated the interactions between Rbx1/Rbx2 and Cul5. We found that either Rbx1 or Rbx2 could promote ubiquitination of APOBE3G (A3G) in vitro. We also found that both Rbx1 and Rbx2 could bind Cul5 in cells and Rbx2 could dose dependently inhibit the interaction of Rbx1 with Cul5. Furthermore, only the decrease of endogenous Rbx2 but not Rbx1 could impair the Vif-induced A3G degradation in cells. These findings indicate that Rbx1 and Rbx2 can both activate Cul5-Vif E3 ligase in vitro, but they may undergo a more delicate selection mechanism in vivo. PMID- 25912141 TI - Ovary-dependent emphysema augmentation and osteopontin induction in adult female mice. AB - Biological differences between the sexes greatly impact the development and severity of pulmonary disorders such as emphysema. Recent studies have demonstrated crucial roles for osteopontin (OPN, also known as SPP1) in lung inflammation and alveolar destruction in human and experimental emphysema, but the impact of gender on OPN action remains unknown. Here, we report ovary dependent induction of Opn mRNA with augmentation of experimental emphysema in adult female mice. Both male and female mice developed emphysematous lungs following intra-tracheal administration of porcine pancreatic elastase; however, compared with male mice, female mice developed more severe injury-related inflammation and pathologic alterations of the lungs. Notably, we observed female specific induction of the Opn gene upon lung injury. Ovariectomy blocked this induction, with attenuation of lung inflammation and alveolar destruction, demonstrating the essential role of ovaries in injury-related Opn induction and augmentation of emphysema in adult female mice. Lastly, pre-treatment of adult female mice with pyridoxalphosphate-6-azophenyl-2',4'-disulfonic acid, which blocks ATP-mediated wound response, suppressed Opn mRNA induction upon lung injury, resulting in attenuation of enhanced lung inflammation. Together, our findings define a novel, ovary-dependent mechanism underlying gender-specific augmentation of emphysema through transcriptional control of the Opn gene. PMID- 25912142 TI - Activation of toll like receptor-3 induces corneal epithelial barrier dysfunction. AB - The epithelial barrier is critical in the maintenance of the homeostasis of the cornea. A number of eye disorders are associated with the corneal epithelial barrier dysfunction. Viral infection is one common eye disease type. This study aims to elucidate the mechanism by which the activation of toll like receptor 3 (TLR3) in the disruption of the corneal epithelial barrier. In this study, HCE cells (a human corneal epithelial cell line) were cultured into epithelial layers using as an in vitro model of the corneal epithelial barrier. PolyI:C was used as a ligand of TLR3. The transepithelial electric resistance (TER) and permeability of the HCE epithelial layer were assessed using as the parameters to evaluate the corneal epithelial barrier integrity. The results showed that exposure to PolyI:C markedly decreased the TER and increased the permeability of the HCE epithelial layers; the levels of cell junction protein, E-cadherin, were repressed by PolyI:C via increasing histone deacetylase-1 (HDAC1), the latter binding to the promoter of E-cadherin and repressed the transcription of E-cadherin. The addition of butyrate (an inhibitor of HDAC1) to the culture blocked the corneal epithelial barrier dysfunction caused by PolyI:C. In conclusion, activation of TLR3 can disrupt the corneal epithelial barrier, which can be blocked by the inhibitor of HDAC1. PMID- 25912143 TI - Charting stormy waters: A commentary on the nomenclature of the equine pathogen variously named Prescottella equi, Rhodococcus equi and Rhodococcus hoagii. PMID- 25912145 TI - Sirolimus for Retinal Astrocytic Hamartoma Associated with Tuberous Sclerosis Complex. PMID- 25912144 TI - The Most Common Barriers to Glaucoma Medication Adherence: A Cross-Sectional Survey. AB - PURPOSE: To evaluate the frequency of 11 commonly cited barriers to optimal glaucoma medication adherence among glaucoma patients and to identify barriers contributing to poor adherence. DESIGN: Prospective, cross-sectional survey. PARTICIPANTS: One hundred ninety adults with glaucoma taking 1 or more glaucoma medication who received care in glaucoma clinics in Ann Arbor, Michigan, and Baltimore, Maryland. METHODS: Participants completed a survey on demographic and disease characteristics, barriers to optimal glaucoma medication adherence, interest in an eye drop aid, and self-reported adherence (measured by the Morisky Adherence Scale). Descriptive statistics and logistic regression analyses were performed. MAIN OUTCOME MEASURES: Frequency and number of barriers to adherence among both adherent and nonadherent patients. Odds ratios (ORs) with 95% confidence intervals (CIs) identifying barriers associated with poor adherence. RESULTS: Twenty-seven percent of the sample reported poor adherence. Sixty-one percent of all participants cited multiple barriers and 10% cited a single barrier as impediments to optimal adherence. Twenty-nine percent of subjects cited no barriers, although only 13% of patients who cited no barriers were nonadherent. Among nonadherent patients, 31% or more cited each of the 11 barriers as important. Logistic regression analysis, adjusted for age, revealed that the following barriers were associated with higher odds of nonadherence: decreased self-efficacy (OR, 4.7; 95% CI, 2.2-9.7; P <= 0.0001), difficulty instilling drops (OR, 2.3; 95% CI, 1.1-4.9; P = 0.03), forgetfulness (OR, 5.6; 95% CI, 2.6-12.1; P <= 0.0001), and difficulties with the medication schedule (OR, 2.9; 95% CI, 1.4-6.0; P = 0.006). For each additional barrier cited as important, there was a 10% increased odds of being nonadherent (OR, 1.1; 95% CI, 1.0-1.2; P = 0.01). CONCLUSIONS: Each of the 11 barriers was important to at least 30% of surveyed patients with poor adherence, with most identifying multiple barriers to adherence. Low self-efficacy, forgetfulness, and difficulty with drop administration and the medication schedule were barriers associated with poor adherence. Interventions to improve medication adherence must address each patient's unique set of barriers. PMID- 25912146 TI - Prenatal diagnosis of CHDs: a simple ultrasound prediction model to estimate the probability of the need for neonatal cardiac invasive therapy. AB - OBJECTIVES: To develop a prediction model based on echocardiographic findings to estimate the probability of the need for neonatal cardiac invasive therapy, including cardiac surgery or catheter-based therapy, in foetuses with CHD. METHODS: Retrospective cohort study: a prediction model was developed based on echocardiographic findings on the examination of the four-chamber, the three vessel, and the three-vessel and tracheal views. We assessed performance using the area under the curve of the receiver operating characteristic. RESULTS: Among 291 patients with prenatal diagnosis of CHD and complete follow-up, 175 (60.1%) required neonatal cardiac invasive therapy. The variables "functionally single ventricle", "great artery reverse flow", and "congenital heart block" had a discrimination value of 100% and were excluded from the model. In univariate and multivariate analysis, "non-visualisation of a great vessel", "asymmetry of the great vessels", "visualisation of one atrioventricular valve", and "ventricular asymmetry" were significantly associated with the need for neonatal cardiac invasive therapy. The area under the receiver operating characteristic curve was 0.9324 (95% CI 0.92-0.97). CONCLUSIONS: A prediction model based on echocardiographic findings in foetuses with CHD, even without a definite diagnosis, allows an accurate estimation of the probability of requiring neonatal cardiac invasive therapy. This can modify patient care, especially in regions where a Foetal Medicine Specialist or a Paediatric Cardiologist is not available and referral may be extremely difficult due to social and economic barriers. PMID- 25912147 TI - Management of severe pulmonary hypertension in patients undergoing mitral valve surgery. AB - OPINION STATEMENT: Pulmonary hypertension (PH) is simply defined as a mean pulmonary artery pressure greater than 25 mmHg at rest; however, may result from varying combinations of abnormal pulmonary artery (PA) blood flow, pulmonary vascular resistance (PVR), PA compliance, and pulmonary venous pressure. Mitral regurgitation (MR) allows for partial transmission of systemic arterial pressure into the pulmonary venous system. Mitral stenosis (MS) prevents pulmonary venous drainage into the left ventricle. In either case, the direct result is marked pressurization of the pulmonary venous system, with the primary cause of PH in significant mitral valve disease (PHMVD) being pulmonary venous hypertension (PVH). Chronic and severe PVH may then lead to muscularization of the pulmonary arterial bed, with a rise in PVR and loss of pulmonary arterial compliance that follows ("reactive" pulmonary vascular disease). Right heart dysfunction ensues once the PVR rises and the compliance falls to a point in which the right ventricle (RV) cannot overcome the increased afterload. However, it is worth emphasizing that in the setting of PHMVD, no matter the degree of mismatch between RV afterload and RV function, the root condition in the patient and cause of the PH remains severe MV disease. Without correction of the primary condition, the patient's heart failure (HF), PH, PVR, and RV dysfunction will remain or progress. Moreover, direct PH medical therapies are ineffective and may actually worsen left heart congestion in the setting of unremediated MVD. Therefore, although surgery may be a higher risk in some patients with PHMVD, the potential benefits justify the risks in the majority of cases. If needed, direct medical management of PH is far simpler and more effective once the MVD is corrected, given the degree of left heart congestion often improves dramatically. Therefore, corrective mitral valve intervention should be considered as the main and definitive treatment for these patients. PMID- 25912148 TI - The risk experience: the social effects of health screening and the emergence of a proto-illness. AB - Those who undergo health screening often experience physical and emotional effects as a result of the screening process. However, the effects of health screening go beyond these physical and mental complications, often having profound social effects for those who are screened. This study explores the social implications of health screening for people who undergo it and are designated as being at risk for potential disease. Through a qualitative analysis of the experiences of individuals with elevated cholesterol levels and men with elevated prostate-specific antigen (PSA) levels, this research offers a description of the experience of being at risk, identifying three primary components: increased medical contact, a restructuring of everyday routines and altered social relationships. Whereas the at-risk health status engendered by current clinical approaches to screening and surveillance has been characterised as proto-disease, this study develops a companion definition of proto-illness to characterise the social experience of life with an identified health risk. Those who are at risk act in ways that are similar to those who are ill. The concept of proto-illness implies that the experience of risk is parallel to the experience of illness and contributes to the sociology of medical screening by establishing a much needed bridge between the two experiences. PMID- 25912149 TI - Ultraviolet C light pathogen inactivation treatment of platelet concentrates preserves integrin activation but affects thrombus formation kinetics on collagen in vitro. AB - BACKGROUND: Ultraviolet (UV) light illumination in the presence of exogenously added photosensitizers has been used to inactivate pathogens in platelet (PLT) concentrates for some time. The THERAFLEX UV-C system, however, illuminates PLT concentrates with UV-C light without additional photoactive compounds. In this study residual PLT function is measured in a comprehensive paired analysis of UV C-treated, gamma-irradiated, and untreated control PLT concentrates. STUDY DESIGN AND METHODS: A pool-and-split design was used with buffy coat-derived PLT concentrates in 65% SSP+ additive solution. Thrombus formation kinetics in microfluidic flow chambers onto immobilized collagen was investigated with real time video microscopy. PLT aggregation, membrane markers, and cellular metabolism were determined concurrently. RESULTS: Compared to gamma-treated and untreated controls, UV-C treatment significantly affected thrombus formation rates on Days 5 and 7, not Day 2. PLT degranulation (P-selectin) and PLT apoptosis (annexin V binding) was slightly but significantly increased from Day 2 on. UV-C treatment moreover induced integrin alphaIIb beta3 conformational changes reminiscent of activation. However, subsequent integrin activation by either PAR1-activating hexapeptide (PAR1AP) or convulxin was unaffected. This was confirmed by PLT aggregation studies induced with collagen, PAR1AP, and ristocetin at two different agonist concentrations. Finally, UV-C slightly increased lactic acid production rates, resulting in significantly decreased pH on Days 5 and 7, but never dropped below 7.2. CONCLUSION: UV-C pathogen inactivation treatment slightly but significantly increases PLT activation markers but does not profoundly influence activatability nor aggregation. The treatment does, however, attenuate thrombus formation kinetics in vitro in microfluidic flow chambers, especially after storage. PMID- 25912150 TI - Freezing of Apheresis Platelet Concentrates in 6% Dimethyl Sulfoxide: The First Preliminary Study in Turkey. AB - OBJECTIVE: Transfusion of platelet suspensions is an essential part of patient care for certain clinical indications. In this pioneering study in Turkey, we aimed to assess the in vitro hemostatic functions of platelets after cryopreservation. MATERIALS AND METHODS: Seven units of platelet concentrates were obtained by apheresis. Each apheresis platelet concentrate (APC) was divided into 2 equal volumes and frozen with 6% dimethyl sulfoxide (DMSO). The 14 frozen units of APCs were kept at -80 degrees C for 1 day. APCs were thawed at 37 degrees C and diluted either with autologous plasma or 0.9% NaCl. The volume and residual numbers of leukocytes and platelets were tested in both before-freezing and post-thawing periods. Aggregation and thrombin generation tests were used to analyze the in vitro hemostatic functions of platelets. Flow-cytometric analysis was used to assess the presence of frozen treated platelets and their viability. RESULTS: The residual number of leukocytes in both dilution groups was <1x106. The mean platelet recovery rate in the plasma-diluted group (88.1+/-9.5%) was higher than that in the 0.9% NaCl-diluted group (63+/-10%). These results were compatible with the European Directorate for the Quality of Medicines quality criteria. Expectedly, there was no aggregation response to platelet aggregation test. The mean thrombin generation potential of post-thaw APCs was higher in the plasma-diluted group (2411 nmol/L per minute) when compared to both the 0.9% NaCl diluted group (1913 nmol/L per minute) and the before-freezing period (1681 nmol/L per minute). The flow-cytometric analysis results for the viability of APCs after cryopreservation were 94.9% and 96.6% in the plasma and 0.9% NaCl groups, respectively. CONCLUSION: Cryopreservation of platelets with 6% DMSO and storage at -80 degrees C increases their shelf life from 7 days to 2 years. Besides the increase in hemostatic functions of platelets, the cryopreservation process also does not affect their viability rates. PMID- 25912151 TI - Development and assessment of a shortened Quality of Life in Childhood Epilepsy Questionnaire (QOLCE-55). AB - OBJECTIVE: To develop and validate a shortened version of the Quality of Life in Childhood Epilepsy Questionnaire (QOLCE). A secondary aim was to compare baseline risk factors predicting health-related quality of life (HRQoL) in children newly diagnosed with epilepsy, as identified using the original and shortened version. METHODS: Data came from the Health-Related Quality of Life in Children with Epilepsy Study (HERQULES, N = 373), a multicenter prospective cohort study. Principal component analysis reduced the number of items from the original QOLCE, and factor analysis was used to assess the factor structure of the shortened version. Convergent and divergent validity was assessed by correlating the Child Health Questionnaire (CHQ) with the shortened QOLCE. Multiple regression identified risk factors at diagnosis for HRQoL at 24 months. RESULTS: A four factor, higher-order, 55-item solution was obtained. A total of 21 items were removed. The final model represents functioning in four dimensions of HRQoL: Cognitive, Emotional, Social, and Physical. The shortened QOLCE demonstrated acceptable fit: Bentler's Comparative Fit Index = 0.944; Tucker-Lewis Index = 0.942; root mean square approximation = 0.058 (90% CI: 0.056-0.061); weighted root mean square residuals (WRMR) = 1.582, and excellent internal consistency (alpha = 0.96, subscales alpha > 0.80). Factor loadings were good (first-order: lambda = 0.66-0.93; higher-order lambda = 0.66-0.85; p < 0.001 for all). The shortened QOLCE scores correlated strongly with similar subscales of the Child Health Questionnaire (rho = 0.38-0.70) while correlating weakly with dissimilar subscales (rho = 0.30-0.31). While controlling for HRQoL at diagnosis, predictors for better HRQoL at 24 months were the following: no cognitive problems reported (p = 0.001), better family functioning (p = 0.014), fewer family demands (p = 0.008), with an interaction between baseline HRQoL and cognitive problems (p = 0.011). SIGNIFICANCE: Results offer initial evidence regarding reliability and validity of the proposed 55-item shortened version of the QOLCE (QOLCE-55). The QOLCE-55 produced results on risk factors consistent with those found using the original measure. Given the fewer items, QOLCE-55 may be a viable option reducing respondent burden when assessing HRQoL in children with epilepsy. PMID- 25912152 TI - Conformational isomerism in solid state of AMG 853--structure studies using solid state nuclear magnetic resonance and X-ray diffraction. AB - Investigation of an additional resonance peak in the (19) F solid-state nuclear magnetic resonance (NMR) spectrum of AMG 853, a dual antagonist of DP and CRTH2 previously in clinical development for asthma, has led to the identification of two conformational isomers coexisting in the crystal lattice in a continuous composition range between 89.7%:10.3% and 96.5%:3.5%. These two isomers differ in the chloro-flurorophenyl moiety orientation-the aromatic ring is flipped by 180 degrees in these two isomers. The level of the minor isomer is directly measured through integration of the two peaks in the (19) F solid-state NMR spectrum. The values obtained from the NMR data are in excellent agreement with the degree of disorder of the fluorine atom in the crystal structure, refined using both single crystal and high-resolution powder X-ray diffraction data. PMID- 25912153 TI - Cordycepin alleviates airway hyperreactivity in a murine model of asthma by attenuating the inflammatory process. AB - Cordycepin (Cor), which is a naturally occurring nucleoside derivative isolated from Cordyceps militaris, has been shown to exert excellent antiinflammatory activity in a murine model of acute lung injury. Thus, this study aimed to evaluate the antiasthmatic activity of Cor (10, 20, and 40 mg/kg) and to investigate the possible underlying molecular mechanisms. We found that Cor attenuated airway hyperresponsiveness, mucus hypersecretion, and ovalbumin (Ova) specific immunoglobulin (Ig) E, and alleviated lung inflammation with decreased eosinophils and macrophages in the bronchoalveolar lavage (BAL) fluid. Notably, Cor reduced the upregulation of eotaxin, intercellular cell adhesion molecule-1 (ICAM-1), IL-4, IL-5, and IL-13 in the BAL fluid. Furthermore, Cor markedly blocked p38-MAPK and nuclear factor-kappaB (NF-kappaB) signalling pathway activation in the Ova-driven asthmatic mice. In conclusion, this study demonstrated that some of the antiasthmatic benefits of Cor attributable to diets and/or tonics may result from reductions in inflammatory processes and that these antiasthmatic properties involve the inhibition of Th2-type responses through the suppression of the p38-MAPK and NF-kappaB signalling pathways. PMID- 25912154 TI - Association between exposure to household cigarette smoking behavior and cigarette smoking in Hispanic adults: Findings from the Hispanic Community Health Study/Study of Latinos. AB - BACKGROUND: Cigarette smoking behavior is highly determined by social influences during childhood and adolescence. This phenomenon has not been fully evaluated in the Hispanic/Latino population. PURPOSE: To examine the association between exposure to household cigarette smoking behavior (HCSB) and adult cigarette smoking among a diverse Hispanic/Latino population living in four US urban centers. The effect of acculturation on cigarette smoking was also evaluated. METHODS: Data from the Hispanic Community Health Study/Study of Latinos (HCHS/SOL) (n=13,231, ages 18-74years, collected between March 2008 and June 2011) were analyzed using logistic regression. RESULTS: HCSB exposure was an independent risk factor for adult current cigarette smoking in Hispanic/Latinos (OR 1.7; 95% CI 1.4, 2.1) after controlling for relevant confounders including socio-demographic and cultural factors. Cubans and Puerto Ricans had the highest prevalence of HCSB exposure (59% and 47% respectively) and highest prevalence of current cigarette smoking (26% and 32%) compared with other Hispanic/Latino groups, (p<.01). CONCLUSIONS: Our data suggest that exposure to HCSB in Hispanics/Latinos living in the US is an independent predictor of adult cigarette smoking, and this association appears to be strongest in Cubans and Puerto Ricans. PMID- 25912156 TI - Twenty-four hour ambulatory blood pressure monitoring to all? Comments to the US Preventive Services Task Force document. PMID- 25912155 TI - Orai1 controls C5a-induced neutrophil recruitment in inflammation. AB - Stromal interaction molecule 1 (STIM1)-dependent store operated calcium-entry (SOCE) through Orai1-mediated calcium (Ca(2+) ) influx is considered a major pathway of Ca(2+) signaling, serving T-cell, mast cell, and platelet responses. Here, we show that Orai1 is critical for neutrophil function. Orai1-deficient neutrophils present defects in fMLP and complement C5a-induced Ca(2+) influx and migration, although they respond normally to another chemoattractant, CXCL2. Up until now, no specific contribution of Orai1 independent from STIM1 or SOCE has been recognized in immune cells. Here, we observe that Orai1-deficient neutrophils exhibit normal STIM1-dependent SOCE and STIM1-deficient neutrophils respond to fMLP and C5a efficiently. Despite substantial cytokine production, Orai1(-/-) chimeric mice show impaired neutrophil recruitment in LPS-induced peritonitis. Moreover, Orai1 deficiency results in profoundly defective C5a triggered neutrophil lung recruitment in hypersensitivity pneumonitis. Comparative evaluation of inflammation in Stim1(-/-) chimeras reveals a distinct pathogenic contribution of STIM1, including its involvement in IgG-induced C5a production. Our data establish Orai1 as key signal mediator of C5aR activation, contributing to inflammation by a STIM1-independent pathway of Ca(2+) -influx in neutrophils. PMID- 25912157 TI - Alertness opens the effective flow of sensory information through rat thalamic posterior nucleus. AB - Behavioural reactions to sensory stimuli vary with the level of arousal, but little is known about the underlying reorganization of neuronal networks. In this study, we use chronic recordings from the somatosensory regions of the thalamus and cortex of behaving rats together with a novel analysis of functional connectivity to show that during low arousal tactile signals are transmitted via the ventral posteromedial thalamic nucleus (VPM), a first-order thalamic relay, to the primary somatosensory (barrel) cortex and then from the cortex to the posterior medial thalamic nucleus (PoM), which plays a role of a higher-order thalamic relay. By contrast, during high arousal this network scheme is modified and both VPM and PoM transmit peripheral input to the barrel cortex acting as first-order relays. We also show that in urethane anaesthesia PoM is largely excluded from the thalamo-cortical loop. We thus demonstrate a way in which the thalamo-cortical system, despite its fixed anatomy, is capable of dynamically reconfiguring the transmission route of a sensory signal in concert with the behavioural state of an animal. PMID- 25912158 TI - Knockdown of S100A4 impairs arecoline-induced invasiveness of oral squamous cell carcinomas. AB - OBJECTIVES: Metastasis is the most common cause of oral squamous cell carcinoma (OSCC)-related death. The physiological function of S100A4 in the pathogenesis of areca quid chewing-associated OSCC has not been uncovered. METHOD: OSCC tissues from areca quid chewers were analyzed by immunohistochemistry for S100A4 expression. The functions of S100A4 in invasiveness of arecoline-treated oral epithelial (OE) cells were determined by loss function approaches. RESULTS: Expression of S100A4 was positively correlated with clinical grading and lymph node metastasis of OSCC. Upregulated S100A4 is correlated with poor survival outcome of OSCC patients. Arecoline led to dose-dependent elevation of S100A4 expression in oral epithelial (OE) cells. Down-regulation of S100A4 significantly reversed arecoline-induced oncogenecity in OE cells. The additions of pharmacological agents LY294002, SP600125, and CAY10585 were found to inhibit arecoline-induced S100A4 expression in OE cells. CONCLUSION: Arecoline-induced S100A4 expression was down-regulated by LY294002, SP600125, or CAY10585 treatment. Targeting S100A4 might offer a new strategy for the treatment of OSCC patients with metastasis. PMID- 25912159 TI - Enhanced differentiation of neural stem cells to neurons and promotion of neurite outgrowth by oxygen-glucose deprivation. AB - Stroke has become the leading cause of mortality worldwide. Hypoxic or ischemic insults are crucial factors mediating the neural damage in the brain tissue of stroke patients. Neural stem cells (NSCs) have been recognized as a promising tool for the treatment of ischemic stroke and other neurodegenerative diseases due to their inducible pluripotency. In this study, we aim to mimick the cerebral hypoxic-ischemic injury in vitro using oxygen-glucose deprivation (OGD) strategy, and evaluate the effects of OGD on the NSC's neural differentiation, as well as the differentiated neurite outgrowth. Our data showed that NSCs under the short term 2h OGD treatment are able to maintain cell viability and the capability to form neurospheres. Importantly, this moderate OGD treatment promotes NSC differentiation to neurons and enhances the performance of the mature neuronal networks, accompanying increased neurite outgrowth of differentiated neurons. However, long-term 6h and 8h OGD exposures in NSCs lead to decreased cell survival, reduced differentiation and diminished NSC-derived neurite outgrowth. The expressions of neuron-specific microtubule-associated protein 2 (MAP-2) and growth associated protein 43 (GAP-43) are increased by short-term OGD treatments but suppressed by long-term OGD. Overall, our results demonstrate that short-term OGD exposure in vitro induces differentiation of NSCs while maintaining their proliferation and survival, providing valuable insights of adopting NSC-based therapy for ischemic stroke and other neurodegenerative disorders. PMID- 25912160 TI - Detection and molecular analysis of Pseudorabies virus strains isolated from dogs and a wild boar in Italy. AB - Aujeszky's disease (AD) is one of the most economically important diseases of farmed pigs. Wild boars can act as reservoirs and might represent a potential threat for domestic animals, including dogs. The aim of this study was to report the results of an AD survey based on the Pseudorabies virus (PRV) genome detection in samples of dogs clinically suspected of AD and of wild boars collected during four consecutive hunting seasons in the period 2010-2014. Genomic characterization was based on the partial gC sequence of the Italian strains and the comparison with those from domestic pigs and European PRV strains circulating in wild boars. The Italian PRV strains were mainly distributed into three different clusters and revealed two interesting findings. First, there was a clear distinction between the viral strains that were isolated from dogs used for hunting and subsequently traced back to wild boars and the strains that were isolated from working dogs and subsequently found to be closely related to domestic pigs. Second, the Italian epidemiological situation was found to be different from those of European countries in that the Italian situation was characterized by the presence of both the typical Italian clades 1 and 2 and supported by new patterns of aa deletions/insertions. Italian clade 1 included strains from hunting dogs and two Italian wild boars, and Italian clade 2 grouped with recent strains from dogs that were unable to hunt and domestic pigs that were related to one old reference strain (S66) and not included elsewhere. Molecular and phylogenetic analyses of PRV strains are therefore necessary to improve the understanding of the distribution of the PRV clusters and their evolution. PMID- 25912161 TI - Late tracheal perforation after total thyroidectomy. Conservative management. PMID- 25912162 TI - [Multinodular focal hepatic steatosis]. PMID- 25912163 TI - Communication between the obese patient and bariatric surgeon. AB - Communication between the bariatric surgeon and the obese patient is very important as it influences the expectations of patients with regard to surgery, aim of the surgery and the understanding of the mechanisms of failure of surgery. Furthermore, the incidence of certain psychopathology in these patients makes it necessary for the surgeon to have the ability to communicate to the patient the need for motivation and the maintenance of healthy life habits. Although the topic is subjective, in this article we review several useful recommendations to optimize communication before and after surgery. Finally, we emphasize the need to create workshops to train the bariatric surgeon in these issues that we consider so important. PMID- 25912164 TI - [Cholestasis as the first symptom of gallbladder hypoplasia]. PMID- 25912165 TI - Chiral environment of catalytic sites in the chiral metal-organic frameworks. AB - Chiral metal-organic frameworks are considered a useful platform in heterogeneous catalysis for enantioselective chemical transformations. However, it has been observed that the enantioselectivity is sensitive to the site at which the reaction takes place, even in a single crystal, since the chiral environment of the catalytic site varies according to its location, e.g., that of the surface is anisotropic, whereas that of the interior is isotropic. PMID- 25912166 TI - Prognostic value of preoperative pyuria in patients with non-muscle-invasive bladder cancer. AB - OBJECTIVES: To investigate the prognostic value of preoperative pyuria in patients with non-muscle-invasive bladder cancer. METHODS: We retrospectively reviewed data from 237 patients diagnosed with non-muscle-invasive bladder cancer. Pyuria was defined as urine containing >=5 white blood cells per high power field. The association between clinicopathological factors and recurrence was assessed by Cox univariate and multivariate analyses. RESULTS: Preoperative pyuria was found in 116 (49.0%) patients. Pyuria was significantly associated with advanced age, positive cytology, multiple tumors, large tumor size, non papillary tumors, T1 tumors and high-grade tumors. In univariate analysis of the entire patient population, pyuria, positive urine cytology, multiple tumors, pT1 tumors and no bacillus Calmette-Guerin were significantly associated with recurrence. Multivariate analysis showed that pyuria was an independent predictor of recurrence (hazard ratio 3.332, 95% confidence interval 2.052-5.410; P < 0.001), along with positive urine cytology, multiple tumors and no bacillus Calmette-Guerin therapy. Subanalysis of the patients who underwent bacillus Calmette-Guerin therapy also showed that pyuria was an independent predictor of recurrence (hazard ratio 2.062, 95% confidence interval 1.085-3.918, P = 0.027). The 2-year recurrence-free survival rate for patients with pyuria was significantly lower than for patients without pyuria (65.5% vs 80.7%; P = 0.027). CONCLUSIONS: Preoperative pyuria seems to be significantly associated with recurrence in patients with non-muscle-invasive bladder cancer, and it might be a useful predictor for recurrence after bacillus Calmette-Guerin therapy. PMID- 25912167 TI - Fetal-maternal interface impedance parallels local NADPH oxidase related superoxide production. AB - Blood flow assessment employing Doppler techniques is a useful procedure in pregnancy evaluation, as it may predict pregnancy disorders coursing with increased uterine vascular impedance, as pre-eclampsia. While the local causes are unknown, emphasis has been put on reactive oxygen species (ROS) excessive production. As NADPH oxidase (NOX) is a ROS generator, it is hypothesized that combining Doppler assessment with NOX activity might provide useful knowledge on placental bed disorders underlying mechanisms. A prospective longitudinal study was performed in 19 normal course, singleton pregnancies. Fetal aortic isthmus (AoI) and maternal uterine arteries (UtA) pulsatility index (PI) were recorded at two time points: 20-22 and 40-41 weeks, just before elective Cesarean section. In addition, placenta and placental bed biopsies were performed immediately after fetal extraction. NOX activity was evaluated using a dihydroethidium-based fluorescence method and associations to PI values were studied with Spearman correlations. A clustering of pregnancies coursing with higher and lower PI values was shown, which correlated strongly with placental bed NOX activity, but less consistently with placental tissue. The study provides evidence favoring that placental bed NOX activity parallels UtA PI enhancement and suggests that an excess in oxidation underlies the development of pregnancy disorders coursing with enhanced UtA impedance. PMID- 25912169 TI - Occupational therapy: what does this look like practised in very remote Indigenous areas? AB - CONTEXT: Occupational therapy in very remote, predominantly Indigenous, settings requires therapists to modify traditional models of practice to make practice applicable, culturally relevant and culturally safe. This article describes some of the author's observations of similarities and differences in what occupational therapy 'does' and 'is' in four different, but in many ways similar, very remote contexts. A Churchill Fellowship allowed the author to travel to visit teams in three very remote regions of Canada and the USA, allowing comparison to practice in the Top End of the Northern Territory in Australia. ISSUES: These very remote settings are unable to support onsite therapy services resulting in fly/drive-in visits from hub towns, influencing service models and extending professional tasks and roles. In many of these remote contexts populations are predominantly Indigenous, which requires therapists to work cross-culturally. This requires occupational therapists to adapt therapy assessments and interventions to make these appropriate to the contexts. LESSONS LEARNED: Therapists perceived a range of therapeutic adaptations and resources as useful in their practice and some barriers to implementing these. These included supports to practice such as cultural liaisons or interpreters; being open and respectful to differences in beliefs around health, wellbeing, desired occupational pursuits and function; using a client/family-directed approach in care planning, goal setting and development of therapeutic strategies; being selective around use of standardised assessment tools; and taking time and developing relationships with family and clients. Therapists in these areas also reported their scope of practice as being broader in remote settings, requiring skills in a greater range of areas. Therapists also reported the increased use of technology to supplement and support remote practice. PMID- 25912170 TI - Excited state investigation of a new Ru(II) complex for dual reactivity with low energy light. AB - The new complex [Ru(tpy)(Me2dppn)(py)](2+) efficiently photodissociates py in CH3CN with Phi500 = 0.053(1) induced by steric bulk from methyl substituents and produces (1)O2 with PhiDelta = 0.69(9) from its long-lived (3)pipi* excited state. The unique excited state processes that result in dual reactivity were investigated using ultrafast transient absorption spectroscopy. PMID- 25912168 TI - Oxygen in human health from life to death--An approach to teaching redox biology and signaling to graduate and medical students. AB - In the absence of oxygen human life is measured in minutes. In the presence of oxygen, normal metabolism generates reactive species (ROS) that have the potential to cause cell injury contributing to human aging and disease. Between these extremes, organisms have developed means for sensing oxygen and ROS and regulating their cellular processes in response. Redox signaling contributes to the control of cell proliferation and death. Aberrant redox signaling underlies many human diseases. The attributes acquired by altered redox homeostasis in cancer cells illustrate this particularly well. This teaching review and the accompanying illustrations provide an introduction to redox biology and signaling aimed at instructors of graduate and medical students. PMID- 25912171 TI - The general base in the thymidylate synthase catalyzed proton abstraction. AB - The enzyme thymidylate synthase (TSase), an important chemotherapeutic drug target, catalyzes the formation of 2'-deoxythymidine-5'-monophosphate (dTMP), a precursor of one of the DNA building blocks. TSase catalyzes a multi-step mechanism that includes the abstraction of a proton from the C5 of the substrate 2'-deoxyuridine-5'-monophosphate (dUMP). Previous studies on ecTSase proposed that an active-site residue, Y94 serves the role of the general base abstracting this proton. However, since Y94 is neither very basic, nor connected to basic residues, nor located close enough to the pyrimidine proton to be abstracted, the actual identity of this base remains enigmatic. Based on crystal structures, an alternative hypothesis is that the nearest potential proton-acceptor of C5 of dUMP is a water molecule that is part of a hydrogen bond (H-bond) network comprised of several water molecules and several protein residues including H147, E58, N177, and Y94. Here, we examine the role of the residue Y94 in the proton abstraction step by removing its hydroxyl group (Y94F mutant). We investigated the effect of the mutation on the temperature dependence of intrinsic kinetic isotope effects (KIEs) and found that these KIEs are more temperature dependent than those of the wild-type enzyme (WT). These results suggest that the phenolic OH of Y94 is a component of the transition state for the proton abstraction step. The findings further support the hypothesis that no single functional group is the general base, but a network of bases and hydroxyls (from water molecules and tyrosine) sharing H-bonds across the active site can serve the role of the general base to remove the pyrimidine proton. PMID- 25912172 TI - ILC2s and T cells cooperate to ensure maintenance of M2 macrophages for lung immunity against hookworms. AB - Defining the immune mechanisms underlying protective immunity to helminth infection remains an important challenge. Here we report that lung CD4(+) T cells and Group 2 innate lymphoid cells (ILC2s) work in concert to block Nippostrongylus brasiliensis (Nb) development in the parenchyma within 48 h in mice. Immune-damaged larvae have a striking morphological defect that is dependent on the expansion of IL-13-producing ILC2 and CD4(+) T cells, and the activation of M2 macrophages. This T-cell requirement can be bypassed by administration of IL-2 or IL-33, resulting in expansion of IL-13-producing ILC2s and larval killing. Depletion of ILC2s inhibits larval killing in IL-2-treated mice. Our results broaden understanding of ILC2's role in immunity to helminths by demonstrating that they not only act as alarmin sensors, but can also be sustained by CD4(+) T cells, ensuring both the prompt activation and the maintenance of IL-13-dependent M2 macrophage immunity in the lung. PMID- 25912173 TI - A unique radiological case of intrathecal methotrexate-induced toxic leukoencephalopathy. PMID- 25912174 TI - Increase in oxidative stress biomarkers in dogs with ascending-descending myelomalacia following spinal cord injury. AB - Multiple biochemical and immunohistochemical tests were performed to elucidate the role of oxidative stress during ascending-descending (A-D) myelomalacia by comparing dogs with this progressive terminal condition to dogs with chronic, focal spinal cord injuries (SCIs) and controls without SCI. Dogs with A-D myelomalacia exhibited increased biochemical markers for oxidative stress, including 8-isoprostane F2alpha and acrolein, as well as decreased endogenous glutathione with greatest changes occurring at the lesion center. Inflammation, as evident by the concentration of CD18+ phagocytes and hemorrhagic necrosis, was also exacerbated in the lesion of A-D myelomalacic spinal cord compared to focal SCI. The greatest differences in oxidative stress occurred at the lesion center and diminished distally in both spinal cords with A-D myelomalacia and focal SCIs. The spatial progression and time course of A-D myelomalacia are consistent with the development of secondary injury post-SCI. Ascending-descending myelomalacia is proposed as a clinical model that may further the understanding of the role of oxidative stress during secondary injury. Our results indicate that the pathology of A-D myelomalacia is also similar to subacute progressive ascending myelopathy in humans, which is characterized by recurrent neurodegeneration of spinal cord post-injury. PMID- 25912175 TI - Hypoglycemia with focal neurological signs as stroke mimic: Clinical and neuroradiological characteristics. AB - Our aim was to investigate the clinical and radiological features of patients with hypoglycemia with focal neurological signs (HFNS). Among 80 consecutive hypoglycemic patients (blood glucose levels less than 50mg/dL), who had been admitted between October 2008 and May 2012, we selected 11 patients (6 men and 5 women; mean age, 73.2 +/- 12 years) with focal neurological signs. The mean initial blood glucose level was 27.9 mg/dL (range, 13-39 mg/dL). The most frequent symptom was unilateral motor weakness (n = 9), which was usually accompanied with mild or moderate alteration of consciousness. All patients had improved initial neurological signs within 1h of glucose injection. The initial DWI demonstrated a hyperintense lesion in the contralateral internal capsule with decreased values on the ADC (apparent diffusion coefficient) map in 2 of the patients (18%). The DWI performed one day later shows only faint lesion. The initial DWI in patients with HFNS may display a hyperintense lesion, which was difficult to distinguish from acute cerebral infarction. Hypoglycemia should be considered in cases with DWI showing a disproportionally small lesion in contrast to neurological signs. PMID- 25912176 TI - The safety and efficacy of early-initiation exercise training after acute venous thromboembolism: a randomized clinical trial. AB - BACKGROUND: Exercise training after myocardial infarction is the standard of care within a cardiac rehabilitation setting. However, there is scant evidence regarding the safety and efficacy of early exercise training following a venous thromboembolism (VTE). METHODS: Eligible consenting participants were randomly allocated, on an individual basis, to either a 3-month exercise and behavioral weight loss intervention group or a control group. The primary clinical outcomes were change in health behavior (body weight and physical activity) and objectively measured fitness (Vo2peak ). RESULTS: From 2013 to 2014, 239 patients presented to a community-based specialty clinic after an acute VTE; 43 (18%) of these met the eligibility criteria for inclusion in the study. Of these, 19 (44%) consented to participate (nine in the intervention group; 10 in the control group). There were no adverse events in either group over a 3-month period. The mean difference in body weight between the intervention and control groups was - 4.6 kg (95% confidence interval [CI] - 11.4 to 2.2) in favor of the intervention. The mean difference in duration of physical activity from baseline to 3 months between the intervention and control groups was 133 min (95% CI 7-248) in favor of the intervention. There was a significant change in fitness over a 3-month period for the intervention group (baseline Vo2peak , 26.1 +/- 5.4 mL O2 kg(-1) min(-1) ; postintervention Vo2peak , 29.8 +/- 5.4 mL O2 kg(-1) min(-1) ). CONCLUSION: Early initiation of exercise training resulted in improvements in physical activity and fitness, and did not result in adverse events while individuals were receiving therapeutic anticoagulation. These are the first data on initiation of an exercise training and behavioral weight loss program in the early post-VTE setting. PMID- 25912177 TI - Distinct trajectories of separation anxiety in the preschool years: persistence at school entry and early-life associated factors. AB - BACKGROUND: Little is known about how children differ in the onset and evolution of separation anxiety (SA) symptoms during the preschool years, and how SA develops into separation anxiety disorder. In a large, representative population based sample, we investigated the developmental trajectories of SA symptoms from infancy to school entry, their early associated risk factors, and their associations with teachers' ratings of SA in kindergarten. METHODS: Longitudinal assessment of SA trajectories and risk factors in a cohort of 1,933 families between the ages of 1.5 and 6 years. RESULTS: Analyses revealed a best-fitting, 4 trajectory solution, including a prevailing, unaffected Low-Persistent group (60.2%), and three smaller groups of distinct developmental course: a High Increasing (6.9%), a High-Decreasing (10.8%), and a Low-Increasing group (22.1%). The High-Increasing group remained high throughout the preschool years and was the only trajectory to predict teacher-assessed SA at age 6 years. Except for the High-Increasing, all trajectories showed substantial reduction in symptoms by age 6 years. The High-Increasing and High-Decreasing groups shared several early risk factors, but the former was uniquely associated with higher maternal depression, maternal smoking during pregnancy, and parental unemployment. CONCLUSIONS: Most children with high SA profile at age 1.5 years are expected to progressively recover by age 4-5. High SA at age 1.5 that persists over time deserves special attention, and may predict separation anxiety disorder. A host of child perinatal, parental and family-contextual risk factors were associated with the onset and developmental course of SA across the preschool years. PMID- 25912178 TI - Prevalence of genital dysplasia after kidney transplantation--a retrospective, non-interventional study from two centers. AB - OBJECTIVE: Renal transplant patients are at increased risk for human papillomavirus-related malignancies of the lower genital tract. Our aim was to describe the incidence of genital dysplasia, assess the most common cervical cancer screening intervals and identify independent risk factors for the development of genital dysplasia in renal transplant patients. DESIGN: Retrospective, non-interventional study from two centers. SETTING: Post transplant nephrologic follow-up visit at the Medical University of Vienna and a Viennese teaching hospital. POPULATION: 262 consecutive female renal transplant patients with renal transplant performed between 1980 and 2012 at the Medical University of Vienna. METHODS: Sociodemographic patient characteristics, frequency of gynecological examinations, histo- and cytopathological test results were collected. MAIN OUTCOME MEASURES: Dysplasia rates in renal transplant patients. RESULTS: 16 patients (6.2%) with genital dysplasia after renal transplant were observed. The 1-year, 3-year and 10-year proportional incidence rates for genital dysplasia in general and cervical dysplasia in particular were 1.3 and 1.3%, 3.3 and 2.7%, and 13.6 and 12.0%, respectively. Patients attended cervical cancer screening on a regular basis once a year in 82.7% of cases. In multivariate analysis re-transplantation [odds ratio 12.1 (1.5-96.3)], and renal transplant at a young age [odds ratio 0.6 (0.4-0.9)] were identified as independent risk factors for the development of female genital dysplasia. CONCLUSIONS: Female renal transplant patients have an increased risk for the development of genital dysplasia in general and of cervical dysplasia in particular. Within this cohort, women at a young age at the time of transplantation and after re-transplantation are at highest risk for the development of genital dysplasia. PMID- 25912179 TI - VEGF, shear stress and muscle angiogenesis: a complicated triangle. PMID- 25912180 TI - Role of nicotinic receptors in the lateral habenula in the attenuation of amphetamine-induced prepulse inhibition deficits of the acoustic startle response in rats. AB - RATIONALE: Prepulse inhibition (PPI) refers to the reduction of the startle response magnitude when a startling stimulus is closely preceded by a weak stimulus. PPI is commonly used to measure sensorimotor gating. In rats, the PPI reduction induced by the dopamine agonist apomorphine can be reversed by systemic administration of nicotine. A high concentration of nicotinic receptors is found in the lateral habenula (LHb), an epithalamic structure with efferent projections to brain regions involved in the modulation of PPI, which has been shown to regulate the activity of midbrain dopamine neurons. OBJECTIVES: The prospective role of nicotinic receptors in the LHb in the regulation of PPI was assessed in this study, using different pharmacological models of sensorimotor gating deficits. METHODS: Interactions between systemic amphetamine and haloperidol and intra-LHb infusions of mecamylamine (10 MUg/side) or nicotine (30 MUg/side) on PPI were analyzed in Experiments 1 and 2. Intra-LHb infusions of different nicotine doses (25, and 50 MUg/side) and their interactions with systemic administration of amphetamine or dizocilpine on PPI were examined in Experiments 3 and 4. RESULTS: Infusions of nicotine into the LHb dose-dependently attenuated amphetamine-induced PPI deficits but had no effect on PPI disruptions caused by dizocilpine. Intra-LHb mecamylamine infusions did not affect PPI nor interact with dopaminergic manipulations. CONCLUSIONS: These results are congruent with previous reports of systemic nicotine effects on PPI, suggesting a role of the LHb in the attenuation of sensorimotor gating deficits caused by the hyperactivity of dopamine systems. PMID- 25912181 TI - Biological impact of recurrent sexually transmitted infections on HIV seroconversion among women in South Africa: results from frailty models. AB - INTRODUCTION: Understanding the impact of curable sexually transmitted infections (STIs) on HIV transmissibility is essential for effective HIV prevention programs. Investigating the impact of longitudinally measured recurrent STIs on HIV seroconversion is the interest of the current paper. METHODS: In this prospective study, data from a total of 1456 HIV-negative women who enrolled in a HIV biomedical trial were used. It was hypothesized that women who had recurrent STI diagnoses during the study share a common biological heterogeneity which cannot be quantified. To incorporate this "unobserved" correlation in the analysis, times to HIV seroconversion were jointly modelled with repeated STI diagnoses using Cox regression with random effects. RESULTS AND DISCUSSION: A total of 110 HIV seroconversions were observed (incidence rate of 6.00 per 100 person-years). In a multivariable model, women who were diagnosed at least once were more likely to seroconvert compared to those who had no STI diagnosis [hazard ratio (HR): 1.63, 95% confidence interval (CI): 1.04, 2.57]; women who had recurrent STI diagnoses during the study were 2.5 times more likely to be at increased risk of HIV infection (95% CI: 1.35, 4.01) with an estimated frailty variance of 1.52, with p<0.001, indicating strong evidence that there is a significant correlation (heterogeneity) among women who had recurrent STIs. In addition to this, factors associated with incidence of STIs, namely not being married and having a new sexual partner during the study follow-up, were all significantly associated with increased risk for HIV seroconversion (HR: 2.92, 95% CI: 1.76, 5.01 and HR: 2.25, 95% CI: 1.63, 3.83 respectively). CONCLUSIONS: The results indicated that women who were at risk for STIs were also at risk of HIV infection. In fact, they share the similar risk factors. In addition to this, repeated STI diagnoses also increased women's susceptibility for HIV infection significantly. Decreasing STIs by increasing uptake of testing and treatment and reducing partner change plays a significant role in the trajectory of the epidemic. PMID- 25912182 TI - Extensive evaluation of DNA polymerase performance for highly degraded human DNA samples. AB - Highly degraded human DNA is commonly encountered in the forensic studies. Despite many efforts, the poor quality and quantity of the DNA often result in unsuccessful DNA analysis. There has been no extensive evaluation of DNA polymerase performance for the successful PCR of highly degraded DNA samples. We evaluated the most efficient DNA polymerases, based on real-time PCR and agarose gel electrophoresis analyses for a single copy gene amplification, with 200 ancient DNA (aDNA) samples of various origins. Nine commercially available DNA polymerases were tested, which included enzymes that are reportedly effective for PCR-inhibitory samples. The first screening test for the polymerases with 20 aDNA samples showed that Pico Maxx HF, FastStart Taq, and Ex Taq HS DNA polymerases were the most effective. Further tests with 180 aDNA samples showed that AmpliTaq Gold (control) amplified PCR products from 52 aDNA samples, PicoMaxx HF from 62, FastStart Taq from 64, and Ex Taq HS from 65. The use of two or more of Ex Taq HS, FastStart Taq, and PicoMaxx HF resulted in a significantly higher success rate than that of AmpliTaq Gold alone. With 37 positive samples tested in duplicate, Ex Taq HS showed the highest reproducibility (13 samples) and AmpliTaq Gold, the lowest (four samples); this difference was significant. The data also showed preferential amplification by the enzymes; Ex Taq HS exclusively produced amplification from two samples, FastStart Taq from one, and PicoMaxx HF from one. We suggest that the initial use of these three DNA polymerases will increase the probability of successfully amplifying DNA from highly degraded human DNA samples. PMID- 25912183 TI - Postmortem distribution of trazodone concentrations. AB - Non-toxic postmortem trazodone tissue (liver) concentrations have not been previously described. Liver trazodone concentrations were compared to peripheral blood and central blood concentrations in 19 medical examiner cases. Postmortem blood specimens were initially screened for alcohol and simple volatiles, drugs of abuse, and alkaline drugs. Trazodone, when detected by the alkaline drug screen, was subsequently confirmed and quantified by a high performance liquid chromatography procedure. Re-analyses showed that there may be degradation of trazodone in postmortem blood stored at 4 degrees C. There was, on average, about a 20% decrease in samples stored up to eight months. These data suggest that postmortem trazodone peripheral blood concentrations may be considered non-toxic to at least 1.0mg/L with liver concentrations to at least 2.2mg/kg. Overall, trazodone concentrations ranged from 0.08-6.1mg/L in peripheral blood, 0.07 7.1mg/L in central blood, and 0.39-26mg/kg in liver. The median trazodone central blood to peripheral blood ratio was 0.98 (N=19). The liver to peripheral blood ratios showed a median value of 2.8L/kg (N=18). Given that a liver to peripheral blood ratio less than 5L/kg is consistent with little to no propensity for postmortem redistribution, these data demonstrate that trazodone is unlikely to show significant redistribution. PMID- 25912184 TI - Important tips and numbers on using the cortical step and diameter difference sign in assessing femoral rotation--should we abandon the technique? AB - Rotational malalignment during femoral nailing is common despite having various intraoperative assessment methods. The cortical step sign and diameter difference sign (CSSDDS) is commonly used because of convenience, yet it lack proper scientific scrutiny and is thought to be error prone. Using a software algorithm, cross-sectional dimensions were obtained from CT scans of 22 intact adult femurs at the proximal, mid and distal diaphysis. With multiple simulated scenarios the sensitivity of CSSDDS was comprehensively determined at all possible C-arm positions. At rotation, cortical width changed most significantly around the thick linea aspera and femoral diameter changed most significantly at the sagittal plane. At 15 degrees of rotation and with the linea aspera in view, CSSDDS thresholds of 0.3mm, 0.6mm and 1mm had sensitivities of 98.8%, 93.1% and 73.8%. With the linea aspera masked behind the femur and out of view, the sensitivities significantly deteriorated to 96.4%, 77.1% and 44.1% respectively. CSSDDS is sufficiently sensitive only when strict rules are followed. It is imperative that the operator position the image intensifier in lateral view under proper magnification so that steps of less than 0.6mm around the linea aspera may be appreciated. PMID- 25912186 TI - Do dietary patterns in older age influence the development of cancer and cardiovascular disease: A longitudinal study of ageing. AB - BACKGROUND: The association between diet and cancer, and diet and cardiovascular disease (CVD) is well established in younger adults, however limited evidence exists to demonstrate that these associations persist for older adults, particularly in the context of dietary patterns. AIMS: To investigate whether the dominant dietary patterns identified in a cohort of older adults are predictive of cancer or CVD development. METHODS: This study was a secondary analysis of data from the Australian Longitudinal Study of Ageing (ALSA). The ALSA is a multi dimensional population based study of human ageing which commenced in 1992 with 2087 participants aged 65 years or more. Data from a 170-item food frequency questionnaire administered at baseline in 1992 to 1034 older adults free from cancer and CVD was explored using factor analysis to identify dominant dietary patterns, being those patterns which comprise foods commonly consumed by the sample. Pooled logistic regression from data available at baseline, 2 and 8 years of follow-up was used to determine whether any associations existed between dietary patterns and development of or death from cancer or CVD. RESULTS: Five dominant dietary patterns were identified and labelled 'discretionary choices and breads and cereals', 'vegetable and fruit', 'white meat and milk products', 'breads and cereals, sweet bakery goods and milk products' and 'red meat and protein alternatives'. None of the dominant dietary patterns demonstrated a significant overall trend for the development of or death from cancer or CVD with the exception of the 'red meat and protein alternatives' pattern where an increased risk of cancer development or death was observed with adjustment for age, gender, smoking, overweight and obesity and total number of comorbidities (tertile 2: OR 1.46, 95% CI 1.03-2.07; tertile 3: OR 1.28, 95% CI 0.87-1.90). CONCLUSIONS: These results suggest that the development of or death from cancer and CVD may be independent of most dietary patterns in those who are free of either condition at age 70 years or older. Importantly, there was an association observed between the 'red meat and protein alternatives' pattern and cancer development and death. If these findings are confirmed then dietary guidelines for older adults may require further revision. PMID- 25912185 TI - Diet quality and diet patterns in relation to circulating cardiometabolic biomarkers. AB - BACKGROUND & AIMS: We examined the effects of diet quality and dietary patterns in relation to biomarkers of risk including leptin, soluble intracellular adhesion molecule 1 (sICAM-1), C-reactive protein (CRP), and irisin. METHODS: We analyzed data from 196 adults cross-sectionally. Dietary patterns were identified by factor analysis and diet quality scores were generated using a validated food frequency questionnaire. RESULTS: Both the alternate healthy eating index-2010 (AHEI-2010) and the Dietary Approaches to Stop Hypertension (DASH) scores were negatively related to CRP, even after controlling for body mass index and total energy intake. Similarly, the prudent diet pattern was negatively related to leptin, sICAM-1, and CRP, whereas the Western diet pattern showed positive associations with these markers; however, after adjusting for all confounders, the associations only remained significant for leptin and sICAM-1. Irisin was positively associated with DASH and the prudent diet after controlling for all confounders (standardized beta = 0.23, P = 0.030; standardized beta = 0.25, P = 0.021, respectively). Irisin showed positive associations with increasing fruit consumption, whereas the levels of irisin decreased as meat consumption increased. CONCLUSIONS: Irisin was directly associated with healthy diet types and patterns. Further studies regarding these mechanisms are warranted. This trial is registered at http://www.clinicaltrials.gov. Identifier: NCT01853332. PMID- 25912188 TI - CALibrating the CALumenin gene: New insights in overcoming the vascular CALcification CALamity? PMID- 25912187 TI - How much protein and energy are needed to equilibrate nitrogen and energy balances in ventilated critically ill children? AB - BACKGROUND & AIMS: Protein and energy requirements in critically ill children are currently based on insufficient data. Moreover, longitudinal measurements of both total urinary nitrogen (TUN) and resting energy expenditure (REE) are lacking. The aim of this study was to investigate how much protein and energy are needed to equilibrate nitrogen and energy balances in ventilated critically ill children on the basis of daily measurements of TUN, REE and protein and energy intakes. Comparisons were made with the guidelines of the American Society for Parenteral and Enteral Nutrition and the Dietary Reference Intakes. METHODS: Children with an expected duration of mechanical ventilation >=72 h were prospectively recruited. TUN was measured by chemiluminescence, and REE was measured by indirect calorimetry. Generalised linear models for longitudinal data were used to study the relation between protein intake and nitrogen balance and to calculate the minimum intake of protein needed to achieve nitrogen equilibrium. A similar approach was used for energy. Results were compared to the recommended values. RESULTS: Based on 402 measurements performed in 74 children (median age: 21 months), the mean TUN was high at 0.20 (95% CI: 0.20, 0.22) g/kg/d and the REE was 55 (95% CI: 54, 57) kcal/kg/d. Nitrogen and energy balances were achieved with 1.5 (95% CI: 1.4, 1.6) g/kg/d of protein and 58 (95% CI: 53, 63) kcal/kg/d for the entire group, but there were differences among children of different ages. Children required more protein and less energy than the Dietary Reference Intakes. CONCLUSIONS: In critically ill children, TUN was elevated and REE was reduced during the entire period of mechanical ventilation. Minimum intakes of 1.5 g/kg/d of protein and 58 kcal/kg/d can equilibrate nitrogen and energy balances in children up to 4 years old. Older children require more protein. PMID- 25912190 TI - Conyza species: distribution and evolution of multiple target-site herbicide resistances. AB - MAIN CONCLUSION: Distribution of Conyza species is well correlated with human interference. Multiple herbicide resistance is caused by the attempt to overcome resistance to one mode of action by overuse of another. Conyza canadensis (CC) and Conyza bonariensis (CB) are troublesome weeds around the world. Extensive use of herbicides has led to the evolution of numerous Conyza spp. herbicide resistant populations. Seeds of 91 CC and CB populations were collected across Israel. They were mostly found (86 %) in roadsides and urban habitats, two disturbed habitats that had been dramatically impacted by human activities, thus we classify these species as anthropogenic. Although pyrithiobac-sodium was only used in cotton fields, 90 % of Conyza spp. populations were identified as pyrithiobac-sodium resistant, suggesting possible natural resistance to pyrithiobac-sodium. CC21 and CC17 C. canadensis populations were highly resistant to all tested ALS inhibitors due to a substitution in the ALS gene from Trp574 to Leu. They were also atrazine resistant due to a substitution in the psbA gene from Ser264 to Gly. The high level of imazapyr and pyrithiobac-sodium resistance observed in the CC10 population was due to an Ala205 to Val substitution. However, high resistance to sulfometuron methyl and pyrithiobac-sodium in population CC6 was due to a point mutation at Pro197 to Ser. All resistant plants of CC21 population showed both psbA (Ser264 to Gly) and ALS (Trp574 to Leu) substitutions, leading us to the conclusion that the attempt to overcome resistance to one mode of action by overuse of another will most likely lead to multiple herbicide resistance. Furthermore, we concluded that only individuals that carry both mutations could survive the shift between the two modes of action and overcome the fitness cost associated with the PSII resistance. PMID- 25912189 TI - Molecular basis of sugar recognition by collectin-K1 and the effects of mutations associated with 3MC syndrome. AB - BACKGROUND: Collectin-K1 (CL-K1, or CL-11) is a multifunctional Ca(2+)-dependent lectin with roles in innate immunity, apoptosis and embryogenesis. It binds to carbohydrates on pathogens to activate the lectin pathway of complement and together with its associated serine protease MASP-3 serves as a guidance cue for neural crest development. High serum levels are associated with disseminated intravascular coagulation, where spontaneous clotting can lead to multiple organ failure. Autosomal mutations in the CL-K1 or MASP-3 genes cause a developmental disorder called 3MC (Carnevale, Mingarelli, Malpuech and Michels) syndrome, characterised by facial, genital, renal and limb abnormalities. One of these mutations (Gly(204)Ser in the CL-K1 gene) is associated with undetectable levels of protein in the serum of affected individuals. RESULTS: In this study, we show that CL-K1 primarily targets a subset of high-mannose oligosaccharides present on both self- and non-self structures, and provide the structural basis for its ligand specificity. We also demonstrate that three disease-associated mutations prevent secretion of CL-K1 from mammalian cells, accounting for the protein deficiency observed in patients. Interestingly, none of the mutations prevent folding or oligomerization of recombinant fragments containing the mutations in vitro. Instead, they prevent Ca(2+) binding by the carbohydrate-recognition domains of CL-K1. We propose that failure to bind Ca(2+) during biosynthesis leads to structural defects that prevent secretion of CL-K1, thus providing a molecular explanation of the genetic disorder. CONCLUSIONS: We have established the sugar specificity of CL-K1 and demonstrated that it targets high-mannose oligosaccharides on self- and non-self structures via an extended binding site which recognises the terminal two mannose residues of the carbohydrate ligand. We have also shown that mutations associated with a rare developmental disorder called 3MC syndrome prevent the secretion of CL-K1, probably as a result of structural defects caused by disruption of Ca(2+) binding during biosynthesis. PMID- 25912191 TI - A deletion mutant ndv200 of the Bacillus thuringiensis vip3BR insecticidal toxin gene is a prospective candidate for the next generation of genetically modified crop plants resistant to lepidopteran insect damage. AB - MAIN CONCLUSION: Ectopic expression of a deletion mutant ( ndv200 ) of Bacillus thuringiensis vip3BR gene in tobacco plant provided almost complete protection against major crop pests cotton boll worm ( Helicoverpa armigera ), black cut worm ( Agrotis ipsilon ) and cotton leaf worm ( Spodoptera littoralis ). Whereas vip3BR transgenic tobacco plant failed to protect themselves from these insects and showed resistance towards cotton leaf worm only. An analogous form of the Bacillus thuringiensis vip3Aa insecticidal toxin gene, named vip3BR, was identified and characterized, and exhibited similar attributes to the well-known Vip3Aa toxin. Vip3BR possessed broad-spectrum lepidopteran-specific insecticidal properties effective against most major crop pests of the Indian subcontinent. A Vip3BR toxin protein N-terminal deletion mutant, Ndv200, showed increased insecticidal potency relative to the native toxin, which conferred efficacy against four major crop pests, including cotton boll worm (Helicoverpa armigera), black cut worm (Agrotis ipsilon), cotton leaf worm (Spodoptera littoralis), and rice yellow stem borer (Scirpophaga incertulas). Ligand blot analysis indicated the Ndv200 toxin recognized the same larval midgut receptors as the native Vip3BR toxin, but differed from receptors recognized by Cry1A toxins. In the present study, we tested the prospect of the vip3BR and ndv200 toxin gene as candidate in development of insect-resistant genetically engineered crop plants by generating transgenic tobacco plant. The study revealed that the ndv200 mutant of vip3BR insecticidal toxin gene is a strong and prospective candidate for the next generation of genetically modified crop plants resistant to lepidopteran insects. PMID- 25912192 TI - Acceptance and Commitment Therapy and nicotine patch for smokers with bipolar disorder: preliminary evaluation of in-person and telephone-delivered treatment. AB - OBJECTIVES: People with bipolar disorder are two to three times more likely to smoke and 50% less likely to quit than the general population. New treatments are needed to improve smoking cessation outcomes in this group. The study aim was to develop and pilot test a novel cessation intervention for smokers with bipolar disorder using Acceptance and Commitment Therapy (ACT) combined with nicotine patches. METHODS: The ten-session ACT intervention was initially evaluated as in person, individual counseling (n = 10), then as telephone-delivered counseling (n = 6). Participants were adult smokers with no more than mild current symptoms of bipolar disorder. RESULTS: For the in-person protocol, end-of-treatment outcomes were: 80% retention, 40% of participants with carbon monoxide (CO)-verified seven day point prevalence abstinence (PPA), 90% satisfied with treatment, 8.3 of ten sessions attended, and 54% increase in acceptance of cravings to smoke (i.e., ACT's theory-based change process) from baseline. The seven-day PPA at one-month follow-up was 30%. For the telephone protocol, end-of-treatment outcomes were: 67% retention, 33% reporting seven-day PPA, 100% satisfied with treatment, 6.7 of ten treatment calls completed, and 55% increase in acceptance from baseline. At one-month follow-up, seven-day PPA was 17%. The proportion of treatment completers who used at least 80% of the nicotine patches was 62.5% for the in person protocol and 0% for the telephone protocol. CONCLUSIONS: Both in-person and telephone-delivered ACT were feasible. Despite low adherence to nicotine patches, the intervention showed preliminary evidence of facilitating quitting and impacting ACT's change mechanism. A randomized, controlled trial of this targeted ACT intervention is now needed. PMID- 25912193 TI - Neuroprotective effect of memantine on the retinal ganglion cells of APPswe/PS1DeltaE9 mice and its immunomodulatory mechanisms. AB - Besides the cognitive impairment and degeneration in the brain, vision dysfunction and retina damage are always prevalent in patients with Alzheimer's disease (AD). The uncompetitive antagonist of the N-methyl-d-aspartate receptor, memantine (MEM), has been proven to improve the cognition of patients with AD. However, limited information exists regarding the mechanism of neurodegeneration and the possible neuroprotective mechanisms of MEM on the retinas of patients with AD. In the present study, by using APPswe/PS1DeltaE9 double transgenic (dtg) mice, we found that MEM rescued the loss of retinal ganglion cells (RGCs), as well as improved visual impairments, including improving the P50 component in pattern electroretinograms and the latency delay of the P2 component in flash visual evoked potentials of APPswe/PS1DeltaE9 dtg mice. The activated microglia in the retinas of APPswe/PS1DeltaE9 dtg mice were also inhibited by MEM. Additionally, the level of glutamine synthetase expressed by Muller cells within the RGC layer was upregulated in APPswe/PS1DeltaE9 dtg mice, which was inhibited by MEM. Simultaneously, MEM also reduced the apoptosis of choline acetyl transferase-immunoreactive cholinergic amacrine cells within the RGC layer of AD mice. Moreover, the phosphorylation level of extracellular regulated protein kinases 1 and 2 was increased in APPswe/PS1DeltaE9 dtg mice, which was blocked by MEM treatment. These findings suggest that MEM protects RGCs in the retinas of APPswe/PS1DeltaE9 dtg mice by modulating the immune response of microglia and the adapted response of Muller cells, making MEM a potential ophthalmic treatment alternative in patients with AD. PMID- 25912194 TI - Early adaptive response of the retina to a pro-diabetogenic diet: Impairment of cone response and gene expression changes in high-fructose fed rats. AB - The lack of plasticity of neurons to respond to dietary changes, such as high fat and high fructose diets, by modulating gene and protein expression has been associated with functional and behavioral impairments that can have detrimental consequences. The inhibition of high fat-induced rewiring of hypothalamic neurons induced obesity. Feeding rodents with high fructose is a recognized and widely used model to trigger obesity and metabolic syndrome. However the adaptive response of the retina to short term feeding with high fructose is poorly documented. We therefore aimed to characterize both the functional and gene expression changes in the neurosensory retina of Brown Norway rats fed during 3 and 8 days with a 60%-rich fructose diet (n = 16 per diet and per time point). Glucose, insulin, leptin, triacylglycerols, total cholesterol, HDL-cholesterol, LDL-cholesterol and fructosamine were quantified in plasma (n = 8 in each group). Functionality of the inner retina was studied using scotopic single flash electroretinography (n = 8 in each group) and the individual response of rod and cone photoreceptors was determined using 8.02 Hz Flicker electroretinography (n = 8 in each group). Analysis of gene expression in the neurosensory retina was performed by Affymetrix genechips, and confirmed by RT-qPCR (n = 6 in each group). Elevated glycemia (+13%), insulinemia (+83%), and leptinemia (+172%) was observed after 8 days of fructose feeding. The cone photoreceptor response was altered at day 8 in high fructose fed rats (Delta = 0.5 log unit of light stimulus intensity). Affymetrix analysis of gene expression highlighted significant modulation of the pathways of eIF2 signaling and endoplasmic reticulum stress, regulation of eIF4 and p70S6K signaling, as well as mTOR signaling and mitochondrial dysfunction. RT-qPCR analysis confirmed the down regulation of Crystallins, Npy, Nid1 and Optc genes after 3 days of fructose feeding, and up regulation of End2. Meanwhile, a trend towards an increased expression of alphaA- and alphaB-crystallin proteins was observed at day 8. Our results are consistent with early alterations of the functioning and gene expression in the retina in a pro diabetogenic environment. PMID- 25912195 TI - Recent advances in glucose-lowering treatment to reduce diabetic kidney disease. AB - INTRODUCTION: The epidemic of diabetes has now taken on epic proportions and therefore reducing the impact of diabetic complications represents one of the major global challenges in improving health and well-being worldwide. Preventing the development of diabetic kidney disease (DKD) is particularly important, as diabetes is one of the main risk factors for the development of chronic kidney disease, which in turn is strongly linked to development of cardiovascular disease, end-stage renal failure, hospitalization and premature death. Intensive glucose-lowering treatment has been shown to prevent and slow progression of DKD, yet to date, only certain populations have benefited from this intervention. AREAS COVERED: We review the evidence for existing glucose-lowering treatments in the prevention of DKD, and research into techniques to better target individuals who will benefit from these therapies. EXPERT OPINION: Diabetic patients with established kidney disease may benefit from glucose-lowering treatment, particularly if a safer side-effect profile of these treatments is achieved. Better understanding of glucose homeostasis and evaluation of compounds inhibiting its downstream effects are required in order to improve the outlook for individuals with DKD. An additional approach to improve the success rate of glucose-lowering treatment is to improve the selection of individuals who may benefit from treatment. A potential means to identify such subjects could involve the use of biomarkers. PMID- 25912196 TI - Danger ahead: dynamic hyperacute T waves. PMID- 25912197 TI - The perils of country life: human monocytic ehrlichiosis. PMID- 25912198 TI - Physician Prevention of Acute Kidney Injury. AB - BACKGROUND: The frequency of acute kidney injury has become substantially greater over the recent past. Acute kidney injury, moreover, is associated with increased mortality and morbidity over both the short and long term. Despite these facts, its therapy has not changed significantly for many decades. Currently, therefore, prevention is the only action that can reduce the frequency and consequences of acute kidney injury. METHODS: Charts of 492 patients were reviewed retrospectively for the presence of acute kidney injury based on creatinine elevation. One hundred seventy patients were found to have acute kidney injury defined as a sustained elevation of serum creatinine >= 0.3 mg/dL for 48 hours or more. An agent or event was determined to be responsible for renal injury if there was the defined increase in serum creatinine within 48 hours of exposure. Charts were reviewed to determine if the renal injury was preventable. RESULTS: Fifty-one cases were considered to be preventable. Of these, 16 had not received saline prophylaxis for intravenous contrast when appropriate, 15 were not treated appropriately for hemodynamic instability or for hypertension, 9 had inappropriate use of medications, and 11 received multiple nephrotoxic agents. CONCLUSIONS: In a retrospective analysis of 170 hospitalized patients who developed acute kidney injury during admission, 30% of episodes could have been avoided if physicians had taken appropriate preventive actions. PMID- 25912199 TI - High incidence of hyponatremia in rowers during a four-week training camp. AB - PURPOSE: To investigate the incidence of hyponatremia and its relationship to plasma copeptin, a surrogate marker for arginine vasopressin (AVP) during 28 days of high-volume rowing training. METHODS: Thirty rowers from the German junior national team (21 male) were studied during a training camp. Serum sodium ([Na(+)]), osmolality, and copeptin were measured before the beginning of the camp (day 0), and at days 7, 13, 18, 24, and 28. Daily fluid intake, body weight, urine parameters, and training volume were recorded. RESULTS: Seventy percent of the rowers developed hyponatremia at least once. At day 18, training volume and incidence of hyponatremia (43%) were highest. [Na(+)] decreased from 143 +/- 9 mmol.L(-1) (day 0) to 135 +/- 5 mmol.L(-1) (day 18, P < .01). Hyponatremia was correlated significantly with weight gain compared with the previous day (P < .01). Copeptin decreased from day 0 to 28 (male: 6.7 +/- 2.8 to 3.6 +/- 1.7 pmol.L(-1); P < .05; female: 4.8 +/- 1.1 to 3.2 +/- 1.5 pmol.L(-1); P < .05), being only partially suppressed. Relative fluid intake per body surface area increased from day 7 (male: 2.79 +/- 0.78 L.m(-2); female: 2.20 +/- 0.70 L.m(-2)) to day 28 (3.88 +/- 0.69 L.m(2) and 2.65 +/- 0.93 L.m(-2); P < .05). No athlete developed symptomatic hyponatremia. CONCLUSION: Prolonged high-volume rowing training can lead to a high incidence of hyponatremia. Overdrinking and inadequate suppression of AVP contribute to its development. PMID- 25912200 TI - From Bradycardia to Tachycardia: Complete Heart Block. PMID- 25912201 TI - Restless Legs Syndrome and Cognitive Function: A Population-based Cross-sectional Study. AB - BACKGROUND: Restless legs syndrome has been speculated to be linked to cognitive impairment through vascular risk factors or through its effect on sleep deprivation. Previous studies on the association between restless legs syndrome and cognitive function have been inconclusive. We performed a cross-sectional analysis of the association between restless legs syndrome and cognitive function using data from a large population-based study of elderly individuals residing in France. METHODS: We used information from 2070 individuals from the Dijon, France center of the Three-City study who had available information on restless legs syndrome and cognitive functioning measures. Restless legs syndrome was assessed using the 4 minimal diagnostic criteria of the International Restless Legs Study Group. During the same wave in which restless legs syndrome status was assessed, cognitive functions also were assessed using 4 tests: Isaacs' test of verbal/category fluency, the Benton Visual Retention Test, the Trail Making Test B, and the Mini-Mental State Examination. We created a summary global cognitive score by summing the z scores for the 4 tests and used analysis of covariance to explore the association between restless legs syndrome and cognitive function. RESULTS: We did not observe any statistically significant differences in any cognitive z-score between those with restless legs syndrome and those without restless legs syndrome. The mean global z-score after multivariate adjustment was -0.003 (SE 0.173) for those with restless legs syndrome and -0.007 (SE 0.129) for those without restless legs syndrome (P-value = .98). CONCLUSION: Data from this large, population-based study do not suggest that restless legs syndrome is associated with prevalent cognitive deficits in elderly individuals. PMID- 25912202 TI - Getting the whole picture: lymphangitic carcinomatosis. PMID- 25912203 TI - Serum bilirubin levels predict future development of metabolic syndrome in healthy middle-aged nonsmoking men. AB - BACKGROUND: Despite epidemiologic research demonstrating an inverse relationship between serum bilirubin levels and the prevalence of metabolic syndrome, prospective data on serum bilirubin as a predictor of incident metabolic syndrome are limited. METHODS: Serum bilirubin was examined as a risk marker for incident metabolic syndrome in a prospective study of 468 Taiwanese middle-aged men who were free of metabolic syndrome and other systemic diseases at baseline. These subjects were followed up in annual health examinations between 2001 and 2009 for the development of metabolic syndrome, which was defined according to unified criteria set by several major organizations. RESULTS: Among the study subjects, 377 were nonsmokers and 91 were current smokers. All individuals were then stratified into 3 groups according to their baseline serum bilirubin levels (low, normal, and high). During a mean follow-up period of 7.58 years, 66 subjects developed metabolic syndrome. The incidence of metabolic syndrome was significantly reduced in the high-bilirubin group compared with the low-bilirubin group (6.4% vs 22.4%, P < .001). Multivariate Cox regression analysis revealed that the hazard ratio for incident metabolic syndrome between the highest and lowest tertiles of serum bilirubin levels was 0.246 (95% confidence interval 0.120-0.503). However, although it remained clearly evident in nonsmokers, the inverse correlation was attenuated in current smokers. CONCLUSIONS: Increased serum bilirubin was associated with a reduced future risk of metabolic syndrome in apparently healthy middle-aged, nonsmoking men. Our findings support the predictive role of serum total bilirubin for future development of metabolic syndrome. PMID- 25912204 TI - Back with a vengeance: microvascular tumor embolism. PMID- 25912205 TI - Serum Albumin and Prealbumin in Calorically Restricted, Nondiseased Individuals: A Systematic Review. AB - PURPOSE: Undernutrition is often suspected in patients when serum albumin or prealbumin levels are low. We asked whether these measures are indeed low in undernourished people if no inflammatory illness is present. METHODS: We did a systematic review to identify otherwise healthy subjects who were severely nutrient-deprived due to poor access to food or unwillingness to eat. We excluded children and pregnant women. We tabulated available measures of nutrient intake, anthropometry, serum albumin and prealbumin, and, when available, changes in these measures during nutritional intervention. RESULTS: In otherwise healthy subjects, serum albumin and prealbumin levels remained normal despite marked nutrient deprivation until the extremes of starvation, that is, body mass index <12 or more than 6 weeks of starvation. CONCLUSIONS: In these otherwise healthy subjects, serum albumin and prealbumin levels are not "markers of nutritional status." The "markers" failed to identify subjects with severe protein-calorie malnutrition until extreme starvation. That is, they failed to identify healthy individuals who would benefit from nutrition support, becoming abnormal only when starvation was already obvious. In contrast, serum albumin and prealbumin levels are known to fall promptly with injury or illness regardless of nutrient intake. They are negative acute-phase reactants. When these measures are low in sick patients, this cannot be assumed to reflect nutritional deprivation. Decisions about nutrition support should be based on evidence of meaningful benefit from this treatment rather than on assessment of "nutritional markers." PMID- 25912206 TI - 'Chest pain typicality' in suspected acute coronary syndromes and the impact of clinical experience. AB - BACKGROUND: Physicians rely upon chest pain history to make management decisions in patients with suspected acute coronary syndromes, particularly where the diagnosis is not immediately apparent through electrocardiography and troponin testing. The objective of this study was to establish the discriminatory value of "typicality of chest pain" and the effect of clinician experience, for the prediction of acute myocardial infarction and presence of significant coronary artery disease. METHODS: This prospective single-center observational study was undertaken in a UK General Hospital emergency department. We recruited consecutive adults with chest pain and a nondiagnostic electrocardiogram, for whom the treating physician determined that delayed troponin testing was necessary. Using their own clinical judgment, physicians recorded whether the chest pain described was typical or atypical for acute coronary syndrome. Physicians were defined as "experienced" or "novice" according to postgraduate experience. Acute myocardial infarction was adjudicated using a high-sensitivity troponin (hs-cTn) assay, whereas coronary artery disease was adjudicated angiographically. RESULTS: Overall, 912 patients had typicality of chest pain assessed, of whom 114/912 (12.5%) had an acute myocardial infarction and 157/912 (17.2%) underwent angiography. In patients undergoing angiography, 90/157 (57.3%) had hs-cTn elevation, of whom 60 (66.7%) had significant coronary artery disease. Sixty-seven of 157 (42.7%) patients had angiography without hs-cTn elevation; of these, 31 (46.2%) had significant coronary artery disease. For the diagnosis of acute myocardial infarction, chest pain typicality had an area under the curve (AUC) of 0.54 (95% confidence interval [CI], 0.49-0.60). For the prediction of significant coronary artery disease with hs-cTn elevation AUC: 0.54 (95% CI, 0.40 0.67), and without hs-cTn elevation AUC: 0.45 (95% CI, 0.31-0.59). When assessed by experienced physicians, specificity for the diagnosis of acute myocardial infarction was higher at 65.8% (95% CI, 63.1%-68.7%) vs 55.4% (95% CI, 53.9% 56.8%) for novices. CONCLUSIONS: Subjective interpretation of "typicality of chest pain" is of limited discriminatory value in the assessment of suspected acute coronary syndromes, in the context of a nondiagnostic electrocardiogram. Greater clinical experience improves accuracy as a rule-in tool but does not improve overall discriminatory ability. PMID- 25912207 TI - A Team-based Model of Primary Care Delivery and Physician-patient Interaction. AB - BACKGROUND: Interprofessional team-based models of primary care delivery may improve efficiency and increase patient-centered time with the physician. The purpose of our study is to evaluate the effect of a new team-based primary care delivery model implemented in our health system on physician-patient face-to-face time and patient experience of the visit compared with usual care. METHODS: We conducted time-motion analyses of ambulatory visits with 20 primary care physicians across 8 practice sites in our health system from June through August 2014. Ten physicians practicing in the team-based model and 10 physicians practicing usual care at the same practice sites were included. The time that the physician was in the room and the duration of physician-patient face-to-face interaction were measured. After each visit, patients answered questions regarding satisfaction with their visit. RESULTS: A total of 98 patient visits were observed (44 in the team-based model and 54 in usual care). Total time that the physician and patient spent together at the visit did not differ significantly between the models. However, total duration of face-to-face interaction and proportion of the visit spent in face-to-face interaction were significantly greater in the team-based model. Patient satisfaction did not differ between the 2 models. CONCLUSIONS: A team-based model of primary care delivery increased physician-patient face-to-face time during the office visit, but did not affect patient satisfaction. PMID- 25912208 TI - Phase II studies to select the formulation of a multivalent HPV L1 virus-like particle (VLP) vaccine. AB - Our objective was to develop a multivalent prophylactic HPV vaccine that protects against infection and disease caused by HPV16/18 (oncogenic types in existing prophylactic vaccines) plus additional oncogenic types by conducting 3 Phase II studies comparing the immunogenicity (i.e., anti-HPV6/11/16/18 geometric mean titers [GMT]) and safety of 7 vaccine candidates with the licensed quadrivalent HPV6/11/16/18 vaccine (qHPV vaccine) in young women ages 16-26. In the first study (Study 1), subjects received one of 3 dose formulations of an 8-valent HPV6/11/16/18/31/45/52/58 vaccine or qHPV vaccine (control). In Study 2, subjects received one of 3 dose formulations (termed low-, mid-, and high-dose formulations, respectively) of a 9-valent HPV6/11/16/18/31/33/45/52/58 vaccine (9vHPV vaccine) or qHPV vaccine (control). In Study 3, subjects concomitantly received qHPV vaccine plus 5-valent HPV31/33/45/52/58 or qHPV vaccine plus placebo (control). All vaccines were administered at day 1/month 2/month 6. In studies 1 and 3, anti-HPV6/11/16/18 GMTs at month 7 were non-inferior in the experimental arms compared with the control arm; however, there was a trend for lower antibody responses for all 4 HPV types. In Study 2, this immune interference was overcome with the mid- and high-dose formulations of the 9vHPV vaccine by increasing antigen and adjuvant doses. In all 3 studies, all vaccine candidates were strongly immunogenic with respect to HPV31/33/45/52/58 and were well tolerated. Based on the totality of the results, the middle dose formulation of the 9vHPV vaccine was selected for Phase III evaluation. Each 0.5mL dose contains 30MUg/40MUg/60MUg/40MUg/20MUg/20MUg/20MUg/20MUg/20MUg of HPV6/11/16/18/31/33/45/52/58 virus-like particles, and 500MUg of amorphous aluminum hydroxyphosphate sulfate adjuvant.ClinicalTrials.gov numbers NCT00260039, NCT00543543, and NCT00551187. PMID- 25912209 TI - Calcium environment in silicate and aluminosilicate glasses probed by 43Ca MQMAS NMR experiments and MD-GIPAW calculations. AB - 43Ca MQMAS NMR spectra of three silica-based glasses in which Ca2+ ions play different structural roles have been collected and processed in order to extract the underlying NMR parameter distributions. The NMR parameters have been interpreted with the help of molecular dynamics simulations and DFT-GIPAW calculations. This synergetic experimental-computational approach has allowed us to investigate the Ca environment, to estimate Ca coordination numbers from MD derived models, and to push further the discussion about 43Ca NMR sensitivity to the first and second coordination spheres: 43Ca deltaiso and Ca-O distance can be successfully correlated as a function of Ca coordination number. PMID- 25912210 TI - A comment on powder averaging in wide line NMR. AB - Computer calculations of wide line NMR spectra of powders usually involve numerical evaluation of double integrals over two Euler angles. Practice confirms intuition-based expectations that the integration results should be independent from the choice of the crystal-fixed (or molecule-fixed) coordinate system used in the calculations. However, a closer inspection of the relevant integration formulas may make one wonder why this is so. The present paper provides a rigorous mathematical proof of the validity of these intuitive predictions, by formulating the problem in terms of surface integrals on a sphere, which has presumably no precedence in the NMR literature. PMID- 25912211 TI - Metabolome analysis and pathway abundance profiling of Yarrowia lipolytica cultivated on different carbon sources. AB - Yarrowia lipolytica, a model microorganism of oleaginous yeasts with developed sophisticated genetic tools, is able to metabolize a wide range of substrates and accumulate large amounts of lipids. However, there is a lack of literature reporting the metabolic characteristics of Y. lipolytica metabolizing these substrates in a systematic view. In this study, Y. lipolytica was cultivated on a variety of carbon sources, among which cell growth and production characteristics on two representative substrates (glucose and oleic acid) were investigated in detail at metabolomic level. Metabolic pathway abundance was computed to interpret the metabolome data in a straightforward way. The results showed that most pathway abundances decreased in the shift from growth to production phase. Specifically, when cultivated on glucose, abundances of twelve pathways decreased markedly between the growth and lipid production phases, while thirteen pathways reduced and only three pathways increased significantly in abundances on oleic acid. In comparison, for the same cultivation phase only a few pathways exhibited significant changes between glucose-grown and oleic acid-grown cells. This study revealed that the pathway abundance could be used to effectively show the activity changes of pathways, providing a new perspective to employ metabolomics data for understanding cell metabolism and enhancing the production of target metabolites. PMID- 25912212 TI - Changes of serum levels of MMP-3, sRANKL, and OPG in juvenile-onset ankylosing spondylitis patients carrying different HLA-B27 subtypes. AB - Ankylosing spondylitis (AS) patients whose symptom onset occurs before 16 years of age are termed juvenile-onset ankylosing spondylitis (JAS). Investigations suggested that JAS had worse functional outcome, and abnormality of bone metabolism can appear in early stage of AS. The objectives of this study are to compare changes of serum inflammatory and bone metabolic markers and to explore the relationship between these biomarkers and disease activity in JAS with different HLA-B27 subtypes. Serum matrix metallopeptidase-3 (MMP-3), soluble receptor activator of nuclear factor-kappaB ligand (sRANKL), and osteoprotegerin (OPG) were detected by ELISA in 56, 62, and 68 JAS patients, respectively, and 32 healthy individuals were as controls. Serum MMP-3 and sRANKL were significantly higher and OPG in JAS was slightly higher than those in controls. There was no significant difference in the level of MMP-3, sRANKL, and OPG among JAS patients with B27 negativity, B*2704, B*2705, and B*2715, respectively. Serum levels of MMP-3 showed positive correlation with BASDAI and BASFI (Bath Ankylosing Spondylitis Disease Activity Index and Functional Index). Serum level of sRANKL showed positive correlation with MMP-3 and negative correlation with disease duration. The significantly higher sRANKL expression suggested the enhanced osteoclast function and imbalance of RANKL/OPG system in the inflammatory process of JAS patients carrying different B27 subtypes. It should be paid attention to the abnormality of bone metabolism during the treatment of JAS. PMID- 25912213 TI - The role of sarcopenia in the risk of osteoporotic hip fracture. AB - Several common age-related mechanisms and factors influence muscle and bone, affecting functionality of both tissues. Sarcopenia is closely linked with osteoporosis, and their combined effect may exacerbate negative health outcomes. Fall-related fractures are some of the most serious consequences of these two systemic pathologies, with hip fracture being a major complication affecting osteoporotic and sarcopenic elderly. This work aims to review the literature on the current state of knowledge about the relations between sarcopenia and osteoporosis and to present the association between sarcopenia and osteoporosis and the risk of hip fracture. A literature search was performed in PubMed and Scopus databases for articles with the predefined terms "sarcopenia," "muscular atrophy," "femoral fractures," "hip fractures," "osteoporosis," and "bone density." There is a growing and significant interest being directed to sarcopenia and associated risk for osteoporotic hip fracture, but there still is a notorious heterogeneity in the methodology and cohort size of the available studies. Collectively, most of the studies herein analyzed indicate that sarcopenia could be a predictor of risk for hip fracture. The simultaneous evaluation of sarcopenia and osteoporosis may be of importance in identifying those patients in higher risk of suffering an osteoporotic hip fracture and who could benefit from preventive or therapeutic interventions, or both. PMID- 25912214 TI - Should all rheumatologists study musculoskeletal anatomy? PMID- 25912216 TI - Eco-Friendly Insecticide Discovery via Peptidomimetics: Design, Synthesis, and Aphicidal Activity of Novel Insect Kinin Analogues. AB - Insect kinin neuropeptides are pleiotropic peptides that are involved in the regulation of hindgut contraction, diuresis, and digestive enzyme release. They share a common C-terminal pentapeptide sequence of Phe(1)-Xaa(2)-Yaa(3)-Trp(4) Gly(5)-NH2 (where Xaa(2) = His, Asn, Phe, Ser, or Tyr; Yaa(3) = Pro, Ser, or Ala). Recently, the aphicidal activity of insect kinin analogues has attracted the attention of researchers. Our previous work demonstrated that the sequence simplified insect kinin pentapeptide analogue Phe-Phe-[Aib]-Trp-Gly-NH2 could retain good aphicidal activity and be the lead compound for the further discovery of eco-friendly insecticides which encompassed a broad array of biochemicals derived from micro-organisms and other natural sources. Using the peptidomimetics strategy, we chose Phe-Phe-[Aib]-Trp-Gly-NH2 as the lead compound, and we designed and synthesized three series, including 31 novel insect kinin analogues. The aphicidal activity of the new analogues against soybean aphid was determined. The results showed that all of the analogues exhibited aphicidal activity. Of particular interest was the analogue II-1, which exhibited improved aphicidal activity with an LC50 of 0.019 mmol/L compared with the lead compound (LC50 = 0.045 mmol/L) or the commercial insecticide pymetrozine (LC50 = 0.034 mmol/L). This suggests that the analogue II-1 could be used as a new lead for the discovery of potential eco-friendly insecticides. PMID- 25912215 TI - Chest pain in lupus patients: the emergency department experience. AB - Heart disease, a major cause of morbidity and mortality in SLE patients, often manifests as chest pain (CP). Our goal was to understand the prevalence and outcome of CP presentations for SLE patients in the emergency department (ED). Billing records of patients who presented to Cedars-Sinai Medical Center ED with ICD-9 codes for SLE and secondary ICD-9 codes for CP (786.50-786.59) between March 2009 and October 2013 were reviewed. Two study groups were formed: discharge from ED versus hospital admission. Visits were evaluated for basic cardiac work-up with an electrocardiogram (EKG) and cardiac enzymes; hospital admissions were evaluated for CP etiology and discharge diagnoses. Of 2675 ED visits with ICD-9 codes for SLE, 397 visits had secondary codes for CP (15%); 173 were discharged and 224 became hospital admissions. While 92% of admissions had basic cardiac work-up, over 50% had chest pain attributed to non-cardiac causes. Only 7.2% had a discharge diagnosis related to cardiovascular disease. Fifteen percent of all SLE coded patients had complaints of CP, a figure higher than the national average for non-SLE CP (10%). There is a majority of non-cardiac diagnoses given to SLE patients at discharge. CP is likely to be a window of opportunity to address the known cardiac morbidity and mortality in SLE patients perhaps at an early stage of development of this complication. Our study strengthens the need for more investigations to assess the etiology of CP in this population. PMID- 25912217 TI - Seasonal Variation in Dry Eye. PMID- 25912218 TI - A case of primary pulmonary diffuse large B-cell lymphoma diagnosed by transbronchial biopsy. AB - A 76-year-old man took a chest X-ray for his medical checkup and an abnormal shadow was detected in the right lower lung field. For more detailed examination, he was referred to our hospital. Chest computed tomography showed a 20-mm nodule with relatively regular margins in the right lower lobe. A compact proliferation of circular to polygonal cells with a high nucleus-cytoplasm ratio was evident in a transbronchial lung biopsy. Based on pathological findings, a mature large B cell lymphoma was diagnosed. Thoracoscopic right lower lobectomy and mediastinal lymphadenectomy were performed. The post-surgical pathological examination showed that the tumor consisted of diffuse to compact proliferation of medium to large atypical lymphocyte-like cells. Immunohistochemical staining yielded positive results for B-cell lineage markers. Five months after surgical resection, neither local recurrence nor accumulation in remote organs was observed on gallium scintigraphy. The diagnosis of primary pulmonary diffuse large B-cell lymphoma was established. PMID- 25912219 TI - Paraneoplastic extralimbic encephalitis associated with thymoma: a case report. AB - Here we a report a rare case of extralimbic encephalitis associated with thymoma. A 66-year-old woman was admitted to our hospital with cramping in her right leg and inability to walk. Magnetic resonance imaging of the brain showed multifocal high intensity signals on T2 flare images in the cerebral cortex, and chest computed tomography showed a 5-cm anterior mediastinal mass, which was considered to be a thymoma. We speculated that she had paraneoplastic encephalitis associated with thymoma. She underwent a thymectomy and was diagnosed with type B1 thymoma. On postoperative day 6, her neurological symptoms began to improve. On postoperative day 31, she was discharged without complications. Limbic encephalitis is a paraneoplastic neurological syndromeassociated with thymoma, but extralimbic encephalitis has been described in the literature very rarely. We report the case of extralimbic encephalitis associated with thymoma along with a literature review. PMID- 25912220 TI - Minimally invasive direct coronary artery bypass surgery with right gastroepiploic artery for redo patients. AB - Coronary artery bypass grafting (CABG) has been widely performed for coronary artery disease. Therefore, cases requiring reoperative CABG are increasing. We performed a minimally invasive direct coronary artery bypass (MIDCAB) procedure on four patients, as reoperative CABG surgery for the right coronary artery (RCA), employing the right gastroepiploic artery (RGEA). The target sites were the distal RCA in two patients and the posterior descending (PD) branch in the other two. Complete revascularization was accomplished in all patients without sternotomy, cardiopulmonary bypass (CPB), or blood transfusion. The mean operative time was 3.0 h (range: 2.4-3.7 h). Postoperative coronary angiography showed all grafts to be patent. All patients were discharged without postoperative complications and remained free from cardiac events during a mean follow-up period of 1.5 years (range: 0.5-3.0 years). MIDCAB for the RCA, employing the RGEA via a subxiphoid incision showed, excellent revascularization in redo CABG cases. This technique is a safe and effective method for redo cases. PMID- 25912222 TI - TNFalpha antagonization alters NOS2 dependent nasopharyngeal carcinoma tumor growth. AB - Tumor necrosis factor (TNFalpha) is a pro-inflammatory cytokine which mediates via nitric oxide (NO) several carcinogenic processes. Increasing evidences suggest that NO promotes inflammation induced growth of nasopharyngeal carcinoma (NPC). In patients, TNFalpha synthesis associates with poor survival. To explore the effect of the cytokine on NO production and NOS2 dependent NPC growth, NO2(-) (nitrite) producing cells in patients were analyzed in vitro. We observed that patients' monocytes/macrophages (Mo/Ma) and primary tumor biopsies synthesized significant amounts of NO2(-). Interestingly, tumor explants derived NO2(-) levels were more important in elderly patients in comparison with juveniles. Endogenous TNFalpha neutralization with an anti-TNFalpha monoclonal antibody (mAb) successfully inhibited NO2(-) synthesis by blood mononuclear cells and tumor explants. Recombinant TNFalpha (rTNFalpha) enhanced NO2(-) synthesis and C666-1 NPC cell proliferation. NOS2 selective inhibition (1400W) and TNFalpha antagonization with an anti-TNFalpha mAb potently inhibited rTNFalpha induced C666-1 proliferation and NO2(-) production. Importantly, primary tumors treated with the anti-TNFalpha mAb also displayed reduced proliferation index (Ki67). Altogether, our results define monocytes/macrophages and the primary tumor as major sources of circulating NO2(-) in NPC patients and support the idea that antibody dependent inhibition of the TNFalpha/NOS2 pathway may alter NPC tumor growth. PMID- 25912223 TI - Does women's education affect breast cancer risk and survival? Evidence from a population based social experiment in education. AB - Breast cancer is a notable exception to the well documented positive education gradient in health. A number of studies have found that highly educated women are more likely to be diagnosed with the disease. Breast cancer is therefore often labeled as a "welfare disease". However, it has not been established whether the strong positive correlation holds up when education is exogenously determined. We estimate the causal effect of education on the probability of being diagnosed with breast cancer by exploiting an education reform that extended compulsory schooling and was implemented as a social experiment. We find that the incidence of breast cancer increased for those exposed to the reform. PMID- 25912221 TI - Safety and efficacy of once-weekly dulaglutide versus sitagliptin after 2 years in metformin-treated patients with type 2 diabetes (AWARD-5): a randomized, phase III study. AB - AIMS: To compare the once-weekly glucagon-like peptide-1 (GLP-1) receptor dulaglutide with the dipeptidyl peptidase-4 (DPP-4) inhibitor sitagliptin after 104 weeks of treatment. METHODS: This AWARD-5 study was a multicentre, double blind trial that randomized participants to dulaglutide (1.5 or 0.75 mg) or sitagliptin 100 mg for 104 weeks or placebo (reported separately) for 26 weeks. Change in glycated haemoglobin (HbA1c) concentration from baseline was the primary efficacy measure. A total of 1098 participants with HbA1c concentrations >=7.0% (>=53.0 mmol/mol) and <=9.5% (<=80.3 mmol/mol) were randomized, and 657 (59.8%) completed the study. We report results for dulaglutide and sitagliptin at the final endpoint. RESULTS: Changes in HbA1c at 104 weeks were (least squares mean +/- standard error) -0.99 +/- 0.06% (-10.82 +/- 0.66 mmol/mol), -0.71 +/- 0.07% (-7.76 +/- 0.77 mmol/mol) and -0.32 +/- 0.06% (-3.50 +/- 0.66 mmol/mol) for dulaglutide 1.5 mg, dulaglutide 0.75 mg and sitagliptin, respectively (p < 0.001, both dulaglutide doses vs sitagliptin). Weight loss was greater with dulaglutide 1.5 mg (p < 0.001) and similar with 0.75 mg versus sitagliptin (2.88 +/- 0.25, 2.39 +/- 0.26 and 1.75 +/- 0.25 kg, respectively). Gastrointestinal adverse events were more common with dulaglutide 1.5 and 0.75 mg versus sitagliptin (nausea 17 and 15% vs 7%, diarrhoea 16 and 12% vs 6%, vomiting 14 and 8% vs 4% respectively). Pancreatic, thyroid, cardiovascular and hypersensitivity safety were similar across groups. CONCLUSIONS: Dulaglutide doses provided superior glycaemic control and dulaglutide 1.5 mg resulted in greater weight reduction versus sitagliptin at 104 weeks, with acceptable safety. PMID- 25912224 TI - Education and health: The role of cognitive ability. AB - We aim to disentangle the relative impact of (i) cognitive ability and (ii) education on health and mortality using a structural equation model suggested by Conti et al. (2010). We extend their model by allowing for a duration dependent variable (mortality), and an ordinal educational variable. Data come from a Dutch cohort born between 1937 and 1941, including detailed measures of cognitive ability and family background in the final grade of primary school. The data are linked to the mortality register 1995-2011, such that we observe mortality between ages 55 and 75. The results suggest that at least half of the unconditional survival differences between educational groups are due to a 'selection effect', primarily on the basis of cognitive ability. Conditional survival differences across those having finished just primary school and those entering secondary education are still substantial, and amount to a 4 years gain in life expectancy, on average. PMID- 25912225 TI - Frog volatile compounds: application of in vivo SPME for the characterization of the odorous secretions from two species of Hypsiboas treefrogs. AB - A novel in vivo design was used in combination with solid-phase microextraction (SPME) and gas chromatography/mass spectrometry (GC/MS) to characterize the volatile compounds from the skin secretion of two species of tree frogs. Conventional SPME-GC/MS also was used for the analysis of volatiles present in skin samples and for the analysis of volatiles present in the diet and terraria. In total, 40 and 37 compounds were identified in the secretion of Hypsiboas pulchellus and H. riojanus, respectively, of which, 35 were common to both species. Aliphatic aldehydes, a low molecular weight alkadiene, an aromatic alcohol, and other aromatics, ketones, a methoxy pyrazine, sulfur containing compounds, and hemiterpenes are reported here for the first time in anurans. Most of the aliphatic compounds seem to be biosynthesized by the frogs following different metabolic pathways, whereas aromatics and monoterpenes are most likely sequestered from environmental sources. The characteristic smell of the secretion of H. pulchellus described by herpetologists as skunk-like or herbaceous is explained by a complex blend of different odoriferous components. The possible role of the volatiles found in H. pulchellus and H. riojanus is discussed in the context of previous hypotheses about the biological function of volatile secretions in frogs (e.g., sex pheromones, defense secretions against predators, mosquito repellents). PMID- 25912226 TI - (Z)-13-Hexadecenyl Acetate: a Novel Moth Sex Pheromone Component from Herpetogramma submarginale (Lepidoptera: Crambidae). AB - The sex pheromone of Herpetogramma submarginale (Swinhoe) was studied by gas chromatography (GC) with electroantennographic detection and GC coupled with mass spectrometry. Two pheromone candidates detected in the gland extracts of females were identified as (Z)-13-hexadecenyl acetate (Z13-16:OAc) and (E)-13-hexadecenyl acetate (E13-16:OAc) in a ratio of 87:13 by mass spectral analysis of the natural pheromone components and their dimethyldisulfide adducts. In field tests, Z13 16:OAc alone attracted H. submarginale males and caught significantly more males than live virgin females. Addition of E13-16:OAc did not enhance the attractiveness of Z13-16:OAc. Derivatives of Z13-16:OAc also were tested as potential pheromone components. Addition of (Z)-13-hexadecen-1-ol significantly reduced the number of males captured, and (Z)-13-hexadecenal had no effect on the attractiveness of the lure. These results suggest that the female-produced sex pheromone of H. submarginale is Z13-16:OAc. This hexadecenyl acetate is a novel moth sex pheromone component. PMID- 25912227 TI - Garlic Mustard (Alliaria petiolata) Glucosinolate Content Varies Across a Natural Light Gradient. AB - Garlic mustard is a well-known invader of deciduous forests of North America, yet the influence of environmental factors on garlic mustard allelochemical production is not well understood. Three experiments were conducted to detect interactions between one garlic mustard allelochemical (glucosinolate) production and light availability. First, to detect patterns of glucosinolate production across a natural light gradient, leaves and roots of mature plants and first-year rosettes were sampled in patches ranging from 100 to 2 % of full sun within an Indiana forest. Second, to determine whether genetic variation drives observed correlations between glucosinolate content and light, seed collected across light gradients within six sites was grown in a common garden and glucosinolate production was measured. Finally, to understand whether local adaptation occurred in garlic mustard's response to light, seed collected from defined light environments across six sites was grown under four light treatments. Results of the field sampling showed that mature plants' root glucosinolate content was elevated in high compared to low light. In the common garden experiment, however, there was no correlation between light availability at seed origin and constitutive glucosinolate content. Additionally, in the common light treatments, there was no evidence for local adaptation to light environment. Overall, the results indicate that plasticity in response to light, not genetic variation among plants growing in different light environments, generates correlations between glucosinolate content and light in the field. Since mature garlic mustard populations in high light may exhibit increased glucosinolate content, it makes them potential targets for management. PMID- 25912228 TI - Sex Pheromone of Anastrepha striata. AB - The guava fruit fly, Anastrepha striata, is a pest of several cultivated species of Myrtaceae in the American tropics and subtropics. During calling, A. striata males release numerous volatiles. This study was conducted to identify which of the male volatiles function as the A. striata sex pheromone and to investigate the effects of age and time of day on the emission of pheromone components. Analysis of the volatiles from males collected by solid phase microextraction using gas chromatography coupled to electroantennographic detection (GC-EAD) showed that three volatile compounds elicited repeatable responses from the antennae of females. The EAD-active compounds were identified by GC/mass spectrometry as ethyl hexanoate, linalool, and ethyl octanoate. In two-choice tests using Multilure traps placed in field cages, traps baited with live males, ethyl hexanoate, or the three-component blend captured more females than unbaited traps. However, there was no difference in catches when traps baited with live males were compared against traps baited with ethyl hexanoate. Although traps baited with the three-component blend caught more females than traps baited with live males, the difference was not significant. Analyses of pheromonal components released by A. striata males 8 to 26 days old showed that there was an effect of age on pheromone production and also a significant effect of time of day on pheromone emission. Release of the volatile compounds occurred from 14.00 to 18.00 hr, although traces of linalool were detected from 08.00 hr. Peak emission of pheromone compounds occurred at 14.00 hr. PMID- 25912229 TI - Profiling peripheral microRNAs in obesity and type 2 diabetes mellitus. AB - Mechanisms of type 2 diabetes mellitus (T2DM) remain elusive, in which obesity (OB) is considered as one of the major risk factors for the disease. A microRNA (miRNA) is a small non-coding RNA molecule functioning in RNA silencing and post transcriptional regulation of gene expression. It has been demonstrated that some miRNAs can exist in serum stably and is closely related to various diseases. The goal of our study was to identify whether the deregulation of serum miRNAs was associated with T2DM and obesity. Twenty-five subjects with T2DM2, 25 healthy controls, 25 subjects with obesity, and 25 subjects with T2DM combined with obesity were included in the study. A total of 536 miRNA serum samples from these four groups were studied by miRNA polymerase chain reaction (PCR) panels. Data showed that miR-152 and miR-17 were significantly elevated in the OB group, whereas miR-138 was significantly decreased in OB group when compared to controls, T2DM, or T2DM+obesity group. In addition, level of MiR-593 was significantly lower in T2DM group and T2DM+obesity group when compared with controls. Further analysis revealed that the four miRNAs can be used as potential biomarkers to distinguish obesity from T2DM, OB+T2DM, and healthy subjects. Our study is one of the pioneer studies showing the differences in peripheral miRNA level in obesity, T2DM and T2DM combined with obesity. The study results suggest the potential utility of miRNAs in the prediction for obesity and T2DM. PMID- 25912230 TI - Prolonged subcutaneous delivery of low molecular weight heparin based on thermoresponsive hydrogels with chitosan nanocomplexes: Design, in vitro evaluation, and cytotoxicity studies. AB - Low molecular weight heparins (LMWHs) have risen in popularity over the past decades. Owing to their appropriate pharmacokinetic profile, they enable long term clinical applications, e.g. prophylaxis of deep vein thrombosis. Although the administration of LMWHs is not as frequent as of heparin, it still requires once daily injection at least. In order to prolong LMWH release, and thus provide less frequent subcutaneous administration, we designed and thoroughly evaluated thermoresponsive poloxamer-based systems combined with LMWH/chitosan pH responsive nanocomplexes. A LMWH/chitosan mass ratio of 1:2 was the most appropriate for preparation of small, homogenous and stable nanocomplexes. Thermoresponsive hydrogels were examined by gelation temperature and time, thermal analysis, gel dissolution, LMWH release, and cytotoxicity in vitro. Hydrogels' behaviour was significantly shifted by gel composition e.g. the addition of hydroxypropylmethylcellulose to poloxamer-based systems decreased gelation temperature and time (from 28.6 degrees C to 25.1 degrees C and from 50s to 44s, respectively), but prolonged gel dissolution and LMWH release (7 and 4 days, respectively). Prolongation of drug release was additionally achieved with incorporation of LMWH/chitosan nanocomplexes into the gelling systems. As formulations demonstrated no cytotoxicity in vitro, it may be concluded that these double-responsive platforms are promising candidates for prolonged subcutaneous LMWH delivery during long-term treatment. PMID- 25912231 TI - Hyper/hypoglycemia and acute kidney injury in critically ill patients. AB - BACKGROUND & AIMS: Abnormalities of blood glucose (BG) concentration (hyper- and hypoglycemia), now referred to with the cumulative term of dysglycemia, are frequently observed in critically ill patients, and significantly affect their clinical outcome. Acute kidney injury (AKI) may further complicate glycemic control in the same clinical setting. This narrative review was aimed at describing the pathogenesis of hyper- and hypoglycemia in the intensive care unit (ICU), with special regard to patients with AKI. Moreover, the complex relationship between AKI, glycemic control, hypoglycemic risk, and outcomes was analyzed. METHODS: An extensive literature search was performed, in order to identify the relevant studies describing the epidemiology, pathogenesis, treatment and outcome of hypo- and hyperglycemia in critically ill patients with AKI. RESULTS AND CONCLUSION: Patients with AKI are at increased risk of both hyper-and hypoglycemia. The available evidence does not support a protective effect on the kidney by glycemic control protocols employing Intensive Insulin Treatment (IIT), i.e. those aimed at maintaining normal BG concentrations (80-110 mg/dl). Recent guidelines taking into account the high risk for hypoglycemia associated with IIT protocols in critically ill patients, now suggest higher BG concentration targets (<180 mg/dl or 140-180 mg/dl) than those previously recommended (80-110 mg/dl). Notwithstanding the limited evidence available, it seems reasonable to extend these indications also to ICU patients with AKI. PMID- 25912232 TI - Double blind exploratory study on de novo lipogenesis in preterm infants on parenteral nutrition with a lipid emulsion containing 10% fish oil. AB - BACKGROUND & AIMS: Provision of long chain polyunsaturated fatty acids (LCP) both of the omega-3 and omega-6 families is recommended for preterm infants (PI). Fish oil (FO) contains omega-3 and omega-6 LCP and it is incorporated in the fat blend of the new generation lipid emulsions (LE). Omega-3 LCP have been shown to reduce the expression of genes involved in lipogenesis, which could be important for several organs development. The aim of this study was to ascertain if the use of intravenous FO has an effect on lipogenesis in PI. METHODS: Forty PI were randomized to receive two LE: MSF (50:40:10 Medium Chain Triglycerides (MCT): Soybean oil (SO): FO) or MS (50:50 MCT:SO). We measured plasma lipids on day 7 and the fractional and absolute synthesis rates (FSR and ASR) of cholesterol and of selected fatty acids (FA) after (2)H2O body water labeling. RESULTS: Plasma phospholipids (PL), free cholesterol (FC), and cholesterol esters (CE) concentrations were all lower in MSF than in MS. In spite of lower plasma FC and CE concentrations, cholesterol biosynthesis was similar between the two study groups (FC: FSR 16.0 +/- 1.4 vs 14.1 +/- 1.1%/d, p = 0.74; ASR 6.8 +/- 0.6 vs 7.1 +/- 0.6 mg kg(-1) d(-1), p = 0.93; CE: FSR 3.6 +/- 0.5 vs 4.2 +/- 0.4%/d, p = 0.38; ASR: 3.3 +/- 0.4 vs 4.4 +/- 0.5 mg kg(-1) d(-1), p = 0.13, in MSF and MS respectively). FSR and ASR of selected FA were, or tended to be, lower in MSF than in MS. ASR of PL palmitate (4.0 +/- 0.3 vs 4.8 +/- 0.4 mg kg(-1) d(-1), p = 0.045), PL oleate (0.2 +/- 0.04 vs 0.4 +/- 0.05 mg kg(-1) d(-1), p = 0.02) and CE oleate (0.5 +/- 0.1 vs 0.9 +/- 0.1 mg kg(-1) d(-1), p = 0.03) were significantly lower in MSF than in MS. There were no differences in plasma TG FA biosynthesis. CONCLUSIONS: Cholesterol biosynthesis was not affected by 10% FO during neonatal parenteral nutrition. Ten percent FO caused a statistically significant reduction in the lipogenesis of selected FA and an overall tendency towards a reduced lipogenesis. The magnitude seems to be limited and the biological significance is unknown. Our data warrant follow-up studies in PI who receive intravenous FO, especially in those infants who receive larger doses than in the present study. Since this trial started in 2007, trial registration was not required. PMID- 25912233 TI - Length bias correction in one-day cross-sectional assessments - The nutritionDay study. AB - BACKGROUND & AIMS: A major problem occurring in cross-sectional studies is sampling bias. Length of hospital stay (LOS) differs strongly between patients and causes a length bias as patients with longer LOS are more likely to be included and are therefore overrepresented in this type of study. To adjust for the length bias higher weights are allocated to patients with shorter LOS. We determined the effect of length-bias adjustment in two independent populations. METHODS: Length-bias correction is applied to the data of the nutritionDay project, a one-day multinational cross-sectional audit capturing data on disease and nutrition of patients admitted to hospital wards with right-censoring after 30 days follow-up. We applied the weighting method for estimating the distribution function of patient baseline variables based on the method of non parametric maximum likelihood. Results are validated using data from all patients admitted to the General Hospital of Vienna between 2005 and 2009, where the distribution of LOS can be assumed to be known. Additionally, a simplified calculation scheme for estimating the adjusted distribution function of LOS is demonstrated on a small patient example. RESULTS AND CONCLUSION: The crude median (lower quartile; upper quartile) LOS in the cross-sectional sample was 14 (8; 24) and decreased to 7 (4; 12) when adjusted. Hence, adjustment for length bias in cross-sectional studies is essential to get appropriate estimates. PMID- 25912234 TI - Threonine 34 phosphorylation by phosphoinositide-dependent protein kinase 1 facilitates dissociation of Akt from the plasma membrane. AB - Akt is a key mediator of cell proliferation, survival and metabolism. After translocation to the membrane and phosphorylation at T308 and S473, the activated Akt dissociates from the plasma membrane to cytoplasm, which is an important step to phosphorylate its downstream targets. In addition to its central role in regulating the kinase activity, phosphorylation of T308 in the kinase loop has been reported to be necessary for this dissociation process. However, it is not clear whether the membrane detachment requires further mechanisms. In the present report, we demonstrate that membrane dissociation of Akt requires phosphoinositide-dependent protein kinase 1 (PDK1) which directly phosphorylates not only T308 but also T34 in the pleckstrin homology (PH) domain. Like T308, T34 was phosphorylated in a phosphatidylinositol 3,4,5-trisphosphate- and phosphatidylserine-dependent manner. Phosphorylation of T34 also occurred in cells following growth factor stimulation, concurrently with T308 phosphorylation. Moreover, when T34 was mutated to aspartic acid (T34D) to mimic its phosphorylation, Akt-membrane association assessed by surface plasmon resonance spectroscopy was significantly reduced. In cells, this mutation impaired the IGF-induced Akt membrane translocation and subsequent phosphorylation at T308 and S473. Taken together, our results demonstrate that T34 phosphorylation by PDK1 promotes the membrane dissociation of activated Akt for its downstream action through attenuating membrane binding affinity. This membrane dissociation mechanism offers a new insight for Akt activation process and provides a potential new target for controlling the Akt-dependent cellular processes. PMID- 25912235 TI - A new combination of sitagliptin and furosemide protects against remote myocardial injury induced by renal ischemia/reperfusion in rats. AB - Acute kidney injury (AKI) is associated with high mortality resulting from extra renal organ damage, particularly the heart. The present study aimed to investigate the protective effect of sitagliptin, a dipeptidyl peptidase-4 (DPP4) inhibitor, against renal and remote cardiac damage induced by ischemia/reperfusion (IR), a leading cause of AKI. In this attempt, we compared the effects of sitagliptin to furosemide, a loop diuretic. Furosemide is commonly used clinically in AKI however, there is a lack of evidence regarding its beneficial effects in AKI. In addition, the combined administration of both drugs was also investigated. Ischemia was induced in anesthetized male Wistar rats by occluding both renal pedicles for 30min followed by reperfusion for 24h. Sitagliptin (5mg kg(-1)), furosemide (245mg kg(-1)) or their combination were administered orally at 5h post-IR and 2h before euthanasia. Administration of sitagliptin or furosemide ameliorated renal and cardiac deterioration induced by renal IR. This was manifested as significant reduction of serum creatinine, urea, cystatin c, creatine kinase-MB, cardiac troponin-I and lactate dehydrogenase (P<0.05). Drug treatment significantly inhibited IR-induced elevation of TNF alpha, NF-kappaB and caspase-3 (P<0.05) in kidney and heart tissue. In addition, they significantly suppressed malondialdehyde, NO and iNOS content, whereas they increased glutathione and antioxidative enzymes activity (P<0.05) in both tissues. Interestingly, a superior protection was observed with the combination compared to the individual drugs. We assume that this combination represents a promising regimen for managing AKI, particularly with the poor clinical outcome obtained with furosemide alone. PMID- 25912236 TI - Ionizing radiation induces neuronal differentiation of Neuro-2a cells via PI3 kinase and p53-dependent pathways. AB - PURPOSE: The influence of ionizing radiation (IR) on neuronal differentiation is not well defined. In this study, we investigated the effects of IR on the differentiation of Neuro-2a mouse neuroblastoma cells and the involvement of tumor protein 53 (p53) and mitogen-activated protein kinases (MAPK) during this process. MATERIALS AND METHODS: The mouse neuroblastoma Neuro-2a cells were exposed to (137)Cs gamma-rays at 4, 8 or 16 Gy. After incubation for 72 h with or without inhibitors of p53, phosphatidylinositol-4, 5-bisphosphate 3-kinase (PI3K) and other kinases, the neuronal differentiation of irradiated Neuro-2a cells was examined through analyzing neurite outgrowth and neuronal maker expression and the activation of related signaling proteins by western blotting and immunocytochemistry. Mouse primary neural stem cells (NSC) were exposed to IR at 1 Gy. The change of neuronal marker was examined using immunocytochemistry. RESULTS: The irradiation of Neuro-2a cells significantly increased the neurite outgrowth and the expression of neuronal markers (neuronal nuclei [NeuN], microtubule-associated protein 2 [Map2], growth associated protein-43 [GAP-43], and Ras-related protein 13 [Rab13]). Immunocytochemistry revealed that neuronal class III beta-tubulin (Tuj-1) positive cells were increased and nestin positive cells were decreased by IR in Neuro-2a cells, which supported the IR-induced neuronal differentiation. However, the IR-induced neuronal differentiation was significantly attenuated when p53 was inhibited by pifithrin-alpha (PFT-alpha) or p53-small interfering RNA (siRNA). The PI3K inhibitor, LY294002, also suppressed the IR-induced neurite outgrowth, the activation of p53, the expression of GAP-43 and Rab13, and the increase of Tuj-1 positive cells. The increase of neurite outgrowth and Tuj-1 positive cells by IR and its suppression by LY294002 were also observed in mouse primary NSC. CONCLUSION: These results suggest that IR is able to trigger the neuronal differentiation of Neuro-2a cells and the activation of p53 via PI3K is an important step for the IR-induced differentiation of Neuro 2a cells. PMID- 25912237 TI - Engaging Chinese American Adults in Advance Care Planning: A Community-Based, Culturally Sensitive Seminar. AB - Ethnic minority groups are less engaged than Caucasian American adults in advance care planning (ACP). Knowledge deficits, language, and culture are barriers to ACP. Limited research exists on ACP and advance directives in the Chinese American adult population. Using a pre-posttest, repeated measures design, the current study explored the effectiveness of a nurseled, culturally sensitive ACP seminar for Chinese American adults on (a) knowledge, completion, and discussion of advance directives; and (b) the relationship between demographic variables, advance directive completion, and ACP discussions. A convenience sample of 72 urban, community-dwelling Chinese American adults (mean age=61 years) was included. Knowledge, advance directive completion, and ACP discussions increased significantly after attending the nurse-led seminar (p<0.01). Increased age correlated with advance directive completion and ACP discussions; female gender correlated with ACP discussions. Nursing education in a community setting increased advance directive knowledge and ACP engagement in Chinese American adults. PMID- 25912238 TI - Policy Implications of a Literature Review of Cardiovascular Disease in Uninsured Immigrant Older Adults. AB - The number of older adults emigrating to the United States is expected to quadruple by 2050. The health of immigrant older adults is complicated by the limited options for low-cost health insurance available to this population. Welfare reform has limited new immigrants' access to public assistance programs, such as Medicaid; and low-cost private insurance options rarely exist for individuals older than 65, even with the passage of the Patient Protection and Affordable Care Act (PPACA). Uninsured immigrant older adults have been found to forgo preventive care due to cost and are among the leading users of emergency departments for preventable complications of chronic disease, primarily cardiovascular disease (CVD). A review of the literature found that insurance coverage has a significant impact on CVD risk among immigrant older adults. The current article discusses the implications of welfare reform initiatives and the shortcomings of the PPACA in addressing the health care needs of immigrant older adults. PMID- 25912239 TI - A Case Study Approach to Nursing Home Placement: Smooth and Difficult Cases and Implications for Nursing. AB - Nursing home placement is one of the most challenging aspects of the caregiving journey. A case study approach was used to understand the experiences of caregivers during the first few months following nursing home placement. Two caregivers were selected from a larger qualitative descriptive study because their experiences exemplified smooth and difficult transitions for both themselves and their older family member. The caregivers were interviewed shortly after placement and 3 months post-placement. Four major contextual issues were identified that indicated the similarities and differences between the two cases, including (a) the caregiver's relationship with the older adult during the home caregiving time and post nursing home placement, (b) the circumstances surrounding placement, (c) support systems, and (d) continued involvement in care post-placement. Nursing home staff who understand these issues and address concerns through family-centered care can ease the transition and promote successful collaborations between staff and families. PMID- 25912240 TI - Behavioral Characteristics of Bowel Movement and Urination Needs in Patients With Dementia in Taiwan. AB - Patients with dementia, especially those with advanced dementia, may not be able to express their bowel movement and urination needs using lucid language, and instead do so through behaviors. The aim of the current study was to understand and compare the behavioral characteristics of bowel movement and urination needs in patients with dementia. Observations were made by caregivers of 187 patients with dementia based on the Behavior Checklist developed by the research team for bowel movement and urination. Sixteen behavioral characteristics were identified for both bowel movement and urination; among these, anxiety, taking off/putting on clothes inappropriately, restlessness, attempting to go elsewhere, scratching skin, repeated behavior, and making strange sounds were commonly reported. Facial expressions of sorrow, restlessness, and anxiety were the three most common behaviors related to bowel movement needs, whereas anxiety, taking off/putting on clothes inappropriately, and constant moaning were the most common behaviors for urination needs. The findings suggest that the common behavioral characteristics could be seen as indicators of excretion need and the others can be used to distinguish between the need for bowel movement and urination. PMID- 25912241 TI - Severe Symptomatic Aortic Stenosis in Older Adults: Pathophysiology, Clinical Manifestations, Treatment Guidelines, and Transcatheter Aortic Valve Replacement (TAVR). AB - The only effective treatment for symptomatic aortic stenosis in the older adult population is surgical aortic valve replacement. However, more than 30% of candidates are denied surgery due to advanced age and multiple comorbidities. Without surgical intervention, death from symptomatic aortic stenosis approximates 2% per month, with mortality rates of approximately 50% within 2 years of symptom onset. There is no effective medical treatment for severe symptomatic aortic stenosis; care has been limited to palliative remedies and end of-life decisions. Nascent advances in miniaturization and catheter technologies provide a new and less invasive approach: transcatheter aortic valve replacement (TAVR). The current article summarizes treatment guidelines; pathophysiology; clinical manifestations, progression, and classification of severe symptomatic aortic stenosis; and introduces TAVR and discusses randomized controlled trials involving three patient populations from the United States, with relevant nursing implications. PMID- 25912242 TI - The serum concentrations of lupine alkaloids in orally-dosed Holstein cattle. AB - Teratogenic alkaloid-containing Lupinus spp. cause congenital defects known as crooked calf disease that is periodically economically devastating for the cattle industry. Previous research indicates that cattle breeds may eliminate plant toxins differently, potentially altering their susceptibility. The objective of this study was to describe the toxicokinetics in Holsteins of anagyrine, the teratogenic lupine alkaloid that produces crooked calf disease. Other alkaloids including lupanine, an unidentified alkaloid and 5,6-dehydrolupanine were also evaluated. Dried ground Lupinus leucophyllus was orally dosed to four Holstein steers and blood samples were collected for 96 h, analyzed for serum alkaloid concentrations and toxicokinetic parameters calculated. The serum elimination of anagyrine in Holstein steers was faster than those reported for beef breeds. This suggests that Holsteins may be less susceptible to lupine-induced crooked calf disease. Additional work is needed to confirm these findings and to verify if there is a breed difference in disease incidence or severity. PMID- 25912243 TI - Physiological roles of peroxido-vanadium complexes: Leitmotif as their signal transduction pathway. AB - Evidence exists that supports the various physiological roles of vanadium compounds, although the amount of vanadium in our body is limited. This limited concentration in our body does not attract much attention of the biological chemists, although the fact is present; even in the 19th century, vanadium derivatives were used for the therapeutic reagents. In the middle of the 20th century, the main focus of vanadium chemistry is mainly on the chemical and material fields. After the first discovery of vanadium compounds expressing ATPase activity, oxidovanadium(IV) sulfate was reported to have insulin mimic activity. Additionally, because some vanadium compounds possess cellular toxicity, trials were also carried out to examine the possible use of vanadium compounds as cancer therapeutics. The application of vanadium complexes was extended in recent years especially in the 21st century. In this review, we briefly explain the historical background of vanadium chemistry and also summarize the physiological role of vanadium complexes mainly focusing on the synthesis and physiological role of peroxidovanadium compounds and their interactions with insulin signal transduction pathways. PMID- 25912244 TI - Serum digoxin concentrations and clinical signs and symptoms of digoxin toxicity in the paediatric population. AB - BACKGROUND: Serum digoxin levels have limited utility for determining digoxin toxicity in adults. Paediatric data assessing the utility of monitoring serum digoxin concentration are scarce. We sought to determine whether serum digoxin concentrations are associated with signs and symptoms of digoxin toxicity in children. METHODS: We carried out a retrospective review of patients 2 ng/ml). RESULTS: There were 87 patients who met study criteria (male 46%, mean age 8.4 years). CHD was present in 67.8% and electrocardiograms were performed in 72.4% of the patients. The most common indication for digoxin toxicity was heart failure symptoms (61.5%). Toxic serum digoxin concentrations were present in 6.9% of patients (mean 2.6 ng/ml). Symptoms associated with digoxin toxicity occurred in 48.4%, with nausea/vomiting as the most common symptom (36.4%), followed by tachycardia (29.5%). Compared with those without toxic serum digoxin concentrations, significantly more patients with toxic serum digoxin concentrations were female (p=0.02). The presence of electrocardiogram abnormalities and/or signs and symptoms of digoxin toxicity was not significantly different between patients with and without serum digoxin concentrations (p>0.05). CONCLUSION: Serum digoxin concentrations in children are not strongly associated with signs and symptoms of digoxin toxicity. PMID- 25912245 TI - What is New in the Management of Epilepsy in Gliomas? AB - OPINION STATEMENT: Seizures represent a common symptom in low- and high-grade gliomas. Tumor location and histology influence the risk for epilepsy. Some molecular factors (BRAF V 600E mutations in glioneuronal tumors and IDH1/2 mutations in diffuse grade II and III gliomas) are molecular factors that are relevant for diagnosis and prognosis and have been associated with the risk of epilepsy as well. Glutamate plays a central role in epileptogenicity and growth of glial and glioneuronal tumors, based on the release of glutamate from tumor cells that enhances excitotoxicity, and a downregulation of the inhibitory GABAergic pathways. Several potential targets for therapy have been identified, and m-TOR inhibitors have already shown activity. Gross total resection is the strongest predictor of seizure freedom in addition to clinical factors, such as preoperative seizure duration, type, and control with antiepileptic drugs (AEDs). Radiotherapy and chemotherapy with alkylating agents (procarbazine, CCNU, vincristine, temozolomide) are effective in reducing the frequency of seizures in patients with pharmacoresistant epilepsy. Newer AEDs (in particular levetiracetam and lacosamide) seem to be better tolerated than the old AEDs (phenobarbital, phenytoin, carbamazepine), but randomized clinical trials are needed to prove their superiority in terms of efficacy. PMID- 25912246 TI - The transition from first-line to second-line therapy in multiple sclerosis. AB - OPINION STATEMENT: Sufficient control of disease activity in multiple sclerosis (MS) patients, particularly in the early phase of the disease, is crucial for the prevention of an unfavorable outcome. While currently available disease modifying drugs are generally clearly assigned as first-line or second-line treatment, no universal guidelines exist that help in the real world setting to decide when and how exactly a transition from first-line to second-line therapy should be initiated. Furthermore, the concept of first and second-line therapies is constantly evolving. In order to facilitate evidence-based decision making in this common situation, we here summarize existing data on the optimization of treatment when the first-line drug needs to be switched. Obviously, a switch of treatment starts with an exploration of the motivation to switch, which usually may be ascribed to either inadequate treatment response or tolerability, safety, or adherence issues. In the latter situation, intra class switching, e.g., from interferon (IFN) beta to glatiramer acetate (GA) or, in case of aversion against injectables, from GA/IFN beta to one of the new orals dimethylfumarate or teriflunomide can be a reasonable option. If treatment failure is the reason for a switch, existing data suggest that escalation to a more powerful drug such as natalizumab, fingolimod or even alemtuzumab is more appropriate. Of note, in some drugs, different formal approvals apply in different countries. For example, while fingolimod is approved as second-line therapy in the European Union, it can be used as first-line drug in the United States and in Switzerland. The flip side of these more powerful drugs might be a less favorable risk-benefit ratio. As long as data are not yet sufficient to allow a direct comparison of efficacy among second-line drugs, the treatment decision should be primarily based on the individual situation and risk profile of the patient. PMID- 25912247 TI - Trust, choice and obligation: a qualitative study of enablers of colorectal cancer screening in South Australia. AB - Colorectal cancer (CRC) has the second highest cancer prevalence and mortality rates in Australia. The Australian National Bowel Cancer Screening Program (NBCSP) aims to increase early detection of CRC by offering free faecal occult blood testing. The NBCSP aims to offer choice to consumers about whether or not to participate in screening. This article presents data on trust, choice and perceived obligation to participate in the NBCSP by population groups with low uptake. A qualitative study was undertaken in South Australia. We interviewed 94 people from four culturally distinct groups: Greek, Iranian, Anglo-Australian and Indigenous peoples. This article demonstrates the complexity of factors shaping the choice, or lack thereof, to participate in the NBCSP. Informed choice is based on adequate knowledge, although this varied among our participants, highlighting the need for more health education in appropriate languages. An obligation to participate was found in the Iranian and Anglo-Australian groups and resulted from an established personal relationship with the doctor, a sense of duty, the acknowledgement of government investment and appreciation. Overall, this article makes a link between trust, choice and obligation, adding to literature on the sociology of trust and medical screening and highlighting important issues in the need of a policy and practice to improve CRC screening rates. PMID- 25912248 TI - Oral candidal carriage in asymptomatic patients. AB - BACKGROUND: Interest in the association between oral cancer risk and Candida associated promotion of mucosal dysplasia continues. However, little is known of the presence and amount of oral yeast in the mouths of healthy patients without mucosal lesions. The purpose of this prospective cross-sectional clinical study was to ascertain the prevalence and degree of carriage of Candida in the oral cavities of a non-cancer population, with reference to a range of parameters affecting the oral environment. METHODS: Oral rinse samples were collected from a sample of 203 patients attending the Royal Dental Hospital of Melbourne and analysed for the presence and degree of colonization of yeast species that were phenotypically identified as albicans and non-albicans species. RESULTS: Oral yeast carriage was found in 98/203 patients (48.3%), and of these, 83 (84.7%) patients carried C. albicans. There was no statistical difference in carriage when comparing gender, age, or presence of a removable prosthesis. CONCLUSIONS: Both smoking and the presence of active carious lesions were found to be positively correlated with the carriage of oral Candida. Individuals who are current smokers are nearly seven times more likely to have oral Candida, and participants with high candidal colonization are more likely to be current smokers. Participants with active carious lesions were also more likely to carry oral Candida. PMID- 25912250 TI - Current state of sludge production, management, treatment and disposal in China. AB - Large amount of sludge has been a great trouble and raised significant concerns in China. This paper reviewed the current situation of sludge production, management, treatment and disposal in China. Total sludge production in China had an average annual growth of 13% from 2007 to 2013, and 6.25 million tons dry solids was produced in 2013. Per Capita sludge production in China is lower than that in developed countries. However, sludge management is poor in China. Administrative agents of sludge are not in accordance with each other. Laws and regulations of sludge management are incomplete and sometimes unrealistic. As to sludge treatment and disposal, many technical routes have been applied in China. Thickening, conditioning, and dewatering are three most used treatment methods, while application ratios of stabilization and drying are low in China. More than 80% of sludge is disposed by improper dumping in China. Regarding proper disposal, sanitary landfill is the commonest, followed by land application, incineration and building materials. According to the overall situation of China, "thickening-anaerobic digestion-dewatering-land application" is the priority technical route of sludge treatment and disposal. Good changes, current challenges and future perspectives of this technical route in China were analyzed and discussed in details. PMID- 25912249 TI - Deregulated Levels of the NF-kappaB1, NF-kappaB2, and Rel Genes in Ukrainian Patients with Leukemia and Lymphoma in the Post-Chernobyl Period. AB - OBJECTIVE: Nuclear factor kappa B (NF-kappaB) is an important transcription factor in cancer and NF-kappaB activation has been seen in angiogenesis, tumor progression, and metastasis. Relationships between specific NF-kappaB gene networks, leukemogenesis, and radiation exposure are still unknown. Our aim was to study the expression levels of the NF-kappaB1, NF-kappaB2, and Rel genes in hematological malignancies in the post-Chernobyl period. MATERIALS AND METHODS: We analyzed gene expression levels of NF-kappaB1, NF-kappaB2, and Rel in 49 B cell chronic lymphocytic leukemia, 8 B-cell non-Hodgkin's lymphoma, 3 acute myeloid leukemia, 3 chronic myeloid leukemia, 2 hairy cell leukemia, 2 myelodysplastic syndrome, and 2 T-cell large granular lymphocytic leukemia patients using real-time polymerase chain reaction. RESULTS: Expression levels of NF-kappaB1, NF-kappaB2, and Rel genes were found to be deregulated. CONCLUSION: These results could be accepted as specific gene traces to radiation-induced leukemia or as potential candidates for new diagnostic biomarker studies. Larger experiments and non-exposed control malignant cell populations are needed to clarify these suggestions. PMID- 25912251 TI - In-situ formation and immobilization of biogenic nanopalladium into anaerobic granular sludge enhances azo dyes degradation. AB - Azo dyes are toxic and recalcitrant wastewater pollutants. An innovative technology based on biogenic nanopalladium (Bio-Pd) supported anaerobic granular sludge (AGS) was developed for azo dyes reduction. In-situ formation of Bio-Pd in the AGS was observed by Scanning Electron Microscopy coupled with Energy Dispersive Spectrometer (SEM-EDS). The Pd associated AGS (Pd-AGS) showed enhanced decolorization rates to the three azo dyes of Congo Red, Evans Blue and Orange II, with the degradation kinetic constants increased by 2.3-10 fold compared to the control AGS in the presence of electron donor formate. Impacts of different electron donors on Orange II decolorization were further investigated. Results showed that formic acid, formate, acetate, glucose, ethanol and lactate could serve as electron and hydrogen donors to stimulate Orange II decolorization by the Pd-AGS, and their activities followed the order: formic acid > formate > ethanol > glucose > lactate > acetate. Most of the Bio-Pd was bound with microbes in the AGS with a small fraction in the extracellular polymer substances (EPS). Transmission Electronic Microscopy analysis revealed that the Bio-Pd formed in the periplasmic space, cytoplasm and on the cell walls of bacteria. This study provides a new concept for azo dye reduction, which couples sludge microbial degradation ability with Bio-Pd catalytic ability via in-situ formation and immobilization of Bio-Pd into AGS, and offers an alternative for the current azo dye treatment technology. PMID- 25912252 TI - Protein disulfide isomerases: Impact of thapsigargin treatment on their expression in melanoma cell lines. AB - Anti-cancer treatments usually elevate the content of unfolded or misfolded proteins in the endoplasmic reticulum (ER). Here we aimed to get insights into the relation between sensitivity of melanoma cell lines to the ER stress inducer thapsigargin (THG) and the genetic expression of protein disulfide isomerase family members (PDIs). The expression of PDIs was analysed by flow cytometry and real-time PCR. The results showed that SK-MEL-30, the less THG sensitive cell line, displays higher basal PDIs' expression levels and the sensitivity is increased by the PDIs inhibitor bacitracin. While SK-MEL-30 PDIs' expression is not THG dose-dependent, an increase in glucose related protein 78 (GRP78), PDIA5, PDIA6, and thioredoxin-related-transmembrane proteins' (TMX3 and TMX4) expression, in response to higher drug concentrations, was observed in MNT-1. The differences in PDIs' gene expression in MNT-1 suggest a different response to ER stress compared to the other cell lines and highlight the importance of understanding the diversity among cancer cells. PMID- 25912254 TI - A comparison of radial and femoral access for cardiac catheterization. AB - Over the past several years, the transradial approach (TRA) for cardiac catheterization has become increasingly adopted in the United States. The increased utilization of the TRA is grounded on 2 decades of research, showing reduced bleeding and vascular complications to complement improved patient quality of life. However, the concern over cost, radiation exposure, and acknowledged "learning curve" has kept the transfemoral approach (TFA) the mainstay of most US catheterization laboratories. More recent larger multi centered randomized studies have aimed to address outcomes and these concerns between the TR and TF approaches. This article will review the changing trends in TRA in the US, discuss clinical (bleeding and mortality) and non-clinical (quality of life and cost) outcomes from recent randomized studies, and finally discuss certain aspects when it comes to adopting TRA. PMID- 25912253 TI - HSP90 inhibitors decrease AID levels and activity in mice and in human cells. AB - Activation induced deaminase (AID) initiates somatic hypermutation and class switch recombination of the Ig genes in antigen-activated B cells, underpinning antibody affinity maturation and isotype switching. AID can also be pathogenic by contributing to autoimmune diseases and oncogenic mutations. Moreover, AID can exert noncanonical functions when aberrantly expressed in epithelial cells. The lack of specific inhibitors prevents therapeutic applications to modulate AID functions. Here, we have exploited our previous finding that the HSP90 molecular chaperoning pathway stabilizes AID in B cells, to test whether HSP90 inhibitors could target AID in vivo. We demonstrate that chronic administration of HSP90 inhibitors decreases AID protein levels and isotype switching in immunized mice. HSP90 inhibitors also reduce disease severity in a mouse model of acute B-cell lymphoblastic leukemia in which AID accelerates disease progression. We further show that human AID protein levels are sensitive to HSP90 inhibition in normal and leukemic B cells, and that HSP90 inhibition prevents AID-dependent epithelial to mesenchymal transition in a human breast cancer cell line in vitro. Thus, we provide proof-of-concept that HSP90 inhibitors indirectly target AID in vivo and that endogenous human AID is widely sensitive to them, which could have therapeutic applications. PMID- 25912255 TI - The implantable cardioverter-defibrillator: An update. AB - The implantable cardioverter-defibrillator (ICD) provides life-saving therapy to prevent sudden cardiac death. ICDs have been implanted in millions of patients worldwide since the first human implant in 1980. Clinical trials have helped establish guidelines for ICD implantation in primary and secondary prevention of sudden cardiac death. Recent trials have also tested and compared various programing strategies to avoid unnecessary shocks and improve survival among ICD recipients. ICDs may also assist with monitoring for heart failure management. In this review, we discuss the clinical science to date that has helped define the role of ICDs in current practice. PMID- 25912256 TI - A case of standardization? Implementing health promotion guidelines in Denmark. AB - Guidelines are increasingly used in an effort to standardize and systematize health practices at the local level and to promote evidence-based practice. The implementation of guidelines frequently faces problems, however, and standardization processes may in general have other outcomes than the ones envisioned by the makers of standards. In 2012, the Danish National Health Authorities introduced a set of health promotion guidelines that were meant to guide the decision making and priority setting of Denmark's 98 local governments. The guidelines provided recommendations for health promotion policies and interventions and were structured according to risk factors such as alcohol, smoking and physical activity. This article examines the process of implementation of the new Danish health promotion guidelines. The article is based on qualitative interviews and participant observation, focusing on the professional practices of health promotion officers in four local governments as well as the field of Danish health promotion more generally. The analysis highlights practices and episodes related to the implementation of the guidelines and takes inspiration from Timmermans and Epstein's sociology of standards and standardization. It remains an open question whether or not the guidelines lead to more standardized policies and interventions, but we suggest that the guidelines promote a risk factor-oriented approach as the dominant frame for knowledge, reasoning, decision making and priority setting in health promotion. We describe this process as a case of epistemic standardization. PMID- 25912257 TI - Oxytocin: parallel processing in the social brain? AB - Early studies attempting to disentangle the network complexity of the brain exploited the accessibility of sensory receptive fields to reveal circuits made up of synapses connected both in series and in parallel. More recently, extension of this organisational principle beyond the sensory systems has been made possible by the advent of modern molecular, viral and optogenetic approaches. Here, evidence supporting parallel processing of social behaviours mediated by oxytocin is reviewed. Understanding oxytocinergic signalling from this perspective has significant implications for the design of oxytocin-based therapeutic interventions aimed at disorders such as autism, where disrupted social function is a core clinical feature. Moreover, identification of opportunities for novel technology development will require a better appreciation of the complexity of the circuit-level organisation of the social brain. PMID- 25912258 TI - Identifying effective computerized strategies to prevent drug-drug interactions in hospital: A user-centered approach. AB - BACKGROUND: Drug-drug interactions (DDIs) are an important and preventable cause of medication errors in hospitals. Recent developments in technology have seen new strategies emerge for preventing DDIs but these computerized strategies are rarely evaluated and are typically implemented with little input from the individuals using them. AIM: To determine the opinions of both experts and users (prescribers) on computerized strategies available to assist in the identification and prevention of DDIs in hospitals. METHOD: Eight drug safety experts and 18 prescribers took part in semi-structured interviews. Participants were asked about their confidence in identifying DDIs and their views on potential computerized strategies to prevent DDIs. RESULTS: No prescribers reported complete confidence in identifying dangerous DDIs, with junior prescribers appearing less confident than senior prescribers. Most prescribers believed that computerized alerts would be the most effective strategy for preventing DDIs, while experts were more critical of alerts. CONCLUSION: The lack of confidence displayed by prescribers in their ability to identify DDIs suggests that an appropriate strategy would be one that does not rely on individuals seeking out the information themselves. While a large number of problems related to DDI alert implementation have been reported in the literature (e.g. alert overload), prescribers appeared to be receptive to the idea of being alerted. By ensuring users are aware of the limitations of the system and involving them in DDI strategy design we expect greater use and satisfaction with the adopted strategy. PMID- 25912259 TI - Seventy kilovolt ultra-low dose CT of the paranasal sinus: first clinical results. AB - AIM: To evaluate the diagnostic image quality and radiation dose of low-dose 70 kV computed tomography (CT) of the paranasal sinus in comparison to 100 and 120 kV CT. MATERIALS AND METHODS: CT of the paranasal sinus was performed in 127 patients divided into three groups using different tube voltages and currents (70 kV/75 mAs, ultra-low dose protocol, n = 44; 100 kV/40 mAs, standard low-dose protocol, n = 42; 120 kV/40 mAs, standard protocol, n = 41). CT dose index (CTDIvol), dose-length product (DLP), attenuation, image noise and signal-to noise ratio (SNR) were compared between the groups using Wilcoxon-Mann-Whitney U test. Subjective diagnostic image quality was compared by using a five-point scale (1 = non-diagnostic, 5 = excellent, read by two readers in consensus) and Cohen's weighted kappa analysis for interobserver agreement. RESULTS: Radiation dose was significantly lower with 70 kV acquisition than 100 and 120 kV (DLP: 31 versus 52 versus 82 mGy.cm; CTDI 2.33 versus 3.95 versus 6.31 mGy, all p < 0.05). Mean SNR (70 kV: 0.37; 100 kV: 0.21; 120 kV: 0.13; p < 0.05) and organ attenuation increased significantly with lower voltages. All examinations showed diagnostic image quality. Subjective diagnostic image quality was higher with standard protocols than the 70 kV protocol (120 kV: 5.0; 100 kV: 4.5; 70 kV: 3.5, p < 0.05) without significant differences with substantial interobserver agreement (kappa > 0.59). CONCLUSION: The ultra-low dose (70 kV) CT imaging of the paranasal sinus allowed for significant dose reduction by 61% and an increased attenuation of organ structures in comparison to standard acquisition while maintaining diagnostic image quality with a slight reduction in subjective image quality. PMID- 25912260 TI - Biological and physiological role of reactive oxygen species--the good, the bad and the ugly. AB - Reactive oxygen species (ROS) are chemically reactive molecules that are naturally produced within biological systems. Research has focused extensively on revealing the multi-faceted and complex roles that ROS play in living tissues. In regard to the good side of ROS, this article explores the effects of ROS on signalling, immune response and other physiological responses. To review the potentially bad side of ROS, we explain the consequences of high concentrations of molecules that lead to the disruption of redox homeostasis, which induces oxidative stress damaging intracellular components. The ugly effects of ROS can be observed in devastating cardiac, pulmonary, neurodegenerative and other disorders. Furthermore, this article covers the regulatory enzymes that mitigate the effects of ROS. Glutathione peroxidase, superoxide dismutase and catalase are discussed in particular detail. The current understanding of ROS is incomplete, and it is imperative that future research be performed to understand the implications of ROS in various therapeutic interventions. PMID- 25912261 TI - Editorial Comment from Dr Rourke to Risk of urethral stricture recurrence increases over time after urethroplasty. PMID- 25912262 TI - Novel flame retardants (N-FRs), polybrominated diphenyl ethers (PBDEs) and dioxin like polychlorinated biphenyls (DL-PCBs) in fish, penguin, and skua from King George Island, Antarctica. AB - Persistent organic pollutants (POPs), including polychlorinated biphenyls (PCBs) and polybrominated diphenyl ethers (PBDEs), are frequently detected in biota from Antarctica, whereas no data are available for their replacements, such as novel flame retardants (N-FRs). This study presented the occurrence of several N-FRs, PBDEs, and PCBs in tissue samples of an Antarctic rock cod (Trematomus bernacchii), a young gentoo penguin (Pygoscelis papua), and a brown skua (Stercorarius antarcticus) collected from King George Island. The total concentrations of N-FRs (SigmaN-FRs; mean: 931 pg/g dry weight (dw)) were comparable to PBDEs (Sigma8PBDEs; 681 pg/gdw), which were much lower than PCBs (SigmaDL-PCBs; 12,800 pg/gdw). Overall, skua contained two to three orders of magnitude higher contamination than penguin and fish. In the future, more attention should be focused on the fate of N-FRs in Antarctica, where usages have increased since PBDEs were banned. To our knowledge, this is the first report of N-FRs in biota from Antarctica. PMID- 25912263 TI - Integrating science education and marine conservation through collaborative partnerships. AB - The Georgia Sea Turtle Center has a mission of conservation based rehabilitation, research, and education. Marine debris is a serious threat to marine species. In an effort to educate local students, the GSTC obtained a grant to provide educational opportunities to local third graders. Third and fourth grade classes in Glynn County, Georgia were offered a Garbage in the Water program and 964 students were reached. After programming, students showed a statistically significant (p<.0001) increase in test scores between the pre and posttests. This success led to repeat funding for additional programming for first grades as well as a formalized relationship with the Glynn County School District. As part of this relationship the Georgia Sea Turtle Center is now the official field trip location for all third grades in the district. PMID- 25912264 TI - Proteomic analysis of the European flounder Platichthys flesus response to experimental PAH-PCB contamination. AB - Platichthys flesus is often used as a sentinel species to monitor the estuarine water quality. In this study, we carried out an experimental contamination of fish using a PAHs/PCBs mixture, which was designed to mimic the concentrations found in the Seine estuary (C1) and 10 times these concentrations (C2). We used a proteomic approach to understand the molecular mechanisms implied in the response of P. flesus to these xenobiotics. We showed that 54 proteins were differentially accumulated in one or several conditions, which 34 displayed accumulation factors higher than two. 18 of these proteins were identified by MALDI TOF-TOF mass spectrometry. The results indicated the deregulation of oxidative stress- and glutathione metabolism-(GST, GPx) proteins as well as of several proteins belonging to the betaine demethylation pathway and the methionine cycle (BHMT, SHMT, SAHH), suggesting a role for these different pathways in the P. flesus response to chemical contamination. PMID- 25912265 TI - An effective seed protection method for planting Zostera marina (eelgrass) seeds: Implications for their large-scale restoration. AB - We describe an innovative method of planting Zostera marina (eelgrass) seeds in which hessian bags filled with high-silted sediments are used as a seed protecting device. Here, we evaluated the effectiveness of the method through a field seed-sowing experiment over a three year period. The suitable seed planting density required by the seeds of Z. marina in this method was also investigated. In the spring following seed distribution, seedling establishment rate of Z. marina subjected to different seed densities of 200-500seedsbag(-1) ranged from 16% to 26%. New eelgrass patches from seed were fully developed and well maintained after 2-3years following distribution. The seed planting density of 400seedsbag(-1) may be the most suitable for the establishment of new eelgrass patches. Our results demonstrate that seed-based restoration can be an effective restoration tool and the technique presented should be considered for future large-scale Z. marina restoration projects. PMID- 25912266 TI - Modeling the dispersion of viable and total Escherichia coli cells in the artificial semi-enclosed bathing area of Santa Marinella (Latium, Italy). AB - Coastal areas are strongly affected by episodes of fecal contamination due to polluted water inflows from inadequately treated sewages. The present study aims to investigate the dispersion of Escherichia coli in the artificial semi-enclosed bathing area of Santa Marinella (Latium, Italy) through in situ samplings carried out in summer 2012 and the application of a dynamic model. Collected samples were analyzed by the Culture-Based technique and the Fluorescent Antibody method in order to estimate both the viable culturable cells and the total E. coli population, respectively. The in situ datasets were used to test the proposed modeling approach and simulate the behavior of bacteria as particles subjected, or not, to decay. Next, the flushing time and the computation of the Microbiological Potential Risk Area allowed the evaluation of the contribution of physical and biological processes to coliform dispersion and the related potential risk for bathers. PMID- 25912267 TI - Skellern Lecture and the Journal of Psychiatric and Mental Health Nursing Lifetime Achievement Award 2015. PMID- 25912268 TI - Seclusion as a necessary vs. an appropriate intervention: a vignette study among mental health nurses. AB - In a vignette study, mental health nurses were asked to score vignettes on necessity and appropriateness using a Likert scale. Sixty-nine clinical nurses from four mental health institutes scored 64 vignettes on necessity (there is no alternative) and appropriateness (seclusion supports patients' treatment) of seclusion simultaneously. Data analysis focused on the differences between both scores, and included general linear model analysis, t-test statistics and Kendall's tau. The t-test resulted in a significantly higher score on necessity than on appropriateness. Differences between both scores could be explained for 32% by a combination of nurse characteristics and vignette variables. Necessity and appropriateness were found to be strongly associated with each other, showing that underpinning patterns were largely the same. This research enhances the understanding of underlying factors that influence the decision of nurses to use seclusion. This is essential for the development of interventions aimed at the reduction of seclusion use in mental health practice. PMID- 25912269 TI - Psychometric evaluation of the Indonesian version of the Impact of Event Scale Revised. AB - The purpose of this research was to translate and to test an Indonesian version of the Impact of Event Scale-Revised (I-IES-R) as a measurement of psychological distress following a natural disaster. Sample of 30 Mt. Merapi residents participated in pilot testing and 110 survivors completed the test-retest of the I-IES-R. Exploratory factor analysis was used to determine construct validity, and Cronbach's alpha was used to assess reliability. The results of the translational phase of the study indicated that the Indonesian version of the IES R captures the content of the original tool with appropriate adaptation for cultural differences. The Indonesian IES-R revealed a Cronbach's alpha of 0.90 for test and 0.92 for retest for the total score. In addition, the Cronbach alpha for subscales intrusion, avoidance and hyper arousal in the initial scale testing were 0.85, 0.75, and 0.74, respectively, and for the retest 0.88, 0.79, and 0.82, respectively. The reliability coefficient of the test-retest results was 0.75 [95% confidence interval = (0.64, 0.83)], and exploratory factor analysis identified three underlying factors: intrusion, avoidance, and hyper arousal. The I-IES-R can be considered a useful screening tool that can be used by mental health nurses to assess the psychological impact of natural disasters on survivors in Indonesia. PMID- 25912270 TI - Validity and reliability study of the Tilburg Pregnancy Distress Scale into Turkish. AB - This study was conducted to adapt the Tilburg Pregnancy Distress Scale (TPDS) into Turkish and test its validity and reliability. The study was conducted in six Family Health Center regions in the province of Kars between 20 February and 10 April 2013. A total of 275 pregnant women, who met the study criteria and agreed to participate in the study, constituted the sample group of the study. For validity and reliability analysis of the scale, content validity analysis, explanatory and confirmatory factor analysis, and Cronbach's alpha coefficient were used. It was found that the two-factor structure of the scale was valid and its fit indices were appropriate. The total Cronbach's alpha coefficient of the scale was 0.83. The cut-off point of the scale was specified as 28 for its total score. As a consequence, the adaptation of the TPDS into Turkish was determined to be a valid and reliable measurement instrument. Assessment of distress levels of pregnant women constitutes an important area for both midwives and mental health nursing. PMID- 25912271 TI - Pavlovian conditioning enhances resistance to disruption of dogs performing an odor discrimination. AB - Domestic dogs are used to aid in the detection of a variety of substances such as narcotics and explosives. Under real-world detection situations there are many variables that may disrupt the dog's performance. Prior research on behavioral momentum theory suggests that higher rates of reinforcement produce greater resistance to disruption, and that this is heavily influenced by the stimulus reinforcer relationship. The present study tests the Pavlovian interpretation of resistance to change using dogs engaged in an odor discrimination task. Dogs were trained on two odor discriminations that alternated every six trials akin to a multiple schedule in which the reinforcement probability for a correct response was always 1. Dogs then received several sessions of either odor Pavlovian conditioning to the S+ of one odor discrimination (Pavlovian group) or explicitly unpaired exposure to the S+ of one odor discrimination (Unpaired group). The remaining odor discrimination pair for each dog always remained an unexposed control. Resistance to disruption was assessed under presession feeding, a food odor disruptor condition, and extinction, with baseline sessions intervening between disruption conditions. Equivalent baseline detection rates were observed across experimental groups and odorant pairs. Under disruption conditions, Pavlovian conditioning led to enhanced resistance to disruption of detection performance compared to the unexposed control odor discrimination. Unpaired odor conditioning did not influence resistance to disruption. These results suggest that changes in Pavlovian contingencies are sufficient to influence resistance to change. PMID- 25912272 TI - Implementation of MALDI-TOF MS technology for the identification of clinical isolates of Mycobacterium spp. in mycobacterial diagnosis. AB - A total of 243 clinical isolates of the Mycobacterium genus were studied, 143 and 100 using two protocols (Protocol v2 and Protocol v3, respectively) provided by the manufacturer. The overall correlation of matrix-assisted laser desorption/ionization time-of-flight mass spectrometry (MALDI-TOF MS) with the standard identification methods was 63.8 %. The rate of misidentification was 3.2 %, mainly affecting very close species. In Protocol v2, the correlation was 57.3 %, being greater in solid than in liquid media (71.7 % vs. 44.7 %, p < 0.05). Albeit not significant, a trend to a greater correlation for M. tuberculosis complex compared to non-tuberculous mycobacteria (NTM) (63.6 % vs. 55.5 %) was observed. In Protocol v3, the correlation was 73 %, with no significant differences between solid and liquid media (70.8 % vs. 75 %). In conclusion, MALDI-TOF MS may play a role in identifying mycobacterial species isolated from clinical samples, being faster than sequencing and hybridization-based techniques. PMID- 25912273 TI - Passive protection of mice against Streptococcus pneumoniae challenge by naturally occurring and vaccine-induced human anti-PhtD antibodies. AB - Currently marketed Streptococcus pneumoniae vaccines are based on polysaccharide capsular antigens from the most common strains. Pneumococcal histidine triad protein D (PhtD) is a conserved surface protein that is being evaluated as a candidate for a vaccine with improved serotype coverage. Here, we measured the functional activity of human anti-PhtD antibodies in a passive protection model wherein mice were challenged with a lethal dose of S. pneumoniae by intravenous injection. This functional activity was compared with anti-PhtD antibody concentrations measured by enzyme-linked immunosorbent assay (ELISA) to estimate the 50% protective dose (ED50). Anti-PhtD antibodies affinity purified from pooled normal human sera passively protected mice with an ED50 of 1679 ELISA units/ml (95% confidence interval, 1420-1946). Sera from subjects injected with aluminum-adjuvanted PhtD in a phase I trial had similar activity per unit of antibody (ED50 = 1331 ELISA units/ml [95% confidence interval, 762-2038]). Vaccine-induced activity in the passive protection model was blocked by pre incubation with recombinant PhtD but not by a control S. pneumoniae antigen (LytB). These results show that human anti-PhtD antibodies, whether naturally acquired or induced by the PhtD candidate vaccine, are functional. This supports the development of the PhtD candidate as part of a broadly protective pneumococcal vaccine. PMID- 25912274 TI - Comparative Analysis of Informal Caregiver Burden in Advanced Cancer, Dementia, and Acquired Brain Injury. AB - CONTEXT: Measurement and improvement of informal caregiver burden are central aims of policy and intervention. Burden itself is a complex construct, and total burden can differ by patient diagnosis, although how diagnosis affects different aspects of caregiver subjective burden is unclear. OBJECTIVES: To compare the subjective burden of caregivers across three diagnostic groups using the 22-item Zarit Burden Inventory. METHODS: We performed a secondary analysis of pooled cross-sectional data from four U.K. studies of informal caregivers of patients with advanced cancer (n = 105), dementia (n = 131), and acquired brain injury (ABI) (n = 215). Zarit Burden Inventory totals, subscales (personal and role strain), and individual mean scores were compared between diagnostic groups using the general linear model, adjusting for caregiver characteristics. RESULTS: Caregiver age (mean years [SD]: cancer 66.1 [12.0]; dementia 61.9 [13.4]; and ABI 53.8 [10.9]) differed significantly across diagnostic groups (P < 0.001); 81.9%, 36.6%, and 59.1% of caregivers were spouse/partners, respectively (P < 0.001). Total burden was highest in ABI caregivers and lowest in cancer (mean total score [SD]: cancer 23.3 [13.4]; dementia 27.9 [16.4]; and ABI 39.1 [17.3]) (P < 0.001). Subscale scores showed similar patterns (mean personal and role subscale scores [SD]: cancer 11.8 [6.9], 5.8 [4.8]; dementia 14.4 [8.8], 7.3 [5.7]; and ABI 18.7 [9.1], 11.8 [6.0]) (P < 0.001 for both subscales). Most (17 of 22) individual item scores differed by diagnosis group (P < 0.05), except concepts of duty, responsibility, and perception of financial situation. CONCLUSION: Our data show that total, subscale, and most individual elements of caregiver subjective burden differ between cancer, dementia, and ABI caregivers. This should be considered when designing future intervention strategies to reduce caregiver burden in these groups. PMID- 25912275 TI - Patient-Reported Outcomes for Determining Prognostic Groups in Veterans With Advanced Cancer. AB - CONTEXT: Physicians overestimate survival in patients with advanced cancer. Patient-reported outcomes could provide another way to estimate survival. We previously reported four prognostic groups based on Karnofsky Performance Status, Functional Assessment of Cancer Therapy physical well-being subscale, and Memorial Symptom Assessment Scale-Short Form physical symptom distress subscale scores. OBJECTIVES: To determine the validity of these four prognostic groups. METHODS: We performed prospective surveys. Data from a total of 880 Veterans Affairs Medical Center patients, 417 in the First Cohort and 463 in the Validation Cohort, were analyzed. Both inpatients and outpatients were prospectively recruited in Institutional Review Board-approved studies from August 1999 to September 2009. Survival was measured from the date of entry until death or December 1, 2009. Patients completed self-assessments with the Functional Assessment of Cancer Therapy and Memorial Symptom Assessment Scale Short Form. Analysis of variance was used to test differences between groups in continuous variables; a generalized Wilcoxon test was used for differences between groups for survival. RESULTS: The average age in the Validation Cohort was 66.5 years and 98% were men. The majority of patients had metastatic cancer (90%), with lung (28%) and prostate (26%) cancers being predominant. The median Karnofsky Performance Status was 70. Median survival was 33, 46.5, 124, and 209.5 days for the four prognostic groups (P < 0.0001, all pair-wise comparisons P < 0.02). CONCLUSION: The four prognostic groups remained distinct in the prospective cohort. Small differences in patient-reported physical well-being can halve survival estimates. Patient-reported outcomes can correct for physician overestimate of prognosis. This study provides a way to use patient-reported outcomes for prognosis in patients with advanced cancer, with important implications for assessment. PMID- 25912276 TI - Implementing Outcome Measures Within an Enhanced Palliative Care Day Care Model. AB - BACKGROUND: Specialist palliative care day care (SPDC) units provide an array of services to patients and their families and can increase continuity of care between inpatient and homecare settings. A multidisciplinary teamwork approach is emphasized, and different models of day care exist. Depending on the emphasis of care, the models can be social, medical, therapeutic, or mixed. We describe our experience of introducing an enhanced therapeutic specialist day care model and using both patient- and carer-rated tools to monitor patient outcomes. MEASURES: Validated tools used to monitor patients' progress were the Edmonton Symptom Assessment System, the Edmonton Functional Assessment Tool, Part A of the McGill Quality of Life (QoL) Index, and the Palliative Care Problem Severity Scale. INTERVENTION: Participating patients received multidisciplinary teamwork input over eight-week cycles of care and completed the validated tools. OUTCOMES: A total of 70.6% of patients showed an improvement in their Edmonton Symptom Assessment System Symptom Distress Scores after one eight-week cycle. An improvement in Edmonton Functional Assessment Tool scores occurred in 53% and remained unchanged in 13% of patients. On a scale of 0-10, overall QoL improved in 56% of patients, remained unchanged in 18%, and worsened in 26%. Palliative Care Problem Severity Scale scores after an eight-week cycle improved in 58%. CONCLUSIONS/LESSONS LEARNED: This enhanced therapeutic model of SPDC allows for the tracking of progress toward specific goals and monitoring of patients' symptoms, functional status, QoL, and complexity. Retrospective analyses of validated tools show SPDC results in both maintenance and improvement of all parameters. PMID- 25912277 TI - The Quantitative Analgesic Questionnaire: A Tool to Capture Patient-Reported Chronic Pain Medication Use. AB - CONTEXT: The extent to which patients take chronic pain medications as prescribed is not well studied, and there are no generally agreed-upon measures. The Quantitative Analgesic Questionnaire (QAQ) is a new instrument designed to comprehensively document patient-reported medication use, generate scores to quantify it (by individual drug, class, and/or overall), and compare it (qualitatively and/or quantitatively) to the regimen as prescribed. OBJECTIVES: The aim of this study was to describe the development and preliminary validation of the QAQ. METHODS: The QAQ was studied in a convenience sample of 149 HIV infected participants. RESULTS: We found that the QAQ scores computed for participants' chronic pain medication regimens were valid based on their correlation with 1) patient-reported pain intensity (r = 0.38; P < 0.001) and 2) experienced pain management physicians' independent quantification of the regimens (r = 0.89; P < 0.001). The QAQ also demonstrated high interrater reliability (r = 0.957; P < 0.001). Detailed examination of the QAQ data in a subset of 34 participants demonstrated that the QAQ revealed suboptimal adherence in 44% of participants and contained information that would not have been gleaned from review of the medical record alone in 94%, including use of over-the-counter medications and quantification of "as needed" dosing. The QAQ also was found to be useful in quantifying change in the medication regimen over time, capturing a change in 50% of the participants from baseline to eight week follow-up. CONCLUSION: The QAQ is a simple tool that can facilitate understanding of patient reported chronic pain medication regimens, including calculation of percent adherence and generation of quantitative scores suitable for estimating and tracking change in medication use over time. PMID- 25912278 TI - Total, dietary, and supplemental calcium intake and mortality from all-causes, cardiovascular disease, and cancer: A meta-analysis of observational studies. AB - AIMS: This systematic review and meta-analysis of observational studies was conducted to summarize the evidence on the association between calcium intake and mortality. METHODS AND RESULTS: PubMed, Institute for Scientific Information (ISI) (Web of Science), SCOPUS, SciRUS, Google Scholar, and Excerpta Medica dataBASE (EMBASE) were searched to identify related articles published through May 2014. We found 22 articles that assessed the association between total, dietary, and supplementary intake with mortality from all-causes, cardiovascular disease (CVD), and cancer. Findings from this meta-analysis revealed no significant association between total and dietary calcium intake and mortality from all-causes, CVD, and cancer. Subgroup analysis by the duration of follow-up revealed a significant positive association between total calcium intake and CVD mortality for cohort studies with a mean follow-up duration of >10 years (relative risk (RR): 1.35; 95% confidence interval (CI): 1.09-1.68). A significant inverse association was seen between dietary calcium intake and all cause (RR: 0.84; 95% CI: 0.70-1.00) and CVD mortality (RR: 0.88; 95% CI: 0.78 0.99) for studies with a mean follow-up duration of <=10 years. Although supplemental calcium intake was not associated with CVD (RR: 0.95; 95% CI: 0.82 1.10) and cancer mortality (RR: 1.22; 95% CI: 0.81-1.84), it was inversely associated with the risk of all-cause mortality (RR: 0.91; 95% CI: 0.88-0.94). CONCLUSIONS: We found a significant relationship between the total calcium intake and an increased risk of CVD mortality for studies with a long follow-up time and a significant protective association between dietary calcium intake and all-cause and CVD mortality for studies with a mean follow-up of <=10 years. Supplemental calcium intake was associated with a decreased risk of all-cause mortality. PMID- 25912279 TI - An experimental and theoretical study of the photoisomerization and thermal reversion on 5-arylmethylene-2-thioxoimidazolidin-4-one. AB - Unraveling the photochemical behaviour of the green fluorescent protein chromophore has lately attracted widespread attention among scientists. In this paper we present the study of the photochemical isomerization Z -> E and the back reaction of the chromophore analog, 5-arylmethylene-2- thioxoimidazolidin-4-one. Experimental results are supported with ab initio calculations at the DFT, (B3LYP/6-31+g(d,p)), TD-DFT (B3LYP/6-311++g(3df,3pd)) and CASSCF levels. A first excitation to the S2 state, where the isomerization occurs, is proposed followed by two conical intersections to S1 and S0 respectively. Three different mechanisms were analyzed for thermal reversion, concluding that the preferred channel involves an intersystem crossing between the S0 and T1 states with the formation of a biradical. PMID- 25912280 TI - Comparison of Full-length Amino Acid Sequences of Chickens BF1 and BF2. PMID- 25912281 TI - [Primary Sjogren's syndrome revealing cerebellar syndrome]. PMID- 25912282 TI - Daily FOUR score assessment provides accurate prognosis of long-term outcome in out-of-hospital cardiac arrest. AB - BACKGROUND: The accurate prediction of outcome after out-of-hospital cardiac arrest (OHCA) is of major importance. The recently described Full Outline of UnResponsiveness (FOUR) is well adapted to mechanically ventilated patients and does not depend on verbal response. OBJECTIVE: To evaluate the ability of FOUR assessed by intensivists to accurately predict outcome in OHCA. METHODS: We prospectively identified patients admitted for OHCA with a Glasgow Coma Scale below 8. Neurological assessment was performed daily. Outcome was evaluated at 6 months using Glasgow-Pittsburgh Cerebral Performance Categories (GP-CPC). RESULTS: Eighty-five patients were included. At 6 months, 19 patients (22%) had a favorable outcome, GP-CPC 1-2, and 66 (78%) had an unfavorable outcome, GP-CPC 3 5. Compared to both brainstem responses at day 3 and evolution of Glasgow Coma Scale, evolution of FOUR score over the three first days was able to predict unfavorable outcome more precisely. Thus, absence of improvement or worsening from day 1 to day 3 of FOUR had 0.88 (0.79-0.97) specificity, 0.71 (0.66-0.76) sensitivity, 0.94 (0.84-1.00) PPV and 0.54 (0.49-0.59) NPV to predict unfavorable outcome. Similarly, the brainstem response of FOUR score at 0 evaluated at day 3 had 0.94 (0.89-0.99) specificity, 0.60 (0.50-0.70) sensitivity, 0.96 (0.92-1.00) PPV and 0.47 (0.37-0.57) NPV to predict unfavorable outcome. CONCLUSION: The absence of improvement or worsening from day 1 to day 3 of FOUR evaluated by intensivists provides an accurate prognosis of poor neurological outcome in OHCA. PMID- 25912283 TI - Hypertension and Life-Threatening Bleeding in Children with Relapsed Acute Myeloblastic Leukemia Treated with FLT3 Inhibitors. AB - Experiences with new multikinase inhibitors are limited, especially in children. In this report we summarize our experience with 2 patients with relapsed acute myeloblastic leukemia (AML), one with FMS-like tyrosine kinase-3-internal tandem duplication mutation and the other with a single base mutation (D835Y). Both patients received sorafenib, one for 19 days and the other for 42 days, with clofarabine-including chemotherapy. One additionally received sunitinib for a total of 20 days. Both patients developed severe pancytopenia, hypertension, life threatening bleedings from the gastrointestinal system, and, finally, intrapulmonary hemorrhage. Although both reached severe aplasia of the bone marrow without blastic infiltration, death occurred with neutropenic sepsis. PMID- 25912284 TI - Key considerations in the preclinical development of biosimilars. AB - Biosimilar development requires several steps: selection of an appropriate reference biologic, understanding the key molecular attributes of that reference biologic and development of a manufacturing process to match these attributes of the reference biologic product. The European Medicines Agency (EMA) and the FDA guidance documents state that, in lieu of conducting extensive preclinical and clinical studies typically required for approval of novel biologics, biosimilars must undergo a rigorous similarity evaluation. The aim of this article is to increase understanding of the preclinical development and evaluation process for biosimilars, as required by the regulatory agencies, that precedes the clinical testing of biosimilars in humans. PMID- 25912285 TI - Chaperonin-Assisted Protein Folding: Relative Population of Asymmetric and Symmetric GroEL:GroES Complexes. AB - The chaperonin GroEL, a cylindrical complex consisting of two stacked heptameric rings, and its lid-like cofactor GroES form a nano-cage in which a single polypeptide chain is transiently enclosed and allowed to fold unimpaired by aggregation. GroEL and GroES undergo an ATP-regulated interaction cycle that serves to close and open the folding cage. Recent reports suggest that the presence of non-native substrate protein alters the GroEL/ES reaction by shifting it from asymmetric to symmetric complexes. In the asymmetric reaction mode, only one ring of GroEL is GroES bound and the two rings function sequentially, coupled by negative allostery. In the symmetric mode, both GroEL rings are GroES bound and are folding active simultaneously. Here, we find that the results of assays based on fluorescence resonance energy transfer recently used to quantify symmetric complexes depend strongly on the fluorophore pair used. We therefore developed a novel assay based on fluorescence cross-correlation spectroscopy to accurately measure GroEL:GroES stoichiometry. This assay avoids fluorophore labeling of GroEL and the use of GroEL cysteine mutants. Our results show that symmetric GroEL:GroES2 complexes are substantially populated only in the presence of non-foldable model proteins, such as alpha-lactalbumin and alpha-casein, which "over-stimulate" the GroEL ATPase and uncouple the negative GroEL inter-ring allostery. In contrast, asymmetric complexes are dominant both in the absence of substrate and in the presence of foldable substrate proteins. Moreover, uncoupling of the GroEL rings and formation of symmetric GroEL:GroES2 complexes is suppressed at physiological ATP:ADP concentration. We conclude that the asymmetric GroEL:GroES complex represents the main folding active form of the chaperonin. PMID- 25912286 TI - The case for a typhoid vaccine probe study and overview of design elements. AB - Recent advances in typhoid vaccine, and consideration of support from Gavi, the Vaccine Alliance, raise the possibility that some endemic countries will introduce typhoid vaccine into public immunization programs. This decision, however, is limited by lack of definitive information on disease burden. We propose use of a vaccine probe study approach. This approach would more clearly assess the total burden of typhoid across different syndromic groups and account for lack of access to care, poor diagnostics, incomplete laboratory testing, lack of mortality and intestinal perforation surveillance, and increasing antibiotic resistance. We propose a cluster randomized trial design using a mass immunization campaign among all age groups, with monitoring over a 4-year period of a variety of outcomes. The primary outcome would be the vaccine preventable disease incidence of prolonged fever hospitalization. Sample size calculations suggest that such a study would be feasible over a reasonable set of assumptions. PMID- 25912287 TI - Towards sustainable public health surveillance for enteric fever. AB - Enteric fever that results from infection by the typhoidal Salmonellas (Salmonella Typhi and Salmonella Paratyphi A, B and C) is a life-threatening preventable illness. Surveillance of enteric fever is important to understand current burden of disease, to track changes in human health burden from increasing antimicrobial resistance and to assess the impact of efforts to reduce disease burden. Since enteric fever occurs predominantly in low income communities, expensive surveillance is not sustainable. Traditional hospital based surveillance does not estimate population burden and intensive community based cohort studies do not capture the severe disease that is crucial to policy decisions. While cohort studies have been considered the gold standard for incidence estimates, the resources required to conduct them are great; as a consequence, estimates of enteric fever burden have been highly geographically and temporally restricted. A hybrid approach combining laboratory diagnosis that is already being conducted in healthcare centers with community-based surveillance of health care facility use offers a low-cost, sustainable approach to generate policy relevant data. PMID- 25912289 TI - VO2max/kg is expected to be lower in obese individuals! PMID- 25912290 TI - Mandatory Child Life Consultation and Its Impact on Pediatric MRI Workflow in an Academic Medical Center. AB - Pediatric patients undergoing MRI often require general anesthesia, which may improve image quality but is associated with significant medical risk and economic cost. It has previously been shown that certified child life specialists using high-tech interventions (eg, MRI-compatible video goggles) significantly reduce the number of pediatric MRI patients who require sedation. Most imaging centers lack such technology, however, and it remains unclear whether simpler and less costly child life interventions may be equally effective in avoiding general anesthesia. The aim of this study was to assess the impact of requiring mandatory child life evaluation for all patients aged 5 to 18 years undergoing MRI before referral for general anesthesia. Inserting this simple step into the scheduling workflow significantly reduced the use of general anesthesia in this population: general anesthesia was required in 564 of 2,433 MRI cases during the 1-year baseline period compared with 484 of 2,526 cases during the 1-year intervention period (P < .01 by z test for proportions; absolute reduction, 4.0%; relative reduction, 14.8%). The authors estimate that instituting mandatory child life evaluation avoided the use of general anesthesia in approximately 102 patients during the intervention period. Further subgroup analysis revealed that avoidance of general anesthesia was highly significant in the 5- to 10-year-old age group, whereas those aged 11 to 18 years experienced only a trend toward modestly decreased use of general anesthesia. These results suggest that mandatory evaluation for standard child life interventions is a worthwhile step that can save many children from unnecessary exposure to the risks, cost, and inconvenience of general anesthesia. PMID- 25912288 TI - Antimicrobial resistance and management of invasive Salmonella disease. AB - Invasive Salmonella infections (typhoidal and non-typhoidal) cause a huge burden of illness estimated at nearly 3.4 million cases and over 600,000 deaths annually especially in resource-limited settings. Invasive non-typhoidal Salmonella (iNTS) infections are particularly important in immunosuppressed populations especially in sub-Saharan Africa, causing a mortality of 20-30% in vulnerable children below 5 years of age. In these settings, where routine surveillance for antimicrobial resistance is rare or non-existent, reports of 50-75% multidrug resistance (MDR) in NTS are common, including strains of NTS also resistant to flouroquinolones and 3rd generation cephalosporins. Typhoid (enteric) fever caused by Salmonella Typhi and Salmonella Paratyphi A remains a major public health problem in many parts of Asia and Africa. Currently over a third of isolates in many endemic areas are MDR, and diminished susceptibility or resistance to fluoroquinolones, the drugs of choice for MDR cases over the last decade is an increasing problem. The situation is particularly worrying in resource-limited settings where the few remaining effective antimicrobials are either unavailable or altogether too expensive to be afforded by either the general public or by public health services. Although the prudent use of effective antimicrobials, improved hygiene and sanitation and the discovery of new antimicrobial agents may offer hope for the management of invasive salmonella infections, it is essential to consider other interventions including the wider use of WHO recommended typhoid vaccines and the acceleration of trials for novel iNTS vaccines. The main objective of this review is to describe existing data on the prevalence and epidemiology of antimicrobial resistant invasive Salmonella infections and how this affects the management of these infections, especially in endemic developing countries. PMID- 25912291 TI - Frustrated N-heterocyclic carbene-silylium ion Lewis pairs. AB - The reaction of the N-heterocyclic carbene 1,3-di-tert-butyl-4,5 dimethylimidazolin-2-ylidene () with trimethylsilyl iodide, triflate and triflimidate [Me3SiX, X = I, CF3SO3 (OTf), (CF3SO2)2N (NTf2)] by mixing the neat, liquid starting materials afforded the corresponding 2 (trimethylsilyl)imidazolium salts [()SiMe3]X as highly reactive, white crystalline solids. Only the triflimidate (X = NTf2) proved to be stable in solution and could be characterized by means of NMR spectroscopy (in C6D5Br) and X-ray diffraction analysis, whereas dissociation into free and Me3SiOTf was observed for the triflate system, in agreement with the trend derived by DFT calculations; the iodide was too insoluble for characterization. The compounds [()SiMe3]X showed the reactivity expected for frustrated carbene-silylium pairs, and treatment with carbon dioxide, tert-butyl isocyanate and diphenylbutadiyne gave the 1,2-addition products [()CO2SiMe3]X (X = I, OTf, NTf2), [()C(NtBu)OSiMe3]OTf and [()C(Ph)C(SiMe3)CCPh]OTf, respectively. Upon reaction with [AuCl(PPh3)], metal-chloride bond activation was observed, with formation of the cationic gold(i) complexes [()Au(PPh3)]X (X = OTf, NTf2). PMID- 25912292 TI - Arterial stiffness in adolescents and young adults with and without type 1 diabetes: the SEARCH CVD study. AB - BACKGROUND: Arterial stiffness is a useful parameter to predict future cardiovascular disease. OBJECTIVE: We sought to compare arterial stiffness in adolescents and young adults with and without type 1 diabetes (T1D) and explore the risk factors associated with the differences observed. SUBJECTS AND METHODS: Carotid-femoral pulse wave velocity (PWV), augmentation index (AI75), and brachial distensibility (BrachD) were measured in 402 adolescents and young adults with T1D (age 18.8 +/- 3.3 yr, T1D duration 9.8 +/- 3.8 yr) and 206 non diabetic controls that were frequency-matched by age, sex, and race/ethnicity in a cross-sectional study. General linear models were used to explore variables associated with an increase in arterial stiffness after adjustment for demographic and metabolic covariates. RESULTS: T1D status was associated with a higher PWV (5.9 +/- 0.05 vs. 5.7 +/- 0.1 m/s), AI75 (1.3 +/- 0.6 vs. -1.9 +/- 0.7%), and lower BrachD (6.2 +/- 0.1 vs. 6.5 +/- 0.1%Delta/mmHg), all p < 0.05. In multivariate models, age, sex, race, adiposity, blood pressure, lipids, and the presence of microalbuminuria were found to be independent correlates of increased arterial stiffness. After adjustment for these risk factors, T1D status was still significantly associated with arterial stiffness (p < 0.05). CONCLUSIONS: Peripheral and central subclinical vascular changes are present in adolescents and young adults with T1D compared to controls. Increased cardiovascular risk factors alone do not explain the observed differences in arterial stiffness among cases and controls. Identifying other risk factors associated with increased arterial stiffness in youth with T1D is critical to prevent future vascular complications. PMID- 25912294 TI - Is impulsive violence an addiction? The Habit Hypothesis. AB - Impulsive violence may be the behavioral consequence of inefficient information processing within specific neuronal networks. Analogous to the hypothetical pathophysiology of addiction, maladaptations within reward pathways may shift goal-directed behaviors to impulsive reactions and then to compulsive habits, in order to create impulsive violence. PMID- 25912293 TI - Preliminary Transcriptome Analysis in Lymphoblasts from Cluster Headache and Bipolar Disorder Patients Implicates Dysregulation of Circadian and Serotonergic Genes. AB - Bipolar disorder (BD) and cluster headache (CH) are distinct conditions with important similarities such as a temporal pattern of disturbances, dysregulation of the sleep-wake cycle, and response to lithium treatment in a proportion of patients. Aiming to identify common transcription signatures in these two disorders, we carried out an exploratory microarray gene expression analysis in lymphoblasts from 8 CH and 10 BD I patients selected for positive response to lithium and 10 healthy controls (CO). Gene expression levels of BD and CH were compared with CO to create two lists of differentially expressed genes. We then matched the two lists and focus on genes showing statistically significant difference and same change direction in both disorders. RNA binding motif protein 3 (RBM3) was the most significantly altered gene in the list (3.17 * 10(-13) in BD, 9.44 * 10(-14) in CH). Pathway analysis identified protein processing in endoplasmic reticulum as the most significantly enriched. For validation with quantitative reverse transcription PCR (qRT-PCR) using the same samples, we selected seven genes. Among these, we were able to validate the RBM3, nuclear receptor subfamily 1, group D, member 1 (NR1D1), and tryptophan hydroxylase 1 (TPH1). These genes encode for elements involved in circadian rhythm regulation (RBM3 and NR1D1) and in serotonin synthesis (TPH1), processes previously involved in both disorders, and in the mechanism of action of lithium. PMID- 25912295 TI - Cavity optomechanics mediated by a quantum two-level system. AB - Coupling electromagnetic waves in a cavity and mechanical vibrations via the radiation pressure of photons is a promising platform for investigations of quantum-mechanical properties of motion. A drawback is that the effect of one photon tends to be tiny, and hence one of the pressing challenges is to substantially increase the interaction strength. A novel scenario is to introduce into the setup a quantum two-level system (qubit), which, besides strengthening the coupling, allows for rich physics via strongly enhanced nonlinearities. Here we present a design of cavity optomechanics in the microwave frequency regime involving a Josephson junction qubit. We demonstrate boosting of the radiation pressure interaction by six orders of magnitude, allowing to approach the strong coupling regime. We observe nonlinear phenomena at single-photon energies, such as an enhanced damping attributed to the qubit. This work opens up nonlinear cavity optomechanics as a plausible tool for the study of quantum properties of motion. PMID- 25912297 TI - Preventive management plans recorded by dental therapists and oral health therapists using clinical vignettes for adolescents accessing public oral health services in New South Wales, Australia. AB - BACKGROUND: The aim of this study was to investigate factors that influence dental therapists and oral health therapists (therapists) plan preventive oral health care for adolescents attending New South Wales public oral health services. METHODS: A cross-sectional postal survey using two clinical vignettes was used to record the preventive care treatment plans offered by therapists working across 15 New South Wales local health districts. Data were tabulated and chi-square statistics used in the analysis. RESULTS: One hundred and seventeen therapists returned questionnaires, giving a 64.6% response rate. The participants highlighted the importance of offering oral hygiene instruction (97.0%), dietary advice (95.0%) and topical fluoride applications (74.0%). Recommended home use products included fluoride toothpaste 5000 ppmF (59.0%) and casein phosphopeptide-amorphous calcium phosphate plus fluoride (CPP-ACPF) paste (57.7%). Over 50% used fissure sealants. More respondents (88%) would utilize motivational interviewing strategies for a patient with dental caries concerns; however, only 63% would use this technique for a patient in pain (p < 0.001). CONCLUSIONS: Considerable variations were noted in therapists' recommendations for stabilizing and managing dental disease, suggesting a need for clinical directors to consider providing more advice to therapists on the scientific basis of preventing dental caries. PMID- 25912296 TI - Randomized Sham Controlled Double-blind Trial of Repetitive Transcranial Magnetic Stimulation for Adults With Severe Tourette Syndrome. AB - BACKGROUND: A small proportion of individuals with Tourette syndrome (TS) have a lifelong course of illness that fails to respond to conventional treatments. Open label studies have suggested that low frequency (1-Hz) repetitive transcranial magnetic stimulation (rTMS) targeting the supplementary motor area (SMA) may be effective in reducing tic severity. OBJECTIVE/HYPOTHESIS: To examine the efficacy of rTMS over the SMA for TS in a randomized double-blind sham-controlled trial (RCT). METHODS: We conducted a two-site RCT-rTMS with 20 adults with severe TS for 3 weeks. Treatment consisted of 15 sessions (1-Hz; 30 min; 1800 pulses per day) of active or sham rTMS at 110% of the motor threshold over the SMA. A subsequent 3 week course of active rTMS treatment was offered. RESULTS: Of the 20 patients (16 males; mean age of 33.7 +/- 12.2 years), 9 received active and 11 received sham rTMS. After 3 weeks, patients receiving active rTMS showed on average a 17.3% reduction in the YGTSS total tic score compared to a 13.2% reduction in those receiving sham rTMS, resulting in no statistically significant reduction in tic severity (P = 0.27). An additional 3 week open label active treatment for those patients (n = 7) initially randomized to active rTMS resulted in a significant overall 29.7% reduction in tic severity compared to baseline (P = 0.04). CONCLUSION: This RCT did not demonstrate efficacy of 3-week SMA-targeted low frequency rTMS in the treatment of severe adult TS. Further studies using longer or alternative stimulation protocols are warranted. PMID- 25912298 TI - Sechium edule Shoot Extracts and Active Components Improve Obesity and a Fatty Liver That Involved Reducing Hepatic Lipogenesis and Adipogenesis in High-Fat Diet-Fed Rats. AB - Excess fat accumulation in the liver increases the risk of developing progressive liver injuries ranging from a fatty liver to hepatocarcinoma. In a previous study, we demonstrated that the polyphenol components of Sechium edule shoots attenuated hepatic lipid accumulation in vitro. Therefore, we investigated the effects and mechanisms of the extract of S. edule shoots (SWE) to modulate fat accumulation in a high-fat-diet (HFD)-induced animal model. In this study, we found that the SWE can reduce the body weight, adipose tissue fat, and regulate hepatic lipid contents (e.g., triglyceride and cholesterol). Additionally, treatment of caffeic acid (CA) and hesperetin (HPT), the main ingredients of SWE, also inhibited oleic acid (OA)-induced lipid accumulation in HepG2 cells. SWE enhanced the activation of AMP-activating protein kinase (AMPK) and decreased numerous lipogenic-related enzymes, such as sterol regulator element-binding proteins (SREBPs), e.g., SREBP-1 and SREBP-2, and HMG-CoA reductase (HMGCoR) proteins, which are critical regulators of hepatic lipid metabolism. Taken together, the results demonstrated that SWE can prevent a fatty liver and attenuate adipose tissue fat by inhibiting lipogenic enzymes and stimulating lipolysis via upregulating AMPK. It was also demonstrated that the main activation components of SWE are both CA and HPT. PMID- 25912299 TI - Spilled gallstones after laparoscopic cholecystectomy associated with pelvic pain. PMID- 25912300 TI - Relation of body mass index to frequency of recurrent preterm birth in women treated with 17-alpha hydroxyprogesterone caproate. AB - OBJECTIVE: The standard weekly dose of 17-alpha hydroxyprogesterone caproate (17OHP-C; 250 mg/wk) to reduce the risk of recurrent preterm birth was adopted without regard to patient characteristics. We examined the relationship between prepregnancy body mass index (BMI) and gestational age at birth after 17OHP-C prophylaxis. We hypothesized that rates of births before 32, 35, and 37 weeks of gestation would be increased in women with a BMI of 25 kg/m(2) or greater. STUDY DESIGN: A retrospective cohort study was conducted from a deidentified database of women treated with 17OHP-C for prior spontaneous preterm birth. The frequency of recurrent preterm delivery before 32, 35, and 37 weeks of gestation was investigated for women with a BMI less than 25 kg/m(2) compared with women with a BMI of 25 kg/m(2) or greater. The adjusted relative risk of preterm delivery was estimated through a modified Poisson regression approach. RESULTS: Of 390 women who met inclusion criteria, 60 (15.4%) delivered before 32 weeks, 89 (22.8%) before 35 weeks, and 156 (40.0%) before 37 weeks. A total of 174 women had a BMI less than 25 kg/m(2) (mean [SD], 21.2 [2.5]) and 216 had a BMI of 25 kg/m(2) or greater (mean [SD], 33.5 [6.7]). Risk of birth before 32 weeks was 1.7 times higher on average (adjusted relative risk, 1.7; 95% confidence interval, 1.05 2.77) in overweight women than in women with a BMI less than 25 kg/m(2), adjusting for age, race, smoking, and short cervix. There was no difference in the risk of preterm birth before 35 or 37 weeks. CONCLUSION: Among pregnant women receiving 17OHP-C prophylaxis for a prior preterm birth, recurrent preterm birth before 32 weeks was significantly more common in those women whose prepregnancy BMI was 25 kg/m(2) or greater than in women with BMI less than 25 kg/m(2). This observation is consistent with pharmacological studies suggesting that dosing regimens of 17OHP-C may affect efficacy. PMID- 25912301 TI - Training for transabdominal villous sampling is feasible and safe. PMID- 25912302 TI - The relationship between timing of postpartum hemorrhage interventions and adverse outcomes. AB - OBJECTIVE: We sought to determine whether the timing of balloon tamponade (BT) and uterine artery embolization is associated with morbidity among women with postpartum hemorrhage (PPH). STUDY DESIGN: This is a cohort study of women with PPH at a single tertiary academic institution. Patient demographics, delivery outcomes (eg, labor augmentation, route of delivery), and PPH-specific data (eg, estimated blood loss at the time when PPH interventions were employed) were abstracted from the chart. Outcomes studied included nadir hemoglobin, packed red blood cell transfusion, intensive care unit admission, and hysterectomy. RESULTS: During the study period, 420 women were eligible for analysis. Women receiving BT at lower estimated blood loss quartiles had higher nadir hemoglobin, less frequent packed red blood cell transfusion, fewer intensive care unit admissions, and fewer hysterectomies. There were no associations found between timing of uterine artery embolization and maternal outcomes. CONCLUSION: Earlier use of BT among women experiencing a PPH is associated with decreased maternal morbidity. PMID- 25912303 TI - For society, state and self: juggling the logics of professionalism in general practice appraisal. AB - Sociologists repeatedly appeal to notions of altruism, bureaucratisation and self interest in their efforts to explain the changing place of the professions in contemporary society. We treat these three readings as institutional logics that are key to understanding the way in which doctors respond to the appraisal system at the heart of the UK's approach to revalidation. Our analysis of a survey of 998 general practitioners (GPs) working in Wales finds an altruistic commitment to learning and improvement, bureaucratic demands for reporting information and self-regarding resentment of changes in the occupational package provided by general practice. But the data also demonstrate that the maintenance of the appraisal regime is dependent on the preparedness and capacity of individual GPs to do micro-level institutional work on all fronts. PMID- 25912304 TI - MicroRNA-144 suppresses osteosarcoma growth and metastasis by targeting ROCK1 and ROCK2. AB - Osteosarcoma (OS) is the most common primary tumor of bone. MicroRNAs (miRNAs) are a class of endogenously expressed small non-coding RNAs that are strongly implicated in cancerous processes. However, our current understanding of the biological role of miRNAs in OS remains incomplete. In the present study, miR-144 was markedly downregulated in OS cell lines and clinical specimens. Low-level expression of miR-144 was significantly associated with distant metastasis and poor prognosis. Functional studies demonstrated that ectopic expression of miR 144 suppresses tumor cell proliferation and metastasis in vitro as well as in vivo. Furthermore, we identified Rho-associated kinases 1 and 2 (ROCK1 and ROCK2) as direct targets for miR-144 binding, resulting in suppression of their expression. Exogenous expression of ROCK1 or ROCK2 in 143B-miR-144 cells partially restored miR-144-inhibited cell proliferation and invasion. In clinical OS specimens, ROCK1 and ROCK2 levels were elevated, relative to that in paired normal bone tissues, and inversely correlated with miR-144 expression. Taken together, miR-144 suppresses OS progression by directly downregulating ROCK1 and ROCK2 expression, and may be a promising therapeutic target for OS. PMID- 25912305 TI - Lung tumorigenesis induced by human vascular endothelial growth factor (hVEGF) A165 overexpression in transgenic mice and amelioration of tumor formation by miR 16. AB - Many studies have shown that vascular endothelial growth factor (VEGF), especially the human VEGF-A165 (hVEGF-A165) isoform, is a key proangiogenic factor that is overexpressed in lung cancer. We generated transgenic mice that overexpresses hVEGF-A165 in lung-specific Clara cells to investigate the development of pulmonary adenocarcinoma. In this study, three transgenic mouse strains were produced by pronuclear microinjection, and Southern blot analysis indicated similar patterns of the foreign gene within the genomes of the transgenic founder mice and their offspring. Accordingly, hVegf-A165 mRNA was expressed specifically in the lung tissue of the transgenic mice. Histopathological examination of the lung tissues of the transgenic mice showed that hVEGF-A165 overexpression induced bronchial inflammation, fibrosis, cysts, and adenoma. Pathological section and magnetic resonance imaging (MRI) analyses demonstrated a positive correlation between the development of pulmonary cancer and hVEGF expression levels, which were determined by immunohistochemistry, qRT PCR, and western blot analyses. Gene expression profiling by cDNA microarray revealed a set of up-regulated genes (hvegf-A165, cyclin b1, cdc2, egfr, mmp9, nrp-1, and kdr) in VEGF tumors compared with wild-type lung tissues. In addition, overexpressing hVEGF-A165 in Clara cells increases CD105, fibrogenic genes (collagen alpha1, alpha-SMA, TGF-beta1, and TIMP1), and inflammatory cytokines (IL-1, IL-6, and TNF-alpha) in the lungs of hVEGF-A165-overexpressing transgenic mice as compared to wild-type mice. We further demonstrated that the intranasal administration of microRNA-16 (miR-16) inhibited lung tumor growth by suppressing VEGF expression via the intrinsic and extrinsic apoptotic pathways. In conclusion, hVEGF-A165 transgenic mice exhibited complex alterations in gene expression and tumorigenesis and may be a relevant model for studying VEGF targeted therapies in lung adenocarcinoma. PMID- 25912306 TI - The long non-coding RNA HOTTIP enhances pancreatic cancer cell proliferation, survival and migration. AB - HOTTIP is a long non-coding RNA (lncRNA) transcribed from the 5' tip of the HOXA locus and is associated with the polycomb repressor complex 2 (PRC2) and WD repeat containing protein 5 (WDR5)/mixed lineage leukemia 1 (MLL1) chromatin modifying complexes. HOTTIP is expressed in pancreatic cancer cell lines and knockdown of HOTTIP by RNA interference (siHOTTIP) in Panc1 pancreatic cancer cells decreased proliferation, induced apoptosis and decreased migration. In Panc1 cells transfected with siHOTTIP, there was a decrease in expression of 757 genes and increased expression of 514 genes, and a limited gene analysis indicated that HOTTIP regulation of genes is complex. For example, Aurora kinase A, an important regulator of cell growth, is coregulated by MLL and not WDR5 and, in contrast to previous studies in liver cancer cells, HOTTIP does not regulate HOXA13 but plays a role in regulation of several other HOX genes including HOXA10, HOXB2, HOXA11, HOXA9 and HOXA1. Although HOTTIP and the HOX-associated lncRNA HOTAIR have similar pro-oncogenic functions, they regulate strikingly different sets of genes in Panc1 cells and in pancreatic tumors. PMID- 25912307 TI - Glucose starvation-mediated inhibition of salinomycin induced autophagy amplifies cancer cell specific cell death. AB - Salinomycin has been used as treatment for malignant tumors in a small number of humans, causing far less side effects than standard chemotherapy. Several studies show that Salinomycin targets cancer-initiating cells (cancer stem cells, or CSC) resistant to conventional therapies. Numerous studies show that Salinomycin not only reduces tumor volume, but also decreases tumor recurrence when used as an adjuvant to standard treatments. In this study we show that starvation triggered different stress responses in cancer cells and primary normal cells, which further improved the preferential targeting of cancer cells by Salinomycin. Our in vitro studies further demonstrate that the combined use of 2-Fluoro 2-deoxy D glucose, or 2-deoxy D-glucose with Salinomycin is lethal in cancer cells while the use of Oxamate does not improve cell death-inducing properties of Salinomycin. Furthermore, we show that treatment of cancer cells with Salinomycin under starvation conditions not only increases the apoptotic caspase activity, but also diminishes the protective autophagy normally triggered by the treatment with Salinomycin alone. Thus, this study underlines the potential use of Salinomycin as a cancer treatment, possibly in combination with short-term starvation or starvation-mimicking pharmacologic intervention. PMID- 25912308 TI - Mitochondrial fission determines cisplatin sensitivity in tongue squamous cell carcinoma through the BRCA1-miR-593-5p-MFF axis. AB - Cisplatin has been widely employed as a cornerstone chemotherapy treatment for a wide spectrum of solid neoplasms; increasing tumor responsiveness to cisplatin has been a topic of interest for the past 30 years. Strong evidence has indicated that mitochondrial fission participates in the regulation of apoptosis in many diseases; however, whether mitochondrial fission regulates cisplatin sensitivity remains poorly understood. Here, we show that MFF mediated mitochondrial fission and apoptosis in tongue squamous cell carcinoma (TSCC) cells after cisplatin treatment and that miR-593-5p was downregulated in this process. miR-593-5p attenuated mitochondrial fission and cisplatin sensitivity by targeting the 3' untranslated region sequence of MFF and inhibiting its translation. In exploring the underlying mechanism of miR-593-5p downregulation, we observed that BRCA1 transactivated miR-593-5p expression and attenuated cisplatin sensitivity in vitro. The BRCA1-miR-593-5p-MFF axis also affected cisplatin sensitivity in vivo. Importantly, in a retrospective analysis of multiple centers, we further found that the BRCA1-miR-593-5p-MFF axis was significantly associated with cisplatin sensitivity and the survival of patients with TSCC. Together, our data reveal a model for mitochondrial fission regulation at the transcriptional and post transcriptional levels; we also reveal a new pathway for BRCA1 in determining cisplatin sensitivity through the mitochondrial fission program. PMID- 25912310 TI - Caffeine-hydrazones as anticancer agents with pronounced selectivity toward T lymphoblastic leukaemia cells. AB - We report design and synthesis of set of novel anticancer agents based on caffeine-hydrazones bearing 2-hydroxyaryl- or 2-N-heteroaryl moiety. Anticancer activity evaluation using seven cancer cell lines and two non-malignant cell lines demonstrated that several derivatives display significant anticancer activity and great selectivity index toward T-lymphoblastic leukaemia cells. In general, hydrazones bearing 2-N-heteroaryl moiety are more active and selective than those with 2-hydroxyaryl moiety. Tested compounds exhibit dose-dependent inhibition of both RNA and DNA synthesis, with some exceptions. Antimicrobial activities were tested on set of twelve bacterial and yeast strains, however prepared compounds were not active, suggesting for a molecular target specific for eukaryotic cells. PMID- 25912311 TI - Pregnancies in women with childhood vesicoureteral reflux. AB - OBJECTIVE: The frequency of pregnancy complications together with renal scarring and voiding dysfunction-related risk factors were investigated in a cohort of women with a history of childhood vesicoureteral reflux (VUR). DESIGN: A retrospective cross-sectional cohort study. POPULATION: Eighty-seven primi- or multiparous middle-aged women diagnosed with primary non-obstructive VUR in childhood. METHODS: Pregnancy outcome was assessed from case records and from patient interviews. Urine flow tests for voiding patterns, renal ultrasound for detecting scars, and blood samples for renal function were investigated. The median follow-up time was 38 years. MAIN OUTCOME MEASURES: Prevalence of pregnancy complications in women with childhood VUR in relation to renal scars and voiding abnormalities. RESULTS: Maternal complications were seen in 64% of the women and fetal complications in 13%. The women with renal scars (48/87) more often had hypertension (33%), proteinuria (40%) and urinary tract infections (42%) during pregnancy than women without scarring. The frequency of fetal complications was not increased by renal scarring or proteinuria during pregnancy. Urinary tract infections during pregnancy (33% of the women) and voiding abnormalities (18%) did not increase the frequency of fetal or maternal complications. The women with fetal complications were more predisposed to frequent urinary tract infections during adult life (55%) than were those without fetal complications (24%) (p = 0.04). CONCLUSIONS: The maternal complication rates in women with childhood VUR were increased only by renal scarring. Frequent urinary tract infections during adulthood seemed to predict an elevated risk of fetal complications. PMID- 25912309 TI - Inhibitor development and mortality in non-severe hemophilia A. AB - BACKGROUND: The life expectancy of non-severe hemophilia A (HA) patients equals the life expectancy of the non-hemophilic population. However, data on the effect of inhibitor development on mortality and on hemophilia-related causes of death are scarce. The development of neutralizing factor VIII antibodies in non-severe HA patients may dramatically change their clinical outcome due to severe bleeding complications. OBJECTIVES: We assessed the association between the occurrence of inhibitors and mortality in patients with non-severe HA. METHODS: In this retrospective cohort study, clinical data and vital status were collected for 2709 non-severe HA patients (107 with inhibitors) who were treated between 1980 and 2011 in 34 European and Australian centers. Mortality rates for patients with and without inhibitors were compared. RESULTS: During 64,200 patient-years of follow-up, 148 patients died (mortality rate, 2.30 per 1000 person-years; 95% confidence interval (CI), 1.96-2.70) at a median age of 64 years (interquartile range [IQR], 49-76). In 62 patients (42%) the cause of death was hemophilia related. Sixteen inhibitor patients died at a median age of 71 years (IQR, 60 81). In ten patients the inhibitor was present at time of death; seven of them died of severe bleeding complications. The all-cause mortality rate in inhibitor patients was > 5 times increased compared with that for those without inhibitors (age-adjusted mortality rate ratio, 5.6). CONCLUSION: Inhibitor development in non-severe hemophilia is associated with increased mortality. High rates of hemophilia-related mortality in this study indicate that non-severe hemophilia is not mild at all and stress the importance of close follow-up for these patients. PMID- 25912312 TI - Acid environments affect biofilm formation and gene expression in isolates of Salmonella enterica Typhimurium DT104. AB - The aim of this study was to examine the survival and potential virulence of biofilm-forming Salmonella Typhimurium DT104 under mild acid conditions. Salmonella Typhimurium DT104 employs an acid tolerance response (ATR) allowing it to adapt to acidic environments. The threat that these acid adapted cells pose to food safety could be enhanced if they also produce biofilms in acidic conditions. The cells were acid-adapted by culturing them in 1% glucose and their ability to form biofilms on stainless steel and on the surface of Luria Bertani (LB) broth at pH7 and pH5 was examined. Plate counts were performed to examine cell survival. RNA was isolated from cells to examine changes in the expression of genes associated with virulence, invasion, biofilm formation and global gene regulation in response to acid stress. Of the 4 isolates that were examined only one (1481) that produced a rigid biofilm in LB broth at pH7 also formed this same structure at pH5. This indicated that the lactic acid severely impeded the biofilm producing capabilities of the other isolates examined under these conditions. Isolate 1481 also had higher expression of genes associated with virulence (hilA) and invasion (invA) with a 24.34-fold and 13.68-fold increase in relative gene expression respectively at pH5 compared to pH7. Although genes associated with biofilm formation had increased expression in response to acid stress for all the isolates this only resulted in the formation of a biofilm by isolate 1481. This suggests that in addition to the range of genes associated with biofilm production at neutral pH, there are genes whose protein products specifically aid in biofilm production in acidic environments. Furthermore, it highlights the potential for the use of lactic acid for the inhibition of Salmonella biofilms. PMID- 25912313 TI - Use of power ultrasound to enhance the thermal inactivation of Clostridium perfringens spores in beef slurry. AB - Clostridium perfringens is a pathogen of concern in pasteurised foods. The main objective of this study was to use power ultrasound to enhance the thermal inactivation of C. perfringens spores in beef slurry. The effect of simultaneous ultrasound and heat (TS, thermosonication) on the spore inactivation in beef slurry was first investigated. At 75 degrees C, a 60 min TS process (24 kHz, 0.33 W/g) resulted in a less than 1.5 log reduction for both C. perfringens NZRM 898 and NZRM 2621 spores. Then, the thermal inactivation first order kinetic parameters of C. perfringens spores in beef slurry were estimated for the two strains. The D105 degrees C- and z-values were 2.5 min and 10.6 degrees C for NZRM 898 and 1.8 min and 10.9 degrees C for NZRM 2621. After, the effect of a spore heat shock followed by ultrasound on its thermal inactivation in beef slurry was investigated. This heat shock+ultrasound pretreatment was able to double the spore thermal inactivation rate in beef slurry. For example at 95 degrees C D-value of 20.2 min decreased to 9.8 min, demonstrating that spore exposure to heat shock followed by ultrasonication enhanced its thermal inactivation. PMID- 25912314 TI - Relations between temperamental fear and risky pedestrian behavior. AB - OBJECTIVE: Child pedestrian injury poses a significant global public health challenge. This study examines relations between temperamental fear and children's risky pedestrian behavior, utilizing mediation analytic strategies to study underlying mechanisms of the hypothesized relation. METHODS: As part of a larger study, 240 seven- and eight-year-old children completed 30 crossings in a virtual reality (VR) pedestrian environment. Three pedestrian behaviors were considered: start gap (lag after a traffic gap appears before child initiates crossing into the gap), time to contact (TTC; gap between avatar and the lead oncoming vehicle), and hits (collisions with vehicles in simulated crossings). Temperamental fear was measured by parent report. RESULTS: Fearful children were more likely to be struck by virtual vehicles, and the relation between fear and risky pedestrian behaviors was mediated by start gap and TTC. Specifically, children who were temperamentally more fearful were more likely to hesitate before initiating crossing, which led to shorter gaps between themselves and the oncoming vehicle, hence causing them to be more likely to be hit by virtual vehicles. Gender interacted with fear, such that fearful girls were most likely to be hit. CONCLUSIONS: Both temperamental fear and gender influenced the risk of child pedestrian injuries. Delayed entry into traffic and shorter gaps between children and oncoming vehicles may underlie this relation. Future research should explore how these factors might influence the effectiveness of prevention programs. PMID- 25912315 TI - Utility of characteristic 'Weak to Absent' INI1/SMARCB1/BAF47 expression in diagnosis of synovial sarcomas. AB - Recently, very few studies have shown value of immunohistochemical (IHC) expression of INI1/SMARCB1 in diagnosis of synovial sarcomas (SSs). This study was aimed at testing reproducibility and utility of this finding. Sixty-eight SSs and 147 other tumours, in the form of various biopsies, were tested for IHC expression of INI1. Twenty-six SSs were further confirmed with positive SS18 rearrangement. Forty monophasic spindle cell type (58.8%), 13 biphasic (19.1%), 12 poorly differentiated (17.6%) and three calcifying SSs (4.4%) were positive for epithelial membrane antigen (EMA) (46/62) (74.1%), pan cytokeratin (AE1/AE3) (31/47) (65.9%), cytokeratin (CK7) (20/31) (64.5%), BCL2 (62/66) (93.9%), MIC2 (61/63) (96.8%), transducin-like enhancer of split 1 (TLE1) (29/31) (93.5%) and CK19 (14/24) (58.3%). INI1 expression was 'weak to absent' in 60/68 (88.2%) SSs; in 1/3 atypical ossifying fibromyxoid tumours (AOFMTs) and in 3/10 (30%) malignant peripheral nerve sheath tumours (MPNSTs) of various types. INI1 was completely absent in 10/10 (100%) epithelioid sarcomas (ESs), 4/4 (100%) malignant rhabdoid tumours, single paediatric undifferentiated sarcoma, 5/19 (26.3%) myoepithelial carcinomas and in 2/4 (50%) epithelioid-subtype of MPNSTs. Remaining 100 tumours, including 12 Ewing sarcomas, 15 carcinomas, eight solitary fibrous tumours (SFT), seven extraskeletal myxoid chondrosarcomas, three fibrosarcomas and other tumours retained INI1 expression. A unique 'weak to absent' IHC expression of INI1 is highly sensitive (88.2%) and specific (97.3%) for a SS, irrespective of its subtypes and types of biopsies. This can be considered useful in diagnosing SSs, especially in settings lacking molecular and/or cytogenetic analysis. A similar INI1 expression is shared by certain AOFMTs and MPNSTs. PMID- 25912316 TI - Photoinduced reduction of the medial FeS center in the hydrogenase small subunit HupS from Nostoc punctiforme. AB - The small subunit from the NiFe uptake hydrogenase, HupSL, in the cyanobacterium Nostoc punctiforme ATCC 29133, has been isolated in the absence of the large subunit (P. Raleiras, P. Kellers, P. Lindblad, S. Styring, A. Magnuson, J. Biol. Chem. 288 (2013) 18,345-18,352). Here, we have used flash photolysis to reduce the iron-sulfur clusters in the isolated small subunit, HupS. We used ascorbate as electron donor to the photogenerated excited state of Ru(II)-trisbipyridine (Ru(bpy)3), to generate Ru(I)(bpy)3 as reducing agent. Our results show that the isolated small subunit can be reduced by the Ru(I)(bpy)3 generated through flash photolysis. PMID- 25912317 TI - Ophthalmic abnormalities secondary to periocular or ocular snakebite (pit vipers) in dogs--11 cases (2012-2014). AB - OBJECTIVE: To describe ophthalmic abnormalities secondary to periocular and ocular snakebite in dogs. ANIMAL STUDIED: Retrospective review of medical records from dogs presenting to the Small Animal Hospital at University of Florida following snakebites to the face (2012-2014). Two groups were identified: periocular bites (PB) and ocular bites (OB). RESULTS: Records from eleven dogs matched the search criteria and were included in the study (PB=9, 81.8%; OB=2, 18.2%). Both OB cases involved the cornea. Facial edema, blepharospasm, chemosis, and conjunctival hyperemia occurred in all cases (100%). Hemorrhage from the eyelids occurred in eight cases (72.7%; PB=7, OB=1). Subconjunctival hemorrhage occurred in seven cases (63.6%; PB=6, OB=1). Third eyelid laceration and nictitans gland prolapse occurred in 1 case each (9%; PB=1). Lagophthalmia was present in three cases (27.3%; PB=3), with secondary corneal ulcer in two cases (18.2%; PB=2). Corneal ulcer due to direct corneal bite occurred in two cases (18.2%-partial thickness with melting (1) and full thickness (1) ). Uveitis was present in 6 cases (54.5%; PB=4, OB=2), with flare and miosis in 4 cases (36.4%; PB=2, OB=2). Hyphema, fibrin in anterior chamber, and cataract occurred in one case (9%; OB=1). Vision loss occurred in two cases (18.2%; PB=2), secondary to retinal degeneration (PB=1) and amaurosis (PB=1). Mean follow-up time was 7 weeks (range: 3 days-11 months). Most clinical signs had resolved by last examination. CONCLUSIONS: Periocular symptoms were more commonly observed than ocular alterations, regardless of bite location. Appropriate supportive therapy should be instituted according to clinical signs. PMID- 25912318 TI - Isolation and characterization of 13 polymorphic microsatellite loci in Hypostomus ancistroides (Teleostei, Loricariidae) and cross-amplification in related species. AB - This study details 13 novel polymorphic microsatellite loci in the armoured catfish Hypostomus ancistroides, and assesses their utility for population genetic studies. The analysis of 30 individuals revealed a total of 99 different alleles (ranging from two to 15 alleles per locus), with an average of 7.62 alleles per locus, with observed and expected heterozygosities ranging from 0.103 to 0.931 and from 0.102 to 0.906, respectively. One of the 13 loci showed significant deviations from Hardy-Weinberg equilibrium, probably due to the presence of null alleles, inferred from the excess of homozygotes. PMID- 25912319 TI - The comparative utility of fluorescence in situ hybridization and reverse transcription-polymerase chain reaction in the diagnosis of alveolar rhabdomyosarcoma. AB - Fluorescence in situ hybridization (FISH) for FOXO1 gene rearrangement and reverse transcription-polymerase chain reaction (PCR) for PAX3/7-FOXO1 fusion transcripts have become routine ancillary tools for the diagnosis of alveolar rhabdomyosarcomas (ARMS). Here we summarize our experience of these adjunct diagnostic modalities at a tertiary center, presenting the largest comparative series of FISH and PCR for suspected or possible ARMS to date. All suspected or possible ARMS tested by FISH or PCR for FOXO1 rearrangement or PAX3/7-FOXO1 fusion transcripts over a 7-year period were included. FISH and PCR results were correlated with clinical and histologic findings. One hundred samples from 95 patients had FISH and/or PCR performed. FISH had higher rates of technical success (96.8 %) compared with PCR (88 %). Where both tests were utilized successfully, there was high concordance rate between them (94.9 %). In 24 histologic ARMS tested for FISH or PCR, 83.3 % were translocation-positive (all for PAX3-FOXO1 by PCR) and included 3 histologic solid variants. In 76 cases where ARMS was excluded, there were 3 potential false-positive cases with FISH but none with PCR. PCR had similar sensitivity (85.7 %) and better specificity (100 %) in aiding the diagnosis of ARMS, compared with FISH (85 and 95.8 %, respectively). All solid variant ARMS harbored FOXO1 gene rearrangements and PAX3 FOXO1 ARMS were detected to the exclusion of PAX7-FOXO1. In comparative analysis, both FISH and PCR are useful in aiding the diagnosis of ARMS and excluding its sarcomatous mimics. FISH is more reliable technically but has less specificity than PCR. In cases where ARMS is in the differential diagnosis, it is optimal to perform both PCR and FISH: both have similar sensitivities for detecting ARMS, but FISH may confirm or exclude cases that are technically unsuccessful with PCR, while PCR can detect specific fusion transcripts that may be useful prognostically. PMID- 25912320 TI - An in vivo mouse model of primary dysmenorrhea. AB - Primary dysmenorrhea (PD) is a common gynecological disorder. Hitherto, animal models which recapitulate clinical features of PD have not been fully established. We aimed to examine whether a pain model in mice could mimic the clinic features of PD. After pretreated with estradiol benzoate (1 mg/kg/day) intraperitoneally (i.p.) for 3 consecutive days, non-pregnant female Imprinting Control Region mice (6-8 weeks old) was injected with 0.4 U of oxytocin to induce the stretching or writhing response which was recorded for a time period of 30 min. During the writhing period, the uterine artery blood flow alterations were examined by Doppler ultrasound detection. After writhing test, the uterine morphological changes were observed by hematoxylin and eosin (H&E) staining histopathology. In addition, enzyme-linked immunosorbent assay kit was used to measure the levels of prostaglandins F2alpha/prostaglandins E2 (PGF2alpha/PGE2) and TXB2 (a metabolite of TXA2)/6-keto-PGF1alpha (a metabolite of PGI2) in the uterine tissue homogenates and plasma, respectively. Western blot analyses were performed to determine the expressions of oxytocin receptor (OTR), beta2 adrenergic receptor (beta2-AR), and cyclooxygenase-2 (COX-2) in uterine, which are responsible for the uterine contraction. The writhing response only occurred in the estrogen pretreated female mice. The area of uterine myometrium significantly decreased along with the increased thickness in the oxytocin induced estrogen pretreated mice model. The uterine artery blood flow velocity dropped, while the pulsatility index and resistance index slightly increased after the injection of oxytocin. The PGF2alpha/PGE2 level significantly increased and the plasma TXB2/6-keto-PGF1alpha level significantly enhanced. Compared with the control group, the uterine histopathology demonstrated moderate to severe edema of endometrium lamina propria. In consistent with the uterine morphological changes, a significant reduction of beta2-AR and a significant increase of OTR and COX-2 in the uterine tissue were observed. The writhing response was caused by the abnormal contraction of uterus. The uterine spasm and ischemia changes of oxytocin-induced estrogen pretreated female mice model were similar to the pathology of human PD. We reported an in vivo mice model, which can be used to study PD and for clinical therapeutic evaluations. PMID- 25912321 TI - Human apolipoprotein B transgenic SHR/NDmcr-cp rats show exacerbated kidney dysfunction. AB - Nephropathy frequently co-occurs with metabolic syndrome in humans. Metabolic syndrome is a cluster of metabolic diseases including obesity, diabetes, hypertension, and dyslipidemia, and some previous studies revealed that dyslipidemia contributes to the progression of kidney dysfunction. To establish a new nephropathy model with metabolic syndrome, we produced human apolipoprotein B (apoB) transgenic (Tg.) SHR/NDmcr-cp (SHR-cp/cp) rats, in which dyslipidemia is exacerbated more than in an established metabolic syndrome model, SHR-cp/cp rats. Human apoB Tg. SHR-cp/cp rats showed obesity, hyperinsulinemia, hypertension, and severe hyperlipidemia. They also exhibited exacerbated early-onset proteinuria, accompanied by increased kidney injury and increased oxidative and inflammatory markers. Histological analyses revealed the characteristic features of human apoB Tg. SHR-cp/cp rats including prominent glomerulosclerosis with lipid accumulation. Our newly established human apoB Tg. SHR-cp/cp rat could be a useful model for the nephropathy in metabolic syndrome and for understanding the interaction between dyslipidemia and renal dysfunction in metabolic syndrome. PMID- 25912322 TI - Ultrastructural analysis between fetal and adult wound healing process of marsupial opossum skin. AB - The opossum delivers a newborn baby equivalent to tremature fetus state by postpregnancy. The peculiarity is advantageous for studies of fetus, because operations to take out fetus from the uterus of a mother are not necessary. When mammalian skin is wounded by full-thickness excision, fetal and adult wound healing processes differ. Fetal-type wound healing does not leave a scar. However, studies of how the fetal wound healing process differs in detail from the adult type are not advanced. We first observed the normal skin development of the gray short-tailed opossum (Monodelphis domestica) using an electron microscope. As for normal skin, an epidermis became multi-layered, and thickened from birth through to 7 days after birth. The quantity of extracellular matrix of the dermis increased thereafter, and several types of cells were found in the dermis. To examine the wound healing, we used material from a 1 day-old newborn baby, and from another 15 days after birth, and compared the wound healing style morphologically. Differences in the constitution of cells and fine structures of the skin were observed, it was obviously suggested that change in the wound healing style from fetal-type to adult-type occurred between 1 to 15 days after birth. PMID- 25912324 TI - Concentration effects on spontaneous and amplified emission in benzo[c]fluorenes. AB - Deep-blue-emitting benzo[c]fluorene-cored compounds featuring twisted peripheral moieties for suppressed concentration quenching of emission were synthesized and investigated as potential materials for light amplification. This detailed study of the effect of concentration on the spontaneous and stimulated emission, excited-state lifetime and susceptibility to form aggregates obtained for different benzofluorenes, has enabled the understanding of the concentration dependence of the amplified spontaneous emission (ASE) threshold and revealed the optimal concentration for the lowest threshold. The weak concentration quenching accompanied by high fluorescence quantum yield (>40%) and radiative decay rate (>5 * 10(8) s(-1)) have enabled the attainment of the lowest ASE threshold in the neat amorphous film of benzofluorene bearing dihexylfluorenyl peripheral moieties. Aggregate formation was found to negligibly affect the emission efficiency of the benzofluorene films; however, it drastically increased ASE threshold via the enhanced scattering of directional stimulated emission, and thereby implied the necessity to utilize homogeneous glassy films as the lasing medium. Although the bulky dihexylfluorenyl groups at the periphery ensured the formation of glassy benzofluorene films with the ASE threshold as low as 900 W cm(-2) (under nanosecond excitation), they adversely affected carrier drift mobility, which implied a tradeoff between ASE and charge transport properties for the lasing materials utilized in the neat form. Such a low ASE threshold attained in air is among the lowest reported for solution-processed neat films. The low threshold and enhanced photostability of benzofluorenes against fluorene compounds in air show great potential for benzofluorene-cored molecular glasses as active media for lasing applications. PMID- 25912323 TI - Songbird: a unique animal model for studying the molecular basis of disorders of vocal development and communication. AB - Like humans, songbirds are one of the few animal groups that learn vocalization. Vocal learning requires coordination of auditory input and vocal output using auditory feedback to guide one's own vocalizations during a specific developmental stage known as the critical period. Songbirds are good animal models for understand the neural basis of vocal learning, a complex form of imitation, because they have many parallels to humans with regard to the features of vocal behavior and neural circuits dedicated to vocal learning. In this review, we will summarize the behavioral, neural, and genetic traits of birdsong. We will also discuss how studies of birdsong can help us understand how the development of neural circuits for vocal learning and production is driven by sensory input (auditory information) and motor output (vocalization). PMID- 25912325 TI - [Complications after TACE in HCC]. PMID- 25912326 TI - Molecular imaging in cardiovascular diseases. AB - Cardiovascular diseases remain the leading cause of morbidity and mortality in industrialized and developing countries. In clinical practice, the in-vivo identification of atherosclerotic lesions, which can lead to complications such as heart attack or stroke, remains difficult. Imaging techniques provide the reference standard for the detection of clinically significant atherosclerotic changes in the coronary and carotid arteries. The assessment of the luminal narrowing is feasible, while the differentiation of stable and potentially unstable or vulnerable atherosclerotic plaques is currently not possible using non-invasive imaging. With high spatial resolution and high soft tissue contrast, magnetic resonance imaging (MRI) is a suitable method for the evaluation of the thin arterial wall. In clinical practice, native MRI of the vessel wall already allows the differentiation and characterization of components of atherosclerotic plaques in the carotid arteries and the aorta. Additional diagnostic information can be gained by the use of non-specific MRI contrast agents. With the development of targeted molecular probes, that highlight specific molecules or cells, pathological processes can be visualized at a molecular level with high spatial resolution. In this review article, the development of pathophysiological changes leading to the development of the arterial wall are introduced and discussed. Additionally, principles of contrast enhanced imaging with non specific contrast agents and molecular probes will be discussed and latest developments in the field of molecular imaging of the vascular wall will be introduced. KEY POINTS: Molecular magnetic resonance imaging has great potential to improve the in vivo characterization of atherosclerotic plaques. Based on the molecular information is feasible to enable a better differentiation of stable and unstable (vulnerable) atherosclerotic plaques. PMID- 25912327 TI - BLADE Sequences in Transverse T2-weighted MR Imaging of the Cervical Spine. Cut off for Artefacts? AB - PURPOSE: The BLADE (PROPELLER) technique reduces artefacts in imaging of the cervical spine in sagittal orientation, but till now failed to do so in axial orientation, because here it increased through plane CSF-flow artefacts, which spoiled the benefit of BLADE artefact reduction "in plane". The aim of this study was to compare a BLADE sequence with optimised measurement parameters in axial orientation to T2-TSE. MATERIALS AND METHODS: Both sequences were compared in 58 patients with 31 discal, 16 bony and 11 spinal cord lesions. Image sharpness, reliability of spinal cord depiction, CSF flow artefacts and lesion detection were evaluated by 3 independent observers. Additionally the observers were asked which sequence they would prefer for diagnostic workup. Statistical evaluations were performed using sign and chi2 test. RESULTS: BLADE was significantly superior concerning image sharpness, spinal cord depiction and overall lesion detection. BLADE was rated better for most pathologies, for bony lesions the differences compared with TSE were statistically significant. Regarding CSF-flow artefacts both sequences showed no difference. All readers preferred BLADE in side by side reading. CONCLUSION: An optimised axial T2 BLADE sequence decreases the problems of increased through plane CSF-flow artefacts in this orientation. By reducing various other artefacts it yields better image quality and has the potential to reduce the number of non-diagnostic examinations especially in uncooperative patients. KEY POINTS: T2 BLADE/PROPELLER sequences proofed to reduce artefacts in sagittal spine imaging. BLADE/PROPELLER improve image quality, but can aggravate CSF flow artefacts in axial orientation. Optimised parameter setting for axial T2 BLADE reduces "through-plane" CSF artefacts aggravation. Optimised axial T2 BLADE reduces non-diagnostic examinations especially in uncooperative patients. PMID- 25912328 TI - Magnetic resonance imaging of the sacroiliac joints in patients with suspected spondyloarthritis--comparison of turbo spin-echo and gradient-echo sequences for the detection of structural alterations. AB - PURPOSE: Magnetic resonance imaging (MRI) is the method of choice for the evaluation of spondyloarthritis (SpA). According to the guidelines of the Assessment of Spondyloarthritis International Society (ASAS) and Outcome Measures in Rheumatology (OMERACT), MRI findings in SpA of the spine and the sacroiliac joints (SIJ) are classified as inflammatory and structural alterations. Modern gradient-echo sequences (GRE) are recommended for optimized detection of structural alterations of the SIJ. We assess the benefit of GRE in the detection of structural alterations of the SIJ in comparison to conventional turbo spin echo sequences (TSE). MATERIAL AND METHODS: Retrospective study of 114 patients who received MRI of the SIJ for the evaluation of SpA. Structural alterations of the SIJ were assessed by two blinded readers separately for T1 TSE and T2* GRE. The findings were classified according to a previously published chronicity score separately for both sides and sequences. Interobserver reliability was calculated with Cohen's Kappa, and the significance of findings was assessed with the Wilcoxon test. P-values <0.05 were required for statistical significance. RESULTS: 68 of 114 (60%) patients showed SpA-typical findings of the SIJ. The average chronicity score for GRE (score 3.3) was significantly higher than for TSE (score 2.6), p=0.001. The Kappa-values for the interobserver reliability were 0.86-0.90 without any statistically significant differences between both sides and sequences. CONCLUSION: Both T1 TSE and T2* GRE showed a high interobserver reliability in the detection of structural alterations in patients with SpA. However, T2* GRE detected significantly more structural alterations than T1 TSE and should be an integral part of a modern MRI protocol for the diagnostic workup of patients with suspected SpA. KEY POINTS: T2* gradient-echo sequences are superior to T1 turbo spin-echo sequences in the detection of structural SI-joint alterations. PMID- 25912329 TI - The Influence of Patient Positioning in Breast CT on Breast Tissue Coverage and Patient Comfort. AB - PURPOSE: The presented study aimed at optimizing a patient table design for breast CT (BCT) systems with respect to breast tissue coverage and patient comfort. Additionally, the benefits and acceptance of an immobilization device for BCT using underpressure were evaluated. MATERIALS AND METHODS: Three different study parts were carried out. In a positioning study women were investigated on an MRI tabletop with exchangeable inserts (flat and cone-shaped with different opening diameters) to evaluate their influence on breast coverage and patient comfort in various positioning alternatives. Breast length and volume were calculated to compare positioning modalities including various opening diameters and forms. In the second study part, an underpressure system was tested for its functionality and comfort on a stereotactic biopsy table mimicking a future CT scanner table. In the last study part, this system was tested regarding breast tissue coverage. RESULTS: Best results for breast tissue coverage were shown for cone-shaped table inserts with an opening of 180 mm. Flat inserts did not provide complete coverage of breast tissue. The underpressure system showed robust function and tended to pull more breast tissue into the field of view. Patient comfort was rated good for all table inserts, with highest ratings for cone-shaped inserts. CONCLUSION: Cone-shaped tabletops appeared to be adequate for BCT systems and to allow imaging of almost the complete breast. An underpressure system proved promising for the fixation of the breast during imaging and increased coverage. Patient comfort appears to be adequate. KEY POINTS: Tissue coverage in breast CT is highly dependent on patient table design. An underpressure fixation system shows potential to increase breast coverage. The proposed breast CT patient table design combines good coverage and patient comfort. PMID- 25912330 TI - [Chronic adhesive small intestine volvulus in adulthood, a rare clinical picture]. PMID- 25912331 TI - [A rare complication of pulmonary tuberculosis - Rasmussen aneurysm - radiologic diagnosis]. PMID- 25912332 TI - [A rare complication: acute ischemic stomach necrosis in non-occlusive mesenteric ischemia]. PMID- 25912335 TI - Altered synchrony and loss of consciousness during frontal lobe seizures. AB - OBJECTIVE: Loss of consciousness (LOC) in frontal lobe epilepsy (FLE) has been rarely specifically studied until now. In this study we evaluated the LOC in a population of patients with FLE and studied the relationship between changes in synchrony and degree of LOC. METHODS: 24 patients undergoing stereoelectroencephalography (SEEG) during pre-surgical evaluation of FLE were studied. The LOC intensity was scored using the Consciousness Seizure Scale (CSS). For each studied seizure (n=52), interdependencies between signals recorded from 5 brain regions were estimated as a function of time by using non linear regression analysis (h(2) coefficient). RESULTS: Seizures were divided into 3 groups according to the CSS scale: group A (no LOC) with a score ?2, group B (intermediate or partial LOC) with a score ranging from 3 to 5, and group C (maximal LOC) with a score ?6. The majority of seizures in FLE patients disclosed significant LOC, particularly for patients with prefrontal lobe seizures. Mean correlation values were significantly different between groups A and C (p<0.001), the maximal values of synchrony being observed in group C. Differences were significant for interaction affecting the external prefrontal cortex (p=0.004) (p=0.01) and the parietal cortex. In addition, a significant correlation was found between CSS scores and correlations values (h(2)) of the prefrontal and the parietal region but not with the premotor cortex. CONCLUSIONS: This study indicates that in FLE, prefrontal seizures frequently alter consciousness. As in other focal seizures, LOC appears to be related to changes in synchrony in prefrontal and parietal associative cortices. SIGNIFICANCE: LOC in FLE is frequent and as in other focal epilepsies is related to an alteration of prefrontal-parietal network. PMID- 25912336 TI - More conditioning stimuli enhance synaptic plasticity in the human spinal cord. AB - OBJECTIVE: To examine whether more paired corticospinal-motoneuronal stimulation (PCMS) is more effective at inducing spinal level plasticity. METHODS: To produce facilitation, corticospinal volleys evoked by motor cortical transcranial magnetic stimulation (TMS) were timed to arrive at corticospinal-motoneuronal synapses prior to antidromic potentials evoked in motoneurones by electrical brachial plexus stimulation. Paired stimuli were delivered repeatedly. 50-pair conditioning (50-PCMS) was compared to 100 pairs in single block (100-PCMSsingle) and spaced (2 blocks of 50, 15-min break; 100-PCMSspaced) patterns, and to 50 single, unpaired TMS (50-TMS). Biceps responses to cervicomedullary stimulation (cervicomedullary motor evoked potentials, CMEPs) and TMS (motor evoked potentials, MEPs) were measured before and for 1h after conditioning (recorded each 5 min). RESULTS: After 100-PCMS, average CMEP areas were increased by 46 +/- 55% (mean +/- SD; n=10; 100-PCMSsingle) and 71 +/- 99% (100-PCMSspaced). 50-PCMS produced a non-significant 6 +/- 40% increase. After 100-PCMSsingle and 100 PCMSspaced, CMEPs were larger than those after 50-TMS from 0 to 60 min (p<0.05). 100-PCMSsingle and 100-PCMSspaced produced more reliable changes than 50-PCMS. Overall, MEPs were larger at 35-60 min; however there were no differences between conditioning protocols. CONCLUSIONS: More PCMS produces more reliable enhancement of corticospinal transmission. SIGNIFICANCE: This technique has therapeutic potential to improve muscle control in patients with reduced descending drive. PMID- 25912337 TI - Are current blinding methods for transcranial direct current stimulation (tDCS) effective in healthy populations? PMID- 25912338 TI - Interrater variability of EEG interpretation in comatose cardiac arrest patients. PMID- 25912339 TI - Familial case reports of stiff-person syndrome. PMID- 25912340 TI - Mussel-inspired nanofibrous sheet for suture-less stomach incision surgery. AB - We report a dopamine-based crosslinker-conjugated gelatin/polycaprolactone nanofibrous sheet. The nanosheet was then employed to treat stomach incisions without sutures during surgery. The mussel-inspired nanosheets, combining the advantages adhesion and tissue repair, show promise for use in treatments of fragile tissues and to avoid suture-caused stress concentration. PMID- 25912341 TI - Effect of extracellular matrix on bovine spermatogonial stem cells and gene expression of niche factors regulating their development in vitro. AB - Extracellular matrix (ECM) could influence cells function through providing structural and functional networks facilitating the cellular interactions. The present study was conducted to evaluate the effect of culture on ECM versus plastic on bovine spermatogonial stem cells (SSCs) and growth factors regulating their development. Following isolation, bovine testicular cells were cultured on ECM-coated or uncoated (control) plates for 12 days. The colonization of SSCs was assessed by inverted microscope and the gene expression was evaluated using quantitative real-time PCR. The colonization rate was greater in ECM than the control group (P<0.05). The expression of markers of undifferentiated spermatogonia increased in response to conventional culture (P<0.05). Conversely, the expression of ckit as a marker for differentiated spermatogonia was reduced following culture in the control and ECM groups (P<0.05), but this decrease was less in ECM group (P<0.05). Accordingly, while cells cultured on uncoated plates had greater expression of markers of undifferentiated spermatogonia (P<0.05), cells cultured on ECM-coated plates showed higher expression of ckit (P<0.05). Moreover, culture on ECM resulted in higher expression of kit ligand (Kitlg; P<0.05), whereas culture on plastic led to greater expression of glial cell line derived neurotrophic factor (Gdnf; P<0.05). In conclusion, the present study revealed that the permissive effect of ECM on bovine SSCs differentiation in vitro, which was probably mediated through upregulation of KITLG expression. Moreover, the results imply that GDNF might contribute to germ cells self-renewal during conventional culture. PMID- 25912342 TI - Two-spoke placement optimization under explicit specific absorption rate and power constraints in parallel transmission at ultra-high field. AB - The spokes method combined with parallel transmission is a promising technique to mitigate the B1(+) inhomogeneity at ultra-high field in 2D imaging. To date however, the spokes placement optimization combined with the magnitude least squares pulse design has never been done in direct conjunction with the explicit Specific Absorption Rate (SAR) and hardware constraints. In this work, the joint optimization of 2-spoke trajectories and RF subpulse weights is performed under these constraints explicitly and in the small tip angle regime. The problem is first considerably simplified by making the observation that only the vector between the 2 spokes is relevant in the magnitude least squares cost-function, thereby reducing the size of the parameter space and allowing a more exhaustive search. The algorithm starts from a set of initial k-space candidates and performs in parallel for all of them optimizations of the RF subpulse weights and the k-space locations simultaneously, under explicit SAR and power constraints, using an active-set algorithm. The dimensionality of the spoke placement parameter space being low, the RF pulse performance is computed for every location in k-space to study the robustness of the proposed approach with respect to initialization, by looking at the probability to converge towards a possible global minimum. Moreover, the optimization of the spoke placement is repeated with an increased pulse bandwidth in order to investigate the impact of the constraints on the result. Bloch simulations and in vivo T2(*)-weighted images acquired at 7 T validate the approach. The algorithm returns simulated normalized root mean square errors systematically smaller than 5% in 10 s. PMID- 25912344 TI - Editorial response to "Representation of women in Cognition". PMID- 25912343 TI - Orally administered DTPA di-ethyl ester for decorporation of (241)Am in dogs: Assessment of safety and efficacy in an inhalation-contamination model. AB - PURPOSE: Currently two injectable products of diethylenetriaminepentaacetic acid (DTPA) are U.S. Food and Drug Administration (FDA)-approved for decorporation of (241)Am; however, an oral product is considered more amenable in a mass casualty situation. The di-ethyl ester of DTPA, named C2E2, is being developed as an oral drug for treatment of internal radionuclide contamination. MATERIALS AND METHODS: Single-dose decorporation efficacy of C2E2 administered 24-h post contamination was determined in beagle dogs using a (241)Am nitrate inhalation contamination model. Single and multiple dose toxicity studies in beagle dogs were performed as part of an initial safety assessment program. In addition, the genotoxic potential of C2E2 was evaluated by the in vitro bacterial reverse mutation Ames test, mammalian cell chromosome aberration cytogenetic assay and an in vivo micronucleus test. RESULTS: Oral administration of C2E2 significantly increased (241)Am elimination over untreated controls and significantly reduced the retention of (241)Am in tissues, especially liver, kidney, lung and bone. Daily dosing of 200 mg/kg/day for 10 days was well tolerated in dogs. C2E2 was found to be neither mutagenic or clastogenic. CONCLUSIONS: The di-ethyl ester of DTPA (C2E2) was shown to effectively enhance the elimination of (241)Am after oral administration in a dog inhalation-contamination model and was well tolerated in toxicity studies. PMID- 25912345 TI - Immunosuppressive activity of pogostone on T cells: Blocking proliferation via S phase arrest. AB - Pogostone (PO) is one of the major chemical constituents of the essential oil of Pogostemon cablin (Blanco) Benth. In the present study, the effect of PO on T cell responsiveness was investigated to explore its potential in immunosuppression by a Concanavalin A (ConA)-stimulation model using splenocytes isolated from C57BL/6 mice. Cytotoxicity by PO on normal splenocytes was evaluated by MTS assays. Characteristics of apoptosis, proliferation, and cell cycle were analyzed by flow cytometry. Related expressions of cyclins and cyclin dependent kinases (CDKs) were also determined by flow cytometry. Inflammatory cytokine profiling was performed emplying cytometric beads assays (CBA). Moreover, the T cell-mediated delayed Type hepersensity (DTH) model was applied to evaluate the immunosuppressive activity of PO. Neither viability reduction in normal splenocytes nor apoptosis in ConA-stimulated splenocytes was observed under PO treatments. Meanwhile, PO remarkably reduced the total population of ConA-stimulated T cell, blocked T cell proliferation induced by Con A, and inhibited the production of IFN-gamma and IL-10. This blockade of stimulated T cell proliferation by PO was likely attributed to down-regulation of cyclin E, cyclin B and CDK1 and the subsequent S-phase arrest. Additionally, PO could inhibit the DTH reaction by alleviating ear swelling and inflammatory infiltrations in the DNCB-challenged ear. Taken together, PO exhibited an immunosuppressive property by directly blocking T cell proliferation as well as altering inflammatory cytokine profile, suggesting that PO may have clinical implications for treating autoimmune diseases and other immune-based disorders. PMID- 25912346 TI - Maternal bacterial infections impact expression of drug transporters in human placenta. AB - BACKGROUND: Several efflux and uptake transporters in the placenta are involved in the transmembrane transport of endogenous substrates and xenobiotics. Their expression and function may be altered in maternal complications associated with inflammation. Our objective was to examine the effect of chorioamnionitis, a bacterial intra-amniotic infection on the expression of clinically important transporters in human placenta. METHODS: Human placental samples were collected from preterm and term pregnancies diagnosed with chorioamnionitis infection and were gestational age-matched with samples from pregnancies with no obstetric complications, using predefined exclusion criteria. Transporter protein expression was quantified using Western blots while cytokine and transporter mRNA expression was measured via real-time polymerase chain reaction. RESULTS: mRNA levels of pro-inflammatory cytokines IL-6, IL-1beta and TNF-alpha were markedly elevated by 2.5- to 3-fold in preterm placentas with infection, relative to preterm controls (p<0.05). Expression of ABCG2 and SLCO2B1 was downregulated by 48 to 57% (p<0.05) in placentas from women with infection and preterm parturition, relative to preterm healthy controls. Protein and mRNA expression changes were generally consistent. At term, ABCG2 mRNA and SLCO2B1 protein expression levels were significantly downregulated, relative to controls. Significant changes in ABCB1 and SLCO4A1 expression were not observed, however ABCB1 transcript levels strongly correlated with IL-6, IL-1beta and TNF-alpha expression (p<0.001), potentially suggesting involvement of cytokine-mediated regulation. CONCLUSIONS: Collectively, these data show that maternal infections impact the expression of key drug transporters in placenta, suggesting that materno-fetal drug transport may be altered by changes in placental expression of ABC and OATP transporters. PMID- 25912347 TI - An informationally structured room for robotic assistance. AB - The application of assistive technologies for elderly people is one of the most promising and interesting scenarios for intelligent technologies in the present and near future. Moreover, the improvement of the quality of life for the elderly is one of the first priorities in modern countries and societies. In this work, we present an informationally structured room that is aimed at supporting the daily life activities of elderly people. This room integrates different sensor modalities in a natural and non-invasive way inside the environment. The information gathered by the sensors is processed and sent to a centralized management system, which makes it available to a service robot assisting the people. One important restriction of our intelligent room is reducing as much as possible any interference with daily activities. Finally, this paper presents several experiments and situations using our intelligent environment in cooperation with our service robot. PMID- 25912349 TI - Design and Field Test of a WSN Platform Prototype for Long-Term Environmental Monitoring. AB - Long-term wildfire monitoring using distributed in situ temperature sensors is an accurate, yet demanding environmental monitoring application, which requires long life, low-maintenance, low-cost sensors and a simple, fast, error-proof deployment procedure. We present in this paper the most important design considerations and optimizations of all elements of a low-cost WSN platform prototype for long-term, low-maintenance pervasive wildfire monitoring, its preparation for a nearly three-month field test, the analysis of the causes of failure during the test and the lessons learned for platform improvement. The main components of the total cost of the platform (nodes, deployment and maintenance) are carefully analyzed and optimized for this application. The gateways are designed to operate with resources that are generally used for sensor nodes, while the requirements and cost of the sensor nodes are significantly lower. We define and test in simulation and in the field experiment a simple, but effective communication protocol for this application. It helps to lower the cost of the nodes and field deployment procedure, while extending the theoretical lifetime of the sensor nodes to over 16 years on a single 1 Ah lithium battery. PMID- 25912348 TI - Stability of the nine sky quality meters in the Dutch night sky brightness monitoring network. AB - In the context of monitoring abundance of artificial light at night, the year-to year stability of Sky Quality Meters (SQMs) is investigated by analysing intercalibrations derived from two measurement campaigns that were held in 2011 and 2012. An intercalibration comprises a light sensitivity factor and an offset for each SQM. The campaigns were concerned with monitoring measurements, each lasting one month. Nine SQMs, together forming the Night Sky Brightness Monitoring network (MHN) in The Netherlands, were involved in both campaigns. The stability of the intercalibration of these instruments leads to a year-to-year uncertainty (standard deviation) of 5% in the measured median luminance occurring at the MHN monitoring locations. For the 10-percentiles and 90-percentiles, we find 8% and 4%, respectively. This means that, for urban and industrial areas, changes in the sky brightness larger than 5% become detectable. Rural and nature areas require an 8%-9% change of the median luminance to be detectable. The light sensitivety agrees within 8% for the whole group of SQMs. PMID- 25912350 TI - A Novel Identification Methodology for the Coordinate Relationship between a 3D Vision System and a Legged Robot. AB - Coordinate identification between vision systems and robots is quite a challenging issue in the field of intelligent robotic applications, involving steps such as perceiving the immediate environment, building the terrain map and planning the locomotion automatically. It is now well established that current identification methods have non-negligible limitations such as a difficult feature matching, the requirement of external tools and the intervention of multiple people. In this paper, we propose a novel methodology to identify the geometric parameters of 3D vision systems mounted on robots without involving other people or additional equipment. In particular, our method focuses on legged robots which have complex body structures and excellent locomotion ability compared to their wheeled/tracked counterparts. The parameters can be identified only by moving robots on a relatively flat ground. Concretely, an estimation approach is provided to calculate the ground plane. In addition, the relationship between the robot and the ground is modeled. The parameters are obtained by formulating the identification problem as an optimization problem. The methodology is integrated on a legged robot called "Octopus", which can traverse through rough terrains with high stability after obtaining the identification parameters of its mounted vision system using the proposed method. Diverse experiments in different environments demonstrate our novel method is accurate and robust. PMID- 25912351 TI - Heat transfer and friction characteristics of the microfluidic heat sink with variously-shaped ribs for chip cooling. AB - This paper experimentally and numerically investigated the heat transfer and friction characteristics of microfluidic heat sinks with variously-shaped micro ribs, i.e., rectangular, triangular and semicircular ribs. The micro-ribs were fabricated on the sidewalls of microfluidic channels by a surface-micromachining micro-electro-mechanical system (MEMS) process and used as turbulators to improve the heat transfer rate of the microfluidic heat sink. The results indicate that the utilizing of micro-ribs provides a better heat transfer rate, but also increases the pressure drop penalty for microchannels. Furthermore, the heat transfer and friction characteristics of the microchannels are strongly affected by the rib shape. In comparison, the triangular ribbed microchannel possesses the highest Nusselt number and friction factor among the three rib types. PMID- 25912352 TI - A Study of a QCM Sensor Based on TiO2 Nanostructures for the Detection of NO2 and Explosives Vapours in Air. AB - The paper deals with investigations concerning the construction of sensors based on a quartz crystal microbalance (QCM) containing a TiO2 nanostructures sensor layer. A chemical method of synthesizing these nanostructures is presented. The prepared prototype of the QCM sensing system, as well as the results of tests for detecting low NO2 concentrations in an atmosphere of synthetic air have been described. The constructed NO2 sensors operate at room temperature, which is a great advantage, because resistance sensors based on wide gap semiconductors often require much higher operation temperatures, sometimes as high as 500 degrees C. The sensors constructed by the authors can be used, among other applications, in medical and chemical diagnostics, and also for the purpose of detecting explosive vapours. Reactions of the sensor to nitroglycerine vapours are presented as an example of its application. The influence of humidity on the operation of the sensor was studied. PMID- 25912353 TI - Immunity to Laser Power Variation in a DFB Diode Laser Based Optical Gas Sensor Using a Division Process. AB - The division process used in a DFB diode laser-based optical gas sensor was studied to improve the immunity to laser power variation. Residual amplitude modulation (RAM) in wavelength modulation spectroscopy (WMS) detection was eliminated by intensity normalization using a division process. As a result the detected harmonic signals showed a significant improvement in line shape. For the first harmonic (1f) signal, Bias was improved from 38.7% to 1.2%; Baseline Difference was improved from 2.7% to 0.69% and Asymmetry was improved from 15.4% to 0.22%. For the second harmonic (2f) signal, the Asymmetry Coefficient was improved from 103% to 5.1%. Moreover the division process can further suppress the influence of unstable laser power. As a result, for the 1f signal, stable detection with a variation coefficient of 0.59% was obtained over a wide dynamic range (0.38-8.1 mW). For the 2f signal, stable detection with a variation coefficient of 0.53% was obtained from 0.64 mW to 8.27 mW. The test results showed a good agreement with the theoretical analysis and the proposed method has considerable potential application in gas sensing. PMID- 25912354 TI - Enhanced Sensitivity of Gas Sensor Based on Poly(3-hexylthiophene) Thin-Film Transistors for Disease Diagnosis and Environment Monitoring. AB - Electronic devices based on organic thin-film transistors (OTFT) have the potential to supply the demand for portable and low-cost gadgets, mainly as sensors for in situ disease diagnosis and environment monitoring. For that reason, poly(3-hexylthiophene) (P3HT) as the active layer in the widely-used bottom-gate/bottom-contact OTFT structure was deposited over highly-doped silicon substrates covered with thermally-grown oxide to detect vapor-phase compounds. A ten-fold organochloride and ammonia sensitivity compared to bare sensors corroborated the application of this semiconducting polymer in sensors. Furthermore, P3HT TFTs presented approximately three-order higher normalized sensitivity than any chemical sensor addressed herein. The results demonstrate that while TFTs respond linearly at the lowest concentration values herein, chemical sensors present such an operating regime mostly above 2000 ppm. Simultaneous alteration of charge carrier mobility and threshold voltage is responsible for pushing the detection limit down to units of ppm of ammonia, as well as tens of ppm of alcohol or ketones. Nevertheless, P3HT transistors and chemical sensors could compose an electronic nose operated at room temperature for a wide range concentration evaluation (1-10,000 ppm) of gaseous analytes. Targeted analytes include not only biomarkers for diseases, such as uremia, cirrhosis, lung cancer and diabetes, but also gases for environment monitoring in food, cosmetic and microelectronics industries. PMID- 25912355 TI - Evolution of akirin family in gene and genome levels and coexpressed patterns among family members and rel gene in croaker. AB - Akirins, which are highly conserved nuclear proteins, are present throughout the metazoan and regulate innate immunity, embryogenesis, myogenesis, and carcinogenesis. This study reports all akirin genes from miiuy croaker and analyzes comprehensively the akirin gene family combined with akirin genes from other species. A second nuclear localization signal (NLS) is observed in akirin2 homologues, which is not in akirin1 homologues in all teleosts and most other vertebrates. Thus, we deduced that the loss of second NLS in akirin1 homologues in teleosts likely occurred in an ancestor to all Osteichthyes after splitting with cartilaginous fish. Significantly, the akirin2(2) gene included six exons interrupted by five introns in the miiuy croaker, which may be caused by the intron insertion event as a novel evidence for the variation of akirin gene structure in some species. In addition, comparison of the genomic neighborhood genes of akirin1, akirin2(1), and akirin2(2) demonstrates a strong level of conserved synteny across the teleost classes, which further proved the deduction of Macqueen and Johnston 2009 that the produce of akirin paralogues can be attributed to whole-genome duplications and the loss of some akirin paralogues after genome duplications. Furthermore, akirin gene family members and relish gene are ubiquitously expressed across all tissues, and their expression levels are increased in three immune tissues after infection with Vibrio anguillarum. Combined with the expression patterns of LEAP-1 and LEAP-2 from miiuy croaker, an intricate network of co-regulation among family members is established. Thus, it is further proved that akirins acted in concert with the relish protein to induce the expression of a subset of downstream pathway elements in the NF-kB dependent signaling pathway. PMID- 25912356 TI - Comparative analysis of two types of CXCL8 from Japanese flounder (Paralichthys olivaceus). AB - A new type of CXCL8, named CXCL8_L1b, was identified in this research. Comparison of amino acid sequences of Japanese flounder CXCL8_L1b and CXCL8_L1a (BAB86884.1) showed only 41.2% identity. Transcripts of CXCL8_L1a were highly detected in spleen, kidney, gill and liver, while transcripts of CXCL8_L1b only were detected highly in spleen and kidney of apparently healthy fish. In fish challenged with E. tarda, transcripts of CXCL8_L1a were significantly increased at day 6, while no significant increase was detected in the mRNA level of CXCL8_L1b. On the other hand, fish infected by S. iniae significantly increased both transcripts of CXCL8_L1a and CXCL8_L1b at days 1 and 3. In VHSV-infected fish, only the transcripts of CXCL8_L1b were significantly induced at day 6. LPS and poly I:C stimulation of PBLs induced a high level of CXCL8_L1a transcripts, while CXCL8_L1b transcripts were significantly increased only post poly I:C treatment. To evaluate the chemotactic activity of CXCL8_L1a and CXCL8_L1b, Japanese flounder were intramuscularly injected with recombinant plasmids pCI-CXCL8_L1a and pCI-CXCL8_L1b. H & E staining showed that injections of both pCI-CXCL8_L1a and pCI-CXCL8_L1b caused strong immune responses in the form of intermuscular cell infiltration and capillary congestion. Injection of pCI-CXCL8_L1a and pCI CXCL8_L1b significantly induced the expressions of genes related to inflammatory response such as IL-6 and CD8alpha on day 1 post-injection. The transcripts of IgM only significantly increased on day 7 post-injection of pCI-CXCL8_L1b. PMID- 25912357 TI - The c-Fos and c-Jun from Litopenaeus vannamei play opposite roles in Vibrio parahaemolyticus and white spot syndrome virus infection. AB - Growing evidence indicates that activator protein-1 (AP-1) plays a major role in stimulating the transcription of immune effector molecules in cellular response to an incredible array of stimuli, including growth factors, cytokines, cellular stresses and bacterial and viral infection. Here, we reported the isolation and characterization of a cDNA from Litopenaeus vannamei encoding the full-length c Fos protein (named as Lvc-Fos). The predicted amino acid sequences of Lvc-Fos contained a basic-leucine zipper (bZIP) domain, which was characteristic of members of the AP-1 family. Immunoprecipitation and native-PAGE assays determined that Lvc-Fos could interact with the Lvc-Jun, a homolog of c-Jun family in L. vannamei, in a heterodimer manner. Further investigation demonstrated that Lvc Fos and Lvc-Jun were expressed in all tested tissues and located in the nucleus. Real-time RT-PCR analysis showed both Lvc-Fos and Lvc-Jun in gills were up regulated during Vibrio parahaemolyticus and white spot syndrome virus (WSSV) challenges. In addition, reporter gene assays indicated Lvc-Fos and Lvc-Jun could activate the expression of antimicrobial peptides (AMPs) of Drosophila and shrimp, as well as WSSV immediate early (IE) genes wsv069 and wsv249, in a different manner. Knockdown of Lvc-Fos or Lvc-Jun by RNA interference (RNAi) resulted in higher mortalities of L. vannamei after infection with V. parahaemolyticus, suggesting that Lvc-Fos and Lvc-Jun might play protective roles in bacterial infection. However, silencing of Lvc-Fos or Lvc-Jun in shrimp caused lower mortalities and virus loads under WSSV infection, suggesting that Lvc-Fos and Lvc-Jun could be engaged for WSSV replication and pathogenesis. In conclusion, our results provided experimental evidence and novel insight into the roles of L. vannamei AP-1 in bacterial and viral infection. PMID- 25912358 TI - CpG ODNs induced autophagy via reactive oxygen species (ROS) in Chinese mitten crab, Eriocheir sinensis. AB - Autophagy is a highly conserved intracellular homeostatic process involved in numerous responses in both vertebrate and invertebrate. In the present study, autophagy in hemocytes of Chinese mitten crab Eriocheir sinensis was observed by Western-blot and immunofluorescence assay, and its induction by CpG oligodeoxynucleotides (ODNs) was investigated. The increase of LC3-conversion (LC3-II/LC3-I) and LC3-puncta formation were observed in hemocytes of crabs after rapamycin injection. And the ratio of LC3-conversion and the percentage of LC3 puncta formation were also significantly increased after CpG ODNs stimulation, and the highest values were 1.89-fold and 3.77-fold compared to that in pUC57 group at 24 h post-injection. Moreover, the mRNA expression levels of autophagy related genes, EsGabarap and EsAtg7, both dramatically increased after CpG ODNs injection, and reached the peak at 6 h post-injection, which were 2.66- and 2.82 fold (P <0.01) for EsGabarap, and 6.16-fold and 6.10-fold (P <0.01) for EsAtg7 compared to saline and pUC57 groups, respectively. The generation of ROS in hemocytes was induced and reached peak at 6 h post-injection in CpG-pUC57 group, which was 1.30-fold (P <0.01) and 1.66-fold (P <0.01) of that in saline and pUC57 group, respectively. The increased ROS generation and autophagy triggered by CpG ODNs were abolished after the treatment of the ROS scavenger, N-acetyl-L-cysteine (NAC). It was suggested that CpG ODNs could induce autophagy and up-regulate the expression levels of autophagy-related genes in crabs via the activation of ROS generation in the hemocytes. The results provided useful information to understand autophagy in crab, and they were also helpful for the application of CpG ODNs as the novel immune stimulants in aquaculture. PMID- 25912359 TI - Molecular cloning, expression and functional characterization of a teleostan cytokine-induced apoptosis inhibitor from rock bream (Oplegnathus fasciatus). AB - Apoptosis plays a key role in the physiology of multicellular organisms and is regulated by different promoting and inhibitory mechanisms. Cytokine-induced apoptotic inhibitor (CIAPI) was recently identified as a key factor involved in apoptosis inhibition in higher vertebrate lineages. However, most of the CIAPIs of lower vertebrate species are yet to be characterized. Herein, we molecularly characterized a teleostan counterpart of CIAPI from rock bream (Oplegnathus fasciatus), designating as RbCIAPI. The complete coding region of RbCIAPI was consisted of 942 nucleotides encoding a protein of 313 amino acids with a predicted molecular mass of ~33 kDa. RbCIAPI gene exhibited a multi-exonic architecture, consisting 9 exons interrupted by 8 introns. Protein sequence analysis revealed that RbCIAPI shares significant homology with known CIAPI counterparts, and phylogenetic reconstruction confirmed its closer evolutionary relationship with its fish counterparts. Ubiquitous spatial distribution of RbCIAPI was detected in our quantitative real time polymerase chain reaction (qPCR) analysis, where more prominent expression levels were observed in the blood and liver tissues. Moreover, the RbCIAPI basal transcription level was found to be modulated by different bacterial and viral stimuli, which could be plausibly supported by our previous observations on the transcriptional modulation of the caspase 3 counterpart of rock bream (Rbcasp3) in response to the same stimuli. In addition, our in vitro functional assay demonstrated that recombinant RbCIAPI could detectably inhibit the proteolysis activity of recombinant Rbcasp3. Collectively, our preliminary results suggest that RbCIAPI may play an anti-apoptotic role in rock bream physiology, likely by inhibiting the caspase-dependent apoptosis pathway. Therefore, RbCIAPI potentially plays an important role in host immunity by regulating the apoptosis process under pathogenic stress. PMID- 25912360 TI - Re: CEA-2015-0096-CR-AJW, Th17 polarization and upper airways: new insights: Clinical relevance of Th17 response in allergic rhinitis: more evidence. PMID- 25912361 TI - Muscle Articulations: Flexible Jaw Joints Made of Soft Tissues. AB - This study surveys animals that use soft tissues rather than rigid links to build jaw joints. Hard biting elements are useful; they are used in piercing or shearing during feeding and interactive behaviors and can directly impact survival and reproduction. The best understood biting systems include biting elements that are mounted on rigid jaw links that form a joint capable of transmitting the bite reaction forces. As such, jaws must incorporate joints that resist compression. Many jaw joints are "sliding joints", in which jaw links come into direct contact and the shape of the sliding contact surfaces dictates possible motions. There are, however, organisms that have biting elements on jaws that are made of flexible muscle and connective tissues. If arranged as a muscular hydrostat, in which multiple orientations of the muscle fibers may co contract to provide turgid skeletal support, the multifunctional joint not only (a) provides the force to move the biting elements, but also (b) creates repositionable pivots and (c) transmits bite reaction forces. Such flexible joints, termed "muscle articulations", may be important to a number of soft bodied animals. In this survey, we review the function of previously described muscle articulations: the joints found between inarticulate brachiopods' valves, cephalopods' beaks, the hooks of kalyptorhynch flatworms, and errant polychaetes' jaws. We also review the morphology, physiology, and feeding behaviors of the hagfish as a putative muscle articulation in an effort to understand how this jawless craniate is capable of biting with surprising force, seemingly without the benefit of any obvious method of opposing the force of the dental plate that is used to remove portions of food. Initial analysis suggests that a muscle articulation may be a key feature in coordinating head and body movements to provide the leverage needed for strong "bites". PMID- 25912362 TI - Do Species Exist in Asexuals? Theory and Evidence from Bdelloid Rotifers. AB - The possibility for independently evolving entities to form and persist in the absence of sexual recombination in eukaryotes has been questioned; nevertheless, there are organisms that are known to be asexual and that have apparently diversified into multiple species as recognized by taxonomists. These organisms have therefore been identified as an evolutionary paradox. We explore three alternative hypotheses attempting to solve the apparent paradox, focusing on bdelloid rotifers, the most studied group of organisms in which all species are considered asexual: (1) they may have some hidden form of sex; (2) species do not represent biological entities but simply convenient names; and (3) sex may not be a necessary requirement for speciation. We provide ample evidence against the first two hypotheses, reporting several studies supporting (1) bdelloids asexuality from different approaches, and (2) the existence of species from genetics, jaw morphology, ecology, and physiology. Thus, we (3) explore the role of sex in speciation comparing bdelloid and monogonont rotifers, and conclude with some caveats that could still change our understanding of bdelloid species. PMID- 25912363 TI - Effects of loss of residual hearing on speech performance with the CI422 and the Hybrid-L electrode. AB - OBJECTIVE: Preservation of residual low-frequency hearing has become a priority in cochlear implantation. The purpose of this study was to compare rates of hearing preservation and effects on performance of loss of low-frequency acoustic hearing with two different length electrodes. STUDY DESIGN: Retrospective chart review. SETTING: Tertiary Care Hospital. PATIENTS: Twelve patients were implanted with the CI422 a slim-straight electrode; the second group consisted of 10 patients implanted with the Hybrid-L, a shorter hearing preservation electrode. MAIN OUTCOME MEASURE: Audiometric thresholds and speech perception measures. RESULTS: At 1 year, 3/10 (30%) patients with the Hybrid-L and 7/12 (58%) patients with the CI422 lost residual acoustic hearing resulting in a profound hearing loss in the implanted ear. In comparing these patients in particular, mean CNC words in the implanted ear were 72% in the CI422 electrode group and 15% in the Hybrid-L electrode group at 1 year (P = 0.03). While hearing preservation rates with the Hybrid-L tended to be better, among recipients who lost residual hearing, speech perception was better in those with the longer CI422 electrode. CONCLUSIONS: With emphasis on preservation of residual hearing, patients need to be counseled regarding possible outcomes and options should loss of residual hearing occur following implantation. While shorter electrodes may have better rates of hearing preservation, the patients with the longer straight electrode in our study had significantly better speech understanding following the loss of residual hearing. PMID- 25912364 TI - Bestrophin-3 is differently expressed in normal and injured mouse glomerular podocytes. AB - AIM: Bestrophins are putative calcium-activated chloride channels. Recently, cell protective functions for Bestrophin-3 (Best3) were proposed. Best3 exists in different splice variants. We have here examined expression, alternative splicing and localization of Best3 in mouse podocytes under normal conditions and during endoplasmic reticulum (ER) stress. METHODS: Best3 expression was determined on the mRNA level using quantitative PCR and on the protein level by immunohistochemistry and Western blotting. RESULTS: Staining for Best3 was pronounced in glomeruli and was detected in cultured mouse podocytes. Best3 did not co-localize with markers for endothelial cells (CD31), podocyte foot processes (synaptopodin) or microtubules (actin). However, immunogold-based electron microscopy and co-localization with nestin showed Best3 presence in podocyte primary processes and cell bodies. Only two splice variants of Best3 mRNA (both lacking exons 2 and 3, and one also lacking exon 6), but no full length variant, were detected. ER stress induced by lipopolysaccharides in vivo transiently elevated mRNA levels of total Best3 and its two splice variants with different time courses. In cultured podocytes under ER stress induced by thapsigargin, the expression of total Best3, its splice variants and nestin transiently increased with similar time courses. The ER stress marker C/EBP homologous protein (CHOP) and nestin mRNA increased during ER stress in vivo and in vitro. CONCLUSIONS: Best3 is localized intracellularly in cell bodies and primary processes of mouse podocytes and is co-localized with nestin. Two splice variants of Best3 are expressed in glomeruli and in cultured podocytes, and their expression is differentially regulated in ER stress. PMID- 25912365 TI - Evaluation of the educational climate for specialty trainees in dermatology. AB - BACKGROUND: Dermatology specialty trainees (STs) in the United Kingdom (UK) are few in number and will join a thinly spread national consultant body. It is of paramount importance to deliver training programmes of the highest quality for these doctors, central to which is the establishment and maintenance of an educational climate conducive to learning. OBJECTIVE: To conduct a pilot study to evaluate the educational climate for dermatology STs in one UK deanery (West Midlands). METHODS: Secondary analysis of published data was performed, from the UK's General Medical Council (GMC) national training survey, and the Job Evaluation Survey Tool (JEST) administered by the West Midlands deanery. A modified online version of the Postgraduate Hospital Educational Environment Measure (PHEEM) was circulated among dermatology STs. RESULTS: The GMC's survey data show that UK dermatology STs rated their training highly in comparison with undifferentiated UK postgraduate trainees. West Midlands dermatology STs (n = 22) scored very similarly to UK dermatology STs. The JEST gave broadly encouraging results, with 21/22 (95%) happy to recommend their posts to colleagues. The modified PHEEM yielded a global mean score of 96.5/152, attracting the descriptor 'more positive than negative but room for improvement'. CONCLUSION: Despite inherent methodological limitations, the GMC, JEST and modified PHEEM surveys have revealed useful comparative triangulated data which allows the conclusion that West Midlands dermatology STs seem to be training in a favourable educational climate. This represents an important facet of the quality assurance process for medical education, and allows insight into areas which may require improvement. PMID- 25912366 TI - Initial UK Experience of Stereotactic Body Radiotherapy for Extracranial Oligometastases: Can We Change the Therapeutic Paradigm? AB - AIMS: To retrospectively review the toxicity and early outcome data from patients who have received stereotactic body radiotherapy (SBRT) for extracranial oligometastases at a single UK institution. MATERIALS AND METHODS: Eligible patients had <=3 extracranial metastases and performance status <=2. Prior systemic therapy and radical treatment of oligometastastic relapse with any standard treatment modality was permitted. Patients with synchronous metastatic disease were excluded unless they had evidence of controlled primary disease after radical therapy. Follow-up consisted of clinical examination, biochemical and radiological assessments in accordance with standard clinical care. Progression events were defined using RECIST. Toxicity was evaluated using CTCAE v4.0. Local control, progression-free survival (PFS), freedom from widespread distant metastasis (defined as disease not amenable to further radical salvage therapy) and overall survival were calculated. RESULTS: Between July 2011 and April 2014, 73 patients with 87 metastases received SBRT (range 1-3 per patient). The median follow-up was 14.5 months (range 0-26.4). The median PFS was 14.5 months (1 year PFS 57%, 2 year 28%); 1 year overall survival 96%, 2 year 79.8%; 2 year local control 88%. At 2 years, 46% of patients were free from widespread distant metastases. No >= grade 3 acute or late toxicity was observed. CONCLUSION: At this time point, observed toxicity is minimal with excellent local control rates. This promising treatment paradigm requires further investigation in the context of a randomised controlled trial to establish if the addition of SBRT to standard care improves survival outcomes. PMID- 25912367 TI - The olfactory bulb volume in patients with idiopathic Parkinson's disease. AB - BACKGROUND AND PURPOSE: This study addresses the question of whether the neuropathological findings on the olfactory bulb (OB) in idiopathic Parkinson's disease (IPD) correspond to a detectable change in volume of the OB. Additionally, the relationship between OB volume and residual olfactory function, clinical disease characteristics and age are investigated. METHODS: Fifty-two IPD patients were investigated and compared to 31 healthy age-matched controls. All participants were scanned using a 3 T magnetic resonance imaging MRI scanner including a T2 DRIVE sequence in coronal slices through the OB. The OB volumes were measured via manual segmentation of the OB. Olfactory testing was carried out using the Sniffin' Sticks test battery. RESULTS: The OB volume in the IPD group was 42.1 mm3 (SD +/- 11.6) for the right and 41.5 mm3 (SD +/- 11.7) for the left OB and showed no difference from the controls. Additionally, there were no significant correlations between OB volume and disease characteristics such as disease duration or Unified Parkinson's Disease Rating Scale motor score. Likewise, patients' residual smell function did not correlate with their OB volume. In contrast, controls indicated a correlation between smell function and OB volume. CONCLUSION: The study shows that high resolution MRI does not show a detectable volume loss of the OB in PD patients. It is concluded that OB measurement using in vivo high resolution MRI at 3 T is not helpful to identify IPD. PMID- 25912368 TI - Prognostic and predictive value of epigenetic biomarkers and clinical factors in upper tract urothelial carcinoma. AB - AIM: We conducted this study to identify gene promoter methylation status and clinical predictors for upper tract urothelial carcinoma (UTUC) patients. MATERIALS & METHODS: Using methylation-sensitive PCR, we examined ten genes promoter methylation status in 687 UTUC patients. RESULTS: A methylated promoter of three genes to predict higher tumor stage (T3 and T4), five genes to predict higher tumor grade (G3) and one gene to predict pN+ were certified in this study. Nine factors were significantly associated with poor cancer-specific survival. Six factors were considered as predictors to develop bladder recurrence after surgery. CONCLUSION: Methylation occurs commonly in UTUCs, may affect carcinogenic mechanisms, and is a well predictive factor for cancer-specific survival and bladder recurrence in UTUCs. PMID- 25912369 TI - Immune response in pigs treated with therapeutic doses of enrofloxacin at the time of vaccination against Aujeszky's disease. AB - The effect of treatment with enrofloxacin was studied on the postvaccinal immune response in pigs. Forty pigs were used (control not vaccinated (C), control vaccinated (CV), vaccinated, received enrofloxacin (ENRO)). From day -1 to day 3 pigs from ENRO group received enrofloxacin at the recommended dose. Pigs from ENRO and CV groups were vaccinated twice against Aujeszky's disease virus (ADV). There was a significant delay in the production of humoral response of enrofloxacin dosed pigs when compared with CV group. Moreover, in ENRO group the significant decrease in IFN-gamma production and significantly lower values of stimulation index after ADV restimulation was noted, as compared with CV group. The secretion of IL-6, IL-10 and TNF-alpha by PBMC after recall stimulation was also affected in ENRO group. The results indicate that enrofloxacin, in addition to its antimicrobial properties, possess significant immunomodulatory effects and may alter the immune response to vaccines. PMID- 25912370 TI - Chondroitin Lyase from a Marine Arthrobacter sp. MAT3885 for the Production of Chondroitin Sulfate Disaccharides. AB - Chondroitin sulfate (CS) saccharides from cartilage tissues have potential application in medicine or as dietary supplements due to their therapeutic bioactivities. Studies have shown that depolymerized CS saccharides may display enhanced bioactivity. The objective of this study was to isolate a CS-degrading enzyme for an efficient production of CS oligo- or disaccharides. CS-degrading bacteria from marine environments were enriched using in situ artificial support colonization containing CS from shark cartilage as substrate. Subsequently, an Arthrobacter species (strain MAT3885) efficiently degrading CS was isolated from a CS enrichment culture. The genomic DNA from strain MAT3885 was pyro-sequenced by using the 454 FLX sequencing technology. Following assembly and annotation, an orf, annotated as family 8 polysaccharide lyase genes, was identified, encoding an amino acid sequence with a similarity to CS lyases according to NCBI blastX. The gene, designated choA1, was cloned in Escherichia coli and expressed downstream of and in frame with the E. coli malE gene for obtaining a high yield of soluble recombinant protein. Applying a dual-tag system (MalE-Smt3-ChoA1), the MalE domain was separated from ChoA1 with proteolytic cleavage using Ulp1 protease. ChoA1 was defined as an AC-type enzyme as it degraded chondroitin sulfate A, C, and hyaluronic acid. The optimum activity of the enzyme was at pH 5.5-7.5 and 40 degrees C, running a 10-min reaction. The native enzyme was estimated to be a monomer. As the recombinant chondroitin sulfate lyase (designated as ChoA1R) degraded chondroitin sulfate efficiently compared to a benchmark enzyme, it may be used for the production of chondroitin sulfate disaccharides for the food industry or health-promoting products. PMID- 25912371 TI - Molecular Cloning, Characterization, and Expression Analysis of a Prolyl 4 Hydroxylase from the Marine Sponge Chondrosia reniformis. AB - Prolyl 4-hydroxylase (P4H) catalyzes the hydroxylation of proline residues in collagen. P4H has two functional subunits, alpha and beta. Here, we report the cDNA cloning, characterization, and expression analysis of the alpha and beta subunits of the P4H derived from the marine sponge Chondrosia reniformis. The amino acid sequence of the alpha subunit is 533 residues long with an M r of 59.14 kDa, while the beta subunit counts 526 residues with an M r of 58.75 kDa. Phylogenetic analyses showed that alphaP4H and betaP4H are more related to the mammalian sequences than to known invertebrate P4Hs. Western blot analysis of sponge lysate protein cross-linking revealed a band of 240 kDa corresponding to an alpha2beta2 tetramer structure. This result suggests that P4H from marine sponges shares the same quaternary structure with vertebrate homologous enzymes. Gene expression analyses showed that alphaP4H transcript is higher in the choanosome than in the ectosome, while the study of factors affecting its expression in sponge fragmorphs revealed that soluble silicates had no effect on the alphaP4H levels, whereas ascorbic acid strongly upregulated the alphaP4H mRNA. Finally, treatment with two different tumor necrosis factor (TNF)-alpha inhibitors determined a significant downregulation of alphaP4H gene expression in fragmorphs demonstrating, for the first time in Porifera, a positive involvement of TNF in sponge matrix biosynthesis. The molecular characterization of P4H genes involved in collagen hydroxylation, including the mechanisms that regulate their expression, is a key step for future recombinant sponge collagen production and may be pivotal to understand pathological mechanisms related to extracellular matrix deposition in higher organisms. PMID- 25912372 TI - Human papillomavirus vaccination among adolescents in Georgia. AB - Human papillomavirus (HPV) vaccination coverage for adolescent females and males remains low in the United States. We conducted a 3-arm randomized controlled trial (RCT) conducted in middle and high schools in eastern Georgia from 2011 2013 to determine the effect of 2 educational interventions used to increase adolescent vaccination coverage for the 4 recommended adolescent vaccines: Tdap, MCV4, HPV and influenza. As part of this RCT, this article focuses on: 1) describing initiation and completion of HPV vaccine series among a diverse population of male and female adolescents; 2) assessing parental attitudes toward HPV vaccine; and 3) examining correlates of HPV vaccine series initiation and completion. Parental attitude score was the strongest predictor of HPV vaccine initiation among adolescents (adjusted odds ratio (aOR): 2.08; 95% confidence interval (CI): 1.80, 2.39). Other correlates that significantly predicted HPV series initiation were gender, study year, and intervention arm. Parental attitudes remained a significant predictor of receipt of 3 doses of HPV vaccine along with gender, race, school type and insurance type. This study demonstrates that positive parental attitudes are important predictors of HPV vaccination and critical to increasing coverage rates. Our findings suggest that more research is needed to understand how parental attitudes are developed and evolve over time. PMID- 25912373 TI - Genome-wide gene expression profiling of low-dose, long-term exposure of human osteosarcoma cells to bisphenol A and its analogs bisphenols AF and S. AB - The bisphenols AF (BPAF) and S (BPS) are structural analogs of the endocrine disruptor bisphenol A (BPA), and are used in common products as a replacement for BPA. To elucidate genome-wide gene expression responses, estrogen-dependent osteosarcoma cells were cultured with 10 nM BPA, BPAF, or BPS, for 8 h and 3 months. Genome-wide gene expression was analyzed using the Illumina Expression BeadChip. Three months exposure had significant effects on gene expression, particularly for BPS, followed by BPAF and BPA, according to the number of differentially expressed genes (1980, 778, 60, respectively), the magnitude of changes in gene expression, and the number of enriched biological processes (800, 415, 33, respectively) and pathways (77, 52, 6, respectively). 'Embryonic skeletal system development' was the most enriched bone-related process, which was affected only by BPAF and BPS. Interestingly, all three bisphenols showed highest down-regulation of genes related to the cardiovascular system (e.g., NPPB, NPR3, TXNIP). BPA only and BPA/BPAF/BPS also affected genes related to the immune system and fetal development, respectively. For BPAF and BPS, the 'isoprenoid biosynthetic process' was enriched (up-regulated genes: HMGCS1, PDSS1, ACAT2, RCE1, DHDDS). Compared to BPA, BPAF and BPS had more effects on gene expression after long-term exposure. These findings stress the need for careful toxicological characterization of BPA analogs in the future. PMID- 25912374 TI - Liver Injury in Psoriasis Patients Receiving Ustekinumab: A Retrospective Study of 44 Patients Treated in the Clinical Practice Setting. AB - INTRODUCTION: The therapy of patients with psoriasis and liver disease can be a challenge due to the increased risk of adverse effects from traditional systemic treatments; in addition, although the anti-tumor necrosis factor agents are considered safer, they have also been associated with drug-induced liver injury and reactivation of viral hepatitis. Ustekinumab has a different mechanism of action and the little that is known of its effects on the liver comes from pivotal studies. The objectives of this study were to estimate the incidence of drug-induced liver injury in patients treated with ustekinumab in daily clinical practice and to analyze liver alterations in those patients with pre-existing liver disease. METHOD: All patients treated with the standard regimen of ustekinumab were included in the study. Variables gathered included age, sex, type of psoriasis, nail involvement, arthritis, previous treatments, history of liver disease, viral serology, Psoriasis Area Severity Index (at baseline and at 12, 16, and 52 weeks), transaminase levels, manifestations of liver disease, liver ultrasound, and factors such as body mass index, alcohol consumption, and ferritin levels. RESULTS: Grade 1 elevation of the transaminases was only observed in 6 patients; no cases of severe hypertransaminasemia were observed. None of the patients with elevation of the transaminases at baseline developed problems during treatment. CONCLUSIONS: Ustekinumab-related liver injury is uncommon and mild. From a hepatic point of view, the drug appears safe, even in patients with pre-existing liver disease and those who have developed altered liver function previously with other drugs. PMID- 25912375 TI - Electrical and thermal transport properties of Pb(1-x)Sn(x)Se solid solution thermoelectric materials. AB - Both lead selenide (PbSe) and tin selenide (SnSe) are promising thermoelectric compounds consisting of earth-abundant elements, between which solid solutions can be formed over a wide composition range. This study investigated the electrical and thermal transport properties of n-type Pb1-xSnxSe (x = 0, 0.01, 0.05, 0.1 and 0.15) solid solutions with emphasis on the effect of Sn substitution. Small amounts of Sn substitution (x <= 0.1) increased electrical conductivity but showed less influence on the Seebeck coefficient, leading to improved power factors, which were revealed to be associated with the generation of native Se vacancies. The electrical conductivity tended to decrease when x > 0.1 due to the alloying effect, consequently the thermoelectric figure of merit was not further increased, even though the thermal conductivity can be reduced by increasing Sn content. A maximum dimensionless figure of merit ZT of up to 1.0 was obtained at moderate temperature (773 K) for the composition of Pb0.9Sn0.1Se. PMID- 25912376 TI - Psychotic experiences are linked to cannabis use in adolescents in the community because of common underlying environmental risk factors. AB - Cannabis users are more likely to have psychotic experiences (PEs). The degree to which these associations are driven by genetic or environmental influences in adolescence is unknown. This study estimated the genetic and environmental contributions to the relationship between cannabis use and PEs. Specific PEs were measured in a community-based twin sample (4830 16-year-old pairs) using self reports and parent-reports. Adolescents reported on ever using cannabis. Multivariate liability threshold structural equation model-fitting was conducted. Cannabis use was significantly correlated with PEs. Modest heritability (37%), common environmental influences (55%) and unique environment (8%) were found for cannabis use. For PEs, modest heritability (27-54%), unique environmental influences (E=12-50%) and little common environmental influences (11-20%), with the exception of parent-rated Negative Symptoms (42%), were reported. Environmental influences explained all of the covariation between cannabis use and paranoia, cognitive disorganization and parent-rated negative symptoms (bivariate common environment=69-100%, bivariate unique environment=28-31%), whilst the relationship between cannabis use and hallucinations indicated familial influences. Cannabis use explains 2-5% of variance in positive, cognitive, and negative PEs. Cannabis use and psychotic experience co-occur due to environmental factors. Focus on specific environments may reveal why adolescent cannabis use and psychotic experiences tend to 'travel together'. PMID- 25912377 TI - Geographical and longitudinal analysis of Listeria monocytogenes genetic diversity reveals its correlation with virulence and unique evolution. AB - Listeria monocytogenes is one of the most important foodborne pathogens causing severe diseases with a mortality rate of 24%. However, the genetic diversity and evolution of L. monocytogenes, particularly at the worldwide level, are poorly defined. In this study, we performed multilocus sequence typing (MLST) and multi virulence locus sequence typing (MVLST) for 86 L. monocytogenes strains derived from 8 countries from 1926 to 2012 in order to better understand the molecular evolution and genetic characteristics of this pathogen. A total of 13 clonal complexes (CCs) were detected, of which CC1, CC2, CC3, CC7, CC9, CC4 are the most prevalent. Notably, polymorphism of housekeeping genes of isolates belong to CC1 (STs = 47) increased more rapidly over the time. MLST-based phylogenetic analysis showed that serotype 1/2b and 4b strains had an "interval-type" evolution pattern, while serotype 1/2a and 1/2c strains had a "progressive-type" evolution pattern. Furthermore, strains from temporally and geographically unrelated outbreaks in different countries were clustered in the same subgroup of phylogenetic tree, indicating that that L. monocytogenes developed highly similar virulence genes and genetic characteristics to adaptation in a special ecological niche. Interestingly, there was a high correlation between the population structure of MVLST and MLST among the isolates of cluster IA corresponding to CC1, CC2, CC4 and CC6 that had the highest potential to cause listeriosis outbreaks, strengthening that surveillance of these CCs is important for prevention of listeriosis. The present study offers insights into the internal relationships between the population structure, distribution and pathogenicity of L. monocytogenes. PMID- 25912378 TI - Smoking, alcohol use, socioeconomic background and oral health among young Finnish adults. AB - OBJECTIVES: The aim of this study was to investigate the prevalence of smoking and alcohol use in association with dental caries experience and signs of periodontal disease in a Finnish male group born in the early 1990s. The impacts of health behaviour and socioeconomic factors were included in the analyses. METHODS: Oral health of 8539 conscripts was screened in a cross-sectional study (DT, DMFT and CPI). They also answered a questionnaire covering their habits of smoking and alcohol use as well as other behaviours and background factors. The bleeding on probing index (BOP) was available on 6529 conscripts. Cross tabulation together with a chi-squared test and generalized linear mixed models were used in the analyses. A mosaic figure was used to illustrate associations of smoking frequency, use of dental services and toothache. RESULTS: Majority (80.9%) in the study group consumed alcohol at least once a month, and 39.4% were daily smokers. Smoking was statistically significantly associated with high caries experience and high bleeding values of gums. Consumption of alcohol was not associated with dental caries and periodontal disease. The high BOP value had the strongest association with infrequent tooth brushing and smoking. The participant's own education level was the main protective factor of oral health. The smokers used dental services more frequently compared to the non-smokers mostly for acute care. CONCLUSIONS: Young men's health behaviour, especially of those with low education, does not promote oral health, which may indicate need for extensive healthcare services in the future. Health promotion should not be neglected. PMID- 25912379 TI - Analysis of circulating plasmacytoid dendritic cells during the course of sepsis. AB - BACKGROUND: Sepsis is characterized as a biphasic immune reaction in response to invading micro-organisms causing a life-threatening condition. This reaction is triggered by the activation of many different immune cells causing a dramatic inflammatory response often followed by immunosuppression. The balance of the immune response in this complex interplay of pro- and anti-inflammatory processes is crucial for the course of sepsis and host survival. For a better understanding of the involved mechanisms, a precise knowledge of participating immune cells in a timely manner is necessary. METHODS: We analyzed circulating plasmacytoid dendritic cells (pDCs) by using multicolor, flow cytometric analysis in septic patients over 28 days. In addition, we assessed disease severity, organ failure, and outcome in these septic patients. RESULTS: The numbers of circulating pDCs started to increase at day 1 after the onset of sepsis and were greatly increased from day 4 after sepsis onset. At days 7 and 14, the numbers of circulating pDCs peaked and returned to normal values at day 28 after the onset of sepsis. These changes were accompanied by increased expression of CD11b, which is known as crucial factor for transendothelial migration. In addition, the circulating pDCs in nonsurvivors showed greatly decreased values compared with survivors over the course of sepsis. CONCLUSION: The results presented here support the concept that circulating pDCs might have an important role in the immune response during sepsis and might function as an early predictive biomarker for the outcome of sepsis. PMID- 25912380 TI - Regarding "Two-year results of intermittent electrical stimulation of the lower esophageal sphincter treatment of gastroesophageal reflux disease". PMID- 25912381 TI - Inclusion Body in a Leukocyte in Crimean-Congo Hemorrhagic Fever. PMID- 25912382 TI - vRNA structured population model for Hepatitis C Virus dynamics. AB - Improvements in the understanding of the Hepatitis C Virus (HCV) life-cycle have led to the identification of targets and the development of drugs affecting the intracellular reproduction of the virus. These advancements have presented new modeling challenges as the classic models have focused on describing the macroscopic viral kinetics only. Our primary objective is to apply the existing theory of Physiologically Structured Population (PSP) modeling to describe dynamics of viral RNA (vRNA) in infected hepatocytes of patients receiving treatment with Direct-acting Antiviral Agents (DAA). Using vRNA as a physiological structure this work expands on previous structured population models allowing exploration of micro- and macroscopic implications of such treatments. The PSP model provides a description of vRNA distribution in the infected cells at steady state and its time evolution following treatment. The long term behavior of the model predicts viral load time courses in plasma and permits to quantify conditions for the virus eradication. Finally, we demonstrate that PSP models can account for additional structures, which are essential for the viral replication process with potentially far reaching implications in our understanding of HCV infections and treatment options. PMID- 25912383 TI - How to stay on mummy's back: Morphological and functional changes of the pretarsus in arachnid postembryonic stages. AB - A specific type of maternal care occurs in several groups of Arachnida: mothers carry their offspring on their back (pulli-carrying behaviour). In scorpions, whip scorpions and whip spiders it is the prenymphal stage that settles on the mother. The prenymph is not yet fully developed for a free life and very limited in its mobility, but its feet are equipped with special adhesive organs (arolia) that become lost at the nymphal stage. Here we study the morphology, ultrastructure and mechanical function of the arolia. In scorpions (Scorpiones) the contact area between arolia and substrate and thus adhesion of the pad is controlled by the antagonistic work of hydrostatic pressure and muscular retraction. Arolia of whip scorpions (Thelyphonida) do not require muscular action for strong attachment. Arrays of long, branching fibres in the mesocuticle lead to high compliancy of the pad. In whip spiders (Amblypygi) the prenymphal pretarsus is already equipped with sclerites and claws. Its arolium is retained in nymphs and adults in some taxa, but acquires a more complex structure. These results contribute to our knowledge on the postembryonic development of arachnids and to the understanding of attachment pad evolution among arthropods. Some of the described developmental, structural, and mechanical phenomena are not known from other animals and might be of potential interest for further biomimetic developments. PMID- 25912384 TI - First bite syndrome after bimaxillary osteotomy: case report. AB - We present what is to the best of our knowledge the first reported case of first bite syndrome as a delayed complication of bimaxillary osteotomy. PMID- 25912385 TI - Getting the message across: Delivering a quality conference presentation. PMID- 25912386 TI - Influencing factors on the cord-blood donation of post-partum women. AB - This study aims to identify the factors on the cord-blood donation of Korean post partum women, who may store, donate, or discard their infant's cord blood. This descriptive research assesses the level of knowledge and attitude of post-partum women in Korea, regarding cord blood and its usage. The participants in this study were 320 post-partum women of which 109 stored, 34 donated, and 177 discarded their cord blood. The knowledge level of women who donated or stored their cord blood was higher than that of those who discarded. The attitude level of the women who donated was higher than that of those who stored or discarded. Knowledge, attitude, income, and source of information were the factors on the cord-blood donation; high knowledge, high attitude, low income, and information source from mass media contributes to cord-blood donation. In order to promote the cord-blood donation, it is necessary to develop guidelines for cord-blood education to improve the knowledge and attitudes of child-bearing women and healthcare professionals. PMID- 25912387 TI - Early standard development assessment characteristics in very low birth weight infants later classified with autism spectrum disorder. AB - BACKGROUND: The prevalence of autism spectrum disorder (ASD) symptoms is high among very low birth weight infants (VLBWIs). Early diagnosis of ASD is crucial, because early intervention for ASD is effective. OBJECTIVE: To evaluate early standard development assessment characteristics in VLBWIs later classified with ASD. METHODS: Thirty-five VLBWIs later diagnosed with ASD were compared with 169 children with typical development who were admitted to the neonatal intensive care unit at Nagano Children's Hospital between 2001 and 2005. We retrospectively evaluated developmental quotient (DQ) using the Kyoto Scale of Psychological Development (KSPD) at 6 and 18months post-term age (PTA) and 3year chronological age. RESULTS: KSPD DQ was significantly lower in ASD infants than in typical development infants at all ages. Postural-motor DQs of ASD infants at 18months PTA and 3year chronological age showed some increase compared to that at 6months PTA. CONCLUSION: Early recognition of ASD using standardized development assessment tools in VLBWIs might be possible. PMID- 25912388 TI - Sensors, wearables and devices in the e-age: tomorrow's world today. PMID- 25912389 TI - IVUS-guided stenting: still not a must? PMID- 25912390 TI - Five-year outcomes of staged percutaneous coronary intervention in the SYNTAX study. AB - AIMS: The SYNTAX study compared PCI with TAXUS Express stents to CABG for the treatment of de novo 3-vessel and/or left main coronary disease. This study aimed to determine patient characteristics and five-year outcomes after a staged PCI strategy compared to single-session PCI. METHODS AND RESULTS: In the SYNTAX trial, staged procedures were discouraged but were allowed within 72 hours or, if renal insufficiency or contrast-induced nephropathy occurred, within 14 days (mean 9.8+/-18.1 days post initial procedure). A total of 125 (14%) patients underwent staged PCI. These patients had greater disease severity and/or required a more complex procedure. MACCE was significantly increased in staged patients (48.1% vs. 35.5%, p=0.004), as was the composite of death/stroke/MI (32.2% vs. 19%, p=0.0007). Individually, cardiac death and stroke occurred more frequently in the staged PCI group (p=0.03). Repeat revascularisation was significantly higher in staged patients (32.8% vs 24.8%, p=0.035), as was stent thrombosis (10.9% vs. 4.7%, p=0.005). CONCLUSIONS: There is a higher incidence of MACCE in patients undergoing staged compared to single-session PCI for 3-vessel and/or left main disease over the first five years of follow-up. However, these patients had more comorbidities and more diffuse disease. PMID- 25912391 TI - Angiographic and clinical comparisons of intravascular ultrasound- versus angiography-guided drug-eluting stent implantation for patients with chronic total occlusion lesions: two-year results from a randomised AIR-CTO study. AB - AIMS: This study sought to compare angiographic endpoints at one-year follow-up after a drug-eluting stent implantation guided by either intravascular ultrasound (IVUS) or angiography in patients with chronic total occlusion (CTO) lesions. METHODS AND RESULTS: Patients with at least one CTO lesion recanalised successfully were randomly assigned to the IVUS-guided or the angiography-guided group. The use of IVUS for penetration of the true lumen and optimisation of stent expansion was only done in the IVUS-guided group. The primary endpoint was in-stent late lumen loss (LLL) at one-year follow-up. A total of 230 patients with CTO lesions after successful recanalisation were enrolled and followed with office visits or telephone contact up to 24 months. In-stent LLL in the IVUS guided group was significantly lower compared to the angiography-guided group at one-year follow-up (0.28+/-0.48 mm vs. 0.46+/-0.68 mm, p=0.025), with a significant difference in restenosis of the "in-true-lumen" stent between the two groups (3.9% vs.13.7%, p=0.021). The minimal lumen diameter and minimal stent cross-section area significantly and negatively correlated with LLL (all p<0.001). The rates of adverse clinical events were comparable between the IVUS- and angiography-guided groups at two-year follow-up (21.7% vs. 25.2%, p=0.641). CONCLUSIONS: The IVUS-guided stenting of the CTO lesion was associated with less LLL and a lower incidence of "in-true-lumen" stent restenosis. Additional study is required to identify the clinical benefit of the IVUS-guided procedure for CTO lesions. [ChiCTR-TRC-10000996]. PMID- 25912392 TI - Preliminary outcomes after transcatheter aortic valve implantation in patients with systemic sclerosis. AB - AIMS: The aim of this study was to report the feasibility and the preliminary outcomes after transcatheter aortic valve implantation (TAVI) in the frail and unique high-risk population of patients with systemic sclerosis (SSc) and severe aortic stenosis (AS). METHODS AND RESULTS: All patients with SSc and severe AS treated with TAVI between November 2007 and June 2013 in our centre were included in the current study. Outcomes were assessed using the Valve Academic Research Consortium 2 (VARC-2) definitions. Of 526 surgical high-risk patients treated in the study period, only six had SSc (1.1%). All SSc patients underwent transfemoral TAVI under conscious sedation. The procedure was successfully performed in all patients. There was one case of a major vascular complication. During a median follow-up time of 550 days (interquartile range 390-1,009 days), five of the six patients were alive, free from any complications and with an NYHA Class I or II. One patient died at 670 days from a stroke of unknown aetiology. CONCLUSIONS: The present case series suggests that the TAVI procedure is feasible in patients with SSc and severe AS. PMID- 25912393 TI - Early feasibility evaluation of thoracoscopically assisted transcatheter ventricular reconstruction in an experimental model of ischaemic heart failure with left anteroapical aneurysm. AB - AIMS: To test the feasibility of a thoracoscopically assisted, off-pump, transcatheter ventricular reconstruction (TCVR) approach in an ovine model of left ventricular (LV) anteroapical aneurysm. METHODS AND RESULTS: Myocardial infarction (MI) was induced by coil occlusion of the middle left anterior descending artery and diagonals. Two months after MI creation, TCVR was performed via a minimal thoracotomy in eight sheep. Under endoscopic and fluoroscopic guidance, trans-interventricular septal puncture was performed from the LV epicardial scar. A guidewire was externalised via a snare placed in the right ventricle from the external jugular vein. An internal anchor was inserted over the wire and positioned on the right ventricular septum and an external anchor was deployed on the LV anterior epicardium. Serial pairs of anchors were placed and plicated together to exclude the scar completely. Immediately after TCVR, echocardiography showed LV end-systolic volume decreased from pre-procedure 58.8+/-16.6 ml to 25.1+/-7.6 ml (p<0.01) and the ejection fraction increased from 32.0+/-7.3% to 52.0+/-7.5% (p<0.01). LV twist significantly improved (3.83+/-2.21 vs. pre-procedure -0.41+/-0.94, p=0.01) and the global peak-systolic longitudinal strain increased from -5.64% to -10.77% (p<0.05). CONCLUSIONS: TCVR using minimally invasive access techniques on the off-pump beating heart is feasible and resulted in significant improvement in LV performance. PMID- 25912395 TI - A singing choir: Understanding the dynamics of hope, hopelessness, and despair in palliative care patients. A longitudinal qualitative study. AB - OBJECTIVE: Hope, despair, and hopelessness are dynamic in nature; however, they have not been explored over time. The objective of the present study was to describe hope, hopelessness, and despair over time, as experienced by palliative care patients. METHOD: We employed a qualitative longitudinal method based on narrative theories. Semistructured interviews with palliative care patients were prospectively conducted, recorded, and transcribed. Data on hope, hopelessness and despair were thematically analyzed, which led to similarities and differences between these concepts. The concepts were then analyzed over time in each case. During all stages, the researchers took a reflexive stance, wrote memos, and did member checking with participants. RESULTS: A total of 29 palliative care patients (mean age, 65.9 years; standard deviation, 14.7; 14 females) were included, 11 of whom suffered from incurable cancer, 10 from severe chronic obstructive pulmonary disease, and 8 from severe heart failure. They were interviewed a maximum of three times. Participants associated hope with gains in the past or future, such as physical improvement or spending time with significant others. They associated hopelessness with past losses, like loss of health, income, or significant others, and despair with future losses, which included the possibility of losing the future itself. Over time, the nature of their hope, hopelessness, and despair changed when their condition changed. These dynamics could be understood as voices in a singing choir that can sing together, alternate with each other, or sing their own melody. SIGNIFICANCE OF RESULTS: Our findings offer insight into hope, hopelessness, and despair over time, and the metaphor of a choir helps to understand the coexistence of these concepts. The findings also help healthcare professionals to address hope, hopelessness, and despair during encounters with patients, which is particularly important when the patients' physical condition has changed. PMID- 25912394 TI - Altered mRNA Levels of Glucocorticoid Receptor, Mineralocorticoid Receptor, and Co-Chaperones (FKBP5 and PTGES3) in the Middle Frontal Gyrus of Autism Spectrum Disorder Subjects. AB - Although stress has been implicated in the pathophysiology of autistic spectrum disorder (ASD), it is not known whether glucocorticoid receptor (GR) levels are altered in the brain of subjects with ASD. The messenger RNA (mRNA) levels of GR isoforms (GRalpha, GRbeta, GRgamma, and GRP), mineralocorticoid receptor (MR), GR co-chaperones (FKBP5, PTGES3, and BAG1), and inflammatory cytokines (IL-6, IL 1beta, and IFN-gamma) were examined in the postmortem middle frontal gyrus tissues of 13 ASD and 13 age-matched controls by qRT-PCR. The protein levels were examined by Western blotting. We found significant decreases in GRalpha (64%), GRgamma (48%), GRP (20%) and MR (46%) mRNA levels in ASD subjects as compared to controls. However, significant increases in FKBP5 (42%) and PTGES3 (35%) mRNA levels were observed in ASD subjects. There were no differences in the mRNA levels of GRbeta and BAG1 in ASD subjects as compared to controls. MR mRNA was found to be negatively correlated with the diagnostic score for abnormality of development. On the protein level, significant reductions in GR and MR, but no change in FKBP5 and PTGES3 were found in ASD subjects as compared to controls. Moreover, we observed significant increases in IL-1beta and IFN-gamma mRNA levels in ASD subjects, and these cytokines were negatively associated with GR levels. Our data, for the first time, reports dysregulation of GR, MR, FKBP5, and PTGES3 in ASD and suggest a possible role of inflammation in altered GR function in ASD. PMID- 25912396 TI - Early feeding after free flap reconstruction for oral cancer. AB - Traditionally, after resection of oral cancer and free flap reconstruction, patients are given nothing by mouth for between 6 and 12 days to allow adequate time for healing and to reduce the risk of dehiscence. To assess the impact of early oral feeding after operation we retrospectively reviewed 10 consecutive patients who had had surgical resection and free flap reconstruction for oral cancer. Details recorded included histopathological findings, stage and site of the primary tumour, and type of reconstruction. Data on the duration of tracheostomy, commencement of clear fluids and diet, complications, and duration of hospital stay, were also recorded. Half of the patients were able to tolerate clear fluids orally by the first postoperatively day and the remaining half by the second. By the fourth day, 8 could manage a pureed diet. There were no complications. A mean duration of hospital stay of 11 days (range 5-16) compared favourably with previous studies. Early oral feeding was not associated with any increased morbidity or adverse outcome. A shorter hospital stay may favour the adoption of an improved recovery programme as seen in other surgical specialties. PMID- 25912397 TI - Dog bites and maxillofacial surgery: what can we do? AB - The number of injuries caused by dog bites is increasing in the United Kingdom. We review patients admitted with dog bites to a single maxillofacial department in a district general hospital over a 21-month period. Data include patients' characteristics, and the site and severity of injury. The relationship of the victim to the animal and its breed and classification were added where possible. In total, 65 patients, mean age 22 years (range 1-71, median 14) were included. There were 84 wounds, and their site and severity were recorded according to the Lackmann classification. Twelve different breeds of dog were responsible for the bites. An appreciable proportion of those injured were young children. Educational strategies should aim to reduce the incidence of all dog bites, particularly in young children, as their needs after initial treatment are complex. We propose specific strategies to reduce the number of these injuries. PMID- 25912398 TI - Self-Motivation Is Associated With Phosphorus Control in End-Stage Renal Disease. AB - OBJECTIVE: Hyperphosphatemia is common in end-stage renal disease and associates with mortality. Phosphate binders reduce serum phosphorus levels; however, adherence is often poor. This pilot study aims to assess patients' self motivation to adhere to phosphate binders, its association with phosphorus control, and potential differences by race. DESIGN AND METHODS: Cross sectional design. Subjects were enrolled from one academic medical center dialysis practice from July to November 2012. Self-motivation to adhere to phosphate binders was assessed with the autonomous regulation (AR) scale (range: 1-7) and self-reported medication adherence with the Morisky Medication Adherence Scale. Linear regression models adjusting for age, sex, health literacy, and medication adherence were applied to determine associations with serum phosphorus level, including any evidence of interaction by race. RESULTS: Among 100 participants, mean age was 51 years (+/-15 years), 53% were male, 72% were non-white, 89% received hemodialysis, and mean serum phosphorus level was 5.7 +/- 1.6 mg/dL. More than half (57%) reported the maximum AR score (7). Higher AR scores were noted in those reporting better health overall (P = .001) and those with higher health literacy (P = .01). AR score correlated with better medication adherence (r = 0.22; P = .02), and medication adherence was negatively associated with serum phosphorus (r = -0.40; P < .001). In subgroup analysis among non-whites, higher AR scores correlated with lower serum phosphorus (high vs lower AR score: 5.55 [1.5] vs 6.96 [2.2]; P = .01). Associations between AR score (beta 95% confidence interval: -0.37 [-0.73 to -0.01]; P = .04), medication adherence (beta 95% confidence interval: -0.25 [-0.42 to -0.07]; P = .01), and serum phosphorus persisted in adjusted analyses. CONCLUSIONS: Self-motivation was associated with phosphate binder adherence and phosphorus control, and this differed by race. Additional research is needed to determine if personalized, culturally sensitive strategies to understand and overcome motivational barriers may optimize mineral bone health in end-stage renal disease. PMID- 25912399 TI - Heparanase is a host enzyme required for herpes simplex virus-1 release from cells. AB - Herpesviruses exemplified by herpes simplex virus-1 (HSV-1) attach to cell surface heparan sulfate (HS) for entry into host cells. However, during a productive infection, the HS moieties on parent cells can trap newly exiting viral progenies and inhibit their release. Here we demonstrate that a HS degrading enzyme of the host, heparanase (HPSE), is upregulated through NF-kB and translocated to the cell surface upon HSV-1 infection for the removal of HS to facilitate viral release. We also find a significant increase in HPSE release in vivo during infection of murine corneas and that knockdown of HPSE in vivo inhibits virus shedding. Overall, we propose that HPSE acts as a molecular switch for turning a virus-permissive 'attachment mode' of host cells to a virus deterring 'detachment mode'. Since many human viruses use HS as an attachment receptor, the HPSE-HS interplay may delineate a common mechanism for virus release. PMID- 25912401 TI - Phantom stent thrombosis: intracoronary imaging insights. PMID- 25912400 TI - Safety and Effectiveness of Everolimus-Eluting Stents in Chronic Total Coronary Occlusion Revascularization: Results From the EXPERT CTO Multicenter Trial (Evaluation of the XIENCE Coronary Stent, Performance, and Technique in Chronic Total Occlusions). AB - OBJECTIVES: This study sought to evaluate procedural and clinical outcomes among patients undergoing chronic total occlusion (CTO) percutaneous coronary intervention (PCI) using contemporary methods and everolimus-eluting stents (EES). BACKGROUND: Limited studies have detailed the procedural and late-term safety and efficacy of CTO revascularization among multiple centers applying modern techniques and with newer-generation drug-eluting stents. METHODS: Among 20 centers, 250 consecutive patients were enrolled for attempted CTO PCI. Procedural and in-hospital clinical outcomes were examined in addition to the 1 year primary endpoint of death, myocardial infarction, and target lesion revascularization (major adverse cardiac events [MACE]). RESULTS: Demographic, lesion, and procedural characteristics included prior bypass surgery: 9.9%; diabetes: 40.1%; lesion length: 36.1 +/- 18.5 mm; and stent length: 51.7 +/- 27.2 mm. Procedural success, defined as guidewire recanalization with no in-hospital MACE, was 96.4%. Success with antegrade-only methods was 97.9% and 86.2% by retrograde/combined methods, respectively. Compared with a pre-specified performance goal derived from 6 prior CTO drug-eluting stent trials (1-year MACE: 24.4%), treatment with EES was associated with significantly lower composite adverse events for both intent-to-treat (18.5%, 1-sided upper confidence interval: 23.4%, p = 0.025) and per-protocol populations (8.2%, 1-sided upper confidence interval: 12.3%, p < 0.0001). Target lesion revascularization at 1 year was 6.3%. Dual antiplatelet therapy adherence was 53.9% at 1 year, yet subacute definite stent thrombosis occurred in only 2 patients (0.9%), and late probable stent thrombosis occurred in 1 patient (0.5%). CONCLUSIONS: In a multicenter registration trial representing contemporary technique and EES, favorable procedural success and late-term clinical outcomes support CTO PCI in a patient population with high lesion complexity. (EXPERT CTO: Evaluation of the XIENCE PRIME LL and XIENCE Nano Everolimus Eluting Coronary Stent Coronary Stents, Performance, and Technique in Chronic Total Occlusions; NCT01435031). PMID- 25912402 TI - A 54-year-old woman with a single coronary artery and watershed ischemia treated with nitrates. PMID- 25912403 TI - Acute Myocardial Infarction Caused by Left Main Coronary Artery Compression as a Result of a Mycotic Aneurysm of the Sinus of Valsalva. PMID- 25912404 TI - Successful stenting with optical frequency domain imaging guidance for spontaneous coronary artery dissection. PMID- 25912405 TI - Successful post-dilation of a Lotus transcatheter aortic valve in a case of prosthesis frame underexpansion due to leaflet calcification. PMID- 25912406 TI - 1-year follow-up optical coherence tomography of a "hybrid" neocarina after T stenting with small protrusion technique using a bioresorbable vascular scaffold and a metallic stent. PMID- 25912407 TI - Determination of vertebral heart score in Goeldi's monkeys (Callimico goeldii). AB - BACKGROUND: Goeldi's monkeys (Callimico goeldii) are callitrichid primates commonly kept in zoological collections, and to date, no cardiac parameters have been recorded. The vertebral heart score (VHS) is an objective method of evaluation of cardiac size well documented in domestic mammals, and the aim of this study was to determine the VHS in Goeldi's monkeys. METHODS: In this retrospective study, right lateral radiographs of thirteen clinically well animals were reviewed and vertebral heart score determined. RESULTS: The vertebral heart score was found to be 9.35 +/- 0.31. CONCLUSIONS: The observed value appears consistent within the study population and with values for other primate species. The value determined may be of benefit in objectively evaluating cardiac size in this species. PMID- 25912408 TI - Ternary polyplex micelles with PEG shells and intermediate barrier to complexed DNA cores for efficient systemic gene delivery. AB - Simultaneous achievement of prolonged retention in blood circulation and efficient gene transfection activity in target tissues has always been a major challenge hindering in vivo applications of nonviral gene vectors via systemic administration. Herein, we constructed novel rod-shaped ternary polyplex micelles (TPMs) via complexation between the mixed block copolymers of poly(ethylene glycol)-b-poly{N'-[N-(2-aminoethyl)-2-aminoethyl]aspartamide} (PEG-b-PAsp(DET)) and poly(N-isopropylacrylamide)-b-PAsp(DET) (PNIPAM-b-PAsp(DET)) and plasmid DNA (pDNA) at room temperature, exhibiting distinct temperature-responsive formation of a hydrophobic intermediate layer between PEG shells and pDNA cores through facile temperature increase from room temperature to body temperature (~37 degrees C). As compared with binary polyplex micelles of PEG-b-PAsp(DET) (BPMs), TPMs were confirmed to condense pDNA into a more compact structure, which achieved enhanced tolerability to nuclease digestion and strong counter polyanion exchange. In vitro gene transfection results demonstrated TPMs exhibiting enhanced gene transfection efficiency due to efficient cellular uptake and endosomal escape. Moreover, in vivo performance evaluation after intravenous injection confirmed that TPMs achieved significantly prolonged blood circulation, high tumor accumulation, and promoted gene expression in tumor tissue. Moreover, TPMs loading therapeutic pDNA encoding an anti-angiogenic protein remarkably suppressed tumor growth following intravenous injection into H22 tumor-bearing mice. These results suggest TPMs with PEG shells and facilely engineered intermediate barrier to inner complexed pDNA have great potentials as systemic nonviral gene vectors for cancer gene therapy. PMID- 25912410 TI - Screening of Anthocyanins and Anthocyanin-Derived Pigments in Red Wine Grape Pomace Using LC-DAD/MS and MALDI-TOF Techniques. AB - Two phenolic extracts were made from a red wine grape pomace (GP) and fractionated first by sequential liquid-liquid extraction with organic solvents. The aqueous fraction was fractionated by low-pressure chromatography on Toyopearl HW-40 gel and on C18. Different fractions were obtained by sequential elution with aqueous/organic solvents, and then analyzed by liquid chromatography and mass spectrometry (LC-DAD/MS and MALDI-TOF). Over 50 anthocyanin-based pigments were detected by LC-DAD/MS in GP, mainly pyranoanthocyanins including A- and B type vitisins and methylpyranoanthocyanins. The presence of oligomeric malvidin-3 O-coumaroylglucoside-based anthocyanins was also detected in GP using both LC DAD/MS and MALDI-TOF. PMID- 25912409 TI - Redox nanoparticles inhibit curcumin oxidative degradation and enhance its therapeutic effect on prostate cancer. AB - Curcumin is a phytochemical with diverse molecular targets and is well known for its anti-tumor potential. However, it has limited application in cancer therapy because curcumin undergoes rapid oxidative degradation at physiological conditions resulting in poor stability and bio-availability. In this study, we were able to suppress curcumin's oxidative degradation by encapsulating it in a nanoparticle that also acts as a radical scavenger. We prepared curcumin-loaded pH-sensitive redox nanoparticles (RNP(N)) by self-assembling amphiphilic block copolymers conjugated with reactive oxygen species (ROS) scavenging nitroxide radicals to ensure the delivery of minimally degraded curcumin to target regions. In vitro analysis confirmed that the entrapment of both curcumin and nitroxide radicals in the hydrophobic core of RNP(N) suppressed curcumin degradation in conditions mimicking the physiological environment. Evaluation of apoptosis related molecules in the cells, such as ceramides, caspases, apoptosis-inducing factor, and acid ceramidase revealed that curcumin loaded RNP(N) induced strong apoptosis compared to free curcumin. Lastly, intravenous injection of curcumin loaded RNP(N) suppressed tumor growth in vivo, which is due to the increased bio availability and significant ROS scavenging at tumor sites. These results demonstrated that RNP(N) is a promising drug carrier with unique ROS-scavenging abilities, and it is able to overcome the crucial hurdle of curcumin's limitations to enhance its therapeutic potential. PMID- 25912411 TI - Features of Turner syndrome among a group of Cameroonian patients. AB - OBJECTIVE: To describe the features of Turner syndrome among a group of Cameroonian patients. METHODS: A descriptive cross-sectional study was conducted among patients with amenorrhea and/or short stature who attended the genetic unit of Yaounde Gynecology, Obstetrics and Pediatric Hospital (Yaounde, Cameroon) for a specialist consultation between July 1, 2007, and December 31, 2008. Sociodemographic, clinical, and cytogenetic data were collected. RESULTS: Turner syndrome was confirmed among 11 of the 14 participants (seven had monosomy of the X chromosome; four had mosaicism involving a structural abnormality of the second X chromosome). The mean age at diagnosis was 18.4+/-2.8years. The reasons for consultation were delayed puberty (n=10) and short stature (n=1). Nine patients had a short neck, nine had a forearm carrying-angle deformity, eight had a low hairline, and two had a webbed neck. Abdominal ultrasonography identified a horseshoe kidney in two patients and a rudimentary uterus in nine patients. None of the patients displayed cardiac abnormalities. Hypergonadotropic hypogonadism was reported among five patients. Eight patients did not receive hormonal treatment owing to advanced bone age or economic reasons. CONCLUSION: Late diagnosis and variable phenotypic expression were key features of Cameroonian patients with Turner syndrome. PMID- 25912412 TI - The ARID1A pathway in ovarian clear cell and endometrioid carcinoma, contiguous endometriosis, and benign endometriosis. AB - OBJECTIVE: To assess ARID1A-encoded protein (BAF250a) and phosphorylated AKT (pAKT) expression, apoptosis, and the DNA damage response pathway in endometrioid and clear cell ovarian cancers (endometriosis-associated ovarian cancers [EAOCs]), and benign endometriotic ovarian cysts. METHODS: In a retrospective study, tissue samples were reviewed from patients who had undergone surgery for EAOC or endometriotic ovarian cysts at a center in Montreal, QC, Canada, between 2000 and 2012. A tissue microarray including cases of endometrioid carcinoma, clear cell carcinoma, contiguous endometriosis (i.e. apparently benign endometriosis near the EAOC), and benign endometriotic ovarian cysts, was analyzed for the expression of various proteins. RESULTS: Loss of BAF250a expression was seen in 13 (22%) of 59 endometrioid cancers, 17 (47%) of 36 clear cell cases, 8 (44%) of 18 contiguous endometriosis cases, and 3 (8%) of 66 benign endometriotic ovarian cysts. In tissues showing loss of BAF250a, expression of pAKT, gammaH2AX, BIM, and BAX was higher in EAOC and contiguous endometriosis than in benign endometriosis (P<0.05), whereas expression of pATM, pCHK2, and Bcl2 was low. All proteins except for Bcl2 showed low expression in benign endometriosis. CONCLUSION: Loss of ARID1A-encoded protein seems to be an early event in EOAC, along with pAKT activation, alteration of gammaH2AX, and concomitant activation of the apoptosis pathway. PMID- 25912413 TI - Management and outcomes of pregnancies among women with HIV in Oxford, UK, in 2008-2012. AB - OBJECTIVE: To evaluate the management and outcomes of pregnancies among women with HIV infection. METHODS: A retrospective cohort study was undertaken of pregnant women with HIV who delivered at one center in the UK in 2008-2012. Case notes were reviewed and detailed information extracted regarding obstetric and virological management. RESULTS: Overall, 61 pregnancies were included; 43% (26/60) were unplanned and 39% (22/57) booked late. HIV infection was diagnosed during pregnancy for 32% (19/60); 71% (12/17) were diagnosed after the first trimester. At booking, 47% of women (28/60) were not on treatment, all but one of whom commenced treatment, either for maternal reasons (CD4 count <350 cells per mm(3); 48% [13/27]) or prevention of mother-to-child-transmission (52% [14/27]). Viral load was high (>50 copies per mL) at delivery for 13% of women (8/61). Delivery was by cesarean for 74% [45/61]. One neonate was diagnosed with HIV infection. There were 6 (10%) preterm births, 9 (15%) cases of low birth weight, 11 (18%) small-for-gestational-age neonates, and 1 (2%) stillbirth. CONCLUSION: Better pregnancy planning, earlier booking and HIV diagnosis, and optimal antiretroviral treatment should increase the proportion of women with a low viral load (<50 copies per mL) at delivery, lead to more vaginal deliveries, and further reduce mother-to-child transmission of HIV. PMID- 25912415 TI - Let's Not "Relax" Evidence Standards when Recommending Risky Preventive Therapeutic Agents. PMID- 25912414 TI - Low vitamin D status among pregnant Latin American and Caribbean women with HIV Infection. AB - OBJECTIVE: To evaluate the prevalence and predictors of low vitamin D status among pregnant women with HIV infection. METHODS: The present cross-sectional study analyzed repository specimens collected at 12-34 weeks of pregnancy among women enrolled across 17 sites in Latin America and the Caribbean between 2002 and 2009. Logistic regression modeling was used to identify factors associated with low vitamin D status (25-hydroxyvitamin D <30 ng/mL). RESULTS: Among 715 women, 218 (30.5%) were vitamin D deficient (<20 ng/mL) and 252 (35.2%) were insufficient (21- /mL). Factors associated with low vitamin D status included residence in subtropical latitudes (adjusted odds ratio [aOR] 1.97, 95% confidence interval [CI] 1.35-2.88), assessment during non-summer seasons (autumn: aOR 1.85, 95% CI 1.20-2.86; spring: 4.3, 2.65-6.95; winter: 10.82, 5.74 20.41), employment (aOR 1.56, 95% CI 1.06-2.38), and assessment before 20 weeks of pregnancy (aOR 1.89, 95% CI 1.18-3.06). Factors protective against low vitamin D status were CD4 count below 200 cells per mm(3) (aOR 0.45, 95% CI 0.26-0.77) and protease inhibitors (aOR 0.62, 95% CI 0.40-0.95). CONCLUSION: Low vitamin D status was prevalent among pregnant women with HIV infection. Further studies are warranted to identify the impact of low maternal vitamin D status. PMID- 25912416 TI - Protocol for rat single muscle fiber isolation and culture. AB - To attain a superior in vitro model of mature muscle fibers, we modified the established protocol for isolating single muscle fibers from rat skeletal muscle. Muscle fiber cultures with high viability were obtained using flexor digitorum brevis muscle and lasted for at least 7 days. We compared the expression levels of adult myosin heavy chain (MyHC) isoforms in these single muscle fibers with myotubes formed from myoblasts; isolated fibers contained markedly more abundant adult MyHC isoforms than myotubes. This muscle fiber model, therefore, will be useful for studying the various functions and cellular processes of mature muscles in vitro. PMID- 25912417 TI - Biotinylated probes of artemisinin with labeling affinity toward Trypanosoma brucei brucei target proteins. AB - We studied the target proteins of artemisinin in Trypanosoma brucei brucei using the affinity-labeling method. We designed and synthesized four biotinylated probes of artemisinin for use as molecular tools. Their in vitro trypanocidal activities (data not shown) proved that they mimicked the biological action of artemisinin. We assessed the chemical stability for all of the probes in the parasite culture medium and lysate using reversed-phase high-performance liquid chromatography (HPLC). After 3-h incubations, the probes remained undecomposed in a range of 40 to 65% in the parasite culture medium, whereas approximately 80% of the probes remained stable in the parasite lysate. Using liquid chromatography mass spectrometry (LC-MS), we demonstrated that, with respect to all of the probes, uptakes into the parasite ranging from 81 to 96% occurred after 30-min incubations. In a competitive binding assay between artemisinin and the four biotinylated probes, we searched for the trypanosomal target protein of artemisinin. Consequently, we observed that only the diazirine-free probe 5 could provide the desired result with high affinity-labeling efficiency. Using the horseradish peroxidase-tagged streptavidin-biotin method, we showed that artemisinin could specifically bind to candidate target proteins of approximately 60, 40, and 39 kDa. PMID- 25912418 TI - Multiplex gene removal by two-step polymerase chain reactions. AB - Precise DNA manipulation is critical for molecular biotechnology. Restriction enzyme-based approaches are limited by their requirement of specific enzyme sites. Restriction-free cloning has greatly improved the flexibility and speed of precise DNA assembly. Most of these approaches focus on DNA assembly rather than gene removal. Here we present a polymerase chain reaction (PCR)-based cloning method that allows removal of multiple gene segments from plasmids without using restriction enzymes and thermostable ligase. We demonstrate simultaneous removal of three gene segments from a plasmid. This approach could be beneficial to DNA library construction, genetic and protein engineering, and synthetic biology. PMID- 25912419 TI - The capture proteasome assay: A method to measure proteasome activity in vitro. AB - Because of its crucial role in various cellular processes, the proteasome is the focus of intensive research for the development of proteasome inhibitors to treat cancer and autoimmune diseases. Here, we describe a new and easy assay to measure the different proteasome activities in vitro (chymotrypsin-like, caspase-like, and trypsin-like) based on proteasome capture on antibody-coated plates, namely the capture proteasome assay (CAPA). Applying the CAPA to lysates from cells expressing standard proteasome, immunoproteasome, or intermediate proteasomes beta5i or beta1i-beta5i, we can monitor the activity of the four proteasome subtypes. The CAPA provided similar results as the standard whole-cell proteasome Glo assay without the problem of contaminating proteases requiring inhibitors. However, the profile of trypsin-like activity differed between the two assays. This could be partly explained by the presence of MgSO4 in the proteasome-Glo buffer, which inhibits the trypsin-like activity of the proteasome. The CAPA does not need MgSO4 and, therefore, provides a more precise measurement of the trypsin like activity. The CAPA provides a quick and accurate method to measure proteasome activity in vitro in a very specific manner and should be useful for the development of proteasome inhibitors. PMID- 25912420 TI - ABO-incompatible renal transplantation without antibody removal using conventional immunosuppression alone. PMID- 25912421 TI - A long pentraxin-3-derived pentapeptide for the therapy of FGF8b-driven steroid hormone-regulated cancers. AB - Fibroblast growth factor-8b (FGF8b) affects the epithelial/stromal compartments of steroid hormone-regulated tumors by exerting an autocrine activity on cancer cells and a paracrine pro-angiogenic function, thus contributing to tumor progression. The FGF8b/FGF receptor (FGFR) system may therefore represent a target for the treatment of steroid hormone-regulated tumors. The soluble pattern recognition receptor long pentraxin-3 (PTX3) binds various FGFs, including FGF2 and FGF8b, thus inhibiting the angiogenic and tumorigenic activity of androgen regulated tumor cells. Nevertheless, the complex/proteinaceous structure of PTX3 hampers its pharmacological exploitation. In this context, the acetylated pentapeptide Ac-ARPCA-NH2 (ARPCA), corresponding to the N-terminal amino acid sequence PTX3(100-104), was identified as a minimal FGF2-binding peptide able to antagonize the biological activity of FGF2. Here, we demonstrate that ARPCA binds FGF8b and inhibits its capacity to form FGFR1-mediated ternary complexes with heparan sulphate proteoglycans. As a FGF8b antagonist, ARPCA inhibits FGFR1 activation and signalling in endothelial cells, hampering the angiogenic activity exerted in vitro and in vivo by FGF8b. Also, ARPCA suppresses the angiogenic and tumorigenic potential of prototypic androgen/FGF8b-dependent Shionogi 115 mammary carcinoma cells and of androgen/FGF8b/FGF2-dependent TRAMP-C2 prostate cancer cells. In conclusion, ARPCA represents a novel FGF8b antagonist with translational implications for the therapy of steroid hormone-regulated tumors. PMID- 25912422 TI - Oxidative stress, genotoxicity and histopathology biomarker responses in Mugil cephalus and Dicentrarchus labrax gill exposed to persistent pollutants. A field study in the Bizerte Lagoon: Tunisia. AB - The use of biomarkers has become an important tool for modern environmental assessment as they can help to predict pollutants involved in the monitoring program. Despite the importance of fish gill in several functions (gaseous exchange, osmotic and ionic regulation, acid-base balance and nitrogenous waste) its use in coastal water biomonitoring focusing on protection and damage is scarce. This field study investigates biochemical (catalase, superoxide dismutase, lipid peroxidation), molecular (DNA integrity) and morphological (histology) parameters in gill of mullet (Mugil cephalus) and sea bass (Dicentrarchus labrax) and originating from Bizerte lagoon (a coastal lagoon impacted by different anthropogenic activities) and from the Mediterranean Sea (a reference site). Remarkable alterations in the activities of oxidative stress enzymes and DNA integrity in the tissue of the two studied fish species were detected in Bizerte Lagoon. The study of histopathological alterations of gills in both two fish species from Bizerte Lagoon suggest thickening of primary lamellae, cellular hyperplasia, aneurism, curving, shortening and fusion of secondary lamellae. The adopted approach, considering simultaneously protection responses and damaging effects, revealed its usefulness on the pollution assessment. PMID- 25912423 TI - Comparative intestinal esterases amongst passerine species: Assessing vulnerability to toxic chemicals in a phylogenetically explicit context. AB - Inhibition of blood esterase activities by organophosphate (OP) pesticides has been used as a sensitive biomarker in birds. Furthermore, compared to mammalian vertebrates, less is known about the role of these enzyme activities in the digestive tracts of non-mammalian vertebrates, as well as the environmental and biological stressors that contribute to their natural variation. To fill this gap, we examined butyrylcholinesterase (BChE) and carboxylesterases (CbE) in the digestive tracts of sixteen passerine species from central Chile. Whole intestine enzyme activities were positively and significantly correlated with body mass. After correcting for body mass and phylogenetic effect, we found only a marginal effect of dietary category on BChE activity, but a positive and significant association between the percentage of dietary nitrogen and the mass-corrected lipase activity. Our results suggest that observed differences may be due to the dietary composition in the case of lipases and BChE, and also we predict that all model species belonging to the same order will probably respond differently to pesticide exposure, in light of differences in the activity levels of esterase activities. PMID- 25912424 TI - The risk of fatal stroke in Finnish postmenopausal hormone therapy users before and after the Women's Health Initiative: A cohort study. AB - OBJECTIVE: The Women's Health Initiative (WHI) study clarified the indications and contraindications for postmenopausal hormone therapy (HT). We studied the impact of the WHI results on the risk of fatal stroke in HT users in Finland. STUDY DESIGN: Retrospective analysis setting: Nationwide registers on postmenopausal HT use and causes of death between 1995 and 2009. POPULATION: Women >=40 years (n=290,272) using systemic estradiol-based postmenopausal HT. METHODS: Follow-up started from the first HT purchase during the pre-WHI era (1995-2001) and post-WHI era (2002-2009). MAIN OUTCOME MEASURES: Stroke deaths in HT users were compared with that in the age-matched background population and expressed as standardized mortality ratio (SMR) with 95% confidence intervals. RESULTS: Overall, 311 HT users died due to stroke. The exposure to HT <=1 year was associated with a similarly reduced 22% (0.67-0.91) risk of stroke death in the pre-WHI era and in the post-WHI era 27% (0.55-0.94). The risk reductions for HT exposure of 1-8 years in the pre-WHI era (47%, 0.42-0.65) did not differ from that in the post-WHI era (32%, 0.48-0.94). The discontinuation of HT was accompanied by a significant 33% (1.02-1.72) increase in stroke death risk in the pre-WHI era and a non-significant 32% (0.84-1.99) increase in the post-WHI era within the first post-treatment year, but no longer after 1-8 years. CONCLUSIONS: The change in prescribing policy after the WHI study did not affect the risk of fatal stroke in Finnish HT users. PMID- 25912425 TI - iCap: Instrumented assessment of physical capability. AB - OBJECTIVES: The aims of this study were to (i) investigate instrumented physical capability (iCap) as a valid method during a large study and (ii) determine whether iCap can provide important additional features of postural control and gait to categorise cohorts not previously possible with manual recordings. STUDY DESIGN: Cross-sectional analysis involving instrumented testing on 74 adults who were recruited as part of a pilot intervention study; LiveWell. Participants wore a single accelerometer-based monitor (lower back) during standardised physical capability tests so that outcomes could be compared directly with manual recordings (stopwatch and measurement tape) made concurrently. MAIN OUTCOME MEASURES: Time, distance, postural control and gait characteristics. RESULTS: Agreement between manual and iCap ranged from moderate to excellent (0.649-0.983) with mean differences between methods low and deemed acceptable. Additionally, iCap successfully quantified (i) postural control characteristics which showed sensitivity to distinguish between 5 variations of the standing balance test and (ii) 14 gait characteristics known to be sensitive to age/pathology. CONCLUSIONS: Our findings show that iCap can provide robust quantitative data about physical capability during standardised tests while also providing sensitive (age/pathology) postural control and gait characteristics not previously quantifiable with manual recordings. The methodology which we propose may have practical utility in a wide range of clinical and public health surveys and studies, including intervention studies, where assessment could be undertaken within diverse settings. This will need to be tested in further validation studies in a wider range of settings. PMID- 25912426 TI - Maternal mid-pregnancy lipids and birthweight. AB - OBJECTIVE: To describe associations between maternal lipids and birthweight and to determine whether pre-pregnancy body mass index (BMI) modifies these associations. DESIGN: Cohort study. SETTING: Multiple communities in Michigan, USA. POPULATION: Participants were a sub-cohort of women from the multi-community Pregnancy Outcomes and Community Health (POUCH) study (1998-2004). METHODS: Maternal total cholesterol, high-density lipoprotein (HDLc), and low-density lipoprotein (LDLc) cholesterol, and triglycerides were assessed at 16-27 weeks' gestation. Women were classified as having normal (< 25 kg/m(2) ) or overweight/obese (>= 25 kg/m(2) ) pre-pregnancy BMI. MAIN OUTCOME MEASURES: Sex- and gestational-age-specific body weight z-score (BWz). RESULTS: Regression models examined associations among lipids (low: 1st quartile, referent: middle quartiles, high: 4th quartile) and BWz for the total sample and stratified by pre pregnancy BMI. In adjusted analyses (n = 1207), low HDLc was associated with lower BWz (beta = -0.23, 95% CI -0.40 to -0.06), whereas high triglycerides were associated with higher BWz (beta = 0.23, 95% CI 0.06-0.41). Once stratified by pre-pregnancy BMI, low total cholesterol was associated with lower BWz in normal BMI women (beta = -0.25, 95% CI -0.47 to -0.03), whereas in overweight/obese BMI women, high HDLc was inversely (beta = -0.29, 95% CI -0.54 to -0.04) and high triglycerides were directly associated with BWz (beta = 0.32, 95% CI 0.07-0.54). Removing women with gestational diabetes/hypertensive disorders did not alter the results. CONCLUSIONS: The associations between maternal lipids and BWz vary by lipid measure and pre-pregnancy BMI. Future work should examine whether lipids and pre-pregnancy BMI make unique contributions to the fetal programming of disease. PMID- 25912427 TI - Cryptanalysis and improvement of an improved two factor authentication protocol for telecare medical information systems. AB - Telecare medical information systems (TMIS) provides rapid and convenient health care services remotely. Efficient authentication is a prerequisite to guarantee the security and privacy of patients in TMIS. Authentication is used to verify the legality of the patients and TMIS server during remote access. Very recently Islam et al. (J. Med. Syst. 38(10):135, 2014) proposed a two factor authentication protocol for TMIS using elliptic curve cryptography (ECC) to improve Xu et al.'s (J. Med. Syst. 38(1):9994, 2014) protocol. They claimed their improved protocol to be efficient and provides all security requirements. However our analysis reveals that Islam et al.'s protocol suffers from user impersonation and server impersonation attacks. Furthermore we proposed an enhanced protocol. The proposed protocol while delivering all the virtues of Islam et al.'s protocol resists all known attacks. PMID- 25912428 TI - An interrogation of cognitive findings in pediatric obsessive-compulsive and related disorders. AB - Current findings in the field of psychology have led to increased interest and a new conceptualization of disorders characterized by repetitive behaviors, namely the obsessive compulsive and related disorders (OCRDs). Scant research, however, has sought to collect and categorize the extant research on pediatric OCRDs. Particularly, no adequate review of the pediatric cognitive literature existed until now, despite the clear implication of abnormalities in neuroanatomical structures and cognitive functioning in adult samples. While evidence for cognitive dysfunction in pediatric samples is presented, this paper also suggests that differences in cognitive dysfunction may indeed exist between adults and youth with OCRDs. Specifically, those irregularities present in said youth at varying developmental stages may impact the origination and maintenance of OCRDs across time. Finally, this paper seeks to formulate potential future goals for the research field, particularly through transdiagnostic approaches to processes linked with symptom presentations. This is of particular importance as an improved understanding of the interaction of cognitive function and growth is key to further comprehension of the OCRDs. PMID- 25912429 TI - Comorbid physical and mental illnesses among pathological gamblers: Results from a population based study in Singapore. AB - The aim of the current study was to examine the comorbidity of pathological gambling with other mental and physical disorders as well as to examine health related quality of life perceived by those with pathological gambling using data from a community survey in Singapore. All respondents were administered the South Oaks Gambling Screen to screen for pathological gambling. The diagnosis of mental disorders was established using the Composite International Diagnostic Interview; while chronic physical conditions were established using a checklist. The weighted lifetime prevalence of pathological gambling was 2.7%. After multiple logistic regression, age 18-34 years (OR=5.3, 95% CI=1.6-17.4), male gender (OR=7.8, CI=3.8-16.2), widowhood (OR=4.2, 95% CI=1.02-17.5), and those with pre primary (OR=17.1, CI=4.9-59.1), primary (OR=5.3, CI=1.7-16.6), and secondary education (OR=6, CI=2.5-14.7) had significantly higher odds of having pathological gambling. Those of Malay (OR=0.1, 95% CI=0.07-0.2) and Indian ethnicity (OR=0.2, 95% CI=0.1-0.3) had significantly lower odds of having pathological gambling compared to those of Chinese ethnicity. Pathological gamblers had significantly higher odds of having comorbid mental and physical disorders than non-gamblers/non-problem gamblers. The significant association of comorbid mental and physical disorders among those with pathological gambling indicates a need to screen for these disorders and for their subsequent treatment. PMID- 25912430 TI - Exogenous beta-amyloid peptide interferes with GLUT4 localization in neurons. AB - Aging represents a major risk factor for numerous illnesses that are of increasing importance to society, including two of the most prevalent: diabetes and Alzheimer's disease. Studies have shown that diabetes is a risk factor for spontaneous Alzheimer's disease. While these studies suggest that diabetes can contribute to Alzheimer's disease, the implications of AD on diabetes are practically unexplored. The major mediator of the pathophysiological effects, the Abeta42 peptide, has been shown to enter neurons and lead to an alteration of the intracellular distribution of the molecular motor myosin Vb. Myosin Vb functions in memory and learning by participating in the strengthening of the long-term potentiation (LTP) of synaptic transmissions. It has also been implicated in the translocation of the glucose transporter, GLUT4, to the plasma membrane in response to insulin, a process that is defective in diabetes. Here, the effect on GLUT4 upon entry of the Abeta42 peptide into cultured chick retinal neurons was explored. The results suggest an alteration in distribution and a reduced level at the cell surface, as well as an increased colocalization with myosin Vb, which can partially explain the changes in glucose metabolism associated with AD. It is also shown that the presence of the Abeta40 peptide inhibits the internalization of the Abeta42 peptide in cultured cells. Together, the results provide additional targets for the development of therapeutics against the progression and effects of Alzheimer's disease. PMID- 25912431 TI - Neural correlates of impaired emotional face recognition in cerebellar lesions. AB - Clinical and neuroimaging data indicate a cerebellar contribution to emotional processing, which may account for affective-behavioral disturbances in patients with cerebellar lesions. We studied the neurophysiology of cerebellar involvement in recognition of emotional facial expression. Participants comprised eight patients with discrete ischemic cerebellar lesions and eight control patients without any cerebrovascular stroke. Event-related potentials (ERP) were used to measure responses to faces from the Karolinska Directed Emotional Faces Database (KDEF), interspersed in a stream of images with salient contents. Images of faces augmented N170 in both groups, but increased late positive potential (LPP) only in control patients without brain lesions. Dipole analysis revealed altered activation patterns for negative emotions in patients with cerebellar lesions, including activation of the left inferior prefrontal area to images of faces showing fear, contralateral to controls. Correlation analysis indicated that lesions of cerebellar area Crus I contribute to ERP deviations. Overall, our results implicate the cerebellum in integrating emotional information at different higher order stages, suggesting distinct cerebellar contributions to the proposed large-scale cerebral network of emotional face recognition. PMID- 25912432 TI - The downregulation of Wnt/beta-catenin signaling pathway is associated with zinc deficiency-induced proliferative deficit of C17.2 neural stem cells. AB - Zinc is an essential nutrient that is important for normal brain development. Zinc deficiency has been linked to aberrant neurological development and functioning. However, the molecular mechanisms underlying Zinc deficiency-induced neurological disorders remain largely elusive. In the present study, we showed that the proliferation of C17.2 neural stem cells (NSCs) was evidently impaired after exposed to low levels of Zinc chelator, N,N,N',N'-tetrakis-(2-pyridylmethy) ethylenediamine (TPEN). In addition, we found that TPEN-induced proliferative deficit of NSCs was related with significant downregulation of Wnt/beta-catenin signaling. Zinc deficiency impaired the proliferation of neural stem cells in dose- and time-dependent manners. Western blot revealed that the levels of p-Ser9 glycogensynthase kinase-3beta (p-GSK-3beta) and beta-catenin were remarkably downregulated during TPEN-induced C17.2 proliferative impairment. Moreover, immunofluorescent analysis indicated that the level of nuclear beta-catenin was apparently decreased following TPEN exposure. Furthermore, application with GSK 3beta inhibitor lithium chloride (LiCl) reversed TPEN-induced downregulation of beta-catenin and impairment of cell proliferation. Flow cytometry analysis also showed that TPEN-induced impairment of NSC proliferation could be reversed by LiCl. Taken together, these findings suggested that the disturbance of canonical Wnt/beta-catenin signaling pathway partially accounted for Zinc deficiency induced proliferative impairment of NSCs. PMID- 25912433 TI - Neurogenin 2 enhances the generation of patient-specific induced neuronal cells. AB - Direct lineage reprogramming of human fibroblasts into functional neurons holds great promise for biomedical applications such as regenerative medicine and cellbased disease modelling. However, clinical applications must consider how to increase neuronal conversion efficiency and at the same time reduce the number of required transcription factors. Here, we investigated whether Neurogenin 2 (Ngn2), which is a proneural gene that directs neuronal differentiation of progenitor cells during development, can enhance the generation of patient specific induced neuronal cells. In this study, we transfected Ascl1, Sox2 and Ngn2 into human fibroblasts from the patients' scalp by lentivirus. Morphological analysis, immunocytochemistry, gene expression and electrophysiological analysis were performed to identify the similarity of induced neuronal cells (iNCs) to human neuronal cells. Ngn2 increase the conversion efficiency from 4% to 13.4%. iNCs express neuronal cell markers and resemble wild-type neurons in their morphology, gene expression profiles and exhibit functional membrane properties of mature neurons. Implanted iNCs can survive and integrate in mouse brains and, unlike iPS cell-derived neural cells, do not generate tumours. PMID- 25912434 TI - Activation of D1-like receptor-dependent phosphatidylinositol signal pathway by SKF83959 inhibits voltage-gated sodium channels in cultured striatal neurons. AB - Dopamine, a key neurotransmitter mediating the rewarding effects, exerts some of its effects by modulating neuronal excitability of striatal medium spiny neurons. A D1-like dopamine receptor-dependent phosphatidylinositol signal pathway exists in the striatum, however little is known about its role in the dopaminergic modulation of striatal neuronal excitability. 3-Methyl-6-chloro-7, 8-hydroxy-1-(3 methylphenyl)-2,3,4,5-tetrahydro-1H-3-benzazepine (SKF83959) is a selective D1 receptor agonist with high-affinity. Here, we observed its effect on the voltage gated sodium channels (VGSCs) in primary cultured striatal neurons by whole cell patch-clamp technique. We found that SKF83959 induced an inhibition on VGSCs in a dose-dependent manner in striatal neurons (IC50 value: 3.31 +/- 0.39 MUM), which could be prevented by antagonist of D1 receptor, but not that of D2, alpha1 adrenergic, or cholinoceptor. The effect of SKF83959 on VGSCs was also prevented by pretreatment with inhibitors of phospholipase C (PLC) and protein kinases C (PKC), but the inositol-1,4,5-phosphate 3 (IP3) antagonist did not occlude SKF83959 (1MUM)-induced reduction of VGSCs. These data indicate that SKF83959 inhibits VGSCs in cultured striatal neurons via D1-like receptor phosphatidylinositol-PKC pathway, which may underlie the dopaminergic modulation on striatal neuronal excitability. PMID- 25912435 TI - Pravastatin acute neuroprotective effects depend on blood brain barrier integrity in experimental cerebral ischemia. AB - Statins have since long been reported to exert acute neuroprotection in experimental stroke models. However, crucial questions still need to be addressed as far as the timing of their cerebral effects after intravascular administration and the role played by the blood brain barrier (BBB) crossing properties. We tested the effects of an hydrophilic statin (pravastatin, 100 nM), which poorly crosses BBB under physiological conditions. Pravastatin was administered either 90 min before or immediately after transient middle cerebral artery occlusion in the in vitro isolated guinea pig brain preparation. A multi-modal outcome assessment was performed, through electrophysiological and cerebral vascular tone recordings, MAP-2 immunohistochemistry, BBB evaluation via ZO-1/FITC-albumin analysis, AKT and ERK activation and whole-cell antioxidant capacity. Pravastatin pre-ischemic administration did not produce any significant effect. Pravastatin post-ischemic administration significantly prevented MAP-2 immunoreactivity loss in ischemic areas, increased ERK phosphorylation in the ischemic hemisphere and enhanced whole-cell antioxidant capacity. Electrophysiological parameters, vascular tone and AKT signaling were unchanged. In all tested ischemic brains, ZO 1 fragmentation and FITC albumin extravasation was observed, starting 30 min from ischemia onset, indicating loss of BBB integrity. Our findings indicate that the rapid anti-ischemic effects of intravascular pravastatin are highly dependent on BBB increased permeability after stroke. PMID- 25912436 TI - Induction frequency affects cortico-striatal synaptic plasticity with implications for frequency filtering. AB - Long-term synaptic depression (LTD) in cortico-striatal circuits is initiated by depolarization of striatal medium spiny neurons through a convergent cortical glutamatergic input. This produces retrograde endocannabinoid signaling to presynaptic cortical terminals and eventually results in long term (>30 min) decreases in glutamate release. These same circuits can also undergo short-term depression (STD) through a less well-defined process in which the magnitude of postsynaptic responses returns to baseline levels within 10 min. Additionally, the cortico-striatal circuit shows characteristics of a GABAA receptor-dependent low-pass filter, which results in significant attenuation of high frequency cortical inputs. The majority of in vitro studies of LTD have used a 100-Hz induction paradigm and it is unclear whether other frequencies, which may also have physiological relevance, have equivalent ability to induce this form of plasticity. Here we have investigated the effectiveness of a range of induction paradigms in producing LTD in cortico-striatal circuits, and demonstrate that some lower frequency paradigms, with perhaps more physiological relevance, are more effective at inducing LTD. We also show that GABAA receptor-dependent frequency filtering in this circuit is altered following the induction of LTD and STD suggesting an important role for synaptic depression in signal processing in these circuits. PMID- 25912437 TI - Immunohistochemical and molecular analysis of PI3K/AKT/mTOR pathway in esophageal carcinoma. AB - Among the numerous signaling pathways involved in tumorigenesis, PI3K-AKT-mTOR is a key one that regulates diverse cellular functions. However, its prognostic value in esophageal carcinoma remains unclear. In our study, we examined the immunohistochemical expression of phosphorylated (p-) AKT, mTOR, p70S6K and 4E BP1 along with the mutational status of PIK3CA and AKT1 genes by High Resolution Melting Analysis and Pyrosequencing in 44 esophageal carcinomas. The results were correlated with the clinicopathological characteristics of the patients in an effort to define their possible prognostic significance. Total p-mTOR cytoplasmic expression, assessed in 10 random areas, was positively correlated with tumor stage (Kruskal-Wallis ANOVA, I/II vs III/IV, p = 0.0500). MUoreover, maximum p mTOR cytoplasmic immunoexpression, estimated in hot spot areas, was positively associated with tumor grade (Mann-Whitney U test, I/II vs III, p = 0.0565). Interestingly, p-4E-BP1 immunoreactivity was negatively correlated with tumor histological grade (Mann-Whitney U test, I/II vs III, p = 0.0427). No mutation was observed in exons 9 and 20 of PIK3CA gene and in exon 4 of AKT1 gene. In conclusion, our findings depict the presence of activated PI3K/AKT/mTOR pathway in esophageal cancer bringing forward p-mTOR and p-4E-BP1 for their potential role in esophageal carcinogenesis. Additional studies are warranted to validate our findings. PMID- 25912438 TI - Retrograde transport of radiolabelled botulinum neurotoxin type A to the CNS after intradetrusor injection in rats. AB - OBJECTIVE: To investigate the potential distribution of radiolabelled botulinum neurotoxin type A (BoNT/A) in the CNS after bladder injection in normal rats, by using the gamma-emitting radionuclide technetium-99 m ((99m) Tc). MATERIALS AND METHODS: BoNT/A was radiolabelled by pretreatment with 2-iminothiolane and incubation with (99m) Tc-gluconate. The labelled toxin (99m) Tc-BoNT/A was purified using size exclusion HPLC. Twenty-four female Wistar rats were evenly injected in the bladder wall with either (99m) Tc-BetaomicronNuTau/Alpha (n = 12) or free (99m) Tc (n = 12). Four rats from each group were killed at 1, 3 and 6 h after injection, respectively. The bladder, L6-S1 spinal cord segment and L6-S1 dorsal root ganglia (DRG) were harvested and their radioactivity counted in a gamma scintillation detector. Results were calculated as % injected dose (I.D.) per gram of tissue. The paired t-test was used for comparison of means of (99m) Tc-BetaomicronNuTau/Alpha radioactivity vs free (99m) Tc in the tissues of interest. RESULTS: Radiolabelled BoNT/A had a high radiochemical stability of 70% after 24 h. Gradual accumulation of (99m) Tc-BetaomicronNuTau/Alpha was observed in the DRG up to 6 h after injection (P = 0.04 and P = 0.029 compared with 1 h and 3 h, respectively), while no accumulation was detected for free (99m) Tc. Consequently, (99m) Tc-BetaomicronNuTau/Alpha radioactivity in the DRG was higher than free (99m) Tc radioactivity (3.18 +/- 0.67% I.D./g vs 0.19 +/- 0.10% I.D./g [P = 0.002] 6 h after injection). Values for (99m) Tc-BetaomicronNuTau/Alpha radioactivity in the spinal cord were higher than those for free (99m) Tc, but not significantly. The bladder retained higher dosages of (99m) Tc BetaomicronNuTau/Alpha than free (99m) Tc at all time points. CONCLUSIONS: Significant accumulation of the radiolabelled toxin in the lumbosacral DRG, together with a less significant uptake in the respective spinal cord segment as opposed to free radioactivity provide first evidence of the retrograde transport of BoNT/A to the CNS after bladder injection in rats. PMID- 25912439 TI - Neurons in the lateral part of the lumbar spinal cord show distinct novel axon trajectories and are excited by short propriospinal ascending inputs. AB - The role of spinal dorsal horn propriospinal connections in nociceptive processing is not yet established. Recently described, rostrocaudally oriented axon collaterals of lamina I projection and local-circuit neurons (PNs and LCNs) running in the dorsolateral funiculus (DLF) may serve as the anatomical substrate for intersegmental processing. Putative targets of these axons include lateral dendrites of superficial dorsal horn neurons, including PNs, and also neurons in the lateral spinal nucleus (LSN) that are thought to be important integrator units receiving, among others, visceral sensory information. Here we used an intact spinal cord preparation to study intersegmental connections within the lateral part of the superficial dorsal horn. We detected brief monosynaptic and prolonged polysynaptic excitation of lamina I and LSN neurons when stimulating individual dorsal horn neurons located caudally, even in neighboring spinal cord segments. These connections, however, were infrequent. We also revealed that some projection neurons outside the dorsal grey matter and in the LSN have distinct, previously undescribed course of their projection axon. Our findings indicate that axon collaterals of lamina I PNs and LCNs in the DLF rarely form functional connections with other lamina I and LSN neurons and that the majority of their targets are on other elements of the dorsal horn. The unique axon trajectories of neurons in the dorsolateral aspect of the spinal cord, including the LSN do not fit our present understanding of midline axon guidance and suggest that their function and development differ from the neurons inside lamina I. These findings emphasize the importance of understanding the connectivity matrix of the superficial dorsal horn in order to decipher spinal sensory information processing. PMID- 25912441 TI - Ketocyanine dyes: impact of conjugation length on optical absorption and third order polarizabilities. AB - Broken symmetry and symmetry adapted cluster-configuration interaction techniques help to understand the structure-property relationships like impact of conjugation length on the electronic structure, small energy optical absorption and third-order polarizabilities in symmetric ketocyanine dyes. The sum-over states approximation truncated to essential states model helped to understand the origin of the negative sign and the most relevant components of average static third-order polarizabilities. The results can be used as a design principle to model the ketocyanine dyes which can absorb in the visible to near-infrared region and show large negative third-order nonlinear activity. PMID- 25912440 TI - Role of large MAF transcription factors in the mouse endocrine pancreas. AB - The members of the MAF family of transcription factors are homologs of v-Maf -the oncogenic component of the avian retrovirus AS42. The MAF family is subdivided into 2 groups, small and large MAFs. To elucidate the role of the large MAF transcription factors in the endocrine pancreas, we analyzed large MAF gene knockout mice. It has been shown that Mafa(-/-) mice develop phenotypes including abnormal islet structure soon after birth. This study revealed that Ins1 and Ins2 transcripts and the protein contents were significantly reduced in Mafa(-/-) mice at embryonic day 18.5. In addition, Mafa(-/-);Mafb(-/-) mice contained less than 10% of the insulin transcript and protein of those of wild-type mice, suggesting that Mafa and Mafb cooperate to maintain insulin levels at the embryonic stage. On the other hand, the number of insulin-positive cells in Mafa(-/-) mice was comparable to that of wild-type mice, and even under a Mafb-deficient background the number of insulin-positive cells was not decreased, suggesting that Mafb plays a dominant role in embryonic beta-cell development. We also found that at 20 weeks of age Mafa(-/-);Mafb(+/-) mice showed a higher fasting blood glucose level than single Mafa(-/-) mice. In summary, our results indicate that Mafa is necessary for the maintenance of normal insulin levels even in embryos and that Mafb is important for the maintenance of fasting blood glucose levels in the Mafa deficient background in adults. PMID- 25912444 TI - [96th German Roentgen Congress 13th to 16th May 2015 - MTRA program]. PMID- 25912445 TI - [University of Jena honors Prof. Dr. Dipl.-Chem. Werner Alois Kaiser - Jena MRI Research Center named after the pioneer in magnetic resonance mammography]]. PMID- 25912446 TI - Signal peptide optimization tool for the secretion of recombinant protein from Saccharomyces cerevisiae. AB - The secretion efficiency of foreign proteins in recombinant microbes is strongly dependent on the combination of the signal peptides (SPs) used and the target proteins; therefore, identifying the optimal SP sequence for each target protein is a crucial step in maximizing the efficiency of protein secretion in both prokaryotes and eukaryotes. In this study, we developed a novel method, named the SP optimization tool (SPOT), for the generation and rapid screening of a library of SP-target gene fusion constructs to identify the optimal SP for maximizing target protein secretion. In contrast to libraries generated in previous studies, SPOT fusion constructs are generated without adding the intervening sequences associated with restriction enzyme digestion sites. Therefore, no extra amino acids are inserted at the N-terminus of the target protein that might affect its function or conformational stability. As a model system, beta-galactosidase (LacA) from Aspergillus oryzae was used as a target protein for secretion from Saccharomyces cerevisiae. In total, 60 SPs were selected from S. cerevisiae secretory proteins and utilized to generate the SP library. While many of the SP LacA fusions were not secreted, several of the SPs, AGA2, CRH1, PLB1, and MF(alpha)1, were found to enhance LacA secretion compared to the WT sequence. Our results indicate that SPOT is a valuable method for optimizing the bioproduction of any target protein, and could be adapted to many host strains. PMID- 25912447 TI - Counterselection method based on conditional silencing of antitoxin genes in Escherichia coli. AB - Counterselection is a genetic engineering technique to eliminate specific genetic fragments containing selectable marker genes. Although the technique is widely used in bacterial genome engineering and plasmid curing experiments, the repertoire of the markers usable in Escherichia coli is limited. Here we developed a novel counterselection method in E. coli based on antisense RNA (asRNA) technology directed against toxin-antitoxin (TA) modules. Under normal conditions, excess antitoxin neutralizes its cognate toxin and thus the module is stably maintained in the genome. We hypothesised that repression of an antitoxin gene would perturb cell growth due to the toxin being released. We designed asRNAs corresponding to all 19 type II antitoxins encoded in the E. coli genome. asRNAs were then conditionally expressed; repression of MqsA in the MqsR/MqsA module had the greatest inhibitory effect, followed by RnlB in the RnlA/RnlB module. The utility of asRNA(MqsA) as a counterselection marker was demonstrated by efficient plasmid curing and strain improvement experiments. PMID- 25912448 TI - (13)C-metabolic flux analysis in S-adenosyl-L-methionine production by Saccharomyces cerevisiae. AB - S-Adenosyl-L-methionine (SAM) is a major biological methyl group donor, and is used as a nutritional supplement and prescription drug. Yeast is used for the industrial production of SAM owing to its high intracellular SAM concentrations. To determine the regulation mechanisms responsible for such high SAM production, (13)C-metabolic flux analysis ((13)C-MFA) was conducted to compare the flux distributions in the central metabolism between Kyokai no. 6 (high SAM-producing) and S288C (control) strains. (13)C-MFA showed that the levels of tricarboxylic acid (TCA) cycle flux in SAM-overproducing strain were considerably increased compared to those in the S228C strain. Analysis of ATP balance also showed that a larger amount of excess ATP was produced in the Kyokai 6 strain because of increased oxidative phosphorylation. These results suggest that high SAM production in Kyokai 6 strains could be attributed to enhanced ATP regeneration with high TCA cycle fluxes and respiration activity. Thus, maintaining high respiration efficiency during cultivation is important for improving SAM production. PMID- 25912449 TI - Novel glucose dehydrogenase from Mucor prainii: Purification, characterization, molecular cloning and gene expression in Aspergillus sojae. AB - Glucose dehydrogenase (GDH) is of interest for its potential applications in the field of glucose sensors. To improve the performance of glucose sensors, GDH is required to have strict substrate specificity. A novel flavin adenine dinucleotide (FAD)-dependent GDH was isolated from Mucor prainii NISL0103 and its enzymatic properties were characterized. This FAD-dependent GDH (MpGDH) exhibited high specificity toward glucose. High specificity for glucose was also observed even in the presence of saccharides such as maltose, galactose and xylose. The molecular masses of the glycoforms of GDH ranged from 90 to 130 kDa. After deglycosylation, a single 80 kDa band was observed. The gene encoding MpGDH was cloned and expressed in Aspergillus sojae. The apparent kcat and Km values of recombinant enzyme for glucose were found to be 749.7 s(-1) and 28.3 mM, respectively. The results indicated that the characteristics of MpGDH were suitable for assaying blood glucose levels. PMID- 25912450 TI - Challenges to production of antibodies in bacteria and yeast. AB - Currently, antibodies play major role in treating a wide variety of human diseases (e.g., cancer, viral infection, inflammation). Those pharmaceutic antibodies have become major therapeutic reagents in the pharmaceutical drug market. In addition to full-length antibodies, the market of antibody fragments, which offer potential advantages in clinical use as well as diagnostics, is gradually growing. As the demand for antibody therapeutics increase, the development of host systems for enhanced, and less expensive, production has also become more important. All therapeutic antibodies approved to date are predominantly produced in mammalian hosts, but due to drawbacks such as high production cost and long-term cultivation, the alternative use of bacteria and yeasts has been seriously considered. Recently, there have been reports of substantial progress in genetic engineering and systems biotechnology, results in development of potential hosts that overcame the critical limitations in bacterial and yeast cells, and much enhanced productivity of functional antibodies. In this review, we highlight recent, significant progress made in the engineering of bacterial and yeast cells for enhanced production of functional antibodies. PMID- 25912451 TI - Application of gas chromatography/flame ionization detector-based metabolite fingerprinting for authentication of Asian palm civet coffee (Kopi Luwak). AB - Development of authenticity screening for Asian palm civet coffee, the world renowned priciest coffee, was previously reported using metabolite profiling through gas chromatography/mass spectrometry (GC/MS). However, a major drawback of this approach is the high cost of the instrument and maintenance. Therefore, an alternative method is needed for quality and authenticity evaluation of civet coffee. A rapid, reliable and cost-effective analysis employing a universal detector, GC coupled with flame ionization detector (FID), and metabolite fingerprinting has been established for discrimination analysis of 37 commercial and non-commercial coffee beans extracts. gas chromatography/flame ionization detector (GC/FID) provided higher sensitivity over a similar range of detected compounds than GC/MS. In combination with multivariate analysis, GC/FID could successfully reproduce quality prediction from GC/MS for differentiation of commercial civet coffee, regular coffee and coffee blend with 50 wt % civet coffee content without prior metabolite details. Our study demonstrated that GC/FID-based metabolite fingerprinting can be effectively actualized as an alternative method for coffee authenticity screening in industries. PMID- 25912452 TI - Fabrication of uniformly cell-laden porous scaffolds using a gas-in-liquid templating technique. AB - Design of porous scaffolds in tissue engineering field was challenging. Uniform immobilization of cells in the scaffolds with high porosity was essential for homogeneous tissue formation. The present study was aimed at fabricating uniformly cell-laden porous scaffolds with porosity >74% using the gas-in-liquid foam templating technique. To this end, we used gelatin, microbial transglutaminase and argon gas as a scaffold material, cross-linker of the protein and porogen of scaffold, respectively. We confirmed that a porosity of >74% could be achieved by increasing the gas volume delivered to a gelatin solution. Pore size in the scaffold could be controlled by stirring speed, stirring time and the pore size of the filter through which the gas passed. The foaming technique enabled us to uniformly immobilize a human hepatoblastoma cell line in scaffold. Engraftment efficiency of the cell line entrapped within the scaffold in nude mice was higher than that of cells in free-form. These results showed that the uniformly cell-laden porous scaffolds were promising for tissue engineering. PMID- 25912453 TI - Mononuclear nonheme iron(III) complexes that show superoxide dismutase-like activity and antioxidant effects against menadione-mediated oxidative stress. AB - This communication describes the superoxide dismutase (SOD)-like activity of mononuclear iron(III) complexes with pentadentate monocarboxylamido ligands. The SOD activity can be controlled by the electronic nature of the substituent group on the ligand. The nitro-substituted complex showed clear cytoprotective activity against menadione-mediated oxidative stress in cultured cells. PMID- 25912454 TI - Growing old and gasping for air. PMID- 25912455 TI - Continuum electrostatic approach for evaluating positions and interactions of proteins in a bilayer membrane. AB - Orientations of proteins in the membranes are crucial to their function and stability. Unfortunately the exact positions of these proteins in the lipid bilayer are mostly undetermined. Here, the spatial orientation of membrane proteins within the lipid membrane was evaluated using a Poisson-Boltzmann solvent continuum approach to calculate the electrostatic free energy of the protein solvation at various orientations in an implicit bilayer. The solvation energy was obtained by computing the difference in electrostatic energies of the protein in water and in lipid/water environments, treating each as an implicit solvent model. The optimal position of transmembrane proteins (TMP) in a lipid bilayer is identified by the minimum in the "downhill" pathway of the solvation energy landscape. The energy landscape pattern was considerably conserved in various TMP classes. Evaluation of the position of 1060 membrane proteins from the orientations of proteins in membranes (OPM) database revealed that most of the polytopic and beta-barrel proteins were in good agreement with those of the OPM database. The study provides a useful scheme for estimating the membrane solvation energy made by lipid-exposed amino acids in membrane proteins. In addition, our results tested with the bacterial potassium channel model demonstrated the potential usefulness of the approach in assessing the quality of membrane protein models. The present approach should be applicable for constructing transmembrane proteins-lipid configuration suitable for membrane protein simulations and will have utility for the structural modeling of membrane proteins. PMID- 25912456 TI - Evolution of structure, stability, and nonlinear optical properties of the heterodinuclear CNLin (n=1-10) clusters. AB - The lowest-energy structures and stabilities of the heterodinuclear clusters, CNLin (n=1-10) and relevant CNLin(+) (n=1-10) cations, are studied using the density functional theory with the 6-311+G(3df) basis set. The CNLi6 and CNLi5(+) clusters are the first three-dimensional ones in the CNLin(0/+) series, respectively, and the CN group always caps the Lin(0/+) moiety in the CNLin(0/+) (n=1-9) configurations. The CN triple bond is found to be completely cleaved in the CNLi10(0/+) clusters where the C and N atoms are bridged by two Li atoms. The CNLin (n=2-10) clusters are hyperlithiated molecules with delocalized valence electrons and consequently possess low VIP values of 3.780-5.674eV. Especially, the CNLi8 and CNLi10 molecules exhibit lower VIPs than that of Cs atom and can be regarded as heterobinuclear superalkali species. Furthermore, these two superalkali clusters show extraordinarily large first hyperpolarizabilities of 19,423 and 42,658au, respectively. For the CNLin(+) cationic species, the evolution of the energetic and electronic properties with the cluster size shows a special stability for CNLi2(+). PMID- 25912457 TI - Cyclooxygenase-2 inhibitor prevents radiation-enhanced infiltration of F98 glioma cells in brain of Fischer rat. AB - PURPOSE: Radiation induces a neuro-inflammation that is characterized by the expression of genes known to increase the invasion of cancer cells. In Fischer rats, brain irradiation increases the infiltration of cancer cells and reduced the median survival of the animals. In this study, we have determined whether these adverse effects of radiation can be prevented with the cyclooxygenase-2 (COX-2) inhibitor meloxicam. MATERIALS AND METHODS: Brain of Fischer rats treated or not with meloxicam were irradiated (15 Gy) and then implanted with the F98 glioma cells. The median survival of the animals, the infiltration of F98 cells, and the expression of inflammatory cytokines and pro-migration molecules were measured. RESULTS: Meloxicam reduced by 75% the production of prostaglandin E2 (bioproduct of COX-2) in irradiated brains validating its anti-inflammatory effect. Median survival was increased to control levels by the treatment of meloxicam following brain irradiation. This protective effect was associated with a reduction of the infiltration of F98 cells in the brain, a complete inhibition of radiation-enhancement of matrix metalloproteinase-2, and a significant reduction of tumor necrosis factor alpha (TNF-alpha) and tumor growth factor beta1 (TGF-beta1) expression. Using invasion chambers, interleukin-1beta (IL 1beta) stimulated by 5-fold the invasiveness of F98 cells, but this stimulation was completely inhibited by meloxicam. This suggests that a cooperation between IL-1beta and COX-2 are involved in radiation-enhancement of F98 cell invasion. CONCLUSIONS: Our results indicate the importance of reducing the inflammatory response of normal brain tissue following irradiation in an effort to extend median survival in F98 tumor-bearing rats. PMID- 25912458 TI - Motility bar: A new tool for motility analysis of endoluminal videos. AB - Wireless Capsule Endoscopy (WCE) provides a new perspective of the small intestine, since it enables, for the first time, visualization of the entire organ. However, the long visual video analysis time, due to the large number of data in a single WCE study, was an important factor impeding the widespread use of the capsule as a tool for intestinal abnormalities detection. Therefore, the introduction of WCE triggered a new field for the application of computational methods, and in particular, of computer vision. In this paper, we follow the computational approach and come up with a new perspective on the small intestine motility problem. Our approach consists of three steps: first, we review a tool for the visualization of the motility information contained in WCE video; second, we propose algorithms for the characterization of two motility building-blocks: contraction detector and lumen size estimation; finally, we introduce an approach to detect segments of stable motility behavior. Our claims are supported by an evaluation performed with 10 WCE videos, suggesting that our methods ably capture the intestinal motility information. PMID- 25912459 TI - Proteomic identification of plasma proteins as markers of growth promoter abuse in cattle. AB - Growth-promoting agents are continually misused for increasing animal growth and fraudulent gain in the meat industry, yet detection rates from conventional targeted testing for drug residues do not reflect this. This is because testing currently relies on direct detection of drugs or related metabolites and administrators of such compounds can take adaptive measures to avoid detection through the use of endogenous or unknown drugs, and low dose or combined mixtures. New detection methods are needed which focus on the screening of biological responses of an animal to such growth-promoting agents as it has been demonstrated that genomic, proteomic and metabolomics profiles are altered by xenobiotic intake. Therefore, an untargeted proteomics approach using comparative two-dimensional gel electrophoresis (2DE) was carried out to identify putative proteins altered in plasma after treatment with oestradiol, dexamethasone or prednisolone. Twenty-four male cattle were randomly assigned to four groups (n = 6) for experimental treatment over 40 days, namely a control group of non-treated cattle, and three groups administered 17beta-oestradiol-3-benzoate (0.01 mg/kg, intramuscular), dexamethasone sodium phosphate (0.7 mg/day, per os) or prednisolone acetate (15 mg/day, per os), respectively. Plasma collected from each animal at day 25 post study initiation was subjected to proteomic analysis by 2DE for comparison of protein expression between treated and untreated animals. Analysis of acquired gel images revealed 22 plasma proteins which differed in expression by more than 50% (p < 0.05) in treated animals compared to untreated animals. Proteins of interest underwent identification by LC-MS/MS analysis and were found to have associated roles in transport, blood coagulation, immune response and metabolism pathways. In this way, seven proteins are highlighted as novel biomarker candidates including transthyretin which is shown to be significantly increased in all treatment groups compared to control animals and potentially may find use as global markers of suspect anabolic practice. PMID- 25912460 TI - Spatial chemo-profiling of hypericin and related phytochemicals in Hypericum species using MALDI-HRMS imaging. AB - Advanced analytical imaging techniques, including matrix-assisted laser desorption/ionization high-resolution mass spectrometry (MALDI-HRMS) imaging, can be used to visualize the distribution, localization, and dynamics of target compounds and their precursors with limited sample preparation. Herein we report an application of MALDI-HRMS imaging to map, in high spatial resolution, the accumulation of the medicinally important naphthodianthrone hypericin, its structural analogues and proposed precursors, and other crucial phytochemical constituents in the leaves of two hypericin-containing species, Hypericum perforatum and Hypericum olympicum. We also investigated Hypericum patulum, which does not contain hypericin or its protoforms. We focused on both the secretory (dark glands, translucent glands, secretory canals, laminar glands, and ventral glands) and the surrounding non-secretory tissues to clarify the site of biosynthesis and localization of hypericin, its possible precursors, and patterns of localization of other related compounds concomitant to the presence or absence of hypericin. Hypericin, pseudohypericin, and protohypericin accumulate in the dark glands. However, the precursor emodin not only accumulates in the dark glands but is also present outside the glands in both hypericin-containing species. In hypericin-lacking H. patulum, however, emodin typically accumulates only in the glands, thereby providing evidence that hypericin is possibly biosynthesized outside the dark glands and thereafter stored in them. The distribution and localization of related compounds were also evaluated and are discussed concomitant to the occurrence of hypericin. Our study provides the basis for further detailed investigation of hypericin biosynthesis by gene discovery and expression studies. PMID- 25912461 TI - Analysis of glipizide binding to normal and glycated human serum albumin by high performance affinity chromatography. AB - In diabetes, the elevated levels of glucose in the bloodstream can result in the nonenzymatic glycation of proteins such as human serum albumin (HSA). This type of modification has been shown to affect the interactions of some drugs with HSA, including several sulfonylurea drugs that are used to treat type II diabetes. This study used high-performance affinity chromatography (HPAC) to examine the interactions of glipizide (i.e., a second-generation sulfonylurea drug) with normal HSA or HSA that contained various levels of in vitro glycation. Frontal analysis indicated that glipizide was interacting with both normal and glycated HSA through two general groups of sites: a set of relatively strong interactions and a set of weaker interactions with average association equilibrium constants at pH 7.4 and 37 degrees C in the range of 2.4-6.0 * 10(5) and 1.7-3.7 * 10(4) M(-1), respectively. Zonal elution competition studies revealed that glipizide was interacting at both Sudlow sites I and II, which were estimated to have affinities of 3.2-3.9 * 10(5) and 1.1-1.4 * 10(4) M(-1). Allosteric effects were also noted to occur for this drug between the tamoxifen site and the binding of R warfarin at Sudlow site I. Up to an 18% decrease in the affinity for glipizide was observed at Sudlow site I ongoing from normal HSA to glycated HSA, while up to a 27% increase was noted at Sudlow site II. This information should be useful in indicating how HPAC can be used to investigate other drugs that have complex interactions with proteins. These results should also be valuable in providing a better understanding of how glycation may affect drug-protein interactions and the serum transport of drugs such as glipizide during diabetes. PMID- 25912462 TI - Aqueous solution/metal interfaces investigated in operando by photoelectron spectroscopy. AB - We describe a new in operando approach for the investigation of heterogeneous processes at solid/liquid interfaces with elemental and chemical specificity which combines the preparation of thin liquid films using the meniscus method with standing wave ambient pressure X-ray photoelectron spectroscopy [Nemsak et al., Nat. Commun., 5, 5441 (2014)]. This technique provides information about the chemical composition across liquid/solid interfaces with sub-nanometer depth resolution and under realistic conditions of solution composition and concentration, pH, as well as electrical bias. In this article, we discuss the basics of the technique and present the first results of measurements on KOH/Ni interfaces. PMID- 25912463 TI - Ex vivo magnetic resonance imaging in South African manganese mine workers. AB - BACKGROUND: Manganese (Mn) exposure is associated with increased T1-weighted magnetic resonance imaging (MRI) signal in the basal ganglia. T1 signal intensity has been correlated with occupational Mn exposure but not with clinical symptomatology or neuropathology. OBJECTIVES: This study investigated predictors of ex vivo T1 MRI basal ganglia signal intensity in neuropathologic tissue obtained from deceased South African mine workers. METHODS: A 3.0 T MRI was performed on ex vivo brain tissue obtained from 19 Mn mine workers and 10 race- and sex-matched mine workers of other commodities. Basal ganglia regions of interest were identified for each subject with T1-weighted intensity indices generated for each region. In a pathology subset, regional T1 indices were compared to neuronal and glial cell density and tissue metal concentrations. RESULTS: Intensity indices were higher in Mn mine workers than non-Mn mine workers for the globus pallidus, caudate, anterior putamen, and posterior putamen with the highest values in subjects with the longest cumulative Mn exposure. Intensity indices were inversely correlated with the neuronal cell density in the caudate (p=0.040) and putamen (p=0.050). Tissue Mn concentrations were similar in Mn and non-Mn mine workers. Tissue iron (Fe) concentration trended lower across all regions in Mn mine workers. CONCLUSIONS: Mn mine workers demonstrated elevated basal ganglia T1 indices when compared to non-Mn mine workers. Predictors of ex vivo T1 MRI signal intensity in Mn mine workers include duration of Mn exposure and neuronal density. PMID- 25912464 TI - Early brain magnetic resonance imaging can predict short and long-term outcomes after organophosphate poisoning in a rat model. AB - INTRODUCTION: Magnetic resonance (MR) imaging is a sensitive modality for demonstrating in vivo alterations in brain structure and function after acute organophosphate (OP) poisoning. The goals of this study were to explore early imaging findings in organophosphate-poisoned animals, to assess the efficacy of centrally acting antidotes and to find whether early MR findings can predict post poisoning cognitive dysfunction. METHODS: Sprague-Dawley rats were poisoned with the agricultural OP paraoxon and were treated with immediate atropine and obidoxime (ATOX) to reduce acute mortality caused by peripheral inhibition of acetylcholinesterase. Animals were randomly divided into three groups based on the protocol of centrally acting antidotal treatment: group 1 - no central antidotal treatment (n=10); group 2 - treated with midazolam (MID) at 30 min after poisoning (n=9), group 3 - treated with a combination of MID and scopolamine (SCOP) at 30 min after poisoning (n=9) and controls (n=6). Each animal had a brain MR examination 3 and 24 h after poisoning. Each MR examination included the acquisition of a T2 map and a single-voxel (1)H MR spectroscopy (localized on the thalami, to measure total creatine [Cr], N-acetyl-aspartate [NAA] and cholines [Cho] levels). Eleven days after poisoning each animal underwent a Morris water maze to assess hippocampal learning. Eighteen days after poisoning, animals were euthanized, and their brains were dissected, fixed and processed for histology. RESULTS: All paraoxon poisoned animals developed generalized convulsions, starting within a few minutes following paraoxon injection. Brain edema was maximal on MR imaging 3 h after poisoning. Both MID and MID+SCOP prevented most of the cortical edema, with equivalent efficacy. Brain metabolic dysfunction, manifested as decreased NAA/Cr, appeared in all poisoned animals as early as 3h after exposure (1.1 +/- 0.07 and 1.42 +/- 0.05 in ATOX and control groups, respectively) and remained lower compared to non poisoned animals even 24h after poisoning. MID and MID+SCOP prevented much of the 3h NAA/Cr decrease (1.22 +/- 0.05 and 1.32 +/- 0.1, respectively). Significant correlations were found between imaging findings (brain edema and spectroscopic changes) and clinical outcomes (poor learning, weight loss and pathological score) with correlation coefficients of 0.4-0.75 (p<0.05). CONCLUSIONS: MR imaging is a sensitive modality to explore organophosphate-induced brain damage. Delayed treatment with midazolam with or without scopolamine provides only transient neuroprotection with some advantage in adding scopolamine. Early imaging findings were found to correlate with clinical consequences of organophosphate poisoning and could be potentially used in the future to predict long-term prognosis of poisoned casualties. PMID- 25912465 TI - An autophosphorylation site database for leucine-rich repeat receptor-like kinases in Arabidopsis thaliana. AB - Leucine-rich repeat receptor-like kinases (LRR RLKs) form a large family of plant signaling proteins consisting of an extracellular domain connected by a single pass transmembrane sequence to a cytoplasmic kinase domain. Autophosphorylation on specific Ser and/or Thr residues in the cytoplasmic domain is often critical for the activation of several LRR RLK family members with proven functional roles in plant growth regulation, morphogenesis, disease resistance, and stress responses. While identification and functional characterization of in vivo phosphorylation sites is ultimately required for a full understanding of LRR RLK biology and function, bacterial expression of recombinant LRR RLK cytoplasmic catalytic domains for identification of in vitro autophosphorylation sites provides a useful resource for further targeted identification and functional analysis of in vivo sites. In this study we employed high-throughput cloning and a variety of mass spectrometry approaches to generate an autophosphorylation site database representative of more than 30% of the approximately 223 LRR RLKs in Arabidopsis thaliana. We used His-tagged constructs of complete cytoplasmic domains to identify a total of 592 phosphorylation events across 73 LRR RLKs, with 497 sites uniquely assigned to specific Ser (268 sites) or Thr (229 sites) residues in 68 LRR RLKs. Multiple autophosphorylation sites per LRR RLK were the norm, with an average of seven sites per cytoplasmic domain, while some proteins showed more than 20 unique autophosphorylation sites. The database was used to analyze trends in the localization of phosphorylation sites across cytoplasmic kinase subdomains and to derive a statistically significant sequence motif for phospho-Ser autophosphorylation. PMID- 25912466 TI - Current management of patients with gastrointestinal stromal tumor receiving the multitargeted tyrosine kinase inhibitor sunitinib. AB - BACKGROUND: Gastrointestinal stromal tumor (GIST), a form of soft tissue sarcoma, is often detected incidentally or at an advanced stage. The tyrosine kinase inhibitor sunitinib malate (Sutent * ) is established as second-line treatment for the management of GIST after disease progression on, or intolerance to, first line imatinib treatment. Several published reviews give guidance on management of side effects in patients with advanced renal cell carcinoma treated with sunitinib, but fewer publications cover side-effect management in patients with GIST. SCOPE: Using published articles and abstracts, prescribing information, and personal experience in managing patients with GIST at a specialized center of excellence for cancer care, I review side-effect management recommendations for patients with GIST treated with sunitinib and provide an overview of GIST. FINDINGS: Sunitinib has a well described side-effect profile: most side effects occurring in patients with GIST can be easily managed by standard medical intervention and/or dose modification. CONCLUSION: Care of patients with GIST can be enhanced through communication, support, knowledge, and education, with the goal of providing effective therapy and optimal symptom control. PMID- 25912467 TI - Dermatitis by Tropical Rat Mite, Ornithonyssus bacoti (Mesostigmata, Macronyssidae) in Italian city-dwellers: a diagnostic challenge. PMID- 25912468 TI - The Framingham cardiovascular risk score in multiple sclerosis. AB - BACKGROUND AND PURPOSE: Cardiovascular risk factors can increase the risk of multiple sclerosis (MS) and modify its course. However, such factors possibly interact, determining a global cardiovascular risk. Our aim was to compare the global cardiovascular risk of subjects with and without MS with the simplified 10 year Framingham General Cardiovascular Disease Risk Score (FR) and to evaluate its importance on MS-related outcomes. METHODS: Age, gender, smoking status, body mass index, systolic blood pressure, type II diabetes and use of antihypertensive medications were recorded in subjects with and without MS to estimate the FR, an individualized percentage risk score estimating the 10-year likelihood of cardiovascular events. RESULTS: In total, 265 MS subjects were identified with 530 matched controls. A t test showed similar FR in cases and controls (P = 0.212). Secondary progressive MS presented significantly higher FR compared to relapsing-remitting MS (P < 0.001). Linear regression analysis showed a direct relationship between FR and Expanded Disability Status Scale (P < 0.001) and MS Severity Scale (P < 0.001). CONCLUSION: The FR, evaluating the global cardiovascular health by the interaction amongst different risk factors, relates to MS disability, severity and course. PMID- 25912469 TI - Treatment of Clostridium difficile infection in pediatric patients. AB - Clostridium difficile causes infections that can either remain asymptomatic or manifest as clinical disease. In this report, problems, possible solutions, and future perspectives on the treatment of C. difficile infections (CDIs) in pediatric patients are discussed. CDI, despite increasing as a consequence of the overuse and misuse of antibiotics, remains relatively uncommon in pediatrics mainly because younger children are poorly susceptible to the action of C. difficile toxins. In most such cases, C. difficile disease is mild to moderate and discontinuation of the administered antibiotics in patients receiving these drugs when CDI develops, or administration of metronidazole, is sufficient to solve this problem. In severe or frequently relapsing cases, vancomycin is the drug of choice. Probiotics do not seem to add significant advantages. Other treatment options must be reserved for severe cases and be considered as a salvage treatment, although potential advantages in pediatric patients remain unclear. PMID- 25912470 TI - Percutaneous left atrial appendage occlusion for stroke prevention in patients with atrial fibrillation and contraindication for anticoagulation. AB - BACKGROUND: Stroke, as the third cause of death in developed countries, is a public health issue. Atrial fibrillation is an important cause of ischemic stroke and its prevention is efficient with oral anticoagulation. However, oral anticoagulation can be contraindicated because of hemorrhagic risk related to these treatments. Percutaneous left atrial appendage occlusion is a new alternative of oral anticoagulation for patients with atrial fibrillation and high risk of cardio-embolic stroke but contraindicated for oral anticoagulation. METHODS: We describe in this paper the procedure of left atrial appendage occlusion with the Amplatzer cardiac plug device, used in our center in Grenoble university hospital, for the first three patients who have been treated with this device. These three patients (one man and two women) have all atrial fibrillation with neurological complication of this arrhythmia, as ischemic stroke. Oral anticoagulation is indicated to prevent another ischemic stroke. However, they all have a high risk of cerebral bleeding for different reasons (cavernomatosis, history of intracerebral hemorrhage and aneurysm of the polygon of Willis). Consequently, they have a high risk of cardio-embolic complication but contraindication for oral anticoagulation. They have been treated by left atrial appendage occlusion with Amplatzer cardiac plug device by percutaneous and trans septal access. Then, they have been followed by neurologist and cardiologist, with clinical and paraclinical evaluation by echocardiography. RESULTS: Our three first patients have been successfully implanted, without periprocedural complication. No latest adverse event was observed, and particularly no cardiac or neurologic adverse event. CONCLUSION: The technique of left atrial appendage occlusion is a very interesting and promising technique for ischemic stroke prevention in patient with high risk of cardio-embolic complication because of atrial fibrillation, but high risk of bleeding and contraindication for oral anticoagulation. Because of frequency of both atrial fibrillation and contraindication for oral anticoagulation, occlusion of the left atrial appendage should become an interesting alternative for many patients. However, it remains an invasive procedure and efficacy and indications need to be evaluated in further clinical trials. Risk/benefit ratio must be carefully assessed and compared to that of the new anticoagulant drugs. PMID- 25912471 TI - Targeted clinical audits immediately following the establishment of clinical practice guidelines for multiple sclerosis in 17 neurology departments: A pragmatic and collaborative study. AB - Following the publication practice guidelines for multiple sclerosis by a group of neurologists (multiple sclerosis study group [GRESEP]), the primary objective of this study was to compare the reality of practice to the guidelines according to the targeted clinical audit (TCA) method. The study was conducted at 17 neurology sites and was administered during two periods of MS care (diagnostic - TCA-DIAG, and disease course - TCA-EVOL). Two complementary surveys were done on the record keeping and the root causes of the deviations. The percentages of compliance ranged from 8 to 98% for the TCA-DIAG, and from 15 to 99% for the TCA EVOL, with wide disparity between sites. The audits were able to identify causes of the flaws in traceability or accessibility. At the end of the study, despite its limitations, we think that the sharing of the results from different sites provided interesting approaches for the use of the assessment criteria defined by GRESEP in a complete audit cycle. This study is to our knowledge the first report of an experiment in which guidelines were created, and subsequently followed by the development of assessment criteria and then the performance of targeted clinical audits using them, all by the same participants. CONTEXT: Clinical practice guidelines (CPGs) are intended to help practitioners and patients make informed treatment choices, but their integration into actual practice remains problematic. This study was done immediately following the publication of CPGs for multiple sclerosis (MS) by the multiple sclerosis study group [GRESEP]. The primary objective was to generate quality criteria, to test them within the same group, and to analyze the observed deviations. MATERIALS AND METHODS: The study was conducted in the 17 voluntary departments that had participated in the development of the CPGs. The targeted clinical audit method was administered during two periods of MS care (diagnostic - TCA-DIAG, and disease course - TCA EVOL). All the files were evaluated by a clinical research technician using digital format, which ensured thoroughness of the collection. Two complementary surveys were done on the record keeping and the potential causes of the deviations. RESULTS: The percentages of compliance to the criteria ranged from 8 to 98% (out of 240 files) for the TCA-DIAG, and from 15 to 99% (221 files) for the TCA-EVOL, with wide disparity between sites (interquartile distance ranges: TCA-DIAG between 0% and 55%; TCA-EVOL between 0% and 70%). The mean percentage of compliance with all the criteria as measured by the TCA-DIAG was 83.9% for the sites with digital files vs. 76.4% for those with only paper files (P<0.01). For the TCA-EVOL, the difference was not significant. Explanations for the observed deviations were suggested (1 to 9 according to the participants). DISCUSSION AND CONCLUSION: The quantified results could not be compared to other studies given the unique nature of the experiment. The importance of the traceability of practices in the patient files was discussed and assessed with regard to continuity and safety of care, as well as the medical-legal perspectives. Causes of lack of compliance were suggested (particularly the absence of reminders, the lack of means and/or time). Despite the limitations of the study, we think it is advisable that when a group becomes involved in the development of CPGs that they follow with the development of assessment criteria in order to evaluate the validity as well as their character as intermediate indicators of the quality of practices. PMID- 25912472 TI - Potential role of anti-VEGF targeted therapies in cervical artery dissection: A case report. PMID- 25912473 TI - Relationship between the velvet-like texture of flower petals and light reflection from epidermal cell surfaces. AB - Texture such as velvet lustre contributes to the ornamental character of a flower, along with shape and colour. This study aims to clarify the relationship between the formation of the velvet lustre texture and the optical characteristics of light reflection from irradiated surfaces of velvety and non velvety petals from 30 cultivars or varieties of ornamental plants representing 19 species from various families. The angle of incident light from the petal surface was set at 90 degrees , 60 degrees or 30 degrees , then light reflection from the petal surfaces was observed using a digital microscope. The observed reflected light was composed of "exterior" reflected light (ERL), which is observed as sparkling white spots on the surface of the epidermal cells, and "interior" reflected light (IRL), which is reflected from inside the petal and determines the base colour of the petals. Velvety petals had two common characteristics: conical-papillate or domed epidermal cells and a dark colour. As the angle between the petal and the incident light decreased, the ERL spots took on a belt-like shape, and total ERL intensity became stronger. We concluded that the velvety texture is derived from characteristic ERL rays coupled with dark IRL. The long sloping surface of the epidermal cells contributes to the higher ERL intensity as petals are observed from more horizontal angles, causing characteristic reverse shading effects on velvety petals. PMID- 25912474 TI - Melatonin delays leaf senescence and enhances salt stress tolerance in rice. AB - Melatonin, an antioxidant in both animals and plants, has been reported to have beneficial effects on the aging process. It was also suggested to play a role in extending longevity and enhancing abiotic stress resistance in plant. In this study, we demonstrate that melatonin acts as a potent agent to delay leaf senescence and cell death in rice. Treatments with melatonin significantly reduced chlorophyll degradation, suppressed the transcripts of senescence associated genes, delayed the leaf senescence, and enhanced salt stress tolerance. Genome-wide expression profiling by RNA sequencing reveals that melatonin is a potent free radical scavenger, and its exogenous application results in enhanced antioxidant protection. Leaf cell death in noe1, a mutant with over-produced H2O2, can be relieved by exogenous application of melatonin. These data demonstrate that melatonin delays the leaf senescence and cell death and also enhances abiotic stress tolerance via directly or indirectly counteracting the cellular accumulation of H2O2. PMID- 25912476 TI - Fluid dynamics simulation of right ventricular outflow tract oversizing. AB - OBJECTIVES: Repair of the right ventricular outflow tract (RVOT) in paediatric cardiac surgery remains challenging due to the high reoperation rate. Intimal hyperplasia and consequent arteriosclerosis is one of the most important limitation factors for graft durability. Since local shear stress and pressure are predictive elements for intimal hyperplasia and wall degeneration, we sought to determine in an oversized 12-mm RVOT model, with computed fluid dynamics simulation, the local haemodynamical factors that may explain intimal hyperplasia. This was done with the aim of identifying the optimal degree of oversizing for a 12-mm native RVOT. METHODS: Twenty domestic pigs, with a weight of 24.6 +/- 0.89 kg and a native RVOT diameter of 12 +/- 1.7 mm, had valve conduits of 12, 16, 18 and 20 mm implanted. Pressure and flow were measured at 75, 100 and 125% of normal flow at RVOT at the pulmonary artery, pulmonary artery bifurcation and at the left and right pulmonary arteries. Three-dimensional computed fluid dynamics (CFD) simulation in all four geometries in all flow modalities was performed. Local shear stress and pressure conditions were investigated. RESULTS: Corresponding to 75, 100 and 125% of steady-state flow, three inlet velocity profiles were obtained, 0.2, 0.29 and 0.36 m/s, respectively. At inflow velocity profiles, low shear stress areas, ranged from 0 to 2 Pa, combined with high-pressure areas ranging from 11.5 to 12.1 mmHg that were found at distal anastomosis, at bifurcation and at the ostia of the left and right pulmonary arteries in all geometries. CONCLUSIONS: In all three oversized geometries, the local reparation of shear stress and pressure in the 16-mm model showed a similar local profile as in the native 12 mm RVOT. According to these findings, we suggest oversizing the natural 12-mm RVOT by not more than 4 mm. The elements responsible for wall degeneration and intimal hyperplasia remain very similar to the conditions present in native RVOT. PMID- 25912475 TI - Evaluation of safety and immunogenicity of a quadrivalent human papillomavirus vaccine in healthy females between 9 and 26 years of age in Sub-Saharan Africa. AB - Due to sporadic and not easily accessible cervical cancer screening, human papillomavirus (HPV)-related cervical cancer is a leading cause of cancer death in Sub-Saharan African women. This study was designed to assess the safety and immunogenicity of a quadrivalent human papillomavirus (qHPV) vaccine in sub Saharan African women. This seven month, double-blind study enrolled 250 healthy, human immunodeficiency virus (HIV)-uninfected females ages 9-26 residing in Ghana, Kenya, and Senegal. Thirty females ages 13-15 and 120 females ages 16-26 received qHPV vaccine. In addition, 100 females ages 9-12 y were randomized in a 4:1 ratio to receive either qHPV vaccine (n = 80) or placebo (n = 20 ). The primary immunogenicity hypothesis was that an acceptable percentage of subjects who received the qHPV vaccine seroconvert to HPV6/11/16/18 at 4 weeks post-dose 3, defined as the lower bound of the corresponding 95% confidence interval (CI) exceeding 90%. The primary safety objective was to demonstrate that qHPV vaccine was generally well tolerated when administered in a 3-dose regimen. The pre specified statistical criterion for the primary immunogenicity hypothesis was met: the lower bound of the 95% exact binomial CI on the seroconversion rate was at least 98% for each vaccine HPV type and all subjects seroconverted by 4 weeks post-dose 3. Across vaccination groups, the most common adverse events (AE) were at the injection site, including pain, swelling, and erythema. No subject discontinued study medication due to an AE and no serious AEs were reported. There were no deaths. This study demonstrated that qHPV vaccination of sub Saharan African women was highly immunogenic and generally well tolerated. PMID- 25912477 TI - Bailout transcatheter closure of patent foramen ovale for refractory hypoxaemia after left ventricular assist device implantation. AB - We describe the interdisciplinary management of a 59-year old man with ischaemic cardiomyopathy on a HeartMate II left ventricular assist device (LVAD) and temporary right extracorporeal membrane oxygenation (ECMO) as a bridge-to-heart transplantation. He suffered refractory hypoxaemia due to massive right-to-left shunting by a patent foramen ovale (PFO), diagnosed after weaning off of temporary right ECMO. Percutaneous closure of the PFO was successfully achieved with an Amplatzer septal occluder device, which allowed the patient's extubation and departure from hospital. The patient received heart transplantation 7 weeks after LVAD implantation and was discharged from the intensive care unit 2 weeks after transplantation. PMID- 25912478 TI - P53-dependent miRNAs mediate nitric oxide-induced apoptosis in colonic carcinogenesis. AB - Both miRNAs and nitric oxide (NO) play important roles in colonic inflammation and tumorigenesis. Resistance of colonic epithelial cells to apoptosis may contribute to tumor development. We hypothesized that some miRNAs could increase the resistance of colonic cancer cells to nitric oxide-induced apoptotic cell death. Here we show that NO induced apoptosis and stimulated expression of some miRNAs. Loss of p53 not only blocked NO-induced apoptosis but also dramatically inhibited the expression of NO-related miRNAs, such as miR-34, miR-203, and miR 1301. In addition, blockage of p53-dependent miRNAs significantly reduced NO induced apoptosis. Furthermore, forced expression of these miRNAs rendered HT-29 cells, which are resistant to apoptosis with mutant p53, more sensitive to NO induced apoptotic cell death. Most interestingly, in a colitis-associated colon cancer mouse model, the level of miRNAs dropped significantly, accompanied by downregulation of p21, which is a key target gene of p53. In human colorectal cancer samples, the expression of miR-34 significantly correlated with the level of inducible nitric oxide synthase (iNOS). We contend that increased NO production may select cells with low levels of p53-dependent miRNAs which contributes to human colonic carcinogenesis and tumor progression. PMID- 25912479 TI - Nrf2--A regulator of keratinocyte redox signaling. AB - The skin is frequently exposed to environmental challenges, such as UV irradiation, toxic chemicals, and mechanical wounding. These insults cause an increase in the levels of reactive oxygen species, resulting in oxidative stress and concomitant inflammation, skin aging, and even cancer development. Therefore, an efficient antioxidant defense strategy is of major importance in this tissue. Since the Nrf2 transcription factor regulates a battery of genes involved in the defense against reactive oxygen species and in compound metabolism, it plays a key role in skin homeostasis, repair, and disease. In this review we summarize current knowledge on the expression and function of Nrf2 in normal skin and its role in the acute and chronic UV response as well as in the pathogenesis of epithelial skin cancer and of different inflammatory skin diseases. Finally, we discuss the potential of Nrf2-activating compounds for skin protection under stress conditions and for the treatment of major human skin disorders. PMID- 25912480 TI - Impact of myeloperoxidase-derived oxidants on the product profile of human 5 lipoxygenase. AB - Human 5-lipoxygenase (5-LOX) oxidizes arachidonic acid to 5S-hydroperoxy-6 E,8 Z,11 Z,14 Z-eicosatetraenoic acid (5-HpETE) and leukotriene (LT) A4. In neutrophils, LTA4 is further converted to the potent chemoattractant LTB4. These cells also contain the heme enzyme myeloperoxidase (MPO), which produces several potent oxidants such as hypochlorous acid (HOCl), which are involved in pathogen defense and immune regulation. Here, we addressed the question whether MPO derived oxidants are able to affect the activity of 5-LOX and the product profile of this enzyme. Human 5-LOX was incubated with increasing amounts of HOCl or HOBr. Afterward, arachidonic acid metabolites of 5-LOX were analyzed by reverse phase high-performance liquid chromatography as well as by liquid chromatography electrospray ionization-tandem mass spectrometry. The incubation of 5-LOX with the MPO-derived oxidants significantly changed the product profile of 5-LOX. Thereby, HOCl and HOBr increased the ratio of 5-H(p)ETE to 6-trans-LTB4 in a concentration-dependent manner. At low oxidant concentrations, there was a strong decrease in the yield of 6-trans-LTB4, whereas 5-HpETE did not change or increased. Additionally, the formation of 8-HpETE and 12-HpETE by 5-LOX rose slightly with increasing HOCl and HOBr. Comparable results were obtained with the MPO-H2O2-Cl(-) system when glucose oxidase and glucose were applied as a source of H2O2. This was necessary because of a strong impairment of 5-LOX activity by H2O2. In summary, MPO-derived oxidants showed a considerable impact on 5-LOX, impairing the epoxidation of 5-HpETE, whereas the hydroperoxidation of arachidonic acid was unaffected. Apparently, this was caused by an oxidative modification of critical amino acid residues of 5-LOX. Further work is necessary to assess the specific type and position of oxidation in the substrate-binding cavity of 5-LOX and to specify whether this interaction between 5-LOX and MPO derived oxidants also takes place in stimulated neutrophils. PMID- 25912481 TI - Evaluation of oxidative stress in the brain of a transgenic mouse model of Alzheimer disease by in vivo electron paramagnetic resonance imaging. AB - Alzheimer disease (AD) is a neurodegenerative disease clinically characterized by progressive cognitive dysfunction. Deposition of amyloid-beta (Abeta) peptides is the most important pathophysiological hallmark of AD. Oxidative stress induced by reactive oxygen species is prominent in AD, and several reports suggest the relationship between a change in redox status and AD pathology containing progressive Abeta deposition, the activation of glial cells, and mitochondrial dysfunction. Therefore, we performed immunohistochemical analysis using a transgenic mouse model of AD (APdE9) and evaluated the activity of superoxide dismutase in brain tissue homogenates of APdE9 mice in vitro. Together with those analyses, in vivo changes in redox status with age in both wild-type (WT) and APdE9 mouse brains were measured noninvasively by three-dimensional electron paramagnetic resonance (EPR) imaging using nitroxide (3-methoxycarbonyl-2,2,5,5 tetramethylpyrrolidine-1-yloxy) as a redox-sensitive probe. Both methods found similar changes in redox status with age, and in particular a significant change in redox status in the hippocampus was observed noninvasively by EPR imaging between APdE9 mice and age-matched WT mice from 9 to 18 months of age. EPR imaging clearly visualized the accelerated change in redox status of APdE9 mouse brain compared with WT. The evaluation of the redox status in the brain of AD model rodents by EPR imaging should be useful for diagnostic study of AD. PMID- 25912482 TI - Insights into the importance for designing curcumin-inspired anticancer agents by a prooxidant strategy: The case of diarylpentanoids. AB - Developing anticancer agents by a prooxidant strategy has attracted increasing attention in recent years, although it is not conventional in medicinal chemistry and is completely opposite to antioxidant therapy. In this work, a panel of diarylpentanoids as the curcumin mono-carbonyl analogs were designed and synthesized, and their cytotoxic and proapoptotic mechanisms against human lung cancer A549 cells were investigated at the frontiers of chemistry and biology. It was found that compared with curcumin, the compounds (A1, B1, and C1) bearing two ortho substituents on the aromatic rings, especially A1, exhibit significantly increased cytotoxic and proapoptotic activities through a Michael acceptor unit dependent prooxidant-mediated mechanism. The prooxidative ability is governed not only by their electrophilicity but also by their geometry, cellular uptake and metabolic stability, and TrxR-inhibitory activity. Mechanistic investigation reveals that the compound A1 could effectively and irreversibly modify the TrxR by virtue of the above optimal biochemical parameters, and convert this antioxidant enzyme into a reactive oxygen species (ROS) promoter, resulting in a burst of the intracellular ROS including H2O2 and O2(-)*. The ROS generation is associated with falling apart in the redox buffering system, and subsequently induces increases in Ca(2+) influx and oxidative stress, collapse of mitochondrial membrane potential, and activation of caspase-9 and caspase-3, ultimately leading to cell apoptosis. This work highlights the feasibility in designing curcumin-inspired anticancer agents by a prooxidant strategy, and gives us useful information on how to design them. PMID- 25912483 TI - Luminescent sensors based on quantum dot-molecule conjugates. AB - Semiconductor quantum dots (QDs) are inorganic nanoparticles that exhibit unique size-dependent optical and electronic properties; in particular, they are strongly luminescent. Their surface can be chemically modified, by either covalent or non-covalent approaches, in order to interface them with molecular units endowed with specific physical and chemical properties. Photoinduced electron- and energy-transfer processes between quantum dots and attached molecular species offer versatile strategies to modulate the photophysical properties of these nanoassemblies in response to a chemical stimulation. Hence, QD-molecule conjugates are appealing platforms for developing luminescent sensors according to a modular design. In this review we discuss the principles underlying the rational construction of this kind of multicomponent species, and we illustrate selected examples of luminescent QD-based sensors taken from the recent literature. PMID- 25912484 TI - Relationship of Salmonella infection and inflammatory intestinal response with hematological and serum biochemical values in laying hens. AB - There are few studies about the blood serum of laying hens infected with Salmonella. The differential leukocyte count and blood chemistry values are an important aid in the diagnosis of human diseases, but blood parameters in the avian species are not well known. On the other hand, invasive forms of bacterial gastroenteritis, like Salmonella, often cause intestinal inflammation so this study was undertaken to find a biomarker of Salmonella infection and inflammatory intestinal response in the hematological or serum biochemical parameters in laying hens. Furthermore, we evaluated the association of some farm characteristics with Salmonella infection and fecal leukocytes (FL). A fecal sample with at least one fecal leukocyte per field was considered positive for inflammatory intestinal response. False positive serum reactions for Salmonella infection, by serum plate agglutination (SPA) test, were reduced by heating the sample to 56 degrees C for 30 min and then diluting it 5-fold. The range of hematological and biochemical parameter values was very wide, in addition, there was a poor agreement between the SPA and FL results. Comparison of the positive and negative samples in SPA and FL showed that 1.3% and 79.8% of the laying hens were positive and negative in both tests, respectively. Hens with a positive SPA result showed a higher percentage of monocytes than those with a negative SPA result. Hens with a positive FL test had a higher percentage of heterophils, ratio of heterophils to lymphocytes and aspartate aminotransferase values, while the percentage of lymphocytes was significantly lower (P < 0.05) than those with a negative FL test. The risk of Salmonella infection increased when the age of laying hens and the number of hens per poultry house was greater than or equal to 18 months old and 10,000 laying hens, compared to less than 18 months old and 10,000 laying hens, respectively. On the other hand, the risk of inflammatory intestinal response was higher in laying hens >= 18 months old than in hens < 18 months old. Despite the fact that we did not find any specific biomarker of Salmonella infection, this is the first report about the change of Salmonella infection and inflammatory response in hematological/serum biochemical values for laying hens. PMID- 25912485 TI - Association between lymphocyte antigen receptor gene rearrangements and histopathological evaluation in canine chronic enteropathy. AB - Although definitive diagnosis of chronic enteropathy (CE) and gastrointestinal (GI) lymphoma requires histopathological evaluation of the GI tract, these conditions are often still difficult to differentiate from each other. Polymerase chain reaction (PCR) for antigen receptor gene rearrangements (PARR) has been applied recently as an adjunctive for diagnosis of lymphoid tumors; however, its clinical value in canine CE and GI lymphoma remains unclear. The purpose of this study was to investigate the relationship between PARR and histopathological diagnosis, degree of enteritis or lymphoma, and long-term prognosis in dogs, in order to evaluate the clinical significance of PARR. Endoscopic biopsy specimens obtained from 96 dogs with chronic enteritis (mild, n=14; moderate, n=20; marked, n=62) and 21 dogs with GI lymphoma were used. Clonality was observed in 51% of the animals with chronic enteritis; interestingly, it was found in 29% of those with only mild enteritis. In dogs with marked enteritis, the rate of PARR was higher in those with lymphocyte epitheliotropism than in those without epitheliotropism. The sensitivity of PARR in animals with GI lymphoma was 76%. There was no significant prognostic difference between chronic enteritis with or without clonal rearrangements. In contrast, dogs histopathologically diagnosed with marked enteritis had a significantly shorter survival time than did those with mild or moderate enteritis. While the significance of PARR in the diagnosis of GI lymphoma remains uncertain, the pathological roles of clonally expanding lymphocytes in canine CE should be investigated further. PMID- 25912486 TI - Sedation or general anesthesia for patients undergoing transcatheter aortic valve implantation--does it affect outcome? An observational single-center study. AB - Aortic stenosis is one of the most common valvular lesions. Nowadays, a new treatment is emerging: the transcatheter aortic valve implantation (TAVI). It is considered a suitable alternative for the surgical approach in selected high-risk patients. This procedure may be performed under sedation (SED) or under general anesthesia (GEA). STUDY OBJECTIVE: Assess the feasibility and safety of TAVI under sedation. DESIGN: Observational study. SETTING: Single-center study conducted between the years 2009 and 2012. PATIENTS: A total of 204 American Society of Anesthesiologists physical status 3 to 4 patients who underwent TAVI in the study period and for whom complete data were obtained were included. Demographic and periprocedural data were acquired from the patients' files. The patients were divided into SED and GEA groups. INTERVENTIONS: The study was not an interventional study. MEASUREMENTS: The study did not include measurements. MAIN RESULTS: The 2 groups had similar demographic characteristics and echocardiographic parameters. The rate of conversion from SED to GEA was 4.6%. The SED group received significantly less catecholamines and intravenous fluids during the procedure. The total procedural time was significantly shorter for the SED group. There was a trend toward more postprocedural pulmonary complications in the GEA group. In-hospital mortality and total length of stay were similar between the groups. CONCLUSIONS: The results of the current study, which included a relatively large number of patients, suggest that both anesthetic modalities are safe for patients undergoing TAVI. The anesthesiologist should thus tailor the anesthetic approach to the patient, taking into account the team's experience as well as the hemodynamic status of the patient. With growing experience, our team recommends performing TAVI under SED and in selected cases under GEA. PMID- 25912487 TI - On table extubation after emergency thoracotomy for mediastinal mass in a neonate. PMID- 25912488 TI - Dysregulation of male sex hormones in chronic hepatitis C patients. AB - Chronic hepatitis C (HCV) infection is a serious problem all over the world and has a special importance in Egypt, where the prevalence of infection is 14.7% of population. In males, HCV is associated with sexual dysfunction and changes in the semen parameters. This study aimed at estimation of a panel of the most important related hormones in the serum of patients and illustration of their correlation to the routine laboratory investigations. The four studied hormones showed alteration in the patients in comparison with the controls. While androstenedione, prolactin and testosterone were significantly increased in patients, dehydroepiandrosterone sulphate was decreased. These changes in the hormones were not related to the liver functions, pathological grade or even viral load. We hypothesised a model of how HCV can induce these hormonal changes and recommended to add these hormones to the follow-up panel of male patients with HCV. PMID- 25912489 TI - Incidence and patterns of late recurrences in colon cancer patients. AB - Long-term recurrences of colon cancer raised questions about the possible benefit of prolonging the recommended active 5-year surveillance. The aim of this study was to determine, for the first time, the incidence and patterns of late 10-year recurrence following curative resection of colon cancer. Data were obtained from two French digestive cancer registries. A total of 3,622 patients under 85 years resected for cure for colon cancer diagnosed between 1985 and 2000 were included. Information regarding recurrences was actively collected. Cumulative failure rates at 10 years were estimated using Kaplan-Meier estimates corrected by cause specific hazards, and multivariable analysis was performed using a model for the subdistribution of a competing risk proposed by Fine and Gray. The overall cumulative recurrence rate between 5 and 10 years after initial surgery was 2.9% for local recurrence and 4.3% for distant metastasis. Among men with no recurrence 5 years after diagnosis of colon cancer, 1 in 12 developed a recurrence between 5 and 10 years, and the corresponding cumulative rate was 7.8%. The frequency was 1 in 19 for women, corresponding to a cumulative rate of 5.2%. In the multivariate analysis, non-emergency diagnostic feature, female sex and age under 75 were associated with a lower risk of recurrence. Stage at diagnosis was not a predictor of late recurrence. Late recurrence after colon cancer resection with curative intent can occur. A regular clinical follow-up is necessary to detect early signs of possible recurrence. PMID- 25912490 TI - Hematopoietic Stem Cell Transplantation in Adult Sickle Cell Disease: Problems and Solutions. AB - Sickle cell disease-related organ injuries cannot be prevented despite hydroxyurea use, infection prophylaxis, and supportive therapies. As a consequence, disease-related mortality reaches 14% in adolescents and young adults. Hematopoietic stem cell transplantation is a unique curative therapeutic approach for sickle cell disease. Myeloablative allogeneic hematopoietic stem cell transplantation is curative for children with sickle cell disease. Current data indicate that long-term disease-free survival is about 90% and overall survival about 95% after transplantation. However, it is toxic in adults due to organ injuries. In addition, this curative treatment approach has several limitations, such as difficulties to find donors, transplant-related mortality, graft loss, graft-versus-host disease (GVHD), and infertility. Engraftment effectivity and toxicity for transplantations performed with nonmyeloablative reduced-intensity regimens in adults are being investigated in phase 1/2 trials at many centers. Preliminary data indicate that GVHD could be prevented with transplantations performed using reduced-intensity regimens. It is necessary to develop novel regimens to prevent graft loss and reduce the risk of GVHD. PMID- 25912491 TI - Patients with Pelvic Floor Muscle Spasm Have a Superior Response to Pelvic Floor Physical Therapy at Specialized Centers. AB - PURPOSE: Chronic prostatitis/chronic pelvic pain syndrome is a common condition that often requires multimodal therapy. Patients with chronic pelvic pain syndrome have a high incidence of pelvic floor spasm, which can be treated with pelvic floor physical therapy. However, this is a specialized skill. We compared outcomes of pelvic floor physical therapy as part of multimodal therapy in patients with chronic pelvic pain syndrome between those treated at our institution and elsewhere. MATERIALS AND METHODS: We identified patients from our chronic pelvic pain syndrome registry with pelvic floor spasm who were seen between 2010 and 2014 for more than 1 visit. Patient phenotype was assessed with the UPOINT system and symptom severity was determined by the National Institutes of Health CPSI. A 6-point decrease in CPSI was used to define patient improvement. RESULTS: A total of 82 patients fit the study criteria. Mean age was 41.6 years (range 19 to 75) and median symptom duration was 24 months (range 3 to 240). Mean CPSI was 26.8 (range 10 to 41), the median number of positive UPOINT domains was 3 (range 1 to 6) and 27 patients (32.9%) were treated locally. At followup 9 patients had refused pelvic floor physical therapy, and 24 and 48 had undergone pelvic floor physical therapy elsewhere and at CCF, respectively. The mean change in CPSI was 1.11 +/- 4.1 in patients who refused, -3.46 +/- 6.7 in those treated elsewhere and -11.3 +/- 7.0 in those treated at CCF (p <0.0001). Individual improvement was seen in 1 patient (11%) who refused, 10 (42%) treated elsewhere and 38 (79.2%) treated at CCF (p <0.0001). On multivariable analysis only physical therapy at CCF (OR 4.23, p = 0.002) and symptom duration (OR 0.52, p = 0.03) predicted improvement. CONCLUSIONS: Pelvic floor physical therapy can be effective for chronic pelvic pain syndrome in patients with pelvic floor spasm. However, the outcome depends on specialty training and experience of therapists. PMID- 25912492 TI - Circulating Tumor Cells as Potential Biomarkers in Bladder Cancer. AB - PURPOSE: We explored the diagnostic use of circulating tumor cells in patients with neoadjuvant bladder cancer using enumeration and next generation sequencing. MATERIALS AND METHODS: A total of 20 patients with bladder cancer who were eligible for cisplatin based neoadjuvant chemotherapy were enrolled in an institutional review board approved study. Subjects underwent blood draws at baseline and after 1 cycle of chemotherapy. A total of 11 patients with metastatic bladder cancer and 13 healthy donors were analyzed for comparison. Samples were enriched for circulating tumor cells using the novel IsoFluxTM System microfluidic collection device. Circulating tumor cell counts were analyzed for repeatability and compared with Food and Drug Administration cleared circulating tumor cells. Circulating tumor cells were also analyzed for mutational status using next generation sequencing. RESULTS: Median circulating tumor cell counts were 13 at baseline and 5 at followup in the neoadjuvant group, 29 in the metastatic group and 2 in the healthy group. The concordance of circulating tumor cell levels, defined as low-fewer than 10, medium-11 to 30 and high-greater than 30, across replicate tubes was 100% in 15 preparations. In matched samples the IsoFlux test showed 10 or more circulating tumor cells in 4 of 9 samples (44%) while CellSearch(r) showed 0 of 9 (0%). At cystectomy 4 months after baseline all 3 patients (100%) with medium/high circulating tumor cell levels at baseline and followup had unfavorable pathological stage disease (T1-T4 or N+). Next generation sequencing analysis showed somatic variant detection in 4 of 8 patients using a targeted cancer panel. All 8 cases (100%) had a medium/high circulating tumor cell level with a circulating tumor cell fraction of greater than 5% purity. CONCLUSIONS: This study demonstrates a potential role for circulating tumor cell assays in the management of bladder cancer. The IsoFlux method of circulating tumor cell detection shows increased sensitivity compared with CellSearch. A next generation sequencing assay is presented with sufficient sensitivity to detect genomic alterations in circulating tumor cells. PMID- 25912493 TI - Laparoscopic Cryoablation for Renal Cell Carcinoma: 100-Month Oncologic Outcomes. AB - PURPOSE: With the incidence of renal cell carcinoma on the rise treatment options for the small renal mass have broadened. Cryoablation is increasingly used as a therapeutic option for renal tumors in select cases. However, studies with long term oncologic outcomes are sparse. We evaluated the long-term oncologic outcomes of laparoscopic renal mass cryoablation. MATERIALS AND METHODS: We reviewed our laparoscopic cryoablation database for patients treated with laparoscopic cryoablation from October 1997 to February 2005. Patients with less than 3 months of followup were excluded from study. Patient and tumor characteristics, and perioperative outcomes, including complications, were recorded. Recurrence-free, cancer specific and overall survival was analyzed using Kaplan-Meier curves. RESULTS: A total of 142 tumors in 138 consecutive patients were treated with laparoscopic cryoablation. Mean age of the cohort was 66.35 years. Of the patients 99 (71.7%) were male and 39 (28.3%) were female. Mean body mass index was 29.15 kg/m(2) and median ASA score was 3. A solitary kidney was present in 23 patients (16.2%). Mean tumor size on cross-sectional imaging was 2.4 cm. The mean preoperative and postoperative estimated glomerular filtration rate was 66.72 and 61.00 ml per minute, respectively. The postoperative estimated glomerular filtration rate was determined at a mean +/- SD of 15.17 +/- 10.99 months of followup. The median R.E.N.A.L. nephrometry score was 5. Of the 142 tumors 100 were diagnosed as renal cell carcinoma after histopathological examination of the biopsy specimen. At 3, 5 and 10 years in patients diagnosed with renal cell carcinoma estimated recurrence-free survival was 91.4%, 86.5% and 86.5%, estimated cancer specific survival was 96.8%, 96.8% and 92.6%, and estimated overall survival was 88.7%, 79.1% and 53.8%, respectively. Mean followup was 98.8 +/- 54.2 months in those diagnosed with renal cell carcinoma. Mean time to recurrence was 2.3 years. The latest experienced recurrence was 4.4 years after laparoscopic cryoablation. There was a postoperative complication rate of 10.6% with a total of 15 complications. CONCLUSIONS: Laparoscopic cryoablation achieves good long-term oncologic outcomes for localized small renal masses. It can safely be used in patients who cannot undergo or are unwilling to accept the risks of partial nephrectomy. Mean time to recurrence was 2.3 years and all recurrences developed within 4.4 years of initial treatment. PMID- 25912495 TI - Survey of Applicant Experience and Cost in the Urology Match: Opportunities for Reform. AB - PURPOSE: The urology match is highly competitive but there is a paucity of published data regarding the costs and barriers that applicants face. We gathered data on contributors to cost in the 2014 urology residency match. MATERIALS AND METHODS: A survey was sent to all applicants offered an interview at each of 18 participating institutions. Information on demographics, interview related costs, access to financial aid, frequency of away rotations and second look invitations was collected. RESULTS: A total of 173 respondents spent a median of $7,000 on the urology match. Applicants attended a mean of 14 interviews with an average per interview cost of $500. Overall 95% of respondents did at least 1 away rotation and 79% reported being asked to return for a second look interview at least once. Of the respondents 66% did not receive any financial aid for interviews and only 28% believed their financial aid departments provided adequate financial planning. Of those surveyed 20% indicated that their financial situation limited the number of interviews they attended. CONCLUSIONS: We estimate that $3,122,000 was spent by applicants on the 2014 urology match. One in 5 applicants reported limiting the number of interviews they attended due to financial concerns. Adequate financial planning resources were not widely available. Nearly all applicants went on an away rotation and encouragement to return for second look interviews was common. These factors may contribute to financial and regional bias in the match process, and are potential targets for reform. PMID- 25912494 TI - The Fate of Nephrons in Congenital Obstructive Nephropathy: Adult Recovery is Limited by Nephron Number Despite Early Release of Obstruction. AB - PURPOSE: Urinary tract obstruction and reduced nephron number often occur together as a result of maldevelopment of the kidneys and the urinary tract. We determined the role of nephron number on adaptation of the remaining nephrons of mice subjected to neonatal partial unilateral ureteral obstruction followed through adulthood. MATERIALS AND METHODS: Wild-type and Os/+ mice (the latter with 50% fewer nephrons) underwent sham operation or partial unilateral ureteral obstruction in the first 2 days of life. Additional mice underwent release of unilateral ureteral obstruction at 7 days. All kidneys were harvested at 3 weeks (weaning) or 6 weeks (adulthood). Glomerular number and area, glomerulotubular junction integrity, proximal tubular volume fraction and interstitial fibrosis were measured by histomorphometry. RESULTS: In the obstructed kidney unilateral ureteral obstruction caused additional nephron loss in Os/+ but not in wild-type mice. Glomerular growth from 3 to 6 weeks was impaired by ipsilateral obstruction and not preserved by release in wild-type or Os/+ mice. Proximal tubular growth was impaired and interstitial collagen was increased by ipsilateral obstruction in all mice. These conditions were attenuated by release of unilateral ureteral obstruction in wild-type mice but were not restored in Os/+ mice. Unilateral ureteral obstruction increased interstitial collagen in the contralateral kidney while release of obstruction enhanced tubular growth and reduced interstitial collagen. CONCLUSIONS: Unilateral ureteral obstruction in early postnatal development impairs adaptation to reduced nephron number and induces additional nephron loss despite release of obstruction. Premature and low birth weight infants with congenital obstructive nephropathy are likely at increased risk for progression of chronic kidney disease. PMID- 25912496 TI - Prostate Cancer Volume Estimation by Combining Magnetic Resonance Imaging and Targeted Biopsy Proven Cancer Core Length: Correlation with Cancer Volume. AB - PURPOSE: Multiparametric magnetic resonance imaging often underestimates or overestimates pathological cancer volume. We developed what is to our knowledge a novel method to estimate prostate cancer volume using magnetic resonance/ultrasound fusion, biopsy proven cancer core length. MATERIALS AND METHODS: We retrospectively analyzed the records of 81 consecutive patients with magnetic resonance/ultrasound fusion, targeted biopsy proven, clinically localized prostate cancer who underwent subsequent radical prostatectomy. As 7 patients each had 2 visible lesions on magnetic resonance imaging, 88 lesions were analyzed. The dimensions and estimated volume of visible lesions were calculated using apparent diffusion coefficient maps. The modified formula to estimate cancer volume was defined as the formula of vertical stretching in the anteroposterior dimension of the magnetic resonance based 3-dimensional model, in which the imaging estimated lesion anteroposterior dimension was replaced by magnetic resonance/ultrasound targeted, biopsy proven cancer core length. Agreement of pathological cancer volume with magnetic resonance estimated volume or the novel modified volume was assessed using a Bland-Altman plot. RESULTS: Magnetic resonance/ultrasound fusion, biopsy proven cancer core length was a stronger predictor of the actual pathological cancer anteroposterior dimension than magnetic resonance estimated lesion anteroposterior dimension (r = 0.824 vs 0.607, each p <0.001). Magnetic resonance/ultrasound targeted, biopsy proven cancer core length correlated with pathological cancer volume (r = 0.773, p <0.001). The modified formula to estimate cancer volume demonstrated a stronger correlation with pathological cancer volume than with magnetic resonance estimated volume (r = 0.824 vs 0.724, each p <0.001). Agreement of modified volume with pathological cancer volume was improved over that of magnetic resonance estimated volume on Bland-Altman plot analysis. Predictability was more enhanced in the subset of lesions with a volume of 2 ml or less (ie if spherical, the lesion was approximately 16 mm in diameter). CONCLUSIONS: Combining magnetic resonance estimated cancer volume with magnetic resonance/ultrasound fusion, biopsy proven cancer core length improved cancer volume predictability. PMID- 25912498 TI - The rugger jersey spine sign. PMID- 25912497 TI - A semiautomatic method to identify vertebral end plate lesions (Schmorl's nodes). AB - BACKGROUND CONTEXT: There are differences in the definitions of end plate lesions (EPLs), often referred to as Schmorl's nodes, that may, to some extent, account for the large range of reported prevalence (3.8%-76%). PURPOSE: The purpose of this study was to develop a technique to measure the size, prevalence, and location of EPLs in a consistent manner. STUDY DESIGN/SETTING: This study proposed a method using a detection algorithm that was applied to five adolescent females (average age, 15.1 [range, 13.0-19.2] years) with idiopathic scoliosis (average major Cobb angle, 60 degrees [range, 55 degrees -67 degrees ]). METHODS: Existing low-dose, computed tomography scans were segmented semiautomatically to extract three-dimensional morphology of each vertebral end plate. Any remaining attachments to the posterior elements of adjacent vertebrae or end plates were then manually sectioned. An automatic algorithm was used to determine the presence and position of EPLs. RESULTS: End plate lesions were identified in 15 of the 170 (8.8%) end plates analyzed with an average depth of 3.1 mm. Eleven of the 15 EPLs were seen in the lumbar spine. The algorithm was found to be most sensitive to changes in the minimum EPL gradient at the edges of the EPL. CONCLUSIONS: This study describes an imaging analysis technique for consistent measurement of the prevalence, location, and size of EPLs. The technique can be used to analyze large populations without observer errors in EPL definitions. PMID- 25912499 TI - Melorheostosis of the spine and ribs. PMID- 25912500 TI - Acute tonsillar cerebellar herniation in a patient with traumatic dural tear and VAC therapy after complex trauma. AB - BACKGROUND CONTEXT: Cases of cerebral hypotension and tonsillar herniation after accidental lumbar cerebrospinal fluid (CSF) drainage or chest tube drainage with intrathoracic CSF leaks have been reported. To the authors' knowledge, this case presents the first report of severe intracranial hypotension because of suction of CSF by a Vacuum-Assisted Closure (VAC) device. PURPOSE: The purpose of this study was to report a life-threatening intracranial hypotension in a polytraumatized patient after VAC therapy. STUDY DESIGN: This study is a case report. METHODS: A 23-year-old woman suffered of a Grade 3 open pelvic fracture after a motor vehicle accident. After a VAC therapy, the patient became nonresponsive. A cranial computer tomography (CCT) showed signs of intracranial hypotension with narrowing of the basal cisterns and sagging of the cerebellar tonsils. The VAC was removed. Further neuroradiological diagnostic showed a tear in the dural sac at the L5-S1 level. The patient consequently underwent neurosurgery. After a dural patch, she was oriented postoperatively and the CCT improved to a normal state. RESULTS: Fifteen days after admission, the patient was discharged without neurologic sequelae. CONCLUSIONS: Severely injured patients undergoing VAC therapy with secondary neurologic deterioration not because of head injury should be appropriately diagnosed to rule out dural laceration and cranial hypotension. PMID- 25912502 TI - The air shady sign (air epidurogram). PMID- 25912501 TI - Fibrin-genipin annulus fibrosus sealant as a delivery system for anti-TNFalpha drug. AB - BACKGROUND CONTEXT: Intervertebral discs (IVDs) are attractive targets for local drug delivery because they are avascular structures with limited transport. Painful IVDs are in a chronic inflammatory state. Although anti-inflammatories show poor performance in clinical trials, their efficacy treating IVD cells suggests that sustained, local drug delivery directly to painful IVDs may be beneficial. PURPOSE: The purpose of this study was to determine if genipin cross linked fibrin (FibGen) with collagen Type I hollow spheres (CHS) can serve as a drug-delivery carrier for infliximab, the anti-tumor necrosis factor alpha (TNFalpha) drug. Infliximab was chosen as a model drug because of the known role of TNFalpha in increasing downstream production of several pro-inflammatory cytokines and pain mediators. Genipin cross-linked fibrin was used as drug carrier because it is adhesive, injectable, and slowly degrading hydrogel with the potential to seal annulus fibrosus (AF) defects. CHS allow simple and nondamaging drug loading and could act as a drug reservoir to improve sustained delivery. STUDY DESIGN/SETTING: This is a study of biomaterials and human AF cell culture to determine drug release kinetics and efficacy. METHODS: Infliximab was delivered at low and high concentrations using FibGen with and without CHS. Gels were analyzed for structure, drug release kinetics, and efficacy treating human AF cells after release. RESULTS: Fibrin showed rapid infliximab drug release but degraded quickly. CHS alone showed a sustained release profile, but the small spheres may not remain in a degenerated IVD with fissures. Genipin cross-linked fibrin showed steady and low levels of infliximab release that was increased when loaded with higher drug concentrations. Infliximab was bound in CHS when delivered within FibGen and was only released after enzymatic degradation. The infliximab released over 20 days retained its bioactivity as confirmed by the sustained reduction of interleukin (IL)-1beta, IL-6, IL-8, and TNFalpha concentrations produced by AF cells. CONCLUSIONS: Direct mixing of infliximab into FibGen was the simplest drug-loading protocol capable of sustained release. Results show feasibility of using drug-loaded FibGen for delivery of infliximab and, in the context with the literature, show potential to seal AF defects and partially restore IVD biomechanics. Future investigations are required to determine if drug-loaded FibGen can effectively deliver drugs, seal AF defects, and promote IVD repair or prevent further IVD degeneration in vivo. PMID- 25912503 TI - Spinal neurenteric cyst presented with lower extremity weakness. PMID- 25912504 TI - Sagittal alignment maintained using anterior discectomy and fusion in a child with postlaminectomy kyphosis after intraspinal tumor excision--a follow-up imaging series. PMID- 25912506 TI - Osteoid osteoma of the dens axis. PMID- 25912505 TI - Comparison of plate-cage construct and stand-alone anchored spacer in the surgical treatment of three-level cervical spondylotic myelopathy: a preliminary clinical study. AB - BACKGROUND CONTEXT: Although stand-alone cages were advocated to be superior to plate-cage construct (PCC) because of comparable clinical outcomes and fewer plate-related complications, cage dislocation and subsidence were frequently mentioned in multilevel fusion. There are some concerns about whether these issues can be effectively prevented in multilevel anterior cervical discectomy and fusion (ACDF) by stand-alone anchored spacer (SAAS). PURPOSE: The aim was to compare clinical outcomes, radiologic parameters, and complications of PCC and SAAS in the treatment of three-level cervical spondylotic myelopathy (CSM). STUDY DESIGN/SETTING: This was a retrospective comparative study. PATIENT SAMPLE: A total of 38 consecutive patients with three-level CSM (ACDF with PCC, 20 patients; ACDF with SAAS, 18 patients) were reviewed. OUTCOME MEASURES: Clinical outcomes were assessed using Japanese Orthopaedic Association and Neck Disability Index. The radiologic evaluations included cervical alignment (CA), segmental angle (SA), postoperative curvature loss (PCL), and incidence of subsidence. METHODS: All the aforementioned parameters were compared before and after surgery between two groups. Besides, the aforementioned results were also compared between the two groups. The complications were also recorded. RESULTS: The mean follow-up period was 30.3 months. No significant differences were observed in clinical outcomes between the two groups (p>.05). Additionally, no significant differences existed in fusion rate between the two groups. There were significant differences in PCL of SA and CA and correction of SA between the two groups (p<.05). Besides, the incidence of subsidence (9 of 54 levels, 16.7%) was recorded in the SAAS group, and the potential of SAAS to reduce the incidence of postoperative dysphagia was not proven. No other complications were observed in this study. CONCLUSIONS: In the surgical treatment of three-level CSM, PCC is superior to SAAS in correction and maintenance of SA and avoiding cage subsidence, although the technique of ACDF with SAAS yielded encouraging clinical outcomes and high fusion rate. PMID- 25912507 TI - A rare cause of backache: epidural lymphangioma of the cervicothoracic spine. PMID- 25912508 TI - Cement extravasation into the C7-T1 neural foramen after C7 vertebroplasty. PMID- 25912509 TI - Immigrant Afghan women's emotional well-being after birth and use of health services in Melbourne, Australia. AB - OBJECTIVE: to investigate immigrant Afghan women's emotional well-being and experiences of postnatal depression after childbirth and their use of health services. DESIGN: telephone interviews were conducted at four months after birth, using a semi-structured questionnaire; and a further in-depth face-to-face interview with a small number of women approximately one year after the birth. Women's emotional health was assessed at four months using the Edinburgh Postnatal Depression Scale (EPDS), as well as women's own descriptions of their emotional well-being since the birth. SETTING: women were recruited from four hospital antenatal clinics or postnatal wards in Melbourne, Australia, between October 2006 and May 2007. PARTICIPANTS: Immigrant women who were born in Afghanistan, spoke Dari/Persian or English, and had given birth to a live and healthy baby. FINDINGS: Thirty nine women were interviewed at four months after birth; 41% reported feeling depressed or very unhappy since the birth and 31% scored as probably depressed on the EPDS. Ten women participated in further in depth face-to-face interviews. Isolation, lack of support and being overwhelmed by life events were the most frequently reported contributing factors to women's emotional distress, and for many being a migrant appeared to intensify their experiences. The themes that emerged from both the telephone and face-to-face interviews revealed that some women were reluctant to discuss their emotional difficulties with health professionals and did not expect that health professionals could necessarily provide assistance. KEY CONCLUSIONS AND IMPLICATIONS FOR PRACTICE: in this study a significant proportion of immigrant Afghan women experienced emotional distress after childbirth. Women's experiences of emotional distress and help-seeking were at times affected by their status as immigrants and their perceptions of possible causes and treatment for their emotional health problems. Understanding the effects of migration on women's lives and paying careful attention to individual needs and preferences are critically important in providing care for immigrant Afghan women. PMID- 25912510 TI - Mighty Mums - An antenatal health care intervention can reduce gestational weight gain in women with obesity. AB - BACKGROUND: overweight and obesity are growing public health problems and around 13% of women assigned to antenatal health care (AHC) in Sweden have obesity (Body Mass Index, BMI >=30). The risk of complications during pregnancy and childbirth increase with increasing BMI. Excessive gestational weight gain (GWG) among obese women further increases the risks of adverse pregnancy outcomes. In this pilot study from AHC in Gothenburg, a co-ordinated project with standardised care, given by midwives and supported by dietitian and aiming at reducing weight gain in obese pregnant women, is evaluated. OBJECTIVE: to evaluate the effects of a behavioural intervention programme for women with BMI >=30, with emphasis on nutrition and physical activity, with regards to GWG and effect on weight at the post partum check-up. METHODS: in the pilot study, the intervention group consisted of the first 50 enrolled obese pregnant women in a large life style project within the AHC in Gothenburg. The control group consisted of 50 obese pregnant women in the same city. The intervention included 60 minutes extra time with the midwife and also offered food discussion group, walking poles and pedometers. The intervention group was prescribed physical activity and could choose from food advice with different content. If needed, the woman was offered referral to the dietitian for a personal meeting. A network was formed with the surrounding community. Outcome measures were GWG, weight change at the postnatal check-up compared with when signing in to antenatal health care, and change in BMI during the same period. FINDINGS: women in the intervention group had a significantly lower GWG (8.6 +/- 4.9 kg versus 12.5 +/- 5.1 kg; p=0.001) and a significantly lower weight at the postnatal check up versus the first contact with AHC (-0.2 +/- 5.7 kg versus +2.0 +/- 4.5 kg; p=0.032), as well as a decrease in BMI (-0.04 +/- 2.1 versus +0.77 +/- 2.0; p=0.037). More women in the intervention than in the control group managed GWG <7 kg [18 (36%) versus 8 (16%); p=0.039]. CONCLUSION: obese pregnant women adhering to a standardised life style project in primary care using restricted resources can limit their weight gain during pregnancy, and show less weight retention after pregnancy compared to controls. PMID- 25912511 TI - The experience of psychological distress, depression, and anxiety during pregnancy: A meta-synthesis of qualitative research. AB - OBJECTIVE: to systematically review qualitative research that explores the experience of maternal antenatal psychological distress, such as depression, anxiety and stress during pregnancy. METHOD: a meta-synthesis was conducted to integrate the findings of qualitative studies. Eight final eligible studies were scrutinised, recurring themes were extracted and compared across studies, and core themes were identified. FINDINGS: five core themes of the experience of pregnancy distress were identified: Recognising that things are not right, Dealing with stigma, Negotiating the transformation, Spiralling down, and Regaining control. In the interpretation of these concepts the experience of maternal antenatal distress was depicted as a process similar to the one of grief and loss, as a result of women's inability to situate their experience within the 'perfect mother' discourse. KEY CONCLUSIONS: women who experience psychological distress undergo a specific process of transformation towards motherhood that begins during pregnancy. This process is exacerbated by their interpretation of their experience as deviant and often as inadequate. IMPLICATIONS FOR PRACTICE: this review will assist health professionals in translating and negotiating the transformation towards motherhood for women experiencing pregnancy distress, in a timely and meaningful manner. PMID- 25912512 TI - Tunable ultrathin membranes with nonvolatile pore shape memory. AB - The concept of a responsive nanoporous thin-film gel membranes whose pores could be tuned to a desired size by a specific "molecular signal" and whose pore geometry becomes "memorized" by the gel is reported. The ~100 nm thick membranes were prepared by dip-coating from a solution mixture of a random copolymer comprising responsive and photo-cross-linkable units and monodisperse latex nanoparticles used as a sacrificial colloidal template. After stabilization of the films by photo-cross-linking the latex template was removed, yielding nanoporous structures with a narrow pore size distribution and a high porosity. The thin-film membranes could be transferred onto porous supports to serve as tunable size-selective barriers in various colloids separation applications. The pore dimensions and hence the membrane's colloidal-particle-size cutoff were reversibly regulated by swelling-shrinking of the polymer network with a specially selected low-molar-mass compound. The attained pore shape was "memorized" in aqueous media and "erased" by treatment in special solvents reverting the membrane to the original state. PMID- 25912513 TI - Monophyletic group of unclassified gamma-Proteobacteria dominates in mixed culture biofilm of high-performing oxygen reducing biocathode. AB - Several mixed microbial communities have been reported to show robust bioelectrocatalysis of oxygen reduction over time at applicable operation conditions. However, clarification of electron transfer mechanism(s) and identification of essential micro-organisms have not been realised. Therefore, the objective of this study was to shape oxygen reducing biocathodes with different microbial communities by means of surface modification using the electrochemical reduction of two different diazonium salts in order to discuss the relation of microbial composition and performance. The resulting oxygen reducing mixed culture biocathodes had complex bacterial biofilms variable in size and shape as observed by confocal and electron microscopy. Sequence analysis of ribosomal 16S rDNA revealed a putative correlation between the abundance of certain microbiota and biocathode performance. The best performing biocathode developed on the unmodified graphite electrode and reached a high current density for oxygen reducing biocathodes at neutral pH (0.9 A/m(2)). This correlated with the highest domination (60.7%) of a monophyletic group of unclassified gamma Proteobacteria. These results corroborate earlier reports by other groups, however, higher current densities and higher presence of these unclassified bacteria were observed in this work. Therefore, members of this group are likely key-players for highly performing oxygen reducing biocathodes. PMID- 25912514 TI - Relationship of ocular accommodation and motor skills performance in developmental coordination disorder. AB - Ocular accommodation provides a well-focussed image, feedback for accurate eye movement control, and cues for depth perception. To accurately perform visually guided motor tasks, integration of ocular motor systems is essential. Children with motor coordination impairment are established to be at higher risk of accommodation anomalies. The aim of the present study was to examine the relationship between ocular accommodation and motor tasks, which are often overlooked, in order to better understand the problems experienced by children with motor coordination impairment. Visual function, gross and fine motor skills were assessed in children with developmental coordination disorder (DCD) and typically developing control children. Children with DCD had significantly poorer accommodation facility and amplitude dynamics compared to controls. Results indicate a relationship between impaired accommodation and motor skills. Specifically, accommodation anomalies correlated with visual motor, upper limb and fine dexterity task performance. Consequently, we argue accommodation anomalies influence the ineffective coordination of action and perception in DCD. Furthermore, reading disabilities were related to poorer motor performance. We postulate the role of the fastigial nucleus as a common pathway for accommodation and motor deficits. Implications of the findings and recommended visual screening protocols are discussed. PMID- 25912515 TI - Genetic analysis of choroideremia families in the Australian population. AB - BACKGROUND: Choroideremia is an X-linked inherited chorioretinal disease known to be caused by mutations in the CHM gene. In this study, Australian families clinically diagnosed with choroideremia were genetically analysed for mutations in the CHM gene. DESIGN: The Australian Inherited Retinal Disease Register and DNA Bank (AIRDR) was investigated to identify a cohort of choroideremia-affected families for genetic analysis. PARTICIPANTS: Participants were sourced from the AIRDR. Thirty-two participants (15 affected, 10 carriers, 7 unaffected) sourced from 11 unrelated families having at least one member clinically diagnosed with choroideremia were included in the study. METHODS: We performed sequence analysis of the CHM gene on the DNA of nine probands. We received the direct sequencing results of two probands by other means. Targeted analysis was subsequently performed for all 32 participants to confirm the direct sequencing results in the 11 probands and to establish the presence or absence of the implicated mutation in the remaining 21 affected, carrier or unaffected family members. MAIN OUTCOME MEASURES: Genetic characterisation of 11 choroideremia families in the Australian population. RESULTS: A CHM mutation was detected in all 11 families. Each family had a different mutation. Mutations segregated within each family according to disease status. Five mutations were novel and six have been previously reported. CONCLUSIONS: Six previously reported and five novel CHM mutations were detected in 11 Australian families clinically diagnosed with choroideremia. We anticipate that this work will facilitate access for AIRDR participants and their progeny to CHM gene therapy trials. PMID- 25912516 TI - Transjugular intrahepatic portosystemic shunt in liver transplant recipients: indications, feasibility, and outcomes. AB - The role of transjugular intrahepatic portosystemic shunt (TIPS) for treating complications of portal hypertension after orthotopic liver transplantation (OLT) is unclear. In this review of 13 retrospective studies and 8 case reports comprising 213 patients, we assessed the indications, technical success, and clinical outcomes of TIPS procedures performed in patients who had undergone OLT. Indications for TIPS were refractory ascites (n = 168), variceal hemorrhage (n = 36), and hydrothorax (n = 9). Technical success was reported in 98% of cases. Five procedures failed because of portal vein thrombosis, caval tear, technical inability, patient instability, and unknown reasons (one each). Clinical success of TIPS after OLT was 57% in patients with refractory ascites, 69% in those with variceal hemorrhage, and 56% in those with hydrothorax. TIPS revision was required in 16% of cases, while 19% of patients underwent subsequent retransplantation. Postprocedural or worsening encephalopathy occurred in 33% of patients. Survival analysis based on 122 cases with data available revealed a 30 day mortality rate of 11%, a 1-year cumulative survival rate of 53%, and a 1-year cumulative retransplantation-free survival rate of 41%. Given the complexity of post-OLT cases with complications of recurrent portal hypertension, it is not surprising that the overall clinical success rate of TIPS was relatively low. Nevertheless, TIPS may remain a viable choice for the treatment of patients who have undergone OLT with recurrent portal hypertensive complications when medical therapy is unsuccessful. PMID- 25912517 TI - Use of computed tomography and mechanical CPR in cardiac arrest to confirm pulmonary embolism: a case study. AB - Precise therapeutic decision-making is vital in managing out-of-hospital cardiac arrest. We present an interesting approach where suspected pulmonary embolism could be confirmed by early computed tomography in cardiac arrest. Chest compressions were performed automatically by mechanical devices also during the acquisition of computed tomography data and subsequent thrombolysis. PMID- 25912518 TI - Development of the good food planning tool: A food system approach to food security in indigenous Australian remote communities. AB - Few frameworks exist to assist food system planning, especially for Indigenous Australian remote communities. We developed a Good Food Planning Tool to support stakeholders to collectively plan and take action for local food system improvement. Development occurred over a four-year period through an evolving four phase participatory process that included literature review, several meetings with representatives of various organisations and communities and application of the Tool with multi-sector groups in each of four Indigenous Australian remote communities. A diverse range of 148 stakeholders, 78 of whom were Indigenous, had input to its development. Five food system domains: (i) Leadership and partnerships; (ii) Traditional food and local food production; (iii) Food businesses; (iv) Buildings, public places and transport; (v) Community and services and 28 activity areas form the framework of the Tool. The Good Food Planning Tool provides a useful framework to facilitate collective appraisal of the food system and to identify opportunities for food system improvement in Indigenous Australian remote communities, with potential for adaptation for wider application. PMID- 25912519 TI - Subterranean atmospheres may act as daily methane sinks. AB - In recent years, methane (CH4) has received increasing scientific attention because it is the most abundant non-CO2 atmospheric greenhouse gas (GHG) and controls numerous chemical reactions in the troposphere and stratosphere. However, there is much that is unknown about CH4 sources and sinks and their evolution over time. Here we show that near-surface cavities in the uppermost vadose zone are now actively removing atmospheric CH4. Through seasonal geochemical tracing of air in the atmosphere, soil and underground at diverse geographic and climatic locations in Spain, our results show that complete consumption of CH4 is favoured in the subsurface atmosphere under near vapour saturation conditions and without significant intervention of methanotrophic bacteria. Overall, our results indicate that subterranean atmospheres may be acting as sinks for atmospheric CH4 on a daily scale. However, this terrestrial sink has not yet been considered in CH4 budget balances. PMID- 25912520 TI - Effects of the Quest to Lava Mountain Computer Game on Dietary and Physical Activity Behaviors of Elementary School Children: A Pilot Group-Randomized Controlled Trial. AB - BACKGROUND: Computer-based educational games present an opportunity for health education in school; however, their feasibility in school settings and effectiveness in changing behavior are poorly understood. OBJECTIVE: To evaluate the feasibility, acceptability, and effects of the Quest to Lava Mountain (QTLM) computer game on dietary behaviors, physical activity behaviors, and psychosocial factors among ethnically diverse children in Texas. DESIGN: Quasi-experimental group-randomized controlled trial conducted during the 2012-2013 school year. PARTICIPANTS/SETTING: A total of 107 children in fourth and fifth grade consented. There was an attrition rate of 8.8% with a final sample size of 44 children in three intervention schools, and a sample of 50 children in three comparison schools. Dietary intake was measured using two random 24-hour recalls, whereas child self-report surveys measured diet, physical activity, and psychosocial factors before and after the intervention. Process data on QTLM usability and back-end server data on QTLM exposure and progress achieved were collected. INTERVENTION: QTLM was implemented as part of the in-school or afterschool program. Recommended game exposure duration was 90 min/wk for 6 weeks. STATISTICAL ANALYSIS: Analysis of covariance or logistic regression models evaluated effects of QTLM on diet, physical activity, and psychosocial factors. Post hoc exploratory analysis examined the changes before and after the intervention in outcome variables among children in the intervention group. Significance was set at P<0.05. RESULTS: Children played an average of 274+/-110 minutes (approximately 4.6 hours) of QTLM during the 6 weeks (51% of recommended dosage). Compared with the comparison group, children in the intervention group reported decreased sugar consumption (P=0.021) and higher nutrition/physical activity attitudes (P=0.041) pre- to postintervention. There were no significant effects of QTLM on physical activity. However, post hoc analysis showed that higher QTLM exposure and gaming progress was associated with increased frequency of physical activity (P<0.05). CONCLUSIONS: QTLM has some promising acceptability and initial effects on diet and physical activity behaviors among children in elementary school. PMID- 25912521 TI - Drug-induced liver injury: Interactions between drug properties and host factors. AB - Idiosyncratic drug-induced liver injury (DILI) is a common cause for drug withdrawal from the market and although infrequent, DILI can result in serious clinical outcomes including acute liver failure and the need for liver transplantation. Eliminating the iatrogenic "harm" caused by a therapeutic intent is a priority in patient care. However, identifying culprit drugs and individuals at risk for DILI remains challenging. Apart from genetic factors predisposing individuals at risk, the role of the drugs' physicochemical and toxicological properties and their interactions with host and environmental factors need to be considered. The influence of these factors on mechanisms involved in DILI is multi-layered. In this review, we summarize current knowledge on 1) drug properties associated with hepatotoxicity, 2) host factors considered to modify an individuals' risk for DILI and clinical phenotypes, and 3) drug-host interactions. We aim at clarifying knowledge gaps needed to be filled in as to improve risk stratification in patient care. We therefore broadly discuss relevant areas of future research. Emerging insight will stimulate new investigational approaches to facilitate the discovery of clinical DILI risk modifiers in the context of disease complexity and associated interactions with drug properties, and hence will be able to move towards safety personalized medicine. PMID- 25912523 TI - Application of single-stage Orbitrap mass spectrometry and differential analysis software to nontargeted analysis of contaminants in dog food: detection, identification, and quantification of glycoalkaloids. AB - The objective of this study was to perform a preliminary investigation of the nontargeted search and quantitative capabilities of a single-stage Exactive High Resolution Mass Spectrometer (HRMS). To do this, the instrument and its associated software performed a non-targeted search for deleterious substances in a dog food sample suspected of causing gastrointestinal problems in dogs. A single-stage Orbitrap/high-performance liquid chromatography method and differential expression analysis software (Sieve) was used to detect and identify, and subsequently quantify, nontargeted compounds occurring only in the suspect dog food sample. When combined with an online database (ChemSpider), a preliminary identification of one of the nontargeted compounds was determined to be potato glycoalkaloids. The diagnostic product ion ratios and quantitative data accuracy generated by the single-stage Orbitrap MS were shown to be similar to results obtained using a triple quadrupole LC-MS/MS. Additionally, the ability of the single-stage Orbitrap instrument to provide precursor and product ion accurate masses and isotope patterns was also investigated. PMID- 25912522 TI - Psychopathy, attention, and oddball target detection: New insights from PCL-R facet scores. AB - Psychopathy is a disorder accompanied by cognitive deficits including abnormalities in attention. Prior studies examining cognitive features of psychopaths using ERPs have produced some inconsistent results. We examined psychopathy-related differences in ERPs during an auditory oddball task in a sample of incarcerated adult males. We extend previous work by deriving ERPs with principal component analysis (PCA) and relate these to the four facets of Hare's Psychopathy Checklist Revised (PCL-R). Features of psychopathy were associated with increased target N1 amplitude (facets 1, 4), decreased target P3 amplitude (facet 1), and reduced slow wave amplitude for frequent standard stimuli (facets 1, 3, 4). We conclude that employing PCA and examining PCL-R facets improve sensitivity and help clarify previously reported associations. Furthermore, attenuated slow wave during standards may be a novel marker for psychopaths' abnormalities in attention. PMID- 25912524 TI - Effect of repeated Kangaroo Mother Care on repeated procedural pain in preterm infants: A randomized controlled trial. AB - BACKGROUND: Preterm infants' repeated exposure to painful procedures may lead to negative consequences. Thus, non-pharmacological pain management is essential due to medication side effects. Kangaroo Mother Care, which aims at offering human care to neonates, has been established for the treatment of a single painful procedure, but the effectiveness of Kangaroo Mother Care across repeated painful procedures is unknown. OBJECTIVE: To test the effectiveness of repeated Kangaroo Mother Care on repeated heel-stick pain in preterm neonates. DESIGN: Randomized controlled trial. SETTING: Level III Neonatal Intensive Care Unit at a large teaching hospital in northeast China. METHOD: Preterm infants (gestational age less than 37 weeks) (n=80) were recruited and randomly assigned using a random table format to either an incubator group (n=40) or Kangaroo Mother Care group (n=40). Pain assessments were carried out during four routine heel stick procedures. For the first heel stick, preterm infants in each group received no intervention (routinely stayed in incubator). During the next three heel sticks, the infants in Kangaroo Mother Care group received heel sticks during Kangaroo Mother Care, while infants in the incubator group received heel sticks in incubator. The procedure of each heel stick included 3 phases: baseline, blood collection and recovery. Crying, grimacing and heart rate in response to pain were evaluated at each phase across four heel sticks by three trained independent observers who were blinded to the purpose of the study. Data were analyzed by analysis of variance (ANOVA), with repeated measures at different evaluation phases of heel stick. RESULTS: 75 preterm infants completed the protocol. Between group comparison revealed that preterm infants' heart rate was significantly lower, and the duration of crying and facial grimacing were both significantly shorter in the Kangaroo Mother Care group (n=38) than the incubator group (n=37) from the blood collection phase to recovery phase during repeated heel sticks. No significant within-group difference was found in heart rate between the baseline phase and recovery phase through repeated heel sticks for Kangaroo Mother Care group. In contrast, the incubator group experienced significant within group differences in heart rate between baseline and recovery through repeated heel sticks. CONCLUSION: The effect of repeated Kangaroo Mother Care analgesia remains stable in preterm infants over repeated painful procedures. Given the many invasive procedures that are part of clinical care in preterm infants and most mothers preferred to provide comfort for their infants during painful procedures, Kangaroo Mother Care may be a safe analgesic alternative in preterm infants in whom it is feasible. PMID- 25912525 TI - The gut microbiome: a new frontier for alcohol investigation. PMID- 25912527 TI - ABOi with conventional immunosuppression alone-antiblood group antibody isn't the only contributor to antibody-mediated rejection and/or thrombotic microangiopathy. PMID- 25912526 TI - Three-dimensional reconstruction of helical polymers. AB - The field of three-dimensional electron microscopy began more than 45years ago with a reconstruction of a helical phage tail, and helical polymers continue to be important objects for three-dimensional reconstruction due to the centrality of helical protein and nucleoprotein polymers in all aspects of biology. We are now witnessing a fundamental revolution in this area, made possible by direct electron detectors, which has led to near-atomic resolution for a number of important helical structures. Most importantly, the possibility of achieving such resolution routinely for a vast number of helical samples is within our reach. One of the main problems in helical reconstruction, ambiguities in assigning the helical symmetry, is overcome when one reaches a resolution where secondary structure is clearly visible. However, obstacles still exist due to the intrinsic variability within many helical filaments. PMID- 25912528 TI - The ethanol extract of Osmanthus fragrans attenuates Porphyromonas gingivalis lipopolysaccharide-stimulated inflammatory effect through the nuclear factor erythroid 2-related factor-mediated antioxidant signalling pathway. AB - BACKGROUND: In the present study, we explored the effect of the ethanol extract of Osmanthus fragrans (EOF) on the growth and collagenase activity of Porphyromonas gingivalis (P. gingivalis). We also investigated the capacity of EOF to attenuate P. gingivalis lipopolysaccharide (LPS)-induced inflammatory responses and the possible signalling pathway. METHODS: EOF was obtained by soaking the O. fragrans powder in the ethanol and concentrating the extracts under reduced pressure. Microplate dilution assays were used to determine the effect of EOF on P. gingivalis growth. Collagenase inhibition was detected using fluorometric and colorimetric assays. The effects of EOF on the production of the cytokines interleukin-6 (IL-6) and IL-8 were assessed using enzyme-linked immunosorbent assays (ELISAs). The oxidative stress biomarkers were assayed using commercial kits. The effects of EOF on the expression of cytoprotective enzymes and nucleoprotein nuclear factor erythroid 2-related factor (Nrf2) were tested by Western blot analysis. RESULTS: EOF significantly inhibited the growth of P. gingivalis, especially in the iron-limited culture medium. The inhibitory effect of EOF on P. gingivalis collagenase activity was time- and concentration dependent. The P. gingivalis LPS-stimulated production of IL-6 and IL-8 was attenuated by EOF. LPS significantly induced the production of nitric oxide (NO) and malondialdehyde (MDA), and decreased the expression of superoxide dismutase (SOD) while pretreatment with EOF alleviated these effects. The presence of EOF markedly upregulated the expression levels of the cytoprotective enzymes and nucleoprotein Nrf2. CONCLUSION: This study suggests that the potent Nrf2 activation capacity of O. fragrans may be useful in the adjunctive treatment of periodontal disease. PMID- 25912529 TI - Portable LED fluorescence instrumentation for the rapid assessment of potable water quality. AB - Characterising the organic and microbial matrix of water are key issues in ensuring a safe potable water supply. Current techniques only confirm water quality retrospectively via laboratory analysis of discrete samples. Whilst such analysis is required for regulatory purposes, it would be highly beneficial to monitor water quality in-situ in real time, enabling rapid water quality assessment and facilitating proactive management of water supply systems. A novel LED-based instrument, detecting fluorescence peaks C and T (surrogates for organic and microbial matter, respectively), was constructed and performance assessed. Results from over 200 samples taken from source waters through to customer tap from three UK water companies are presented. Excellent correlation was observed between the new device and a research grade spectrophotometer (r(2)=0.98 and 0.77 for peak C and peak T respectively), demonstrating the potential of providing a low cost, portable alternative fluorimeter. The peak C/TOC correlation was very good (r(2)=0.75) at low TOC levels found in drinking water. However, correlations between peak T and regulatory measures of microbial matter (2 day/3 day heterotrophic plate counts (HPC), E. coli, and total coliforms) were poor, due to the specific nature of these regulatory measures and the general measure of peak T. A more promising correlation was obtained between peak T and total bacteria using flow cytometry. Assessment of the fluorescence of four individual bacteria isolated from drinking water was also considered and excellent correlations found with peak T (Sphingobium sp. (r(2)=0.83); Methylobacterium sp. (r(2)=1.0); Rhodococcus sp. (r(2)=0.86); Xenophilus sp. (r(2)=0.96)). It is notable that each of the bacteria studied exhibited different levels of fluorescence as a function of their number. The scope for LED based instrumentation for in-situ, real time assessment of the organic and microbial matrix of potable water is clearly demonstrated. PMID- 25912530 TI - BTEX in indoor air of waterpipe cafes: Levels and factors influencing their concentrations. AB - BTEX (benzene, toluene, ethylbenzene and xylene) concentrations, factors affecting their levels, and the exposure risks related to these compounds were studied in waterpipe (Ghalyun/Hookah) cafes of Ardabil city in Islamic Republic of Iran. 81 waterpipe cafes from different districts of Ardabil city were selected and their ambient air was monitored for BTEX compounds. Air samples were taken from standing breathing zone of employees, ~150 cm above the ground level, and were analyzed using GC-FID. In each case, the types of smoked tobacco (regular, fruit flavored), types of ventilation systems (natural/artificial), and the floor level at which the cafe was located were investigated. A high mean concentration of 4.96+/-2.63 mg/m(3) corresponding to long term exposure to benzene-related cancer risk of 4314*10(-6) was estimated. The levels of the remaining compounds were lower than the national guideline limits, but their hazard quotients (HQ) for long term exposure to ethylbenzene (1.15) and xylene (17.32) exceeded the HQ unit value. Total hazard indices (HI) of 63.23 were obtained for non-cancer risks. Type of the smoked tobacco was the most important factor influencing BTEX concentrations in the cafes. BTEX concentrations in indoor ambient air of Ardabil waterpipe cafes were noticeably high, and therefore may pose important risks for human health on both short and long term exposures. PMID- 25912531 TI - Sonochemical degradation of the pharmaceutical fluoxetine: Effect of parameters, organic and inorganic additives and combination with a biological system. AB - Fluoxetine (FLX), one of the most widely used antidepressants in the world, is an emergent pollutant found in natural waters that causes disrupting effects on the endocrine systems of some aquatic species. This work explores the total elimination of FLX by sonochemical treatment coupled to a biological system. The biological process acting alone was shown to be unable to remove the pollutant, even under favourable conditions of pH and temperature. However, sonochemical treatment (600 kHz) was shown to be able to remove the pharmaceutical. Several parameters were evaluated for the ultrasound application: the applied power (20 60 W), dissolved gas (air, Ar and He), pH (3-11) and initial concentration of fluoxetine (2.9-162.0 MUmol L(-1)). Additionally, the presence of organic (1 hexanol and 2-propanol) and inorganic (Fe(2+)) compounds in the water matrix and the degradation of FLX in a natural mineral water were evaluated. The sonochemical treatment readily eliminates FLX following a kinetic Langmuir. After 360 min of ultrasonic irradiation, 15% mineralization was achieved. Analysis of the biodegradability provided evidence that the sonochemical process transforms the pollutant into biodegradable substances, which can then be mineralized in a subsequent biological treatment. PMID- 25912532 TI - The 'disconnect' between initial judgments of lamotrigine vs. its real-world effectiveness in managing bipolar disorder. A tale with wider ramifications. AB - OBJECTIVE: To detail the disconnect between the quantified efficacy of the mood stabilizer lamotrigine in its registration controlled trials and its later judged clinical effectiveness and consider some determinants of disconnects between some efficacy trial findings and 'real-world' clinical effectiveness judgments. METHOD: Published articles considering lamotrigine as a treatment for the bipolar I or II disorders were selected for review. While randomized controlled trials were weighted, we also consider open trials and effectiveness observations from clinician researchers and demonstrate that lamotrigine has been quite variably judged over time. RESULTS: We suggest that the early trials evaluating lamotrigine for acute bipolar disorder depression focused on a suboptimal clinical target, and in so doing, ensured less lamotrigine efficacy compared with trials of bipolar disorder preventative treatment. Moreover, a number of additional methodological limitations compromised analyses. We also detail variable reporting of actual study results. The initial sharp disconnect (between efficacy and effectiveness judgments) has narrowed as lamotrigine has been evaluated and progressively taken up as a maintenance mood stabilizer. CONCLUSION: The lamotrigine disconnect story provides a number of salutary lessons that are salient to evaluating the effectiveness and ecological niche of any psychotropic medication. The lamotrigine story presented here argues strongly for the wisdom of encouraging an iterative process between efficacy studies and clinical observation. PMID- 25912533 TI - Tobacco use in bipolar disorder. AB - Tobacco use in mental health in general and bipolar disorder in particular remains disproportionally common, despite declining smoking rates in the community. Furthermore, interactions between tobacco use and mental health have been shown, indicating the outcomes for those with mental health disorders are impacted by tobacco use. Factors need to be explored and addressed to improve outcomes for those with these disorders and target specific interventions for people with psychiatric illness to cease tobacco smoking. In the context of bipolar disorder, this review explores; the effects of tobacco smoking on symptoms, quality of life, suicidal behavior, the biological interactions between tobacco use and bipolar disorder, the interactions between tobacco smoking and psychiatric medications, rates and factors surrounding tobacco smoking cessation in bipolar disorder and suggests potential directions for research and clinical translation. The importance of this review is to bring together the current understanding of tobacco use in bipolar disorder to highlight the need for specific intervention. PMID- 25912534 TI - N-acetyl cysteine in the treatment of obsessive compulsive and related disorders: a systematic review. AB - OBJECTIVE: Obsessive compulsive and related disorders are a collection of debilitating psychiatric disorders in which the role of glutamate dysfunction in the underpinning neurobiology is becoming well established. N-acetyl cysteine (NAC) is a glutamate modulator with promising therapeutic effect. This paper presents a systematic review of clinical trials and case reports exploring the use of NAC for these disorders. A further objective was to detail the methodology of current clinical trials being conducted in the area. METHODS: PubMed, Web of Science and Cochrane Library Database were searched for human clinical trials or case reports investigating NAC in the treatment of obsessive compulsive disorder (OCD) or obsessive compulsive related disorders. Researchers with known involvement in NAC studies were contacted for any unpublished data. RESULTS: Four clinical trials and five case reports/series were identified. Study durations were commonly 12-weeks, using 2,400-3,000 mg/day of NAC. Overall, NAC demonstrates activity in reducing the severity of symptoms, with a good tolerability profile and minimal adverse effects. Currently there are three ongoing randomized controlled trials using NAC for OCD (two adults and one pediatric), and one for excoriation. CONCLUSIONS: Encouraging results have been demonstrated from the few pilot studies that have been conducted. These results are detailed, in addition to a discussion of future potential research. PMID- 25912535 TI - Pharmacotherapy of bipolar disorder with quetiapine: a recent literature review and an update. AB - Bipolar disorder is a chronic, recurrent condition with the usual onset during adolescence or early adulthood. In the Diagnostic and Statistical Manual of Mental Disorders 5th edition, it is conceptualized as a spectrum disorder usually associated with such comorbidities as anxiety disorders and substance use disorders. It is a relatively prevalent condition often complicated by mixed episodes, rapid cycling, subsyndromal symptoms, and treatment refractoriness. In spite of carrying substantial morbidity and mortality, effective treatments are few and far between and conventional mood stabilizers are often unsuccessful in controlling the various manifestations of the disorder. In this scenario, second generation antipsychotics are emerging as treatments with valid efficacy in all phases of bipolar disorder. Quetiapine is a versatile atypical antipsychotic which was first approved for the treatment of schizophrenia, but latter on the basis of controlled studies earned United States Food and Drug Administration's approval for acute as well as maintenance treatment of this difficult to treat condition. In this review, recently published studies in the last 10 years were examined to update the knowledge about the efficacy and safety of quetiapine in the treatment of bipolar disorder. The medication's clinical pharmacology was first considered followed by a literature review summarizing its uses in bipolar disorder. The conclusion was that quetiapine was efficacious in manic, mixed and depressive episodes and as a maintenance agent with a good tolerability profile. PMID- 25912536 TI - Understanding schizophrenia as a disorder of consciousness: biological correlates and translational implications from quantum theory perspectives. AB - From neurophenomenological perspectives, schizophrenia has been conceptualized as "a disorder with heterogeneous manifestations that can be integrally understood to involve fundamental perturbations in consciousness". While these theoretical constructs based on consciousness facilitate understanding the 'gestalt' of schizophrenia, systematic research to unravel translational implications of these models is warranted. To address this, one needs to begin with exploration of plausible biological underpinnings of "perturbed consciousness" in schizophrenia. In this context, an attractive proposition to understand the biology of consciousness is "the orchestrated object reduction (Orch-OR) theory" which invokes quantum processes in the microtubules of neurons. The Orch-OR model is particularly important for understanding schizophrenia especially due to the shared 'scaffold' of microtubules. The initial sections of this review focus on the compelling evidence to support the view that "schizophrenia is a disorder of consciousness" through critical summary of the studies that have demonstrated self-abnormalities, aberrant time perception as well as dysfunctional intentional binding in this disorder. Subsequently, these findings are linked with 'Orch-OR theory' through the research evidence for aberrant neural oscillations as well as microtubule abnormalities observed in schizophrenia. Further sections emphasize the applicability and translational implications of Orch-OR theory in the context of schizophrenia and elucidate the relevance of quantum biology to understand the origins of this puzzling disorder as "fundamental disturbances in consciousness". PMID- 25912537 TI - Dimensions of Delusions in Major Depression: Socio-demographic and Clinical Correlates in an Unipolar-Bipolar Sample. AB - OBJECTIVE: The present study aims at exploring associations between a continuous measure of distorted thought contents and a set of demographic and clinical features in a sample of unipolar/bipolar depressed patients. METHODS: Our sample included 1,833 depressed subjects. Severity of mood symptoms was assessed by the 21 items Hamilton Depression Rating Scale (HAM-D). The continuous outcome measure was represented by a delusion (DEL) factor, extracted from HAM-D items and including items: 2 ("Feelings of guilt"), 15 ("Hypochondriasis"), and 20 ("Paranoid symptoms"). Each socio-demographic and clinical variable was tested by a generalized linear model test, having depressive severity (HAM-D score?DEL score) as the covariate. RESULTS: A family history of major depressive disorder (MDD; p=0.0006), a diagnosis of bipolar disorder, type I ( p=0.0003), a comorbid general anxiety disorder (p<0.0001), and a higher number of manic episodes during lifetime (p<0.0001), were all associated to higher DEL scores. Conversely, an older age at onset (p<0.0001) and a longer duration of hospitalization for depression over lifetime (p=0.0003) had a negative impact over DEL scores. On secondary analyses, only the presence of psychotic features (p<0.0001) and depressive severity (p<0.0001) were found to be independently associated to higher DEL scores. CONCLUSIONS: The retrospective design and a non validated continuous measure for distorted thought contents were the main limitations of our study. Excluding the presence of psychotic features and depressive severity, no socio-demographic or clinical variable was found to be associated to our continuous measure of distorted thinking in depression. PMID- 25912538 TI - Effects of persisting emotional impact from child abuse and norepinephrine transporter genetic variation on antidepressant efficacy in major depression: a pilot study. AB - OBJECTIVE: Previous studies suggest child abuse and serotonergic polymorphism influence depression susceptibility and antidepressant efficacy. Polymorphisms of the norepinephrine transporter (NET) may also be involved. Research in the area is possibly clouded by under reporting of abuse in researcher trials. METHODS: Adults (n=51) with major depressive disorder has 8 weeks treatment with escitalopram or venlafaxine. Abuse history was obtained, the ongoing emotional impact of which was measured with the 15-item impact of event scale (IES-15). The 17-item Hamilton Depression Rating Scale (HDRS) was applied serially. Two NET polymorphisms (rs2242446 and rs5569) were assayed, blinded to HDRS ratings and abuse history. RESULTS: No subjects reporting abuse with high impact in adulthood (IES-15 >=26, n=12) remitted; whereas 77% reporting low impact (IES-15 <26; n=26) remitted (p<0.001). Subjects reporting high impact abuse (n=12) had a 50-fold (95% confidence interval=4.85-514.6) greater odds of carrying rs2242446-TT genotype, but the small sample size leaves this finding vulnerable to type I error. CONCLUSIONS: The level of persisting impact of child abuse appears relevant to antidepressant efficacy, with susceptibility to such possibly being influence by NET rs2242446 polymorphism. Larger studies may be merited to expand on this pilot level finding given potential for biomarker utility. PMID- 25912539 TI - An Open Study of Sulforaphane-rich Broccoli Sprout Extract in Patients with Schizophrenia. AB - OBJECTIVE: Schizophrenia is a mental disorder characterized by severe cognitive impairment. Accumulating evidence suggests a role for oxidative stress in the pathophysiology of schizophrenia. Sulforaphane (SFN) extracted from broccoli sprout is an agent with potent anti-oxidant and anti-inflammatory activity. In this study, we attempted to evaluate the effect of SFN on cognitive impairment in medicated patients with schizophrenia. METHODS: We recruited a total of 10 outpatients with schizophrenia, all of whom gave informed consent. Participants took 3 tablets of SFN, consisting of 30 mg of SFN-glucosinolate per day, for 8 weeks. Clinical symptoms using the Positive and Negative Syndrome Scale (PANSS) and cognitive function using the Japanese version of CogState battery were evaluated at the beginning of the study and at week 8. RESULTS: A total of 7 patients completed the trial. The mean score in the Accuracy component of the One Card Learning Task increased significantly after the trial. However, we detected no other significant changes in participants. CONCLUSIONS: This result suggests that SFN has the potential to improve cognitive function in patients with schizophrenia. PMID- 25912540 TI - Effect of polymorphisms of three genes mediating monoamine signalling on brain morphometry in schizophrenia and healthy subjects. AB - OBJECTIVE: We examined the effect of risk alleles of polymorphisms of three schizophrenia risk genes that mediate monoamine signalling in the brain on regional brain volumes of schizophrenia and healthy control subjects. The risk alleles and the gene polymorphisms studied were: Val allele of catechol o methyltransferase (COMT) rs4680 polymorphism; short allele of 5-hydroxy tryptamine transporter linked polymorphic region (5HTTLPR) polymorphism; and T allele of 5-hydroxy tryptamine 2A (5HT2A) rs6314 polymorphism. METHODS: The study was carried out on patients with recent onset schizophrenia (n=41) recruited from the outpatient department of National Institute of Mental Health and Neurosciences, Bangalore, India and healthy control subjects (n=39), belonging to South Indian Dravidian ethnicity. Individual and additive effects of risk alleles of the above gene polymorphisms on brain morphometry were explored using voxel based morphometry. RESULTS: Irrespective of phenotypes, individuals with the risk allele T of the rs6314 polymorphism of 5HT2A gene showed greater (at cluster extent equivalent to family wise error-correction [FWEc] p<0.05) regional brain volumes in the left inferior temporal and left inferior occipital gyri. Those with the risk alleles of the other two polymorphisms showed a trend (at p<0.001, uncorrected) towards lower regional brain volumes. A trend (at p<0.001, uncorrected) towards additive effects of the above 3 risk alleles (subjects with 2 or 3 risk alleles vs. those with 1 or no risk alleles) on brain morphology was also noted. CONCLUSIONS: The findings of the present study have implications in understanding the role of individual and additive effects of genetic variants in mediating regional brain morphometry in health and disease. PMID- 25912542 TI - Shared and distinct neurocognitive endophenotypes of schizophrenia and psychotic bipolar disorder. AB - OBJECTIVE: Schizophrenia and bipolar disorder are characterized by the presence of neurocognitive impairments on the psychosis continuum. The present study aimed to explore the shared and distinct endophenotypes between these disorders. METHODS: The study included 34 probands with remitted schizophrenia and 34 probands with euthymic bipolar disorder who had a history of psychotic symptoms that met the Diagnostic and Statistical Manual of Mental Disorders 4th edition (DSM-IV) criteria, unaffected first-degree relatives of probands (31 relatives of probands with schizophrenia and 29 relatives of probands with bipolar disorder), and 34 healthy controls. Cognitive assessments were performed using the digit span, continuous performance, Rey auditory and visual learning, complex figure, verbal fluency, Wisconsin card sorting, and finger tapping tests. RESULTS: Probands with schizophrenia showed the most generalized and severe cognitive deficits across cognitive domains (working memory, verbal learning and memory, visual memory, verbal fluency, and executive function). Some domains of cognitive function (working memory, verbal learning, and memory) were also impaired in probands with bipolar disorder, but to a lesser degree than in probands with schizophrenia. All probands and relatives showed a common deficit in working memory compared to healthy controls. Relatives of probands with schizophrenia also showed verbal fluency dysfunction. Cognitive performance of all relatives was intermediate to the performance of both patients and healthy controls. CONCLUSIONS: These findings suggest that a deficit in working memory could be a shared endophenotype of genetic vulnerability to schizophrenia and psychotic bipolar disorder, and verbal fluency could be a candidate endophenotype for schizophrenia specifically. PMID- 25912541 TI - The influence of levetiracetam in cognitive performance in healthy individuals: neuropsychological, behavioral and electrophysiological approach. AB - OBJECTIVE: The present study sought to analyze the influence of Levetiracetam (LEV) in cognitive performance by identifying the changes produced by LEV in reaction time, in neuropsychological assessment of attention and memory and in absolute theta power in frontal activity. METHODS: Twelve healthy subjects (5 men and 7 women; mean age, 30.08 years, standard deviation, 4.71) were recruited for this study. The neuropsychological tests: Trail Making Test (A and B), Digit Span (direct and indirect numerical orders/working memory); Stroop test (inhibitory control of attention); Tower of London (planning and decision-making) and a quantitative electroencephalography were applied in 2 different days after and before the participants ingested the capsule of placebo or 500 mg LEV. RESULTS: A two-way-ANOVA was implemented to observe the interaction between conditions (placebo or LEV 500 mg) and moments (pre- and post-ingestion of LEV or placebo). The data were analyzed by the SPSS statistical package (p<0.05). For the neuropsychological parameter, the Trail Making Test (A) was the only test that showed significant difference for condition in the task execution time (p=0.026). Regarding the reaction time in the behavioral parameter, an interaction between both factors (p=0.034) was identified through a two-way-ANOVA (condition versus moment). Electrophysiological measures showed a significant interaction for electrodes: F7, F3, and FZ. CONCLUSIONS: The findings showed that LEV promotes an important cognitive enhancement in the executive functions. PMID- 25912543 TI - The Relationship between Cognitive Decline and Psychopathology in Patients with Schizophrenia and Bipolar Disorder. AB - OBJECTIVE: The primary goals of the present study were to assess intellectual function in participants with schizophrenia or bipolar disorder (BD) and to investigate the relationships between cognitive decline and the severity of each type of psychopathology. METHODS: The present study included 51 patients with schizophrenia and 42 with BD who were recruited from the psychiatry outpatient clinic of Jeju University Hospital between March 2011 and March 2014. The Korean Wechsler Adult Intelligence Scale (K-WAIS) was administered to each of the 93 participants, and they were categorized into two groups based on their current intelligence quotient (IQ) and their estimated premorbid IQ: severely impaired group (SIG) and mildly impaired group (MIG). The Minnesota Multiple Personality Inventory (MMPI) and the Brief Psychiatric Rating Scale (BPRS) were used to assess psychopathology. RESULTS: The SIG schizophrenia participants exhibited significantly higher scores on the frequent (F) and schizophrenia (Sc) subscales of the MMPI, but significantly lower scores on the correction (K) and psychopathic deviate (Pd) subscales compared with the MIG schizophrenia participants. Furthermore, the BPRS scores were significantly higher in the SIG schizophrenia participants relative to the MIG schizophrenia participants. The SIG BD participants had significantly higher F, masculinity-femininity (Mf), paranoia (Pa), and Sc but significantly lower Pd scores compared with the MIG BD participants. CONCLUSIONS: The present findings revealed a significant discrepancy between the estimated premorbid levels of cognitive function and current cognitive function in participants with schizophrenia or BD. Moreover, this discrepancy was correlated with severity of psychopathology in both groups. PMID- 25912544 TI - Effect of Scopolamine Butylbromide on Clozapine-induced Hypersalivation in Schizophrenic Patients: A Case Series. AB - Clozapine has been demonstrated to be useful for treating refractory schizophrenia. However, hypersalivation occurs in 31.0- 97.4% of the patients treated with clozapine. Accordingly, some patients who are disturbed by their hypersalivation refuse to continue with clozapine treatment. This study investigated the efficacy of the anticholinergic agent scopolamine butylbromide against clozapine-induced hypersalivation. Five schizophrenia patients were coadministered scopolamine butylbromide (30-60 mg/ day) for 4 weeks. At the baseline and after 4 weeks' treatment, we subjectively evaluated hypersalivation using a visual analog scale and objectively assessed it using the Drooling Severity Scale and Drooling Frequency Scale. As a result, improvements in the patients' Drooling Severity Scale and Drooling Frequency Scale scores, but no improvements in their visual analog scale scores, were observed after scopolamine butylbromide treatment. These results indicate that at least some schizophrenic patients with clozapine-induced hypersalivation would benefit from scopolamine butylbromide treatment. We conclude that clozapine-induced hypersalivation is one factor of stress to patients. Subjective hypersalivation was not improved, but objective hypersalivation was, by scopolamine butylbromide treatment. However, scopolamine butylbromide and clozapine possess anticholinergic effects so clinicians should closely monitor patients who take scopolamine butylbromide. PMID- 25912545 TI - Olanzapine-induced Orthostatic Hypotension. AB - Olanzapine is an atypical antipsychotic which is efficacious in the treatment of schizophrenia. The adverse effect profile for olanzapine is benign except for higher rates of metabolic events. Orthostatic hypotension is less commonly reported with olanzapine as compared to first-generation and few atypical antipsychotics. We report a case where olanzapine, in a dose dependent fashion, caused transient postural hypotension. PMID- 25912546 TI - Dystonia in an adolescent on risperidone following the discontinuation of methylphenidate: a case report. AB - Attention-deficit/hyperactivity disorder (ADHD) is a neurodevelopmental disorder with common comorbidities that include oppositional defiant disorder, conduct disorder, anxiety disorder, and affective disorders. Because of these comorbidities, drug combination treatments and drug-drug interactions are becoming increasingly more frequent. The present case report describes an acute dystonic reaction following the abrupt discontinuation of methylphenidate from a drug regimen with risperidone. The patient experienced acute dystonic reactions on three separate occasions when he forgot to take his methylphenidate medication. The present report informs clinicians about the possible side effects, such as dystonia, when psychostimulant and antipsychotic drug combinations are altered and suggests that the abrupt cessation of stimulants may lead to the development of movement disorders. Therefore, appropriate care is necessary when changing the dose of a drug or abruptly discontinuing a drug from a combination of psychostimulants and antipsychotics. PMID- 25912547 TI - Combination of Nitrous Oxide with Isoflurane or Scopolamine for Treatment resistant Major Depression. PMID- 25912548 TI - Transcriptional modulation of mitochondria biogenesis pathway at and above critical speed in mice. AB - High- or moderate-intensity endurance training leads to mitochondrial biogenesis via the peroxisome proliferator-activated receptor gamma co-activator 1alpha (PGC 1alpha)/mitochondrial transcription factor A (Tfam) signaling pathway. Although this pathway is stimulated during acute exercise, the relationship between its activity and the intensity of the exercise has not been characterized. In animal studies, individualized running speeds have not previously been assessed. Here, we sought to determine whether this pathway was modulated after a bout of exhaustive exercise at different relative intensities (at and over critical speed (CS)). Our starting hypotheses were that (i) exercise-induced overexpression of PGC-1alpha in skeletal muscle falls at intensities above CS, and (ii) transcriptional activity of the mitochondrial biogenesis signaling cascade is intensity-sensitive at and above CS. To test these hypothesis, male Friend Virus B-Type mice were divided into a control group and three exercise groups (exercising at CS, peak velocity (vPeak) and 150 % CS, respectively). mRNA expression levels for genes involved in mitochondrial biogenesis signaling were analyzed in the quadriceps muscle. PGC-1alpha was overexpressed at all exercise intensities. We also identified that, PGC-1alpha mRNA expression was negatively correlated with exercise intensity and blood lactate levels but not with maximal oxygen uptake, vPeak, or CS. Expression of the PGC-1alpha co-activator peroxisome proliferator-activated receptor beta was negatively correlated with the exercise intensity. In contrast, expression levels of Tfam were dissociated from exercise intensity. Our data indicate that at the intensities used in endurance training, the expression of mitochondrial biogenesis genes is finely modulated by the relative intensity of exhaustive exercise. PMID- 25912549 TI - Low inducible expression of p21Cip1 confers resistance to paclitaxel in BRAF mutant melanoma cells with acquired resistance to BRAF inhibitor. AB - The therapeutic efficacy of oncogenic BRAF inhibitor is limited by the onset of acquired resistance. In this study, we investigated the potential therapeutic effects of the mitotic inhibitor paclitaxel on three melanoma cell lines with differing sensitivity to the BRAF inhibitor. Of the two BRAF inhibitor-resistant cell lines, A375P/Mdr cells harboring the BRAF V600E mutant were resistant and the wild-type BRAF SK-MEL-2 cells were sensitive to paclitaxel. In particular, paclitaxel caused the growth inhibition of SK-MEL-2 cells to a much greater extent than it caused growth inhibition of A375P cells. Paclitaxel exhibited no significant effect on the phosphorylation of MEK-ERK in any cell lines tested, regardless of both the BRAF mutation and the drug resistance, implying that paclitaxel activity is independent of MEK-ERK inhibition. In A375P cells, paclitaxel treatment resulted in a marked emergence of apoptotic cells after mitotic arrest, concomitant with a remarkable induction of p21(Cip1). However, paclitaxel only moderately increased the levels of p21(Cip1) in A375P/Mdr cells, which exhibited a strong resistance to paclitaxel. The p21(Cip1) overexpression partially conferred paclitaxel sensitivity to A375P/Mdr cells. Interestingly, we found an extremely low background expression level of p21(Cip1) in SK-MEL-2 cells lacking normal p53 function, which caused much greater G2/M arrest than that seen in A375P cells. Taken together, these results suggest that paclitaxel may be an effective anticancer agent through regulating the expression of p21(Cip1) for the treatment of BRAF mutant melanoma cells resistant to BRAF inhibitors. PMID- 25912550 TI - Cryptotanshinone, a Stat3 inhibitor, suppresses colorectal cancer proliferation and growth in vitro. AB - Cryptotanshinone (CPT) is a natural compound extracted from herbal medicine that has been previously shown to possess antitumor properties in various types of human cancer cells. In the present study, we examined the potential role of CPT in the treatment of colorectal cancer. Using SW480, HCT116, and LOVO colorectal cancer cell lines, the effects of CPT on cell viability, apoptosis, and tumorigenicity were evaluated. The results showed that CPT significantly inhibited the growth and viability of SW480, HCT116, and LOVO cell lines by inducing apoptosis and prevented anchorage dependent growth on agar. In addition, CPT inhibited the activation of Signal transducer and activator of transcription 3 (Stat3) pathways in colorectal cancer cells. Stat3 is a transcription factor that mediates the expression of various genes associated with many cellular processes, such as inflammation and cell growth, and has been shown to promote several cancer types, including colorectal cancer. These findings indicate that CPT may be a potential candidate for the treatment and prevention of colorectal cancer in part by inhibiting the activation of Stat3. PMID- 25912551 TI - Comparative analysis of sphingomyelin synthase 1 gene expression at the transcriptional and translational levels in human tissues. AB - Sphingomyelin synthase 1 (SMS1) catalyses the biosynthesis of sphingomyelin in eukaryotic cells. We have previously determined the structure of the SGMS1 gene encoding this enzyme and a number of its alternative transcripts. Here, we describe a study of the expression of the full-length SMS1 protein and the sum of the alternative transcripts encoding this protein in human tissues. The SMS1 protein and mRNA levels in tissues differed significantly and were not correlated, implying the active post-transcriptional regulation of SMS1 protein expression. The putative truncated isoforms of the SMS1 protein, which are encoded by a number of alternative transcripts, were not detected by immunoblotting and thus may be absent or present in only small amounts. PMID- 25912552 TI - Genomic identification and quantification of microbial species adhering to toothbrush bristles after disinfection: A cross-over study. AB - PURPOSE: The aim of this clinical investigation was to identify and quantify the microbial species adhering to toothbrush bristles after controlled brushing and storage in different antimicrobial agents. METHODS: Sixteen healthy participants were enrolled in this study and randomly submitted to 4 interventions in a cross over design: brushing and toothbrush storage in (I) Periogard/(II) Periobio (Chlorhexidine gluconate 0.12%), (III) Cepacol (cetylpyridinium chloride 0.05%) and (IV) distilled water (positive control). Thirty-eight bacterial species including putative pathogens and 5 Candida spp. were assessed by Checkerboard DNA DNA hybridization. RESULTS: The results of the study have shown a striking reduction of the total microbial counts, including bacteria and Candida spp., on the toothbrush bristles after storage in cetylpyridinium chloride 0.05% (p < 0.0001). Chlorhexidine gluconate 0.12% showed no differences on the total bacterial count when compared to distilled water (p > 0.05). Cetylpyridinium chloride solution also presented the lowest genome counts and frequency of detection for individual target species; distilled water showed the highest individual genome counts (p < 0.05). Potential pathogenic species were recorded in moderate to high levels for chlorhexidine gluconate and distilled water. CONCLUSION: Cetylpyridinium chloride 0.05% was the most effective storage solution in the reduction of total and individual microbial counts, including pathogenic species. PMID- 25912553 TI - Assessment of immune response in periparturient dairy cows using ex vivo whole blood stimulation assay with lipopolysaccharides and carrageenan skin test. AB - The transition period is known to be the most critical phase in the life of high yielding dairy cow. Changes in the immune functions have been observed during the transition period which may account for the onset of clinical and subclinical (e.g. inflammatory response) problems at calving or at the beginning of lactation however this relationship has not yet been adequately investigated. Thus, to establish the potential of the periparturient dairy cow's immune system to respond to stimuli, two challenges [an ex vivo whole blood stimulation assay (WBA) with lipopolysaccharides and a carrageenan skin test (CST)] were performed in addition to characterizing the metabolic and inflammatory profile. The WBA was performed using 0, 0.01 and 5 MUg LPS/mL on whole blood and CST was administered by subcutaneous injection of 0.7 mL solution containing 4.2mg of carrageenan to the shoulder region of the cows. These tests were performed on 10 Holstein Friesian cows at -45 +/- 2, -20 +/- 2, -3, 3, 7, 28 +/- 2 days from parturition (DFP). Cows were also monitored for health status, body condition score, milk yield. The results demonstrate a higher production of IL-1beta and IL-6 from leukocytes after LPS stimulation around calving (from -3 to 3 DFP) compared to 45 DFP (P < 0.05). Moreover, IL-6 (but not IL-1beta) was able to reach close to the maximum response at the lower stimulus intensity (0.01 MUg LPS/mL), maintaining a higher response over a longer time in early lactation. The release of higher levels of IL-6 in the transition period, with low LPS dose, suggests its crucial role in the regulation of inflammatory response around calving. The response of cows to CST decreased a few days before calving (-3 DFP) compared with response at -45 and 28 DFP (P<0.05), and remained low in the first week of lactation. This result suggests the reduction of the functionality of some vascular factors, which decreases diapedesis. Overall, the WBA and CST tests confirm changes in immunocompetence around calving. These tests are able to better describe the changes of the innate immune response at a local and systemic level, mainly when combined with conventional metabolic and inflammatory indices. PMID- 25912554 TI - Acute and sub-chronic oral toxicity profiles of lipopeptides from Bacillus mojavensis A21 and evaluation of their in vitro anticoagulant activity. AB - The aim of the present study was to evaluate the acute and sub-chronic toxicity of lipopeptides mixture produced by Bacillus mojavensis A21 as well as their in vitro anticoagulant activity. A21 lipopeptides was given to mice at single dose from 75 mg to 1000 mg/kg body weight (bw). The median lethal dose (LD50) of A21 lipopeptides was about 550 mg/kg bw. Sub-chronic toxicity study for 28 days was done by daily oral administration of A21 lipopeptides at doses of 40 and 400 mg/kg bw in rats. Results showed that A21 lipopeptides did not cause any change in body weights and they did not produce any marked alterations in the hematological blood parameters including hematocrit concentration, hemoglobin level, white and red cells count. However, the platelets level decreased significantly compared to control value. Moreover, no significant differences in the serum biochemical characteristics were observed for rats treated by the lowest dose. In contrast, a little enhancement of alanine-aminotransferase (ALT) activity and decrease in total cholesterol were observed with the highest dose. A21 lipopeptides were also found to cause a prolongation of the thrombin time (TT), the prothrombin time (PT) and the activated partial thromboplastin time (APTT). Overall, A21 lipopeptides may be very promising compounds for therapeutic purposes. PMID- 25912555 TI - AC-93253 triggers the downregulation of melanoma progression markers and the inhibition of melanoma cell proliferation. AB - A major challenge in anti-melanoma therapy is to develop treatments that are effective for advanced melanoma patients. Unfortunately, the currently used regimens are not efficient and have unsatisfactory effects on disease progression, thus increasing the pressure to develop new, profitable drugs and to identify new molecular targets. Here, we show for the first time that AC-93253, a SIRT2 inhibitor, exerts a negative effect on the expression of a set of genes involved in the progression and chemoresistance (e.g., oncogenes, apoptosis related genes, ABC transporter genes, and cell cycle control genes) of melanoma cells. Furthermore, melanoma cells exposed to AC-93253 and doxorubicin displayed altered biological responses, including apoptosis and proliferation, compared to cells exposed to single treatments. Taken together, we conclude that the usage of AC-93253 in combined therapy could be a promising strategy for melanoma patients. PMID- 25912556 TI - Chrysin and its emerging role in cancer drug resistance. AB - This letter illustrates the significant chemosensitizing effects of chrysin to resistance cancer cells and refers to the article on "Combination of chrysin and cisplatin promotes the apoptosis of Hep G2 cells by up-regulating p53" by Li et al., published in your journal recently. Recent studies have demonstrated that chrysin is able to sensitize or kill cancer cells which are resistant to chemotherapeutic drugs such as cisplatin, doxorubicin and adriamycin. Owing to its potential anti-cancer effects and devoid of toxicity to non-transformed cells, further research is required to completely explore its chemosensitizing effects in other cancers and also assess and evaluate its safety, before going for possible human application. PMID- 25912557 TI - Elevated circulating Th17 and follicular helper CD4(+) T cells in patients with rheumatoid arthritis. AB - It remains not fully elucidated the potential functions of Th17 cells and follicular helper T (Tfh) cells and secreting cytokines in the pathogenesis of rheumatoid arthritis (RA) and their association with disease activity. In this study, the frequencies of Th17 and Tfh cells were determined by flow cytometry, and the levels of interleukin (IL)-17, IL-21, and IL-22 were measured by ELISA in RA patients with different disease activities. The dynamic changes of cell subsets were also detected in response to disease-modify antirheumatic drugs (DMARDs) therapy. The percentages of CD3(+) CD4(+) IL-17A(+) (Th17) cells and CD3(+) CD4(+) CXCR5(+) ICOS(high) (Tfh) cells, as well as the concentrations of IL-17, IL-21, and IL-22 were significantly elevated in RA patients than those in healthy individuals. Furthermore, Tfh cells, IL-21, and IL-22 in the serum was positively correlated with the values of disease activity score. Concentrations of IL-21 and IL-22 in the serum were remarkably reduced following the DMARDs therapies. Our data suggested that Th17 cells, Tfh cells as well as the secreting cytokines may be involved in the pathogenesis of RA. The frequency of circulating Tfh cells and the productions of IL-21 and IL-22 were associated with the disease activity of RA patients, and might be potential therapeutic targets for treatment of RA. PMID- 25912558 TI - Synthesis of oleyl oleate wax esters in Arabidopsis thaliana and Camelina sativa seed oil. AB - Seed oil composed of wax esters with long-chain monoenoic acyl moieties represents a high-value commodity for industry. Such plant-derived sperm oil-like liquid wax esters are biodegradable and can have excellent properties for lubrication. In addition, wax ester oil may represent a superior substrate for biodiesel production. In this study, we demonstrate that the low-input oil seed crop Camelina sativa can serve as a biotechnological platform for environmentally benign wax ester production. Two biosynthetic steps catalysed by a fatty alcohol forming acyl-CoA reductase (FAR) and a wax ester synthase (WS) are sufficient to achieve wax ester accumulation from acyl-CoA substrates. To produce plant-derived sperm oil-like liquid wax esters, the WS from Mus musculus (MmWS) or Simmondsia chinensis (ScWS) were expressed in combination with the FAR from Mus musculus (MmFAR1) or Marinobacter aquaeolei (MaFAR) in seeds of Arabidopsis thaliana and Camelina sativa. The three analysed enzyme combinations Oleo3:mCherry:MmFAR1?c/Oleo3:EYFP:MmWS, Oleo3:mCherry:MmFAR1?c/ScWS and MaFAR/ScWS showed differences in the wax ester molecular species profiles and overall biosynthetic performance. By expressing MaFAR/ScWS in Arabidopsis or Camelina up to 59% or 21% of the seed oil TAGs were replaced by wax esters, respectively. This combination also yielded wax ester molecular species with highest content of monounsaturated acyl moieties. Expression of the enzyme combinations in the Arabidopsis fae1 fad2 mutant background high in oleic acid resulted in wax ester accumulation enriched in oleyl oleate (18:1/18:1 > 60%), suggesting that similar values may be obtained with a Camelina high oleic acid line. PMID- 25912559 TI - Rapid discrimination of malignant lesions from normal gastric tissues utilizing Raman spectroscopy system: a meta-analysis. AB - OBJECTIVES: To systematically analyze the diagnostic accuracy of Raman spectroscopy system (RAS) in the rapid diagnosis of gastric cancer with histopathology as the reference standard. METHODS: We searched a wide range of electronic databases for all published researches that assessed the diagnostic accuracy of RAS to detect gastric carcinoma. Full papers were obtained for potentially eligible studies and evaluated according to predefined criteria. The Quality Assessment of Diagnostic Accuracy Studies checklist was used to assess the quality of included studies. From each study, we extracted information on diagnostic performance of RAS. After exploring heterogeneity, we adopted a random effects model to pool related effect sizes. RESULTS: The initial literature search identified 257 reference articles in which 15 relevant articles with 15 data sets were selected and reviewed. The pooled sensitivity and specificity of RAS in diagnosing gastric cancer were 0.89 (95 % CI 0.84-0.92) and 0.92 (95 % CI 0.88-0.95), respectively. The positive likelihood ratio, the negative likelihood ratio, and the area under the curve were 10 (95 % CI 6.5-15.3), 0.13 (95 % CI 0.08-0.22), and 0.96 (95 % CI 0.94-0.97), respectively. All the pooled estimates, calculated by random and fixed effect models, were similar. There was no evidence of considerable publication bias. CONCLUSIONS: RAS is an objective and sensitive optical diagnostic technology for detecting gastric cancer and has advantages of being noninvasive to the body, real-time diagnosis, and ease of use. Consequently, it does deserve to be recommended. PMID- 25912561 TI - Safety and Efficacy of Autologous Skeletal Myoblast Sheets (TCD-51073) for the Treatment of Severe Chronic Heart Failure Due to Ischemic Heart Disease. AB - BACKGROUND: Poor survival outcomes for patients with severe heart failure (HF) and the donor shortage for heart transplantation warrant the development of myocardial regenerative therapy. We performed a multicenter, phase II study to evaluate the safety and efficacy of autologous skeletal myoblast sheets (TCD 51073). METHODS AND RESULTS: In 3 study sites, we enrolled 7 patients with severe chronic HF due to ischemic heart disease despite maximal therapy, all of whom underwent transplantation of TCD-51073. No serious arrhythmia was reported, and no changes were noted in the frequency of ventricular extrasystole frequency. The primary efficacy endpoint of the change in left ventricular ejection fraction (LVEF) on gated blood-pool scintigraphy at 26 weeks after transplantation showed that 5 subjects were responders (classified as "improved" or "unchanged"). In addition, LVEF on echocardiography improved over time, with a change in LVEF of 7.1+/-2.8% at 26 weeks posttransplantation. Among the 7 subjects, 6 showed improvement in New York Heart Association functional class by at least 1 class. The 6-min walk distance was 410.1+/-136.1 m before transplantation and 455.4+/ 103.7 m at 26 weeks after transplantation. CONCLUSIONS: This study demonstrated the feasibility and safety of the transplantation of TCD-51073 in the patients with severe chronic HF due to ischemic heart disease, suggesting that TCD-51073 might maintain or improve cardiac function, symptoms, and physical function. PMID- 25912562 TI - Comparison of cardiovascular mortality in the Great East Japan and the Great Hanshin-Awaji Earthquakes - a large-scale data analysis of death certificates. AB - BACKGROUND: Large earthquakes have been associated with cardiovascular disease (CVD) mortality. In Japan, the 1995 Great Hanshin-Awaji (H-A) Earthquake was an urban-underground-type earthquake, whereas the 2011 Great East Japan (GEJ) Earthquake was an ocean-trench type. In the present study, we examined how these different earthquake types affected CVD mortality. METHODS AND RESULTS: We examined death certificate data from 2008 to 2012 for 131 municipalities in Iwate, Miyagi, and Fukushima prefectures (n=320,348) and from 1992 to 1996 for 220 municipalities in Hyogo, Osaka, and Kyoto prefectures (n=592,670). A Poisson regression model showed significant increases in the monthly numbers of acute myocardial infarction (AMI)-related deaths (incident rate ratio [IRR] GEJ=1.34, P=0.001; IRR of H-A=1.57, P<0.001) and stroke-related deaths (IRR of GEJ=1.42, P<0.001; IRR of H-A=1.33, P<0.001) after the earthquakes. Two months after the earthquakes, AMI deaths remained significant only for H-A (IRR=1.13, P=0.029). When analyzing the standardized mortality ratio (SMR) after the earthquakes using the Cochran-Armitage trend test, seismic intensity was significantly associated with AMI mortality for 2 weeks after both the GEJ (P for trend=0.089) and H-A earthquakes (P for trend=0.005). CONCLUSIONS: Following the GEJ and H-A earthquakes, there was a sharp increase in CVD mortality. The effect of the disaster was sustained for months after the H-A earthquake, but was diminished after the GEJ Earthquake. PMID- 25912565 TI - Detecting temperature fluctuations at equilibrium. AB - The Gibbs and the Boltzmann definition of temperature agree only in the macroscopic limit. The ambiguity in identifying the equilibrium temperature of a finite-sized 'small' system exchanging energy with a bath is usually understood as a limitation of conventional statistical mechanics. We interpret this ambiguity as resulting from a stochastically fluctuating temperature coupled with the phase space variables giving rise to a broad temperature distribution. With this ansatz, we develop the equilibrium statistics and dynamics of small systems. Numerical evidence using an analytically tractable model shows that the effects of temperature fluctuations can be detected in the equilibrium and dynamical properties of the phase space of the small system. Our theory generalizes statistical mechanics to small systems relevant in biophysics and nanotechnology. PMID- 25912560 TI - Adaptive servo-ventilation therapy for patients with chronic heart failure in a confirmatory, multicenter, randomized, controlled study. AB - BACKGROUND: Adaptive servo-ventilation (ASV) therapy is expected to be novel nonpharmacotherapy with hemodynamic effects on patients with chronic heart failure (CHF), but sufficient evidence has not been obtained. METHODS AND RESULTS: A 24-week, open-label, randomized, controlled study was performed to confirm the cardiac function-improving effect of ASV therapy on CHF patients. At 39 institutions, 213 outpatients with CHF, whose left ventricular ejection fraction (LVEF) was <40% and who had mild to severe symptoms [New York Heart Association (NYHA) class: >=II], were enrolled. After excluding 8 patients, 102 and 103 underwent ASV plus guideline-directed medical therapy (GDMT) [ASV group] and GDMT only [control group], respectively. The primary endpoint was LVEF, and the secondary endpoints were HF deterioration, B-type natriuretic peptide (BNP), and clinical composite response (CCR: NYHA class+HF deterioration). LVEF and BNP improved significantly at completion against the baseline values in the 2 groups. However, no significant difference was found between these groups. HF deterioration tended to be suppressed. The ASV group showed a significant improvement in CCR corroborated by significant improvements in NYHA class and ADL against the control group. CONCLUSIONS: Under the present study's conditions, ASV therapy was not superior to GDMT in the cardiac function-improving effect but showed a clinical status-improving effect, thus indicating a given level of clinical benefit. PMID- 25912566 TI - Prognostic value of PUMA expression in patients with HBV-related hepatocellular carcinoma. PMID- 25912567 TI - About a case of unilateral perirenal retroperitoneal fibrosis without aorta involvement. PMID- 25912568 TI - Remission of type 2 diabetes after bariatric surgery. PMID- 25912569 TI - The discrepancy between recommendations and clinical practice for viscosupplementation in osteoarthritis: mind the gap! AB - Recently AAOS, ACR and OARSI revised their recommendations for the management of knee osteoarthritis (OA) and for hand, knee and hip joints. During ISIAT (International Symposium on Intra-Articular Treatments) 2013 round table on recommendations about the use of intra-articular Hyaluronic Acid (IAHA) in OA, several considerations were elaborated by the ISIAT Technical Expert Panel (TEP) regarding discrepancy between recommendations and clinical practice. The ISIAT TEP gathered the following eight suggestions regarding the drawing of recommendations on the use of IAHA in OA and its comparison with other treatments. It is necessary to merge data coming from both RCTs and registers. Only studies with a strong level of evidence should be taken into account. A common threshold of efficacy should be assessed for comparing treatments. Evaluation of hard outcomes is essential. The effect size of placebo as comparator should be attentively considered in RCTs. Particular attention should be given to different phenotypes of OA that may possibly respond differently to each treatment. Compliance and long-term side effects of different therapeutic approaches should be evaluated. Pharmacoeconomic evaluation should be performed on the long term. PMID- 25912570 TI - Folic acid attenuates dexamethasone-induced placental growth restriction. AB - OBJECTIVE: Intrauterine glucocorticoid (GC) exposure is associated with disturbances in feto-placental growth. This study aimed to investigate whether folic acid supplementation can prevent dexamethasone (Dex)-induced feto-placental growth restriction. MATERIALS AND METHODS: Female C57BL/6J mice were subject to four different treatments, respectively: normal drinking water plus saline injection (NN), normal drinking water plus Dex injection (ND), drinking water supplemented with folic acid plus saline injection (FN), and drinking water supplemented with folic acid plus Dex injection (FD). Folic acid (100 ug/L) was administrated since 2 weeks before the mating and throughout pregnancy. Dex injection (100 ug/kg*d) was performed from E12.5 to E16.5. The placentas were collected at E17.5. RESULTS: The parameters including placental and fetal weight, the maximum placental diameter, volume of junctional and labyrinthine zones, and vascular density in the ND group were significantly smaller compared to the NN group. Except the maximum placental diameter, each of the above parameters in the FD group was significantly larger compared to the ND group. The levels of glucocorticoid receptor (GR) protein, and endothelial growth factor A, C (VEGFA, VEGFC) and placental growth factor (PIGF) mRNAs were significantly lower in the ND group compared to NN group. The VEGFA and PIGF mRNA level in the FD group was significantly higher than that in the ND group, as well as VEGFA and VEGFC protein level. CONCLUSIONS: Folic acid may attenuate Dex-induced restriction on placental growth by elevating the expression of VEGFA and PIGF, and further raising vascular density. PMID- 25912571 TI - Demodex folliculorum in polycystic ovary syndrome patients. AB - OBJECTIVE: In this study, we aimed to investigate frequency of Demodex (D.) folliculorum infestation in Polycystic Ovary Syndrome patients. PATIENTS AND METHODS: The study population consisted of 30 PCOS patients and 30 matched healthy control subjects admitted to the Hospital of Mustafa Kemal University, Gynecology and Obstetrics Clinic between March 2013 and January 2014. The demographic characteristics of the patients were recorded. Samples from the face region of the subjects were taken by standard method of superficial skin biopsy and evaluated by microscopy. Presence of five or more D. species in a cm2 was considered as positive. RESULTS: There were no significant differences in age, body mass index, diabetes mellitus incidence between PCOS patients and the control group. However, D. folliculorum infestation was found to increased in PCOS patients (n = 9; 30%) when compared to the control group (n = 2; 6, 7%) (p: 0.04). CONCLUSIONS: Our study results revealed that Demodex folliculorum appearance increased in PCOS patients. PMID- 25912572 TI - Diagnostic findings in adenomyosis: a pictorial review on the major concerns. AB - Adenomyosis is a benign pathology with a marked impact on women in reproductive age. The prevalence of adenomyosis ranges from 5 to 70%. Dysmenorrhea, metrorrhagia, chronic pelvic pain, dyspareunia and infertility often occur, while a third of the women is asymptomatic. This pictorial review focuses on the peculiar patterns of presentation in adenomyosis. They are identified by means of non-invasive or minimally invasive techniques, with particular reference to 2D- and 3D-transvaginal sonography, sonohysterosalpingography, magnetic resonance imaging, and endoscopic techniques (i.e. hysteroscopy and laparoscopy). PMID- 25912573 TI - Reconstructed ACLs have different cross-sectional areas compared to the native contralaterals on postoperative MRIs. A pilot study. AB - OBJECTIVE: The current trends in anterior cruciate ligament (ACL) reconstruction aim not only to restore the position and footprint of the native ACL, but also its shape and biomechanical function. The objective of our study was to determine whether the in vivo shape of the healed graft differs from the native ACL. PATIENTS AND METHODS: We performed bilateral MRI examinations on patients with successful unilateral ACL reconstruction for an average period of 3 years. The imaging acquisitions were performed using 1.5 T field strength and T2 FSE axial oblique sequence at 2 mm spacing. We than averaged the ratio between the maximum width and thickness as well as the surface area in pixels using ImageJ (National Institutes for Health) and compared it with the native ACLs using the paired t test. RESULTS: For both quadrupled hamstrings and B-PT-B neoligaments, the mid portion area was significantly higher (p < 0.001) than the native contralateral ACL: 41.82/31.39 mm2 and 37.05/32.08 mm2, respectively. The surface area of the neoligaments mid-portion was on average 33.23% higher than the native ACL for the quadrupled hamstrings and 15.49% for the B-PT-B, respectively. The native contralateral ACL was also significantly thinner throughout the mid-portion (p < 0.001) than both B-PT-B and quadrupled hamstrings neoligaments, with a width thickness ratio of 2.57 vs 1.97 and 2.57 vs 1.39, respectively. CONCLUSIONS: Our study showed that, several years after successful anatomic single bundle ACL reconstruction using an ipsilateral autograft, the mid-portion shape and cross sectional area are not restored compared to the uninjured contralateral knee. This effect was more prevalent with hamstrings and less prominent when B-PT-B were used. PMID- 25912574 TI - A case of bone marrow infection by Staphylococcus saccharolyticus. AB - We report a case of fatal bone marrow infection caused by Staphylococcus saccharolyticus in a 26 year old female. The causative organism was isolated by anaerobic culture on blood agar, and was identified by PCR amplification of the gap gene and genotyping of the resultant sequence. PMID- 25912575 TI - The preliminary application of assessment system for cancer pain management. AB - OBJECTIVE: To apply the assessment system for cancer pain management preliminarily, explore the issues in cancer pain diagnosis and treatment, and analyze the differences between oncology department and non-oncology in cancer pain diagnosis and treatment. PATIENTS AND METHODS: The validated questionnaires were collected from department of medical oncology of three hospitals including Xuzhou Central Hospital. Subjects included 41 doctors, 43 nurses, 50 patients, and 12 wards. The data was analyzed to find the main issues as far in cancer pain management. Twelve units of oncology department and 15 units of non-oncology in three hospitals including Xuzhou Central Hospital were assessed with assessment system for cancer pain management. Rank test was conducted to analyze the differences in cancer pain diagnosis and treatment between oncology department and non-oncology. RESULTS: The average scores of doctors, nurses, wards were 85.4, 88.5, 83.8, respectively, while the average score of patients was 68.7. The percentile of analgesic efficacy and safety in patients was 81.7 and the percentile of analgesic opinion changes was only 55.8, indicating that it was necessary to enhance the education of concept about pain management. The average scores of assessment were 82.2 +/- 2.1 and 39.9 +/- 3.6 for oncology and non oncology, respectively. The Wilcoxon value of Rank test was 120.0, indicating the significant difference between the two (p < 0.01). It suggests that there is still a great shortage in cancer pain diagnosis and treatment in non-oncology, and there is an urgent need to further strengthen the cancer pain management related continuing education. CONCLUSIONS: In cancer pain treatment-related clinical work, patients' pain education still needs to be strengthened; in comparison with oncology, the cancer pain management-related continuing education for non-oncology also needs to be strengthened. PMID- 25912576 TI - Norepinephrine attenuates CXCR4 expression and the corresponding invasion of MDA MB-231 breast cancer cells via beta2-adrenergic receptors. AB - OBJECTIVE: The growing evidence from laboratory and clinical studies has shown that the stress hormone, norepinephrine, and chronic stress promote tumor progression in a variety of tumor types. Chemokines and chemokine receptors have been shown to play a pivotal role in tumor progression. Recently, norepinephrine was reported to have a significant effect on macrophage migration by altering the expression of the chemokine receptor CCR2. MATERIALS AND METHODS: We investigated whether chemokines and their receptors are involved in the effects of norepinephrine on breast cancer. First, we used microarray analyses to detect the alteration of 128 chemotactically relevant genes after MDA-MB-231 cells were treated for 12 h with 100 MUM norepinephrine. The CXCR4 gene demonstrated the greatest response to norepinephrine treatment, with a reduction of transcription of 95.7%, and was the focus of subsequent investigations. Real-time reverse transcription-PCR was used to determine the level of CXCR4 transcription after treatment with norepinephrine at various concentrations and for different durations. RESULTS: The results revealed that norepinephrine reduced CXCR4 transcription in a dose-dependent manner. Norepinephrine was also found to exert a negative effect on CXCR4 translational expression, as evidenced by a 44 +/- 1.7% reduction in expression after a 12-h treatment with 10 uM norepinephrine. A Matrigel assay demonstrated a 51.3 +/- 9.1% reduction in the number of MDA-MB-231 cells driven to migrate by CXCR4. Finally, we found the specific beta2-adrenergic antagonist, ICI 118,551, eliminated the impact of norepinephrine on CXCR4 expression. CONCLUSIONS: Norepinephrine attenuates CXCR4 expression and the corresponding invasion of MDA-MB-231 tumor cells via the beta2-adrenergic receptor. The complexity of the beta2-adrenergic receptor signaling pathway might contribute to these unexpected observations in our research, and this justifies further investigation into the intricate mechanisms involved. PMID- 25912577 TI - LY2109761 inhibits metastasis and enhances chemosensitivity in osteosarcoma MG-63 cells. AB - OBJECTIVE: Studies have shown that transforming growth factor-beta (TGF-beta) is associated with metastasis and chemoresistance of osteosarcoma. The TGF-beta kinase inhibitor LY2109761 could inhibits metastasis and enhances chemosensitivity in several cancers, but its role and mechanisms in osteosarcoma (OS) is unclear. Here, we investigated the role and mechanism of LY2109761 on metastasis and chemosensitivity of OS MG-63 cells. MATERIALS AND METHODS: MG-63 cells were treated with LY2109761 or/and cisplatin. The cell viability and apoptosis of MG-63 cells were detected by MTT and ELISA. Matrigel invasion assay was used to detect cell invasion in vitro. pSMAD2 and S100A4 was detected by western blot assay. Furthermore, the efficacy of LY2109761 combined with S100A4 cDNA plaismid transfection on cell viability, apoptosis and chemosensitivity to cisplatin in OS MG-63 cells was further examined. RESULTS: LY2109761 was sufficient to induce apoptosis and inhibited growth of MG-63 cells in vitro. Combination with LY2109761 significantly augmented the cytotoxicity of cisplatin in MG-63 cells. LY2109761 significantly inhibited invasion of MG-63 cells in vitro. The LY2109761-induced increase in cell apoptosis and the cytotoxicity of cisplatin, and decrease in cell invasion was blocked completely when S100A4 expression was restored in the MG-63 cells by S100A4 cDNA plasmid transfection. CONCLUSIONS: Our data indicate that LY2109761 suppresses OS metastasis and enhanced chemosensitivity by targeting S100A4. LY2109761 may have important implications for the development of strategies for inhibiting metastasis and overcoming OS cell resistance to chemotherapy. PMID- 25912578 TI - Bicluster and pathway enrichment analysis related to tumor progression of hepatocellular carcinoma. AB - OBJECTIVE: Hepatocellular carcinoma is one of the most aggressive cancers with poor prognosis worldwide. Tumor progression remains a significant cause of high mortality in patients with hepatocellular carcinoma. However, the molecular mechanism underlying tumor progression of hepatocellular carcinoma has not been completely unraveled currently. The aim of this study was to gain insight into the molecular mechanisms of tumor progression of hepatocellular carcinoma. MATERIALS AND METHODS: We performed microarray analysis on 24 tissue specimens obtained at the time of surgical resection or liver transplantation from 24 patients with hepatocellular carcinoma downloaded from the Gene Expression Omnibus database. RESULTS: Our analysis indicated that several differentially expressed genes might play crucial roles in the progression of hepatocellular carcinoma, such as GADD45G, SPTBN1, CDC27, TPD52 and INSIG1. GADD45G and SPTBN1 not only contribute to tumor progression in hepatocellular carcinoma, but also correlate with poor prognosis in esophageal squamous cell carcinoma and pancreatic cancer respectively. Futhermore, we performed pathway enrichment analysis and found enriched pathways, including "Proteasome", "Alanine, aspartate and glutamate metabolism", "TGF-beta signaling pathway", "Wnt signaling pathway", and so on. CONCLUSIONS: Our findings confirmed the presence of multiple molecular alterations during tumor progression and indicated the differentially expressed genes might be involved in tumor progression though multiple pathways. Genes GADD45G and SPTBN1 might correlate with poor prognosis in hepatocellular carcinoma as has already been shown for other malignancies of the gastrointestinal tract. PMID- 25912579 TI - Effects of psychotropic drugs on Nuclear Factor kappa B. AB - Mental disorders affect millions of people worldwide and are associated with a huge suffering and unbearable burden for patients and their care givers. The pathophysiology of mental disorders is not fully understood. In recent years, accumulating data suggest that inflammation may play a role in the pathogenesis of these illnesses and that psychotropic drugs exert some anti-inflammatory effects. Nuclear Factor kappaB (NF-kappaB) is a cellular pathway that has a prominent influence on immune and inflammatory responses in humans. Numerous studies examined the effects of psychotropic drugs on different inflammatory mediators (particularly cytokines) both in vitro and in vivo. However, relatively few studies investigated the effects of those drugs on NF-kappaB. This is quite surprising considering the pivotal role of NF-kappaB in promoting inflammation. The aim of this article is to review the data over the effects of psychotropic drugs on the NF-kappaB pathway. Overall, the summarized studies suggest that some psychotropic drugs (such as lithium and imipramine) exert potent inhibitory effects on NF-kappaB, while the results on other drugs are not conclusive and occasionally contradicting. The discrepancy in the results of different studies seems to derive from the various experimental conditions under which the drugs were tested. PMID- 25912580 TI - Music therapy for coma patients: preliminary results. AB - OBJECTIVE: The application of quantitative EEG (delta+theta/alpha+beta value) and GCS value to evaluate the role of music therapy for traumatic brain injury coma patients. PATIENTS AND METHODS: Forty patients of traumatic brain injury coma were selected to meet the inclusion criteria. Twenty cases were selected for the rehabilitation, neurology and neurosurgery ward, whose families could actively cooperate with, and the patients could receive a long-term fixed nursing staff with formal music therapy (music group). Twenty cases were in the intensive care unit of the rehabilitation, neurology and neurosurgery ward. Their families members cooperated poorly, had often changing nursing staff, and without a formal music therapy (control group). After a one monthe follow up, the GCS value and quantitative EEG (delta+theta/alpha+beta value) were compared between the two groups. Between the two groups, except for the presence or absence of formal music therapy, the rest of treatment had no significant difference and was matched by age, gender, and injury types. RESULTS: In 40 cases of traumatic brain injury patients, the GCS value increased in the music group after treatment when compared to the control group. The difference between the two groups was significant (p < 0.05). The quantitative EEG value (delta+theta/alpha+beta value) of music group values were decreased after treatment, and the difference was significant compared with the control group (p < 0.05). CONCLUSIONS: Through the quantitative EEG (delta+theta/alpha+beta value) and the GCS observation score, music therapy in patients with craniocerebral trauma coma has obviously an effect on promoting to regain consciousness. The quantitative EEG (delta+theta/alpha+beta value) can be used as an objective index to evaluate the state of brain function. PMID- 25912581 TI - Gaucher disease: a lysosomal neurodegenerative disorder. AB - Gaucher disease is a multisystemic disorder that affects men and woman in equal numbers and occurs in all ethnic groups at any age with racial variations and an estimated worldwide incidence of 1/75,000. It is caused by a genetic deficient activity of the lysosomal enzyme glucocerebrosidase due to mutations in the beta glucocerebrosidase gene, and resulting in lack of glucocerebroside degradation. The subsequent accumulation of glucocerebroside in lysosomes of tissue macrophages primarily in the liver, bone marrow and spleen, causes damage in haematological, skeletal and nervous systems. The clinical manifestations show a high degree of variability with symptoms that varies according to organs involved. In many cases, these disorders do not correlate with mutations in the beta-glucocerebrosidase gene. Although several mutations have been identified as responsible for the deficient activity of glucocerebrosidase, mechanisms by which this enzymatic defect leads to Gaucher disease remain poorly understood. Recent reports indicate the implication of complex mechanisms, including enzyme deficiency, substrate accumulation, unfolded protein response, and macrophage activation. Further elucidating these mechanisms will advance understanding of Gaucher disease and related disorders. PMID- 25912582 TI - Clinical application of solitaire AB stents in the embolization of intracranial aneurysms. AB - OBJECTIVE: To evaluate the clinical value of Solitaire AB stents in the embolization of intracranial aneurysms. PATIENTS AND METHODS: Solitaire AB stents were applied in treating 69 aneurysms in 65 patients. Among them, there were 67 "wide neck" aneurysms and two "narrow neck" aneurysms. Of the 69 aneurysms, there were 40 aneurysms in the posterior communicating artery, 13 in the ophthalmic artery segment, one in the cavernous segment of the internal carotid artery, three in the middle cerebral artery, one in the anterior communicating artery, eight in the vertebral artery, and three in the basilar artery. The treatment techniques used included transposition, parallel technique, post-release technique, and salvage stenting. RESULTS: Immediate angiographic results showed complete thrombosis in 63 cases, residual aneurysm neck in two cases and partial embolism in four cases. Intraoperative aneurysm rupture was found in two cases, of which bleeding was stopped with continued filling. Postoperative hydrocephalus cerebrospinal fluid shunt was performed in one case. Coil shift was observed in two cases. No further bleeding cases occurred during the clinical follow-up. Of 14 patients who had undergone angiographic follow-up, three cases had recurrence and one case received re-embolization. CONCLUSIONS: Solitaire AB stent is clinically feasible when applied for the embolization of intracranial aneurysms using multiple techniques and, thus, warrants clinical promotion. PMID- 25912583 TI - Glycosides of cistanche improve learning and memory in the rat model of vascular dementia. AB - OBJECTIVE: Glycosides of cistanche (GC) is extracted from Xin Jiang Cistanche, which is widely used as a Chinese herb. This study aims to evaluate the effects of GC on vascular dementia (VD). MATERIALS AND METHODS: The VD model was established by the ligature of the bilateral common carotid artery in adult Wistar rats, who received daily i. p. administration of saline, GC (10 mg/kg body weight/d, i.p.) or oxiracetam (450 mg/kg body weight/d, i.p) for 14 days. Morris Water Maze test valued cognitive performance of the rats. The hippocampus was dissected and subjected to proteomics and immunohistochemical analysis. RESULTS: The GC group showed significantly lower escape latency than the VD group at four and five days after surgery. They showed no significant difference when compared with sham-operated group and the oxiracetam control group. In the hippocampus, the 21 protein spots in the GC group showed different expression levels compared with the VD group. This included the four proteins that showed a significant difference: three upregulated proteins thioredoxin-like protein 1, dual specificity mitogen-activated protein kinase kinase 1 and dihydropyrimidinase related protein 2 (CRMP-2), and one down-regulated protein glutathione synthetase. Immunohistochemistry analysis showed that P-tau protein level was significantly higher in the VD model group than the sham-operated group (p < 0.05). After GC treatment, P-tau protein level in VD model rats showed a significant decrease compared with VD group treated with saline (p < 0.05). CONCLUSIONS: The GC plays a critical role in protecting the hippocampal neurons in the VD, by decreasing P-tau phosphorylation and increasing the CRMP-2 expression level. Pharmacological manipulation of GC offers a new opportunity for VD treatment. PMID- 25912584 TI - Paroxysmal atrial fibrillation in myotonic dystrophy type 1 patients: P wave duration and dispersion analysis. AB - OBJECTIVE: Myotonic dystrophy type 1 (MD1) is characterized by cardiac involvement, in about 80% of case, that predominantly affects the conduction system. Aim of our study was to evaluate the P-wave duration and dispersion (PD) in MD1 patients underwent pacemaker implantation with conserved systolic and diastolic function. PATIENTS AND METHODS: We enrolled 60 MD1 patients (age 51.3 +/- 5 years; 11 females) underwent dual chamber pacemaker implantation for various grade of atrioventricular (AV) block. Sixty sex-and age matched non-MD1 subjects were recruited as controls. P-wave duration and dispersion were carefully measured using 12-lead electrocardiogram. RESULTS: Compared with healthy control group, MD1 patients presented increased maximum P wave duration (106.4 +/- 20.9 vs 65.9 +/- 8.2 ms, p = 0.03) and PD values (40.1 +/- 11 vs 27.1 +/- 4.2 ms, p = 0.003). No statistically significant difference was found in minimum P wave duration (69.7 +/- 11.8 vs 65.4 +/- 8.1 ms, p = 0.4). The MD1 patients with paroxysmal atrial fibrillation, compared with MD1 patients without evidence of atrial fibrillation, presented increased maximum P wave duration (108.1 +/- 10.4 vs 78.1 +/- 7.9 ms, p = 0.001) and PD values (41.1 +/- 8.5 vs 33.2 +/- 4.2 ms, p = 0.003). Minimum P wave duration (68.4 +/- 8.2 vs 67.1 +/- 4.9 ms, p = 0.5) didn't differ between the two groups. CONCLUSIONS: Our data showed a significantly increased P wave duration and dispersion in MD1 patients compared with age and sex-matched healthy controls. We showed a statistically significant increase in PD and P max in MD1 patients subgroup with AF compared to MD1 patients with no arrhythmias. PMID- 25912585 TI - A plea for the single-lead ICD with atrial sensing due to anatomical considerations. AB - We present the case of a 46-year old male patient suffering from non-ischemic cardiomyopathy and intermittent atrial tachycardia. According to guidelines an implantable cardioverter defibrillator (ICD) was planned to implant through the left subclavian vein. During the procedure the angiography revealed a persistent left superior vena cava (PLSVC) with moderate stenosis of the subclavian vein. Due to this we decided not to implant a dual chamber ICD but to implant a single chamber lead with additional atrial sensing capacity. The procedure as well as the follow-up was uneventful. Follow-up revealed good ventricular as well as atrial signals. PMID- 25912586 TI - The proliferative and migratory effects of physical injury and stromal cell derived factor-1alpha on rat cardiomyocytes and fibroblasts. AB - OBJECTIVE: This study aims to explore the effects of physical injury and stromal cell-derived factor-1alpha (SDF-1alpha) on the proliferation of cardiomyocytes and chemotactic effects of cardiomyocytes on the migration of cardiac fibroblasts. MATERIALS AND METHODS: Isolation and primary culture of rat cardiomyocytes and cardiac fibroblasts were performed; scratching was employed to induce physical injury on cells which were cultured with SDF-1alpha at different concentrations; proliferation ability of cardiomyocytes was checked with CCK-8 assay and migratory ability of cardiac fibroblasts under the chemotaxis of cardiomyocytes was detected with Transwell assay. RESULTS: SDF-1alpha enhanced the proliferation ability of cardiomyocytes with physical injury, especially at the concentration of 80 ug/L when the proliferation rate of cardiomyocytes increased most markedly. Moreover, physically injured cardiomyocyte that was cultured with SDF-1alpha significantly elevated migratory ability of cardiac fibroblasts, which tended to be more obvious along with the chemotactic culture time. CONCLUSIONS: SDF-1alpha enhanced the proliferation ability of cardiomyocytes with physical injury, and physically injured cardiomyocyte that was cultured with SDF-1alpha promoted the migration of cardiac fibroblasts. PMID- 25912587 TI - Contribution of cardiovascular risk factors in the thrombotic complications of essential thrombocythaemia: a Hungarian single-institute retrospective analysis. AB - OBJECTIVE: Essential thrombocythaemia (ET) is a myeloproliferative neoplasm in which there is an increased risk of thrombotic complications. The conventional thrombosis risk assessment of these patients is based on an age over 60 and a history of thrombosis. The aim of this report is to analyse the contribution of cardiovascular risk (CV) factors as possible additional thrombotic risk factors in the thrombotic complications seen in ET. PATIENTS AND METHODS: One hundred and one ET patients (72 females and 29 males with a median age of 61 years) were enrolled between 1999 and 2011. Mann-Whitney and multivariate binary logistic regression tests were performed. The Kaplan-Meier method followed by the log-rank test was used to evaluate the probability of thrombosis-free survival. RESULTS: The presence of one or two or more CV risk factors significantly increased the risk of thrombosis. Separately, the contribution of high blood pressure and hyperlipidaemia proved to be influential, whereas tobacco use, diabetes mellitus and obesity were not significant. Significant differences were revealed in the probability of thrombosis-free survival between patients without CV risk factors and those with at least one CV risk factor, and between those with at most one CV risk factor and those with two or more CV risk factors. CONCLUSIONS: On the basis of the results on the current cohort, it is suggested that CV risk factors may influence the thrombotic complications in ET. PMID- 25912588 TI - Comparison of valsartan and benazepril when combined with atorvastatin in protecting patients with early cardio-renal syndrome (CRS). AB - OBJECTIVE: The aims to investigate the different protective effects of valsartan and benazepril when combined with atorvastatin in the cardio-renal functions of cardio-renal syndrome (CRS) patients. PATIENTS AND METHODS: A total of 200 early CRS patients were enrolled in the present study, including 104 males and 96 females, with an average age of 62.2 +/- 7.7 years. The same group of patients were set as the control group prior to treatment, and then randomly divided into two groups; the A group was treated with valsartan (80 mg/d) and atorvastatin (20 mg/d); the B group was treated with benazepril (10 mg/d) and atorvastatin (20 mg/d). The treatment period was 24 months. RESULTS: The clinical efficacy and clinical events were observed and the following parameters of each patient were measured before and after treatment: 24h urine protein; creatinine clearance; serum brain natriuretic peptide (BNP); high sensitivity C-reactive protein (hsCRP); blood lipid level; liver function and ejection fraction (EF) value. Compared with the control group, the clinical symptoms of the treatment groups were improved with decreased blood lipid levels, significantly decreased serum BNP and hsCRP levels and significantly increased EF values and creatinine clearance rates (p < 0.01). The differences between the two treatment groups were not statistically significant. The number of patients that stopped treatment due to the development of a cough was significantly higher in the B group than the A group (p < 0.01). CONCLUSIONS: When combined with atorvastatin, both valsartan and benazepril effectively improved the cardio-renal functions of early CRS patients. There was no significant difference between the two treatments however, valsartan appeared to be better tolerated by patients. PMID- 25912589 TI - Adequacy of peritoneal dialysis: Kt/V revisited. AB - OBJECTIVE: Kt/V urea has been used to assess adequacy of peritoneal dialysis. However, Kt/V urea only reflects the clearance of solute without taking into consideration the effects of dietary protein intake (DPI). The objective of this study is to evaluate the value of Kt/V based on nitrogen balance and to observe if it is the best adequacy index. METHODS: On the premise that nitrogen balance is obtained, we calculated the minimal adequate dialysate volume and dialysis index (DI), Kt/V and solute removal index (SRI). We compared the values of DI, Kt/V and SRI to evaluate the adequacy of peritoneal dialysis. RESULTS: Kt/V was changed with DPI and body weight of continuous ambulatory peritoneal dialysis (CAPD) patients. We cannot define adequate dialysis with a single value while DPI and body weight are different since CAPD, SRI and Kt/V are numerically equal. However, dialysis index (DI) can reflect the minimal adequate dialysate volume when DPI and body weight are different and, thus, reflects the adequacy of dialysis. CONCLUSIONS: DI reflects the balance between DPI and solute clearance; thus, it is more useful to evaluate dialysis adequacy than Kt/V and SRI in clinically stable peritoneal dialysis patients. PMID- 25912590 TI - Peritonsillar infiltration with levobupivacaine for posttonsillectomy pain relief: does concentration have any effect? A double-blind randomized controlled clinical study. AB - OBJECTIVE: Post-tonsillectomy pain is believed to be mediated by noxious stimulation of C-fiber afferents located in the peritonsillary space, and local anesthetic infiltration to this area may decrease pain by blocking the sensory pathways and thus preventing the nociceptive impulses. We aimed to compare the effects of different concentrations of preincisional peritonsillar levobupivacaine (0.25% and 0.5%) infiltration on postoperative pain and bleeding in a placebo-controlled design. PATIENTS AND METHODS: After obtaining Institutional Ethics Committee approval, 72 ASA I-II patients between 3 and 12 years of age, scheduled to undergo tonsillectomy were enrolled and randomly assigned to one of the three groups using the sealed envelope technique, as Group I (Control group), Group II, and Group III receiving preincisional bilateral peritonsillar infiltration with saline, 0.25% levobupivacaine and 0.5% levobupivacaine, respectively (3 mL to each tonsil). Pain, fever, dysphagia; nausea-vomiting and hemorrhage were evaluated at postoperative 0, 30, and 60 minutes and 2, 6, 12, and 24 hours. Oral paracetamol was administered at a dose of 15 mg/kg when FLACC score was > 4. The number of paracetamol administrations within the first 24 hours were recorded. RESULTS: The patients in Groups I, II and III defined pain (FLACC > 4) at a rate of 87%, 60.9%, and 54.2% within the postoperative first 24 hours, respectively. The total number of additional analgesic requirements was significantly low in Group II and III when compared with Group I. There was no difference between groups in terms of fever, dysphagia, nausea-vomiting, hemorrhage. CONCLUSIONS: Both concentrations (0.50% and 0.25%) of levobupivacaine were found to be equally safe and effective during preincisional peritonsillar infiltration in children. NCT number: 02322346. PMID- 25912591 TI - Exendin-4, glucagon-like peptide-1 receptor agonist, enhances isoflurane-induced preconditioning against myocardial infarction via caveolin-3 expression. AB - OBJECTIVE: To investigate the cardioprotective effects of isoflurane and exendin 4 against myocardial ischemia/reperfusion injury and the signaling pathways through which these effects are mediated. MATERIALS AND METHODS: For infarct size measurements, anesthetized mice were subjected to 30 min of coronary artery occlusion followed by 2 h of reperfusion. Wild-type or caveolin-3 knockout mice received isoflurane, exendin-4, or isoflurane with exendin-4 before ischemia index determination. Caveolin-3 expression in the heart was measured by immunoblotting. RESULTS: Myocardial infarct size was smaller in the isoflurane- [1.0 minimum alveolar concentration (MAC)] or exendin-4- (30 ng/kg i.v.) treated groups than the controls. Infarct size was not affected by isoflurane at 0.5 MAC or 3 ng/kg i.v. exendin-4, but the combination of these treatments reduced infarct size. Pharmacological preconditioning (isoflurane at 1.0 MAC, 30 ng/kg i.v. exendin-4, or isoflurane at 0.5 MAC with 3 ng/kg i.v. exendin-4) increased caveolin-3 protein expression in the heart after infarct induction. The cardioprotective effects of isoflurane, exendin-4, and isoflurane with exendin-4 were abolished in caveolin-3 knockout mice. CONCLUSIONS: The combination of isoflurane and exendin-4 reduced infarct size, but it was not more effective than either agent alone, and the cardioprotective effects of these agents are mediated by caveolin-3 expression. PMID- 25912592 TI - Can nausea and vomiting be treated with ginger extract? AB - Ginger (Zingiber officinale) is a spice traditionally used to treat indigestion, nausea and vomiting. Ginger extracts accelerate gastric emptying and stimulate gastric antral contractions. These effects are mainly due to the presence of gingerols and shogaols and their activity on cholinergic M receptors and serotonergic 5-HT and 5-HT receptors. Various researches on this subject have led to controversial results, due to the chemical instability of ginger extracts and particularly of gingerols, which are readily-oxidizable substances. A systematic review of double-blind, placebo-controlled, randomized studies highlighted the potential efficacy of ginger on the prevention and treatment of nausea and vomiting of various origins, even though additional controlled studies are needed. This review focuses on pregnancy-induced nausea and vomiting and on chemotherapy induced nausea, and hypothesizes a therapeutic role for ginger extracts in case of side effects, as an alternative to traditional prokinetic drugs such as domperidone, levosulpiride or metoclopramide. PMID- 25912593 TI - Metamucil as an additional source of dietary fiber: impact of the quality of healthcare professionals' recommendations on users' experience. AB - OBJECTIVE: Metamucil(r) is a fiber supplementation formed by 100% natural psyllium. This study, conducted in Italy, assessed the impact of quality of pharmacists' instruction to use this product on subjects' adherence to and overall satisfaction with this test product. SUBJECTS AND METHODS: Open-label post-marketing study involving adult subjects who had purchased Metamucil(r) (follow-up: 14 +/- 7 days). Information was collected using questionnaires dedicated to the participating subject and pharmacy. RESULTS: In total, 1480 subjects and 182 pharmacies returned their questionnaires. The mean age of the subjects was 49 years, two-thirds were female and 87% went to the pharmacy with problems related to bowel movements. The median daily dose taken over the 21-day period was 1. Adherence to the test product was associated with the quality of pharmacist's counseling (p = 0.005). Similarly, satisfaction with the tested product was associated with the quality of counseling (p < 0.001). Consumers' satisfaction was also associated with the quality of pharmacist's explanation of the benefits of the test product (p < 0.001) and with adherence (p < 0.001). 93% and 83% of subjects, respectively, stated the ease of use and their overall satisfaction with the test product, with 73% of subjects agreeing that they would continue using it. Similar findings were observed in subjects who had previously taken the most commonly used branded fiber supplements containing either partially hydrated guar gum or psyllium in the previous 6 months. 92% of pharmacists stated they would recommend Metamucil(r) for bowel regularity and 90% as it provides multiple benefits. CONCLUSIONS: Pharmacists' counseling is associated with consumers' adherence and satisfaction to Metamucil(r). A large proportion of subjects were satisfied and would continue taking the tested product as a fiber supplement. PMID- 25912594 TI - The effect of curcumin on NF-kappaB expression in rat with lumbar intervertebral disc degeneration. AB - OBJECTIVE: To observe the effect of curcumin on the expression levels of nuclear factor kappaB-p65 (NF-kappaB-p65) and tumour necrosis factor alpha (TNF-alpha) in the nucleus pulposus in rats with lumbar intervertebral disc degeneration. And to investigate of the mechanism underlying the role of curcumin in decelerating the process of lumbar intervertebral disc degeneration. MATERIALS AND METHODS: The model of lumbar intervertebral disc degeneration was established in Sprague Dawley (SD) rats followed by a curcumin treatment. The ultra-microstructure histomorphological variations in the lumbar intervertebral disc of SD rats were evaluated. The protein and gene expression levels of NF-kappaB-p65 and TNF-alpha in the lumbar intervertebral disc were measured. RESULTS: Magnetic resonance imaging (MRI) and histomorphology confirmed the establishment of a successful lumbar intervertebral disc degeneration model. The results from the MRI and the ultra-microstructures revealed a significant improvement in lumbar intervertebral disc degeneration in the curcumin-treated groups (low dose and high dose). No significant change was observed in the solvent control group treated with dimethyl sulfoxide (DMSO) alone. Based on the results of Western blot analysis and real-time PCR, the curcumin treatment (low dose and high dose) significantly reduced the expression levels of NF-kappaB-p65 and TNF-alpha in the lumbar intervertebral disc tissue compared with the groups without curcumin treatment and with the DMSO treatment alone. No significant difference, however, was observed between the low-dose and high-dose curcumin treatment groups. CONCLUSIONS: Curcumin may inhibit the activation of NF-kappaB by inhibiting the translocation of NF-kappaB-p65 and reducing the release of inflammatory factors which, thereby, decelerates the process of lumbar intervertebral disc degeneration. PMID- 25912595 TI - Novel strategies to treat alcohol dependence with sodium oxybate according to clinical practice. AB - OBJECTIVE: The treatment of alcohol dependence (AD) with sodium oxybate (SMO) was introduced in Italy and Austria more than 20 years and 15 years ago respectively, and it is now widely employed. In addition to the data obtained from clinical trials, little information is available on specific clinical practices. Thus, the aim of this study was to present and discuss the results of a consensus meeting held after twenty years of using SMO in clinical practice in Italy. MATERIALS AND METHODS: A validated questionnaire study was conducted to investigate the modalities of treatment of AD with SMO currently used in Italy. A group of four referees first drew up the questionnaire which was distributed to fifty experts in the field of alcohol use disorders. The questionnaire consisted of 125 items with five different modalities of response and two or three answer possibilities. RESULTS: The results of this survey showed a broad consensus on some issues regarding, for example, the duration of treatment, and the dose regimen of the drug; however, some aspects of the treatment of AD with SMO still remain controversial. CONCLUSIONS: This is the first consensus study investigating the use of SMO for the treatment of AD through the opinions gained in over twenty years of clinical practice provided by fifty Italian expert clinicians. A consensus on good practice for the correct administration of SMO has clearly emerged; these opinions, along with those derived from previous clinical investigations, will help physicians to use SMO in a better way. However, some issues remain controversial, and others remain unresolved. PMID- 25912596 TI - Chlorhexidine--pharmaco-biological activity and application. AB - OBJECTIVES: Chlorhexidine (CHX) is one of the most widely used antiseptic, especially in dentistry. At low concentrations CHX is bacteriostatic and at high concentrations acts bactericidal causing cell death by cytolysis. In this study, we performed a systematic review of pharmaco-biological activity and application of CHX. MATERIALS AND METHODS: Articles for inclusion in this review were retrieved from online databases PubMed/Medline. The selected papers were included in the present manuscript according to their relevance for the topic. RESULTS: Totally 75 papers were enrolled in this research. CHX has strong biocidal activity against Gram-positive bacteria and weaker activity against Gram-negative bacteria. It is also active against yeasts, some dermatophytes and some lipophilic viruses. The most widely application CHX has found in dentistry and antisepsis. Numerous studies have confirmed the beneficial effects of CHX in reducing of plaque accumulation, in tooth caries, gingivitis, periodontitis and in alveolar osteitis. Unfortunately, CHX exhibits cytotoxic activity on human cells, can cause colorization of teeth and fillings, and its activity depends on the pH of the environment and the presence of organic substances. CONCLUSIONS: CHX play a valuable role in the dentistry and antisepsis. However, it can also cause side effects, limiting its application time. PMID- 25912597 TI - Subjective sleep quality in sarcoidosis. AB - BACKGROUND: Poor sleep is common among patients with medical disorders. Sleep disturbances can be a cause of fatigue and poor quality of life for patients suffering from sarcoidosis. Studies on subjective sleep quality or prevalence of insomnia have not been reported so far. OBJECTIVES: The aim of this study was to investigate the subjectively reported sleep quality and its relation to psychological and physical factors in sarcoidosis patients. METHODS: 1197 patients from Germany diagnosed with sarcoidosis were examined using the Pittsburgh Sleep Quality Index (PSQI), the Medical Research Council (MRC) dyspnea scale, the Hospital Anxiety and Depression Scale (HADS) and the Multidimensional Fatigue Inventory (MFI). RESULTS: 802 patients (67%) had PSQI global scores >5, indicating subjectively poor quality of sleep. The mean PSQI score was 7.79 +/- 4.00. Women reported a significantly inferior individual quality of sleep than men. The subjective quality of sleep was lowered significantly with increasing dyspnea for men and women. 294 patients (25%) had PSQI global scores >10 usually found in patients with clinically relevant insomnia. In this group 86% had high values for fatigue, 69% for anxiety, and 59% for depression. The prevalence of known sleep apnea was 8.7% and 15.7% for restless legs. CONCLUSION: Poor subjective sleep quality in sarcoidosis patients is about twice as common as in the general population and is associated with fatigue, anxiety, depression and dyspnea. Questions about sleep complaints should therefore be included in the management of sarcoidosis. PMID- 25912598 TI - Effect of respiration on heartbeat-evoked potentials during sleep in children with sleep-disordered breathing. AB - OBJECTIVE: Heartbeat-evoked potentials (HEPs) in electroencephalogram (EEG) provide a quantitative measure of cardiac interoception during sleep. We previously reported reduced HEPs in children with sleep-disordered breathing (SDB), indicative of attenuated cardiac information processing. The objective of this study was to investigate the link between HEP and respiration. PATIENTS/METHODS: From the overnight polysomnograms of 40 healthy children and 40 children with SDB, we measured HEPs during epochs of stage 2, slow-wave and rapid eye movement (REM) sleep free of abnormal respiratory events. HEPs were analysed with respect to respiratory phase. RESULTS: We observed a marked association between respiratory phase and HEP in children with SDB during REM sleep, but not in normal children. In children with SDB, HEP waveforms were attenuated during expiration compared to inspiration. Following adenotonsillectomy, expiratory HEP peak amplitude increased in the SDB children and was no longer different from those of normal children. CONCLUSIONS: The expiratory phase of respiration is primarily associated with attenuated cardiac information processing in children with SDB, establishing a pathophysiological link between breathing and HEP attenuation. PMID- 25912600 TI - Sleep-onset tome by actigraphy in patients with Parkinson's disease. PMID- 25912599 TI - Impairment of sleep-related memory consolidation in schizophrenia: relevance of sleep spindles? AB - OBJECTIVES: Deficits in declarative memory performance are among the most severe neuropsychological impairments in schizophrenia and contribute to poor clinical outcomes. The importance of sleep for brain plasticity and memory consolidation is widely accepted, and sleep spindles seem to play an important role in these processes. The aim of this study was to test the associations of sleep spindles and picture memory consolidation in patients with schizophrenia and healthy controls. METHODS: We studied 16 patients with schizophrenia on stable antipsychotic medication (mean age +/- standard deviation, 29.4 +/- 6.4 years) and 16 healthy controls matched for age and educational level. Sleep was recorded and scored according to American Academy of Sleep Medicine (AASM) standard criteria. We performed a picture recognition paradigm and compared recognition performance for neutral and emotional pictures in sleep and wake conditions. RESULTS: Recognition accuracy was better in healthy controls than in patients with schizophrenia in the sleep and wake conditions. However, the memory promoting effect of sleep was significantly lower in schizophrenia patients than in controls. Sleep spindle activity was reduced in patients, and sleep spindle density was correlated with sleep-associated facilitation of recognition accuracy for neutral pictures. CONCLUSION: Reduced sleep spindles seem to play an important role as a possible mechanism or biomarker for impaired sleep-related memory consolidation in patients with schizophrenia, and are a new target for treatment to improve memory functions and clinical outcomes in these patients. PMID- 25912601 TI - High false-positive rate of questionnaire-based restless legs syndrome diagnosis in multiple sclerosis. AB - BACKGROUND/OBJECTIVES: Restless legs syndrome (RLS) is diagnosed by self-reported symptoms. Multiple sclerosis (MS) patients have disease-related symptoms which could mimic RLS. This study assessed the: (1) false-positive rate for questionnaire-based RLS diagnosis in MS patients and (2) utility of periodic leg movements during wakefulness (PLMW) on overnight polysomnography (PSG) in identifying true-positive RLS patients. METHODS: Ambulatory MS patients without known sleep disorders were recruited. Subjects completed the International RLS Study Group (IRLSG) diagnostic questionnaire (IRLDQ) and underwent full overnight PSG. IRLDQ-positive patients underwent clinical evaluation to confirm the diagnosis and completed the RLS severity scale (IRLS). RESULTS: Seventy-one MS patients (mean age 46.8 +/- 10.4 years) were evaluated. Thirty-eight had a positive IRLDQ. RLS diagnosis was confirmed in 22, yielding a false-positive rate of 42% [95% confidence interval (CI) 26-59%], predominantly attributable to paresthesiae (n = 7), and cramps and/or muscle spasms (n = 4). IRLS scores were not significantly different between subjects with confirmed and nonconfirmed RLS. The PLMW index was significantly higher in patients with confirmed RLS (55.4 +/- 41.9 vs. 29.7 +/- 18.8, p = 0.03). The sensitivity of a PLMW index >70/h for true positive IRLDQ was 8/22 = 36%, 95% CI: 17.2-59.3, and the specificity was 16/16 = 100%, 95% CI: 79.4-100. CONCLUSIONS: MS patients have a high false-positive rate of RLS diagnosis using a standardized questionnaire largely attributable to MS related sensorimotor symptoms. While detailed clinical evaluation is essential for confirming RLS diagnosis, the PLMW index may provide useful adjunctive information. PMID- 25912602 TI - Inflammatory bowel disease and risk of coronary heart disease. AB - Emerging data have shown consistent evidence of an association between inflammation and development of atherosclerosis. Systemic autoimmune diseases are characterized by chronic inflammation and immune dysregulation, and diseases such as rheumatoid arthritis and lupus erythematosus are now commonly accepted to associate with development of cardiovascular disease, including coronary artery disease. However, the risk of cardiovascular disease in inflammatory bowel disease (IBD), a chronic inflammatory disease of the gut, is still unclear and the magnitude of a potentially increased risk is continuously debated. The aim of this review is to give an update on the existing literature on the association between inflammatory bowel disease and risk of cardiovascular disease, in particular coronary artery disease, and further to discuss traditional and non traditional risk factors in patients with inflammatory bowel disease. PMID- 25912603 TI - Synthesis of chiral cyclobutanes via rhodium/diene-catalyzed asymmetric 1,4 addition: a dramatic ligand effect on the diastereoselectivity. AB - A highly diastereo- and enantioselective rhodium-catalyzed arylation of cyclobutenes for the efficient synthesis of chiral cyclobutanes has been developed. Chiral diene ligands exhibited excellent capability for the reaction diastereoselectivity control. PMID- 25912604 TI - Atypical Fibroxanthoma: A case series and review of literature. AB - INTRO/OBJECTIVE: Atypical Fibroxanthoma (AFX) is a rare cutaneous neoplasm arising from myofibroblast or fibroblast-like cells that predominantly affects the head and neck region. It commonly mimics more invasive neoplasms and is a diagnostic challenge to clinicians. The aim of this study was to develop a better understanding of AFX, focusing on recent developments in diagnosis and management. METHODS: A retrospective case series and review of recent literature were carried out. RESULTS: Over a 17-year period, seven cases were identified (six male, mean age at presentation was 75.9 years). Two patients underwent complete excision and five patients had curettage and cauterisation. Two patients developed local recurrence but none demonstrated signs suggestive of metastatic spread. Histologically all seven lesions displayed a spindle cell pattern. Where performed, immunohistochemical staining was positive for Vimentin, CD10, CD68 and actin, and negative for CAM 5.2, CD34, Melan-A, S100 protein, HMB45, Cytokeratin A1/A3. CONCLUSION: Our patient demographics, histopathology and immunohistochemistry are comparable to previous studies. Although advances have been made in immunohistochemical analysis, we are yet to discover a specific diagnostic immunostain for AFX. Clinical findings should therefore be correlated with histology and a panel of immunohistochemical stains should be used. Given the potential for recurrence or metastases, Moh's Micrographic Surgery with regular follow-up may be the preferred management. PMID- 25912606 TI - Rapid eye movements to a virtual target are biased by illusory context in the Poggendorff figure. AB - In order to determine the influence of perceptual input upon oculomotor responses, we examined rapid saccadic eye movements made by healthy human observers to a virtual target defined by the extrapolated intersection of a pointer with a distant landing line. While corresponding perceptual judgments showed no evidence of systematic bias, eye movements showed a strong bias, in the direction of assimilation of the saccade trajectory to the shortest path between the end of the pointer and the landing line. Adding an abutting vertical inducing line to make an angle of 45 deg with the pointer led to a larger bias in the same direction as the classical Poggendorff illusion. This additional Poggendorff effect was similar in direction and magnitude for the eye movements and the perceptual responses. Latency and dynamics of the eye movements were closely similar to those recorded for a control task in which observers made a saccade from the start fixation to an explicit target on the landing line. Further experiments with inducing lines presented briefly at various times during the saccade latency period showed that the magnitude of the saccade bias was affected by inducer presentation during the saccade planning process, but not during the saccade itself. We conclude that the neural mechanisms for extrapolation can feed into the control of eye movements without obvious penalties in timing and accuracy and that this information can instantaneously modify motor response throughout the planning phase, suggesting close association between perceptual and motor mechanisms in the process of visuo-spatial extrapolation. PMID- 25912607 TI - Influence of workspace constraints on directional preferences of 3D arm movements. AB - We previously demonstrated a tendency to perform arm movements by using a trailing joint control pattern during which either the shoulder or elbow is rotated actively and the other (trailing) joint is rotated predominantly passively, by interaction torque during horizontal movements and by interaction and gravitational torque during 3D arm movements. This tendency was established with a free-stroke drawing task that required production of series of strokes in randomly selected directions from the center to the perimeter of a horizontal circle. The studies demonstrated that within a planar workspace, the usage of the trailing pattern depends on movement direction and the most frequently selected directions are those providing the opportunity to use the trailing pattern. Here, we studied whether the opportunity to use the preferred trailing pattern also depends on the orientation of the planar workspace. The free-stroke drawing task was performed with unconstrained arm movements within circles of a left-diagonal (LD) and right-diagonal (RD) orientation. Two pronounced preferred directions were revealed in the LD condition, and they were the directions in which the trailing pattern was used. Directional preferences were less pronounced, and the trailing pattern was not observed in any directions in the RD condition. Also, subjects identified the RD condition as inconvenient. The results reinforce the previous finding of the propensity to use the trailing pattern during arm movements. They also suggest that orientations of the workspaces in manual activities should be designed to support the trailing pattern as a favored type of joint control. PMID- 25912608 TI - Faces distort eye movement trajectories, but the distortion is not stronger for your own face. AB - It is currently unclear whether a person's own face has greater capacity in absorbing his/her attention than faces of others. With two visual distractor tasks, the present study assessed the extent to which a person's own face attracts his/her attention, by measuring face distractor elicited distortion of saccade trajectories. Experiment 1 showed that upright faces induced stronger distortion of saccade trajectories than inverted ones. This face inversion effect, however, was not stronger for the participant's own face than for unfamiliar other's faces. By manipulating fixation stimulus offset and using peripheral onset target, Experiment 2 further demonstrated that these observations were not contingent on saccade latency. Together, these findings suggest that a person's own face is not more salient or attention-absorbing than unfamiliar other's faces. PMID- 25912609 TI - Development of kinesthetic-motor and auditory-motor representations in school aged children. AB - In two experiments using a center-out task, we investigated kinesthetic-motor and auditory-motor integrations in 5- to 12-year-old children and young adults. In experiment 1, participants moved a pen on a digitizing tablet from a starting position to one of three targets (visuo-motor condition), and then to one of four targets without visual feedback of the movement. In both conditions, we found that with increasing age, the children moved faster and straighter, and became less variable in their feedforward control. Higher control demands for movements toward the contralateral side were reflected in longer movement times and decreased spatial accuracy across all age groups. When feedforward control relies predominantly on kinesthesia, 7- to 10-year-old children were more variable, indicating difficulties in switching between feedforward and feedback control efficiently during that age. An inverse age progression was found for directional endpoint error; larger errors increasing with age likely reflect stronger functional lateralization for the dominant hand. In experiment 2, the same visuo motor condition was followed by an auditory-motor condition in which participants had to move to acoustic targets (either white band or one-third octave noise). Since in the latter directional cues come exclusively from transcallosally mediated interaural time differences, we hypothesized that auditory-motor representations would show age effects. The results did not show a clear age effect, suggesting that corpus callosum functionality is sufficient in children to allow them to form accurate auditory-motor maps already at a young age. PMID- 25912610 TI - Miniaturization of a micro-optics array for highly sensitive and parallel detection on an injection moulded lab-on-a-chip. AB - A miniaturised array of supercritical angle fluorescence (SAF) micro-optics embedded in a microfluidic chamber was fabricated by injection moulding. The fabricated chip could enhance the fluorescence signal around 46 times compared to a conventional microscope. Collection of the fluorescence signal from the SAF array is almost independent of the numerical aperture, and the limit of detection was improved 36-fold using a simple and inexpensive optical detection system. PMID- 25912611 TI - Full-length transcriptome sequences and splice variants obtained by a combination of sequencing platforms applied to different root tissues of Salvia miltiorrhiza and tanshinone biosynthesis. AB - Danshen, Salvia miltiorrhiza Bunge, is one of the most widely used herbs in traditional Chinese medicine, wherein its rhizome/roots are particularly valued. The corresponding bioactive components include the tanshinone diterpenoids, the biosynthesis of which is a subject of considerable interest. Previous investigations of the S. miltiorrhiza transcriptome have relied on short-read next-generation sequencing (NGS) technology, and the vast majority of the resulting isotigs do not represent full-length cDNA sequences. Moreover, these efforts have been targeted at either whole plants or hairy root cultures. Here, we demonstrate that the tanshinone pigments are produced and accumulate in the root periderm, and apply a combination of NGS and single-molecule real-time (SMRT) sequencing to various root tissues, particularly including the periderm, to provide a more complete view of the S. miltiorrhiza transcriptome, with further insight into tanshinone biosynthesis as well. In addition, the use of SMRT long-read sequencing offered the ability to examine alternative splicing, which was found to occur in approximately 40% of the detected gene loci, including several involved in isoprenoid/terpenoid metabolism. PMID- 25912612 TI - Epidemiologic characteristics of dengue in China (2010-2014). PMID- 25912613 TI - In vitro susceptibility of Aerococcus urinae isolates to antibiotics used for uncomplicated urinary tract infection. PMID- 25912614 TI - Microbiological characterisation of prosthetic vascular graft infection. PMID- 25912615 TI - A critical analysis of the proposal of the Institute of Medicine to replace myalgic encephalomyelitis and chronic fatigue syndrome by a new diagnostic entity called systemic exertion intolerance disease. AB - The Institute of Medicine (IOM) recently published their report in response to an assignment "to define diagnostic criteria for Myalgic Encephalomyelitis (ME)/chronic fatigue syndrome (CFS), to propose a process for reevaluation of these criteria in the future, and to consider whether a new name for this disease is warranted". The basic pre-assumption of the IOM committee for the development of evidence-based diagnostic criteria for ME/CFS was that ME and CFS denote conditions with similar symptoms, hence ME/CFS. The IOM committee recommends: (1) that ME/CFS will be renamed 'systemic exertion intolerance disease' (SEID); and that a new code should be assigned to SEID in the International Classification of Diseases (ICD), replacing the existing codes for ME (a neurological disease: G93.3) and CFS ('signs, symptoms, and abnormal clinical and laboratory findings, not elsewhere classified': R53.82); (2) that a diagnosis of SEID should be made if the new diagnostic criteria are met; (3) that the Department of Health and Human Services develops a toolkit appropriate for screening and diagnosing patients; and (4) that a multidisciplinary group re-examines the new diagnostic criteria when necessary. This editorial reviews the working procedure of the IOM and two of the outcomes: the recommendation to introduce a new clinical entity (SEID) and new diagnostic criteria. Based upon the contents of the report, and the arguments of the IOM, a search of PubMed and the archive of the Journal of Chronic Fatigue Syndrome using the search terms ME (and old synonyms) and CFS, and a search of PubMed related to the five core symptoms of SEID was conducted. Reviewing the working method and the recommendations, it is concluded that the new diagnostic criteria for SEID are based upon important methodological shortcomings and that the introduction of SEID to replace both ME and CFS has several profound negative consequences outweighing the advantages. PMID- 25912616 TI - Tattooing may cause life-threatening latex allergy. PMID- 25912618 TI - Effects of dietary CLA on n-3 HUFA score and N-acylethanolamides biosynthesis in the liver of obese Zucker rats. AB - We have recently shown that PPAR alpha agonists induce N-oleoylethanolamide (OEA) and N-palmitoylethanolamide (PEA) biosynthesis. Conjugated linoleic acid (CLA), a known dietary PPAR alpha inducer, may therefore increase OEA and PEA levels and favor docosahexaenoic acid (DHA) biosynthesis by enhancing peroxisomal beta oxidation via induction of liver PPARalpha. To evaluate whether CLA is able to increase DHA, OEA and PEA levels and thereby influencing liver lipid deposition in a model of visceral obesity-induced fatty liver, Zucker rats were fed a background diet rich in saturated fat with or without 1% of CLA for 4 weeks. Our data showed that CLA intake increased DHA, OEA and PEA levels in the liver by 24%, 31% and 36% respectively, and reduced hepatic lipid accumulation by 16%. We may conclude that dietary CLA is able to influence not only fatty acid metabolism but also the biosynthesis of bioactive mediators such as OEA and PEA which may contribute to ameliorate fatty liver. PMID- 25912617 TI - Southern Hemisphere Influenza and Vaccine Effectiveness Research and Surveillance. AB - The 2009 influenza A(H1N1)pdm09 pandemic highlighted the need for improved scientific knowledge to support better pandemic preparedness and seasonal influenza control. The Southern Hemisphere Influenza and Vaccine Effectiveness Research and Surveillance (SHIVERS) project, a 5-year (2012-2016) multiagency and multidisciplinary collaboration, aimed to measure disease burden, epidemiology, aetiology, risk factors, immunology, effectiveness of vaccination and other prevention strategies for influenza and other respiratory infectious diseases of public health importance. Two active, prospective, population-based surveillance systems were established for monitoring influenza and other respiratory pathogens among those hospitalized patients with acute respiratory illness and those enrolled patients seeking consultations at sentinel general practices. In 2015, a sero-epidemiological study will use a sample of patients from the same practices. These data will provide a full picture of the disease burden and risk factors from asymptomatic infections to severe hospitalized disease and deaths and related economic burden. The results during the first 2 years (2012-2013) provided scientific evidence to (a) support a change to NZ's vaccination policy for young children due to high influenza hospitalizations in these children; (b) contribute to the revision of the World Health Organization's case definition for severe acute respiratory illness for global influenza surveillance; and (c) contribute in part to vaccine strain selection using vaccine effectiveness assessment in the prevention of influenza-related consultations and hospitalizations. In summary, SHIVERS provides valuable international platforms for supporting seasonal influenza control and pandemic preparedness, and responding to other emerging/endemic respiratory-related infections. PMID- 25912619 TI - The EPIC study: a lesson to learn. AB - INTRODUCTION: Inhibitory antibodies to factor VIII occur in about 30% of previously untreated patients (PUPs) and are the most serious complication of haemophilia A. It is unclear why some patients develop inhibitors and others do not. AIMS: The Early Prophylaxis Immunologic Challenge (EPIC) study was designed to test the hypothesis that inhibitor incidence in PUPs with severe or moderately severe haemophilia A could be reduced when a once-weekly FVIII prophylaxis starts with 25 IU kg(-1) rAHF-PFM before 1 year of age and immunological danger signals are minimized. METHODS: These signals were minimized by avoiding: surgery; the first FVIII infusion during severe bleeding or an infection; central venous access devices and administering vaccinations intramuscularly 3-4 days before or after FVIII. RESULTS: Eight of the 19 treated subjects (42.1%) developed confirmed inhibitors. Eleven of the 19 treated subjects were PUPs without any prior exposure to FVIII. Three of them (27.3%) developed a confirmed inhibitor together with FVIII-binding antibodies. The study was stopped because the likelihood to reach the primary objective was minimal, a decision endorsed by the data safety monitoring board. CONCLUSION: Because of early termination, the EPIC study hypothesis could not be corroborated. Nonetheless, our data analyses indicate that the current definition of an inhibitor only based on plasma inhibitor activity >=0.6 BU mL(-1) may not always reflect the presence of FVIII neutralizing antibodies. The findings of this study teach us that low-level inhibitor activity results need in addition a confirmatory test and/or the assessment of the therapeutic response. PMID- 25912620 TI - Which patients with inflammatory bowel disease should receive combination therapy? AB - Traditionally, patients with inflammatory bowel disease underwent 'step-up' therapy to induce a clinical remission. However, when step-up treatment is used, the more efficacious anti-TNF agents are reserved for patients unable to achieve remission with immune suppressants (IS). Several pivotal trials have demonstrated the superiority of early combination therapy of IS and anti-TNF to 'step-up' therapy and azathioprine or infliximab monotherapy. Concerns about treatment cost and adverse events of combination therapy have precluded widespread adoption of early combination therapy. Recent studies have demonstrated that combination treatment followed by withdrawal of IS or infliximab was not associated with an increased rate of relapse. Providers must include the benefits and risks of combination therapy in shared decision-making discussions with patients about to start treatment. Improved diagnostic and prognostic tests in the future are likely to help providers select the ideal patient for combination therapy. PMID- 25912621 TI - The don't know option in progress testing. AB - Formula scoring (FS) is the use of a don't know option (DKO) with subtraction of points for wrong answers. Its effect on construct validity and reliability of progress test scores, is subject of discussion. Choosing a DKO may not only be affected by knowledge level, but also by risk taking tendency, and may thus introduce construct-irrelevant variance into the knowledge measurement. On the other hand, FS may result in more reliable test scores. To evaluate the impact of FS on construct validity and reliability of progress test scores, a progress test for radiology residents was divided into two tests of 100 parallel items (A and B). Each test had a FS and a number-right (NR) version, A-FS, B-FS, A-NR, and B NR. Participants (337) were randomly divided into two groups. One group took test A-FS followed by B-NR, and the second group test B-FS followed by A-NR. Evidence for impaired construct validity was sought in a hierarchical regression analysis by investigating how much of the participants' FS-score variance was explained by the DKO-score, compared to the contribution of the knowledge level (NR-score), while controlling for Group, Gender, and Training length. Cronbach's alpha was used to estimate NR and FS-score reliability per year group. NR score was found to explain 27 % of the variance of FS [F(1,332) = 219.2, p < 0.0005], DKO-score, and the interaction of DKO and Gender were found to explain 8 % [F(2,330) = 41.5, p < 0.0005], and the interaction of DKO and NR 1.6 % [F(1,329) = 16.6, p < 0.0005], supporting our hypothesis that FS introduces construct-irrelevant variance into the knowledge measurement. However, NR-scores showed considerably lower reliabilities than FS-scores (mean year-test group Cronbach's alphas were 0.62 and 0.74, respectively). Decisions about FS with progress tests should be a careful trade-off between systematic and random measurement error. PMID- 25912622 TI - Checkpoint modulation--A new way to direct the immune system against renal cell carcinoma. AB - The introduction of targeted therapies like the tyrosine kinase (TKI) and mammalian target of rapamycin (mTOR) inhibitors has improved patients' survival in general. Nevertheless the prognosis remains limited. Therapies with a new mode of action are urgently warranted, especially those who would provoke long-term responders or long-lasting complete remissions as observed with unspecific immunotherapy with the cytokines interleukin-2 and interferon-alpha. In the recent years a deeper understanding of the underlying immunology of T cell activation led to the development of checkpoint inhibitors, which are mainly monocloncal antibodies and which enhances the presence of the co-stimulatory signals needed for T cell activation or priming. This review discusses the clinical data and ongoing studies available for the inhibition of the PD-1 (CD279) and CTLA-4 (CD152) axis in mRCC. In addition, potential future immunological targets are discussed. This approach of T-cell activation or re activation by immunological checkpoint inhibition holds the inherent promise to directly affect the tumor cell and thereby to potentially cure a subset of patients with mRCC. PMID- 25912625 TI - Multiphysics modelling, quantum chemistry and risk analysis for corrosion inhibitor design and lifetime prediction. AB - Organic corrosion inhibitors can provide an effective means to extend the life of equipment in aggressive environments, decrease the environmental, economic, health and safety risks associated with corrosion failures and enable the use of low cost steels in place of corrosion resistant alloys. To guide the construction of advanced models for the design and optimization of the chemical composition of organic inhibitors, and to develop predictive tools for inhibitor performance as a function of alloy and environment, a multiphysics model has been constructed following Staehle's principles of "domains and microprocesses". The multiphysics framework provides a way for science-based modelling of the various phenomena that impact inhibitor efficiency, including chemical thermodynamics and speciation, oil/water partitioning, effect of the inhibitor on multiphase flow, surface adsorption and self-assembled monolayer formation, and the effect of the inhibitor on cathodic and anodic reaction pathways. The fundamental tools required to solve the resulting modelling from a first-principles perspective are also described. Quantification of uncertainty is significant to the development of lifetime prediction models, due to their application for risk management. We therefore also discuss how uncertainty analysis can be coupled with the first principles approach laid out in this paper. PMID- 25912624 TI - Computed tomography-gastro-colonography for percutaneous endoscopic gastrostomy using a helical computed tomography. AB - BACKGROUND: Despite the widespread use of percutaneous endoscopic gastrostomy (PEG) tubes, their placement may be associated with a variety of complications, including gastrocolic fistula. METHODS: In total, 48 individuals underwent computed tomography-gastro-colonography (CT-GC)-guided PEG placement. Study end points included success of CT-GC, inability to thread the PEG tube, the eventual tube location, tube adjustments needed, adverse events, operating time, and PEG tube-related infection. RESULTS: A successful CT-GC was achieved in all 48 patients (100%), and we successfully used a standard PEG technique to place the gastrostomy tube in 44 patients (92%). In 4 patients (8%), the laparoscopic assisted PEG technique was used because the transverse colon became interposed between the abdominal wall and the anterior wall of the stomach. The overall procedure-related minor complication rate was 8%. CONCLUSION: CT-GC is an optional method for the estimation of intra-abdominal, anatomical orientations that may minimize the risk of complications before PEG placement. PMID- 25912626 TI - Inventorying Toronto's single detached housing stocks to examine the availability of clay brick for urban mining. AB - This study examines the stocks of clay brick in Toronto's single detached housing, to provide parameters for city scale material reuse and recycling. Based on consensus from the literature and statistics on Toronto's single detached housing stocks, city scale reusable and recyclable stocks were estimated to provide an understanding of what volume could be saved from landfill and reintroduced into the urban fabric. On average 2523-4542 m(3) of brick was determined to be available annually for reuse, which would account for 20-36% of the volume of virgin brick consumed in new house construction in 2012. A higher volume, 6187 m(3) of brick, was determined to be available annually for recycling because more of the prevalence of cement-based mortar, which creates challenges for brick reuse in Toronto. The results demonstrated that older housing containing reusable brick were being mostly landfilled and replaced with housing that contained only recyclable brick. PMID- 25912623 TI - Combined effects of prenatal polycyclic aromatic hydrocarbons and material hardship on child IQ. AB - IMPORTANCE: Polycyclic aromatic hydrocarbons are common carcinogenic and neurotoxic urban air pollutants. Toxic exposures, including air pollution, are disproportionately high in communities of color and frequently co-occur with chronic economic deprivation. OBJECTIVES: We examined whether the association between child IQ and prenatal exposure to polycyclic aromatic hydrocarbons differed between groups of children whose mothers reported high vs. low material hardship during their pregnancy and through child age 5. We tested statistical interactions between hardships and polycyclic aromatic hydrocarbons, as measured by DNA adducts in cord blood, to determine whether material hardship exacerbated the association between adducts and IQ scores. DESIGN: Prospective cohort. Participants were recruited from 1998 to 2006 and followed from gestation through age 7 years. SETTING: Urban community (New York City) PARTICIPANTS: A community based sample of 276 minority urban youth EXPOSURE MEASURE: Polycyclic aromatic hydrocarbon-DNA adducts in cord blood as an individual biomarker of prenatal polycyclic aromatic hydrocarbon exposure. Maternal material hardship self reported prenatally and at multiple timepoints through early childhood. MAIN OUTCOME MEASURE: Child IQ at 7 years assessed using the Wechsler Intelligence Scale for Children. RESULTS: Significant inverse effects of high cord PAH-DNA adducts on full scale IQ, perceptual reasoning and working memory scores were observed in the groups whose mothers reported a high level of material hardship during pregnancy or recurring high hardship into the child's early years, and not in those without reported high hardship. Significant interactions were observed between high cord adducts and prenatal hardship on working memory scores (beta = 8.07, 95% CI (-14.48, -1.66)) and between high cord adducts and recurrent material hardship (beta = -9.82, 95% CI (-16.22, -3.42)). CONCLUSION: The findings add to other evidence that socioeconomic disadvantage can increase the adverse effects of toxic physical "stressors" like air pollutants. Observed associations between high cord adducts and reduced IQ were significant only among the group of children whose mothers reported high material hardship. These results indicate the need for a multifaceted approach to prevention. PMID- 25912627 TI - Acute colonic pseudo-obstruction in a child taking trihexyphenidyl for drooling: Prescribers beware. AB - Colonic pseudo-obstruction (Ogilvie's Syndrome) in children is relatively uncommon. We report an unusual case of colonic pseudo-obstruction in an 8-year old child with cerebral palsy and long-term hypomotility issues being treated for drooling with the anticholinergic medication trihexyphenidyl. He presented as an emergency with severe abdominal distension, abdominal tenderness and vomiting. An emergency laparotomy revealed colonic dilatation and a defunctioning ileostomy was created. To our knowledge, this is the first case reporting colonic pseudo obstruction as a possible complication of treatment with trihexyphenidyl. We suggest prescribers should exercise caution when prescribing trihexyphenidyl in patients with long-term intestinal hypomotility issues. PMID- 25912628 TI - Characteristics of children under 2 years of age undergoing tonsillectomy for upper airway obstruction. AB - INTRODUCTION: To study characteristics of children less than 2 years who underwent a tonsillectomy for sleep disordered breathing (SDB) or obstructive sleep apnea (OSA) to assess for factors associated with requesting a preoperative polysomnogram (PSG) and to identify predictors of upper airway obstruction in this group. MATERIALS AND METHODS: A retrospective chart review of children under 2 years who underwent a tonsillectomy over a 7-year period at a tertiary care pediatric hospital was undertaken. Patient demographics, characteristics and polysomnography results, when applicable, were collected. In order to determine if the gathered demographics of our cohort differed from the non-surgical population, we compared our data with available Colorado data for each variable. Children were stratified by OSA severity using their obstructive apnea-hypopnea index (OAHI). RESULTS: 197 (2.2%) of 9038 patients who underwent tonsillectomy for SDB or OSA were <= 24 months. The proportions of male, African-American, Hispanic, obese, underweight, premature, syndromic and daycare patients in our cohort were significantly different than in the general population. In a multivariate model, the odds of African-Americans having severe OSA were 12.5 times greater than the odds of Caucasians. The odds of patients with syndromes or craniofacial anomalies were 11 times greater (p < 0.0001), and the odds of patients in daycare were 2.2 times lower (p = 0.04) of undergoing a PSG before tonsillectomy. Weight did not influence polysomnogram requests. CONCLUSIONS: In children under 2 years, ethnicity seems to be a predictor of OSA severity. African-American, prematurity, daycare and Down syndrome patients were significantly more represented in our study population. PSG is more likely to be requested for syndromic children. PMID- 25912629 TI - Clinical and logopaedic results of simultaneous and sequential bilateral implants in children with severe and/or profound bilateral sensorineural hearing loss: A literature review. AB - This article carries out a literature review of the advantages and limitations of the simultaneous bilateral cochlear implantation (SCI) compared to those of the sequential bilateral cochlear implantation (SBCI) and the unilateral cochlear implantation (UCI). The variables analysed in said comparison are: safety and surgical technique, SCI incidence, effectiveness, impact of the inter-implant interval, costs and financing, impact on brain plasticity, impact on speech and language development, main benefits, main disadvantages and concerns, and predictive factors of prognosis. Although the results are not conclusive, all variables analysed seem to point towards observable benefits of SCI in comparison with SBCI or UCI. This tendency should be studied in more depth in multicentre studies with higher methodological rigour, more comprehensive samples and periods and other determining variables (age at the time of implantation, duration and degree of the hearing loss, rehabilitation methodologies used, family involvement, etc.). PMID- 25912630 TI - Reliability, validity and normative data of a quick repetition test for Italian children. AB - OBJECTIVES: A quick repetition test can be useful as a screening or preliminary investigation to select children who need to be assessed with a more specific articulation test. Schindler's repetition test lasts about 2 min and requires the repetition of a 30 words list, each word targeting a specific phoneme or cluster. The aims of the study are: to assess reliability of Schindler's repetition test; to establish normative data for speech development in Italian-speaking children; to analyse validity of this instrument. METHODS: Six-hundred-two Italian children, aged range between 3;0 and 10;8 years, were included in the study: 557 without clinical sign of speech impairment and 45 had a speech sound disorder. Reliability. One-hundred-five children were tested the same day by two examiners (inter-rater reliability); the administration of the repetition test to 45 children was audio-recorded (intra-rater reliability); 105 children underwent the repetition test twice, with a 2 weeks interval (test-retest reliability). Data were compared through Intraclass Correlation Coefficient (ICC). Normative data. Percentages of children without clinical sign of speech impairment in each age group who repeated correctly, omitted or produced distorted target phonemes of Schindler's repetition test were reported. VALIDITY: To assess the ability of the test to record improvement in mean values with age (construct validity), the proportion of correct repetitions obtained by children from different age groups were compared through logistic regression. The speech abilities of 45 children were also analysed through a more comprehensive articulation test (concurrent validity). Scores were compared through Bland-Altman plot. RESULTS: Reliability. All ICC were superior to 0.9. Normative data. Despite language-specific pattern of acquisition emerged, data showed many similarities to data reported in international studies on speech sound development. VALIDITY: Logistic regression demonstrated a significant effect of age groups. Bland-Altman plot showed relatively narrow limits of agreement between Schindler's repetition and Rossi's articulation test. CONCLUSIONS: Schindler's repetition test can be considered a reliable and valid instrument for preliminary assessment of speech abilities in Italian-speaking children aged from 3 to 6 years old. Application of Schindler's repetition test is recommended in clinical practice, as a screening test or as a first clinical assessment instrument. PMID- 25912631 TI - Healthcare costs of acute and chronic tonsillar conditions in the pediatric population in the United States. AB - OBJECTIVE: To determine the prevalence and healthcare costs associated with the diagnosis and treatment of acute and chronic tonsillar conditions (ACT) in children. DESIGN: Cross-sectional analysis of the 2006, 2008, and 2010 Medical Expenditure Panel Surveys. METHODS: Pediatric patients (age < 18 years) were examined from the above mentioned database. From the linked medical conditions file, cases with a diagnosis of ACT were extracted. Ambulatory visit rates, prescription refills, and ambulatory healthcare costs were then compared between children with and without a diagnosis of ACT and acute versus chronic tonsillitis, with multivariate adjustment for age, sex, ethnicity, region, insurance coverage and comorbid conditions (e.g., asthma and otitis media). RESULTS: A total of 74.3 million children (mean age 8.55 years, 51% male) were sampled (raw N = 28,873). Of these, 804,229 children (1.1 +/- 0.1%) were diagnosed with ACT annually (mean age 7.24 years, 49.1% male); 64.6 +/- 2.0% had acute tonsillitis diagnoses and 35.4 +/- 2.0% suffered from chronic tonsillitis. Children with ACT incurred an additional 2.3 office visits and 2.1 prescription fills (both p < 0.001) annually compared with those without ACT, adjusting for demographic variables and medical comorbidities, but did not have an increase in emergency department visits (p = 0.123). Children with acute tonsillar diagnoses carried total healthcare expenditures of $1303 +/- 390 annually versus $2401 +/- 618 for those with chronic tonsillitis (p = 0.193). ACT was associated with an incremental increase in total healthcare expense of $1685 per child, annually (p < 0.001). CONCLUSION: The diagnosis of ACT confers a significant incremental healthcare utilization and healthcare cost burden on children, parents and the healthcare system. With its prevalence in the United States, pediatric tonsillitis accounts for approximately $1.355 billion in incremental healthcare expense and is a significant healthcare utilization concern. LEVEL OF EVIDENCE: 2C. PMID- 25912632 TI - Protective effects of Artocarpus altilis (Moraceae) on cadmium-induced changes in sperm characteristics and testicular oxidative damage in rats. AB - Cadmium (Cd) is a major environmental toxicant and an endocrine disruptor. We investigated the protective effects of methanol extract of Artocarpus altilis (AA) against Cd-induced testicular damage in rats while quercetin (Que) served as standard. The total flavonoids and phenolic contents (TFC and TPC), 2, 2-diphenyl 1-picrylhydrazyl (DPPH) and hydroxyl (OH) radicals scavenging activities of AA were determined. In vivo, thirty male Wistar rats were assigned to six groups and orally treated with corn oil (control), Cd alone, Cd+Que, Cd+AA, Que and AA alone. Que and AA were given at doses of 25 and 200 mg kg(-1), respectively, for 3 weeks and challenged with two doses of Cd (1.5 mg kg(-1)). Results showed that TFC and TPC of AA increased with increase in concentration. AA scavenged DPPH and OH radicals in a dose-dependent manner. Administration of Cd significantly increased the relative weight of testis of rats. Lipid peroxidation was significantly increased while antioxidant parameters decreased in testis of Cd treated rats. Also, Cd-treated rats had significantly reduced sperm count, motility, sialic acid, luteinising hormone and testosterone relative to controls. Pre-treatment with AA or Que significantly attenuated the biochemical alterations observed in Cd-treated rats. Overall, AA protects against Cd-induced testicular damage via antioxidative mechanism. PMID- 25912633 TI - Root development of non-accumulating and hyperaccumulating plants in metal contaminated soils amended with biochar. AB - Biochar may be used as an amendment in contaminated soils in phytoremediation processes. The mechanisms controlling plant metal uptake in biochar-amended soils remain however unclear. This work aimed at evaluating the influence of biochar on root development and its consequence on plant metal uptake, for two non hyperaccumulating plants (Zea mays and Lolium perenne) and one hyperaccumulator of Cd and Zn (Noccaea caerulescens). We conducted rhizobox experiments using one acidic and one alkaline soil contaminated with Cd, Pb and Zn. Biochar was present either homogeneously in the whole soil profile or localized in specific zones. A phenomenon of root proliferation specific to biochar-amended zones was seen on the heterogeneous profiles of the acidic soil and interpreted by a decrease of soil phytotoxicity in these zones. Biochar amendments also favored root growth in the alkaline soil as a result of the lower availability of certain nutrients in the amended soil. This increase of root surface led to a higher accumulation of metals in roots of Z.mays in the acidic soil and in shoots of N. caerulescens in the alkaline soil. In conclusion, biochar can have antagonist effects on plant metal uptake by decreasing metal availability, on one hand, and by increasing root surface and inducing root proliferation, on the other hand. PMID- 25912634 TI - Acute toxicity assessment of ANAMMOX substrates and antibiotics by luminescent bacteria test. AB - Acute toxicities of anaerobic ammonia oxidation (ANAMMOX) substrates and four antibiotics from pharmaceutical wastewaters on ANAMMOX process were reported. Individual and joint acute toxicity assays were performed using 50% inhibitory concentration (IC50). Results showed that IC50 values and their 95% confidence interval of ammonium chloride (A), sodium nitrite (B), penicillin G-Na (C), polymyxin B sulfate (D), chloramphenicol (E) and kanamycin sulfate (F) were 2708.9 (2247.9-3169.9), 1475.4 (1269.9-1680.9), 5114.4 (4946.4-5282.4), 10.2 (1.8 18.6), 409.9 (333.7-486.1) and 5254.1 (3934.4-6573.8) mgL(-1) respectively, suggesting toxicities were in the order of D>E>B>A>C>F. Joint acute toxicities of bicomponent mixtures A and B, C and D, C and F, D and F were independent; D and E, E and F were additive while C and E were synergistic. Joint acute toxicities of multicomponent mixtures were synergistic or additive. Luminescent bacteria test is an easy and robust method for forecasting the feasibility of ANAMMOX process for pharmaceutical wastewater treatment. PMID- 25912635 TI - Efficacy of phosphatidylinositol-3 kinase inhibitors with diverse isoform selectivity profiles for inhibiting the survival of chronic lymphocytic leukemia cells. AB - Pharmacological inhibition of phosphatiylinositide-3-kinase (PI3K)-mediated signaling holds great promise for treating chronic lymphocytic leukemia (CLL). Therefore we assessed three structurally related PI3K inhibitors targeting the PI3K-delta isoform for their ability to inhibit the survival of freshly isolated CLL cells. The purely PI3K-delta-selective inhibitor idelalisib was compared to copanlisib (BAY 80-6946) and duvelisib (IPI-145), with isoform target profiles that additionally include PI3K-alpha or PI3K-gamma, respectively. The concentrations leading to half-maximal reduction of the survival of CLL cells were more than ten-fold lower for copanlisib than for idelalisib and duvelisib. At concentrations reflecting the biological availability of the different inhibitors, high levels of apoptotic response among CLL samples were attained more consistently with copanlisib than with idelalisib. Copanlisib selectively reduced the survival of CLL cells compared to T cells and to B cells from healthy donors. In addition copanlisib and duvelisib impaired the migration of CLL cells towards CXCL12 to a greater extent than equimolar idelalisib. Similarly copanlisib and duvelisib reduced the survival of CLL cells in co-cultures with the bone marrow stroma cell line HS-5 more strongly than idelalisib. Survival inhibition by copanlisib and idelalisib was enhanced by the monoclonal CD20 antibodies rituximab and obinutuzumab (GA101), while antibody-dependent cellular cytotoxicity mediated by alemtuzumab and peripheral blood mononuclear cells was not substantially impaired by both PI3K inhibitors for the CLL-derived JVM-3 cell line as target cells. Taken together, targeting the alpha- and delta- p110 isoforms with copanlisib may be a useful strategy for the treatment of CLL and warrants further clinical investigation. PMID- 25912636 TI - The Changing Epidemiology of Bloodstream Infections and Resistance in Hematopoietic Stem Cell Transplantation Recipients. AB - OBJECTIVE: Patients receiving hematopoietic stem cell transplantation (HSCT) are exposed to highly immunosuppressive conditions and bloodstream infections (BSIs) are one of the most common major complications within this period. Our aim, in this study, was to evaluate the epidemiology of BSIs in these patients retrospectively. MATERIALS AND METHODS: The epidemiological properties of 312 patients with HSCT were retrospectively evaluated. RESULTS: A total of 312 patients, followed between 2000 and 2011, who underwent autologous (62%) and allogeneic (38%) HSCT were included in the study. The most common underlying malignancies were multiple myeloma (28%) and Hodgkin lymphoma (21.5%). A total of 142 (45%) patients developed at least 1 episode of BSI and 193 separate pathogens were isolated from the blood cultures. There was a trend of increase in the numbers of BSIs in 2005-2008 and a relative increase in the proportion of gram positive infections in recent years (2009-2011), and central venous catheter related BSI was found to be most common source. Coagulase-negative staphylococci (49.2%) and Acinetobacter baumannii (8.8%) were the most common pathogens. Extended-spectrum beta-lactamase-producing strains were 23% and 22% among Escherichia coli and Klebsiella spp. isolates, respectively. Quinolone resistance was detected in 10% of Enterobacteriaceae. Resistance to carbapenems was not detected in Enterobacteriaceae, while it was seen at 11.1% and 23.5% in Pseudomonas and Acinetobacter strains, respectively. CONCLUSION: A shift was detected from gram-negative bacteria to gram-positive in the etiology over the years and central lines were the most common sources of BSIs. PMID- 25912638 TI - Nurse-patient assignment models considering patient acuity metrics and nurses' perceived workload. AB - Patient classification systems (PCSs) are commonly used in nursing units to assess how many nursing care hours are needed to care for patients. These systems then provide staffing and nurse-patient assignment recommendations for a given patient census based on these acuity scores. Our hypothesis is that such systems do not accurately capture workload and we conduct an experiment to test this hypothesis. Specifically, we conducted a survey study to capture nurses' perception of workload in an inpatient unit. Forty five nurses from oncology and surgery units completed the survey and rated the impact of patient acuity indicators on their perceived workload using a six-point Likert scale. These ratings were used to calculate a workload score for an individual nurse given a set of patient acuity indicators. The approach offers optimization models (prescriptive analytics), which use patient acuity indicators from a commercial PCS as well as a survey-based nurse workload score. The models assign patients to nurses in a balanced manner by distributing acuity scores from the PCS and survey based perceived workload. Numerical results suggest that the proposed nurse patient assignment models achieve a balanced assignment and lower overall survey based perceived workload compared to the assignment based solely on acuity scores from the PCS. This results in an improvement of perceived workload that is upwards of five percent. PMID- 25912637 TI - Group II mGluRs modulate baseline and arthritis pain-related synaptic transmission in the rat medial prefrontal cortex. AB - The medial prefrontal cortex (mPFC) serves executive control functions that are impaired in neuropsychiatric disorders and pain. Therefore, restoring normal synaptic transmission and output is a desirable goal. Group II metabotropic glutamate receptors mGluR2 and mGluR3 are highly expressed in the mPFC, modulate synaptic transmission, and have been targeted for neuropsychiatric disorders. Their pain-related modulatory effects in the mPFC remain to be determined. Here we evaluated their ability to restore pyramidal output in an arthritis pain model. Whole-cell patch-clamp recordings of layer V mPFC pyramidal cells show that a selective group II mGluR agonist (LY379268) decreased synaptically evoked spiking in brain slices from normal and arthritic rats. Effects were concentration-dependent and reversed by a selective antagonist (LY341495). LY379268 decreased monosynaptic excitatory postsynaptic currents (EPSCs) and glutamate-driven inhibitory postsynaptic currents (IPSCs) in the pain model. Effects on EPSCs preceded those on IPSCs and could explain the overall inhibitory effect on pyramidal output. LY379268 decreased frequency, but not amplitude, of miniature EPSCs without affecting miniature IPSCs. LY341495 alone increased synaptically evoked spiking under normal conditions and in the pain model. In conclusion, group II mGluRs act on glutamatergic synapses to inhibit direct excitatory transmission and feedforward inhibition onto pyramidal cells. Their net effect is decreased pyramidal cell output. Facilitatory effects of a group II antagonist suggest the system may be tonically active to control pyramidal output. Failure to release the inhibitory tone and enhance mPFC output could be a mechanism for the development or persistence of a disease state such as pain. PMID- 25912640 TI - Facile Decoration of Polyaniline Fiber with Ag Nanoparticles for Recyclable SERS Substrate. AB - Facile synthesis of polyaniline@Ag composite has been successfully demonstrated by a simple solution-dipping method using high-aspect-ratio benzene tetracarboxylic acid-doped polyaniline (BDP) fiber as a nontoxic reducing agent as well as template cum stabilizer. In BDP@Ag composite, BDP fibers are decorated with spherical Ag nanoparticles (Ag NPs), and the population of Ag NPs on BDP fibers is controlled by changing the molar concentration of AgNO3. Importantly, Ag-NP-decorated BDP fibers (BDP@Ag composites) have been evolved as a sensitive materials for the detection of trace amounts of 4-mercaptobenzoic acid and rhodamine 6G as an analyte of surface-enhanced Raman scattering (SERS), and the detection limit is down to nanomolar concentrations with excellent recyclability. Furthermore, synthesized BDP@Ag composites are applied simultaneously as an active SERS substrate and a superior catalyst for reduction of 4-nitrothiophenol. PMID- 25912639 TI - Augmentation of failed human vertebrae with critical un-contained lytic defect restores their structural competence under functional loading: An experimental study. AB - BACKGROUND: Lytic spinal lesions reduce vertebral strength and may result in their fracture. Vertebral augmentation is employed clinically to provide mechanical stability and pain relief for vertebrae with lytic lesions. However, little is known about its efficacy in strengthening fractured vertebrae containing lytic metastasis. METHODS: Eighteen unembalmed human lumbar vertebrae, having simulated uncontained lytic defects and tested to failure in a prior study, were augmented using a transpedicular approach and re-tested to failure using a wedge fracture model. Axial and moment based strength and stiffness parameters were used to quantify the effect of augmentation on the structural response of the failed vertebrae. Effects of cement volume, bone mineral density and vertebral geometry on the change in structural response were investigated. FINDINGS: Augmentation increased the failed lytic vertebral strength [compression: 85% (P<0.001), flexion: 80% (P<0.001), anterior-posterior shear: 95%, P<0.001)] and stiffness [(40% (P<0.05), 53% (P<0.05), 45% (P<0.05)]. Cement volume correlated with the compressive strength (r(2)=0.47, P<0.05) and anterior posterior shear strength (r(2)=0.52, P<0.05) and stiffness (r(2)=0.45, P<0.05). Neither the geometry of the failed vertebrae nor its pre-fracture bone mineral density correlated with the volume of cement. INTERPRETATION: Vertebral augmentation is effective in bolstering the failed lytic vertebrae compressive and axial structural competence, showing strength estimates up to 50-90% of historical values of osteoporotic vertebrae without lytic defects. This modest increase suggests that lytic vertebrae undergo a high degree of structural damage at failure, with strength only partially restored by vertebral augmentation. The positive effect of cement volume is self-limiting due to extravasation. PMID- 25912641 TI - Failed validation of risk prediction model for intervention in renal colic patients after emergency department evaluation. AB - BACKGROUND: It has been reported that three criteria (size of calculus >=6 mm, visual analogue scale pain score at discharge >=2 cm and location above mid ureter; the Papa criteria) were sensitive for predicting patients who require intervention (surgery or lithotripsy) within 28 days of index emergency department (ED) visit for ureteric colic. It was suggested that absence of these criteria identified a group for whom early follow-up may not be needed. No validation has been reported. We aimed to validate these criteria. METHODS: Retrospective cohort study of patients with clinical presentation of ureteric colic and radiologically proven renal tract stones. Data collected included demographics, clinical features, features of the stone, imaging results and 28 day outcome. Outcome of interest was performance of the Papa criteria for prediction of urological intervention by clinical performance analysis. We also undertook a post hoc analysis to identify predictors of urological intervention for the group overall and for the subgroup discharged from ED. RESULTS: Two hundred and twenty-four patients were studied (median age 49, 79% male) with 75 (33%) requiring urological intervention within 28 days. The presence of any of the Papa criteria had sensitivity for urological intervention of 83.9% (95% confidence interval (CI) 71.2-91.9%) with specificity of 47.7% (95% CI 38.9 56.6%), positive predictive value of 40.9% (95% CI 31.9-50.4%) and negative predictive value of 87.3% (95% CI 76.8-93.7%). Nine patients with no Papa criteria had intervention: 12.7% (95% CI 6.8-22.4%). CONCLUSION: The Papa criteria are not sufficiently accurate to determine which patients require intervention or a subgroup who do not need specialist urological follow-up. PMID- 25912642 TI - Fluorescently labeled recombinant RNAP system to probe archaeal transcription initiation. AB - The transcriptional apparatus is one of the most complex cellular machineries and in order to fully appreciate the behavior of these protein-nucleic acid assemblies one has to understand the molecular details of the system. In addition to classical biochemical and structural studies, fluorescence-based techniques turned out as an important--and sometimes the critical--tool to obtain information about the molecular mechanisms of transcription. Fluorescence is not only a multi-modal parameter that can report on molecular interactions, environment and oligomerization status. Measured on the single-molecule level it also informs about the heterogeneity of the system and gives access to distances and distance changes in the molecular relevant nanometer regime. A pre-requisite for fluorescence-based measurements is the site-specific incorporation of one or multiple fluorescent dyes. In this respect, the archaeal transcription system is ideally suited as it is available in a fully recombinant form and thus allows for site-specific modification via sophisticated labeling schemes. The application of fluorescence based approaches to the archaeal transcription apparatus changed our understanding of the molecular mechanisms and dynamics that drive archaeal transcription and unraveled the architecture of transcriptional complexes not amenable to structural interrogation. PMID- 25912643 TI - Very late stent thrombosis caused by neoatherosclerotic plaque rupture. PMID- 25912644 TI - Two-month healing evaluation of an everolimus Pt-Cr DES with erodible polymer and two bioresorbable scaffolds implanted in the same vessel of the same patient. PMID- 25912645 TI - Coronary perforation after bioresorbable vascular scaffold implantation. PMID- 25912646 TI - Percutaneous closure of ruptured sinus of Valsalva aneurysms using a retrograde approach without formation of an arteriovenous loop. PMID- 25912647 TI - How should I treat a DeBakey type I acute aortic dissection four weeks after transcatheter aortic valve implantation in an old, fragile patient? PMID- 25912648 TI - Synovial Chondromatosis of the Temporomandibular Joint Successfully Treated by Surgery. AB - Synovial chondromatosis (SC) is a chronic process, defined as a reactive cartilaginous proliferation, characterized by formation of cartilaginous nodules, usually loose in the joint space of the synovial membrane. It mainly affects large joints such as knee, hip, shoulder, and elbow, commonly in male patients. However, its manifestation in the Temporomandibular joint (TMJ), is a rare finding, occurring predominantly in females. This paper reports a case of a woman who presented to the service of Stomatology complaining of mouth opening limitations and pain in her left pre-auricular region. After clinical and radiographic analyses, the condition was diagnosed as SC of the TMJ. The loose bodies within the TMJ were removed under general anesthesia. Histological and follow-up features of this lesion are also discussed. To our knowledge, this is the second report of SC of the TMJ in Brazil. PMID- 25912649 TI - Use of re-esterified palm oils, differing in their acylglycerol structure, in weaning-piglet diets. AB - Re-esterified oils are new fat sources obtained from chemical esterification of acid oils with glycerol (both economically interesting by-products from oil refining and biodiesel industries, respectively). The different fatty acid (FA) positional distribution and acylglycerol composition of re-esterified oils may enhance the apparent absorption of saturated fatty acids (SFA) and, thus, their overall nutritive value. The aim of the present study was to investigate the potential use of re-esterified palm oils, in comparison with their corresponding acid and native oils, and also with an unsaturated fat source in weaning-piglet diets. The parameters assessed were: FA apparent absorption, acylglycerol and free fatty acid (FFA) composition of feces, and growth performance. One-hundred and twenty weaning piglets (average weight of 8.50+/-1.778 kg) were blocked by initial BW (six blocks) and randomly assigned to five dietary treatments, resulting in four piglets per pen and six replicates per treatment. Dietary treatments were a basal diet supplemented with 10% (as-fed basis) of native soybean oil (SN), native palm oil (PN), acid palm oil (PA), re-esterified palm oil low in mono- (MAG) and diacylglycerols (DAG) (PEL), or re-esterified palm oil high in MAG and DAG (PEH). Results from the digestibility balance showed that SN reached the greatest total FA apparent absorption, and statistically different from PN, PA and PEL (P0.05), but PEH achieved the greatest total FA apparent absorption. Animals fed PEL, despite the fact that PEL oil contained more sn-2 SFA, did not show an improved absorption of SFA (P>0.05). Animals fed PA and PN showed similar apparent absorption coefficients (P>0.05), despite the high FFA content of PA oil. The acylglycerol and FFA composition of feces was mainly composed of FFA. There were no significant differences in growth performance (P>0.05). Results of the present study suggest that, despite the different acylglycerol structure of re-esterified oils, there were no significant differences in digestibility or performance with respect to their corresponding PN and PA oils in weaning-piglet diets. PMID- 25912650 TI - The role of loops on the order of eukaryotes and prokaryotes. AB - The study of the three-dimensional organization of chromatin has recently gained much focus in the context of novel techniques for detecting genome-wide contacts using next-generation sequencing. These chromosome conformation capture-based methods give a deep topological insight into the architecture of the genome inside the nucleus. Several recent studies observe a compartmentalization of chromatin interactions into spatially confined domains. This structural feature of interphase chromosomes is not only supported by conventional studies assessing the interaction data of millions of cells, but also by analysis on the level of a single cell. We first present and examine the different models that have been proposed to elucidate these topological domains in eukaryotes. Then we show that a model which relies on the dynamic formation of loops within domains can account for the experimentally observed contact maps. Interestingly, the topological domain structure is not only found in mammalian genomes, but also in bacterial chromosomes. PMID- 25912651 TI - Structural organization of human replication timing domains. AB - Recent analysis of genome-wide epigenetic modification data, mean replication timing (MRT) profiles and chromosome conformation data in mammals have provided increasing evidence that flexibility in replication origin usage is regulated locally by the epigenetic landscape and over larger genomic distances by the 3D chromatin architecture. Here, we review the recent results establishing some link between replication domains and chromatin structural domains in pluripotent and various differentiated cell types in human. We reconcile the originally proposed dichotomic picture of early and late constant timing regions that replicate by multiple rather synchronous origins in separated nuclear compartments of open and closed chromatins, with the U-shaped MRT domains bordered by "master" replication origins specified by a localized (~200-300 kb) zone of open and transcriptionally active chromatin from which a replication wave likely initiates and propagates toward the domain center via a cascade of origin firing. We discuss the relationships between these MRT domains, topologically associated domains and lamina-associated domains. This review sheds a new light on the epigenetically regulated global chromatin reorganization that underlies the loss of pluripotency and the determination of differentiation properties. PMID- 25912652 TI - Multifractality of random eigenfunctions and generalization of Jarzynski equality. AB - Systems driven out of equilibrium experience large fluctuations of the dissipated work. The same is true for wavefunction amplitudes in disordered systems close to the Anderson localization transition. In both cases, the probability distribution function is given by the large-deviation ansatz. Here we exploit the analogy between the statistics of work dissipated in a driven single-electron box and that of random multifractal wavefunction amplitudes, and uncover new relations that generalize the Jarzynski equality. We checked the new relations theoretically using the rate equations for sequential tunnelling of electrons and experimentally by measuring the dissipated work in a driven single-electron box and found a remarkable correspondence. The results represent an important universal feature of the work statistics in systems out of equilibrium and help to understand the nature of the symmetry of multifractal exponents in the theory of Anderson localization. PMID- 25912654 TI - Cultivation and Characterisation of New Species of Apusomonads (the Sister Group to Opisthokonts), Including Close Relatives of Thecamonas (Chelonemonas n. gen.). AB - Apusomonads comprise an understudied and undersampled group of heterotrophic flagellates that is closely related to opisthokonts, the supergroup containing animals and fungi. We cultured representatives of a new clade of apusomonads, Chelonemonas n. gen., which is sister to marine forms of Thecamonas in SSU rRNA gene phylogenies. Scanning electron microscopy shows that members of Chelonemonas have a hexagonal patterning to their submembranous pellicle, which is not known to exist in other apusomonads. We propose that the subfamily Thecamonadinae refer to the marine Thecamonas/Chelonomonas clade. We also report two new strains of Multimonas, one of which is genetically divergent from previously described strains, and here described as a new species, Multimonas koreensis. Both strains of Multimonas have appendages on their dorsal surface that could be extrusomes, and a frilled appearance to the border of their pellicle. Explorations of taxon sampling in SSU rRNA gene phylogenies confirm the new strains' evolutionary affinities, but do not resolve relationships among the five main apusomonad clades. These phylogenies also separate the freshwater species "Thecamonas" oxoniensis from the marine members of the genus Thecamonas. The new strains described here may provide valuable genetic and morphological data for evaluating the relationships and evolution of apusomonads. PMID- 25912653 TI - The Protective Effects of Intimate Partner Relationships on Depressive Symptomatology Among Adult Parents Maltreated as Children. AB - PURPOSE: We examined whether intimate partner relationships in general, and satisfying and stable intimate partner relationships in particular, protect victims of child maltreatment from depressive symptoms during young adulthood. METHODS: Prospective, longitudinal data on 485 parents, 99 maltreated during childhood, were used. Longitudinal multilevel models (12 annual interviews, conducted from 1999 to 2010, nested in individuals) were specified to estimate the effects of relationship characteristics on depressive symptomatology by maltreatment status. RESULTS: Relationship characteristics operated as direct protective factors for maltreated and not maltreated individuals. Higher relationship satisfaction and stability were prospectively predictive of less depressive symptomatology. Models of inter and intraindividual variability were also consistent with significant direct protective effects. Between persons, a more satisfying and stable relationship was associated with fewer depressive symptoms. Within person, periods when an individual moved into a relationship and periods of enhanced satisfaction and stability were associated with fewer depressive symptoms. Relationship satisfaction and stability operated as significant buffering protective factors for the effect of maltreatment on depressive symptoms in most models, suggesting that positive intimate partner relationships may reduce the risk that childhood maltreatment poses for adult depressive symptoms. CONCLUSIONS: The Centers for Disease Control and Prevention identifies safe, stable, and nurturing relationships as key in preventing maltreatment and its consequences. This study adds to the evidence on the protective role of safe, stable, and nurturing relationships by identifying intimate partner relationship factors that may protect parents who were maltreated during childhood from depressive symptoms. PMID- 25912655 TI - Management of acquired peanut allergy following solid-organ transplant. PMID- 25912656 TI - A case of systemic contact dermatitis secondary to edetate disodium. PMID- 25912657 TI - Ovalbumin content in the yellow fever vaccine. PMID- 25912658 TI - The mesmiRizing complexity of microRNAs for striated muscle tissue engineering. AB - microRNAs (miRs) are small non-protein-coding RNAs, able to post transcriptionally regulate many genes and exert pleiotropic effects. Alteration of miR levels in tissues and in the circulation has been associated with various pathological and regenerative conditions. In this regard, tissue engineering of cardiac and skeletal muscles is a fascinating context for harnessing the complexity of miR-based circuitries and signals. In this review, we will focus on miR-driven regulation of cardiac and skeletal myogenic routes in homeostatic and challenging states. Furthermore, we will survey the intriguing perspective of exosomal and circulating miRs as novel paracrine players, potentially useful for current and future approaches of regenerative medicine for the striated muscles. PMID- 25912660 TI - Letter from the editors. PMID- 25912661 TI - Validation of airway resistance models for predicting pressure loss through anatomically realistic conducting airway replicas of adults and children. AB - This work describes in vitro measurement of the total pressure loss at varying flow rate through anatomically realistic conducting airway replicas of 10 children, 4 to 8 years old, and 5 adults. Experimental results were compared with analytical predictions made using published airway resistance models. For the adult replicas, the model proposed by van Ertbruggen et al. (2005. J. Appl. Physiol. 98, 970-980) most accurately predicted central conducting airway resistance for inspiratory flow rates ranging from 15 to 90 L/min. Models proposed by Pedley et al. (1970. J. Respir. Physiol. 9, 371-386) and by Katz et al. (2011. J. Biomech. 44, 1137-1143) also provided reasonable estimates, but with a tendency to over predict measured pressure loss for both models. For child replicas, the Pedley and Katz models both provided good estimation of measured pressure loss at flow rates representative of resting tidal breathing, but under predicted measured values at high inspiratory flow rate (60 L/min). The van Ertbruggen model, developed based on flow simulations performed in an adult airway model, tended to under predict measured pressure loss through the child replicas across the range of flow rates studied (2 to 60 L/min). These results are intended to provide guidance for selection of analytical pressure loss models for use in predicting airway resistance and ventilation distribution in adults and children. PMID- 25912659 TI - DNA and RNA derivatives to optimize distribution and delivery. AB - Synthetic, complementary DNA single strands and short interfering RNA double strands have been found to inhibit the expression of animal, plant, and viral genes in cells, animals, and patients, in a dose dependent and sequence specific manner. DNAs and RNAs, however, are readily digested in biological systems. Hence, chemists are obliged to design and synthesize nuclease-resistant analogs of normal DNA (Fig. 1). PMID- 25912662 TI - Finite element modeling of hyper-viscoelasticity of peripheral nerve ultrastructures. AB - The mechanical characteristics of ultrastructures of rat sciatic nerves were investigated through animal experiments and finite element analyses. A custom designed dynamic testing apparatus was used to conduct in vitro transverse compression experiments on the nerves. The optical coherence tomography (OCT) was utilized to record the cross-sectional images of nerve during the dynamic testing. Two-dimensional finite element models of the nerves were built based on their OCT images. A hyper-viscoelastic model was employed to describe the elastic and stress relaxation response of each ultrastructure of the nerve, namely the endoneurium, the perineurium and the epineurium. The first-order Ogden model was employed to describe the elasticity of each ultrastructure and a generalized Maxwell model for the relaxation. The inverse finite element analysis was used to estimate the material parameters of the ultrastructures. The results show the instantaneous shear modulus of the ultrastructures in decreasing order is perineurium, endoneurium, and epineurium. The FE model combined with the first order Ogden model and the second-order Prony series is good enough for describing the compress-and-hold response of the nerve ultrastructures. The integration of OCT and the nonlinear finite element modeling may be applicable to study the viscoelasticity of peripheral nerve down to the ultrastructural level. PMID- 25912663 TI - Wear and damage of articular cartilage with friction against orthopedic implant materials. AB - The objective of this study was to measure the wear response of immature bovine articular cartilage tested against glass or alloys used in hemiarthroplasties. Two cobalt chromium alloys and a stainless steel alloy were selected for these investigations. The surface roughness of one of the cobalt chromium alloys was also varied within the range considered acceptable by regulatory agencies. Cartilage disks were tested in a configuration that promoted loss of interstitial fluid pressurization to accelerate conditions believed to occur in hemiarthroplasties. Results showed that considerably more damage occurred in cartilage samples tested against stainless steel (10 nm roughness) and low carbon cobalt chromium alloy (27 nm roughness) compared to glass (10 nm) and smoother low or high carbon cobalt chromium (10 nm). The two materials producing the greatest damage also exhibited higher equilibrium friction coefficients. Cartilage damage occurred primarily in the form of delamination at the interface between the superficial tangential zone and the transitional middle zone, with much less evidence of abrasive wear at the articular surface. These results suggest that cartilage damage from frictional loading occurs as a result of subsurface fatigue failure leading to the delamination. Surface chemistry and surface roughness of implant materials can have a significant influence on tissue damage, even when using materials and roughness values that satisfy regulatory requirements. PMID- 25912664 TI - Mechanical analysis of the human cadaveric thoracic spine with intact rib cage. AB - The goal of this study was to characterize the overall in-plane and basic coupled motion of a cadaveric human thoracic spine with intact true ribs. Researchers are becoming increasingly interested in the thoracic spine due to both the high prevalence of injury and pain in the region and also innovative surgical techniques that utilize the rib cage. Computational models can be useful tools to predict loading patterns and understand effects of surgical procedures or medical devices, but they are often limited by insufficient cadaveric input data. In this study, pure moments to +/-5 Nm were applied in flexion-extension, lateral bending, and axial rotation to seven human cadaveric thoracic spine specimens (T1 T12) with intact true ribs to determine symmetry of in-plane motion, differences in neutral and elastic zone motion and stiffness, and significance of out-of plane rotations and translations. Results showed that lateral bending and axial rotation exhibited symmetric motion, neutral and elastic zone motion and stiffness values were significantly different for all modes of bending (p<0.05), and out-of-plane rotations and translations were greater than zero for most rotations and translations. Overall in-plane rotations were 7.7+/-3.4 degrees in flexion, 9.6+/-3.7 degrees in extension, 23.3+/-8.4 degrees in lateral bending, and 26.3+/-12.2 degrees in axial rotation. Results of this study could provide inputs or validation comparisons for computational models. Future studies should characterize coupled motion patterns and local and regional level biomechanics of cadaveric human thoracic spines with intact true ribs. PMID- 25912665 TI - Commentary: sex differences in the pathways to symptoms of alcohol use disorder: a study of opposite-sex twin pairs. PMID- 25912666 TI - Validity of the Neuromuscular Recovery Scale: a measurement model approach. AB - OBJECTIVE: To determine how well the Neuromuscular Recovery Scale (NRS) items fit the Rasch, 1-parameter, partial-credit measurement model. DESIGN: Confirmatory factor analysis (CFA) and principal components analysis (PCA) of residuals were used to determine dimensionality. The Rasch, 1-parameter, partial-credit rating scale model was used to determine rating scale structure, person/item fit, point measure item correlations, item discrimination, and measurement precision. SETTING: Seven NeuroRecovery Network clinical sites. PARTICIPANTS: Outpatients (N=188) with spinal cord injury. INTERVENTIONS: Not applicable. MAIN OUTCOME MEASURE: NRS. RESULTS: While the NRS met 1 of 3 CFA criteria, the PCA revealed that the Rasch measurement dimension explained 76.9% of the variance. Ten of 11 items and 91% of the patients fit the Rasch model, with 9 of 11 items showing high discrimination. Sixty-nine percent of the ratings met criteria. The items showed a logical item-difficulty order, with Stand retraining as the easiest item and Walking as the most challenging item. The NRS showed no ceiling or floor effects and separated the sample into almost 5 statistically distinct strata; individuals with an American Spinal Injury Association Impairment Scale (AIS) D classification showed the most ability, and those with an AIS A classification showed the least ability. Items not meeting the rating scale criteria appear to be related to the low frequency counts. CONCLUSIONS: The NRS met many of the Rasch model criteria for construct validity. PMID- 25912667 TI - Reliability, Validity, and Responsiveness of the QuickDASH in Patients With Upper Limb Amputation. AB - OBJECTIVES: To examine the internal consistency, test-retest reliability, validity, and responsiveness of the shortened version of the Disabilities of the Arm, Shoulder and Hand (QuickDASH) questionnaire in persons with upper limb amputation. DESIGN: Cross-sectional and longitudinal. SETTING: Three sites participating in the U.S. Department of Veterans Affairs Home Study of the DEKA Arm. PARTICIPANTS: A convenience sample of upper limb amputees (N=44). INTERVENTIONS: Training with a multifunction upper limb prosthesis. MAIN OUTCOME MEASURES: Multiple outcome measures including the QuickDASH were administered twice within 1 week, and for a subset of 20 persons, after completion of in laboratory training with the DEKA Arm. Scale alphas and intraclass correlation coefficient type 3,1 (ICC3,1) were used to examine reliability. Minimum detectable change (MDC) scores were calculated. Analyses of variance, comparing QuickDASH scores by the amount of prosthetic use and amputation level, were used for known-group validity analyses with alpha set at .05. Pairwise correlations between QuickDASH and other measures were used to examine concurrent validity. Responsiveness was measured by effect size (ES) and standardized response mean (SRM). RESULTS: QuickDASH alpha was .83, and ICC was .87 (95% confidence interval, .77-.93). MDC at the 95% confidence level (MDC95%) was 17.4. Full- or part-time prosthesis users had better QuickDASH scores compared with nonprosthesis users (P=.021), as did those with more distal amputations at both baseline (P=.042) and with the DEKA Arm (P=.024). The QuickDASH was correlated with concurrent measures of activity limitation as expected. The ES and SRM after training with the DEKA Arm were 0.6. CONCLUSIONS: This study provides evidence of reliability and validity of the QuickDASH in persons with upper limb amputation. Results provide preliminary evidence of responsiveness to prosthetic device type/training. Further research with a larger sample is needed to confirm results. PMID- 25912668 TI - Pilates Method for Women's Health: Systematic Review of Randomized Controlled Trials. AB - OBJECTIVE: To critically analyze the benefits of Pilates on health outcomes in women. DATA SOURCES: CINAHL, MEDLINE, PubMed, Science Direct, SPORTDiscus, Physiotherapy Evidence Database (PEDro), Cochrane Central Register of Controlled Trials, and Web of Science. STUDY SELECTION: Databases were searched using the terms Pilates and Pilates Method. Published randomized controlled trials (RCTs) were included if they comprised female participants with a health condition and a health outcome was measured, Pilates needed to be administered, and the article was published in English in a peer-reviewed journal from 1980 to July 2014. DATA EXTRACTION: Two authors independently applied the inclusion criteria to potential studies. Methodological quality was assessed using the PEDro scale. A best evidence grading system was used to determine the strength of the evidence. DATA SYNTHESIS: Thirteen studies met the inclusion criteria. PEDro scale values ranged from 3 to 7 (mean, 4.5; median, 4.0), indicating a relatively low quality overall. In this sample, Pilates for breast cancer was most often trialed (n=2). The most frequent health outcomes investigated were pain (n=4), quality of life (n=4), and lower extremity endurance (n=2), with mixed results. Emerging evidence was found for reducing pain and improving quality of life and lower extremity endurance. CONCLUSIONS: There is a paucity of evidence on Pilates for improving women's health during pregnancy or for conditions including breast cancer, obesity, or low back pain. Further high-quality RCTs are warranted to determine the effectiveness of Pilates for improving women's health outcomes. PMID- 25912669 TI - Potential hurdles to ABO-incompatible living donor kidney transplantation without augmented immunosuppression. PMID- 25912670 TI - Decreasing body dissatisfaction using a brief conditioning intervention. AB - OBJECTIVE: Body dissatisfaction in females is common and a risk factor for the development of an eating disorder. This study tested whether body dissatisfaction could be improved using a brief conditioning intervention in which photographs of participants' bodies were selectively paired with positive social stimuli (smiling faces) and photographs of other bodies were paired with neutral or negative social stimuli (neutral and frowning faces). METHOD: 39 women (mean age = 22.46; 64.1% Caucasian) with high body dissatisfaction were randomized to either the evaluative conditioning intervention (n = 22) or to a delayed waitlist control condition (n = 17). Body dissatisfaction (specifically, shape and weight concern), restraint, eating concern, and self-esteem were assessed at baseline, post treatment and again after four and 12 weeks. RESULTS: Compared to women in the delayed waitlist control condition, women in the treatment condition demonstrated a significant decrease in shape and weight concern, and a significant increase in self-esteem. Similar trends were found for the control condition after they completed the intervention. Changes at post treatment related to body dissatisfaction were maintained at 12-week follow-up. CONCLUSIONS: Repeatedly pairing photographs of an individual's body with positive social feedback may lead to improved body image and self-esteem. PMID- 25912671 TI - Risk of pneumonia in new users of cholinesterase inhibitors for dementia. AB - OBJECTIVES: To compare the risk of pneumonia in older adults receiving donepezil, galantamine, or rivastigmine for dementia. DESIGN: Retrospective cohort study. SETTING: Nationally representative 5% sample of Medicare databases. PARTICIPANTS: Medicare beneficiaries aged 65 and older who newly initiated cholinesterase inhibitor therapy between 2006 and 2009. MEASUREMENTS: Pneumonia, defined as the presence of a diagnosis code for pneumonia as the primary diagnosis on an inpatient claim or on an emergency department claim followed by dispensing of appropriate antibiotics. Cox proportional hazards models were used to estimate the risk of pneumonia. Subgroup analyses and sensitivity analyses were conducted using alternative pneumonia definitions and adjustments using high-dimensional propensity scores to test the robustness of the results. RESULTS: The mean age of 35,570 new users of cholinesterase inhibitors (30,174 users of donepezil, 1,176 users of galantamine, 4,220 users of rivastigmine) was 82; 75% were women, and 82% were white. The cumulative incidence of pneumonia was 51.9 per 1,000 person years. The risk of pneumonia for rivastigmine users was 24% lower than that of donepezil users (hazard ratio (HR)=0.75, 95% confidence interval (CI)=0.60-0.93). Risk in galantamine users (HR=0.87, 95% CI=0.62-1.23) was not significantly different from risk in donepezil users. Results of subgroup and sensitivity analyses were similar to the primary results. CONCLUSION: The risk of pneumonia was lower in individuals receiving rivastigmine than in those receiving donepezil. Additional studies are needed to confirm the findings of pneumonia risk between the oral and transdermal forms of rivastigmine and in users of galantamine. PMID- 25912673 TI - Binding cooperativity between a ligand carbonyl group and a hydrophobic side chain can be enhanced by additional H-bonds in a distance dependent manner: A case study with thrombin inhibitors. AB - One of the underappreciated non-covalent binding factors, which can significantly affect ligand-protein binding affinity, is the cooperativity between ligand functional groups. Using four different series of thrombin inhibitors, we reveal a strong positive cooperativity between an H-bond accepting carbonyl functionality and the adjacent P3 hydrophobic side chain. Adding an H-bond donating amine adjacent to the P3 hydrophobic side chain further increases this positive cooperativity thereby improving the Ki by as much as 546-fold. In contrast, adding an amidine multiple H-bond/salt bridge group in the distal S1 pocket does not affect this cooperativity. An analysis of the crystallographic B factors of the ligand groups inside the binding site indicates that the strong cooperativity is mainly due to a significant mutual reduction in the residual mobility of the hydrophobic side chain and the H-bonding functionalities that is absent when the separation distance is large. This type of cooperativity is important to encode in binding affinity prediction software, and to consider in SAR studies. PMID- 25912672 TI - Identification of protein kinase CK2 inhibitors using solvent dipole ordering virtual screening. AB - Novel protein kinase CK2 inhibitors were identified using the solvent dipole ordering virtual screening method. A total of 26 compounds categorized in 15 distinct scaffold classes inhibited greater than 50% of enzyme activity at 50 MUM, and eight exhibited IC50 values less than 10 MUM. Most of the identified compounds are lead-like and dissimilar to known inhibitors. The crystal structures of two of the CK2 complexes revealed the high accuracy of the predicted binding modes. PMID- 25912674 TI - Synthesis, carbonic anhydrase inhibition and cytotoxic activity of novel chromone based sulfonamide derivatives. AB - Four series of sulfonamides incorporating chromone moieties were synthesized and assessed for their cytotoxic activity against MCF-7 and A-549 cell lines, considering the fact that some of these tumors overexpress isoforms of carbonic anhydrase (CA, EC 4.2.1.1) which is inhibited by sulfonamides. Most new sulfonamides showed weak inhibitory activity against the offtarget, cytosolic isoforms hCA I, II but effectively inhibited the tumor-associated hCA IX and XII. The most active compounds featured a primary SO2NH2 group and were active in the low micromolar range against MCF-7 and A-549 cell lines. Compound 4a showed IC50 of 0.72 and 0.50 MUM against MCF-7 and A-549 cell lines, respectively, and was further evaluated for its proapoptotic activity which proved enhanced in both tumor types. PMID- 25912676 TI - Heavy social drinkers score higher on implicit wanting and liking for alcohol than alcohol-dependent patients and light social drinkers. AB - BACKGROUND AND OBJECTIVES: Automatic hedonic ("liking") and incentive ("wanting") processes are assumed to play an important role in addiction. Whereas some neurobiological theories suggest that these processes become dissociated when drug use develops into an addiction (i.e., "liking" becomes weaker, whereas "wanting" becomes exaggerated; e.g., Robinson & Berridge, 1993), other theories suggest that there is a linear relationship between these two processes (i.e., both "liking" and "wanting" increase equally; e.g., Koob & Le Moal, 1997). Our aim was to examine "wanting" and "liking" in three groups of participants: alcohol-dependent patients, heavy social drinkers, and light social drinkers. METHODS: Participants performed two different single target implicit association tests (ST-IATs; e.g., Bluemke & Friese, 2007) and explicit ratings that were designed to measure "liking" and "wanting" for alcohol. RESULTS: Our results are in sharp contrast with the theories of both Robinson and Berridge and Koob and Le Moal: heavy drinkers had higher scores than light drinkers and alcohol-dependent patients on both the wanting ST-IAT and the liking ST-IAT. There were no differences between alcohol-dependent patients and light drinkers. Explicit ratings mirrored these results. LIMITATIONS: These findings suggest that our ST IATs are not valid measures of "wanting" and "liking". Instead, they might assess more complex knowledge regarding participants' experiences and goals. CONCLUSIONS: These findings suggest that the relationship between drug consumption and appetitive drug associations is not linear, highlighting the importance of testing both sub-clinical and clinical samples in future research. PMID- 25912677 TI - Dissociation between the cognitive and interoceptive components of mindfulness in the treatment of chronic worry. AB - OBJETIVES: Despite the increasing interest in mindfulness, the basic components and action mechanisms of mindfulness remain controversial. The present study aims at testing the specific contribution of two components of mindfulness -attention to cognitive experience (metacognition) and awareness of interoceptive sensations (metainteroception)- in the treatment of chronic worry. METHOD: Forty five female university students with high scores in the Penn State Worry Questionnaire were split into three groups: a mindfulness cognitive training group, a mindfulness interoceptive training group, and a non-intervention control group. Participants were assessed before and after the intervention using physiological indices of autonomic regulation (skin conductance, heart rate, heart rate variability, and respiratory sinus arrhythmia) and self-report indices of mindfulness and clinical symptoms (chronic worry, depression, positive and negative affect, and perceived stress). RESULTS: Both mindfulness training groups showed significant improvement after the intervention in self-report indices of mindfulness and clinical symptoms. However, the interoceptive training group was superior in also showing significant improvement in the physiological indices of autonomic regulation. LIMITATIONS: The relatively small sample size may have increased the probabilities of type I and II errors. Our Intervention program was relatively short. The participants were all female. CONCLUSIONS: These results support the hypothesis that, in the context of treating chronic worry, the interoceptive and cognitive components can be somewhat dissociated and that, when both components are applied separately, compared to a non-intervention condition, the interoceptive component is more effective. PMID- 25912675 TI - Hyperglycemia promotes p53-Mdm2 interaction but reduces p53 ubiquitination in RINm5F cells. AB - The apoptosis of beta cells induced by hyperglycemia has been associated with p53 mobilization to mitochondria and p53 phosphorylation. Murine double minute 2 (Mdm2) induces the degradation of p53 and thereby protects cells from apoptosis. We studied the effect of glucose at high concentration on the ability of Mdm2 to ubiquitinate p53 and promote its degradation. RINm5F cells were grown in RPMI 1640 medium with 5 or 30 mM glucose for varying periods of time. After this treatment, the expression of Mdm2 was measured using real-time PCR. The phosphorylation of Mdm2 at Ser166, p53 at Ser15, and the kinases Akt and ATM were measured by Western blotting. The formation of the p53-Mdm2 complex and p53 ubiquitination was assessed by p53 immunoprecipitation and immunofluorescence. Our results showed that high glucose reduced Mdm2 mRNA expression and protein concentration and increased Mdm2 and Akt phosphorylation, albeit with slower kinetics for Akt. It also promoted p53-Mdm2 complex formation, whereas p53 ubiquitination was suppressed. Furthermore, phosphorylation of both p53 Ser15 and ATM was increased in the presence of 30 mM glucose. These data indicate that high concentration glucose decrease the mRNA expression and cytosolic concentration of Mdm2. However, although the increase in glucose promoted the phosphorylation of Mdm2, it also decreased p53 ubiquitination, thus avoiding p53 degradation. In hyperglycemic conditions, such as diabetes mellitus, the reduction of pancreatic beta cells mass is favored by stabilization of p53 in association with low p53 ubiquitination and reduced expression of Mdm2. PMID- 25912679 TI - Replacing antibodies with aptamers in lateral flow immunoassay. AB - Aptamers have been identified against various targets as a type of chemical or nucleic acid ligand by systematic evolution of ligands by exponential enrichment (SELEX) with high sensitivity and specificity. Aptamers show remarkable advantages over antibodies due to the nucleic acid nature and target-induced structure-switching properties and are widely used to design various fluorescent, electrochemical, or colorimetric biosensors. However, the practical applications of aptamer-based sensing and diagnostics are still lagging behind those of antibody-based tests. Lateral flow immunoassay (LFIA) represents a well established and appropriate technology among rapid assays because of its low cost and user-friendliness. The antibody-based platform is utilized to detect numerous targets, but it is always hampered by the antibody preparation time, antibody stability, and effect of modification on the antibody. Seeking alternatives to antibodies is an area of active research and is of tremendous importance. Aptamers are receiving increasing attention in lateral flow applications because of a number of important potential performance advantages. We speculate that aptamer-based LFIA may be one of the first platforms for commercial use of aptamer-based diagnosis. This review first gives an introduction to aptamer including the selection process SELEX with its focus on aptamer advantages over antibodies, and then depicts LFIA with its focus on aptamer opportunities in LFIA over antibodies. Furthermore, we summarize the recent advances in the development of aptamer-based lateral flow biosensing assays with the aim to provide a general guide for the design of aptamer-based lateral flow biosensing assays. PMID- 25912678 TI - An aptameric graphene nanosensor for label-free detection of small-molecule biomarkers. AB - This paper presents an aptameric graphene nanosensor for detection of small molecule biomarkers. To address difficulties in direct detection of small molecules associated with their low molecular weight and electrical charge, we incorporate an aptamer-based competitive affinity assay in a graphene field effect transistor (FET), and demonstrate the utility of the nanosensor with dehydroepiandrosterone sulfate (DHEA-S), a small-molecule steroid hormone, as the target analyte. In the competitive affinity assay, DHEA-S specifically binds to aptamer molecules pre-hybridized to their complementary DNA anchor molecules immobilized on the graphene surface. This results in the competitive release of the strongly charged aptamer from the DNA anchor and hence a change in electrical properties of the graphene, which can be measured to achieve the detection of DHEA-S. We present experimental data on the label-free, specific and quantitative detection of DHEA-S at clinically appropriate concentrations with an estimated detection limit of 44.7 nM, and analyze the trend observed in the experiments using molecular binding kinetics theory. These results demonstrate the potential of our nanosensor in the detection of DHEA-S and other small molecules in biomedical applications. PMID- 25912680 TI - A simple and rapid label-free fluorimetric biosensor for protamine detection based on glutathione-capped CdTe quantum dots aggregation. AB - A novel fluorescent biosensor is developed, based on glutathione-capped CdTe quantum dots aggregation, for the determination of trace amount of an important drug, protamine. In this method with increasing the protamine concentration, the fluorescence of the quantum dots was quenched due to their aggregation. Different parameters affect the sensitivity, such as pH and the amount of the quantum dots, were optimized. Using the new optical biosensor, under the optimized conditions, protamine could be measured in the range of 2.0-200 ng mL(-1) with a detection limit of 1.0 ng mL(-)(1). The relative standard deviation for five replicates determination of 30.0 ng mL(-)(1) protamine was 1.26%. The influence of common interfering species on the protamine detection was studied. The results showed that the biosensor is highly selective and sensitive for the detection of protamine. The optical biosensor was successfully used for the determination of protamine in real samples. PMID- 25912681 TI - A clinical demonstration of the application of audiovisual biofeedback in the treatment of puberphonia. AB - PURPOSE: The objective of this study was to demonstrate the effect of vocal audiovisual biofeedback in the treatment of puberphonia. METHOD: This is a report of a single subject research study encompassing intervention and observation of results, involving three phases: baseline, treatment, and follow-up. Therefore, this study applied an A-B case study experimental design with follow-up for observation of treatment outcomes. Self-reported complementary data regarding feelings of voice usage included comparisons between pre and post intervention scores of the Voice Handicap Index (VHI) survey. RESULTS: In this study, acoustic voice parameters measured revealed changes in vocal performance in the desired direction, as demonstrated by visual inspection and estimation of effect size of the data; changes were maintained during the follow-up phase. Examination of VHI results suggested post intervention improvement in functional and psychosocial aspects related to voice use. CONCLUSIONS: Based on the results of this study, audiovisual feedback approaches are effective in the treatment of puberphonia. Results will apply to future considerations in the application of technology support for treatment of puberphonia and other voice related disorders. PMID- 25912682 TI - Vocal characteristics of congenital anterior glottic webs in children: A case report. AB - This case report describes a 5-year-old girl with chronic dysphonia and high pitched voice since birth. Vocal quality was noted to be harsh. Videostroboscopy revealed significant hyperfunction and a Type II congenital anterior glottic web. Endoscopic division of the anterior glottic web was performed with significant improvement in vocal quality and quality of life. This paper describes methods of analyzing, diagnosing, and treating anterior glottic web with a focus on quality of life. Also, unique acoustic and aerodynamic voice features are identified. No other descriptions of a voice characteristic for anterior glottic web currently exist in the literature. PMID- 25912683 TI - Autism spectrum disorder 101: A primer for pediatric otolaryngologists. AB - Based on a comprehensive review of the literature as well as personal experiences at a tertiary children's hospital, we present an encompassing guide of the management of children with autism spectrum disorder (ASD) in the otolaryngology practice. ASD is a disorder involving persistent deficits in social communication and interaction across multiple contexts with restricted and repetitive patterns of behavior, which presents early in age and causes significant impairment in function. With the increasing prevalence of autism, the otolaryngologist's understanding of the disease and how it affects the management of patients is of paramount importance in order to provide a safe medical and surgical environment. Special considerations in the outpatient visit and peri-operative setting in the management of ASD patients can enhance the patient-provider relationship and improve the quality of care delivered. We discuss several strategies, such as utilization of communication devices and use of pre-medication prior to surgery, to facilitate the clinical experience. PMID- 25912684 TI - A meta-analysis of the long-term hearing outcomes and complications associated with atresiaplasty. AB - OBJECTIVE: To summarize peer-reviewed literature to evaluate the stability of long-term hearing outcomes with prolonged follow-up, and describe the incidence of complications related to atresiaplasty. DESIGN: A literature search of EMBASE, MEDLINE, PubMed, Google Scholar, and Web of Science was performed to identify studies of congenital aural atresia (CAA). STUDY SAMPLE: Selected studies were published between 1997 and 2014. The 19 studies covered 964 CAA ears. RESULTS: Stenosis and bony regrowth occurred in 14.2% (range from 0% to 30.3%). Lateralization of tympanic membrane (TM) occurred in 7.5% (range from 0% to 18.2%). Facial nerve palsy occurred in 0.5% (range from 0% to 5.0%). Six studies used Air-bone Gap (ABG) to evaluate the short-term and long-term hearing outcomes. The hearing outcomes were performed using meta-analysis, there was no significantly heterogeneity (I(2) = 0%, p = 0.997), and there was a degradation of hearing outcomes with prolonged follow-up (RR = 1.13, 95%CI: 0.98-1.30). CONCLUSION: Nearly all studies focus on postoperative stenosis and bony regrowth, but some studies neglect lateralization of TM. Based on available data, which shows a lack of major complications, such as facial nerve palsy, atresiaplasty is a safe procedure. Our meta-analysis indicated that there was a degradation of hearing outcomes with prolonged follow-up. PMID- 25912685 TI - A conserved MST1/2-YAP axis mediates Hippo signaling during lung growth. AB - Hippo signaling is a critical player in controlling the growth of several tissues and organs in diverse species. The current model of Hippo signaling postulates a cascade of kinase activity initiated by the MST1/2 kinases in response to external stimuli. This leads to inactivation of the transcriptional coactivators, YAP/TAZ, due to their cytoplasmic retention and degradation that is correlated with YAP/TAZ phosphorylation. In most tissues examined, YAP plays a more dominant role than TAZ. Whether a conserved Hippo pathway is utilized during lung growth and development is unclear. In particular, the regulatory relationship between MST1/2 and YAP/TAZ in the lung remains controversial. By employing the Shh-Cre mouse line to efficiently inactivate genes in the lung epithelium, we show that loss of MST1/2 kinases in the epithelium can lead to neonatal lethality caused by lung defects. This is manifested by perturbation of lung epithelial cell proliferation and differentiation. These phenotypes are more severe than those produced by Nkx2.1-Cre, highlighting the effects of differential Cre activity on phenotypic outcomes. Importantly, expression of YAP targets is upregulated and the ratio of phospho-YAP to total YAP protein levels is reduced in Mst1/2 deficient lungs, all of which are consistent with a negative role of MST1/2 in controlling YAP function. This model gains further support from both in vivo and in vitro studies. Genetic removal of one allele of Yap or one copy of both Yap and Taz rescues neonatal lethality and lung phenotypes due to loss of Mst1/2. Moreover, knockdown of Yap in lung epithelial cell lines restores diminished alveolar marker expression caused by Mst1/2 inactivation. These results demonstrate that MST1/2 inhibit YAP/TAZ activity and establish a conserved MST1/2 YAP axis in coordinating lung growth during development. PMID- 25912687 TI - Mesodermal expression of Moz is necessary for cardiac septum development. AB - Ventricular septal defects (VSDs) are the most commonly occurring congenital heart defect. They are regularly associated with complex syndromes, including DiGeorge syndrome and Holt-Oram syndrome, which are characterised by haploinsufficiency for the T-box transcription factors TBX1 and TBX5, respectively. The histone acetyltransferase monocytic leukaemia zinc finger protein, MOZ (MYST3/KAT6A), is required for the expression of the Tbx1 and Tbx5 genes. Homozygous loss of MOZ results in DiGeorge syndrome-like defects including VSD. The Moz gene is expressed in the ectodermal, mesodermal and endodermal aspects of the developing pharyngeal apparatus and heart; however it is unclear in which of these tissues MOZ is required for heart development. The role of MOZ in the activation of Tbx1 would suggest a requirement for MOZ in the mesoderm, because deletion of Tbx1 in the mesoderm causes VSDs. Here, we investigated the tissue-specific requirements for MOZ in the mesoderm. We demonstrate that Mesp1 cre-mediated deletion of Moz results in high penetrance of VSDs and overriding aorta and a significant decrease in MOZ-dependant Tbx1 and Tbx5 expression. Together, our data suggest that the molecular pathogenesis of VSDs in Moz germline mutant mice is due to loss of MOZ-dependant activation of mesodermal Tbx1 and Tbx5 expression. PMID- 25912686 TI - Macrophages engulf endothelial cell membrane particles preceding pupillary membrane capillary regression. AB - Programmed capillary regression and remodeling are essential developmental processes. However, the cellular and molecular mechanisms that regulate vessel regression are only the beginning to be understood. Here, using in vivo, dynamic, confocal imaging of mouse transgenic reporters as well as static confocal and electron microscopy, we studied the embryonic development and postnatal regression of the transient mouse pupillary membrane (PM) vasculature. This approach allowed us to directly observe the precise temporal sequence of cellular events preceding and during the elimination of the PM from the mouse eye. Imaging of Tcf/Lef-H2B::GFP Wnt-reporter mice uncovered that, unlike the hyaloid vasculature of the posterior eye, a PM endothelial cell (EC) Wnt/beta-catenin response is unlikely to be part of the regression mechanism. Live imaging of EC and macrophage dynamics revealed highly active Csf1r-GFP+ macrophages making direct contact with the Flk1-myr::mCherry+ vessel surface and with membrane protrusions or filopodia extending from the ECs. Flk1-myr::mCherry+ EC membrane particles were observed on and around ECs as well as within macrophages. Electron microscopy studies confirmed that they were in phagosomes within macrophages, indicating that the macrophages engulfed the membrane particles. Interestingly, EC plasma membrane uptake by PM macrophages did not correlate with apoptosis and was found shortly after vessel formation at mid-gestation stages in the embryo; long before vessel regression begins during postnatal development. Additionally, genetic ablation of macrophages showed that EC membrane particles were still shed in the absence of macrophages suggesting that macrophages do not induce the formation or release of EC microparticles. These studies have uncovered a novel event during programmed capillary regression in which resident macrophages scavenge endothelial cell microparticles released from the PM vessels. This finding suggests that there may be an initial disruption in vessel homeostasis embryonically as the PM forms that may underlie its ultimate regression postnatally. PMID- 25912688 TI - PIAS-like protein Zimp7 is required for the restriction of the zebrafish organizer and mesoderm development. AB - The Zmiz2 (Zimp7) protein and its homolog Zmiz1 (Zimp10) were initially identified in humans as androgen receptor co-activators. Sequence analysis revealed the presence of an SP-RING/Miz domain, which is highly conserved in members of the PIAS family and confers SUMO-conjugating activity. Zimp7 has been shown to interact with components of the Wnt/beta-Catenin signaling pathway and with Brg1 and BAF57, components of the ATP-dependent mammalian SWI/SNF-like BAF chromatin-remodeling complexes. In this work, we analyze the role of zygotic Zimp7 in zebrafish development. We describe evidence indicating that Zimp7 is required for mesoderm development and dorsoventral patterning. Morpholino mediated reduction of zygotic Zimp7 produced axial mesodermal defects that were preceded by up-regulation of organizer genes such as bozozok, goosecoid and floating head at the onset of gastrulation and by down-regulation of the ventral markers vox, vent and eve1 indicating loss of the ventrolateral mesoderm. Consistently, embryos overexpressing zimp7 RNA exhibited midline defects such as loss of forebrain and cyclopia accompanied by transcriptional changes directly opposite of those found in the morphants. In addition, the patterning of ventralized embryos produced by the overexpression of vox and vent was restored by a reduction of Zimp7 activity. Altogether, our findings indicate that Zimp7 is involved in transcriptional regulation of factors that are essential for patterning in the dorsoventral axis. PMID- 25912689 TI - The transcription factors Ets1 and Sox10 interact during murine melanocyte development. AB - Melanocytes, the pigment-producing cells, arise from multipotent neural crest (NC) cells during embryogenesis. Many genes required for melanocyte development were identified using mouse pigmentation mutants. The variable spotting mouse pigmentation mutant arose spontaneously at the Jackson Laboratory. We identified a G-to-A nucleotide transition in exon 3 of the Ets1 gene in variable spotting, which results in a missense G102E mutation. Homozygous variable spotting mice exhibit sporadic white spotting. Similarly, mice carrying a targeted deletion of Ets1 exhibit hypopigmentation; nevertheless, the function of Ets1 in melanocyte development is unknown. The transcription factor Ets1 is widely expressed in developing organs and tissues, including the NC. In the chick, Ets1 is required for the expression of Sox10, a transcription factor critical for the development of various NC derivatives, including melanocytes. We show that Ets1 is required early for murine NC cell and melanocyte precursor survival in vivo. Given the importance of Ets1 for Sox10 expression in the chick, we investigated a potential genetic interaction between these genes by comparing the hypopigmentation phenotypes of single and double heterozygous mice. The incidence of hypopigmentation in double heterozygotes was significantly greater than in single heterozygotes. The area of hypopigmentation in double heterozygotes was significantly larger than would be expected from the addition of the areas of hypopigmentation of single heterozygotes, suggesting that Ets1 and Sox10 interact synergistically in melanocyte development. Since Sox10 is also essential for enteric ganglia development, we examined the distal colons of Ets1 null mutants and found a significant decrease in enteric innervation, which was exacerbated by Sox10 heterozygosity. At the molecular level, Ets1 was found to activate an enhancer critical for Sox10 expression in NC-derived structures. Furthermore, enhancer activation was significantly inhibited by the variable spotting mutation. Together, these results suggest that Ets1 and Sox10 interact to promote proper melanocyte and enteric ganglia development from the NC. PMID- 25912691 TI - Trypanosoma cruzi infection and benznidazole therapy independently stimulate oxidative status and structural pathological remodeling of the liver tissue in mice. AB - This study used a murine model of Chagas disease to investigate the isolated and combined impact of Trypanosoma cruzi infection and benznidazole (BZ) therapy on liver structure and function. Male C57BL/6 mice were challenged with T. cruzi and BZ for 15 days. Serum levels of cytokines and hepatic enzymes, liver oxidative stress, morphology, collagen, and glycogen content were monitored. Separately, T. cruzi infection and BZ treatment resulted in a pro-oxidant status and hepatic reactive damage. Concurrently, both T. cruzi infection and BZ treatment induced upregulation of antioxidant enzymes and pathological reorganization of the liver parenchyma and stroma. T. cruzi infection increased serum levels of Th1 cytokines, which were reduced by BZ in both infected and non-infected animals. BZ also induced functional organ damage, increasing serum levels of liver enzymes. When combined, T. cruzi infection and BZ therapy elicited intense hepatic reactive damage that was not compensated by antioxidant enzymatic reaction, subsequently culminating in more severe morphofunctional hepatic injury. Taken together, these findings indicate that during specific treatment of Chagas disease, hepatic pathology may be a result of an interaction between BZ metabolism and specific mechanisms activated during the natural course of T. cruzi infection, rather than an isolated toxic effect of BZ on liver structure and function. PMID- 25912690 TI - Imprinted expression in cystic embryoid bodies shows an embryonic and not an extra-embryonic pattern. AB - A large subset of mammalian imprinted genes show extra-embryonic lineage (EXEL) specific imprinted expression that is restricted to placental trophectoderm lineages and to visceral yolk sac endoderm (ysE). Isolated ysE provides a homogenous in vivo model of a mid-gestation extra-embryonic tissue to examine the mechanism of EXEL-specific imprinted gene silencing, but an in vitro model of ysE to facilitate more rapid and cost-effective experiments is not available. Reports indicate that ES cells differentiated into cystic embryoid bodies (EBs) contain ysE, so here we investigate if cystic EBs model ysE imprinted expression. The imprinted expression pattern of cystic EBs is shown to resemble fetal liver and not ysE. To investigate the reason for this we characterized the methylome and transcriptome of cystic EBs in comparison to fetal liver and ysE, by whole genome bisulphite sequencing and RNA-seq. Cystic EBs show a fetal liver pattern of global hypermethylation and low expression of repeats, while ysE shows global hypomethylation and high expression of IAPEz retroviral repeats, as reported for placenta. Transcriptome analysis confirmed that cystic EBs are more similar to fetal liver than ysE and express markers of early embryonic endoderm. Genome-wide analysis shows that ysE shares epigenetic and repeat expression features with placenta. Contrary to previous reports, we show that cystic EBs do not contain ysE, but are more similar to the embryonic endoderm of fetal liver. This explains why cystic EBs reproduce the imprinted expression seen in the embryo but not that seen in the ysE. PMID- 25912692 TI - Synthesis and antiproliferative activity of 2,7-diamino l0-(3,5-dimethoxy)benzyl 9(10H)-acridone derivatives as potent telomeric G-quadruplex DNA ligands. AB - A novel series of l0-(3,5-dimethoxy)benzyl-9(10H)-acridone derivatives with terminal ammonium substituents at C2 and C7 positions on the acridone ring were successfully synthesized as antiproliferation agents. The biologic activity of the acridone compounds against leukemia CCRF-CEM cells demonstrated that some of the compounds displayed good antiproliferative activity, among which compound 6a containing dimethylamine substituents at the terminal C2 and C7 positions exhibited the highest cytotoxicity with IC50 at 0.3MUM. In addition compound 6a showed little toxicity against normal 293T cells proliferation with IC50 more than 100MUM. Further study indicated that compound 6a had strong binding activity to human telomeric G-quadruplex DNA, as detected by mass spectrometry, CD spectroscopy, UV absorption, FRET and fluorescence quenching assays. Our data suggested that the activity of 6a might be associated with its stabilization of G quadruplex DNA, which can be developed as potent antitumor agent. PMID- 25912693 TI - SYMPLICITY HTN-Japan - First Randomized Controlled Trial of Catheter-Based Renal Denervation in Asian Patients - . AB - BACKGROUND: SYMPLICITY HTN-Japan is a prospective, randomized, controlled trial comparing renal artery denervation (RDN) with standard pharmacotherapy for treatment of resistant hypertension (systolic blood pressure [SBP] >=160 mmHg on >=3 anti-hypertensive drugs including a diuretic for >=6 weeks). When SYMPLICITY HTN-3 failed to meet the primary efficacy endpoint, the HTN-Japan enrollment was discontinued before completion. METHODS AND RESULTS: The 6-month change in office and 24-h ambulatory SBP were compared between RDN (n=22) and control (n=19) subjects. Mean baseline office SBP was 181.0+/-18.0 mmHg and 178.7+/-17.8 mmHg for the RDN and control groups, respectively. The 6-month office SBP change was 16.6+/-18.5 mmHg for RDN subjects (P<0.001) and -7.9+/-21.0 mmHg for control subjects (P=0.117); the difference between the 6-month change in RDN and control subjects was -8.64 (95% CI: -21.12 to 3.84, P=0.169). Mean 24-h SBP was 164.7+/ 18.3 (RDN group) and 163.3+/-17.2 mmHg (control group). The 24-h 6-month SBP change for the RDN group was -7.52+/-11.98 mmHg (P=0.008) and -1.38+/-10.2 mmHg (P=0.563) for control subjects; the between-group difference in SBP change was 6.15 (95% CI: -13.23 to 0.94, P=0.087). No major adverse events were reported. CONCLUSIONS: SYMPLICITY HTN-Japan, the first randomized controlled trial of RDN in an Asian population, was underpowered for the primary endpoint analysis and did not demonstrate a significant difference in 6-month BP change between RDN and control subjects. PMID- 25912694 TI - Effect of Abciximab Therapy in Patients Undergoing Coronary Angioplasty for Acute ST-Elevation Myocardial Infarction Complicated by Cardiogenic Shock. AB - BACKGROUND: The effect of abciximab on survival in patients with ST-elevation myocardial infarction (STEMI) complicated by cardiogenic shock (CS) undergoing primary percutaneous coronary intervention (PCI) is not clear. METHODS AND RESULTS: We evaluated outcome in 410 consecutive patients with STEMI and CS who underwent PCI treated without (n=123) or with (n=287) abciximab. The endpoint was survival at 1-year follow-up. The predictors of death at 1 year were also investigated. The groups with and without abciximab had similar survival at 1 year follow-up. Propensity score-adjusted Cox proportional hazards model identified age (adjusted hazard ratio [HR], 1.02; 95% confidence interval [95% CI]: 1.01-1.03, P=0.001), oro-tracheal intubation (HR, 1.49; 95% CI: 1.12-1.96, P=0.05), post-PCI TIMI flow grade 0-1 (HR, 2.08; 95% CI: 1.52-2.83, P=0.0001) but not abciximab use (HR, 1.08; 95% CI: 0.70-1.60, P=0.60) as independent predictors of death at 1-year follow-up. Cox adjusted 1-year survival rates were 42.8% and 51.6%, (P=0.56) in patients treated without vs. with abciximab, respectively. CONCLUSIONS: Patients with STEMI complicated by CS undergoing PCI treated with or without abciximab have similar 1-year survival rates; age, final TIMI 0-1 and oro tracheal intubation are predictors of death. PMID- 25912695 TI - Apixaban for the Treatment of Japanese Subjects With Acute Venous Thromboembolism (AMPLIFY-J Study). AB - BACKGROUND: Anticoagulation is recommended as standard of care for venous thromboembolism (VTE) (pulmonary embolism [PE]/deep vein thrombosis [DVT]), for which unfractionated heparin (UFH) and warfarin are used in Japan. In the multi regional AMPLIFY study, a fixed-dose regimen of apixaban alone was non-inferior to conventional therapy for treatment of PE/DVT and was associated with significantly fewer bleeding events. METHODS AND RESULTS: Japan phase 3 study (AMPLIFY-J), randomized, active-controlled, open-label study in Japanese subjects with acute PE/DVT, was designed based on AMPLIFY. Key objectives were to investigate safety and efficacy of apixaban in symptomatic PE/DVT subjects during 24-week treatment. UFH/warfarin was used as control treatment. Apixaban was initiated at 10 mg twice daily for 7 days, followed by 5 mg twice daily for 23 weeks. All endpoints and imaging for thrombotic burden were assessed by an event adjudication committee. Eighty subjects were randomized, 33 subjects (41.3%) were aged <65 years. Proportion of major/clinically relevant non-major bleeding was lower in apixaban (7.5%) compared with well-controlled UFH/warfarin (28.2%; median TTR, 70.4%). [corrected]. Recurrent VTE occurred in no subjects in apixaban and in 1 subject in UFH/warfarin. Thrombotic burden results were similar in both groups. Proportions of subjects with adverse events was generally similar in both groups. CONCLUSIONS: Apixaban was well-tolerated and had a favorable safety profile. No clinically important efficacy difference compared with UFH/warfarin was observed. PMID- 25912696 TI - Clinical Presentation, Management and Outcome of Japanese Patients With Acute Myocardial Infarction in the Troponin Era - Japanese Registry of Acute Myocardial Infarction Diagnosed by Universal Definition (J-MINUET) - . AB - BACKGROUND: New criteria for diagnosis of acute myocardial infarction (AMI) were proposed in 2000 as a universal definition, in which cardiac troponin (cTn) was the preferred biomarker. A large number of patients formerly classified by creatine kinase (CK) as unstable angina are now ruled-in by cTn as non-ST elevation myocardial infarction (NSTEMI). METHODS AND RESULTS: The Japanese registry of acute Myocardial INfarction diagnosed by Universal dEfiniTion (J MINUET) is a prospective and multicenter registry conducted in 28 institutions. We enrolled 3,283 consecutive patients with AMI diagnosed by cTn-based criteria who were admitted to participating institutions within 48 h of symptom onset. There were 2,262 patients (68.9%) with STEMI and 1,021 (31.1%) with NSTEMI. CK was not elevated more than twice the upper limit of normal in 458 patients (44.9%) with NSTEMI (NSTEMI-CK). Although there was no significant difference in the in-hospital mortality of STEMI and NSTEMI with CK elevation (NSTEMI+CK) patients (7.1% vs. 7.8%, P=0.57), it was significantly lower in patients with NSTEMI-CK than in those with STEMI or NSTEMI+CK (1.7%, P<0.001 for each). CONCLUSIONS: J-MINUET revealed the clinical presentation, management and outcomes of Japanese patients with AMI in the current cTn era. We should be aware of the difference between AMI diagnosed by CK-based criteria and AMI diagnosed by cTn based criteria when using universal definitions for the diagnosis of AMI. PMID- 25912698 TI - Two-dimensional electronic-vibrational spectra: modeling correlated electronic and nuclear motion. AB - We calculate 2D electronic-vibrational (2D-EV) spectra of solvated organic dyes modeled in terms of a reduced set of electronic diabatic states (the essential states) non-adiabatically coupled to molecular vibrations. An effective overdamped coordinate, whose dynamics is described by the Smoluchowski diffusion equation, accounts for polar solvation. Results are discussed for two dyes with distinctively different spectroscopic behavior: 4-(dicyanomethylene)-2-methyl-6 (4-dimethylaminostyryl)-4H-pyran (DCM) and 8-(N,N-dibutylamino)-2-azachrysene (AAC). Linear absorption and fluorescence spectra of DCM are well reproduced based on a minimal two-state model. The same model leads to 2D-EV spectra in good agreement with the recent experimental data reported by Oliver and coworkers for DCM in DMSO. In contrast, linear spectra of AAC show a subtle interplay between a locally-excited (LE) and a charge-transfer (CT) excitation, calling for a three state model. Calculated 2D-EV spectra for AAC show a qualitatively different behavior, demonstrating that the experimental data for DCM do not support a LE/CT interplay. This resolves the long-lasting discussion about the nature of low lying excitations of DCM in favor of the simplest picture. PMID- 25912697 TI - Multicenter, Randomized, Double-Blinded, Placebo-Controlled Phase II Study of Serelaxin in Japanese Patients With Acute Heart Failure. AB - BACKGROUND: Serelaxin, a recombinant form of human relaxin-2, is in development for treating acute heart failure (AHF) and a Phase II study in Japanese AHF patients was conducted. METHODS AND RESULTS: A randomized, double-blind, placebo controlled study of serelaxin at 10 and 30 ug.kg(-1).day(-1)continuous intravenous infusion for up to 48 h, added to standard care for Japanese AHF patients. Primary endpoints were adverse events (AEs) through Day 5, serious AEs (SAEs) through Day 14, and serelaxin pharmacokinetics. Secondary endpoints included changes in systolic blood pressure (SBP) and cardiorenal biomarkers. A total of 46 patients received the study drug and were followed for 60 days. The observed AE profile was comparable between the groups, with no AEs of concern. Dose-dependent increase in the serum concentration of serelaxin was observed across the 2 dose rates of serelaxin. A greater reduction in SBP was observed with serelaxin 30 ug.kg(-1).day(-1)vs. placebo (-7.7 [-16.4, 1.0] mmHg). A greater reduction in NT-proBNP was noted with serelaxin (-50.8% and -54.9% for 10 and 30 ug.kg(-1).day(-1), respectively at Day 2). CONCLUSIONS: Serelaxin was well tolerated in this study with Japanese AHF patients, with no AEs of concern and favorable beneficial trends on efficacy. These findings support further evaluation of serelaxin 30 ug.kg(-1).day(-1)in this patient population. PMID- 25912699 TI - [Prefrontal clinical symptoms in daily living: screening assessment by means of the short Prefrontal Symptoms Inventory (PSI-20)]. AB - INTRODUCTION: Estimation of daily symptoms of frontal dysfunction is considered to be essential in order to endow neuro-psychological assessments with ecological validity. The questionnaires available today were constructed to estimate executive problems in daily life in populations with neurological damage. There is a need for instruments focused on measuring these behaviours in the general population or in clinical populations with mild or moderate impairment. AIM: To examine the factorial validity and to find evidence of concurrent validity of the short version of the Prefrontal Symptoms Inventory. SUBJECTS AND METHODS: Three samples were obtained: the first, from the Internet (n = 504); the second, in a non-clinical population by means of paper and pencil (n = 1,257); and the third, from patients being treated for substance addiction (n = 602). A factorial analysis without restraints was used on the first sample and the results were submitted to confirmatory factorial analysis on the other two samples. RESULTS: The three-factor structure that was found was confirmed with excellent indicators of fit in the other two samples. Evidence of concurrent validity was found with quality of life and mental health tests. CONCLUSIONS: We propose a short questionnaire for detecting failures of a prefrontal origin in daily living, which improves on the psychometric qualities of similar tests, but is oriented towards severe neurological pathologies. The structural stability of the test ensures it can be used in the general population, for the early detection of cognitive impairment, and in clinical populations with mild or moderate deterioration. A set of criteria are proposed for use in interpreting the results. PMID- 25912700 TI - [Status epilepticus in paediatrics: a retrospective study and review of the literature]. AB - INTRODUCTION: Status epilepticus (SE) is the most common neurological emergency on pediatric. Given the possibility of neurological sequelae and mortality associated, it requires an early aggressive treatment. PATIENTS AND METHODS: Retrospective descriptive study based on the review of medical histories of patients admitted to our hospital from 2010 to 2013 with a diagnosis of SE. The objective was to describe the epidemiology characteristics and the management of these patients, and to review the available literature on this topic. RESULTS: We collected 39 patients (25 males) and 51 episodes of SE. Average age: 4.8 years. Twenty-two patients had an underlying disease, 18 were known epileptic and 5 had a previous SE. With a total of 51 SE, 33 were symptomatic, 15 were febrile and 3 were cryptogenic. Types of SE: 25 were partial (16 of them complex) and 26 were generalized. TREATMENT: 47 benzodiazepines as treatment of choice (40 diazepam), 3 phenytoin and 1 valproic acid. Twenty-seven patients required second-line drugs: 16 valproic acid, 8 phenytoin, 2 phenobarbital and 1 levetiracetam. Ten patients required third-line drugs for the induction of barbiturate-induced coma: midazolam was the most used in our center, followed by thiopental and propofol. Two super-refractory SE required immunoglobulins and systemic corticosteroids for appearing on the course of autoimmune encephalitis. CONCLUSIONS: The therapeutic scheme of SE should be considered since the start of any seizure. The treatment is staggered with benzodiazepines in the first stage, broad spectrum antiepileptic drugs, and intravenous availability in the second (valproic acid, levetiracetam in the generalized SE and phenytoin in the focal), while the third level varies depending on the experience of each team. PMID- 25912701 TI - [Traumatic spinal cord injury in children and adolescents in Asturias]. AB - INTRODUCTION: Traumatic spinal cord injury (TSCI) is rare in childhood, but it has serious complications. AIM: To assess incidence, causes and socio-demographic aspects of TSCI among children and adolescents in Asturias. PATIENTS AND METHODS: It was made a census of children among aged 0-17 years codified as 'TSCI with or without vertebral fracture' in Asturias between 1934 and 2013. Socio-demographic, hospital and clinical variables were picked up. RESULTS: In total 72 patients were registered, most of them males (79.2%), with an average age of 16 (range: 5 17). The estimated incidence in 2011 was found to be 7.3/million children/year for children aged 0-17 years. Complete TSCIs (68.1%) and dorsal localization (44.4%) were found to be more common. There was bone injury in 95.8% with two or more vertebras affected in a half of the cases. The main cause was traffic accidents (52.1%) mainly the four wheels vehicles (63.4%), most of them males with an average age of 17 and dorsal localization (46.3%). On second and third place were work-related injuries and sports-related injuries, with the same number of cases. In work related injuries, males were the majority, with dorsal level (77.8%) and the direct blow was the fundamental mechanism. In sports there were males also the dominant, being diving the most important cause, with cervical level. CONCLUSIONS: It is necessary to carry out studies focused on this population group in order to indentify the own characteristics, to establish care and preventive programs, adapted to their necessities. PMID- 25912702 TI - [Arnold-Chiari malformation in Noonan syndrome and other syndromes of the RAS/MAPK pathway]. AB - INTRODUCTION: Noonan syndrome (NS) and other syndromes with a similar phenotype, such as LEOPARD, cardiofaciocutaneous, Costello and Legius, are associated to mutations in genes included in the RAS/MAPK pathway (RASopathies), which is an important signalling pathway related to cell proliferation. Tonsillar descent into the upper cervical spinal canal, known as Arnold-Chiari malformation (ACM), has been reported in patients with NS and this has led some researchers to suggest that ACM could be part of the phenotypic spectrum of NS. We report two cases of NS and ACM. CASE REPORTS: Case 1: 29-year-old female with Noonan phenotype who underwent surgery at the age of nine years due to pulmonary valve stenosis. At the age of 27, she presented symptomatic ACM that required surgical decompression. She presented the c.922A>G (N308D) mutation in the gene PTPN that belongs to the RAS/MAPK pathway. Case 2: a 10-year-old female with Noonan phenotype and asymptomatic ACM detected in magnetic resonance imaging of the brain. She was a carrier of the c.923A>G (N308S) mutation in gene PTPN11. CONCLUSIONS: Six patients with this association have been found in the literature, four with the Noonan phenotype and two with LEOPARD. Our two patients provide supplementary evidence that backs up the hypothesis by which ACM would be part of the phenotypic spectrum of NS. The small number of reported cases of patients with this association does not allow us to draw up recommendations about when and how often neuroimaging studies should be performed; a careful neurological examination, however, should be included in the anticipatory health guidelines in syndromes involving the RAS/MAPK pathway. PMID- 25912703 TI - [Neurotology and cochlear implants]. AB - In this review we analyse cochlear implantation in terms of the fundamental aspects of the functioning of the auditory system. Concepts concerning neuronal plasticity applied to electrical stimulation in perinatal and adult deep hypoacusis are reviewed, and the latest scientific bases that justify early implantation following screening for congenital deafness are discussed. Finally, this review aims to serve as an example of the importance of fostering the sub specialty of neurotology in our milieu, with the aim of bridging some of the gaps between specialties and thus improving both the knowledge in the field of research on auditory pathologies and in the screening of patients. The objectives of this review, targeted above all towards specialists in the field of otorhinolaryngology, are to analyse some significant neurological foundations in order to reach a better understanding of the clinical events that condition the indications and the rehabilitation of patients with cochlear implants, as well as to use this means to foster the growth of the sub-specialty of neurotology. PMID- 25912704 TI - [Neurological appraisal of children and adolescents with psychotic symptoms]. AB - INTRODUCTION: Psychotic manifestations in childhood are not infrequent, yet the existing literature dealing with the neurological appraisal of children and adolescents with a clinical picture of psychosis is very scant. AIM: To conduct a non-systematic review of the literature that provides an answer to these three questions: When must a neurological appraisal be performed in a child with psychotic traits? What medical conditions can include signs and symptoms of psychosis in their development? And, what diagnostic procedure should be followed? DEVELOPMENT: The diseases that can present psychotic symptoms at onset or during their course are reviewed and grouped by pathologies: inborn errors of metabolism, genetic diseases, autoimmune and infectious diseases, malformations of the central nervous system, epilepsy, vascular pathology, rheumatologic processes, brain tumours, and psychoactive substances and drugs. A diagnostic regimen is proposed in which both the information obtained from the anamnesis and examination and the findings from each of the diagnostic tests are evaluated. CONCLUSIONS: A huge number of processes can display psychotic symptoms during their course and the key information offered by the anamnesis and examination must be taken into account. This review can help neuropaediatricians and other specialists perform a more systematised appraisal of children and adolescents with psychotic signs and symptoms. PMID- 25912705 TI - [Atherogenic dyslipidemia and residual risk in patients with ischemic stroke]. PMID- 25912706 TI - [Mobile stroke treatment units]. PMID- 25912707 TI - [On the treatment of epileptic seizures in Spanish emergency services]. PMID- 25912708 TI - [On the treatment of epileptic seizures in Spanish emergency services. Reply]. PMID- 25912709 TI - [Amplatzer(r) Vascular Plug III, for closing residual mitral paravalvular leak: three-dimensional transesophageal echocardiography image]. AB - Paravalvular leak is a significant complication after surgical valve replacement. Traditionally, redo surgery has been considered the treatment of choice, but is associated with high morbidity and mortality as well as increase risk of developing new leaks. Percutaneous treatment of paravalvular leak appears as an attractive alternative. Such treatment has been made possible by the current ability to integrate multiple imaging modalities that have helped to define the anatomy of the defect and planning and guiding the percutaneous closure procedure, thus resulting in better outcomes. The Amplatzer(r) Vascular Plug III (St. Jude Medical) is the first device specifically designed for percutaneous closure of paravalvular leak with promising results. We present the three dimensional transesophageal echocardiographic images of a successful outcome of percutaneous closure of a residual mitral paravalvular leak with an Amplatzer(r) Vascular Plug III device (St. Jude Medical), after an initial procedure of percutaneous closure with an Amplatzer(r) duct occluder (St. Jude Medical). PMID- 25912710 TI - Engineering of Sn-porphyrin networks on the silica surface: sensing of nitrophenols in water. AB - Sn-porphyrin networks were engineered on the surface of a thin layer chromatography (TLC) plate via Sonogashira coupling of the Sn-porphyrin building block and 1,4-diiodobenzene. The Sn-porphyrin film showed a strong Soret band absorption at 422 nm, emission at 600-630 nm, and excellent sensing performance toward nitrophenols in water. PMID- 25912711 TI - From maternal sensitivity in infancy to adult attachment representations: a longitudinal adoption study with secure base scripts. AB - We examined whether differences in adult attachment representations could be predicted from early and later maternal sensitivity, controlling for early and later assessments of attachment. In this longitudinal study on 190 adoptees, attachment at 23 years was measured with the Attachment Script Assessment. Maternal sensitivity was observed in infancy and at seven and 14 years. Attachment was also measured in infancy and at 14 years. Higher maternal sensitivity in infancy predicted more secure attachment in infancy and more secure attachment representations in young adulthood. Higher maternal sensitivity in middle childhood also predicted more secure attachment representations in young adulthood. There was no continuity of attachment from infancy to young adulthood, but attachment in adolescence and young adulthood were significantly related. Even in genetically unrelated families, maternal sensitivity in early and middle childhood predicts attachment representations in young adults, confirming the importance of sensitive parenting for human development. PMID- 25912712 TI - Characteristics and drug utilization patterns for heavy users of prescription drugs among the elderly: a Danish register-based drug utilization study. AB - PURPOSE: The objectives of this study were to (1) identify and characterize heavy users of prescription drugs among persons aged 60 years and above; (2) investigate the association of demographic, socioeconomic, and health-related variables with being a heavy drug user; and (3) study the most frequently used drugs among heavy drug users and development in use over time. METHOD: This is a descriptive study. Heavy drug users were defined as the accumulated top 1 percentile who accounted for the largest share of prescription drug use measured in number of dispensed defined daily doses (DDDs). The nationwide Danish registers were used to obtain data. Multivariable logistic binary regression was used to determine which factors were associated with being a heavy drug user. RESULTS: Heavy drug users among persons aged 60 years and above accounted for 6.8, 6.0, and 5.5% of prescription drug use in 2002, 2007, and 2012, respectively. Male gender, those aged 60-69 years, being divorced, shorter education, low annual income, and recent hospitalization were all significantly associated with being in the top 1 percentile group of drug users (p < 0.05). The ten most frequently used drug classes among heavy drug users accounted for 75.4% of their use in 2012, and five of these were cardiovascular drugs. The development over time for the ten most used drug classes followed the same pattern among heavy drug users and in the general population. CONCLUSION: There is a skewed utilization of prescription drugs. Contrary to earlier findings, being male was associated with heavy prescription drug use both with respect to number of drugs used and drug expenditure. PMID- 25912713 TI - Serological evidence of hantavirus infection in apparently healthy people from rural and slum communities in southern Chile. AB - Hantavirus disease in America has been recognizable because of its rapid progression in clinical cases, occurrence in previously healthy young adults, and high case fatality rate. Hantavirus disease has been proposed now to define the diversity of clinical manifestations. Since 1995, a total of 902 cases of hantavirus pulmonary syndrome have been reported in Chile, caused by Andes virus (ANDV), with overall fatality of 32%. This report describes the sero-epidemiology of hantavirus in apparently healthy people in rural and urban slum communities from southern Chile. Ten of 934 samples yielded a positive result resulting in a seroprevalence of 1.07% (95% confidence intervals: 0.05%-2.0%). A higher proportion of positive samples was found among individuals from rural villages (1.3%) and slums (1.5%) compared with farms (0.5%). Seropositivity was associated with age (p = 0.011), low education level (p = 0.006) and occupations linked to the household (homemaker, retired, or student) (p = 0.016). No evidence of infection was found in 38 sigmodontinae rodents trapped in the peri-domestic environment. Our findings highlight that exposure risk was associated with less documented risk factors, such as women in slum and rural villages, and the occurrence of infection that may have presented as flu-like illness that did not require medical attention or was misdiagnosed. PMID- 25912714 TI - Frequent infection of human cancer xenografts with murine endogenous retroviruses in vivo. AB - Infection of human cancer xenografts in mice with murine leukemia viruses (MLVs) is a long-standing observation, but the likelihood of infection in vivo and its biological consequences are poorly understood. We therefore conducted a prospective study in commonly used xenograft recipient strains. From BALB/c nude mice engrafted with MCF7 human mammary carcinoma cells, we isolated a virus that was virtually identical to Bxv1, a locus encoding replication-competent xenotropic MLV (XMLV). XMLV was detected in 9/17 (53%) independently isolated explants. XMLV was not found in primary leukemias or in THP1 leukemia cells grown in Bxv1-negative NSG (NOD/SCID/gammaCnull) mice, although MCF7 explants harbored replication-defective MLV proviruses. To assess the significance of infection for xenograft behavior in vivo, we examined changes in growth and global transcription in MCF7 and the highly susceptible Raji Burkitt lymphoma cell line chronically infected with XMLV. Raji cells showed a stronger transcriptional response that included up-regulation of chemokines and effectors of innate antiviral immunity. In conclusion, the risk of de novo XMLV infection of xenografts is high in Bxv1 positive mice, while infection can have positive or negative effects on xenograft growth potential with significant consequences for interpretation of many xenograft studies. PMID- 25912716 TI - Genome variability and gene content in chordopoxviruses: dependence on microsatellites. AB - To investigate gene loss in poxviruses belonging to the Chordopoxvirinae subfamily, we assessed the gene content of representative members of the subfamily, and determined whether individual genes present in each genome were intact, truncated, or fragmented. When nonintact genes were identified, the early stop mutations (ESMs) leading to gene truncation or fragmentation were analyzed. Of all the ESMs present in these poxvirus genomes, over 65% co-localized with microsatellites-simple sequence nucleotide repeats. On average, microsatellites comprise 24% of the nucleotide sequence of these poxvirus genomes. These simple repeats have been shown to exhibit high rates of variation, and represent a target for poxvirus protein variation, gene truncation, and reductive evolution. PMID- 25912717 TI - BST2/tetherin inhibition of alphavirus exit. AB - Alphaviruses such as chikungunya virus (CHIKV) and Semliki Forest virus (SFV) are small enveloped RNA viruses that bud from the plasma membrane. Tetherin/BST2 is an interferon-induced host membrane protein that inhibits the release of many enveloped viruses via direct tethering of budded particles to the cell surface. Alphaviruses have highly organized structures and exclude host membrane proteins from the site of budding, suggesting that their release might be insensitive to tetherin inhibition. Here, we demonstrated that exogenously-expressed tetherin efficiently inhibited the release of SFV and CHIKV particles from host cells without affecting virus entry and infection. Alphavirus release was also inhibited by the endogenous levels of tetherin in HeLa cells. While rubella virus (RuV) and dengue virus (DENV) have structural similarities to alphaviruses, tetherin inhibited the release of RuV but not DENV. We found that two recently identified tetherin isoforms differing in length at the N-terminus exhibited distinct capabilities in restricting alphavirus release. SFV exit was efficiently inhibited by the long isoform but not the short isoform of tetherin, while both isoforms inhibited vesicular stomatitis virus exit. Thus, in spite of the organized structure of the virus particle, tetherin specifically blocks alphavirus release and shows an interesting isoform requirement. PMID- 25912715 TI - Baculovirus-mediated gene delivery and RNAi applications. AB - Baculoviruses are widely encountered in nature and a great deal of data is available about their safety and biology. Recently, these versatile, insect specific viruses have demonstrated their usefulness in various biotechnological applications including protein production and gene transfer. Multiple in vitro and in vivo studies exist and support their use as gene delivery vehicles in vertebrate cells. Recently, baculoviruses have also demonstrated high potential in RNAi applications in which several advantages of the virus make it a promising tool for RNA gene transfer with high safety and wide tropism. PMID- 25912719 TI - Glucagon-like peptide 1 protects INS-1E mitochondria against palmitate-mediated beta-cell dysfunction: a proteomic study. AB - Prolonged exposure to palmitate impairs insulin secretion and leads to beta-cell death. Some evidence suggests that palmitate could induce these effects through defects in mitochondrial function. However, the mechanisms of lipotoxicity are not well understood. In particular, little is known about mitochondrial response to induced-palmitate stress and the mechanisms through which glucagon-like peptide-1 (GLP-1) exerts its potential protective effect in beta-cell mitochondrial dysfunction. The aim of this study was to analyze the protein expression profiles of enriched mitochondrial preparations of INS-1E beta-cells treated with palmitate in the presence and in the absence of GLP-1 using gel based and gel-free proteomic approaches. INS1E beta-cells were incubated in the presence of 0.5 mM palmitate for 24 h, in the presence and in the absence of 10 nM GLP-1, and mitochondria were isolated. Co-incubation of palmitate-treated beta cell lines with GLP-1 identified several GLP-1 responsive mitochondrial proteins from different functional classes indicating major changes in ATP production, oxidative stress, apoptosis, lipid and amino acid metabolism. Moreover, an interaction network analysis of proteins and metabolites found to be differentially expressed has been performed to understand the pathways involved in the palmitate and GLP-1 activity at the mitochondrial level. In summary, our results provided a snapshot of mitochondrial proteins and potential pathways affected by palmitate treatment and gave us information on the potential protective role of GLP-1. PMID- 25912718 TI - A phylogeographic investigation of African monkeypox. AB - Monkeypox is a zoonotic disease caused by a virus member of the genus Orthopoxvirus and is endemic to Central and Western African countries. Previous work has identified two geographically disjuct clades of monkeypox virus based on the analysis of a few genomes coupled with epidemiological and clinical analyses; however, environmental and geographic causes of this differentiation have not been explored. Here, we expand previous phylogenetic studies by analyzing a larger set of monkeypox virus genomes originating throughout Sub-Saharan Africa to identify possible biogeographic barriers associated with genetic differentiation; and projected ecological niche models onto environmental conditions at three periods in the past to explore the potential role of climate oscillations in the evolution of the two primary clades. Analyses supported the separation of the Congo Basin and West Africa clades; the Congo Basin clade shows much shorter branches, which likely indicate a more recent diversification of isolates within this clade. The area between the Sanaga and Cross Rivers divides the two clades and the Dahomey Gap seems to have also served as a barrier within the West African clade. Contraction of areas with suitable environments for monkeypox virus during the Last Glacial Maximum, suggests that the Congo Basin clade of monkeypox virus experienced a severe bottleneck and has since expanded its geographic range. PMID- 25912720 TI - The MYB96-HHP module integrates cold and abscisic acid signaling to activate the CBF-COR pathway in Arabidopsis. AB - Various environmental stresses limit plant growth, development, and reproductive success. Plants have therefore evolved sophisticated adaptive responses to deal with environmental challenges. The responses of plants to environmental stresses are mainly mediated by abscisic acid (ABA)-dependent and ABA-independent signaling pathways. While these two pathways have been implicated to play discrete roles in abiotic stress responses, accumulating evidence suggests that they are also intertwined. Here, we report that an R2R3-type MYB transcription factor, MYB96, integrates the ABA and cold signaling pathways. In addition to its role in ABA-mediated drought responses, MYB96 is also induced by cold stress in an ABA-independent manner and subsequently activates freezing tolerance. Notably, MYB96 regulates HEPTAHELICAL PROTEIN (HHP) genes by binding to their promoters. The HHP proteins, in turn, interact with C-REPEAT BINDING FACTOR (CBF) upstream regulators, such as INDUCER OF CBF EXPRESSION 1 (ICE1), ICE2, and CALMODULIN BINDING TRANSCRIPTION ACTIVATOR 3 (CAMTA3). The specific interactive networks of HHPs with the CBF upstream regulators are necessary to facilitate transcriptional activation of the CBF regulon under stressful conditions. Together, the MYB96-HHP module integrates ABA-dependent and ABA-independent signals and activates the CBF pathway, ensuring plant adaptation to a wide range of adverse environmental fluctuations. PMID- 25912721 TI - Nano- and micro-based inhaled drug delivery systems for targeting alveolar macrophages. AB - INTRODUCTION: Macrophages are the most versatile cells in the hematopoietic system and are strategically distributed in tissues to fight pathogens or other foreign particles. In the lung, however, for intracellular infections such as tuberculosis, pneumonia and aspergillosis, bacteria and fungi utilize the alveolar macrophage as a breeding ground. This has become a challenge for the treatment of these infections, as most drugs do not effectively reach the macrophages at therapeutic levels. Alveolar macrophages also play an important role to initiative adaptive immunity toward combating inflammation and cancer in the lung. AREAS COVERED: This review focuses on the development of micro- and nanotechnology-based drug delivery systems to target alveolar macrophages in association with intracellular infections, cancer and lung inflammation. Aspects of nanoparticle and micron-sized particle engineering through exploitation of particles' physicochemical characteristics such as particle size, surface charge and geometry of particles are discussed. In addition, the application of nanocarriers such as liposomes, polymeric nanoparticles and dendrimers are covered with respect to macrophage targeting. EXPERT OPINION: Drug delivery targeted to alveolar macrophages in the lung is becoming a reality thanks to micro- and nanotechnology breakthrough. The literature review shows that regulation of physicochemical parameters of particles could be a recipe to enhance macrophage targeting and uptake. However, there is still a need to identify more target-specific receptors in order to facilitate drug targeting. Besides that, the toxicity of nanocarriers arising from prolonged residence in the lung should be taken into consideration during formulation. PMID- 25912722 TI - Toll-like receptor 2 agonist Pam3CSK4 up-regulates FcepsilonRI receptor expression on monocytes from patients with severe extrinsic atopic dermatitis. AB - BACKGROUND: Both microbial antigens and allergens are important factors that can trigger atopic dermatitis (AD). Monocytes from patients with AD have been found to express increased and sustained levels of high-affinity IgE receptor (FcepsilonRI) and Toll-like receptor 2 (TLR2). We hypothesized that putative interactions exist between TLR2 and FcepsilonRI on monocytes in the pathogenesis of AD. OBJECTIVE: This study aimed to understand whether activation of TLR2 by Pam3CSK4 would influence the expression of FcepsilonRI, and whether mitogen activated protein kinase (MAPK) signalling pathways were involved in such regulation. METHODS: Peripheral blood monocytes from patients with severe extrinsic AD or healthy control patients were treated with the TLR2 agonist Pam3CSK4. The expression of FcepsilonRI, intracellular TNF-alpha and MAPK family members were analysed by real-time quantitative PCR, flow cytometry and western blotting. RESULTS: Monocytes from patients with severe extrinsic AD expressed higher levels of surface FcepsilonRIalpha than were found in monocytes from healthy controls. Stimulation of human monocytes from patients with Pam3CSK4, but not lipopolysaccharide (LPS), resulted in the up-regulation of surface FcepsilonRI expression by inducing p38 phosphorylation. Pretreatment with a specific inhibitor of p38 kinase inhibited the Pam3CSK4-induced up-regulation of FcepsilonRIalpha, suggesting the involvement of the p38 pathway in the regulation of this process. CONCLUSION: Our findings indicated interactions between TLR2 and FcepsilonRI occurred via the activation of p38 in patients with severe extrinsic AD, which might indicate insights into understanding the mechanisms of how bacterial infection can exacerbate the clinical features of AD. PMID- 25912723 TI - Detection of Cucurbit chlorotic yellows virus from Bemisia tabaci captured on sticky traps using reverse transcription loop-mediated isothermal amplification (RT-LAMP) and simple template preparation. AB - Cucurbit chlorotic yellows virus (CCYV) of the genus Crinivirus within the family Closteroviridae is an emerging infectious agent of cucurbits leading to severe disease and significant economic losses. Effective detection and identification methods for this virus are urgently required. In this study, a reverse transcription loop-mediated isothermal amplification (RT-LAMP) assay was developed to detect CCYV from its vector Bemisia tabaci. LAMP primer sets to detect CCYV were evaluated for their sensitivity and specificity, and a primer set designed from the HSP70h gene with corresponding loop primers were selected. The RT-LAMP assay was applied to detect CCYV from viruliferous B. tabaci trapped on sticky traps. A simple extraction procedure using RNAsecureTM was developed for template preparation. CCYV was detected in all of the B. tabaci 0, 1, 7 and 14 days after they were trapped. Although the rise of turbidity was delayed in reactions using RNA from B. tabaci trapped for 7 and 14 days compared with those from 0 and 1 day, the DNA amplification was sufficient to detect CCYV in all of the samples. These findings therefore present a simple template preparation method and an effective RT-LAMP assay, which can be easily and rapidly performed to monitor CCYV-viruliferous B. tabaci in the field. PMID- 25912724 TI - Identification of novel transaminases from a 12-aminododecanoic acid-metabolizing Pseudomonas strain. AB - A Pseudomonas species [Pseudomonas sp. strain amino alkanoate catabolism (AAC)] was identified that has the capacity to use 12-aminododecanoic acid, the constituent building block of homo-nylon-12, as a sole nitrogen source. Growth of Pseudomonas sp. strain AAC could also be supported using a range of additional omega-amino alkanoates. This metabolic function was shown to be most probably dependent upon one or more transaminases (TAs). Fourteen genes encoding putative TAs were identified from the genome of Pseudomonas sp. AAC. Each of the 14 genes was cloned, 11 of which were successfully expressed in Escherichia coli and tested for activity against 12-aminododecanoic acid. In addition, physiological functions were proposed for 9 of the 14 TAs. Of the 14 proteins, activity was demonstrated in 9, and of note, 3 TAs were shown to be able to catalyse the transfer of the omega-amine from 12-aminododecanoic acid to pyruvate. Based on this study, three enzymes have been identified that are promising biocatalysts for the production of nylon and related polymers. PMID- 25912725 TI - Current and future trends in multimodality imaging of coronary artery disease. AB - Nowadays, there is a wide array of imaging studies available for the evaluation of coronary artery disease, each with its particular indications and strengths. Cardiac single photon emission tomography is mostly used to evaluate myocardial perfusion, having experienced recent marked improvements in image acquisition. Cardiac PET has its main utility in perfusion imaging, atherosclerosis and endothelial function evaluation, and viability assessment. Cardiovascular computed tomography has long been used as a reference test for non-invasive evaluation of coronary lesions and anatomic characterization. Cardiovascular magnetic resonance is currently the reference standard for non-invasive ventricular function evaluation and myocardial scarring delineation. These specific strengths have been enhanced with the advent of hybrid equipment, offering a true integration of different imaging modalities into a single, simultaneous and comprehensive study. PMID- 25912726 TI - Response to Croteau & Neufeld Editorial: 'Transition considerations for extended half-life factor products'. PMID- 25912727 TI - Insuring clear declaration of corporate conflicts of interest in all medical journals: the highest priority. PMID- 25912728 TI - Readability evaluation of Internet-based patient education materials related to the anesthesiology field. AB - STUDY OBJECTIVE: The main objective of the current investigation was to assess the readability of Internet-based patient education materials related to the field of anesthesiology. We hypothesized that the majority of patient education materials would not be written according to current recommended readability grade level. SETTING: Online patient education materials describing procedures, risks, and management of anesthesia-related topics were identified using the search engine Google (available at www.google.com) using the terms anesthesia, anesthesiology, anesthesia risks, and anesthesia care. DESIGN: Cross-sectional evaluation. INTERVENTIONS: None. MEASUREMENTS: Assessments of content readability were performed using validated instruments (Flesch-Kincaid Grade Formulae, the Gunning Frequency of Gobbledygook, the New Dale-Chall Test, the Fry graph, and the Flesch Reading Ease score). MAIN RESULTS: Ninety-six Web sites containing Internet patient education materials (IPEMs) were evaluated. The median (interquartile range) readability grade level for all evaluated IPEMs was 13.5 (12.0-14.6). All the evaluated documents were classified at a greater readability level than the current recommended readability grade, P < .001. Readability grades were not significantly different among different IPEM sources. Assessment by the Flesch Reading Ease test classified all but 4 IPEMs as at least fairly difficult to read. CONCLUSIONS: Internet-based patient education materials related to the field of anesthesiology are currently written far above the recommended readability grade level. High complexity of written education materials likely limits access of information to millions of American patients. Redesign of online content of Web sites that provide patient education material regarding anesthesia could be an important step in improving access to information for patients with poor health literacy. PMID- 25912729 TI - Delayed emergence after anesthesia. AB - In most instances, delayed emergence from anesthesia is attributed to residual anesthetic or analgesic medications. However, delayed emergence can be secondary to unusual causes and present diagnostic dilemmas. Data from clinical studies is scarce and most available published material is comprised of case reports. In this review, we summarize and discuss less common and difficult to diagnose reasons for delayed emergence and present cases from our own experience or reference published case reports/case series. The goal is to draw attention to less common reasons for delayed emergence, identify patient populations that are potentially at risk and to help anesthesiologists identifying a possible cause why their patient is slow to wake up. PMID- 25912730 TI - Remifentanil versus fentanyl in total intravenous anesthesia for lumbar spine surgery: a retrospective cohort study. AB - STUDY OBJECTIVE: The aim of this study was to compare the speed of anesthetic recovery and the perioperative analgesic requirements in patients who received total intravenous anesthesia (TIVA) with either remifentanil-propofol or fentanyl propofol for lumbar spine surgery. DESIGN: Retrospective cohort study. SETTING: Operating room, postanesthesia care unit, and general surgical ward. PATIENTS: One hundred six patients (53 in each group) with American Society of Anesthesiologists status I, II, or III who received either remifentanil-propofol TIVA or fentanyl-propofol TIVA for elective lumbar vertebral disc surgery. MEASUREMENTS: Patient demographics, total duration of anesthesia relative to surgical duration, time to emergence from anesthesia after completion of surgery, length of stay in the postanesthesia care unit, and requirements for opioid analgesia, nonopioid analgesia, and antiemetics in the perioperative period. MAIN RESULTS: No differences in anesthesia time, emergence time, or length of stay in the postanesthesia care unit were found between the remifentanil-propofol and fentanyl-propofol groups. Postoperative opioid and nonopioid analgesic use was significantly higher in the remifentanil-propofol group. CONCLUSIONS: Remifentanil and fentanyl are equally efficient with regard to the speed of patient turnover when used as part of TIVA for lumbar disc surgery, but remifentanil use is associated with increased perioperative analgesic requirements. PMID- 25912731 TI - Spiculisporic acid analogues of the marine-derived fungus, Aspergillus candidus strain HDf2, and their antibacterial activity. AB - Two novel antibiotic spiculisporic acid analogues, named as spiculisporic acid F (1) and G (2), and two known compounds, (-)-spiculisporic acid (3) and secospiculisporic acid B (4), were isolated by bioactivity-guided fractionation from the fermentation broth of the sea urchin-derived Aspergillus candidus strain HDf2. Their structures were unambiguously established by comprehensive analysis of 1D and 2D NMR, and high-resolution MS spectra, and by comparison with known compounds. Biological experiments demonstrated that compounds 1 and 2 displayed antibacterial activity against Gram-negative Pseudomonas solanacearum and Gram positive Staphylococcus aureus, but showed no cytotoxicity against SGC-7901 human gastric adenocarcinoma and SPC-A-1 human lung adenocarcinoma tumor cell lines. This is the first critical evidence identifying spiculisporic acid derivatives as a potential bio-control agent for the soil borne pathogen P. solanacearum (E. F. Smith) Smith. These findings provide further insight into the chemical and biological activity diversity of this class of compounds. PMID- 25912732 TI - Novosphingobium tardum sp. nov., isolated from sediment of a freshwater lake. AB - A Gram-negative, non-motive, aerobic and non-spore-forming strain 16-28-2(T) isolated from freshwater sediment of Taihu Lake was characterized by using a polyphasic approach. The optimum growth conditions were found to be as follows: 28 degrees C, pH 6.5 and 0-0.5 % NaCl in YG liquid medium. The major fatty acids were identified to be summed feature 3 (consisting of C16:1 omega7c and/or C16:1 omega6c), summed feature 8 (consisting of C18:1 omega7c and/or C18:1 omega6c), C14:0 2-OH, C17:1 omega6c, C16:0 and C18:1 omega7c 11-methyl (>5 %). Strain 16-28 2(T) was found to contain diphosphatidylglycerol, phosphatidylglycerol, phosphatidylethanolamine, phosphatidylcholine and sphingoglycolipid as the major polar lipids; and ubiquinone 10 (Q-10) as the major respiratory quinone. DNA G+C content of strain 16-28-2(T) was 63.5 mol % (Tm). A phylogenetic study of 16S rRNA gene indicated that strain 16-28-2(T) is a member of the genus Novosphingobium, with the highest 16S rRNA gene sequence similarity of 96.3 % with Novosphingobium lentum MT1(T) and below 96 % with the other Novosphingobium species. On the basis of the phylogenetic, phenotypic analyses and biochemical characterization, we suggest that strain 16-28-2(T) is a novel species in the genus Novosphingobium, for which the name Novosphingobium tardum sp. nov. is proposed. The type strain of N. tardum is 16-28-2(T) (=CGMCC 1.12989(T) =NBRC 110956(T)). PMID- 25912733 TI - Prevention of pertussis through adult vaccination. AB - Pertussis is a vaccine preventable respiratory infection. Young infants are at high risk of developing severe complications from infection. Despite high rates of pediatric vaccine uptake, there continues to be increases in pertussis cases, likely due to waning immunity from childhood vaccine and increased transmission through adults. Currently, pertussis booster vaccine (Tdap) is recommended for unimmunized adults and for women in the third trimester of each pregnancy; yet adult Tdap coverage remains low. Administering Tdap vaccine at non-traditional vaccination clinics and at sites where adults are accessing care for their children are effective in improving adult Tdap uptake. While most are willing to receive vaccine when recommended by their provider, lack of provider recommendation is a major obstacle to immunization. Future studies to understand barriers to provider vaccine recommendations need to be undertaken to develop interventions to improve adult Tdap vaccine uptake and reduce pertussis infection in the susceptible population. PMID- 25912734 TI - TIPE2 protein prevents injury-induced restenosis in mice. AB - Proliferation of vascular smooth muscle cells (VSMCs) plays an important role in restenosis, a disease characterized by smooth muscle cell hyperplasia and neointimal formation. How proliferation signals are controlled to avoid restenosis is not fully understood. Here we report that TIPE2, the tumor necrosis factor (TNF) alpha-induced protein 8-like 2 (TNFAIP8L2), suppresses injury induced restenosis by inhibiting VSMCs proliferation. TIPE2 was significantly upregulated in VSMCs in response to PDGF-BB stimuli and injury. Enforced TIPE2 expression significantly suppressed VSMCs proliferation and cell cycle progression, whereas TIPE2 deficiency in VSMCs promoted cell proliferation and upregulated the expression of Cyclins D1 and D3. TIPE2 likely regulated VSMC proliferation via Rac1-STAT3 and ERK1/2 signaling pathways. It blocked STAT3 activation and nuclear translocation in a Rac1-dependent manner. As a result, TIPE2-deficient VSMCs exhibited enhanced proliferation whereas TIPE2-deficient mice developed more severe restenosis in response to vascular injury. Conversely, adenovirus-mediated gene transfer of TIPE2 significantly reduced injury-induced restenosis in mice. These results indicate that TIPE2 plays a suppressive role in injury-induced restenosis and may serve as a new therapeutic target for treating the disease. PMID- 25912735 TI - EGFR over-expression in non-small cell lung cancers harboring EGFR mutations is associated with marked down-regulation of CD82. AB - Epidermal growth factor receptor (EGFR) gene mutations are strongly associated with lung adenocarcinoma and favorable response to EGFR tyrosine kinase inhibitor. The mutated EGFR proteins (EGFRs) are hyper-phosphorylated and refractory to receptor down-regulation. To address the discrepancy between hyper phosphorylation and lack of down-regulation of mutant EGFRs, we have examined the expression of EGFR negative regulators in non-small cell lung cancer (NSCLC) cell lines. We found that NSCLC cell lines expressing mutant EGFRs often had low expression of various negative regulators for EGFR. Among them, tumor suppressor CD82 was up-regulated by wild type (WT) EGFR but down-regulated by mutant EGFRs. Reconstitution of CD82 exerted stronger suppressive effects on mutant EGFRs than on WT EGFR. Active exportation of CD82 through the exosome was one of the mechanisms involved in achieving the overall CD82 down-regulation in mutant EGFR expressing lung cancer cell lines. Over-expression of mutant EGFR protein frequently occurred in the lung cancer tissues of mutant EGFR-transgenic mice and also associated with CD82 down-regulation. Immunoblot analyses on the tumor tissues from 23 lung adenocarcinoma patients (12 with WT EGFR, and 11 with mutant EGFRs) also identified significantly stronger down-regulation of CD82 in tumors with mutant EGFRs than WT. Our data indicate that CD82 down-regulation could be a critical step involved in the EGFR over-expression and the stronger tumorigenic activity triggered by EGFR mutations. Up-regulation of the CD82 level may become a promising new treatment strategy for lung adenocarcinoma. PMID- 25912736 TI - 17beta-Estradiol enhances the activation of IFN-alpha signaling in B cells by down-regulating the expression of let-7e-5p, miR-98-5p and miR-145a-5p that target IKKepsilon. AB - The activation of IFN-alpha signaling in B cells contributes to the pathogenesis of systemic lupus erythematosus (SLE). Many studies suggest that estrogens are closely related to the gender difference in the prevalence of SLE. However, the underlying mechanism of the interaction between estrogens and the activation of IFN-alpha signaling in SLE B cells remains incompletely understood. In the present study, we first found that healthy female mice showed an up-regulated type I IFN-induced gene signature in B cells compared with age-matched male mice, and an in vivo study revealed that the gender difference was related to 17beta estradiol. Moreover, we found that 17beta-estradiol could enhance the activation of IFN-alpha signaling in an ERalpha-dependent manner by down-regulating the expression of three microRNAs, including let-7e-5p, miR-98-5p and miR-145a-5p. These microRNAs could target the 3'UTR of the IKKepsilon-encoding gene IKBKE directly and regulate the expression of IKKepsilon, which can promote the activation of IFN-alpha signaling. In addition, compared with age-matched male mice, female mice showed a higher level of IKKepsilon and lower levels of let-7e 5p, miR-98-5p and miR-145a-5p in B cells. Moreover, peripheral blood mononuclear cells from women showed a higher level of IKKepsilon and lower levels of let-7e 5p, miR-98-5p and miR-145a-5p compared with those from age-matched men. These data suggest that 17beta-estradiol amplifies the activation of IFN-alpha signaling in B cells via IKKepsilon by down-regulating the expression of let-7e 5p, miR-98-5p and miR-145a-5p. Our findings may provide a new perspective for understanding the mechanism underlying the gender difference in the prevalence of SLE. PMID- 25912737 TI - Sequence-dependent abnormal aggregation of human Tau fragment in an inducible cell model. AB - A pathological hallmark of Alzheimer disease (AD) is the accumulation of misfolded hyperphosphorylated microtubule-associated protein Tau within neurons, forming neurofibrillary tangles and leading to synaptic dysfunction and neuronal death. Here we study sequence-dependent abnormal aggregation of human fragment Tau244-372 in an inducible cell model. As evidenced by confocal laser scanning microscopy, Western blot, and immunogold electron microscopy, fibril-forming motifs are essential and sufficient for abnormal aggregation of Tau244-372 in SH SY5Y neuroblastoma cells induced by Congo red: when its two fibril-forming segments PHF6 and PHF6* are deleted, Tau244-372 does lose its ability to form fibrils in SH-SY5Y cells, and the replacement of PHF6 and PHF6* with an unrelated amyloidogenic sequence IFQINS from human lysozyme does rescue the fibril-forming ability of Tau244-372 in SH-SY5Y cells. By contrast, insertion of a non-fibril forming peptide GGGGGG does not drive the disabled Tau244-372 to misfold in SH SY5Y cells. Furthermore, as revealed by quantum dots based probes combined with annexin V staining, annexin V-FITC apoptosis detection assay, and immunofluorescence, fibril-forming motifs are essential and sufficient for early apoptosis of living SH-SY5Y cells induced by abnormal aggregation of Tau244-372. Our results suggest that fibril-forming motifs could be the determinants of Tau protein tending to misfold in living cells, thereby inducing neuronal apoptosis and causing the initiation and development of AD. PMID- 25912738 TI - A mechanistic model for oxide growth and dissolution during corrosion of Cr containing alloys. AB - We have developed a corrosion model that can predict metal oxide growth and dissolution rates as a function of time for a range of solution conditions. Our model considers electrochemical reactions at the metal/oxide and oxide/solution interfaces, and the metal cation flux from the metal to the solution phase through a growing oxide layer, and formulates the key processes using classical chemical reaction rate or flux equations. The model imposes mass and charge balance and hence, is labeled as the Mass Charge Balance (MCB) model. Mass and charge balance dictate that at any given time the oxidation (or metal cation) flux must be equal to the sum of the oxide growth flux and the dissolution flux. For each redox reaction leading to the formation of a specific oxide, the metal oxidation flux is formulated using a modified Butler-Volmer equation with an oxide-thickness-dependent effective overpotential. The oxide growth and dissolution fluxes have a first-order dependence on the metal cation flux. The rate constant for oxide formation also follows an Arrhenius dependence on the potential drop across the oxide layer and hence decreases exponentially with oxide thickness. This model is able to predict the time-dependent potentiostatic corrosion behaviour of both pure iron, and Co-Cr and Fe-Ni-Cr alloys. PMID- 25912739 TI - Posterior Intercostal Nerve Block With Liposomal Bupivacaine: An Alternative to Thoracic Epidural Analgesia. AB - BACKGROUND: Pain relief using regional neuroaxial blockade is standard care for patients undergoing major thoracic surgery. Thoracic epidural analgesia (TEA) provides effective postoperative analgesia but has unwanted side effects, including hypotension, urinary retention, nausea, and vomiting, and is highly operator dependent. Single-shot intercostal nerve and paravertebral blockade have not been widely used because of the short duration of action of most local anesthetics; however, the recent availability of liposomal bupivacaine (LipoB) offers the potential to provide prolonged blockade of intercostal nerves (72 to 96 hours). We hypothesized that a five-level unilateral posterior intercostal nerve block using LipoB would provide effective analgesia for patients undergoing thoracic surgery. METHODS: We identified patients who underwent lung resection using intraoperative LipoB posterior intercostal nerve blockade and retrospectively compared them with a group of patients who had TEA and who were matched for age, sex, type of surgery, and surgical approach. We analyzed perioperative morbidity, pain scores and narcotic requirements. RESULTS: There were 54 patients in each group. Mean hospital stay was 3.5 days and 4.5 days (p = 0.004) for LipoB group and TEA group, respectively. There were no significant differences in perioperative complications, postoperative pain scores, or in narcotic utilization between LipoB group and TEA group. No acute toxicity related to LipoB was observed. CONCLUSIONS: Posterior intercostal nerve blockade using LipoB is safe and provides effective analgesia for patients undergoing thoracic surgery. It may be considered as a suitable alternative to TEA. PMID- 25912740 TI - Predictors and Outcome of Extracorporeal Life Support After Pediatric Heart Transplantation. AB - BACKGROUND: Extracorporeal life support (ECLS) has proven success after conventional cardiac surgery. Its use after pediatric heart transplantation is less well documented. We reviewed ECLS after pediatric heart transplantation, to understand better predisposing factors, morbidity, and mortality. METHODS: The notes of all patients at Great Ormond Street Hospital undergoing orthotopic heart transplantation from 1999 to 2009 were reviewed (202 transplants; patients aged 0.06 to 17.91 years). Patients were grouped by diagnosis: restrictive cardiomyopathy (n = 17), nonrestrictive cardiomyopathy (n = 134), and anatomic heart disease (n = 51). RESULTS: Twenty-eight patients (13.9%) required ECLS after transplantation. Those requiring ECLS had longer ischemic times (4.2 versus 3.7 hours, p = 0.02). More restrictive cardiomyopathy patients (35.3%) required ECLS-higher than dilated cardiomyopathy (10.4%) or anatomic heart disease (15.7%; chi(2) 7.99; p = 0.018). Factors associated with posttransplant ECLS were restrictive cardiomyopathy, longer ischemic time, and extracorporeal membrane oxygenation before transplant. Graft survival was higher in the non-ECLS group, with 1-year survival of 98.2% versus 57.7%; however, medium-term survival was comparable, with 5-year survival for those surviving to hospital discharge being 84.7% versus 100%. CONCLUSIONS: The requirement for ECLS was higher than expected for conventional cardiac surgery. Although just over one half of patients requiring ECLS survived to discharge, they had excellent medium-term survival, with all still alive. Although ECLS is an expensive, invasive therapy, with significant morbidity and mortality, without it, those patients would have perished. Its judicious use, therefore, can be recommended. PMID- 25912741 TI - One Hundred Transports on Extracorporeal Support to an Extracorporeal Membrane Oxygenation Center. AB - BACKGROUND: Extracorporeal life support technology has gained acceptance as a salvage mode for patients in respiratory or cardiac failure. Patients who are sick enough to require extracorporeal membrane oxygenation (ECMO) support are often too unstable for transfer to a hospital with ECMO capabilities. We highlight the progressive development of an ECMO transport team and the manner in which it provides reliable transport with excellent outcomes. METHODS: All data were collected retrospectively from our hospital's electronic medical record. Patient outcomes are reported through April 2, 2014. RESULTS: Our institution began an ECMO transport program in 2008, with the initial phase involving transport of highly selected patients for short distances. With experience we refined our intake and evaluation process. We also consolidated care for ECMO patients into two intensive care units and developed a dedicated ECMO intensivist position. As the program has matured, patient selection has become more inclusive and we have extended our capabilities to include interstate and international transport. All 100 patients were successfully placed on ECMO and transported to our center. Seventy-nine patients were placed on venovenous ECMO, 19 on venoarterial ECMO, and 2 on venovenous arterial ECMO. The median transport distance was 16 miles and ranged from 2.5 to 7,084 miles. CONCLUSIONS: Extracorporeal membrane oxygenation transport can be performed safely and reliably with excellent outcomes with a dedicated team that maintains stringent adherence to well-designed management protocols. PMID- 25912742 TI - Preoperative Aspirin Use and Its Effect on Adverse Events in Patients Undergoing Cardiac Operations. AB - BACKGROUND: Preoperative aspirin use within 5 days of cardiac operations is controversial. Aspirin could reduce cardiovascular complications and yet might increase risk of bleeding. Recent reports showed conflicting results, and whether aspirin has variable effects for different cardiac surgical procedures is unclear. METHODS: A single-center retrospective cohort analysis was performed. After propensity score matching (PSM) for identified confounders, the relationship between preoperative aspirin use and 30-day all-cause mortality, postoperative renal failure, major adverse cardiocerebral events (MACE), blood transfusion, reoperation for bleeding, and postoperative infection were estimated with separate logistic regression models. RESULTS: Preoperative aspirin therapy was associated with a 49% (p = 0.04) increased risk of reoperation for bleeding among 868 matched pairs of patients undergoing valve operations. Among 725 matched patients undergoing coronary artery bypass grafting (CABG), preoperative aspirin therapy was not associated with a statistically significant higher risk of reoperation for bleeding. However, preoperative aspirin use, compared with nonuse, was not associated with risks of MACE, 30-day mortality, postoperative renal failure, blood transfusion, or postoperative infection in the entire cohort, in patients undergoing valve operations only, and in patients undergoing CABG only after PSM. CONCLUSIONS: Preoperative aspirin use in all patients undergoing cardiac operations was not associated with risks of major cardiac, cerebral, or renal complications and infections and death; however, the risk of reoperation for bleeding was elevated among preoperative aspirin users compared with nonusers in a subpopulation of patients undergoing valve operations only. PMID- 25912743 TI - Evolution in the Management of Aberrant Subclavian Arteries and Related Kommerell Diverticulum. AB - BACKGROUND: Various options have been described to treat aberrant subclavian arteries and associated Kommerell diverticulum. We describe our experience with the management of this entity over a 15-year period. METHODS: Twenty-two patients underwent repair of aberrant subclavian arteries and associated Kommerell diverticulum. Indications for intervention included a large Kommerell diverticulum (n = 18), dysphagia lusoria (n = 12), rupture (n = 4), type B aortic dissection (n = 4), thoracic aortic aneurysm (n = 2), and coarctation (n = 1). Patients were treated with either open surgery (n = 9) or an endovascular approach (n = 13). For the open surgical patients, hypothermic circulatory arrest (n = 7) or left heart bypass (n = 2) was used. For those patients undergoing an endovascular approach (n = 13), carotid to subclavian arterial bypasses were performed preoperatively in 11 patients and intraoperatively in 2 patients. Bilateral revascularization was more frequently performed with endovascular repair compared with open surgery (69% vs 22%, p = 0.01). RESULTS: Early outcomes included in-hospital mortality (n = 1), stroke (n = 1), and permanent spinal cord ischemia (n = 1) after endovascular approaches, and renal failure requiring dialysis (n = 1) and need for tracheostomy (n = 1) after open repair. The frequency of endovascular repair increased after the commercialization of thoracic endovascular aortic repair in 2005 from 33% to 63%. Four patients developed type I (n = 1) or type II (n = 3) endoleaks, of which 1 required reintervention. Median hospital stay was 7 days (interquartile range 4 to 17). Five-year survival was 81.8%. No late aortic ruptures occurred and 3 patients required late reintervention; 1 after an open and 2 after an endovascular approach. Dysphagia lusoria was relieved in all patients except for 1 in the open repair and 1 in the endovascular group. CONCLUSIONS: Aberrant subclavian arteries and associated Kommerell diverticulum can be treated with acceptable rates of mortality and morbidity. The evolution toward an endovascular approach did not appear to affect late outcomes, suggesting that the choice of treatment should be based on patient-specific anatomy and associated comorbidities. PMID- 25912744 TI - Clinical Outcome Score Predicts Adverse Neurodevelopmental Outcome After Infant Heart Surgery. AB - BACKGROUND: The purpose of this study was to determine whether a clinical outcome score derived from early postoperative events is associated with Bayley-III scores at 18 to 24 months among infants undergoing cardiopulmonary bypass surgery. METHODS: Included were infants aged 6 weeks or less who underwent surgery between 2005 and 2009, all of whom were referred for neurodevelopmental evaluation at 18 to 24 months. We excluded children with chromosomal abnormalities. The prespecified clinical outcome score had a range of 0 to 7. Lower scores indicated a more rapid postoperative recovery. Patients requiring extracorporeal life support were assigned a score of 7. RESULTS: One hundred and ninety-nine subjects were included. Surgical procedures were arterial switch (72), Norwood (60), repair of total anomalous pulmonary venous connection (29), and other (38). Nine subjects had postoperative extracorporeal life support. Mean clinical outcome score in the Norwood group was 4.0 +/- 1.4 versus the arterial switch group (2.6 +/- 1.5, p < 0.001), total anomalous pulmonary venous connection group (2.8 +/- 1.8, p < 0.01), and other group (4.0 +/- 1.8, p = not significant). Among children who had a clinical outcome score of 4 or greater, there was a decrease in Bayley-III cognitive score of 5.7 (95% confidence interval: 1.5 to 9.9, p = 0.009), a decrease in language score of 10.0 (95% confidence interval: 4.9 to 15.1, p < 0.001), and a decrease in motor score of 9.7 (95% confidence interval: 4.8 to 14.5, p < 0.001). Time until lactate of 2.0 mmol/L or less and highest 24-hour inotrope score increased with increasing clinical outcome score (p < 0.0001). CONCLUSIONS: Clinical outcome scores of 4 or greater were associated with significantly lower Bayley-III scores at 18 to 24 months. This score may be valuable as an endpoint when evaluating novel potential therapies for this high-risk population. PMID- 25912745 TI - Results of Neoadjuvant Chemoradiotherapy With Docetaxel and 5-Fluorouracil Followed by Esophagectomy to Treat Locally Advanced Esophageal Cancer. AB - BACKGROUND: Esophageal cancer is most frequently treated with platinum-based chemoradiotherapy (CRT). We previously described a phase I study of definitive CRT with docetaxel (DOC) and 5-fluorouracil (5FU) in patients with advanced esophageal cancer. This regimen had low toxicity and was effective without platinating agents. The present study aims to determine the antitumor effects of neoadjuvant CRT with DOC and 5FU and surgical outcomes. METHODS: We reviewed data from 38 patients with locally advanced cancer of the esophagus or esophagogastric junction who underwent trimodality therapy comprising neoadjuvant CRT with DOC and 5FU followed by esophagectomy between 2003 and 2008. RESULTS: Esophagitis was the most common toxicity associated with neoadjuvant CRT (grade 3; 26.3%), and hematologic toxicity was mild. Transthoracic esophagectomy and pharyngolaryngoesophagectomy proceeded in 36 (94.7%) and 2 (5.3%) patients, respectively, and 35 (92.1%) underwent R0 resection. Five (13.2%) patients had complete pathologic responses (pCR) of the primary tumor, and 23 (60.5%) had pathologic reductions of over two-thirds of the primary tumor. The T or N status was also down-staged in 26 (68.4%) patients. Overall postoperative morbidity developed in 21 (55.3%) patients, and mortality due to postoperative morbidity was zero. The 5-year recurrence-free and overall survival rates were 39.5% and 44.7%, respectively. CONCLUSIONS: The rates of neoadjuvant CRT toxicity and postoperative complications were acceptable, and the complete resection rate and survival data were favorable. This regimen is promising as neoadjuvant CRT for esophageal cancer and very useful as an alternative regimen for treating patients with esophageal cancer who cannot tolerate cisplatin. PMID- 25912746 TI - Intrapleural Photodynamic Therapy for Mesothelioma: What Place and Which Future? AB - In the surgical multimodal management of malignant pleural mesothelioma, it seems crucial to proceed with an efficient local adjuvant treatment to kill residual tumor cells. Intrapleural photodynamic therapy has recently emerged as a potential candidate in this goal. In this review, we analyzed and classified 16 articles in which patients with malignant pleural mesothelioma received intrapleural photodynamic therapy after maximal surgical resection. The toxicity, effect on survival, and development of the technique were assessed. After two decades of clinical studies, intrapleural photodynamic therapy after surgical resection became a safe treatment that significantly improved the survival of patients. PMID- 25912747 TI - Agreement of Mediastinal Lymph Node Size Between Computed Tomography and Endobronchial Ultrasonography: A Study of 617 Patients. AB - BACKGROUND: Endobronchial ultrasound (EBUS) is the preferred minimally invasive technique for the evaluation of intrathoracic lymphadenopathy. Enlarged lymph nodes on computed tomography (CT) are defined as those 1 cm or larger in short axis diameter. Whether there is agreement between the measurements of lymph node size on CT and EBUS remains unknown. METHODS: This was a retrospective analysis of prospectively collected data from patients who underwent EBUS-guided transbronchial needle aspiration (TBNA) for intrathoracic lymphadenopathy. The diameters of lymph nodes were measured in an axis perpendicular to the airway on both CT and EBUS. The correlation and agreement between the two measurements were analyzed. RESULTS: During the study period, 617 patients (mean age, 46.0 years [standard deviation, 15.2]), of whom 239 (38.7%) were women, underwent EBUS. A total of 1,153 lymph nodes were measured by CT and EBUS. Although there was a moderate correlation between the two modalities for lymph node size (Pearson correlation coefficient = 0.49, p < 0.001), the limits of agreement between CT and EBUS were wide (mean bias, 0.1; limits of agreement, -15.6 to 15.9 mm). The limits of agreement were wide for all categories of lymph nodes (benign vs malignant, distinct vs indistinct margin, and <=2-cm vs >2-cm nodes). CONCLUSIONS: Despite a significant correlation between CT of the chest and EBUS for measuring the size of intrathoracic lymph nodes, the limits of agreement were fairly wide enough to be clinically acceptable for allowing the use of the two modalities interchangeably for this purpose. PMID- 25912748 TI - Role for Surgical Resection in the Multidisciplinary Treatment of Stage IIIB Non Small Cell Lung Cancer. AB - BACKGROUND: The role of multimodality therapy in stage IIIB non-small cell lung cancer (NSCLC) remains inadequately studied. Although chemoradiation is currently the mainstay of treatment, randomized trials evaluating surgical intervention are lacking, and resection is offered selectively. METHODS: Data from patients with clinical stage IIIB NSCLC (T4N2 or any N3) undergoing definitive multimodality therapy were obtained from the National Cancer Database (NCDB). Multivariable Cox regression models were fitted to evaluate variables influencing overall survival (OS). RESULTS: From 1998 to 2010, 7,459 patients with clinical stage IIIB NSCLC were treated with definitive chemoradiation (CR group), whereas 1,714 patients underwent chemotherapy, radiation, and surgical intervention in any sequence (CRS group). CRS patients were more likely to be younger and white and have slightly smaller tumors (all p < 0.01). There was no difference in Charlson Comorbidity Index (CCI) between the groups (p = 0.5). In the CRS group, 79% of patients received neoadjuvant therapy. Thirty-day surgical mortality was 3%. Factors associated with improved OS in multivariate analysis included younger age, female sex, decreased CCI, smaller tumor size, and surgical resection (hazard ratio [HR], 0.57; 95% confidence interval [CI], 0.52-0.63). Among patients treated with surgical intervention, incomplete resection was associated with decreased OS (HR, 1.52; 95% CI, 1.20-1.92). Median OS was longer in the CRS group (25.9 months versus 16.3 months; p < 0.001). Propensity matched analysis on 631 patient pairs treated with CRS versus CR confirmed these findings (median OS, 28.9 versus 17.2 months; p < 0.001). CONCLUSIONS: Surgical resection as a part of multimodality therapy may be associated with improved OS in highly selected patients with stage IIIB NSCLC. Multidisciplinary evaluation of these patients is critical. PMID- 25912749 TI - Contemporary Outcomes of Surgical Repair of Total Anomalous Pulmonary Venous Connection in Patients With Heterotaxy Syndrome. AB - BACKGROUND: Total anomalous pulmonary venous connection (TAPVC) is prevalent in patients with atriovisceral heterotaxy. Although functionally univentricular heart defects are common in heterotaxy syndromes, the extent to which this association influences overall risk for TAPVC repair is undefined. This study examines multiinstitutional experience with TAPVC repair in infants with heterotaxy using a national clinical registry. METHODS: The Society of Thoracic Surgeons Congenital Heart Surgery Database (STS-CHSD) (2002-2012) was queried for patients with heterotaxy syndrome who underwent TAPVC repair, with or without concomitant procedures at age of 90 days or younger. The cohort was divided into single ventricle (SV) and non-single ventricle (non-SV) groups based on STS-CHSD codes. Patient characteristics and in-hospital outcomes were described. RESULTS: Sixty-five centers reported 261 TAPVC repair operations (females, 115 [44%]; median [interquartile range] age and weight, 7 days [3-19 days] and 3.1 kg [2.7 3.5 kg]). Overall, 180 (69%) patients were identified with asplenia or right atrial isomerism, and 167 (64%) had SV diagnoses. Discharge mortality was 38%. Postoperatively, the median length of stay was 18 days (7-32 days), 20 (8%) patients required extracorporeal membrane oxygenation support, and 11 (4%) had reoperation for pulmonary vein stenosis. Mortality was higher for patients with SV defects (SV, 43% versus non-SV, 30%; p = 0.03). Length of stay, postoperative extracorporeal membrane oxygenation, and reoperation for pulmonary vein stenosis was similar between SV and non-SV groups. Overall, there was no difference in mortality for patients undergoing concomitant systemic-to-pulmonary artery shunt (p = 0.134) or surgery within 48 hours of birth (p = 0.876). CONCLUSIONS: Total anomalous pulmonary venous connection repair in heterotaxy patients carries a high mortality risk, particularly with functionally univentricular physiology. These multiinstitutional data serve as an important benchmark and may be useful for risk stratification and counseling. PMID- 25912750 TI - Midterm Follow-Up After Biventricular Repair of the Hypoplastic Left Heart Complex. AB - BACKGROUND: In neonates with hypoplastic left heart complex (HLHC), biventricular repair is considered superior to univentricular repair. The Z-scores of the mitral and the aortic valve annulus are primary factors for the choice of repair. Predictive cutoff values for the feasibility and optimal outcome of biventricular repair are unknown. This study assesses the growth of left side heart structures and the midterm outcome after biventricular repair with an interatrial fenestration in our HLHC population. METHODS: Retrospective study of 19 HLHC patients who underwent biventricular repair in a single tertiary referral center between 2004 and 2013. The cardiac dimensions (mitral and aortic valve annulus, left ventricle inlet length, left ventricular internal diastolic dimension) were measured before and at 6, 12, 24, and 48 months after biventricular repair. RESULTS: The follow-up ranged from 2 to 98 months. There was no early mortality, and the midterm survival rate was 95%. One patient died of a noncardiac- and nonintervention-related cause. Seven patients (37%) required a total of 8 reinterventions because of recurring or residual obstructive lesions. After biventricular repair, the left cardiac structures grew significantly. CONCLUSIONS: Neonatal biventricular repair is successful and safe in HLHC patients, even with preoperative mitral and aortic valve annulus Z-scores of -4.5 and -5.5, respectively. Residual or restenosis required reintervention in 37% of our HLHC population, but was not significantly correlated with the magnitude of the preoperative Z-scores. Within the first 6 months of follow-up, the Z-scores almost normalized. PMID- 25912751 TI - Initial phase of adaptation of Memory Alteration Test (M@T) in a Portuguese sample. AB - OBJECTIVE: The Memory Alteration Test is a screening test able to discriminate the amnestic mild cognitive impairment (A-MCI) and mild Alzheimer disease from subjective memory complain group (SMC-G). The aim of this study was to analyze the European Portuguese experimental version of the Memory Alteration Test (M@T PT). METHODS: Were described the successive stages of the translation and adaptation procedure used to develop the M@T-PT. The psychometric properties were explored using principal component analysis (PCA) with varimax rotation, internal consistence, convergent validity and receiver operating characteristics (ROC) curves. Chi-squared, ANOVAs and Pearson's correlation were also analyzed. A total of 330 people with an age greater or equal to 54 years old participated. According to their cognitive state they were classified as normal controls (n=28), SMC-G (n=81) or A-MCI (n=221). RESULTS: The PCA for the M@T-PT indicated that the total variance explained by three components was 48.07%. A high internal consistent was obtained (alpha=0.93). Convergent validity was verified using M@T PT and Mini-Mental State Examination (r=0.83, p<0.001) and Montreal Cognitive Assessment (r=0.86, p<0.001). An optimal cut-off point was 32 points with sensitivity of 97%, specificity of 71% to differentiate SMC-G from A-MCI. CONCLUSIONS: M@T-PT is an easily applicable screening test with discriminants validity and is a psychometrically sound instrument for use in older people in Portugal. PMID- 25912752 TI - A phase IIb multicentre study comparing the efficacy of trabectedin to doxorubicin in patients with advanced or metastatic untreated soft tissue sarcoma: the TRUSTS trial. AB - PURPOSE: To evaluate whether trabectedin as first-line chemotherapy for advanced/metastatic soft tissue sarcoma prolongs progression-free survival (PFS), compared to doxorubicin and, in the phase IIb part here, to select the most appropriate trabectedin treatment schedule (3-hour or 24-hour infusion) in terms of safety, convenience and efficacy. PATIENTS AND METHODS: In this randomised multicentre prospective dose-selection phase IIb superiority trial, 133 patients were randomised between doxorubicin (n=43), trabectedin (3-hour infusion, T3h) (n=47) and trabectedin (24-hour infusion, T24h) (n=43). PFS was defined as time from random assignment until objective progression by response evaluation criteria in solid tumours (RECIST 1.1), a global deterioration of the health status requiring discontinuation of the treatment, or death from any cause. RESULTS: The study was terminated due to lack of superiority in both trabectedin treatment arms as compared to the doxorubicin control arm. Median PFS was 2.8months in the T3h arm, 3.1months in the T24h arm and 5.5months in the doxorubicin arm. No significant improvements in PFS were observed in the trabectedin arms as compared to the doxorubicin arm (T24h versus doxorubicin: hazard ratio (HR) 1.13, 95% confidence interval (CI) 0.67-1.90, P=.675; T3h versus doxorubicin: HR 1.50, 95% CI 0.91-2.48, P=.944). Only one toxic death occurred in the T3h arm, but treatment had to be stopped due to toxicity in 7 (15.2%) (T3h), 8 (19.5%) (T24h) and 1 (2.5%) doxorubicin patients. CONCLUSION: Doxorubicin continues to be the standard treatment in eligible patients with advanced/metastatic soft-tissue sarcoma (STS). Trabectedin 1.5mg/m(2)/24-hour infusion is the overall proven approach to delivering this agent in the second line setting for patients with advanced or metastatic STS. PMID- 25912753 TI - Influence of clinical and pathologic features on the pathologist's diagnosis of mycosis fungoides: a pilot study. AB - Although clinicopathologic correlation is critical in the diagnosis of early mycosis fungoides (MF), how clinical information directly affects the pathologist's interpretation is unknown. This pilot study aimed to assess the influence of provided clinical information and specific histopathologic features on the histopathologic diagnosis of MF vs. its inflammatory simulants. A computerized survey recorded diagnostic impressions by 24 dermatopathologists of 30 hematoxylin-eosin stained images, including 15 MF images and 15 dermatitis images. Images were accompanied by concordant clinical descriptions (33%), no clinical information (33%) or discordant clinical descriptions (33%). Percentage of correctly classified MF histopathologic images for the three scenarios of concordant clinical information, no clinical information or discordant clinical information were 32% (kappa 0.19), 56% (kappa 0.12) and 16% (kappa 0.33), respectively. The percentage of correctly classified slides presented with no clinical information was different from the other two groups (p < 0.0001). Pautrier collections were most associated with correct classification. Clinical information may play a significant role in the histopathologic diagnosis of MF, although there may be some value in initial blinded histopathologic interpretation. Specific histopathologic features differ in relative importance in the diagnosis of MF. PMID- 25912754 TI - Apc-driven colon carcinogenesis in Pirc rat is strongly reduced by polyethylene glycol. AB - Polyethylene glycol (PEG) is one of the most powerful agents in reducing chemically induced carcinogenesis in rat colon. However, contrasting results in Min mice dampened the enthusiasm on this potentially strong and virtually safe, cancer chemopreventing agent. Pirc (F344/NTac-Apc (am1137) ) rats carrying a germline heterozygous mutation in the Apc gene, spontaneously develop multiple tumours in the colon thus modelling both familial adenomatous polyposis (FAP) and sporadic colorectal cancer (CRC). Given this similarity, we thought that these rats could be appropriate to test the efficacy of PEG 8000 in reducing carcinogenesis. Pirc male rats aged one month were treated with 5% PEG in drinking water for 2 or 6 months. Precancerous lesions were dramatically reduced after 2 months of PEG treatment (Mucin depleted foci (MDF)/colon were 99 +/- 17 and 12 +/- 8 in Controls and PEG-treated rats, respectively; p < 0.001; mean +/- SD). Similarly, colon tumors were significantly reduced after 6 months of treatment (tumors/rat were 8.1 +/- 2.3 and 3.6 +/- 2.2 in Controls and PEG treated rats, respectively; p < 0.05; mean +/- SD). Colon proliferation, a parameter correlated to cancer risk, was also significantly lower in PEG-treated rats than in Controls, while apoptosis was not significantly affected. In conclusion, PEG markedly reduces colon carcinogenesis in Pirc rats mutated in Apc; we thus suggest that PEG may be used as chemopreventive agent to reduce cancer risk in FAP and CRC patients. PMID- 25912755 TI - Pseudocarcinomatous hyperplasia associated with primary lymphoma in the urinary bladder: a case report. AB - A case of pseudocarcinomatous hyperplasia of the urothelium associated with primary extranodal marginal-type lymphoma of the urinary bladder in an 81-year old man is described. To the best of our knowledge, this is the first report in the literature of a primary lymphoma of the bladder associated with pseudocarcinomatous hyperplasia of the urothelium, closely mimicking the nested variant of urothelial carcinoma. The lesion enters in the differential diagnosis with a collision tumor, which has been described rarely in the bladder. PMID- 25912756 TI - Unusual clear cell, lymphoplasmacyte-rich, dural-based tumor with divergent differentiation: a tricky case mimicking a meningioma. AB - We describe an unusual case of a recurrent dural neoplasm, previously diagnosed as meningioma. Histopathologically, the tumor is characterized by aggregates of divergently differentiated clear cells embedded in an abundant lymphoplasmacyte rich stroma, mimicking a lymphoplasmacyte-rich meningioma. This study focuses on the histologic and immunohistochemical characterization of a unique dural-based tumor and provides useful guidelines for differentiating meningioma from other uncommon dural-based neoplasms. We propose that this recurrent dural neoplasm is a distinctive entity and, therefore, enlarges the spectrum of dural-based neoplasms that enter the differential diagnosis with meningiomas. Awareness of this tumor entity could prove useful for appropriate patient management. PMID- 25912757 TI - Protease-activated receptor 2 modulates proliferation and invasion of oral squamous cell carcinoma cells. AB - Based on our previous finding that protease-activated receptor 2 (PAR-2) regulates hemophagocytosis of oral squamous cell carcinoma (SCC) cells, which induces their heme oxygenase 1-dependent keratinization, we have formulated a hypothesis that PAR-2 functions in wider activities of SCC cells. To confirm this hypothesis, we investigated immunohistochemical profiles of PAR-2 in oral SCC tissues and its functional roles in cell proliferation and invasion in SCC cells in culture. The PAR-2 expression modes were determined in 48 surgical tissue specimens of oral SCC. Using oral SCC-derived cell systems, we determined both gene and protein expression levels of PAR-2. SCC cell proliferation and invasive properties were also examined in conditions in which PAR-2 was activated by the synthetic peptide SLIGRL. PAR-2 was immunolocalized in oral SCC and carcinoma in situ cells, especially in those on the periphery of carcinoma cell foci (100% of cases), but not in normal oral epithelia. Its expression at both gene and protein levels was confirmed in 3 oral SCC cell lines including ZK-1. Activation of PAR-2 induced ZK-1 cell proliferation in a dose-dependent manner. PAR-2-activated ZK-1 cells invaded faster than nonactivated ones. The expression of PAR-2 is specific to oral malignancies, and PAR-2 regulates the growth and invasion of oral SCC cells. PMID- 25912758 TI - The significance of Pax2 expression in the ureter epithelium of children with vesicoureteric reflux. AB - Vesicoureteral reflux (VUR) is the retrograde passage of urine from the bladder to the urinary tract; this leads to renal scarring and end-stage renal disease in children. Pax2 is a nuclear transcription factor that is involved in urinary system development. We measured the expression of Pax2 in the ureters of 47 patients with VUR. The messenger RNA expression and the protein level of Pax2 were significantly increased in patients with VUR, suggesting a correlation with VUR. Further studies demonstrated that Pax2 was hypomethylated, and Dnmt3a messenger RNA expression was significantly lower than in the control group. We speculate that the low level of Dnmt2a might decrease PAX2 gene methylation and up-regulate the Pax2 protein. The high level of Pax2 might be related to cellular apoptosis and functional lesions in ureters. In conclusion, our results revealed that the level of Pax2 is correlated with VUR; thus, Pax2 represents a possible target for VUR therapy. PMID- 25912759 TI - A Rare Complication Developing After Hematopoietic Stem Cell Transplantation: Wernicke's Encephalopathy. AB - Thiamine is a water-soluble vitamin. Thiamine deficiency can present as a central nervous system disorder known as Wernicke's encephalopathy, which classically manifests as confusion, ataxia, and ophthalmoplegia. Wernicke's encephalopathy has rarely been reported following hematopoietic stem cell transplantation. Herein, we report Wernicke's encephalopathy in a patient with acute myeloid leukemia who had been receiving prolonged total parenteral nutrition after haploidentical allogeneic hematopoietic stem cell transplantation. To the best of our knowledge, this is the first case reported from Turkey in the literature. PMID- 25912760 TI - Clinical impact of gait training enhanced with visual kinematic biofeedback: Patients with Parkinson's disease and patients stable post stroke. AB - As the world's population ages, falls, physical inactivity, decreased attention and impairments in balance and gait arise as a consequence of decreased sensation, weakness, trauma and degenerative disease. Progressive balance and gait training can facilitate postural righting, safe ambulation and community participation. This small randomized clinical trial evaluated if visual and kinematic feedback provided during supervised gait training would interfere or enhance mobility, endurance, balance, strength and flexibility in older individuals greater than one year post stroke (Gobbi et al., 2009) or Parkinson's disease (PD) (Gobbi et al., 2009). Twenty-four individuals consented to participate. The participants were stratified by diagnosis and randomly assigned to a control (usual gait training (Gobbi et al., 2009)) or an experimental group (usual gait training plus kinematic feedback (Gobbi et al., 2009)). At baseline and 6 weeks post training (18 h), subjects completed standardized tests (mobility, balance, strength, range of motion). Gains were described across all subjects, by treatment group and by diagnosis. Then they were compared for significance using nonparametric statistics. Twenty-three subjects completed the study with no adverse events. Across all subjects, by diagnosis (stroke and PD) and by training group (control and experimental), there were significant gains in mobility (gait speed, step length, endurance, and quality), balance (Berg Balance), range of motion and strength. There were no significant differences in the gain scores between the control and experimental groups. Subjects chronic post stroke made greater strength gains on the affected side than subjects with PD but otherwise there were no significant differences. In summary, during supervised gait training, dynamic visual kinematic feedback from wireless pressure and motion sensors had similar, positive effects as verbal, therapist feedback. A wireless kinematic feedback system could be used at home, to provide feedback and motivation for self correction of gait while simultaneously providing data to the therapist (at a distance). PMID- 25912761 TI - I find you more attractive ... after (prefrontal cortex) stimulation. AB - Facial attractiveness seems to be perceived immediately. Neuroimaging evidence suggests that the appraisal of facial attractiveness is mediated by a network of cortical and subcortical regions, mainly encompassing the reward circuit, but also including prefrontal cortices. The prefrontal cortex is involved in high level processes, so how does its activity relate to beauty appreciation? To shed light on this, we asked male and female participants to evaluate the attractiveness of faces of the same and other sex prior and after transcranial direct current stimulation (tDCS) over the dorsolateral prefrontal cortex (DLPFC). We found that increasing excitability via anodal tDCS in the right but not in the left DLPFC increased perceived attractiveness of the faces, irrespective of the sex of the faces or the sex of the viewers. Identical stimulation over the same site did not affect estimation of other facial characteristics, such as age, thereby suggesting that the effects of anodal tDCS over the right DLPFC might be selective for facial attractiveness, and might not generalize to decisions concerning other facial attributes. Overall, our data suggest that the right DLPFC plays a causal role in explicit judgment of facial attractiveness. The mechanisms mediating such effect are discussed. PMID- 25912762 TI - Restoring abnormal aftereffects of prismatic adaptation through neuromodulation. AB - Adaptation to optical prisms displacing the visual scene laterally is a widely investigated instance of visuo-motor plasticity, also because prism adaptation (PA) has been extensively used as a treatment for right-brain-damaged patients suffering from left spatial neglect. The lateral visual displacement brought about by prisms, as indexed by a pointing error in the direction of the displacement, is progressively corrected through repeated pointings: after prism removal, a shift in the direction opposite to the prism-induced deviation occurs in visual, proprioceptive, and visuo-proprioceptive straight-ahead tasks (aftereffects, AEs). The cerebellum and the posterior parietal cortex (PPC) are key components of the bilateral cerebral network subserving the AEs, and the reduction of the pointing error during prism exposure in PA. We report the experimental study of a patient with bilateral occipital and left cerebellar damage, who showed a preserved reduction of the pointing errors to rightward displacing prisms, but not the leftward AEs in the proprioceptive straight-ahead task; instead, visual-proprioceptive and visual AEs were preserved. Anodal transcranial Direct Current Stimulation (tDCS) over the left PPC restored the leftward proprioceptive AEs, and anodal tDCS over the left cerebellum abolished the rightward deviation. Conversely, stimulation over the right PPC or the right cerebellum was ineffective. These results provide novel evidence for neuromodulatory effects of tDCS on defective AEs, through the stimulation over dedicated cortical regions. PMID- 25912763 TI - Ginsenoside Rb1 attenuates angiotensin II-induced abdominal aortic aneurysm through inactivation of the JNK and p38 signaling pathways. AB - BACKGROUND: Abdominal aortic aneurysm (AAA), a life-threatening vascular disease, accounts for approximately 10% of the morbidity in people over 65 years old. No satisfactory approach is available to treat AAA. Ginsenosides Rb1 and Rg1 are primary ingredients of Panax notoginseng for the treatment of cardiovascular diseases, but their impact on AAA is unknown. METHODS AND RESULTS: An AAA model was established using an Ang II infusion in ApoE(-/-) mice. After continuous stimulation of Ang II for 28 days, suprarenal aortic aneurysms developed in 77% mice and 12% mice died suddenly due to AAA rupture. Administration of ginsenoside Rb1 (20 mg/kg/day), but not ginsenoside Rg1, significantly reduced the incidence and mortality of AAA. Ginsenoside Rb1 treatment dramatically suppressed Ang II induced diameter enlargement, extracellular matrix degradation, matrix metalloproteinase (MMP) production, inflammatory cell infiltration, and vascular smooth muscle cell (VSMC) dysfunction. Mechanistic studies indicated that the protective effects of ginsenoside Rb1 were associated with the inactivation of JNK and p38 MAPK signaling pathways. A specific activator of JNK and p38, anisomycin, nearly abolished ginsenoside Rb1-driven suppression of MMP secretion by VSMCs. CONCLUSIONS: Ginsenoside Rb1, as a potential anti-AAA agent, suppressed AAA through inhibiting the JNK and p38 signaling pathways. PMID- 25912765 TI - Lemon detox diet reduced body fat, insulin resistance, and serum hs-CRP level without hematological changes in overweight Korean women. AB - The lemon detox program is a very low-calorie diet which consists of a mixture of organic maple and palm syrups, and lemon juice for abstinence period of 7 days. We hypothesized that the lemon detox program would reduce body weight, body fat mass, thus lowering insulin resistance and known risk factors of cardiovascular disease. We investigated anthropometric indices, insulin sensitivity, levels of serum adipokines, and inflammatory markers in overweight Korean women before and after clinical intervention trial. Eighty-four premenopausal women were randomly divided into 3 groups: a control group without diet restriction (Normal-C), a pair-fed placebo diet group (Positive-C), and a lemon detox diet group (Lemon-D). The intervention period was 11 days total: 7 days with the lemon detox juice or the placebo juice, and then 4 days with transitioning food. Changes in body weight, body mass index, percentage body fat, and waist-hip ratio were significantly greater in the Lemon-D and Positive-C groups compared to the Normal C group. Serum insulin level, homeostasis model assessment insulin resistance scores, leptin, and adiponectin levels decreased in the Lemon-D and Positive-C groups. Serum high-sensitive C-reactive protein (hs-CRP) levels were also reduced only in the Lemon-D group. Hemoglobin and hematocrit levels remained stable in the Lemon-D group while they decreased in the Positive-C and Normal-C groups. Therefore, we suppose that the lemon detox program reduces body fat and insulin resistance through caloric restriction and might have a potential beneficial effect on risk factors for cardiovascular disease related to circulating hs-CRP reduction without hematological changes. PMID- 25912766 TI - Highly Dense ZnO Nanowires Grown on Graphene Foam for Ultraviolet Photodetection. AB - Growth of highly dense ZnO nanowires (ZnO NWs) is demonstrated on three dimensional graphene foam (GF) using resistive thermal evaporation technique. Photoresponse of the as-grown hybrid structure of ZnO NWs on GF (ZnO NWs/GF) is evaluated for ultraviolet (UV) detection. Excellent photoresponse with fast response and recovery times of 9.5 and 38 s with external quantum efficiency of 2490.8% is demonstrated at low illumination power density of 1.3 mW/cm(2). In addition, due to excellent charge carrier transport, mobility of graphene reduces the recombination rate of photogenerated charge carriers, hence the lifetime of photogenerated free charge carriers enhances in the photodetectors. PMID- 25912764 TI - Trace elements as predictors of preeclampsia in type 1 diabetic pregnancy. AB - Preeclampsia (PE) affects approximately 5% of all pregnancies, but is increased several-fold in women with pre-gestational type 1 diabetes mellitus (T1DM). Increased oxidative stress and altered maternal plasma trace elements that modulate the antioxidant system have been implicated in PE. In non-diabetic women, increased plasma copper and iron and decreased manganese, selenium, and zinc have been associated with PE in cross-sectional studies. In a longitudinal study, we hypothesized that plasma levels of trace elements differ between T1DM women with vs. without subsequent PE. Samples were collected during the first (gestation 12.2 +/- 1.9 weeks, [mean +/- SD]), second (21.6 +/- 1.5 weeks), and third (31.5 +/- 1.7 weeks) trimesters of pregnancy, all before the onset of PE. We compared 23 T1DM women who subsequently developed PE with 24 T1DM women who remained normotensive; and we included 19 non-diabetic (non-DM) normotensive pregnant women as reference controls. Trace elements were measured using inductively coupled plasma mass spectroscopy. In T1DM women with subsequent PE vs normotensive, only plasma zinc was significantly higher at the first trimester, while copper:zinc and copper:high-density lipoprotein cholesterol ratios were higher throughout gestation (all P < .05). These findings persisted after adjustment for covariates. Higher copper:zinc ratios may contribute to oxidative stress in T1DM women who develop PE. Ratios of pro- to anti-oxidant factors may predict risk for PE in diabetic pregnancies more effectively than individual trace element levels. PMID- 25912767 TI - Can modular psychological concepts like affect and emotion be assigned to a distinct subset of regional neural circuits?: Comment on "The quartet theory of human emotions: An integrative and neurofunctional model" by S. Koelsch et al. PMID- 25912768 TI - Regulating with imagery and the complexity of basic emotions: Comment on "The quartet theory of human emotions: An integrative and neurofunctional model" by S. Koelsch et al. PMID- 25912769 TI - Bridges from affect to language: Comment on "The quartet theory of human emotions: An integrative and neurofunctional model" by S. Koelsch et al. PMID- 25912770 TI - The quartet theory: Implications for autism spectrum disorder: Comment on "The quartet theory of human emotions: An integrative and neurofunctional model" by S. Koelsch et al. PMID- 25912771 TI - "Anything is good that stimulates thought" in the hippocampus: Comment on "The quartet theory of human emotions: An integrative and neurofunctional model" by S. Koelsch et al. PMID- 25912772 TI - Levels of analysis in neuroscientific studies of emotion: Comment on "The quartet theory of human emotions: an integrative and neurofunctional model" by S. Koelsch et al. PMID- 25912773 TI - Anderson-Hynes pyeloplasty: are we all really on the same page? AB - BACKGROUND: The Anderson-Hynes pyeloplasty (AHP) is a surgical technique used in the management of pelvi-ureteric junction obstruction. This operation has been performed for over six decades and has etched its name in the annals of urology. But are we all really referring to the same procedure? METHODS: A systematic review of the Ovid MEDLINE(R) and Ovid OLDMEDLINE(R) database from 1946 to 20 June 2014 was performed for the terms 'Anderson and Hynes' and 'Anderson-Hynes', with later restriction to the title of journal article. Each respective author's descriptive images (figures/photographic) of technique performed was compared with the original procedure. Non-English figure legends were translated using online translational tools. RESULTS: In total, 242 articles were retrieved. Streamlining this search to articles with the above search terms restricted to article title revealed 58 (34 English/24 non-English) articles. Only 29/58 papers had referenced the original procedure. Operative images were present in 17/58 of the articles claiming to have performed the AHP. Within these papers, only 7/17 articles depicted both the L-shaped cut and pelvic flap. Diverse variations were observed in the remainder 10/17 articles. This was a worldwide phenomenon, observed more commonly in recent decades and when minimally invasive techniques were used. CONCLUSION: The AHP is often not performed as was originally described. Over the decades, surgeons have unknowingly attributed variations to this procedure. Based on this review, a novel 'geometric classification' system has been proposed to better define the dismembered pyeloplasty. PMID- 25912774 TI - Venous Thromboembolism after Allogeneic Pediatric Hematopoietic Stem Cell Transplantation: A Single-Center Study. AB - INTRODUCTION: Venous thromboembolism (VTE) in children who undergo hematopoietic stem cell transplantation (HSCT) has high morbidity. The aim of this study is to assess the incidence of VTE in allogeneic pediatric HSCT recipients and the contribution of pretransplant prothrombotic risk factors to thrombosis. METHODS: We retrospectively evaluated 92 patients between April 2010 and November 2012 undergoing allogeneic HSCT who had completed 100 days post-HSCT. Before HSCT, coagulation profiles; acquired and inherited prothrombotic risk factors including factor V Leiden, prothrombin G20210A, methylenetetrahydrofolate reductase (MTHFR) C677T, and MTHFR A1298C mutations; and serum homocysteine and lipoprotein(a), plasma antithrombin III, protein C, and protein S levels were obtained from all patients. RESULTS: In the screening of thrombophilia, 8 patients (9%) were heterozygous for factor V Leiden, 5 (6%) were homozygous for MTHFR 677TT, 12 (14%) were homozygous for MTHFR 1298CC, and 2 (2%) were heterozygous for prothrombin G20210A mutation. We observed VTE in 5 patients (5.4%); a prothrombotic risk factor was found in 3 out of these 5 patients, while 4 out of 5 patients had central venous catheters. It was determined there was no significant relationship between VTE and inherited prothrombotic risk factors. DISCUSSION AND CONCLUSION: VTE after HSCT seems to be a low-frequency event that may be due to low-dose, low-molecular-weight heparin prophylaxis, and the role of inherited prothrombotic risk factors cannot be entirely excluded without a prospective study. PMID- 25912775 TI - "Slow food" post-qualitative research in psychology: old craft skills in new disguise? AB - The present paper addresses several aspects discussed in the special issue on the future of qualitative research in psychology. Particularly, it asks whether in light of the overhomogenization of the term "qualitative methods" researchers actually can still assume that they talk about the same thing when using this terminology. In addressing the topic of what constitutes the object of psychological research and what accordingly could be a genuinely psychological qualitative research it acknowledges the need to return to the study of persons' unique experience. In light of the risk of "McDonaldization" in present qualitative research, it argues that we need to return to learning research methods as craft skills. It will then give an outlook on how recent developments in discursive and narrative psychology offer a fruitful avenue for studying unique psychological experience as people manage to 'move on' in a material world and in irreversible time. PMID- 25912776 TI - DNA and bone structure preservation in medieval human skeletons. AB - Morphological and ultrastructural data from archaeological human bones are scarce, particularly data that have been correlated with information on the preservation of molecules such as DNA. Here we examine the bone structure of macroscopically well-preserved medieval human skeletons by transmission electron microscopy and immunohistochemistry, and the quantity and quality of DNA extracted from these skeletons. DNA technology has been increasingly used for analyzing physical evidence in archaeological forensics; however, the isolation of ancient DNA is difficult since it is highly degraded, extraction yields are low and the co-extraction of PCR inhibitors is a problem. We adapted and optimised a method that is frequently used for isolating DNA from modern samples, Chelex((r)) 100 (Bio-Rad) extraction, for isolating DNA from archaeological human bones and teeth. The isolated DNA was analysed by real-time PCR using primers targeting the sex determining region on the Y chromosome (SRY) and STR typing using the AmpFlSTR((r)) Identifiler PCR Amplification kit. Our results clearly show the preservation of bone matrix in medieval bones and the presence of intact osteocytes with well preserved encapsulated nuclei. In addition, we show how effective Chelex((r)) 100 is for isolating ancient DNA from archaeological bones and teeth. This optimised method is suitable for STR typing using kits aimed specifically at degraded and difficult DNA templates since amplicons of up to 250bp were successfully amplified. PMID- 25912777 TI - Prostaglandin D2 modulates calcium signals induced by prostaglandin E2 in neurons of rat dorsal root ganglia. AB - Fever in response to a localized subcutaneous stimulation with a low dose of lipopolysaccharide (LPS) can be attenuated by co-administration of a local anesthetic or the non-selective cyclooxygenase (COX) inhibitor diclofenac at doses, which do not exert systemic effects when injected at sites remote from the area of inflammatory stimulation. These results suggest a participation of neuronal afferent signals mediated by COX-products in the manifestation of fever under these conditions. We therefore, measured intracellular Ca(2+) concentrations in cultured neurons from rat dorsal root ganglia (DRG) stimulated with the pyrogenic mediator prostaglandin E2 (PGE2), the anti-inflammatory and antipyretic mediator PGD2, mixtures of both PGs, and menthol using the fura-2 ratio imaging technique. Neurons could be grouped according to their size with diameters of about 15MUm (small), 35MUm (medium sized), or 55MUm (large). 96 out of 264 neurons responded to PGE2 with pronounced Ca(2+)-signals, 53 of them being also responsive to menthol, indicative of their function as cold-sensors. 80% of these neurons belonged to the medium sized group. In a next experiment, we tested whether Ca(2+)-signals of PGE2 responsive neurons were modulated by PGD2. In 60% of all neurons investigated (n=57), the strength of the PGE2-induced Ca(2+) signals was reduced by co-administration of PGD2. This effect was also observed in those neurons that were responsive to PGE2 and menthol (n=23; p<0.001). This observation indicates antagonistic effects of PGE2 and PGD2 on a neuronal pathway that involves cold sensors and is activated during a localized subcutaneous inflammation. This finding might provide an explanation for the reported antipyretic and anti-inflammatory capacities of PGD2. PMID- 25912778 TI - Lower expression level of two RAGE alternative splicing isoforms in Alzheimer's disease. AB - Alternative splicing (AS) is a common phenomenon in gene expression of eukaryotic organisms, especially in mammals, producing multiple gene isoforms from a single gene that involve in physiological and pathological processes. Receptor for advanced glycation end products (RAGE) has multiple AS isoforms with significant tissue and organism specificity. RAGE signaling has been reported involved in the onset and development of Alzheimer's disease (AD) and the roles of RAGE AS isoforms have not yet been fully illustrated in AD pathogenesis. In the present study, two of RAGE AS isoforms (RAGEDelta and sRAGEDelta) were investigated in the human brain specimens from AD and age-matched control subjects. The expression of these isoforms was found brain-region specific, and significant lower expression levels of both RAGEDelta and sRAGEDelta were detected in multiple brain regions of AD subjects than control subjects. Data indicated tight association between the AS isoforms (RAGEDelta and sRAGEDelta) and neurodegeneration. An antagonistic pairing model has been suggested to explain the working mechanism of AS isoforms on gene regulation and pathological development. PMID- 25912779 TI - University Hospital Struck Deaf and Silent by Lightning: Lessons to Learn. AB - We describe how an electromagnetic wave after a lightning strike affected a university hospital, including the communication shutdown that followed, the way it was handled, and the lessons learned from this incident. PMID- 25912780 TI - Resolution of Thoracic and Abdominal Lymphangioleiomyomas in a Patient With Lymphangioleiomyomatosis Treated With Sirolimus. PMID- 25912781 TI - Thoracic Angiolipoma: The Risk of Being Original. PMID- 25912782 TI - Revealing the role of organic cations in hybrid halide perovskite CH3NH3PbI3. AB - The hybrid halide perovskite CH3NH3PbI3 has enabled solar cells to reach an efficiency of about 20%, demonstrating a pace for improvements with no precedents in the solar energy arena. Despite such explosive progress, the microscopic origin behind the success of such material is still debated, with the role played by the organic cations in the light-harvesting process remaining unclear. Here van der Waals-corrected density functional theory calculations reveal that the orientation of the organic molecules plays a fundamental role in determining the material electronic properties. For instance, if CH3NH3 orients along a (011) like direction, the PbI6 octahedral cage will distort and the bandgap will become indirect. Our results suggest that molecular rotations, with the consequent dynamical change of the band structure, might be at the origin of the slow carrier recombination and the superior conversion efficiency of CH3NH3PbI3. PMID- 25912783 TI - Plant adaptations to severely phosphorus-impoverished soils. AB - Mycorrhizas play a pivotal role in phosphorus (P) acquisition of plant roots, by enhancing the soil volume that can be explored. Non-mycorrhizal plant species typically occur either in relatively fertile soil or on soil with a very low P availability, where there is insufficient P in the soil solution for mycorrhizal hyphae to be effective. Soils with a very low P availability are either old and severely weathered or relatively young with high concentrations of oxides and hydroxides of aluminium and iron that sorb P. In such soils, cluster roots and other specialised roots that release P-mobilising carboxylates are more effective than mycorrhizas. Cluster roots are ephemeral structures that release carboxylates in an exudative burst. The carboxylates mobilise sparingly-available sources of soil P. The relative investment of biomass in cluster roots and the amount of carboxylates that are released during the exudative burst differ between species on severely weathered soils with a low total P concentration and species on young soils with high total P concentrations but low P availability. Taking a modelling approach, we explore how the optimal cluster-root strategy depends on soil characteristics, thus offering insights for plant breeders interested in developing crop plants with optimal cluster-root strategies. PMID- 25912784 TI - Long-Term Outcomes of Older Adults with and Without Delirium Immediately After Recovery from General Anesthesia for Surgery. AB - OBJECTIVE: Postoperative delirium, occurring days after surgery, is associated with both short- and long-term adverse events. Postanesthesia care unit (PACU) delirium, immediately after recovery from anesthesia, is associated with continued delirium in the succeeding days and adverse cognitive outcomes at discharge. Longer-term consequences are unclear. The objective was to evaluate 18 month outcomes of patients with versus without delirium in the PACU after surgery with general anesthesia. METHODS: In a prospective, observational, cohort study, 91 consecutive English-speaking patients, aged at least 70 years and capable of independently providing informed consent before surgery, were followed after admission for a surgical procedure in one teaching hospital. Patients completed cognitive testing before surgery. After recovery from general anesthesia, they were evaluated for a DSM-IV diagnosis of delirium. Participants or proxies were evaluated, at a median of 19 months after surgery (interquartile range: 18-20 months), for survival, cognitive and physical functioning, and healthcare utilization outcomes. RESULTS: All 91 patients or proxies (41 with delirium [45%]) were contacted at follow-up, with 7 deaths (8%) and 3 declining further participation (3%); 81 (96% of survivors) completed follow-up evaluations, demonstrating no significant cognitive or functional decline from baseline, with 75% of the cohort living independently in the community, and no differences in any outcomes between patients with versus without PACU delirium. CONCLUSION: In a small cohort of older patients evaluated 18 months after surgery, we could not detect an association of delirium diagnosed in the PACU with patient survival, cognitive/physical functioning, and healthcare utilization. PMID- 25912785 TI - Pseudomonas aeruginosa uses T3SS to inhibit diabetic wound healing. AB - Diabetic foot ulcers are responsible for more hospitalizations than any other complication of diabetes. Bacterial infection is recognized as an important factor associated with impaired healing in diabetic ulcers. Pseudomonas aeruginosa is the most frequently detected Gram-negative pathogen in diabetic ulcers. P. aeruginosa infection has been shown to impair healing in diabetic wounds in a manner that correlates with its ability to form biofilm. While the majority of infections in diabetic ulcers are biofilm associated, 33% of infections are nonbiofilm in nature. P. aeruginosa is the most prevalent Gram negative pathogen in all diabetic wound types, which suggests that the deleterious impact of P. aeruginosa on healing in diabetic wounds goes beyond its ability to form biofilm and likely involves other factors. The Type III Secretion System (T3SS) virulence structure is required for the pathogenesis of all P. aeruginosa clinical isolates, suggesting that it may also play a role in the inhibition of wound repair in diabetic skin ulcers. We evaluated the role of T3SS in mediating P. aeruginosa-induced tissue damage in the wounds of diabetic mice. Our data demonstrate that P. aeruginosa establishes a robust and persistent infection in diabetic wounds independent of its ability to form biofilm and causes severe wound damage in a manner that primarily depends on its T3SS. PMID- 25912786 TI - Nutrition therapy in cachectic cancer patients. The Tight Caloric Control (TiCaCo) pilot trial. AB - BACKGROUND: Cancer is a common disease and many patients are diagnosed with advanced stages. Due to cancer generalization, patients may become ill-nourished and even cachectic. Malignancy-related cachexia is associated with worsening physical function, reduced tolerance to anticancer therapy and increased mortality. We assessed the effect of a patient-tailored nutritional approach in newly discovered, treatment-naive cancer patients with cachexia. METHODS: In a randomized, single-blinded, controlled pilot study, patients were treated with either intensive, biometric parameter-oriented dietary counseling (nutrition therapy) compared to regular dietary counseling (control), before and during conventional cancer treatment. Twenty patients were enrolled over a one-year period, 10 receiving nutrition therapy and 10 controls. The primary endpoint was recovery of body composition after nutrition therapy. Secondary endpoints declined in morbidity and mortality with nutrition therapy. RESULTS: Average weight evolution in the control group after 3, 6 and 12 months was 0.19 +/- 7.87 kg, -9.78 +/- 7.00 kg and -5.8 kg, and in the nutrition therapy group 0.69 +/- 2.4 kg, 0.77 +/- 2.58 kg and 1.29 +/- 3.76 kg. Control patients had a significantly longer average hospital stay than subjects from the nutrition therapy group (37.6 vs. 3.4 days). Eight nutrition therapy patients and 1 control patient were still alive after 2 years. CONCLUSIONS: Nutrition therapy based on patient-specific biophysical parameters helps to maintain body weight and induces a more optimal nutritional balance in cachectic cancer patients. Moreover, survival in cancer patients improved when their nutritional status, even partially, ameliorated. PMID- 25912787 TI - The Herzenberg lecture: how to make a B-1 cell? AB - This essay presents a short historical perspective on B-1 cells and a synopsis of contemporary work in my laboratory on generating B-1 from B-2 cells via B cell receptor exchange. PMID- 25912788 TI - Analysis and improved characterization of minor antioxidants from leaves of Malus doumeri using a combination of major constituents' knockout with high-performance liquid chromatography-diode array detector-quadrupole time-of-flight tandem mass spectrometry. AB - Due to the complexity of natural products, efficient identification of bioactive compounds, especially for minor compounds, would require a huge effort. Here, we developed an effective strategy based on combining major constituents' knockout with high-performance liquid chromatography-diode array detector-quadrupole time of-flight tandem mass spectrometry (HPLC-DAD-QTOF-MS/MS) to comprehensively identify minor antioxidants in Malus doumeri, one of the longest known and most used tonic plant in Taiwan. First, five major compounds (I-V) in M. doumeri were knocked out by two-step stepwise high-speed countercurrent chromatography (HSCCC). Second, minor antioxidants were screened by 1,1-diphenyl-2 picrylhydrazyl radical-HPLC (DPPH-HPLC) assay. Third, structures of thirty minor antioxidants, including 11 dihydrochalcones, 4 flavanones, 3 flavonols, 2 flavones, 3 aurones and 7 phenolic acids, were unambiguously or tentatively identified by matching their characteristic UV spectra, accurate mass signals and key diagnostic fragment ions with standards or previously reported compounds. Twenty-six of them, as far as was known, were discovered from M. doumeri for the first time. The results indicated that the proposed method was a useful approach to explore minor bioactive compounds from complex natural products. PMID- 25912789 TI - Incidence and Risk Factor Analysis for Gastrointestinal Bleeding and Pump Thrombosis in Left Ventricular Assist Device Recipients. AB - Left ventricular assist devices (LVADs) are associated with hemostatic complications. We describe the incidence and risk factors for gastrointestinal bleeding (GIB) and pump thrombosis (PT) to optimize patient selection/management. An IRB-approved retrospective review of first LVAD implants between October 1, 2011 and September 30, 2013 at a single center was conducted. Endpoints included epidemiological and risk factor analyses for GIB and PT. Descriptive statistics, chi-squared, and t-tests were used. Sixty-four patients received continuous-flow LVADs. The 12-month incidence of GIB and PT was 23.4% and 12.5%. Time to first GIB was 72.6 days (9-160). The 1-, 3-, and 6-month rate of PT was 1.6%, 6.25%, and 12.5%, respectively. All PT required pump exchange. Females (50% vs. 16%, P = 0.026) and patients without antiplatelet therapy (12.5% vs. 50%, P = 0.046) were at increased risk of PT. No pre-implant comorbidities were associated with PT. Infection was not identified as a risk factor in our cohort (25% vs. 51.8%, P = 0.156). Mean INR preceding event was not different from nonevent patients (2.1 vs. 2.24, P = 0.24). Regarding biomarkers preceding event, elevated plasma free hemoglobin (pfHg) did not reach significance (75% vs. 58%, P = 0.383) while lactate dehydrogenase was elevated significantly (744 vs. 298, P < 0.001). Receiver operating characteristic (ROC) analysis demonstrated that an LDH of >500 was highly sensitive and specific for PT. No pre-implant factors were associated with GIB. Post-implant risk factors for GIB included infection (80% vs. 38.8%, P = 0.005) and infrequent elevations in pfHg (13.3% vs. 63.3%, P < 0.001). Increased pump speed as a GIB risk factor was confirmed (HeartMate II 9560 rpm vs. 9490 rpm, P < 0.001; HeartWare 2949 rpm vs. 2710 rpm, P < 0.001). Anticoagulation/antiplatelet therapy did not affect GIB: mean INR preceding event was not different from nonevent patients (2.21 vs. 2.27, P = 0.67) and antiplatelet use was not different (46.7% vs. 46.9%, P = 0.985). LVADs are associated with early hemostatic-related morbidity. Few pre-implantation risk factors were elucidated; however, post-implantation factors including antiplatelet therapy, infection, and pump speed were identified. PMID- 25912790 TI - The Parkinson-associated human P5B-ATPase ATP13A2 protects against the iron induced cytotoxicity. AB - P-type ion pumps are membrane transporters that have been classified into five subfamilies termed P1-P5. The ion transported by the P5-ATPases is not known. Five genes named ATP13A1-ATP13A5 that belong to the P5-ATPase group are present in humans. Loss-of-function mutations in the ATP13A2 gene (PARK9, OMIM 610513) underlay a form of Parkinson's disease (PD) known as the Kufor-Rakeb syndrome (KRS), which belongs to the group of syndromes of neurodegeneration with brain iron accumulation (NBIA). Here we report that the cytotoxicity induced by iron exposure was two-fold reduced in CHO cells stably expressing the ATP13A2 recombinant protein (ATP13A2). Moreover, the iron content in ATP13A2 cells was lower than control cells stably expressing an inactive mutant of ATP13A2. ATP13A2 expression caused an enlargement of lysosomes and late endosomes. ATP13A2 cells exhibited a reduced iron-induced lysosome membrane permeabilization (LMP). These results suggest that ATP13A2 overexpression improves the lysosome membrane integrity and protects against the iron-induced cell damage. PMID- 25912791 TI - Feasibility of "rapid" magnetic resonance imaging in pediatric acute head injury. AB - OBJECTIVE: The objective was to determine the feasibility of "rapid" magnetic resonance imaging (rMRI) versus noncontrast computed tomography (NCCT) for pediatric patients with possible traumatic brain injury and to compare the populations receiving imaging in an urban tertiary care emergency department ED. METHODS: We retrospectively reviewed the electronic medical records of ED patients younger than 19 years with possible traumatic brain injury over 4 years who received an rMRI and then age-matched with NCCT patients. Data collection and analysis included demographic and clinical variables, ED length of stay (LOS), and follow-up outcomes. RESULTS: The final cohort had 45 rMRIs and 45 NCCTs. The mean age was 2.7 years, 63% were male, and 65% sustained a fall. Age, sex, and injury mechanism were similar. Time parameters were longer for rMRI patients: ED arrival to completion of imaging (172 vs 93 minutes, P < .001) and ED LOS (266 vs 225 minutes, P = .008). The NCCT group had higher-acuity patients with higher pediatric intensive care unit admission rates (33% vs 7%, P = .002). No patients returned to the ED within 72 hours. Follow-up was available on 78% patients. No clinically significant intracranial injuries were missed. CONCLUSIONS: Rapid MRI may be a viable imaging modality for moderate-risk pediatric head injury. Although rMRI took longer to obtain during this pilot study, scan time was only 3 to 4 minutes; and LOS was only 41 minutes longer. Further integration of rMRI in patient care should decrease time variation. Future study of rMRI reliability and satisfaction is needed. PMID- 25912792 TI - Allograft Pancreatectomy: Indications and Outcomes. AB - This study evaluated the indications, surgical techniques, and outcomes of allograft pancreatectomy based on a single center experience. Between 2003 and 2013, 47 patients developed pancreas allograft failure, excluding mortality with a functioning pancreas allograft. Early graft loss (within 14 days) occurred in 16, and late graft loss in 31. All patients with early graft loss eventually required allograft pancreatectomy. Nineteen of 31 patients (61%) with late graft loss underwent allograft pancreatectomy. The main indication for early allograft pancreatectomy included vascular thrombosis with or without severe pancreatitis, whereas one recipient required urgent allograft pancreatectomy for gastrointestinal hemorrhage secondary to an arterioenteric fistula. In cases of late allograft pancreatectomy, graft failure with clinical symptoms such as abdominal discomfort, pain, and nausea were the main indications (13/19 [68%]), simultaneous retransplantation without clinical symptoms in 3 (16%), and vascular catastrophes including pseudoaneurysm and enteric arterial fistula in 3 (16%). Postoperative morbidity included one case each of pulmonary embolism leading to mortality, formation of pseudoaneurysm requiring placement of covered stent, and postoperative bleeding requiring relaparotomy eventually leading to femoro femoral bypass surgery 2 years after allograftectomy. Allograft pancreatectomy can be performed safely, does not preclude subsequent retransplantation, and may be lifesaving in certain instances. PMID- 25912793 TI - Association between healthy diet and exercise and greater muscle mass in older adults. AB - OBJECTIVES: To examine the association between healthy diet and exercise, individually and combined, and low muscle mass in older Korean adults. DESIGN: Population-based cross-sectional study from the Fourth and Fifth Korea National Health and Nutrition Examination Surveys from 2008 to 2011. SETTING: Community. PARTICIPANTS: Nationally representative sample aged 65 and older (1,486 men, 1,799 women) in the Republic of Korea. MEASUREMENTS: A food frequency questionnaire was used to determine frequency of food group consumption (meat, fish, eggs, legumes; vegetables; fruits). Participation in exercise (aerobic and resistance) was based on self-report. Combined healthy lifestyle factors were calculated as the number of recommendations met regarding consumption of food groups and exercise performed. Appendicular skeletal muscle mass (ASM) was measured using dual-energy X-ray absorptiometry, and low muscle mass was defined using the variable of ASM adjusted for weight. Logistic regression analysis was performed to examine the association between healthy lifestyle factors and low muscle mass, adjusting for sociodemographic characteristics and health-related variables. RESULTS: In women, after controlling for covariates, vegetable consumption (odds ratio (OR)=0.52, 95% confidence interval (CI)=0.30-0.89) and aerobic exercise (OR=0.62, 95% CI=0.39-1.00) were inversely associated with low muscle mass. Also, the odds of low muscle mass was lower in women with three or more healthy lifestyle factors versus none (OR=0.45, 95% CI=0.23-0.87). In men, there were no associations between food group consumption and exercise and low muscle mass. CONCLUSION: Older women who exercise and consume a healthy diet have lower odds of low muscle mass. Engaging in multiple healthy behaviors may be important in preventing low muscle mass in late life. PMID- 25912794 TI - Enhancing the performance of polymer solar cells using CuPc nanocrystals as additives. AB - There is an increasing interest in the use of different nanoparticles as additives in polymer solar cells for enhancing the light absorption of active layers as well as their power conversion efficiency (PCE). In this paper, we report a PCE enhancement by simply adding copper phthalocyanine (CuPc) nanocrystals into photovoltaic devices based on a poly(3-hexylthiophene) (P3HT): fullerene system. Two kinds of device structure were studied: the first one is a CuPc nanocrystal suspension spin coated on the poly(3,4-ethylenedioxythiophene) polystyrene sulfonate-coated substrate; the second one is the CuPc nanocrystal suspension added into the active layer solutions. It is proved that incorporating organic semiconductor nanocrystals into the active layer can help trap light and enhance the crystallinity of the active layers, thus improving the device performance. This strategy might be generally compatible with a broad range of organic photovoltaic materials and offers an effective approach to enhance the device performance. PMID- 25912795 TI - Distribution of radionuclides in a marine sediment core off the waterspout of the nuclear power plants in Daya Bay, northeastern South China Sea. AB - A sediment core was collected and dated using (210)Pbex dating method off the waterspout of nuclear power base of Daya Bay, northeastern South China Sea. The gamma-emitting radionuclides were analyzed using HPGe gamma spectrometry, gross alpha and beta radioactivity as well as other geochemical indicators were deliberated to assess the impact of nuclear power plants (NPP) operation and to study the past environment changes. It suggested that NPP provided no new radioactivity source to sediment based on the low specific activity of (137)Cs. Two broad peaks of TOC, TC and LOI accorded well with the commercial operations of Daya Bay NPP (1994.2 and 1994.5) and LNPP Phase I (2002.5 and 2003.3), implying that the mass input of cooling water from NPP may result into a substantial change in the ecological environment and Daya Bay has been severely impacted by human activities. PMID- 25912796 TI - Which Fungus Originally was Trichophyton mentagrophytes? Historical Review and Illustration by a Clinical Case. AB - Several dermatophytes producing numerous pyriform or round microconidia were called Trichophyton mentagrophytes. Among these dermatophytes are the teleomorph species Arthroderma benhamiae, Arthroderma vanbreuseghemii and Arthroderma simii, and other species such as Trichophyton interdigitale, Trichophyton erinacei and Trichophyton quinckeanum for which only the anamorph is known. Confusion exists about which fungus should be really called T. mentagrophytes and about the rational use of this name in practice. We report a case of beard ringworm (tinea barbae) with A. vanbreuseghemii. According to both clinical signs and the type of hair parasitism, this case was exactly compatible to the first description of a non-favic dermatophytosis by Gruby under the name of "mentagrophyte" from which was derived the dermatophyte epithet mentagrophytes. In addition, the phenotypic characters of the isolated fungus in cultures perfectly matched with those of the first description of a dermatophyte under T. mentagrophytes by Blanchard (Parasites animaux et parasites vegetaux a l'exclusion des Bacteries, Masson, Paris, 1896). In conclusion, T. mentagrophytes corresponds to the fungus later named A. vanbreuseghemii. However, because the neotype of T. mentagrophytes was not adequately designated in regard to the ancient literature, we would privilege the use of A. vanbreuseghemii and abandon the name of T. mentagrophytes. PMID- 25912797 TI - Recovery of critical metals using biometallurgy. AB - The increased development of green low-carbon energy technologies that require platinum group metals (PGMs) and rare earth elements (REEs), together with the geopolitical challenges to sourcing these metals, has spawned major governmental and industrial efforts to rectify current supply insecurities. As a result of the increasing critical importance of PGMs and REEs, environmentally sustainable approaches to recover these metals from primary ores and secondary streams are needed. In this review, we define the sources and waste streams from which PGMs and REEs can potentially be sustainably recovered using microorganisms, and discuss the metal-microbe interactions most likely to form the basis of different environmentally friendly recovery processes. Finally, we highlight the research needed to address challenges to applying the necessary microbiology for metal recovery given the physical and chemical complexities of specific streams. PMID- 25912798 TI - Improved in vitro antitumor potential of (O,O'-Diisobutyl-ethylenediamine-N,N'-di 3-propionate)tetrachloridoplatinum(IV) complex under normoxic and hypoxic conditions. AB - (O,O'-Diisobutyl-ethylenediamine-N,N'-di-3-propionate)tetrachloridoplatinum(IV), [PtCl4(iBu2eddp)], shows an improved pharmacological profile in comparison to cisplatin. This is manifested through accelerated dying process led by necrotic cell death, reflected through mitochondrial collapse, strong ATP depletion and reactive oxygen species production. Loss of mitochondrial potential was further followed with intensive apoptosis that finalized with DNA fragmentation. Different dynamic of tumoricidal action could be partly ascribed to less affected repair mechanisms in comparison to cisplatin. Importantly, [PtCl4(iBu2eddp)] did not induce necrosis in primary fibroblasts suggesting different intracellular response of normal vs. tumor cells. This selectivity toward malignant phenotype is further confirmed by retained tumoricidal potential in hypoxic conditions, while cisplatin became completely inefficient. PMID- 25912799 TI - Biochemical characterization and molecular dynamic simulation of beta-sitosterol as a tubulin-binding anticancer agent. AB - Betaeta-sitosterol (beta-SITO), a phytosterol present in pomegranate, peanut, corn oil, almond, and avocado, has been recognized to offer health benefits and potential clinical uses. beta-SITO is orally bioavailable and, as a constituent of edible natural products, is considered to have no undesired side effects. It has also been considered as a potent anticancer agent. However, the molecular mechanism of action of beta-SITO as a tubulin-binding anticancer agent and its binding site on tubulin are poorly understood. Using a combination of biochemical analyses and molecular dynamic simulation, we investigated the molecular details of the binding interactions of beta-SITO with tubulin. A polymer mass assay comparing the effects of beta-SITO and of taxol and vinblastine on tubulin assembly showed that this phytosterol stabilized microtubule assembly in a manner similar to taxol. An 8-anilino-1-naphthalenesulfonic acid assay confirmed the direct interaction of beta-SITO with tubulin. Although beta-SITO did not show direct binding to the colchicine site on tubulin, it stabilized the colchicine binding. Interestingly, no sulfhydryl groups of tubulin were involved in the binding interaction of beta-SITO with tubulin. Based on the results from the biochemical assays, we computationally modeled the binding of beta-SITO with tubulin. Using molecular docking followed by molecular dynamic simulations, we found that beta-SITO binds tubulin at a novel site (which we call the 'SITO site') adjacent to the colchicine and noscapine sites. Our data suggest that beta SITO is a potent anticancer compound that interferes with microtubule assembly dynamics by binding to a novel site on tubulin. PMID- 25912800 TI - Berberine as a promising anti-diabetic nephropathy drug: An analysis of its effects and mechanisms. AB - Diabetic nephropathy is a progressive kidney disorder and is pathologically characterized by thickened glomerular and tubular basement membranes, accumulation of the extracellular matrix and increased mesangial hypertrophy. Growing evidence has suggested that diabetic nephropathy is induced by multiple factors, such as dyslipidemia, hyperglycemia, hemodynamic abnormalities and oxidative stress, based on genetic susceptibility. Berberine (BBR; [C20H18NO4](+)), an isoquinoline alkaloid, is the major active constituent of Rhizoma coptidis and Cortex phellodendri. Recent studies have demonstrated that berberine has various pharmacological activities, including lowering blood glucose, regulating blood lipids and reducing inflammation in addition to its antioxidant activity. These findings suggest that berberine has potential applications as a therapeutic drug for diabetic nephropathy, and has significant research value. However, the possible mechanisms have not been fully established. The purpose of this paper is to investigate the renoprotective mechanisms of berberine in diabetic nephropathy and highlight the importance of berberine as a potential therapeutic reagent for diabetic nephropathy treatment. PMID- 25912801 TI - Pretreatment with obestatin reduces the severity of ischemia/reperfusion-induced acute pancreatitis in rats. AB - Obestatin, as ghrelin, has been originally extracted from the stomach, which remains its major source. Previous studies have shown that administration of obestatin exhibits protective and healing-promoting effects in several organs, including the stomach and kidney. In pancreas, pretreatment with obestatin inhibits the development of cerulein-induced acute pancreatitis and promotes survival of pancreatic beta cells and human islets. The aim of the present study was to check the universality of protective effect of obestatin in the pancreas. For this reason we investigated the influence of obestatin administration on the development of ischemia/reperfusion-induced pancreatitis. Acute pancreatitis was induced by pancreatic ischemia followed by reperfusion of the gland. Obestatin (4, 8 or 16 nmol/kg/dose) was administered intraperitoneally twice: 0.5h before exposure to ischemia, and 3h after the first injection. The effect of obestatin on the course of necrotizing pancreatitis was assessed after 6-h reperfusion, and included histological, functional, and biochemical analyses. Treatment with obestatin reduced morphological signs of pancreatic damage including edema, vacuolization of acinar cells, hemorrhages, acinar necrosis, and leukocyte infiltration of the gland. These effects were accompanied by an improvement of pancreatic DNA synthesis and superoxide dismutase activity, and a decrease in serum level of lipase and pro-inflammatory interleukin-1beta. Moreover pretreatment with obestatin reduced myeloperoxidase activity and malondialdehyde concentration in pancreatic tissue of rats with acute pancreatitis. CONCLUSIONS: Administration of obestatin inhibits the development of ischemia/reperfusion induced acute pancreatitis. This observation, taken together with previous findings that obestatin protects the pancreas against cerulein-induced pancreatitis, indicates that protective effect of obestatin in the pancreas is universal and independent of the primary cause of acute pancreatitis. PMID- 25912802 TI - Honokiol improves learning and memory impairments induced by scopolamine in mice. AB - Honokiol, a lignan isolated from the bark of Magnolia officinalis, has been reported to ameliorate the learning and memory impairments in senesed (SAMP8) mice. However, whether honokiol could improve scopolamine (SCOP)-induced learning and memory deficits in mice is still unknown. In this study, we aimed to investigate whether honokiol could reverse the SCOP-induced learning and memory impairments in mice and to elucidate its underlying mechanisms of action. Mice were given daily intraperitoneal injection of honokiol (10 and 20mg/kg) for 21 consecutive days. The results showed that honokiol significantly improved spatial learning and memory function (as assessed by the Morris water maze test) in the SCOP-treated mice. In addition, treatment with honokiol significantly decreased the protein and mRNA levels of interleukin (IL)-1beta and the activity of acetylcholinesterase (AChE), while significantly increased the protein and mRNA levels of IL-10, and the level of acetylcholine (Ach) in the brain of the SCOP treated mice. Moreover, honokiol also significantly suppressed the production of prostaglandin E 2 (PGE2) and mRNA expression of cyclooxygenase-2 (COX-2) in the brain of the SCOP-treated mice. Mechanistic investigations revealed that honokiol could markedly reverse the amount of phosphorylated Akt and extracellular regulated kinases 1/2 (ERK1/2) changes in the brain of the SCOP-treated mice. These results amply demonstrated that honokiol could improve learning and memory impairments induced by SCOP in mice, and the protective action may be mediated, at least in part, by inhibition of AChE activity, and amelioration of the neuroinflammatory processes in the SCOP-treated mice. PMID- 25912804 TI - Erratum to: Deciphering the core instructions of neuronal differentiation. PMID- 25912803 TI - The monoacylglycerol lipase inhibitor JZL184 decreases inflammatory response in skeletal muscle contusion in rats. AB - Muscle wound healing process is a typical inflammation-evoked event. The monoacylglycerol lipase (MAGL) inhibitor (4-nitrophenyl)4-[bis(1,3-benzodioxol -5 yl)-hydroxymethyl]piperidine-1-carboxylate (JZL184) has been previously reported to reduce inflammation in colitis and acute lung injury in mice, which provide a new strategy for primary care of skeletal muscle injury. We investigated the effect of JZL184 on inflammation in rat muscle contusion model, and found decreased neutrophil and macrophage infiltration and pro-inflammatory cytokine expression. With extension of post-traumatic interval, myofiber regeneration was significantly hindered with increased collagen types I and III mRNAfibroblast infiltration as well as promoted fibrosis. Furthermore, 1-(2,4-dichlorophenyl)-5 (4-iodophenyl)-4-methyl-N-morpholin-4-ylpyrazole-3-carboxamide (AM281, a selective cannabinoid CB1 receptor antagonist) and [6-iodo-2-methyl-1-(2 morpholin-4-ylethyl)indol-3-yl]-(4-methoxyphenyl)methanone (AM630, a selective cannabinoid CB2 receptor antagonist) treatment alleviated the anti-inflammatory effect of JZL184. Our findings demonstrate that JZL184 is able to inhibit the inflammatory response and interfere with contused muscle healing, in which the anti-inflammatory action may be mediated through cannabinoid CB1 and CB2 receptors. PMID- 25912805 TI - Relative contribution of persistent organic pollutants to marine phytoplankton biomass dynamics in the North Sea and the Kattegat. AB - In this paper, we use concentrations of persistent organic pollutants (POPs) and of chlorophyll a to infer POP-induced effects on marine primary production in the Kattegat and the North Sea between the 1990s and the 2000s. To do so, we modelled phytoplankton dynamics using four classical drivers (light and nutrient availability, temperature and zooplankton grazing) and tested whether extending this model with a POP-induced phytoplankton growth limitation term improved model fit to observed chlorophyll a concentrations. Including monitored concentrations of PCBs and pesticides did not lead to a better model fit, suggesting that POP induced growth limitation of marine phytoplankton in the North Sea and the Kattegat is small compared to the limitations caused by the classical drivers. In an attempt to more fully represent the multitude of POPs in the marine environment, the monitored concentrations were multiplied with a factor 10 and 100. Under these two configurations, region-specific contributions of POPs in the phytoplankton growth limitation were found. The inferred contribution of POPs to phytoplankton growth limitation was ca. 1% in Belgian marine waters, but in the Kattegat POPs explained ca. 10% of the phytoplankton growth limitation. These results suggest that there are regional differences in the contribution of POPs to the phytoplankton growth limitation. PMID- 25912806 TI - New Index Obtained From Intrathoracic Impedance Measurements - Could MOMOTARO Find the Key to Heart Failure Management in the Modern Treasure Chest? - . PMID- 25912808 TI - sp(2)-sp(3) diboranes: astounding structural variability and mild sources of nucleophilic boron for organic synthesis. AB - Despite the widespread use of organoborane reagents in organic synthesis and catalysis, a major challenge still remains: very few boron-centered nucleophiles exist for the direct construction of B-C bonds. Perhaps the most promising emerging solution to this problem is the use of sp(2)-sp(3) diboranes, in which one boron atom of a conventional diborane(4) is quaternised by either a neutral or anionic nucleophile. These compounds, either isolated or generated in situ, serve as relatively mild and convenient sources of the boryl anion [BR2](-) for use in organic synthesis and have already proven their efficacy in metal-free as well as metal-catalysed borylation reactions. This Feature article documents the history of sp(2)-sp(3) diborane synthesis, their properties and surprising structural variability, and their burgeoning utility in organic synthesis. PMID- 25912807 TI - Rapid and reliable discrimination between Shigella species and Escherichia coli using MALDI-TOF mass spectrometry. AB - E. coli-Shigella species are a cryptic group of bacteria in which the Shigella species are distributed within the phylogenetic tree of E. coli. The nomenclature is historically based and the discrimination of these genera developed as a result of the epidemiological need to identify the cause of shigellosis, a severe disease caused by Shigella species. For these reasons, this incorrect classification of shigellae persists to date, and the ability to rapidly characterize E. coli and Shigella species remains highly desirable. Until recently, existing matrix-assisted laser desorption/ionization-time of flight mass spectrometry (MALDI-TOF MS) assays used to identify bacteria could not discriminate between E. coli and Shigella species. Here we present a rapid classification method for the E. coli-Shigella phylogroup based on MALDI-TOF MS which is supported by genetic analysis. E. coli and Shigella isolates were collected and genetically characterized by MLVA. A custom reference library for MALDI-TOF MS that represents the genetic diversity of E. coli and Shigella strains was developed. Characterization of E. coli and Shigella species is based on an approach with Biotyper software. Using this reference library it was possible to distinguish between Shigella species and E. coli. Of the 180 isolates tested, 94.4% were correctly classified as E. coli or shigellae. The results of four (2.2%) isolates could not be interpreted and six (3.3%) isolates were classified incorrectly. The custom library extends the existing MALDI-TOF MS method for species determination by enabling rapid and accurate discrimination between Shigella species and E. coli. PMID- 25912809 TI - Water-quality analysis of an intensively used on-farm storage reservoir in the northeast Arkansas delta. AB - The use of farm reservoirs for supplemental irrigation is gaining popularity in the Mississippi Alluvial Plain (MAP). Due to depletions of several aquifers, many counties within the MAP have been designated as critical-use groundwater areas. To help alleviate stress on these aquifers, many farmers are implementing storage reservoirs for economic and conservation benefits. When used in tandem with a tailwater recovery system, reservoirs have the potential to trap and transform potential contaminants (e.g., nutrients and pesticides) rather than releasing them through drainage into receiving systems such as lakes, rivers, and streams. Roberts Reservoir is an intensively used, 49-ha on-farm storage reservoir located in Poinsett County, Arkansas. Water-quality analyses and toxicity assessments of the reservoir and surrounding ditches indicated a stable water-quality environment with no observed toxicity present in collected samples. Results of this study suggest that water released into a local receiving stream poses no contaminant risk and could be maintained for irrigation purposes, thereby decreasing the need for additional groundwater depletion. PMID- 25912810 TI - Optimization of LipL32 PCR assay for increased sensitivity in diagnosing leptospirosis. AB - Early diagnosis of leptospirosis in humans is critical with regard to initiation of appropriate treatment; however, the gold standard serological test cannot detect antibodies until nearly a week after symptom onset. PCR has been shown to be sensitive and specific in the early phase of leptospirosis. Previously, we developed and validated a TaqMan PCR assay targeting lipL32. We reoptimized and validated this assay using PerfeCTa(r) qPCR ToughMix(r), Low ROXTM (Quanta Biosciences, Gaithersburg, MD, USA). For optimization with the new mix, the final primer concentrations were increased from 0.5 MUmol/L to 0.9 MUmol/L compared to our previous assay, and the probe concentration increased from 0.1 MUmol/L to 0.125 MUmol/L. This newly optimized assay resulted in a lower limit of detection and increased diagnostic sensitivity. Here, we present the performance data of the improved assay and describe several clinical cases that were initially negative but tested positive using the optimized assay. PMID- 25912811 TI - Hepatitis C-associated glomerulonephritis mimicking systemic lupus erythematosus. PMID- 25912812 TI - PtaRHE1, a Populus tremula * Populus alba RING-H2 protein of the ATL family, has a regulatory role in secondary phloem fibre development. AB - REALLY INTERESTING NEW GENE (RING) proteins play important roles in the regulation of many processes by recognizing target proteins for ubiquitination. Previously, we have shown that the expression of PtaRHE1, encoding a Populus tremula * Populus alba RING-H2 protein with E3 ubiquitin ligase activity, is associated with tissues undergoing secondary growth. To further elucidate the role of PtaRHE1 in vascular tissues, we have undertaken a reverse genetic analysis in poplar. Within stem secondary vascular tissues, PtaRHE1 and its corresponding protein are expressed predominantly in the phloem. The downregulation of PtaRHE1 in poplar by artificial miRNA triggers alterations in phloem fibre patterning, characterized by an increased portion of secondary phloem fibres that have a reduced cell wall thickness and a change in lignin composition, with lower levels of syringyl units as compared with wild-type plants. Following an RNA-seq analysis, a biological network involving hormone stress signalling, as well as developmental processes, could be delineated. Several candidate genes possibly associated with the altered phloem fibre phenotype observed in amiRPtaRHE1 poplar were identified. Altogether, our data suggest a regulatory role for PtaRHE1 in secondary phloem fibre development. PMID- 25912813 TI - Genetic management of Dutch golden retriever dogs with a simulation tool. AB - Excessive inbreeding rates and small effective population sizes are an important problem in many populations of dogs. Proper genetic management of these populations can decrease the problem, and several measures are available. However, the effectiveness of these measures is not clear beforehand. Therefore, a simulation model was developed to test measures that aim to decrease the rate of inbreeding. The simulation program was used to evaluate inbreeding restriction measures in the Dutch golden retriever dog population. This population consisted of approximately 600 dams and 150 sires that produce 300 litters each year. The five most popular sires sire approximately 25% of the litters in a year. Simulations show that the small number of popular sires and their high contribution to the next generation are the main determinants of the inbreeding rates. Restricting breeding to animals with a low average relatedness to all other animals in the population was the most effective measure and decreased the rate of inbreeding per generation from 0.41 to 0.12%. Minimizing co-ancestry of parents was not effective in the long run, but decreased variation in inbreeding rates. Restricting the number of litters per sire generally decreased the generation interval because sires were replaced more quickly, once they met their restriction. In some instances, this lead to an increase in inbreeding rates because the next generations were more related. The simulation tool proved to be a powerful and educational tool for deciding which breeding restrictions to apply, and can be effective in different breeds and species as well. PMID- 25912814 TI - Nanomedicine and neurodegenerative disorders: so close yet so far. AB - This editorial provides an overview of the main advantages of the use of nanomedicine-based approach for innovation in the treatment of neurodegenerative diseases. Besides these aspects, a critical analysis on the main causes that slow the application of nanomedicine to brain disorders is given along with the identification of possible solutions and possible interventions. Better communication between the main players of research in this field and a detailed understanding of the most critical issues to be addressed should help in defining future directions towards the improvement and, finally, the clinical application of nanomedicine to neurodegenerative diseases. PMID- 25912815 TI - Metabolites and chloroplast retrograde signaling. AB - Intracellular signaling from chloroplast to nucleus followed by a subsequent response in the chloroplast is called retrograde signaling. It not only coordinates the expression of nuclear and chloroplast genes, which is essential for chloroplast biogenesis, but also maintains chloroplast function at optimal levels in response to fluxes in metabolites and changes in environmental conditions. In recent years several putative retrograde signals have been identified and signaling pathways have been proposed. Here we review retrograde signals derived from tetrapyrroles, carotenoids, nucleotides and isoprene precursors in response to abiotic stresses, including oxidative stress. We discuss the responses that these signals elicit and show that they not only modify chloroplast function but also influence other aspects of plant development and adaptation. PMID- 25912816 TI - Exploitation of complement regulatory proteins by Borrelia and Francisella. AB - Pathogens have developed sophisticated mechanisms of complement evasion such as binding to the host complement regulatory proteins (CRPs) on their surface or expression of CRP mimicking molecules. The ability of pathogens to evade the complement system has been correlated with pathogenesis and host selectivity. Hitherto, little work has been undertaken to determine whether Borrelia and Francisella exploit various CRPs to block complement attack. Seventeen Borrelia (twelve species) and six Francisella (three subspecies) strains were used to assess their ability to bind human, sheep and cattle CRPs or mimic membrane associated complement regulators. A series of experiments including affinity ligand binding experiments, pull-down assays and mass spectrometry based protein identification, revealed an array of CRP binding proteins of Borrelia and Francisella. Unlike Francisella, Borrelia strains were able to bind multiple human CRPs. Three strains of Borrelia (SKT-4, SKT-2 and HO14) showed the presence of a human CD46-homologous motif, indicating their ability to possess putative human CD46 mimicking molecules. Similarly, five strains of Borrelia and two strains of Francisella may have surface proteins with human CD59-homologous motifs. Among ovine and bovine CRPs, the only CRP bound by Francisella (LVS, Tul4 strain) was vitronectin, while ovine C4BP, ovine factor H and bovine factor H were bound to Borrelia strains SKT-2, DN127 and Co53. This study presents an array of proteins of Borrelia and Francisella that bind CRPs or may mimic membrane-CRPs, thus enabling multiphasic complement evasion strategies of these pathogens. PMID- 25912817 TI - The dengue virus NS5 protein as a target for drug discovery. AB - The non-structural protein 5 (NS5) of flaviviruses is the most conserved amongst the viral proteins. It is about 900 kDa and bears enzymatic activities that play vital roles in virus replication. Its N-terminal domain encodes dual N7 and 2'-O methyltransferase activities (MTase), and possibly guanylyltransferase (GTase) involved in RNA cap formation. The C-terminal region comprises a RNA-dependent RNA polymerase (RdRp) required for viral RNA synthesis. Both MTase and RdRp activities of dengue virus NS5 are well characterized, structurally and functionally. Numerous crystal structures of the flavivirus MTase and RdRp domains have been solved. Inhibitors of both functions have been identified through screening activities using biochemical and cell-based assays, as well as via rational design approaches. This review summaries the current knowledge as well as prospective views on these aspects. This article forms part of a symposium on flavivirus drug discovery in Antiviral Research. PMID- 25912818 TI - Saururus chinensis (Lour.) Baill blocks enterovirus 71 infection by hijacking MEK1-ERK signaling pathway. AB - The aerial parts of Saururus chinensis (Lour.) Baill are a Chinese herbal medicine used for the treatment of edema and inflammatory diseases. However, the effect of this medicine on enterovirus 71 (EV71) infection has not been explored. Previous studies showed that MEK1-ERK signal pathway was required for efficient replication of EV71 infection and inhibition of this signal pathway has been shown to suppress virus infection. Here we show that the water extract of S. chinensis (Lour.) Baill (SCB) significantly blocks EV71 infection by inhibiting the activation of MEK1-ERK signal pathway with an IC50 of 8.9MUg/mL. SCB at 30 and 60 MUg/mL blocked EV71-induced cytopathic effect (CPE) and production of infectious virion by 1.9 and 5.1 logs, respectively. Virucidal assay suggested that SCB had no virucidal activity against EV71 and probably exerted its effect by targeting multiple steps in EV71 infection. Knockdown of MEK1 but not MEK2 blocked EV71 replication. And SCB treatment inhibited the activation of MEK1-ERK signal during EV71 infection. Furthermore, we found that rutin at 200 MUM, one of the major components of SCB, significantly suppressed EV71 induced CPE and inhibited viral replication in a dose dependent manner. Taken together, SCB inhibited EV71 infection by hijacking MEK1-ERK signal pathway and rutin was the responsible antiviral component of SCB. PMID- 25912819 TI - Knockout of the adp gene related with colonization in Bacillus nematocida B16 using customized transcription activator-like effectors nucleases. AB - Bacillus nematocida B16 is able to dominate in the intestines of the worm Caenorhabditis elegans in 'Trojan horse' pathogenic mechanism. The adp is one candidate gene which potentially play a vital role in the colonization from our previous random mutagenesis screening results. To analyse the functional role of this gene, we constructed the adp knockout mutant through customized transcription activator-like effectors nucleases (TALEN), which has been successfully used in yeasts, nematodes, zebrafish and human pluripotent cells. Here, we first time report this knockout method in bacteria on this paper. Bioassay experiments demonstrated that the adp knockout mutant of B16 showed considerably lower colonization activity, reduced numbers of intestines and less than 80% nematocidal activity compared with the wild-type strain when infected for 48 h. However, no obvious change on proteolytic activity was observed in the mutant. Conversely, the complementation of adp gene restored most of the above deficient phenotypes. These results indicated that the adp gene was involved in surface adhesion and played a comparatively important role in colonizing host nematodes. Moreover, TALENs successfully disrupt target genes in bacteria. PMID- 25912820 TI - A new approach for deciphering between single and multiple accumulation events using intra-tooth isotopic variations: Application to the Middle Pleistocene bone bed of Schoningen 13 II-4. AB - It is often difficult to differentiate between archaeological bonebeds formed by one event such as a mass kill of a single herd, and those formed by multiple events that occurred over a longer period of time. The application of high temporal resolution studies such as intra-tooth isotopic profiles on archaeological mammal cohorts offers new possibilities for exploring this issue, allowing investigators to decipher between single and multiple accumulation events. We examined (18)O and (13)C isotopic variations from the enamel carbonate of 23 horse third molars from the Middle Pleistocene archaeological site of Schoningen. We employed a new approach to investigate processes of fossil accumulation that uses both bulk and intra-tooth isotopic variations and takes into account animal behavior, age at death and dental development to test the degree of isotopic affinity of animals from the same fossil assemblage. Oxygen and carbon isotope bulk values indicate that the horses from Schoningen 13 II-4 experienced relatively similar climatic and dietary regimes. Inter-individual differences of the bulk values of the horses sampled in the current study present nevertheless inter-individual variability similar to individuals from multi layered localities. In addition, the intra-tooth isotopic variation of specimens of the same age at death seems to indicate that the studied cohort corresponds to a mix of individuals that recorded both similar and different isotopic histories. Finally, the conditions recorded in the isotopic signal shortly before death (i.e., for teeth not fully mineralized) varied between sampled individuals, suggesting possible differences in the seasonality of death. Considering those results, we discuss the possibility that the horses from Schoningen 13 II-4 correspond to an accumulation of different death events. PMID- 25912821 TI - Predicting the emergence of anemia--A large cohort study. AB - BACKGROUND AND OBJECTIVES: We aimed to find predictors for development of anemia in a large cohort of adults. PATIENTS AND METHODS: Cohort study of a large health database from a screening center at the Rabin Medical Center in Israel, between the years 2000-2013. We asked which variables, known at the first visit, would predict anemia at the last visit. Multivariable analysis was conducted using stepwise logistic regression analysis. Odds ratios (ORs) for anemia with 95% confidence intervals (CIs) were calculated. RESULTS: Our cohort included 10,577 people. At baseline 4.4% were diagnosed with anemia and excluded. Therefore, 10,093 subjects, with a mean age of 42.3 +/- 9 years comprised our study sample. At the end of follow-up of 4.7 +/- 3.1 years, 307 developed anemia (3%). In men, independent predictors for development of anemia were diabetes mellitus (OR 3.00, 95% CI 1.41-6.39), age (OR 1.03, 95% CI 1.03-1.05, for 1 year increment), low MCV (OR 0.92, 95% CI 0.89-0.96, for every 1 fL unit increment) and elevated platelet count (OR 1.004, 95% CI 1.00-1.01 for 1000/MUL unit increment). For women, high total serum protein level was a strong predictor for anemia (OR 3.44, 95% CI 2.33 5.08 for 1mg/dL increment) as well as low triglycerides (OR 0.996, 95% CI 0.993 1.000 for 1mg/dL increment). CONCLUSIONS: Subgroups who are prone to develop anemia include men with diabetes, and women with an elevated serum protein level and low triglycerides. PMID- 25912822 TI - Association of tuberculosis and deep venous thromboembolism in patients with autoimmune diseases. PMID- 25912823 TI - Nutrient- and other stress-responsive microRNAs in plants: Role for thiol-based redox signaling. AB - Now it is well recognized that the microRNA (miRNA) expression is altered in response to internal (developmental or hormonal) or external stimuli such as biotic and abiotic stresses in plants. It is also known that several miRNAs are induced in response to deficiency of specific nutrients within the plant or in the external sources, i.e., soil/nutrient media. For instance, P-deprivation induces miR399, S-deprivation induces miR395 and Cu-deprivation induces miR398, miR397 and miR408 in several plant species. Although the transcription factors (PHR1, SLIM1 and SPB7) that regulate these nutrient-deprivation inducible miRNAs have been identified but the upstream biochemical pathway that activates them is relatively unknown. In a recent study, we demonstrated for the first time that redox signaling plays a critical role in S-deprivation-inducible miR395 expression in Arabidopsis. In this short review, we draw additional hypotheses for the involvement of redox signaling and/or reactive oxygen species (ROS) signaling in inducing other nutrient or stress-responsive miRNAs in plants. PMID- 25912824 TI - Therapeutic targeting of Bcl-2 family for treatment of B-cell malignancies. AB - The BCL2 gene was discovered nearly 30 years ago, launching a field of scientific inquiry and medical research with the potential for delivering transformational therapeutics. Revealed by its involvement in chromosomal translocations of B-cell lymphomas, BCL2 is the founding member of a family of cell survival genes that endow cells with long life spans and provide protection from a myriad of cellular stresses, including chemotherapy. Anti-apoptotic Bcl-2 family members are commonly overexpressed in a variety of human malignancies through a diversity of genetic and epigenetic mechanisms. Here, we review therapeutic strategies for targeting Bcl-2 family members with an emphasis on B-cell malignancies, providing insights into their current promise and remaining challenges. PMID- 25912825 TI - Prediction of Symptom Change in Placebo Versus No-Treatment Group in Experimentally Induced Motion Sickness. AB - The long-standing question of who responds to placebo and who does not is of great theoretical and clinical relevance and has received increasing attention in recent years. We therefore performed a post hoc analysis of one of our previously published studies on placebo responses (PRs). In the analysis, fourteen potential predictors for the PR on experimentally induced motion sickness in 32 healthy volunteers were explored using moderated multiple regression. Generalized self efficacy, generalized self, internal locus of control and cognitive flexibility were significantly associated with symptom improvement in the placebo group, as compared to the untreated control group. Notably, the directions of the associations were such that the "unfavorable" side of the constructs (e.g. low self-efficacy) predicted a higher PR. Instead, the "favorable" side predicted symptom improvement in the control group. Results fit well with prior research into psychological influences on motion sickness. Although PRs in motion sickness are not well established, it is suggested to include the identified constructs in future research involving motion sickness-related symptoms such as nausea and vertigo. Concerning PRs in general, the results may have implications for clinical as well as experimental research on other symptoms and disorders, such as pain or depression. PMID- 25912826 TI - The similarity question for biologicals and non-biological complex drugs. AB - For small - low molecular weight - molecule medicines a robust regulatory system has evolved over the years. This system guarantees high and constant quality of our (generic) medicines. Pharmaceutical equivalence and bioequivalence assessment are the pillars under that system. But there are complex medicines where the question of equivalence is more challenging to answer. For biologicals the paradigm of similarity rather than equality (the emergence of 'biosimilars') was developed in the past decade. This has been a program where an evolutionary, science based approach has been chosen by the frontrunner regulatory body, the EMA, with a 'learn and confirm' character. In addition, there is another group of complex drugs, the non-biological complex drugs, NBCDs, where the generic paradigm can be challenged as well. The NBCDs are defined as: 1. consisting of a complex multitude of closely related structures; 2. the entire multitude is the active pharmaceutical ingredient; 3. the properties cannot be fully characterized by physicochemical analysis and 4. the consistent, tightly controlled manufacturing process is fundamental to reproduce the product. NBCDs encompass product families such as the glatiramoids, liposomes, iron-carbohydrate colloids and many candidates of the group of the upcoming nanoparticulate systems. Following the main principles of regulatory pathways for biologicals (with appropriate product-by-product adjustments), instead of that for small molecules, would be the more logical strategy for these NBCDs. The status and outstanding regulatory issues for biosimilars and NBCD-similars/follow on versions were discussed at a conference in Budapest, Hungary (October 2014) and this commentary touches upon the issues brought up in the presentations, deliberations and conclusions. PMID- 25912827 TI - Quality improvement of melt extruded laminar systems using mixture design. AB - This study investigates the application of melt extrusion for the development of an oral retard formulation with a precise drug release over time. Since adjusting the formulation appears to be of the utmost importance in achieving the desired drug release patterns, different formulations of laminar extrudates were prepared according to the principles of Experimental Design, using a design for mixtures to assess the influence of formulation composition on the in vitro drug release from the extrudates after 1h and after 8h. The effect of each component on the two response variables was also studied. Ternary mixtures of theophylline (model drug), monohydrate lactose and microcrystalline wax (as thermoplastic binder) were extruded in a lab scale vertical ram extruder in absence of solvents at a temperature below the melting point of the binder (so that the crystalline state of the drug could be maintained), through a rectangular die to obtain suitable laminar systems. Thanks to the desirability approach and a reliability study for ensuring the quality of the formulation, a very restricted optimal zone was defined within the experimental domain. Among the mixture components, the variation of microcrystalline wax content played the most significant role in overall influence on the in vitro drug release. The formulation theophylline:lactose:wax, 57:14:29 (by weight), selected based on the desirability zone, was subsequently used for in vivo studies. The plasma profile, obtained after oral administration of the laminar extruded system in hard gelatine capsules, revealed the typical trend of an oral retard formulation. The application of the mixture experimental design associated to a desirability function permitted to optimize the extruded system and to determine the composition space that ensures final product quality. PMID- 25912828 TI - In situ monitoring of corrosion mechanisms and phosphate inhibitor surface deposition during corrosion of zinc-magnesium-aluminium (ZMA) alloys using novel time-lapse microscopy. AB - In situ time-lapse optical microscopy was used to examine the microstructural corrosion mechanisms in three zinc-magnesium-aluminium (ZMA) alloy coated steels immersed in 1% NaCl pH 7. Preferential corrosion of MgZn(2) lamellae within the eutectic phases was observed in all the ZMA alloys followed by subsequent dissolution of Zn rich phases. The total extent and rate of corrosion, measured using time-lapse image analysis and scanning vibrating electrode technique (SVET) estimated mass loss, decreased as Mg and Al alloying additions were increased up to a level of 3 wt% Mg and 3.7 wt% Al. This was probably due to the increased presence of MgO and Al(2)O(3) at the alloy surface retarding the kinetics of cathodic oxygen reduction. The addition of 1 * 10(-2) mol dm(-3) Na(3)PO(4) to 1% NaCl pH 7 had a dramatic influence on the corrosion mechanism for a ZMA with passivation of anodic sites through phosphate precipitation observed using time lapse image analysis. Intriguing rapid precipitation of filamentous phosphate was also observed and it is postulated that these filaments nucleate and grow due to super saturation effects. Polarisation experiments showed that the addition of 1 * 10(-2) mol dm(-3) Na(3)PO(4) to the 1% NaCl electrolyte promoted an anodic shift of 50 mV in open circuit potential for the ZMA alloy with a reduction in anodic current of 2.5 orders of magnitude suggesting that it was acting primarily as an anodic inhibitor supporting the inferences from the time-lapse investigations. These phosphate additions resulted in a 98% reduction in estimated mass loss as measured by SVET demonstrating the effectiveness of phosphate inhibitors for this alloy system. PMID- 25912829 TI - S100A14 is a novel independent prognostic biomarker in the triple-negative breast cancer subtype. AB - Triple-negative breast cancer (TNBC) represents a heterogeneous subgroup with generally poor outcome and lack of an effective targeted therapy. Prognostic or predictive biomarkers to guide treatment decisions for this group of patients are needed. To evaluate the potential of S100A14 protein as a novel biomarker in TNBC, the protein expression of S100A14 was correlated with clinical outcomes in a Pilot Sample set and a Danish cohort of predominantly TNBC patients. Kaplan Meier analysis identified a prognostic impact of S100A14 on disease-free survival and overall survival, showing that tumors with high S100A14 protein expression levels were significantly correlated with poor outcome in TNBC patients (p = 0.017; p = 0.038), particularly those in the basal-like subgroup (p = 0.006; p = 0.037). Importantly, TNBC patients with high S100A14 expression, but tumor negative axillary lymph nodes (N-), had equally poor outcomes as those with tumor positive axillary lymph nodes (N+), while TNBC/N- patients with low S100A14 expression had a significantly better disease free survival (p = 0.013). Multivariate analysis revealed that S100A14 is an independent prognostic factor for TNBC patients (p = 0.024; p = 0.05). At the cellular level, S100A14 was found to be expressed in epithelial-like, but not in mesenchymal-like, TNBC cells in vitro. S100A14 is an independent prognostic factor in TNBC and a novel potential therapeutic target in TNBC. PMID- 25912830 TI - Diagnosis: Melanoderma after Hematopoietic Stem Cell Transplantation. PMID- 25912831 TI - Self-assembly and coverage dependent thermally induced conformational changes of Ni(II)-meso-tetrakis (4-tert-butylphenyl) benzoporphyrin on Cu(111). AB - A systematic scanning tunnelling microscopy investigation of the self-assembly and of thermally induced conformational changes of Ni(II)-meso-tetrakis (4-tert butylphenyl) benzoporphyrin (Ni-TTBPBP) on Cu(111) is presented. At room temperature, Ni-TTBPBPs diffuse on the surface and self-assemble into ordered islands with well-defined registry to the substrate, with two different azimuthal orientations. The formation of the characteristic supramolecular structure is attributed to van der Waals interactions between the tert-butyl groups. Upon moderate heating, the intramolecular conformation changes irreversibly due to a dehydrogenative intramolecular aryl-aryl coupling reaction. This reaction is coverage dependent, with a lower rate at higher initial coverage; this behaviour is attributed to a stabilization of Ni-TTBPBP in the ordered islands at higher coverage. PMID- 25912832 TI - In vitro cytotoxicity induced by Clostridium perfringens isolate carrying a chromosomal cpe gene is exclusively dependent on sporulation and enterotoxin production. AB - Clostridium perfringens type A is a common source of food poisoning (FP) and non food-borne (NFB) gastrointestinal diseases in humans. In the intestinal tract, the vegetative cells sporulate and produce a major pathogenic factor, C. perfringens enterotoxin (CPE). Most type A FP isolates carry a chromosomal cpe gene, whereas NFB type A isolates typically carry a plasmid-encoded cpe. In vitro, the purified CPE protein binds to a receptor and forms pores, exerting a cytotoxic activity in epithelial cells. However, it remains unclear if CPE is indispensable for C. perfringens cytotoxicity. In this study, we examined the cytotoxicity of cpe-harboring C. perfringens isolates co-cultured with human intestinal epithelial Caco-2 cells. The FP strains showed severe cytotoxicity during sporulation and CPE production, but not during vegetative cell growth. While Caco-2 cells were intact during co-culturing with cpe-null mutant derivative of strain SM101 (a FP strain carrying a chromosomal cpe gene), the wild-type level cytotoxicity was observed with cpe-complemented strain. In contrast, both wild-type and cpe-null mutant derivative of the NFB strain F4969 induced Caco-2 cell death during both vegetative and sporulation growth. Collectively, the Caco-2 cell cytotoxicity caused by C. perfringens strain SM101 is considered to be exclusively dependent on CPE production, whereas some additional toxins should be involved in F4969-mediated in vitro cytotoxicity. PMID- 25912833 TI - Newborns prefer the odor of milk and nipples from females matched in lactation age: Comparison of two mouse strains. AB - Newborn mice are attracted to mammary odor cues carried in murine milk and nipple secretions. However, murine milk odor is not equally attractive along lactation. The present study focuses on the differential response of 2day-old mouse pups of C57Bl/6 (C) and Balb/C (B) strains to the odor of milk (Experiment 1) and nipples (Experiment 2) that are matched/unmatched in terms of pup's age or strain. In Experiment 1, C and B pups were tested in a series of tests simultaneously opposing either murine milk and a blank (water), or two milks collected in early and late lactation (lactation days 2 and 15, respectively) from females belonging to their own or the other strain. Results showed that C and B pups were attracted to the odor of the different milks regardless of the lactation age and the strain of the donor female. Nevertheless, C and B pups preferred the odor conveyed by early- than late-lactation milk of either strain. Moreover, early-lactation milk from C females was more attractive than early-lactation milk from B females for pups of either strain. In Experiment 2, differential nipple grasping response of C and B pups was measured when they were exposed to nipples of females in early or late lactation. The proportion of C pups that grasped a nipple was greater when they were exposed to a nipple in early lactation regardless of the strain of the donor females, whereas the proportion of B pups that grasped a nipple was greater when they were exposed to a nipple in early lactation, but only from own strain. Thus, newborn mice prefer the odor of milk and nipples from females that are matched in lactation age. This result is discussed in terms of reciprocally adaptive mechanisms between lactating females and their newborn offspring. PMID- 25912834 TI - Light colour and intensity alters reproductive/seasonal responses in Japanese quail. AB - An extensive literature is available on the photoperiodic responses of avian species but studies on light colour and wavelength from light emitting diode (LED) sources on reproduction are limited. Hence, an experiment was designed to study the effect of different colours and intensities of light on the reproductive responses of Japanese quail. Three-week old quail were exposed to five different light conditions with a long photoperiod (LD 16:8): WT (white fluorescent light 100 lux as control), W LED (white light emitting diode, 30 lux), B LED (blue LED, 30 lux), G LED (green LED, 30 lux) and R-LED (red LED, 30 lux). The cloacal gland size, an indicator of androgenic activity, was monitored weekly. The results indicated an early initiation of gonadal growth in WT quail which continued and maintained a plateau throughout the period of study. On the other hand, in general low intensity light, there was a decreased amplitude of the reproductive cycle and the quail exposed to different colour lights (green, red and blue lights) used different incubation times to initiate their gonadal growth and exhibited a gonadal cycle of a different duration up to 15.5 weeks. Thereafter, the gonad of quail of all the LED groups started developing again (including the blue LED exposed quail which remained undeveloped until this age) and attained the increased degree of growth until 26.5 weeks of age. During the second cycle, gonads of green and red light exposed quail continued to increase and maintained a plateau of development similar to WT exposed control while white and blue LED exposed quail exhibited spontaneous regression and attained complete sexual quiescence. Based on our study, it is suggested that long term exposure to blue LED light of low intensity may induce gonadal regression even under long-day conditions (LD 16:8), while exposure to green and red lights appears to maintain a constant photosensitivity after one complete gonadal cycle. PMID- 25912835 TI - Hepatitis E Virus Infection as a Possible Cause of Acute Liver Failure in Europe. AB - BACKGROUND & AIMS: In Western countries, infection with the hepatitis E virus (HEV) is considered to be rare and imported from endemic regions. However, the prevalence of HEV infection has increased among adults in central Europe. HEV infection can cause acute liver failure (ALF), but there have been only a few confirmed cases of HEV-associated ALF in Europe. We investigated the number of cases of indeterminate ALF associated with HEV infection. METHODS: We performed a retrospective analysis of 80 patients diagnosed with ALF or acute hepatitis at the University Hospital Essen in Germany from November 2006 through December 2013. Clinical data were collected from the hospital databases; archived sera were tested for IgG and IgM against HEV, as well as HEV RNA. RESULTS: Sera from 12 patients (15%) tested positive for IgG against HEV IgG; 7 of these samples did not test positive for HEV IgM or HEV RNA. Sera from 64 patients (80%) did not test positive for IgG or IgM against HEV or HEV RNA. Sera from 8 patients (10%) tested positive for HEV RNA (only 4 of these were positive for HEV IgG) and had clinical findings to support acute HEV infection. CONCLUSIONS: In a hospital in Germany, approximately 10% to 15% of patients with ALF had evidence for HEV infection. Serologic tests for IgG against HEV are insufficient to identify or exclude HEV infection; tests for HEV RNA also should be performed on patients with ALF of ambiguous etiology. PMID- 25912836 TI - Emergency Double-Stenting and Surgery for the Successful Management of Massive Upper Gastrointestinal Bleeding Caused by Mycotic Aortic Aneurysm. PMID- 25912837 TI - Elastography in Overweight and Obese Patients With Chronic Liver Disease. PMID- 25912838 TI - Association Between Severe Portal Hypertension and Risk of Liver Decompensation in Patients With Hepatitis C, Regardless of Response to Antiviral Therapy. AB - BACKGROUND & AIMS: Hepatic venous pressure gradient (HVPG) is associated with a risk of liver events in patients with chronic hepatitis C. Antiviral therapies that lead to a sustained virologic response (SVR) reduce portal pressure and prevent liver disease progression. However, it is not clear to what extent the progression of hepatitis C is modified once patients develop cirrhosis with severe portal hypertension (CSPH) (HVPG >= 10 mm Hg). We assessed the effects of HVPG and SVR on the risk of liver decompensation, hepatocellular carcinoma, and/or death in patients with hepatitis C-related cirrhosis. METHODS: We collected data from 100 patients with hepatitis C and compensated cirrhosis who underwent HVPG measurement 3 months or less before (baseline) and 24 weeks after therapy with pegylated interferon alfa-2a and ribavirin at 4 hospitals in Spain, from 2001 through 2009. SVR was defined as undetectable serum HCV RNA level 24 weeks after treatment ended. Clinical data were collected until death, liver transplantation, or December 2012 (median, 5 y; interquartile range, 1.4-7 y). RESULTS: Seventy-four patients had CSPH at baseline and 35% of patients achieved an SVR. During the follow-up period, 19 patients developed liver decompensation (ascites, variceal bleeding, or encephalopathy). The actuarial probability values for liver decompensation at 1, 5, and 7 years were 3%, 19% and 22%, respectively. The baseline level of HVPG, but not SVR, was associated independently with the risk of liver decompensation. CONCLUSIONS: Patients with CSPH, regardless of an SVR to therapy for hepatitis C, remain at risk for liver decompensation within the first 5 years after treatment; they should be monitored closely. PMID- 25912839 TI - Features of Gastric Carcinoma With Lymphoid Stroma Associated With Epstein-Barr Virus. AB - BACKGROUND & AIMS: Gastric carcinoma with lymphoid stroma (GCLS) is a distinct histologic subtype of gastric cancer that is characterized by undifferentiated carcinoma mixed with prominent lymphoid infiltration. More than 80% of GCLS cases are associated with Epstein-Barr virus (EBV) infection, but it is unclear if the virus affects disease progression. We investigated how EBV infection affects the clinical and pathologic features of GCLS, as well as patients' outcomes. METHODS: We performed a retrospective analysis of 274 patients (mean age, 56.8 y; 85.4% male) diagnosed with GCLS, based on pathology findings, from March 1998 through December 2012 at the Asan Medical Center in Seoul, South Korea. Their data were compared with those from 822 age- and sex-matched patients who underwent resection for gastric adenocarcinoma. EBV was detected in tumor samples by in situ hybridization. RESULTS: Of the 274 patients with GCLS, 236 had EBV-positive tumors (86.1%) and 38 had EBV-negative tumors (13.9%). EBV-positive GCLS was more prevalent than EBV-negative GCLS in younger patients, tended to be located proximally, and was more frequently of an early stage macroscopic type. The 10 year, disease-specific rates of survival were 89.1% for patients with EBV positive GCLS and 66.9% for patients with EBV-negative GCLS (P = .009). Patients with EBV-negative GCLS had clinical and pathologic features and survival times similar to those of patients with conventional adenocarcinoma. By multivariate analysis, longer survival time was associated with EBV-positive tumors (P = .007), younger patient age (P = .002), smaller tumor size (P = .046), lower stage (based on American Joint Committee on Cancer classification; P < .001), and lack of lymphovascular invasion (P = .012). The proportion of undifferentiated tumor cells was not associated significantly with patient survival time. CONCLUSIONS: Clinical and pathologic features of GCLS differ based on EBV infection status. EBV-negative GCLS is similar to conventional adenocarcinoma, and patients have similar survival times. EBV status may be more important than the proportion of undifferentiated tumor cells in the diagnosis of GCLS and management of patients. PMID- 25912840 TI - Ciprofloxacin pharmacokinetics in critically ill patients receiving concomitant continuous venovenous hemodialysis. PMID- 25912841 TI - Applying thermosettable zwitterionic copolymers as general fouling-resistant and thermal-tolerant biomaterial interfaces. AB - We introduced a thermosettable zwitterionic copolymer to design a high temperature tolerance biomaterial as a general antifouling polymer interface. The original synthetic fouling-resistant copolymer, poly(vinylpyrrolidone)-co poly(sulfobetaine methacrylate) (poly(VP-co-SBMA)), is both thermal-tolerant and fouling-resistant, and the antifouling stability of copolymer coated interfaces can be effectively controlled by regulating the VP/SBMA composition ratio. We studied poly(VP-co-SBMA) copolymer gels and networks with a focus on their general resistance to protein, cell, and bacterial bioadhesion, as influenced by the thermosetting process. Interestingly, we found that the shape of the poly(VP co-SBMA) copolymer material can be set at a high annealing temperature of 200 degrees C while maintaining good antifouling properties. However, while the zwitterionic PSBMA polymer gels were bioinert as expected, control of the fouling resistance of the PSBMA polymer networks was lost in the high temperature annealing process. A poly(VP-co-SBMA) copolymer network composed of PSBMA segments at 32 mol % showed reduced fibrinogen adsorption, tissue cell adhesion, and bacterial attachment, but a relatively higher PSBMA content of 61 mol % was required to optimize resistance to platelet adhesion and erythrocyte attachment to confer hemocompatibility to human blood. We suggest that poly(VP-co-SBMA) copolymers capable of retaining stable fouling resistance after high temperature shaping have a potential application as thermosettable materials in a bioinert interface for medical devices, such as the thermosettable coating on a stainless steel blood-compatible metal stent investigated in this study. PMID- 25912842 TI - Laparoscopic nephron sparing surgery: an Australian experience. AB - BACKGROUND: The objective of this study was to evaluate clinical outcomes from our initial experience with laparoscopic nephron sparing surgery (LNSS) for small renal masses in Australian practice. METHODS: A retrospective review was performed on an initial 50 patients undergoing LNSS. All procedures performed between April 2006 and September 2012 were included with median follow-up of 30 months. Outcomes measured were: positive surgical margin, warm ischaemic time, total operative time, blood transfusion and complications in the first 30 days after surgery. RESULTS: The mean age of patients was 57 years. The mean pre operative creatinine was 85 MUmol/L and the mean post-operative creatinine was 89 MUmol/L. Sixty-four per cent of the tumours were malignant tumours. The mean size of tumours was 2.5 cm. There were two malignant positive surgical margins on histology. The mean total operative time was 224 min and the mean warm ischaemic time was 24 min. Nine patients had complications with Clavien-Dindo grade III or lower. There was no grade IV or V complication. No patients were lost to follow up and there have been no tumour recurrences to date. CONCLUSIONS: LNSS is emerging as a viable alternative to open NSS for small renal tumours with lower morbidity and equivalent oncological and functional outcomes. There is, however, a steep learning curve associated with the procedure. PMID- 25912843 TI - Relationship between 18-F-fluoro-deoxy-D-glucose uptake and expression of glucose transporter 1 and pyruvate kinase M2 in intrahepatic cholangiocarcinoma. AB - BACKGROUND: Cholangiocellular carcinoma is characterized by elevated glucose consumption, resulting in an increased uptake of 18F-2-fluoro-2-deoxy-d-glucose (18F-FDG). This study investigates the relationship between 18F-FDG uptake and tumour glucose metabolism. METHODS: This was a retrospective analysis of 19 patients with cholangiocellular carcinoma. Immunohistochemistry for glucose transporter 1 and pyruvate kinase type M2 were performed. Overall tumour glucose metabolism was evaluated by measuring 18F-FDG uptake and the protein expression levels of glucose transporter 1 and pyruvate kinase type M2. RESULTS: 18F-FDG uptake had a strong positive correlation with histological differentiation. Both tumour status (p=0.044) and tumour size (p=0.011) were correlated with primary tumour 18F-FDG uptake. Glucose transporter 1 expression correlated with histological differentiation (p=0.017), while pyruvate kinase type M2 expression tended to correlate with lymph node metastasis (p=0.051). Glucose transporter 1 expression was strongly related to the standard uptake value (p=0.001), but that of pyruvate kinase type M2 was not (p=0.461). CONCLUSIONS: Glucose transporter 1 expression exhibits a strong correlation with 18F-FDG uptake in cholangiocellular carcinoma tissue, while pyruvate kinase type M2 expression was not associated with fluoro-2-deoxy-d-glucose uptake. In addition to its glycolytic function, pyruvate kinase type M2 has a variety of roles and its expression may enhance tumour cell invasion and promote the lymph node metastasis of intrahepatic cholangiocarcinoma. PMID- 25912844 TI - Can Positron Emission Tomography and Computed Tomography Be a Substitute for Bone Marrow Biopsy in Detection of Bone Marrow Involvement in Patients with Hodgkin's or Non-Hodgkin's Lymphoma? AB - INTRODUCTION: Positron emission tomography and computed tomography (PET/CT) has become an important part of staging and treatment evaluation algorithms of lymphoma. We aimed to compare the results of PET/CT with bone marrow biopsy (BMB) with respect to bone marrow involvement (BMI) in patients with Hodgkin's lymphoma (HL) and aggressive non-Hodgkin's lymphoma (aNHL). METHODS: The medical files of a total of 297 patients diagnosed with HL or aNHL and followed at the hematology clinics of 3 major hospitals in Istanbul between 2008 and 2012 were screened retrospectively and 161 patients with classical HL and aNHL were included in the study. The patients were referred for PET/CT and BMB at the initial staging. BMB was performed as the reference standard for the evaluation of BMI. RESULTS: There were 61 (38%) HL and 100 (62%) aNHL patients. Concordant results were revealed between PET/CT and BMB in 126 patients (78%) (52 HL, 74 aNHL), 20 with positive PET/CT and BMB results and 106 with negative PET/CT and BMB results. There were discordant results in 35 patients (9 HL, 26 aNHL), 16 of them with positive BMB and negative PET/ CT results and 19 of them with negative BMB and positive PET/CT results. DISCUSSION AND CONCLUSION: We observed that PET/CT is effective to detect BMI, despite it alone not being sufficient to evaluate BMI in HL and aNHL. Bone marrow trephine biopsy and PET/CT should be considered as mutually complementary methods for detection of BMI in patients with lymphoma. In suspected focal involvement, combining biopsy and PET/CT might improve staging results. PMID- 25912845 TI - Isolation of pathogenic Yersinia enterocolitica strains from different sources in Izmir region, Turkey. AB - Yersinia enterocolitica is a foodborne pathogen that is very rarely encountered in Turkey. In this work, several human, porcine, and environmental samples collected from Izmir region in Turkey were examined for the presence of Y. enterocolitica using different cultivation and enrichment methods. A total of nine pathogenic Y. enterocolitica strains were isolated; five strains from pig stool and manure samples and four strains from waste water samples. On the other hand, no Y. enterocolitica was isolated from human diarrheal stool samples (n = 102) and from 12 gulf, canal, municipal pool, and well water samples. Biochemical and serological characterization of the nine Y. enterocolitica strains revealed that they belonged to three different bioserotypes: 4/O:3, 2/O:9, and 2/O:5,27. All the strains were deemed pathogenic based on virulence factor-specific PCR analysis. Detection of pathogenic Y. enterocolitica strains from the pig and waste water samples from the Izmir region indicates that Y. enterocolitica is a potential risk for public health. PMID- 25912846 TI - Modified isolation method of Arcobacter spp. from different environmental and food samples. AB - This study provides information on the occurrence of Arcobacter in several types of water and food products of animal origin in the Czech Republic. We processed 190 samples using the modified method, and the occurrence of Arcobacter spp. was confirmed in 36.8 % of these. This total incidence consisted of Arcobacter butzleri (27.3 %), Arcobacter cryaerophilus (8.4 %) and Arcobacter skirrowii (1.1 %). We newly described the common presence of Arcobacter spp. in sewage water in the Czech Republic that is released into waterways after processing in water treatment plants (86.7 %). All the acquired isolates were subject to detailed confirmation with subsequent species classification using multiplex PCR and matrix-assisted laser desorption/ionization time-of-flight mass spectrometry (MALDI-TOF MS). In this study, we used a modification of a method using passive filtration of an enriched sample, which could be suitable for the isolation of Arcobacter, especially in combination with Campylobacter selective agar chromogenic medium. Our studies have shown this agar to be quite suited to the isolation of Arcobacter and that it can be an appropriate instrument for accelerating culture diagnostics. PMID- 25912847 TI - A qualitative, and quantitative determination and pharmacokinetic study of four polyacetylenes from Radix Bupleuri by UPLC-PDA-MS. AB - This study was carried out to identify some new antidepressant compounds present in Radix Bupleuri (RB) and to develop a method for their quantitative analysis in rat serum for the first time. Four polyacetylenes, including two new compounds, were isolated from Bupleurum scorzonerifoliu and identified. An in vitro uptake study using rat synaptosomes showed that the polyacetylenes potently inhibited serotonin, norepinephrine and dopamine reuptake, and exhibited an antidepressant activity with a potency comparable with or better than their corresponding specific inhibitors. An ultra-performance liquid chromatography coupled with photodiode array detector (UPLC-PDA) method was developed for their quantitative analysis in rat serum. The analysis was performed on a Waters BEH C18 column (1.7 MUm, 100 * 2.1 mm i.d.) using a gradient system of acetonitrile and 0.03% trifluoroacetic acid water, with a detector wavelength of 315 nm. Only two polyacetylenes, ((2 Z,8 E,10 E)-pentadecatriene-4,6-diyn-1-ol (RB-2) and bupleurynol (RB-4)), were detected in the primarily pharmacokinetic study of the petroleum ether fraction of RB. Both were rapidly absorbed and slowly eliminated. The rat exposure was approximately linear under the studied dosages ranging from 22.5 to 90 g/kg herb. In summary, polyacetylenes appear to be the key components responsible for the antidepressant activity of RB, and could be used as chemical standards for the quality evaluation of RB. PMID- 25912848 TI - Metabolites identification and multi-component pharmacokinetics of ergostane and lanostane triterpenoids in the anticancer mushroom Antrodia cinnamomea. AB - Antrodia cinnamomea is a precious medicinal mushroom popularly used for adjuvant cancer therapy in Taiwan. Its major bioactive constituents are ergostane and lanostane triterpenoids. Although clinical trials for A. cinnamomea have been recently initiated, its metabolism remains unclear. The present study aims to elucidate the metabolism and pharmacokinetics of A. cinnamomea in rats. After oral administration of an ethanol extract, 18 triterpenoids and 8 biotransformed metabolites were detected in rats plasma by UHPLC/qTOF-MS. Four of the metabolites were prepared by semi-synthesis and fully identified by NMR, while the others were tentatively characterized by comparing with the metabolites of single compounds (antcins B, C, H and K). Furthermore, a multi-component pharmacokinetic study of A. cinnamomea was carried out to monitor the plasma concentrations of 14 triterpenoids (ergostanes 1-3, 5-8, 14-16; lanostanes 9, 10, 17, 19) and 2 metabolites (M5, M6) by LC/MS/MS in rats after oral administration of the ethanol extract (1.0 g/kg). The results showed that ergostanes and Delta(7,9(11)) lanostanes, but not Delta(8) lanostanes, could get into circulation. The low-polarity ergostanes (antcins B and C) undertook hydrogenation (C-3 or C-7 carbonyl groups) or hydroxylation to produce polar metabolites. High-polarity ergostanes (antcins H and K) and Delta(7,9(11)) lanostanes were metabolically stable. We also discovered that ergostanes and lanostanes showed remarkably different pharmacokinetic patterns. The ergostanes were generally absorbed and eliminated rapidly, whereas the lanostanes remained in the plasma at a low concentration for a relatively long time. The results indicate that high-polarity ergostanes are the major plasma-exposed components of A. cinnamomea, and may play an important role in its therapeutic effects. PMID- 25912849 TI - Identification of the absorbed components and metabolites of Zhi-Zi-Da-Huang decoction in rat plasma by ultra-high performance liquid chromatography coupled with quadrupole-time-of-flight mass spectrometry. AB - Zhi-Zi-Da-Huang decoction (ZZDHD), consisting of Gardenia jasminoides Ellis, Rheum palmatum L., Citrus aurantium L. and Sojae Semen Praeparatum, is a widely used traditional Chinese medicine preparation for the treatment of acute or chronic hepatic diseases. In the present study, a sensitive and selective ultra high performance liquid chromatography coupled with quadrupole-time-of-flight mass spectrometry (UHPLC-Q-TOF-MS) method was developed to separate and identify the absorbed components and metabolites in rat plasma after oral administration of ZZDHD. The plasma samples were pretreated by protein precipitation and separated on a Shim-pack XR-ODS C18 column (75 mm * 3.0 mm, 2.2 MUm) using a gradient elution program. Mass spectrometric detection was performed on an Agilent 6520 Q-TOF mass spectrometer equipped with electrospray ionization (ESI) source in positive and negative ion modes. By comparing the retention time, high resolution mass data of blank plasma and dosed plasma, a total of 43 constituents, including 21 prototype compounds and 22 metabolites were identified or tentatively characterized. Results indicated that glucuronidation and sulfation were the main metabolic pathways of iridoid glycosides and anthraquinones, glucuronidation was the main metabolic pathways of flavanone related compounds. It is concluded the developed UHPLC-Q-TOF-MS method with high sensitivity and resolution is suitable for identifying and characterizing the absorbed components and metabolites of ZZDHD, and the results will provide essential data for further studying the relationship between the chemical components and pharmacological activity of ZZDHD. PMID- 25912850 TI - Applying a Behavioral Model Framework for Disaster Recovery Research in Local Public Health Agencies: A Conceptual Approach. AB - The local public health agency (LPHA) workforce is at the center of the public health emergency preparedness system and is integral to locally driven disaster recovery efforts. Throughout the disaster recovery period, LPHAs have a primary responsibility for community health and are responsible for a large number of health services. In the face of decreasing preparedness funding and increasing frequency and severity of disasters, LPHAs continue to provide essential disaster life cycle services to their communities. However, little is known about the confidence that LPHA workers have in performing disaster recovery-related duties. To date, there is no widely used instrument to measure LPHA workers' sense of efficacy, nor is there an educational intervention designed specifically to bolster disaster recovery-phase efficacy perceptions. Here, we describe the important role of the LPHA workforce in disaster recovery and the operational- and efficacy-related research gaps inherent in today's disaster recovery practices. We then propose a behavioral framework that can be used to examine LPHA workers' disaster recovery perceptions and suggest a research agenda to enhance LPHA workforce disaster recovery efficacy through an evidence-informed educational intervention. PMID- 25912851 TI - Effect of alpha-asarone on angiogenesis and matrix metalloproteinase. AB - alpha-Asarone is a main component of Acorus gramineus widely known as an oriental traditional medicinal stuff. A. gramineus has been known to have a variety of medicinal efficacies such as anti-gastric ulcer and anti-allergic activities, inhibition of histamine release and antioxidant effect. However, its effect on angiogenesis remains unclear. The aim of this study was to investigate the effect of alpha-asarone on induction of angiogenesis through modulation of matrix metalloproteinase (MMP). First of all, MTT assay was performed to evaluate the effect of alpha-asarone on cell viability using MTT assay, and then tube formation assay with human umbilical vein endothelial cells (HUVEC) in vitro and rat aorta ring assay ex vivo were carried out to elucidate its effect on angiogenesis. Treatment with alpha-asarone below 6MUM showed no cytotoxicity in human fibrosarcoma cells (HT1080) and HUVEC. It was observed that alpha-asarone not only promotes tube formation of HUVEC but also induces angiogenesis of rat aorta. In addition, the effects of alpha-asarone on the expressions of protein and gene were evaluated using western blot analysis and RT-PCR assay. alpha Asarone increased the expression levels of MMP-2 and MMP-9 stimulated by phenazine methosulfate (PMS) and phorbol 12-myristate 13-acetate (PMA) in HT1080. Especially, the expression level of antioxidant enzyme such as glutathione reductase was increased in the presence of alpha-asarone. Therefore, above findings suggest that alpha-asarone may play an important role in pathological diseases related to MMP and angiogenesis. PMID- 25912852 TI - Effects of pentoxifylline and alpha lipoic acid on methotrexate-induced damage in liver and kidney of rats. AB - The aim of the current study was to investigate the probable protective effects of Pentoxifylline (PTX) and Alpha Lipoic Acid (ALA), which display anti-oxidative efficacy against hepatotoxicity and nephrotoxicity, those being the major side effects of Methotrexate (MTX). Rats were divided into four groups: a control group; MTX (20mg/kg/day) group; MTX+PTX (20mg/kg/day+50mg/kg/day) group; and an MTX+ALA (20mg/kg/day+100mg/kg/day) group. At the end of the experiment, biochemical, histochemical and immunohistochemical analyses were performed on liver and kidney tissues of rats. We determined Glutathione Peroxidase (GSH-Px), Superoxide Dismutase (SOD), Catalase (CAT), Malondialdehyde (MDA), Nitric Oxide (NO) and Xanthine Oxidase (XO) levels in the liver and kidney. Moreover, Gamma Glutamyl Transferase (GGT), Direct Bilirubin (DBil), Blood Urea Nitrogen (BUN), and urea levels were measured in the serum. The histochemical evaluation revealed a significant decrease in MTX caused damage in the PTX- and ALA-treated groups (especially in ALA group). On the other hand, the immune staining of iNOS and TNF alpha were observed most densely in the MTX group, while the density decreased in the PTX- and ALA-administered groups. We determined increased GGT, BUN, urea and levels of CAT, MDA, NO, and XO values in both groups, while GSH-Px (an increase in liver tissue) and DBil levels were decreased in the group that received MTX. However, we determined decreased SOD levels in liver tissue. In the PTX and ALA groups, the levels of GGT, BUN and urea as well as the levels of CAT, MDA, NO and XO decreased (SOD increased in the liver tissue), and the levels of GSH-Px and DBil increased. In conclusion, it can be stated that, although ALA is more effective in preventing the toxic effects of MTX on the liver and kidney, PTX also has a preventive effect. As a result, we can readily suggest that ALA and PTX can have protective effects by decreasing MDA, NO, BUN and urea values as antioxidants against MTX-induced damage in liver and kidney of rats. PMID- 25912853 TI - Effect of sulfur dioxide inhalation on the expression of KATP and L-Ca(2+) channels in rat hearts. AB - Epidemiological studies have revealed an association between sulfur dioxide (SO2) exposure and cardiovascular diseases. This study is designed to investigate the SO2 effect on the expression of ATP-sensitive K(+) (KATP) channel and L-type calcium (L-Ca(2+)) channel in rat hearts. The results show that the mRNA and protein levels of the KATP channel subunits Kir6.2 and SUR2A of rat hearts in SO2 groups were higher than those in control group. SO2 at 14mg/m(3) significantly decreased the expression of the L-Ca(2+) channel subunits Cav1.2 and Cav1.3. This suggests that SO2 can activate the KATP channels by up-regulating the expression of Kir6.2 and SUR2A, while it inhibits the L-Ca(2+) channels by down-regulating the expression of Cav1.2 and Cav1.3 in rat hearts. The molecular mechanism of SO2 induced negative inotropic effect might be linked to the expression changes of these subunits, which may contribute to the pathogenesis of SO2-associated cardiovascular diseases. PMID- 25912854 TI - Antibiotic Treatment and Surgery for Acute Hematogenous Calcaneal Osteomyelitis of Childhood. AB - Acute hematogenous calcaneal osteomyelitis characteristically affects children. A recent trend has emerged toward shorter courses of antibiotics. In our randomized, prospective treatment trial of children aged 3 months to 15 years, the intravenous antibiotic (clindamycin or a first-generation cephalosporin) was given only for the first 2 to 4 days and the remainder of the 20- to 30-day course was completed orally. A bone sample for culture was to be taken routinely, but all additional surgery was performed on special demand. We performed a retrospective subanalysis of cases affecting the calcaneus. The follow-up period was 1 year. Of the 14 participants enrolled, 11 completed the 1-year follow-up period, and their data were analyzed. Staphylococcus aureus was the cause of 10 cases; all strains were methicillin sensitive. The median intravenous treatment duration was 3 days. Four patients required open incisional trepanation (trephination). All participants attending the 1-year follow-up examination had fully recovered. The outcome of calcaneal osteomyelitis caused by methicillin sensitive S. aureus in a child will be good, if the patient seeks treatment early and antibiotic therapy is started promptly. A bone biopsy is needed to obtain a representative sample for bacteriology. PMID- 25912855 TI - [Suture of lingual nerve: Technical note]. AB - INTRODUCTION: Because of its anatomical position, the lingual nerve may be severed during oral surgical procedures, such as third molar removal. Early suturing of the nerve promotes better recovery. We describe the end-to-end suture of this nerve. OPERATIVE PROCEDURE: The suture is carried-out under general anesthesia. The approach is made in the mouth floor, in the same way as for submandibular gland lithiasis transoral removal. This approach allows good exposure and some laxity to displace the nerve stumps. The latter can then be sutured under microscope assistance before closing the mucosa. DISCUSSION: Lingual nerve suture is a simple, quick and inexpensive procedure. Unlike other procedures, it cannot be used in case of large loss of substance because of the small amount of laxity of the nerve. Nerve function recovery is better if performed before the 6th post-traumatic month, and in young patients. PMID- 25912857 TI - Palladium-Catalyzed Alkoxycarbonylation of Conjugated Enyne Oxiranes: A Diastereoselective Method for the Synthesis of 7-Hydroxy-2,3,5-trienoates. AB - Palladium-catalyzed alkoxycarbonylative 1,5-substitution of conjugated enyne oxiranes provides a diastereoselective route to (E)-configured 7-hydroxy-2,3,5 trienoates. The reactions proceeded in a highly stereoselective manner, possibly through sequential formation of pi-allylpalladium and sigma-vinylallenyl palladium complexes. The major diastereomeric form of the product is determined by the configuration of the alkenyl moiety of the substrate. PMID- 25912858 TI - Phenotypic antimicrobial susceptibility and occurrence of selected resistance genes in gram-positive mastitis pathogens isolated from Wisconsin dairy cows. AB - In the United States, few intramammary antimicrobials exist that are approved for treatment of bovine mastitis; thus, ensuring judicious use of these products is a priority. The objectives of this study were to determine phenotypic susceptibility and presence of selected antimicrobial resistance genes from staphylococci, streptococci, and streptococcal-like organisms recovered from cases of clinical mastitis occurring in cows on large Wisconsin farms. Staphylococcus aureus (n=35 from 19 herds), coagulase-negative staphylococci (n=51 from 30 herds), Streptococcus spp. (n=78 from 36 herds), and streptococcal like organisms (n=31 from 19 herds) were used in this study. All Staphylococcus spp. were susceptible to ceftiofur, cephalothin, and the combination of penicillin and novobiocin. Of all staphylococci, only a single Staphylococcus epidermidis exhibited phenotypic resistance to oxacillin. Phenotypic susceptibility to erythromycin was observed in only 8.6 and 15.7% of Staphylococcus aureus and coagulase-negative staphylococci, respectively. Approximately 20% of staphylococci and 13 to 22% of streptococci and streptococcal-like organisms exhibited phenotypic resistance to pirlimycin. All Streptococcus spp. exhibited phenotypic susceptibility to ceftiofur, cephalothin, and oxacillin. The proportion of isolates exhibiting phenotypic susceptibility to pirlimycin and sulfadimethoxine differed among Streptococcus dysgalactiae and Streptococcus uberis. All streptococcal-like organisms exhibited phenotypic susceptibility to ceftiofur, cephalothin, oxacillin, penicillin, and the combination of penicillin and novobiocin. Of all organisms tested, 36.9% did not carry any of the resistance genes (ermC, blaZ, tetK, or tetM), 35.4% carried 1 gene, and 27.7% carried multiple genes (usually blaZ in combination with a tet gene). Eighteen (51.4%) Staph. aureus and 12 (48.0%) Staphylococcus chromogenes carried multiple resistance genes. Six (12.2%) Strep. dysgalactiae and no Strep. uberis carried multiple resistance genes. Results indicate that most gram positive mastitis organisms were susceptible to most antimicrobials used for intramammary administration, but some resistance to drugs used for systemic treatment of mastitis was noted. The presence of selected resistance genes was not proportional to the occurrence of phenotypic resistance. PMID- 25912859 TI - Conformational changes of beta-lactoglobulin induced by shear, heat, and pH Effects on antigenicity. AB - Structural modifications influence the immune-reactivity of food proteins. We investigated effects of pH (3, 5, 7), temperature (80, 100, 120 degrees C), and shear (100, 500, and 1,000 s(-1)) on conformational changes (monitored by surface hydrophobicity, total thiol content, Fourier transform infrared spectroscopy, and gel electrophoresis) and their relation to antigenicity (determined by indirect ELISA) of beta-lactoglobulin (beta-LG). Overall, heating at low pH (3) caused unfolding of proteins and fragmentation due to partial acid hydrolysis and thereby exposed beta-strands that contributed to appearance of some hidden epitopes, resulting in higher antigenicity. Heating at pH 5 and 7 decreased the allergenic response due to covalently bonded molecular polymerization and aggregation, which destroyed or masked some epitopes. Shear alone had no effect on the antigenic response of beta-LG but may have an effect in combination with pH or temperature. Overall, heating beta-LG solutions to 120 degrees C at pH 5 with shearing (100-1,000 s(-1)) resulted in minimal antigenicity. Structural modifications of beta-LG via denaturation or disulfide- or thiol-mediated interactions can either enhance or decrease its antigenicity. PMID- 25912856 TI - Stress is a principal factor that promotes tobacco use in females. AB - Tobacco use is a major economic and health problem. It is particularly concerning that women consume more tobacco products, have a more difficult time quitting smoking, and are less likely to benefit from smoking cessation therapy than men. As a result, women are at higher risk of developing tobacco-related diseases. Clinical evidence suggests that women are more susceptible to anxiety disorders, and are more likely to smoke in order to cope with stress than men. During smoking abstinence, women experience more intense anxiety than men and report that the anxiety-reducing effects of smoking are the main reason for their continued tobacco use and relapse. Consistent with this, pre-clinical studies using rodent models suggest that females display more intense stress during nicotine withdrawal than males. This review posits that in women, stress is a principal factor that promotes the initiation of tobacco use and relapse behavior during abstinence. Studies are reviewed at both the clinical and pre-clinical levels to provide support for our hypothesis that stress plays a central role in promoting tobacco use vulnerability in females. The clinical implications of this work are also considered with regard to treatment approaches and the need for more research to help reduce health disparities produced by tobacco use in women. PMID- 25912860 TI - The associations between postpartum serum haptoglobin concentration and metabolic status, calving difficulties, retained fetal membranes, and metritis. AB - Measurement of serum haptoglobin (Hapto) concentrations results in only moderate reported specificity and sensitivity for the detection of metritic cows. The objective of this study was to evaluate associations between different variables and haptoglobin concentrations after calving. Parity, periparturient metabolic stress indicated by beta-hydroxybutyric acid (BHBA) and nonesterified fatty acids (NEFA), calving difficulties, retained fetal membranes (RFM), and acute puerperal metritis (APM) were evaluated. A total of 443 Holstein Friesian cows were enrolled in this retrospective observational study. Acute puerperal metritis was diagnosed when a cow had fetid, reddish-brown, watery vaginal discharge in combination with rectal temperature >=39.5 degrees C. The retention of the fetal membranes has been defined as the failure to expel the fetal membranes within 12h after calving. Results of blood samples from 2 and 5 d in milk (DIM) were analyzed for Hapto, BHBA, and NEFA. Primiparous cows had a greater median Hapto concentration than multiparous cows at 5 DIM [primiparous: 2.25g/L, interquartile range (IQR) 1.45-2.50, n=146; multiparous: 1.13g/L, IQR 0.52-2.22, n=302; P<0.05]. Therefore, different Hapto thresholds based on references from literature for all cows (1.4g/L), primiparous cows (2.49g/L), and multiparous cows (1.4g/L) were used for further analysis. Periparturient metabolic stress indicated by elevated BHBA (>=1.2mmol/L) at 5 DIM was associated with elevated Hapto (odds ratio 2.39-2.87) regardless of parity. In contrast, elevated NEFA (>=0.6mmol/L) at 2 DIM was not a risk factor for elevated Hapto. Multiparous cows with assisted calving had a 2.46 times higher risk for elevated Hapto, whereas primiparous cows with assisted calving had no elevated risk for elevated Hapto at 5 DIM. Moreover, multiparous cows with RFM were 5.51 times more likely to have elevated Hapto at 5 DIM than cows without RFM. Acute puerperal metritis within the first 5 DIM was associated with elevated Hapto (odds ratio 2.74-5.01), regardless of parity. We speculate that the association of calving ease, RFM, and periparturient metabolic stress could explain the moderate sensitivity and specificity reported for the detection of metritic cows by measuring Hapto. PMID- 25912861 TI - Essential amino acid infusions stimulate mammary expression of eukaryotic initiation factor 2Bepsilon but milk protein yield is not increased during an imbalance. AB - Essential amino acid (EAA) deficiencies and imbalances were created in lactating cows by using an infusion subtraction protocol to explore effects on milk protein yield and activity state of regulators of mRNA translation in the mammary glands. Six lactating cows on a diet of 11.2% protein were infused abomasally for 5d with saline, 563g/d of a complete EAA mix, or EAA without His, Met, Phe, or Trp in a 6*6 Latin square design. Infusion of complete and imbalanced EAA solutions increased mammalian target of rapamycin (mTOR) signaling in the mammary glands, as evidenced by higher ribosomal S6 kinase 1 (S6K1) phosphorylation compared with saline infusion. Total S6K1 abundance was decreased by imbalanced AA infusions. Except for the mixture lacking Phe, infusion of EAA, whether imbalanced or not, increased abundance of total eukaryotic initiation factor 2Bepsilon (eIF2Bepsilon). A correlation of 0.33 between phosphorylation state of S6K1 and total eIF2Bepsilon abundance suggests that an mTOR-mediated upregulation of eIF2Bepsilon translation occurred. Despite increased mTOR/eIF2Bepsilon signaling, milk protein yields increased only with the complete EAA mixture compared with saline. Low plasma concentrations of His, Met, and Phe during their respective imbalances likely interfered with protein synthesis. Total abundance and phosphorylation state of eukaryotic initiation factor 2alpha were not responsible for the interference. Further study of eIF2Bepsilon as a regulator of milk protein yield is warranted. PMID- 25912862 TI - Providing supplementary milk to suckling dairy calves improves performance at separation and weaning. AB - Dam rearing can provide health and welfare benefits, but separation and weaning are major welfare challenges. We investigated whether access to an additional source of milk from an automatic milk feeder (AMF) would improve weight gains after separation and weaning. During the first 6wk of life (dam phase), calves were assigned to 1 of 3 treatments using a parallel group design with repeated measures: nursing (n=10) and combined (n=10) calves could suckle from their dams at night (between 2000 and 0800h), and combined calves also had access to 12 L of milk/d accessible 24h/d from an AMF. Milk feeder calves (n=10) also had access to an AMF 24h/d and were housed with the dam at night but were prevented from suckling by an udder net. Separation from the dam occurred after 6wk in 2 phases with decreasing contact between cow and calf: partial separation (duration 4d) and total separation (duration 3d). At separation, all calves were granted access to 12 L of milk 24h/d from the AMF until weaning began at 7wk of age. We hypothesized that access to an AMF during the dam phase would result in less weight loss at separation and weaning compared with calves that had been nutritionally dependent upon the cow (i.e., nursing calves). Calf weight gain during the dam phase averaged (+/-SD) 1.1+/-0.26kg/d and did not vary with treatment. Combined calves drank less milk from the AMF compared with milk feeder calves during the dam phase (mean +/- SEM daily milk intake: 1.1+/-0.38 vs. 8.2+/ 0.34 L/d) and tended to drink less during partial separation (6.7+/-1.28 vs. 9.8+/-1.02 L/d), but milk intake from the AMF did not differ between these treatments in the later phases. During the same phases, nursing calves consumed less milk from the AMF than the other treatments; of the 10 calves, 6 did not use the AMF (consuming <1.5 L/d) after the dam phase. After separation, nursing calves gained less weight than calves in both the milk feeder and combined treatments (0.8+/-0.16 vs. 1.2+/-0.08kg/d). Calves using the AMF after separation (n=23; 4 nursing calves, 9 combined calves, and 10 milk feeder calves) had a higher average daily gain compared with calves that did not (n=7; 6 nursing calves and 1 combined calf; 1.2+/-0.07 vs. 0.6+/-0.21kg, respectively). In conclusion, use of the AMF after separation varied, but providing an additional milk source reduced nutritional dependency on the dam, improving calf performance at weaning and separation. PMID- 25912863 TI - A novel method for screening of potential probiotics for high adhesion capability. AB - To screen for potential probiotics with high adhesion capability, a chemostat model-based cultured human feces and denaturing gradient gel electrophoresis methods were applied, and the adhesion capability of the isolates was evaluated in vitro and in vivo. Lactobacillus plantarum (HM218749), Lactobacillus reuteri (EU547310), and Enterococcus faecalis (HM218543) were isolated from the slime on the chemostat wall, as these organisms could grow better at 37 degrees C in an anaerobic environment and could resist harsh conditions (pH 1.5 and 0.30% bile salt). Lactobacillus plantarum, L. reuteri, and E. faecalis could adhere to HT-29 cells and reduce the adhesion of Shigella dysenteriae 2457, Staphylococcus aureus Cowan1, Enterobacter sakazakii 45401, and Escherichia coli 44102 to HT-29 cells. Moreover, the animal experiment showed that L. plantarum could adhere to mice intestine, increasing the number of lactobacilli and decreasing the number of enterococci. PMID- 25912864 TI - Clock circadian regulator (CLOCK) gene network expression patterns in bovine adipose, liver, and mammary gland at 3 time points during the transition from pregnancy into lactation. AB - The transition from late gestation to early lactation is the most critical phase of the lactation cycle for mammals. Research in rodents has revealed changes in the clock circadian regulator (CLOCK) gene network expression around parturition. However, their expression profiles and putative functions during the periparturient period in ruminants remain to be determined. The present study aimed to investigate the expression pattern of the CLOCK network and selected metabolic genes simultaneously in mammary gland (MG), liver (LIV), and subcutaneous adipose tissue (AT). Seven dairy cows were biopsied at -10 (+/-2), 7, and 21 d relative to parturition. A day * tissue interaction was observed for ARNTL, CRY1, and PER2 due to upregulation at 7 and 21 d postpartum, with their expression being greater in AT and MG compared with LIV. No interaction was detected for CLOCK, CRY2, PER1, and PER3. In general, the expression of NPAS2, NR1D1, NR2F2, ALAS1, FECH, FBXW11, CCRN4L, PPARA, PPARGC1A, and FGF21 was lower at -10 d but increased postpartum in all tissues. The interaction detected for CSNK1D was associated with increased expression postpartum in AT and MG but not LIV. The interaction detected for CPT1A was due to upregulation in AT and LIV postpartum without a change in MG. In contrast, the interaction for PPARG was due to upregulation in AT and MG postpartum but a downregulation in LIV. Leptin was barely detectable in LIV, but there was an interaction effect in AT and MG associated with upregulation postpartum in MG and downregulation in AT. Together, these results suggest that the control of metabolic adaptations in LIV, MG, and AT around parturition might be partly regulated through the CLOCK gene network. Although the present study did not specifically address rhythmic control of tissue metabolism via the CLOCK gene network, the difference in expression of genes studied among tissues confirms that the behavior of circadian-controlled metabolic genes around parturition differs by tissue and, as such, is closely associated with the metabolic function of the organ. PMID- 25912865 TI - Effect of feed-related farm characteristics on relative values of genetic traits in dairy cows to reduce greenhouse gas emissions along the chain. AB - Breeding has the potential to reduce greenhouse gas (GHG) emissions from dairy farming. Evaluating the effect of a 1-unit change (i.e., 1 genetic standard deviation improvement) in genetic traits on GHG emissions along the chain provides insight into the relative importance of genetic traits to reduce GHG emissions. Relative GHG values of genetic traits, however, might depend on feed related farm characteristics. The objective of this study was to evaluate the effect of feed-related farm characteristics on GHG values by comparing the values of milk yield and longevity for an efficient farm and a less efficient farm. The less efficient farm did not apply precision feeding and had lower feed production per hectare than the efficient farm. Greenhouse gas values of milk yield and longevity were calculated by using a whole-farm model and 2 different optimization methods. Method 1 optimized farm management before and after a change in genetic trait by maximizing labor income; the effect on GHG emissions (i.e., from production of farm inputs up to the farm gate) was considered a side effect. Method 2 optimized farm management after a change in genetic trait by minimizing GHG emissions per kilogram of milk while maintaining labor income and milk production at least at the level before the change in trait; the effect on labor income was considered a side effect. Based on maximizing labor income (method 1), GHG values of milk yield and longevity were, respectively, 279 and 143kg of CO2 equivalents (CO2e)/unit change per cow per year on the less efficient farm, and 247 and 210kg of CO2e/unit change per cow per year on the efficient farm. Based on minimizing GHG emissions (method 2), GHG values of milk yield and longevity were, respectively, 538 and 563kg of CO2e/unit change per cow per year on the less efficient farm, and 453 and 441kg of CO2e/unit change per cow per year on the efficient farm. Sensitivity analysis showed that, for both methods, the absolute effect of a change in genetic trait depends on model inputs, including prices and emission factors. Substantial changes in relative importance between traits due to a change in model inputs occurred only in case of maximizing labor income. We concluded that assumptions regarding feed-related farm characteristics affect the absolute level of GHG values, as well as the relative importance of traits to reduce emissions when using a method based on maximizing labor income. This is because optimizing farm management based on maximizing labor income does not give any incentive for lowering GHG emissions. When using a method based on minimizing GHG emissions, feed-related farm characteristics affected the absolute level of the GHG values, but the relative importance of the traits scarcely changed: at each level of efficiency, milk yield and longevity were equally important. PMID- 25912866 TI - Effects of recombinant bovine somatotropin during the periparturient period on innate and adaptive immune responses, systemic inflammation, and metabolism of dairy cows. AB - The aim of this experiment was to determine effects of treating peripartum dairy cows with body condition score >=3.75 with recombinant bovine somatotropin (rbST) on immune, inflammatory, and metabolic responses. Holstein cows (253+/-1d of gestation) were assigned randomly to 1 of 3 treatments: untreated control (n=53), rbST87.5 (n=56; 87.5mg of rbST), and rbST125 (n=57; 125mg of rbST). Cows in the rbST87.5 and rbST125 treatments received rbST weekly from -21 to 28d relative to calving. Growth hormone, insulin-like growth factor 1, haptoglobin, tumor necrosis factor alpha, nonesterified fatty acids, beta-hydroxybutyrate, glucose, and cortisol concentrations were determined weekly from -21 to 21d relative to calving. Blood sampled weekly from -14 to 21d relative to calving was used for hemogram and polymorphonuclear leukocyte (PMNL) expression of adhesion molecules, phagocytosis, and oxidative burst. Cows were vaccinated with ovalbumin at -21, 7, and 7d relative to calving, and blood was collected weekly from -21 to 21d relative to calving to determine IgG anti-ovalbumin concentrations. A subsample of cows had liver biopsied -21, -7, and 7d relative to calving to determine total lipids, triglycerides, and glycogen content. Growth hormone concentrations prepartum (control=11.0+/-1.2, rbST87.5=14.1+/-1.2, rbST125=15.1+/-1.3ng/mL) and postpartum (control=14.4+/-1.1, rbST87.5=17.8+/-1.2, rbST125=21.8+/-1.1ng/mL) were highest for rbST125 cows. Cows treated with rbST had higher insulin-like growth factor 1 concentrations than control cows (control=110.5+/-4.5, rbST87.5=126.2+/-4.5, rbST125=127.2+/-4.5ng/mL) only prepartum. Intensity of L selectin expression was higher for rbST125 than for control and rbST87.5 cows [control=3,590+/-270, rbST87.5=3,279+/-271, rbST125=4,371+/-279 geometric mean fluorescence intensity (GMFI)] in the prepartum period. The PMNL intensities of phagocytosis (control=3,131+/-130, rbST87.5=3,391+/-133, rbST125=3,673+/-137 GMFI) and oxidative burst (control=9,588+/-746, rbST87.5=11,238+/-761, rbST125=12,724+/-781 GMFI) were higher for rbST125 cows than for control cows during the prepartum period. Concentrations of serum IgG anti-ovalbumin tended to be higher for rbST125 cows than for control cows (control=0.75+/-0.11, rbST87.5=0.94+/-0.10, rbST125=1.11+/-0.11 optical density) in the prepartum period. Haptoglobin concentration was significantly reduced 7d postpartum for rbST125 treatment compared with control and rbST87.5 treatments (control=2.74+/ 0.28, rbST87.5=2.81+/-0.28, rbST125=1.87+/-0.28 optical density). Although treatment tended to affect postpartum beta-hydroxybutyrate (control=747.5+/-40.2, rbST87.5=753.2+/-40.1, rbST125=648.8+/-39.7 umol/L), it did not affect liver contents of total lipids, triglycerides, or glycogen. Incidence of metritis among rbST125 cows was reduced compared with that in control cows (control=23.1, rbST87.5=18.0, rbST125=7.8%). Treatment of dairy cows with 125mg of rbST improved innate immune responses and IgG concentration, with limited effects on metabolism. PMID- 25912867 TI - Short communication: Latin-style fresh cheese enhances lactic acid bacteria survival but not Listeria monocytogenes resistance under in vitro simulated gastrointestinal conditions. AB - Different studies in humans have provided evidence about the health benefits of probiotics. However, most probiotic strains do not maintain good viability in the harsh conditions of the gastrointestinal tract (GIT). In the present study, Latin style fresh cheese produced with potential probiotic bacteria was tested to evaluate this cheese type as a food carrier for the delivery of viable microorganisms after exposure to simulated GIT conditions. The resistance of 28 lactic acid bacteria (LAB) strains and Listeria monocytogenes upon exposure to acidic conditions (pH 2.5) and bile and pancreatic enzymes (0.3% of bile salts and 0.1% of pancreatin) was evaluated in vitro. When compared with fresh cultures, fresh cheese greatly improved LAB survival to simulated GIT conditions, as no loss of viability was observed in either acidic conditions (pH 2.5) or bile salts and pancreatin environment over a 3-h period. In opposition, L. monocytogenes did not survive after 1h under acidic conditions. These data demonstrated that Latin-style fresh cheese could play an important role in probiotic protection against gastrointestinal juices, enhancing delivery within the gut and thereby maximizing potential health benefits of LAB. PMID- 25912868 TI - Inclusion of tallow and soybean oil to calf starters fed to dairy calves from birth to four months of age on calf performance and digestion. AB - Energy demands for calves can increase during periods of heat and cold stress. One way to potentially increase energy intake is to increase the energy density of the feed with fat. Trial 1a compared a control starter with no added fat or oil (CON) to starters with 2% tallow (TAL) and 2% soybean oil (SBO). Starters were 20% crude protein (CP) and 45 to 47% starch. Male Holstein calves that were initially 3 to 5d of age were fed a 27% CP, 17% fat milk replacer at 0.66kg of dry matter daily and fully weaned by 42d of a 56-d trial. Trial 1b estimated the digestion of the diets (employed chromic oxide as an indigestible digesta flow marker) using a subset of 5 weaned calves per treatment between d 52 and 56. Trial 2 used Holstein calves initially 59 to 61d of age fed starters CON and SBO blended with 5% chopped grass hay over a 56-d trial. Trial 3 used Holstein calves initially 59 to 61d of age fed starters CON and TAL blended with 5% chopped grass hay over a 56-d trial. Treatments were compared using repeated measures (where appropriate) in a completely randomized design. In trials 1a and 1b, preplanned contrasts compared CON versus TAL and CON versus SBO. Compared with CON, calves fed SBO had reduced starter intake, average daily gain, and digestion of dry matter, organic matter, and CP before 8wk of age. Compared with CON, calves fed SBO had reduced average daily gain and change in hip width from 2 to 4 mo of age. Compared with CON, calves fed TAL had reduced average daily gain and tended to have reduced change in hip width from 2 to 4 mo of age. Calculated metabolizable energy intake was not increased in any trial by added fat or oil. Tallow and soybean oil inclusion at 2% of the starter feed was not advantageous for calf growth before 4 mo of age. PMID- 25912869 TI - Information from later lactations improves accuracy of genomic predictions of fertility-related disorders in Norwegian Red. AB - Our aim was to investigate whether including information from later lactations improves accuracy of genomic breeding values for 4 fertility-related disorders: cystic ovaries, retained placenta, metritis, and silent heat. Data consisted of health records from 6,015,245 lactations from 2,480,976 Norwegian Red cows, recorded from 1979 to 2012. These were daughters of 3,675 artificial insemination bulls. The mean frequency of these disorders for cows in lactation 1 to 5 ranged from 0.6 to 2.4% for cystic ovaries, 1.0 to 1.5% for metritis, 1.9 to 4.1% for retained placenta, and 2.4 to 3.8% for silent heat. Genomic information was available for all sires, and the 312 youngest bulls were used for validation. After standard editing of a 25K/54K single nucleotide polymorphism data set that was imputed both ways, a total of 48,249 single nucleotide polymorphism loci were available for genomic predictions. Genomic breeding values were predicted using univariate genomic BLUP for the first lactation only and for the first 5 lactations and multivariate genomic BLUP with 5 lactations for each disorder was also used for genomic predictions. Correlations between estimated breeding values for the 4 traits in 5 lactations with predicted genomic breeding values were compared. Accuracy ranged from 0.47 and 0.51 for cystic ovaries, 0.50 to 0.74 for retained placenta, 0.21 to 0.47 for metritis, and 0.22 to 0.60 for silent heat. Including later lactations in a multitrait genomic BLUP improved accuracy of genomic estimated breeding values for cystic ovaries, retained placenta, and silent heat, whereas for metritis no obvious advantage in accuracy was found. PMID- 25912870 TI - Effect of galactooligosaccharide addition on the physical, optical, and sensory acceptance of vanilla ice cream. AB - The effect of the addition of galactooligosaccharide (GOS) on the physicochemical, optical, and sensory characteristics of ice cream was investigated. Vanilla ice cream was supplemented with 0, 1.5, and 3.0% (wt/wt) GOS and characterized for pH, firmness, color, melting, overrun, as well as subjected to a discriminative sensory test (triangle test). For comparison purposes, ice creams containing fructooligosaccharide were also manufactured. The GOS ice creams were characterized by increased firmness and lower melting rates. Different perceptions were reported in the sensory evaluation for the 3.0% GOS ice cream when compared with the control, which was not observed for the fructooligosaccharide ice cream. Overall, the findings suggest it is possible to produce GOS ice cream with improved stability in relation to the physicochemical parameters and sensory perception. PMID- 25912871 TI - Preliminary validation of a calf-side test for diagnosis of failure of transfer of passive immunity in dairy calves. AB - The objective of this study was to evaluate the utility of an initial version of a calf-side test (ZAPvet Bovine IgG test, ZBx Corp., Toronto, ON, Canada) for diagnosis of failure of transfer of passive immunity (FTPI) in dairy calves. Blood samples (n=202) were collected from calves from 1 to 11d of age. Serum IgG concentration was determined by radial immunodiffusion (RID) assay. The mean IgG concentration was 1,764+/-1,035mg/dL, with a range from 133 to 5,995mg/dL. The ZAPvet Bovine IgG test was used to assess FTPI (serum IgG <1,000mg/dL) and test characteristics were calculated. The number of samples that had FTPI from the RID assay and ZAPvet test was 55 and 96 samples, resulting in a true prevalence of 27% and an apparent prevalence of 47.5%, respectively. The sensitivity, specificity, and positive and negative predictive values of the ZAPvet test were 0.82, 0.65, 0.47, and 0.91, respectively. The results of the ZAPvet test were derived from 2 observers, and the overall level of agreement between the results of the 2 observers was 84%, with a kappa value of 0.67. The ZAPvet Bovine IgG test showed good potential for further development as a cost-effective, rapid calf-side test for monitoring FTPI in dairy calves. PMID- 25912872 TI - Relationships between circulating plasma concentrations and duodenal flows of essential amino acids in lactating dairy cows. AB - The objective of this study was to better define essential AA (EAA) requirements in lactating dairy cows through examination of the relationship between plasma essential AA concentration (p[EAA]) and predicted duodenal flow of essential AA (EAAduo). Our hypothesis was that at a given level of milk protein output, p[EAA] would remain steady in response to increasing EAAduo until the EAA requirement was met, at which point p[EAA] would increase rapidly in response to greater duodenal flow of EAA until p[EAA] reached a plateau as other body processes degraded excess EAA to avoid toxicity. Thus, the requirement of each EAA would be fulfilled when p[EAA] increased rapidly. To investigate this hypothesis, we compiled a literature database that included 102 studies with 420 treatment means that reported p[EAA], dietary nutrient content, body weight, and milk production. A second database was produced to validate relationships developed in the first database and included 32 studies with 98 treatment means. All relationships were evaluated as regression equations with study as a random factor. Breed, days in milk, body weight, and milk protein production had no effect on the plasma concentration of any EAA. Other than metabolizable protein supply, nutritional content of the rations did not affect p[EAA]. Only p[Arg] was affected by parity, with primiparous cows having higher concentrations of Arg than older cows. No break points in the relationship between p[EAA] versus EAAduo were detected as either steep increases or plateaus. Plasma Arg, Ile, Lys, Thr, and Val concentrations were best associated with their respective EAAduo as quadratic equations, whereas His, Leu, Met, and Phe were associated only linearly. Adding a quadratic term improved the adjusted R(2) or decreased the root mean square error marginally (<2.0%). Thus, we conclude that the main effect of EAAduo on p[EAA] is linear. Abomasal or duodenal infusions of Met, Lys, His, Lys+Met, and casein revealed that Met or Lys infused alone increased the plasma concentration of the infused EAA and lowered the concentration of other EAA, particularly His. Infusion of Lys+Met or His alone was associated with increases in concentrations of these EAA without affecting others. We conclude that over a wide range of protein intakes in lactating cows, plasma levels of EAA increase linearly with duodenal flow. No evidence was found that EAA requirements are reflected in blood plasma concentrations. PMID- 25912873 TI - An Alternative Approach for Perioperative Extracorporeal Life Support Implantation. AB - Central veno-arterial extracorporeal membrane oxygenation (ECMO) is traditionally implanted using direct cannulation of the aorta and right atrium. We aim to summarize the outcome of patients who underwent perioperative central ECMO implantation using an alternative surgical approach, which allows sternum closure and does not require resternotomy at the time of explantation. We retrospectively reviewed patients who required veno-arterial ECMO support at our institution between January 2013 and July 2014. Inclusion criteria were patients undergoing central ECMO implantation using the above-mentioned implantation technique. Nine patients (65 +/- 14 years) were supported using this technique. Four patients underwent coronary bypass surgery as a primary surgery and the other five patients had combined coronary and valve surgeries. The average duration of ECMO support was 9 +/- 7 days (range 1-24 days). The dominant postoperative complication was renal failure, which occurred in eight patients (89%). In four patients (44%), the ECMO was successfully removed. Survival rate to discharge was 22%. In conclusion, this study showed the feasibility of this alternative ECMO implantation technique. No technical issues were encountered. Extended support duration and reducing resternotomy risks may be the main advantages of this technique compared with conventional ECMO implantation methods. PMID- 25912874 TI - Influence of dietary sugar on cholesterol and bile acid metabolism in the rat: Marked reduction of hepatic Abcg5/8 expression following sucrose ingestion. AB - Previous studies have indicated that dietary intake of sugar may lower bile acid production, and may promote cholesterol gallstone formation in humans. We studied the influence of dietary sucrose on cholesterol and bile acid metabolism in the rat. In two different experiments, rats received high-sucrose diets. In the first, 60% of the weight of standard rat chow was replaced with sucrose (high sucrose diet). In the second, rats received a diet either containing 65% sucrose (controlled high-sucrose diet) or 65% complex carbohydrates, in order to keep other dietary components constant. Bile acid synthesis, evaluated by measurements of the serum marker 7-alpha-hydroxy-4-cholesten-3-one (C4) and of the hepatic mRNA expression of Cyp7a1, was markedly reduced by the high-sucrose diet, but not by the controlled high-sucrose diet. Both diets strongly reduced the hepatic - but not the intestinal - mRNA levels of Abcg5 and Abcg8. The differential patterns of regulation of bile acid synthesis induced by the two sucrose-enriched diets indicate that it is not sugar per se in the high-sucrose diet that reduces bile acid synthesis, but rather the reduced content of fiber or fat. In contrast, the marked reduction of hepatic Abcg5/8 observed is an effect of the high sugar content of the diets. PMID- 25912875 TI - NDR1 modulates the UV-induced DNA-damage checkpoint and nucleotide excision repair. AB - Nucleotide excision repair (NER) is the sole mechanism of UV-induced DNA lesion repair in mammals. A single round of NER requires multiple components including seven core NER factors, xeroderma pigmentosum A-G (XPA-XPG), and many auxiliary effector proteins including ATR serine/threonine kinase. The XPA protein helps to verify DNA damage and thus plays a rate-limiting role in NER. Hence, the regulation of XPA is important for the entire NER kinetic. We found that NDR1, a novel XPA-interacting protein, modulates NER by modulating the UV-induced DNA damage checkpoint. In quiescent cells, NDR1 localized mainly in the cytoplasm. After UV irradiation, NDR1 accumulated in the nucleus. The siRNA knockdown of NDR1 delayed the repair of UV-induced cyclobutane pyrimidine dimers in both normal cells and cancer cells. It did not, however, alter the expression levels or the chromatin association levels of the core NER factors following UV irradiation. Instead, the NDR1-depleted cells displayed reduced activity of ATR for some set of its substrates including CHK1 and p53, suggesting that NDR1 modulates NER indirectly via the ATR pathway. PMID- 25912876 TI - MicroRNA-129-5p inhibits hepatocellular carcinoma cell metastasis and invasion via targeting ETS1. AB - MiR-129-5p is deregulated in various human cancers and has been associated with hepatocellular carcinoma (HCC) progression. However, the underlying mechanisms of miR-129-5p involvement in the development and progression of HCC and the effects of miR-129-5p deregulation on the clinical characteristics observed in HCC patients remain poorly understood. We therefore investigated the correlation between low miR-129-5p expression and vascular invasion, intrahepatic metastasis, and poor patient survival. Ectopic restoration of miR-129-5p expression in HCC cells suppressed cellular migration and invasion and the expression of v-ets erythroblastosis virus E26 oncogene homolog 1 (ETS1), while inhibition of endogenous miR-129-5p caused an increase in these parameters. We identified the ETS1 gene as a novel direct target of miR-129-5p. SiRNA-mediated ETS1 knockdown rescued the effects of anti-miR-129-5p inhibitor in HCC cell lines, while the effects of miR-129-5p overexpression were partially phenocopied in the knockdown model. In addition, miR-129-5p levels inversely correlated with those of ETS1 in HCC cells and tissues. Taken together, our findings indicate an important role for miR-129-5p in the molecular etiology of invasive HCC and suggest that miR-129 5p could have potential therapeutic applications in HCC. PMID- 25912877 TI - Colocalization of insulin and glucagon in insulinoma cells and developing pancreatic endocrine cells. AB - A significant portion of human and rat insulinomas coexpress multiple hormones. This character termed as multihormonality is also observed in some early pancreatic endocrine cells which coexpress insulin and glucagon, suggesting an incomplete differentiation status of both cells. Here we demonstrate that insulinoma cells INS-1 and INS-1-derived single cell clone INS-1-15 coexpressed insulin and glucagon in a portion of cells. These two hormones highly colocalized in the intracellular vesicles within a cell. Due to the existence of both PC1/3 and PC2 in INS-1-derived cells, proglucagon could be processed into glucagon, GLP 1 and GLP-2. These glucagon-family peptides and insulin were secreted simultaneously corresponding to the elevating glucose concentrations. The coexpression and partial colocalization of insulin and glucagon was also observed in rat fetal pancreatic endocrine cells, but the colocalization rate was generally lower and more diverse, suggesting that in the developing pancreatic endocrine cells, insulin and glucagon may be stored in nonidentical pools of secreting vesicles and might be secreted discordantly upon stimulus. PMID- 25912878 TI - Effects of KRC-108 on the Aurora A activity and growth of colorectal cancer cells. AB - Aurora A is involved in regulating multiple steps of mitosis. Over-expression of Aurora A is related to tumorigenesis and poor prognosis. KRC-108 is a novel multi kinase inhibitor which has anti-tumor activity in vivo. In this study, we identified the inhibitory effects of KRC-108 on Aurora A kinase and growth inhibitory characteristics of KRC-108. The in vitro kinase activity assay, immunoblot, and immunofluorescence analyses demonstrated that KRC-108 inhibited Aurora A activity. KRC-108 exhibited cytotoxicity against human colorectal cancer cell line HT-29. Colony formation assays showed that KRC-108 reduced the colony growth of HT-29 cells. KRC-108 also inhibited migration of HT-29 cells. The expression levels of cyclin B1 and CDC2 were decreased by KRC-108 in HT-29 cells. Cell cycle analysis and flow cytometry indicated that the inhibitory effects of KRC-108 on cell growth are due to induction of G2/M arrest and apoptosis by inhibition of Aurora A. KRC-108 induces cell-cycle arrest and apoptosis in colorectal cancer cell line by Aurora A inhibition. The reported in vivo anti tumor effects of KRC-108 might partly be due to anti-Aurora A effects. This study suggests that KRC-108 has potential for development as an anti-tumor agent, although further studies are needed. PMID- 25912879 TI - Cocaine-Induced Acute Aortic Dissection. PMID- 25912881 TI - Nonionic amphiphile nanoarchitectonics: self-assembly into micelles and lyotropic liquid crystals. AB - Amphiphiles, molecules that possess both hydrophilic and hydrophobic moieties, are architecturally simple molecules that can spontaneously self-assemble into complex hierarchical structures from lower to higher dimensions either in the bulk phase or at an interface. Recent developments in multifunctional nanostructure design using the advanced concept of nanoarchitectonics utilize this simple process of assembly. Amphiphilic self-assemblies involving lipids or proteins mimic the structure of biological systems, thus highlighting the necessity of a fundamental physical understanding of amphiphilic self-assembly towards a realization of the complex mechanisms operating in nature. Herein, we describe self-assembled microstructures of biocompatible and biodegradable tetraglycerol lauryl ether (C12G4) nonionic surfactant in an aqueous solvent system. Temperature-composition analyses of equilibrium phases identified by using small-angle x-ray scattering (SAXS) provide strong evidence of various spontaneously self-assembled mesostructures, such as normal micelles (Wm), hexagonal liquid crystal (H1), and reverse micelles (Om). In contrast to conventional poly(oxyethylene) nonionic surfactants, C12G4 did not exhibit the clouding phenomenon at higher temperatures (phase separation was not observed up to 100 degrees C), demonstrating the greater thermal stability of the self assembled mesophases. Generalized indirect Fourier transformation (GIFT) evaluation of the SAXS data confirmed the formation of core-shell-type spherical micelles with a maximum dimension ca. 8.7 nm. The shape and size of the C12G4 micelles remained apparently unchanged over a wide range of concentrations (up to 20%), but intermicellar interactions increased and could be described by the Percus-Yevick (PY) theory (after Carnahan and Starling), which provides a very accurate analytical expression for the osmotic pressure of a monodisperse hard sphere. PMID- 25912880 TI - Physiological and behavioral effects of amphetamine in BACE1(-/-) mice. AB - beta-Site APP-cleaving Enzyme 1 (BACE1) is a protease that has been linked to schizophrenia, a severe mental illness that is potentially characterized by enhanced dopamine (DA) release in the striatum. Here, we used acute amphetamine administration to stimulate neuronal activity and investigated the neurophysiological and locomotor-activity response in BACE1-deficient (BACE1(-/-) ) mice. We measured locomotor activity at baseline and after treatment with amphetamine (3.2 and 10 mg/kg). While baseline locomotor activity did not vary between groups, BACE1(-/-) mice exhibited reduced sensitivity to the locomotor enhancing effects of amphetamine. Using high-performance liquid chromatography (HPLC) to measure DA and DA metabolites in the striatum, we found no significant differences in BACE1(-/-) compared with wild-type mice. To determine if DA neuron excitability is altered in BACE1(-/-) mice, we performed patch-clamp electrophysiology in putative DA neurons from brain slices that contained the substantia nigra. Pacemaker firing rate was slightly increased in slices from BACE1(-/-) mice. We next measured G protein-coupled potassium currents produced by activation of D2 autoreceptors, which strongly inhibit firing of these neurons. The maximal amplitude and decay times of D2 autoreceptor currents were not altered in BACE1(-/-) mice, indicating no change in D2 autoreceptor sensitivity and DA transporter-mediated reuptake. However, amphetamine (30 um) induced potassium currents produced by efflux of DA were enhanced in BACE1(-/-) mice, perhaps indicating increased vesicular DA content in the midbrain. This suggests a plausible mechanism to explain the decreased sensitivity to amphetamine-induced locomotion, and provides evidence that decreased availability of BACE1 can produce persistent adaptations in the dopaminergic system. PMID- 25912882 TI - Social Development Measures Associated with Problem Behaviours and Weight Status in Australian Adolescents. AB - During the adolescent years, substance use, anti-social behaviours and overweight/obesity are amongst the major public health concerns. We investigate if risk and protective factors associated with adolescent problem behaviours and substance use are also associated with weight status in young Australian adolescents. Data comes from the 2006 Healthy Neighbourhoods study, a cross sectional survey of students attending primary (grade 6, mean age 11) and secondary (grade 8, mean age 12) schools in 30 communities across Australia. Adolescents were classified as not overweight, overweight or obese according to international definitions. Logistic and linear regression analyses, adjusted for age, gender and socio-economic disadvantage quartile, were used to quantify associations between weight status (or BMI z-score) and the cumulative number of problem behaviour risk and protective factors. Prevalence of overweight and obesity was 22.6 % (95 % confidence interval (CI), 21.2-24.0 %) and 7.2 % (CI, 6.3-8.3 %). Average number of risk and protective factors present was 4.0 (CI, 3.7-4.2) and 6.2 (CI, 6.1-6.3). Independently, total number of risk factors present was positively associated with likelihood of overweight and obesity, while number of protective factors present was inversely associated with the likelihood of being above a healthy weight. When both risk and protective factors were included in a regression model, only risk factors were associated with the likelihood of being overweight or obese. Average BMI z-score increased by 0.03 units with each additional risk factor present. Prevention programmes targeting developmental risk and protective factors in adolescents that reduce substance use and problem behaviours may also benefit physical health. PMID- 25912883 TI - Motor primitives--new data and future questions. AB - Motor primitives allow integration across scales in the motor system and may link movement construction and circuit organization. This review examines support for primitives, and new data relating primitives to concrete circuit elements across species. Both kinematic motor primitives and muscle synergy/kinetic motor primitives are reviewed. Motor primitives allow a modular hierarchy that may be re-used by volitional systems in novel ways. They can provide a developmental bootstrap for ethologically important actions. Collections of primitives somewhat constrain motor acts, but at the same time sets of primitives facilitate the rapid construction of these constrained actions, and can allow use of simpler controls. Novel motor skill likely requires augmentation to transcend the constraints present in initial collections of low level motor primitives. The benefits and limitations of motor primitives and the recognized knowledge gaps and needs for future research are briefly discussed. PMID- 25912884 TI - Habitat selection and utilization of white croaker (Genyonemus lineatus) in the Los Angeles and Long Beach Harbors and the development of predictive habitat use models. AB - White croaker (Genyonemus lineatus) are a sentinel fish species for contamination due to their direct interaction with contaminated sediments through benthic foraging. White croaker within the Los Angeles (LA) and Long Beach (LB) Harbor exhibited hierarchical habitat selection: avoiding dredged areas while selecting for areas of high sediment total organic carbon (4.8-8.1%), high polychaete density (406-700 polychaetes/0.1 m(2)), and small sediment grain size (<23.5 MUm). Model results suggest that these fish are moving into shallower waters at night, which may be to forage and refuge more during the day presumably to avoid predation. The predictive model for white croaker habitat use indicated three important areas of use within the LA-LB Harbor: Consolidated Slip, Inner Long Beach Harbor, and Fish Harbor. The areas containing the most frequently selected habitats by white croaker are also often areas of high sediment contamination, and thus are likely locations where these fish are acquiring contaminants. While many sediment mitigation alternatives exist, identifying and remediating sediments in key white croaker habitat may lead to a decrease in white croaker tissue concentrations over time if the fish continue to utilize these areas post remediation. PMID- 25912885 TI - A column evaluation of Appalachian coal mine spoils' temporal leaching behavior. AB - Appalachian surface coal mine overburden affects water quality as drainage percolates through spoil disposal fills. This study evaluated leaching potentials of 15 spoils from south-central Appalachia. Most bulk samples were non acid forming, all were low in total-S, (<=0.34%), and initial saturated paste specific conductance (SC) ranged from 264 to 3560 MUS cm(-1). Samples were leached unsaturated (40 cycles) and leachates analyzed for pH, SC, and ion composition. Overall, leachates from unweathered spoils were higher in pH and SC than leachates from weathered spoils. Fine-textured spoils generally produced higher SCs than more coarsely textured spoils. Mean SC for all spoils decreased rapidly from an initial peak of 1468 MUS cm(-1) (+/-150) to 247 MUS cm(-1) (+/-23). Release patterns for most major ions reflected declining SC. Bicarbonate typically increased with successive leaches, replacing sulfate as the dominant anion. Column SC values were comparable to relevant published field data. PMID- 25912886 TI - The mismatch between bioaccumulation in field and laboratory environments: Interpreting the differences for metals in benthic bivalves. AB - Laboratory-based bioaccumulation and toxicity bioassays are frequently used to predict the ecological risk of contaminated sediments in the field. This study investigates the bioassay conditions most relevant to achieving environmentally relevant field exposures. An identical series of metal-contaminated marine sediments were deployed in the field and laboratory over 31 days. Changes in metal concentrations and partitioning in both sediments and waters were used to interpret differences in metal exposure and bioaccumulation to the benthic bivalve Tellina deltoidalis. Loss of resuspended sediments and deposition of suspended particulate matter from the overlying water resulted in the concentrations of Cu, Pb and Zn (major contaminants) becoming lower in the 1-cm surface layer of field-deployed sediments. Lower exchange rates of overlying waters in the laboratory resulted in higher dissolved metal exposures. The prediction of metal bioaccumulation by the bivalves in field and laboratory was improved by considering the metal partitioning within the surface sediments. PMID- 25912887 TI - Increase in polycyclic aromatic hydrocarbon (PAH) emissions due to briquetting: A challenge to the coal briquetting policy. AB - Both China and UNEP recommend replacing raw coal chunks with coal briquettes in household sector as clean coal technology (CCT), which has been confirmed by the decreased emissions of particulate matter and black carbon. However, the clean effect has never been systematically checked by other pollutants like polycyclic aromatic hydrocarbons (PAHs). In this study, 5 coals with different geological maturities were processed as both chunks and briquettes and burned in 3 typical coal stoves for the measurement of emission factors (EFs) of particle-bound PAHs. It was found that the EFs of 16 parent PAHs, 26 nitrated PAHs, 6 oxygenated PAHs, and 8 alkylated PAHs for coal briquettes were 6.90 +/- 7.89, 0.04 +/- 0.03, 0.65 +/- 0.40, and 72.78 +/- 18.23 mg/kg, respectively, which were approximately 3.1, 3.7, 1.9, and 171 times those for coal chunks, respectively. Such significant increases in PAH emissions increased human health risk and challenged the policy of CCT. PMID- 25912888 TI - Application of chemometric analysis and self Organizing Map-Artificial Neural Network as source receptor modeling for metal speciation in river sediment. AB - Present study deals with the river Ganga water quality and its impact on metal speciation in its sediments. Concentration of physico-chemical parameters was highest in summer season followed by winter and lowest in rainy season. Metal speciation study in river sediments revealed that exchangeable, reducible and oxidizable fractions were dominant in all the studied metals (Cr, Ni, Cu, Zn, Cd, Pb) except Mn and Fe. High pollution load index (1.64-3.89) recommends urgent need of mitigation measures. Self-organizing Map-Artificial Neural Network (SOM ANN) was applied to the data set for the prediction of major point sources of pollution in the river Ganga. PMID- 25912889 TI - A New Correction for Multiple Testing in Gene-Gene Interaction Studies. AB - A major problem in gene-gene interaction studies in large marker panels is how to correct for multiple testing while accounting for the dependence between marker pairs due to the presence of linkage disequilibrium. The "gold standard" approach is to perform permutations of case/control labels. However, this is often not feasible in practice, due to computational demands. Here, we propose a correction based on the effective number of independent tests of interaction between marker pairs. This number depends on the effective number of independent single-marker tests. We tested its validity using simulated samples, as well as that of another correction of marker pair tests. We showed that our approach was valid while the other correction strongly underestimated the effective number of independent tests. Our method provides estimates of the effective number of independent tests close to those reported in the literature for a Genome-Wide Interaction Study on a 550K chip. Our correction method is quick and simple, and can be applied whatever the marker panel and the underlying linkage disequilibrium pattern. PMID- 25912890 TI - WITHDRAWN: Efficacy and safety of short-term treatment of naproxcinod in patients with osteoarthritis (OA) of the hip: A prospective, randomized study. AB - This article has been withdrawn at the request of the author(s) and/or editor. The Publisher apologizes for any inconvenience this may cause. The full Elsevier Policy on Article Withdrawal can be found at http://www.elsevier.com/locate/withdrawalpolicy. PMID- 25912891 TI - Assessment of functional capability and on-going falls-risk in older institutionalized people after total hip arthroplasty for femoral neck fractures. AB - PURPOSE: To estimate functional capability and attendant falls-risk in older institutionalized people after total hip arthroplasty (THA) for femoral neck fractures. METHODS: The study population comprised 149 consecutive patients (F104, M45; mean age 83.4 years) who were permanent residents of nursing care facilities four weeks after THA for femoral neck fractures. Individual mental and functional capability status was assessed using the Mini Mental State Examination (MMSE), Timed Up and Go test (TUG) and Tinetti's Performance Oriented Mobility Assessment (POMA) which includes sub-scales for balance (B) and gait (G), in conjunction with identifying any concomitant disorders, reviewing individual pharmacotherapy and leisure time activities. RESULTS: The subjects' mean MMSE was 23.1 points, whereas in Tinetti's POMA they scored 19 points on average, which translated into a five-fold greater falls-risk, whereas average TUG scores of 23.9s effectively corroborated this assertion. Multiple regression analysis effectively highlighted that TUG scores were strongly correlated with the actual number of concomitant disorders, number of regularly taken medications, and usual manner of spending leisure time. CONCLUSIONS: Institutionalized older people after THA for femoral neck fracture continue to be exposed to high risk of recurrent, possibly injurious falls, which is closely correlated with significantly diminished individual functional capabilities. PMID- 25912892 TI - Parallel language activation and inhibitory control in bimodal bilinguals. AB - Findings from recent studies suggest that spoken-language bilinguals engage nonlinguistic inhibitory control mechanisms to resolve cross-linguistic competition during auditory word recognition. Bilingual advantages in inhibitory control might stem from the need to resolve perceptual competition between similar-sounding words both within and between their two languages. If so, these advantages should be lessened or eliminated when there is no perceptual competition between two languages. The present study investigated the extent of inhibitory control recruitment during bilingual language comprehension by examining associations between language co-activation and nonlinguistic inhibitory control abilities in bimodal bilinguals, whose two languages do not perceptually compete. Cross-linguistic distractor activation was identified in the visual world paradigm, and correlated significantly with performance on a nonlinguistic spatial Stroop task within a group of 27 hearing ASL-English bilinguals. Smaller Stroop effects (indexing more efficient inhibition) were associated with reduced co-activation of ASL signs during the early stages of auditory word recognition. These results suggest that inhibitory control in auditory word recognition is not limited to resolving perceptual linguistic competition in phonological input, but is also used to moderate competition that originates at the lexico-semantic level. PMID- 25912893 TI - The working memory Ponzo illusion: Involuntary integration of visuospatial information stored in visual working memory. AB - Visual working memory (VWM) has been traditionally viewed as a mental structure subsequent to visual perception that stores the final output of perceptual processing. However, VWM has recently been emphasized as a critical component of online perception, providing storage for the intermediate perceptual representations produced during visual processing. This interactive view holds the core assumption that VWM is not the terminus of perceptual processing; the stored visual information rather continues to undergo perceptual processing if necessary. The current study tests this assumption, demonstrating an example of involuntary integration of the VWM content, by creating the Ponzo illusion in VWM: when the Ponzo illusion figure was divided into its individual components and sequentially encoded into VWM, the temporally separated components were involuntarily integrated, leading to the distorted length perception of the two horizontal lines. This VWM Ponzo illusion was replicated when the figure components were presented in different combinations and presentation order. The magnitude of the illusion was significantly correlated between VWM and perceptual versions of the Ponzo illusion. These results suggest that the information integration underling the VWM Ponzo illusion is constrained by the laws of visual perception and similarly affected by the common individual factors that govern its perception. Thus, our findings provide compelling evidence that VWM functions as a buffer serving perceptual processes at early stages. PMID- 25912894 TI - Risk taking in adversarial situations: Civilization differences in chess experts. AB - The projections of experts in politics predict that a new world order will emerge within two decades. Being multipolar, this world will inevitably lead to frictions where civilizations and states will have to decide whether to risk conflict. Very often these decisions are informed if not taken by experts. To estimate risk-taking across civilizations, we examined strategies used in 667,599 chess games played over eleven years by chess experts from 11 different civilizations. We show that some civilizations are more inclined to settle for peace. Similarly, we show that once engaged in the battle, the level of risk taking varies significantly across civilizations, the boldest civilization using the riskiest strategy about 35% more than the most conservative civilization. We discuss which psychological factors might underpin these civilizational differences. PMID- 25912895 TI - Laying date, incubation and egg breakage as determinants of bacterial load on bird eggshells: experimental evidence. AB - Exploring factors guiding interactions of bacterial communities with animals has become of primary importance for ecologists and evolutionary biologists during the last years because of their likely central role in the evolution of animal life history traits. We explored the association between laying date and eggshell bacterial load (mesophilic bacteria, Enterobacteriaceae, Staphylococci, and Enterococci) in natural and artificial magpie (Pica pica) nests containing fresh commercial quail (Coturnix coturnix) eggs. We manipulated hygiene conditions by spilling egg contents on magpie and artificial nests and explored experimental effects during the breeding season. Egg breakage is a common outcome of brood parasitism by great spotted cuckoos (Clamator glandarius) on the nests of magpie, one of its main hosts. We found that the treatment increased eggshell bacterial load in artificial nests, but not in magpie nests with incubating females, which suggests that parental activity prevents the proliferation of bacteria on the eggshells in relation to egg breakage. Moreover, laying date was positively related to eggshell bacterial load in active magpie nests, but negatively in artificial nests. The results suggest that variation in parental characteristics of magpies rather than climatic variation during the breeding season explained the detected positive association. Because the eggshell bacterial load is a proxy of hatching success, the detected positive association between eggshell bacterial loads and laying date in natural, but not in artificial nests, suggests that the generalized negative association between laying date and avian breeding success can be, at least partially, explained by differential bacterial effects. PMID- 25912896 TI - The effects of morbid obesity on maternal and neonatal health outcomes: a systematic review and meta-analyses. AB - Morbidly obese (Class III, body mass index [BMI] >= 40 kg m(-2)) women constitute 8% of reproductive-aged women and are an increasing proportion; however, their pregnancy risks have not yet been well understood. Hence, we performed meta analyses following the MOOSE (Meta-Analysis of Observational Studies in Epidemiology) guideline, searching Medline and Embase from their inceptions. To examine graded relationships, we compared Class III obesity to Class I and I/II, and separately to normal weight. We found important effects on all three primary outcomes in morbidly obese women: preterm birth <37 weeks was 31% higher compared with Class I (relative risk [RR] 1.31 [1.19, 1.43]) and 20% higher than Class I/II (RR 1.20 [1.13, 1.27]), large-for-gestational age was higher (RR 1.37 [1.29, 1.45] and RR 1.30 [1.24, 1.36] compared with Class I and I/II, respectively), while small-for-gestational age was lower (RR 0.89 [0.84, 0.93] compared with Class I, with nearly identical reductions for Class I/II). Morbidly obese women have higher risks of preterm birth, large-for-gestational age and numerous other adverse maternal and infant health outcomes, relative to not only normal weight but also Class I or I/II obese women. These findings have important implications for screening and care of morbidly obese pregnant women, to try to decrease adverse outcomes. PMID- 25912897 TI - Erratum: fulminant type 1 diabetes mellitus and fulminant viral myocarditis. PMID- 25912898 TI - High Level of von Willebrand Factor in Non-ST Segment Elevation Myocardial Infarction Patients Predicted Cardiovascular Ischemic Events After Off-Pump Coronary Artery Bypass Surgery. AB - The aim of our study was to determine the characteristics and value of plasma von Willebrand factor antigen (vWF: Ag) levels after off-pump coronary artery bypass grafting (OPCAB) surgery in predicting the risk of cardiovascular ischemic events.A retrospective cohort analysis of 203 non-ST-segment elevation myocardial infarction patients was performed. Patients were divided into a poor recovery group and a stable condition group according to whether ischemic events occurred or not within 90 days postoperatively. The level of vWF: Ag was detected using a blood coagulation analyzer. SPSS17.0 statistical software was used for data analysis. The Friedman rank sum test and Mann-Whitney U test were used for intra group and inter-group data analysis, respectively. The diagnostic performance of vWF: Ag was evaluated by receiver operating characteristic (ROC) curve analysis.Plasma vWF: Ag levels at postoperative days 14, 30, 60, and 90 in the poor recovery group were significantly higher than those at the corresponding time points in the stable group. The area under the ROC curve in diagnosing adverse events was 0.927 (95% CI: 0.867~0.987) with 96.6% sensitivity and 58.6% specificity when the cut-off value of vWF: Ag was 233% at postoperative day 30.The changing characteristics of plasma vWF: Ag sensitively reflect the degree of vascular endothelial injury of OP-CAB patients and might serve as a surrogate marker of the adverse event of non-ST segment elevation myocardial infarction. PMID- 25912899 TI - Biventricular pacing with ventricular fusion by intrinsic activation in cardiac resynchronization therapy. AB - We sought to evaluate the impact of biventricular (BiV) pacing with ventricular fusion by intrinsic atrioventricular nodal (AVN) conduction (BiV + intrinsic pacing) on clinical outcomes in patients with chronic heart failure (CHF) receiving cardiac resynchronization therapy (CRT).A total of 44 patients were randomized to receive either BiV or BiV + intrinsic pacing for one month. Echocardiographic optimization was performed for the BiV pacing mode, while the BiV + intrinsic pacing mode was achieved by titrating AV delay under electrocardiography (ECG) monitoring. Symptoms, quality of life, ECG, echocardiography, and cardiovascular events were recorded at baseline and the end of the follow-up for each pacing mode.Patients undergoing BiV + intrinsic pacing mode had shorter QRS duration compared to those with conventional BiV pacing (118.4 +/- 21.6 ms versus 146.4 +/- 5.3 ms, P < 0.0001). Also, these patients had improved echocardiographic left ventricular fractional shortening (LVFS) (17.4 +/ 5.9 versus 15.7 +/- 4.9, P = 0.019), higher left ventricular ejection fraction (LVEF) (35.5 +/- 9.7 versus 32.7 +/- 9.7, P = 0.048), longer 6-minute walk test (6MWT) (372.5 +/- 80.9 m versus 328.7 +/- 108.9 m, P = 0.0001), and better Minnesota Living with Heart Failure Questionnaire (MLHFQ) scores (12.5 +/- 6.6 versus 18.2 +/- 12.3, P = 0.0001).Treating CHF patients with BiV+intrinsic pacing resulted in improved cardiac function and quality of life. BiV + intrinsic pacing can be used in CHF patients with sinus rhythm and normal AV nodal conduction to improve CRT efficacy. PMID- 25912900 TI - Platelet Glycoprotein IIb/IIIa Inhibitor Tirofiban Ameliorates Cardiac Reperfusion Injury. AB - There are many published articles on the effects of the antithrombolytic function of platelet glycoprotein IIb/IIIa inhibitors (GP IIb/IIIa inhibitors) in myocardial infarction. However, few studies have explored the effects and optimal concentration of tirofibans in diminishing the extent of myocardial reperfusion injury (RI).Rats received 120 minutes of coronary ligation and 180 minutes of reperfusion. The rats were then divided into 7 groups based on the concentration of tirofiban administered intravenously 30 minutes prior to coronary reperfusion to the end of reperfusion. The ratio of myocardial necrotic area to area at risk (AAR), and myocardial malondialdehyde (MDA) and plasma myeloperoxidase (MPO) activities were measured. The apoptotic index (AI) was the percentage of myocytes positive for terminal deoxynucleotidyl transferase-mediated dUTP-biotin nick-end labeling (TUNEL) out of all myocytes stained by 4', 6-diamidino-2-phenylindole (DAPI).The ratio of myocardial necrotic area to AAR significantly decreased in all tirofiban subgroups. The MDA activity for tirofiban concentrations of 2 and 5 ug/kg/minute showed a slight reduction. MPO activity was significantly decreased at a tirofiban concentration of 2 ug/kg/minute. The AI was significantly decreased at a tirofiban concentration of >= 0.4 ug/kg/minute.The results indicate that a tirofiban can significantly ameliorate the cardiac RI and myocyte apoptosis in rats. PMID- 25912902 TI - Evaluation of right ventricle by speckle tracking and conventional echocardiography in rats with right ventricular heart failure. AB - Speckle tracking echocardiography (STE) has been reported to be a promising technique for evaluating right ventricular (RV) function in the clinical setting. On the other hand, the usefulness of STE for RV evaluation in small animal models has not been clarified, although the rat model is among the most commonly used animal models to develop novel effective treatments against pulmonary hypertension and RV heart failure (HF).We validated the use of STE and conventional echocardiographic variables for evaluating RV functions in a rat model by comparing the echocardiographic values of RVHF rats (n = 12) induced by monocrotaline injection with those of control rats (n = 12).Most conventional echocardiographic variables demonstrated that RVHF rats have significant RV dysfunction. The area under the curve (AUC) values to distinguish RV dysfunction in RVHF rats from normal RV function in control rats using fractional area change (FAC), tricuspid annular plane systolic excursion (TAPSE), RV myocardial performance index (MPI), peak tissue Doppler tricuspid annular velocities at systole (Sa), and at early diastole (Ea) were 0.71, 0.98, 0.79, 0.92, and 0.91, respectively. However, using STE analysis for RV evaluation, limited reproducibility was observed (variability 19-37 %, ICC 0.74-0.88) and the only circumferential strain showed significantly lower absolute values (P = 0.039, AUC = 0.76).To evaluate RV function in rat models, circumferential strain may be useful, however, the reproducibility and diagnostic utility were limited. Conventional echocardiographic variables such as TAPSE, tissue Doppler Sa, and Ea have superior diagnostic utility. PMID- 25912901 TI - Clinical significance of high-sensitivity cardiac troponin T in patients with dilated cardiomyopathy. AB - Although conventional cardiac troponin T (cTnT) and I (cTnI) markers have been reported to predict adverse outcome in dilated cardiomyopathy (DCM), the usefulness of a new-generation high-sensitivity assay of cardiac troponin T (hs cTnT) compared with these conventional biomarkers is unclear.We performed clinical evaluation including measurements of troponin markers in 54 patients with DCM under a clinically stable condition. At baseline, the serum concentration of hs-cTnT was 0.014 +/- 0.016 ng/mL and 17 (31%) of the patients showed abnormal hs-cTnT values (> 0.014 ng/mL). During a mean follow-up period of 5.1 +/- 1.6 years, there were 16 cardiac events: heart failure death in 6 patients, sudden cardiac death in 2 patients, and hospitalization for heart failure in 8 patients. Patients with abnormal hs-cTnT or abnormal cTnT (> 0.01 ng/mL) values had significantly more frequent cardiac events than did those with normal hs-cTnT or cTnT values. On the other hand, abnormal cTnI (> 0.03 ng/mL) value did not reach statistical significance for these adverse events. Multivariate analysis showed that only an abnormal hs-cTnT value was an independent predictor of all cardiac events (HR: 5.68, P = 0.003). When the patients were divided into 4 groups according to the degree of hs-cTnT levels, the clinical course was significantly worse in patients with higher hs-cTnT values.These results suggest that the serum concentration of hs-cTnT provides better risk stratification in DCM patients. PMID- 25912903 TI - Association between left atrial appendage morphology evaluated by trans esophageal echocardiography and ischemic cerebral stroke in patients with atrial fibrillation. AB - The left atrial appendage (LAA) represents one of the major sources of cardiac thrombi responsible for embolic stroke in patients with atrial fibrillation (AF). The aim of the present study was to evaluate LAA structure and functions by transesophageal echocardiography (TEE) in patients with AF to investigate the possible association between the different LAA morphologies and the patients' history of ischemic cerebral stroke. We included 50 patients with non-valvular AF (29 chronic, 21 paroxysmal), 24 patients (13 men) without stroke; and 26 patients (9 men) with a history of ischemic stroke. All patients underwent TEE evaluation of LAA morphology and functions. Compared to patients without stroke, patients with ischemic stroke had significantly higher CHADS2 scores (4.19 +/- 0.89 versus 1.67 +/- 1.13; P < 0.001) and C-reactive protein levels (8.3 +/- 1.6 versus 7.6 +/- 0.83 mg/L; P = 0.023), and lower peak filling (21.7 +/- 11.3 versus 31.2 +/- 9.5 cm/second; P = 0.033) and emptying (22.2 +/- 9.7 versus 33.4 +/- 13.4 cm/second, P = 0.030) velocities. Triangular LAA morphology had a higher prevalence in patients with stroke (36% versus 12% in non-stroke group); and in half of them an LAA thrombus was present. LAA thrombi were detected in 9 patients (18%) with stroke and in 5 patients (10%) without stroke. On multivariate logistic regression analysis, age (OR = 1.202 [1.042-1.585]; P = 0.041), LAA orifice diameter (OR = 1.275 [1.102-1.748]; P = 0.028), and triangular LAA morphology (OR = 4.53 [1.629-8.381]; P = 0.011) were significantly and independently associated with ischemic stroke in AF patients. LAA morphology evaluated by TEE may be useful for predicting ischemic cerebral stroke in patients with non-valvular AF, especially in those with a low CHADS2 score. PMID- 25912904 TI - Improvement of Predictive Value for Thromboembolic Risk by Incorporating Left Atrial Functional Parameters in the CHADS2 and CHA2DS2-VASc Scores. AB - The discriminative ability of the widely used CHADS2 and CHA2DS2-VASc scores for risk stratification of thromboembolism in atrial fibrillation (AF) is known as modest. Some echocardiographic parameters are known risk factors for thromboembolism. This study aimed to evaluate whether combining echocardiographic parameters with CHADS2 and CHA2DS2-VASc scores can improve the predictive power for embolic risk in AF.A total of 526 (F/M = 83/433, mean age = 57.6 +/- 10.7 years) patients with non-valvular AF were enrolled. The predictability for left atrial (LA) thrombus or dense spontaneous echo contrast (SEC) using clinical scores or echocardiographic parameters or combining clinical scores and echocardiographic parameters was calculated and compared.Dense SEC or thrombus was present in 51 patients. The predicting powers of the CHADS2 and CHADS2-VASc scores for the presence of dense SEC or thrombus were modest (c-statistics 0.65 and 0.68, respectively, 95% confidence interval [CI] 0.61-0.69 and 0.64-0.74, respectively, both P < 0.001). Impaired LA function was the most descriptive predictor for the presence of thrombus or dense SEC among echocardiographic parameters. Combining impaired LA function (LA emptying fraction < 30%) with the CHADS2 and CHA2DS2-VASc scores showed the improvement of predictive power in detecting dense SEC or thrombus (c-statistics 0.78 and 95% CI 0.74-0.81 and c statistics 0.77 and 95% CI 0.73-0.81, respectively, both P < 0.001).Adding LA functional markers to the CHADS2 or CHA2DS2-VASc score improved the predictive value of the presence of thrombus or dense SEC. In clinical situations, anticoagulation should be considered to prevent embolism in patients with low risk scores when they have LA dysfunction. PMID- 25912905 TI - Clinical implications of increased Nogo-B levels in patients with acute coronary syndromes and stable angina pectoris. AB - Although the relationship between arteriosclerosis and inflammatory response has been recognized in recent years, little is known regarding the change in plasma Nogo-B in coronary artery disease (CAD). Thus, we investigated the expression levels of Nogo-B in CAD patients and examined this relation with disease stages. We recruited 92 CAD patients including 64 with acute coronary syndromes (ACS) and 28 with stable angina pectoris (SAP) cases and 28 healthy controls. The serum concentrations of Nogo-B were measured by enzyme-linked immunosorbent assay (ELISA). The plasma Nogo-B level was significantly higher in patients with ACS and SAP when compared with the healthy controls (both P < 0.05). Multivariate logistic regression analysis revealed that the level of Nogo-B was associated with CAD (odds ratio 1.006, 95% CI: 1.000-1.013, P < 0.05). In conclusion, an increased plasma Nogo-B level may be associated with CAD. PMID- 25912906 TI - Pathological role of adipose tissue dysfunction in cardio-metabolic disorders. AB - Obesity has dramatically increased throughout the world, and has become one of the chief healthcare problems in many societies. Evidence has emerged that adipose tissue dysfunction associated with obesity is critically involved in the development of cardiovascular and metabolic disorders. In this review, we delineate the link between adipose tissue abnormalities and systemic metabolic dysfunction in patients with cardio-metabolic diseases and discuss the underlying mechanisms. PMID- 25912907 TI - Pleiotropic Effects of Angiotensin II Receptor Signaling in Cardiovascular Homeostasis and Aging. AB - Most of the pathophysiological actions of angiotensin II (Ang II) are mediated through the Ang II type 1 (AT1) receptor, a member of the seven-transmembrane G protein-coupled receptor family. Essentially, AT1 receptor signaling is beneficial for organismal survival and procreation, because it is crucial for normal organ development, and blood pressure and electrolyte homeostasis. On the other hand, AT1 receptor signaling has detrimental effects, such as promoting various aging-related diseases that include cardiovascular diseases, diabetes, chronic kidney disease, dementia, osteoporosis, and cancer. Pharmacological or genetic blockade of AT1 receptor signaling in rodents has been shown to prevent the progression of aging-related phenotypes and promote longevity. In this way, AT1 receptor signaling exerts antagonistic and pleiotropic effects according to the ages and pathophysiological conditions. Here we review the pleiotropic effects of AT1 receptor signaling in cardiovascular homeostasis and aging. PMID- 25912908 TI - Effects of high vs. low cadence training on cyclists' brain cortical activity during exercise. AB - OBJECTIVES: As brain cortical activity depends on cadence, exercise at different pedaling frequencies could provide efficient stimuli for functional adaptations of the brain. Therefore, the purpose of the study was to investigate the effects of cadence-specific training on brain cortical activity as well as endurance performance. DESIGN: Randomized, controlled experimental trial in a repeated measure design. METHODS: Male (n=24) and female (n=12) cyclists were randomly assigned to either a high cadence group (HCT), a low cadence group (LCT) or a control group (CON) for a 4 week intervention period. All groups performed 4h of basic endurance training per week. Additionally, HCT and LCT completed four cadence-specific 60min sessions weekly. At baseline and after 4 weeks subjects performed an incremental test with spirometry as well as an interval session (constant load; varying cadences) with continuous recording of electroencephalographic (EEG) rhythms. RESULTS: In contrast to CON, HCT and LCT elicited similar improvements of maximal oxygen uptake and power at the individual anaerobic threshold. Additionally, there was a reduction of alpha-, beta- and overall-power spectral density in HCT, which was more pronounced at high cadences. Improvements of endurance performance were correlated with reductions of EEG spectral power at 90 and 120rpm. CONCLUSIONS: Whereas high and low cadence training elicit similar improvements in endurance performance, brain cortical activity is especially sensitive to high cadence training. Its reduction can be interpreted in the sense of the neural efficiency hypothesis and might as well influence the sensation of central fatigue positively. PMID- 25912909 TI - The switch from ER stress-induced apoptosis to autophagy via ROS-mediated JNK/p62 signals: A survival mechanism in methotrexate-resistant choriocarcinoma cells. AB - BACKGROUND: Human choriocarcinoma, a highly curable solid tumour, is exceptionally sensitive to methotrexate-based chemotherapy at the metastatic stage. The present study aimed to investigate the molecular basis for this resistance to methotrexate therapy occurs in some cases, and these patients subsequently die from progressive and advanced disease. METHODS: The autophagy and apoptotic activity regulated by PERK/ATF4 axis in methotrexate-resistant JEG 3 and parental cells were evaluated with western blotting and chromatin immunoprecipitation (ChIP). The regulatory relationships among the reactive oxygen species (ROS), JNK/p62 axis, PERK/ATF4-mediated apoptosis and autophagy were assessed with western blotting, RT-PCR, fluorescence-activated cell sorting as well as ChIP. RESULTS: The decreased apoptosis in methotrexate-resistant JEG-3 cells was observed with an up-regulation of protective autophagy, suggesting a switch from apoptosis to autophagy, which was regulated via the PERK/ATF4 pathway under condition of endoplasmic reticulum (ER) stress. Further experiments demonstrated that this cell death switch was regulated by ROS-mediated JNK/p62 pathway and subsequently lead to the resistance of choriocarcinoma cells to methotrexate treatment. CONCLUSIONS: This study provides evidence to explain a survival mechanism of the switch from ER stress-induced apoptosis to autophagy via ROS-mediated JNK/p62 signals in methotrexate-resistant choriocarcinoma cells and may implicate the chemotherapy of methotrexate resistance in choriocarcinoma. PMID- 25912910 TI - Reductive dechlorination of carbon tetrachloride using buffered alkaline ascorbic acid. AB - Alkaline ascorbic acid (AA) was recently discovered as a novel in-situ chemical reduction (ISCR) reagent for remediating chlorinated solvents in the subsurface. For this ISCR process, the maintenance of an alkaline pH is essential. This study investigated the possibility of the reduction of carbon tetrachloride (CT) using alkaline AA solution buffered by phosphate and by NaOH. The results indicated that CT was reduced by AA, and chloroform (CF) was a major byproduct at a phosphate buffered pH of 12. However, CT was completely reduced by AA in 2M NaOH without CF formation. In the presence of iron/soil minerals, iron could be reduced by AA and Fe(2+) tends to precipitate on the mineral surface to accelerate CT degradation. A simultaneous transfer of hydrogenolysis and dichloroelimination would occur under phosphate buffered pH 12. This implies that a high alkaline environment is a crucial factor for maintaining the dominant pathway of two electron transfer from dianionic AA to dehydroascorbic acid, and to undergo dichloroelimination of CT. Moreover, threonic acid and oxalic acid were identified to be the major AA decomposition products in alkaline solutions. PMID- 25912911 TI - Population-The long view. PMID- 25912912 TI - The Death of the West: An alternative view. AB - Much has been written about the 'Death of the West', a demise threatened by the low level of reproduction in Western countries. That fate is contrasted unfavourably with the rapid growth of the populations and economies of less developed countries, and the prospect of the numerical and political marginalization of the formerly dominant developed world. We believe that trends in European fertility have been misunderstood and that, with effort and some pain, their consequences for age structure are manageable. Many European societies also enjoy the advantages of demographic and social maturity, the resilience of established consensual democratic institutions, the rule of law, and civil society. The sizes of China and India raise problems of resource sustainability and vulnerability to climate change. China risks falling into a low-fertility trap, reinforced by urban working conditions unfriendly to family formation. Traditional patriarchal and familist cultures may depress fertility rates to unhelpfully low levels in other less developed countries. PMID- 25912913 TI - Integrating macro- and micro-level approaches in the explanation of population change. AB - Demographers study population change across time and place, and traditionally they place a strong emphasis on a long-range view of population change. This paper builds on current reflections on how to structure the study of population change and proposes a two-stage perspective. The first stage, discovery, focuses on the production of novel evidence at the population level. The second stage, explanation, develops accounts of demographic change and tests how the action and interaction of individuals generate what is discovered in the first stage. This explanatory stage also provides the foundation for the prediction of demographic change. The transformation of micro-level actions and interactions into macro level population outcomes is identified as a key challenge for the second stage. Specific instances of research are discussed. PMID- 25912914 TI - What we can and cannot learn from the history of world population. AB - Mankind is passing through an exceptional phase of accelerated population growth that generates anxiety about the future. How many billion people will share the limited resources of our globe a century from now? What will be the consequences of globalization for human behaviour? How will individuals react to emerging new constraints? What will be the consequences of climate change for human society? Obviously enough, history cannot offer operational answers to these crucial questions. Nevertheless, history offers some interesting insights into demographic behaviour experienced in the past that could be replicated in the future, with the variations and adaptations dictated by the changing contexts. In other words, there are constants and structures in human behaviour, and there are robust mechanisms in the functioning of demographic systems that are of some help in preparing us to deal with the future. PMID- 25912915 TI - Population theory-A long view. AB - Any attempt to take a long view of population research, its findings, and applications is bound to raise questions about the state of population theory. Recent research on the history of population thought enables us to include a much more complete account of classical and early modern sources, and of parallel and complementary developments in population biology. This paper considers four major shifts in the conceptual and empirical ambitions of population inquiry over the long term. In general, major conceptual developments in ideas about population reflect major shifts in political and biological theory. The nature of population in European science and society was substantially established before demography emerged as a twentieth-century academic discipline focused chiefly on fertility and mortality. A long view suggests that demography is currently in the course of a shift that constructively re-integrates it with the wider field of scientific and historical population thinking. PMID- 25912916 TI - Evolutionary contributions to the study of human fertility. AB - Demography, lacking an overarching theoretical framework of its own, has drawn on theories in many other social sciences to inform its analyses. The aim of this paper is to bring to the demographic community's attention research in the evolutionary sciences on fertility, and to demonstrate that evolutionary theory can be another useful tool in the demographer's toolkit. I first dispel some myths which impede the incorporation of evolutionary theory into demography: I make it clear that evolutionary explanations do not assume that all human behaviour is hardwired and functions to maximize genetic fitness; that they are able to explain variation in human behaviour; and that they are not necessarily alternatives to social science explanations. I then describe the diversity of work on fertility by evolutionary researchers, particularly human evolutionary ecologists and cultural evolutionists, and illustrate the usefulness of the evolutionary approach with examples of its application to age at first birth and the fertility transition. PMID- 25912917 TI - Baby booms, busts, and population ageing in the developed world. AB - The key challenge facing contemporary society is a process of population ageing rooted mainly in past fertility cycles. The goals of the study reported in this paper were (i) to analyse jointly the post-1930s baby boom and the baby bust that followed, (ii) to consider the specific ways this particular combination influenced the process of ageing in different societies, and (iii) to evaluate some possible implications for policy of different historical experiences. Demographic time series for 27 nations in the developed world were used. The main results confirm the importance of the boom and bust fertility cycle of the second half of the twentieth century for population ageing. Some countries will experience ageing processes driven mainly by the growth of elderly populations while others will age largely as a result of declines in working-age populations. These differences underscore the need to tailor policy priorities for specific patterns of ageing. PMID- 25912918 TI - Demographic aspects of climate change mitigation and adaptation. AB - This paper addresses the contribution of changes in population size and structures to greenhouse gas emissions and to the capacity to adapt to climate change. The paper goes beyond the conventional focus on the changing composition by age and sex. It does so by addressing explicitly the changing composition of the population by level of educational attainment, taking into account new evidence about the effect of educational attainment in reducing significantly the vulnerability of populations to climatic challenges. This evidence, which has inspired a new generation of socio-economic climate change scenarios, is summarized. While the earlier IPCC-SRES (Intergovernmental Panel on Climate Change-Special Report on Emissions Scenarios) scenarios only included alternative trajectories for total population size (treating population essentially as a scaling parameter), the Shared Socio-economic Pathways (SSPs) in the new scenarios were designed to capture the socio-economic challenges to climate change mitigation and adaptation, and include full age, sex, and education details for all countries. PMID- 25912919 TI - Sub-replacement fertility in national populations: Can it be raised? AB - This paper comments on the four main functions demographers perform: fact finding, analysis, prediction, and policymaking. Successes in the first two of these are counterbalanced by weakness in predictive ability. The focus of the comments, however, is on policy. Demographers were influential in promoting efforts to lower very high fertility but are ineffectual in proposing policies that could reverse the tendency of fertility to sink well below replacement levels. The paper argues for a break from exclusive reliance on the standard measures of modern welfare states intended to raise fertility and urges exploration of radically new approaches. Two promising innovations are briefly outlined: one would give the right to vote to all citizens regardless of age, the voting right of minors being exercised by parental proxy, and another that would reform state-administered pension schemes by arranging a direct transfer of working children's mandatory contributions to social security funds to their retired parents. PMID- 25912920 TI - Political demography: Powerful trends under-attended by demographic science. AB - The interconnections between politics and the dramatic demographic changes under way around the world have been neglected by the two research disciplines that could contribute most to their understanding: demography and political science. Instead, this area of 'political demography' has largely been ceded to political activists, pundits, and journalists, leading often to exaggerated or garbled interpretation. The terrain includes some of the most politically sensitive and contested issues: alleged demographically determined shifts in the international balance of power; low fertility, population decline, and demographic ageing; international migration; change in national identity; and compositional shifts in politically sensitive social categories and human rights. Meanwhile many governments and non-governmental actors have actively pursued varieties of 'strategic demography', deploying fertility, mortality, or migration as instruments of domestic or international policy. Political scientists and demographers could and should use their knowledge and analytic techniques to improve understanding and to moderate excessive claims and fears on these topics. PMID- 25912921 TI - Fertility in China: An uncertain future. AB - As one of the world's two population 'billionaires', the future of China's population is truly of global significance. With its very low fertility and a rapidly ageing population, it might appear that the country's famous (or notorious) family planning restrictions are somewhat anachronistic. Here, we explore the process of reform seen over the past three decades and, most recently, in late 2013. We suggest that the popular notion that the family planning restrictions are acting as a pressure valve suppressing a pent-up demand for childbearing, particularly in rural China, is likely to be inaccurate. We also suggest that further reform of the restrictions will not solve the problems of population ageing or many of the other issues widely associated with the restrictions. We conclude that the prospects for further reform are wide-ranging, but likely to be beset by many challenges. PMID- 25912923 TI - A novel, colorimetric method for biogenic amine detection based on arylalkylamine N-acetyltransferase. AB - We developed a novel colorimetric method for rapid detection of biogenic amines based on arylalkylamine N-acetyltransferase (aaNAT). The proposed method offers distinct advantages including simple handling, high speed, low cost, good sensitivity and selectivity. PMID- 25912922 TI - Vertical Distribution of Functional Potential and Active Microbial Communities in Meromictic Lake Kivu. AB - The microbial community composition in meromictic Lake Kivu, with one of the largest CH4 reservoirs, was studied using 16S rDNA and ribosomal RNA (rRNA) pyrosequencing during the dry and rainy seasons. Highly abundant taxa were shared in a high percentage between bulk (DNA-based) and active (RNA-based) bacterial communities, whereas a high proportion of rare species was detected only in either an active or bulk community, indicating the existence of a potentially active rare biosphere and the possible underestimation of diversity detected when using only one nucleic acid pool. Most taxa identified as generalists were abundant, and those identified as specialists were more likely to be rare in the bulk community. The overall number of environmental parameters that could explain the variation was higher for abundant taxa in comparison to rare taxa. Clustering analysis based on operational taxonomic units (OTUs at 0.03 cutoff) level revealed significant and systematic microbial community composition shifts with depth. In the oxic zone, Actinobacteria were found highly dominant in the bulk community but not in the metabolically active community. In the oxic-anoxic transition zone, highly abundant potentially active Nitrospira and Methylococcales were observed. The co-occurrence of potentially active sulfur oxidizing and sulfate-reducing bacteria in the anoxic zone may suggest the presence of an active yet cryptic sulfur cycle. PMID- 25912924 TI - Toxoplasma's ways of manipulating the host transcriptome via secreted effectors. AB - The obligate intracellular parasite Toxoplasma gondii strikes a subtle balance with the host immune system that not only prevents host death but also promotes parasite persistence. Although being enclosed within a parasitophorous vacuole, the parasite actively interfaces with host cell signaling pathways, thereby directing host cell responses. To this end, T. gondii delivers effector proteins into the host cell that co-opt host transcription factors and eventually modulate gene expression. Aside from the secretory Rhoptry organelles initially described as the main source of such effectors, Dense Granules are now recognized as critical in delivering products that remain confined at the vacuolar space or traffic beyond the vacuole membrane to the host cell nucleus and contribute to rewire host gene expression. This review highlights the latest breakthroughs in T. gondii effector discovery and their modus operandi during infection. PMID- 25912925 TI - In vitro metacyclogenesis of Trypanosoma cruzi induced by starvation correlates with a transient adenylyl cyclase stimulation as well as with a constitutive upregulation of adenylyl cyclase expression. AB - The Trypanosoma cruzi adenylyl cyclase (AC) multigene family encodes different isoforms (around 15) sharing a variable large N-terminal domain, which is extracellular and receptor-like, followed by a transmembrane helix and a conserved C-terminal catalytic domain. It was proposed that these key enzymes in the cAMP signalling pathway allow the parasite to sense its changing extracellular milieu in order to rapidly adapt to its new environment, which is generally achieved through a differentiation process. One of the critical differentiation events the parasitic protozoan T. cruzi undergoes during its life cycle, known as metacyclogenesis, occurs in the digestive tract of the insect and corresponds to the differentiation from noninfective epimastigotes to infective metacyclic trypomastigote forms. By in vitro monitoring the activity of AC during metacyclogenesis, we showed that both the activity of AC and the intracellular cAMP content follow a similar pattern of transient stimulation in a two-step process, with a first activation peak occurring during the first hours of nutritional stress and a second peak between 6 and 48 h, corresponding to the cellular adhesion. During this differentiation process, a general mechanism of upregulation of AC expression of both mRNA and protein is triggered and in particular for a major subclass of these enzymes that are present in various gene copies commonly associated to the THT gene clusters. Although the scattered genome distribution of these gene copies is rather unusual in trypanosomatids and seems to be a recent acquisition in the evolution of the T. cruzi clade, their encoded product redistributed on the flagellum of the parasite upon differentiation could be important to sense the extracellular milieu. PMID- 25912926 TI - Improved preservation of warm ischemia-damaged porcine kidneys after cold storage in Ecosol, a novel preservation solution. AB - BACKGROUND: Ecosol, an extracellular-type, colloid-based preservation solution, has recently been introduced for washout, cold storage, and machine perfusion preservation of kidney grafts. Here, we assessed the efficacy of Ecosol compared to the widely used Histidine-Tryptophan-Ketoglutarate solution (HTK) for 24-h cold storage preservation of warm ischemia-damaged kidney grafts. MATERIAL AND METHODS: Before recovery, warm ischemia was induced by clamping the renal pedicle for 45-min. Thereafter, kidneys were washed-out and cold-stored for 24-h in Ecosol or HTK solution. Kidneys recovered without warm ischemia and cold-stored for 24-h in HTK served as controls (n=5). Renal function and damage parameters were assessed during 1-h normothermic reperfusion using the isolated perfused porcine kidney model. RESULTS: Renal function did not differ between Ecosol and controls and was significantly reduced in HTK compared to controls. Total output of urine was higher in Ecosol compared to HTK. Intrarenal resistance and urine protein concentrations in Ecosol were lower compared to HTK and equal to controls. In the Ecosol group, oxygen consumption during reperfusion was higher and reduced tissue lipid peroxidation products were detected compared to HTK. CONCLUSIONS: The preservation quality of warm ischemia-damaged, cold-stored porcine kidneys was improved using the recently developed Ecosol preservation solution compared to HTK. PMID- 25912927 TI - Professor Harry Smith (1935-2015). PMID- 25912928 TI - Detection of mild inherited disorders of blood coagulation: current options and personal recommendations. AB - Although assessment of prior personal and familial bleeding history is an important aspect of the diagnosis of bleeding disorders, patients with mild inherited bleeding disorders are sometimes clinically asymptomatic until presented with a hemostatic challenge. However, bleeding may occur after incursion of trauma or surgery, so detection of these conditions reflects an important facet of clinical and laboratory practice. Mild bleeding disorders may be detected as a result of family studies or following identification of abnormal values in first-line screening tests such as activated partial thromboplastin time, prothrombin time, fibrinogen and global platelet function screen testing, such as the platelet function analyzer. Following determination of abnormal screening tests, subsequent investigation should follow a systematic approach that targets specific diagnostic tests, and including factor assays, full platelet function assays and more extensive specialized hemostasis testing. The current report provides a personal overview on inherited disorders of blood coagulation and their detection. PMID- 25912930 TI - Leukemic progenitor cells are susceptible to targeting by stimulated cytotoxic T cells against immunogenic leukemia-associated antigens. AB - Leukemic stem cells (LSC) might be the source for leukemic disease self-renewal and account for disease relapse after treatment, which makes them a critical target for further therapeutic options. We investigated the role of cytotoxic T lymphocytes (CTL) counteracting and recognizing LSC. Leukemia-associated antigens (LAA) represent immunogenic structures to target LSC. We enriched the LSC containing fraction of 20 AML patients and hematopoietic stem cells (HSC) of healthy volunteers. Using microarray analysis and qRT-PCR we detected high expression of several LAA in AML cells but also in LSC. PRAME (p = 0.0085), RHAMM (p = 0.03), WT1 (p = 0.04) and Proteinase 3 (p = 0.04) showed significant differential expression in LSC compared with HSC. PRAME, RHAMM and WT1 are furthermore also lower expressed on leukemic bulk. In contrast, Proteinase 3 indicates a higher expression on leukemic bulk than on LSC. In colony forming unit (CFU) immunoassays, T cells stimulated against various LAA indicated a significant inhibition of CFUs in AML patient samples. The LAA PRAME, RHAMM and WT1 showed highest immunogenic responses with a range up to 58-83%. In a proof of principle xenotransplant mouse model, PRAME-stimulated CTL targeted AML stem cells, reflected by a delayed engraftment of leukemia (p = 0.0159). Taken together, we demonstrated the expression of several LAA in LSC. LAA-specific T cells are able to hamper LSC in immunoassays and in a mouse model, which suggests that immunotherapeutic approaches have the potential to target malignant stem cells. PMID- 25912929 TI - Everolimus and sirolimus in transplantation-related but different. AB - INTRODUCTION: The inhibitors of the mammalian target of rapamycin (mTOR) sirolimus and everolimus are used not only as immunosuppressants after organ transplantation in combination with calcineurin inhibitors (CNIs) but also as proliferation signal inhibitors coated on drug-eluting stents and in cancer therapy. Notwithstanding their related chemical structures, both have distinct pharmacokinetic, pharmacodynamic and toxicodynamic properties. AREAS COVERED: The additional hydroxyethyl group at the C(40) of the everolimus molecule results in different tissue and subcellular distribution, different affinities to active drug transporters and drug-metabolizing enzymes as well as differences in drug target protein interactions including a much higher potency in terms of interacting with the mTOR complex 2 than sirolimus. Said mechanistic differences as well as differences found in clinical trials in transplant patients are reviewed. EXPERT OPINION: In comparison to sirolimus, everolimus has higher bioavailability, a shorter terminal half-life, different blood metabolite patterns, the potential to antagonize the negative effects of CNIs on neuronal and kidney cell metabolism (which sirolimus enhances), the ability to stimulate mitochondrial oxidation (which sirolimus inhibits) and to reduce vascular inflammation to a greater extent. A head-to-head, randomized trial comparing the safety and tolerability of these two mTOR inhibitors in solid organ transplant recipients is merited. PMID- 25912931 TI - Fondaparinux in pregnancy: Could it be a safe option? A review of the literature. AB - During pregnancy thrombo-prophylaxis could be required in high risk women. If a severe allergic reaction to low-molecular-weight-heparin (LMWH) or a heparin induced-thrombocytopenia (HIT) occurs, it's mandatory to stop the drug. Fondaparinux could be an effective option. In the present review, the maternal and pregnancy outcomes of 65 pregnancies in women using Fondaparinux were reported. It was well-tolerated and rate of pregnancy complications was similar to that observed in general population. Regarding congenital malformations, further studies are necessary to investigate the safety of the drug. PMID- 25912932 TI - The economic burden of gout: A systematic review. AB - OBJECTIVE: Gout is a painful and disabling joint disease that constitutes the most common inflammatory arthritis in the US. To clarify the economic impact of gout, we systematically reviewed the literature on the direct and indirect costs associated with this disease. METHODS: We conducted a literature search of MEDLINE, EMBASE, International Pharmaceutical Abstracts, NHS Economic Evaluation, and CINAHL databases to identify studies of gout and economics. We systematically reviewed published studies that met our inclusion criteria and extracted and summarized all relevant economic parameters. Reported costs were inflation adjusted to 2013 US dollars (USD). RESULTS: A total of 15 studies met all eligibility criteria. Three controlled studies reported all-cause total direct costs based on specific populations (i.e., $4733, $16,925, and $18,362 per capita among employed, elderly, and treatment-refractory gout populations, respectively, and $2562, $10,590, and $7188 among corresponding non-gout patients). Two additional studies, although uncontrolled, allowed for estimation of total all cause direct costs in unselected gout populations ($11,080 and $13,170). Gout related costs ranged from $172 to $6179, depending on population characteristics. Six studies reported positive associations of direct costs with SUA level, gout attack frequency, or presence of tophi. Four studies reported on indirect costs, which were estimated to be as high as $4341 USD. CONCLUSION: The available data suggest that gout patients incur substantially greater direct and indirect costs as compared with gout-free individuals among elderly and treatment-refractory gouty patients, whereas the costs are considerably less among younger, employed gouty patients. Further, direct costs increased with worsening disease characteristics. PMID- 25912934 TI - MtHc: a motif-based hierarchical method for clustering massive 16S rRNA sequences into OTUs. AB - The recent sequencing revolution driven by high-throughput technologies has led to rapid accumulation of 16S rRNA sequences for microbial communities. Clustering short sequences into operational taxonomic units (OTUs) is an initial crucial process in analyzing metagenomic data. Although many methods have been proposed for OTU inferences, a major challenge is the balance between inference accuracy and computational efficiency. To address these challenges, we present a novel motif-based hierarchical method (namely MtHc) for clustering massive 16S rRNA sequences into OTUs with high clustering accuracy and low memory usage. Suppose all the 16S rRNA sequences can be used to construct a complete weighted network, where sequences are viewed as nodes, each pair of sequences is connected by an imaginary edge, and the distance of a pair of sequences represents the weight of the edge. MtHc consists of three main phrases. First, heuristically search the motif that is defined as n-node sub-graph (in the present study, n = 3, 4, 5), in which the distance between any two nodes is less than a threshold. Second, use the motif as a seed to form candidate clusters by computing the distances of other sequences with the motif. Finally, hierarchically merge the candidate clusters to generate the OTUs by only calculating the distances of motifs between two clusters. Compared with the existing methods on several simulated and real life metagenomic datasets, we demonstrate that MtHc has higher clustering performance, less memory usage and robustness for setting parameters, and that it is more effective to handle the large-scale metagenomic datasets. The MtHC software can be freely download from for academic users. PMID- 25912933 TI - Airway epithelial cytokine responses in childhood wheeze are independent of atopic status. AB - BACKGROUND: Airway epithelial cells (AEC) are key contributors to immune function in the lungs but little is known about their role and function in children. OBJECTIVES: Having previously established that nasal AEC mediator release correlates with that of bronchial AEC, we assessed AEC responses in children with and without a history of wheeze. METHODS: Nasal AEC cultures were established from children (0.6-14.9 years) undergoing elective surgical procedures under general anaesthetic categorised as atopic asthmatic (n = 12), virus-induced wheeze (n = 8) or children without wheeze (n = 32). Mediator release by AEC monolayers at passage 2 was determined by cytometric bead array assay or ELISA. RESULTS: Unstimulated AEC from children with a history of wheeze produced significantly less IL-8, IL-6, MCP-1 and G-CSF than AEC from healthy controls. There were no group differences in AEC release of VEGF, RANTES, MMP-9 or TIMP-1. After stimulation with the pro-inflammatory cytokines IL-1beta and TNFalpha, AEC from children with current wheeze produced significantly less IL-8, IL-6 and MCP 1 than children without wheeze. Release of G-CSF, VEGF, MMP-9 and TIMP-1 did not differ between the wheeze and control group. There were no differences in mediator release between subjects with atopic asthma and those with virus-induced wheeze or between atopic and non-atopic controls. On multivariate analysis, wheeze was the only significant predictor of AEC mediator release. CONCLUSION & CLINICAL RELEVANCE: Intrinsic differences in AEC from children with a history of wheeze may reflect a defect in cytokine production in vivo or an altered state of differentiation in vitro, independent of atopic status. PMID- 25912935 TI - Diagnosis: Congenital Dyserythropoietic Anemia Type 2 Due to Compound Heterozygote Mutation in SEC23B Gene. PMID- 25912936 TI - Facile method to disperse nonporous metal organic frameworks: composite formation with a porous metal organic framework and application in adsorptive desulfurization. AB - It is generally not easy to utilize nonporous metal organic frameworks (MOFs) with a large crystal size (especially for catalysis or adsorption) because their surface area is low and the majority of the active sites exist inside the MOFs. Composing with porous materials may be one way to disperse the nonporous materials. In this study, a nonporous/nonsoluble MOF (in which the particle size was much larger than the cavity size of the porous MOFs) containing Cu(I) ((Cu2(pyz)2(SO4)(H2O)2)n, denoted as CP) was composed with typical porous MOFs such as MIL100(Fe) (iron-benzenetricarboxylate) and CuBTC (cupper benzenetricarboxylate). The Cu(I) species of the nonporous MOF was effectively utilized for the adsorptive desulfurization (ADS) of model fuel. Even though the porosities of the composed MOFs decreased as the content of CP increased, the adsorption capacity increased as the content of CP increased (up to a certain content). Considering the negligible capacity of CP for ADS, the enhanced adsorption capacity may be a result of the well-dispersed Cu(I), which is known to be beneficial for ADS via pi-complexation. The dispersed CP was also observed by transmission electron microscopy mapping. Therefore, composing a nonporous MOF with porous MOF is a new and facile way to disperse/utilize the active sites of a nonporous MOF. PMID- 25912937 TI - Economic Assessment and Budgetary Impact of a Telemedicine Procedure and Spirometry Quality Control in the Primary Care Setting. AB - OBJECTIVE: To evaluate the economic impact of a telemedicine procedure designed to improve the quality of lung function testing (LFT) in primary care in a public healthcare system, compared with the standard method. MATERIALS AND METHODS: The economic impact of 9,039 LFTs performed in 51 health centers (2010-2013) using telespirometry (TS) compared to standard spirometry (SS) was studied. RESULTS: TS costs more per unit than SS (?47.80 vs. ?39.70) (2013), but the quality of the TS procedure is superior (84% good quality, compared to 61% using the standard procedure). Total cost of TS was ?431,974 (compared with ?358,306? for SS), generating an economic impact of ?73,668 (2013). The increase in cost for good quality LFT performed using TS was ?34,030 (2010) and ?144,295 (2013), while the costs of poor quality tests fell by ?15,525 (2010) and 70,627? (2013). CONCLUSION: The cost-effectiveness analysis concludes that TS is 23% more expensive and 46% more effective. Healthcare costs consequently fall as the number of LFTs performed by TS rises. Avoiding poor quality, invalid LFTs generates savings that compensate for the increased costs of performing LFTs with TS, making it a cost-effective method. PMID- 25912938 TI - Aging, chronicity and pulmonary care. PMID- 25912939 TI - Sulfasalazine-induced Hypereosinophilic Obliterative Bronchiolitis. PMID- 25912941 TI - Deep UV excited muscle cell autofluorescence varies with the fibre type. AB - The rat skeletal muscle consists of four pure types of muscle cells called type I, type IIA, type IIX and type IIB, and their hybrids in different proportions. They differ in their contraction speeds and metabolic pathways. The intracellular composition is adapted to the fibre function and therefore to fibre types. Given that small differences in composition are likely to alter the optical properties of the cells, we studied the impact of the cell type on the fluorescence response following excitation in the deep UV region. Rat soleus and extensor digitorum longus (EDL) muscle fibres, previously identified based on their cell types by immunohistofluorescence analysis, were analyzed by synchrotron fluorescence microspectroscopy on stain-free serial muscle cross-sections. Muscle fibres excited at 275 nm showed differences in the fluorescence emission intensity among fibre types at 302, 325, 346 and 410 nm. The 410/325 ratio decreased significantly with contractile and metabolic features in EDL muscle, in the order of I > IIA > IIX > IIB fibres (p < 0.01). Compared to type I fibres, the 346/302 ratio of IIA fibres decreased significantly in both EDL and soleus muscles (p < 0.01). This study highlights the usefulness of autofluorescence spectral signals to characterize histological cross-sections of muscle fibres with no staining chemicals. PMID- 25912940 TI - Characterization of Arabidopsis thaliana GCN2 kinase roles in seed germination and plant development. AB - Eukaryotic GCN2 (general control nonderepressible 2) is a serine/threonine protein kinase that plays an essential role in modulating amino acid metabolism in response to nutrient deprivation. A wide spectrum of GCN2 functions in yeast and mammals has been characterized that spans from responses to amino acid deficiency, development, differentiation and proper functions of mammalian organs to organism's life span, tumor cell survival and immune responses. Here we demonstrate that Arabidopsis thaliana GCN2 (AtGCN2) plays crucial roles in plant growth and development. We present evidence that AtGCN2 negatively regulates seed germination under diverse environmental conditions. Our genetic data supported the notion that AtGCN2 is required for leaf morphology and normal cellular physiology by controlling chlorophyll contents. Our gene expression analyses revealed that AtGCN2 negatively regulates several transcription factor genes that play important roles in plant gibberellic acid-related crosstalk. We concluded that AtGCN2 plays pivotal roles in various cellular processes essential for normal growth and development, hence expanding the functions of this general regulator beyond being merely a stress player. PMID- 25912942 TI - Exploration of endogenous substrate cleavage by various forms of botulinum neurotoxins. AB - Botulinum neurotoxins are the most potent protein neurotoxin known to human. The dual roles of BoNTs as both the causative agent of human botulism and a widely used protein-based therapeutic agent for treatment of numerous neuromuscular disorders/cosmetic uses make it an extremely hot topic of research. Biochemical characterization of these toxins was mainly confined to the recombinant light chains and substrate and little is known about their efficiency on the cleavage of endogenous substrates. In the present study, we showed that BoNTs exhibited variable activities on their endogenous substrates and that their efficiency to cleave recombinant and endogenous substrate was not consistent, presumably due to the differential recognition of their respective substrates in the natural SNARE complex format. Through testing the combinatorial effects of different BoNTs on cleavage of endogenous substrates, we showed that the combinations of LC/A and LC/B, as well as LC/A and LC/F, could enhance the activity of each individual BoNT. This finding may shed light on the future development of new BoNT serotypes for clinical application, and formulation of combinatorial uses of different BoNTs to minimize the development of immuno-resistance by using a lower amount of individual type. PMID- 25912943 TI - Amino acid residue Y196E substitution and C-terminal peptide synergistically alleviate the toxicity of Clostridium perfringens epsilon toxin. AB - Epsilon toxin (ETX) is produced by Clostridium perfringens type B and D strains, and is the causative agent of a lethal enterotoxemia in livestock animals and possibly in humans. However, many details of ETX structure and activity are not known. Therefore, it is important to clarify the relationship between ETX structure and activity. To explore the effect and mechanism of ETX amino acid residue Y196E substitution and C-terminal peptide on toxicity, four recombinant proteins, rETX (without 13 N-terminal peptides and 23 C-terminal peptides), rETX C (rETX with 23 C-terminal peptides), rETX(Y196E) (rETX with an amino acid residue substitution at Y196) and rETX(Y196E)-C (rETX-C with a Y196E mutation), were constructed in this study. Both the amino acid residue Y196E substitution and the C-terminal peptide reduce ETX toxicity to a similar extent, and the two factors synergistically alleviate ETX toxicity. In addition, we demonstrated that the C-terminal peptides and Y196E amino acid mutation reduce the toxin toxicity in two different pathways: the C-terminal peptides inhibit the binding activity of toxins to target cells, and the Y196E amino acid mutation slightly inhibits the pore-forming or heptamer-forming process. Interaction between the two factors was not observed in pore-forming or binding assays but toxicity assays, which demonstrated that the relationship between domains of the toxin is more complicated than previously appreciated. However, the exact mechanism of synergistic action is not yet clarified. PMID- 25912944 TI - Hemiscorpius lepturus venom induces expression and production of interluckin-12 in human monocytes. AB - The objective of this study was to evaluate the capacity of the venom from Hemiscorpius lepturus to induce expression and production of interleukin-12 (IL 12) on isolated human monocytes. For this purpose, isolated human monocytes (250,000-300,000 cells/ml) were exposed to different concentrations of the venom (0.625, 1.25, 2.5, 5, 10 and 20 MUg/ml) in 96-well plates for varying incubation periods (6, 12, and 24 h). The end point of assessment included LDH cytotoxicity assay, measurement of expression of IL-12,p40 mRNA by real-time PCR, and quantification of IL-12 release using sandwich ELISA technique. The results showed that this venom produced concentration- and time of incubation-dependent cytotoxicity. The level of enhancement of expression and production of IL-12 were found significantly higher with lowest concentration and after 6 h of incubation. The findings demonstrated that the venom from this scorpion contains active constituents which can direct the immune system to produce IL-12. PMID- 25912945 TI - Post-transcriptional control of Amblyomin-X on secretion of vascular endothelial growth factor and expression of adhesion molecules in endothelial cells. AB - Angiogenesis is a pivotal process of homeostasis and tissue repair, but it also favours neovascularisation syndromes and cancer nutrition. The chemical mediation of angiogenesis is complex, involving a balance between serine proteases and their inhibitors. We addressed the mechanisms of action of a Kunitz serine protease inhibitor (KPI) on spontaneous angiogenesis, using Amblyomin-X, a KPI designed from the cDNA library of the Amblyomma cajennense tick. Amblyomin-X treatment (10-1000 ng/10 MUL; each 48 h; 3 times) reduced the number of vessels in the subcutaneous dorsal tissue of male Swiss mice, as measured by intravital microscopy, haematoxylin-eosin staining, and PECAM-1 immunofluorescence labeling. Incubation of Amblyomin-X with t-End endothelial cells, a murine endothelial microvascular lineage, did not alter cell proliferation, cell-cycle phases, necrosis and apoptosis, and the production of nitric oxide and prostaglandin E2. Nevertheless, Amblyomin-X treatment reduced t-End migration and adhesion to Matrigel((r)), and inhibited the VEGF-A secretion and VCAM-1 and beta3 integrin expressions by posttranscriptional pathways. Together, data herein outline novel posttranscriptional mechanisms of KPIs on endothelial cells during angiogenesis and point out the possible application of Amblyomin-X as a local inhibitor to undesired neovascularisation process. PMID- 25912946 TI - The structure-function relationship of thrombin-like enzymes from the green pit viper (Trimeresurus albolabris). AB - Pit viper venoms can decrease fibrinogen levels in snakebite patients. Studies have shown that the hypofibrinogenemia is a consequence of snake venom thrombin like enzymes (TLEs), the serine proteases that have the potential to be both diagnostic and therapeutic agents. Exosites of thrombin are the molecular regions that determine the substrate specificities, but its presence and significance in TLEs are unclear. Therefore, the putative exosites of recombinant TLEs derived from Green pit viper (Trimeresurus albolabris), GPV-TL1 and GPV-TL2, were mutated in a Pichia pastoris system. In a previous report, GPV-TL1 showed a strong fibrinogenolytic activity on the Aalpha and Bbeta chains of fibrinogen, as well as a plasma clotting activity. Compared with GPV-TL1, the GPV-TL1m mutated in the putative exosite (TRN to RRR at residues 60-62) showed a weaker fibrinogenolytic activity with a similar clotting activity of 207.1 thrombin units/mg. GPV-TL2 contained two-residue differences from GPV-TL1 in the putative exosite (N73M and V74Y). GPV-TL2 selectively cleaved only the Aalpha chain of fibrinogen without detectable clotting activity. The mutated GPV-TL2 (GPV-TL2m) showed a weaker fibrinogenolytic activity compared with that of the wild type. These results support the important roles of the putative exosite in snake venom TLE activities. This information is helpful for future protein engineering. PMID- 25912947 TI - Testing and application of a refined rapid detection method for paralytic shellfish poisoning toxins in UK shellfish. AB - The Scotia Rapid Test for PSP is designed for qualitative identification of saxitoxins at levels in shellfish equivalent to the limit of detection of the biological reference method. However, issues with the method have been reported, including the low assay cross reactivity for some toxins, high numbers of false positive results and the subjective test interpretation. This study focussed on approaches to improve each of these issues. A refined test was found to improve GTX1&4 test sensitivity in samples containing high proportions of GTX1&4. The subjectivity of the test was successfully eliminated through use of an automated scanner, which enabled both the reliable identification of test results as well as the provision of a numerical result which could be utilised for more refined results interpretation. Finally the high proportion of false positive results in comparison with the LC-FLD was investigated, with a modified approach incorporating an additional extract dilution applied to a range of shellfish samples with different toxicities. Results showed highly variable limits of detection of the method and no significant reduction in false positive results when applying the additional dilution, which may be of concern to laboratories in receipt of high numbers of samples containing low concentrations of toxins. PMID- 25912948 TI - Proton ordering dynamics of H2O ice. AB - From high precision measurements of the complex dielectric constant of especially prepared samples of H2O, we identify the onset temperatures of the phase transition into and out of ice XI from ice Ih to occur at TIh-XI = 58.9 K and TXI Ih = 73.4 K. For D2O, TIh-XI = 63.7 K and TXI-Ih = 78.2 K. A triple point is identified to exist at 0.07 GPa and 73.4 K for H2O and 0.08 GPa and 78.2 K for D2O where ices Ih, II and XI coexist. A first order phase transition with kinetic broadening associated with proton ordering dynamics is identified at 100 K. PMID- 25912950 TI - Outcomes of curettage and anhydrous alcohol adjuvant for low-grade chondrosarcoma of long bone. AB - BACKGROUND: Low-grade chondrosarcoma of long bones can be treated successfully with extended intralesional curettage using adjuvants. However, there is no study reporting the use of anhydrous alcohol as an adjuvant in the treatment of low grade chondrosarcoma. We asked (1) whether intralesional curettage and anhydrous alcohol adjuvant for low-grade chondrosarcoma is associated with good oncologic outcomes; and we report (2) the complications of the procedure. METHODS: Thirty six patients (13 men, 23 women) with a mean age of 46 years (range, 18-67 years) were treated for low-grade chondrosarcoma and followed up for a median of 62 months (range, 24-169 months). After intralesional curettage, and additional burring, anhydrous alcohol was used as an adjuvant therapy. RESULTS: At the time of last follow-up, there were no local recurrences or distant metastases. Six patients developed complications: 4 postoperative fractures (11%), 1 intra articular loose body (3%) and 1 postoperative joint stiffness (3%). CONCLUSION: Anhydrous alcohol is a reasonable adjuvant for the curettage of low-grade chondrosarcoma of long bones. A long-term follow-up study is necessary, considering the slow biological progression of low-grade chondrosarcoma. PMID- 25912951 TI - Metastatic lymph node ratio successfully predicts prognosis in western gastric cancer patients. AB - BACKGROUND: Lymph node positivity is a strong prognostic indicator in many cancers including gastric cancer. The extent of surgical resection directly influences the number of lymph nodes available for staging, with the lesser D1 resection that is standard practice in non-Asian countries typically providing fewer nodes for analysis. The widely used AJCC TNM staging system has been criticized for under-staging and stage migration where fewer than 15 nodes are resected, which is often the case in these populations. The ratio of positive to total nodes harvested--Lymph Node Ration (LNR)--has been proposed as an improved and more widely applicable prognostic indicator. HYPOTHESIS: The LNR is a reliable and accurate prognostic indicator of survival in a Western gastric cancer population. METHODS: 9357 patients were acquired via a SEER case listing session with 2004-2011 gastric adenocarcinoma diagnoses. AJCC 7th edition nodal staging (N0: 0, N1:1-2, N2:3-6, N3:>=7 positive lymph nodes) and LNR positive nodal staging (PN0: 0%, PN1: 1-20%, PN2: 21-50%, PN3: 51-100% of examined nodes positive) were compared as respects seven year survivorship. RESULTS: Adjusted survival time ratios for AJCC nodal curves were less evenly distributed than were the percent positive nodal curves. Results of multiple regression reflected that survival time ratios of the percent positive nodal schema being more evenly spaced than those of the AJCC schema. Because BIC for AJCC, 41071.48, was larger than that for percent positive nodes, 41024.25, the LNR nodal system better explained survival than the AJCC nodal classification system. CONCLUSION: LNR produced reliable and internally consistent survival curves for this population. LNR is an effective tool to predict survival in a western gastric cancer patient population, where the majority of the patients have limited lymph node dissection. PMID- 25912952 TI - Reproductive parameters of Tetranychus urticae (Acari: Tetranychidae) affected by neonicotinoid insecticides. AB - Two-spotted spider mite is a major pest of many agricultural and ornamental crops worldwide. Some reports have indicated that application of neonicotinoid insecticides may lead to increased fecundity of this pest. If this is found to be true, the use of these pesticides may cause an outbreak of spider mite populations. Sublethal effects of three neonicotinoids, namely thiacloprid, acetamiprid and thiamethoxam were studied on T. urticae adults at field recommended doses. The experiments were carried out using bean leaf pieces in plastic Petri dishes. The adult mites were treated using two methods: (1) drench application and (2) spraying of leaves with Potter Spray Tower. Our results indicated that all neonicotinoids tested increased T. urticae population. In both treatment methods, acetamiprid treated mites had the highest intrinsic rate of population increase (rm) and finite rate of population increase (lambda); and the lowest mean generation time (T) and doubling time among the treatments. If similar results are obtained from greenhouse and field trials, the use of these insecticides requires necessary precautions such as avoiding repeated use of neonicotinoid insecticide for controlling insect pests. PMID- 25912953 TI - Development of "best practices" for sampling of an important surface-dwelling soil mite in pastoral landscapes. AB - In this study, we analyzed 1145 vacuum samples of redlegged earth mites (RLEM) [Halotydeus destructor (Tucker) (Acari: Penthaleidae)] from 18 sampling events at six locations in pastoral landscapes of Western Australia during three growing seasons (2012-2014) (total of 228,299 RLEM individuals). The specific objectives were to determine: (1) presence/absence effects of a range of vegetation characteristics, (2) possible factors influencing RLEM sampling performance during the course of the season and day, (3) effects of size of area sampled and duration of sampling, (4) the spatial structure of RLEM counts in uniform pastoral vegetation, and (5) develop "best practices" regarding field-based vacuum sampling of surface dwelling soil mites in pastoral landscapes. We found that sampling of completely bare ground will lead to very low RLEM counts but spots with sparse vegetation (presence of bare ground) probably increases the presence of microhabitats for mites to shelter in and therefore lead to higher RLEM counts. RLEM counts were positively associated with the height of vegetation, at least up to about 15 cm in height. In early season (May-August), highest RLEM counts will be obtained in the afternoon hours (2-4 pm), whereas in late season sampling (August-November), highest RLEM counts will be obtained around noon. Higher RLEM counts should be expected from spots with grazed/mowed vegetation including cape weed and without presence of grasses and stubble. Variogram analyses of high-resolution data sets suggested that considerable range of spatial autocorrelation should be expected from fields with fairly uniform vegetation, especially if RLEM population densities are high. We are therefore recommending that samples are collected at least 30 m apart, if the objective is to obtain independent (spatially non-correlated) counts. The results from this study may be used to develop effective sampling protocols deployed in field ecology studies of soil surface dwelling mesofauna in pastoral landscapes and other ecosystems. PMID- 25912949 TI - Tumor angiogenesis: MMP-mediated induction of intravasation- and metastasis sustaining neovasculature. AB - Metastasis is a distinct stage of cancer progression that requires the development of angiogenic blood vessels serving as conduits for tumor cell dissemination. An accumulated body of evidence indicates that metastasis supporting neovasculature should possess certain structural characteristics allowing for the process of tumor cell intravasation, an active entry of cancer cells into the vessel interior. It appears that the development of tumor vessels with lumens of a distinctive size and support of these vessels by a discontinuous pericyte coverage constitute critical microarchitectural requirements to: (a) provide accessible points for vessel wall penetration by primary tumor cells; (b) provide enough lumen space for a tumor cell or cell aggregate upon intravasation; and (c) allow for sufficient rate of blood flow to carry away intravasated cells from the primary tumor to the next, proximal or distal site. This review will primarily focus on the functional roles of matrix metalloproteinases (MMPs), which catalytically trigger the development of an intravasation-sustaining neovasculature at the early stages of tumor growth and are also required for the maintenance of a metastasis-supporting state of blood vessels at later stages of cancer progression. PMID- 25912954 TI - Interaction of ectoparasites (Mesostigmata, Phthiraptera and Siphonaptera) with small mammals in Cerrado fragments, western Brazil. AB - We describe ectoparasite fauna associated with small mammals in fragments of Cerrado biome, central-western Brazil. We analyzed the level of associations and the aggregation patterns according to seasonal and host variations. Small mammals were systematically captured in 54 woodland fragments from February 2012 to July 2013. A total of 1040 animals belonging to eight marsupial and 12 rodent species were sampled; 354 individuals were parasitized by 33 ectoparasite species (twenty five Mesostigmata, seven Phthiraptera and one Siphonaptera). A total of 49 ecological relationships between ectoparasites and small mammals were observed, 24 being new association records. The overall specialization index of all ectoparasites and host species was 0.91 with significant deviation from a random host-parasite association, suggesting a high host-parasite specialization in this system. Specialization indices for ectoparasites ranged from moderate to high, while among host was high, for most species. Contrary to the overall pattern, some ectoparasites had higher prevalence and mean intensity of infestation in the dry season. Overall, ectoparasite prevalence and mean intensity of infestation were not significantly associated with host gender. This study provides significant information about the ectoparasites ecology in relation to specificity, seasonality and hosts gender, contributing to the understanding of host-parasite relationships in Brazilian savannah. PMID- 25912955 TI - Detection and Significance of CD4+CD25+CD127dim Regulatory T Cells in Individuals with Severe Aplastic Anemia. AB - INTRODUCTION: To investigate the relationship between CD4(+)CD25(+)CD127(dim) regulatory T cells (Tregs) and immune imbalance in acquired severe aplastic anemia (SAA). METHODS: The quantity of CD4(+)CD25(+)CD127(dim) Tregs in 44 SAA patients and 23 normal controls were measured by flow cytometry. Correlations between Tregs and T cell subsets, dendritic cell (DC) subsets, granulocyte counts and percentage of reticulocytes (RET%) were analyzed. RESULTS: The percentage of CD4(+)CD25(+)CD127(dim) Tregs in peripheral blood lymphocytes (PBL) of untreated patients was lower than in recovery patients and normal controls (0.83 +/- 0.44% vs 2.91 +/- 1.24% and 2.18 +/- 0.55%, respectively, p<0.05). The percentage of CD4(+)CD25(+)CD127(dim) Tregs in CD4(+) T lymphocytes of recovery patients was higher than for untreated patients and normal controls (9.39 +/- 3.51% vs 7.61 +/ 5.3% and 6.83 +/- 1.4%, respectively, p<0.05). The percentage of CD4(+) T lymphocytes in PBL of untreated patients was lower than for recovery patients and normal controls (13.55 +/- 7.37% vs 31.82 +/- 8.43% and 32.12 +/- 5.88%, respectively, p<0.05). T cell subset (CD4(+)/CD8(+) ratio) was 0.41 +/- 0.24 in untreated patients, which was lower than recovery patients (1.2 +/- 0.4) and normal controls (1.11 +/- 0.23) (p<0.05). DC subset (myeloid DC/plasmacytoid DC ratio, DC1/DC2 ratio) was 3.08 +/- 0.72 in untreated patients, which was higher than recovery patients (1.61 +/- 0.49) and normal controls (1.39 +/- 0.36) (p<0.05). The percentage of CD4(+)CD25(+)CD127(dim) Tregs in PBL was positively associated with T cell subset (r=0.955, p<0.01), and negatively associated with DC subset (r=-0.765, p<0.01). There were significant positive correlations between CD4(+)CD25(+)CD127(dim) Tregs/PBL and granulocyte counts and RET% (r=0.739, 0.749 respectively, p<0.01). DISCUSSION AND CONCLUSION: The decrease of CD4(+)CD25(+)CD127(dim) Tregs in SAA patients may cause excessive functions of T lymphocytes and thus lead to hematopoiesis failure in SAA. PMID- 25912956 TI - Calciphylaxis and Ecthyma Gangrenosum in Chronic Kidney Disease: Clinical Similarities. PMID- 25912957 TI - Influence of bed rest on plasma galanin and adrenomedullin at presyncope. AB - BACKGROUND: The role of hormones in reduced orthostatic tolerance following long term immobilization remains uncertain. We have previously shown that plasma concentrations of adrenomedullin and galanin, two peptides with vasodepressor properties, rise significantly during orthostatic challenge. We tested the hypothesis that bedrest immobilization increases the rise in adrenomedullin and galanin during orthostatic challenge leading to presyncope. MATERIALS AND METHODS: We measured baseline (supine), presyncope and recovery (10 min postpresyncope, supine) levels of adrenomedullin and galanin in 8 healthy men, before and after 21 days of -6 degrees head-down bed rest (HDBR). Presyncope was elicited using a combined head-up tilt and graded lower body negative pressure protocol. Orthostatic tolerance was defined as the time taken from the commencement of head-up tilt to the development of presyncope. RESULTS: Orthostatic tolerance time after HDBR reduced by 8.36 +/- 5.39 min (P = 0.0032). HDBR increased plasma adrenomedullin concentration to orthostatic challenge (P = 0.0367). Compared to pre-HDBR, a significant rise in post-HDBR presyncopal (P < 0.001) and recovery adrenomedullin concentration (P < 0.01) was demonstrated. In contrast, we observed no change in pre- and post-HDBR galanin levels to orthostatic challenge. CONCLUSIONS: Bedrest immobilization appears to affect adrenomedullin levels in that greater increases in adrenomedullin occur at presyncope following bedrest immobilization. Due to its peripheral vasculature hypotensive effect, the greater levels of adrenomedullin at presyncope following bedrest immobilization may have contributed to the reduced orthostatic capacity postbedrest. PMID- 25912959 TI - A farewell to subjectivity using multivariate analytical models to improve patient outcomes and lower costs. PMID- 25912960 TI - Why did Jacques Monod make the choice of mechanistic determinism? AB - The development of molecular biology placed in the foreground a mechanistic and deterministic conception of the functioning of macromolecules. In this article, I show that this conception was neither obvious, nor necessary. Taking Jacques Monod as a case study, I detail the way he gradually came loose from a statistical understanding of determinism to finally support a mechanistic understanding. The reasons of the choice made by Monod at the beginning of the 1950s can be understood only in the light of the general theoretical schema supported by the concept of mechanistic determinism. This schema articulates three fundamental notions for Monod, namely that of the rigidity of the sequence of the genetic program, that of the intrinsic stability of macromolecules (DNA and proteins), and that of the specificity of molecular interactions. PMID- 25912958 TI - Developing the IVIG biomimetic, hexa-Fc, for drug and vaccine applications. AB - The remarkable clinical success of Fc-fusion proteins has driven intense investigation for even more potent replacements. Using quality-by-design (QbD) approaches, we generated hexameric-Fc (hexa-Fc), a ~20 nm oligomeric Fc-based scaffold that we here show binds low-affinity inhibitory receptors (FcRL5, FcgammaRIIb, and DC-SIGN) with high avidity and specificity, whilst eliminating significant clinical limitations of monomeric Fc-fusions for vaccine and/or cancer therapies, in particular their poor ability to activate complement. Mass spectroscopy of hexa-Fc reveals high-mannose, low-sialic acid content, suggesting that interactions with these receptors are influenced by the mannose-containing Fc. Molecular dynamics (MD) simulations provides insight into the mechanisms of hexa-Fc interaction with these receptors and reveals an unexpected orientation of high-mannose glycans on the human Fc that provides greater accessibility to potential binding partners. Finally, we show that this biosynthetic nanoparticle can be engineered to enhance interactions with the human neonatal Fc receptor (FcRn) without loss of the oligomeric structure, a crucial modification for these molecules in therapy and/or vaccine strategies where a long plasma half-life is critical. PMID- 25912961 TI - Pharmacokinetics and pharmacodynamics of rilotumumab: a decade of experience in preclinical and clinical cancer research. AB - Rilotumumab is a fully human monoclonal antibody against hepatocyte growth factor, the only known ligand of the MET receptor. Over the last decade, rilotumumab has been extensively tested in preclinical studies and in clinical studies in a variety of cancer types. In this review, we examine the pharmacokinetic and pharmacodynamic data that have been collected in the rilotumumab programme to date, and discuss retrospectively how the knowledge acquired in this programme can be applied to a number of key issues in oncology drug development, including: (i) using preclinical data to inform first-in-human study design; (ii) the role of biomarkers in the identification of a target patient population; (iii) the potential for drug interactions between therapeutic proteins and other anticancer agents; and (iv) pharmacokinetic and pharmacodynamic considerations in phase 3 study design. PMID- 25912962 TI - The Association Between Medical Treatment of Physical Diseases and Psychological Distress After the Great East Japan Earthquake: The Shichigahama Health Promotion Project. AB - OBJECTIVE: Physical disease patients are known to experience high levels of psychological distress. This study examined the association between the medical treatment of physical diseases and psychological distress in the coastal area affected by the Great East Japan Earthquake. METHODS: Using cross-sectional data, we studied 3032 individuals aged >=40 years who lived in Shichigahama, Miyagi, Japan. We examined the associations between 8 medical treatments for physical diseases and psychological distress, defined as Kessler Psychological Distress scale score >=13 of 24 points. To investigate the associations, we performed multiple logistic regression analyses. RESULTS: There were statistically significant associations between psychological distress and medical treatments for myocardial infarction/angina pectoris (odds ratio [OR]=1.8, 95% confidence interval [CI]=1.0-3.0) and liver disease (OR=3.1, 95% CI=1.0-7.7). The other 4 medical treatments for physical diseases had ORs of 1.3 or higher and were positively associated with psychological distress: cancer, hyperlipidemia, kidney disease, and diabetes mellitus. The degree of damage to homes did not affect the association between most of the medical treatments for physical diseases and psychological distress. CONCLUSIONS: In the disaster area, most of the medical treatments for physical diseases had positive associations with psychological distress, irrespective of the degree of damage to homes. PMID- 25912963 TI - Evidence for the antisense transcription in the proviral R29-127 strain of bovine immunodeficiency virus. PMID- 25912964 TI - In vitro and in vivo evaluation of therapy targeting epithelial-cell adhesion molecule aptamers for non-small cell lung cancer. AB - Targeted, disease-specific delivery of therapeutic nanoparticles shows wonderful promise for transmitting highly cytotoxic anti-cancer agents. Using the reaction of non-small cell lung cancer (SK-MES-1 and A549 cell lines) as representative of other cancer types', the present study examines the effects of EpCAM fluoropyrimidine RNA aptamer-decorated, DOX-loaded, PLGA-b-PEG nanopolymersomes that bond specifically to the extracellular domain of epithelial-cell adhesion molecules. Results demonstrate that EpCAM aptamer-conjugated DOX-NPs (Apt-DOX-NP) significantly enhance cellular nanoparticle uptake in SK-MES-1 and A549 cell lines and increase the cytotoxicity of the DOX payload as compared with non targeted DOX-NP (P<0.05). Additionally, Apt-DOX-NP exhibits greater tumor inhibition in nude mice bearing SK-MES-1 non-small cell lung-cancer xenografts and reduces toxicity, as determined by loss of body weight, cardiac histopathology and animal survival rate in vivo. After a single intravenous injection of Apt-DOX-NP and DOX-NPs, tumor volume decreased 60.9% and 31.4%, respectively, in SK-MES-1-xenograft nude mice compared with members of a saline injected control group. This study proves the potential utility of Apt-DOX-NP for therapeutic application in non-small cell lung cancer. In the future, EpCAM targeted therapies might play a key role in treating non-small cell lung cancer, the most common type of lung cancer. PMID- 25912965 TI - First data on trace elements in Haliotis tuberculata (Linnaeus, 1758) from southern Italy: Safety issues. AB - This study evaluated for the first time the concentrations of 10 metals in wild specimens of abalone, Haliotis tuberculata (Ht) (Linnaeus, 1758) from three sites along the southern Italian coast: Gulf of Catania (CT), the Northern Coast of Messina (ME) and the harbor of Villa San Giovanni (VSG). The species is commonly found in the area and has significant commercial value. Additionally, it is long lived, thus suitable as bioindicator of the environmental monitoring. The potential human health risks due to consumption of Ht have been assessed by estimated average daily intake (EDI) and target hazard quotient (THQ) of metals, respectively. In particular arsenic (As), cadmium (Cd), copper (Cu), chromium (Cr), iron (Fe), lead (Pb), manganese (Mn), mercury (Hg), selenium (Se) and vanadium (V) were quantified in the edible tissue of specimens by acid digestion of the samples and ICP-MS determination. The highest concentrations were found in CT sample area for most metals analyzed. Mean values for Pb, Cd and Hg were lower than the maximum levels (MLs) set for bivalve mollusks by Regulation (CE) no. 1881/2006 in all sites, and average intake values below the risk levels for human consumption. PMID- 25912966 TI - Perioperative bleed from superior mesenteric vein to abdominal wall portosystemic shunt via small bowel adhesion. PMID- 25912967 TI - Adaptation to Phosphene Parameters Based on Multi-Object Recognition Using Simulated Prosthetic Vision. AB - Retinal prostheses for the restoration of functional vision are under development and visual prostheses targeting proximal stages of the visual pathway are also being explored. To investigate the experience with visual prostheses, psychophysical experiments using simulated prosthetic vision in normally sighted individuals are necessary. In this study, a helmet display with real-time images from a camera attached to the helmet provided the simulated vision, and experiments of recognition and discriminating multiple objects were used to evaluate visual performance under different parameters (gray scale, distortion, and dropout). The process of fitting and training with visual prostheses was simulated and estimated by adaptation to the parameters with time. The results showed that the increase in the number of gray scale and the decrease in phosphene distortion and dropout rate improved recognition performance significantly, and the recognition accuracy was 61.8 +/- 7.6% under the optimum condition (gray scale: 8, distortion: k = 0, dropout: 0%). The adaption experiments indicated that the recognition performance was improved with time and the effect of adaptation to distortion was greater than dropout, which implies the difference of adaptation mechanism to the two parameters. PMID- 25912968 TI - Re: Development and Utilization of a Web-Based Application as a Robust Radiology Teaching Tool (RadStax) for Medical Student Anatomy Teaching. PMID- 25912969 TI - Breast Necrosis after Chemotherapy for Recurrent Ovarian Cancer: Report of a Case and Review of the Literature. AB - Breast necrosis is a rare event due to abundant blood supply of the breast. We present an unusual case of partial breast necrosis after chemotherapy for recurrent ovarian cancer. Necrotic tissue sloughed with conservative management and the wound was repaired surgically. We believe that this is the first case report of breast necrosis as a systemic complication of chemotherapy. PMID- 25912970 TI - Atomic switch networks-nanoarchitectonic design of a complex system for natural computing. AB - Self-organized complex systems are ubiquitous in nature, and the structural complexity of these natural systems can be used as a model to design new classes of functional nanotechnology based on highly interconnected networks of interacting units. Conventional fabrication methods for electronic computing devices are subject to known scaling limits, confining the diversity of possible architectures. This work explores methods of fabricating a self-organized complex device known as an atomic switch network and discusses its potential utility in computing. Through a merger of top-down and bottom-up techniques guided by mathematical and nanoarchitectonic design principles, we have produced functional devices comprising nanoscale elements whose intrinsic nonlinear dynamics and memorization capabilities produce robust patterns of distributed activity and a capacity for nonlinear transformation of input signals when configured in the appropriate network architecture. Their operational characteristics represent a unique potential for hardware implementation of natural computation, specifically in the area of reservoir computing-a burgeoning field that investigates the computational aptitude of complex biologically inspired systems. PMID- 25912971 TI - Changes in phosphorus fractions during organic wastes composting from different sources. AB - The study was conducted to investigate the changes in different fractions of phosphorus (P) and the relationship between different P fractions and their corresponding physicochemical parameters during organic wastes composting. There were distinct differences in the concentration of P fractions for the composts generated from different sources, highest in chicken manure and pig manure. The availability P (including water soluble P, Olsen P and citric acid P) declined from 44% to 36% in all composts, except for KW, following the thermophilic phase during composting, while moderately available P and non-available P increased from 48% to 59%. Different P fractions (inorganic P, organic P, Olsen P, water soluble P and citric acid P) were positively correlated with each other. The composts were clustered into two groups in our hierarchical cluster analysis. Conclusively, we suggested an optimized mode of composting based on the characteristics of the P fractions from different raw materials. PMID- 25912972 TI - Ingestive behavior of lambs fed diets containing castor seed meal. AB - The objective of this study was to evaluate the substitution of soybean meal for castor seed meal (CSM) in diets for feedlot lambs and the effects of these diets on their ingestive behavior. Fifty male Santa Ines lambs were used. The diets were composed of Tifton 85 hay and a concentrate containing detoxified CSM substituting 0, 25, 50, 75, or 100 % of the soybean meal. There was no effect (P > 0.05) of the CSM levels on the feeding, rumination, idle times, chews and time spent chewing per bolus, total chewing time, number of boli chewed, and number of chews per day. The dry matter (DM) intake decreased linearly (P < 0.05), but did not affect the neutral detergent fiber (NDF) intake. The feeding and rumination efficiencies had a quadratic response (P < 0.05). The experimental diets did not affect (P > 0.05) the numbers of feeding, rumination, and idle periods, but had a quadratic effect (P < 0.05) on the time per feeding activity and on the chewing periods. Substitution of soybean meal for detoxified CSM reduces the DM intake but does not change the ingestive behavior. PMID- 25912973 TI - Effect of feeding strategies on weaning weight and milk production of Holstein * Zebu calves in dual purpose milk production systems. AB - The objective of this study was to evaluate the effect of five feeding strategies on calf weaning weight, and cow milk production and composition in Brazilian Holstein * Zebu cows. A total of 60 cows and their calves were allocated to each of five treatments. Cows in treatments 1, 2 and 3 were milked for 270 days and cows in treatments 4 and 5 were milked for 180 days. Calves in treatment 1 (CON) were not supplemented with concentrate whereas calves from treatment 2 (CLPN) received 1 kg of concentrate daily from 90 to 270 days of age and calves from treatment 3 received 1 kg of concentrated from 180 to 270 days of age. Calves in treatment 4 (CCPS) were supplemented with 1 kg of concentrate from 90 to 180 days of age and calves in treatment 5 (CLPS) were supplemented with 1 kg of concentrate from 90 to 270 days of age. Calves from the CLPS treatment had greater milk and protein intakes (P < 0.05) and greater growth rate than calves from the other treatments. Our results indicate that the traditional system of feeding calves with no concentrate results in a weight gain of 600 g/day. The CLPS treatment produced calves with the highest live weight and growth rate. The nutritional strategy with restricted supply of milk for the calves with concomitantly short-term concentrate supplementation does not improve performance of calves but did increase feed costs. PMID- 25912975 TI - Spatial auditory regularity encoding and prediction: Human middle-latency and long-latency auditory evoked potentials. AB - By encoding acoustic regularities present in the environment, the human brain can generate predictions of what is likely to occur next. Recent studies suggest that deviations from encoded regularities are detected within 10-50ms after stimulus onset, as indicated by electrophysiological effects in the middle latency response (MLR) range. This is upstream of previously known long-latency (LLR) signatures of deviance detection such as the mismatch negativity (MMN) component. In the present study, we created predictable and unpredictable contexts to investigate MLR and LLR signatures of the encoding of spatial auditory regularities and the generation of predictions from these regularities. Chirps were monaurally delivered in an either regular (predictable: left-right-left right) or a random (unpredictable left/right alternation or repetition) manner. Occasional stimulus omissions occurred in both types of sequences. Results showed that the Na component (peaking at 34ms after stimulus onset) was attenuated for regular relative to random chirps, albeit no differences were observed for stimulus omission responses in the same latency range. In the LLR range, larger chirp-and omission-evoked responses were elicited for the regular than for the random condition, and predictability effects were more prominent over the right hemisphere. We discuss our findings in the framework of a hierarchical organization of spatial regularity encoding. This article is part of a Special Issue entitled SI: Prediction and Attention. PMID- 25912974 TI - Automatic SVM classification of sudden cardiac death and pump failure death from autonomic and repolarization ECG markers. AB - BACKGROUND: Considering the rates of sudden cardiac death (SCD) and pump failure death (PFD) in chronic heart failure (CHF) patients and the cost-effectiveness of their preventing treatments, identification of CHF patients at risk is an important challenge. In this work, we studied the prognostic performance of the combination of an index potentially related to dispersion of repolarization restitution (Deltaalpha), an index quantifying T-wave alternans (IAA) and the slope of heart rate turbulence (TS) for classification of SCD and PFD. METHODS: Holter ECG recordings of 597 CHF patients with sinus rhythm enrolled in the MUSIC study were analyzed and Deltaalpha, IAA and TS were obtained. A strategy was implemented using support vector machines (SVM) to classify patients in three groups: SCD victims, PFD victims and other patients (the latter including survivors and victims of non-cardiac causes). Cross-validation was used to evaluate the performance of the implemented classifier. RESULTS: Deltaalpha and IAA, dichotomized at 0.035 (dimensionless) and 3.73 MUV, respectively, were the ECG markers most strongly associated with SCD, while TS, dichotomized at 2.5 ms/RR, was the index most strongly related to PFD. When separating SCD victims from the rest of patients, the individual marker with best performance was Deltaalpha>=0.035, which, for a fixed specificity (Sp) of 90%, showed a sensitivity (Se) value of 10%, while the combination of Deltaalpha and IAA increased Se to 18%. For separation of PFD victims from the rest of patients, the best individual marker was TS <= 2.5 ms/RR, which, for Sp=90%, showed a Se of 26%, this value being lower than Se=34%, produced by the combination of Deltaalpha and TS. Furthermore, when performing SVM classification into the three reported groups, the optimal combination of risk markers led to a maximum Sp of 79% (Se=18%) for SCD and Sp of 81% (Se=14%) for PFD. CONCLUSIONS: The results shown in this work suggest that it is possible to efficiently discriminate SCD and PFD in a population of CHF patients using ECG-derived risk markers like Deltaalpha, TS and IAA. PMID- 25912976 TI - Regioselective Synthesis of Multisubstituted Furans via Copper-Mediated Coupling between Ketones and beta-Nitrostyrenes. AB - A copper-mediated intermolecular annulation of alkyl ketones and beta nitrostyrenes has been developed for the regioselective synthesis of multisubstituted furan derivatives in good yields. This protocol is applicable to both cyclic and acyclic ketones. PMID- 25912977 TI - Impact of foot-and-mouth disease on milk production on a large-scale dairy farm in Kenya. AB - The economic impact of foot-and-mouth disease (FMD) has been poorly characterised particularly in endemic settings where such knowledge is important for decision making on disease control with limited resources. In order to address this, a study was designed using individual animal data from a large-scale dairy farm in Kenya to estimate the impact of an FMD outbreak due to serotype SAT2 virus on milk yield. Daily milk yields from 218 mainly European-breed cattle that were lactating during the 29-day outbreak period were considered in the analysis. At the herd level, the average daily yields decreased from around 20 to 13kg per cow, recovering approximately 2 months after the commencement of the outbreak. Generalised estimating equations (GEE) and an autoregressive correlation matrix were used to compare yields of reported clinical FMD cases and non-cases. No difference was found between reported clinical and non-clinical cases suggesting inaccurate case recording, poor sensitivity of the case definition and subclinical infections being present. To further investigate the impact of FMD, yields were predicted for each individual animal based on historic data from the same herd using a similar GEE approach. For cattle lactating during the outbreak, comparisons were made between actual and predicted yields from the commencement of the outbreak to 305 days lactation using a linear regression model. Animals produced significantly less than predicted if in parity 2 or greater and between 0 and 50 days in milk (DIM) at the start of the outbreak period. The maximum effect was seen among animals in parity >=4 and between 0 and 50 DIM at the start of the outbreak, producing on average 688.7kg (95%CI 395.5, 981.8) less milk than predicted for their remaining lactation, representing an average 15% reduction in the 305 day production for these animals. Generalisation of the results requires caution as the majority of Kenyan milk is produced in smallholder farms. However, such farms use similar genetics and feeding practices to the study farm, and such systems are increasingly important in the supply of milk globally. These results make an important and unique contribution to the evidence base on FMD impact among dairy cattle in an endemic setting. PMID- 25912978 TI - Psychological correlates of fatigue in rheumatoid arthritis: a systematic review. AB - Fatigue is common and debilitating in Rheumatoid Arthritis (RA). A focus on the psychological variables associated with fatigue may help to identify targets for intervention which could enhance the treatment of fatigue in RA. The purpose of this review was to systematically identify psychological variables related to fatigue in RA, with the overall aim of suggesting evidence-based targets for fatigue intervention in RA. Twenty-nine studies met inclusion criteria and were included in the narrative synthesis. A wide range of psychological variables were addressed, spanning 6 categories: affect and common mental disorders; RA-related cognitions; non-RA-related cognitions; personality traits; stress and coping; and social support/interpersonal relationships. The most consistent relationship was found between mood and fatigue, with low mood frequently associated with increased fatigue. Some evidence also highlighted the relationship between RA related cognitions (such as RA self-efficacy) and fatigue, and non-RA-cognitions (such as goal ownership) and fatigue. Limited evidence was found to support the relationship between stress and coping or personality traits and fatigue, although mixed evidence was found for the relationship between social support and fatigue. The results of this review suggest the interventions for fatigue in RA may benefit from a focus on mental health, and disease-related cognitions. PMID- 25912979 TI - African Bioethics vs. Healthcare Ethics in Africa: A Critique of Godfrey Tangwa. AB - It is nearly two decades now since the publication of Godfrey Tangwa's article, 'Bioethics: African Perspective', without a critical review. His article is important because sequel to its publication in Bioethics, the idea of 'African bioethics' started gaining some attention in the international bioethics literature. This paper breaks this relative silence by critically examining Tangwa's claim on the existence of African bioethics. Employing conceptual and critical methods, this paper argues that Tangwa's account of African bioethics has some conceptual, methodic and substantive difficulties, which altogether do not justify the idea of African bioethics, at least for now. Contra Tangwa, this article establishes that while African bioethics remains a future possibility, it is more cogent that current efforts in the name of 'African bioethics' be primarily re-intensified towards 'Healthcare ethics in Africa'. PMID- 25912980 TI - Connect or stagnate: the future of indoor air sciences. PMID- 25912981 TI - Pre-eclampsia, solid-fuel cooking, and magnesium. PMID- 25912982 TI - Author's reply. PMID- 25912983 TI - Design and implementation of a multiband digital filter using FPGA to extract the ECG signal in the presence of different interference signals. AB - In this paper, we propose a practical way to synthesize and filter an ECG signal in the presence of four types of interference signals: (1) those arising from power networks with a fundamental frequency of 50Hz, (2) those arising from respiration, having a frequency range from 0.05 to 0.5Hz, (3) muscle signals with a frequency of 25Hz, and (4) white noise present within the ECG signal band. This was done by implementing a multiband digital filter (seven bands) of type FIR Multiband Least Squares using a digital programmable device (Cyclone II EP2C70F896C6 FPGA, Altera), which was placed on an education and development board (DE2-70, Terasic). This filter was designed using the VHDL language in the Quartus II 9.1 design environment. The proposed method depends on Direct Digital Frequency Synthesizers (DDFS) designed to synthesize the ECG signal and various interference signals. So that the synthetic ECG specifications would be closer to actual ECG signals after filtering, we designed in a single multiband digital filter instead of using three separate digital filters LPF, HPF, BSF. Thus all interference signals were removed with a single digital filter. The multiband digital filter results were studied using a digital oscilloscope to characterize input and output signals in the presence of differing sinusoidal interference signals and white noise. PMID- 25912984 TI - Improving PLS-RFE based gene selection for microarray data classification. AB - Gene selection plays a crucial role in constructing efficient classifiers for microarray data classification, since microarray data is characterized by high dimensionality and small sample sizes and contains irrelevant and redundant genes. In practical use, partial least squares-based gene selection approaches can obtain gene subsets of good qualities, but are considerably time-consuming. In this paper, we propose to integrate partial least squares based recursive feature elimination (PLS-RFE) with two feature elimination schemes: simulated annealing and square root, respectively, to speed up the feature selection process. Inspired from the strategy of annealing schedule, the two proposed approaches eliminate a number of features rather than one least informative feature during each iteration and the number of removed features decreases as the iteration proceeds. To verify the effectiveness and efficiency of the proposed approaches, we perform extensive experiments on six publicly available microarray data with three typical classifiers, including Naive Bayes, K-Nearest-Neighbor and Support Vector Machine, and compare our approaches with ReliefF, PLS and PLS RFE feature selectors in terms of classification accuracy and running time. Experimental results demonstrate that the two proposed approaches accelerate the feature selection process impressively without degrading the classification accuracy and obtain more compact feature subsets for both two-category and multi category problems. Further experimental comparisons in feature subset consistency show that the proposed approach with simulated annealing scheme not only has better time performance, but also obtains slightly better feature subset consistency than the one with square root scheme. PMID- 25912985 TI - Mathematical model of a heterogeneous pulmonary acinus structure. AB - The pulmonary acinus is a gas exchange unit distal to the terminal bronchioles. A model of its structure is important for the computational investigation of mechanical phenomena at the acinus level. We propose a mathematical model of a heterogeneous acinus structure composed of alveoli of irregular sizes, shapes, and locations. The alveoli coalesce into an intricately branched ductal tree, which meets the space-filling requirement of the acinus structure. Our model uses Voronoi tessellation to generate an assemblage of the alveolar or ductal airspace, and Delaunay tessellation and simulated annealing for the ductal tree structure. The modeling condition is based on average acinar and alveolar volume characteristics from published experimental information. By applying this modeling technique to the acinus of healthy mature rats, we demonstrate that the proposed acinus structure model reproduces the available experimental information. In the model, the shape and size of alveoli and the length, generation, tortuosity, and branching angle of the ductal paths are distributed in several ranges. This approach provides a platform for investigating the heterogeneous nature of the acinus structure and its relationship with mechanical phenomena at the acinus level. PMID- 25912986 TI - An extended Cellular Potts Model analyzing a wound healing assay. AB - A suitable Cellular Potts Model is developed to reproduce and analyze an in vitro wound-healing assay. The proposed approach is able both to quantify the invasive capacity of the overall cell population and to evaluate selected determinants of single cell movement (velocity, directional movement, and final displacement). In this respect, the present CPM allows us to capture differences and correlations in the migratory behavior of cells initially located at different distances from the wound edge. In the case of an undifferentiated extracellular matrix, the model then predicts that a maximal healing can be obtained by a chemically induced increment of cell elasticity and not by a chemically induced downregulation of intercellular adhesive contacts. Moreover, in the case of two component substrates (formed by a mesh of collagenous-like threads and by a homogeneous medium), CPM simulations show that both fiber number and cell-fiber adhesiveness influence cell speed and wound closure rate in a biphasic fashion. On the contrary, the topology of the fibrous network affects the healing process by mediating the productive directional cell movement. The paper, also equipped with comments on the computational cost of the CPM algorithm, ends with a throughout discussion of the pertinent experimental and theoretical literature. PMID- 25912987 TI - Automated breast-region segmentation in the axial breast MR images. AB - PURPOSE: The purpose of this study was to develop a robust breast-region segmentation method independent from the visible contrast between the breast region and surrounding chest wall and skin. MATERIALS AND METHODS: A fully automated method for segmentation of the breast region in the axial MR images is presented relying on the edge map (EM) obtained by applying a tunable Gabor filter which sets its parameters according to the local MR image characteristics to detect non-visible transitions between different tissues having a similar MRI signal intensity. The method applies the shortest-path search technique by incorporating a novel cost function using the EM information within the border search area obtained based on the border information from the adjacent slice. It is validated on 52 MRI scans covering the full American College of Radiology Breast Imaging-Reporting and Data System (BI-RADS) breast-density range. RESULTS: The obtained results indicate that the method is robust and applicable for the challenging cases where a part of the fibroglandular tissue is connected to the chest wall and/or skin with no visible contrast, i.e. no fat presence, between them compared to the literature methods proposed for the axial MR images. The overall agreement between automatically- and manually-obtained breast-region segmentations is 96.1% in terms of the Dice Similarity Coefficient, and for the breast-chest wall and breast-skin border delineations it is 1.9mm and 1.2mm, respectively, in terms of the Mean-Deviation Distance. CONCLUSION: The accuracy, robustness and applicability for the challenging cases of the proposed method show its potential to be incorporated into computer-aided analysis systems to support physicians in their decision making. PMID- 25912988 TI - Heat treatment modelling using strongly continuous semigroups. AB - In this paper, mathematical simulation of bioheat transfer phenomenon within the living tissue is studied using the thermal wave model. Three different sources that have therapeutic applications in laser surgery, cornea laser heating and cancer hyperthermia are used. Spatial and transient heating source, on the skin surface and inside biological body, are considered by using step heating, sinusoidal and constant heating. Mathematical simulations describe a non-Fourier process. Exact solution for the corresponding non-Fourier bioheat transfer model that has time lag in its heat flux is proposed using strongly continuous semigroup theory in conjunction with variational methods. The abstract differential equation, infinitesimal generator and corresponding strongly continuous semigroup are proposed. It is proved that related semigroup is a contraction semigroup and is exponentially stable. Mathematical simulations are done for skin burning and thermal therapy in 10 different models and the related solutions are depicted. Unlike numerical solutions, which suffer from uncertain physical results, proposed analytical solutions do not have unwanted numerical oscillations. PMID- 25912989 TI - Classification of laryngeal disorders based on shape and vascular defects of vocal folds. AB - Vocal fold disorders such as laryngitis, vocal nodules, and vocal polyps may cause hoarseness, breathing and swallowing difficulties due to vocal fold malfunction. Despite the fact that state of the art medical imaging techniques help physicians to obtain more detailed information, difficulty in differentiating minor anomalies of vocal folds encourages physicians to research new strategies and technologies to aid the diagnostic process. Recent studies on vocal fold disorders note the potential role of the vascular structure of vocal folds in differential diagnosis of anomalies. However, standards of clinical usage of the blood vessels have not been well established yet due to the lack of objective and comprehensive evaluation of the vascular structure. In this paper, we present a novel approach that categorizes vocal folds into healthy, nodule, polyp, sulcus vocalis, and laryngitis classes exploiting visible blood vessels on the superior surface of vocal folds and shapes of vocal fold edges by using image processing techniques and machine learning methods. We first detected the vocal folds on videolaryngostroboscopy images by using Histogram of Oriented Gradients (HOG) descriptors. Then we examined the shape of vocal fold edges in order to provide features such as size and splay portion of mass lesions. We developed a new vessel centerline extraction procedure that is specialized to the vascular structure of vocal folds. Extracted vessel centerlines were evaluated in order to get vascular features of vocal folds, such as the amount of vessels in the longitudinal and transverse form. During the last step, categorization of vocal folds was performed by a novel binary decision tree architecture, which evaluates features of the vocal fold edge shape and vascular structure. The performance of the proposed system was evaluated by using laryngeal images of 70 patients. Sensitivity of 86%, 94%, 80%, 73%, and 76% were obtained for healthy, polyp, nodule, laryngitis, and sulcus vocalis classes, respectively. These results indicate that visible vessels of vocal folds can act as a prognostic marker for vocal fold pathologies, as well as the vocal fold shape features, and may play a critical role in more effective diagnosis. PMID- 25912990 TI - Computer-aided diagnosis of Myocardial Infarction using ultrasound images with DWT, GLCM and HOS methods: A comparative study. AB - Myocardial Infarction (MI) or acute MI (AMI) is one of the leading causes of death worldwide. Precise and timely identification of MI and extent of muscle damage helps in early treatment and reduction in the time taken for further tests. MI diagnosis using 2D echocardiography is prone to inter-/intra-observer variability in the assessment. Therefore, a computerised scheme based on image processing and artificial intelligent techniques can reduce the workload of clinicians and improve the diagnosis accuracy. A Computer-Aided Diagnosis (CAD) of infarcted and normal ultrasound images will be useful for clinicians. In this study, the performance of CAD approach using Discrete Wavelet Transform (DWT), second order statistics calculated from Gray-Level Co-Occurrence Matrix (GLCM) and Higher-Order Spectra (HOS) texture descriptors are compared. The proposed system is validated using 400 MI and 400 normal ultrasound images, obtained from 80 patients with MI and 80 normal subjects. The extracted features are ranked based on t-value and fed to the Support Vector Machine (SVM) classifier to obtain the best performance using minimum number of features. The features extracted from DWT coefficients obtained an accuracy of 99.5%, sensitivity of 99.75% and specificity of 99.25%; GLCM have achieved an accuracy of 85.75%, sensitivity of 90.25% and specificity of 81.25%; and HOS obtained an accuracy of 93.0%, sensitivity of 94.75% and specificity of 91.25%. Among the three techniques presented DWT yielded the highest classification accuracy. Thus, the proposed CAD approach may be used as a complementary tool to assist cardiologists in making a more accurate diagnosis for the presence of MI. PMID- 25912991 TI - Clustering high throughput biological data with B-MST, a minimum spanning tree based heuristic. AB - To address important challenges in bioinformatics, high throughput data technologies are needed to interpret biological data efficiently and reliably. Clustering is widely used as a first step to interpreting high dimensional biological data, such as the gene expression data measured by microarrays. A good clustering algorithm should be efficient, reliable, and effective, as demonstrated by its capability of determining biologically relevant clusters. This paper proposes a new minimum spanning tree based heuristic B-MST, that is guided by an innovative objective function: the tightness and separation index (TSI). The TSI presented here obtains biologically meaningful clusters, making use of co-expression network topology, and this paper develops a local search procedure to minimize the TSI value. The proposed B-MST is tested by comparing results to: (1) adjusted rand index (ARI), for microarray data sets with known object classes, and (2) gene ontology (GO) annotations for data sets without documented object classes. PMID- 25912992 TI - Successful diagnosis and laparoscopic management of haemorrhagic ovarian pregnancy with haemorrhagic contralateral corpus luteum. PMID- 25912994 TI - Corticosteroids for the initial episode of steroid-sensitive nephrotic syndrome. PMID- 25912993 TI - Risk factors for acute kidney injury during aminoglycoside therapy in patients with cystic fibrosis. AB - BACKGROUND: Aminoglycoside (AG) therapy is a common cause of acute kidney injury (AKI) in cystic fibrosis (CF) patients. The aim of this study was to identify factors associated with AKI during intravenous AG courses in this population. METHODS: This was a matched case-control study utilizing two independent cohorts of hospitalized CF patients receiving >= 3 days of intravenous AG at Cincinnati Children's Hospital Medical Center and Children's of Alabama. All admissions with AKI (cases, N = 82) were matched to two randomly selected admissions without AKI (controls, N = 164) by center, gender, and age +/-3 years of the case. AKI was defined as a 1.5-fold increase in the baseline serum creatinine (SCr) level or by an increase in SCr level of 0.3 mg/dL within 48 h. Admissions with AKI before day 4 or without at least weekly SCr monitoring were excluded from the analysis. Factors were compared between cases and controls using simple and multiple conditional logistic regression. RESULTS: Multivariable analysis identified receipt of an AG within 90 days prior to admission, longer duration of AG therapy, low serum albumin, and receipt of trimethoprim/sulfamethoxazole as independent risk factors for developing AKI. Infection with Staphylococcus aureus diminished the odds of developing AKI. CONCLUSIONS: This study identifies risk factors contributing to AG-associated AKI in CF patients. These findings can be used to anticipate high-risk scenarios and limit AKI in CF patients under clinical care. PMID- 25912995 TI - Ethnic differences in coronary artery revascularisation in New Zealand: does the inverse care law still apply? AB - BACKGROUND: In 2002 striking differences in cardiac revascularisation rates were reported between New Zealand Maori, Pacific and European ethnicities. This paper examines whether this inequity still exists, taking into account ethnic differences in need. METHODS: Age-standardised time trends in intervention rates for coronary artery bypass grafts (CABG), percutaneous coronary intervention (PCI) and ST elevation myocardial infarction (STEMI) were calculated by ethnicity. Ethnic-specific trends were also calculated in the ratio of observed to expected CABG and PCI interventions based on the rate of hospitalisation with a diagnosis of STEMI. RESULTS: On a per capita basis, standardised CABG intervention rates were significantly higher for Pacific (both sexes) and female Maori than Other throughout 2000-2012, and were significantly higher for Maori males than Other in 2009-12. Population based PCI rates were significantly lower for male Maori from 2000-2012, while for female Maori they were significantly lower in 2000-2004 but significantly higher in 2009-12. However, and despite some improvement since 2000-2004, Maori and Pacific intervention numbers for PCI in 2009-2012 were still 22%-32% lower than expected for the rate of STEMI hospitalisation they experience. Overall revascularisation ratios were significantly lower than expected for Maori (both sexes) and Pacific females. CONCLUSIONS: Large increases in the PCI population intervention rates in Maori and Pacific over the period 2000-2012 have not been sufficient to eliminate inequalities in relation to need, except perhaps for Pacific men. PMID- 25912996 TI - Serum adropin level in patients with stable coronary artery disease. AB - OBJECTIVES: Adropin is a newly identified secreted protein implicated in the regulation of insulin sensitivity and vascular endothelial function. Recent studies have shown that lower serum adropin level is related to acute myocardial infarction and coronary atherosclerosis. The primary objective of this study was to ascertain the association of serum adropin level with stable coronary artery disease (SCAD). METHODS: We prospectively recruited a cohort of patients with SCAD and similar sample size subjects without coronary artery disease as controls. Their serum adropin levels were measured, and the severity of coronary atherosclerosis in SCAD patients was quantified with the syntax score. RESULTS: A total of 116 patients with SCAD and 116 control subjects without coronary artery disease were recruited. Patients with SCAD had lower serum adropin levels when compared with the controls (59.2+/-19.3 versus 70.0+/-18.2 pg/mL, P<0.001). The multiple logistic regression revealed that low serum adropin level was a significant predictor of SCAD (AOR 0.976, 95% CI 0.960-0.992; p=0.003). Through the gamma regression model, it was further revealed that serum adropin level is significantly associated with syntax score (coefficient: -0.134, 95% CI: -0.212- 0.056; p=0.001). CONCLUSIONS: Low serum adropin level is a significant predictor of SCAD. It is also associated with syntax score, thus indicating the close relationship between adropin and coronary atherosclerosis. PMID- 25912997 TI - Ebselen by modulating oxidative stress improves hypoxia-induced macroglial Muller cell and vascular injury in the retina. AB - Oxidative stress is an important contributor to glial and vascular cell damage in ischemic retinopathies. We hypothesized that ebselen via its ability to reduce reactive oxygen species (ROS) and augment nuclear factor-like 2 (Nrf2) anti oxidants would attenuate hypoxia-induced damage to macroglial Muller cells and also lessen retinal vasculopathy. Primary cultures of rat Muller cells were exposed to normoxia (21% O2), hypoxia (0.5% O2) and ebselen (2.5 MUM) for up to 72 h. Oxygen-induced retinopathy (OIR) was induced in C57BL/6J mice while control mice were housed in room air. Mice received vehicle (saline, 5% dimethyl sulfoxide) or ebselen (10 mg/kg) each day between postnatal days 6-18. In cultured Muller cells, flow cytometry for dihydroethidium revealed that ebselen reduced the hypoxia-induced increase in ROS levels, whilst increasing the expression of Nrf2-regulated anti-oxidant genes, heme oxygenase 1, glutathione peroxidase-1, NAD(P)H dehydrogenase quinone oxidoreductase 1 and glutamate cysteine ligase. Moreover, in Muller cells, ebselen reduced the hypoxia-induced increase in protein levels of pro-angiogenic and pro-inflammatory factors including vascular endothelial growth factor, interleukin-6, monocyte chemoattractant-protein 1 and intercellular adhesion molecule-1, and the mRNA levels of glial fibrillary acidic protein (GFAP), a marker of Muller cell injury. Ebselen improved OIR by attenuating capillary vaso-obliteration and neovascularization and a concomitant reduction in Muller cell gliosis and GFAP. We conclude that ebselen protects against hypoxia-induced injury of retinal Muller cells and the microvasculature, which is linked to its ability to reduce oxidative stress, vascular damaging factors and inflammation. Agents such as ebselen may be potential treatments for retinopathies that feature oxidative stress-mediated damage to glia and the microvasculature. PMID- 25912998 TI - Elevated intracranial pressure causes optic nerve and retinal ganglion cell degeneration in mice. AB - The purpose of this study was to develop a novel experimental system for the modulation and measurement of intracranial pressure (ICP), and to use this system to assess the impact of elevated ICP on the optic nerve and retinal ganglion cells (RGCs) in CD1 mice. This system involved surgical implantation of an infusion cannula and a radiowave based pressure monitoring probe through the skull and into the subarachnoid space. The infusion cannula was used to increase ICP, which was measured by the probe and transmitted to a nearby receiver. The system provided robust and consistent ICP waveforms, was well tolerated, and was stable over time. ICP was elevated to approximately 30 mmHg for one week, after which we assessed changes in optic nerve structure with transmission electron microscopy in cross section and RGC numbers with antibody staining in retinal flat mounts. ICP elevation resulted in optic nerve axonal loss and disorganization, as well as RGC soma loss. We conclude that the controlled manipulation of ICP in active, awake mice is possible, despite their small size. Furthermore, ICP elevation results in visual system phenotypes of optic nerve and RGC degeneration, suggesting that this model can be used to study the impact of ICP on the visual system. Potentially, this model can also be used to study the relationship between ICP and IOP, as well diseases impacted by ICP variation such as glaucoma, idiopathic intracranial hypertension, and the spaceflight-related visual impairment intracranial pressure syndrome. PMID- 25912999 TI - Perforating corneal injury in rat and pentadecapeptide BPC 157. AB - Based on its healing effects in various tissues, we hypothesized that the stable gastric pentadecapeptide BPC 157 heals corneal ulcerations in rats and effects corneal transparency. We made a penetrant linear 2-mm incision in the paralimbal region of the left cornea at the 5 o'clock position with a 20-gauge MVR incision knife at 45 degrees under an operating microscope. Medication was BPC 157 (2 pg/mL, 2 ng/mL, and 2 MUg/mL distilled water, two eye drops/left rat eye) immediately after injury induction and then every 8 h up to 120 h; controls received an equal volume of distilled water. In contrast to the poor healing response in controls, BPC 157 significantly accelerated the healing process in 2 MUg and 2 ng BPC 157-treated eyes, starting 24 h after the injury, and the fluorescein and Seidel tests became negative. The epithelial defects were completely healed at 72 h (2 MUg BPC 157-treated group) and at 96 h (2 ng BPC 157 treated group) after injury. Aqueous cells were absent at 96 h and 120 h after injury in the 2 MUg and 2 ng BPC 157-treated groups, respectively. In conclusion, BPC 157 effects the rapid regaining of corneal transparency. Whereas controls developed new vessels that grew from the limbus to the penetrated area, BPC 157 treated rats generally had no new vessels, and those that did form in the limbus did not make contact with the penetrated area. Thus, BPC 157 eye drops successfully close perforating corneal incisions in rats. PMID- 25913001 TI - Long-Term Mortality After Ablation of Ischemic Ventricular Tachycardia: Not Inducible Is Not Enough. PMID- 25913000 TI - Predictive value of programmed ventricular stimulation after catheter ablation of post-infarction ventricular tachycardia. AB - BACKGROUND: A recent meta-analysis demonstrated a survival benefit in post infarction patients whose ventricular tachycardia (VT) was rendered noninducible by catheter ablation. Furthermore, patients with noninducible VT had a lower VT recurrence rate than did patients whose VT remained inducible after ablation. OBJECTIVES: The purpose of this multicenter cohort study was to assess whether noninducibility after VT ablation is independently associated with improved survival. METHODS: Data from 1,064 patients who underwent VT ablation for post infarction VT at seven international centers were analyzed. The ablation procedure was considered successful if no VT was inducible at the end of the procedure and unsuccessful if VT remained inducible or if programmed stimulation was not performed at the end of the ablation. RESULTS: Median follow-up time was 633 days. Noninducibility was independently associated with lower mortality (adjusted hazard ratio: 0.65; 95% confidence interval: 0.53 to 0.79; p<0.001). Atrial fibrillation, diabetes, and age were other independent predictors of higher mortality. Ablation of only the clinical VT in patients who also had inducible, nonclinical VTs was not associated with improved survival. CONCLUSIONS: Noninducibility after VT ablation in patients with post-infarction VT is independently associated with lower mortality during long-term follow-up. PMID- 25913002 TI - Soybean beta-conglycinin improves carbohydrate and lipid metabolism in Wistar rats. AB - The effects of dietary soybean beta-conglycinin on lipid metabolism and energy consumption were studied in Wistar adult rats. Rats were fed, a diet containing casein (control group) or beta-conglycinin (beta-conglycinin group), for 4 weeks. Carbohydrate consumption was higher and fat consumption was lower in the beta conglycinin group than in the control group, whereas the total energy consumption was the same between the two groups. Serum adiponectin was higher in the beta conglycinin group than in the control group. Serum triacylglycerol levels in the beta-conglycinin group were significantly lower than those in the control group. The secretion rate of triacylglycerols from the liver after the administration of tyloxapol, an inhibitor of lipolysis, was significantly lower in the beta conglycinin group than in the control group. These results suggest the possibility that beta-conglycinin exerts hypolipidemic effects through an acceleration in carbohydrate consumption associated with an increase in adiponectin in rats. PMID- 25913003 TI - Mass balance and life cycle assessment of the waste electrical and electronic equipment management system implemented in Lombardia Region (Italy). AB - Waste electrical and electronic equipment (WEEE) is one of the fastest growing waste streams in Europe, whose content of hazardous substances as well as of valuable materials makes the study of the different management options particularly interesting. The present study investigates the WEEE management system in Lombardia Region (Italy) in the year 2011 by applying the life cycle assessment (LCA) methodology. An extensive collection of primary data was carried out to describe the main outputs and the energy consumptions of the treatment plants. Afterwards, the benefits and burdens associated with the treatment and recovery of each of the five categories in which WEEE is classified according to the Italian legislation (heaters and refrigerators - R1, large household appliances - R2, TV and monitors - R3, small household appliances - R4 and lighting equipment - R5) were evaluated. The mass balance of the treatment and recovery system of each of the five WEEE categories showed that steel and glass are the predominant streams of materials arising from the treatment; a non negligible amount of plastic is also recovered, together with small amounts of precious metals. The LCA of the regional WEEE management system showed that the benefits associated with materials and energy recovery balance the burdens of the treatment processes, with the sole exception of two impact categories (human toxicity-cancer effects and freshwater ecotoxicity). The WEEE categories whose treatment and recovery resulted more beneficial for the environment and the human health are R3 and R5. The contribution analysis showed that overall the main benefits are associated with the recovery of metals, as well as of plastic and glass. Some suggestions for improving the performance of the system are given, as well as an indication for a more-in-depth analysis for the toxicity categories and a proposal for a new characterisation method for WEEE. PMID- 25913004 TI - Epicocconone, a sensitive and specific fluorescent dye for in situ quantification of extracellular proteins within bacterial biofilms. AB - Biofilms are ecosystems of closely associated bacteria encapsulated in an extracellular matrix mainly composed of polysaccharides and proteins. A novel approach was developed for in situ quantification of extracellular proteins (ePNs) in various bacterial biofilms using epicocconone, a natural, fluorescent compound that binds amine residues of proteins. Six commercial proteins were tested for their reaction with epicocconone, and bovine serum albumin (BSA) was selected for assay optimization. The optimized protocol, performed as a microassay, allowed protein amounts as low as 0.7 MUg to as high as 50 MUg per well to be detected. Addition of monosaccharides or polysaccharides (glucose, dextran or alginate) to the standard BSA solutions (0 to 250 MUg ml(-1)) showed little or no sugar interference up to 2000 MUg ml(-1), thus providing an assessment of the specificity of epicocconone for proteins. The optimized protocol was then applied to three different biofilms, and in situ quantification of ePN showed contrasted protein amounts of 22.1 +/- 3.1, 38.3 +/- 7.1 and 0.3 +/ 0.1 MUg equivalent BSA of proteins for 48-h biofilms of Pseudomonas aeruginosa, Bacillus licheniformis and Weissella confusa, respectively. Possible interference due to global matrix compounds on the in situ quantification of proteins was also investigated by applying the standard addition method (SAM). Low error percentages were obtained, indicating a correct quantification of both the ePN and the added proteins. For the first time, a specific and sensitive assay has been developed for in situ determination of ePN produced by bacterial cells. This advance should lead to an accurate, rapid tool for further protein labelling and microscopic observation of the extracellular matrix of biofilms. PMID- 25913005 TI - cAMP receptor protein (CRP)-mediated resistance/tolerance in bacteria: mechanism and utilization in biotechnology. AB - Cyclic AMP receptor protein (CRP) is one of the seven global regulators in Escherichia coli, which regulates the expression of over 490 genes. It contains a cAMP binding N-terminal domain and a DNA binding C-terminal domain, connected via a short hinge region. Various stress-tolerant E. coli mutants had been obtained through transcriptional engineering of CRP. This review aims to shed some light on the possible mechanism behind these CRP variants, from the change in CRP structure, transcription profile, and DNA binding affinity. The amino acid substitutions are distributed along the protein-certain mutations have shown higher frequency than others, such as T127N and D138Y. beta-Galactosidase reporter gene assay revealed that CRP mutants had lower binding affinity with all three classes of CRP-dependent promoters as compared to native CRP, which probably would change cellular transcription profile. Different CRP mutants would induce different cellular transcription profile in E. coli, but there are common genes differentially expressed in these variants, including upregulated gadAB and downregulated nontransporter genes aspA and tnaA, and transporter/poringenes malE, mglB, cstA, and lamB. We believe that transcriptional engineering of CRP can provide an alternative strain engineering method for E. coli and its detailed mechanism may need further investigations. PMID- 25913006 TI - Adaptive mutation related to cellulose producibility in Komagataeibacter medellinensis (Gluconacetobacter xylinus) NBRC 3288. AB - Gluconacetobacter xylinus (formerly Acetobacter xylinum and presently Komagataeibacter medellinensis) is known to produce cellulose as a stable pellicle. However, it is also well known to lose this ability very easily. We investigated the on and off mechanisms of cellulose producibility in two independent cellulose-producing strains, R1 and R2. Both these strains were isolated through a repetitive static culture of a non-cellulose-producing K. medellinensis NBRC 3288 parental strain. Two cellulose synthase operons, types I and II, of this strain are truncated by the frameshift mutation in the bcsBI gene and transposon insertion in the bcsCII gene, respectively. The draft genome sequencing of R1 and R2 strains revealed that in both strains the bcsBI gene was restored by deletion of a nucleotide in its C-rich region. This result suggests that the mutations in the bcsBI gene are responsible for the on and off mechanism of cellulose producibility. When we looked at the genomic DNA sequences of other Komagataeibacter species, several non-cellulose-producing strains were found to contain similar defects in the type I and/or type II cellulose synthase operons. Furthermore, the phylogenetic relationship among cellulose synthase genes conserved in other bacterial species was analyzed. We observed that the cellulose genes in the Komagataeibacter shared sequence similarities with the gamma proteobacterial species but not with the alpha-proteobacteria and that the type I and type II operons could be diverged from a same ancestor in Komagataeibacter. PMID- 25913007 TI - Silver(I) NHC mediated C-C bond activation of alkyl nitriles and catalytic efficiency in oxazoline synthesis. AB - Preparation of silver triazolylidene (trz) species from triazolium salts and Ag2O in refluxing MeCN leads to a selective C-C bond cleavage and the formation of complexes of general formula [(trz)Ag(CN)] from Calkyl-CN bond activation. Moreover, these silver carbene complexes are precursors of highly active catalysts for oxazoline formation via aldol condensation. PMID- 25913008 TI - A preliminary examination of Loss of Control Eating Disorder (LOC-ED) in middle childhood. AB - Loss of Control Eating Disorder (LOC-ED) has been proposed as a diagnostic category for children 6-12years with binge-type eating. However, characteristics of youth with LOC-ED have not been examined. We tested the hypothesis that the proposed criteria for LOC-ED would identify children with greater adiposity, more disordered eating attitudes, and greater mood disturbance than those without LOC ED. Participants were 251 youth (10.29years+/-1.54, 53.8% female, 57.8% White, 35.5% Black, 2.0% Asian, 4.8% Hispanic, 53.0% overweight). Youth were interviewed regarding eating attitudes and behaviors, completed questionnaires to assess general psychopathology, and underwent measurements of body fat mass. Using previously proposed criteria for LOC-ED, children were classified as LOC-ED (n=19), LOC in the absence of the full disorder (subLOC, n=33), and youth not reporting LOC (noLOC, n=199). LOC-ED youth had higher BMIz (p=0.001) and adiposity (p=0.003) and reported greater disordered eating concerns (p<0.001) compared to noLOC youth. Compared to subLOC youth, LOC-ED youth had non significantly higher BMIz (p=0.11), and significantly higher adiposity (p=0.04) and disordered eating attitudes (p=0.02). SubLOC youth had greater disordered eating concerns (p<0.001) and BMIz (p=0.03) but did not differ in adiposity (p=0.33) compared to noLOC youth. These preliminary data suggest that LOC-ED youth are elevated on disordered eating cognitions and anthropometric measures compared to youth without LOC-ED. Longitudinal studies are needed to determine if those with LOC-ED are at particularly increased risk for progression of disordered eating and excess weight gain. PMID- 25913009 TI - Restrictive rules of Dutch mothers regarding their children's dietary intake between meals. AB - The use of restrictive food rules by parents has been found to be associated with dietary intake in their children. The aim of this study was to explore the use of restrictive rules of Dutch mothers regarding their child's food intake between main meals in detail, to generate necessary input for setting priorities for further research and intervention development. A cross-sectional questionnaire study on nine restrictive rules was completed by 359 mothers of primary school children aged 4-12years. Mothers reported to use an average of 4.1 (SD 2.1) out of nine restrictive food rules and all rules measured in this study were used. The rules mother's reported to use most were not eating shortly before meals, not eating certain foods too often and not eating too much of certain foods. The rules varied according to different foods, but particularly applied to the intake of potato chips, nuts and savory snacks, candy and chocolate. Mothers of a younger age, lower educated mothers and mothers with a higher BMI were less likely to use (certain) restrictive rules. This study showed that mothers use a large variety of rules, particularly to restrict the intake of unhealthy foods and reported on several subgroups that were less likely to use (certain) rules. Our results direct further research and inform the development of interventions. PMID- 25913010 TI - Pericarditis-induced hyponatremia after cardiac electronic implantable device (CEID) procedures. AB - BACKGROUND: Pericardial effusion along with pleural effusion is one of the rare complications of permanent pacemaker placement. Although extremely uncommon, it is more prevalent in elderly patients and may be complicated with hyponatremia. CASE REPORT: We observed development of hyponatremia in association with pericardial effusion and pleural effusion, within one month after pacemaker placement in two women with BMI of <20. Case 1: An 87-year-old woman underwent implantation of a transvenous AV sequential pacemaker because of severe bradycardia and complete heart block. Three weeks later, she complained of progressive left-sided rib cage pain and poor oral intake. Her echocardiography showed a moderately large amount of pericardial effusion, but no evidence of tamponade. She also had hyponatremia (Na=119 mEq/dl). Extensive work-up suggested hyponatremia presumably due to SIADH, caused by pericardial/pleural effusion. Case 2: An 83-year-old woman with history of severe sick sinus syndrome required a transvenous Av sequential pacemaker 3 weeks before. She then presented with generalized weakness, fatigue, and poor oral intake of over one week. There was a small-moderate pericardial effusion echocardiographically, and her serum sodium was 116 mEq/dl. CONCLUSIONS: Although extremely uncommon, pericarditis can develop following transvenous pacemaker insertion, which may result in hyponatremia, likely due to SIADH. The most common scenario is an elderly, petite woman with low BMI (<20), usually after using a helical screw/active fixation pacing leads, several weeks post-implant. Early recognition and therapy can significantly improve outcome and morbidity. PMID- 25913011 TI - The Divergent Roles of STAYGREEN (SGR) Homologs in Chlorophyll Degradation. AB - Degradation of chlorophyll (Chl) by Chl catabolic enzymes (CCEs) causes the loss of green color that typically occurs during senescence of leaves. In addition to CCEs, staygreen1 (SGR1) functions as a key regulator of Chl degradation. Although sgr1 mutants in many plant species exhibit a stay-green phenotype, the biochemical function of the SGR1 protein remains elusive. Many recent studies have examined the physiological and molecular roles of SGR1 and its homologs (SGR2 and SGR-LIKE) in Chl metabolism, finding that these proteins have different roles in different species. In this review, we summarize the recent studies on SGR and discuss the most likely functions of SGR homologs. PMID- 25913013 TI - The AKT/mTOR signaling pathway plays a key role in statin-induced myotoxicity. AB - Statins are drugs that lower blood cholesterol levels and reduce cardiovascular morbidity and mortality. They are generally well-tolerated, but myopathy is a potentially severe adverse reaction of these compounds. The mechanisms by which statins induce myotoxicity are not completely understood, but may be related to inhibition of the AKT signaling pathway. The current studies were performed to explore the down-stream effects of the statin-associated inhibition of AKT within the AKT signaling pathway and on myocyte biology and morphology in C2C12 myotubes and in mice in vivo. We exposed C2C12 myotubes to 10 MUM or 50 MUM simvastatin, atorvastatin or rosuvastatin for 24 h. Simvastatin and atorvastatin inhibited AKT phosphorylation and were cytotoxic starting at 10 MUM, whereas similar effects were observed for rosuvastatin at 50 MUM. Inhibition of AKT phosphorylation was associated with impaired phosphorylation of S6 kinase, ribosomal protein S6, 4E binding protein 1 and FoxO3a, resulting in reduced protein synthesis, accelerated myofibrillar degradation and atrophy of C2C12 myotubes. Furthermore, impaired AKT phosphorylation was associated with activation of caspases and PARP, reflecting induction of apoptosis. Similar findings were detected in skeletal muscle of mice treated orally with 5 mg/kg/day simvastatin for 3 weeks. In conclusion, this study highlights the importance of the AKT/mTOR signaling pathway in statin induced myotoxicity and reveals potential drug targets for treatment of patients with statin-associated myopathies. PMID- 25913014 TI - Safety of medication options for treating pediatric esophagitis. AB - INTRODUCTION: The management of gastro-esophageal reflux and esophagitis in infants and children is challenging, and there are currently no clear practice guidelines. Given a paucity of evidence in the treatment of pediatric esophagitis, there are concerns over both the efficacy and safety of proton-pump inhibitors, histamine type 2 receptor antagonists, and prokinetics. AREAS COVERED: Comprehensive data from randomized-controlled trials, meta-analyses and observational studies have helped to illustrate the efficacy and safety of various pharmacologic and non-pharmacologic treatments in pediatric esophagitis. We review the evidence on the risks of antacid therapy including bone mineral density, respiratory infections and enteric infections including necrotizing enterocolitis. EXPERT OPINION: Evidence pertaining to the safety of proton-pump inhibitors and histamine 2 receptor antagonists in pediatric populations is lacking. Largely based on small observational and randomized controlled trials, it does appear both antacids pose an increased risk of respiratory and enteric infections, which can occur even with a short course of treatment. The benefits of treatment, especially in pediatric esophagitis, must be weighed against the potential risks. More large-scale studies are needed to better quantify short term and long-term risks of treatment. Anti-secretory medications, mostly proton pump inhibitors, have substantially improved the management of pediatric esophagitis. Nevertheless, because of possible infectious safety concerns, their use must be restricted to validated indications only. PMID- 25913012 TI - Phosphorylation of ezrin on Thr567 is required for the synergistic activation of cell spreading by EPAC1 and protein kinase A in HEK293T cells. AB - Recent studies have demonstrated that the actin binding protein, ezrin, and the cAMP-sensor, EPAC1, cooperate to induce cell spreading in response to elevations in intracellular cAMP. To investigate the mechanisms underlying these effects we generated a model of EPAC1-dependent cell spreading based on the stable transfection of EPAC1 into HEK293T (HEK293T-EPAC1) cells. We found that direct activation of EPAC1 with the EPAC-selective analogue, 8-pCPT-2'-O-Me-cAMP (007), promoted cell spreading in these cells. In addition, co-activation of EPAC1 and PKA, with a combination of the adenylate cyclase activator, forskolin, and the cAMP phosphodiesterase inhibitor, rolipram, was found to synergistically enhance cell spreading, in association with cortical actin bundling and mobilisation of ezrin to the plasma membrane. PKA activation was also associated with phosphorylation of ezrin on Thr567, as detected by an electrophoretic band mobility shift during SDS-PAGE. Inhibition of PKA activity blocked ezrin phosphorylation and reduced the cell spreading response to cAMP elevation to levels induced by EPAC1-activation alone. Transfection of HEK293T-EPAC1 cells with inhibitory ezrin mutants lacking the key PKA phosphorylation site, ezrin Thr567Ala, or the ability to associate with actin, ezrin-Arg579Ala, promoted cell arborisation and blocked the ability of EPAC1 and PKA to further promote cell spreading. The PKA phospho-mimetic mutants of ezrin, ezrin-Thr567Asp had no effect on EPAC1-driven cell spreading. Our results indicate that association of ezrin with the actin cytoskeleton and phosphorylation on Thr567 are required, but not sufficient, for PKA and EPAC1 to synergistically promote cell spreading following elevations in intracellular cAMP. PMID- 25913015 TI - Strategies for decision-making on vaccine use: the French experience. AB - France enjoys benefits of a good organization of its healthcare system. National Health Insurance is reimbursing vaccines if they are used according to the national recommendation guidelines. Vaccination is the responsibility of the government, advised by its National Immunization Technical Advisory Group (Comite Technique des vaccinations). But France, like many other countries, faces insufficient involvement from the public in immunization programs and, consequently, numerous outbreaks of vaccine-preventable diseases. The French government launched a 5-year national program for improvement in vaccination policy in 2012 to simplify the guidelines, facilitate access to vaccination, invest in research and evaluate its vaccine policy. The role of the public and healthcare professionals to encourage vaccination is crucial for the future. PMID- 25913016 TI - Editorial Comment. PMID- 25913017 TI - Differential reinforcement of other behavior increases untargeted behavior. AB - Differential reinforcement of other behavior (DRO) is a commonly used technique for behavior reduction, yet there has been little to no emphasis on the possible strengthening effects on other behavior. We included 2 responses (target and other) across 3 treatment schedules (DRO, extinction, and fixed time [FT]) in a human-operant procedure to determine the extent to which reinforcer presentation at the completion of the DRO interval could strengthen other responding. A computer program arranged for unsignaled changes in contingencies to a target response and never provided reinforcers for the other response. All 13 college student participants exhibited more other responses than target responses during at least 1 exposure to DRO. Although there was a slight increase in other behavior during extinction, overall rates of other responding were never higher than that of the target response. Furthermore, 7 of 13 participants never emitted the other response during the FT condition. The findings provide some support for the response-strengthening effects of DRO. PMID- 25913019 TI - Predicting the binding modes and sites of metabolism of xenobiotics. AB - Metabolism studies are an essential integral part of ADMET profiling of drug candidates to evaluate their safety and efficacy. Cytochrome P-450 (CYP) metabolizes a wide variety of xenobiotics/drugs. The binding modes of these compounds with CYP and their intrinsic reactivities decide the metabolic products. We report here a novel computational protocol, which comprises docking of ligands to heme-containing CYPs and prediction of binding energies through a newly developed scoring function, followed by analyses of the docked structures and molecular orbitals of the ligand molecules, for predicting the sites of metabolism (SOM) of ligands. The calculated binding free energies of 121 heme containing protein-ligand docked complexes yielded a correlation coefficient of 0.84 against experiment. Molecular orbital analyses of the resultant top three unique poses of the docked complexes provided a success rate of 87% in identifying the experimentally known sites of metabolism of the xenobiotics. The SOM prediction methodology is freely accessible at . PMID- 25913018 TI - Short-term food restriction followed by controlled refeeding promotes gorging behavior, enhances fat deposition, and diminishes insulin sensitivity in mice. AB - Rodents are commonly used in food restriction refeeding studies to investigate weight regain. Mice that are rationed food every 24 h may consume all allocated food in a short time (gorge) and therefore undergo a brief well-fed period followed by an extended fasted period until the next day's food allotment. These exaggerated metabolic states are not typical in mice fed ad libitum (nibbling). The aim of the current study was to elucidate the intraday and cumulative metabolic consequences of gorging (induced by food restriction) in mice during controlled refeeding. Accordingly, following a temporary food restriction, mice were fed rations similar to intakes of controls fed ad libitum. Temporary food restriction initiated gorging behavior that persisted during refeeding; consequently, metabolism-related measurements were obtained in the gorging mice during their daily fed and fasted metabolic states. Robust differences in adipose tissue lipogenic and inflammatory gene expression were found in the gorging mice by metabolic state (fed versus fasted). Additionally, despite a reduced cumulative food intake compared to mice fed ad libitum, restriction-induced gorging mice had increased intraabdominal fat accumulation, diminished hepatic and peripheral insulin sensitivity, and a gene expression profile favoring lipid deposition. Our findings highlight the intraday differences in gene expression in gorging mice before and after feeding that confound comparisons with mice fed ad libitum, or nibbling. The present study also provides evidence that weight regain following food restriction is associated with cumulative metabolic and behavioral abnormalities in mice. PMID- 25913020 TI - Radiologic Image of a Child with Leukemia Who Developed Sepsis and Fulminant Thrombosis during Induction Therapy. PMID- 25913021 TI - 5-HT1A Receptor-Mediated Autoinhibition and the Control of Serotonergic Cell Firing. AB - The idea that serotonergic synaptic transmission plays an essential role in the control of mood and the pharmacotherapy of anxiety and depression is one of the cornerstones of modern biological psychiatry. As a result, there is intense interest in understanding the mechanisms controlling the activity of serotonin synthesizing (serotonergic) neurons. One of the oldest and most durable ideas emerging from this work is that serotonergic neurons are capable of autonomously regulating their own basal firing rate. Serotonergic neurons express on their surface 5-HT1A receptors (autoreceptors) that, when activated, induce the opening of potassium channels that hyperpolarize and thereby inhibit cell firing. Activity-dependent release of serotonin within serotonergic nuclei is thought to activate these autoreceptors, thus completing an autoinhibitory feedback loop. This concept, which was originally proposed in the 1970s, has proven to be enormously fruitful and has guided the interpretation of a broad range of clinical and preclinical work. Yet, remarkably, electrophysiological studies seeking to directly demonstrate this phenomenon, especially in in vitro brain slices, have produced mixed results. Here, we critically review this work with a focus on electrophysiological studies, which directly assess neuronal activity. We also highlight recent work suggesting that 5-HT1A receptor-mediated autoinhibition may play other roles in the control of firing besides acting as a feedback regulator for the pacemaker-like firing rate of serotonergic neurons. PMID- 25913024 TI - To pi or not to pi--how does methanol dock onto anisole? AB - Anisole offers two similarly attractive hydrogen bond acceptor sites to an incoming hydrogen bond donor: its oxygen atom and its delocalized pi electron system. Electronic structure calculations up to the CCSD(T)/AVTZ level suggest an isoenergetic situation for methanol after harmonic zero point energy correction, within less than 1 kJ mol(-1). Linear infrared absorption spectroscopy in the OH stretching fundamental range applied to a cold supersonic jet expansion of anisole and methanol in helium shows that the oxygen binding site is preferred, with about 20 times less pi-bonded than O-bonded dimers despite the non equilibrium collisional environment. Accidental band overlap is ruled out by OH overtone and OD stretching spectroscopy. Furthermore, the diagonal anharmonicity constant of the OH stretching mode is derived from experiment and reaches 80% of the monomer distortion found in the methanol dimer, as expected for a weaker hydrogen bond to the aromatically substituted oxygen. To reconcile these experimental findings with ab initio theory, accurate nuclear and electronic structure calculations involving AVQZ basis sets are required. Dispersion corrected double-hybrid density functional theory provides a less expensive successful structural approach. PMID- 25913023 TI - A simple assay for glutathione in whole blood. AB - A method for detecting glutathione selectively in whole blood deposited on filter paper is described. GSH is fractionated from proteins, hemoglobin and other potentially interfering components and determined using a resorufin-acrylate fluorescent probe. The relative standard deviation is lower than 5% (n = 5). Recoveries of GSH from whole blood are between 94% and 108.6%. PMID- 25913025 TI - Biophysical properties of photoreceptors in Corixa punctata facilitate diurnal life-style. AB - Measurement of evolutionary adaptations of a visual system to its visual and operational ecology requires comparison of visual function in different species with similar morphologies and visual ecologies, occupying the same habitats but displaying differences in visually-guided behavior. The goal here was to document the biophysical properties of photoreceptors in the lesser water boatman Corixa punctata, which shares many features with the previously studied aquatic predator water boatman backswimmer Notonecta glauca. However, unlike the backswimmer, which heavily relies on vision to catch its prey, Corixa is a detritivore. Using the patch-clamp method, I found that the average whole-cell capacitance of Corixa photoreceptors was 441+/-206 pF, higher than in any other insect studied so far, and that absolute sensitivity was positively correlated with capacitance (Spearman rank correlation coefficient, 0.73). Interestingly, both the sensitivity distribution median and variation in Corixa were similar to the corresponding values in the diurnal water strider Gerris lacustris and were substantially smaller than in the noctidial N. glauca or the nocturnal/crepuscular cockroach Periplaneta americana. Furthermore, capacitance was correlated with the amplitudes of light-induced (0.70) and delayed rectifier K(+) (0.46) currents, membrane corner frequency (0.68) and maximal information rate (IRmax, 0.74). No correlation was observed between capacitance and transient K(+) current. Average IRmax in Corixa was 36.0+/-21.3 bits s(-1), much higher than in G. lacustris but smaller than in N. glauca. These findings support the hypothesis that Corixa's retinal function is adapted to its diurnal life-style, which is also consistent with field observations. PMID- 25913026 TI - Comparison of visual information processing in school-age dyslexics and normal readers via motion-onset visual evoked potentials. AB - Standard pattern-reversal visual evoked potentials (VEPs) and motion-onset VEPs (M-VEPs) were tested in 19 dyslexics and 19 normal readers aged 7-13 years in order to evaluate the feasibility of M-VEPs for the objective diagnostics of a visual subtype of dyslexia, in which a dysfunction of the magnocellular subsystem/dorsal stream of the visual pathway is suspected. The set of VEPs consisted of the pattern-reversal VEPs with check sizes of 20', two types of translational motion (with low and high contrast) and two types of radial motion (in the full field or the periphery). While the P100 peak parameters in pattern reversal VEPs did not differ between the group of dyslexics and controls, the group of dyslexics displayed significantly longer N2 latencies in all types of M VEPs. Abnormal N2 latencies were found in 35-56% of dyslexics in different types of M-VEPs, with translational motion with high contrast being the most sensitive stimulation. A receiver operating characteristic analysis showed that the latencies of M-VEPs displayed higher discrimination potential than M-VEPs amplitudes. The study confirms a "magnocellular pathway/dorsal stream deficit" in approximately half of dyslexics. PMID- 25913027 TI - Quickly making the correct choice. AB - In daily life, unconscious choices guide many of our on-going actions. Such choices need to be made quickly, because the options change as the action progresses. We confirmed that people make reasonable choices when they have to quickly decide between two alternatives, and studied the basis of such decisions. The task was to tap with their finger on as many targets as possible within 2 min. A new target appeared after every tap, sometimes accompanied by a second target that was easier to hit. When there was only one target, subjects had to find the right balance between speed and accuracy. When there were two targets, they also had to choose between them. We examined to what extent subjects switched to the target that was easier to hit when it appeared some time after the original one. Subjects generally switched to the easier target whenever doing so would help them hit more targets within the 2-min session. This was so, irrespective of whether the different delays were presented in separate sessions or were interleaved within one session. Whether or not they switched did not depend on how successful they were at hitting the targets on earlier attempts, but it did depend on the position of the finger at the moment that the easy target appeared. We conclude that people have continuous access to reasonable estimates of how long various movement options would take and of how precise the endpoints are likely to be, given the instantaneous circumstances. PMID- 25913028 TI - Vitamin E and neurodegeneration. AB - Alpha-tocopherol (vitamin E) is a plant-derived antioxidant that is essential for human health. Studies with humans and with animal models of vitamin E deficiency established the critical roles of the vitamin in protecting the central nervous system, and especially the cerebellum, from oxidative damage and motor coordination deficits. We review here the established roles of vitamin E in protecting cerebellar functions, as well as emerging data demonstrating the critical roles of alpha-tocopherol in preserving learning, memory and emotive responses. We also discuss the importance of vitamin E adequacy in seemingly unrelated neurological disorders. PMID- 25913029 TI - Reconstruction of brain circuitry by neural transplants generated from pluripotent stem cells. AB - Pluripotent stem cells (embryonic stem cells, ESCs, and induced pluripotent stem cells, iPSCs) have the capacity to generate neural progenitors that are intrinsically patterned to undergo differentiation into specific neuronal subtypes and express in vivo properties that match the ones formed during normal embryonic development. Remarkable progress has been made in this field during recent years thanks to the development of more refined protocols for the generation of transplantable neuronal progenitors from pluripotent stem cells, and the access to new tools for tracing of neuronal connectivity and assessment of integration and function of grafted neurons. Recent studies in brains of neonatal mice or rats, as well as in rodent models of brain or spinal cord damage, have shown that ESC- or iPSC-derived neural progenitors can be made to survive and differentiate after transplantation, and that they possess a remarkable capacity to extend axons over long distances and become functionally integrated into host neural circuitry. Here, we summarize these recent developments in the perspective of earlier studies using intracerebral and intraspinal transplants of primary neurons derived from fetal brain, with special focus on the ability of human ESC- and iPSC-derived progenitors to reconstruct damaged neural circuitry in cortex, hippocampus, the nigrostriatal system and the spinal cord, and we discuss the intrinsic and extrinsic factors that determine the growth properties of the grafted neurons and their capacity to establish target-specific long-distance axonal connections in the damaged host brain. PMID- 25913030 TI - Usage of pumice as bulking agent in sewage sludge composting. AB - In this study, the impacts of reused and sucrose-decorated pumice as bulking agents on the composting of sewage sludge were evaluated in the lab-scale reactor. The variations of temperature, pH, NH3 and CO2 emission rate, moisture content (MC), volatile solid, dissolved organic carbon, C/N and the water absorption characteristics of pumice were detected during the 25days composting. The MC of pumice achieved 65.23% of the 24h water absorptivity within the first 2h at the mass ratio of 0.6:1 (pumice:sewage sludge). Reused pumice increased 23.68% of CO2 production and reduced 21.25% of NH3 emission. The sucrose decorated pumice reduced 43.37% of nitrogen loss. These results suggested that adding pumice and sucrose-decorated pumice in sludge composting matrix could not only adjust the MC of materials, but also improve the degradation of organic matters and reduce nitrogen loss. PMID- 25913031 TI - Single- and two-step hydrothermal liquefaction of microalgae in a semi-continuous reactor: Effect of the operating parameters. AB - This work investigated an influence of operating conditions on the biocrude yield and properties obtained from hydrothermal liquefaction (HTL) of Coelastrum sp. microalgae in a two-step sequential HTL (THTL) and a single-step HTL (SHTL) using a semi-continuous system. A higher biocrude yield with a lower nitrogen content was obtained with the THTL process than the SHTL one. The operating temperature, pressure and water flow rate were sequentially varied in a univariate analysis for a 2 h reaction time to optimize the obtained biocrude yield. Increasing the temperature improved the biocrude yield, but the second step temperature should not be higher than 320 degrees C to prevent the thermal cracking to gaseous compounds. The optimal conditions of THTL were preliminarily temperature of 200 and 320 degrees C and pressure of 7 and 20 MPa for the first and second step, respectively, both with a water flow rate of 0.50 mL/min. PMID- 25913032 TI - The role of character displacement in the molarization of hominin mandibular premolars. AB - Closely related species are likely to experience resource competition in areas where their ranges overlap. Fossil evidence suggests that hominins in East Africa c. 2-1.5 million years ago may have lived synchronically and sympatrically, and that competition may have contributed to the different tooth sizes observed in Homo and Paranthropus. To assess the likelihood that these taxa overlapped, we applied a character displacement model to the postcanine tooth size of fossil hominins and validated this model in populations of living primates. Mandibular fourth premolar (P4 ) crown size was measured from fossil taxa and from living primate species where dietary overlap is established. Dimensions of the P4 crown were fitted to a character matrix and described as the response variables of a generalized linear model that took taxon and location as input variables. The model recovered significant divergence in samples of closely related, living primates. When applied to fossil hominins the same model detected strong indications of character displacement between early Homo and Paranthropus (P = 0.002) on the basis of their P4 crown size. Our study is an example of how ecologically informed morphologies measured in appropriate extant referents can provide a comparative context for assessing community and ecological evolution in the fossil record. PMID- 25913033 TI - Chemical basis of unwettability in Liacaridae (Acari, Oribatida): specific variations of a cuticular acid/ester-based system. AB - Oribatid mites of the family Liacaridae comprise a large number of species with smooth and shiny body surfaces that display extraordinary anti-wetting properties. The principle of liacarid unwettability is not related to micro structured surfaces as present in many Oribatida ("Lotus effect") but the formation of raincoat-like lipid layers covering the epicuticle. We here conducted a comparative study on the chemistry of cuticular lipid layers in a selection of Liacaridae, including representatives of all major Central European genera, Liacarus, Dorycranosus, Adoristes, and Xenillus. Cuticular lipids of unwettable individuals were removed from mite bodies by hexane extraction, and were analyzed by GC-MS. Basically, two chemically distinguishable systems were found. Type I: cuticular lipids of Liacarus subterraneus, L. coracinus, L. nitens, Dorycranosus curtipilis, and Xenillus tegeocranus contained different carboxylic acids (C8-, C10-, C10:1-, C10:2-acids) and their corresponding di glycerides in species-specific combinations. Type II: Adoristes ovatus exhibited a system of cuticular lipids composed of esters of pentanoic- and heptanoic acids with C14-, C15-, C16- and C17-alcohols. Interestingly, the chemistry of surface lipids did not reflect the morphology of the cuticle in the species investigated. Smooth and shiny cuticles, though exhibiting a specific pattern of round or slit like pores, were found in representatives of Liacarus, Dorycranosus (all of which exhibiting cuticular chemistry of type I) and Adoristes (exhibiting cuticular chemistry of type II). Xenillus, possessing a rough, cerotegumental cement layer covered surface, showed type I-chemistry. The acid-esters systems herein investigated are considered characteristic for the cuticular chemistry of Liacaridae or a lineage of these, and provide first insights into the comparative chemistry of the inner (=lipid) layer of the oribatid cerotegument. PMID- 25913034 TI - Pin1 liberates the human immunodeficiency virus type-1 (HIV-1): Must we stop it? AB - Acquired immune deficiency syndrome (AIDS) is mainly caused by the human immunodeficiency virus type-1 (HIV-1). To our knowledge, this is the first review focusing on the vital role of Pin1 in the infection of HIV-1 and the development of AIDS. We and others have demonstrated that Pin1, the only known cis-to-trans isomerase recognizing the pThr/pSer-Pro motifs in proteins, plays striking roles in several human diseases. Interestingly, recent evidence gradually indicates that Pin1 regulates several key steps of the life cycle of HIV-1, including the uncoating of the HIV-1 core, the reverse transcription of the RNA genome of HIV 1, and the integration of the HIV-1 cDNA into human chromosomes. Whereas inhibiting Pin1 suppresses all of these key steps and attenuates the replication of HIV-1, at the same time different PIN1 gene variants are correlated with the susceptibility to HIV-1 infection. Furthermore, Pin1 potentially promotes HIV-1 infection by activating multiple oncogenes and inactivating multiple tumor suppressors, extending the life span of HIV-infected cells. These descriptions suggest Pin1 as a promising therapeutic target for the prevention of HIV-1 and highlight the possibility of blocking the development of AIDS by Pin1 inhibitors. PMID- 25913035 TI - Secondary Infections in Febrile Neutropenia in Hematological Malignancies: More Than Another Febrile Neutropenic Episode. AB - INTRODUCTION: Febrile neutropenic episodes (FNEs) are among major causes of mortality in patients with hematological malignancies. Secondary infections develop either during the empirical antibiotic therapy or one week after cessation of therapy for a FNE. The aim of the study was to investigate the risk factors associated with secondary infections in febrile neutropenic patients. METHODS: We retrospectively analyzed 750 FNEs in 473 patients between January 2000 and December 2006. RESULTS: Secondary infections were diagnosed in 152 (20%) of 750 FNEs. The median time to develop secondary infection was 10 days (range 2 34 days). The duration of neutropenia over 10 days significantly increased the risk of secondary infections (p<0.001). The proportion of patients with microbiologically documented infections was found to be higher in primary infections (271/750, 36%) compared to secondary infections (43/152, 28%) (p=0.038). Age, sex, underlying disease, antibacterial, antifungal or antiviral prophylaxis, blood transfusion or bone marrow transplantation, central venous catheter or severity of neutropenia did not differ significantly between primary and secondary infections (p>0.05) While fever of unknown origin (FUO) (p=0.005) and catheter-related bacteremia (p<0.001) were less frequently observed in secondary infections, the frequency of microbiologically (p=0.003) and clinically (p<0.001) documented infections, fungal pneumonias (p<0.001), infections related with gram positive bacteria (p=0.04) and fungi (p<0.001) and 30-day mortality rate (p<0.001) were significantly higher in secondary infections (p<0.001). DISCUSSION AND CONCLUSION: Secondary infections should be regarded as life threatening complications of febrile neutropenia. Secondary infections represent a more severe and mortal complication and cannot be regarded just as another febrile neutropenic episode. PMID- 25913022 TI - Therapeutic hypothermia after out-of-hospital cardiac arrest in children. AB - BACKGROUND: Therapeutic hypothermia is recommended for comatose adults after witnessed out-of-hospital cardiac arrest, but data about this intervention in children are limited. METHODS: We conducted this trial of two targeted temperature interventions at 38 children's hospitals involving children who remained unconscious after out-of-hospital cardiac arrest. Within 6 hours after the return of circulation, comatose patients who were older than 2 days and younger than 18 years of age were randomly assigned to therapeutic hypothermia (target temperature, 33.0 degrees C) or therapeutic normothermia (target temperature, 36.8 degrees C). The primary efficacy outcome, survival at 12 months after cardiac arrest with a Vineland Adaptive Behavior Scales, second edition (VABS-II), score of 70 or higher (on a scale from 20 to 160, with higher scores indicating better function), was evaluated among patients with a VABS-II score of at least 70 before cardiac arrest. RESULTS: A total of 295 patients underwent randomization. Among the 260 patients with data that could be evaluated and who had a VABS-II score of at least 70 before cardiac arrest, there was no significant difference in the primary outcome between the hypothermia group and the normothermia group (20% vs. 12%; relative likelihood, 1.54; 95% confidence interval [CI], 0.86 to 2.76; P=0.14). Among all the patients with data that could be evaluated, the change in the VABS-II score from baseline to 12 months was not significantly different (P=0.13) and 1-year survival was similar (38% in the hypothermia group vs. 29% in the normothermia group; relative likelihood, 1.29; 95% CI, 0.93 to 1.79; P=0.13). The groups had similar incidences of infection and serious arrhythmias, as well as similar use of blood products and 28-day mortality. CONCLUSIONS: In comatose children who survived out-of-hospital cardiac arrest, therapeutic hypothermia, as compared with therapeutic normothermia, did not confer a significant benefit in survival with a good functional outcome at 1 year. (Funded by the National Heart, Lung, and Blood Institute and others; THAPCA OH ClinicalTrials.gov number, NCT00878644.). PMID- 25913036 TI - Biallelic Mutations of Methionyl-tRNA Synthetase Cause a Specific Type of Pulmonary Alveolar Proteinosis Prevalent on Reunion Island. AB - Methionyl-tRNA synthetase (MARS) catalyzes the ligation of methionine to tRNA and is critical for protein biosynthesis. We identified biallelic missense mutations in MARS in a specific form of pediatric pulmonary alveolar proteinosis (PAP), a severe lung disorder that is prevalent on the island of Reunion and the molecular basis of which is unresolved. Mutations were found in 26 individuals from Reunion and nearby islands and in two families from other countries. Functional consequences of the mutated alleles were assessed by growth of wild-type and mutant strains and methionine-incorporation assays in yeast. Enzyme activity was attenuated in a liquid medium without methionine but could be restored by methionine supplementation. In summary, identification of a founder mutation in MARS led to the molecular definition of a specific type of PAP and will enable carrier screening in the affected community and possibly open new treatment opportunities. PMID- 25913037 TI - Acrofacial Dysostosis, Cincinnati Type, a Mandibulofacial Dysostosis Syndrome with Limb Anomalies, Is Caused by POLR1A Dysfunction. AB - We report three individuals with a cranioskeletal malformation syndrome that we define as acrofacial dysostosis, Cincinnati type. Each individual has a heterozygous mutation in POLR1A, which encodes a core component of RNA polymerase 1. All three individuals exhibit varying degrees of mandibulofacial dysostosis, and two additionally have limb anomalies. Consistent with this observation, we discovered that polr1a mutant zebrafish exhibited cranioskeletal anomalies mimicking the human phenotype. polr1a loss of function led to perturbed ribosome biogenesis and p53-dependent cell death, resulting in a deficiency of neural crest-derived skeletal precursor cells and consequently craniofacial anomalies. Our findings expand the genotypic and phenotypic heterogeneity of congenital acrofacial disorders caused by disruption of ribosome biogenesis. PMID- 25913038 TI - Tunneling nanotubes between rat primary astrocytes and C6 glioma cells alter proliferation potential of glioma cells. AB - The tunneling nanotube (TNT) is a newly discovered, long and thin tubular structure between cells. In this study, we established a co-culture system for rat primary astrocytes and C6 glioma cells and found that TNTs formed between them. Most of the TNTs initiated from astrocytes towards C6 glioma cells. The formation of TNTs depended on p53. In addition, hydrogen peroxide increased the number of TNTs in the co-culture system. Established TNTs reduced the proliferation of C6 glioma cells. Our data suggest that TNTs between astrocytes and glioma cells facilitate substance transfer and therefore alter the properties, including the proliferation potential, of glioma cells. PMID- 25913039 TI - Early hypoactivity of hippocampal rhythms during epileptogenesis after prolonged febrile seizures in freely-moving rats. AB - Prospective and experimental studies have shown that individuals with early-life complex/prolonged febrile seizures (FSs) have a high incidence of temporal lobe epilepsy during adulthood, revealing a close relationship between FSs and epilepsy. However, little is known about how epileptogenesis develops after FSs. The present study was designed to investigate acquired seizure susceptibility and analyze local field potentials during the latent period after FSs. We found that the seizure susceptibility decreased in 35-day-old (P35) FS rats but increased in P60 FS rats. Consistently, hippocampal electroencephalogram (EEG) power in every band was decreased at P35 but increased at P60 in FS rats. Our results provide direct evidence for hypoactivity but not hyperactivity during the early phase of the latent period, displaying a broad decrease in hippocampal rhythms. These characteristic EEG changes can be a useful biomarker for the early diagnosis of epileptogenesis induced by FSs. PMID- 25913041 TI - Strategical incoherence regulates cooperation in social dilemmas on multiplex networks. AB - Cooperation is a very common, yet not fully-understood phenomenon in natural and human systems. The introduction of a network within the population is known to affect the outcome of cooperative dynamics, allowing for the survival of cooperation in adverse scenarios. Recently, the introduction of multiplex networks has yet again modified the expectations for the outcome of the Prisoner's Dilemma game, compared to the monoplex case. However, much remains unstudied regarding other social dilemmas on multiplex, as well as the unexplored microscopic underpinnings of it. In this paper, we systematically study the evolution of cooperation in all four games in the T-S plane on multiplex. More importantly, we find some remarkable and previously unknown features in the microscopic organization of the strategies, that are responsible for the important differences between cooperative dynamics in monoplex and multiplex. Specifically, we find that in the stationary state, there are individuals that play the same strategy in all layers (coherent), and others that don't (incoherent). This second group of players is responsible for the surprising fact of a non full-cooperation in the Harmony Game on multiplex, never observed before, as well as a higher-than-expected cooperation rates in some regions of the other three social dilemmas. PMID- 25913040 TI - No relevant pharmacokinetic interaction between pantoprazole and mycophenolate in renal transplant patients: a randomized crossover study. AB - AIMS: Mycophenolic acid (MPA) suppresses lymphocyte proliferation through inosine monophosphate dehydrogenase (IMPDH) inhibition. Two formulations have been approved: mycophenolate mofetil (MMF) and enteric-coated mycophenolate sodium (EC MPS). Pantoprazole (PAN) inhibits gastric acid secretion, which may alter MPA exposure. Data from healthy volunteers suggest a significant drug-drug interaction (DDA) between pantoprazole and MPA. In transplant patients, a decreased MPA area under the concentration-time curve (AUC) may lead to higher IMPDH activity, which may lead to higher acute rejection risk. Therefore this DDA was evaluated in renal transplant patients under maintenance immunosuppressive therapy. METHODS: In this single-centre, open, randomized, four-sequence, four treatment crossover study, the influence of PAN 40 mg on MPA pharmacokinetics such as (dose-adjusted) AUC0-12 h (dAUC) was analysed in 20 renal transplant patients (>6 months post-transplantation) receiving MMF (1-2 g day(-1) ) and EC MPS in combination with ciclosporin. The major metabolite MPA glucuronide (MPAG) and the IMPDH activity were also examined. RESULTS: MMF + PAN intake led to a lowest mean dAUC for MPA of 41.46 ng h ml(-1) mg(-1) [95% confidence interval (CI) 32.38, 50.54], while MPA exposure was highest for EC-MPS + PAN [dAUC: 46.30 ng h ml(-1) mg(-1) (95% CI 37.11, 55.49)]. Differences in dAUC and dose-adjusted maximum concentration (dCmax) were not significant. Only for MMF [dAUC: 41.46 ng h ml(-1) mg(-1) (95% CI 32.38, 50.54)] and EC-MPS [dAUC: 43.39 ng h ml(-1) mg(-1) (95% CI 33.44, 53.34)] bioequivalence was established for dAUC [geometric mean ratio: 101.25% (90% CI 84.60, 121.17)]. Simultaneous EC-MPS + PAN intake led to an earlier time to Cmax (tmax) [median: 2.0 h (min-max: 0.5-10.0)] than EC-MPS intake alone [3 h (1.5-12.0); P = 0.037]. Tmax was not affected for MMF [1.0 h (0.5-5.0)] +/- pantoprazole [1.0 h (0.5-6.0), P = 0.928). No impact on MPAG pharmacokinetics or IMPDH activity was found. CONCLUSION: Pantoprazole influences EC-MPS and MMF pharmacokinetics but as it had no impact on MPA pharmacodynamics, the immunosuppressive effect of the drug was not impaired. PMID- 25913042 TI - Cross-talk in host-parasite associations: What do past and recent proteomics approaches tell us? AB - A cross-talk in host-parasite associations begins when a host encounters a parasite. For many host-parasite relationships, this cross-talk has been taking place for hundreds of millions of years. The co-evolution of hosts and parasites, the familiar 'arms race' results in fascinating adaptations. Over the years, host parasite interactions have been studied extensively from both the host and parasitic point of view. Proteomics studies have led to new insights into host parasite cross-talk and suggest that the molecular strategies used by parasites attacking animals and plants share many similarities. Likewise, animals and plants use several common molecular tactics to counter parasite attacks. Based on proteomics surveys undertaken since the post-genomic era, a synthesis is presented on the molecular strategies used by intra- and extracellular parasites to invade and create the needed habitat for growth inside the host, as well as strategies used by hosts to counter these parasite attacks. Pitfalls in deciphering host-parasite cross-talk are also discussed. To conclude, helpful advice is given with regard to new directions that are needed to discover the generic and specific molecular strategies used by the host against parasite invasion as well as by the parasite to invade, survive, and grow inside their hosts, and to finally discover parasitic molecular signatures associated with their development. PMID- 25913043 TI - Replication of genome wide association studies on hepatocellular carcinoma susceptibility loci of STAT4 and HLA-DQ in a Korean population. AB - A recent genome-wide association study (GWAS) for hepatitis B virus (HBV)-related hepatocellular carcinoma (HCC) identified two loci (rs7574865 in STAT4 and rs9275319 in HLA-DQ) in a Chinese population. We attempted to replicate the associations between the two SNP loci and the risk of HCC in a Korean population. The rs7574865 in STAT4 and rs9275319 in HLA-DQ were genotyped in a total of 3838 Korean subjects composed of 287 HBV-related hepatocellular carcinoma patients, 671 chronic hepatitis B virus (CHB) patients, and 2880 population controls using TaqMan genotyping assay. Gene expression was measured by microarray. A logistic regression analysis revealed that rs7574865 in STAT4 and rs9275319 in HLA-DQ were associated with the risk of CHB (OR = 1.25, P = 0.0002 and OR = 1.57, P= 1.44 * 10(-10), respectively). However, these loci were no association with the risk of HBV-related HCC among CHB patients. In the gene expression analyses, although no significant differences in mRNA expression of nearby genes according to genotypes were detected, a significantly decreased mRNA expression in HCC subjects was observed in STAT4, HLA-DQA1, and HLA-DQB1. Although the genetic effects of two HCC susceptibility loci were not replicated, the two loci were found to exert susceptibility effects on the risk of CHB in a Korean population. In addition, the decreased mRNA expression of STAT4, HLA-DQA1, and HLA-DQB1 in HCC tissue might provide a clue to understanding their role in the progression to HCC. PMID- 25913044 TI - The Role of Public Knowledge, Resources, and Innovation in Responding to the Ebola Outbreak. AB - Since the beginning of the recent Ebola outbreak, a sense of fear has developed among the public due to the novelty of our exposure to the virus and the ill equipped nature of our health care systems. Media sensationalism, coupled with improper knowledge of Ebola, may have contributed to mass hysteria. Most support to tackle Ebola has been direct monetary aid. However, others are working on innovative methods to control the epidemic, including the development of rapid detection methods, experimental treatments, and a viable vaccine. Rapid screening and vaccine ideas are promising, but it is unlikely that they will be ready in the coming months. This raises the question of what other tools and technological innovation can be developed to effectively stem the spread of the outbreak. Although we hope the continued outpouring of aid and health care workers to West Africa will greatly reduce the impact of Ebola, communication, screenings, treatment, and vaccine are of central importance to stop this outbreak. PMID- 25913045 TI - Peri-intraventricular hemorrhage and oxidative and inflammatory stress markers in very-low birth weight newborns. AB - OBJECTIVES: To evaluate the association between oxidative and inflammatory stress markers with peri-intraventricular hemorrhage (PIVH) in very-low birth weight newborns. METHODS: This was a prospective study conducted in a level III neonatal unit. Basal and stimulated reactive oxygen intermediates (ROIs), reduced glutathione (GSH), and interleukin-6 (IL-6) levels were measured in umbilical cord blood. Newborns underwent serial ultrasound at the bedside, at 6, 12, 24, and 72hours of life and at seven days for the diagnosis of PIVH, classified as grades I to IV. Two groups were assessed, those with and without PIVH; maternal and neonatal control variables were used for comparison. Univariate and multiple regression analyses were applied. RESULTS: A total of 125 newborns were assessed. PIVH incidence rate was 12.0%. In the univariate analysis, basal ROI, the use of two or more doses of corticosteroids, birth weight<1,000g, ventilatory support use, and SNAPPE II value >= 22 were significantly associated with PIVH. However, in the multivariate analysis, only antenatal steroid use was independently associated with the disease (OR 0,194; 95% CI: 0,048 to 0,773; p=0,02). CONCLUSION: ROI, GSH, and IL-6 levels were not associated with the occurrence of PIVH in very-low birth weight infants. PMID- 25913047 TI - Quality Assessment of Neonatal Transport performed by the Mobile Emergency Medical Services (SAMU). AB - OBJECTIVE: To assess the quality of neonatal transport performed by the Mobile Emergency Medical Services (Servico de Atendimento Movel de Urgencia [SAMU]). METHODS: This was a cross-sectional before-and-after observational study. The study was carried out from March to August of 2013 using a validated instrument, the Transport Risk Index of Physiologic Stability (TRIPS), to assess the characteristics of the newborn, medical and mechanical complications (equipment and ambulance), and stability of newborns before and after transport. Tests were conducted with 95% confidence level. Numerical variables are represented by measures of central tendency and dispersion. Categorical variables were compared by Fisher's exact test. In the comparison of variables between the groups, the Student's t-test was used for variables with normal distribution, Fisher exact test, when appropriate, and the Mann-Whitney test, for non-normal distribution. RESULTS: 33 newborns were transported from low-risk units to neonatal intensive care units. Male gender (57.6%) and full-term gestational age (63.6%) were more prevalent. Birth weight<2,500g was found in 39.4% of newborns. Respiratory failure accounted for 42.4% of the requests. The mean transport time was 58 minutes without medical or mechanical complications. The TRIPS score worsened in 15% of neonates; in this group of infants, the mean initial temperature of 36.46+/-0.19 decreased significantly to 36.08+/-0.22 (p=0.041). CONCLUSION: The transport performed by the SAMU was adequate for most newborns. The oscillation in body temperature was the only significant variable for the alteration in the TRIPS score. PMID- 25913046 TI - Comparison of two maintenance electrolyte solutions in children in the postoperative appendectomy period: a randomized, controlled trial. AB - OBJECTIVE: To compare two electrolyte maintenance solutions in the postoperative period in children undergoing appendectomy, in relation to the occurrence of hyponatremia and water retention. METHODS: A randomized clinical study involving 50 pediatric patients undergoing appendectomy, who were randomized to receive 2,000mL/m(2)/day of isotonic (Na 150 mEq/L or 0.9% NaCl) or hypotonic (Na 30 mEq/L NaCl or 0.18%) solution. Electrolytes, glucose, urea, and creatinine were measured at baseline, 24h, and 48h after surgery. Volume infused, diuresis, weight, and water balance were analyzed. RESULTS: Twenty-four patients had initial hyponatremia; in this group, 13 received hypotonic solution. Seventeen patients remained hyponatremic 48h after surgery, of whom ten had received hypotonic solution. In both groups, sodium levels increased at 24h (137.4+/-2.2 and 137.0+/-2.7mmol/L), with no significant difference between them (p=0.593). Sodium levels 48h after surgery were 136.6+/-2.7 and 136.2+/-2.3mmol/L in isotonic and hypotonic groups, respectively, with no significant difference. The infused volume and urine output did not differ between groups during the study. The water balance was higher in the period before surgery in patients who received hypotonic solution (p=0.021). CONCLUSIONS: In the post-appendectomy period, the use of hypotonic solution (30 mEq/L, 0.18%) did not increase the risk of hyponatremia when compared to isotonic saline. The use of isotonic solution (150 mEq/L, 0.9%) did not favor hypernatremia in these patients. Children who received hypotonic solution showed higher cumulative fluid balance in the preoperative period. PMID- 25913048 TI - Association between gestational age and birth weight on the language development of Brazilian children: a systematic review. AB - OBJECTIVE: To review the literature that addresses the relationship between prematurity, birth weight, and development of language in Brazilian children. SOURCES: A systematic review of studies published between 2003 and 2012 in English and Portuguese and indexed in PubMed, LILACS, and SciELO. The following key words were used in the searches: Prematuro, Prematuridade, Linguagem, Prematurity, Language, Speech-Language Pathology. Fifty-seven articles were retrieved, 13 of which were included in the systematic review. SUMMARY OF THE FINDINGS: The results showed an association between prematurity, low birth weight, and language development. In studies that made comparisons between preterm and term infants, there was evidence that preterm infants had poorer performance on indicators of language. It was also observed that children born with lower birth weight had a poorer performance on measures of language when compared to children with higher weight and closer to 37 weeks of gestational age. Regarding the type of language assessed, expression proved to be more impaired than reception. Higher parental education and family income were indicated as protective factors for the development of language. Conversely, lower birth weight and higher degree of prematurity emerged as risk factors. CONCLUSIONS: Preterm birth and low birth weight poses risks for the language development of children, especially in the first years of life. Therefore, it is essential that pediatricians are aware of the language development of these children to ensure proper treatment. PMID- 25913049 TI - Internal herniation through the foramen of Winslow: a rare cause of bowel obstruction. PMID- 25913050 TI - Performance of Bridging Stent Grafts in Fenestrated and Branched Aortic Endografting. AB - OBJECTIVE/BACKGROUND: Bridging stent grafts (BSGs) are used to connect the target vessel with the main body during fenestrated or branched aortic endografting (f/bEVAR). No dedicated devices are available for BSG. The aims of this study were to assess the performance of BSGs. METHODS: Between January 2004 and May 2014 the data of patients treated with f/bEVAR were prospectively collected. Only patients treated after January 2010 were included. The main measurement outcome was any BSG related complications. A logistic regression analysis, including target vessel type, type of joint (fenestration or cuff), and type of BSG identified potential risk factors. RESULTS: One hundred and fifty consecutive patients underwent f/bEVAR, and 523 target vessels were involved. These included 104 celiac, 140 superior mesenteric, 275 renal, and four other arteries. The technical success rate was 99% (520/523 target vessels). Balloon expandable BSGs were mainly used (n = 494; 95%), and in 336 (65%) relining stents were combined. The primary reasons for technical failure were the dislocation of the main body (n = 1) and unsuccessful cannulation (n = 2). One was revascularized by means of the periscope technique. Four target vessel injuries were recorded and four renal arteries occluded peri-operatively. After a median follow up of 14 months (interquartile range 5.5-23.0), 13 (2%) BSGs occluded and 19 (4%) required re interventions. Two SMA occlusions occurred, leading to death in both patients. The patency and freedom from re-intervention rates at 3 years amounted to 85% and 91%, respectively. Use of a branched main body was the only independent risk factor for re-intervention and for the composite event (hazard ratio [HR] 3.5, 95% confidence interval [CI] 1.3-9.9 [p = .02]; and HR 2.8, 95% CI 1.2-7.0 [p < .01], respectively). Of note, the use of relining stents seemed not to prevent BSG related complications. CONCLUSION: The currently used BSGs had low occlusion and re-intervention rates. Modifications of the branched design or dedicated BSG devices may improve outcome, especially after bEVAR. PMID- 25913051 TI - Electroacupuncture via Chronically Implanted Electrodes: Potential Treatment for Chemotherapy-Induced Delayed Emesis. AB - OBJECTIVES: We proposed a novel method of chronic electroacupuncture (EA) using implanted electrodes for the treatment of chronic chemotherapy-induced nausea and vomiting (CINV). We aimed to establish a rodent model of delayed emesis and explore EA effects on kaolin intake. MATERIALS AND METHODS: Saline-treated and cisplatin-treated rats underwent chronic placement of electrodes at bilateral PC6 and ST36 acupoints. Tested EA parameters included sham EA; EA at frequency of 10, 20, or 40 Hz; duration of one, three, or six hours; pulse width of 0.3, 0.6, or 1.2 msec; and amplitude of 0.4-2.0 mA. Kaolin intake was measured following each treatment. RESULTS: 1) Cisplatin increased kaolin intake (p <= 0.01 vs. saline). 2) In terms of reduction of kaolin intake vs. sham EA: a) EA at a frequency of 10 Hz was effective only when given for three hours (p = 0.0004). b) EA at a frequency of 20 Hz was effective when given for either one or three hours, with three hours being most effective (p = 0.007 and 0.005, respectively). c) EA at a frequency of 40 Hz was effective at six hours only (p = 0.04). 3) All different pulse widths significantly reduced kaolin intake, with 0.3 msec being most effective. 4) Using EA on both acupoints is superior to using EA on PC6 only (p = 0.005). CONCLUSION: EA with parameters of 20 Hz, 0.3 msec for three hours on both PC6 and ST36 acupoints was found to be the best in reducing kaolin intake. Chronic EA with appropriate parameters is effective in reducing pica in a rodent model of CINV. PMID- 25913052 TI - A prospective, randomized trial to evaluate the efficacy of clean intermittent catheterization versus triamcinolone ointment and contractubex ointment of catheter following internal urethrotomy: long-term results. AB - PURPOSE: Our aim was to evaluate clean intermittent catheterization (CIC) results in combination with triamcinolone ointment and contractubex ointment for lubrication of the catheter after optical internal urethrotomy (OIU). METHODS: Ninety patients who underwent OIU were randomized into three groups. Two weeks after operation, patients were treated with CIC (group A), triamcinolone ointment CIC (group B), and contractubex ointment CIC (group C). Follow-up continued for 24 months after the OIU. Postoperative results were compared between the three groups. RESULTS: There were no significant differences in the baseline characteristics of the patients or the etiology of the urethral stricture between the three groups. The mean preoperative Q max was 4.31 ml/s. The average score of preoperative international prostate symptom score (IPSS) was 23.1 points. In both groups, after treatment, significant improvements in Q max and IPSS were noted at all follow-up period (p < 0.05). But for Q max and IPSS, there were not any significant differences between groups at all follow-up period (p > 0.05). Overall recurrence rate was 28.9 % (26 out of 90 patients) at the end of the study. Recurrence rates were, however, not found to be statistically significant between these three groups (p > 0.05). CONCLUSION: Our results indicate that the urethral dilation protocol with CIC after first OIU is a safe, simple, well tolerated, office-based procedure. Triamcinolone or contractubex ointments of the CIC do not provide an additional benefit. Currently, urethral dilation with CIC after first OIU seems to be the only proven procedure that decreased the recurrence rate. PMID- 25913053 TI - Comparison of the learning curves and frustration level in performing laparoscopic and robotic training skills by experts and novices. AB - INTRODUCTION: Robotic assistance may provide for distinct technical advantages over conventional laparoscopic technique. The goals of this study were (1) to objectively evaluate the difference in the learning curves by novice and expert surgeons in performing fundamental laparoscopic skills using conventional laparoscopic surgery (CLS) and robotic-assisted laparoscopic surgery (RALS) and (2) to evaluate the surgeons' frustration level in performing these tasks. METHODS: Twelve experienced and 31 novices in laparoscopy were prospectively evaluated in performing three standardized laparoscopic tasks in five consecutive, weekly training sessions. Analysis of the learning curves was based on the magnitude, rate, and quickness in performance improvement. The participant's frustration and mood were also evaluated during and after every session. RESULTS: For the novice participants, RALS allowed for shorter time to task completion and greater accuracy. However, significant and rapid improvement in performance as measured by magnitude, rate, and quickness at each session was also seen with CLS. For the experienced surgeons, RALS only provided a slight improvement in performance. For all participants, the use of RALS was associated with less number of sessions in which they felt frustrated, less number of frustration episodes during a session, lower frustration score during and after the session, and higher good mood score. CONCLUSION: The advantages of RALS may be of most benefit when doing more complex tasks and by less experienced surgeons. RALS should not be used as a replacement for CLS but rather in specific situations in which it has the greatest advantages. PMID- 25913054 TI - Depth profile and mobility of (129)I and (137)Cs in soil originating from the Fukushima Dai-ichi Nuclear Power Plant accident. AB - The (129)I derived from the FDNPP accident were clearly identified near the surface and showed a trend of rapid decrease with depth. The FDNPP (129)I and (137)Cs was 51.6 +/- 1.7 mBq cm(-2) and 88.2 +/- 27.1 kBq cm(-2) (average of four cores inventory) respectively. On average, 91% of the FDNPP (129)I existed within the top 5 g cm(-2) and 98% within the top 10 g cm(-2) and average of 100% of the FDNPP (137)Cs existed within the top 5 g cm(-2). From the observation of the temporal variation of depth profiles from the same upland field (Kawauchi village, 20 km away from the FDNPP to the southwest direction), downward migration rates of 0.81 +/- 0.32 g cm(-2) yr(-1) for the FDNPP (129)I and 0.19 +/ 0.17 g cm(-2) yr(-1) for the FDNPP (137)Cs were estimated. A simple diffusion model was introduced to evaluate the downward mobility of the FDNPP-derived (129)I and (137)Cs. The apparent diffusion coefficients D of 0.0086 +/- 0.0034 and 0.0011 +/- 0.0010 g(2) cm(-)(4) d(-)(1) were obtained for (129)I and (137)Cs, respectively. These values might be representative for Haplic Gray lowland soils in near the steady state under humid temperate climate. PMID- 25913055 TI - Long-term monitoring of radioactivity in fish from New York waters. AB - As part of an environmental surveillance program operated by the New York State (NYS) Department of Health, measurements of various radionuclides in aquatic life (primarily fish) collected from waterways in NYS have occurred for decades. An investigation was undertaken to gain a better understanding of the occurrence, activity levels, and extent of radionuclide variations in aquatic life obtained from local waterways in relation to concentrations reported in fish from sites outside NYS (e.g., Pacific Ocean tuna). The man-made isotopes (137)Cs and (90)Sr were detectable at activities below 1 Bq/kg in the edible portions of fish from most NYS waterways, with the exception of greater activities in fish collected downstream of Brookhaven National Laboratory. Calculated effective doses resulting from eating the fish, estimated as 11-390 nSv/yr for (137)Cs and 0.3 7.9 nSv/yr for (90)Sr, are considered extremely low. PMID- 25913056 TI - OBT analysis method using polyethylene beads for limited quantities of animal tissue. AB - This study presents a polyethylene beads method for OBT determination in animal tissues and animal products for cases where the amount of water recovered by combustion is limited by sample size or quantity. In the method, the amount of water recovered after combustion is enhanced by adding tritium-free polyethylene beads to the sample prior to combustion in an oxygen bomb. The method reduces process time by allowing the combustion water to be easily collected with a pipette. Sufficient water recovery was achieved using the polyethylene beads method when 2 g of dry animal tissue or animal product were combusted with 2 g of polyethylene beads. Correction factors, which account for the dilution due to the combustion water of the beads, are provided for beef, chicken, pork, fish and clams, as well as egg, milk and cheese. The method was tested by comparing its OBT results with those of the conventional method using animal samples collected on the Chalk River Laboratories (CRL) site. The results determined that the polyethylene beads method added no more than 25% uncertainty when appropriate correction factors are used. PMID- 25913057 TI - Uranium ((234)U, (235)U and (238)U) contamination of the environment surrounding phosphogypsum waste heap in Wislinka (northern Poland). AB - The aim of this work was to determine the uranium concentration ((234)U, (235)U and (238)U) and values of the activity ratio (234)U/(238)U in soil samples collected near phosphogypsum waste heap in Wislinka (northern Poland). On the basis of the studies it was found that the values of the (234)U/(238)U activity ratio in the analyzed soils collected in the vicinity of phosphogypsum dump in Wislinka are in most cases close to one and indicate the phosphogypsum origin of the analyzed nuclides. The obtained results of uranium concentrations are however much lower than in previous years before closing of the phosphogypsum stockpile. After this process and covering the phosphogypsum stockpile in Wislinka with sewage sludge, phosphogypsum particles are successfully immobilized. In the light of the results the use of phosphate fertilizers seems to be a major problem. Prolonged and heavy rains can cause leaching accumulated uranium isotopes in the phosphogypsum stockpile, which will be washed into the Martwa Wisla and on the fields in the immediate vicinity of this storage. PMID- 25913058 TI - Diabetes, race, and functional limitations in older U.S. men and women. AB - AIMS: The presence of diabetes is associated with increased odds of difficulties in functional tasks but it remains unclear if the burden is similar by race. METHODS: Our study included 122,004 non-Hispanic Black (NHB) and non-Hispanic White (NHW) adults >=50 years from the U.S. National Health Interview Survey (2001-2012). Diabetes was defined as self-reported diagnosis or medication use. Functional limitations were defined as any self-reported difficulty in performing mobility tasks, general physical activities (GPA), or leisure and social activities (LSA). Logistic regression models were created to investigate the relationship of race with functional limitations accounting for key covariates, among men and women, by diabetes status. RESULTS: Among older U.S. adults, NHB versus NHW women without diabetes had a higher odds of limitations in mobility (OR=1.39, 1.30-1.49) and LSA (OR=1.13, 1.05-1.23) without diabetes but a similar odds of these limitations with diabetes by race, after adjusting for age, income, education, obesity, arthritis, heart disease, stroke, COPD, and cancer. Interestingly, NHB versus NHW women had significantly lower odds of GPA, irrespective of diabetes status. However, NHB versus NHW men with diabetes had a persistently higher odds for mobility and LSA limitations with diabetes as follows: mobility (OR=1.30, 1.12-1.51) and LSA limitations (OR=1.07, 1.06-1.34). The interaction of race and diabetes was significant among women for mobility limitations (p<0.01), but not men. CONCLUSIONS: The burden of functional limitations differs by race among both men and women with diabetes. Future studies should examine mechanisms underlying these differences to prevent progression to disability in older adults with diabetes. PMID- 25913059 TI - Prognostic value of metastatic lymph node ratio as an additional tool to the TNM stage system in gastric cancer. AB - BACKGROUND: Gastric cancer is one of most common malignancies in the world. Currently the prognostic prediction is entirely based on the TNM staging system. In this study, we evaluated whether metastatic lymph node ratio (rN) at the time of surgery would improve the prognostic prediction in conjunction with the TNM staging system. METHODS: This retrospective study includes 745 patients, who had been referred for surgery due to gastric cancer between 1995 and 2007 and had at least 15 lymph nodes examined at the time of surgery without preoperative treatment. Clinicopathologic features and overall survival were analyzed using univariate and multivariate modes to identify the risk factors for overall survival. RESULTS: Median overall survival of all patients analyzed is 57.8 months and 5-year overall survival is 49.5%. Tumor site, macroscopic type, pTNM stage, and rN stage are identified as independent prognostic factors. Increased positive lymph node ratio correlates with shorter survival in all patients and in each T and N stage. In stage III gastric cancer patients, rN stage shows additional prognostic value on overall survival (p < 0.001). CONCLUSIONS: rN stage is a simple and promising prognostic factor of gastric cancer after surgery in addition to the TNM stage system especially in stage III patients. But the independent prognostic value of rN stage in stage I, II and IV gastric cancer is yet to be determined. PMID- 25913060 TI - Outcome after laparoscopic versus open wedge resection for suspected gastric gastrointestinal stromal tumors: A matched-pair case-control study. AB - BACKGROUND: Laparoscopic resection of gastric gastrointestinal stromal tumors (GISTs) has been shown by several retrospective studies to be technically feasible and associated with favorable outcomes when compared to the open approach. This study aims to mitigate potential selection bias by performing a case control study of laparoscopic (LWR) versus open wedge resection (OWR) matched by resection type, location and tumor size. METHODS: We retrospectively identified 50 consecutive patients who underwent LWR for a suspected gastric GIST from a prospective database and matched this cohort with 50 patients who underwent OWR. RESULTS: There was no statistical difference between the key baseline clinicopathological features of patients' who underwent LWR versus OWR. Patients who underwent LWR had longer operating times [150 (range, 65-270) minutes vs 92.5 (25-200) minutes, P < .001] but decreased median blood loss [0 (0 300) ml vs 0 (0-1200) ml, P = .015], decreased frequency of intraoperative or postoperative blood transfusion [1 (2%) vs 8 (16%), P = .031], decreased median time to liquid diet [2 (0-5) vs 3 (1-7) days, P < .001], decreased median time to solid diet [3 (1-6) vs 5 (2-11) days, P < .001] and decreased postoperative stay [4 (2-10) vs 4.5 (3-17), P < .001] compared to OWR. There was no difference in oncological outcomes such as frequency of close margins (<= 1 mm) and recurrence free survival. CONCLUSION: This matched case-control study provides supporting evidence that LWR results in superior perioperative outcomes compared to OWR without compromising on oncological outcomes. PMID- 25913061 TI - Recognition of personally familiar faces and functional connectivity in Alzheimer's disease. AB - Studies have reported that patients in the severe stages of Alzheimer's disease (AD) experience difficulties recognizing their own faces in recent photographs. Two case reports of late-stage AD showed that this loss of self-face recognition was temporally graded: photographs from the remote past were recognized more easily than more recent photographs. Little is known about the neural correlates of own face recognition abilities in AD patients, while neuroimaging studies in healthy adults have related these abilities to a bilateral fronto-parieto occipital network. In this study, two behavioral experiments (experiments 1 and 2) and one functional magnetic resonance imaging (fMRI) experiment (second part of experiment 2) were conducted to compare mild AD patients (experiment 1) and moderate AD patients (experiment 2) with healthy older participants in a recognition task involving self and familiar faces from different decades of the participants' life. In moderate AD patients, variable performance allowed us to examine correlations between scores and resting-state fMRI in order to link behavioral data to cerebral activity. At the behavioral level, the results revealed that, in mild AD, self and familiar face recognition was preserved. Moreover, mild AD patients and healthy older participants showed an inverse temporal gradient, with faster recognition of self and familiar recent photographs than self and familiar remote photographs. However, in moderate AD, both self and familiar face recognition were affected. fMRI results showed that the higher the connectivity between the dorsomedial prefrontal cortex (dMPFC) and the right superior frontal gyrus (rSFG), the lower the self and familiar face recognition scores in moderate AD patients. Given that previous studies have related the superior frontal region to control processes rather than face recognition processes, these results might reflect less segregation and more interference between brain networks in AD. In other words, impaired face recognition in AD may be related to functional dedifferentiation of specific brain regions. PMID- 25913062 TI - Functional role of frontal alpha oscillations in creativity. AB - Creativity, the ability to produce innovative ideas, is a key higher-order cognitive function that is poorly understood. At the level of macroscopic cortical network dynamics, recent electroencephalography (EEG) data suggests that cortical oscillations in the alpha frequency band (8-12 Hz) are correlated with creative thinking. However, whether alpha oscillations play a functional role in creativity has remained unknown. Here we show that creativity is increased by enhancing alpha power using 10 Hz transcranial alternating current stimulation (10 Hz-tACS) of the frontal cortex. In a study of 20 healthy participants with a randomized, balanced cross-over design, we found a significant improvement of 7.4% in the Creativity Index measured by the Torrance Test of Creative Thinking (TTCT), a comprehensive and most frequently used assay of creative potential and strengths. In a second similar study with 20 subjects, 40 Hz-tACS was used instead of 10 Hz-tACS to rule out a general "electrical stimulation" effect. No significant change in the Creativity Index was found for such frontal 40 Hz stimulation. Our results suggest that alpha activity in frontal brain areas is selectively involved in creativity; this enhancement represents the first demonstration of specific neuronal dynamics that drive creativity and can be modulated by non-invasive brain stimulation. Our findings agree with the model that alpha recruitment increases with internal processing demands and is involved in inhibitory top-down control, which is an important requirement for creative ideation. PMID- 25913063 TI - Lost in spatial translation - A novel tool to objectively assess spatial disorientation in Alzheimer's disease and frontotemporal dementia. AB - Spatial disorientation is a prominent feature of early Alzheimer's disease (AD) attributed to degeneration of medial temporal and parietal brain regions, including the retrosplenial cortex (RSC). By contrast, frontotemporal dementia (FTD) syndromes show generally intact spatial orientation at presentation. However, currently no clinical tasks are routinely administered to objectively assess spatial orientation in these neurodegenerative conditions. In this study we investigated spatial orientation in 58 dementia patients and 23 healthy controls using a novel virtual supermarket task as well as voxel-based morphometry (VBM). We compared performance on this task with visual and verbal memory function, which has traditionally been used to discriminate between AD and FTD. Participants viewed a series of videos from a first person perspective travelling through a virtual supermarket and were required to maintain orientation to a starting location. Analyses revealed significantly impaired spatial orientation in AD, compared to FTD patient groups. Spatial orientation performance was found to discriminate AD and FTD patient groups to a very high degree at presentation. More importantly, integrity of the RSC was identified as a key neural correlate of orientation performance. These findings confirm the notion that i) it is feasible to assess spatial orientation objectively via our novel Supermarket task; ii) impaired orientation is a prominent feature that can be applied clinically to discriminate between AD and FTD and iii) the RSC emerges as a critical biomarker to assess spatial orientation deficits in these neurodegenerative conditions. PMID- 25913064 TI - Re: Byron H. Lee, Adam S. Kibel, Jay P. Ciezki, et al. Are biochemical recurrence outcomes similar after radical prostatectomy and radiation therapy? Analysis of prostate cancer-specific mortality by nomogram-predicted risks of biochemical recurrence. Eur Urol 2015;67:204-9. PMID- 25913065 TI - The aging prostate is never "normal": implications from the genomic characterization of multifocal prostate cancers. AB - We argue against the recently published statement that tumor-specific molecular alterations found in "normal" prostate tissue from cancer patients challenge focal therapy approaches that only target a visible cancer lesion and not the adjacent molecular field. PMID- 25913066 TI - A Brief Survey of Active Surveillance. PMID- 25913067 TI - Re: Gunnar Steineck, Anders Bjartell, Jonas Hugosson, et al. Degree of preservation of the neurovascular bundles during radical prostatectomy and urinary continence 1 year after surgery. Eur Urol 2015;67:559-68. PMID- 25913069 TI - Environmentally benign and facile reduction of graphene oxide by flash light irradiation. AB - In this work, we demonstrate an environmentally benign and facile flash light irradiation process to reduce graphene oxide (GO). GO thin films were prepared by a vacuum filtration process, and these films were reduced by exposure to flash light irradiation for a few milliseconds at room temperature under ambient conditions. Flash light conditions such as energy, pulse width, and pulse number were varied to determine optimal conditions for this photothermal reduction of GO. The flash light irradiation treatment completely reduced the GO thin films, transforming them into pure graphene films. The resulting graphene films were characterized by x-ray diffraction, x-ray photoelectron spectroscopy, Raman spectroscopy, transmission electron microscopy, and thermogravimetric analysis. PMID- 25913068 TI - Synaptic vesicle exocytosis and increased cytosolic calcium are both necessary but not sufficient for activity-dependent bulk endocytosis. AB - Activity-dependent bulk endocytosis (ADBE) is the dominant synaptic vesicle (SV) endocytosis mode in central nerve terminals during intense neuronal activity. By definition this mode is triggered by neuronal activity; however, key questions regarding its mechanism of activation remain unaddressed. To determine the basic requirements for ADBE triggering in central nerve terminals, we decoupled SV fusion events from activity-dependent calcium influx using either clostridial neurotoxins or buffering of intracellular calcium. ADBE was monitored both optically and morphologically by observing uptake of the fluid phase markers tetramethylrhodamine-dextran and horse radish peroxidase respectively. Ablation of SV fusion with tetanus toxin resulted in the arrest of ADBE, but had no effect on other calcium-dependent events such as activity-dependent dynamin I dephosphorylation, indicating that SV exocytosis is necessary for triggering. Furthermore, the calcium chelator EGTA abolished ADBE while leaving SV exocytosis intact, demonstrating that ADBE is triggered by intracellular free calcium increases outside the active zone. Activity-dependent dynamin I dephosphorylation was also arrested in EGTA-treated neurons, consistent with its proposed role in triggering ADBE. Thus, SV fusion and increased cytoplasmic free calcium are both necessary but not sufficient individually to trigger ADBE. Activity-dependent bulk endocytosis (ADBE) is the dominant synaptic vesicle (SV) endocytosis mode in central nerve terminals during intense neuronal activity. To determine the minimal requirements for ADBE triggering, we decoupled SV fusion events from activity-dependent calcium influx using either clostridial neurotoxins or buffering of intracellular calcium. We found that SV fusion and increased cytoplasmic free calcium are both necessary but not sufficient to trigger ADBE. PMID- 25913070 TI - IAEA-HypoX. A randomized multicenter study of the hypoxic radiosensitizer nimorazole concomitant with accelerated radiotherapy in head and neck squamous cell carcinoma. AB - PURPOSE: To test the hypothesis that radiotherapy (RT) of head and neck squamous cell carcinoma (HNSCC) can be improved by hypoxic modification using nimorazole (NIM) in association with accelerated fractionation. MATERIALS AND METHODS: The protocol was activated in March 2012 as an international multicenter randomized trial in patients with HNSCC. Tumors were treated to a dose of 66-70Gy, 33-35 fractions, 6 fractions per week. NIM was administered in a dose of 1.2gperm(2), 90min before the first daily RT fraction. The primary endpoint was loco-regional failure. The trial was closed prematurely by June 2014 due to poor recruitment. An associated quality assurance program was performed to ensure the consistency of RT with the protocol guidelines. RESULTS: The trial was dimensioned to include 600 patients in 3years, but only 104 patients were randomized between March 2012 and May 2014 due to the inability to involve three major centers and the insufficient recruitment rate from the other participating centers. Twenty patients from two centers had to be excluded from the analysis due to the unavailability of the follow-up data. Among the remaining 84 patients, 82 patients were evaluable (39 and 43 patients in the RT+NIM and the RT-alone arms, respectively). The treatment compliance was good with only six patients not completing the full planned RT course, and 31 patients (79%) out of 39 allocated for NIM, achieving at least 90% of the prescribed drug dose. At the time of evaluation, 40 patients had failed to achieve persistent loco-regional tumor control, and a total of 45 patients had died. The use of NIM improved the loco regional tumor control with an 18month post-randomization cumulative failure rate of 33% versus 51% in the control arm, yielding a risk difference of 18% (CI -3% to 39%; P=0.10). The corresponding values for overall death was 43% versus 62%, yielding a risk difference of 19% (CI -3% to 42%; P=0.10). Sixteen patients, out of 55 patients analyzed for hypoxic gene expression, were classified as having more hypoxic tumors. Such patients, if treated with RT alone, had a higher loco regional tumor failure rate as compared to the rest of the patients with known hypoxic status (P=0.05). CONCLUSION: Although the trial was incomplete and suffered from a small number of patients, the results suggested an improvement in loco-regional tumor control and overall survival in patients with advanced HNSCC given the hypoxic modifier NIM in addition to accelerated fractionation RT. However, the trial also revealed that conducting multicenter and multinational study combining drug and RT in developing countries may suffer from uncontrolled and unsolvable problems. PMID- 25913072 TI - alpha-Chaconine isolated from a Solanum tuberosum L. cv Jayoung suppresses lipopolysaccharide-induced pro-inflammatory mediators via AP-1 inactivation in RAW 264.7 macrophages and protects mice from endotoxin shock. AB - In this study, we investigated the molecular mechanisms underlying the anti inflammatory effects of alpha-chaconine in lipopolysaccharide (LPS)-induced RAW 264.7 macrophages and in LPS-induced septic mice. alpha-Chaconine inhibited the expressions of cyclooxygenase-2 (COX-2), interleukin-1beta (IL-1beta), IL-6, and tumor necrosis factor-alpha (TNF-alpha) at the transcriptional level, and attenuated the transcriptional activity of activator protein-1 (AP-1) by reducing the translocation and phosphorylation of c-Jun. alpha-Chaconine also suppressed the phosphorylation of TGF-beta-activated kinase-1 (TAK1), which lies upstream of mitogen-activated protein kinase kinase 7 (MKK7)/Jun N-terminal kinase (JNK) signaling. JNK knockdown using siRNA prevented the alpha-chaconine-mediated inhibition of pro-inflammatory mediators. In a sepsis model, pretreatment with alpha-chaconine reduced the LPS-induced lethality and the mRNA and production levels of pro-inflammatory mediators by inhibiting c-Jun activation. These results suggest that the anti-inflammatory effects of alpha-chaconine are associated with the suppression of AP-1, and support its possible therapeutic role for the treatment of sepsis. PMID- 25913071 TI - DNA methylation and healthy human aging. AB - The process of aging results in a host of changes at the cellular and molecular levels, which include senescence, telomere shortening, and changes in gene expression. Epigenetic patterns also change over the lifespan, suggesting that epigenetic changes may constitute an important component of the aging process. The epigenetic mark that has been most highly studied is DNA methylation, the presence of methyl groups at CpG dinucleotides. These dinucleotides are often located near gene promoters and associate with gene expression levels. Early studies indicated that global levels of DNA methylation increase over the first few years of life and then decrease beginning in late adulthood. Recently, with the advent of microarray and next-generation sequencing technologies, increases in variability of DNA methylation with age have been observed, and a number of site-specific patterns have been identified. It has also been shown that certain CpG sites are highly associated with age, to the extent that prediction models using a small number of these sites can accurately predict the chronological age of the donor. Together, these observations point to the existence of two phenomena that both contribute to age-related DNA methylation changes: epigenetic drift and the epigenetic clock. In this review, we focus on healthy human aging throughout the lifetime and discuss the dynamics of DNA methylation as well as how interactions between the genome, environment, and the epigenome influence aging rates. We also discuss the impact of determining 'epigenetic age' for human health and outline some important caveats to existing and future studies. PMID- 25913073 TI - Alteration of metabolomic profiles by titanium dioxide nanoparticles in human gingivitis model. AB - Although nanoparticles (NPs) has afforded considerable benefits in various fields of sciences, several reports have shown their harmful effects, suggesting the necessity of adequate risk assessment. To clarify the mechanism of titanium dioxide nanoparticles (TiO2 NPs)-enhanced gingival inflammation, we conducted the full-scale metabolomic analyses of human gingival fibroblast cells treated with IL-1beta alone or in combination with TiO2 NPs. Observation with transmission electron microscope demonstrated the incorporation of TiO2 NPs into vacuoles of the cells. TiO2 NPs significantly enhanced the IL-1beta-induced prostaglandin E2 production and COX-1 and COX-2 protein expression. IL-1beta reduced the intracellular concentrations of overall primary metabolites especially those of amino acid, urea cycle, polyamine, S-adenosylmethione and glutathione synthetic pathways. The addition of TiO2 NPs further augmented these IL-1beta-induced metabolic changes, recommending careful use of dental materials containing TiO2 NPs towards patients with gingivitis or periodontitis. The impact of the present study is to identify the molecular targets of TiO2 NPs for the future establishment of new metabolic markers and therapeutic strategy of gingival inflammation. PMID- 25913074 TI - Successful balloon dilatation for postoperative caval stenosis caused by primary venorrhaphy for traumatic retro-hepatic caval injury in a three-year-old child: Report of a case. AB - Inferior vena cava injuries are highly lethal. We experienced a case of retrohepatic inferior vena cava injury as a result of blunt trauma in a three year-old female. Because the site of bleeding of the IVC was identified, we repaired it with running sutures. An attempt at primary repair resulted in postoperative narrowing of the vena cava. There was pressure gradient of the right atrium and inferior vena cava, and collateral circulation developed. Since it was also found that the haemodynamics was unstable, the child underwent another intervention before the stenosis of the IVC was fixed. To the best of our knowledge, there have been no previous reports of therapeutic radiological intervention for stenosis that developed after treatment of a traumatic IVC injury. The IVC in the present case recovered enough patency so that the collateral venous flow could be decreased after balloon dilatation angioplasty. PMID- 25913075 TI - Hyperoxia depletes (6R)-5,6,7,8-tetrahydrobiopterin levels in the neonatal retina: implications for nitric oxide synthase function in retinopathy. AB - Retinopathy of prematurity is a sight-threatening complication of premature birth caused by nitro-oxidative insult to the developing retinal vasculature during therapeutic hyperoxia exposure and later ischemia-induced neovascularization on supplemental oxygen withdrawal. In the vasodegenerative phase, during hyperoxia, defective endothelial nitric oxide synthase (NOS) produces reactive oxygen and nitrogen free radicals rather than vasoprotective nitric oxide for unclear reasons. Crucially, normal NOS function depends on availability of the cofactor (6R)-5,6,7,8-tetrahydrobiopterin (BH4). Because BH4 synthesis is controlled enzymatically by GTP cyclohydrolase (GTPCH), we used GTPCH-depleted mice [hyperphenylalaninemia strain (hph1)] to investigate the impact of hyperoxia on BH4 bioavailability and retinal vascular pathology in the neonate. Hyperoxia decreased BH4 in retinas, lungs, and aortas in all experimental groups, resulting in a dose-dependent decrease in NOS activity and, in the wild-type group, elevated NOS-derived superoxide. Retinal dopamine levels were similarly diminished, consistent with the dependence of tyrosine hydroxylase on BH4. Despite greater depletion of BH4, the hph(+/-) and hph1(-/-) groups did not show exacerbated hyperoxia-induced vessel closure, but exhibited greater vascular protection and reduced progression to neovascular disease. This vasoprotective effect was independent of enhanced circulating vascular endothelial growth factor (VEGF), which was reduced by hyperoxia, but to local retinal ganglion cell layer derived VEGF. In conclusion, a constitutively higher level of VEGF expression associated with retinal development protects GTPCH-deficient neonates from oxygen induced vascular damage. PMID- 25913077 TI - Characterization of solid tumors induced by polycyclic aromatic hydrocarbons in mice. AB - BACKGROUND: To assess the effects of single polycyclic aromatic hydrocarbons (PAHs) on solid tumor initiation, and investigate their roles in immune response regulation. MATERIAL AND METHODS: Mice (100) were randomly divided into 5 groups (n=20) to be intraperitoneally injected with 10 daily doses of DMSO (control), anthracene (50 mg/kg), benzo-(a)-pyrene (10 mg/kg), benzo-(a)-pyrene (20 mg/kg), and benzo-[G, H, I])-perylene (5 mg/kg), respectively. Three months later, serum IL-2 and IL-6 levels were assessed by ELISA; liver, kidney, stomach and lung tissues were subjected to histopathological examinations. RESULTS: Liver cancer incidences after benzo-[G, H, I]-perylene, benzo-(a)-pyrene (10 mg/kg), benzo-(a) pyrene (20 mg/kg), and anthracene were 21.1, 26.3, 35.3, and 27.8%, respectively; 21.1, 0, 41.2, and 0% showed stomach cancer, respectively; 0, 0, 11.8 and 0% displayed kidney cancer, respectively. The occurrences of precancerous liver lesions for benzo-[G, H, I]-perylene, benzo-(a)-pyrene (10 mg/kg), benzo-(a) pyrene (20 mg/kg) and anthracene groups, respectively, were 68.4, 73.7, 64.7, and 55.6%; 78.9, 68.4, 29.4, and 27.8% showed precancerous stomach lesions, while 42.1, 47.4, 58.8, and 33.3% had precancerous kidney lesions; respectively. No obvious lung lesions were found in any group. Serum IL-2 and IL-6 levels in treatment groups were significantly lower compared with control values (P<0.01). CONCLUSIONS: PAHs induce cancer and precancerous lesions in the liver, stomach, and kidney. Benzo (a) pyrene initiates gastric cancer in a dose-dependent manner, but does not induce precancerous lung lesions. Lower IL-2 and IL-6 levels in treatment groups compared with controls suggest that PAHs cause overt immune inhibition. PMID- 25913078 TI - Annual incidence of mortality related to hypertensive disease in Canada and associations with heliophysical parameters. AB - Increasing research into heliobiology and related fields has revealed a myriad of potential relationships between space weather factors and terrestrial biology. Additionally, many studies have indicated cyclicity in incidence of various diseases along with many aspects of cardiovascular function. The current study examined annual mortality associated with hypertensive diseases in Canada from 1979 to 2009 for periodicities and linear relationships with a range of heliophysical parameters. Analyses indicated a number of significant lagged correlations between space weather and hypertensive mortality, with solar wind plasma beta identified as the likely source of these relationships. Similar periodicities were observed for geomagnetic activity and hypertensive mortality. A significant rhythm was revealed for hypertensive mortality centered on a 9.6 year cycle length, while geomagnetic activity was fit with a 10.1-year cycle. Cross-correlograms of mortality with space weather demonstrated a 10.67-year periodicity coinciding with the average 10.6-year solar cycle length for the time period examined. Further quantification and potential implications are discussed. PMID- 25913079 TI - Uniting mathematics and biology for control of visceral leishmaniasis. AB - The neglected tropical disease (NTD) visceral leishmaniasis (VL) has been targeted by the WHO for elimination as a public health problem on the Indian subcontinent by 2017 or earlier. To date there is a surprising scarcity of mathematical models capable of capturing VL disease dynamics, which are widely considered central to planning and assessing the efficacy of interventions. The few models that have been developed are examined, highlighting the necessity for better data to parameterise and fit these and future models. In particular, the characterisation and infectiousness of the different disease stages will be crucial to elimination. Modelling can then assist in establishing whether, when, and how the WHO VL elimination targets can be met. PMID- 25913080 TI - Ultrasonography for foreign bodies in the soft tissue. PMID- 25913081 TI - Comparison of infant intubation through the TruView EVO2, TruView PCD, and Miller laryngoscope by paramedics during simulated infant cardiopulmonary resuscitation: A randomized crossover manikin study. AB - INTRODUCTION: The aim of the study was to compare the efficacy of the TruView EVO2, TruView PCD, and Miller laryngoscopes for tracheal intubation during cardiopulmonary resuscitation with and without chest compressions (CCs) by paramedics in an infant manikin model. METHODS: This was an open, prospective, randomized, simulated trial. After a brief didactic session, 78 volunteer paramedics attempted to intubate a manikin using TruView EVO2, TruView PCD, and Miller laryngoscopes during resuscitation with and without CC scenarios. Primary end point was intubation success rate and secondary was time to intubation with each device. Glottic view using a Cormack-Lehane grade in using each device was also assessed. RESULTS: In scenario with uninterrupted CCs, the median time to intubation using the TruView EVO2, TruView PCD, and Miller varied with the times being 25.3 seconds (interquartile range [IQR], 23-30.5 seconds) vs 20.2 seconds (IQR, 18-23 seconds) vs 24.4 seconds (IQR, 21-28 seconds), respectively. The overall success rate of intubation during CC for the devices were 94.9% vs 100% vs 92.1%. During intubation without CC, median time to intubation varied and amounted to 24.9 seconds (IQR, 21-29.6 seconds) for TruView EVO2, 18.3 seconds (IQR, 16-21.3 seconds) for TruView PCD, and 19.4 seconds (IQR, 17-23.3 seconds) for Miller laryngoscope. The overall success rate of intubation without CC for all devices was 100%. CONCLUSIONS: For infant tracheal intubation with TruView PCD, when used by paramedics, the malleable TruView PCD showed shorter intubation time and higher overall success rate in a simulated CC scenario than TruView EVO2 or Miller laryngoscopes. Further clinical studies are necessary to confirm these initial positive findings. PMID- 25913082 TI - Cardiac arrest due to airway obstruction in hereditary angioedema. AB - Hereditary angioedema (HAE) is a rare genetic disease caused by a deficiency of functional C1 esterase inhibitor that causes swelling attacks in various body tissues. We hereby report a case of out-of-hospital cardiac arrest due to airway obstruction in HAE. Cutaneous swelling and abdominal pain attacks caused by gastrointestinal wall swelling are common symptoms in HAE, whereas laryngeal swelling is rare. Emergency physicians may have few chances to experience cases of life-threatening laryngeal edema resulting in a delay from symptom onset to the diagnosis of HAE. Hereditary angioedema is diagnosed by performing complement blood tests. Because safe and effective treatment options are available for the life-threatening swellings in HAE, the diagnosis potentially reduces the risk of asphyxiation in patients and their blood relatives. PMID- 25913083 TI - Association of plasma diamine oxidase and intestinal fatty acid-binding protein with severity of disease in patient with heat stroke. AB - OBJECTIVES: The aim of this study was to describe the role of intestinal fatty acid-binding protein (iFABP) and allergy-related diamine oxidase (DAO) in patients with heat stroke (HS). METHODS: A total of 10 patients with HS in intensive care unit and 10 healthy volunteers were enrolled in this study. The plasma intestinal permeability markers iFABP and DAO were measured since the time of admission. The whole blood endotoxin was also assessed. The associations between iFABP, DAO, and endotoxin level were analyzed. Then, white blood cell count, procalcitonin, and C-reactive protein were examined. In addition, we also determined the levels of proinflammatory cytokines such as IL-1alpha, IL-6, and TNF-alpha. RESULTS: Comparing with the healthy control, the plasma iFABP and DAO level in patients with HS increased significantly (P < .05). The kinetic curve showed that plasma iFABP and DAO level reached peak value at day 3 and day 4 after admission, respectively. The endotoxin level was positively correlated with iFABP and DAO level. We also observed a significantly increased level of procalcitonin and C-reactive protein but not white blood count in patients with HS. After treatment, the iFABP and DAO level decreased significantly (P < .05). A significant increase in level of IL-1alpha and IL-6 was also found in patients with HS. CONCLUSIONS: The plasma concentrations of DAO and iFABP could reflect a better function of the intestinal mucosa barrier in patients with HS. Plasma iFABP and DAO level decreased significantly after the treatment and, thus, might be a predictor for the severity of HS. PMID- 25913084 TI - In reply to "Utility of shock index calculation in hemorrhagic trauma". PMID- 25913085 TI - Time-Resolved Transient Optical Absorption Study of Bis(terpyridyl)oligothiophenes and Their Metallo-Supramolecular Polymers with Zn(II) Ion Couplers. AB - alpha,omega-Bis(terpyridyl)oligothiophenes spontaneously assemble with Zn(II) ions giving conjugated constitutional dynamic polymers (dynamers) of the metallo supramolecular class, which potentially might be utilized in optoelectronics. Their photophysical properties, which are of great importance in this field of application, are strongly influenced by the dynamic morphology. It was assessed in this study by using ultrafast pump-probe optical absorption spectroscopy. We identified and characterized relaxation processes running in photoexcited molecules of these oligomers and dynamers and show impacts of disturbed coplanarity of adjacent rings (twisting the thiophene-thiophene and thiophene terpyridyl bonds by attached hexyl side groups) and Zn(II) ion couplers on these processes. Major effects are seen in the time constants of rotational relaxation, intersystem crossing, and de-excitation lifetimes. The photoexcited states formed on different repeating units within the same dynamer chain do not interact with each other even at very high excitation density. The method is presented that allows determining the equilibrium fraction of unbound oligothiophene species in a dynamer solution, from which otherwise hardly accessible values of the average degree of polymerization of constitutionally dynamic chains in solution can be estimated. PMID- 25913086 TI - Toxoplasma gondii isolate with genotype Chinese 1 triggers trophoblast apoptosis through oxidative stress and mitochondrial dysfunction in mice. AB - Congenital toxoplasmosis may result in abortion, severe mental retardation and neurologic damage in the offspring. Placental damage is considered as the key event in this disease. Here we show that maternal infection with Toxoplasma gondii Wh3 isolate of genotype Chinese 1, which is predominantly prevalent in China, induced trophoblast apoptosis of pregnant mouse. PCR array analysis of 84 key genes in the biogenesis and functions of mouse mitochondrion revealed that ten genes were up-regulated at least 2-fold in the Wh3 infection group, compared with those in the control. The elevated levels of reactive oxygen species (ROS), malondialdehyde (MDA) and 8-hydroxydeoxyguanosine (8-OHdG), as well as the decreased glutathione (GSH), were observed in the infected mice. The mRNA levels of NADPH oxidase 1 and glutathione peroxidase 6 (GPx6) were significantly increased. The production of excessive ROS was NADPH oxidase-dependent, which contributed to mitochondrial structural damage and mitochondrial dysfunction in placentas, followed by the cleavage of caspase-9 and caspase-3, and finally resulted in apoptosis of trophoblasts. All the above-mentioned phenomena were inhibited by pretreatment with the antioxidant of N-acetylcysteine (NAC). Taken together, we concluded that Wh3 infection during pregnancy may contribute to trophoblast apoptosis by oxidative stress-induced mitochondrial dysfunction and activation of the downstream signaling pathway. PMID- 25913087 TI - The beneficial effect of dietary zinc supplementation on anaemia and immunosuppression in Trypanosoma brucei infected rats. AB - Zinc is an essential trace element crucial for normal development and function of cells mediating nonspecific immunity and protects bio-molecules from oxidative damage. This study was designed to assess the effects of dietary zinc supplementation on anaemia and immunity of trypanosome-infected rats. Thirty rats, divided into five groups (A-E) of 6 each, were used for the study. Parameters used to assess the effect of the supplementation are antibody response to Sheep RBC using direct haemagglutination test, parasitaemia using the rapid matching method, WBC count using the improved Neubauer haemocytometer method, haemoglobin concentration using the cynomethaemoglobin technique while PCV was determined using the microhaematocrit method. The pre-infection supplementation did not prolong the pre-patent period significantly (p > 0.05). However, it significantly (p < 0.05) increased the packed cell volume (PCV), haemoglobin (Hb) concentration, leucocyte count, and antibody titre by day 7 on the supplementation (OTS). Following infection on day 7 OTS, the PCV and Hb decreased but remained significantly (p < 0.05) higher than the infected not supplemented (INS) group, while on day 14 OTS, they maintained a significantly (p < 0.05) higher antibody titre as compared to other groups. On day 21 OTS, theweight of 8 ppm and not infected not supplemented (NINS) groups was significantly (p < 0.05) higher but the relative organ weight of their liver and spleen was significantly (p < 0.05) lower than 2 ppm, 4 ppm and INS groups. On day 21 OTS, the parasitaemia levels of INS group was significantly (p < 0.05) higher than the supplemented groups. From the results, dietary zinc supplementation can be useful in the management of anaemia and immunosupression caused by trypanosomes in rats. PMID- 25913089 TI - Molecular detection of Capillaria philippinensis: An emerging zoonosis in Egypt. AB - Human infection with Capillaria philippinensis is accidental; however, it may end fatally if not diagnosed and treated in the proper time. The first case was detected in the Philippines in 1963, but later reported in other countries around the world, including Egypt. In this report, molecular diagnosis using a specific nested PCR for detection of C. philippinensis in faeces is described based on the amplification of small ribosomal subunit. The test showed sensitivity and specificity, as it detected all the positive cases and gave no cross-reaction with human DNA and DNA of other tested parasites. This method can be very useful not only for improvement of diagnosis, but also to understand the different environmental routes of transmission by detection of C. philippinensis DNA-stages in the possible fish intermediate hosts and reservoir animal host, helping to improve strategies for surveillance and prevention of human disease. PMID- 25913088 TI - Dendritic cell expression of the C-type lectin receptor CD209a: A novel innate parasite-sensing mechanism inducing Th17 cells that drive severe immunopathology in murine schistosome infection. AB - Following infection with the trematode helminth Schistosoma mansoni, CBA mice develop severe parasite egg-induced hepatic granulomatous inflammation as well as prominent CD4(+) T helper 17 (Th17) cell responses driven by dendritic cell (DC) derived IL-1beta and IL-23. By comparison, C57BL/6 mice develop mild hepatic immunopathology, egg stimulation of DCs does not result in IL-1beta and IL-23 production, and Th17 cells fail to develop. To investigate the reasons for strain specific differences in antigen presenting cell (APC) reactivity to eggs, we performed a comparative gene profiling analysis of normal bone marrow-derived DCs (BMDCs) and found that CBA DCs display markedly elevated expression of C-type lectin receptors (CLRs). In particular, expression of CD209a, a murine homologue of human DC-specific ICAM-3-grabbing non-integrin (DC-SIGN, CD209), was strikingly higher in CBA than BL/6 DCs. High CD209a surface expression was observed in various CBA splenic and granuloma APC subpopulations; however, only DCs, and not macrophages, B cells or neutrophils, were able to induce Th17 cell differentiation in response to schistosome eggs. Lentiviral gene silencing in CBA DCs, and over-expression in BL/6 DCs, demonstrated CD209a to be critical for egg induced DC IL-1beta and IL-23 production necessary for Th17 cell differentiation and expansion. These findings reveal a novel innate parasite-sensing mechanism promoting CD4(+) Th17 cells that mediate severe immunopathology in schistosomiasis. PMID- 25913090 TI - Comparative immunoprophylactic efficacy of Haemonchus contortus recombinant enolase (rHcENO) and Con A purified native glycoproteins in sheep. AB - Haemonchus contortus is the most economically important blood feeding nematode parasite of sheep and goats all over the world. Enolase in helminth parasites is a multi-functional enzyme which involves in glycolysis and host tissue invasion. In this study, the recombinant H. contortus enolase (rHcENO) was evaluated for its immunoprophylactic efficacy in sheep along with Con A purified native glycoproteins in a vaccine challenge trial. Group I and Group II experimental sheep were immunized thrice with rHcENO and Con A purified native glycoproteins along with Montanide ISA 61 VG adjuvant. The animals were challenged with 5000 L3 stage active H. contortus larvae after 21 days of third immunization. A significant increase in the IgG titre was observed in rHcENO and Con A purified native glycoproteins immunized animals as compared to the control animals. Immunoprotective efficacy of Con A purified native glycoproteins was comparatively higher than rHcENO antigen. PMID- 25913091 TI - Development of monoclonal antibodies against Plasmodium falciparum thioredoxin peroxidase 1 and its possible application for malaria diagnosis. AB - Rapid diagnostic tests (RDTs) have been considered as an ideal alternative for light microscopy to detect malaria parasites especially in remote areas. The development and improvement of RDTs is an area of intensive research in the last decade. To date, few parasite proteins have been targeted in RDTs which are known to have certain deficiencies and made the researchers to look for other promising candidates to address this problem. Plasmodium falciparum thioredoxin peroxidase 1 (PfTPx-1) is abundantly expressed in the cytoplasm of the parasite and well conserved across Plasmodium species, making this antigen a promising target for malaria diagnosis. Several monoclonal antibodies (mAbs) were produced against PfTPx-1. The binding affinities of mAbs were measured. Several immunochromatographic tests (ICTs) were developed using different combination of mAbs. All mAbs showed promising affinities to be used for diagnosis. The sensitivities of ICTs were evaluated using recombinant PfTPx-1 whose results lead us to the preparation of 4 different ICTs. These tests showed positive reaction with P. falciparum in vitro culture supernatant indicating the release of PfTPx-1 during schizont rupture. Altogether, these findings suggest that PfTPx-1 is a promising biomarker to diagnose P. falciparum infection. However, the diagnostic performance of this antigen should be further validated using clinical samples. PMID- 25913092 TI - Effects of sleep deprivation on serum cortisol level and mental health in servicemen. AB - This study aimed to investigate the effects of sleep deprivation on serum cortisol level and mental health and explore the correlations between them in servicemen. A total of 149 out of the 207 Chinese servicemen were randomly selected to go through 24hour sleep deprivation, leaving the rest (58) as the control group, before and after which their blood samples were drawn for cortisol measurement. Following the procedure, all the participants were administered the Military Personnel Mental Disorder Prediction Scale, taking the military norm as baseline. The results revealed that the post-deprivation serum cortisol level was positively correlated with the factor score of mania in the sleep deprivation group (rSp=0.415, p<0.001). Sleep deprivation could significantly increase serum cortisol level and may affect mental health in servicemen. The increase of serum cortisol level is significantly related to mania disorder during sleep deprivation. PMID- 25913093 TI - Clarifying the functional process represented by P50 suppression. AB - P50 suppression refers to the amplitude-reduction of the P50 event related potential to the second (S2) relative to the first (S1) of identical auditory stimuli presented 500ms apart. Theory suggests that refractory periods (RPs) and/or inhibitory inputs (II) underlie P50 suppression. The present study manipulated interval between stimulus pairs (IPI: 2, 8s) and direction of participants' attention (Attention, Non-Attention) in order to determine which theory best explains P50 suppression. The rationale is that: 1/ RP and II predict opposite effects of manipulating the functionality of the mechanism responsible for S2P50 suppression (e.g. reducing function would increase S2P50 according to the II and decrease S2P50 according to the RP hypothesis); 2/ IPI2 (relative to IPI8) will reduce functionality of the mechanism responsible for S2P50 suppression, as it results in less recovery of (and a greater challenge to) that mechanism - RP would thus predict reduced S2P50, whereas II would predict enhanced S2P50 amplitude; and 3/ where the mechanism responsible for S2P50 suppression is challenged (i.e. at IPI2, due to insufficient recovery), Attention (relative to Non-Attention) will enhance functionality of this mechanism - RP would thus predict increased S2P50, whereas II would predict reduced S2P50 amplitude. In the Non-Attention paradigm, reducing IPI from 8 to 2s tended to increase S2P50 amplitude (and consequently impaired P50 suppression), and in the 2s IPI paradigm, directing attention towards the stimuli reduced S2P50 amplitude (and improved P50 suppression), with both effects supporting the II hypothesis only. PMID- 25913094 TI - Startle eye-blink modulation by facial self-resemblance and current mood. AB - Although salient stimuli are known to modulate startle eye-blink responses, and one's own face is considered of particular salience, effects of facial self resemblance on startle responsiveness have not been systematically investigated. For the present study, pictures from the FACES database (rated as neutral) were digitally morphed to resemble the participants' (N=37) faces to varying degrees (25-50-75%). Perceptually matched geometrical shapes served as a control condition. At SOAs of either 300ms or 3000ms after picture onset, startle responses were elicited by white noise (50ms, 105dB), and recorded at the orbicularis oculi via EMG. Prior to the experiment, self-reported mood was assessed by means of the PANAS. Relative to non-face stimuli, the presentation of faces reduced startle magnitude at short, but not long, lead intervals. Furthermore, for probes presented at a SOA of 300ms, a linear decrease in startle magnitude with higher levels of self-resemblance was observed, presumably reflecting higher salience of the self-face. The startle modulating effect of self-resembling faces during longer lead intervals was moderated by the participants' current mood: negative affect predicted stronger patterns of attenuation, which might be interpreted as an increase in self-focus resulting from more negative mood. PMID- 25913095 TI - Dopamine and executive function: Increased spontaneous eye blink rates correlate with better set-shifting and inhibition, but poorer updating. AB - The central dopamine system (DA) has a significant role in the executive function (EF). The spontaneous eye blink rate (EBR) is an effective clinical and non invasive measure, which is strongly related to the activity of the central dopaminergic system. Previous studies show significant relationships between the two main dimensions of EF (i.e., shifting and inhibition) and the central DA system as measured by EBR. However, most of these studies involve only one EF task for shifting or inhibition; whether or not these relationships are replicated by other EF tasks remains unclear. Besides, the relationship between EBR and another important EF dimension-updating-also remains unknown. The present study examined the correlation between EBR and several EF tasks that captured all the three EF dimensions: shifting, inhibition, and updating. A total of 61 healthy participants were subjected to EBR testing and EF tasks. Results showed that EBR had a different relationship with each of the three tested EF dimensions. An increase in EBR levels was related to an increase in accuracy in shifting and inhibition tasks, a decrease in shifting and inhibition cost, and a decrease in accuracy in updating tasks. These results imply that the role of the central DA system in shifting and inhibition differs from its role in updating. PMID- 25913096 TI - Integration of Random Forest with population-based outlier analyses provides insight on the genomic basis and evolution of run timing in Chinook salmon (Oncorhynchus tshawytscha). AB - Anadromous Chinook salmon populations vary in the period of river entry at the initiation of adult freshwater migration, facilitating optimal arrival at natal spawning. Run timing is a polygenic trait that shows evidence of rapid parallel evolution in some lineages, signifying a key role for this phenotype in the ecological divergence between populations. Studying the genetic basis of local adaptation in quantitative traits is often impractical in wild populations. Therefore, we used a novel approach, Random Forest, to detect markers linked to run timing across 14 populations from contrasting environments in the Columbia River and Puget Sound, USA. The approach permits detection of loci of small effect on the phenotype. Divergence between populations at these loci was then examined using both principle component analysis and FST outlier analyses, to determine whether shared genetic changes resulted in similar phenotypes across different lineages. Sequencing of 9107 RAD markers in 414 individuals identified 33 predictor loci explaining 79.2% of trait variance. Discriminant analysis of principal components of the predictors revealed both shared and unique evolutionary pathways in the trait across different lineages, characterized by minor allele frequency changes. However, genome mapping of predictor loci also identified positional overlap with two genomic outlier regions, consistent with selection on loci of large effect. Therefore, the results suggest selective sweeps on few loci and minor changes in loci that were detected by this study. Use of a polygenic framework has provided initial insight into how divergence in a trait has occurred in the wild. PMID- 25913098 TI - First-principles investigation of novel polymorphs of Mg2C. AB - On the basis of the evolutionary methodology for crystal structure prediction, the potential crystal structures of magnesium carbide with a chemical composition of Mg2C are explored. Except the known cubic phase (Fm3m), two novel tetragonal structures (P42/mnm and I41/Amd) and two novel hexagonal structures (P63/mmc and P6M2) of Mg2C are found. All these four new phases are mechanically and dynamically stable by the calculated elastic constants and phonon dispersions. Furthermore, the effects of pressure and temperature on the phase transitions among different Mg2C polymorphs are investigated, implying that some new phases especially the P42/mnm phase may be synthesized in future. The ratio values of B/G are also calculated in order to analyze the brittle and ductile nature of these Mg2C phases. In addition, electronic structure calculations suggest that the I41/Amd phase is semimetallic and the other three new phases are all metallic, which is different from the previously proposed magnesium carbides. Meanwhile, the calculated electronic density maps reveal that strong ionic bonding exists between the Mg and C atoms. PMID- 25913097 TI - Current knowledge and importance of dGEMRIC techniques in diagnosis of hip joint diseases. AB - Accurate assessment of early hip joint cartilage alterations may help optimize patient selection and follow-up of hip joint preservation surgery. Delayed gadolinium-enhanced magnetic resonance imaging of cartilage (dGEMRIC) is sensitive to the glycosaminoglycan content in cartilage that is lost early in the development of osteoarthritis (OA). Hence, the dGEMRIC technique holds promise for the development of new diagnostic and therapeutic procedures. However, because of the location of the hip joint deep within the body and due to the fairly thin cartilage layers that require high spatial resolution, the diagnosis of early hip joint cartilage alterations may be problematic. The purpose of this review is to outline the current status of dGEMRIC in the assessment of hip joint cartilage. A literature search was performed with PubMed, using the terms "cartilage, osteoarthritis, hip joint, MRI, and dGEMRIC", considering all levels of studies. This review revealed that dGEMRIC can be reliably used in the evaluation of early stage cartilage pathology in various hip joint disorders. Modifications in the technique, such as the operation of three-dimensional imaging and dGEMRIC after intra-articular contrast medium administration, have expanded the range of application. Notably, the studies differ considerably in patient selection and technical prerequisites. Furthermore, there is a need for multicenter prospective studies with the required technical conditions in place to establish outcome based dGEMRIC data to obtain, in conjunction with clinical data, reliable threshold values for normal and abnormal cartilage, and for hips that may benefit from conservative or surgical treatment. PMID- 25913099 TI - Retraction. PMID- 25913100 TI - Cardiometabolic and skeletal risk factors in black men with prostate cancer starting androgen deprivation therapy. AB - BACKGROUND: Androgen deprivation therapy (ADT) for prostate cancer (PCa) is associated with multiple metabolic complications, previously predominantly evaluated in the white population. METHODS: A chart-based retrospective review was conducted on black patients with PCa, considered for ADT, from September 2007 to July 2010. Baseline data were collected on body mass index (BMI), vitamin-D status, bone mineral density (BMD), dyslipidemia and diabetes. Overweight and obesity were classified as BMI >= 25 and BMI >= 30, respectively. Vitamin-D sufficiency was defined as levels >=30 ng/mL, insufficiency as <30 ng/mL and deficiency as <=20 ng/mL. Osteopenia was defined as T scores between -1 to -2.5 and osteoporosis when T scores <=-2.5. RESULTS: Of the initial cohort of 130 black men, 111 (85.4%) patients underwent ADT. At baseline, average BMI was 28.1 +/- 5.9 with 43.3% of men being overweight and 30.8% obese. More than one-third of the patients had pre-existing dyslipidemia while 28.8% were diabetics. 50% were vitamin-D deficient while 41% had low bone mass. CONCLUSIONS: Black men with PCa presenting for consideration of ADT have a high prevalence of existing metabolic risk factors. Close monitoring of this patient population is needed during ADT to prevent and treat metabolic complications. PMID- 25913101 TI - To tell or not to tell: male partner engagement in a Phase 3 microbicide efficacy trial in South Africa. AB - Gender norms that privilege men's sexual power and pleasure, and distrust of condom use in intimate relationships, leave women vulnerable to HIV and other sexually transmitted infections. Vaginal microbicides allow women to exert a degree of control over their sexual health, through responsibility for product insertion as well as the possibility of covert use. In practice, however, the uptake of new HIV-prevention products is heavily influenced by partnership dynamics. This paper presents a secondary analysis of data from two qualitative sub-studies conducted during a Phase 3 microbicide efficacy trial in South Africa. Using transcripts from in-depth interviews and focus group discussions with 278 female trial participants and 27 male partners, we investigated the extent to which women disclosed microbicide use to their partners, and the level and types of male engagement with microbicide use. Most women chose to communicate with their partners about the trial, but the timing and content of associated discussions differed according to their motivation for disclosure. Men provided their partners with both moral and practical support, but reported a desire for greater involvement in decision-making surrounding microbicide uptake and use. The findings inform recommendations for constructive male participation in future trials and, ultimately, introduction of a marketed product. PMID- 25913102 TI - From mother to child: orbitofrontal cortex gyrification and changes of drinking behaviour during adolescence. AB - Adolescence is a common time for initiation of alcohol use and alcohol use disorders. Importantly, the neuro-anatomical foundation for later alcohol-related problems may already manifest pre-natally, particularly due to smoking and alcohol consumption during pregnancy. In this context, cortical gyrification is an interesting marker of neuronal development but has not been investigated as a risk factor for adolescent alcohol use. On magnetic resonance imaging scans of 595 14-year-old adolescents from the IMAGEN sample, we computed whole-brain mean curvature indices to predict change in alcohol-related problems over the following 2 years. Change of alcohol use-related problems was significantly predicted from mean curvature in left orbitofrontal cortex (OFC). Less gyrification of OFC was associated with an increase in alcohol use-related problems over the next 2 years. Moreover, lower gyrification in left OFC was related to pre-natal alcohol exposure, whereas maternal smoking during pregnancy had no effect. Current alcohol use-related problems of the biological mother had no effect on offsprings' OFC gyrification or drinking behaviour. The data support the idea that alcohol consumption during pregnancy mediates the development of neuro-anatomical phenotypes, which in turn constitute a risk factor for increasing problems due to alcohol consumption in a vulnerable stage of life. Maternal smoking during pregnancy or current maternal alcohol/nicotine consumption had no significant effect. The OFC mediates behaviours known to be disturbed in addiction, namely impulse control and reward processing. The results stress the importance of pre-natal alcohol exposure for later increases in alcohol use-related problems, mediated by structural brain characteristics. PMID- 25913103 TI - Physical activity, fitness, and vascular health in patients with asthma. PMID- 25913105 TI - A comparison of error-correction procedures on skill acquisition during discrete trial instruction. AB - Previous research supports the use of a variety of error-correction procedures to facilitate skill acquisition during discrete-trial instruction. We used an adapted alternating treatments design to compare the effects of 4 commonly used error-correction procedures on skill acquisition for 2 children with attention deficit hyperactivity disorder and 3 children with autism spectrum disorder. For all participants, multiple error-correction procedures were effective; however, 1 or 2 specific error-correction procedures led to more efficient skill acquisition for each individual. These results highlight the importance of evaluating the effectiveness and efficiency of error-correction procedures for individual learners during discrete-trial instruction. We discuss the use of discrete-trial instruction with different populations, implications for using multiple measures of procedural efficiency, and several areas for future research. PMID- 25913104 TI - Genome-wide expression profiles identify potential targets for gene-environment interactions in asthma severity. AB - BACKGROUND: Gene-environment interaction studies using genome-wide association study data are often underpowered after adjustment for multiple comparisons. Differential gene expression in response to the exposure of interest can capture the most biologically relevant genes at the genome-wide level. OBJECTIVE: We used differential genome-wide expression profiles from the Epidemiology of Home Allergens and Asthma birth cohort in response to Der f 1 allergen (sensitized vs nonsensitized) to inform a gene-environment study of dust mite exposure and asthma severity. METHODS: Polymorphisms in differentially expressed genes were identified in genome-wide association study data from the Childhood Asthma Management Program, a clinical trial in childhood asthmatic patients. Home dust mite allergen levels (<10 or >=10 MUg/g dust) were assessed at baseline, and (>=1) severe asthma exacerbation (emergency department visit or hospitalization for asthma in the first trial year) served as the disease severity outcome. The Genetics of Asthma in Costa Rica Study and a Puerto Rico/Connecticut asthma cohort were used for replication. RESULTS: IL9, IL5, and proteoglycan 2 expression (PRG2) was upregulated in Der f 1-stimulated PBMCs from dust mite sensitized patients (adjusted P < .04). IL9 polymorphisms (rs11741137, rs2069885, and rs1859430) showed evidence for interaction with dust mite in the Childhood Asthma Management Program (P = .02 to .03), with replication in the Genetics of Asthma in Costa Rica Study (P = .04). Subjects with the dominant genotype for these IL9 polymorphisms were more likely to report a severe asthma exacerbation if exposed to increased dust mite levels. CONCLUSIONS: Genome-wide differential gene expression in response to dust mite allergen identified IL9, a biologically plausible gene target that might interact with environmental dust mite to increase severe asthma exacerbations in children. PMID- 25913106 TI - Utilisation of MR spectroscopy and diffusion weighted imaging in predicting and monitoring of breast cancer response to chemotherapy. AB - Neoadjuvant chemotherapy (NACT) is the standard treatment option for breast cancer as more data shows that pathologic complete response (pCR) after NACT correlates with improved prognosis. MRI is accepted as the best imaging modality for evaluating the response to NACT in many studies as compared with clinical examination and other imaging modalities. In vivo magnetic resonance spectroscopy (MRS) and diffusion-weighted imaging (DWI) studies have both emerged as potential tools to provide early response indicators based on the changes in the metabolites and the apparent diffusion coefficient (ADC) respectively. In this review article, we aim to discuss the strength and limitations of MRS and DWI in monitoring of early response breast cancer to NACT. PMID- 25913107 TI - Prohibiting juvenile access to tobacco: Violation rates, cigarette sales, and youth smoking. AB - BACKGROUND: Scholars who examine the efficacy of juvenile tobacco sales restrictions, especially the 1992 "Synar Amendment" that led all of fifty U.S. states to enact prohibitions on tobacco sales to minors, are notably divided as to impact on youth smoking. Some researchers claim that such policies have failed and ought to be abandoned (Craig & Boris, 2007; Etter, 2006; Glantz, 2002), while others insist that enforcement has indeed led to reduced tobacco use (DiFranza, 2011b; SAMHSA, 2011). The present study is the first to combine data on Synar violation rates from all states and years available since the amendment's implementation, assessing the connection to national rates of cigarette sales and youth smoking behavior. METHODS: Using national data from the United States Substance Abuse and Mental Health Services Administration, the Tobacco Institute, and the Centers for Disease Control's Youth Risk Behavior Surveillance System across all U.S. states between 1996 and 2007, we employ hierarchical linear modeling to examine the connection between retailer Synar violations and youth smoking. RESULTS: Controlling for state-level demographic variables, results indicate that retailer violation rates are significantly associated with greater youth smoking prevalence, as well as higher overall cigarette sales. CONCLUSION: While critiques of Synar policies are substantive and should be addressed, laws prohibiting the sale of tobacco to juveniles appear to have had some degree of success. PMID- 25913108 TI - Current treatment of bulk single walled carbon nanotubes to heal defects without structural change for increased electrical and thermal conductivities. AB - By applying electrical current with heat, we succeeded in improving the graphitization of single walled carbon nanotubes (SWCNTs) without increasing the diameter and wall number. At 800 degrees C, 150 A cm(-2) (1150 W cm(-2)) for 1 min, we achieved a 3.2-times increase in the Raman G- to D-band ratio, a 3.1 times increase in electrical conductivity (from 25.2 to 78.1 S cm(-1)), a 3.7 times increase in thermal conductivity (from 3.5 to 12.8 W m(-1) K(-1)), and even a 1.7-times increase in dispersibility (from 1.7 to 2.9 mg L(-1)). The electrical and thermal conductivities did not only increase simultaneously, but their relative increases were identical across our experimental range that stems from defect healing without any change in diameter and wall number. In contrast, a significant increase in diameter and wall number was observed when current was not applied. These results demonstrate the importance of applying current to improve the graphitization of SWCNTs while maintaining their structure as SWCNTs. PMID- 25913110 TI - On-chip optofluidic single-particle method for rapid microscale equilibrium solubility screening of biologically active substances. AB - Solubility is the primary physicochemical property determining the absorption and bioavailability of substances. Here, we present an optofluidic single-particle technique for microscale equilibrium solubility determination, based on on-chip hydrodynamic particle trapping and optical particle size monitoring. The method combines the rapidity, universality, and substance sparing nature of physical analysis, with the accuracy traditionally associated with chemical analysis. Applying the diffusion layer theory, we determined the equilibrium solubility from individual pure substance microparticles of as little as 14 MUg in initial mass, in a matter of seconds to minutes. The reduction in time and substance consumption, when compared to the golden standard method, is above 2 orders of magnitude. With a simultaneous improvement above 3-fold in accuracy of the solubility data, the applicability of optofluidics based analytics for small scale high-throughput quantitative solubility and biological activity screening is demonstrated. PMID- 25913109 TI - The psychosis-like effects of Delta(9)-tetrahydrocannabinol are associated with increased cortical noise in healthy humans. AB - BACKGROUND: Drugs that induce psychosis may do so by increasing the level of task irrelevant random neural activity or neural noise. Increased levels of neural noise have been demonstrated in psychotic disorders. We tested the hypothesis that neural noise could also be involved in the psychotomimetic effects of delta 9-tetrahydrocannabinol (Delta(9)-THC), the principal active constituent of cannabis. METHODS: Neural noise was indexed by measuring the level of randomness in the electroencephalogram during the prestimulus baseline period of an oddball task using Lempel-Ziv complexity, a nonlinear measure of signal randomness. The acute, dose-related effects of Delta(9)-THC on Lempel-Ziv complexity and signal power were studied in humans (n = 24) who completed 3 test days during which they received intravenous Delta(9)-THC (placebo, .015 and .03 mg/kg) in a double blind, randomized, crossover, and counterbalanced design. RESULTS: Delta(9)-THC increased neural noise in a dose-related manner. Furthermore, there was a strong positive relationship between neural noise and the psychosis-like positive and disorganization symptoms induced by Delta(9)-THC, which was independent of total signal power. Instead, there was no relationship between noise and negative-like symptoms. In addition, Delta(9)-THC reduced total signal power during both active drug conditions compared with placebo, but no relationship was detected between signal power and psychosis-like symptoms. CONCLUSIONS: At doses that produced psychosis-like effects, Delta(9)-THC increased neural noise in humans in a dose dependent manner. Furthermore, increases in neural noise were related with increases in Delta(9)-THC-induced psychosis-like symptoms but not negative-like symptoms. These findings suggest that increases in neural noise may contribute to the psychotomimetic effects of Delta(9)-THC. PMID- 25913111 TI - Increasing incidence of the neonatal abstinence syndrome in U.S. neonatal ICUs. AB - BACKGROUND: The incidence of the neonatal abstinence syndrome, a drug-withdrawal syndrome that most commonly occurs after in utero exposure to opioids, is known to have increased during the past decade. However, recent trends in the incidence of the syndrome and changes in demographic characteristics and hospital treatment of these infants have not been well characterized. METHODS: Using multiple cross sectional analyses and a deidentified data set, we analyzed data from infants with the neonatal abstinence syndrome from 2004 through 2013 in 299 neonatal intensive care units (NICUs) across the United States. We evaluated trends in incidence and health care utilization and changes in infant and maternal clinical characteristics. RESULTS: Among 674,845 infants admitted to NICUs, we identified 10,327 with the neonatal abstinence syndrome. From 2004 through 2013, the rate of NICU admissions for the neonatal abstinence syndrome increased from 7 cases per 1000 admissions to 27 cases per 1000 admissions; the median length of stay increased from 13 days to 19 days (P<0.001 for both trends). The total percentage of NICU days nationwide that were attributed to the neonatal abstinence syndrome increased from 0.6% to 4.0% (P<0.001 for trend), with eight centers reporting that more than 20% of all NICU days were attributed to the care of these infants in 2013. Infants increasingly received pharmacotherapy (74% in 2004-2005 vs. 87% in 2012-2013, P<0.001 for trend), with morphine the most commonly used drug (49% in 2004 vs. 72% in 2013, P<0.001 for trend). CONCLUSIONS: From 2004 through 2013, the neonatal abstinence syndrome was responsible for a substantial and growing portion of resources dedicated to critically ill neonates in NICUs nationwide. PMID- 25913112 TI - Tetraphenylethene-pyridine salts as the first self-assembling chemosensor for pyrophosphate. AB - We presented a novel approach for pyrophosphate (PPi) sensing. Two tetraphenylethene (TPE)-functionalised pyridine salts (TPM and TPH) were designed and synthesized. Both of them exhibited weak emission in the solution state that originates from intramolecular charge transfer (ICT) from TPE to the pyridine; the addition of PPi into the TPM aqueous solution would enhance the fluorescence intensity, which eliminates the emission quenching effect of the iodide ion by the formation of PPi-sensor nanoparticles. The detection limit of TPM was determined to be as low as 133 nM. Meanwhile, a thin solid film of TPM that could detect PPi rapidly was conveniently prepared. PMID- 25913113 TI - Treating retinoblastoma in the first year of life in a national tertiary paediatric hospital in Mexico. AB - AIM: Retinoblastoma is the most common primary ocular malignancy in childhood, but little has been documented on the clinical and biological differences in children diagnosed before one year of age. We observed patients in this age group and followed them for up to 19 years. METHODS: This retrospective, descriptive, observational study reviewed the medical records of Mexican patients, who were diagnosed with retinoblastoma before one year of age at a national paediatric hospital from 1995 to 2014. The variables analysed were age at diagnosis, weight, presenting signs, the time from first symptoms to diagnosis, family history, laterality, ocular rescue and survival rate. RESULTS: The 108 patients had a mean age of 7.65 months and 15.7% had a family history of retinoblastoma. The majority (55.5%) had bilateral retinoblastoma, the most common presenting sign was leukocoria (86.1%), and the most common stage of diagnosis was Group V (84.1%). More than half were underweight for their age. The overall survival rate was 92% and the disease-free survival rate was 84%. CONCLUSION: Retinoblastoma is a malignancy that can be present at birth, especially if it is a bilateral hereditary form of the disease. Leukocoria was the main presenting sign. Early diagnosis dramatically improved the prognosis for ocular rescue. PMID- 25913114 TI - Synthesis and bioactivity of 2',3'-benzoabscisic acid analogs. AB - 2',3'-Benzoabscisic acid 4a is significantly more active than (+/-)-ABA and can be potentially used as a plant growth regulator for agriculture. In this study, six 4a analogs were designed and synthesized. Bioassay showed that 4a displayed greater activity than (+/-)-ABA and the six analogs produced less inhibition than 4a itself. Specially, some analogs displayed markedly different activities to different physiological and biochemical process, which were largely different from ABA and 4a. Compared to (+/-)-ABA, 4b and 4c were more effective germination inhibitors for lettuce, but less effective inhibitors for rice elongation. Five membered analog 5 was higher or slightly weaker in inhibiting Arabidopsis seed germination and rice elongation, respectively, but at least 10 times less effective than (+/-)-ABA in lettuce seed germination. Dual acid 6 and alkyne acid 20 nearly produced no inhibitory activity for Arabidopsis seed germination, but displayed excellent activity in inhibiting rice seedling growth. The preference of the analogs to different physiology process indicated that they might provide a strategy to develop novel ABA agonists or antagonist and be used as probe to investigate the function of different ABA receptors. PMID- 25913115 TI - Synthesis of new ent-labdane diterpene derivatives from andrographolide and evaluation on cytotoxic activities. AB - There are many reports for andrographolide modification regarding antitumor effects. Transformation of the five-membered lactone ring to furan aromatic ring still results in compounds with good cytotoxicity. To determine further the importance of the five-membered lactone ring and to obtain better lead compounds, we transformed the five-membered lactone ring in andrographolide. New types of ent-labdane diterpene derivatives were made, whose cytotoxic activities were measured in vitro. Preliminary SAR was summarized and two compounds, 7 and 26, with good cytotoxic activity were obtained, which have the potential to be developed into new antitumor drugs. PMID- 25913116 TI - N-((1,3-Diphenyl-1H-pyrazol-4-yl)methyl)anilines: A novel class of anti-RSV agents. AB - A series of N-((1,3-diphenyl-1H-pyrazol-4-yl)methyl)anilines were synthesized and evaluated in vitro for cytotoxicity and antiviral activity against a large panel of viruses. Most of the tested compounds interfered with RSV replication in the micromolar concentrations (EC50s ranging from 5 MUM to 28 MUM). SAR studies suggested that the presence of a trifluoromethyl group in R(1) abolished the anti RSV activity and enhanced the cytotoxicity while the best results in term of both anti-RSV activity and selectivity were obtained by the introduction in R(1) of a chlorine or a bromine atom. PMID- 25913117 TI - Discovery of novel small-molecule antagonists for GluK2. AB - KA receptors have shown to be potential therapeutic targets in CNS diseases such as schizophrenia, depression, neuropathic pain and epilepsy. Through the use of our docking tool Fitted, we investigated the relationship between ligand activity towards GluK2 and the conformational state induced at the receptor level. By focusing our rational design on the interaction between the ligand and a tyrosine residue in the binding site, we synthesized a series of molecules based on a glutamate scaffold, and carried out electrophysiological recordings. The observed ability of some of these molecules to inhibit receptor activation shows the potential of our design for the development of effective antagonists with a molecular size comparable to that of the endogenous neurotransmitter L-glutamate. PMID- 25913118 TI - Synthesis of Schiff base derivatives of 4-(2-aminoethyl)-benzenesulfonamide with inhibitory activity against carbonic anhydrase isoforms I, II, IX and XII. AB - Schiff base derivatives were obtained by reaction of 4-(2 aminoethyl)benzenesulfonamide with aromatic aldehydes. The corresponding secondary amine derivatives were also prepared by reduction of the imine compounds with NaBH4. These derivatives were investigated as inhibitors of four human carbonic anhydrase (CA, EC 4.2.1.1) isoforms, the cytosolic isozymes hCA I and II, as well as, the transmembrane, tumor-associated hCA IX and XII. Some of the newly synthesised compounds showed effective inhibitory activities against these CA isozymes. Many low nanomolar inhibitors were detected against all isoforms among the secondary amines whereas the Schiff bases were by far less active compared to the corresponding reduced derivatives among all investigated isoforms. PMID- 25913119 TI - Sandensone A, a novel sesquiterpenoid from the Formosan soft coral Sinularia sandensis. AB - A chromatographic and NMR spectroscopy-based fractionation on the acetone extracts of the soft coral Sinularia sandensis led to the isolation of a novel sesquiterpenoid, sandensone A (1). The structure of 1 was elucidated based on comprehensive 1D and 2D NMR spectroscopic data as well as HRESIMS spectrometry. The absolute configuration at C-12 of 1 was determined as R using a modified Mosher's method. The cytotoxicity against A549 (human lung carcinoma), HT-29 (human colon adenocarcinoma), and P-388 (mouse lymphocytic leukemia) cancer cell lines as well as antiviral activity against HCMV (human cytomegalovirus) were evaluated in vitro. PMID- 25913120 TI - Development and evaluation of a tampering resistant transdermal fentanyl patch. AB - With the increasing number of misuse and abuse of opioids, the resistance to tampering becomes an important attribute for transdermal opioid patches. In this study, drug-containing geopolymer granules were integrated into an adhesive matrix to improve the resistance of fast drug release against some common abuse techniques. Bench testing showed that fentanyl loaded geopolymer granules had better resistance to tampering compared to a commercial fentanyl patch. Moreover, in a pilot in vivo study on a few rats, the granules showed potential to give similar drug plasma concentrations as the commercial fentanyl patch. After integrating geopolymer granules into an adhesive matrix, the new patch showed a better resistance against the investigated tampering tests compared with the commercially available patch. In this study, we showed that incorporating drug loaded geopolymer granules into a patch adhesive has potential to improve the resistance of the fentanyl patch against tampering without compromising the drug release. PMID- 25913121 TI - [Neurenteric cysts; an uncommon cause of intestinal bleeding]. PMID- 25913122 TI - [The introduction of gluten into the infant diet. Expert group recommendations]. AB - At present there is a degree of uncertainty regarding when, how and in what form gluten should be introduced into the infant diet. For years the recommendations of the ESPGHAN Committee on Nutrition have prevailed, which include avoiding early introduction, before 4 months, and late, after 7 months, and gradually introducing gluten into the diet while the infant is being breastfed, with the aim of reducing the risk of celiac disease, diabetes and gluten allergy. However, 2 independent studies published in The New England Journal of Medicine in October 2014 reached the conclusion that the age of introduction of gluten does not modify the risk of developing celiac disease, and that breastfeeding at any age does not confer protection against celiac disease development. On the other hand, according to available scientific evidence, the introduction of foods other than breast milk or formula into the infants diet is generally recommended around 6 months of age, since the introduction before 4 months could be associated with an increased risk of food allergy and autoimmune diseases, and delaying it beyond 7 months would not have a protective effect. In this context, a group of experts has considered it appropriate to produce a consensus document based on the current scientific evidence and present general recommendations for daily clinical practice on the introduction of gluten into the diet. PMID- 25913123 TI - Fructose induces mitochondrial dysfunction and triggers apoptosis in skeletal muscle cells by provoking oxidative stress. AB - Mitochondrial dysfunction in skeletal muscle has been implicated in the development of insulin resistance, a major characteristic of type 2 diabetes. There is evidence that oxidative stress results from the increased production of reactive oxygen species and reactive nitrogen species leads to mitochondrial dysfunction, tissue damage, insulin resistance, and other complications observed in type 2 diabetes. It has been suggested that intake of high fructose contributes to insulin resistance and other metabolic disturbances. However, there is limited information about the direct effect of fructose on the mitochondrial function of skeletal muscle, the major metabolic determinant of whole body insulin activity. Here, we assessed the effect of fructose exposure on mitochondria-mediated mechanisms in skeletal muscle cells. Exposure of L6 myotubes to high fructose stimulated the production of mitochondrial reactive oxygen species and nitric oxide (NO), and the expression of inducible NO synthase. Fructose-induced oxidative stress was associated with increased translocation of nuclear factor erythroid 2-related factor-2 to the nucleus, decreases in mitochondrial DNA content and mitochondrial dysfunctions, as evidenced by decreased activities of citrate synthase and mitochondrial dehydrogenases, loss of mitochondrial membrane potential, decreased activity of the mitochondrial respiratory complexes, and impaired mitochondrial energy metabolism. Furthermore, positive Annexin-propidium iodide staining and altered expression of Bcl-2 family members and caspases in L6 myotubes indicated that the cells progressively became apoptotic upon fructose exposure. Taken together, these findings suggest that exposure of skeletal muscle cells to fructose induced oxidative stress that decreased mitochondrial DNA content and triggered mitochondrial dysfunction, which caused apoptosis. PMID- 25913124 TI - Antifungal Treatment in Stem Cell Transplantation Centers in Turkey. AB - Despite the development of various guidelines, the approach to antifungal treatment in stem cell transplantation centers differs according to country or even between centers. This led to the development of another survey that aims to understand the antifungal treatment policies of Turkish stem cell transplantation centers. Although there has been an increasing trend towards the use of diagnostic-based treatments in Turkey in the last few years, empirical treatment is still the main approach. The practices of the stem cell transplantation centers reflect the general trends and controversies in this area, while there is a considerable use of antifungal combination therapy. PMID- 25913125 TI - Three-dimensional sp(2)-hybridized carbons consisting of orthogonal nanoribbons of graphene and net C. AB - We identify two sp(2) hybridized network models of carbon, namely GT-8 and CT-12, based on first-principles calculation results. Parallel nanoribbon rows of graphene and net C are found to be interlinked with orthogonal nanoribbons to construct GT-8 and CT-12, and their series of isomorphic analogs (named GTs and CTs) are assembled with the widening of the nanoribbon components. GTs and CTs are dynamically and mechanically stable and energetically more favorable than many previous sp(2) carbons, including K4, C20, and H6 carbon. They are two dimensional conductors with insulating properties along the z-axis. Remarkably, GTs are superconductive with increased superconducting transition temperatures, Tc, as the nanoribbons widen. The Tcs of GT-8 and GT-16 are 5.2 and 14.0 K respectively, which are higher than that of boron-doped diamond under the same value of Coulomb pseudopotential MU*. They possess higher bulk moduli than graphite and behave as excellent ductile materials. The Young's modulus of GT-8 along the z-axis is comparable with that of graphene and it significantly increases as the nanoribbons widen. PMID- 25913126 TI - Genomic ancestry and ethnoracial self-classification based on 5,871 community dwelling Brazilians (The Epigen Initiative). AB - Brazil never had segregation laws defining membership of an ethnoracial group. Thus, the composition of the Brazilian population is mixed, and its ethnoracial classification is complex. Previous studies showed conflicting results on the correlation between genome ancestry and ethnoracial classification in Brazilians. We used 370,539 Single Nucleotide Polymorphisms to quantify this correlation in 5,851 community-dwelling individuals in the South (Pelotas), Southeast (Bambui) and Northeast (Salvador) Brazil. European ancestry was predominant in Pelotas and Bambui (median = 85.3% and 83.8%, respectively). African ancestry was highest in Salvador (median = 50.5%). The strength of the association between the phenotype and median proportion of African ancestry varied largely across populations, with pseudo R(2) values of 0.50 in Pelotas, 0.22 in Bambui and 0.13 in Salvador. The continuous proportion of African genomic ancestry showed a significant S-shape positive association with self-reported Blacks in the three sites, and the reverse trend was found for self reported Whites, with most consistent classifications in the extremes of the high and low proportion of African ancestry. In self-classified Mixed individuals, the predicted probability of having African ancestry was bell-shaped. Our results support the view that ethnoracial self-classification is affected by both genome ancestry and non biological factors. PMID- 25913127 TI - Hypnotizability and Performance on a Prism Adaptation Test. AB - The susceptibility to hypnosis, which can be measured by scales, is not merely a cognitive trait. In fact, it is associated with a number of physiological correlates in the ordinary state of consciousness and in the absence of suggestions. The hypnotizability-related differences observed in sensorimotor integration suggested a major role of the cerebellum in the peculiar performance of healthy subjects with high scores of hypnotic susceptibility (highs). In order to provide behavioral evidence of this hypothesis, we submitted 20 highs and 21 low hypnotizable participants (lows) to the classical cerebellar Prism Adaptation Test (PAT). We found that the highs' performance was significantly less accurate and more variable than the lows' one, even though the two groups shared the same characteristics of adaptation to prismatic lenses. Although further studies are required to interpret these findings, they could account for earlier reports of hypnotizability-related differences in postural control and blink rate, as they indicate that hypnotizability influences the cerebellar control of sensorimotor integration. PMID- 25913128 TI - The distribution of fitness effects in an uncertain world. AB - The distribution of fitness effects (DFE) among new mutations plays a critical role in adaptive evolution and the maintenance of genetic variation. Although fitness landscape models predict several key features of the DFE, most theory to date focuses on predictable environmental conditions, while ignoring stochastic environmental fluctuations that feature prominently in the ecology of many organisms. Here, we derive an extension of Fisher's geometric model that incorporates two common effects of environmental variation: (1) nonadaptive genotype-by-environment interactions (G * E), in which the phenotype of a given genotype varies across environmental contexts; and (2) random fluctuation of the fitness optimum, which generates fluctuating selection. We show that both factors cause a mismatch between the DFE within single generations and the distribution of geometric mean fitness effects (averaged over multiple generations) that governs long-term evolutionary change. Such mismatches permit strong evolutionary constraints-despite an abundance of beneficial fitness variation within single environmental contexts-and to conflicting DFE estimates from direct versus indirect inference methods. Finally, our results suggest an intriguing parallel between the genetics and ecology of evolutionary constraints, with environmental fluctuations and pleiotropy placing qualitatively similar limits on the availability of adaptive genetic variation. PMID- 25913129 TI - Metformin and endometrial cancer risk in Chinese women with type 2 diabetes mellitus in Taiwan. AB - OBJECTIVE: To evaluate metformin effects on endometrial cancer risk in Chinese female patients with type 2 diabetes mellitus (T2DM) in Taiwan. METHODS: This is a retrospective cohort analysis using the National Health Insurance database of Taiwan. Female patients with newly diagnosed T2DM and without endometrial cancer in 1998-2002 were followed to end of 2009 (n=478,921). Among them, 285,916 were never-users and 193,005 were ever-users of metformin. A time-dependent approach was used to calculate endometrial cancer incidence and estimate hazard ratios by Cox regression for ever-users, never-users, and subgroups of metformin exposure (tertiles of cumulative duration and cumulative dose). Sensitivity analyses were conducted in various subgroups. RESULTS: During follow-up, 728 metformin ever users and 2157 never-users developed endometrial cancer, representing an incidence of 60.00 and 121.69 per 100,000 person-years, respectively. The overall hazard ratio (95% confidence intervals) for ever- versus never-users after adjustment for propensity score (PS) was 0.675 (0.614-0.742). The PS-adjusted hazard ratios for the first, second, and third tertiles of cumulative duration of metformin therapy were 1.089 (0.966-1.228), 0.707 (0.616-0.812) and 0.313 (0.262 0.374), respectively (P-trend<0.0001); and 1.062 (0.942-1.197), 0.620 (0.538 0.715) and 0.376 (0.317-0.447), respectively (P-trend<0.0001), for cumulative dose of metformin. The dose-response relationship was demonstrated in various models and an overall reduced risk was consistently supported by sensitivity analyses. CONCLUSIONS: The use of metformin in women with T2DM was associated with an overall significantly lower risk of endometrial cancer with dose-response relationship. PMID- 25913130 TI - Development of a prediction model for residual disease in newly diagnosed advanced ovarian cancer. AB - OBJECTIVES: To construct a tool, using computed tomography (CT) imaging and preoperative clinical variables, to estimate successful primary cytoreduction for advanced epithelial ovarian cancer (EOC). METHODS: Women who underwent primary cytoreductive surgery for stage IIIC/IV EOC at Mayo Clinic between 1/2/2003 and 12/30/2011 and had preoperative CT images of the abdomen and pelvis within 90days prior to their surgery available for review were included. CT images were reviewed for large-volume ascites, diffuse peritoneal thickening (DPT), omental cake, lymphadenopathy (LP), and spleen or liver involvement. Preoperative factors included age, body mass index (BMI), Eastern Cooperative Oncology Group performance status (ECOG PS), American Society of Anesthesiologists (ASA) score, albumin, CA-125, and thrombocytosis. Two prediction models were developed to estimate the probability of (i) complete and (ii) suboptimal cytoreduction (residual disease (RD) >1cm) using multivariable logistic analysis with backward and stepwise variable selection methods. Internal validation was assessed using bootstrap resampling to derive an optimism-corrected estimate of the c-index. RESULTS: 279 patients met inclusion criteria: 143 had complete cytoreduction, 26 had suboptimal cytoreduction (RD>1cm), and 110 had measurable RD <=1cm. On multivariable analysis, age, absence of ascites, omental cake, and DPT on CT imaging independently predicted complete cytoreduction (c-index=0.748). Conversely, predictors of suboptimal cytoreduction were ECOG PS, DPT, and LP on preoperative CT imaging (c-index=0.685). CONCLUSIONS: The generated models serve as preoperative evaluation tools that may improve counseling and selection for primary surgery, but need to be externally validated. PMID- 25913131 TI - PI3K/mTOR pathway inhibition overcomes radioresistance via suppression of the HIF1-alpha/VEGF pathway in endometrial cancer. AB - Radiation therapy is a key therapeutic strategy for endometrial carcinomas. However, biomarkers that predict radiosensitivity and drugs to enhance this sensitivity have not yet been established. We aimed to investigate the roles of TP53 and MAPK/PI3K pathways in endometrial carcinomas and to identify appropriate radiosensitizing therapeutics. D10 values (the irradiating dose required to reduce a cell population by 90%) were determined in eight endometrial cancer cell lines with known mutational statuses for TP53, PIK3CA, and KRAS. Cells were exposed to ionizing radiation (2-6Gy) and either a dual PI3K/mTOR inhibitor (NVP BEZ235) or a MEK inhibitor (UO126), and their radiosensitizing effects were evaluated using clonogenic assays. The effects of silencing hypoxia-inducible factor-1 alpha (HIF-1alpha) expression with small interfering RNAs (siRNAs) were evaluated following exposure to ionizing radiation (2-3Gy). D10 values ranged from 2.0 to 3.1Gy in three cell lines expressing wild-type TP53 or from 3.3 to more than 6.0Gy in five cell lines expressing mutant TP53. NVP-BEZ235, but not UO126, significantly improved radiosensitivity through the suppression of HIF 1alpha/vascular endothelial growth factor-A expression. HIF-1alpha silencing significantly increased the induction of the sub-G1 population by ionizing radiation. Our study data suggest that TP53 mutation and PI3K pathway activation enhances radioresistance in endometrial carcinomas and that targeting the PI3K/mTOR or HIF-1alpha pathways could improve radiosensitivity. PMID- 25913132 TI - Socioeconomic status as a predictor of adherence to treatment guidelines for early-stage ovarian cancer. AB - OBJECTIVE: Investigate the impact of socioeconomic status and other demographic variables on adherence to the National Comprehensive Cancer Network ovarian cancer treatment guidelines among patients with stage I/II disease. METHODS: Patients diagnosed with stage I/II epithelial ovarian cancer between 1/1/96 12/31/06 were identified from the California Cancer Registry. Univariate analysis and multivariate logistic regression models were used to evaluate differences in surgical procedures, chemotherapy regimens, and overall adherence to the NCCN guidelines according to increasing SES quintiles (SES-1 to SES-5). RESULTS: A total of 5445 stage I and II patients were identified. The median age at diagnosis was 54.0years (range=18-99years); 72.5% of patients had stage I disease, while 27.5% had stage II disease. With a median follow-up time of 5years, the 5-year ovarian cancer-specific survival for all patients was 82.7% (SE=0.6%). Overall, 23.7% of patients received care that was adherent to the NCCN guidelines. Compared to patients in the highest SES quintile (SES-5), patients in the lowest SES quintile (SES-1) were significantly less likely to receive proper surgery (27.3% vs 47.9%, p<0.001) or chemotherapy (42.4% vs 53.6%, p<0.001). There were statistically significant trends between increasing SES and the likelihood of overall treatment plan adherence to the NCCN guidelines: SES 1=16.4%, SES-2=19.0%, SES-3=22.4%, SES-4=24.2% and SES-5=31.6% (p<0.001). Multivariate logistic regression analysis revealed that compared to SES-5, decreasing SES was independently predictive of a higher risk of non-standard overall care. CONCLUSIONS: For patients with early-stage ovarian cancer, low SES is a significant and independent predictor of deviation from the NCCN guidelines for surgery, chemotherapy, and overall treatment. PMID- 25913133 TI - Formation of stable small cell number three-dimensional ovarian cancer spheroids using hanging drop arrays for preclinical drug sensitivity assays. AB - BACKGROUND: Ovarian cancer grows and metastasizes from multicellular spheroidal aggregates within the ascites fluid. Multicellular tumor spheroids are therefore physiologically significant 3D in vitro models for ovarian cancer research. Conventional hanging drop cultures require high starting cell numbers, and are tedious for long-term maintenance. In this study, we generate stable, uniform multicellular spheroids using very small number of ovarian cancer cells in a novel 384 well hanging drop array platform. METHODS: We used novel tumor spheroid platform and two ovarian cancer cell lines (A2780 and OVCAR3) to demonstrate the stable incorporation of as few as 10 cells into a single spheroid. RESULTS: Spheroids had uniform geometry, with projected areas (42.60*10(3)MUm 475.22*10(3)MUm(2) for A2780 spheroids and 37.24*10(3)MUm(2)-281.01*10(3)MUm(2) for OVCAR3 spheroids) that varied as a function of the initial cell seeding density. Phalloidin and nuclear stains indicated cells formed tightly packed spheroids with demarcated boundaries and cell-cell interaction within spheroids. Cells within spheroids demonstrated over 85% viability. 3D tumor spheroids demonstrated greater resistance (70-80% viability) to cisplatin chemotherapy compared to 2D cultures (30-50% viability). CONCLUSIONS: Ovarian cancer spheroids can be generated from limited cell numbers in high throughput 384 well plates with high viability. Spheroids demonstrate therapeutic resistance relative to cells in traditional 2D culture. Stable incorporation of low cell numbers is advantageous when translating this research to rare patient-derived cells. This system can be used to understand ovarian cancer spheroid biology, as well as carry out preclinical drug sensitivity assays. PMID- 25913134 TI - Pretreatment serum CYFRA 21-1 level correlates significantly with survival of cervical cancer patients: a multivariate analysis of 506 cases. AB - OBJECTIVE: To determine whether pretreatment CYFRA 21-1 levels can be a useful prognostic indicator in cervical cancer with reference to squamous cell carcinoma antigen (SCC-Ag). METHODS: We retrospectively analyzed data on 506 consecutive cervical cancer patients who were treated by radical hysterectomy or primary concurrent chemoradiation therapy. The pretreatment serum SCC-Ag and serum CYFRA 21-1 levels were measured in these patients. A multivariate analysis using Cox's proportional hazard model was performed to evaluate the prognostic significance of pretreatment variables. RESULTS: In patients who underwent radical hysterectomy, there was a significant correlation between pretreatment serum SCC Ag/CYFRA 21-1 levels and patient age, advanced FIGO stage, large tumor size, lymph node metastasis, and deep stromal invasion. In the stepwise Cox regression analysis, large tumor size >4cm was an independent prognostic factor for disease free survival (OR, 3.110; [95% CI, 1.588-6.093], P=0.001) and overall survival (OR, 8.497; [95% CI, 1.797-40.184], P=0.007) in patients with squamous cell carcinoma, while pretreatment CYFRA 21-1 (P=0.010) serum levels had a significant independent effect on overall survival. Likewise, pretreatment CYFRA 21-1 (P<0.001 and P=0.006) serum levels were the only independent prognostic factor for disease-free survival and overall survival in patients with non-squamous cell carcinoma. CONCLUSION: Pretreatment CYFRA 21-1 levels may be considered as a useful prognostic indicator in cervical cancer with reference to SCC-Ag. PMID- 25913135 TI - Microwave-assisted hydrothermal synthesis and characterization of ZnO nanorods. AB - For the purpose of this study, the nanorods of zinc oxide were synthesized by rapid microwave-assisted hydrothermal route. The microstructure and surface morphology of the sensitized nanorods were characterized by X-ray diffraction (XRD), field emission scanning electron microscope (FE-SEM) and transmission electron microscope (TEM). XRD results indicate that synthesized ZnO nanorods have wurtzite phase. The calculated value of the particle size using Debye Scherrer formula and Williamson Hall plot was found to be 20-28 nm and 35.3 nm, respectively. Low uniformity distribution of rod-like morphology (60-80 nm in diameter and average length about 250 nm) are seen in TEM micrographs. The optical parameters of the prepared ZnO nanorods have been calculated using Kubeleka-Munk approach for the UV-vis diffuse reflectance spectrum. It is found that the direct transition optical band gap of the studied sample is 3.17 eV. The direct current electrical conductivity (sigma) was increased from 6.7*10(-8) to 3*10(-7) Omega(-1) cm(-1) with increasing the temperature (T) in the range (300 425 K). The obtained variation of sigma with T refers that the conductivity mechanism is controlled by thermally activated process. PMID- 25913136 TI - Vibrational spectroscopy and density functional theory study of 4-mercaptobenzoic acid. AB - In this paper, 4-mercaptobenzoic acid (4-MBA/pMBA) was designed as a model molecule for theoretical and experimental studies of the molecule structure. Density functional theory (DFT) calculations have been performed to predict the IR and Raman spectra for the molecule. In addition, Fourier transform infrared (FTIR) and Raman spectra of the compound have been obtained experimentally. Based on the modeling results obtained at the B3LYP/6-311++G(**) level, all FTIR and Raman bands of the compound obtained experimentally were assigned. Our calculated vibrational frequencies are in good agreement with the experimental vales. The molecular electrostatic potential surface calculation was performed and the result suggested that the 4-MBA had two hydrogen bond donors and three hydrogen bond acceptors. HOMO-LUMO gap was also obtained theoretically at B3LYP/6 311++G(**) level. PMID- 25913137 TI - Spectroscopic and density functional theory studies of 7-hydroxy-3' methoxyisoflavone: A new isoflavone from the seeds of Indigofera heterantha (Wall). AB - A new isoflavone 7-hydroxy 3'-methoxyisoflavone (1) is isolated from the seeds of Indigofera heterantha. The structure of this new compound was established using spectroscopic techniques such as ID, 2D NMR, and mass spectrometry. Density functional theory calculations are carried out for the first time for geometric, electronic and spectroscopic properties of 1 (isoflavone). DFT calculations have been performed at B3LYP/6-311G(d,p) level of theory for obtaining geometric and spectroscopic properties of compound 1. The simulated vibrational spectrum of compound 1 at B3LYP/6-311G(d,p) shows nice correlation with the experimental IR spectrum after a scaling factor of 0.973. (1)H and (13)C NMR chemical shifts were calculated using Cramer's re-parameterized function WP04 at 6-311G(d,p) basis set, and show nice correlation with the experimental data. Four conformers were considered for NMR chemical shift calculations. Electronic properties such as band gap, Ionization potential and electron affinities were also simulated for the first time; however, no comparison could be made with the experiment. PMID- 25913138 TI - Humoral autoimmunity: a failure of regulatory T cells? AB - Regulatory T cells (Tregs) are essential in maintaining tolerance to self. Several lines of evidence indicate that Tregs are functionally impaired in a variety of autoimmune diseases, leading to inefficient regulation of autoimmune T cells. Recent findings also suggest that Tregs are essential in controlling autoreactive B cells. The recently identified follicular regulatory T cell subset (TFR) is thought to regulate the production of autoantibodies in the germinal center (GC) response. Here we provide an update on the role of Tregs in controlling the GC response, and whether defective control over B cell tolerance contributes to autoimmunity. PMID- 25913139 TI - Revisiting the role of mast cells in autoimmunity. AB - Beside their well known role in allergy, mast cells (MCs) are capable to sense multiple signals and have therefore the potential to be involved in many immune responses. MCs are actively present in the target tissues of some autoimmune disorders, suggesting a possible function in the manifestation of such diseases. This idea is strengthened by the evidence that KIT-dependent MC-deficient mice are protected from disease in many mouse models of autoimmunity, including multiple sclerosis, rheumatoid arthritis and autoimmune skin blistering diseases. Thus, the essential role of MCs in autoimmunity not only significantly extends the knowledge of MCs in the immune response but also provides novel therapeutic targets for the treatment of such diseases. However, recent studies using a new generation of KIT-independent MC-deficient strains could not confirm an essential participation of MCs in autoimmune diseases. Therefore, it is necessary to clarify the observed discrepancies and to elucidate the role of MCs in autoimmune diseases. Here, we review the impact of MCs on the development of autoimmune diseases with focus on the controversial effects of MC deficiency in different mouse models of autoimmune diseases. We also try to clarify contradictory findings in mouse studies to finally elucidate the role of MCs in autoimmunity. PMID- 25913140 TI - Evaluation of the efficacy of potassium nitrate and sodium fluoride as desensitizing agents during tooth bleaching treatment-A systematic review and meta-analysis. AB - OBJECTIVES: This meta-analysis was performed to evaluate the efficacy of potassium nitrate and sodium fluoride as desensitizing agents during tooth bleaching treatment. DATA, SOURCES AND STUDY SELECTION: An electronic systematic literature search was conducted in Cochrane Center Register of Controlled Trials, MEDLINE (PubMed) and EmBase in April, 2014 in English and without time restrictions. Study information extraction and methodological quality assessments were accomplished by two reviewers independently. Methodological quality was assessed by using the "Criteria for judging risk of bias in the 'Risk of bias' assessment tool". Dichotomous data was summarized by odds ratio (OR) with 95% confidence interval (CI) and continuous data was summarized by mean difference (MD) or standardised mean difference (SMD) with 95% confidence interval (CI). Statistical analyses were carried out by using Review Manager 5.2. For evaluation of percent of patients experiencing tooth sensitivity (POTS), the pooled OR of desensitizers vs. placebo was 0.45 (95% CI: 0.28-0.73, P=0.29). The pooled SMD of desensitizers vs. placebo was -0.47 (95% CI: -0.77 to -0.18, P=0.13) in evaluation of level of tooth sensitivity (LOTS). The results of shade evaluation remained inconsistent by evaluating subjective shade guide unit difference (DeltaSGU or SGU) and objective colour difference (DeltaE). CONCLUSIONS: This meta-analysis was performed to evaluate the efficacy of desensitizing agents, potassium nitrate and sodium fluoride, for tooth bleaching treatments. Potassium nitrate and sodium fluoride reduce tooth sensitivity while no consistent conclusion of tooth colour change was found. CLINICAL SIGNIFICANCE: Tooth sensitivity is a typical side effect associated with tooth bleaching procedures. Potassium nitrate and sodium fluoride are used widely to treat tooth sensitivity. This meta-analysis was performed to evaluate the efficacy of potassium nitrate and sodium fluoride as desensitizing agents during tooth bleaching treatment. PMID- 25913141 TI - Clinical survival of indirect, anterior 3-unit surface-retained fibre-reinforced composite fixed dental prosthesis: Up to 7.5-years follow-up. AB - OBJECTIVES: This prospective clinical study evaluated the performance of indirect, anterior, surface-retained, fibre-reinforced-composite restorations (ISFRCR). METHODS: Between June-2003 and January-2011, a total of 134 patients (83 females, 51 males, 16-68 years old) received 175 ISFRCRs (local ethical registration number: 14/9/4). All restorations were made indirectly on a plaster model using unidirectional E-glass fibres (everStick C&B, StickTech) in combination with a laboratory resin composite (Dialogue, Schutz Dental) and cemented according to the instructions of 4 resin cements [(RelyX ARC, 3M-ESPE, n=61), Bifix DC, VOCO, n=45), Variolink II (Ivoclar Vivadent, n=32) and Multilink (Ivoclar Vivadent, n=37)]. After baseline recordings, patients were followed at 6 months and thereafter annually up to 7.5 years. The evaluation protocol involved technical (chipping, debonding or fracture of tooth/restoration) and biological failures (caries). RESULTS: Mean observation period was 58 months. Altogether, 13 failures were observed [survival rate: 97.7%] (Kaplan-Meier). One catastrophic fracture [(cement: RelyX ARC), eight partial debonding (cement: Bifix DC (5), Multilink (1), RelyX ARC (1), Variolink II (1)] and four delaminations of veneering composite [(cement: Bifix DC (2), RelyX ARC (1), Multilink (1)] were observed. Except one replacement, all defective restorations were repaired or recemented. Annual failure rate of ISFRCRs was 1.73%. The survival rates with the four resin cements did not show significant differences (RelyX ARC: 98.3%; Bifix DC: 93.5%; Variolink 2: 100%; Multilink: 100%) (p=0.114). Secondary caries did not occur in any of the teeth. CONCLUSION: The 3-unit anterior indirect surface retained resin-bonded FRC FDPs showed similar clinical survival rate when cemented with the resin cements tested. Experienced failures in general were due to debonding of the restoration or delamination of the veneering composite. CLINICAL SIGNIFICANCE: 3-unit surface retained resin-bonded FRC FDPs could be considered minimal invasive and cost-effective alternatives to conventional tooth or implant-borne FDPs. Failures were mainly repairable in the form of chipping or debonding depending on the resin cement type. PMID- 25913142 TI - Effect of sterilization techniques prior to antimicrobial testing on physical properties of dental restorative materials. AB - OBJECTIVES: The aim of this study was to investigate any changes to the microstructure and surface properties of selected dental materials after sterilization carried out prior to subjecting them to antimicrobial testing. Initial microbial contamination on the material, as well as other possible sources of contamination were also assessed. METHODS: The materials investigated included dentine replacement materials Chemfil Superior((r)), Ionoseal((r)), Dyract Extra((r)) and SDR((r)). The materials were characterized by scanning electron microscopy (SEM) and energy dispersive spectroscopy (EDS). The test materials were sterilized using alcohol, steam, ultraviolet light (UV) and ethylene oxide and any changes to these materials were then assessed by SEM, microhardness testing and Fourier transform infrared (FT-IR) spectroscopy. Material microbial levels before treatments were assessed by plate counting technique and turbidity tests. Possible contamination through dispensers was assessed by analysing the CFU/sample. RESULTS: Ethylene oxide affected the microstructure of the Chemfil, Ionoseal and Dyract, resulting in flattening of the SiO stretching vibrations and deposition of chlorine and calcium respectively in Chemfil and Dyract. Varied contamination was demonstrated on all materials when incubated in anaerobic conditions. CONCLUSIONS: The different sterilization techniques affected the microstructure of the materials under investigation. Samples of materials produced in sterile conditions could also be contaminated with bacteria, either from the material itself or through the dispensing apparatus. CLINICAL SIGNIFICANCE: Results of antimicrobial studies cannot be extrapolated clinically as the material sterilization treatment results in changes to material chemistry and microstructure, which could in turn affect the materials' antimicrobial activity. PMID- 25913143 TI - Arabidopsis C3HC4-RING finger E3 ubiquitin ligase AtAIRP4 positively regulates stress-responsive abscisic acid signaling. AB - Degradation of proteins via the ubiquitin system is an important step in many stress signaling pathways in plants. E3 ligases recognize ligand proteins and dictate the high specificity of protein degradation, and thus, play a pivotal role in ubiquitination. Here, we identified a gene, named Arabidopsis thaliana abscisic acid (ABA)-insensitive RING protein 4 (AtAIRP4), which is induced by ABA and other stress treatments. AtAIRP4 encodes a cellular protein with a C3HC4-RING finger domain in its C-terminal side, which has in vitro E3 ligase activity. Loss of AtAIRP4 leads to a decrease in sensitivity of root elongation and stomatal closure to ABA, whereas overexpression of this gene in the T-DNA insertion mutant atairp4 effectively recovered the ABA-associated phenotypes. AtAIRP4 overexpression plants were hypersensitive to salt and osmotic stresses during seed germination, and showed drought avoidance compared with the wild-type and atairp4 mutant plants. In addition, the expression levels of ABA- and drought induced marker genes in AtAIRP4 overexpression plants were markedly higher than those in the wild-type and atairp4 mutant plants. Hence, these results indicate that AtAIRP4 may act as a positive regulator of ABA-mediated drought avoidance and a negative regulator of salt tolerance in Arabidopsis. PMID- 25913144 TI - Intrabolus pressure on high-resolution manometry distinguishes fibrostenotic and inflammatory phenotypes of eosinophilic esophagitis. AB - The aim of this investigation was to determine the motility patterns of inflammatory and fibrostenotic phenotypes of eosinophilic esophagitis (EoE) utilizing high-resolution manometry (HRM). Twenty-nine patients with a confirmed diagnosis of EoE according to clinicopathological criteria currently being managed at the Joy McCann Culverhouse Swallowing Center at the University of South Florida were included in the retrospective analysis. Only patients who completed HRM studies were included in the analysis. Patients were classified into inflammatory or fibrostenotic subtypes based on baseline endoscopic evidence. Their baseline HRM studies prior to therapy were analyzed. Manometric data including distal contractile integral, integrated relaxation pressure, and intrabolus pressure (IBP) values were recorded. HRM results were interpreted according to the Chicago Classification system. Statistical analysis was performed with SPSS software (Version 22, IBM Co., Armonk, NY, USA). Data were compared utilizing Student's t-test, chi(2) test, Pearson correlation, and Spearman correlation tests. Statistical significance was set at P < 0.05. A total of 29 patients with EoE were included into the retrospective analysis. The overall average age among patients was 40 years. Male patients comprised 62% of the overall population. Both groups were similar in age, gender, and overall clinical presentation. Seventeen patients (58%) had fibrostenotic disease, and 12 (42%) displayed inflammatory disease. The average IBP for the fibrostenotic and inflammatory groups were 18.6 +/- 6.0 mmHg and 12.6 +/- 3.5 mmHg, respectively (P < 0.05). Strictures were only seen in the fibrostenotic group. Of the fibrostenotic group, 6 (35%) demonstrated proximal esophageal strictures, 7 (41%) had distal strictures, 3 (18%) had mid-esophageal strictures, and 1 (6%) patient had pan-esophageal strictures. There was no statistically significant correlation between the level of esophageal stricture and degree of IBP. Integrated relaxation pressure, distal contractile integral, and other HRM metrics did not demonstrate statistical significance between the two subtypes. There also appeared no statistically significant correlation between patient demographics and esophageal metrics. Patients with the fibrostenotic phenotype of EoE demonstrated an IBP that was significantly higher than that of the inflammatory group. PMID- 25913145 TI - Efficacy of Mechanical versus Non-Mechanical Sterile Preoperative Skin Preparation With Chlorhexidine Gluconate 4% Solution. AB - OBJECTIVE: To compare the efficacy of sterile preoperative skin antisepsis using either a 5-minute mechanical preparation or 5-minute non-mechanical preparation with chlorhexidine gluconate 4% solution. STUDY DESIGN: Matched design, ANOVA. ANIMALS: Healthy adult Thoroughbred horses (n = 30). METHODS: Each horse had both surgical preparation methods randomly assigned to identical sites on the left or right upper thigh. Prepared sites were sampled and cultured for bacteria after each preparation step. RESULTS: Mechanical and non-mechanical preparation techniques significantly reduced bacteria isolated from surface swab samples compared with samples taken from unprepared skin and after the preliminary rough prepared skin (P < 0.05). No difference in the number of skin-associated bacteria was detected between the mechanical and non-mechanical sterile preoperative preparation techniques (P = 0.77). Ten species of bacteria were identified by 16s PCR after final skin preparation. CONCLUSIONS: Pre-surgical skin preparation without repeated mechanical scrubbing using chlorhexidine gluconate 4% solution (total contact time, 225 seconds) is effective in reducing bacterial counts. PMID- 25913146 TI - Pharmaceuticals and personal care products alter the holobiome and development of a medically important mosquito. AB - The increasing demand for fresh water has forced many countries to use reclaimed wastewater for agricultural purposes. This water contains pharmaceuticals and personal care products (PPCPs) that remain biologically active following passage through wastewater treatment plants. Run-off from farms and contaminated water from treatment facilities exposes aquatic ecosystems to PPCPs. This study examined the effects of PPCPs on a lower trophic organism. Culex quinquefasciatus larvae were reared in water contaminated with environmentally relevant concentrations of common PPCPs. Acetaminophen alone and a mixture of contaminants were found to increase developmental time of larvae. Susceptibility to Bti increased in larvae exposed to antibiotics, acetaminophen, or a mixture of PPCPs. Antibiotics, hormones, and the mixture altered the mosquito bacterial microbiome. Overall, the results indicate that at environmentally relevant concentrations, PPCPs in reclaimed water can have biologically important effects on an ecologically and medically important lower trophic level insect. PMID- 25913147 TI - Recurrent sigmoid volvulus in pregnancy. PMID- 25913148 TI - Relationships between sleep apnea, cardiovascular disease risk factors, and aortic pulse wave velocity over 18 years: the Wisconsin Sleep Cohort. AB - PURPOSE: The purpose of this study is to determine if apnea-hypopnea index (AHI) severity predicts future aortic pulse wave velocity (PWV) in the Wisconsin Sleep Cohort. METHODS: Applanation tonometry was used to derive carotid-to-femoral PWV a mean of 18 years (standard deviation 4) after overnight polysomnography. Multivariable regression models were created to describe prospective associations between baseline AHI and future PWV. RESULTS: The 618 adults were mean 65 (7) years old (55 % male) with a mean body mass index of 31 (7) kg/m(2) at the tonometry visit. Mean baseline AHI was 4.6 (9.7) events/h. In multiple linear regression models adjusted for age (beta = 0.13/year, standard error [SE] = 0.01, p < 0.001) and sex, higher log10AHI (beta = 0.43/events/h, SE = 0.18, p = 0.02) was associated with PWV. After adjustment for waist circumference (beta = 0.01/cm, SE = 0.01, p = 0.05) and height, the association between baseline log10AHI and future PWV was not statistically significant (p = 0.11), although the association with age persisted unchanged. Addition of covariates such as smoking status (current smoker beta = 0.66, SE = 0.22, p = 0.002), diabetes mellitus status (beta = 2.89, SE = 0.59, p < 0.001), and systolic blood pressure (BP, beta = 0.03/mmHg, SE = 0.01, p < 0.001) did not change the association. AHI did not interact with age or smoking status to predict PWV. A secondary analysis of nocturnal oxygen saturation parameters in 517 participants, 9 (2) years prior also did not show any significant relationships with future PWV. CONCLUSIONS: The prospective association between AHI and PWV is confounded by body size and influenced by smoking, diabetes mellitus, and BP. Weight management, BP control, and smoking cessation may help prevent arterial stiffening associated with obstructive sleep apnea. PMID- 25913149 TI - Prepared Food Availability in U.S. Food Stores: A National Study. AB - INTRODUCTION: Prepared, ready-to-eat foods comprise a significant part of Americans' diets and are increasingly obtained from food stores. Yet, little is known about the availability and healthfulness of prepared, ready-to-eat food offerings at stores. This study examines associations among community characteristics (racial/ethnic composition, poverty level, urbanicity) and availability of both healthier and less-healthy prepared foods in U.S. supermarkets, grocery stores, and convenience stores. METHODS: Observational data were collected from 4,361 stores in 317 communities spanning 42 states in 2011 and 2012. Prepared food availability was assessed via one healthier food (salads or salad bar), three less-healthy items (pizza, hot dog/hamburger, taco/burrito/taquito), and one cold sandwich item. In 2014, multivariable generalized linear models were used to test associations with community characteristics. RESULTS: Overall, 63.6% of stores sold prepared foods, with 20.0% offering prepared salads and 36.4% offering at least one less-healthy item. Rural stores were 26% less likely to carry prepared salads (prevalence ratio [PR]=0.74, 95% CI=0.62, 0.88) and 14% more likely to carry at least one less healthy prepared food item (PR=1.14, 95% CI=1.00, 1.30). Convenience stores in high-poverty communities were less likely to carry prepared salads than those in low-poverty communities (PR=0.64, 95% CI=0.47, 0.87). Among supermarkets, prepared salads were more likely to be carried in majority-white, low-poverty communities than in non-white, high-poverty communities. CONCLUSIONS: Increasing the healthfulness of prepared foods within stores may offer an important opportunity to improve the food environment. PMID- 25913150 TI - Decreased thyroid hormone signaling accelerates the reinnervation of the optic tectum following optic nerve crush in adult zebrafish. AB - The regenerative capacity of the adult mammalian central nervous system (CNS) is poor and finding ways to stimulate long distance axonal regeneration in humans remains a challenge for neuroscientists. Thyroid hormones, well known for their key function in CNS development and maturation, more recently also emerged as molecules influencing regeneration. While several studies investigated their influence on peripheral nerve regeneration, in vivo studies on their role in adult CNS regeneration remain scarce. We therefore investigated the effect of lowering T3 signaling on the regeneration of the optic nerve (ON) following crush in zebrafish, a species where full recovery occurs spontaneously. Adult zebrafish were exposed to iopanoic acid (IOP), which lowered intracellular 3,5,3' triiodothyronine (T3) availability, or to the thyroid hormone receptor beta antagonist methylsulfonylnitrobenzoate (C1). Both treatments accelerated optic tectum (OT) reinnervation. At 7days post injury (7dpi) there was a clear increase in the biocytin labeled area in the OT following anterograde tracing as well as an increased immunostaining of Gap43, a protein expressed in outgrowing axons. This effect was attenuated by T3 supplementation to IOP-treated fish. ON crush induced very limited cell death and proliferation at the level of the retina in control, IOP- and C1-treated fish. The treatments also had no effect on the mRNA upregulation of the regeneration markers gap43, tub1a, and socs3b at the level of the retina at 4 and 7dpi. We did, however, find a correlation between the accelerated OT reinnervation and a more rapid resolution of microglia/macrophages in the ON and the OT of IOP-treated fish. Taken together these data indicate that lowering T3 signaling accelerates OT reinnervation following ON crush in zebrafish and that this is accompanied by a more rapid resolution of the inflammatory response. PMID- 25913151 TI - Rapid transient isoform-specific neuregulin1 transcription in motor neurons is regulated by neurotrophic factors and axon-target interactions. AB - The neuregulins (NRGs) are a family of alternatively spliced factors that play important roles in nervous system development and disease. In motor neurons, NRG1 expression is regulated by activity and neurotrophic factors, however, little is known about what controls isoform-specific transcription. Here we show that NRG1 expression in the chick embryo increases in motor neurons that have extended their axons and that limb bud ablation before motor axon outgrowth prevents this induction, suggesting a trophic role from the developing limb. Consistently, NRG1 induction after limb bud ablation can be rescued by adding back the neurotrophic factors BDNF and GDNF. Mechanistically, BDNF induces a rapid and transient increase in type I and type III NRG1 mRNAs that peak at 4h in rat embryonic ventral spinal cord cultures. Blocking MAPK or PI3K signaling or blocking transcription with Actinomycin D blocks BDNF induced NRG1 gene induction. BDNF had no effect on mRNA degradation, suggesting that transcriptional activation rather than message stability is important. Furthermore, BDNF activates a reporter construct that includes 700bp upstream of the type I NRG1 start site. Protein synthesis is also required for type I NRG1 mRNA transcription as cycloheximide produced a super-induction of type I, but not type III NRG1 mRNA, possibly through a mechanism involving sustained activation of MAPK and PI3K. These results reveal the existence of highly responsive, transient transcriptional regulatory mechanisms that differentially modulate NRG1 isoform expression as a function of extracellular and intracellular signaling cascades and mediated by neurotrophic factors and axon-target interactions. PMID- 25913153 TI - Feasibility and informative value of environmental sample collection in the National Children's Vanguard Study. AB - BACKGROUND: Birth cohort studies provide the opportunity to advance understanding of the impact of environmental factors on childhood health and development through prospective collection of environmental samples. METHODS: We evaluated the feasibility and informative value of the environmental sample collection methodology in the initial pilot phase of the National Children's Study, a planned U.S. environmental birth cohort study. Environmental samples were collected from January 2009-September 2010 at up to three home visits: pre pregnancy (n=306), pregnancy (n=807), and 6-months postnatal (n=117). Collections included air for particulate matter <=2.5 um (PM2.5), nitrogen dioxide, ozone, volatile organic compounds (VOCs), and carbonyls; vacuum dust for allergens/endotoxin; water for VOCs, trihalomethanes (THMs), and haloacetic acids (HAAs); and wipe samples for pesticides, semi-volatile organics, and metals. We characterized feasibility using sample collection rates and times and informative value using analyte detection frequencies (DF). RESULTS: Among the 1230 home visits, environmental sample collection rates were high across all sample types (mean=89%); all samples except the air PM2.5 samples had collection times <30 min. Informative value was low for water VOCs (median DF=0%) and pesticide floor wipes (median DF=5%). Informative value was moderate for air samples (median DF=35%) and high for water THMs and HAAs (median DF=91% and 75%, respectively). CONCLUSIONS: Though collection of environmental samples was feasible, some samples (e.g., wipe pesticides and water VOCs) yielded limited information. These results can be used in conjunction with other study design considerations, such as target population size and hypotheses of interest, to inform the method selection of future environmental health birth cohort studies. PMID- 25913152 TI - Persistent organic pollutants and biomarkers of diabetes risk in a cohort of Great Lakes sport caught fish consumers. AB - BACKGROUND: Exposure to persistent organic pollutants (POPs) is associated with increased diabetes risk, although the mechanism of action is not well delineated. METHODS: We investigated established diabetes biomarkers that could implicate potential mechanistic pathways, including C-reactive protein (CRP), a marker of systemic inflammation; gamma glutamyl transferase (GGT), a liver enzyme associated with oxidative stress; and adiponectin, an adipokine modulating glucose regulation and fatty acid oxidation. These biomarkers as well as hemoglobin A1c (HA1c), and POPs [polychlorinated biphenyls (PCBs), p,p dichlorodiphenyldichloroethylene (DDE) and polybrominated diphenyl ethers (PBDEs)] were measured in a cohort of Great Lakes sport caught fish (GLSCF) consumers. We examined associations of POPs and fish consumption with HA1c and incident diabetes, and evaluated mediation and moderation by the diabetes biomarkers. RESULTS: Odds of incident diabetes were elevated with exposure to DDE and PCBs. DDE and PCB 118 were positively, and fish meals were inversely, associated with HA1c. CRP was inversely associated with saltwater and total fish meals, particularly in persons with higher adiposity, but did not mediate the associations of fish meals with HA1c. There were few associations of POPs with adiponectin, CRP and GGT, with the exception of positive associations of PCB 118 with GGT, PBDEs with GGT in older persons, and PBDEs with adiponectin. Adiponectin, CRP and GGT did not mediate associations of DDE and PCBs with HA1c or incident diabetes. However, the association of DDE with HA1c was stronger in persons with higher CRP, GGT and BMI, and lower adiponectin, while the association of PCB 118 with HA1c was stronger in persons with higher GGT. CONCLUSIONS: These findings suggest that adiponectin, CRP and GGT did not mediate effects of POPs on diabetes or HA1c. However, POPs may have stronger effects on blood glucose in persons at higher risk for diabetes. PMID- 25913154 TI - Paraoxonase 2 gene polymorphisms and prenatal phthalates' exposure in Chinese newborns. AB - BACKGROUND: Phthalates were reported to be associated with increased risk of LBW in newborns, but the mechanism and potential influencing factor was still unclear. The objectives of this study were to investigate whether paraoxonase-2 (PON2) Ala148Gly (A148G) polymorphisms have impacts on fetal growth, and evaluate potential modifying effect on the association between phthalate exposures and LBW and short birth length. METHODS: In the current case-control study, 185 mother newborn pairs including 74 low birth weight (LBW) cases and 111 controls were enrolled. Newborns' meconium specimens were collected and detected for mono-n butyl phthalate (MBP) and mono-2-ethyhexyl phthalate (MEHP) by the method of high performance liquid chromatography-tandem mass spectrometry (LC-MS/MS). Umbilical vein blood samples were used to identify PON2 A148G polymorphisms by using the polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) method. RESULTS: Newborns prenatally exposed to higher level of phthalates had lower birth weight (beta=-0.92. p=0.045 for MBP, beta=-0.62, p=0.013 for MEHP) and short birth length (SBL) (beta=-0.024. p=0.049 for MBP, beta=-0.023, p=0.007 for MEHP). Comparing with low-phthalate-exposed subjects with PON2 148AA genotype, newborns with PON2 148AG/GG genotype exposed to high concentrations of MBP and MEHP had higher risks of LBW and short birth length (LBW: OR: 5.0, p=0.017 for MEHP; OR: 2.6, p=0.023 for MBP; SBL: OR: 6.6, p=0.005 for MEHP; OR: 6.4, p=0.017 for MBP). Effects of MBP and MEHP on LBW were significantly modified by PON2 A148G (p=0.044 and 0.034, respectively), while the modifying effect of PON2 A148G polymorphisms on the association of two phthalate metabolites with SBL was not significant. CONCLUSION: Prenatal exposure to phthalates affected birth weight and length in newborns. PON2 A148G polymorphisms modified the effects of prenatal phthalates' exposure on fetal development. Newborns with PON2 148AG/GG genotype and exposed to high concentrations of MBP and MEHP had higher risks of LBW and SBL. PMID- 25913155 TI - Prenatal exposure to phthalates, bisphenol A and perfluoroalkyl substances and cord blood levels of IgE, TSLP and IL-33. AB - The fetal time period is a critical window of immune system development and resulting heightened susceptibility to the adverse effects of environmental exposures. Epidemiologists and toxicologists have hypothesized that phthalates, bisphenol A (BPA) and perfluoroalkyl substance have immunotoxic properties. Immunotoxic effects of chemicals may manifest in an altered immune system profile at birth. Immunoglobulin E, thymic stromal lymphopoietin (TSLP), and interleukin 33 (IL-33) are integral in the etiology of childhood allergy and detectable at birth. The objective of this study was to determine the association between maternal levels of phthalates, bisphenol A (BPA), and perfluoroalkyl substances and elevated umbilical cord blood levels of IgE, TSLP, and IL-33. This study utilized data collected in the Maternal-Infant Research on Environmental Chemicals (MIREC) Study, a trans-Canada cohort study of 2001 pregnant women. Of these women, 1258 had a singleton, term birth and cord blood sample. A Bayesian hierarchical model was employed to determine associations between log-transformed continuous variables and immune system biomarkers while adjusting for potential confounding from correlated environmental contaminants. Inverse, nonlinear associations were observed between maternal urinary MCPP levels and elevated levels of both IL-33/TSLP and IgE and between maternal urinary BPA levels and elevated levels of IL-33/TSLP. In this primarily urban Canadian population of pregnant women and their newborns, maternal urinary and plasma concentrations of phthalate metabolites, BPA, and perfluoroalkyl substances were not associated with immunotoxic effects that manifest as increased odds of elevated levels of IgE, TSLP or IL-33. PMID- 25913156 TI - Pseudogenization of sopA and sopE2 is functionally linked and contributes to virulence of Salmonella enterica serovar Typhi. AB - The difference in host range between Salmonella enterica serovar Typhimurium (S. Typhimurium) and S. enterica serovar Typhi (S. Typhi) can be partially attributed to pseudogenes. Pseudogenes are genomic segments homologous to functional genes that do not encode functional products due to the presence of genetic defects. S. Typhi lacks several protein effectors implicated in invasion or other important processes necessary for full virulence of S. Typhimurium. SopA and SopE2, effectors that have been lost by pseudogenization in S. Typhi, correspond to an ubiquitin ligase involved in cytokine production by infected cells, and to a guanine exchange factor necessary for invasion of epithelial cells, respectively. We hypothesized that sopA and/or sopE pseudogenization contributed to the virulence of S. Typhi. In this work, we found that S. Typhi expressing S. Typhimurium sopE2 exhibited a decreased invasion in different epithelial cell lines compared with S. Typhi WT. S. Typhimurium sopA completely abolished the hypo-invasive phenotype observed in S. Typhi expressing S. Typhimurium sopE2, suggesting that functional SopA and SopE2 participate concertedly in the invasion process. Finally, the expression of S. Typhimurium sopA and/or sopE2 in S. Typhi, determined changes in the secretion of IL-8 and IL-18 in infected epithelial cells. PMID- 25913157 TI - Genomic characterization of uncommon human G3P[6] rotavirus strains causing diarrhea in children in Italy in 2009. AB - Group A rotaviruses (RVA) are the leading cause of acute gastroenteritis in young children, causing up to 450,000 deaths worldwide, mostly in developing countries. Most of RVA human infections in developed countries are related to five major G/P combinations: G1P[8], G2P[4], G3P[8], G4P[8] and G9P[8]. During the surveillance activity of RotaNet-Italy, three uncommon G3P[6] RVA strains, designated as RVA/Human-wt/ITA/NA01/2009/G3P[6], RVA/Human-wt/ITA/NA06/2009/G3P[6], and RVA/Human-wt/ITA/NA19/2009/G3P[6], were identified in the stools of children with diarrhea hospitalized in Southern Italy in 2009. Samples NA01, NA06 and NA19 were characterized as genotype G3P[6]. To investigate the three strains further, partial sequencing of the eleven genomic segments was performed. RVA strains NA01, NA06 and NA19 were found to share the rare genotype constellation: G3-P[6] I2-R2-C2-M2-A2-N2-T2-E2-H2, which had not been reported previously in continental Italy. The phylogenetic analysis of the eleven genomic segments showed no evidence of zoonosis or inter-species reassortment at the origin of the Italian G3P[6] strains, indicating that they possessed DS-1-like genomic constellations similar to those detected previously in human cases in Africa and Europe. The analysis of the hypervariable regions of VP7 and VP4 (VP8*) revealed high amino acid identity between the Italian G3P[6] RVA strains involved in this study. PMID- 25913158 TI - Loss of diversity within Mycoplasma bovis isolates collected in France from bovines with respiratory diseases over the last 35 years. AB - Mycoplasma (M.) bovis has recently emerged as a major, worldwide etiological agent of bovine respiratory diseases leading to huge economic losses mainly due to high morbidity and mortality as well as poor growth rates. The spread of M. bovis infections between different animals, herds, regions or countries has been often reported to be connected to the movement of animals. However, despite recent considerable efforts, no universal subtyping method is yet available to trace M. bovis isolates circulation at an international scale. Moreover in France, the overall population diversity of M. bovis isolates has not been assessed since the early 1990s. This study was conducted to fill in these gaps. The genotypic diversity between sixty isolates collected in France over the last 35 years was assessed using two molecular subtyping methods that addressed either the long-term epidemiological relationships (Multi Locus Sequence Typing, MLST) or the genetic microvariations (Multiple Locus VNTR Analysis, MLVA) between isolates. Phenotypic diversity was also analyzed by using Matrix-Assisted Laser Desorption Ionization-Time of Flight Mass Spectrometry (MALDI-TOF MS) to compare the main protein patterns of isolates. All proposed subtyping approaches were optimized and led to the same pattern in the French M. bovis population that consisted of two clusters, the first one comprising isolates collected before 2000 and the second, those collected after 2000. Recent strains were further shown to be more homogeneous than older ones, which is consistent with the spread of a single clone throughout the country. Because this spread was concomitant with the emergence of multiresistant M. bovis isolates, several hypotheses are discussed to explain the homogeneity of M. bovis isolates in France, even though the M. bovis species is fully equipped to generate diversity. PMID- 25913159 TI - ClosIndb: A resource for computationally derived information from clostridial genomes. AB - Over the past few years, several clostridial genomes have been sequenced, and since then new sequencing projects are also under way. Clostridia is one of the most sequenced genera, and presently, complete genome sequences of 49 clostridial species are available in public archives. Unraveling this wealth of genomic information opens up potential avenues in clostridial research. In the present study, we have carried out in silico analysis to decipher the genomic data. Subsequently, a web resource, ClosIndb, has been developed which collates the computationally derived information associated with all clostridial genes. It features various aspects of coding regions as well as non-coding regions, such as putative orthologs, proteins physicochemical properties, operons and cis regulatory elements. It provides users with comparative details of all clostridial proteins across the firmicutes. ClosIndb is a comprehensive resource for all completely sequenced clostridial genomes and is under constant development. ClosIndb is freely accessible at http://bif.uohyd.ac.in/closindb/. PMID- 25913160 TI - Do ultrasonographic semiquantitative indices predict histological changes in NASH irrespective of steatosis extent? PMID- 25913162 TI - AtRBP1, which encodes an RNA-binding protein containing RNA-recognition motifs, regulates root growth in Arabidopsis thaliana. AB - AtRBP1 is an RNA-binding protein containing RNA-recognition motifs in Arabidopsis thaliana, homologues of which are not observed in metazoa. Transgenic plants expressing artificial microRNAs for repressing AtRBP1 expression displayed a stunted primary root phenotype during germination. Transgenic plants overexpressing AtRBP1 also displayed the same phenotype. Tight regulation of the AtRBP1 transcript may be required for normal root growth. An in vitro binding assay showed that AtRBP1 preferentially binds to sequences containing UUAGG, GUAGG and/or UUAGU. In vivo selection of RNAs bound to AtRBP1 suggests that transcripts of At3g06780, At4g15910, At5g11760 and At5g07350 are target RNAs of AtRBP1. PMID- 25913161 TI - Macrophages treated with particulate matter PM2.5 induce selective neurotoxicity through glutaminase-mediated glutamate generation. AB - Exposure to atmospheric particulate matter PM2.5 (aerodynamic diameter <= 2.5 MUm) has been epidemiologically associated with respiratory illnesses. However, recent data have suggested that PM2.5 is able to infiltrate into circulation and elicit a systemic inflammatory response. Potential adverse effects of air pollutants to the central nervous system (CNS) have raised concerns, but whether PM2.5 causes neurotoxicity remains unclear. In this study, we have demonstrated that PM2.5 impairs the tight junction of endothelial cells and increases permeability and monocyte transmigration across endothelial monolayer in vitro, indicating that PM2.5 is able to disrupt blood-brain barrier integrity and gain access to the CNS. Exposure of primary neuronal cultures to PM2.5 resulted in decrease in cell viability and loss of neuronal antigens. Furthermore, supernatants collected from PM2.5 -treated macrophages and microglia were also neurotoxic. These macrophages and microglia significantly increased extracellular levels of glutamate following PM2.5 exposure, which were negatively correlated with neuronal viability. Pre-treatment with NMDA receptor antagonist MK801 alleviated neuron loss, suggesting that PM2.5 neurotoxicity is mediated by glutamate. To determine the potential source of excess glutamate production, we investigated glutaminase, the main enzyme for glutamate generation. Glutaminase was reduced in PM2.5 -treated macrophages and increased in extracellular vesicles, suggesting that PM2.5 induces glutaminase release through extracellular vesicles. In conclusion, these findings indicate PM2.5 as a potential neurotoxic factor, crucial to understanding the effects of air pollution on the CNS. PMID- 25913164 TI - Mean corpuscular volume and red blood cell distribution width are independent predictors of serum potassium concentration in healthy individuals. PMID- 25913163 TI - Cross-sectional and longitudinal associations between serum uric acid and metabolic syndrome: Results from Fangchenggang Area Male Health and Examination Survey in China. AB - BACKGROUND: It is controversial whether serum uric acid (SUA) is a risk factor for the prevalence of metabolic syndrome (MetS). The current study was designed to highlight the association of SUA and MetS and its components. METHODS: Data on 3675 healthy male subjects, aged 17-88 years, were collected for the cross sectional study. A representative sample of 2575 individuals who did not suffer from MetS at baseline was involved in the cohort study. A cox regression model was applied to evaluate causality for the 2- and 4-year large scale longitudinal study. RESULTS: In the cross-sectional analysis, SUA showed a statistically significant negative correlation with high-density lipoprotein cholesterol (HDL c) and a positive correlation with blood pressure (BP), triglycerides (TG), waist circumference (WC), and body mass index (BMI) (all P<0.001). In longitudinal analysis, examining the risk of developing MetS, SUA concentrations (hazard ratios comparing fourth quartile to the first quartile of 1.75; 95% CI, 1.26 2.41) were positively associated with incident MetS after adjusted for age, blood pressure, glucose, TG, HDL-c, smoking, alcohol drinking and education. CONCLUSION: SUA is positively correlated with the prevalence of MetS. Increased SUA concentration may be an independent risk factor for MetS. PMID- 25913165 TI - Directed self-assembly of end-functionalized nanofibers: from percolated networks to liquid crystal-like phases. AB - We explore the directed self-assembly (DSA) process of end-functionalized nanofibers (NFs) by performing coarse-grained molecular dynamics simulations. We find that by tuning their interactions, NFs aggregate and self-organize into networks with specific topologies ranging from percolated networks to liquid crystal-like long-chain phases. The underlying mechanism is explained through an analytical model from a minimum energy perspective. In addition to offering microscopic understandings of the DSA process, the findings reported here can also guide robust target-specified design of nanofibrous materials into organized network structures. PMID- 25913166 TI - Diltiazem vs. Metoprolol in the Management of Atrial Fibrillation or Flutter with Rapid Ventricular Rate in the Emergency Department. AB - BACKGROUND: Diltiazem (calcium channel blocker) and metoprolol (beta-blocker) are both commonly used to treat atrial fibrillation/flutter (AFF) in the emergency department (ED). However, there is considerable regional variability in emergency physician practice patterns and debate among physicians as to which agent is more effective. To date, only one small prospective, randomized trial has compared the effectiveness of diltiazem and metoprolol for rate control of AFF in the ED and concluded no difference in effectiveness between the two agents. OBJECTIVE: Our aim was to compare the effectiveness of diltiazem with metoprolol for rate control of AFF in the ED. METHODS: A convenience sample of adult patients presenting with rapid atrial fibrillation or flutter was randomly assigned to receive either diltiazem or metoprolol. The study team monitored each subject's systolic and diastolic blood pressures and heart rates for 30 min. RESULTS: In the first 5 min, 50.0% of the diltiazem group and 10.7% of the metoprolol group reached the target heart rate (HR) of <100 beats per minute (bpm) (p < 0.005). By 30 min, 95.8% of the diltiazem group and 46.4% of the metoprolol group reached the target HR < 100 bpm (p < 0.0001). Mean decrease in HR for the diltiazem group was more rapid and substantial than that of the metoprolol group. From a safety perspective, there was no difference between the groups with respect to hypotension (systolic blood pressure < 90 mm Hg) and bradycardia (HR < 60 bpm). CONCLUSIONS: Diltiazem was more effective in achieving rate control in ED patients with AFF and did so with no increased incidence of adverse effects. PMID- 25913167 TI - Emergency Department Extremity Radiographs in the Setting of Pain Without Trauma: Are They Worth the Pain? AB - BACKGROUND: Few data exist that correlate acute radiographic findings of extremity imaging with patients' complaints in the acute care setting. OBJECTIVE: We hypothesize that plain radiographs performed for a complaint of pain in the absence of trauma or signs and symptoms of infection are of low yield. METHODS: We retrospectively analyzed the imaging and charts of 1331 patients who presented to our emergency department (ED) and received extremity radiographs with complaints related to limb trauma, infection, and pain alone. Imaging and outcomes of cases interpreted as positive for acute pathology and those interpreted as indeterminate were analyzed using Fisher's exact tests to evaluate the value of extremity radiographs in the setting of isolated limb pain. RESULTS: Of the patients analyzed, 935 presented with trauma, 234 presented with nontraumatic pain, and 161 presented with signs or symptoms of infection. The rate of definitively positive cases was 30.6% for trauma, 20.6% for infection, and 1.3% for pain. When indeterminate cases were included in the analysis, the rate of acutely positive cases rose to 33.4% for trauma, 28.0% for infection, and 3.0% for pain. Among the three definitively positive pain cases, all three were fractures, none of which resulted in emergent surgery or orthopedic consults. Among the four indeterminately positive pain cases, three proved to be false positives. CONCLUSIONS: Our data suggest that ED imaging of patients presenting with nontraumatic pain is of extremely low yield, resulting in few acute positive findings that require immediate attention in the ED. PMID- 25913168 TI - Does moderate iron deficiency protect against childhood illness? A test of the optimal iron hypothesis in Tanzania. AB - OBJECTIVES: To test the hypothesis that moderate iron deficiency among children is associated with lower likelihood of infection. MATERIALS AND METHODS: We use data from a population representative cross sectional study of 1164 Tanzanian children aged 6-59 months from the Tanzania Demographic and Health Survey. Respondents' iron levels were assessed through serum transferrin receptor (sTfR) and anemia was assessed using hemoglobin. C-reactive protein (CRP) was used as a marker of infection. RESULTS: Nearly 25% of the children were categorized as normal (iron replete, non-anemic); 45% were IDE (low iron, non-anemic), 24% were classified as IDA (low iron, anemic), and 69 children (5.9%) were anemic but had no evidence of iron deficiency. IDE was not associated with a lower likelihood of elevated CRP compared to iron replete, non-anemic children; 45% of normal children had elevated CRP compared to 51% of IDE children (P = 0.10). IDA, by contrast, was associated with a higher likelihood of elevated CRP (68%, P < 0.001). These results were unchanged when child, maternal, and household controls were added to a logistic regression model. DISCUSSION: Our results do not support the optimal iron hypothesis as conventionally formulated. The fact that we did not find an effect where some other studies have may be due to differences in study design, sample (e.g., age), or the baseline pathogenic ecology. Alternatively, it may be more fruitful to investigate iron regulation as an allostatic system that responds to infections adaptively, rather than to expect an optimal pre-infection value. PMID- 25913169 TI - Breastfeeding knowledge among Polish healthcare practitioners supporting breastfeeding mothers. AB - INTRODUCTION: The aim of the study was to evaluate the level of breastfeeding knowledge among healthcare practitioners taking care for mothers and children in the perinatal period, the training needs for such practitioners, and the forms of breastfeeding support in Poland. RESEARCH DESIGN: The study involved a group of 361 health care practitioners, of whom 168 had followed a professional development course in breastfeeding knowledge, whilst the remaining 193 had not. A ten-point test was used with this group to assess their 2nd level of lactation knowledge as defined by Wellstart International guidelines. RESULTS: The study included 227 midwives, 58 medical doctors, 40 nurses, 8 educators and psychologists and 28 members of other professions. Breastfeeding support was being provided by 309 of the participants (86.3%). The highest mean test score (7.58 points) was obtained by medical doctors who had completed a professional development course in the field of breastfeeding knowledge. The probability of achieving a high score was increased by: following a professional course in breastfeeding knowledge (OR = 8.73; 95% CI: 4.99-15.32), following the longest breastfeeding support skills training (OR = 4.80; 95% CI: 2.83-8.14) and IBLCE certification (OR = 5.07; 95% CI: 2.71-9.47). CONCLUSION: Specialist professional development courses are effective sources of knowledge for practitioners who provide breastfeeding support. There is a need to include breastfeeding education in curriculum for undergraduate medical training, as well as to organize professional development courses to provide evidence-based knowledge and practice to support breastfeeding mothers and babies. PMID- 25913170 TI - The experiences of patients receiving care from nursing students at a Dedicated Education Unit: A phenomenological study. AB - The purpose of this study is to describe how patients perceive being cared for by student nurses, in a clinical context in the form of a Dedicated Education Unit (DEU). The study has been performed with a Reflective Lifeworld Research (RLR) approach grounded in phenomenology. Lifeworld interviews were conducted with patients who had received care from student nurses on an orthopaedic DEU and data have been analysed for meanings. The findings reveal how patients experience to be carried along as a part of the students' learning process. This is described in more detail via the constituents: a mutual invitation to participate, the importance of genuine encounters, and essential support. Patients experience both a stable and a less stable care in a learning environment and it is thus essential for them to be invited to be a part of both the students' learning process and their own health process. The findings also highlight the key role of the supervisors for patients' sense of security. Finally there are indications that concepts such as DEU with a lifeworld-led didactic, based on reflection on both the patients' stories and the students' experiences, can create learning environments that support patients' health processes and also students' learning processes. PMID- 25913171 TI - Effects of olmesartan on endothelial progenitor cell mobilization and function in carotid atherosclerosis. AB - BACKGROUND: Olmesartan is a type of angiotensin II receptor inhibitor that can reduce the incidence of cardiovascular events. However, its role in the function of endothelial progenitor cells in atherosclerosis patients is still unclear. Our study aimed to explore the effects and mechanism of olmesartan on endothelial progenitor cell mobilization and function in carotid atherosclerosis. MATERIAL/METHODS: Forty carotid atherosclerosis patients were enrolled. Patients were administrated olmesartan 20 mg/day for 3 months. Flow cytometry was used for counting circulating endothelial progenitor cells; colorimetric method was used to measure the serum levels of endothelial nitric oxide synthase and nitric oxide. Cell migration, adhesion, and proliferation capacity, and related signaling pathway were also analyzed. Spearman rank correlation analysis was used to investigate the influence of olmesartan on endothelial progenitor cells and clinical characteristics (e.g., sex, age, blood pressure). RESULTS: Compared with the control group, the number of circulating endothelial progenitor cells was significantly decreased. Olmesartan can increase circulating endothelial progenitor cells number and the serum levels of eNOS and NO. Furthermore, it can improve cell migration, adhesion, and proliferation capacities. Spearman rank correlation analysis showed there is no relationship between olmesartan promotion effects on endothelial progenitor cell mobilization and the clinical characteristics (P>0.05). P-eNOS and P-Akt expression can be unregulated by RNH 6270 treatment and blocked by LY294002. CONCLUSIONS: Olmesartan can effectively promote the endothelial progenitor cells mobilization and improve their function in patients with carotid atherosclerosis, independent of basic characteristics. This process relies on the PI3K/Akt/eNOS signaling pathway. PMID- 25913172 TI - Relationship between palliative care consultation service and end-of-life outcomes. AB - PURPOSE: Palliative care consultation service (PCCS) is currently utilized to provide care to terminal patients in Taiwan. However, there is little research on the relationship between PCCS and end-of-life outcomes. This study aimed to elucidate the association between PCCS and end-of-life outcomes in terminal cancer patients. METHODS: Retrospective chart reviews of terminal cancer patients who consulted the PCCS of a medical center in Taiwan from January 2007 to December 2012 were performed. Data on 1369 patients were recorded, which included details of outcomes such as discharge from hospital, transfer to hospice ward, and death after PCCS termination. Other variables such as demographics, disease related information, symptoms, and psychosocial needs were also evaluated. Logistic regression models were employed to estimate the adjusted odds ratios and related 95% confidence intervals. RESULTS: The Eastern Cooperative Oncology Group performance status, timing of do-not-resuscitate (DNR) signature, constipation, and spiritual problems experienced by the patients were important predictors for terminal cancer patients who were discharged from the hospital or had expired at the time of PCCS termination. Age, gender, primary cancer diagnosis, timing of DNR signature, constipation, and other physical symptoms were the key predictors for patients who were transferred to the hospice ward or had expired. CONCLUSIONS: This study confirms the outcomes of PCCS and highlights the important predictors for patients at PCCS termination. These factors can be targeted to improve and enhance the quality of PCCS rendered in the future. PMID- 25913173 TI - A modular gene targeting system for sequential transgene stacking in plants. AB - A modular, selection-based method was developed for site-specific integration of transgenes into a genomic locus to create multigene stacks. High-frequency gene targeting was obtained using zinc finger nuclease (ZFN)-mediated double-strand break (DSB) formation at a pre-defined target genomic location using a unique intron directly downstream of a promoter driving a selectable marker gene to facilitate homology between target and donor sequences. In this system, only insertion into the target locus leads to a functional selectable marker, and regeneration from random insertions of the promoterless donor construct are reduced on selection media. A new stack of transgenes can potentially be loaded with each successive cycle of gene targeting by exchanging the selectable marker gene using the intron homology. This system was tested in maize using the pat selectable marker gene, whereby up to 30% of the plants regenerated on Bialaphos containing medium were observed to have the donor construct integrated into the target locus. Unlike previous gene targeting methods that utilize defective or partial genes for selecting targeted events, the present method exchanges fully functional genes with every cycle of targeting, thereby allowing the recycling of selectable marker genes, hypothetically for multiple generations of gene targeting. PMID- 25913174 TI - Complete genome sequence of Bacillus licheniformis BL-09, a probiotic strain isolated from naturally fermented congee. AB - Bacillus licheniformis BL-09 is a probiotic strain isolated from naturally fermented congee in Inner Mongolia of China. The genome of this strain contains a 4.39 Mb circular chromosome with an average GC content of 45.9%. The analysis of the genome revealed two gene clusters that are related to the peptide biosynthesis. The available genetic information of these peptides makes it possible to construct an improved strain for the industrial production of antimicrobial agents. PMID- 25913175 TI - Heterologous expression of proteorhodopsin enhances H2 production in Escherichia coli when endogenous Hyd-4 is overexpressed. AB - Proteorhodopsin (PR) is a light harvesting protein widely distributed among bacterioplankton that plays an integral energetic role in a new pathway of marine light capture. The conversion of light into chemical energy in non-chlorophyll based bacterial systems could contribute to overcoming thermodynamic and metabolic constraints in biofuels production. In an attempt to improve biohydrogen production yields, H2 evolution catalyzed by endogenous hydrogenases, Hyd-3 and/or Hyd-4, was measured when recombinant proteorhodopsin (PR) was concomitantly expressed in Escherichia coli cells. Higher amounts of H2 were obtained with recombinant cells in a light and chromophore dependent manner. This effect was only observed when HyfR, the specific transcriptional activator of the hyf operon encoding Hyd-4 was overexpressed in E. coli, suggesting that an excess of protons generated by PR activity could increase hydrogen production by Hyd-4 but not by Hyd-3. Although many of the subunits of Hyd-3 and Hyd-4 are very similar, Hyd-4 possesses three additional proton-translocating NADH-ubiquinone oxidoreductase subunits, suggesting that it is dependent upon DeltaMUH(+). Altogether, these results suggest that protons generated by proteorhodopsin in the periplasm can only enhance hydrogen production by hydrogenases with associated proton translocating subunits. PMID- 25913176 TI - Methods for protein complex prediction and their contributions towards understanding the organisation, function and dynamics of complexes. AB - Complexes of physically interacting proteins constitute fundamental functional units responsible for driving biological processes within cells. A faithful reconstruction of the entire set of complexes is therefore essential to understand the functional organisation of cells. In this review, we discuss the key contributions of computational methods developed till date (approximately between 2003 and 2015) for identifying complexes from the network of interacting proteins (PPI network). We evaluate in depth the performance of these methods on PPI datasets from yeast, and highlight their limitations and challenges, in particular at detecting sparse and small or sub-complexes and discerning overlapping complexes. We describe methods for integrating diverse information including expression profiles and 3D structures of proteins with PPI networks to understand the dynamics of complex formation, for instance, of time-based assembly of complex subunits and formation of fuzzy complexes from intrinsically disordered proteins. Finally, we discuss methods for identifying dysfunctional complexes in human diseases, an application that is proving invaluable to understand disease mechanisms and to discover novel therapeutic targets. We hope this review aptly commemorates a decade of research on computational prediction of complexes and constitutes a valuable reference for further advancements in this exciting area. PMID- 25913177 TI - Diversifying mechanisms in the on-farm evolution of crop mixtures. AB - While modern agriculture relies on genetic homogeneity, diversifying practices associated with seed exchange and seed recycling may allow crops to adapt to their environment. This socio-genetic model is an original experimental evolution design referred to as on-farm dynamic management of crop diversity. Investigating such model can help in understanding how evolutionary mechanisms shape crop diversity submitted to diverse agro-environments. We studied a French farmer-led initiative where a mixture of four wheat landraces called 'Melange de Touselles' (MDT) was created and circulated within a farmers' network. The 15 sampled MDT subpopulations were simultaneously submitted to diverse environments (e.g. altitude, rainfall) and diverse farmers' practices (e.g. field size, sowing and harvesting date). Twenty-one space-time samples of 80 individuals each were genotyped using 17 microsatellite markers and characterized for their heading date in a 'common-garden' experiment. Gene polymorphism was studied using four markers located in earliness genes. An original network-based approach was developed to depict the particular and complex genetic structure of the landraces composing the mixture. Rapid differentiation among populations within the mixture was detected, larger at the phenotypic and gene levels than at the neutral genetic level, indicating potential divergent selection. We identified two interacting selection processes: variation in the mixture component frequencies, and evolution of within-variety diversity, that shaped the standing variability available within the mixture. These results confirmed that diversifying practices and environments maintain genetic diversity and allow for crop evolution in the context of global change. Including concrete measurements of farmers' practices is critical to disentangle crop evolution processes. PMID- 25913178 TI - Evolution of structure and local magnetic fields during crystallization of HITPERM glassy alloys studied by in situ diffraction and nuclear forward scattering of synchrotron radiation. AB - Evolution of structure and local magnetic fields in (Fe(1-x)Co(x))76Mo8Cu1B15 (HITPERM) metallic glass ribbons with various amounts of Co (x = 0, 0.25, 0.5) were studied in situ using diffraction and nuclear forward scattering of synchrotron radiation. It was found that crystallization of all three glasses proceeds in two stages. In the first stage, bcc (Fe,Co) nanocrystals are formed, while in the second stage additional crystalline phases evolve. For all three glasses, the crystallization temperatures at the wheel side were found to be lower than at the air side of the ribbon. The crystallization temperatures were found to decrease with increasing Co content. The lattice parameters of the bcc nanocrystals decrease up to about 550 degrees C and then increase pointing to squeezing Mo atoms out of the nanograins or to interface effects between the nanocrystals and the glassy matrix. Nuclear forward scattering enabled separate evaluation of the contributions that stem from structurally different regions within the investigated samples including the newly formed nanocrystals and the residual amorphous matrix. Even minor Co content (x = 0.25) has a substantial effect not only upon the magnetic behaviour of the alloy but also upon its structure. Making use of hyperfine magnetic fields, it was possible to unveil structurally diverse positions of Fe atoms that reside in a nanocrystalline lattice with different numbers of Co nearest neighbours. PMID- 25913179 TI - Influence of Macrophages on the Rooster Spermatozoa Quality. AB - The goal of this study was to evaluate the occurrence of macrophages in rooster semen and to investigate their impact on the spermatozoa quality. Ross 308 breeder males (n = 30) with no evidence of genital tract infections were used to determine the concentration of macrophages using fluorescently conjugated acetylated low-density lipoprotein (AcLDL). Subsequently, the roosters were divided into two groups on the basis of semen macrophage concentration, and semen quality was compared in two heterospermic samples. We applied computer-assisted semen analysis (CASA) system to determine motility parameters. Fluorescence microscopy and flow cytometry were used to evaluate occurrence of apoptotic and dead spermatozoa. Spermatozoa fertility potential was examined after intravaginal artificial insemination of hens. Eighteen roosters (control group) contained 0.2 3% of macrophages within spermatozoa population and ten roosters (macrophage group) had 10-15% of macrophages. Males from macrophage group had lower (p < 0.05) motility parameters (total and progressive movement, velocity curved line) and increased concentration of dead spermatozoa detected by flow cytometry and fluorescence microscopy (p < 0.001 and p ? 0.05, respectively). Differences (p < 0.05) between fluorescent microscopy and flow cytometry in results on spermatozoa apoptosis and viability were observed. No significant difference was found between groups in fertility of spermatozoa. In conclusion, the higher presence of macrophages in rooster semen may have a negative effect on some parameters of rooster spermatozoa evaluated in vitro. Furthermore, our study suggests that flow cytometry allows more precise examination of spermatozoa viability and apoptosis in a very short time compared with the fluorescent microscopy. PMID- 25913181 TI - A role for the intranasal formulation of azelastine hydrochloride/fluticasone propionate in the treatment of allergic rhinitis. AB - Rhinitis is a very common disease and represents a health problem for both children and adults globally. Rhinitis can be allergic or occur without any IgE mediated sensitization to aeroallergens. Common symptoms include nasal congestion, postnasal drainage, nasal itching, rhinorrhea and sneezing. The most effective drugs for the treatment of rhinitis are antihistamines and topical glucocorticoids. MP29-02 (Dymista((r))) is a novel intranasal formulation combining the second-generation antihistamine, azelastine hydrochloride, with fluticasone propionate in a single device that has recently been developed. Here, we review the efficacy and safety profile of this intranasal formulation in the treatment of allergic and nonallergic rhinitis. PMID- 25913180 TI - Sertoli cells are the target of environmental toxicants in the testis - a mechanistic and therapeutic insight. AB - INTRODUCTION: Sertoli cells support germ cell development in the testis via an elaborate network of cell junctions that confers structural, communicating, and signaling support. However, Sertoli cell junctions and cytoskeletons are the target of environmental toxicants. Because germ cells rely on Sertoli cells for the provision of structural/functional/nutritional support, exposure of males to toxicants leads to germ cell exfoliation due to Sertoli cell injuries. Interestingly, the molecular mechanism(s) by which toxicants induce cytoskeletal disruption that leads to germ cell exfoliation is unclear, until recent years, which are discussed herein. This information can possibly be used to therapeutically manage toxicant-induced infertility/subfertility in human males. AREAS COVERED: In this review, we provide a brief update on the use of Sertoli cell system developed for rodents and humans in vitro, which can be deployed in any research laboratory with minimal upfront setup costs. These systems can be used to collect reliable data applicable to studies in vivo. We also discuss the latest findings on the mechanisms by which toxicants induce Sertoli cell injury, in particular cytoskeletal disruption. We also identify candidate molecules that are likely targets of toxicants. EXPERT OPINION: We provide two hypothetical models delineating the mechanism by which toxicants induce germ cell exfoliation and blood-testis barrier disruption. We also discuss molecules that are the targets of toxicants as therapeutic candidates. PMID- 25913182 TI - Mental health benefits of long-term exposure to residential green and blue spaces: a systematic review. AB - Many studies conducted during the last decade suggest the mental health benefits of green and blue spaces. We aimed to systematically review the available literature on the long-term mental health benefits of residential green and blue spaces by including studies that used standardized tools or objective measures of both the exposures and the outcomes of interest. We followed the PRISMA statement guidelines for reporting systematic reviews and meta-analysis. In total 28 studies were included in the systematic review. We found limited evidence for a causal relationship between surrounding greenness and mental health in adults, whereas the evidence was inadequate in children. The evidence was also inadequate for the other exposures evaluated (access to green spaces, quality of green spaces, and blue spaces) in both adults and children. The main limitation was the limited number of studies, together with the heterogeneity regarding exposure assessment. Given the increase in mental health problems and the current rapid urbanization worldwide, results of the present systematic review should be taken into account in future urban planning. However, further research is needed to provide more consistent evidence and more detailed information on the mechanisms and the characteristics of the green and blue spaces that promote better mental health. We provide recommendations for future studies in order to provide consistent and evidence-based recommendations for policy makers. PMID- 25913183 TI - An investigation into the lifestyle, health habits and risk factors of young adults. AB - This project examined the lifestyle, health habits and risk factors of young adults at Qatar University. It explored the clustering and differences in dietary habits, body mass index (BMI) and physical activity (PA) amongst male and female students, both Qatari and non-Qatari. Seven hundred thirty two students aged 18 25 years completed a self-reported questionnaire and an objective measure of BMI. Males and females had a high prevalence of being overweight and obesity and low levels of PA, according to well-established international standards. Three clusters were identified based on the students' lifestyle and dietary habits. Cluster 1 (high risk factors) included those who engaged the least in healthy dietary practices and consumed the most unhealthy foods, participated in less PA and had the highest BMI. Cluster 2 (moderate risk factors) included those with considerably more habits falling into the moderate category, engagement in the most PA, the least TV and computer viewing time and had the lowest BMI. Cluster 3 (low risk factors) included those who engaged the most with the four healthy dietary practices, the least with the four unhealthy dietary practices and participated in moderate PA per week. This project provides valuable data that could be used by policy makers to address issues concerning student's health. PMID- 25913184 TI - Isolated diastolic hypertension associated risk factors among Chinese in Anhui Province, China. AB - OBJECTIVE: To explore potential risk factors of isolated diastolic hypertension (IDH) among young and middle-aged Chinese. METHODS: A community-based cross sectional study was conducted among 338 subjects, aged 25 years and above, using random sampling technique. There were 68 cases of IDH, 46 cases of isolated systolic hypertension (ISH), 89 cases of systolic and diastolic hypertension (SDH), and 135 of subjects with normal blood pressure. Cases and controls were matched on sex by frequency matching. Demographic characteristics, blood pressure and other relevant information were collected. RESULTS: Compared with controls, patients with IDH and ISH had significant higher level of triglyceride, high density lipoprotein, blood glucose and body mass index (BMI) (p < 0.05); while patients with SDH had significantly higher level of total cholesterol, triglyceride, glucose and BMI (p < 0.05). Linear mixed effects model showed that drinking tea, family history of hypertension (FHH), higher blood glucose, triglyceride and low density lipoprotein were related with elevated diastolic blood pressure (DBP) (p < 0.01); HFH, blood glucose, creatinine and BMI have positive effect on systolic blood pressure (SBP) (p < 0.05). CONCLUSIONS: Drinking tea, FHH, high levels of triglyceride, high density lipoprotein, blood glucose and BMI are associated with IDH among young and middle-aged Chinese. PMID- 25913185 TI - Early exposure to intermediate-frequency magnetic fields alters brain biomarkers without histopathological changes in adult mice. AB - Recently we have reported that intermediate-frequency magnetic field (IF-MF) exposure transiently altered the mRNA expression levels of memory function related genes in the hippocampi of adult male mice. However, the effects of IF-MF exposure during brain development on neurological biomarkers have not yet been clarified. In the present study, we investigated the effect of IF-MF exposure during development on neurological and immunological markers in the mouse hippocampus in 3- and 7-week-old male mice. Pregnant C57BL/6J mice were exposed to IF-MF (21 kHz, 3.8 mT) for one hour per day from organogenesis period day 7 to 17. At adolescence, some IF-MF-exposed mice were further divided into exposure, recovery, and sham-exposure groups. The adolescent-exposure groups were exposed again to IF-MF from postnatal day 27 to 48. The expression of mRNA in the hippocampi was examined using a real-time RT-PCR method, and microglia activation was examined by immunohistochemical analysis. The expression levels of NR1 and NR2B as well as transcription factors (CaMKIV, CREB1), inflammatory mediators (COX2, IL-1 b,TNF-alpha), and the oxidative stress marker heme-oxygenase (HO)-1 were significantly increased in the IF-MF-exposed mice, compared with the control group, in the 7-week-old mice, but not in the 3-week-old mice. Microglia activation was not different between the control and other groups. This study provides the first evidence that early exposure to IF-MF reversibly affects the NMDA receptor, its related signaling pathways, and inflammatory mediators in the hippocampus of young adult mice; these changes are transient and recover after termination of exposure without histopathological changes. PMID- 25913186 TI - BMI, overweight status and obesity adjusted by various factors in all age groups in the population of a city in Northeastern Brazil. AB - OBJECTIVE: In Brazil, demographic, socioeconomic and epidemiological changes over time have led to a transition in nutritional standards, resulting in a gradual reduction of malnutrition and an increased prevalence of overweight and obese individuals, similar to the situation in developed countries in previous decades. This study assessed the body mass index (BMI) and the prevalence of an overweight status and obesity, adjusted for various factors, in a population in northeastern Brazil including all age groups. METHODS: This is a cross-sectional population based epidemiological study using single sampling procedure composed of levels. Given the heterogeneity of the variable "income" and the relationship between income, prevalence of diseases and nutrition, a stratified sampling on blocks in the first level was used. In this, city districts were classified by income into 10 strata, according to information obtained from IBGE. A systematic sampling was applied on randomly selected blocks in order to choose the residences that would be part of the sample (second level), including 1165 participants from all age groups. RESULTS AND DISCUSSION: The prevalence of an overweight status or obesity was adjusted for demographic, socioeconomic and lifestyle variables. When the Chi square test was applied, a relationship was observed between the prevalence of an overweight status or obesity and the age group, gender, educational level and income of the participants. Regarding lifestyle parameters, only smoking was associated with the prevalence of an overweight status or obesity, in both adults and in the total sample. The results for the following groups were significant (p < 0.05): the age group from 20 to 59 years, when the individual presented an educational level greater than or equal to high school; and the age group >= 60 years, when the individual was female. It is noteworthy that educational level and being female were significant in adjusting for the total population as major factors influencing an increased BMI, followed by the variables physical activity and family income. CONCLUSIONS: The adjusted results justify the adoption of intervention and prevention policies to combat these clinical conditions for the study population as a whole, particularly directed toward adults with higher education level as well as elderly females. PMID- 25913187 TI - Rehabilitation living lab in the mall community of practice: learning together to improve rehabilitation, participation and social inclusion for people living with disabilities. AB - Communities of practice (CoP) can facilitate collaboration between people who share a common interest, but do not usually work together. A CoP was initiated and developed including stakeholders from clinical, research, community and governmental backgrounds involved in a large multidisciplinary and multi sectorial project: the Rehabilitation Living Lab in a Mall (RehabMaLL). This study aimed to evaluate the structure, process and outcomes of this CoP. A single case-study, using mixed-methods, evaluated the RehabMaLL CoP initiative after one year, based on Donabedian's conceptual evaluation model. Forty-three participants took part in the RehabMaLL CoP with 60.5% (n = 26) participating at least once on the online platform where 234 comments were posted. Four in-person meetings were held. Members expressed satisfaction regarding the opportunity to share knowledge with people from diverse backgrounds and the usefulness of the CoP for the RehabMaLL project. Collaboration led to concrete outcomes, such as a sensitization activity and a research project. Common challenges included lack of time and difficulty finding common objectives. A CoP can be a useful strategy to facilitate knowledge sharing on disability issues. Future research is necessary to determine strategies of increasing knowledge creation between members. PMID- 25913188 TI - The impact of the free swimming programme in a local community in the South East of England: giving with one hand, taking away with the other. AB - The purpose of this study is to examine the impact of the introduction of the Free Swimming Programme (FSP) in a local community (not identified to preserve anonymity) in the South East of England. The question has been approached in a variety of ways: by using primary quantitative data from leisure centres and logistic regressions based on the Active People Survey (APS). Problems are identified related to the introduction of the FSP in this community and suggestions are made for future policy. A brief examination of swimming participation in England enables researchers to place this community into a national context. The problems and policies of sport organisation developed in this community are not dissimilar to a more general application reflecting the English experience; in this sense it is anticipated that the findings will enable managers of sport organisations, along with public health policy makers, to focus more effectively on raising sport participation. The unique selling points of this article are the examination of FSP for adult participants, the local analysis of junior and senior participation, and the overall assessment of the policy based on APS. PMID- 25913189 TI - Adaptation of the Mishel Uncertainty of Illness Scale (MUIS) for chronic patients in Italy. AB - RATIONALE, AIMS AND OBJECTIVES: Uncertainty is a component of the illness experience and is likely to increase the burden of managing chronic illness, as cardiac pathologies and renal diseases. The impact of uncertainty should be taken into account and addressed with targeted intervention programmes. The purpose of this study is to contribute to the diffusion of the assessment of uncertainty in illness by validating the Mishel uncertainty in illness scale (MUIS) on chronic Italian patients. METHOD: The MUIS questionnaire was administered to 200 patients suffering from cardiac diseases and 50 patients with renal diseases. A confirmatory factor analysis was run for each of the MUIS dimensions (ambiguity, inconsistency, complexity and unpredictability). RESULTS: After some item reduction, three of the four MUIS scales, namely, ambiguity, inconsistency and complexity, exhibited satisfactory reliability coefficients (with Cronbach's alphas of, respectively, 0.796, 0.778 and 0.705), highly significant standardized regression weights and satisfactory/highly satisfactory fit indexes. Nevertheless, as the correlations among the scales mentioned earlier were high (all above 0.8) and statistically significant, the three subsets of ambiguity, complexity and inconsistency items were allowed to load onto a new single factor. A monodimensional uncertainty construct, grouping the majority of the items encompassed by these three MUIS scales, was successfully validated. CONCLUSIONS: This study provides researchers with an easy-to-administer instrument which is useful to investigate a crucial aspect related with patients' quality of life. Although a unique uncertainty construct is proposed, the in-depth analysis of the replies to each single item of the MUIS could help to monitor patients' emotional responses to the diagnosis and to the course of this disease and it might be useful to define appropriate strategies of coping and to focus on patients' quests for simplicity and clarity of treatment. PMID- 25913190 TI - DNA barcoding implicates 23 species and four orders as potential pollinators of Chinese knotweed (Persicaria chinensis) in Peninsular Malaysia. AB - Chinese knotweed (Persicaria chinensis) is of ecological and economic importance as a high-risk invasive species and a traditional medicinal herb. However, the insects associated with P. chinensis pollination have received scant attention. As a widespread invasive plant we would expect P. chinensis to be associated with a diverse group of insect pollinators, but lack of taxonomic identification capacity is an impediment to confirm this expectation. In the present study we aimed to elucidate the insect pollinators of P. chinensis in peninsular Malaysia using DNA barcoding. Forty flower visitors, representing the range of morphological diversity observed, were captured at flowers at Ulu Kali, Pahang, Malaysia. Using Automated Barcode Gap Discovery, 17 morphospecies were assigned to 23 species representing at least ten families and four orders. Using the DNA barcode library (BOLD) 30% of the species could be assigned a species name, and 70% could be assigned a genus name. The insects visiting P. chinensis were broadly similar to those previously reported as visiting Persicaria japonica, including honey bees (Apis), droneflies (Eristalis), blowflies (Lucilia) and potter wasps (Eumedes), but also included thrips and ants. PMID- 25913191 TI - Rapid Elimination of the Persistent Synergid through a Cell Fusion Mechanism. AB - In flowering plants, fertilization-dependent degeneration of the persistent synergid cell ensures one-on-one pairings of male and female gametes. Here, we report that the fusion of the persistent synergid cell and the endosperm selectively inactivates the persistent synergid cell in Arabidopsis thaliana. The synergid-endosperm fusion causes rapid dilution of pre-secreted pollen tube attractant in the persistent synergid cell and selective disorganization of the synergid nucleus during the endosperm proliferation, preventing attractions of excess number of pollen tubes (polytubey). The synergid-endosperm fusion is induced by fertilization of the central cell, while the egg cell fertilization predominantly activates ethylene signaling, an inducer of the synergid nuclear disorganization. Therefore, two female gametes (the egg and the central cell) control independent pathways yet coordinately accomplish the elimination of the persistent synergid cell by double fertilization. PMID- 25913192 TI - Neuronal Activity Promotes Glioma Growth through Neuroligin-3 Secretion. AB - Active neurons exert a mitogenic effect on normal neural precursor and oligodendroglial precursor cells, the putative cellular origins of high-grade glioma (HGG). By using optogenetic control of cortical neuronal activity in a patient-derived pediatric glioblastoma xenograft model, we demonstrate that active neurons similarly promote HGG proliferation and growth in vivo. Conditioned medium from optogenetically stimulated cortical slices promoted proliferation of pediatric and adult patient-derived HGG cultures, indicating secretion of activity-regulated mitogen(s). The synaptic protein neuroligin-3 (NLGN3) was identified as the leading candidate mitogen, and soluble NLGN3 was sufficient and necessary to promote robust HGG cell proliferation. NLGN3 induced PI3K-mTOR pathway activity and feedforward expression of NLGN3 in glioma cells. NLGN3 expression levels in human HGG negatively correlated with patient overall survival. These findings indicate the important role of active neurons in the brain tumor microenvironment and identify secreted NLGN3 as an unexpected mechanism promoting neuronal activity-regulated cancer growth. PMID- 25913194 TI - Treg(s) in Cancer: Friends or Foe? AB - Immune escape is a hallmark of cancer. Regulatory T cells (Treg) have been described to maintain peripheral tolerance. The role of Treg in cancer is ambiguous, as they are central inhibitory regulators in solid tumors, whereas during inflammation-driven tumorigenesis they prevent cancer initiation by restraining inflammation. As a consequence, under conditions with chronic inflammation that may initiate malignant transformation, application rather than depletion of Treg may be helpful. In solid tumors, however, the success story of immune-activating antibodies targeting checkpoint molecules of T cell activation fuels the hope that Treg inactivation or depletion may additionally boost anti tumor immune response. In this review we summarize important aspects on the dual role of Treg in cancer to provide a rationale for future Treg targeting attempts. PMID- 25913193 TI - Structure of the Angiotensin receptor revealed by serial femtosecond crystallography. AB - Angiotensin II type 1 receptor (AT(1)R) is a G protein-coupled receptor that serves as a primary regulator for blood pressure maintenance. Although several anti-hypertensive drugs have been developed as AT(1)R blockers (ARBs), the structural basis for AT(1)R ligand-binding and regulation has remained elusive, mostly due to the difficulties of growing high-quality crystals for structure determination using synchrotron radiation. By applying the recently developed method of serial femtosecond crystallography at an X-ray free-electron laser, we successfully determined the room-temperature crystal structure of the human AT(1)R in complex with its selective antagonist ZD7155 at 2.9-A resolution. The AT(1)R-ZD7155 complex structure revealed key structural features of AT(1)R and critical interactions for ZD7155 binding. Docking simulations of the clinically used ARBs into the AT(1)R structure further elucidated both the common and distinct binding modes for these anti-hypertensive drugs. Our results thereby provide fundamental insights into AT(1)R structure-function relationship and structure-based drug design. PMID- 25913195 TI - Interpreting the flock algorithm from a statistical perspective. AB - We show that the algorithm in the program flock (Duchesne & Turgeon 2009) can be interpreted as an estimation procedure based on a model essentially identical to the structure (Pritchard et al. 2000) model with no admixture and without correlated allele frequency priors. Rather than using MCMC, the flock algorithm searches for the maximum a posteriori estimate of this structure model via a simulated annealing algorithm with a rapid cooling schedule (namely, the exponent on the objective function ->infinity). We demonstrate the similarities between the two programs in a two-step approach. First, to enable rapid batch processing of many simulated data sets, we modified the source code of structure to use the flock algorithm, producing the program flockture. With simulated data, we confirmed that results obtained with flock and flockture are very similar (though flockture is some 200 times faster). Second, we simulated multiple large data sets under varying levels of population differentiation for both microsatellite and SNP genotypes. We analysed them with flockture and structure and assessed each program on its ability to cluster individuals to their correct subpopulation. We show that flockture yields results similar to structure albeit with greater variability from run to run. flockture did perform better than structure when genotypes were composed of SNPs and differentiation was moderate (FST= 0.022-0.032). When differentiation was low, structure outperformed flockture for both marker types. On large data sets like those we simulated, it appears that flock's reliance on inference rules regarding its 'plateau record' is not helpful. Interpreting flock's algorithm as a special case of the model in structure should aid in understanding the program's output and behaviour. PMID- 25913196 TI - Reduction in allergen-specific IgE binding as measured by microarray: A possible surrogate marker for effects of specific immunotherapy. PMID- 25913197 TI - Discriminating sputum-eosinophilic asthma: Accuracy of cutoffs in blood eosinophil measurements versus a composite index, ELEN. PMID- 25913198 TI - Stereoselective synthesis of 11-phenylundeca-5Z,9Z-dienoic acid and investigation of its human topoisomerase I and IIalpha inhibitory activity. AB - (5Z,9Z)-11-Phenylundeca-5,9-dienoic acid was stereoselectively synthesized, based on original cross-cyclomagnesiation of 2-(hepta-5,6-dien-1-yloxy)tetrahydro-2H pyran and buta-2,3-dien-1-ylbenzene with EtMgBr in the presence of Cp2TiCl2 catalyst giving 2,5-dialkylidenemagnesacyclopentane in 86% yield. The acid hydrolysis of the product and the Jones oxidation of the resulting 2-{[(5Z,9Z)-11 phenylundeca-5,9-dien-1-yl]oxy}tetrahydro-2N-pyran afforded (5Z,9Z)-11 phenylundeca-5,9-dienoic acid in an overall yield of 75%. A high inhibitory activity of the synthesized acid with respect to human topoisomerase I (hTop1) and II (hTop2alpha) was determined. PMID- 25913199 TI - Sulfonamide inhibition study of the beta-class carbonic anhydrase from the caries producing pathogen Streptococcus mutans. AB - Streptococcus mutans, the oral pathogenic bacterium provoking dental caries formation, encodes for a beta-class carbonic anhydrase (CA, EC 4.2.1.1), SmuCA. This enzyme was cloned, characterized and investigated for its inhibition profile with the major class of CA inhibitors, the primary sulfonamides. SmuCA has a good catalytic activity for the CO2 hydration reaction, with a kcat of 4.2*10(5) s(-1) and kcat/Km of 5.8*10(7) M(-1)*s(-1), and is efficiently inhibited by most sulfonamides (KIs of 246 nM-13.5 MUM). The best SmuCA inhibitors were bromosulfanilamide, deacetylated acetazolamide, 4 hydroxymethylbenzenesulfonamide, a pyrimidine-substituted sulfanilamide derivative, aminobenzolamide and compounds structurally similar to it, as well as acetazolamide, methazolamide, indisulam and valdecoxib. These compounds showed inhibition constants ranging between 246 and 468 nM. Identification of effective inhibitors of this enzyme may lead to pharmacological tools useful for understanding the role of S. mutans CAs in dental caries formation, and eventually the development of pharmacological agents with a new mechanism of antibacterial action. PMID- 25913200 TI - Fluorescence reporting of G-quadruplex structures and modulating their DNAzyme activity using polyethylenimine-pyrene conjugate. AB - Four-stranded G-quadruplex structure is one of the most important non-canonical secondary structures of DNA formed by guanine (G)-rich sequences. G-rich DNA sequences are known to occur in the human genome, especially in the telomere 3' end and in oncogene promoters such as c-MYC and c-KIT. In this context, we designed pyrene-conjugated polyethylenimine (PEI-Py) as a fluorescence reporter for the recognition and detection of G-quadruplex structures of G-rich deoxyoligonucleotides and human telomere and gene promoter sequences, under ambient conditions. PEI-Py exhibited prominent pyrene excimer emission in the presence of G-quadruplex structures of G-rich deoxyoligonucleotides and biologically relevant DNA sequences. PEI-Py further displayed the modulation of DNAzyme activity of various G-quadruplex structures in the presence of hemin and hydrogen peroxide. PMID- 25913201 TI - Combined chemo- and photo-thermal therapy delivered by multifunctional theranostic gold nanorod-loaded microcapsules. AB - A polyelectrolyte microcapsule-based, cancer-targeting, and controlled drug delivery system has been developed as a multifunctional theranostic agent for synergistic cancer treatment. This new system, called FA-MC@GNR, is composed of folic acid (FA)-modified, multi-layered, hollow microcapsules loaded with gold nanorods (GNRs), and undergoes thermal degradation under near infrared (NIR) light. Either an NIR dye (MPA) or anti-cancer drug (doxorubicin, DOX) was loaded into the microcapsules via physical adsorption, yielding FA-MC@GNRs/MPA or FA MC@GNRs/DOX, both of which exhibit no obvious toxicity, high stability, and remarkably improved tumor-targeting capabilities in vivo. Utilizing the strong NIR absorption of FA-MC@GNRs/DOX, we demonstrate the system's ability to simultaneously elicit photothermal therapy and controlled chemotherapy, achieving synergistic cancer treatment both in vitro cellular and in vivo animal experiments. Our study presents a new type of multifunctional micro-carrier for the delivery of chemotherapeutic drugs and photothermal agents, which has been shown to be an effective therapeutic approach for combined cancer treatment. PMID- 25913203 TI - Simple and Excellent Selective Chemiluminescence-Based CS2 On-Line Detection System for Rapid Analysis of Sulfur-Containing Compounds in Complex Samples. AB - To study the interesting chemical reaction phenomenon can greatly contribute to the development of an innovative analytical method. In this paper, a simple CL reaction cell was constructed to study the chemiluminescence (CL) emission from the thermal oxidation of carbon disulfide (CS2). We found that the CL detection of CS2 exhibits unique characteristics of excellent selectivity and rapid response capacity. Experimental investigations together with theoretical calculation were performed to study the mechanism behind the CL reaction. The results revealed that the main luminous intermediates generated during the thermal degradation of CS2 are SO2* and CO2*. Significantly, this CL emission phenomenon has a wide application due to many sulfur-containing compounds that can convert to CS2 under special conditions. On the basis of this scheme, a CS2 generating and detection system was developed for rapid measurement of CS2 or other compounds that can convert to CS2. The usefulness of the system was demonstrated by measuring dithiocarbamate (DTC) pesticides (selected mancozeb as a representative analyte) based on the evolution of CS2 in spiked agricultural products. Results showed that the system allows online and large volume detection of CS2 under nonequilibrium condition, which greatly reduces the analytical time. The concentrations of mancozeb in the spiked samples were well-quantified with satisfied recoveries of 76.9-97.3%. The system not only addresses the urgent need for rapid in-field screening of DTC residues in foodstuffs but also opens a new opportunity for the fast, convenient, and cost-effective detection of CS2 and some other sulfur-containing compounds in complex samples. PMID- 25913202 TI - Sry-type HMG box 18 contributes to the differentiation of bone marrow-derived mesenchymal stem cells to endothelial cells. AB - OBJECTIVE: Mesenchymal stem cells (MSC) have shown therapeutic potential to engraft and either differentiate into or support differentiation of vascular endothelial cells (EC), smooth muscle cells and cardiomyocytes in animal models of ischemic heart disease. Following intracoronary or transendocardial delivery of MSCs, however, only a small fraction of cells engraft and the majority of those persist as an immature cell phenotype. The goal of the current study was to decipher the molecular pathways and mechanisms that control MSC differentiation into ECs. Vascular endothelial growth factor (VEGF-165) treatment is known to enhance in vitro differentiation of MSCs into ECs. We tested the possible involvement of the Sry-type HMG box (Sox) family of transcription factors in this process. METHOD AND RESULTS: MSCs were isolated from the bone marrow of Yucatan microswine and underwent a 10 day differentiation protocol. VEGF-165 (50ng/ml) treatment of MSCs in vitro induced a significant increase in the protein expression of VEGFR-2, Sox9 and Sox18, in addition to the EC markers PECAM-1, VE cadherin and vWF, as determined by Western blot or flow cytometry. siRNA-mediated knockdown of Sox18, as opposed to Sox9, in MSCs prevented VEGF-165-mediated induction of EC markers and capillary tube formation. Inhibition of VEGFR-2 signaling (SC-202850) reduced Sox18 and reduced VEGF-165-induced differentiation of MSCs to ECs. CONCLUSION: Here we demonstrate that VEGF-165 mediates MSC differentiation into ECs via VEGFR-2-dependent induction of Sox18, which ultimately coordinates the transcriptional upregulation of specific markers of the EC phenotype. PMID- 25913204 TI - chipPCR: an R package to pre-process raw data of amplification curves. AB - MOTIVATION: Both the quantitative real-time polymerase chain reaction (qPCR) and quantitative isothermal amplification (qIA) are standard methods for nucleic acid quantification. Numerous real-time read-out technologies have been developed. Despite the continuous interest in amplification-based techniques, there are only few tools for pre-processing of amplification data. However, a transparent tool for precise control of raw data is indispensable in several scenarios, for example, during the development of new instruments. RESULTS: chipPCR is an R: package for the pre-processing and quality analysis of raw data of amplification curves. The package takes advantage of R: 's S4 object model and offers an extensible environment. chipPCR contains tools for raw data exploration: normalization, baselining, imputation of missing values, a powerful wrapper for amplification curve smoothing and a function to detect the start and end of an amplification curve. The capabilities of the software are enhanced by the implementation of algorithms unavailable in R: , such as a 5-point stencil for derivative interpolation. Simulation tools, statistical tests, plots for data quality management, amplification efficiency/quantification cycle calculation, and datasets from qPCR and qIA experiments are part of the package. Core functionalities are integrated in GUIs (web-based and standalone shiny applications), thus streamlining analysis and report generation. AVAILABILITY AND IMPLEMENTATION: http://cran.r-project.org/web/packages/chipPCR. Source code: https://github.com/michbur/chipPCR. CONTACT: stefan.roediger@b-tu.de SUPPLEMENTARY INFORMATION: Supplementary data are available at Bioinformatics online. PMID- 25913205 TI - Genome-scale strain designs based on regulatory minimal cut sets. AB - MOTIVATION: Stoichiometric and constraint-based methods of computational strain design have become an important tool for rational metabolic engineering. One of those relies on the concept of constrained minimal cut sets (cMCSs). However, as most other techniques, cMCSs may consider only reaction (or gene) knockouts to achieve a desired phenotype. RESULTS: We generalize the cMCSs approach to constrained regulatory MCSs (cRegMCSs), where up/downregulation of reaction rates can be combined along with reaction deletions. We show that flux up/downregulations can virtually be treated as cuts allowing their direct integration into the algorithmic framework of cMCSs. Because of vastly enlarged search spaces in genome-scale networks, we developed strategies to (optionally) preselect suitable candidates for flux regulation and novel algorithmic techniques to further enhance efficiency and speed of cMCSs calculation. We illustrate the cRegMCSs approach by a simple example network and apply it then by identifying strain designs for ethanol production in a genome-scale metabolic model of Escherichia coli. The results clearly show that cRegMCSs combining reaction deletions and flux regulations provide a much larger number of suitable strain designs, many of which are significantly smaller relative to cMCSs involving only knockouts. Furthermore, with cRegMCSs, one may also enable the fine tuning of desired behaviours in a narrower range. The new cRegMCSs approach may thus accelerate the implementation of model-based strain designs for the bio based production of fuels and chemicals. AVAILABILITY AND IMPLEMENTATION: MATLAB code and the examples can be downloaded at http://www.mpi magdeburg.mpg.de/projects/cna/etcdownloads.html. CONTACT: krishna.mahadevan@utoronto.ca or klamt@mpi-magdeburg.mpg.de SUPPLEMENTARY INFORMATION: Supplementary data are available at Bioinformatics online. PMID- 25913206 TI - kSNP3.0: SNP detection and phylogenetic analysis of genomes without genome alignment or reference genome. AB - We announce the release of kSNP3.0, a program for SNP identification and phylogenetic analysis without genome alignment or the requirement for reference genomes. kSNP3.0 is a significantly improved version of kSNP v2. AVAILABILITY AND IMPLEMENTATION: kSNP3.0 is implemented as a package of stand-alone executables for Linux and Mac OS X under the open-source BSD license. The executable packages, source code and a full User Guide are freely available at https://sourceforge.net/projects/ksnp/files/ CONTACT: barryghall@gmail.com. PMID- 25913207 TI - DockStar: a novel ILP-based integrative method for structural modeling of multimolecular protein complexes. AB - MOTIVATION: Atomic resolution modeling of large multimolecular assemblies is a key task in Structural Cell Biology. Experimental techniques can provide atomic resolution structures of single proteins and small complexes, or low resolution data of large multimolecular complexes. RESULTS: We present a novel integrative computational modeling method, which integrates both low and high resolution experimental data. The algorithm accepts as input atomic resolution structures of the individual subunits obtained from X-ray, NMR or homology modeling, and interaction data between the subunits obtained from mass spectrometry. The optimal assembly of the individual subunits is formulated as an Integer Linear Programming task. The method was tested on several representative complexes, both in the bound and unbound cases. It placed correctly most of the subunits of multimolecular complexes of up to 16 subunits and significantly outperformed the CombDock and Haddock multimolecular docking methods. AVAILABILITY AND IMPLEMENTATION: http://bioinfo3d.cs.tau.ac.il/DockStar CONTACT: naamaamir@mail.tau.ac.il or wolfson@tau.ac.il SUPPLEMENTARY INFORMATION: Supplementary data are available at Bioinformatics online. PMID- 25913208 TI - phylogeo: an R package for geographic analysis and visualization of microbiome data. AB - MOTIVATION: We have created an R package named phylogeo that provides a set of geographic utilities for sequencing-based microbial ecology studies. Although the geographic location of samples is an important aspect of environmental microbiology, none of the major software packages used in processing microbiome data include utilities that allow users to map and explore the spatial dimension of their data. phylogeo solves this problem by providing a set of plotting and mapping functions that can be used to visualize the geographic distribution of samples, to look at the relatedness of microbiomes using ecological distance, and to map the geographic distribution of particular sequences. By extending the popular phyloseq package and using the same data structures and command formats, phylogeo allows users to easily map and explore the geographic dimensions of their data from the R programming language. AVAILABILITY AND IMPLEMENTATION: phylogeo is documented and freely available http://zachcp.github.io/phylogeo CONTACT: : zcharlop@rockefeller.edu. PMID- 25913209 TI - Selective enrichment of metal-binding proteins based on magnetic core/shell microspheres functionalized with metal cations. AB - Metal binding proteins play many important roles in a broad range of biological processes. Characterization of metal binding proteins is important for understanding their structure and biological functions, thus leading to a clear understanding of metal associated diseases. The present study is the first to investigate the effectiveness of magnetic microspheres functionalized with metal cations (Ca(2+), Cu(2+), Zn(2+) and Fe(3+)) as the absorbent matrix in IMAC technology to enrich metal containing/binding proteins. The putative metal binding proteins in rat liver were then globally characterized by using this strategy which is very easy to handle and can capture a number of metal binding proteins effectively. In total, 185 putative metal binding proteins were identified from rat liver including some known less abundant and membrane-bound metal binding proteins such as Plcg1, Acsl5, etc. The identified proteins are involved in many important processes including binding, catalytic activity, translation elongation factor activity, electron carrier activity, and so on. PMID- 25913210 TI - Severe congenital actin related myopathy with myofibrillar myopathy features. AB - Mutations in ACTA1 have been associated with different pathologic findings including nemaline myopathy, intranuclear rod myopathy, actin myopathy, cap myopathy, congenital fiber type disproportion, and core myopathy. Myofibrillar myopathies are morphologically distinct but genetically heterogeneous muscular dystrophies arising from mutations in Z-disk related proteins. We report a 26 month-old boy with significantly delayed motor development requiring mechanical ventilation and tube-feeding since birth. The muscle biopsy displayed typical features of myofibrillar myopathy with abnormal expression of multiple proteins. Whole exome sequencing revealed two-amino-acid duplication in ACTA1. In cell culture system, mutant actin was expressed at ~11% of wild-type, and mutant actin formed pleomorphic cytoplasmic aggregates whereas wild-type actin appeared in filamentous structures. We conclude that mutations in ACTA1 can cause pathologic features consistent with myofibrillar myopathy, and mutations in ACTA1 should be considered in patients with severe congenital hypotonia associated with muscle weakness and features of myofibrillar myopathy. PMID- 25913212 TI - A traditional Chinese medicine, Lujiao prescription, as a potential therapy for hypertrophic cardiomyocytes by acting on histone acetylation. AB - BACKGROUND: Chronic heart failure (CHF) is a complex clinical syndrome, and a serious stage of various heart diseases. Dysfunction of histone acetylation is involved in pathogenesis of CHF. Lujiao is a clinical and traditional prescription that has been previously used in the treatment of heart failure. The objective of our study was to explore the effects of traditional Chinese Medicine intervention with Lujiao prescription on hypertrophic cardiomyocytes with histone acetylation abnormality. METHODS: Myocardial cells from neonatal rats were stimulated via phenylephrine (PE) and then randomly divided into seven groups: normal group (without any treatment), model group (treated with saline), TSA group (treated with trichostatin A), perindopril group (treated with perindopril), and the high, medium, and low dose of Lujiao groups (treated with 2.4 g/mL, 1.2 g/mL, and 0.6 g/mL of Lujiao, respectively). The test drug of perindopril group or Lujiao group was derived from serum after drug treatment in rats. Real-time polymerase chain reaction and Western blot were performed to analyze expression of myocyte enhancer factor 2 (MEF-2), alpha-major histocompatibility complex (MHC), and beta-MHC and acetylation level of histone H3. RESULTS: Expressions of MEF-2 and beta-MHC were significantly increased after PE treatment and decreased after drug treatment. Expression of alpha-MHC mRNA was significantly reduced after PE treatment and increased after being treated with Lujiao prescription, perindopril, and TSA. The acetylation level of histone H3 decreased in rat myocardial cells stimulated by PE 48 for hours and this decrease was reversed after treatment with high and medium doses of Lujiao prescription, perindopril and TSA. CONCLUSION: Histone acetylation-MEF-2-alpha-MHC/beta-MHC axis was discovered in myocardial hypertrophy, and intervention of Lujiao prescription exhibited good effects. PMID- 25913211 TI - A functional scale for spinal and bulbar muscular atrophy: Cross-sectional and longitudinal study. AB - We aimed to develop, validate, and evaluate a disease-specific outcome measure for SBMA: the Spinal and Bulbar Muscular Atrophy Functional Rating Scale (SBMAFRS). We examined the Japanese version (SBMAFRS-J) in 80 Japanese SBMA subjects to evaluate its validity and reliability. We then assessed this scale longitudinally in 41 additional SBMA subjects. The English version (SBMAFRS-E) was also tested in 15 US subjects. The total score of the SBMAFRS-J was distributed normally without an extreme ceiling or floor effect. For SBMAFRS-J, the high intra- and inter-rater agreement was confirmed (intra-class correlation coefficients [ICCs] 0.910 and 0.797, respectively), and internal consistency was satisfactory (Cronbach's alpha 0.700-0.822). In addition, SBMAFRS-J demonstrated concurrent, convergent, and discriminant validity, except for the respiratory subscale. The inter-rater reliability and internal consistency of SBMAFRS-E were also satisfactory. Longitudinally, SBMAFRS-J showed a higher sensitivity to disease progression than the existing clinical measures. In conclusion, we developed and validated a disease-specific functional rating scale for SBMA in both Japanese and English versions, although it needs to be re-assessed in interventional studies with a larger sample size including English speaking subjects. PMID- 25913213 TI - A comparative study of microbial communities in four soil slurries capable of RDX degradation using illumina sequencing. AB - The nitramine explosive hexahydro-1,3,5-trinitro-1,3,5-triazine (RDX) has contaminated many military sites. Recently, attempts to remediate these sites have focused on biostimulation to promote RDX biodegradation. Although many RDX degrading isolates have been obtained in the laboratory, little is known about the potential of microorganisms to degrade this chemical while existing in a soil community. The current study examined and compared the RDX degrading communities in four soil slurries to elucidate the potential of natural systems to degrade this chemical. These soils were selected as they had no previous exposure to RDX, therefore their microbial communities offered an excellent baseline to determine changes following RDX degradation. High throughput sequencing was used to determine which phylotypes experienced an increase in relative abundance following RDX degradation. For this, total genomic DNA was sequenced from (1) the initial soil, (2) soil slurry microcosms following RDX degradation and (3) control soil slurry microcosms without RDX addition. The sequencing data provided valuable information on which phylotypes increased in abundance following RDX degradation compared to control microcosms. The most notable trend was the increase in abundance of Brevundimonas and/or unclassified Bacillaceae 1 in the four soils studied. Although isolates of the family Bacillaceae 1 have previously been linked to RDX degradation, isolates of the genus Brevundimonas have not been previously associated with RDX degradation. Overall, the data suggest these two phylotypes have key roles in RDX degradation in soil communities. PMID- 25913215 TI - Recent advances in automotive catalysis for NOx emission control by small-pore microporous materials. AB - The ever increasing demand to develop highly fuel efficient engines coincides with the need to minimize air pollution originating from the exhaust gases of internal combustion engines. Dramatically improved fuel efficiency can be achieved at air-to-fuel ratios much higher than stoichiometric. In the presence of oxygen in large excess, however, traditional three-way catalysts are unable to reduce NOx. Among the number of lean-NOx reduction technologies, selective catalytic reduction (SCR) of NOx by NH3 over Cu- and Fe-ion exchanged zeolite catalysts has been extensively studied over the past 30+ years. Despite the significant advances in developing a viable practical zeolite-based catalyst for lean NOx reduction, the insufficient hydrothermal stabilities of the zeolite structures considered cast doubts about their real-world applicability. During the past decade renewed interest in zeolite-based lean NOx reduction was spurred by the discovery of the very high activity of Cu-SSZ-13 (and the isostructural Cu SAPO-34) in the NH3-SCR of NOx. These new, small-pore zeolite-based catalysts not only exhibited very high NOx conversion and N2 selectivity, but also exhibited exceptionally high hydrothermal stability at high temperatures. In this review we summarize the key discoveries of the past ~5 years that led to the introduction of these catalysts into practical applications. This review first briefly discusses the structure and preparation of the CHA structure-based zeolite catalysts, and then summarizes the key learnings of the rather extensive (but not complete) characterisation work. Then we summarize the key findings of reaction kinetic studies, and provide some mechanistic details emerging from these investigations. At the end of the review we highlight some of the issues that still need to be addressed in automotive exhaust control catalysis. PMID- 25913214 TI - Comparison of the Efficiencies of Buffers Containing Ankaferd and Chitosan on Hemostasis in an Experimental Rat Model with Femoral Artery Bleeding. AB - OBJECTIVE: In the first assessment of trauma patients with major vascular injuries, we need effective and rapid-acting homeostatic materials. In this study we compare the efficiencies of Ankaferd Blood Stopper(r) and a chitosan linear polymer (Celox(r)) in an experimental rat model with femoral artery bleeding. MATERIALS AND METHODS: Thirty male Wistar albino rats weighing 200-250 g were divided into 3 groups: control, Ankaferd, and chitosan. The femoral artery and vein were visualized and bleeding was started by an incision. The bleeding time was recorded and categorized as 'bleeding stopped at the second minute', 'bleeding stopped at the fourth minute', and 'unsuccessful' if bleeding continued after the fourth minute. RESULTS: In the control group, 60% of the bleeding did not stop. In the first 4 min in the Ankaferd group, the bleeding stopped in all rats; only in 1 of the rats in the chitosan group did the bleeding not stop. In stopping the bleeding in the first 4 min, Ankaferd was similar to chitosan but better than the control group; the chitosan group was similar to the control, but the p-value was close to significance. CONCLUSION: For major arterial bleeding, the main treatment is surgical bleeding control, but outside of the hospital we can use buffers containing Ankaferd and chitosan on the bleeding region. The results of this study should be supported with larger studies. Furthermore, in our study, healthy rats were used. New studies are needed to evaluate the results of hypovolemic and hypotensive cases with major artery bleeding. PMID- 25913216 TI - The expression of astrocyte elevated gene-1 in human non-small-cell lung cancer and its relationship with postoperative chemotherapy and radiotherapy. AB - AIMS: To examine the expression of astrocyte elevated gene-1 (AEG-1) in non-small cell lung cancer (NSCLC) and analyse the correlation between AEG-1 expression and the prognosis of the patients, particularly the relationship between AEG-1 expression and postoperative chemotherapy and radiotherapy. METHODS: The expression of AEG-1 was analysed by immunohistochemistry in 225 primary NSCLC specimens and 42 adjacent normal lung tissue specimens. Statistical analyses were performed to evaluate the correlation between AEG-1 expression and the clinicopathological characteristics of the patients as well as the predictive value of AEG-1. RESULTS: The expression of AEG-1 was associated with the pathological stage (P < 0.001) and lymph node status (P = 0.028). A multivariate analysis indicated that AEG-1 expression was an independent prognostic factor for both overall survival (OS) and disease-free survival (DFS). In the postoperative chemotherapy group, the OS (P = 0.014) and DFS (P = 0.009) in the low AEG-1 expression group were longer than the survival times in the high AEG-1 expression group. In the postoperative radiotherapy group, the local recurrence-free survival was significantly shorter in patients whose tumours showed high AEG-1 expression (P = 0.016). CONCLUSIONS: AEG-1 expression could be a predictor for OS and DFS in NSCLC patients. Patients with low AEG-1 expression received the greatest benefit from both postoperative chemotherapy and radiotherapy. PMID- 25913217 TI - Ultra-Small, High-Frequency, and Substrate-Immune Microtube Inductors Transformed from 2D to 3D. AB - Monolithic on-chip inductors are key passive devices in radio frequency integrated circuits (RFICs). Currently, 70-80% of the on-wafer area of most RFIC chips is occupied by the sprawling planar spiral inductors, and its operation frequency is limited to a few GHz. With continuous scaling of the transistor technology, miniaturization and high frequency operation of inductors have become the bottleneck to meet future demands of wireless communication systems. Here we report on-chip self-rolled-up 3D microtube inductors with extremely small footprint, unprecedented high frequency performance and weak dependence on substrate conductivity. The serpentine metal strips are deposited on an oppositely strained silicon nitrides (SiNx) bilayer. After releasing from the sacrificial layer underneath, the metal/SiNx layer is scrolled into a 3D hollow tubular structure by the strain induced unidirectional self-rolled-up technology. Compared to the planar spiral inductors with similar inductances and quality (Q) factors, the footprint of tube inductors is reduced by as much as two orders of magnitude, and the frequency at peak Q factor improves more than 5 times on doped substrates. The self-rolled-up 3D nanotechnology platform employed here, that "processes in 2D but functions in 3D", is positioned to serve as a global solution for extreme RFIC miniaturization with improved performance. PMID- 25913218 TI - Patient reported burden of asthma on resource use and productivity across 11 countries in Europe. AB - INTRODUCTION: Asthma affects 30 million people in Western Europe, leading to substantial burden on healthcare systems and economies. REcognise Asthma and LInk to Symptoms and Experience (REALISETM) was a large European survey across 11 countries assessing patient attitudes and behaviors towards their asthma. The present study utilizes REALISETM data to understand resource use and absenteeism in asthma. METHODS: Data were collected on absenteeism and healthcare resource use from 8000 asthma patients (aged 18-50 years) across the 11 countries. All data were patient reported. Odds ratios (ORs) were calculated against the country with the lowest proportion of respondents for hospitalization (as a proxy for lowest resource use). RESULTS: Patient characteristics were broadly similar across countries. However, self-reported asthma control status varied. More than 50% of respondents in most countries considered primary healthcare professionals (HCPs), i.e., general practitioners and nurses, the main HCP they see about their asthma. However, in some countries, specialists or nurses were considered the main HCP. Hospitalization was lowest amongst patients in the Netherlands. Resource use and productivity loss varied widely across the countries; ORs for hospitalization ranged from 1 in Sweden to 4 in Norway and for productivity loss from 0.6 in Sweden to 2.6 in Italy, compared with the Netherlands. CONCLUSION: This study quantified utilization of healthcare resources in asthma (number of visits of HCPs, hospitalization, and accident and emergency visits) as well as absenteeism and showed that differences exist across countries. The differences in primary care and specialist use suggest a possible difference in healthcare delivery across countries. FUNDING: Mundipharma International Limited, Cambridge, UK. PMID- 25913219 TI - Are depressive symptomatology, self-efficacy, and perceived social support related to disability and quality of life in patients with chronic migraine associated to medication overuse? Data from a cross-sectional study. AB - BACKGROUND: Chronic migraine with medication overuse (CM-MO) impairs quality of life (QoL) and causes disability. Psychosocial variables such as depressive symptomatology, self-efficacy, and social support have been sparingly investigated, and their impact on disability and QoL is unknown. METHODS: Patients with CM-MO under withdrawal were consecutively enrolled. Standardized measures of disability and QoL were used as outcomes; psychosocial (ie, mood state, self-efficacy, social support) and clinical (ie, headache frequency and intensity) variables were considered as associated variables. Associations between these variables, disability, and QoL were tested with Pearson's correlations. Hierarchical multiple regression was used to assess the cumulative contribution of psychosocial variables on disability and QoL variation when added to clinical variables. RESULTS: One hundred ninety-four patients were enrolled; 82.5% were females and mean age was 43.9. Disability and QoL were moderately or little correlated to clinical and psychosocial variables. Models based on clinical variables explained 7.5-14.3% of disability and QoL variation, with pain intensity being the only significant predictor; when psychosocial variables were added, the explained variation increased to 21.5-35.2%, with depressive symptomatology always having independent predictive power and perceived social support having independent predictive power in the regression model over role prevention component of QoL. CONCLUSIONS: Adding information on psychosocial variables to headache features improved our ability to understand disability and QoL of CM-MO patients. We deem that the inclusion of psychosocial variables in standard evaluation protocols may contribute to the global assessment of CM-MO patients, and eventually to their success in reducing the personal and social impact of this condition. Future longitudinal studies are needed to confirm this hypothesis. PMID- 25913221 TI - beta-Ga2O3:Cr(3+) nanoparticle: A new platform with near infrared photoluminescence for drug targeting delivery and bio-imaging simultaneously. AB - Multifunctional nanoparticles which integrate the therapeutic agents and bio imaging agents into one carrier are emerging as a promising therapeutic platform. Herein, GaOOH:Cr(3+) was firstly synthesized using improved hydrothermal method (atmospheric pressure, 95 degrees C), and by manipulating the pH of the reaction medium, GaOOH:Cr(3+) with different sizes (125.70 nm, 200.60 nm and 313.90 nm) were synthesized. Then beta-Ga2O3:Cr(3+) nanoparticles with porous structures were developed as a result of the calcination of GaOOH:Cr(3+). The fabricated, porous beta-Ga2O3:Cr(3+) nanoparticles could effectively absorb doxorubicin hydrochloride (DOX) (loading rate: 8% approximately) and had near infrared photoluminescence with a 695 nm emission. Furthermore, beta-Ga2O3:Cr(3+) nanoparticles were coated with l-Cys modified hyaluronic acid (HA-Cys) by exploiting the electrostatic interaction and the cross-link effect of disulfide bond to improve the stability. The DOX loaded HA-Cys coated beta-Ga2O3:Cr(3+) nanoparticles (HA/beta-Ga2O3:Cr(3+)/DOX) showed an oxidation-reduction sensitive drug release behavior. The HA-Cys coated beta-Ga2O3:Cr(3+) nanoparticles showed a low cytotoxicity on MCF-7 and Hela cell lines. The cellular uptake of HA/beta Ga2O3:Cr(3+)/DOX using the near infrared photoluminescence of beta-Ga2O3:Cr(3+) nanoparticles and the fluorescence of DOX demonstrated the HA/beta Ga2O3:Cr(3+)/DOX could internalize into tumor cells quickly, which was affected by the size and shape of beta-Ga2O3:Cr(3+)nanoparticles. PMID- 25913220 TI - Neuroendocrine control of the onset of puberty. AB - This chapter is based on the Geoffrey Harris Memorial Lecture presented at the 8th International Congress of Neuroendocrinology, which was held in Sydney, August 2014. It provides the development of our understanding of the neuroendocrine control of puberty since Harris proposed in his 1955 monograph (Harris, 1955) that "a major factor responsible for puberty is an increased rate of release of pituitary gonadotrophin" and posited "that a neural (hypothalamic) stimulus, via the hypophysial portal vessels, may be involved." Emphasis is placed on the neurobiological mechanisms governing puberty in highly evolved primates, although an attempt is made to reverse translate a model for the timing of puberty in man and monkey to non-primate species. PMID- 25913223 TI - A quality improvement initiative to optimize use of a mechanical chest compression device within a high-performance CPR approach to out-of-hospital cardiac arrest resuscitation. AB - BACKGROUND: Minimizing the chest compression pause associated with application of a mechanical CPR device is a key component of optimal integration into the overall resuscitation process. As part of a multi-agency implementation project, Anchorage Fire Department deployed LUCAS CPR devices on BLS and ALS fire apparatus for initiation early in resuscitation efforts. A 2012 report identified the pause interval for device application as a key opportunity for quality improvement (QI). In early 2013 we began a QI initiative to reduce device application time interval and optimize the overall CPR process. To assess QI initiative effectiveness, we compared key CPR process metrics from before to during and after its implementation. METHODS: We included all cases of EMS treated out-of-hospital cardiac arrest during 2012 and 2013 in which a mechanical CPR device was used and the defibrillator electronic record was available. Continuous ECG and impedance data were analyzed to measure chest compression fraction, duration of the pause from last manual to first mechanical compression, and duration of the longest overall pause in the resuscitation effort. RESULTS: Compared to cases from 2012 (n = 61), median duration of the pause prior to first mechanical compression for cases from 2013 (n = 71) decreased from 21 (15, 31) to 7 (4, 12)s (p < 0.001), while median chest compression fraction increased from 0.90 (0.88, 0.93) to 0.95 (0.93, 0.96) (p < 0.001). Median duration of the longest pause decreased from 25 (20, 35) to 13 (10, 20)s (p < 0.001), while the proportion of cases where the longest pause was for mechanical CPR application decreased from 74% to 31% (p < 0.001). CONCLUSIONS: Our QI initiative substantially reduced the duration of the pause prior to first mechanical compression. Combined with the simultaneous significant increase in compression fraction and significant decrease in duration of the longest pause, this finding strongly suggests a large improvement in mechanical CPR device application efficiency within an overall high-performance CPR process. PMID- 25913222 TI - Enzymatically degradable poly(ethylene glycol) hydrogels for the 3D culture and release of human embryonic stem cell derived pancreatic precursor cell aggregates. AB - This study aimed to develop a three dimensional culture platform for aggregates of human embryonic stem cell (hESC)-derived pancreatic progenitors that enables long-term culture, maintains aggregate size and morphology, does not adversely affect differentiation and provides a means for aggregate recovery. A platform was developed with poly(ethylene glycol) hydrogels containing collagen type I, for cell-matrix interactions, and peptide crosslinkers, for facile recovery of aggregates. The platform was first demonstrated with RIN-m5F cells, showing encapsulation and subsequent release of single cells and aggregates without adversely affecting viability. Aggregates of hESC-derived pancreatic progenitors with an effective diameter of 82 (15)MUm were either encapsulated in hydrogels or cultured in suspension for 28 days. At day 14, aggregate viability was maintained in the hydrogels, but significantly reduced (88%) in suspension culture. However by day 28, viability was reduced under both culture conditions. Aggregate size was maintained in the hydrogels, but in suspension was significantly higher (~ 2 fold) by day 28. The ability to release aggregates followed by a second enzyme treatment to achieve single cells enabled assessment by flow cytometry. Prior to encapsulation, there were 39% Pdx1(+)/Nkx6.1(+) cells, key endocrine markers required for beta-cell maturation. The fraction of doubly positive cells was not affected in hydrogels but was slightly and significantly lower in suspension culture by 28 days. In conclusion, we demonstrate that a MMP-sensitive PEG hydrogel containing collagen type I is a promising platform for hESC-derived pancreatic progenitors that maintains viable aggregates, aggregate size, and progenitor state and offers facile recovery of aggregates. PMID- 25913224 TI - Re-emergence of porcine epidemic diarrhea virus in the global pig population. PMID- 25913225 TI - Choroid plexus papilloma arising in a mature cystic teratoma of the ovary: A short case report and literature review. PMID- 25913226 TI - Metabolic control of signalling pathways and metabolic auto-regulation. AB - Metabolic alterations have emerged as an important hallmark in the development of various diseases. Thus, understanding the complex interplay of metabolism with other cellular processes such as cell signalling is critical to rationally control and modulate cellular physiology. Here, we review in the context of mammalian target of rapamycin, AMP-activated protein kinase and p53, the orchestrated interplay between metabolism and cellular signalling as well as transcriptional regulation. Moreover, we discuss recent discoveries in auto regulation of metabolism (i.e. how metabolic parameters such as metabolite levels activate or inhibit enzymes and thus metabolic pathways). Finally, we review functional consequences of post-translational modification on metabolic enzyme abundance and/or activities. PMID- 25913227 TI - Colorectal multidisciplinary meetings: how do they affect the timeliness of treatment? AB - BACKGROUND: The aim of this study is to determine whether multidisciplinary team (MDT) meetings alter the length of time to treatment (LOTT) for patients with colorectal cancer. METHODS: We conducted a retrospective audit of all patients with colorectal cancer from the Geelong Hospital (TGH) mandatory colorectal database from 1 January 2006 to 3 February 2011. To be included, patients had to have had elective surgical intervention for primary colorectal adenocarcinoma. A comparison of historical controls was conducted between patients discussed in MDT meetings and those managed prior to the introduction of MDT meetings (3 October 2006) to determine the LOTT in days from definitive diagnosis (colonoscopy) to definitive management (surgery, radiotherapy or chemotherapy). RESULTS: In total, the median LOTT for the historical control and MDT era patient populations were 19.5 and 20 days, respectively. Within the MDT era, we noticed significantly longer times to treatment for patients with rectal cancer who were seen in an MDT meeting prior to definitive management than patients who did not have an intervening MDT meeting (P < 0.001). With a difference of 7.5 days, the clinical significance of these findings remains contentious. However, it is worthwhile recognizing this trend in patients who are exhibiting symptoms due to near obstruction or significant bleeding. The LOTT for colon cancer patients remained unchanged. CONCLUSION: The introduction of MDT meetings to TGH has prolonged the LOTT for patients with rectal cancer. These findings pave the way for further revision of the efficiency of MDT meeting at TGH. PMID- 25913229 TI - Exposure to dust-bound PAHs and associated carcinogenic risk in primitive and traditional cooking practices in Pakistan. AB - The aim of this study was to determine the abundance and distribution of polycyclic aromatic hydrocarbons (PAHs) in dust samples collected from the selected professional cooking workplaces (WCs) and residential household cooking areas (WRs), where traditional and primitive cooking practices are still prevelent. Another aim of this study was to investigate the carcinogenic risk for Pakistani human exposure to dust-bound PAHs via the routes of inhalation, ingestion, and dermal contact. Generally, the concentration of individual congeners of PAHs in surface dust samples of WC sites was higher than those measured in WR sites (p < 0.05). The benzo(a)pyrene (B(a)P), a very high carcinogenic compound, was present in the dust samples from WC sites in the highest mean concentration (630 ng g(-1) dry weight (d.w.)). The BaP mean concentration in WC workplaces was almost eight times higher than the mean value found in WR exposure sites. Moreover, the average concentration of ?PAHs, combustion origin PAHs (?COMB) and sum total of 7-carcinogenic PAHs (?7 carcinogens) were also significantly higher in WC dusts samples than that in WR workplaces. Principal component analysis (PCA) and diagnostic ratios suggested coal/wood combustion as major PAH emission sources in both exposure sites. The average incremental lifetime cancer risk (ILCR) suggested a moderate to potential high cancer risk for adults and children exposed to dust-bound PAHs in both exposure sites, in particular via both dermal and ingestion contact pathways. PMID- 25913230 TI - Characteristics of clinical N0 metastatic non-small cell lung cancer. AB - OBJECTIVES: Non-small cell lung cancer (NSCLC) patients who have clinically no mediastinal lymph node metastasis but have distant metastasis are occasionally found in clinical practice. Such clinical N0 metastatic NSCLC may be a different subtype from the clinical N1-3 patients with regional lymph node metastasis. The aim of this study was to evaluate the prognosis, clinical features, and incidence of clinical N0 NSCLC patients with metastasis. METHODS: All metastatic NSCLC patients (n=761) diagnosed at our hospitals from April 1999 to August 2012 were retrospectively analyzed. They were divided into two groups: N0 and N1-3. Staging was recorded according to the UICC 7th edition of the TNM classification. Differences between the two groups were analyzed using a Chi-square test. Prognostic factors were analyzed by the Kaplan-Meier method and Cox proportional hazards analysis. A probability value less than 0.05 was considered to be significant. RESULTS: A total of 761 patients with NSCLC were registered. 124 patients (16.3%) were N0 and 637 (83.7%) were N1-3. There were no differences between the two groups in age, sex, smoking history, performance status, and histological type. The ratio of adrenal gland metastasis was low in the N0 group (N0 7.3%, N1-3 13.4%, p=0.002). Median survival time was longer in the N0 group (N0 11.9 months vs N1-3 7.2 months, p<0.001). N0 was an independent favorable prognostic factor. CONCLUSION: Metastatic NSCLC patients with clinical N0 had a favorable prognosis and a lower ratio of adrenal gland metastasis than those with clinical N1-3. Our results suggest that a certain type of adrenal metastasis may result from direct lymphatic spread from a primary lung tumor. About one sixth of metastatic NSCLC cases are clinical N0. Therefore, clinical evaluations for detecting metastasis are important even in clinical N0 patients. PMID- 25913231 TI - Surgical Dislocation of the Hip for the Treatment of Pre-Arthritic Hip Disease. AB - The purpose of this study was to report the clinical results of surgical dislocation of the hip in the treatment of pre-arthritic hip disease. Between 2005 and 2010, eighty-two patients (89 hips) underwent a surgical dislocation of the hip at a mean age of 30.5 years (range 14.8-51.7); 10 females and 72 males. At a mean follow-up of 7.1 years (range 5-9.6) clinical function improved significantly. 6 patients were converted to total hip arthroplasty and 3 patients underwent an arthroscopy and an additional three patients had >1mm of joint space narrowing at latest follow-up giving us a 9-year cumulative Kaplan-Meier survivorship of 86.4% (CI, 79% to 94%). Thirty-four patients underwent internal fixation removal at a mean of 12.0 months (range 0.3-40.8 months). Although effective in the treatment of early hip disease, the surgical dislocation approach carries a high re-operation rate for removal of internal fixation; consequently, less invasive approaches should be considered for less complex deformities. PMID- 25913232 TI - Does Pre-Operative Physiotherapy Improve Outcomes in Primary Total Knee Arthroplasty? - A Systematic Review. AB - We undertook a systematic review of 11 randomised controlled trials comparing patient outcomes in total knee arthroplasty in those who had undergone pre operative physiotherapy-based interventions against control groups. Results show that there is little evidence that pre-operative physiotherapy brings about significant improvements in patient outcome scores, lower limb strength, pain, range of movement and hospital length of stay following total knee arthroplasty. The overall quality of the studies was moderate to poor, mostly due to the small sample sizes. PMID- 25913228 TI - Spatial and temporal trends of the Stockholm Convention POPs in mothers' milk -- a global review. AB - Persistent organic pollutants (POPs) have been of environmental and health concern for more than half a century and have their own intergovernmental regulation through the Stockholm Convention, from 2001. One major concern is the nursing child's exposure to POPs, a concern that has led to a very large number of scientific studies on POPs in mothers' milk. The present review is a report on the assessment on worldwide spatial distributions of POPs and of their temporal trends. The data presented herein is a compilation based on scientific publications between 1995 and 2011. It is evident that the concentrations in mothers' milk depend on the use of pesticides and industrial chemicals defined as POPs. Polychlorinated biphenyls (PCBs) and "dioxins" are higher in the more industrialized areas, Europe and Northern America, whereas pesticides are higher in Africa and Asia and polybrominated diphenyl ethers (PBDEs) are reported in higher concentrations in the USA. POPs are consequently distributed to women in all parts of the world and are thus delivered to the nursing child. The review points out several major problems in the reporting of data, which are crucial to enable high quality comparisons. Even though the data set is large, the comparability is hampered by differences in reporting. In conclusion, much more detailed instructions are needed for reporting POPs in mothers' milk. Temporal trend data for POPs in mothers' milk is scarce and is of interest when studying longer time series. The only two countries with long temporal trend studies are Japan and Sweden. In most cases, the trends show decreasing concentrations of POPs in mothers' milk. However, hexabromocyclododecane is showing increasing temporal concentration trends in both Japan and Sweden. PMID- 25913233 TI - Low-dimensional recurrent neural network-based Kalman filter for speech enhancement. AB - This paper proposes a new recurrent neural network-based Kalman filter for speech enhancement, based on a noise-constrained least squares estimate. The parameters of speech signal modeled as autoregressive process are first estimated by using the proposed recurrent neural network and the speech signal is then recovered from Kalman filtering. The proposed recurrent neural network is globally asymptomatically stable to the noise-constrained estimate. Because the noise constrained estimate has a robust performance against non-Gaussian noise, the proposed recurrent neural network-based speech enhancement algorithm can minimize the estimation error of Kalman filter parameters in non-Gaussian noise. Furthermore, having a low-dimensional model feature, the proposed neural network based speech enhancement algorithm has a much faster speed than two existing recurrent neural networks-based speech enhancement algorithms. Simulation results show that the proposed recurrent neural network-based speech enhancement algorithm can produce a good performance with fast computation and noise reduction. PMID- 25913234 TI - Association between new onset diabetic retinopathy and monocyte chemoattractant protein-1 (MCP-1) polymorphism in Japanese type 2 diabetes. AB - We longitudinally evaluated the association between monocyte chemoattractant protein-1 (MCP-1) A-2518G polymorphism and new onset of diabetic retinopathy in 758 type 2 diabetic patients. The new onset of retinopathy increased with the increase of the number of G alleles, even after adjustment for age, HbA1c levels, and duration of diabetes. PMID- 25913235 TI - Liver metastases from meningeal hemangiopericytoma. PMID- 25913236 TI - A large-scale initiative to disseminate an evidence-based drug abuse prevention program in Italy: Lessons learned for practitioners and researchers. AB - Across developed countries, experimentation with alcohol, tobacco, and other drugs often begins in the early adolescent years. Several evidence-based programs have been developed to prevent adolescent substance use. Many of the most rigorously tested and empirically supported prevention programs were initially developed and tested in the United States. Increasingly, these interventions are being adopted for use in Europe and throughout the world. This paper reports on a large-scale comprehensive initiative designed to select, adapt, implement, and sustain an evidence-based drug abuse prevention program in Italy. As part of a large-scale regionally funded collaboration in the Lombardy region of Italy, we report on processes through which a team of stakeholders selected, translated and culturally adapted, planned, implemented and evaluated the Life Skills Training (LST) school-based drug abuse prevention program, an evidence-based intervention developed in the United States. We discuss several challenges and lessons learned and implications for prevention practitioners and researchers attempting to undertake similar international dissemination projects. We review several published conceptual models designed to promote the replication and widespread dissemination of effective programs, and discuss their strengths and limitations in the context of planning and implementing a complex, large-scale real-world dissemination effort. PMID- 25913237 TI - Microbial secondary metabolites in homes in association with moisture damage and asthma. AB - We aimed to characterize the presence of microbial secondary metabolites in homes and their association with moisture damage, mold, and asthma development. Living room floor dust was analyzed by LC-MS/MS for 333 secondary metabolites from 93 homes of 1-year-old children. Moisture damage was present in 15 living rooms. At 6 years, 8 children had active and 15 lifetime doctor-diagnosed asthma. The median number of different metabolites per house was 17 (range 8-29) and median sum load 65 (4-865) ng/m(2) . Overall 42 different metabolites were detected. The number of metabolites present tended to be higher in homes with mold odor or moisture damage. The higher sum loads and number of metabolites with loads over 10 ng/m(2) were associated with lower prevalence of active asthma at 6 years (aOR 0.06 (95% CI <0.001-0.96) and 0.05 (<0.001-0.56), respectively). None of the individual metabolites, which presence tended (P < 0.2) to be increased by moisture damage or mold, were associated with increased risk of asthma. Microbial secondary metabolites are ubiquitously present in home floor dust. Moisture damage and mold tend to increase their numbers and amount. There was no evidence indicating that the secondary metabolites determined would explain the association between moisture damage, mold, and the development of asthma. PMID- 25913238 TI - Novel splice variants in the 5'UTR of Gtf2i expressed in the rat brain: alternative 5'UTRs and differential expression in the neuronal dendrites. AB - General transcription factor II-I (Gtf2i) is a transcription factor and one of the genes implicated in Willams-Beuren syndrome, an autism spectrum disorder. In this study, we investigated splice variants of the Gtf2i gene in both the 5'untranslated region (5'UTR) and the coding region. To search for novel 5'UTRs of Gtf2i, we utilized the cap analysis gene expression database of the mouse. We identified seven novel Gtf2i transcripts with alternatively spliced 5'UTRs in the rat brain. We also identified four novel splice variants in the coding sequence of Gtf2i. Furthermore, we identified a selective usage of certain types of 5'UTR by coding variants. In situ hybridization demonstrated a differential pattern of expression of Gtf2i mRNAs with alternatively spliced 5'UTRs among neuronal cells, and the localization of one of the variants in neuronal dendrites in the rat brain. Immunohistochemistry also demonstrated a distribution of Gtf2i immunoreactivity in the dendrites. These results suggest multiple pathways of expression of Gtf2i gene in the brain. The expression patterns may be under the control of alternative promoters coupled to the alternative splicing in the coding region. Differential localization of mRNA to neuronal dendrites suggests spatiotemporal-specific translation at the post-synaptic sites that is involved in transfer of synaptic activity to expression of specific sets of genes in the nucleus. Gtf2i is a transcription factor and implicated in Willams-Beuren syndrome. We identified seven novel Gtf2i transcripts with alternatively spliced 5'UTRs in the rat brain. In situ hybridization demonstrated a differential expression of Gtf2i mRNAs with different 5'UTRs in somas and dendrites of neuronal cells. Differential localization of mRNA to neuronal dendrites suggests spatiotemporal-specific translation at the postsynaptic sites. The scheme shows genomic structure showing the positions of the potential transcription start tags (rDEC695, rDEC3D7, rDEC1D3, rDEC104, rDEC072 and rDEBE25). Newly identified exons (1.1-1.6) are shown with the white boxes. The distances from rDEC695-5'end are indicated in bp. PMID- 25913239 TI - Antiplatelet effect of a newly developed AMP-activated protein kinase activator YLF-466D. AB - AMP-activated protein kinase (AMPK) acts as a major regulator of cellular energy homeostasis. In platelets, AMPK activation stimulates endothelial nitric oxide synthase (eNOS) and its downstream signaling, and thereby inhibits platelet aggregation. In this study, a newly developed AMPK activator 3-[[(3E)-3-[(4 chlorophenyl)phenylmethylene]-2,3-dihydro-2-oxo-1H-indol-1-yl]methyl]-benzoic acid (YLF-466D) was tested for its antiplatelet activity. Treatment of isolated platelets with YLF-466D resulted in AMPK activation in a concentration-dependent manner in a range of 50-150 MUM. Under the same experimental condition, YLF-466D effectively inhibited aggregation induced by platelet agonists including thrombin, ADP and collagen. Such AMPK activation and aggregation inhibition were abolished by pretreatment with the AMPK inhibitors compound C (CC) and ara-A, indicating that antiaggregatory effect of YLF-466D is mediated by AMPK. YLF-466D induced an activation-dependent eNOS phosphorylation at Ser1177, an elevation of cyclic nucleotides cGMP and cAMP, and subsequent phosphorylation of vasodilator stimulated phosphoprotein (VASP) at Ser239 and Ser157. All these events were prevented by CC and ara-A. In addition to isolated platelets, YLF-466D attenuated whole blood aggregation induced by collagen. Taken together, YLF-466D is capable of inhibiting platelet aggregation by activating AMPK and its downstream eNOS cGMP-PKG signaling axis. This study reconfirms the antiplatelet activity of AMPK activators and suggests the potential application of YLF-466D to antiplatelet therapy, although the in vivo and clinical validation remains to be assessed. PMID- 25913240 TI - Basal activity of voltage-gated Ca(2+) channels controls the IP3-mediated contraction by alpha(1)-adrenoceptor stimulation of mouse aorta segments. AB - alpha1-Adrenoceptor stimulation of mouse aorta causes intracellular Ca(2+) release from sarcoplasmic reticulum Ca(2+) stores via stimulation of inositoltriphosphate (IP3) receptors. It is hypothesized that this Ca(2+) release from the contractile and IP3-sensitive Ca(2+) store is under the continuous dynamic control of time-independent basal Ca(2+) influx via L-type voltage-gated Ca(2+) channels (LCC) residing in their window voltage range. Mouse aortic segments were alpha1-adrenoceptor stimulated with phenylephrine in the absence of external Ca(2+) (0Ca) to measure phasic isometric contractions. They gradually decreased with time in 0Ca, were inhibited with 2-aminoethoxydiphenyl borate, and declined with previous membrane potential hyperpolarization (levcromakalim) or with previous inhibition of LCC (diltiazem). Former basal stimulation of LCC with depolarization (15 mM K(+)) or with BAY K8644 increased the subsequent phasic contractions by phenylephrine in 0Ca. Although exogenous NO (diethylamine NONOate) reduced the phasic contractions by phenylephrine, stimulation of endothelial cells with acetylcholine in 0Ca failed to attenuate these phasic contractions. Finally, inhibition of the basal release of NO with N(Omega)-nitro L-arginine methyl ester also attenuated the phasic contractions by phenylephrine. Results indicated that alpha1-adrenoceptor stimulation with phenylephrine causes phasic contractions, which are controlled by basal LCC and endothelial NO synthase activity. Endothelial NO release by acetylcholine was absent in 0Ca. Given the growing interest in the active regulation of arterial compliance, the dependence of contractile SR Ca(2+) store-refilling in basal conditions on the activity of LCC and basal eNOS may contribute to a more thorough understanding of physiological mechanisms leading to arterial stiffness. PMID- 25913241 TI - Heterogeneous growth-induced prestrain in the heart. AB - Even when entirely unloaded, biological structures are not stress-free, as shown by Y.C. Fung's seminal opening angle experiment on arteries and the left ventricle. As a result of this prestrain, subject-specific geometries extracted from medical imaging do not represent an unloaded reference configuration necessary for mechanical analysis, even if the structure is externally unloaded. Here we propose a new computational method to create physiological residual stress fields in subject-specific left ventricular geometries using the continuum theory of fictitious configurations combined with a fixed-point iteration. We also reproduced the opening angle experiment on four swine models, to characterize the range of normal opening angle values. The proposed method generates residual stress fields which can reliably reproduce the range of opening angles between 8.7+/-1.8 and 16.6+/-13.7 as measured experimentally. We demonstrate that including the effects of prestrain reduces the left ventricular stiffness by up to 40%, thus facilitating the ventricular filling, which has a significant impact on cardiac function. This method can improve the fidelity of subject-specific models to improve our understanding of cardiac diseases and to optimize treatment options. PMID- 25913242 TI - Exercise capacity in the Bidirectional Glenn physiology: Coupling cardiac index, ventricular function and oxygen extraction ratio. AB - In Bi-directional Glenn (BDG) physiology, the superior systemic circulation and pulmonary circulation are in series. Consequently, only blood from the superior vena cava is oxygenated in the lungs. Oxygenated blood then travels to the ventricle where it is mixed with blood returning from the lower body. Therefore, incremental changes in oxygen extraction ratio (OER) could compromise exercise tolerance. In this study, the effect of exercise on the hemodynamic and ventricular performance of BDG physiology was investigated using clinical patient data as inputs for a lumped parameter model coupled with oxygenation equations. Changes in cardiac index, Qp/Qs, systemic pressure, oxygen extraction ratio and ventricular/vascular coupling ratio were calculated for three different exercise levels. The patient cohort (n=29) was sub-grouped by age and pulmonary vascular resistance (PVR) at rest. It was observed that the changes in exercise tolerance are significant in both comparisons, but most significant when sub-grouped by PVR at rest. Results showed that patients over 2 years old with high PVR are above or close to the upper tolerable limit of OER (0.32) at baseline. Patients with high PVR at rest had very poor exercise tolerance while patients with low PVR at rest could tolerate low exercise conditions. In general, ventricular function of SV patients is too poor to increase CI and fulfill exercise requirements. The presented mathematical model provides a framework to estimate the hemodynamic performance of BDG patients at different exercise levels according to patient specific data. PMID- 25913244 TI - Localized surface plasmon sensing based investigation of nanoscale metal oxidation kinetics. AB - The localized surface plasmon resonance (LSPR) of nanoparticles can be a powerful and sensitive probe of chemical changes in nanoscale volumes. Here we have used the LSPR of silver (Ag) to study the oxidation kinetics of nanoscopic volumes of cobalt (Co) metal. Bimetal nanoparticles of the immiscible Co-Ag system prepared by pulsed laser dewetting were aged in ambient air and the resulting changes to the LSPR signal and bandwidth were used to probe the oxidation kinetics. Co was found to preferentially oxidize first. This resulted in a significant enhancement by a factor of 8 or more in the lifetime of stable Ag plasmons over that of pure Ag. Theoretical modeling based on optical mean field approximation was able to predict the oxidation lifetimes and could help design stable Ag-based plasmonic nanoparticles for sensing applications. PMID- 25913243 TI - Biomechanics of head impacts associated with diagnosed concussion in female collegiate ice hockey players. AB - Epidemiological evidence suggests that female athletes may be at a greater risk of concussion than their male counterparts. The purpose of this study was to examine the biomechanics of head impacts associated with diagnosed concussions in a cohort of female collegiate ice hockey players. Instrumented helmets were worn by 58 female ice hockey players from 2 NCAA programs over a three year period. Kinematic measures of single impacts associated with diagnosed concussion and head impact exposure on days with and without diagnosed concussion were evaluated. Nine concussions were diagnosed. Head impact exposure was greater in frequency and magnitude on days of diagnosed concussions than on days without diagnosed concussion for individual athletes. Peak linear accelerations of head impacts associated with diagnosed concussion in this study are substantially lower than those previously reported in male athletes, while peak rotational accelerations are comparable. Further research is warranted to determine the extent to which female athletes' biomechanical tolerance to concussion injuries differs from males. PMID- 25913245 TI - Learning from marketing: Rapid development of medication messages that engage patients. AB - OBJECTIVE: To adapt marketing approaches in a health services environment. METHODS: Researchers and advertising professionals partnered in developing advertising-style messages designed to activate patients pre-identified as having chronic kidney disease to ask providers about recommended medications. We assessed feasibility of the development process by evaluating partnership structure, costs, and timeframe. We tested messages with patients and providers using preliminary surveys to refine initial messages and subsequent focus groups to identify the most persuasive ones. RESULTS: The partnership achieved an efficient structure, $14,550 total costs, and 4-month timeframe. The advertising team developed 11 initial messages. The research team conducted surveys and focus groups with a total of 13 patients and 8 providers to identify three messages as most activating. Focus group themes suggested the general approach of using advertising-style messages was acceptable if it supported patient-provider relationships and had a credible evidence base. Individual messages were more motivating if they elicited personal identification with imagery, particular emotions, active patient role, and message clarity. CONCLUSION: We demonstrated feasibility of a research-advertising partnership and acceptability and likely impact of advertising-style messages on patient medication-seeking behavior. PRACTICE IMPLICATIONS: Healthcare systems may want to replicate our adaptation of marketing approaches to patients with chronic conditions. PMID- 25913247 TI - The impact on ovarian reserve of haemostasis by bipolar coagulation versus suture following surgical stripping of ovarian endometrioma: a meta-analysis. AB - Concern is increasing that the use of bipolar coagulation or suturing to obtain haemostasis after surgical stripping of ovarian endometrioma could affect ovarian reserve. To compare the ovarian damage associated with the use of bipolar coagulation with ovarian suture as determined by anti-Mullerian hormone (AMH), FSH and antral follicle count, 21 studies were identified. Pooled analysis of 312 patients showed the average serum level of AMH was lower in the coagulation group than in the suture group (3-month follow-up: weighted mean difference (WMD) -0.75 ng/ml, 95% confidence interval (CI) -1.82 to 0.31; 6 months: WMD -1.45 ng/ml, 95% CI -2.43 to -0.47; 12 months: WMD -1.01 ng/ml; 95% CI -1.85 to -0.17), although heterogeneity was high. The weighted overall average levels of FSH between the two groups were not statistically significantly different 3 months after surgery (WMD 0.37 mIU/ml; 95% CI -1.56 to 1.30). The mean antral follicle count in the coagulation group was significantly less than in the suture group at 3 months' follow-up (WMD -2.53, with 95% CI -4.94 to -0.12). This study showed bipolar coagulation did more harm to the ovarian reserve than the suture haemostasis during excision of ovarian cyst as shown by a significant postoperative reduction in AMH. PMID- 25913248 TI - Low serum levels of alpha1 anti-trypsin (alpha1-AT) and risk of airflow obstruction in non-primary alpha1-AT-deficient patients with compensated chronic liver disease. AB - BACKGROUND: Alpha1 anti-trypsin (alpha1-AT), a serine protease inhibitor synthesized in the liver, is a major circulating antiprotease that provides defense against proteolytic damage in several tissues. Its deficiency is associated with airflow obstruction. The present study aimed to explore the role of alpha1-AT as a biomarker of airflow performance in chronic liver disease (CLD). MATERIAL/METHODS: Serum alpha1-AT levels and lung function (spirometry) were evaluated in non-primary alpha1-AT-deficient, alcoholic CLD patients without evident respiratory limitations. RESULTS: Thirty-four patients with airflow obstruction (n=11), airflow restriction (n=12), and normal airflow (n=11, age matched controls) were eligible. alpha1-AT was decreased in the airflow obstruction group. ROC-cutoff alpha1-AT=24 mg/dL effectively discriminated airflow obstruction (AUC=0.687) and was associated with a 10-fold higher risk (p=0.0007). CONCLUSIONS: Lower alpha1-AT increased the risk of airflow obstruction in CLD patients without primary alpha1-AT deficiency. PMID- 25913249 TI - Single agent nanoparticle for radiotherapy and radio-photothermal therapy in anaplastic thyroid cancer. AB - Anaplastic thyroid carcinoma (ATC) is one of the most aggressive human malignancies. The aggressive behavior of ATC and its resistance to traditional treatment limit the efficacy of radiotherapy, chemotherapy, and surgery. The purpose of this study is aimed at enhancing the therapeutic efficacy of radiotherapy (RT) combined with photothermal therapy (PTT) in murine orthotopic model of ATC, based on our developed single radioactive copper sulfide (CuS) nanoparticle platform. We prepare a new dual-modality therapy for ATC consisting of a single-compartment nanoplatform, polyethylene glycol-coated [(64)Cu]CuS NPs, in which the radiotherapeutic property of (64)Cu is combined with the plasmonic properties of CuS NPs. Mice with Hth83 ATC were treated with PEG-[(64)Cu]CuS NPs and/or near infrared laser. Antitumor effects were assessed by tumor growth and animal survival. We found that in mice bearing orthotopic human Hth83 ATC tumors, micro-PET/CT imaging and biodistribution studies showed that about 50% of the injected dose of PEG-[(64)Cu]CuS NPs was retained in tumor 48 h after intratumoral injection. Human absorbed doses were calculated from biodistribution data. In antitumor experiments, tumor growth was delayed by PEG-[(64)Cu]CuS NP mediated RT, PTT, and combined RT/PTT, with combined RT/PTT being most effective. In addition, combined RT/PTT significantly prolonged the survival of Hth83 tumor bearing mice compared to no treatment, laser treatment alone, or NP treatment alone without producing acute toxic effects. These findings indicate that this single-compartment multifunctional NPs platform merits further development as a novel therapeutic agent for ATC. PMID- 25913250 TI - Clinical study and stability assessment of a novel transcutaneous influenza vaccination using a dissolving microneedle patch. AB - Transcutaneous immunization (TCI) is an attractive vaccination method compared with conventional injectable vaccines because it is easier to administer without pain. We developed a dissolving microneedle patch (MicroHyala, MH) made of hyaluronic acid and showed that transcutaneous vaccination using MH induced a strong immune response against various antigens in mice. In the present study, we investigated the clinical safety and efficacy of a novel transcutaneous influenza vaccine using MH (flu-MH), which contains trivalent influenza hemagglutinins (15 MUg each). Subjects of the TCI group were treated transcutaneously with flu-MH, and were compared with subjects who received subcutaneous injections of a solution containing 15 MUg of each influenza antigen (SCI group). No severe local or systemic adverse events were detected in either group and immune responses against A/H1N1 and A/H3N2 strains were induced equally in the TCI and SCI groups. Moreover, the efficacy of the vaccine against the B strain in the TCI group was stronger than that in the SCI group. Influenza vaccination using MH is promising for practical use as an easy and effective method to replace conventional injections systems. PMID- 25913251 TI - CAD based design sensitivity analysis and shape optimization of scaffolds for bio root regeneration in swine. AB - Tooth root supports dental crown and bears occlusal force. While proper root shape and size render the force being evenly delivered and dispersed into jawbone. Yet it remains unclear what shape and size of a biological tooth root (bio-root), which is mostly determined by the scaffold geometric design, is suitable for stress distributing and mastication performing. Therefore, this study hypothesized scaffold fabricated in proper shape and size is better for regeneration of tooth root with approving biomechanical functional features. In this study, we optimized shape and size of scaffolds for bio-root regeneration using computer aided design (CAD) modeling and finite element analysis (FEA). Statical structural analysis showed the total deformation (TD) and equivalent von mises stress (EQV) of the restored tooth model mainly concentrated on the scaffold and the post, in accordance with the condition in a natural post restored tooth. Design sensitivity analysis showed increasing the height and upper diameter of the scaffold can tremendously reduce the TD and EQV of the model, while increasing the bottom diameter of scaffold can, to some extent, reduce the EQV in post. However, increase on post height had little influence on the whole model, only slightly increased the native EQV stress in post. Through response surface based optimization, we successfully screened out the optimal shape of the scaffold used in tissue engineering of tooth root. The optimal scaffold adopted a slightly tapered shape with the upper diameter of 4.9 mm, bottom diameter of 3.4 mm; the length of the optimized scaffold shape was 9.4 mm. While the analysis also suggested a height of about 9 mm for a metal post with a diameter of 1.4 mm suitable for crown restoration in bio-root regeneration. In order to validate the physiological function of the shape optimized scaffold in vivo, we transplanted the shape optimized treated dentin matrix (TDM) scaffold, seeding with dental stem cells, into alveolar bone of swine and further installed porcelain crown. Results showed that tooth root has not only been successfully regenerated histologically but also performed masticatory function and maintained stable for three months after crown restoration. Our results suggested that TDM scaffold with 9.4 mm in length and 4.9 mm/3.4 mm in upper/bottom diameter is a suitable biological scaffold for tooth root regeneration. These results also provided a recommendable design protocol for fabricating other scaffolds in tooth root reconstruction. PMID- 25913253 TI - Nano-assemblies of J-aggregates based on a NIR dye as a multifunctional drug carrier for combination cancer therapy. AB - The combination of chemotherapy with photothermal therapy, which may lead to improved therapeutic efficacies and reduced side effects of conventional chemotherapy, would require safe drug delivery systems (DDSs) with strong near infrared (NIR) absorbance, efficient drug loading, and effective tumor homing ability. Herein, we fabricate nano-assemblies containing J-aggregates of a NIR dye, IR825, for drug delivery and combined photothermal & chemotherapy of cancer. It is found that IR825 could be complexed with a low-molecular-weight cationic polymer polyethylenimine (PEI), forming IR825@PEI J-aggregates with greatly enhanced NIR absorbance red-shifted to 915 nm. Those nano-assemblies of J aggregates are further modified with polyethylene glycol (PEG), obtaining IR825@PEI-PEG nano-complex which exhibits great dispersity in physiological solutions, excellent photostability, and is able to efficiently load chemotherapeutic drug doxorubicin (DOX) via a unique strategy different from drug loading in conventional amphiphilic polymer-based DDSs. In vivo animal experiments uncover that IR825@PEI-PEG/DOX upon intravenous injection into tumor bearing mice shows rather high tumor uptake as illustrated by photoacoustic imaging. In vivo combined photothermal & chemotherapy is then carried out, demonstrating great synergistic anti-tumor therapeutic effect remarkably superior to those achieved by the respective mono-therapies. Hence, we present a novel type of nanoscale DDSs based on nano-assemblies of small molecules without involving amphiphilic polymers, promising for imaging-guided combination cancer therapy. PMID- 25913252 TI - Pharmacokinetics and osteogenic potential of PEGylated NELL-1 in vivo after systemic administration. AB - Osteoporosis is a skeletal disorder attributable to an imbalance in osteoblast and osteoclast activity. NELL-1, a secretory protein that promotes osteogenesis while suppressing osteoclastic activity, holds potential as an osteoporosis therapy. Recently, we demonstrated that PEGylation of NELL-1 significantly improves its thermostability while preserving its bioactivity in vitro. However, the effect of PEGylation on the pharmacokinetics and osteogenic potential of NELL 1 in vivo have yet to be investigated. The present study demonstrated that PEGylation of NELL-1 significantly increases the elimination half-life time of the protein from 5.5 h to 15.5 h while distributing more than 2-3 times the amount of protein to bone tissues (femur, tibia, vertebrae, calvaria) in vivo when compared to naked NELL-1. In addition, microCT and DXA analyses demonstrated that systemic NELL-PEG therapy administered every 4 or 7 days significantly increases not only femoral and lumbar BMD and percent bone volume, but also new bone formation throughout the overall skeleton after four weeks of treatment. Furthermore, immunohistochemistry revealed increased osteocalcin expression, while TRAP staining showed reduced osteoclast numbers in NELL-PEG groups. Our findings suggest that the PEGylation technique presents a viable and promising approach to further develop NELL-1 into an effective systemic therapeutic for the treatment of osteoporosis. PMID- 25913254 TI - Doxorubicin-loaded NaYF4:Yb/Tm-TiO2 inorganic photosensitizers for NIR-triggered photodynamic therapy and enhanced chemotherapy in drug-resistant breast cancers. AB - The combination therapy has exhibited important potential for the treatment of cancers, especially for drug-resistant cancers. In this report, bi-functional nanoprobes based on doxorubicin (DOX)-loaded NaYF4:Yb/Tm-TiO2 inorganic photosensitizers (FA-NPs-DOX) were synthesized for in vivo near infrared (NIR) triggered inorganic photodynamic therapy (PDT) and enhanced chemotherapy to overcome the multidrug resistance (MDR) in breast cancers. Using the up conversion luminescence (UCL) performance of NaYF4:Yb/Tm converting near-infrared (NIR) into ultraviolent (UV) lights, reactive oxygen species (ROS) were triggered from TiO2 inorganic photosensitizers for PDT under the irradiation of a 980 nm laser, by which the deep-penetration and low photo-damage could be reached. Moreover, nanocarrier delivery and folic acid (FA) targeting promoted the cellular uptake, and accelerated the release of DOX in drug-sensitive MCF-7 and resistant MCF-7/ADR cells. The toxicity assessment in vitro and in vivo revealed the good biocompatibility of the as-prepared FA-NPs-DOX nanocomposites. By the combination of enhanced chemotherapy and NIR-triggered inorganic PDT, the viability of MCF-7/ADR cells could decrease by 53.5%, and the inhibition rate of MCF-7/ADR tumors could increase up to 90.33%, compared with free DOX. Therefore, the MDR of breast cancers could be obviously overcome by enhanced chemotherapy and NIR-triggered inorganic PDT of FA-NPs-DOX nanocomposites under the excitation of a 980 nm laser. PMID- 25913255 TI - Mitochondrial delivery of antisense RNA by MITO-Porter results in mitochondrial RNA knockdown, and has a functional impact on mitochondria. AB - Mitochondrial genome-targeting nucleic acids are promising therapeutic candidates for treating mitochondrial diseases. To date, a number of systems for delivering genetic information to the cytosol and the nucleus have been reported, and several successful gene therapies involving gene delivery targeted to the cytosol and the nucleus have been reported. However, much less progress has been made concerning mitochondrial gene delivery systems, and mitochondrial gene therapy has never been achieved. Here, we report on the mitochondrial delivery of an antisense RNA oligonucleotide (ASO) to perform mitochondrial RNA knockdown to regulate mitochondrial function. Mitochondrial delivery of the ASO was achieved using a combination of a MITO-Porter system, which contains mitochondrial fusogenic lipid envelopes for mitochondrial delivery via membrane fusion and D arm, a mitochondrial import signal of tRNA to the matrix. Mitochondrial delivery of the ASO induces the knockdown of the targeted mitochondria-encoded mRNA and protein, namely cytochrome c oxidase subunit II, a component of the mitochondrial respiratory chain. Furthermore, the mitochondrial membrane potential was depolarized by the down regulation of the respiratory chain as the result of the mitochondrial delivery of ASO. This finding constitutes the first report to demonstrate that the nanocarrier-mediated mitochondrial genome targeting of antisense RNA effects mitochondrial function. PMID- 25913256 TI - Effects of topical and intravenous JM-1232(-) infusion on cerebrovascular reactivity in rats. AB - A novel short-acting benzodiazepine receptor agonist, JM-1232(-), has been shown to have a sedative/hypnotic effect and wide safety margin. However, its effect on cerebral vessels is not well known. Therefore, we investigated the cerebrovascular reactivity to topical and intravenous JM-1232(-) and during hypotension or hypercapnia with intravenous administration of JM-1232(-). We used a closed cranial window preparation to measure the changes of cerebral pial arteriolar diameters in isoflurane-anesthetized Sprague-Dawley rats. We first measured the direct effect of topical JM-1232(-). We then determined the effect of intravenous JM-1232(-) and then we measured the response to hypercapnia before and after JM-1232(-) infusion. Finally, we measured the reaction to stepwise induction of hypotension before and after JM-1232(-) infusion. Topical infusion of JM-1232(-) dilated pial arterioles. Intravenous infusion of JM-1232(-) changed pial arterioles by 4.5 +/- 2.7 %, 5.0 +/- 3.9 %, and -2.8 +/- 2.6 % (at 0.1, 0.3, and 1.0 mg/kg/min, respectively). Hypercapnia dilated pial arterioles before and after JM-1232(-) infusion. The diameters of pial arterioles did not change during hypotension before or after intravenous JM-1232(-) infusion. These results indicate that topical JM-1232(-) has a dilative effect on pial arterioles and that intravenous administration of JM-1232(-) may not affect cerebrovascular reactivity to hypotension or hypercapnia. PMID- 25913257 TI - Overexpression of feline tripartite motif-containing 25 interferes with the late stage of feline leukemia virus replication. AB - Tripartite motif-containing 25 (TRIM25) regulates various cellular processes through E3 ubiquitin ligase activity. Previous studies have revealed that the expression of TRIM25 is induced by type I interferon and that TRIM25 is involved in the host cellular innate immune response against retroviral infection. Although retroviral infection is prevalent in domestic cats, the roles of feline TRIM25 in the immune response against these viral infections are poorly understood. Because feline TRIM25 is expected to modulate the infection of feline leukemia virus (FeLV), we investigated its effects on early- and late-stage FeLV replication. This study revealed that ectopic expression of feline TRIM25 in HEK293T cells reduced viral protein levels leading to the inhibition of FeLV release. Our findings show that feline TRIM25 has a potent antiviral activity and implicate an antiviral mechanism whereby feline TRIM25 interferes with late-stage FeLV replication. PMID- 25913258 TI - Treatment with corticosterone delays cutaneous wound healing in male and female salamanders. AB - In vertebrates, exposure to stressors and stress hormones has a number of physiological effects including modulation of immune function. These effects on immune function have been well studied in mammals, but less is known in other groups, in particular amphibians. To analyze the effects of exposure to stressors and the stress hormone corticosterone, we monitored cutaneous wound healing as a measure of integrated immunity in male and female semi-terrestrial salamanders (Desmognathus ochrophaeus) that were chased to induce endogenous release of corticosterone or were treated with physiologically relevant doses of corticosterone. As predicted, subjects treated daily with corticosterone healed more slowly than did controls. In contrast, subjects that had been chased daily healed at the same rate as controls. Surprisingly, repeated chasing did not elevate plasma corticosterone despite causing drops in body mass and survival. Additionally, females healed more slowly than males, possibly due to energetic constraints. PMID- 25913259 TI - Sources of diel variation in energetic physiology in an Arctic-breeding, diving seaduck. AB - Diel variation in baseline glucocorticoid (GC) secretion influences energetics and foraging behaviors. In temperate breeding, diurnal vertebrates, studies have shown that daily patterns of baseline GC secretion are influenced by environmental photoperiod, with baseline GCs peaking prior to sunrise to stimulate waking and foraging behaviors. Measures of physiological energy acquisition are also expected to peak in response to foraging activity, but their relationship to GC levels have not been well studied. In contrast to temperate breeding species, virtually nothing is known about diel GC and energetic metabolite secretion in Arctic breeding species, which experience almost constant photoperiods in spring and summer. Using a ten-year dataset, we examined the daily, 24-h pattern of baseline corticosterone (CORT) and triglyceride (TRIG) secretion in approximately 800 female pre-breeding Arctic-nesting common eiders (Somateria mollissima). We related these traits to environmental photoperiod and to tidal cycle. In contrast to temperate breeding species, we found that that neither time of day nor tidal trend predicted diel variation in CORT or TRIG secretion in Arctic-breeding eiders. Given the narrow window of opportunity for breeding in polar regions, we suggest that eiders must decouple their daily foraging activity from light and tidal cycles if they are to accrue sufficient energy for successful breeding. As CORT is known to influence foraging behavior, the absence of a distinct diel pattern of CORT secretion may therefore be an adaptation to optimize reproductive investment and likelihood for success in some polar-breeding species. PMID- 25913260 TI - Reproductive workers show queenlike gene expression in an intermediately eusocial insect, the buff-tailed bumble bee Bombus terrestris. AB - Bumble bees represent a taxon with an intermediate level of eusociality within Hymenoptera. The clear division of reproduction between a single founding queen and the largely sterile workers is characteristic for highly eusocial species, whereas the morphological similarity between the bumble bee queen and the workers is typical for more primitively eusocial hymenopterans. Also, unlike other highly eusocial hymenopterans, division of labour among worker subcastes is plastic and not predetermined by morphology or age. We conducted a differential expression analysis based on RNA-seq data from 11 combinations of developmental stage and caste to investigate how a single genome can produce the distinct castes of queens, workers and males in the buff-tailed bumble bee Bombus terrestris. Based on expression patterns, we found males to be the most distinct of all adult castes (2411 transcripts differentially expressed compared to nonreproductive workers). However, only relatively few transcripts were differentially expressed between males and workers during development (larvae: 71 and pupae: 162). This indicates the need for more distinct expression patterns to control behaviour and physiology in adults compared to those required to create different morphologies. Among female castes, reproductive workers and their nonreproductive sisters displayed differential expression in over ten times more transcripts compared to the differential expression found between reproductive workers and their mother queen. This suggests a strong shift towards a more queenlike behaviour and physiology when a worker becomes fertile. This contrasts with eusocial species where reproductive workers are more similar to nonreproductive workers than the queen. PMID- 25913261 TI - Reply to comments on Fadel et al.: Ilizarov external fixation versus plate osteosynthesis in the management of extra-articular fractures of the distal tibia. PMID- 25913262 TI - Early history of operative treatment of patellar fractures. AB - The presented overview shows that the first efforts to address patellar fractures by operative treatment, although sporadic, emerged in the pre-antiseptic era. Introduction of Lister's antiseptic method in Great Britain, Germany and the USA in 1877-1882 contributed to a new, progressive trend in the treatment of fractures of the patella as well as of other bones. The authors, using Lister's antiseptic method, evaluated three basic aspects in their operations, namely healing of the surgical wound without infective complications, achievement of bony union and a good functional outcome, i.e. restoring the range of motion in the knee, even if limited in most cases. The majority of them used a longitudinal incision and fixation by a silver wire. PMID- 25913263 TI - Distal locked and unlocked nailing for perthrochanteric fractures--a prospective comparative randomized study. AB - PURPOSE: Intramedullary nailing is widely used in the treatment of stable pertrochanteric fractures. However, it remains controversial whether the distal locking with intramedullary nailing is necessary. METHOD: In this study, 70 patients over the age of 65 with pertrochanteric fractures (AO/OTA 31-A1 and A2) were enrolled and randomly divided into two groups for treatment by intramedullary nails either with or without distal locking. Intra-operative variables such as operation time, volume of blood loss, total fluoroscopy time, total length of incision, postoperative complications and clinical outcomes were recorded and compared between the two groups. RESULTS: A total of 29 patients in the locking group and 30 patients in the unlocking group completed one year of follow up. Operation time (39.2 +/- 7.6 min), blood loss (158.6 +/- 63.6 ml), fluoroscopy time (53.7 +/- 3.9 s), and total length of incision (13.1 +/- 2.1 cm) in the unlocking group were significantly decreased compared with the locking group (48.5 +/- 9.0 min; 194.3 +/- 61.6 ml; 57.8 +/- 4.3 s; 10.9 +/- 1.7 cm) (p < 0.05). No significant differences in postoperative complications and fracture union were identified between the two groups. Most patients in the locking group (80.0 %) and the unlocking group (77.1 %) recovered to their pre-injury activity levels. CONCLUSION: This study suggests that intramedullary nails without distal locking may be a reliable and acceptable option for treating stable pertrochanteric fractures (AO/OTA 31-A1 and A2) in elderly people. Distal unlocked nails showed subtle advantages in reducing blood loss, operation time, fluoroscopy exposure time, and size of the incision. PMID- 25913264 TI - Anchor suture fixation of distal pole fractures of patella: twenty seven cases and comparison to partial patellectomy. AB - PURPOSE: Partial patellectomy (PP) and reattachment of the patellar ligament with transosseous suturing is the mainstay of surgical treatment for distal pole patellar fractures. An anchor suturing (AS) technique has recently been reported as an alternative to PP in such fractures and allows for bone-to-bone interface and possibly superior fracture healing than bone-to-tendon interface with PP. We present our experience with AS and compare it to PP. METHODS: Between 2006 and 2011, 60 patients with distal pole patellar fracture underwent either AS (n = 27) or PP (n = 33). We retrospectively gathered their demographic data and information on fracture type, fixation technique, operation time, postoperative complications and knee range of motion. A telephone survey was performed to grade functional outcomes with standard questionnaires (the SF-12 for quality of life, the Kujala score for patellofemoral function and a visual analog scale [VAS] pain score). RESULTS: AS was equivalent to PP in terms of residual pain and functional outcomes (VAS: 2.45 vs. 2.26, p = 0.83 and Kujala score: 74.3 vs. 69, p = 0.351, respectively) as well as for knee range of motion. Complications included three cases of infection in each group, two cases of early hardware failure and one case of non-union in the AS group. Operation time was significantly shorter for AS compared to PP (68.5 vs. 79.1 min, p = 0.03). CONCLUSIONS: AS is non-inferior to PP for function and pain after distal pole patellar fractures and is superior to PP with regard to operative time. Common complications of this technique are hardware failure and infections. LEVEL OF EVIDENCE: Therapeutic Level III. PMID- 25913265 TI - One-stage combined anterior-posterior approach treatment of multiple cervicothoracic spinal tuberculosis with kyphosis. AB - OBJECTIVE: The purpose of this study was to investigate the clinical efficacy and feasibility of one-stage posterior fixation, anterior debridement, bone grafting and anterior fixation for multiple cervicothoracic spinal tuberculosis with kyphosis. METHODS: From December 2006 to June 2011, fifteen patients (seven males, eight females) suffering from cervicothoracic spinal tuberculosis with kyphosis were admitted. The pathologic change regions were as follows: two in the C6-C7 segment, two in the C6-T1 segment, one in the C6-T2 segment, three in the C7-T1 segment, two in the T1-T2 segment, two in the C7-T2 segment, one in the T1 T3 segment, and two in the T2-T3 segment. All patients were treated with one stage surgical treatment by posterior fixation, anterior debridement, bone grafting, and anterior fixation. Then, the clinical efficacy was evaluated using statistical analysis based on the materials about the Cobb angle of kyphosis, Frankel grade and erythrocyte sedimentation rate (ESR), which were collected at certain times. RESULTS: All patients ages ranged from 17 to 67 years (average, 40.9 years). Operation time ranged from 180 to 290 min (average, 226 minutes). Intra-operative blood loss ranged from 400 to 1000 ml (average, 650 ml). All patients were followed up for 18-46 months postoperatively (average, 27.7 months). The kyphosis angle was changed significantly between pre-operation and postoperation (P < 0.05), and there was no obvious loss at the last follow-up. The ESR recovered to normal within three months postoperatively in all patients (P < 0.05). Bone fusion was achieved within three to six months (average, 5.5 months). In the 15 cases, no postoperative severe complications occurred and neurologic function was improved in various degrees. CONCLUSION: The outcomes of follow-up showed that the one-stage combined anterior-posterior approach can be an effective treatment method for multiple cervicothoracic spinal tuberculosis with kyphosis. PMID- 25913266 TI - Interposition sleeve as treatment option for interprosthetic fractures of the femur: a biomechanical in vitro assessment. AB - PURPOSE: The number of patients having hip and knee arthroplasties on the ipsilateral leg is going to rise. In this regard, the prevalence of interprosthetic femoral fractures is going to increase further. The treatment of these fractures is difficult and sometimes it is impossible to perform an osteosynthesis because of worse bone quality. The goal of this study was to investigate the use of an interposition sleeve as an alternative treatment option for interprosthetic fractures with major bone loss. METHODS: Six human cadaveric femurs were instrumented using cemented hip- and knee prosthesis. Interprosthetic fractures were induced during a four-point-bending test and then treated using the interposition sleeve. Afterwards the constructs were tested using the four point-bending test again. RESULTS: Load-to-failure of the construct before fracturing was significantly higher than after treatment with the interposition sleeve (10681 N vs. 5083 N; p = 0.002). The failure mechanism of the femurs with the interposition sleeve was plastic deformation of the hip or knee prosthesis. The interposition sleeve did not fail in any specimen. CONCLUSION: The interposition sleeve is a valuable treatment option for interprosthetic fractures in situations in which osteosynthesis is impossible or insecure due to major bone defects. However, fracture healing should be preferred whenever possible. PMID- 25913267 TI - Kinetic and mechanistic study of the reaction of OH radicals with methylated benzenes: 1,4-dimethyl-, 1,3,5-trimethyl-, 1,2,4,5-, 1,2,3,5- and 1,2,3,4 tetramethyl-, pentamethyl-, and hexamethylbenzene. AB - The reaction of OH radicals with a series of methylated benzenes was studied in a temperature range 300-350 K using a flash-photolysis resonance fluorescence technique. Reversible OH additions led to complex OH decays dependent on the number of distinguishable adducts. Except for hexamethylbenzene, triexponential OH decay curves were obtained, consistent with formation of at least two adduct species. For three compounds that can strictly form two adduct isomers for symmetry reasons (1,4-dimethyl-, 1,3,5-trimethyl-, and 1,2,4,5 tetramethylbenzene) with OH bound ortho or ipso with respect to the methyl groups, OH decay curves were analysed in terms of a reaction mechanism in which the two adducts can be formed directly by OH addition or indirectly by isomerization. In all cases one adduct (add1) is dominating the decomposition back to OH. The other (add2) is more elusive and only detectable at elevated temperatures, similar to the single OH adduct of hexamethylbenzene. Two limiting cases of the general reaction mechanism could be examined quantitatively: reversible formation of add2 exclusively in the OH reaction or by isomerization of add1. Total OH rate constants, adduct loss rate constants and products of forward and reverse rate constants of reversible reactions were determined. From these quantities, adduct yields, equilibrium constants, as well as reaction enthalpies and entropies were derived for the three aromatics. Adduct yields strongly depend on the selected reaction model but generally formation of add1 predominates. For both models equilibrium constants of OH reactions lie between those of OH + benzene from the literature and those obtained for OH + hexamethylbenzene. The corresponding reaction enthalpies of add1 and add2 formations are in a range -87 +/- 20 kJ mol(-1), less exothermic than for hexamethylbenzene (-101 kJ mol(-1)). Reaction enthalpies of possible add1 -> add2 isomerizations are comparatively small. Because results for 1,3,5 trimethylbenzene are partly inconsistent with a direct formation of add2, we promote the existence of isomerization reactions. Moreover, based on available theoretical work in the literature, add1 and add2 are tentatively identified as ortho and ipso adducts, respectively. Total OH rate constants were obtained for all title compounds. They can be described by Arrhenius equations: kOH = A * exp( B/T). The parameters ln(A/(cm(3) s(-1))) = -25.6 +/- 0.3, -25.3 +/- 0.6, -27.3 +/ 0.3, -24.6 +/- 0.3, -26.2 +/- 0.4, -26.2 +/- 0.4 and -24.5 +/- 0.2, and B/K = 160 +/- 90, -550 +/- 180, -1120 +/- 90, -330 +/- 100, -820 +/- 100, -980 +/- 130, and -570 +/- 40 were determined for 1,4-dimethyl-, 1,3,5-trimethyl-, 1,2,4,5-, 1,2,3,5- and 1,2,3,4-tetramethyl-, pentamethyl-, and hexamethylbenzene. PMID- 25913268 TI - VACTERL associations in children undergoing surgery for esophageal atresia and anorectal malformations: Implications for pediatric surgeons. AB - PURPOSE: The aim of this study was to compare the frequency and nature of VACTERL associations between children who underwent surgery for esophageal atresia/tracheoesophageal fistula (EA/TEF) and anorectal malformation (ARM). METHODS: We identified all children who underwent surgery for EA/TEF and/or ARM at hospitals participating in the Pediatric Health Information System (PHIS) database between 2004 and 2012. PHIS is an administrative database of free standing children's hospitals managed by the Child Health Corporation of America (Overland Park, KS) that contains patient-level care data from 43 hospitals. The complete records of patients in this cohort were cross-referenced for diagnoses of vertebral, cardiac, renal and limb anomalies. RESULTS: 2689 children underwent repair of esophageal atresia. Mean gestational age was 36.5+/-3.2weeks and mean birth weight was 2536.0+/-758.7g. Associated VACTERL diagnoses included vertebral anomaly in 686 (25.5%), ARM in 312 (11.6%), congenital heart disease in 1588 (59.1%), renal disease in 587 (21.8%) and limb defect in 192 (7.1%). 899 (33.4%) had 3 or more anomalies and met criteria for a VACTERL diagnosis. 4962 children underwent repair of ARM. Mean gestational age was 37.4+/-2.7weeks and mean birth weight was 2895.2+/-765.1g. Associated VACTERL diagnoses included vertebral anomaly in 1562 (31.5%), congenital heart disease in 2007 (40.4%), EA/TEF in 348 (7.0%), renal disease in 1723 (34.7%) and limb defect in 359 (7.2%). 1795 (36.2%) had 3 or more anomalies and met criteria for a VACTERL diagnosis. CONCLUSION: VACTERL associations are relatively common in children with EA/TEF and ARM and occur in specific clusters, with cardiac disease more common in EA/TEF and spinal and renal/urinary anomalies more common in ARM. PMID- 25913269 TI - Collective efficacy at the Rugby World Cup 2015--The role of imagery and observation. AB - The Rugby World Cup in 2015 will present each competing team with unique psychological challenges not usually encountered in normal international fixtures. In the "pressure-pot" environment of the tournament, teams that have the strongest sense of collective efficacy will most likely perform to their best and respond positively to the outside stressors (e.g., media interest, public expectations). In this review, the importance of collective efficacy to team performance at the World Cup in terms of team resiliency and minimising process losses is discussed. In addition, the relationship between collective efficacy and other psychological factors such as team cohesion is highlighted. From a practical perspective, an introduction to interventions to develop collective efficacy is provided. In particular, the neuroscience evidence for the use of imagery and observation interventions to improve individual collective efficacy perceptions is highlighted. It is emphasised how these interventions are particularly suited to international teams who compete together sporadically. Finally, specific recommendations are made such that practitioners might be able to implement these strategies with their teams before the World Cup. PMID- 25913270 TI - Muscle loss and obesity: the health implications of sarcopenia and sarcopenic obesity. AB - This paper reviews the health implications of obesity, sarcopenia and sarcopenic obesity on CVD and mortality in older adults and discusses the obesity paradox seen in patients with CVD. Obesity is a major public health problem with increasing prevalence worldwide. It is an established risk factor for cardiovascular morbidity and mortality in adult populations. However, there is controversy surrounding the effects of obesity as measured by BMI in older people, and overweight and obesity (BMI ? 25 kg/m2) are apparently associated with increased survival in those with CVD (obesity paradox). Ageing is associated with an increase in visceral fat and a progressive loss of muscle mass which have opposing effects on mortality. Thus BMI is not a good indicator of obesity in older adults. Sarcopenia, the age-associated loss of skeletal muscle mass, is a major concern in ageing populations and has been associated with metabolic impairment, CVD risk factors, physical disability and mortality. Sarcopenia often coexists with obesity. Sarcopenic obesity is a new category of obesity in older adults who have high adiposity coupled with low muscle mass. To fully understand the effect of obesity on mortality in the elderly it is important to take muscle mass into account. The evidence suggests that sarcopenia with obesity may be associated with higher levels of metabolic disorders and an increased risk of mortality than obesity or sarcopenia alone. Efforts to promote healthy ageing should focus on both preventing obesity and maintaining or increasing muscle mass. PMID- 25913271 TI - Final results from a pivotal phase 3 malaria vaccine trial. PMID- 25913272 TI - Efficacy and safety of RTS,S/AS01 malaria vaccine with or without a booster dose in infants and children in Africa: final results of a phase 3, individually randomised, controlled trial. AB - BACKGROUND: The efficacy and safety of the RTS,S/AS01 candidate malaria vaccine during 18 months of follow-up have been published previously. Herein, we report the final results from the same trial, including the efficacy of a booster dose. METHODS: From March 27, 2009, until Jan 31, 2011, children (age 5-17 months) and young infants (age 6-12 weeks) were enrolled at 11 centres in seven countries in sub-Saharan Africa. Participants were randomly assigned (1:1:1) at first vaccination by block randomisation with minimisation by centre to receive three doses of RTS,S/AS01 at months 0, 1, and 2 and a booster dose at month 20 (R3R group); three doses of RTS,S/AS01 and a dose of comparator vaccine at month 20 (R3C group); or a comparator vaccine at months 0, 1, 2, and 20 (C3C [control group]). Participants were followed up until Jan 31, 2014. Cases of clinical and severe malaria were captured through passive case detection. Serious adverse events (SAEs) were recorded. Analyses were by modified intention to treat and per protocol. The coprimary endpoints were the occurrence of malaria over 12 months after dose 3 in each age category. In this final analysis, we present data for the efficacy of the booster on the occurrence of malaria. Vaccine efficacy (VE) against clinical malaria was analysed by negative binomial regression and against severe malaria by relative risk reduction. This trial is registered with ClinicalTrials.gov, number NCT00866619. FINDINGS: 8922 children and 6537 young infants were included in the modified intention-to-treat analyses. Children were followed up for a median of 48 months (IQR 39-50) and young infants for 38 months (34-41) after dose 1. From month 0 until study end, compared with 9585 episodes of clinical malaria that met the primary case definition in children in the C3C group, 6616 episodes occurred in the R3R group (VE 36.3%, 95% CI 31.8-40.5) and 7396 occurred in the R3C group (28.3%, 23.3-32.9); compared with 171 children who experienced at least one episode of severe malaria in the C3C group, 116 children experienced at least one episode of severe malaria in the R3R group (32.2%, 13.7 to 46.9) and 169 in the R3C group (1.1%, -23.0 to 20.5). In young infants, compared with 6170 episodes of clinical malaria that met the primary case definition in the C3C group, 4993 episodes occurred in the R3R group (VE 25.9%, 95% CI 19.9-31.5) and 5444 occurred in the R3C group (18.3%, 11.7-24.4); and compared with 116 infants who experienced at least one episode of severe malaria in the C3C group, 96 infants experienced at least one episode of severe malaria in the R3R group (17.3%, 95% CI -9.4 to 37.5) and 104 in the R3C group (10.3%, 17.9 to 31.8). In children, 1774 cases of clinical malaria were averted per 1000 children (95% CI 1387-2186) in the R3R group and 1363 per 1000 children (995 1797) in the R3C group. The numbers of cases averted per 1000 young infants were 983 (95% CI 592-1337) in the R3R group and 558 (158-926) in the R3C group. The frequency of SAEs overall was balanced between groups. However, meningitis was reported as a SAE in 22 children: 11 in the R3R group, ten in the R3C group, and one in the C3C group. The incidence of generalised convulsive seizures within 7 days of RTS,S/AS01 booster was 2.2 per 1000 doses in young infants and 2.5 per 1000 doses in children. INTERPRETATION: RTS,S/AS01 prevented a substantial number of cases of clinical malaria over a 3-4 year period in young infants and children when administered with or without a booster dose. Efficacy was enhanced by the administration of a booster dose in both age categories. Thus, the vaccine has the potential to make a substantial contribution to malaria control when used in combination with other effective control measures, especially in areas of high transmission. FUNDING: GlaxoSmithKline Biologicals SA and the PATH Malaria Vaccine Initiative. PMID- 25913273 TI - The Immunomodulatory and Therapeutic Effects of Mesenchymal Stromal Cells for Acute Lung Injury and Sepsis. AB - It is increasingly recognized that immunomodulation represents an important mechanism underlying the benefits of many stem cell therapies, rather than the classical paradigm of transdifferentiation and cell replacement. In the former paradigm, the beneficial effects of cell therapy result from paracrine mechanism(s) and/or cell-cell interaction as opposed to direct engraftment and repair of diseased tissue and/or dysfunctional organs. Depending on the cell type used, components of the secretome, including microRNA (miRNA) and extracellular vesicles, may be able to either activate or suppress the immune system even without direct immune cell contact. Mesenchymal stromal cells (MSCs), also referred to as mesenchymal stem cells, are found not only in the bone marrow, but also in a wide variety of organs and tissues. In addition to any direct stem cell activities, MSCs were the first stem cells recognized to modulate immune response, and therefore they will be the focus of this review. Specifically, MSCs appear to be able to effectively attenuate acute and protracted inflammation via interactions with components of both innate and adaptive immune systems. To date, this capacity has been exploited in a large number of preclinical studies and MSC immunomodulatory therapy has been attempted with various degrees of success in a relatively large number of clinical trials. Here, we will explore the various mechanism employed by MSCs to effect immunosuppression as well as review the current status of its use to treat excessive inflammation in the context of acute lung injury (ALI) and sepsis in both preclinical and clinical settings. PMID- 25913274 TI - Effect of cinnamon (Cinnamomum zeylanicum) bark oil on heat stress-induced changes in sperm production, testicular lipid peroxidation, testicular apoptosis, and androgenic receptor density in developing Japanese quails. AB - The aim of this study was to investigate the effect of cinnamon bark oil (CBO) on heat stress (HS)-induced changes in sperm production, testicular lipid peroxidation, testicular apoptosis, and androgenic receptor (AR) density in developing Japanese quails. Fifteen-day-old 90 male chicks were assigned to two main groups. The first group (45 chicks) was kept in a thermoneutral room at 22 degrees C for 24 h/day. The second group (45 chicks) was kept in a room with high ambient temperature at 34 degrees C for 8 h/day (from 9 AM-5 PM) and at 22 degrees C for 16 h/day. Each of these two main groups was then divided into three subgroups (CBO groups 0, 250, 500 ppm) consisting of 15 chicks (six treatment groups in 2 * 3 factorial order). Each of subgroups was replicated for three times and each replicate included five chicks. Heat stress caused significant decreases in body weight, spermatid and testicular sperm numbers, the density of testicular Bcl-2 (antiapoptotic marker) and AR immunopositivity, and significant increases in testicular lipid peroxidation level, the density of testicular Bax (apoptotic marker) immunopositivity, and a Bax/Bcl-2 ratio along with some histopathologic damages. However, 250 and 500 ppm CBO supplementation provided significant improvements in HS-induced increased level of testicular lipid peroxidation, decreased number of spermatid and testicular sperm, decreased densities of Bcl-2 and AR immunopositivity, and some deteriorated testicular histopathologic lesions. In addition, although HS did not significantly affect the testicular glutathione level, addition of both 250 and 500 ppm CBO to diet of quails reared in both HS and thermoneutral conditions caused a significant increase when compared with quails without any consumption of CBO. In conclusion, HS-induced lipid peroxidation causes testicular damage in developing male Japanese quails and, consumption of CBO, which has antiperoxidative effect, protects their testes against HS. PMID- 25913275 TI - First evidence of molecular characterization of rohu carp Sox2 gene being expressed in proliferating spermatogonial cells. AB - Because little is known about the function of Sox2 (Sry-related box-2) in teleosts, the objective of this study was to clone and characterize Sox2 complementary DNA (cDNA) from the testis of Indian major carp, Labeo rohita (rohu). The full-length cDNA contained an open reading frame of 936 nucleotides bearing the typical structural features. Phylogenetically, Sox2 of L rohita was most closely related to freshwater counterparts than marine water. The sequence information of cDNA and genomic DNA together revealed that the Sox2 gene is encoded by an uninterrupted exon. Furthermore, comparative mRNA expression profile in various organs including proliferating spermatogonial stem cells (SSCs) suggested about the participatory role of Sox2 during fish male germ cell development and maintenance of stem cells. In support, we have also provided evidence that Sox2 protein is indeed present in rohu SSCs by Western blot analysis. The evolutionarily conserved high-mobility group box domain indicated its possible involvement in common networking pathways for stem cell maintenance and pluripotency between mammals and nonmammals. Our findings could be the first step toward the use of Sox2 as a potential biomarker for proliferating SSCs and understanding the transcriptional regulatory network involved during male germ cell development and maintenance in fish species. PMID- 25913276 TI - The effect of extender, method of thawing, and duration of storage on in vitro fertility measures of frozen-thawed boar sperm. AB - Frozen-thawed boar sperm (FTS) has reduced in vitro and in vivo life span compared to liquid semen. Experiments tested whether extenders, thawing procedures, and storage temperatures could extend the fertile life span of FTS. Experiment 1 tested the effect of six extenders on postthaw motility (MOT) and viability (VIA). Straws from boars (n = 6) were thawed, diluted into each extender, and evaluated at 20, 60, and 120 minutes. There was a trend (P = 0.08) for an extender-by-time interaction for MOT and effect of extender and time for MOT (P < 0.0001) and extender (P = 0.10) and time (P < 0.0001) for VIA. Experiment 2 evaluated the effect of temperature and time of thawing on in vitro fertility at intervals after thawing. Straws (0.5 mL) from different boar ejaculates (n = 15) were thawed at 50 degrees C for 10, 20, or 30 seconds or at 70 degrees C for 5, 10, or 20 seconds and evaluated at 5, 30, and 60 minutes. There was an effect of thawing treatment on MOT, VIA, and ACR (viable sperm with intact acrosomes, P < 0.0001) and an effect of time of evaluation (P < 0.0001) on MOT and ACR. Thawing at 70 degrees C for 20 seconds reduced (P < 0.05) MOT, VIA, and ACR compared to other treatments. Experiment 3 tested the effects of storage temperature and time after thawing using 20 ejaculates. Samples were thawed, diluted, and allotted to storage at 17 degrees C, 26 degrees C, or 37 degrees C with evaluation at 2, 6, 12, and 24 hours. There was a storage temperature and time effect and an interaction for MOT and VIA (P < 0.0001). Storage at 17 degrees C and 26 degrees C increased (P < 0.05) MOT over all times (38.5%) compared to 37 degrees C (26%), whereas MOT was reduced at intervals. Viability was also greatest with 17 degrees C and 26 degrees C compared to 37 degrees C and was also affected by time and decreased with time. These results indicate that FTS can be held at 17 degrees C or 26 degrees C for up to 2 hours before use and would allow for preparation of multiple doses. These data suggest in vitro fertility of FTS is affected by extenders, thawing, and storage. PMID- 25913277 TI - Antioxidative effect of carboxyethylgermanium sesquioxide (Ge-132) on IVM of porcine oocytes and subsequent embryonic development after parthenogenetic activation and IVF. AB - Carboxyethylgermanium sesquioxide (Ge-132) is an organogermanium compound known to exert biological activities, such as antioxidant and anticancer effects. In this study, we investigated the effect of Ge-132 on the IVM of porcine oocytes via analysis of nuclear maturation, intracellular glutathione (GSH) and reactive oxygen species (ROS) levels, and subsequent embryonic development after parthenogenetic activation (PA) and IVF. After 40 hours of IVM, no significant difference in nuclear maturation was observed in the 100, 200, and 400 MUg/mL of Ge-132 treatment groups (89.9%, 91.3%, and 90.4%, respectively) compared with the control group (89.0%). However, intracellular GSH levels in oocytes treated with 200 MUg/mL of Ge-132 increased significantly (P < 0.05), and the 200 and 400 MUg/mL of Ge-132 treatment groups exhibited a significant (P < 0.05) decrease in intracellular ROS levels compared with the control group. Oocytes matured with 200 and 400 MUg/mL of Ge-132 during IVM displayed significantly higher cleavage rates (78.7% and 82.7% vs. 67.5%, respectively), and the 200 MUg/mL of Ge-132 treatment group displayed higher blastocyst formation rates and greater total cell numbers after PA (59.5% and 67.8 vs. 38.2% and 55.3, respectively) than the control group. Furthermore, oocytes matured with 200 MUg/mL of Ge-132 during IVM failed to display significantly higher blastocyst formation rates (31.6% vs. 36.7%) but exhibited greater total cell numbers after IVF (71.5 vs. 101.3, respectively) than the control group. We also found that the Ge-132-treated oocytes showed significantly higher messenger RNA (mRNA) expression levels of the oxidative-related gene Nrf-2 and lower mRNA expression levels of the proapoptotic gene Bax than the control group (P < 0.05). In conclusion, our results suggest that treatment with Ge-132 during IVM improves the developmental potential of PA and IVF porcine embryos by increasing the intracellular GSH levels, thereby decreasing the intracellular ROS levels and reducing oxidative stress-induced apoptosis, thereby regulating the mRNA expression of oocytes during oocyte maturation. PMID- 25913278 TI - Resolution of aquaporin-4 antibodies in a woman with neuromyelitis optica treated with human autologous stem cell transplant. AB - We report a 47-year-old woman with highly active neuromyelitis optica (NMO) and persistent high titre anti-aquaporin-4 antibodies (anti-AQP-4) who was resistant to multiple immune therapies until she underwent autologous hematopoietic stem cell transplant (auto-HSCT). NMO is the only demyelinating disease with a clinically useful serum biomarker, aquaporin-4, a water channel protein expressed on astrocytes. Anti-AQP-4 antibodies correlate with NMO disease activity and animal models strongly suggest the antibody is pathogenic. Auto-HSCT was associated with clinical and radiological remission, improved disability and resolution of AQP-4 antibodies which are still undetectable 12 months later. The utility of auto-HSCT for refractory NMO warrants further investigation, particularly with regards to pre-conditioning regimens and the utility of AQP-4 antibodies as a biomarker for immunological and clinical remission. PMID- 25913280 TI - A scalable chemical route to soluble acidified graphitic carbon nitride: an ideal precursor for isolated ultrathin g-C3N4 nanosheets. AB - We propose an efficient method to synthesize large-scale soluble acidified graphitic carbon nitride (g-C3N4). The as-prepared material exhibits the characteristics of a poly-ammonium salt and is soluble in several solvents with good dissolution-recrystallization reversible equilibrium. The pH value- and temperature-dependent solubility of the acidified g-C3N4 facilitates its separation and purification. After dissolution, acidified g-C3N4 forms isolated ultrathin nanosheets, making it an ideal precursor for large quantities of g-C3N4 nanosheets. This study raises the possibility of liquid assembly for g-C3N4 nanosheets based composite materials, expanding the functionalization and application of g-C3N4. PMID- 25913279 TI - Operative results of keyhole supracerebellar-infratentorial approach to the pineal region. AB - The supracerebellar-infratentorial approach to the pineal region is typically accomplished with a craniotomy that extends to at least the rim of the foramen magnum. Minimally invasive techniques that limit the inferior extent of the craniotomy have been described for this approach but, to our knowledge, no operative results have been published demonstrating the feasibility and safety of such techniques. We present a series of patients who underwent surgical resection of pineal region lesions using the minimally invasive method at our institution. Clinical, radiologic, and operative data were prospectively collected on patients treated for lesions of the pineal region by the senior author from January 2012 to July 2014. Seven patients were identified. The sitting position was employed in each patient. Keyhole craniotomies were limited to a maximum diameter of 2.5 cm. Adequate working corridors were attained, and in no patient was resection limited by the exposure. No neurological or systemic complications were seen in the perioperative and early follow-up periods. In this feasibility study, we demonstrate that it is not necessary to extend a craniotomy inferiorly to the rim of the foramen magnum in order to gain access to the pineal region via relaxation of the cerebellum. The same surgical goals can be safely accomplished with a smaller craniotomy. PMID- 25913281 TI - Bimodal Multiparameter-Based Approach for Benign-Malignant Classification of Breast Tumors. AB - Proposed here is a breast tumor classification technique using conventional ultrasound B-mode imaging and a new elasticity imaging-based bimodal multiparameter index. A set of conventional ultrasound (US) and ultrasound elastography (UE) parameters are studied, and among those, the effective ones whose independent as well as combined performance is found satisfactory are selected. To improve the combined US performance, two new US parameters are proposed: edge diffusivity, which assesses edge blurriness to differentiate malignant from benign lesions, and the shape asymmetry factor, which quantifies tumor shape irregularity by comparing the tumor boundary with an ellipse fitted to the lesion. Then a new bimodal multiparameter characterization index is defined to discriminate 201 pathologically confirmed breast tumors of which 56 are malignant lesions, 79 are fibroadenomas, 42 are cysts and 24 are inflammatory lesions. The weights of the multiparameter bimodal index are optimally computed using a genetic algorithm (GA). To evaluate the performance variation of the index on different data sets, the tumors are categorized into three classes: malignant lesion versus fibroadenoma, malignant lesion versus fibroadenoma and cyst and malignant lesion versus fibroadenoma, cyst and inflammation. The test results reveal that the proposed bimodal index achieves satisfactory quality metrics (e.g., 94.64%-98.21% sensitivity, 97.24%-100.00% specificity and 96.52% 99.44% accuracy) for classification of the aforementioned three classes of breast tumors. Its performance is also observed to be better in totality of the quality metrics sensitivity, specificity, accuracy, positive predictive value and negative predictive value as compared with that of a conventional bimodal index as well as unimodal multiparameter indices based on US or UE. It is suggested that the proposed simple bimodal linear classifier may assist radiologists in better diagnosis of breast tumors and help reduce the number of unnecessary biopsies. PMID- 25913282 TI - Colorimetric sensor array for detection and identification of organophosphorus and carbamate pesticides. AB - Due to relatively low persistence and high effectiveness for insect and pest eradication, organophosphates (OPs) and carbamates are the two major classes of pesticides that broadly used in agriculture. Hence, the sensitive and selective detection of OPs and carbamates is highly significant. In this current study, a colorimetric sensor array comprising five inexpensive and commercially available thiocholine and H2O2 sensitive indicators for the simultaneous detection and identification of OPs and carbamates is developed. The sensing mechanism of this array is based on the irreversible inhibition capability of OPs and carbamates to the activity of acetylcholinesterase (AChE), preventing production of thiocholine and H2O2 from S-acetylthiocholine and acetylcholine and thus resulting in decreased or no color reactions to thiocholine and H2O2 sensitive indicators. Through recognition patterns and standard statistical methods (i.e., hierarchical clustering analysis and principal component analysis), the as-developed array demonstrates not only discrimination of OPs and carbamates from other kinds of pesticides but, more interestingly, identification of them exactly from each other. Moreover, this array is experimentally confirmed to have high selectivity and sensitivity, good anti-interference capability, and potential applications in real samples for OPs and carbamates. PMID- 25913283 TI - Practical 3DCT imaging of the vestibular aqueduct for Meniere's disease. AB - CONCLUSION: Radiographic visualization of the vestibular aqueduct (VA) from a lateral inside view was effective in assessing patients with Meniere's disease (MD). There were no VA shapes specific to MD on radiography, except for an obliterated VA. This technique could yield more accurate images and functional assessment of the VA for MD evaluation in a clinically useful and convenient manner, without requiring morphologic measurement. OBJECTIVE: To visualize the detailed images of the VA using three-dimensional (3D) computed tomography (CT) and discuss its clinical utility in assessing MD. SUBJECTS AND METHODS: The VAs in 13 healthy subjects and 25 MD patients, who were definitely diagnosed according to criteria described by the Committee on Hearing and Equilibrium of the American Academy of Otolaryngology, Head and Neck Surgery (AAO-HNS), were imaged from the medial and lateral sides using 3DCT and compared to conventional CT images. RESULTS: Examination of the VA from both the lateral outside and inside views on 3DCT yielded more precise images than generated by conventional CT and could be useful to estimate the VA function. The estimated VA function in the MD ears was significantly abnormal compared to the function in healthy ears. An obliterated VA was characteristic of affected MD ears. PMID- 25913284 TI - Ion conducting Li2SiO3-coated lithium-rich layered oxide exhibiting high rate capability and low polarization. AB - Lithium-rich Li(1.13)Ni(0.30)Mn(0.57)O2 has been functionally modified with fast Li(+)-ion conducting Li2SiO3via a facile and novel method, based on the reaction between Ni(0.35)Mn(0.65)C2O4.xH2O and Si(OC2H5)4. Due to the unique Li2SiO3 coating layer which greatly improves the Li(+) ion diffusion rate, Li2SiO3@Li(1.13)Ni(0.30)Mn(0.57)O2 exhibits outstanding rate capability, cycle stability and low polarization. PMID- 25913285 TI - Developments in biospecimen research. AB - INTRODUCTION: Biobanking refers to the infrastructure, policies and practices involved in collecting, processing, storing and disseminating biological samples. Biospecimen methods research to support biobanking through evidence-based practices is now recognized as critical to the success of biobanking and translational research. SOURCES OF DATA: Data concerning biospecimen research have appeared in the literature for many years, primarily in journals and textbooks focused on clinical chemistry, epidemiology and pathology. Recently, new efforts have been initiated to support the development of evidence-based biobanking practices. AREAS OF AGREEMENT: Generally, researchers who are engaged in studies involving biospecimen collection are aware of the effects of pre analytical variables on their downstream analyses, and they normally take steps to control those variables to publish reproducible results. Knowledge of such biospecimen research data is often unknown in the clinical setting unless the researchers are engaged in a project requiring strict protocols. AREAS OF CONTROVERSY: There is broad agreement of the need to develop evidence-based practices to achieve consistent quality for biospecimens and data. However, due to inconsistencies in the literature, there is some disagreement on whether biospecimens need to be collected according to a 'platinum' standard or local biobank standards for collecting samples as 'fit-for-purpose' will be sufficient. GROWING POINTS: New and expanded efforts, on an international basis where possible, need to be developed to better harmonize biospecimen management practices. AREAS TIMELY FOR DEVELOPING RESEARCH: Additional biospecimen methods research leading to the development of evidence-based practices is critical to translational research and personalized medicine. PMID- 25913286 TI - Titanium dioxide nanoparticles provide protection against polycyclic aromatic hydrocarbon BaP and chrysene-induced perturbation of DNA repair machinery: A computational biology approach. AB - We examined the interaction of polycyclic hydrocarbons (PAHs) like benzo-alpha pyrene (BaP), chrysene, and their metabolites 7,8-dihydro-7,8 dihydroxybenzo(a)pyrene,9,10-oxide (BPDE) and chrysene 1,2-diol-3,4-epoxide-2 (CDE), with the enzymes involved in DNA repair. We investigated interaction of 120 enzymes with PAHs and screened out 40 probable targets among DNA repair enzymes, on the basis of higher binding energy than positive control. Out of which, 20 enzymes lose their function in the presence of BaP, chrysene, and their metabolites, which may fetter DNA repair pathways resulting in damage accumulation and finally leading to cancer formation. We propose the use of nanoparticles as a guardian against the PAH's induced toxicity. PAHs enter the cell via aryl hydrocarbon receptor (AHR). TiO2 NP showed a much higher docking score with AHR (12,074) as compared with BaP and chrysene with AHR (4,600 and 4,186, respectively), indicating a preferential binding of TiO2 NP with the AHR. Further, docking of BaP and chrysene with the TiO2 NP bound AHR complex revealed their strong adsorption on TiO2 NP itself, and not on their original binding site (at AHR). TiO2 NPs thereby prevent the entry of PAHs into the cell via AHR and hence protect cells against the deleterious effects induced by PAHs. PMID- 25913287 TI - Long term HER2+ metastatic breast cancer survivors treated by trastuzumab: Results from the French cohort study LHORA. AB - PURPOSE: The LORHA study described the clinical features of patients and tumours in long-term responders from a subset of breast cancer patients who responded to 1st-line trastuzumab and without disease progression. METHODS: This was an ambispective, multicentre, non-interventional study conducted in 57 centres in France. Eligible patients were women with HER2+metastatic or locally-advanced breast cancer, treated with 1st-line therapy, progression-free for >=3 years after starting trastuzumab, and followed-up for 12 months. RESULTS: 160 patients were recruited, 128 were included in the efficacy analysis subset (median age: 61 years; [34-95 years]). A majority (88%) had invasive ductal carcinoma; 53% had SBR grade III carcinoma, and 58% were positive for hormonal receptors. The median time since diagnosis was 8 years [3-26 years]. The most frequent metastatic sites were the bone, liver, lymph nodes, and lungs in 43%, 35%, 20% and 19% of patients, respectively. The median duration of 1st-line trastuzumab was 4.5 years [0.8-12.1], combined with paclitaxel and docetaxel in 35 and 72 patients, respectively. Median PFS (progression-free survival) was 6.4 years [5.7; Not Reached]. No trastuzumab-related deaths were observed. In the safety analysis subset (N = 134), 3 cardiac adverse events considered related to trastuzumab were recorded in 3 patients (2.2%), and only one prospective congestive cardiac failure was of grade >=3. CONCLUSIONS: The LORHA study showed that long term responders to 1st-line trastuzumab for locally advanced or metastatic breast cancer could achieve a median PFS of more than 6 years, with an acceptable safety profile. PMID- 25913289 TI - The dynamic, size-dependent properties of [5]-[12]cycloparaphenylenes. AB - [n]Cycloparaphenylenes (or "carbon nanohoops") are cyclic fragments of carbon nanotubes that consist of n para linked benzene rings. These strained, all sp(2) hybridized macrocycles, have size-dependent optical and electronic properties that are the most dynamic at the smallest size regime where n = 5-12. This review highlights the unique physical phenomena surrounding this class of polycyclic aromatic hydrocarbons, specifically emphasizing the novel structural, optical, and electronic properties of [5]-[12]CPPs. PMID- 25913288 TI - Outcome of oncoplastic breast-conserving surgery following bracketing wire localization for large breast cancer. AB - PURPOSE: The purpose of this study was to evaluate the outcome of breast conserving surgery comparing oncoplastic surgery (OS) and standard lumpectomy (SL) after preoperative bracketing wire localization of large neoplastic lesions. METHODS: We retrospectively reviewed the medical records and the mammograms of patients operated on at the Institut Curie between May 2005 and September 2011 after bracketing wire localization under mammographic and/or sonographic guidance. RESULTS: 113 patients underwent surgery for a pre-operative diagnosis of DCIS (n = 80), micro-invasive carcinoma (n = 9) or invasive carcinoma (n = 24), by OS (n = 73) or SL (n = 40). In the OS group, radiological size (52 mm vs 39 mm, p < 0.001) and resection volumes (246 cc vs 88 cc, p < 0.00001) were significantly higher than in the SL group. Rates of clear histologic margins (60 vs 62%, NS), complete excision of microcalcifications (78% vs 72%, NS) and re intervention rate (40% vs 42%, NS) were equivalent. The rate of local recurrence at 24 months was 3% [0-7.1] in patients with conservative treatment (n = 3). With a median follow-up of 40 months, 5 local relapses (two with axillary metastatic involvement), two distant metastatic evolution, one contralateral breast cancer and one death unrelated to cancer occurred. CONCLUSION: Following bracketing wire localization, OS allowed the conserving management of significantly larger lesions with wider resection volumes, without significant increase in margin involvement or re-intervention rate, and equivalent rate of microcalcifications clearance compared to SL. PMID- 25913291 TI - ARID1A expression in ovarian clear cell carcinoma with an adenofibromatous component. AB - AIMS: The carcinogenesis of ovarian clear cell carcinoma (CCC) has been hypothesized to comprise two different pathways: an adenofibroma-carcinoma sequence and an endometriosis-carcinoma sequence. However, the difference in the genetic basis of these two pathways remains unclear. Recent studies have suggested that an ARID1A mutation and the loss of the corresponding protein, BAF250a, are frequent events in CCC. Herein, we investigated the difference in the loss of BAF250a expression in adenofibroma-related CCC and endometriosis related CCC. METHODS AND RESULTS: In total, 93 cases of surgically treated CCC were evaluated. The presence of adenofibroma and endometriosis associated with carcinoma was determined by reviewing haematoxylin and eosin-stained slides for each case. BAF250a expression in carcinoma was examined immunohistochemically. The loss of BAF250a expression was detected in carcinomas in 50 of 93 (54%) cases, including five of 18 (28%) with adenofibroma alone, 30 of 45 (67%) with endometriosis alone, eight of 18 (44%) with both conditions and seven of 12 (58%) with neither condition. The loss of BAF250a expression was significantly less frequent in CCC cases with adenofibroma than in cases with endometriosis (P = 0.01, Fisher's exact test). CONCLUSIONS: The action of ARID1A in carcinogenesis differs between adenofibroma-related CCC and endometriosis-related CCC. PMID- 25913290 TI - Management of Invasive Fungal Infections in Pediatric Acute Leukemia and the Appropriate Time for Restarting Chemotherapy. AB - OBJECTIVE: Rapid and effective treatment of invasive fungal infection (IFI) in patients with leukemia is important for survival. In this study, we aimed to describe variations regarding clinical features, treatment modalities, time of restarting chemotherapy, and outcome in children with IFI and acute leukemia (AL). MATERIALS AND METHODS: The charts of all pediatric AL patients in our clinic between the years of 2001 and 2013 were retrospectively reviewed. All patients received prophylactic fluconazole during the chemotherapy period. RESULTS: IFI was identified in 25 (14%) of 174 AL patients. Most of them were in the consolidation phase of chemotherapy and the patients had severe neutropenia. The median time between leukemia diagnosis and definition of IFI was 122 days. Twenty-four patients had pulmonary IFI. The most frequent finding on computed tomography was typical parenchymal nodules. The episodes were defined as proven in 4 (16%) patients, probable in 7 (28%) patients, and possible in 14 (56%) patients. The median time for discontinuation of chemotherapy was 27 days. IFI was treated successfully in all patients with voriconazole, amphotericin B, caspofungin, or posaconazole alone or in combination. Chemotherapy was restarted in 50% of the patients safely within 4 weeks and none of those patients experienced reactivation of IFI. All of them were given secondary prophylaxis. The median time for antifungal treatment and for secondary prophylaxis was 26 and 90 days, respectively. None of the patients died due to IFI. CONCLUSION: Our data show that rapid and effective antifungal therapy with rational treatment modalities may decrease the incidence of death and that restarting chemotherapy within several weeks may be safe in children with AL and IFI. PMID- 25913292 TI - Magnetic fabric from red clay sediments in the Chinese Loess Plateau. AB - Well-distributed eolian red clay in a wide area of northern China is believed to imply the onset of an ancient East Asian monsoon system since Late Miocene. Two continuous red clay sequences spanning the time interval 7-2.6 Ma and 11-2.6 Ma in the Chinese Loess Plateau was investigated to determine the magnetic orientation and grain alignment in the primary fabric of eolian sediments. The north-westerly orientation of the AMS of the eolian red clay sequences parallels the material transportation direction, which differs from the model that suggests that airborne dust from overlying loess-paleosol sequences were transported by the East Asian winter monsoon and fixed by the East Asian summer monsoon. Our results further reveal that present-day climate and air circulation patterns differ from those of the pre-Quaternary, and may provide evidence of a prevailing wind during deposition of the red clay. PMID- 25913293 TI - Fusaric acid induces a notochord malformation in zebrafish via copper chelation. AB - Over a thousand extracts were tested for phenotypic effects in developing zebrafish embryos to identify bioactive molecules produced by endophytic fungi. One extract isolated from Fusarium sp., a widely distributed fungal genus found in soil and often associated with plants, induced an undulated notochord in developing zebrafish embryos. The active compound was isolated and identified as fusaric acid. Previous literature has shown this phenotype to be associated with copper chelation from the active site of lysyl oxidase, but the ability of fusaric acid to bind copper ions has not been well described. Isothermal titration calorimetry revealed that fusaric acid is a modest copper chelator with a binding constant of 4.4 * 10(5) M(-1). These results shed light on the toxicity of fusaric acid and the potential teratogenic effects of consuming plants infected with Fusarium sp. PMID- 25913294 TI - Influence of probiotic administration on the fecal microbiota in diarrhea predominant irritable bowel syndrome. PMID- 25913296 TI - Supplemental morphine infusion into the posterior ventral tegmentum extends the satiating effects of self-administered intravenous heroin. AB - Rats learn to self-administer intravenous heroin; well-trained animals lever press at a slow and regular pace over a wide range of intravenous doses. The pauses between successive earned infusions are proportional to the dose of the previous injection and are thought to reflect periods of drug satiety. Rats will also self-administer opiates by microinjection directly into sites in the posterior regions of the ventral tegmentum. To determine if the pauses between self-administered intravenous injections are due to opiate actions in posterior ventral tegmentum, we delivered supplemental morphine directly into this region during intravenous self-administration sessions in well-trained rats. Reverse dialysis of morphine into the posterior ventral tegmentum increased the intervals between earned injections. The inter-response intervals were greatest for infusion into the most posterior ventral tegmental sites, sites in a region variously known as the tail of the ventral tegmental area or as the rostromedial tegmental nucleus. These sites at which morphine prolongs inter-response intervals, correspond to the sites at which opiates have been found most effective in reinforcing instrumental behavior. PMID- 25913295 TI - Immunogenetic control of the intestinal microbiota. AB - All vertebrates contain a diverse collection of commensal, symbiotic and pathogenic microorganisms, such as bacteria, viruses and fungi, on their various body surfaces, and the ecological community of these microorganisms is referred to as the microbiota. Mucosal sites, such as the intestine, harbour the majority of microorganisms, and the human intestine contains the largest community of commensal and symbiotic bacteria. This intestinal community of bacteria is diverse, and there is a significant variability among individuals with respect to the composition of the intestinal microbiome. Both genetic and environmental factors can influence the diversity and composition of the intestinal bacteria with the predominant environmental factor being diet. So far, studies have shown that diet-dependent differences in the composition of intestinal bacteria can be classified into three groups, called enterotypes. Other environmental factors that can influence the composition include antibiotics, probiotics, smoking and drugs. Studies of monozygotic and dizygotic twins have proven that genetics plays a role. Recently, MHC II genes have been associated with specific microbial compositions in human infants and transgenic mice that express different HLA alleles. There is a growing list of genes/molecules that are involved with the sensing and monitoring of the intestinal lumen by the intestinal immune system that, when genetically altered, will significantly alter the composition of the intestinal microflora. The focus of this review will be on the genetic factors that influence the composition of the intestinal microflora. PMID- 25913297 TI - Should fee-for-service be for all guideline-advocated acute coronary syndrome (ACS) care? Observations from the Snapshot ACS study. AB - OBJECTIVE: The aim of the present study was to explore the association of health insurance status on the provision of guideline-advocated acute coronary syndrome (ACS) care in Australia. METHODS: Consecutive hospitalisations of suspected ACS from 14 to 27 May 2012 enrolled in the Snapshot study of Australian and New Zealand patients were evaluated. Descriptive and logistic regression analysis was performed to evaluate the association of patient risk and insurance status with the receipt of care. RESULTS: In all, 3391 patients with suspected ACS from 247 hospitals (23 private) were enrolled in the present study. One-third of patients declared private insurance coverage; of these, 27.9% (304/1088) presented to private facilities. Compared with public patients, privately insured patients were more likely to undergo in-patient echocardiography and receive early angiography; furthermore, in those with a discharge diagnosis of ACS, there was a higher rate of revascularisation (P < 0.001). Each of these attracts potential fee-for-service. In contrast, proportionately fewer privately insured ACS patients were discharged on selected guideline therapies and were referred to a secondary prevention program (P = 0.056), neither of which directly attracts a fee. Typically, as GRACE (the Global Registry of Acute Coronary Events) risk score rose, so did the level of ACS care; however, propensity-adjusted analyses showed lower in-hospital adverse events among the insured group (odds ratio 0.68; 95% confidence interval 0.52-0.88; P = 0.004). CONCLUSION: Fee-for-service reimbursement may explain differences in the provision of selected guideline advocated components of ACS care between privately insured and public patients. PMID- 25913298 TI - Selective immediate responders to amoxicillin and clavulanic acid tolerate penicillin derivative administration after confirming the diagnosis. AB - BACKGROUND: An increasing number of patients show immediate selective hypersensitivity reactions to clavulanic acid (CLV) and amoxicillin (AX), probably due to their increased prescription. The maintenance of this response should be established. OBJECTIVE: To assess that the immediate hypersensitivity selective response to AX or to CLV is maintained after repeated administration of penicillin G (PG)/penicillin V (PV) and AX. METHODS: Patients with proven immediate hypersensitivity to AX (Group A) or CLV (Group B) were included. Diagnosis was performed using skin tests with major and minor determinants of PG (PPL/MDM), AX and CLV and by drug provocation test (DPT) if required. Selectivity was established by confirming tolerance to PG/PV (Group A) and to PG/PV and AX (Group B). The maintenance of the selective response was verified by repeating DPT, 15 days after the initial investigation, with the same procedure. RESULTS: Of 51 patients, 78% belonged to Group A and 22% to Group B. Most had anaphylaxis. In Group A, 72% were skin test positive; 28% required DPT. In Group B, 63% were skin test positive; 37% required DPT. Only two AX-selective cases developed positive responses after re-provocation with PG/PV. No cases selective for CLV developed a positive response to PG, PV or AX. DISCUSSION: The selective response to AX appears consistent, and a response to penicillin determinants only develops in a minority of cases. For the case of CLV, the selective response appears not to be modified by exposure to penicillin determinants, meaning that patients with CLV allergy can take penicillin derivatives safely. PMID- 25913299 TI - Identification of diagnostic biomarkers and metabolic pathway shifts of heat stressed lactating dairy cows. AB - Controlling heat stress (HS) is a global challenge for the dairy industry. However, simple and reliable biomarkers that aid the diagnoses of HS-induced metabolic disorders have not yet been identified. In this work, an integrated metabolomic and lipidomic approach using (1)H nuclear magnetic resonance and ultra-fast LC-MS was employed to investigate the discrimination of plasma metabolic profiles between HS-free and HS lactating dairy cows. Targeted detection using LC-MS in multiple reaction monitoring mode was used to verify the reliability of the metabolites as biomarker candidates. Overall, 41 metabolites were identified as candidates for lactating dairy cows exposed to HS, among which 13 metabolites, including trimethylamine, glucose, lactate, betaine, creatine, pyruvate, acetoacetate, acetone, beta-hydroxybutyrate, C16 sphinganine, lysophosphatidylcholine (18:0), phosphatidylcholine (16:0/14:0), and arachidonic acid, had high sensitivity and specificity in diagnosing HS status, and are likely to be the potential biomarkers of HS dairy cows. All of these potentially diagnostic biomarkers were involved in carbohydrate, amino acid, lipid, or gut microbiome-derived metabolism, indicating that HS affected the metabolic pathways in lactating dairy cows. Further research is warranted to evaluate these biomarkers in practical applications and to elucidate the physiological mechanisms of HS-induced metabolic disorders. BIOLOGICAL SIGNIFICANCE: Heat stress (HS) annually causes huge losses to global dairy industry, including animal performance decrease, metabolic disorder and health problem. So far, physiological mechanisms underlying HS of dairy cows still remain elusive. To our best knowledge, this is the first attempt to elucidate the HS-induced metabolic disorders of dairy cows using integrated (1)H NMR and LC-MS-based metabolic study. The results not only provided potential diagnostic biomarkers for HS lactating dairy cows, but also significantly explored the related physiological mechanisms of metabolic pathway shifts induced by HS environment. This work offers comprehensive insights into the global metabolic alterations of dairy cows exposed to HS and provides a new perspective for further study. PMID- 25913300 TI - Proteomic analysis of Yersinia enterocolitica biovar 1A under iron-rich and iron poor conditions indicate existence of efficiently regulated mechanisms of iron homeostasis. AB - The pathogenicity of Yersinia enterocolitica biovar 1A strains is controversial as these lack most of the known virulence factors. Acquisition of iron and presence of well-regulated iron homeostasis in bacteria represents an important virulence trait. Differential abundance of proteins was examined under iron-rich and iron-poor conditions in a clinical Y. enterocolitica biovar 1A strain IP27407. Whole cell protein profiles were analysed by 2D gel electrophoresis (2D GE). Following statistical and MALDI-TOF MS analyses, 28 differentially abundant proteins were identified. Significant iron-responsive changes were observed in the proteins involved in iron acquisition or storage namely, hemin receptor (HemR), periplasmic Fe(2+) transport protein (Tpd), periplasmic chelated iron binding protein (YfeA) and bacterioferritin (Bfr). Quantitative real-time PCR (qRT-PCR) of eight mRNA transcripts revalidated the differential protein abundance. In silico analysis of iron homeostasis mediated by the bacterioferritin and bacterioferritin-associated ferredoxin (Bfr-Bfd) complex suggested two pathways for the release of reserve iron which might be operating under conditions of different iron availability. The study, for the first time, showed the existence of highly competent iron homeostasis mechanisms in Y. enterocolitica biovar 1A and identified the key proteins involved thereof. Such mechanisms might have implications for the pathogenicity of Y. enterocolitica biovar 1A strains. BIOLOGICAL SIGNIFICANCE: Although, a few studies have identified the differentially abundant bacterial proteins in response to iron starvation, little information is available in this regard for Y. enterocolitica (especially, the biovar 1A strains). In the present study, differential abundance of several proteins was identified under iron-rich and iron-poor conditions by 2D GE and MALDI-TOF/MS analysis. These included proteins which may not only be directly implicated in iron acquisition or storage but also play crucial role in cellular metabolism. Given the absence of most known virulence factors in Y. enterocolitica biovar 1A strains, demonstration of well-regulated mechanisms for efficient iron homeostasis constitutes an important observation. The proteins, as identified in the present study, provide useful insights to further unravel the potential pathogenicity of the biovar 1A strains. PMID- 25913302 TI - Almutairi's Critical Cultural Competence model for a multicultural healthcare environment. AB - The increasing demographic changes of populations in many countries require an approach for managing the complexity of sociocultural differences. Such an approach could help healthcare organizations to address healthcare disparities and inequities, and promote cultural safety for healthcare providers and patients alike. Almutairi's critical cultural competence (CCC) is a comprehensive approach that holds great promise for managing difficulties arising from sociocultural and linguistic issues during cross-cultural interactions. CCC has addressed the limitations of many other cultural competence approaches that have been discussed in the literature. Therefore, the purpose of this study is to define the construct of CCC and the theoretical components of the CCC. PMID- 25913301 TI - Validation of candidate anxiety disorder genes using a carbon dioxide challenge task. AB - Few replicable genetic variants have been identified in the etiology of heritable anxiety disorders such as panic disorder. Endophenotypic measures that have reduced heterogeneity may provide more powerful targets for gene identification. We assessed hypersensitivity to carbon dioxide (a reliable endophenotype of panic and anxiety) in 174 Caucasian college students, who were genotyped on 26 polymorphic markers from 11 genes previously associated with panic/anxiety. Individual trajectories of respiratory and subjective anxiety response to carbon dioxide were measured and tested for association with these genetic markers. One marker in the acid-sensing ion channel 1 (ASIC1) gene, rs1108923, had a significant association with respiratory rate. No genes had a significant association with subjective anxiety response. Our findings support previously reported associations between ASIC1 and panic/anxiety, but not other genes previously associated with anxiety disorders. The use of endophenotypic markers is a promising avenue for gene identification in anxiety and other complex disorders. PMID- 25913304 TI - An assessment of adhesion, aggregation and surface charges of Lactobacillus strains derived from the human oral cavity. AB - There is limited information concerning the adhesion and aggregation of human oral lactobacilli. In this study, the adhesion of 10 Lactobacillus species was investigated using H357 oral keratinocyte cells as an in vitro model for oral mucosa. Coaggregation with the representative oral pathogen, Streptococcus mutans ATCC 25175, and the physicochemical cell properties was also evaluated. The results demonstrated significant variations in adhesion (42-96%) and aggregation (autoaggregation, 14-95%; coaggregation, 19-65%). All strains showed a high affinity for chloroform, and most strains had a moderate-to-high hydrophobicity. All strains, except Lactobacillus casei and Lactobacillus gasseri, showed a moderate affinity for ethyl acetate. There was a strong association of autoaggregation with coaggregation (rs = 0.883, P < 0.001). The highest mean for autoaggregation (74%) and coaggregation (47%) belonged to the Lact. gasseri strains. Correlations between the adhesion and surface characteristics and aggregation were observed among the Lactobacillus fermentum and Lactobacillus paracasei strains; however, there was a variation in the strains properties within and between species. This study indicated that the Lact. gasseri, Lact. fermentum, and Lact. paracasei strains might be potential probiotics for the human oral cavity given their desirable properties. It should also be emphasized that a selective process for probiotic strains is required. SIGNIFICANCE AND IMPACT OF THE STUDY: Adhesion to host tissues and bacterial aggregation (auto- and coaggregation) are the highly important criteria for selecting strains with probiotic potential. These abilities are commonly involved with surface-charged characteristics. This is the first study to investigate the oral Lactobacillus species using an oral keratinocyte cell line. Significant results were found for the correlations between the adhesion and surface charge characteristics and for aggregation among certain strains of Lactobacillus gasseri, Lactobacillus fermentum and Lactobacillus paracasei. This observation could be useful when collecting background information for the selection of probiotic strains for use in oral health. PMID- 25913303 TI - beta-Estradiol results in a proprotein convertase subtilisin/kexin type 9 dependent increase in low-density lipoprotein receptor levels in human hepatic HuH7 cells. AB - The lower risk of coronary artery disease in premenopausal women than in men and postmenopausal women implicates sex steroids in cardioprotective processes. beta Estradiol upregulates liver low-density lipoprotein receptor (LDLR), which, in turn, decreases circulating levels of low-density lipoprotein, which is a risk factor for coronary artery disease. Conversely, LDLR protein is negatively regulated by proprotein convertase subtilisin/kexin type 9 (PCSK9). Herein, we investigated PCSK9 regulation by beta-estradiol and its impact on LDLR in human hepatocarcinoma HuH7 cells grown in the presence or absence of beta-estradiol. Immunoblot analysis showed upregulation of LDLR at 3 MUm beta-estradiol (140%), and the upregulation reached 220% at 10 MUm beta-estradiol; only at the latter dose was an increase in LDLR mRNA detected by qPCR, suggesting post-translational regulation of LDLR. No changes in PCSK9 mRNA or secreted protein levels were detected by qPCR or ELISA, respectively. beta-estradiol-conditioned medium devoid of PCSK9 failed to upregulate LDLR. Similarly, PCSK9 knockdown cells showed no upregulation of LDLR by beta-estradiol. Together, these results indicate a requirement for PCSK9 in the beta-estradiol-induced upregulation of LDLR. A radiolabeling assay showed a significant, dose-dependent decrease in the ratio of secreted phosphoPCSK9 to total secreted PCSK9 with increasing beta-estradiol levels, suggesting a change in the functional state of PCSK9 in the presence of beta-estradiol. Our results indicate that the protein upregulation of LDLR at subtranscriptionally effective doses of beta-estradiol, and its supratranscriptional upregulation at 10 MUm beta-estradiol, occur through an extracellular PCSK9-dependent mechanism. PMID- 25913305 TI - Follicular helper T-cell lymphoma: a B-cell-rich variant of T-cell lymphoma. AB - Follicular helper T-cell lymphoma is a recently described variant of T-cell lymphoma sharing the cell of origin with angioimmunoblastic T-cell lymphoma and with primary cutaneous CD4-positive small/medium T-cell lymphoma. To better characterize the morphologic and immunophenotypic features of follicular helper T cell lymphoma, a series of 4 confidently diagnosed cases are analyzed. The overall morphologic pattern significantly overlaps with that of progressive transformation of germinal centers in 3 cases and with follicular hyperplasia in 1. Detection of large, clustered, atypical T-cells is an important feature differentiating follicular T-cell lymphoma from benign, reactive processes such as progressive transformation of germinal centers. The abnormal T-cells have an immunophenotype identical to that of follicular helper T-cells in all cases. Clonal T-cell populations are detected in all cases. A characteristic setting follicular T-cell lymphomas apart from most other T-cell lymphomas is the abundance of small, mature B-cells. Differences from angioimmunoblastic T-cell lymphoma include the absence of proliferating vessels or of Epstein-Barr virus positive immunoblasts. PMID- 25913306 TI - Rapid adaptation of herbivore consumers to nutrient limitation: eco-evolutionary feedbacks to population demography and resource control. AB - Humans alter biogeochemical cycles of essential elements such as phosphorus (P). Prediction of ecosystem consequences of altered elemental cycles requires integration of ecology, evolutionary biology and the framework of ecological stoichiometry. We studied micro-evolutionary responses of a herbivorous rotifer to P-limited food and the potential consequences for its population demography and for ecosystem properties. We subjected field-derived, replicate rotifer populations to P-deficient and P-replete algal food, and studied adaptation in common garden transplant experiments after 103 and 209 days of selection. When fed P-limited food, populations with a P-limitation selection history suffered 37% lower mortality, reached twice the steady state biomass, and reduced algae by 40% compared to populations with a P-replete selection history. Adaptation involved no change in rotifer elemental composition but reduced investment in sex. This study demonstrates potentially strong eco-evolutionary feedbacks from shifting elemental balances to ecosystem properties, including grazing pressure and the ratio of grazer:producer biomass. PMID- 25913307 TI - Response of extracellular carboxylic and thiol ligands (oxalate, thiol compounds) to Pb2+ stress in Phanerochaete chrysosporium. AB - When exposed to higher Pb(2+) concentration, Phanerochaete chrysosporium secreted higher content of oxalate and thiol compounds. An earlier and faster increase in oxalate was observed after short-term exposure, comparing with a gentle increase in the thiol compounds. In the extracellular polymeric substances (EPS) extract, more oxalate and T-SH were detected when the initial Pb(2+) was higher, and the variations were different from the situation in the culture medium. In EPS solution, the oxalate amount was more closely related with Pb than that of thiol compounds. pH condition in the whole Pb removal process by P. chrysosporium ranged from 4 to 6.5 and was more beneficial for the binding of Pb(2+) to carboxylic groups in the oxalic acid. More Pb(2+) induced more EPS amount, and the increase of EPS amount influenced the immobilized oxalate more seriously. The present study can supply more comprehensive information about the metal passivation mechanism in white-rot fungi and provide meaningful references for an enhanced removal of heavy metals. PMID- 25913308 TI - Development of a sediment-contact test with rice for the assessment of sediment bound pollutants. AB - Despite the key role of higher plants in aquatic ecosystems as functional and structural elements, sediment-contact tests with macrophytes are still scarce. Moreover, due to large differences in exposure routes for pollutants as well as in life cycles between the diverse taxa of macrophytes, sensitivities to pollutants vary between taxa. Therefore, the development of new test systems with aquatic macrophytes, in general, is favorable. This study proposes a protocol for a sediment-contact test with Oryza sativa and addresses the main question whether the rice plant is a suitable test organism for sediment toxicity testing with higher plants. As a first evaluation step, the variability and sensitivity of the test was investigated using spiked artificial sediments. Thus, according to the protocol, rice was exposed to arsenic-, cadmium-, chromium-, and nickel-spiked sediments. Additionally, it was investigated which classical endpoints for plant bioassays, such as root and shoot elongation, are suitable for this bioassay. As a second evaluation step, the test system was used for assessment of natural sediments. Thereupon, a sensitivity profile of the presented test protocol was analyzed in comparison to other plant-based test systems. Inhibition of root and shoot elongation turned out to be the most sensitive endpoints for single substance testing in spiked artificial sediments. However, regarding testing of natural sediments, rice shoots responded more sensitive than rice roots. In conclusion, the rice plant clearly showed pollutant-induced effects on growth in sediments, and thus, it is likely a promising test organism to complement sediment-contact tests with higher plants. PMID- 25913309 TI - Hospital and urban effluent waters as a source of accumulation of toxic metals in the sediment receiving system of the Cauvery River, Tiruchirappalli, Tamil Nadu, India. AB - Hospital and urban effluents contain a variety of toxic and/or persistent substances in a wide range of concentrations, and most of these compounds belong to the group of emerging contaminants. The release of these substances into the aquatic ecosystem can lead to the pollution of water resources and may place aquatic organisms and human health at risk. Sediments receiving untreated and urban effluent waters from the city of Tiruchirappalli in the state of Tamil Nadu, India, are analyzed for potential environmental and human health risks. The sediment samples were collected from five hospital outlet pipes (HOP) and from the Cauvery River Basin (CRB) both of which receive untreated municipal effluent waters (Tiruchirappalli, Tamil Nadu, India). The samples were characterized for grain size, organic matter, toxic metals, and ecotoxicity. The results highlight the high concentration of toxic metals in HOP, reaching values (mg kg(-1)) of 1851 (Cr), 210 (Cu), 986 (Zn), 82 (Pb), and 17 (Hg). In contrast, the metal concentrations in sediments from CRB were lower than the values found in the HOP (except for Cu, Pb), with maximum values (mg kg(-1)) of 75 (Cr), 906 (Cu), 649 (Zn), 111 (Pb), and 0.99 (Hg). The metal concentrations in all sampling sites largely exceed the Sediment Quality Guidelines (SQGs) and the Probable Effect Concentration (PEC) for the Protection of Aquatic Life recommendation. The ecotoxicity test with ostracods exposed to the sediment samples presents a mortality rate ranging from 22 to 100 % (in sediments from HOP) and 18-87 % (in sediments from CRB). The results of this study show the variation of toxic metal levels as well as toxicity in sediment composition related to both the type of hospital and the sampling period. The method of elimination of hospital and urban effluents leads to the pollution of water resources and may place aquatic organisms and human health at risk. PMID- 25913310 TI - Changes in chemical forms, subcellular distribution, and thiol compounds involved in Pb accumulation and detoxification in Athyrium wardii (Hook.). AB - Athyrium wardii is one of the dominant plant species flourishing on the Pb-Zn mine tailings in Sichuan Province, China. A greenhouse pot experiment was conducted to evaluate the chemical forms, subcellular distribution, and thiol compounds in A. wardii under different Pb treatments. The results showed that plants of the mining ecotype (ME) of A. wardii were more tolerant to Pb than those of the non-mining ecotype (NME) in spite of accumulation of higher Pb concentrations. The Pb concentrations in shoots and roots of the ME were 3.2~8.6 times and 3.0~24.6 times higher than those of the NME, respectively. The ME was more efficient in Pb uptake than the NME. Moreover, 27.8~39.0% of the total Pb in ME was sodium chloride (NaCl) extractable and 38.0~48.5% was acetic acid (HAc) extractable, whereas only a minority of total Pb was in ethanol and H2O extractable. In subcellular level, 77.4~88.8% of total Pb was stored in the cell walls of ME and 9.0~18.9% in soluble fractions. Increasing Pb concentrations enhanced sequestration of Pb into the cell walls and soluble fractions of ME tissues to protect organelles against Pb. Synthesis of non-protein thiols (NP-SH) and phytochelatins (PCs) in roots of ME significantly enhanced in response to Pb stress, and significant increases in glutathione (GSH) were observed in shoots of ME. Higher levels of NP-SH, GSH, and PCs were observed in roots of the ME comparing with NME, especially under high Pb treatments. The results indicated that Pb was localized mainly in cell wall and soluble fraction of ME plants with low biological activity by cell wall deposition and vacuolar compartmentalization, which might be the important adapted Pb detoxification mechanisms of ME. PMID- 25913311 TI - Assessing the impacts of wastewater treatment implementation on the water quality of a small urban river over the past 40 years. AB - This paper studies the effects of the implementation of wastewater treatment (WWT) on the water quality of small urban river systems by considering as an extreme case study (volumetric contribution of wastewaters >50%) the evolution of the Zenne River waters (Belgium) over the last 40 years. In urban rivers, organic matter (OM), oxygen, and nutrients are primarily controlled by wastewater releases which depend on the population and the WWT capacity in the river basin, the latter being dependent on environmental policy decisions. We introduce a novel basin-scale evaluation method that considers the evolution of annual pollutant loads at the outlet of the river basin directly as a function of WWT capacity. Based on this approach, we could prove that the load reductions observed after the implementation of WWT in the river basin was a good indicator of the global treatment efficiency of the WWT plants. We also show that high self purification processes within the river basin may lead to reach minimum levels of OM before the completion of WWT. In addition, the effects of wet weather conditions did also change as a function of the WWT capacity going from positive effects at low capacity to negative effects at high capacity. Finally, the full implementation of WWT in urban river basins does not necessarily guarantee a good status for water quality, mostly because of the high volumetric proportion of treated wastewaters, which do not have the quality standards of river waters. PMID- 25913312 TI - Nonlinear QSAR modeling for predicting cytotoxicity of ionic liquids in leukemia rat cell line: an aid to green chemicals designing. AB - Safety assessment and designing of safer ionic liquids (ILs) are among the priorities of the chemists and toxicologists today. Computational approaches have been considered as appropriate methods for prior safety assessment of chemicals and tools to aid in structural designing. The present study is an attempt to investigate the chemical attributes of a wide variety of ILs towards their cytotoxicity in leukemia rat cell line IPC-81 through the development of nonlinear quantitative structure-activity relationship (QSAR) models in the light of the OECD principles for QSAR development. Here, the cascade correlation network (CCN), probabilistic neural network (PNN), and generalized regression neural networks (GRNN) QSAR models were established for the discrimination of ILs in four categories of cytotoxicity and their end-point prediction using few simple descriptors. The diversity and nonlinearity of the considered dataset were evaluated through computing the Euclidean distance and Brock-Dechert-Scheinkman statistics. The constructed QSAR models were validated with external test data. The predictive power of these models was established through a variety of stringent parameters recommended in QSAR literature. The classification QSARs rendered the accuracy of >86%, and the regression models yielded correlation (R(2)) of >0.90 in test data. The developed QSAR models exhibited high statistical confidence and identified the structural elements of the ILs responsible for their cytotoxicity and, hence, could be useful tools in structural designing of safer and green ILs. PMID- 25913313 TI - Effects of wind wave turbulence on the phytoplankton community composition in large, shallow Lake Taihu. AB - Wind waves are responsible for some of the spatio-temporal gradients observed in the biotic and abiotic variables in large shallow lakes. However, their effects on the phytoplankton community composition are still largely unexplored especially in freshwater systems such as lakes. In this paper, using field observations and mesocosm bioassay experiments, we investigated the impact of turbulence generated by wind waves on the phytoplankton community composition (especially on harmful cyanobacteria) in Lake Taihu, a large, shallow eutrophic lake in China. The composition of the phytoplankton community varied with the intensity of wind waves in the different areas of the lake. During summer, when wind waves were strong in the central lake, diatoms and green algae seemed to dominate while harmful cyanobacteria dominated in the weakly influenced Meiliang Bay. Turbulence bioassays also showed that diatoms and green algae were favoured by turbulent mixing. The critical time for the shift of the phytoplankton community composition was approximately 10 days under turbulent conditions. However, short-term (6 days) turbulence is rather beneficial for the dominance of cyanobacteria. This study suggests that the duration of wind events and their associated hydrodynamics are key factors to understanding the temporal and spatial changes of phytoplankton communities. PMID- 25913314 TI - High abundances of dicarboxylic acids, oxocarboxylic acids, and alpha-dicarbonyls in fine aerosols (PM2.5) in Chengdu, China during wintertime haze pollution. AB - Daytime and nighttime fine aerosol (PM2.5) samples were collected during a haze episode in January 2013 within the urban area of Chengdu, southwest China. Aerosol samples were analyzed for low-molecular-weight homologous dicarboxylic acids, oxocarboxylic acids and alpha-dicarbonyls, as well as organic carbon and elemental carbon. Concentration ranges of diacids, oxoacids, and alpha dicarbonyls were 1,400-5,250, 272-1,380, and 88-220 ng m(-3), respectively. Molecular distributions of diacids (mean 3,388 +/- 943 ng m(-3)) were characterized by a predominance of oxalic acid (C2; 1,373 +/- 427 ng m(-3)), followed by succinic (C4), terephthalic (tPh), and phthalic (Ph) acids. Such high levels of tPh and Ph were different from those in other Asian cities where malonic acid (C3) is the second or third highest species, mostly owing to significant emissions from coal combustion and uncontrolled waste incineration. High contents of diacids, oxoacids, and alpha-dicarbonyls were detected on hazy days, suggesting an enhanced emission and/or formation of these organics during such a weather condition. Concentrations of unsaturated aliphatic diacids (e.g., maleic acid) and phthalic acids were higher in nighttime than in daytime. Good positive correlations of C2 with C3, C4, ketomalonic (kC3), pyruvic (Pyr), and glyoxylic (omegaC2) acids in daytime suggest secondary production of C2 via the photooxidation of longer chain diacids and omegaC2. This study demonstrated that both primary emissions and secondary production are important sources of dicarboxylic acids and related compounds in atmospheric aerosols in the Sichuan Basin. PMID- 25913315 TI - Effects of winter covering crop residue incorporation on CH4 and N2O emission from double-cropped paddy fields in southern China. AB - Residue management in cropping systems is useful to improve soil quality. However, the studies on the effects of residue management on methane (CH4) and nitrous oxide (N2O) emission from paddy field in southern China are few. Therefore, the emissions of CH4 and N2O were investigated in double cropping rice (Oryza sativa L.) systems with different winter covering crops using the static chamber-gas chromatography technique to assess the effects of different covering crops on the emissions of greenhouse gases. The experiment was established in 2004 in Hunan Province, China. Three winter cropping systems were used: rice-rice rape (Brassica napus L.) (T1), rice-rice-potato with straw mulching (Solanum tuberosum L.) (T2), and rice-rice with winter fallow (CK). A randomized block design was adopted in plots, with three replications. The results showed that T2 plots had the largest CH4 emissions during the early and late rice growing season with 12.506 and 32.991 g m(-2), respectively. When compared to CK, total N2O emissions in the early rice growth period and the emissions of the gas increased by 0.013 g m(-2) in T1 and 0.045 g m(-2) in T2, respectively. Similar results were obtained in the late rice growth period; the total N2O emissions increased by 0.027 g m(-2) in T1 and 0.084 g m(-2) in T2, respectively. The mean value of global warming potentials (GWPs) of CH4 and N2O emissions over 100 years was in the order of T2 > T1 > CK, which indicated CK and T1 was significantly lower than T2 (P < 0.05). This suggests that adoption of T1 would be beneficial for greenhouse gas emission mitigation and could be a good option cropping pattern in double rice cropped regions. PMID- 25913316 TI - Detoxification strategies and regulation of oxygen production and flowering of Platanus acerifolia under lead (Pb) stress by transcriptome analysis. AB - Toxic metal pollution is a major environmental problem that has received wide attention. Platanus acerifolia (London plane tree) is an important greening tree species that can adapt to environmental pollution. The genetic basis and molecular mechanisms associated with the ability of P. acerifolia to respond lead (Pb) stress have not been reported so far. In this study, 16,246 unigenes differentially expressed unigenes that were obtained from P. acerifolia under Pb stress using next-generation sequencing. Essential pathways such as photosynthesis, and gibberellins and glutathione metabolism were enriched among the differentially expressed unigenes. Furthermore, many important unigenes, including antioxidant enzymes, plants chelate compounds, and metal transporters involved in defense and detoxification mechanisms, were differentially expressed in response to Pb stress. The unigenes encoding the oxygen-evolving enhancer Psb and OEE protein families were downregulated in Pb-stressed plants, implying that oxygen production might decrease in plants under Pb stress. The relationship between gibberellin and P. acerifolia flowering is also discussed. The information and new insights obtained in this study will contribute to further investigations into the molecular regulation mechanisms of Pb accumulation and tolerance in greening tree species. PMID- 25913317 TI - Sediment metal bioavailability in Lake Taihu, China: evaluation of sequential extraction, DGT, and PBET techniques. AB - The European "Community Bureau of Reference" (BCR) sequential extraction procedure, diffusive gradient in thin-films technique (DGT), and physiologically based extraction test were applied to assess metal bioavailability in sediments of Lake Taihu (n = 13). Findings from the three methods showed that Cd was a significant problem in the western lake whereas Cu, Zn, and Ni pollution was most severe in the northern lake. Results from the sequential extraction revealed that more than 50 % of the Cu and Zn were highly mobile and defined within the extractable fraction (AS1 + FM2 + OS3) in the majority of the sediments, in contrast extractable fractions of Ni and Cd were lower than 50 % in most of the sampling sites. Average Cu, Zn, Ni, and Cd bioaccessibilities were <50 % in the gastric phase. Zn and Cd bioaccessibility in the intestinal phase was ~50 % lower than the gastric phase while bioaccessibilities of Cu and Ni were 47-57 % greater than the gastric phase. Linear regression analysis between DGT and BCR measurements indicated that the extractable fractions (AS1 + FM2 + OS3) in the reducing environment were the main source of DGT uptake, suggesting that DGT is a good in situ evaluation tool for metal bioavailability in sediments. PMID- 25913318 TI - The effects of a fungicide and chytrid fungus on anuran larvae in aquatic mesocosms. AB - The amphibian disease chytridiomycosis, caused by the pathogenic fungus Batrachochytrium dendrobatidis (Bd), has been linked to significant amphibian declines over the past three decades. The most severe effects of the pathogen have been primarily observed in relatively pristine areas that are not affected by many anthropogenic factors.One hypothesis concerning improved amphibian persistence with Bd in disturbed landscapes is that contaminants may abate the effects of Bd on amphibians. Recent laboratory studies have shown that pesticides, specifically the fungicide thiophanate-methyl (TM), can kill Bd outside of hosts and clear Bd infections within hosts. Using aquatic mesocosms, we tested the hypothesis that TM (0.43 mg/L) would alter growth and development of Lithobates sphenocephalus (southern leopard frog) tadpoles and Bd-infection loads in infected individuals. We hypothesized that the scope of such alterations and infection clearing would be affected by aquatic community variables, specifically zooplankton. TM altered zooplankton diversity (reduced cladoceran and increased copepod and ostracod abundances) and caused mortality to all tadpoles in TM-exposed tanks. In TM-free tanks, Bd-exposed tadpoles in high density treatments metamorphosed smaller than Bd-unexposed, effects that were reversed in low-density treatments. Our study demonstrates the potential adverse effects of a fungicide and Bd on tadpoles and aquatic systems. PMID- 25913319 TI - DEHP reduces thyroid hormones via interacting with hormone synthesis-related proteins, deiodinases, transthyretin, receptors, and hepatic enzymes in rats. AB - Di-(2-ethylhexyl) phthalate (DEHP) is used extensively in many personal care and consumer products, resulting in widespread nonoccupational human exposure through multiple routes and media. Limited studies suggest that exposure to DEHP may be associated with altered thyroid function, but detailed mechanisms are unclear. In order to elucidate potential mechanisms by which DEHP disturbs thyroid hormone homeostasis, Sprague-Dawley (SD) rats were dosed with DEHP by gavage at 0, 250, 500, and 750 mg/kg/day for 30 days and sacrificed within 24 h after the last dose. Gene expressions of thyroid hormone receptors, deiodinases, transthyretin, and hepatic enzymes were measured by RT-PCR; protein levels of transthyretin were also analyzed by Western blot. Results showed that DEHP caused histological changes in the thyroid and follicular epithelial cell hypertrophy and hyperplasia were observed. DEHP significantly reduced thyroid hormones (T3, T4) and thyrotropin releasing hormone (TRH) levels, whereas thyroid stimulating hormone (TSH) was not affected. After exposure to DEHP, biosynthesis of thyroid hormones was suppressed, and sodium iodide symporter (NIS) and thyroid peroxidase (TPO) levels were significantly reduced. Additionally, levels of deiodinases and transthyretin were also affected. TSH receptor (TSHr) level was downregulated, while TRH receptor (TRHr) level was upregulated. Metabolism of thyroid hormones was accelerated due to elevated gene expression of hepatic enzymes (UDPGTs and CYP2B1) by DEHP. Taken together, observed findings indicate that DEHP could reduce thyroid hormones through influencing biosynthesis, biotransformation, biotransport, receptor levels, and metabolism of thyroid hormones. PMID- 25913320 TI - Equilibrium and kinetic models for colloid release under transient solution chemistry conditions. AB - We present continuum models to describe colloid release in the subsurface during transient physicochemical conditions. Our modeling approach relates the amount of colloid release to changes in the fraction of the solid surface area that contributes to retention. Equilibrium, kinetic, equilibrium and kinetic, and two site kinetic models were developed to describe various rates of colloid release. These models were subsequently applied to experimental colloid release datasets to investigate the influence of variations in ionic strength (IS), pH, cation exchange, colloid size, and water velocity on release. Various combinations of equilibrium and/or kinetic release models were needed to describe the experimental data depending on the transient conditions and colloid type. Release of Escherichia coli D21g was promoted by a decrease in solution IS and an increase in pH, similar to expected trends for a reduction in the secondary minimum and nanoscale chemical heterogeneity. The retention and release of 20nm carboxyl modified latex nanoparticles (NPs) were demonstrated to be more sensitive to the presence of Ca(2+) than D21g. Specifically, retention of NPs was greater than D21g in the presence of 2mM CaCl2 solution, and release of NPs only occurred after exchange of Ca(2+) by Na(+) and then a reduction in the solution IS. These findings highlight the limitations of conventional interaction energy calculations to describe colloid retention and release, and point to the need to consider other interactions (e.g., Born, steric, and/or hydration forces) and/or nanoscale heterogeneity. Temporal changes in the water velocity did not have a large influence on the release of D21g for the examined conditions. This insensitivity was likely due to factors that reduce the applied hydrodynamic torque and/or increase the resisting adhesive torque; e.g., macroscopic roughness and grain-grain contacts. Our analysis and models improve our understanding and ability to describe the amounts and rates of colloid release and indicate that episodic colloid transport is expected under transient physicochemical conditions. PMID- 25913321 TI - Sofosbuvir and simeprevir is effective for recurrent hepatitis C in liver transplant recipients. AB - BACKGROUND & AIMS: Hepatitis C is the most common indication for liver transplantation (LT). Recurrent infection is universal and can lead to progressive liver disease. Widespread use of interferon-based therapy has been limited by intolerability and adverse effects. METHODS: We retrospectively evaluated the safety, tolerability, and efficacy of sofosbuvir and simeprevir in the treatment of recurrent hepatitis C in adult (age >18) LT recipients. RESULTS: Seventy-six percent of the recipients were male and the mean age [+/-standard deviation (SD)] was 61 (+/-6.0) years. The mean time (+/-SD) from LT to treatment initiation was 71.8 (+/-77.1) months. Of the 26 patients with viral levels measured 4 weeks after starting antiviral therapy, 58% were undetectable. At the end of therapy, viral load was undetectable in all transplant recipients. The 12 week sustained viral response (SVR) was 93%. All recipients were able to complete therapy and no patients required growth factors of blood product transfusion during treatment. No patient required drug interruption of their immunosuppressant therapy. CONCLUSION: The use of sofosbuvir and simeprevir is efficacious, safe, and tolerable and should be considered in LT recipients with recurrent HCV who are candidates for antiviral therapy. PMID- 25913322 TI - Geographical modeling of exposure risk to cyanobacteria for epidemiological purposes. AB - The cyanobacteria-derived neurotoxin beta-methylamino-L-alanine (BMAA) represents a plausible environmental trigger for amyotrophic lateral sclerosis (ALS), a debilitating and fatal neuromuscular disease. With the eutrophication of water bodies, cyanobacterial blooms and their toxins are becoming increasingly prevalent in France, especially in the Brittany region. Cyanobacteria are monitored at only a few recreational sites, preventing an estimation of exposure of the human population. By contrast, phosphorus, a limiting nutrient for cyanobacterial growth and thus considered a good proxy for cyanobacteria exposure, is monitored in many but not all surface water bodies. Our goal was to develop a geographic exposure indicator that could be used in epidemiological research. We considered the total phosphorus (TP) concentration (mg/L) of samples collected between October 2007 and September 2012 at 179 monitoring stations distributed throughout the Brittany region. Using readily available spatial data, we computed environmental descriptors at the watershed level with a Geographic Information System. Then, these descriptors were introduced into a backward stepwise linear regression model to predict the median TP concentration in unmonitored surface water bodies. TP concentrations in surface water follow an increasing gradient from West to East and inland to coast. The empirical concentration model included five predictor variables with a fair coefficient of determination (R(2) = 0.51). The specific total runoff and the watershed slope correlated negatively with the TP concentrations (p = 0.01 and p< 10(-9), respectively), whereas positive associations were found for the proportion of built-up area, the upstream presence of sewage treatment plants, and the algae volume as indicated by the Landsat red/green reflectance ratio (p < 0.01, p < 10( 6) and p < 0.01, respectively). Complementing the monitoring networks, this geographical modeling can help estimate TP concentrations at the watershed level, delivering a proxy for cyanobacteria exposure that can be used along with other risk factors in further ALS epidemiologic case-control studies. PMID- 25913323 TI - Does human activity impact the natural antibiotic resistance background? Abundance of antibiotic resistance genes in 21 Swiss lakes. AB - Antibiotic resistance genes (ARGs) are emerging environmental contaminants, known to be continuously discharged into the aquatic environment via human and animal waste. Freshwater aquatic environments represent potential reservoirs for ARG and potentially allow sewage-derived ARG to persist and spread in the environment. This may create increased opportunities for an eventual contact with, and gene transfer to, human and animal pathogens via the food chain or drinking water. However, assessment of this risk requires a better understanding of the level and variability of the natural resistance background and the extent of the human impact. We have analyzed water samples from 21 Swiss lakes, taken at sampling points that were not under the direct influence of local contamination sources and analyzed the relative abundance of ARG using quantitative real-time PCR. Copy numbers of genes mediating resistance to three different broad-spectrum antibiotic classes (sulfonamides: sul1, sul2, tetracyclines: tet(B), tet(M), tet(W) and fluoroquinolones: qnrA) were normalized to copy numbers of bacterial 16S rRNA genes. We used multiple linear regression to assess if ARG abundance is related to human activities in the catchment, microbial community composition and the eutrophication status of the lakes. Sul genes were detected in all sampled lakes, whereas only four lakes contained quantifiable numbers of tet genes, and qnrA remained below detection in all lakes. Our data indicate higher abundance of sul1 in lakes with increasing number and capacity of wastewater treatment plants (WWTPs) in the catchment. sul2 abundance was rather related to long water residence times and eutrophication status. Our study demonstrates the potential of freshwater lakes to preserve antibiotic resistance genes, and provides a reference for ARG abundance from lake systems with low human impact as a baseline for assessing ARG contamination in lake water. PMID- 25913324 TI - Achilles tendon loading patterns during barefoot walking and slow running on a treadmill: An ultrasonic propagation study. AB - Measurement of tendon loading patterns during gait is important for understanding the pathogenesis of tendon "overuse" injury. Given that the speed of propagation of ultrasound in tendon is proportional to the applied load, this study used a noninvasive ultrasonic transmission technique to measure axial ultrasonic velocity in the right Achilles tendon of 27 healthy adults (11 females and 16 males; age, 26 +/- 9 years; height, 1.73 +/- 0.07 m; weight, 70.6 +/- 21.2 kg), walking at self-selected speed (1.1 +/- 0.1 m/s), and running at fixed slow speed (2 m/s) on a treadmill. Synchronous measures of ankle kinematics, spatiotemporal gait parameters, and vertical ground reaction forces were simultaneously measured. Slow running was associated with significantly higher cadence, shorter step length, but greater range of ankle movement, higher magnitude and rate of vertical ground reaction force, and higher ultrasonic velocity in the tendon than walking (P < 0.05). Ultrasonic velocity in the Achilles tendon was highly reproducible during walking and slow running (mean within-subject coefficient of variation < 2%). Ultrasonic maxima (P1, P2) and minima (M1, M2) were significantly higher and occurred earlier in the gait cycle (P1, M1, and M2) during running than walking (P < 0.05). Slow running was associated with higher and earlier peaks in loading of the Achilles tendon than walking. PMID- 25913325 TI - NCK is critical for the development of deleted in colorectal cancer (DCC) sensitive spinal circuits. AB - As our understanding of motor circuit function increases, our need to understand how circuits form to ensure proper function becomes increasingly important. Recently, deleted in colorectal cancer (DCC) has been shown to be important in the development of spinal circuits necessary for gait. Importantly, humans with mutation in DCC show mirror movement disorders pointing to the significance of DCC in the development of spinal circuits for coordinated movement. Although DCC binds a number of ligands, the intracellular signaling cascade leading to the aberrant spinal circuits remains unknown. Here, we show that the non-catalytic region of tyrosine kinase adaptor (NCK) proteins 1 and 2 are distributed in the developing spinal cord. Using dissociated dorsal spinal neuron cultures we show that NCK proteins are necessary for the outgrowth and growth cone architecture of DCC(+ve) dorsal spinal neurons. Consistent with a role for NCK in DCC signaling, we show that loss of NCK proteins leads to a reduction in the thickness of TAG1(+ve) commissural bundles in the floor plate and loss of DCC mRNA in vivo. We suggest that DCC signaling functions through NCK1 and NCK2 and that both proteins are necessary for the establishment of normal spinal circuits necessary for gait. Reduction in NCK proteins in the developing CNS leads to a reduction in TAG1(+ve) commissural tract thickness, a reduction in growth cone complexity of DCC(+ve) spinal interneurons, and a reduction in DCC mRNA. These are consistent with an in vivo role for NCK in the development of critical DCC spinal circuits, and may be important for the normal development of spinal circuits critical for walking. PMID- 25913326 TI - A thirty-five nucleotides BCR-ABL1 insertion mutation of controversial significance confers resistance to imatinib in a patient with chronic myeloid leukemia (CML). AB - Tyrosine kinase inhibitors (TKI) have improved the management of patients with chronic myeloid leukemia (CML). However, a significant proportion of patients does not achieve the optimal response or are resistant to TKI. ABL1 kinase domain mutations have been extensively implicated in the pathogenesis of TKI resistance. Although deletion or insertion of nucleotides in BCR-ABL1 has rarely been described, we identified a CML patient with an already described 35 nucleotides insertion (BCR-ABL1(35INS)) of controversial significance, that confers resistance to imatinib but sensitivity to dasatinib. PMID- 25913327 TI - Induction of a heparin-stimulated serine proteinase in sex accessory gland tumors of the Lobund-Wistar rat. AB - Induction of new proteinase activities that may process growth factors, modify cell surface receptors, cleave extracellular matrix proteins, etc. is considered fundamental in carcinogenesis. The purpose of this study was to characterize a novel proteinase activity induced in sex accessory gland cancers (about 70% in seminal vesicles) of adult male Lobund-Wistar rats by a single injection of N nitroso-N-methylurea (NMU; 25mg/kg) followed by implanted testosterone propionate (45mg in silastic tubing every 2months) treatment for 10-14months. A 28kDa proteinase activity was detected in tumor extracts using SDS-gelatin gel zymography with incubations done without CaCl2. Its activity was stimulated 15 fold by heparin (optimal activity 1.5-3.0MUg/lane) added to the tissue extract SDS sample buffer prior to electrophoresis. No 28kDa heparin-stimulated proteinase (H-SP) was found in the dorsal, lateral and anterior (coagulating gland) prostate lobes or seminal vesicles of untreated adult rats, but there was a 26-30kDa Ca(2+)-independent proteinase activity in the ventral prostate that showed limited heparin stimulation. The 28kDa H-SP was completely inhibited by 1.0mM 4-(2-aminoethyl)benzenesulfonylfluoride (AESBF) indicating that it was a serine-type proteinase. Other types of proteinase inhibitors were without effect, including serine proteinase inhibitors benzamidine, tranexamic acid and epsilon aminocaproic acid. Proteinase activities of about 28kDa were found with casein, fibrinogen or carboxymethylated transferrin as substrate, however, these activities were not stimulated by heparin. Similar levels of activities of the 28kDa H-SP were found in primary tumors and their metastases, but little/no activity was detected in serum, even from rats with large tumor volume and metastases. These data demonstrate overexpression of a heparin-stimulated 28kDa serine proteinase in the primary tumors of sex accessory gland cancers and their metastases. This proteinase either does not leak into or is inactivated in the blood. The role of this proteinase remains to be determined, but its possible interaction with extracellular glycosaminoglycans could focus its proteolytic activity in the tumor microenvironment and affect tumor growth. PMID- 25913328 TI - Electroplating of nanostructured polyaniline-polypyrrole composite coating in a stainless-steel tube for on-line in-tube solid phase microextraction. AB - In this work, a novel and efficient on-line in-tube solid phase microextraction method followed by high performance liquid chromatography was developed for preconcentration and determination of trace amounts of parabens. A nanostructured polyaniline-polypyrrole composite was electrochemically deposited on the inner surface of a stainless steel tube and used as the extraction phase. Several important factors that influence the extraction efficiency, including type of solid-phase coating, extraction and desorption times, flow rates of the sample solution and eluent, pH, and ionic strength of the sample solution were investigated and optimized. Under the optimal conditions, the limits of detection were in the range of 0.02-0.04 MUg L(-1). This method showed good linearity for parabens in the range of 0.07-50 MUg L(-1), with coefficients of determination better than 0.998. The intra- and inter-assay precisions (RSD%, n=3) were in the range of 5.9-7.0% and 4.4-5.7% at three concentration levels of 2, 10, and 20 MUg L(-1), respectively. The extraction recovery values for the spiked samples were in the acceptable range of 80.3-90.2%. The validated method was successfully applied for analysis of methyl-, ethyl-, and propyl parabens in some water, milk, and juice samples. PMID- 25913330 TI - Fractionation of technical octabromodiphenyl ether by countercurrent chromatography combined with gas chromatography/mass spectrometry and offline and online (1)H nuclear magnetic resonance spectroscopy. AB - Countercurrent chromatography (CCC) is a technique, which uses two immiscible liquid phases for a separation process in a long and hollow tube. The technique allows the separation of high amounts of sample (50mg to several grams) with a low consumption of solvents. In this study, we fractionated 50mg technical octabromodiphenyl ether (DE-79) and analyzed the fractions by gas chromatography with mass spectrometry (GC/MS) and proton nuclear magnetic resonance ((1)H NMR) spectroscopy. CCC separations were performed with n-hexane/acetonitrile as solvent system in tail-to-head (i.e. the upper phase is mobile) mode. Twelve CCC fractions were studied for the PBDE composition. CCC elution of PBDE congeners was dependent both on the degree of bromination and substitution pattern. Higher brominated congeners eluted faster than lower brominated congeners and isomers with vicinal hydrogen atoms eluted last. In addition to several known PBDE congeners in DE-79, we were able to unequivocally identify BDE 195 in DE-79 and we could verify the presence of BDE 184. Finally, we also established the online hyphenation of CCC with (1)H NMR. The use of deuterated solvents could be avoided by using n-hexane/acetonitrile as two-phase system. By online CCC-(1)H NMR in stop-flow mode we were able to detect eight PBDE congeners in the mixture. PMID- 25913331 TI - Making the social determinants of health a routine part of medical care. PMID- 25913329 TI - Profiling pneumococcal type 3-derived oligosaccharides by high resolution liquid chromatography-tandem mass spectrometry. AB - Pneumococcal type-3 polysaccharide (Pn3P) is considered a major target for the development of a human vaccine to protect against Streptococcus pneumoniae infection. Thus, it is critical to develop methods for the preparation and analysis of Pn3P-derived oligosaccharides to better understand its immunological properties. In this paper, we profile oligosaccharides, generated by the free radical depolymerization of Pn3P, using liquid chromatography (LC)-tandem mass spectrometry (MS/MS). Hydrophilic liquid interaction chromatography (HILIC)-mass spectrometry (MS) revealed a series of oligosaccharides with an even- and odd number of saccharide residues, ranging from monosaccharide, degree of polymerization (dp1) to large oligosaccharides up to dp 20, generated by free radical depolymerization. Isomers of oligosaccharides with an even number of sugar residues were easily separated on a HILIC column, and their sequences could be distinguished by comparing MS/MS of these oligosaccharides and their reduced alditols. Fluorescent labeling with 2-aminoacridone (AMAC) followed by reversed phase (RP)-LC-MS/MS was applied to analyze and sequence poorly separated product mixtures, as RP-LC affords higher resolution of AMAC-labeled oligosaccharides than does HILIC-based separation. The present methodology can be potentially applied to profiling other capsular polysaccharides. PMID- 25913332 TI - Teaching Bioethics at Historically Black Colleges and Universities (HBCUs). AB - This article describes a two-pronged, pilot bioethics education program implemented at a historically Black college/university to determine the interest in bioethics education and begin increasing the program's visibility. The pilot program included a Train-the-Trainer (TtT) component for selected faculty members and a simultaneously-running film- and-speaker series for the entire campus. PMID- 25913333 TI - Racial/ethnic and Weight Status Differences in Food Preparation among WIC Participants. AB - The main purpose of this study was to examine whether the Supplemental Nutrition Program for Women, Infants and Children (WIC) helped mothers of overweight/obese preschool children to cut down on dietary fat and sugar intake for their families. Data from the Children Eating Well for Health (CHEW) Nutrition Survey, a probability sample of 150 (50 each White, Black and Hispanic) families with preschoolers participating in the WIC program in Nashville/Davidson County, Tennessee, were analyzed using logistic regression modeling. Mothers who reported that the WIC program helped them reduce fat intake were 2.5 times more likely to have an overweight/obese child and 2.1 times more likely to be obese themselves. No significant effects were found for adding sugar. These results suggest that the mothers in this sample were applying WIC nutritional counseling to use food preparation techniques that cut down on added fats for themselves and their children who were at risk due to weight status. PMID- 25913334 TI - Traumatic Brain Injury Focus Groups as a Means to Understand Violence among Adolescent Males in the NYC Jail System. AB - Because we previously identified high rates of past TBI among adolescents arriving in the New York City (NYC) jail system we engaged adolescents in nine TBI focus groups to characterize better the level of understanding regarding the relationship between TBI and violence. During these groups, the following themes emerged: 1) physical and psychological impacts of violence; 2) roots of violence; 3) the use of violence as capital in the face of a marginalized social status; and 4) the inevitability of violence, particularly in a jail setting. Although these focus groups were initiated as a means to engage adolescents around the clinical problem of TBI, their observations are strongly centered in the larger context of violence. These results suggest that intervening in the problem of TBI among our patients will require broad-based changes in the environmental and interpersonal realities, both in the jail setting, and the communities where these adolescents reside. PMID- 25913335 TI - Outcomes for Children with Chronic Conditions Associated with Parent- and Provider-reported Measures of the Medical Home. AB - PURPOSE: Assess relationships between having a patient-centered medical home (PCMH) and health care utilization among low-income children with chronic conditions using parent and practice perspectives. METHODS: We analyzed data from 240 publicly insured children with chronic conditions. Parents completed surveys assessing PCMH access and their child's primary care practice completed the Medical Home Index (MHI) self-assessment. Multivariate negative binomial analyses were conducted to investigate relationships between PCMH and service use. RESULTS: Parent-report of a usual source of care was associated with lower rates of emergency care (ED) encounters and hospitalizations. Practice report of higher organizational capacity (e.g., communication, staff education) was associated with lower rates of ED visits and hospitalizations. Parent report of a PCMH was positively associated with practice MHI score. CONCLUSIONS: Among low-income children with chronic conditions, having a usual source of care and higher quality organizational capacity were associated with lower rates of ED visits and hospitalizations. PMID- 25913336 TI - Colorectal Cancer Screening Rates at Community Health Centers that Use Electronic Health Records: A Cross Sectional Study. AB - BACKGROUND: This study was conducted to validate use of electronic health record (EHR) data for measuring colorectal cancer (CRC) screening rates at community health centers (CHCs). METHODS: Electronic health records were queried to assess screening via colonoscopy, flexible sigmoidoscopy, or fecal occult blood testing (FOBT) in 2011. RESULTS: Multiple iterations were required to maximize query accuracy. Manual chart reviews, stratified by screening modality, confirmed query results for 112 of 113 (99.1%) reviewed colonoscopies, 110 of 110 (100%) reviewed FOBTs, and 111 of 120 (92.5%) unscreened patients. At participating CHCs, CRC screening rates ranged from 9.7% to 67.2% (median, 30.6%). Adherence to annual FOBT ranged from 3.3% to 59.0% (median, 18.6%). Most screening was done by colonoscopy. CONCLUSIONS: Colorectal cancer screening varies substantially across CHCs. Electronic health record data can validly measure CRC screening, but repeated assessments of programming accuracy are required. Community health centers may need support to measure quality using EHR data and increase screening. PMID- 25913337 TI - Association between Family Communication and Health Literacy among Underserved Racial/Ethnic Women. AB - Health literacy and the family can be used to promote cancer screenings. We examined the associations of socio-demographic factors, family communication, and cancer literacy in a diverse population. Baseline data from the Kin Keeper(SM) Cancer Prevention randomized controlled trial were analyzed for Black (n=216), Latino (n=65), and Arab (n=235) women. Key variables were based on the Family Adaptability and Cohesion Scale IV, and the Cancer Literacy Assessment Tool. Among Blacks, cervical cancer literacy was positively associated with family communication. Cancer literacy was associated with higher educational level, employment, and family self-rated health status among Black and Arab women. Among Latinas, who were the least educated and had the lowest literacy scores, family communication was inversely related to breast cancer literacy. Family-centered networks may be a viable resource for the transmission of health cancer literacy information, inform health care decision-making, and contribute to decreasing breast and cervical cancer mortality. PMID- 25913338 TI - The health implications of deportation policy. AB - The United States detains and deports over 400,000 people annually. This large scale effort has important consequences for the health of affected individuals and communities. A growing body of research suggests that deportation increases stress and mental illness, economic deprivation, and individual exposure to violence, while also contributing to destabilization and crime at the community level. The challenges to reintegration experienced by deportees are additional push factors that increase their desire to re-emigrate. Furthermore, the related destabilization of local communities also contributes to the push, not just for deportees, but for all affected people in the region. This phenomenon has important implications for the long-term effectiveness of current U.S. deportation policies, which may be contributing to destabilization in home countries and thus potentiating further unauthorized emigration to the U.S. PMID- 25913339 TI - No Association between Obesity and Behavior in Low-income, Preschool Latino Children. AB - BACKGROUND: The relationship between behavioral problems and obesity in early childhood in Latinos is largely unknown. METHODS: Cross-sectional anthropometric and behavioral data of children at three years of age were gathered from a cohort of 174 children of Latina mothers at two San Francisco hospitals. Child behaviors were assessed using the preschool Child Behavior Checklist (CBCL/11/2-5). Logistic regression was used to analyze the association between behavior and obesity. RESULTS: At three years, 27.7% were obese. There were no associations between affective (OR = 1.89; 95% confidence interval [CI] 0.42-8.59), anxiety (OR = 1.86; 95% CI 0.53-6.47), pervasive developmental (OR = 0.42; 95% CI 0.13 1.36), attention deficit hyperactivity (OR = 0.58; 95% CI 0.12-2.76), or oppositional defiant (OR = 6.49; 95% CI 0.65-64.49) problems and obesity. CONCLUSIONS: Though psychological problems and obesity are associated among older children and adolescents, there was no association in Latino three-year olds in a low-income sample. PMID- 25913340 TI - The effect of living in the United States on body mass index in refugee patients. AB - BACKGROUND: We describe body mass index (BMI) trajectories over 20 months in newly settled refugees in the United States. METHODS: Growth curves were modeled in in hierarchical linear modeling for cohorts from Southeast Asia, Africa, and the Middle East. RESULTS: For refugees from Southeast Asia and Africa, coefficients suggest an increase of greater than 1.0 kg/m2 per three-month time period, though the best fit function differed between the two groups. A non linear model was the best fit for refugees from the Middle East, with an average increase of just under 1.0 kg/m2 over the study period. DISCUSSION: A significant increase in BMI was observed for all refugees but of a different form, predicted by the refugee's region of origin. This may be related to food insecurity, acculturation, environmental factors, and cultural influences prior to and after arrival in the United States, though further study is needed to develop causal relationships. PMID- 25913341 TI - Economic evaluation of a community health worker-led health literacy intervention to promote cancer screening among Korean American women. AB - OBJECTIVE: The study's objectives were to calculate the costs and evaluate the cost-effectiveness of implementing a health literacy-focused intervention to promote breast and cervical cancer screenings among Korean American women overdue for these tests. METHODS: Researchers estimated the costs of a cluster-randomized controlled trial that evaluated this intervention. Effectiveness was measured as the number of breast or cervical cancer screenings received by women in either the intervention and control arms of the study. Cost-effectiveness was calculated as the incremental cost of each additional screening received by the intervention group. RESULTS: Comparing the intervention and control group, the incremental cost-effectiveness ratio was estimated to be US$236 per screening, without program development costs. CONCLUSION: These findings suggest this program, when compared with others, offered a more cost-effective approach for promoting cancer screening. Local health officials could use this information to guide decisions about reducing cancer disparities among recent immigrant women. PMID- 25913342 TI - Patient Reported Outcomes of 'Eat, Walk, Sleep': A Cardiometabolic Lifestyle Program for Cambodian Americans Delivered by Community Health Workers. AB - BACKGROUND: This study investigated a community health worker-delivered lifestyle intervention for prevention of cardiometabolic disease, called Eat, Walk, Sleep. It was designed for traumatized, low-literacy Cambodian American refugees. METHODS: We used a single group, pre-post design to evaluate the effects of the program on self-reported health behaviors. As a control for threats to internal validity, we also measured a nonequivalent dependent variable, i.e., perceived discrimination by health care providers. RESULTS: Of 140 participants enrolled, 114 completed one-year assessments. In intent-to-treat analysis with correction for multiple comparisons, compared with baseline, participants at one year scored higher on cardiometabolic prevention knowledge, self-rated health, physical activity, medication compliance, and preventive screenings, and they reported improved sleep, a modest shift from white to brown rice, and reduced barriers to care. As expected, perceptions of discrimination by health care providers did not change. CONCLUSIONS: Self-reported behavioral risk factors improved. A randomized, controlled study with objective measures is warranted. PMID- 25913343 TI - Tales from the Miami Healthy Heart Initiative: the experiences of two community health workers. AB - Community health workers (CHWs) have been bridging the gap between under-served populations and health care systems for centuries; however, their experiences are rarely recounted. The Miami Healthy Heart Initiative is a randomized control trial designed to examine the effectiveness of CHWs on reducing the risk for cardiovascular disease among Hispanics with poorly controlled diabetes in South Florida. This manuscript, told from the perspective of CHWs, is a summary of cases that were successful and some that did not achieve optimal outcomes. These case summaries include anecdotal data and clinical variables that demonstrate each patient's progress during the intervention. PMID- 25913344 TI - Latino Parents' Beliefs about Television Viewing by Infants and Toddlers. AB - OBJECTIVE: To determine Latino parents' beliefs regarding the effects of television viewing on infants and toddlers. METHODS: We conducted interviews with 26 Latino parents of infants and toddlers. We evaluated parents' beliefs about the health effects of television viewing, sources of information on this topic and facilitators and barriers to following the American Academy of Pediatrics (AAP) screen-time guidelines. RESULTS: Parents believed that television viewing was educational for children but were concerned that watching television could worsen children's vision. Parents would be motivated to limit television viewing by children if it were recommended by a health care provider. Most parents were confident that they could limit their children's television viewing, although some perceived logistical challenges to following guidelines. CONCLUSIONS: Parents in our study had limited knowledge of the effects of television. Counseling on television by health care providers for Latino parents may decrease Latino infants and toddlers' television exposure. PMID- 25913345 TI - Non-communicable diseases in an older, aging population: a developing country perspective (Jamaica). AB - Changes in the non-communicable disease (NCD) profile of older adults living in a rapidly-aging, developing country are described. METHODS: Data from a 2012 nationally representative survey of 2,943 older adults were used to determine the burden of NCDs important to elder health. Additionally, the percentage change in NCD prevalence over a 23-year period (1989-2012) was determined. RESULTS: In 2012, approximately 75.3% of the sample reported at least one NCD; 47.5% reported comorbidities. High blood pressure (61%), arthritis (35%) and diabetes (26%) were the most reported conditions, peaking in the 70-79 age group. Females reported higher rates of disease than males. Significant increases in prevalence occurred for all conditions except arthritis; the most significant were in diabetes (157%) and cancer (118%). CONCLUSION: Rapid increases in NCDs are of great public health importance. Strengthening of primary health care and improvements in human resources must occur if the well-being of older adults is to be improved. PMID- 25913347 TI - Improving Access to Mental Health Services for Racialized Immigrants, Refugees, and Non-Status People Living with HIV/AIDS. AB - The demographic characteristics of people living with HIV/AIDS (PHAs) in Canada are increasingly diverse. Despite literature suggesting a potentially heightened mental health burden borne by racialized immigrant, refugee, and non-status PHAs (IRN-PHAs), researchers have hitherto paid insufficient attention to whether existing services adequately address this need and how services might be improved. Employing community-based research methodology involving PHAs from five ethnoracial groups in Toronto, Ontario, this study explored IRN-PHAs' mental health service-seeking behaviors, service utilization experiences, and suggestions for service improvements. Results showed that while most IRN-PHAs were proactive in improving their mental health, their attempts to obtain support were commonly undermined by service provider mistreatment, unavailability of appropriate services, and multiple access barriers. A three-pronged approach involving IRN-PHA empowerment, anti-stigma and cultural competence promotion, and greater service integration is proposed for improving IRN-PHAs' mental health service experience. PMID- 25913346 TI - Feasibility of conducting a longitudinal, transnational study of filipino migrants to the United States: a dual-cohort design. AB - Most studies of immigrant health are cross-sectional and fail to collect information prior to migration, leading to potential bias and confounding. The present pilot study examines the feasibility of studying migrants prospectively, with baseline data collected before migration. The study followed two cohorts of Filipinos for one year, a migrant cohort (n=27) that emigrated to the U.S. and a second non-migrant cohort (n=26) that remained in the Philippines. The one-year retention rate was 96%. The migrant cohort arrived in the U.S. within two months of their baseline assessment. Migrants and non-migrants did not differ with regard to body mass index, waist circumference, or waist to hip ratio at baseline or at follow-up. It is feasible to conduct a transnational, longitudinal study of two cohorts of Filipinos. This design provides important pre-migration information, is analogous to a natural experiment, can be upscaled, and allows for a rigorous examination of immigrant health. PMID- 25913348 TI - Preventive Counseling Services during Primary Care Visits: A Comparison of Health Centers versus Other Physician Offices. AB - We compared preventive counseling services provided by health centers versus other physician offices. Cross-sectional data came from the 2008 National Ambulatory Medical Care Survey, including 25,177 patient visits in physician offices and 3,345 patient visits in health centers. Despite serving disproportionately more vulnerable patients, health centers provided comparable rates of preventive counseling services, compared with other physician offices: health education (39% vs. 36%), disease management (34% vs. 41%), asthma education (21% vs. 13%), tobacco education (19% for both), and weight reduction education (6% vs. 9%) (p>.05 for all). Adjusted analyses showed no association between health care setting and preventive counseling. PMID- 25913349 TI - Strategies to balance fidelity to Housing First principles with local realities: lessons from a large urban centre. AB - The importance of program implementation in achieving desired outcomes is well documented, but there remains a need for concrete guidance on how to achieve fidelity to evidence-based models within dynamic local contexts. Housing First (HF), an evidence-based model for people experiencing homelessness and mental illness, provides an important test-case for such guidance; it targets a uniquely underserved subpopulation with complex needs, and is delivered by practitioners with varying knowledge and skill levels. Scientific evidence affirms HF's effectiveness, but its rapid dissemination has outpaced the ability to monitor not only whether it is being implemented with fidelity, but also how this can be achieved within variable local contexts and challenges. This qualitative study contributes to this need by capturing insights from practitioners on implementation challenges and specific strategies developed to overcome them. Findings reinforce the importance of developing HF-specific implementation guidelines, and of engaging relevant stakeholders throughout all phases of that development. PMID- 25913350 TI - Defining and Rating the Effectiveness of Enabling Services Using a Multi stakeholder Expert Panel Approach. AB - The Affordable Care Act provides opportunities to reimburse non-medical enabling services that promote the delivery of medical care for patients with social barriers. However, limited evidence exists to guide delivery of these services. We addressed this gap by convening community health center patients, providers, and other stakeholders in two panels that developed a framework for defining and evaluating these services. We adapted a group consensus method where the panelists rated services for effectiveness in increasing access to, use, and understanding of medical care. Panelists defined six broad categories, 112 services, and 21 variables including the type of provider delivering the service. We identified 16 highest-rated services and found that the service provider's level of training affected effectiveness for some but not all services. In a field with little evidence, these findings provide guidance to decision-makers for the targeted spread of services that enable patients to overcome social barriers to care. PMID- 25913351 TI - Low birth weight in Kansas. AB - CONTEXT: Low birth weight (LBW) is associated with infant morbidity and mortality. This is the first study of LBW in Kansas using vital statistics to determine maternal and health care system factors associated with LBW. OUTCOMES: Low birth weight. OBJECTIVE: Determine if prenatal care, maternal socio demographic or medical factors, or insurance status were associated with LBW. METHODS: Birth certificate data were merged with Medicaid eligibility data and subjected to logistic regression analysis. RESULTS: Of the 37,081 single vaginal births, LBW rates were 5.5% overall, 10.8% for African Americans, and 5% for White Americans. Lacking private insurance was associated with 34% more LBW infants (AOR 1.34; 95% CI 1.13-1.58), increased comorbidity, and late or less prenatal care. Low birth weight was associated with maternal medical comorbidity and with previous adverse birth outcomes. CONCLUSIONS: Insurance status, prenatal care, and maternal health during pregnancy are associated with LBW. Private insurance was consistently associated with more prenatal care and better outcomes. This study has important implications regarding health care reform. PMID- 25913354 TI - Amplicon-based next-generation sequencing: an effective approach for the molecular diagnosis of epidermolysis bullosa. AB - BACKGROUND: Epidermolysis bullosa (EB) is caused by mutations in genes that encode proteins belonging to the epidermal-dermal junction assembly. Due to the extreme clinical/genetic heterogeneity of the disease, the current methods available for diagnosing EB involve immunohistochemistry of biopsy samples and transmission electron microscopy followed by single-candidate gene Sanger sequencing (SS), which are labour-intensive and expensive clinical pathways. OBJECTIVES: According to the recently published recommendations for the diagnosis and treatment of EB, the assessment of the mutational landscape is now a fundamental step for developing a comprehensive diagnostic path. We aimed to develop a customized, cost-effective amplicon panel for the complete and accurate sequencing of all the pathogenic genes already identified in EB, and to minimize the processing time required for the execution of the test and to refine the analysis pipeline to achieve cost-effective results from the perspective of a routine laboratory set-up. Next-generation sequencing (NGS) via the parallel ultra-deep sequencing of many genes represents a proper method for reducing the processing time and costs of EB diagnostics. MATERIALS AND METHODS: We developed an EB disease-comprehensive AmpliSeq panel to accomplish the NGS on an Ion Torrent Personal Genome Machine platform. The panel was performed on 10 patients with known genetic diagnoses and was then employed in eight family trios with unknown molecular footprints. RESULTS: The panel was successful in finding the causative mutations in all 10 patients with known mutations, fully confirming the SS data and providing proof of concept of the sensitivity, specificity and accuracy of this procedure. In addition to being consistent with the clinical diagnosis, it was also effective in the trios, identifying all of the variants, including ones that the SS missed or de novo mutations. CONCLUSIONS: The NGS and AmpliSeq were shown to be an effective approach for the diagnosis of EB, resulting in a cost- and time-effective 72-h procedure. PMID- 25913355 TI - Driving force-dependent block by internal Ba(2+) on the Kir2.1 channel: Mechanistic insight into inward rectification. AB - The Kir2.1 channel is characterized by strong inward rectification; however, the mechanism of the steep voltage dependence near the equilibrium potential remains to be investigated. Here, we studied the internal Ba(2+) block of the Kir2.1 channel expressed in Xenopus oocytes. We showed that the driving force and thus the K(+) ion flux significantly influenced the apparent affinity of the block by internal Ba(2+). Kinetic analysis revealed that the binding rate shifted with the driving force and changed steeply near the equilibrium point, either in the presence or absence of the transmembrane electrical field. The unbinding rate was determined by the intrinsic affinity of the site. Mutagenesis studies revealed that the high-affinity binding site for Ba(2+) was located near T141 at the internal entrance of the selectivity filter. The steep change of the blocking affinity near the equilibrium potential may result from the flux-coupling effect in the single-file, multi-ion cytoplasmic pore. PMID- 25913356 TI - Biomimetic monolayer films of monogalactosyldiacylglycerol incorporating plastoquinone. AB - Photosynthetic organisms use light to convert the inorganic matter in organic one. Photosynthetic process consists on several steps, and one of them involves plastoquinone (PQ) that acts as electron and proton shuttle between photosystem II and cytochrome. We prepared membranes that mimic the characteristics and composition of natural photosynthetic membranes and we characterized them using several techniques in order to obtain both the PQ molecules disposition in the membrane and their electrochemical behavior. The selected lipid was monogalactosyldiacylglycerol (MGDG) that represents the 50% of the lipid content of the thylakoid membrane. Both MGDG and PQ, and the MGDG:PQ mixtures have been studied using surface pressure-area isotherms and the presence of PQ alters the physical state and compactness of the MGDG matrix. Langmuir-Blodgett (LB) films have been obtained by transferring a monolayer that mimics half of the bilayer of a biological membrane. The AFM topographical characterization of the monolayers on mica indicates the presence of differentiated domains, corresponding to different physical states linked to the influence of the PQ content. Moreover, the electrochemical behavior of the monolayers has been studied when transferred on ITO, observing one main electrochemical process that is due to the diving position of PQ molecules in the lipid matrix. PMID- 25913357 TI - Structural studies and cytotoxicity assays of "aggregation-prone" IAPP(8-16) and its non-amyloidogenic variants suggest its important role in fibrillogenesis and cytotoxicity of human amylin. AB - Amyloid deposits to the islets of Langerhans are responsible for the gradual loss of pancreatic beta-cells leading to type II diabetes mellitus. Human mature islet amyloid polypeptide (hIAPP), a 37-residue pancreatic hormone, has been identified as the primary component of amyloid fibrils forming these deposits. Several individual segments along the entire sequence length of hIAPP have been nominated as regions with increased amyloidogenic potential, such as regions 8-20, 20-29, and 30-37. A smaller fragment of the 8-20 region, spanning residues 8-16 of hIAPP has been associated with the formation of early transient alpha-helical dimers that promote fibrillogenesis and also as a core part of hIAPP amyloid fibrils. Utilizing our aggregation propensity prediction tools AmylPred and AmylPred2, we have identified the high aggregation propensity of the 8-16 segment of hIAPP. A peptide analog corresponding to this segment was chemically synthesized and its amyloidogenic properties were validated using electron microscopy, X-ray fiber diffraction, ATR FT-IR spectroscopy, and polarized microscopy. Additionally, two peptides introducing point mutations L12R and L12P, respectively, to the 8-16 segment, were chemically synthesized. Both mutations disrupt the alpha-helical properties of the 8-16 region and lower its amyloidogenic potential, which was confirmed experimentally. Finally, cytotoxicity assays indicate that the 8-16 segment of hIAPP shows enhanced cytotoxicity, which is relieved by the L12R mutation but not by the L12P mutation. Our results indicate that the chameleon properties and the high aggregation propensity of the 8-16 region may significantly contribute to the formation of amyloid fibrils and the overall cytotoxic effect of hIAPP. PMID- 25913358 TI - Warm autoimmune hemolytic anemia with mimicking anti-e specificity causing intravascular hemolysis in a chronic ITP patient. AB - A 12-year-old male child presented to the emergency room with three days history of cola-colored urine, mild icterus, dyspnea, palpitation and fatigue. He had a history of chronic ITP two years ago and had since been on steroid for maintenance of platelet count. He was subsequently diagnosed as a case of warm autoimmune hemolytic anemia. Laboratory investigations were suggestive of intravascular hemolysis, and on immuno-hematological evaluation it was diagnosed that the patient had autoantibody with mimicking anti-e specificity. The specificity of autoantibody was further confirmed by adsorption study. The patient was successfully managed by transfusion of Rh(e)-negative red cells,steroid and rituximab therapy. So an autoantibody with mimicking anti-e specificity was identified in this case, which was significant in clinical point of view. PMID- 25913359 TI - Effect of vacuum-assisted closure combined with open bone grafting to promote rabbit bone graft vascularization. AB - BACKGROUND: Patients with composite bone non-union and soft tissue defects are difficult to treat. Vacuum-assisted closure (VAC) combined with open bone grafting is one of the most effective treatments at present. The aim of the present study was to preliminarily investigate the effect and mechanism of VAC combined with open bone grafting to promote rabbit bone graft vascularization, and to propose a theoretical basis for clinical work. MATERIAL/METHODS: Twenty four New Zealand white rabbits were randomly divided into an experimental and a control group. Allogeneic bones were grafted and banded with the proximal femur with a suture. The experimental group had VAC whereas the control group had normal wound closure. The bone vascularization rate was compared based on X-ray imaging, fluorescent bone labeling (labeled tetracycline hydrochloride and calcein), calcium content in the callus, and expression of fibroblast growth factor-2 (FGF-2) in bone allografts by Western blot analysis at the 4th, 8th, and 12th week after surgery. RESULTS: At the 4th, 8th, and 12th week after surgery, the results of the tests demonstrated that the callus was larger, contained more calcium (p<0.05), and expressed FGF-2 at higher levels (p<0.05) in the experimental group than in the control group. Fluorescent bone labeling showed the distance between the two fluorescent ribbons was significantly shorter in the control group than in the experimental group at the 8th and 12th week after surgery. CONCLUSIONS: VAC combined with open bone grafting promoted rabbit bone graft vascularization. PMID- 25913360 TI - VIGILANCE POISON: Illegal poisoning and lead intoxication are the main factors affecting avian scavenger survival in the Pyrenees (France). AB - A specific surveillance program has been set up to monitor avian scavenger populations in the French Pyrenean Mountains, hosting a high proportion of the French populations. The two main purposes of the study were to identify all causes of death and to investigate poisoning cases. All 170 birds found dead during the 7-year program were submitted to full necropsy, X-Ray, parasitological investigations and consistent analytical toxicology screenings (Cholinesterase inhibitors, anticoagulant rodenticides, organochlorine insecticides, Pb, Cd). Over the study period, 8 Bearded Vultures, 120 Griffon Vultures, 8 Egyptian Vultures and 34 Red kites were eventually collected. Mortality events were often multifactorial, but poisoning was by far the most common cause of death (24.1%), followed by trauma/fall (12%), bacterial diseases and starvation (8%) and electrocution (6%). Illicit use of banned pesticides was identified as a common cause of poisoning (53% of all poisoning cases) and lead poisoning was also identified as a significant toxicant issue (17% of all poisoning cases). Lead isotopic signature could be associated primarily with ammunition. Last, a positive association between trauma and lead contamination was detected, indicating that lead could be a significant contributor to different causes of death. These results urge for severe restrictions on the use of lead ammunition to prevent scavengers from detrimental exposure. PMID- 25913361 TI - Accurate assessment of the biodegradation of cationic surfactants in activated sludge reactors (OECD TG 303A). AB - The continuous-fed activated sludge test (OECD TG 303A) was used to predict the removal of cationic surfactants from wastewater in activated sludge plants. However, a method to differentiate between adsorption and biodegradation is not provided in these guidelines. Assessment of removal by biodegradation was possible with analysis of the surfactant present in mixed liquid suspended solids in combination with a simple equation. This equation was derived from the mass balance of the activated sludge unit in steady state. The removal by biodegradation of decylamine, tetradecylamine, octadecylamine, dioctadecylmethylamine and dioctadecyldimethylammonium chloride that have different capacities to adsorb was >99.9%, >99.9%, 98.2%, 94.2%, and 69.0%, respectively. The total removal of all five cationic surfactants from the influent was >=98.8%. The removal of octadecylamine spiked at different influent concentrations indicated first order kinetics. PMID- 25913362 TI - Mercury in muscle and brain of catfish from the Madeira river, Amazon, Brazil. AB - The central nervous system is a critical target for Hg toxicity in all living organisms. Total Hg (THg) was determined in brain and muscle samples of 165 specimens of eight species of catfish (Brachyplatystoma filamentosum; Brachyplatystoma platynemum; Brachyplatystoma rousseauxii; Brachyplatystoma vaillantii; Phractocephalus hemiliopterus; Pseudoplatystoma punctifer; Pseudoplatystoma tigrinum; Zungaro zungaro) from the Madeira River, Brazilian Amazon. Despite the narrow range of Fishbase trophic level (4.2-4.6) the median THg concentrations ranged from 0.39 to 1.99mg/kg and from 0.03 to 0.29mg/kg respectively in muscle and brain from the studied species. Overall, the median concentration for all samples analyzed was 0.93mg/kg and 0.16mg/kg respectively in muscle and brain; most samples (76%) showed muscle Hg concentrations >0.5mg/kg. There were statistically significant THg differences between sex (female>males). The correlation between THg concentrations in muscle and brain was statistically significant (r=0.9170; p<0.0001). In the studied specimens, fish total length was significantly correlated with muscle (r=0.3163; p=0.0001) and brain (r=0.3039; p=0.0003) THg; however, fish age was negatively and significantly correlated (r=-0.2991; p=0.0012) with THg in muscle but not with THg in brain (r=-0.0190; p=0.8492). Amazonian catfish accumulate high levels of Hg in muscle and brain; however, brain-THg concentrations can be predicted from muscle-THg. Muscle-Hg in catfish can be a tool to detect brain-Hg concentrations associated with environmental Hg. PMID- 25913363 TI - Answer to the Letter to the Editor of Jianqiang Ni et al. concerning "ALIF and total disc replacement versus 2-level circumferential fusion with TLIF: a prospective, randomized, clinical and radiological trial" by Hoff EK, Strube P, Pumberger M, et al. (2015) Eur Spine J. doi:10.1007/s00586-015-3852-y. PMID- 25913364 TI - Disassembling bacterial extracellular matrix with DNase-coated nanoparticles to enhance antibiotic delivery in biofilm infections. AB - Infections caused by biofilm-forming bacteria are a major threat to hospitalized patients and the main cause of chronic obstructive pulmonary disease and cystic fibrosis. There is an urgent necessity for novel therapeutic approaches, since current antibiotic delivery fails to eliminate biofilm-protected bacteria. In this study, ciprofloxacin-loaded poly(lactic-co-glycolic acid) nanoparticles, which were functionalized with DNase I, were fabricated using a green-solvent based method and their antibiofilm activity was assessed against Pseudomonas aeruginosa biofilms. Such nanoparticles constitute a paradigm shift in biofilm treatment, since, besides releasing ciprofloxacin in a controlled fashion, they are able to target and disassemble the biofilm by degrading the extracellular DNA that stabilize the biofilm matrix. These carriers were compared with free-soluble ciprofloxacin, and ciprofloxacin encapsulated in untreated and poly(lysine) coated nanoparticles. DNase I-activated nanoparticles were not only able to prevent biofilm formation from planktonic bacteria, but they also successfully reduced established biofilm mass, size and living cell density, as observed in a dynamic environment in a flow cell biofilm assay. Moreover, repeated administration over three days of DNase I-coated nanoparticles encapsulating ciprofloxacin was able to reduce by 95% and then eradicate more than 99.8% of established biofilm, outperforming all the other nanoparticle formulations and the free-drug tested in this study. These promising results, together with minimal cytotoxicity as tested on J774 macrophages, allow obtaining novel antimicrobial nanoparticles, as well as provide clues to design the next generation of drug delivery devices to treat persistent bacterial infections. PMID- 25913365 TI - Therapeutic gas delivery via microbubbles and liposomes. AB - Gaseous molecules including nitric oxide, hydrogen sulfide, carbon monoxide and oxygen mediate numerous cell signaling pathways and have important physiological roles. Several noble gasses have been shown to elicit biological responses. These bioactive gasses hold great therapeutic potential, however, their controlled delivery remains a significant challenge. Recently, researchers have begun using microbubbles and liposomes to encapsulate such gasses for parenteral delivery. The resultant particles are acoustically active, and ultrasound can be used to stimulate and/or image gas release in a targeted region. This review provides a summary of recent advances in therapeutic gas delivery using microbubbles and liposomes. PMID- 25913367 TI - MHC class II-assortative mate choice in European badgers (Meles meles). AB - The major histocompatibility complex (MHC) plays a crucial role in the immune system, and in some species, it is a target by which individuals choose mates to optimize the fitness of their offspring, potentially mediated by olfactory cues. Under the genetic compatibility hypothesis, individuals are predicted to choose mates with compatible MHC alleles, to increase the fitness of their offspring. Studies of MHC-based mate choice in wild mammals are under-represented currently, and few investigate more than one class of MHC genes. We investigated mate choice based on the compatibility of MHC class I and II genes in a wild population of European badgers (Meles meles). We also investigated mate choice based on microsatellite-derived pairwise relatedness, to attempt to distinguish MHC specific effects from genomewide effects. We found MHC-assortative mating, based on MHC class II, but not class I genes. Parent pairs had smaller MHC class II DRB amino acid distances and smaller functional distances than expected from random pairings. When we separated the analyses into within-group and neighbouring-group parent pairs, only neighbouring-group pairs showed MHC-assortative mating, due to similarity at MHC class II loci. Our randomizations showed no evidence of genomewide-based inbreeding, based on 35 microsatellite loci; MHC class II similarity was therefore the apparent target of mate choice. We propose that MHC assortative mate choice may be a local adaptation to endemic pathogens, and this assortative mate choice may have contributed to the low MHC genetic diversity in this population. PMID- 25913368 TI - Direct and interactive effects of parent, friend and schoolmate drinking on alcohol use trajectories. AB - OBJECTIVE: This study considered the unique and interactive roles of social norms from parents, friends and schools in predicting developmental trajectories of adolescent drinking and intoxication. DESIGN AND OUTCOME MEASURES: Using data from the National Longitudinal Study of Adolescent Health, which followed adolescents (N = 18,921) for 13 years, we used discrete mixture modelling to identify unique developmental trajectories of drinking and of intoxication. Next, multilevel multinomial regression models examined the role of alcohol-related social norms from parents, friends and schoolmates in the prediction of youths' trajectory group membership. RESULTS: Results demonstrated that social norms from parents, friends and schoolmates that were favourable towards alcohol use uniquely predicted drinking and intoxication trajectory group membership. Interactions between social norms revealed that schoolmate drinking played an important moderating role, frequently augmenting social norms from parents and friends. The current findings suggest that social norms from multiple sources (parents, friends and schools) work both independently and interactively to predict longitudinal trajectories of adolescent alcohol use. CONCLUSIONS: Results highlight the need to identify and understand social messages from multiple developmental contexts in efforts to reduce adolescent alcohol consumption and alcohol-related risk-taking. PMID- 25913366 TI - Maternal high-fat diet programming of the neuroendocrine system and behavior. AB - This article is part of a Special Issue "SBN 2014". Maternal obesity, metabolic state, and diet during gestation have profound effects on offspring development. The prevalence of neurodevelopmental and mental health disorders has risen rapidly in the last several decades in parallel with the rise in obesity rates. Evidence from epidemiological studies indicates that maternal obesity and metabolic complications increase the risk of offspring developing behavioral disorders such as attention deficit hyperactivity disorder (ADHD), autism spectrum disorders (ASD), and schizophrenia. Animal models show that a maternal diet high in fat similarly disrupts behavioral programming of offspring, with animals showing social impairments, increased anxiety and depressive behaviors, reduced cognitive development, and hyperactivity. Maternal obesity, metabolic conditions, and high fat diet consumption increase maternal leptin, insulin, glucose, triglycerides, and inflammatory cytokines. This leads to increased risk of placental dysfunction, and altered fetal neuroendocrine development. Changes in brain development that likely contribute to the increased risk of behavioral and mental health disorders include increased inflammation in the brain, as well as alterations in the serotonergic system, dopaminergic system and hypothalamic pituitary-adrenal (HPA) axis. PMID- 25913369 TI - Self-diffusion in nanocrystalline alloys. AB - We report an operando XRD/MS experiment on a nanocrystalline Pd(70%)Ag(30%) alloy supported on silica (10 wt% of metal) monitoring slow reversible Pd (in CO) and subsequently Ag (in He) surface segregation at 673 K. XRD data following CO and He flow show structural changes that can be modeled and interpreted in terms of the diffusion phenomena within a typical metal nanocluster. Qualitative differences in the rate of both segregation processes suggest different diffusion mechanisms as the Pd segregation involves vacancy depletion. The experimental details suggest that this kind of experiment can provide a very sensitive response to subtle changes at the surface of nanoclusters. Segregation processes can be stopped at any time by lowering the temperature below 573 K which allows engineering of the metal surface e.g. preparing for a catalytic low temperature reaction on a well-defined surface. PMID- 25913370 TI - Efficient production of a correctly folded mouse alpha-defensin, cryptdin-4, by refolding during inclusion body solubilization. AB - Mammalian alpha-defensins contribute to innate immunity by exerting antimicrobial activity against various pathogens. To perform structural and functional analysis of alpha-defensins, large amounts of alpha-defensins are essential. Although many expression systems for the production of recombinant alpha-defensins have been developed, attempts to obtain large amounts of alpha-defensins have been only moderately successful. Therefore, in this study, we applied a previously developed aggregation-prone protein coexpression method for the production of mouse alpha-defensin cryptdin-4 (Crp4) in order to enhance the formation of inclusion bodies in Escherichia coli expression system. By using this method, we succeeded in obtaining a large amount of Crp4 in the form of inclusion bodies. Moreover, we attempted to refold Crp4 directly during the inclusion-body solubilization step under oxidative conditions. Surprisingly, even without any purification, Crp4 was efficiently refolded during the solubilization step of inclusion bodies, and the yield was better than that of the conventional refolding method. NMR spectra of purified Crp4 suggested that it was folded into its correct tertiary structure. Therefore, the method described in this study not only enhances the expression of alpha-defensin as inclusion bodies, but also eliminates the cumbersome and time-consuming refolding step. PMID- 25913371 TI - Conservative orthodontic-prosthodontic approach for excessive gingival display: A clinical report. AB - A differential diagnosis of excessive gingival display is critical in determining appropriate treatment options and sequence. Anterior tooth malposition for patients with deep vertical overlap has been suggested as one of the 3 main causes of excessive gingival display. Specifically, patients with Angle class II, division 2 malocclusions show an occlusal scheme that might be responsible for additional anterior tooth wear when compared with individuals without malocclusion. In the long term, this condition can cause dentoalveolar compensation and overeruption of maxillary incisors with concomitant coronal movement of the gingival margin with excessive gingival display. A combined orthodontic and restorative treatment was proposed as a conservative treatment to reposition maxillary anterior teeth and their gingival margins to a more ideal position and create the necessary interocclusal restorative space to restore worn teeth with ceramic restorations, enhance dental and facial esthetics, and reestablish anterior guidance. PMID- 25913372 TI - Influence of surface sealant agents on the surface roughness and color stability of artificial teeth. AB - STATEMENT OF PROBLEM: Although various surface sealant agents are available and recommended for chairside polishing procedures, their effect on the surface roughness and color stability of denture teeth is not clear. PURPOSE: The purpose of this in vitro study was to evaluate the effect of sealant agents on the surface roughness and color stability of various denture tooth materials. MATERIAL AND METHODS: Eighty disk-shaped specimens were prepared for each type of denture tooth material (SR Vivodent, PMMA; Vitapan, reinforced-PMMA; SR Phonares II, composite resin). The specimens were assigned to 4 groups according to the surface treatment used (n=20): surface sealant agents (Palaseal; Heraeus Kulzer GmbH, Optiglaze; GC Corp Biscover; Bisco Inc) and a conventional laboratory polishing technique (control group). A thermal cycling procedure was applied for half of the specimens (n=10). The surface roughness (Ra) values of thermocycled and nonthermocycled specimens were measured with a profilometer. The CIELab color parameters of both thermocycled and nonthermocycled specimens were measured with a spectrophotometer at baseline and after 7-day storage in a coffee solution. The color differences were calculated from the CIEDE2000 (DeltaE00) formula. Data were statistically analyzed with 3-way ANOVA and the Tukey HSD test (alpha=.05). RESULTS: The type of tooth material, surface treatment technique, and their interactions were significant for Ra values, and each variable and their interactions were also significant for DeltaE00 values (P<.05). Thermal cycling had a significant effect only on DeltaE00 values (P<.05). CONCLUSIONS: Palaseal and Optiglaze sealant agents provided smoother and more color-stable denture tooth surfaces than the conventional polishing technique. The use of the Biscover agent with SR Vivodent and Phonares II teeth increased the Ra values. The color of conventionally polished SR Vivodent and Phonares II teeth changed more with thermal cycling. PMID- 25913373 TI - Sedation scoring and managing abilities of intensive care nurses post educational intervention. AB - BACKGROUND: Inappropriate sedation assessment can jeopardize patient comfort and safety. Therefore, nurses' abilities in assessing and managing sedation are vital for effective care of mechanically ventilated patients. AIMS AND OBJECTIVES: This study assessed nurses' sedation scoring and management abilities as primary outcomes following educational interventions. Nurses' perceived self-confidence and barriers to effective sedation management were assessed as secondary outcomes. DESIGN: A post-test-only quasi-experimental design was used. Data were collected at 3 and 9 months post-intervention. METHODS: A total of 66 nurses from a 14-bed intensive care unit of a Malaysian teaching hospital participated. The educational interventions included theoretical sessions, hands-on sedation assessment practice using the Richmond Agitation Sedation Scale, and a brief sedation assessment tool. Nurses' sedation scoring and management abilities and perceived self-confidence level were assessed at both time points using self administered questionnaires with case scenarios. Sedation assessment and management barriers were assessed once at 9 months post-intervention. RESULTS: Median scores for overall accurate sedation scoring (9 months: 4.00; 3 months: 2.00, p = 0.0001) and overall sedation management (9 months: 14.0; 3 months: 7.0, p = 0.0001) were significantly higher at 9 months compared to 3 months post intervention. There were no significant differences in the perceived self confidence level for rating sedation level. Overall perceived barrier scores were low (M = 27.78, SD = 6.26, possible range = 11.0-55.0). Patient conditions (M = 3.68, SD = 1.13) and nurses' workload (M = 3.54, SD = 0.95) were the greatest barriers to effective sedation assessment and management. Demographic variables did not affect sedation scoring or management abilities. CONCLUSIONS: Positive changes in nurses' sedation assessment and management abilities were observed, indicating that adequate hands-on clinical practice following educational interventions can improve nurses' knowledge and skills. RELEVANCE TO CLINICAL PRACTICE: Educational initiatives are necessary to improve ICU practice, particularly in ICUs with inexperienced nurses. PMID- 25913374 TI - The changes of angiogenesis and immune cell infiltration in the intra- and peri tumoral melanoma microenvironment. AB - Malignant melanoma (MM) urgently needs identification of new markers with better predictive value than currently-used clinical and histological parameters. Cancer cells stimulate the formation of a specialized tumor microenvironment, which reciprocally affects uncontrolled proliferation and migration. However, this microenvironment is heterogeneous with different sub-compartments defined by their access to oxygen and nutrients. This study evaluated microvascular density (MVD), CD3+ lymphocytes (TILs) and FOXP3+ T-regulatory lymphocytes (Tregs) on formalin-fixed paraffin-embedded tissue sections using light microscopy. We analyzed 82 malignant melanomas, divided according to the AJCC TNM classification into four groups--pT1 (35), pT2 (17), pT3 (18) and pT4 (12)--and 25 benign pigmented nevi. All parameters were measured in both the central areas of tumors (C) and at their periphery (P). A marked increase in all parameters was found in melanomas compared to nevi (p = 0.0001). There was a positive correlation between MVD, TILs, FOXP3+ Tregs and the vertical growth phase. The results show that MVD, TILs and FOXP3+ Tregs substantially influence cutaneous melanoma microenvironment. We found significant topographic differences of the parameters between central areas of tumors and their boundaries. PMID- 25913375 TI - Reconciling experiment and theory in the use of aryl-extended calix[4]pyrrole receptors for the experimental quantification of chloride-pi interactions in solution. AB - In this manuscript we consider from a theoretical point of view the recently reported experimental quantification of anion-pi interactions (the attractive force between electron deficient aromatic rings and anions) in solution using aryl extended calix[4]pyrrole receptors as model systems. Experimentally, two series of calix[4]pyrrole receptors functionalized, respectively, with two and four aryl rings at the meso positions, were used to assess the strength of chloride-pi interactions in acetonitrile solution. As a result of these studies the contribution of each individual chloride-pi interaction was quantified to be very small (<1 kcal/mol). This result is in contrast with the values derived from most theoretical calculations. Herein we report a theoretical study using high level density functional theory (DFT) calculations that provides a plausible explanation for the observed disagreement between theory and experiment. The study reveals the existence of molecular interactions between solvent molecules and the aromatic walls of the receptors that strongly modulate the chloride-pi interaction. In addition, the obtained theoretical results also suggest that the chloride-calix[4]pyrrole complex used as reference to dissect experimentally the contribution of the chloride-pi interactions to the total binding energy for both the two and four-wall aryl-extended calix[4]pyrrole model systems is probably not ideal. PMID- 25913376 TI - Novel systems modeling methodology in comparative microbial metabolomics: identifying key enzymes and metabolites implicated in autism spectrum disorders. AB - Autism spectrum disorders are a group of mental illnesses highly correlated with gastrointestinal dysfunction. Recent studies have shown that there may be one or more microbial "fingerprints" in terms of the composition characterizing individuals with autism, which could be used for diagnostic purposes. This paper proposes a computational approach whereby metagenomes characteristic of "healthy" and autistic individuals are artificially constructed via genomic information, analyzed for the enzymes coded within, and then these enzymes are compared in detail. This is a text mining application. A custom-designed online application was built and used for the comparative metabolomics study and made publically available. Several of the enzyme-catalyzing reactions involved with the amino acid glutamate were curiously missing from the "autism" microbiome and were coded within almost every organism included in the "control" microbiome. Interestingly, there exists a leading hypothesis regarding autism and glutamate involving a neurological excitation/inhibition imbalance; but the association with this study is unclear. The results included data on the transsulfuration and transmethylation pathways, involved with oxidative stress, also of importance to autism. The results from this study are in alignment with leading hypotheses in the field, which is impressive, considering the purely in silico nature of this study. The present study provides new insight into the complex metabolic interactions underlying autism, and this novel methodology has potential to be useful for developing new hypotheses. However, limitations include sparse genome data availability and conflicting literature experimental data. We believe our software tool and methodology has potential for having great utility as data become more available, comprehensive and reliable. PMID- 25913377 TI - A two-step nanofiltration process for the production of phenolic-rich fractions from artichoke aqueous extracts. AB - Commercial nanofiltration (NF) membranes in spiral-wound configuration (NP030 from Microdyn Nadir and Desal DK from GE Water & Process Technologies) were used in a sequential design in order to produce a separated fraction of phenolic and sugar compounds from an aqueous artichoke extract. For both membranes, the effect of transmembrane pressure (TMP) on the permeation flux was evaluated. In optimized conditions of TMP, the NP030 membrane exhibited high rejections of apigenin, cynarin and chlorogenic acid (higher than 85%); on the other hand, very low rejections of fructose, glucose and sucrose (lower than 4%) were measured. Starting from an extract with a total antioxidant activity (TAA) of 5.28 mM trolox a retentate fraction with a TAA of 47.75 mM trolox was obtained. The NF permeate from the NP030 membrane was processed with the Desal DK membrane in optimized conditions of TMP producing a permeate stream free of phenolic and sugar compounds. Accordingly, as most part of phenolic compounds was removed in the first NF step, the concentration of sugar compounds in the NF retentate had much higher results than that of phenolic compounds. PMID- 25913378 TI - Xeroderma pigmentosum: low prevalence of germline XPA mutations in a Brazilian XP population. AB - Xeroderma pigmentosum (XP) is a rare autosomal recessive disorder characterized by DNA repair defects that cause photophobia, sunlight-induced cancers, and neurodegeneration. Prevalence of germline mutations in the nucleotide excision repair gene XPA vary significantly in different populations. No Brazilian patients have been reported to carry a germline mutation in this gene. In this study, the germline mutational status of XPA was determined in Brazilian patients exhibiting major clinical features of XP syndrome. The study was conducted on 27 unrelated patients from select Brazilian families. A biallelic inactivating transition mutation c.619C>T (p.Arg207Ter) was identified in only one patient with a history of neurological impairment and mild skin abnormalities. These findings suggest that XP syndrome is rarely associated with inherited disease causing XPA mutations in the Brazilian population. Additionally, this report demonstrates the effectiveness of genotype-phenotype correlation as a valuable tool to guide direct genetic screening. PMID- 25913379 TI - Economically viable components from Jerusalem artichoke (Helianthus tuberosus L.) in a biorefinery concept. AB - Biorefinery applications are receiving growing interest due to climatic and waste disposal issues and lack of petroleum resources. Jerusalem artichoke (Helianthus tuberosus L.) is suitable for biorefinery applications due to high biomass production and limited cultivation requirements. This paper focuses on the potential of Jerusalem artichoke as a biorefinery crop and the most viable products in such a case. The carbohydrates in the tubers were found to have potential for production of platform chemicals, e.g., succinic acid. However, economic analysis showed that production of platform chemicals as a single product was too expensive to be competitive with petrochemically produced sugars. Therefore, production of several products from the same crop is a must. Additional products are protein based ones from tubers and leaves and biogas from residues, although both are of low value and amount. High bioactive activity was found in the young leaves of the crop, and the sesquiterpene lactones are of specific interest, as other compounds from this group have shown inhibitory effects on several human diseases. Thus, future focus should be on understanding the usefulness of small molecules, to develop methods for their extraction and purification and to further develop sustainable and viable methods for the production of platform chemicals. PMID- 25913380 TI - Crystal structure, chemical bonding and magnetism studies for three quinary polar intermetallic compounds in the (Eu(1-x)Ca(x))9In8(Ge(1-y)Sn(y))8 (x = 0.66, y = 0.03) and the (Eu(1-x)Ca(x))3In(Ge(3-y)Sn(1+y)) (x = 0.66, 0.68; y = 0.13, 0.27) phases. AB - Three quinary polar intermetallic compounds in the (Eu(1-x)Ca(x))9In8(Ge(1 y)Sn(y))8 (x = 0.66, y = 0.03) and the (Eu(1-x)Ca(x))3In(Ge(3-y)Sn(1+y)) (x = 0.66, 0.68; y = 0.13, 0.27) phases have been synthesized using the molten In metal flux method, and the crystal structures are characterized by powder and single-crystal X-ray diffractions. Two orthorhombic structural types can be viewed as an assembly of polyanionic frameworks consisting of the In(Ge/Sn)4 tetrahedral chains, the bridging Ge2 dimers, either the annulene-like "12 membered rings" for the (Eu(1-x)Ca(x))9In8(Ge(1-y)Sn(y))8 series or the cis-trans Ge/Sn-chains for the (Eu(1-x)Ca(x))3In(Ge(3-y)Sn(1+y)) series, and several Eu/Ca mixed cations. The most noticeable difference between two structural types is the amount and the location of the Sn-substitution for Ge: only a partial substitution (11%) occurs at the In(Ge/Sn)4 tetrahedron in the (Eu(1 x)Ca(x))9In8(Ge(1-y)Sn(y))8 series, whereas both a complete and a partial substitution (up to 27%) are observed, respectively, at the cis-trans Ge/Sn-chain and at the In(Ge/Sn)4 tetrahedron in the (Eu(1-x)Ca(x))3In(Ge(3-y)Sn(1+y)) series. A series of tight-binding linear muffin-tin orbital calculations is conducted to understand overall electronic structures and chemical bonding among components. Magnetic susceptibility measurement indicates a ferromagnetic ordering of Eu atoms below 5 K for Eu1.02(1)Ca1.98InGe2.87(1)Sn1.13. PMID- 25913381 TI - Foster care assessment: A study of the placement decision process in Flanders. AB - Family foster care placement decision-making has a weak scientific underpinning. Mostly a 'variable-oriented approach' is taken, which requires a lot of information that is not always available. The identification of clusters of foster children with similar characteristics may be a more viable decision strategy. In this study we investigated if foster children could indeed be clustered, which problems were identified at the time of placement, and the influence of placement history. It proved possible to group foster children into two clusters: (1) young children with familial problems and few behavioral problems, and (2) older children with prominent child problems and behavioral problems. For foster children with and without placement history, problems associated with placement proved identical. Considering that a foster care placement did not result in fundamental change in the problems present at time of placement, the importance is stressed of approaching foster care assessment as part of a decision making process which looks back as well as forward. Placement decisions should be based on an appraisal of the appropriateness of foster placement as a solution for the child. In conjunction with this appraisal a decision is required on how parents can be supported toward reunification. Or--if this is not an option--whether long term foster care is the best option for the child and if so, what conditions need to be met. PMID- 25913382 TI - Development of an instrument to understand the child protective services decision making process, with a focus on placement decisions. AB - When children come to the attention of the child welfare system, they become involved in a decision-making process in which decisions are made that have a significant effect on their future and well-being. The decision to remove children from their families is particularly complex; yet surprisingly little is understood about this decision-making process. This paper presents the results of a study to develop an instrument to explore, at the caseworker level, the context of the removal decision, with the objective of understanding the influence of the individual and organizational factors on this decision, drawing from the Decision Making Ecology as the underlying rationale for obtaining the measures. The instrument was based on the development of decision-making scales used in prior decision-making studies and administered to child protection caseworkers in several states. Analyses included reliability analyses, principal components analyses, and inter-correlations among the resulting scales. For one scale regarding removal decisions, a principal components analysis resulted in the extraction of two components, jointly identified as caseworkers' decision-making orientation, described as (1) an internal reference to decision-making and (2) an external reference to decision-making. Reliability analyses demonstrated acceptable to high internal consistency for 9 of the 11 scales. Full details of the reliability analyses, principal components analyses, and inter-correlations among the seven scales are discussed, along with implications for practice and the utility of this instrument to support the understanding of decision-making in child welfare. PMID- 25913383 TI - Comparison of two in situ corneal donation technique: morgue trephination or scleracorneal removal technique. AB - PURPOSE: To compare the two different 'in situ' methods of corneal trephination technique under morgue condition (morgue trephination technique, MTT) and classic scleracorneal removal technique (SRT). METHODS: A total of 1179 cases were evaluated for cornea donation at Gazi University Faculty of Medicine mortuary between the years 2008 and 2013 and were included to the study. Suitable donor corneas were retrieved with in situ trephination technique under morgue condition (group 1, MTT) or with in situ classic SRT (group 2, SRT). The two different 'in situ' methods were compared in terms of donor corneal biological quality (endothelial cell count, ECC) and functional outcome (presence of infection and primary graft failure). RESULTS: One hundred and fifty-two of 1179 cases were suitable for corneal donation. Two hundred and twenty-nine corneas of 152 cases were transplanted, 108 corneas were obtained with MTT and 121 corneas were obtained with SRT. Pretransplant and post-transplant ECCs were 2402.5 +/- 115.6 and 2108.3 +/- 108.23 (p = 0.065) in MTT, respectively, and 2512.7 +/- 130.4 and 2235.4 +/- 201.8 (p = 0.059) in SRT, respectively. The incidence of primary graft failure and infection was not statistically significantly different between two method [2.7% and 1.6% (p = 0.223), 0.9% and 0.8% (p = 0.115)]. CONCLUSION: The two different 'in situ' methods, MTT and SRT, were similar in terms of donor ECC, presence of infection and primary graft failure. Cornea excision performed through the technique described herein may increase the corneal donation rates as result of reduced disfigurement to donor body and offer important contributions during surgery with good anatomic adaptation of tissues. PMID- 25913384 TI - Pediatric Emergency Update: Lethality of Liquid Nicotine in E-Cigarettes. PMID- 25913385 TI - Handle With Care: Preventing Abusive Head Trauma. PMID- 25913386 TI - The relationship between the growth rate and the lifetime in carbon nanotube synthesis. AB - We report an inverse relationship between the carbon nanotube (CNT) growth rate and the catalyst lifetime by investigating the dependence of growth kinetics for ~330 CNT forests on the carbon feedstock, carbon concentration, and growth temperature. We found that the increased growth temperature led to increased CNT growth rate and shortened catalyst lifetime for all carbon feedstocks, following an inverse relationship of a fairly constant maximum height. For the increased carbon concentration, the carbon feedstocks fell into two groups where ethylene/butane showed an increased/decreased growth rate and a decreased/increased lifetime indicating different rate-limiting growth processes. In addition, this inverse relationship held true for different types of CNTs synthesized by various chemical vapor deposition techniques and continuously spanned a 1000-times range in both the growth rate and catalyst lifetime, indicating the generality and fundamental nature of this behavior originating from the growth mechanism of CNTs itself. These results suggest that it would be fundamentally difficult to achieve a fast growth with a long lifetime. PMID- 25913387 TI - Cancer Risk in Relatives of Testicular Cancer Patients by Histology Type and Age at Diagnosis: A Joint Study from Five Nordic Countries. AB - BACKGROUND: None of the population-based epidemiologic studies to date has had a large enough sample size to show the familial risk of testicular cancer (TC) by age at diagnosis for patients and their relatives or for rare histologic subtypes. OBJECTIVE: To estimate absolute and relative risks of TC in relatives of TC patients by age at diagnosis in patients and their relatives and histological subtypes. DESIGN, SETTING, AND PARTICIPANTS: In a joint population based cohort study, 97 402 first-degree relatives of 21 254 TC patients who were diagnosed between 1955 and 2010 in five European countries were followed for cancer incidence. OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS: Standardized incidence ratios (SIRs) were estimated using histology-, age-, period-, and country-specific incidence rates as references. Lifetime cumulative risks were also calculated. RESULTS AND LIMITATIONS: The lifetime cumulative risk of TC in brothers of a patient with TC was 2.3%, which represents a fourfold increase in risk (SIR 4.1, 95% confidence interval [CI] 3.6-4.6) compared to the general population. TC in a father increased the risk by up to twofold in his son (95% CI 1.7-2.4; lifetime risk 1.2%) and vice versa. When there were two or more TC patients diagnosed in a family, the lifetime TC risk for relatives was 10-11%. Depending on age at diagnosis, twins had a 9-74% lifetime risk of TC. Family history of most of the histologic subtypes of TC increased the risk of concordant and most discordant subtypes. There was a tendency toward concordant age at diagnosis of TC among relatives. CONCLUSIONS: This study provides clinically relevant age-specific cancer risk estimates for relatives of TC patients. Familial TC patients tended to develop TC at an age close to the age at diagnosis of TC among their relatives, which is a novel finding of this study. PATIENT SUMMARY: This joint European population study showed that sons and brothers of testicular cancer patients are at higher risk of developing this cancer at an age close to the age at diagnosis of their relatives. PMID- 25913388 TI - Translating Testicular Cancer Epidemiology into Clinical Practice. PMID- 25913389 TI - Adverse Pathologic Features at Radical Prostatectomy: Effect of Preoperative Risk on Oncologic Outcomes. AB - BACKGROUND: Up to 30% of patients with low-risk prostate cancer (PCa) are found to have features of aggressive disease at radical prostatectomy (RP). Several predictive nomograms and novel genomic markers have been developed to estimate the risk of adverse pathology in men eligible for active surveillance (AS). However, oncologic risk associated with these findings remains unknown. OBJECTIVE: To determine if the presence of adverse pathologic features at RP in patients eligible for AS is prognostic of poor oncologic outcome independent of pretreatment risk status. DESIGN, SETTING, AND PARTICIPANTS: A total of 2660 patients underwent immediate RP at our institution between 1998 and 2008. Patients were stratified as low, intermediate, or high risk according to the D'Amico clinical risk criteria. OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS: The rates of adverse pathology were reported, and the 5-yr risk of biochemical recurrence (BCR) was calculated in the presence of aggressive disease. RESULTS AND LIMITATIONS: The 5-yr risk of BCR in patients with extracapsular extension (n=937) was 43% (95% confidence interval [CI], 40-46) overall but only 15% (95% CI, 11-22) for those who met the criteria for low risk (n=181). For the 473 patients with pathologic Gleason score 4+3, the risk of recurrence at 5 yr was 41% (95% CI, 37-46) overall, 13% (95% CI, 5-27) for low-risk men (n=41), 41% (95% CI, 35-47) for intermediate-risk men (n=287), and 51% (95% CI, 43-60) for high risk men (n=145). Limitations include use of BCR as the study end point and surrogate for oncologic outcome in men who received curative treatment. CONCLUSIONS: The presence of pathologically unfavorable disease in patients eligible for AS is not informative as to the safety of this treatment modality. We question the relevance of adverse pathology as the end point for predictive tools designed to guide treatment decisions in low-risk PCa. PATIENT SUMMARY: The risk of biochemical recurrence associated with adverse pathologic findings at prostatectomy is reduced by approximately 50% in men with clinically low-risk prostate cancer. PMID- 25913390 TI - Genomic Predictors of Outcome in Prostate Cancer. AB - CONTEXT: Given the highly variable behavior and clinical course of prostate cancer (PCa) and the multiple available treatment options, a personalized approach to oncologic risk stratification is important. Novel genetic approaches offer additional information to improve clinical decision making. OBJECTIVE: To review the use of genomic biomarkers in the prognostication of PCa outcome and prediction of therapeutic response. EVIDENCE ACQUISITION: Systematic literature review focused on human clinical studies reporting outcome measures with external validation. The literature search included all Medline, Embase, and Scopus articles from inception through July 2014. EVIDENCE SYNTHESIS: An improved understanding of the genetic basis of prostate carcinogenesis has produced an increasing number of potential prognostic and predictive tools, such as transmembrane protease, serine2:v-ets avian erythroblastosis virus E26 oncogene homolog (TMPRSS2:ERG) gene fusion status, loss of the phosphatase and tensin homolog (PTEN) gene, and gene expression signatures utilizing messenger RNA from tumor tissue. Several commercially available gene panels with external validation are now available, although most have yet to be widely used. The most studied commercially available gene panels, Prolaris, Oncotype DX Genomic Prostate Score, and Decipher, may be used to estimate disease outcome in addition to clinical parameters or clinical nomograms. ConfirmMDx is an epigenetic test used to predict the results of repeat prostate biopsy after an initial negative biopsy. Additional future strategies include using genetic information from circulating tumor cells in the peripheral blood to guide treatment decisions at the initial diagnosis and at subsequent decision points. CONCLUSIONS: Major advances have been made in our understanding of PCa biology in recent years. Our field is currently exploring the early stages of a personalized approach to augment traditional clinical decision making using commercially available genomic tools. A more comprehensive appreciation of value, limitations, and cost is important. PATIENT SUMMARY: We summarized current advances in genomic testing in prostate cancer with a special focus on the estimation of disease outcome. Several commercial tests are currently available, but further understanding is needed to appreciate the potential benefits and limitations of these novel tests. PMID- 25913391 TI - Flexible cystourethroscopy in the follow-up of posturethroplasty patients and characterisation of recurrences. AB - BACKGROUND: Urethral strictures can be difficult to diagnose at an early stage because the urinary flow rate does not diminish until the urethral calibre is <=3mm. In the past, posturethral surgery follow-up has relied upon flow rates and contrast imaging. OBJECTIVE: To evaluate the role of flexible urethroscopy in the follow-up of patients undergoing urethroplasty. DESIGN, SETTING, AND PARTICIPANTS: Prospective flexible urethroscopy follow-up of 144 male patients who underwent urethroplasty by a single surgeon over a 10-yr period at a tertiary referral centre. INTERVENTION: Flexible urethroscopy at 3, 6, and 12 mo postoperatively, and annually thereafter. OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS: Type of recurrence, based on urethroscopy findings, and further interventions were measured. Actuarial analysis was performed using Kaplan-Meier curves and a log-rank test. RESULTS AND LIMITATIONS: All 144 patients underwent flexible urethroscopy follow-up over a median postoperative follow-up of 22 mo (range: 1-96 mo). No further intervention was required for 117 patients (81.25%); 27 (18.75%) developed recurrences that required further treatment. Recurrences included diaphragms (13 patients) or significant restenosis (14 patients). Diaphragms were treated by urethrotomy, gentle dilatation, or a short course of intermittent self-dilatation. Restenosis required repeated simple procedures or surgical revision. Most recurrences (26 of 27, 96%) were detected within the first year. Urinary peak flow-rate data were available for 11 of 27 of these recurrences; 7 patients had flow rates >15ml/s. Anastomotic procedures had greater success than augmentation urethroplasty (p=0.0136); there was no significant difference in outcomes between redo and non-redo surgery (p=0.2093) CONCLUSIONS: Endoscopic follow-up of patients after urethroplasty enables earlier identification and treatment of recurrences compared to the use of urinary flow rates alone. It also enables the identification of two different morphologic recurrence patterns that require different types of intervention. PATIENT SUMMARY: Endoscopy detects most stricture recurrences within 1 yr after urethroplasty and is more sensitive than using urinary flow rates alone. PMID- 25913392 TI - The Importance of Accurate Life Expectancy Prediction in Men with Prostate Cancer. PMID- 25913393 TI - Revisiting weight reduction and management in the diabetic patient: Novel therapies provide new strategies. AB - Weight gain has been so synonymous with diabetes care that overweight/obesity is considered an intractable aspect of diabetes and its management. A healthy body mass index (BMI) is paramount, however, in preserving the cardiometabolic profile, slowing the course of the disease and extending the life expectancy of patients. It is also key to fostering a healthy and productive society at large. Two trends in care press us to challenge our assumptions about weight control in this population by reconsidering traditional approaches to the management of diabetes. First, new anti-diabetes drug classes have emerged that are more "weight-friendly" than previously available treatments and "gentler" on the faltering beta cell. Second, novel anti-obesity agents are proving efficacious in patients with diabetes. This paper presents the composite of newer and older anti obesity and anti-diabetic drugs. It makes recommendations for anti-diabetic regimens and processes of care that engender weight loss, or neutralize or minimize weight gain, while getting many patients to their glycated hemoglobin (HbA1c) goal. Anti-obesity agents that can be safely and effectively incorporated into these regimens for the patient needing supplemental support are reviewed in detail. PMID- 25913394 TI - Rational Design of QCM-D Virtual Sensor Arrays Based on Film Thickness, Viscoelasticity, and Harmonics for Vapor Discrimination. AB - Herein, we demonstrate an alternative strategy for creating QCM-based sensor arrays by use of a single sensor to provide multiple responses per analyte. The sensor, which simulates a virtual sensor array (VSA), was developed by depositing a thin film of ionic liquid, either 1-octyl-3-methylimidazolium bromide ([OMIm][Br]) or 1-octyl-3-methylimidazolium thiocyanate ([OMIm][SCN]), onto the surface of a QCM-D transducer. The sensor was exposed to 18 different organic vapors (alcohols, hydrocarbons, chlorohydrocarbons, nitriles) belonging to the same or different homologous series. The resulting frequency shifts (Deltaf) were measured at multiple harmonics and evaluated using principal component analysis (PCA) and discriminant analysis (DA) which revealed that analytes can be classified with extremely high accuracy. In almost all cases, the accuracy for identification of a member of the same class, that is, intraclass discrimination, was 100% as determined by use of quadratic discriminant analysis (QDA). Impressively, some VSAs allowed classification of all 18 analytes tested with nearly 100% accuracy. Such results underscore the importance of utilizing lesser exploited properties that influence signal transduction. Overall, these results demonstrate excellent potential of the virtual sensor array strategy for detection and discrimination of vapor phase analytes utilizing the QCM. To the best of our knowledge, this is the first report on QCM VSAs, as well as an experimental sensor array, that is based primarily on viscoelasticity, film thickness, and harmonics. PMID- 25913395 TI - Urinary cysteinyl progestogens: Occurrence and origin. AB - The presence of two cysteinyl progestogens, 16-cysteinyl-progesterone (16-Cys Prog) and 16-cysteinyl-pregnenolone (16-Cys-Preg), in human urine is described for the first time. Their occurrence was unequivocally confirmed by comparison with synthesized material by using mass spectrometric detectors. Several experiments were performed in order to clarify their origin. The adrenal origin of both 16-Cys-Prog and 16-Cys-Preg can be inferred from the increase in their concentrations after ACTH stimulatory test, together with their circadian variation similar to the one observed for cortisol. Moreover, the notable increase in excretions of 16-Cys-Prog during the luteal phase of the menstrual cycle points towards an ovarian production for this progestogen. However, the analysis of samples during the course of two pregnancies revealed that, in spite of the large amounts of progesterone produced during gestation, the human placenta lacks the capacity to make 16-Cys-Prog. The adrenal and ovarian origin has been further indicated by the absence of both metabolites in samples collected from a subject with bilateral adrenalectomy and hypogonadotrophyic hypogonadism. Regarding liver action, in vitro studies with hepatocytes and progesterone indicate that, although the liver is able to metabolize progesterone to 6-dehydroprogesterone, it has not the enzymatic machinery for the generation of 16-dehydroprogesterone. Taken together, these results open the possibility for a noninvasive test for the simultaneous evaluation of progesterone biosynthesis in different organs. PMID- 25913396 TI - Highly stable CuInS2@ZnS:Al core@shell quantum dots: the role of aluminium self passivation. AB - A simple approach was introduced to enhance the photostability of CuInS2@ZnS core@shell quantum dots (QDs) by doping aluminium into the ZnS shell. Aluminium in the as-prepared QDs was oxidized to Al2O3, which formed a passivation oxide layer that effectively prevents photo-degradation of QDs during long-term light irradiation. PMID- 25913397 TI - Affective modulation of the startle response among children at high and low risk for anxiety disorders. AB - BACKGROUND: Identifying early markers of risk for anxiety disorders in children may aid in understanding underlying mechanisms and informing prevention efforts. Affective modulation of the startle response indexes sensitivity to pleasant and unpleasant environmental contexts and has been shown to relate to anxiety, yet the extent to which abnormalities in affect-modulated startle reflect vulnerability for anxiety disorders in children has yet to be examined. The current study assessed the effects of parental psychopathology on affective modulation of startle in offspring. METHOD: Nine-year-old children (n = 144) with no history of anxiety or depressive disorders completed a passive picture viewing task in which eye-blink startle responses were measured during the presentation of pleasant, neutral, and unpleasant images. RESULTS: Maternal anxiety was associated with distinct patterns of affective modulation of startle in offspring, such that children with maternal histories of anxiety showed potentiation of the startle response while viewing unpleasant images, but not attenuation during pleasant images, whereas children with no maternal history of anxiety exhibited attenuation of the startle response during pleasant images, but did not exhibit unpleasant potentiation - even when controlling for child symptoms of anxiety and depression. No effects of maternal depression or paternal psychopathology were observed. CONCLUSIONS: These findings suggest that both enhanced startle responses in unpleasant conditions and failure to inhibit startle responses in pleasant conditions may reflect early emerging vulnerabilities that contribute to the later development of anxiety disorders. PMID- 25913398 TI - Relationship between lean body mass and serum renal biomarkers in healthy dogs. AB - BACKGROUND: Symmetric dimethylarginine (SDMA) is an accurate and precise biomarker for estimating glomerular filtration rate (GFR) in humans and cats. Serum creatinine (sCr) also correlates with GFR, but has limitations as a biomarker of renal function because nonrenal factors can influence its concentration. HYPOTHESIS: Differences in lean body mass (LBM) influence sCr, but not serum SDMA concentrations. ANIMALS: Forty-one healthy Beagles, mean age 9.9 years (range: 3.1-14.8 years), were studied over a 6 month period. METHODS: Serum biomarkers of renal function were measured prospectively at baseline, and 1, 3, and 6 months. SDMA concentrations were measured by liquid chromatography-mass spectroscopy and sCr concentrations by enzymatic colorimetry. Body composition was determined by dual energy x-ray absorptiometry. RESULTS: LBM (P < .001) and age (P = .006) were significant explanatory variables for sCr concentration (R(2) = 0.38), but not SDMA concentration. Time on food was the only significant explanatory variable for SDMA concentration (R(2) = 0.49). SDMA concentrations decreased across time (P < .001). LBM was affected by sex (males > females; P = .02). Mature adult dogs (<8 years) had greater LBM compared with geriatric dogs (>=8 years; P < .001). CONCLUSION AND CLINICAL IMPORTANCE: sCr concentrations, but not SDMA concentrations, are influenced by LBM, which limits sCr utility as a biomarker for monitoring renal function in dogs with decreased LBM. Reductions in LBM can lower sCr concentration and overestimate GFR. SDMA concentrations, but not sCr concentrations were influenced by time on food. SDMA could have clinical advantages over sCr in monitoring response to nutritional interventions. PMID- 25913399 TI - Gene loss from a plant sex chromosome system. AB - Sex chromosomes have evolved independently in numerous animal and plant lineages. After recombination becomes suppressed between two homologous sex chromosomes, genes on the non-recombining Y chromosomes (and W chromosomes in ZW systems) undergo genetic degeneration, losing functions retained by their X- or Z-linked homologs, changing their expression, and becoming lost [1, 2]. Adaptive changes may also occur, both on the non-recombining Y chromosome, to shut down expression of maladapted genes [3], and on the X chromosome (or the Z in ZW systems), which may evolve dosage compensation to increase low expression or compensate for poor protein function in the heterogametic sex [2, 4, 5]. Although empirical approaches to studying genetic degeneration have been developed for model species [3, 6], the onset and dynamics of these changes are still poorly understood, particularly in de novo evolving sex chromosomes. Sex chromosomes of some plants evolved much more recently than those of mammals, birds, and Drosophila [7-9], making them suitable for studying the early stages of genetic degeneration in de novo evolving sex chromosomes. In plants, haploid selection should oppose gene loss from Y chromosomes, but recent work on sex chromosomes of two plant species has estimated that Y-linked transcripts are lacking for 10%-30% of X-linked genes [10-12]. Here, we provide evidence that, in Silene latifolia, this largely involved losses of Y-linked genes, and not suppressed expression of Y-linked alleles, or gene additions to the X chromosome. Our results also suggest that chromosome-wide dosage compensation does not occur in this plant. PMID- 25913400 TI - Transcriptional coordination of synaptogenesis and neurotransmitter signaling. AB - During nervous system development, postmitotic neurons face the challenge of generating and structurally organizing specific synapses with appropriate synaptic partners. An important unexplored question is whether the process of synaptogenesis is coordinated with the adoption of specific signaling properties of a neuron. Such signaling properties are defined by the neurotransmitter system that a neuron uses to communicate with postsynaptic partners, the neurotransmitter receptor type used to receive input from presynaptic neurons, and, potentially, other sensory receptors that activate a neuron. Elucidating the mechanisms that coordinate synaptogenesis, neuronal activation, and neurotransmitter signaling in a postmitotic neuron represents one key approach to understanding how neurons develop as functional units. Using the SAB class of Caenorhabditis elegans motor neurons as a model system, we show here that the phylogenetically conserved COE-type transcription factor UNC-3 is required for synaptogenesis. UNC-3 directly controls the expression of the ADAMTS-like protein MADD-4/Punctin, a presynaptically secreted synapse-organizing molecule that clusters postsynaptic receptors. UNC-3 also controls the assembly of presynaptic specializations and ensures the coordinated expression of enzymes and transporters that define the cholinergic neurotransmitter identity of the SAB neurons. Furthermore, synaptic output properties of the SAB neurons are coordinated with neuronal activation and synaptic input, as evidenced by UNC-3 also regulating the expression of ionotropic neurotransmitter receptors and putative stretch receptors. Our study shows how synaptogenesis and distinct, function-defining signaling features of a postmitotic neuron are hardwired together through coordinated transcriptional control. PMID- 25913402 TI - Intracranial Mapping of a Cortical Tinnitus System using Residual Inhibition. AB - Tinnitus can occur when damage to the peripheral auditory system leads to spontaneous brain activity that is interpreted as sound [1, 2]. Many abnormalities of brain activity are associated with tinnitus, but it is unclear how these relate to the phantom sound itself, as opposed to predisposing factors or secondary consequences [3]. Demonstrating "core" tinnitus correlates (processes that are both necessary and sufficient for tinnitus perception) requires high-precision recordings of neural activity combined with a behavioral paradigm in which the perception of tinnitus is manipulated and accurately reported by the subject. This has been previously impossible in animal and human research. Here we present extensive intracranial recordings from an awake, behaving tinnitus patient during short-term modifications in perceived tinnitus loudness after acoustic stimulation (residual inhibition) [4], permitting robust characterization of core tinnitus processes. As anticipated, we observed tinnitus linked low-frequency (delta) oscillations [5-9], thought to be triggered by low frequency bursting in the thalamus [10, 11]. Contrary to expectation, these delta changes extended far beyond circumscribed auditory cortical regions to encompass almost all of auditory cortex, plus large parts of temporal, parietal, sensorimotor, and limbic cortex. In discrete auditory, parahippocampal, and inferior parietal "hub" regions [12], these delta oscillations interacted with middle-frequency (alpha) and high-frequency (beta and gamma) activity, resulting in a coherent system of tightly coupled oscillations associated with high-level functions including memory and perception. PMID- 25913401 TI - Molecular signatures of major depression. AB - Adversity, particularly in early life, can cause illness. Clues to the responsible mechanisms may lie with the discovery of molecular signatures of stress, some of which include alterations to an individual's somatic genome. Here, using genome sequences from 11,670 women, we observed a highly significant association between a stress-related disease, major depression, and the amount of mtDNA (p = 9.00 * 10(-42), odds ratio 1.33 [95% confidence interval [CI] = 1.29 1.37]) and telomere length (p = 2.84 * 10(-14), odds ratio 0.85 [95% CI = 0.81 0.89]). While both telomere length and mtDNA amount were associated with adverse life events, conditional regression analyses showed the molecular changes were contingent on the depressed state. We tested this hypothesis with experiments in mice, demonstrating that stress causes both molecular changes, which are partly reversible and can be elicited by the administration of corticosterone. Together, these results demonstrate that changes in the amount of mtDNA and telomere length are consequences of stress and entering a depressed state. These findings identify increased amounts of mtDNA as a molecular marker of MD and have important implications for understanding how stress causes the disease. PMID- 25913404 TI - Grid cells form a global representation of connected environments. AB - The firing patterns of grid cells in medial entorhinal cortex (mEC) and associated brain areas form triangular arrays that tessellate the environment [1, 2] and maintain constant spatial offsets to each other between environments [3, 4]. These cells are thought to provide an efficient metric for navigation in large-scale space [5-8]. However, an accurate and universal metric requires grid cell firing patterns to uniformly cover the space to be navigated, in contrast to recent demonstrations that environmental features such as boundaries can distort [9-11] and fragment [12] grid patterns. To establish whether grid firing is determined by local environmental cues, or provides a coherent global representation, we recorded mEC grid cells in rats foraging in an environment containing two perceptually identical compartments connected via a corridor. During initial exposures to the multicompartment environment, grid firing patterns were dominated by local environmental cues, replicating between the two compartments. However, with prolonged experience, grid cell firing patterns formed a single, continuous representation that spanned both compartments. Thus, we provide the first evidence that in a complex environment, grid cell firing can form the coherent global pattern necessary for them to act as a metric capable of supporting large-scale spatial navigation. PMID- 25913403 TI - Sleep restores behavioral plasticity to Drosophila mutants. AB - Given the role that sleep plays in modulating plasticity, we hypothesized that increasing sleep would restore memory to canonical memory mutants without specifically rescuing the causal molecular lesion. Sleep was increased using three independent strategies: activating the dorsal fan-shaped body, increasing the expression of Fatty acid binding protein (dFabp), or by administering the GABA-A agonist 4,5,6,7-tetrahydroisoxazolo-[5,4-c]pyridine-3-ol (THIP). Short term memory (STM) or long-term memory (LTM) was evaluated in rutabaga (rut) and dunce (dnc) mutants using aversive phototaxic suppression and courtship conditioning. Each of the three independent strategies increased sleep and restored memory to rut and dnc mutants. Importantly, inducing sleep also reverses memory defects in a Drosophila model of Alzheimer's disease. Together, these data demonstrate that sleep plays a more fundamental role in modulating behavioral plasticity than previously appreciated and suggest that increasing sleep may benefit patients with certain neurological disorders. PMID- 25913405 TI - A scalable population code for time in the striatum. AB - To guide behavior and learn from its consequences, the brain must represent time over many scales. Yet, the neural signals used to encode time in the seconds-to minute range are not known. The striatum is a major input area of the basal ganglia associated with learning and motor function. Previous studies have also shown that the striatum is necessary for normal timing behavior. To address how striatal signals might be involved in timing, we recorded from striatal neurons in rats performing an interval timing task. We found that neurons fired at delays spanning tens of seconds and that this pattern of responding reflected the interaction between time and the animals' ongoing sensorimotor state. Surprisingly, cells rescaled responses in time when intervals changed, indicating that striatal populations encoded relative time. Moreover, time estimates decoded from activity predicted timing behavior as animals adjusted to new intervals, and disrupting striatal function led to a decrease in timing performance. These results suggest that striatal activity forms a scalable population code for time, providing timing signals that animals use to guide their actions. PMID- 25913406 TI - Architecture dependence of actin filament network disassembly. AB - Turnover of actin networks in cells requires the fast disassembly of aging actin structures. While ADF/cofilin and Aip1 have been identified as central players, how their activities are modulated by the architecture of the networks remains unknown. Using our ability to reconstitute a diverse array of cellular actin organizations, we found that ADF/cofilin binding and ADF/cofilin-mediated disassembly both depend on actin geometrical organization. ADF/cofilin decorates strongly and stabilizes actin cables, whereas its weaker interaction to Arp2/3 complex networks is correlated with their dismantling and their reorganization into stable architectures. Cooperation of ADF/cofilin with Aip1 is necessary to trigger the full disassembly of all actin filament networks. Additional experiments performed at the single-molecule level indicate that this cooperation is optimal above a threshold of 23 molecules of ADF/cofilin bound as clusters along an actin filament. Our results indicate that although ADF/cofilin is able to dismantle selectively branched networks through severing and debranching, stochastic disassembly of actin filaments by ADF/cofilin and Aip1 represents an efficient alternative pathway for the full disassembly of all actin networks. Our data support a model in which the binding of ADF/cofilin is required to trigger a structural change of the actin filaments, as a prerequisite for their disassembly by Aip1. PMID- 25913407 TI - Complete genomes reveal signatures of demographic and genetic declines in the woolly mammoth. AB - The processes leading up to species extinctions are typically characterized by prolonged declines in population size and geographic distribution, followed by a phase in which populations are very small and may be subject to intrinsic threats, including loss of genetic diversity and inbreeding. However, whether such genetic factors have had an impact on species prior to their extinction is unclear; examining this would require a detailed reconstruction of a species' demographic history as well as changes in genome-wide diversity leading up to its extinction. Here, we present high-quality complete genome sequences from two woolly mammoths (Mammuthus primigenius). The first mammoth was sequenced at 17.1 fold coverage and dates to ~4,300 years before present, representing one of the last surviving individuals on Wrangel Island. The second mammoth, sequenced at 11.2-fold coverage, was obtained from an ~44,800-year-old specimen from the Late Pleistocene population in northeastern Siberia. The demographic trajectories inferred from the two genomes are qualitatively similar and reveal a population bottleneck during the Middle or Early Pleistocene, and a more recent severe decline in the ancestors of the Wrangel mammoth at the end of the last glaciation. A comparison of the two genomes shows that the Wrangel mammoth has a 20% reduction in heterozygosity as well as a 28-fold increase in the fraction of the genome that comprises runs of homozygosity. We conclude that the population on Wrangel Island, which was the last surviving woolly mammoth population, was subject to reduced genetic diversity shortly before it became extinct. PMID- 25913408 TI - Altered communicative decisions following ventromedial prefrontal lesions. AB - Damage to the human ventromedial prefrontal cortex (vmPFC) leads to profound changes in everyday social interactions [1, 2]. Yet, in the lab, vmPFC patients show surprising proficiency in reasoning about other agents [3-8]. These conflicting observations suggest that what vmPFC patients lack in everyday social interactions might be the ability to guide their decisions with knowledge about a social partner [9-13], despite preserved access to that knowledge [2, 14]. Quantification of socially relevant decisions during live interaction with different partners offers the possibility of testing this hypothesis. Eight patients with vmPFC damage, eight patients with brain damage elsewhere, and 15 healthy participants were asked to communicate non-verbally with two different addressees, an adult or a child, in an experimentally controlled interactive setting [15, 16]. In reality, a confederate blindly performed the role of both adult and child addressee, with matched performance and response times, such that the two addressees differed only in terms of the communicator's beliefs. Patients with vmPFC damage were able-and motivated-to generate communicatively effective behaviors. However, unlike patient and healthy controls, vmPFC patients failed to adjust their communicative decisions to the presumed abilities of their addressee. These findings indicate that the human vmPFC is necessarily involved in social interactions, insofar as those interactions need to be tailored toward knowledge about a social partner. In this perspective, the known contribution of this region to disparate domains like value-based decision-making [17-19], schema based memory-processing [20-22], and person-specific mentalizing [11-13] might be instances of decisions based on contingently updated conceptual knowledge. PMID- 25913409 TI - Differential impact of behavioral relevance on quantity coding in primate frontal and parietal neurons. AB - Prefrontal cortex (PFC) and posterior parietal cortex are key brain areas for magnitude representations. Whether active discrimination of numerosity changes neuronal representations is still not known. We simultaneously recorded from the same recording sites in the PFC and ventral intraparietal area (VIP) before and after monkeys learned to actively discriminate the number of items in a set. Only PFC neurons, and not VIP neurons, exhibited heightened representation of number after numerosity training. Increased responsiveness of PFC was evidenced by enhanced differentiation of numerosity by the population of neurons, as well as increased numerosity encoding by individual selective neurons. None of these effects were observed in the VIP, in which neurons responded invariably to numerosity irrespective of behavioral relevance. This suggests elevated PFC participation during numerical task demands and executive control, whereas VIP encodes quantity as a perceptual category regardless of behavioral relevance. PMID- 25913410 TI - Evolution from the TUG to PAP flap for breast reconstruction: Comparison and refinements of technique. AB - BACKGROUND: Limitations of the transverse upper gracilis (TUG) flap for autologous breast reconstruction include: short pedicle, modest volume, muscle sacrifice and a problematic donor site. The Profunda Artery Perforator (PAP) flap utilises large perforators posterior to the gracilis muscle. We describe our preliminary experience of its use and compare it to our large series of TUG flaps. METHOD: Our technique has evolved from frog-leg to lithotomy position, and from an anterio-posterior to cranio-caudal raise. This allows either the descending branch of the inferior gluteal artery perforators (IGAP) or the TUG flap as alternatives should PAP perforators be unsuitable intra-operatively. A prospective database was utilised to compare TUG and PAP flaps undertaken 2010 2013. RESULTS: 54 TUG and 22 PAP flaps were performed. 4 PAP flaps were converted to IGAP flaps and 1 to TUG intra-operatively. 97% of all flaps were successful. Mean flap weight was 295 g (TUG) and 242 g (PAP). Donor site complications for both series included seroma (4 TUG, 1 PAP) sensory disturbance (2 TUG, 1 PAP) and scar revision (3 TUG, 1 PAP). CONCLUSION: Our preliminary experience of the PAP flap has not been universally favourable compared to the TUG flap. It is a more challenging flap to raise, which carries with it a learning curve, especially if raised in the supine position; we present our learning points for safer flap harvest, allowing the TUG as a bail out option. The benefits of the PAP include a longer pedicle, without the need to sacrifice muscle; the perforators should have a more defined and larger perfusion zone. The scar is better hidden, but we have not yet proven significant improvements to the donor site compared to the TUG flap. LEVEL OF EVIDENCE: III. PMID- 25913411 TI - The synthesis and characterisation of coordination and hydrogen-bonded networks based on 4-(3,5-dimethyl-1H-pyrazol-4-yl)benzoic acid. AB - The synthesis, structural and thermal characterisation of a number of coordination complexes featuring the N,O-heteroditopic ligand 4-(3,5-dimethyl-1H pyrazol-4-yl)benzoate, HL are reported. The reaction of H2L with cobalt(II) and nickel(II) nitrates at room temperature in basic DMF/H2O solution gave discrete mononuclear coordination complexes with the general formula {[M(HL)2(H2O)4].2DMF} (M = Co (1), Ni (2)), whereas the reaction with zinc(II) nitrate gave [Zn(HL)2]infinity, 3, a coordination polymer with distorted diamondoid topology and fourfold interpenetration. Coordination about the tetrahedral Zn(II) nodes in 3 are furnished by two pyrazolyl nitrogen atoms and two carboxylate oxygen atoms to give a mixed N2O2 donor set. Isotopological coordination polymers of zinc(II), {[Zn(HL)2].2CH3OH.H2O}infinity, 4, and cobalt(II), [Co(HL)2]infinity, 5, are formed when the reactions are carried out under solvothermal conditions in methanol (80 degrees C) and water (180 degrees C), respectively. The reaction of H2L with cadmium(II) nitrate at room temperature in methanol gives {[Cd(HL)2(MeOH)2].1.8MeOH}infinity6, a 2-D (4,4)-connected coordination polymer, whereas with copper(II) the formation of green crystals that transform into purple crystals is observed. The metastable green phase [Cu3(HL)4(MU2 SO4)(H2O)3]infinity, 7, crystallises with conserved binding domains of the heteroditopic ligand and contains two different metal nodes: a dicopper carboxylate paddle wheel motif, and, a dicopper unit bridged by sulfate ions and coordinated by ligand pyrazolyl nitrogen atoms. The resultant purple phase {[Cu(HL)2].4CH3OH.H2O}infinity, 8, however, has single copper ion nodes coordinated by mixed N2O2 donor sets with trans-square planar geometry and is threefold interpenetrated. The desolvation of 8 was followed by powder X-ray diffraction and single crystal X-ray diffraction which show desolvation induces the transition to a more closely packed structure while the coordination geometry about the copper ions and the network topology is retained. Powder X-ray diffraction and microanalysis were used to characterise the bulk purity of the coordination materials 1-6 and 8. The thermal characteristics of 1-2, 4-6 and 8 were studied by TG-DTA. This led to the curious observation of small exothermic events in networks 4, 6, and 8 that appear to be linked to their decomposition. In addition, the solid state structures of H2L and that of its protonated salt, H2L.HNO3, were also determined and revealed that H2L forms a 2-D hydrogen bonded polymer incorporating helical chains formed through N-HO and O-HN interactions, and that [H3L]NO3 forms a 1-D hydrogen-bonded polymer. PMID- 25913412 TI - Microcystic stromal tumour of the ovary: frequent mutations of beta-catenin (CTNNB1) in six cases. AB - AIMS: To analyse the clinicopathological, immunohistochemical and beta-catenin (CTNNB1) mutation characteristics of six cases of microcystic stromal tumour of the ovary (MCST). METHODS AND RESULTS: Six Chinese patients with MCST who ranged in age from 29 to 69 years (mean 50 years) were included in the study. Five patients were detected with a pelvic mass during routine health examinations and one patient presented initially with opsomenorrhoea. All tumours involved the left ovary, with solid-cystic cut surface in five cases and cystic cut surface in one case. Microscopically, microcysts, solid nests and hyaline degenerated fibrous stroma were variably mixed. Immunohistochemically, the tumour cells in all cases were diffusely positive for CD10, vimentin and WT-1 and negative for alpha-inhibin and calretinin. beta-catenin expression was observed in both the nucleus and the cytoplasm in five cases and only in the cytoplasm in one case. The results of CTNNB1 mutation analysis revealed four missense point mutations in four cases, which were c.97T>C, c.101G>A, c.110C>G and c.122C>T. CONCLUSIONS: MCST shows a unique morphology with characteristic immunophenotype. beta-catenin expression in the nucleus and beta-catenin mutations were identified in the majority of cases, which suggests that the Wnt/beta-catenin pathway may play a crucial role in the tumorigenesis of MCST. PMID- 25913413 TI - FOXO3 variants are beneficial for longevity in Southern Chinese living in the Red River Basin: A case-control study and meta-analysis. AB - Forkhead box class O (FOXO) transcription factors play a crucial role in longevity across species. Several polymorphisms in FOXO3 were previously reported to be associated with human longevity. However, only one Chinese replication study has been performed so far. To verify the role of FOXO3 in southern Chinese in the Red River Basin, a community-based case-control study was conducted, and seven polymorphisms were genotyped in 1336 participants, followed by a meta analysis of eight case-control studies that included 5327 longevity cases and 4608 controls. In our case-control study, we found rs2802288*A and rs2802292*G were beneficial to longevity after Bonferroni correction (pallele = 0.005, OR = 1.266; pallele = 0.026, OR = 1.207). In addition, in the longevity group, carriers with rs2802288*A and rs2802292*G presented reduced HbA1c (p = 0.001), and homozygotes of rs2802292*GG presented improved HOMA-IR (p = 0.014). The meta analysis further revealed the overall contribution of rs2802288*A and rs2802292*G to longevity. However, our stratified analysis revealed that rs2802292*G might act more strongly in Asians than Europeans, for enhancement of longevity. In conclusion, our study provides convincing evidence for a significant association between the rs2802288*A and rs2802292*G gene variants in FOXO3 and human longevity, and adds the Southern Chinese in the Red River Basin to the growing number of human replication populations. PMID- 25913414 TI - Bortezomib and Arsenic Trioxide Activity on a Myelodysplastic Cell Line (P39): A Gene Expression Study. AB - INTRODUCTION: We aimed to understand the molecular pathways affected by bortezomib and arsenic trioxide treatment on myelomonocytoid cell line P39. METHODS: Oligonucleotide microarray platforms were used for gene expression and pathway analysis. Confirmation studies were performed using quantitative real time PCR. RESULTS: Bortezomib treatment has shown upregulated DIABLO and NF kappaBIB (a NF-kappaB inhibitor) and downregulated NF-kappaB1, NF-kappaB2, and BIRC1 gene expressions. Combination treatment of the two compounds showed gene expression deregulations in concordance by the results of single bortezomib treatment. Especially, P53 was a pathway more significantly modified and a gene network centralized around the beta estradiol gene. Beta estradiol, BRCA2, and FOXA1 genes were remarkable deregulations in our findings. DISCUSSION AND CONCLUSION: Results support the suggestions about possible use of proteasome inhibitors in the treatment of high-risk myelodysplastic syndrome (MDS). NF kappaB was observed as an important modulator in leukemic transformation of MDS. PMID- 25913415 TI - DC immunotherapy in HIV-1 infection induces a major blood transcriptome shift. AB - OBJECTIVE: This study aimed to evaluate the effect of dendritic cell (DC) vaccination against HIV-1 on host gene expression profiles. DESIGN: Longitudinal PBMC samples were collected from participants of the DC-TRN trial for immunotherapy against HIV. Microarray-assisted gene expression profiling was performed to evaluate the effects of vaccination and subsequent interruption of antiretroviral therapy on host genome expression. Data from the DC-TRN trial were compared with results from other vaccination trials. METHODS: We used Affymetrix GeneChips for microarray gene expression analysis. Data were analyzed by principal component analysis and differential gene expression was assessed using linear modeling. Gene ontology enrichment and gene set analysis were used to characterize differentially expressed genes. Transcriptome analysis included comparison with PBMCs obtained from DC-vaccinated melanoma patients and of healthy individuals who received seasonal influenza vaccination. RESULTS: DC-TRN immunotherapy in HIV-infected individuals resulted in a major shift in the transcriptome. Longitudinal analysis demonstrated that changes in the transcriptome sustained also during interruption of antiretroviral therapy. After DC-vaccination, the transcriptome was enriched for cellular immunity associated genes that were also induced in healthy adults who received live attenuated influenza virus vaccination. These beneficial responses were accompanied by detrimental signals of general immune activation. CONCLUSIONS: The DC-TRN induced changes in the transcriptome were profound, lasting, and consisted of both protective signals and signatures of inflammation and immune exhaustion, with a net result of decreased viral load, without clinical benefit. Thus transcriptome analysis provides useful information, dissecting both positive and negative effects, for the evaluation of safety and efficacy of immunotherapeutic strategies. PMID- 25913416 TI - Genome-wide analysis of alternative transcripts in human breast cancer. AB - Transcript variants play a critical role in diversifying gene expression. Alternative splicing is a major mechanism for generating transcript variants. A number of genes have been implicated in breast cancer pathogenesis with their aberrant expression of alternative transcripts. In this study, we performed genome-wide analyses of transcript variant expression in breast cancer. With RNA Seq data from 105 patients, we characterized the transcriptome of breast tumors, by pairwise comparison of gene expression in the breast tumor versus matched healthy tissue from each patient. We identified 2839 genes, ~10 % of protein coding genes in the human genome, that had differential expression of transcript variants between tumors and healthy tissues. The validity of the computational analysis was confirmed by quantitative RT-PCR assessment of transcript variant expression from four top candidate genes. The alternative transcript profiling led to classification of breast cancer into two subgroups and yielded a novel molecular signature that could be prognostic of patients' tumor burden and survival. We uncovered nine splicing factors (FOX2, MBNL1, QKI, PTBP1, ELAVL1, HNRNPC, KHDRBS1, SFRS2, and TIAR) that were involved in aberrant splicing in breast cancer. Network analyses for the coordinative patterns of transcript variant expression identified twelve "hub" genes that differentiated the cancerous and normal transcriptomes. Dysregulated expression of alternative transcripts may reveal novel biomarkers for tumor development. It may also suggest new therapeutic targets, such as the "hub" genes identified through the network analyses of transcript variant expression, or splicing factors implicated in the formation of the tumor transcriptome. PMID- 25913417 TI - Impact of intermittent hypoxia and exercise on blood pressure and metabolic features from obese subjects suffering sleep apnea-hypopnea syndrome. AB - Strategies designed to reduce adiposity and cardiovascular-accompanying manifestations have been based on nutritional interventions conjointly with physical activity programs. The aim of this 13-week study was to investigate the putative benefits associated to hypoxia plus exercise on weight loss and relevant metabolic and cardiorespiratory variables, when prescribed to obese subjects with sleep apnea syndrome following dietary advice. The participants were randomly distributed in the following three groups: control, normoxia, and hypoxia. All the subjects received dietary advice while, additionally, normoxia group was trained under normal oxygen concentration and Hypoxia group under hypoxic conditions. There was a statistically significant decrease in fat-free mass (Kg) and water (%) on the control compared to normoxia group (p < 0.05 and p < 0.01, respectively). Body weight, body mass index, and waist circumference decreased in all the groups after the study. Moreover, leukocyte count was increased after the intervention in hypoxia compared to control group (p < 0.05). There were no statistically significant variations within groups in other variables, although changes in appetite were found after the 13-week period. In addition, associations between the variations in the leukocyte count and fat mass have been found. The hypoxia group showed some specific benefits concerning appetite and cardiometabolic-related measurements as exertion time and diastolic blood pressure, with a therapeutical potential. PMID- 25913418 TI - A 4-year assessment of a new water-fluoridation scheme in New South Wales, Australia. AB - OBJECTIVE: To monitor the changes in dental caries prevalence of 5- to 7-year-old children living in a fluoridated area, a newly fluoridated area and in an area without water fluoridation, in NSW, Australia. METHODS: Dental caries prevalence was recorded for 5- to 7-year-old children, living in the three study locations, by six trained and calibrated examiners in 2008, 2010 and 2012. A questionnaire recorded demographic data, toothbrushing behaviour and sugary drink consumption. Caries experience was measured using the decayed, missing, and filled teeth (dmft) index for primary teeth, the percentage of children who were caries free and the significant caries index. Univariate analysis was undertaken to determine independent predictors of caries. RESULTS: The caries prevalence changed over time. In 2008, the mean dmft index was 1.40 for the fluoridated area, 2.02 for the area about to fluoridate and 2.09 for the unfluoridated control. By 2012, these mean dmft scores were 0.69, 0.72 and 1.21, respectively. In the two areas where children received fluoridated water, the significant caries index was 2.30 for the fluoridated area and 2.40 for the newly fluoridated area. The significant caries score for children in the unfluoridated location was 3.93. Multivariate analysis showed that over time the differences in dental caries prevalence between the established fluoride area and the newly fluoridated area diminished. However, children in the unfluoridated control area continued to demonstrate significant differences in the mean number of decayed teeth compared with children in the fluoridated comparator sites, and the proportions of children free from decay were significantly higher in the fluoridated areas than in the unfluoridated area. CONCLUSION: Fluoridation of public water supplies in Gosford and Wyong offers young children better dental health than those children who do not have access to this public health measure. PMID- 25913419 TI - Effect of smoke-free patio policy of restaurants and bars on exposure to second hand smoke. AB - OBJECTIVE: While there is increasing support for restricting smoking in restaurant and bar patios, there is limited evidence on the effectiveness of this policy. This study examined the effect of smoke-free patio policy of restaurants and bars on adult second-hand smoke (SHS) exposure. METHODS: Data were drawn from the 2005-2012 Canadian Tobacco Use Monitoring Survey (n=89,743), a repeated cross sectional survey of youth and adult. Regression analysis, a quasi-experimental design was used to examine the effect of provincial smoke-free patio policy on self-reported exposure to SHS. RESULTS: Analyses suggest that exposure to SHS on patios of bars and restaurants declined following the adoption of provincial smoke-free patio policy. Relative to pre-policy SHS exposure, regression results showed a reduction in the probability of SHS exposure of up to 25% in Alberta. Similarly, in Nova Scotia, the probability of SHS exposure declined by up to 21%. Analyses stratified by smoking status found similar significant effect on both smokers and non-smokers. CONCLUSIONS: Findings suggest that provincial patio smoking ban on bars and restaurants had the intended effect of protecting non smokers from SHS exposure. This study is consistent with a large body of evidence showing that a strong smoke-free legislation is an effective public health measure. PMID- 25913420 TI - Accelerometer-measured sedentary time and cardiometabolic biomarkers: A systematic review. AB - OBJECTIVE: We conducted a systematic review to investigate the cross-sectional and prospective associations of accelerometer-measured total sedentary time and breaks in sedentary time with individual cardiometabolic biomarkers in adults >=18years of age. METHODS: Ovid Medline, Embase, Web of Science and the Cochrane Library were searched for studies meeting the inclusion criteria. Due to inconsistencies in the measurement and analysis of sedentary time, data was synthesised and presented narratively rather than as a meta-analysis. RESULTS: Twenty-nine studies were included in the review; twenty-eight reported on total sedentary time and six on breaks in sedentary time. There was consistent evidence from cross-sectional data of an unfavourable association between total sedentary time and insulin sensitivity. There was also some evidence that total sedentary time was unfavourably associated with fasting insulin, insulin resistance and triglycerides. Furthermore, there was some evidence from cross-sectional data of a favourable association between breaks in sedentary time and triglycerides. CONCLUSION: Total sedentary time was consistently shown to be associated with poorer insulin sensitivity, even after adjusting for time spent in physical activity. This finding supports the proposed association between sedentary time and the development of Type 2 diabetes and reinforces the need to identify interventions to reduce time spent sedentary. PMID- 25913422 TI - The 'unnecessary' use of emergency departments by older people: findings from hospital data, hospital staff and older people. AB - OBJECTIVE: Increasing demands are being placed on emergency departments in Australia and there is a view that older Australians are more likely than other age groups to attend for non-urgent conditions. The objective of this paper is to compare and contrast administrative data with the views of hospital staff and older people with regard to their presentation at two emergency departments in metropolitan Adelaide and how this aligns with the Australian Institute of Health and Welfare definition of 'potentially avoidable general practitioner-type presentations'. METHODS: The study used three sources of data from two emergency departments: hospital data for the financial year 2010-11 for patients aged 65 years and over and identified as triage category four or five; three focus groups with medical, nursing and allied staff from these two hospitals; and interviews with 58 older people who presented at the two emergency departments over a two week period. RESULTS: The hospital administrative data provided a very limited insight into why older people attended the emergency department, other than the medical diagnosis. Professional staff identified individual determinants, societal determinants and the health services system as explanations. Older people attended the emergency department for a range of reasons that may not necessarily reflect the opinions of health professionals. CONCLUSIONS: For many older people the emergency department was an appropriate place to attend considering their condition, though some presentations could be circumvented with appropriate and increased services in the community. However, as many older people suffer comorbidities, careful consideration needs to be given as to the best possible practices to achieve this. PMID- 25913423 TI - Evaluation of plasma microsampling for dried plasma spots (DPS) in quantitative LC-MS/MS bioanalysis using ritonavir as a model compound. AB - Quantitative bioanalysis of dried plasma spots (DPS) is not subject to the impact of hematocrit and sample non-homogeneity that are often encountered in dried blood spot (DBS) assay. In the present report, an evaluation of plasma microsampling for DPS has been conducted for the first time using ritonavir as a model compound orally administered to dogs. For this evaluation, an LC-MS/MS method was developed and validated according to the current health authorities' guidance and industry practice for the analysis of ritonavir in DPS samples. The measured ritonavir concentrations in the DPS samples prepared using SAFE-TEC devices and directly from the conventional wet plasma using standard pipette were compared with each other and against those of conventional wet plasma. Both DPS results correlated well with each other and were comparable to those of the wet plasma. Good incurred sample reanalysis results were obtained for the two sets of DPS samples and wet plasma as well. The current plasma microsampling for DPS can serve as an alternative to DPS sampling via standard pipetting and wet plasma in in vivo studies. PMID- 25913421 TI - Are allergic multimorbidities and IgE polysensitization associated with the persistence or re-occurrence of foetal type 2 signalling? The MeDALL hypothesis. AB - Allergic diseases [asthma, rhinitis and atopic dermatitis (AD)] are complex. They are associated with allergen-specific IgE and nonallergic mechanisms that may coexist in the same patient. In addition, these diseases tend to cluster and patients present concomitant or consecutive diseases (multimorbidity). IgE sensitization should be considered as a quantitative trait. Important clinical and immunological differences exist between mono- and polysensitized subjects. Multimorbidities of allergic diseases share common causal mechanisms that are only partly IgE-mediated. Persistence of allergic diseases over time is associated with multimorbidity and/or IgE polysensitization. The importance of the family history of allergy may decrease with age. This review puts forward the hypothesis that allergic multimorbidities and IgE polysensitization are associated and related to the persistence or re-occurrence of foetal type 2 signalling. Asthma, rhinitis and AD are manifestations of a common systemic immune imbalance (mesodermal origin) with specific patterns of remodelling (ectodermal or endodermal origin). This study proposes a new classification of IgE-mediated allergic diseases that allows the definition of novel phenotypes to (i) better understand genetic and epigenetic mechanisms, (ii) better stratify allergic preschool children for prognosis and (iii) propose novel strategies of treatment and prevention. PMID- 25913424 TI - High speed capillary zone electrophoresis-mass spectrometry via an electrokinetically pumped sheath flow interface for rapid analysis of amino acids and a protein digest. AB - While capillary zone electrophoresis (CZE) has been used to produce very rapid and efficient separations, coupling these high-speed separations with mass spectrometry (MS) has been challenging. Now, with much faster and sensitive mass spectrometers, it is possible to take full advantage of the CZE speed and reconstruct the fast migrating peaks. Here are three high-speed CZE-MS analyses via an electrokinetically pumped sheath-flow interface. The first separation demonstrates CZE-ESI-MS of an amino acid mixture with a 2-min separation, >50,000 theoretical plates, low micromolar concentration detection limits, and subfemtomole mass detection limits (LTQ XL mass spectrometer). The second separation with our recently improved third-generation CE-MS interface illustrates a 20 amino acid separation in ~7min with an average over 200,000 plate counts, and results in almost-baseline resolution of structural isomers, leucine and isoleucine. The third separation is of a BSA digest with a reproducible CZE separation and mass spectrometry detection in 2min. CZE-MS/MS analysis of the BSA digest identified 31 peptides, produced 52% sequence coverage, and generated a peak capacity of ~40 across the 1-min separation window (Q-Exactive mass spectrometer). PMID- 25913425 TI - Cationic polyelectrolyte functionalized magnetic particles assisted highly sensitive pathogens detection in combination with polymerase chain reaction and capillary electrophoresis. AB - Pathogenic bacteria cause significant morbidity and mortality to humans. There is a pressing need to establish a simple and reliable method to detect them. Herein, we show that magnetic particles (MPs) can be functionalized by poly(diallyl dimethylammonium chloride) (PDDA), and the particles (PDDA-MPs) can be utilized as adsorbents for capture of pathogenic bacteria from aqueous solution based on electrostatic interaction. The as-prepared PDDA-MPs were characterized by Fourier transform infrared spectroscopy, zeta potential, vibrating sample magnetometry, X ray diffraction spectrometry, scanning electron microscopy, and transmission electron microscopy. The adsorption equilibrium time can be achieved in 3min. According to the Langmuir adsorption isotherm, the maximum adsorption capacities for E. coli O157:H7 (Gram-negative bacteria) and L. monocytogenes (Gram-positive bacteria) were calculated to be 1.8*10(9) and 3.1*10(9)cfumg(-1), respectively. The bacteria in spiked mineral water (1000mL) can be completely captured when applying 50mg of PDDA-MPs and an adsorption time of 5min. In addition, PDDA-MPs based magnetic separation method in combination with polymerase chain reaction and capillary electrophoresis allows for rapid detection of 10(1)cfumL(-1) bacteria. PMID- 25913426 TI - Development of LC-MS/MS methodology for the detection/determination and confirmation of chloramphenicol, chloramphenicol 3-O-beta-d-glucuronide, florfenicol, florfenicol amine and thiamphenicol residues in bovine, equine and porcine liver. AB - A method for the detection and confirmation of organic solvent extractable residues of the neutral, acidic, and basic analytes of the amphenicol class veterinary drugs and selected metabolites was developed and validated. Using a modified QuEChERS extraction with SPE cleanup and LC-MS/MS analysis, limits of detection and confirmation for the different analytes in bovine, equine, and porcine liver ranged from 0.1ng/g for chloramphenicol to 1ng/g for florfenicol amine. Tissue homogenization with an ammonium formate/EDTA solution and subsequent analyte partitioning against 7:3 acetonitrile:isopropanol solution and mixed-mode strong-cation exchange solid-phase extraction cartridge cleanup allowed for the extraction of all compounds from tissues with mean recoveries ranging from 50% (chloramphenicol 3-O-beta-d-glucuronide) to 90% (thiamphenicol). Matrix effects ranged from greater than 85% suppression for florfenicol amine to 70% matrix enhancement for chloramphenicol 3-O-beta-d-glucuronide. Quantitation and confirmation were accomplished using commercially available penta-deuterated chloramphenicol as internal standard and multiple reaction monitoring (MRM) of two or three transitions per target analyte. Method accuracy was greater than 15% for all compounds except the glucuronide metabolite. Intra-lab method repeatability estimates ranged from 73% RSD for chloramphenicol 3-O-beta-d glucuronide to 14% RSD for chloramphenicol. Only chloramphenicol 3-O-beta-d glucuronide and florfenicol amine at the low end of their calibration ranges (0.25 and 1ng/g, respectively) did not meet AOAC recommended HorRatr guidelines for intra-lab repeatabilities. Preliminary tests show that the method's extraction protocol can be used to recover analytes of the beta-agonists, corticosteroids, fluoroquinolones, sulfonamides, and tetracycline drug classes from the same matrices. Requirements for use in national chemical monitoring programs as a detection/confirmatory (florfenicol amine and chloramphenicol 3-O beta-d-glucuronide) and determinative/confirmatory (chloramphenicol, florfenicol, thiamphenicol) analytical methodology are met. PMID- 25913427 TI - One step affinity recovery of 3alpha-hydroxysteroid dehydrogenase from cloned Escherichia coli. AB - 3alpha-Hydroxysteroid dehydrogenase (3alpha-HSD), from Comamonas Testosterone, catalyze reversibly the oxidoreduction of 3alpha-hydroxyl groups of the steroid hormones. The gene encoding 3alpha-HSD (hsdA) from Comamonas Testosterone was expressed in Escherchia coli BL21 (DE3). A protocol for recovering 3alpha-HSD based on affinity strategy was designed and employed. Deoxycholic acid was chosen as the affinity ligand, and it was linked to Sepharose 4B with the aid of the spacers as cyanuric chloride and ethanediamine. With this specific affinity medium, the enzyme recovery process consisted of only one chromatography step to capture 3alpha-HSD. The target protein, analyzed on HPLC Agilent SEC-5 column, was of 94% pure among the captured protein, and 98% with SDS-PAGE analysis. The yield of the expressed enzyme was 8.8% of crude extracted proteins; the recovery yield of 3alpha-HSD was 73.2%. 3alpha-HSD was revealed as a non-covalent homodimer with molecular mass of ~56kDa by 15.0% SDS-PAGE analysis and SE-HPLC analysis. The desorption constant Kd and the theoretical maximum absorption Qmax on the affinity medium were 4.5MUg/g medium and 21.3mg/g medium, respectively. PMID- 25913428 TI - The Legacy of Henry Molaison (1926-2008) and the Impact of His Bilateral Mesial Temporal Lobe Surgery on the Study of Human Memory. AB - In 1953, neurosurgeon William Beecher Scoville performed a bilateral mesial temporal lobe resection on patient Henry Molaison, who suffered from epilepsy. The operation was novel as a treatment for epilepsy and had an unexpected consequence: a severe compromise of Molaison's anterograde memory. In a landmark 1957 publication, Scoville and Milner concluded that mesial temporal lobe structures, particularly the hippocampi, were integral to the formation of new, recent memories. Over the next 5 decades, more than 100 researchers studied Molaison's memory, behavior, and learning skills, making him one of the most famous patients in the history of cognitive neuroscience. Following his death in 2008, his brain was scanned in situ and ex vivo and then sectioned into 2401 sections. Histological evaluation of Molaison's brain further elucidated which mesial temporal lobe structures were preserved or resected in his operation, shedding new light on the neuroanatomic underpinnings of short-term memory. Scoville regretted Molaison's surgical outcome and spoke vigorously about the dangers of bilateral mesial temporal lobe surgery. This report is the first historical account of Molaison's case in the neurosurgical literature, serving as a reminder of Molaison's contributions and of the perils of bilateral mesial temporal lobe surgery. PMID- 25913429 TI - Pure Neuroendoscopic Resection of Cystic Cerebellar Tumors. AB - BACKGROUND: We describe the resection of cerebellar cystic tumors using pure neuroendoscopy. This technique consists of performing all of the procedures under an endoscopic view, with the instruments introduced into the operative field coaxially to the endoscope through a trocar. CASE DESCRIPTION: Three cases of cerebellar cystic lesions (two pilocytic astrocytomas and one hemangioblastoma) were approached using the pure neuroendoscopic technique. Under general anesthesia and prone positioning, a suboccipital burr hole was created. The endoscope was introduced into the tumor cavity, and a reddish nodule was identified. The monopolar electrode was used to coagulate and dissect the surrounding nodular tissue. Grasping forceps were used to remove the nodule. There were no complications related to tumor removal, and the patients recovered from their symptoms. The follow-up images showed reduction of the cavity with no contrast enhancement. CONCLUSION: The pure neuroendoscopic technique was shown to be minimally invasive and a successful and secure method to treat cystic cerebellar tumors. PMID- 25913430 TI - A Poorly Known Cerebrospinal Fluid Shunt Complication: Miyazaki Syndrome. AB - We studied a poorly known form of cerebrospinal fluid hypotension characterized by cervical myelopathy, a considerable growth in volume of the venous plexus of the cervical spine, and absence of headache. This form was first described by Miyazaki. We reported a case brought to our attention, reviewed the literature, and formulated etiopathogenic theories that might explain all the various clinical aspects of this pathology. PMID- 25913431 TI - Spontaneous Temporal Pole Encephalocele Presenting with Epilepsy: Report of Two Cases. AB - BACKGROUND: Refractory temporal lobe epilepsy due to spontaneous temporal pole encephalocele is a rare but increasingly recognized condition. Optimal surgical management is complicated by the lack of knowledge regarding both the extent of the epileptogenic area and the need for repair of the encephalocele. CASE DESCRIPTION: We report two cases that add significant information to these issues. In Case 1, with a 5-year history of refractory seizures, implantation of diagnostic subdural electrodes into the anterior temporal base happened to abolish the seizures completely. No structural changes were evident on postoperative magnetic resonance imaging. In Case 2, with a large encephalocele and a 5-year history of refractory seizures, surgical disconnection of the temporal pole successfully abolished seizures without any need for encephalocele repair. CONCLUSIONS: These two cases support the view that the epileptogenic area is confined to within the temporal pole for spontaneous temporal pole encephalocele. Temporopolar disconnection represents one surgical option for this entity that achieves seizure cessation without requiring extra repair procedures. PMID- 25913432 TI - Latent carcinogenicity of early-life exposure to dichloroacetic acid in mice. AB - Environmental exposures occurring early in life may have an important influence on cancer risk later in life. Here, we investigated carryover effects of dichloroacetic acid (DCA), a small molecule analog of pyruvate with metabolic programming properties, on age-related incidence of liver cancer. The study followed a stop-exposure/promotion design in which 4-week-old male and female B6C3F1 mice received the following treatments: deionized water alone (dH2O, control); dH2O with 0.06% phenobarbital (PB), a mouse liver tumor promoter; or DCA (1.0, 2.0 or 3.5g/l) for 10 weeks followed by dH2O or PB (n = 20 30/group/sex). Pathology and molecular assessments were performed at 98 weeks of age. In the absence of PB, early-life exposure to DCA increased the incidence and number of hepatocellular tumors in male and female mice compared with controls. Significant dose trends were observed in both sexes. At the high dose level, 10 weeks of prior DCA treatment induced comparable effects (>=85% tumor incidence and number) to those seen after continuous lifetime exposure. Prior DCA treatment did not enhance or inhibit the carcinogenic effects of PB, induce persistent liver cytotoxicity or preneoplastic changes on histopathology or alter DNA sequence variant profiles within liver tumors compared with controls. Distinct changes in liver messenger RNA and micro RNA profiles associated with prior DCA treatment were not apparent at 98 weeks. Our findings demonstrate that early-life exposure to DCA may be as carcinogenic as life-long exposures, potentially via epigenetic-mediated effects related to cellular metabolism. PMID- 25913433 TI - Influence of clerkship sites on National Board of Medical Examiners surgery subject examination performance. AB - BACKGROUND: As one measure of comparability of student experiences on a 2-month surgery clerkship, scores on the National Board of Medical Examiners Surgery Subject Examination (NSSE) were evaluated against a number of variables. METHODS: NSSE scores for 701 students completing the surgery clerkship over 3.5 years were analyzed. Students rotated at academic, VA, and community hospitals with 1 month of general surgery paired with 1 month of a surgical subspecialty. The effect of 15 rotation site pairings on NSSE performance was analyzed by analysis of variance. The relationship of site-specific student evaluation variables and NSSE scores was examined by stepwise multivariate linear regression. RESULTS: No statistical differences were demonstrated between NSSE scores and site-specific parameters of duty hours, resident participation, or type of hospital, nor between NSSE scores and paired sites constituting the overall clerkship experience. CONCLUSION: Performance on the NSSE was not impacted by any assigned paired sites, supporting comparability of overall clerkship experiences. PMID- 25913434 TI - Targets in schizophrenia. PMID- 25913435 TI - Obituary. PMID- 25913436 TI - Inter-domain electron transfer in cellobiose dehydrogenase: modulation by pH and divalent cations. AB - The flavocytochrome cellobiose dehydrogenase (CDH) is secreted by wood decomposing fungi, and is the only known extracellular enzyme with the characteristics of an electron transfer protein. Its proposed function is reduction of lytic polysaccharide mono-oxygenase for subsequent cellulose depolymerization. Electrons are transferred from FADH2 in the catalytic flavodehydrogenase domain of CDH to haem b in a mobile cytochrome domain, which acts as a mediator and transfers electrons towards the active site of lytic polysaccharide mono-oxygenase to activate oxygen. This vital role of the cytochrome domain is little understood, e.g. why do CDHs exhibit different pH optima and rates for inter-domain electron transfer (IET)? This study uses kinetic techniques and docking to assess the interaction of both domains and the resulting IET with regard to pH and ions. The results show that the reported elimination of IET at neutral or alkaline pH is caused by electrostatic repulsion, which prevents adoption of the closed conformation of CDH. Divalent alkali earth metal cations are shown to exert a bridging effect between the domains at concentrations of > 3 mm, thereby neutralizing electrostatic repulsion and increasing IET rates. The necessary high ion concentration, together with the docking results, show that this effect is not caused by specific cation binding sites, but by various clusters of Asp, Glu, Asn, Gln and the haem b propionate group at the domain interface. The results show that a closed conformation of both CDH domains is necessary for IET, but the closed conformation also increases the FAD reduction rate by an electron pulling effect. PMID- 25913437 TI - Low-fasting triglyceride levels are associated with non-invasive markers of advanced liver fibrosis among adults in the United States. AB - BACKGROUND: Elevated fasting triglyceride is often associated with metabolic syndrome and non-alcoholic fatty liver disease (NAFLD), the most common form of chronic liver disease. On the other hand, as liver disease progresses, patients may develop hepatocellular dysfunction that impairs triglyceride production. AIM: To test the hypothesis that lower fasting triglyceride levels may paradoxically indicate more advanced liver disease. METHODS: A cross-sectional analysis of 11 947 adults aged 20 years or older without chronic viral hepatitis from the National Health and Nutrition Examination Survey 1999-2010 was performed to analyze the relationships between fasting triglyceride levels and five validated non-invasive indices of liver fibrosis, including Fibrosis 4 Score (FIB4), NAFLD Fibrosis Score (NFS), Ast-Platelet Ration Index, AST/ALT ratio and BARD. RESULTS: Low-fasting triglyceride levels were consistently associated with elevated liver fibrosis indices. Individuals in the lowest quintile of triglycerides (TG) had an adjusted odds ratio (OR) of 3.0 (95% CI, 1.7-5.2; P < 0.001) for advanced fibrosis estimated by FIB4 score and OR of 1.8 (95% Cl, 1.2-2.7; P = 0.009) estimated by NFS, compared to individuals in the highest quintile. This association remained highly significant when restricted to individuals with abnormal LFTs from suspected NAFLD. This inverse relationship was continuous, and more pronounced among men and whites (P interaction <0.001 and 0.008 respectively), but not modified by age or body mass index. In addition, fasting TG had a stronger, more direct association with liver fibrosis indices than did albumin or total bilirubin. CONCLUSIONS: Fasting triglyceride levels were inversely associated with liver fibrosis indicators in American adults, especially among white men. Our findings suggest that sequential lipid measurements may serve as a useful disease marker in the management of chronic liver disease patients. PMID- 25913438 TI - [P. Rozenberg in reply to the correspondence between D. Philopoulos and C. Racinet concerning the article by C. Racinet et al.: Can caesarean delivery prevent cerebral palsy? Medico-legal implications of a French ecological study. Gynecol Obstet Fertil 2015:43:8-12]. PMID- 25913440 TI - [Acquired ocular toxoplasmosis]. PMID- 25913441 TI - [Clinical evaluation of the new screening procedures for hydroxychloroquine retinopathy, according to the American Academy of Ophthalmology guidelines. Prospective study of 184 patients]. AB - PURPOSE: To compare the results, in clinical practice, of screening procedures for hydoxychloroquine retinopathy, according to the new recommendations of the American Academy of Ophthalmology of 2011. METHODS: Hundred and eighty-four patients on long-term hydroxychloroquine underwent ophthalmologic evaluation, including fundus examination, 10.2 automated visual field, fundus autofluorescence, SD-OCT optical coherence tomography, and multifocal ERG, whenever possible, in a prospective monocentric study. RESULTS: There was a significant correlation (P<0.05) between cumulative HCQ dose and positive results on SD-OCT and 10.2 visual field. There were no significant correlations between high cumulative HCQ dose and positive results for fundus examination, autofluorescence, or multifocal ERG. Average cumulative doses between the healthy group (946g) and the maculopathy group (1427g) were significantly different (P<0.05). Out of 184 patients, 12 toxic maculopathies were found (prevalence 6.5%). For these 12 cases, 5 were diagnosed at clinical stages, and 7 were diagnosed in the early preclinical stage. Ten patients had positive visual fields, and 8 patients had pathological SD-OCT signs. Autofluorescence was affected in the clinical stage, but not in the preclinical stage. In four out of the twelve cases of maculopathy, patients had pathological ERG results. CONCLUSION: The significant correlation between cumulative HCQ dose, considered as the main risk factor for maculopathy, and positive SD-OCT and 10.2 visual field results render the combination of these two tests the basis of the screening strategy for plaquenil maculopathy. These results suggest using a simplified screening procedure, including annual SD-OCT and 10.2 visual field while taking the cumulative dose into account. Multifocal ERG seems more helpful for diagnostic confirmation than screening, especially for the preclinical stage. Fundus autofluorescence is not an efficient test for early diagnosis. PMID- 25913442 TI - ICG cine-angiography demonstrates choroidal reperfusion after vortex vein occlusion in AMD. PMID- 25913443 TI - Ranibizumab for exudative age-related macular degeneration: A five year study of adherence to follow-up in a real-life setting. AB - PURPOSE: To analyze adherence to follow-up over 5 years in patients treated with intravitreal ranibizumab for exudative age-related macular degeneration (AMD) in a tertiary health care center. To investigate factors associated with failure to continue follow-up. METHODS: Retrospective chart review of all consecutive patients with exudative AMD, who received their first intravitreal ranibizumab injection at the Creteil Intercommunal University Hospital Eye Clinic between October 1, 2006 and March 31, 2007. Patient clinical characteristics at baseline and at the last follow-up visit were recorded. Distance from home to hospital was measured for each patient. A multiple-choice telephone survey was conducted for patients lost to follow-up to determine the main reasons for failure to continue follow-up. RESULTS: Two hundred and one patients were included. The rate of loss to follow-up over the 5-year period was 57% (115/201). Fifty-eight patients lost to follow-up completed the questionnaire. The main reasons reported by patients for follow-up discontinuation were long distance from home to hospital (51.7%, 30/58), subjective dissatisfaction with the benefits of intravitreal injections (34.5%, 20/58), and the excessive burden of periodic follow-up visits (24.1%, 14/58). Three factors were significantly associated with follow-up discontinuation: high age at baseline (82.2 vs. 76.5 years, P<0.001), poor best corrected visual acuity (BCVA) at baseline (42.5 vs. 51.0 letters, P=0.020), and long distance from home to hospital (132 vs. 17.1km, P<0.001). CONCLUSION: In this study, adherence to follow-up over 5 years was poor. Age and BCVA at baseline and distance from home to hospital were independently associated with long-term adherence. PMID- 25913444 TI - Variability of the LDL-C lowering response to ezetimibe and ezetimibe + statin therapy in hypercholesterolemic patients. AB - OBJECTIVE: We compared the variability of LDL-C-lowering responses to treatment with ezetimibe + statins versus statins in hypercholesterolemic patients. METHODS: An analysis of patient-level data pooled from 27 double-blind, placebo and/or active-controlled studies in 21,671 patients treated with ezetimibe + statins versus statins on first-line (statin-naive/wash-out) or second-line (on statin, randomized to ezetimibe versus placebo [add-on] or ezetimibe versus uptitrated statin [uptitrate]) for 6-24 wks. Variances (standard deviation [SD], coefficient of variation [CV], and root mean squared error [RMSE] adjusted for various factors) for % change from baseline in LDL-C were compared. RESULTS: In first-line and second-line add-on studies, the variability (SD, RMSE) of % change from baseline in LDL-C was lower in ezetimibe + statin-treated patients versus statin-treated patients, +/-covariates. Differences were small but statistically significant due to the large sample size. In second-line uptitrate studies, ezetimibe + statin treatment resulted in greater unadjusted variability (SD) versus statin therapy, while the adjusted variability (RMSE) was significantly lower. Relative variability (CV=SD/mean) was lower for ezetimibe + statins versus statin therapy for all study types, being more pronounced in second-line add-on and uptitrate studies, attributed to larger mean LDL-C reductions for ezetimibe + statins versus statin groups. When assessed by individual study/type, statin brand, potency or dose, the CVs remained lower for ezetimibe + statins versus statins in second-line studies. The SDs showed no consistent trend for either therapy. CONCLUSION: In hypercholesterolemic patients, the absolute variability of LDL-C-lowering responses to ezetimibe + statins was not greater versus statins alone and appeared lower when adjusted for other factors. Relative variability was lower in patients treated with statins + ezetimibe. A better understanding of the variability of the LDL-C lowering response may help guide clinicians in making therapeutic decisions. PMID- 25913445 TI - An amplified electrochemical strategy using DNA-QDs dendrimer superstructure for the detection of thymine DNA glycosylase activity. AB - A triple-signal amplification strategy was proposed for highly sensitive and selective detection of thymine DNA glycosylase (TDG) by coupling a dendrimer-like DNA label with the electrochemical method and quantum dots (QDs) tagging. The DNA QDs dendrimer-like superstructure was designed by DNA hybridization and covalent assembling. Benefiting from outstanding performance of the amplification strategy, this assay showed high sensitivity, extraordinary stability, and easy operation. The limit of detection could reach 0.00003 U uL(-1) with a splendid specificity. The TDG content in different concentration of HeLa cell was also determined. This assay opens a new horizon for both qualitative and quantitative detection of TDG, holding great promise for potential application in cancer cell research and clinical diagnostics. PMID- 25913446 TI - Development of ELISA and colloidal gold immunoassay for tetrodotoxin detetcion based on monoclonal antibody. AB - A monoclonal hybridoma cell named 5B9 against tetrodotoxin (TTX) was obtained after fusion of myeloma SP2/0 cells with spleen cells isolated from the immunized Balb/c mice. The 5B9 monoclonal antibody (McAb) with high affinity (about 2.55 * 10(9)) is specific to TTX, and this McAb belongs to the immunoglobulin G (IgG) isotype. Finally, an enzyme-linked immunosorbent assay (ELISA) and colloidal gold immunoassay were established based on this McAb. The linear range of ELISA to detect TTX was 5-500 ng/mL, and the limit of detection (LOD) was 4.44 ng/mL. The average CV of intra- and inter-assay was less than 8%, with the samples recovery range of 70.93-99.99%. A competitive format colloidal gold strip was developed for detection of TTX in real samples, and the LOD for TTX is 20 ng/mL, and the assay time of the qualitative test can be finished in less than 10 min without any equipment. The result from test strip revealed that the test strip has a good agreement with those obtained from ELISA. PMID- 25913447 TI - A third-order mode high frequency biosensor with atomic resolution. AB - An atomic resolution ultra-high sensitivity surface acoustic wave (SAW) biosensor for DNA sequences and cells detection is proposed. Interdigitated transducers (IDTs) fabricated on LiNbO3 substrate achieve a high quality factor (Q) of over 4000 at a frequency of 6.4 GHz (third-order harmonic mode) using an optimized design and process. The biosensor shows excellent linear responses to target DNA in the range from 1 MUg/ml to 1 ng/ml with a high sensitivity of 6.7 * 10( 16)g/cm(2)/Hz, hence the difference of a single hybridized DNA base can also be distinguished. With such a high mass resolution, the biosensor is capable of quantitative detection of living cancer cells. The frequency responses of single mouse mammary adenocarcinoma (EMT6) cell and mouse fibroblast (3T3) cell are studied. The interferences in the experiments show insignificant influence on the frequency shift, which verifies the high selectivity of the biosensor. The biosensor is also able to repeat the sensing ability after rough cleaning, therefore cost reduction is achieved from the recycling process in practical applications. The detection limit is defined from the noise analysis of the device, atomic resolution is realized according to the calculation, thereby initiating a potential tool for high-precision medical diagnoses and phenomena observation at the atomic-level. PMID- 25913449 TI - A novel ultrasensitive phosphate amperometric nanobiosensor based on the integration of pyruvate oxidase with highly ordered gold nanowires array. AB - A novel phosphate amperometric nanobiosensor, based on an intimate integration of pyruvate oxidase (PyOx) and its cofactors, thiamine pyrophosphate (TPP) and flavin adenine dinucleotide (FAD), with a highly ordered gold nanowires array (AuNWA) has been developed. The successful integration of PyOx and the co factors, via crosslinking with bovine serum albumin (BSA) and glutaraldehyde (GLA), onto the AuNWA was confirmed by cyclic voltammetry and amperometry. The resulting nanobiosensor achieved a detection limit of 0.1 uM, a linear concentration range of 12.5-1000 uM, and a sensitivity of 140.3 uA mM(-1)cm(-2). Notably, the incorporation of the AuNWA reduced the required PyOx concentration by 70-120 fold and the presence of common interferants, such as chloride, sulfate, fluoride, nitrite and nitrate ions did not interfere with phosphate detection. Furthermore, the nanobiosensor demonstrated a very high stability with repeated use over two weeks and was successfully used for the determination of phosphate in water samples with an average recovery of 96.6 +/- 4.9%. PMID- 25913450 TI - Good for the group? Explaining apparent group-level adaptation. AB - The idea that group selection can explain adaptive trait evolution is still controversial. Recent empirical work proposes evidence for group-level adaptation in a social spider, but the findings can also be explained from an individual level perspective. The challenge remains to identify situations where one can separate group and individual selection. PMID- 25913448 TI - Electronic platform for real-time multi-parametric analysis of cellular behavior post-exposure to single-walled carbon nanotubes. AB - Single-walled carbon nanotubes (SWCNTs) implementation in a variety of biomedical applications from bioimaging, to controlled drug delivery and cellular-directed alignment for muscle myofiber fabrication, has raised awareness of their potential toxicity. Nanotubes structural aspects which resemble asbestos, as well as their ability to induce cyto and genotoxicity upon interaction with biological systems by generating reactive oxygen species or inducing membrane damage, just to name a few, have led to focused efforts aimed to assess associated risks prior their user implementation. In this study, we employed a non-invasive and real time electric cell impedance sensing (ECIS) platform to monitor behavior of lung epithelial cells upon exposure to a library of SWCNTs with user-defined physico chemical properties. Using the natural sensitivity of the cells, we evaluated SWCNT-induced cellular changes in relation to cell attachment, cell-cell interactions and cell viability respectively. Our methods have the potential to lead to the development of standardized assays for risk assessment of other nanomaterials as well as risk differentiation based on the nanomaterials surface chemistry, purity and agglomeration state. PMID- 25913451 TI - Effect of photoinitiator combinations on hardness, depth of cure, and color of model resin composites. AB - OBJECTIVE: This study aims to determine the influence of photoinitiators' combinations on the hardness, depth of cure, and color of model resin composites. MATERIALS AND METHODS: The composites were formulated by a mixture of BisGMA and triethyleneglycol dimethacrylate (60:40 mol), with barium-aluminum-silicate glass and silicon dioxide particles as inorganic fillers (60 wt%). Three photoinitiator types were tested: camphorquinone/amine (CQ), monoacylphosphine oxide (TPO), and bysacylphosphine oxide (BAPO). Six experimental groups were formed by differences in photoinitiator systems: CQ, TPO, BAPO, CQ+TPO, CQ+BAPO, and CQ+TPO+BAPO. Hardness was determined by Knoop indentation at the top and bottom surfaces (n = 5). Depth of cure was performed according to ISO 4049 scraping method (n = 5). Color was obtained by the CIELAB method (n = 10), 24 hours after curing (baseline), after 30 days storage in distilled water, and after 30 days storage in coffee solution. CIELAB color difference (DeltaE*) was calculated for both periods. Data were submitted to analysis of variance, followed by Student-Newman Keuls method (alpha = 0.05). RESULTS: The photoinitiator system influenced hardness, where CQ presented the lowest top and bottom values. No statistical difference among groups was observed for the bottom/top hardness ratio. Regarding the depth of cure, the CQ and those formulated with CQ associations presented higher values than TPO and BAPO. Regarding color, BAPO and CQ+BAPO presented the highest DeltaE* after 30 days in water immersion, whereas CQ+TPO and CQ+TPO+BAPO presented the lowest after 30 days in coffee immersion. CONCLUSION: The associations CQ+TPO and CQ+TPO+BAPO presented improved color stability and hardness when compared with CQ, and did not influence the depth of cure. CLINICAL SIGNIFICANCE: The combination of alternative photoinitiators with the traditional camphorquinone/amine system improved the color stability of the model resin composites and maintaining their mechanical properties. PMID- 25913452 TI - Screening and analysis of Hc-ubq and Hc-gst related to desiccation survival of infective Haemonchus contortus larvae. AB - Infective Haemonchus contortus larvae (L3s) are able to protect themselves from desiccation. To explore the molecular mechanisms of desiccation survival, mRNA differential display RT-PCR was used to screen differentially expressed genes in L3s upon desiccation, followed by RNAi experiments to define gene functions. In this, 58 differentially expressed transcripts were obtained. Among these, the BF U01A and CH-U02A fragments represent genes with the highest identity percentage in bioinformatic analysis. They were named Hc-ubq and Hc-gst based on their respective homologous ubiquitin in Caenorhabditis elegans and glutathione S transferase in H. contortus. Quantitive RT-PCR results indicated that they were both up-regulated in desiccated L3s. Hc-ubq and Hc-gst RNAi in H. contortus showed reduced survival rate of L3s, with unchanged locomotion behavior. Homologous Ce-ubq-2 and Ce-gst-7 RNAi in C. elegans also displayed higher larval death rate. These results suggest that ubq and gst may play important roles in nematode desiccation tolerance. Our study analyzed desiccation resistance related genes in H. contortus L3s, and revealed significant research implications on the mechanisms behind nematode desiccation survival. PMID- 25913453 TI - Ticks imported to Europe with exotic reptiles. AB - It is known that traded exotic animals carry with them an immense number of associated symbionts, including parasites. Reptiles are no exception. Most of the imported reptiles originate from tropical countries and their possibility to carry potentially dangerous pathogens is high. According to CITES, Europe is currently the main reptile importer in the world. Despite this, there is no review or analysis available for the risk related to the importation of tick borne diseases with traded reptile to the EU. The main aim of the manuscript is to provide a review on the available literature on ticks introduced to and exchanged between European countries via the live reptile trade. So far, the published reports of ticks imported on reptiles are limited to few European countries: Italy, Poland, Spain, Netherlands, Belgium, Slovenia and UK. The following species have been reported: Hyalomma aegyptium, Amblyomma dissimile, Amblyomma exornatum, Amblyomma flavomaculatum, Amblyomma fuscolineatum, Amblyomma latum, Amblyomma quadricavum, Amblyomma marmoreum, Amblyomma nuttalli, Amblyomma sparsum, Amblyomma sphenodonti, Amblyomma transversale and Amblyomma varanense. The majority of species are of African origin, followed by American and Asian species. All groups of reptiles (chelonians, snakes, lizards, crocodiles, tuataras) were involved. However, it seems that certain groups (i.e. tortoises of genus Testudo, monitor lizards of genus Varanus, snakes of genus Python) are more important as host for imported ticks, but this may be related to higher levels of international trade. Even fewer are the reports of tick-borne pathogens associated with imported reptile ticks. Despite the diversity of tick species reported on imported reptiles, the situations of truly invasive species are atypical and are limited in natural environments to maximum two cases where H. aegyptium was involved. Otherwise, the risk associated with reptile trade for introduction of invasive tick to Europe is low. Nevertheless, veterinary control is still to be reinforced for collecting more data. PMID- 25913454 TI - Reply to letter to the editor. PMID- 25913455 TI - Measuring larval nematode contamination on cattle pastures: Comparing two herbage sampling methods. AB - Assessing levels of pasture larval contamination is frequently used to study the population dynamics of the free-living stages of parasitic nematodes of livestock. Direct quantification of infective larvae (L3) on herbage is the most applied method to measure pasture larval contamination. However, herbage collection remains labour intensive and there is a lack of studies addressing the variation induced by the sampling method and the required sample size. The aim of this study was (1) to compare two different sampling methods in terms of pasture larval count results and time required to sample, (2) to assess the amount of variation in larval counts at the level of sample plot, pasture and season, respectively and (3) to calculate the required sample size to assess pasture larval contamination with a predefined precision using random plots across pasture. Eight young stock pastures of different commercial dairy herds were sampled in three consecutive seasons during the grazing season (spring, summer and autumn). On each pasture, herbage samples were collected through both a double-crossed W-transect with samples taken every 10 steps (method 1) and four random located plots of 0.16 m(2) with collection of all herbage within the plot (method 2). The average (+/- standard deviation (SD)) pasture larval contamination using sampling methods 1 and 2 was 325 (+/- 479) and 305 (+/- 444)L3/kg dry herbage (DH), respectively. Large discrepancies in pasture larval counts of the same pasture and season were often seen between methods, but no significant difference (P = 0.38) in larval counts between methods was found. Less time was required to collect samples with method 2. This difference in collection time between methods was most pronounced for pastures with a surface area larger than 1 ha. The variation in pasture larval counts from samples generated by random plot sampling was mainly due to the repeated measurements on the same pasture in the same season (residual variance component = 6.2), rather than due to pasture (variance component = 0.55) or season (variance component = 0.15). Using the observed distribution of L3, the required sample size (i.e. number of plots per pasture) for sampling a pasture through random plots with a particular precision was simulated. A higher relative precision was acquired when estimating PLC on pastures with a high larval contamination and a low level of aggregation compared to pastures with a low larval contamination when the same sample size was applied. In the future, herbage sampling through random plots across pasture (method 2) seems a promising method to develop further as no significant difference in counts between the methods was found and this method was less time consuming. PMID- 25913456 TI - Prevalence and species distribution of caprine trypanosomosis in Sinazongwe and Kalomo districts of Zambia. AB - African animal trypanosomosis is one of the key livestock diseases hindering full exploitation of livestock production potential covering 37 countries across sub Saharan Africa. Many studies have been carried out to investigate the prevalence of the disease in cattle and humans in many tropical African countries but very little attention has been directed towards generating the disease prevalence rates in goats. The current study was conducted between December 2013 and January 2014 to establish the prevalence of caprine trypanosomosis in Sinazongwe and Kalomo districts, southern Zambia. It involved 422 goats which were first examined by palpation for possible enlargement of superficial lymph nodes. Blood samples were then collected from the goats and subjected to laboratory diagnosis using the microscope and Loop Mediated Isothermal Amplification (LAMP). None of the examined goats displayed enlargement of superficial lymph nodes. On microscopy only one goat was found to be positive. The results of investigation using the LAMP method showed that 100 goats were infected with trypanosomes giving an overall prevalence rate of 23.7%. The prevalence of infection in Sinazongwe was 22.4% (n=183) while in Kalomo it was 24.7% (n=239); and the difference between the two districts was statistically significant at 95% CL (x(2)=4.4, df=1, p<0.05). Trypanosoma brucei, Trypanasoma vivax and Trypanasoma congolense were detected in 82.0%, 31.0% and 23.0% of the infected goats, respectively. Mixed infections were detected among 33.0% of the positive samples. The high prevalence rate of trypanosomes detected in the study area confirms the earlier reports that trypanosomosis is re-emerging in the areas previously aerial sprayed by Government. The detection of trypanosomes in naturally infected goats outlines the important role goats play in the epidemiology of African animal trypanosomosis. PMID- 25913457 TI - Organizational socialization in team sport environments. AB - Socialization tactics are often used to manage initial group member interactions in a way that facilitates transition experiences. Although this process is heavily researched in organizational contexts, we sought to extend this line of inquiry to sport by examining the nature of socialization tactics used to integrate new members into existing teams. Interviews were conducted with 12 coaches and 12 athletes from several Canadian Interuniversity Sport teams to explore the nature of socialization and the circumstances underscoring why certain approaches are taken over others. A key process involved establishing congruency of role expectations between incoming athletes and group leaders, and socialization processes balanced expectations of conformity with encouragement of individual personalities within the group. A conceptual basis to examine socialization into team sport environments is discussed in relation to the extant organizational theories, and the practical implications of delineating sport socialization tactics are forwarded. PMID- 25913458 TI - Acetyl-11-keto-beta-boswellic acid reduces retinal angiogenesis in a mouse model of oxygen-induced retinopathy. AB - Retinal diseases characterized by pathologic retinal angiogenesis are the leading causes of blindness worldwide. Although therapies directed toward vascular endothelial growth factor (VEGF) represent a significant step forward in the treatment of proliferative retinopathies, further improvements are needed. In the last few years, an intense research activity has focused around the use of herbal and traditional natural medicines as an alternative for slowing down the progression of proliferative retinopathies. In the present study, we investigated the antiangiogenic effects of acetyl-11-keto-beta-boswellic acid (AKBA), one of the active principles derived from the plant Boswellia serrata, used in Ayurvedic systems of medicine. We studied the antiangiogenic properties of AKBA using the mouse model of oxygen-induced retinopathy (OIR), which mimics the neovascular response seen in human retinopathy of prematurity. We first evaluated the effects of subcutaneously administered AKBA on the expression/activity of proteins which are known to play a role in the OIR model. In the retina, AKBA increased expression and activity of Src homology region 2 domain-containing phosphatase 1 and reduced the phosphorylation of the transcription factor signal transducer and activator of transcription 3 (STAT3) as well as VEGF expression and VEGF receptor (VEGFR)-2 phosphorylation. Likely as a result of these effects, AKBA significantly reduced retinal neovascularization in OIR mice without affecting retinal cell survival and retinal function. Using retinal explants cultured in hypoxia and an activator of STAT3 phosphorylation, we showed that the AKBA induced inhibition of VEGFR-2 phosphorylation is likely to be mediated by a mechanism depending on an SHP-1/STAT3/VEGF axis. In the OIR model, neovascularization results from the activation of retinal endothelial cells, therefore we evaluated whether AKBA affected the angiogenic response of human retinal microvascular endothelial cells (HRMECs). We observed that AKBA reduced proliferation, migration and tube formation in HRMECs stimulated with exogenous VEGF, while it reduced migration and tube formation in untreated HRMECs. Taken together, our results demonstrate the antiangiogenic effects of AKBA in a model of pathologic neovascularization, providing a rationale for further investigation of AKBA as a promising therapeutic agent to reduce the impact of proliferative retinopathies. PMID- 25913459 TI - Comments on the paper "Application of Mn/MCM-41 as an adsorbent to remove Methyl Blue from aqueous solution". PMID- 25913460 TI - Overweight, diabetes and disease duration influence clinical severity in hidradenitis suppurativa-acne inversa: evidence from the national Italian registry. PMID- 25913461 TI - "By expresse experiment": the doubting midwife Salome in late medieval England. AB - This article examines late medieval English representations of the startling and apocryphal story of Salome, the skeptical midwife who dares to touch, or at least attempt to touch, the Virgin Mary "in sexu secreto" during a postpartum examination at the nativity. Salome's story originated in the second century, but its late medieval iterations are inflected by a culture interested in evaluating and examining sensory evidence, in both medicine and religion. The story appears in sermon collections, devotional texts, the cycle nativity plays, and John Lydgate's Life of Our Lady, and these variations demonstrate the intersection of gender and experience-based knowledge in medical and devotional contexts. Salome's story provides a unique opportunity to study late medieval interpretations of female medicine, materialism, and spirituality. PMID- 25913462 TI - John Buchanan's Philadelphia Diploma Mill and the Rise of State Medical Boards. AB - The absence of medical licensing laws in most states during the years following the American Civil War made it possible for unscrupulous individuals to capitalize upon the weak governmental role in medical practice and educational charters. The practices of John Buchanan during much of his tenure at the Eclectic Medical College of Pennsylvania, in issuing thousands of dubiously earned diplomas, caused a national and international scandal. The traffic in diplomas became so flagrant that regulatory oversight of physicians and their practice, such as that conducted by the Illinois Board of Health led by Dr. John Rauch, developed rapidly across the United States. Though multiple factors prompted the rebirth of medical licensing laws, professional, educational, journalistic, and public concerns for bogus diplomas played an important role. PMID- 25913463 TI - Collaboration of Art and Science in Albert Edelfelt's Portrait of Louis Pasteur: The Making of an Enduring Medical Icon. AB - Historians of medicine--and even Louis Pasteur's biographers--have paid little attention to his close relationship with the Finnish artist Albert Edelfelt. A new look at Edelfelt's letters to his mother, written in Swedish and never quoted at length in English, reveals important aspects of Pasteur's working habits and personality. By understanding the active collaboration through which this very famous portrait was made, we also discover unnoticed things in the painting itself, gain a new appreciation of its original impact on the French public's image of science, and better understand its enduring influence on the portrayal of medicine in the art and the popular culture of many countries even to the present day. PMID- 25913464 TI - The Entangled History of Sadoka (Rinderpest) and Veterinary Science in Tanzania and the Wider World, 1891-1901. AB - Scholarship on the Tanzanian Rinderpest epizootic of the 1890s has assumed that German colonizers understood from the start that they were confronting the same disease that had afflicted Eurasia for centuries. Outward indicators of the epizootic, known locally as sadoka, especially wildlife destruction, were unknown in Europe, leading German veterinarians to doubt that the African disease was Rinderpest. Financial constraints and conflicting development agendas, especially tension between ranching and pastoralism, deterred early colonial applications of veterinary science that might have led to an early diagnosis. European veterinarians, guarding their authority against medical researchers, opposed inoculation therapies in the case of Rinderpest in favor of veterinary policing despite recent breakthroughs in vaccine research. The virus was not identified before reaching South Africa in 1896, but this breakthrough had little influence on policy in East Africa. Yet emergent international disease conventions directed at bubonic plague entangled with veterinary policy in East Africa. PMID- 25913466 TI - Anaerobic digestion of thermal pre-treated sludge at different solids concentrations--Computation of mass-energy balance and greenhouse gas emissions. AB - The effect of thermal pre-treatment on sludge anaerobic digestion (AD) efficiency was studied at different total solids (TS) concentrations (20.0, 30.0 and 40.0 g TS/L) and digestion times (0, 5, 10, 15, 20 and 30 days) for primary, secondary and mixed wastewater sludge. Moreover, sludge pre-treatment, AD and disposal processes were evaluated based on a mass-energy balance and corresponding greenhouse gas (GHG) emissions. Mass balance revealed that the least quantity of digestate was generated by thermal pre-treated secondary sludge at 30.0 g TS/L. The net energy (energy output-energy input) and energy ratio (energy output/energy input) for thermal pre-treated sludge was greater than control in all cases. The reduced GHG emissions of 73.8 * 10(-3) g CO2/g of total dry solids were observed for the thermal pre-treated secondary sludge at 30.0 g TS/L. Thermal pre-treatment of sludge is energetically beneficial and required less retention time compared to control. PMID- 25913467 TI - Degradation and COD removal of catechol in wastewater using the catalytic ozonation process combined with the cyclic rotating-bed biological reactor. AB - The effect of ozonation catalyzed with MgO/granular activated carbon (MgO/GAC) composite as a pretreatment process on the performance of cyclic rotating-bed biological reactor (CRBR) for the catechol removal from wastewater has been investigated. CRBR with acclimated biomasses could efficiently remove catechol and its related COD from wastewater at organic loading rate (OLR) of 7.82 kg COD/m(3).d (HRT of 9 h). Then, OLR increased to 15.64 kg COD/m(3).d (HRT of 4.5 h) and CRBR failed. Catalytic ozonation process (COP) used as a pre-treatment and could improve the performance of the failed CRBR. The overall removal efficiency of the combined process attained respective steady states of 91% and 79% for degradation and COD removal of catechol. Therefore, the combined process is more effective in degradation and COD removal of catechol; it is also a viable alternative for upgrading industrial wastewater treatment plant. PMID- 25913468 TI - Cost-benefit analysis as a part of sustainability assessment of remediation alternatives for contaminated land. AB - There is an increasing demand amongst decision-makers and stakeholders for identifying sustainable remediation alternatives at contaminated sites, taking into account that remediation typically results in both positive and negative consequences. Multi-criteria analysis (MCA) is increasingly used for sustainability appraisal, and the Excel-based MCA tool Sustainable Choice Of REmediation (SCORE) has been developed to provide a relevant and transparent assessment of the sustainability of remediation alternatives relative to a reference alternative, considering key criteria in the economic, environmental and social sustainability domains, and taking uncertainty into explicit account through simulation. The focus of this paper is the use of cost-benefit analysis (CBA) as a part of SCORE for assessing the economic sustainability of remediation alternatives. An economic model is used for deriving a cost-benefit rule, which in turn motivates cost and benefit items in a CBA of remediation alternatives. The empirical part of the paper is a CBA application on remediation alternatives for the Hexion site, a former chemical industry area close to the city of Goteborg in SW Sweden. The impact of uncertainties in and correlations across benefit and cost items on CBA results is illustrated. For the Hexion site, the traditional excavation-and-disposal remediation alternative had the lowest expected net present value, which illustrates the importance of also considering other alternatives before deciding upon how a remediation should be carried out. PMID- 25913469 TI - Accurate modeling of ionic surfactants at high concentration. AB - Molecular dynamics (MD) simulation is a useful tool for simulating formulations of surfactant mixtures from first-principles, which can be used to predict surfactant morphology and other industrially relevant thermodynamic properties. However, the surfactant structure is sensitive to the parameters used in MD simulations, and in the absence of extensive validation against experimental data, it is often not obvious a priori which range of parameter sets to choose. In this work, we compare the performance of ion parameters implemented in nonpolarizable classical MD simulations, and its effect on simulations of an idealized solution of sodium dodecyl sulfate (SDS). We find that previous artifacts reported in simulations of larger SDS constructs are a direct consequence of using parameters that poorly model ionic interactions at high concentration. Using osmotic pressure and/or other thermodynamic properties measured at finite concentration, such as Kirkwood-Buff integrals, is shown to be the most cost-effective means to validate and parametrize existing force fields. Our findings highlight the importance of optimizing intermolecular parameters for simulations of systems with a high local concentration, which may be applicable in other contexts, such as in molecular crowding, hotspot mapping, protein folding, and modeling pH effects. PMID- 25913470 TI - A small molecule--DNA binding landscape. AB - This brief account traces the development of a "competition dialysis" method used to characterize the structural and sequence selectivity of DNA binding compounds. The method was inspired by a simple "differential dialysis" method pioneered by Don Crothers to explore base-selective intercalator binding. Results from compiled competition dialysis studies provide a small-molecule DNA binding landscape that shows a rich diversity of interactions and molecular recognition. PMID- 25913471 TI - Very high repair rate using minimally invasive surgery for the treatment of degenerative mitral insufficiency. AB - BACKGROUND: Minimally invasive mitral valve surgery (MIMVS) is an established alternative to median sternotomy for mitral valve repair. However, this technique has yet to gain widespread adoption, partly because of concerns that this approach might yield lower repair rates or repairs that are less durable than those performed through a sternotomy. The purpose of this study was to report our inaugural experience with MIMVS, with a focus on mitral valve repair rate and midterm outcomes. METHODS: Between May 2006 and April 2012, minimally invasive mitral valve repair was attempted in 200 consecutive patients with degenerative mitral disease. The approach used was a 4- to 5-cm right anterolateral minithoracotomy with femorofemoral cannulation for cardiopulmonary bypass. Mean follow-up was 2.9 +/- 1.8 years, and follow-up was 99% complete. RESULTS: The mitral valve was successfully repaired in all but 2 patients, yielding a repair rate of 99%. Hospital mortality occurred in 2 patients (1%). Intraoperative conversion to sternotomy was necessary in 12 patients (6%), including 1 of the 2 unsuccessful repairs. Mean cardiopulmonary bypass and aortic cross-clamp times were 130.8 +/- 41.3 minutes and 104.8 +/- 35.6 minutes, respectively. Median hospital stay was 5 days. The 5-year survival and freedom from reoperation were 97.9% +/- 1.5% and 98.1% +/- 1.3%, respectively. CONCLUSIONS: A very high repair rate can be achieved using MIMVS for the treatment of degenerative mitral regurgitation, including during the learning phase. Midterm survival and freedom from valve-related reoperation are excellent. MIMVS is a safe and effective alternative to mitral valve repair through a sternotomy. PMID- 25913472 TI - Echocardiography vs. Cardiac Magnetic Resonance Imaging for the Diagnosis of Left Ventricular Thrombus: A Systematic Review. AB - BACKGROUND: Left ventricular (LV) thrombi can occur in the setting of LV dysfunction especially in the acute postmyocardial infarction period. The ideal imaging strategy to detect LV thrombi is currently unknown. The objective of this study was to conduct a systematic review to compare the accuracy of transthoracic echocardiography (TTE) with that of cardiac magnetic resonance (CMR) imaging for the detection of LV thrombi. METHODS: OvidMEDLINE, EMBASE, and Cochrane databases were searched for articles published between January 1, 1946 and July 31, 2013. After screening of all potentially relevant abstracts and articles, 7 studies were ultimately selected for this review. RESULTS: Our results suggest that late gadolinium enhancement CMR imaging is the most accurate modality for the detection of LV thrombi (sensitivity 88%, specificity 99%), followed by cine-CMR imaging (sensitivity 58%-79%, specificity 99%, accuracy 95%, positive predictive value 93%-95%, negative predictive value 95%-96%), contrast TTE (sensitivity 23% 61%, specificity 96%-99%, accuracy 92%, positive predictive value 93%, negative predictive value 91%), and, finally, noncontrast TTE (sensitivity 24%-33%, specificity 94%-95%, accuracy 82%, positive predictive value 57%, negative predictive value 85%). Accuracy of TTE might be improved if a clear clinical indication is provided and with routine use of LV opacifying contrast agents. CONCLUSIONS: Our findings indicate that late gadolinium enhancement CMR imaging is the most accurate sequence in the detection of LV thrombus, and should be favoured when there is a high index of suspicion. When CMR is contraindicated, unavailable, or impractical, our analysis argues for contrast-TTE in patients at high risk for developing LV thrombi. PMID- 25913473 TI - Comparison of Dual-antiplatelet Therapy to Mono-antiplatelet Therapy After Transcatheter Aortic Valve Implantation: Systematic Review and Meta-analysis. AB - BACKGROUND: Post-transcatheter aortic valve implantation (TAVI) dual-antiplatelet therapy (DAPT) with acetylsalicylic acid and clopidogrel is common practice to reduce ischemic complications despite the lack of clinical trial evidence demonstrating superiority over mono-antiplatelet therapy (MAPT). METHODS: A systematic search was conducted to retrieve studies that investigated DAPT vs MAPT in patients who have undergone TAVI. Outcomes of interest included both ischemic and bleeding events at 30 days and 6 months. RESULTS: Four studies met inclusion criteria-2 randomized control trials and 2 observational studies, with 286 patients in the DAPT group and 354 patients in the MAPT group. For the primary outcome of a combined end point of 30-day major stroke, spontaneous myocardial infarction (MI), all-cause mortality, and combined lethal and major bleeding, there was a trend toward increased harm in the DAPT group (29%) compared with the MAPT group (16%), with an odds ratio (OR) of 1.88 (P = 0.05). Secondary outcome analysis revealed that there was no significant difference between groups regarding 30-day stroke, 30-day spontaneous MI, and 30-day all cause mortality. Patients who received DAPT had a significant increase in combined 30-day lethal and major bleeding (OR, 2.62; P = 0.008). Further analysis revealed that increased adverse events were driven by observational studies, with no difference in outcomes between groups in randomized controlled trials. CONCLUSIONS: DAPT in patients who have undergone TAVI demonstrated no benefit over MAPT in reduction of ischemic events, with a trend toward increased harm because of bleeding. Future considerations should be given to MAPT with clopidogrel alone, as well as the omission of clopidogrel loading before the procedure. PMID- 25913474 TI - Thrombocytopenia in acute coronary syndromes: etiologies and proposed management. AB - Thrombocytopenia in acute coronary syndromes (ACS) can arise from a variety of etiologies. Glycoprotein IIb/IIIa receptor antagonists have improved clinical outcomes in ACS, however, profound thrombocytopenia can occur with use of these agents. We present a case of profound thrombocytopenia due to administration of a glycoprotein IIb/IIIa receptor antagonist, eptifibatide, after percutaneous coronary intervention for an inferior ST-elevation myocardial infarction. We review the major causes and suggest an approach for diagnosis and management of thrombocytopenia in ACS. PMID- 25913475 TI - Is routine excision of testicular remnants in testicular regression syndrome indicated? AB - BACKGROUND: Undescended testicles are a common finding in full-term male infants. In the majority of these infants, the testicle spontaneously descends in the first year of life. However, in others, it remains impalpable in an abnormal position or there may only be a small abnormal testicular remnant present. For these infants there is still controversy surrounding inguinal exploration and/or excision of these testicular remnants at the time of operative intervention. The controversy centres on their potential future malignant potential. AIM: The aim of the study was to ascertain the incidence of the presence of either germ cells (GCs) or seminiferous tubules (SNTS) in the excised testicular remnants. This was performed at a paediatric surgical tertiary centre and contributes to the evidence base for this condition. METHOD: A retrospective data analysis occurring over a 15-year period of all excised testicular remnants. The testicular remnants were analysed for age, laterality, histological analysis and clinical diagnosis. Subset analysis included subdivision into both intra-abdominal or inguinal positions, and age ranges. Statistical analysis was using Fisher's exact test and a P-value of <0.05 was considered to be significant. RESULTS: A total of 140 paediatric male patients were identified as having had a testicular remnant excised during the study period. Their demographics and also the main results are summarised in the overall summary Table. The mean age at intervention was 3.5 years (range: 3 months to 17 years). A total of 132/140 of the boys underwent excision of an inguinal testicular regression syndrome (TRS) remnant and 8/140 an intra-abdominal remnant. Comparison of these two groups revealed no significant difference for the presence of GCs (12 (9%) vs 2 (25%), P = 0.18). However, intra abdominal TRS remnants were much more likely to contain SNTs (27 (21%) vs 7 (88%), P = 0.0002). There was no decreased incidence of either GCs or SNTs with increased patient age. DISCUSSION: The main reason for the debate over the management of boys with TRS is the variable incidence of viable germ cells reported in different studies: it has been reported between 0 and 16%. The incidence of GCs (10%) and also SNT (24%) in the present series therefore contributes to this evidence base and is in the middle of this range. It is still unclear as to whether these remnants have a future malignancy risk, as there is only one case of intratubular germ cell neoplasia (ITGCN) in a testicular remnant reported in the literature and this was not immunohistochemically supported. The presence of ITGCN, although considered as a precursor to the development of a testicular germ cell tumour in adult patients, has also not been established in paediatric patients. The natural history of the GCs in TRS specimens is also unknown. In the present series, however, there was no decreased incidence demonstrated with increased patient age, although older patient numbers limited this subset analysis. Despite this controversy, as these patients were already under general anaesthetic, an inguinal exploration and excision of any TRS remnant that was present did not significantly increase the operative procedure or time, and removed any potential malignancy risk. CONCLUSION: This evidence supports the exploration and excision of inguinal testicular remnants, as one in ten boys have GCs present and one in four have SNTs, which may have a potential future malignant transformation risk. PMID- 25913476 TI - Role of PTEN in neutrophil extracellular trap formation. AB - NETosis has been associated with a particular mode of cell death although it is still controversial as to what extent autophagy is involved in NETosis. Class I/AKT/mTOR pathway is a key regulator of autophagy. PTEN tumor suppressor gene encodes a dual specificity phosphatase that antagonizes the phosphatidylinositol 3-kinase in class the I/AKT/mTOR pathway. In this study, we investigated the effects of PTEN down-regulation as well as overexpression on NETosis. Our results show that 35% of HL-60 differentiated neutrophil-like cells generated NETs by PMA. The portion of the population that produced NETs in PTEN knockdown HL-60 differentiated neutrophils was 9% and in PTEN overexpressed HL-60 differentiated neutrophils, it was 56%. Our results show that increasing PTEN expression increases NETs formation in neutrophils, and its suppression reduces NETs. PMID- 25913477 TI - Perturbation of the intestinal microbiota of mice infected with Cryptosporidium parvum. AB - Understanding the interaction between the intestinal microbiota (microbiome) and enteric pathogens is of interest in the development of alternative treatments that do not rely on chemotherapy and do not lead to drug resistance. We undertook research in a rodent model of cryptosporidiosis to assess whether the bacterial gut microbiota is impacted by infection with the protozoan pathogen Cryptosporidium parvum. The profile of the faecal bacterial microbiota in infected and uninfected animals was compared using 16S amplicon sequencing. In four independent experiments, the intestinal microbiota of infected mice differed from that of uninfected animals, regardless of the C. parvum isolate used to infect mice. The use of replicated treatment groups demonstrated that microbiota divergence between treatments was driven by the infection and did not result from spontaneous changes in the intestinal ecosystem unrelated to the infection. Microbiota perturbation induced by C. parvum appeared to be reversible, as we observed a tendency for the phylogenetic distance between infected and uninfected mice to diminish after mice cleared the infection. As mice infected with C. parvum do not develop diarrhoea, these observations indicate that microbiota perturbation results from other mechanisms than an accelerated movement of gut content. PMID- 25913478 TI - Laparoscopic Roux-en-Y gastric bypass in obese Korean patients: efficacy and potential adverse events. AB - PURPOSE: This study aimed to evaluate the medium-term efficacy and adverse events of laparoscopic Roux-en-Y gastric bypass (LRYGB) performed at a single center in Korea. METHODS: The records of 412 consecutive patients who underwent LRYGB between January 2011 and February 2014 were retrospectively reviewed. The preoperative demographics, surgical outcomes, and follow-up data including anthropometrics indices and late complications were analyzed. RESULTS: The mean preoperative body mass index was 38.0 +/- 5.8 kg/m(2) and 338 patients (82.0 %) had at least one obesity-related comorbidity. Seven patients (1.7 %) developed severe complications requiring invasive intervention or reoperation. The %EWL of the eligible patients was 63.1, 74.3, 79.2, 65.4, and 89.8 % at 6, 12, 18, 24, and 36 months, respectively. Diabetes was resolved in 63.5 % of the followed up patients. Twenty-two out of 256 patients (8.6 %) with available follow-up data failed to achieve %EWL >=50 % by 12 months after the surgery. The most frequent late complications were marginal ulcers (24.5 %) and anemia (18.0 %). CONCLUSION: LRYGB achieves excellent weight loss and significant short- to medium-term comorbidity resolution in Korean obese patients with acceptable perioperative risks. However, late complications including marginal ulcers and nutritional deficiencies are not negligible. Therefore, regular and lifelong surveillance is mandatory in patients undergoing LRYGB. PMID- 25913479 TI - Improved outcome of pediatric patients with acute megakaryoblastic leukemia in the AML-BFM 04 trial. AB - Despite recent advances in the treatment of children with acute megakaryoblastic leukemia (AMKL) using intensified treatment protocols, clear prognostic indicators, and treatment recommendations for this acute myeloid leukemia (AML) subgroup are yet to be defined. Here, we report the outcome of 97 pediatric patients with de novo AMKL (excluding Down syndrome [DS]) enrolled in the prospective multicenter studies AML-BFM 98 and AML-BFM 04 (1998-2014). AMKL occurred in 7.4 % of pediatric AML cases, at younger age (median 1.44 years) and with lower white blood cell count (mean 16.5 * 10(9)/L) as compared to other AML subgroups. With 60 +/- 5 %, children with AMKL had a lower 5-year overall survival (5-year OS; vs. 68 +/- 1 %, P log rank = 0.038). Yet, we achieved an improved 5-year OS in AML-BFM 04 compared to AML-BFM 98 (70 +/- 6 % vs. 45 +/- 8 %, P log rank = 0.041). Allogeneic hematopoietic stem cell transplantation in first remission did not provide a significant survival benefit (5-year OS 70 +/- 11 % vs. 63 +/- 6 %; P Mantel-Byar = 0.85). Cytogenetic data were available for n = 78 patients. AMKL patients with gain of chromosome 21 had a superior 5-year OS (80 +/- 9 %, P log rank = 0.034), whereas translocation t(1;22)(p13;q13) was associated with an inferior 5-year event-free survival (38 +/- 17 %, P log rank = 0.04). However, multivariate analysis showed that treatment response (bone marrow morphology on day 15 and 28) was the only independent prognostic marker (RR = 4.39; 95 % CI, 1.97-9.78). Interestingly, GATA1-mutations were detected in six patients (11 %) without previously known trisomy 21. Thus, AMKL (excluding DS) remains an AML subgroup with inferior outcome. Nevertheless, with intensive therapy regimens, a steep increase in the survival rates was achieved. PMID- 25913480 TI - Eosinophilic gastroenteritis after allogeneic bone marrow transplantation. PMID- 25913481 TI - Apolipoproteins A1, B, and other prognostic biochemical cardiovascular risk factors in patients with beta-thalassemia major. AB - OBJECTIVES: The occurrence of cardiac iron deposition is one of the late effect of iron over load which causes cardiovascular disease (CVD) in patients who are affected by beta-thalassemia major. Evaluation of some cardiovascular risk factors plays a crucial role in prediction and prevention of CVD. SUBJECTS AND METHODS: This study consisted of 70 young adult subjects with beta-thalassemia major (beta-TM) (aged <30 years) and 71 age- and sex-matched healthy subjects as control group in the range of 20-30 years. Hematological and biochemical laboratory parameters including apolipoprotein (Apo)A1 and ApoB, oxidative stress biomarker pro-oxidant-antioxidant balance (PAB), homocysteine, serum high sensitivity C-reactive protein (hs-CRP), and lipid profile were evaluated. RESULTS: ApoA1, ApoB, lipid profiles, and homocysteine were significantly decreased in patients group (P < 0.001); however, very low-density lipoprotein and also mean corpuscular hemoglobin concentration (P > 0.05) were different. Some elements included ferritin (P < 0.001), PAB (P < 0.001), and ApoB/apoA1 ratio (P < 0.05) statistically increased in patients, whereas hs-CRP (P > 0.05) was not significantly different in study groups. Exception of high-density lipoprotein (P > 0.05), other lipid profiles, and apoB had a negative meaningful correlation with PAB (P < 0.05). Likewise, apoA1, apoB, apoB/A1 ratio with apoB and homocysteine showed a strong correlation (P < 0.05). We did not find a slight correlation between apoB/A1 ratio in the company of oxidative stress marker PAB (r = -0.366; P = 0.086). We found a statistical correlation between apoB/A1 and homocysteine (P < 0.05). DISCUSSION: Higher level of some risk factors like PAB values, apoB/A1 ratio concentration, and lipid profiles is able to involve in the prognostic pathological consequences in patients with beta-thalassemia major. Even so, they contribute toward the gradual development of CVD. PMID- 25913482 TI - Numerically accurate linear response-properties in the configuration-interaction singles (CIS) approximation. AB - In the present work, we report an efficient implementation of configuration interaction singles (CIS) excitation energies and oscillator strengths using the multi-resolution analysis (MRA) framework to address the basis-set convergence of excited state computations. In MRA (ground-state) orbitals, excited states are constructed adaptively guaranteeing an overall precision. Thus not only valence but also, in particular, low-lying Rydberg states can be computed with consistent quality at the basis set limit a priori, or without special treatments, which is demonstrated using a small test set of organic molecules, basis sets, and states. We find that the new implementation of MRA-CIS excitation energy calculations is competitive with conventional LCAO calculations when the basis-set limit of medium-sized molecules is sought, which requires large, diffuse basis sets. This becomes particularly important if accurate calculations of molecular electronic absorption spectra with respect to basis-set incompleteness are required, in which both valence as well as Rydberg excitations can contribute to the molecule's UV/VIS fingerprint. PMID- 25913483 TI - Poor sleep quality is associated with a negative cognitive bias and decreased sustained attention. AB - Poor sleep quality has been demonstrated to diminish cognitive performance, impair psychosocial functioning and alter the perception of stress. At present, however, there is little understanding of how sleep quality affects emotion processing. The aim of the present study was to determine the extent to which sleep quality, measured through the Pittsburg Sleep Quality Index, influences affective symptoms as well as the interaction between stress and performance on an emotional memory test and sustained attention task. To that end, 154 undergraduate students (mean age: 21.27 years, standard deviation = 4.03) completed a series of measures, including the Pittsburg Sleep Quality Index, the Sustained Attention to Response Task, an emotion picture recognition task and affective symptom questionnaires following either a control or physical stress manipulation, the cold pressor test. As sleep quality and psychosocial functioning differ among chronotypes, we also included chronotype and time of day as variables of interest to ensure that the effects of sleep quality on the emotional and non-emotional tasks were not attributed to these related factors. We found that poor sleep quality is related to greater depressive symptoms, anxiety and mood disturbances. While an overall relationship between global Pittsburg Sleep Quality Index score and emotion and attention measures was not supported, poor sleep quality, as an independent component, was associated with better memory for negative stimuli and a deficit in sustained attention to non emotional stimuli. Importantly, these effects were not sensitive to stress, chronotype or time of day. Combined, these results suggest that individuals with poor sleep quality show an increase in affective symptomatology as well as a negative cognitive bias with a concomitant decrease in sustained attention to non emotional stimuli. PMID- 25913484 TI - CTF Challenge: Result summary. AB - Image formation in bright field electron microscopy can be described with the help of the contrast transfer function (CTF). In this work the authors describe the "CTF Estimation Challenge", called by the Madrid Instruct Image Processing Center (I2PC) in collaboration with the National Center for Macromolecular Imaging (NCMI) at Houston. Correcting for the effects of the CTF requires accurate knowledge of the CTF parameters, but these have often been difficult to determine. In this challenge, researchers have had the opportunity to test their ability in estimating some of the key parameters of the electron microscope CTF on a large micrograph data set produced by well-known laboratories on a wide set of experimental conditions. This work presents the first analysis of the results of the CTF Estimation Challenge, including an assessment of the performance of the different software packages under different conditions, so as to identify those areas of research where further developments would be desirable in order to achieve high-resolution structural information. PMID- 25913485 TI - Analysis of flow dynamics in right ventricular outflow tract. AB - BACKGROUND: The mechanism behind early graft failure after right ventricular outflow tract (RVOT) reconstruction is not fully understood. Our aim was to establish a three-dimensional computational fluid dynamics (CFD) model of RVOT to investigate the hemodynamic conditions that may trigger the development of intimal hyperplasia and arteriosclerosis. METHODS: Pressure, flow, and diameter at the RVOT, pulmonary artery (PA), bifurcation of the PA, and left and right PAs were measured in 10 normal pigs with a mean weight of 24.8 +/- 0.78 kg. Data obtained from the experimental scenario were used for CFD simulation of pressure, flow, and shear stress profile from the RVOT to the left and right PAs. RESULTS: Using experimental data, a CFD model was obtained for 2.0 and 2.5-L/min pulsatile inflow profiles. In both velocity profiles, time and space averaged in the low shear stress profile range from 0-6.0 Pa at the pulmonary trunk, its bifurcation, and at the openings of both PAs. These low-shear stress areas were accompanied to high-pressure regions 14.0-20.0 mm Hg (1866.2-2666 Pa). Flow analysis revealed a turbulent flow at the PA bifurcation and ostia of both PAs. CONCLUSIONS: Identified local low-shear stress, high pressure, and turbulent flow correspond to a well-defined trigger pattern for the development of intimal hyperplasia and arteriosclerosis. As such, this real-time three-dimensional CFD model may in the future serve as a tool for the planning of RVOT reconstruction, its analysis, and prediction of outcome. PMID- 25913486 TI - M1 to M2 macrophage polarization in heparin-binding epidermal growth factor-like growth factor therapy for necrotizing enterocolitis. AB - BACKGROUND: Macrophages can be polarized into proinflammatory (M1) and anti inflammatory (M2) subtypes. However, whether macrophage polarization plays a role in necrotizing enterocolitis (NEC) remains unknown. MATERIALS AND METHODS: Macrophages were derived from the THP-1 human monocyte cell line. Apoptosis of human fetal small intestinal epithelial FHs-74 cells was determined by Annexin V/propidium iodide flow cytometry and by Western blotting to detect cleaved caspase-3. The effect of heparin-binding epidermal growth factor-like growth factor (HB-EGF) on macrophage polarization was determined by flow cytometry with M1/M2 markers and real time polymerase chain reaction. In vivo, experimental NEC was induced in mouse pups by repeated exposure to hypoxia, hypothermia, and hypertonic feedings. Intestinal histologic sections were subjected to immunohistochemical staining for the detection of M1 and M2 macrophages. RESULTS: In vitro, FHs-74 cell apoptosis was increased after coculture with macrophages and lipopolysaccharide (LPS). This apoptosis was increased by exposure to M1 conditioned medium and suppressed by exposure to M2-conditioned medium. HB-EGF significantly decreased LPS-induced M1 polarization and promoted M2 polarization via signal transducers and activators of transcription 3 activation. Addition of HB-EGF to LPS-stimulated macrophages suppressed the proapoptotic effects of the macrophages on FHs-74 cells. In vivo, we found enhanced intestinal macrophage infiltration in pups subjected to NEC, most of which were M1 macrophages. HB-EGF treatment of pups subjected to experimental NEC significantly reduced M1 and increased M2 polarization and protected the intestines from NEC. CONCLUSIONS: M1 macrophages promote NEC by increasing intestinal epithelial apoptosis. HB-EGF protects the intestines from NEC by preventing M1 and promoting M2 polarization. PMID- 25913487 TI - Mastectomy skin necrosis after microsurgical breast reconstruction. AB - BACKGROUND: Mastectomy skin necrosis represents a significant clinical morbidity after immediate breast reconstruction. In addition to aesthetic deformity, necrosis of the native mastectomy skin may require debridement, additional reconstruction, or prolonged wound care and potentially delay oncologic treatment. This study aims to evaluate patient and procedural characteristics to identify predictors of mastectomy skin necrosis after microsurgical breast reconstruction. METHODS: A retrospective review was performed of all immediate microsurgical breast reconstructions performed at a single academic center. Patient records were queried for age, diabetes, active smoking, previous breast surgery, preoperative radiation, preoperative chemotherapy, body mass index, mastectomy type, mastectomy weight, flap type, autologous flap type, and postoperative mastectomy skin flap necrosis. RESULTS: There were 746 immediate autologous microsurgical flaps performed by three plastic surgeons at our institution during the study period. The incidence of mastectomy skin flap necrosis was 13.4%. Univariate analysis revealed a significantly higher incidence of mastectomy skin necrosis in patients with higher mastectomy weight (P < 0.001), higher autologous flap weight (P < 0.001), higher body mass index (0.002), and diabetes (P = 0.021). No significant association was found for age, smoking, prior breast surgery, preoperative chemotherapy or radiation, or mastectomy type. Multivariate analysis demonstrated statistically significant associations between mastectomy skin necrosis and both increasing mastectomy weight (odds ratio 1.348 per quartile increase, P = 0.009) and diabetes (odds ratio 2.356, P = 0.011). CONCLUSIONS: Increasing mastectomy weight and coexisting diabetes are significantly associated with postoperative mastectomy skin necrosis after microsurgical reconstruction. These characteristics should be considered during patient counseling, procedure selection, operative planning, and intraoperative tissue viability assessment. PMID- 25913488 TI - Epigallocatechin-3-gallate reduces tubular cell apoptosis in mice with ureteral obstruction. AB - BACKGROUND: Tubular cell apoptosis plays a crucial role in different kinds of renal diseases. Epigallocatechin-3-gallate (EGCG), a polyphenol extracted from green tea, has been shown to inhibit renal fibrosis in unilateral ureteral obstruction (UUO) mice, but its role in preventing tubular cell apoptosis and the underlying signaling mechanisms still remains unclear. MATERIALS AND METHODS: Mice subjected to UUO were intraperitoneally administered EGCG (5 mg/kg) for 14 d. Normal rat kidney proximal tubular epithelial cell line NRK-52E was induced by transforming growth factor beta1 (TGF-beta1). Periodic acid-schiff and Masson's trichrome staining was used for histologic study. TUNEL, Hoechst staining, and flow cytometry analysis were used to measure the apoptotic status of tubular cells. Western blotting was used to determine the expression of apoptotic associated proteins and mitogen-activated protein kinase pathway proteins. RESULTS: EGCG significantly attenuated tubular injury and renal tubulointerstitial fibrosis in the obstructed kidneys of UUO mice. In addition, EGCG prevented UUO and TGF-beta1-induced tubular apoptosis in a dose-dependent manner. In parallel, protein expression of B-clell lymphoma-2 (Bcl-2) was upregulated and protein expressions of Bcl-2 accosiated X protein (Bax), cleaved caspase 3, and cleaved poly ADP-ribose polymerase (PARP) were downregulated by EGCG. Furthermore, UUO and TGF-beta1-stimulated phosphorylation of mitogen activated protein kinase was inhibited by EGCG. CONCLUSIONS: EGCG effectively reduces tubular cell apoptosis induced by UUO and may have potential as a clinical treatment in patients with chronic kidney disease. PMID- 25913489 TI - The Uppsala anatomist Ivar Sandstrom and the parathyroid gland. PMID- 25913490 TI - Cross-priming amplification targeting the coagulase gene for rapid detection of coagulase-positive Staphylococci. AB - AIMS: To develop and evaluate cross-priming amplification (CPA) combined with immuno-blotting for the detection of coagulase-positive Staphylococci including Staphylococcus aureus. METHODS AND RESULTS: Twenty-four sets of cross and detection primers were designed according to four sequences of coagulase gene in Staph. aureus. The most specific primer pair was screened out for the next amplification and interaction. The specificity was evaluated in a total of 53 species of Staph. aureus and non-Staph. aureus. Two red lines indicating positive were always observed on the BioHelix Express strip for 12 subspecies of Staph. aureus. In contrast, only one signal line showing negative results was detected in all of non-Staph. aureus samples. The limit of detection (LOD) of CPA was 3.6 +/- 2.7 fg for the genomic DNA, which is about 100 and 10 times sensitive than those of PCR and loop-mediated isothermal amplification respectively. For the pure culture of Staph. aureus and milk powders, the LODs of CPA were about 1.34 CFU per reaction and 5.2 +/- 3.7 CFU per 100 g of milk powder respectively. The CPA method was also successfully applied to evaluate the contamination of Staph. aureus in 318 samples of daily food. CONCLUSIONS: CPA is a very sensitive and rapid method to detect Staph. aureus by simple laboratory instrument. SIGNIFICANCE AND IMPACT OF THE STUDY: It is the first report on the application of the CPA with immuno-blotting for detection of coagulase-positive Staphylococci including Staph. aureus. PMID- 25913491 TI - Current surgical management of penile cancer. PMID- 25913492 TI - Nocturnal blood pressure in primary open-angle glaucoma. AB - PURPOSE: To evaluate the nocturnal blood pressure (BP) dipping-pattern in patients with manifest primary open-angle glaucoma (POAG) and to find possible associations with the severity of visual field damage. METHODS: A number of 314 patients suffering from POAG were consecutively enrolled in this cross-sectional hospital-based study. Each patient had diurnal intraocular pressure (IOP) measurements, 24-hr BP monitoring and computerized perimetry with the Humphrey 30 2 sita Standard program. Inclusion criteria were a mean IOP of less than 15 mmHg with fluctuations of less than 5 mmHg and a visual acuity of at least 20/40. One eye was randomly selected. Based on the night-day BP ratio, a mean arterial nocturnal BP drop of less than 10% was considered as non-dipping, between 10% and 20% as physiological dipping and of more than 20% as over-dipping. RESULTS: Glaucoma patients with daytime systemic normotension on the average had more visual field loss in the over-dipper group (MD = - 16.6 dB, IQR = -18.9 to -2.7 dB) than glaucoma patients with daytime systemic hypertension, who had less visual field defects in the over-dipper group (MD = -3.9 dB, IQR = -6.2 to -1.9 dB) (p = 0.004). This result was also found taking age, glaucoma duration, visual acuity, gender, systemic and topical medication as covariates into account. CONCLUSIONS: To judge the nocturnal BP situation of an individual patient, it is important to do this in relation to the daytime BP level. Twenty-four-hour BP evaluation might be important for all patients with POAG, as nocturnal BP could be a modifiable risk factor for glaucoma severity and progression. PMID- 25913493 TI - [Infectious complications after surgical splenectomy in children with sickle cell anemia disease]. AB - OBJECTIVE: To evaluate the frequency of infectious complications in children with sickle cell disease (SCD) after surgical splenectomy for acute splenic sequestration crisis. METHODS: Retrospective cohort of children with SCD who were born after 2002 and were regularly monitored until July 2013. Patients were divided into two groups: cases (children with SCD who underwent surgical splenectomy after an episode of splenic sequestration) and controls (children with SCD who did not have splenic sequestration and surgical procedures), in order to compare the frequency of invasive infections (sepsis, meningitis, bacteremia with positive blood cultures, acute chest syndrome and/or pneumonia) by data collected from medical records. Data were analyzed by descriptive statistical analysis. RESULTS: 44 patients were included in the case group. The mean age at the time of splenectomy was 2.6 years (1-6.9 years) and the mean postoperative length of follow-up was 6.1 years (3.8-9.9 years). The control group consisted of 69 patients with a mean age at the initial follow-up visit of 5.6 months (1-49 months) and a mean length of follow-up of 7.2 years (4-10.3 years). All children received pneumococcal conjugate vaccine. No significant difference was observed between groups in relation to infections during the follow-up. CONCLUSIONS: Surgical splenectomy in children with sickle cell disease that had splenic sequestration did not affect the frequency of infectious complications during 6 years of clinical follow-up. PMID- 25913494 TI - [Anthropometric indices to identify metabolic syndrome and hypertriglyceridemic waist phenotype: a comparison between the three stages of adolescence]. AB - OBJECTIVE: To determine the prevalence of metabolic syndrome (MS) and the hypertriglyceridemic waist phenotype (HW) in a representative adolescent sample; as well as to establish which anthropometric indicator better identifies MS and HW, according to gender and adolescent age. METHODS: This cross sectional study had the participation of 800 adolescents (414 girls) from 10-19 years old. Anthropometric indicators (body mass index, waist perimeter, waist/stature ratio, waist/hip ratio, and central/peripheral skinfolds) were determined by standard protocols. For diagnosis of MS, the criteria proposed by de Ferranti et al. (2004) were used. HW was defined by the simultaneous presence of increased waist perimeter (>75th percentile for age and sex) and high triglycerides (>100mg/dL). The ability of anthropometric indicators was evaluated by Receiver Operating Characteristic curve. RESULTS: The prevalence of MS was identical to HW (6.4%), without differences between genders and the adolescence phases. The waist perimeter showed higher area under the curve for the diagnosis of MS, except for boys with 17-19 years old, for whom the waist/stature ratio exhibited better performance. For diagnosing HW, waist perimeter also showed higher area under the curve, except for boys in initial and final phases, in which the waist/stature ratio obtained larger area under the curve. The central/peripheral skinfolds had the lowest area under the curve for the presence of both MS and HW phenotype. CONCLUSIONS: The waist perimeter and the waist/stature showed a better performance to identify MS and HW in both genders and in all three phases of adolescence. PMID- 25913496 TI - Sulfur poisoning of emergent and current electrocatalysts: vulnerability of MoS2, and direct correlation to Pt hydrogen evolution reaction kinetics. AB - The recent surge in interest in the utilisation of transition metal dichalcogenides for the hydrogen evolution reaction (HER), as well as the long standing problem of sulfur poisoning suffered by the established Pt HER electrocatalyst, motivated us to examine the impacts of sulfur poisoning on both emergent and current electrocatalysts. Through a comparative study between MoS2 and Pt/C on the effects of sulfur poisoning, we demonstrate that MoS2 is not invulnerable to poisoning. Additionally, using X-ray photoelectron spectroscopy, correlations have also been established between the atomic percentages of Pt-S bonds and normalised HER parameters e.g. Tafel slope and potential at -10 mA cm( 2). These findings are of high importance for potential hydrogen evolution catalysis. PMID- 25913495 TI - [Noncirrhotic portal hypertension in a human immunodeficiency virus (HIV) infected adolescent]. AB - OBJECTIVE: To alert the pediatrician who is following up HIV-infected patients about the possibility of non-cirrhotic portal hypertension (NCPH) in this period of life, in order to avoid the catastrophic consequences of this disease as bleeding esophageal varices. CASE DESCRIPTION: A 13 years old HIV-infected patient by vertical route was receiving didanosine (ddI) for 12 years. Although the HIV viral load had been undetectable for 12 years, this patient showed gradual decrease of CD4+ T cells, prolonged thrombocytopenia and high alkaline phosphatase. Physical examination detected splenomegaly, which triggered the investigation that led to the diagnosis of severe liver fibrosis by transient elastography, probably due to hepatic toxicity by prolonged use of ddI. COMMENTS: This is the first case of NCPH in HIV-infected adolescent described in Brazil. Although, the NCPH is a rare disease entity in seropositive patients in the pediatric age group, it should be investigated in patients on long-term ddI or presenting clinical and laboratories indicators of portal hypertension, as splenomegaly, thrombocytopenia and increased alkaline phosphatase. PMID- 25913497 TI - Classification of headache. PMID- 25913498 TI - Low-dose SoluMatrix diclofenac in the treatment of osteoarthritis: A 1-year, open label, Phase III safety study. AB - INTRODUCTION: Diclofenac is used for the treatment of osteoarthritis (OA); however, like other nonsteroidal anti-inflammatory drugs (NSAIDs) it can be associated with serious dose-related adverse events (AEs). Low-dose SoluMatrix(r) diclofenac has been developed to provide efficacy at lower diclofenac doses. A recently published Phase III study evaluated the efficacy and safety of SoluMatrix diclofenac 35 mg twice daily (b.i.d.) and thrice daily (t.i.d.) in patients with OA pain treated for 12 weeks. METHODS: This Phase III multicenter, open-label study assessed the safety of SoluMatrix diclofenac in patients with OA dosed up to 52 weeks (ClinicalTrials.gov: NCT01510912). The study enrolled 602 chronic NSAID/acetaminophen users, aged >=40 years with OA of the knee or hip. Patients received SoluMatrix diclofenac 35 mg b.i.d., which could be increased to t.i.d. and subsequently reduced to b.i.d. as needed. Safety assessments included AEs, vital signs, physical examination findings, 12-lead electrocardiogram, and clinical laboratory test results. Patient-reported outcomes were evaluated by the Short Form-36 (SF-36). RESULTS: A total of 601 patients received SoluMatrix diclofenac; 373 of 601 patients (62.1%) received treatment for >=11 months. The most frequent AEs included upper respiratory tract infection, headache, urinary tract infection, diarrhea, nasopharyngitis, and nausea. Serious gastrointestinal, cardiovascular, renal, and hepatic AEs were uncommon. A small proportion (99 patients, 16.5%) of patients discontinued participation in the study due to AEs. Clinically meaningful improvements from baseline in Physical Component Summary Scores of the SF-36 were noted at week 12 and were sustained through week 52. Improvements in six of the eight individual physical and mental SF-36 domains were also noted. CONCLUSION: SoluMatrix diclofenac treatment for up to 1 year was generally well tolerated in patients with OA pain and associated with improvement in quality of life measures. TRIAL REGISTRATION: www.clinicaltrials.gov identifier: NCT01510912. PMID- 25913499 TI - Low-Cost, High-Throughput Sequencing of DNA Assemblies Using a Highly Multiplexed Nextera Process. AB - In recent years, next-generation sequencing (NGS) technology has greatly reduced the cost of sequencing whole genomes, whereas the cost of sequence verification of plasmids via Sanger sequencing has remained high. Consequently, industrial scale strain engineers either limit the number of designs or take short cuts in quality control. Here, we show that over 4000 plasmids can be completely sequenced in one Illumina MiSeq run for less than $3 each (15* coverage), which is a 20-fold reduction over using Sanger sequencing (2* coverage). We reduced the volume of the Nextera tagmentation reaction by 100-fold and developed an automated workflow to prepare thousands of samples for sequencing. We also developed software to track the samples and associated sequence data and to rapidly identify correctly assembled constructs having the fewest defects. As DNA synthesis and assembly become a centralized commodity, this NGS quality control (QC) process will be essential to groups operating high-throughput pipelines for DNA construction. PMID- 25913500 TI - A linear graphene edge nanoelectrode. AB - A nanometer-thick linear graphene edge nanoelectrode was constructed based on the edge plane of chemical vapor deposition (CVD) grown few-layer graphene, which showed much better electrochemical performance compared with traditional carbon fibre microelectrodes. PMID- 25913501 TI - Outbreak of Clostridium difficile Infections at an Outpatient Hemodialysis Facility-Michigan, 2012-2013. AB - Investigation of an outbreak of Clostridium difficile infection (CDI) at a hemodialysis facility revealed evidence that limited intrafacility transmission occurred despite adherence to published infection control standards for dialysis clinics. Outpatient dialysis facilities should consider CDI prevention, including environmental disinfection for C. difficile, when formulating their infection control plans. PMID- 25913502 TI - Pharmacologic Treatment of Common Symptoms in Dialysis Patients: A Narrative Review. AB - End-stage renal disease (ESRD) patients receiving hemodialysis experience a heavy burden of disease-related symptoms, which lead to reduced quality of life. This review focuses on aspects of ESRD-related pharmacokinetics and on efficacy of drugs for treatment of somatic symptoms. Fatigue, pruritus, insomnia, and cramps are the most common symptoms in ESRD, and studies suggest that they are often undertreated. However, few evidence-based guidelines exist to guide therapy in patients received dialysis. In the context of this review, we examine the role of l-Carnitine in the treatment of fatigue and cramps; human growth hormone analog Norditropin and anabolic steroid Nandrolone for the treatment of fatigue; Gabapentin and other agents for the management of pruritis; Vitamin and creatine supplementation in the management of dialysis-associated cramps, and somnambulates in the treatment of dialysis-related insomnia. Treatment decisions should be made in consultation with patients with a full accounting of the potential risks and benefits of these therapies. PMID- 25913503 TI - Children with cerebral palsy effectively modulate postural control to perform a supra-postural task. AB - The purpose of this study was to determine whether signatures of adaptive postural control remain present in children with cerebral palsy (CP) when they performed a supra-postural task (i.e., a task performed above and beyond the control of posture) requiring them to balance a marble inside a tube held in the hands. Measures of center of pressure (COP) dynamics (how regular or predictable were the COP data as quantified by the sample entropy metric) and variability (as quantified by the COP standard deviation) were obtained from a sample of children with CP (n=30) and compared to the same measures taken from typically developing (TD) children. Children with CP demonstrated an apparent inefficiency in postural control (greater irregularity, greater sway variability) relative to TD peers during a quiet-stance (no supra-postural task) condition (p<.05). During supra postural task performance, those differences were attenuated, though they remained statistically different (p<.05). The findings illustrate flexibility and adaptability in the postural control system, despite the pathological features associated with CP. PMID- 25913506 TI - Three sra topological lanthanide-organic frameworks built from 2,2'-dimethoxy 4,4'-biphenyldicarboxylic acid. AB - Three 3D lanthanide-organic frameworks (LOFs), [LnL(HCO2)(DMF)]n (Ln = Eu (1), Gd (2), Dy (3); H2L = 2,2'-dimethoxy-4,4'-biphenyldicarboxylic acid), have been prepared by the solvothermal reaction of Ln(NO3)3.6H2O and H2L in DMF-H2O mixed solvent. Crystallographic data show that LOFs 1-3 are isomorphous and crystallize in the orthorhombic space group Pna21. Each Ln(III) is eight-coordinated to four O atoms from four L2- ligands, one O atom from the DMF molecule and three O atoms from HCO2-. The adjacent Ln(III) ions are linked by the carboxylate groups of the L2- ligands and HCO2- to form a 1D inorganic rod-shaped [Ln(CO2)2(HCO2)]n chain as a secondary building unit (SBU). The infinite 1D chains are interconnected by the biphenyl groups, giving rise to a 3D framework along the c axis. LOFs 1-3 are the first neutral Ln-carboxylate/HCO2- chain-based sra-nets. 1 exhibits characteristic luminescence of Eu3+ upon 343 nm excitation. The investigation of magnetic properties shows very weak ferromagnetic interactions (J = 0.0092(3) cm 1) between Gd(III) ions in 2 with a Gd-O-Gd bridging angle of 125.6(1) degrees , and theta = -1.9(2) K in 3 due to thermal depopulation of the Stark levels of Dy(III) ions and/or the possible antiferromagnetic interactions between Dy(III) ions in contrast to the single-ion behavior observed in 1. PMID- 25913505 TI - Childhood obesity: evidence for distinct early and late environmental determinants a 12-year longitudinal cohort study (EarlyBird 62). AB - BACKGROUND/OBJECTIVE: The prevalence of childhood obesity continues to rise in most countries, but the exposures responsible remain unclear. The shape of the body mass index (BMI) distribution curve defines how a population responds, and can be described by its three parameters-skew (L), median (M) and variance (S). We used LMS analysis to explore differences in the BMI trajectories of contemporary UK children with those of 25 years ago, and to draw inferences on the exposures responsible. SUBJECTS/METHODS: We applied Cole's LMS method to compare the BMI trajectories of 307 UK children (EarlyBird cohort) measured annually from 5-16 years (2000-2012) with those of the BMI data set used to construct the UK 1990 growth centiles, and used group-based trajectory modelling (GBTM) to establish whether categorical trajectories emerged. RESULTS: Gender specific birth weights were normally distributed and similar between both data sets. The skew and variance established by 5 years in the 1990 children remained stable during the remainder of their childhood, but the pattern was different for children 25 years on. The skew at 5 years among the EarlyBird children was greatly exaggerated, and involved selectively the offspring of obese parents, but returned to 1990 levels by puberty. As the skew diminished, so the variance in BMI rose sharply. The median BMI of the EarlyBird children differed little from that of 1990 before puberty, but diverged from it as the variance rose. GBTM uncovered four groups with distinct trajectories, which were related to parental obesity. CONCLUSIONS: There appear to be two distinct environmental interactions with body mass among contemporary children, the one operating selectively according to parental BMI during early childhood, the second more generally in puberty. PMID- 25913504 TI - Interrelationships between obesity, obstructive sleep apnea syndrome and cardiovascular risk in obese adolescents. AB - BACKGROUND/OBJECTIVES: Obstructive sleep apnea syndrome (OSAS) may be a cardiovascular disease (CVD) risk factor independently of obesity in adults. Pediatric studies have associated OSAS with endothelial dysfunction, but few studies have examined relationships between OSAS and macrovascular sequelae. Our objective was to examine OSAS's independent contribution to macrovascular CVD risk measures in obese adolescents. SUBJECTS/METHODS: This cross-sectional observational study was conducted at Children's Hospital of Philadelphia Clinical Research and Academic Sleep Centers, and University of Pennsylvania Vascular Research Unit. Thirty-one obese non-diabetic adolescents underwent anthropometric measurements, overnight polysomnography, fasting laboratory draw and cardiovascular imaging. Cardiovascular outcome measures included maximal carotid intima-media thickness (cIMTmax), a measure of carotid structural changes, and carotid-femoral pulse wave velocity (CFPWV), an aortic stiffness measure whose relationship vis-a-vis OSAS in children has not been previously examined. Carotid diameter and augmentation index (AIx, measuring central pressure augmentation from wave reflections) were assessed. Potential confounding variables examined included blood pressure, lipoproteins, high-sensitivity C-reactive protein, insulin and glucose. RESULTS: The apnea hypopnea index, a primary OSAS measure, was not associated with cIMTmax, carotid diameter, CFPWV or AIx. body mass index (BMI) associated positively with cIMTmax (r=0.52, P=0.006) and CFPWV (r=0.45, P=0.01). Mean asleep end-tidal CO2 was negatively associated with carotid diameter (r=-0.63, P<0.0005). Insulin levels were negatively associated with AIx (r=-0.53, P=0.02). CONCLUSIONS: OSAS did not predict carotid structural changes or arterial stiffness independently of BMI in obese adolescents. Higher insulin levels associated with lower central pressure wave augmentation. Finally, long term hypercapnia may predispose to carotid narrowing. PMID- 25913507 TI - Impact of the 2013 American Society of Clinical Oncology/College of American Pathologists guideline recommendations for human epidermal growth factor receptor 2 (HER2) testing of invasive breast carcinoma: a focus on tumours assessed as 'equivocal' for HER2 gene amplification by fluorescence in-situ hybridization. AB - AIMS: The updated 2013 American Society of Clinical Oncology/College of American Pathologists (ASCO/CAP) human epidermal growth factor receptor 2 (HER2) testing guidelines include changes to HER2 in-situ hybridization (ISH) interpretation criteria. We conducted a retrospective review of a consecutive cohort of primary breast carcinomas to assess the impact of updated guidelines on HER2 classification and laboratory resource utilization, and to characterize the pathobiology of HER2 equivocal tumours. METHODS AND RESULTS: A total of 904 dual probe HER2/chromosome enumeration probe (CEP17) FISH tests on invasive breast carcinomas were studied. Eighty-five (9.4%) cases had a classification change with the updated guidelines; 66 (7.3%) went from HER2-negative to -equivocal, 15 cases (1.7%) were reclassified as HER2-positive and four cases from HER2 equivocal to -negative. A subset of primary breast cancers, reported initially as HER2-negative but -equivocal by 2013 guidelines, was identified. Traditional pathological factors of this subset were compared to HER2-negative and -positive control cases. The three HER2 groups demonstrated statistically significant differences with respect to prognostic factors, including tumour size, grade and nodal involvement. CONCLUSIONS: The updated HER2 testing guidelines will result in the reclassification of approximately 9.4% of primary breast cancers with uncertainty regarding the clinical impact of this reclassification in the majority of cases. Resource utilization will increase as a result of the recommendation for retesting. PMID- 25913508 TI - Nucleotide sequence-homology-independent breakdown of transgenic resistance by more virulent virus strains and a potential solution. AB - Controlling plant viruses by genetic engineering, including the globally important Papaya ringspot virus (PRSV), mainly involves coat protein (CP) gene mediated resistance via post-transcriptional gene silencing (PTGS). However, the breakdown of single- or double-virus resistance in CP-gene-transgenic papaya by more virulent PRSV strains has been noted in repeated field trials. Recombination analysis revealed that the gene silencing suppressor HC-Pro or CP of the virulent PRSV strain 5-19 is responsible for overcoming CP-transgenic resistance in a sequence-homology-independent manner. Transient expression assays using agro infiltration in Nicotiana benthamiana plants indicated that 5-19 HC-Pro exhibits stronger PTGS suppression than the transgene donor strain. To disarm the suppressor from the virulent strain, transgenic papaya lines were generated carrying untranslatable 5-19 HC-Pro, which conferred complete resistance to 5-19 and other geographic PRSV strains. Our study suggested the potential risk of the emergence of more virulent virus strains, spurred by the deployment of CP-gene transgenic crops, and provides a strategy to combat such strains. PMID- 25913509 TI - Impact of JAK2V617F Mutational Status on Phenotypic Features in Essential Thrombocythemia and Primary Myelofibrosis. AB - OBJECTIVE: The JAK2V617F mutation is present in the majority of patients with essential thrombocythemia (ET) and primary myelofibrosis (PMF). The impact of this mutation on disease phenotype in ET and PMF is still a matter of discussion. This study aims to determine whether there are differences in clinical presentation and disease outcome between ET and PMF patients with and without the JAK2V617F mutation. MATERIALS AND METHODS: In this single-center study, a total of 184 consecutive Philadelphia-negative chronic myeloproliferative neoplasms, 107 cases of ET and 77 cases of PMF, were genotyped for JAK2V617F mutation using the JAK2 Ipsogen MutaScreen assay, which involves allele-specific polymerase chain reaction. RESULTS: ET patients positive for JAK2V617F mutation had higher hemoglobin (Hb) and hematocrit (Hct) levels, lower platelet counts, and more prevalent splenomegaly at diagnosis compared to patients negative for the JAK2V617F mutation, but rates of major thrombotic events, arterial thrombosis, and venous thrombosis were comparable between the groups. At presentation, PMF patients with JAK2V617F mutation had significantly higher Hb and Hct levels and leukocyte counts than patients without the mutation. Similar to the findings of ET patients, thromboembolic rates were similar in PMF patients with and without theJAK2V617F mutation. For ET and PMF patients, no difference was observed in rates of death with respect to JAK2V617F mutational status. Moreover, leukemic transformation rate was not different in our PMF patients with and without JAK2V617F mutation. CONCLUSION: We conclude that JAK2V617F-mutated ET patients express a polycythemia vera-like phenotype and JAK2V617F mutation in PMF patients is associated with a more pronounced myeloproliferative phenotype. PMID- 25913511 TI - Reply: To PMID 25234529. PMID- 25913510 TI - Simultaneous Removal of Third Molars During a Sagittal Split Does Not Increase the Incidence of Bad Splits in Patients Aged 30 Years or Older. AB - PURPOSE: An increasing number of patients who are 30 years old or older have been presenting for orthognathic surgery, some of whom have impacted third molars. The purpose of our report was to review the incidence of bad splits in this age group, both with and without third molars (3Ms). MATERIALS AND METHODS: A retrospective cohort analysis of all patients who had undergone sagittal split osteotomy (SSO) who were 30 years old or older was performed. The inclusion criteria were age 30 years or older and performance of an SSO. Those with incomplete data or who were younger than 30 years old were excluded. A history and radiographic review was performed to find cases with a bad split that had occurred during the surgical procedures. The fractures were correlated with the presence or absence of the lower 3Ms, the degree of impaction of the 3Ms, and patient age and gender. For this aged sample, the variables of 3M presence and gender were analyzed using the Fisher exact test. For patient age, analysis of variance was applied, and for the degree of impaction, the Pearson test was used. All the tests used the level significance of 0.05%. RESULTS: Of the 220 patients who underwent SSO during the study period, 52 were older than 30 years (24%). Of these, 8 patients (15%) had had at least 1 3M present at surgery. Most of the patients had undergone sagittal splits without complications. A total of 3 patients had had bad splits in this sample, 1 of whom had a 3M present at surgery and 2 of whom did not. No association was found between the occurrence of a bad split and the variables studied, including the presence of a 3M (P = .089), degree of impaction (P = .074), age (P = .963), and gender (P = .266). CONCLUSIONS: From the results in this small subset of patients, 3Ms can be removed in patients older than 30 years concomitant with bilateral SSO. PMID- 25913512 TI - The "Origami" Composite Free Fibula Flap for Complex Defects of the Mandible, Floor of the Mouth, and Tongue. AB - PURPOSE: The fibula flap serves as the workhorse for many mandibular defect types. For massive defects that include the mandible, floor of the mouth, and tongue, reconstruction might mandate a 2-flap approach. This report describes a systematic yet flexible design of a single composite osseocutaneous fibula flap for such cases. PATIENTS AND METHODS: From 2003 through 2011, 5 patients underwent surgery for T4 squamous cell carcinoma and adenoid cystic carcinoma. They underwent wide resection of the mandible and floor of the mouth with hemi- to subtotal glossectomy. A large skin paddle was designed on the leg using a customized template consisting of 3 components matching the alveolar, floor-of mouth, and tongue segments. The round tongue component was folded using its thickness to provide 3-dimensional volume and form in place of the missing tongue. The other 2 components had a crescent shape and were adjusted intraoperatively to match the resected defect. RESULTS: All 5 flaps survived, with 1 case of flap loss that was successfully replaced. Delayed healing of the leg donor site was encountered in 4 patients. CONCLUSION: The proposed single 3 dimensionally folded flap design provides ample tissue to replace bony and soft tissue elements for major anterior or lateral segment defects. There was morbidity owing to donor-site complications but these were treatable, with recorded functional restoration. PMID- 25913513 TI - Full-Arch Rehabilitation of a Patient With Cyclic Neutropenia. AB - The purpose of this report is to discuss the treatment of a patient with cyclic neutropenia. This patient presented with flared teeth, thin alveolar bone, and mobile teeth. A staged approach was used to remove her teeth, augment the bone, use immediate fixed provisional to determine the type of final prostheses, and ultimately to use cone-shaped overdenture attachments to retain her final prostheses. The result was rehabilitation of the patient with esthetic full-arch fixed-removable dentures with no adverse sequelae in this patient with this systemic disease. PMID- 25913514 TI - Percutaneous Treatment of Large Venous Malformations in the Oral and Maxillofacial Regions Using Electrochemical Therapy Combined With Pingyangmycin. AB - PURPOSE: The aim of the present study was to evaluate the therapeutic outcome of using electrochemical therapy (ECT) combined with a sclerosing agent, pingyangmycin (bleomycin A5 hydrochloride; PYM), for large (>3 cm in diameter) venous malformations (VMs) in the oral and maxillofacial regions. PATIENTS AND METHODS: Thirty-five patients (15 male and 20 female; age range, 10 to 69 yr; mean age, 32 yr) with large VMs in the oral and maxillofacial region were treated with a combination of ECT and PYM under general anesthesia in the authors' department from June 2012 through May 2014. The size of the lesions varied from 3 * 3 to 12 * 15 cm. A repeated course of ECT and PYM was administered for larger VMs. The therapeutic interval was 3 months for ECT and 2 to 4 weeks for PYM. The dose of PYM for patients was 8 mg each time, and the injection concentration of PYM was 1.6 mg/mL. Patients were followed for 6 to 36 months. Therapeutic results were evaluated by clinical examination and Doppler ultrasonography before and after treatment. RESULTS: Of the 35 patients, 29 (82.9%) received 1 ECT treatment, 5 (14.3%) received 2 ECT treatments, and 1 (2.8%) received 3 ECT treatments. The number of PYM injection sessions was 1 to 5 (average, 2.5 times). According to the therapeutic criteria, the clinical outcome was excellent in 22 patients (62.9%), good in 10 patients (28.6%), and fair in 3 patients (8.5%). All patients (100%) had local swelling postoperatively that lasted approximately 1 to 2 weeks. Two patients (5.7%) had fever. No skin necrosis or nerve damage was found. CONCLUSIONS: Percutaneous treatment using ECT and PYM was a straightforward, safe, and reliable treatment modality for large VMs. PMID- 25913515 TI - Two less common human microRNAs miR-875 and miR-3144 target a conserved site of E6 oncogene in most high-risk human papillomavirus subtypes. AB - Human papillomaviruses (HPVs) including high-risk (HR) and low-risk (LR) subtypes have distinguishable variation on both genotypes and phenotypes. The co-infection of multiple HR-HPVs, headed by HPV16, is common in cervical cancer in female. Recently accumulating reports have focused on the interaction between virus and host, particularly the role of human microRNAs (miRNAs) in anti-viral defense by targeting viral genome. Here, we found a well-conserved target site of miRNAs in the genomes of most HR-HPVs, not LR-HPVs, by scanning all potential target sites of human miRNAs on 24 HPVs of unambiguous subtypes of risk. The site is targeted by two less common human miRNAs, miR-875 and miR-3144, and is located in E6 oncogene open reading frame (ORF) and overlap with the first alternative splice exon of viral early transcripts. In validation tests, miR-875 and miR-3144 were identified to suppress the target reporter activity markedly and inhibit the expression of both synthetically exogenous E6 and endogenous E6 oncogene. High level of two miRNAs can inhibit cell growth and promote apoptosis in HPV16 positive cervical cancer cells. This study provides a promising common target of miRNAs for most HR-HPVs and highlights the effects of two low expressed human miRNAs on tumour suppression. PMID- 25913516 TI - Age-related trends in vertebral dimensions. AB - Several studies have demonstrated age-related changes in vertebral dimensions. Vertebral size has been reported to increase among elderly adults, with periosteal apposition resulting in increased cross-sectional area (CSA) of the vertebral corpus combined with reduction in bone mineral density. These changes in CSA are observed to be sex-specific, as the pronounced increase of vertebral CSA is found only in elderly males. However, the reduction in bone mineral density in old age is apparent within both sexes. It is thus hypothesized that higher fracture risk in elderly women is a result of their incapacity to increase vertebral size and thus adapt to bone mineral reduction. In this study, our aim was to explore whether the onset of these changes could be ascribed to specific age intervals and whether the proposed differences between the sexes are as great as previously suggested. To conduct this study we utilized two large early 20th century skeletal collections known as Terry and Bass (n = 181). We also utilized data from two lumbar spine magnetic resonance imaging samples as a modern-day reference (n = 497). Age, sex and ethnicity of all individuals were known. Vertebral CSA was determined by measuring three width and length dimensions from the corpus of the fourth lumbar vertebra (L4). Our results indicate only a moderate association between age and vertebral CSA. This association was observed to be relatively similar in both sexes, and we thus conclude that there is no clear sex-specific compensatory mechanism for age-related bone loss in vertebral size. PMID- 25913517 TI - Hydrogen sulfide and cardioprotection--Mechanistic insights and clinical translatability. AB - Hydrogen sulfide (H2S) has been long recognized as a highly poisonous gas that is rapidly lethal in intoxicating dosage. However, discoveries during the last decade on the endogenous synthesis of H2S in the mammalian system and its protective role in combating cellular necrosis, apoptosis, oxidative stress, inflammation as well as promoting angiogenesis and modulation of mitochondrial respiration in the setting of myocardial ischemia and reperfusion injury have prompted vast interest in the possibility of developing new therapies based around mimicry or facilitation of endogenous H2S for cardioprotection. These observations have inspired rapid development of H2S-releasing drugs in hopes of swift clinical translation in patients with cardiovascular disease. This review will discuss our current understanding of the protective signaling pathways elicited by H2S in the heart with an emphasis on the versatile benefits of this gasotransmitter and its potential for clinical translation in patients with cardiovascular disease. PMID- 25913518 TI - Transcranial magnetic stimulation identifies cortical excitability changes in monosymptomatic nocturnal enuresis. AB - OBJECTIVES: A limited number of electroencephalography (EEG) studies in nocturnal enuresis (NE) have reported cortical dysmaturity. The aim of the present study was to test this notion by examining cortical excitability in subjects with nocturnal enuresis (NE) using transcranial magnetic stimulation (TMS). MATERIAL AND METHODS: We investigated 41 patients with NE meeting the DSM-IV diagnostic criteria for NE, and 18 age- and sex-matched controls. Each subject was assessed clinically regarding frequency, duration of enuresis and Health Survey Measurement. Neurophysiological measures included resting and active motor thresholds (RMT, AMT), motor evoked potentials (MEP) of upper and lower limbs, cortical silent period duration (CSP) and transcallosal inhibition (TCI), in the upper limbs. RESULTS: Patients had a significantly lower Health Survey Measurement score for both physical and mental health components compared to the control group. RMT and AMT of both upper and lower limbs as well as the duration of the CSP and TCI were significantly reduced compared with the control group. There was significant positive correlation between RMT, AMT and Health Survey Measurement scores, especially Social Functioning. CONCLUSION: Patients with nocturnal enuresis are characterized by pathologically increased excitability and reduced inhibitory processing in the motor cortex, which could contribute to the pathogenesis of nocturnal enuresis. PMID- 25913520 TI - Patient experience of expanded-scope-of-practice musculoskeletal physiotherapy in the emergency department: a qualitative study. AB - OBJECTIVE: The increasing number of people presenting to hospital with musculoskeletal conditions places pressure on existing services, and has resulted in expanding the scope of practice of musculoskeletal physiotherapists working in emergency departments (ED). The aim of the present study was to qualitatively explore the perspectives of patients presenting with an isolated musculoskeletal condition seen by a musculoskeletal physiotherapist in the ED of two Australian hospitals situated in contrasting geographical locations. METHODS: Semistructured interviews were conducted with nine participants from a major metropolitan hospital and 16 participants from a remote hospital. Interviews were transcribed, coded and analysed using a thematic approach. RESULTS. The emerging themes from the two datasets were remarkably similar, so the final themes were merged. The major themes were: (1) participants were satisfied with the process and service provided by the physiotherapist; (2) the personal attributes of the physiotherapists were important to participants; (3) participant confidence in the skills and attributes of the physiotherapist made them a suitable alternative to a doctor in these situations; and (4) the timing and efficiency of the physiotherapy service was better than expected and valued. CONCLUSIONS: Participants from both settings described their experience in positive terms, reflecting satisfaction with their management by an expanded scope of practice musculoskeletal physiotherapist. PMID- 25913519 TI - Clinical contraindications to allergen immunotherapy: an EAACI position paper. AB - Clinical indications for allergen immunotherapy (AIT) in respiratory and Hymenoptera venom allergy are well established; however, clinical contraindications to AIT are not always well documented. There are some discrepancies when classifying clinical contraindications for different forms of AIT as 'absolute' or 'relative'. EAACI Task Force on 'Contraindications to AIT' was created to evaluate and review current literature on clinical contraindications, and to update recommendations for both sublingual and subcutaneous AIT for respiratory and venom immunotherapy. An extensive review of the literature was performed on the use of AIT in asthma, autoimmune disorders, malignant neoplasias, cardiovascular diseases, acquired immunodeficiencies and other chronic diseases (including mental disorders), in patients treated with beta-blockers, ACE inhibitors or monoamine oxidase inhibitors, in children under 5 years of age, during pregnancy and in patients with poor compliance. Each topic was addressed by the following three questions: (1) Are there any negative effects of AIT on this concomitant condition/disease? (2) Are more frequent or more severe AIT-related side-effects expected? and (3) Is AIT expected to be less efficacious? The evidence, for the evaluation of these clinical conditions as contraindications, was limited, and most of the conclusions were based on case reports. Based on an extended literature research, recommendations for each medical condition assessed are provided. The final decision on the administration of AIT should be based on individual evaluation of any medical condition and a risk/benefit assessment for each patient. PMID- 25913521 TI - Why Can't This Patient Look Up? Bilateral Vertical Gaze Palsy. AB - We report a case of a patient with profound bilateral vertical gaze palsy resulting from a unilateral thalamic lesion-one of only a handful of such cases ever reported. The patient had significant symptomatic vertical diplopia that was disabling functionally and vocationally. We discuss pathways whereby a unilateral lesion can cause bilateral gaze palsy. We also report on the successful functional and vocational rehabilitation of the patient's vertical diplopia. To our knowledge, this is the first report of successful rehabilitation of a patient with bilateral vertical diplopia due to a central lesion. PMID- 25913522 TI - Oleic acid complex of bovine alpha-lactalbumin induces eryptosis in human and other erythrocytes by a Ca(2+)-independent mechanism. AB - BACKGROUND: Complexes of oleic acid (OA) with milk alpha-lactalbumin, received remarkable attention in view of their selective toxicity towards a spectrum of tumors during the last two decades. OA complexes of some structurally related/unrelated proteins are also tumoricidal. Erythrocytes are among the few differentiated cells that are sensitive and undergo hemolysis when exposed to the complexes. METHODS: The effects of OA complex of bovine alpha-lactalbumin (Bovine Alpha-lactalbumin Made LEthal to Tumor cells, BAMLET) on human, goat and chicken erythrocytes on calcein leakage, phosphatidylserine exposure, morphological changes and hemolysis were studied by confocal microscopy, FACS analysis, scanning electron microscopy and measuring hemoglobin release. RESULTS: Erythrocytes exposed to BAMLET undergo eryptosis-like alterations as revealed by calcein leakage, surface phosphatidylserine exposure and transformation to echinocytes at low concentrations and hemolysis when the concentration of the complex was raised. Ca(2+) was not essential and restricted the alterations when included in the medium. The BAMLET-induced alterations in human erythrocytes were prevented by the cation channel inhibitors, amiloride and BaCl2 but not by inhibitors of thiol proteases, sphingomyelinase and by the antioxidant N-acetyl cysteine. CONCLUSIONS: The work shows for the first time that low concentrations of BAMLET induces eryptosis in erythrocytes by a novel mechanism not requiring Ca(2+) and hemolysis by detergent-like action by the released OA at higher concentrations. GENERAL SIGNIFICANCE: The study points out to the need for a comprehensive evaluation of the toxicity of OA complexes of alpha-lactalbumin and other proteins towards erythrocytes and other differentiated cells before being considered for therapy. PMID- 25913523 TI - Auto-immune hypoparathyroidism. PMID- 25913524 TI - Benefits and place of calcimimetics in the management of primary hyperparathyroidism. PMID- 25913525 TI - New scintigraphic methods for parathyroid imaging. PMID- 25913526 TI - Multiple hormonal resistances: Diagnosis, evaluation and therapy. AB - Molecular alterations of cAMP-mediated signaling affect primarily the signaling of the PTH/PTHrp receptor, and, with different severities the signaling of other hormones, including TSH. The identification of PTH and other hormonal resistances implies to look for the genetic disorder supporting the metabolic disorder. PMID- 25913527 TI - Snaps and mends: DNA breaks and chromosomal translocations. AB - Integrity in entirety is the preferred state of any organism. The temporal and spatial integrity of the genome ensures continued survival of a cell. DNA breakage is the first step towards creation of chromosomal translocations. In this review, we highlight the factors contributing towards the breakage of chromosomal DNA. It has been well-established that the structure and sequence of DNA play a critical role in selective fragility of the genome. Several non-B-DNA structures such as Z-DNA, cruciform DNA, G-quadruplexes, R loops and triplexes have been implicated in generation of genomic fragility leading to translocations. Similarly, specific sequences targeted by proteins such as Recombination Activating Genes and Activation Induced Cytidine Deaminase are involved in translocations. Processes that ensure the integrity of the genome through repair may lead to persistence of breakage and eventually translocations if their actions are anomalous. An insufficient supply of nucleotides and chromatin architecture may also play a critical role. This review focuses on a range of events with the potential to threaten the genomic integrity of a cell, leading to cancer. PMID- 25913528 TI - Pneumonia and venous thromboembolism: Is the evidence catching up with the guidelines? PMID- 25913529 TI - Faster droplet production by delayed surfactant-addition in two-phase microfluidics to form thermo-sensitive microgels. AB - Microfluidic droplet templating produces monodisperse particles of well controllable sizes, but this is limited by the necessity to operate microfluidic devices at low flow rates in the dripping regime. Here, the per-channel rate of droplet production could be substantially increased by delayed surfactant addition as applied and verified for microfluidic production of N isopropylacrylamide based microgels. PMID- 25913530 TI - Systematic review with meta-analysis: the prevalence of bile acid malabsorption in the irritable bowel syndrome with diarrhoea. AB - BACKGROUND: Irritable bowel syndrome is a widespread disorder with a marked socioeconomic burden. Previous studies support the proposal that a subset of patients with features compatible with diarrhoea-predominant IBS (IBS-D) have bile acid malabsorption (BAM). AIM: To perform a systematic review and meta analysis to assess the prevalence of BAM in patients meeting the accepted criteria for IBS-D. METHODS: MEDLINE and EMBASE were searched up to March 2015. Studies recruiting adults with IBS-D, defined by the Manning, Kruis, Rome I, II or III criteria and which used 23-seleno-25-homotaurocholic acid (SeHCAT) testing for the assessment of BAM were included. BAM was defined as 7 day SeHCAT retention of <10%. We calculated the rate of BAM and 95% confidence intervals (CI) using a random effects model. The methodological quality of included studies was evaluated using the Quality Assessment for Diagnostic Accuracy Studies (QUADAS-2). RESULTS: The search strategy identified six relevant studies comprising 908 individuals. The rate of BAM ranged from 16.9% to 35.3%. The pooled rate was 28.1% (95% CI: 22.6-34%). There was significant heterogeneity in effect sizes (Q-test chi(2) = 17.9, P < 0.004; I(2) = 72.1%). The type of diagnostic criteria used or study country did not significantly modify the effect. CONCLUSIONS: These data provide evidence that in excess of one quarter of patients meeting accepted criteria for IBS-D have bile acid malabsorption. This distinction has implications for the interpretation of previous studies, as well as contemporaneous clinical practice and future guideline development. PMID- 25913531 TI - Nurses' perspectives of the impact of the older person on nursing resources in the emergency department and their profile: A mixed methods study. AB - BACKGROUND: Nurses provide the majority of care in the ED, so increases in the number of older people (>=60 years) may impact nursing workload and provision of care. AIM: To determine whom, of older people, emergency nurses perceive as using the most nursing resources and to profile this subgroup from the ED dataset, including illustrative cases. METHOD: A mixed-methods design study in a metropolitan hospital. Data were collected from focus group interviews with emergency nursing staff (n = 27), from the patient dataset for the corresponding year, and an audit of 13 patients' medical records. RESULTS: Emergency nurses perceived that the highest demand for their resources came from the older persons representing multiple times in short timeframes (cluster presenter). Cluster presenters had a longer length of stay and required intensive nursing time and vigilance because they had one or more chronic illnesses and comorbid conditions such as limited mobility and dementia. Cluster presenters had to have a full assessment each presentation, were usually admitted to the hospital and admitting specialists were reluctant to assume care. CONCLUSION: Emergency nurses associate a high workload with cluster presenters for reasons including ED processes and availability of expertise. Further research should examine more objectively and precisely nursing workload in this area. PMID- 25913532 TI - CT and MRI findings for Brunner's gland hamartoma: report of three cases. AB - Brunner's gland hamartoma (BGH) is an uncommon, benign, tumor-like lesion of the duodenum. Endoscopic diagnosis of larger BGH is sometimes difficult. We describe computed tomography (CT) and magnetic resonance imaging (MRI) findings for three patients with BGH. In all three cases, CT and MRI revealed internal cystic changes within the mass and a stalk originating in the duodenal bulb. These findings may be useful for diagnosis of BGH. PMID- 25913533 TI - A phase II, multicenter, open-label, 3-cohort trial evaluating the efficacy and safety of vismodegib in operable basal cell carcinoma. AB - BACKGROUND: Vismodegib is approved for treatment of advanced basal cell carcinoma. OBJECTIVE: We sought to characterize vismodegib efficacy and safety in operable basal cell carcinoma. METHODS: Patients with new, operable, nodular basal cell carcinoma received vismodegib (150 mg/d) followed by excision and Mohs micrographic surgery to ensure clear margins. Cohort 1 received vismodegib for 12 weeks; cohort 2 received vismodegib for 12 weeks, then 24 weeks of observation before excision; and cohort 3 received vismodegib for 8 weeks on/4 weeks off/8 weeks on. RESULTS: In all, 24 patients enrolled in cohort 1, and 25 in cohorts 2 and 3. Complete histologic clearance was achieved by 42%, 16%, and 44% of patients in cohorts 1, 2, and 3, respectively. Muscle spasms (76%), alopecia (58%), and dysgeusia (50%) were the most frequent adverse events (AEs). Five (7%) patients discontinued treatment because of an AE. AE reversibility was evaluated in cohort 2 with 24 weeks of observation after treatment discontinuation. LIMITATIONS: Nonrandomized, small cohort sizes, and short observation durations for some patients are limitations. CONCLUSION: Primary efficacy end points were not met (predefined complete histologic clearance rate: >50% in cohorts 1 and 3; >30% in cohort 2). Safety was comparable when dosed continuously versus intermittently. Posttreatment reversibility of vismodegib-related AEs was demonstrated. PMID- 25913534 TI - Characterisation of clinical meticillin-resistant Staphylococcus epidermidis demonstrating high levels of linezolid resistance (>256 MUg/ml) resulting from transmissible and mutational mechanisms. AB - Staphylococcus epidermidis (S. epidermidis), one of the leading etiological agents of nosocomial infections poses a significant economic burden globally. Introduced in 2000, linezolid (LZD) has become an important antibiotic, used in nearly seventy countries worldwide to treat infections caused by Gram-positive pathogens such as meticillin-resistant Staphylococcus and Streptococcus species along with vancomycin-resistant enterococci. Resistance to LZD in clinical settings remains rare. Here, we report the emergence of meticillin resistant S. epidermidis (MRSE) clinical isolates from two voluntary general acute hospitals exhibiting higher than typically reported levels of LZD resistance (MIC>256 MUg/ml). The MRSE ST-2 clone isolated from eight patients (2010-2011) not only possessed resistance-conferring mutations such as G2576T in domain V of 23S rRNA gene (as determined by HRM-PCR analysis) and R172C substitution in the ribosomal protein L3, but also carried the cfr gene (the only known transmissible mechanism of LZD resistance). All isolates possessed several key biofilm-associated genes (such as icaA, icaD, aap and atlE) and resistance to multiple clinically significant antibiotics was recorded. This study reports the earliest incidence (2010) of clinical MRSE in the Republic of Ireland demonstrating multiple LZD resistance mechanisms both mutational and potentially transmissible, and characterises this emerging resistance from a molecular perspective. PMID- 25913535 TI - Abiotic soil changes induced by engineered nanomaterials: A critical review. AB - A large number of research papers on the fate of engineered nanomaterials (ENMs) in the soil-water system have appeared in recent years, focusing on ENM transport, persistence and toxicological impact. It is clear from these publications that soil is a major sink for ENMs, and that only a small portion degrades or is mobilized further into groundwater. However, to date, very few studies have examined the impact of ENMs on the natural soil-subsurface matrix and its properties. Moreover, it is now well accepted that chemical contaminants are capable of changing soil properties either by inducing direct chemical or physical changes, or through indirect changes by, e.g., influencing biological activity that in turn modifies soil properties. Here, we review studies on the deposition, retention, and accumulation of ENMs in soil, indicative of the extent to which soil acts as a major sink of ENMs. We then examine evidence of how these retained particles lead to modification of surface properties, which are manifested by changes in the sorption capacity of soil for other (organic and inorganic) solutes, and by surface charges and composition different than the natural surfaces. Finally, we demonstrate how this results in physical and hydrological changes to soil properties, including hydraulic conductivity, swelling capacity and wettability. The overall picture revealed in this critical review sheds light on a perspective that has received little attention thus far. These aspects of soil change, due to exposure and subsequent accumulation of ENMs, may ultimately prove to be one of the most important impacts of ENM releases to the environment. PMID- 25913537 TI - Effect of Light-Activated Tooth Whitening on Color Change Relative to Color of Artificially Stained Teeth. AB - PURPOSE: There is still controversy as to the efficacy of light activation used in tooth whitening. The purpose of this study was to evaluate the effect of light activation on tooth color change relative to the artificial dye color. MATERIALS AND METHODS: Extracted human third molars (160) were randomly distributed into eight groups of 20 specimens each based on artificial staining and use of light activation. All groups received three 45-minute sessions of in-office whitening at 3-day intervals. Color measurements were performed with an intraoral spectrophotometer at baseline prior to staining (T0), after artificial staining (T1), 1-day--(T2), and 1-week--(T3) post-whitening. Color differences were calculated relative to after artificial staining color parameters (L*1, a*1, b*1) with the use of a software analysis program enabling synchronization of two images. RESULTS: Within the same staining groups, the light-activated samples exhibited a greater color change than their nonlight-activated counterparts. However, only in the case of the yellow-stained samples at 1-day post-whitening was there a significant difference between the nonlight-activated and light activated groups (Tukey's post hoc multiple comparison test for pairwise comparisons, p < 0.05). CONCLUSIONS: Light activation is a valid method for enhancing the efficacy of tooth whitening with respect to overall color change and works best with yellow stains. CLINICAL SIGNIFICANCE: Light activation is a valid method for enhancing the efficacy of tooth whitening with respect to overall color change and works best with yellow stains. PMID- 25913536 TI - Computational characterization of structural dynamics underlying function in active membrane transporters. AB - Active transport of materials across the cellular membrane is one the most fundamental processes in biology. In order to accomplish this task, membrane transporters rely on a wide range of conformational changes spanning multiple time and size scales. These molecular events govern key functional aspects in membrane transporters, namely, coordinated gating motions underlying the alternating access mode of operation, and coupling of uphill transport of substrate to various sources of energy, for example, transmembrane electrochemical gradients and ATP binding and hydrolysis. Computational techniques such as molecular dynamics simulations and free energy calculations have equipped us with a powerful repertoire of biophysical tools offering unparalleled spatial and temporal resolutions that can effectively complement experimental methodologies, and therefore help fill the gap of knowledge in understanding the molecular basis of function in membrane transporters. PMID- 25913538 TI - Predictors of depressive disorder following acute coronary syndrome: Results from K-DEPACS and EsDEPACS. AB - INTRODUCTION: Depression is common and associated with poor prognosis in acute coronary syndrome (ACS). There are few reports on the predictors of incident and persistent post-discharge depressive disorders in ACS. This study aimed to investigate the incidence and persistence of depressive disorder over a one year follow-up, and predictors of these outcomes. METHODS: 1152 patients with recently developed ACS were recruited at baseline, and 828 were followed one year thereafter. Depressive disorder (major and minor) was diagnosed according to DSM IV criteria, and analyzed according to baseline prevalence, and follow up incidence and persistence. Of 446 baseline participants with depressive disorders, 300 were randomized to a 24-week double blind trial of escitalopram or placebo, while the remaining 146 received medical treatment as usual. Associations of baseline socio-demographic and clinical characteristics with depressive disorder were investigated using logistic regression models. RESULTS: Two-week prevalence, and one-year incidence and persistence of depressive disorder were 38.7%, 13.1%, and 46.3%, respectively. Baseline depressive disorder was independently associated with female, lower educational level, previous ACS and higher heart rate. Incident depressive disorder was independently predicted by current unemployment, family history of depression, higher baseline Hamilton Depression Rating Scale(HAMD) score and lower left ventricular ejection fraction, and persistent depressive disorder by higher baseline HAMD score and the placebo or medical treatment as usual group in the 24-week trial. LIMITATIONS: The generalizability should be considered since this study conducted in a single center. CONCLUSIONS: Depressive disorder in ACS patients is common and often persistent, and is associated with baseline characteristics and insufficient treatment. Appropriate detection and treatment of depressive disorder are clearly important in ACS patients. PMID- 25913539 TI - Suicidal ideation is associated with reduced prefrontal activation during a verbal fluency task in patients with major depressive disorder. AB - BACKGROUND: Despite the known relationship between prefrontal function and increased suicidality during major depressive episodes, the links between prefrontal function and suicidality remain unclear in major depressive disorder (MDD). Suicidal ideation usually precedes a suicide attempt. If prefrontal cortex (PFC) activity is a biomarker for suicidal ideation in depression, monitoring it could be useful for suicide prevention. Therefore, in this study, we assessed the association between prefrontal function and suicidal ideation in MDD. METHODS: Prefrontal function in 67 patients with MDD (31 with suicidal ideation and 36 without) and 67 age-, gender-, and intelligence quotient-matched healthy controls (HCs) was evaluated using near-infrared spectroscopy (NIRS) during a verbal fluency task (VFT). Suicidal ideation was assessed using item 3 of the Hamilton Depression Rating Scale (HAMD). RESULTS: Regional hemodynamic changes were significantly smaller in patients with MDD than in HCs in prefrontal and temporal regions. Hemodynamic changes in the right dorsolateral PFC (DLPFC), orbitofrontal cortex (OFC), and right frontopolar cortex (FPC) regions in patients with MDD with suicidal ideation were significantly smaller than in those without suicidal ideation. In addition, hemodynamic changes correlated negatively with the severity of suicidal ideation in the DLPFC, OFC, and FPC in patients with MDD. LIMITATIONS: Further studies with a larger sample size are required to verify our findings. CONCLUSIONS: These results suggest that the DLPFC, OFC, and FPC are brain substrates of suicidal ideation in depressive states in patients with MDD, and that NIRS data can be employed as a clinically useful biomarker for the assessment of suicide risk. PMID- 25913540 TI - Can Alzheimer patients receive information without using it? PMID- 25913541 TI - Hypothesis about an existent biomechanical cause-effect relationship between Scheuermann's kyphosis and scoliosis. AB - Scheuermanns kyphosis is usually observed with a mild idiopathic scoliosis, and there is parity between these two diseases. The aim of this work is to establish a hypothesis about the existence of a biomechanical causal relationship between Scheuermann's kyphosis and scoliosis. To achieve this, a literature review was conducted. A simple mechanical model of the passive thoracolumbar subsystem was created to support part of the discussion. This mechanical model describes the passive thoracolumbar subsystem under ideal conditions of equilibrium. After giving consideration to the system under these conditions, some of the geometrical changes that may be found in Scheuermanns kyphosis are considered. Next, this work discusses the evolution of the spine, taking into account its relationship with stable equilibrium, which the passive subsystem tends toward. We hypothesized about the postural response of the body to compensate for possible situations of imbalance. In conclusion, it can be found that a change in the alignment of the spine may occur due to the postural adaptation of the body to an inadequate mechanical situation that may lead to scoliotic deformity of the spine. PMID- 25913542 TI - Modified sitting position for the placement of epidural catheter in parturients. PMID- 25913543 TI - WITHDRAWN: The potential contribution of endocrine disrupting chemicals to acne. AB - This article has been withdrawn at the request of the author(s) and/or editor. The Publisher apologizes for any inconvenience this may cause. The full Elsevier Policy on Article Withdrawal can be found at http://www.elsevier.com/locate/withdrawalpolicy. PMID- 25913544 TI - Adropin as a novel energy factor likely has the ability to regulate blood pressure. PMID- 25913545 TI - Evaluation of an oesophageal Doppler device for monitoring cardiac output in anaesthetised healthy normotensive dogs. AB - OBJECTIVES: To compare cardiac output measured by oesophageal Doppler and by thermodilution monitoring and to correlate the Doppler cardiac output-generated minute distance with thermodilution cardiac output in healthy anaesthetised beagle dogs. MATERIALS AND METHODS: Prospective experimental study. Six healthy adult beagle dogs were pre-medicated with intramuscular acepromazine (0 . 05 mg/kg) and methadone (0 . 3 mg/kg). Anaesthesia was induced with intravenous propofol (dose-effect) and maintained with isoflurane in oxygen. Simultaneously, a constant rate infusion of dopamine (3 ug/kg/minute) was administered to the dogs to prevent hypotension. The minute distance, Doppler and thermodilution cardiac outputs were assessed at three different end-tidal concentrations of isoflurane (1 . 0, 1 . 3 and 2 . 0%). RESULTS: Correlation between Doppler and thermodilution cardiac output (r(2) = 0 . 582) and between minute distance and thermodilution cardiac output (r(2) = 0 . 658) were moderately good, but the limits of agreement between Doppler and thermodilution cardiac outputs were above the recommended values (+/-39%, for a recommended value up to 30%). CLINICAL SIGNIFICANCE: Doppler and minute distance cannot be considered as an alternative method to thermodilution to monitor cardiac output in the healthy anaesthetised dog. PMID- 25913546 TI - The biomechanics of running in athletes with previous hamstring injury: A case control study. AB - Hamstring injury is prevalent with persistently high reinjury rates. We aim to inform hamstring rehabilitation by exploring the electromyographic and kinematic characteristics of running in athletes with previous hamstring injury. Nine elite male Gaelic games athletes who had returned to sport after hamstring injury and eight closely matched controls sprinted while lower limb kinematics and muscle activity of the previously injured biceps femoris, bilateral gluteus maximus, lumbar erector spinae, rectus femoris, and external oblique were recorded. Intergroup comparisons of muscle activation ratios and kinematics were performed. Previously injured athletes demonstrated significantly reduced biceps femoris muscle activation ratios with respect to ipsilateral gluteus maximus (maximum difference -12.5%, P = 0.03), ipsilateral erector spinae (maximum difference 12.5%, P = 0.01), ipsilateral external oblique (maximum difference -23%, P = 0.01), and contralateral rectus femoris (maximum difference -22%, P = 0.02) in the late swing phase. We also detected sagittal asymmetry in hip flexion (maximum 8 degrees , P = 0.01), pelvic tilt (maximum 4 degrees , P = 0.02), and medial rotation of the knee (maximum 6 degrees , P = 0.03) effectively putting the hamstrings in a lengthened position just before heel strike. Previous hamstring injury is associated with altered biceps femoris associated muscle activity and potentially injurious kinematics. These deficits should be considered and addressed during rehabilitation. PMID- 25913547 TI - Size estimates of action-relevant space remain invariant in the face of systematic changes to postural stability and arousal. AB - Perceptual estimates of action-relevant space have been reported to vary dependent on postural stability and concomitant changes in arousal. These findings contribute to current theories proposing that perception may be embodied. However, systematic manipulations to postural stability have not been tested, and a causal relationship between postural stability and perceptual estimates remains to be proven. We manipulated postural stability by asking participants to stand in three differently stable postures on a force plate measuring postural sway. Participants looked at and imagined traversing wooden beams of different widths and then provided perceptual estimates of the beams' widths. They also rated their level of arousal. Manipulation checks revealed that the different postures resulted in systematic differences in body sway. This systematic variation in postural stability was accompanied by significant differences in self-reported arousal. Yet, despite systematic differences in postural stability and levels of arousal perceptual estimates of the beams' widths remained invariant. PMID- 25913548 TI - The influence of the cage environment on rodent physiology and behavior: Implications for reproducibility of pre-clinical rodent research. AB - The reproducibility of pre-clinical research is an important concern that is now being voiced by constituencies that include the National Institutes of Health, the pharmaceutical industry, Congress, the public and the scientific community. An important facet of performing and publishing well-controlled reproducible pre clinical research is to stabilize and more completely define the environment of the animal subjects. Scientists who use rodents in research generally recognize the importance of maintaining a stable animal environment. However, despite a theoretical and general awareness of these issues, many may lack a true appreciation of how significantly even seemingly minor variations in the environment can affect research outcomes. The purpose of this article is to help investigators gain a more comprehensive and substantiated understanding of the potentially significant impact of even seemingly minor environmental changes on the animals and the data. An important caveat to this article is that the examples presented were selected from a very large literature, admittedly in order to illustrate certain points. The goal of this article is not to provide an overview of the entire literature on how the environment affects rodents but rather to make preclinical scientists more aware of how these factors can potentially influence the experimental data and contribute to poor reproducibility of research. PMID- 25913549 TI - A novel eye-tracking method to assess attention allocation in individuals with and without aphasia using a dual-task paradigm. AB - Numerous authors report that people with aphasia have greater difficulty allocating attention than people without neurological disorders. Studying how attention deficits contribute to language deficits is important. However, existing methods for indexing attention allocation in people with aphasia pose serious methodological challenges. Eye-tracking methods have great potential to address such challenges. We developed and assessed the validity of a new dual task method incorporating eye tracking to assess attention allocation. Twenty-six adults with aphasia and 33 control participants completed auditory sentence comprehension and visual search tasks. To test whether the new method validly indexes well-documented patterns in attention allocation, demands were manipulated by varying task complexity in single- and dual-task conditions. Differences in attention allocation were indexed via eye-tracking measures. For all participants significant increases in attention allocation demands were observed from single- to dual-task conditions and from simple to complex stimuli. Individuals with aphasia had greater difficulty allocating attention with greater task demands. Relationships between eye-tracking indices of comprehension during single and dual tasks and standardized testing were examined. Results support the validity of the novel eye-tracking method for assessing attention allocation in people with and without aphasia. Clinical and research implications are discussed. LEARNING OUTCOMES: Readers will be able to: (1) summarize the nature of dual-task paradigms, (2) identify shortcomings of existing dual-task measures of attention allocation for application to people with aphasia, (3) describe how eye-tracking measures may be recorded and analyzed to reflect differences in attention allocation across conditions, and (4) summarize potential clinical applications for eye-tracking measures of attention allocation. PMID- 25913550 TI - Impact of early vs. late disease onset on treatment response to etanercept in patients with psoriasis. PMID- 25913551 TI - Noise pollution and annoyance: an urban soundscapes study. AB - Since 1972, the World Health Organization (WHO) has declared noise as a pollutant. Over the last decades, the quality of the urban environment has attracted the interest of researchers due to the growing urban sprawl, especially in developing countries. The objective of this study was to evaluate the effects of noise exposure in six urban soundscapes: Areas with high and low levels of noise in scenarios of leisure, work, and home. Cross-sectional study. The study was conducted in two steps: Evaluation of noise levels, with the development of noise maps, and health related inquiries. 180 individuals were interviewed, being 60 in each scenario, divided into 30 exposed to high level of noise and 30 to low level. Chi-Square test and Ordered Logistic Regression Model (P < 0,005). 70% of the interviewees reported noticing some source of noise in the selected scenarios and it was observed an association between exposure and perception of some source of noise (P < 0.001). 41.7% of the interviewees reported some degree of annoyance, being that this was associated with exposure (P < 0.001). There was also an association between exposure in different scenarios and reports of poor quality of sleep (P < 0.001). In the scenarios of work and home, the chance of reporting annoyance increased when compared with the scenario of leisure. We conclude that the use of this sort of assessment may clarify the relationship between urban noise exposure and health. PMID- 25913552 TI - Farm and rural adolescents' perspective on hearing conservation: reports from a focus group study. AB - This study explored the attitudes, beliefs, and behaviors of rural and farm adolescents regarding hearing conservation strategies. This qualitative study took place at two high schools in rural Michigan. Twenty-five adolescents living and working on farms or living in rural areas participated in one of two focus groups. Interviews were audio-recorded and transcribed verbatim. Transcripts were coded and analyzed by two researchers and checked by an additional researcher to ensure reliability. Noise exposure was ubiquitous among participants, both in farm-related (e.g., equipment, livestock) and non-farm-related (e.g., music, firearms) activities. Perceived barriers to use of hearing protection devices outweighed perceived benefits, resulting in uncommon use of protection. When hearing protection was used, it was usually earmuffs or earplugs. Participants indicated a lack of training in noise hazards and protective strategies. Despite their acknowledged risk of hearing loss, participants did not associate their use of hearing protection today with their hearing ability later in life. Categories emerging that relate to hearing protector use included: Barriers, benefits, self efficacy, situational influences, impersonal influences, cues to action, susceptibility, and severity. Farm and rural adolescents are at risk for noise exposure and hearing loss. The findings stress the significance of work environment and adult modeling in facilitating hearing conservation behaviors. As indicated by the youths' recommendations, school-based interventions may be an effective approach to address this health concern. Intervention studies are needed to test various approaches that can effectively promote use of hearing conservation strategies among rural and farm adolescents. PMID- 25913553 TI - Noise stress changes mRNA expressions of corticotropin-releasing hormone, its receptors in amygdala, and anxiety-related behaviors. AB - Noise is a psychological, environmental stressor that activates limbic sites in the brain. Limbic sites such as the amygdala and the amygdaloid corticotropin releasing hormone (CRH) system play an important role in integrating stress response. We investigated the association between noise exposures, CRH-related molecules in the amygdala, and behavioral alterations. In total 54 Sprague-Dawley rats were divided into the following three groups: Control (CON), acute noise exposure (ANE), and chronic noise exposure (CNE). The ANE group was exposed to 100 dB white noise only once in 4 h and the CNE group was exposed to the same for 4 h per day for 30 days. Expression profiles of CRH and its receptors CRH-R1 and CRH-R2 were analyzed by quantitative real-time polymerase chain reaction (qPCR). The same stress procedure was applied to the ANE and CNE groups for behavior testing. The anxiety responses of the animals after acute and chronic stress exposure were measured in the defensive withdrawal test. CNE upregulated CRH and CRH-R1 mRNA levels but downregulated CRH-R2 mRNA levels. ANE led to a decrease in both CRH-R1 and CRH-R2 expression. In the defensive withdrawal test, while the ANE increased, CNE reduced anxiety-like behaviors. The present study shows that the exposure of rats to white noise (100 dB) leads to behavioral alterations and molecule-specific changes in the CRH system. Behavioral alterations can be related to these molecular changes in the amygdala. PMID- 25913554 TI - The impact of road traffic noise on cognitive performance in attention-based tasks depends on noise level even within moderate-level ranges. AB - Little empirical evidence is available regarding the effects of road traffic noise on cognitive performance in adults, although traffic noise can be heard at many offices and home office workplaces. Our study tested the impact of road traffic noise at different levels (50 dB(A), 60 dB(A), 70 dB(A)) on performance in three tasks that differed with respect to their dependency on attentional and storage functions, as follows: The Stroop task, in which performance relied predominantly on attentional functions (e.g., inhibition of automated responses; Experiment 1: n = 24); a non-automated multistage mental arithmetic task calling for both attentional and storage functions (Exp. 2: n = 18); and verbal serial recall, which placed a burden predominantly on storage functions (Experiment 3: n = 18). Better performance was observed during moderate road traffic noise at 50 dB(A) compared to loud traffic noise at 70 dB(A) in attention-based tasks (Experiments 1-2). This contrasted with the effects of irrelevant speech (60 dB(A)), which was included in the experiments as a well-explored and common noise source in office settings. A disturbance impact of background speech was only given in the two tasks that called for storage functions (Experiments 2-3). In addition to the performance data, subjective annoyance ratings were collected. Consistent with the level effect of road traffic noise found in the performance data, a moderate road traffic noise at 50 dB(A) was perceived as significantly less annoying than a loud road traffic noise at 70 dB(A), which was found, however, independently of the task at hand. Furthermore, the background sound condition with the highest detrimental performance effect in a task was also rated as most annoying in this task, i.e., traffic noise at 70 dB(A) in the Stroop task, and background speech in the mental arithmetic and serial recall tasks. PMID- 25913555 TI - Exposure to music and noise-induced hearing loss (NIHL) among professional pop/rock/jazz musicians. AB - Noise-induced hearing loss (NIHL) has been extensively studied in industrial work environments. With the advent of new technologies, loud music has been increasingly affecting listeners outside of the industrial setting. Most research on the effects of music and hearing loss has focused on classical musicians. The purpose of the current study was to examine the relationship between the amount of experience a professional pop/rock/jazz musician has and objective and subjective variables of the musician's hearing loss. This study also examined professional pop/rock/jazz musicians' use of hearing protection devices in relation to the extent of their exposure to amplified music. Forty-four pop/rock/jazz musicians were interviewed using the Pop/Rock/Jazz Musician's Questionnaire (PRJMQ) in order to obtain self-reported symptoms of tinnitus and hyperacusis. Forty-two of the subjects were also tested for air-conduction hearing thresholds in the frequency range of 1-8 kHz. Results show that the extent of professional pop/rock/jazz musicians' exposure to amplified music was related to both objective and subjective variables of hearing loss: Greater musical experience was positively linked to higher hearing thresholds in the frequency range of 3-6 kHz and to the subjective symptom of tinnitus. Weekly hours playing were found to have a greater effect on hearing loss in comparison to years playing. Use of hearing protection was not linked to the extent of exposure to amplified music. It is recommended that further research be conducted with a larger sample, in order to gain a greater understanding of the detrimental effects of hours playing versus years playing. PMID- 25913556 TI - Elucidating the relationship between noise sensitivity and personality. AB - Sensitivity to unwanted sounds is common in general and clinical populations. Noise sensitivity refers to physiological and psychological internal states of an individual that increase the degree of reactivity to noise in general. The current study investigated the relationship between the Big Five personality dimensions and noise sensitivity using the 240-item NEO Personality Inventory (NEO-PI) and 35-item The Noise-Sensitivity-Questionnaire (NoiSeQ) scales, respectively. Overall, the Big Five accounted for 33% of the variance in noise sensitivity, with the Introversion-Extroversion dimension explaining the most variability. Furthermore, the Big Five personality dimensions (neuroticism, extroversion, openness, agreeableness, and conscientiousness) had an independent effect on noise sensitivity, which were linear. However, additional analyses indicated that the influence of gender and age must be considered when examining the relationship between personality and noise sensitivity. The findings caution against pooling data across genders, not controlling for age, and using personality dimensions in isolation. PMID- 25913557 TI - Comment on "Concerns with amplitude variation in calibrated audiometer systems in clinical simulations". PMID- 25913558 TI - Joining hands with World Health Organization initiative make listening safe. PMID- 25913559 TI - Proton transfer in ionic and neutral reverse micelles. AB - Proton-transfer kinetics in both ionic and neutral reverse micelles were studied by time-correlated single-photon counting investigations of the fluorescent photoacid 8-hydroxypyrene-1,3,6-trisulfonate (HPTS). Orientational dynamics of dissolved probe molecules in the water pools of the reverse micelles were also investigated by time-dependent fluorescence anisotropy measurements of MPTS, the methoxy derivative of HPTS. These experiments were compared to the same experiments in bulk water. It was found that in ionic reverse micelles (surfactant Aerosol OT, AOT), orientational motion (fluorescence anisotropy decay) of MPTS was relatively unhindered, consistent with MPTS being located in the water core of the reverse micelle away from the water-surfactant interface. In nonionic reverse micelles (surfactant Igepal CO-520, Igepal), however, orientational anisotropy displayed a slow multiexponential decay consistent with wobbling-in-a-cone behavior, indicating MPTS is located at the water-surfactant interface. HPTS proton transfer in ionic reverse micelles followed kinetics qualitatively like those in bulk water, albeit slower, with the long-time power law time dependence associated with recombination of the proton with the dissociated photoacid, suggesting a modified diffusion-controlled process. However, the power law exponents in the ionic reverse micelles are smaller (~ 0.55) than that in bulk water (-1.1). In neutral reverse micelles, proton transfer kinetics did not show discernible power law behavior and were best represented by a two-component model with one relatively waterlike population and a population with a faster fluorescence lifetime and negligible proton transfer. We explain the Igepal results on the basis of close association between the probe and the neutral water-surfactant interface, with the probe experiencing a distribution of more and less waterlike environments. In addition, the observation in bulk water of a power law t(-1.1) for diffusion-controlled recombination is in contrast to the theoretical prediction of t(-1.5) and previously reported observations. The difference from prior experimental results is discussed. PMID- 25913560 TI - The Accuracy of a Mechanical Cup Alignment Guide in Total Hip Arthroplasty (THA) Through Direct Anterior and Posterior Approaches Measured with CT-Based Navigation. AB - The purpose of this study was to compare the accuracy of a mechanical cup alignment guide using CT-based navigation between a direct anterior approach (DAA) in both supine and lateral positions and a posterior approach (PA) in the lateral position. A trial cup was placed with a mechanical guide that aimed at 47 degrees of radiographic inclination and 14 degrees of anteversion. The average cup inclination and anteversion were measured using CT-based navigation. The average radiographic anteversion in the DAA supine and lateral group was larger, and that in the PA group was smaller than the target angle. In conclusion, there are no differences in the accuracy or precision of cup angles among the DAA supine, DAA lateral position, and PA groups using a mechanical guide. PMID- 25913561 TI - The Diagnosis of Periprosthetic Joint Infection. AB - Periprosthetic joint infection remains one of the most common failure modes following total hip and total knee arthroplasty. As such, a systematic and cost effective approach to the evaluation and work-up of a patient with a suspected periprosthetic joint infection should be undertaken in every patient with a painful total joint. Although we have many diagnostic tools, a history and physical remain the most important. Many of the current laboratory tests are indirect measure of infection, lack specificity for diagnosis of infection, but serve as sensitive and cost effective screening tools. In addition, a new definition of periprosthetic infection helps to standardize the diagnosis. Biomarkers hold the promise of improved specificity and are becoming increasingly popular as a diagnostic tool. PMID- 25913562 TI - Abstracts from the Society of Academic and Research Surgery (SARS) Annual Meeting, Durham University, UK, 7-8 January 2015. PMID- 25913563 TI - Measuring quality of maternity care. AB - Health-care organisations are required to monitor and measure the quality of their maternity services, but measuring quality is complex, and no universal consensus exists on how best to measure it. Clinical outcomes and process measures that are important to stakeholders should be measured, ideally in standardised sets for benchmarking. Furthermore, a holistic interpretation of quality should also reflect patient experience, ideally integrated with outcome and process measures, into a balanced suite of quality indicators. Dashboards enable reporting of trends in adverse outcomes to stakeholders, staff and patients, and they facilitate targeted quality improvement initiatives. The value of such dashboards is dependent upon high-quality, routinely collected data, subject to robust statistical analysis. Moving forward, we could and should collect a standard, relevant set of quality indicators, from routinely collected data, and present these in a manner that facilitates ongoing quality improvement, both locally and at regional/national levels. PMID- 25913564 TI - Comment on: inhaled antimicrobial therapy--barriers to effective treatment, by J. Weers, inhaled antimicrobial therapy - barriers to effective treatment, Adv. Drug Deliv. Rev. (2015), http://dx.doi.org/10.1016/j.addr.2014.08.013. PMID- 25913565 TI - Comment on: inhaled antimicrobial therapy-Barriers to effective treatment, by J.Weers, Adv. Drug Deliv. Rev. (2014), http://dx.doi.org/ 10.1016/j.addr.2014.08.013. PMID- 25913566 TI - Reply to the comment by Cipolla et al. on: inhaled antimicrobial therapy- barriers to effective treatment, by J. Weers, Adv. Drug Deliv. Rev. (2015), http://dx.doi.org/10.1016/j.addr.2014.08.013. PMID- 25913567 TI - Reply to the comment by de Boer and Hoppentocht on: inhaled antimicrobial therapy - barriers to effective treatment, by J. Weers, Adv. Drug Deliv. Rev. (2015), http://dx.doi.org/10.1016/j.addr.2014.08.013. PMID- 25913568 TI - The impact of maternal characteristics, infant temperament and contextual factors on maternal responsiveness to infant. AB - Postnatal maternal depressive symptoms are consistently associated with impairments in maternal attunement (i.e., maternal responsiveness and bonding). There is a growing body of literature examining the impact of maternal cognitive factors (e.g., rumination) on maternal attunement and mood. However, little research has examined the role of infant temperament and maternal social support in this relationship. This study investigated the hypothesis that rumination would mediate (1) the relationship between depressive symptoms and attunement and (2) the relationship between social support and attunement. We further predicted that infant temperament would moderate these relationships, such that rumination would demonstrate mediating effects on attunement when infant difficult temperament was high, but not low. Two hundred and three mothers completed measures on rumination, depressive symptoms, attunement, perceived social support and infant temperament. Rumination mediated the effect of postnatal maternal depressive mood on maternal self-reported responsiveness to the infant when infants were low, but not high, in negative temperament. When infants had higher negative temperament, there were direct relationships between maternal depressive symptoms, social support and maternal self-reported responsiveness to the infant. This study is limited by its cross-sectional and correlational nature and the use of self-report measures to assess a mother's awareness of her infant needs and behaviours, rather than observational measures of maternal sensitivity. These findings suggest potentially different pathways to poor maternal responsiveness than those expected and provide new evidence about the contexts in which maternal cognitive factors, such as rumination, may impact on the mother-infant relationship. PMID- 25913569 TI - Food-mediated modulation of immunity in a phytophagous insect: An effect of nutrition rather than parasitic contamination. AB - Inherent to the cost of immunity, the immune system itself can exhibit tradeoffs between its arms. Phytophagous insects face a wide range of microbial and eukaryotic parasites, each activating different immune pathways that could compromise the activity of the others. Feeding larvae are primarily exposed to microbes, which growth is controlled by antibiotic secondary metabolites produced by the host plant. The resulting variation in abundance of microbes on plants is expected to differentially stimulate the insect antimicrobial immune defenses. Under the above tradeoff hypothesis, stimulation of the insect antimicrobial defenses is expected to compromise immune activity against eukaryote parasites. In the European grape berry moth, Eupoecilia ambiguella, immune effectors directed towards microbes are negatively correlated to those directed towards eukaryotic parasites among host plants. Here, we hypothesize this relationship is caused by a variable control of the microbial community among host plants by their antibiotic metabolites. To test this hypothesis, we first quantified antimicrobial activity in berries of several grape varieties. We then measured immune defenses of E. ambiguella larvae raised on artificial diets in which we mimicked levels of antimicrobial activity of grape berries using tetracycline to control the abundance of growing microbes. Another group of larvae was raised on artificial diets made of berry extracts only to control for the effect of nutrition. We found that controlling microbe abundance with tetracycline in diets did not explain variation in the immune function whereas the presence of berry extracts did. This suggests that variation in immune defenses of E. ambiguella among grape varieties is caused by nutritional difference among host plants rather than microbe abundance. Further study of the effects of berry compounds on larval immune parameters will be needed to explain the observed tradeoff among immune system components. PMID- 25913570 TI - Conjugated linoleic acid-enriched butter improved memory and up-regulated phospholipase A2 encoding-genes in rat brain tissue. AB - Reduced phospholipase A2 (PLA2) activity has been reported in blood cells and in postmortem brains of patients with Alzheimer disease (AD), and there is evidence that conjugated linoleic acid (CLA) modulates the activity of PLA2 groups in non brain tissues. As CLA isomers were shown to be actively incorporated and metabolized in the brains of rats, we hypothesized that feeding a diet naturally enriched in CLA would affect the activity and expression of Pla 2 -encoding genes in rat brain tissue, with possible implications for memory. To test this hypothesis, Wistar rats were trained for the inhibitory avoidance task and fed a commercial diet (control) or experimental diets containing either low CLA- or CLA enriched butter for 4 weeks. After this period, the rats were tested for memory retrieval and killed for tissue collection. Hippocampal expression of 19 Pla 2 genes was evaluated by qPCR, and activities of PLA2 groups (cPLA2, iPLA2, and sPLA2) were determined by radioenzymatic assay. Rats fed the high CLA diet had increased hippocampal mRNA levels for specific PLA2 isoforms (iPla 2 g6gamma; cPla 2 g4a, sPla 2 g3, sPla 2 g1b, and sPla 2 g12a) and higher enzymatic activity of all PLA2 groups as compared to those fed the control and the low CLA diet. The increment in PLA2 activities correlated significantly with memory enhancement, as assessed by increased latency in the step-down inhibitory avoidance task after 4 weeks of treatment (rs = 0.69 for iPLA2, P < 0.001; rs = 0.81 for cPLA2, P < 0.001; and rs = 0.69 for sPLA2, P < 0.001). In face of the previous reports showing reduced PLA2 activity in AD brains, the present findings suggest that dairy products enriched in cis-9, trans-11 CLA may be useful in the treatment of this disease. PMID- 25913571 TI - Dual-source cardiac computed tomography angiography (CCTA) in the follow-up of cardiac transplant: comparison of image quality and radiation dose using three different imaging protocols. AB - OBJECTIVES: To prospectively evaluate image quality (IQ) and radiation dose of dual-source cardiac computed tomography (CCTA) using different imaging protocols. METHODS: CCTA was performed in 150 patients using the retrospective ECG-gated spiral technique (rECG) the prospective ECG-gated technique (pECG), or the prospective ECG-gated technique with systolic imaging and automated tube voltage selection (pECGsys). IQ was rated using a 16-segment coronary artery model. Techniques were compared for overall IQ, IQ of the large and the small coronary artery segments. Effective dose was used for comparison of radiation dose. RESULTS: Overall IQ and IQ of the large segments showed no differences between the groups. IQ analysis of the small segments showed lowered IQ in pECGsys compared to rECG (p = 0.02), but not to pECG (p = 0.6). Effective dose did not differ significantly between rECG and pECG (p = 0.13), but was significantly lower for pECGsys (p < 0.001 vs. rECG and pECG). CONCLUSION: Radiation dose of dual-source CCTA in heart transplant recipients is significantly reduced by using prospective systolic scanning and automated tube voltage selection, while overall IQ and IQ of the large coronary segments are maintained. IQ appears to be lower compared to retrospective techniques with regard to small coronary segments. KEY POINTS: * Cardiac computed tomography angiography is useful for cardiac allograft vasculopathy assessment. * Despite elevated heart rate, dose reduction in cardiac computed tomography is possible. * Prospective systolic gating and automated tube voltage selection enable 50 % dose reduction. PMID- 25913572 TI - Asymmetric dimethyl-arginine metabolism in a murine model of cigarette smoke mediated lung inflammation. AB - There is increasing evidence that the endogenous nitric oxide synthase (NOS) inhibitor asymmetric dimethyl-arginine (ADMA) is involved in the pathogenesis of chronic lung diseases. One important regulator of this molecule is the ADMA metabolizing enzyme dimethyl-arginine dimethyl-aminohydrolase (DDAH). The objective of this study was to determine whether perturbation of the ADMA-DDAH pathway contributes to lung inflammation following exposure to cigarette smoke (CS). For these studies, wild-type and DDAH transgenic mice were sham or CS exposed. Serum ADMA levels were determined by mass spectrometry. ADMA content and DDAH expression were also visualized in mouse lung tissue by immunohistochemistry. DDAH expression was determined by real-time quantitative PCR (qPCR). Inflammation was assessed by H&E staining and analyses of total cell counts and fluid tumor necrosis factor (TNF)-alpha levels (using ELISA) in lung lavage fluid. NF-kappaB binding activity in mouse lung epithelial (LA-4) cells was assessed by a transcription factor-binding assay. The results indicated that the concentration of serum ADMA was increased following exposure to CS, and this corresponded with increased ADMA content in bronchial epithelial cells in lung tissue. Total lung DDAH expression was significantly decreased in lung tissue and cultured LA-4 cells following CS exposure. Addition of exogenous ADMA increased CSE-mediated NF-kappaB binding activity and TNFalpha production in LA-4 cells more than 2-fold compared to that in CSE-exposed controls. CS-mediated lung inflammation was significantly attenuated in DDAH transgenic mice compared to in wild-type controls. These findings demonstrated that lung ADMA metabolism was altered in mice following CS exposure and suggested that ADMA played a role in CS mediated inflammation through increasing the presence of inflammatory mediators in lung epithelial cells. PMID- 25913573 TI - A case of late-onset riboflavin responsive multiple acyl-CoA dehydrogenase deficiency (MADD) with a novel mutation in ETFDH gene. AB - We report a novel mutation in the electron transfer flavoprotein dehydrogenase (EFTDH) gene in an adolescent Chinese patient with late-onset riboflavin responsive multiple acyl-CoA dehydrogenase deficiency (MADD) characterized by muscle weakness as early symptom. At the age of 9 years, the patient experienced progressive muscle weakness. Blood creatine kinase level and aminotransferase were higher than normal. The muscle biopsy revealed lipid storage myopathy. Serum acylcarnitine and urine organic acid analyses were consistent with MADD. Genetic mutation analysis revealed a compound heterozygous mutation in EFTDH gene. The patients showed good response to riboflavin and l-carnitine treatment. PMID- 25913574 TI - Realization of a p-n junction in a single layer boron-phosphide. AB - Two-dimensional (2D) materials have attracted growing interest due to their potential use in the next generation of nanoelectronic and optoelectronic applications. On the basis of first-principles calculations based on density functional theory, we first investigate the electronic and mechanical properties of single layer boron phosphide (h-BP). Our calculations show that h-BP is a mechanically stable 2D material with a direct band gap of 0.9 eV at the K-point, promising for both electronic and optoelectronic applications. We next investigate the electron transport properties of a p-n junction constructed from single layer boron phosphide (h-BP) using the non-equilibrium Green's function formalism. The n- and p-type doping of BP are achieved by substitutional doping of B with C and P with Si, respectively. C(Si) substitutional doping creates donor (acceptor) states close to the conduction (valence) band edge of BP, which are essential to construct an efficient p-n junction. By modifying the structure and doping concentration, it is possible to tune the electronic and transport properties of the p-n junction which exhibits not only diode characteristics with a large current rectification but also negative differential resistance (NDR). The degree of NDR can be easily tuned via device engineering. PMID- 25913575 TI - The effects of sodium oxybate on core body and skin temperature regulation in narcolepsy. AB - Patients suffering from narcolepsy type 1 show altered skin temperatures, resembling the profile that is related to sleep onset in healthy controls. The aim of the present study is to investigate the effects of sodium oxybate, a widely used drug to treat narcolepsy, on the 24-h profiles of temperature and sleep-wakefulness in patients with narcolepsy and controls. Eight hypocretin deficient male narcolepsy type 1 patients and eight healthy matched controls underwent temperature measurement of core body and proximal and distal skin twice, and the sleep-wake state for 24 h. After the baseline assessment, 2 * 3 g of sodium oxybate was administered for 5 nights, immediately followed by the second assessment. At baseline, daytime core body temperature and proximal skin temperature were significantly lower in patients with narcolepsy (core: 36.8 +/- 0.05 degrees C versus 37.0 +/- 0.05 degrees C, F = 8.31, P = 0.01; proximal: 33.4 +/- 0.26 degrees C versus 34.3 +/- 0.26 degrees C, F = 5.66, P = 0.03). In patients, sodium oxybate administration increased proximal skin temperature during the day (F = 6.46, P = 0.04) to a level similar as in controls, but did not affect core body temperature, distal temperature or distal-proximal temperature gradient. Sodium oxybate administration normalised the predictive value of distal skin temperature and distal-proximal temperature gradient for the onset of daytime naps (P < 0.01). In conclusion, sodium oxybate administration resulted in a partial normalisation of the skin temperature profile, by increasing daytime proximal skin temperature, and by strengthening the known relationship between skin temperature and daytime sleep propensity. These changes seem to be related to the clinical improvement induced by sodium oxybate treatment. A causal relationship is not proven. PMID- 25913577 TI - Proceedings of the Upsala Medical Society: How it all started 150 years ago. PMID- 25913576 TI - Calmodulin of the tropical sea cucumber: Gene structure, inducible expression and contribution to nitric oxide production and pathogen clearance during immune response. AB - Calmodulin (CaM) is an essential second messenger protein that transduces calcium signals by binding calcium ions (Ca(2+)) and modulating its interactions with various target proteins. In contrast to vertebrates, where CaM is well established as a cofactor for Ca(2+)-dependent physiological and cellular functions including host defense, there is a paucity of understanding on CaM in invertebrates (such as echinoderms) in response to immune challenge or microbial infections. In this study, we obtained and described the gene sequence of CaM from the tropical sea cucumber Stichopus monotuberculatus, a promising yet poorly characterized aquacultural species. mRNA expression of StmCaM could be detected in the intestine and coelomic fluid after Vibrio alginolyticus injection. Transcriptional and translational expression of StmCaM was inducible in nature, as evidenced by the expression patterns in primary coelomocytes following Vibrio challenge. This response could be mimicked by the Vibrio cells membrane components or lipopolysaccharides (LPS), and blocked by co-treatment of the LPS neutralizing agent polymyxin B (PMB). Furthermore, inhibition of CaM activity by incubation with its inhibitor trifluoroperazine dihydrochloride (TFP) blunted the production of Vibrio-induced nitric oxide (NO) and augmented the survival of invading Vibrio in coelomocytes. Collectively, our study here supplied the first evidence for echinoderm CaM participation in innate immunity, and provided a functional link between CaM expression and antibacterial NO production in sea cucumber. PMID- 25913578 TI - A meta-analysis of extended versus standard lymphadenectomy in patients undergoing pancreatoduodenectomy for pancreatic adenocarcinoma. AB - BACKGROUND: Lymph node involvement in pancreatic adenocarcinoma is a key prognostic factor. Therefore, extending the number of lymph node stations excised in pancreatoduodenectomy may be beneficial to patients with pancreatic adenocarcinoma. This systematic review and meta-analysis examines the outcomes of extended versus standard lymphadenectomy in the published literature. METHODS: A meta-analysis of randomized controlled trials (RCTs) comparing extended with standard lymphadenectomy in patients undergoing pancreatoduodenectomy for pancreatic adenocarcinoma was performed. Perioperative outcomes were assessed as pooled odds ratios (ORs) and weighted mean differences. Overall survival was analysed for patients with positive and negative lymph nodes. Results were reported according to the PRISMA statement. RESULTS: Five RCTs were included, accounting for 724 patients. Extended lymphadenectomy was associated with greater operative time [mean difference: 63 min, 95% confidence interval (CI) 29-96; P < 0.001], increased need for blood transfusions (mean difference: 0.20, 95% CI 0.01 0.30; P = 0.030) and greater postoperative morbidity (OR 1.5, 95% CI 1.25-2.00; P = 0.030), as well as with prolonged diarrhoea after circumferential autonomic nerve dissection around major vessels (OR 12.2, 95% CI 5.3-28.5; P < 0.001). Median survival was similar across the groups in the whole cohort, as well as in subgroups of patients with, respectively, positive and negative lymph nodes. CONCLUSIONS: Extended lymphadenectomy has a harmful impact on patients undergoing oncological pancreatoduodenectomy compared with standard lymphadenectomy. PMID- 25913579 TI - The Da Vinci European BioBank: A Metabolomics-Driven Infrastructure. AB - We present here the organization of the recently-constituted da Vinci European BioBank (daVEB, https://www.davincieuropeanbiobank.org/it). The biobank was created as an infrastructure to support the activities of the Fiorgen Foundation (http://www.fiorgen.net/), a nonprofit organization that promotes research in the field of pharmacogenomics and personalized medicine. The way operating procedures concerning samples and data have been developed at daVEB largely stems from the strong metabolomics connotation of Fiorgen and from the involvement of the scientific collaborators of the foundation in international/European projects aimed to tackle the standardization of pre-analytical procedures and the promotion of data standards in metabolomics. PMID- 25913580 TI - Influence of phosphoproteins' biomimetic analogs on remineralization of mineral depleted resin-dentin interfaces created with ion-releasing resin-based systems. AB - OBJECTIVE: The study aimed at evaluating the remineralization of acid-etched dentin pre-treated with primers containing biomimetic analogs and bonded using an ion-releasing light-curable resin-based material. METHODS: An experimental etch and-rinse adhesive system filled with Ca(2+), PO4(3-)-releasing Ca-Silicate micro fillers was created along with two experimental primers containing biomimetic analogs such as sodium trimetaphosphate (TMP) and/or polyaspartic acid (PLA). Dentin specimens etched with 37% H3PO4 were pre-treated with two different aqueous primers containing the polyanionic biomimetic analogs or deionized water and subsequently bonded using the experimental resin-based materials. The specimens were sectioned and analyzed by AFM/nanoindentation to evaluate changes in the modulus of elasticity (Ei) across the resin-dentin interface at different AS storage periods (up to 90 days). Raman cluster analysis was also performed to evaluate the chemical changes along the interface. The phosphate uptake by the acid-etched dentin was evaluated using the ATR-FTIR. Additional resin-dentin specimens were tested for microtensile bond strength. SEM examination was performed after de-bonding, while confocal laser microscopy was used to evaluate the interfaces ultramorphology and micropermeability. RESULTS: Both biomimetic primers induced phosphate uptake by acid-etched dentin. Specimens created with the ion-releasing resin in combination with the pre-treatment primers containing either PLA and TMA showed the greatest recovery of the Ei of the hybrid layer, with no decrease in MUTBS (p>0.05) after 3-month AS storage. The ion-releasing resin applied after use of the biomimetic primers showed the greatest reduction in micropermeability due to mineral precipitation; these results were confirmed using SEM. SIGNIFICANCE: The use of the ion-releasing resin-based system applied to acid-etched dentin pre-treated with biomimetic primers containing analogs of phosphoproteins such as poly-l-aspartic acid and/or sodium trimetaphosphate provides a suitable bonding approach for biomimetic remineralization of resin dentin interfaces. PMID- 25913581 TI - Practice Guidelines on Endoscopic Surgery for qualified surgeons by the Endoscopic Surgical Skill Qualification System. PMID- 25913582 TI - Gastroenterological surgery: esophagus. PMID- 25913583 TI - Neuroendoscopic surgery for ventriculitis and hydrocephalus after shunt infection and malfunction: Preliminary report of a new strategy. AB - If not controlled in the early stage, ventriculitis is difficult to treat neurosurgically and can lead to serious sequelae, a long course of treatment, and hospitalization. We report two cases of ventriculitis and progressive hydrocephalus after shunt infection. Both were successfully treated by neuroendoscopic septostomy in combination with thorough intraventricular irrigation through a single burr hole followed by single shunt revision. Although surgical intervention has not been established as a first-choice treatment for ventriculitis, including early-stage ventriculitis, prompt neuroendoscopic surgery appears effective for the management of ventriculitis and hydrocephalus after shunt infection. The strategy described in this report might be useful to avoid recurrent shunt infections and malfunctions, simplify a shunt, and reduce the overall duration of hospitalization. PMID- 25913584 TI - Case report of a laparoscopically resected rectal villous tumor associated with electrolyte depletion syndrome. AB - A 70-year-old woman had been aware of lower extremity weakness and anal discomfort for 3 years. A soft, elastic, palm-sized mass covered by a large amount of mucus was found protruding from the anus. Biopsy revealed a villous adenoma. On the basis of these results, a villous adenoma associated with electrolyte depletion syndrome was diagnosed. After electrolyte abnormalities were improved by fluid replacement therapy, laparoscopic abdominoperineal resection was performed. The surgically resected specimen was a circumferential villous tumor measuring 210 * 140 mm. The histopathological diagnosis was an intramucosal papillary adenocarcinoma. The patient recovered uneventfully after surgery, and the electrolyte abnormalities gradually improved. She was discharged on the 28th postoperative day. The electrolyte levels normalized about 3 months after surgery. PMID- 25913585 TI - Laparoscopic right hemicolectomy for metachronous ascending colon cancer with preservation of an ileal conduit constructed after previous radical cystectomy for bladder cancer. AB - A 79-year-old woman who had undergone laparoscopic radical cystectomy and ileal conduit construction for bladder cancer 4 years earlier presented to our hospital with anemia. We diagnosed advanced ascending colon cancer (cT4bN2M1) and documented tumor regression after six courses of folinic acid, 5-fluorouracil, and oxaliplatin therapy. We then performed laparoscopic right hemicolectomy. Intraoperatively, we found that the right colic artery was the feeding artery of the tumor, whereas the ileocolic artery, which was the main feeder of the conduit, was not. We performed lymph node dissection along the surgical trunk with central vascular ligation of the right colic artery and the right branch of the middle colic artery while preserving the ileal conduit and its blood supply (ileocolic artery and ileal branches). The postoperative course was uneventful, and the patient remains well and cancer-free 2 years after colonic surgery. We believe that this is the first report of laparoscopic right colectomy in a patient with an ileal conduit. PMID- 25913586 TI - Severe cellulitis and abdominal wall emphysema following laparoscopic colonic surgery: A case report. AB - Abdominal wall emphysema is a common complication of laparoscopic surgery. This condition is usually harmless; however, if an infection occurs, it can develop into a serious condition such as necrotizing fasciitis. We report a case of a 51 year-old woman suffering from severe cellulitis that spread from an area of abdominal wall emphysema after laparoscopic surgery for sigmoid colon cancer. Recognizing this complication, early diagnosis, and prompt treatment are cornerstones for successful management of this potentially fatal disease. PMID- 25913587 TI - Pulmonary edema after laparoscopic hepatectomy in a patient with Budd-Chiari syndrome-associated hepatocellular carcinoma. AB - An 84-year-old man diagnosed with Budd-Chiari syndrome (BCS) developed a 20-mm hepatocellular carcinoma. We performed laparoscopic hepatectomy without complications, but the patient's percutaneous oxygen saturation gradually worsened and pulmonary edema was detected 50 minutes after extubation. He was subsequently re-intubated and received diuretic therapy. He was discharged on postoperative day 32. Patients with severe BCS have been reported to have an expanded plasma volume. In addition, pneumoperitoneum during laparoscopic surgery has been reported to decrease the venous flow in the portal vein and/or renal vein, the collateral pathways in BCS. The cause of pulmonary edema in the present case may have involved increased venous return following decompression of pneumoperitoneum pressure under the state of an expanded plasma volume. This case suggests that clinicians should pay special attention to achieving volume control in patients with BCS, particularly during laparoscopic surgery and minimizing the duration of pneumoperitoneum. PMID- 25913588 TI - Laparoscopic resection of a paraganglioma located on the border of the thoracic and abdominal cavities using a transabdominal-transdiaphragmatic approach. AB - We treated a 64-year-old woman with high blood pressure. Catecholamine metabolite levels were elevated in the blood and urine. CT revealed a densely stained tumor on the right side of the descending aorta dorsal to the inferior vena cava. PET CT revealed abnormal accumulation of (18) F-fluorodeoxyglucose, and (123) I-meta iodo-benzylguanidine uptake was apparent on scintigraphy. The tumor was determined to be a paraganglioma located on the border between the thoracic and abdominal cavities, and laparoscopic tumorectomy was performed. The patient was placed in the left lateral position. The right lobe of the liver was turned over, and we cut the diaphragm to expose the front of the tumor. We resected the straight artery flowing in from the aorta and removed the tumor safely. Herein, we describe the removal of a paravertebral paraganglioma located in the border of the thoracic and abdominal cavities with a laparoscopic transabdominal transdiaphragmatic approach. PMID- 25913589 TI - Small bowel obstruction caused by endometriosis in a postmenopausal woman. AB - We report a rare case of small bowel obstruction (SBO) caused by endometriosis in a postmenopausal woman. A 54-year-old postmenopausal woman presented with severe abdominal pain and vomiting. Before menopause, she sometimes had abdominal pain associated with menses. Axial multi-dimensional CT images revealed a SBO with small nodules near the terminal ileum. The obstruction was diagnosed as being caused by small bowel endometriosis. Curved planar reconstruction images showed a complicated obstruction of the small intestine 15 cm from the terminal ileum. Based on the stenotic lesion, a SILS procedure was performed. The patient's SBO diagnosis was histologically confirmed as being caused by small bowel endometriosis. SILS was deemed to be a safe, feasible procedure for treating this bowel obstruction. Curved planar reconstruction images were useful in preoperative imaging and diagnosis of SBO, especially as they were able to highlight the constricting legion. PMID- 25913590 TI - V-locTM capable of grasping surrounding tissue causes obstruction at the jejunojejunostomy after Roux-en-Y laparoscopic gastric bypass. AB - Because of the increasing number of morbidly obese patients, laparoscopic Roux-en Y gastric bypass surgery is increasingly being performed to treat these patients and achieve sustained weight loss. Postoperative abdominal symptoms suggestive of impaired gastrointestinal passage are a diagnostic challenge after Roux-en-Y gastric bypass. Here, we present the case of a V-locTM-induced obstruction at the jejunojejunostomy caused by the ability of the V-loc suture to grasp surrounding tissue that required re-laparoscopy. To our knowledge, this specific type of postoperative complication after Roux-en-Y gastric bypass has not been described previously. PMID- 25913591 TI - Laparoscopic repair of Morgagni hernia with composite mesh in an elderly woman: Report of a case. AB - A 78-year-old woman was admitted to another hospital with vomiting. Chest X-ray showed an abnormal shadow in the lower right lung field, and CT indicated a Morgagni hernia containing the stomach and transverse colon. The patient was transferred to our hospital and underwent laparoscopic surgery. After the hernia contents were repositioned into the abdominal cavity, we repaired the hernia orifice with a prosthetic mesh to achieve a tension-free repair. There were no complications after the surgery, and there has been no recurrence. The patient has remained free of clinical symptoms since 10 months after the surgery. Laparoscopic repair with a prosthetic mesh for Morgagni hernia is a simple and safety procedure for elderly patients. PMID- 25913592 TI - Thoracoscopic repair of a large neonatal congenital diaphragmatic hernia using Gerota's fascia. AB - A large congenital diaphragmatic hernia needing patch repair has a high risk of recurrence. Thus, managing these large congenital diaphragmatic hernias under thoracoscopy has become a problem. Here, a large congenital diaphragmatic hernia that was repaired using Gerota's fascia under thoracoscopy is reported. In the present case, it was impossible to close the hernia directly under thoracoscopy because the hernia was too large. Gerota's fascia was raised up by the left kidney and used for the repair. The left colon adhering to Gerota's fascia was mobilized, and a large space was made under thoracoscopy. Gerota's fascia was fixed to the diaphragmatic defect. The patient's postoperative course was good, and there was no recurrence. This technique could be one option for repairing a large hernia under thoracoscopy. PMID- 25913593 TI - Homemade specimen retrieval bag for laparoscopic cholecystectomy: A solution in the time of fiscal crisis. AB - INTRODUCTION: Due to the current economic crisis in Greece, major cutbacks on healthcare costs have been imposed, resulting in a shortage of surgical supplies, including laparoscopic materials. In an attempt to reduce costs, we developed a homemade specimen retrieval bag for laparoscopic cholecystectomy. MATERIALS AND SURGICAL TECHNIQUE: We used the polyethylene bag containing the catheter of a Redon drainage set. The bag was cut in half and pleated longitudinally; then, the gallbladder was placed in the bag and removed through the umbilicus with a grasping forceps. DISCUSSION: From September 2011 to June 2012, we used our homemade bag on 85 patients undergoing laparoscopic cholecystectomy. No rupture, accidental opening, or bile leak was observed. The learning curve was found to be five cases. Our homemade specimen retrieval bag seems to be a safe, effective, and easy tool for tissue extraction. Further studies need to be conducted to evaluate its full potential. PMID- 25913594 TI - Transanal extracorporeal anvil fixation to the proximal colon during laparoscopic rectal resection. PMID- 25913595 TI - BINOL-Al catalysed asymmetric cyclization and amplification: preparation of optically active menthol analogs. AB - We report a highly selective asymmetric ring-closing ene reaction catalysed by aluminum complexes with chiral BINOL. This reaction yields optically active 6 membered cyclized alcohols from unsaturated aldehydes, with good diastereo- and enantioselectivities. Asymmetric amplification of this reaction was investigated by varying the ee of the BINOL employed in the catalyst. PMID- 25913596 TI - Trichinella pseudospiralis in the Iberian peninsula. AB - Nematode worms of the genus Trichinella are zoonotic parasites circulating in most continents, including Europe. In Spain, Trichinella spiralis and Trichinella britovi are highly prevalent in wildlife but seldom in domestic pigs. In Portugal, only T. britovi was documented in wild carnivores. In the period 2006 2013 in Spain, 384 (0.0001%) pigs and 1399 (0.20%) wild boars (Sus scrofa) were positive for Trichinella spp. larvae, which were identified as T. spiralis or T. britovi. In 2014, Trichinella pseudospiralis larvae were isolated from a wild boar hunted in the Gerona province, Cataluna region, North-East of Spain, near the border to France. This is the first report of T. pseudospiralis in the Iberian peninsula, which suggests a broad distribution area of this zoonotic nematode in Europe. Since larvae of this Trichinella species do not encapsulate in the host muscles, they can be detected only by artificial digestion of muscle samples. T. pseudospiralis is the only Trichinella species infecting both mammals and birds. Birds can spread this pathogen over great distances including islands triggering new foci of infections in areas previously considered at low risk for this pathogen. PMID- 25913597 TI - Otitis media with effusion. AB - Otitis media with effusion (OME) is a common problem facing general practitioners, pediatricians and otolaryngologists. This article reviews the etiopathogenesis, epidemiology, presentation, natural history and management of OME. The literature was reviewed by using the PubMed search engine and entering a combination of terms including 'otitis media with effusion', 'epidemiology' and 'management'. Relevant articles were identified and examined for content. What is the take home message? While OME is a very common entity in the pediatric population, the majority of cases will resolve spontaneously. Surgery in the form of grommet insertion, with or without adenoidectomy is the most effective treatment in persistent symptomatic cases. PMID- 25913598 TI - Acute otitis media. AB - Acute otitis media (AOM) is a common problem facing general practitioners, paediatricians and otolaryngologists. This article reviews the aetiopathogenesis, epidemiology, presentation, natural history, complications and management of AOM. The literature was reviewed by using the PubMed search engine and entering a combination of terms including 'AOM', 'epidemiology' and 'management'. Relevant articles were identified and examined for content. What is the take-home message? AOM is a very common problem affecting the majority of children at least once and places a large burden on health care systems throughout the world. Although symptomatic relief is often enough for most children, more severe and protracted cases require treatment with antibiotics, especially in younger children. PMID- 25913599 TI - Chronic otitis media. AB - Chronic otitis media (COM) is a common problem facing general practitioners, pediatricians and otolaryngologists. This article reviews the aetiopathogenesis, epidemiology, presentation, natural history, complications and management of COM. The literature was reviewed by using the PubMed search engine and entering a combination of terms including "COM", "diagnosis", "incidence", "complications" and "management". Relevant articles were identified and examined for content. What is the "take-home" message for the clinician? COM is a common problem with various sub-categories according to the disease state. It most commonly presents with painless otorrhoea and hearing loss. Treatment options vary according to the activity and type of disease encountered. COM carries significant patient morbidity. PMID- 25913600 TI - Heteroaggregation of titanium dioxide nanoparticles with natural clay colloids. AB - To better understand and predict the fate of engineered nanoparticles in the water column, we assessed the heteroaggregation of TiO2 nanoparticles with a smectite clay as analogues for natural colloids. Heteroaggregation was evaluated as a function of water salinity (10(-3) and 10(-1) M NaCl), pH (5 and 8), and selected nanoparticle concentration (0-4 mg/L). Time-resolved laser diffraction was used, coupled to an aggregation model, to identify the key mechanisms and variables that drive the heteroaggregation of the nanoparticles with colloids. Our data show that, at a relevant concentration, nanoparticle behavior is mainly driven by heteroaggregation with colloids, while homoaggregation remains negligible. The affinity of TiO2 nanoparticles for clay is driven by electrostatic interactions. Opposite surface charges and/or high ionic strength favored the formation of primary heteroaggregates via the attachment of nanoparticles to the clay. The initial shape and dispersion state of the clay as well as the nanoparticle/clay concentration ratio also affected the nature of the heteroaggregation mechanism. With dispersed clay platelets (10(-3) M NaCl), secondary heteroaggregation driven by bridging nanoparticles occurred at a nanoparticle/clay number ratio of greater than 0.5. In 10(-1) M NaCl, the clay was preaggregated into larger and more spherical units. This favored secondary heteroaggregation at lower nanoparticle concentration that correlated to the nanoparticle/clay surface area ratio. In this latter case, a nanoparticle to clay sticking efficiency could be determined. PMID- 25913601 TI - The effect of amorphous calcium phosphate on protein protection against thermal denaturation. AB - The hybrid nanoparticles of amorphous calcium phosphate (ACP)-catalase (CAT) developed by in situ biomineralization can create a stable semi-aqueous nanoscale environment for entrapped proteins against thermal denaturation. This finding indicates the importance of an amorphous mineral phase in the preservation of organic macromolecules. PMID- 25913602 TI - Impact of Mandatory Public Reporting of Central Line-Associated Bloodstream Infections on Blood Culture and Antibiotic Utilization in Pediatric and Neonatal Intensive Care Units. AB - BACKGROUND: As mandatory public reporting of healthcare-associated infections increases, there is concern that clinicians could attempt to decrease rates by avoiding the diagnosis of reportable infections. OBJECTIVE: To determine whether blood culture and antibiotic utilization changed after mandatory public reporting of central line-associated bloodstream infection (CLABSI). DESIGN: Interrupted time-series of blood culture and antibiotic rates before and after state-specific implementation of mandatory public reporting. We analyzed data from pediatric and neonatal intensive care units (ICUs) at 17 children's hospitals that contributed to the Pediatric Health Information System administrative database. We used multivariable regression with generalized linear mixed-effects models to determine adjusted rate ratios (ARRs) after implementation of mandatory public reporting. We conducted subgroup analysis on patients with central venous catheters. To assess temporal trends, we separately analyzed data from 4 pediatric hospitals in states without mandatory public reporting. RESULTS: There was no significant effect of mandatory public reporting on rates of blood culture (pediatric ICU ARR, 1.03 [95% CI, 0.82-1.28]; neonatal ICU ARR, 1.06 [0.85-1.33]) or antibiotic utilization (pediatric ICU ARR, 0.86 [0.72-1.04]; neonatal ICU ARR, 1.09 [0.87-1.35]). Results were similar in the subgroup of patients with central venous catheter codes. Hospitals with and without mandatory public reporting experienced small decreases in blood culture and antibiotic use across the study period. CONCLUSIONS: Mandatory public reporting of central line-associated bloodstream infection did not impact blood culture and antibiotic utilization, suggesting that clinicians have not shifted their practice in an attempt to detect fewer infections. PMID- 25913603 TI - Anticoagulation in Chronic Hemodialysis: Progress Toward an Optimal Approach. AB - Appropriate anticoagulation for hemodialysis (HD) requires a subtle balance between under- and over-heparinization to prevent extracorporeal circuit (ECC) clotting and bleeding, respectively. We discuss five key issues relating to anticoagulation therapy for chronic HD in adults following a review of relevant literature published since 2002: (i) options for standardization of anticoagulation in HD settings. The major nephrology societies have issued low evidence level recommendations on this subject. Interventional studies have generally investigated novel low-molecular weight heparins and provided data on safety of dosing regimens that cannot readily be extrapolated to clinical practice; (ii) identification of clinical and biological parameters to aid individualization of anticoagulation treatment. We find that use of clinical and biological monitoring of anticoagulation during HD sessions is currently not clearly defined in routine clinical practice; (iii) role of ECC elements (dialysis membrane and blood lines), dialysis modalities, and blood flow in clotting development; (iv) options to reduce or suppress systemic heparinization during HD sessions. Alternative strategies have been investigated, especially when the routine mode of anticoagulation was not suitable in patients at high risk of bleeding or was contraindicated; (v) optimization of anticoagulation therapy for the individual patient. We conclude by proposing a standardized approach to deliver anticoagulation treatment for HD based on an individualized prescription prepared according to the patient's profile and needs. PMID- 25913604 TI - Transient solid-fluid interactions in rat brain tissue under combined translational shear and fixed compression. AB - An external mechanical insult to the brain may create internal deformation waves, which have shear and longitudinal components that induce combined shear and compression of the brain tissue. To isolate such interactions and to investigate the role of the extracellular fluid (ECF) in the transient mechanical response, translational shear stretch up to 1.25 under either 0 or 33% fixed normal compression is applied without preconditioning to heterogeneous sagittal slices which are nearly the full length of the rat brain cerebrum. The normal stress contribution is estimated by separate unconfined compression stress-stretch curves at 0.0667/s and 1/s engineering strain rates to 33% strain. Unconfined compression deformation causes lateral dimension expansion less than that predicted for an incompressible material under large deformation and often a visible loss of internal fluid from the specimen so that the bulk brain tissue is not incompressible in vitro, as sometimes assumed for mathematical modeling. The response to both slow 0.001/s and moderate 1/s shear translational stretch rates is deformation rate dependent and hardening under no compression but under 33% compression is nearly linear perhaps because of increased solid-solid friction. Both shear and normal stress relaxation are faster after the fast rate deformation possibly because higher deformation rates produce higher ECF hydrostatic pressure that primarily drives stress relaxation. The experimental results on ECF behavior guide the form of our nonlinear viscoelastic mathematical model. Our data are closely fit by non-equilibrium evolution equations that involve at most three specimen-specific empirical parameters and that are based on the idea that stretch of axons and glial processes resists load-induced ECF pressure. PMID- 25913605 TI - The biaxial active mechanical properties of the porcine primary renal artery. AB - The mechanical response of arteries under physiological loads can be delineated into passive and active components. The passive response is governed by the load bearing constituents within the arterial wall, elastin, collagen, and water, while the active response is a result of vascular smooth muscle cell (SMC) contraction. In muscular blood vessels, such as the primary renal artery, high SMC wall content suggests an elevated importance of the active response in determining overall vessel behavior. This study is a continuation of our previous investigation, in which a four-fiber constitutive model of the passive response of the primary porcine renal artery was identified. Here we focus on the active response of this vessel, specifically in the case of maximal SMC contraction, and develop a constitutive model of the active stress-stretch relations. The results of this study demonstrate the existence of biaxial active stress in the vessel wall, and suggest the active mechanical response is a critical component of renal arterial performance. PMID- 25913606 TI - Evaluation of polyvinyl alcohol composite membranes containing collagen and bone particles. AB - Composite biomaterials provide alternative materials that improve on the properties of the individual components and can be used to replace or restore damaged or diseased tissues. Typically, a composite biomaterial consists of a matrix, often a polymer, with one or more fillers that can be made up of particles, sheets or fibres. The polymer matrix can be chosen from a wide range of compositions and can be fabricated easily and rapidly into complex shapes and structures. In the present study we have examined three size fractions of collagen-containing particles embedded at up to 60% w/w in a poly(vinyl alcohol) (PVA) matrix. The particles used were bone particles, which are a mineral collagen composite and demineralised bone, which gives naturally cross-linked collagen particles. SEM showed well dispersed particles in the PVA matrix for all concentrations and sizes of particles, with FTIR suggesting collagen to PVA hydrogen bonding. Tg of membranes shifted to a slightly lower temperature with increasing collagen content, along with a minor amount of melting point depression. The modulus and tensile strength of membranes were improved with the addition of both particles up to 10 wt%, and were clearly strengthened by the addition, although this effect decreased with higher collagen loadings. Elongation at break decreased with collagen content. Cell adhesion to the membranes was observed associated with the collagen particles, indicating a lack of cytotoxicity. PMID- 25913607 TI - Reflection effects during the radiation sterilization of ultra high molecular weight polyethylene for total knee replacements. AB - Ultra high molecular weight polyethylene has been subject to gamma irradiation whilst in contact with a stainless steel backing. This leads to reflection of the incident radiation and to backscattered electrons, both of which contribute to an effective increase in dose received. Radiation induced damage through scission of inter-lamellae tie chains results in an increase in crystallinity. At a nominal received dose of 100 kGy the effect of the metal backing is to increase crystallinity by approximately a third relative to the increase observed in materials irradiated in the absence of the backing. The metal backing induced reflections cause a bimodal recrystallization distribution giving rise to a more refined crystal population. As implant materials are subject to intermittent, but high, stress levels it is clearly of importance to examine how these reflection induced structural changes influence mechanical properties. Stress/strain results have indicated that subsequent yielding behavior is governed by the counteracting mechanisms of crystal growth and lamella reorganization mechanisms and in metal backed components the resulting morphological inhomogeneity may have important property consequences for wear induced failures in total knee replacement materials. PMID- 25913608 TI - Strong similarities in the creep and damage behaviour of a synthetic bone model compared to human trabecular bone under compressive cyclic loading. AB - Understanding the failure modes which instigate vertebral collapse requires the determination of trabecular bone fatigue properties, since many of these fractures are observed clinically without any preceding overload event. Alternatives to biological bone tissue for in-vitro fatigue studies are available in the form of commercially available open cell polyurethane foams. These test surrogates offer particular advantages compared to biological tissue such as a controllable architecture and greater uniformity. The present study provides a critical evaluation of these models as a surrogate to human trabecular bone tissue for the study of vertebral augmentation treatments such as balloon kyphoplasty. The results of this study show that while statistically significant differences were observed for the damage response of the two materials, both share a similar three phase modulus reduction over their life span with complete failure rapidly ensuing at damage levels above 30%. No significant differences were observed for creep accumulation properties, with greater than 50% of creep strains being accumulated during the first quarter of the life span for both materials. A significant power law relationship was identified between damage accumulation rate and cycles to failure for the synthetic bone model along with comparable microarchitectural features and a hierarchical composite structure consistent with biological bone. These findings illustrate that synthetic bone models offer potential as a surrogate for trabecular bone to an extent that warrants a full validation study to define boundaries of use which compliment traditional tests using biological bone. PMID- 25913609 TI - Relationship between micro-porosity, water permeability and mechanical behavior in scaffolds for cartilage engineering. AB - In tissue engineering the design and optimization of biodegradable polymeric scaffolds with a 3D-structure is an important field. The porous scaffold provide the cells with an adequate biomechanical environment that allows mechanotransduction signals for cell differentiation and the scaffolds also protect the cells from initial compressive loading. The scaffold have interconnected macro-pores that host the cells and newly formed tissue, while the pore walls should be micro-porous to transport nutrients and waste products. Polycaprolactone (PCL) scaffolds with a double micro- and macro-pore architecture have been proposed for cartilage regeneration. This work explores the influence of the micro-porosity of the pore walls on water permeability and scaffold compliance. A Poly(Vinyl Alcohol) with tailored mechanical properties has been used to simulate the growing cartilage tissue inside the scaffold pores. Unconfined and confined compression tests were performed to characterize both the water permeability and the mechanical response of scaffolds with varying size of micro-porosity while volume fraction of the macro-pores remains constant. The stress relaxation tests show that the stress response of the scaffold/hydrogel construct is a synergic effect determined by the performance of the both components. This is interesting since it suggests that the in vivo outcome of the scaffold is not only dependent upon the material architecture but also the growing tissue inside the scaffold's pores. On the other hand, confined compression results show that compliance of the scaffold is mainly controlled by the micro-porosity of the scaffold and less by hydrogel density in the scaffold pores. These conclusions bring together valuable information for customizing the optimal scaffold and to predict the in vivo mechanical behavior. PMID- 25913610 TI - Analysis of the mechanical response of biomimetic materials with highly oriented microstructures through 3D printing, mechanical testing and modeling. AB - Many biomineralized organisms have evolved highly oriented nanostructures to perform specific functions. One key example is the abrasion-resistant rod-like microstructure found in the radular teeth of Chitons (Cryptochiton stelleri), a large mollusk. The teeth consist of a soft core and a hard shell that is abrasion resistant under extreme mechanical loads with which they are subjected during the scraping process. Such remarkable mechanical properties are achieved through a hierarchical arrangement of nanostructured magnetite rods surrounded with alpha chitin. We present a combined biomimetic approach in which designs were analyzed with additive manufacturing, experiments, analytical and computational models to gain insights into the abrasion resistance and toughness of rod-like microstructures. Staggered configurations of hard hexagonal rods surrounded by thin weak interfacial material were printed, and mechanically characterized with a cube-corner indenter. Experimental results demonstrate a higher contact resistance and stiffness for the staggered alignments compared to randomly distributed fibrous materials. Moreover, we reveal an optimal rod aspect ratio that lead to an increase in the site-specific properties measured by indentation. Anisotropy has a significant effect (up to 50%) on the Young's modulus in directions parallel and perpendicular to the longitudinal axis of the rods, and 30% on hardness and fracture toughness. Optical microscopy suggests that energy is dissipated in the form of median cracks when the load is parallel to the rods and lateral cracks when the load is perpendicular to the rods. Computational models suggest that inelastic deformation of the rods at early stages of indentation can vary the resistance to penetration. As such, we found that the mechanical behavior of the system is influenced by interfacial shear strain which influences the lateral load transfer and therefore the spread of damage. This new methodology can help to elucidate the evolutionary designs of biomineralized microstructures and understand the tolerance to fracture and damage of chiton radular teeth. PMID- 25913611 TI - Rapid maxillary expansion in alveolar cleft repaired with a tissue-engineered bone in a canine model. AB - This study aims to investigate the effects of orthodontic expansion on graft area of a tissue-engineered bone (TEB) BMSCs/beta-TCP, and to find an alternative strategy for the therapy of alveolar cleft. A unilateral alveolar cleft canine model was established and then treated with BMSCs/beta-TCP under rapid maxillary expansion (RME). Sequential fluorescent labeling, radiography and helical computed tomography were used to evaluate new bone formation and mineralization in the graft area. Hematoxylin-eosin staining and Van Gieson's picro fuchsin staining were performed for histological and histomorphometric observation. ALP activity, mineralization and the expression of osteogenic differentiation related genes of BMSCs that grew on the beta-TCP scaffold were promoted by their cultivation in osteogenic medium. Based on fact, TEB was constructed. After 8 weeks of treatment with BMSCs/beta-TCP followed by RME, new bone formation and mineralization of the dogs were markedly accelerated, and bone resorption was significantly reduced, compared with the untreated dogs, or those only treated with autogenous iliac bone. The treatment with both TEB and RME evidently made the bone trabecula more abundant and the area of bone formation larger. What is more, there were no significant differences between BMSCs/beta-TCP group and the group treated with autogenous bone and RME. This study further revealed that TEB was not only a feasible clinical approach for patients with alveolar cleft, but also a potential substituent of autogenous bone, and its combination with RME might be an alternative strategy for the therapy of alveolar cleft. PMID- 25913612 TI - Whole-genome sequence comparisons reveal the evolution of Vibrio cholerae O1. AB - The analysis of the whole-genome sequences of Vibrio cholerae strains from previous and current cholera pandemics has demonstrated that genomic changes and alterations in phage CTX (particularly in the gene encoding the B subunit of cholera toxin) were major features in the evolution of V. cholerae. Recent studies have revealed the genetic mechanisms in these bacteria by which new variants of V. cholerae are generated from type-specific strains; these mechanisms suggest that certain strains are selected by environmental or human factors over time. By understanding the mechanisms and driving forces of historical and current changes in the V. cholerae population, it would be possible to predict the direction of such changes and the evolution of new variants; this has implications for the battle against cholera. PMID- 25913613 TI - Novel role of DNA in neutrophil extracellular traps. AB - Neutrophil extracellular traps (NETs) have been shown to play a crucial role in health and disease. In a recent paper in PLoS Pathogens, Halverson et al. demonstrate that the DNA backbone of NETs contributes to its antibacterial activity and serves as signal for entrapped microbes to employ immune evasion strategies. PMID- 25913614 TI - Inhibition of KRAS codon 12 mutants using a novel DNA-alkylating pyrrole imidazole polyamide conjugate. AB - Despite extensive efforts to target mutated RAS proteins, anticancer agents capable of selectively killing tumour cells harbouring KRAS mutations have remained unavailable. Here we demonstrate the direct targeting of KRAS mutant DNA using a synthetic alkylating agent (pyrrole-imidazole polyamide indole-seco-CBI conjugate; KR12) that selectively recognizes oncogenic codon 12 KRAS mutations. KR12 alkylates adenine N3 at the target sequence, causing strand cleavage and growth suppression in human colon cancer cells with G12D or G12V mutations, thus inducing senescence and apoptosis. In xenograft models, KR12 infusions induce significant tumour growth suppression, with low host toxicity in KRAS-mutated but not wild-type tumours. This newly developed approach may be applicable to the targeting of other mutant driver oncogenes in human tumours. PMID- 25913615 TI - Geometric and electronic structures of five-coordinate manganese(ii) "picket fence" porphyrin complexes. AB - Three five-coordinate, high spin manganese(ii) "picket fence" porphyrin complexes, [Mn(TpivPP)(L)] (TpivPP = alpha,alpha,alpha,alpha-tetrakis(o pivalamidophenyl)porphyrinato; L = 1-MeIm (1-methylimidazole), 1-EtIm (1 ethylimidazole) and 2-MeHIm (2-methylimidazole)), are synthesized and studied by single-crystal X-ray, UV-vis and electronic paramagnetic resonance (EPR) spectroscopy. Structural parameters are investigated and compared with analogues. Low temperature (90 K), high field EPR studies of [Mn(TpivPP)(1-MeIm)] and [Mn(TpivPP)(2-MeHIm)] showed five resonances including characteristic signals at ~5.9 and ~2.0. The simulations of the EPR spectra give the zero field splitting (zfs) parameters (D, E and lambda) and the hyperfine coupling constant (A). PMID- 25913616 TI - Adenoma-like adenocarcinoma: a subtype of colorectal carcinoma with good prognosis, deceptive appearance on biopsy and frequent KRAS mutation. AB - AIMS: A subset of colorectal carcinomas (CRCs) architecturally and cytologically resembles adenomatous change, making them difficult to diagnose on biopsy. This subset has not been well characterized to date. METHODS AND RESULTS: For 35 carcinomas with adenomatous-like areas (cytological and surface architectural appearance that would be insufficient to warrant a diagnosis of adenocarcinoma if evaluated on biopsy), we recorded staging information, molecular data, clinical outcome, whether precursor adenoma was present and whether previous biopsy had been diagnosed as malignant. Despite advanced T-category in 23 (66%) tumours, only seven (20%) had nodal metastases, and only five patients (15%) developed distant metastases. Fifteen cases (43%) had been diagnosed as adenoma on biopsy. Twenty-one resections (60%) showed no residual associated adenoma, including nine called adenoma on biopsy. Median follow-up was 44 months. Four patients (12%) died of disease; 22 were alive at last follow-up. KRAS mutation was seen in 14 of 24 (58%) and four of 17 (24%) were microsatellite-unstable. Patients had significantly improved survival compared to a cohort of patients with conventional well-differentiated CRC after controlling for age and stage (P = 0.011). CONCLUSIONS: Adenoma-like adenocarcinoma is an uncommon variant of CRC with a low rate of metastasis and good prognosis. Biopsy diagnosis of this lesion may be challenging. PMID- 25913617 TI - Provitamin A retention and sensory acceptability of amahewu, a non-alcoholic cereal-based beverage made with provitamin A-biofortified maize. AB - BACKGROUND: Vitamin A deficiency is a major public health problem in sub-Saharan Africa. Amahewu is a popular southern African lactic acid fermented non-alcoholic maize-based beverage, which is deficient in vitamin A. In this study, provitamin A retention and sensory acceptability of amahewu processed using provitamin A biofortified maize and three types of inoculums during fermentation (malted maize, wheat bran and Lactobacillus starter culture) were investigated. RESULTS: The total provitamin A content of amahewu samples, estimated as beta-carotene, beta-cryptoxanthin and alpha-carotene content, ranged from 3.3 to 3.8 g kg(-1) (dry weight). Provitamin A was substantially retained (79- 90% beta-carotene equivalent) in amahewu after fermentation. Amahewu samples prepared with added starter cultures had the lowest retention of provitamin A. Consumers (approx. 69%) liked provitamin A-biofortified amahewu either moderately or very much. Principal component analysis of amahewu sensory data showed that 71% of variation was due to maize types and 18% of variation could be due to the inoculum used during fermentation. Amahewu samples prepared using provitamin A-biofortified maize were slightly more liked (mean score: 7.0 +/- 1.2) compared to those of white maize reference samples. The use of starter culture combined with either malted maize or wheat bran as inoculum during fermentation improved the taste and aroma of amahewu and hence its acceptability. CONCLUSION: Provitamin A is substantially retained in amahewu after fermentation. The slightly high acceptability of amahewu prepared using provitamin A-biofortified maize compared to that of white maize thus suggests that fermented product like amahewu can potentially be used to deliver provitamin A to vulnerable individuals. PMID- 25913618 TI - Fluorescence-Activated Cell Sorting Analysis of Heterotypic Cell-in-Cell Structures. AB - Cell-in-cell structures (CICs), characterized by the presence of one or more viable cells inside another one, were recently found important player in development, immune homeostasis and tumorigenesis etc. Incompatible with ever increasing interests on this unique phenomenon, reliable methods available for high throughput quantification and systemic investigation are lacking. Here, we report a flow cytometry-based method for rapid analysis and sorting of heterotypic CICs formed between lymphocytes and tumor cells. In this method, cells were labeled with fluorescent dyes for fluorescence-activated cell sorting (FACS) by flow cytometry, conditions for reducing cell doublets were optimized such that high purity (>95%) of CICs could be achieved. By taking advantage of this method, we analyzed CICs formation between different cell pairs, and found that factors from both internalized effector cells and engulfing target cells affect heterotypic CICs formation. Thus, flow cytometry-based FACS analysis would serve as a high throughput method to promote systemic researches on CICs. PMID- 25913619 TI - Immune Thrombocytopenic Purpura During Maintenance Phase of Acute Lymphoblastic Leukemia: A Rare Coexistence Requiring a High Degree of Suspicion, a Case Report and Review of the Literature. AB - Thrombocytopenia may develop in patients with acute lymphoblastic leukemia (ALL) due to myelosuppression of chemotherapy or relapse. Here we report a pediatric patient with ALL whose platelet counts decreased at the 102nd week of maintenance treatment. Thrombocytopenia was refractory to platelet infusions and bone marrow aspiration revealed remission status for ALL along with increased megakaryocytes. The cessation of chemotherapy for 2 weeks caused no increase in thrombocyte counts. The viral serology was unrevealing. A diagnosis of immune thrombocytopenic purpura (ITP) was established. After administration of intravenous immunoglobulin, the thrombocytopenia resolved. When thrombocytopenia occurs in patients with ALL in remission, ITP should be kept in mind after exclusion of the more common etiologies. PMID- 25913620 TI - Tumor suppressor miR-145 reverses drug resistance by directly targeting DNA damage-related gene RAD18 in colorectal cancer. AB - Colorectal cancer (CRC) is one of the most common cancers worldwide. Although chemotherapy is used as a palliative treatment, ultimately, nearly all patients develop drug resistance. Therefore, the cell-inherent DNA repair pathway must reverse the DNA-damaging effect of cytotoxic drugs that mediates therapeutic resistance to chemotherapy. RAD18, a DNA damage-activated E3 ubiquitin ligase, is known to play a critical role in DNA damage repair in cancer cells. Here, we show that RAD18 is highly expressed in human 5-fluorouracil (5-FU)-resistant cancer cells after 5-FU treatment. In addition, RAD18 increases in CRC cells could induce DNA damage repair, suggesting that RAD18 might be a possible target for overcoming drug resistance. Moreover, the expression of tumor suppressor microRNA 145 (miR-145) was negatively correlated with RAD18 expression in CRC tissues of 140 patients. Using luciferase reporters carrying the 3'-untranslated region of RAD18 combined with Western blotting, we identified RAD18 as a direct target of miR-145. Also of interest, suppression of RAD18 by miR-145 enhanced DNA damage in CRC cells after 5-FU treatment. Finally, the 5-FU-resistant cancer cells could be selectively ablated by treatment with miR-145. Taken together, these results suggest that miR-145 can act as an RAD18 inhibitor and contribute as an important factor in reversing drug resistance after chemotherapy. PMID- 25913621 TI - The role of C-reactive protein in predicting post-metastatic survival of patients with metastatic bone and soft tissue sarcoma. AB - Although elevated preoperative serum C-reactive protein (CRP) level is an indicator of a poorer prognosis in many cancers including non-metastatic bone and soft tissue sarcoma, there have been no reports focused on sarcoma patients with advanced stage who had distant metastases. The aim of this study is to determine whether the serum CRP level after metastasis is associated with post-metastatic survival in patients with bone and soft tissue sarcoma. A total of 71 patients were studied including 38 male and 33 female. Of all patients, 22 patients had metastases at presentation. The remaining 49 patients developed initial metastasis after the treatment of primary tumor. The average age at the diagnosis of metastasis was 55 years. Blood was obtained after initial detection of metastasis. CRP levels ranged from 0.1 to 165 mg/L with an average of 16.4 mg/L in all patients. Elevated CRP levels (>3 mg/L) were seen in 31 patients (range 3.1-165). The disease-specific survival after metastasis estimates at 3 and 5 years was 17.1 and 17.1 % for those with an elevated CRP vs. 59.5 and 45.3 % for those with a normal CRP (p < 0.0001). In 49 patients who developed lung metastasis after initial primary treatment, patients with elevated CRP levels also had a poorer post-metastatic survival than patients with normal CRP levels (p < 0.0001). In conclusion, we recommend routine measurement of CRP level to identify the patients who have high risk of death after metastasis. PMID- 25913623 TI - Long-term effect of rice-based farming systems on soil health. AB - Integrated rice-fish culture, an age-old farming system, is a technology which could produce rice and fish sustainably at a time by optimizing scarce resource use through complementary use of land and water. An understanding of microbial processes is important for the management of farming systems as soil microbes are the living part of soil organic matter and play critical roles in soil C and N cycling and ecosystem functioning of farming system. Rice-based integrated farming system model for small and marginal farmers was established in 2001 at Central Rice Research Institute, Cuttack, Odisha. The different enterprises of farming system were rice-fish, fish-fingerlings, fruits, vegetables, rice-fish refuge, and agroforestry. This study was conducted with the objective to assess the soil physicochemical properties, microbial population, carbon and nitrogen fractions, soil enzymatic activity, and productivity of different enterprises. The effect of enterprises induced significant changes in the chemical composition and organic matter which in turn influenced the activities of enzymes (urease, acid, and alkaline phosphatase) involved in the C, N, and P cycles. The different enterprises of long-term rice-based farming system caused significant variations in nutrient content of soil, which was higher in rice-fish refuge followed by rice-fish enterprise. Highest microbial populations and enzymatic properties were recorded in rice-fish refuge system because of waterlogging and reduced condition prolonged in this system leading to less decomposition of organic matter. The maximum alkaline phosphatase, urease, and FDA were observed in rice-fish enterprise. However, highest acid phosphatase and dehydrogenase activity were obtained in vegetable enterprise and fish-fingerlings enterprise, respectively. PMID- 25913622 TI - Expression of SIP1 is strongly correlated with LDHA and shows a significantly poor outcome in gastric cancer. AB - Smad interacting protein 1 (SIP1) plays an important role in the epithelial mesenchymal transition (EMT) process by downregulating E-cadherin. Lactate dehydrogenase A (LDHA) is a crucial enzyme that plays an important role in the final step of the Warburg effect by converting pyruvate to lactate irreversibly. EMT and Warburg effect are the hallmarks of advanced gastric cancer progression. Recently, EMT has been thought to be implicated in cancer metabolism. In this study, we want to find whether there was a correlation between the expressions of SIP1 and LDHA in gastric cancer and whether expression of SIP1 alone or in combination with LDHA is associated with the progression of gastric cancer. In the present study, we examined SIP1 and LDHA expression by immunohistochemistry analysis on tissue microarray (TMA) containing tumor tissues and matched non neoplastic mucosa (NNM). Prognostic value and correlation with other clinicopathologic factors were evaluated. In this study, we investigated the expression of SIP1 and LDHA in 261 cancer tissues and their matched NNM using tissue microarray. The immunohistochemistry analysis showed that the expression of SIP1 and LDHA was significantly higher in cancer tissues than in NNM (P = 0.002 P = 0.000, respectively). The expression of SIP1was significantly associated with age, Lauren grade, and histologic differentiation (P < 0.05). The expression of SIP1 was strongly correlated with LDHA expression in gastric cancer (P = 0.000, R = 0.589). The combined expression of SIP1 and LDHA was significantly associated with age, Lauren grade, and histologic differentiation (P < 0.05). Survival analysis demonstrated that the expression of SIP1 or LDHA was associated with significantly shorter overall survival (OS) (P = 0.003, P = 0.000, respectively) and disease-free survival (DFS) (P = 0.003, P = 0.000, respectively). The combined expression of SIP1 and LDHA was associated with less survival time in gastric cancer patients (P = 0.000). The multivariate analysis showed that the expressions of SIP1 and LDHA in gastric cancer (GC) were independent prognostic factors for OS (hazard ratio = 1.465, 95 %CI 1.128-1.901, P = 0.004, hazard ratio = 1.514, 95 %CI 1.091-2.101 P = 0.013, respectively) and DFS (hazard ratio = 1.461, 95 %CI 1.130-1.890, P = 0.004, hazard ratio = 1.550 95 %CL1.119-2.147 P = 0.008, respectively). Our study indicated that expressions of SIP1 and LDHA are independent prognostic factors in gastric cancer patients and may be predictive of poor outcomes. PMID- 25913624 TI - Post-hatchling cranial ontogeny in the Early Triassic diapsid reptile Proterosuchus fergusi. AB - The phylogenetic position of Proterosuchus fergusi (Lower Triassic of South Africa) as one of the most basal archosauriforms means that it is critically important for understanding the successful evolutionary radiation of archosaurs during the Mesozoic. The excellent sample of the species provides a unique opportunity to understand early archosauriform ontogeny. Qualitative and quantitative analyses of cranial ontogenetic variation were conducted on an ontogenetic sequence, in which the smallest individual is 37% of the size of the largest one and osteohistological evidence suggests that four of 11 collected specimens had not reached sexual maturity. Through ontogeny the skull of Proterosuchus became proportionally taller, the infratemporal fenestra larger, and the teeth more isodont and numerous but with smaller crowns. The sequence of somatic maturity supports relatively high growth rates during early ontogeny. The skull of juvenile specimens of Proterosuchus closely resembles adults of the basal archosauromorph Prolacerta, whereas adult specimens resemble adults of more derived archosauriforms. As a result, a plausible hypothesis is that ontogenetic modification events (e.g., heterochrony) may have been key drivers of the evolution of the general shape of the skull at the base of Archosauriformes. These changes may have contributed to the occupation of a new morphospace by the clade around the Permo-Triassic boundary. PMID- 25913625 TI - The role of hematopoietic stem cell transplantation for relapsed and refractory Hodgkin lymphoma. PMID- 25913626 TI - Cutting-edge methods for EEG research on cognition. PMID- 25913627 TI - Assessment of the reproductive physiology of the potto (Perodicticus potto) through fecal hormone metabolite analyses and trans-abdominal ultrasonography. AB - Potto (Perodicticus potto) reproductive biology has been minimally studied. Noninvasive endocrinology and ultrasonography are proven tools for reproductive assessment in other primates. In this study, we used fecal hormone metabolite analysis to monitor one adult male potto and four females at different life stages. Validated testosterone (T), estrone conjugate (EC), and progesterone (P4) enzyme immunoassays (EIA) were used to assess male testicular function and female ovarian and placental activity. The male excreted mean T concentrations of 4.72 (+/-1.66) MUg/g feces, that did not differ (P > 0.05) over time or when paired with alternate females. Baseline concentrations of EC (range: 47.93-78.81 ng/g feces) and P4 (range: 2.29-12.46 MUg/g feces) differed among adult females. Follicular phases averaged 9.1 days (+/-3.43, n = 30 phases), whereas luteal phases averaged 19.89 days (+/-9.49, n = 19 phases). Gestation length (n = 2 pregnancies) was 170 days. Gestational EC and P4 concentrations were positively correlated (pregnancy A, r (132) = 0.71; pregnancy B, r (145) = 0.76) and returned to non-pregnant luteal phase levels 3-7 days post parturition. Extreme differences between pregnant and non-pregnant EC and P4 concentrations may allow for one-sample pregnancy diagnosis. Trans-abdominal ultrasonography was validated for pregnancy diagnosis with the fetus observed between 100 and 110 days post breeding. To our knowledge, this is the first use of fecal endocrinology and ultrasonography to monitor reproductive function and pregnancy in this species, and the only study in any lorisid to measure progestagens in correlation with reproductive events. PMID- 25913628 TI - Assessment of free microvascular flap perfusion by intraoperative fluorescence angiography in craniomaxillofacial surgery. AB - Microsurgical tissue transfer represents a standard technique for reconstruction in craniomaxillofacial surgery. The transferred tissue is anastomosed to vessels of varying diameters and different physiological conditions. The aim of this study was to evaluate the blood flow in free flaps at their origin and compare this with the flow after reperfusion. In 24 patients undergoing microsurgical procedures (13 radial forearm free flaps (RFFF) and 11 parascapular/scapular free flaps (PSFF)), blood flow was evaluated by intraoperative fluorescence angiography after flap raising and again after reperfusion in the neck area (Flow800, Carl Zeiss AG, Oberkochen, Germany). Flow is expressed by the blood flow index (BFI), maximum intensity (MaxInt) and half-time to MaxInt (t1/2) and was measured in the flap pedicle itself, as well as in the supplying vessels. Following anastomosis of the free flaps in the head and neck area, both the arterial and the venous BFI and MaxInt significantly increased, whereas t1/2 decreased significantly. There was no significant difference in the perfusion parameters between RFFF and PSFF. Intraoperative fluorescence angiography is a reliable method for assessing the perfusion of free microvascular flaps. In the head and neck area, free flaps undergo a significant increase in perfusion but show no differences between varying flap types. PMID- 25913629 TI - The influence of geranylgeraniol on human oral keratinocytes after bisphosphonate treatment: An in vitro study. AB - This in vitro study analyzed the influence of geranylgeraniol (GGOH) on human oral keratinocytes (HOK) after exposure to bisphosphonates. HOK were incubated with four different bisphosphonates (clodronate, ibandronate, pamidronate, zoledronate) in two experimental set-ups: with and without GGOH. MTT and PrestoBlue assays were used to analyze HOK cell viability. HOK migration ability was examined with Boyden and Scratch assays, and Tunel and ToxiLight assays were used to detect the HOK apoptosis rate. No significant differences between the experimental set-ups, with and without GGOH, could be found for clodronate (p each >0.3). For the nitrogen-containing bisphosphonates, negative effects could be shown in the experimental set-ups without GGOH in all assays. In the GGOH experimental set-ups, the levels of HOK cell viability were significantly increased (MTT: p each <=0.001; PrestoBlue: p each <=0.012). The HOK migration ability was also greater (Boyden: p each <0.001; Scratch: p each <=0.015). Regarding the apoptosis rate, reduced numbers of apoptotic HOK in the Tunel assay (p each <0.001) and decreased adenylate kinase release in the ToxiLight assay (p each <=0.002) were observed. GGOH reversed the negative effects of bisphosphonates on HOK. These findings provide evidence that GGOH could be a promising treatment option for BP-ONJ. PMID- 25913630 TI - The treatment of oral leukoplakia with the CO2 laser: A retrospective study of 65 patients. AB - The use of CO2 laser has become a routine procedure for the treatment of oral leukoplakia. In this retrospective study, we evaluated 65 patients with oral leukoplakia treated with CO2 laser vaporization. The main location was the tongue (n = 21/65, 32.3%). The initial biopsy showed mild/moderate dysplasia in almost half the patients (n = 29, 44.6%) and hyperplasia without dysplasia in around a third of the patients (n = 21, 32.3%). The recurrence and malignant transformation rates were 33.8% (n = 22) and 15.4% (n = 10), respectively. The follow-up mean (standard deviation) was 15.0 (10.6) months. The procedure-related complications rate was 7.7% (n = 5). The Kaplan-Meier curves for time to recurrence showed differences only for gingiva lesions compared to tongue lesions (log rank, p = 0.032). Malignant leukoplakia transformation is independent of treatment, although it seems advisable to treat leukoplakia with or without dysplasia. PMID- 25913631 TI - Modified in vivo comet assay detects the genotoxic potential of 14 hydroxycodeinone, an alpha,beta-unsaturated ketone in oxycodone. AB - 14-Hydroxycodeinone (14-HC) is an alpha,beta-unsaturated ketone impurity found in oxycodone drug substance and has a structural alert for genotoxicity. 14-HC was tested in a combined Modified and Standard Comet Assay to determine if the slight decrease in % Tail DNA noted in a previously conducted Standard Comet Assay with 14-HC could be magnified to clarify if the response was due to cross-linking activity. One limitation of the Standard Comet Assay is that DNA cross-links cannot be reliably detected. However, under certain modified testing conditions, DNA cross-links and chemical moieties that elicit such cross-links can be elucidated. One such modification involves the induction of additional breakages of DNA strands by gamma or X-ray irradiation. To determine if 14-HC is a DNA crosslinker in vivo, a Modified Comet Assay was conducted using X-ray irradiation as the modification to visualize crosslinking activity. In this assay, 14-HC was administered orally to mice up to 320 mg/kg/day. Results showed a statistically significant reduction in percent tail DNA in duodenal cells at 320 mg/kg/day, with a nonstatistically significant but dose-related reduction in percent tail DNA also observed at the mid dose of 160 mg/kg/day. Similar decreases were not observed in cells from the liver or stomach, and no increases in percent tail DNA were noted for any tissue in the concomitantly conducted Standard Comet Assay. Taken together, 14-HC was identified as a cross-linking agent in the duodenum in the Modified Comet Assay. PMID- 25913632 TI - Australian doctors' non-clinical activities: results from the Medicine in Australia: Balancing Employment and Life (MABEL) survey of doctors. AB - OBJECTIVE: The aim of the present study was to investigate non-clinical work conducted by Australian doctors. METHODS: This study was an exploratory descriptive study using data from Wave 5 of the Medicine in Australia: Balancing Employment and Life (MABEL) longitudinal survey, collected in 2012 from Australian medical practitioners (2200 general practitioners (GPs), 3455 specialists, 1270 specialists in training and 1656 hospital non-specialists). The main outcome measure was the number of hours worked per week in non-clinical work. Regression analysis was used to determine associations between non-clinical activities (i.e. education-related, management and administration and other) and personal and professional characteristics, including age, gender, job and life satisfaction, total clinical working hours, sector of practice (public or private) and doctor type. RESULTS: Australian doctors spend an average of just under 7 h per week, or 16% of their working time, on non-clinical activities. Doctors who worked more hours on non-clinical activities overall, and in education-related and management and administration specifically, were male, younger, had lower life satisfaction and generally spent fewer hours on clinical work. Lower job satisfaction was associated with longer management and administration hours, but not with time spent in education-related activities. Specialists were more likely to work long non-clinical hours, whereas GPs were more likely to report none. Hospital non-specialists reported relatively high management and administration hours. CONCLUSIONS: Further work is required to better understand the full range of non-clinical activities doctors are involved in and how this may impact future workforce projections. PMID- 25913633 TI - Effects of diabetes drugs on the skeleton. AB - Type 2 diabetes is associated with increased fracture risk and the mechanisms underlying the detrimental effects of diabetes on skeletal health are only partially understood. Antidiabetic drugs are indispensable for glycemic control in most type 2 diabetics, however, they may, at least in part, modulate fracture risk in exposed patients. Preclinical and clinical data clearly demonstrate an unfavorable effect of thiazolidinediones on the skeleton with impaired osteoblast function and activated osteoclastogenesis. The negative effect of thiazolidinediones on osteoblastogenesis includes decreased activity of osteoblast-specific transcription factors (e.g. Runx2, Dlx5, osterix) and decreased activity of osteoblast-specific signaling pathways (e.g. Wnt, TGF beta/BMP, IGF-1). In contrast, metformin has a positive effect on osteoblast differentiation due to increased activity of Runx2 via the AMPK/USF-1/SHP regulatory cascade resulting in a neutral or potentially protective effect on bone. Recently marketed antidiabetic drugs include incretin-based therapies (GLP 1 receptor agonists, DPP-4 inhibitors) and sodium-glucose co-transporter 2 (SGLT2)-inhibitors. Preclinical studies indicate that incretins (GIP, GLP-1, and GLP-2) play an important role in the regulation of bone turnover. Clinical safety data are limited, however, meta-analyses of trials investigating the glycemic lowering effect of both, GLP-1 receptor agonists and DPP4-inhibitors, suggest a neutral effect of incretin-based therapies on fracture risk. For SGLT2-inhibitors recent data indicate that due to their mode of action they may alter calcium and phosphate homeostasis (secondary hyperparathyroidism induced by increased phosphate reabsorption) and thereby potentially affect bone mass and fracture risk. Clinical studies are needed to elucidate the effect of SGLT2-inhibitors on bone metabolism. Meanwhile SGLT2-inhibitors should be used with caution in patients with high fracture risk, which is specifically true for the use of thiazolidinediones. PMID- 25913634 TI - Regional variation of bone tissue properties at the human mandibular condyle. AB - The temporomandibular joint (TMJ) bears different types of static and dynamic loading during occlusion and mastication. As such, characteristics of mandibular condylar bone tissue play an important role in determining the mechanical stability of the TMJ under the macro-level loading. Thus, the objective of this study was to examine regional variation of the elastic, plastic, and viscoelastic mechanical properties of human mandibular condylar bone tissue using nanoindentation. Cortical and trabecular bone were dissected from mandibular condyles of human cadavers (9 males, 54-96 years). These specimens were scanned using microcomputed tomography to obtain bone tissue mineral distribution. Then, nanoindentation was conducted on the surface of the same specimens in hydration. Plastic hardness (H) at a peak load, viscoelastic creep (Creep/Pmax), viscosity (eta), and tangent delta (tan delta) during a 30 second hold period, and elastic modulus (E) during unloading were obtained by a cycle of indentation at the same site of bone tissue. The tissue mineral and nanoindentation parameters were analyzed for the periosteal and endosteal cortex, and trabecular bone regions of the mandibular condyle. The more mineralized periosteal cortex had higher mean values of elastic modulus, plastic hardness, and viscosity but lower viscoelastic creep and tan delta than the less mineralized trabecular bone of the mandibular condyle. These characteristics of bone tissue suggest that the periosteal cortex tissue may have more effective properties to resist elastic, plastic, and viscoelastic deformation under static loading, and the trabecular bone tissue to absorb and dissipate time-dependent viscoelastic loading energy at the TMJ during static occlusion and dynamic mastication. PMID- 25913636 TI - Astrocytes in neuroprotection and neurodegeneration: The role of connexin43 and pannexin1. AB - The World Health Organization has predicted that by 2040 neurodegenerative diseases will overtake cancer to become the world's second leading cause of death after cardiovascular disease. This has sparked the development of several European and American brain research initiatives focusing on elucidating the underlying cellular and molecular mechanisms of neurodegenerative diseases. Connexin (Cx) and pannexin (Panx) membrane channel proteins are conduits through which neuronal, glial, and vascular tissues interact. In the brain, this interaction is highly critical for homeostasis and brain repair after injury. Understanding the molecular mechanisms by which these membrane channels function, in health and disease, might be particularly influential in establishing conceptual frameworks to develop new therapeutics against Cx and Panx channels. This review focuses on current insights and emerging concepts, particularly the impact of connexin43 and pannexin1, under neuroprotective and neurodegenerative conditions within the context of astrocytes. PMID- 25913635 TI - Inhibition of temporomandibular joint input to medullary dorsal horn neurons by 5HT3 receptor antagonist in female rats. AB - Repeated forced swim (FS) conditioning enhances nociceptive responses to temporomandibular joint (TMJ) stimulation in female rats. The basis for FS induced TMJ hyperalgesia remains unclear. To test the hypothesis that serotonin 3 receptor (5HT3R) mechanisms contribute to enhanced TMJ nociception after FS, ovariectomized female rats were treated with estradiol and subjected to FS for three days. On day 4, rats were anesthetized with isoflurane and TMJ-responsive neurons were recorded from superficial and deep laminae at the trigeminal subnucleus caudalis/upper cervical (Vc/C1-2) region and electromyographic (EMG) activity was recorded from the masseter muscle. Only Vc/C1-2 neurons activated by intra-TMJ injections of ATP were included for further analysis. Although neurons in both superficial and deep laminae were activated by ATP, only neurons in deep laminae displayed enhanced responses after FS. Local application of the 5HT3R antagonist, ondansetron (OND), at the Vc/C1-2 region reduced the ATP-evoked responses of neurons in superficial and deep laminae and reduced the EMG response in both sham and FS rats. OND also decreased the spontaneous firing rate of neurons in deep laminae and reduced the high-threshold convergent cutaneous receptive field area of neurons in superficial and deep laminae in both sham and FS rats. These results revealed that central application of a 5HT3R antagonist, had widespread effects on the properties of TMJ-responsive neurons at the Vc/C1-2 region and on jaw muscle reflexes under sham and FS conditions. It is concluded that 5HT3R does not play a unique role in mediating stress-induced hyperalgesia related to TMJ nociception. PMID- 25913637 TI - Amyotrophic lateral sclerosis affects cortical and subcortical activity underlying motor inhibition and action monitoring. AB - Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disorder characterized by muscular atrophy, spasticity, and bulbar signs caused by loss of upper and lower motor neurons. Evidence suggests that ALS additionally affects other brain areas including premotor cortex and supplementary motor area. Here, we studied movement execution and inhibition in ALS patients using a stop-signal paradigm and functional magnetic resonance imaging. Seventeen ALS patients and 17 age matched healthy controls performed a stop-signal task that required responding with a button press to a right- or left-pointing black arrow (go-stimuli). In stop-trials, a red arrow (stop-stimulus) was presented shortly after the black arrow indicating to withhold the prepared movement. Patients had by trend higher reaction times in go-trials but did not differ significantly in their inhibition performance. Patients showed stronger inhibition-related activity in inferior, superior, and middle frontal gyri as well as in putamen and pallidum. Error related activity, conversely, was found to be stronger in healthy controls, particularly in the insula bilaterally. Patients also showed increased activity in the motor cortex during button presses. The results provide evidence for altered prefrontal and subcortical networks underlying motor execution, motor inhibition, and error monitoring in ALS. PMID- 25913638 TI - Evolving treatment paradigms in lung cancer: role of immuno-oncology. PMID- 25913639 TI - Role of immunotherapy in lung cancer: Preliminary results of new vaccines and immune checkpoint inhibitors. AB - The two dominant approaches to manipulating cancer immunotherapeutics are active, where the immune system is directly stimulated, and passive, where antitumor antibodies stimulate an indirect immune response. At this point, the active approach is receiving more attention in the arena of lung cancer, with ongoing vaccine clinical trials and studies investigating the role of immune checkpoint inhibitors, in particular those that block the programmed death 1(PD-1) receptor and its ligands. Early results from trials of PD-1/PD-L1 ligand inhibitors in nonsmall cell lung cancer are promising, with patients experiencing rapid and durable responses in the first-, second- and third-line setting as well as in combination with chemotherapy and other immune checkpoint inhibitors. Although the number of patients in these trials is small and the results are preliminary, lung cancer physicians are encouraged that they may soon have agents that confer benefits in excess of those seen with chemotherapy to offer their patients. Further results of ongoing trials are highly anticipated. PMID- 25913640 TI - Impact of pharmacist intervention on antibiotic use and prophylactic antibiotic use in urology clean operations. AB - WHAT IS KNOWN AND OBJECTIVE: The use of prophylactic antibiotics in clean operations was routine in China before 2011. Along with the appeal for using antibiotics rationally by WHO in 2011, China launched a national special rectification scheme on clinical use of antibiotics from April that year. The scheme, aimed at achieving rational use of antibiotics, made pharmacists part of the responsible medical team. Our objective was to describe the impacts of pharmacist intervention on the use of antibiotics, particularly in urology clean operations. METHODS: Pharmacists participated in antibiotic stewardship programmes of the hospital and urological clinical work and conducted real-time interventions at the same time from 2011 to 2013. Data on the use of antibiotics between 2010 and 2013 in urology were collected. RESULTS: Comparison of the 2013 data with those of 2010 showed that antibiotic use density [AUD= DDDs*100/(The number of patients who were treated the same period*Average days in hospital). DDDs = Total drug consumption (g)/DDD. DDD is the Defined Daily Dose] decreased by 57.8(58.8%); average antibiotic cost decreased by 246.94 dollars; the cost of antibiotics as a percentage of total drug cost decreased by 27.7%; the rate of use of antibiotics decreased from 100% to 7.3%. WHAT IS NEW AND CONCLUSION: The study illustrates how an antibiotic stewardship programme with pharmacist participation including real-time interventions can promote improved antibiotic prescribing and significantly decrease costs. PMID- 25913641 TI - Clinical trials in ulcerative colitis: a historical perspective. AB - The clinical trial landscape in ulcerative colitis has evolved significantly in recent decades. Study endpoints have been shifting from mere clinical response to mucosal healing. It has become clear that the choice of combined clinical and endoscopic outcome criteria leads to a reduction in placebo responses, especially when central reading of the endoscopic images is performed. Accumulating evidence suggests that histological remission yields better long-term outcomes for ulcerative colitis patients than mucosal healing alone, and clinical trials with prolonged follow-up will have to address whether histological remission should be the ultimate treatment goal in ulcerative colitis. In recent years there has also been increasing interest in the implementation of patient-reported outcomes in clinical practice and research, and the regulatory authorities have set up guidelines for the development of such outcomes. This paper aims to provide a comprehensive review of historical aspects of clinical trials in ulcerative colitis and to discuss challenges and perspectives for clinical trials in the near future. A thorough analysis of all available landmark literature (both original papers and reviews) on clinical trials in ulcerative colitis was performed. PMID- 25913642 TI - Ischemic LTP: NMDA-dependency and dorso/ventral distribution within the hippocampus. AB - A transient ischemic episode causes a reduction in evoked EPSPs in hippocampal slices, followed by an NMDA dependent LTP. We explored the relations between ischemic LTP (iLTP) and the more conventional tetanic LTP (tLTP) in CA1 region of slices along the dorsal/ventral axis of the hippocampus. Dorsal hippocampal (DH) slices produced a much larger iLTP than their ventral hippocampal (VH) counterparts. In both regions, iLTP and tLTP shared the same NMDA mediated potentiation, such that one LTP saturated the ability of the other treatment to generate LTP. The smaller LTP in VH was correlated with a lower NMDA-mediated EPSP, and a parallel lower density of NMDA receptors. Calcium permeable AMPA receptors did not contribute to the DH/VH disparity. We conclude that a differential distribution of NMDA receptor subunits along the septotemporal axis of the hippocampus controls the diverse ability to evoke iLTP and tLTP in the two regions and may underlie their characteristic behavioral outputs as well as their differential sensitivity to ischemia. PMID- 25913643 TI - Incidence and risk factors of bacterial vaginosis among pregnant women: a prospective study in Maanshan city, Anhui Province, China. AB - AIM: The aim of this study was to identify the incidence and risk factors of bacterial vaginosis among pregnant women. MATERIAL AND METHODS: Prospective data from a cohort of 668 pregnant women were used to identify potential risk factors for bacterial vaginosis during pregnancy by Cox proportional hazards regression. RESULTS: A total of 204 incident cases of bacterial vaginosis were diagnosed in 274.8 woman-years of follow-up. The bacterial vaginosis incidence rate was 0.74 per 1 woman-year and median prevalence during follow-up was 15.6%. In the adjusted model, changing underwear nearly everyday, miscarriage history, urinary tract infection during follow-up, husbands' education level, and concurrent trichomoniasis and candidiasis remained significantly associated with bacterial vaginosis (adjusted hazard ratio and 95% confidence interval were 1.87 [1.26 2.77]; 2.96 [1.96-4.47]; 2.41 [1.05-5.49]; 0.50 [0.32-0.77]; 1.82 [1.02-3.25]; 1.88 [1.30-2.70], respectively). CONCLUSION: Bacterial vaginosis during pregnancy can be affected by many factors, and some are indirectly acting factors. Further prospective studies that include a larger sample size and more information on the development of bacterial vaginosis are needed. PMID- 25913644 TI - A new method for ABO genotyping using fluorescence melting curve analysis based on peptide nucleic acid probes. AB - ABO genotyping has been routinely used to identify suspects or unknown remains in crime investigations. Probe-based fluorescence melting curve analysis (FMCA) is a powerful tool for mutation detection and is based on melting temperature shifts due to thermal denaturation. In the present study, we developed a new method for ABO genotyping using peptide nucleic acid (PNA) probe-based FMCA. This method allowed for the simultaneous detection of three single nucleotide polymorphism (SNP) sites in the ABO gene (nucleotide positions 261, 526, and 803) and the determination of 14 ABO genotypes (A/A, A/O01 or A/O02, A/O03, B/B, B/O01 or B/O02, B/O03, O01/O01 or O01/O02 or O02/O02, O01/O03 or O02/O03, O03/O03, A/B, cis-AB01/A, cis-AB01/B, cis-AB01/O01 or cis-AB01/O02, and cis-AB01/cis-AB01). Using this method, we analyzed 80 samples and successfully identified ABO genotypes (A/A [n=5], A/O01 or A/O02 [n=23], B/B [n=3], B/O01 or B/O02 [n=18], A/B [n=9], O01/O01 or O01/O02 or O02/O02 [n=20], cis-AB01/A [n=1], and cis AB01/O01 or cis-AB01/O02 [n=1]). In addition, all steps in the method, including polymerase chain reaction, PNA probe hybridization, and FMCA, could be performed in one single closed tube in less than 3h. Since no processing or separation steps were required during analysis, this method was more convenient and rapid than traditional methods and reduced the risk of contamination. Thus, this method may be an effective and helpful tool in forensic investigations. PMID- 25913645 TI - Different neural modifications underpin PTSD after different traumatic events: an fMRI meta-analytic study. AB - Post-traumatic stress disorder (PTSD) is an anxiety condition that can develop after exposure to trauma such as physical or sexual assault, injury, combat related trauma, natural disaster or death. Although an increasing number of neurobiological studies carried out over the past 20 years have allowed clarifying the neural substrate of PTSD, the neural modifications underpinning PTSD are still unclear. Here we used activation likelihood estimation meta analysis (ALE) to determine whether PTSD has a consistent neural substrate. We also explored the possibility that different traumatic events produce different alterations in the PTSD neural network. In neuroimaging studies of PTSD, we found evidence of a consistent neural network including the bilateral insula and cingulate cortex as well as the parietal, frontal and limbic areas. We also found that specific networks of brain areas underpin PTSD after different traumatic events and that these networks may be related to specific aspects of the traumatic events. We discuss our results in light of the functional segregation of the brain areas involved in PTSD. PMID- 25913646 TI - Personality Assessment Inventory profiles of veterans: Differential effects of mild traumatic brain injury and psychopathology. AB - OBJECTIVE: Neuropsychiatric complaints often accompany mild traumatic brain injury (mTBI), a common condition in post-deployed Veterans. Self-report, multi scale personality inventories may elucidate the pattern of psychiatric distress in this cohort. This study investigated valid Personality Assessment Inventory (PAI) profiles in post-deployed Veterans. METHOD: Measures of psychopathology and mTBI were examined in a sample of 144 post-deployed Veterans divided into groups: healthy controls (n = 40), mTBI only (n = 31), any mental health diagnosis only (MH; n = 25), comorbid mTBI and Posttraumatic Stress Disorder (mTBI/PTSD; n = 23), and comorbid mTBI, PTSD, and other psychological diagnoses (mTBI/PTSD/MDD+; n = 25). RESULTS: There were no significant differences between the mTBI and the control group on mean PAI subscale elevation, or number of subscale elevations above 60T or 70T. The other three groups had significantly higher overall mean scores, and more elevations above 60 and 70T compared to both controls and mTBI only. The mTBI/PTSD/MDD+ group showed the highest and most elevations. After entering demographics, PTSD, and number of other psychological diagnoses into hierarchical regressions using the entire sample, mTBI history did not predict mean PAI subscale score or number of elevations above 60T or 70T. PTSD was the only significant predictor. There were no interaction effects between mTBI and presence of PTSD, or between mTBI and total number of diagnoses. CONCLUSIONS: This study suggests that mTBI alone is not uniquely related to psychiatric distress in Veterans, but that PTSD accounts for self-reported symptom distress. PMID- 25913647 TI - Bordetella pertussis infection in paediatric healthcare workers. AB - An increased incidence of pertussis has been observed recently in adults, and healthcare workers (HCWs) are considered a risk group for transmission to infants. Prevalence of recent pertussis infection was assessed in HCWs from a paediatric department of a tertiary care hospital in Brazil. Serum pertussis toxin IgG antibodies were measured by enzyme-linked immunosorbent assay. Of 388 HCWs included in the analysis, 6.4% had serology suggestive of recent infection. Medical residents [odds ratio (OR): 4.15; 95% confidence interval (CI): 1.42 12.14; P = 0.009] and those working >40 h a week (OR: 3.29; 95% CI: 1.17-9.26; P = 0.024) had increased risk of pertussis infection. PMID- 25913648 TI - Hospital management of Clostridium difficile infection: a review of the literature. AB - BACKGROUND: The emergence of the epidemic Clostridium difficile 027 strain has renewed interest in infection control practices. AIM: To review the effectiveness of different practices to reduce hospital C. difficile infection (CDI) in non outbreak settings. METHODS: Data sources were identified by a MEDLINE search in English and French. The ORION statement was used to extract key data from articles describing interventions to manage CDI. FINDINGS: Twenty-one studies, published between 1982 and December 2013, were reviewed. Most studies were before after interventions, and a few studies were planned, formal, prospective investigations. The effects of the following single or combined interventions were described: antibiotic management; environmental disinfection and/or cleaning; hand hygiene; bathing; surveillance; cohorting; and isolation of infected patients in private rooms. CONCLUSION: With many methodological weaknesses and some inadequate research reporting, the observed reduction in CDI may not be entirely attributable to interventions. Although infection control programmes involving education and handwashing/gloving protocols were found to have contributed to a reduction in the incidence of CDI, these measures were usually a component of multi-faceted interventions that did not provide for evaluation of the relative impact of each factor. Appropriate environmental disinfection and antibiotic stewardship would appear to offer the most effective benefits. PMID- 25913649 TI - Faecal microbiota transplantation for stool decolonization of OXA-48 carbapenemase-producing Klebsiella pneumoniae. PMID- 25913650 TI - Prenatal substance exposure and child self-regulation: Pathways to risk and protection. AB - A conceptual model of the association between prenatal cocaine exposure (PCE) and child self-regulation via maternal harshness and language development was examined. Specifically, the model tested whether PCE was associated with self regulation either directly or indirectly via high maternal harshness and poor language development. The role of child sex, autonomic reactivity, and cumulative environmental risk as potential moderators was also explored. The sample was 216 mother-child dyads recruited at birth and assessed at 2, 7, 13, 24, 36, and 48 months of child ages. Participating mothers were primarily African American (72%). Results indicated a significant indirect association between PCE and child effortful control at 36 months via higher maternal harshness. Autonomic reactivity moderated the association between maternal harshness and self regulation such that among children with poor autonomic reactivity, high maternal harshness was associated with lower conscience at 3 years. Child sex and environmental risk did not moderate the association between PCE and self regulation. Thus, the quality of caregiving experience played a significant role in the development of self-regulation among PCE children, especially those at higher autonomic risk. In particular, PCE children who also exhibit poor autonomic reactivity may be particularly susceptible to environmental influences such as parenting. PMID- 25913651 TI - Potential explosion hazard of carbonaceous nanoparticles: Explosion parameters of selected materials. AB - Following a previous explosion screening study, we have conducted concentration and ignition energy scans on several carbonaceous nanopowders: fullerene, SWCNT, carbon black, MWCNT, graphene, CNF, and graphite. We have measured minimum explosive concentration (MEC), minimum ignition energy (MIE), and minimum ignition temperature (MITcloud) for these materials. The nanocarbons exhibit MEC ~10(1)-10(2) g/m(3), comparable to the MEC for coals and for fine particle carbon blacks and graphites. The nanocarbons are confirmed mainly to be in the St-1 explosion class, with fullerene, at K(St) ~200 bar-m/s, borderline St-1/St-2. We estimate MIE ~ 10(2)-10(3) J, an order of magnitude higher than the MIE for coals but an order of magnitude lower than the MIE for fine particle graphites. While the explosion severity of the nanocarbons is comparable to that of the coals, their explosion susceptibility (ease of ignition) is significantly less (i.e., the nanocarbons have higher MIEs than do the coals); by contrast, the nanocarbons exhibit similar explosion severity to the graphites but enhanced explosion susceptibility (i.e., the nanocarbons have lower MIEs than do the graphites). MIT(cloud) > 550 degrees C, comparable to that of the coals and carbon blacks. PMID- 25913652 TI - Long-Term Follow-Up of 2.5-mm Narrow-Diameter Implants Supporting a Fixed Prostheses. AB - BACKGROUND: The use of narrow-diameter implants (NDIs; <3.75 mm) constitutes an alternative to bone augmentation procedure. Long-term evaluation of NDIs with a diameter <3.0 mm is still lacking. PURPOSE: Analyze the long-term outcomes of 2.5 mm NDIs splinted to regular-sized implants for supporting partial and complete fixed prostheses. MATERIALS AND METHODS: Patients charts were retrospectively analyzed to select patients treated by the insertion of at least one 2.5-mm two piece implant before July 2005. The study was based on the available charts (no patient was recalled). Patient's demographic data were described. The known implant length was used as a reference to calibrate the linear measurements of marginal bone loss on digital periapical radiograph. Implant details, survival and prosthetic complications were analyzed. RESULTS: Thirty-seven 2.5-mm implants placed in 20 patients (mean age at surgery: 54.05 +/- 9.7 years) in maxilla and mandible were included and evaluated. The implants' mean follow-up time since insertion was 6.5 +/- 3.2 years (range 0 to 9.7 years). The follow-up time was more than 7 years for 22 implants. One implant failed due to lack of osseointegration. Two prosthetic complications (connector and porcelain fracture) occurred. The survival rate was 97.3% for implants and 92.0% for prostheses. The mean marginal bone loss at the mesial and distal aspect was 0.70 +/- 0.55 and 0.72 +/- 0.56 mm, respectively. CONCLUSIONS: When dental implants of 2.5 mm in diameter are splinted by a fixed prosthesis, long-term favorable outcomes could be obtained. PMID- 25913653 TI - Trifluoromethylthiolation of aryl iodides and bromides enabled by a bench-stable and easy-to-recover dinuclear palladium(I) catalyst. AB - While palladium catalysis is ubiquitous in modern chemical research, the recovery of the active transition-metal complex under routine laboratory applications is frequently challenging. Described herein is the concept of alternative cross coupling cycles with a more robust (air-, moisture-, and thermally-stable) dinuclear Pd(I) complex, thus avoiding the handling of sensitive Pd(0) species or ligands. Highly efficient C-SCF3 coupling of a range of aryl iodides and bromides was achieved, and the recovery of the Pd(I) complex was accomplished via simple open-atmosphere column chromatography. Kinetic and computational data support the feasibility of dinuclear Pd(I) catalysis. A novel SCF3-bridged Pd(I) dimer was isolated, characterized by X-ray crystallography, and verified to be a competent catalytic intermediate. PMID- 25913654 TI - [Ocular complications of the NewColorIris((r)) colored cosmetic implant]. PMID- 25913655 TI - [Acute multifocal placoid pigment epitheliopathy and sarcoidosis, an association not to be missed]. PMID- 25913656 TI - [A rare form of bilateral ischemic optic neuropathy]. PMID- 25913657 TI - [Meretoja syndrome: Identification of a family and description of the corneal involvement by confocal microscopy]. PMID- 25913658 TI - [Double corneo-scleral graft]. PMID- 25913659 TI - [Epidemiology of open globe injuries in the Tunisian region of Cap Bon: Retrospective study of 100 cases]. AB - PURPOSE: The goal of our study was to assess the epidemiological characteristics of ocular injuries in the Cap Bon region. PATIENTS AND METHODS: We retrospectively reviewed the records of 100 patients, hospitalized and treated in the department of ophthalmology at the Mohamed Taher Maamouri university medical center in Nabeul, Tunisia for an open globe injury between January 2006 and November 2013. The mean duration of follow-up was 15.9 months. RESULTS: The average age of the patients was 31.9 years. Domestic accidents accounted for 30% of cases of trauma, followed by violence (29%). The trauma was sharp in most cases (54%). The injury was penetrating in most cases (65.7%). The initial visual acuity was <= 1/10 in 69.8% of cases. The wound was isolated to the cornea in 59.7% of cases and scleral in 25% of cases. The most common associated ocular lesions were traumatic cataract (35%), followed by hyphema (32%). An intraocular foreign body was present in 4% of cases. At the final examination, 41.8% had a final visual acuity <= 1/10. CONCLUSION: Open globe injuries represent a real public health problem given their psychological and functional repercussions. The best treatment is preventative, involving better awareness in the family, school and work environment. PMID- 25913660 TI - Conservative Treatment Versus Arthroscopic-Assisted Screw Fixation of Scaphoid Waist Fractures--A Randomized Trial With Minimum 4-Year Follow-Up. AB - PURPOSE: To evaluate clinical and radiological outcomes after conservative treatment and arthroscopic-assisted screw fixation of acute non- or minimally displaced scaphoid waist fractures in a randomized controlled trial. METHODS: Consecutive patients with acute non- or minimally displaced scaphoid waist fractures were prospectively randomized to conservative or surgical treatment. All patients were screened using radiographs, computed tomography, and magnetic resonance imaging. Conservative treatment consisted of a below-elbow thumb spica cast until radiological signs of union appeared. Surgical treatment consisted of wrist arthroscopy and percutaneous antegrade screw fixation. Clinical examination, radiographs, and computed tomography were used to follow the patients. Twenty-four patients were treated conservatively and 14 patients underwent surgery. The patients were followed at regular intervals for 1 year after surgery. Twenty-one patients treated conservatively and 14 treated surgically were available for follow-up after a median of 6 years (range, 4-8 y). RESULTS: At 26 weeks, the conservatively treated group had significantly better range of motion and had reached almost normal value compared with the contralateral wrist. There were no significant differences between the 2 groups concerning grip or pinch strengths at any measure point. At follow-up after a median of 6 years, radiographic signs of arthritis in the radioscaphoid joint were more common in the surgically treated group (3 of 14) than in the conservative group (2 of 21). CONCLUSIONS: Non- and minimally displaced scaphoid waist fractures are best treated conservatively. Operative treatment may provide an improved functional outcome in the short term but at the price of a possible increased risk of arthritis in the long term. TYPE OF STUDY/LEVEL OF EVIDENCE: Therapeutic II. PMID- 25913661 TI - Growth duration is a better predictor of stem increment than carbon supply in a Mediterranean oak forest: implications for assessing forest productivity under climate change. AB - Understanding whether tree growth is limited by carbon gain (source limitation) or by the direct effect of environmental factors such as water deficit or temperature (sink limitation) is crucial for improving projections of the effects of climate change on forest productivity. We studied the relationships between tree basal area (BA) variations, eddy covariance carbon fluxes, predawn water potential (Psipd ) and temperature at different timescales using an 8-yr dataset and a rainfall exclusion experiment in a Quercus ilex Mediterranean coppice. At the daily timescale, during periods of low temperature (< 5 degrees C) and high water deficit (< -1.1 MPa), gross primary productivity and net ecosystem productivity remained positive whereas the stem increment was nil. Thus, stem increment appeared limited by drought and temperature rather than by carbon input. Annual growth was accurately predicted by the duration of BA increment during spring (Deltatt0-t1 ). The onset of growth (t0 ) was related to winter temperatures and the summer interruption of growth (t1 ) to a threshold Psipd value of -1.1 MPa. We suggest that using environmental drivers (i.e. drought and temperature) to predict stem growth phenology can contribute to an improvement in vegetation models and may change the current projections of Mediterranean forest productivity under climate change scenarios. PMID- 25913662 TI - Xenotransplantation of islet cells: what can the non-human primate model bring for the evaluation of efficacy and safety? PMID- 25913663 TI - Management of hidradenitis suppurativa: a U.K. survey of current practice. PMID- 25913665 TI - Clinical manifestations and genetic variation of Leishmania infantum and Leishmania tropica in Southern Turkey. AB - L. infantum was isolated from cutaneous leishmaniasis (CL) skin lesions in patients having no signs and symptoms of visceral leishmaniasis (VL). Similarly, L. tropica had previously been isolated from patients with VL in the absence of cutaneous lesions. It was not certain how visceralization occurred. Smears (207) and bone marrow samples (135) were taken from CL and VL-suspected patients, respectively. Microscopic examination, ITS1-PCR, RFLP and DNA sequencing for all samples were analyzed. The microscopic examination of smears was found to be 61.3% (127/207) in CL-suspected cases and bone marrow samples were found to be positive 8.8% (12/135) in VL-suspected cases. L. tropica 48.6% (72/148), L. infantum 35.8% (53/148), L. major 15.6% (23/148) in CL, and L. infantum 56.3% (18/32), L. donovani 31.2% (10/32), L. tropica 12.5% (4/32) in VL were found with PCR-RFLP. In addition, the DNA sequencing revealed a genetic variation in L. infantum (variants 1-3) and L. tropica (variants 1-5). We assume that the increased disease occurrence may have resulted from geographical expansion of disease, changing patterns of international travel, population migrations, non immune people into endemic regions of infected people into non-endemic regions. In this study, L. infantum (variant 3) only in CL-patients and L. tropica (variant 2) only in VL-patients were identified. We hypothesize that genetic variation might play a role in the causation of CL and VL in southern Turkey and the genetic variants may differ according to the geographical location among Leishmania strains. PMID- 25913664 TI - The effect of BMS-582949, a P38 mitogen-activated protein kinase (P38 MAPK) inhibitor on arterial inflammation: a multicenter FDG-PET trial. AB - OBJECTIVES: This study evaluated the effect of p38 mitogen-activated protein kinase (p38MAPK) inhibitor, BMS-582949, on atherosclerotic plaque inflammation, using (18)FDG-PET imaging. p38MAPK is an important element of inflammatory pathways in atherothrombosis and its inhibition may lead to reduced inflammation within atherosclerotic plaques. METHODS: Subjects with documented atherosclerosis (n = 72) on stable low-dose statin therapy and having at least one lesion with active atherosclerotic plaque inflammation in either aorta or carotid arteries were randomized to BMS-582949 (100 mg once daily), placebo, or atorvastatin (80 mg once daily), for 12 weeks. Arterial inflammation was assessed using (18)FDG PET/CT imaging of the carotid arteries and aorta. Uptake of arterial (18)FDG was assessed as target-to-background ratio (TBR): 1) as a mean of all slices of the index vessel, and 2) within active slices of all vessels (AS: which includes only slices with significant inflammation (TBR >= 1.6) at the baseline). RESULTS: Treatment with BMS-582949 did not reduce arterial inflammation relative to placebo, (DeltaTBR index: 0.10 [95% CI: -0.11, 0.30], p = 0.34; DeltaTBR AS: 0.01 [-0.31, 0.28], p = 0.93) or hs-CRP (median %DeltaCRP [IQR]: 33.83% [153.91] vs. 16.71% [133.45], p = 0.61). In contrast, relative to placebo, statin intensification was associated with significant reduction of hs-CRP (%DeltaCRP [IQR]: -17.44% [54.68] vs. 16.71% [133.45], p = 0.04) and arterial inflammation in active slices (DeltaTBRAS = -0.24 [95% CI: -0.46, -0.01], p = 0.04). CONCLUSIONS: The findings of this study demonstrates that in stable atherosclerosis, 12 weeks of treatment with BMS-582949 did not reduce arterial inflammation or hs-CRP compared to placebo, whereas intensification of statin therapy significantly decreased arterial inflammation. PMID- 25913666 TI - Isolation and molecular characterization of a new Neospora caninum isolate from cattle in Argentina. AB - Neospora caninum is one of the most important causes of bovine abortion, but isolation of live parasites from infected tissue is difficult. The aims of the present study were to obtain new isolates of N. caninum from congenitally infected asymptomatic newborn cattle in Argentina and to perform characterization by multilocus-microsatellite analysis. Five clinically normal born calves, with demonstrable N. caninum antibodies in precolostrum serum by indirect fluorescent antibody test, were euthanized and their brain samples were processed for histopathological, immunohistochemical, polymerase chain reaction (PCR) analysis, and for bioassay in gamma-interferon knockout (GKO) mice. Although N. caninum DNA was detected in brain from all the calves by PCR, viable N. caninum was isolated in GKO mice from only one calf. Neospora caninum tachyzoites of this Argentinean isolate, designated NC-Argentina LP1, were propagated in VERO cell cultures seeded with tachyzoites from the infected GKO mice tissues. Multilocus microsatellite typing on DNA derived from cell cultured tachyzoites revealed a unique genetic pattern, different from reported isolates. This is the first bovine isolation and genetic characterization of N. caninum in Argentina. PMID- 25913667 TI - Teflubenzuron as a tool for control of trichodinids in freshwater fish: Acute toxicity and in vivo efficacy. AB - In this study we describe the anti-Trichodina effects of teflubenzuron (TFB) for Oreochromis niloticus and for Piaractus mesopotamicus. We also evaluated the acute toxicity, for both species, by using TFB in the concentrations of 700.0, 800.0, 900.0 and 1000.0 mg L(-1) and a control, without the drug. To assess the efficacy of TFB against Trichodina spp., we used the concentrations of 30.0 or 50.0 mg L(-1) for one hour exposure in tilapia, and the concentration of 30.0, 50.0 and 80.0 mg L(-1) for one hour and 50 mg L(-1) for two hours exposures in pacu. Teflubenzuron did not present significant toxicity in either species, with LC50;48h > 1000.0 mg L(-1). The drug effectiveness was observed against four identified Trichodina species: T. magna, T. heterodentata, T. compacta and T. centrostrigeata, with 87.9% parasite reduction with one hour exposure to 50.0 mg L(-1) TFB on O. niloticus and 96.1% with two hours exposure to 50.0 mg L(-1) TFB on P. mesopotamicus. Teflubenzuron is a drug with potential to be used in Brazilian aquaculture; it attends to important requirements, such as low toxicity and high efficacy in controlling Trichodina spp. infection in O. niloticus and P. mesopotamicus. PMID- 25913668 TI - Downregulation of plasma miR-451 and miR-16 in Plasmodium vivax infection. AB - Malaria is a common parasitic disease in tropical countries, causing one to two million deaths every year. To establish the new biomarker, we analyzed plasma miRNAs obtained from 19 malaria patients and 19 normal subjects, using reverse transcription-based quantitative polymerase chain reaction (RT-qPCR). The average levels of plasma miR-451 and miR-16 were significantly lower in malaria patients, (8.9-fold; p <0.001 and 10.4-fold; p = 0.01, respectively). The levels of other abundant miRNAs in plasma (miR-223, miR-226-3p) did not change significantly in malaria patients. Our data suggest that plasma miR-451 and miR-16 are relevant biomarkers for malaria infection. PMID- 25913669 TI - A Successful Case of a Patient Undergoing Warfarin and S-1 Therapy Using Internet based Control of Home-measured PT-INR. AB - To avoid major bleeding events in warfarin and S-1 combination therapy, PT-INR levels should be monitored frequently to allow for precise adjustments of the warfarin dose and to verify any side effects reported by the patient. We therefore developed a support system where outpatients obtain a home-measured PT INR value using the CoaguChek((r)) system and submit it along with details of any side effects to us via the Internet using their mobile phone. A 59-year-old man was started on warfarin (1.5 mg/d) and S-1 (100 mg/d), a combination preparation of tegafur, gimeracil, and oteracil potassium, to treat cholangiocarcinoma. The patient sent his data to the hospital pharmacist every two days after starting S 1 therapy. When the PT-INR was outside the target range of 1.5-2.7, the pharmacist, after consulting the physician, instructed the patient to change his warfarin dose by 0.5 mg. On day 24 after starting S-1, PT-INR had increased from 1.6 to 2.8, so the dose was decreased by 0.5 mg. Thereafter, the dose was adjusted by 0.5-1.0 mg during the observation period so that the patient was able to maintain the therapeutic range approximately 90% of the time. We anticipate this system can be applied to S-1 which interact with warfarin, thereby enabling safer anticoagulation therapy. PMID- 25913670 TI - Minimal important change (MIC) based on a predictive modeling approach was more precise than MIC based on ROC analysis. AB - OBJECTIVES: To present a new method to estimate a "minimal important change" (MIC) of health-related quality of life (HRQOL) scales, based on predictive modeling, and to compare its performance with the MIC based on receiver operating characteristic (ROC) analysis. To illustrate how the new method deals with variables that modify the MIC across subgroups. STUDY DESIGN AND SETTING: The new method uses logistic regression analysis and identifies the change score associated with a likelihood ratio of 1 as the MIC. Simulation studies were conducted to investigate under which distributional circumstances both methods produce concordant or discordant results and whether the methods differ in accuracy and precision. RESULTS: The "predictive MIC" and the ROC-based MIC were identical when the variances of the change scores in the improved and not improved groups were equal and the distributions were normal or oppositely skewed. The predictive MIC turned out to be more precise than the ROC-based MIC. The predictive MIC allowed for the testing and estimation of modifying factors such as baseline severity. CONCLUSION: In many situations, the newly described MIC based on predictive modeling yields the same value as the ROC-based MIC but with significantly greater precision. This advantage translates to increased statistical power in MIC studies. PMID- 25913671 TI - Visual & reversible sensing of cyanide in real samples by an effective ratiometric colorimetric probe & logic gate application. AB - A novel anion probe 3 (2,4-di-tert-butyl-6-((2(2,4-dinitrophenyl) hydrazono) methyl) phenol) has been unveiled as an effective ratiometric and colorimetric sensor for selective and rapid detection of cyanide. The sensing behavior was demonstrated by UV-vis experiments and NMR studies. This sensory system exhibited prominent visual color change toward cyanide ion over other testing anions in DMSO (90%) solvent, with a 1:1 binding stoichiometry and a detection limit down to 3.6*10(-8) mol L(-1). Sensor reveals specific anti-jamming activity and reversible in the presence of Cu(2+) ions. This concept has been applied to design a logic gate circuit at the molecular level. Further we developed coated graphite electrode using probe 3 as ionophore and studied the performance characteristics of electrode. The sensitivity of ratiometric-based colorimetric assay is below the 1.9 MUM, accepted by the World Health Organization as the highest permissible cyanide concentration in drinking water. So it can be applied for both quantitative determination and qualitative supervising of cyanide concentrations in real samples. PMID- 25913672 TI - Release and control of hydrogen sulfide during sludge thermal drying. AB - The release of hydrogen sulfide (H2S) during sludge drying is a major environmental problem because of its toxicity to human health. A series of experiments were performed to investigate the mechanisms and factors controlling the H2S release. Results of this study show that: (1) the biomass and activity of sulfate-reducing bacteria (SRB) in sludge were the major factors controlling the amount of H2S release, (2) the sludge drying temperature had an important effect on both the extent and the timing of H2S release from the sludge, and (3) decreasing sludge pH increased the H2S release. Based on the findings from this study, a new system that integrates sludge drying and H2S gas treatment was developed, by which 97.5% of H2S and 99.7% of smoke released from sludge treatments was eliminated. PMID- 25913673 TI - Externally predictive single-descriptor based QSPRs for physico-chemical properties of polychlorinated-naphthalenes: Exploring relationships of logS(W), logK(OA), and logK(OW) with electron-correlation. AB - Quantitative structure-property relationships (QSPRs), based only on a single parameter, are proposed for the prediction of physico-chemical properties, namely, aqueous solubility (logSW), octanol-water partition coefficient (logKOW) and octanol-air partition coefficient (logKOA) of polychloronaphthalenes (PCNs) including all the 75 chloronaphthalene congeners. The QSPR models are developed using molecular descriptors computed through quantum mechanical methods including ab-initio as well as advanced semi-empirical methods. The predictivity of the developed models is tested through state-of-the-art external validation procedures employing an external prediction set of compounds. To analyse the role of instantaneous interactions between electrons (the electron-correlation), the models are also compared with those developed using only the electron-correlation contribution of the quantum chemical descriptor. The electron-correlation contribution towards the chemical hardness and the LUMO energy are observed to be the best predictors for octanol-water partition coefficient, whereas for the octanol-air partition coefficient, the total electronic energy and electron correlation energy are found to be reliable descriptors, in fact, even better than the polarisability. For aqueous solubility of PCNs, the absolute electronegativity is observed to be the best predictor. This work suggests that the electron-correlation contribution of a quantum-chemical descriptor can be used as a reliable indicator for physico-chemical properties, particularly the partition coefficients. PMID- 25913674 TI - Responses of the alga Pseudokirchneriella subcapitata to long-term exposure to metal stress. AB - The green alga Pseudokirchneriella subcapitata has been widely used in ecological risk assessment, usually based on the impact of the toxicants in the alga growth. However, the physiological causes that lead algal growth inhibition are not completely understood. This work aimed to evaluate the biochemical and structural modifications in P. subcapitata after exposure, for 72 h, to three nominal concentrations of Cd(II), Cr(VI), Cu(II) and Zn(II), corresponding approximately to 72 h-EC10 and 72 h-EC50 values and a high concentration (above 72 h-EC90 values). The incubation of algal cells with the highest concentration of Cd(II), Cr(VI) or Cu(II) resulted in a loss of membrane integrity of ~16, 38 and 55%, respectively. For all metals tested, an inhibition of esterase activity, in a dose-dependent manner, was observed. Reduction of chlorophyll a content, decrease of maximum quantum yield of photosystem II and modification of mitochondrial membrane potential was also verified. In conclusion, the exposure of P. subcapitata to metals resulted in a perturbation of the cell physiological status. Principal component analysis revealed that the impairment of esterase activity combined with the reduction of chlorophyll a content were related with the inhibition of growth caused by a prolonged exposure to the heavy metals. PMID- 25913675 TI - Structure-dependent degradation of polar compounds in weathered oils observed by atmospheric pressure photo-ionization hydrogen/deuterium exchange ultrahigh resolution mass spectrometry. AB - The resin fractions of fresh mixtures of three oils spilled during the M/V Hebei Spirit oil spill, as well as weathered oils collected at weathering stages II and IV from the oil spill site were analyzed and compared by atmospheric pressure photo-ionization hydrogen/deuterium exchange mass spectrometry (HDX MS). The significantly decreased abundance of N(+) and [N-H+D](+) ions suggested that secondary and tertiary amine-containing compounds were preferentially degraded during the early stage of weathering. [N+H](+) and [N+D](+) ions previously attributed to pyridine-type compounds degraded more slowly than secondary and tertiary amine-containing compounds. The preferential degradation of nitrogen containing compounds was confirmed by photo-degradation experiments using 15 standard compounds. In addition, significant increases of [S1O1+H](+) and [S1O1+D](+) ions with higher DBE values were observed from fresh oil mixtures as compared to stages II and IV samples, and that could be linked with the decrease of higher DBE compounds of the S1 class. This study presented convincing arguments and evidence demonstrating that secondary and tertiary amines were more vulnerable to photo-degradation than compounds containing pyridine, and hence, preferential degradation depending on chemical structures must be considered in the production of hazardous or toxic components. PMID- 25913676 TI - Adsorption and adhesiveness of kapok fiber to different oils. AB - Adsorption and adhesiveness of single kapok to various oils, such as diesel, vegetable oil, used motor oil and motor oil were quantitatively evaluated by size and adhesive energy distribution of adsorbed oil droplets on fiber via drop-on fiber micro-sorption experiments based on Carroll's theory of droplet morphology. Meanwhile, another micro polyester fiber was investigated as comparison. It was found that kapok fibers exihibited low surface energy of 40.64 mN/m with highly hydrophobicity and oil wettability. It had high water contact angle up to 151 degrees , adsorbing four oils with average droplet size varying from emulsified state(0.1-25 MUm) to dispersed state (25-100 MUm). The average adhesive energies of kapok to four oils were 3.78*10(-11)-9.40*10(-11) J, with the highest for vegetable oil. Compared with kapok, polyester fiber adsorbed a large number of smaller oil droplets with their average size within emulsified state for its large specific surface area contributed by micro-fine of the fiber, but showed bad adhesiveness to retain the adsorbed oils with average droplet adhesive energy among 1.49*10(-11)-2.27*10(-11)J due to its relative higher surface energy of 59.15 mN/m. It is more suitable to be used as filter for secondary fine filtration under low inflow rate. PMID- 25913677 TI - Hydrodechlorination of polychlorinated molecules using transition metal phosphide catalysts. AB - Ni2P and CoP catalysts (5 wt.% of metal) supported on a commercial SiO2 were tested in the gas phase catalytic hydrodechlorination (HDCl) of mono (chlorobenzene-ClB) and polychlorobenzenes (PCBs) (1,2- dichlorobenzene (1,2 DClB), 1,3-dichlorobenzene (1,3-DClB), 1,4-dichlorobenzene (1,4-DClB), and 1,2,4 trichlorobenzene (1,2,4-TClB)) at atmospheric pressure. It was investigated how the number and position of chlorine atoms in the molecule influence the HDCl activity. The prepared catalysts were characterized by X-ray diffraction (XRD), CO chemisorption, N2 adsorption-desorption at -196 degrees C, and X-ray photoelectron spectroscopy (XPS). Characterization results indicated better active phase dispersion and greater amount of P on the Ni2P catalyst surface. Catalytic results showed that the Ni2P was more active and stable in this type of reactions. The hydrodechlorination activity decreased by increasing the number of chlorine atoms in the molecule and chlorine substituents in close proximity. The observed trend in the HDCl activity was: ClB>1,4-DClB>1,3-DClB>1,2-DClB>1,2,4 TClB. The exception was the catalytic response after 24h on stream observed for the Ni2P in the HDCl reaction of 1,2,4-TClB, which was equal to that observed for the 1,4-DClB molecule, and also yielding benzene as the main reaction product. PMID- 25913678 TI - Evaluation of PCB dechlorination pathways in anaerobic sediment microcosms using an anaerobic dechlorination model. AB - A detailed quantitative analysis of anaerobic dechlorination (AD) pathways of polychlorinated biphenyls (PCBs) in sediment microcosms was performed by applying an anaerobic dechlorination model (ADM). The purpose of ADM is to systematically analyze changes in a contaminant profile that result from microbial reductive dechlorination according to empirically determined dechlorination pathways. In contrast to prior studies that utilized modeling tools to predict dechlorination pathways, ADM also provides quantification of individual pathways. As only microbial reductive dechlorination of PCBs occurred in the modeled laboratory microcosms, extensive analysis of AD pathways was possible without the complicating effect of concurrent physico-chemical or other weathering mechanisms. The results from this study showed: (1) ninety three AD pathways are active; (2) tetra- to hepta-chlorobiphenyl (CB) congeners were common intermediates in several AD pathways, penta-CBs being the most frequently observed; (3) the highest rates of dechlorination were for penta-CB homologs during the initial 185 days; (4) the dominant terminal products of AD were PCB 32(26-4), 49(24-25), 51(24-26), 52(25-25), 72(25-35), 73(26-35) and 100(246-24), (5) potential toxicity of the sediment was reduced. ADM serves as a powerful tool not only for a thorough analysis of AD pathways, but also for providing necessary input for numerical fate models (as a degradation term) that investigate dechlorination products or outcome of natural attenuation, or bioremediation/bioaugmentation of PCB-impacted sediments. PMID- 25913679 TI - Sulfate radicals induced from peroxymonosulfate by cobalt manganese oxides (Co(x)Mn(3-x)O4) for Fenton-Like reaction in water. AB - A series of CoxMn3-xO4 particles as Fenton-like solid catalysts were synthesized, and their catalytic performance in oxidative degradation of organic dye compounds in water was investigated. The surface morphology and structure of the CoxMn3-xO4 catalysts were characterized by field emission scanning electron microscopy (FESEM), energy-dispersive X-ray spectroscopy (EDX), transmission electron microscopy (TEM), powder X-ray diffraction (XRD), and X-ray photoelectron spectroscopy (XPS). The results showed that, as an oxide composite of Co and Mn elements, CoMn2O4 showed much stronger catalytic activity in peroxymonosulfate (PMS) oxidation than Co3O4, Mn2O3, and their physical mixture. Typically, the uses of 0.02 g/dm(3) CoMn2O4 and 0.2 g/dm(3) PMS yielded a nearly complete removal of Rhodamine B (0.03 g/dm(3)) in 80 min at 25 degrees C. The efficiency of Rhodamine B decomposition increased with increasing temperature (15-55 degrees C), but decreased with the increase of fulvic acid concentration (0-0.08 g/dm(3)). Furthermore, CoMn2O4 could maintain its catalytic activity in the repeated batch experiments. Moreover, HO. and SO4(.-) radicals participating in the process were evidenced using quenching experiments, and a rational mechanism was proposed. PMS oxidation with CoMn2O4 is an efficient technique for remediation of organic contaminants in wastewater. PMID- 25913681 TI - Adsorptive capacity and evolution of the pore structure of alumina on reaction with gaseous hydrogen fluoride. AB - Brunauer-Emmet-Teller (BET) specific surface areas are generally used to gauge the propensity of uptake on adsorbents, with less attention paid to kinetic considerations. We explore the importance of such parameters by modeling the pore size distributions of smelter grade aluminas following HF adsorption, an industrially important process in gas cleaning at aluminum smelters. The pore size distributions of industrially fluorinated aluminas, and those contacted with HF in controlled laboratory trials, are reconstructed from the pore structure of the untreated materials when filtered through different models of adsorption. These studies demonstrate the presence of three distinct families of pores: those with uninhibited HF uptake, kinetically limited porosity, and pores that are surface blocked after negligible scrubbing. The surface areas of the inaccessible and blocked pores will overinflate estimates of the adsorption capacity of the adsorbate. We also demonstrate, contrary to conventional understanding, that porosity changes are attributed not to monolayer uptake but more reasonably to pore length attenuation. The model assumes nothing specific regarding the Al2O3 HF system and is therefore likely general to adsorbate/adsorbent phenomena. PMID- 25913682 TI - Sexual dysfunction induced by lacosamide: An underreported side effect? PMID- 25913680 TI - A phase 2 trial of lenvatinib (E7080) in advanced, progressive, radioiodine refractory, differentiated thyroid cancer: A clinical outcomes and biomarker assessment. AB - BACKGROUND: Lenvatinib is an oral, multitargeted tyrosine kinase inhibitor of the vascular endothelial growth factor receptors 1 through 3 (VEGFR1-VEGFR3), fibroblast growth factor receptors 1 through 4 (FGFR1-FGFR4), platelet-derived growth factor receptor alpha (PDGFRalpha), ret proto-oncogene (RET), and v-kit Hardy-Zuckerman 4 feline sarcoma viral oncogene homolog (KIT) signaling networks implicated in tumor angiogenesis. Positive phase 1 results in solid tumors prompted a phase 2 trial in patients with advanced, radioiodine-refractory, differentiated thyroid cancer (RR-DTC). METHODS: Fifty-eight patients with RR-DTC who had disease progression during the previous 12 months received lenvatinib 24 mg once daily in 28-day cycles until disease progression, unmanageable toxicity, withdrawal, or death. Previous VEGFR-targeted therapy was permitted. The primary endpoint was the objective response rate (ORR) based on independent imaging review. Secondary endpoints included progression-free survival (PFS) and safety. Serum levels of 51 circulating cytokines and angiogenic factors also were assessed. RESULTS: After >=14 months of follow-up, patients had an ORR of 50% (95% confidence interval [CI], 37%-63%) with only partial responses reported. The median time to response was 3.6 months, the median response duration was 12.7 months, and the median PFS was 12.6 months (95% CI, 9.9-16.1 months). The ORR for patients who had received previous VEGF therapy (n = 17) was 59% (95% CI, 33% 82%). Lower baseline levels of angiopoietin-2 were suggestive of tumor response and longer PFS. Grade 3 and 4 treatment-emergent adverse events, regardless of their relation to treatment, occurred in 72% of patients and most frequently included weight loss (12%), hypertension (10%), proteinuria (10%), and diarrhea (10%). CONCLUSIONS: In patients with and without prior exposure to VEGF therapy, the encouraging response rates, median time to response, and PFS for lenvatinib have prompted further investigation in a phase 3 trial. Cancer 2015;121:2749 2756. (c) 2015 American Cancer Society. PMID- 25913683 TI - Sustainable food consumption. Product choice or curtailment? AB - Food consumption is an important factor in shaping the sustainability of our food supply. The present paper empirically explores different types of sustainable food behaviors. A distinction between sustainable product choices and curtailment behavior has been investigated empirically and predictors of the two types of behavior have been identified. Respondents were classified into four segments based on their sustainable food behaviors: unsustainers, curtailers, product oriented consumers, and sustainers. Significant differences between the segments were found with regard to food choice motives, personal and social norms, food involvement, subjective knowledge on sustainable food, ability to judge how sustainably a product has been produced and socio-demographics. It is concluded that distinguishing between behavioral strategies toward sustainable food consumption is important as consumer segments can be identified that differ both in their level of sustainable food consumption and in the type of behavior they employ. PMID- 25913684 TI - Using traffic light labels to improve food selection in recreation and sport facility eating environments. AB - Many recreation and sports facilities have unhealthy food environments, however managers are reluctant to offer healthier foods because they perceive patrons will not purchase them. Preliminary evidence indicates that traffic light labeling (TLL) can increase purchase of healthy foods in away-from-home food retail settings. We examined the effectiveness of TLL of menus in promoting healthier food purchases by patrons of a recreation and sport facility concession, and among various sub-groups. TLL of all menu items was implemented for a 1-week period and sales were assessed for 1-week pre- and 1-week post implementation of TLL (n = 2101 transactions). A subset of consumers completed a survey during the baseline (n = 322) and intervention (n = 313) periods. We assessed change in the proportion of patrons' purchases that were labeled with green, yellow and red lights from baseline to the TLL intervention, and association with demographic characteristics and other survey responses. Change in overall revenues was also assessed. There was an overall increase in sales of green (52.2% to 55.5%; p < 0.05) and a reduction in sales of red (30.4% to 27.2%; p < 0.05) light items from baseline to the TLL period. The effectiveness of TLL did not differ according to any of the demographic or other factors examined in the survey. Average daily revenues did not differ between the baseline and TLL periods. TLL of menus increased purchase of healthy, and reduced purchase of unhealthy foods in a publicly funded recreation and sport facility, with no loss of revenue. Policymakers should consider extending menu labeling laws to public buildings such as recreation and sports facilities to promote selection of healthier items. PMID- 25913685 TI - A nudge in a healthy direction. The effect of nutrition labels on food purchasing behaviors in university dining facilities. AB - BACKGROUND: Despite legislation that requires restaurants to post nutritional labels on their products or menu items, the scientific literature provides inconsistent support for the idea that adding labels to foods will change buying patterns. Lack of success of previous research may be that sample sizes have been too small and durations of studies too short. OBJECTIVE: To assess the effect of nutrition labeling on pre-packaged food purchases in university dining facilities. DESIGN: Weekly sales data for a sample of pre-packaged food items were obtained and analyzed, spanning three semesters before and three semesters after nutritional labels were introduced on to the sample of foods. The labels summarized caloric content and nutrient composition information. Mean nutrient composition purchased were calculated for the sample of foods. Labeled food items were categorized as high-calorie, low-calorie, high-fat, or low-fat foods and analyzed for change as a function of the introduction of the labels. SETTING: Data were obtained from all retail dining units located at Cornell University, Ithaca, NY where the pre-packaged food items were sold. RESULTS: Results indicated that the introduction of food labels resulted in a 7% reduction of the mean total kcals purchased per week (p < 0.001) from the labeled foods. Total fat purchased per week were also reduced by 7% (p < 0.001). Percent of sales from "low-calorie" and "low-fat" foods (p < 0.001) increased, while percent of sales from "high-calorie" and "high-fat" foods decreased (p < 0.001). CONCLUSIONS: The results suggest that nutrition labels on pre-packaged foods in a large university dining hall produces a small but significant reduction of labeled high calorie and high fat foods purchased and an increase in low calorie, low fat foods. PMID- 25913686 TI - Chocolate versions of the Food Cravings Questionnaires. Associations with chocolate exposure-induced salivary flow and ad libitum chocolate consumption. AB - The Food Cravings Questionnaires are the most commonly used instruments for the assessment of trait and state food craving. Chocolate is the most frequently craved food in Western societies. In the current studies, the Food Cravings Questionnaire-Trait-reduced (FCQ-T-r) and the Food Cravings Questionnaire-State (FCQ-S) were adapted to capture strong urges for chocolate. In study 1, students (n = 492; 81.3% female) completed chocolate versions of the FCQ-T-r and FCQ-S among other measures online. The FCQ-T-r (alpha = .94) comprised two subscales representing lack of control (alpha = .91) and thoughts about chocolate (alpha = .91). The FCQ-S (alpha = .87) comprised two subscales representing chocolate craving (alpha = .90) and hunger (alpha = .85). FCQ-T-r scores were significantly and positively correlated with self-reported frequency of consuming chocolate and with scores on the Attitudes to Chocolate Questionnaire, indicating good convergent validity. In study 2, students (n = 76; 73.7% female) underwent a chocolate exposure in the laboratory. FCQ-S scores increased during chocolate exposure and increases in momentary chocolate craving were significantly positively correlated with increases in salivary flow. Higher momentary chocolate craving was positively correlated with higher laboratory chocolate consumption. Exploratory analyses revealed that increases in salivary flow were only associated with increased chocolate consumption in participants scoring high, but not low on trait chocolate craving. The chocolate versions of the FCQ-T-r and FCQ S represent reliable and valid self-report measures for the assessment of trait and state chocolate craving. PMID- 25913687 TI - Acceptability of new formulations of corn-soy blends and lipid-based nutrient supplements in Province du Passore, Burkina Faso. AB - The objective of this study was to evaluate the acceptability of new formulations of six corn-soy blended flours (CSB) and six lipid-based nutrient supplements (LNS) with different quantities of milk and qualities of soy to be used for the treatment of moderate acute malnutrition (MAM). Furthermore, we wanted to explore the acceptability of foods currently used for the prevention and treatment of malnutrition in Burkina Faso to identify possible barriers that could affect the acceptability of the new formulations of supplementary foods. The study was carried out prior to a randomized controlled trial evaluating the effectiveness of these new formulations. The study involved an observed test-meal and a three day take-home ration of the experimental food supplements to 6- to 30-months-old healthy children, followed by questionnaire-based interviews about the acceptability of these supplements. Interviews and focus group discussions were carried out to explore the acceptability of foods currently used for the prevention and treatment of malnutrition. The results suggest that both LNS and CSB products with different quantities of milk and qualities of soy are equally well accepted among healthy children in rural Burkina Faso based on general appreciation of the supplements and organoleptic properties. All experimental foods received good ratings and there was no significant difference between the foods. However, after the take-home ration, 58% of participants receiving CSB reported having left-overs at the end of the day compared to 37% (n = 33) of the participants receiving LNS (p = 0.004), suggesting that CSB was not as readily consumed as LNS. Yet, both CSB and LNS products were perceived as easy to administer and the frequency of feeding was estimated to be adequate. The study also found that similar foods, used for the prevention and treatment of malnutrition, were well appreciated in the study location. LNS were to a higher degree associated with medicine or foods with medicinal properties, but both LNS and CSB were perceived as beneficial to child health. PMID- 25913689 TI - Comparative study of the different activities of hepatitis B virus whole-X protein and HBx in hepatocarcinogenesis by proteomics and bioinformatics analysis. AB - The hepatitis B virus (HBV) whole-X gene comprises the HBV X gene and the 168-bp region immediately upstream. Although the functions of HBx in hepatocarcinogenesis are well known, the activity of the HBV whole-X protein (HBwx), with 56 additional amino acids, has not yet been explored. In this study, proteomic and bioinformatic analysis was done to determine the protein interaction profiles of HBwx and HBx and to describe their functions in carcinogenesis. A total of 203 proteins were identified that interacted with HBwx, of which 149 were unique, the rest interacting also with HBx, and 73% (148/203) of these proteins are involved in carcinogenesis. Gene ontology (GO) analysis showed that HBwx- and HBx-interacting proteins are involved in different processes, the former mainly in biosynthetic processes (glycolysis, cell-cycle functions, and protein folding), and the latter mainly in localization, viral transcription, biological adhesion and angiogenesis. Pathway networks analysis revealed that proteins interacting with HBx participate mainly in oxidative phosphorylation, localization, the cytoskeleton, and cell adhesion. In contrast, more-specific functional analysis showed that proteins interacting with HBwx are involved in apoptosis and survival, cell-cycle functions, glycolysis, and gluconeogenesis (Pathway Maps); to cellular macromolecular complex assembly, protein folding and mRNA metabolic process (GO Processes); and to regulation of protein folding in the endoplasmic reticulum and cytoplasm, transcription, cell cycle G2-M and cytoskeleton rearrangement (Process Networks). In conclusion, this study shows that HBwx functions in carcinogenesis in a way that is different from that of HBx. PMID- 25913690 TI - First detection of wheat streak mosaic virus in Germany: molecular and biological characteristics. AB - Wheat streak mosaic virus is a serious threat in wheat-producing countries. In Germany, the virus was first recorded in 2013 near Hoym. The complete sequence of isolate Hoym was obtained and compared to all other known complete WSMV sequences, including newly collected and sequenced isolates from France and Austria. Phylogenetic analysis revealed that the European isolates group together with those from the Middle East to form a separate cluster characterized by a distinct putative P1 protease cleavage site. By means of quantitative reverse transcription polymerase chain reaction, it was shown that RNA of the USA type strain PV57 accumulated to higher levels in infected wheat cv. Alcedo than did RNA of isolate Hoym. PMID- 25913691 TI - Molecular characterization of a citrus yellow vein clearing virus strain from China. AB - The complete nucleotide sequence of an isolate of citrus yellow vein clearing virus from Yunnan, China (CYVCV-RL), was determined following whole-genome amplification by RT-PCR. The CYVCV-RL genome was 7529 nt in length, excluding the 3' poly (A) tail, and contained six open reading frames (ORFs), resembling that of viruses belonging to the genus Mandarivirus in the family Alphaflexiviridae. Sequence analysis showed that the CYVCV-RL shared the greatest nucleotide sequence identity with the CYVCV-Y1 (JX040635) isolate from Turkey for the whole genome (97.1%), 5' UTR (98.7%), 3' UTR (100.0%), and each of six ORFs (96.5% to 97.8%), suggesting that there is apparent genetic stability among CYVCV isolates of different geographic origin. PMID- 25913688 TI - Mutations in the Yeast Hsp70, Ssa1, at P417 Alter ATP Cycling, Interdomain Coupling, and Specific Chaperone Functions. AB - The major cytoplasmic Hsp70 chaperones in the yeast Saccharomyces cerevisiae are the Ssa proteins, and much of our understanding of Hsp70 biology has emerged from studying ssa mutant strains. For example, Ssa1 catalyzes multiple cellular functions, including protein transport and degradation, and to this end, the ssa1 45 mutant has proved invaluable. However, the biochemical defects associated with the corresponding Ssa1-45 protein (P417L) are unknown. Consequently, we characterized Ssa1 P417L, as well as a P417S variant, which corresponds to a mutation in the gene encoding the yeast mitochondrial Hsp70. We discovered that the P417L and P417S proteins exhibit accelerated ATPase activity that was similar to the Hsp40-stimulated rate of ATP hydrolysis of wild-type Ssa1. We also found that the mutant proteins were compromised for peptide binding. These data are consistent with defects in peptide-stimulated ATPase activity and with results from limited proteolysis experiments, which indicated that the mutants' substrate binding domains were highly vulnerable to digestion. Defects in the reactivation of heat-denatured luciferase were also evident. Correspondingly, yeast expressing P417L or P417S as the only copy of Ssa were temperature sensitive and exhibited defects in Ssa1-dependent protein translocation and misfolded protein degradation. Together, our studies suggest that the structure of the substrate binding domain is altered and that coupling between this domain and the nucleotide binding domain is disabled when the conserved P417 residue is mutated. Our data also provide new insights into the nature of the many cellular defects associated with the ssa1-45 allele. PMID- 25913692 TI - Ratification vote on taxonomic proposals to the International Committee on Taxonomy of Viruses (2015). AB - Changes to virus taxonomy approved and ratified by the International Committee on Taxonomy of Viruses in February 2015 are listed. PMID- 25913693 TI - Induction of insulin-producing cells from umbilical cord blood-derived stromal cells by activation of the c-Met/HGF axis. AB - Efficient and effective therapies are required for diabetes mellitus. The use of adult stem cells for treating diabetes represents a major focus of current research. We have attempted to differentiate adult stem cells produced from umbilical cord blood-derived stromal cells into insulin-producing cells (IPCs). By activating the c-Met/HGF axis through temporal hypoxia treatment and hepatocyte growth factor (HGF) supplementation, our protocol resulted in the differentiation of cells into functional pancreatic endocrine cells with increased viability. Glucose stimulation test results showed that significantly greater amounts of C-peptide and insulin were released from the differentiated cells than from undifferentiated cells. These IPCs were capable of reversing the hyperglycemia of diabetic mice. In conclusion, targeting the c-Met/HGF axis can be considered an effective and efficient means of obtaining IPCs from adult stem cells. PMID- 25913694 TI - Stress physiology in marine mammals: how well do they fit the terrestrial model? AB - Stressors are commonly accepted as the causal factors, either internal or external, that evoke physiological responses to mediate the impact of the stressor. The majority of research on the physiological stress response, and costs incurred to an animal, has focused on terrestrial species. This review presents current knowledge on the physiology of the stress response in a lesser studied group of mammals, the marine mammals. Marine mammals are an artificial or pseudo grouping from a taxonomical perspective, as this group represents several distinct and diverse orders of mammals. However, they all are fully or semi aquatic animals and have experienced selective pressures that have shaped their physiology in a manner that differs from terrestrial relatives. What these differences are and how they relate to the stress response is an efflorescent topic of study. The identification of the many facets of the stress response is critical to marine mammal management and conservation efforts. Anthropogenic stressors in marine ecosystems, including ocean noise, pollution, and fisheries interactions, are increasing and the dramatic responses of some marine mammals to these stressors have elevated concerns over the impact of human-related activities on a diverse group of animals that are difficult to monitor. This review covers the physiology of the stress response in marine mammals and places it in context of what is known from research on terrestrial mammals, particularly with respect to mediator activity that diverges from generalized terrestrial models. Challenges in conducting research on stress physiology in marine mammals are discussed and ways to overcome these challenges in the future are suggested. PMID- 25913695 TI - Modelling proton tunnelling in the adenine-thymine base pair. AB - The energies of the canonical (standard, amino-keto) and tautomeric (non standard, imino-enol) charge-neutral forms of the adenine-thymine base pair (A-T and A*-T*, respectively) are calculated using density functional theory. The reaction pathway is then computed using a transition state search to provide the asymmetric double-well potential minima along with the barrier height and shape, which are combined to create the potential energy surface using a polynomial fit. The influence of quantum tunnelling on proton transfer within a base pair H-bond (modelled as the DFT deduced double-well potential) is then investigated by solving the time-dependent master equation for the density matrix. The effect on a quantum system by its surrounding water molecules is explored via the inclusion of a dissipative Lindblad term in the master equation, in which the environment is modelled as a heat bath of harmonic oscillators. It is found that quantum tunnelling, due to transitions to higher energy eigenstates with significant amplitudes in the shallow (tautomeric) side of the potential, is unlikely to be a significant mechanism for the creation of adenine-thymine tautomers within DNA, with thermally assisted coupling of the environment only able to boost the tunnelling probability to a maximum of 2 * 10(-9). This is barely increased for different choices of the starting wave function or when the geometry of the potential energy surface is varied. PMID- 25913696 TI - Robotic pancreaticoduodenectomy in the presence of aberrant or anomalous hepatic arterial anatomy: safety and oncologic outcomes. AB - BACKGROUND: Hepatic arterial anomalies (HAAs) are not infrequently encountered during pancreatic resections. In view of the current emergence of the robotic platform as a safe alternative to open surgery in experienced centres, this study sought to determine the implications of HAAs on the safety and oncologic outcomes of robotic pancreaticoduodenectomy (RPD). METHODS: A prospectively maintained database of patients with HAAs who underwent RPD (RPD + HAA) at a single institution between 2008 and 2013 was retrospectively reviewed. Demographic information and perioperative outcomes of RPD were compared for patients with and without HAAs. RESULTS: A total of 142 patients underwent RPD; 112 (78.9%) did not have and 30 (21.1%) did have HAAs. The majority (90.0%) of RPDs in patients with HAAs were performed for malignant indications and all aberrant vessels were preserved without conversion to laparotomy. There were no statistically significant differences between RPD patients with and without HAAs with respect to preoperative demographics, tumour characteristics, operative metrics (operative time, estimated blood loss, conversion) and postoperative outcomes, including complications, length of stay and readmissions. Negative margin (R0) rates were similar in both groups. CONCLUSIONS: Robot-assisted pancreaticoduodenectomy is safe and feasible in patients with HAAs and has outcomes similar to those in patients with normal arterial anatomy. PMID- 25913698 TI - Prevention of homicidal behaviour in men with psychiatric disorders. AB - OBJECTIVES: Homicide is overwhelmingly committed by men compared to women. Conservative estimates suggest that more than a third of these individuals have a treatable psychiatric disorder. These data present an opportunity to mental health clinicians to assist in the prevention of homicide by improving men's mental health. METHODS: We review the current literature on men's mental health with a focus on assessing and reducing homicide risk in men with psychiatric conditions. RESULTS: Bipolar disorder and schizophrenia appear to share a neural endophenotype that is a risk factor for homicide. Dual disorders, or the presence of a substance use disorder with other major mental illness, are a major risk factor for homicide in males. Dual diagnosis disorders, personality disorders and pathological traits and male depression share emotion dysregulation, irritability, and reactive aggression. Promoting physician education, addressing firearm safety, reducing the reluctance of men relative to women to engage in help-seeking behaviour, and using targeted risk interviews which integrate these data are all currently recommended. CONCLUSIONS: The main focus in prevention of homicidal behaviour in males with psychiatric disorders should be to identify high risk groups, to provide adequate treatment, and to facilitate compliance with long-term treatment while considering male specific problems and needs. PMID- 25913697 TI - Specialty substance use disorder services following brief alcohol intervention: a meta-analysis of randomized controlled trials. AB - BACKGROUND AND AIMS: Brief alcohol interventions in medical settings are efficacious in improving self-reported alcohol consumption among those with low severity alcohol problems. Screening, Brief Intervention and Referral to Treatment initiatives presume that brief interventions are efficacious in linking patients to higher levels of care, but pertinent evidence has not been evaluated. We estimated main and subgroup effects of brief alcohol interventions, regardless of their inclusion of a referral-specific component, in increasing the utilization of alcohol-related care. METHODS: A systematic review of English language papers published in electronic databases to 2013. We included randomized controlled trials (RCTs) of brief alcohol interventions in general health-care settings with adult and adolescent samples. We excluded studies that lacked alcohol services utilization data. Extractions of study characteristics and outcomes were standardized and conducted independently. The primary outcome was post-treatment alcohol services utilization assessed by self-report or administrative data, which we compared across intervention and control groups. RESULTS: Thirteen RCTs met inclusion criteria and nine were meta-analyzed (n = 993 and n = 937 intervention and control group participants, respectively). In our main analyses the pooled risk ratio (RR) was = 1.08, 95% confidence interval (CI) = 0.92-1.28. Five studies compared referral-specific interventions with a control condition without such interventions (pooled RR = 1.08, 95% CI = 0.81 1.43). Other subgroup analyses of studies with common characteristics (e.g. age, setting, severity, risk of bias) yielded non-statistically significant results. CONCLUSIONS: There is a lack of evidence that brief alcohol interventions have any efficacy for increasing the receipt of alcohol-related services. PMID- 25913699 TI - Optimization of methylene blue using Ca(2+) and Zn(2+) bio-polymer hydrogel beads: A comparative study. AB - Recently noted that the methylene blue cause severe central nervous system toxicity. It is essential to optimize the methylene blue from aqueous environment. In this study, a comparison of an optimization of methylene blue was investigated by using modified Ca(2+) and Zn(2+) bio-polymer hydrogel beads. A batch mode study was conducted using various parameters like time, dye concentration, bio-polymer dose, pH and process temperature. The isotherms, kinetics, diffusion and thermodynamic studies were performed for feasibility of the optimization process. Freundlich and Langmuir isotherm equations were used for the prediction of isotherm parameters and correlated with dimensionless separation factor (RL). Pseudo-first order and pseudo-second order Lagegren's kinetic equations were used for the correlation of kinetic parameters. Intraparticle diffusion model was employed for diffusion of the optimization process. The Fourier Transform Infrared Spectroscopy (FTIR) shows different absorbent peaks of Ca(2+) and Zn(2+) beads and the morphology of the bio-polymer material analyzed with Scanning Electron Microscope (SEM). The TG & DTA studies show that good thermal stability with less humidity without production of any non degraded products. PMID- 25913700 TI - Changes of individual BrainAGE during the course of the menstrual cycle. AB - Brain morphology varies during the course of the menstrual cycle, with increases in individual gray matter volume at the time of ovulation. This study implemented our previously presented BrainAGE framework to analyze short-term neuroanatomical changes in healthy young women due to hormonal changes during the menstrual cycle. The BrainAGE approach determines the complex multidimensional aging pattern within the whole brain by applying established kernel regression methods to anatomical brain MRIs. The "Brain Age Gap Estimation" (i.e., BrainAGE) score is then calculated as the difference between chronological age and estimated brain age. Eight women (21-31 years) completed three to four MRI scans during their menstrual cycle (i.e., at (t1) menses, (t2) time of ovulation, (t3) midluteal phase, (t4) next menses). Serum levels of estradiol and progesterone were evaluated at each scanning session. Individual BrainAGE scores significantly differed during the course of the menstrual cycle (p<0.05), with a significant decrease of -1.3 years at ovulation (p<0.05). Moreover, higher estradiol levels significantly correlated with lower BrainAGE scores (r=-0.42, p<0.05). In future, the BrainAGE approach may serve as a sensitive as well as easily implementable tool to further explore the short-term and maybe long-term effects of hormones on brain plasticity and its modulating effects in lifestyle-related diseases and dementia. PMID- 25913701 TI - Functional connectivity hubs of the mouse brain. AB - Recent advances in functional connectivity methods have made it possible to identify brain hubs - a set of highly connected regions serving as integrators of distributed neuronal activity. The integrative role of hub nodes makes these areas points of high vulnerability to dysfunction in brain disorders, and abnormal hub connectivity profiles have been described for several neuropsychiatric disorders. The identification of analogous functional connectivity hubs in preclinical species like the mouse may provide critical insight into the elusive biological underpinnings of these connectional alterations. To spatially locate functional connectivity hubs in the mouse brain, here we applied a fully-weighted network analysis to map whole-brain intrinsic functional connectivity (i.e., the functional connectome) at a high-resolution voxel-scale. Analysis of a large resting-state functional magnetic resonance imaging (rsfMRI) dataset revealed the presence of six distinct functional modules related to known large-scale functional partitions of the brain, including a default-mode network (DMN). Consistent with human studies, highly-connected functional hubs were identified in several sub-regions of the DMN, including the anterior and posterior cingulate and prefrontal cortices, in the thalamus, and in small foci within well-known integrative cortical structures such as the insular and temporal association cortices. According to their integrative role, the identified hubs exhibited mutual preferential interconnections. These findings highlight the presence of evolutionarily-conserved, mutually-interconnected functional hubs in the mouse brain, and may guide future investigations of the biological foundations of aberrant rsfMRI hub connectivity associated with brain pathological states. PMID- 25913702 TI - The ties that bind: Group membership shapes the neural correlates of in-group favoritism. AB - Across species, including non-human primates, rodents, and humans, prosocial behavior, the act of helping others, is preferentially provided to members of one's own group. Whereas a particularly ubiquitous example of this is kinship, whereby humans and animals expend greater resources and take more risks for their own kin, in-group prosocial behavior has been demonstrated among diverse shared social groups, including race and culture. In the current study, we made group membership salient by recruiting Chinese and American participants to engage in a prosocial decision-making task during fMRI with an American and Chinese confederate. We found across all participants that donations to the in-group relative to out-group was associated with increased activation in the ventral striatum. Moreover, participants with a greater sense of group identity and Chinese participants relative to American participants, showed heightened activation in self-control (VLPFC, ACC) and mentalizing (TPJ, DMPFC) regions when contributing to the out-group relative to in-group. Our findings provide novel evidence about the neural mechanisms involved in intergroup prosocial behavior. PMID- 25913703 TI - Empathic control through coordinated interaction of amygdala, theory of mind and extended pain matrix brain regions. AB - Brain regions in the "pain matrix", can be activated by observing or reading about others in physical pain. In previous research, we found that reading stories about others' emotional suffering, by contrast, recruits a different group of brain regions mostly associated with thinking about others' minds. In the current study, we examined the neural circuits responsible for deliberately regulating empathic responses to others' pain and suffering. In Study 1, a sample of college-aged participants (n=18) read stories about physically painful and emotionally distressing events during functional magnetic resonance imaging (fMRI), while either actively empathizing with the main character or trying to remain objective. In Study 2, the same experiment was performed with professional social workers, who are chronically exposed to human suffering (n=21). Across both studies activity in the amygdala was associated with empathic regulation towards others' emotional pain, but not their physical pain. In addition, psychophysiological interaction (PPI) analysis and Granger causal modeling (GCM) showed that amygdala activity while reading about others' emotional pain was preceded by and positively coupled with activity in the theory of mind brain regions, and followed by and negatively coupled with activity in regions associated with physical pain and bodily sensations. Previous work has shown that the amygdala is critically involved in the deliberate control of self-focused distress - the current results extend the central importance of amygdala activity to the control of other-focused empathy, but only when considering others' emotional pain. PMID- 25913704 TI - Activation of the silent secondary metabolite production by introducing neomycin resistance in a marine-derived Penicillium purpurogenum G59. AB - Introduction of neomycin-resistance into a marine-derived, wild-type Penicillium purpurogenum G59 resulted in activation of silent biosynthetic pathways for the secondary metabolite production. Upon treatment of G59 spores with neomycin and dimethyl sulfoxide (DMSO), a total of 56 mutants were obtained by single colony isolation. The acquired resistance of mutants to neomycin was testified by the resistance test. In contrast to the G59 strain, the EtOAc extracts of 28 mutants inhibited the human cancer K562 cells, indicating that the 28 mutants have acquired the capability to produce bioactive metabolites. HPLC-photodiode array detector (PDAD)-UV and HPLC-electron spray ionization (ESI)-MS analyses further indicated that diverse secondary metabolites have been newly produced in the bioactive mutant extracts. Followed isolation and characterization demonstrated that five bioactive secondary metabolites, curvularin (1), citrinin (2), penicitrinone A (3), erythro-23-O-methylneocyclocitrinol (4) and 22E-7alpha methoxy-5alpha, 6alpha-epoxyergosta-8(14),22-dien-3beta-ol (5), were newly produced by a mutant, 4-30, compared to the G59 strain. All 1-5 were also not yet found in the secondary metabolites of other wild type P. purpurogenum strains. Compounds 1-5 inhibited human cancer K562, HL-60, HeLa and BGC-823 cells to varying extents. Both present bioassays and chemical investigations demonstrated that the introduction of neomycin-resistance into the marine-derived fungal G59 strain could activate silent secondary metabolite production. The present work not only extended the previous DMSO-mediated method for introducing drug resistance in fungi both in DMSO concentrations and antibiotics, but also additionally exemplified effectiveness of this method for activating silent fungal secondary metabolites. This method could be applied to other fungal isolates to elicit their metabolic potentials to investigate secondary metabolites from silent biosynthetic pathways. PMID- 25913705 TI - Synthesis and in vitro antiproliferative evaluation of some B-norcholesteryl Benzimidazole and Benzothiazole derivatives. AB - Taking orostanal (a compound from a Japanese marine sponge, Stelletta hiwasaensis) as a lead compound, some novel B-norcholesteryl benzimidazole and benzothiazole derivatives were synthesized. The antiproliferative activity of the compounds against human cervical carcinoma (HeLa), human lung carcinoma (A549), human liver carcinoma cells (HEPG2) and normal kidney epithelial cells (HEK293T) was assayed. The results revealed that the benzimidazole group was a better substituent than benzothiazole group for increasing the antiproliferative activity of compounds. 2-(3beta'-Acetoxy-5beta'-hydroxy-6'-B norcholesteryl)benzimidazole (9b) with the structure of 6-benzimidazole displays the best antiproliferative activity to the cancer cells in all compounds, but is almost inactive to normal kidney epithelial cells (HEK293T). The assay of compound 9b to cancer cell apoptosis by flow cytometry showed that the compound was able to effectively induce cancer cell apoptosis. The research provided a theoretical reference for the exploration of new anti-cancer agents and may be useful for the design of novel chemotherapeutic drugs. PMID- 25913706 TI - Xyloketal B suppresses glioblastoma cell proliferation and migration in vitro through inhibiting TRPM7-regulated PI3K/Akt and MEK/ERK signaling pathways. AB - Glioblastoma, the most common and aggressive type of brain tumors, has devastatingly proliferative and invasive characteristics. The need for finding a novel and specific drug target is urgent as the current approaches have limited therapeutic effects in treating glioblastoma. Xyloketal B is a marine compound obtained from mangrove fungus Xylaria sp. (No. 2508) from the South China Sea, and has displayed antioxidant activity and protective effects on endothelial and neuronal oxidative injuries. In this study, we used a glioblastoma U251 cell line to (1) explore the effects of xyloketal B on cell viability, proliferation, and migration; and (2) investigate the underlying molecular mechanisms and signaling pathways. MTT assay, colony formation, wound healing, western blot, and patch clamp techniques were employed. We found that xyloketal B reduced cell viability, proliferation, and migration of U251 cells. In addition, xyloketal B decreased p Akt and p-ERK1/2 protein expressions. Furthermore, xyloketal B blocked TRPM7 currents in HEK-293 cells overexpressing TRPM7. These effects were confirmed by using a TRPM7 inhibitor, carvacrol, in a parallel experiment. Our findings indicate that TRPM7-regulated PI3K/Akt and MEK/ERK signaling is involved in anti proliferation and migration effects of xyloketal B on U251 cells, providing in vitro evidence for the marine compound xyloketal B to be a potential drug for treating glioblastoma. PMID- 25913707 TI - New polyphenols from a deep sea Spiromastix sp. Fungus, and their antibacterial activities. AB - Eleven new polyphenols namely spiromastols A-K (1-11) were isolated from the fermentation broth of a deep sea-derived fungus Spiromastix sp. MCCC 3A00308. Their structures were determined by extensive NMR data and mass spectroscopic analysis in association with chemical conversion. The structures are classified as diphenyl ethers, diphenyl esters and isocoumarin derivatives, while the n propyl group in the analogues is rarely found in natural products. Compounds 1-3 exhibited potent inhibitory effects against a panel of bacterial strains, including Xanthomanes vesicatoria, Pseudomonas lachrymans, Agrobacterium tumefaciens, Ralstonia solanacearum, Bacillus thuringensis, Staphylococcus aureus and Bacillus subtilis, with minimal inhibitory concentration (MIC) values ranging from 0.25 to 4 ug/mL. The structure-activity relationships are discussed, while the polychlorinated analogues 1-3 are assumed to be a promising structural model for further development as antibacterial agents. PMID- 25913708 TI - UPLC-MSE profiling of Phytoplankton metabolites: application to the identification of pigments and structural analysis of metabolites in Porphyridium purpureum. AB - A fast and high-resolution UPLC-MSE analysis was used to identify phytoplankton pigments in an ethanol extract of Porphyridium purpureum (Pp) devoid of phycobiliproteins. In a first step, 22 standard pigments were analyzed by UPLC MSE to build a database including retention time and accurate masses of parent and fragment ions. Using this database, seven pigments or derivatives previously reported in Pp were unequivocally identified: beta,beta-carotene, chlorophyll a, zeaxanthin, chlorophyllide a, pheophorbide a, pheophytin a, and cryptoxanthin. Minor amounts of Divinyl chlorophyll a, a chemotaxonomic pigment marker for prochlorophytes, were also unequivocally identified using the database. Additional analysis of ionization and fragmentation patterns indicated the presence of ions that could correspond to hydroxylated derivatives of chlorophyll a and pheophytin a, produced during the ethanolic extraction, as well as previously described galactosyldiacylglycerols, the thylakoid coenzyme plastoquinone, and gracilamide B, a molecule previously reported in the red seaweed Gracillaria asiatica. These data point to UPLC-MSE as an efficient technique to identify phytoplankton pigments for which standards are available, and demonstrate its major interest as a complementary method for the structural elucidation of ionizable marine molecules. PMID- 25913710 TI - Stereoselective construction of functionalized tetracyclic and pentacyclic coumarinopyranpyrazole/pyrimidinedione/coumarin scaffolds using a solid-state melt reaction. AB - An assembly of tetra / pentacyclic hybrid scaffolds have been synthesized for the first time using a solid-state melt reaction in a stereoselective fashion with excellent yields. PMID- 25913709 TI - Phthalate metabolites and bisphenol-A in association with circulating angiogenic biomarkers across pregnancy. AB - INTRODUCTION: Phthalates and bisphenol-a (BPA) are endocrine disrupting compounds with widespread exposure that have been linked to adverse birth outcomes and developmental effects. We hypothesized that these associations may be mediated in part through altered placental development and function consequent to exposure. To investigate this question, we examined associations between plasma biomarkers of angiogenesis and urinary biomarkers of exposure to phthalates and bisphenol-a (BPA) measured at repeated time points across pregnancy. METHODS: We utilized a nested case-control population of 130 mothers who delivered preterm and 352 who delivered term from a prospective birth cohort. Placental growth factor (PlGF) and soluble fms-like tyrosine kinase-1 (sFlt-1) were measured in plasma samples collected from up to four visits during pregnancy (median 10, 18, 26, and 35 weeks). Phthalate metabolites and BPA were measured in urine samples collected at the same visits as indices of exposure. RESULTS: In linear mixed effects models adjusted for urine dilution and gestational age at sample collection, oxidized di 2-ethylhexyl phthalate (DEHP) metabolites were associated with decreases in PlGF as well as increases in the sFlt-1 to PlGF ratio. These results were slightly attenuated in fully adjusted models. Other phthalate metabolites did not show consistent relationships with either sFlt-1 or PlGF. BPA, however, was associated with increased sFlt-1 as well as the sFlt-1 to PlGF ratio in both crude and adjusted models. DISCUSSION: We observed associations between urinary DEHP metabolites and BPA and biomarkers of angiogenesis during pregnancy that may be indicative of disrupted placental development and/or function during gestation. PMID- 25913711 TI - Exposure of the population of Catalonia (Spain) to musk fragrances through seafood consumption: Risk assessment. AB - The occurrence of ten synthetic musks in samples of 10 widely consumed fish and shellfish species from Tarragona (Catalonia, Spain) was determined. The most used nitro and polycyclic musks, as well as a well-known transformation product in tissues, were analyzed. Furthermore, the human health risks derived from the musk exposure through seafood consumption were characterized. None of the nitro musks were detected in any of the analyzed samples. In contrast, most of the polycyclic musks were found, being galaxolide (HHCB) and tonalide (AHTN) present in all the samples. HHCB was the greatest contributor, with maximum levels in sardine and mackerel (367 and 304 ng g(-1) (d.w.) (dry weight), respectively). The highest exposure to individual musks was estimated for HHCB and HHCB-Lactone, with average values of 19.7 and 6.8 ng kg(-1)bw day(-1), respectively, in adults. A notably lower mean exposure was calculated for AHTN, cashmeran (DPMI) and traseolide (ATII), being ranged between 1.1 and 3.7 ng kg(-1)bw day(-1). The current concentrations of musks in fish and shellfish should not mean human health risks for the adult population living in Tarragona. However, a continuous monitoring would be desirable to assure that the exposure does not follow increasing temporal trends. PMID- 25913712 TI - Helmets, head injury and concussion in sport. AB - Research on the mechanism of concussion in recent years has been focused on the mechanism of injury as well as strategies to minimize or reverse injury. Sports related head injury research has led to the development of head protective gear that has evolved over the years. Headgears have been designed to protect athletes from skull fractures, subdural hemorrhages and concussions. Over the years, through experience of athletes and continued scientific research, improvements in helmet design have been made. Although these advances have decreased the number of catastrophic injuries throughout sports, the effects on concussions are promising, but largely unproven. In this review, we will discuss development of helmets and studies analyzing their level of protection for both concussion and head injury. This will help us understand what future developments are still needed to minimize the risk of concussion among athletes in various forms of sports. PMID- 25913713 TI - Drug induced osteonecrosis of the jaw. AB - Despite the widespread use of bisphosphonates and their unequivocal efficacy for the treatment of various disease states, osteonecrosis of the jaw remains one of the most feared complications associated with their use. Current evidence, however, suggests that there is also a relationship between occurrence of osteonecrosis of the jaw and use of other classes of pharmacotherapies namely RANKL inhibitors as well as angiogenesis inhibitors. Although these drugs have different mechanisms of action than bisphosphonates, they all seem to interfere with the bone remodeling process i.e. alter the balance between bone resorption and bone formation which may be the most plausible explanation for pathogenesis of osteonecrosis of the jaw. The main objective of this review is to introduce the readership to a number of relatively new medications that may cause osteonecrosis of the jaw. Accordingly, we will summarize latest findings from clinical studies, meta analyses and case reports published in medical literature on this topic. For some of these medications, the evidence may not appear as robust as that for bisphosphonates; yet, the possibility of this adverse event occurring with these non bisphosphonate drugs should never be precluded unless proven otherwise. Thus, it is imperative that health care providers implement preventive measures so as to circumvent the incidence of osteonecrosis of the jaw. In this day of age where medical care is becoming personalized, we will highlight some of significant findings from studies seeking to identify genetic markers that may potentially play a role in development of osteonecrosis of the jaw. PMID- 25913714 TI - Available evidence on re-irradiation with stereotactic ablative radiotherapy following high-dose previous thoracic radiotherapy for lung malignancies. AB - Patients affected with intra-thoracic recurrences of primary or secondary lung malignancies after a first course of definitive radiotherapy have limited therapeutic options, and they are often treated with a palliative intent. Re irradiation with stereotactic ablative radiotherapy (SABR) represents an appealing approach, due to the optimized dose distribution that allows for high dose delivery with better sparing of organs at risk. This strategy has the goal of long-term control and even cure. Aim of this review is to report and discuss published data on re-irradiation with SABR in terms of efficacy and toxicity. Results indicate that thoracic re-irradiation may offer satisfactory disease control, however the data on outcome and toxicity are derived from low quality retrospective studies, and results should be cautiously interpreted. As SABR may be associated with serious toxicity, attention should be paid for an accurate patients' selection. PMID- 25913715 TI - Primary mediastinal large B-cell lymphoma. AB - The management of primary mediastinal large B-cell lymphoma (PMBCL) requires a balance between optimizing chances of cure and reducing risk of long-term toxicities. The combination of rituximab to cyclophosphamide, doxorubicin, vincristine and prednisone (RCHOP) followed by mediastinal radiation results in a plateau in progression-free survival after first few years of follow-up. In rituximab era, a negative positron emission tomography (PET) scan performed after the completion of immunochemotherapy has a high predictive value for durable remission. Consequently, end-of-therapy PET may be utilizable to avoid radiation without compromising survival. Additionally, intensified chemotherapy alone has shown excellent survival. PMBCL is frequently associated with amplification of programmed death ligand (PDL) 1/2 and constitutive activation of JAK-STAT and NFKB pathways; these may serve as promising therapeutic targets. Clinical trials that integrate novel therapies into upfront immunochemotherapy and utilize end-of therapy PET scan to guide mediastinal radiation have potential to further enhance survival and prevent long-term toxicities. PMID- 25913716 TI - Incorporation of ammonium fluoride into clathrate hydrate lattices and its significance in inhibiting hydrate formation. AB - The stability of hydrate frameworks is influenced by guest molecules capable of hydrogen bonding with surrounding water molecules. Four remarkable features from the ammonium fluoride incorporation into a crystalline hydrate matrix provide important information on the thermodynamic stability, formation kinetics, structural characteristics, and molecular behavior in clathrate hydrate systems. PMID- 25913717 TI - Inconsistency and features of single nucleotide variants detected in whole exome sequencing versus transcriptome sequencing: A case study in lung cancer. AB - Whole exome sequencing (WES) and RNA sequencing (RNA-Seq) are two main platforms used for next-generation sequencing (NGS). While WES is primarily for DNA variant discovery and RNA-Seq is mainly for measurement of gene expression, both can be used for detection of genetic variants, especially single nucleotide variants (SNVs). How consistently variants can be detected from WES and RNA-Seq has not been systematically evaluated. In this study, we examined the technical and biological inconsistencies in SNV detection using WES and RNA-Seq data from 27 pairs of tumor and matched normal samples. We analyzed SNVs in three categories: WES unique - those only detected in WES, RNA-Seq unique - those only detected in RNA-Seq, and shared - those detected in both. We found a small overlap (average ~14%) between the SNVs called in WES and RNA-Seq. The WES unique SNVs were mainly due to low coverage, low expression, or their location on the non-transcribed strand in RNA-Seq data, while the RNA-Seq unique SNVs were primarily due to their location out of the WES-capture boundary regions (accounting ~71%), as well as low coverage of the regions, low coverage of the mutant alleles or RNA-editing. The shared SNVs had high locus-specific coverage in both WES and RNA-Seq and high gene expression levels. Additionally, WES unique and RNA-Seq unique SNVs showed different nucleotide substitution patterns, e.g., ~55% of RNA-Seq unique variants were A:T->G:C, a hallmark of RNA editing. This study provides an important evaluation on the inconsistencies of somatic SNVs called in WES and RNA-Seq data. PMID- 25913719 TI - Lateralisation abnormalities in obsessive-compulsive disorder: a line bisection study. AB - OBJECTIVE: Asymmetry in brain structure and function is implicated in the pathogenesis of psychiatric disorders. Although right hemisphere abnormality has been documented in obsessive-compulsive disorder (OCD), cerebral asymmetry is rarely examined. Therefore, in this study, we examined anomalous cerebral asymmetry in OCD patients using the line bisection task. METHODS: A total of 30 patients with OCD and 30 matched healthy controls were examined using a reliable and valid two-hand line bisection (LBS) task. The comparative profiles of LBS scores were analysed using analysis of covariance. RESULTS: Patients with OCD bisected significantly less number of lines to the left and had significant rightward deviation than controls, indicating right hemisphere dysfunction. The correlations observed in this study suggest that those with impaired laterality had more severe illness at baseline. CONCLUSIONS: The findings of this study indicate abnormal cerebral lateralisation and right hemisphere dysfunction in OCD patients. PMID- 25913718 TI - Human platelets and their capacity of binding viruses: meaning and challenges? AB - Blood platelets are first aimed at ensuring primary hemostasis. Beyond this role, they have been acknowledged as having functions in the maintenance of the vascular arborescence and, more recently, as being also innate immune cells, devoted notably to the detection of danger signals, of which infectious ones. Platelets express pathogen recognition receptors that can sense bacterial and viral moieties. Besides, several molecules that bind epithelial or sub endothelial molecules and, so forth, are involved in hemostasis, happen to be able to ligate viral determinants, making platelets capable of either binding viruses or even to be infected by some of them. Further, as platelets express both Fc-receptors for Ig and complement receptors, they also bind occasionally virus-Ig or virus-Ig-complement immune complexes. Interplays of viruses with platelets are very complex and viral infections often interfere with platelet number and functions. Through a few instances of viral infections, the present review aims at presenting some of the most important interactions from pathophysiological and clinical points of view, which are observed between human viruses and platelets. PMID- 25913720 TI - Manipulation of B-cell responses with histone deacetylase inhibitors. AB - Histone deacetylase inhibitors (HDACi) are approved for treating certain haematological malignancies, however, recent evidence also illustrates they are modulators of the immune system. In experimental models, HDACi are particularly potent against malignancies originating from the B-lymphocyte lineage. Here we examine the ability of this class of compounds to modify both protective and autoimmune antibody responses. In vitro, HDACi affect B-cell proliferation, survival and differentiation in an HDAC-class-dependent manner. Strikingly, treatment of lupus-prone Mrl/lpr mice with the HDACi panobinostat significantly reduces autoreactive plasma-cell numbers, autoantibodies and nephritis, while other immune parameters remain largely unaffected. Immunized control mice treated with panobinostat or the clinically approved HDACi vorinostat have significantly impaired primary antibody responses, but these treatments surprisingly spare circulating memory B cells. These studies indicate that panobinostat is a potential therapy for B-cell-driven autoimmune conditions and HDACi do not induce major long-term detrimental effects on B-cell memory. PMID- 25913721 TI - Faecal excretion of total and acid extractable phosphorus in dairy cows fed rations with different levels of phosphorus. AB - BACKGROUND: The phosphorus (P) originating from livestock operations causes eutrophication. Determination of acid extractable P (AEP) in cattle faeces has been proposed as a tool to identify excessive P feeding. The method has not yet been evaluated in controlled studies with cows subjected to individual recording of P intake. Thus the present study focused on investigating the relationship between different P fractions in faeces from cows fed rations with varying P content. The study also investigated whether AEP in faeces could be used to estimate dietary P intake in relation to the P requirement. RESULTS: The results showed that acid extractable P predicted P overfeeding. P fed in excess of requirements was largely excreted as acid extractable P. The unavailable and/or inevitably lost P fractions in the diets were smaller than assumed. CONCLUSION: This study demonstrates in experimental studies a positive relationship between measured AEP and indirectly calculated regulated P. Any P fed in excess of requirements was largely excreted as AEP. This fraction is thought to be the most mobile P fraction with regard to potential runoff losses. However, the unavailable and/or inevitably lost P fractions in the diets were smaller than assumed. PMID- 25913722 TI - beta-hCG-Secreting Anaplastic Large Cell Lymphoma. PMID- 25913723 TI - Bivalirudin versus heparin in patients with acute myocardial infarction: A meta analysis of randomized trials. AB - BACKGROUND: The aim of this study was to assess the impact of bivalirudin, as compared to unfractionated heparin, on clinical outcomes in patients with ST segment elevation myocardial infarction (STEMI). METHODS: A meta-analysis of randomized trials comparing bivalirudin versus heparin in patients with STEMI undergoing primary percutaneous coronary intervention was performed. Three randomised trials enrolling 7,612 patients were included. Analysis was by intention to treat. RESULTS: At 30 days, bivalirudin, as compared to heparin, was associated with a similar risk of all-cause mortality (3.03% vs. 3.38%, odds ratio (OR) 0.90, 95% confidence intervals (CI) [0.63 to 1.29], P = 0.57). Bivalirudin significantly increased the risk of definite (2.39% vs. 1.06%, OR 2.49, 95% CI [1.30 to 4.76], P = 0.006); definite or probable (2.55% vs. 1.35%, OR 2.26, 95% CI [1.07 to 4.79], P = 0.03), and acute stent thrombosis (1.69% vs. 0.39%, OR 4.34, 95% CI [2.30 to 8.16], P < 0.001); leading to nonsignificantly higher reinfarction rates (2.0% vs. 1.31%, OR 1.72, 95% CI [0.89 to 3.35], P = 0.11), and to a significantly increased risk of ischemia driven revascularization (2.50% vs. 1.52%, OR 1.80, 95% CI [1.02 to 3.18], P = 0.04) at 30 days. No firm evidence for a reduction in major bleeding associated with bivalirudin use was found (3.93% vs. 6.39%, OR 0.63, 95% CI [0.39 to 1.04], P = 0.07). CONCLUSIONS: In patients with STEMI, bivalirudin, as compared to heparin, increases the risk of stent thrombosis and ischemia driven repeat revascularization at 30 days. There is no strong evidence that bivalirudin significantly reduces major bleeding at 30 days. Bivalirudin does not have an effect on all-cause mortality at 30 days. PMID- 25913724 TI - Chemistry-enabled methods for the visualization of cell-surface glycoproteins in Metazoans. AB - The majority of cell-surface and secreted proteins are glycosylated, which can directly affect their macromolecular interactions, stability, and localization. Investigating these effects is critical to developing a complete understanding of the role of glycoproteins in fundamental biology and human disease. The development of selective and unique chemical reactions have revolutionized the visualization, identification, and characterization of glycoproteins. Here, we review the chemical methods that have been created to enable the visualization of the major types of cell-surface glycoproteins in living systems, from mammalian cells to whole animals. PMID- 25913725 TI - Chemical approach for target-selective degradation of oligosaccharides using photoactivatable organic molecules. AB - Molecular design, chemical synthesis, and biological evaluation of several organic molecules, which can target-selectively photodegrade oligosaccharides by irradiation with a specific wavelength of light under mild conditions without any additives, are introduced. These novel class of photochemical agents promise bright prospects for finding not only molecular-targeted bioprobes for understanding of the structure-activity relationships of oligosaccharides but also novel therapeutic drugs targeting biologically important oligosaccharides. PMID- 25913726 TI - Oral anticoagulants and risk of nephropathy. AB - Anticoagulant-related nephropathy, a recently recognized entity, manifests as unexplained acute kidney injury in the setting of excessive anticoagulation with oral agents. Histologic findings in warfarin-related nephropathy include glomerular hemorrhage and renal tubular obstruction by red blood cells. Affected patients are at increased risk of mortality as well as irreversible kidney injury. Patients with chronic kidney disease are particularly vulnerable to this complication. Similar case reports of anticoagulant-related nephropathy have been linked to the more novel oral anticoagulant, dabigatran. Anticoagulant-related nephropathy has been successfully reproduced in rat models. These animal models shed light on the pathogenesis of the disease including the potential role of direct thrombin and protease-activated receptor-1 inhibition. Warfarin and dabigatran also cause an increase in systolic blood pressure in rats, a risk factor for developing nephropathy. This article reviews the current evidence for anticoagulant-related nephropathy and provides data for the suggested possible mechanisms underlying this adverse effect. PMID- 25913727 TI - Identification of a premature stop codon mutation in the PHGDH gene in severe Neu Laxova syndrome-evidence for phenotypic variability. AB - In some cases Neu-Laxova syndrome (NLS) is linked to serine deficiency due to mutations in the phosphoglycerate dehydrogenase (PHGDH) gene. We describe the prenatal and postnatal findings in a fetus with one of the most severe NLS phenotypes described so far, caused by a homozygous nonsense mutation of PHGDH. Serial ultrasound (US) and pre- and postnatal magnetic resonance imaging (MRI) evaluations were performed. Prenatally, serial US evaluations suggested symmetric growth restriction, microcephaly, hypoplasia of the cerebellar vermis, micrognathia, hydrops, shortened limbs, arthrogryposis, and talipes equinovarus. The prenatal MRI confirmed these findings prompting a diagnosis of NLS. After birth, radiological imaging did not detect any gross bone abnormalities. DNA was extracted from fetal and parental peripheral blood, all coding exons of PHGDH were PCR-amplified and subjected to Sanger sequencing. Sequencing of PHGDH identified a homozygous premature stop codon mutation (c.1297C>T; p.Gln433*) in fetal DNA, both parents (first-cousins) being heterozygotes. Based on previous associations of mutations in this gene with a milder NLS phenotype, as well as cases of serine deficiency, these observations lend further support to a genotype phenotype correlation between the degree of PHGDH inactivation and disease severity. PMID- 25913728 TI - Development of a colloidal gold immunochromatographic strip for the rapid detection of soft-shelled turtle systemic septicemia spherical virus. AB - A colloidal gold immunochromatographic strip (ICS) test based on a competitive format was developed for the rapid detection of soft-shelled turtle systemic septicemia spherical virus (STSSSV) in turtle and fecal samples. Specific egg yolk antibodies (IgY) against STSSSV were labeled with colloidal gold and used as probes in the one-step test strip. Antigen (STSSSV) and goat anti-chicken IgY were drawn on the nitrocellulose membrane as the test line and control line, respectively. When STSSSV standard samples (0-100MUg/mL) were detected by the strips, the visual limit of detection (LOD) was found to be 50.0MUg/mL. The ICS test showed high stability; the strips were stable for at least 3 months at 4 degrees C without significant loss of activity. There was no obvious cross reactivity with other aquatic pathogens. The assay can be performed within 5 10min. Analysis of STSSSV in turtle samples revealed that data obtained from the ICS test were in a good agreement with those obtained by ELISA. The positive results of fecal samples suggested that this method could be used to detect STSSSV while protecting the animals' welfare. The ICS assay does not need specialized equipment or a technician and can be used as a reliable, rapid, cost effective and convenient qualitative tool for on-site diagnosis. PMID- 25913729 TI - Deconstructing cartilage shape and size into contributions from embryogenesis, metamorphosis, and tadpole and frog growth. AB - Understanding skeletal diversification involves knowing not only how skeletal rudiments are shaped embryonically, but also how skeletal shape changes throughout life. The pharyngeal arch (PA) skeleton of metamorphosing amphibians persists largely as cartilage and undergoes two phases of development (embryogenesis and metamorphosis) and two phases of growth (larval and post metamorphic). Though embryogenesis and metamorphosis produce species-specific features of PA cartilage shape, the extents to which shape and size change during growth and metamorphosis remain unaddressed. This study uses allometric equations and thin-plate spline, relative warp and elliptic Fourier analyses to describe shape and size trajectories for the ventral PA cartilages of the frog Xenopus laevis in tadpole and frog growth and metamorphosis. Cartilage sizes scale negatively with body size in both growth phases and cartilage shapes scale isometrically or close to it. This implies that most species-specific aspects of cartilage shape arise in embryogenesis and metamorphosis. Contributions from growth are limited to minor changes in lower jaw (LJ) curvature that produce relative gape narrowing and widening in tadpoles and frogs, respectively, and most cartilages becoming relatively thinner. Metamorphosis involves previously unreported decreases in cartilage size as well as changes in cartilage shape. The LJ becomes slightly longer, narrower and more curved, and the adult ceratohyal emerges from deep within the resorbing tadpole ceratohyal. This contrast in shape and size changes suggests a fundamental difference in the underlying cellular pathways. The observation that variation in PA cartilage shape decreases with tadpole growth supports the hypothesis that isometric growth is required for the metamorphic remodeling of PA cartilages. It also supports the existence of shape regulating mechanisms that are specific to PA cartilages and that resist local adaptation and phenotypic plasticity. PMID- 25913730 TI - Should central lymph node dissection be considered for all papillary thyroid microcarcinoma? AB - BACKGROUND: Central lymph node dissection (CLND) in patients with papillary thyroid microcarcinoma (PTMC) is still controversial. The aim of this study was to examine the risk factors and the incidence of central lymph node metastases (CLNMs) in patients with PTMC who underwent thyroidectomy and CLND. PATIENTS AND METHODS: Between 2002 and 2013, 613 patients were enrolled who underwent thyroidectomy with routine CLND for PTMC at the Korea University Medical Center, Ansan Hospital and risk factors and the incidence of CLNM were analyzed. In addition, we also evaluated the complications after thyroidectomy with CLND. RESULTS: Out of 613 patients, 239 (39.0%) were found to have CLNM. Male sex (p = 0.012), tumor size >= 0.5 cm (p = 0.001), capsular invasion or extrathyroidal extension (p = 0.029), and multifocality (p = 0.004) were independent risk factors for CLNM. Among the 69 patients who had PTMC without these risk factors, CLNM was identified in 12 (17.4%). In this study group, two (0.3%) had permanent recurrent laryngeal nerve injury, two (0.3%) had persistent hypocalcemia, and two (0.3%) developed postoperative hemorrhage. CONCLUSION: CLNM in PTMC is highly prevalent in male sex, tumor size >= 0.5 cm, extrathyroidal extension, and multifocality. Even in PTMC patients without these risk factors, the incidence of CLNM is rather higher than expected, and the complication rate of thyroidectomy with CLND is acceptable. Thus, CLND should be considered in all patients with PTMC. PMID- 25913731 TI - Surgical results of reduced port laparoscopic adrenalectomy using a multichannel port in comparison with conventional laparoscopic adrenalectomy. AB - BACKGROUND: We introduced a modified laparoscopic technique, dual-incision laparoscopic adrenalectomy (DILA), using a newly designed multichannel trocar, and we evaluated its perioperative outcomes and operative costs and compared them to those of conventional laparoscopic adrenalectomy (CLA). METHODS: We retrospectively reviewed the medical records of 127 patients who underwent CLA with four trocars or DILA with two trocars at Seoul St. Mary's Hospital, Seoul, Korea between October 2007 and September 2014. We analyzed the patients' surgical outcomes and perioperative morbidities. RESULTS: DILA was performed in 45 patients and CLA in 82 patients. There were no significant differences in operative time (DILA: 77.1 +/- 28.4 minutes vs. CLA: 76.6 +/- 28.0 minutes, p = 0.595) or estimated blood loss during surgery (DILA: 150.0 +/- 85.5 mL vs. CLA: 175.5 +/- 50.5 mL, p = 0.697). There were no differences in postoperative hospital stay, visual analog scale pain score, or postoperative complication rates between the two groups. However, the operative cost was significantly lower in the DILA group (DILA 813,603 +/- 48,600 Korean won vs. CLA 968,368 +/- 56,456 Korean won, p < 0.001). CONCLUSION: This study demonstrated that DILA is a safe and feasible surgical approach for adrenal diseases. DILA may reduce the operative cost significantly compared with CLA. PMID- 25913732 TI - Meta-analysis of pancreaticogastrostomy versus pancreaticojejunostomy on occurrences of postoperative pancreatic fistula after pancreaticoduodenectomy. AB - BACKGROUND/OBJECTIVE: Pancreatic fistula (PF) is the most common and challenging complication after pancreaticoduodenectomy (PD). This meta-analysis aimed to evaluate the impact of pancreaticogastrostomy (PG) versus pancreaticojejunostomy (PJ) on occurrences of postoperative PF. METHODS: A systematic literature search in the Medline, EMBASE, OVID, and Cochrane databases was performed to identify all eligible randomized controlled trials (RCTs). Pooled estimates were presented with 95% confidence intervals (CI). RESULTS: Six RCTs involving 1005 patients met the inclusion criteria. The incidence of PF [odds ratio (OR) 0.58, 95% CI, 0.42 0.81; p = 0.001], intra-abdominal abscess or collections (OR 0.43, 95% CI, 0.28 0.65; p < 0.001), and biliary fistula (OR 0.28, 95% CI, 0.11-0.74; p = 0.01) were found to be significantly lower in the PG group than in the PJ group. There was no significant difference in overall morbidity, other complications, hospital mortality, or length of hospital stay between the two groups. CONCLUSION: The meta-analysis showed that PG following PD represents a safe procedure associated with fewer PFs compared with PJ. PMID- 25913733 TI - Cryopreservation of Sambar deer semen in Thailand. AB - Little is known of the different freezing and thawing techniques for post-thaw survival of spermatozoa in Sambar deer. So, this study determined the effect of seminal plasma, egg yolk and glycerol extenders and their concentrations, plus cooling, freezing, and thawing protocols on the post-thaw quality of their semen. Semen samples were collected by electro-ejaculation from four Thai Sambar deer stags (Cervus unicolor equinus). As evaluated by post-thaw progressive motility and acrosome integrity removal of seminal plasma was beneficial; Tris-egg yolk was the most efficient extender; a 20% egg yolk concentration was better than the 0%, 10%, or 30%; and a 3% glycerol concentration was better than 5%, 7%, or 9%. Using the optimum dilution techniques, semen was loaded in 0.5 ml plastic straws. Cooling times from ambient temperature to 5 degrees C in 3 hr resulted in higher post-thaw progressive motility and acrosome integrity than 1, 2, or 4 hr. Suspending the straws 4 cm above the surface for 15 min before plunging into liquid nitrogen was better than suspending at 2 or 6 cm. For thawing frozen semen, an intermediate thawing (50 degrees C, 8 sec) protocol was more effective than the slower (37 degrees C, 10 sec) or faster (70 degrees C, 5 sec) thawing rates. Timed insemination following estrus synchronization of 10 hinds resulted in six confirmed pregnancies at 60 days. Five hinds delivered live fawns. This study provides an effective approach for semen cryopreservation and artificial insemination (AI), which should be valuable to scientists for genetics and reproductive management of Sambar deer in developing countries. PMID- 25913735 TI - Plasmodium falciparum population structure in Sudan post artemisinin-based combination therapy. AB - Over the past decade, Sudan has stepped up malaria control backed by WHO, and this has resulted in significant reduction in parasite rate, malaria morbidity and mortality. The present study analyzed Plasmodium falciparum parasites in four geographical separated areas, to examine whether the success in malaria control following the use of artemisinin-based combination therapy (ACT) has disrupted the population structure and evolution of the parasite. We examined 319 P. falciparum isolates collected between October 2009 and October 2012 in four different areas in Sudan (Jazira [central Sudan], Southern Darfur [western Sudan], Upper Nile [southern Sudan] and Kasala [eastern Sudan]). Twelve microsatellites were analyzed for allelic diversity, multi-locus haplotype and inter-population differentiation. Level of diversity was compared to that detected for three of the above microsatellites among P. falciparum parasites in central and eastern Sudan in 1999, prior to introduction of ACT. Diversity at each locus (unbiased heterozygosity [H]) was high in all areas (Jazira, H=0.67), (Southern Darfur, H=0.71), (Upper Nile, H=0.71), and (Kasala, H=0.63). Microsatellites were distributed widely and private alleles, detected in a single population, were rare. The extent of diversity in the above sites was similar to that seen, in 1999, in central (Khartoum, H=0.73) and eastern Sudan (Gedaref, H=0.75). Significant Linkage disequilibrium (LD) was observed between the microsatellites in all populations. Pairwise FST analysis revealed that parasites in the four areas could be considered as one population. However, the parasites in Sudan clustered away from parasites in West Africa and the Arabian Peninsula. Despite marked reduction in malaria risk in Sudan, the extent of diversity and parasite genetic structure are indicative of a large population size. Further considerable reduction in transmission would be needed before fragmented sub population can be seen. In addition, the large divergence of P. falciparum in Sudan from West Africa and Arabian Peninsula populations may result from differential evolutionary pressures acting at the population level, which shall be considered in eradication plans. PMID- 25913734 TI - Fibroblast growth factor signaling in oligodendrocyte-lineage cells facilitates recovery of chronically demyelinated lesions but is redundant in acute lesions. AB - Remyelination is a potent regenerative process in demyelinating diseases, such as multiple sclerosis, the effective therapeutic promotion of which will fill an unmet clinical need. The development of proregenerative therapies requires the identification of key regulatory targets that are likely to be involved in the integration of multiple signaling mechanisms. Fibroblast growth factor (FGF) signaling system, which comprises multiple ligands and receptors, potentially provides one such target. Since the FGF/FGF receptor (FGFR) interactions are complex and regulate multiple diverse functions of oligodendrocyte lineage cells, it is difficult to predict their overall therapeutic potential in the regeneration of oligodendrocytes and myelin. Therefore, to assess the integrated effects of FGFR signaling on this process, we simultaneously inactivated both FGFR1 and FGFR2 in oligodendrocytes and their precursors using two Cre-driver mouse lines. Acute and chronic cuprizone-induced or lysolecithin-induced demyelination was established in Fgfr1/Fgfr2 double knockout mice (dKO). We found that in the acute cuprizone model, there was normal differentiation of oligodendrocytes and recovery of myelin in the corpus callosum of both control and dKO mice. Similarly, in the spinal cord, lysolecithin-induced demyelinated lesions regenerated similarly in the dKO and control mice. In contrast, in the chronic cuprizone model, fewer differentiated oligodendrocytes and less efficient myelin recovery were observed in the dKO compared to control mice. These data suggest that while cell-autonomous FGF signaling is redundant during recovery of acute demyelinated lesions, it facilitates regenerative processes in chronic demyelination. Thus, FGF-based therapies have potential value in stimulating oligodendrocyte and myelin regeneration in late-stage disease. PMID- 25913737 TI - Health professionals as politicians. PMID- 25913736 TI - Medium-chain dicarboxylic acylcarnitines as markers of n-3 PUFA-induced peroxisomal oxidation of fatty acids. AB - SCOPE: Omega-3 polyunsaturated fatty acids (n-3 PUFA) found in fish oil activate PPAR-alpha, stimulate peroxisomal fatty acid (FA) beta-oxidation and prevent impairments on glucose homeostasis. METHODS AND RESULTS: Glucose metabolism and FA oxidation were studied in C57/Bl6 mice fed with diets containing either 3.6 and 31.5% fish oil or lard. To assess the effects of peroxisomal proliferation on FA oxidation independent of n-3 PUFA intake, mice were treated with the PPAR alpha agonist WY-14643. n-3 PUFA-fed mice were protected from glucose intolerance and dyslipidemia compared to animals fed a lard-based high-fat diet. Most importantly, mice fed on the hyperlipidic diet based on fish oil as well as the WY-14643 treated mice showed twofold increase of odd, medium-chain, dicarboxylic acylcarnitines in the liver suggesting that not only beta-oxidation, but also alpha- and omega-oxidation of FA were increased. Finally, an oxidation assay using liver homogenates and palmitic acid as substrate revealed an over tenfold increased production of similar acylcarnitines, indicating that FA are their precursors. CONCLUSION: This study shows at the metabolite level that peroxisome proliferation induced either by fish oil or WY-14643 is associated with increased alpha- and omega-oxidation of FA producing specific acylcarnitines that can be utilized as biomarkers of peroxisomal FA oxidation. PMID- 25913738 TI - Transcriptome and MassARRAY analysis for identification of transcripts and SNPs for growth traits of the swimming crab Portunus trituberculatus. AB - Portunus trituberculatus is an important farmed crustacean in China. Growth traits are important economic traits that are controlled by many genes. The aim of this study was to screen growth-related genes using Illumina paired-end sequencing technology, and to identify growth-related SNPs in P. trituberculatus by association analysis. A total of 36,599,712 and 29,247,160 qualified Illumina read pairs for small size (SG) and large size crabs (LG) were obtained, giving rise to total clean bases of 7.14 and 5.72 G, respectively. A gene expression comparison showed that a total of 117 unigenes were differentially expressed between SG and LG, including 49 up-regulated and 68 down-regulated unigenes in SG and LG, respectively. GO functional enrichment analysis results showed up regulated genes in LG were involved in three biological processes. These were cell communication, ovarian follicle cell development and cell division. Down regulated genes in LG were involved in five biological processes, which were chitin metabolism, carbohydrate metabolism, ATP hydrolysis coupled proton transport, the steroid hormone mediated signaling pathway and fatty acid biosynthesis. Association analysis identified one growth-associated SNP, which was located in hemocyanin (comp58070-R31). This research has provided information on key genes, SNPs and biological processes related to growth, which will increase the efficiency of selective breeding programs for this important species. PMID- 25913739 TI - A novel homozygous mutation IVS6+5G>T in CYP11B1 gene in a Vietnamese patient with 11beta-hydroxylase deficiency. AB - Congenital adrenal hyperplasia (CAH) is an autosomal recessive disease which is characterized by a deficiency of one of the enzymes involved in the synthesis of cortisol from cholesterol by the adrenal cortex. CAH cases arising from impaired 11beta-hydroxylase are the second most common form. Mutations in the CYP11B1 gene are the cause of 11beta-hydroxylase deficiency. This study was performed on a patient with congenital adrenal hyperplasia and with premature development such as enlarged penis, muscle development, high blood pressure, and bone age equivalent of 5 years old at 2 years of chronological age. Biochemical tests for steroids confirmed the diagnosis of CAH. We used PCR and sequencing to screen for mutations in CYP11B1 gene. Results showed that the patient has a novel homozygous mutation of guanine (G) to thymine (T) in intron 6 (IVS6+5G>T). The analysis of this mutation by MaxEntScan boundary software indicated that this mutant could affect the gene splicing during transcription. PMID- 25913740 TI - Retrospective analysis of FFPE based Wilms' Tumor samples through copy number and somatic mutation related Molecular Inversion Probe Based Array. AB - In this report, retrospectively, we analyzed fifteen histo-pathologically characterized FFPE based Wilms' Tumor (WT) samples following an integrative approach of copy number (CN) and loss of heterozygosity (LOH) imbalances. The isolated-DNA was tested on CN and somatic-mutation related Molecular-Inversion Probe based-Oncoscan ArrayTM and was analyzed through Nexus-Express OncoScan-3.0 and 7.0 software. We identified gain of 3p13.0-q29, 4p16.3-14.0, 7, 12p13.33 q24.33, and losses of 1p36.11-q44, 11p15.5-q25, 21q 22.2-22.3 and 22q11.21-13.2 in six samples (W1-6) and validated them in nine more samples (W7-9, W12-15, W17 18). Some observed that discrete deletions (1p, 1q, 10p, 10q, 13q, 20p) were specific to our samples. Maximum-LOH was observed in Ch11 as reported in previous studies. However, LOH was also observed in different regions of Ch7 including some cancer genes. The identified LOH-regions (1q21.2-q21.3, 2p24.1-23.3, 2p24.3 24.3, 3p21.3-21.1, 4p16.3, 7p11.2-p11.1, 7q31.2-31.32, 7q34-q35 and Ch 8) in W1 W6 were also validated in W7-9, W12-15 and W18. In addition, previously reported LOH of 1p and 16q region was also observed in our cases. The proven and novel onco (OG)- and tumor-suppressor genes (TSGs) involved in the CNV regions affected the major pathways like Chromatin Modification, RAS, PI3K; RAS in 14/15 cases, NOTCH/TGF-beta and Cell Cycle Apoptosis in 10/15 cases, APC in 9/15 cases and Transcriptional Regulation in 7/15 cases, PI3K and genome maintenance in 6/15 cases. This exhaustive profiling of OG and TG may help in prognosis and diagnosis of the disease after validation of all the relevant results, especially the novel ones, obtained in this research in a larger number of samples. PMID- 25913741 TI - Individual genome sequencing identified a novel enhancer element in exon 7 of the CSFR1 gene by shift of expressed allele ratios. AB - The sequencing of individual genetic information may provide a powerful tool for elucidating the mechanism by which individual SNPs affect promoter function. Here, we assessed the genome of a Russian male that was previously sequenced. The RNA-Seq data from blood cells revealed 234 candidate transcripts with shifts of greater than 1.5-fold from equal biallelic transcription. Of these genes, the CSF1R gene had variations in genic regions that affected the association of RORalpha with its target binding site in vivo. The results of a reporter assay confirmed that a single nucleotide substitution, rs2228422, within the RORalpha recognition motif altered the ability of the enhancer to regulate CSF1R gene transcription. Notably, 31% of Europeans and only 3% of Asians are homozygous for a RORalpha responsive "A" allele, but no association with diseases of rs2228422 has been found thus far. PMID- 25913742 TI - Identification of rare protein disulfide isomerase gene variants in amyotrophic lateral sclerosis patients. AB - Disruption of endoplasmic reticulum (ER) proteostasis is a salient feature of amyotrophic lateral sclerosis (ALS). Upregulation of ER foldases of the protein disulfide isomerase (PDI) family has been reported in ALS mouse models and spinal cord tissue and body fluids derived from sporadic ALS cases. Although in vitro studies suggest a neuroprotective role of PDIs in ALS, the possible contribution of genetic mutations of these ER foldases in the disease process remains unknown. Interestingly, intronic variants of the PDIA1 gene were recently reported as a risk factor for ALS. Here, we initially screened for mutations in two major PDI genes (PDIA1/P4HB and PDIA3/ERp57) in a US cohort of 96 familial and 96 sporadic ALS patients using direct DNA sequencing. Then, 463 familial and 445 sporadic ALS patients from two independent cohorts were also screened for mutations in these two genes using whole exome sequencing. A total of nine PDIA1 missense variants and seven PDIA3 missense variants were identified in 16 ALS patients. We have identified several novel and rare single nucleotide polymorphisms (SNPs) in both genes that are enriched in ALS cases compared with a large group of control subjects showing a frequency of around 1% in ALS cases. The possible biological and structural impact of these ALS-linked PDI variants is also discussed. PMID- 25913743 TI - EBprot: Statistical analysis of labeling-based quantitative proteomics data. AB - Labeling-based proteomics is a powerful method for detection of differentially expressed proteins (DEPs). The current data analysis platform typically relies on protein-level ratios, which is obtained by summarizing peptide-level ratios for each protein. In shotgun proteomics, however, some proteins are quantified with more peptides than others, and this reproducibility information is not incorporated into the differential expression (DE) analysis. Here, we propose a novel probabilistic framework EBprot that directly models the peptide-protein hierarchy and rewards the proteins with reproducible evidence of DE over multiple peptides. To evaluate its performance with known DE states, we conducted a simulation study to show that the peptide-level analysis of EBprot provides better receiver-operating characteristic and more accurate estimation of the false discovery rates than the methods based on protein-level ratios. We also demonstrate superior classification performance of peptide-level EBprot analysis in a spike-in dataset. To illustrate the wide applicability of EBprot in different experimental designs, we applied EBprot to a dataset for lung cancer subtype analysis with biological replicates and another dataset for time course phosphoproteome analysis of EGF-stimulated HeLa cells with multiplexed labeling. Through these examples, we show that the peptide-level analysis of EBprot is a robust alternative to the existing statistical methods for the DE analysis of labeling-based quantitative datasets. The software suite is freely available on the Sourceforge website http://ebprot.sourceforge.net/. All MS data have been deposited in the ProteomeXchange with identifier PXD001426 (http://proteomecentral.proteomexchange.org/dataset/PXD001426/). PMID- 25913745 TI - An iron(ii) spin-crossover metallacycle from a back-to-back bis [dipyrazolylpyridine]. AB - The syntheses of 4-mercapto-2,6-di(pyrazol-1-yl)pyridine (bppSH) and bis[2,6 di(pyrazol-1-yl)pyrid-4-yl]disulfide (bppSSbpp) are reported. In contrast to previously published "back-to-back" bis-[2,6-di(pyrazol-1-yl)pyridine] derivatives, which form coordination polymers with transition ions that are usually insoluble, bppSSbpp yields soluble oligomeric complexes with iron(ii) and zinc(ii). Mass spectrometry and DOSY data show that [{Fe(MU-bppSSbpp)}n](2n+) and [{Zn(MU-bppSSbpp)}n](2n+) form tetranuclear metallacycles in nitromethane solution (n = 4), although (1)H NMR and conductivity measurements imply the iron compound may undergo more fragmentation than its zinc congener. Both [{Fe(bppSH)2](2+) and [{Fe(MU-bppSSbpp)}n](2n+) exhibit thermal spin-crossover in CD3NO2 solution, with midpoint temperatures near 245 K. The similarity of these equilibria implies there is little cooperativity between the iron centres in the metallacyclic structures. PMID- 25913744 TI - Noggin-Mediated Retinal Induction Reveals a Novel Interplay Between Bone Morphogenetic Protein Inhibition, Transforming Growth Factor beta, and Sonic Hedgehog Signaling. AB - It has long been known that the depletion of bone morphogenetic protein (BMP) is one of the key factors necessary for the development of anterior neuroectodermal structures. However, the precise molecular mechanisms that underlie forebrain regionalization are still not completely understood. Here, we show that Noggin1 is involved in the regionalization of anterior neural structures in a dose dependent manner. Low doses of Noggin1 expand prosencephalic territories, while higher doses specify diencephalic and retinal regions at the expense of telencephalic areas. A similar dose-dependent mechanism determines the ability of Noggin1 to convert pluripotent cells in prosencephalic or diencephalic/retinal precursors, as shown by transplant experiments and molecular analyses. At a molecular level, the strong inhibition of BMP signaling exerted by high doses of Noggin1 reinforces the Nodal/transforming growth factor (TGF)beta signaling pathway, leading to activation of Gli1 and Gli2 and subsequent activation of Sonic Hedgehog (SHH) signaling. We propose a new role for Noggin1 in determining specific anterior neural structures by the modulation of TGFbeta and SHH signaling. PMID- 25913747 TI - Treatment of os odontoideum in a patient with spastic quadriplegic cerebral palsy. AB - Severe atlantoaxial instability due to os odontoideum in a patient with spastic cerebral palsy has not been well described. There is no consensus on treatment, particularly with regard to conservative or surgical options. Our patient was a 9 year-old girl with spastic cerebral palsy and unstable os odontoideum as an incidental finding. During the waiting period for elective surgical treatment, the patient developed respiratory compromise. Surgery was performed to reduce the subluxation and for C1-C2 arthrodesis and the girl regained baseline respiratory function. A CT scan was obtained 1 year after the initial surgery and revealed adequate maintenance of reduction and patency of the spinal canal. This patient highlights the fact that unstable os odontoideum can cause mortality due to respiratory distress in patients with spastic cerebral palsy. This is an important factor in deciding treatment options for cerebral palsy patients with low functional demand. We review the relevant literature. PMID- 25913746 TI - Repeat radiosurgery for cerebral arteriovenous malformations. AB - We perform a systematic review of repeat radiosurgery for cerebral arteriovenous malformations (AVM) with an emphasis on lesion obliteration rates and complications. Radiosurgery is an accepted treatment modality for AVM located in eloquent cortex or deep brain structures. For residual or persistent lesions, repeat radiosurgery can be considered if sufficient time has passed to allow for a full appreciation of treatment effects, usually at least 3years. A systematic review was performed in accordance with Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines. References for this review were identified by searches of MEDLINE, Web of Science and Google Scholar databases. A total of 14 studies comprising 733 patients met the review criteria and were included. For series that reported target dose at both first and repeat treatments, the weighted means were 19.42Gy and 19.06Gy, respectively. The mean and median obliteration rate for the repeat radiosurgery treatments were 61% (95% confidence interval 51.9-71.7%) and 61.5%, respectively. The median follow up following radiosurgery ranged from 19.5 to 80months. Time to complete obliteration after the repeat treatment ranged from 21 to 40.8months. The most common complications of repeat radiosurgery for AVM included hemorrhage (7.6%) and radiation-induced changes (7.4%). Repeat radiosurgery can be used to treat incompletely obliterated AVM with an obliteration rate of 61%. Complications are related to treatment effect latency (hemorrhage risk) as well as radiation induced changes. Repeat radiosurgery can be performed at 3 years following the initial treatment, allowing for full realization of effects from the initial treatment prior to commencing therapy. PMID- 25913748 TI - Adult phenylketonuria presenting with subacute severe neurologic symptoms. AB - We report a 48-year-old Japanese woman with phenylketonuria (PKU) who presented with severe neurological symptoms more than 30 years after discontinuation of dietary treatment. She was diagnosed with PKU at 6-years-old and was treated with a phenylalanine restricted diet until she was 15 years old. When she was 48-years old she started having difficulty walking. After several months, she presented with severe disturbance of consciousness and was admitted. She was diagnosed as having neurological complications associated with PKU. We observed temporal changes in her laboratory data, brain MRI and single-photon emission computed tomography (SPECT) scan findings. Brain MRI on T2-weighted, fluid-attenuated inversion recovery and diffusion-weighted images revealed high intensity lesions in her bilateral frontal lobes and 123I-IMP SPECT showed marked and diffuse hypoperfusion in the bilateral cerebrum and cerebellum. After the resumption of dietary treatment, serum phenylalanine concentrations immediately decreased to the normal range. However, her neurological symptoms took longer to improve. We also found no clear temporal association between MRI findings and clinical severity. SPECT abnormalities showed marked improvement after treatment. It is well known that PKU patients who discontinue the dietary restriction from their childhood develop minor neurological impairments. However, PKU patients with late onset severe neurological symptoms are very rare. To our knowledge, this is the first report regarding SPECT findings of PKU patients with late-onset severe neurological deterioration. PMID- 25913749 TI - A novel translaminar crossover approach for pathologies in the lumbar hidden zone. AB - We report eight patients with disc herniations who underwent sequestrectomy via a crossover translaminar technique. The lateral lumbar spinal canal can be divided into several regions: the subarticular, foraminal and extraforaminal zone. Due to its difficult surgical exposure, some authors refer to part of the subarticular and foraminal region as the hidden zone. Conventional approaches involve partial or total facet joint resection, introducing risk of postoperative instability. Under fluoroscopic guidance, a high speed drill was used to create a small, angled fenestration at the base of the spinous process aimed at the contralateral hidden zone. The nerve root was visualized and disc fragments were removed without facet joint violation. Patients were registered in the International Spine Registry, Spine Tango. Numeric rating scale (NRS), Oswestry disability index (ODI) and core outcome measures index (COMI) were used to evaluate outcome after 6 weeks and 3 months. Outcome was further statistically matched with the Spine Tango pool of patients who underwent sequestrectomy via conventional techniques. Postoperative CT scans showed the translaminar crossover approach with the preserved facet joints. There was significant postoperative improvement of NRS scores and ODI at all follow-up intervals. COMI achieved significant improvement at 3 months. Statistical comparison with Spine Tango data confirmed that the translaminar crossover approach matches the clinical results of the conventional techniques. This series is a proof of principle for a successful translaminar crossover approach to the lumbar hidden zone. The outcome is not inferior to conventional inter- and translaminar routes and the technique potentially offers risk reduction for postoperative instability by preserving facet joint function, especially in the case of recurrent disease. PMID- 25913750 TI - Lamotrigine-induced severe cutaneous adverse reaction: Update data from 1999 2014. AB - We systematically reviewed and analyzed published patients with Stevens-Johnson syndrome (SJS) or toxic epidermal necrolysis (TEN) associated with lamotrigine therapy to identify characteristics of these reactions. We identified a total of 70 patients (42 SJS, five SJS/TEN, 23 TEN). The female to male ratio was 2.83:1 in the TEN group and 1.47:1 in the SJS group. Patients in the TEN group were younger than in the SJS group but this difference was not significant (28.35 versus 32.71 years, respectively; p=0.27). The median time to onset was 25.33 versus 18.42 days for SJS and TEN, respectively. The median dosage at onset was 36.46 versus 57.29mg, and final dosage 111.25 versus 97.92mg/day for SJS and TEN, respectively. The median final dosages did not significantly differ. Concomitant use of valproate acid was reported in 54.55% of the SJS patients and 50.00% of the TEN patients. Three fatal reactions were reported, of which two patients deteriorated rapidly and died within 12h of admission, indicating that this disease can develop rapidly before effective treatment. There was no significant difference between the SJS and TEN groups in any of the clinical factors examined which confirmed the opinion that SJS and TEN are part of a single disease spectrum. PMID- 25913751 TI - Objective and Subjective Aspects of Voice in Pregnancy. AB - OBJECTIVE: This study aimed to evaluate vocal changes in pregnancy according to trimesters both objectively and subjectively. METHODS: Fifty pregnant women and 15 nonpregnant women were included in the study. Eighteen of the 50 pregnant women were in the first trimester, 17 in the second trimester, and 15 in the third trimester of their pregnancies. The fundamental frequency (F0), jitter, shimmer, noise-to-harmonics ratio (NHR), and minimum and maximum pitch were determined during acoustic voice analysis. Laryngologic examination was evaluated via reflux finding score (RFS). Voice Handicap Index 10 (VHI-10) was used for subjective analysis. RESULTS: Maximum phonation time (MPT), VHI-10, and RFS were the parameters that differed significantly. MPT was significantly shorter in the third trimester. Acoustic analysis revealed that F0, jitter, shimmer, NHR, and minimum and maximum pitch values were not significantly different in any groups. RFS was higher in the first and third trimesters than the second trimester and control groups. VHI-10 scores were significantly higher in the third trimester. CONCLUSIONS: Our results showed that MPT is decreased during the third trimester, although acoustic parameters did not differ. VHI-10 results deteriorated in the third trimester significantly. PMID- 25913752 TI - Relationship Between Subglottal Pressure and Sound Pressure Level in Untrained Voices. AB - OBJECTIVES: Subglottal pressure (P(s)) is strongly correlated with sound pressure level (SPL) and is easy to measure by means of commonly available equipment. The SPL/Ps ratio is strongly dependent on the efficiency of the phonatory apparatus and should be of great relevance to clinical practice. However, published normative data are still missing. METHOD: The subjects produced sequences of the syllable [pae], and P(s) was measured as the oral pressure during the [p] occlusion. The P(s) to SPL relationship was determined at four pitches produced by 16 female and 15 male healthy voices and analyzed by means of regression analysis. Average correlation between P(s) and SPL, average SPL produced with a P(s) of 10 cm H(2)O, and average SPL increase produced by a doubling of P(s) were calculated for the female and for the male subjects. The significance of sex and pitch conditions was analyzed by means of analysis of variance (ANOVA). RESULTS: Pitch was found to be an insignificant condition. The average correlation between P(s) and SPL was 0.83 and did not differ significantly between the female and male subjects. In female and male subjects, P(s) = 10 cm H(2)O produced 78.1 dB and 80.0 dB SPL at 0.3 m, and a doubling of P(s) generated 11.1 dB and 9.3 dB increase of SPL. Both these gender differences were statistically significant. CONCLUSIONS: The relationship between Ps and SPL can be reliably established from series of repetitions of the syllable [pae] produced with a continuously changing degree of vocal loudness. Male subjects produce slightly higher SPL for a given pressure than female subjects but gain less for a doubling of P(s). As these relationships appear to be affected by phonation type, it seems possible that in the future, the method can be used for documenting degree of phonatory hypofunction and hyperfunction. PMID- 25913753 TI - Novel mechanism of bioluminescence: oxidative decarboxylation of a moiety adjacent to the light emitter of Fridericia luciferin. AB - A novel luciferin from a bioluminescent Siberian earthworm Fridericia heliota was recently described. In this study, the Fridericia oxyluciferin was isolated and its structure elucidated. The results provide insight into a novel bioluminescence mechanism in nature. Oxidative decarboxylation of a lysine fragment of the luciferin supplies energy for light generation, while a fluorescent CompX moiety remains intact and serves as the light emitter. PMID- 25913754 TI - Evaluation of a multi-target direct thrombin inhibitor dosing and titration guideline for patients with suspected heparin-induced thrombocytopenia. PMID- 25913755 TI - Treatment of Leaks Following Sleeve Gastrectomy by Endoscopic Internal Drainage (EID). AB - BACKGROUND: Leaks are considered one of the major complications of laparoscopic sleeve gastrectomy (LSG) with a reported rate up to 7 %. Drainage of the collection coupled with SEMS deployment is the most frequent treatment. Its success is variable and burdened by high morbidity and not irrelevant mortality. The aim of this paper is to suggest and establish a new approach by endoscopic internal drainage (EID) for the management of leaks. METHODS: Since March 2013, 67 patients presenting leak following LSG were treated with deployment of double pigtail plastic stents across orifice leak, positioning one end inside the collection and the other end in remnant stomach. The aim of EID is to internally drain the collection and at the same time promote leak healing. RESULTS: Double pigtails stent were successfully delivered in 66 out of 67 patients (98.5 %). Fifty patients were cured by EID after a mean time of 57.5 days and an average of 3.14 endoscopic sessions. Two died for event not related to EID. Nine are still under treatment; five failure had been registered. Six patients developed late stenosis treated endoscopically. CONCLUSIONS: EID proved to be a valid, curative, and safe mini-invasive approach for treatment of leaks following SG. EID achieves complete drainage of perigastric collections and stimulates mucosal growth over the stent. EID is well tolerated, allows early re-alimentation, and it is burdened by fewer complications than others technique. Long-term follow-up confirms good outcomes with no motility or feeding alterations. PMID- 25913756 TI - Effects of coenzyme Q10 supplementation on metabolic profile in diabetes: a systematic review and meta-analysis. AB - WHAT IS KNOWN AND OBJECTIVE: CoenzymeQ10 (CoQ10 ), or ubiquinone, is an endogenous enzyme cofactor produced by most human cells. It is a potent antioxidant and is necessary for energy production in mitochondria. Diabetes mellitus is a chronic disease with multiple metabolic abnormalities, principally resulting from the inflammation and oxidative stress associated with mitochondrial dysfunctions. Clinical trials of the effects of supplementary CoQ10 on metabolic control in diabetes have reported inconsistent results. We undertook a systematic review and meta-analysis of randomized controlled trials to assess the effects of CoQ10 supplementation on glycaemic control, lipid profile and blood pressure in patients with diabetes. METHODS: A systematic search was conducted on MEDLINE, The Cochrane Library, CINAHL, NCCAM, Web of Science, Scopus, ClinicalTrials.gov and historical search of reference lists of relevant articles. The bibliographic databases were searched from inception to February 2015. We included randomized, placebo-controlled trials of CoQ10 in diabetes lasting at least 12 weeks. HbA1c or fasting plasma glucose had to be reported. Primary outcome was glycemic control, and secondary outcomes were lipid profile and blood pressure. Treatment effect was estimated with mean difference. RESULTS AND DISCUSSION: Seven trials were included in the meta-analysis, involving 356 patients. Neither CoQ10 alone nor CoQ10 plus fenofibrate improved glycemic control. In addition, CoQ10, alone or in combination with fenofibrate, did not alter LDL-C, HDL-C and blood pressure. Triglycerides levels were significantly reduced with CoQ10 (mean difference -0.26 mmol/L, 95% CI -0.05 mmol/L to -0.47 mmol/L, P = 0.02) and CoQ10 plus fenofibrate (mean difference -0.72 mmol/L, 95% CI -0.32 mmol/L to -1.12 mmol/L, P = 0.0004). CoQ10 plus fenofibrate also effectively reduced total cholesterol (mean difference: -0.45 mmol/L, 95% CI 0.06 mmol/L to -0.84 mmol/L, P = 0.02). WHAT IS NEW AND CONCLUSIONS: CoQ10 supplementation has no beneficial effects on glycemic control, lipid profile or blood pressure in patients with diabetes. However, it may reduce triglycerides levels. Due to limited data availability, well-powered and well-designed randomized controlled trials are needed to clearly determine the effect of CoQ10 on metabolic profile in diabetes. Dosage effects should also be explored. PMID- 25913757 TI - Differentiation-inducing factor-3 inhibits intestinal tumor growth in vitro and in vivo. AB - Differentiation-inducing factor-1 (DIF-1) produced by Dictyostelium discoideum strongly inhibits the proliferation of various types of cancer cells by suppression of the Wnt/beta-catenin signal transduction pathway. In the present study, we examined the effect of differentiation-inducing factor-3 (DIF-3), a monochlorinated metabolite of DIF-1 that is also produced by D. discoideum, on human colon cancer cell lines HCT-116 and DLD-1. DIF-3 strongly inhibited cell proliferation by arresting the cell cycle at the G0/G1 phase. DIF-3 reduced the expression levels of cyclin D1 and c-Myc by facilitating their degradation via activation of GSK-3beta in a time and dose-dependent manner. In addition, DIF-3 suppressed the expression of T-cell factor 7-like 2, a key transcription factor in the Wnt/beta-catenin signaling pathway, thereby reducing the mRNA levels of cyclin D1 and c-Myc. Subsequently, we examined the in vivo effects of DIF-3 in Mutyh(-/-) mice with oxidative stress-induced intestinal cancers. Repeated oral administration of DIF-3 markedly reduced the number and size of cancers at a level comparable to that of DIF-1. These data suggest that DIF-3 inhibits intestinal cancer cell proliferation in vitro and in vivo, probably by mechanisms similar to those identified in DIF-1 actions, and that DIF-3 may be a potential novel anti-cancer agent. PMID- 25913758 TI - Liver hydrolysate attenuates the sickness behavior induced by concanavalin A in mice. AB - Liver hydrolysate (LH) is used as a pharmaceutical agent in Japan, to enhance liver function. However, the effects of LH on sickness behavior are unknown. This study investigated the effect of LH on sickness behaviors, such as concanavalin A (ConA)-induced reduction of locomotor activity. ConA treatment significantly decreased locomotor activity. The striatal tyrosine hydroxylase (TH) levels were also significantly decreased following ConA treatment. The decreased locomotor activity and TH levels were significantly reversed by LH treatment. LH may prove beneficial for preventing sickness behavior following ConA treatment, at least in part, by activating TH in the striatum. PMID- 25913759 TI - Decreased DNA methylation in the promoter region of the WNT5A and GDNF genes may promote the osteogenicity of mesenchymal stem cells from patients with ossified spinal ligaments. AB - Mesenchymal stem cells (MSCs) isolated from spinal ligaments with ectopic ossification have a propensity toward the osteogenic lineage. To explore epigenetic control of the osteogenic features of MSCs, we treated MSCs obtained from the spinal ligaments of ossification of yellow ligament (OYL) patients and non-OYL patients with the DNA methyltransferase inhibitor, 5-aza-2'-deoxycytidine (5AdC). We compared the non-OYL groups (untreated and treated with 5AdC) with the OYL groups (untreated and treated with 5AdC) by genome-wide microarray analysis. Next, we used methylated DNA immunoprecipitation combined with quantitative real time PCR to assess gene methylation. Ninety-eight genes showed expression significantly increased by 5AdC treatment in MSCs from non-OYL patients but not from OYL patients. In contrast, only two genes, GDNF and WNT5A, showed significantly higher expression in OYL MSCs compared with non-OYL MSCs without 5AdC treatment. Both genes were hypermethylated in non-OYL MSCs but not in OYL MSCs. Small interfering RNA targeted to each gene decreased expression of the target gene and also several osteogenic genes. Both small interfering RNAs also suppressed the activity of alkaline phosphatase, a typical marker of osteogenesis. These results suggest that the osteogenic features of MSCs from OYL patients are promoted by unmethylated WNT5A and GDNF genes. PMID- 25913760 TI - LX0702, a novel snake venom peptide derivative, inhibits thrombus formation via affecting the binding of fibrinogen with GPIIb/IIIa. AB - Based on the structure of AAP, a novel anti-thrombotic peptide from snake venom which we discovered in our previous study, more than 60 compounds were designed and synthesized. One of these termed as LX0702 exhibited stronger anti-platelet aggregation activity than AAP. This study aims to investigate the effects of LX0702 on anti-thrombotic formation and its underlying mechanism. We found that LX0702 inhibited platelet aggregation induced by ADP, thrombin and collagen in a dose dependent manner, with IC50 values of 49.90 +/- 2.03, 50.65 +/- 0.34 and 83.90 +/- 2.06 MUM, respectively. It also inhibited thrombus formation in the rat arterio-venous shunt model. In addition, the effect of LX0702 on hemostasis system was tested. Compared to control saline, bleeding time was not prolonged. Furthermore, the ELISA revealed that LX0702 inhibited fibrinogen binding with GPIIb/IIIa in a dose dependent manner with an IC50 value of 1.26 +/- 0.13 MUM. These findings clearly demonstrate that LX0702 has anti-platelet/anti-thrombotic effects without increased bleeding risk. Therefore it might be developed into an effective drug for the prevention or treatment of thrombotic diseases. PMID- 25913761 TI - Characterizations of the alpha1-adrenoceptor subtypes mediating contractions of the human internal anal sphincter. AB - Human internal anal sphincter (IAS) is contracted by alpha1-adrenoceptor stimulation and thus alpha1-adrenoceptor agonists may be useful in treating fecal incontinence. This study characterizes the contribution of alpha1-adrenoceptor subtypes in contraction of human IAS and to investigate the age-related risk of patients with fecal incontinence. IAS and inferior mesenteric artery (IMA), as a predictor of systemic arterial pressure, were obtained from 11 patients. Both muscle strips were assessed by isometric-contraction experiments using phenylephrine, further in IAS, in the presence of various subtype selective alpha1-adrenoceptor antagonists. Immunohistochemistry and gene expression studies were performed in the same samples. The mean pEC50 values with SEM of phenylephrine in IAS (6.30 +/- 0.13) were higher than those of IMA (5.60 +/- 0.10). Furthermore, the age-related pEC50 change of IAS was observed between age <70 and >=70 (6.58 +/- 0.13 and 6.07 +/- 0.16, respectively (P < 0.05)). In IAS, rightward shift of the concentration-response curves of phenylephrine was observed with three alpha1-adrenoceptor antagonists. Each pKB value of silodosin, BMY-7378 and prazosin was 9.36 +/- 0.53, 7.28 +/- 0.20 and 8.89 +/- 0.12, respectively. These pKB values and gene expression studies indicated that alpha1A adrenoceptor subtypes predominantly contributed to human IAS contraction. PMID- 25913762 TI - Older adults' decoding of emotions: age-related differences in interpreting dynamic emotional displays and the well-preserved ability to recognize happiness. AB - AIM: Although the ability to recognize emotions through bodily and facial muscular movements is vital to everyday life, numerous studies have found that older adults are less adept at identifying emotions than younger adults. The message gleaned from research has been one of greater decline in abilities to recognize specific negative emotions than positive ones. At the same time, these results raise methodological issues with regard to different modalities in which emotion decoding is measured. The main aim of the present study is to identify the pattern of age differences in the ability to decode basic emotions from naturalistic visual emotional displays. METHOD: The sample comprised a total of 208 adults from Greece, aged from 18 to 86 years. Participants were examined using the Emotion Evaluation Test, which is the first part of a broader audiovisual tool, The Awareness of Social Inference Test. The Emotion Evaluation Test was designed to examine a person's ability to identify six emotions and discriminate these from neutral expressions, as portrayed dynamically by professional actors. RESULTS: The findings indicate that decoding of basic emotions occurs along the broad affective dimension of uncertainty, and a basic step in emotion decoding involves recognizing whether information presented is emotional or not. Age was found to negatively affect the ability to decode basic negatively valenced emotions as well as pleasant surprise. Happiness decoding is the only ability that was found well-preserved with advancing age. CONCLUSION: The main conclusion drawn from the study is that the pattern in which emotion decoding from visual cues is affected by normal ageing depends on the rate of uncertainty, which either is related to decoding difficulties or is inherent to a specific emotion. PMID- 25913763 TI - Effects of square-stepping exercise on cognitive functions of older people. AB - AIM: Cognitive functions can decline with age, and interventions focusing on stimulating them may have positive results. Previous studies have shown that square-stepping exercise (SSE) has a good influence on balance, but this exercise also seems to promote cognitive stimulation. Therefore, the purpose of the present study was to analyse the effect of 16 weeks of SSE on cognitive functions in non-demented community-dwelling older people. METHODS: This was a longitudinal, non-randomized study. Forty-one older adults (60 years and older) were recruited, and 21 participated in the SSE group (practised only SSE sequences) and 20 were in the control group (continued with their activities of daily living). Both groups were evaluated using the Mini-Mental State Examination, the Digit Span test, the Toulouse-Pieron Attention Test and the Modified Card Sorting Test. RESULTS: The SSE group showed a significant improvement in global cognitive status, concentrated attention and mental flexibility after 16 weeks of the SSE intervention. CONCLUSION: Evidence shows that SSE is a physical activity that positively influences cognitive functions in non-demented older people. PMID- 25913764 TI - Neuropsychological differentiation between Alzheimer's disease and dementia with Lewy bodies in a memory clinic. AB - OBJECTIVE: The aim of this study was to identify a useful neuropsychological instrument for making a differential clinical diagnosis between Alzheimer's disease (AD) and dementia with Lewy bodies (DLB). METHODS: We examined 402 AD and 38 DLB patients with neuropsychological tests that covered general cognition, frontal lobe cognitive function, non-verbal abstract reasoning, working memory and attention, and verbal memory. Discriminant analysis using a stepwise method was performed to identify the measures best able to discriminate between AD and DLB. RESULTS: The AD patients performed significantly worse than the DLB patients on orientation to time, delayed recall subtests on the Mini-Mental State Examination, and logical memory subtests 1 and 2 of the Revised Wechsler Memory Scale. The DLB patients performed significantly worse than the AD patients on the attention, repetition, and pentagon copying subtests of the Mini-Mental State Examination, the constructional praxis subtests of the Alzheimer's Disease Assessment Scale-cognitive component-Japanese version, the Frontal Assessment Battery total score, Raven's Coloured Progressive Matrices (RCPM) sets A, AB, and B, and backward digit span. Discriminant analyses between AD and DLB established the key variables as Logical Memory 1, Logical Memory 2, backward digit span, RCPM, and delayed recall on the Mini-Mental State Examination. We inferred the AD DLB discriminant index from the following discriminant analyses: AD-DLB discriminant index = (Backward digit span score + RCPM set B score) - (Logical Memory 1 score + Logical Memory 2 score), which offered a highly favourable value for diagnostic utility. CONCLUSIONS: The AD-DLB discriminant index, consisting of backward digit span, RCPM set B, and logical memory 1 and 2, is useful to differentiate between AD and DLB. PMID- 25913765 TI - Higher serum insulin-like growth factor-1 is associated with better cognitive performance in persons with mild cognitive impairment. AB - BACKGROUND: Serum insulin-like growth factor-1 (IGF-1) is a mitogenic peptide involved in the regulation of cell proliferation, differentiation, and apoptosis in a wide variety of cells and tissues. Recent research suggests higher circulating levels of IGF-1 are associated with better cognitive performance in healthy older adults and in early stages of Alzheimer's disease, although the cognitive profile associated with elevated IGF-1 has not been examined in persons with mild cognitive impairment. METHODS: Thirty-one participants (age: 83.71 +/- 3.59 years; 58% women) with mild cognitive impairment completed neuropsychological testing and 12-hour fasting blood draw to assess serum IGF-1. RESULTS: Partial correlations between serum IGF-1 and neuropsychological measures were conducted, adjusting for insulin, body mass index, and age. Higher IGF-1 values were associated with better global cognition (Modified Mini Mental State Exam: r = 0.39, P = 0.04) and verbal list learning (Hopkins Verbal Learning Test learning: r = 0.38, P = 0.05), Hopkins Verbal Learning Test free recall (r = 0.41, P = 0.03), and Hopkins Verbal Learning Test recognition discriminability (r = 0.46, P = 0.01). A similar trend emerged for executive function as tested by the Frontal Assessment Battery (r = 0.33, P = 0.09). CONCLUSION: Results suggest higher levels of serum IGF-1 are associated with better cognitive performance in persons with mild cognitive impairment, particularly on tests of learning and memory. These findings suggest IGF-1 may be neuroprotective not only in healthy older adults, but also in adults in the earliest stages of Alzheimer's disease. Further investigation is needed to clarify the nature of this relationship, particularly prospective studies. PMID- 25913766 TI - Subacute cognitive deterioration with high serum anti-thyroid peroxidase antibodies: two cases and a plea for pragmatism. AB - Autoimmune encephalopathy is a rare but potentially reversible cause of cognitive deterioration and neuropsychiatric disturbances. We describe two older female patients with subacute cognitive decline and marked neuropsychiatric disturbances in the presence of high serum anti-thyroid peroxidase antibodies and with normal dosage of free thyroxine 4. One patient recovered almost completely after oral corticotherapy. Differential diagnosis and the role of biomarkers, in particular, are discussed. We support a pragmatic approach involving a short empirical therapeutic trial with intravenous or oral corticoids; this should be considered in all patients with subacute encephalopathy and with laboratory arguments for an underlying autoimmune aetiology. PMID- 25913767 TI - Memantine-associated hyperkalaemia in a patient with Alzheimer's disease. AB - Memantine is an N-methyl-D-aspartate glutamate receptor antagonist that may improve cognitive functions in patients with Alzheimer's disease. It is predominantly excreted unchanged via the kidneys, and patients with decreased creatinine clearance must be treated with lower doses of memantine. However, it is unclear whether memantine itself can lead to renal dysfunction and/or hyperkalaemia. We report a patient with renal impairment and hyperkalaemia possibly associated with memantine administration. PMID- 25913768 TI - Theories and measures of elder abuse. AB - Elder abuse is a pervasive phenomenon around the world with devastating effects on the victims. Although it is not a new phenomenon, interest in examining elder abuse is relatively new. This paper aims to provide an overview of the aetiological theories and measures of elder abuse. The paper briefly reviews theories to explain causes of elder abuse and then discusses the most commonly used measures of elder abuse. Based on the reviewed theories, it can be concluded that elder abuse is a multifactorial problem that may affect elderly people from different backgrounds and involve a wide variety of potential perpetrators, including caregivers, adult children, and partners. The review of existing measurement instruments notes that many different screening and assessment instruments have been developed to identify elders who are at risk for or are victims of abuse. However, there is a real need for more measurements of elder abuse, as the current instruments are limited in scope. PMID- 25913769 TI - Dopamine agonist-responsive depression. AB - Dopaminergic dysfunction is implicated in the pathophysiology of treatment resistant depression. In this review, we describe the putative role of dopamine in depression, summarize the evidence for the efficacy of dopamine receptor agonists in the treatment of treatment-resistant depression, and discuss the underlying mechanisms by which these medications work. Both preclinical and clinical data suggest that adjunctive dopamine agonists could be a promising option for the treatment of such a condition, indicating that there is a dopamine agonist-responsive subgroup of depression. Future clinical studies are warranted to clarify unresolved issues regarding dopamine agonists such as long-term efficacy, efficacy as a monotherapy, and efficacy for juvenile and senile depression. Further basic research is also necessary to fully understand how dopamine acts in the brain of depressed patients. PMID- 25913770 TI - A review of recent case reports of cenesthopathy in Japan. AB - Idiopathic abnormal bodily sensations, or cenesthesic symptoms, are exhibited in a wide variety of mental illnesses. In Japan, patients with abnormal bodily sensations are often diagnosed with cenesthopathy. This study reviewed recent case reports of cenesthopathy. Of the 100 identified cases, young patients were more commonly men with predominant bodily cenesthesic symptoms, while older patients (>=40 years) were more commonly women with cenesthesic symptoms restricted to the oral cavity (oral cenesthopathy). PMID- 25913771 TI - Sortase A-mediated synthesis of ligand-grafted cyclized peptides for modulating a model protein-protein interaction. AB - Specific ligand-grafted cyclic peptides are promising drug candidates that can modulate protein-protein interactions (PPIs) with increased proteolytic stability. In this study, we aimed to demonstrate that Sortase A (SrtA)-mediated peptide transpeptidation can be applied to produce bioactive sequence-grafted, stable, cyclic peptides. A naturally occurring cyclic peptide, sunflower trypsin inhibitor 1 (SFTI-1), was selected as the scaffold, and a tetrapeptide motif, Glu Ser-Asp-Val (ESDV), was grafted into the scaffold as a model ligand. The linear precursor of the grafted peptide with SrtA-recognition motifs at the N- and C termini was cyclized in good yield simply by co-incubation with SrtA. The ESDV grafted cyclic SFTI-1 obtained was confirmed to have high stability against proteolysis by human serum and bound to the target PDZ2 domain of postsynaptic density-95 protein. An optimized sequence-grafted cyclic SFTI-1 could competitively suppress the interaction of PDZ2 with its natural ligand, the C terminal peptide of the NR2B subunit of the N-methyl-D-aspartate receptor. These results show that a strategy combining peptide grafting into the SFTI-1 scaffold with SrtA-catalyzed cyclization can be a simple and effective method for producing stable peptide drugs. PMID- 25913772 TI - Plateau iris secondary to iridociliary cysts. AB - CASE REPORT: We present a case of plateau iris and glaucoma due to multiple unilateral iridociliary cysts. The patient was treated with iridotomy Nd: YAG laser and 360 degrees iridoplasty, without achieving pressure control. Phacoemulsification improved the hypertension. Dynamic gonioscopy and OCT of the anterior chamber was also performed before and after treatment. DISCUSSION: Iridociliary cysts are a benign condition that can cause iris plateau configuration, and can produce a difficult to treat ocular hypertension. Cystotomy, peripheral iridoplasty, and other treatments have been proposed. PMID- 25913773 TI - The zinc-binding nuclear protein HIPP3 acts as an upstream regulator of the salicylate-dependent plant immunity pathway and of flowering time in Arabidopsis thaliana. AB - Biotic and abiotic stress responses of plants are linked to developmental programs. Proteins involved in different signaling pathways are the molecular basis of this concerted interplay. In our study, we show that Arabidopsis thaliana HEAVY METAL-ASSOCIATED ISOPRENYLATED PLANT PROTEIN3 (HIPP3; At5g60800) acts as an upstream regulator of stress- and development-related regulatory networks. Localization, metal-binding and stress-responsive gene expression of HIPP3 were analyzed via microscopy, protein and inductively coupled plasma (ICP) MS analyses and quantitative real-time PCR. In addition, transcriptome and phenotype analyses of plants overexpressing HIPP3 were used to unravel its function. Our data show that HIPP3 is a nuclear, zinc-binding protein. It is repressed during drought stress and abscisic acid (ABA) treatment and, similar to other pathogen-related genes, is induced after infection with Pseudomonas syringae pv. tomato. HIPP3 overexpression affects the regulation of > 400 genes. Strikingly, most of these genes are involved in pathogen response, especially in the salicylate pathway. In addition, many genes of abiotic stress responses and seed and flower development are affected by HIPP3 overexpression. Plants overexpressing HIPP3 show delayed flowering. We conclude that HIPP3 acts via its bound zinc as an upstream regulator of the salicylate-dependent pathway of pathogen response and is also involved in abiotic stress responses and seed and flower development. PMID- 25913774 TI - The Search for High-Impact Diagnostic and Management Tools for Low- and Middle Income Countries: A Self-Powered Low-Cost Blood Pressure Measurement Device Powered by a Solid-State Vibration Energy Harvester. AB - The World Health Organization has established recommendations for blood pressure measurement devices for use in low-resource venues, setting the "triple A" expectations of Accuracy, Affordability, and Availability. Because of issues related to training and assessment of proficiency, the pendulum has swung away from manual blood pressure devices and auscultatory techniques towards automatic oscillometric devices. As a result of power challenges in the developing world, there has also been a push towards semiautomatic devices that are not dependent on external power sources or batteries. Beyond solar solutions, disruptive technology related to solid-state vibrational energy harvesting may be the next iterative solution to attain the ultimate goal of a self-powered low-cost validated device that is simple to use and reliable. PMID- 25913775 TI - Adult-born dentate neurons are recruited in both spatial memory encoding and retrieval. AB - Adult neurogenesis occurs in the dentate gyrus (DG) of the hippocampus, which is a key structure in learning and memory. Adult-generated granule cells have been shown to play a role in spatial memory processes such as acquisition or retrieval, in particular during an immature stage when they exhibit a period of increased plasticity. Here, we demonstrate that immature and mature neurons born in the DG of adult rats are similarly activated in spatial memory processes. By imaging the activation of these two different neuron generations in the same rat and by using the immediate early gene Zif268, we show that these neurons are involved in both spatial memory acquisition and retrieval. These results demonstrate that adult-generated granule cells are involved in memory beyond their immaturity stage. PMID- 25913776 TI - Isolated cutaneous leiomyosarcoma revealing a novel germline mutation of the fumarate hydratase gene. PMID- 25913777 TI - Surface charge control for zwitterionic polymer brushes: Tailoring surface properties to antifouling applications. AB - HYPOTHESIS: Electrostatic interactions play an important role in adhesion phenomena particularly for biomacromolecules and microorganisms. Zero charge valence of zwitterions has been claimed as the key to their antifouling properties. However, due to the differences in the relative strength of their acid and base components, zwitterionic materials may not be charge neutral in aqueous environments. Thus, their charge on surfaces should be further adjusted for a specific pH environment, e.g. physiological pH typical in biomedical applications. EXPERIMENTS: Surface zeta potential for thin polymeric films composed of polysulfobetaine methacrylate (pSBMA) brushes is controlled through copolymerizing zwitterionic SBMA and cationic methacryloyloxyethyltrimethyl ammonium chloride (METAC) via surface-initiated atom transfer polymerization. Surface properties including zeta potential, roughness, free energy and thickness are measured and the antifouling performance of these surfaces is assessed. FINDINGS: The zeta potential of pSBMA brushes is -40 mV across a broad pH range. By adding 2% METAC, the zeta potential of pSBMA can be tuned to zero at physiological pH while minimally affecting other physicochemical properties including dry brush thickness, surface free energy and surface roughness. Surfaces with zero and negative zeta potential best resist fouling by bovine serum albumin, Escherichia coli and Staphylococcus aureus. Surfaces with zero zeta potential also reduce fouling by lysozyme more effectively than surfaces with negative and positive zeta potential. PMID- 25913778 TI - Nitrogen-doped hierarchical porous carbon microsphere through KOH activation for supercapacitors. AB - A porous carbon microsphere with moderate specific surface area and superior specific capacitance for supercapacitors is fabricated from polyphosphazene microsphere as the single heteroatoms source by the carbonization and subsequent KOH activation under N2 atmosphere. With KOH activation, X-ray photoelectron spectroscopy analysis confirms that the phosphorus of polyphosphazene microsphere totally vanishes, and the doping content of nitrogen and its population of various functionalities on porous carbon microsphere surface are tuned. Compared with non-porous carbon microsphere, the texture property of the resultant porous carbon microsphere subjected to KOH activation has been remarkably developed with the specific surface area growing from 315 to 1341 m(2) g(-1)and the pore volume turning from 0.17 to 0.69 cm(3) g(-1). Prepared with the KOH/non-porous carbon microsphere weight ratio at 1.0, the porous carbon microsphere with moderate specific surface area of 568 m(2) g(-1), exhibits intriguing electrochemical behavior in 1 M H2SO4 aqueous electrolyte, with superior specific capacitance (278 F g(-1) at 0.1 A g(-1)), good rate capability (147 F g(-1) remained at 10 A g(-1)) and robust cycling durability (No capacitance loss after 5000 cycles). The promising electrochemical performance could be ascribed to the synergy of nitrogen heteroatom functionalities and the porous morphology. PMID- 25913779 TI - Extranodal lymphoma of the posterior auricle. AB - BACKGROUND: Malignant lymphoma of the head and neck represents the most common non-epithelial head and neck cancer. Approximately one third of these occur outside of lymph nodes and have been described in most sub-sites of the head and neck. CASE: We describe a case of an elderly woman who presented with a non healing ulcer on the posterior aspect of her right pinna. Biopsy was performed and found to be a diffuse large B-cell lymphoma. This patient was treated with chemotherapy and local radiation therapy. CONCLUSIONS: This is the first reported case of an extranodal lymphoma affecting the auricle. We review lymphoma of the head and neck and the role of the otolaryngologist. PMID- 25913780 TI - Capacity of dental equipment to interfere with cardiac implantable electrical devices. AB - Patients with cardiac implantable electrical devices should take precautions when exposed to electromagnetic fields. Possible interference as a result of proximity to electromagnets or electricity flow from electronic tools employed in clinical odontology remains controversial. The objective of this study was to examine in vitro the capacity of dental equipment to provoke electromagnetic interference in pacemakers and implantable cardioverter defibrillators. Six electronic dental instruments were tested on three implantable cardioverter defibrillators and three pacemakers from different manufacturers. A simulator model, submerged in physiological saline, with elements that reproduced life-size anatomic structures was used. The instruments were analyzed at differing distances and for different time periods of application. The dental instruments studied displayed significant differences in their capacity to trigger electromagnetic interference. Significant differences in the quantity of registered interference were observed with respect to the variables manufacturer, type of cardiac implant, and application distance but not with the variable time of application. The electronic dental equipment tested at a clinical application distance (20 cm) provoked only slight interference in the pacemakers and implantable cardioverter defibrillators employed, irrespective of manufacturer. PMID- 25913781 TI - Gamma-glutamyl transferase is associated with sarcopenia and sarcopenic obesity in community-dwelling older adults: results from the Fifth Korea National Health and Nutrition Examination Survey, 2010-2011. AB - Although elevated serum gamma-glutamyl transferase activity (GGT) has been linked with metabolic risk factors for sarcopenia, including non-alcoholic fatty liver disease, adiposity, and insulin resistance, whether GGT independently associated with sarcopenia and sarcopenic obesity has not yet been investigated. We analyzed cross-sectional data of 3,193 community-dwelling adults (42.2% men, age 63.4 +/- 8.7) aged >=50 years from the Fifth Korean National Health and Nutrition Examination Survey, 2010-2011. Sarcopenia was defined as a calculated value of the appendicular skeletal muscle mass divided by body weight (ASM/Wt, %) <1 standard deviation below the sex-specific mean for healthy young adults. Sarcopenic obesity was defined as sarcopenia combined with a waist circumference >=90 cm for men and >=85 cm for women. The prevalence of sarcopenia and sarcopenic obesity increased stepwise from the lowest to highest GGT quintiles (sarcopenia, 20.2-39.7%; sarcopenic obesity, 7.5-27.3%; P for trend, <0.001). Serum GGT activity was associated negatively with ASM and positively with waist circumference. In multivariate logistic regression analyses, participants in the highest GGT quintile had a 2.3-fold increased risk of sarcopenia and 3.4-fold risk of sarcopenic obesity versus those in the lowest quintile, whereas each single-unit increase in natural log-GGT associated independently with a 35% increased risk of sarcopenia and 62% increased risk of sarcopenic obesity after adjusting for age, sex, body mass index, and other confounders. Elevated serum GGT activity was independently associated with sarcopenia and sarcopenic obesity in community-dwelling older adults. PMID- 25913782 TI - Structure and organization of chromatin fiber in the nucleus. AB - Eukaryotic genomes are organized hierarchically into chromatin structures by histones. Despite extensive research for over 30 years, not only the fundamental structure of the 30-nm chromatin fiber is being debated, but the actual existence of such fiber remains hotly contested. In this review, we focus on the most recent progress in elucidating the structure of the 30-nm fiber upon in vitro reconstitution, and its possible organization inside the nucleus. In addition, we discuss the roles of linker histone H1 as well as the importance of specific nucleosome-nucleosome interactions in the formation of the 30-nm fiber. Finally, we discuss the involvement of structural variations and epigenetic mechanisms available for the regulation of this chromatin form. PMID- 25913783 TI - Hypothalamic ER stress: A bridge between leptin resistance and obesity. AB - The prevalence of obesity has increased worldwide at an alarming rate. However, non-invasive pharmacological treatments remain elusive. Leptin resistance is a general feature of obesity, thus strategies aimed at enhancing the sensitivity to this hormone may constitute an excellent therapeutical approach to counteract current obesity epidemics. Nevertheless, the etiology and neuronal basis of leptin resistance remains an enigma. A recent hypothesis gaining substantial experimental support is that hypothalamic endoplasmic reticulum (ER) stress plays a causal role in the development of leptin resistance and obesity. The objective of this review article is to provide an updated view on current evidence connecting hypothalamic ER stress with leptin resistance. We discuss the experimental findings supporting this hypothesis, as well as the potential causes and underlying mechanisms leading to this metabolic disorder. Understanding these mechanisms may provide key insights into the development of novel intervention approaches. PMID- 25913784 TI - Structure, function and evolution of topologically associating domains (TADs) at HOX loci. AB - Hox genes encode transcription factors necessary for patterning the major developing anterior to posterior embryonic axis. In addition, during vertebrate evolution, various subsets of this gene family were co-opted along with the emergence of novel body structures, such as the limbs or the external genitalia. The morphogenesis of these axial structures thus relies in part upon the precisely controlled transcription of specific Hox genes, a mechanism involving multiple long-range enhancers. Recently, it was reported that such regulatory mechanisms were largely shared between different developing tissues, though with some specificities, suggesting the recruitment of ancestral regulatory modalities from one tissue to another. The analysis of chromatin architectures at HoxD and HoxA loci revealed the existence of two flanking topologically associating domains (TADs), precisely encompassing the adjacent regulatory landscapes. Here, we discuss the function of these TADs in the control of Hox gene regulation and we speculate about their capacity to serve as structural frameworks for the emergence of novel enhancers. In this view, TADs may have been used as genomic niches to evolve pleiotropic regulations found at many developmental loci. PMID- 25913785 TI - Myocardial fibrosis of the left ventricular posterior wall can be a target for early detection of cardiac involvement in patients with Duchenne muscular dystrophy. PMID- 25913786 TI - Developmental plasticity in the control and functional recovery of motor behavior. PMID- 25913789 TI - Blending and Morphology Control To Turn Hydrophobic SEBS Electrospun Mats Superhydrophilic. AB - Thermoplastic elastomer SEBS, a triblock copolymer composed of styrene (S) and ethylene-co-butylene (EB) blocks, can be dissolved and processed by electrospinning to produce flexible nonwoven mats that can be interesting for applications like filtration or separation membranes. Controlling surface properties such as hydrophobicity/hydrophilicity is critical to achieving a desired performance. In this study, hydrophobic electrospun SEBS mats were obtained, following which an amphiphilic molecule (Pluronic F127) was solution blended with SEBS prior to electrospinning, in a bid to produce a hydrophilic membrane. The result was a fast-spreading superhydrophilic mat with thinner fibers that preserved the flexibility of the SEBS. The morphologies of nonwoven mats, flat films (prepared by dip-coating using identical solutions) and of the surface of individual fibers were characterized using different microscopy techniques (optical, scanning electron microscopy and atomic force microscopy). Chemical analysis by X-ray photoelectron spectroscopy (XPS) revealed a large F127 concentration in the outermost surface layer. In addition, an analysis of dip coated flat films revealed that for 20 wt % of F127, there was a change in the blend morphology from dispersed F127-rich regions in the SEBS matrix to an interconnected phase homogeneously distributed across the film that resembled grain boundaries of micellar crystals. Our results indicated that this morphology change at 20 wt % of F127 also occurred to some extent in the electrospun fibers and this, combined with the large surface area of the mats, led to a drastic reduction in the contact angle and fast water absorption, turning hydrophobic electrospun mats superhydrophilic. PMID- 25913790 TI - Impact of CO2-driven acidification on the development of the sea cucumber Apostichopus japonicus (Selenka) (Echinodermata: Holothuroidea). AB - We evaluated the impact of ocean acidification on the early development of sea cucumber Apostichopus japonicus. The effect of pH-levels (pH 8.04, 7.85, 7.70 and 7.42) were tested on post-fertilization success, developmental (stage duration) and growth rates. Post-fertilization success decreased linearly with pH leading to a 6% decrease at pH 7.42 as compared to pH 8.1. The impact of pH on developmental time was stage-dependent: (1) stage duration increased linearly with decreasing pH in early-auricularia stage; (2) decreased linearly with decreasing pH in the mid-auricularia stage; but (3) pH decline had no effect on the late-auricularia stage. At the end of the experiment, the size of doliolaria larvae linearly increased with decreasing pH. In conclusion, a 0.62 unit decrease in pH had relatively small effects on A. japonicus early life-history compared to other echinoderms, leading to a maximum of 6% decrease in post-fertilization success and subtle effects on growth and development. PMID- 25913787 TI - Hippocampal neuron populations are reduced in vervet monkeys with fetal alcohol exposure. AB - Prenatal exposure to beverage alcohol is a major cause of mild mental retardation and developmental delay. In nonendangered alcohol-preferring vervet monkeys, we modeled the most common nondysmorphic form of fetal alcohol syndrome disorder with voluntary drinking during the third trimester of pregnancy. Here, we report significant numerical reductions in the principal hippocampal neurons of fetal alcohol-exposed (FAE) offspring, as compared to age-matched, similarly housed conspecifics with isocaloric sucrose exposure. These deficits, particularly marked in CA1 and CA3, are present neonatally and persist through infancy (5 months) and juvenile (2 years) stages. Although the volumes of hippocampal subdivisions in FAE animals are not atypical at birth, by age 2, they are only 65 70% of those estimated in age-matched controls. These data suggest that moderate, naturalistic alcohol consumption during late pregnancy results in a stable loss of hippocampal neurons and a progressive reduction of hippocampal volume. PMID- 25913791 TI - Effects of low seawater pH on the marine polychaete Platynereis dumerilii. AB - An important priority for any organism is to maintain internal cellular homeostasis including acid-base balance. Yet, the molecular level impacts of changing environmental conditions, such as low pH, remain uncharacterised. Herein, we isolate partial Na(+)/H(+)exchangers (NHE), carbonic anhydrase (CA), and calmodulin (CaM) genes from a polychaete, Platynereis dumerilii and investigate their relative expression in acidified seawater conditions. mRNA expression of NHE was significantly down-regulated after 1h and up-regulated after 7days under low pH treatment (pH 7.8), indicating changes in acid-base transport. Furthermore, the localisation of NHE expression was also altered. A trend of down regulation in CA after 1h was also observed, suggesting a shift in the CO2 and HCO3(-) balance. No change in CaM expression was detected after 7days exposure to acidified seawater. This study provides insight into the molecular level changes taking place following exposure to acidified seawater in a non calcifying, ubiquitous, organism. PMID- 25913792 TI - Impact of cigarette butt leachate on tidepool snails. AB - In urban areas, cigarette butts are the most common discarded refuse articles. In marine intertidal zones, they often fall into tidepools. We tested how common intertidal molluscs were affected by butt leachate in a laboratory experiment, where snails were exposed to various leachate concentrations. Mortality was very high, with all species showing 100% mortality at the full leachate concentration (5 butts per litre and 2h soak time) after 8days. However, Austrocochlea porcata showed higher mortality than the other 2 species at lower concentrations (10%, 25%) which may affect the relative abundance of the 3 snails under different concentrations of leachate pollution. Also, sublethal effects of leachate on snail activity were observed, with greater activity of Nerita atramentosa than the other 2 species at higher concentrations, suggesting it is more resilient than the other 2 species. While human health concerns predominate with respect to smoking, we show strong lethal and sublethal (via behavioural modifications) impacts of discarded butts on intertidal organisms, with even closely-related taxa responding differently. PMID- 25913793 TI - Heavy metal concentrations in wild fishes captured from the South China Sea and associated health risks. AB - Heavy metal concentrations were measured in 29 marine wild fish species from the South China Sea. Concentrations (wet weight) were 0.51-115.81 ng/g (Cd), 0.54 27.31 ng/g (Pb), 0.02-1.26 MUg/g (Cr), 8.32-57.48 ng/g (Ni), 0.12-1.13 MUg/g (Cu), 2.34-6.88 MUg/g (Zn), 2.51-22.99 MUg/g (Fe), and 0.04-0.81 MUg/g (Mn), respectively. Iron concentrations in all and Mn in some fish species were higher than the acceptable daily upper limit, suggesting human consumption of these wild fish species may pose a health risk. Human health risk assessment, however, indicated no significant adverse health effects with consumption. PMID- 25913794 TI - Eutrophication assessment and bioremediation strategy using seaweeds co-cultured with aquatic animals in an enclosed bay in China. AB - Intensive mariculture results in a rise in nutrient concentrations, then leads to serious eutrophication in coastal waters. Based on the sampling data obtained between August 2012 and July 2013, the eutrophication status in Yantian Bay was assessed, and the proportion of marine animals co-cultured with seaweeds was evaluated. The nutritional quality index (NQI) ranged from 4.37 to 13.20, indicating serious eutrophication conditions. The annual average ratio of nitrogen/phosphorus (N/P) was 25.19, indicating a nitrogen surplus in this system. DIN was selected as the best parameter to balance seaweed absorption and marine animal DIN production. Gracilaria lemaneiformis and Laminaria japonica were selected as co-cultured seaweeds. The optimal proportion of G. lemaneiformis production was assessed as 20074.14 tonnes. The optimal proportion of L. japonica production was evaluated as 15890.68 tonnes. High-temperature adapted seaweeds should be introduced for removing nutrients releasing by farmed aquatic animals in the summer in Yantian Bay. PMID- 25913795 TI - Antibiotics in the coastal environment of the Hailing Bay region, South China Sea: Spatial distribution, source analysis and ecological risks. AB - In this study, the occurrence and spatial distribution of 38 antibiotics in surface water and sediment samples of the Hailing Bay region, South China Sea, were investigated. Twenty-one, 16 and 15 of 38 antibiotics were detected with the concentrations ranging from <0.08 (clarithromycin) to 15,163ng/L (oxytetracycline), 2.12 (methacycline) to 1318ng/L (erythromycin-H2O), <1.95 (ciprofloxacin) to 184ng/g (chlortetracycline) in the seawater, discharged effluent and sediment samples, respectively. The concentrations of antibiotics in the water phase were correlated positively with chemical oxygen demand and nitrate. The source analysis indicated that untreated domestic sewage was the primary source of antibiotics in the study region. Fluoroquinolones showed strong sorption capacity onto sediments due to their high pseudo-partitioning coefficients. Risk assessment indicated that oxytetracycline, norfloxacin and erythromycin-H2O posed high risks to aquatic organisms. PMID- 25913796 TI - Surface sediment properties and heavy metal pollution assessment in the near shore area, north Shandong Peninsula. AB - Samples of surface sediment were collected off the north Shandong Peninsula for grain size and element analyses. Based on the grain size analysis, the surface sediments were dominated by silt and sand, with a small portion of clay, and were probably from the coastal erosion of the Shandong Peninsula. The spatial distribution patterns of the heavy metals were primarily controlled by the sediment types. The geo-accumulation indexes suggest that there was no Cu, Zn and Cr pollution in the study area; Pb and Cd contaminations appeared only at a few stations, while As pollution was distributed widely. The enrichment factors indicated that Cu, Zn and Cr were primarily from terrigenous materials. By contrast, Cd, Pb and As, and especially Cd and As, were probably largely provided by anthropogenic sources. Due to the dilution of coarse-grained matters, there was no contamination at some of the stations at which the influence of human activities was obvious. PMID- 25913797 TI - Toxic metal (Pb, Cd, Cr, and Hg) levels in Rapana venosa (Valenciennes, 1846), Eriphia verrucosa (Forskal, 1775), and sediment samples from the Black Sea littoral (Thrace, Turkey). AB - Rapana venosa (Valenciennes, 1846) and Eriphia verrucosa (Forskal, 1775) are the dominant benthic invertebrate species along the Thrace Coast of the western Black Sea. The aim of this study was to determine toxic metal (Hg, Cr, Cd, and Pb) accumulation levels in these species, as well as within littoral sediments from this area. Our results showed that all of the metals, except for Cd, were below that in average shale. The measured accumulation levels were mostly within the range of what is naturally found within the earth's crust. However, some study stations did have increased concentrations, indicating anthropogenic pollution in these areas. The Cd contents of E. verrucosa collected from all our study stations were well above the limits set by the Turkish Food Codex, especially in Kiyikoy, whereas Pb content was close to the limit at all stations and exceeded the limit in Kiyikoy, but Hg content was below the limit at all stations. Cd content of R. venosa exceeded the limit only in Kumkoy. Pb content was below the limit, and Hg was at or slightly above the limit at all stations. PMID- 25913798 TI - An unusual cancer involving the rectum: two cases of localized primary peritoneal carcinoma mimicking rectal carcinoma. PMID- 25913800 TI - Equilibration processes during gas uptake inside narrow pores. AB - We analyze the adsorption kinetics of a gas in contact with the open ends of a narrow longitudinal pore, where gas transport along its interior occurs via single-file diffusion mechanisms. By implementing a Kinetic Monte Carlo simulation of the gas dynamics, we obtain the overall change in gas uptake inside the pore and the concentration profile of the adsorbed phase as the system evolves towards equilibrium. Typically, higher external pressure leads to faster kinetics as it happens for adsorption on open surfaces. However, when the pore is exposed to gas at very high pressures, blockage events near the ends of longer pores can slow down the overall adsorption, with desorption and internal diffusion eventually becoming the rate limiting processes. We determine the dependence of these phenomena on the amount of gas adsorbed, binding energy and length of the pore. PMID- 25913799 TI - Colorectal neoplasia in IBD--a single-center analysis of patients undergoing proctocolectomy. AB - PURPOSE: The risk, prevention, and treatment of colorectal neoplasia in inflammatory bowel disease (IBD) are still a matter of debate. The aim of this study was to analyze the occurrence of colorectal neoplasia in IBD patients who underwent proctocolectomy. METHODS: The study population comprised of 123 IBD patients who underwent proctocolectomy because of neoplasia, therapy refractivity, or complications between January 2000 and July 2011. RESULTS: One hundred fourteen (92.7%) patients were pre-operatively diagnosed with ulcerative colitis, 5 (4.1%) with colitis indeterminata, and 4 (3.3%) with colonic Crohn's disease. Colectomy was indicated in 39 (31.7%) patients because of a neoplasia, in 68 (55.3%) because of a refractory course of the disease, and in 16 (13.0%) because of complications. Neoplasia was found in 36 patients on a histopathologic evaluation of the colectomy specimens. Ten (8.1%) patients post-operatively showed a pre-operatively not described advanced neoplasia. In three (2.4%) of these patients, the detection of advanced neoplasia (two high-grade intraepithelial neoplasias (IENs), one carcinoma) was a complete de novo finding. Carcinoma had not been diagnosed pre-operatively in six (4.9%) patients. A multifocal distribution of neoplasia was seen in 66.7% of patients with neoplasia. The median duration of disease was 15.5 years in case of neoplasia opposed to 6.0 years in those without neoplasia detection. CONCLUSION: Our data demonstrate a high rate of pre-operatively undetected high-grade IENs and carcinoma and a frequent multifocal occurrence in IBD patients with long-standing inflammation of the colon. This should be kept in mind for treatment decisions particularly in patients with a chronic refractory course of the disease. PMID- 25913802 TI - The correlation between biochemical abnormalities in frontal white matter, hippocampus and serum thyroid hormone levels in first-episode patients with major depressive disorder. AB - BACKGROUND: Previous neuroimaging studies found evidence of potential brain biochemical abnormalities in patients with major depressive disorder (MDD). Abnormal serum thyroid hormone levels were also found in MDD patients, which may correlated with the abnormal biochemical metabolism of brain. However, they rarely excluded the compounding effects of medication, and brain degeneration. This study sought to investigate the relationship between the biochemical metabolism and the serum thyroid hormone levels in first-episode, treatment naive, non-late-life patients with MDD. METHODS: 26 first-episode, treatment naive, non-late-life patients with MDD and 13 healthy controls were enrolled in this study. Participants underwent two-dimensinal multivoxel proton magnetic resonance spectroscopy ((1)H MRS) [repetition time (TR)=1000ms; echo-time (TE)=144ms] at 1.5T to obtain bilateral metabolite levels from the white matter in prefrontal (WMP) lobe, anterior cingulate cortex (ACC), and hippocampus. The ratios of N-acetylaspartate (NAA)/creatine (Cr) and choline containg compounds (Cho)/creatine (Cr) were calculated. Morning serum free triiodothyronine (FT3), free thyroxin (FT4), total triiodothyronine (T3), total thyroxin (T4), and thyroid-stimulating hormone (TSH) were measured before antidepressant treatment. RESULTS: On the comparison of brain biochemical changes, MDD patients had a significantly lower NAA/Cr ratio in the left WMP, and lower NAA/Cr and Cho/Cr ratios in the right WMP when compared to the controls. There were no significant differences in the metabolite ratios in the bilateral ACC, and hippocampus. On the comparison of serum thyroid hormone levels, MDD patients had a significantly decreased T3 and TSH levels. On the comparison of correlation of brain biochemical changes and serum thyroid hormone levels in patients with MDD, the NAA/Cr ratio in the right WMP was positively correlated with the level of TSH. CONCLUSION: These findings suggest that biochemical abnormalities and thyroid dysfunction may emerge early in the course of MDD. Dysfunction of neuronal function in the WMP may correlate with the abnormal TSH in patients with MDD, which may be related to the neuropathology of depression. PMID- 25913803 TI - A tale of two diatheses: Temperament, BIS, and BAS as risk factors for mood disorder. AB - OBJECTIVE: Learning more about how biological traits, like temperament and sensitivity in the behavioral inhibition (BIS) and behavioral activation (BAS) systems, relate to mood pathology is consistent with the Research Domain Criteria initiative's goal of investigating mechanisms of risk. METHOD: Korean young adults (n=128) and American young adults (n=630, of whom 23 has recent treatment for bipolar disorder, and 21for depression) completed self-report questionnaires, including the TEMPS-A, the BIS/BAS scales, Beck Depression Inventory (BDI), and Hypomanic Checklist (HCL-32). Linear regression quantified relations between mood symptoms, sample characteristics, temperament, and BIS/BAS. RESULTS: Temperament styles explained 49% of the variance in BDI scores. BIS explained an additional 1% of the variance in BDI scores. BAS Fun and Reward (p<.01), in addition to cyclothymic and hyperthymic temperaments (p<.001) explained 21% of the variance in HCL-32 scores. Sample characteristics were not significant predictors in the full model. LIMITATIONS: Differences in sample size, the cross-sectional study design, and lack of collateral report or behavioral measures of constructs are limitations. CONCLUSIONS: Affective temperament and BIS/BAS are complementary but distinct constructs. Affective temperament, particularly cyclothymic, may represent a stronger diathesis for mood pathology, and seems potent irrespective of culture or diagnosis. Assessing temperament may help overcome some challenges in diagnosing mood disorders. PMID- 25913804 TI - Adapted behavioural activation for the treatment of depression in Muslims. AB - BACKGROUND: Incorporating religious beliefs into mental health therapy is associated with positive treatment outcomes. However, evidence about faith sensitive therapies for minority religious groups is limited. METHODS: Behavioural Activation (BA), an effective psychological therapy for depression emphasising client values, was adapted for Muslim patients using a robust process that retained core effective elements of BA. The adapted intervention built on evidence synthesised from a systematic review of the literature, qualitative interviews with 29 key informants and findings from a feasibility study involving 19 patients and 13 mental health practitioners. RESULTS: Core elements of the BA model were acceptable to Muslim patients. Religious teachings could potentially reinforce and enhance BA strategies and concepts were more familiar to patients and more valued than the standard approaches. Patients appreciated therapist professionalism and empathy more than shared religious identity but did expect therapist acceptance that Islamic teachings could be helpful. Patients were generally enthusiastic about the approach, which proved acceptable and feasible to most participants; however, therapists needed more support than anticipated to implement the intervention. LIMITATIONS: The study did not re-explore effectiveness of the intervention within this specific population. Strategies to address implementation issues highlighted require further research. CONCLUSIONS: The adapted intervention may be more appropriate for Muslim patients than standard therapies and is feasible in practice. Therapist comfort is an important issue for services wishing to introduce the adapted therapy. The fusion of conceptual frameworks within this approach provides increased choice to Muslim patients, in line with policy and research recommendations. PMID- 25913807 TI - A commentary on the importance of the article by Abed, Khalil, and Moser for "Awareness of modifiable acute myocardial infarction risk factors has little impact on risk perception for heart attack among vulnerable patients". PMID- 25913805 TI - Epidemiology of MRI-defined vascular depression: A longitudinal, community-based study in Korean elders. AB - BACKGROUND: There are no cross-sectional or longitudinal epidemiological studies present on MRI-defined vascular depression in community populations. The purpose of this study was to estimate the prevalence rates of both vascular and non vascular late life depression (LLD) at baseline, to examine the natural course of LLD, and to investigate the influence of White matter hyperintensities (WMHs) on depression after three years. METHOD: The baseline study employed a two-stage design, Phase I population survey (n=783) and Phase II diagnostic evaluation (n=122). In the 3-year follow-up study, baseline participants completing the second phase were reassessed with the same methodology. WMHs severity was rated visually by the modified Fazekas scale and WMHs volume was calculated using an automated method. RESULTS: The prevalence rates of vascular major depressive disorder (MDD) and vascular non-major depressive disorder (nMDD) were 2.39% (56.2% of MDD) and 4.24% (34.0% of nMDD). Subjects with a score of 2 or more on the modified Fazekas scale in either deep white matter hyperintensities or subcortical gray matter ratings had an 8.1 times greater risk of developing a depressive disorder in the 3-year follow-up study. Greater Log WMHs volume (odds ratio=5.78, 95% CI, 1.04-31.72) at baseline was an independent predictor for depressive disorder in the 3-year assessment. LIMITATIONS: Response rate and follow-up rate were relatively low. CONCLUSIONS: Vascular depression is common and makes up about a half of MDD in elders. Greater WMHs severity is a crucial factor predicting future depression risk, which supports the previous vascular depression hypothesis. PMID- 25913808 TI - Outcome of extracorporeal membrane oxygenation support for complex high-risk elective percutaneous coronary interventions: A single-center experience. AB - OBJECTIVE: We report our initial experience with extracorporeal membrane oxygenation (ECMO) use in elective high-risk complex percutaneous coronary intervention (PCI). BACKGROUND: ECMO has been employed as hemodynamic support in patients with cardiac arrest and hemodynamic shock. METHODS: We performed a single-center prospectical study, enrolling all patients at very high-risk for coronary artery bypass grafting (CABG). Major adverse cardiac and cerebrovascular events (MACCE) were defined as a composite of death, acute myocardial infarction (MI), stroke and further need for revascularization. RESULTS: Twelve patients underwent elective high-risk PCI with ECMO support (mean age = 63.5 +/- 8.7 years). The mean SYNTAX score was 30.1 +/- 10.1. All PCI procedures were successful and no in-hospital MACCE was observed. At 6-months, neither death nor MI was noticed. Two patients (17%) required further revascularization, and one patient required chronic hemodialysis. CONCLUSIONS: Elective high-risk PCI supported by ECMO is a viable alternative for patients who are at very high risk for CABG. PMID- 25913809 TI - The suppression and promotion of DNA charge inversion by mixing counterions. AB - In the preset study, we report the suppression and promotion of DNA charge inversion by mixing a quadrivalent counterion (spermine) with mono-, di- and trivalent counterions by dynamic light scattering (DLS) and single molecule electrophoresis (SME) methods. We find that the electrophoretic mobility of DNA in spermine solution decreases in the presence of monovalent sodium ions and divalent magnesium ions. It means that the charge neutralization of DNA by the quadrivalent counterion is suppressed when adding extra mono- or divalent counterions. More specifically, at a high concentration of spermine, the positive mobility can switch back to a negative value by adding mono- and divalent counterions. Thus, charge neutralization and inversion of DNA by quadrivalent counterions is suppressed in the mono- and divalent ion solution. However, the scenario changes dramatically when we add trivalent ions into the solution of DNA and spermine. In this case, the charge neutralization and inversion of DNA is promoted rather than suppressed by mixing with trivalent ions. The negative electrophoretic mobility can be promoted to a positive value, which corresponds to the charge inversion, by trivalent counterions. Thus trivalent and quadrivalent counterions work cooperatively in DNA charge neutralization and inversion. This promotion also occurs when highly positively charged chitosan is introduced into the solution. We explain the observation by the counterion complexation that is related to DNA condensation, which is supported by the images of atomic force microscopy (AFM). PMID- 25913810 TI - An update on the Boston Marathon as a research laboratory. AB - PURPOSE/METHODS: The Boston Athletic Association's annual marathon, also referred to as BAA in this article, continues to be a source of subjects for exercise and endurance performance research. We performed a systematic literature review of BAA studies published in the 7 years since our prior report. RESULTS: We identified 20 articles published from January 2008 to February 2015. Nine were related to cardiology; six were related to exercise physiology; four were related to metabolism; and one was related to marathon qualifying times. As in our prior, report cardiovascular studies remained the dominant topic, but with risk factors for atherosclerosis and thrombosis as the present focus. CONCLUSION: Cardiac issues remain the largest subject area for BAA studies, but with more emphasis on the effect of prolonged exercise on atherosclerotic and thrombotic risk factors. This shift is associated with an increase in marathon participation by older, recreational runners at increased risk of cardiac complications due to exercise. PMID- 25913811 TI - DPP-4 inhibition improves a sexual condition? AB - Erectile dysfunction (ED) is a condition of persistent inability to achieve or maintain an erection sufficient for satisfactory sexual intercourse. The etiology of ED is predominantly vascular, explained by nitric oxide metabolism disturbances being in the background. Nitric oxide enhancing drugs like phosphodiesterase 5 inhibitors, which delay the breakdown of nitric oxide, are widely used, but still without complete success. Restauration of endogenous nitric oxide production focused on improving endothelial dysfunction could be a more effective way of treatment, addressing also other vessels in the body and preventing more serious cardiovascular disease. Endothelial progenitor cells are bone marrow-derived cells found also in human circulation, and may under circumstances be embedded into the vascular intima leading to improvements in nitric oxide production and thus in endothelial function in many organs, including the penis. In this article we hypothesize the potential role of DPP-4 inhibitors, a novel class of antidiabetic drugs in increasing the number of circulating endothelial progenitor cells. Speculated mechanisms include several substrates for DPP-4 inhibitors: GLP-1, SDF-1alpha, substance P, and PACAP. As DPP-4 inhibitors show favorable safety profiles and do not cause hypoglycemia, they seem to be an attractive treatment option, at least in diabetic patients, and could become a part of vascular regenerative pharmacotherapy, ameliorating also symptoms related to erectile dysfunction. Since erectile dysfunction may precede other cardiovascular vascular events, because the penile arteries are smaller in size and therefore more susceptible to decreased nitric oxide production, treating this condition with an agent affecting positively also other blood vessels could help in preventing other cardiovascular events, including myocardial infarction and stroke. However, caution is required, because DPP-4 inhibitors are a heterogenous class of drugs, with variations regarding strength and duration of action, as well as selectivity and cardiovascular safety profile, which may affect properties other than those important in glucocontrol. PMID- 25913812 TI - Connections between online harassment and offline violence among youth in Central Thailand. AB - Increasing evidence indicates that face-to-face (offline) youth violence and online harassment are closely interlinked, but evidence from Asian countries remains limited. This study was conducted to quantitatively assess the associations between offline violence and online harassment among youth in Central Thailand. Students and out-of-school youth (n=1,234, age: 15-24 years) residing, studying, and/or working in a district in Central Thailand were surveyed. Participants were asked about their involvement in online harassment and in verbal, physical, sexual, and domestic types of offline violence, as perpetrators, victims, and witnesses within a 1-year period. Multivariable logistic regression was used to assess independent associations between different kinds of involvement in offline violence and online harassment. Perpetration and victimization within the past year were both reported by roughly half of the youth both online and offline. Over three quarters had witnessed violence or harassment. Perpetrating online harassment was independently associated with being a victim online (adjusted odds ratio [AOR]=10.1; 95% CI [7.5, 13.6]), and perpetrating offline violence was independently associated with being a victim offline (AOR=11.1; 95% CI [8.1, 15.0]). Perpetrating online harassment was independently associated with perpetrating offline violence (AOR=2.7; 95% CI [1.9, 3.8]), and being a victim online was likewise independently associated with being a victim offline (AOR=2.6; 95% CI [1.9, 3.6]). Online harassment and offline violence are interlinked among Thai youth, as in other countries studied so far. Interventions to reduce either might best address both together. PMID- 25913813 TI - Some reflections from the past and some ideas for the future: The 2014 Kempe Oration. AB - Although the physical features of child abuse had been described before 1962, it was Henry Kempe et al.'s article "The Battered Child Syndrome" that is regarded as the beginning of widespread awareness and acceptance of this previously hidden problem. It was another 15 years before child sex abuse started to receive similar widespread recognition. As awareness of child abuse increased, its size became apparent. Funds were poured into child abuse detection and Child Protective Services, although evaluation of the effects of these initiatives did not proceed at the same pace. In those early days, child abuse was conceived in pathological terms, as a problem found only in particular types of families. We now know it is more helpful to use an ecological model and in so doing to consider societal, community, family, and individual factors in interaction. As for the future, we have much to learn from areas such as: public health, where a preventive approach is emphasized; the interaction between researchers and front line workers and insights from high reliability organizations that have been so beneficial to the patient safety movement. In particular, new research about the way our environment and our experiences can influence the way our genes function may reveal new opportunities for prevention, early intervention, and treatment. PMID- 25913814 TI - Spectacular photocatalytic hydrogen evolution using metal-phosphide/CdS hybrid catalysts under sunlight irradiation. AB - A highly efficient and robust heterogeneous photocatalytic hydrogen evolution system was established for the first time by using the CoP/CdS hybrid catalyst in water under solar irradiation. The H2-production rate can reach up to 254,000 MUmol h(-1) g(-1) during 4.5 h of sunlight irradiation, which is one of the highest values ever reported on CdS photocatalytic systems in the literature. PMID- 25913815 TI - The impact of diabetes mellitus on outcomes of endoscopic sinus surgery: a nested case-control study. AB - BACKGROUND: Given the immune impairment associated with diabetes mellitus (DM), its impact on chronic rhinosinusitis (CRS) is a potentially relevant concern; however, it has not been well-studied. A single retrospective study reported worse postoperative quality of life outcomes in DM patients with CRS. Our study evaluated the effect of comorbid DM on outcomes of endoscopic sinus surgery (ESS) using a prospective study design. METHODS: Using a multicentered, prospective cohort of patients (n = 437) undergoing ESS for recalcitrant CRS, a nested case control comparison was performed between 20 adult DM patients (cases) and 20 non DM patients (controls), matched 1:1 for age and Lund-Mackay computed tomography (CT) scores. Outcome measures included 22-item Sinonasal Outcome Test (SNOT-22), Rhinosinusitis Disability Index (RSDI), Patient Health Questionnaire (PHQ-2), and Brief Smell Identification Test (BSIT). RESULTS: Mean follow-up was similar between cases (mean +/- standard deviation: 12.6 +/- 6.0 months) and controls (12.9 +/- 5.9 months; p = 0.862). All preoperative scores were statistically equivalent between DM and non-DM cohorts. Both cohorts showed significant post ESS improvement in SNOT-22 (p = 0.001) and RSDI scores (p < 0.001), and no significant change in PHQ-2 or BSIT scores. The magnitude of score changes was statistically equivalent between the 2 cohorts for all outcome measures with no differences in postoperative score changes between insulin-dependent DM patients and those managed by oral hypoglycemics or dietary restriction (p >= 0.444). CONCLUSION: DM patients with CRS experience similar degrees of symptomatic benefit from ESS compared to controls. Insulin dependence does not appear to adversely affect surgical outcome but a larger cohort would better assess the effect of DM type and control on surgical outcomes in CRS. PMID- 25913816 TI - Amino acid interaction networks provide a new lens for therapeutic antibody discovery and anti-viral drug optimization. AB - Identification of epitopes on viral proteins for the design/identification of broadly-neutralizing monoclonal antibodies (bnAbs) or specific immunogens for vaccine development is hampered by target amino acid diversity. Recently, bnAbs have been isolated for variable viruses by screening B cells from infected individuals for neutralization breadth. Epitope mapping and structural analysis of bnAbs revealed, while some of these bnAbs target glycan moieties, most target protein regions that are conserved in sequence and/or structure. However, almost universally viruses develop mutations that allow escape from neutralization suggesting protein function may not be dependent on the observed conservation. An alternative method for identification of conserved amino acid sequences utilizes an amino acid network-based approach. Calculation of a significant interaction network (SIN) score allows for selection of amino acids that are conserved and constrained within the protein system. Amino acids with high SIN scores are predicted to mutate at lower frequency due to the impact mutation has on the structure/function of a protein. By ascertaining regions of high SIN score, therapeutics can be appropriately designed to target these regions of low mutability. Further, the use of atomic interaction networks to examine protein structure and protein-protein interfaces can complement existing structure-based computational approaches for therapeutic engineering. PMID- 25913817 TI - Lessons from hepatitis E vaccine design. AB - Acute hepatitis E is still a major public health issue, especially in developing countries, and hepatitis E virus (HEV) infection will likely only be preventable through prophylactic vaccines. In this review, we describe the lessons learnt from developing the first commercial hepatitis E vaccine (Hecolin), launched to market in China in 2012. The antigenicity and immunogenicity of VLP immunogens concomitant with the scalable Escherichia coli system and our large-scale clinical verification resulted in the success of our vaccine. The structures of the HEV capsid protein in complex with different antibodies provide important molecular insights into capsid assembly and antibody neutralization of the virus, providing a paradigm for B-cell epitope-based vaccine design. PMID- 25913819 TI - Neutrino oscillation studies with reactors. AB - Nuclear reactors are one of the most intense, pure, controllable, cost-effective and well-understood sources of neutrinos. Reactors have played a major role in the study of neutrino oscillations, a phenomenon that indicates that neutrinos have mass and that neutrino flavours are quantum mechanical mixtures. Over the past several decades, reactors were used in the discovery of neutrinos, were crucial in solving the solar neutrino puzzle, and allowed the determination of the smallest mixing angle theta13. In the near future, reactors will help to determine the neutrino mass hierarchy and to solve the puzzling issue of sterile neutrinos. PMID- 25913818 TI - Strategies to guide the antibody affinity maturation process. AB - Antibodies with protective activity are critical for vaccine efficacy. Affinity maturation increases antibody activity through multiple rounds of somatic hypermutation and selection in the germinal center. Identification of HIV-1 specific and influenza-specific antibody developmental pathways, as well as characterization of B cell and virus co-evolution in patients, has informed our understanding of antibody development. In order to counteract HIV-1 and influenza viral diversity, broadly neutralizing antibodies precisely target specific sites of vulnerability and require high levels of affinity maturation. We present immunization strategies that attempt to recapitulate these natural processes and guide the affinity maturation process. PMID- 25913820 TI - Effects of dietary oat proteins on cholesterol metabolism of hypercholesterolaemic hamsters. AB - BACKGROUND: The aim of present study was to investigate the hypocholesterolaemic effects of oat proteins (OP) in hamsters fed with a hypercholesterolaemic diet. The hamsters were divided into five groups and fed with the experimental diets containing oat, OP, oat beta-glucan (OG), or OP+OG for 30 days. RESULTS: OP and the OG significantly lowered the concentrations of plasma low-density lipoprotein cholesterol and liver total cholesterol (TC), and increased the excretion of faecal bile acid and TC. Plasma and liver TC in the OP+OG group were significantly lower than those in the OP or OG groups. Both OP and OG increased the activity of liver cholesterol 7alpha-hydroxylase (CYP7A1), while its activity in the OP+OG group was strongly increased compared with the OP or OG groups. CONCLUSION: These results indicated that dietary OP could improve hypercholesterolaemia, while dietary OP and OG together would have better hypocholesterolaemic effects. PMID- 25913821 TI - The Efficacy and Safety of Procedural Sedoanalgesia with Midazolam and Ketamine in Pediatric Hematology. AB - OBJECTIVE: The aim of this study is to investigate the efficacy and safety of sedoanalgesia performed outside the operating room by pediatricians trained in advanced airway management and life support. MATERIALS AND METHODS: Midazolam and ketamine were administered consecutively by intravenous route under cardiorespiratory monitoring for painful procedures of pediatric hematology. RESULTS: A total of 115 patients had 237 sedoanalgesia sessions. Sedation time was 24.02+/-23.37 s and sedation success was 92.5% (Ramsay scores of >=5). Patient satisfaction was high. The recovery time was 28.81+/-14.4 min. Although statistically significant (p<0.01) increases in systolic and diastolic blood pressure, heart rate, and respiratory rate were observed without clinical importance, they improved without any intervention. No severe adverse events were observed. CONCLUSION: Sedoanalgesia with intravenous midazolam and ketamine for pediatric hematology and oncology patients' painful minor invasive procedures performed in an optimally equipped setting outside the operating room by pediatricians trained and certificated in advanced airway management and life support is effective and safe. PMID- 25913822 TI - Cytoplasmic sulfur trafficking in sulfur-oxidizing prokaryotes. AB - Persulfide groups are chemically versatile and participate in a wide array of biochemical pathways. Although it is well documented that persulfurated proteins supply a number of important and elaborate biosynthetic pathways with sulfane sulfur, it is far less acknowledged that the enzymatic generation of persulfidic sulfur, the successive transfer of sulfur as a persulfide between multiple proteins, and the oxidation of sulfane sulfur in protein-bound form are also essential steps during dissimilatory sulfur oxidation in bacteria and archaea. Here, the currently available information on sulfur trafficking in sulfur oxidizing prokaryotes is reviewed, and the idea is discussed that sulfur is always presented to cytoplasmic oxidizing enzymes in a protein-bound form, thus preventing the occurrence of free sulfide inside of the prokaryotic cell. Thus, sulfur trafficking emerges as a central element in sulfur-oxidizing pathways, and TusA homologous proteins appear to be central and common elements in these processes. PMID- 25913823 TI - Effectiveness and cost-effectiveness of a self-management group program to improve social participation in patients with neuromuscular disease and chronic fatigue: protocol of the Energetic study. AB - BACKGROUND: Chronic fatigue is present in more than 60% of the patients with a neuromuscular disease and can be their most disabling symptom. In combination with other impairments, fatigue often results in low levels of physical activity and decreased social participation, leading to high societal costs. 'Energetic' is a self-management group program aimed at improving social participation, physical endurance and alleviating fatigue in these patients. The primary aim of this study is to evaluate the effectiveness and cost-effectiveness of the Energetic program. METHODS/DESIGN: A multicentered, assessor-blinded, two-armed randomized controlled trial is conducted with evaluations at inclusion and four, seven and fifteen months later. The study includes patients with a neuromuscular disease and chronic fatigue and, when present, their caregivers. The participants are randomized (ratio 1:1) to either an intervention group, receiving the Energetic program, or a control group, receiving usual care (i.e., no specific intervention). The Energetic program covers four months and includes four modules: 1) individually tailored aerobic exercise training; 2) education about aerobic exercise; 3) self-management training in applying energy conservation strategies; and 4) implementation and relapse prevention in daily life. Two months after cessation of the program a booster session is provided. The primary outcome is the perceived performance score of the Canadian Occupational Performance Measure (COPM). Secondary outcomes include the COPM-satisfaction score, and measures of fatigue, physical endurance, activity engagement, mood, and self-efficacy. Caregiver burden is also evaluated as a secondary outcome. Health-related quality of life and medical and societal costs are assessed to estimate cost-effectiveness of the program. DISCUSSION: The Energetic study is the first randomized controlled trial to evaluate the effectiveness and cost effectiveness of a combined physical and self-management group training program for improving social participation, physical endurance and alleviating fatigue in patients with neuromuscular diseases. It will generate new insights in (cost )effective rehabilitation strategies for these incurable conditions. TRIAL REGISTRATION: Clinicaltrials.gov NCT02208687 . PMID- 25913824 TI - Video-assisted thoracoscopic surgery versus open lobectomy for primary non-small cell lung cancer: a propensity-matched analysis of outcome from the European Society of Thoracic Surgeon database. AB - OBJECTIVES: Video-assisted thoracoscopic anatomical resections are increasingly used in Europe to manage primary lung cancer. The purpose of this study was to compare the outcome following thoracoscopic versus open lobectomy in case-matched groups of patients from the European Society of Thoracic Surgeon (ESTS) database. METHODS: All patients having lobectomy as the primary procedure via thoracoscopy [video-assisted thoracoscopic surgery (VATS)-L)] or thoracotomy (TH-L) were identified in the ESTS database (January 2007 to December 2013). A propensity score was constructed using several patients' baseline characteristics. The matching using the propensity score was responsible for the minimization of selection bias. A propensity score-matched analysis was performed to compare the incidence of postoperative major complications (according to the ESTS database definitions) and mortality at hospital discharge between the matched groups. After exclusions, 28 771 patients were identified: 26 050 having thoracotomy and 2721 having thoracoscopy. Propensity score yielded two well-matched groups of 2721 patients. Numeric variables were compared by Student's t-tests and categorical variables were compared by McNemar's tests. RESULTS: Compared with TH L, VATS-L was associated with a lower incidence of total complications [n = 792 (29.1%) vs 863 (31.7%), P = 0.0357], major cardiopulmonary complications [n = 316 (15.9%) vs 435 (19.6%), P = 0.0094], atelectasis requiring bronchoscopy [n = 65 (2.4%) vs 150 (5.5%), P < 0.0001], initial ventilation >48 h [n = 18 (0.7%) vs 38 (1.4%), P = 0.0075] and wound infection [n = 6 (0.2%) vs 17 (0.6%), P = 0.0218]. There was no difference in the incidence of postoperative atrial fibrillation between the two groups (P = 0.14). Postoperative hospital stay was 2 days shorter in the VATS-L patients (mean: 7.8 vs 9.8 days; P = 0.0003). In terms of outcome at hospital discharge, there were 27 deaths in the VATS-L group (1%) versus 50 in the TH-L group (1.9%, P = 0.0201). CONCLUSIONS: Data from the ESTS database confirmed that lobectomy performed through VATS is associated with a lower incidence of complications compared with thoracotomy. PMID- 25913825 TI - Allogeneic blood transfusion in bilateral lung transplantation: impact on early function and mortality. AB - OBJECTIVES: Blood transfusion is associated with higher morbidity and mortality after general cardiothoracic surgery but its impact within the transplant population is unclear. We investigated the profile of blood product transfusion in the bilateral lung transplant population and its impact on function and mortality. METHODS: Three hundred and eleven adult patients who underwent bilateral lung transplant between 2003 and 2013 were retrospectively reviewed. Patients were stratified according to pretransplant diagnoses and amount of blood products transfused within 24 h of transplant. All-cause mortality at the 1-year follow-up was analysed using a Cox proportional hazards regression model. RESULTS: One hundred and seventy-four male patients and 137 female patients (mean age = 41.4 +/- 14.0 years) underwent bilateral lung transplant using cardiopulmonary bypass for cystic fibrosis (48.9%), fibrotic lung disease (12.2%), emphysema (27.0%), bronchiectasis (5.8%), pulmonary hypertension (1.3%) and others (4.5%). The median number of red blood cells in the first 24 h was 3 (0-40) units, fresh frozen plasma (FFP) = 2 (0-26) units and platelets = 1 (0-7) units. The unadjusted all-cause mortality at the 1-year follow-up did not appear to be different between patient subgroups stratified by the median number of units of red blood cells (P = 0.827) or FFP transfused (P = 0.456). However, 1 year mortality was adversely affected when more than the median number of units of platelets was transfused (P = 0.010). Upon adjustment for confounding variables, 1-year mortality was noted to be greater among patients transfused more than the median unit of platelets (adjusted hazard ratios: 2.3, 95% confidence interval: 1.15-4.61, P = 0.019) and those with longer bypass times (P = 0.046). No significant difference in the number of units transfused was noted when patients were stratified by pretransplant diagnosis. Predicted lung function at 3 and 6 months was not significantly affected by greater blood product use. CONCLUSIONS: Unlike general cardiothoracic surgery, blood transfusion had no effect on all-cause mortality, whereas a greater administration of platelets was observed to be associated with higher adjusted 1-year mortality. Transfusion rates were not significantly influenced by pretransplant diagnoses. Interestingly, lung function at 3 and 6 months was similar for patients who received more blood product transfusion. PMID- 25913826 TI - Red cell distribution width improves the prediction of prognosis after transcatheter aortic valve implantation. AB - OBJECTIVES: The aim of this study was to determine if red cell distribution width (RDW) could improve the prediction of prognosis after transcatheter aortic valve implantation (TAVI). METHODS: In this single-centre study, 197 consecutive patients underwent TAVI (median age 82 (77-86), 46.2% men). Normal RDW at baseline was defined as <=15.5%, elevated RDW at baseline was defined as >15.5%. Ouctomes according to the Valve Academic Research Consortium 2 and survival up to one year were compared between these groups. RESULTS: Compared with the patients with RDW <=15.5% (n = 168), those with RDW >15.5% (n = 29) had a higher Society of Thoracic Surgeon (STS) score (7.2 vs 5.0%, P = 0.041), higher systolic pulmonary arterial pressure (50 vs 41 mmHg, P = 0.021) and lower haemoglobin (11.5 vs 12.4 mg/dl, P = 0.003). Patients with RDW >15.5% developed significantly more adverse events after TAVI (major vascular complications: 10.3 vs 1.8%, P = 0.042; aortic regurgitation grade II-IV: 50.0 vs 18.0%, P = 0.001) and survival up to 1 year was significantly lower (85.6 vs 65.2%, log-rank: P = 0.007). In addition, RDW >15.5% at baseline was the most significant predictor for mortality (hazard ratio: 2.701 (1.279-5.704), P = 0.009), even when the STS score was added to the model [RDW >15.5%: hazard ratio: 2.276 (1.045-4.954), P = 0.038]. CONCLUSIONS: Elevated RDW is a significant predictor for adverse events and increased 1-year mortality after TAVI. Adding RDW to the classical STS score could be a valuable strategy to improve preoperative risk assessment in potential TAVI candidates. PMID- 25913827 TI - Re: Retrograde in situ versus antegrade pulmonary preservation in clinical lung transplantation: a single-centre experience. PMID- 25913829 TI - Commentary to: Guide to tailoring immunization programmes in the WHO European Region. PMID- 25913828 TI - Safety, tolerability, and immunogenicity of 15-valent pneumococcal conjugate vaccine in healthy adults. AB - BACKGROUND: Pneumococcal disease remains an important health priority despite successful implementation of pneumococcal conjugate vaccines (PCVs) in infant immunization programs, mainly due to the emergence of diseases caused by serotypes not included in licensed PCVs. A 15-valent pneumococcal conjugate vaccine (PCV-15) containing the 7 serotypes (4, 6B, 9V, 14, 18C, 19F, and 23F) included in licensed PCV-7 available at study initiation plus 8 additional serotypes (1, 3, 5, 6A, 7F, 19A, 22F, 33F) was developed and evaluated in healthy adults 18-45 years of age. METHODS: Sixty subjects received one dose of PCV-15 or PCV-7. Injection-site and systemic adverse events (AEs) were collected for 14 days postvaccination and serious AEs were collected for 30-days postvaccination. Safety laboratory tests (hematology, chemistry, and urinalysis) were evaluated prior to vaccination and 14-days postvaccination. Serotype-specific IgG and opsonophagocytic killing activity (OPA) responses to 15 serotypes included in PCV 15 were measured immediately prior to vaccination and 30-days postvaccination. RESULTS: AE incidences were comparable between vaccine groups although numerically higher frequencies of erythema (33.3% versus 13.3%), swelling (50.0% versus 23.3%), and myalgia (63.3% versus 36.7%) were reported among PCV-15 versus PCV-7 recipients. Majority of AEs, irrespective of vaccine received, were transient and of mild-to-moderate intensity. No clinically significant differences were observed when comparing AE duration and severity. No laboratory abnormalities, vaccine-related SAEs or discontinuations from the study due to AEs were reported. IgG concentrations for the shared serotypes substantially increased postvaccination at comparable levels between recipients of PCV-15 and PCV-7. Substantial increases in antibody (IgG and OPA) responses to 8 serotypes unique to PCV-15 were observed in PCV-15 recipients. Slight increases to 2 serotypes unique to PCV-15, serotypes 6A and 19A, were also noted in PCV-7 recipients. CONCLUSION: PCV-15 displays an acceptable safety profile and induces IgG and OPA responses to all serotypes included in the vaccine. PMID- 25913831 TI - Erratum to: Prioritization strategies for patient evacuations. PMID- 25913830 TI - Measuring the efficiency of the Greek rural primary health care using a restricted DEA model; the case of southern and western Greece. AB - This is a study to measure the efficiency of the rural Health Centres (HCs) and their Regional Surgeries (RSs) of the 6th Health Prefecture (HP) of Greece, which covers Southern and Western Greece. Data Envelopment Analysis (DEA) was applied under Constant and Variable Returns to Scale, using a weight-restricted, output oriented model, to calculate pure technical efficiency (PTauEpsilon), scale efficiency (SE) and total technical efficiency (TE). The selection of inputs, outputs and their relative weights in the model was based on two consecutive consensus panels of experts on Primary Health Care (PHC). Medical personnel, nursing personnel and technological equipment were chosen as inputs and were attributed appropriate weight restrictions. Acute, chronic and preventive consultations where chosen as outputs; each output was constructed by smaller subcategories of different relative importance. Data were collected through a questionnaire sent to all HCs of the covered area. From the 42 HCs which provided complete data, the study identified 9 as technical efficient, 5 as scale efficient and 2 as total efficient. The mean TE, PTE and SE scores of the HCs of the 6th Health Prefecture were 0.57, 0.67 and 0.87, respectively. The results demonstrate noteworthy variation in efficiency in the productive process of the HCs of Southern and Western Greece. The dominant form of inefficiency was technical inefficiency. The HCs of the 6th HP can theoretically produce 33 % more output on average, using their current production factors. These results indicated potential for considerable efficiency improvement in most rural health care units. Emphasis on prevention and chronic disease management, as well as wider structural and organisational reforms, are discussed from the viewpoint of how to increase efficiency. PMID- 25913832 TI - Finasteride administration potentiates the disruption of prepulse inhibition induced by forced swim stress. AB - Acute stress has been demonstrated to alter sensory gating processes, measured by the prepulse inhibition of the startle response (PPI). It is well known that brain and plasma levels of the neurosteroid allopregnanolone (ALLO) increase after acute environmental stress, fact that has been considered a homeostatic mechanism in restoring normal function following stress. Thus, it is of great interest to study the contribution of stress-altered plasma ALLO levels on PPI function. For this purpose, animals were injected with finasteride, an ALLO synthesis inhibitor, and submitted to swim stress before PPI testing. In order to obtain ALLO plasma levels, a separate set of animals that followed the same experimental procedure was used. We hypothesize that the blockade of ALLO production in response to stress can increase the stress-induced PPI disruption. In accordance with other authors, our results indicate that acute swim stress disrupted the normal PPI evolution (increase) related to the increase in prepulse intensities, and also decreased PPI at the highest prepulse intensity level (15 db above background). Finasteride potentiated the PPI decrease induced by swim stress in the intermediate prepulse intensity (10 db above background). As expected, plasma ALLO levels were increased in stressed animals and this increase was neutralized by prior finasteride administration. These results indicate that the neutralization of the physiological plasma ALLO levels increase after acute stress potentiates stress-induced PPI disruption. This data suggests that alterations in homeostatic ALLO synthesis mechanism may be linked to some neuropsychiatric disorders related to stress, such as anxiety/depression disorders. PMID- 25913833 TI - Nobiletin, a citrus flavonoid, improves cognitive impairment and reduces soluble Abeta levels in a triple transgenic mouse model of Alzheimer's disease (3XTg-AD). AB - Alzheimer's disease (AD), the most common form of dementia among the elderly, is characterized by the progressive decline of cognitive function. Increasing evidence indicates that the production and accumulation of amyloid beta (Abeta), particularly soluble Abeta oligomers, is central to the pathogenesis of AD. Our recent studies have demonstrated that nobiletin, a polymethoxylated flavone from citrus peels, ameliorates learning and memory impairment in olfactory bulbectomized mice, amyloid precursor protein transgenic mice, NMDA receptor antagonist-treated mice, and senescence-accelerated mouse prone 8. Here, we present evidence that this natural compound improves cognitive impairment and reduces soluble Abeta levels in a triple transgenic mouse model of AD (3XTg-AD) that progressively develops amyloid plaques, neurofibrillary tangles, and cognitive impairments. Treatment with nobiletin (30 mg/kg) for 3 months reversed the impairment of short-term memory and recognition memory in 3XTg-AD mice. Our ELISA analysis also showed that nobiletin reduced the levels of soluble Abeta1-40 in the brain of 3XTg-AD mice. Furthermore, nobiletin reduced ROS levels in the hippocampus of 3XTg-AD as well as wild-type mice. These results suggest that this natural compound has potential to become a novel drug for the treatment and prevention of AD. PMID- 25913842 TI - Glioblastoma multiforme with epithelial differentiation: a potential diagnostic pitfall in cerebrospinal fluid cytology. AB - Cerebrospinal fluid (CSF) cytology provides valuable diagnostic and prognostic information for diseases of the central nervous system (CNS) and remains the gold standard for the detection of neoplastic meningitis. Metastatic involvement of the CSF by non-CNS neoplasms far surpasses that of primary brain tumors, although conventional glioblastoma multiforme (GBM) can occasionally be identified in the CSF. GBM with epithelial differentiation is an uncommon variant that may contain features such as adenoid structures, signet ring cells, or squamous metaplasia. Herein, we present a case of GBM with epithelial differentiation to highlight a potential diagnostic pitfall in CSF cytology. A 55-year-old man presented with neurological symptoms and a 6.4 cm left temporal lobe cystic mass. Primary resection revealed GBM with focal epithelial differentiation confirmed by cytokeratin, epithelial membrane antigen, and glial fibrillary acidic protein immunohistochemical studies. Four months following primary resection, the patient developed severe headache for which a lumbar puncture with CSF cytologic evaluation was performed. The cytospin preparation showed numerous malignant epithelioid cells with high nuclear-cytoplasmic ratio and prominent cytoplasmic vacuoles resembling metastatic carcinoma. However, the lesional cells were cytomorphologically identical to the epithelial component present in the patient's recently diagnosed GBM. This case illustrates the potential for GBM with epithelial differentiation to closely mimic metastatic carcinoma from a non CNS site in CSF cytology, which expands the differential diagnosis and emphasizes the necessity of clinical correlation. PMID- 25913843 TI - Retrieval of a detached transseptal sheath tip from a right pulmonary artery branch following catheter ablation. AB - Transseptal introducer sheaths are being used with increasing frequency for left sided arrhythmia ablations and structural heart disease interventions. Sheath tip detachment and embolization is an uncommon but known complication, and several sheaths have been recalled due to such complications. We report a unique case of a fractured transseptal sheath tip that embolized to a branch of the right pulmonary artery in a patient who had undergone ablation of a left-sided atypical atrial flutter. During final removal of one of the two long 8.5-French SL1 transseptal sheaths used routinely as part of the ablation, the radiopaque tip of the sheath fractured and first embolized to the right atrium and subsequently to a secondary right pulmonary artery branch. Using techniques derived from percutaneous interventional approaches, including a multipurpose catheter, coronary guidewire, and monorail angioplasty balloon, the sheath tip was successfully wired through its inner lumen, trapped from the inside with the balloon, and removed from the body via a large femoral vein sheath, without complications. The approach detailed in this case may guide future cases and circumvent urgent surgical intervention. PMID- 25913844 TI - Cancer stem cells in oesophageal squamous cell carcinoma: Identification, prognostic and treatment perspectives. AB - Cancer stem cells (CSCs) are a vital subpopulation of cells to target for the treatment of cancers. In oesophageal squamous cell carcinoma (ESCC), there are several markers such as CD44, ALDH, Pygo2, MAML1, Twist1, Musashi1, Side population (SP), CD271 and CD90 that have been proposed to identify the cancer stem cells in individual cancer masses. It has also been demonstrated that stem cell markers like ALDH1, HIWI, Oct3/4, ABCG2, SOX2, SALL4, BMI-1, NANOG, CD133 and podoplanin are associated with patient's prognosis, pathological stages, cancer recurrence and therapy resistance. Finding new cancer stem cell targets or designing drugs to manipulate the known molecular targets in CSCs could be useful for improvements in clinical outcomes of the disease. To conclude, data suggest that CSCs in oesophageal squamous cell carcinoma are related to resistance to therapy and poor prognosis of patients with ESCC. Therefore, innovative insights into CSC biology and CSC-targeted therapies will help to achieve more effective management of patients with oesophageal squamous cell carcinoma. PMID- 25913845 TI - Extracellular matrix production by nucleus pulposus and bone marrow stem cells in response to altered oxygen and glucose microenvironments. AB - Bone marrow (BM) stem cells may be an ideal source of cells for intervertebral disc (IVD) regeneration. However, the harsh biochemical microenvironment of the IVD may significantly influence the biological and metabolic vitality of injected stem cells and impair their repair potential. This study investigated the viability and production of key matrix proteins by nucleus pulposus (NP) and BM stem cells cultured in the typical biochemical microenvironment of the IVD consisting of altered oxygen and glucose concentrations. Culture-expanded NP cells and BM stem cells were encapsulated in 1.5% alginate and ionically crosslinked to form cylindrical hydrogel constructs. Hydrogel constructs were maintained under different glucose concentrations (1, 5 and 25 mM) and external oxygen concentrations (5 and 20%). Cell viability was measured using the Live/Dead(r) assay and the production of sulphated glycosaminoglycans (sGAG), and collagen was quantified biochemically and histologically. For BM stem cells, IVD like micro-environmental conditions (5 mM glucose and 5% oxygen) increased the accumulation of sGAG and collagen. In contrast, low glucose conditions (1 mM glucose) combined with 5% external oxygen concentration promoted cell death, inhibiting proliferation and the accumulation of sGAG and collagen. NP encapsulated alginate constructs were relatively insensitive to oxygen concentration or glucose condition in that they accumulated similar amounts of sGAG under all conditions. Under IVD-like microenvironmental conditions, NP cells were found to have a lower glucose consumption rate compared with BM cells and may in fact be more suitable to adapt and sustain the harsh microenvironmental conditions. Considering the highly specialised microenvironment of the central NP, these results indicate that IVD-like concentrations of low glucose and low oxygen are critical and influential for the survival and biological behaviour of stem cells. Such findings may promote and accelerate the translational research of stem cells for the treatment of IVD degeneration. PMID- 25913846 TI - Muscle weakness in children with neurofibromatosis type 1. AB - AIM: To investigate if children with neurofibromatosis type 1 (NF1) have reduced muscle strength compared with children with typical development. METHOD: Maximal isometric strength of 15 upper and lower limb muscle groups was evaluated in 30 children with NF1 (16 males, 14 females; aged 4-16y) and 30 age-, sex-, height-, and weight-matched controls using hand-held dynamometry by a single evaluator. Both the left and right sides were assessed. RESULTS: Children with NF1 were significantly weaker than children with typical development across all 15 muscle groups assessed (p<0.05). Apart from elbow flexion, there were no differences between the left and right sides (p>0.05). Magnitude of differences between the children with NF1 compared with the controls ranged from 3% to 43%. Males and females were equally affected. INTERPRETATION: This study shows that children with NF1 have reduced muscle strength compared with children with typical development. This muscle weakness is present from the earliest stages of the disease assessed and persists throughout childhood with no sex difference. These results support recent evidence from mouse studies that NF1 is associated with a primary myopathy. PMID- 25913847 TI - Maternal factors associated with the occurrence of gastroschisis. AB - We sought to identify age group specific maternal risk factors for gastroschisis. Maternal characteristics and prenatal factors were compared for 1,279 live born infants with gastroschisis and 3,069,678 without. Data were obtained using the California database containing linked hospital discharge, birth certificate and death records from 1 year prior to the birth to 1 year after the birth. Backwards stepwise logistic regression models were used with maternal factors where initial inclusion was determined by a threshold of p < 0.10 on initial crude analyses. Due to the strong association of gastroschisis with young maternal age, models were stratified by age groups and odds ratios were calculated. These final models identified maternal infection as the only risk factor common to all age groups and a protective effect of obesity and gestational hypertension. In addition, age specific risk factors were identified. Although gestation at the time of infection was not available, a sexually transmitted disease complicating pregnancy was associated with increased risk in the less than 20 years of age grouping whereas viral infection was associated with increased risk only in the 20-24 and more than 24 years of age groupings. Urinary tract infection remained in the final logistic model for women less than 20 years. Short interpregnancy interval was not found to be a risk factor for any age group. Our findings support the need to explore maternal infection by type and gestational timing. PMID- 25913848 TI - High fat challenges with different fatty acids affect distinct atherogenic gene expression pathways in immune cells from lean and obese subjects. AB - SCOPE: Early perturbations in vascular health can be detected by imposing subjects to a high fat (HF) challenge and measure response capacity. Subtle responses can be determined by assessment of whole-genome transcriptional changes. We aimed to magnify differences in health by comparing gene-expression changes in peripheral blood mononuclear cells toward a high MUFA or saturated fatty acids (SFA) challenge between subjects with different cardiovascular disease risk profiles and to identify fatty acid specific gene-expression pathways. METHODS AND RESULTS: In a cross-over study, 17 lean and 15 obese men (50-70 years) received two 95 g fat shakes, high in SFAs or MUFAs. Peripheral blood mononuclear cell gene-expression profiles were assessed fasted and 4-h postprandially. Comparisons were made between groups and shakes. During fasting, 294 genes were significantly differently expressed between lean and obese. The challenge increased differences to 607 genes after SFA and 2516 genes after MUFA. In both groups, SFA decreased expression of cholesterol biosynthesis and uptake genes and increased cholesterol efflux genes. MUFA increased inflammatory genes and PPAR-alpha targets involved in beta-oxidation. CONCLUSION: Based upon gene expression changes, we conclude that an HF challenge magnifies differences in health, especially after MUFA. Our findings also demonstrate how SFAs and MUFAs exert distinct effects on lipid handling pathways in immune cells. PMID- 25913849 TI - The extracellular matrix compartment of neural stem and glial progenitor cells. AB - Neuroepithelial and radial GLIA stem cells generate the majority of the cellular constituents of the central nervous system. Following precisely timed phases of neurogenesis and gliogenesis the stem cells recede, with the exception of adult neural stem cells that persist in two generally accepted canonical neurogenic regions, the subventricular zone of the lateral ventricle and the subgranular zone in the dentate gyrus of the hippocampus. It is believed that adult stem cells reside in privileged stem cell niche environments that provide favorable conditions for self-renewal and maintenance of this cellular compartment. Factors such as morphogens, cytokines, and growth factors influence the developmental pathway of neural stem/progenitor cells. By comparison, less is known about the regulatory roles of glycoproteins and proteoglycans of the extracellular matrix (ECM) and their receptors, although they represent important constituents of the micromolecular environment of the niche. Here, we summarize studies that indicate pivotal roles of the ECM micromilieu for the biology and instrumental use of glial stem and progenitor cells of the CNS. Advancing our understanding of structure-function relationships, signaling motifs and complementary receptors and their signal transduction pathways will be of central importance for the application of these cell types in regenerative medicine. PMID- 25913850 TI - Evaluation of outcomes from a national patient-initiated second-opinion program. AB - BACKGROUND: We examined outcomes of patient-initiated second opinions provided by a national second-opinion program. METHODS: We independently examined data collected from January 1, 2011 to December 31, 2012 from a second-opinion program (Best Doctors, Inc.) that allows employee-beneficiaries to request free second opinions. Clinical intake included ascertaining why patients sought second opinions and acquiring patients' complete medical records. Trained physicians summarized the cases; identified key, unresolved clinical questions; and forwarded the cases to expert specialists who provided independent assessments and recommendations. Second opinions were discussed with and returned to patients for review with their physicians. Nurses determined whether second opinions confirmed, clarified, or changed initial diagnoses and treatments, and physicians estimated their clinical impact. Patient satisfaction also was surveyed. RESULTS: A total of 6791 patient-initiated second opinions were completed across medical specialties. Patients primarily sought second opinions for help choosing treatment options (41.3%) and for diagnostic concerns (34.8%). Second opinions often resulted in changes in diagnosis (14.8%), treatment (37.4%), or changes in both (10.6%). Clinical impact was estimated as moderate/major in 20.9% of cases for diagnosis and 30.7% of cases for treatment. Changes in diagnoses and/or treatments and clinical impact varied across medical specialties. In patients surveyed (n = 2683), most (94.7%) were satisfied with the experience, but fewer (61.2%) planned to follow the recommendations. CONCLUSIONS: Patient-initiated second opinions led to recommended changes in diagnosis for about 15% and in treatment for about 37% of participants. Further evaluation is needed to determine whether this impacts clinical outcomes, such as the reduction of diagnosis and treatment errors. PMID- 25913851 TI - A non-invasive method to evaluate gastrointestinal transit behavior in rat. AB - INTRODUCTION: Many factors alter gastrointestinal transit. Animal models are useful for preclinical studies of gastrointestinal transit, but terminal methods do not allow later study, and stressful assessment methods will likely alter the transit of the animal. To overcome these factors, we developed a new method to assay rat total gastrointestinal transit. METHODS: Standard plastic cages with their bottoms cut off were placed on wire mesh floors. Custom apparatuses were built to contain fecal pellets as they fell through the floors. Webcams connected to a computer running a security program were placed to image the pellets at regular intervals. Custom food was obtained with and without blue pigment. After habituating to the cages and the non-pigmented food, the pigmented food was administered. The duration to the appearance of the first pigmented pellet was determined by reviewing the photographs. This duration represents the complete gastrointestinal behavior, including feeding. We compared 24-hour fecal pellet counts using images to counts by visual inspection, and also made hourly counts. After establishing baseline transit times and hourly fecal pellet discharge, rats were given buprenorphine, known to alter gastrointestinal transit. Transit times and hourly discharge were obtained again and compared to the baselines. RESULTS: The methods were successful in determining transit times. Baseline measures were consistent between three groups of 8 rats. Visual and image-based counts were highly correlated. Transit times and hourly pellet discharge were reduced by buprenorphine. DISCUSSION: The described method offers a relatively simple, inexpensive, and non-invasive means to measure rat gastrointestinal behavior. The method has potential for any study where altered total gastrointestinal transit is an experimental concern. PMID- 25913852 TI - Proteomic identification of mitochondrial carbonylated proteins in two maturation stages of pepper fruits. AB - Pepper fruits in green and red maturation stages were selected to study the protein pattern modified by oxidation measuring carbonylated proteins in isolated mitochondria, together with the accumulation of superoxide radical and hydrogen peroxide in the fruits. MALDI-TOF/TOF analysis identified as carbonylated proteins in both green and red fruits, formate dehydrogenase, NAD-dependent isocitrate dehydrogenase, porin, and defensin, pointing to a common regulation by carbonylation of these proteins independently of the maturation stage. However, other proteins such as glycine dehydrogenase P subunit and phosphate transporter were identified as targets of carbonylation only in green fruits, whereas aconitase, ATPase beta subunit, prohibitin, orfB protein, and cytochrome C oxidase, were identified only in red fruits. In general, the results suggest that carbonylation of mitochondrial proteins is a PTM that drives the complex ripening process, probably establishing the accumulation and functionality of some mitochondrial proteins in the nonclimacteric pepper fruit. PMID- 25913853 TI - Novel homozygous mutation, c.400C>T (p.Arg134*), in the PVRL1 gene underlies cleft lip/palate-ectodermal dysplasia syndrome in an Asian patient. AB - Cleft lip/palate-ectodermal dysplasia syndrome is a rare, autosomal recessive disorder caused by homozygous loss-of-function mutations of the poliovirus receptor-like 1 (PVRL1) gene encoding nectin-1. Nectin-1 is a cell-cell adhesion molecule that is important for the initial step in the formation of adherens junctions and tight junctions; it is expressed in keratinocytes, neurons, and the developing face and palate. Clinical manifestations comprise a unique facial appearance with cleft lip/palate, ectodermal dysplasia, cutaneous syndactyly of the fingers and/or toes, and in some cases, mental retardation. We present the first report, to our knowledge, of an Asian individual with cleft lip/palate ectodermal dysplasia syndrome with a novel PVRL1 mutation. A 7-year-old Japanese boy, the first child of a consanguineous marriage, showed hypohidrotic ectodermal dysplasia with sparse, brittle, fine, dry hair and hypodontia, the unique facial appearance with cleft lip/palate, cutaneous syndactyly of the fingers and mild mental retardation. Scanning electron microscopic examination of the hair demonstrated pili torti and pili trianguli et canaliculi. Mutation analysis of exon 2 of PVRL1 revealed a novel homozygous nonsense mutation, c.400C>T (p.Arg134*). His parents were heterozygous for the mutant alleles. All four PVRL1 mutations identified in cleft lip/palate-ectodermal dysplasia syndrome to date, including this study, resulted in truncated proteins that lack the transmembrane domain and intracellular domain of nectin-1, which is necessary to initiate the cell-cell adhesion process. PMID- 25913854 TI - Epigallocatechin-3-gallate treatment reduces thermal hyperalgesia after spinal cord injury by down-regulating RhoA expression in mice. AB - BACKGROUND: (-)-Epigallocatechin-3-gallate (EGCG) is the major polyphenolic constituent found in green tea. It has been reported that may be a natural agent for reducing thermal and mechanical pain after nervous system injuries. However, the molecular pathways implicated in these beneficial effects have not been completely elucidated. This study aimed to assess the EGCG treatment effects on thermal hyperalgesia, spinal cord gliosis and modulation of Ras homologue gene family member A (RhoA), fatty acid synthase (FASN) and tumour necrosis factor alpha (TNF-alpha) expression after spinal cord contusion in mice. METHODS: Animals were subjected to a spinal cord contusion. Thirty minutes after contusion and daily during the first week post-surgery, animals were treated with EGCG or dimethyl sulfoxide-saline (DMSO-saline). At 7 and 14 days post-operation, motor recovery was evaluated using the Basso Mouse Scale, and nociceptive response was evaluated using the Hargreaves test. Furthermore, at 14 days, the expression of RhoA, FASN and TNF-alpha proteins was quantified in the lesion site of spinal cord by Western blot technique. Finally, spinal cord samples were processed by immunohistochemical techniques for observing astrocytes, microglia and afferent nerve fibres. RESULTS: At short time, EGCG treatment reduced significantly thermal hyperalgesia but had no effect on locomotor recovery in spinal cord injured mice. Furthermore, EGCG treatment down-regulated the RhoA, FASN and TNF alpha proteins expression, and decreased astro- and microglia reactivity in spinal cord. CONCLUSION: These findings suggest that at short time EGCG treatment reduces thermal hyperalgesia and gliosis via FASN and RhoA pathway, causing a decrease in cytokines in spinal cord. PMID- 25913855 TI - Sustained increases in plasma C-type natriuretic peptides fail to increase concentrations in cerebrospinal fluid: Evidence from pregnant sheep. AB - C-type natriuretic peptide (CNP) is a paracrine growth factor with high abundance in CNS tissues and cerebrospinal fluid (CSF). Consistent with findings of CNP transcripts in the cerebral microvasculature and hypothalamus, CNP increases the permeability of the blood-brain barrier and reduces food intake when administered intracerebroventricularly in rodents. Whether high concentrations of CNP in plasma can affect CSF levels is unknown. Accordingly we have studied changes (days 4, 87 and 116) in concurrent plasma and CSF concentrations of CNP peptides in pregnant sheep - a physiologically unique setting in which plasma CNP is elevated for prolonged periods. Preliminary studies in non pregnant sheep showed stable CNP levels in CSF during repetitive sampling. Compared with values in non pregnant controls, plasma concentrations of CNP peptides were markedly raised (30 fold) at days 87 and 116 in pregnant sheep, yet CSF levels in the two groups did not differ. CNP peptides in CSF decreased from day 4 to day 87 in pregnant sheep, possibly reflecting an adaptive response of the cerebral vasculature to increased hemodynamic load. We conclude that sustained high concentrations of CNP - far exceeding levels encountered in human pathophysiology - fail to affect CNP peptide levels in CSF. PMID- 25913857 TI - Top-Down Regulation of Laminar Circuit via Inter-Area Signal for Successful Object Memory Recall in Monkey Temporal Cortex. AB - Memory retrieval in primates is orchestrated by a brain-wide neuronal circuit. To elucidate the operation of this circuit, it is imperative to comprehend neuronal mechanisms of coordination between area-to-area interaction and information processing within individual areas. By simultaneous recording from area 36 (A36) and area TE (TE) of the temporal cortex while monkeys performed a pair association memory task, we found two distinct inter-area signal flows during memory retrieval: A36 spiking activity exhibited coherence with low-frequency field activity in either the supragranular or infragranular layer of TE. Of these two flows, only signal flow targeting the infragranular layer of TE was further translaminarly coupled with gamma activity in the supragranular layer of TE. Moreover, this coupling was observed when monkeys succeeded in the retrieval of the sought object but not when they failed. The results suggest that local translaminar processing can be recruited via a layer-specific inter-area network for memory retrieval. PMID- 25913856 TI - A corticothalamic switch: controlling the thalamus with dynamic synapses. AB - Corticothalamic neurons provide massive input to the thalamus. This top-down projection may allow the cortex to regulate sensory processing by modulating the excitability of thalamic cells. Layer 6 corticothalamic neurons monosynaptically excite thalamocortical cells, but also indirectly inhibit them by driving inhibitory cells of the thalamic reticular nucleus. Whether corticothalamic activity generally suppresses or excites the thalamus remains unclear. Here we show that the corticothalamic influence is dynamic, with the excitatory inhibitory balance shifting in an activity-dependent fashion. During low frequency activity, corticothalamic effects are mainly suppressive, whereas higher-frequency activity (even a short bout of gamma frequency oscillations) converts the corticothalamic influence to enhancement. The mechanism of this switching depends on distinct forms of short-term synaptic plasticity across multiple corticothalamic circuit components. Our results reveal an activity dependent mechanism by which corticothalamic neurons can bidirectionally switch the excitability and sensory throughput of the thalamus, possibly to meet changing behavioral demands. PMID- 25913858 TI - Molecular substrates of altered axonal growth and brain connectivity in a mouse model of schizophrenia. AB - 22q11.2 deletion carriers show specific cognitive deficits, and ~30% of them develop schizophrenia. One of the disrupted genes is ZDHHC8, which encodes for a palmitoyltransferase. We show that Zdhhc8-deficient mice have reduced palmitoylation of proteins that regulate axonal growth and branching. Analysis of axonal projections of pyramidal neurons from both Zdhhc8-deficient and Df(16)A(+/ ) mice, which model the 22q11.2 deletion, revealed deficits in axonal growth and terminal arborization, which can be prevented by reintroduction of active ZDHHC8 protein. Impaired terminal arborization is accompanied by a reduction in the strength of synaptic connections and altered functional connectivity and working memory. The effect of ZDHHC8 is mediated in part via Cdc42-dependent modulation of Akt/Gsk3beta signaling at the tip of the axon and can be reversed by pharmacologically decreasing Gsk3beta activity during postnatal brain development. Our findings provide valuable mechanistic insights into the cognitive and psychiatric symptoms associated with a schizophrenia-predisposing mutation. PMID- 25913859 TI - A Cellular Resolution Map of Barrel Cortex Activity during Tactile Behavior. AB - Comprehensive measurement of neural activity remains challenging due to the large numbers of neurons in each brain area. We used volumetric two-photon imaging in mice expressing GCaMP6s and nuclear red fluorescent proteins to sample activity in 75% of superficial barrel cortex neurons across the relevant cortical columns, approximately 12,000 neurons per animal, during performance of a single whisker object localization task. Task-related activity peaked during object palpation. An encoding model related activity to behavioral variables. In the column corresponding to the spared whisker, 300 layer (L) 2/3 pyramidal neurons (17%) each encoded touch and whisker movements. Touch representation declined by half in surrounding columns; whisker movement representation was unchanged. Following the emergence of stereotyped task-related movement, sensory representations showed no measurable plasticity. Touch direction was topographically organized, with distinct organization for passive and active touch. Our work reveals sparse and spatially intermingled representations of multiple tactile features. VIDEO ABSTRACT. PMID- 25913860 TI - Sensory Cortical Control of a Visually Induced Arrest Behavior via Corticotectal Projections. AB - Innate defense behaviors (IDBs) evoked by threatening sensory stimuli are essential for animal survival. Although subcortical circuits are implicated in IDBs, it remains largely unclear whether sensory cortex modulates IDBs and what the underlying neural pathways are. Here, we show that optogenetic silencing of corticotectal projections from layer 5 (L5) of the mouse primary visual cortex (V1) to the superior colliculus (SC) significantly reduces an SC-dependent innate behavior (i.e., temporary suspension of locomotion upon a sudden flash of light as short as milliseconds). Surprisingly, optogenetic activation of SC-projecting neurons in V1 or their axon terminals in SC sufficiently elicits the behavior, in contrast to other major L5 corticofugal projections. Thus, via the same corticofugal projection, visual cortex not only modulates the light-induced arrest behavior, but also can directly drive the behavior. Our results suggest that sensory cortex may play a previously unrecognized role in the top-down initiation of sensory-motor behaviors. PMID- 25913861 TI - A Cdh1-APC/FMRP Ubiquitin Signaling Link Drives mGluR-Dependent Synaptic Plasticity in the Mammalian Brain. AB - Deregulation of synaptic plasticity may contribute to the pathogenesis of developmental cognitive disorders. In particular, exaggerated mGluR-dependent LTD is featured in fragile X syndrome, but the mechanisms that regulate mGluR-LTD remain incompletely understood. We report that conditional knockout of Cdh1, the key regulatory subunit of the ubiquitin ligase Cdh1-anaphase-promoting complex (Cdh1-APC), profoundly impairs mGluR-LTD in the hippocampus. Mechanistically, we find that Cdh1-APC operates in the cytoplasm to drive mGluR-LTD. We also identify the fragile X syndrome protein FMRP as a substrate of Cdh1-APC. Endogenous Cdh1 APC forms a complex with endogenous FMRP, and knockout of Cdh1 impairs mGluR induced ubiquitination and degradation of FMRP in the hippocampus. Knockout of FMRP suppresses, and expression of an FMRP mutant protein that fails to interact with Cdh1 phenocopies, the Cdh1 knockout phenotype of impaired mGluR-LTD. These findings define Cdh1-APC and FMRP as components of a novel ubiquitin signaling pathway that regulates mGluR-LTD in the brain. PMID- 25913862 TI - Identification of p-hydroxybenzyl alcohol, tyrosol, phloretin and its derivate phloridzin as tyrosinase substrates. AB - In recent years, the hydroxyalkylphenols p-hydroxybenzyl alcohol and tyrosol, and the compound phloretin and its derivate phloridzin have been described as inhibitors of the enzyme tyrosinase. When the monophenolase and the diphenolase activities of tyrosinase on its physiological substrates l-dopa and/or l-tyrosine are measured in the presence of these compounds, the rate of action of the enzyme decreases. These findings led to the identification of these compounds as inhibitors. However, these molecules show an unusual behavior as inhibitors of the enzyme indeed, in this study, we demonstrate that they are not true inhibitors but alternative substrates of the enzyme. PMID- 25913863 TI - Enhanced detection of type C botulinum neurotoxin by the Endopep-MS assay through optimization of peptide substrates. AB - It is essential to have a simple, quick and sensitive method for the detection and quantification of botulinum neurotoxins, the most toxic substances and the causative agents of botulism. Type C botulinum neurotoxin (BoNT/C) represents one of the seven members of distinctive BoNT serotypes (A to G) that cause botulism in animals and avians. Here we report the development of optimized peptide substrates for improving the detection of BoNT/C and /CD mosaic toxins using an Endopep-MS assay, a mass spectrometry-based method that is able to rapidly and sensitively detect and differentiate all types of BoNTs by extracting the toxin with specific antibodies and detecting the unique cleavage products of peptide substrates. Based on the sequence of a short SNAP-25 peptide, we conducted optimization through a comprehensive process including length determination, terminal modification, single and multiple amino acid residue substitution, and incorporation of unnatural amino acid residues. Our data demonstrate that an optimal peptide provides a more than 200-fold improvement over the substrate currently used in the Endopep-MS assay for the detection of BoNT/C1 and /CD mosaic. Using the new substrate in a four-hour cleavage reaction, the limit of detection for the BoNT/C1 complex spiked in buffer, serum and milk samples was determined to be 0.5, 0.5 and 1mouseLD50/mL, respectively, representing a similar or higher sensitivity than that obtained by traditional mouse bioassay. PMID- 25913864 TI - From hybrid compounds to targeted drug delivery in antimalarial therapy. AB - The discovery of new drugs to treat malaria is a continuous effort for medicinal chemists due to the emergence and spread of resistant strains of Plasmodium falciparum to nearly all used antimalarials. The rapid adaptation of the malaria parasite remains a major limitation to disease control. Development of hybrid antimalarial agents has been actively pursued as a promising strategy to overcome the emergence of resistant parasite strains. This review presents the journey that started with simple combinations of two active moieties into one chemical entity and progressed into a delivery/targeted system based on major antimalarial classes of drugs. The rationale for providing different mechanisms of action against a single or additional targets involved in the multiple stages of the parasite's life-cycle is highlighted. Finally, a perspective for this polypharmacologic approach is presented. PMID- 25913865 TI - Synthesis and antibacterial activities of cadiolides A, B and C and analogues. AB - The one-pot multicomponent synthesis of natural butenolides named cadiolides A, B, C and analogues has been realized. The antibacterial structure activity relationship shows that the presence of phenolic hydroxyl groups and the number and position of bromine atoms on the different aromatic rings are important features for antibacterial activity, besides it was demonstrated the tolerance of both benzene and furan ring at position 3 of the butenolide nucleus. Furthermore, none of the most relevant antibacterial compounds showed any cytotoxicity in freshly isolated human neutrophils. PMID- 25913866 TI - Initial Experience of Left Ventricular Assist Device Support for Adult Patients with Transposition of the Great Vessels. PMID- 25913867 TI - Transcriptome analysis of gill tissue of Atlantic cod Gadus morhua L. from the Baltic Sea. AB - The Atlantic cod (Gadus morhua L.) is one of the most ecologically and economically important marine fish species in the North Atlantic Ocean. Using Roche GS-FLX 454 pyrosequencing technique 962,516 reads, representing 379Mbp of the Baltic cod transcriptome, were obtained. Data was assembled into 14,029 contigs of which 100% displayed homology to the Atlantic cod transcriptome. Despite a high similarity between transcripts, evidence for significant differences between Baltic and Atlantic cod was found. PMID- 25913868 TI - Preparation and reactivity of diazoalkane complexes of ruthenium stabilised by an indenyl ligand. AB - Diazoalkane complexes [Ru(eta(5)-C9H7)(N2CAr1Ar2)(PPh3)L]BPh4 (1-3) [L = PPh3, P(OMe)3, P(OEt)3; Ar1 = Ar2 = Ph; Ar1 = Ph, Ar2 = p-tolyl; Ar1Ar2 = C12H8 fluorenyl] were prepared by allowing chloro-complexes [RuCl(eta(5)-C9H7)(PPh3)L] to react with an excess of diazoalkane in ethanol. Complexes 1-3 reacted with ethylene CH2=CH2 (1 atm) and maleic anhydride [ma, CH=CHCO(O)CO] to afford eta(2) alkene complexes [Ru(eta(5)-C9H7)(eta(2)-CH2=CH2)(PPh3)L]BPh4 (4, 5) and [Ru(eta(5)-C9H7){eta(2)-CH=CHCO(O)CO}(PPh3)L]BPh4 (7). Further, complexes 1-3 underwent cycloaddition with acrylonitrile CH2=C(H)CN, giving 1H-pyrazoline derivatives [Ru(eta(5)-C9H7){eta(1)-N=C(CN)CH2C(Ar1Ar2)NH}(PPh3)L]BPh4 (6). Treatment of diazoalkane complexes 1-3 with acetylene CH[triple bond, length as m dash]CH under mild conditions (1 atm, room temperature) led to dipolar cycloaddition, affording 3H-pyrazole complexes [Ru(eta(5)-C9H7)-{eta(1) N=NC(Ar1Ar2)CH=CH}(PPh3)L]BPh4 (8), whereas reaction with terminal alkynes RC=CH (R = Ph, p-tolyl, Bu(t)) gave vinylidene derivatives [Ru(eta(5) C9H7){=C=C(H)R}(PPh3)L]BPh4 (9). The latter reacted with nucleophiles such as amines and alcohols to give amino- and alkoxy-carbene derivatives [Ru(eta(5) C9H7){=C(NHPr(n))(CH2Ph)}(PPh3)L]BPh4 (11) and [Ru(eta(5) C9H7){=C(CH3)(OEt)}(PPh3)L]BPh4 (10), respectively. In addition, complexes 9 reacted with phenylhydrazine to afford nitrile derivatives [Ru(eta(5) C9H7)(N[triple bond, length as m-dash]CCH2R)(PPh3)L]BPh4 (12) and phenylamine, whereas the reaction with water led to hydrolysis of the alkyne and formation of carbonyl complexes [Ru(eta(5)-C9H7)(CO)(PPh3)L]BPh4 (13). Lastly, treatment of vinylidene complexes with the phosphines PPh3 and P(OMe)3 afforded alkenylphosphonium derivatives [Ru(eta(5)-C9H7){C(H)=C(R)PPh3}(PPh3)L]BPh4 (14) and [Ru(eta(5)-C9H7){C(R)=C(H)P(OMe)3}(PPh3)L]BPh4 (15), respectively. Compound [Ru(eta(5)-C9H7){C(H)=C(H)PPh3}(PPh3)L]BPh4 (16) was also prepared. The complexes were characterised by spectroscopy (IR and NMR) and X-ray crystal structure determinations of [Ru(eta(5)-C9H7){N2C(C12H8)}(PPh3){P(OEt)3}]BPh4 (3c), [Ru(eta(5)-C9H7){=C=C(H)Ph}(PPh3){P(OEt)3}]BPh4 (9d) and [Ru(eta(5) C9H7){C(H)=C(Ph)PPh3}(PPh3){P(OEt)3}]BPh4 (14d). PMID- 25913869 TI - Potential-Dependent Adlayer Structure and Dynamics at the Ionic Liquid/Au(111) Interface: A Molecular-Scale In Situ Video-STM Study. AB - Room-temperature ionic liquids are of great current interest for electrochemical applications in material and energy science. Essential for understanding the electrochemical reactivity of these systems are detailed data on the structure and dynamics of the interfaces between these compounds and metal electrodes, which distinctly differ from those in traditional electrolytes. In situ studies are presented of Au(111) electrodes in 1-butyl-1-methylpyrrolidinium bis(trifluoromethylsulfonyl)imide ([BMP][TFSA]) by high-speed scanning tunneling microscopy (video-STM). [BMP][TFSA] is one of the best-understood air and water stable ionic liquids. The measurements provide direct insights into the potential dependent molecular arrangement and surface dynamics of adsorbed [BMP](+) cations in the innermost layer on the negatively charged Au electrode surface. In particular, two distinct subsequent transitions in the adlayer structure and lateral mobility are observed with decreasing potential. PMID- 25913870 TI - Reply: To PMID 25631192. PMID- 25913871 TI - Professor Robert JP Williams FRS (25/2/1926-21/3/2015). PMID- 25913872 TI - A historical review of optometry research and its publication: are optometry journals finally catching up? PMID- 25913873 TI - Elevated light levels in schools have a protective effect on myopia. AB - PURPOSE: To determine whether elevated light levels in classrooms in rural areas can protect school-age children from myopia onset or myopia progression. METHODS: A total of 317 subjects from 1713 eligible students aged six to 14 in four schools located in northeast China participated in the study. Students received a comprehensive eye examination including cycloplegic refraction and ocular biometry, which included axial length (AL), anterior chamber depth (ACD), and corneal curvature (CC) measurement, and completed a questionnaire. The intervention arm included 178 students in two schools with rebuilt elevated lighting systems and the control arm included 139 students in which lighting systems were unchanged. Results for the two arms were compared with a Wilcoxon rank sum test, a chi-squared test or a t-test, as appropriate. Factors that might help explain any differences were explored with multivariate linear regression analysis. RESULTS: The median average illuminance of blackboards and desks and uniformity of desk lighting were significantly improved, however, the uniformity of blackboard lighting declined after intervention. At baseline, the mean refraction, AL, CC, ACD and myopia prevalence between the two arms were not significantly different. After 1 year, compared with the control arm the intervention arm had a lower incidence of new myopia onset (4% vs 10%; p = 0.029), a smaller decrease in refractive error among no myopic subjects (-0.25 dioptre [D] vs -0.47 D; p = 0.001), and shorter axial growth for both non-myopic (0.13 vs 0.18 mm; p = 0.023) and myopic subjects (0.20 vs 0.27 mm; p = 0.0001). Multivariate linear regression analysis showed the intervention program, lower hyperopic baseline refraction, lower father's education level, longer time sleeping and less time in screen-viewing activities were associated with less refractive shift in the direction of myopia in non-myopic children. For myopic subjects, myopia progression was significantly associated with family income only. The intervention program and older age had a protective effect on axial growth for both myopic and non-myopic subjects. The father's education level and sleep duration were significantly associated with axial growth in non-myopic children. CONCLUSIONS: Elevated light levels in classrooms have a significant effect on myopia onset, decreases in refraction, and axial growth; if the findings of lighting intervention are reproduced in future studies, the ambient light levels in schools should be improved. PMID- 25913874 TI - Methodology and reporting of diagnostic accuracy studies of automated perimetry in glaucoma: evaluation using a standardised approach. AB - PURPOSE: To evaluate methodological and reporting quality of diagnostic accuracy studies of perimetry in glaucoma and to determine whether there had been any improvement since the publication of the Standards for Reporting of Diagnostic Accuracy (STARD) guidelines. METHODS: A systematic review of English language articles published between 1993 and 2013 reporting the diagnostic accuracy of perimetry in glaucoma. Articles were appraised for methodological quality using the 14-item Quality assessment tool for diagnostic accuracy studies (QUADAS) and evaluated for quality of reporting by applying the STARD checklist. RESULTS: Fifty-eight articles were appraised. Overall methodological quality of these studies was moderate with a median number of QUADAS items rated as 'yes' equal to nine (out of a maximum of 14) (IQR 7-10). The studies were often poorly reported; median score of STARD items fully reported was 11 out of 25 (IQR 10-14). A comparison of the studies published in 10-year periods before and after the publication of the STARD checklist in 2003 found quality of reporting had not substantially improved. CONCLUSIONS: Methodological and reporting quality of diagnostic accuracy studies of perimetry is sub-optimal and appears not to have improved substantially following the development of the STARD reporting guidance. This observation is consistent with previous studies in ophthalmology and in other medical specialities. PMID- 25913875 TI - Comparison of reading performance tests concerning difficulty of sentences and paragraphs and their reliability. AB - PURPOSE: In research and practice, sentences or paragraphs of reading tests may be randomly chosen to assess reading performance. This means that in addition to test reliability, all sentences or paragraphs should be reliable and equally difficult to read. The sentences and paragraphs of five (un-) standardised Dutch reading tests were investigated in this regard. METHODS: Tests were performed with 71 normally sighted persons (mean age 55 [18-86] years). All sentences and paragraphs had equal print size. The relative difficulty of sentences and paragraphs from the five Dutch reading tests was tested with linear mixed models (reading speed) and generalised linear models (mistakes). RESULTS: Reading speed in standard words per min ranged from 179 (Radner) to 142 (De Nederlanders). Reading mistakes per 100 characters ranged from 0.25 (Radner) to 0.40 (Colenbrander). On the Colenbrander charts 7/24 sentences were read significantly faster vs 5/24 read slower (sentence reliability 0.56-0.87); International Reading Speed Texts 3/10 vs 3/10 [0.94-0.97]; Laboratory of Experimental Ophthalmology 14/55 vs 15/55 [0.64-0.92]; De Nederlanders 2/6 vs 3/6 [0.83-0.94]; Radner 4/24 vs 3/24 [0.73-0.87]. Agreement between tests differed from 1 to 36 standard words per minute and 0.01 to 0.14 mistakes per 100 characters. CONCLUSION: The Radner, with the highest number of equally difficult sentences, is appropriate to measure reading acuity as well as reading speed in a heterogeneous population; the International Reading Speed Texts, with the highest paragraph reliability, provides long paragraphs to measure reading speed. The Colenbrander and Laboratory of Experimental Ophthalmology are suitable for daily practice; however, for research or inspection purposes, reliable sentences must be chosen. Although the clinical relevance of the differences between the tests is debatable, use of the De Nederlanders as a reading test remains questionable. PMID- 25913876 TI - Comment on: Statistical methods for conducting agreement (comparison of clinical tests) and precision (repeatability or reproducibility) studies in optometry and ophthalmology. PMID- 25913877 TI - Treatment-related risk factors for arm lymphedema among long-term breast cancer survivors. AB - INTRODUCTION: Treatment-related factors may increase the risk for arm lymphedema, which may occur after surgery or even many years after initial treatment for breast cancer. The association between treatment-related risk factors and development of arm lymphedema was examined for women who participated in the long term quality of life (LTQOL) study, a 12-15-year follow-up of a breast cancer case-control study of Hispanic and non-Hispanic white women. METHODS: Among 199 cases, 43 women (15 Hispanic, 28 non-Hispanic white) reported physician-diagnosed lymphedema during follow-up. Multivariable logistic regression analysis was used to calculate the odds ratios (OR) and 95% confidence intervals (CI) for the association of risk factors with lymphedema, adjusting for relevant covariates. RESULTS: Tamoxifen had a non-significant, positive association with lymphedema (OR = 2.07, 95% CI 0.94-4.55, p =0.07). There were no significant associations with type of surgery, radiation, or chemotherapy. Risk was increased specifically in overweight and obese women (body mass index (BMI) > =25 kg/m(2)) treated with tamoxifen (OR = 2.62, 95% CI 0.99-6.93, p = 0.05). CONCLUSIONS: This study suggests that breast cancer survivors with a BMI >25 who report the use of tamoxifen therapy may be at increased risk for arm lymphedema. IMPLICATIONS FOR CANCER SURVIVORS: Larger case-control studies and clinical trials should investigate the long-term association of tamoxifen treatment with arm lymphedema especially in overweight and obese women. Lymphedema risk may be another indication to consider a weight reduction program in breast cancer survivors. PMID- 25913878 TI - Lipase catalysed synthesis of cetyl oleate using ultrasound: Optimisation and kinetic studies. AB - The current paper exemplifies the application of ultrasound technology to enzymatic synthesis of a cosmetic emollient ester, cetyl oleate. Fermase CALBTM10000, a commercial Candida antarctica lipase B was used as a catalyst to accomplish the ultrasound supported synthesis. Multiple process parameters like reaction time, temperature, enzyme dose, alcohol to acid molar ratio, ultrasound power, frequency and speed of agitation were optimised. Maximum conversion of ~95.96% was discerned at optimum conditions, i.e., 60 degrees C temperature, 5% enzyme dose, 2:1 alcohol:acid ratio, 60 W ultrasound power, 25 kHz ultrasound frequency, 80% duty cycle and 80 rpm speed of agitation after purification steps. It was observed that the reaction reached equilibrium in a short duration of 30 min under the optimised conditions. This was considerably lesser than the time required for attaining equilibrium in conventional mechanical stirring method which was over 2h. Bisubstrate kinetic models like random bi-bi, ping pong bi-bi and ordered bi-bi were applied to the experimental data to determine initial rates and other kinetic parameters. Ordered bi-bi model showed the best fit with kinetic parameters, Vmax=0.029 M/min/gcatalyst, KA=0.00001 M, KB=4.8002 M, KiA=0.00014 M, KiB=3.7914 M & SSE=0.00022 for enzymatic cetyl oleate synthesis under ultrasound irradiation with inhibition by both acid and alcohol at high concentrations. PMID- 25913879 TI - Phogly-PseAAC: Prediction of lysine phosphoglycerylation in proteins incorporating with position-specific propensity. AB - Large-scale characterization of post-translational modifications (PTMs), such as posphorylation, acetylation and ubiquitination, has highlighted their importance in the regulation of a myriad of signaling events. However, as another type of PTMs-lysine phosphoglycerylation, the data of phosphoglycerylated sites has just been manually experimented in recent years. Given an uncharacterized protein sequence that contains many lysine residues, which one of them can be phosphoglycerylated and which one not? This is a challenging problem. In view of this, establishing a useful computational method and developing an efficient predictor are highly desired. Here a new predictor named Phogly-PseAAC was developed which incorporated with the position specific amino acid propensity. The feature importance through F-score value has also been ranked. The predictor with the best feature set obtained the accuracy 75.10%, sensitivity 68.87%, specificity 75.57% and MCC 0.2538 in LOO test cross validation with center nearest neighbor algorithm. Meanwhile, a web-server for Phogly-PseAAC is accessible at http://app.aporc.org/Phogly-PseAAC/. For the convenience of most experimental scientists, we have further provided a brief instruction for the web server, by which users can easily get their desired results without the need to follow the complicated mathematics presented in this paper. It is anticipated that Phogly-PseAAC may become a useful high throughput tool for identifying the lysine phosphoglycerylation sites. PMID- 25913880 TI - A spatially-averaged mathematical model of kidney branching morphogenesis. AB - Kidney development is initiated by the outgrowth of an epithelial ureteric bud into a population of mesenchymal cells. Reciprocal morphogenetic responses between these two populations generate a highly branched epithelial ureteric tree with the mesenchyme differentiating into nephrons, the functional units of the kidney. While we understand some of the mechanisms involved, current knowledge fails to explain the variability of organ sizes and nephron endowment in mice and humans. Here we present a spatially-averaged mathematical model of kidney morphogenesis in which the growth of the two key populations is described by a system of time-dependant ordinary differential equations. We assume that branching is symmetric and is invoked when the number of epithelial cells per tip reaches a threshold value. This process continues until the number of mesenchymal cells falls below a critical value that triggers cessation of branching. The mathematical model and its predictions are validated against experimentally quantified C57Bl6 mouse embryonic kidneys. Numerical simulations are performed to determine how the final number of branches changes as key system parameters are varied (such as the growth rate of tip cells, mesenchyme cells, or component cell population exit rate). Our results predict that the developing kidney responds differently to loss of cap and tip cells. They also indicate that the final number of kidney branches is less sensitive to changes in the growth rate of the ureteric tip cells than to changes in the growth rate of the mesenchymal cells. By inference, increasing the growth rate of mesenchymal cells should maximise branch number. Our model also provides a framework for predicting the branching outcome when ureteric tip or mesenchyme cells change behaviour in response to different genetic or environmental developmental stresses. PMID- 25913881 TI - Association of cerebrospinal fluid tap-related oscillatory activity and shunt outcome in idiopathic normal-pressure hydrocephalus. AB - BACKGROUND: Idiopathic normal-pressure hydrocephalus (iNPH) is a neuropsychiatric syndrome characterized by the clinical triad of gait disturbance, urinary dysfunction, and cognitive impairment. The aim of the present study was to find specific EEG patterns associated with shunt response in iNPH. METHODS: Twenty five iNPH patients (10 shunt responders and 15 non-responders) were enrolled in this study. We performed current source density (CSD) analysis in several frequency bands (delta: 2-4 Hz, theta: 4-8 Hz, alpha: 8-13 Hz, beta: 13-30 Hz, gamma: 30-60 Hz) using exact Low Resolution Brain Electromagnetic Tomography (eLORETA). CSD distribution was compared between shunt responders and non responders for each frequency band before and after CSF tap test. RESULTS: Shunt responders showed increased gamma CSD in the left temporal cortex before CSF tapping relative to non-responders. However, after CSF tapping, shunt response was associated with significantly higher CSDs in several frequency bands, specifically theta, alpha, beta and gamma, involving mainly the frontal and temporal areas. Using eLORETA analysis, we were able to identify cortical oscillatory activity before and after CSF tap test related to clinical recovery due to shunt operation in iNPH. CONCLUSION: Our findings support and extend the results of previous studies examining the effects of CSF tap test and shunt operation in patients with iNPH, possibly indicating electrophysiological features of shunt response in this disease. These findings warrant future studies to use EEG for prediction of shunt response in iNPH. PMID- 25913882 TI - Evaluation of batch and semi-continuous culture of Porphyridium purpureum in a photobioreactor in high latitudes using Fourier Transform Infrared spectroscopy for monitoring biomass composition and metabolites production. AB - The culture strategy (batch or semi-continuous) was evaluated for biomass and metabolite formation in Porphyridium purpureum cultures in higher latitudes (>50 degrees N). FTIR was used technology to characterise macromolecule biomass composition and the quality of the metabolites produced. Semi-continuous culture was found to be the most feasible strategy to develop microalgal biomass production facilities in higher latitudes, due to their average results in terms of growth rate (0.27 day(-1)), duplication time (2.5-4 days), maximum cell density achieved (1.43*10(7) cells m L(-1)), biomass productivity of 47.04 mg L( 1) day(-1) and an exopolysaccharides production of 2.1 g L(-1). FTIR technology applied to microalgal production is a valuable and reliable tool to determine on a daily basis not just the evolution of macromolecules composition (lipids, carbohydrates and proteins) but also for the characterisation of the metabolites produced such as phycoerythrin or exopolysaccharides in P. purpureum cultures. PMID- 25913883 TI - Synergetic effect of conductive polymer poly(3,4-ethylenedioxythiophene) with different structural configuration of anode for microbial fuel cell application. AB - PEDOT was synthesized by chemical polymerisation and characterised for its electrochemical insights. Three different anode configuration, namely graphite plate (GP), carbon cloth (CC) and graphite felt (GF) were then loaded with a fixed amount of PEDOT (2.5 mg/m(2)) denoted as GP-P, CC-P and GF-P respectively. The PEDOT coating improved the electrochemical characteristics and electron transfer capabilities of the anodes. They also contributed for enhanced MFC performances with maximum energy generation along with coulombic efficiency than the unmodified anodes. The morphological characteristics like higher surface area and open structure of felt material promoted both microbial formation and electrochemical active area. A maximum current density of 3.5A/m(2) was achieved for GF-P with CE and COD of 51% and 86% respectively. Thus, the GF-P anode excelled among the studied anodes with synergetic effect of PEDOT coating and structural configuration, making it as a potential optimum anode for MFC application. PMID- 25913884 TI - Methanol induces low temperature resilient methanogens and improves methane generation from domestic wastewater at low to moderate temperatures. AB - Low temperature (<20 degrees C) limits bio-methanation of sewage. Literature shows that hydrogenotrophic methanogens can adapt themselves to low temperature and methanol is a preferred substrate by methanogens in cold habitats. The study hypothesizes that methanol can induce the growth of low-temperature resilient, methanol utilizing, hydrogenotrophs in UASB reactor. The hypothesis was tested in field conditions to evaluate the impact of seasonal temperature variations on methane yield in the presence and absence of methanol. Results show that 0.04% (v/v) methanol increased methane up to 15 times and its effect was more pronounced at lower temperatures. The qPCR analysis showed the presence of Methanobacteriales along with Methanosetaceae in large numbers. This indicates methanol induced the growth of both the hydrogenotrophic and acetoclastic groups through direct and indirect routes, respectively. This study thus demonstrated that methanol can impart resistance in methanogenic biomass to low temperature and can improve performance of UASB reactor. PMID- 25913885 TI - Utilising biohydrogen to increase methane production, energy yields and process efficiency via two stage anaerobic digestion of grass. AB - Real time measurement of gas production and composition were used to examine the benefits of two stage anaerobic digestion (AD) over a single stage AD, using pelletized grass as a feedstock. Controlled, parallel digestion experiments were performed in order to directly compare a two stage digestion system producing hydrogen and methane, with a single stage system producing just methane. The results indicated that as well as producing additional energy in the form of hydrogen, two stage digestion also resulted in significant increases to methane production, overall energy yields, and digester stability (as indicated by bicarbonate alkalinity and volatile fatty acid removal). Two stage AD resulted in an increase in energy yields from 10.36 MJ kg(-1) VS to 11.74 MJ kg(-1) VS, an increase of 13.4%. Using a two stage system also permitted a much shorter hydraulic retention time of 12 days whilst maintaining process stability. PMID- 25913887 TI - Going into the groin: Injection into the femoral vein among people who inject drugs in three urban areas of England. AB - BACKGROUND: There have been increasing concerns about injection into the femoral vein - groin injecting - among people who inject drugs in a number of countries, though most studies have been small. The extent, reasons and harms associated with groin injecting are examined. METHOD: Participants were recruited using respondent driven sampling (2006-2009). Weighted data was examined using bivariate analyses and logistic regression. RESULTS: The mean age was 32 years; 25% were women (N=855). During the preceding 28 days, 94% had injected heroin and 13% shared needles/syringes. Overall, 53% reported ever groin injecting, with 9.8% first doing so at the same age as starting to inject. Common reasons given for groin injecting included: "Can't get a vein elsewhere" (68%); "It is discreet" (18%); and "It is quicker" (14%). During the preceding 28 days, 41% had groin injected, for 77% this was the only body area used (for these "It is discreet" was more frequently given as a reason). In the multivariable analysis, groin injection was associated with: swabbing injection sites; saving filters for reuse; and receiving opiate substitution therapy. It was less common among those injecting into two body areas, and when other people (rather than services) were the main source of needles. Groin injection was more common among those with hepatitis C and reporting ever having deep vein thrombosis or septicaemia. CONCLUSIONS: Groin injection was common, often due to poor vascular access, but for some it was out of choice. Interventions are required to reduce injecting risk and this practice. PMID- 25913886 TI - Co-occurring psychiatric and drug use disorders among sexual minority men with lifetime alcohol use disorders. AB - BACKGROUND: Emerging evidence indicates multiple health risks associated with harmful alcohol use among sexual minority men in the United States. In particular, sexual minority men with alcohol use disorders (AUD) might have greater co-occurring health problems compared with heterosexual men. We used nationally representative data to compare the prevalence of diagnostic co occurring psychiatric disorders and drug use disorders (DUD) among sexual minority men with AUD compared with heterosexual males with a lifetime AUD diagnosis. METHODS: We analyzed data from 6899 adult males with AUD participating in Wave 2 of the National Epidemiologic Survey on Alcohol and Related Conditions (NESARC). Using weighted multivariable logistic regression models, we compared the odds of lifetime diagnosis of mood disorders, anxiety disorders, and drug use disorders in sexual minority and heterosexual adult males with AUD. RESULTS: Of participants included in this analysis, 176 (2.6%) self-identified as a sexual minority. In adjusted analyses, sexual minority men with AUD were more likely than heterosexual men with AUD to have any mood disorder (including major depressive episode), any anxiety disorder (including panic disorder without agoraphobia, specific phobia, posttraumatic stress disorder, and generalized anxiety disorder), and lifetime DUD. CONCLUSIONS: The elevated co-occurrence of psychiatric disorders and DUD among sexual minority men with AUD suggests that future research is warranted. A better understanding of the etiology of diagnostic co-occurring mental health and substance use disorders among sexual minority men is needed in order to develop effective integrated prevention and treatment programs. PMID- 25913888 TI - The stage-specific in vitro efficacy of a malaria antigen cocktail provides valuable insights into the development of effective multi-stage vaccines. AB - Multicomponent vaccines targeting different stages of Plasmodium falciparum represent a promising, holistic concept towards better malaria vaccines. Additionally, an effective vaccine candidate should demonstrate cross-strain specificity because many antigens are polymorphic, which can reduce vaccine efficacy. A cocktail of recombinant fusion proteins (VAMAX-Mix) featuring three diversity-covering variants of the blood-stage antigen PfAMA1, each combined with the conserved sexual-stage antigen Pfs25 and one of the pre-erythrocytic-stage antigens PfCSP_TSR or PfCelTOS, or the additional blood-stage antigen PfMSP1_19, was produced in Pichia pastoris and used to immunize rabbits. The immune sera and purified IgG were used to perform various assays determining antigen specific titers and in vitro efficacy against different parasite stages and strains. In functional in vitro assays we observed robust inhibition of blood-stage (up to 90%), and sexual-stage parasites (up to 100%) and biased inhibition of pre erythrocytic parasites (0-40%). Cross-strain blood-stage efficacy was observed in erythrocyte invasion assays using four different P. falciparum strains. The quantification of antigen-specific IgGs allowed the determination of specific IC50 values. The significant difference in antigen-specific IC50 requirements, the direct correlation between antigen-specific IgG and the relative quantitative representation of antigens within the cocktail, provide valuable implementations for future multi-stage, multi-component vaccine designs. PMID- 25913889 TI - Stress memory induced transcriptional and metabolic changes of perennial ryegrass (Lolium perenne) in response to salt stress. AB - Preexposure to a stress could induce stable signals and reactions on plant physiology and gene expression during future encounters as a 'stress memory'. In this study, we found that two trainable genes, BPSP encoding putative brown plant hopper susceptibility protein and sucs encoding sucrose synthase displayed transcriptional memory for their considerably higher transcript levels during two or more subsequent stresses (S3, S4) relative to the initial stress (S0), and their expression returning to basal transcript levels (non-stressed) during the recovery states (R1, R2 and R3). Removing the repetitive stress/recovery exercise, activated transcriptional memory from two trainable genes persisted for at least 4 days in perennial ryegrass. The pretrainable genes with stress memory effort had higher response to the subsequent elevated NaCl concentration treatment than the non-trainable plants, which was confirmed by lower electrolyte leakage and minimum H2 O2 and O2 (-) accumulation. Salt stress elevated the content of 41 metabolites in perennial ryegrass leaves, and sugars and sugar alcohol accounted for more than 74.1% of the total metabolite content. The salt stress memory was associated with higher contents of 11 sugars and 1 sugar alcohol in the pretrainable grass leaves. Similarly, six sugars showed greater content in the pretrainable grass roots. These novel phenomena associated with transcriptional memory and metabolite profiles could lead to new insights into improving plant salinity acclimation process. PMID- 25913890 TI - Grid cells in 3-D: Reconciling data and models. AB - It is well documented that place cells and grid cells in echolocating bats show properties similar to those described in rodents, and yet, continuous theta frequency oscillations, proposed to play a central role in grid/place cell formation, are not present in bat recordings. These comparative neurophysiological data have raised many questions about the role of theta frequency oscillations in spatial memory and navigation. Additionally, spatial navigation in three-dimensions poses new challenges for the representation of space in neural models. Inspired by the literature on space representation in the echolocating bat, we have developed a nonoscillatory model of 3-D grid cell creation that shares many of the features of existing oscillatory-interference models. We discuss the model in the context of current knowledge of 3-D space representation and highlight directions for future research. PMID- 25913891 TI - Immunobullous disease and ulcerative colitis: a case series of six patients. AB - Cases of immunobullous skin disease associated with ulcerative colitis (UC) have been previously reported in the literature. There is no clear explanation for this association. In this series, we report six cases of immunobullous disease in patients with UC and discuss potential mechanisms of pathogenesis proposed to explain these concomitant diseases. The clinical presentation, immunopathology and treatment of six new cases are described and analysed. We report six patients, two with linear IgA bullous dermatosis (LABD), one with bullous pemphigoid (BP), one with mucous membrane pemphigoid (MMP) and two with IgA pemphigus. The patients' ages ranged from 33 to 66 years at the onset of their skin disease, and all but one case had a documented age of UC onset, confirmed with colonoscopy, prior to the development of skin disease. Direct immunofluorescence results in these patients demonstrated IgA basement membrane zone (BMZ) antibodies in the LABD cases, IgG antibodies at the BMZ in the BP and MMP cases, and IgA cell surface antibodies in the patients with IgA pemphigus. Additionally, indirect immunofluorescence was positive in one of the patients with LABD, the patient with BP and both of the patients with IgA pemphigus. The temporal association of UC and skin disease, in addition to the resolution of skin disease with total colectomy in one case, suggests colonic mucosal antigenic stimulation driving immune activation and leading to immunobullous skin disease. PMID- 25913892 TI - Liar, liar, working memory on fire: Investigating the role of working memory in childhood verbal deception. AB - The aim of the current study was to investigate the role of working memory in verbal deception in children. We presented 6- and 7-year-olds with a temptation resistance paradigm; they played a trivia game and were then given an opportunity to peek at the final answers on the back of a card. Measures of both verbal and visuospatial working memory were included. The good liars performed better on the verbal working memory test in both processing and recall compared with the bad liars. However, there was no difference in visuospatial working scores between good liars and bad liars. This pattern suggests that verbal working memory plays a role in processing and manipulating the multiple pieces of information involved in lie-telling. PMID- 25913893 TI - A prospective, randomized placebo-controlled clinical trial on the effects of a fluoride rinse on white spot lesion development and bleeding in orthodontic patients. AB - Demineralizations around orthodontic brackets are a main disadvantage of orthodontic treatment. Several methods have been advocated to prevent their development, such as fluoride rinses or varnishes. In this randomized clinical trial, a fluoride rinse (a combination of sodium fluoride and amine fluoride) was compared with a placebo rinse, to be used every evening after toothbrushing. A total of 81 participants (mean age: 13.3 yr) completed the study (mean treatment period: 24.5 months). Demineralizations, measured using quantitative light induced fluorescence and the decayed, missing, and filled surfaces (DMFS) index, were assessed before treatment (baseline) and around 6 wk after debonding (post treatment). Bleeding scores were measured at baseline, and during and post treatment. The incidence rate ratio for demineralizations was 2.6 (95% CI: 1.1 6.3) in the placebo group vs. the fluoride group. In the fluoride group, 31% of participants developed at least one demineralization, compared with 47% in the placebo group. Relative to baseline, gingival bleeding increased significantly in the placebo group 1 yr after the start of treatment and onwards. For the fluoride group, bleeding scores during treatment were not different from those at baseline. In conclusion, using a fluoride rinse helps to maintain better oral health during fixed appliance treatment, resulting in fewer demineralizations. PMID- 25913894 TI - Long-term outcomes after elective ileocecal resection in children with active localized Crohn's disease--a multicenter European study. AB - PURPOSE: The aim of this study was to investigate the therapeutic role of an elective ileocecal resection in children with active localized Crohn's disease. METHODS: This was a retrospective multicenter study which included five European referral centers which included all children with Crohn's disease who underwent ileocecal surgery from 2000 to 2011 and had a minimum of 12 months follow-up. RESULTS: Altogether 68 patients fulfilled inclusion criteria. Median age at diagnosis was 13.7 years (6.6-17.9 years) and at surgery 15.2 years (8.6-18.5 years). Median duration of postoperative clinical remission was 20 months (3-95 months). Overall 54 patients (79.4%) were in remission one year after surgery and 38 (55.9%) during the total postsurgical follow up (median 30 months; range 12-95 months). Z score height for age significantly improved postoperatively in children who were at the time of surgery younger than 16 years of age (mean difference 0.232 SD; p=0.029). Cox proportional hazard regression model failed to indicate risk factors associated with postsurgical relapse. CONCLUSION: Elective ileocecal resection is a valid treatment option which should be considered in a subset of pediatric patients with localized Crohn's disease with the aim of achieving clinical remission and to improve growth. PMID- 25913895 TI - Cystoscopic-assisted excision of rectourethral fistulas in males with anorectal malformations. AB - INTRODUCTION: We report a novel technique to label rectourethral fistulas in males with anorectal malformations who are undergoing posterior sagittal anorectoplasty (PSARP) to facilitate complete excision of the fistula. METHODS: Prior to performing PSARP in 21 male patients with rectourethral fistulas, cystoscopy was carried out to identify the orifice of the fistula within the urethra. A 3Fr ureteral catheter with calibrations was then inserted into the orifice to label the fistula. During the PSARP procedure, the rectourethral fistula was dissected to the junction of the urethra, as identified by the presence of the ureteral catheter, and the fistula tract was completely excised. RESULTS: Six prostatic and 15 bulbar rectourethral fistulas were found by cystoscopy. The orifices of the rectourethral fistulas were all located in the midline along the dorsal wall of the posterior urethra. The average length of the rectourethral fistulas was 10mm (range=5-15mm). During the PSARP procedure, the rectourethral fistula could be clearly identified, easily dissected and completely excised. Patients were followed up for 7-24 months. During the length of follow-up, micturition was normal and no urethral complications were found in any of the 21 patients. CONCLUSION: Intraoperative cystoscopy with placement of a ureteral catheter in the fistula tract facilitates complete excision of rectourethral fistulas in males with anorectal malformations without risking injury to the urethra. PMID- 25913896 TI - Urachal rhabdomyosarcoma in childhood: a rare entity with a poor outcome. AB - BACKGROUND/PURPOSE: Rhabdomyosarcoma (RMS) of the urachus is rare and gathered in the "abdominal and other locations" group for oncological treatment purpose, and therefore not well characterized. Our aim was to assess the clinical and prognostic specific features of urachal primary RMS in childhood. METHODS: We retrospectively reviewed the charts of 8 patients with an urachal RMS treated between 1984 and 2013 in two Pediatric Oncology Departments. Median follow-up was 42 months (18-100). RESULTS: Urachal RMSs were embryonal in 6, alveolar in 1, and not otherwise specified in 1. Age at diagnosis was 4.4 years (2.6-6). All patients had advanced locoregional extension (IRS IIIIV) and 1 had distant metastasis. All had chemotherapy and surgical resection. Six had external radiotherapy. Four had extensive peritoneal recurrence including 2 with distant metastasis, within a median of 25 months (11-82) after the end of treatment. One had metastatic progression under primary treatment. Four of them died between 18 and 57 months after diagnosis, and 1 is still under treatment for a late recurrence. Only 3 are free of disease after 3.3 to 7.9 years of follow-up. CONCLUSIONS: Pediatric urachal cancer is rare and poorly identified. In our series, RMS was exclusive in this location. Locoregional extension was always advanced. Prognosis was poor despite current multimodal therapy. We underline the need for new therapeutical strategies. PMID- 25913897 TI - Reply to Letter to the Editor. PMID- 25913898 TI - Predictable communities of soil bacteria in relation to nutrient concentration and successional stage in a laboratory culture experiment. AB - It is difficult to understand the processes that structure immensely complex bacterial communities in the soil environment, necessitating a simplifying experimental approach. Here, we set up a microcosm culturing experiment with soil bacteria, at a range of nutrient concentrations, and compared these over time to understand the relationship between soil bacterial community structure and time/nutrient concentration. DNA from each replicate was analysed using HiSeq2000 Illumina sequencing of the 16S rRNA gene. We found that each nutrient treatment, and each time point during the experiment, produces characteristic bacterial communities that occur predictably between replicates. It is clear that within the context of this experiment, many soil bacteria have distinct niches from one another, in terms of both nutrient concentration, and successional time point since a resource first became available. This fine niche differentiation may in part help to explain the coexistence of a diversity of bacteria in soils. In this experiment, we show that the unimodal relationship between nutrient concentration/time and species diversity often reported in communities of larger organisms is also evident in microbial communities. PMID- 25913899 TI - Real time detection of farm-level swine mycobacteriosis outbreak using time series modeling of the number of condemned intestines in abattoirs. AB - Mycobacteriosis in swine is a common zoonosis found in abattoirs during meat inspections, and the veterinary authority is expected to inform the producer for corrective actions when an outbreak is detected. The expected value of the number of condemned carcasses due to mycobacteriosis therefore would be a useful threshold to detect an outbreak, and the present study aims to develop such an expected value through time series modeling. The model was developed using eight years of inspection data (2003 to 2010) obtained at 2 abattoirs of the Higashi Mokoto Meat Inspection Center, Japan. The resulting model was validated by comparing the predicted time-dependent values for the subsequent 2 years with the actual data for 2 years between 2011 and 2012. For the modeling, at first, periodicities were checked using Fast Fourier Transformation, and the ensemble average profiles for weekly periodicities were calculated. An Auto-Regressive Integrated Moving Average (ARIMA) model was fitted to the residual of the ensemble average on the basis of minimum Akaike's information criterion (AIC). The sum of the ARIMA model and the weekly ensemble average was regarded as the time-dependent expected value. During 2011 and 2012, the number of whole or partial condemned carcasses exceeded the 95% confidence interval of the predicted values 20 times. All of these events were associated with the slaughtering of pigs from three producers with the highest rate of condemnation due to mycobacteriosis. PMID- 25913900 TI - Language-related gamma EEG frontal reduction is associated with positive symptoms in schizophrenia patients. AB - OBJECTIVES: Frontal hypoactivation has been consistently found in schizophrenia. We hypothesized that patients' deficit is asymmetrical, i.e., centred over the left frontal locations, associated with loss of language-related asymmetry, and correlated with positive symptoms. METHOD: The amplitude of EEG gamma band (36 48Hz) was measured during the processing of three linguistic (Phonological vs. Semantic vs. Visuo-perceptual) tasks and used as index of activation/connectivity in 18 schizophrenia patients and 18 healthy participants. RESULTS: Healthy controls showed higher gamma in frontal sites, revealing a significantly greater left vs. right asymmetry in all linguistic tasks, whereas patients exhibited decreased and bilateral gamma amplitude (i.e., reduced activation/connectivity) in frontal regions. The patients' left hypofrontality during phonological processing was positively correlated with higher levels of Delusions (P1) and Hallucination (P3) PANSS subscales. A significantly greater left posterior gamma amplitude was found in patients compared with controls. CONCLUSION: Results suggest, in schizophrenia patients, a functional deficit of left frontal regions including Broca's area, a key site playing a fundamental hierarchical role between and within hemispheres which integrates many basic processes in linguistic and conceptual organization. The significant correlation between lack of the left anterior asymmetry and increased positive symptoms is in line with Crow's hypothesis postulating the aetiological role of disrupted linguistic frontal asymmetry on the onset of the key symptoms of schizophrenia. PMID- 25913901 TI - Public speaking in front of an unreceptive audience increases implicit power motivation and its endocrine arousal signature. AB - The present study explored the motivational characteristics of the Trier Social Stress Test (TSST; Kirschbaum, Pirke, & Hellhammer, 1993). Seventy-two participants either completed the public-speaking component of the TSST or, as a control condition, the friendly TSST (Wiemers, Schoofs, & Wolf, 2013) and wrote picture stories both before and after treatment. Stories were coded for motivational imagery related to power, achievement, and affiliation as well as for activity inhibition, a marker of functional brain lateralization during stress. The TSST had a specific arousing effect on power motivation, but not on other motivational needs, on activity inhibition, or on story length. TSST elicited increases in power imagery, but not in achievement or affiliation imagery, were associated with a relatively greater salivary alpha-amylase response and with a relatively lesser salivary cortisol response. These findings suggest that the TSST specifically induces power-related stress. PMID- 25913902 TI - Animals may act as social buffers: Skin conductance arousal in children with autism spectrum disorder in a social context. AB - Children with autism spectrum disorder (ASD) experience high rates of social stress and anxious arousal. Preliminary evidence suggests that companion animals can act as buffers against the adverse effects of social stress in adults. We measured continuous physiological arousal in children with ASD and typically developing (TD) children in a social context during four conditions: (a) a baseline of reading silently, (b) a scripted classroom activity involving reading aloud, (c) free play with peers and toys, and (d) free play with peers and animals (guinea pigs). Our results confirmed heightened arousal among children with ASD compared to TD children in all conditions, except when the animals were present. Children with ASD showed a 43% decrease in skin conductance responses during free play with peers in the presence of animals, compared to toys. Thus, animals may act as social buffers for children with ASD, conferring unique anxiolytic effects. PMID- 25913903 TI - Scanning tunneling microscope observation of the phosphatidylserine domains in the phosphatidylcholine monolayer. AB - A mixed monolayer of 1,2-dihexanoyl-sn-glycero-3-phospho-l-serine (DHPS) and 1,2 dihexanoyl-sn-glycero-3-phosphocholine (DHPC) on an 1-octanethiol-modified gold substrate was visualized on the nanometer scale using in situ scanning tunneling microscopy (STM) in aqueous solution. DHPS clusters were evident as spotty domains. STM enabled us to distinguish DHPS molecules from DHPC molecules depending on their electronic structures. The signal of the DHPS domains was abolished by neutralization with Ca(2+). The addition of the PS + Ca(2+)-binding protein of annexin V to the Ca(2+)-treated monolayer gave a number of spots corresponding to a single annexin V molecule. PMID- 25913904 TI - Aggressive Intrinsic Subtypes in Breast Cancer: A Predictor of Guideline Adherence in Older Patients With Breast Cancer? AB - BACKGROUND: Treatment side effects, comorbidities, and guideline-adherent treatment (GL+) influence the oncologic outcome of older breast cancer patients (oBCP) (age >= 70 years). The focus of this analysis was to investigate the associations among tumor characteristics, guideline adherence, and outcome and to compare these associations between younger breast cancer patients (yBCP) (age 50 69 years) and oBCP. METHODS: This is a retrospective multicenter cohort study with 17 participating certified breast cancer centers. The analysis of 10,897 patient records collected from 1992 to 2008 for GL+ and clinical outcome was performed. Tumor and patient characteristics and their associations with GL+ were compared between oBCP and yBCP. RESULTS: Nonguideline-adherent treatment (GL-) was associated with higher tumor stages and comorbidities. This effect was stronger in the oBCP group (P < .001). GL+ was significantly more common in yBCP than in oBCP (P < .001). The oBCP had significantly higher tumor stages, including tumor size (P < .001), nodal status (P < .001), and positive hormone receptors (P = .001). Tumor grading was lower (P = .001), and HER2neu overexpression was less frequent (P = .003) in oBCP. Overall survival and disease free survival are significantly impaired if GL- occurred in patients with breast cancer independently of age. CONCLUSIONS: GL- is associated with decreased disease-free survival and overall survival in both age groups. GL+ decreases advanced tumor characteristics in all age groups but significantly more in oBCP. If patients received GL+, we were unable to detect a statistical significant difference in the survival parameters. PMID- 25913905 TI - Phase II Randomized Study of Ixabepilone Versus Observation in Patients With Significant Residual Disease After Neoadjuvant Systemic Therapy for HER2-Negative Breast Cancer. AB - BACKGROUND: Residual disease (RD) after neoadjuvant chemotherapy carries an increased risk for recurrence. Ixabepilone has activity in anthracycline/taxanes resistant breast cancer. We explored adjuvant ixabepilone in patients with significant RD HER2-negative breast cancer. METHODS: A phase II study in patients with residual cancer burden II or III randomized to ixabepilone versus observation was conducted. Circulating tumor cells (CTCs) were measured at baseline and at 9 and 18 weeks. Survival probabilities were estimated by Kaplan Meier product limit. Toxicities were reported as proportions in the ixabepilone arm. RESULTS: Accrual was stopped because of ixabepilone toxicity. Sixty-seven patients were registered; 43 were randomized, 19 received ixabepilone, and 24 went to observation. One patient (9.1%) in the observation arm versus 2 patients (18.2%) in the ixabepilone arm had CTCs at 18 weeks (P = 1.0). Three-year recurrence-free survival and overall survival were 94% and 82%, and 100% and 79% in the observation and ixabepilone arms (P = .35 and .18), respectively. Most common adverse events (AEs) included fatigue, pain, neuropathy, constipation, nausea, rash, anorexia, and diarrhea. Serious AEs included pain (63.2%), fatigue (31.6%), and neuropathy (31.6%). CONCLUSIONS: Adjuvant ixabepilone in patients with significant RD after neoadjuvant chemotherapy was difficult to administer because of AEs and did not change the presence of CTC or affect survival outcomes. NCT00877500. PMID- 25913906 TI - The effect of postoperative wound infections on functional outcome following intra-articular calcaneal fractures. AB - INTRODUCTION: High rates of postoperative wound infections (POWI) are reported following the operative treatment of calcaneal fractures. This leads to additional therapy, prolonged hospital stay, burden for patients and increased costs. The primary aim of this study is to evaluate the effect of POWI following the extended lateral approach of displaced intra-articular calcaneal fractures on functional outcome. Secondary aims are assessment of health-related quality of life and patient satisfaction. PATIENTS AND METHODS: All consecutive adult patients with a calcaneal fracture treated between 2000 and 2011 with open reduction and internal fixation through an extended lateral approach were retrospectively included and sent a questionnaire. Functional outcome was measured using the Foot Function Index (FFI, best score 0 points) and the American Orthopaedic Foot and Ankle Society (AOFAS, best score 100 points) hindfoot score. The EuroQOL-5D was used for quality of life (QOL) and a Visual Analogue Scale (VAS, best score 10 points) for overall patients satisfaction. RESULTS: Of 135 eligible patients, 94 returned the questionnaire (response rate 70 %). The median FFI was 12 points (IQR 3-33) and AOFAS 79 points (IQR 61-90). The FFI and AOFAS were, respectively, 17 and 9 points higher in favour of patients without POWI (n = 69) compared to patients with POWI (n = 25). Albeit large differences, they were not statistically significant given the current number of patients. Patients without POWI scored better on all health-related aspects of QOL in the EQ-5D, but this did not reach statistical significance. However, the VAS on overall patient satisfaction did show a statistically significant difference of 1.3 points (9.0 vs 7.7; p = 0.01) in favour of patients without POWI. Importantly, a clinically relevant difference was found with the FFI as the estimated minimal clinical important difference of the FFI is 10 points. CONCLUSION: Our results implicate that postoperative wound infection leads lower functional outcome scores following calcaneal fracture surgery, but no statistical significance was reached. In addition, patients do not report significant worse QOL or physical impairment. Overall patient satisfaction measured by a VAS was significantly lower in case of a POWI, reflecting the burden caused by a wound complication. PMID- 25913907 TI - [Electronic medical record in clinical trials of effectiveness of drugs integrated in clinical practice]. PMID- 25913908 TI - [Children's relative age in class and medication for attention deficit/hyperactivity disorder. A population-based study in a health department in Spain]. AB - BACKGROUND AND OBJECTIVE: Previous studies in various countries have shown that the youngest school children in the same class-grade are more likely to be treated for attention-deficit/hyperactivity disorder (ADHD) than their older classmates. The aim of this study is to determine in the Spanish setting whether younger relative age children in each grade have a higher prevalence of treatment for ADHD. SUBJECTS AND METHODS: Population, observational, cross-sectional study in a health department, using prevalence data (November 2013) of treatment for ADHD in children aged 6-12 years. Data was obtained from the information systems of the Valencia Ministry of Health and multivariate models were used to estimate the prevalence ratio of treatment according to the month of birth of children in each grade. RESULTS: Twenty thousand two hundred and thirty-seven children were included of whom 1.73% were treated for ADHD (boys: 2.70%; girls: 0.71%) in October 2013. The prevalence of treatment increased with age, in males, and in youngest children (born in the last months of each year). In the multivariate analysis, the prevalence of treatment in the youngest children (born in the months of August to December) was 2.5 to 3 times higher than in their older classmates (born in January). CONCLUSIONS: The younger children relative to their classmates are more likely to be treated pharmacologically with methylphenidate and/or atomoxetine. PMID- 25913909 TI - [Skin and mucous vascular malformations in a 65 years old man]. PMID- 25913910 TI - [Treatment of perioperative anemia in hip fracture]. PMID- 25913911 TI - Transdermal patches: how common are application site reactions and how severe are they? PMID- 25913912 TI - Reduction of angiotensin inhibition in older CKD patients with heart failure led to improved renal and mortality outcomes - the results of a Spanish open RCT. PMID- 25913913 TI - COPD: early diagnosis and treatment to slow disease progression. PMID- 25913914 TI - The Micromort: a unit for comparing and communicating risk to patients. PMID- 25913915 TI - Dynamics of aqueous binary glass-formers confined in MCM-41. AB - Dielectric permittivity measurements were performed on water solutions of propylene glycol (PG) and propylene glycol monomethyl ether (PGME) confined in 21 A pores of the silica matrix MCM-41 C10 in wide frequency (10(-2)-10(6) Hz) and temperature (130-250 K) ranges. The aim was to elucidate how the formation of large hydrogen bonded structural entities, found in bulk solutions of PGME, was affected by the confined geometry, and to make comparisons with the dynamic behavior of the PG-water system. For all solutions the measurements revealed four almost concentration independent relaxation processes. The intensity of the fastest process is low compared to the other relaxation processes and might be caused by both hydroxyl groups of the pore surfaces and by local motions of water and solute molecules. The second fastest process contains contributions from both the main water relaxation as well as the intrinsic beta-relaxation of the solute molecules. The third fastest process is the viscosity related alpha-relaxation. Its concentration independency is very different compared to the findings for the corresponding bulk systems, particularly for the PGME-water system. The experimental data suggests that the surface interactions induce a micro-phase separation of the two liquids, resulting in a full molecular layer of water molecules coordinating to the hydrophilic hydroxyl groups on the surfaces of the silica pores. This, in turn, increases the geometrical confinement effect for the remaining solution even more and prevents the building up of the same type of larger structural entities in the PGME-water system as in the corresponding bulk solutions. The slowest process is mainly hidden in the high conductivity contribution at low frequencies, but its temperature dependence can be extracted for the PGME-water system. However, its origin is not fully clear, as will be discussed. PMID- 25913916 TI - The effect of age and sex on cost of inpatient facility encounters among patients with multiple sclerosis. AB - OBJECTIVE: To explore the effect of age and sex on cost of all-cause and multiple sclerosis (MS)-related inpatient facility encounters. METHODS: Adult patients with an initial MS diagnosis were identified from a national managed-care database (IMS LifeLink Health Plans Database). The analysis included newly diagnosed MS patients with 12 months insurance eligibility before and after their first MS diagnosis. Inpatient facility encounters (stays) were analyzed for all cause and MS-related events (ICD-9-CM = 340.XX), other demyelinating CNS disease (ICD-9-CM = 341.XX), rehabilitation (ICD-9-CM = V57.89), and a group of symptom related diagnoses. Costs and length of stay were evaluated using a general linear model controlling for age and sex. RESULTS: A total of 57,236 patients met study criteria; 74.3% were female. Mean age for females was 45.5 years and for males it was 47.5 years. In total, 17.0% had an all-cause inpatient stay in the 360-day post index, and 3.2% had an in patient stay with a MS relapse-related diagnosis as primary discharge diagnosis. Additional MS-related diagnoses that led to inpatient stays included other demyelinating CNS disease (0.3%), symptom-related diagnoses (1.0%), and rehabilitation (1.1%). All-cause inpatient cost was higher for males vs females across all age groups; however, cost for females increased at a greater rate as age increased (p = 0.0007). Symptom-related inpatient cost was flat for males, was lower for females than males at an average age of 30, and was greater for females than males at an average age of 60 (p = 0.0199). Cost for MS inpatient stays ($11,931), other demyelinating CNS-related stays ($14,931), and rehabilitation ($23,643) did not differ by age and sex. The average cost for any MS-related relapse inpatient stay was $13,761 and varied with increasing age (p < 0.0001). CONCLUSION: Burden of illness for relapse among MS patients is substantial. Costs vary by age and sex depending on the discharge diagnosis. Inclusion of symptom-related and rehabilitation inpatient stays may account for an under-recognized proportion of total expenditures. PMID- 25913917 TI - Sex allocation according to multiple sexually dimorphic traits of both parents in the barn swallow (Hirundo rustica). AB - Parents should differentially invest in sons or daughters depending on the sex specific fitness returns from male and female offspring. In species with sexually selected heritable male characters, highly ornamented fathers should overproduce sons, which will be more sexually attractive than sons of less ornamented fathers. Because of genetic correlations between the sexes, females that express traits which are under selection in males should also overproduce sons. However, sex allocation strategies may consist in reaction norms leading to spatiotemporal variation in the association between offspring sex ratio (SR) and parental phenotype. We analysed offspring SR in barn swallows (Hirundo rustica) over 8 years in relation to two sexually dimorphic traits: tail length and melanin-based ventral plumage coloration. The proportion of sons increased with maternal plumage darkness and paternal tail length, consistently with sexual dimorphism in these traits. The size of the effect of these parental traits on SR was large compared to other studies of offspring SR in birds. Barn swallows thus manipulate offspring SR to overproduce 'sexy sons' and potentially to mitigate the costs of intralocus sexually antagonistic selection. Interannual variation in the relationships between offspring SR and parental traits was observed which may suggest phenotypic plasticity in sex allocation and provides a proximate explanation for inconsistent results of studies of sex allocation in relation to sexual ornamentation in birds. PMID- 25913918 TI - Negative affectivity, depression, and anxiety: Does rumination mediate the links? AB - BACKGROUND: Negative affectivity (NA) is thought to be a vulnerability factor for depressive and anxiety symptoms; however, the mechanism through which this process takes place is yet to be fully ascertained. Rumination, a negative thought process, however, is believed a likely candidate in the association between NA and symptoms of depression and anxiety. Moreover, a thought-provoking advance in the understanding of rumination is the identification of a two-factor structure, with 'brooding' and 'reflection' as its subtypes. Thus, the present study sought to clarify the meditational effects of brooding and reflection in the relationships between NA and symptoms of depression and anxiety. METHOD: Self report questionnaires tapping rumination, NA, and symptoms of depression and anxiety were administered to a sample of 77 psychiatric patients aged 30-40. RESULTS: In line with study expectations, brooding, reflection, NA, anxiety, and depressive symptoms correlated substantially with each other. Both, brooding and reflection completely mediated the association between NA and depressive symptoms; however, the relationship between NA and anxiety was not mediated by either brooding or reflection. LIMITATIONS: The current study is limited in terms of its cross sectional nature, sample size, sample selection, and methods of assessment. CONCLUSIONS: Despite these limitations, the present study demonstrated that a temperamental construct NA significantly predicts brooding and reflection and these in turn predict depressive symptoms but not anxiety. Thus, NA, a temperamental construct, may be more related to anxiety rather than depression. PMID- 25913919 TI - A review of nutrient treatments for paediatric depression. AB - Paediatric depression is estimated to affect 15-20% of youths prior to adulthood and is associated with significant social, educational and physical impairment. Current treatments comprise moderately efficacious psychological therapies and pharmaceutical antidepressants. However, nutritional therapies are also available and are regularly sought by people with depressive illnesses and parents of depressed youths. In this narrative review, studies examining the antidepressant effects of individual nutritional supplements in child and adolescent populations are appraised. Epidemiological studies examining the relationship between nutritional status and paediatric depression, or depressive symptoms are also reviewed. Nutrients covered in this article include: omega-3 polyunsaturated fatty acids, s-adenosylmethionine, vitamin C, vitamin D, zinc, iron and B vitamins. Although several of these nutrients present as promising treatments for paediatric depression, there is a lack of high-quality studies examining the antidepressant effects of all the aforementioned ingredients. Before nutritional treatments are accepted as validated treatments for paediatric depression, further high-quality studies are required. PMID- 25913920 TI - Role of the Pharmacist in Medication Therapy Management Services in Patients With Osteoporosis. AB - PURPOSE: This study aimed to review and summarize clinical trial data, updated guidelines, and expert opinions on the recommendations for drug holidays in patients being treated for osteoporosis. METHODS: Three unique PubMed searches using the terms osteoporosis drug holiday, osteoporosis discontinuation, and osteoporosis extension produced 149 articles, of which 16 with relevance to postmenopausal osteoporosis and treatment discontinuation were selected. A separate search of 6 national societies with interest in the treatment of osteoporosis produced 2 guideline statements with specific mention of therapy duration. FINDINGS: No pharmacologic therapy for osteoporosis should be considered indefinite. After 3 to 5 years of therapy, a comprehensive patient assessment of individualized risk for fracture should occur. In patients who are at mild to moderate risk for fracture after initial treatment, therapy with a bisphosphonate may be discontinued, whereas patients who remain at high risk for fracture should continue therapy. Although discontinuation with bisphosphonate agents may be appropriate due to mechanism of action and expected residual effects, which may last several years after discontinuation, discontinuation of shorter-acting agents (nonbisphosphonate agents) will result in a rapid reversal of therapeutic benefits and may not be appropriate. Patients who undergo a drug holiday should be monitored and reassessed for re-initiation of therapy. Caution should be employed by readers generalizing results to male patients with osteoporosis as pivotal trial data are limited to postmenopausal women with osteoporosis. IMPLICATIONS: Pharmacists play a crucial role in ensuring that patients achieve optimal therapeutic outcomes. This achievement is partly accomplished through medication-adherence monitoring and education. Most chronic disease states require that patients remain on therapy, even when asymptomatic, for an indefinite period to meet and maintain therapeutic goals. To improve health-related outcomes, some pharmacist-managed medication therapy management programs are devoted entirely to treatment adherence. However, osteoporosis is a chronic disease state for which indefinite therapy may no longer be recommended due to potential long-term tolerability issues. It is crucial that the pharmacist understand the data and new guidelines addressing the optimal duration of therapy in osteoporotic patients so that they recognize which patients qualify for a drug holiday, do not mistakenly categorize a patient as nonadherent when therapy is stopped, and recommend when therapy should be restarted. This understanding will result in better patient management and health system cost-savings. PMID- 25913921 TI - Recent Developments and Future Directions of Pneumococcal Vaccine Recommendations. AB - PURPOSE: The goal of this article was to review the key clinical trials that resulted in the recent recommendation from the Advisory Committee on Immunization Practices (ACIP) to vaccinate all adults aged >=65 years with the 13-valent pneumococcal polysaccharide conjugate vaccine (PCV13) in addition to the previously recommended 23-valent pneumococcal polysaccharide vaccine (PPSV23). METHODS: Pertinent articles were identified through searches of EMBASE and MEDLINE by using the terms pneumococcal polysaccharide conjugate vaccine, pneumococcal vaccine, and PCV13. Searches were limited to articles published between January 1, 2013, and January 31, 2015, and were limited to clinical trials. Resources from the Centers for Disease Control and Prevention's ACIP recommendations and cited references were also reviewed. FINDINGS: Recent clinical trials have focused on the order of administration of PPSV23 and PCV13, comparisons in immunogenicity of PPSV23 and PCV13, and efficacy of PCV13 in adults aged >=65 years. Immunogenicity trials have shown that PCV13 elicits an equal or greater immune response than PPSV23 for most of the serotypes that both vaccines share. The evidence suggests that PCV13 should be administered before PPSV23 when possible. Most recently, clinical data demonstrated the efficacy of PCV13 in adults aged >=65 years. IMPLICATIONS: Recent randomized clinical trials and disease trends have prompted the ACIP to recommend that all adults aged >=65 years receive a single dose of PCV13. This is in addition to the previous recommended single dose of PPSV23 in the same population. The ACIP and the Centers for Disease Control and Prevention plan to monitor disease trends and clinical data to determine if this recommendation will need to be changed in the future. PMID- 25913922 TI - Effects of Febuxostat on Oxidative Stress. AB - PURPOSE: We previously examined factors that affect the measured derivatives of reactive oxygen metabolites (d-ROMs), an indicator of reactive oxygen species production, and biological antioxidant potential (BAP), an indicator of antioxidant capacity, in typical health checkup examinees and reported the usefulness of measuring both indicators simultaneously. In addition, a positive correlation reportedly exists between d-ROMs and the visceral fat area measured by using computed tomography. A recent study of the relationship between uric acid levels and various obesity-related factors found that visceral fat was the factor most strongly related to uric acid levels. Uric acid is itself a potent endogenous antioxidant, but because reactive oxygen species are produced during uric acid generation, it is suggested that uric acid may have opposing effects. The objective of this study was to analyze the effect of febuxostat, a novel xanthine oxidase inhibitor, on oxidative stress. METHODS: Study subjects were 43 hyperuricemia outpatients receiving care in the internal medicine department of our institution. The subjects were divided into a new administration group (29 patients) and a switched administration group (14 patients); the latter were allopurinol-treated patients with hyperuricemia who were switched to febuxostat. In addition to measuring the patients' uric acid and creatinine levels and estimated glomerular filtration rate before and after treatment, their d-ROMs and BAP as well as the BAP/d-ROMs ratio were also measured. FINDINGS: Both groups exhibited significant decreases in uric acid levels, as well as significant decreases in d-ROMs and BAP. No significant changes were observed in the BAP/dROMs ratio or renal function, including creatinine levels and estimated glomerular filtration rate. IMPLICATIONS: Febuxostat could significantly reduce d ROMs. However, BAP levels were also significantly reduced concurrently. No changes were observed in the BAP/d-ROMs ratios. This regulatory mechanism is believed to have counteracted changes in the in vivo oxidative stress balance caused by febuxostat administration. PMID- 25913923 TI - Tolerability of Biphasic-Release Hydrocodone Bitartrate/Acetaminophen Tablets (MNK-155): A Phase III, Multicenter, Open-Label Study in Patients With Osteoarthritis or Chronic Low Back Pain. AB - PURPOSE: This study aimed to assess the tolerability of the extended use (<=35 days) of MNK-155, a biphasic (immediate-release/extended-release) hydrocodone bitartrate/N-acetyl-p-aminophenol (acetaminophen) (IR/ER HB/APAP) 7.5/325-mg fixed-dose combination analgesic agent, in patients with chronic noncancer pain (CNCP) caused by osteoarthritis or chronic low back pain. IR/ER HB/APAP tablets deliver 25% of the HB dose and 50% of the APAP dose by IR and the remainder by ER over a 12-hour dosing interval. Although IR/ER HB/APAP is being developed for the management of moderate to severe acute pain, this model of CNCP was used for assessing tolerability over a term longer than would be possible in a model of acute pain. METHODS: This Phase III, multicenter, open-label study enrolled patients with moderate to severe OA (knee or hip) pain despite the use of nonopioid or opioid analgesic agents, or with moderate to severe CLBP present for several hours per day for >=3 months. Patients received a 3-tablet initial dose of IR/ER HB/APAP (total dose, 22.5/975 mg) on day 1, followed by 2 tablets of IR/ER HB/APAP (total dose, 15/650 mg) q12h for up to 35 days. Tolerability, the primary end point, was assessed using time to treatment discontinuation, the prevalence of treatment-emergent adverse events (TEAEs), vital sign measurements, pulse oximetry, clinical laboratory tests, and compliance. Secondary outcomes included the modified Brief Pain Inventory-Short Form, the Western Ontario and McMaster Universities Arthritis Index, and The Roland-Morris Low Back Pain and Disability Questionnaire. FINDINGS: Of the 153 patients enrolled (95 women [62.1%]; mean age, 53.9 [14.5] years; OA, n = 73; CLBP, n = 80), 37 (24.2%) discontinued the study early (mean time to discontinuation, 21.3 days). Thirteen patients (8.5%) discontinued because of TEAEs. A total of 88 patients (57.5%) reported >=1 TEAE, 65 (42.5%) of whom experienced AEs considered by the investigator as treatment related. The most frequent TEAEs were nausea (16.3%), somnolence (14.4%), and constipation (11.1%). Eight severe TEAEs were experienced by 6 (3.9%) patients and included single occurrences of nausea, fatigue, nasopharyngitis, elevated liver enzymes, headache, nightmare, and ejaculation delay. No serious treatment-related AEs were reported. Clinically significant changes in laboratory values were reported in 13 patients, 6 of whom had abnormal liver function test results that did not meet Hy's law criteria for acute liver failure. Most laboratory abnormalities were mild and transient. Measures of pain intensity, function, and quality of life improved from baseline but in an open label study these changes cannot be attributed to treatment. IMPLICATIONS: The safety profile of IR/ER HB/APAP during extended use was consistent with those of other low-dose opioid/APAP combination products. IR/ER HB/APAP is intended for acute pain; its efficacy for relief of CNCP would require further evaluation in an active- or placebo-controlled study. ClinicalTrials.gov Identifier: NCT01722864. PMID- 25913925 TI - Phytochemicals and Estrogen-Receptor Agonists from the Aerial Parts of Liriope platyphylla. AB - One new benzofuran, (2R)-(2',4'-dihydroxybenzyl)-6,7-methylenedioxy-2,3 dihydrobenzofuran (1), one new phenylisocoumarin, 3-(2'-hydroxyphenyl)-6,8 dihydroxy-7-methoxy-isocoumarin (2), and one new benzofuroisocoumarin, platyphyllarin C (3), were isolated from the ethanolic extract of Liriope platyphylla aerial parts, along with seventeen known compounds. The structures of the isolates were established by spectroscopic analysis and comparison with the literature data. The results indicated that structures 1-3 are uncommon in Nature. Benzofuroisocoumarin 4, flavonoids 9, 10, and 13-15, and homoisoflavonoids 19 and 20 exhibited significant binding activity to estrogen receptor alpha and/or beta as demonstrated by the SEAP reporter assay system in an MCF-7 cell-line. PMID- 25913926 TI - Efficient synthesis of readily water-soluble sulfonic Acid carbamates. AB - A series of various readily water-soluble carbamates were synthesized with good yields. These compounds are useful chemical tracers for assessing the cooling progress in a georeservoir during geothermal power plant operation. Acylation of primary amines was carried out as well as using a solution of sodium bicarbonate and without the presence of salt. Products were characterized by 1H-NMR and 13C NMR. Purity was confirmed through elemental analysis. PMID- 25913928 TI - Anti-Inflammatory Effect of Wogonin on RAW 264.7 Mouse Macrophages Induced with Polyinosinic-Polycytidylic Acid. AB - Wogonin (5,7-dihydroxy-8-methoxyflavone) is an active flavonoid compound originally isolated from Scutellaria radix, which has been used to treat lung inflammation in Korea, China, and Japan. Wogonin has been known to inhibit inducible nitric oxide synthase and have the anti-tumor properties. However, the effects of wogonin on virus-induced macrophages are not fully reported. In this study, the anti-inflammatory effect of wogonin on double-stranded RNA (dsRNA) induced macrophages was examined. Wogonin restored the cell viability in dsRNA [polyinosinic-polycytidylic acid]-induced RAW 264.7 mouse macrophages at concentrations of up to 50 MUM. Wogonin significantly inhibited the production of nitric oxide, IL-1alpha, IL-1beta, IL-6, IL-10, IP-10, G-CSF, GM-CSF, LIF (IL-6 class cytokine), LIX/CXCL5, MCP-1, M-CSF, MIP-1alpha, MIP-1beta, MIP-2, RANTES/CCL5, TNF-alpha, and VEGF as well as calcium release and mRNA expression of signal transducer and activated transcription 1 (STAT1) and STAT3 in dsRNA induced RAW 264.7 cells (P < 0.05). In conclusion, wogonin has anti-inflammatory properties related with its inhibition of nitric oxide, cytokines, chemokines, and growth factors in dsRNA-induced macrophages via the calcium-STAT pathway. PMID- 25913929 TI - Simultaneous Quantification of Diazepam and Dexamethasone in Plasma by High Performance Liquid Chromatography with Tandem Mass Spectrometry and Its Application to a Pharmacokinetic Comparison between Normoxic and Hypoxic Rats. AB - In order to investigate the pharmacokinetics of a combination of diazepam and dexamethasone under hypoxic conditions, a novel, sensitive and specific liquid chromatography with tandem mass spectrometry (LC-MS/MS) method for the simultaneous determination of diazepam and dexamethasone in rat plasma was developed and validated. The chromatographic separation of analytes was successfully achieved on an XTerra(r) MS C18 column using a gradient elution of methanol and water containing 0.1% formic acid at a flow rate of 0.5 mL/min. This method demonstrated good linearity and no endogenous material interferences. The linear ranges were 1.0-100 ng/mL for diazepam and 2.0-200 ng/mL for dexamethasone. The intra- and inter-day precision for the two compounds in plasma were lower than 10.0%, and the accuracy was between -7.9% and 11.5%. Our method was then successfully applied in a pharmacokinetic comparison between normoxic and hypoxic rats. The results indicated that there were significant differences in the main pharmacokinetics parameters of diazepam and dexamethasone between normoxic and hypoxic rats. The results provide the important and valuable information for discovering and developing novel anti-hypoxia drug combinations, as well as a better understanding of the safety and efficacy of these drugs. PMID- 25913927 TI - Predicting the Uncertain Future of Aptamer-Based Diagnostics and Therapeutics. AB - Despite the great promise of nucleic acid aptamers in the areas of diagnostics and therapeutics for their facile in vitro development, lack of immunogenicity and other desirable properties, few truly successful aptamer-based products exist in the clinical or other markets. Core reasons for these commercial deficiencies probably stem from industrial commitment to antibodies including a huge financial investment in humanized monoclonal antibodies and a general ignorance about aptamers and their performance among the research and development community. Given the early failures of some strong commercial efforts to gain government approval and bring aptamer-based products to market, it may seem that aptamers are doomed to take a backseat to antibodies forever. However, the key advantages of aptamers over antibodies coupled with niche market needs that only aptamers can fill and more recent published data still point to a bright commercial future for aptamers in areas such as infectious disease and cancer diagnostics and therapeutics. As more researchers and entrepreneurs become familiar with aptamers, it seems inevitable that aptamers will at least be considered for expanded roles in diagnostics and therapeutics. This review also examines new aptamer modifications and attempts to predict new aptamer applications that could revolutionize biomedical technology in the future and lead to marketed products. PMID- 25913930 TI - Accumulation of GD1alpha Ganglioside in MDA-MB-231 Breast Cancer Cells Expressing ST6GalNAc V. AB - alpha-Series gangliosides define a particular sub-class of glycosphingolipids containing sialic acid alpha2,6-linked to GalNAc residue that was isolated as a minor compound from the brain. The sialyltransferase ST6GalNAc V was cloned from mouse brain and showed alpha2,6-sialyltransferase activity almost exclusively for GM1b, to form GD1alpha and is considered as the main enzyme involved in the biosynthesis of alpha-series gangliosides. Recently, ST6GALNAC5 was identified as one of the genes over-expressed in breast cancer cell populations selected for their ability to produce brain metastasis. However, the capacity of human breast cancer cells to produce alpha-series gangliosides has never been clearly demonstrated. Here, we show by stable transfection and MS-MS analysis of total glycosphingolipids that ST6GALNAC5 expressing MDA-MB-231 breast cancer cells accumulate GD1alpha ganglioside (IV3Neu5Ac1, III6Neu5Ac1Gg4-Cer). PMID- 25913931 TI - Identification of the chemical constituents in aqueous extract of Zhi-Qiao and evaluation of its antidepressant effect. AB - The immature fruit of Citrus aurantium L. (Zhi-Qiao, ZQ) has been used as a traditional medicine in China. Our previous study has shown that ZQ decoction may contribute to the antidepressant-like action of Chaihu-Shu-Gan-San. However, there are no reports on the chemical constituents of ZQ aqueous extract or its anti-depression effects. Firstly, this research reported the on-line identification of the chemical constituents in the aqueous extract of ZQ by coupling ultra-performance liquid chromatography/time-of-flight mass spectrometry (UPLC-Q-TOF/MS). A total of 31 chemical constituents were identified in ZQ aqueous extract, including one tannic acid, five flavones, 13 flavanones, one limonoid, three coumarins, three cyclic peptides, and five polymethoxylated flavonoids. The antidepressant effect of ZQ aqueous extract was evaluated in vivo and the results indicated that the mice immobility time during the forced swimming test and the tail suspension test were significantly reduced with ZQ treatment. MTT assays showed both ZQ aqueous extract and its major constituents (naringin, hesperidin, neohesperidin, and nobiletin) had neuroprotective effect on corticosterone-induced neurotoxicity in PC12 cells. The in vivo and in vitro results suggest that ZQ has an antidepressant effect. PMID- 25913932 TI - NKCS, a Mutant of the NK-2 Peptide, Causes Severe Distortions and Perforations in Bacterial, But Not Human Model Lipid Membranes. AB - NKCS is an improved mutant of the bioactive peptide NK-2, which shows strong activity against Escherichia coli and low toxicity towards human cells. The different activity demonstrates the relevance of the physico-chemical nature of the target membrane for the biological effect of this peptide. We studied the effect of this potent antimicrobial peptide on model membranes by activity studies, differential scanning calorimetry, single molecule tracking and tracer efflux experiments. We found that NKCS severely distorted, penetrated and perforated model lipid membranes that resembled bacterial membranes, but not those that were similar to human cell membranes. The interactions of NKCS with phosphatidylethanolamine, which is abundant in bacterial membranes, were especially strong and are probably responsible for its antimicrobial activity. PMID- 25913933 TI - Kinugasa reactions in water: from green chemistry to bioorthogonal labelling. AB - The Kinugasa reaction has become an efficient method for the direct synthesis of beta-lactams from substituted nitrones and copper(I) acetylides. In recent years, the reaction scope has been expanded to include the use of water as the solvent, and with micelle-promoted [3+2] cycloadditions followed by rearrangement furnishing high yields of beta-lactams. The high yields of stable products under aqueous conditions render the modified Kinugasa reaction amenable to metabolic labelling and bioorthogonal applications. Herein, the development of methods for use of the Kinugasa reaction in aqueous media is reviewed, with emphasis on its potential use as a bioorthogonal coupling strategy. PMID- 25913934 TI - Alkylamides of Acmella oleracea. AB - Phytochemical investigation of the flowers of Acmella oleracea had resulted in the isolation of one new alkylamide, (2E,5Z)-N-isobutylundeca-2,5-diene-8,10 diynamide (1), together with four known analogues (2-5). The structures of these compounds were determined by the interpretation of spectroscopic methods, especially NMR technologies (COSY, HSQC, HMBC, and NOESY). In addition, a convenient method for concentrating the alkylamide-rich fraction and analyzing fingerprint profile of A. oleracea was established. PMID- 25913936 TI - Force-dependent persistence length of DNA-intercalator complexes measured in single molecule stretching experiments. AB - By using optical tweezers with an adjustable trap stiffness, we have performed systematic single molecule stretching experiments with two types of DNA intercalator complexes, in order to investigate the effects of the maximum applied forces on the mechanical response of such complexes. We have explicitly shown that even in the low-force entropic regime the persistence length of the DNA-intercalator complexes is strongly force-dependent, although such behavior is not exhibited by bare DNA molecules. We discuss the possible physicochemical effects that can lead to such results. In particular, we propose that the stretching force can promote partial denaturation on the highly distorted double helix of the DNA-intercalator complexes, which interfere strongly in the measured values of the persistence length. PMID- 25913935 TI - Discovery of Metal Ions Chelator Quercetin Derivatives with Potent Anti-HCV Activities. AB - Analogues or isosteres of alpha,gamma-diketoacid (DKA) 1a show potent inhibition of hepatitis C virus (HCV) NS5B polymerase through chelation of the two magnesium ions at the active site. The anti-HCV activity of the flavonoid quercetin (2) could partly be attributed to it being a structural mimic of DKAs. In order to delineate the structural features required for the inhibitory effect and improve the anti-HCV potency, two novel types of quercetin analogues, 7-O arylmethylquercetins and quercetin-3-O-benzoic acid esters, were designed, synthesized and evaluated for their anti-HCV properties in cell-based assays. Among the 38 newly synthesized compounds, 7-O-substituted derivative 3i and 3-O substituted derivative 4f were found to be the most active in the corresponding series (EC50 = 3.8 MUM and 9.0 MUMU, respectively). Docking studies suggested that the quercetin analogues are capable of establishing key coordination with the two magnesium ions as well as interactions with residues at the active site of HCV NS5B. PMID- 25913938 TI - Ice hockey injuries among United States high school athletes from 2008/2009 2012/2013. AB - BACKGROUND: The popularity of ice hockey has grown in recent years and injuries are a concern given the physical nature of the sport. We sought to report the rates, mechanisms, and severity of boys' US high school ice hockey injuries. We hypothesized that body checking would be a major source of injury and that concussions would be common. We also expected to find that competition would have a higher rate of injury than practice. DESIGN: Descriptive epidemiology study. METHODS: Boys' US high school ice hockey injury data from 2008/2009 through 2012/2013 academic years were obtained from the National High School Sports Related Injury Surveillance System, High School Reporting Information Online database. The primary outcome was rate of injury per 10,000 athlete exposures (AEs). RESULTS: Overall, 724 boys ice hockey injuries occurred during 311,817 AEs for an injury rate of 23.2 per 10,000 AEs. Injury rates were significantly higher during competition compared to practice (rate ratio = 7.8, 95% confidence interval: 6.5-9.4). Concussion was the most frequent injury reported at a rate of 6.4 per 10,000 AEs. Body checking was the mechanism of injury in over 46% of injuries. The head/face/neck region (33.8%) and upper arm/shoulder region (20.6%) were the most commonly injured body sites. Just over 6% of injuries resulted in surgical intervention. CONCLUSION: Injuries among high school ice hockey athletes are common. Increases in the number of high school ice hockey injuries will likely parallel the increase in high school ice hockey participation in the United States. PMID- 25913937 TI - High-intensity interval training: Modulating interval duration in overweight/obese men. AB - INTRODUCTION: High-intensity interval training (HIIT) is a time-efficient strategy shown to induce various cardiovascular and metabolic adaptations. Little is known about the optimal tolerable combination of intensity and volume necessary for adaptations, especially in clinical populations. OBJECTIVES: In a randomized controlled pilot design, we evaluated the effects of two types of interval training protocols, varying in intensity and interval duration, on clinical outcomes in overweight/obese men. METHODS: Twenty-five men [body mass index (BMI) > 25 kg . m(2)] completed baseline body composition measures: fat mass (FM), lean mass (LM) and percent body fat (%BF) and fasting blood glucose, lipids and insulin (IN). A graded exercise cycling test was completed for peak oxygen consumption (VO2peak) and power output (PO). Participants were randomly assigned to high-intensity short interval (1MIN-HIIT), high-intensity interval (2MIN-HIIT) or control groups. 1MIN-HIIT and 2MIN-HIIT completed 3 weeks of cycling interval training, 3 days/week, consisting of either 10 * 1 min bouts at 90% PO with 1 min rests (1MIN-HIIT) or 5 * 2 min bouts with 1 min rests at undulating intensities (80%-100%) (2MIN-HIIT). RESULTS: There were no significant training effects on FM (Delta1.06 +/- 1.25 kg) or %BF (Delta1.13% +/- 1.88%), compared to CON. Increases in LM were not significant but increased by 1.7 kg and 2.1 kg for 1MIN and 2MIN-HIIT groups, respectively. Increases in VO2peak were also not significant for 1MIN (3.4 ml.kg(-1) . min(-1)) or 2MIN groups (2.7 ml . kg(-1) . min(-1)). IN sensitivity (HOMA-IR) improved for both training groups (Delta-2.78 +/- 3.48 units; p < 0.05) compared to CON. CONCLUSION: HIIT may be an effective short-term strategy to improve cardiorespiratory fitness and IN sensitivity in overweight males. PMID- 25913939 TI - Abstracts of the Safe States 2015 Annual Meeting, April 29th-May 1st, 2015, Atlanta, GA. PMID- 25914018 TI - External Fixation and Adjuvant Pins Versus Volar Locking Plate Fixation in Unstable Distal Radius Fractures: A Randomized, Controlled Study With a 5-Year Follow-Up. AB - PURPOSE: To determine whether volar locking plates (VLP) are superior to external fixation (EF) with adjuvant pins in unstable distal radius fractures after 5 years of follow-up. METHODS: We randomized 111 unstable distal radius fractures to treatment with either a VLP or EF using adjuvant pins. The patients' mean age was 54 years (range, 20-84 y). Twenty patients were lost to follow-up. At 5 years, 91 patients (82%) were assessed using the visual analog scale (VAS) pain score, Mayo wrist score, Quick Disabilities of the Arm, Shoulder and Hand (QuickDASH) questionnaire, range of motion, and radiological evaluation. The QuickDASH score at 5 years was the primary outcome measure. RESULTS: The QuickDASH score was not statistically significantly different between the groups (VLP 10 vs EF 13) at 5 years. Patients with VLP had statistically significant better supination (85 degrees vs 81 degrees ), better radial deviation (18 degrees vs 16 degrees ), and less radial shortening (1 mm vs 2 mm). For AO/OTA type C2 fractures, the VLP had statistically significant better supination (84 degrees vs 78 degrees ), flexion (64 degrees vs 56 degrees ), grip strength (34 kg vs 28 kg), Mayo wrist score (92 vs 76), and less ulnar shortening (1 mm vs 3 mm). The QuickDASH score in the C2 subset analysis showed a difference of 10 (VLP 8 vs EF 18), but this was not statistically significant. In the VLP group, 11 patients (21%) had their plates removed owing to surgically related complications. In the EF group, 5 patients had proximal radial scar correction surgery owing to skin contracture. CONCLUSIONS: The findings were satisfactory for both groups at 5 years. The VLP provided statistically significantly better results for several clinical outcomes in the C2 subset analysis. However, 21% of the VLPs were removed because of surgical complications. TYPE OF STUDY/LEVEL OF EVIDENCE: Therapeutic I. PMID- 25914019 TI - Spectroscopic definition of the copper active sites in mordenite: selective methane oxidation. AB - Two distinct [Cu-O-Cu](2+) sites with methane monooxygenase activity are identified in the zeolite Cu-MOR, emphasizing that this Cu-O-Cu active site geometry, having a ?Cu-O-Cu ~140 degrees , is particularly formed and stabilized in zeolite topologies. Whereas in ZSM-5 a similar [Cu-O-Cu](2+) active site is located in the intersection of the two 10 membered rings, Cu-MOR provides two distinct local structures, situated in the 8 membered ring windows of the side pockets. Despite their structural similarity, as ascertained by electronic absorption and resonance Raman spectroscopy, the two Cu-O-Cu active sites in Cu MOR clearly show different kinetic behaviors in selective methane oxidation. This difference in reactivity is too large to be ascribed to subtle differences in the ground states of the Cu-O-Cu sites, indicating the zeolite lattice tunes their reactivity through second-sphere effects. The MOR lattice is therefore functionally analogous to the active site pocket of a metalloenzyme, demonstrating that both the active site and its framework environment contribute to and direct reactivity in transition metal ion-zeolites. PMID- 25914020 TI - Profibrotic transforming growth factor beta 1 and activin A are increased in nasal polyp tissue and induced in nasal polyp epithelium by cigarette smoke and Toll-like receptor 3 ligation. AB - BACKGROUND: The mechanism of airway remodeling in chronic rhinosinusitis with nasal polyposis (CRSwNP) remains unknown. We wished to determine whether profibrotic transforming growth factor beta 1 (TGF-beta1) and activin A and their downstream signaling proteins are increased in CRSwNP and if they are regulated in epithelial cells by noxious or inflammatory stimuli. METHODS: Frozen tissue from CRSwNP patients, healthy control (HC) middle turbinates, and sinus tissue from CRS without NP (CRSsNP) patients were immunostained for TGF-beta1, activin A, and downstream signaling proteins. Primary nasal epithelial cells (PNECs) from HCs and CRSwNP patients were cultured in media, cigarette smoke extract (CSE), or double-stranded RNA (dsRNA) (a ligand for Toll-like receptor-3) and examined for inflammatory and profibrotic genes using real-time polymerase chain reaction (PCR). RESULTS: CRSwNP patients showed increased TGF-beta1 and activin A in the stroma, increased TGF-beta1 signaling (phosphorylated Smad2/3) in the stroma and epithelium, and increased Smad3-dependent Snail1 in the stroma. Immunostaining for TGF-beta1, pSmad2/3, and Snail1 in CRSwNP patients was highly correlated. Immunostaining for pSmad2/3 and Snail1 was similar in CRSwNP and CRSsNP patients. Compared to HCs, PNECs from CRSwNP patients were more responsive to CSE and dsRNA in terms of TGF-beta1 and activin A and more strongly induced by dsRNA in terms of chemokines. CONCLUSION: Increased TGF-beta1 and activin A and increased downstream TGF-beta1 signaling is present in CRSwNP patients, primarily in the stroma. This may contribute to features of airway remodeling previously described. PNECs from CRSwNP patients are induced to produce TGF-beta1 and activin A by CSE and dsRNA, suggesting that cigarette smoke and viral infection might also contribute to airway remodeling. PMID- 25914021 TI - Heterologous strategy enhancing the sensitivity of the fluorescence polarization immunoassay of clinafloxacin in goat milk. AB - BACKGROUND: Clinafloxacin is used for the treatment of disease in food-producing animals, e.g. Brucella melitensis, which often occurs in goats; however, the clinafloxacin residue in goat milk may harm human health and result in the development of drug-resistant bacterial strains or allergies. Despite this, there is not a rapid, sensitive and accurate analytical method in goat milk for rapid screening or monitoring purposes. RESULTS: One homologous and five heterologous tracers were designed and compared for fluorescence polarization immunoassay (FPIA) optimization. Based on the combination of a heterologous tracer (PAZ-FITC, synthesized with pazufloxacin and FITC) and the antibody against clinafloxacin, a highly sensitive FPIA was established for the detection of clinafloxacin residue in goat milk for the first time. The IC50 value was 29.3 ug L(-1) for clinafloxacin in the heterologous format - six times lower than that of the combination of the homologous tracers and the antibody. The recoveries ranged from 86.8% to 104.5%, with the relative standard deviation ranging from 4.1% to 7.2%. Validation by high-performance liquid chromatography (HPLC) confirmed that the results obtained from the proposed FPIA were in agreement with those of HPLC. CONCLUSION: This proposed heterologous strategy for enhanced FPIA is sensitive and rapid enough for the high-throughput detection of clinafloxacin residue in goat milk. PMID- 25914022 TI - The history and market impact of CRISPR RNA-guided nucleases. AB - The interface between viruses and their hosts' are hot spots for biological and biotechnological innovation. Bacteria use restriction endonucleases to destroy invading DNA, and industry has exploited these enzymes for molecular cut-and paste reactions that are central to many recombinant DNA technologies. Today, another class of nucleases central to adaptive immune systems that protect bacteria and archaea from invading viruses and plasmids are blazing a similar path from basic science to profound biomedical and industrial applications. PMID- 25914023 TI - Plant architecture, plasticity, and adaptation strategies of two oat genotypes under different competition intensities. AB - BACKGROUND: The hypothesis that positive and negative interactions account for adaptive strategies was tested in a controlled study with two oat (Avena sativa) genotypes: 'Manotick' with erect leaves and 'Oa1316-1' with prostrate leaves. An increasing competition pattern was designed by varying the number of seeds planted in each container and the space between containers, thus creating different planting density regimes (i.e. alternative and solid treatments). RESULTS: Total biomass of individual plants tended to decrease exponentially with increasing density in both genotypes. Under high density stress, Manotick allocated more biomass to the roots and produced 50% more tillers, leading to more non-productive tillers and lower harvest index in the alternative than in the solid treatment. In contrast, Oa1316-1 allocated more biomass to panicles and stems, and less to the roots, with fewer tillers. CONCLUSIONS: With increasing density and strengthening intraspecific competition, Manotick reduced aboveground biomass allocation, leading to lower yield, while Oa1316-1 decreased allocation to the roots, but increased allocation to the panicles under an increasingly competitive environment. These adjustments were mechanically derived from negative and positive interactions, ensuring greater yield in the prostrate type. Our findings provided a novel rationale for a planting strategy based on plant type selections. PMID- 25914024 TI - Programmable definition of nanogap electronic devices using self-inhibited reagent depletion. AB - Electrodes exhibiting controlled nanoscale separations are required in devices for light detection, semiconductor electronics and medical diagnostics. Here we use low-cost lithography to define micron-separated electrodes, which we downscale to create three-dimensional electrodes separated by nanoscale gaps. Only by devising a new strategy, which we term electrochemical self-inhibited reagent depletion, were we able to produce a robust self-limiting nanogap manufacturing technology. We investigate the method using experiment and simulation and find that, when electrodeposition is carried out using micron spaced electrodes simultaneously poised at the same potential, these exhibit self inhibited reagent depletion, leading to defined and robust nanogaps. Particularly remarkable is the formation of fractal electrodes that exhibit interpenetrating jagged elements that consistently avoid electrical contact. We showcase the new technology by fabricating photodetectors with responsivities (A/W) that are one hundred times higher than previously reported photodetectors operating at the same low (1-3 V) voltages. The new strategy adds to the nanofabrication toolkit method that unites top-down template definition with bottom-up three-dimensional nanoscale features. PMID- 25914025 TI - Eltrombopag for the Treatment of Immune Thrombocytopenia: The Aegean Region of Turkey Experience. AB - OBJECTIVE: Immune thrombocytopenia (ITP) is an immune-mediated disease characterized by transient or persistent decrease of the platelet count to less than 100x109/L. Although it is included in a benign disease group, bleeding complications may be mortal. With a better understanding of the pathophysiology of the disease, thrombopoietin receptor agonists, which came into use in recent years, seem to be an effective option in the treatment of resistant cases. This study aimed to retrospectively assess the efficacy, long-term safety, and tolerability of eltrombopag in Turkish patients with chronic ITP in the Aegean region of Turkey. MATERIALS AND METHODS: Retrospective data of 40 patients with refractory ITP who were treated with eltrombopag in the Aegean region were examined and evaluated. RESULTS: The total rate of response was 87%, and the median duration of response defined as the number of the platelets being over 50x109/L was 19.5 (interquartile range: 5-60) days. In one patient, venous sinus thrombosis was observed with no other additional risk factors due to or related to thrombosis. Another patient with complete response and irregular follow-up for 12 months was lost due to sudden death as the result of probable acute myocardial infarction. CONCLUSION: Although the responses to eltrombopag were satisfactory, patients need to be monitored closely for overshooting platelet counts as well as thromboembolic events. PMID- 25914026 TI - Downregulation of solute carriers of glutamate in gliosomes and synaptosomes may explain local brain metastasis in anaplastic glioblastoma. AB - Advanced grades of glioblastoma are highly aggressive, especially in terms of multisite spread within the brain or even to distant sites at the spinal cord. In advanced grades of glioblastoma, glutamate and glutamine are reported to be increased in concentration in the extracellular fluid. It has been reported that glutamate acts as an extracellular signaling molecule for facilitating local spread of advanced grades of glioblastoma. In the present study, we aimed to examine whether glutamate uptake mechanisms is impaired in advanced glioblastoma. The possible downregulated mechanisms of glutamate uptake would facilitate persistence of glutamate in the extracellular environment, rather than intracellular uptake. We obtained biobanked human specimens of glioblastoma and tested expression of proteins belonging to the solute carrier families of proteins that are known to function as membrane-located excitatory amino acid like glutamate transporters. The present study provides preliminary evidence of the downregulation of membrane expression of excitatory amino acid transporters solute carrier family 1 member 3 (SLC1A3) and its palmitoylated form in gliosomes, as well as SLC1A2 in the glio-synaptosomes. Compounds like riluzole used in the treatment of amyotrophic lateral sclerosis and the antibiotic ceftriaxone have the potential to facilitate glutamate uptake. These medications may be examined as adjunct chemotherapy in the massively aggressive tumor glioblastoma multiforme. PMID- 25914032 TI - Systemic Lipopolysaccharide Administration-Induced Cognitive Impairments are Reversed by Erythropoietin Treatment in Mice. AB - Sepsis-associated encephalopathy (SAE) is a frequent complication in critically ill patients and is associated with long-term cognitive impairments. However, the pathophysiology underlying SAE is poorly understood and the pharmacologic treatment is lacking. The purpose of the present study was to investigate the effects of erythropoietin (EPO) on cognitive impairments in an animal model of SAE induced by peripheral administration of lipopolysaccharide (LPS). Mice were randomly divided into the sham + vehicle, sham + EPO, LPS + vehicle, and LPS + EPO groups. EPO was administrated 30 min after the LPS administration and daily afterward for 2 days. Behavioral tests were performed on days 6 and 7 with open field and fear conditioning tests, respectively. The survival rate was estimated by the Kaplan-Meier method. The levels of proinflammatory responses, oxidative stress, and apoptosis-related markers were measured in the hippocampus at the indicated time points. The synaptic morphometry changes in the CA1 region were observed with transmission electron microscopy. Our results showed that LPS administration resulted in high mortality rate and cognitive impairments, which were accompanied by increased expressions of interleukin-1beta, malondialdehyde, cleaved caspase-3, and abnormal synaptic morphometry changes in the hippocampus. Notably, EPO treatment reversed the cognitive impairments and rescued the brain pathology induced by LPS administration. In conclusion, our data suggested that treatment with EPO reduced the mortality rate and ameliorated cognitive impairments in an animal model of SAE. PMID- 25914033 TI - Cytologic features of the normal pineal gland of adults. AB - It is well known that the histology of normal pineal gland may resemble not only pineal tumors but also gliomas, owing to its cellularity which is much greater than that of normal white or gray matter. Our recent experience with a case in which part of a normal gland was submitted for intraoperative consultation, together with the scarcity of cytologic descriptions, led us to perform a cyto histologic correlation study. In addition to the intraoperative case, we collected five pineal glands from consecutive adult autopsies. During the squash procedure, we often noted the presence of calcified grains. Smears were hypercellular, distributed in tissue fibrillary fragments and as numerous single cells, with crystalline structures. Pineal gland cells (pineocytes) were large, round, epithelioid with ill-defined cytoplasms and moderate nuclear pleomorphism. Spindle cells with greater fibrillary quality were less common. One of the most remarkable findings seen in all cases was the presence of cytoplasmic pigment. Histological evaluation and immunohistochemical staining confirmed that the tissue was normal pineal gland. The histology showed a characteristic lobular aspect and frequent corpora arenacea. The pigment seen cytologically was also encountered in histology and corresponded to lipofuscin. Cytologic features of the pineal gland are peculiar when compared to other normal structures of the central nervous system. These features correlate closely with what is seen on histology. In an adequate clinical context, and in combination with frozen sections, cytology allows a specific recognition of the pineal gland during intraoperative pathologic consultations. PMID- 25914034 TI - Transcatheter repair of aortic leaflet perforation in a patient with prior surgical bicuspid aortic valve repair. AB - A 47-year-old male underwent surgery for functional bicuspid aortic valve severe regurgitation with a fused right and left coronary cusp. The patient presents nine years after surgical bicuspid aortic valve repair with symptomatic severe aortic regurgitation, diagnosed by TEE and MRI, caused primarily from a perforation located at the base of the surgically fused coronary cusps. The patient had a minimally dilated aortic root that did not yet necessitate surgical intervention. We present a novel percutaneous bicuspid aortic valve perforation repair that potentially decreases the number of surgical operations the patient must undergo during his lifetime. PMID- 25914035 TI - Isolation of a conjugative F-like plasmid from a multidrug-resistant Escherichia coli strain CM6 using tandem shock wave-mediated transformation. AB - Genetic characterization of plasmids from bacterial strains provides insight about multidrug resistance. Ten wild type Escherichia coli (E. coli) strains isolated from cow fecal samples were characterized by their antibiotic resistance profile, plasmid patterns and three different identification methods. From one of the strains, a fertility factor-like plasmid was replicated using tandem shock wave-mediated transformation. Underwater shock waves with a positive pressure peak of up to approximately 40 MPa, followed by a pressure trough of approximately -19 MPa were generated using an experimental piezoelectric shock wave source. Three different shock wave energies and a fixed delay of 750 MUs were used to study the relationship between energy and transformation efficiency (TE), as well as the influence of shock wave energy on the integrity of the plasmid. Our results showed that the mean shock wave-mediated TE and the integrity of the large plasmid (~70 kb) were reduced significantly at the energy levels tested. The sequencing analysis of the plasmid revealed a high identity to the pHK17a plasmid, including the replication system, which was similar to the plasmid incompatibility group FII. It also showed that it carried an extended spectrum beta-lactamase gene, ctx-m-14. Furthermore, diverse genes for the conjugative mechanism were identified. Our results may be helpful in improving methodologies for conjugative plasmid transfer and directly selecting the most interesting plasmids from environmental samples. PMID- 25914036 TI - Comparison of the effects of five dietary fibers on mucosal transcriptional profiles, and luminal microbiota composition and SCFA concentrations in murine colon. AB - SCOPE: The aim of our study was to investigate and compare the effects of five fibers on the mucosal transcriptome, together with alterations in the luminal microbiota composition and SCFA concentrations in the colon. METHODS AND RESULTS: Mice were fed fibers that differed in carbohydrate composition or a control diet for 10 days. Colonic gene expression profiles and luminal microbiota composition were determined by microarray techniques, and integrated using multivariate statistics. Our data showed a distinct reaction of the host and microbiota to resistant starch, a fiber that was not completely fermented in the colon, whereas the other fibers induced similar responses on gene expression and microbiota. Consistent associations were revealed between fiber-induced enrichment of Clostridium cluster IV and XIVa representatives, and changes in mucosal expression of genes related to energy metabolism. The nuclear receptor PPAR-gamma was predicted to be an important regulator of the mucosal responses. CONCLUSION: Results of this exploratory study suggest that despite different sources and composition, fermentable fibers induce a highly similar mucosal response that may at least be partially governed by PPAR-gamma. PMID- 25914037 TI - Non-invasive nuclear myocardial perfusion imaging improves the diagnostic yield of invasive coronary angiography. AB - AIMS: Several studies reported on the moderate diagnostic yield of elective invasive coronary angiography (ICA) regarding the presence of coronary artery disease (CAD), but limited data are available on how prior testing for ischaemia may contribute to improve the diagnostic yield in an every-day clinical setting. This study aimed to assess the value and use of cardiac myocardial perfusion single photon emission computed tomography (MPS) in patient selection prior to elective ICA. METHODS AND RESULTS: The rate of MPS within 90 days prior to elective ICA was assessed and the non-invasive test results were correlated with the presence of obstructive CAD on ICA (defined as stenosis of >=50% of a major epicardial coronary vessel). Multivariate logistic regression analysis was performed to identify predictors of obstructive CAD. A total of 7530 consecutive patients were included. At catheterization, 3819 (50.7%) were diagnosed as having obstructive CAD. Patients with a positive result on MPS (performed in 23.5% of patients) were significantly more likely to have obstructive CAD as assessed by ICA than those who did not undergo non-invasive testing (74.4 vs. 45.6%, P < 0.001). Furthermore, a pathological MPS result was a strong, independent predictor for CAD findings among traditional risk factors and symptoms. CONCLUSION: In an every-day clinical setting, the use of MPS substantially increases the diagnostic yield of elective ICA and provides incremental value over clinical risk factors and symptoms in predicting obstructive CAD, thus emphasizing its importance in the decision-making process leading to the use of diagnostic catheterization. PMID- 25914038 TI - Two balls around aortic root: multiple huge unruptured aneurysms of the Valsalva sinus. PMID- 25914039 TI - Clerodane diterpenes from Polyalthia longifolia (Sonn) Thw. var. pendula: Potential antimalarial agents for drug resistant Plasmodium falciparum infection. AB - BACKGROUND: Plasmodium falciparum drug resistance is a major public health challenge in sub-Sahara Africa. Many people are now resorting to the use of herbs in managing malaria due to the increasing treatment failures with the conventional drugs. In this study the ethanolic extract of Polyalthia longifolia (Sonn) Thw. var. pendula, a variety fondly used in folklore medicine in Ghana was investigated for potential antimalarial drug development. METHOD: The ethanolic extract of P. longifolia (Sonn) Thw. var. pendula stem bark was screened against the multidrug resistant, K1 strain of P. falciparum by the parasite lactate dehydrogenase (pLDH) assay and a good antiplasmodial activity (IC50 22.04+/- 4.23ug/ml) was observed which led to further chromatographic analysis in search for actives. RESULTS: Bioassay guided fractionation of the extract yielded; three clerodane diterpenes [16-hydroxycleroda-3,13-dien-16,15-olide (1), 16-oxocleroda 3,13E-dien-15-oic acid (2) and 3,16-dihydroxycleroda-4(18),13(14)Z-dien-15,16 olide (3)], a steroid [beta-stigmasterol (4)] and two alkaloids [darienine (5) and stepholidine (6)]. While compounds 4, 5 and 6 exhibited weak antiplasmodial activity (IC50 22-105ug/ml), the clerodane diterpenes exhibited significantly potent (p<0.005) blood schizonticidal activity (IC50: 3-6ug/ml). This is the first report of the antiplasmodial activity of compounds 2 and 3. In combination assay with chloroquine, compounds 1, 2, 3 and 5 antagonized the antiplasmodial activity of chloroquine while 4 and 6 demonstrated a synergistic action. CONCLUSION: The potent antiplasmodial activity of the extract of P. longifolia (Sonn) Thw. var. pendula and compounds therein strongly suggests its usefulness as an antimalarial agent and supports its inclusion or exploitation in formulations of herbal remedies for malaria in Ghana. PMID- 25914040 TI - Wuling San protects kidney dysfunction by inhibiting renal TLR4/MyD88 signaling and NLRP3 inflammasome activation in high fructose-induced hyperuricemic mice. AB - ETHNOPHARMACOLOGICAL RELEVANCE: Wuling San, a famous prescription in Chinese medicine, is composed of Polyporus, Poria, Alismatis rhizoma, Cinnamomi cortex and Atractylodis macrocephalae rhizoma, and promotes kidney function and diuresis. The main purpose of this study was to investigate its renal protective effect in high fructose-induced hyperuricemic mice. MATERIALS AND METHODS: ICR mice were fed with 30% fructose in drinking water for 6 weeks to induce hyperuricemia and renal dysfunction. Then mice were orally administrated for other 6 weeks with Wuling San (987, 1316, 1755 and 2340mg/kg), allopurinol (5mg/kg) and water daily, respectively. Serum and urine levels of uric acid, creatinine and blood urea nitrogen (BUN) were measured. Hematoxylin and eosin staining was used to assess renal histological changes. Renal interleukin (IL) 1beta concentrations were measured using ELISA kit. Renal protein levels of organic ion transporters, as well as toll-like receptor 4 (TLR4)/myeloid differentiation factor 88 (MyD88) signaling and pyrin domain containing 3 (NLRP3) inflammasome were determined by Western blot assay. RESULTS: Wuling San significantly decreased serum uric acid, creatinine and BUN levels, increased fractional excretion of uric acid (FEUA) in fructose-fed mice. It restored fructose-induced dysregulation of renal urate transporter 1 (URAT1), glucose transporter 9 (GLUT9), ATP-binding cassette subfamily G member 2 (ABCG2) and organic anion transporter 1 (OAT1), as well as organic cation transporter 1 (OCT1) and OCT2 in mice. Wuling San obviously alleviated infiltration of inflammation cells in kidney glomerulus of fructose-fed mice. Moreover, Wuling San suppressed the activation of TLR4/ MyD88 signaling to inhibit nuclear factor kappaB (NF-kappaB) signaling and mitogen-activated protein kinases (MAPKs) activation in fructose-fed mice. Additionally, Wuling San decreased NLRP3 inflammasome activation and IL-1beta secretion in the kidney of fructose-fed mice. CONCLUSION: Wuling San exerts renal protective effect by modulating renal organic ion transporters in fructose-induced hyperuricemic mice. The molecular mechanism of its action may be associated with the suppression of TLR4/MyD88 signaling and NLRP3 inflammasome activation to reduce IL-1beta production in high fructose-induced hyperuricemic mice. PMID- 25914041 TI - Study of pharmacological properties of the methanolic extract of Dichrostachys cinerea bark (L.) Wight et Arn (Leguminosae) in isolated myometrium from pregnant rats. AB - ETHNOPHARMACOLOGICAL RELEVANCE: The use of medicinal plants in Gabon contributes widely to the primary health care of the people of this area of Central Africa. This paper investigates the pharmacological properties of Dichrostachys cinerea, the plant barks are traditionally used by Gabonese and Ivorian populations to treat bronchial asthma, rheumatism, and other various diseases. Although D. cinerea barks have been reported to be used by population to facilitate childbirth, to the best of our knowledge no scientific evidence has been published. AIM OF STUDY: In the present study, we investigated the pharmacological properties of D. cinerea methanolic extract, on isolated uterine smooth muscle and compared its effects to those of oxytocin, which is used by obstetricians to facilitate childbirth. We also explored the possible mechanism pathways of the in vitro uterine contraction induced by D. cinerea. MATERIALS AND METHODS: The effects of different concentrations (3.2ug/ml, 16ug/ml, 80ug/ml, 400ug/ml, and 2mg/ml) of the methanolic extract of D. cinerea on isolated strips of the uteri of pregnant rats were studied. These effects were compared to those of oxytocin (8.4*10(-5)ug/ml, 8.4*10(-4)ug/ml, 8.4*10(-3)ug/ml, 8.4*10(-2)ug/ml). The EC (50) and E (max) was determined graphically and statistically analysed using one-way ANOVA and Dunnett post hoc test. RESULTS: Cumulative concentrations of D. cinerea have caused rise in the contractile force of the uterine fragments that were isolated from the pregnant rats, as seen with oxytocin concentrations. We observed contractions amplitude of 30.41mN (12%) at 80ug/ml and amplitude of 39.68mN (14.17%) at 400ug/ml for D. cinerea. In parallel, oxytocin concentration of 8.4*10(-3)ug/ml induced contractions of 45.82mN with the highest concentration (8.4*10(-2)ug/ml) that induced contractions of 55.82mN. CONCLUSIONS: Our results revealed that D. cinerea increased the contractile force and the frequency of muscle contractions. These findings support the use of D. cinerea to facilitate childbirth, as it has been used in traditional medicine. PMID- 25914042 TI - Recurrence of Ocular Surface Squamous Neoplasia Treated With Excisional Biopsy and Cryotherapy. AB - PURPOSE: To evaluate the recurrence rate of ocular surface squamous neoplasias (OSSN) after excision and cryotherapy in an academic cornea practice and to determine factors associated with recurrence. DESIGN: Retrospective interventional case series. METHODS: All cases of OSSN from 1998 through 2013 that were treated with excisional biopsy and adjunctive cryotherapy were retrospectively reviewed. Clinical characteristics upon presentation including size of lesion, location, and atypical features were noted. All recurrences of OSSN after excision and cryotherapy were noted and categorized in relation to clinical characteristics, pathologic grade, and margin involvement. RESULTS: Forty-three cases of OSSN from 42 patients were analyzed with a median follow-up of 29 months. A total of 32.6% of subjects had dysplasia and 67.4% had squamous cell carcinoma (SCC). A total of 83.7% of subjects had both corneal and conjunctival involvement while 16.3% had conjunctival involvement only. Overall, 3 recurrences were observed, all of which had margin involvement; nonetheless, the majority of incompletely excised OSSN (25/28) showed no recurrence. The recurrence rate at 6 months was 2.3%. Recurrence at 1 year, 2 years, and 5 years remained stable at 7.1%. CONCLUSIONS: Excision with cryotherapy is an effective treatment for the majority of OSSN cases, even among cases with pathologic evidence of tumor at the margin, with an overall recurrence rate of 7.1% at 1 year, 2 years, and 5 years. PMID- 25914043 TI - Appearance of fetal posterior fossa at 11-14 weeks in fetuses with Dandy-Walker malformation or chromosomal anomalies. AB - OBJECTIVE: To describe the sonographic appearance of fetal posterior fossa anatomy at 11-14 weeks of pregnancy and to assess the outcome of fetuses with increased intracranial translucency (IT) and/or brainstem-to-occipital bone (BSOB) diameter. METHODS: Reference ranges for brainstem (BS), IT and cisterna magna (CM) measurements, BSOB diameter and the BS : BSOB ratio were obtained from the first-trimester ultrasound examination of 233 fetuses with normal postnatal outcome (control group). The intraobserver and interobserver variability of measurements were investigated using 73 stored ultrasound images. In addition, a study group of 17 fetuses with increased IT and/or BSOB diameter was selected to assess outcome. RESULTS: No significant intraobserver or interobserver variability was found for any measurement in the control group. In the study group, IT was increased in all cases and BSOB diameter was above the 95(th) centile of the calculated normal range in all but two (88%) cases. In 13/17 study cases, only two of the three posterior brain spaces were recognized on ultrasound. These 13 fetuses had a larger BSOB diameter than did the four cases that showed all three posterior brain spaces, and had severe associated anomalies including Dandy-Walker malformation (DWM) and/or chromosomal anomalies. CONCLUSIONS: Visualization of the fetal posterior fossa anatomy at 11-14 weeks' gestation is feasible. Increased fluid in the posterior brain at 11-14 weeks, particularly in the case of non-visibility of the septation that divides the future fourth ventricle from the CM, is an important risk factor for cystic posterior fossa malformations, in particular DWM, and/or chromosomal aberrations. Copyright (c) 2015 ISUOG. Published by John Wiley & Sons Ltd. PMID- 25914044 TI - Effectiveness of low-level laser therapy in patients with knee osteoarthritis: a systematic review and meta-analysis. AB - OBJECTIVE: To investigate the efficacy of low-level laser therapy (LLLT) treatment of knee osteoarthritis (KOA) by a systematic literature search with meta-analyses on selected studies. DESIGN: MEDLINE, EMBASE, ISI Web of Science and Cochrane Library were systematically searched from January 2000 to November 2014. Included studies were randomized controlled trials (RCTs) written in English that compared LLLT (at least eight treatment sessions) with sham laser in KOA patients. The efficacy effective size was estimated by the standardized mean difference (SMD). Standard fixed or random-effects meta-analysis was used, and inconsistency was evaluated by the I-squared index (I(2)). RESULTS: Of 612 studies, nine RCTs (seven double-blind, two single-blind, totaling 518 patients) met the criteria for inclusion. Based on seven studies, the SMD in visual analog scale (VAS) pain score right after therapy (RAT) (within 2 weeks after the therapy) was not significantly different between LLLT and control (SMD = -0.28 [95% CI = -0.66, 0.10], I(2) = 66%). No significant difference was identified in studies conforming to the World Association of Laser Therapy (WALT) recommendations (four studies) or on the basis of OA severity. There was no significant difference in the delayed response (12 weeks after end of therapy) between LLLT and control in VAS pain (five studies). Similarly, there was no evidence of LLLT effectiveness based on Western Ontario and McMaster Universities Arthritis Index (WOMAC) pain, stiffness or function outcomes (five and three studies had outcome data right after and 12 weeks after therapy respectively). CONCLUSION: Our findings indicate that the best available current evidence does not support the effectiveness of LLLT as a therapy for patients with KOA. PMID- 25914045 TI - Connexin43 and connexin47 alterations after neural precursor cells transplantation in experimental autoimmune encephalomyelitis. AB - Exogenous transplanted neural precursor cells (NPCs) exhibit miscellaneous immune modulatory effects in models of autoimmune demyelination. However, the regional interactions of NPCs with the host brain tissue in remissive inflammatory events have not been adequately studied. In this study we used the chronic MOG-induced Experimental Autoimmune Encephalomyelitis (EAE) model in C57BL/six mice. Based on previous data, we focused on neuropathology at Day 50 post-induction (D50) and studied the expression of connexin43 (Cx43) and Cx47, two of the main glial gap junction (GJ) proteins, in relation to the intraventricular transplantation of GFP(+) NPCs and their integration with the host tissue. By D50, NPCs had migrated intraparenchymally and were found in the corpus callosum at the level of the lateral ventricles and hippocampus. The majority of GFP(+) cells differentiated with simple or ramified processes expressing mainly markers of mature GLIA (GFAP and NogoA) and significantly less of precursor glial cells. GFP(+) NPCs expressed connexins and formed GJs around the hippocampus more than lateral ventricles. The presence of NPCs did not alter the increase in Cx43 GJ plaques at D50 EAE, but prevented the reduction of oligodendrocytic Cx47, increased the number of oligodendrocytes, local Cx47 levels and Cx47 GJ plaques per cell. These findings suggest that transplanted NPCs may have multiple effects in demyelinating pathology, including differentiation and direct integration into the panglial syncytium, as well as amelioration of oligodendrocyte GJ loss, increasing the supply of potent myelinating cells to the demyelinated tissue. PMID- 25914046 TI - Low pathogenicity of anti-desmoglein 3 immunoglobulin G autoantibodies contributes to the atypical clinical phenotypes in pemphigus. AB - The clinical phenotypes of pemphigus can be explained by the desmoglein (Dsg) compensation theory. However, some atypical cases such as cutaneous pemphigus vulgaris (cPV), in which patients have anti-Dsg3 antibodies without oral erosions, do not conform to this theory. To explain the discrepancy between clinical phenotypes and anti-Dsg antibody profiles, the pathogenic strength of immunoglobulin (Ig)G autoantibodies against Dsg3 must be taken into consideration. We analyzed the epitopes and blister-inducing pathogenic strength of the sera from three patients having IgG against Dsg3 without oral erosions with domain-swapped recombinant proteins and dissociation assay using cultured normal human epidermal keratinocytes. The results showed that all sera contained IgG directed against the amino terminal EC1 domain of Dsg3, as is found in most PV sera. However, dissociation assays revealed that the pathogenic strength of the anti-Dsg3 antibodies in all three cases was extremely lower than that of typical PV cases with mucosal involvement. In conclusion, when anti-Dsg3 IgG antibodies are not sufficient to inhibit the expression of Dsg3 in the oral mucosa, but can inhibit the expression in the skin, skin blisters can result. Therefore, the pathogenicity of anti-Dsg3 antibodies should be regarded as a key factor contributing to the clinical phenotype in pemphigus patients with conflicting antibody profiles. PMID- 25914047 TI - Prognostic role of Oct4, CD44 and c-Myc in radio-chemo-resistant oral cancer patients and their tumourigenic potential in immunodeficient mice. AB - OBJECTIVE: In the present study, we have investigated the prognostic value of known stem cell-associated molecules such as Oct4, CD44 and c-Myc in patients with oral SCC who had received post-surgery radio- and/or chemotherapy. MATERIALS AND METHODS: Immunohistochemistry was performed to analyse the expression of Oct4, CD44 and c-Myc in 87 tumour tissues, and the expression profile obtained was correlated with clinicopathological parameters of the patients with oral cancer. Tumourigenic potential of these molecules was also evaluated by in vivo studies. RESULTS: Our results showed significant correlation of Oct4 (OS, p = 0.003; DFS, p = 0.001) and c-Myc (OS, p = 0.01; DFS, p = 0.03) with overall survival and disease-free survival independently. Furthermore, all the three markers in combinations of two markers each, i.e. Oct4 + CD44 (OS, p = 0.003; DFS, p = 0.001), Oct4 + c-Myc (OS, p = 0.0001; DFS, p = 0.0001), CD44 + c-Myc (OS, p = 0.008; DFS, p = 0.02) and in combinations of three markers each, i.e. Oct4 + CD44 + c-Myc (OS, p = 0.0001; DFS, p = 0.0001) also significantly correlated with overall survival and disease-free survival. Univariate and multivariate analyses further established the independent prognostic value of Oct4. Oct4-, CD44- and c-Myc-enriched populations independently induced sarcomatoid carcinomas whereas primary keratinocytes developed poorly differentiated carcinomas in immunodeficient mice. CONCLUSIONS: Oct4 and c-Myc independently as well as in combination with CD44 might be useful for the prediction of local recurrence and poor survival of patients with oral cancer which is the novel finding of this study. CLINICAL RELEVANCE: Oct4, c-Myc and CD44 can be used to predict local recurrence and the outcome of treatment in oral cancer patients. In addition, these molecules may find use as molecular targets for effective therapy. PMID- 25914049 TI - Favourable response to ketogenic dietary therapies: undiagnosed glucose 1 transporter deficiency syndrome is only one factor. AB - AIM: We aimed to determine whether response to ketogenic dietary therapies (KDT) was due to undiagnosed glucose transporter type 1 deficiency syndrome (GLUT1-DS). METHOD: Targeted resequencing of the SLC2A1 gene was completed in individuals without previously known GLUT1-DS who received KDT for their epilepsy. Hospital records were used to obtain demographic and clinical data. Response to KDT at various follow-up points was defined as seizure reduction of at least 50%. Seizure freedom achieved at any follow-up point was also documented. Fisher's exact and gene-burden association tests were conducted using the PLINK/SEQ open source genetics library. RESULTS: Of the 246 participants, one was shown to have a novel variant in SLC2A1 that was predicted to be deleterious. This individual was seizure-free on KDT. Rates of seizure freedom in cases without GLUT1-DS were below 8% at each follow-up point. Two cases without SLC2A1 mutations were seizure free at every follow-up point recorded. No significant results were obtained from Fisher's exact or gene-burden association tests. INTERPRETATION: A favourable response to KDT is not solely explained by mutations in SLC2A1. Other genetic factors should be sought to identify those who are most likely to benefit from dietary treatment for epilepsy, particularly those who may achieve seizure freedom. PMID- 25914048 TI - Performance of a light fluorescence device for the detection of microbial plaque and gingival inflammation. AB - OBJECTIVES: The hypothesis to be tested was that using the SOPROCARE system in fluorescence perio-mode allows scoring of microbial plaque that is comparable to the Turesky modification of the Quigley Hein plaque index (T-QH) and scoring of gingival inflammation comparable to the Silness and Loe gingival inflammation index (GI). MATERIALS AND METHODS: Fifty-five subjects with various amounts of microbial plaque were recruited. The T-QH and GI index were recorded. SOPROCARE pictures were recorded in fluorescence perio-mode and in daylight mode. Finally, conventional digital photographs were taken. All pictures were assessed using the same criteria as described for the clinical indices. RESULTS: The average T-QH was 1.1 +/- 1.2 (mean +/- SD). Scoring with SOPROCARE perio-mode led to a slightly higher average than the T-QH scores. SOPROCARE daylight mode and digital photography showed the highest plaque scores. The average GI index was 0.7 +/- 0.9. SOPROCARE in perio-mode scored slightly lower. Linear regression fits between the different clinical indices and SOPROCARE scores were significantly different from zero demonstrating high goodness of fit. CONCLUSIONS: The study demonstrated that the SOPROCARE fluorescence assessment tool in perio-mode allows reliable judgment of microbial plaque and gingival inflammation levels similar to the established Turesky-modified Quigley Hein index and the Silness and Loe gingival inflammation index. Training on plaque-free teeth will actually reduce scoring errors. CLINICAL RELEVANCE: The SOPROCARE fluorescence tool in perio-mode provides reliable evaluation of microbial plaque and gingival inflammation for the dental clinician. PMID- 25914050 TI - Positron emission tomography in spinal infections. AB - Magnetic resonance imaging is the imaging method of choice for diagnosing infection of the spine in unoperated cases. 2-[(18)F]-fluoro-2deoxy-d-glucose positron emission tomography/computed tomography study is recommended to distinguish between spinal infection and common Modic change in patients with metallic implants and prosthetic replacements and for differentiating tuberculous from pyogenic spondylitis in ambiguous cases, reflecting the activity of the infection. Also, it seems to have a strong clinical impact in more than half of patients with infectious spondylitis, while it is superior to other imaging techniques in revealing residual disease after treatment and early response to therapy. New tracers as well as new hybrid modalities are under investigation. PMID- 25914053 TI - The SH3 Domain Acts as a Scaffold for the N-Terminal Intrinsically Disordered Regions of c-Src. AB - Regulation of c-Src activity by the intrinsically disordered Unique domain has recently been demonstrated. However, its connection with the classical regulatory mechanisms is still missing. Here we show that the Unique domain is part of a long loop closed by the interaction of the SH4 and SH3 domains. The conformational freedom of the Unique domain is further restricted through direct contacts with SH3 that are allosterically modulated by binding of a poly-proline ligand in the presence and in the absence of lipids. Our results highlight the scaffolding role of the SH3 domain for the c-Src N-terminal intrinsically disordered regions and suggest a connection between the regulatory mechanisms involving the SH3 and Unique domains. PMID- 25914052 TI - Architecture of the ubiquitylation module of the yeast Ccr4-Not complex. AB - The Ccr4-Not complex regulates eukaryotic gene expression at multiple levels, including mRNA turnover, translational repression, and transcription. We have studied the ubiquitylation module of the yeast Ccr4-Not complex and addressed how E3 ligase binds cognate E2 and how it is tethered to the complex. The 2.8-A resolution crystal structure of the N-terminal RING domain of Not4 in complex with Ubc4 shows the detailed interactions of this E3-E2 complex. The 3.6-A resolution crystal structure of the C-terminal domain of the yeast Not4 in complex with the C-terminal domain of Not1 reveals how a largely extended region at the C-terminus of Not4 wraps around a HEAT-repeat region of Not1. This C terminal region of Not4 is only partly conserved in metazoans, rationalizing its weaker Not1-binding properties. The structural and biochemical data show how Not1 can incorporate both the ubiquitylation module and the Not2-Not3/5 module concomitantly in the Ccr4-Not complex. PMID- 25914054 TI - AnchorDock: Blind and Flexible Anchor-Driven Peptide Docking. AB - The huge conformational space stemming from the inherent flexibility of peptides is among the main obstacles to successful and efficient computational modeling of protein-peptide interactions. Current peptide docking methods typically overcome this challenge using prior knowledge from the structure of the complex. Here we introduce AnchorDock, a peptide docking approach, which automatically targets the docking search to the most relevant parts of the conformational space. This is done by precomputing the free peptide's structure and by computationally identifying anchoring spots on the protein surface. Next, a free peptide conformation undergoes anchor-driven simulated annealing molecular dynamics simulations around the predicted anchoring spots. In the challenging task of a completely blind docking test, AnchorDock produced exceptionally good results (backbone root-mean-square deviation <= 2.2A, rank <=15) for 10 of 13 unbound cases tested. The impressive performance of AnchorDock supports a molecular recognition pathway that is driven via pre-existing local structural elements. PMID- 25914051 TI - N-terminal modifications of cellular proteins: The enzymes involved, their substrate specificities and biological effects. AB - The vast majority of eukaryotic proteins are N-terminally modified by one or more processing enzymes. Enzymes acting on the very first amino acid of a polypeptide include different peptidases, transferases, and ligases. Methionine aminopeptidases excise the initiator methionine leaving the nascent polypeptide with a newly exposed amino acid that may be further modified. N-terminal acetyl-, methyl-, myristoyl-, and palmitoyltransferases may attach an acetyl, methyl, myristoyl, or palmitoyl group, respectively, to the alpha-amino group of the target protein N-terminus. With the action of ubiquitin ligases, one or several ubiquitin molecules are transferred, and hence, constitute the N-terminal modification. Modifications at protein N-termini represent an important contribution to proteomic diversity and complexity, and are essential for protein regulation and cellular signaling. Consequently, dysregulation of the N-terminal modifying enzymes is implicated in human diseases. We here review the different protein N-terminal modifications occurring co- or post-translationally with emphasis on the responsible enzymes and their substrate specificities. PMID- 25914055 TI - Tertiary structural propensities reveal fundamental sequence/structure relationships. AB - Extracting useful generalizations from the continually growing Protein Data Bank (PDB) is of central importance. We hypothesize that the PDB contains valuable quantitative information on the level of local tertiary structural motifs (TERMs). We show that by breaking a protein structure into its constituent TERMs, and querying the PDB to characterize the natural ensemble matching each, we can estimate the compatibility of the structure with a given amino acid sequence through a metric we term "structure score." Considering submissions from recent Critical Assessment of Structure Prediction (CASP) experiments, we found a strong correlation (R = 0.69) between structure score and model accuracy, with poorly predicted regions readily identifiable. This performance exceeds that of leading atomistic statistical energy functions. Furthermore, TERM-based analysis of two prototypical multi-state proteins rapidly produced structural insights fully consistent with prior extensive experimental studies. We thus find that TERM based analysis should have considerable utility for protein structural biology. PMID- 25914056 TI - Integrative Modeling of Biomolecular Complexes: HADDOCKing with Cryo-Electron Microscopy Data. AB - Protein-protein interactions play a central role in all cellular processes. Insight into their atomic architecture is therefore of paramount importance. Cryo electron microscopy (cryo-EM) is capable of directly imaging large macromolecular complexes. Unfortunately, the resolution is usually not sufficient for a direct atomic interpretation. To overcome this, cryo-EM data are often combined with high-resolution atomic structures. However, current computational approaches typically do not include information from other experimental sources nor a proper physico-chemical description of the interfaces. Here we describe the integration of cryo-EM data into our data-driven docking program HADDOCK and its performance on a benchmark of 17 complexes. The approach is demonstrated on five systems using experimental cryo-EM data in the range of 8.5-21 A resolution. For several cases, cryo-EM data are integrated with additional interface information, e.g. mutagenesis and hydroxyl radical footprinting data. The resulting models have high-quality interfaces, revealing novel details of the interactions. PMID- 25914057 TI - Cryo-electron microscopy structure of human peroxiredoxin-3 filament reveals the assembly of a putative chaperone. AB - Peroxiredoxins (Prxs) are a ubiquitous class of thiol-dependent peroxidases that play an important role in the protection and response of cells to oxidative stress. The catalytic unit of typical 2-Cys Prxs are homodimers, which can self associate to form complex assemblies that are hypothesized to have signaling and chaperone activity. Mitochondrial Prx3 forms dodecameric toroids, which can further stack to form filaments, the so-called high-molecular-weight (HMW) form that has putative holdase activity. We used single-particle analysis and helical processing of electron cryomicroscopy images of human Prx3 filaments induced by low pH to generate a ~7-A resolution 3D structure of the HMW form, the first such structure for a 2-Cys Prx. The pseudo-atomic model reveals interactions that promote the stacking of the toroids and shows that unlike previously reported data, the structure can accommodate a partially folded C terminus. The HMW filament lumen displays hydrophobic patches, which we hypothesize bestow holdase activity. PMID- 25914059 TI - Measurement of Acceptor-TPsiC Helix Length of tRNA for Terminal A76-Addition by A Adding Enzyme. AB - The 3'-terminal CCA (C74C75A76-3') of tRNA is required for protein synthesis. In Aquifex aeolicus, the CCA-3' is synthesized by CC-adding and A-adding enzymes, although in most organisms, CCA is synthesized by a single CCA-adding enzyme. The mechanisms by which the A-adding enzyme adds only A76, but not C74C75, onto tRNA remained elusive. The complex structures of the enzyme with various tRNAs revealed the presence of a single tRNA binding site on the enzyme, with the enzyme measuring the acceptor-TPsiC helix length of tRNA. The 3'-C75 of tRNA lacking A76 can reach the active site and the size and shape of the nucleotide binding pocket at the insertion stage are suitable for ATP. The 3'-C74 of tRNA lacking C75A76 cannot reach the active site, although CTP or ATP can bind the active pocket. Thus, the A-adding enzyme adds only A76, but not C74C75, onto tRNA. PMID- 25914058 TI - The ssDNA Mutator APOBEC3A Is Regulated by Cooperative Dimerization. AB - Deaminase activity mediated by the human APOBEC3 family of proteins contributes to genomic instability and cancer. APOBEC3A is by far the most active in this family and can cause rapid cell death when overexpressed, but in general how the activity of APOBEC3s is regulated on a molecular level is unclear. In this study, the biochemical and structural basis of APOBEC3A substrate binding and specificity is elucidated. We find that specific binding of single-stranded DNA is regulated by the cooperative dimerization of APOBEC3A. The crystal structure elucidates this homodimer as a symmetric domain swap of the N-terminal residues. This dimer interface provides insights into how cooperative protein-protein interactions may affect function in the APOBEC3 enzymes and provides a potential scaffold for strategies aimed at reducing their mutation load. PMID- 25914060 TI - An Inverted-Sandwich Diuranium MU-eta(5):eta(5)-Cyclo-P5 Complex Supported by U P5 delta-Bonding. AB - Reaction of [U(Tren(TIPS))] [1, Tren(TIPS)=N(CH2CH2NSiiPr3)3] with 0.25 equivalents of P4 reproducibly affords the unprecedented actinide inverted sandwich cyclo-P5 complex [{U(Tren(TIPS))}2(MU-eta(5):eta(5)-cyclo-P5)] (2). All prior examples of cyclo-P5 are stabilized by d-block metals, so 2 shows that cyclo-P5 does not require d-block ions to be prepared. Although cyclo-P5 is isolobal to cyclopentadienyl, which usually bonds to metals via sigma- and pi interactions with minimal delta-bonding, theoretical calculations suggest the principal bonding in the U(P5)U unit is polarized delta-bonding. Surprisingly, the characterization data are overall consistent with charge transfer from uranium to the cyclo-P5 unit to give a cyclo-P5 charge state that approximates to a dianionic formulation. This is ascribed to the larger size and superior acceptor character of cyclo-P5 compared to cyclopentadienyl, the strongly reducing nature of uranium(III), and the availability of uranium delta-symmetry 5f orbitals. PMID- 25914061 TI - LONGITUDINAL COURSE OF POSTTRAUMATIC GROWTH AMONG U.S. MILITARY VETERANS: RESULTS FROM THE NATIONAL HEALTH AND RESILIENCE IN VETERANS STUDY. AB - BACKGROUND: Posttraumatic growth (PTG) is increasingly recognized as an important psychosocial phenomenon, but few studies have evaluated the longitudinal course of PTG. This study identified courses of PTG over a 2-year period in a contemporary, nationally representative sample of U.S. military veterans, and examined sociodemographic, military, trauma, medical, and psychosocial predictors of PTG course. METHODS: Data were based on a Web-based survey of a nationally representative sample of 1,838 U.S. veterans who reported at least one potentially traumatic event and provided data at two time points (October December 2011 and September-October 2013). RESULTS: Five different courses of PTG were identified--Consistently Low (33.6%), Moderately Declining (19.4%), Increasing PTG (16.8%), Dramatically Declining (15.7%), and Consistently High (14.5%). More than half (59.4%) of veterans who reported at least "moderate" PTG maintained that level of PTG 2 years later. Posttraumatic stress disorder symptoms, medical conditions, purpose in life, altruism, gratitude, religiosity, and an active reading lifestyle predicted maintenance or increase in PTG. CONCLUSIONS: PTG has a heterogeneous course and is not only common, but can persist over time especially in the presence of posttraumatic stress and certain psychosocial factors. Clinicians and researchers should consider the personal growth that can result from trauma and help trauma survivors find ways to maintain this growth over time. PMID- 25914062 TI - Antipsychotics can induce pre-shock in very elderly patients: a report of two cases. AB - Antipsychotics have often been administered to treat delirium and intractable insomnia in elderly patients with or without dementia. However, antipsychotics sometimes cause severe adverse effects. We report two cases of very elderly patients who developed pre-shock after the administration of antipsychotics in a clinical consultation-liaison setting. These cases suggest that antipsychotics can induce fatal adverse events in very elderly patients. Although there has been little evidence regarding the most appropriate kind of drug and dosage for such patients, psychiatrists should exercise great caution in the use of antipsychotics for the very elderly, including deciding to prescribe the lowest dose or not prescribing them at all. PMID- 25914063 TI - Ataxia-telangiectasia with female fertility. PMID- 25914064 TI - Effect of metabotropic glutamate receptor-3 variants on prefrontal brain activity in schizophrenia: An imaging genetics study using multi-channel near-infrared spectroscopy. AB - BACKGROUND: The glutamatergic system is essential for learning and memory through its crucial role in neural development and synaptic plasticity. Genes associated with the glutamatergic system, including metabotropic glutamate receptor (mGluR or GRM) genes, have been implicated in the pathophysiology of schizophrenia. Few studies, however, have investigated a relationship between polymorphism of glutamate-related genes and cortical function in vivo in patients with schizophrenia. We thus explored an association between genetic variations in GRM3 and brain activation driven by a cognitive task in the prefrontal cortex in patients with schizophrenia. MATERIALS AND METHODS: Thirty-one outpatients with schizophrenia and 48 healthy controls participated in this study. We measured four candidate single nucleotide polymorphisms (rs274622, rs2299225, rs1468412, and rs6465084) of GRM3, and activity in the prefrontal and temporal cortices during a category version of a verbal fluency task, using a 52-channel near infrared spectroscopy instrument. RESULTS AND DISCUSSION: The rs274622 C carriers with schizophrenia were associated with significantly smaller prefrontal activation than patients with TT genotype. This between-genotype difference tended to be confined to the patient group. GRM3 polymorphisms are associated with prefrontal activation during cognitive task in schizophrenia. PMID- 25914065 TI - Complications from robot-assisted radical cystectomy: Where do we stand? AB - INTRODUCTION: Radical cystectomy with extended lymphadenectomy is the surgical treatment of choice for muscle-invasive bladder cancer. The technical and technological improvements and the positive results from robot-assisted kidney and prostate surgery have led to the progressive development of robot-assisted radical cystectomy (RARC). We provide a global structured overview and an update on the complications of RARC, recorded according to the Clavien-Dindo classification system. ACQUISITION OF EVIDENCE: We conducted a search on PubMed of all publications on RARC to date (2014). Of the 259 publications found, we excluded review articles and cost analyses, publications with less than 30 cases, updates of previous studies and those whose main objective was the study of other issues related to RARC other than complications, leaving a total of 38 articles for the final analysis. SUMMARY OF THE EVIDENCE: The most common complications associated with RARC are gastrointestinal, infectious and genitourinary system, mainly Clavien 1-2, followed by Clavien 3-4. RARC had lower overall complication rates than open radical cystectomy and laparoscopic radical cystectomy and had a lower incidence of severe complications, less intraoperative bleeding and better postoperative recovery. CONCLUSIONS: Although further scientific evidence is needed, RARC is an increasingly widespread technique that appears to reduce complications as well as the need for transfusion, and it improves recovery times. PMID- 25914066 TI - Is polyomavirus BK the cause of hemorrhagic cystopathy in patients who undergo allogeneic hematopoietic progenitor cell transplantation? PMID- 25914067 TI - Current Perioperative Anticoagulation Practices in Children with Prosthetic Mechanical Heart Valves. AB - OBJECTIVE: This study investigated the clinician practices on perioperative anticoagulation in children with prosthetic mechanical heart valves who undergo elective surgeries. DESIGN: An online survey was administered to members of PediHeartNet. The survey consisted of multiple choice questions and clinical scenarios. OUTCOME MEASURES: The study described clinical practice patterns and variables that influence the clinicians' bridging anticoagulation decisions. RESULTS: Ninety-one respondents completed the survey; 68% were affiliated with university settings; 91% were pediatric cardiologists, and 49% had >=10 years of experience in pediatric cardiology. Approximately one-half of the respondents (54%) independently provided perioperative anticoagulation management to their patients, while 46% utilized cardiac or hematology anticoagulation services. Resources that influenced bridging decisions included hematology experts (20%), American College of Chest Physicians guidelines (34%), and the clinicians' personal experience (56%). In planning for major surgeries, 47% of the respondents hospitalized patients for unfractionated heparin (UFH) and 46% prescribed outpatient low molecular weight heparin (LMWH). For minor surgeries, 58% hospitalized patients for UFH, 22% prescribed outpatient LMWH, and 17% opted out of bridging anticoagulation. Immediately after mitral valve replacement, 23% used bridging anticoagulation with UFH. When LMWH was used, there were no reports of thromboembolic complications. Major bleeding complications were rare and reported by 2% of the respondents. CONCLUSIONS: This was the first documentation that clinical practice of bridging perioperative anticoagulation in children with mechanical heart valves varies widely among pediatric cardiac specialists. There is poor adoption of published guidelines and a tendency toward more conservative strategies. Further studies comparing the safety and efficacy of LMWH vs. UFH as perioperative anticoagulation agents in children with mechanical heart valves are needed to further clarify our findings. Quality assurance initiatives and education are also needed to improve guidelines adherence and standardize practice management. PMID- 25914068 TI - A questionnaire survey of Japanese non-psychiatrists' attitudes on management of depression in a general hospital. PMID- 25914069 TI - Assessment of barriers to establish OSH: a country report. AB - In addition to its merits, industrial growth is associated with many issues and problems, including occupational injuries and diseases. The adverse effects of industrialization are function of economic, social, cultural, political and geographical condition of a country, and therefore it varies widely between different countries, especially, developed and developing countries. Establishment of occupational safety and health (OSH) is one of the important solutions to predict, prevent, reduce and harness of the related harms. Despite many relevant protocols and guidelines for establishment of OSH and decades of efforts, still, there are debates and lack of success on different approaches towards implementation of OSH, especially in developing countries. Iran has experienced industrialized growth and has gained some advancement in establishment of OSH in the region. The purpose of this study was to reach to a consensus among Iranian experts about barriers to establish OSH in developing countries, using Delphi technique. 48 experts participated in this study. Two rounds of Delphi were conducted and main barriers were identified, then the identified barriers were prioritized and weighted by the experts. Among all barriers, 17 barriers which were reported by 15 experts or more were selected and categorized as structural, managerial and implementation barriers. PMID- 25914070 TI - The extent and influence of Asbestos Safety Awareness training among managers who had previously commissioned an asbestos survey in their workplace buildings. AB - A telephone survey was conducted among a sample of managers (n=30) in Ireland who had previously commissioned an asbestos survey in their workplace buildings. The aims of the telephone survey were to examine the extent to which managers had completed Asbestos Safety Awareness (ASA) training, and to assess how such training might influence (i) their instinctive thoughts on asbestos, and (ii) their approach to aspects of asbestos management within their buildings. Managers' motivations for commissioning the asbestos survey were also identified. The study found that ASA-trained managers (n=11) were not significantly more likely to work in larger organisations or in organisations which operated an accredited management system. Though ASA-trained managers' instinctive thoughts on asbestos were of a slightly poorer technical quality compared with those of non-ASA-trained managers, they were still significantly more cognisant of their responsibilities towards those of their employees at specific risk of asbestos exposure. Most managers (n=28) commissioned the asbestos survey to satisfy a pre requisite of external contractors for commencing refurbishment/demolition work in their buildings. Given its potential to positively influence the occupational management of asbestos, the authors recommend the general promotion of suitably tailored ASA-training programmes among building managers and external contractors alike. PMID- 25914071 TI - Menstrual characteristics and night work among nurses. AB - Night work has been associated with adverse effects in terms of reproductive health. Specifically, menstruation has been suggested to be negatively impacted by night work, which again may influence fertility. This study investigated whether working nights is related to menstrual characteristics and if there is a relationship between shift work disorder (SWD) and menstruation. The study was cross-sectional, response rate 38%. The sample comprised female nurses who were members of the Norwegian Nurses Association; below 50 yr of age, who were not pregnant, did not use hormonal pills or intrauterine devices and who had not reached menopause (n=766). The nurses answered a postal survey including questions about night work and menstrual characteristics. Fifteen per cent reported to have irregular menstruations. Thirty-nine per cent of the nurses were classified as having SWD. Logistic regression analyses concerning the relationship between irregular menstruations and night work did not show any associations. Furthermore, no associations were found between cycle length or bleeding period and night work parameters. No associations were found between menstrual characteristics and SWD. PMID- 25914072 TI - Low job control is associated with higher diastolic blood pressure in men with mildly elevated blood pressure: the Rosai Karoshi study. AB - Job strain is a risk factor for hypertension, but it is not fully understood if components of job strain, or job demand or job control per se could be related to blood pressure (BP), and if so, whether the relationship differs between normotension and mildly elevated BP. We examined resting BP, and job stress components in 113 Japanese male hospital clerks (38.1 +/- 4.4 yr). Subjects were classified into normotensive (NT) (<130/85 mmHg, n=83) and mildly elevated BP (ME) (>=130/85 mmHg) groups. Diastolic BP (DBP) showed a significant interaction between group and job control level (p=0.013). Subjects with low job control demonstrated higher DBP than those with high job control (89.1 +/- 2.1 vs. 82.3 +/- 2.3 mmHg, p=0.042) in ME group even after adjustments for covariates while DBP did not differ between low and high job control subjects in NT group. Systolic BP (SBP) did not differ between high and low job control subjects in both groups. Neither SBP nor DBP differed between high and low demand groups in either group. Among job strain components, job control may be independently related to BP in Japanese male workers with mildly elevated BP. PMID- 25914073 TI - Opportunistic salpingectomies for the prevention of a high-grade serous carcinoma: a statement by the Kommission Ovar of the AGO. AB - The detection of premalignant cells in the epithelium of the fallopian tube has resulted in revolutionary theories regarding the origin of epithelial ovarian cancer (EOC). Serous tubal intra-epithelial carcinomas (STIC) have been detected in patients with BRCA 1 or 2 mutations and are considered as the most likely precursors of the high-grade serous ovarian cancer (HGSOC), which is the most common histological subtype in patients with EOC. A bilateral salpingo oophorectomy is associated with a significant reduction in risk of developing EOC. According to various national guidelines, prophylactic bilateral salpingo oophorectomy should be performed in the age group 40-45 years. As in patients with BRCA mutations, the prophylactic removal of the fallopian tubes is also performed in women without an increased genetic risk, for example, in surgical treatments of benign conditions. There is a current debate as to whether prophylactic or so-called opportunistic salpingectomy will influence the overall incidence of EOC in the coming years. Opponents of this theory warn of a higher surgical morbidity and the higher risk of a premature menopause through impaired vascular supply to the ovaries. The value of opportunistic salpingectomies has not yet been clarified since there are currently no systematic risk-benefit evaluations. This review will attempt to give an overview of the current body of evidence regarding the risks and benefits of opportunistic salpingectomies. PMID- 25914074 TI - Five years' experience treating locally advanced cervical cancer with concurrent chemoradiotherapy: results from a single institution. AB - INTRODUCTION: Cervical cancer is the second most common cause of female cancer death. In Morocco it is the second most common cancer, our department recruits more than 500 patients each year and proximally half of the cases are diagnosed at an advanced stage. PATIENTS AND METHODS: Between January 2008 and December 2008, all patients with diagnosis of locally advanced cervical cancer referred to our department and treated with concurrent chemoradiotherapy were retrieved. We analyzed outcomes for this particular population; overall survival, local control, and toxicities, we also retrieved prognostic factors influencing outcomes for this population. RESULTS: The overall survival rate for the cohort was 68 % at 2 years, and reached 47 % at 5 years. The overall LC rate was 71 % at 2 years and 58 % at 5 years. The most important prognostic factors for OS and LC were the pretreatment hemoglobin, the tumor size, total duration of treatment, and the use of brachytherapy. For OS, the presence of enlarged lymph nodes was also important. For LC, the number of chemotherapy's courses was important. Of the included patients, 20 % experienced late grade 3 or 4 toxicity. CONCLUSION: The results of our study have shown that despite all the treatment strategies available, locally advanced cervical cancer is associated with bad outcomes. In this cohort, the most important prognostic factors were the pretreatment hemoglobin level and the tumor size. PMID- 25914075 TI - Prevention from port-site metastasis. PMID- 25914076 TI - Comment to the letter: Prevention from port site metastasis. PMID- 25914077 TI - Modulating secretory pathway pH by proton channel co-expression can increase recombinant protein stability in plants. AB - Eukaryotic expression systems are used for the production of complex secreted proteins. However, recombinant proteins face considerable biochemical challenges along the secretory pathway, including proteolysis and pH variation between organelles. As the use of synthetic biology matures into solutions for protein production, various host-cell engineering approaches are being developed to ameliorate host-cell factors that can limit recombinant protein quality and yield. We report the potential of the influenza M2 ion channel as a novel tool to neutralize the pH in acidic subcellular compartments. Using transient expression in the plant host, Nicotiana benthamiana, we show that ion channel expression can significantly raise pH in the Golgi apparatus and that this can have a strong stabilizing effect on a fusion protein separated by an acid-susceptible linker peptide. We exemplify the utility of this effect in recombinant protein production using influenza hemagglutinin subtypes differentially stable at low pH; the expression of hemagglutinins prone to conformational change in mildly acidic conditions is considerably enhanced by M2 co-expression. The co-expression of a heterologous ion channel to stabilize acid-labile proteins and peptides represents a novel approach to increasing the yield and quality of secreted recombinant proteins in plants and, possibly, in other eukaryotic expression hosts. PMID- 25914079 TI - Corrigendum. PMID- 25914078 TI - [From Comte to Carnap. Marcel Boll and the introduction of the Vienna Circle in France]. AB - The issue of the introduction of viennese "scientific philosophy" in France appears to be resolved. However, the rediscovery of the positivist physicist Marcel Boll (1886-1971), who was the first-well before Louis Rougier-to draw the French public's attention to the works of Schlick, Frank, and Carnap, obliges us to rethink the passage from traditional positivism to neo-positivism during the 1920s and 1930s. The French reception of the Vienna circle can be dated earlier than accepted and is more profound than usualy assumed. PMID- 25914080 TI - Individual phases of contextual fear conditioning differentially modulate dorsal and ventral hippocampal GluA1-3, GluN1-containing receptor complexes and subunits. AB - In contextual fear conditioning (CFC), the use of pharmacological and lesion approaches has helped to understand that there are differential roles for the dorsal hippocampus (DH) and the ventral hippocampus (VH) in the acquisition, consolidation and retrieval phases. Concomitant analysis of the DH and the VH in individual phases with respect to alpha-amino-3-hydroxy-5-methyl-4-isoxazole propionate receptors and N-methyl-D-aspartate receptor subtype N1 (GluN1) containing complexes (RCC) and subunits has not been reported so far. Herein, CFC was performed in mice that were euthanized at different time points. DH and VH samples were taken for the determination of RCC and subunit levels using BN- and SDS-PAGE, respectively, with subsequent Western blotting. Evaluation of spine densities, morphology, and immunohistochemistry of GluA1 and GluA2 was performed. In the acquisition phase levels of GluA1-RCC and subunits in VH were increased. In the consolidation phase GluA1- and GluA2-RCC levels were increased in DH and VH, while both receptor subunit levels were increased in the VH only. In the retrieval phase GluA1-RCC, subunits thereof and GluA2-RCC were increased in DH and VH, whereas GluA2 subunits were increased in the VH only. GluN1-RCC levels were increased in acquisition and consolidation phase, while subunit levels in the acquisition phase were increased only in the DH. The immunohistochemical studies in the individual phases in subareas of hippocampus supported immunochemical changes of GluA1 and GluA2 RCC's. Dendritic spine densities and the prevalence of thin spines in the acquisition phase of VH and mushroom spines in the retrieval phase of the VH and DH were increased. The findings from the current study suggest different receptor and receptor complex patterns in the individual phases in CFC and in DH and VH. The results propose that different RCCs are formed in the individual phases and that VH and DH may be involved in CFC. PMID- 25914081 TI - Hair shedding in women: how much is too much? PMID- 25914084 TI - Retrospective analysis of 30 severe autoimmune hemolytic anemia patients treated by whole blood exchange transfusion. AB - BACKGROUND: Autoimmune hemolytic anemia (AIHA) results from the excessive destruction of red blood cells (RBCs). Nowadays, there is no exact treatment for severe AIHA and our current medical therapies do not effectively stop the progression of severe AIHA. Therapeutic plasma exchange (TPE) is used as emergency therapy that is sometimes helpful. Whole blood exchange (WBE) is based on TPE while its replacement liquids are donor RBCs and fresh plasma. We hypothesized that WBE transfusion might be able to control the process of acute hemolysis, avoid the hemolytic crisis, and improve severe hemolytic anemic symptoms rapidly. The objective was to investigate the efficiency of WBE on severe AIHA. STUDY DESIGN AND METHODS: Thirty severe AIHA patients were treated with WBE in our hospital from June 2003 to August 2013. An apheresis instrument (COBE Spectra, TerumoBCT) was employed in WBE procedure. We retrospectively analyzed the results of these severe anemic patients. RESULTS: Twelve hours after WBE treatment, 26 of 30 (86.7%) patients' Hb levels were elevated immediately. Their total bilirubin concentration, direct bilirubin levels, and titers of antibodies were decreased, and clinical symptoms were relieved rapidly. Two (6.7%) patients' hemolysis was stopped from deteriorating, one (3.3%) patient's hemolysis was not controlled by the treatment due to malignancy, and another (3.3%) patient died from pleural hemorrhage of Evans syndrome. CONCLUSION: This study suggests that WBE is an effective therapy for severe AIHA. Further investigation of this application is warranted. PMID- 25914082 TI - The role of adherens junctions in the developing neocortex. AB - The disproportional enlargement of the neocortex through evolution has been instrumental in the success of vertebrates, in particular mammals. The neocortex is a multilayered sheet of neurons generated from a simple proliferative neuroepithelium through a myriad of mechanisms with substantial evolutionary conservation. This developing neuroepithelium is populated by progenitors that can generate additional progenitors as well as post-mitotic neurons. Subtle alterations in the production of progenitors vs. differentiated cells during development can result in dramatic differences in neocortical size. This review article will examine how cadherin adhesion proteins, in particular alpha-catenin and N-cadherin, function in regulating the neural progenitor microenvironment, cell proliferation, and differentiation in cortical development. PMID- 25914083 TI - Cadherins and catenins in dendrite and synapse morphogenesis. AB - Neurons are highly polarized specialized cells. Neuronal integrity and functional roles are critically dependent on dendritic architecture and synaptic structure, function and plasticity. The cadherins are glycosylated transmembrane proteins that form cell adhesion complexes in various tissues. They are associated with a group of cytosolic proteins, the catenins. While the functional roles of the complex have been extensively investigates in non-neuronal cells, it is becoming increasingly clear that components of the complex have critical roles in regulating dendritic and synaptic architecture, function and plasticity in neurons. Consistent with these functional roles, aberrations in components of the complex have been implicated in a variety of neurodevelopmental disorders. In this review, we discuss the roles of the classical cadherins and catenins in various aspects of dendrite and synapse architecture and function and their relevance to human neurological disorders. Cadherins are glycosylated transmembrane proteins that were initially identified as Ca(2+)-dependent cell adhesion molecules. They are present on plasma membrane of a variety of cell types from primitive metazoans to humans. In the past several years, it has become clear that in addition to providing mechanical adhesion between cells, cadherins play integral roles in tissue morphogenesis and homeostasis. The cadherin family is composed of more than 100 members and classified into several subfamilies, including classical cadherins and protocadherins. Several of these cadherin family members have been implicated in various aspects of neuronal development and function. (1-3) The classical cadherins are associated with a group of cytosolic proteins, collectively called the catenins. While the functional roles of the cadherin-catenin cell adhesion complex have been extensively investigated in epithelial cells, it is now clear that components of the complex are well expressed in central neurons at different stages during development. (4,5) Recent exciting studies have shed some light on the functional roles of cadherins and catenins in central neurons. In this review, we will provide a brief overview of the cadherin superfamily, describe cadherin family members expressed in central neurons, cadherin-catenin complexes in central neurons and then focus on role of the cadherin-catenin complex in dendrite morphogenesis and synapse morphogenesis, function and plasticity. The final section is dedicated to discussion of the emerging list of neural disorders linked to cadherins and catenins. While the roles of cadherins and catenins have been examined in several different types of neurons, the focus of this review is their role in mammalian central neurons, particularly those of the cortex and hippocampus. Accompanying this review is a series of excellent reviews targeting the roles of cadherins and protocadherins in other aspects of neural development. PMID- 25914085 TI - Suicidality in Australian Vietnam veterans and their partners. AB - Lifetime suicidality was assessed in a cohort of 448 ageing Australian Vietnam veterans and 237 female partners during in-person structured psychiatric interviews that permitted direct comparison with age-sex matched Australian population statistics. Relative risks for suicidal ideation, planning and attempts were 7.9, 9.7 and 13.8 times higher for veterans compared with the Australian population and for partners were 6.2, 3.5 and 6.0 times higher. Odds ratios between psychiatric diagnoses and suicidality were computed using multivariate logistic regression, and suicidality severity scores were assigned from ideation, planning and attempt, and analysed using ordinal regression. PTSD, depression alcohol disorders, phobia and agoraphobia were prominent predictors of ideation, attempts and suicidal severity among veterans, while depression, PTSD, social phobia and panic disorder were prominent predictors among partners. For veterans and their partners, PTSD is a risk factor for suicidality even in the presence of other psychiatric disorders, and is stronger in Vietnam veterans than their partners. PMID- 25914086 TI - Endocytosis and its regulation in plants. AB - Endocytosis provides a major route of entry for membrane proteins, lipids, and extracellular molecules into the cell. Recent evidence indicates that multiple cellular processes require endocytosis, including nutrient uptake, signaling transduction, and plant-microbe interactions. Also, advanced microscopy, combined with biochemical and genetic approaches, has provided more insights into the molecular machinery and functions of endocytosis in plants. Here we review mechanisms of the clathrin-dependent and membrane microdomain-associated endocytic routes in plant cells. In addition, degradation of endocytosed proteins and endosomal sorting complex required for transport (ESCRT)-mediated vesicle formation at the endosome are discussed. Finally, we summarize the essential roles of various regulators during plant endocytosis. PMID- 25914087 TI - Contribution of sensory nerves to LPS-induced hyperresponsiveness of human isolated bronchi. AB - AIMS: Bacterial lipopolysaccharide (LPS) can induce bronchial hyperresponsiveness (BHR), but the underlying mechanisms remain to be determined. Here, the possible contribution of sensory nerves to LPS-induced BHR was examined in human isolated bronchi to pharmacologically identify the mechanisms underlying this phenomenon. MAIN METHODS: Human isolated bronchial tone was induced by electrical field stimulation (EFS). The responses of airways to LPS, with or without capsaicin desensitization or thiorphan treatment were studied and the transient receptor potential vanilloid type 1 (TRPV1) expression was assessed. We performed similar experiments in the presence of a TRPV1 or a neurokinin (NK) 2 receptor antagonist using SB366791 and GR159897, respectively. KEY FINDINGS: LPS increased (?2.3 fold, P<0.001) the contraction induced by EFS, compared to control tissues. Acute administration of capsaicin enhanced (?2.3-fold, P<0.001) the EFS-mediated contraction, but did not potentiate the effect of LPS. Thiorphan increased (?1.3 fold, P<0.05) the contractile response of LPS treated tissues and, at lower frequencies, it enhanced (?1.7-fold, P<0.001) the capsaicin-induced contraction. In capsaicin-desensitized bronchi, LPS did not modify (P>0.05) the EFS contractile response, nor after treatment with thiorphan. Capsaicin desensitization reduced (?0.4-fold, P<0.001) the LPS-induced BHR. SB366791 and GR159897 prevented the LPS-induced BHR and the release of NKA. LPS increased (+85.3+/-9.5%, P<0.01) the surface membrane expression of TRPV1 in parasympathetic ganglia. SIGNIFICANCE: Our results demonstrate the involvement of capsaicin-sensitive sensory nerves and neutral endopeptidases in LPS-induced BHR of the human bronchi, associated with an upregulation of TRPV1 and release of NKA. PMID- 25914088 TI - Molecular epidemiology of carbapenemase-producing Klebsiella pneumoniae in a hospital in Madrid: Successful establishment of an OXA-48 ST11 clone. AB - Here we report a retrospective clinical and molecular study conducted in a tertiary care facility in southern Madrid, Spain, from January 2009 to February 2014 to investigate the epidemiology of carbapenemase-producing Klebsiella pneumoniae (CPKp). Carbapenemase genes were identified in 97 non-duplicate K. pneumoniae isolates, including 59 harbouring blaOXA-48, 37 harbouring blaVIM-1 and 1 harbouring blaKPC-2. Pulsed-field gel electrophoresis (PFGE) analysis verified the presence of 20 different clonal types, whilst multilocus sequence typing (MLST) assigned the isolates to eight sequence types (STs). A gradual increase was noted in the number of CPKp isolated, ranging from 0.8% in 2009 to 4.3% in 2013. A large outbreak was also identified, initiated in 2013 owing to a blaOXA-48 and blaCTX-M-15 co-producing ST11 clone and involving a total of 44 patients. Whole-genome sequencing was used to characterise the resistome of a representative isolate from this outbreak. Bioinformatics analysis revealed the presence of 121 genes related to antibiotic and antiseptic resistance, mutations in the ompk35 and ompk36 genes, and the presence of the blaOXA-48 gene on a 62 811bp IncL/M-type plasmid as part of a Tn1999.2 composite transposon. These results portray the increasing trend in carbapenemase-producing isolates in this hospital and highlight the successful establishment of a blaOXA-48 and blaCTX-M 15 co-producing ST11 clone that has led to the displacement of previous circulating clones. PMID- 25914089 TI - Optimal reference genes for qPCR in resting and activated human NK cells--Flow cytometric data correspond to qPCR gene expression analysis. AB - Natural killer cells (NK cells) are cytotoxic lymphocytes critical to the innate immune system engaged in rapid response against tumor or virus infected cells. After activation NK cells acquire enhanced cytotoxicity and are capable of producing cytokines to stimulate other immune cells. Quantitative PCR (qPCR) is a method of choice for gene expression analysis but the usage of reliable reference genes for the normalization process is critical. Commonly used reference genes may vary in expression level between different experimental conditions providing wrong quantitative results of the studied genes' expression levels. Fourteen potential endogenous control genes were analyzed by qPCR method in NK-92 cell line that shows characteristics of human natural killer cells and is often used in studies on biology of NK lymphocytes. NK-92 cells were stimulated with IL-2 or TNF for 2, 24 or 72 h. Results were analyzed with RefFinder, a program which enables evaluation and screening of reference genes and integrates the currently available major computational programs (Genorm, Normfinder, BestKeeper and Delta Ct). The most stable gene in activated and non-activated NK cells was B2M, followed by IPO-8 and GAPDH and the least stable were HPRT1, PPIA and RPL32. The normalization process was performed on SOD2 gene and the results of qPCR experiments were confirmed by flow cytometry. The flow cytometric data corresponded to the results of qPCR gene expression analysis performed for the reference genes qualified by RefFinder as the most stable. PMID- 25914090 TI - Tracking the kinetics of intrahepatic immune responses by repeated fine needle aspiration of the liver. AB - Liver disease is an increasing global health burden. The final sequalae of cirrhosis, liver failure and hepatocellular carcinoma are often the result of inflammation driven by intrahepatic lymphocytes. Accurate assessment of organ specific diseases ideally employs tissue sampling though this is rarely performed. Here we report our experiences of utilising repeated fine needle aspirations (FNAs) to assess liver-derived leukocytes. In 88 patient samples, we obtained a mean of 36,959 lymphocytes from each FNA-derived biopsy (SD 22,319 cells, range 5034-91,242 cells) measured by flow cytometry. This quick technique required minimal analgesia compared to liver biopsy (p = 0.03); was well tolerated and safe, and hence repeated sampling up to 3 times within a week was feasible. We detail the technique to rapidly derive a single cell suspension suitable for multiparameter flow cytometry analysis. Finally we illustrate the importance of organ-derived sampling by showing that natural killer (NK) cells from FNA samples have a markedly altered phenotype compared to those assessed in peripheral blood. In combination these data validate FNA as a powerful and well tolerated method of sampling intrahepatic lymphocytes to study the immunology of acute and chronic liver diseases. PMID- 25914091 TI - Genome analyses suggest the presence of polyploidy and recent human-driven expansions in eight global populations of the honeybee pathogen Nosema ceranae. AB - Nosema ceranae is a microsporidian pathogen whose infections have been associated with recent global declines in the populations of western honeybees (Apis mellifera). Despite the outstanding economic and ecological threat that N. ceranae may represent for honeybees worldwide, many aspects of its biology, including its mode of reproduction, propagation and ploidy, are either very unclear or unknown. In the present study, we set to gain knowledge in these biological aspects by re-sequencing the genome of eight isolates (i.e. a population of spores isolated from one single beehive) of this species harvested from eight geographically distant beehives, and by investigating their level of polymorphism. Consistent with previous analyses performed using single gene sequences, our analyses uncovered the presence of very high genetic diversity within each isolate, but also very little hive-specific polymorphism. Surprisingly, the nature, location and distribution of this genetic variation suggest that beehives around the globe are infected by a population of N. ceranae cells that may be polyploid (4n or more), and possibly clonal. Lastly, phylogenetic analyses based on genome-wide single-nucleotide polymorphism data extracted from these parasites and mitochondrial sequences from their hosts all failed to support the current geographical structure of our isolates. PMID- 25914092 TI - Making sense of nickel accumulation and sub-lethal toxic effects in saline waters: Fate and effects of nickel in the green crab, Carcinus maenas. AB - In freshwater, invertebrates nickel (Ni) is considered an ionoregulatory toxicant, but its mechanism of toxicity in marine settings, and how this varies with salinity, is poorly understood. This study investigated Ni accumulation and physiological mechanisms of sub-lethal Ni toxicity in the euryhaline green crab Carcinus maenas. Male crabs were exposed to 8.2MUg/L (the US EPA chronic criterion concentration for salt waters) of waterborne Ni (radiolabelled with (63)Ni) at three different salinities, 20%, 60% and 100% SW for 24h. Whole body Ni accumulation in 20% SW was 3-5 fold greater than in 60% or 100% SW, and >80% of accumulated Ni was in the carapace at all salinities. Ni also accumulated in posterior gill 8, which showed a higher accumulation in 20% SW than in other salinities, a pattern also seen at higher exposure concentrations of Ni (500 and 3000MUg/L). Gill perfusion experiments revealed that Ni was taken up by both anterior and posterior gills, but in 20% SW the posterior gill 8, which performs ionoregulatory functions, accumulated more Ni than the anterior gill 5, which primarily has a respiratory function. The sub-lethal consequences of Ni exposure were investigated by placing crabs in Ni concentrations of 8.2, 500, and 3000MUg/L at 20, 60 or 100% SW for 24h. In 20% SW, haemolymph Ca levels were significantly decreased by exposure to Ni concentrations of 8.2MUg/L or higher, whereas Na concentrations were depressed only at 3000MUg/L. Na(+)/K(+)-ATPase activity was inhibited at both 500 and 3000MUg/L in gill 8, but only in 20% SW. Haemolymph K, Mg, and osmolality were unaffected throughout, though all varied with salinity in the expected fashion. These data suggest that Ni impacts ionoregulatory function in the green crab, in a gill- and salinity-dependent manner. PMID- 25914094 TI - Structural evolution of Ag-Cu nano-alloys confined between AlN nano-layers upon fast heating. AB - The structural evolution of a Ag-Cu/AlN nano-multilayer (NML), as prepared by magnetron-sputtering on a alpha-Al2O3 substrate, was monitored during fast heating by real-time in situ XRD analysis (at the synchrotron), as well as by ex situ microstructural analysis using SEM, XPS and in-house XRD. The as-deposited NML is constituted of alternating nano-layers (thickness ~ 10 nm) of a chemically inert AlN barrier and a eutectic Ag-Cu(40at%) nano-alloy. The nano-alloy in the as-deposited state is composed of a fcc matrix of Ag nano-grains (~6 nm), which are supersaturated by Cu, and some smaller embedded Cu rich nano-grains (~4 nm). Heating up to 265 degrees C activates segregation of Cu out of the supersaturated Ag nano-grains phase, thus initiating phase separation. At T > 265 degrees C, the phase-separated Cu metal partially migrates to the top NML surface, thereby relaxing thermally-accumulated compressive stresses in the confined alloy nano-layers and facilitating grain coarsening of (still confined) phase-separated nano-crystallites. Further heating and annealing up to 420 degrees C results in complete phase separation, forming extended Ag and Cu domains with well-defined coherent Ag/AlN interfaces. The observed outflow of Cu well below the eutectic melting point of the bulk Ag-Cu alloy might provide new pathways for designing low-temperature nano-structured brazing materials. PMID- 25914093 TI - Dioxin disrupts cranial cartilage and dermal bone development in zebrafish larvae. AB - 2,3,7,8-Tetrachlorodibenzo-p-dioxin (TCDD or dioxin) disrupts craniofacial development in zebrafish larvae. However, the cellular changes responsible for the decreased jaw size remain poorly understood. We show that smaller jaw size is due to a decrease in both the size and number of chondrocytes in the developing craniofacial cartilages. TCDD was found to decrease ossification of osteoblasts in the perichondrium of craniofacial cartilages. We also discovered that TCDD caused clefting of the parasphenoid, an effect with similarity to TCDD-induced cleft palate in mice. Thus, dermal and perichondrial bone development of the craniofacial skeleton are clearly disrupted by TCDD exposure in the zebrafish larvae. This dysmorphic response of the zebrafish craniofacial skeleton after exposure to TCDD is consistent with findings demonstrating disruption of axial bone development in medaka and repression of sox9b in zebrafish. PMID- 25914095 TI - Variability in targeted arterial oxygenation levels in patients with severe sepsis or septic shock. AB - BACKGROUND: Supplemental oxygen therapy is used for intensive care (ICU) patients with severe sepsis, but with no general guidelines and few safety data. The aim of this observational study was to describe the variability in oxygen administration as well as the association between partial pressure of arterial oxygen (PaO2 ) and mortality. METHODS: We extracted data from two Scandinavian clinical trials of ICU patients with severe sepsis or septic shock. We calculated average PaO2 and fraction of inspired oxygen (FiO2 ) from trial inclusion and the following 5 days, and assessed the association between PaO2 and 90-day mortality. RESULTS: The median PaO2 was 9.8 kPa [5-95% range 6.4-19.9] and FiO2 was 0.51 [5 95% range 0.27-1.00], respectively. Eight hundred and five of 1,770 patients (45%) died. The relative risk of mortality was 1.43 [95% CI: 1.19-1.65] in patients with average PaO2 < 8 kPa and 1.29 [95% CI: 0.84-1.68] in patients with average PaO2 >= 16 kPa, as compared to patients with average PaO2 10-12 kPa. The relative risk of mortality was 1.38 [95% CI: 1.17-1.58] in patients with an average FiO2 0.60-0.80 and 2.10 [95% CI: 1.88-2.23] in patients with an average FiO2 >= 0.80 as compared to patients with an average FiO2 <= 0.40. CONCLUSION: Administration of oxygen in patients with severe sepsis resulted in a wide range of PaO2 . Significantly higher mortality was observed in patients with an average PaO2 < 8 kPa and FiO2 >= 0.60. The results do not imply causation and the associations between average PaO2 and adverse outcomes have to be assessed further. PMID- 25914096 TI - Deoxyribonucleic acid methylation profiling of single human blastocysts by methylated CpG-island amplification coupled with CpG-island microarray. AB - OBJECTIVE: To study whether methylated CpG-island (CGI) amplification coupled with microarray (MCAM) can be used to generate DNA (deoxyribonucleic acid) methylation profiles from single human blastocysts. DESIGN: A pilot microarray study with methylated CpG-island amplification applied to human blastocyst genomic DNA and hybridized on CpG-island microarrays. SETTING: University research laboratory. PATIENT(S): Five cryopreserved sibling 2-pronuclear zygotes that were surplus to requirements for clinical treatment by in vitro fertilization were donated with informed consent from a patient attending Bourn Hall Clinic, Cambridge, United Kingdom. INTERVENTION(S): None. MAIN OUTCOME MEASURE(S): Successful generation of genome-wide DNA methylation profiles at CpG islands from individual human blastocysts, with common genomic regions of DNA methylation identified between embryos. RESULT(S): Between 472 and 734 CpG islands were methylated in each blastocyst, with 121 CpG islands being commonly methylated in all 5 blastocysts. A further 159 CGIs were commonly methylated in 4 of the 5 tested blastocysts. Methylation was observed at a number of CGIs within imprinted-gene, differentially methylated regions (DMRs), including placental and preimplantation-specific DMRs. CONCLUSION(S): The MCAM method is capable of providing comprehensive DNA methylation data in individual human blastocysts. PMID- 25914097 TI - Clinical significance of intercellular contact at the four-cell stage of human embryos, and the use of abnormal cleavage patterns to identify embryos with low implantation potential: a time-lapse study. AB - OBJECTIVE: To investigate the clinical significance of intercellular contact point (ICCP) in four-cell stage human embryos and the effectiveness of morphology and abnormal cleavage patterns in identifying embryos with low implantation potential. DESIGN: Retrospective cohort study. SETTING: Private IVF center. PATIENT(S): A total of 223 consecutive IVF and intracytoplasmic sperm injection treatment cycles, with all resulting embryos cultured in the Embryoscope, and a subset of 207 cycles analyzed for ICCP number where good-quality four-cell embryos were available on day 2 (n = 373 IVF and n = 392 intracytoplasmic sperm injection embryos). INTERVENTION(S): None. MAIN OUTCOME MEASURE(S): Morphologic score on day 3, embryo morphokinetic parameters, incidence of abnormal biological events, and known implantation results. RESULT(S): Of 765 good-quality four-cell embryos, 89 (11.6%) failed to achieve six ICCPs; 166 of 765 (21.7%) initially had fewer than six ICCPs but were able to establish six ICCPs before subsequent division. Embryos with fewer than six ICCPs at the end of four-cell stage had a lower implantation rate (5.0% vs. 38.5%), with lower embryology performance in both conventional and morphokinetic assessments, compared with embryos achieving six ICCPs by the end of four-cell stage. Deselecting embryos with poor morphology, direct cleavage, reverse cleavage, and fewer than six ICCPs at the four-cell stage led to a significantly improved implantation rate (33.6% vs. 22.4%). CONCLUSION(S): Embryos with fewer than six ICCPs at the end of the four cell stage show compromised subsequent development and reduced implantation potential. Deselection of embryos with poor morphology and abnormal cleavage revealed via time-lapse imaging could provide the basis of a qualitative algorithm for embryo selection. PMID- 25914098 TI - Informatics to support the IOM social and behavioral domains and measures. AB - Consistent collection and use of social and behavioral determinants of health can improve clinical care, prevention and general health, patient satisfaction, research, and public health. A recent Institute of Medicine committee defined a panel of 11 domains and 12 measures to be included in electronic health records. Incorporating the panel into practice creates a number of informatics research opportunities as well as challenges. The informatics issues revolve around standardization, efficient collection and review, decision support, and support for research. The informatics community can aid the effort by simultaneously optimizing the collection of the selected measures while also partnering with social science researchers to develop and validate new sources of information about social and behavioral determinants of health. PMID- 25914100 TI - Helical inner-wall texture prevents jamming in granular pipe flows. AB - Granular pipe flows are characterized by intermittent behavior and large, potentially destructive solid fraction variations in the transport direction. By means of particle-based numerical simulations of gravity-driven flows in vertical pipes, we show that it is possible to obtain steady material transport by adding a helical texture to the inner-wall of the pipe. The helical texture leads to a more homogeneous mass flux along the pipe, prevents the emergence of large density waves and substantially reduces the probability of plug formation thus avoiding jamming of the particulate flow. We show that the granular mass flux Q through a pipe of diameter D with a helical texture of wavelength lambda follows the equation Q = Q0.{1 - B sin[arctan(2piD/lambda)]}, where Q0 is the flow without helix, predicted from the well-known Beverloo equation. Our new expression yields, thus, a modification of the Beverloo equation with only one additional fit parameter, B, and describes the particle mass flux with the helical texture with excellent quantitative agreement with simulation results. Future application of the method proposed here has the potential to improve granular pipe flows in a broad range of processes without the need for energy input from any external source. PMID- 25914099 TI - Disparities in registration and use of an online patient portal among older adults: findings from the LitCog cohort. AB - OBJECTIVE: To document disparities in registration and use of an online patient portal among older adults. MATERIALS AND METHODS: Data from 534 older adults were linked with information from the Northwestern Medicine Electronic Data Warehouse on patient portal registration and use of functions (secure messaging, prescription reauthorizations, checking test results, and monitoring vital statistics). Age, gender, race, education, self-reported chronic conditions, and the Newest Vital Sign health literacy measure were available from cohort data. RESULTS: Most patients (93.4%) had a patient portal access code generated for them, and among these 57.5% registered their accounts. In multivariable analyses, White patients (P < .001) and college graduates were more likely to have registered their patient portal (P = .015). Patients with marginal (P = .034) or adequate (P < .001) health literacy were also more likely to have registered their patient portal. Among those registering their accounts, most had messaged their physician (90%), checked a test result (96%), and ordered a reauthorization (55%), but few monitored their vital statistics (11%). Adequate health literacy patients were more likely to have used the messaging function (P = .003) and White patients were more likely to have accessed test results (P = .004). Higher education was consistently associated with prescription reauthorization requests (all P < .05). DISCUSSION: Among older American adults, there are stark health literacy, educational, and racial disparities in the registration, and subsequent use of an online patient portal. These population sub-group differences may exacerbate existing health disparities. CONCLUSIONS: If patient portals are implemented, intervention strategies are needed to monitor and reduce disparities in their use. PMID- 25914101 TI - Childhood fever: a qualitative study on GPs' experiences during out-of-hours care. AB - BACKGROUND: Fever in children is common and mostly caused by self-limiting infections. However, parents of febrile children often consult in general practice, in particular during out-of-hours care. To improve management, it is important to understand experiences of GPs managing these consultations. OBJECTIVE: To describe GPs' experiences regarding management of childhood fever during out-of-hours care. METHODS: A descriptive qualitative study using purposeful sampling, five focus group discussions were held among 37 GPs. Analysis was based on constant comparative technique using open and axial coding. RESULTS: Main categories were: (i) Workload and general experience; (ii) GPs' perceptions of determinants of consulting behaviour; (iii) Parents' expectations from the GP's point of view; (iv) Antibiotic prescribing decisions; (v) Uncertainty of GPs versus uncertainty of parents and (vi) Information exchange during the consultation. GPs felt management of childhood fever imposes a considerable workload. They perceived a mismatch between parental concerns and their own impression of illness severity, which combined with time-pressure can lead to frustration. Diagnostic uncertainty is driven by low incidences of serious infections and dealing with parental demand for antibiotics is still challenging. CONCLUSION: Children with a fever account for a high workload during out-of-hours GP care which provides a diagnostic challenge due to the low incidence of serious illnesses and lacking long-term relationship. This can lead to frustration and drives antibiotics prescription rates. Improving information exchange during consultations and in the general public to young parents, could help provide a safety net thereby enhancing self-management, reducing consultations and workload, and subsequent antibiotic prescriptions. PMID- 25914102 TI - In vitro functional properties of crude extracts and isolated compounds from banana pseudostem and rhizome. AB - BACKGROUND: Pseudostem and rhizome are the significant bio-waste generated (43.48%) from the banana plant post fruit harvest, which are usually left in the plantation or incinerated and wasted. Amounts used in production for consumption are negligible. However, the material has an important part to play in indigenous systems of medicine. Based on the huge volume of bio-waste generated and its traditional medicinal use, it is worth exploiting it as a source of natural bioactive compounds. In the current study, sequential extracts from banana pseudostem (BPS) and rhizome (BR), and isolated compounds including chlorogenic acid, 4-epicyclomusalenone and cycloeucalenol acetate, were tested for their antimicrobial activity, antiplatelet aggregation and cytotoxicity. RESULTS: Isolated compounds and crude extracts exhibited strong antimicrobial activity against a wide range of bacterial and fungal strains, platelet aggregation induced by collagen and cytotoxicity towards human liver cancer (HepG2) cells. CONCLUSION: Banana plant bio-waste, pseudostem and rhizome may serve as a potential source of multifunctional bioactive compounds and functional ingredient in food and other allied industries. PMID- 25914103 TI - Ovarian response is a better predictor of clinical pregnancy rate following embryo transfer than is thin endometrium or presence of an endometrioma. AB - OBJECTIVES: To examine whether endometrial thickness and the presence of endometrioma are independent predictors of clinical pregnancy rate or simply associated with poor ovarian response (POR). METHODS: This was a retrospective cohort study assessing the first cycle of all women undergoing in-vitro fertilization (IVF) or intracytoplasmic sperm injection (ICSI) in a university hospital in Brazil between January 2011 and December 2012. Only the first cycle of each woman within the study period was considered. Women over 40 years of age and those who used clomiphene citrate during controlled ovarian stimulation (COS) or did not undergo embryo transfer were excluded from analysis. POR was defined as <= three oocytes retrieved and a thin endometrium was defined as endometrial thickness <= 7.0 mm on the day of human chorionic gonadotropin (hCG) administration. We performed a multiple regression analysis to identify which of the following parameters were independent predictors of clinical pregnancy: age, number of oocytes retrieved, endometrial thickness or the presence of endometrioma. RESULTS: Within the study period, 787 women began COS, but 270 were excluded from analysis. Among the 517 women analyzed, those who achieved pregnancy were younger and yielded more oocytes. The proportion of POR was higher in women with a thin endometrium (17/57 (29.8%) vs 80/460 (17.4%); P = 0.03) and in women with endometrioma (15/39 (38.5%) vs 82/478 (17.2%); P = 0.002). The results of regression analysis showed that only age and the number of oocytes retrieved were independent predictors of pregnancy. Additionally, we observed higher clinical pregnancy rates in women with a thin endometrium from whom >= seven oocytes were retrieved (11/25 (44.0%)) compared to women with normal endometrial thickness (99/241 (41.1%)). Considering only women from whom >= four oocytes were retrieved, we observed reasonable pregnancy rates in those with a thin endometrium (14/40 (35.0%)) and in those with endometrioma (9/24 (37.5%)). CONCLUSION: Both a thin endometrium and the presence of endometrioma are associated with POR but are not important independent predictors of clinical pregnancy. Good pregnancy rates can be observed when these conditions are present in women with a good ovarian response. PMID- 25914104 TI - Electrothermal cautery artifact in a urine cytology specimen. PMID- 25914105 TI - Transcobalamin II Deficiency in Four Cases with Novel Mutations. AB - OBJECTIVE: Transcobalamin II deficiency is one of the rare causes of inherited vitamin B12 disorders in which the patients have characteristically normal or high vitamin B12 levels related to the transport defect of vitamin B12 into the cell, ending up with intracellular cobalamin depletion and high homocysteine and methylmalonic acid levels. MATERIALS AND METHODS: Herein, we describe the findings at presentation of four patients who were diagnosed to have transcobalamin II deficiency with novel mutations. RESULTS: These patients with transcobalamin II deficiency were found to have novel mutations, of whom 2 had the same large deletion (homozygous c.1106+1516-1222+1231del). CONCLUSION: Transcobalamin II deficiency should be considered in differential diagnosis of any infant with pancytopenia, failure to thrive, diarrhea, and vomiting. PMID- 25914106 TI - UPLC-PDA quantification of chemical constituents of two different varieties (golden and royal) of apple leaves and their antioxidant activity. AB - BACKGROUND: Malus domestica is the most widely cultivated fruit tree and is well known for its therapeutic value. Apple leaves are known to contain phenolic compounds but the nature of these has not been explored to the same extent as in apple fruit. A simple, rapid and sensitive ultra-performance liquid chromatography-diode array detection (UPLC-DAD) quantification method has been developed. Total polyphenol and flavonoid contents, as well as the antioxidant activity of golden and royal apple leaves were evaluated. RESULTS: Four compounds, namely rutin, 3-hydroxyphloridzin, phloridzin and quercetin-3-O arabinoside were identified by UPLC. The separation was achieved in less than 7 min. Total polyphenol and flavonoid contents were found to be slightly higher in apple golden variety than royal variety. The IC50 values determined by the DPPH assay were 49.94 ug mL(-1) for golden apple leaves and 43.89 ug mL(-1) for royal apple leaves. IC50 values determined by the ABTS assay were 47.10 and 66.53 ug mL(-1) for golden and royal apple leaves, respectively. Antioxidant activity was determined as 24.45 and 21.15 mg ascorbic acid g(-1) for golden and royal apple leaves, respectively, by using the FRAP assay. CONCLUSION: This study showed that apple leaves (both varieties) contain considerable amounts of polyphenols and flavonoids and are also a promising source of phloridzin. PMID- 25914107 TI - Sex hormones and oxytocin augmentation strategies in schizophrenia: A quantitative review. AB - INTRODUCTION: Sex differences in incidence, onset and course of schizophrenia suggest sex hormones play a protective role in the pathophysiology. Such a role is also proposed for oxytocin, another important regulator of reproduction function. Evidence on the efficacy of sex hormones and oxytocin in the treatment of schizophrenia is summarized. METHODS: Double-blind, placebo-controlled, randomized studies were included, examining augmentation with estrogens, selective estrogen receptor modulators (SERMs), testosterone, dehydroepiandrosterone (DHEA), pregnenolone, and oxytocin. Outcome measures were total symptom severity, positive and negative symptom subscores, and cognition. In meta-analyses, combined weighted effect sizes (Hedges' g) per hormone were calculated. RESULTS: Twenty-four studies were included, examining 1149 patients. Significant effects were found for estrogen action (k=10), regarding total symptoms (Hedges' g=0.63, p=0.001), positive (Hedges' g=0.42, p<0.001), and negative symptoms (Hedges' g=0.35, p=0.001). Subgroup analyses yielded significant results for estrogens in premenopausal women (k=6) for total, positive, and negative symptoms, and for the SERM raloxifene in postmenopausal women (k=3) for total and negative, but not positive symptoms. Testosterone augmentation in males (k=1) was beneficial only for negative symptoms (Hedges' g=0.82, p=0.027). No overall effects were found for DHEA (k=4), pregnenolone (k=4), and oxytocin (k=6). Results for cognition (k=12) were too diverse for meta analyses, and inspection of these data showed no consistent benefit. CONCLUSIONS: Estrogens and SERMs could be effective augmentation strategies in the treatment of women with schizophrenia, although potential side effects, partially associated with longer duration use, should be taken into account. Future trials are needed to study long-term effects and effects on cognition. PMID- 25914108 TI - Interest of clozapine and paliperidone palmitate plasma concentrations to monitor treatment in schizophrenic patients on chronic hemodialysis. PMID- 25914109 TI - Effects of antibodies to phosphorylated and non-phosphorylated tau on in vitro tau phosphorylation at Serine-199: Preliminary report. AB - Phosphorylation of multiple amino acids on tau protein ("hyperphosphorylation") is required for the development of tau pathology in Alzheimer's disease. Administration of anti-tau antibodies to transgenic "tauopathy mice" has been shown to reduce their tau pathology but the mechanisms responsible are unclear. To examine the effects of anti-tau antibodies on tau phosphorylation, we used western blots to study the effects of three antibodies to phosphorylated tau (pTau), namely anti-pTau S199, T231, and S396, and three antibodies to non phosphorylated tau on in vitro phosphorylation of recombinant human tau-441 at S199. Inclusion of an anti-pTau T231 antibody in the phosphorylation reaction reduced the intensity of monomeric pTau S199 in western blots of denaturing gels, but the other antibodies had no apparent effects on this process. Surprisingly, including all three anti-phospho-tau antibodies in the reaction did not reduce the intensity of the monomer band, possibly due to steric hindrance between the antibodies. CONCLUSIONS: These preliminary findings suggest that anti-tau antibodies may have minimal direct effects on tau phosphorylation. Limitations of using western blots to examine the effects of anti-tau antibodies on this process were found to include between-experiment variability in pTau band densities and poor resolution of high molecular weight pTau oligomers. The presence of bands representing immunoglobulins as well as pTau may also complicate interpretation of the western blots. Further studies are indicated to examine the effects of anti-pTau antibodies on phosphorylation of other tau amino acids in addition to S199. PMID- 25914110 TI - Differences in ischemic damage between young and old hearts--Effects of blood cardioplegia. AB - OBJECTIVE: Senescent patients exhibit an elevated perioperative risk for cardiac dysfunction, hemodynamic depression and subsequent cardiac death compared to young patients. Despite the fact that a growing proportion of cardiac surgery patients are octogenarians, cardioplegic regimes remain comparable across patients of all ages. We compared the hemodynamic performance, metabolic parameters and ultrastructural changes in adult and senescent rat hearts after application of Buckberg's blood cardioplegia (BCP) to evaluate differences between the age groups regarding postischemic myocardial function and cellular ultrastructure. METHODS: Hearts of adult (young adult group, 3-4 months) and senescent (old group, 24 months) male Wistar rats were excised and inserted into a blood perfused isolated heart apparatus (Langendorff perfusion). After a stabilization period of 30 min, in 16 adult and 16 senescent hearts, Buckberg BCP was administered antegradely and repeated every 20 min. Six young adult and 3 senescent hearts served as ischemia control. After an aortic clamping time of 90 min an antegrade hot shot was administered. During reperfusion ex vivo cardiac functional parameters were recorded, including coronary blood flow, left ventricular developed pressure (LVDP) and velocity of myocardial contraction or relaxation (+/-dp/dt). Oxygen consumption and lactate production of the hearts were calculated. After perfusion fixation, the hearts of five rats in each BCP group and 3 rats in each ischemia group were investigated for cellular edema and mitochondrial damage by morphometry using transmission electron microscopy. RESULTS: While recovery of cardiac function after 90 min of unprotected ischemia was significantly impaired in senescent hearts, functional recovery after ischemia protected by BCP was similar in adult and senescent hearts. Mitochondrial ultrastructure was severely damaged in both age groups after 90 min ischemia, but well preserved in both BCP groups. The qualitative analysis was confirmed by the morphometric cellular edema index and the volume-to-surface ratio of the mitochondria. Myocardial oxygen consumption was highest and lactate production was lowest in senescent hearts. CONCLUSION: Senescent rat hearts were more susceptible to unprotected ischemia/reperfusion injury than young adult hearts. When protected by BCP, we found no difference in hemodynamic performance between adult and senescent hearts indicating preserved myocardial protection even in senescent individuals. PMID- 25914111 TI - Can inflammation regulate systemic aging? PMID- 25914112 TI - Social development of children born very preterm: a systematic review. AB - AIM: To review systematically studies examining the development of social competence in children born very preterm (VPT) (gestation <33 wks) and identify neonatal and family predictors. METHOD: Peer-reviewed original articles were extracted from PubMed and PsycINFO following Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines. Selection criteria included children born VPT and comparison children born at term, sample born after 1990, and children assessed between 0 and 17 years on at least one measure of social competence spanning social adjustment, performance, and/or social skills. RESULTS: Twenty-three studies were included. Seven focused on social competence and another 16 examined social competence within a range of outcomes. Study quality was low. Limitations included reliance on single informant data, cross-sectional measurement, use of brief screening tools, absence of child or peer report, and no conceptual model. In terms of social adjustment, 16 out of 21 studies found children born VPT had more peer problems and social withdrawal. Findings of social performance were mixed, with some studies suggesting differences in prosocial behavior (4/14) and others not. Social skills were assessed in four studies and showed children born VPT had poorer skills than children born at term. Predictors of social competence included gestational age, neonatal brain abnormalities, and family socio-economic status. INTERPRETATION: Children born VPT have poorer social competence. These difficulties emerge early and persist throughout childhood. PMID- 25914113 TI - Toward an Understanding of Diamond sp(2)-Defects with Unsaturated Diamondoid Oligomer Models. AB - Nanometer-sized doubly bonded diamondoid dimers and trimers, which may be viewed as models of diamond with surface sp(2)-defects, were prepared from corresponding ketones via a McMurry coupling and were characterized by spectroscopic and crystallographic methods. The neutral hydrocarbons and their radical cations were studied utilizing density functional theory (DFT) and ab initio (MP2) methods, which reproduce the experimental geometries and ionization potentials well. The van der Waals complexes of the oligomers with their radical cations that are models for the self-assembly of diamondoids, form highly delocalized and symmetric electron-deficient structures. This implies a rather high degree of sigma-delocalization within the hydrocarbons, not too dissimilar to delocalized pi-systems. As a consequence, sp(2)-defects are thus also expected to be nonlocal, thereby leading to the observed high surface charge mobilities of diamond-like materials. In order to be able to use the diamondoid oligomers for subsequent surface attachment and modification, their C-H-bond functionalizations were studied, and these provided halogen and hydroxy derivatives with conservation of unsaturation. PMID- 25914114 TI - Keeping bugs in check: The mucus layer as a critical component in maintaining intestinal homeostasis. AB - In the mammalian gastrointestinal tract the close vicinity of abundant immune effector cells and trillions of commensal microbes requires sophisticated barrier and regulatory mechanisms to maintain vital host-microbial interactions and tissue homeostasis. During co-evolution of the host and its intestinal microbiota a protective multilayered barrier system was established to segregate the luminal microbes from the intestinal mucosa with its potent immune effector cells, limit bacterial translocation into host tissues to prevent tissue damage, while ensuring the vital functions of the intestinal mucosa and the luminal gut microbiota. In the present review we will focus on the different layers of protection in the intestinal tract that allow the successful mutualism between the microbiota and the potent effector cells of the intestinal innate and adaptive immune system. In particular, we will review some of the recent findings on the vital functions of the mucus layer and its site-specific adaptations to the changing quantities and complexities of the microbiota along the (gastro-) intestinal tract. Understanding the regulatory pathways that control the establishment of the mucus layer, but also its degradation during intestinal inflammation may be critical for designing novel strategies aimed at maintaining local tissue homeostasis and supporting remission from relapsing intestinal inflammation in patients with inflammatory bowel diseases. PMID- 25914115 TI - Proteomics analysis of digestive juice from silkworm during Bombyx mori nucleopolyhedrovirus infection. AB - Previous studies have analyzed the midgut transcriptome and proteome after challenge with Bombyx mori nucleopolyhedrovirus (BmNPV), however little information is available on the digestive juice proteome after BmNPV challenge. This study investigated BmNPV infection-induced protein changes in the digestive juice of silkworms using shotgun proteomics and MS sequencing. From the digestive juice of normal third-day, fifth-instar silkworm larvae, 75 proteins were identified, 44 of which were unknown; from larvae 6 h after inoculation with BmNPV, 106 proteins were identified, of which 39 were unknown. After BmNPV challenge, more secreted proteins appeared that had antiviral and digestive features. GO annotation analysis clustered most proteins in the lumen into catalytic, binding, and metabolic processes. Numerous proteins were reported to have BmNPV interactions. Hsp70 protein cognate, lipase-1, and chlorophyllide A binding protein precursor were upregulated significantly after BmNPV challenge. Levels of trypsin-like serine protease, beta-1,3-glucanase, catalase, and serine protease transcripts decreased or were not significantly change after BmNPV challenge. Taken together, these findings provided insights into the interaction between host and BmNPV and revealed potential functions of digestive juice after per os BmNPV infection. PMID- 25914117 TI - Enhanced Field Emission from a Carbon Nanotube Array Coated with a Hexagonal Boron Nitride Thin Film. AB - A high-quality field emission electron source made of a highly ordered array of carbon nanotubes (CNTs) coated with a thin film of hexagonal boron nitride (h-BN) is fabricated using a simple and scalable method. This method offers the benefit of reproducibility, as well as the simplicity, safety, and low cost inherent in using B(2)O(3) as the boron precursor. Results measured using h-BN-coated CNT arrays are compared with uncoated control arrays. The optimal thickness of the h BN film is found to be 3 nm. As a result of the incorporation of h-BN, the turn on field is found to decrease from 4.11 to 1.36 V MUm(-1), which can be explained by the significantly lower emission barrier that is achieved due to the negative electron affinity of h-BN. Meanwhile, the total emission current is observed to increase from 1.6 to 3.7 mA, due to a mechanism that limits the self-current of any individual emitting tip. This phenomenon also leads to improved emission stability and uniformity. In addition, the lifetime of the arrays is improved as well. The h-BN-coated CNT array-based field emitters proposed in this work may open new paths for the development of future high-performance vacuum electronic devices. PMID- 25914116 TI - Nanoparticles that deliver triplex-forming peptide nucleic acid molecules correct F508del CFTR in airway epithelium. AB - Cystic fibrosis (CF) is a lethal genetic disorder most commonly caused by the F508del mutation in the cystic fibrosis transmembrane conductance regulator (CFTR) gene. It is not readily amenable to gene therapy because of its systemic nature and challenges including in vivo gene delivery and transient gene expression. Here we use triplex-forming peptide nucleic acids and donor DNA in biodegradable polymer nanoparticles to correct F508del. We confirm modification with sequencing and a functional chloride efflux assay. In vitro correction of chloride efflux occurs in up to 25% of human cells. Deep-sequencing reveals negligible off-target effects in partially homologous sites. Intranasal delivery of nanoparticles in CF mice produces changes in the nasal epithelium potential difference assay, consistent with corrected CFTR function. Also, gene correction is detected in the nasal and lung tissue. This work represents facile genome engineering in vivo with oligonucleotides using a nanoparticle system to achieve clinically relevant levels of gene editing without off-target effects. PMID- 25914118 TI - Successful coil embolization for Fontan-rout to aorta communication-recovery from complication of Brockenbrough procedure in Fontan patient. AB - The Brockenbrough (BB) procedure is becoming the necessary procedure for radiofrequency ablation for supravalvular tachycardia in patients after a Fontan procedure. We experience Fontan-rout to aorta communication caused by the BB procedure. The communication was successfully occluded using a detachable coil. This complication was rare but could still happen as an increasing necessity of the catheter ablation in patients with a Fontan procedure. Coil embolization is a potential option for recovery from this complication. PMID- 25914119 TI - Effects of smartphone overuse on hand function, pinch strength, and the median nerve. AB - INTRODUCTION: In this study we investigated the flexor pollicis longus (FPL) tendon and median nerve in smartphone users by ultrasonography to assess the effects of smartphone addiction on the clinical and functional status of the hands. METHODS: One hundred two students were divided into 3 groups: non-users, and high or low smartphone users. Smartphone Addiction Scale (SAS) scores and grip and pinch strengths were recorded. Pain in thumb movement and rest and hand function were evaluated on the visual analog scale (VAS) and the Duruoz Hand Index (DHI), respectively. The cross-sectional areas (CSAs) of the median nerve and the FPL tendon were calculated bilaterally using ultrasonography. RESULTS: Significantly higher median nerve CSAs were observed in the dominant hands of the high smartphone users than in the non-dominant hands (P<0.001). SAS scores correlated with VAS pain for movement and rest, DHI scores, and pinch strength (P<0.05; r=0.345, 0.272, 0.245, and 0.281, respectively). CONCLUSIONS: Smartphone overuse enlarges the median nerve, causes pain in the thumb, and decreases pinch strength and hand functions. PMID- 25914120 TI - PP2A (PR65) in Silver Carp: cDNA Cloning and Expression Analysis. AB - The full-length sequence of the protein phosphatase 2A subunit A (PP2A-A) cDNA from silver carp was cloned and sequenced. Additionally, the transcription of PP2A-A in the liver, kidney, and spleen of fish after microcystin (MC)-exposure were also determined in this study. The results reveal that PP2A-A cDNA is 2833 base pair (bp) long and contains an open reading frame of 1767 bp encoding a protein of 589 amino acids. Sequence analysis demonstrates that PP2A is highly conserved in fish. Furthermore, the results of quantitative real-time PCR indicate that PP2A-A is constitutively expressed in all examined silver carp tissues and primarily in the brain and liver. Additionally, we found that 50 or 200 MUg/kg of crude MC exposure significantly downregulated PP2A-A transcription in fish liver, kidney, and spleen, suggesting that PP2A-A may be involved in MC toxicity in silver carp. PMID- 25914121 TI - Centrifugal frontal sinus dissection technique: addressing anterior and posterior frontoethmoidal air cells. PMID- 25914122 TI - Conformational stability of PCID2 upon DSS1 binding with molecular dynamics simulation. AB - DSS1 is a small acidic intrinsically disordered protein (IDP) that can fold upon binding with PCID2 TREX-2. The resulting complex plays a key role in mRNA export. However, the binding mechanism between DSS1 and PCID2 is unsolved. Here, three independent 500-ns molecular dynamics (MD) simulations were performed to study the DSS1-PCID2 binding mechanism by comparing apo-PCID2 and bound PCID2. The results show that the conformational variation of bound PCID2 is smaller than that of apo-PCID2, especially in the binding domain of two helices (helix IV and VIII). The probability of coil formation between helix III and helix IV of bound PCID2 increases, and a short anti-parallel beta-sheet forms upon DSS1 binding. The decomposition of binding free energy into protein and residue pairs suggests that electrostatic and hydrophobic interactions play key roles in the recognition between DSS1 and PCID2. There is a hydrophobic core of seven residues in DSS1 favorable to the binding of PCID2. These analytical methods can be used to reveal the recognition mechanisms of other IDPs and their partners. PMID- 25914123 TI - Development of a coarse-grained alpha-chitin model on the basis of MARTINI forcefield. AB - At nanoscale, atomistic simulation is widely used for investigating crystalline chitin fibers, the structural component for many biological materials. However, the longitudinal dimension of naturally occurring chitin fibers exceeds hundreds of nanometer, beyond the investigation range of all-atom simulation due to the limitation of computational power. Under this context, coarse-grained simulation is a useful alternative that facilitates the investigation of a large system. We develop a coarse-grained model for describing the structural and mechanical properties of alpha-chitin. The developed coarse-grained model can reasonably predict these properties. Moreover, this model is consistent with existing coarse grained force fields for proteins. The present model of alpha-chitin possesses good potential and applicability in the investigation of natural chitin-based materials at the length scale of several hundred nanometers. PMID- 25914124 TI - Aminobisphenolate supported tungsten disulphido and dithiolene complexes. AB - Dioxotungsten(vi) complexes with tetradentate amino bisphenolates were converted into the corresponding Cs-symmetric amino bisphenolate disulphido complexes by a reaction with either Lawesson's reagent or P2S5. Further reaction with diethyl acetylenedicarboxylate leads to the formation of diamagnetic tungsten(iv) dithiolene compounds. The syntheses, crystal structures, spectroscopic and electrochemical characterization of such disulphido and dithiolene complexes are presented. PMID- 25914125 TI - Reply: To PMID 25605615. PMID- 25914126 TI - The inflammasome: Learning from bacterial evasion strategies. AB - The innate immune system plays a critical role in defense against microbial infection and employs germline-encoded pattern recognition receptors to detect broadly conserved microbial structures or activities. Pattern recognition receptors of the nucleotide binding domain/leucine rich repeat (NLR) family respond to particular microbial products or disruption of cellular physiology, and mediate the activation of an arm of the innate immune response termed the inflammasome. Inflammasomes are multiprotein complexes that are inducibly assembled in response to the contamination of the host cell cytosol by microbial products. Individual NLRs sense the presence of their cognate stimuli, and initiate assembly of inflammasomes via the adaptor protein apoptosis-associated speck-like protein containing a caspase recruitment domain (ASC) and the effector pro-enzyme caspase-1. Inflammasome activation leads to rapid release of pro inflammatory mediators of the IL-1 family as well as the release of intracellular alarmins due to a lytic form of programmed cell death termed pyroptosis. Over the past 15 years, a great deal has been learned about the mechanisms that drive inflammasome activation in response to infection by diverse pathogens. However, pathogens have also evolved mechanisms to evade or suppress host defenses, and the mechanisms by which pathogens evade inflammasome activation are not well understood. Here, we will discuss emerging evidence on how diverse pathogens evade inflammasome activation, and what these studies have revealed about inflammasome biology. Deeper understanding of pathogen evasion of inflammasome activation has the potential to lead to development of novel classes of immunomodulatory factors that could be used in the context of human inflammatory diseases. PMID- 25914128 TI - Central muscarinic cholinergic involvement in serial pattern learning: Atropine impairs acquisition and retention in a serial multiple choice (SMC) task in rats. AB - Atropine sulfate is a muscarinic cholinergic antagonist which impairs acquisition and retention performance on a variety of cognitive tasks. The present study examined the effects of atropine on acquisition and retention of a highly structured serial pattern in a serial multiple choice (SMC) task. Rats were given daily intraperitoneal injections of either saline or atropine sulfate (50mg/kg) and trained in an octagonal operant chamber equipped with a lever on each wall. They learned to press the levers in a particular order (the serial pattern) for brain-stimulation reward in a discrete-trial procedure with correction. The two groups learned a pattern composed of eight 3-element chunks ending with a violation element: 123-234-345-456-567-678-781-818 where the digits represent the clock-wise positions of levers in the chamber, dashes indicate 3-s pauses, and other intertrial intervals were 1s. Central muscarinic cholinergic blockade by atropine caused profound impairments during acquisition, specifically in the encoding of chunk-boundary elements (the first element of chunks) and the violation element of the pattern, but had a significant but negligible effect on the encoding of within-chunk elements relative to saline-injected rats. These effects persisted when atropine was removed, and similar impairments were also observed in retention performance. The results indicate that intact central muscarinic cholinergic systems are necessary for learning and producing appropriate responses at places in sequences where pattern structure changes. The results also provide further evidence that multiple cognitive systems are recruited to learn and perform within-chunk, chunk-boundary, and violation elements of a serial pattern. PMID- 25914127 TI - Astrocytic glutamate uptake is slow and does not limit neuronal NMDA receptor activation in the neonatal neocortex. AB - Glutamate uptake by astrocytes controls the time course of glutamate in the extracellular space and affects neurotransmission, synaptogenesis, and circuit development. Astrocytic glutamate uptake has been shown to undergo post-natal maturation in the hippocampus, but has been largely unexplored in other brain regions. Notably, glutamate uptake has never been examined in the developing neocortex. In these studies, we investigated the development of astrocytic glutamate transport, intrinsic membrane properties, and control of neuronal NMDA receptor activation in the developing neocortex. Using astrocytic and neuronal electrophysiology, immunofluorescence, and Western blot analysis we show that: (1) glutamate uptake in the neonatal neocortex is slow relative to neonatal hippocampus; (2) astrocytes in the neonatal neocortex undergo a significant maturation of intrinsic membrane properties; (3) slow glutamate uptake is accompanied by lower expression of both GLT-1 and GLAST; (4) glutamate uptake is less dependent on GLT-1 in neonatal neocortex than in neonatal hippocampus; and (5) the slow glutamate uptake we report in the neonatal neocortex corresponds to minimal astrocytic control of neuronal NMDA receptor activation. Taken together, our results clearly show fundamental differences between astrocytic maturation in the developing neocortex and hippocampus, and corresponding changes in how astrocytes control glutamate signaling. PMID- 25914129 TI - Unprecedented Mechanism Employed by the Salmonella enterica EutT ATP:Co(I)rrinoid Adenosyltransferase Precludes Adenosylation of Incomplete Co(II)rrinoids. AB - Three distinct families of ATP:corrinoid adenosyltransferases (ACATs) exist that are capable of converting vitamin B12 derivatives into coenzyme B12 by catalyzing the thermodynamically challenging reduction of Co(II) rrinoids to form "supernucleophilic" Co(I) intermediates. While the structures and mechanisms of two of the ACAT families have been studied extensively, little is known about the EutT enzymes beyond the fact that they exhibit a unique requirement for a divalent metal cofactor for enzymatic activity. In this study we have obtained compelling evidence that EutT converts cob(II)alamin into an effectively four coordinate Co(II) species so as to facilitate Co(II)->Co(I) reduction. Intriguingly, EutT fails to promote axial ligand dissociation from the substrate analogue cob(II)inamide, a natural precursor of cob(II)alamin. This unique substrate specificity of EutT has important physiological implications. PMID- 25914131 TI - Re: "The need to resume chest compressions immediately after defibrillation attempts: An analysis of post-shock rhythms and duration of pulselessness following out-of-hospital cardiac arrest". PMID- 25914130 TI - Phenotypic modifications of patients with full chromosome aneuploidies and concurrent suspected or confirmed second diagnoses. AB - The coexistence of two or more distinct genetic conditions is known to be a rare phenomenon. Full chromosome aneuploidies can be associated with a broad variety of cytogenetic abnormalities or single gene disorders resulting in phenotypic modifications that confuse the diagnostic process. We present six patients with primary aneuploidies and a suspected or confirmed secondary genetic diagnosis or unusual birth defect. Among the cases included, we report the first patients with concurrent Down syndrome in combination with Prader-Willi, Craniofacial Microsomia, and Stickler syndromes. We also describe only the second reported case of a neonate with Down syndrome and Marfan syndrome. In all cases, the unusual clinical presentations lead to further molecular cytogenetic studies as well as single or multi-gene molecular evaluations. We make emphasis on the importance of entertaining the possibility of coexistent diagnoses when the phenotype is not what is expected for aneuploidies rather than attributing the unusual findings to rare or unreported associations of the primary aneuploidy. PMID- 25914132 TI - The Palatal Approach to Distraction Osteogenesis of the Anterior Maxillary Alveolus. AB - PURPOSE: This report describes the palatal approach to gain access for osteodistraction of the anterior maxilla to improve the vector of force during distraction. PATIENT AND METHODS: This case report illustrates a novel approach to anterior maxillary osteodistraction. The palatal approach allows the maxillary segment to be moved anteriorly and inferiorly. This is in contrast to the buccal approach, in which the palatal tissue creates a vector of force toward the palate. The vascular pedicle for the transport segment is the labial mucosa and musculature. RESULTS: In the present case, the alveolar segment was advanced 3.6 mm anteriorly and 12.2 mm inferiorly as measured by pre- and postoperative computed tomograms. This patient with a large vertical alveolar defect and high smile line had successful restoration with dental implants. The result has been stable for 14 months. CONCLUSION: In this case, the palatal approach to the anterior maxillary osteotomy was shown to be an effective method of reconstructing a large vertical anterior defect. PMID- 25914133 TI - Inferior Alveolar Nerve Injury in Trauma-Induced Mandible Fractures. AB - PURPOSE: This prospective observational cohort study sought to determine the prevalence of inferior alveolar nerve (IAN) injury after mandibular fractures before and after treatment and to elucidate factors associated with the incidence of post-treatment IAN injury and time to normalization of sensation. MATERIALS AND METHODS: Consenting patients with mandibular fractures (excluding dentoalveolar, pathologic, previous fractures, or mandibular surgery) were prospectively evaluated for subjective neurosensory disturbance (NSD) and underwent neurosensory testing before treatment and then 1 week, 1.5, 3, 6, and 12 months after treatment. RESULTS: Eighty patients (men, 83.8%; mean age, 30.0 yr; standard deviation, 12.6 yr) with 123 mandibular sides (43 bilateral) were studied. Injury etiology included assault (33.8%), falls (31.3%), motor vehicle accidents (25.0%), and sports injuries (6.3%). Half the fractures (49.6%) involved the IAN-bearing posterior mandible; all condylar fractures (13.0%) had no NSD. Treatment included open reduction and internal fixation (ORIF; 74.8%), closed reduction and fixation (22.0%), or no treatment (3.3%). Overall prevalence of IAN injury was 33.7% (95% confidence interval [CI], 24.8-42.6) before treatment and 53.8% (95% CI, 46.0-61.6) after treatment. In the IAN-bearing mandible, the prevalence was 56.2% (95% CI, 43.2-69.2) before treatment and 72.9% (95% CI, 63.0-82.7) after treatment. In contrast, this prevalence in the non-IAN bearing mandible was 12.6% (95% CI, 4.1-21.1) before treatment and 31.6% (95% CI, 20.0-43.3) after treatment. Factors associated with the development of post treatment IAN injury included fracture site and gap distance (a 1-mm increase was associated with a 27% increase in odds of post-treatment sensory alteration). Time to normalization after treatment was associated with type of treatment (ORIF inhibited normalization) and fracture site (IAN-bearing sites took longer to normalize). CONCLUSION: IAN injury was 4 times more likely in IAN-bearing posterior mandibular fractures (56.2%) than in non-IAN-bearing anterior mandibular fractures (12.6%). After treatment, IAN injury prevalence (in 12 months) was higher (72.9% in posterior mandible, 31.6% in anterior mandible). PMID- 25914134 TI - What Are the Types and Frequencies of Complications Associated With Mandibular Third Molar Coronectomy? A Follow-Up Study. AB - PURPOSE: Coronectomy has been proposed for impacted third molars in close proximity to the inferior alveolar nerve (IAN) to avoid neurologic injury. Immediate (up to 1 month) and late (2 to 36 months) postoperative complications were investigated. MATERIALS AND METHODS: A prospective cohort study was performed on healthy patients treated in the dental clinic of the Department of Oral Surgery, University of Bologna. The predictor variables examined were experience of the surgeon (<10 vs >=10 yr), length of surgery, type of mandibular third molar inclusion, and patient age. To assess the rate of postoperative complications, outcome variables were neurologic injuries, postoperative pain, swelling, fever, alveolitis, pulpitis, and root exposure. The success rate and need for a second surgery also were investigated. Univariate and bivariate descriptive statistics, Kaplan-Meier analysis, and Cox hazards modeling were performed to evaluate the variables. RESULTS: The study involved 94 healthy patients (mean age, 28.99 +/- 8.9 yr; range, 17 to 56 yr; 37 men and 57 women) who had 116 third mandibular molars treated with coronectomy. During the 3-year follow-up period, 28 patients (29 coronectomy procedures) dropped out of the study. There was no case of neurologic injury to the inferior alveolar nerve (IAN) or to the lingual nerve (LN). In total, 30 complications were observed (25 within 1 month; 5 at 2 to 12 months). Surgeons with less than 10 years of training exposed patients to a greater risk of complications (hazard ratio = 2.069; 95% confidence interval, 1.004-4.263). An overall success rate of 74% at 6 months was estimated, and a second surgery was needed in 6% of cases. Of the retained roots analyzed, 80% showed postoperative root migration. CONCLUSIONS: In this study, coronectomy of mandibular third molars did not result in temporary or permanent injury to the IAN or LN. Coronectomy showed a low rate of postoperative complications. However, within the first year, a second surgery was needed in 6% of coronectomy procedures to remove migrated root fragments. Additional studies with larger patient samples are recommended to further investigate differences in postoperative complications in relation to patient age. PMID- 25914135 TI - Molecular and physiological changes in response to salt stress in Citrus macrophylla W plants overexpressing Arabidopsis CBF3/DREB1A. AB - Plant stress induced by high salinity has leading to an important reduction in crop yields. Due to their tropical origin, citrus fruits are highly sensitive to salts. Rootstocks are the root system of fruit trees, regulating ion uptake and transport to the canopy. Therefore, increasing their salt tolerance could improve the salt tolerance of the fruit tree. For this, we genetically-transformed an important rootstock for lemon, Citrus macrophylla W, to constitutively express the CBF3/DREB1A gene from Arabidopsis, a well-studied salinity tolerance transcription factor. Transgenic lines showed normal size, with no dwarfism. Under salt stress, some transgenic lines showed greater growth, similar accumulation of chloride and sodium in the leaves and better stomatal conductance, in comparison to wild-type plants. Quantitative real-time analyses showed a similar expression of several CBF3/DREB1A target genes, such as COR15A, LEA 4/5, INV, SIP1, P5CS, GOLS, ADC2 and LKR/SDH, in transgenic lines and wild type plants, with the exception of INV that shows increased expression in line 4C15. Under salt stress, all measured transcript increased in both wild type and transgenics lines, with the exception of INV. Altogether, these results suggest a higher salt tolerance of transgenic C. macrophylla plants induced by the overexpression of AtCBF3/DREB1A. PMID- 25914136 TI - ALK rearrangement testing and treatment patterns for patients with ALK-positive non-small cell lung cancer. AB - INTRODUCTION: Approximately 2-8% of non-small cell lung cancer (NSCLC) patients have rearrangements in the anaplastic lymphoma kinase gene (ALK). ALK-targeted therapy is available to patients with tumors known to be ALK+. This chart review study described characteristics of patients with ALK+ NSCLC, patterns of ALK testing and subsequent treatments, and oncologists' experience with ALK testing in the US. METHODS: US oncologists provided information in September and October of 2013 on patients from their practice diagnosed with ALK+ locally advanced or metastatic NSCLC, including the timing of ALK testing and treatment received after testing. Participating oncologists were also surveyed about their experience with ALK testing. RESULTS: 27 oncologists provided data on 273 ALK+ NSCLC patients. Patients' median age was 67 years upon NSCLC diagnosis. Smoking history varied, with 33% nonsmokers, 33% light smokers, and 33% heavy smokers. Patients were racially diverse: 59% White, 18% Black, 13% Asian, and 10% other. Upon diagnosis of advanced/metastatic NSCLC, patients who were either not tested (19%) or initially tested negative/inconclusive (1%) all received first-line chemotherapy; the other 219 patients (80%) tested positive, with 133 (61%) receiving an ALK inhibitor and 78 (29%) receiving chemotherapy as first-line treatment. Many oncologists stated being more likely to test for ALK rearrangements among Asians, nonsmokers, and light smokers. CONCLUSIONS: In this sample, ALK+ NSCLC patients were racially diverse with mixed smoking history. One in five patients were not tested before first-line therapy. Oncologists reported being more likely to consider ALK testing for patients with particular smoking and race characteristics. PMID- 25914137 TI - Data quality at the Bulgarian National Cancer Registry: An overview of comparability, completeness, validity and timeliness. AB - Reporting of neoplasms in Bulgaria has been compulsory since a directive from the Ministry of Health in 1951. The quality of cancer registry data has been estimated rather infrequently in past years. We aimed to provide a comprehensive evaluation of the quality of the data at the Bulgarian National Cancer Registry (BNCR). Quantitative and semi-quantitative methods were applied for cancers diagnosed during the whole period 1993-2010, and also for cases diagnosed in 2006 2010. The methods used include historic data methods, mortality-to-incidence ratios (M:I), capture-recapture and death-certificate methods, proportions of morphologically verified cases (MV%), death-certificate-only cases (DCO%), and cases with missing information (primary site unknown, PSU%; stage unknown, SU%). The BNCR coding and classification systems follow international standards. The overall completeness was estimated at 92.6-94.7% for the period 2006-2010, with variations between cancer sites (86.7-98.5%). During the period 1993-2010, M:I decreased to 0.5 for males and 0.4 for females, MV increased to 87.4%, DCO and SU decreased to 4.8% and 18.8%, respectively, and PSU remained at the same level of about 4% for both sexes together. Sub-analysis revealed differences by site, sex and age groups. The comparison with other registries from the region showed similar incidence rates and directions of trends: M:I, MV% and DCO% that were not significantly different. The underreporting in 2008 and 2009 due to timely publication was estimated at an overall 0.8% and 0.5%, respectively. The present review showed that the BNCR yields internationally comparable data that are reasonably accurate, timely, and close to complete, especially in recent years. This is a prerequisite for the BNCR to expand its role to more areas of cancer control. PMID- 25914138 TI - Regulation of Hepatic Cholesteryl Ester Transfer Protein Expression and Reverse Cholesterol Transport by Inhibition of DNA Topoisomerase II. AB - Cholesteryl ester transfer protein (CETP) transfers cholesteryl esters from high density lipoprotein to triglyceride-rich lipoproteins. CETP expression can be transcriptionally activated by liver X receptor (LXR). Etoposide and teniposide are DNA topoisomerase II (Topo II) inhibitors. Etoposide has been reported to inhibit atherosclerosis in rabbits with un-fully elucidated mechanisms. In this study we determined if Topo II activity can influence cholesterol metabolism by regulating hepatic CETP expression. Inhibition of Topo II by etoposide, teniposide, or Topo II siRNA increased CETP expression in human hepatic cell line, HepG2 cells, which was associated with increased CETP secretion and mRNA expression. Meanwhile, inhibition of LXR expression by LXR siRNA attenuated induction of CETP expression by etoposide and teniposide. Etoposide and teniposide induced LXRalpha expression and LXRalpha/beta nuclear translocation while inhibiting expression of receptor interacting protein 140 (RIP140), an LXR co-repressor. In vivo, administration of teniposide moderately reduced serum lipid profiles, induced CETP expression in the liver, and activated reverse cholesterol transport in CETP transgenic mice. Our study demonstrates a novel function of Topo II inhibitors in cholesterol metabolism by activating hepatic CETP expression and reverse cholesterol transport. PMID- 25914139 TI - Extensive screen for bacterial endosymbionts reveals taxon-specific distribution patterns among bees (Hymenoptera, Anthophila). AB - Bacterial endosymbionts play key roles in arthropod biology, ranging from beneficial mutualists to parasitic sex ratio manipulators. The number of described endosymbiotic bacterial taxa has accumulated continuously in recent years. While the understanding of arthropod-microbe interactions has advanced significantly, especially in model organisms, relatively little is known about symbiont distribution and effects in non-model organisms. As a first step to alleviate this gap in understanding, we performed an endosymbiont survey in bees (Anthophila), an ecologically and economically important group of hymenopterans. To this end, we sampled 170 bee species and screened by PCR for the presence of Wolbachia, Rickettsia, Arsenophonus and Cardinium. Detected strains were then further diagnosed by additional markers. Additionally, we tested if certain ecological traits, bee phylogeny or geographic origin of bees explain endosymbiont distribution. Our results indicate that supergroup A Wolbachia are very common in bees and that their distribution can be significantly correlated to both host ecology and phylogeny, although a distinction of these factors is not possible. Furthermore, bees from the same region (Old World or New World) are more likely to harbour identical Wolbachia strains than expected by chance. Other endosymbionts (Rickettsia, Arsenophonus) were less common, and specific to particular host taxa, suggesting that host phylogeny is a major predictor for endosymbiont distribution in bees. PMID- 25914140 TI - Aberrant astrocytes impair vascular reactivity in Huntington disease. AB - OBJECTIVE: Huntington disease (HD) is an inherited neurodegenerative disease caused by the mutant huntingtin gene (mHTT), which harbors expanded CAG repeats. We previously reported that the brain vessel density is higher in mice and patients with HD than in controls. The present study determines whether vascular function is altered in HD and characterizes the underlying mechanism. METHODS: The brain vessel density and vascular reactivity (VR) to carbogen challenge of HD mice were monitored by 3D DeltaR2 -mMRA and blood oxygenation level-dependent (BOLD)/flow-sensitive alternating inversion recovery (FAIR) magnetic resonance imaging (MRI), respectively. The amount of vascular endothelial growth factor (VEGF)-A and the pericyte coverage were determined by immunohistochemistry and enzyme-linked immunosorbent assay in human and mouse brain sections, primary mouse astrocytes and pericytes, and human astrocytes derived from induced pluripotent stem cells. RESULTS: Expression of mHTT in astrocytes and neurons is sufficient to increase the brain vessel density in HD mice. BOLD and FAIR MRI revealed gradually impaired VR to carbogen in HD mice. Astrocytes from HD mice and patients contained more VEGF-A, which triggers proliferation of endothelial cells and may be responsible for the augmented neurovascular changes. Moreover, an astrocytic inflammatory response, which reduces the survival of pericytes through an IkappaB kinase-dependent pathway, mediates the low pericyte coverage of blood vessels in HD brains. INTERPRETATION: Our findings suggest that the inflammation-prone HD astrocytes provide less pericyte coverage by promoting angiogenesis and reducing the number of pericytes and that these changes can explain the inferior VR in HD mice. The resultant impaired VR might hinder cerebral hemodynamics and increase brain atrophy during HD progression. PMID- 25914142 TI - Brain structure associated with automatic thoughts predicted depression symptoms in healthy individuals. AB - Previous behavioral studies have examined the correlation between personality and depression, and between negative automatic thoughts and depression. Little is known, however, about the relationships among these three factors. Even less is known about how variations in brain structure are related to negative automatic thoughts, which are thought to mediate the association between personality traits and depressive symptoms. A total of 298 healthy participants underwent magnetic resonance imaging and completed the following questionnaires: a Neuroticism scale, the Automatic Thoughts Questionnaire (ATQ), and the Self-Rating Depression Scale (SDS). We first investigated the relationships among the three questionnaires and found that the ATQ was a mediator between the Neuroticism scale and the SDS. Then, we investigated the neuroanatomical correlates of the ATQ in the participants using voxel-based morphometry. We found that the ATQ was significantly positively correlated with the gray matter volume of the parahippocampal gyrus (PHG). Structural Equation Modeling revealed that negative automatic thoughts mediated the relationship between the GMV of the parahippocampal gyrus and depression. Moreover, the interaction between parahippocampal gyrus volume and neuroticism predicted automatic thoughts. These findings highlight that negative automatic thoughts might be a good predictor of depression outcome. PMID- 25914143 TI - The role of population inertia in predicting the outcome of stage-structured biological invasions. AB - Deterministic dynamic models for coupled resident and invader populations are considered with the purpose of finding quantities that are effective at predicting when the invasive population will become established asymptotically. A key feature of the models considered is the stage-structure, meaning that the populations are described by vectors of discrete developmental stage- or age classes. The vector structure permits exotic transient behaviour-phenomena not encountered in scalar models. Analysis using a linear Lyapunov function demonstrates that for the class of population models considered, a large so called population inertia is indicative of successful invasion. Population inertia is an indicator of transient growth or decline. Furthermore, for the class of models considered, we find that the so-called invasion exponent, an existing index used in models for invasion, is not always a reliable comparative indicator of successful invasion. We highlight these findings through numerical examples and a biological interpretation of why this might be the case is discussed. PMID- 25914141 TI - Sex differences, hormones, and fMRI stress response circuitry deficits in psychoses. AB - Response to stress is dysregulated in psychosis (PSY). fMRI studies showed hyperactivity in hypothalamus (HYPO), hippocampus (HIPP), amygdala (AMYG), anterior cingulate (ACC), orbital and medial prefrontal (OFC; mPFC) cortices, with some studies reporting sex differences. We predicted abnormal steroid hormone levels in PSY would be associated with sex differences in hyperactivity in HYPO, AMYG, and HIPP, and hypoactivity in PFC and ACC, with more severe deficits in men. We studied 32 PSY cases (50.0% women) and 39 controls (43.6% women) using a novel visual stress challenge while collecting blood. PSY males showed BOLD hyperactivity across all hypothesized regions, including HYPO and ACC by FWE-correction. Females showed hyperactivity in HIPP and AMYG and hypoactivity in OFC and mPFC, the latter FWE-corrected. Interaction of group by sex was significant in mPFC (F = 7.00, p = 0.01), with PSY females exhibiting the lowest activity. Male hyperactivity in HYPO and ACC was significantly associated with hypercortisolemia post-stress challenge, and mPFC with low androgens. Steroid hormones and neural activity were dissociated in PSY women. Findings suggest disruptions in neural circuitry-hormone associations in response to stress are sex-dependent in psychosis, particularly in prefrontal cortex. PMID- 25914144 TI - Tissue Doppler imaging in fetuses with aortic stenosis and evolving hypoplastic left heart syndrome before and after fetal aortic valvuloplasty. AB - OBJECTIVES: Fetal aortic valvuloplasty can improve filling and reduce afterload of the left ventricle in critical aortic stenosis. Success of an intrauterine intervention is currently measured by technical success, clinical survival and eventual postnatal biventricular physiology. In the present study we investigated the use of tissue Doppler imaging (TDI) to evaluate changes in ventricular function assessed before and after prenatal aortic valvuloplasty. METHODS: Between October 2008 and December 2012, cardiac function was assessed by TDI before and after intervention in 23 fetuses that underwent technically successful valvuloplasty for critical aortic stenosis and in which postnatal outcome was known. The measurements were transformed into gestational age-independent Z scores where appropriate. RESULTS: Mean +/- SD gestational age at intervention was 27.5 +/- 3.1 weeks. Of the 23 fetuses, 14 had biventricular outcome. Before intervention all left ventricular (LV) TDI-derived parameters and mitral annular plane systolic excursion (MAPSE) were severely abnormal. It was possible to demonstrate considerably improved cardiac function after technically successful valvuloplasty. Among fetuses with postnatal biventricular outcome, TDI-derived LV myocardial peak velocity during early diastole (E') and myocardial peak velocity during systole in the ejection phase (S') significantly increased, E'/myocardial peak velocity during late diastole with atrial contraction (A') increased towards normal values, and LV transmitral-to-mitral-annular diastolic velocity ratio (E/E') and myocardial performance index (MPI') decreased but remained abnormally elevated. In addition, right ventricular A', S' and MPI' significantly improved after intervention. CONCLUSION: Technically successful fetal aortic valvuloplasty led to significantly improved myocardial performance. It was possible to use TDI to detect distinct changes in ventricular function and TDI-derived parameters correlated with a biventricular outcome after birth. Copyright (c) 2015 ISUOG. Published by John Wiley & Sons Ltd. PMID- 25914147 TI - Controlling toxicity of Peptide-drug conjugates by different chemical linker structures. AB - The side effects of chemotherapy can be overcome by linking toxic agents to tumor targeting peptides with cleavable linkers. Herein, this concept is demonstrated by addressing the human Y1 receptor (hY1 R), overexpressed in breast tumors, with analogues of the hY1 R-preferring [F(7) ,P(34) ]NPY. First, carboxytetramethylrhodamine was connected to [F(7) ,P(34) ]NPY by an amide, ester, disulfide, or enzymatic linkage. Live imaging revealed hY1 R-mediated delivery and allowed visualization of time-dependent intracellular release. Next, the fluorophore was replaced by the toxic agent methotrexate (MTX). In addition to linkage through the amide, ester, disulfide bond, or enzymatic cleavage site, a novel disulfide/ester linker was designed and coupled to [F(7) ,P(34) ]NPY by solid-phase peptide synthesis. Internalization studies showed hY1 R subtype selective uptake, and cell viability experiments demonstrated hY1 R-mediated toxicity that was clearly dependent on the linkage type. Fast release profiles for fluorophore-[F(7) ,P(34) ]NPY analogues correlated with high toxicities of MTX conjugates carrying the same linker types and emphasize the relevance of new structures connecting the toxophore and the carrier. PMID- 25914148 TI - Benign chondroblastoma on fine-needle aspiration smears: A seven-case experience and review of the literature. AB - We report seven cases of chondroblastoma (CB) of bone, diagnosed by Fine-Needle Aspiration Cytology (FNAC), and confirmed by histomorphological examination. The concurrence of some cytomorphologic findings - mononucleated cells, multinucleated cells, and intercellular chondroid substance - unequivocally suggested the cytological diagnosis of CB. We also reviewed the literature on this topic in order to discuss morphological criteria and the importance of needle size. The differential diagnosis between CB, Giant Cell Tumor of Bone, and Eosinophilic Granuloma is further discussed. PMID- 25914149 TI - Improved quantification and mapping of anomalous pulmonary venous flow with four dimensional phase-contrast MRI and interactive streamline rendering. AB - BACKGROUND: Cardiac MRI is routinely performed for quantification of shunt flow in patients with anomalous pulmonary veins, but can be technically-challenging to perform. Four-dimensional phase-contrast (4D-PC) MRI has potential to simplify this exam. We sought to determine whether 4D-PC may be a viable clinical alternative to conventional 2D phase-contrast MR imaging. METHODS: With institutional review board approval and HIPAA-compliance, we retrospectively identified all patients with anomalous pulmonary veins who underwent cardiac MRI at either 1.5 Tesla (T) or 3T with parallel-imaging compressed-sensing (PI-CS) 4D PC between April, 2011 and October, 2013. A total of 15 exams were included (10 male, 5 female). Algorithms for interactive streamline visualization were developed and integrated into in-house software. Blood flow was measured at the valves, pulmonary arteries and veins, cavae, and any associated shunts. Pulmonary veins were mapped to their receiving atrial chamber with streamlines. The intraobserver, interobserver, internal consistency of flow measurements, and consistency with conventional MRI were then evaluated with Pearson correlation and Bland-Altman analysis. RESULTS: Triplicate measurements of blood flow from 4D PC were highly consistent, particularly at the aortic and pulmonary valves (cv 2 3%). Flow measurements were reproducible by a second observer (rho = 0.986 0.999). Direct measurements of shunt volume from anomalous veins and intracardiac shunts matched indirect estimates from the outflow valves (rho = 0.966). Measurements of shunt fraction using 4D-PC using any approach were more consistent with ventricular volumetric displacements than conventional 2D-PC (rho = 0.972-0.991 versus 0.929). CONCLUSION: Shunt flow may be reliably quantified with 4D-PC MRI, either indirectly or with detailed delineation of flow from multiple shunts. The 4D-PC may be a more accurate alternative to conventional MRI. PMID- 25914151 TI - Designing Heterogeneous 1D Nanostructure Arrays Based on AAO Templates for Energy Applications. AB - In order to fulfill the multiple requirements for energy production, storage, and utilization in the future, the conventional planar configuration of current energy conversion/storage devices has to be reformed, since technological evolution has promoted the efficiency of the corresponding devices to be close to the theoretical values. One promising strategy is to construct multifunctional 1D nanostructure arrays to replace their planar counterparts for device fabrication, ascribing to the significant superiorities of such 1D nanostructure arrays. In the last three decades, technologies based on anodic aluminium oxide (AAO) templates have turned out to be valuable meaning for the realization of 1D nanostructures and have attracted tremendous interest. In this review, recent progress in energy-related devices equipped with heterogeneous 1D nanostructure arrays that fabricated through the assistance of AAO templates is highlighted. Particular emphasis is given on how to develop efficient devices via optimizing the componential and morphological parameters of the 1D nanostructure arrays. Finally, aspects relevant to the further improvement of device performance are discussed. PMID- 25914150 TI - Compartmentalization, Viral Evolution, and Viral Latency of HIV in the CNS. AB - Human immunodeficiency virus type 1 (HIV-1) infection occurs throughout the body and can have dramatic physical effects, such as neurocognitive impairment in the central nervous system (CNS). Furthermore, examining the virus that resides in the CNS is challenging due to its location and can only be done using samples collected either at autopsy, indirectly form the cerebral spinal fluid (CSF), or through the use of animal models. The unique milieu of the CNS fosters viral compartmentalization as well as evolution of viral sequences, allowing for new cell types, such as macrophages and microglia, to be infected. Treatment must also cross the blood-brain barrier adding additional obstacles in eliminating viral populations in the CNS. These long-lived infected cell types and treatment barriers may affect functional cure strategies in people on highly active antiretroviral therapy (HAART). PMID- 25914152 TI - Unravelling the proteome of degenerative human mitral valves. AB - Degenerative mitral valve disease (DMVD), which includes the syndromes of mitral valve prolapse (MVP) and flail leaflet, is a common valvular condition which can be complicated by mitral regurgitation and adverse cardiovascular outcomes. Although several genetic and other studies of MVP in dog models have provided some information regarding the underlying disease mechanisms, the proteins and molecular events mediating human MVP pathogenesis have not been unraveled. In this study, we report the first large-scale proteome profiling of mitral valve tissue resected from patients with MVP. A total of 1134 proteins were identified, some of which were validated using SWATH-MS and western blotting. GO annotation of these proteins confirmed the validity of this proteome database in various cardiovascular processes. Among the list of proteins, we found several structural and extracellular matrix proteins, such as asporin, biglycan, decorin, lumican, mimecan, prolargin, versican, and vinculin, that have putative roles in the pathophysiology of MVP. These proteins could also be involved in the cardiac remodeling associated with mitral regurgitation. All MS data have been deposited in the ProteomeXchange with identifier PXD000774 (http://proteomecentral.proteomexchange.org/dataset/PXD000774). PMID- 25914153 TI - Ambulatory children with cerebral palsy do not exhibit unhealthy weight gain following selective dorsal rhizotomy. AB - AIM: The aim of this study was to retrospectively analyze changes in age- and sex adjusted body mass index (BMI) in ambulatory children with cerebral palsy (CP) who underwent selective dorsal rhizotomy (SDR). METHOD: Raw BMI, age- and sex adjusted BMI z-scores, weight classification status, energy expenditure, and ambulation function were calculated before and after SDR at multiple post-SDR time points: 6 to <24 months, 24 to <48 months, 48 to <72, and 72 to <96 months. Linear mixed models were used to analyze changes in raw BMI, BMI z-scores, energy expenditure, and ambulation function. RESULTS: Pre- and post-surgical data were available for 363 children diagnosed with CP who underwent SDR (219 males, 144 females; mean age 6y [SD 2y 1mo]; mean BMI z-score 0.09 [SD 1.21]). Data from additional post-surgical time points were collected on subsamples. Although raw BMI significantly increased (p<0.01), these increases were consistent with anticipated growth. BMI z-scores did not significantly change over the 10-year study period. INTERPRETATION: Concerns of unhealthy weight gain following SDR are not supported by this study. Further work examining possible risk factors for BMI increase following SDR, as well as examining disparities in existing criteria for patient selection, is merited. PMID- 25914154 TI - Triplet state delocalization in a conjugated porphyrin dimer probed by transient electron paramagnetic resonance techniques. AB - The delocalization of the photoexcited triplet state in a linear butadiyne-linked porphyrin dimer is investigated by time-resolved and pulse electron paramagnetic resonance (EPR) with laser excitation. The transient EPR spectra of the photoexcited triplet states of the porphyrin monomer and dimer are characterized by significantly different spin polarizations and an increase of the zero-field splitting parameter D from monomer to dimer. The proton and nitrogen hyperfine couplings, determined using electron nuclear double resonance (ENDOR) and X- and Q-band HYSCORE, are reduced to about half in the porphyrin dimer. These data unequivocally prove the delocalization of the triplet state over both porphyrin units, in contrast to the conclusions from previous studies on the triplet states of closely related porphyrin dimers. The results presented here demonstrate that the most accurate estimate of the extent of triplet state delocalization can be obtained from the hyperfine couplings, while interpretation of the zero-field splitting parameter D can lead to underestimation of the delocalization length, unless combined with quantum chemical calculations. Furthermore, orientation selective ENDOR and HYSCORE results, in combination with the results of density functional theory (DFT) calculations, allowed determination of the orientations of the zero-field splitting tensors with respect to the molecular frame in both porphyrin monomer and dimer. The results provide evidence for a reorientation of the zero-field splitting tensor and a change in the sign of the zero-field splitting D value. The direction of maximum dipolar coupling shifts from the out of-plane direction in the porphyrin monomer to the vector connecting the two porphyrin units in the dimer. This reorientation, leading to an alignment of the principal optical transition moment and the axis of maximum dipolar coupling, is also confirmed by magnetophotoselection experiments. PMID- 25914155 TI - Succesful antegrade subintimal bypass restenting of in-stent chronic total occlusion. AB - Coronary chronic total occlusions (CTOs) are known to cause significant patient morbidity. Over the past several years, the techniques and devices for treating these CTOs have advanced tremendously. The interventional management of CTOs within previously placed coronary stents, however, remains challenging. Here, we present a case of an in-stent restenosis of the right coronary artery CTO bypassed using a controlled subintimal dissection re-entry technique via antegrade approach creating side-by-side stents. PMID- 25914156 TI - Altered voltage-gated calcium channels in rat inferior colliculus neurons contribute to alcohol withdrawal seizures. AB - We have previously reported that enhanced susceptibility to alcohol withdrawal seizures (AWS) parallels the enhancement of the current density of high-threshold voltage-gated Ca(2+) (CaV) channels in rat inferior colliculus (IC) neurons. However, whether this increased current density is a cause or consequence of AWS is unclear. Here, I report changes in the current density of CaV channels in IC neurons during the course of alcohol withdrawal and the potential anticonvulsant effect of intra-IC infusions of L- and P-type CaV channel antagonists. Whole-cell currents were activated by depolarizing pulses using barium as the charge carrier. Currents and seizure susceptibility were evaluated in control animals 3h after alcohol intoxication, as well as 3h (before AWS), 24h (when AWS susceptibility is maximal), and 48h (when AWS susceptibility is no longer present) after alcohol withdrawal. Nifedipine, nimodipine (L-type antagonists) or omega-agatoxin TK (P-type antagonist) were infused intra-IC to probe the role of CaV channels in the pathogenesis of AWS. CaV current density and conductance in IC neurons were significantly increased 3 and 24h after alcohol withdrawal compared with the control group or the group tested 3h following ethanol intoxication. Blockade of L-type CaV channels within the IC completely suppressed AWS, and inhibition of P-type channels reduced AWS severity. These findings suggest that the enhancement of CaV currents in IC neurons occurs prior to AWS onset and that alterations in L- and P-type CaV channels in these neurons may underlie the pathogenesis of AWS. PMID- 25914157 TI - Antidepressant-like effect of geniposide on chronic unpredictable mild stress induced depressive rats by regulating the hypothalamus-pituitary-adrenal axis. AB - Geniposide as the major active component of Gardenia jasminoides Ellis has neuroprotective activity. This study elucidated the potential antidepressant-like effect of geniposide and its related mechanisms using a depression rat model induced by 3 consecutive weeks of chronic unpredictable mild stress (CUMS). Sucrose preference test, open field test (OFT) and forced swimming test (FST) were applied to evaluate the antidepressant effect of geniposide. Adrenocorticotropic hormone (ACTH) and corticosterone (CORT) serum levels, adrenal gland index and hypothalamic corticotrophin-releasing hormone (CRH) mRNA expression were measured to assess the activity of hypothalamus-pituitary-adrenal (HPA) axis. Hypothalamic glucocorticoid receptor alpha (GRalpha) mRNA expression and GRalpha protein expression in hypothalamic paraventricular nucleus (PVN) were also determined by real-time PCR and immunohistochemistry, respectively. We found that geniposide (25, 50, 100mg/kg) treatment reversed the CUMS-induced behavioral abnormalities, as suggested by increased sucrose intake, improved crossing and rearing behavior in OFT, shortened immobility and prolonged swimming time in FST. Additionally, geniposide treatment normalized the CUMS-induced hyperactivity of HPA axis, as evidenced by reduced CORT serum level, adrenal gland index and hypothalamic CRH mRNA expression, with no significant effect on ACTH serum level. Moreover, geniposide treatment upregulated the hypothalamic GRalpha mRNA level and GRalpha protein expression in PVN, suggesting geniposide could recover the impaired GRalpha negative feedback on CRH expression and HPA axis. These aforementioned therapeutic effects of geniposide were essentially similar to fluoxetine. Our results indicated that geniposide possessed potent antidepressant like properties that may be mediated by its effects on the HPA axis. PMID- 25914158 TI - 5-HT2A receptors are involved in cognitive but not antidepressant effects of fluoxetine. AB - The prefrontal cortex (PFC) plays a crucial role in cognitive and affective functions. It contains a rich serotonergic (serotonin, 5-HT) innervation and a high density of 5-HT receptors. Endogenous 5-HT exerts robust actions on the activity of pyramidal neurons in medial PFC (mPFC) via excitatory 5-HT2A and inhibitory 5-HT1A receptors, suggesting the involvement of 5-HT neurotransmission in cortical functions. However, the underlying mechanisms must be elucidated. Here we examine the role of 5-HT2A receptors in the processing of emotional and cognitive signals evoked by increasing the 5-HT tone after acute blockade of the 5-HT transporter. Fluoxetine (5-20mg/kg i.p.) dose-dependently reduced the immobility time in the tail-suspension test in wild-type (WT) and 5-HT2Aknockout (KO2A) mice, with non-significant differences between genotypes. Fluoxetine (10mg/kg i.p.) significantly impaired mice performance in the novel object recognition test 24h post-administration in WT, but not in KO2A mice. The comparable effect of fluoxetine on extracellular 5-HT in the mPFC of both genotypes suggests that presynaptic differences are not accountable. In contrast, single unit recordings of mPFC putative pyramidal neurons showed that fluoxetine (1.8-7.2mg/kg i.v.) significantly increased neuronal discharge in KO2A but not in WT mice. This effect is possibly mediated by an altered excitatory/inhibitory balance in the PFC in KO2A mice. Overall, the present results suggest that 5-HT2A receptors play a detrimental role in long-term memory deficits mediated by an excess 5-HT in PFC. PMID- 25914159 TI - Distinct roles of the endocannabinoids anandamide and 2-arachidonoylglycerol in social behavior and emotionality at different developmental ages in rats. AB - To date, our understanding of the relative contribution and potential overlapping roles of the endocannabinoids anandamide (AEA) and 2-arachidonoylglycerol (2-AG) in the regulation of brain function and behavior is still limited. To address this issue, we investigated the effects of systemic administration of JZL195, that simultaneously increases AEA and 2-AG signaling by inhibiting their hydrolysis, in the regulation of socio-emotional behavior in adolescent and adult rats. JZL195, administered at the dose of 0.01mg/kg, increased social play behavior, that is the most characteristic social activity displayed by adolescent rats, and increased social interaction in adult animals. At both ages, these behavioral effects were antagonized by the CB1 cannabinoid receptor antagonist SR141716A and were associated with increased brain levels of 2-AG, but not AEA. Conversely, at the dose of 1mg/kg, JZL195 decreased general social exploration in adolescent rats without affecting social play behavior, and induced anxiogenic like effects in the elevated plus-maze test both in adolescent and adult animals. These effects, mediated by activation of CB1 cannabinoid receptors, were paralleled by simultaneous increase in AEA and 2-AG levels in adolescent rats, and by an increase of only 2-AG levels in adult animals. These findings provide the first evidence for a role of 2-AG in social behavior, highlight the different contributions of AEA and 2-AG in the modulation of emotionality at different developmental ages and suggest that pharmacological inhibition of AEA and 2-AG hydrolysis is a useful approach to investigate the role of these endocannabinoids in neurobehavioral processes. PMID- 25914160 TI - Enzymatic characterization of recombinant nitrate reductase expressed and purified from Neurospora crassa. AB - We established an expression and purification procedure for recombinant protein production in Neurospora crassa (N. crassa). This Strep-tag(r) based system was successfully used for purifying recombinant N. crassa nitrate reductase (NR), whose enzymatic activity was compared to recombinant N. crassa NR purified from Escherichia coli. The purity of the two different NR preparations was similar but NR purified from N. crassa showed a significantly higher nitrate turnover rate. Two phosphorylation sites were identified for NR purified from the endogenous expression system. We conclude that homologous expression of N. crassa NR yields a higher active enzyme and propose that NR phosphorylation causes enhanced enzymatic activity. PMID- 25914161 TI - Reply: To PMID 25132233. PMID- 25914162 TI - Fructosylation generates neo-epitopes on human serum albumin. AB - Hyperglycemia is the defining feature of diabetes mellitus. The persistently high levels of reducing sugars like glucose and fructose cause glycation of various macromolecules in the body. Human serum albumin (HSA), the most abundant serum protein with a myriad of functions, is prone to glycation and consequent alteration in its structural and biological properties. This study aimed to assess the role of fructose-modified human serum albumin as a marker of diabetic pathophysiology. We carried out modification of HSA with fructose and the changes induced were studied by various physicochemical studies. Fructose modified-HSA showed hyperchromicity in UV spectrum and increased AGE-specific fluorescence as well as quenching of tryptophan fluorescence. In SDS-PAGE protein aggregation was seen. Amadori products were detected by NBT. The fructose modified HSA had higher content of carbonyls along with perturbations in secondary structure as revealed by CD and FT-IR. A greater hydrodynamic radius of fructose-modified HSA was evident by DLS measurement. The fructose-modified HSA induced high titre antibodies in experimental animals exhibiting high specificity towards the immunogen. PMID- 25914163 TI - Diurnal and day-to-day variation of isometric muscle strength in myasthenia gravis. AB - INTRODUCTION: In patients with myasthenia gravis (MG), muscle strength is expected to decrease gradually during the day due to physical activities. METHODS: Isometric muscle strength at the shoulder, knee, and ankle was determined in 10 MG patients (MGFA class II-IV) who were receiving usual medical treatment and in 10 control subjects. To determine diurnal and day-to-day variation, muscle strength was measured 4 times during day 1 and once at day 2. RESULTS: Knee extension strength decreased during the day in both patients and controls. Neither diurnal nor day-to-day variation of muscle strength was higher in patients compared with controls. CONCLUSIONS: Patients with mild to moderate MG did not have increased variation of isometric muscle strength during the day or from day-to-day compared with controls. This suggests that isometric muscle performance can be determined with high reproducibility in similar groups of MG patients without regard to time of day. PMID- 25914164 TI - Enantioselective Syntheses of Heteroyohimbine Natural Products: A Unified Approach through Cooperative Catalysis. AB - Alstonine and serpentine are pentacyclic indoloquinolizidine alkaloids (referred to as "anhydronium bases") containing three contiguous stereocenters. Each possesses interesting biological activity, with alstonine being the major component of a plant-based remedy to treat psychosis and other nervous system disorders. This work describes the enantioselective total syntheses of these natural products with a cooperative hydrogen bonding/enamine-catalyzed Michael addition as the key step. PMID- 25914165 TI - Poor survival of females with bladder cancer is limited to those aged 70 years or over: a population-wide linkage study, New South Wales, Australia. AB - Although men are diagnosed with bladder cancer (BC) with a rate three times higher than women, women experience poorer survival. The cause of this gender difference is not clear. The aim of this study was to investigate the discrepancy in survival from BC by gender and explore potential explanations for the difference using a population-wide linkage study. Using the New South Wales (NSW) Central Cancer Registry, all invasive BC cases diagnosed between 2001 and 2009 were identified. Records were linked to the NSW Admitted Patient Data Collection (APDC), to retrieve treatment details, and to the Registry of Births Deaths and Marriages and Australian Bureau of Statistics to obtain death details. A total of 5377 new cases of BC were identified. No differences were identified in the proportions of patients presenting at different stages between genders. However, disease-specific survival (DSS) was worse for females compared to males with localized and regional disease (P < 0.05). This difference was only apparent in individuals aged >= 70 years and no difference was identified in those younger. Multivariable Cox-regression analysis of the cohort of individuals aged >= 70 years revealed that stage, age, comorbidity, and sex remained independent variables (P < 0.05) predicting DSS. In a population wide analysis, females aged 70 years or more suffer worse DSS compared to males. The differences are not accounted for by stage at presentation or comorbidity and are independent of age. BC in postmenopausal females may be biologically more aggressive. PMID- 25914167 TI - IL-6 trans-signaling plays important protective roles in acute liver injury induced by acetaminophen in mice. AB - Our study was undertaken to evaluate the important role of interleukin-6 (IL-6) trans-signaling in acetaminophen (AAP)-induced liver injury. A soluble gp130 protein (sgp130Fc) exclusively inhibits IL-6 trans-signaling, whereas an IL 6/soluble IL-6 receptor (sIL-6R) fusion protein (hyper-IL-6) mimics IL-6 trans signaling. Using these tools, we investigated the role of IL-6 trans-signaling in AAP-induced liver injury. Blockade of IL-6 trans-signaling during AAP-induced liver injury remarkably increased the levels of serum aspartate aminotransferase and alanine aminotransferase; lowered the level of serum sIL-6R; aggravated liver injury; inhibited the expression of phosphorylation of STAT3 (pSTAT3), proliferating cell nuclear antigen, vascular endothelial growth factor, and glycogen synthesis; and induced the expression of Caspase3, cytochrome P450 2E1 (CYP2E1), and hepatocyte apoptosis in the liver of mice. In summary, our study suggested that IL-6 trans-signaling plays important protective roles by regulating the hepatocyte proliferation and apoptosis, angiogenesis, CYP2E1 expression, and glycogen metabolism during AAP-induced liver injury in mice. PMID- 25914166 TI - An attenuated phenotype of Costello syndrome in three unrelated individuals with a HRAS c.179G>A (p.Gly60Asp) mutation correlates with uncommon functional consequences. AB - Heterozygous germline mutations in the proto-oncogene HRAS cause Costello syndrome (CS), an intellectual disability condition with severe failure to thrive, cardiac abnormalities, predisposition to tumors, and neurologic abnormalities. More than 80% of patients share the HRAS mutation c.34G>A (p.Gly12Ser) associated with the typical, relatively homogeneous phenotype. Rarer mutations occurred in individuals with an attenuated phenotype and less characteristic facial features. Most pathogenic HRAS alterations affect hydrolytic HRAS activity resulting in constitutive activation. "Gain-of-function" and "hyperactivation" concerning downstream pathways are widely used to explain the molecular basis and dysregulation of the RAS-MAPK pathway is the biologic mechanism shared amongst rasopathies. Panel testing for rasopathies identified a novel HRAS mutation (c.179G>A; p.Gly60Asp) in three individuals with attenuated features of Costello syndrome. De novo paternal origin occurred in two, transmission from a heterozygous mother in the third. Individuals showed subtle facial features; curly hair and relative macrocephaly were seen in three; atrial tachycardia and learning difficulties in two, and pulmonic valve dysplasia and mildly thickened left ventricle in one. None had severe failure to thrive, intellectual disability or cancer, underscoring the need to consider HRAS mutations in individuals with an unspecific rasopathy phenotype. Functional studies revealed strongly increased HRAS(Gly60Asp) binding to RAF1, but not to other signaling effectors. Hyperactivation of the MAPK downstream signaling pathways was absent. Our results indicate that an increase in the proportion of activated RAS downstream signaling components does not entirely explain the molecular basis of CS. We conclude that the phenotypic variability in CS recapitulates variable qualities of molecular dysfunction. PMID- 25914168 TI - A pharmacogenetic study implicates SLC9a9 in multiple sclerosis disease activity. AB - OBJECTIVE: A proportion of multiple sclerosis (MS) patients experience disease activity despite treatment. The early identification of the most effective drug is critical to impact long-term outcome and to move toward a personalized approach. The aim of the present study is to identify biomarkers for further clinical development and to yield insights into the pathophysiology of disease activity. METHODS: We performed a genome-wide association study in interferon beta (IFNbeta)-treated MS patients followed by validation in 3 independent cohorts. The role of the validated variant was examined in several RNA data sets, and the function of the presumed target gene was explored using an RNA interference approach in primary T cells in vitro. RESULTS: We found an association between rs9828519(G) and nonresponse to IFNbeta (pdiscovery = 4.43 * 10(-8)) and confirmed it in a meta-analysis across 3 replication data sets (preplication = 7.78 * 10(-4)). Only 1 gene is found in the linkage disequilibrium block containing rs9828519: SLC9A9. Exploring the function of this gene, we see that SLC9A9 mRNA expression is diminished in MS subjects who are more likely to have relapses. Moreover, SLC9A9 knockdown in T cells in vitro leads an increase in expression of IFNgamma, which is a proinflammatory molecule. INTERPRETATION: This study identifies and validates the role of rs9828519, an intronic variant in SLC9A9, in IFNbeta-treated subjects, demonstrating a successful pharmacogenetic screen in MS. Functional characterization suggests that SLC9A9, an Na(+) -H(+) exchanger found in endosomes, appears to influence the differentiation of T cells to a proinflammatory fate and may have a broader role in MS disease activity, outside of IFNbeta treatment. PMID- 25914169 TI - Alkylindole-sensitive receptors modulate microglial cell migration and proliferation. AB - Ligands targeting G protein-coupled receptors (GPCR) expressed by microglia have been shown to regulate distinct components of their activation process, including cell proliferation, migration and differentiation into M1 or M2 phenotypes. Cannabinoids, including the active component of the Cannabis plant, tetrahydrocannabinol (THC), and the synthetic alkylindole (AI) compound, WIN55212 2 (WIN-2), activate two molecularly identified GPCRs: CB1 and CB2 . Previous studies reported that WIN-2 activates an additional unknown GPCR that is not activated by plant-derived cannabinoids, and evidence indicates that microglia express these receptors. Detailed studies on the role of AI-sensitive receptors in microglial cell activation were difficult as no selective pharmacological tools were available. Here, three newly-developed AI analogues allowed us to determine if microglia express AI-sensitive receptors and if so, study how they regulate the microglial cell activation process. We found that mouse microglia in primary culture express functional AI-sensitive receptors as measured by radioligand binding and changes in intracellular cAMP levels, and that these receptors control both basal and ATP-stimulated migration. AI analogues inhibit cell proliferation stimulated by macrophage-colony stimulating factor (M-CSF) without affecting basal cell proliferation. Remarkably, AI analogues do not control the expression of effector proteins characteristic of M1 or M2 phenotypes; yet activating microglia with M1 and M2 cytokines reduces the microglial response to AI analogues. Our results suggest that microglia express functional AI-sensitive receptors that control select components of their activation process. Agonists of these novel targets might represent a novel class of therapeutics to influence the microglial cell activation process. PMID- 25914170 TI - All-trans retinoic acid induces oxidative phosphorylation and mitochondria biogenesis in adipocytes. AB - A positive effect of all-trans retinoic acid (ATRA) on white adipose tissue (WAT) oxidative and thermogenic capacity has been described and linked to an in vivo fat-lowering effect of ATRA in mice. However, little is known about the effects of ATRA on mitochondria in white fat. Our objective has been to characterize the effect of ATRA on mitochondria biogenesis and oxidative phosphorylation (OXPHOS) capacity in mature white adipocytes. Transcriptome analysis, oxygraphy, analysis of mitochondrial DNA (mtDNA), and flow cytometry-based analysis of mitochondria density were performed in mature 3T3-L1 adipocytes after 24 h incubation with ATRA (2 uM) or vehicle. Selected genes linked to mitochondria biogenesis and function and mitochondria immunostaining were analyzed in WAT tissues of ATRA treated as compared with vehicle-treated mice. ATRA upregulated the expression of a large set of genes linked to mtDNA replication and transcription, mitochondrial biogenesis, and OXPHOS in adipocytes, as indicated by transcriptome analysis. Oxygen consumption rate, mtDNA content, and staining of mitochondria were increased in the ATRA-treated adipocytes. Similar results were obtained in WAT depots of ATRA-treated mice. We conclude that ATRA impacts mitochondria in adipocytes, leading to increased OXPHOS capacity and mitochondrial content in these cells. PMID- 25914171 TI - Long term ingestion of a preload containing fructo-oligosaccharide or guar gum decreases fat mass but not food intake in mice. AB - Fermentable dietary fibre such as fructo-oligosaccharide and viscous dietary fibers such as guar gum and alginate affect energy homeostasis. The goal of this study was to compare the impact of long term intake of these three dietary fibers on food intake, meal pattern, body weight and fat accumulation in mice. Over a period of 3weeks, the mice were fed daily with a preload containing 32mg of fructo-oligosaccharide or alginate or 13mg of guar gum. Food intake and body weight were monitored weekly, while meal patterns, adiposity and the expression of hypothalamic neuropeptide genes were evaluated at the end of the study period. The 3 dietary fibers produced a similar decrease in total daily food intake (14 to 22%) at the end of the first week, and this effect disappeared over time. The 3 dietary fibers induced a slight variation in satiation parameters. Body weight and expression of hypothalamic neuropeptide genes were not affected by any of the treatment. Preload of fructo-oligosaccharide and guar gum induced a similar and substantial decrease in the development of adiposity (17% and 14%, respectively), while alginate had no effect. Our results demonstrate mainly that the inhibitory effect of dietary fiber on food intake is lost over time, and that guar gum limits fat storage. PMID- 25914172 TI - Coadministration of hydroxysafflor yellow A with levodopa attenuates the dyskinesia. AB - Levodopa (L-DOPA) is used as the most effective drug available for the symptomatic treatment of Parkinson's disease (PD). However, long-term treatment of L-DOPA frequently causes complications, including abnormal involuntary movements such as dyskinesia and response fluctuations in PD patients. In the present work, we investigated whether hydroxysafflor yellow A (HSYA) ameliorates L-DOPA-induced dyskinesia and motor fluctuations in the 6-hydroxydopamine lesioned rat model of PD. Valid PD rats were treated daily with vehicle, HSYA alone, L-DOPA, or a combination of HSYA plus L-DOPA for 21days, respectively. L DOPA (8mg/kg) and benserazide (15mg/kg) were treated intraperitoneally. HSYA was administrated intraperitoneally at a dose of 10mg/kg. The abnormal involuntary movements and rotational behavior were evaluated. The expression of the dopamine D3 receptor in the striatum was also assayed. The results demonstrated that daily administration of L-DOPA to PD rats for 21days induced a steady expression of dyskinesia. Coadministration of HSYA with L-DOPA significantly ameliorated L-DOPA induced dyskinesia. The combination treatment also prevented the shortening of the motor response duration that defines wearing off motor fluctuations. HSYA also inhibited the increase of expression of the dopamine D3 receptor in the striatum. These findings demonstrated that HSYA provided anti-dyskinetic relief against L-DOPA in a preclinical model of PD via regulating the expression of the dopamine D3 receptor. The combination of L-DOPA and HSYA also reduced the likelihood of wearing off development, and may thus support the utility of such compounds for the improved treatment of PD. PMID- 25914173 TI - GABAA-benzodiazepine receptors in the dorsomedial (Dm) telencephalon modulate restraint-induced antinociception in the fish Leporinus macrocephalus. AB - The possibility that fish experience pain has been denied based on the absence of the neural substrates to support this "experience". In this context, the identification of brain regions involved in nociception modulation could provide important insights regarding the processing of nociceptive information in fish. Our study evaluated the participation of the GABAA-benzodiazepine receptor in the dorsomedial (Dm) telencephalon in restraint-induced antinociception in the fish Leporinus macrocephalus through the microinjection of the anxiolytic drug midazolam. The microinjection of midazolam in the Dm did not alter the nocifensive response; however, this drug did block the inhibition of the nocifensive response to formaldehyde promoted by restraint stress. The fish that received midazolam (40nmol) microinjection prior to restraint (3 or 5min), followed by subcutaneous injection with formaldehyde presented a higher distance traveled than the fish that received saline microinjection. This effect might reflect the specific action of midazolam on benzodiazepine receptors in the Dm telencephalon, as pre-treatment with flumazenil, a benzodiazepine receptor antagonist, inhibited the effects of this drug. In the present study, we present the first evidence demonstrating a role for the dorsomedial telencephalic region in the modulation of stress-induced antinociception in fish, revealing new perspectives in the understanding of nociceptive information processing in this group. PMID- 25914174 TI - Mice age - Does the age of the mother predict offspring behaviour? AB - Increasing paternal age is known to be associated with a great variety of psychiatric disorders such as schizophrenia or autism. Hence the factor "age" may be taken as strategic tool to analyse specific scientific hypotheses. Additionally, this finding also needs to be addressed in rather pragmatically performed breeding protocols of model organisms, since otherwise artefacts may challenge the validity of the results. Our study was performed to investigate influences of advanced age of mouse dams (30 vs. 16weeks) on maternal- and offspring behaviour. Adult offspring of both sexes was analysed in a test battery comprising paradigms for exploration, anxiety and depressive-like behaviours. Final blood sampling was conducted for stressphysiological analysis. Interestingly, advanced age of the mothers was associated with increased nest building quality while maternal activity was unaffected. Moreover "maternal (mice) age" (MA) affected emotionality in the offspring, which became apparent in the dark-light box and the social recognition paradigm. These findings not only emphasize MA to model a potent risk factor with regard to emotional stability, but also underscore the vast necessity to include information about breeding protocols into the methods section of any animal study. PMID- 25914176 TI - Role of fetal blood sampling in cases of non-visualization of fetal gallbladder. PMID- 25914175 TI - Aryloxyethyl Thiocyanates Are Potent Growth Inhibitors of Trypanosoma cruzi and Toxoplasma gondii. AB - As a part of our project aimed at searching for new safe chemotherapeutic agents against parasitic diseases, several compounds structurally related to the antiparasitic agent WC-9 (4-phenoxyphenoxyethyl thiocyanate), which were modified at the terminal phenyl ring, were designed, synthesized, and evaluated as growth inhibitors against Trypanosoma cruzi, the etiological agent of Chagas disease, and Toxoplasma gondii, the parasite responsible of toxoplasmosis. Most of the synthetic analogues exhibited similar antiparasitic activity and were slightly more potent than our lead WC-9. For example, two trifluoromethylated derivatives exhibited ED50 values of 10.0 and 9.2 MUM against intracellular T. cruzi, whereas they showed potent action against tachyzoites of T. gondii (ED50 values of 1.6 and 1.9 MUM against T. gondii). In addition, analogues of WC-9 in which the terminal aryl group is in the meta position with respect to the alkyl chain bearing the thiocyanate group showed potent inhibitory action against both T. cruzi and T. gondii at the very low micromolar range, which suggests that a para phenyl substitution pattern is not necessary for biological activity. PMID- 25914177 TI - Ossifying fibromyxoid tumor: report of a case with cytomorphologic description. AB - Ossifying fibromyxoid tumor (OFMT) is a rare soft tissue neoplasm with uncertain histogenesis. Most cases behave in a clinically benign fashion; however, a small percentage of tumors may locally recur or metastasize. Herein we present a case of a 56-year-old man who presented with an enlarging left groin mass, left inner thigh numbness, burning paresthesia and discomfort in his left groin. The mass sampled by fine- needle aspiration and needle core biopsy. Cytology showed bland appearing epithelioid cells with round nuclei and fine chromatin, with fragments of fibromyxoid stroma in the background. Immunohistochemical stains performed on the core biopsy showed that the lesional cells were focally positive for S100 protein and negative for desmin, smooth muscle actin, CD34 and cytokeratin AE1/AE3. A benign neoplasm was favored with ossifying fibromyxoid tumor as the main entity in the differential diagnosis. A subsequent resection showed a well circumscribed 5 cm mass with firm consistency and focal areas of calcifications. Histologically, the tumor had a nodular growth pattern with relatively bland spindle cells containing round to oval nuclei suspended in a variably collagenous to myxoid stroma. Significant ossification and bone formation was also noted. There was no significant atypia, necrosis or increased mitoses. Ossifying fibromyxoid tumors have distinct cytologic features and should be considered in the differential diagnosis of soft tissue tumors with prominent ossification. PMID- 25914179 TI - Gravity-Driven Multiple Collision-Enhanced Catalytic Soot Combustion over a Space Open Array Catalyst Consisting of Ultrathin Ceria Nanobelts. AB - More than 122 times higher contact efficiency between soot and catalysts is achieved over the as-prepared CeO(2) nanobelt array catalysts as compared with the powder nanoparticle catalyst. A novel gravity-driven multiple collision enhanced soot combustion mechanism is proposed for the first time. PMID- 25914178 TI - Assessment of tumor morphology on diffusion-weighted (DWI) breast MRI: Diagnostic value of reduced field of view DWI. AB - PURPOSE: To compare the diagnostic value of conventional, bilateral diffusion weighted imaging (DWI) and high-resolution targeted DWI of known breast lesions. MATERIALS AND METHODS: Twenty-one consecutive patients with known breast cancer or suspicious breast lesions were scanned with the conventional bilateral DWI technique, a high-resolution, reduced field of view (rFOV) DWI technique, and dynamic contrast-enhanced magnetic resonance imaging (DCE-MRI) (3.0 T). We compared bilateral DWI and rFOV DWI quantitatively by measuring the lesions' apparent diffusion coefficient (ADC) values. For qualitative comparison, three dedicated breast radiologists scored image quality and performed lesion interpretation. RESULTS: In a phantom, ADC values were in good agreement with the reference values. Twenty-one patients (30 lesions: 14 invasive carcinomas, 10 benign lesions [of which 5 cysts], 3 high-risk, and 3 in situ carcinomas) were included. Cysts and high-risk lesions were excluded from the quantitative analysis. Quantitatively, both bilateral and rFOV DWI measured lower ADC values in invasive tumors than other lesions. In vivo, rFOV DWI gave lower ADC values than bilateral DWI (1.11 * 10(-3) mm(2) /s vs. 1.24 * 10(-3) mm(2) /s, P = 0.002). Regions of interest (ROIs) were comparable in size between the two techniques (2.90 vs. 2.13 cm(2) , P = 0.721). Qualitatively, all three radiologists scored sharpness of rFOV DWI images as significantly higher than bilateral DWI (P <= 0.002). Receiver operating characteristic (ROC) curve analysis showed a higher area under the curve (AUC) in BI-RADS classification for rFOV DWI compared to bilateral DWI (0.71 to 0.93 vs. 0.61 to 0.76, respectively). CONCLUSION: Tumor morphology can be assessed in more detail with high-resolution DWI (rFOV) than with standard bilateral DWI by providing significantly sharper images. PMID- 25914180 TI - Purification of mRNA-programmed translation initiation complexes suitable for mass spectrometry analysis. AB - Liquid Chromatography coupled to tandem mass spectrometry (nanoLC-MS/MS) is a powerful analytical technique for the identification and mass analysis of complex protein mixtures. Here, we present a combination of methods developed for the extensive/deep proteomic analysis of purified ribosome/mRNA particles assembled in rabbit reticulocyte lysate (RRL). Ribosomes are assembled on chimeric biotinylated mRNA-DNA molecules immobilized on streptavidin-coated beads and incubated with RRL to form initiation complexes. After washing steps, the complexes are trypsin-digested directly on the beads in semi-native condition or after their elution from the beads in denaturing Laemmli buffer. The nanoLC-MS/MS analysis performed on complexes assembled on beta-globin, viral HCV, and histone H4 mRNAs revealed significant differences in initiation factors composition in agreement with models of translation initiation used by these different types of mRNAs. Using Laemmli-denaturing condition induces release of deeply buried peptides from the ribosome and eukaryotic initiation factor 3 (eIF3) allowing the identification of the nearly complete set of ribosomal proteins. PMID- 25914181 TI - Free flow-through anterolateral thigh flap for complex knee defect including the popliteal artery. AB - Reconstruction of complex knee defects including the popliteal artery presents a challenging problem in reconstructive microsurgery. Reconstruction of the popliteal artery and soft-tissue coverage should be performed simultaneously for limb salvage. We present the one-stage reconstruction of a complex knee defect including the popliteal artery using a free flow-through anterolateral thigh (ALT) flap as a bypass flap in two patients with sarcomas. In both patients, the popliteal artery and vein were reconstructed using branches of the lateral circumflex femoral arterial system. The flaps survived without vascular compromise and the limbs were preserved successfully. Free flow-through ALT flap enables simultaneous leg revascularization and soft-tissue coverage with a single free flap. The lateral circumflex femoral arterial system has many branches with large diameters, making it suitable for reconstruction of multiple infrapopliteal arteries. PMID- 25914182 TI - Photoswitchable Magnetic Resonance Imaging Contrast by Improved Light-Driven Coordination-Induced Spin State Switch. AB - We present a fully reversible and highly efficient on-off photoswitching of magnetic resonance imaging (MRI) contrast with green (500 nm) and violet-blue (435 nm) light. The contrast change is based on intramolecular light-driven coordination-induced spin state switch (LD-CISSS), performed with azopyridine substituted Ni-porphyrins. The relaxation time of the solvent protons in 3 mM solutions of the azoporphyrins in DMSO was switched between 3.5 and 1.7 s. The relaxivity of the contrast agent changes by a factor of 6.7. No fatigue or side reaction was observed, even after >100,000 switching cycles in air at room temperature. Electron-donating substituents at the pyridine improve the LD-CISSS in two ways: better photostationary states are achieved, and intramolecular binding is enhanced. PMID- 25914183 TI - Novel platensimycin derivatives with herbicidal activity. AB - BACKGROUND: Faced with the need to develop herbicides with different modes of action on account of weed resistance to existing herbicides, the sesquiterpene lactones can be the starting point in the search for new bioactive compounds. Lumisantonin and five novel amides have been evaluated against two monocotyledons and three dicotyledons. RESULTS: An efficient and versatile synthesis of lumisantonin and the five novel amides has been accomplished from readily available alpha-santonin. These compounds were subjected to evaluation for their biological activity against Sorghum bicolor (sorghum), Allium cepa (onion), Cucumis sativus (cucumber), Solanum lycopersicum (tomato) and Bidens pilosa (beggartick). Lumisantonin has inhibited the development of the aerial parts of sorghum and onion by 76 and 67% at 1000 uM respectively. One of the novel amides has prevented the growth of shoots and radicles of sorghum by 80 and 71% at 1000 uM respectively. CONCLUSION: All of the tested compounds have been found to exhibit promising seed germination inhibition. We can conclude that lumisantonin was on average the most lethal against all plant species evaluated; however, two of the novel amides have exhibited inhibition selectivity against monocotyledons when compared with dicotyledons. (c) 2015 Society of Chemical Industry. PMID- 25914184 TI - Natural killer T cells: novel players in biliary disease? PMID- 25914185 TI - Alterations of TMEM16a allostery in human retinal microarterioles in long standing hypertension. AB - We hypothesized that the calcium-activated chloride channel (CACC) transmembrane member 16A (TMEM16A) ionic mechanism may be a general mechanism in remodeling of vascular smooth muscles, including the retina. These vascular remodeling may have a critical impact on retinal ischemia during chronic hypertension. In this study, we examined TMEM16A protein interactions with calmodulin and CaMKIIdelta likely cause efflux of chloride, thus resulting in increased vascular resistance by increasing vascular wall tone in long-standing hypertension. Control experiments were performed in static concentrations of calcium and using the specific TMEM16A inhibitor T16Ainh-A01 [2-[(5-ethyl-1,6-dihydro-4-methyl-6-oxo-2-pyrimidinyl)thio] N-[4-(4-methoxyphenyl)-2-thia zolyl]acetamide]. The results of our study provide preliminary evidence that CACC shows altered pharmacologic and biochemical properties in retinal vessel in long-standing hypertension. PMID- 25914186 TI - Mortality in myasthenia gravis: A nationwide population-based follow-up study in Denmark. AB - INTRODUCTION: In previous studies of myasthenia gravis (MG), increased mortality has been reported. The aim of this study was to estimate mortality in patients with acetylcholine receptor antibody-positive (AChR-Ab-seropositive) MG in a nationwide population-based, long-term follow-up study. METHODS: All AChR-Ab seropositive MG patients, diagnosed between 1985 and 2005, were identified. Defined by age at diagnosis (<= 50 or >50 years), patients were classified as having early- or late-onset MG. For comparison, 10 non-MG individuals from the general population were matched with each patient. All patients and controls were followed until January 1, 2009. Mortality rates and estimated mortality rate ratios (MRRs) were calculated. RESULTS: Of 702 AChR-Ab-seropositive MG patients, 302 died during follow-up. Overall mortality was higher for patients with MG (MRR = 1.41, range 1.24-1.60). In late-onset women and men, the MRRs were 1.64 (1.36 1.99) and 1.22 (1.02-1.46), respectively. Total MRR was highest during the first 5 years after diagnosis. CONCLUSIONS: MG diagnosis is still associated with increased mortality. PMID- 25914187 TI - Enzymatic Chemoselective Aldehyde-Ketone Cross-Couplings through the Polarity Reversal of Methylacetoin. AB - The thiamine diphosphate (ThDP) dependent enzyme acetoin:dichlorophenolindophenol oxidoreductase (Ao:DCPIP OR) from Bacillus licheniformis was cloned and overexpressed in Escherichia coli. The recombinant enzyme shared close similarities with the acetylacetoin synthase (AAS) partially purified from Bacillus licheniformis suggesting that they could be the same enzyme. The product scope of the recombinant Ao:DCPIP OR was expanded to chiral tertiary alpha hydroxy ketones through the rare aldehyde-ketone cross-carboligation reaction. Unprecedented is the use of methylacetoin as the acetyl anion donor in combination with a range of strongly to weakly activated ketones. In some cases, Ao:DCPIP OR produced the desired tertiary alcohols with stereochemistry opposite to that obtained with other ThDP-dependent enzymes. The combination of methylacetoin as acyl anion synthon and novel ThDP-dependent enzymes considerably expands the available range of C-C bond formations in asymmetric synthesis. PMID- 25914189 TI - Therapeutic potential of targeting protein for Xklp2 silencing for pancreatic cancer. AB - The targeting protein for Xklp2 (TPX2) is a microtubule- and, cell cycle associated protein who's overexpression has been reported in various malignancies. In this study, we verified the overexpression of TPX2 in both surgically resected specimens of pancreatic cancer and multiple pancreatic cancer cell lines. Subsequently, we found that TPX2 siRNA effectively suppressed the proliferation of pancreatic cancer cells in culture, and the direct injection of TPX2 siRNA into subcutaneously implanted pancreatic cancer cells in nude mice revealed antiproliferative effects. These results implied a therapeutic potential of TPX2 siRNA in pancreatic cancer. Among 56 angiogenesis-related factors examined using angiogenesis arrays, the average protein levels of insulin-like growth factor-binding protein-3 (IGFBP-3) were significantly higher in TPX2 siRNA treated tumors than in the Control siRNA-treated tumors. Moreover, we demonstrated that CD34-positive microvessels were significantly reduced in tumors treated with TPX2 siRNA compared to tumors that treated with Control siRNA. The attenuated expression of CD34 in TPX2 siRNA-treated tumors coincided with the overexpression of IGFBP-3. These results indicated that TPX2 has an impact on tumor angiogenesis in pancreatic cancer. The results also implied that the antiangiogenic effect observed in TPX2 siRNA-treated pancreatic cancer cells may be partly explained by the upregulation of IGFBP-3. PMID- 25914188 TI - Mutations in epilepsy and intellectual disability genes in patients with features of Rett syndrome. AB - Rett syndrome and neurodevelopmental disorders with features overlapping this syndrome frequently remain unexplained in patients without clinically identified MECP2 mutations. We recruited a cohort of 11 patients with features of Rett syndrome and negative initial clinical testing for mutations in MECP2. We analyzed their phenotypes to determine whether patients met formal criteria for Rett syndrome, reviewed repeat clinical genetic testing, and performed exome sequencing of the probands. Using 2010 diagnostic criteria, three patients had classical Rett syndrome, including two for whom repeat MECP2 gene testing had identified mutations. In a patient with neonatal onset epilepsy with atypical Rett syndrome, we identified a frameshift deletion in STXBP1. Among seven patients with features of Rett syndrome not fulfilling formal diagnostic criteria, four had suspected pathogenic mutations, one each in MECP2, FOXG1, SCN8A, and IQSEC2. MECP2 mutations are highly correlated with classical Rett syndrome. Genes associated with atypical Rett syndrome, epilepsy, or intellectual disability should be considered in patients with features overlapping with Rett syndrome and negative MECP2 testing. While most of the identified mutations were apparently de novo, the SCN8A variant was inherited from an unaffected parent mosaic for the mutation, which is important to note for counseling regarding recurrence risks. PMID- 25914190 TI - Acetylcholinesterase inhibitory and antioxidant activities of novel symmetric sulfamides derived from phenethylamines. AB - The antioxidant and acetylcholinesterase inhibitory properties of novel symmetric sulfamides derived from phenethylamines were evaluated. Phenethylamines 8-11 were reacted with SO2Cl2 in the presence of Et3N to afford sulfamides in good yields. The synthesized sulfamides were converted to their phenolic derivatives with BBr3. We elucidated the antioxidant activity of novel symmetric sulfamides by using different bioanalytical assays. For this purpose, the radical scavenging activities of the novel symmetric sulfamides were assessed by DPPH(*), ABTS(*+), DMPD(*+), and O2(*-) radical scavenging tests. In addition, the reducing abilities of the novel symmetric sulfamides were evaluated by Fe(3+)-Fe(2+) reducing, Cu(2+)-Cu(+) reducing, and [Fe(3+)-(TPTZ)2](3+)-[Fe(2+)-(TPTZ)2](2+) reducing activity tests. Also, the Fe(2+) chelating activity by the pipyrdyl reagent and the acetylcholinesterase inhibitory activities of the novel symmetric sulfamides were studied. Especially, the novel phenolic and symmetric sulfamides 16-19 showed high antioxidant and acetylcholinesterase inhibitory properties. On the other hand, IC50 values were calculated for the DPPH(*), ABTS(*+), DMPD(*+), and O2(*-) scavenging, the metal chelating, and the acetylcholinesterase inhibition effects of the novel symmetric sulfamides. PMID- 25914191 TI - Clinical cardiac structural anatomy reconstructed within the cardiac contour using multidetector-row computed tomography: Atrial septum and ventricular septum. AB - Cardiologists are increasingly becoming involved in procedures associated with the atrial septum and ventricular septum, such as transseptal puncture and selective site pacing. Moreover, detailed knowledge about the architecture of the atrial septum and ventricular septum is now available from studies by radiologists and anatomists. However, from the viewpoint of clinical cardiologists, many questions about the three-dimensional cardiac structural anatomy that relate closely to routine invasive procedures remain unresolved. Although modern multidetector-row computed tomography could provide answers, interventional cardiologists might have not considered the potential of this equipment, as only a few have performed studies with both radiological imaging and cadaveric hearts. Detailed knowledge of the three-dimensional fluoroscopic cardiac structural anatomy could help to reduce the need for contrast medium injection and radiation exposure, and to perform safe interventions. In this article, we present a series of cardiac structural images, including images of the atrial septum and ventricular septum, reconstructed in combination with the cardiac contour using multidetector-row computed tomography. We also discuss the clinical implications of the findings on the basis of accumulated insights of research pioneers. We hope that the present images will serve as a bridge between the fields of cardiology, radiology, and anatomy, and encourage cardiologists to integrate their accumulated insights into the three-dimensional clinical images of the living heart. PMID- 25914192 TI - Rational Design of Ruthenium Complexes Containing 2,6-Bis(benzimidazolyl)pyridine Derivatives with Radiosensitization Activity by Enhancing p53 Activation. AB - The rational design of metal-based complexes is an effective strategy for the discovery of potent sensitizers for use in cancer radiotherapy. In this study, we synthesized three ruthenium complexes containing bis-benzimidazole derivatives: Ru(bbp)Cl3 (1), [Ru(bbp)2 ]Cl2 (2 a) (in which bbp=2,6-bis(benzimidazol-1 yl)pyridine), and [Ru(bbp)2]Cl2 (2 b) (where bbp=2,6-bis-(6-nitrobenzimidazol-2 yl)pyridine). We evaluated their radiosensitization capacities in vitro and mechanisms of action. Complex 2 b was found to be particularly effective in sensitizing human melanoma A375 cells toward radiation, with a sensitivity enhancement ratio of 2.4. Along with this potency, complex 2 b exhibited a high degree of selectivity between human cancer and normal cells. Mechanistic studies revealed that 2 b promotes radiation-induced accumulation of intracellular reactive oxygen species (ROS) by reacting with cellular glutathione (GSH) and then causing DNA stand breaks. The subsequent DNA damage induces phosphorylation of p53 (p-p53) and upregulates the expression levels of p21, which inhibits the expression of cyclin-B, leading to G2M arrest. Moreover, p-p53 activates caspases 3 and -8, triggers cleavage of poly(ADP-ribose) polymerase (PARP), finally resulting in apoptosis. Taken together, the results of this study provide a strategy for the design of ruthenium-based radiosensitizers for use in cancer therapy. PMID- 25914193 TI - Early prediction and aspirin for prevention of pre-eclampsia (EPAPP) study: a randomized controlled trial. AB - OBJECTIVE: To estimate the effect of early administration of aspirin on the prevention of pre-eclampsia in high-risk women. METHODS: This was planned as a randomized, double-blind, placebo-controlled trial of aspirin for women with risk factors for pre-eclampsia. Participants were randomized to start either aspirin (81 mg/day) or placebo at 11 + 0 to 13 + 6 weeks of gestation. The primary outcome was pre-eclampsia and secondary outcomes included gestational hypertension and small-for-gestational age at birth. RESULTS: The trial suffered from slow recruitment, leading to a protocol change to broaden the inclusion criteria (from a minimum score of multiple risk factors to at least one risk factor for pre-eclampsia). The trial was then terminated prematurely due to continuing slow recruitment and a lack of equipoise given a change in national guidelines to administer aspirin to high-risk women. From the 53 women who were randomized, 30 were included in the final analysis. There was no evidence that the primary outcome of pre-eclampsia was prevented by low-dose aspirin (relative risk (RR) 0.88, 95% CI 0.21-3.66). Gestational hypertension was seen in two women, both in the aspirin group. There was no evidence that the occurrence of small-for-gestational age was reduced by aspirin (RR 0.88, 95% CI 0.06-12.72). CONCLUSIONS: Although this study was underpowered to show effectiveness of aspirin compared to placebo due to the premature termination and difficulties encountered, it highlights practical issues to inform future studies. PMID- 25914194 TI - The diagnostic accuracy of ultrasound-guided fine-needle aspiration biopsy for thyroid nodules three centimeters or larger in size. AB - BACKGROUND AND PURPOSE: Whether under ultrasonography (US) guidance or not, fine needle aspiration biopsy (FNAB) has some limitations, particularly in larger nodules. In this study, we aimed to evaluate the diagnostic value of US-guided fine-needle aspiration biopsy (US-FNAB) in thyroid nodules equal to or larger than 3 cm. MATERIALS AND METHODS: Data of 267 patients operated for nodular goiter in the period of January 2006 and March 2012 were reviewed retrospectively. The study group (40 males, 104 females; mean age 42.3 +/- 12.3, between 17 and 71) consisted of patients with nodules with a diameter of 3 cm or larger. Patients with nodules less than 3 cm in diameter were considered as the control group (27 males, 96 females; mean age 44.4 +/- 11.9, between 18 and 71). RESULTS: For nodules smaller than 3 cm, US-FNAB had an accuracy rate of 60% and a false negativity rate of 21.9%. In nodules equal to or larger than 3 cm, the accuracy rate of US-FNAB was 80%, with a false negativity rate of 6.7%. Malignancy was observed in 16% of the study group and 42.3% of the control group. CONCLUSION: This study showed that increased nodule diameter is not associated with limitations in the diagnostic value of US-FNAB. We also found that the malignancy rate was smaller for larger nodules. This finding reflects the importance of accurate and rational diagnostic work-up and clinical management for detecting malignancy and surgical decision-making. PMID- 25914195 TI - Employing Tryptone as a General Phase Transfer Agent to Produce Renal Clearable Nanodots for Bioimaging. AB - Hydrophobic ultrasmall nanoparticles synthesized in nonpolar solvents exhibit great potential in biomedical applications. However, a major challenge when applying these nanomaterials in biomedical research is the lack of a versatile strategy to render them water dispersible while preserving the hydrodynamic diameter (HD) to be less than 8 nm for efficient renal clearance. To address this problem, tryptone is employed as the novel ligand to fabricate a simple, versatile, and inexpensive strategy for transferring hydrophobic NaGdF(4) nanodots (3 nm in diameter) from organic phase into aqueous phase without any complicated organic synthesis. The paramagnetic properties of NaGdF(4) nanodots are well retained after the phase transfer process. In particular, the tryptone NaGdF(4) nanodots have ultrasmall HD (ca., 7.5 nm), which greatly improves their tumor accumulation and facilitates renal clearance within 24 h postinjection. The as-prepared tryptone-NaGdF(4) nanodots can also be further functionalized with other molecules for extensively biomedical and bioanalytical applications. Furthermore, the proposed strategy can easily be extended to transfer other types of inorganic nanoparticles from hydrophobic to hydrophilic for facilitating biomedical applications. PMID- 25914196 TI - Comparing tract-based spatial statistics and manual region-of-Interest labeling as diffusion analysis methods to detect white matter abnormalities in infants with hypoxic-Ischemic encephalopathy. AB - PURPOSE: To compare manual region of interest (ROI) labeling and tract-based spatial statistics (TBSS) by their ability to detect group-wise differences in fractional anisotropy (FA) in the neonatal brain. MATERIALS AND METHODS: Diffusion-weighted data were obtained for nine infants with hypoxic-ischemic encephalopathy (HIE) (six males, three females; gestational age [GA] range, 36-40 weeks; mean GA, 37.8 weeks) and 11 healthy-control infants (10 males, 1 female; GA range, 36-40 weeks; mean GA, 38.4 weeks) at 3T. For manual ROI labeling, ROIs were drawn freehand for each subject in eight, clinically relevant brain regions. For TBSS, all FA data underwent an optimized, automated protocol for neonates. Each method was evaluated for detection of decreased FA in HIE infants, sensitivity, specificity, and variability. RESULTS: FA values from manual ROI and TBSS were strongly correlated (r = 0.94, P < 0.0001). Both methods found decreased FA in most ROIs for HIE infants. There was no significant interaction between method and group, indicating a similar ability to detect FA differences (F(1,19) = 0.599, P = 0.449). Sensitivity (manual: 0.709, TBSS: 0.694, 95% CI [ 0.136, 0.163], P = 0.856), specificity (manual and TBSS: 0.716, 95% CI [-0.133, 0.133], P = 1), and standard error (manual: 0.009, TBSS: 0.007) were comparable. CONCLUSION: Manual ROI labeling and TBSS are comparable methods of diffusion analysis to detect group differences in FA in the neonatal brain. PMID- 25914198 TI - Genetic changes in influenza A(H3N2) viruses circulating during 2011 to 2013 in northern India (Lucknow). AB - Genetic variability in the hemagglutinin (HA1) and the neuraminidase (NA) genes of influenza viruses results in the emergence of new strains which differ in pathogenicity and severity. The present study was undertaken for genotypic characterization of the HA1 and NA genes of the influenza A(H3N2) strains, detected during the 2011-2013. A total of fifty five influenza A(H3N2) positive samples [2011 (n = 20), 2012 (n = 4) and 2013 (n = 31)] were studied. The 824 bp segment of HA1 gene and 931 bp segment of NA gene were amplified and sequenced by Big-Dye terminator kit on ABI3130, Genetic analyzer. Molecular and phylogenetic analysis was done by MEGA 5.05 software and PhyML program (v3.0). Mutations were determined by comparing the deduced amino acid sequences of study strains with that of 2009-2013 vaccine strains. The studied influenza A(H3N2) strains showed 98.1-99.6% similarity in HA1 and NA amino acid sequences with the influenza A/Victoria/361/2011 vaccine strain. Four mutations in the HA1 amino acid sequences (T128A, R142G, L157S and N278K) and three unique mutations in the NA amino acid sequences [D251V, S315G and V313A] were found. These mutations were observed only in strains from the year 2013 (cluster II). None of the strains showed the presence of mutations, N294S and R292K, markers of oseltamivir resistance. In conclusion, Lucknow strains have accumulated the significant number of mutations in the antigenic sites of the HA and the NA coding sequences and continue to be evolving from the 2013 vaccine strain [A/Victoria/361/2011], however, mutations specific for oseltamivir resistance were not detected. PMID- 25914197 TI - Microbial metaproteomics for characterizing the range of metabolic functions and activities of human gut microbiota. AB - The human gastrointestinal tract is a complex, dynamic ecosystem that consists of a carefully tuned balance of human host and microbiota membership. The microbiome is not merely a collection of opportunistic parasites, but rather provides important functions to the host that are absolutely critical to many aspects of health, including nutrient transformation and absorption, drug metabolism, pathogen defense, and immune system development. Microbial metaproteomics provides the ability to characterize the human gut microbiota functions and metabolic activities at a remarkably deep level, revealing information about microbiome development and stability as well as their interactions with their human host. Generally, microbial and human proteins can be extracted and then measured by high performance MS-based proteomics technology. Here, we review the field of human gut microbiome metaproteomics, with a focus on the experimental and informatics considerations involved in characterizing systems ranging from low-complexity model gut microbiota in gnotobiotic mice, to the emerging gut microbiome in the GI tract of newborn human infants, and finally to an established gut microbiota in human adults. PMID- 25914199 TI - 4D spiral imaging of flows in stenotic phantoms and subjects with aortic stenosis. AB - PURPOSE: The utility of four-dimensional (4D) spiral flow in imaging of stenotic flows in both phantoms and human subjects with aortic stenosis is investigated. METHODS: The method performs 4D flow acquisitions through a stack of interleaved spiral k-space readouts. Relative to conventional 4D flow, which performs Cartesian readout, the method has reduced echo time. Thus, reduced flow artifacts are observed when imaging high-speed stenotic flows. Four-dimensional spiral flow also provides significant savings in scan times relative to conventional 4D flow. RESULTS: In vitro experiments were performed under both steady and pulsatile flows in a phantom model of severe stenosis (one inch diameter at the inlet, with 87% area reduction at the throat of the stenosis) while imaging a 6-cm axial extent of the phantom, which included the Gaussian-shaped stenotic narrowing. In all cases, gradient strength and slew rate for standard clinical acquisitions, and identical field of view and resolution were used. For low steady flow rates, quantitative and qualitative results showed a similar level of accuracy between 4D spiral flow (echo time [TE] = 2 ms, scan time = 40 s) and conventional 4D flow (TE = 3.6 ms, scan time = 1:01 min). However, in the case of high steady flow rates, 4D spiral flow (TE = 1.57 ms, scan time = 38 s) showed better visualization and accuracy as compared to conventional 4D flow (TE = 3.2 ms, scan time = 51 s). At low pulsatile flow rates, a good agreement was observed between 4D spiral flow (TE = 2 ms, scan time = 10:26 min) and conventional 4D flow (TE = 3.6 ms, scan time = 14:20 min). However, in the case of high flow-rate pulsatile flows, 4D spiral flow (TE = 1.57 ms, scan time = 10:26 min) demonstrated better visualization as compared to conventional 4D flow (TE = 3.2 ms, scan time = 14:20 min). The feasibility of 4D spiral flow was also investigated in five normal volunteers and four subjects with mild-to-moderate aortic stenosis. The approach achieved TE = 1.68 ms and scan time = 3:44 min. The conventional sequence achieved TE = 2.9 ms and scan time = 5:23 min. In subjects with aortic stenosis, we also compared both MRI methods with Doppler ultrasound (US) in the measurement of peak velocity, time to peak systolic velocity, and eject time. Bland-Altman analysis revealed that, when comparing peak velocities, the discrepancy between Doppler US and 4D spiral flow was significantly less than the discrepancy between Doppler and 4D Cartesian flow (2.75 cm/s vs. 10.25 cm/s), whereas the two MR methods were comparable (-5.75 s vs. -6 s) for time to peak. However, for the estimation of eject time, relative to Doppler US, the discrepancy for 4D conventional flow was smaller than that of 4D spiral flow (-16.25 s vs. -20 s). CONCLUSION: Relative to conventional 4D flow, 4D spiral flow achieves substantial reductions in both the TE and scan times; therefore, utility for it should be sought in a variety of in vivo and complex flow imaging applications. PMID- 25914200 TI - Cell-type specific functions of epidermal growth factor receptor are involved in development of hepatocellular carcinoma. PMID- 25914201 TI - Azole fungicides - understanding resistance mechanisms in agricultural fungal pathogens. AB - Plant fungal pathogens can have devastating effects on a wide range of crops, including cereals and fruit (such as wheat and grapes), causing losses in crop yield, which are costly to the agricultural economy and threaten food security. Azole antifungals are the treatment of choice; however, resistance has arisen against these compounds, which could lead to devastating consequences. Therefore, it is important to understand how these fungicides are used and how the resistance arises in order to tackle the problem fully. Here, we give an overview of the problem and discuss the mechanisms that mediate azole resistance in agriculture (point mutations in the CYP51 amino acid sequence, overexpression of the CYP51 enzyme and overexpression of genes encoding efflux pump proteins). (c) 2015 Society of Chemical Industry. PMID- 25914202 TI - N-Benzylcinnamide induces apoptosis in HPV16 and HPV18 cervical cancer cells via suppression of E6 and E7 protein expression. AB - Seventy percent of all cervical cancers are caused by human papillomavirus (HPV) infections. Natural products are being extensively explored for their potential ability to prevent and treat cervical cancers. N-benzylcinnamide (PT-3) is a natural product purified from Piper submultinerve. Whether or not PT-3 has an effect on cervical cancer cells is as yet unknown. Therefore, we set out to explore the mechanism of action behind PT-3 and how it affects cells that either contain or lack HPV DNA. Our results demonstrate that PT-3 slows the growth kinetics of CaSki (HPV-16 positive) and HeLa (HPV-18 positive) cells in a dose dependent manner, but does not slows HPV-negative cells. Importantly, we also found that PT-3 induces apoptosis by suppressing expression of E6 and E7 viral oncogenes in HPV-infected cervical cancer CaSki and HeLa cells. Moreover, we found that suppression of E6 and E7 expression leads to modulations in p53 and protein retinoblastomas, which are not changed in HPV-negative cervical cancer C33A cells. These findings demonstrate that PT-3 can effectively promote apoptosis by downregulating expression of E6 and E7. PMID- 25914203 TI - Musculoskeletal Symptoms in Nurses in the Early Implementation Phase of California's Safe Patient Handling Legislation. AB - Musculoskeletal injuries and symptoms are prevalent in nurses and are largely associated with strenuous patient handling. In 2011, California enacted legislation that required acute-care hospitals to implement safe patient handling (SPH) policies and programs. To assess the early phase of this legislation, we conducted an epidemiological assessment of organizational SPH practices, musculoskeletal symptoms, and perceptions in a random sample of 396 registered nurses. Among those who worked in hospitals and had patient handling duties (n = 220), the 12 month prevalence of work-related musculoskeletal symptoms was 69% (lower back 54%, neck 41%, shoulders 34%, and hands/wrists 26%). Twenty-two percent of the nurses reported that their hospitals had a "no-lift" policy, 37% reported that their hospitals had lift teams, and 61% reported the availability of mechanical lift equipment such as floor or ceiling lifts. Nurses whose facilities employed lift teams were significantly less likely to report low back pain (OR = 0.54, 95% CI [0.30-0.97]). Nurses whose units had ceiling lifts were significantly less likely to report shoulder pain than nurses with no access to lifts (OR = 0.32, 95% CI [0.10-0.98]). Roughly 60% of respondents were aware of the SPH law, and 33% reported changes in their hospital's patient handling policies or programs since the law went into effect. Hospital SPH practices reported by the nurses in our sample were generally sub-optimal, but our findings suggest positive effects of elements required by SPH legislation. These data will serve as the baseline for future evaluation of the impact of this law in California. PMID- 25914204 TI - Respiratory motile cilia dysfunction in a patient with cranioectodermal dysplasia. AB - Ciliopathies such as cranioectodermal dysplasia, Sensenbrenner syndrome, short rib polydactyly, and Jeune syndrome are associated with respiratory complications arising from rib cage dysplasia. While such ciliopathies have been demonstrated to involve primary cilia defects, we show motile cilia dysfunction in the airway of a patient diagnosed with cranioectodermal dysplasia. While this patient had mild thoracic dystrophy not requiring surgical treatment, there was nevertheless newborn respiratory distress, restrictive airway disease with possible obstructive airway involvement, repeated respiratory infections, and atelectasis. High-resolution videomicroscopy of nasal epithelial biopsy showed immotile/dyskinetic cilia and nasal nitric oxide was reduced, both of which are characteristics of primary ciliary dyskinesia, a sinopulmonary disease associated with mucociliary clearance defects due to motile cilia dysfunction in the airway. Exome sequencing analysis of this patient identified compound heterozygous mutations in WDR35, but no mutations in any of the 30 known primary ciliary dyskinesia genes or other cilia-related genes. Given that WDR35 is only known to be required for primary cilia function, we carried out WDR35 siRNA knockdown in human respiratory epithelia to assess the role of WDR35 in motile cilia function. This showed WDR35 deficiency disrupted ciliogenesis in the airway, indicating WDR35 is also required for formation of motile cilia. Together, these findings suggest patients with WDR35 mutations have an airway mucociliary clearance defect masked by their restrictive airway disease. PMID- 25914205 TI - Direct imaging of octahedral distortion in a complex molybdenum vanadium mixed oxide. AB - Complex Mo,V-based mixed oxides that crystallize in the orthorhombic M1-type structure are promising candidates for the selective oxidation of small alkanes. The oxygen sublattice of such a complex oxide has been studied by annular bright field scanning transmission electron microscopy. The recorded micrographs directly display the local distortion in the metal oxygen octahedra. From the degree of distortion we are able to draw conclusions on the distribution of oxidation states in the cation columns at different sites. The results are supported by X-ray diffraction and electron paramagnetic resonance measurements that provide integral details about the crystal structure and spin coupling, respectively. PMID- 25914206 TI - Quantifying surface albedo and other direct biogeophysical climate forcings of forestry activities. AB - By altering fluxes of heat, momentum, and moisture exchanges between the land surface and atmosphere, forestry and other land-use activities affect climate. Although long recognized scientifically as being important, these so-called biogeophysical forcings are rarely included in climate policies for forestry and other land management projects due to the many challenges associated with their quantification. Here, we review the scientific literature in the fields of atmospheric science and terrestrial ecology in light of three main objectives: (i) to elucidate the challenges associated with quantifying biogeophysical climate forcings connected to land use and land management, with a focus on the forestry sector; (ii) to identify and describe scientific approaches and/or metrics facilitating the quantification and interpretation of direct biogeophysical climate forcings; and (iii) to identify and recommend research priorities that can help overcome the challenges of their attribution to specific land-use activities, bridging the knowledge gap between the climate modeling, forest ecology, and resource management communities. We find that ignoring surface biogeophysics may mislead climate mitigation policies, yet existing metrics are unlikely to be sufficient. Successful metrics ought to (i) include both radiative and nonradiative climate forcings; (ii) reconcile disparities between biogeophysical and biogeochemical forcings, and (iii) acknowledge trade offs between global and local climate benefits. We call for more coordinated research among terrestrial ecologists, resource managers, and coupled climate modelers to harmonize datasets, refine analytical techniques, and corroborate and validate metrics that are more amenable to analyses at the scale of an individual site or region. PMID- 25914207 TI - Electrocardiographic effects of class 1 selective histone deacetylase inhibitor romidepsin. AB - Romidepsin is a histone deacetylase inhibitor approved by the FDA for the treatment of patients with cutaneous or peripheral T-cell lymphoma who have received prior systemic therapy. The objective of this analysis was to evaluate the potential QTc effects of romidepsin. Patients with advanced malignancy received 4-h infusions of 14 mg/m(2) romidepsin on days 1, 8, and 15 of a 28-day cycle. In cycle 2, a subset of patients received 1-h infusions of 8-12 mg/m(2) romidepsin. Patients were administered antiemetics before each romidepsin dose and electrolyte supplementation as needed. Electrocardiogram readings were performed prior to antiemetic administration, prior to romidepsin administration, and at specified time points over the subsequent 24 h. Romidepsin exposure and heart rate were also assessed. In the electrocardiogram-evaluable population, 26 patients received romidepsin at 14 mg/m(2) over 4 h. The maximum mean increases from the preantiemetic baseline for QTcF and heart rate were 10.1 msec (upper 90% CI, 14.5 msec) and 18.2 beats per minute, respectively. No patient in this study had an absolute QTcF value >450 msec and only one patient had an increase from the preantiemetic baseline of >60 msec. There was a mild reduction in the PR interval and no meaningful changes in the QRS interval. Despite the use of QT prolonging antiemetics, treatment with romidepsin did not markedly prolong the QTc interval through 24 h. Increases in calculated QTc may have been exaggerated as a consequence of transient increases in heart rate. PMID- 25914208 TI - Generated 3D-common feature hypotheses using the HipHop method for developing new topoisomerase I inhibitors. AB - The continued interest in designing novel topoisomerase I (Topo I) inhibitors and the lack of adequate ligand-based computer-aided drug discovery efforts combined with the drawbacks of structure-based design prompted us to explore the possibility of developing ligand-based three-dimensional (3D) pharmacophore(s). This approach avoids the pitfalls of structure-based techniques because it only focuses on common features among known ligands; furthermore, the pharmacophore model can be used as 3D search queries to discover new Topo I inhibitory scaffolds. In this article, we employed the HipHop module using Discovery Studio to construct plausible binding hypotheses for clinically used Topo I inhibitors, such as camptothecin, topotecan, belotecan, and SN-38, which is an active metabolite of irinotecan. The docked pose of topotecan was selected as a reference compound. The first hypothesis (Hypo 01) among the obtained 10 hypotheses was chosen for further analysis. Hypo 01 had six features, which were two hydrogen-bond acceptors, one hydrogen-bond donor, one hydrophob aromatic and one hydrophob aliphatic, and one ring aromatic. Our obtained hypothesis was checked by using some of the aromathecin derivatives which were published for their Topo I inhibitory potency. Moreover, five structures were found to be possible anti-Topo I compounds from the DruglikeDiverse database. From this research, it can be suggested that our model could be useful for further studies in order to design new potent Topo I-targeting antitumor drugs. PMID- 25914209 TI - Morphology of the humeral insertion of the supraspinatus and infraspinatus tendons: Application to rotator cuff repair. AB - In shoulder surgery, a precise understanding of anatomical relationships is required for accurate reconstruction. Reports in recent literature have challenged the traditional definitions of the humeral footprints of the supraspinatus and infraspinatus tendons. This study aims to precisely delineate these footprints. The rotator cuffs of 54 shoulders from 27 Australian Caucasoid donor cadavers were examined. The tendinous portions were dissected down to their region/footprint of attachment upon the humerus. Measurements of those footprints, upon the greater and lesser tuberosities, were made. Those measurements were statistically analyzed for any association with age, sex, height, or side. Twenty-seven cadavers had an average age at death of 74.9 (+/- 12.8), 56% were male, average height was 168 (+/- 8.6) cm. Due to premorbid fracture, or degeneration, 11 shoulders were excluded. The footprint of the supraspinatus was triangular, with a medial, anteroposterior length of 20.4 +/- 4.2 mm. Its lateral anteroposterior length was 6.3 +/- 1.6 mm and its maximal mediolateral width was 6.6 +/- 2.7 mm. Its calculated area was 122.0 +/- 66.6 mm(2). The footprint of the infraspinatus was trapezoidal, with a medial anteroposterior length 22.6 +/- 3.0 mm. Its lateral anteroposterior length was 25.4 +/- 3.3mm and its maximal mediolateral width was 12.0 +/- 2.7 mm. Its calculated area was 294.9 +/- 74.1 mm(2). There was no statistical correlation between size of the footprint and age, sex, side, or height. The humeral footprints of the supraspinatus and infraspinatus tendons upon the greater tuberosity were distinct. The lateral border of the infraspinatus' humeral attachment extended much farther anteriorly upon the highest facet of the greater tuberosity than in traditional descriptions. PMID- 25914210 TI - Resilience and Disruption in Observed Family Interactions in Youth With and Without Spina Bifida: An Eight-Year, Five-Wave Longitudinal Study. AB - OBJECTIVE: To examine differences between families of youth with spina bifida (SB) and families of typically developing (TD) youth on family-, parent-, and youth-level variables across preadolescence and adolescence. METHODS: Participants were 68 families of youth with SB and 68 families of TD youth. Ratings of observed family interactions were collected every 2 years at 5 time points (Time 1: ages 8-9 years; Time 5: ages 16-17 years). RESULTS: For families of youth with SB: families displayed less cohesion and more maternal psychological control during preadolescence (ages 8-9 years); parents presented as more united and displayed less dyadic conflict, and youth displayed less conflict behavior during the transition to adolescence (ages 10-13 years); mothers displayed more behavioral control during middle (ages 14-15 years) and late (ages 16-17 years) adolescence; youth displayed less engagement and more dependent behavior at every time point. CONCLUSIONS: Findings highlight areas of resilience and disruption in families of youth with SB across adolescence. PMID- 25914211 TI - Proteomic approach to understand metastatic spread. AB - The majority of tumor-related deaths are due to metastasis. Despite the clinical importance of understanding metastasis, we lack knowledge of the molecular mechanisms underlying tumor cell spreading and cell survival far from the primary tumor. Elucidating the molecular characteristics of highly metastatic carcinoma cells would help identify biomarkers or therapeutic targets relevant to predicting or combatting metastasis, and for this the phenotype of metastatic cells could be much more important than their genotype. Hence, proteomic approaches have wide potential utility. This review discusses possibilities of analyzing metastasis-specific protein patterns in a range of sample types, including in vitro and in vivo cancer models, and tissues and biological fluids from patients. Proteome approaches can identify proteins involved in regulating the metastatic capacities of tumors. PMID- 25914212 TI - Umbilical vein vasomotion detected in vivo by serial three-dimensional pixelwise spatially angle-corrected volume flow measurements. AB - OBJECTIVE: To explore changes in volume flow in the umbilical vein in healthy second-trimester fetuses. METHODS: This was a prospective observational pilot study performed at Stavanger University Hospital, Norway, between May and October 2013. Serial three-dimensional ultrasound recordings from the umbilical vein were acquired every 30 s in a 5-min period in 43 fetuses at 17-20 weeks' gestation. The recordings were analyzed with pixelwise spatially angle-corrected volume flow measurements. RESULTS: We observed variation in the umbilical vein volume flow in all fetuses, ranging from a mean minimum of 1.01 mL/s to a mean maximum of 2.60 mL/s. The minimum of all measurements was 57% compared with the mean value and the maximum was 148% of the mean value. The individual flow volume measurements ranged between 0.11 and 4.14 mL/s (mean, 1.76 mL/s). Within this range, an undulating course of all perfusion parameters was observed, with a full period of 4-5 min duration. CONCLUSION: Healthy second-trimester fetuses show cyclical variation in blood flow in the umbilical vein. Copyright (c) 2015 ISUOG. Published by John Wiley & Sons Ltd. PMID- 25914213 TI - Characterization of brown adipose tissue by water-fat separated magnetic resonance imaging. AB - BACKGROUND: To evaluate the possibility of quantifying brown adipose tissue (BAT) volume and fat concentration with a high resolution, long echo time, dual-echo Dixon imaging protocol. METHODS: A 0.42 mm isotropic resolution water-fat separated MRI protocol was implemented by using the second opposite-phase echo and third in-phase echo. Fat images were calibrated with regard to the intensity of nearby white adipose tissue (WAT) to form relative fat content (RFC) images. To evaluate the ability to measure BAT volume and RFC contrast dynamics, rats were divided into two groups that were kept at 4 degrees or 22 degrees C for 5 days. The rats were then scanned in a 70 cm bore 3.0 Tesla MRI scanner and a human dual energy CT. Interscapular, paraaortal, and perirenal BAT (i/pa/pr-BAT) depots as well as WAT and muscle were segmented in the MRI and CT images. Biopsies were collected from the identified BAT depots. RESULTS: The biopsies confirmed that the three depots identified with the RFC images consisted of BAT. There was a significant linear correlation (P < 0.001) between the measured RFC and the Hounsfield units from DECT. Significantly lower iBAT RFC (P = 0.0064) and significantly larger iBAT and prBAT volumes (P = 0.0017) were observed in the cold stimulated rats. CONCLUSION: The calibrated Dixon images with RFC scaling can depict BAT and be used to measure differences in volume, and fat concentration, induced by cold stimulation. The high correlation between RFC and HU suggests that the fat concentration is the main RFC image contrast mechanism. PMID- 25914214 TI - Proteomic profile of the plant-pathogenic oomycete Phytophthora capsici in response to the fungicide pyrimorph. AB - Pyrimorph is a novel fungicide from the carboxylic acid amide (CAA) family used to control plant-pathogenic oomycetes such as Phytophthora capsici. The proteomic response of P. capsici to pyrimorph was investigated using the iTRAQ technology to determine the target site of the fungicide and potential biomarker candidates of drug efficacy. A total of 1336 unique proteins were identified from the mycelium of wild-type P. capsici isolate (Hd3) and two pyrimorph-resistant mutants (R3-1 and R3-2) grown in the presence or absence of pyrimorph. Comparative analysis revealed that the three P. capsici isolates Hd3, R3-1, and R3-2 produced 163, 77, and 13 unique proteins, respectively, which exhibited altered levels of abundance in response to the pyrimorph treatment. Further investigations, using Cluster of Orthologous Groups of Proteins (COG) analysis and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway analysis identified 35 proteins related to the mode of action of pyrimorph against P. capsici and 62 proteins involved in the stress response of P. capsici to pyrimorph. Many of the proteins with altered expression were associated with glucose and energy metabolism. Biochemical analysis using d-[U-(14) C]glucose verified the proteomics data, suggesting that the major mode of action of pyrimorph in P. capsici is the inhibition of cell wall biosynthesis. These results also illustrate that proteomics approaches are useful tools for determining the pathways targeted by novel fungicides as well as for evaluating the tolerance of plant pathogens to environmental challenges, such as the presence of fungicides. PMID- 25914215 TI - Comparison of clinical performances among Roche Cobas HPV, RFMP HPV PapilloTyper and Hybrid Capture 2 assays for detection of high-risk types of human papillomavirus. AB - The cervical cancer screening guidelines suggest that early detection of HPV16 and HPV18 is helpful for identifying women with cervical intraepithelial neoplasia (CIN) grade two or higher. We comparatively evaluated three HPV DNA assays, Roche Cobas HPV, RFMP HPV PapilloTyper, and Hybrid Capture 2 (HC2). A total of 861 cervical swab samples from women over 30 years of age were classified into two groups, that is, high grade squamous intraepithelial lesion (HSIL) and non-HSIL, according to cervical cytology results and analyzed by three assays. The results of direct sequencing or Linear array HPV genotyping test were considered true when the three assays presented discrepancies. The concordance rates between Roche Cobas HPV versus RFMP HPV PapilloTyper, RFMP HPV PapilloTyper versus HC2, and Roche Cobas versus HC2 were 94.5%, 94.3%, and 95.9%, respectively. For detection of HPV16 and HPV18, Roche Cobas HPV showed the concordance rates of 98.3% (kappa = 0.73) and 99.4% (kappa = 0.40) with the confirmation tests, respectively; and RFMP HPV PapilloTyper showed the concordance rates of 99.5% (kappa = 0.92) and 100.0% (kappa = 1.00), respectively. In conclusion, Roche Cobas HPV, RFMP HPV PapilloTyper, and HC2 showed high agreement rates. Roche Cobas HPV and RFMP HPV PapilloTyper are particularly useful, since both provide HPV specific genotypes, HPV16 and HPV18. PMID- 25914216 TI - Neurophysiological fingerprints of X-linked dystonia-parkinsonism: A model basal ganglia disease. PMID- 25914217 TI - Impact of clinically evident portal hypertension on the course of hepatocellular carcinoma in patients listed for liver transplantation. AB - Liver transplantation (LT) is the best curative treatment for early hepatocellular carcinoma (HCC) in patients with cirrhosis. However, the current shortage of organs causes prolonged waiting times and poorer intention-to-treat (ITT) survival (i.e., after listing) owing to tumor progression and dropout. Portal hypertension (PH) is a recognized risk factor of HCC development in patients with cirrhosis and its recurrence after resection. The aim of this study was to evaluate the potential impact of PHT on the results of LT on an ITT basis. Patients with cirrhosis listed for LT for HCC were included and their outcomes after listing were compared according to the presence or absence of PH defined as presence of esophageal varices or ascites or low platelet count and splenomegaly. Among 243 consecutively listed patients, 70% were affected by PH, which was associated with a significantly higher risk of tumor progression (38% vs. 22%; P = 0.017) and a higher risk of dropout (22% vs. 8%; P = 0.01). Transarterial chemoembolization (TACE) was similarly applied to the two groups (60% vs. 67%; P = 0.325). An absence of TACE was the only other independent risk factor of dropout owing to tumor progression. Under an ITT analysis, PH reduced overall survival (OS), but there was no difference in OS and time to recurrence post-LT. The only pathological feature that could potentially explain this observation was the lower complete response to TACE in the PHT group (12% vs. 36%; P = 0.001). CONCLUSION: PH should be regarded as a major risk factor of dropout owing to tumor progression and should be taken into consideration when managing patients with HCC who are waiting for LT. PMID- 25914218 TI - Sublethal effects of the insecticidal fusion protein omega-ACTX-Hv1a/GNA on the parasitoid Eulophus pennicornis via its host Lacanobia oleracea. AB - BACKGROUND: The neurotoxin peptide omega-ACTX-Hv1a, fused to the carrier molecule GNA, presents potential for insect control as a biopesticide, being orally toxic to insect pests from different orders. However, thorough evaluation is required to assure its safety towards non-target invertebrates. Effects of this novel biopesticide on the parasitoid Eulophus pennicornis via its host Lacanobia oleracea are presented. RESULTS: Hv1a/GNA did not cause mortality when injected or fed to fifth-stage L. oleracea, but caused up to 39% reduction in mean larval weight (P < 0.05) and increased developmental time when injected. When fed, GNA, but not Hv1a/GNA, caused ~35% reduction in larval weight, indicating that host quality was not affected by the fusion protein. Although GNA and Hv1a/GNA were internalised by the hosts following ingestion, and thus were available to higher trophic levels, no significant changes in the rate of E. pennicornis parasitism occurred. Number of parasitoid pupae per host, adult emergence and sex ratio were unaffected by GNA- or Hv1a/GNA-treated hosts (P > 0.05). The fusion protein was degraded by parasitoid larvae, rendering it non-toxic. CONCLUSION: Hv1a/GNA has negligible effects on the parasitoid, even under worst-case scenarios. This low toxicity to these insects is of interest in terms of biopesticide specificity and safety to non-target organisms. PMID- 25914219 TI - A conversation analysis of verbal interactions and social processes in interpreter-mediated primary care encounters. AB - Language asymmetry between patients with limited English proficiency and health care providers increases the complexity of patient-provider communication. In this research, we used conversation analysis to examine the content and processes of five triadic clinical communication encounters between Spanish-speaking adult patients, English-speaking nurse practitioners, and clinic-based interpreters. Data collection included audio-recordings of the triadic clinical encounters and self-administered post-encounter surveys of the nurse practitioners and interpreters. Our findings revealed communication trouble spots that, when directly addressed by the interactants, facilitated processes of negotiating relationships, and coming to a mutual understanding. Exemplars labeled Making Assumptions; Colloquialisms as Signaling Potential for Trouble; Repairing a Mis Statement; and Turn-Taking, Silences, and Laughter illustrated how the parties identified and navigated such trouble spots. The final exemplar, Attaining Intersubjectivity, represented a successful multi-lingual triadic communication. While the role of the interpreter often is seen as a conduit of information from one language to another, in practice they also enacted roles of communication collaborators and coconstructors. Future interdisciplinary research can include closer examination of occurrences of communication trouble spots and further exploration of how interpretermediated communication is conceptualized and problematized in diverse clinical settings, to promote language interpretation policies and practices that contribute to reducing health disparities among limited-English-proficient populations. PMID- 25914220 TI - A postzygotic NRAS mutation in a patient with Schimmelpenning syndrome. PMID- 25914221 TI - Validity of the Family Quality of Life Survey-2006. AB - BACKGROUND: Family Quality of Life (FQOL) is an important construct in the Intellectual Disabilities field. Several measures exist, including one developed by an international group, the Family Quality of Life Survey-2006 (FQOLS-2006; Brown et al.2006). However, the psychometric properties of this measure have yet to be fully investigated. This study was designed to examine its concurrent validity compared to the well established Beach Center FQOL Scale. MATERIALS AND METHODS: In a sample of 62 families of school-aged Canadian children with intellectual disability and/or autism spectrum disorder, both the FQOLS-2006 and the Beach Center FQOL scale were administered and the scores compared. RESULTS: The total scores of the two measures were strongly correlated, as were particular subscales that would be expected to correlate. However, there were several surprising correlations as well. CONCLUSIONS: The FQOLS-2006 shows good concurrent validity relative to the Beach Center scale, although some domains show unexpected relationships, suggesting further research is needed. PMID- 25914222 TI - The mechanism of color change in the neon tetra fish: a light-induced tunable photonic crystal array. AB - The fresh water fish neon tetra has the ability to change the structural color of its lateral stripe in response to a change in the light conditions, from blue green in the light-adapted state to indigo in the dark-adapted state. The colors are produced by constructive interference of light reflected from stacks of intracellular guanine crystals, forming tunable photonic crystal arrays. We have used micro X-ray diffraction to track in time distinct diffraction spots corresponding to individual crystal arrays within a single cell during the color change. We demonstrate that reversible variations in crystal tilt within individual arrays are responsible for the light-induced color variations. These results settle a long-standing debate between the two proposed models, the "Venetian blinds" model and the "accordion" model. The insight gained from this biogenic light-induced photonic tunable system may provide inspiration for the design of artificial optical tunable systems. PMID- 25914224 TI - Notch-1 promotes stemness and epithelial to mesenchymal transition in colorectal cancer. AB - Colorectal cancer (CRC) is the third leading cause of cancer death in the United States, resulting in an average of 50,000 deaths per year. Surgery and combination chemotherapy comprise current treatment strategies. However, curative options are limited if surgery and chemotherapy are unsuccessful. Several studies have indicated that CRC aggressiveness and potential for metastatic spread are associated with the acquisition of stem cell like properties. The Notch-1 receptor and its cognate signaling pathway is well known for controlling cell fate decisions and stem-cell phenotypes. Alterations in Notch receptors and Notch signaling has been reported for some colon cancers. Herein, we examine a potential role for Notch-1 signaling in CRC. In CRC patient samples, Notch-1 expression was increased in colon tumor tissue as compared with normal colon tissue. Retroviral transduction of constitutively active Notch-1 (ICN1) into the colon tumor cell line HCT-116 resulted in increased expression of the EMT/stemness associated proteins CD44, Slug, Smad-3, and induction of Jagged-1 expression. These changes in ICN1 expressing cells were accompanied by increased migration and increased anchorage independent growth by 2.5-fold and 23%, respectively. Experiments with the pan-Notch inhibitor DAPT, and soluble Jagged-1 Fc protein provided evidence that Notch-1 signaling activates CD44, Slug, and Smad-3 via a cascade of other Notch-receptors through induction of Jagged-1 expression. These data indicate a key role for Notch signaling in the phenotype of CRC and suggest that targeting of Notch signaling may be of therapeutic value in colon cancers. PMID- 25914223 TI - At what age should screening mammography be recommended for Asian women? AB - Although regular screening mammography has been suggested to be associated with improvements in the relative survival of breast cancer in recent years, the appropriate age to start screening mammography remains controversial. In November 2009, the United States Preventive Service Task Force published updated guidelines for breast cancer, which no longer support routine screening mammography for women aged 40-49 years, but instead, defer the choice of screening in that age group to the patient and physician. The age to begin screening differs between guidelines, including those from the Task Force, the American Cancer Society and the World Health Organization. It remains unclear how this discrepancy impacts patient survival, especially among certain subpopulations. Although the biological characteristics of breast cancer and peak age of incidence differ among different ethnic populations, there have been few reports that evaluate the starting age for screening mammography based on ethnicity. Here, we discuss the benefits and harm of screening mammography in the fifth decade, and re-evaluate the starting age for screening mammography taking ethnicity into account, focusing on the Asian population. Breast cancer incidence peaked in the fifth decade in Asian women, which has been thought to be due to a combination of biological and environmental factors. Previous reports suggest that Asian women in their 40s may receive more benefit and less harm from screening mammography than the age-matched non-Asian US population. Therefore, starting screening mammography at age 40 may be beneficial for women of Asian ethnicity in well-resourced countries, such as Japanese women who reside in Japan. PMID- 25914225 TI - Biomechanical effects of the transcondylar approach on the craniovertebral junction. AB - The transcondylar variation of the far-lateral, retrosigmoid approach is intended for pathologies in the anterolateral portion of the foramen magnum. That area is more clearly visualized when a fraction of the ipsilateral occipital condyle is removed. In this study, the biomechanical effect of this approach on occiput-C2 rotation was investigated. Our hypothesis was that the biomechanical characteristics are significantly altered following the transcondylar approach. Five human cadaveric upper cervical spine specimens (occiput-C7) were used in the study. Torsional moments were applied from zero to a maximum of 1.5 N m to the left and to the right using a mechanical testing machine. The resulting rotational motions of the O-C1, C1-2, and O-C2 segments were measured in the intact specimen and after a simulated right-sided transcondylar approach with resection of 2/3 of the condyle, confirmed by CT scanning and visual inspection. After the posterior two-thirds of the occipital condyle were removed, the neutral zone (NZ) increased 1.3 degrees to the left and 2 degrees to the right at C0 C1, and 7.4 degrees to the left and 6.2 degrees to the right at C1-2. The cumulative increase in NZ between O and C2 was 8.7 degrees to the left and 8.2 degrees to the right. The transcondylar approach also resulted in significant increases in range of motion (ROM) in axial rotation to both sides in all segments. ROM increased 2.8 degrees to the left and 2.4 degrees to the right between C0 and C1, 7.3 degrees to the left and 5.4 degrees to the right between C1 and C2, and 10.1 degrees to the left and 7.8 degrees to the right between CO and C2. Upon inspection, the area of the occipital condyle where the alar ligament attaches had been completely removed in three of the five specimens. Removing the posteromedial two-thirds of one occipital condyle alters the normal axial rotational movements of the craniovertebral junction on both sides. The insertion of the alar ligament can be inadvertently removed during condylar resection, and this could contribute to atlanto-axial instability. There is a biomechanical substrate to cranio-cervical instability following a transcondylar approach; these patients may need to be followed over several years to ensure it does not progress and necessitate occipito-cervical fusion. PMID- 25914226 TI - Secretome analysis of human articular chondrocytes unravels catabolic effects of nicotine on the joint. AB - PURPOSE: Osteoarthritis (OA) is a degenerative joint pathology characterized by articular cartilage degradation that lacks from efficient therapy. Since previous epidemiological data show a high controversy regarding the role of smoking in OA, we aimed to evaluate the effects of nicotine (the most physiologically active compound of tobacco) on the joint. EXPERIMENTAL DESIGN: Secretome analyses, based on metabolic labeling followed by LC-MALDI-TOF/TOF analysis, were carried out using an in vitro model of articular inflammation (primary human articular chondrocytes treated with interleukin-1beta), and also on osteoarthritic cells. ELISA and Western blot assays were performed to verify some of the results. RESULTS: Nineteen proteins were altered by nicotine in the model of articular inflammation, including several cytokines and proteases. We confirmed the increased secretion by nicotine of matrix metalloproteinase 1 and two proposed markers of OA, fibronectin, and chitinase 3-like protein 1. Finally, four components of the extracellular matrix of cartilage were decreased by nicotine in OA chondrocytes. CONCLUSIONS AND CLINICAL RELEVANCE: Our data contribute to a better understanding of the molecular mechanisms that are modulated by nicotine in cartilage cells, suggesting a negative effect of this drug on the joint. PMID- 25914229 TI - Identification of Stevens-Johnson syndrome and toxic epidermal necrolysis in electronic health record databases. AB - BACKGROUND: Stevens-Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN) carry a high mortality risk. While identifying clinical and genetic risk factors for these conditions has been hindered by their rarity, large electronic health databases hold promise for identifying large numbers of cases for study, especially with the introduction in 2008 of ICD-9 codes more specific for these conditions. OBJECTIVE: The objective of this study is to estimate the validity of ICD-9 codes for ascertaining SJS/TEN in 12 collaborating research units in the USA, covering almost 60 million lives. METHODS: From the electronic databases at each site, we ascertained potential cases of SJS/TEN using ICD-9 codes. At five sites, a subset of medical records was abstracted and standardized criteria applied by board-certified dermatologists to adjudicate diagnoses. Multivariate logistic regression was used to identify factors independently associated with validated SJS/TEN cases. RESULTS: A total of 56 591 potential cases of SJS/TEN were identified. A subset of 276 charts was selected for adjudication and 39 (of the 276) were confirmed as SJS/TEN. Patients with the ICD-9 codes introduced after 2008 were more likely to be confirmed as cases (OR 3.32; 95%CI 0.82, 13.47) than those identified in earlier years. Likelihood of case status increased with length of hospitalization. Applying the probability of case status to the 56 591 potential cases, we estimated 475-875 to be valid SJS/TEN cases. CONCLUSION: Newer ICD-9 codes, along with length of hospitalization, identified patients with a high likelihood of SJS/TEN. This is important for identification of subjects for future pharmacogenomics studies. PMID- 25914230 TI - Five years of experience with biochemical cystic fibrosis newborn screening based on IRT/PAP in Germany. AB - BACKGROUND: Evidence from recent studies suggests that IRT/PAP protocols may be successfully used as a purely biochemical newborn screening (NBS) for cystic fibrosis (CF) that does not require genetic screening. However, the experience with the performance of different IRT/PAP protocols remains limited. In this study, we evaluated the performance of IRT/PAP-based CF-NBS used in two German regions between 2008 and 2013 in a large cohort. METHODS: In both regions slightly different IRT/PAP protocols were used to screen newborns for CF. In contrast to the original IRT/PAP protocol published by Sarles et al., both German protocols contained an IRT-dependent safety net strategy (CF-NBS positive, if IRT>=99.9th percentile). Positive rating of the screening result led to confirmatory diagnostics using sweat chloride testing and clinical assessment. FINDINGS: A total of 328,181 newborns were tested with IRT/PAP in Germany within 5 years. 639 of these newborns (0.19%) were tested positive, and 60 infants were diagnosed with CF leading to a sensitivity of 0.968 and a PPV (positive predictive value) of 0.097. Compared to IRT/DNA protocols, the PPV of IRT/PAP is lower, but PAP used as second tier test has the advantage of a lower detection rate of healthy carriers and CF patients with equivocal results. CONCLUSIONS: Our results obtained in a large cohort of ~330,000 newborns support the use of a purely biochemical IRT/PAP protocol as an acceptable alternative when genetic CF NBS has to be avoided. PMID- 25914231 TI - Interface-free two-dimensional heart-cutting capillary electrophoresis for the separation and stacking of anionic and neutral analytes. AB - Interface-free two-dimensional heart-cutting capillary electrophoresis for two different classes of analytes (anionic and neutral) in a single capillary is presented. Simultaneous sample stacking and orthogonal separation were demonstrated. The anionic species were first analyzed by capillary zone electrophoresis in the first dimension. Then, the neutral compounds were separated in the second dimension by micellar electrokinetic chromatography using the common anionic surfactant sodium dodecyl sulfate. The first and second dimensions occurred automatically without changing the electrolyte and without polarity switching. Artificial mixtures (five anions and four neutral compounds) were successfully analyzed with sensitivity enhancement factors from 7 to 28. The orthogonal separation was complete within 8 min. Some analytical features and application to a spiked real river water sample were also studied. PMID- 25914232 TI - Bioorthogonal mimetics of palmitoyl-CoA and myristoyl-CoA and their subsequent isolation by click chemistry and characterization by mass spectrometry reveal novel acylated host-proteins modified by HIV-1 infection. AB - Protein acylation plays a critical role in protein localization and function. Acylation is essential for human immunodeficiency virus 1 (HIV-1) assembly and budding of HIV-1 from the plasma membrane in lipid raft microdomains and is mediated by myristoylation of the Gag polyprotein and the copackaging of the envelope protein is facilitated by colocalization mediated by palmitoylation. Since the viral accessory protein NEF has been shown to alter the substrate specificity of myristoyl transferases, and alter cargo trafficking lipid rafts, we hypothesized that HIV-1 infection may alter protein acylation globally. To test this hypothesis, we labeled HIV-1 infected cells with biomimetics of acyl azides, which are incorporated in a manner analogous to natural acyl-Co-A. A terminal azide group allowed us to use a copper catalyzed click chemistry to conjugate the incorporated modifications to a number of substrates to carry out SDS-PAGE, fluorescence microscopy, and enrichment for LC-MS/MS. Using LC-MS/MS, we identified 103 and 174 proteins from the myristic and palmitic azide enrichments, with 27 and 45 proteins respectively that differentiated HIV-1 infected from uninfected cells. This approach has provided us with important insights into HIV-1 biology and is widely applicable to many virological systems. PMID- 25914233 TI - Hypermutation in the E2 gene of human papillomavirus type 16 in cervical intraepithelial neoplasia. AB - Persistent infection with oncogenic human papillomavirus (HPV) causes cervical cancer. However, viral genetic changes during cervical carcinogenesis are not fully understood. Recent studies have revealed the presence of adenine/thymine clustered hypermutation in the long control region of the HPV16 genome in cervical intraepithelial neoplasia (CIN) lesions, and suggested that apolipoprotein B mRNA editing enzyme, catalytic polypeptide-like (APOBEC) proteins, which play a key role in innate immunity against retroviral infection, potentially introduce such hypermutation. This study reports for the first time the detection of adenine/thymine-clustered hypermutation in the E2 gene of HPV16 isolated from clinical specimens with low- and high-grade CIN lesions (CIN1/3). Differential DNA denaturation PCR, which utilizes lower denaturation temperatures to selectively amplify adenine/thymine-rich DNA, identified clusters of adenine/thymine mutations in the E2 gene in 4 of 11 CIN1 (36.4%), and 6 of 27 CIN3 (22.2%) samples. Interestingly, the number of mutations per sample was higher in CIN3 than in CIN1. Although the relevance of E2 hypermutation in cervical carcinogenesis remains unclear, the observed hypermutation patterns strongly imply involvement of APOBEC3 proteins in editing the HPV16 genome during natural viral infection. PMID- 25914234 TI - Successful treatment of functional palatal tremor: Insights into pathogenesis and management. PMID- 25914235 TI - Chrysin-organogermanium (IV) complex induced Colo205 cell apoptosis-associated mitochondrial function and anti-angiogenesis. AB - Colorectal cancer, a kind of malignant cancer, has more than 1 million new patients and results in 0.5 million deaths every year globally based on the estimation of Globocan in 2008. One of the most important issues against colon cancer is tumor metastasis. Anti-angiogenesis, a form of targeted therapy uses drugs or other substances to prevent the new blood vessel formation, which is critical for tumor metastasis. In our previous studies, we have demonstrated a simple method to synthesize Chry-Ge complex through the reaction between chrysin and triphenylgermanium bromide. In this work, we investigated the mechanism of Chry-Ge induced Colo205 cell apoptosis. We found that Chry-Ge could induce apoptosis in Colo205 cells in mitochondrial-dependent pathway, cause the reorganization of cytoskeleton and induce the damage of nucleus in Colo205 cells. Besides, Chry-Ge was also found to induce membrane ultrastructural changes in Colo205 cells by AFM. Further, we found that Chry-Ge can inhibit tube formation of human umbilical vascular endothelial cell in vitro. Chry-Ge was also tested in vivo in the chicken chorioallantoic membrane (CAM) assay and found to inhibit bFGF-treated CAMs development. These results suggested that Chry-Ge could induce Colo205 cell apoptosis by mitochondrial pathway and anti-angiogenesis, highlighting the use of organic germanium agents for the treatment of colorectal cancer. PMID- 25914236 TI - Binding of the respiratory chain inhibitor ametoctradin to the mitochondrial bc1 complex. AB - BACKGROUND: Ametoctradin is an agricultural fungicide that inhibits the mitochondrial bc1 complex of oomycetes. The bc1 complex has two quinone binding sites that can be addressed by inhibitors. Depending on their binding sites and binding modes, the inhibitors show different degrees of cross-resistance that need to be considered when designing spray programmes for agricultural fungicides. The binding site of ametoctradin was unknown. RESULTS: Cross resistance analyses, the reduction of isolated Pythium sp. bc1 complex in the presence of different inhibitors and molecular modelling studies were used to analyse the binding site and binding mode of ametoctradin. All three approaches provide data supporting the argument that ametoctradin binds to the Pythium bc1 complex similarly to stigmatellin. CONCLUSION: The binding mode of ametoctradin differs from other agricultural fungicides such as cyazofamid and the strobilurins. This explains the lack of cross-resistance with strobilurins and related inhibitors, where resistance is mainly caused by G143A amino acid exchange. Accordingly, mixtures or alternating applications of these fungicides and ametoctradin can help to minimise the risk of the emergence of new resistant isolates. PMID- 25914237 TI - Can noninvasive biomarkers replace liver biopsy for chronic hepatitis B? PMID- 25914239 TI - Peer Interactions among Children with Profound Intellectual and Multiple Disabilities during Group Activities. AB - BACKGROUND: Children with profound intellectual and multiple disabilities (PIMD) meet other children with PIMD in day care centres or schools. This study explores the peer-directed behaviours of children with PIMD, the peer interaction influencing behaviour of the direct support workers and the children's positioning. METHOD: Group activities for children with PIMD initiated by a direct support worker were video-recorded. The behaviour and positioning of the children and the behaviour of the direct support workers were coded. RESULTS: Limited peer-directed behaviour of the children with PIMD and peer interaction influencing behaviour of the direct support workers are observed. Weak associations were found between the positioning or peer interaction-influencing behaviours and the behaviour of children with PIMD. CONCLUSIONS: Children with PIMD show social interest in each other during group activities. More knowledge is needed to create an environment which facilitates peer-directed behaviours of persons with PIMD. PMID- 25914238 TI - Prognostic significance of prospectively detected bone marrow micrometastases in esophagogastric cancer: 10-year follow-up confirms prognostic significance. AB - We have previously reported that most patients with esophagogastric cancer (EGC) undergoing potentially curative resections have bone marrow micrometastases (BMM). We present 10-year outcome data of patients with EGC whose rib marrow was examined for micrometastases and correlate the findings with treatment and conventional pathologic tumor staging. A total of 88 patients with localized esophagogastric tumors had radical en-bloc esophagectomy, with 47 patients receiving neoadjuvant (5-fluorouracil/cisplatin based) chemoradiotherapy (CRT) and the remainder being treated with surgery alone. Rib marrow was examined for cytokeratin-18-positive cells. Standard demographic and pathologic features were recorded and patients were followed for a mean 10.04 years. Disease recurrences and all deaths in the follow-up period were recorded. No patients were lost to follow-up. 46 EGC-related and 10 non-EGC-related deaths occurred. Multivariate Cox analysis of interaction of neoadjuvant chemotherapy, nodal status, and BMM positivity showed that the contribution of BMM to disease-specific and overall survival is significant (P = 0.014). There is significant interaction with neoadjvant CRT (P < 0.005), and lymph node positivity (P < 0.001) but BMM positivity contributes to increase in risk of cancer-related death in patients treated with either CRT or surgery alone. Bone marrow micrometastases detected at the time of surgery for EGC is a long-term prognostic marker. Detection is a readily available, technically noncomplex test which offers a window on the metastatic process and a refinement of pathologic staging and is worthy of routine consideration. PMID- 25914240 TI - Cobalt-catalyzed hydrogenation of esters to alcohols: unexpected reactivity trend indicates ester enolate intermediacy. AB - The atom-efficient and environmentally benign catalytic hydrogenation of carboxylic acid esters to alcohols has been accomplished in recent years mainly with precious-metal-based catalysts, with few exceptions. Presented here is the first cobalt-catalyzed hydrogenation of esters to the corresponding alcohols. Unexpectedly, the evidence indicates the unprecedented involvement of ester enolate intermediates. PMID- 25914242 TI - Planar CH3NH3PbI3 Perovskite Solar Cells with Constant 17.2% Average Power Conversion Efficiency Irrespective of the Scan Rate. PMID- 25914241 TI - Notch signaling promotes osteoclast maturation and resorptive activity. AB - The role of Notch signaling in osteoclast differentiation is controversial with conflicting experimental evidence indicating both stimulatory and inhibitory roles. Differences in experimental protocols and in vivo versus in vitro models may explain the discrepancies between studies. In this study, we investigated cell autonomous roles of Notch signaling in osteoclast differentiation and function by altering Notch signaling during osteoclast differentiation using stimulation with immobilized ligands Jagged1 or Delta-like1 or by suppression with gamma-secretase inhibitor DAPT or transcriptional inhibitor SAHM1. Stimulation of Notch signaling in committed osteoclast precursors resulted in larger osteoclasts with a greater number of nuclei and resorptive activity whereas suppression resulted in smaller osteoclasts with fewer nuclei and suppressed resorptive activity. Conversely, stimulation of Notch signaling in osteoclast precursors prior to induction of osteoclastogenesis resulted in fewer osteoclasts. Our data support a mechanism of context-specific Notch signaling effects wherein Notch stimulation inhibits commitment to osteoclast differentiation, but enhances the maturation and function of committed precursors. PMID- 25914243 TI - Comparable vitamin D3 metabolism in the endometrium of patients with recurrent spontaneous abortion and fertile controls. AB - Vitamin D exerts important roles during pregnancy, and its deficiency may be associated with several pregnancy complications, including pregnancy loss, yet no data are available for molecules involved in vitamin D metabolism in patients with unexplained recurrent spontaneous abortion. In this study, we investigated possible difference in endometrial expression of vitamin D3 receptor (VDR), 1alpha-hydroxylase (CYP27B1), and 24-hydroxylase (CYP24A1) in women with recurrent spontaneous abortion (n = 8) and healthy controls (n = 8). Gene expression of VDR, CYP27B1, and CYP24A1 was determined by real-time PCR, while VDR and CYP27B1 proteins were localized by immunohistochemistry and their abundance was validated by Western blot. We found that both patient and control groups expressed comparable levels of endometrial VDR, CYP27B1, and CYP24A1 transcripts. In line with the gene-expression results, CYP27B1 and different isoforms of VDR protein were present at the same abundance in the endometria of both groups. No significant alteration in VDR and CYP27B1 immunoreactivity pattern was found in the endometrium of patients compared to fertile controls, however. The results of the present study, therefore, do not support the hypothesis of differential expression of key molecules involved in vitamin D3 metabolism in the endometrium of recurrent spontaneous abortion patients and fertile controls. PMID- 25914244 TI - Loneliness in patients with cancer: the first year after cancer diagnosis. AB - OBJECTIVES: We studied the frequency and evolution of social and emotional loneliness in older cancer patients in comparison with younger cancer patients and older people without cancer. We evaluated if changes in common cancer-related and ageing-related problems such as fatigue, cognitive functioning and functional status contributed to the occurrence of loneliness. METHODS: This study was part of the KLIMOP study (Dutch acronym for project on older cancer patients in Belgium and the Netherlands) and included older (>=70 years) and younger cancer patients (50-69 years) and older people without cancer. Data were collected at baseline and 1-year follow-up. Loneliness was measured with the loneliness scale of De Jong-Gierveld. The relationship between loneliness after 1 year and changes in fatigue, cognitive functioning and functional status was tested in multivariate logistic regression analyses. RESULTS: Data were available for 475 participants. At baseline, older cancer patients were less lonely compared with older people without cancer. After 1 year, the frequency of emotional loneliness had significantly increased for older cancer patients (26-42%, p < 0.001) and had reached levels of older people without cancer. Emotional loneliness also increased for younger cancer patients (25-34%, p = 0.02), but not for older people without cancer (40-38%, p = 0.69). Frequency of social loneliness did not change significantly. People who were persistently fatigued and people who became or were persistently impaired on cognitive functioning were at increased risk of becoming lonely. CONCLUSION: Loneliness, in particular emotional loneliness, is a common problem in cancer patients, and its frequency changes considerably over time. PMID- 25914245 TI - Simultaneous quantitation of six major quassinoids in Tongkat Ali dietary supplements by liquid chromatography with tandem mass spectrometry. AB - Tongkat Ali (Eurycoma longifolia) is one of the most popular traditional herbs in Southeast Asia and generally consumed as forms of dietary supplements, tea, or drink additives for coffee or energy beverages. In this study, the liquid chromatography with tandem mass spectrometry method for the simultaneous quantitation of six major quassinoids of Tongkat Ali (eurycomanone, 13,21 dihydroeurycomanone, 13alpha(21)-epoxyeurycomanone, 14,15beta dihydroxyklaineanone, eurycomalactone, and longilactone) was developed and validated. Using the developed method, the content of the six quassinoids was measured in Tongkat Ali containing dietary supplement tablets or capsules, and the resulting data were used to confirm the presence of Tongkat Ali in those products. Among the six quassinoids, eurycomanone was the most abundant quassinoid in all samples tested. The developed method would be useful for the quality assessment of Tongkat Ali containing dietary supplements. PMID- 25914246 TI - Proteomic analysis of lipid body from the alkenone-producing marine haptophyte alga Tisochrysis lutea. AB - Lipid body (LB) is recognized as the cellular carbon and energy storage organelle in many organisms. LBs have been observed in the marine haptophyte alga Tisochrysis lutea that produces special lipids such as long-chain (C37 -C40) ketones (alkenones) with 2-4 trans-type double bonds. In this study, we succeeded in developing a modified method to isolate LB from T. lutea. Purity of isolated LBs was confirmed by the absence of chlorophyll auto-fluorescence and no contamination of the most abundant cellular protein ribulose-1,5-bisphosphate carboxylase/oxygenase. As alkenones predominated in the LB by GC-MS analysis, the LB can be more appropriately named as "alkenone body (AB)." Extracted AB containing proteins were analyzed by the combination of 1DE (SDS-PAGE) and MS/MS for confident protein identification and annotated using BLAST tools at National Center for Biotechnology Information. Totally 514 proteins were identified at the maximum. The homology search identified three major proteins, V-ATPase, a hypothetical protein EMIHUDRAFT_465517 found in other alkenone-producing haptophytes, and a lipid raft-associated SPFH domain-containing protein. Our data suggest that AB of T. lutera is surrounded by a lipid membrane originating from either the ER or the ER-derived four layer-envelopes chloroplast and function as the storage site of alkenones and alkenes. PMID- 25914247 TI - Subthalamic nucleus stimulation improves Parkinsonian gait via brainstem locomotor centers. AB - BACKGROUND: Subthalamic deep brain stimulation (STN-DBS) can ameliorate gait disturbances in Parkinson's disease (PD). Using motor imagery and positron emission tomography (PET), we investigated how STN-DBS interacts with supraspinal locomotor centers in PD. METHODS: Ten PD patients with bilateral STN-DBS actually walked or stood still under STN-DBS ON or OFF conditions. Directly thereafter, subjects imagined walking or standing while changes in regional cerebral blood flow were measured by PET. RESULTS: Independent of STN-DBS, imagined walking distance correlated with imagery duration. Compared with STN-DBS OFF, STN-DBS ON improved actual gait and increased imagined walking distance. Imagery of gait (vs. stance) induced activity in the supplementary motor area and the right superior parietal lobule for both STN-DBS conditions. The improvement of imagined gait during STN-DBS ON led to activity changes in the pedunculopontine nucleus/mesencephalic locomotor region (PPN/MLR). CONCLUSIONS: Data suggest that STN-DBS improves Parkinsonian gait by modulating PPN/MLR activity. PMID- 25914248 TI - A European single centre experience of management of hepatitis C virus genotype 4 infection with pegylated-interferon and ribavirin. AB - New direct acting antiviral agents are revolutionising hepatitis C virus (HCV) treatment. However, to date limited clinical trial data exists for outcomes in genotype 4 (GT4) HCV patients. GT4 HCV is more common in Africa, the Middle East, and Asia, and limited data exists to date for outcomes in Europe. We report the first "real-life" sustained virological response (SVR) outcomes using pegylated interferon and ribavirin for HCV GT4 in the UK, and the largest European single centre cohort. HCV GT4 patients treated at a London, UK centre between 2002 and 2014 were assessed for SVR outcomes. Patient age, sex, region of origin, co infection with HIV, pre-treatment liver biopsy histological assessment, genotype subtyping, treatment duration, and dose reductions were compared against SVR outcomes on univariate analysis. Multivariate analysis was performed on results with P < 0.1. A total of 118 patients were treated with HCV GT4 during the study period, 57 achieved SVR (48%). On univariate analysis age >=45 (P < 0.0001), high viral load (P < 0.0001), Ishak staging 5-6 (P < 0.0001), and non-Egyptian Africans (P = 0.0059) were all negatively associated with SVR. Eastern Europeans appeared to have higher SVR (P < 0.0001). Using multivariate correlation viral load (P = 0.0005); Ishak staging (P = 0.0031) and age (P = 0.0003) were associated with SVR but not country of origin (P = 0.0645). Outcomes with pegylated interferon and ribavirin for HCV GT4 in this "real-life" setting were sub-optimal especially in the context of newer regimens. Patients with older age, high viral loads, and advanced disease need prioritisation for alternative treatments. PMID- 25914249 TI - SEM-Evaluation of enamel surfaces after orthodontic debonding: a 6 and 12-month follow-up in vivo study. AB - The purpose of this in vivo study was to compare the morphology of the enamel surfaces before bracket bonding and 6 and 12 months after debonding. Replicas of thirty-two maxillary second premolars of 16 volunteers were made before bracket bonding (T0), after debonding (T1), 6 months (T2), and 12 months (T3) later. Scanning electron microscope (SEM) images of the labial enamel surfaces were taken at T0, T1, T2, and T3 at increasing magnifications and analyzed according to the enamel damage index EDI. Data evaluation by using Friedman test followed by Wilcoxon signed ranks test with Bonferroni adjustment did not reveal statistically significant differences in the mean EDI at T0, T2, and T3, whereas the mean EDI at T1 was significantly higher than at T0, T2, and T3 (p < 0.05). The debonding procedure tested in this study produces no clinically relevant enamel damage. These alterations are reversible indeed, as a progressive restoration to pretreatment condition is evident after 6 months already and even more after 12 months. PMID- 25914250 TI - The (II)logic of iron reduction therapy for steatohepatitis. PMID- 25914252 TI - Flow cytometric analysis of intracellular phosphoproteins in human monocytes. AB - BACKGROUND: Using antibodies against intracellular phosphoproteins, flow cytometry can be used to monitor simultaneously multiple signaling pathways. Here, we tested a recently released procedure to analyze phosphorylation events in human monocytes upon different types of stimulation. METHODS: Whole blood was treated by lipopolysaccharide (LPS) or granulocyte-macrophage colony-stimulating factor (GM-CSF), then cells were labeled by antibodies recognizing cell surface and cytosolic proteins. Human monocytes were identified by a CD14 - CD45 staining and three phosphorylated proteins such as AKT, ERK-1/2, and STAT5, were simultaneously detected by multicolor phosphoflow analysis. RESULTS: By this rapid method, we are able to detect directly from a blood sample several signaling events in human monocytes where LPS stimulation induces preferentially ERK-1/2 phosphorylation where as GM-CSF stimulation induces STAT5 phosphorylation. CONCLUSIONS: This procedure provides a simultaneous measurement of multiple activated signaling molecules using a simplified and rapid protocol. (c) 2015 International Clinical Cytometry Society. PMID- 25914254 TI - Benzene-Fused Azacorannulene Bearing an Internal Nitrogen Atom. AB - A novel nitrogen-doped corannulene derivative, 8-tert-butyl-6b(2) azapentabenzo[bc,ef,hi,kl,no]corannulene, was synthesized by 1,3-dipolar cycloaddition of a polycyclic aromatic azomethine ylide with a diarylethyne and subsequent palladium-catalyzed intramolecular cyclization. This molecule represents the first example of a corannulene derivative bearing an internal heteroatom, and exhibits unique structural and physical properties caused by the introduction of the nitrogen atom and extended pi-conjugation, as compared to the parent corannulene. PMID- 25914253 TI - Current practices in cancer pain management in Asia: a survey of patients and physicians across 10 countries. AB - In order to implement more effective policies for cancer pain management, a better understanding of current practices is needed. Physicians managing cancer pain and patients experiencing cancer pain were randomly surveyed across 10 Asian countries to assess attitudes and perceptions toward cancer pain management. A total of 463 physicians (77.3% oncologists) with a median experience of 13 years were included. Medical school training on opioid use was considered inadequate by 30.5% of physicians and 55.9% indicated <= 10 h of continuing medical education (CME). Of the 1190 patients included, 1026 reported moderate-to-severe pain (median duration, 12 months). Discordance was observed between physician and patient outcomes on pain assessment with 88.3% of physicians reporting pain quantification, while 49.5% of patients claimed that no scale was used. Inadequate assessment of pain was recognized as a barrier to therapy optimization by 49.7% of physicians. Additional barriers identified were patients' reluctance owing to fear of addiction (67.2%) and adverse events (65.0%), patients' reluctance to report pain (52.5%), excessive regulations (48.0%) and reluctance to prescribe opioids (42.8%). Opioid use was confirmed only in 53.2% (286/538) of patients remembering their medication. Pain affected the activities of daily living for 81.3% of patients. These findings highlight the need for better training and CME opportunities for cancer pain management in Asia. Collaborative efforts between physicians, patients, policy makers, and related parties may assist in overcoming the barriers identified. Addressing the opioid stigma and enhancing awareness is vital to improving current standards of patient care. PMID- 25914255 TI - May 2015 at a glance. PMID- 25914256 TI - Combined neprilysin and RAS inhibition for the failing heart: straining the kidney to help the heart? PMID- 25914257 TI - Monolayer Field-Effect Transistors of Nonplanar Organic Semiconductors with Brickwork Arrangement. PMID- 25914259 TI - Molecularly imprinted polymers on a silica surface for the adsorption of tobacco specific nitrosamines in mainstream cigarette smoke. AB - Tobacco-specific nitrosamines are one of the most important groups of carcinogens in tobacco products. Using adsorbents as filter additives is an effective way to reduce tobacco-specific nitrosamines in cigarette smoke. Molecularly imprinted polymers (MIPs) using nicotinamide as template were grafted on the silica gel surface to obtain MIP@SiO2 and employed as filter additives to absorb tobacco specific nitrosamines in mainstream cigarette smoke. Four milligrams of MIP@SiO2 per cigarette was added to the interface between filter and tobacco rod to prepare a binary filter system. The mainstream smoke was collected on an industry standard Cambridge filter pad and extracted with ammonium acetate aqueous solution before analysis. Compared to the cigarette smoke of the control group, the levels of tobacco-specific nitrosamines with silica gel and with MIP@SiO2 were both reduced, and the adsorption rates of N-nitrosonornicotine, N nitrosoanabasine, N-nitrosoanatabine, and 4-(methylnitrosamino)-1-(3-pyridine)-1 butanone with silica gel and with MIP@SiO2 were 20.76, 15.32, 18.79, and 18.01%, and 41.33, 34.04, 37.86, and 35.53%, respectively. Furthermore the content of total particle materials in cigarette smoke with silica gel was decreased evidently but showed no observable change with MIP@SiO2 . It indicated MIP@SiO2 could selectively reduce tobacco-specific nitrosamines in the mainstream cigarette smoke with no change to the cigarette flavor. PMID- 25914258 TI - Compensatory fetal membrane mechanisms between biglycan and decorin in inflammation. AB - Preterm premature rupture of fetal membranes (PPROM) is associated with infection, and is one of the most common causes of preterm birth. Abnormal expression of biglycan and decorin, two extracellular matrix proteoglycans, leads to preterm birth and aberrant fetal membrane morphology and signaling in the mouse. In humans and mice, decorin dysregulation is associated with inflammation in PPROM. We therefore investigated the link between biglycan and decorin and inflammation in fetal membranes using mouse models of intraperitoneal Escherichia coli injections superimposed on genetic biglycan and decorin deficiencies. We assessed outcomes in vivo as well as in vitro using quantitative PCR, Western blotting, and enzyme-linked immunosorbent assays. Our results suggest that biglycan and decorin compensate for each other in the fetal membranes, but lose the ability to do so under inflammation, leading to decreased latency to preterm birth. Furthermore, our findings suggest that biglycan and decorin play discrete roles in fetal membrane signaling pathways during inflammation, leading to changes in the abundance of MMP8 and collagen alpha1VI, two components of the fetal membrane extracellular matrix that influence the pathophysiology of PPROM. In summary, these findings underline the importance of biglycan and decorin as targets for the manipulation of fetal membrane extracellular matrix stability in the context of inflammation. PMID- 25914260 TI - Evaluation of Surface Microtopography Engineered by Direct Laser Interference for Bacterial Anti-Biofouling. AB - Modification of the biomaterial surface topography is a promising strategy to prevent bacterial adhesion and biofilm formation. In this study, we use direct laser interference patterning (DLIP) to modify polystyrene surface topography at sub-micrometer scale. The results revealed that three-dimensional micrometer structures have a profound impact on bacterial adhesion. Thus, line- and pillar like patterns enhanced S. aureus adhesion, whereas complex lamella microtopography reduced S. aureus adhesion in static and continuous flow culture conditions. Interestingly, lamella-like textured surfaces retained the capacity to inhibit S. aureus adhesion both when the surface is coated with human serum proteins and when the material is implanted subcutaneously in a foreign-body associated infection model. PMID- 25914261 TI - Reply to letter: Novel compound heterozygous mutations in PRKRA cause pure dystonia. PMID- 25914262 TI - Establishing proper scanning conditions in atomic force microscopy on polyimide and polyurethane samples and their effect on 3D surface texture parameters. AB - Several atomic force microscopy (AFM) tests have been carried out on both smooth (polyimide) and rough (polyurethane) surfaces so that to obtain the best results; subsequently, the optimization of experiments performed is presented. A special emphasis has been put on the effect of tip geometry, image pre-processing procedure, scanning area, resolution, pixel size, and cantilever oscillation amplitude in tapping mode, as well as on the quality of the topographical images and 3D surface texture parameters. After viewing the scanning tip and finding out its sharpness, degradation, and contamination, a simultaneous calibration in X, Y, and Z directions, lateral calibration of SPM scanners and detection of lateral non-linearity, hysteresis, creep, and cross-coupling effects has been made. We have established the following experimental parameters: proper scanning resolution (512 * 512 pixels), adequate pixel size (between 2.9 and 19.5 nm) and suitable intermittent contact region (moderate tapping) for which the AFM images present good contrast and resolution. Using these parameters, the values of 3D texture parameters remain constant. These kinds of measurements are extremely important to conduct further AFM experiments on polyimide and polyurethane surfaces under optimal conditions, thus avoiding unwanted artifacts on the morphological images or unrealistic values for the 3D surface texture parameters that might occur. PMID- 25914263 TI - Preliminary Evaluation of a New German Translated Tobacco Quality of Life Impact Tool to Discriminate Between Healthy Current and Former Smokers and to Explore the Effect of Switching Smokers to a Reduced Toxicant Prototype Cigarette. AB - BACKGROUND: Assessment of health-related quality of life (HRQoL) is well established in clinical research, but ceiling effects in validated tools might prevent detection of changes in well respondents. Tobacco Quality of Life Impact Tool (TQOLITv1) uses conceptual and psychometric advances to enhance detection of HRQoL changes. METHODS: In a 6-month, forced-switch study, the German TQOLITv1 was assessed in healthy adult (age 23-55 years) current and matched former smokers. At baseline, smokers were switched to reduced toxicant prototype (RTP) or conventional cigarette for 6 months. TQOLITv1 responses were collected at baseline, 3 and 6 months from current smokers whilst former smokers completed it at the latter two time points. TQOLITv1 includes SF-36v2 and new smoking specific, physical and general-health measures. RESULTS: Reliability at baseline was good (Cronbach's coefficient alpha > 0.70) for all measures. The baseline percentage with the best possible score (ceiling effect) for former and current smokers was substantially better for the new physical function than SF-36 physical function measure (35% vs. 59% at ceiling, respectively). New smoking specific measures discriminated current from former smokers better than general health measures. Smoking-specific symptoms (r = 0.73) were more stable from baseline to 6 months than other measures (r = 0.38-0.54) particularly more than the SF-36 mental component score (r = 0.24). Although both product smoking groups worsened in most HRQoL measures, changes in general and smoking-specific HRQoL impact measures favored RTP smokers. CONCLUSIONS: The German TQOLITv1 is sufficiently reliable and valid to assess HRQoL and may be more useful than SF 36v2 in evaluation of interventions in well smoking populations including those consuming RTPs. PMID- 25914264 TI - Myeloid cells in hepatocellular carcinoma. AB - Hepatocellular carcinoma (HCC) is highly associated with inflammation. Myeloid cells, including tumor-associated macrophages and myeloid-derived suppressor cells, are abundant in the HCC microenvironment and are often associated with poor prognosis. Myeloid cells in HCC play a vital role in supporting tumor initiation, progression, angiogenesis, metastasis, and therapeutic resistance. Here, we summarize our current knowledge about myeloid cells in HCC and focus on their immune-suppressive activities and tumor-promoting functions, as well as the relevance to potential new therapies in HCC. PMID- 25914266 TI - Aberrant lymphatic drainage and risk for melanoma recurrence after negative sentinel node biopsy in middle-aged and older men. AB - BACKGROUND: Aberrant lymphatic drainage is believed to contribute to the high recurrence rate of head and neck melanomas. The purpose of this study was to identify the clinical significance of unexpected lymphatic drainage patterns. METHODS: A single institution retrospective analysis was performed of middle-aged and older men (mean age, 66.2 years; range, 41-87 years) who underwent successful lymphoscintigraphy with sentinel lymph node biopsy (SLNB) from 1997 through 2012. Node status, distribution, and recurrence were assessed comparing patients with expected and unexpected drainage patterns. RESULTS: Sixty-six patients were identified with 55.8 months median follow-up (range, 5.6-206.1 months). Unexpected sentinel lymph node drainage was associated with multiple basin drainage (p < .01) and greater recurrence after negative SLNB (p = .03). Both groups had similar anatomic distribution, sentinel lymph node sampling, histopathologic characteristics, follow-up, and survival. CONCLUSION: Lymphatic drainage differing from expected patterns is associated with greater recurrence after negative SLNB in middle-aged and older men. (c) 2015 Wiley Periodicals, Inc. Head Neck 38: E754-E760, 2016. PMID- 25914267 TI - Can the rapid identification of mature spermatozoa during microdissection testicular sperm extraction guide operative planning? AB - The minimum sperm count and quality that must be identified during microdissection testicular sperm extraction (micro-TESE) to deem the procedure successful remains to be established. We conducted a retrospective study of 81 consecutive men with non-obstructive azoospermia who underwent a primary (first) micro-TESE between March 2007 and October 2013. Final assessment of sperm recovery [reported on the day of (intracytoplasmic sperm injection) ICSI] was recorded as (i) successful (available spermatozoa for ICSI) or (ii) unsuccessful (no spermatozoa for ICSI). The decision to perform a unilateral (with limited or complete microdissection) or bilateral micro-TESE was guided by the intra operative identification of sperm recovery (>=5 motile or non-motile sperm) from the first testicle. Overall, sperm recovery was successful in 56% (45/81) of the men. A unilateral micro-TESE was performed in 47% (38/81) of the men (based on intra-operative identification of sperm) and in 100% (38/38) of these men, spermatozoa was found on final assessment. In 42% (16/38) of the unilateral cases, a limited microdissection was performed (owing to the rapid intra operative identification of sperm). The remaining 43 men underwent a bilateral micro-TESE and 16% (7/43) of these men had sperm identified on final assessment. The cumulative ICSI pregnancy rates (per cycle started and per embryo transfer) were 47% (21/45) and 60% (21/35), respectively, with a mean (+/-SD) of 1.9 +/- 1.0 embryos transferred. The data demonstrate that intra-operative assessment of sperm recovery can correctly identify those men that require a unilateral micro TESE. Moreover, the rapid identification of sperm recovery can allow some men to undergo a limited unilateral micro-TESE and avoid the need for complete testicular microdissection. PMID- 25914269 TI - Chemistry and the Max Planck Society: a stable bond resonating into the future. PMID- 25914268 TI - The effects of obesity on CD47 expression in erythrocytes. AB - BACKGROUND: To investigate the effects of obesity on CD47, phosphatidylserine (PS) exposure, and Caspase-8 and Caspase-3 activities in erythrocytes. METHODS: The study included 25 morbidly obese patients and 20 healthy people as the control group. We evaluated CD47 expression on the red blood cell (RBC) membrane surface and eryptosis markers such as PS externalization and caspase activity using flow cytometric analyses. RESULTS: CD47 expression on the RBC surface was significantly lower in obese patients than in the control group (P = 0.000001). We did not find significant differences in the Caspase-3 and Caspase-8 activities between the obese and nonobese control groups. Additionally, we did not find differences in PS exposure on erythrocyte membranes. The fibrinogen levels were higher in the obese group than they were in the control group (P = 0.00002). Correlations between CD47 expression and body mass index (r = -0.65; P = 0.0004), waist circumference (r = -0.54; P = 0.0052), and fibrinogen (r = 0.57; P = 0.0024) were found. Univariate analyses revealed that body mass index, waist circumference, hip circumference, and fibrinogen levels were potential predictors of CD47 expression. Multivariate analyses found that fibrinogen levels (beta = 0.4708; P = 0.045) independently predicted CD47 expression. CONCLUSIONS: The study demonstrated that CD47 expression is decreased on the surface of RBCs in obese subjects. These changes in CD47 expression on the RBC surface may be an adaptive response to hyperfibrinogenemia associated with obesity. (c) 2015 International Clinical Cytometry Society. PMID- 25914270 TI - Development of double-layer coupled coil for improving S/N in 7 T small-animal MRI. AB - The purpose of this study was to develop a new double-layer coupled (DLC) surface radiofrequency (RF) coil using a combination of single-layer planar (SLP) and single-layer circular (SLC) coils, for enhancement of magnetic flux (B1 ) sensitivity and RF penetration in 7 T rat-body magnetic resonance imaging (MRI). The proposed DLC surface coil was fabricated according to an electromagnetic (EM) simulation and validated based on the B1 distribution and bench measurements. The DLC coil performance was quantitatively evaluated based on the signal-to-noise ratio (S/N) and coil-response signal intensity curves in phantom and in vivo rat body images. In the computational EM calculation and 7 T in vivo experimental results, the DLC surface coil clearly showed an increased S/N and higher RF transmit (B1 (+) ) profiles, compared to those of the SLP and SLC coils. While all surface coils displayed a rapid decrease in the MR signal from the near-coil region to the subject, the results reveal that the DLC coil concept may be used to provide sufficient RF penetration and high S/N and degrees of freedom for use in partial body imaging for 7 T ultra-high-field small-animal MRI. PMID- 25914265 TI - ExtraHF survey: the first European survey on implementation of exercise training in heart failure patients. AB - AIMS: In heart failure (HF), exercise training programmes (ETPs) are a well recognized intervention to improve symptoms, but are still poorly implemented. The Heart Failure Association promoted a survey to investigate whether and how cardiac centres in Europe are using ETPs in their HF patients. METHODS AND RESULTS: The co-ordinators of the HF working groups of the countries affiliated to the European Society of Cardiology (ESC) distributed and promoted the 12-item web-based questionnaire in the key cardiac centres of their countries. Forty-one country co-ordinators out of the 46 contacted replied to our questionnaire (89%). This accounted for 170 cardiac centres, responsible for 77,214 HF patients. The majority of the participating centres (82%) were general cardiology units and the rest were specialized rehabilitation units or local health centres. Sixty-seven (40%) centres [responsible for 36,385 (48%) patients] did not implement an ETP. This was mainly attributed to the lack of resources (25%), largely due to lack of staff or lack of financial provision. The lack of a national or local pathway for such a programme was the reason in 13% of the cases, and in 12% the perceived lack of evidence on safety or benefit was cited. When implemented, an ETP was proposed to all HF patients in only 55% of the centres, with restriction according to severity or aetiology. CONCLUSIONS: With respect to previous surveys, there is evidence of increased availability of ETPs in HF in Europe, although too many patients are still denied a highly recommended therapy, mainly due to lack of resources or logistics. PMID- 25914271 TI - Practical method for the rapid screening of xanthine oxidase inhibitors in herbal extracts by high-performance liquid chromatography based on on-line precolumn enzymatic reaction. AB - A high-performance liquid chromatography method with on-line precolumn enzymatic reaction for the screening of xanthine oxidase inhibitors in natural extracts was developed. In this method, the enzymatic reaction occurred at the capillary inlet during a predetermined waiting period, after which the reaction product, uric acid, was separated and detected by liquid chromatography using ultraviolet absorption at 295 nm. Enzyme inhibition can be read out directly from the reduced peak area of uric acid in comparison to a reference chromatogram obtained in the absence of any inhibitor. In the present study, the availability of on-line precolumn enzymatic reaction with ultraviolet detection was firstly evaluated by determining the inhibitory mechanism and IC50 values of allopurinol, a commercially available positive drug. Then, the newly developed method was applied to screening of ten natural extracts from traditional Chinese medicine and as a result, the extract of Epimedium sagittatum (Sieb. et Zucc.) Maxim was found to be most positive for xanthine oxidase inhibition. The results obtained were compared with those obtained by offline enzyme assay and the effectiveness of the present method was confirmed. A rapid, low-cost, and fully automated method for xanthine oxidase inhibitor screening was proposed. PMID- 25914272 TI - Political pugilists: recuperative gender strategies in canadian electoral politics. AB - This paper offers the concept recuperative gender strategies to describe how political leaders work to restore their public gender identities. The author examines a charity-boxing match between two Canadian politicians, Justin Trudeau and Patrick Brazeau. Trudeau is the current leader of the Liberal Party of Canada and son of former Prime Minister, Pierre Trudeau. Brazeau was a Conservative Senator. Through a discourse analysis of 222 national newspaper articles published on the match, this paper chronicles Justin Trudeau's transition from "precariously masculine" to "sufficiently masculine" and discusses the significance of this transformation for Trudeau's suitability for Liberal Party leadership. Cet article propose le concept de strategies de recuperation des sexes pour decrire et expliquer comment des dirigeants politiques travaillent a retablir leurs identites sexuelles publiques. J'analyse la couverture mediatique du combat de boxe caritatif datant de mars 2012 et opposant deux politiciens canadiens : Justin Trudeau, le chef du Parti liberal du Canada, et Patrick Brazeau, un senateur conservateur. En m'appuyant sur une analyse de discours de 222 articles de journaux nationaux publies au sujet de ce combat, je detaille la transition de Justin Trudeau d'une forme de masculinite " precaire " a une " masculinite suffisante ", et je discute de l'importance de cette transformation pour l'aptitude percue de Trudeau comme chef du Parti liberal. PMID- 25914273 TI - Class Position and Musical Tastes: A Sing-Off between the Cultural Omnivorism and Bourdieusian Homology Frameworks. AB - The longstanding debate between the homology and omnivorism approaches to the class bases of cultural tastes and practices rages on in cultural sociology. The homology thesis claims that class positions throughout the class hierarchy are accompanied by specified cultural tastes and specialized modes of appreciating them while the cultural omnivorism thesis contends that elites are (increasingly) characterized by a breadth of cultural tastes of any and all kinds. This study tests the applicability of these theses to musical tastes in Canada through the application of multiple correspondence analysis, latent class analysis, and logistic regression modeling to original telephone survey data (n = 1,595) from Toronto and Vancouver. I find that musical omnivorism, an appreciation for diverse musical styles, is not dispersed along class lines. Instead I find a homology between class position and musical tastes that designates blues, choral, classical, jazz, musical theater, opera, pop, reggae, rock, and world/international as relatively highbrow and country, disco, easy listening, golden oldies, heavy metal, and rap as relatively lowbrow. Of the highbrow tastes, all but jazz are disliked by lower class people, and of the lowbrow tastes, country, easy listening, and golden oldies are concurrently disliked by higher class people. Consistent with the homology thesis, it appears that class position is aligned with specific musical likes and dislikes. Le vieux debat entre les approches de l'homologie et de l'omnivorisme aux bases des classes des gouts et des pratiques culturels fait rage dans la sociologie culturelle. La these de l'homologie pretend que les positions des classes a travers la hierarchie des classes sont accompagnees par des gouts culturels specifies et des modes specialises permettant leur appreciation. La these de l'omnivorisme culturel, en revanche, soutient que les elites sont (de plus en plus) caracterisees par un eventail de gouts culturels de toutes sortes. Cette etude experimente l'applicabilite de ces theses aux gouts musicaux au Canada a travers l'application de l'analyse des correspondances multiples, de l'analyse des classes latentes et du modele de regression logistique aux donnees d'origine de l'etude collectees par telephone (n = 1,595) de Toronto et de Vancouver. Je me rends compte que l'omnivorisme musical, une appreciation de styles musicaux divers, n'est pas disperse le long des classes sociales. Bien au contraire, je trouve qu'il existe une homologie entre la position des classes et les gouts musicaux qui designe les blues, la chorale, la musique classique, le jazz, le theatre musical, l'opera, la pop, le reggae, le rock et la musique du monde/internationale comme des styles des classes au niveau intellectuel relativement eleve. Cette homologie designe la country, la disco, la musique d'ambiance, les anciens succes, le heavy metal et le rap comme des styles des classes au niveau intellectuel relativement bas. Des gouts des classes au niveau intellectuel eleve, tous les styles a l'exception du jazz ne sont pas apprecies de la basse classe. De meme, des gouts des classes au niveau intellectuel bas, le country, la musique d'ambiance et les anciens succes ne sont pas apprecies de la haute classe. Selon la these de l'homologie, il apparait que la position des classes est fonction des preferences et des aversions musicales specifiques. PMID- 25914274 TI - Factory to faculty: socioeconomic difference and the educational experiences of university professors. AB - Numerous essays exist on the lived experiences of academics from working-class or poverty-class origins. Yet, to date, there exists no systematic analysis of the class origins of university faculty members. This study utilizes surveys from a random sample of full-time university professors at all 95 Canadian universities affiliated with the Association of Universities and Colleges of Canada (AUCC) to analyze the ways in which socioeconomic background impacts experiences within university and graduate school. Findings indicate that several measures of socioeconomic background are indeed significant predictors of this experience. Qualitative data reveal that working-class faculty members are hyper-aware of the ways in which their class backgrounds affected their educational trajectories; while conversely, academics from middle-class backgrounds were also reflective about the ways in which they were privileged. The paper concludes with implications for developing public policy that shifts focus away from apolitical discussions of diversity, toward promoting inclusivity for those from working class or lower-income backgrounds. Il existe de nombreux travaux concernant les experiences vecues par des academiques qui font parties de differentes classes sociales, particulierement les classes ouvrieres. Par contre, jusqu'a date, il n'existe aucune analyse systematique concernant les classes d'origines des membres du corps professoral qui travaillent aux universites. Cette etude utilise des enquetes qui ont ete obtenues avec un echantillon aleatoire de professeurs qui travaillent a temps plein aux 95 universites Canadiennes affiliees avec "L'association des Universites et Colleges du Canada" (AUCC). Cette etude analyse les facons que le statut socio-economique de la famille affecte les experiences a l'universite et aux etudes superieures. Les resultats quantitatifs demontrent que plusieurs mesures de statut socio-economique predisent ces experiences. En plus, les resultats qualitatifs demontrent que les membres du corps professoral qui viennent la classe ouvriere sont tres conscients des facons que leur statut socio economique affecte leurs trajectoires academiques. Par contre, les membres du corps professoral qui viennent la classe moyenne sont aussi conscients et meme reflechissant des facons qu'ils sont privilegies a cause de leur statut socio economique. Les resultats indiquent la necessite de developper des politiques publiques qui detourne l'attention et les discussions apolitiques sur la diversite, aux discussions sur les facons de promouvoir, aux universites, l'inclusion de ceux qui viennent des milieux socio-economiques inferieurs et defavorises. PMID- 25914275 TI - Metier de sociologue, approche inductive et objet d'analyse. Breves remarques a partir de Bourdieu. AB - This article seeks to reveal the role played by the inductive approach in sociology. Grounded Theory assumes its full importance in formulating sociological explanations. However, the theory does pose a problem, in that the "method" is not based on clearly defined operations, which remain implicit. This article attempts to show that the object of analysis-what is being analyzed-makes perceptible the operations implicitly conceived by the analyst, based on Grounded Theory. With qualitative analysis software, such as Atlas.ti, it is possible to shed light on these operations. The article is illustrated by the theory of Pierre Bourdieu and the epistemological considerations he developed as a result of his qualitative inquiry, La Misere du monde. Cet article cherche a montrer le role que joue l'approche inductive en sociologie. La Grounded Theory revet son importance pour formuler l'explication sociologique. Celle-ci pose toutefois probleme. En effet, la "methode" ne repose pas sur des operations clairement definies et celles-ci restent implicites. Dans cet article, on cherche a montrer que l'objet d'analyse-ce sur quoi porte l'analyse-rend perceptibles les operations que l'analyste concoit implicitement en s'appuyant sur la Grounded Theory. Les logiciels d'analyse qualitative, comme Atlas.ti, permettent d'autre part de les mettre en evidence. L'article est illustre par la theorie de Pierre Bourdieu et les considerations epistemologiques qu'a developpees cet auteur a la suite de son enquete qualitative sur la Misere du monde. PMID- 25914276 TI - Introduction: critical feminist sociologies of families, work, and care. PMID- 25914278 TI - Feminist scholarship and family sociology: new ways of thinking, outstanding questions. PMID- 25914277 TI - Feminism on family sociology: interpreting trends in family life. PMID- 25914279 TI - Family finances: fragility, class, and gender. PMID- 25914280 TI - Raising children to cope with climate change? PMID- 25914281 TI - Rivastigmine for mild cognitive impairment in Parkinson disease: a placebo controlled study. AB - Mild cognitive impairment (MCI) in Parkinson's disease (PD) may be associated with subtle functional impairment and worse quality of life. The objective of this study was to determine the efficacy and tolerability of rivastigmine for PD MCI. Patients with PD-MCI (n = 28) were enrolled in a 24-week, randomized, double blind, placebo-controlled, crossover, single-site study of the rivastigmine transdermal patch. The primary outcome measure was the Alzheimer's Disease Cooperative Study-Clinical Global Impression of Change (ADCS-CGIC). Secondary outcomes included the Montreal Cognitive Assessment (MoCA), Dementia Rating Scale 2 (DRS-2), Neurotrax computerized cognitive battery, the Everyday Cognition Battery (ECB), and the Parkinson's Disease Questionnaire (PDQ-8). Twenty-six participants (92.9%) completed both study phase assessments, and 23 (82.1%) completed both phases on study medication. The CGIC response rate demonstrated a trend effect in favor of rivastigmine (regression coefficient for interaction term in linear mixed-effects model = 0.44, F[df] = 3.01 [1, 24], P = 0.096). For secondary outcomes, a significant rivastigmine effect on the ECB (regression coefficient = -2.41, F[df] = 5.81 [1, 22.05], P = 0.03) was seen, but no treatment effect was found on any cognitive measures. Trend effects also occurred in favor of rivastigmine on the PDQ-8 (regression coefficient = 4.55, F[df] = 3.93 [1, 14. 79], P = 0.09) and the State Anxiety Inventory (regression coefficient = -1.24, F[df] = 3.17 [1, 33], P = 0.08). Rivastigmine in PD-MCI showed a trend effect for improvements on a global rating of cognition, disease related health status, and anxiety severity, and significant improvement on a performance-based measure of cognitive abilities. (c) 2015 International Parkinson and Movement Disorder Society. PMID- 25914282 TI - Crossing Over: Nanostructures that Move Electrons and Ions across Cellular Membranes. AB - Critical biological processes such as energy generation and signal transduction are driven by the flow of electrons and ions across the membranes of living cells. As a result, there is substantial interest in creating nanostructured materials that control transport of these charged species across biomembranes. Recent advances in the synthesis of de novo and protein nanostructures for transmembrane ion and electron transport and the mechanistic understanding underlying this transport are described. This body of work highlights the promise such nanostructures hold for directing transmembrane transport of charged species as well as challenges that must be overcome to realize that potential. PMID- 25914283 TI - Erythropoietin-producing hepatocellular receptor B2 receptor tyrosine kinase: A novel regulator of infection- and inflammation-induced liver fibrosis. PMID- 25914284 TI - Receptor occupancy and blocking of STAT5 signaling by an anti-IL-7 receptor alpha antibody in cynomolgus monkeys. AB - BACKGROUND: Interleukin-7 receptor alpha (IL-7Ralpha) is associated with autoimmune disease. Blocking its activation by interleukin-7 (IL-7) with a therapeutic monoclonal antibody may reduce pathogenic T cells and effectively control the autoimmune response in these disorders. METHODS: Two flow cytometry based assays were developed and implemented to evaluate the interaction between cell surface IL-7Ralpha and an anti-IL-7Ralpha monoclonal antibody (Ab1). The receptor occupancy assay utilized competing and noncompeting commercial detection antibodies for "free" and "total" IL-7Ralpha, respectively. STAT5 phosphorylation (pSTAT5) was measured as a proximal biomarker of IL-7Ralpha inhibition by Ab1. RESULTS: Monkeys administered Ab1 had no free IL-7Ralpha detectable on the CD3+ T cell surface at 0.25 hours postdose through day 4, in all treatment groups. Ab1 treatment resulted in a significant reduction in total IL-7Ralpha, dropping to 53%, 44%, and 55% on day 4 at 0.3, 3, and 30 mg/kg, respectively, compared to predose levels. There were treatment-related decreases in the ability of IL-7 to induce STAT5 phosphorylation in both CD4+ and CD8+ T cells in monkey blood samples from all treated animals from 0.25 hours through Day 4 postdose. CONCLUSIONS: The nonclinical receptor occupancy assay was developed and applied to detect free and total IL-7Ralpha on the surface of CD3+ T cells in cynomolgus monkeys treated with Ab1. The results showed good correlation with the phosphorylation of STAT5 and serum concentration of Ab1. The approach for IL 7Ralpha occupancy and pSTAT5 measurements established in monkeys can be utilized in clinical trials for pharmacokinetic/pharmacodynamic evaluation of Ab1 effect in humans. PMID- 25914286 TI - Using fibers for rapid extraction of proteins from urine. AB - The method for rapid extraction of proteins from urine published in this special issue (Manard, B. T. et al., Proteomics Clin. Appl. 2015, 9, 522-530) may have more profound implications than the authors have claimed, simply because urine is more important than most biomarker researchers realized. Unlike blood that is tightly controlled by homeostatic mechanisms of the body, urine tolerates, and accumulates a much larger degree of changes in its components, making it a more important biomarker source than blood. PMID- 25914287 TI - Modulation of alternative splicing by anticancer drugs. AB - Pre-mRNA alternative splicing is a highly regulated process that generates multiple mRNAs coding different protein isoforms. These protein isoforms may have similar, different, or even opposing functions. Expression of genes involved in cell growth and apoptosis are often altered in cancer cells. Studying the alternative splicing patterns of these important genes can have a significant role in the treatment of cancer. Resistance to chemotherapy is often caused due to overexpression of anti-apoptotic isoforms or suppression of pro-apoptotic isoforms. Anticancer drugs are capable of modulating the expression of different transcript isoforms of genes. Some anticancer drugs induce pro-apoptotic transcript isoforms leading to apoptosis or at least sensitizing cells to chemotherapy. However, in other cases, they shift the splicing toward isoforms having anti-apoptotic functions thus conferring resistance to chemotherapy. This mini-review summarizes the current knowledge about alternative splicing of some important genes involved in cancers. Furthermore, splicing patterns as well as generation of functionally distinct protein isoforms have also been mentioned. Role of various anticancer drugs in modulating alternative splicing of these genes has been reported along with a brief insight into their mechanism of action. Modulation of alternative splicing toward production of pro-apoptotic isoforms of various genes by anticancer drugs offers great therapeutic potential in the treatment of cancer. PMID- 25914288 TI - Microscopic visualization of intravasal spermatozoa is positively associated with patency after bilateral microsurgical vasovasostomy. AB - We evaluated pre-operative and intraoperative factors associated with successful patency following bilateral microsurgical vasovasostomy (VV). We retrospectively reviewed the charts of 1331 men who underwent bilateral VV by two surgeons between 2006 and 2013. Vasal fluid was examined intraoperatively for gross quality (i.e., clear or opaque and creamy/thick) and for the presence of spermatozoa on microscopy (i.e., whole spermatozoa, sperm fragments, or azoospermia). Post-operative patency was assessed by semen analysis or patient report of conception. Perioperative factors were explored using descriptive statistics and examined in logistic regression models for associations with post operative patency. The median age at VV was 39 years [interquartile range (IQR): 35-44] and the median obstructive interval (OI) was 7 years (IQR: 4-11). Overall, 1307 patients achieved post-operative patency (98%) while 24 remained obstructed (2%). Among those who became patent, 410 reported conception. After adjustment for potential confounders, only microscopic examination of the intravasal fluid for the presence of spermatozoa (bilateral or unilateral whole spermatozoa vs. sperm parts/azoospermia) at the time of VV was significantly associated with post operative patency with an odds ratio (OR) of 14.2 (95% CI: 5.8-34.9; p = <1 * 10( 8) ). Identification of bilateral or unilateral sperm fragments vs. azoospermia was also associated with increased odds of post-operative patency with an OR of 3.5 (95% CI: 0.9-13.6; p = 0.08). There was no statistically significant association between age at VV, OI, presence of granuloma, gross fluid quality, or surgeon and post-operative patency after controlling for potential confounders. Identification of whole spermatozoa in the vasal fluid at the time of VV was positively associated with post-operative patency. Our findings stress the need for intraoperative microscopy to aid in post-operative patient counseling. PMID- 25914291 TI - Development of an enzyme-linked immunosorbent assay and immunoaffinity chromatography for glycyrrhizic acid using an anti-glycyrrhizic acid monoclonal antibody. AB - In this work, a new monoclonal antibody specific for glycyrrhizic acid was prepared and characterized. A hybridoma secreting an anti-glycyrrhizic acid monoclonal antibody was produced by fusing splenocytes from a mouse immunized against a glycyrrhizic acid-bovine serum albumin conjugate with the hypoxanthine aminopterin-thymidine-sensitive mouse myeloma cell line (Sp2/0-Ag14). Subsequently, an indirect, competitive enzyme-linked immunosorbent assay for glycyrrhizic acid was developed using the monoclonal antibody. In this assay, we detected an effective measuring range of 78.12-2500 ng/mL. Both intra-assay and inter-assay repeatability and precision were achieved, with relative standard deviations lower than 10%. In addition, glycyrrhizic acid levels in both formulated Chinese medicines and biological samples were determined with high sensitivity and efficiency. We then successfully developed a reliable immunoaffinity chromatography to separate glycyrrhizic acid completely from its parent medicine. These methods will contribute to further research investigations to better understand the interactions of glycyrrhizic acid with other drugs in the complex system of traditional Chinese medicine. PMID- 25914292 TI - Convallaria keiskei as a novel therapeutic alternative for salivary gland cancer treatment by targeting myeloid cell leukemia-1. AB - BACKGROUND: Various chemotherapeutic agents have been used largely for the treatment of salivary gland cancer. However, results are disappointing, and these agents can cause some serious side effects. Therefore, recent studies have focused on the possible roles of natural products to overcome these limitations. METHODS: Salivary gland cancer cells treated with or without Convallaria keiskei (MECK) for 24 hours. Apoptotic changes were evaluated by live/dead assay, immunoblotting, and expression levels of caspase-3 and B-cell lymphoma-2 family member. RESULTS: MECK significantly inhibited salivary gland cancer growth. At the molecular level, MECK dramatically reduced myeloid cell leukemia-1 (Mcl-1) in a translation-dependent manner and thereby induced apoptosis through Bax/Bid. Furthermore, we found that Mcl-1 could be a potential therapeutic target of MECK induced apoptosis and its stability is regulated by extracellular signal regulated kinases 1/2 (ERK1/2) signaling CONCLUSION: MECK can be used as a safe and efficient therapeutic alternative for the treatment of salivary gland cancer. (c) 2015 Wiley Periodicals, Inc. Head Neck 38: E761-E770, 2016. PMID- 25914293 TI - Impact of Parkinson's disease risk loci on age at onset. AB - BACKGROUND: The aim of this study was to assess whether recently identified Parkinson's disease (PD) risk genes also influence age at onset in PD. METHODS: We genotyped 23 single-nucleotide polymorphisms in 1,526 Danish PD patients and performed linear regression analyses with age at onset. The combined impact of PD risk loci on age at onset was assessed by linear regression analyses using a weighted genetic risk score. RESULTS: The strongest effects were observed with rs12726330 in GBA (beta = -3.63, P = 2.0 * 10(-5) ) and rs34311866 in TMEM175/GAK (beta = -1.19, P = 4.0 * 10(-3) ), corresponding to a 3.6-y and 1.2-y decrease of age at onset per risk allele, respectively. The weighted genetic risk score yielded significant association with reduced onset age (P = 3.98 * 10(-3) ), although the variance explained was small (0.6%), and the effect was mostly driven by polymorphisms in GBA and TMEM175/GAK. CONCLUSIONS: Overall, our study indicates that GBA and TMEM175/GAK significantly alter age at onset in PD. PMID- 25914294 TI - Graphite Oxide to Graphene. Biomaterials to Bionics. AB - The advent of implantable biomaterials has revolutionized medical treatment, allowing the development of the fields of tissue engineering and medical bionic devices (e.g., cochlea implants to restore hearing, vagus nerve stimulators to control Parkinson's disease, and cardiac pace makers). Similarly, future materials developments are likely to continue to drive development in treatment of disease and disability, or even enhancing human potential. The material requirements for implantable devices are stringent. In all cases they must be nontoxic and provide appropriate mechanical integrity for the application at hand. In the case of scaffolds for tissue regeneration, biodegradability in an appropriate time frame may be required, and for medical bionics electronic conductivity is essential. The emergence of graphene and graphene-family composites has resulted in materials and structures highly relevant to the expansion of the biomaterials inventory available for implantable medical devices. The rich chemistries available are able to ensure properties uncovered in the nanodomain are conveyed into the world of macroscopic devices. Here, the inherent properties of graphene, along with how graphene or structures containing it interface with living cells and the effect of electrical stimulation on nerves and cells, are reviewed. PMID- 25914295 TI - Ovarian structure protein 1: A sensitive molecular biomarker of gonadal intersex in female Japanese medaka after androgen exposure. AB - Intersex in gonochoristic fish can be induced after exposure to androgens and estrogens. The main objective of the present study was to identify biomarkers that would be predictive of intersex in Japanese medaka (Oryzias latipes) after exposure to synthetic hormones. First a gene was identified, ovarian structure protein 1 (osp1), with strong female-specific expression during gonadal differentiation. The authors hypothesized that osp1 expression would decrease to male levels in females after the exposure of larvae (15-25 d postfertilization [dpf]) to 17beta-trenbolone (TRB; 5 ng/L) and would increase to female levels in males exposed to 17alpha-ethinylestradiol (EE2; 5 ng/L) and that gonadal intersex would be induced later in life (60 dpf). Tissue distribution and cellular localization of OSP1 was investigated using Western blot and immunohistochemistry. The results indicate that this exposure regime delays testicular maturation in males and development of ovarian intersex in females. Although decreased osp1 expression in females exposed to TRB correlated to changes in ovarian phenotype, up-regulation of osp1 was not observed in males exposed to EE2. In addition, OSP1 was only observed in ovaries and localized in the cytoplasm and follicular layer of immature and mature oocytes. The authors conclude that osp1 is a promising biomarker of androgen exposure and gonadal intersex in female medaka. PMID- 25914298 TI - Acute phase proteins altered in the plasma of patients with congenital ventricular septal defect. AB - PURPOSE: Ventricular septal defect (VSD) has intracardiac left-to-right shunt and increased pulmonary flow that may affect the acute phase response (APR). We examined the hypothesis that plasma proteins of VSD patients may be altered. EXPERIMENTAL DESIGN: 2DE and MS were used to detect differential plasma proteins in VSD patients (n = 55) and controls (n = 70). Candidate APR proteins were confirmed by ELISA in new samples. RESULTS: Among three differentially expressed APR proteins from 322 protein spots detected, haptoglobin (0.4 +/- 0.04 versus 0.6 +/- 0.07 mg/mL; p = 0.016) and serum amyloid P-component (SAP) (3.8 +/- 0.2 versus 6.3 +/- 0.8 ng/mL; p = 0.003) were significantly lower and orosomucoid 2 (3.1 +/- 0.1 mg/mL versus 2.3 +/- 0.1 mg/mL; p < 0.001) was significantly higher in VSD patients than in normal controls. CONCLUSIONS AND CLINICAL RELEVANCE: The plasma concentration of three acute phase proteins, haptoglobin, SAP, and orosomucoid 2 are altered that may reflect inflammation, be associated with decreased innate immune system function, and predispose the VSD patients to vulnerability to infections and pulmonary disease. These three proteins in plasma may also be developed as biomarkers for the function of innate immune system in patients with congenital heart disease. PMID- 25914296 TI - Association of nonalcoholic fatty liver disease with subclinical myocardial remodeling and dysfunction: A population-based study. AB - Nonalcoholic fatty liver disease (NAFLD) and heart failure (HF) are obesity related conditions with high cardiovascular mortality. Whether NAFLD is independently associated with subclinical myocardial remodeling or dysfunction among the general population is unknown. We performed a cross-sectional analysis of 2,713 participants from the multicenter, community-based Coronary Artery Risk Development in Young Adults (CARDIA) study who underwent concurrent computed tomography (CT) quantification of liver fat and comprehensive echocardiography with myocardial strain measured by speckle tracking during the Year-25 examination (age, 43-55 years; 58.8% female and 48.0% black). NAFLD was defined as liver attenuation <=40 Hounsfield units after excluding other causes of liver fat. Subclinical left ventricular (LV) systolic dysfunction was defined using values of absolute peak global longitudinal strain (GLS). Diastolic dysfunction was defined using Doppler and tissue Doppler imaging markers. Prevalence of NAFLD was 10.0%. Participants with NAFLD had lower early diastolic relaxation (e') velocity (10.8 +/- 2.6 vs. 11.9 +/- 2.8 cm/s), higher LV filling pressure (E/e' ratio: 7.7 +/- 2.6 vs. 7.0 +/- 2.3), and worse absolute GLS (14.2 +/- 2.4% vs. 15.2 +/- 2.4%) than non-NAFLD (P < 0.0001 for all). When adjusted for HF risk factors or body mass index, NAFLD remained associated with subclinical myocardial remodeling and dysfunction (P < 0.01). The association of NAFLD with e' velocity (beta = -0.36 [standard error = 0.15] cm/s; P = 0.02), E/e' ratio (beta = 0.35 [0.16]; P = 0.03), and GLS (beta = -0.42 [0.18]%; P = 0.02) was attenuated after controlling for visceral adipose tissue. Effect modification by race and sex was not observed. CONCLUSIONS: NAFLD is independently associated with subclinical myocardial remodeling and dysfunction and provides further insight into a possible link between NAFLD and HF. PMID- 25914299 TI - From the bench to the field in low-cost diagnostics: two case studies. AB - Despite the growth of research in universities on point-of-care (POC) diagnostics for global health, most devices never leave the laboratory. The processes that move diagnostic technology from the laboratory to the field--the processes intended to evaluate operation and performance under realistic conditions--are more complicated than they might seem. Two case studies illustrate this process: the development of a paper-based device to measure liver function, and the development of a device to identify sickle cell disease based on aqueous multiphase systems (AMPS) and differences in the densities of normal and sickled cells. Details of developing these devices provide strategies for forming partnerships, prototyping devices, designing studies, and evaluating POC diagnostics. Technical and procedural lessons drawn from these experiences may be useful to those designing diagnostic tests for developing countries, and more generally, technologies for use in resource-limited environments. PMID- 25914300 TI - Computational Biology in microRNA. AB - MicroRNA (miRNA) is a class of small endogenous noncoding RNA species, which regulate gene expression post-transcriptionally by forming imperfect base-pair at the 3' untranslated regions of the messenger RNAs. Since the 1993 discovery of the first miRNA let-7 in worms, a vast number of studies have been dedicated to functionally characterizing miRNAs with a special emphasis on their roles in cancer. A single miRNA can potentially target ~ 400 distinct genes, and there are over a 1000 distinct endogenous miRNAs in the human genome. Thus, miRNAs are likely involved in virtually all biological processes and pathways including carcinogenesis. However, functionally characterizing miRNAs hinges on the accurate identification of their mRNA targets, which has been a challenging problem due to imperfect base-pairing and condition-specific miRNA regulatory dynamics. In this review, we will survey the current state-of-the-art computational methods to predict miRNA targets, which are divided into three main categories: (1) sequence-based methods that primarily utilizes the canonical seed match model, evolutionary conservation, and binding energy; (2) expression-based target prediction methods using the increasingly available miRNA and mRNA expression data measured for the same sample; and (3) network-based method that aims identify miRNA regulatory modules, which reflect their synergism in conferring a global impact to the biological system of interest. We hope that the review will serve as a good reference to the new comers to the ever-growing miRNA research field as well as veterans, who would appreciate the detailed review on the technicalities, strength, and limitations of each representative computational method. PMID- 25914301 TI - Response to comment on "a randomized study comparing the use of a pelvic lead shield during trans-radial interventions: Threefold decrease in radiation to the operator but double exposure to the patient". PMID- 25914302 TI - Enhanced fertility prediction of cryopreserved boar spermatozoa using novel sperm function assessment. AB - Due to reduced fertility, cryopreserved semen is seldom used for commercial porcine artificial insemination (AI). Predicting the fertility of individual frozen ejaculates for selection of higher quality semen prior to AI would increase overall success. Our objective was to test novel and traditional laboratory analyses to identify characteristics of cryopreserved spermatozoa that are related to boar fertility. Traditional post-thaw analyses of motility, viability, and acrosome integrity were performed on each ejaculate. In vitro fertilization, cleavage, and blastocyst development were also determined. Finally, spermatozoa-oviduct binding and competitive zona-binding assays were applied to assess sperm adhesion to these two matrices. Fertility of the same ejaculates subjected to laboratory assays was determined for each boar by multi sire AI and defined as (i) the mean percentage of the litter sired and (ii) the mean number of piglets sired in each litter. Means of each laboratory evaluation were calculated for each boar and those values were applied to multiple linear regression analyses to determine which sperm traits could collectively estimate fertility in the simplest model. The regression model to predict the percent of litter sired by each boar was highly effective (p < 0.001, r(2) = 0.87) and included five traits; acrosome-compromised spermatozoa, percent live spermatozoa (0 and 60 min post-thaw), percent total motility, and the number of zona-bound spermatozoa. A second model to predict the number of piglets sired by boar was also effective (p < 0.05, r(2) = 0.57). These models indicate that the fertility of cryopreserved boar spermatozoa can be predicted effectively by including traditional and novel laboratory assays that consider functions of spermatozoa. PMID- 25914303 TI - Analysis of risk factors for flap loss and salvage in free flap head and neck reconstruction. AB - BACKGROUND: Risk factors and techniques for free flap salvage in head and neck reconstruction are poorly described. METHODS: We conducted a retrospective review of all head and neck free flaps performed from 2000 to 2010. RESULTS: Overall, 151 of 2296 flaps (6.6%) underwent salvage for microvascular complications. Age, comorbidities, surgeon experience (p = .88), vein grafts, and supercharging (p = .45) did not affect flap salvage. Muscle-only flaps (p = .002) were associated with significantly worse outcomes. Coupled venous anastomoses were superior to handsewn anastomoses (p = .03). Arteriovenous thrombosis had worse outcomes than a venous or arterial thrombosis alone (p < .0001). Anticoagulation, thrombolytics, and thrombectomy did not improve survival. Multiple takebacks (p = .003) and late takebacks (>3 days) had significantly worse outcomes (p = .003). Flap salvage was 60.3% successful with 60 total flap losses (2.6%). CONCLUSION: Although flap salvage should be attempted, multiple attempts are not recommended, especially for muscle-only flaps. Combined arteriovenous and late thrombosis has a dismal prognosis regardless of different salvage techniques. (c) 2015 Wiley Periodicals, Inc. Head Neck 38: E771-E775, 2016. PMID- 25914304 TI - When do patient-reported outcome measures inform readmission risk? AB - OBJECTIVE: To characterize changes in patient-reported outcome measures from hospital discharge to assess when they best inform risk of utilization as defined by readmissions or emergency department use. PARTICIPANTS: Patients discharged from an urban safety-net hospital. DESIGN: Longitudinal cohort study. MAIN MEASURES: We serially administered the Memorial Symptom Assessment Scale (MSAS) and the PROMIS Global Health short form assessing General Self-Rated Health (GSRH), Global Physical (GPH), and Mental (GMH) Health at 0, 30, 90, and 180 days from hospital discharge. Time to first utilization from each survey was plotted by dichotomizing our sample on each patient-reported measure, and equivalence of the time-to-event curves was assessed using the log-rank test. Cox proportional hazard models were used to control for available covariates including prior utilization during the study, Charlson score, age, gender, and race/ethnicity. We assessed each measure's effect on the fit of the predictive models using the likelihood ratio test. KEY RESULTS: We recruited 196 patients, of whom 100%, 98%, 90%, and 88% completed each respective survey wave. Participants' mean age was 52 years, 51% were women, 60% were non-Hispanic black, and 21% completed the questionnaires in Spanish. In-hospital assessments revealed high symptom burden and poor health status. In-hospital assessments of GMH and GSRH predicted 14-day reutilization, whereas posthospitalization assessments of MSAS and GPH predicted subsequent utilizations. Each measure selectively improved predictive model fit. CONCLUSIONS: Routine measurement of patient-reported outcomes can help identify patients at higher risk for utilizations. At different time points, MSAS, GPH, GMH, and GSRH all informed utilization risk. PMID- 25914305 TI - Evaluation of adsorption and desorption steps in the solid-phase extraction of explosives using carbon/silica gel nanocomposites. AB - New series of carbon/silica gel nanocomposites, carbosils, prepared by the carbonization of starch bound to silica gel, and carbosils additionally silylated with octadecyldimethylchlorosilane were synthesized. These materials were applied as adsorbents in the solid-phase extraction of explosive nitrate esters and nitroaromatics from aqueous solutions. The adsorption and desorption steps were evaluated separately. It was found that both the molecular properties of explosives (dipole moments, orbital energies, solvation effects) and textural properties influenced by carbon deposits or octadecyl moieties have a large impact on the recovery rates. It was shown that the composites with moderate content of carbon deposits or with the highest amounts of carbon deposits and additionally silylated can be used as materials tailored for extraction of explosives from the aqueous solutions. PMID- 25914308 TI - The impact of opioid prescription dose and duration during a workers compensation claim, on post-claim continued opioid use: A retrospective population-based study. AB - BACKGROUND: Workers Compensation Board (WCB) recipients are a group commonly prescribed opioids. METHODS: We explored factors influencing post-claim opioid dose and duration by linking data from 22,451 claims with the Manitoba Center for Population Health registry. RESULTS: On average, the WCB paid for 94.55% of opioids prescribed during a claim. The amount paid for by the WCB varied significantly by total opioids prescribed. The main predictors of high opioid dosage (120 + morphine equivalents (ME)/day) during the first year post-claim (logistic regression), and of longer post-claim opioid usage (survival analysis), included opioid dosage during the final month of the claim both paid for and not paid for by the WCB. CONCLUSIONS: Amongst low dose opioid claims, the WCB covers most opioids prescribed. Higher opioid dose WCB recipients are often prescribed opioids not covered by the WCB. Both opioids paid for and not paid for by the WCB are associated with post-claim opioid use. PMID- 25914306 TI - DOCK 6: Impact of new features and current docking performance. AB - This manuscript presents the latest algorithmic and methodological developments to the structure-based design program DOCK 6.7 focused on an updated internal energy function, new anchor selection control, enhanced minimization options, a footprint similarity scoring function, a symmetry-corrected root-mean-square deviation algorithm, a database filter, and docking forensic tools. An important strategy during development involved use of three orthogonal metrics for assessment and validation: pose reproduction over a large database of 1043 protein-ligand complexes (SB2012 test set), cross-docking to 24 drug-target protein families, and database enrichment using large active and decoy datasets (Directory of Useful Decoys [DUD]-E test set) for five important proteins including HIV protease and IGF-1R. Relative to earlier versions, a key outcome of the work is a significant increase in pose reproduction success in going from DOCK 4.0.2 (51.4%) -> 5.4 (65.2%) -> 6.7 (73.3%) as a result of significant decreases in failure arising from both sampling 24.1% -> 13.6% -> 9.1% and scoring 24.4% -> 21.1% -> 17.5%. Companion cross-docking and enrichment studies with the new version highlight other strengths and remaining areas for improvement, especially for systems containing metal ions. The source code for DOCK 6.7 is available for download and free for academic users at http://dock.compbio.ucsf.edu/. PMID- 25914309 TI - Novel candidate blood-based transcriptional biomarkers of Machado-Joseph disease. AB - BACKGROUND: Machado-Joseph disease (or spinocerebellar ataxia type 3) is a late onset polyglutamine neurodegenerative disorder caused by a mutation in the ATXN3 gene, which encodes for the ubiquitously expressed protein ataxin-3. Previous studies on cell and animal models have suggested that mutated ataxin-3 is involved in transcriptional dysregulation. Starting with a whole-transcriptome profiling of peripheral blood samples from patients and controls, we aimed to confirm abnormal expression profiles in Machado-Joseph disease and to identify promising up-regulated genes as potential candidate biomarkers of disease status. METHODS: The Illumina Human V4-HT12 array was used to measure transcriptome-wide gene expression in peripheral blood samples from 12 patients and 12 controls. Technical validation and validation in an independent set of samples were performed by quantitative real-time polymerase chain reaction (PCR). RESULTS: Based on the results from the microarray, twenty six genes, found to be up regulated in patients, were selected for technical validation by quantitative real-time PCR (validation rate of 81% for the up-regulation trend). Fourteen of these were further tested in an independent set of 42 patients and 35 controls; 10 genes maintained the up-regulation trend (FCGR3B, CSR2RA, CLC, TNFSF14, SLA, P2RY13, FPR2, SELPLG, YIPF6, and GPR96); FCGR3B, P2RY13, and SELPLG were significantly up-regulated in patients when compared with controls. CONCLUSIONS: Our findings support the hypothesis that mutated ataxin-3 is associated with transcription dysregulation, detectable in peripheral blood cells. Furthermore, this is the first report suggesting a pool of up-regulated genes in Machado Joseph disease that may have the potential to be used for fine phenotyping of this disease. (c) 2015 International Parkinson and Movement Disorder Society. PMID- 25914310 TI - Active Matrix Electronic Skin Strain Sensor Based on Piezopotential-Powered Graphene Transistors. PMID- 25914311 TI - DNA damage and genetic methylation changes caused by Cd in Arabidopsis thaliana seedlings. AB - Amplified fragment length polymorphism (AFLP) and methylation-sensitive amplification polymorphism (MASP) techniques are sensitive to deoxyribonucleic acid (DNA) damage and genetic methylation, respectively. Using these 2 techniques, Arabidopsis thaliana cultured with 0 mg/L (control), 0.5 mg/L, 1.5 mg/L, and 5.0 mg/L Cd(2+) for 16 d was used to analyze the DNA damage and methylation changes as a result of cadmium (Cd). The DNA was amplified by 14 AFLP primer pairs and 13 MSAP primer combinations. In the AFLP experiment, 62 polymorphic sites were found in the patterns of 11 primer combinations and a total of 1116 fragments were obtained in these patterns. There were no polymorphic bands in the remaining 3 pairs. The proportions of polymorphic sites in the 0.5-mg/L Cd(2+) and 5.0-mg/L Cd(2+) treatments were significantly different. Seven polymorphic fragments were then separated and successfully sequenced, yielding 6 nucleobase substitutions and 1 nucleobase deletion. Similarly, in the MSAP experiment, the MSAP% and number of demethylated-type bands were unchanged after Cd treatment, but the number of methylated-type bands was increased significantly in the 5.0-mg/L Cd(2+) treatment group, a finding that may be associated with the AFLP results. The polymorphic bands were also sequenced and the functions of their homologous genes were determined. The DNA damage and methylation changes may be the primary cause of certain pathology changes as a result of Cd uptake in plants. PMID- 25914312 TI - Enhancing Antibody Response against Small Molecular Hapten with Tobacco Mosaic Virus as a Polyvalent Carrier. AB - Virus nanoparticles (VNPs) have been applied as carrier proteins for effective vaccine development. In this paper, we report the usage of tobacco mosaic virus (TMV) as a carrier for the display of the small molecule estriol (E3), a weakly immunogenic hapten. A highly efficient copper (I)-catalyzed azide-alkyne cycloaddition reaction (CuAAC) was performed for the conjugation of E3 onto TMV capsid at tyrosine (Tyr) 139, by which the antigen density could be controlled. The immune properties of these constructs were evaluated in mice. We found that a strong and long-term antibody response was elicited by conjugating a high density of small molecular haptens on TMV through an oligo(ethylene glycol) (OEG) linker, likely due to the effective activation of B-cells. This study suggests that TMV can serve as a promising platform to induce strong humoral immune responses and that the optimized conjugation strategy was critical to produce high quality antibodies. PMID- 25914315 TI - Comments on "A randomized study comparing the use of a pelvic lead shield during trans-radial interventions: Threefold decrease in radiation to the operator but double exposure to the patient". PMID- 25914316 TI - High-Pressure Synthesis of Cd(NH3)2[B3O5(NH3)]2: Pioneering the Way to the Substance Class of Ammine Borates. AB - To date, the access to the substance class of borates containing nitrogen, for example, nitridoborates, oxonitridoborates, or amine borates, was an extreme effort owing to the difficult starting materials and reaction conditions. Although a number of compounds containing boron and nitrogen are known, no adduct of ammonia to an inorganic borate has been observed so far. A new synthetic approach starting from the simple educts CdO, B2O3, and aqueous ammonia under conditions of 4.7 GPa and 800 degrees C led to the synthesis of Cd(NH3)2[B3O5(NH3)]2 as the first ammine borate. We thoroughly characterized this compound on the basis of low-temperature single-crystal and powder X-ray diffraction data, IR and Raman spectroscopy, and by quantum theoretical calculations. This contribution shows that the adduct of NH3 to the BO3 group of a complex B-O network can be stabilized, opening up a fundamentally new synthetic route to nitrogen-containing borates. PMID- 25914317 TI - Reply: To PMID 25205246. PMID- 25914318 TI - Testicular histomorphometry and the proliferative and apoptotic activities of the seminiferous epithelium in Syrian hamster (Mesocricetus auratus) during regression owing to short photoperiod. AB - During the non-breeding season some animals exhibit testicular atrophy, decreased testicular weight and reduced seminiferous tubule diameter accompanied by depletion of the seminiferous epithelium. Some cellular factors involved in this depletion are changes in germ cell proliferation and apoptosis. In the Syrian hamster this depletion has been studied histologically and in terms of the involvement of proliferation and apoptosis in the seminiferous epithelium of fully regressed testes. The objectives of this study included the histomorphometrical characterization of the testis and the determination of the proliferative and apoptotic activity of germ cells in the seminiferous epithelium during testicular regression owing to short photoperiod. The study was performed using conventional light microscopy (hematoxylin and eosin), proliferating cell nuclear antigen and terminal deoxynucleotidyl transferase (TdT)-mediated dUTP in situ nick end labelling staining, image analysis software, and transmission electron microscopy in three established regression groups: mild regression (MR), strong regression (SR), and total regression (TR). Morphometrically a gradual decrease in total tubular area and in the testicular, tubular, and epithelial volumes was observed during testicular regression. Interstitial and luminal volumes decreased from the MR group onwards. The tubular length decreased from MR to SR. As regards spermatogonial proliferation, only an initial decrease in proliferative activity was observed, whereas apoptotic germ cell activity increased throughout regression. The number of germ cells studied decreased throughout the process of testicular regression. In conclusion, testicular regression in Syrian hamster comprises two histomorphometrical phases, the first involving a decrease in seminiferous tubular diameter and volume and the second involving shortening of the seminiferous tubule and a decrease in interstitial volume. At the cellular level, there is an initial decrease in proliferation and increase in apoptosis involving all germ cells. At the end of regression, the proliferative and apoptotic activities of the spermatogonia recover the values observed prior to regression in preparation for recrudescence. PMID- 25914319 TI - Immortalization of epithelial cells in oral carcinogenesis as revealed by genome wide array comparative genomic hybridization: A meta-analysis. AB - BACKGROUND: This purpose of this meta-analysis study was to identify the most frequent and potentially significant copy number alteration (CNA) in oral carcinogenesis. METHODS: Seven oral squamous cell carcinoma (OSCC)-related publications, corresponding to 312 samples, were identified for this meta analysis. The data were analyzed in a 4-step process that included the genome assembly coordination of multiple platforms, assignment of chromosomal position anchors, calling gains and losses, and functional annotation analysis. RESULTS: Gains were more frequent than losses in the entire dataset. High-frequency gains were identified in chromosomes 5p, 14q, 11q, 7p, 17q, 20q, 8q, and 3q, whereas high-frequency losses were identified in chromosomes 3p, 8p, 6p, 18q, and 4q. Ingenuity pathway analysis showed that the top biological function was associated with immortalization of the epithelial cells (p = 1.93E-04). CONCLUSION: This study has identified multiple recurrent CNAs that are involved in various biological annotations associated with oral carcinogenesis. (c) 2015 Wiley Periodicals, Inc. Head Neck 38: E783-E797, 2016. PMID- 25914320 TI - Growing concerns regarding long-term opioid use: the hospitalization hazard. PMID- 25914322 TI - Complicated silicotuberculosis in a South African gold miner: A case report. AB - We present a case of complicated silicotuberculosis in a former gold miner with a sufficiently heavy silica dust exposure to cause International Labor Organization grade 2/2 silicosis after a cumulative exposure duration of 11 years. We describe a cascade of complications-active pulmonary tuberculosis despite recent isoniazid prophylactic therapy, non-tuberculous mycobacterial disease, chronic airways obstruction, and spontaneous pneumothorax-and the difficulties, which arose, in diagnosis and management of such combined disease. We highlight three implications of such cases: the need to understand the interaction of silicosis and tuberculosis in this setting, the importance of maintaining continuity of care in the management of these conditions in miners and former miners, and control of silica dust exposure as a primary form of prevention of tuberculosis. PMID- 25914321 TI - Comparison of intracerebral transplantation effects of different stem cells on rodent stroke models. AB - In the present study, induced pluripotent stem cells (iPSCs), induced neural stem cells (iNSCs), mesenchymal stem cells (MSCs) and an immortalized cell line (RMNE6), representing different characteristics of stem cells, were transplanted into normal and/or injured brain areas of rodent stroke models, and their effects were compared to select suitable stem cells for cell replacement stroke therapy. The rat and mice ischaemic models were constructed using the middle cerebral artery occlusion technique. Both electrocoagulation of the artery and the intraluminal filament technique were used. The behaviour changes and fates of grafted stem cells were determined mainly by behaviour testing and immunocytochemistry. Following iPSC transplantation into the corpora striata of normal mice, a tumour developed in the brain. The iNSCs survived well and migrated towards the injured area without differentiation. Although there was no tumourigenesis in the brain of normal or ischaemic mice after the iNSCs were transplanted in the cortices, the behaviour in ischaemic mice was not improved. Upon transplanting MSC and RMNE6 cells into ischaemic rat brains, results similar to iNSCs in mice were seen. However, transplantation of RMNE6 caused a brain tumour. Thus, tumourigenesis and indeterminate improvement of behaviour are challenging problems encountered in stem cell therapy for stroke, and the intrinsic characteristics of stem cells should be remodelled before transplantation. PMID- 25914323 TI - Heterometal-Embedded Organic Conjugate Frameworks from Alternating Monomeric Iron and Cobalt Metalloporphyrins and Their Application in Design of Porous Carbon Catalysts. PMID- 25914325 TI - Activity-Fed Translation (AFT) Assay: A New High-Throughput Screening Strategy for Enzymes in Droplets. AB - There is an increasing demand for the development of sensitive enzymatic assays compatible with droplet-based microfluidics. Here we describe an original strategy, activity-fed translation (AFT), based on the coupling of enzymatic activity to in vitro translation of a fluorescent protein. We show that methionine release upon the hydrolysis of phenylacetylmethionine by penicillin acylase enabled in vitro expression of green fluorescent protein. An autocatalytic setup where both proteins are expressed makes the assay highly sensitive, as fluorescence was detected in droplets containing single PAC genes. Adding a PCR step in the droplets prior to the assay increased the sensitivity further. The strategy is potentially applicable for any activity that can be coupled to the production of an amino acid, and as the microdroplet volume is small the use of costly reagents such as in vitro expression mixtures is not limiting for high-throughput screening projects. PMID- 25914326 TI - Metallo-deuteroporphyrin as a biomimetic catalyst for the catalytic oxidation of lignin to aromatics. AB - A series of metallo-deuteroporphyrins derived from hemin were prepared as models of the cytochrome P450 enzyme. With the aid of the highly active Co(II) deuteroporphyrin complex, the catalytic oxidation system was applied for the oxidation of several lignin model compounds, and high yields of monomeric products were obtained under mild reaction conditions. It was found that the modified cobalt deuteroporphyrin that has no substituents at the meso sites but does have the disulfide linkage in the propionate side chains at the beta sites exhibited much higher activity and stability than the synthetic tetraphenylporphyrin. The changes in the propionate side chains can divert the reactivity of cobalt deuteroporphyrins from the typical C?C bond cleavage to C?O bond cleavage. Furthermore, this novel oxidative system can convert enzymolysis lignin into depolymerized products including a significant portion of well defined aromatic monomers. PMID- 25914327 TI - Comparison between two- and three-dimensional quantitative coronary angiography bifurcation analyses for the assessment of bifurcation lesions: A subanalysis of the TRYTON pivotal IDE coronary bifurcation trial. AB - BACKGROUND: Three-dimensional (3D) quantitative coronary angiography (QCA) provides more accurate measurements by minimizing inherent limitations of two dimensional (2D) QCA. The aim of this study was to compare the measurements between 2D and 3D QCA analyses in bifurcation lesions. METHODS AND RESULTS: A total of 114 cases with non-left main bifurcation lesions in the TRYTON pivotal IDE Coronary Bifurcation Trial (ClinicalTrials.gov: NCT01258972) were analyzed using a validated bifurcation QCA software (CAAS 5.10, Pie Medical Imaging, Maastricht, the Netherlands). All cases were analyzed in matched projections between pre- and post-procedure. The 2D analysis was performed using one of two angiographic images used for 3D reconstruction showing a larger distal bifurcation angle. In the treated segments (stent and balloon), there were no differences in minimal luminal diameter (MLD) between 2D and 3D, while diameter stenosis (DS) was significantly higher in 2D compared to 3D both pre-procedure and post-procedure (53.9% for 2D vs. 52.1% for 3D pre-procedure, P < 0.01; 23.2% for 2D vs. 20.9% for 3D post-procedure, P = 0.01). In the sub-segment level analysis, lengths of proximal main branch, distal main branch, and side branch were consistently shorter in 2D compared to 3D both pre-procedure and post procedure. Using 3D QCA, the anatomic location of the smallest MLD or the highest DS was relocated to a different bifurcation sub-segment in a considerable proportion of the patients compared to when 2D-QCA was used (kappa values: 0.50 for MLD, 0.55 for DS). CONCLUSIONS: Our data showed differences in addressing anatomical severity and location of coronary bifurcation lesions between in vivo 2D and 3D QCA analyses. More studies are needed to investigate potential clinical benefits in using 3D approach over 2D QCA for the assessment of bifurcation lesions. PMID- 25914328 TI - Distinct Proton and Water Reduction Behavior with a Cobalt(III) Electrocatalyst Based on Pentadentate Oximes. AB - A new pentadentate oxime has been designed to drive the preferential coordination favored by Co(I) in catalysts used for proton/water reduction. The ligand incorporates water upon metal coordination and is water soluble. This Co(III) species is doubly reduced to Co(I) and exhibits H(+) reduction activity in the presence of weak acids in MeCN and evolves H2 upon protonation suggesting that the ligand design increases catalyst effectiveness. Superior catalysis is observed in water with a turnover number (TON) of 5700 over 18 h. However, the catalyst yields Co-based nanoparticles, indicating that the solvent media may dictate the nature of the catalyst. PMID- 25914329 TI - An Interdomain KCNH2 Mutation Produces an Intermediate Long QT Syndrome. AB - Hereditary long QT syndrome is caused by deleterious mutation in one of several genetic loci, including locus LQT2 that contains the KCNH2 gene (or hERG, human ether-a-go-go related gene), causing faulty cardiac repolarization. Here, we describe and characterize a novel mutation, p.Asp219Val in the hERG channel, identified in an 11-year-old male with syncope and prolonged QT interval. Genetic sequencing showed a nonsynonymous variation in KCNH2 (c.656A>T: amino acid p.Asp219Val). p.Asp219Val resides in a region of the channel predicted to be unstructured and flexible, located between the PAS (Per-Arnt-Sim) domain and its interaction sites in the transmembrane domain. The p.Asp219Val hERG channel produced K(+) current that activated with modest changes in voltage dependence. Mutant channels were also slower to inactivate, recovered from inactivation more readily and demonstrated a significantly accelerated deactivation rate compared with the slow deactivation of wild-type channels. The intermediate nature of the biophysical perturbation is consistent with the degree of severity in the clinical phenotype. The findings of this study demonstrate a previously unknown role of the proximal N-terminus in deactivation and support the hypothesis that the proximal N-terminal domain is essential in maintaining slow hERG deactivation. PMID- 25914330 TI - Identification of drug-induced toxicity biomarkers for treatment determination. AB - Drug-induced organ toxicity (DIOT) that leads to the removal of marketed drugs or termination of candidate drugs has been a leading concern for regulatory agencies and pharmaceutical companies. In safety studies, the genomic assays are conducted after the treatment so that drug-induced adverse effects can occur. Two types of biomarkers are observed: biomarkers of susceptibility and biomarkers of response. This paper presents a statistical model to distinguish two types of biomarkers and procedures to identify susceptible subpopulations. The biomarkers identified are used to develop classification model to identify susceptible subpopulation. Two methods to identify susceptibility biomarkers were evaluated in terms of predictive performance in subpopulation identification, including sensitivity, specificity, and accuracy. Method 1 considered the traditional linear model with a variable-by-treatment interaction term, and Method 2 considered fitting a single predictor variable model using only treatment data. Monte Carlo simulation studies were conducted to evaluate the performance of the two methods and impact of the subpopulation prevalence, probability of DIOT, and sample size on the predictive performance. Method 2 appeared to outperform Method 1, which was due to the lack of power for testing the interaction effect. Important statistical issues and challenges regarding identification of preclinical DIOT biomarkers were discussed. In summary, identification of predictive biomarkers for treatment determination highly depends on the subpopulation prevalence. When the proportion of susceptible subpopulation is 1% or less, a very large sample size is needed to ensure observing sufficient number of DIOT responses for biomarker and/or subpopulation identifications. PMID- 25914331 TI - Relationship between dietary energy density and dietary quality in overweight young children: a cross-sectional analysis. AB - BACKGROUND: Observational research has found that lower energy density (ED) diets are related to reduced intake of fat and greater intake of fruits and vegetables. No study has examined the relationship between dietary ED and dietary quality, as determined by the Healthy Eating Index-2005 (HEI), in children who are overweight and obese. OBJECTIVE: Examine the relationship between dietary ED and HEI, determined from 3-d food records, in 156 children, aged 4-9 years, who had >=85th percentile body mass index presenting for family-based obesity treatment. METHOD: Dietary ED, in kcal/g, was calculated using two methods: food and all beverages consumed (food+bev) and food only consumed (food). For calculation of HEI, all components of the HEI were included except oils. RESULTS: Participants were classified as consuming a low-ED, medium-ED or high-ED diet using tertile cut-off points with ED calculated using food and beverages(food+bev) or food only(food) . After controlling for group difference in child sex and race and parent sex, LOW(food+bev) and LOWfood had significantly (P < 0.05) higher total HEI scores, and total fruit, total vegetable and saturated fat HEI scores than HIGH(food+bev) and HIGHfood , with higher scores indicating greater quality. CONCLUSIONS: Lower dietary ED is associated with higher dietary quality in children presenting for obesity treatment. Additional research investigating an ED prescription on dietary quality in children who are overweight or obese is needed to better understand this relationship. PMID- 25914332 TI - Role of radiosurgery in the management of glomus tumors. AB - BACKGROUND: Glomus tumors are benign slow-growing hypervascular neoplasms. The role of radiosurgery for the treatment of these tumors has increased. The purpose of this study was to show our experience with glomus tumors and to analyze different prognostic factors. METHODS: Data from 39 adult patients were retrospectively analyzed. All of them underwent head frame stereotactic radiosurgery with linear accelerator (LINAC). Tumor and symptomatic control were calculated using the Kaplan-Meier method. Bivariate statistical analyses were performed to examine different prognostic factors. RESULTS: The median follow-up was 71 months. The radiological local and symptomatic control was achieved in 37 patients (94.8%) and 29 patients (74.3%), respectively. Toxicity was detected in 4 patients (10%). In the bivariate analysis, dose coverage and maximum dose were associated with tumor control with an odds ratio (OR) of 5.29 (p = .041) and 2.67 (p = .056), respectively. CONCLUSION: Stereotactic radiosurgery is a safe and efficient treatment for glomus tumors that is associated with high probability of radiological and symptomatic control and low incidence of morbidity. (c) 2015 Wiley Periodicals, Inc. Head Neck 38: E798-E804, 2016. PMID- 25914333 TI - Amyloid beta peptide (1-42)-mediated antioxidant imbalance is associated with activation of protein kinase C in red blood cells. AB - Glycolysis and pentose phosphate pathway (PPP) in red blood cell (RBC) are modulated by the cell oxygenation state. This metabolic modulation is connected to variations in intracellular nicotinamide adenine dinucleotide phosphate reduced form (NADPH) and adenosine triphosphate (ATP) levels as a function of the oxygenation state of the cell, and, consequently, it should have physiologic relevance. In the present study, we analysed the effects of amyloid beta peptide (1-42) (Abeta) on RBC metabolism and its relationship with the activity of protein kinase C (PKC). Our results showed that metabolic response to Abeta depended on the degree of cell oxygenation. In particular, under high O2 pressure, in Abeta-treated RBC, glucose metabolized through PPP approached that metabolized by RBC under low O2 pressure, differently to that observed in untreated cells. The effect of Abeta on RBC metabolism was paralleled by increase in PKC enzyme activity, but cytosolic Ca2+ concentration does not seem to be involved in this mechanism. Incubation of Abeta-treated RBC with a specific inhibitor of PKC partially restores PPP flux. A possible rationalization of the different metabolic behaviours shown by RBC following Abeta treatment is proposed. It takes into account the known post-translational modifications to cytoskeleton proteins induced by PKC. The reduction in PPP flux may lead to a weakened defence system of antioxidant reserve in RBC, becoming a source of reactive species, and, consequently, its typical, structural and functional features are lost. Therefore, oxidative stress may outflow from the RBC and trigger damage events in adjacent cells and tissue, thus contributing to vascular damage. PMID- 25914334 TI - Influence of a Specialized Trigonella foenum-graecum Seed Extract (Libifem), on Testosterone, Estradiol and Sexual Function in Healthy Menstruating Women, a Randomised Placebo Controlled Study. AB - The aim of the study was to evaluate the effect of Trigonella foenum-graecum (fenugreek) seed extract on sex hormones and sexual function in healthy menstruating women who reported low sexual drive. This short term, single site, double blind, randomised, placebo-controlled study was conducted on 80 women, aged 20 to 49 years. Participants were randomised to either an oral dose of a standardised T. foenum-graecum seed extract (libifem) at a dose of 600 mg/day or placebo over two menstrual cycles. Dehydroepiandrosterone sulfate, progesterone, androstenedione, total and free testosterone, estradiol (E2), luteinizing hormone, follicle stimulating hormone, sex hormone binding globulin and cholesterol were measured at baseline and 8 weeks. The individual aspects of sexual function were measured using the Derogatis interview for sexual functioning and female sexual function index self-administered questionnaires. Stress, fatigue and quality of the relationship with partner were also measured using the PSS (Perceived Stress Scale), MFI-20 (Multidimensional Fatigue Inventory) and DAS (Dyadic Adjustment Scale) quality of life measures, respectively. There was a significant increase in free testosterone and E2 in the active group as well as sexual desire and arousal compared with the placebo group. The results indicate that this extract of T. foenum-graecum may be a useful treatment for increasing sexual arousal and desire in women. PMID- 25914335 TI - Nail gun injuries treated in U.S emergency departments, 2006-2011: not just a worker safety issue. AB - BACKGROUND: Nail guns increase productivity in residential building but with a corresponding increase in worker injuries. They are also easily accessible, at low cost, to consumers. METHODS: Data from the occupational supplement to the National Electronic Injury Surveillance System (NEISS-Work) were used to calculate national estimates of work-related injuries from nail guns between 2006 and 2011. These were compared to estimates of consumer injuries obtained through online access to the Consumer Product Safety Commission's (CPSC) NEISS data. RESULTS: Approximately 25,000 ED-treated work-related and consumer nail gun injuries were estimated each year. During the construction economy collapse, injuries among workers declined markedly, closely following patterns of reduced residential employment. Reduction in consumer injuries was much more modest. CONCLUSIONS: Current nail gun injury patterns suggest marked blurring of work and home exposures. A united effort of CPSC, NIOSH, and OSHA is warranted to address these preventable injuries. PMID- 25914336 TI - The effect of dopamine D4 receptor density on novelty seeking, activity, social interaction, and alcohol binge drinking in adult mice. AB - The dopamine D4 receptor has been postulated to play a role in the pathophysiology of alcoholism. This study examined how varying levels of D4 expression and their associated behaviors in male and female mice correlate with future alcohol intake. We hypothesized that: (1) mice with low (Drd4(+/-) ) or deficient (Drd4(-/-) ) in D4 receptors would show enhanced ethanol consumption compared with control mice (Drd4(+/+) ), and (2) a specific phenotype in these mice is associated with future vulnerability for alcohol consumption. Individually housed mice were allowed free access to ethanol (20% vv) in the dark (DID). The behaviors measured in male and female mice were: novel object recognition, open-field locomotor activity, and social interaction. Correlation analyses showed that in male Drd4(-/-) mice (relative to Drd4(+/+) controls), anxiolytic behavior was significantly correlated with increased alcohol consumption. Also, in male Drd4(-/-) mice, there was a significant positive correlation between increased exploratory behavior and increased alcohol consumption. These findings were not observed in females. In conclusion, our data suggest that the dopamine D4 receptor gene has an important role in increased exploratory and anxiolytic behavior only in males and these behaviors were positively correlated with increased alcohol consumption. This interaction between sex hormones and dopamine D4 receptor genotype/function predicting future alcohol abuse and correlation with anxiolytic and exploratory behavior in male mice could have important implications for better understanding of vulnerabilities associated with addiction. PMID- 25914337 TI - Intravesical botulinum toxin-A injections reduce bladder pain of interstitial cystitis/bladder pain syndrome refractory to conventional treatment - A prospective, multicenter, randomized, double-blind, placebo-controlled clinical trial. AB - PURPOSE: Intravesical onabotulinumtoxinA (BoNT-A) injection is a beneficial treatment for interstitial cystitis/bladder pain syndrome (IC/BPS), yet its therapeutic efficacy remains to be validated. This study tests efficacy and safety of intravesical BoNT-A injections for treatment of IC/BPS. MATERIALS AND METHODS: A multicenter, randomized, double-blind, placebo-controlled trial in patients with IC/BPS refractory to conventional treatment. Patients were randomized in a 2:1 ratio to hydrodistention plus suburothelial injections of BoNT-A 100 U (Botox group) or the equivalent amount of normal saline (N/S group). The primary endpoint was a decrease in pain assessed using a visual analog scale (VAS) at week 8 after treatment. Secondary endpoints included voiding diary and urodynamic variables. The Wilcoxon sign rank and rank sum tests were used for statistical analyses. RESULTS: A total of 60 patients (8 males, 52 females, age 50.8 +/- 13.9 years) including 40 in the Botox and 20 in the N/S groups were enrolled. At week 8, a significantly greater reduction of pain was observed in the Botox group compared to the N/S group (-2.6 +/- 2.8 vs. -0.9 +/- 2.2, P = 0.021). The other variables did not differ significantly between groups except for cystometric bladder capacity, which was increased significantly in the Botox group. The overall success rates were 63% (26/40) in the Botox group and 15% (3/20) in the N/S group (P = 0.028). Adverse events did not differ between the groups. CONCLUSION: Intravesical injections of 100 U of BoNT-A effectively reduced bladder pain symptoms in patients with IC/BPS. The adverse events were acceptable. Neurourol. Urodynam. 35:609-614, 2016. (c) 2015 Wiley Periodicals, Inc. PMID- 25914338 TI - Genetic Incorporation of N(epsilon)-Formyllysine, a New Histone Post translational Modification. AB - Lysine formylation is a newly discovered post-translational modification (PTM) in histones and other nuclear proteins; it has a well-recognized but poorly defined role in chromatin conformation modulation and gene expression. To date, there is no general method to site-specifically incorporate N(epsilon)-formyllysine at a defined site of a protein. Here we report the highly efficient genetic incorporation of the unnatural amino acid N(epsilon)-formyllysine into proteins produced in Escherichia coli and mammalian cells, by using an orthogonal N(epsilon)-formyllysine tRNAsynthetase/tRNACUA pair. This technique can be applied to study the role of lysine formylation in epigenetic regulation. PMID- 25914339 TI - Adolescent vulnerability to cardiovascular consequences of chronic social stress: Immediate and long-term effects of social isolation during adolescence. AB - It has been demonstrated that disruption of social bonds and perceived isolation (loneliness) are associated with an increased risk of cardiovascular morbidity and mortality. Adolescence is proposed as a period of vulnerability to stress. Nevertheless, the impact of chronic social stress during this ontogenic period in cardiovascular function is poorly understood. Therefore, the purpose of this study was to compare the impact in cardiovascular function of social isolation for 3 weeks in adolescent and adult male rats. Also, the long-term effects of social isolation during adolescence were investigated longitudinally. Social isolation reduced body weight in adolescent, but not in adult animals. Disruption of social bonds during adolescence increased arterial pressure without affecting heart rate and pulse pressure (PP). Nevertheless, social isolation in adulthood reduced systolic arterial pressure and increased diastolic arterial pressure, which in turn decreased PP without affecting mean arterial pressure. Cardiovascular changes in adolescents, but not adults, were followed by facilitation of both baroreflex sensitivity and vascular reactivity to the vasodilator agent acetylcholine. Vascular responsiveness to either the vasodilator agent sodium nitroprusside or the vasoconstrictor agent phenylephrine was not affected by social isolation. Except for the changes in body weight and baroreflex sensitivity, all alterations evoked by social isolation during adolescence were reversed in adulthood after moving animals from isolated to collective housing. These findings suggest a vulnerability of adolescents to the effects of chronic social isolation in cardiovascular function. However, results indicate minimal cardiovascular consequences in adulthood of disruption of social bonds during adolescence. PMID- 25914340 TI - Large-scale adenovirus and poxvirus-vectored vaccine manufacturing to enable clinical trials. AB - Efforts to make vaccines against infectious diseases and immunotherapies for cancer have evolved to utilize a variety of heterologous expression systems such as viral vectors. These vectors are often attenuated or engineered to safely deliver genes encoding antigens of different pathogens. Adenovirus and poxvirus vectors are among the viral vectors that are most frequently used to develop prophylactic vaccines against infectious diseases as well as therapeutic cancer vaccines. This mini-review describes the trends and processes in large-scale production of adenovirus and poxvirus vectors to meet the needs of clinical applications. We briefly describe the general principles for the production and purification of adenovirus and poxvirus viral vectors. Currently, adenovirus and poxvirus vector manufacturing methods rely on well-established cell culture technologies. Several improvements have been evaluated to increase the yield and to reduce the overall manufacturing cost, such as cultivation at high cell densities and continuous downstream processing. Additionally, advancements in vector characterization will greatly facilitate the development of novel vectored vaccine candidates. PMID- 25914341 TI - Controllable Synthesis of Mesoporous Peapod-like Co3O4@Carbon Nanotube Arrays for High-Performance Lithium-Ion Batteries. AB - Transition metal oxides are regarded as promising anode materials for lithium-ion batteries because of their high theoretical capacities compared with commercial graphite. Unfortunately, the implementation of such novel anodes is hampered by their large volume changes during the Li(+) insertion and extraction process and their low electric conductivities. Herein, we report a specifically designed anode architecture to overcome such problems, that is, mesoporous peapod-like Co3O4@carbon nanotube arrays, which are constructed through a controllable nanocasting process. Co3O4 nanoparticles are confined exclusively in the intratubular pores of the nanotube arrays. The pores between the nanotubes are open, and thus render the Co3O4 nanoparticles accessible for effective electrolyte diffusion. Moreover, the carbon nanotubes act as a conductive network. As a result, the peapod-like Co3O4 @carbon nanotube electrode shows a high specific capacity, excellent rate capacity, and very good cycling performance. PMID- 25914342 TI - Transcatheter balloon dilation for recurrent right ventricular outflow tract obstruction following valve-sparing repair of tetralogy of Fallot. AB - BACKGROUND: Valve-sparing repair in patients with tetralogy of Fallot (TOF) carries the risk of residual or recurrent right ventricular outflow tract (RVOT) obstruction, which is often treated with transcatheter balloon dilation (BD). The outcomes and associated complications of BD of the RVOT in this scenario remain unknown. METHODS: Retrospective review of the records of the Department of Cardiology at Boston Children's Hospital from 2000 to 2013 was performed. RESULTS: 34 patients had initial valve-sparing repair of tetralogy of Fallot followed by BD of the RVOT during the study period. Following BD, the RVOT gradient decreased from a median of 43 mm Hg (range 13 to 79 mm Hg) to 28 mm Hg (range 0 to 73 mm Hg) (P < 0.001). Freedom from reintervention was 64% at 1 year and 46% at 3 years. Trivial to mild PR pre-BD was present in 56% (n = 19) of patients and decreased to 37% (n = 11) post-BD. Exclusively valvar obstruction was associated with a longer freedom from reintervention (P = 0.05), while a ratio of RV pressure to aortic systolic pressure pre-BD of >1 and a final RVOT gradient of >=40 post-BD were associated with shorter freedom from reintervention (P < 0.001). CONCLUSION: BD in patients with recurrent RVOT obstruction following valve-sparing repair of TOF acutely reduces the RVOT gradient, but commonly results in increased PR and is associated with a high reintervention rate. Patients with stenosis solely at the level of the valve had a better response to this type of intervention. PMID- 25914343 TI - McArdle Disease: Update of Reported Mutations and Polymorphisms in the PYGM Gene. AB - McArdle disease is an autosomal-recessive disorder caused by inherited deficiency of the muscle isoform of glycogen phosphorylase (or "myophosphorylase"), which catalyzes the first step of glycogen catabolism, releasing glucose-1-phosphate from glycogen deposits. As a result, muscle metabolism is impaired, leading to different degrees of exercise intolerance. Patients range from asymptomatic to severely affected, including in some cases, limitations in activities of daily living. The PYGM gene codifies myophosphoylase and to date 147 pathogenic mutations and 39 polymorphisms have been reported. Exon 1 and 17 are mutational hot-spots in PYGM and 50% of the described mutations are missense. However, c.148C>T (commonly known as p.R50X) is the most frequent mutation in the majority of the studied populations. No genotype-phenotype correlation has been reported and no mutations have been described in the myophosphorylase domains affecting the phosphorylated Ser-15, the 280's loop, the pyridoxal 5'-phosphate, and the nucleoside inhibitor binding sites. A newly generated knock-in mouse model is now available, which renders the main clinical and molecular features of the disease. Well-established methods for diagnosing patients in laboratories around the world will shorten the frequent ~20-year period stretching from first symptoms appearance to the genetic diagnosis. PMID- 25914344 TI - Matted nodes: High distant-metastasis risk and a potential indication for intensification of systemic therapy in human papillomavirus-related oropharyngeal cancer. AB - BACKGROUND: The purpose of this study was to determine whether matted nodes uniquely identify patients with human papillomavirus (HPV)-positive oropharyngeal cancer at disproportionately high distant failure risk who may benefit from intensified systemic therapy. METHODS: One hundred seventy-eight patients with stage III/IV HPV-positive oropharyngeal cancer who completed definitive chemoradiotherapy were stratified by risk group (low-risk = T1-3/N0-2c/<10 pack years; intermediate-risk = T1-3/N0-2c/>=10 pack-years; and high-risk = T4 or N3). Prognostic impact of matted nodes was assessed. RESULTS: At the 52-month median follow-up, event rates with and without matted nodes were: locoregional failure: 23.3% versus 12.8% (p = .16), distant failure: 50.0% versus 1.4% (p < .01), any failure: 73.3% versus 14.2% (p < .01); cause-specific mortality: 56.7% versus 5.4% (p < .01), and death: 56.7% versus 13.5% (p < .01). In multivariate analyses, including risk group and individual risk factors, matted nodes were the strongest predictor for all endpoints except locoregional failure. Among patients without matted nodes, risk-group discriminated locoregional failure (at 3 years: low-risk = 2.0%; intermediate-risk = 14.4%; and high-risk = 24.2%; p < .01), but not distant failure (low-risk = 0.0%; intermediate-risk = 2.1%; and high-risk = 3.8%; p = .53). CONCLUSION: Matted nodes portended dramatically increased distant failure and death risks in HPV-positive oropharyngeal cancer, identifying a candidate population for consideration of chemo-intensification. (c) 2015 Wiley Periodicals, Inc. Head Neck 38: E805-E814, 2016. PMID- 25914345 TI - JNK and NFkappaB dependence of apoptosis induced by vinblastine in human acute promyelocytic leukaemia cells. AB - The relationship between the mitogen-activated protein kinase response, nuclear factor-kappaB (NFkappaB) expression and the apoptosis in human acute promyelocytic leukaemia NB4 cells treated with vinblastine was investigated in this work. Cell viability, subdiploid DNA and cell cycle were analysed by propidium iodide permeability and flow cytometry analyses. Apoptosis was determined by annexin V-Fluorescein isothiocyanate assays. Western-blot analysis was used for determination of expression levels of apoptotic factors (p53, Bax and Bcl2), intracellular kinases [serine/threonine-specific protein kinase, extracellular signal-regulated kinase and c-Jun N-terminal kinase (JNK)], NFkappaB factor and caspases. Electrophoretic mobility shift assay was usefully applied to study DNA-NFkappaB interaction. In NB4 cells, vinblastine produces alteration of p53 and DNA fragmentation. Vinblastine treatment had an antiproliferative effect via the induction of apoptosis producing Bax/Bcl-2 imbalance. Vinblastine treatment suppressed NFkappaB expression and depressed NFkappaB-DNA binding activity while maintaining JNK activation that subsequently resulted in apoptotic response through caspase-dependent pathway. Our study provides a possible anti-cancer mechanism of vinblastine action on NB4 cells by deregulation of the intracellular signalling cascade affecting to JNK activation and NFkappaB expression. Moreover, JNK activation and NFkappaB depression can be very significant factors in apoptosis induction by vinblastine. PMID- 25914347 TI - Meta-analysis of clinical trials with rare events. AB - Meta-analysis of rare event studies has recently become a subject of controversy and debate. We will argue and demonstrate in this paper that the occurrence of zero events in clinical trials or cohort studies, even if zeros occur in both arms (the case of a double-zero trial), is less problematic, at least from a statistical perspective, if the available statistical tools are applied in the appropriate way. In particular, it is neither necessary nor advisable to exclude studies with zero events from the meta-analysis. In terms of statistical tools, we will focus here on Mantel-Haenszel techniques, mixed Poisson regression and related regression models. PMID- 25914348 TI - 5-HT1B receptor imaging and cognition: a positron emission tomography study in control subjects and Parkinson's disease patients. AB - INTRODUCTION: The serotonin 5-HT1B receptor subtype is involved in the modulation of serotonin release and is a target of interest for neuroreceptor imaging. Previous studies have shown that the serotonin system is affected in Parkinson's disease (PD). Cognitive function, frequently impaired in PD, has been linked to the serotonin system. The aim of this study was to examine whether 5-HT1B receptor availability in the brain of healthy subjects and PD patients is associated with measures of cognitive function. METHODS: Twelve control subjects and ten PD patients with normal mini-mental state examination scores were included in this study. Cognitive function was evaluated by assessment of semantic, episodic, and working memory, as well as fluency and visual attention. Creative ability, a measure of divergent thinking, was examined with the alternative uses of objects task. PET measurements were performed with the 5-HT1B receptor-radioligand [(11) C]AZ10419369 using the HRRT system. RESULTS: PD patients showed statistically significant lower measures of semantic and episodic memory, as well as creative ability, compared with control subjects. Statistically significant positive correlations were found in control subjects between creative ability and average 5-HT1B receptor availability in grey matter, and in PD patients between scores of Beck Depression Inventory-II and creative ability. CONCLUSION: Though creativity has been conventionally linked to dopamine function, our findings in control subjects suggest a link between 5-HT1B receptor availability and creative ability. In PD patients, creative ability was significantly associated with depressive symptoms but not with 5-HT1B receptor availability. This finding deserves further investigation in future studies. PMID- 25914349 TI - Different number of intravesical onabotulinumtoxinA injections for patients with refractory detrusor overactivity do not affect treatment outcome: A prospective randomized comparative study. AB - AIMS: To examine the therapeutic effects and safety of different numbers of intravesical onabotulinumtoxinA (BoNT-A) injection for patients with detrusor overactivity (DO) refractory to antimuscarinics. METHODS: Patients with DO, at least one daily episode of urgency or urgency incontinence refractory to previous antimuscarinics were randomly assigned to receive 10, 20, or 40 intravesical BoNT A injections 100 U in 10 mL in the bladder body. Treatment results were assessed with global response assessment GRA, OAB symptom score OAB-SS, urgency severity scale USS, patient perception of bladder condition PPBC, voiding diary, and urodynamic parameters. The primary endpoint was the comparison of the rates of successful treatment, which was defined as GRA >= 1 after treatment, between the groups. The secondary endpoints were the comparisons of the changes in the voiding diary, urodynamic parameters, individual AEs between the groups. RESULTS: Sixty-seven patients were randomized into three groups. Patients with GRA >= 1 at 1, 3, and 6 months after treatment were comparable between the groups. The average OAB-SS and USS and PPBC scores decreased whereas the average postvoid residual urine volume increased in all three groups. Changes in urodynamic and voiding diary parameters were also comparable between the groups. There were no significant differences in the rates of AEs and urinary tract infection after treatment. CONCLUSIONS: Different numbers of intravesical BoNT-A injections produced similar therapeutic and adverse effects. We therefore believe that 1 ml BoNT-A injections (10 U) at 10 sites are adequate to achieve an optimal therapeutic effect in OAB patients. Neurourol. Urodynam. 35:717-723, 2016. (c) 2015 Wiley Periodicals, Inc. PMID- 25914350 TI - Fe K-Edge X-ray Absorption Fine Structure Determination of gamma-Al2 O3 Supported Iron-Oxide Species. AB - The structure of FeOx species supported on gamma-Al2 O3 was investigated by using Fe K-edge X-ray absorption fine structure (XAFS) and X-ray diffraction (XRD) measurements. The samples were prepared through the impregnation of iron nitrate on Al2 O3 and co-gelation of aluminum and iron sulfates. The dependence of the XRD patterns on Fe loading revealed the formation of alpha-Fe2 O3 particles at an Fe loading of above 10 wt %, whereas the formation of iron-oxide crystals was not observed at Fe loadings of less than 9.0 wt %. The Fe K-edge XAFS was characterized by a clear pre-edge peak, which indicated that the Fe?O coordination structure deviates from central symmetry and that the degree of Fe?O?Fe bond formation is significantly lower than that in bulk samples at low Fe loading (<9.0 wt %). Fe K-edge extended XAFS oscillations of the samples with low Fe loadings were explained by assuming an isolated iron-oxide monomer on the gamma-Al2 O3 surface. PMID- 25914351 TI - New (or not-so-new) tricks for old dogs: ultrasound imaging in anatomy laboratories. PMID- 25914354 TI - Tandem Z-Selective Cross-Metathesis/Dihydroxylation: Synthesis of anti-1,2-Diols. AB - A stereoselective synthesis of anti-1,2-diols has been developed using a multitasking Ru catalyst in an assisted tandem catalysis protocol. A cyclometalated Ru complex catalyzes first a Z-selective cross-metathesis of two terminal olefins, followed by a stereospecific dihydroxylation. Both steps are catalyzed by Ru, as the Ru complex is converted to a dihydroxylation catalyst upon addition of NaIO4. A variety of olefins were transformed into valuable, highly functionalized, and stereodefined molecules. Mechanistic experiments were performed to probe the nature of the oxidation step and catalyst inhibition pathways. These experiments point the way to more broadly applicable tandem catalytic transformations. PMID- 25914355 TI - Aortic annulus and root characteristics in severe aortic stenosis due to bicuspid aortic valve and tricuspid aortic valves: implications for transcatheter aortic valve therapies. AB - BACKGROUND: Patients with severe aortic stenosis due to BAV are excluded from transcatheter aortic valve replacement (TAVR) due to concern for asymmetric expansion and valve dysfunction. We sought to characterize the aortic root and annulus in bicuspid aortic valve (BAV) and tricuspid aortic valves (TAV). METHODS AND RESULTS: We identified patients with severe AS who underwent multi-detector computed tomographic (MDCT) imaging prior to surgical aortic valve replacement (SAVR, n = 200) for BAV and TAVR (n = 200) for TAV from 2010 to 2013. The presence of a BAV was confirmed on surgical and pathological review. Annulus measurements of the basal ring (short- and long-axis, area-derived diameter), coronary ostia height, sinus area (SA), sino-tubular junction area (STJ), calcification and eccentricity index (EI, 1-short axis/long axis) were made. Patients with TAV were older (78.8 years vs. 57.8 years, P = 0.04) than those with BAV. The aortic annulus area (5.21 +/- 2.1 cm(2) vs. 4.63 +/- 2.0 cm(2) , P = 0.0001), sinus of Valsalva diameter (3.7 +/- 0.9 cm vs. 3.1 +/- 0.1 cm, P = 0.001) and ascending aorta diameter (3.5 +/- 0.7 cm vs. 2.97 +/- 0.6 cm, P = 0.001) were significantly larger with BAV. Bicuspid aortic annuli were significantly less elliptical (EI, 1.24 +/- 0.1 vs. 1.29 +/- 0.1, P = 0.006) and more circular (39% vs. 4%, P < 0.001) compared to the TAV annulus. There was more eccentric annular calcification in BAV vs. TAV (68% vs. 32%, P < 0.001). The mean distance from the aortic annulus to the left main coronary ostium was less than the right coronary ostium. Less than 10% of the BAV annuli would not fit a currently available valved stents. CONCLUSION: Bicuspid aortic valves have a larger annulus size, sinus of Valsalva and ascending aorta dimensions. In addition, the BAV aortic annuli appear circular and most will fit currently available commercial valved stents. PMID- 25914356 TI - Westward ho! for early anthropoids. PMID- 25914357 TI - Are you a "Darwinian"? Even Academics have Totems, but it's not Clear What they Imply. PMID- 25914359 TI - An evolutionary theory of large-scale human warfare: Group-structured cultural selection. AB - When humans wage war, it is not unusual for battlefields to be strewn with dead warriors. These warriors typically were men in their reproductive prime who, had they not died in battle, might have gone on to father more children. Typically, they are also genetically unrelated to one another. We know of no other animal species in which reproductively capable, genetically unrelated individuals risk their lives in this manner. Because the immense private costs borne by individual warriors create benefits that are shared widely by others in their group, warfare is a stark evolutionary puzzle that is difficult to explain. Although several scholars have posited models of the evolution of human warfare, these models do not adequately explain how humans solve the problem of collective action in warfare at the evolutionarily novel scale of hundreds of genetically unrelated individuals. We propose that group-structured cultural selection explains this phenomenon. PMID- 25914360 TI - A new research strategy for integrating studies of paleoclimate, paleoenvironment, and paleoanthropology. AB - Paleoanthropologists (scientists studying human origins) universally recognize the evolutionary significance of ancient climates and environments for understanding human origins. Even those scientists working in recent phases of human evolution, when modern humans evolved, agree that hunter-gatherer adaptations are tied to the way that climate and environment shape the food and technological resource base. The result is a long tradition of paleoanthropologists engaging with climate and environmental scientists in an effort to understand if and how hominin bio-behavioral evolution responded to climate and environmental change. Despite this unusual consonance, the anticipated rewards of this synergy are unrealized and, in our opinion, will not reach potential until there are some fundamental changes in the way the research model is constructed. Discovering the relation between climate and environmental change to human origins must be grounded in a theoretical framework and a causal understanding of the connection between climate, environment, resource patterning, behavior, and morphology, then move beyond the strict correlative research that continues to dominate the field. PMID- 25914361 TI - Was monogamy a key step on the hominin road? Reevaluating the monogamy hypothesis in the evolution of cooperative breeding. AB - Because human mothers routinely rely on others to help raise their young, humans have been characterized as cooperative breeders.(1-9) Several large-scale phylogenetic analyses have presented compelling evidence that monogamy preceded the evolution of cooperative breeding in a wide variety of nonhuman animals.(10 14) These studies have suggested that monogamy provides a general rule (the monogamy hypothesis) for explaining evolutionary transitions to cooperative breeding.(15) Given the prevalence of cooperative breeding in contemporary human societies, we evaluate whether this suggests a monogamous hominin past. PMID- 25914362 TI - Editorial: Can GPR43 Sensing of Short-Chain Fatty Acids Unchain Inflammasome Driven Arthritis? PMID- 25914363 TI - Air emissions associated with decommissioning California's offshore oil and gas platforms. AB - The 27 oil and gas platforms offshore southern California are nearing the end of their productive lives and will be decommissioned in the near future. Many are in deep water and are correspondingly large, with the largest, Harmony, in 1200 feet of water and weighing approximately 43,000 tons. Nearly 30% of California's platforms are in water depths that exceed those of any previous decommissioning project anywhere in the world. Decommissioning will involve the operation of diesel-powered heavy equipment for long periods in virtually all phases of the operation (e.g, at the platform, in transit to and from the platform, in port, at offloading, salvage, and recycling facilities) in a region where air quality is a crucial concern for state, federal, and local regulatory agencies, as well as the public. To support future decision making about the choice between decommissioning options, we consider potential air emissions generated under complete and partial (removal to 85 feet below water line) removal options. We describe major emissions categories, and the environmental and human health issues associated with each, and examine how the regulatory system would operate in specific projects. We then describe methods to estimate emissions for a worst case example involving the largest platform, Harmony. We estimate that complete versus partial removal of Harmony would result, respectively, in 600 or 89 tons of NOx, 50 or 7 tons of carbon monoxide, 29,400 or 4400 tons of CO2 , 21 or 3 tons of PM10, and 20 or 3 tons of PM2.5. Complete removal of Harmony's jacket and topsides creates approximately 6.75 times more air pollution than partial removal down to 85 feet below the sea surface. We discuss how the Harmony estimate can be used as a baseline to roughly estimate emissions from decommissioning other platforms, using expected time on station for the major categories of decommissioning equipment. PMID- 25914364 TI - Euphorbiasteroid, a component of Euphorbia lathyris L., inhibits adipogenesis of 3T3-L1 cells via activation of AMP-activated protein kinase. AB - The purpose of this study is to investigate the effects of euphorbiasteroid, a component of Euphorbia lathyris L., on adipogenesis of 3T3-L1 pre-adipocytes and its underlying mechanisms. Euphorbiasteroid decreased differentiation of 3T3-L1 cells via reduction of intracellular triglyceride (TG) accumulation at concentrations of 25 and 50 MUM. In addition, euphorbiasteroid altered the key regulator proteins of adipogenesis in the early stage of adipocyte differentiation by increasing the phosphorylation of AMP-activated protein kinase (AMPK) and acetyl-CoA carboxylase. Subsequently, levels of adipogenic proteins, including fatty acid synthase, peroxisome proliferator-activated receptor-gamma and CCAAT/enhancer-binding protein alpha, were decreased by euphorbiasteroid treatment at the late stage of adipocyte differentiation. The anti-adipogenic effect of euphorbiasteroid may be derived from inhibition of early stage of adipocyte differentiation. Taken together, euphorbiasteroid inhibits adipogenesis of 3T3-L1 cells through activation of the AMPK pathway. Therefore, euphorbiasteroid and its source plant, E. lathyris L., could possibly be one of the fascinating anti-obesity agent. PMID- 25914366 TI - Calbindin-D28K is increased in the ventral horn of spinal cord by neuroprotective factors for motor neurons. AB - Slow glutamate-mediated neuronal degeneration is implicated in the pathophysiology of motor neuron diseases such as amyotrophic lateral sclerosis (ALS). The calcium-binding proteins calbindin-D28K and parvalbumin have been reported to protect neurons against excitotoxic insults. Expression of calbindin D28K is low in adult human motor neurons, and vulnerable motor neurons additionally may lack parvalbumin. Thus, it has been speculated that the lack of calcium-binding proteins may, in part, be responsible for early degeneration of the population of motor neurons most vulnerable in ALS. Using a rat organotypic spinal cord slice system, we examined whether the most potent neuroprotective factors for motor neurons can increase the expression of calbindin-D28K or parvalbumin proteins in the postnatal spinal cord. After 4 weeks of incubation of spinal cord slices with 1) glial cell line-derived neurotrophic factor (GDNF), 2) neurturin, 3) insulin-like growth factor I (IGF-I), or 4) pigment epithelium derived factor (PEDF), the number of calbindin-D28K -immunopositive large neurons (>20 MUm) in the ventral horn was higher under the first three conditions, but not after PEDF, compared with untreated controls. Under the same conditions, parvalbumin was not upregulated by any neuroprotective factor. The same calbindin increase was true of IGF-I and GDNF in a parallel glutamate toxicity model of motor neuron degeneration. Taken together with our previous reports from the same model, which showed that all these neurotrophic factors can potently protect motor neurons from slow glutamate injury, the data here suggest that upregulation of calbindin-D28K by some of these factors may be one mechanism by which motor neurons can be protected from glutamate-induced, calcium-mediated excitotoxicity. PMID- 25914367 TI - Re: Lehmann C, Zipponi I, Baumann MU, et al. Standardized pelvic floor exercises improve stress urinary incontinence in women with intrinsic sphincter deficiency. Neurourol. Urodyn. 2016;35:711-6. PMID- 25914365 TI - Mapping human brain capillary water lifetime: high-resolution metabolic neuroimaging. AB - Shutter-speed analysis of dynamic-contrast-agent (CA)-enhanced normal, multiple sclerosis (MS), and glioblastoma (GBM) human brain data gives the mean capillary water molecule lifetime (tau(b)) and blood volume fraction (v(b); capillary density-volume product (rho(?)V)) in a high-resolution (1)H2O MRI voxel (40 MUL) or ROI. The equilibrium water extravasation rate constant, k(po) (tau(b)(-1)), averages 3.2 and 2.9 s(-1) in resting-state normal white matter (NWM) and gray matter (NGM), respectively (n = 6). The results (italicized) lead to three major conclusions. (A) k(po) differences are dominated by capillary water permeability (P(W)(?)), not size, differences. NWM and NGM voxel k(po) and v(b) values are independent. Quantitative analyses of concomitant population-averaged k(po), v(b) variations in normal and normal-appearing MS brain ROIs confirm P(W)(?) dominance. (B) P(W)(?) is dominated (>95%) by a trans(endothelial)cellular pathway, not the P(CA)(?) paracellular route. In MS lesions and GBM tumors, P(CA)(?) increases but P(W)(?) decreases. (C) k(po) tracks steady-state ATP production/consumption flux per capillary. In normal, MS, and GBM brain, regional k(po) correlates with literature MRSI ATP (positively) and Na(+) (negatively) tissue concentrations. This suggests that the P(W)(?) pathway is metabolically active. Excellent agreement of the relative NGM/NWM k(po)v(b) product ratio with the literature (31)PMRSI-MT CMR(oxphos) ratio confirms the flux property. We have previously shown that the cellular water molecule efflux rate constant (k(io)) is proportional to plasma membrane P-type ATPase turnover, likely due to active trans-membrane water cycling. With synaptic proximities and synergistic metabolic cooperativities, polar brain endothelial, neuroglial, and neuronal cells form "gliovascular units." We hypothesize that a chain of water cycling processes transmits brain metabolic activity to k(po), letting it report neurogliovascular unit Na(+),K(+)-ATPase activity. Cerebral k(po) maps represent metabolic (functional) neuroimages. The NGM 2.9 s(-1) k(po) means an equilibrium unidirectional water efflux of ~10(15) H2O molecules s(-1) per capillary (in 1 MUL tissue): consistent with the known ATP consumption rate and water co transporting membrane symporter stoichiometries. PMID- 25914368 TI - Mutagenicity monitoring following battlefield exposures: Longitudinal study of HPRT mutations in Gulf War I veterans exposed to depleted uranium. AB - A total of 70 military Veterans have been monitored for HPRT T-cell mutations in five separate studies at 2-year intervals over an 8-year period. Systemic depleted uranium (DU) levels were measured at the time of each study by determining urinary uranium (uU) excretion. Each HPRT study included 30-40 Veterans, several with retained DU-containing shrapnel. Forty-nine Veterans were evaluated in multiple studies, including 14 who were in all five studies. This permitted a characterization of the HPRT mutation assay over time to assess the effects of age, smoking and non-selected cloning efficiencies, as well as the inter- and intra-individual variability across time points. Molecular analyses identified the HPRT mutation and T-cell receptor (TCR) gene rearrangement in 1,377 mutant isolates. An unexpected finding was that in vivo clones of HPRT mutant T-cells were present in some Veterans, and could persist over several years of the study. The calculated HPRT mutant frequencies (MFs) were repeatedly elevated in replicate studies in three outlier Veterans with elevated urinary uranium excretion levels. However, these three outlier Veterans also harbored large and persistent in vivo HPRT mutant T-cell clones, each of which was represented by a single founder mutation. Correction for in vivo clonality allowed calculation of HPRT T-cell mutation frequencies (MutFs). Despite earlier reports of DU associated increases in HPRT MFs in some Veterans, the results presented here demonstrate that HPRT mutations are not increased by systemic DU exposure. Additional battlefield exposures were also evaluated for associations with HPRT mutations and none were found. PMID- 25914369 TI - Thermodynamics and Kinetics of Prenucleation Clusters, Classical and Non Classical Nucleation. AB - Recent observations of prenucleation species and multi-stage crystal nucleation processes challenge the long-established view on the thermodynamics of crystal formation. Here, we review and generalize extensions to classical nucleation theory. Going beyond the conventional implementation as has been used for more than a century now, nucleation inhibitors, precursor clusters and non-classical nucleation processes are rationalized as well by analogous concepts based on competing interface and bulk energy terms. This is illustrated by recent examples of species formed prior to/instead of crystal nucleation and multi-step nucleation processes. Much of the discussed insights were obtained from molecular simulation using advanced sampling techniques, briefly summarized herein for both nucleation-controlled and diffusion-controlled aggregate formation. PMID- 25914370 TI - Adaptation to high throughput batch chromatography enhances multivariate screening. AB - High throughput process development offers unique approaches to explore complex process design spaces with relatively low material consumption. Batch chromatography is one technique that can be used to screen chromatographic conditions in a 96-well plate. Typical batch chromatography workflows examine variations in buffer conditions or comparison of multiple resins in a given process, as opposed to the assessment of protein loading conditions in combination with other factors. A modification to the batch chromatography paradigm is described here where experimental planning, programming, and a staggered loading approach increase the multivariate space that can be explored with a liquid handling system. The iterative batch chromatography (IBC) approach is described, which treats every well in a 96-well plate as an individual experiment, wherein protein loading conditions can be varied alongside other factors such as wash and elution buffer conditions. As all of these factors are explored in the same experiment, the interactions between them are characterized and the number of follow-up confirmatory experiments is reduced. This in turn improves statistical power and throughput. Two examples of the IBC method are shown and the impact of the load conditions are assessed in combination with the other factors explored. PMID- 25914374 TI - The synthesis and biological evaluation of desepoxyisotedanolide and a comparison with desepoxytedanolide. AB - The tedanolides are biologically active polyketides that exhibit a macrolactone constructed from a primary alcohol. Since polyketidal transformations only generate secondary alcohols, it has been hypothesized by Taylor that this unique lactone could arise from a postketidal transesterification. In order to probe this hypothesis and to investigate the biological profile of the putative precursor of all members of the tedanolide family, we embarked on the synthesis of desepoxyisotedanolide and its biological evaluation in comparison to desepoxytedanolide. The biological experiments unraveled a second target for desepoxytedanolide and provided evidence that the proposed transesterification indeed provides a survival advantage for the producing microorganism. PMID- 25914375 TI - Simultaneous transcatheter implantation of systemic and pulmonary venous baffle stents after mustard operation for d-transposition of the great arteries. AB - We report a case of simultaneous transcatheter systemic and pulmonary venous baffle obstruction stenting in a post operative Mustard patient with d transposition of the great arteries. PMID- 25914376 TI - Redefining Outcome Measurement: A Model for Brief Psychotherapy. AB - CONTEXT: The zeitgeist for short-term psychotherapy efficacy has fundamentally shifted away from evidence-based practices to include evidence-informed practices, resulting in an equally important paradigm shift in outcome measurement designed to reflect change in this short-term modality. OBJECTIVE: The present article delineates a short-term psychotherapy structure which defines four fundamental stages that all brief therapies may have in common, and are represented through Cognitive Behavioral Therapy, Solution-Focused Brief Therapy, Narrative Therapy, and Emotion-Focused Therapy. METHOD: These four theoretical approaches were analyzed via a selected literature review through comparing and contrasting specific and common tasks as they relate to the process of psychotherapy and change. Once commonalities were identified within session, they were categorized or grouped into themes or general stages of change within the parameters of a four to six session model of short-term therapy. Commonalities in therapeutic stages of change may more accurately and uniformly measure outcome in short-term work, unlike the symptom-specific psychometric instruments of longer term psychotherapy. RESULTS: A systematic framework for evaluating the client and clinician adherence to 20 specific tasks for these four short-term therapies is presented through the newly proposed, Brief Task Acquisition Scale (BTAS). It is further proposed that the client-clinicians' adherence to these tasks will track and ultimately increase treatment integrity. CONCLUSION: Thus, when the client clinician relationship tracks and evaluates the three pillars of (1) stage/process change, (2) task acquisition, and (3) treatment integrity, the culmination of these efforts presents a new way of more sensitively measuring outcome in short-term psychotherapy. Data collection is suggested as a first step to empirically evaluate the testable hypotheses suggested within this current model. Copyright (c) 2015 John Wiley & Sons, Ltd. Key Practitioner Message The clinician practitioner will note that the proposed Brief Services model removes the subjectivity of client satisfaction as a reliable outcome measure, and relies upon client and therapist adherence to specific tasks and stages of change within and across short-term psychotherapy. The clinical significance of the BTAS for the practitioner is three fold. The psychometric instrument (1) tracks stage or process change, (2) guides task acquisition, and (3) incorporates greater treatment integrity unlike other outcome measures. The BTAS present a new way of conceptualizing change in short-term psychotherapy regardless of modality or presenting issue, making it a more flexible and usable instrument for the clinician. The BTAS may measure outcome more sensitively and accurately, thus offering the client, therapist and client-therapist more information regarding change at each stage and at the end of short-term psychotherapy. PMID- 25914377 TI - A Role for Gut Microbiota and the Metabolite-Sensing Receptor GPR43 in a Murine Model of Gout. AB - OBJECTIVE: Host-microbial interactions are central in health and disease. Monosodium urate monohydrate (MSU) crystals cause gout by activating the NLRP3 inflammasome, leading to interleukin-1beta (IL-1beta) production and neutrophil recruitment. This study was undertaken to investigate the relevance of gut microbiota, acetate, and the metabolite-sensing receptor GPR43 in regulating inflammation in a murine model of gout. METHODS: Gout was induced by the injection of MSU crystals into the knee joints of mice. Macrophages from the various animals were stimulated to determine inflammasome activation and production of reactive oxygen species (ROS). RESULTS: Injection of MSU crystals caused joint inflammation, as seen by neutrophil influx, hypernociception, and production of IL-1beta and CXCL1. These parameters were greatly decreased in germ free mice, mice treated with antibiotics, and GPR-43-deficient mice. Recolonization or administration of acetate to germ-free mice restored inflammation in response to injection of MSU crystals. In vitro, macrophages produced ROS and assembled the inflammasome when stimulated with MSU. Macrophages from germ-free animals produced little ROS, and there was little inflammasome assembly. Similar results were observed in macrophages from GPR-43-deficient mice. Treatment of germ-free mice with acetate restored in vitro responsiveness of macrophages to MSU crystals. CONCLUSION: In the absence of microbiota, there is decreased production of short-chain fatty acids that are necessary for adequate inflammasome assembly and IL-1beta production in a manner that is at least partially dependent on GPR43. These results clearly show that the commensal microbiota shapes the host's ability to respond to an inflammasome-dependent acute inflammatory stimulus outside the gut. PMID- 25914378 TI - A costing model for offshore decommissioning in California. AB - California's 27 offshore oil and gas platforms will reach the end of their useful lifetimes sometime in the near future and will require decommissioning. Although existing leases require complete removal of all platforms and associated infrastructure, the underlying laws and regulations have changed in recent years to allow a number of alternative uses after decommissioning. In particular, AB 2503, signed into law in September 2010, provides for a rigs-to-reefs program that allows the state to accept ownership of decommissioned platforms in federal waters. Decisions about whether to remove platforms completely or leave them in place as artificial reefs will depend in part on the relative cost of the 2 options. In this study, we describe the design and use of a mathematical decision model that provides detailed cost estimates of complete and partial removal (to 85 feet below the water line) for California's offshore platforms. The model, PLATFORM, is loaded with Bureau of Safety and Environmental Enforcement (BSEE) and Bureau of Ocean Energy Management (BOEM) costs for complete removal, along with costs for partial removal calculated for this study and estimates of the uncertainty associated with decommissioning cost estimates. PLATFORM allows users to define a wide range of decommissioning and costing scenarios (e.g., number of platforms, choice of heavy lift vessel, shell mound removal, reef enhancement). As a benchmark cost, complete removal of all 27 offshore platforms, grouped into the 7 decommissioning projects defined by the most recent federal cost estimates produced in 2010, would cost an estimated $1.09 billion, whereas partial removal of these platforms, grouped into the same set of projects, would cost $478 million, with avoided costs of $616 million (with minor rounding). PMID- 25914380 TI - In vitro studies of primary explosive blast loading on neurons. AB - In a military setting, traumatic brain injury (TBI) is frequently caused by blast waves that can trigger a series of neuronal biochemical changes. Although many animal models have been used to study the effects of primary blast waves, elucidating the mechanisms of damage in a whole-animal model is extremely complex. In vitro models of primary blast, which allow for the deconvolution of mechanisms, are relatively scarce. It is largely unknown how structural damage at the cellular level impacts the functional activity at variable time scales after the TBI event. A novel in vitro system was developed to probe the effects of explosive blast (ranging from ~25 to 40 psi) on dissociated neurons. PC12 neurons were cultured on laminin-coated substrates, submerged underwater, and subjected to single and multiple blasts in a controlled environment. Changes in cell membrane permeability, viability, and cell morphology were evaluated. Significant increases in axonal beading were observed in the injured cells. In addition, although cell death was minimal after a single insult, cell viability decreased significantly following repeated blast exposure. PMID- 25914379 TI - On the theoretical limits of detecting cyclic changes in cardiac high-energy phosphates and creatine kinase reaction kinetics using in vivo 31P MRS. AB - Adenosine triphosphate (ATP) is absolutely required to fuel normal cyclic contractions of the heart. The creatine kinase (CK) reaction is a major energy reserve reaction that rapidly converts creatine phosphate (PCr) to ATP during the cardiac cycle and at times of stress and ischemia, but is significantly impaired in conditions such as hypertrophy and heart failure. Because the magnitudes of possible in vivo cyclic changes in cardiac high-energy phosphates (HEPs) during the cardiac cycle are not well known from previous work, this study uses mathematical modeling to assess whether, and to what extent, cyclic variations in HEPs and in the rate of ATP synthesis through CK (CK flux) could exist in the human heart, and whether they could be measured with current in vivo (31)P MRS methods. Multi-site exchange models incorporating enzymatic rate equations were used to study the cyclic dynamics of the CK reaction, and Bloch equations were used to simulate (31)P MRS saturation transfer measurements of the CK reaction. The simulations show that short-term buffering of ATP by CK requires temporal variations over the cardiac cycle in the CK reaction velocities modeled by enzymatic rate equations. The maximum variation in HEPs in the normal human heart beating at 60 min(-1) was approximately 0.4 mM and proportional to the velocity of ATP hydrolysis. Such HEP variations are at or below the current limits of detection by in vivo (31)P MRS methods. Bloch equation simulations show that (31)P MRS saturation transfer estimates the time-averaged, pseudo-first-order forward rate constant, k(f,ap)', of the CK reaction, and that periodic short-term fluctuations in kf ' and CK flux are not likely to be detectable in human studies employing current in vivo (31)P MRS methods. PMID- 25914381 TI - Development and validation of an RP-HPLC method for the quantitation of odanacatib in rat and human plasma and its application to a pharmacokinetic study. AB - A simple, specific, sensitive and reproducible high-performance liquid chromatography (HPLC) assay method has been developed and validated for the estimation of odanacatib in rat and human plasma. The bioanalytical procedure involves extraction of odanacatib and itraconazole (internal standard, IS) from a 200 MUL plasma aliquot with simple liquid-liquid extraction process. Chromatographic separation was achieved on a Symmetry Shield RP18 using an isocratic mobile phase at a flow rate of 0.7 mL/min. The UV detection wave length was 268 nm. Odanacatib and IS eluted at 5.5 and 8.6 min, respectively with a total run time of 10 min. Method validation was performed as per US Food and Drug Administration guidelines and the results met the acceptance criteria. The calibration curve was linear over a concentration range of 50.9-2037 ng/mL (r(2) = 0.994). The intra- and inter-day precisions were in the range of 2.06-5.11 and 5.84-13.1%, respectively, in rat plasma and 2.38-7.90 and 6.39-10.2%, respectively, in human plasma. The validated HPLC method was successfully applied to a pharmacokinetic study in rats. PMID- 25914382 TI - Mutagenicity monitoring following battlefield exposures: Molecular analysis of HPRT mutations in Gulf War I veterans exposed to depleted uranium. AB - Molecular studies that involved cDNA and genomic DNA sequencing as well as multiplex PCR of the HPRT gene were performed to determine the molecular mutational spectrum for 1,377 HPRT mutant isolates obtained from 61 Veterans of the 1991 Gulf War, most of whom were exposed to depleted uranium (DU). Mutant colonies were isolated from one to four times from each Veteran (in 2003, 2005, 2007, and/or 2009). The relative frequencies of the various types of mutations (point mutations, deletions, insertions, etc.) were compared between high versus low DU exposed groups, (based on their urine U concentration levels), with HPRT mutant frequency (as determined in the companion paper) and with a database of historic controls. The mutational spectrum includes all classes of gene mutations with no significant differences observed in Veterans related to their DU exposures. PMID- 25914383 TI - Aspects of digestive anatomy, feed intake and digestion in the Chinese pangolin (Manis pentadactyla) at Taipei zoo. AB - Pangolins are considered difficult to maintain in zoos, often attributed to problems in feeding management. Taipei Zoo's designation as a wildlife rescue center for Chinese pangolins (Manis pentadactyla) has resulted in long term feeding experience with development of diets that support recovery, maintenance, and reproduction, as well as experimental opportunities to further understand digestive physiology to optimize nutrition. Opportunistic dissection of 10 animals revealed details of the tongue, salivary glands, stomach and gastrointestinal tract (GIT), including confirmation of anatomical differences between Asian and African pangolin species. Length of the total GIT relative to body length (~ 9:1) was greater than found in domestic carnivores, more similar to omnivorous species. Intake and digestion trials conducted with 4 animals demonstrated that pangolins maintained body weights (BW; 6-9 kg) consuming diets containing 32-40% crude protein, 20-25% crude fat, and 13-28% crude fiber (DM basis). Daily DM intakes ranged from ~40 to 70 g per animal, with digestible energy intake 51.5-87.5 kcal /kg BW(0.75) /day; pangolins consumed 9.4-15.2 g DM/kg BW(0.75) /day. Dietary energy data support observations of low metabolism and maintenance requirements for this species, similar to values reported for other myrmecophageous species. Addition of 5% ground chitin to diets improved fecal consistency, and decreased digestibility of DM, protein, and energy; addition of chitosan (chitin treated with NaOH) resulted in diet rejection. This information may assist in enhancement of captive diets, as well as in controlling obesity in pangolins. PMID- 25914384 TI - System design and animal experiment study of a novel minimally invasive surgical robot. AB - BACKGROUND: Robot-assisted minimally invasive surgery has shown tremendous advances over the traditional technique. However, currently commercialized systems are large and complicated, which vastly raises the system cost and operation room requirements. METHODS: A MIS robot named 'MicroHand' was developed over the past few years. The basic principle and the key technologies are analyzed in this paper. Comparison between the proposed robot and the da Vinci system is also presented. Finally, animal experiments were carried out to test the performance of MicroHand. RESULTS: Fifteen animal experiments were carried out from July 2013 to December 2013. All animal experiments were finished successfully. CONCLUSIONS: The proposed design method is an effective way to resolve the drawbacks of previous generations of the da Vinci surgical system. The animal experiment results confirmed the feasibility of the design. PMID- 25914385 TI - An Air- and Water-Tolerant Zinc Hydride Cluster That Reacts Selectively With CO2. AB - The reaction of [Zn3Cl3L], in which L(3-) is a tris(beta-diketiminate) cyclophane, with K(sBu)3BH afforded [Zn3(MU-H)3L] (2), as confirmed by NMR spectroscopy, NOESY, and X-ray crystallography. The complex 2 was air-stable and unreactive towards water, methanol, and other substrates (e.g., nitriles) at room temperature over 24 h but reacted with CO2 (ca. 1 atm) to generate [Zn3(MU-H)2(MU 1,1-O2CH)] (3). In contrast, [Zn3(OH)3L] (4) was found to be unreactive toward CO2 over the course of several days at 90 degrees C. PMID- 25914386 TI - Network pharmacodynamic models for customized cancer therapy. AB - Pharmacokinetics (PKs) and pharmacodynamics (PDs) have always been integral to the design of rational drug dosing regimens. Early on PK-driven approaches came under the auspices of therapeutic drug monitoring that progressed into population based PK and PK/PD modeling analyses. As the availability of tissue samples for measurement of drug concentrations is limited in patients, the bulk of such model based methods relied on plasma drug concentrations to both build models and monitor therapy. The continued advances in systems biology and the spawning of systems pharmacology propelled the creation of enhanced PD (ePD) models. One of the main characteristic of ePD models is that they are derived from mechanistically grounded biochemical reaction networks. These models are commonly represented as systems of coupled ordinary differential equations with the ability to tailor each reaction and protein concentration to an individual's genomic/proteomic profile. As patient genomic analyses become more common, many genetic and protein abnormalities can be represented in the ePD models, and thus offer a path toward personalized anticancer therapies. By linking PK models to ePD models, a full spectrum of pharmacological simulation tools is available to design sophisticated multidrug regimens. However, ePD models are not a panacea and face challenges in model identifiability, scaling and parameter estimation. Nonetheless, as new technologies evolve and are coupled with fresh ideas on model implementation, it is likely that ePD and PK/ePD models will be considered a viable enterprise to customize anticancer drug therapy. PMID- 25914387 TI - The role of children's bone marrow mesenchymal stromal cells in the ex vivo expansion of autologous and allogeneic hematopoietic stem cells. AB - The recognition of the role of Mesenchymal Stromal Cells (MSC) in hematopoiesis, as part of the bone marrow microenvironment, renewed the interest for cord blood (CB) ex vivo expansion as a source of HSC for transplantation. MSC from children are recognized to have different biological properties compared to the ones from adults. The current study focuses on the evaluation of the effects of children's bone marrow MSC on the ex vivo expansion capacity of both allogeneic cord blood and autologous bone marrow (BM) CD34(+) hematopoietic stem cells (HSCs) when used as a cell feeder layer with or without recombinant cytokines. Our results showed that children's bone marrow-derived MSC expand more primitive populations in co culture with CD34 and that the expansion is further enhanced when the culture is supplemented with growth factors. No additive effect was seen either with the early- or late-acting growth factors' cocktails used. Biological features of CB hematopoietic progenitors seem to make them more suitable than their BM counterparts for ex vivo expansion. Clinical implementation will be facilitated by methodological standardization and guidelines' establishment. PMID- 25914388 TI - Short- and long-term outcomes in diabetes patients undergoing percutaneous coronary intervention with bivalirudin compared with heparin and glycoprotein IIb/IIIA inhibitors: A meta-analysis of randomized trials. AB - BACKGROUND: Diabetes patients undergoing percutaneous coronary intervention (PCI) have more complications than nondiabetes patients, including increased long-term mortality. Use of bivalirudin versus heparin and glycoprotein IIb/IIIa inhibitors (GPI) in diabetes patients undergoing PCI and its effect on long-term mortality were evaluated in few randomized trials, but with conflicting results. METHODS: We searched the literature for randomized controlled trials that compared heparin and GPI therapy with bivalirudin in diabetes patients undergoing PCI. The incidence of major adverse cardiovascular events (MACE), death from any cause, myocardial infarction (MI), urgent revascularization, major and minor bleeding (at 30 days), as well as all-cause mortality at 1 year were included, and meta analysis was performed. RESULTS: A total of 5,137 patients with diabetes were included in four randomized trials. At 30 days, bivalirudin, compared with heparin and GPI, caused less major bleeding (odds ratio (OR), 0.68; 95% confidence interval (CI), 0.52-0.89; P = 0.005) and less minor bleeding (OR, 0.48; 95% CI, 0.41-0.57; P < 0.00001) and similar rates of MACE (OR, 0.87; 95% CI, 0.70-1.08; P = 0.21), MI (OR, 0.87; 95% CI, 0.68-1.10; P = 0.25), and urgent revascularization (OR, 1.12; 95% CI, 0.76-1.65; P = 0.57). Death from any cause at 30 day was numerically lower with bivalirudin use but not statistically significant (OR, 0.72; 95% CI, 0.46-1.13; P = 0.15). Mortality at 1 year was significantly lower in diabetes patients treated with bivalirudin compared with heparin and GPI (OR, 0.72; 95% CI, 0.52-0.99; P = 0.04). A secondary analysis suggests that the major bleeding benefit with bivalirudin may be driven by mandated use of GPI in heparin arm. CONCLUSION: Among patients with diabetes undergoing PCI, bivalirudin caused less major and minor bleeding compared with heparin and GPI, with similar rates of MACE, death, MI, and urgent revascularization at 30 days, but significantly lower mortality rates at 1 year. PMID- 25914389 TI - Changes in Cytokines and Aggrecan ARGS Neoepitope in Synovial Fluid and Serum and in C-Terminal Crosslinking Telopeptide of Type II Collagen and N-Terminal Crosslinking Telopeptide of Type I Collagen in Urine Over Five Years After Anterior Cruciate Ligament Rupture: An Exploratory Analysis in the Knee Anterior Cruciate Ligament, Nonsurgical Versus Surgical Treatment Trial. AB - OBJECTIVE: To prospectively monitor levels of proinflammatory cytokines and aggrecan ARGS neoepitope in synovial fluid and serum as well as levels of C terminal crosslinking telopeptide of type II collagen (CTX-II) and N-terminal crosslinking telopeptide of type I collagen (NTX-I) in urine after acute anterior cruciate ligament (ACL) rupture. METHODS: Synovial fluid, serum, and urine were collected from 121 adults on 6 occasions over 5 years after acute ACL injury. Reference samples were obtained from subjects without knee injury. Concentrations of interleukin-6 (IL-6), IL-8, IL-10, interferon-gamma (IFNgamma), tumor necrosis factor (TNF), aggrecan ARGS neoepitope, CTX-II, and NTX-I were measured by enzyme linked immunosorbent assay. RESULTS: Shortly after ACL injury, cytokine concentrations in synovial fluid were elevated 6-fold (TNF) to 1,050-fold (IL-6) compared to reference levels, while concentrations of aggrecan ARGS neoepitope in synovial fluid and serum and CTX-II in urine were elevated 1.4-fold to 8-fold. Thereafter, concentrations of cytokines and aggrecan ARGS neoepitope in synovial fluid decreased with different half-lives (in years: IL-6 0.9, IL-8 2.2, IL-10 2.3, IFNgamma 3.1, TNF 3.6, aggrecan ARGS neoepitope 4.0). After 5 years, the TNF concentration in synovial fluid remained higher than the reference level. There was a correlation between the concentrations of aggrecan ARGS neoepitope in synovial fluid and serum (rs = 0.36). Concentrations of aggrecan ARGS neoepitope in synovial fluid and of CTX-II and NTX-I in urine were correlated with concentrations of cytokines in synovial fluid (rs = 0.41-0.49 and rs = 0.21 0.31, respectively). CONCLUSION: Acute ACL injury induced highly increased levels of inflammatory cytokines in the joint, and these were associated with proteolysis of aggrecan and type II collagen. Cytokine levels remained increased up to 5 years after injury, indicative of extended local inflammation in the joint. PMID- 25914390 TI - Distribution of serum transferrin, and its associations with metabolic disorders among Chinese: A nation-wide, health and nutrition survey. AB - SCOPE: This study examined the associations of serum transferrin and metabolic disorders among Chinese population. METHODS AND RESULTS: This study is based on nation-wide, population-based China Health and Nutrition survey including 8564 men and women aged 18 years or older. Anthropometric and fasting blood glucose, insulin, lipids, and transferrin data were collected. Elevated transferrin concentrations associated with higher body mass index, waist circumference, lipids, insulin, glucose (all p < 0.0001). Serum transferrin concentrations increased gradually with increasing numbers of metabolic syndrome (MetS) components among men and women (p = 0.0003). Elevated concentrations of transferrin were significantly related with higher risk of MetS (p = 0.0006), obesity (p = 0.0089), overweight (p < 0.0001). No associations between transferrin concentrations and risk of diabetes and high blood pressure were observed in both men and women. CONCLUSION: Elevated transferrin concentrations were positively associated with risk of MetS and obesity, but not with risk of diabetes among Chinese. PMID- 25914391 TI - Considerations in evaluating potential socioeconomic impacts of offshore platform decommissioning in California. AB - The 27 oil and gas platforms offshore southern California will eventually reach the end of their useful lifetimes (estimated between 2015 and 2030) and will be decommissioned. Current state and federal laws and regulations allow for alternative uses in lieu of the complete removal required in existing leases. Any decommissioning pathway will create a complex mix of costs, benefits, opportunities, and constraints for multiple user groups. To assist the California Natural Resources Agency in understanding these issues, we evaluated the potential socioeconomic impacts of the 2 most likely options: complete removal and partial removal of the structure to 85 feet below the waterline with the remaining structure left in place as an artificial reef-generally defined as a manmade structure with some properties that mimic a natural reef. We estimated impacts on commercial fishing, commercial shipping, recreational fishing, nonconsumptive boating, and nonconsumptive SCUBA diving. Available data supported quantitative estimates for some impacts, semiquantitative estimates for others, and only qualitative approximations of the direction of impact for still others. Even qualitative estimates of the direction of impacts and of user groups' likely preferred options have been useful to the public and decision makers and provided valuable input to the project's integrative decision model. Uncertainty surrounds even qualitative estimates of the likely direction of impact where interactions between multiple impacts could occur or where user groups include subsets that would experience the same option differently. In addition, we were unable to quantify effects on ecosystem value and on the larger regional ecosystem, because of data gaps on the population sizes and dynamics of key species and the uncertainty surrounding the contribution of platforms to available hard substrate and related natural populations offshore southern California. PMID- 25914392 TI - Re: Non-invasive prenatal testing for trisomies 21, 18 and 13: clinical experience from 146 958 pregnancies. H. Zhang, Y. Gao, F. Jiang, M. Fu, Y. Yuan, Y. Guo, Z. Zhu, M. Lin, Q. Liu, Z. Tian, H. Zhang, F. Chen, T. K. Lau, L. Zhao, X. Yi, Y. Yin and W. Wang. Ultrasound Obstet Gynecol 2015; 45: 530-538. PMID- 25914393 TI - Re: Accuracy of ultrasonography performed by examiners with varied training and experience in predicting specific pathology of adnexal masses. A. Sayasneh, J. Kaijser, J. Preisler, A. A. Smith, F. Raslan, S. Johnson, R. Husicka, L. Ferrara, C. Stalder, S. Ghaem-Maghami, D. Timmerman and T. Bourne. Ultrasound Obstet Gynecol 2015; 45: 605-612. PMID- 25914394 TI - Re: Prediction of early- and late-onset pregnancy-induced hypertension using placental volume on three-dimensional ultrasound and uterine artery Doppler. T. Arakaki, J. Hasegawa, M. Nakamura, S. Hamada, M. Muramoto, H. Takita, K. Ichizuka and A. Sekizawa. Ultrasound Obstet Gynecol 2015; 45: 539-543. PMID- 25914395 TI - Additional value of fetal magnetic resonance imaging in the prenatal diagnosis of central nervous system anomalies: a systematic review of the literature and related correspondence. A plea to assess oranges only. PMID- 25914396 TI - Reply: Fruit and fetal brain MRI--the cherry-picking approach to systematic reviews. PMID- 25914397 TI - Prospective multicentre clinical performance evaluation of second and third generation zotarolimus-eluting stents to treat patients with bifurcated coronary lesions. AB - AIM: To assess the "real world" clinical outcome of patients with bifurcated lesions undergoing percutaneous coronary intervention with implantation of second and third generations of zotarolimus-eluting stent. METHODS AND RESULTS: Nine Italian centres participated in a prospective multicentre clinical project evaluating the outcome of patients receiving zotarolimus-eluting Resolute stent and Resolute Integrity stents. Patients with bifurcated lesions entered this evaluation. Clinical characteristics and angiographic and procedural details were prospectively recorded. Clinical outcome was prospectively assessed to evaluate the occurrence of major adverse cardiac events (MACE). A total of 577 patients were enrolled. The target lesion was distal left main in 11.1% and left anterior descending artery in 52.8%, and 30.3% of lesions were Medina 1,1,1. At a mean follow-up time of 27.0 +/- 13.5 months, the survival free from MACE was 91.8%. Survival free from MACE was similar in patients grouped according to different bifurcated lesion complexity. On the contrary, patients receiving a single stent had better survival free from MACE as compared with those with double stent (P = 0.005). At multivariable analysis, double stenting (but not bifurcated lesion complexity) was found to be a significant predictor of MACE (hazard ratio, 2.52; 95% confidence interval, 1.28-4.94; P = 0.007). Of note, patients receiving the second stent as a bail-out had worse survival free from MACE compared with those who received it as a planned technique (P = 0.045). CONCLUSION: The treatment of patients with bifurcated lesions with second and third generation zotarolimus eluting stents is associated with good long-term clinical outcomes. Clinical outcome seems to be independent of lesion complexity, but may be influenced by the stenting technique (single or double stenting as well as elective or bail-out double stenting). (c) 2015 Wiley Periodicals, Inc. PMID- 25914398 TI - Development and validation of an ESI-LC-MS/MS method for simultaneous identification and quantification of 24 analytes of forensic relevance in vitreous humour, whole blood and plasma. AB - Detection and quantification of drugs from various biological matrices are of immense importance in forensic toxicological analysis. Despite the various reported methods, development of a new method for the detection and quantification of drugs is still an active area of research. However, every method and biological matrix has its own limitation, which further encourage forensic toxicologists to develop new methods and to explore new matrices for the analysis of drugs. In this study, an electrospray ionization-liquid chromatograph tandem mass spectrometry (ESI-LC-MS/MS) method is developed and validated for simultaneous identification and quantification of 24 drugs of forensic relevance in various body fluids, namely, whole blood, plasma and vitreous humour. The newly developed method has been validated for intra-day and inter-day accuracy, precision, selectivity and sensitivity. Absolute recovery shows a mean of 84.5, 86.2, and 103% in the vitreous humour, whole blood and plasma respectively, which is suitable for the screening procedure. Further, the absolute matrix effect (AME) shows a mean of 105, 96.5, and 109% in the vitreous humour, whole blood and plasma, respectively. In addition, to examine the practical utility of this method, it has been applied for screening of drugs in post-mortem samples of the vitreous humour, whole blood and plasma collected at autopsy from ten cadavers. Experimental results show that the newly developed method is well applicable for screening of analytes in all the three matrices. PMID- 25914399 TI - Systematic review of text messaging as an intervention for adolescent obesity. AB - PURPOSE: Adolescent overweight and obesity is a significant problem for health care with associated quality of life and financial concerns. This systematic review investigated text messaging as an intervention to treat or prevent obesity in adolescent populations. DATA SOURCES: The Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) statement was used as a guideline for the literature search and interpretation of findings. CINAHL, Medline, Cochrane Database of Systematic Reviews, PsycINFO, and SocINDEX were searched using a combination of search terms. The initial 95 articles that met the search criteria were narrowed to seven that fit the focus. CONCLUSIONS: Text messaging is acceptable to adolescents as an obesity treatment but data about content and timing of messages vary. The effects of text messaging on body mass index (BMI) were difficult to determine because messaging was often part of a multicomponent intervention. Text messaging as an intervention for adolescent obesity was used in various settings. There were no included studies from primary care settings. IMPLICATIONS FOR PRACTICE: Further research is needed to determine the effect of messages on BMI and the most helpful content, timing, and frequency. This information may provide advanced practice nurses with effective, affordable tools to manage adolescent obesity in different settings. PMID- 25914400 TI - Enhanced glutathione production by evolutionary engineering of Saccharomyces cerevisiae strains. AB - Glutathione is an important natural tripeptide mainly used because of its antioxidative properties. Commercial glutathione is microbially synthesized by yeasts and the growing demand requires the development of new production strains. An adaptive laboratory evolution strategy using acrolein as a selection agent was employed to obtain strains with an enhanced glutathione accumulation phenotype accompanied by an acrolein resistance phenotype. Two particularly interesting isolates were obtained: one with a high volumetric productivity for glutathione reaching 8.3 mg(glutathione)/L h, which is twice as high as the volumetric productivity of its parental strain. This strain reached an elevated intracellular glutathione content of 3.9%. A second isolate with an even higher acrolein tolerance exhibited a lower volumetric productivity of 5.8 mg(glutathione)/L h due to a growth phenotype. However, this evolved strain accumulated glutathione in 3.3-fold higher concentration compared to its parental strain and reached a particularly high glutathione content of almost 6%. The presented results demonstrate that acrolein is a powerful selection agent to obtain high glutathione accumulation strains in an adaptive laboratory evolution experiment. PMID- 25914401 TI - Evaluating alternatives for decommissioning California's offshore oil and gas platforms. AB - This paper introduces a series of 6 additional papers in this issue that describe an in-depth analysis of options for decommissioning oil and gas platforms offshore southern California. Although current leases require lessees in both state and federal waters to completely remove all production facilities and restore the seafloor to its pre-platform condition, other options have emerged since these leases were signed. Laws and regulations in other jurisdictions (particularly in federal waters) have evolved to allow a number of other uses such as aquaculture, alternative energy production, and artificial reefing. In response, the California Natural Resources Agency initiated an effort to investigate the issues associated with these and other decommissioning alternatives. The papers in this series are the result of the second phase in this process, a broad investigation of the engineering, economic, and environmental costs and benefits of the most feasible and likely options. In addition to the project's final report, the authors produced an interactive mathematical decision model, PLATFORM, that enables users to explore the implications of different decommissioning projects and options, as well as the effects of different approaches to valuing the associated costs and benefits. PMID- 25914403 TI - Risk stratification using cytomorphologic features in endoscopic ultrasonographic guided fine-needle aspiration diagnosis of pancreatic ductal adenocarcinoma. AB - BACKGROUND: Endoscopic ultrasonographic-guided fine-needle aspiration (EUS-FNA) is the procedure of choice for the investigation of pancreatic lesions. It shows good sensitivity and excellent specificity. Diagnostic criteria have been published but not statistically validated for the diagnosis of malignancy and stratification of risk for malignancy. METHODS: A training set of 57 EUS-FNAs and the validation set of 107 EUS-FNAs were selected. Slides were independently evaluated by three pathologists. Sixteen morphologic features were evaluated in the training set. Average absolute agreement, kappa scores, and association with malignancy were statistically evaluated. Recursive partitioning and multivariant analyses were performed on the features tested in the training set. Agreement data, univariate-odds ratios, and discriminatory power were calculated for the diagnostic features selected from the training set. The selected morphologic features formed a scoring rule that was then applied to the validation set. RESULTS: The average absolute agreement in the training set was 72%. Anisonucleosis, nuclear crowding, macro nucleoli, single atypical epithelial cells, and intracytoplasmic mucin showed the highest interrater reliability. Anisonucleosis, macronucleoli, single atypical epithelial cells, and intracytoplasmic mucin were most predictive of malignancy. A simple scoring rule was developed combining these morphologic features and applied to the validation set. Analysis of the area under the receiver operating characteristic (ROC) curve confirmed the statistical validity of the scoring rule. CONCLUSION: A scoring system utilizing the presence or absence of anisonucleosis, macronucleoli, single atypical epithelial cells, and mucinous metaplasia yielded good discriminatory power (area under ROC curve = 0.87). PMID- 25914404 TI - A joint-space numerical model of metabolic energy expenditure for human multibody dynamic system. AB - Metabolic energy expenditure (MEE) is a critical performance measure of human motion. In this study, a general joint-space numerical model of MEE is derived by integrating the laws of thermodynamics and principles of multibody system dynamics, which can evaluate MEE without the limitations inherent in experimental measurements (phase delays, steady state and task restrictions, and limited range of motion) or muscle-space models (complexities and indeterminacies from excessive DOFs, contacts and wrapping interactions, and reliance on in vitro parameters). Muscle energetic components are mapped to the joint space, in which the MEE model is formulated. A constrained multi-objective optimization algorithm is established to estimate the model parameters from experimental walking data also used for initial validation. The joint-space parameters estimated directly from active subjects provide reliable MEE estimates with a mean absolute error of 3.6 +/- 3.6% relative to validation values, which can be used to evaluate MEE for complex non-periodic tasks that may not be experimentally verifiable. This model also enables real-time calculations of instantaneous MEE rate as a function of time for transient evaluations. Although experimental measurements may not be completely replaced by model evaluations, predicted quantities can be used as strong complements to increase reliability of the results and yield unique insights for various applications. PMID- 25914405 TI - What does Medicare pay rhinologists? An analysis of Medicare payment data. AB - BACKGROUND: Information about charges and payments for physician services continues to be scrutinized. Recently, the Centers for Medicare and Medicaid Services (CMS) released data regarding Medicare charges and payments to all physicians for calendar year 2012. The purpose of this study was to investigate the variability and patterns in Medicare charges and payments among a large sample of rhinologists. METHODS: Charge and payment data were obtained from publicly available CMS datasets (http://www.cms.gov). Data for all otolaryngologists and rhinology subsets were extracted. Charges, payments, fee multipliers, and total submitted claims were compared. Unequal variance 2-tailed t tests were used for analysis. RESULTS: Mean submitted charges for rhinologists were $291,464 compared to $211,209 for all otolaryngologists (p = 0.0014). Mean payments to rhinologists were $70,172 compared to $77,275 for all otolaryngologists (p = 0.24). Fees for services ranged from 1.33 to 14.29 times Medicare reimbursement rates (mean = 4.47). The fee multiplier was significantly higher for operating room-based codes compared to office-based codes (9.43 vs 3.44, p < 0.001). Academic rhinologists submitted fewer claims and had a higher fee multiplier than private rhinologists (p < 0.001). Academic and private rhinologists had no difference in submitted charges (p = 0.28). CONCLUSION: The wide availability of Medicare payment information makes it important for physicians to understand how their individual data compares to that of their colleagues. Medicare payments to rhinologists were comparable to otolaryngologists as a whole. Charges for services commonly performed by rhinologists vary widely. Academic rhinologists submitted fewer claims than their private colleagues, but overall charges and payments were comparable between the 2 groups. PMID- 25914406 TI - When to screen for lupus anticoagulant? Influence of testing during acute phase and consequences for clinical practise. PMID- 25914407 TI - Combined transplantation of autologous hematopoietic stem cells and allogenic mesenchymal stem cells increases T regulatory cells in systemic lupus erythematosus with refractory lupus nephritis and leukopenia. AB - Autologous hematopoietic stem cell (HSC) and mesenchymal stem cell (MSC) transplantation is currently being evaluated as a novel treatment for autoimmune diseases, such as systemic lupus erythematosus (SLE). Here we report a case of autologous HSC transplantation combined with MSCs in a 25-year-old severe SLE patient with multiple life-threatening complications and refractory to conventional cyclophosphamide (CYC) therapy. After being pretreated with CYC, fludarabine and antithymocyte globulin, the patient was transplanted with autologous CD34+HSCs and MSCs by intravenous infusion. Hematopoietic regeneration was observed on day 12 thereafter. After HSC and MSC transplantation, the patient's clinical symptoms caused by SLE were remitted, and the SLEDAI score decreased. Moreover, CD4+CD25+FoxP3+Treg cells increased in peripheral blood mononuclear cells (PBMCs) after transplantation. This result suggests that the combined transplantation of HSCs and MSCs may reset the adaptive immune system to re-establish self-tolerance in SLE. A 36-month follow-up showed that the clinical symptoms remained in remission. Although a longer follow-up is required for assessing the long-term efficacy, our present results suggest that the combined transplantation of HSCs and MSCs may be a novel and effective therapy for refractory SLE. PMID- 25914408 TI - The role of netupitant and palonosetron in chemotherapy-induced nausea and vomiting. AB - The combination of netupitant and palonosetron was approved by the Food and Drug Administration in October 2014 for the prevention of acute and delayed chemotherapy-induced nausea and vomiting associated with initial and repeat courses of moderately and highly emetogenic chemotherapy. Netupitant and palonosetron is available as a single capsule to be administered prior to each cycle of chemotherapy. The approval was based on phase II and III data in patients undergoing treatment with moderately and highly emetogenic chemotherapy. Netupitant and palonosetron's benefits include a convenient dosage form, dual targeted mechanism, and favorable side effect profile, while its main limitations are cost and potential logistical issues surrounding administration. More studies are needed to adequately determine its role in therapy as well as which patients will derive the most benefit from its use. PMID- 25914409 TI - The association between HPV, intraepithelial lesions and HIV-1 shedding in anogenital specimens in two contrasting populations: Senegalese women and American MSM. AB - In light of observational evidence showing an association between human papillomavirus (HPV) and HIV acquisition risk, the potential of HPV vaccination as a HIV prevention strategy is being considered. However, the relationship between HPV and HIV infectiousness is unclear. In this analysis, the relationship between HPV and anogenital HIV shedding (a proxy for transmissibility) was assessed in two diverse populations: HIV-infected Senegalese women and American men who have sex with men (MSM). Data from two longitudinal studies with similar protocols were analysed. In both studies, anogenital specimens underwent cytologic, HPV DNA, and HIV-1 RNA testing. Analyses utilised multivariable generalised estimating equations that controlled for age, hormonal contraceptive use (women only), plasma viral load, CD4 count and treatment status. Among Senegalese women, cervical lesions were significantly associated with the detection of HIV RNA (aRR = 1.16 [1.05, 1.28]) and log10 cervicovaginal fluids viral load (adjusted beta = 0.56 [0.12, 1.01]). No association was detected between HPV (of any type) and cervicovaginal HIV shedding (aRRDetection = 0.90 [0.77, 1.06]; betaQuantity = -0.31 [-0.78, 0.16]). Among MSM, having multiple HPV infections (versus no HPV infection) was associated with anal HIV shedding (aRRDetection = 1.05 [1.01, 1.09]; betaQuantity = 0.11 [0.01, 0.21]). Anal lesions were not associated with anal HIV shedding (aRRLESIONS = 0.99 [0.96, 1.03], betaLESIONS = -0.05 [-0.13, 0.03]). Although HPV and intraepithelial lesions were associated with anogenital HIV shedding in crude analyses, the measures of effect were attenuated in adjusted analyses. Our data suggest that the prevention of HPV through vaccination is unlikely to substantially affect HIV infectiousness among persons living with HIV. PMID- 25914410 TI - All that seems to be miliary mottling is not always due to tuberculosis: A case report. PMID- 25914411 TI - Locomotion pattern and trunk musculoskeletal architecture among Urodela. AB - We comparatively examined the trunk musculature and prezygapophyseal angle of mid trunk vertebra in eight urodele species with different locomotive modes (aquatic Siren intermedia, Amphiuma tridactylum, Necturus maculosus and Andrias japonicus; semi-aquatic Cynops pyrrhogaster, Cynops ensicauda; and terrestrial Hynobius nigrescens, Hynobius lichenatus and Ambystoma tigrinum). We found that the more terrestrial species were characterized by larger dorsal and abdominal muscle weight ratios compared with those of the more aquatic species, whereas muscle ratios of the lateral hypaxial musculature were larger in the more aquatic species. The lateral hypaxial muscles were thicker in the more aquatic species, whereas the M. rectus abdominis was more differentiated in the more terrestrial species. Our results suggest that larger lateral hypaxial muscles function for lateral bending during underwater locomotion in aquatic species. Larger dorsalis and abdominal muscles facilitate resistance against sagittal extension of the trunk, stabilization and support of the ventral contour line against gravity in terrestrial species. The more aquatic species possessed a more horizontal prezygapophyseal angle for more flexible lateral locomotion. In contrast, the more terrestrial species have an increasingly vertical prezygapophyseal angle to provide stronger column support against gravity. Thus, we conclude trunk structure in urodeles differs clearly according to their locomotive modes. PMID- 25914412 TI - Adverse Selection and an Individual Mandate: When Theory Meets Practice. AB - We develop a model of selection that incorporates a key element of recent health reforms: an individual mandate. Using data from Massachusetts, we estimate the parameters of the model. In the individual market for health insurance, we find that premiums and average costs decreased significantly in response to the individual mandate. We find an annual welfare gain of 4.1% per person or $51.1 million annually in Massachusetts as a result of the reduction in adverse selection. We also find smaller post-reform markups. PMID- 25914413 TI - Comparative analysis of electric field influence on the quantum wells with different boundary conditions.: I. Energy spectrum, quantum information entropy and polarization. AB - Analytical solutions of the Schrodinger equation for the one-dimensional quantum well with all possible permutations of the Dirichlet and Neumann boundary conditions (BCs) in perpendicular to the interfaces uniform electric field [Formula: see text] are used for the comparative investigation of their interaction and its influence on the properties of the system. Limiting cases of the weak and strong voltages allow an easy mathematical treatment and its clear physical explanation; in particular, for the small [Formula: see text], the perturbation theory derives for all geometries a linear dependence of the polarization on the field with the BC-dependent proportionality coefficient being positive (negative) for the ground (excited) states. Simple two-level approximation elementary explains the negative polarizations as a result of the field-induced destructive interference of the unperturbed modes and shows that in this case the admixture of only the neighboring states plays a dominant role. Different magnitudes of the polarization for different BCs in this regime are explained physically and confirmed numerically. Hellmann-Feynman theorem reveals a fundamental relation between the polarization and the speed of the energy change with the field. It is proved that zero-voltage position entropies [Formula: see text] are BC independent and for all states but the ground Neumann level (which has [Formula: see text]) are equal to [Formula: see text] while the momentum entropies [Formula: see text] depend on the edge requirements and the level. Varying electric field changes position and momentum entropies in the opposite directions such that the entropic uncertainty relation is satisfied. Other physical quantities such as the BC-dependent zero-energy and zero polarization fields are also studied both numerically and analytically. Applications to different branches of physics, such as ocean fluid dynamics and atmospheric and metallic waveguide electrodynamics, are discussed. PMID- 25914414 TI - Comparative analysis of electric field influence on the quantum wells with different boundary conditions: II. Thermodynamic properties. AB - Thermodynamic properties of the one-dimensional (1D) quantum well (QW) with miscellaneous permutations of the Dirichlet (D) and Neumann (N) boundary conditions (BCs) at its edges in the perpendicular to the surfaces electric field [Formula: see text] are calculated. For the canonical ensemble, analytical expressions involving theta functions are found for the mean energy and heat capacity [Formula: see text] for the box with no applied voltage. Pronounced maximum accompanied by the adjacent minimum of the specific heat dependence on the temperature T for the pure Neumann QW and their absence for other BCs are predicted and explained by the structure of the corresponding energy spectrum. Applied field leads to the increase of the heat capacity and formation of the new or modification of the existing extrema what is qualitatively described by the influence of the associated electric potential. A remarkable feature of the Fermi grand canonical ensemble is, at any BC combination in zero fields, a salient maximum of [Formula: see text] observed on the T axis for one particle and its absence for any other number N of corpuscles. Qualitative and quantitative explanation of this phenomenon employs the analysis of the chemical potential and its temperature dependence for different N. It is proved that critical temperature [Formula: see text] of the Bose-Einstein (BE) condensation increases with the applied voltage for any number of particles and for any BC permutation except the ND case at small intensities [Formula: see text] what is explained again by the modification by the field of the interrelated energies. It is shown that even for the temperatures smaller than [Formula: see text] the total dipole moment [Formula: see text] may become negative for the quite moderate [Formula: see text]. For either Fermi or BE system, the influence of the electric field on the heat capacity is shown to be suppressed with N growing. Different asymptotic cases of, e.g., the small and large temperatures and low and high voltages are derived analytically and explained physically. Parallels are drawn to the similar properties of the 1D harmonic oscillator, and similarities and differences between them are discussed. PMID- 25914415 TI - Prognostic Relevance of Circulating Tumor Cells in Molecular Subtypes of Breast Cancer. AB - Circulating tumor cells (CTCs) can be detected in the peripheral blood of breast cancer patients with early and metastatic disease. Recent data suggest that immune pathologic characteristics between the primary tumor, metastatic colonies and CTCs are discordant and that CTCs possess an independent phenotype that is associated with prognosis and treatment efficacy. Large scale gene expression analysis has provided the possibility to stratify breast cancer according to the gene expression fingerprint of primary tumor tissue into five intrinsic molecular subtypes which can be associated with different clinical outcome. As a consequence of the different prognostic power of primary tumors' characteristics and CTCs several groups have started to investigate if CTCs might be disseminated differentially within these breast cancer subtypes. They determined the CTC number in immunohistochemical subtypes to validate if CTCs may provide differential and more specific prognostic information within each subtype. This review provides an overview of the outcome of some recently published data gathered from early and metastatic breast cancer. PMID- 25914416 TI - Induction of Labour: Change of Method and its Effects. AB - Aim: The combination of mechanical and drug procedures for the induction of labour seems to be beneficial. Accordingly, the normal procedure in clinical routine has been changed and induction of labour by means of a balloon catheter has been implemented. The aim of this study was to find out if this procedural change has resulted in a more effective induction of labour. Materials and Method: In this historical cohort study 230 inductions of labour at term in the year 2012 were compared with 291 inductions of labour in the year 2013, all at the University of Erlangen Perinatal Centre. Exclusion criteria were, among others, a multiple pregnancy, a premature rupture of membranes and a prior Caesarean section. In 2012 births were induced solely by use of the drugs dinoprostone and misoprostol, in 2013 not only with misoprostol but also mainly by use of a balloon catheter. The primary target parameter was the rate of failed labour inductions, defined as "no birth within 72 hours". Results: Altogether 521 inductions of labour were analysed. The rate of failed inductions of labour could be reduced by the changes in induction method (first-time mothers: 23 vs. 9 %, p = 0.0059; multiparous women: 10 vs. 1 %, p = 0.0204). Furthermore, the rate of primary Caesarean sections due to failed induction of labour (5.7 vs. 1.4 %, p = 0.0064), that of the observation of green amniotic fluid (first-time mothers: 23 vs. 9 %, p = 0.0059; multiparous women: 10 vs. 1 %, p = 0.0204) and of infantile infections (first-time mothers: 23 vs. 9 %, p = 0.0059; multiparous women: 10 vs. 1 %, p = 0.0204) were all reduced as well. Conclusion: The routine use of a balloon catheter for induction of labour has markedly improved the procedure. There were fewer failed labour inductions and fewer Caesarean sections due to failed induction of labour. PMID- 25914417 TI - Screening Performance and Costs of Different Strategies in Prenatal Screening for Trisomy 21. AB - Objective: Cell-free fetal DNA (cffDNA) testing has opened new options in prenatal screening for trisomy 21. Due to the higher costs of cffDNA testing there is an ongoing debate on how to combine different screening strategies. Methods: For this study, a model-based approach was used to evaluate all births in Germany in 2012 together with the percentage of euploid and trisomic pregnancies. Detection rates (DR), false positive rates (FPR), the costs of different screening strategies for trisomy 21 and combinations of these strategies were compared. The number of fetuses with trisomy 21 at 12 + 0 weeks of gestation was estimated based on maternal age distribution. We examined the screening performance of a screening strategy based on maternal age, first trimester screening (FTS) and cffDNA testing as well as the combinations "maternal age and cffDNA" and "FTS and cffDNA". Results: In 2012 673 544 children were born. Median maternal age at delivery was 30.2 years (25th-75th quartile: 27.0-34.0). Based on maternal age distribution the expected number of fetuses with trisomy 21 at 12 weeks' gestation was 1788. Our study population therefore consisted of 675 332 pregnancies. Screening based only on maternal age or FTS or cffDNA resulted in detection rates of 63.3 %, 92.2 % and 99.0 % and false positive rates of 21.8 %, 8.0 % and 0.1 %, respectively. When maternal age was combined with cffDNA, cffDNA testing was only offered to women over a certain age; if a cut-off of 30 years was used, this resulted in a DR of 85.2 % and a FPR of 1.7 %. If primary screening consisted of FTS with cffDNA testing only done when the risk was between 1 : 10 and 1 : 1000, the detection rate was 96.7 % and the false positive rate was 1.2 %. Conclusion: In this model-based study we showed that prenatal screening for trisomy 21 can be improved even more by combining FTS and cffDNA. Further studies are necessary to examine whether these results can be reproduced in reality. PMID- 25914418 TI - Possible Effect of Extended Use of Hormonal Contraception on Increased Levels of Antiphospholipid Antibodies in Infertile Women. AB - Purpose: Increased levels of antiphosholipid antibodies (aPLs) are associated with the autoimmune disorder antiphospholipid syndrome (APS) and are known to play a role in infertility. We investigated the possible effect of prolonged use of hormonal contraception (HC) on autoimmunity after discontinuing HC in women with infertility problems. Material and Methods: We analyzed hormonal status including ovulation and the humoral autoimmune response to eight phospholipids detected by ELISA in 1190 infertile women aged 21-46 (mean age: 29.3) years. Results: Long-term HC did not affect ovulation, but in the absence of ovulation HC masked the hormonal disorders. The majority of patients taking HC for more than 10 years with fertility failure had significantly higher levels of aPLs of the IgG isotype against phosphatidylinositol and phosphatidylserine (p > 0.001) than against beta2-glycoprotein I and annexin V. Discussion: Thus, high levels of aPLs are significant for the anticoagulant treatment before and during pregnancy to prevent pregnancy loss. PMID- 25914419 TI - Vaginal Revision of a Haematoma after Placement of Retropubic Tapes in Two Cases. AB - Formation of a haematoma after placement of retropubic tapes for stress incontinence is a rare but typical complication potentially requiring a subsequent operation. Under certain circumstances, haematoma removal by a vaginal approach represents a milder alternative to the subperitoneal laparotomy approach under general anaesthesia. We present two cases of vaginal haematoma revision after placement of retropubic tapes. By means of this gentle alternative to the standard laparotomy approach we could avoid general anaesthesia in one case and perform the operation under analgosedative local anaesthesia. In the second case, use of the vaginal approach enabled us to avoid a laparotomy in this obese patient with a superinfected haematoma that could have led to a possible secondary wound healing problem. PMID- 25914420 TI - Severe Maternal Pre- and Postpartum Intra-Abdominal Bleeding due to Deciduosis. AB - The term "deciduosis" is used to describe the severe pregnancy-associated occurrence of ectopic decidua with a usually asymptomatic course. We report on two cases of massive maternal intra-abdominal bleeding due to such symptomatic changes. The complications arose at different time points for the two cases: prepartum (26th week of pregnancy) or, respectively, - reported here for the first time - seven days postpartum. As well as differential diagnostic aspects we describe the management of the disease and its possible effects on subsequent pregnancies. PMID- 25914421 TI - Light-Sharing Interface for dMiCE Detectors Using Sub-Surface Laser Engraving. AB - We have previously reported on dMiCE, a method of resolving depth or interaction (DOI) in a pair of discrete crystals by encoding light sharing properties as a function of depth in the interface of a crystal-element pair. A challenge for this method is the cost and repeatability of interface treatment for each crystal pair. In this work, we report our preliminary results on using sub-surface laser engraving (SSLE) as a means of forming this depth-dependent interface in a dMiCE detector. A surplus first-generation SSLE system was used to create a partially reflective layer 100-microns thick at the boundary between two halves of a 1.4-by 2.9-by-20 mm3 LYSO crystal. The boundary of these paired crystal elements was positioned between two 3-mm wide Silicon photomultiplier arrays. The responses of these two photodetectors were acquired for an ensemble of 511-keV photons collimated to interact at a fixed depth in just one crystal element. Interaction position was then varied to measure detector response as a function of depth, which was then used to maximum-likelihood positions. Despite use of sub-optimal SSLE processing we found an average DOI resolution of 3.4 mm for front-sided readout and 3.9 mm for back-sided readout while obtaining energy resolutions on the order of 10%. We expect DOI resolution can be improved significantly by optimizing the SSLE process and pattern. PMID- 25914422 TI - Second order Method for Solving 3D Elasticity Equations with Complex Interfaces. AB - Elastic materials are ubiquitous in nature and indispensable components in man made devices and equipments. When a device or equipment involves composite or multiple elastic materials, elasticity interface problems come into play. The solution of three dimensional (3D) elasticity interface problems is significantly more difficult than that of elliptic counterparts due to the coupled vector components and cross derivatives in the governing elasticity equation. This work introduces the matched interface and boundary (MIB) method for solving 3D elasticity interface problems. The proposed MIB elasticity interface scheme utilizes fictitious values on irregular grid points near the material interface to replace function values in the discretization so that the elasticity equation can be discretized using the standard finite difference schemes as if there were no material interface. The interface jump conditions are rigorously enforced on the intersecting points between the interface and the mesh lines. Such an enforcement determines the fictitious values. A number of new techniques has been developed to construct efficient MIB elasticity interface schemes for dealing with cross derivative in coupled governing equations. The proposed method is extensively validated over both weak and strong discontinuity of the solution, both piecewise constant and position-dependent material parameters, both smooth and nonsmooth interface geometries, and both small and large contrasts in the Poisson's ratio and shear modulus across the interface. Numerical experiments indicate that the present MIB method is of second order convergence in both Linfinity and L2 error norms for handling arbitrarily complex interfaces, including biomolecular surfaces. To our best knowledge, this is the first elasticity interface method that is able to deliver the second convergence for the molecular surfaces of proteins.. PMID- 25914423 TI - Plant responses to soil heterogeneity and global environmental change. AB - Recent evidence suggests that soil nutrient heterogeneity, a ubiquitous feature of terrestrial ecosystems, modulates plant responses to ongoing global change (GC). However, we know little about the overall trends of such responses, the GC drivers involved, and the plant attributes affected.We synthesized literature to answer the question: Does soil heterogeneity significantly affect plant responses to main GC drivers, such as elevated atmospheric carbon dioxide concentration (CO2), nitrogen (N) enrichment and changes in rainfall regime?Overall, most studies have addressed short-term effects of N enrichment on the performance of model plant communities using experiments conducted under controlled conditions. The role of soil heterogeneity as a modulator of plant responses to elevated CO2 may depend on the plasticity in nutrient uptake patterns. Soil heterogeneity does interact with N enrichment to determine plant growth and nutrient status, but the outcome of this interaction has been found to be both synergistic and inhibitory. The very few studies published on interactive effects of soil heterogeneity and changes in rainfall regime prevented us from identifying any general pattern.We identify the long-term consequences of soil heterogeneity on plant community dynamics in the field, and the ecosystem level responses of the soil heterogeneity * GC driver interaction, as the main knowledge gaps in this area of research.In order to fill these gaps and take soil heterogeneity and GC research a step forward, we propose the following research guidelines: 1) combining morphological and physiological plant responses to soil heterogeneity with field observations of community composition and predictions from simulation models; and 2) incorporating soil heterogeneity into a trait-based response-effect framework, where plant resource-use traits are used as both response variables to this heterogeneity and GC, and predictors of ecosystem functioning.Synthesis. There is enough evidence to affirm that soil heterogeneity modulates plant responses to elevated atmospheric CO2 and N enrichment. Our synthesis indicates that we must explicitly consider soil heterogeneity to accurately predict plant responses to GC drivers. PMID- 25914424 TI - Soil nutrient heterogeneity modulates ecosystem responses to changes in the identity and richness of plant functional groups. AB - Recent research has shown that biodiversity may has its greatest impact on ecosystem functioning in heterogeneous environments. However, the role of soil heterogeneity as a modulator of ecosystem responses to changes in biodiversity remains poorly understood, as few biodiversity studies have explicitly considered this important ecosystem feature.We conducted a microcosm experiment over two growing seasons to evaluate the joint effects of changes in plant functional groups (grasses, legumes, non-legume forbs and a combination of them), spatial distribution of soil nutrients (homogeneous and heterogeneous) and nutrient availability (50 and 100 mg of nitrogen [N] added as organic material) on plant productivity and surrogates of carbon, phosphorous and N cycling (beta glucosidase and acid phosphatase enzymes and in situ N availability, respectively).Soil nutrient heterogeneity interacted with nutrient availability and plant functional diversity to determine productivity and nutrient cycling responses. All the functional groups exhibited precise root foraging patterns. Above- and belowground productivity increased under heterogeneous nutrient supply. Surrogates of nutrient cycling were not directly affected by soil nutrient heterogeneity. Regardless of their above- and belowground biomass, legumes increased the availability of soil inorganic N and the activity of the acid phosphatase and beta-glucosidase enzymes.Our study emphasizes the role of soil nutrient heterogeneity as a modulator of ecosystem responses to changes in functional diversity beyond the species level. Functional group identity, rather than richness, can play a key role in determining the effects of biodiversity on ecosystem functioning.Synthesis. Our results highlight the importance of explicitly considering soil heterogeneity in diversity-ecosystem functioning experiments, where the identity of the plant functional group is of major importance. Such consideration will improve our ability to fully understand the role of plant diversity on ecosystem functioning in ubiquitous heterogeneous environments. PMID- 25914425 TI - Insufficient Sampling to Identify Species Affected by Turbine Collisions. AB - We compared the number of avian species detected and the sampling effort during fatality monitoring at 50 North American wind facilities. Facilities with short intervals between sampling events and high effort detected more species, but many facilities appeared undersampled. Species accumulation curves for 2 wind facilities studied for more than 1 year had yet to reach an asymptote. The monitoring effort that is typically invested is likely inadequate to identify all of the species killed by wind turbines. This may understate impacts for rare species of conservation concern that collide infrequently with turbines but suffer disproportionate consequences from those fatalities. Published 2015. This article is a U.S. Government work and is in the public domain in the USA. PMID- 25914426 TI - Evolutionary relationships can be more important than abiotic conditions in predicting the outcome of plant-plant interactions. AB - Positive and negative plant-plant interactions are major processes shaping plant communities. They are affected by environmental conditions and evolutionary relationships among the interacting plants. However, the generality of these factors as drivers of pairwise plant interactions and their combined effects remain virtually unknown. We conducted an observational study to assess how environmental conditions (altitude, temperature, irradiance and rainfall), the dispersal mechanism of beneficiary species and evolutionary relationships affected the co-occurrence of pairwise interactions in 11 Stipa tenacissima steppes located along an environmental gradient in Spain. We studied 197 pairwise plant-plant interactions involving the two major nurse plants (the resprouting shrub Quercus coccifera and the tussock grass S. tenacissima) found in these communities. The relative importance of the studied factors varied with the nurse species considered. None of the factors studied were good predictors of the co ocurrence between S. tenacissima and its neighbours. However, both the dispersal mechanism of the beneficiary species and the phylogenetic distance between interacting species were crucial factors affecting the co-occurrence between Q. coccifera and its neighbours, while climatic conditions (irradiance) played a secondary role. Values of phylogenetic distance between 207-272.8 Myr led to competition, while values outside this range or fleshy-fruitness in the beneficiary species led to positive interactions. The low importance of environmental conditions as a general driver of pairwise interactions was caused by the species-specific response to changes in either rainfall or radiation. This result suggests that factors other than climatic conditions must be included in theoretical models aimed to generally predict the outcome of plant-plant interactions. Our study helps to improve current theory on plant-plant interactions and to understand how these interactions can respond to expected modifications in species composition and climate associated to ongoing global environmental change. PMID- 25914427 TI - Matrix models for quantifying competitive intransitivity. AB - Assessing the relative importance of intransitive competition networks in nature has been difficult because it requires a large number of pairwise competition experiments linked to observed field abundances of interacting species. Here we introduce metrics and statistical tests for evaluating the contribution of intransitivity to community structure using two kinds of data: competition matrices derived from the outcomes of pairwise experimental studies (C matrices) and species abundance matrices. We use C matrices to develop patch transition matrices (P) that predict community structure in a simple Markov chain model. We propose a randomization test to evaluate the degree of intransitivity from these P matrices in combination with empirical or simulated C matrices. Benchmark tests revealed that the methods could correctly detect intransitive competition networks, even in the absence of direct measures of pairwise competitive strength. These tests represent the first tools for estimating the degree of intransitivity in competitive networks from observational datasets. They can be applied to both spatio-temporal data sampled in homogeneous environments or across environmental gradients, and to experimental measures of pairwise interactions. To illustrate the methods, we analyzed empirical data matrices on the colonization of slug carrion by necrophagous flies and their parasitoids. PMID- 25914428 TI - Biocrusts modulate warming and rainfall exclusion effects on soil respiration in a semi-arid grassland. AB - Soil surface communities composed of cyanobacteria, algae, mosses, liverworts, fungi, bacteria and lichens (biocrusts) largely affect soil respiration in dryland ecosystems. Climate change is expected to have large effects on biocrusts and associated ecosystem processes. However, few studies so far have experimentally assessed how expected changes in temperature and rainfall will affect soil respiration in biocrust-dominated ecosystems. We evaluated the impacts of biocrust development, increased air temperature and decreased precipitation on soil respiration dynamics during dry (2009) and wet (2010) years, and investigated the relative importance of soil temperature and moisture as environmental drivers of soil respiration, in a semiarid grassland from central Spain. Soil respiration rates were significantly lower in the dry than during the wet year, regardless of biocrust cover. Warming increased soil respiration rates, but this response was only significant in biocrust-dominated areas (> 50% biocrust cover). Warming also increased the temperature sensitivity (Q10 values) of soil respiration in biocrust-dominated areas, particularly during the wet year. The combination of warming and rainfall exclusion had similar effects in low biocrust cover areas. Our results highlight the importance of biocrusts as a modulator of soil respiration responses to both warming and rainfall exclusion, and indicate that they must be explicitly considered when evaluating soil respiration responses to climate change in drylands. PMID- 25914429 TI - Changes in rainfall amount and frequency do not affect the outcome of the interaction between the shrub Retama sphaerocarpa and its neighbouring grasses in two semiarid communities. AB - We evaluated the net outcome of the interaction between the shrub Retama sphaerocarpa, our target plant, and different herbaceous neighbours in response to changes in the magnitude and frequency of rainfall events during three years. The experiment was conducted in natural and anthropogenic grasslands dominated by a perennial stress-tolerator and ruderal annual species, respectively. In spite of the neutral or positive effects of neighbours on water availability, neighbouring plants reduced the performance of Retama juveniles, suggesting competition for resources other than water. The negative effects of grasses on the photochemical efficiency of Retama juveniles decreased with higher water availabilities or heavier irrigation pulses, depending on the grassland studied; however, these effects did not extent to the survival and growth of Retama juveniles. Our findings show the prevalence of competitive interactions among the studied plants, regardless of the water availability and its temporal pattern. These results suggest that positive interactions may not prevail under harsher conditions when shade-intolerant species are involved. This study could be used to further refine our predictions of how plant-plant interactions will respond to changes in rainfall, either natural or increased by the ongoing climatic change, in ecosystems where grass-shrubs interactions are prevalent. PMID- 25914430 TI - Feeding and Bleeding: The Institutional Banalization of Risk to Healthy Volunteers in Phase I Pharmaceutical Clinical Trials. AB - Phase I clinical trials are the first stage of testing new pharmaceuticals in humans. The majority of these studies are conducted under controlled, inpatient conditions using healthy volunteers who are paid for their participation. This article draws on an ethnographic study of six phase I clinics in the United States, including 268 semistructured interviews with research staff and healthy volunteers. In it, I argue that an institutional banalization of risk structures the perceptions of research staff and healthy volunteers participating in the studies. For research staff, there are three mechanisms by which risk becomes banal: a perceived homogeneity of studies, Fordist work regimes, and data-centric discourse. For healthy volunteers, repeat study participation contributes to the institutional banalization of risk both through the process of desensitization to risk and the formation of trust in the clinics. I argue that the institutional banalization of risk also renders invisible ethical concerns about exploitation of underprivileged groups in pharmaceutical research. PMID- 25914431 TI - Managing dynamic epidemiological risks through trade. AB - There is growing concern that trade, by connecting geographically isolated regions, unintentionally facilitates the spread of invasive pathogens and pests - forms of biological pollution that pose significant risks to ecosystem and human health. We use a bioeconomic framework to examine whether trade always increases private risks, focusing specifically on pathogen risks from live animal trade. When the pathogens have already established and traders bear some private risk, we find two results that run counter to the conventional wisdom on trade. First, uncertainty about the disease status of individual animals held in inventory may increase the incentives to trade relative to the disease-free case. Second, trade may facilitate reduced long-run disease prevalence among buyers. These results arise because disease risks are endogenous due to dynamic feedback processes involving valuable inventories, and markets facilitate the management of private risks that producers face with or without trade. PMID- 25914432 TI - U.S. internal migration and occupational attainment: Assessing absolute and relative outcomes by region and race. AB - This paper investigates the occupational implications of contemporary migration flows by region and race. Even though the expectation of a positive link between geographic and social mobility is a central tenet in the stratification literature, empirical assessments are rare and have produced inconsistent results. Our analysis departs from traditional frameworks by integrating both absolute and relative notions of occupational standing for evaluating migration outcomes, comparing migrants against non-migrant peers both at origin and destination. Results document that for whites migration is associated with higher occupational attainment both in absolute and relative terms, irrespective of the regional direction of the move. For blacks, on the other hand, absolute occupational gains are markedly absent for migration to the South, which is instead characterized by significant improvement in relative terms. The differences in absolute and relative gains by race and direction of the move helps contextualize the considerable black over representation in north-south migration and highlights the implications of current internal mobility for racial stratification. PMID- 25914433 TI - Gender Equity, Opportunity Costs of Parenthood, and Educational Differences in Unintended First Births: Insights from Japan. AB - We examine educational differences in the intendedness of first births in Japan using data from a nationally representative survey of married women (N = 2,373). We begin by describing plausible scenarios for a negative, null, and positive educational gradient in unintended first births. In contrast to well-established results from the U.S., we find evidence of a positive educational gradient in Japan. Net of basic demographic controls, university graduates are more likely than less-educated women to report first births as unintended. This pattern is consistent with a scenario emphasizing the high opportunity costs of motherhood in countries such as Japan where growing opportunities for women in employment and other domains of public life have not been accompanied by changes in the highly asymmetric roles of men and women within the family. We discuss potential implications of this suggestive finding for other low-fertility settings. PMID- 25914434 TI - From a state to a trait: Trajectories of state mindfulness in meditation during intervention predict changes in trait mindfulness. AB - Theory suggests that heightening state mindfulness in meditation practice over time increases trait mindfulness, which benefits psychological health. We prospectively examined individual trajectories of state mindfulness in meditation during a mindfulness-based intervention in relation to changes in trait mindfulness and psychological distress. Each week during the eight-week intervention, participants reported their state mindfulness in meditation after a brief mindfulness meditation. Participants also completed pre- and post intervention measures of trait mindfulness and psychological symptoms. Tests of combined latent growth and path models suggested that individuals varied significantly in their rates of change in state mindfulness in meditation during the intervention, and that these individual trajectories predicted pre-post intervention changes in trait mindfulness and distress. These findings support that increasing state mindfulness over repeated meditation sessions may contribute to a more mindful and less distressed disposition. However, individuals' trajectories of change may vary and warrant further investigation. PMID- 25914435 TI - Do changes in grazing pressure and the degree of shrub encroachment alter the effects of individual shrubs on understorey plant communities and soil function? AB - : Shrub canopies in semi-arid environments often produce positive effects on soil fertility, and on the richness and biomass of understorey plant communities. However, both positive and negative effects of shrub encroachment on plant and soil attributes have been reported at the landscape-level. The contrasting results between patch- and landscape-level effects in shrublands could be caused by differences in the degree of shrub encroachment or grazing pressure, both of which are likely to reduce the ability of individual shrubs to ameliorate their understorey environment.We examined how grazing and shrub encroachment (measured as landscape-level shrub cover) influence patch-level effects of shrubs on plant density, biomass and similarity in species composition between shrub understories and open areas, and on soil stability, nutrient cycling, and infiltration in two semi-arid Australian woodlands.Individual shrubs had consistently positive effects on all plant and soil variables (average increase of 23% for all variables). These positive patch-level effects persisted with increasing shrub cover up to our maximum of 50% cover. Heavy grazing negatively affected most of the variables studied (average decline of 11%). It also altered, for some variables, how individual shrubs affected their sub-canopy environment with increasing shrub cover. Thus for species density, biomass and soil infiltration, the positive effect of individual shrubs with increasing shrub cover diminished under heavy grazing. SYNTHESIS: Our study refines predictions of the effects of woody encroachment on ecosystem structure and functioning by showing that heavy grazing, rather than differences in shrub cover, explains the contrasting effects on ecosystem structure and function between individual shrubs and those in dense aggregations. We also discuss how species-specific traits of the encroaching species, such as their height or its ability to fix N, might influence the relationship between their patch-level effects and their cover within the landscape. PMID- 25914436 TI - Proton affinity of the histidine-tryptophan cluster motif from the influenza A virus from ab initio molecular dynamics. AB - Ab initio molecular dynamics calculations have been used to compare and contrast the deprotonation reaction of a histidine residue in aqueous solution with the situation arising in a histidine-tryptophan cluster. The latter is used as a model of the proton storage unit present in the pore of the M2 proton conducting ion channel. We compute potentials of mean force for the dissociation of a proton from the Ndelta and Nepsilon positions of the imidazole group to estimate the pKa's. Anticipating our results, we will see that the estimated pKa for the first protonation event of the M2 channel is in good agreement with experimental estimates. Surprisingly, despite the fact that the histidine is partially desolvated in the M2 channel, the affinity for protons is similar to that of a histidine in aqueous solution. Importantly, the electrostatic environment provided by the indoles is responsible for the stabilization of the charged imidazolium. PMID- 25914438 TI - Pollination by nocturnal Lepidoptera, and the effects of light pollution: a review. AB - 1. Moths (Lepidoptera) are the major nocturnal pollinators of flowers. However, their importance and contribution to the provision of pollination ecosystem services may have been under-appreciated. Evidence was identified that moths are important pollinators of a diverse range of plant species in diverse ecosystems across the world. 2. Moth populations are known to be undergoing significant declines in several European countries. Among the potential drivers of this decline is increasing light pollution. The known and possible effects of artificial night lighting upon moths were reviewed, and suggest how artificial night lighting might in turn affect the provision of pollination by moths. The need for studies of the effects of artificial night lighting upon whole communities of moths was highlighted. 3. An ecological network approach is one valuable method to consider the effects of artificial night lighting upon the provision of pollination by moths, as it provides useful insights into ecosystem functioning and stability, and may help elucidate the indirect effects of artificial light upon communities of moths and the plants they pollinate. 4. It was concluded that nocturnal pollination is an ecosystem process that may potentially be disrupted by increasing light pollution, although the nature of this disruption remains to be tested. PMID- 25914439 TI - Matched Interface and Boundary Method for Elasticity Interface Problems. AB - Elasticity theory is an important component of continuum mechanics and has had widely spread applications in science and engineering. Material interfaces are ubiquity in nature and man-made devices, and often give rise to discontinuous coefficients in the governing elasticity equations. In this work, the matched interface and boundary (MIB) method is developed to address elasticity interface problems. Linear elasticity theory for both isotropic homogeneous and inhomogeneous media is employed. In our approach, Lame's parameters can have jumps across the interface and are allowed to be position dependent in modeling isotropic inhomogeneous material. Both strong discontinuity, i.e., discontinuous solution, and weak discontinuity, namely, discontinuous derivatives of the solution, are considered in the present study. In the proposed method, fictitious values are utilized so that the standard central finite different schemes can be employed regardless of the interface. Interface jump conditions are enforced on the interface, which in turn, accurately determines fictitious values. We design new MIB schemes to account for complex interface geometries. In particular, the cross derivatives in the elasticity equations are difficult to handle for complex interface geometries. We propose secondary fictitious values and construct geometry based interpolation schemes to overcome this difficulty. Numerous analytical examples are used to validate the accuracy, convergence and robustness of the present MIB method for elasticity interface problems with both small and large curvatures, strong and weak discontinuities, and constant and variable coefficients. Numerical tests indicate second order accuracy in both Linfinity and L2 norms. PMID- 25914437 TI - Climate and soil attributes determine plant species turnover in global drylands. AB - AIM: Geographic, climatic, and soil factors are major drivers of plant beta diversity, but their importance for dryland plant communities is poorly known. This study aims to: i) characterize patterns of beta diversity in global drylands, ii) detect common environmental drivers of beta diversity, and iii) test for thresholds in environmental conditions driving potential shifts in plant species composition. LOCATION: 224 sites in diverse dryland plant communities from 22 geographical regions in six continents. METHODS: Beta diversity was quantified with four complementary measures: the percentage of singletons (species occurring at only one site), Whittake's beta diversity (beta(W)), a directional beta diversity metric based on the correlation in species occurrences among spatially contiguous sites (beta(R2)), and a multivariate abundance-based metric (beta(MV)). We used linear modelling to quantify the relationships between these metrics of beta diversity and geographic, climatic, and soil variables. RESULTS: Soil fertility and variability in temperature and rainfall, and to a lesser extent latitude, were the most important environmental predictors of beta diversity. Metrics related to species identity (percentage of singletons and beta(W)) were most sensitive to soil fertility, whereas those metrics related to environmental gradients and abundance ((beta(R2)) and beta(MV)) were more associated with climate variability. Interactions among soil variables, climatic factors, and plant cover were not important determinants of beta diversity. Sites receiving less than 178 mm of annual rainfall differed sharply in species composition from more mesic sites (> 200 mm). MAIN CONCLUSIONS: Soil fertility and variability in temperature and rainfall are the most important environmental predictors of variation in plant beta diversity in global drylands. Our results suggest that those sites annually receiving ~ 178 mm of rainfall will be especially sensitive to future climate changes. These findings may help to define appropriate conservation strategies for mitigating effects of climate change on dryland vegetation. PMID- 25914440 TI - A Subspace Semi-Definite programming-based Underestimation (SSDU) method for stochastic global optimization in protein docking. AB - We propose a new stochastic global optimization method targeting protein docking problems. The method is based on finding a general convex polynomial underestimator to the binding energy function in a permissive subspace that possesses a funnel-like structure. We use Principal Component Analysis (PCA) to determine such permissive subspaces. The problem of finding the general convex polynomial underestimator is reduced into the problem of ensuring that a certain polynomial is a Sum-of-Squares (SOS), which can be done via semi-definite programming. The underestimator is then used to bias sampling of the energy function in order to recover a deep minimum. We show that the proposed method significantly improves the quality of docked conformations compared to existing methods. PMID- 25914441 TI - Double complexes and local cochain projections. AB - The construction of projection operators, which commute with the exterior derivative and at the same time are bounded in the proper Sobolev spaces, represents a key tool in the recent stability analysis of finite element exterior calculus. These so-called bounded cochain projections have been constructed by combining a smoothing operator and the unbounded canonical projections defined by the degrees of freedom. However, an undesired property of these bounded projections is that, in contrast to the canonical projections, they are nonlocal. The purpose of this article is to discuss a recent alternative construction of bounded cochain projections, which also are local. A key tool for the new construction is the structure of a double complex, resembling the Cech-de Rham double complex of algebraic topology. PMID- 25914442 TI - The Effect of Realistic Contexts on Ontological Judgments of Novel Entities. AB - Although a great deal of research has focused on ontological judgments in preschoolers, very little has examined ontological judgments in older children. The present study asked 10-year-olds and adults (N = 94) to judge the reality status of known real, known imagined, and novel entities presented in simple and elaborate contexts and to explain their judgments. Although judgments were generally apt, participants were more likely to endorse imagined and novel entities when the entities were presented in elaborate contexts. When asked to explain their reasoning, participants at both ages cited firsthand experience for real entities and general knowledge for imagined entities. For novel entities, participants referred most to indirect experiences when entities were presented in simple contexts and to general knowledge when those entities were presented in elaborate contexts. These results suggest that rich contextual information continues to be an important influence on ontological judgments past the preschool years. PMID- 25914443 TI - Angled-focused 45 MHz PMN-PT single element transducer for intravascular ultrasound imaging. AB - A transducer with an angled and focused aperture for intravascular ultrasound imaging has been developed. The acoustic stack for the angled-focused transducer was made of PMN-PT single crystal with one matching layer, one protective coating layer, and a highly damped backing layer. It was then press-focused to a desired focal length and inserted into a thin needle housing with an angled tip. A transducer with an angled and unfocused aperture was also made, following the same fabrication procedure, to compare the performance of the two transducers. The focused and unfocused transducers were tested to measure their center frequencies, bandwidths, and spatial resolutions. Lateral resolution of the angled-focused transducer (AFT) improved more than two times compared to that of the angled-unfocused transducer (AUT). A tissue-mimicking phantom in water and a rabbit aorta tissue sample in rabbit blood were scanned using AFT and AUT. Imaging with AFT offered improved contrast, over imaging with AUT, of the tissue mimicking phantom and the rabbit aorta tissue sample by 23 dB and 8 dB, respectively. The results show that AFT has strong potential to provide morphological and pathological information of coronary arteries with high resolution and high contrast. PMID- 25914444 TI - Fibro-porous poliglecaprone/polycaprolactone conduits: synergistic effect of composition and in vitro degradation on mechanical properties. AB - Blends of poliglecaprone (PGC) and polycaprolactone (PCL) of varying compositions were electrospun into tubular conduits and their mechanical, morphological, thermal and in vitro degradation properties were evaluated under simulated physiological conditions. Generally, mechanical strength, modulus and hydrophilic nature were enhanced by the addition of PGC to PCL. An in vitro degradation study in phosphate-buffered saline (pH 7.3) was carried out for up to 1 month to understand the hydrolytic degradation effect on the mechanical properties in both the longitudinal and circumferential directions. Pure PCL and 4:1 PCL/PGC blend scaffolds exhibited considerable elastic stiffening after a 1 month in vitro degradation. Fourier transform infrared spectroscopic and DSC techniques were used to understand the degradation behavior and the changes in structure and crystallinity of the polymeric blends. A 3:1 PCL/PGC blend was concluded to be a judicious blend composition for tubular grafts based on overall results on the mechanical properties and performance after a 1 month in vitro degradation study. PMID- 25914445 TI - Computational identification and analysis of MADS box genes in Camellia sinensis. AB - MADS (Minichromosome Maintenance1 Agamous Deficiens Serum response factor) box genes encode transcription factors and they play a key role in growth and development of flowering plants. There are two types of MADS box genes- Type I (serum response factor (SRF)-like) and Type II (myocyte enhancer factor 2 (MEF2) like). Type II MADS box genes have a conserved MIKC domain (MADS DNA-binding domain, intervening domain, keratin-like domain, and c-terminal domain) and these were extensively studied in plants. Compared to other plants very little is known about MADS box genes in Camellia sinensis. The present study aims at identifying and analyzing the MADS-box genes present in Camellia sinensis. A comparative bioinformatics and phylogenetic analysis of the Camellia sinensis sequences along with Arabidopsis thaliana MADS box sequences available in the public domain databases led to the identification of 16 genes which were orthologous to Type II MADS box gene family members. The protein sequences were classified into distinct clades which are associated with the conserved function of flower and seed development. The identified genes may be used for gene expression and gene manipulation studies to elucidate their role in the development and flowering of tea which may pave the way to improve the crop productivity. PMID- 25914446 TI - Modularity in the evolution of yeast protein interaction network. AB - Protein interaction networks are known to exhibit remarkable structures: scale free and small-world and modular structures. To explain the evolutionary processes of protein interaction networks possessing scale-free and small-world structures, preferential attachment and duplication-divergence models have been proposed as mathematical models. Protein interaction networks are also known to exhibit another remarkable structural characteristic, modular structure. How the protein interaction networks became to exhibit modularity in their evolution? Here, we propose a hypothesis of modularity in the evolution of yeast protein interaction network based on molecular evolutionary evidence. We assigned yeast proteins into six evolutionary ages by constructing a phylogenetic profile. We found that all the almost half of hub proteins are evolutionarily new. Examining the evolutionary processes of protein complexes, functional modules and topological modules, we also found that member proteins of these modules tend to appear in one or two evolutionary ages. Moreover, proteins in protein complexes and topological modules show significantly low evolutionary rates than those not in these modules. Our results suggest a hypothesis of modularity in the evolution of yeast protein interaction network as systems evolution. PMID- 25914447 TI - Computer aided identification of sodium channel blockers in the clinical treatment of epilepsy using molecular docking tools. AB - Phenytoin (PHT) and Carbamazepine (CBZ) are excellent sodium channel blockers administered in clinical treatment of epileptic seizures. However, the narrow therapeutic range and limited pharmacokinetics of these drugs have raised serious concerns in the proper management of epilepsy. To overcome this, the present study attempts to identify a candidate molecule with superior pharmacological profile than PHT and CBZ through In silico approaches. PHT and CBZ served as query small molecules for Tanimoto based similarity search with a threshold of 95% against PubChem database. Aided by MolDock algorithm, high affinity similar compound against each query was retrieved. PHT and CBZ and their respective similar were further tested for toxicity profiles, LC 50 values and biological activity. Compounds, NSC403438 and AGN-PC-0BPCBP respectively similar to PHT and CBZ demonstrated higher affinity to sodium channel protein than their respective leads. Of particular relevance, NSC403438 demonstrated highest binding affinity bestowed with least toxicity, better LC 50 values and optimal bioactivity. NSC403438 was further mapped for its structure based pharmacophoric features. In the study, we report NSC403438 as potential sodium channel blocker as a better candidate than PHT and CBZ which can be put forth for pharmacodynamic and pharmacokinetic studies. ABBREVIATIONS: AEDs - Antiepileptic drugs, BLAST - Basic Local Alignment Search Tool, CBZ - Carbamazepine, GEFS+ - Generalized Epilepsy with Febrile Seizures Plus, GPCR - G Protein Coupled Receptor, Nav - Sodium channel with specific voltage conduction, PDB - Protein Data Bank, PHT - Phenytoin, PIR - Protein Information resources, SAVES - Structural Analysis and Verification Server, VGSC - Voltage-gated Sodium channels. PMID- 25914448 TI - Phyto-extraction of heavy metals and biochemical changes with Brassica nigra L. grown in rayon grade paper mill effluent irrigated soil. AB - In this study, distribution of metal accumulation and their biological changes of Indian mustard plants (Brassica nigra L.) grown in soil irrigated with different concentration of rayon grade paper effluent (RGPE, 25%, 50%, 75%, 100%, v/v) were studied. A pronounced effect was recorded at 50% (v/v) RGPE on germination of seeds, amylase activity and other growth parameters in Indian mustard plants. An increase in the chlorophyll and protein contents was also recorded at <50% (v/v) RGPE followed by a decrease at higher concentrations of RGPE (>75%). A significant increase lipid peroxidation was recorded, which was evidenced by the increased malondialdehyde (MDA) content in shoot, leaves and seeds in tested plant at all the concentrations of RGPE. This Indian mustard plants (Brassica nigra L.) are well adapted for tolerance of significant amount of heavy metals due to increased level of antioxidants (cysteine and ascorbic acid) in root shoot and leaves of treated plants at all concentration of RGPE. Moreover, it is also important that RGPE should be treated to bring down the metal concentration well within the prescribed limit prior to use in agricultural soil for ferti irrigation. PMID- 25914449 TI - Molecular characterization of full-length Tat in HIV-1 subtypes B and C. AB - HIV-1Tat (trans-acting activator of transcription) plays essential roles in the replication through viral mRNA and genome transcription from the HIV-1 LTR promoter. However, Tat undergoes continuous amino acid substitutions. As a consequence, the virus escapes from host immunity indicating that genetic diversity of Tat protein in major HIV-1 subtypes is required to be continuously monitored. We analyzed available full-length HIV-1 sequences of subtypes B (n=493) and C (n=280) strains circulating worldwide. We observed 81% and 84% nucleotide sequence identities of HIV-1 Tat for subtypes B and C, respectively. Based on phylogenetic and mutation analyses, global diversity of subtype B was apparently higher compared to that of subtype C. Positively selected sites, such as positions Ser68 and Ser70 in both subtypes, were located in the Tat transactivation responsive RNA (TAR) interaction domain. We also found positively selected sites in exon 2, such as positions Ser75, Pro77, Asp80, Pro81 and Ser87 for both subtypes. Our study provides useful information on the full-length HIV-1 Tat sequences in globally circulating strains. PMID- 25914450 TI - A method to associate all possible combinations of genetic and environmental factors using GxE landscape plot. AB - Genome-wide association studies (GWAS) and linkage analysis has identified many single nucleotide polymorphisms (SNPs) related to disease. There are many unknown SNPs whose minor allele frequencies (MAFs) as low as 0.005 having intermediate effects with odds ratio between 1.5~3.0. Low frequency variants having intermediate effects on disease pathogenesis are believed to have complex interactions with environmental factors called gene-environment interactions (GxE). Hence, we describe a model using 3D Manhattan plot called GxE landscape plot to visualize the association of p-values for gene-environment interactions (GxE). We used the Gene-Environment iNteraction Simulator 2 (GENS2) program to simulate interactions between two genetic loci and one environmental factor in this exercise. The dataset used for training contains disease status, gender, 20 environmental exposures and 100 genotypes for 170 subjects, and p-values were calculated by Cochran-Mantel-Haenszel chi-squared test on known data. Subsequently, we created a 3D GxE landscape plot of negative logarithm of the association of p-values for all the possible combinations of genetic and environmental factors with their hierarchical clustering. Thus, the GxE landscape plot is a valuable model to predict association of p-values for GxE and similarity among genotypes and environments in the context of disease pathogenesis. ABBREVIATIONS: GxE - Gene-environment interactions, GWAS - Genome wide association study, MAFs - Minor allele frequencies, SNPs - Single nucleotide polymorphisms, EWAS - Environment-wide association study, FDR - False discovery rate, JPT+CHB - HapMap population of Japanese in Tokyo, Japan - Han Chinese in Beijing. PMID- 25914451 TI - Treatment of esophagogastric junction carcinoma: an unsolved debate. AB - The incidence of esophagogastric junction adenocarcinoma (AEG) is increasing worldwide. Barrett's esophagus (BE) associated with dysplasia is the main risk factor for the development of cancer. Currently, screening programs to individuate and eradicate BE represent the best way to reduce AEG cancer. Several endoscopic approaches are here discussed. Surgical strategies for different types of AEG cancer are now fairly standardized, and multidisciplinary strategies using chemotherapy or chemoradiotherapy may improve the outcome of these patients. Here we briefly discuss the keypoints, main topics, and critical issues, according to accumulating evidence and taking into account our own experience. PMID- 25914452 TI - Noninvasive imaging assessment of non-alcoholic fatty liver disease: focus on liver scintigraphy. AB - Noninvasive diagnoses of nonalcoholic fatty-liver disease (NAFLD) involve the use of serologic markers and imaging methods, such as conventional ultrasonography (US), computed tomography, and magnetic resonance imaging. Although these methods are reliable for the noninvasive detection of moderate to severe fatty changes in the liver, they are not reliable for detecting nonalcoholic steatohepatitis (NASH) and fibrosis. New imaging technologies, such as US-based transient elastography, acoustic radiation force impulse and magnetic resonance-based elastography, can reportedly be used to determine the severity of liver fibrosis associated with NASH. In this context, the field of nuclear medicine through liver scintigraphy has recently been proposed, and is being explored for use in the diagnosis of NASH. More importantly, nuclear medicine may contribute to the distinction between simple steatosis and NASH. For example, the enhanced release of cytokines and the decrease in the phagocytic activity of Kupffer cells play important roles in the pathogenesis of NASH. Removal of technetium-99m colloid from circulation by Kupffer cell phagocytosis therefore provides a valuable imaging technique. Thus, nuclear medicine is poised to provide useful tools for the evaluation of patients with NAFLD. However, the evidence is still scarce, and more studies with larger samples are needed to identify their role before they are used in clinical practice. PMID- 25914453 TI - Technical and instrumental prerequisites for single-port laparoscopic solo surgery: state of art. AB - With the aid of advanced surgical techniques and instruments, single-port laparoscopic surgery (SPLS) can be accomplished with just two surgical members: an operator and a camera assistant. Under these circumstances, the reasonable replacement of a human camera assistant by a mechanical camera holder has resulted in a new surgical procedure termed single-port solo surgery (SPSS). In SPSS, the fixation and coordinated movement of a camera held by mechanical devices provides fixed and stable operative images that are under the control of the operator. Therefore, SPSS primarily benefits from the provision of the operator's eye-to-hand coordination. Because SPSS is an intuitive modification of SPLS, the indications for SPSS are the same as those for SPLS. Though SPSS necessitates more actions than the surgery with a human assistant, these difficulties seem to be easily overcome by the greater provision of static operative images and the need for less lens cleaning and repositioning of the camera. When the operation is expected to be difficult and demanding, the SPSS process could be assisted by the addition of another instrument holder besides the camera holder. PMID- 25914454 TI - Management of hepatitis C infection before and after liver transplantation. AB - Chronic hepatitis C (CHC) is the most common indication for liver transplantation (LT). Aggressive treatment of hepatitis C virus (HCV) infection before cirrhosis development or decompensation may reduce LT need and risk of HCV recurrence post LT. Factors associated with increased HCV risk or severity of recurrence include older age, immunosuppression, HCV genotype 1 and high viral load at LT. HCV recurrence post-LT leads to accelerated liver disease and cirrhosis development with reduced graft and patient survival. Currently, interferon (IFN)-based regimens can be used in dual-agent regimens with ribavirin, in triple-agent antiviral strategies with direct-acting antivirals (e.g., protease inhibitors telaprevir or boceprevir), or before transplant in compensated patients to reduce HCV viral load to prevent or reduce the risk of post-LT recurrence and complications; they cannot be used in patients with decompensated cirrhosis. IFN based regimens are used in less than half of HCV-infected patients waiting for LT due to extremely low efficacy and poor tolerability. However, antiviral therapy is indicated after LT in patients with histologically confirmed CHC despite tolerability issues. Improvements in side effect management have increased survival in patients achieving therapeutic targets. HCV treatment pre- and post LT results in significant health care costs especially when lack of efficacy leads to disease worsening, although studies have shown sofosbuvir treatment before LT vs conventional post-LT dual antiviral is cost effective. The suboptimal efficacy and tolerability of IFN-based therapies, plus the significant economic burden, means the need for effective and well tolerated IFN-free anti HCV therapy for pre- and post-LT remains high. PMID- 25914455 TI - Tools for primary care management of inflammatory bowel disease: do they exist? AB - Healthcare systems throughout the world continue to face emerging challenges associated with chronic disease management. Due to the likely increase in chronic conditions in the future it is now vital that cooperation and support between specialists, generalists and primary health care physicians is conducted. Inflammatory bowel disease (IBD) is one such chronic disease. Despite specialist care being essential, much IBD care could and probably should be delivered in primary care with continued collaboration between all stakeholders. Whilst most primary care physicians only have few patients currently affected by IBD in their caseload, the proportion of patients with IBD-related healthcare issues cared for in the primary care setting appears to be widespread. Data suggests however, that primary care physician's IBD knowledge and comfort in management is suboptimal. Current treatment guidelines for IBD are helpful but they are not designed for the primary care setting. Few non-expert IBD management tools or guidelines exist compared with those used for other chronic diseases such as asthma and scant data have been published regarding the usefulness of such tools including IBD action plans and associated supportive literature. The purpose of this review is to investigate what non-specialist tools, action plans or guidelines for IBD are published in readily searchable medical literature and compare these to those which exist for other chronic conditions. PMID- 25914457 TI - Role of associating liver partition and portal vein ligation for staged hepatectomy in colorectal liver metastases: a review. AB - Colorectal cancer is the third most common cancer in the Western world. Approximately half of patients will develop liver metastases, which is the most common cause of death. The only potentially curative treatment is surgical resection. However, many patients retain a to small future liver remnant (FLR) to allow for resection directly. There are therefore strategies to decrease the tumor with neoadjuvant chemotherapy and to increase the FLR. An accepted strategy to increase the FLR is portal vein occlusion (PVO). A concern with this strategy is that a large proportion of patients will never be operated because of progression during the interval between PVO and resection. ALPPS (associating liver partition and portal vein ligation for staged hepatectomy) is a new procedure with a high resection rate. A concern with this approach is the rather high frequency of complications and high mortality, compared to PVO. In this review, it is shown that with ALPPS the resection rate was 97.1% for CRLM and the mortality rate for all diagnoses was 9.6%. The mortality rate was likely lower for patients with CRLM, but some data were lacking in the reports. Due to the novelty of ALPPS, the indications and technique are not yet established but there are arguments for ALPPS in the context of CRLM and a small FLR. PMID- 25914458 TI - Intestinal genetic inactivation of caspase-8 diminishes migration of enterocytes. AB - AIM: To verify the hypothesis that caspase-8 (Casp8), which regulates cellular apoptosis and necroptosis, is critically involved in enterocyte migration. METHODS: Casp8-silenced Caco2 cells were used in migration assays. In addition, enterocyte-specific Casp8 heterozygous (Casp8(+/?int)) or homozygous knockout mice (Casp8(?int)) were generated by crossing genetically modified mice carrying loxP recombination sites in intron 2 and 4 of the murine Casp8 gene with transgenic animals expressing a cre-transgene under control of the villin promoter in a pure C57/BL6 genetic background. The nucleoside analog BrdU was injected i.p. in male Casp8(+/?int) and Casp8(?int) animals 4 h, 20 h, or 40 h before performing morphometric studies. Locations of anti-BrdU-immunostained cells (cell(max)) in at least 50 hemi-crypts of 6 histoanatomically distinct intestinal mucosal regions were numbered and extracted for statistical procedures. For the mice cohort (n = 28), the walking distance of enterocytes was evaluated from cell(max) within crypt (n = 57), plateau (n = 19), and villus (n = 172) positions, resulting in a total of 6838 observations. Data analysis was performed by fitting a three-level mixed effects model to the data. RESULTS: In cell culture experiments with Caco2 cells, Casp8 knockdown efficiency mediated by RNA interference on Casp8 transcripts was 80% controlled as determined by Western blotting. In the scratch assay, migration of Casp8-deleted Caco2 cells was significantly diminished when compared with controls (Casp8(?scramble) and Caco2). In BrdU-labeled Casp8(?int) mice, cell(max) locations were found along the hemi-crypts in a lower position than it was for Casp8(+/?int) or control (cre negative) animals. Statistical data analysis with a three-level mixed effects model revealed that in the six different intestinal locations (distinct segments of the small and large intestine), cell movement between the three mice groups differed widely. Especially in duodenal hemi-crypts, enterocyte movement was different between the groups. At 20 h, duodenal cell(max) location was significantly lower in Casp8(?int) (25.67 +/- 2.49) than in Casp8(+/?int) (35.67 +/- 4.78; P < 0.05) or control littermates (44.33 +/- 0.94; P < 0.01). CONCLUSION: Casp8-dependent migration of enterocytes is likely involved in intestinal physiology and inflammation-related pathophysiology. PMID- 25914456 TI - Herbal traditional Chinese medicine and its evidence base in gastrointestinal disorders. AB - Herbal traditional Chinese medicine (TCM) is used to treat several ailments, but its efficiency is poorly documented and hence debated, as opposed to modern medicine commonly providing effective therapies. The aim of this review article is to present a practical reference guide on the role of herbal TCM in managing gastrointestinal disorders, supported by systematic reviews and evidence based trials. A literature search using herbal TCM combined with terms for gastrointestinal disorders in PubMed and the Cochrane database identified publications of herbal TCM trials. Results were analyzed for study type, inclusion criteria, and outcome parameters. Quality of placebo controlled, randomized, double-blind clinical trials was poor, mostly neglecting stringent evidence based diagnostic and therapeutic criteria. Accordingly, appropriate Cochrane reviews and meta-analyses were limited and failed to support valid, clinically relevant evidence based efficiency of herbal TCM in gastrointestinal diseases, including gastroesophageal reflux disease, gastric or duodenal ulcer, dyspepsia, irritable bowel syndrome, ulcerative colitis, and Crohn's disease. In conclusion, the use of herbal TCM to treat various diseases has an interesting philosophical background with a long history, but it received increasing skepticism due to the lack of evidence based efficiency as shown by high quality trials; this has now been summarized for gastrointestinal disorders, with TCM not recommended for most gastrointestinal diseases. Future studies should focus on placebo controlled, randomized, double-blind clinical trials, herbal product quality and standard criteria for diagnosis, treatment, outcome, and assessment of adverse herb reactions. This approach will provide figures of risk/benefit profiles that hopefully are positive for at least some treatment modalities of herbal TCM. Proponents of modern herbal TCM best face these promising challenges of pragmatic modern medicine by bridging the gap between the two medicinal cultures. PMID- 25914459 TI - Contrast-enhanced ultrasound for quantitative assessment of portal pressure in canine liver fibrosis. AB - AIM: To explore the feasibility of non-invasive quantitative estimation of portal venous pressure by contrast-enhanced ultrasound (CEUS) in a canine model. METHODS: Liver fibrosis was established in adult canines (Beagles; n = 14) by subcutaneous injection of carbon tetrachloride (CCl4). CEUS parameters, including the area under the time-intensity curve and intensity at portal/arterial phases (Qp/Qa and Ip/Ia, respectively), were used to quantitatively assess the blood flow ratio of the portal vein/hepatic artery at multiple time points. The free portal venous pressures (FPP) were measured by a multi-channel baroreceptor using a percutaneous approach at baseline and 8, 16, and 24 wk after CCl4 injections in each canine. Liver biopsies were obtained at the end of 8, 16, and 24 wk from each animal, and the stage of the fibrosis was assessed according to the Metavir scoring system. A Pearson correlation test was performed to compare the FPP with Qp/Qa and Ip/Ia. RESULTS: Pathologic examination of 42 biopsies from the 14 canines at weeks 8, 16, and 24 revealed that liver fibrosis was induced by CCl4 and represented various stages of liver fibrosis, including F0 (n = 3), F1 (n = 12), F2 (n = 14), F3 (n = 11), and F4 (n = 2). There were significant differences in the measurements of Qp/Qa (19.85 +/- 3.30 vs 10.43 +/- 1.21, 9.63 +/- 1.03, and 8.77 +/- 0.96) and Ip/Ia (1.77 +/- 0.37 vs 1.03 +/- 0.12, 0.83 +/- 0.10, and 0.69 +/- 0.13) between control and canine fibrosis at 8, 16, and 24 wk, respectively (all P < 0.001). There were statistically significant negative correlations between FPP and Qp/Qa (r = -0.707, P < 0.001), and between FPP and Ip/Ia (r = -0.759, P < 0.001) in the canine fibrosis model. Prediction of elevated FPP based on Qp/Qa and Ip/Ia was highly sensitive, as assessed by the area under the receiver operating curve (0.866 and 0.895, respectively). CONCLUSION: CEUS is a potential method to accurately, but non-invasively, estimate portal venous pressure through measurement of Qp/Qa and Ip/Ia parameters. PMID- 25914460 TI - MicroRNA-185-5p mediates regulation of SREBP2 expression by hepatitis C virus core protein. AB - AIM: To investigate the molecular mechanism for regulation of cholesterol metabolism by hepatitis C virus (HCV) core protein in HepG2 cells. METHODS: HCV genotype 1b core protein was cloned and expressed in HepG2 cells. The cholesterol content was determined after transfection. The expression of sterol regulatory element binding protein 2 (SREBP2) and the rate-limiting enzyme in cholesterol synthesis (HMGCR) was measured by quantitative real-time PCR and immunoblotting after transfection. The effects of core protein on the SREBP2 promoter and 3' untranslated region were analyzed by luciferase assay. We used different target predictive algorithms, microRNA (miRNA) mimics/inhibitors, and site-directed mutation to identify a putative target of a particular miRNA. RESULTS: HCV core protein expression in HepG2 cells increased the total intracellular cholesterol level (4.05 +/- 0.17 vs 6.47 +/- 0.68, P = 0.001), and this increase corresponded to an increase in SREBP2 and HMGCR mRNA levels (P = 0.009 and 0.037, respectively) and protein expression. The molecular mechanism study revealed that the HCV core protein increased the expression of SREBP2 by enhancing its promoter activity (P = 0.004). In addition, miR-185-5p expression was tightly regulated by the HCV core protein (P = 0.041). Moreover, overexpression of miR-185-5p repressed the SREBP2 mRNA level (P = 0.022) and protein expression. In contrast, inhibition of miR-185-5p caused upregulation of SREBP2 protein expression. miR 185-5p was involved in the regulation of SREBP2 expression by HCV core protein. CONCLUSION: HCV core protein disturbs the cholesterol homeostasis in HepG2 cells via the SREBP2 pathway; miR-185-5p is involved in the regulation of SREBP2 by the core protein. PMID- 25914461 TI - Growth inhibition and apoptosis induction by alternol in pancreatic carcinoma cells. AB - AIM: To investigate the effect of alternol on pancreatic cancer cells. METHODS: Pancreatic cancer cells PANC-1 and BxPC3 were treated with various concentrations of alternol for 24, 48 and 72 h. Cell proliferation was measured by cell counting. Cell cycle distribution and mitochondrial membrane potential were determined by flow cytometry. Apoptosis was determined by a TdT-mediated dUTP nick end labeling assay and Hoechst staining. Expression of caspase 3, Bcl-2, p53 and p21 was measured by western blotting. RESULTS: Alternol showed dose- and time dependent inhibition of the proliferation of PANC-1 and BxPC3 cells in vitro. Alternol induced apoptosis and cell cycle arrest at S phase and decreased mitochondrial membrane potential. Alternol activated caspase 3, upregulated p53 and p21 expression, and downregulated Bcl-2 expression in a dose-dependent manner. CONCLUSION: Our results suggested that alternol is a candidate for treatment of pancreatic cancer. PMID- 25914462 TI - Tong Xie Yao Fang relieves irritable bowel syndrome in rats via mechanisms involving regulation of 5-hydroxytryptamine and substance P. AB - AIM: To investigate whether the Chinese medicine Tong Xie Yao Fang (TXYF) improves dysfunction in an irritable bowel syndrome (IBS) rat model. METHODS: Thirty baby rats for IBS modeling were separated from mother rats (1 h per day) from days 8 to 21, and the rectum was expanded by angioplasty from days 8 to 12. Ten normal rats were used as normal controls. We examined the effects of TXYF on defection frequency, colonic transit function and smooth muscle contraction, and the expression of 5-hydroxytryptamine (5-HT) and substance P (SP) in colonic and hypothalamus tissues by Western blot and RT-PCT techniques in both normal rats and IBS model rats with characterized visceral hypersensitivity. RESULTS: Defecation frequency was 1.8 +/- 1.03 in normal rats and 4.5 +/- 1.58 in IBS model rats (P < 0.001). However, the defecation frequency was significantly decreased (3.0 +/- 1.25 vs 4.5 +/- 1.58, P < 0.05), while the time (in seconds) of colon transit function was significantly increased (256.88 +/- 20.32 vs 93.36 +/- 17.28, P < 0.001) in IBS + TXYF group rats than in IBS group rats. Increased colonic smooth muscle tension and contract frequency in IBS model rats were significantly decreased by administration of TXYF. Exogenous agonist stimulants increased spontaneous activity and elicited contractions of colon smooth muscle in IBS model rats, and all of these actions were significantly reduced by TXYF involving 5-HT and SP down-regulation. CONCLUSION: TXYF can modulate the activity of the enteric nervous system and alter 5-HT and SP activities, which may contribute to the symptoms of IBS. PMID- 25914463 TI - Down-regulation of aquaporin3 expression by lipopolysaccharide via p38/c-Jun N terminal kinase signalling pathway in HT-29 human colon epithelial cells. AB - AIM: To investigate the influence of lipopolysaccharide (LPS) through the p38/c Jun N-terminal kinase (JNK) signalling pathway on aquaporin 3 (AQP3) expression in HT-29 human colon epithelial cells. METHODS: HT-29 cells were treated with LPS, and then the membrane localisation of AQP3 was examined by immunofluorescence staining. The mRNA and protein expression of AQP3 with LPS exposure was measured by real-time reverse transcription-PCR and Western blot, respectively. Activation of p38 and JNK was evaluated by detection of phosphorylation of p38 and JNK using Western blot assay. AQP3 protein expression was determined by Western blot in cells after treatment with SB203580, a selective p38 MAPK inhibitor, or SP600125, a selective JNK inhibitor. RESULTS: In HT-29 cells, the transcription and protein expression of AQP3 were decreased by LPS in a dose- and time-dependent manner, the expression of AQP3 was significantly decreased with the increased concentration of LPS, and at a dose of 100 MUg/mL LPS, AQP3 mRNA and protein levels were decreased by a maximum (P < 0.05) of 1.51-fold and 1.49-fold, respectively. When cells were treated with 100 MUg/mL LPS for 0, 3, 6, 12, and 24 h, the AQP3 mRNA level was significantly decreased at an early time point of 3 h, and reached about 10% of the control level at 24 h post-treatment (P < 0.05). Down-regulation of AQP3 expression was significantly inhibited by the p38 inhibitor (SB203580) and JNK inhibitor (SP600125). CONCLUSION: p38 and JNK may be promising targets for the preservation of AQP3 expression and may be beneficial to the clinical management of diarrhoea. PMID- 25914464 TI - H2S mitigates severe acute pancreatitis through the PI3K/AKT-NF-kappaB pathway in vivo. AB - AIM: To study the effect of hydrogen sulfide (H2S) on severe acute pancreatitis (SAP) in a rat model. METHODS: Sprague-Dawley (SD) rats were administered an intraperitoneal injection of saline containing 20% L-Arg (250 mg/100 g) hourly for over 2 h to induce SAP. The rats were treated with DL-propargylglycine (PAG, 50 mg/kg) or different dosages of NaHS (5 mg/kg, 10 mg/kg, 20 mg/kg or 100 mg/kg). PAG or NaHS was administered 1 h before induction of pancreatitis. Rats were sacrificed 24 h after the last L-Arg injection. Blood and pancreas tissues were collected. RESULTS: The H2S and cystathionine-gamma-lyase mRNA levels in SAP rats were significantly lower than those in the control group, and treatment with PAG further reduced the H2S level. Nevertheless, H2S was significantly increased after NaHS administration compared with the SAP group, and the degree of upregulation was associated with the NaHS dosage. NaHS reduced the levels of plasma amylase, interleukin-6 and myeloperoxidase in pancreatic tissue. NaHS suppressed the degradation of IkappaBalpha and the activity of nuclear factor kappaB, as well as the phosphorylation of PI3K/AKT. CONCLUSION: H2S plays an anti inflammatory role in SAP in vivo. PMID- 25914465 TI - MiR-19a promotes epithelial-mesenchymal transition through PI3K/AKT pathway in gastric cancer. AB - AIM: To investigate the mechanism by which miR-19a is up-regulated in gastric cancer (GC), which plays an oncogenic role. METHODS: In the present study, we investigated the role of miR-19a in gastric tissues as well as two GC cell lines. In vivo, we detected the basal expression level of miR-19a using real-time reverse transcription-PCR (RT-PCR), and the relevance between expression of miR 19a and clinicopathological information was analyzed. In vitro, miR-19a was ectopically expressed using overexpression and knock-down strategies. RESULTS: Overexpression of miR-19a was significantly associated with metastasis of GC and inferior overall prognosis. However, no significant correlation was found between miR-19a expression and other characteristics such as age, gender, tobacco, alcohol or tumor size. Cell proliferation, migration and invasion assays showed that overexpression of miR-19a promoted the proliferation, migration and invasion, and that overexpression of miR-19a promoted the epithelial-mesenchymal transition through activating the PI3K/AKT pathway. Blocking the PI3K/AKT pathway could cancel the effect of miR-19a. CONCLUSION: All together, our results suggest that miR-19a could be used as a promising therapeutic target in the treatment of GC. PMID- 25914466 TI - Predisposing factors for positive D-Xylose breath test for evaluation of small intestinal bacterial overgrowth: a retrospective study of 932 patients. AB - AIM: To investigate, in the largest cohort to date, patient characteristics and associated risk factors for developing small intestinal bacterial overgrowth (SIBO) using the D-Xylose breath test (XBT). METHODS: We performed a retrospective cross-sectional study to analyze patient characteristics who underwent the XBT for evaluation of SIBO. Diagnostic testing with the XBT was performed based on a clinical suspicion for SIBO in patients with symptoms of bloating, abdominal pain, abdominal distension, weight loss, diarrhea, and/or constipation. Consecutive electronic medical records of 932 patients who completed the XBT at the University of Florida between 2005 and 2009 were reviewed. A two-way Analysis of Variance (ANOVA) was used to test for several associations including age, gender, and body mass index (BMI) with a +XBT. A two way ANOVA was also performed to control for the differences and interaction with age and between genders. A similar analysis was repeated for BMI. Associations between medical conditions and prior surgical histories were conducted using the Mantel-Haenszel method for 2 by 2 contingency tables, stratified for gender. Reported odds ratio estimates reflect the odds of the prevalence of a condition within the +XBT group to that of the -XBT group. P values of less than 0.05 (two sided) were considered statistically significant. RESULTS: In the 932 consecutive eligible subjects studied, 513 had a positive XBT. A positive association was found between female gender and a positive XBT (P = 0.0025), and females with a positive test were, on average, greater than 5 years older than those with a negative test (P = 0.024). The mean BMI of positive XBT subjects was normal (24.5) and significantly lower than the subjects with a negative XBT (29.5) (P = 0.0050). A positive XBT was associated with gastroesophageal reflux disease (GERD) (OR = 1.35; 95%CI: 1.02-1.80, P = 0.04), peptic ulcer disease (PUD) (OR = 2.61; 95%CI: 1.48-4.59, P < 0.01), gastroparesis (GP) (OR = 2.04; 95%CI: 1.21 3.41, P < 0.01) and steroid use (OR = 1.35; 95%CI: 1.02-1.80, P = 0.01). Irritable bowel syndrome, independent proton-pump inhibitor (PPI) usage, or previous abdominal surgery was not significantly associated with a positive XBT. No single subdivision by gender or PPI use was associated with a significant difference in the odds ratios between any of the subsets. CONCLUSION: Female gender, lower BMI, steroid use, PUD, GERD (independent of PPI use), and GP were more prevalent in patients with SIBO, determined by a positive XBT. Increasing age was associated with SIBO in females, but not in males. PMID- 25914467 TI - Factors predicting aggressiveness of non-hypervascular hepatic nodules detected on hepatobiliary phase of gadolinium ethoxybenzyl diethylene-triamine-pentaacetic acid magnetic resonance imaging. AB - AIM: To establish a prognostic formula that distinguishes non-hypervascular hepatic nodules (NHNs) with higher aggressiveness from less hazardous one. METHODS: Seventy-three NHNs were detected in gadolinium ethoxybenzyl diethylene triamine-pentaacetic-acid magnetic resonance imaging (Gd-EOB-DTPA-MRI) study and confirmed to change 2 mm or more in size and/or to gain hypervascularity. All images were interpreted independently by an experienced, board-certified abdominal radiologist and hepatologist; both knew that the patients were at risk for hepatocellular carcinoma development but were blinded to the clinical information. A formula predicting NHN destiny was developed using a generalized estimating equation model with thirteen explanatory variables: age, gender, background liver diseases, Child-Pugh class, NHN diameter, T1-weighted imaging/T2 weighted imaging detectability, fat deposition, lower signal intensity in arterial phase, lower signal intensity in equilibrium phase, alpha-fetoprotein, des-gamma-carboxy prothrombin, alpha-fetoprotein-L3, and coexistence of classical hepatocellular carcinoma. The accuracy of the formula was validated in bootstrap samples that were created by resampling of 1000 iterations. RESULTS: During a median follow-up period of 504 d, 73 NHNs with a median diameter of 9 mm (interquartile range: 8-12 mm) grew or shrank by 68.5% (fifty nodules) or 20.5% (fifteen nodules), respectively, whereas hypervascularity developed in 38.4% (twenty eight nodules). In the fifteen shrank nodules, twelve nodules disappeared, while 11.0% (eight nodules) were stable in size but acquired vascularity. A generalized estimating equation analysis selected five explanatories from the thirteen variables as significant factors to predict NHN progression. The estimated regression coefficients were 0.36 for age, 6.51 for lower signal intensity in arterial phase, 8.70 or 6.03 for positivity of hepatitis B virus or hepatitis C virus, 9.37 for des-gamma-carboxy prothrombin, and -4.05 for fat deposition. A formula incorporating the five coefficients revealed sensitivity, specificity, and accuracy of 88.0%, 86.7%, and 87.7% in the formulating cohort, whereas these of 87.2% +/- 5.7%, 83.8% +/- 13.6%, and 87.3% +/- 4.5% in the bootstrap samples. CONCLUSION: These data suggest that the formula helps Gd-EOB-DTPA-MRI detect a trend toward hepatocyte transformation by predicting NHN destiny. PMID- 25914468 TI - Individual having a parent with early-onset gastric cancer may need screening at younger age. AB - AIM: To evaluate whether individuals with gastric cancer (GC) are diagnosed earlier if they have first-degree relatives with GC. METHODS: A total of 4282 patients diagnosed with GC at National Cancer Center Hospital from 2002 to 2012 were enrolled in this retrospective study. We classified the patients according to presence or absence of first-degree family history of GC and compared age at diagnosis and clinicopathologic characteristics. In addition, we further classified patients according to specific family member with GC (father, mother, sibling, or offspring) and compared age at GC diagnosis among these patient groups. Baseline characteristics were obtained from a prospectively collected database. Information about the family member's age at GC diagnosis was obtained by questionnaire. RESULTS: A total of 924 patients (21.6%) had a first-degree family history of GC. The mean age at GC diagnosis in patients having paternal history of GC was 54.4 +/- 10.4 years and was significantly younger than in those without a first-degree family history (58.1 +/- 12.0 years, P < 0.001). However, this finding was not observed in patients who had an affected mother (57.2 +/- 10.0 years) or sibling (62.2 +/- 9.8 years). Among patients with family member having early-onset GC (< 50 years old), mean age at diagnosis was 47.7 +/- 10.3 years for those with an affected father, 48.6 +/- 10.4 years for those with an affected mother, and 57.4 +/- 11.5 years for those with an affected sibling. Thus, patients with a parent diagnosed before 50 years of age developed GC 10.4 or 9.5 years earlier than individuals without a family history of GC (both P < 0.001). CONCLUSION: Early-onset GC before age of 50 was associated with parental history of early-onset of GC. Individual having such family history need to start screening earlier. PMID- 25914469 TI - Influence of proton pump inhibitors on gastritis diagnosis and pathologic gastric changes. AB - AIM: To investigate the influence of proton pump inhibitors (PPIs) exposure on the diagnosis of Helicobacter pylori (H. pylori) gastritis and intestinal metaplasia. METHODS: Chronic PPI use is associated with masking of H. pylori infection. Patients with H. pylori infection are predisposed to gastric and duodenal ulcers, and long-term infection with this organism has been associated with gastric mucosal atrophy and serious long-term complications, such as gastric lymphoma and adenocarcinoma. Three hundred patients diagnosed with gastritis between January 2008 and April 2010 were included in our study. The computerized medical database of these patients was reviewed retrospectively in order to assess whether the type of gastritis diagnosed (H. pylori vs non-H. pylori gastritis) is influenced by PPI exposure. H. pylori density was graded as low, if corresponding to mild density following the Updated Sydney System, or high, if corresponding to moderate or severe densities in the Updated Sydney System. RESULTS: Patients were equally distributed between males and females with a median age at the time of diagnosis of 50 years old (range: 20-87). The histological types of gastritis were classified as H. pylori gastritis (n = 156, 52%) and non-H. pylori gastritis (n = 144, 48%). All patients with non-H. pylori gastritis had inactive chronic gastritis. Patients with no previous PPI exposure were more likely to be diagnosed with H. pylori gastritis than those with previous PPI exposure (71% vs 34.2%, P < 0.001). Intestinal metaplasia was more likely to be detected in the latter patients (1.4% vs 6.5%, P = 0.023). Multivariate analysis has also demonstrated that in the presence of previous PPI exposure (OR = 0.217, 95%CI: 0.123-0.385), GERD (OR = 0.317, 95%CI: 0.132-0.763, P = 0.01), alcohol intake (OR = 0.396, 95%CI: 0.195-0.804, P = 0.01), the detection of H. pylori was less likely. Chronic use of PPIs may mask H. pylori infections promoting the diagnosis of non-H. pylori gastritis and leads to a significant drop in H. pylori densities and to an increased risk of intestinal metaplasia. CONCLUSION: The use of PPIs masks H. pylori infection, promotes the diagnosis of non-H. pylori inactive chronic gastritis diagnosis, and increases the incidence of intestinal metaplasia. PMID- 25914470 TI - Three-dimensional morphometric analysis for hepatectomy of centrally located hepatocellular carcinoma: a pilot study. AB - AIM: To describe a three-dimensional model (3DM) to accurately reconstruct anatomic relationships of centrally located hepatocellular carcinomas (HCCs). METHODS: From March 2013 to July 2014, reconstructions and visual simulations of centrally located HCCs were performed in 39 patients using a 3D subject-based computed tomography (CT) model with custom-developed software. CT images were used for the 3D reconstruction of Couinaud's pedicles and hepatic veins, and the calculation of corresponding tumor territories and hepatic segments was performed using Yorktal DMIT software. The respective volume, surgical margin, and simulated virtual resection of tumors were also estimated by this model preoperatively. All patients were treated surgically and the results were retrospectively assessed. Clinical characteristics, imaging data, procedure variables, pathologic features, and postoperative data were recorded and compared to determine the reliability of the model. RESULTS: 3D reconstruction allowed stereoscopic identification of the spatial relationships between physiologic and pathologic structures, and offered quantifiable liver resection proposals based on individualized liver anatomy. The predicted values were consistent with the actual values for tumor mass volume (82.4 +/- 109.1 mL vs 84.1 +/- 108.9 mL, P = 0.910), surgical margin (10.1 +/- 6.2 mm vs 9.1 +/- 5.9 mm, P = 0.488), and maximum tumor diameter (4.61 +/- 2.16 cm vs 4.53 +/- 2.14 cm, P = 0.871). In addition, the number and extent of portal venous ramifications, as well as their relation to hepatic veins, were visualized. Preoperative planning based on simulated resection facilitated complete resection of large tumors located in the confluence of major vessels. And most of the predicted data were correlated with intraoperative findings. CONCLUSION: This 3DM provides quantitative morphometry of tumor masses and a stereo-relationship with adjacent structures, thus providing a promising technique for the management of centrally located HCCs. PMID- 25914471 TI - Surgical procedure determination based on tumor-node-metastasis staging of gallbladder cancer. AB - AIM: To investigate the impact of surgical procedures on prognosis of gallbladder cancer patients classified with the latest tumor-node-metastasis (TNM) staging system. METHODS: A retrospective study was performed by reviewing 152 patients with primary gallbladder carcinoma treated at Peking Union Medical College Hospital from January 2003 to June 2013. Postsurgical follow-up was performed by telephone and outpatient visits. Clinical records were reviewed and patients were grouped based on the new edition of TNM staging system (AJCC, seventh edition, 2010). Prognoses were analyzed and compared based on surgical operations including simple cholecystectomy, radical cholecystectomy (or extended radical cholecystectomy), and palliative surgery. Simple cholecystectomy is, by definition, resection of the gallbladder fossa. Radical cholecystectomy involves a wedge resection of the gallbladder fossa with 2 cm non-neoplastic liver tissue; resection of a suprapancreatic segment of the extrahepatic bile duct and extended portal lymph node dissection may also be considered based on the patient's circumstance. Palliative surgery refers to cholecystectomy with biliary drainage. Data analysis was performed with SPSS 19.0 software. Kaplan-Meier survival analysis and Logrank test were used for survival rate comparison. P < 0.05 was considered statistically significant. RESULTS: Patients were grouped based on the new 7(th) edition of TNM staging system, including 8 cases of stage 0, 10 cases of stage I, 25 cases of stage II, 21 cases of stage IIIA, 21 cases of stage IIIB, 24 cases of stage IVA, 43 cases of stage IVB. Simple cholecystectomy was performed on 28 cases, radical cholecystectomy or expanded gallbladder radical resection on 57 cases, and palliative resection on 28 cases. Thirty-nine cases were not operated. Patients with stages 0 and I disease demonstrated no statistical significant difference in survival time between those receiving radical cholecystectomy and simple cholecystectomy (P = 0.826). The prognosis of stage II patients with radical cholecystectomy was better than that of simple cholecystectomy. For stage III patients, radical cholecystectomy was significantly superior to other surgical options (P < 0.05). For stage IVA patients, radical cholecystectomy was not better than palliative resection and non-surgical treatment. For stage IVB, patients who underwent palliative resection significantly outlived those with non-surgical treatment (P < 0.01) CONCLUSION: For stages 0 and I patients, simple cholecystectomy is the optimal surgical procedure, while radical cholecystectomy should be actively operated for stages II and III patients. PMID- 25914472 TI - Adjuvant transarterial chemoembolization after curative resection of hepatocellular carcinoma: propensity score analysis. AB - AIM: To compare survival and recurrence in hepatocellular carcinoma (HCC) patients who did or did not receive adjuvant transarterial chemoembolization (TACE). METHODS: A consecutive sample of 229 patients who underwent curative resection between March 2007 and March 2010 in our hospital was included. Of these 229 patients, 91 (39.7%) underwent curative resection followed by adjuvant TACE and 138 (60.3%) underwent curative resection alone. In order to minimize confounds due to baseline differences between the two patient groups, comparisons were conducted between propensity score-matched patients. Survival data and recurrence rates were compared using the Kaplan-Meier method. Independent predictors of overall survival and recurrence were identified using Cox proportional hazard regression. RESULTS: Among 61 pairs of propensity score matched patients, the 1-, 2-, and 3-year overall survival rates were 95.1%, 86.7%, and 76.4% in the TACE group and 86.9%, 78.5%, and 73.2% in the control group, respectively. At the same time, the TACE and control groups also showed similar recurrence rates at 1 year (13.4% vs 24.8%), 2 years (30.6% vs 32.1%), and 3 years (40.1% vs 34.0%). Multivariate Cox regression identified serum alpha fetoprotein level >= 400 ng/mL and tumor size > 5 cm as independent risk factors of mortality (P < 0.05). CONCLUSION: As postoperative adjuvant TACE does not improve overall survival or reduce recurrence in HCC patients, further study is needed to clarify its clinical benefit. PMID- 25914473 TI - Comparison of hepatic resection and transarterial chemoembolization for solitary hepatocellular carcinoma. AB - AIM: To compare the outcomes of hepatic resection and transarterial chemoembolization (TACE) for solitary hepatocellular carcinoma (HCC) according to the Barcelona Clinic Liver Cancer (BCLC) staging system. METHODS: A consecutive sample of 540 patients with solitary HCC who underwent liver resection (n = 312) or TACE (n = 128) were included in the present study. Baseline characteristics, tumor characteristics, and post-operative complications were compared between the two groups. The Kaplan-Meier method was used for long-term survival analysis. Independent prognostic predictors were identified using the Cox proportional hazards model (univariate and multivariate analyses). RESULTS: The TACE and liver resection groups had similar baseline demographic and clinicopathological characteristics. The TACE group showed a significantly lower rate of major complications than the liver resection group (3.9% vs 17.4%, P < 0.001). Univariate and multivariate analyses indicated that TACE did not contribute to poor overall survival compared with liver resection; however, a solitary tumor diameter of greater than 6 cm should be considered a risk factor for poor overall survival (HR = 1.328, 95%CI: 1.002-1.783, P = 0.048). The liver resection and TACE groups had comparable overall survival rates at 1 year, 3 years, and 5 years (86.2%, 62.8%, and 44.0% vs 88.3%, 59.8%, and 40.6%, respectively, P = 0.419). In cases with tumor diameters equal to or less than 6 cm, the liver resection group showed a survival benefit compared with the TACE group at 1 year, 3 years, and 5 years (P = 0.030). The 1-, 3-, and 5-year overall survival rates of HCC cases with tumor diameters of more than 6 cm were similar among the liver resection and TACE groups (P = 0.467). CONCLUSION: A tumor diameter of 6 cm should be the cutoff for deciding between liver resection and TACE. PMID- 25914474 TI - Covalently closed-circular hepatitis B virus DNA reduction with entecavir or lamivudine. AB - AIM: To investigate the reduction in hepatitis B virus (HBV) covalently closed circular DNA (cccDNA) with entecavir (ETV) or lamivudine (LAM). METHODS: This analysis included patients who had participated in the randomized Phase III study ETV-022 comparing ETV vs LAM in nucleos(t)ide-naive, HBeAg-positive patients. Patients received ETV (0.5 mg daily) or LAM (100 mg daily) for a minimum of 52 wk. Patients were eligible to participate in this sub-study if they had paired biopsies at baseline and week 48 with evaluable measurements for hepatic HBV cccDNA and total hepatic HBV DNA. The main objective was to compare changes in hepatic HBV cccDNA and total hepatic HBV DNA at week 48 of ETV or LAM treatment, which was a secondary endpoint of study ETV-022. Additional post hoc analyses included linear regression analyses to assess associations of baseline levels and on-treatment changes of cccDNA with other baseline factors [sex, age, serum HBV DNA, alanine aminotransferase (ALT), Knodell necroinflammatory score, Ishak fibrosis score, total hepatic HBV DNA, and HBV genotype], or on-treatment factors (changes from baseline at week 48 in serum HBV DNA, ALT, Knodell necroinflammatory score, Ishak fibrosis score, total hepatic HBV DNA, and HBeAg loss at week 48). RESULTS: Overall, 305 patients (ETV = 159; LAM = 146) of ETV 022 had paired baseline and week 48 liver biopsies with evaluable measurements for hepatic HBV cccDNA and total hepatic HBV DNA, and were included in this analysis. Baseline demographics and disease characteristics were comparable between the two arms. After 48 wk, ETV resulted in significantly greater reductions in hepatic HBV cccDNA [-0.9 log10 copies/human genome equivalent (HGEq) vs -0.7 log10 copies/HGEq; P = 0.0033] and total hepatic DNA levels (-2.1 log10 copies/HGEq vs -1.6 log10 copies/HGEq; P < 0.0001) than LAM. Virologic, biochemical, and histologic response rates at week 48 were also greater with ETV than with LAM. Baseline HBV cccDNA levels were positively associated with baseline levels of serum HBV DNA and total hepatic HBV DNA, and negatively associated with HBV genotype F. On-treatment changes in HBV cccDNA levels were negatively associated with baseline levels of serum HBV DNA and baseline ALT, and were positively associated with on-treatment changes in the levels of serum HBV DNA, total hepatic HBV DNA levels, and ALT, change in Knodell necroinflammatory score, and HBeAg loss. CONCLUSION: Forty-eight weeks of ETV resulted in greater reductions in cccDNA and total hepatic HBV DNA than LAM, but long-term therapy may be needed for cccDNA elimination. PMID- 25914475 TI - Effect of clinician-patient communication on compliance with flupentixol melitracen in functional dyspepsia patients. AB - AIM: To explore whether clinician-patient communication affects adherence to psychoactive drugs in functional dyspepsia (FD) patients with psychological symptoms. METHODS: A total of 262 FD patients with psychological symptoms were randomly assigned to four groups. The patients in Groups 1-3 were given flupentixol-melitracen (FM) plus omeprazole treatment. Those in Group 1 received explanations of both the psychological and gastrointestinal (GI) mechanisms of the generation of FD symptoms and the effects of FM. In Group 2, only the psychological mechanisms were emphasized. The patients in Group 3 were not given an explanation for the prescription of FM. Those in Group 4 were given omeprazole alone. The primary endpoints of this study were compliance rate and compliance index to FM in Groups 1-3. Survival analyses were also conducted. The secondary end points were dyspepsia and psychological symptom improvement in Groups 1-4. The correlations between the compliance indices and the reductions in dyspepsia and psychological symptom scores were also evaluated in Groups 1-3. RESULTS: After 8 wk of treatment, the compliance rates were 67.7% in Group 1, 42.4% in Group 2 and 47.7% in Group 3 (Group 1 vs Group 2, P = 0.006; Group 1 vs Group 3, P = 0.033). The compliance index (Group 1 vs Group 2, P = 0.002; Group 1 vs Group 3, P = 0.024) with the FM regimen was significantly higher in Group 1 than in Groups 2 and 3. The survival analysis revealed that the patients in Group 1 exhibited a significantly higher compliance rate than Groups 2 and 3 (Group 1 vs Group 2, P = 0.002; Group 1 vs Group 3, P = 0.018). The improvement in dyspepsia (Group 1 vs Group 2, P < 0.05; Group 1 vs Group 3, P < 0.05; Group 1 vs Group 4, P < 0.01) and psychological symptom scores (anxiety: Group 1 vs Group 2, P < 0.01; Group 1 vs Group 3, P < 0.05; Group 1 vs Group 4, P < 0.01; depression: Group 1 vs Group 2, P < 0.01; Group 1 vs Group 3, P < 0.01; Group 1 vs Group 4, P < 0.01) in Group 1 were greater than those in Groups 2-4. The compliance indices were positively correlated with the reduction in symptom scores in Groups 1-3. CONCLUSION: Appropriate clinician-patient communication regarding the reasons for prescribing psychoactive drugs that emphasizes both the psychological and GI mechanisms might improve adherence to FM in patients with FD. PMID- 25914476 TI - Expression of circulating microRNA-20a and let-7a in esophageal squamous cell carcinoma. AB - AIM: To investigate the expressions of microRNA-20a (miR-20a) and let-7a in esophageal squamous cell carcinoma (ESCC) and their diagnostic value. METHODS: Seventy patients with ESCC and 40 healthy subjects were enrolled to investigate the expression of miR-20a and let-7a using quantitative real-time PCR. The expression of miR-20a and let-7a was compared between ESCC patients and healthy subjects. The plasma levels of miR-20a and let-7a in relation to patient clinicopathologic parameters, the receiver operating characteristic (ROC) curve, and the sensitivity and specificity of miR-20a and let-7a in ESCC diagnosis were analyzed. RESULTS: Plasma levels of miR-20a were significantly higher in ESCC patients than in healthy controls, and plasma levels of let-7 were lower in ESCC patients than in healthy controls (both P < 0.05). The area under the ROC curve of miR-20a was 0.767 (95%CI: 0.677-0.857; P < 0.001), when the cut-off value was set at 4.77, the sensitivity and specificity were 64.3% and 75.0%, respectively. The area under the ROC curve of let-7a was 0.829 (95%CI: 0.754-0.904; P < 0.001), when the cut-off value was set at 6.22, the sensitivity and specificity were 74.3% and 85.0%, respectively. Thus, the sensitivity and specificity of let-7a were higher than those of miR-20a. The median relative plasma expression of let 7a in clinical stage III/IV (0.24) was lower than that in stage I/II (0.42), while the expression of miR-20a according to stage was not statistically different. The expressions of miR-20a and let-7a were not related to gender, age, tumor diameter, tumor grade, or pathologic stage. CONCLUSION: Plasma miR-20a and let-7a levels are significantly altered in patients with ESCC and can be used as potential biomarkers in the diagnosis of ESCC. PMID- 25914477 TI - Epstein-Barr virus is related with 5-aminosalicylic acid, tonsillectomy, and CD19(+) cells in Crohn's disease. AB - AIM: To study anti-Epstein-Barr virus (EBV) IgG antibodies in Crohn's disease in relation to treatment, immune cells, and prior tonsillectomy/appendectomy. METHODS: This study included 36 CD patients and 36 healthy individuals (controls), and evaluated different clinical scenarios (new patient, remission and active disease), previous mucosa-associated lymphoid tissue removal (tonsillectomy and appendectomy) and therapeutic regimens (5-aminosalicylic acid, azathioprine, anti-tumor necrosis factor, antibiotics, and corticosteroids). T and B cells subsets in peripheral blood were analyzed by flow cytometry (markers included: CD45, CD4, CD8, CD3, CD19, CD56, CD2, CD3, TCRalphabeta and TCRgammadelta) to relate with the levels of anti-EBV IgG antibodies, determined by enzyme-linked immunosorbent assay. RESULTS: The lowest anti-EBV IgG levels were observed in the group of patients that were not in a specific treatment (95.4 +/- 53.9 U/mL vs 131.5 +/- 46.2 U/mL, P = 0.038). The patients that were treated with 5-aminosalicylic acid showed the highest anti-EBV IgG values (144.3 U/mL vs 102.6 U/mL, P = 0.045). CD19(+) cells had the largest decrease in the group of CD patients that received treatment (138.6 vs 223.9, P = 0.022). The analysis of anti-EBV IgG with respect to the presence or absence of tonsillectomy showed the highest values in the tonsillectomy group of CD patients (169.2 +/- 20.7 U/mL vs 106.1 +/- 50.3 U/mL, P = 0.002). However, in the group of healthy controls, no differences were seen between those who had been tonsillectomized and subjects who had not been operated on (134.0 +/- 52.5 U/mL vs 127.7 +/- 48.1 U/mL, P = 0.523). CONCLUSION: High anti-EBV IgG levels in CD are associated with 5-aminosalicylic acid treatment, tonsillectomy, and decrease of CD19(+) cells. PMID- 25914478 TI - Discrepancies in the histologic type between biopsy and resected specimens: a cautionary note for mixed-type gastric carcinoma. AB - AIM: To evaluate discrepancies between biopsy and resected specimens using the Japanese Classification of Gastric Carcinoma (JCGC) and tumor-node-metastasis (TNM) classification. METHODS: A total of 376 consecutive paired samples from biopsy and resected gastric specimens, which were derived from curative gastrectomy for gastric cancer between 2008 and 2011, were retrospectively analyzed. RESULTS: (1) Discrepancies in the histologic type were observed between biopsy and resected specimens; 11.7% (44/376) in the JCGC and 18.1% (68/376) in TNM. In specimens diagnosed as the differentiated type from biopsy specimens, 14.4% (28/195) in the JCGC and 41.1% (67/163) in TNM were finally diagnosed as the undifferentiated type from resected specimens; and (2) the incidence of mixed type gastric cancer was significantly higher in specimens with discrepancies than in those without in both the JCGC and TNM (both P < 0.0001); 93.2% (41/44) of specimens with discrepancies in the JCGC and 97.1% (66/68) of specimens with discrepancies in TNM were mixed-type gastric cancers. CONCLUSION: Mixed-type gastric cancer was associated with a high incidence of histologic discrepancies between biopsy and resected specimens in both the JCGC and TNM definitions. Care should be taken in deciding treatments based on diagnosis of the histologic type for mixed-type gastric cancer from biopsy specimens. PMID- 25914479 TI - Human epidermal growth factor receptor 2 expression in mixed gastric carcinoma. AB - AIM: To investigate human epidermal growth factor receptor 2 (HER2) amplification and protein expression in mixed gastric carcinoma. METHODS: Fluorescence in situ hybridization and immunohistochemistry were used to detect HER2 amplification and protein expression in 277 cases of mixed gastric carcinoma. Protein staining intensity was rate as 1+, 2+, or 3+. RESULTS: Of the 277 cases, 114 (41.2%) expressed HER2 protein. HER2 3+ staining was observed in 28/277 (10.1%) cases, 2+ in 37/277 (13.4%) cases, and 1+ in 49/277 (17.7%) cases. A HER2 amplification rate of 17% was detected, of which 25/28 (89.3%) were observed in the HER2 3+ staining group, 17/37 (45.9%) in 2+, and 5/49 (10.2%) in 1+. Of the 47 patients with HER2 amplification who received chemotherapy plus trastuzumab, 22 demonstrated median progression-free and overall survivals of 9.1 mo and 16.7 mo, respectively, which were significantly better than those achieved with chemotherapy alone (5.6 mo and 12.1 mo, respectively) in 19 previously treated patients (Ps < 0.05). CONCLUSION: HER2 detection in mixed gastric carcinoma displays high heterogeneity. Relatively quantitative parameters are needed for assessing the level of HER2 amplification and protein expression. PMID- 25914480 TI - Pancreatic fat and beta-cell function in overweight/obese children with nonalcoholic fatty liver disease. AB - AIM: To analyze the associations of pancreatic fat with other fat depots and beta cell function in pediatric nonalcoholic fatty liver disease (NAFLD). METHODS: We examined 158 overweight/obese children and adolescents, 80 with NAFLD [hepatic fat fraction (HFF) >= 5%] and 78 without fatty liver. Visceral adipose tissue (VAT), pancreatic fat fraction (PFF) and HFF were determined by magnetic resonance imaging. Estimates of insulin sensitivity were calculated using the homeostasis model assessment of insulin resistance (HOMA-IR), defined by fasting insulin and fasting glucose and whole-body insulin sensitivity index (WBISI), based on mean values of insulin and glucose obtained from oral glucose tolerance test and the corresponding fasting values. Patients were considered to have prediabetes if they had either: (1) impaired fasting glucose, defined as a fasting glucose level >= 100 mg/dL to < 126 mg/dL; (2) impaired glucose tolerance, defined as a 2 h glucose concentration between >= 140 mg/dL and < 200 mg/dL; or (3) hemoglobin A1c value of >= 5.7% to < 6.5%. RESULTS: PFF was significantly higher in NAFLD patients compared with subjects without liver involvement. PFF was significantly associated with HFF and VAT, as well as fasting insulin, C peptide, HOMA-IR, and WBISI. The association between PFF and HFF was no longer significant after adjusting for age, gender, Tanner stage, body mass index (BMI)-SD score, and VAT. In multiple regression analysis with WBISI or HOMA-IR as the dependent variables, against the covariates age, gender, Tanner stage, BMI-SD score, VAT, PFF, and HFF, the only variable significantly associated with WBISI (standardized coefficient B, -0.398; P = 0.001) as well as HOMA-IR (0.353; P = 0.003) was HFF. Children with prediabetes had higher PFF and HFF than those without. PFF and HFF were significantly associated with prediabetes after adjustment for clinical variables. When all fat depots where included in the same model, only HFF remained significantly associated with prediabetes (OR = 3.38; 95%CI: 1.10-10.4; P = 0.034). CONCLUSION: In overweight/obese children with NAFLD, pancreatic fat is increased compared with those without liver involvement. However, only liver fat is independently related to prediabetes. PMID- 25914481 TI - Direct-acting antiviral-based triple therapy on alpha-fetoprotein level in chronic hepatitis C patients. AB - AIM: To investigate the impact of telaprevir-based triple therapy on the serum alpha-fetoprotein (AFP) level of chronic hepatitis C patients. METHODS: A total of 210 patients with chronic hepatitis C genotype 1 of high viral load (baseline serum hepatitis C virus RNA > 5.0 log10 IU/mL) were divided into two groups by type of treatment: triple therapy with telaprevir, pegylated-interferon-alpha (PEG-IFNalpha), and ribavirin (RBV) for 24 wk (n = 88), or dual therapy with PEG IFNalpha and RBV for 48 wk (n = 122). The relationship between virological response and the change in the serum AFP level from baseline to 24 wk after the end of treatment was examined. RESULTS: No significant difference in mean baseline AFP level was found between the triple and dual therapy groups (8.8 ng/mL vs 7.8 ng/mL). Triple therapy produced significant declines in the AFP level in sustained virological response (SVR) and non-SVR patients (7.8 ng/mL at baseline to 3.5 ng/mL at 24 wk after the end of treatment, P < 0.001 and 14.3 ng/mL to 9.5 ng/mL, P = 0.004, respectively). In contrast, dual therapy resulted in a significant decline in AFP level only in SVR patients (4.7 ng/mL to 2.8 ng/mL, P < 0.001), but not in non-SVR patients (10.2 ng/mL to 10.1 ng/mL). Among patients with a high-baseline AFP level (>= 10 ng/mL), the decline in the AFP level was significantly higher in the triple therapy than in the dual therapy group (15.9 ng/mL vs 1.6 ng/mL, P = 0.037). CONCLUSION: Regardless of virological response, telaprevir-based triple therapy reduced the serum AFP level. PMID- 25914482 TI - Visual distraction alone for the improvement of colonoscopy-related pain and satisfaction. AB - AIM: To evaluate the effect of a relaxing visual distraction alone on patient pain, anxiety, and satisfaction during colonoscopy. METHODS: This study was designed as an endoscopist-blinded randomized controlled trial with 60 consecutively enrolled patients who underwent elective colonoscopy at Yokohama City University Hospital, Japan. Patients were randomly assigned to two groups: group 1 watched a silent movie using a head-mounted display, while group 2 only wore the display. All of the colonoscopies were performed without sedation. We examined pain, anxiety, and the satisfaction of patients before and after the procedure using questionnaires that included the Visual Analog Scale. Patients were also asked whether they would be willing to use the same method for a repeat procedure. RESULTS: A total of 60 patients were allocated to two groups. Two patients assigned to group 1 and one patient assigned to group 2 were excluded after the randomization. Twenty-eight patients in group 1 and 29 patients in group 2 were entered into the final analysis. The groups were similar in terms of gender, age, history of prior colonoscopy, and pre-procedural anxiety score. The two groups were comparable in terms of the cecal insertion rate, the time to reach the cecum, the time needed for the total procedure, and vital signs. The median anxiety score during the colonoscopy did not differ significantly between the two groups (median scores, 20 vs 24). The median pain score during the procedure was lower in group 1, but the difference was not significant (median scores, 24.5 vs 42). The patients in group 1 reported significantly higher median post-procedural satisfaction levels, compared with the patients in group 2 (median scores, 89 vs 72, P = 0.04). Nearly three-quarters of the patients in group 1 wished to use the same method for repeat procedures, and the difference in rates between the two groups was statistically significant (75.0% vs 48.3%, P = 0.04). Patients with greater levels of anxiety before the procedure tended to feel a painful sensation. Among patients with a pre-procedural anxiety score of 50 or higher, the anxiety score during the procedure was significantly lower in the group that received the visual distraction (median scores, 20 vs 68, P = 0.05); the pain score during the colonoscopy was also lower (median scores, 23 vs 57, P = 0.04). No adverse effects arising from the visual distraction were recognized. CONCLUSION: Visual distraction alone improves satisfaction in patients undergoing colonoscopy and decreases anxiety and pain during the procedure among patients with a high pre-procedural anxiety score. PMID- 25914483 TI - Antimicrobial prophylaxis in patients with colorectal lesions undergoing endoscopic resection. AB - AIM: To investigate the effect of prophylaxis with antibiotics on clinical adverse events in patients who underwent endoscopic submucosal dissection (ESD) or endoscopic mucosal resection (EMR) for colorectal lesions. METHODS: From June 2011 to December 2013, a total of 428 patients were enrolled into the study, of which 214 patients admitted to hospital underwent EMR or ESD procedures. These patients were randomized to an antibiotic group, in which patients were given cefuroxime 1.5 g iv half an hour before and 6 h after surgery respectively, and a control group, in which patients were not given any antibiotic. A further 214 outpatients with small polyps treated by polypectomy were compared with controls that were matched by age and gender, and operations were performed as outpatient surgery. Recorded patient parameters were demographics, characteristics of lesions and treatment modality, and the size of the wound area. The primary outcome measures were clinical adverse events, including abdominal pain, diarrhea, hemotachezia, and fever. Secondary outcome measures were white blood cell count, C-reactive protein and blood culture. Additionlly, the relationship between the size of the wound area and clinical adverse events was analyzed. RESULTS: A total of 409 patients were enrolled in this study, with 107 patients in the control group, 107 patients in the antibiotic group, and another 195 cases in the follow-up outpatient group. The patients' demographic characteristics, including age, gender, characteristics of lesions, treatment modality, and the size of the wound area were similar between the 2 groups. The rates of adverse events in the antibiotic group were significantly lower than in the control group: abdominal pain (2.8% vs 14.9%, P < 0.01), diarrhea (2.0% vs 9.3%, P < 0.05), and fever (0.9% vs 8.4%, P < 0.05) respectively. The levels of inflammatory markers also decreased significantly in the antibiotic group compared with the control group: leukocytosis (2.0% vs 11.2%, P < 0.01), and C reactive protein (2.0% vs 10.7%, P < 0.05). Additionally, clinical adverse events were related to the size of the surgical wound area. When the surgical wound area was larger than 10 mm * 10 mm, there were more clinical adverse events. CONCLUSION: Clinical adverse events are not uncommon after EMR or ESD procedures. Prophylactic antibiotics can reduce the incidence of clinical adverse events. This should be further explored. PMID- 25914485 TI - Clinical literature review of 1858 Crohn's disease cases requiring surgery in China. AB - AIM: To summarize the clinical characteristics of Crohn's disease (CD) patients who underwent surgery in China. METHODS: We searched four main Chinese electronic databases: CBM, VIP, CNKI, and Wanfang (from January 1990 to October 2013). Then, we selected and carefully read 97 studies and extracted the surgical data for CD. We found that 1858 patients with CD underwent surgery between 1961 and 2012. The patients were stratified into two groups according to the year of surgery: 1961 2000 and 2000-2012. The clinical characteristics of these CD cases were compared between the two groups. RESULTS: The mean age at the time of surgery was 38.13 years. The most common locations of disease were the small intestine (40.84%), the colon (33.60%) and the ileocolon (23.09%). The primary indications for surgery were intestinal obstruction or stricture (23.84%), failure of drug therapy (14.80%), acute abdominal disease (13.46%), abdominal mass (10.93%), intestinal fistulae (9.90%), intestinal perforation (8.45%), perianal disease (6.73%), gastrointestinal bleeding (4.79%), and abdominal abscess (4.04%). The rate of diagnosis of CD before surgery was low (34.78%), and the misdiagnosis rate was 20.49%. The predominant surgical procedure for CD was bowel resection (69.54%). The rate of surgical complications was 20.34%, and the primary complications of surgery were infection (39.44%) and intestinal fistulae (26.09%). The relapse rate after surgery was 27.71%. For the periods of 1961-2000 and 2000-2013, the rates of both misdiagnosis before surgery and surgery related death decreased (34.90% vs 12.10%, P < 0.001, and 23.53% vs 5.26%, P < 0.001, respectively). CONCLUSION: The rates of surgical complications and misdiagnosis were higher, whereas the rate of CD-associated tumor and the relapse rate were lower in China than in West countries. PMID- 25914484 TI - Per oral cholangiopancreatoscopy in pancreatico biliary diseases--expert consensus statements. AB - AIM: To provide consensus statements on the use of per-oral cholangiopancreatoscopy (POCPS). METHODS: A workgroup of experts in endoscopic retrograde cholangiopancreatography (ERCP), endosonography, and POCPS generated consensus statements summarizing the utility of POCPS in pancreaticobiliary disease. Recommendation grades used validated evidence ratings of publications from an extensive literature review. RESULTS: Six consensus statements were generated: (1) POCPS is now an important additional tool during ERCP; (2) in patients with indeterminate biliary strictures, POCS and POCS-guided targeted biopsy are useful for establishing a definitive diagnosis; (3) POCS and POCS guided lithotripsy are recommended for treatment of difficult common bile duct stones when standard techniques fail; (4) in patients with main duct intraductal papillary mucinous neoplasms (IPMN) POPS may be used to assess extent of tumor to assist surgical resection; (5) in difficult pancreatic ductal stones, POPS-guided lithotripsy may be useful in fragmentation and extraction of stones; and (6) additional indications for POCPS include selective guidewire placement, unexplained hemobilia, assessing intraductal biliary ablation therapy, and extracting migrated stents. CONCLUSION: POCPS is important in association with ERCP, particularly for diagnosis of indeterminate biliary strictures and for intra-ductal lithotripsy when other techniques failed, and may be useful for pre operative assessment of extent of main duct IPMN, for extraction of difficult pancreatic stones, and for unusual indications involving selective guidewire placement, assessing unexplained hemobilia or intraductal biliary ablation therapy, and extracting migrated stents. PMID- 25914486 TI - Integrin antagonists are effective and safe for Crohn's disease: a meta-analysis. AB - AIM: To evaluate the efficacy and safety of integrin antagonists, including natalizumab and vedolizumab, in Crohn's disease (CD). METHODS: We carried out a literature search in PubMed, MEDLINE, EMBASE and the Cochrane Library to screen for citations from January 1990 to August 2014. Data analysis was performed using Review Manager version 5.2. RESULTS: A total of 1340 patients from five studies were involved in this meta-analysis. During 6-12 wk treatment, integrin antagonists increased the rate of clinical response and remission with OR = 1.69, 95%CI: 1.37-2.09 and 1.84, 95%CI: 1.44-2.34, respectively. No significant difference was found between integrin antagonists and placebo treatments regarding their adverse reactions (OR = 1.07, 95%CI: 0.83-1.38) and serious adverse reactions (OR = 0.81, 95%CI: 0.57-1.15). CONCLUSION: The results prove the efficacy and safety of integrin antagonists for CD treatment, although the treatment strategies varied. PMID- 25914487 TI - Helicobacter pylori infection and inflammatory bowel disease in Asians: a meta analysis. AB - AIM: To investigate the relationship between Helicobacter pylori infection and inflammatory bowel disease (IBD) in an Asian population. METHODS: The PubMed, EMBASE, and Cochrane Library databases were searched for observational studies published up until June 2014, without language restrictions. Additional references were obtained from reviewed articles. RESULTS: Ten studies involving 1299 IBD patients and 1817 controls were included in the meta-analysis (24.9% of IBD patients had H. pylori infection vs 48.3% of the controls). The pooled risk ratio for H. pylori infection in IBD patients compared with controls was 0.48 (95%CI: 0.43-0.54; P < 0.001). There was no significant heterogeneity in the included studies (I (2) = 21%). Egger's linear regression indicated that there was no significant publication bias (P = 0.203). CONCLUSION: The H. pylori infection rate in Asian IBD patients is significantly lower than in non-IBD patients, indicating that infection protects against the development of IBD. PMID- 25914488 TI - Hand-sewn vs linearly stapled esophagogastric anastomosis for esophageal cancer: a meta-analysis. AB - AIM: To compare the outcomes of hand-sewn (HS) and linearly stapled (LS) esophagogastric anastomosis for esophageal cancer. METHODS: Before beginning this study, a rigorous protocol was established according to the recommendations of the Cochrane Collaboration. Databases and references were searched for all randomized controlled trials and comparative clinical studies that compared LS with HS esophagogastric anastomosis for esophageal cancer. The primary outcomes compared were anastomotic leak and stricture. Subgroup analyses were performed according to site of anastomosis. RESULTS: Fifteen studies were used, comprising 3203 patients (n = 2027 LS and 1176 HS). Primary outcome analysis revealed a significant decrease in anastomotic leakage (RR = 0.51, 95%CI: 0.41-0.65; P < 0.00001) associated with LS anastomosis. A significantly reduced rate of anastomotic stricture associated with LS was also found (RR = 0.56, 95%CI: 0.49 0.64; P < 0.00001). A subgroup analysis according to the site of anastomosis revealed a significantly reduced rate of anastomotic stricture (P < 0.00001). Although there was no significant difference in the decrease in thoracic anastomotic leakage, there was a significant decrease in cervical anastomotic leakage associated with LS (P < 0.00001). CONCLUSION: This meta-analysis indicates that the LS technique contributes to a reduced rate of leakage and stricture compared with the HS method. PMID- 25914489 TI - Cholecystocolic fistula caused by gallbladder carcinoma: preoperatively misdiagnosed as hepatic colon carcinoma. AB - Cholecystocolic fistula secondary to gallbladder carcinoma is extremely rare and has been reported in very few studies. Most cholecystocolic fistulae are late complications of gallstone disease, but can also develop following carcinoma of the gallbladder when the necrotic tumor penetrates into the adjacent colon. Although no currently available imaging technique has shown great accuracy in recognizing cholecystocolic fistula, abdominopelvic computed tomography may show fistulous communication and anatomical details. Herein we report an unusual case of cholecystocolic fistula caused by gallbladder carcinoma, which was preoperatively misdiagnosed as hepatic flexure colon carcinoma. PMID- 25914490 TI - Air leak syndrome after endoscopic retrograde cholangiopancreatography: a rare and fatal complication. AB - Endoscopic retrograde cholangiopancreatography (ERCP) is a state of the art diagnostic and therapeutic procedure for various pancreatic and biliary problems. In spite of the well-established safety of the procedure, there is still a risk of complications such as pancreatitis, cholangitis, bleeding and perforation. Air leak syndrome has rarely been reported in association with ERCP and the optimal management of this serious condition can be difficult to establish. Our group successfully managed a case of air leak syndrome following ERCP which was caused by a 3cm Stapfer type I perforation in the posterolateral aspect of the second part of the duodenum and was repaired surgically. Hereby, we describe the presentation and subsequent therapeutic approach. PMID- 25914491 TI - Multi-atlas-based Segmentation of the Parotid Glands of MR Images in Patients Following Head-and-neck Cancer Radiotherapy. AB - Xerostomia (dry mouth), resulting from radiation damage to the parotid glands, is one of the most common and distressing side effects of head-and-neck cancer radiotherapy. Recent MRI studies have demonstrated that the volume reduction of parotid glands is an important indicator for radiation damage and xerostomia. In the clinic, parotid-volume evaluation is exclusively based on physicians' manual contours. However, manual contouring is time-consuming and prone to inter observer and intra-observer variability. Here, we report a fully automated multi atlas-based registration method for parotid-gland delineation in 3D head-and-neck MR images. The multi-atlas segmentation utilizes a hybrid deformable image registration to map the target subject to multiple patients' images, applies the transformation to the corresponding segmented parotid glands, and subsequently uses the multiple patient-specific pairs (head-and-neck MR image and transformed parotid-gland mask) to train support vector machine (SVM) to reach consensus to segment the parotid gland of the target subject. This segmentation algorithm was tested with head-and-neck MRIs of 5 patients following radiotherapy for the nasopharyngeal cancer. The average parotid-gland volume overlapped 85% between the automatic segmentations and the physicians' manual contours. In conclusion, we have demonstrated the feasibility of an automatic multi-atlas based segmentation algorithm to segment parotid glands in head-and-neck MR images. PMID- 25914492 TI - Ultrasound 2D Strain Estimator Based on Image Registration for Ultrasound Elastography. AB - In this paper, we present a new approach to calculate 2D strain through the registration of the pre- and post-compression (deformation) B-mode image sequences based on an intensity-based non-rigid registration algorithm (INRA). Compared with the most commonly used cross-correlation (CC) method, our approach is not constrained to any particular set of directions, and can overcome displacement estimation errors introduced by incoherent motion and variations in the signal under high compression. This INRA method was tested using phantom and in vivo data. The robustness of our approach was demonstrated in the axial direction as well as the lateral direction where the standard CC method frequently fails. In addition, our approach copes well under large compression (over 6%). In the phantom study, we computed the strain image under various compressions and calculated the signal-to-noise (SNR) and contrast-to-noise (CNS) ratios. The SNR and CNS values of the INRA method were much higher than those calculated from the CC-based method. Furthermore, the clinical feasibility of our approach was demonstrated with the in vivo data from patients with arm lymphedema. PMID- 25914493 TI - Enhanced detection of dentinal lesions in OCT images using the RKT transformation. AB - Several studies have shown that optical coherence tomography (OCT) can be used to measure the remaining enamel thickness and detect the location of subsurface lesions hidden under the sound enamel. The purpose of this study was to develop algorithms to enhance the visibility of subsurface structures such as hidden occlusal lesions and the dentinal-enamel junction. Extracted teeth with natural occlusal lesions were imaged with OCT with and without added high index fluids. A Rotating Kernel Transformation (RKT) nonlinear image processing filter was applied to PS-OCT images to enhance the visibility of the subsurface lesions under the sound enamel. The filter significantly increased (P<0.05) the visibility of the subsurface lesions. PMID- 25914494 TI - Assessment of remineralization in simulated enamel lesions via dehydration with near-IR reflectance imaging. AB - Previous studies have demonstrated that near-IR imaging can be used to nondestructively monitor the severity of enamel lesions. Arrested lesions typically have a highly mineralized surface layer that reduces permeability and limits diffusion into the lesion. The purpose of this study was to investigate whether the rate of water loss correlates with the degree of remineralization using near-IR reflectance imaging. Artificial bovine (n=15) enamel lesions were prepared by immersion in a demineralization solution for 24 hours and they were subsequently placed in an acidic remineralization solution for different periods. The samples were dehydrated using an air spray for 30 seconds and surfaces were imaged using an InGaAs camera at 1300-1700 nm wavelengths. Near-IR reflectance intensity differences before and after dehydration decreased with longer periods of remineralization. This study demonstrated that near-IR reflectance imaging was suitable for the detection of remineralization in simulated caries lesions and near-IR wavelengths longer than 1400 nm are well suited for the assessment of remineralization. PMID- 25914495 TI - In vitro near-infrared imaging of natural secondary caries. AB - Secondary caries stands as the leading reason for the failure of composite restorations and dentists spend more time replacing existing restorations than placing new ones. Current clinical strategies, and even modern visible light methods designed to detect decay, lack the sensitivity to distinguish incipient lesions, are confounded by staining on the surface and within the tooth, or are limited to detecting decay on the tooth surface. Near-IR (NIR) imaging methods, such as NIR reflectance and transillumination imaging, and optical coherence tomography are promising strategies for imaging secondary caries. Wavelengths longer than 1300-nm avoid interference from stain and exploit the greater transparency of sound enamel and dental composites, to provide increased contrast with demineralized tissues and improved imaging depth. The purpose of this study was to determine whether NIR transillumination (lambda=1300-nm) and NIR cross polarized reflectance (lambda=1500-1700-nm) images can serve as reliable indicators of demineralization surrounding composite restorations. Twelve composite margins (n=12) consisting of class I, II & V restorations were chosen from ten extracted teeth. The samples were imaged in vitro using NIR transillumination and reflectance, polarization sensitive optical coherence tomography (PS-OCT) and a high-magnification digital visible light microscope. Samples were serially sectioned into 200-MUm slices for histological analysis using polarized light microscopy (PLM) and transverse microradiography (TMR). The results presented demonstrate the utility of NIR light for detecting recurrent decay and suggest that NIR images could be a reliable screening tool used in conjunction with PS-OCT for the detection and diagnosis of secondary caries. PMID- 25914496 TI - Selective removal of dental caries with a diode-pumped Er:YAG laser. AB - Selective removal of caries lesions with high precision is best accomplished using lasers operating at high pulse repetition rates utilizing small spot sizes. Conventional flash-lamp pumped Er:YAG lasers are poorly suited for this purpose, but new diode-pumped Er:YAG lasers have become available operating at high pulse repetition rates. The purpose of this study was to measure the ablation rate and selectivity of sound and demineralized enamel and dentin for a 30 W diode-pumped Er:YAG laser operating with a pulse duration of 20-30-MUs and evaluate it's potential for the selective removal of natural occlusal lesions on extracted teeth. Microradiography was used to determine the mineral content of the demineralized enamel and dentin of 300-MUm thick sections with natural caries lesions prior to laser ablation. The ablation rate was calculated for varying mineral content. In addition, near-IR reflectance measurements at 1500-1700-nm were used to guide the laser for the selective ablation of natural occlusal caries lesions on extracted teeth. PMID- 25914497 TI - Selective removal of demineralized enamel using a CO2 laser coupled with near-IR reflectance imaging. AB - Detection and diagnosis of early dental caries lesions can be difficult due to variable tooth coloration, staining of the teeth and poor contrast between sound and demineralized enamel. These problems can be overcome by using near-infrared (NIR) imaging. Previous studies have demonstrated that lasers can be integrated with NIR imaging devices, allowing image-guided ablation. The aim of this study was to demonstrate that NIR light at 1500 - 1700 nm can be used to guide a 9.3 MUm CO2 laser for the selective ablation of early demineralization on tooth occlusal surfaces. The occlusal surfaces of ten sound human molars were used in this in-vitro study. Shallow simulated caries lesions of varying depth and position were produced on tooth occlusal surfaces using a demineralization solution. Sequential NIR reflectance images at 1500 - 1700 nm were used to guide the laser for selective ablation of the lesion areas. Digital microscopy and polarization sensitive optical coherence tomography (PS-OCT) were used to assess the selectivity of removal. This study demonstrates that high contrast NIR reflectance images can be used for the image-guided laser ablation of early demineralization from tooth occlusal surfaces. PMID- 25914498 TI - Image-guided removal of occlusal caries lesions with a lambda= 9.3-um CO2 laser using near-IR transillumination. AB - Previous studies have shown that near-IR transillumination is well suited for imaging deep occlusal lesions. The purpose of this study was to determine if near IR images can be used to guide a CO2 laser for the selective removal of natural occlusal lesions on extracted teeth. Near-IR occlusal transillumination images of extracted human teeth with natural occlusal caries lesions were acquired using an InGaAs camera and near-IR light at wavelengths from 1290 to 1470-nm from a filtered tungsten halogen source. A CO2 laser operating at 9.3-um with a pulse duration of 10-15-us and a pulse repetition rate of 100-300-Hz was used for caries removal. Optical Coherence tomography was used to confirm lesion presence and serial scans were used to assess selective removal. Teeth were also sectioned for histological examination using polarized light microscopy. This study suggests that near-infrared transillumination is a promising method for the image guided laser ablation of occlusal caries lesions but the use of serial near-IR transillumination imaging for monitoring lesion removal was limited. PMID- 25914499 TI - Serial removal of caries lesions from tooth occlusal surfaces using near-IR image guided IR laser ablation. AB - Previous studies have established that caries lesions can be imaged with high contrast without the interference of stains at near-IR wavelengths greater than 1300-nm. It has been demonstrated that computer controlled laser scanning systems utilizing IR lasers operating at high pulse repetition rates can be used for serial imaging and selective removal of caries lesions. In this study, we report our progress towards the development of algorithms for generating rasterized ablation maps from near-IR reflectance images for the removal of natural lesions from tooth occlusal surfaces. An InGaAs camera and a filtered tungsten-halogen lamp producing near-IR light in the range of 1500-1700-nm were used to collect crosspolarization reflectance images of tooth occlusal surfaces. A CO2 laser operating at a wavelength of 9.3- MUm with a pulse duration of 10-15-MUs was used for image-guided ablation. PMID- 25914500 TI - Advancing Molecular-Guided Surgery through probe development and testing in a moderate cost evaluation pipeline. AB - Molecular guided oncology surgery has the potential to transform the way decisions about resection are done, and can be critically important in areas such as neurosurgery where the margins of tumor relative to critical normal tissues are not readily apparent from visual or palpable guidance. Yet there are major financial barriers to advancing agents into clinical trials with commercial backing. We observe that development of these agents in the standard biological therapeutic paradigm is not viable, due to the high up front financial investment needed and the limitations in the revenue models of contrast agents for imaging. The hypothesized solution to this problem is to develop small molecular biologicals tagged with an established fluorescent reporter, through the chemical agent approval pathway, targeting a phase 0 trials initially, such that the initial startup phase can be completely funded by a single NIH grant. In this way, fast trials can be completed to de-risk the development pipeline, and advance the idea of fluorescence-guided surgery (FGS) reporters into human testing. As with biological therapies the potential successes of each agent are still moderate, but this process will allow the field to advance in a more stable and productive manner, rather than relying upon isolated molecules developed at high cost and risk. The pathway proposed and tested here uses peptide synthesis of an epidermal growth factor receptor (EGFR)-binding Affibody molecules, uniquely conjugated to IRDye 800CW, developed and tested in academic and industrial laboratories with well-established records for GMP production, fill & finish, toxicity testing, and early phase clinical trials with image guidance. PMID- 25914501 TI - Beyond isolated cells: microfluidic transport of large tissue for pancreatic cancer diagnosis. AB - For cancer diagnoses, core biopsies (CBs) obtained from patients using coring needles (CNs) are traditionally visualized and assessed on microscope slides by pathologists after samples are processed and sectioned. A fundamental gain in optical information (i.e., diagnosis/staging) may be achieved when whole, unsectioned CBs (L = 5-20, D = 0.5-2.0 mm) are analyzed in 3D. This approach preserves CBs for traditional pathology and maximizes the diagnostic potential of patient samples. To bridge CNs/CBs with imaging, our group developed a microfluidic device that performs biospecimen preparation on unsectioned CBs for pathology. The ultimate goal is an automated and rapid point-of-care system that aids pathologists by processing tissue for advanced 3D imaging platforms. An inherent, but essential device feature is the microfluidic transport of CBs, which has not been previously investigated. Early experiments demonstrated proof of-concept: pancreas CBs (D = 0.3-2.0 mm) of set lengths were transported in straight/curved microchannels, but dimensional tolerance and flow rates were variable, and preservation of CB integrity was uncontrolled. A second study used metal cylinder substitutes (L = 10, D = 1 mm) in microchannels to understand the transport mechanism. However, CBs are imperfectly shaped, rough, porous and viscoelastic. In this study, fresh/formalin-fixed porcine and human pancreas CBs were deposited into our device through a custom interface using clinical CNs. CB integrity (i.e., sample viability) may be assessed at every stage using an optomechanical metric: physical breaks were determined when specimen intensity profile data deviated beyond xavg + 2sigma. Flow rates for human CBs were determined for several CNs, and microfluidic transport of fresh and formalin fixed CBs was analyzed. PMID- 25914502 TI - Evaluation of Five Image Registration Tools for Abdominal CT: Pitfalls and Opportunities with Soft Anatomy. AB - Image registration has become an essential image processing technique to compare data across time and individuals. With the successes in volumetric brain registration, general-purpose software tools are beginning to be applied to abdominal computed tomography (CT) scans. Herein, we evaluate five current tools for registering clinically acquired abdominal CT scans. Twelve abdominal organs were labeled on a set of 20 atlases to enable assessment of correspondence. The 20 atlases were pairwise registered based on only intensity information with five registration tools (affine IRTK, FNIRT, Non-Rigid IRTK, NiftyReg, and ANTs). Following the brain literature, the Dice similarity coefficient (DSC), mean surface distance, and Hausdorff distance were calculated on the registered organs individually. However, interpretation was confounded due to a significant proportion of outliers. Examining the retrospectively selected top 1 and 5 atlases for each target revealed that there was a substantive performance difference between methods. To further our understanding, we constructed majority vote segmentation with the top 5 DSC values for each organ and target. The results illustrated a median improvement of 85% in DSC between the raw results and majority vote. These experiments show that some images may be well registered to some targets using the available software tools, but there is significant room for improvement and reveals the need for innovation and research in the field of registration in abdominal CTs. If image registration is to be used for local interpretation of abdominal CT, great care must be taken to account for outliers (e.g., atlas selection in statistical fusion). PMID- 25914503 TI - Evaluation of Atlas-Based White Matter Segmentation with Eve. AB - Multi-atlas labeling has come in wide spread use for whole brain labeling on magnetic resonance imaging. Recent challenges have shown that leading techniques are near (or at) human expert reproducibility for cortical gray matter labels. However, these approaches tend to treat white matter as essentially homogeneous (as white matter exhibits isointense signal on structural MRI). The state-of-the art for white matter atlas is the single-subject Johns Hopkins Eve atlas. Numerous approaches have attempted to use tractography and/or orientation information to identify homologous white matter structures across subjects. Despite success with large tracts, these approaches have been plagued by difficulties in with subtle differences in course, low signal to noise, and complex structural relationships for smaller tracts. Here, we investigate use of atlas-based labeling to propagate the Eve atlas to unlabeled datasets. We evaluate single atlas labeling and multi-atlas labeling using synthetic atlases derived from the single manually labeled atlas. On 5 representative tracts for 10 subjects, we demonstrate that (1) single atlas labeling generally provides segmentations within 2mm mean surface distance, (2) morphologically constraining DTI labels within structural MRI white matter reduces variability, and (3) multi atlas labeling did not improve accuracy. These efforts present a preliminary indication that single atlas labels with correction is reasonable, but caution should be applied. To purse multi-atlas labeling and more fully characterize overall performance, more labeled datasets would be necessary. PMID- 25914504 TI - Revealing Latent Value of Clinically Acquired CTs of Traumatic Brain Injury Through Multi-Atlas Segmentation in a Retrospective Study of 1,003 with External Cross-Validation. AB - Medical imaging plays a key role in guiding treatment of traumatic brain injury (TBI) and for diagnosing intracranial hemorrhage; most commonly rapid computed tomography (CT) imaging is performed. Outcomes for patients with TBI are variable and difficult to predict upon hospital admission. Quantitative outcome scales (e.g., the Marshall classification) have been proposed to grade TBI severity on CT, but such measures have had relatively low value in staging patients by prognosis. Herein, we examine a cohort of 1,003 subjects admitted for TBI and imaged clinically to identify potential prognostic metrics using a "big data" paradigm. For all patients, a brain scan was segmented with multi-atlas labeling, and intensity/volume/texture features were computed in a localized manner. In a 10-fold cross-validation approach, the explanatory value of the image-derived features is assessed for length of hospital stay (days), discharge disposition (five point scale from death to return home), and the Rancho Los Amigos functional outcome score (Rancho Score). Image-derived features increased the predictive R2 to 0.38 (from 0.18) for length of stay, to 0.51 (from 0.4) for discharge disposition, and to 0.31 (from 0.16) for Rancho Score (over models consisting only of non-imaging admission metrics, but including positive/negative radiological CT findings). This study demonstrates that high volume retrospective analysis of clinical imaging data can reveal imaging signatures with prognostic value. These targets are suited for follow-up validation and represent targets for future feature selection efforts. Moreover, the increase in prognostic value would improve staging for intervention assessment and provide more reliable guidance for patients. PMID- 25914505 TI - Constructing a statistical atlas of the radii of the optic nerve and cerebrospinal fluid sheath in young healthy adults. AB - Optic neuritis is a sudden inflammation of the optic nerve (ON) and is marked by pain on eye movement, and visual symptoms such as a decrease in visual acuity, color vision, contrast and visual field defects. The ON is closely linked with multiple sclerosis (MS) and patients have a 50% chance of developing MS within 15 years. Recent advances in multi-atlas segmentation methods have omitted volumetric assessment. In the past, measuring the size of the ON has been done by hand. We utilize a new method of automatically segmenting the ON to measure the radii of both the ON and surrounding cerebrospinal fluid (CSF) sheath to develop a normative distribution of healthy young adults. We examine this distribution for any trends and find that ON and CSF sheath radii do not vary between 20-35 years of age and between sexes. We evaluate how six patients suffering from optic neuropathy compare to this distribution of controls. We find that of these six patients, five of them qualitatively differ from the normative distribution which suggests this technique could be used in the future to distinguish between optic neuritis patients and healthy controls. PMID- 25914506 TI - Efficient Abdominal Segmentation on Clinically Acquired CT with SIMPLE Context Learning. AB - Abdominal segmentation on clinically acquired computed tomography (CT) has been a challenging problem given the inter-subject variance of human abdomens and complex 3-D relationships among organs. Multi-atlas segmentation (MAS) provides a potentially robust solution by leveraging label atlases via image registration and statistical fusion. We posit that the efficiency of atlas selection requires further exploration in the context of substantial registration errors. The selective and iterative method for performance level estimation (SIMPLE) method is a MAS technique integrating atlas selection and label fusion that has proven effective for prostate radiotherapy planning. Herein, we revisit atlas selection and fusion techniques for segmenting 12 abdominal structures using clinically acquired CT. Using a re-derived SIMPLE algorithm, we show that performance on multi-organ classification can be improved by accounting for exogenous information through Bayesian priors (so called context learning). These innovations are integrated with the joint label fusion (JLF) approach to reduce the impact of correlated errors among selected atlases for each organ, and a graph cut technique is used to regularize the combined segmentation. In a study of 100 subjects, the proposed method outperformed other comparable MAS approaches, including majority vote, SIMPLE, JLF, and the Wolz locally weighted vote technique. The proposed technique provides consistent improvement over state of-the-art approaches (median improvement of 7.0% and 16.2% in DSC over JLF and Wolz, respectively) and moves toward efficient segmentation of large-scale clinically acquired CT data for biomarker screening, surgical navigation, and data mining. PMID- 25914507 TI - Toward Content Based Image Retrieval with Deep Convolutional Neural Networks. AB - Content-based image retrieval (CBIR) offers the potential to identify similar case histories, understand rare disorders, and eventually, improve patient care. Recent advances in database capacity, algorithm efficiency, and deep Convolutional Neural Networks (dCNN), a machine learning technique, have enabled great CBIR success for general photographic images. Here, we investigate applying the leading ImageNet CBIR technique to clinically acquired medical images captured by the Vanderbilt Medical Center. Briefly, we (1) constructed a dCNN with four hidden layers, reducing dimensionality of an input scaled to 128*128 to an output encoded layer of 4*384, (2) trained the network using back-propagation 1 million random magnetic resonance (MR) and computed tomography (CT) images, (3) labeled an independent set of 2100 images, and (4) evaluated classifiers on the projection of the labeled images into manifold space. Quantitative results were disappointing (averaging a true positive rate of only 20%); however, the data suggest that improvements would be possible with more evenly distributed sampling across labels and potential re-grouping of label structures. This prelimainry effort at automated classification of medical images with ImageNet is promising, but shows that more work is needed beyond direct adaptation of existing techniques. PMID- 25914508 TI - Multi-Atlas Segmentation for Abdominal Organs with Gaussian Mixture Models. AB - Abdominal organ segmentation with clinically acquired computed tomography (CT) is drawing increasing interest in the medical imaging community. Gaussian mixture models (GMM) have been extensively used through medical segmentation, most notably in the brain for cerebrospinal fluid/gray matter/white matter differentiation. Because abdominal CT exhibit strong localized intensity characteristics, GMM have recently been incorporated in multi-stage abdominal segmentation algorithms. In the context of variable abdominal anatomy and rich algorithms, it is difficult to assess the marginal contribution of GMM. Herein, we characterize the efficacy of an a posteriori framework that integrates GMM of organ-wise intensity likelihood with spatial priors from multiple target-specific registered labels. In our study, we first manually labeled 100 CT images. Then, we assigned 40 images to use as training data for constructing target-specific spatial priors and intensity likelihoods. The remaining 60 images were evaluated as test targets for segmenting 12 abdominal organs. The overlap between the true and the automatic segmentations was measured by Dice similarity coefficient (DSC). A median improvement of 145% was achieved by integrating the GMM intensity likelihood against the specific spatial prior. The proposed framework opens the opportunities for abdominal organ segmentation by efficiently using both the spatial and appearance information from the atlases, and creates a benchmark for large-scale automatic abdominal segmentation. PMID- 25914509 TI - Imaging tooth enamel using zero echo time (ZTE) magnetic resonance imaging. AB - In an event where many thousands of people may have been exposed to levels of radiation that are sufficient to cause the acute radiation syndrome, we need technology that can estimate the absorbed dose on an individual basis for triage and meaningful medical decision making. Such dose estimates may be achieved using in vivo electron paramagnetic resonance (EPR) tooth biodosimetry, which measures the number of persistent free radicals that are generated in tooth enamel following irradiation. However, the accuracy of dose estimates may be impacted by individual variations in teeth, especially the amount and distribution of enamel in the inhomogeneous sensitive volume of the resonator used to detect the radicals. In order to study the relationship between interpersonal variations in enamel and EPR-based dose estimates, it is desirable to estimate these parameters nondestructively and without adding radiation to the teeth. Magnetic Resonance Imaging (MRI) is capable of acquiring structural and biochemical information without imparting additional radiation, which may be beneficial for many EPR dosimetry studies. However, the extremely short T2 relaxation time in tooth structures precludes tooth imaging using conventional MRI methods. Therefore, we used zero echo time (ZTE) MRI to image teeth ex vivo to assess enamel volumes and spatial distributions. Using these data in combination with the data on the distribution of the transverse radio frequency magnetic field from electromagnetic simulations, we then can identify possible sources of variations in radiation-induced signals detectable by EPR. Unlike conventional MRI, ZTE applies spatial encoding gradients during the RF excitation pulse, thereby facilitating signal acquisition almost immediately after excitation, minimizing signal loss from short T2 relaxation times. ZTE successfully provided volumetric measures of tooth enamel that may be related to variations that impact EPR dosimetry and facilitate the development of analytical procedures for individual dose estimates. PMID- 25914510 TI - Integrating histology and MRI in the first digital brain of common squirrel monkey, Saimiri sciureus. AB - This effort is a continuation of development of a digital brain atlas of the common squirrel monkey, Saimiri sciureus, a New World monkey with functional and microstructural organization of central nervous system similar to that of humans. Here, we present the integration of histology with multi-modal magnetic resonance imaging (MRI) atlas constructed from the brain of an adult female squirrel monkey. The central concept of this work is to use block face photography to establish an intermediate common space in coordinate system which preserves the high resolution in-plane resolution of histology while enabling 3-D correspondence with MRI. In vivo MRI acquisitions include high resolution T2 structural imaging (300 um isotropic) and low resolution diffusion tensor imaging (600 um isotropic). Ex vivo MRI acquisitions include high resolution T2 structural imaging and high resolution diffusion tensor imaging (both 300 um isotropic). Cortical regions were manually annotated on the co-registered volumes based on published histological sections in-plane. We describe mapping of histology and MRI based data of the common squirrel monkey and construction of a viewing tool that enable online viewing of these datasets. The previously descried atlas MRI is used for its deformation to provide accurate conformation to the MRI, thus adding information at the histological level to the MRI volume. This paper presents the mapping of single 2D image slice in block face as a proof of concept and this can be extended to map the atlas space in 3D coordinate system as part of the future work and can be loaded to an XNAT system for further use. PMID- 25914511 TI - Regression analysis of clustered interval-censored failure time data with the additive hazards model. AB - This paper discusses regression analysis of clustered failure time data, which means that the failure times of interest are clustered into small groups instead of being independent. Clustering occurs in many fields such as medical studies. For the problem, a number of methods have been proposed, but most of them apply only to clustered right-censored data. In reality, the failure time data is often interval-censored. That is, the failure times of interest are known only to lie in certain intervals. We propose an estimating equation-based approach for regression analysis of clustered interval-censored failure time data generated from the additive hazards model. A major advantage of the proposed method is that it does not involve the estimation of any baseline hazard function. Both asymptotic and finite sample properties of the proposed estimates of regression parameters are established and the method is illustrated by the data arising from a lymphatic filariasis study. PMID- 25914512 TI - Inferring sparse representations of continuous signals with continuous orthogonal matching pursuit. AB - Many signals, such as spike trains recorded in multi-channel electrophysiological recordings, may be represented as the sparse sum of translated and scaled copies of waveforms whose timing and amplitudes are of interest. From the aggregate signal, one may seek to estimate the identities, amplitudes, and translations of the waveforms that compose the signal. Here we present a fast method for recovering these identities, amplitudes, and translations. The method involves greedily selecting component waveforms and then refining estimates of their amplitudes and translations, moving iteratively between these steps in a process analogous to the well-known Orthogonal Matching Pursuit (OMP) algorithm [11]. Our approach for modeling translations borrows from Continuous Basis Pursuit (CBP) [4], which we extend in several ways: by selecting a subspace that optimally captures translated copies of the waveforms, replacing the convex optimization problem with a greedy approach, and moving to the Fourier domain to more precisely estimate time shifts. We test the resulting method, which we call Continuous Orthogonal Matching Pursuit (COMP), on simulated and neural data, where it shows gains over CBP in both speed and accuracy. PMID- 25914513 TI - How to Study the Influence of Intensity of Treatment on Generalized Skill and Knowledge Acquisition in Students with Disabilities. AB - Seven empirical studies from this special issue and an overview chapter are reviewed to illustrate several points about studying the possible effects of treatment intensity manipulations on generalized skill or knowledge acquisition in students with disabilities. First, we make a case in favor of studying intensity as separate from complexity and expense of treatment. Second, we encourage researchers to define dependent variables in a way that allows us to determine whether treatment intensity effects on child skills and knowledge are highly generalized versus potentially context bound. Third, we acknowledge that effects of treatment intensity on generalized knowledge and skills likely vary according to student characteristics. Finally, we discuss important research design and measurement issues that are relevant to isolating the likely conditional effects of treatment intensity on generalized outcomes. PMID- 25914514 TI - Integrating Data Transformation in Principal Components Analysis. AB - Principal component analysis (PCA) is a popular dimension reduction method to reduce the complexity and obtain the informative aspects of high-dimensional datasets. When the data distribution is skewed, data transformation is commonly used prior to applying PCA. Such transformation is usually obtained from previous studies, prior knowledge, or trial-and-error. In this work, we develop a model based method that integrates data transformation in PCA and finds an appropriate data transformation using the maximum profile likelihood. Extensions of the method to handle functional data and missing values are also developed. Several numerical algorithms are provided for efficient computation. The proposed method is illustrated using simulated and real-world data examples. PMID- 25914515 TI - Introduction to Special Issue: Translational Research to Help Parents Respond to Adolescent Substance Use Problems. AB - Parents experience a variety of challenges when they are confronted with the fact that their adolescent child is drinking alcohol or using other substances. This special issue is focused on the work being conducted at the NIDA-funded Parents Translational Research Center (PTRC) at the Treatment Research Institute in Philadelphia. By translating scientific evidence and elements of proven clinical interventions into practical tools for parents, the work of the PTRC aims to assist parents with assistance in intervening early, finding appropriate services and facilitating treatment entry for their substance-using child. PMID- 25914516 TI - Equality Hypocrisy, Inconsistency, and Prejudice: The Unequal Application of the Universal Human Right to Equality. AB - In Western culture, there appears to be widespread endorsement of Article 1 of the Universal Declaration of Human Rights (which stresses equality and freedom). But do people really apply their equality values equally, or are their principles and application systematically discrepant, resulting in equality hypocrisy? The present study, conducted with a representative national sample of adults in the United Kingdom (N = 2,895), provides the first societal test of whether people apply their value of "equality for all" similarly across multiple types of status minority (women, disabled people, people aged over 70, Blacks, Muslims, and gay people). Drawing on theories of intergroup relations and stereotyping we examined, relation to each of these groups, respondents' judgments of how important it is to satisfy their particular wishes, whether there should be greater or reduced equality of employment opportunities, and feelings of social distance. The data revealed a clear gap between general equality values and responses to these specific measures. Respondents prioritized equality more for "paternalized" groups (targets of benevolent prejudice: women, disabled, over 70) than others (Black people, Muslims, and homosexual people), demonstrating significant inconsistency. Respondents who valued equality more, or who expressed higher internal or external motivation to control prejudice, showed greater consistency in applying equality. However, even respondents who valued equality highly showed significant divergence in their responses to paternalized versus nonpaternalized groups, revealing a degree of hypocrisy. Implications for strategies to promote equality and challenge prejudice are discussed. PMID- 25914517 TI - Synthesis and anti-cancer activities of a water soluble gold(III) porphyrin. AB - Gold(III) compounds continue to be explored for their potential utility as anticancer agents. A recognized limitation is the reactivity of gold(III), which is typically reduced to the more labile gold(I) state under physiological conditions. The use of porphyrins can overcome this problem. However, to date the stabilization provided by the use a strongly chelating porphyrin is offset by the poor solubility of the resulting complex in aqueous media. In this work, we describe the synthesis and in vitro anti-cancer activity of a gold(III)porphyrin complex with relatively good aqueous solubility. As judged from standard antiproliferation assays, this complex displays an IC50 of 9 MUM for the A2780 human ovarian cancer cell line. This is a higher level of potency than displayed by two related control systems. PMID- 25914518 TI - Evaluation of Semi-supervised Learning for Classification of Protein Crystallization Imagery. AB - In this paper, we investigate the performance of two wrapper methods for semi supervised learning algorithms for classification of protein crystallization images with limited labeled images. Firstly, we evaluate the performance of semi supervised approach using self-training with naive Bayesian (NB) and sequential minimum optimization (SMO) as the base classifiers. The confidence values returned by these classifiers are used to select high confident predictions to be used for self-training. Secondly, we analyze the performance of Yet Another Two Stage Idea (YATSI) semi-supervised learning using NB, SMO, multilayer perceptron (MLP), J48 and random forest (RF) classifiers. These results are compared with the basic supervised learning using the same training sets. We perform our experiments on a dataset consisting of 2250 protein crystallization images for different proportions of training and test data. Our results indicate that NB and SMO using both self-training and YATSI semi-supervised approaches improve accuracies with respect to supervised learning. On the other hand, MLP, J48 and RF perform better using basic supervised learning. Overall, random forest classifier yields the best accuracy with supervised learning for our dataset. PMID- 25914519 TI - Evaluation of Normalization and PCA on the Performance of Classifiers for Protein Crystallization Images. AB - In this paper, we investigate the performance of classification of protein crystallization images captured during protein crystal growth process. We group protein crystallization images into 3 categories: noncrystals, likely leads (conditions that may yield formation of crystals) and crystals. In this research, we only consider the subcategories of noncrystal and likely leads protein crystallization images separately. We use 5 different classifiers to solve this problem and we applied some data preprocessing methods such as principal component analysis (PCA), min-max (MM) normalization and z-score (ZS) normalization methods to our datasets in order to evaluate their effects on classifiers for the noncrystal and likely leads datasets. We performed our experiments on 1606 noncrystal and 245 likely leads images independently. We had satisfactory results for both datasets. We reached 96.8% accuracy for noncrystal dataset and 94.8% accuracy for likely leads dataset. Our target is to investigate the best classifiers with optimal preprocessing techniques on both noncrystal and likely leads datasets. PMID- 25914520 TI - Safety and efficacy of switching from dorzolamide 1.0%/timolol maleate 0.5% eye drops to brinzolamide 1.0%/timolol maleate 0.5% eye drops. AB - PURPOSE: To evaluate the safety and efficacy of switching from dorzolamide 1.0%/timolol maleate 0.5% fixed-combination (DTFC) eye drops to brinzolamide 1.0%/timolol maleate 0.5% fixed-combination (BTFC) eye drops in patients with primary open-angle glaucoma or ocular hypertension. METHODS: A total of 35 eyes of 35 patients with primary open-angle glaucoma or ocular hypertension using DTFC eye drops were included. Participants discontinued DTFC drops and immediately began using BTFC drops. All other eye drops currently being used were continued. Intraocular pressure (IOP) 1 and 3 months after switching medications was compared with baseline IOP. One month after switching medications, participant preference and adherence were evaluated. Adverse reactions were monitored at each study visit. RESULTS: The IOP was 17.9+/-2.6 mmHg at baseline and 18.3+/-4.1 mmHg and 17.8+/-3.4 mmHg 1 month and 3 months after switching medications, respectively (P=0.633). The frequency of missing a dose was not different before (6.1%) and after (6.1%) switching to BTFC. Significantly fewer participants reported stinging after switching to BTFC (15.2%) than while using DTFC (51.5%, P,0.01). Blurred vision was reported with the same frequency before (39.4%) and after (42.4%) switching to BTFC. A total of 33.3% and 27.3% of patients preferred DTFC and BTFC, respectively. Several patients withdrew from the study because of discomfort (n=2, 5.7%), discharge (n=1, 2.9%), dizziness (n=1, 2.9%), or increased IOP (n=2, 5.7%). CONCLUSION: Switching from DTFC to BTFC was well tolerated and did not result in IOP changes or a decreased patient adherence. When glaucoma patients complain of stinging with DTFC administration, switching to BTFC is an acceptable treatment option. PMID- 25914521 TI - Symptoms and signs of ocular surface disease related to topical medication in patients with glaucoma. AB - PURPOSE: The aim of this study was to assess signs and symptoms of ocular surface disease (OSD) and the cytomorphological changes of ocular surface in glaucoma patients using preserved antiglaucoma drops. METHODS: In this cross-sectional study, 109 participants (79 patients with topical medication and 30 untreated controls) completed the Ocular Surface Diseases Index (OSDI) questionnaire and underwent an ophthalmic examination, including Schirmer test, tear film breakup time (TBUT), and fluorescein staining. Conjunctival specimens were collected by impression cytology and analyzed by light microscopy using Nelson's grading scheme (grades 0-3). This classification is based on the nucleus-to-cytoplasm ratios of epithelial cells and the numbers of goblet cells, with grade 2 considered abnormal. RESULTS: The medication group had significantly shorter TBUT (median [interquartile range]: 6.0 seconds [5.0-8.0 seconds] vs 9.5 seconds [6.0 12.3 seconds]; P<0.03), greater fluorescein staining (1.0 [0.75-1.25] vs 0 [0 0.25]; P<0.001), and higher impression cytology grade than the control group (median [range]: 1.0 [1:2 to 1:6] vs 0.6 [1:2 to 1:4]; P<0.001). The increasing number of drops instilled per day was associated with an increase in fluorescein staining (Spearman's rho r=0.475; P<0.001) and shorter TBUT (r=-0.278; P=0.014). The OSDI did not discriminate between the two groups. CONCLUSION: Clinical tests and impression cytology showed ocular surface damage in patients using preserved antiglaucoma medications. However, there was no statistically and clinically significant difference in symptoms measured by OSDI score between the medication and control groups. PMID- 25914522 TI - Safety and efficacy of travoprost solution for the treatment of elevated intraocular pressure. AB - Travoprost is a prostaglandin analogue widely used for reducing intraocular pressure (IOP) in patients affected with glaucoma and ocular hypertension. It exerts its ocular hypotensive effect through the prostaglandin FP receptors, located in the ciliary muscle and the trabecular meshwork. Several studies have shown that topical administration of travoprost induces a mean IOP reduction ranging from 25% to 32%, and sustained throughout the 24-hour cycle. When compared with timolol, travoprost is more effective at reducing IOP, while generally no difference has been found in the head-to-head comparison with other prostaglandin analogues. The fixed combination of travoprost and timolol has demonstrated a hypotensive efficacy comparable to the concomitant administration of the two drugs. Recently, a new preservative-free formulation of travoprost 0.004% has been marketed for reducing tolerability-related problems in subjects affected with ocular surface disease. Low rates of topical and systemic adverse reactions, strong ocular hypotensive efficacy, and once-a-day dosing make travoprost a first-line treatment for patients affected with elevated IOP. PMID- 25914523 TI - Update on the management of severe hypertriglyceridemia--focus on free fatty acid forms of omega-3. AB - High levels of plasma triglycerides (TG) are a risk factor for cardiovascular diseases, often associated with anomalies in other lipids or lipoproteins. Hypertriglyceridemia (HTG), particularly at very high levels, significantly increases also the risk of acute pancreatitis. Thus, interventions to lower TG levels are required to reduce the risk of pancreatitis and cardiovascular disease. Several strategies may be adopted for TG reduction, including lifestyle changes and pharmacological interventions. Among the available drugs, the most commonly used for HTG are fibrates, nicotinic acid, and omega-3 polyunsaturated fatty acids (usually a mixture of eicosapentaenoic acid, or EPA, and docosahexaenoic acid, or DHA). These last are available under different concentrated formulations containing high amounts of omega-3 fatty acids, including a mixture of EPA and DHA or pure EPA. The most recent formulation contains a free fatty acid (FFA) form of EPA and DHA, and exhibits a significantly higher bioavailability compared with the ethyl ester forms contained in the other formulations. This is due to the fact that the ethyl ester forms, to be absorbed, need to be hydrolyzed by the pancreatic enzymes that are secreted in response to fat intake, while the FFA do not. This higher bioavailability translates into a higher TG-lowering efficacy compared with the ethyl ester forms at equivalent doses. Omega-3 FFA are effective in reducing TG levels and other lipids in hypertriglyceridemic patients as well as in high cardiovascular risk patients treated with statins and residual HTG. Currently, omega-3 FFA formulation is under evaluation to establish whether, in high cardiovascular risk subjects, the addition of omega-3 to statin therapy may prevent or reduce major cardiovascular events. PMID- 25914524 TI - The effects of differential injection sites of cold saline on transpulmonary thermodilution parameter values. AB - AIM: To investigate the effects of differential sites for cold saline injection on transpulmonary thermodilution parameter values. METHODS: This was a prospective study. Twelve patients were recruited for the following examinations: control condition (injection site at proximal injection end of the Swan-Ganz catheter), proximal end condition (injection site at sheath of the Swan-Ganz catheter), and distal end condition (injection site at PA end of the Swan-Ganz catheter). Sixty measurements were performed for each condition. The cardiac index, global end diastolic volume index (GEDI), and extravascular lung water index for the three different injection sites were recorded from each patient. In addition, the mean transmission time (MTt), downslope time, and area under the curve obtained from PiCCO-VoLEF-Win software were compared among different groups. RESULTS: There were no differences in cardiac index and extravascular lung water index values among the three conditions (P>0.05). There were no differences in GEDI between the proximal end condition and control condition (P>0.05), while the GEDI was significantly lower for the distal end condition (493.33+/-254.65 mL/m(2)) than for the control condition (645.53+/-234.46 mL/m(2)) (P<0.05) and proximal end condition (717.96+/-321.63 mL/m(2)) (P<0.01). There were no differences in downslope time and area under the curve among the three conditions (P>0.05). There were no differences in MTt between the proximal end condition and control condition (P>0.05), while the MTt was significantly lower for distal end condition (40.22+/-16.37 seconds) than for the control condition (42.91+/-17.93 seconds) (P<0.05) and proximal end condition (47.16+/ 16.64 seconds) (P<0.01). CONCLUSION: The differential sites for cold saline injection impacted transpulmonary thermodilution parameter values. PMID- 25914525 TI - Understanding the patient multidimensional experience: a qualitative study on coping in hospitals of Assistance Publique-Hopitaux de Paris, France. AB - OBJECTIVE: Time spent in hospitals is complex and entails a number of distinct phases that fluctuate depending on many variables. Attempts to understand patients' experiences often involve focusing on their needs using self evaluation, but this does not clearly highlight the complexity of coping. Questionnaires based on telephone surveys and emails do not facilitate a sufficient assessment of the coping effort. However, when patients express themselves through spontaneous narration, different dimensions may emerge in their experience at the hospital. This qualitative study explores the various forms of coping among patients with a hospital experience. METHODS: Interviews were conducted with 75 patients in six hospital departments. Transcripts from interviews were thematically analyzed and a conceptual, multidimensional model was developed to explain the relationship between patient experience and coping complexity. RESULTS: Patients used a set of about 50 different terms to describe their experiences in the hospital. They described with the greatest number of words the aspects that triggered their stress or distress and forced them to cope. Stress resulting from the experienced situation was classifiable into five dimensions: trauma, environment, medical, interpersonal affective, and social impact, which constitute invariants that may require individual complex coping strategies. CONCLUSION: Patient experience is hard to evaluate, and this represents a permanent challenge for medical teams. Considering the five coping dimensions delineated in this study may be helpful in improving the patient's hospital experience. PMID- 25914526 TI - Patients' self-reported adherence to capecitabine on XELOX treatment in metastatic colorectal cancer: findings from a retrospective cohort analysis. AB - BACKGROUND: Capecitabine plus oxaliplatin (XELOX) has been established as a first line treatment for metastatic colorectal cancer. Adherence is particularly important with capecitabine to maintain appropriate curative effect. In this study, we monitored the adherence to capecitabine on XELOX treatment and investigated which factors might decrease compliance. METHODS: The study included 242 consecutive patients who received XELOX treatment for metastatic colorectal cancer between October 2009 and March 2012. Adherence to capecitabine was checked by pharmacists with a patient-reported treatment diary at a pharmaceutical outpatient clinic. Adherence rate was defined as the number of times that a patient took capecitabine in a 14-day cycle/28 prescribed doses. We retrospectively surveyed median relative dose intensities of capecitabine and the factors deteriorating adherence across eight cycles from electronic patient records and examined differences in compliance rates according to age. RESULTS: The study included 144 male and 98 female patients. The overadherence rate was 1.5% (n=23). The median adherence rate was 93.5% (n=242) in the first cycle of XELOX treatment, which gradually rose to 96.1% (n=148) in the eighth cycle. The median relative dose intensity of capecitabine was 79.2%. The main factors contributing to decreased adherence to capecitabine were diarrhea (22.5%, 352 instances) and nausea/vomiting (13.8%, 215 instances). The rate of missed dose was 12.1%. Analysis of adherence issues in relation to patient age showed a trend toward worse adherence to capecitabine therapy in the group of patients aged >=80 years (hazard ratio =3.83; 95% confidence interval 2.48-5.91, P<0.001 versus 70 80 years group and versus <70 years group, chi-square test). CONCLUSION: Patient reported adherence to capecitabine on XELOX treatment in clinical practice is high but adversely affected by side effects. Patients aged 80 years or more exhibit a significant decrease in compliance compared with younger patients. PMID- 25914527 TI - Mild cognitive impairment and its management in older people. AB - Mild cognitive impairment (MCI) is a common condition in the elderly. It is characterized by deterioration of memory, attention, and cognitive function that is beyond what is expected based on age and educational level. MCI does not interfere significantly with individuals' daily activities. It can act as a transitional level of evolving dementia with a range of conversion of 10%-15% per year. Thus, it is crucial to protect older people against MCI and developing dementia. The preventive interventions and appropriate treatments should improve cognitive performance, and retard or prevent progressive deficits. The avoidance of toxins, reduction of stress, prevention of somatic diseases, implementation of mental and physical exercises, as well as the use of dietary compounds like antioxidants and supplements can be protective against MCI. The modification of risk factors such as stopping smoking, as well as the treatment of deficiency in vitamins and hormones by correcting behaviors and lifestyle, can prevent cognitive decline in the elderly. The progressive increase in the growth rate of the elderly population can enhance the rate of MCI all over the world. There is no exact cure for MCI and dementia; therefore, further studies are needed in the future to determine causes of MCI and risk factors of progression from MCI to dementia. This will help to find better ways for prevention and treatment of cognitive impairment worldwide. PMID- 25914528 TI - The impact of hearing loss on language performance in older adults with different stages of cognitive function. AB - PURPOSE: The possible relationship between audiometric hearing thresholds and cognitive performance on language tests was analyzed in a cross-sectional cohort of older adults aged >=65 years (N=98) with different degrees of cognitive impairment. MATERIALS AND METHODS: Participants were distributed into two groups according to Reisberg's Global Deterioration Scale (GDS): a normal/predementia group (GDS scores 1-3) and a moderate/moderately severe dementia group (GDS scores 4 and 5). Hearing loss (pure-tone audiometry) and receptive and production based language function (Verbal Fluency Test, Boston Naming Test, and Token Test) were assessed. RESULTS: Results showed that the dementia group achieved significantly lower scores than the predementia group in all language tests. A moderate negative correlation between hearing loss and verbal comprehension (r= 0.298; P<0.003) was observed in the predementia group (r=-0.363; P<0.007). However, no significant relationship between hearing loss and verbal fluency and naming scores was observed, regardless of cognitive impairment. CONCLUSION: In the predementia group, reduced hearing level partially explains comprehension performance but not language production. In the dementia group, hearing loss cannot be considered as an explanatory factor of poor receptive and production based language performance. These results are suggestive of cognitive rather than simply auditory problems to explain the language impairment in the elderly. PMID- 25914529 TI - Early indications that low mental quality of life scores in recently unwell older people predict downstream functional decline. AB - BACKGROUND: Accurately detecting markers of early functional decline (FD) are essential to support older people to successfully age in place; however, these markers are poorly understood. We tested the hypothesis that compromised mental quality of life after a minor health crisis could be an early predictor of FD. METHODS: This longitudinal observational cohort study was conducted in the emergency department (ED) of a large Australian hospital and in the community. Data were collected from 148 community-dwelling people aged 65+ years, who provided data at recruitment (baseline), and at 1 month and 3 months post discharge from the ED. Short Form-12 mental quality of life component scores (MCS) were regressed with patient descriptors taken at baseline (age, sex, socioeconomic status, education, Mini-Mental State Examination, and primary language), and over-time estimates of FD taken at baseline, and at 1 and 3 months post discharge (instrumental activities of daily living, frequency of falls and hospitalizations, use of gait aids, receipt of community services, living status, and requiring a carer). RESULTS: MCS at 1 month (MCS1) post ED discharge was significantly associated with instrumental activities of daily living at 1 (r=0.45, P<0.001) and 3 months (r=0.401, P=0.001) post ED discharge, but not at baseline (r=0.010, P>0.05). Subjects with lower than the population median MCS showed a significant linear decline in total instrumental activities of daily living scores over 3 months (P=0.025). There was no linear trend over time in the relationship between MCS1 with frequency of falls (P=0.20) or hospitalizations (P=0.42); however, there was a significant difference at 3 months post ED discharge for falls (P=0.036) and hospitalizations (P=0.039) between low and high MCS1 groups. There were no significant confounders. CONCLUSION: Low MCS scores 1 month after a minor health crisis appear to significantly predict downstream FD. This finding needs to be tested in a larger sample. PMID- 25914530 TI - Patient preferences in severe COPD and asthma: a comprehensive literature review. AB - BACKGROUND: Management of chronic incurable diseases such as chronic obstructive pulmonary disease (COPD) and asthma is difficult. Incorporation of patient preferences is widely encouraged. PURPOSE: To summarize original research articles determining patient preference in moderate-to-severe disease. METHODS: Acceptable articles consisted of original research determining preferences for any aspect of care in patients with COPD/asthma. The target population included those with severe disease; however, articles were accepted if they separated outcomes by severity or if the majority had at least moderate-to-severe disease. We also accepted simulation research based on scenarios describing situations involving moderate-to-severe disease that elicited preferences. Two reviewers searched Medline and Embase for articles published from the date of inception of the databases until the end of November 2014, with differences resolved through consensus discussion. Data were tabulated and analyzed descriptively. RESULTS: About 478 articles identified, 448 were rejected and 30 analyzed. There were 25 on COPD and five on asthma. Themes identified as most important in COPD were symptom relief (dyspnea/breathlessness), a positive patient-physician relationship, quality-of-life impairments, and information availability. Patients strongly preferred sponsors' inhalers. At end-of-life, 69% preferred receiving CPR, 70% wanted noninvasive, and 58% invasive mechanical intervention. While patients with asthma preferred treatments that increased symptom-free days, they were willing to trade days without symptoms for a reduction in adverse events and greater convenience. Asthma patients were willing to pay for waking up once and not needing their inhaler over waking up once overnight and needing their inhaler. CONCLUSION: Few studies have examined patient preference in these diseases. More research is needed to fill in knowledge gaps. PMID- 25914532 TI - Thermal properties and physicochemical behavior in aqueous solution of pyrene labeled poly(ethylene glycol)-polylactide conjugate. AB - A fluorescence-labeled bioresorbable polymer was prepared by a coupling reaction of poly(ethylene glycol)-polylactide (PEG-PLA) with carboxyl pyrene, using N,N' diisopropylcarbodiimide/1-hydroxy-7-azabenzotriazole (DIC/HOAt) as a coupling agent and 4-dimethylaminopyridine (DMAP) as a catalyst. The obtained copolymer, termed PEG-PLA-pyrene, was characterized using various analytical techniques, such as gel permeation chromatography (GPC), matrix-assisted laser desorption/ionization time-of-flight mass spectrometry (MALDI-TOF MS), proton nuclear magnetic resonance ((1)H-NMR), infrared spectroscopy (IR), differential scanning calorimetry (DSC), and thermogravimetric analysis (TGA), to identify the molecular structure and to monitor the thermal property changes before and after the reaction. The presence of a pyrene moiety at the end of polylactide (PLA) did not alter the crystallization ability of the poly(ethylene glycol) (PEG) blocks, indicating that the conjugate preserved the inherent thermal properties of PEG PLA. However, the presence of PEG-PLA blocks strongly reduced the melting of pyrene, indicating that the thermal characteristics were sensitive to PEG-PLA incorporation. Regarding the physicochemical behavior in aqueous solution, a higher concentration of PEG-PLA-pyrene resulted in a higher ultraviolet-visible (UV-vis) absorbance and fluorescence emission intensity. This is of great interest for the use of this conjugate as a fluorescence probe to study the in vivo distribution as well as the internalization and intracellular localization of polymeric micelles. PMID- 25914531 TI - Differential changes in quality of life components over 5 years in chronic obstructive pulmonary disease patients. AB - BACKGROUND: The aim of the study was to examine the longitudinal change in quality of life components of patients with chronic obstructive pulmonary disease (COPD). METHODS: In the Hokkaido COPD Cohort Study, 261 subjects were appropriately treated and followed over 5 years with a 74% follow-up rate at the end. The longitudinal changes in St George's Respiratory Questionnaire (SGRQ) scores were annually evaluated with forced expiratory volume in 1 second (FEV1). The subjects were classified into the rapid decliners, slow decliners, and sustainers based on DeltaFEV1/year. RESULTS: The activity component of SGRQ generally deteriorated over time, and its annual decline was the greatest in the rapid decliners (<25th percentile). In contrast, the symptom component improved significantly year by year in the sustainers (>75 percentile), and it did not deteriorate even in the rapid decliners. Of the baseline data, predictors for worsening of the activity component were older age and lower body mass index. Larger reversibility was related to symptom component improvement. Of the follow up data, DeltaFEV1/year was the best predictor for worsening of the components of SGRQ. Continuous smoking was another factor for worsening of the activity component. For the symptom component, a history of exacerbation by admission definition was the determinant of its deterioration, whereas use of beta agonists was related to improvement. CONCLUSION: The longitudinal changes of quality of life and their determinants are markedly different and independent between its components. The activity component of SGRQ generally deteriorated over years, while the symptom component rather improved in some patients with COPD under appropriate treatment. PMID- 25914533 TI - Inhibition of colon cancer cell growth by nanoemulsion carrying gold nanoparticles and lycopene. AB - Lycopene (LP), an important functional compound in tomatoes, and gold nanoparticles (AN), have received considerable attention as potential candidates for cancer therapy. However, the extreme instability and poor bioavailability of LP limits its in vivo application. This study intends to develop a nanoemulsion system incorporating both LP and AN, and to study the possible synergistic effects on the inhibition of the HT-29 colon cancer cell line. LP-nanogold nanoemulsion containing Tween 80 as an emulsifier was prepared, followed by characterization using transmission electron microscopy (TEM), dynamic light scattering (DLS) analysis, ultraviolet spectroscopy, and zeta potential analysis. The particle size as determined by TEM and DLS was 21.3+/-3.7 nm and 25.0+/-4.2 nm for nanoemulsion and 4.7+/-1.1 nm and 3.3+/-0.6 nm for AN, while the zeta potential of nanoemulsion and AN was -32.2+/-1.8 mV and -48.5+/-2.7 mV, respectively. Compared with the control treatment, both the combo (AN 10 ppm plus LP 12 MUM) and nanoemulsion (AN 0.16 ppm plus LP 0.4 MUM) treatments resulted in a five- and 15-fold rise in early apoptotic cells of HT-29, respectively. Also, the nanoemulsion significantly reduced the expressions of procaspases 8, 3, and 9, as well as PARP-1 and Bcl-2, while Bax expression was enhanced. A fivefold decline in the migration capability of HT-29 cells was observed for this nanoemulsion when compared to control, with the invasion-associated markers being significantly reversed through the upregulation of the epithelial marker E cadherin and downregulation of Akt, nuclear factor kappa B, pro-matrix metalloproteinase (MMP)-2, and active MMP-9 expressions. The TEM images revealed that numerous nanoemulsion-filled vacuoles invaded cytosol and converged into the mitochondria, resulting in an abnormally elongated morphology with reduced cristae and matrix contents, demonstrating a possible passive targeting effect. The nanoemulsion containing vacuoles were engulfed and internalized by the nuclear membrane envelop for subsequent invasion into the nucleoli. Taken together, LP-nanogold nanoemulsion could provide synergistic effects at AN and LP doses 250 and 120 times lower than that in the combo treatment, respectively, demonstrating the potential of nanoemulsion developed in this study for a possible application in colon cancer therapy. PMID- 25914535 TI - Social cognitive and neurocognitive deficits in inpatients with unilateral thalamic lesions - pilot study. AB - BACKGROUND: The essential role of the thalamus in neurocognitive processes has been well documented. In contrast, relatively little is known about its involvement in social cognitive processes such as recognition of emotion, mentalizing, or empathy. THE AIM OF THE STUDY: This study was designed to compare the performance of eight patients (five males, three females, mean age +/- SD: 63.7+/-7.9 years) at early stage of unilateral thalamic lesions and eleven healthy controls (six males, five females, 49.6+/-12.2 years) in neurocognitive tests (CogState Battery: Groton Maze Learning Test, GML; Groton Maze Learning Test-Delayed Recall, GML-DR; Detection Task, DT; Identification Task, IT; One Card Learning Task, OCLT; One Back Task, OBT; Two Back Task, TBT; Set-Shifting Task, S-ST) and other well-known tests (Benton Visual Retention Test, BVRT; California Verbal Learning Test, CVLT; The Rey-Osterrieth Complex Figure Test, ROCF; Trail Making Test, TMT part A and B; Color - Word Stroop Task, CWST; Verbal Fluency Test, VFT), and social cognitive tasks (The Penn Emotion Recognition Test, ER40; Penn Emotion Discrimination Task, EmoDiff40; The Penn Emotional Acuity Test, PEAT40; Reading the Mind in the Eyes Test, revised version II; Toronto Alexithymia Scale, TAS-20). METHODS: Thalamic-damaged subjects were included if they experienced a single-episode ischemic stroke localized in right or left thalamus. The patients were examined at 3 weeks after the stroke onset. All were right handed. In addition, the following clinical scales were used: the Mini-Mental State Examination (MMSE), Spielberger State-Trait Anxiety Inventory (STAI), Beck Depression Inventory (BDI II). An inclusion criteria was a minimum score of 23/30 in MMSE. RESULTS: Compared with the healthy controls, patients revealed significantly lower scores in CVLT, GML-DR, and VFT. Furthermore, compared to healthy controls, patients showed significantly delayed recognition of "happiness" in EmoDiff40 and significantly worse performance on Reading the Mind in the Eyes Test, revised version II. Neuropsychological assessment demonstrated some statistically significant deficits in learning and remembering both verbal and visual material, long-term information storing, problem solving, and executive functions such as verbal fluency. CONCLUSION: Patients at early stage of unilateral thalamic stroke showed both neurocognitive and social cognitive deficits. Further research is needed to increase understanding about diagnosis, early treatment, and prognosis of patients with thalamic lesions. PMID- 25914536 TI - The severe complication of Stevens-Johnson syndrome induced by long-term clozapine treatment in a male schizophrenia patient: a case report. AB - INTRODUCTION: Stevens-Johnson syndrome (SJS) is a severe adverse drug reaction that can result in disability and mortality. SJS is defined as having a widespread distribution throughout the whole body surface area with <10% extent of skin detachment and skin lesions. Some drugs, such as carbamazepine, have been reported to have a greater correlation to SJS. Although clozapine use has been mentioned as a risk factor for development of SJS, no report has clearly described the features of SJS as a reaction to clozapine use. Herein, we report the case of a patient presenting SJS after long-term clozapine treatment. CASE REPORT: Mr A was a 54-year-old male with a diagnosis of chronic schizophrenia. He was hospitalized in a mental institute and received clozapine 200 mg/day for 2 years, without discomfort or drug side effects. He developed acute-onset mouth edema, multiple oral and ocular ulcers, oral and ocular mucosa swelling, and multiple erythematous skin rashes over his entire body and extremities with hypertension and high fever. SJS was diagnosed after referral to a general hospital. RESULTS: The SJS subsided under supportive treatment. CONCLUSION: Accumulated lymphocytes and macrophages in the epidermis and elevated TNF-alpha might cause an immune reaction and apoptosis and result in the clinical presentation of SJS. Clozapine is believed to modulate the immunologic reaction, and therefore might induce SJS through immunomodulation. This case highlights the importance of considering the possibility of SJS resulting from the use of drugs for which there are no reports of such a severe complication. PMID- 25914537 TI - Prevalence of distorted body image in young Koreans and its association with age, sex, body weight status, and disordered eating behaviors. AB - PURPOSE: To define the prevalence of distorted body image in 10-24-year-old Koreans and determine its relationship with sex, age, body weight status, and disordered eating behaviors. METHODS: A total of 3,227 young Koreans were recruited from elementary, middle, and high schools, as well as from universities. The participants completed a self-reported questionnaire on body image, eating behaviors (Eating Attitude Test-26), and body weight status. RESULTS: The prevalence of a distorted body image in males was 49.7% and that in females was 51.2%. Distorted body image was more frequent in adolescents (age, 10 17 years) than in young adults (age, 18-24 years). The highest prevalence (55.3%) was reported in female elementary school students (age, 10-12 years). Distorted body image was associated with disordered eating behaviors and abnormal body weight status. CONCLUSION: These results suggest that distorted body image is a public health problem, given its high frequency in young Koreans, and that it is associated with abnormal body weight status and disordered eating behaviors. PMID- 25914534 TI - Activation of mTOR: a culprit of Alzheimer's disease? AB - Alzheimer's disease (AD) is characterized by cognitive impairment in clinical presentation, and by beta-amyloid (Abeta) production and the hyper phosphorylation of tau in basic research. More highlights demonstrate that the activation of the mammalian target of rapamycin (mTOR) enhances Abeta generation and deposition by modulating amyloid precursor protein (APP) metabolism and upregulating beta- and gamma-secretases. mTOR, an inhibitor of autophagy, decreases Abeta clearance by scissoring autophagy function. mTOR regulates Abeta generation or Abeta clearance by regulating several key signaling pathways, including phosphoinositide 3-kinase (PI3-K)/protein kinase B (Akt), glycogen synthase kinase 3 [GSK-3], AMP-activated protein kinase (AMPK), and insulin/insulin-like growth factor 1 (IGF-1). The activation of mTOR is also a contributor to aberrant hyperphosphorylated tau. Rapamycin, the inhibitor of mTOR, may mitigate cognitive impairment and inhibit the pathologies associated with amyloid plaques and neurofibrillary tangles by promoting autophagy. Furthermore, the upstream and downstream components of mTOR signaling are involved in the pathogenesis and progression of AD. Hence, inhibiting the activation of mTOR may be an important therapeutic target for AD. PMID- 25914539 TI - Pneumoscrotum: report of two different cases and review of the literature. AB - Pneumoscrotum is the term used to describe the presence of air within the scrotum and includes scrotal emphysema as well as pneumatocele. The etiology varies; in some cases, pneumoscrotum may be due to life-threatening disease like pneumothorax or Fournier gangrene. Despite this, pneumoscrotum is a rarely debated issue. We present two different cases of pneumoscrotum and a review of the literature. The first case report is about a 29 year old male patient affected by Duchenne syndrome who showed pneumoscrotum after cardiopulmonary resuscitation that was performed for asphyxic crisis and cardiovascular arrest. We carried out local puncture with an 18-gauge needle, and the pneumoscrotum was successfully solved. The second case report is about a 56 year old male with pneumoscrotum due to Fournier gangrene who underwent radical exeresis of all necrotic tissues and drainage. This is why most of the scrotal skin and all of the penis skin were removed; as a result, the testicles, epididymis, and cavernosa corpora were externalized. On postoperative day one, the patient was feverless and underwent hyperbaric chamber therapy. No postoperative complications occurred. Accurate evaluation of the pneumoscrotum is always needed. Despite the benign course of most of the clinically evident pneumoscrotum cases, this condition should never be underestimated. PMID- 25914538 TI - Current perspectives on deep brain stimulation for severe neurological and psychiatric disorders. AB - Deep brain stimulation (DBS) has become a well-accepted therapy to treat movement disorders, including Parkinson's disease, essential tremor, and dystonia. Long term follow-up studies have demonstrated sustained improvement in motor symptoms and quality of life. DBS offers the opportunity to selectively modulate the targeted brain regions and related networks. Moreover, stimulation can be adjusted according to individual patients' demands, and stimulation is reversible. This has led to the introduction of DBS as a treatment for further neurological and psychiatric disorders and many clinical studies investigating the efficacy of stimulating various brain regions in order to alleviate severe neurological or psychiatric disorders including epilepsy, major depression, and obsessive-compulsive disorder. In this review, we provide an overview of accepted and experimental indications for DBS therapy and the corresponding anatomical targets. PMID- 25914540 TI - Copeptin: a new predictor for severe obstructive sleep apnea. AB - INTRODUCTION: Copeptin which is the C-terminal fragment of antidiuretic hormone (ADH), is a biomarker that has been reported to be increased in various cardiovascular disorders, cerebrovascular diseases and associated with prognosis. Patients with obstructive sleep apnea syndrome (OSAS) have a tendency to develop coronary and cerebral atherosclerotic diseases. OBJECTIVES: The aim of the present study was to study copeptin levels in patients with obstructive sleep apnea and in a control group in order to determine whether copeptin could be used as a biomarker predicting the severity of OSAS and possible complications in this group. METHODS: A total of 116 patients with OSAS, diagnosed by polysomnography, and 27 controls were included in the study. Blood samples were collected after overnight fasting, and copeptin levels were measured with enzyme-linked immunosorbent assay. RESULTS: Copeptin levels were significantly higher in the OSAS group compared to control group (2,156+/-502; 1,845+/-500 pg/mL, respectively, P=0.004). Mean copeptin level of the patients having apnea-hypopnea index (AHI) >=30 was significantly higher than that of the patients having AHI <30 (2,392+/-415; 2,017+/-500 pg/mL, respectively, P<0.001). A multivariate regression analysis showed that copeptin level, (hazard ratio: 1.58; 95% confidence interval: 1.09-2.30) was a predictor of severe OSAS (P=0.016). Copeptin levels showed significant positive correlation with AHI (r=0.32; P<0.001), desaturation index (r=0.23; P=0.012), arousal index (r=0.24; P=0.010) and CRP (r=0.26; P=0.011) respectively. CONCLUSION: Copeptin levels are high in OSAS patients and copeptin is a potential marker for identifying patients with a high risk of early cardiovascular complications of OSAS. Copeptin has modest sensitivity (84%) for discriminating severe OSAS patients who are candidates for severe cardiovascular complications. PMID- 25914542 TI - A case study of asthma care in school age children using nurse-coordinated multidisciplinary collaborative practices. AB - AIM: To describe the role of school nursing in leading and coordinating a multidisciplinary networked system of support for children with asthma, and to analyze the strengths and challenges of undertaking and supporting multiagency interprofessional practice. BACKGROUND: The growth of networked and interprofessional collaborations arises from the recognition that a number of the most pressing public health problems cannot be addressed by single-discipline or agency interventions. This paper identifies the potential of school nursing to provide the vision and multiagency leadership required to coordinate multidisciplinary collaboration. METHOD: A mixed-method single-case study design using Yin's approach, including focus groups, interviews, and analysis of policy documents and public health reports. RESULTS: A model that explains the integrated population approach to managing school-age asthma is described; the role of the lead school nurse coordinator was seen as critical to the development and sustainability of the model. CONCLUSION: School nurses can provide strategic multidisciplinary leadership to address pressing public health issues. Health service managers and commissioners need to understand how to support clinicians working across multiagency boundaries and to identify how to develop leadership skills for collaborative interprofessional practice so that the capacity for nursing and other health care professionals to address public health issues does not rely on individual motivation. In England, this will be of particular importance to the commissioning of public health services by local authorities from 2015. PMID- 25914543 TI - Implications of observing and writing field notes through different lenses. AB - BACKGROUND: From a philosophy of science perspective, the literature has posited that different research approaches influence field studies. Studies addressing interdisciplinary research have focused on the challenges of organizing and running interdisciplinary teams, cultural differences between and within disciplines, and constraints in conducting interdisciplinary research. Studies exploring and discussing the process and outcome of transferring observations to notes from an interdisciplinary point of view are not identified. The aim of this paper is to explore the characteristics of field notes created by researchers representing different disciplines and experiences. METHODS: A case study using a modified dynamic observation method was employed. The analyses were initiated by a researcher who had not been involved in the data collection. The field notes were analyzed using three main steps. RESULTS: The structures of both researchers' field notes were characterized by similarities in their descriptions, but the notes' foci and analytical levels differed. CONCLUSION: The findings contribute new insights concerning the execution of interdisciplinary observational studies. Our findings demonstrate that entering the field with different lenses produced richer and more varied data, providing a broader platform from which to discuss and interpret a study's findings. From a theoretical point of view, the findings enable a more nuanced discussion and a conceptual elaboration regarding how observational approaches should be pursued in future studies. On a practical level, the findings show that even if the researchers agree on what the overall focus in the observations should be, differences can occur in both their focus and analytical level throughout the study. PMID- 25914541 TI - Alogliptin benzoate for management of type 2 diabetes. AB - Dipeptidyl peptidase-4 (DPP-4) inhibitors, a new class of oral hypoglycemic agents, augment glucose-dependent insulin secretion and suppress glucagon levels through enhancement of the action of endogenous incretin by inhibiting DPP-4, an incretin-degrading enzyme. DPP-4 inhibitors are generally well tolerated because of their low risk of hypoglycemia and other adverse events. Moreover, with their potential to improve beta cell function, a core defect of type 2 diabetes, DPP-4 inhibitors are becoming a major component of treatment of type 2 diabetes. Alogliptin benzoate is a newly developed, highly selective DPP-4 inhibitor which has been approved in many countries throughout the world. Once-daily administration of alogliptin as either monotherapy or combination therapy with other oral antidiabetic drugs or insulin has a potent glucose-lowering effect which is similar to that of other DPP-4 inhibitors, with a low risk of hypoglycemia and weight gain. The cardiovascular safety of this drug has been confirmed in a recent randomized controlled trial. This review summarizes the efficacy and safety of alogliptin, and discusses the role of DPP-4 inhibitors in the treatment of type 2 diabetes. PMID- 25914544 TI - Gene expression profile analysis of colorectal cancer to investigate potential mechanisms using bioinformatics. AB - This study aimed to explore the underlying molecular mechanisms of colorectal cancer (CRC) using bioinformatics analysis. Using GSE4107 datasets downloaded from the Gene Expression Omnibus, the differentially expressed genes (DEGs) were screened by comparing the RNA expression from the colonic mucosa between 12 CRC patients and ten healthy controls using a paired t-test. The Gene Ontology (GO) functional and pathway enrichment analyses of DEGs were performed using the Database for Annotation, Visualization and Integrated Discovery (DAVID) software followed by the construction of a protein-protein interaction (PPI) network. In addition, hub gene identification and GO functional and pathway enrichment analyses of the modules were performed. A total of 612 up- and 639 downregulated genes were identified. The upregulated DEGs were mainly involved in the regulation of cell growth, migration, and the MAPK signaling pathway. The downregulated DEGs were significantly associated with oxidative phosphorylation, Alzheimer's disease, and Parkinson's disease. Moreover, FOS, FN1, PPP1CC, and CYP2B6 were selected as hub genes in the PPI networks. Two modules (up-A and up B) in the upregulated PPI network and three modules (d-A, d-B, and d-C) in the downregulated PPI were identified with the threshold of Molecular Complex Detection (MCODE) Molecular Complex Detection (MCODE) score >=4 and nodes >=6. The genes in module up-A were significantly enriched in neuroactive ligand receptor interactions and the calcium signaling pathway. The genes in module d-A were enriched in four pathways, including oxidative phosphorylation and Parkinson's disease. DEGs, such as FOS, FN1, PPP1CC, and CYP2B6, may be used as potential targets for CRC diagnosis and treatment. PMID- 25914545 TI - The human immunodeficiency virus protease inhibitor ritonavir is potentially active against urological malignancies. AB - The human immunodeficiency virus protease inhibitor ritonavir has recently been shown to have antineoplastic activity, and its use in urological malignancies is under investigation with an eye toward drug repositioning. Ritonavir is thought to exert its antineoplastic activity by inhibiting multiple signaling pathways, including the Akt and nuclear factor-kappaB pathways. It can increase the amount of unfolded proteins in the cell by inhibiting both the proteasome and heat shock protein 90. Combinations of ritonavir with agents that increase the amount of unfolded proteins, such as proteasome inhibitors, histone deacetylase inhibitors, or heat shock protein 90 inhibitors, therefore, induce endoplasmic reticulum stress cooperatively and thereby kill cancer cells effectively. Ritonavir is also a potent cytochrome P450 3A4 and P-glycoprotein inhibitor, increasing the intracellular concentration of combined drugs by inhibiting their degradation and efflux from cancer cells and thereby enhancing their antineoplastic activity. Furthermore, riotnavir's antineoplastic activity includes modulation of immune system activity. Therapies using ritonavir are thus an attractive new approach to cancer treatment and, due to their novel mechanisms of action, are expected to be effective against malignancies that are refractory to current treatment strategies. Further investigations using ritonavir are expected to find new uses for clinically available drugs in the treatment of urological malignancies as well as many other types of cancer. PMID- 25914546 TI - The effects of PGC-1alpha on the proliferation and energy metabolism of malignant endometrial cancer cells. AB - BACKGROUND: It is well known that peroxisome proliferator-activated receptor gamma coactivator-1 alpha (PGC-1alpha) plays an important role in tissue energy metabolism. However, the roles of PGC-1alpha in malignant endometrial cancer remain unknown. METHODS: Forty cases of endometrial carcinoma, 15 cases with proliferative endometrial tissues, and 21 cases with normal endometrial tissues were collected. Real-time polymerase chain reaction was used to detect the mRNA levels of PGC-1alpha and estrogen-related receptor gamma (ERRgamma). ELISA (enzyme-linked immunosorbent assay) was used to detect the concentrations of pyruvate kinase and isocitrate dehydrogenase. The results were analyzed using medical statistical methods. RESULTS: The mRNA levels of PGC-1alpha and ERRgamma in the endometrial carcinoma tissues and hyperplasic endometrial tissues were significantly greater than those in the normal endometria. The mRNA levels of PGC 1alpha and ERRgamma in the endometrial carcinoma patients with type 2 diabetes were higher than those in patients without diabetes. The mRNA levels of PGC 1alpha and ERRgamma in the endometrial adenocarcinomas increased with clinical staging, depth of myometrial invasion, and increases in the number of metastatic lymph nodes. The PGC-1alpha mRNA level was positively correlated with ERRgamma in the endometrial carcinoma tissues. The mRNA levels of PGC-1alpha were positively correlated with the concentrations of pyruvate kinase and isocitrate dehydrogenase in the endometrial carcinoma tissues, and similar results were found for ERRgamma. CONCLUSION: Our results suggested that the upregulation of PGC-1alpha and ERRgamma in endometrial cancer might be a requirement for cancer cell energy metabolism, which contributes to the development of endometrial cancer. PMID- 25914547 TI - The clinical activity of arsenic trioxide, ascorbic acid, ifosfamide and prednisone combination therapy in patients with relapsed and refractory multiple myeloma. AB - This study aimed to investigate the activity of arsenic trioxide (As2O3) combined with ascorbic acid, ifosfamide, and prednisone chemotherapy in patients with repeatedly relapsed and refractory multiple myeloma (MM). Here, we retrospectively analyzed medical data of 30 MM patients showing progressive disease after receiving at least two previous lines of treatment including an immunomodulatory agent (thalidomide or lenalidomide) and a proteasome inhibitor. There were 19 men and eleven women, aged 54-73 (median 65) years, in this study. The distribution of different isotypes included immunoglobulin G(IgG) (12 patients), IgA (six patients), IgD (three), and light chain (nine patients). All the patients were Durie-Salmon stage III and had relapsed at least three times; the median cycles of prior therapies was 15 (range 10-18). The patients were treated with As2O3, ascorbic acid, and CP (ifosfamide 1 g on day 1, day 3, day 5, and day 7; prednisone 30 mg taken orally for 2 weeks). As2O3 was administered as an intravenous infusion at a dose of 10 mg/d and ascorbic acid at a dose of 2 g/d for 14 days of each 4-week cycle. The results showed that after 2 cycles of therapy, there were five patients that attained partial response, 15 had minimal response, five had no change, and five had progressive disease. The overall response rate was 66.7% (20/30 cases), 50% (10/20 cases), and 40% (2/5 cases), respectively, after 2, 4, and 6 cycles of the therapy. But there were no patients that attained complete remission. The median time of overall survival and progression-free survival were 48 (29-120) and 6 (2-8) months, respectively. The most common treatment-related adverse events included neutropenia, fatigue, anemia, thrombocytopenia, and infection that could be tolerated. The results showed that As2O3 combined with ascorbic acid, ifosfamide, and prednisone chemotherapy may be a choice treatment for repeatedly relapsed and refractory MM patients. PMID- 25914548 TI - A case of EGFR mutant lung adenocarcinoma that acquired resistance to EGFR tyrosine kinase inhibitors with MET amplification and epithelial-to-mesenchymal transition. AB - EGFR mutant lung cancer responds to EGFR tyrosine kinase inhibitors (TKIs), but all patients eventually develop resistance to EGFR-TKIs. Herein we report a case of EGFR mutant lung adenocarcinoma that acquired resistance to EGFR-TKI with MET amplification and epithelial-to-mesenchymal transition (EMT). A 73-year-old woman was diagnosed with adenocarcinoma harboring an EGFR exon 19 deletion. She received gefitinib as second-line therapy. Tumors were reduced 1 month after gefitinib therapy. However, only a few months later, chest computed tomography results indicated cancer progression. Gefitinib therapy was stopped and docetaxel therapy started. However, she died 13 days after admission. Microscopic examination of postmortem specimens revealed a diffuse proliferation of atypical giant cells in primary and metastatic lesions, but no adenocarcinomatous components as in the antemortem specimens. Immunohistochemical analyses showed that antemortem tumor specimens were positive for CDH1 but negative for VIM. In contrast, postmortem tumor specimens were positive for VIM but negative for CDH1. Genetic analyses revealed MET amplification. We concluded that resistance to EGFR TKI might be caused by MET amplification and EMT. To our knowledge, no clinical studies have reported that MET amplification and EMT together may be associated with acquired resistance to EGFR-TKI. Second biopsy after the development of EGFR TKI resistance may be recommended to determine the best therapeutic strategy. PMID- 25914549 TI - Prognostic significance of neutrophil-to- lymphocyte ratio in esophageal cancer: a meta-analysis. AB - BACKGROUND: The neutrophil-to-lymphocyte ratio (NLR) is a useful predictive factor in several cancers. However, the prognostic value of NLR in patients with esophageal cancer (EC) is still controversial. Therefore, it was necessary for us to perform a meta-analysis to evaluate the prognostic value of NLR in patients with EC. METHODS: A systematic literature search was performed by using Web of Science, PubMed Central, and Medline to evaluate the prognostic value of NLR in patients with EC. The deadline of our primary search was July 10, 2014. This meta analysis was conducted in accordance with PRISMA guidelines. Pooled hazard ratio (HR) with 95% confidence interval (CI) was used to assess the association of NLR and overall survival (OS) and disease-free survival (DFS). RESULTS: Six studies involving 1,633 patients were included in our meta-analysis. Our pooled results demonstrated that high NLR was associated with poor OS (HR: 1.54, 95% CI: 1.32 1.80, I2=25.3%, P=0.254) and DFS (HR: 1.74, 95% CI: 1.25-2.43, I2=63.9%, P=0.096). Subgroup analysis between NLR and OS was performed in a further investigation. When the patients were segregated according to country, sample size, and pathological type, high NLR was also significantly correlated with OS. CONCLUSION: High NLR is associated with poor prognosis in patients with EC. NLR may be a significant predictive biomarker in patients with EC. PMID- 25914550 TI - The combination of preoperative serum C-reactive protein and carcinoembryonic antigen is a useful prognostic factor in patients with esophageal squamous cell carcinoma: a combined ROC analysis. AB - BACKGROUND: The prognostic value of inflammatory index in esophageal cancer (EC) has not been established. In the present study, therefore, we initially evaluated a novel prognostic system, named the COCC (COmbination of C-reactive protein [CRP] and carcinoembryonic antigen [CEA]), for making a prognosis in patients with esophageal squamous cell carcinoma (ESCC). METHODS: A total of 327 patients with ESCC between January 2006 and December 2008 were included in this retrospective study. The COCC was calculated by combined CRP and CEA according to the logistic equation. The Kaplan-Meier method was used to calculate the cancer specific survival (CSS), and the difference was assessed by the log-rank test. Cox regression analyses were performed to evaluate the prognostic factors. RESULTS: In our study, COCC was defined as CRP +0.71 CEA according to the logistic equation. Receiver operating characteristic curves for CSS prediction were plotted to verify the optimum cutoff points for CRP, CEA, and COCC, which were 9.8 mg/L, 4.2 ng/mL, and 8.0, respectively. Patients with COCC <=8.0 had a significantly better CSS than patients with COCC >8.0 (53.1% vs 15.3%, P<0.001). Multivariate analysis revealed that COCC was an independent prognostic factor in patients with ESCC (P=0.006). In addition, the area under the curve (AUC) was 0.722 for COCC, 0.645 for CRP, and 0.618 for CEA, indicating that COCC was superior to CRP or CEA for CSS prediction. CONCLUSION: The COCC is an independent prognostic factor in patients with ESCC. We conclude that COCC was superior to CRP or CEA as a more precise prognostic factor in patients with ESCC. PMID- 25914551 TI - Health economic evaluations of medical devices in the People's Republic of China: A systematic literature review. AB - BACKGROUND: The objective of this study is to identify and review the methodological quality of health economic evaluations of medical devices performed in the People's Republic of China. To our knowledge, no such investigations have been performed to date. METHODS: A systematic literature review involving searches of Medline, Medline In-Process, the National Health Service Economic Evaluation Database, the Cost-Effectiveness Analysis Registry of the Tufts Medical Center, and the Wanfang Database was performed. The search spanned the period from 1990 to 2013. Studies on health economic evaluations of medical devices, in-vitro diagnostics, procedures, and the use of medical devices in Chinese health care settings were included. Full-text articles and conference abstracts in English and Chinese were included. RESULTS: Fifty-seven publications were included, 26 (46%) of which were in English and 31 (54%) of which were in Chinese. The included publications covered a wide range of clinical areas, such as surgery (n=23, 40%), screening (n=9, 16%), imaging use (n=6, 11%), kidney intervention (n=4, 7%), and nine other technological areas. Most of the studies (n=31, 54%) were cost analyses. Among the others, 13 (50%) studies used modeling, and another 13 (50%) were within-trial evaluations. Among studies that used modeling, eleven (85%) conducted sensitivity analyses, six of which had one-way sensitivity analysis, whereas one conducted both one-way and two-way sensitivity analyses; four of these eleven modeling-based analyses included probabilistic sensitivity analyses. The incremental cost-effectiveness ratio was reported in ten (18%) studies, eight of which were screening studies. The remaining two modeling studies were in areas of imaging and oncology. CONCLUSION: This study indicates that there are major limitations and deficiencies in the health economic evaluations on medical devices performed in the People's Republic of China. Further efforts are required from different stakeholders - academic, governmental, and privatized - to improve health economic research capacity and to put it to use when informative decisions are made in the health care setting. PMID- 25914552 TI - An innovative approach to the topical treatment of acne. AB - Acne is characterized by primary lesions on the face, chest, and back, and by a variety of other signs and symptoms. In particular, acne inflammatory lesions result from Propionibacterium acnes colonization and are of particular relevance as they can cause permanent scarring. Acne also causes significant psychological morbidity in affected patients. Products currently available for the treatment of acne include systemic and topical treatments. As these products can cause severe side effects, new, innovative therapies are needed. Farmaka Acne Cream (FAC) is a novel, film-forming cream developed to treat mild and moderate acne. In vitro studies have demonstrated that FAC is as effective as 5% benzoyl peroxide in inhibiting growth of P. acnes. In 32 subjects with mild or moderate acne, FAC reduced all the major signs and symptoms of the disease. These included itching, erythema, and scaling, as well as reductions in the numbers of papules, pustules, and open and closed comedones. Acne severity improved in 38% of subjects, while none worsened. FAC was found to be effective in controlling sebum secretion, and was non-comedogenic. Most subjects (90%) reported tolerability as good or very good, while clinical efficacy and cosmetic acceptability were judged as good. For assessment of contact sensitization and photosensitization, FAC was applied daily to the backs of 29 subjects in two symmetric areas for 10 days. Using a solar stimulator, one minimal erythema dose was delivered to one side of the back from days 11 to 13. The four different subareas of treated/untreated and irradiated/nonirradiated and combinations thereof were compared. No cases of contact sensitization or photosensitization were observed, and FAC is considered safe for use in intense sunlight. In vitro and in vivo studies provide evidence for the safety and clinical benefits of FAC, a promising candidate for the treatment of mild and moderate acne. PMID- 25914553 TI - A dermocosmetic containing bakuchiol, Ginkgo biloba extract and mannitol improves the efficacy of adapalene in patients with acne vulgaris: result from a controlled randomized trial. AB - BACKGROUND: Acne vulgaris is an inflammatory disorder of the pilosebaceous unit. AIM: To confirm that BGM (bakuchiol, Ginkgo biloba extract, and mannitol) complex increases the established clinical efficacy of adapalene 0.1% gel in patients with acne. METHODS: A clinical trial was conducted in acne patients. A total of 111 subjects received adapalene 0.1% gel and BGM complex or vehicle cream for 2 months. Assessments comprised Investigator Global Assessment (IGA), global efficacy, seborrhea intensity, inflammatory and non-inflammatory lesions, and subject perception, as well as overall safety and local tolerance and quality of life. RESULTS: At the end of the trial, inflammatory and non-inflammatory lesions, IGA, global efficacy, and seborrhea intensity had significantly improved in both treatment groups. Differences were statistically significant (P<0.05) in favor of BGM complex for inflammatory lesions as well as IGA and seborrhea intensity. Global efficacy assessments and subject perception confirmed the superiority of BGM complex-including treatment over the comparative combination. Quality of life had improved more with the active combination than with the vehicle combination. In the active group, four subjects had to interrupt temporarily BGM complex and 12 adapalene compared to seven subjects interrupting the vehicle and eleven adapalene in the vehicle group. One subject withdrew from the trial due to an allergy to adapalene. The majority of all events were mild. CONCLUSION: BGM complex improves the treatment outcome of adapalene 0.1% gel in patients with acne vulgaris. Overall, safety and local tolerance of BGM complex were good. PMID- 25914554 TI - Oral submucous fibrosis: an update. AB - Oral submucous fibrosis (OSF) is a premalignant condition caused by betel chewing. It is very common in Southeast Asia but has started to spread to Europe and North America. OSF can lead to squamous cell carcinoma, a risk that is further increased by concomitant tobacco consumption. OSF is a diagnosis based on clinical symptoms and confirmation by histopathology. Hypovascularity leading to blanching of the oral mucosa, staining of teeth and gingiva, and trismus are major symptoms. Major constituents of betel quid are arecoline from betel nuts and copper, which are responsible for fibroblast dysfunction and fibrosis. A variety of extracellular and intracellular signaling pathways might be involved. Treatment of OSF is difficult, as not many large, randomized controlled trials have been conducted. The principal actions of drug therapy include antifibrotic, anti-inflammatory, and antioxygen radical mechanisms. Potential new drugs are on the horizon. Surgery may be necessary in advanced cases of trismus. Prevention is most important, as no healing can be achieved with available treatments. PMID- 25914555 TI - Managing refractory Crohn's disease: challenges and solutions. AB - The goals of treatment for active Crohn's disease (CD) are to achieve clinical remission and improve quality of life. Conventional therapeutics for moderate-to severe CD include 5-aminosalicylic acid, corticosteroids, purine analogs, azathioprine, and 6-mercaptopurine. Patients who fail to respond to conventional therapy are treated with tumor necrosis factor (TNF)-alpha inhibitors such as infliximab and adalimumab, but their efficacy is limited due to primary nonresponse or loss of response. It is suggested that this requires switch to another TNF-alpha inhibitor, a combination therapy with TNF-alpha blockade plus azathioprine, or granulocyte and monocyte adsorptive apheresis, and that other therapeutic options having different mechanisms of action, such as blockade of inflammatory cytokines or adhesion molecules, are needed. Natalizumab and vedolizumab are neutralizing antibodies directed against integrin alpha4 and alpha4beta7, respectively. Ustekinumab is a neutralizing antibody directed against the receptors for interleukin-12 and interleukin-23. Here, we provide an overview of therapeutic treatments that are effective and currently available for CD patients, as well as some that likely will be available in the near future. We also discuss the advantages of managing patients with refractory CD using a combination of TNF-alpha inhibitors plus azathioprine or intensive monocyte adsorptive apheresis. PMID- 25914556 TI - Validation of algorithms to detect distant metastases in men with prostate cancer using routine registry data in Denmark. AB - OBJECTIVE: Among patients with prostate cancer, diagnostic codes for bone metastases in the Danish National Registry of Patients have a sensitivity of 44%. In an attempt to improve the sensitivity of registry-based identification of metastases from prostate cancer, we tested a series of algorithms, combining elevated prostate-specific antigen (PSA) levels, use of antiresorptive therapy, and performed bone scintigraphy. PATIENTS AND METHODS: We randomly selected 212 men diagnosed with prostate cancer in 2005-2010 in the Central Denmark Region with prespecified PSA values, antiresorptive therapy, and bone scintigraphy who did not have a registry-based diagnostic code indicating presence of distant metastases. We defined three candidate algorithms for bone metastases: 1) PSA >50 MUg/L and bone scintigraphy, 2) PSA >50 MUg/L and antiresorptive therapy, and 3) PSA <=50 MUg/L with antiresorptive therapy or bone scintigraphy. An algorithm for distant metastasis site other than bone was defined as PSA >50 MUg/L alone. Medical chart review was used as the reference standard to establish the presence or absence of metastases. Validity was expressed as a positive predictive value (PPV) or a negative predictive value, based on whether the algorithms correctly classified metastases compared with the reference standard. RESULTS: We identified 113 men with evidence of metastases according to the candidate algorithms, and 99 men without evidence of metastases according to the candidate algorithm. The PPVs of PSA >50 MUg/L were 0.10 (95% confidence interval [CI] 0.04 0.19) for bone metastases and 0.14 (95% CI 0.07-0.24) for nonbone metastases, regardless of receipt of antiresorptive therapy or presence of bone scintigraphy. The PPVs for any metastases were 0.16 (95% CI 0.06-0.32) for PSA >50 MUg/L and 0.28 (95% CI 0.14-0.47) for PSA >50 MUg/L with bone scintigraphy. Adding antiresorptive treatment to the algorithm did not improve PPV. All negative predictive values approached 1.00. CONCLUSION: Algorithms based on elevated PSA, antiresorptive therapy, or bone scintigraphy are not suitable for supplementing diagnostic codes to identify additional cases of distant metastases among men with prostate cancer. However, it is possible that in this setting, medical chart review is not a gold standard to identify metastases. PMID- 25914557 TI - Sociodemographic drivers of multiple sexual partnerships among women in three rural districts of Tanzania. AB - BACKGROUND: This study examines prevalence and correlates of multiple sexual partnerships (MSP) among women aged 15+ years in Rufiji, Kilombero, and Ulanga districts of Tanzania. MATERIALS AND METHODS: Data were collected in a cross sectional household survey in Rufiji, Kilombero, and Ulanga districts in Tanzania in 2011. From the survey, a total of 2,643 sexually active women ages 15+ years were selected for this analysis. While the chi-square test was used for testing association between MSP and each of the independent variables, logistic regression was used for multivariate analysis. RESULTS: Number of sexual partners reported ranged from 1 to 7, with 7.8% of the women reporting multiple sexual partners (2+) in the past year. MSP was more likely among both ever married women (adjusted odds ratio [AOR] =3.83, 95% confidence interval [CI] 1.40-10.49) and single women (AOR =6.13, 95% CI 2.45-15.34) than currently married women. There was an interaction between marital status and education, whereby MSP was 85% less likely among single women with secondary or higher education compared to married women with no education (AOR =0.15, 95% CI 0.03-0.61). Furthermore, women aged 40+ years were 56% less likely compared to the youngest women (<20 years) to report MSP (AOR =0.44, 95% CI 0.24-0.80). The odds of MSP among Muslim women was 1.56 times as high as that for Christians women (AOR =1.56, 95% CI 1.11-2.21). Ndengereko women were 67% less likely to report MSP compared to Pogoro women (AOR =0.33, 95% CI 0.18-0.59). CONCLUSION: Eight percent of the women aged 15+ in Rufiji, Kilombero, and Ulanga districts of Tanzania are engaged in MSP. Encouraging achievement of formal education, especially at secondary level or beyond, may be a viable strategy toward partner reduction among unmarried women. Age, religion, and ethnicity are also important dimensions for partner reduction efforts. PMID- 25914558 TI - Factors influencing CD4 cell count in HIV-positive pregnant women in a secondary health center in Lagos, Nigeria. AB - BACKGROUND: Immunity in pregnancy is physiologically compromised, and this may affect CD4 count levels. It is well-established that several factors affect CD4 count level in pregnancy. This study aimed to determine the mean and reference range of CD4 count in human immunodeficiency virus (HIV)-positive pregnant women in Lagos, Nigeria. METHODS: A retrospective study was carried out at antenatal clinics of the Maternal and Child Center of a secondary health center in Lagos State, Nigeria. Records of HIV-positive pregnant women at various gestational ages, including CD4+ cell count at booking, packed cell volume (PCV) at booking and labor, gestational age at delivery, and infant weight and sex were retrieved. The descriptive data was given as mean +/- standard deviation (SD). Pearson's chi squared test and correlation were used for analytical assessment. RESULTS: Data were retrieved for a total of 143 patients. The mean age was 31.15+/-3.78 years. The mean PCV was 31.01%+/-3.79% at booking and 30.49%+/-4.80% during labor. The mean CD4 count was 413.87+/-212.09 cells/MUL, with a range of 40 to 1,252 cells/MUL. The mean infant weight was 3.05+/-0.45 kg, with a range of 2 to 5 kg. Age of the mother, gestational age, and PCV at booking were not statistically significantly associated with CD4 count. CONCLUSION: Maternal age, gestational age, and PCV at booking had no significant effects on CD4+ cell count levels in pregnancy. The mean CD4+ cell count of HIV-positive pregnant women in Lagos is 413.87+/-212.09 cells/MUL. PMID- 25914559 TI - Planned home birth: benefits, risks, and opportunities. AB - While the number of women in developed countries who plan a home birth is low, the number has increased over the past decade in the US, and there is evidence that more women would choose this option if it were readily available. Rates of planned home birth range from 0.1% in Sweden to 20% in the Netherlands, where home birth has always been an integrated part of the maternity system. Benefits of planned home birth include lower rates of maternal morbidity, such as postpartum hemorrhage, and perineal lacerations, and lower rates of interventions such as episiotomy, instrumental vaginal birth, and cesarean birth. Women who have a planned home birth have high rates of satisfaction related to home being a more comfortable environment and feeling more in control of the experience. While maternal outcomes related to planned birth at home have been consistently positive within the literature, reported neonatal outcomes during planned home birth are more variable. While the majority of investigations of planned home birth compared with hospital birth have found no difference in intrapartum fetal deaths, neonatal deaths, low Apgar scores, or admission to the neonatal intensive care unit, there have been reports in the US, as well as a meta-analysis, that indicated more adverse neonatal outcomes associated with home birth. There are multiple challenges associated with research designs focused on planned home birth, in part because conducting randomized controlled trials is not feasible. This report will review current research studies published between 2004 and 2014 related to maternal and neonatal outcomes of planned home birth, and discuss strengths, limitations, and opportunities regarding planned home birth. PMID- 25914560 TI - Red blood cell parameters in antenatal nonsickling hemoglobinopathy screening. AB - OBJECTIVE: To find a hematological parameter and the cut-off level for identification of nonsickling hemoglobinopathies in pregnant women. MATERIALS AND METHODS: Venous blood samples of 849 women with singleton pregnancies were collected at the first visit. All women who met inclusion criteria were examined for nonsickling hemoglobinopathy. On the basis of the sensitivity and the specificity of different cut-off levels for hematological parameters, we calculated the optimal clinically practicable parameter for screening of nonsickling hemoglobinopathies in pregnant women. RESULTS: On the basis of the sensitivity and the specificity, the best screening parameters for the identification of nonsickling hemoglobinopathies among nonanemic pregnant women are mean corpuscular volume (MCV) with cut-off <=80 fL (Youden's index 91.2%), mean corpuscular hemoglobin (MCH) <27.5 pg (Youden's index 90.7%), and microcytosis (MRC) >=3% (Youden's index 90.2%). An analysis using receiver operating characteristic curves and the calculated Youden's index showed that MCV <=76 fL, MCH <=24 pg, or MRC >=10% are the best red blood cell indices for the screening of nonsickling hemoglobinopathy among anemic women with iron deficiency. CONCLUSION: Our results suggest targeted screening for nonsickling hemoglobinopathies in nonanemic pregnant women with MCV <=80 fL, MCH <=27.5 pg, or MRC >=3% and in anemic women with MCV <=76 fL, MCH <=24 pg, or MRC >=10%. PMID- 25914561 TI - Magnetic localization and orientation of the capsule endoscope based on a random complex algorithm. AB - The development of the capsule endoscope has made possible the examination of the whole gastrointestinal tract without much pain. However, there are still some important problems to be solved, among which, one important problem is the localization of the capsule. Currently, magnetic positioning technology is a suitable method for capsule localization, and this depends on a reliable system and algorithm. In this paper, based on the magnetic dipole model as well as magnetic sensor array, we propose nonlinear optimization algorithms using a random complex algorithm, applied to the optimization calculation for the nonlinear function of the dipole, to determine the three-dimensional position parameters and two-dimensional direction parameters. The stability and the antinoise ability of the algorithm is compared with the Levenberg-Marquart algorithm. The simulation and experiment results show that in terms of the error level of the initial guess of magnet location, the random complex algorithm is more accurate, more stable, and has a higher "denoise" capacity, with a larger range for initial guess values. PMID- 25914562 TI - Complications following arthroscopic fixation of acromioclavicular separations: a systematic review of the literature. AB - PURPOSE: Over the past decade, a number of arthroscopic or arthroscopically assisted reconstruction techniques have emerged for the management of acromioclavicular (AC) separations. These techniques provide the advantage of superior visualization of the base of the coracoid, less soft tissue dissection, and smaller incisions. While these techniques have been reported to provide excellent functional results with minimal complications, discrepancies exist within the literature. This systematic review aims to assess the rate of complications following these procedures. METHODS: Two independent reviewers completed a search of Medline, Embase, PubMed, and the Cochrane Library entries up to December 2013. The terms "Acromioclavicular Joint (MeSH)" OR "acromioclavicular* (text)" OR "coracoclavicular* (text)" AND "Arthroscopy (MeSH)" OR "Arthroscop* (text)" were used. Pooled estimates and 95% confidence intervals were calculated assuming a random-effects model. Statistical heterogeneity was quantified using the I(2) statistic. LEVEL OF EVIDENCE: IV. RESULTS: A total of 972 abstracts met the search criteria. After removal of duplicates and assessment of inclusion/exclusion criteria, 12 articles were selected for data extraction. The rate of superficial infection was 3.8% and residual shoulder/AC pain or hardware irritation occurred at a rate of 26.7%. The rate of coracoid/clavicle fracture was 5.3% and occurred most commonly with techniques utilizing bony tunnels. Loss of AC joint reduction occurred in 26.8% of patients. CONCLUSION: Arthroscopic AC reconstruction techniques carry a distinct complication profile. The TightRope/Endobutton techniques, when performed acutely, provide good radiographic outcomes at the expense of hardware irritation. In contrast, graft reconstructions in patients with chronic AC separations demonstrated a high risk for loss of reduction. Fractures of the coracoid/clavicle remain a significant complication occurring predominately with techniques utilizing bony tunnels. PMID- 25914563 TI - All-cause mortality from obstructive sleep apnea in male and female patients with and without continuous positive airway pressure treatment: a registry study with 10 years of follow-up. AB - BACKGROUND: More information is needed about the effect on mortality of continuous positive airway pressure (CPAP) in patients with obstructive sleep apnea (OSA), especially in women. METHODS: We employed a historical cohort study design, using data from 25,389 patients with a diagnosis of OSA selected from the Danish National Patient Registry for the period 1999-2009. We used Cox proportional hazard function to evaluate the all-cause mortality from OSA in middle-aged and elderly males and females who were treated, or not, with CPAP. RESULTS: Female OSA patients had a lower mortality than males, irrespective of whether they received CPAP treatment. CPAP treatment improved survival, as illustrated by the hazard ratio of 0.62 (P<0.001). This effect was dependent on gender: CPAP had no significant effect on 20- to 39-year-old males and females, but the overall mortality in this age group was small. Survival was increased by CPAP in 40- to 59-year-old and >=60-year-old males, but no such effect was observed in females. Positive predictors of survival were young age, female gender, higher educational level, and low 3-year prior comorbidity as estimated by the Charlson Comorbidity Index. Negative predictors for survival were male gender, age >=60 years, no CPAP treatment, prior comorbidity, and low educational level. CONCLUSION: CPAP therapy is associated with reduced all-cause mortality in middle-aged and elderly males, but no significant effect was found in females. PMID- 25914564 TI - Predictors of self-reported academic performance among undergraduate medical students of Hawassa University, Ethiopia. AB - BACKGROUND: This study was conducted to identify predictors of self-reported academic performance in undergraduate medical students at Hawassa University. METHODS: An analytical cross-sectional study involving 592 undergraduate medical students was conducted in November 2012. The academic performance of the study subjects was measured by self-reported cumulative grade point average (GPA) using a self-administered questionnaire. Data were entered and analyzed using Statistical Package for the Social Sciences version 16 software. Pearson's bivariate correlations, multiple linear regression, and multiple logistic regression were used to identify predictors of academic performance. RESULTS: The self-reported academic performance of students had been decreasing as the academic years progressed, with the highest and lowest performance being in the premedicine (mean GPA 3.47) and clinical I (mean GPA 2.71) years, respectively. One hundred and fifty-eight (26.7%) of the participants had ever been delayed, 37 (6.2%) had ever re-sat for examination, and two (0.3%) had ever been warned due to academic failure. The overall variation in self-reported academic performance of the students was 32.8%. Participant age alone explained 21.9% of the variation. On the other hand, university entrance examination results, substance use at university, and medicine as first choice by students were identified as predictors of variation in self-reported academic performance, accounting for 6.9%, 2.7%, and <1% of the variation, respectively. Students who had never used tobacco, alcohol, or khat after starting university were twice as likely to score a self-reported cumulative GPA above 3.0 (adjusted odds ratio 1.95, 95% confidence interval 1.25-3.02) and less likely to be delayed, have to re-sit an examination, or be warned (adjusted odds ratio 0.47, 95% confidence interval 0.29 0.77). CONCLUSION: Only 32.8% of the variation in self-reported academic performance was explained by the studied variables. Hence, efficacious mechanisms should be designed to combat the intervenable determinants of self-reported academic performance, like substance use and a low medical school entrance examination result. Further studies should also be undertaken to gain a better understanding of other unstudied determinants, like personality, learning style, cognitive ability, and the system used for academic evaluation. PMID- 25914565 TI - Workplace-based assessment; learner and assessor perspectives. AB - OBJECTIVE: To examine the acceptability and educational impact of the workplace based assessment program for international medical graduates on candidates and assessors. METHOD: A grounded theory-based qualitative analysis of the experiences of 17 candidates and eleven assessors using focus groups, interviews, and surveys. RESULTS: Both candidates and assessors identified positive opportunities for improved performance of international medical graduates. Their integration into the workforce was facilitated by improved communication and peer acceptance, from ongoing multifaceted feedback and time to practice skills. CONCLUSION: This study showed a high level of acceptability of the Newcastle workplace-based assessment program among candidates and assessors. PMID- 25914566 TI - A sense of connection. PMID- 25914567 TI - Paediatric palliative care: There is always more we can do. PMID- 25914568 TI - Canadian paediatic palliative care: Challenges and promises. PMID- 25914569 TI - Questions to consider when caring for a child with a high risk of dying before adulthood. PMID- 25914570 TI - When health care professionals say "more" and parents say "enough". PMID- 25914571 TI - When parents say "more" and health care professionals say "enough". PMID- 25914572 TI - Charting the Territory: Children and families living with progressive life threatening conditions. AB - OBJECTIVES: To increase awareness of the topic of paediatric palliative care among practicing physicians in Canada by exploring the impact of a child's neurological or rare genetic life-threatening condition on the affected child and his/her parents. METHODS: Cross-sectional, baseline results from an observational, longitudinal study, Charting the Territory, which followed 275 children and 390 parents from 258 families. Parents completed multiple surveys, for themselves and their child. RESULTS: These children had a high symptom burden. The three most common symptoms were pain, sleep problems and feeding difficulties; on average, they had 3.2 symptoms of concern. Despite analgesic use, the frequency of pain episodes and distress were invariant over time, suggesting that treatments were not successful. Parents experienced anxiety, depression and burden; at the same time they also reported positive life change and a high degree of spirituality. The child's condition resulted in parental changes in living arrangements, work status and hours devoted to caregiving. Nearly two-thirds of families were involved with a palliative care team; the size of the community in which a family resided did not make a significant difference in such involvement. CONCLUSIONS: These families experience many challenges, for the patient, other individual members and the family as a whole. At least some of these challenges may be alleviated by early and organized palliative care. Effective interventions are needed to enhance symptom management for the ill child and to alleviate the various negative impacts on the family. PMID- 25914573 TI - Quality indicators for paediatric palliative care. AB - OBJECTIVES: To apply quality indicators for paediatric palliative care and evaluate performance in one service provision area. METHODS: After institutional review board approval, medical records were abstracted for well-defined and measurable quality indicators for children with chronic complex conditions (CCCs) between January 2006 and December 2011 (n=50) at a university medical centre. RESULTS: Of the 50 children with a CCC (mean age 64 months, 48% female), 39 (78%) died in hospital, 11 (22%) died at home and 13 (26%) were <1 month of age. In the final month of their life, 10 patients (20%) required an unplanned visit to the emergency department and seven (14%) were admitted. Only four patients (8%) were admitted for >14 days in their final month of life. Goals of care were addressed in a timely manner 60% of the time. An invasive procedure was performed in the final month of life in 27 (44%) patients. Bereavement follow-up was offered to 25 (50%) families. A palliative care consultant was involved with 17 (34%) patients. Palliative care was associated with less frequent invasive procedures in the final month of life and more frequent documentation of the preferred place of death. CONCLUSION: Performance on these particular quality indicators was unsatisfactory across a diverse group of children with CCCs, indicating important opportunities for improvement. Methods used to improve the quality of other aspects of paediatric care, including emphasis on efficient work systems, practical tools and interdisciplinary teamwork, should be used for ensuring delivery of high-quality palliative care. PMID- 25914574 TI - Re: P Mang'oli, J Theuri, T Kollmann, NE MacDonald. Ponseti clubfoot management: Experience with the Steenbeek foot abduction brace. Paediatr Child Health 2014;19(10):513-514. PMID- 25914575 TI - Case 1: A primary care provider enhances family support in perinatal palliative care. PMID- 25914576 TI - Case 2: A 10-year-old boy with leg pain and swelling. PMID- 25914577 TI - Paediatric palliative care in Canada: A national survey of paediatricians. PMID- 25914578 TI - Introducing a lexicon of terms for paediatric palliative care. PMID- 25914579 TI - Challenging neurological symptoms in paediatric palliative care: An approach to symptom evaluation and management in children with neurological impairment. AB - Neurological symptoms are very common in children with life-limiting conditions and are challenging in terms of burden of illness. Moreover, neurological symptoms can significantly impact the child's quality of life and contribute to distress among parents, families, caregivers and health care providers. Knowing how to manage and alleviated these symptoms is essential for providing good palliative care. In the present article, the more common neurological symptoms of agitation/irritability, spasticity and dystonia will be reviewed. The aim of the present brief review is to provide a basic approach to both the identification and treatment of these neurological symptoms. A medication table is provided for quick reference. A brief commentary and guidance for the management of pain are also incorporated, with reference to further literature sources. PMID- 25914580 TI - Erratum: Re: Wong PD, Dave MG, Tulloch T, et al. Community health centres: Potential opportunities for community paediatrics. From interprofessional clinical care to board governance. Paediatr Child Health 2015;20(1):12-14. AB - [This corrects the article on p. 12 in vol. 20, PMID: 25722635.]. PMID- 25914581 TI - Identification of a novel gene (Apq1) from the indica rice cultivar 'Habataki' that improves the quality of grains produced under high temperature stress. AB - The appearance of brown rice grown under high temperature conditions is an important characteristic for improvement in Japanese rice breeding programs. We performed a QTL analysis of the appearance quality of brown rice using chromosome segment substitution lines of the indica cultivar 'Habataki' in the 'Koshihikari' genetic background. A line carrying a 'Habataki' segment on chromosome 7 showed a high percentage of perfect grains produced under high temperature conditions during the ripening period. To verify the role of this segment, and to narrow down the region containing the useful allele, substitution mapping was performed using multiple paired lines. As a result, the chromosomal location of a gene that we named Appearance quality of brown rice 1 (Apq1) was delimited to a 48-kb region. In addition, we developed an Apq1-near isogenic line (NIL) to evaluate the effect of Apq1 on various agronomic traits. Under high temperature conditions during the ripening period, the Apq1-NIL produced significantly higher percentages of perfect grains than 'Koshihikari'. Other agronomic traits, including yield and palatability, were similar between the Apq1-NIL and 'Koshihikari'. Therefore, the 'Habataki' allele of Apq1 will be useful in breeding programs aimed at improving the quality of grains ripened under high temperature conditions. PMID- 25914582 TI - Mapping quantitative trait loci for yield-related traits in soybean (Glycine max L.). AB - Development of soybean cultivars with high seed yield is a major focus in soybean breeding programs. This study was conducted to identify genetic loci associated with seed yield-related traits in soybean and also to clarify consistency of the detected QTLs with QTLs found by previous researchers. A population of 135 F2:3 lines was developed from a cross between a vegetable soybean line (MJ0004-6) and a landrace cultivar from Myanmar (R18500). They were evaluated in the experimental field of Kasetsart University, Kamphaeng Saen, Nakhon Pathom, Thailand in a randomized complete block design with two replications each in 2011 and 2012 growing seasons. The two parents exhibited contrasting characteristics for most of the traits that were mapped. Analysis of variance showed that the main effects of genotype and environment (year) were significant for all studied traits. Genotype by environment interaction was also highly significant for all the traits. The population was genotyped by 149 polymorphic SSR markers and the genetic map consisted of 129 SSR loci which converged into 38 linkage groups covering 1156 cM of soybean genome. There were 10 QTLs significantly associated with seed yield-related traits across two seasons with single QTLs explaining between 5.0% to 21.9% of the phenotypic variation. Three of these QTLs were detected in both years for days to flowering, days to maturity and 100 seed weight. Most of the detected QTLs in our research were consistent with earlier QTLs reported by previous researchers. However, four novel QTLs including SF1, SF2 and SF3 on linkage groups L and N for seed filling period and PN1 on linkage group D1b for pod number were identified in the present study. PMID- 25914583 TI - Rapid genotyping with DNA micro-arrays for high-density linkage mapping and QTL mapping in common buckwheat (Fagopyrum esculentum Moench). AB - For genetic studies and genomics-assisted breeding, particularly of minor crops, a genotyping system that does not require a priori genomic information is preferable. Here, we demonstrated the potential of a novel array-based genotyping system for the rapid construction of high-density linkage map and quantitative trait loci (QTL) mapping. By using the system, we successfully constructed an accurate, high-density linkage map for common buckwheat (Fagopyrum esculentum Moench); the map was composed of 756 loci and included 8,884 markers. The number of linkage groups converged to eight, which is the basic number of chromosomes in common buckwheat. The sizes of the linkage groups of the P1 and P2 maps were 773.8 and 800.4 cM, respectively. The average interval between adjacent loci was 2.13 cM. The linkage map constructed here will be useful for the analysis of other common buckwheat populations. We also performed QTL mapping for main stem length and detected four QTL. It took 37 days to process 178 samples from DNA extraction to genotyping, indicating the system enables genotyping of genome-wide markers for a few hundred buckwheat plants before the plants mature. The novel system will be useful for genomics-assisted breeding in minor crops without a priori genomic information. PMID- 25914584 TI - Quantitative trait loci associated with lodging tolerance in soybean cultivar 'Toyoharuka'. AB - Lodging tolerance (LT) is an important trait for high yield and combine harvesting efficiency in soybean [Glycine max (L.) Merr.]. Many previous studies have investigated quantitative trait loci (QTLs) for lodging score (LS) in soybean. Most of the investigated QTLs were located in the proximal region of maturity or growth habit loci. The aim of this study was to identify genetic factors for LT not associated with maturity or growth habit. QTL analysis was performed using a recombinant inbred line (RIL) population derived from a cross between 'Toyoharuka' (TH), a lodging-tolerant cultivar, and 'Toyomusume' (TM). The genotypes of TH and TM were estimated as both e1e2E3E4 and dt1. The average LS over 4 years was used for QTL analysis, identifying a major and stable QTL, qLS19-1, on chromosome 19. The LS of the near-isogenic line (NIL) with the TH allele at Sat_099, the nearest marker to qLS19-1, was significantly lower than the NIL with the TM allele at that position. The TH allele at Sat_099 rarely had a negative influence on seed yield or other agronomic traits in both NILs and the TM-backcrossed lines. Our results suggest that marker-assisted selection for qLS19-1 is effective for improving LT in breeding programs. PMID- 25914585 TI - Two linked genes on rice chromosome 2 for F1 pollen sterility in a hybrid between Oryza sativa and O. glumaepatula. AB - Hybrid incompatibility plays an important role in establishment of post-zygotic reproductive isolation. To unveil genetic basis of hybrid incompatibilities between diverged species of genus Oryza AA genome species, we conducted genetic dissection of hybrid sterility loci, S22(t), which had been identified in backcross progeny derived from Oryza sativa ssp. japonica (recurrent parent) and South American wild rice O. glumaepatula near the end of the short arm of chromosome 2. The S22(t) region was found to be composed of two loci, designated S22A and S22B, that independently induce F1 pollen sterility. Pollen grains containing either of the sterile alleles (S22A-glum (s) or S22B-glum (s) ) were sterile if produced on a heterozygous plant. No transmission of the S22A-glum (s) allele via pollen was observed, whereas a low frequency of transmission of S22B glum (s) was observed. Cytological analysis showed that the sterile pollen grains caused by S22A could reach the bicellular or tricellular stage, and the nearly sterile pollen grains caused by S22B could reach the tricellular stage. Our genetic analysis showed repulsion linkage effect is possible to induce strong reproductive barrier by high pollen sterility based on recombination value and transmission ratio of hybrid sterility gene to the progeny was influenced by frequency of competitors on fertilization. PMID- 25914586 TI - Assessing and broadening genetic diversity of a rapeseed germplasm collection. AB - Assessing the level of genetic diversity within a germplasm collection contributes to evaluating the potential for its utilization as a gene pool to improve the performance of cultivars. In this study, 45 high-quality simple sequence repeat (SSR) markers were screened and used to estimate the genetic base of a world-wide collection of 248 rapeseed (Brassica napus) inbred lines. For the whole collection, the genetic diversity of A genome was higher than that of C genome. The genetic diversity of C genome for the semi-winter type was the lowest among the different germplasm types. Because B. oleracea is usually used to broaden the genetic diversity of C genome in rapeseed, we evaluated the potential of 25 wild B. oleracea lines. More allelic variations and a higher genetic diversity were observed in B. oleracea than in rapeseed. One B. oleracea line and one oilseed B. rapa line were used to generate a resynthesized Brassica napus line, which was then crossed with six semi-winter rapeseed cultivars to produce 7 F1 hybrids. Not only the allele introgression but also mutations were observed in the hybrids, resulting in significant improvement of the genetic base. PMID- 25914587 TI - Major QTLs associated with green stem disorder insensitivity of soybean (Glycine max (L.) Merr.). AB - Green stem disorder (GSD) is one of the most serious syndromes affecting soybean (Glycine max) cultivation in Japan. In GSD, stems remain green even when pods mature. When soybean plants develop GSD, seed surfaces are soiled by tissue fluid and seed quality is deteriorated during machine harvesting. We performed quantitative trait locus (QTL) analyses for GSD insensitivity using recombinant inbred lines (RILs; n = 154) derived from a cross between an insensitive line ('Touhoku 129') and a sensitive leading cultivar ('Tachinagaha') during a 6-year evaluation. Three effective QTLs were detected. The influences of these QTLs were in the following order: qGSD1 (LG_H) > qGSD2 (LG_F) > qGSD3 (LG_L). At these three QTLs, 'Touhoku 129' genotypes exhibited more GSD insensitivity than 'Tachinagaha' genotypes. The lower incidence of GSD for 'Touhoku129' was attributable primarily to these three QTLs because RILs harboring a 'Touhoku 129' genotype at the three QTLs exhibited a GSD incidence similar to that of 'Touhoku 129.' Although a limitation of this study is that only one mapping population was evaluated, this QTL information and the flanking markers of these QTLs would be effective tools for resolving GSD in soybean breeding programs. PMID- 25914588 TI - Discovery and genetic analysis of non-bitter Tartary buckwheat (Fagopyrum tataricum Gaertn.) with trace-rutinosidase activity. AB - In a screening of about 500 lines of Tartary buckwheat, we identified lines that contained no detectable rutinosidase isozymes using an in-gel detection assay. We confirmed that seeds of these individuals had only a trace level of in-vitro rutinosidase activity. To investigate the heritability of the trace-rutinosidase characteristic, we analyzed the progeny of crosses between rutinosidase trace lines, 'f3g-162', and the 'Hokkai T8'. The F2 progeny clearly divided into two groups: those with rutinosidase activity under 1.5 nkat/g seed (trace rutinosidase) and those with activity over 400 nkat/g seed (normal rutinosidase). The segregation pattern of this trait in F2 progeny exhibited 1 : 3 ratio (trace rutinosidase : normal rutinosidase), suggesting that the trace-rutinosidase trait is conferred by a single recessive gene; rutinosidase-trace A (rutA). In addition, sensory panelists evaluated the bitterness of flour from trace rutinosidase individuals and did not detect bitterness, whereas flour from normal rutinosidase individuals was found to have strong bitterness. Although at least three bitter compounds have been reported in Tartary buckwheat seeds, our present findings indicate that rutin hydrolysis is the major contributing factor to bitterness. In addition, the trace-rutinosidase line identified here, 'f3g-162', is a promising material for generating a non-bitter Tartary buckwheat variety. PMID- 25914589 TI - Breeding of 'Manten-Kirari', a non-bitter and trace-rutinosidase variety of Tartary buckwheat (Fagopyrum tataricum Gaertn.). AB - Here, we developed a new Tartary buckwheat cultivar 'Manten-Kirari', whose flour contains only trace amounts of rutinosidase and lacked bitterness. The trace rutinosidase breeding line 'f3g-162' (seed parent), which was obtained from a Nepalese genetic resource, was crossed with 'Hokkai T8' (pollen parent), the leading variety in Japan, to improve its agronomic characteristics. The obtained progeny were subjected to performance test. 'Manten-Kirari' had no detectable rutinosidase isozymes in an in-gel detection assay and only 1/266 of the rutinosidase activity of 'Hokkai T8'. Dough prepared from 'Manten-Kirari' flour contained almost no hydrolyzed rutin, even 6 h after the addition of water, whereas the rutin in 'Hokkai T8' dough was completely hydrolyzed within 10 min. In a sensory evaluation of the flour from the two varieties, nearly all panelists detected strong bitterness in 'Hokkai T8', whereas no panelists reported bitterness in 'Manten-Kirari'. This is the first report to describe the breeding of a Tartary buckwheat cultivar with reduced rutin hydrolysis and no bitterness in the prepared flour. Notably, the agronomic characteristics of 'Manten-Kirari' were similar to those of 'Hokkai T8', which is the leading variety in Japan. Based on these characteristics, 'Manten-Kirari' is a promising for preparing non bitter, rutin-rich foods. PMID- 25914590 TI - Identification of QTLs controlling harvest time and fruit skin color in Japanese pear (Pyrus pyrifolia Nakai). AB - Using an F1 population from a cross between Japanese pear (Pyrus pyrifolia Nakai) cultivars 'Akiakari' and 'Taihaku', we performed quantitative trait locus (QTL) analysis of seven fruit traits (harvest time, fruit skin color, flesh firmness, fruit weight, acid content, total soluble solids content, and preharvest fruit drop). The constructed simple sequence repeat-based genetic linkage map of 'Akiakari' consisted of 208 loci and spanned 799 cM; that of 'Taihaku' consisted of 275 loci and spanned 1039 cM. Out of significant QTLs, two QTLs for harvest time, one for fruit skin color, and one for flesh firmness were stably detected in two successive years. The QTLs for harvest time were located at the bottom of linkage group (LG) Tai3 (nearest marker: BGA35) and at the top of LG Tai15 (nearest markers: PPACS2 and MEST050), in good accordance with results of genome wide association study. The PPACS2 gene, a member of the ACC synthase gene family, may control harvest time, preharvest fruit drop, and fruit storage potential. One major QTL associated with fruit skin color was identified at the top of LG 8. QTLs identified in this study would be useful for marker-assisted selection in Japanese pear breeding programs. PMID- 25914591 TI - Identification of quantitative trait loci associated with boiled seed hardness in soybean. AB - Boiled seed hardness is an important factor in the processing of soybean food products such as nimame and natto. Little information is available on the genetic basis for boiled seed hardness, despite the wide variation in this trait. DNA markers linked to the gene controlling this trait should be useful in soybean breeding programs because of the difficulty of its evaluation. In this report, quantitative trait locus (QTL) analysis was performed to reveal the genetic factors associated with boiled seed hardness using a recombinant inbred line population developed from a cross between two Japanese cultivars, 'Natto-shoryu' and 'Hyoukei-kuro 3', which differ largely in boiled seed hardness, which in 'Natto-shoryu' is about twice that of 'Hyoukei-kuro 3'. Two significantly stable QTLs, qHbs3-1 and qHbs6-1, were identified on chromosomes 3 and 6, for which the 'Hyoukei-kuro 3' alleles contribute to decrease boiled seed hardness for both QTLs. qHbs3-1 also showed significant effects in progeny of a residual heterozygous line and in a different segregating population. Given its substantial effect on boiled seed hardness, SSR markers closely linked to qHbs3 1, such as BARCSOYSSR_03_0165 and BARCSOYSSR_03_0185, could be useful for marker assisted selection in soybean breeding. PMID- 25914592 TI - A novel GmFAD3-2a mutant allele developed through TILLING reduces alpha-linolenic acid content in soybean seed oil. AB - Soybean (Glycine max (L.) Merr.) oil typically contains 8% alpha-linolenic acid that is highly unstable and easily oxidized. This property is undesirable in many food and industrial applications. Genetic strategies for reducing alpha-linolenic acid content would enhance the commercial value. However, genetic resources for low alpha-linolenic acid content are limited among natural soybean variations. Microsomal omega-3-fatty acid desaturase (FAD3) is responsible for the synthesis of alpha-linolenic acid in the polyunsaturated fatty acid pathway. There are four FAD3 homologs (Glyma02g39230, Glyma11g27190, Glyma14g37350 and Glyma18g06950) in the soybean genome. While non-functional alleles have been reported for Glyma02g39230 (GmFAD3-1a) and Glyma14g37350 (GmFAD3-1b), little variation is seen in Glyma18g06950 (GmFAD3-2a). We isolated seven mutant GmFAD3-2a alleles, each containing a single-nucleotide substitution, from 39,100 independent mutant lines by using targeting induced local lesions in genomes (TILLING). Analysis of GmFAD3 2a transcripts and enzyme activities revealed that one missense mutant, 'P1-A9', contains a non-functional allele of GmFAD3-2a. By combining three non-functional alleles (GmFAD3-1a, GmFAD3-1b, and GmFAD3-2a), we generated soybean lines containing <2% alpha-linolenic acid in their seeds. The reverse-genetics-based development of novel mutant alleles in the fatty acid metabolic pathway will allow the improvement of soybean with better oil quality through conventional breeding. PMID- 25914593 TI - Detection of QTLs for salt tolerance in Asian barley (Hordeum vulgare L.) by association analysis with SNP markers. AB - Two hundred ninety-six Asian barley (Hordeum vulgare L.) accessions were assessed to detect QTLs underlying salt tolerance by association analysis using a 384 single nucleotide polymorphism (SNP) marker system. The experiment was laid out at the seedling stage in a hydroponic solution under control and 250 mM NaCl solution with three replications of four plants each. Salt tolerance was assessed by leaf injury score (LIS) and salt tolerance indices (STIs) of the number of leaves (NL), shoot length (SL), root length (RL), shoot dry weight (SDW) and root dry weight (RDW). LIS was scored from 1 to 5 according to the severity of necrosis and chlorosis observed on leaves. There was a wide variation in salt tolerance among Asian barley accessions. LIS and STI (SDW) were the most suitable traits for screening salt tolerance. Association was estimated between markers and traits to detect QTLs for LIS and STI (SDW). Seven significant QTLs were located on chromosomes 1H (2 QTLs), 2H (2 QTLs), 3H (1 QTL), 4H (1 QTL) and 5H (1 QTL). Five QTLs were associated with LIS and 2 QTLs with STI (SDW). Two QTLs associated with LIS were newly identified on chromosomes 3H and 4H. PMID- 25914594 TI - Kernel number as a positive target trait for prediction of hybrid performance under low-nitrogen stress as revealed by diallel analysis under contrasting nitrogen conditions. AB - Environmental sustainability concerns make improving yield under lower N input a desirable breeding goal. To evaluate genetic variation and heterosis for low-N tolerance breeding, 28 F1 hybrids from a diallel scheme, along with their eight parental lines, were tested for agronomic traits including kernel number per ear (KNE) and grain yield per plant (GY), in replicated plots over two years under low-nitrogen (LN, without nitrogen application) and normal-nitrogen (NN, 220 kg N ha(-1)) conditions. Taken together the heritability in this and our previous studies, the correlation with grain yield, and the sensitivity to the stress for target trait selection, KNE was a good secondary target trait for LN selection in maize breeding. KNE also showed much higher mid-parent heterosis than hundred kernel weight under both nitrogen levels, particularly under LN, indicating that KNE contributed the majority of GY heterosis, particularly under LN. Therefore, KNE can be used as a positive target trait for hybrid performance prediction in LN tolerance breeding. Our results also suggest that breeding hybrids for LN tolerance largely relies on phenotypic evaluation of hybrids under LN condition and yield under LN might be improved more by selection for KNE than by direct selection for GY per se. PMID- 25914595 TI - Genetic characterization of wild barley populations (Hordeum vulgare ssp. spontaneum) from Kazakhstan based on genome wide SNP analysis. AB - The wild ancestral form of barley, Hordeum vulgare ssp. spontaneum, is a valuable source for gene enrichment of cultivated barley. The purpose of this work was to study the area of distribution as well as the extent and structure of genetic variation of wild barley populations grown in Kazakhstan. It was found that distribution of wild barley populations in Kazakhstan is restricted to the most southern province. A genome wide single nucleotide polymorphism (SNP) analysis was performed in order to study the level of the genetic diversity in 96 accessions representing 14 wild barley populations from Kazakhstan and 25 accessions from the Middle East which is the center of diversity of this subspecies. The oligonucleotide pooled assay was used to genotype 384 SNPs distributed throughout the genome. In total 233 polymorphic SNPs were selected for further statistical analysis. The level of genetic diversity of wild barley populations from Kazakhstan was predictably narrower (He = 0.19 +/- 0.01) in comparison with wild barley samples from the Middle East (He = 0.29 +/- 0.01). The results suggested that H. vulgare ssp. spontaneum populations in Kazakhstan probably represent a recent spread of a limited number of plants from the primary distribution area and might be well adapted to winter low temperature. PMID- 25914596 TI - Development and validation of DNA markers linked to Sdvy-1, a common bean gene conferring resistance to the yellowing strain of Soybean dwarf virus. AB - The yellowing strain of Soybean dwarf virus (SbDV-YS) causes yellowing and yield loss in common bean (Phaseolus vulgaris). The most effective control is achieved through breeding for resistance. An indeterminate climbing cultivar with a white seed coat, 'Oofuku', is resistant to SbDV-YS in inoculation tests. We crossed 'Oofuku' with an elite cultivar, 'Taisho-Kintoki', which is SbDV-YS-susceptible, determinate dwarf with a red-purple seed coat, and performed amplified-fragment length polymorphism analysis of F3 lines. From nucleotide sequences of the resistant-specific fragments and their flanking regions, we developed five DNA markers, of which DV86, DV386, and DV398 were closely linked to Sdvy-1, a resistance gene. Using the markers, we developed 'Toiku-B79' and 'Toiku-B80', the near-isogenic lines (NILs) incorporating Sdvy-1 in the background of 'Taisho Kintoki'. The NILs had similar growth habit, maturity date and seed shape to those of 'Taisho-Kintoki'. The quality of boiled beans was also similar, except that the NILs had more seed coat cracking than 'Taisho-Kintoki'. The NILs showed no SbDV-YS infection in inoculation tests. We suggest that Sdvy-1 is a useful source of SbDV-YS resistance in common bean. PMID- 25914597 TI - Wide genetic variation in phenolic compound content of seed coats among black soybean cultivars. AB - Black soybeans have been used as a food source and also in traditional medicine because their seed coats contain natural phenolic compounds such as proanthocyanidin and anthocyanin. The objective of this research is to reveal the genetic variation in the phenolic compound contents (PCCs) of seed coats in 227 black soybean cultivars, most of which were Japanese landraces and cultivars. Total phenolics were extracted from seed coats using an acidic acetone reagent and the proanthocyanidin content, monomeric anthocyanin content, total flavonoids content, total phenolics content, and radical scavenging activity were measured. The cultivars showed wide genetic variation in PCCs. Each of the contents was highly correlated with one another, and was closely associated with radical scavenging activity. PCCs were also moderately associated by flowering date but not associated by seed weight. Cultivars with purple flowers had a tendency to produce higher PCCs compared with cultivars with white flowers, suggesting that the W1 locus for flower color can affect phenolic compound composition and content. Our results suggest that developing black soybean cultivars with high functional phenolic compounds activity is feasible. PMID- 25914598 TI - Precision phenotyping of imidazolinone-induced chlorosis in sunflower. AB - Chlorosis level is a useful parameter to assess imidazolinone resistance in sunflower (Helianthus annuus L.). The aim of this study was to quantify chlorosis through two different methods in sunflower plantlets treated with imazapyr. The genotypes used in this study were two inbred lines reported to be different in their resistance to imidazolinones. Chlorosis was evaluated by spectrophotometrical quantification of photosynthetic leaf pigments and by a bioinformatics-based color analysis. A protocol for pigment extraction was presented which improved pigment stability. Chlorophyll amount decreased significantly when both genotypes were treated with 10 MUM of imazapyr. Leaf color was characterized using Tomato Analyzer((r)) color test software. A significant positive correlation between color reduction and chlorophyll concentration was found. It suggests that leaf color measurement could be an accurate method to estimate chlorosis and infer chlorophyll levels in sunflower plants. These results highlight a strong relationship between imidazolinone induced chlorosis and variations in leaf color and in chlorophyll concentration. Both methods are quantitative, rapid, simple, and reproducible. Thus, they could be useful tools for phenotyping and screening large number of plants when breeding for imidazolinone resistance in this species. PMID- 25914599 TI - A rapid and reliable PCR-restriction fragment length polymorphism (RFLP) marker for the identification of Amaranthus cruentus species. AB - A rapid and reliable PCR-restriction fragment length polymorphism (RFLP) marker was developed to identify the Amaranthus cruentus species by comparing sequences of the starch branching enzyme (SBE) locus among the three cultivated grain amaranths. We determined the partial SBE genomic sequence in 72 accessions collected from diverse locations around the world by direct sequence analysis. Then, we aligned the gene sequences and searched for restriction enzyme cleavage sites specific to each species for use in the PCR-RFLP analysis. The result indicated that MseI would recognize the sequence 5'-T/TAA-3' in intron 11 from A. cruentus SBE. A restriction analysis of the amplified 278-bp portion of the SBE gene using the MseI restriction enzyme resulted in species-specific RFLP patterns among A. cruentus, Amaranthus caudatus and Amaranthus hypochondriacus. Two different bands, 174-bp and 104-bp, were generated in A. cruentus, while A. caudatus and A. hypochondriacus remained undigested (278-bp). Thus, we propose that the PCR-RFLP analysis of the amaranth SBE gene provides a sensitive, rapid, simple and useful technique for identifying the A. cruentus species among the cultivated grain amaranths. PMID- 25914600 TI - 'Niigata S3' is a new strawberry cultivar suitable for forcing culture under low temperature and insolation conditions. AB - 'Niigata S3' is a new strawberry (Fragaria * ananassa Duch.) cultivar that is early flowering and possesses high soluble solid content and good coloration. It was selected from a cross between Kei812 (seed parent) and 'Asuka-Ruby' (pollen parent). The first harvest date of 'Niigata S3' was December 27, 34 days earlier than 'Echigohime' and 9 days earlier than 'Asuka-Ruby' (means of 2007 and 2008). The marketable yield of 'Niigata S3' was 85% of 'Echigohime', 107% of 'Asuka Ruby', while the early yield was 145% of 'Echigohime', 85% of 'Asuka-Ruby' (based on 2007 and 2008 means). The shape of the fruit is long conical, and its skin color medium-red. The fruit skin hardness of 'Niigata S3' was 31.5 g/mm(2), which was harder than 'Echigohime', and its average soluble solid content was 11.4%, which was higher than the values for 'Echigohime' and 'Asuka-Ruby' (2008). Furthermore, 'Niigata S3' did not bear apical overripe fruit. This new cultivar is adaptable to the climatic conditions of Niigata, as well as other regions that experience low winter temperatures and insolation. PMID- 25914601 TI - Microhabitat amelioration and reduced competition among understorey plants as drivers of facilitation across environmental gradients: towards a unifying framework. AB - Studies of facilitative interactions as drivers of plant richness along environmental gradients often assume the existence of an overarching stress gradient equally affecting the performance of all the species in a given community. However, co-existing species differ in their ecophysiological adaptations, and do not experience the same stress level under particular environmental conditions. Moreover, these studies assume a unimodal richness biomass curve, which is not as general as previously thought. We ignored these assumptions to assess changes in plant-plant interactions, and their effect on local species richness, across environmental gradients in semi-arid areas of Spain and Australia. We aimed to understand the relative importance of direct (microhabitat amelioration) and indirect (changes in the competitive relationships among the understorey species: niche segregation, competitive exclusion or intransitivity) mechanisms that might underlie the effects of nurse plants on local species richness. By jointly studying these direct and indirect mechanisms using a unifying framework, we were able to see how our nurse plants (trees, shrubs and tussock grasses) not only increased local richness by expanding the niche of neighbouring species, but also by increasing niche segregation among them, though the latter was not important in all cases. The outcome of the competition-facilitation continuum changed depending on the study area, likely because the different types of stress gradient considered. When driven by both rainfall and temperature, or rainfall alone, the community-wide importance of nurse plants remained constant (Spanish sites), or showed a unimodal relationship along the gradient (Australian sites). This study expands our understanding of the relative roles of plant-plant interactions and environmental conditions as drivers of local species richness in semi-arid environments. These results can also be used to refine predictions about the response of plant communities to environmental change, and to clarify the relative importance of biotic interactions as a driver of such responses. PMID- 25914602 TI - Nurse plant effects on plant species richness in drylands: the role of grazing, rainfall and species specificity. AB - The outcome of plant-plant interactions depends on environmental (e.g. grazing, climatic conditions) and species-specific attributes (e.g. life strategy and dispersal mode of the species involved). However, the joint effects of such factors on pairwise plant-plant interactions, and how they modulate the role of these interactions at the community level, have not been addressed before. We assessed how these species-specific (life strategy and dispersal) and environmental (grazing and rainfall) factors affected the co-occurrence of 681 plant species pairs on open woodlands in south-eastern Australia. Species specific attributes affected the co-occurrence of most species pairs, with higher co-occurrence levels dominating for drought-intolerant species. The dispersal mechanism only affected drought-tolerant beneficiaries, with more positive co occurrences for vertebrate-dispersed species. Conversely, the percentage of facilitated species at the community scale declined under higher rainfall availabilities. A significant grazing * rainfall interaction on the percentage of facilitated species suggests that grazing-mediated protection was important under low to moderate, but not high, rainfall availabilities. This study improves our ability to predict changes in plant-plant interactions along environmental gradients, and their effect on community species richness, by highlighting that: 1) species-specific factors were more important than environmental conditions as drivers of a large amount (~30%) of the pairwise co-occurrences evaluated; 2) grazing and rainfall interaction drive the co-occurrence among different species in the studied communities, and 3) the effect of nurse plants on plant species richness will depend on the relative dominance of particular dispersal mechanisms or life strategies prone to be facilitated. PMID- 25914603 TI - Plant-plant interactions, environmental gradients and plant diversity: a global synthesis of community-level studies. AB - Previous syntheses on the effects of environmental conditions on the outcome of plant-plant interactions summarize results from pairwise studies. However, the upscaling to the community-level of such studies is problematic because of the existence of multiple species assemblages and species-specific responses to both the environmental conditions and the presence of neighbors. We conducted the first global synthesis of community-level studies from harsh environments, which included data from 71 alpine and 137 dryland communities. Here we: i) test how important are facilitative interactions as a driver of community structure, ii) evaluate whether the frequency of positive plant-plant interactions across differing environmental conditions and habitats is predictable, and iii) assess whether thresholds in the response of plant-plant interactions to environmental gradients exists between "moderate" and "extreme" stress levels. We also used those community-level studies performed across gradients of at least three points to evaluate how the average environmental conditions, the length of the gradient studied, and the number of points sampled across such gradient affect the form and strength of the facilitation-environment relationship. Over 25% of the species present were more spatially associated to nurse plants than expected by chance in both alpine and dryland areas, illustrating the high importance of positive plant-plant interactions for the maintenance of plant diversity. Facilitative interactions were more frequent, and more related to environmental conditions, in alpine than in dryland areas, perhaps because drylands are generally characterized by a larger variety of environmental stress factors and plant functional traits. The frequency of facilitative interactions in alpine communities peaked at 1000 mm of annual rainfall, and globally decreased with elevation. The frequency of positive interactions in dryland communities decreased globally with water scarcity or temperature annual range. Positive facilitation-drought stress relationships are more likely in shorter regional gradients, but these relationships are obscured in regions with a greater species turnover or with complex environmental gradients. By showing the different climatic drivers and behaviors of plant-plant interactions in dryland and alpine areas, our results will improve predictions regarding the effect of facilitation on the assembly of plant communities and their response to changes in environmental conditions. PMID- 25914604 TI - Functional traits determine plant co-occurrence more than environment or evolutionary relatedness in global drylands. AB - Plant-plant interactions are driven by environmental conditions, evolutionary relationships (ER) and the functional traits of the plants involved. However, studies addressing the relative importance of these drivers are rare, but crucial to improve our predictions of the effects of plant-plant interactions on plant communities and of how they respond to differing environmental conditions. To analyze the relative importance of -and interrelationships among- these factors as drivers of plant-plant interactions, we analyzed perennial plant co-occurrence at 106 dryland plant communities established across rainfall gradients in nine countries. We used structural equation modeling to disentangle the relationships between environmental conditions (aridity and soil fertility), functional traits extracted from the literature, and ER, and to assess their relative importance as drivers of the 929 pairwise plant-plant co-occurrence levels measured. Functional traits, specifically facilitated plants' height and nurse growth form, were of primary importance, and modulated the effect of the environment and ER on plant plant interactions. Environmental conditions and ER were important mainly for those interactions involving woody and graminoid nurses, respectively. The relative importance of different plant-plant interaction drivers (ER, functional traits, and the environment) varied depending on the region considered, illustrating the difficulty of predicting the outcome of plant-plant interactions at broader spatial scales. In our global-scale study on drylands, plant-plant interactions were more strongly related to functional traits of the species involved than to the environmental variables considered. Thus, moving to a trait based facilitation/competition approach help to predict that: 1) positive plant plant interactions are more likely to occur for taller facilitated species in drylands, and 2) plant-plant interactions within woody-dominated ecosystems might be more sensitive to changing environmental conditions than those within grasslands. By providing insights on which species are likely to better perform beneath a given neighbour, our results will also help to succeed in restoration practices involving the use of nurse plants. PMID- 25914605 TI - Gambling and Substance Use: Co-occurrence among Adults in a Recent General Population Study in the United States. AB - This study is an up-to-date examination of gambling behaviors as well as gambling problems and their relationships to substance use and abuse. Further, the co occurrence between problem gambling and substance abuse is studied using a large scale, representative sample of adults aged 18 years and older in the United States. This random-digit-dial national survey was carried out in 2011-2013 with completed interviews from 2,963 respondents. Of the four gambling and substance use behaviors considered, past year gambling was the most prevalent (76.9%), followed by alcohol use (67.6%), tobacco use (28.7%) and marijuana use (11.2%). Problem gambling and the three substance abuse measures were highly related. Current problem gambling (3+ DIS criteria) was predicted by being male, being black, having low socioeconomic status and by alcohol abuse/dependence, tobacco dependence, and marijuana abuse/dependence. Thus, problem gambling is linked to other problem behaviors, especially substance abuse. Consequently, effective treatment approaches should screen and intervene for both problem gambling as well as co-occurring substance abuse. PMID- 25914606 TI - Insomnia Symptom, Mental Disorder and Suicide: A Case-Control Study in Chinese Rural Youths. AB - Insomnia has been reported as a risk factor of suicidal behaviors, but few studies have examined the association among insomnia, mental disorder and suicide, especially among Chinese populations. In this study, we examined the effect of insomnia symptoms on completed suicide in a large sample of suicides and their controls in Chinese rural youths. Subjects were 388 consecutively recruited suicides and 416 community living controls aged 15-34 years in the rural areas of three provinces in China. Established psychological autopsy method was used for the data collection. Insomnia symptoms were assessed with sleep questions in the Hamilton Depression Rating Scale (HAMD) about insomnia, including difficulty initiating sleep (DIS), difficulty maintaining sleep (DMS) and early morning awakening (EMA). The results showed that DIS (OR=12.01, p<0.001), DMS (OR=12.82, p<0.001) or EMA (OR=12.08, p<0.001) was significantly associated with increased risk of suicide even after mental disorder was controlled for. Our study showed that insomnia can be an independent risk factor for suicide. Mental disorders mediated the association between insomnia and suicide. Insomnia should be assessed and treated for individuals at risk of suicide. PMID- 25914607 TI - Plant diversity and ecosystem multifunctionality peak at intermediate levels of woody cover in global drylands. AB - AIM: The global spread of woody plants into grasslands is predicted to increase over the coming century. While there is general agreement regarding the anthropogenic causes of this phenomenon, its ecological consequences are less certain. We analyzed how woody vegetation of differing cover affects plant diversity (richness and evenness) and multiple ecosystem functions (multifunctionality) in global drylands, and how this changes with aridity. LOCATION: 224 dryland sites from all continents except Antarctica widely differing in their environmental conditions (from arid to dry-subhumid sites) and woody covers (from 0 to 100%). METHODS: Using a standardized field survey, we measured the cover, richness and evenness of perennial vegetation. At each site, we measured 14 ecosystem functions related to soil fertility and the build-up of nutrient pools. These functions are critical for maintaining ecosystem function in drylands. RESULTS: Species richness and ecosystem multifunctionality were strongly influenced by woody vegetation, with both variables peaking at relative woody covers (RWC) of 41-60%. This relationship shifted with aridity. We observed linear positive effects of RWC in dry-subhumid sites. These positive trends shifted to hump-shaped RWC-diversity and multifunctionality relationships under semiarid environments. Finally, hump-shaped (richness, evenness) or linear negative (multifunctionality) effects of RWC were found under the most arid conditions. MAIN CONCLUSIONS: Plant diversity and multifunctionality peaked at intermediate levels of woody cover, although this relationship became increasingly positive under wetter environments. This comprehensive study accounts for multiple ecosystem attributes across a range of woody covers and environmental conditions. Our results help us to reconcile contrasting views of woody encroachment found in current literature and can be used to improve predictions of the likely effects of encroachment on biodiversity and ecosystem services. PMID- 25914608 TI - ATF4 is a novel regulator of MCP-1 in microvascular endothelial cells. AB - BACKGROUND: Monocyte chemoattractant protein-1 (MCP-1) is a major chemokine that recruits monocyte/macrophage to the site of tissue injury and plays a critical role in microvascular complications of diabetes. However, the mechanisms underlying the regulation of MCP-1 are not fully understood. The present study aims to explore the role of activating transcription factor 4 (ATF4), an ER stress-inducible transcription factor, in regulation of MCP-1 expression and production in brain and retinal microvascular endothelial cells. METHODS: For in vitro study, primary brain microvascular endothelial cells isolated from ATF4 knockout mice or mouse retinal endothelial cells were treated with lipopolysaccharide (LPS) to induce MCP-1 expression. ATF4 expression/function was manipulated by adenoviruses expressing wild type ATF4 (Ad-ATF4) or a dominant negative mutant of the protein (Ad-ATF4DN). For in vivo study, MCP-1 expression was induced by intravitreal injection of LPS or Ad-ATF4 in heterozygous ATF4 knockout or wild type mice. RESULTS: LPS treatment induced a dose- and time dependent increase in ATF4 expression, ER stress and MCP-1 production in brain and retinal microvascular endothelial cells. Overexpression of ATF4 in endothelial cells significantly increased the secretion of MCP-1 and promoted THP 1 monocyte-endothelial cell adhesion. Conditioned medium from ATF4 overexpressiing endothelial cells significantly enhanced THP-1 cell migration. Consistently, intravitreal injection of Ad-ATF4 remarkably enhanced retinal levels of MCP-1 and promoted inflammatory cell infiltration into the vitreous and retina. In contrast, LPS-induced MCP-1 upregulation was markedly attenuated in ATF4-deficient endothelial cells and in retinas of ATF4 knockout mice, suggesting that ATF4 is essential for LPS-induced MCP-1 production in endothelial cells and in the retina. Mechanistically, overexpression of ATF4 enhanced, while inhibition of ATF4, attenuated the basal and LPS-stimulated phosphorylation of NF-kappaB, P38, and JNK. Furthermore, pharmacological inhibition of NF-kappaB, P38, or JNK significantly reduced ATF4-stimulated MCP-1 secretion from endothelial cells. CONCLUSIONS: Taken together, our results suggest a critical role of ATF4 in the regulation of MCP-1 production in retinal and brain microvascular endothelial cells, which may contribute to inflammation-related endothelial injury in diseases such as diabetic retinopathy. PMID- 25914609 TI - A 180-Vpp Integrated Linear Amplifier for Ultrasonic Imaging Applications in a High-Voltage CMOS SOI Technology. AB - This brief presents a monolithically integrated fully differential linear HV amplifier as the driver of an ultrasonic transducer. The linear amplifier is capable of transmitting HV arbitrary signals with a very low harmonic distortion, which is suitable for tissue harmonic imaging and other ultrasonic modes for enhanced imaging quality. The amplifier is designed and implemented using the 0.7 MUm CMOS silicon-on-insulator process with 120-V devices. The amplifier, when driving a load of 300 pF in parallel with 100 Omega, is capable of transmitting a sine-wave signal with a frequency of up to 4.4 MHz, a maximum signal swing of 180 Vpp, and a second-order harmonic distortion (HD2) of -56 dBc but only dissipating an average power of 62 mW with a 0.1% duty cycle. PMID- 25914611 TI - Navigating the road ahead: addressing challenges for use of metabolomics in epidemiology studies. AB - Metabolomics platforms allow for the measurement of hundreds to thousands of unique small chemical entities, as well as offer extensive coverage of metabolic markers related to obesity, diet, smoking, and other exposures of high interest to health scientists. Nevertheless, its potential use as a tool in population based study design has not been fully explored. As the field of metabolomics continues to mature, and in part, accelerate through the National Institutes of Health (NIH) investment of <=65 million in the Common Fund's Metabolomics Program (https://common fund.nih.gov/metabolomics/index), it is time to consider those challenges most pertinent to epidemiologic studies. PMID- 25914610 TI - A randomized trial of clozapine vs. other antipsychotics for cannabis use disorder in patients with schizophrenia. AB - OBJECTIVE: Cannabis use disorder is the most common co-occurring drug use disorder in people with schizophrenia and is associated with poor outcomes. We launched a randomized controlled trial to assess the impact of clozapine compared with treatment as usual on cannabis use in patients with schizophrenia and co occurring cannabis use disorder. METHODS: Thirty-one patients with schizophrenia and co-occurring cannabis use disorder were randomly assigned to switch to clozapine or to stay on their current antipsychotic and were then followed weekly for 12 weeks. Blinded raters assessed participants weekly with the Timeline Follow-back for substance use and the expanded Brief Psychiatric Rating Scale for symptoms. Longitudinal random effects models were used to investigate the time varying differences in cannabis use and other outcomes between the treatment as usual and clozapine groups. RESULTS: The two groups differed in average intensity of cannabis use by approximately 4.5 joints/week, with lesser use in the clozapine group (t = -1.77; df = 28.5; p=.086; effect size ~ 0.6). Symptoms and functioning were not different between the two groups. CONCLUSIONS: Clozapine may reduce cannabis use among patients with schizophrenia and co-occurring cannabis use disorder. Further controlled trials are warranted. PMID- 25914612 TI - Development of measures assessing attitudes toward contraband tobacco among a web based sample of smokers. AB - BACKGROUND: As regulation of tobacco products tightens, there are concerns that illicit markets may develop to supply restricted products. However, there are few validated measures to assess attitudes or purchase intentions toward contraband tobacco (CT). As such, it is important to investigate individual level characteristics that are associated with the purchase and use of contraband tobacco. METHODS: In May 2013, a pilot survey assessed attitudes, behaviors, and purchase intentions for contraband tobacco based on previous research regarding non-tobacco contraband. The survey was administered via Amazon Mechanical Turk, a crowdsourcing resource, among current smoking respondents in the United States and Canada. Structural equation modeling was used to evaluate the validity of the proposed model for understanding attitudes toward contraband tobacco. RESULTS: CT purchasers were more likely to report norms supportive of counterfeit products, more intentions toward purchasing counterfeit products, a lowered risk associated with these products, and to have more favorable attitudes toward CT than those who had not purchased CT. Attitudes toward CT mediated the relationship between subjective norms and prior purchase with behavior intentions. Perceived risk had a significant direct effect on intentions and an indirect effect through attitudes toward CT. The structural model fit the data well and accounted for over half (53%) of the variance in attitudes toward tobacco. CONCLUSIONS: Understanding the mechanisms associated with CT attitudes and purchase behaviors may provide insight for how to mitigate possible iatrogenic consequences of newly implemented regulations. The measures developed here elucidate some elements that influence attitudes and purchase intentions for CT and may inform policy efforts to curtail the development of illicit markets. PMID- 25914613 TI - Utility-free heuristic models of two-option choice can mimic predictions of utility-stage models under many conditions. AB - Economists often model choices as if decision-makers assign each option a scalar value variable, known as utility, and then select the option with the highest utility. It remains unclear whether as-if utility models describe real mental and neural steps in choice. Although choices alone cannot prove the existence of a utility stage, utility transformations are often taken to provide the most parsimonious or psychologically plausible explanation for choice data. Here, we show that it is possible to mathematically transform a large set of common utility-stage two-option choice models (specifically ones in which dimensions are can be decomposed into additive functions) into a heuristic model (specifically, a dimensional prioritization heuristic) that has no utility computation stage. We then show that under a range of plausible assumptions, both classes of model predict similar neural responses. These results highlight the difficulties in using neuroeconomic data to infer the existence of a value stage in choice. PMID- 25914615 TI - Corrigendum: the FMRFamide-like peptide family in nematodes. AB - [This corrects the article on p. 90 in vol. 5, PMID: 24982652.]. PMID- 25914614 TI - The "ram effect": new insights into neural modulation of the gonadotropic axis by male odors and socio-sexual interactions. AB - Reproduction in mammals is controlled by the hypothalamo-pituitary-gonadal (HPG) axis under the influence of external and internal factors such as photoperiod, stress, nutrition, and social interactions. Sheep are seasonal breeders and stop mating when day length is increasing (anestrus). However, interactions with a sexually active ram during this period can override the steroid negative feedback responsible for the anoestrus state, stimulate luteinizing hormone (LH) secretion and eventually reinstate cyclicity. This is known as the "ram effect" and research into the mechanisms underlying it is shedding new light on HPG axis regulation. The first step in the ram effect is increased LH pulsatile secretion in anestrus ewes exposed to a sexually active male or only to its fleece, the latter finding indicating a "pheromone-like" effect. Estradiol secretion increases in all ewes and this eventually induces a LH surge and ovulation, just as during the breeding season. An exception is a minority of ewes that exhibit a precocious LH surge (within 4 h) with no prior increase in estradiol. The main olfactory system and the cortical nucleus of the amygdala are critical brain structures in mediating the ram effect since it is blocked by their inactivation. Sexual experience is also important since activation (increased c-fos expression) in these and other regions is greatly reduced in sexually naive ewes. In adult ewes kisspeptin neurons in both arcuate and preoptic regions and some preoptic GnRH neurons are activated 2 h after exposure to a ram. Exposure to rams also activates noradrenergic neurons in the locus coeruleus and A1 nucleus and increased noradrenalin release occurs in the posterior preoptic area. Pharmacological modulation of this system modifies LH secretion in response to the male or his odor. Together these results show that the ram effect can be a fruitful model to promote both a better understanding of the neural and hormonal regulation of the HPG axis in general and also the specific mechanisms by which male cues can overcome negative steroid feedback and trigger LH release and ovulatory cycles. PMID- 25914616 TI - Global cortical activity predicts shape of hand during grasping. AB - Recent studies show that the amplitude of cortical field potentials is modulated in the time domain by grasping kinematics. However, it is unknown if these low frequency modulations persist and contain enough information to decode grasp kinematics in macro-scale activity measured at the scalp via electroencephalography (EEG). Further, it is unclear as to whether joint angle velocities or movement synergies are the optimal kinematics spaces to decode. In this offline decoding study, we infer from human EEG, hand joint angular velocities as well as synergistic trajectories as subjects perform natural reach to-grasp movements. Decoding accuracy, measured as the correlation coefficient (r) between the predicted and actual movement kinematics, was r = 0.49 +/- 0.02 across 15 hand joints. Across the first three kinematic synergies, decoding accuracies were r = 0.59 +/- 0.04, 0.47 +/- 0.06, and 0.32 +/- 0.05. The spatial temporal pattern of EEG channel recruitment showed early involvement of contralateral frontal-central scalp areas followed by later activation of central electrodes over primary sensorimotor cortical areas. Information content in EEG about the grasp type peaked at 250 ms after movement onset. The high decoding accuracies in this study are significant not only as evidence for time-domain modulation in macro-scale brain activity, but for the field of brain-machine interfaces as well. Our decoding strategy, which harnesses the neural "symphony" as opposed to local members of the neural ensemble (as in intracranial approaches), may provide a means of extracting information about motor intent for grasping without the need for penetrating electrodes and suggests that it may be soon possible to develop non-invasive neural interfaces for the control of prosthetic limbs. PMID- 25914617 TI - Transcranial random noise stimulation-induced plasticity is NMDA-receptor independent but sodium-channel blocker and benzodiazepines sensitive. AB - BACKGROUND: Application of transcranial random noise stimulation (tRNS) between 0.1 and 640 Hz of the primary motor cortex (M1) for 10 min induces a persistent excitability increase lasting for at least 60 min. However, the mechanism of tRNS induced cortical excitability alterations is not yet fully understood. OBJECTIVE: The main aim of this study was to get first efficacy data with regard to the possible neuronal effect of tRNS. METHODS: Single-pulse transcranial magnetic stimulation (TMS) was used to measure levels of cortical excitability before and after combined application of tRNS at an intensity of 1 mA for 10 min stimulation duration and a pharmacological agent (or sham) on eight healthy male participants. RESULTS: The sodium channel blocker carbamazepine showed a tendency toward inhibiting MEPs 5-60 min poststimulation. The GABA A agonist lorazepam suppressed tRNS-induced cortical excitability increases at 0-20 and 60 min time points. The partial NMDA receptor agonist D-cycloserine, the NMDA receptor antagonist dextromethorphan and the D2/D3 receptor agonist ropinirole had no significant effects on the excitability increases seen with tRNS. CONCLUSIONS: In contrast to transcranial direct current stimulation (tDCS), aftereffects of tRNS are seem to be not NMDA receptor dependent and can be suppressed by benzodiazepines suggesting that tDCS and tRNS depend upon different mechanisms. PMID- 25914618 TI - Potentiation of NMDA receptor-mediated transmission in striatal cholinergic interneurons. AB - Pauses in the tonic firing of striatal cholinergic interneurons (CINs) emerge during reward-related learning in response to conditioning of a neutral cue. We have previously reported that augmenting the postsynaptic response to cortical afferents in CINs is coupled to the emergence of a cell-intrinsic afterhyperpolarization (AHP) underlying pauses in tonic activity. Here we investigated in a bihemispheric rat-brain slice preparation the mechanisms of synaptic plasticity of excitatory afferents to CINs and the association with changes in the AHP. We found that high frequency stimulation (HFS) of commissural corticostriatal afferents from the contralateral hemisphere induced a robust long term depression (LTD) of postsynaptic potentials (PSP) in CINs. Depression of the PSP of smaller magnitude and duration was observed in response to HFS of the ipsilateral white matter or cerebral cortex. In Mg(2+)-free solution HFS induced NMDA receptor-dependent potentiation of the PSP, evident in both the maximal slope and amplitude of the PSP. The increase in maximal slope corroborates previous findings, and was blocked by antagonism of either D1-like dopamine receptors with SCH23390 or D2-like dopamine receptors with sulpiride during HFS in Mg(2+)-free solution. Potentiation of the slower PSP amplitude component was due to augmentation of the NMDA receptor-mediated potential as this was completely reversed on subsequent application of the NMDA receptor antagonist AP5. HFS similarly potentiated NMDA receptor currents isolated by blockade of AMPA/kainate receptors with CNQX. The plasticity-induced increase in the slow PSP component was directly associated with an increase in the subsequent AHP. Thus plasticity of cortical afferent synapses is ideally suited to influence the cue induced firing dynamics of CINs, particularly through potentiation of NMDA receptor-mediated synaptic transmission. PMID- 25914619 TI - Characterization of optic nerve regeneration using transgenic zebrafish. AB - In contrast to the adult mammalian central nervous system (CNS), fish are able to functionally regenerate severed axons upon injury. Although the zebrafish is a well-established model vertebrate for genetic and developmental studies, its use for anatomical studies of axon regeneration has been hampered by the paucity of appropriate tools to visualize re-growing axons in the adult CNS. On this account, we used transgenic zebrafish that express enhanced green fluorescent protein (GFP) under the control of a GAP-43 promoter. In adult, naive retinae, GFP was restricted to young retinal ganglion cells (RGCs) and their axons. Within the optic nerve, these fluorescent axons congregated in a distinct strand at the nerve periphery, indicating age-related order. Upon optic nerve crush, GFP expression was markedly induced in RGC somata and intra-retinal axons at 4 to at least 14 days post injury. Moreover, individual axons were visualized in their natural environment of the optic nerve using wholemount tissue clearing and confocal microscopy. With this novel approach, regenerating axons were clearly detectable beyond the injury site as early as 2 days after injury and grew past the optic chiasm by 4 days. Regenerating axons in the entire optic nerve were labeled from 6 to at least 14 days after injury, thereby allowing detailed visualization of the complete regeneration process. Therefore, this new approach could now be used in combination with expression knockdown or pharmacological manipulations to analyze the relevance of specific proteins and signaling cascades for axonal regeneration in vivo. In addition, the RGC-specific GFP expression facilitated accurate evaluation of neurite growth in dissociated retinal cultures. This fast in vitro assay now enables the screening of compound and expression libraries. Overall, the presented methodologies provide exciting possibilities to investigate the molecular mechanisms underlying successful CNS regeneration in zebrafish. PMID- 25914620 TI - Neuron-astrocyte interaction enhance GABAergic synaptic transmission in a manner dependent on key metabolic enzymes. AB - Gamma aminobutric acid (GABA) is the major inhibitory neurotransmitter in the adult brain and mechanisms of GABAergic inhibition have been intensely investigated in the past decades. Recent studies provided evidence for an important role of astrocytes in shaping GABAergic currents. One of the most obvious, but yet poorly understood, mechanisms of the cross-talk between GABAergic currents and astrocytes is metabolism including neurotransmitter homeostasis. In particular, how modulation of GABAergic currents by astrocytes depends on key enzymes involved in cellular metabolism remains largely unknown. To address this issue, we have considered two simple models of neuronal culture (NC): nominally astrocyte-free NC and neuronal-astrocytic co-cultures (ANCC). Miniature Inhibitory Postsynaptic Currents (mIPSCs) were recorded in control conditions and in the presence of different enzyme blockers. We report that enrichment of NC with astrocytes results in a marked increase in mIPSC frequency. This enhancement of GABAergic activity was accompanied by increased number of GAD65 and vGAT puncta, indicating that at least a part of the frequency enhancement was due to increased number of synaptic contacts. Inhibition of glutamine synthetase (Glns) (with MSO) strongly reduced mIPSC frequency in ANCC but had no effect in NC. Moreover, treatment of ANCC with inhibitor of glycogen phosphorylase (Gys) (BAYU6751) or with selective inhibitor of astrocytic Krebs cycle, fluoroacetate, resulted in a marked reduction of mIPSC frequency in ANCC having no effect in NC. We conclude that GABAergic synaptic transmission strongly depends on neuron-astrocyte interaction in a manner dependent on key metabolic enzymes as well as on the Krebs cycle. PMID- 25914622 TI - Identification of the antiepileptic racetam binding site in the synaptic vesicle protein 2A by molecular dynamics and docking simulations. AB - Synaptic vesicle protein 2A (SV2A) is an integral membrane protein necessary for the proper function of the central nervous system and is associated to the physiopathology of epilepsy. SV2A is the molecular target of the anti-epileptic drug levetiracetam and its racetam analogs. The racetam binding site in SV2A and the non-covalent interactions between racetams and SV2A are currently unknown; therefore, an in silico study was performed to explore these issues. Since SV2A has not been structurally characterized with X-ray crystallography or nuclear magnetic resonance, a three-dimensional (3D) model was built. The model was refined by performing a molecular dynamics simulation (MDS) and the interactions of SV2A with the racetams were determined by docking studies. A reliable 3D model of SV2A was obtained; it reached structural equilibrium during the last 15 ns of the MDS (50 ns) with remaining structural motions in the N-terminus and long cytoplasmic loop. The docking studies revealed that hydrophobic interactions and hydrogen bonds participate importantly in ligand recognition within the binding site. Residues T456, S665, W666, D670 and L689 were important for racetam binding within the trans-membrane hydrophilic core of SV2A. Identifying the racetam binding site within SV2A should facilitate the synthesis of suitable radio ligands to study treatment response and possibly epilepsy progression. PMID- 25914624 TI - Editorial on "New perspectives in neurosteroids action: a special player allopregnanolone". PMID- 25914623 TI - Reduction in focal ictal activity following transplantation of MGE interneurons requires expression of the GABAA receptor alpha4 subunit. AB - Despite numerous advances, treatment-resistant seizures remain an important problem. Loss of neuronal inhibition is present in a variety of epilepsy models and is suggested as a mechanism for increased excitability, leading to the proposal that grafting inhibitory interneurons into seizure foci might relieve refractory seizures. Indeed, transplanted medial ganglionic eminence interneuron progenitors (MGE-IPs) mature into GABAergic interneurons that increase GABA release onto cortical pyramidal neurons, and this inhibition is associated with reduced seizure activity. An obvious conclusion is that inhibitory coupling between the new interneurons and pyramidal cells underlies this effect. We hypothesized that the primary mechanism for the seizure-limiting effects following MGE-IP transplantation is the tonic conductance that results from activation of extrasynaptic GABAA receptors (GABAA-Rs) expressed on cortical pyramidal cells. Using in vitro and in vivo recording techniques, we demonstrate that GABAA-R alpha4 subunit deletion abolishes tonic currents (Itonic) in cortical pyramidal cells and leads to a failure of MGE-IP transplantation to attenuate cortical seizure propagation. These observations should influence how the field proceeds with respect to the further development of therapeutic neuronal transplants (and possibly pharmacological treatments). PMID- 25914621 TI - Environmental pollutants as risk factors for neurodegenerative disorders: Alzheimer and Parkinson diseases. AB - Neurodegenerative diseases including Alzheimer (AD) and Parkinson (PD) have attracted attention in last decades due to their high incidence worldwide. The etiology of these diseases is still unclear; however the role of the environment as a putative risk factor has gained importance. More worryingly is the evidence that pre- and post-natal exposures to environmental factors predispose to the onset of neurodegenerative diseases in later life. Neurotoxic metals such as lead, mercury, aluminum, cadmium and arsenic, as well as some pesticides and metal-based nanoparticles have been involved in AD due to their ability to increase beta-amyloid (Abeta) peptide and the phosphorylation of Tau protein (P Tau), causing senile/amyloid plaques and neurofibrillary tangles (NFTs) characteristic of AD. The exposure to lead, manganese, solvents and some pesticides has been related to hallmarks of PD such as mitochondrial dysfunction, alterations in metal homeostasis and aggregation of proteins such as alpha synuclein (alpha-syn), which is a key constituent of Lewy bodies (LB), a crucial factor in PD pathogenesis. Common mechanisms of environmental pollutants to increase Abeta, P-Tau, alpha-syn and neuronal death have been reported, including the oxidative stress mainly involved in the increase of Abeta and alpha-syn, and the reduced activity/protein levels of Abeta degrading enzyme (IDE)s such as neprilysin or insulin IDE. In addition, epigenetic mechanisms by maternal nutrient supplementation and exposure to heavy metals and pesticides have been proposed to lead phenotypic diversity and susceptibility to neurodegenerative diseases. This review discusses data from epidemiological and experimental studies about the role of environmental factors in the development of idiopathic AD and PD, and their mechanisms of action. PMID- 25914625 TI - Cross-talk and regulation between glutamate and GABAB receptors. AB - Brain function depends on co-ordinated transmission of signals from both excitatory and inhibitory neurotransmitters acting upon target neurons. NMDA, AMPA and mGluR receptors are the major subclasses of glutamate receptors that are involved in excitatory transmission at synapses, mechanisms of activity dependent synaptic plasticity, brain development and many neurological diseases. In addition to canonical role of regulating presynaptic release and activating postsynaptic potassium channels, GABAB receptors also regulate glutamate receptors. There is increasing evidence that metabotropic GABAB receptors are now known to play an important role in modulating the excitability of circuits throughout the brain by directly influencing different types of postsynaptic glutamate receptors. Specifically, GABAB receptors affect the expression, activity and signaling of glutamate receptors under physiological and pathological conditions. Conversely, NMDA receptor activity differentially regulates GABAB receptor subunit expression, signaling and function. In this review I will describe how GABAB receptor activity influence glutamate receptor function and vice versa. Such a modulation has widespread implications for the control of neurotransmission, calcium-dependent neuronal function, pain pathways and in various psychiatric and neurodegenerative diseases. PMID- 25914626 TI - Additional mechanisms conferring genetic susceptibility to Alzheimer's disease. AB - Familial Alzheimer's disease (AD), mostly associated with early onset, is caused by mutations in three genes (APP, PSEN1, and PSEN2) involved in the production of the amyloid beta peptide. In contrast, the molecular mechanisms that trigger the most common late onset sporadic AD remain largely unknown. With the implementation of an increasing number of case-control studies and the upcoming of large-scale genome-wide association studies there is a mounting list of genetic risk factors associated with common genetic variants that have been associated with sporadic AD. Besides apolipoprotein E, that presents a strong association with the disease (OR~4), the rest of these genes have moderate or low degrees of association, with OR ranging from 0.88 to 1.23. Taking together, these genes may account only for a fraction of the attributable AD risk and therefore, rare variants and epistastic gene interactions should be taken into account in order to get the full picture of the genetic risks associated with AD. Here, we review recent whole-exome studies looking for rare variants, somatic brain mutations with a strong association to the disease, and several studies dealing with epistasis as additional mechanisms conferring genetic susceptibility to AD. Altogether, recent evidence underlines the importance of defining molecular and genetic pathways, and networks rather than the contribution of specific genes. PMID- 25914628 TI - Blockage of transient receptor potential vanilloid 4 inhibits brain edema in middle cerebral artery occlusion mice. AB - Brain edema is an important pathological process during stroke. Activation of transient receptor potential vanilloid 4 (TRPV4) causes an up-regulation of matrix metalloproteinases (MMPs) in lung tissue. MMP can digest the endothelial basal lamina to destroy blood brain barrier, leading to vasogenic brain edema. Herein, we tested whether TRPV4-blockage could inhibit brain edema through inhibiting MMPs in middle cerebral artery occlusion (MCAO) mice. We found that the brain water content and Evans blue extravasation at 48 h post-MCAO were reduced by a TRPV4 antagonist HC-067047. The increased MMP-2/9 protein expression in hippocampi of MCAO mice was attenuated by HC-067046, but only the increased MMP-9 activity was blocked by HC-067047. The loss of zonula occludens-1 (ZO-1) and occludin protein in MCAO mice was also attenuated by HC-067047. Moreover, MMP 2/9 protein expression increased in mice treated with a TRPV4 agonist GSK1016790A, but only MMP-9 activity was increased by GSK1016790A. Finally, ZO-1 and occludin protein expression was decreased by GSK1016790A, which was reversed by an MMP-9 inhibitor. We conclude that blockage of TRPV4 may inhibit brain edema in cerebral ischemia through inhibiting MMP-9 activation and the loss of tight junction protein. PMID- 25914627 TI - Comparison of dendritic calcium transients in juvenile wild type and SOD1(G93A) mouse lumbar motoneurons. AB - Previous studies of spinal motoneurons in the SOD1 mouse model of amyotrophic lateral sclerosis have shown alterations long before disease onset, including increased dendritic branching, increased persistent Na(+) and Ca(2+) currents, and impaired axonal transport. In this study dendritic Ca(2+) entry was investigated using two photon excitation fluorescence microscopy and whole-cell patch-clamp of juvenile (P4-11) motoneurons. Neurons were filled with both Ca(2+) Green-1 and Texas Red dextrans, and line scans performed throughout. Steps were taken to account for different sources of variability, including (1) dye filling and laser penetration, (2) dendritic anatomy, and (3) the time elapsed from the start of recording. First, Ca(2+) Green-1 fluorescence was normalized by Texas Red; next, neurons were reconstructed so anatomy could be evaluated; finally, time was recorded. Customized software detected the largest Ca(2+) transients (area under the curve) from each line scan and matched it with parameters above. Overall, larger dendritic diameter and shorter path distance from the soma were significant predictors of larger transients, while time was not significant up to 2 h (data thereafter was dropped). However, Ca(2+) transients showed additional variability. Controlling for previous factors, significant variation was found between Ca(2+) signals from different processes of the same neuron in 3/7 neurons. This could reflect differential expression of Ca(2+) channels, local neuromodulation or other variations. Finally, Ca(2+) transients in SOD1(G93A) motoneurons were significantly smaller than in non-transgenic motoneurons. In conclusion, motoneuron processes show highly variable Ca(2+) transients, but these transients are smaller overall in SOD1(G93A) motoneurons. PMID- 25914629 TI - Peripheral injury of pelvic visceral sensory nerves alters GFRalpha (GDNF family receptor alpha) localization in sensory and autonomic pathways of the sacral spinal cord. AB - GDNF (glial cell line-derived neurotrophic factor), neurturin and artemin use their co-receptors (GFRalpha1, GFRalpha2 and GFRalpha3, respectively) and the tyrosine kinase Ret for downstream signaling. In rodent dorsal root ganglia (DRG) most of the unmyelinated and some myelinated sensory afferents express at least one GFRalpha. The adult function of these receptors is not completely elucidated but their activity after peripheral nerve injury can facilitate peripheral and central axonal regeneration, recovery of sensation, and sensory hypersensitivity that contributes to pain. Our previous immunohistochemical studies of spinal cord and sciatic nerve injuries in adult rodents have identified characteristic changes in GFRalpha1, GFRalpha2 or GFRalpha3 in central spinal cord axons of sensory neurons located in DRG. Here we extend and contrast this analysis by studying injuries of the pelvic and hypogastric nerves that contain the majority of sensory axons projecting to the pelvic viscera (e.g., bladder and lower bowel). At 7 d, we detected some effects of pelvic but not hypogastric nerve transection on the ipsilateral spinal cord. In sacral (L6-S1) cord ipsilateral to nerve injury, GFRalpha1-immunoreactivity (IR) was increased in medial dorsal horn and CGRP-IR was decreased in lateral dorsal horn. Pelvic nerve injury also upregulated GFRalpha1- and GFRalpha3-IR terminals and GFRalpha1-IR neuronal cell bodies in the sacral parasympathetic nucleus that provides the spinal parasympathetic preganglionic output to the pelvic nerve. This evidence suggests peripheral axotomy has different effects on somatic and visceral sensory input to the spinal cord, and identifies sensory-autonomic interactions as a possible site of post-injury regulation. PMID- 25914630 TI - Sensitivity to microstimulation of somatosensory cortex distributed over multiple electrodes. AB - Meaningful and repeatable tactile sensations can be evoked by electrically stimulating primary somatosensory cortex. Intracortical microstimulation (ICMS) may thus be a viable approach to restore the sense of touch in individuals who have lost it, for example tetraplegic patients. One of the potential limitations of this approach, however, is that high levels of current can damage the neuronal tissue if the resulting current densities are too high. The limited range of safe ICMS amplitudes thus limits the dynamic range of ICMS-evoked sensations. One way to get around this limitation would be to distribute the ICMS over multiple electrodes in the hopes of intensifying the resulting percept without increasing the current density experienced by the neuronal tissue. Here, we test whether stimulating through multiple electrodes is a viable solution to increase the dynamic range of ICMS-elicited sensations without increasing the peak current density. To this end, we compare the ability of non-human primates to detect ICMS delivered through one vs. multiple electrodes. We also compare their ability to discriminate pulse trains differing in amplitude when these are delivered through one or more electrodes. We find that increasing the number of electrodes through which ICMS is delivered only has a marginal effect on detectability or discriminability despite the fact that 2-4 times more current is delivered overall. Furthermore, the impact of multielectrode stimulation (or lack thereof) is found whether pulses are delivered synchronously or asynchronously, whether the leading phase of the pulses is cathodic or anodic, and regardless of the spatial configuration of the electrode groups. PMID- 25914631 TI - The Variable Vector Countermeasure Suit (V2Suit) for space habitation and exploration. AB - The "Variable Vector Countermeasure Suit (V2Suit) for Space Habitation and Exploration" is a novel system concept that provides a platform for integrating sensors and actuators with daily astronaut intravehicular activities to improve health and performance, while reducing the mass and volume of the physiologic adaptation countermeasure systems, as well as the required exercise time during long-duration space exploration missions. The V2Suit system leverages wearable kinematic monitoring technology and uses inertial measurement units (IMUs) and control moment gyroscopes (CMGs) within miniaturized modules placed on body segments to provide a "viscous resistance" during movements against a specified direction of "down"-initially as a countermeasure to the sensorimotor adaptation performance decrements that manifest themselves while living and working in microgravity and during gravitational transitions during long-duration spaceflight, including post-flight recovery and rehabilitation. Several aspects of the V2Suit system concept were explored and simulated prior to developing a brassboard prototype for technology demonstration. This included a system architecture for identifying the key components and their interconnects, initial identification of key human-system integration challenges, development of a simulation architecture for CMG selection and parameter sizing, and the detailed mechanical design and fabrication of a module. The brassboard prototype demonstrates closed-loop control from "down" initialization through CMG actuation, and provides a research platform for human performance evaluations to mitigate sensorimotor adaptation, as well as a tool for determining the performance requirements when used as a musculoskeletal deconditioning countermeasure. This type of countermeasure system also has Earth benefits, particularly in gait or movement stabilization and rehabilitation. PMID- 25914632 TI - Corrigendum: Homocysteine levels in schizophrenia and affective disorders-focus on cognition. AB - [This corrects the article on p. 343 in vol. 8, PMID: 25339876.]. PMID- 25914633 TI - Interoception in insula subregions as a possible state marker for depression-an exploratory fMRI study investigating healthy, depressed and remitted participants. AB - BACKGROUND: Interoceptive awareness (iA), the awareness of stimuli originating inside the body, plays an important role in human emotions and psychopathology. The insula is particularly involved in neural processes underlying iA. However, iA-related neural activity in the insula during the acute state of major depressive disorder (MDD) and in remission from depression has not been explored. METHODS: A well-established fMRI paradigm for studying (iA; heartbeat counting) and exteroceptive awareness (eA; tone counting) was used. Study participants formed three independent groups: patients suffering from MDD, patients in remission from MDD or healthy controls. Task-induced neural activity in three functional subdivisions of the insula was compared between these groups. RESULTS: Depressed participants showed neural hypo-responses during iA in anterior insula regions, as compared to both healthy and remitted participants. The right dorsal anterior insula showed the strongest response to iA across all participant groups. In depressed participants there was no differentiation between different stimuli types in this region (i.e., between iA, eA and noTask). Healthy and remitted participants in contrast showed clear activity differences. CONCLUSIONS: This is the first study comparing iA and eA-related activity in the insula in depressed participants to that in healthy and remitted individuals. The preliminary results suggest that these groups differ in there being hypo responses across insula regions in the depressed participants, whilst non psychiatric participants and patients in remission from MDD show the same neural activity during iA in insula subregions implying a possible state marker for MDD. The lack of activity differences between different stimulus types in the depressed group may account for their symptoms of altered external and internal focus. PMID- 25914634 TI - Antecedent acute cycling exercise affects attention control: an ERP study using attention network test. AB - The purpose of this study was to investigate the after-effects of an acute bout of moderate intensity aerobic cycling exercise on neuroelectric and behavioral indices of efficiency of three attentional networks: alerting, orienting, and executive (conflict) control. Thirty young, highly fit amateur basketball players performed a multifunctional attentional reaction time task, the attention network test (ANT), with a two-group randomized experimental design after an acute bout of moderate intensity spinning wheel exercise or without antecedent exercise. The ANT combined warning signals prior to targets, spatial cueing of potential target locations and target stimuli surrounded by congruent or incongruent flankers, which were provided to assess three attentional networks. Event-related brain potentials and task performance were measured during the ANT. Exercise resulted in a larger P3 amplitude in the alerting and executive control subtasks across frontal, central and parietal midline sites that was paralleled by an enhanced reaction speed only on trials with incongruent flankers of the executive control network. The P3 latency and response accuracy were not affected by exercise. These findings suggest that after spinning, more resources are allocated to task relevant stimuli in tasks that rely on the alerting and executive control networks. However, the improvement in performance was observed in only the executively challenging conflict condition, suggesting that whether the brain resources that are rendered available immediately after acute exercise translate into better attention performance depends on the cognitive task complexity. PMID- 25914635 TI - Neural mechanisms of goal-directed behavior: outcome-based response selection is associated with increased functional coupling of the angular gyrus. AB - Goal-directed behavior is based on representations of contingencies between a certain situation (S), a certain (re)action (R) and a certain outcome (O). These S-R-O representations enable flexible response selection in different situations according to the currently pursued goal. Importantly however, the successful formation of such representations is a necessary but not sufficient precondition for goal-directed behavior which additionally requires the actual usage of the contingency information for action control. The present fMRI study aimed at identifying the neural basis of each of these two aspects: representing vs. explicitly using experienced S-R-O contingencies. To this end, we created three experimental conditions: S-R-O contingency present and used for outcome-based response selection, S-R-O contingency present but not used, and S-R-O contingency absent. The comparison between conditions with and without S-R-O contingency revealed that the angular gyrus is relevant for representing S-R-O contingencies. The explicit usage of learnt S-R-O representations in turn was associated with increased functional coupling between angular gyrus and several subcortical (hippocampus, caudate head), prefrontal (lateral orbitofrontal cortex (OFC), rostrolateral prefrontal cortex (RLPFC)) and cerebellar areas, which we suggest represent different explicit and implicit processes of goal-directed action control. Hence, we ascribe a central role to the angular gyrus in associating actions to their sensory outcomes which is used to guide behavior through coupling of the angular gyrus with multiple areas related to different aspects of action control. PMID- 25914636 TI - Photographic but not line-drawn faces show early perceptual neural sensitivity to eye gaze direction. AB - Our brains readily decode facial movements and changes in social attention, reflected in earlier and larger N170 event-related potentials (ERPs) to viewing gaze aversions vs. direct gaze in real faces (Puce et al., 2000). In contrast, gaze aversions in line-drawn faces do not produce these N170 differences (Rossi et al., 2014), suggesting that physical stimulus properties or experimental context may drive these effects. Here we investigated the role of stimulus induced context on neurophysiological responses to dynamic gaze. Sixteen healthy adults viewed line-drawn and real faces, with dynamic eye aversion and direct gaze transitions, and control stimuli (scrambled arrays and checkerboards) while continuous electroencephalographic (EEG) activity was recorded. EEG data from 2 temporo-occipital clusters of 9 electrodes in each hemisphere where N170 activity is known to be maximal were selected for analysis. N170 peak amplitude and latency, and temporal dynamics from Event-Related Spectral Perturbations (ERSPs) were measured in 16 healthy subjects. Real faces generated larger N170s for averted vs. direct gaze motion, however, N170s to real and direct gaze were as large as those to respective controls. N170 amplitude did not differ across line drawn gaze changes. Overall, bilateral mean gamma power changes for faces relative to control stimuli occurred between 150-350 ms, potentially reflecting signal detection of facial motion. Our data indicate that experimental context does not drive N170 differences to viewed gaze changes. Low-level stimulus properties, such as the high sclera/iris contrast change in real eyes likely drive the N170 changes to viewed aversive movements. PMID- 25914637 TI - Imaging the passionate stage of romantic love by dopamine dynamics. AB - Using [(11)C]raclopride, a dopamine D2/D3 receptor antagonist, we undertook a positron emission tomography (PET) study to investigate the involvement of the dopaminergic neurotransmitter system when subjects viewed the pictures of partners to whom they were romantically attached. Ten subjects viewed pictures of their romantic partners and, as a control, of friends of the same sex for whom they had neutral feelings during the PET study. We administered [(11)C]raclopride to subjects using a timing for injecting the antagonist which had been determined in previous studies to be optimal for detecting increases in the amount of dopamine released by stimulation. The results demonstrated statistically significant activation of the dopaminergic system in two regions, the medial orbitofrontal cortex (mOFC) and medial prefrontal cortex, the former of which has been strongly implicated in a variety of rewarding experiences, including that of beauty and love. A positive correlation was obtained in mOFC between excitement levels and dopaminergic activation only in the love but not in the control condition. PMID- 25914638 TI - New insights into the pathophysiology of post-stroke spasticity. AB - Spasticity is one of many consequences after stroke. It is characterized by a velocity-dependent increase in resistance during passive stretch, resulting from hyperexcitability of the stretch reflex. The underlying mechanism of the hyperexcitable stretch reflex, however, remains poorly understood. Accumulated experimental evidence has supported supraspinal origins of spasticity, likely from an imbalance between descending inhibitory and facilitatory regulation of spinal stretch reflexes secondary to cortical disinhibition after stroke. The excitability of reticulospinal (RST) and vestibulospinal tracts (VSTs) has been assessed in stroke survivors with spasticity using non-invasive indirect measures. There are strong experimental findings that support the RST hyperexcitability as a prominent underlying mechanism of post-stroke spasticity. This mechanism can at least partly account for clinical features associated with spasticity and provide insightful guidance for clinical assessment and management of spasticity. However, the possible role of VST hyperexcitability cannot be ruled out from indirect measures. In vivo measure of individual brainstem nuclei in stroke survivors with spasticity using advanced fMRI techniques in the future is probably able to provide direct evidence of pathogenesis of post-stroke spasticity. PMID- 25914639 TI - NeuroVault.org: a web-based repository for collecting and sharing unthresholded statistical maps of the human brain. AB - Here we present NeuroVault-a web based repository that allows researchers to store, share, visualize, and decode statistical maps of the human brain. NeuroVault is easy to use and employs modern web technologies to provide informative visualization of data without the need to install additional software. In addition, it leverages the power of the Neurosynth database to provide cognitive decoding of deposited maps. The data are exposed through a public REST API enabling other services and tools to take advantage of it. NeuroVault is a new resource for researchers interested in conducting meta- and coactivation analyses. PMID- 25914640 TI - Ontology-based approach for in vivo human connectomics: the medial Brodmann area 6 case study. AB - Different non-invasive neuroimaging modalities and multi-level analysis of human connectomics datasets yield a great amount of heterogeneous data which are hard to integrate into an unified representation. Biomedical ontologies can provide a suitable integrative framework for domain knowledge as well as a tool to facilitate information retrieval, data sharing and data comparisons across scales, modalities and species. Especially, it is urgently needed to fill the gap between neurobiology and in vivo human connectomics in order to better take into account the reality highlighted in Magnetic Resonance Imaging (MRI) and relate it to existing brain knowledge. The aim of this study was to create a neuroanatomical ontology, called "Human Connectomics Ontology" (HCO), in order to represent macroscopic gray matter regions connected with fiber bundles assessed by diffusion tractography and to annotate MRI connectomics datasets acquired in the living human brain. First a neuroanatomical "view" called NEURO-DL-FMA was extracted from the reference ontology Foundational Model of Anatomy (FMA) in order to construct a gross anatomy ontology of the brain. HCO extends NEURO-DL FMA by introducing entities (such as "MR_Node" and "MR_Route") and object properties (such as "tracto_connects") pertaining to MR connectivity. The Web Ontology Language Description Logics (OWL DL) formalism was used in order to enable reasoning with common reasoning engines. Moreover, an experimental work was achieved in order to demonstrate how the HCO could be effectively used to address complex queries concerning in vivo MRI connectomics datasets. Indeed, neuroimaging datasets of five healthy subjects were annotated with terms of the HCO and a multi-level analysis of the connectivity patterns assessed by diffusion tractography of the right medial Brodmann Area 6 was achieved using a set of queries. This approach can facilitate comparison of data across scales, modalities and species. PMID- 25914641 TI - SET: a pupil detection method using sinusoidal approximation. AB - Mobile eye-tracking in external environments remains challenging, despite recent advances in eye-tracking software and hardware engineering. Many current methods fail to deal with the vast range of outdoor lighting conditions and the speed at which these can change. This confines experiments to artificial environments where conditions must be tightly controlled. Additionally, the emergence of low cost eye tracking devices calls for the development of analysis tools that enable non-technical researchers to process the output of their images. We have developed a fast and accurate method (known as "SET") that is suitable even for natural environments with uncontrolled, dynamic and even extreme lighting conditions. We compared the performance of SET with that of two open-source alternatives by processing two collections of eye images: images of natural outdoor scenes with extreme lighting variations ("Natural"); and images of less challenging indoor scenes ("CASIA-Iris-Thousand"). We show that SET excelled in outdoor conditions and was faster, without significant loss of accuracy, indoors. SET offers a low cost eye-tracking solution, delivering high performance even in challenging outdoor environments. It is offered through an open-source MATLAB toolkit as well as a dynamic-link library ("DLL"), which can be imported into many programming languages including C# and Visual Basic in Windows OS (www.eyegoeyetracker.co.uk). PMID- 25914642 TI - Organotypic vibrosections from whole brain adult Alzheimer mice (overexpressing amyloid-precursor-protein with the Swedish-Dutch-Iowa mutations) as a model to study clearance of beta-amyloid plaques. AB - Alzheimer's disease is a severe neurodegenerative disorder of the brain, pathologically characterized by extracellular beta-amyloid plaques, intraneuronal Tau inclusions, inflammation, reactive glial cells, vascular pathology and neuronal cell death. The degradation and clearance of beta-amyloid plaques is an interesting therapeutic approach, and the proteases neprilysin (NEP), insulysin and matrix metalloproteinases (MMP) are of particular interest. The aim of this project was to establish and characterize a simple in vitro model to study the degrading effects of these proteases. Organoytpic brain vibrosections (120 MUm thick) were sectioned from adult (9 month old) wildtype and transgenic mice (expressing amyloid precursor protein (APP) harboring the Swedish K670N/M671L, Dutch E693Q, and Iowa D694N mutations; APP_SDI) and cultured for 2 weeks. Plaques were stained by immunohistochemistry for beta-amyloid and Thioflavin S. Our data show that plaques were evident in 2 week old cultures from 9 month old transgenic mice. These plaques were surrounded by reactive GFAP+ astroglia and Iba1+ microglia. Incubation of fresh slices for 2 weeks with 1-0.1-0.01 MUg/ml of NEP, insulysin, MMP-2, or MMP-9 showed that NEP, insulysin, and MMP-9 markedly degraded beta-amyloid plaques but only at the highest concentration. Our data provide for the first time a potent and powerful living brain vibrosection model containing a high number of plaques, which allows to rapidly and simply study the degradation and clearance of beta-amyloid plaques in vitro. PMID- 25914644 TI - Effect of murine exposure to gamma rays on the interplay between Th1 and Th2 lymphocytes. AB - Gamma radiation radiotherapy is one of the widely used treatments for cancer. There is an accumulating evidence that adaptive immunity is significantly contributes to the efficacy of radiotherapy. This study is carried out to investigate the effect of gamma rays on the interplay between Th1/Th2 response, splenocyte lymphoproliferative response to polyclonal mitogenic activators and lymphocytic capacity to produce IL-12 and IL-10 in mice. Results showed that exposure of intact spleens to different doses of gamma-rays (5, 10, 20 Gy) caused spontaneous and dose-dependent immune stimulation manifested by enhanced cell proliferation and elevated IL-12 production with decreased IL-10 release (i.e., Th1 bias). While exposure of splenocytes suspension to different doses of gamma rays (5, 10, 20 Gy) showed activation in splenocytes stimulated by PWM at 5 Gy then a state of conventional immune suppression that is characterized by being dose-dependent and is manifested by decreased cell proliferation and IL-12 release accompanied by increase in IL-10 production (i.e., Th2 bias). In addition, we investigated the exposure of whole murine bodies to different doses of gamma-rays and found that the exposure to low dose gamma-rays (0.2 Gy) caused a state of immune stimulation terminated by a remarkable tendency for immune suppression. Exposure to 5 or 10 Gy of gamma-rays resulted in a state of immune stimulation (Th1 bias), but exposure to 20 Gy showed a standard state of immune suppression (Th2 bias). The results indicated that apparently we can control the immune response by controlling the dose of gamma-rays. PMID- 25914643 TI - Engineering muscle tissue for the fetus: getting ready for a strong life. AB - Congenital malformations frequently involve either skeletal, smooth or cardiac tissues. When large parts of those tissues are damaged, the repair of the malformations is challenged by the fact that so much autologous tissue is missing. Current treatments require the use of prostheses or other therapies and are associated with a significant morbidity and mortality. Nonetheless, affected children have generally good survival rates and mostly normal schooling. As such, new therapeutic modalities need to represent significant improvements with clear safety profiles. Regenerative medicine and tissue engineering technologies have the potential to dramatically improve the treatment of any disease or disorder involving a lack of viable tissue. With respect to congenital soft tissue anomalies, the development of, for example, implantable muscle constructs would provide not only the usual desired elasticity and contractile proprieties, but should also be able to grow with the fetus and/or in the postnatal life. Such an approach would eliminate the need for multiple surgeries. However, the more widespread clinical applications of regenerative medicine and tissue engineering technologies require identification of the optimal indications, as well as further elucidation of the precise mechanisms and best methods (cells, scaffolds/biomaterials) for achieving large functional tissue regeneration in those clinical indications. In short, despite some amazing scientific progress, significant safety and efficacy hurdles remain. However, the rapid preclinical advances in the field bode well for future applications. As such, translational researchers and clinicians alike need be informed and prepared to utilize these new techniques for the benefit of their patients, as soon as they are available. To this end, we review herein, the clinical need(s), potential applications, and the relevant preclinical studies that are currently guiding the field toward novel therapeutics. PMID- 25914645 TI - Interactions of antiretroviral drugs with the SLC22A1 (OCT1) drug transporter. AB - The SLC22A1 influx transporter is expressed on the basolateral membrane of hepatocytes and is involved in the excretion of numerous cations. Inhibition of SLC22A1 by several antiretrovirals, such as the protease inhibitor darunavir, has not previously been determined. In order to better understand and predict drug SLC22A1 interactions, a range of antiretrovirals were screened for SLC22A1 associated inhibition and transport. Stable SLC22A1-expressing KCL22 cells were produced previously by nucleofection. Control KCL22 cells were transfected with the empty vector pcDNA3.1. Accumulation of tetraethylammonium (5.5 MUM, 30 min) was determined in SLC22A1-expressing and mock-transfected cells with and without 50 MUM of SLC22A1 inhibitor prazosin, or 50 MUM of each antiretroviral drug. SLC22A1 IC50 values for efavirenz, darunavir, and prazosin were determined. Cellular accumulation of efavirenz and darunavir was also assessed in SLC22A1 expressing KCL22 cells and reversibility of this accumulation was assessed using prazosin. Tetraethylammonium accumulation was higher in SLC22A1-expressing cells compared to mock-transfected cells (10.6 +/- 0.8 MUM vs. 0.3 +/- 0.004 MUM, p = 0.009) and was significantly reduced in SLC22A1-expressing cells when co incubated with all antiretrovirals tested except atazanavir, lamivudine, tenofovir, zidovudine, and raltegravir. Particularly noticeable was the predominance of SLC22A1 inhibitors in the protease inhibitor and non-nucleoside reverse transcriptase inhibitor classes. Absolute SLC22A1 IC50 values for efavirenz, darunavir, and prazosin were 21.8, 46.2, and 2.8 MUM, respectively. Efavirenz accumulation was higher in SLC22A1-expressing cells compared to mock transfected cells (17% higher, p = 0.009) which was reversed using prazosin, whereas no difference was observed for darunavir (p = 0.86). These data inform the mechanistic basis for disposition, drug-drug interactions and pharmacogenetic candidate gene selection for antiretroviral drugs. PMID- 25914646 TI - Cholesterol removal from adult skeletal muscle impairs excitation-contraction coupling and aging reduces caveolin-3 and alters the expression of other triadic proteins. AB - Cholesterol and caveolin are integral membrane components that modulate the function/location of many cellular proteins. Skeletal muscle fibers, which have unusually high cholesterol levels in transverse tubules, express the caveolin-3 isoform but its association with transverse tubules remains contentious. Cholesterol removal impairs excitation-contraction (E-C) coupling in amphibian and mammalian fetal skeletal muscle fibers. Here, we show that treating single muscle fibers from adult mice with the cholesterol removing agent methyl-beta cyclodextrin decreased fiber cholesterol by 26%, altered the location pattern of caveolin-3 and of the voltage dependent calcium channel Cav1.1, and suppressed or reduced electrically evoked Ca(2+) transients without affecting membrane integrity or causing sarcoplasmic reticulum (SR) calcium depletion. We found that transverse tubules from adult muscle and triad fractions that contain ~10% attached transverse tubules, but not SR membranes, contained caveolin-3 and Cav1.1; both proteins partitioned into detergent-resistant membrane fractions highly enriched in cholesterol. Aging entails significant deterioration of skeletal muscle function. We found that triad fractions from aged rats had similar cholesterol and RyR1 protein levels compared to triads from young rats, but had lower caveolin-3 and glyceraldehyde 3-phosphate dehydrogenase and increased Na(+)/K(+)-ATPase protein levels. Both triad fractions had comparable NADPH oxidase (NOX) activity and protein content of NOX2 subunits (p47(phox) and gp91(phox)), implying that NOX activity does not increase during aging. These findings show that partial cholesterol removal impairs E-C coupling and alters caveolin-3 and Cav1.1 location pattern, and that aging reduces caveolin-3 protein content and modifies the expression of other triadic proteins. We discuss the possible implications of these findings for skeletal muscle function in young and aged animals. PMID- 25914647 TI - Macropinocytosis: a pathway to protozoan infection. AB - Among the various endocytic mechanisms in mammalian cells, macropinocytosis involves internalization of large amounts of plasma membrane together with extracellular medium, leading to macropinosome formation. These structures are formed when plasma membrane ruffles are assembled after actin filament rearrangement. In dendritic cells, macropinocytosis has been reported to play a role in antigen presentation. Several intracellular pathogens are internalized by host cells via multiple endocytic pathways and macropinocytosis has been described as an important entry site for various organisms. Some bacteria, such as Legionella pneumophila, as well as various viruses, use this pathway to penetrate and subvert host cells. Some protozoa, which are larger than bacteria and virus, can also use this pathway to invade host cells. As macropinocytosis is characterized by the formation of large uncoated vacuoles and is triggered by various signaling pathways, which is similar to what occurs during the formation of the majority of parasitophorous vacuoles, it is believed that this phenomenon may be more widely used by parasites than is currently appreciated. Here we review protozoa host cell invasion via macropinocytosis. PMID- 25914648 TI - The interplay between aerobic metabolism and antipredator performance: vigilance is related to recovery rate after exercise. AB - When attacked by a predator, fish respond with a sudden fast-start motion away from the threat. Although this anaerobically-powered swimming necessitates a recovery phase which is fueled aerobically, little is known about links between escape performance and aerobic traits such as aerobic scope (AS) or recovery time after exhaustive exercise. Slower recovery ability or a reduced AS could make some individuals less likely to engage in a fast-start response or display reduced performance. Conversely, increased vigilance in some individuals could permit faster responses to an attack but also increase energy demand and prolong recovery after anaerobic exercise. We examined how AS and the ability to recover from anaerobic exercise relates to differences in fast-start escape performance in juvenile golden gray mullet at different acclimation temperatures. Individuals were acclimated to either 18, 22, or 26 degrees C, then measured for standard and maximal metabolic rates and AS using intermittent flow respirometry. Anaerobic capacity and the time taken to recover after exercise were also assessed. Each fish was also filmed during a simulated attack to determine response latency, maximum speed and acceleration, and turning rate displayed during the escape response. Across temperatures, individuals with shorter response latencies during a simulated attack are those with the longest recovery time after exhaustive anaerobic exercise. Because a short response latency implies high preparedness to escape, these results highlight the trade-off between the increased vigilance and metabolic demand, which leads to longer recovery times in fast reactors. These results improve our understanding of the intrinsic physiological traits that generate inter-individual variability in escape ability, and emphasize that a full appreciation of trade-offs associated with predator avoidance and energy balance must include energetic costs associated with vigilance and recovery from anaerobic exercise. PMID- 25914649 TI - In vivo administration of dental epithelial stem cells at the apical end of the mouse incisor. AB - Cell-based tissue regeneration is an attractive approach that complements traditional surgical techniques for replacement of injured and lost tissues. The continuously growing rodent incisor provides an excellent model system for investigating cellular and molecular mechanisms that underlie tooth renewal and regeneration. An active population of dental epithelial progenitor/stem cells located at the posterior part of the incisor, commonly called cervical loop area, ensures the continuous supply of cells that are responsible for the secretion of enamel matrix. To explore the potential of these epithelial cells in therapeutic approaches dealing with enamel defects, we have developed a new method for their in vivo administration in the posterior part of the incisor. Here, we provide the step-by-step protocol for the isolation of dental epithelial stem cells and their delivery at targeted areas of the jaw. This simple and yet powerful protocol, consisting in drilling a hole in the mandibular bone, in close proximity to the cervical loop area of the incisor, followed up by injection of stem cells, is feasible, reliable, and effective. This in vivo approach opens new horizons and possibilities for cellular therapies involving pathological and injured dental tissues. PMID- 25914650 TI - Apelin and energy metabolism. AB - A wide range of adipokines identified over the past years has allowed considering the white adipose tissue as a secretory organ closely integrated into overall physiological and metabolic control. Apelin, a ubiquitously expressed peptide was known to exert different physiological effects mainly on the cardiovascular system and the regulation of fluid homeostasis prior to its characterization as an adipokine. This has broadened its range of action and apelin now appears clearly as a new player in energy metabolism in addition to leptin and adiponectin. Apelin has been shown to act on glucose and lipid metabolism but also to modulate insulin secretion. Moreover, different studies in both animals and humans have shown that plasma apelin concentrations are usually increased during obesity and type 2 diabetes. This mini-review will focus on the various systemic apelin effects on energy metabolism by addressing its mechanisms of action. The advances concerning the role of apelin in metabolic diseases in relation with the recent reports on apelin concentrations in obese and/or diabetic subjects will also be discussed. PMID- 25914651 TI - Representing number in the real-time processing of agreement: self-paced reading evidence from Arabic. AB - In the processing of subject-verb agreement, non-subject plural nouns following a singular subject sometimes "attract" the agreement with the verb, despite not being grammatically licensed to do so. This phenomenon generates agreement errors in production and an increased tendency to fail to notice such errors in comprehension, thereby providing a window into the representation of grammatical number in working memory during sentence processing. Research in this topic, however, is primarily done in related languages with similar agreement systems. In order to increase the cross-linguistic coverage of the processing of agreement, we conducted a self-paced reading study in Modern Standard Arabic. We report robust agreement attraction errors in relative clauses, a configuration not particularly conducive to the generation of such errors for all possible lexicalizations. In particular, we examined the speed with which readers retrieve a subject controller for both grammatical and ungrammatical agreeing verbs in sentences where verbs are preceded by two NPs, one of which is a local non subject NP that can act as a distractor for the successful resolution of subject verb agreement. Our results suggest that the frequency of errors is modulated by the kind of plural formation strategy used on the attractor noun: nouns which form plurals by suffixation condition high rates of attraction, whereas nouns which form their plurals by internal vowel change (ablaut) generate lower rates of errors and reading-time attraction effects of smaller magnitudes. Furthermore, we show some evidence that these agreement attraction effects are mostly contained in the right tail of reaction time distributions. We also present modeling data in the ACT-R framework which supports a view of these ablauting patterns wherein they are differentially specified for number and evaluate the consequences of possible representations for theories of grammar and parsing. PMID- 25914652 TI - Task-dependency and structure-dependency in number interference effects in sentence comprehension. AB - We report three experiments on French that explore number mismatch effects in intervention configurations in the comprehension of object A'-dependencies, relative clauses and questions. The study capitalizes on the finding of object attraction in sentence production, in which speakers sometimes erroneously produce a verb that agrees in number with a plural object in object relative clauses. Evidence points to the role of three critical constructs from formal syntax: intervention, intermediate traces and c-command (Franck et al., 2010). Experiment 1, using a self-paced reading procedure on these grammatical structures with an agreement error on the verb, shows an enhancing effect of number mismatch in intervention configurations, with faster reading times with plural (mismatching) objects. Experiment 2, using an on-line grammaticality judgment task on the ungrammatical versions of these structures, shows an interference effect in the form of attraction, with slower response times with plural objects. Experiment 3 with a similar grammaticality judgment task shows stronger attraction from c-commanding than from preceding interveners. Overall, the data suggest that syntactic computations in performance refer to the same syntactic representations in production and comprehension, but that different tasks tap into different processes involved in parsing: whereas performance in self-paced reading reflects the intervention of the subject in the process of building an object A'-dependency, performance in grammaticality judgment reflects intervention of the object on the computation of the subject-verb agreement dependency. The latter shows the hallmarks of structure-dependent attraction effects in sentence production, in particular, a sensitivity to specific characteristics of hierarchical representations. PMID- 25914653 TI - It does belong together: cross-modal correspondences influence cross-modal integration during perceptual learning. AB - Experiencing a stimulus in one sensory modality is often associated with an experience in another sensory modality. For instance, seeing a lemon might produce a sensation of sourness. This might indicate some kind of cross-modal correspondence between vision and gustation. The aim of the current study was to explore whether such cross-modal correspondences influence cross-modal integration during perceptual learning. To that end, we conducted two experiments. Using a speeded classification task, Experiment 1 established a cross-modal correspondence between visual lightness and the frequency of an auditory tone. Using a short-term priming procedure, Experiment 2 showed that manipulation of such cross-modal correspondences led to the creation of a crossmodal unit regardless of the nature of the correspondence (i.e., congruent, Experiment 2a or incongruent, Experiment 2b). However, a comparison of priming effects sizes suggested that cross-modal correspondences modulate cross-modal integration during learning, leading to new learned units that have different stability over time. We discuss the implications of our results for the relation between cross-modal correspondence and perceptual learning in the context of a Bayesian explanation of cross-modal correspondences. PMID- 25914654 TI - Magically deceptive biological motion-the French Drop Sleight. AB - Intentional deception, as is common in the performance of magic tricks, can provide valuable insight into the mechanisms of perception and action. Much of the recent investigations into this form of deception revolve around the attention of the observer. Here, we present experiments designed to investigate the contributions of the performer to the act of deception. An experienced magician and a naive novice performed a classic sleight known as the French Drop. Video recordings of the performance were used to measure the quality of the deception-e.g., if a non-magician observer could discriminate instances where the sleight was performed (a deceptive performance) from those where it was not (a veridical performace). During the performance we recorded the trajectory of the hands and measured muscle activity via EMG to help understand the biomechanical mechanisms of this deception. We show that expertise plays a major role in the quality of the deception and that there are significant variations in the motion and muscular behaviors between successful and unsuccessful performances. Smooth, minimal movements with an exaggerated faux-transfer of muscular tension were characteristic of better deception. This finding is consistent with anecdotal reports and the magic performance literature. PMID- 25914655 TI - Updating in working memory predicts greater emotion reactivity to and facilitated recovery from negative emotion-eliciting stimuli. AB - That emotions change in response to emotion-eliciting events is a natural part of human life. However, it is equally important for emotions to return to baseline once the emotion-eliciting events have passed. This suggests that the ability to emotionally react to and recover from emotion-eliciting events is critical for healthy psychological functioning. But why do individuals differ in their emotion reactivity and recovery? The present work postulates that the ability to update emotional information in working memory (WM) may explain individual differences in emotion reactivity and recovery. Two studies are presented, which examined whether updating ability was related to emotion reactivity and recovery. In Study 1, we assessed participants' self-reported affect as they viewed negative and positive films. Our results revealed that better updating ability was related to greater emotion reactivity and facilitated (i.e., quicker) recovery from watching negative films. In Study 2, participants recalled a recent angering event, and were then instructed to either ruminate about or reappraise the event. Results revealed that updating ability was again related to greater emotion reactivity and facilitated (i.e., successful) emotion recovery in response to the angering event, and that this was unrelated to the emotion regulation strategy used. These findings identify the ability to update emotional information in WM as a possible mechanism in emotion responding. PMID- 25914656 TI - Visual attractiveness is leaky: the asymmetrical relationship between face and hair. AB - Predicting personality is crucial when communicating with people. It has been revealed that the perceived attractiveness or beauty of the face is a cue. As shown in the well-known "what is beautiful is good" stereotype, perceived attractiveness is often associated with desirable personality. Although such research on attractiveness used mainly the face isolated from other body parts, the face is not always seen in isolation in the real world. Rather, it is surrounded by one's hairstyle, and is perceived as a part of total presence. In human vision, perceptual organization/integration occurs mostly in a bottom up, task-irrelevant fashion. This raises an intriguing possibility that task irrelevant stimulus that is perceptually integrated with a target may influence our affective evaluation. In such a case, there should be a mutual influence between attractiveness perception of the face and surrounding hair, since they are assumed to share strong and unique perceptual organization. In the current study, we examined the influence of a task-irrelevant stimulus on our attractiveness evaluation, using face and hair as stimuli. The results revealed asymmetrical influences in the evaluation of one while ignoring the other. When hair was task-irrelevant, it still affected attractiveness of the face, but only if the hair itself had never been evaluated by the same evaluator. On the other hand, the face affected the hair regardless of whether the face itself was evaluated before. This has intriguing implications on the asymmetry between face and hair, and perceptual integration between them in general. Together with data from a post hoc questionnaire, it is suggested that both implicit non-selective and explicit selective processes contribute to attractiveness evaluation. The findings provide an understanding of attractiveness perception in real-life situations, as well as a new paradigm to reveal unknown implicit aspects of information integration for emotional judgment. PMID- 25914657 TI - Using decision trees to characterize verbal communication during change and stuck episodes in the therapeutic process. AB - Methods are needed for creating models to characterize verbal communication between therapists and their patients that are suitable for teaching purposes without losing analytical potential. A technique meeting these twin requirements is proposed that uses decision trees to identify both change and stuck episodes in therapist-patient communication. Three decision tree algorithms (C4.5, NBTree, and REPTree) are applied to the problem of characterizing verbal responses into change and stuck episodes in the therapeutic process. The data for the problem is derived from a corpus of 8 successful individual therapy sessions with 1760 speaking turns in a psychodynamic context. The decision tree model that performed best was generated by the C4.5 algorithm. It delivered 15 rules characterizing the verbal communication in the two types of episodes. Decision trees are a promising technique for analyzing verbal communication during significant therapy events and have much potential for use in teaching practice on changes in therapeutic communication. The development of pedagogical methods using decision trees can support the transmission of academic knowledge to therapeutic practice. PMID- 25914658 TI - Hyper-active gap filling. AB - Much work has demonstrated that speakers of verb-final languages are able to construct rich syntactic representations in advance of verb information. This may reflect general architectural properties of the language processor, or it may only reflect a language-specific adaptation to the demands of verb-finality. The present study addresses this issue by examining whether speakers of a verb-medial language (English) wait to consult verb transitivity information before constructing filler-gap dependencies, where internal arguments are fronted and hence precede the verb. This configuration makes it possible to investigate whether the parser actively makes representational commitments on the gap position before verb transitivity information becomes available. A key prediction of the view that rich pre-verbal structure building is a general architectural property is that speakers of verb-medial languages should predictively construct dependencies in advance of verb transitivity information, and therefore that disruption should be observed when the verb has intransitive subcategorization frames that are incompatible with the predicted structure. In three reading experiments (self-paced and eye-tracking) that manipulated verb transitivity, we found evidence for reading disruption when the verb was intransitive, although no such reading difficulty was observed when the critical verb was embedded inside a syntactic island structure, which blocks filler-gap dependency completion. These results are consistent with the hypothesis that in English, as in verb-final languages, information from preverbal noun phrases is sufficient to trigger active dependency completion without having access to verb transitivity information. PMID- 25914659 TI - Intonation processing deficits of emotional words among Mandarin Chinese speakers with congenital amusia: an ERP study. AB - BACKGROUND: Congenital amusia is a disorder that is known to affect the processing of musical pitch. Although individuals with amusia rarely show language deficits in daily life, a number of findings point to possible impairments in speech prosody that amusic individuals may compensate for by drawing on linguistic information. Using EEG, we investigated (1) whether the processing of speech prosody is impaired in amusia and (2) whether emotional linguistic information can compensate for this impairment. METHOD: Twenty Chinese amusics and 22 matched controls were presented pairs of emotional words spoken with either statement or question intonation while their EEG was recorded. Their task was to judge whether the intonations were the same. RESULTS: Amusics exhibited impaired performance on the intonation-matching task for emotional linguistic information, as their performance was significantly worse than that of controls. EEG results showed a reduced N2 response to incongruent intonation pairs in amusics compared with controls, which likely reflects impaired conflict processing in amusia. However, our EEG results also indicated that amusics were intact in early sensory auditory processing, as revealed by a comparable N1 modulation in both groups. CONCLUSION: We propose that the impairment in discriminating speech intonation observed among amusic individuals may arise from an inability to access information extracted at early processing stages. This, in turn, could reflect a disconnection between low-level and high-level processing. PMID- 25914660 TI - Contributions of emotional state and attention to the processing of syntactic agreement errors: evidence from P600. AB - The classic account of language is that language processing occurs in isolation from other cognitive systems, like perception, motor action, and emotion. The central theme of this paper is the relationship between a participant's emotional state and language comprehension. Does emotional context affect how we process neutral words? Recent studies showed that processing of word meaning - traditionally conceived as an automatic process - is affected by emotional state. The influence of emotional state on syntactic processing is less clear. One study reported a mood-related P600 modulation, while another study did not observe an effect of mood on syntactic processing. The goals of this study were: First, to clarify whether and if so how mood affects syntactic processing. Second, to shed light on the underlying mechanisms by separating possible effects of mood from those of attention on syntactic processing. Event-related potentials (ERPs) were recorded while participants read syntactically correct or incorrect sentences. Mood (happy vs. sad) was manipulated by presenting film clips. Attention was manipulated by directing attention to syntactic features vs. physical features. The mood induction was effective. Interactions between mood, attention and syntactic correctness were obtained, showing that mood and attention modulated P600. The mood manipulation led to a reduction in P600 for sad as compared to happy mood when attention was directed at syntactic features. The attention manipulation led to a reduction in P600 when attention was directed at physical features compared to syntactic features for happy mood. From this we draw two conclusions: First, emotional state does affect syntactic processing. We propose mood-related differences in the reliance on heuristics as the underlying mechanism. Second, attention can contribute to emotion-related ERP effects in syntactic language processing. Therefore, future studies on the relation between language and emotion will have to control for effects of attention. PMID- 25914661 TI - A review of empirical evidence on different uncanny valley hypotheses: support for perceptual mismatch as one road to the valley of eeriness. AB - The uncanny valley hypothesis, proposed already in the 1970s, suggests that almost but not fully humanlike artificial characters will trigger a profound sense of unease. This hypothesis has become widely acknowledged both in the popular media and scientific research. Surprisingly, empirical evidence for the hypothesis has remained inconsistent. In the present article, we reinterpret the original uncanny valley hypothesis and review empirical evidence for different theoretically motivated uncanny valley hypotheses. The uncanny valley could be understood as the naive claim that any kind of human-likeness manipulation will lead to experienced negative affinity at close-to-realistic levels. More recent hypotheses have suggested that the uncanny valley would be caused by artificial human categorization difficulty or by a perceptual mismatch between artificial and human features. Original formulation also suggested that movement would modulate the uncanny valley. The reviewed empirical literature failed to provide consistent support for the naive uncanny valley hypothesis or the modulatory effects of movement. Results on the categorization difficulty hypothesis were still too scarce to allow drawing firm conclusions. In contrast, good support was found for the perceptual mismatch hypothesis. Taken together, the present review findings suggest that the uncanny valley exists only under specific conditions. More research is still needed to pinpoint the exact conditions under which the uncanny valley phenomenon manifests itself. PMID- 25914662 TI - ACTonFOOD: opportunities of ACT to address food addiction. PMID- 25914663 TI - Learning your way in a city: experience and gender differences in configurational knowledge of one's environment. AB - Males tend to outperform females in their knowledge of relative and absolute distances in spatial layouts and environments. It is unclear yet in how far these differences are innate or develop through life. The aim of the present study was to investigate whether gender differences in configurational knowledge for a natural environment might be modulated by experience. In order to examine this possibility, distance as well as directional knowledge of the city of Utrecht in the Netherlands was assessed in male and female inhabitants who had different levels of familiarity with this city. Experience affected the ability to solve difficult distance knowledge problems, but only for females. While the quality of the spatial representation of metric distances improved with more experience, this effect was not different for males and females. In contrast directional configurational measures did show a main gender effect but no experience modulation. In general, it seems that we obtain different configurational aspects according to different experiential time schemes. Moreover, the results suggest that experience may be a modulating factor in the occurrence of gender differences in configurational knowledge, though this seems dependent on the type of measurement. It is discussed in how far proficiency in mental rotation ability and spatial working memory accounts for these differences. PMID- 25914664 TI - Bifactor analysis and construct validity of the five facet mindfulness questionnaire (FFMQ) in non-clinical Spanish samples. AB - The objective of the present study was to examine the dimensionality, reliability, and construct validity of the Five Facet Mindfulness Questionnaire (FFMQ) in three Spanish samples using structural equation modeling (SEM). Pooling the FFMQ data from 3 Spanish samples (n = 1191), we estimated the fit of two competing models (correlated five-factor vs. bifactor) via confirmatory factor analysis. The factorial invariance of the best fitting model across meditative practice was also addressed. The pattern of relationships between the FFMQ latent dimensions and anxiety, depression, and distress was analyzed using SEM. FFMQ reliability was examined by computing the omega and omega hierarchical coefficients. The bifactor model, which accounted for the covariance among FFMQ items with regard to one general factor (mindfulness) and five orthogonal factors (observing, describing, acting with awareness, non-judgment, and non-reactivity), fit the FFMQ structure better than the correlated five-factor model. The relationships between the latent variables and their manifest indicators were not invariant across the meditative experience. Observing items had significant loadings on the general mindfulness factor, but only in the meditator sub-sample. The SEM analysis revealed significant links between mindfulness and symptoms of depression and stress. When the general factor was partialled out, the acting with awareness facet did not show adequate reliability. The FFMQ shows a robust bifactor structure among Spanish individuals. Nevertheless, the Observing subscale does not seem to be adequate for assessing mindfulness in individuals without meditative experience. PMID- 25914665 TI - Single stimulus color can modulate vection. AB - In the present study, we investigated the effects of single color on forward and backward vection. The approaching or receding optical flow observed during forward or backward locomotion was simulated by using random dots with changing size, velocity, and disparity. The dots were presented on a black (Experiments 1 and 2) or white background (Experiment 3) in equiluminant colors; namely, white (or gray), red, yellow, green, or blue. The participant's task was to press and hold one of three buttons whenever they felt vection. The three buttons corresponded to the subjective strength of vection: strong, same, and weak relative to vection induced by the standard modulus. In Experiments 1 and 2, the participants were also asked to rate the strength and direction of vection after each trial. In Experiment 3, they rated the visibility and the perceived velocity of dot motion. Experiment 1 showed that the induced vection was stronger for the chromatic than for the achromatic dots. Particularly at low velocity conditions (+/-10 km/h), the vection induced for red dots was stronger than that for the other colored dots. Experiment 2 showed that the order effects of stimulus presentation could not explain the findings of Experiment 1. Experiment 3's pattern of results was similar to that of Experiment 1, and this suggested that a luminance artifact between color conditions could not account for Experiment 1's findings. These results suggest that a stimulus color can modulate vection even when a single color is added to the optical flow. PMID- 25914666 TI - Unlocking the potential of smart grid technologies with behavioral science. AB - Smart grid systems aim to provide a more stable and adaptable electricity infrastructure, and to maximize energy efficiency. Grid-linked technologies vary widely in form and function, but generally share common potentials: to reduce energy consumption via efficiency and/or curtailment, to shift use to off-peak times of day, and to enable distributed storage and generation options. Although end users are central players in these systems, they are sometimes not central considerations in technology or program design, and in some cases, their motivations for participating in such systems are not fully appreciated. Behavioral science can be instrumental in engaging end-users and maximizing the impact of smart grid technologies. In this paper, we present emerging technologies made possible by a smart grid infrastructure, and for each we highlight ways in which behavioral science can be applied to enhance their impact on energy savings. PMID- 25914667 TI - Appetite, reward, and obesity: the causes and consequences of eating behaviors. PMID- 25914668 TI - Positive affect: phenotypic and etiologic associations with prosocial behaviors and internalizing problems in toddlers. AB - Despite evidence for the associations of positive affect to prosocial behaviors and internalizing problems, relatively little is known about the underlying etiology. The sample comprised over 300 twin pairs at age 3. Positive affect, prosocial behaviors, and internalizing problems were assessed using the Toddler Behavior Assessment Questionnaire (Goldsmith, 1996), the Revised Rutter Parent Scale for Preschool Children (Hogg et al., 1997), and the Child Behavior Checklist for ages 1.5-5 (Achenbach, 1991), respectively. Positive affect correlated positively with prosocial behaviors, and negatively with internalizing problems. Prosocial behaviors were negatively associated with internalizing problems. The relations of positive affect to prosocial behaviors and internalizing problems were due to environmental effects (shared and non-shared). In contrast, the link between prosocial behaviors and internalizing problems was entirely explained by genetic effects. The current study has moved beyond prior emphasis on negative affect and elucidated the less understood etiology underlying the associations between positive affect, prosocial behaviors, and internalizing problems. This study could guide the development of programs for promoting prosocial behaviors and alleviating internalizing problems in children. PMID- 25914669 TI - The effect of sad facial expressions on weight judgment. AB - Although the body weight evaluation (e.g., normal or overweight) of others relies on perceptual impressions, it also can be influenced by other psychosocial factors. In this study, we explored the effect of task-irrelevant emotional facial expressions on judgments of body weight and the relationship between emotion-induced weight judgment bias and other psychosocial variables including attitudes toward obese persons. Forty-four participants were asked to quickly make binary body weight decisions for 960 randomized sad and neutral faces of varying weight levels presented on a computer screen. The results showed that sad facial expressions systematically decreased the decision threshold of overweight judgments for male faces. This perceptual decision bias by emotional expressions was positively correlated with the belief that being overweight is not under the control of obese persons. Our results provide experimental evidence that task irrelevant emotional expressions can systematically change the decision threshold for weight judgments, demonstrating that sad expressions can make faces appear more overweight than they would otherwise be judged. PMID- 25914670 TI - Can the humped animal's knee conceal its name? Commentary on: "The roles of shared vs. distinctive conceptual features in lexical access". PMID- 25914671 TI - Preschool-aged children recognize ambivalence: emerging identification of concurrent conflicting desires. AB - We examined the ability of preschool-aged children to identify conflicting, or ambivalent, desire states (e.g., "I want to go to the birthday party because there will be cake, but I also don't want to go because I'm having fun playing at home"). Participants were 4- and 5-year-old children, and a group of undergraduate students (n = 20 in each age group). They were presented with 14 scenarios involving both "single desire" and "dual desire" states, including both approach (i.e., "want") and avoidance (i.e., "not want") desires. Our primary interest was children's ability to identify concurrent conflicting "dual desire" states, and this ability was found in most of the 5-year-old age group tested and in about half of the 4-year-old age group. As such, these results provide evidence that children can identify ambivalence at earlier ages than previously reported. In addition, results showed that the challenge in recognizing ambivalence is the presence of desires of opposite valence directed at the same target. PMID- 25914672 TI - Erratum: Taking perspective the next time around. Commentary on: "Perceived perspective taking: when others walk in our shoes". AB - [This corrects the article on p. 941 in vol. 106, PMID: 24841098.]. PMID- 25914673 TI - Is CT-Based Perfusion and Collateral Imaging Sensitive to Time Since Stroke Onset? AB - PURPOSE: CT-based perfusion and collateral imaging is increasingly used in the assessment of patients with acute stroke. Time of stroke onset is a critical factor in determining eligibility for and benefit from thrombolysis. Animal studies predict that the volume of ischemic penumbra decreases with time. Here, we evaluate if CT is able to detect a relationship between perfusion or collateral status, as assessed by CT, and time since stroke onset. MATERIALS AND METHODS: We studied 53 consecutive patients with proximal vessel occlusions, mean (SD) age of 71.3 (14.9) years, at a mean (SD) of 125.2 (55.3) minutes from onset, using whole-brain CT perfusion (CTp) imaging. Penumbra was defined using voxel based thresholds for cerebral blood flow (CBF) and mean transit time (MTT); core was defined by cerebral blood volume (CBV). Normalized penumbra fraction was calculated as Penumbra volume/(Penumbra volume + Core volume) for both CBF and MTT (PenCBF and PenMTT, respectively). Collaterals were assessed on CT angiography (CTA). CTp ASPECTS score was applied visually, lower scores indicating larger lesions. ASPECTS ratios were calculated corresponding to penumbra fractions. RESULTS: Both PenCBF and PenMTT showed decremental trends with increasing time since onset (Kendall's tau-b = -0.196, p = 0.055, and 0.187, p = 0.068, respectively). The CBF/CBV ASPECTS ratio, which showed a relationship to PenCBF (Kendall's tau-b = 0.190, p = 0.070), decreased with increasing time since onset (Kendall's tau-b = -0.265, p = 0.006). Collateral response did not relate to time (Kendall's tau-b = -0.039, p = 0.724). CONCLUSION: Even within 4.5 h since stroke onset, a decremental relationship between penumbra and time, but not between collateral status and time, may be detected using perfusion CT imaging. The trends that we demonstrate merit evaluation in larger datasets to confirm our results, which may have potential wider applications, e.g., in the setting of strokes of unknown onset time. PMID- 25914675 TI - Ebola virus infection modeling and identifiability problems. AB - The recent outbreaks of Ebola virus (EBOV) infections have underlined the impact of the virus as a major threat for human health. Due to the high biosafety classification of EBOV (level 4), basic research is very limited. Therefore, the development of new avenues of thinking to advance quantitative comprehension of the virus and its interaction with the host cells is urgently needed to tackle this lethal disease. Mathematical modeling of the EBOV dynamics can be instrumental to interpret Ebola infection kinetics on quantitative grounds. To the best of our knowledge, a mathematical modeling approach to unravel the interaction between EBOV and the host cells is still missing. In this paper, a mathematical model based on differential equations is used to represent the basic interactions between EBOV and wild-type Vero cells in vitro. Parameter sets that represent infectivity of pathogens are estimated for EBOV infection and compared with influenza virus infection kinetics. The average infecting time of wild-type Vero cells by EBOV is slower than in influenza infection. Simulation results suggest that the slow infecting time of EBOV could be compensated by its efficient replication. This study reveals several identifiability problems and what kind of experiments are necessary to advance the quantification of EBOV infection. A first mathematical approach of EBOV dynamics and the estimation of standard parameters in viral infections kinetics is the key contribution of this work, paving the way for future modeling works on EBOV infection. PMID- 25914676 TI - Tyrosine decarboxylase activity of enterococci grown in media with different nutritional potential: tyramine and 2-phenylethylamine accumulation and tyrDC gene expression. AB - The ability to accumulate tyramine and 2-phenylethylamine by two strains of Enterococcus faecalis and two strains Enterococcus faecium was evaluated in two cultural media added or not with tyrosine. All the enterococcal strains possessed a tyrosine decarboxylase (tyrDC) which determined tyramine accumulation in all the conditions tested, independently on the addition of high concentration of free tyrosine. Enterococci differed in rate and level of biogenic amines accumulation. E. faecalis EF37 and E. faecium FC12 produced tyramine in high amount since the exponential growth phase, while 2-phenylethylamine was accumulated when tyrosine was depleted. E. faecium FC12 and E. faecalis ATCC 29212 showed a slower tyraminogenic activity which took place mainly in the stationary phase up to 72 h of incubation. Moreover, E. faecalis ATCC 29212 produced 2-phenylethylamine only in the media without tyrosine added. In BHI added or not with tyrosine the tyrDC gene expression level differed considerably depending on the strains and the growth phase. In particular, the tyrDC gene expression was high during the exponential phase in rich medium for all the strains and subsequently decreased except for E. faecium FC12. Even if tyrDC presence is common among enterococci, this study underlines the extremely variable decarboxylating potential of strains belonging to the same species, suggesting strain-dependent implications in food safety. PMID- 25914674 TI - A review on computational systems biology of pathogen-host interactions. AB - Pathogens manipulate the cellular mechanisms of host organisms via pathogen-host interactions (PHIs) in order to take advantage of the capabilities of host cells, leading to infections. The crucial role of these interspecies molecular interactions in initiating and sustaining infections necessitates a thorough understanding of the corresponding mechanisms. Unlike the traditional approach of considering the host or pathogen separately, a systems-level approach, considering the PHI system as a whole is indispensable to elucidate the mechanisms of infection. Following the technological advances in the post-genomic era, PHI data have been produced in large-scale within the last decade. Systems biology-based methods for the inference and analysis of PHI regulatory, metabolic, and protein-protein networks to shed light on infection mechanisms are gaining increasing demand thanks to the availability of omics data. The knowledge derived from the PHIs may largely contribute to the identification of new and more efficient therapeutics to prevent or cure infections. There are recent efforts for the detailed documentation of these experimentally verified PHI data through Web-based databases. Despite these advances in data archiving, there are still large amounts of PHI data in the biomedical literature yet to be discovered, and novel text mining methods are in development to unearth such hidden data. Here, we review a collection of recent studies on computational systems biology of PHIs with a special focus on the methods for the inference and analysis of PHI networks, covering also the Web-based databases and text-mining efforts to unravel the data hidden in the literature. PMID- 25914677 TI - The geomicrobiology of CO2 geosequestration: a focused review on prokaryotic community responses to field-scale CO2 injection. AB - Our primary research paper (Mu et al., 2014) demonstrated selective changes to a deep subsurface prokaryotic community as a result of CO2 stress. Analyzing geochemical and microbial 16S rRNA gene profiles, we evaluated how in situ prokaryotic communities responded to increased CO2 and the presence of trace organic compounds, and related temporal shifts in phylogeny to changes in metabolic potential. In this focused review, we extend upon our previous discussion to present analysis of taxonomic unit co-occurrence profiles from the same field experiment, to attempt to describe dynamic community behavior within the deep subsurface. Understanding the physiology of the subsurface microbial biosphere, including how key functional groups integrate into the community, will be critical to determining the fate of injected CO2. For example, community-wide network analyses may provide insights to whether microbes cooperatively produce biofilm biomass, and/or biomineralize the CO2, and hence, induce changes to formation porosity or changes in electron flow. Furthermore, we discuss potential impacts to the feasibility of subsurface CO2 storage of selectively enriching for particular metabolic functions (e.g., methanogenesis) as a result of CO2 injection. PMID- 25914678 TI - Combining genomic sequencing methods to explore viral diversity and reveal potential virus-host interactions. AB - Viral diversity and virus-host interactions in oxygen-starved regions of the ocean, also known as oxygen minimum zones (OMZs), remain relatively unexplored. Microbial community metabolism in OMZs alters nutrient and energy flow through marine food webs, resulting in biological nitrogen loss and greenhouse gas production. Thus, viruses infecting OMZ microbes have the potential to modulate community metabolism with resulting feedback on ecosystem function. Here, we describe viral communities inhabiting oxic surface (10 m) and oxygen-starved basin (200 m) waters of Saanich Inlet, a seasonally anoxic fjord on the coast of Vancouver Island, British Columbia using viral metagenomics and complete viral fosmid sequencing on samples collected between April 2007 and April 2010. Of 6459 open reading frames (ORFs) predicted across all 34 viral fosmids, 77.6% (n = 5010) had no homology to reference viral genomes. These fosmids recruited a higher proportion of viral metagenomic sequences from Saanich Inlet than from nearby northeastern subarctic Pacific Ocean (Line P) waters, indicating differences in the viral communities between coastal and open ocean locations. While functional annotations of fosmid ORFs were limited, recruitment to NCBI's non-redundant "nr" database and publicly available single-cell genomes identified putative viruses infecting marine thaumarchaeal and SUP05 proteobacteria to provide potential host linkages with relevance to coupled biogeochemical cycling processes in OMZ waters. Taken together, these results highlight the power of coupled analyses of multiple sequence data types, such as viral metagenomic and fosmid sequence data with prokaryotic single cell genomes, to chart viral diversity, elucidate genomic and ecological contexts for previously unclassifiable viral sequences, and identify novel host interactions in natural and engineered ecosystems. PMID- 25914679 TI - Rhizosphere bacterial carbon turnover is higher in nucleic acids than membrane lipids: implications for understanding soil carbon cycling. AB - Using a pulse chase (13)CO2 plant labeling experiment we compared the flow of plant carbon into macromolecular fractions of rhizosphere soil microorganisms. Time dependent (13)C dilution patterns in microbial cellular fractions were used to calculate their turnover time. The turnover times of microbial biomolecules were found to vary: microbial RNA (19 h) and DNA (30 h) turned over fastest followed by chloroform fumigation extraction-derived soluble cell lysis products (14 days), while phospholipid fatty acids (PLFAs) had the slowest turnover (42 days). PLFA/NLFA (13)C analyses suggest that both mutualistic arbuscular mycorrhizal and saprophytic fungi are dominant in initial plant carbon uptake. In contrast, high initial (13)C enrichment in RNA hints at bacterial importance in initial C uptake due to the dominance of bacterial derived RNA in total extracts of soil RNA. To explain this discrepancy, we observed low renewal rate of bacterial lipids, which may therefore bias lipid fatty acid based interpretations of the role of bacteria in soil microbial food webs. Based on our findings, we question current assumptions regarding plant-microbe carbon flux and suggest that the rhizosphere bacterial contribution to plant assimilate uptake could be higher. This highlights the need for more detailed quantitative investigations with nucleic acid biomarkers to further validate these findings. PMID- 25914681 TI - Improvement of the quantitation method for the tdh (+) Vibrio parahaemolyticus in molluscan shellfish based on most-probable- number, immunomagnetic separation, and loop-mediated isothermal amplification. AB - Vibrio parahaemolyticus is a marine microorganism that can cause seafood-borne gastroenteritis in humans. The infection can be spread and has become a pandemic through the international trade of contaminated seafood. Strains carrying the tdh gene encoding the thermostable direct hemolysin (TDH) and/or the trh gene encoding the TDH-related hemolysin (TRH) are considered to be pathogenic with the former gene being the most frequently found in clinical strains. However, their distribution frequency in environmental isolates is below 1%. Thus, very sensitive methods are required for detection and quantitation of tdh (+) strains in seafood. We previously reported a method to detect and quantify tdh (+) V. parahaemolyticus in seafood. This method consists of three components: the most probable-number (MPN), the immunomagnetic separation (IMS) targeting all established K antigens, and the loop-mediated isothermal amplification (LAMP) targeting the tdh gene. However, this method faces regional issues in tropical zones of the world. Technicians have difficulties in securing dependable reagents in high-temperature climates where we found MPN underestimation in samples having tdh (+) strains as well as other microorganisms present at high concentrations. In the present study, we solved the underestimation problem associated with the salt polymyxin broth enrichment for the MPN component and with the immunomagnetic bead-target association for the IMS component. We also improved the supply and maintenance of the dependable reagents by introducing a dried reagent system to the LAMP component. The modified method is specific, sensitive, quick and easy and applicable regardless of the concentrations of tdh (+) V. parahaemolyticus. Therefore, we conclude this modified method is useful in world tropical, sub tropical, and temperate zones. PMID- 25914680 TI - Marine-derived fungi: diversity of enzymes and biotechnological applications. AB - The ocean is considered to be a great reservoir of biodiversity. Microbial communities in marine environments are ecologically relevant as intermediaries of energy, and play an important role in nutrient regeneration cycles as decomposers of dead and decaying organic matter. In this sense, marine-derived fungi can be considered as a source of enzymes of industrial and/or environmental interest. Fungal strains isolated from different substrates, such as invertebrates, decaying wood, seawater, sediments, and mangrove detritus, have been reported to be producers of hydrolytic and/or oxidative enzymes, with alginate lyase, amylase, cellulase, chitinase, glucosidase, inulinase, keratinase, ligninase, lipase, nuclease, phytase, protease, and xylanase being among the enzymes produced by fungi of marine origin. These enzymes present temperature and pH optima ranging from 35 to 70(?)C, and 3.0 to 11.0, respectively. High-level production in bioreactors is mainly performed using submerged-state fermentation. Certain marine-derived fungal strains present enzymes with alkaline and cold activity characteristics, and salinity is considered an important condition in screening and production processes. The adaptability of marine-derived fungi to oceanic conditions can be considered an attractive point in the field of fungal marine biotechnology. In this review, we focus on the advances in discovering enzymes from marine-derived fungi and their biotechnological relevance. PMID- 25914682 TI - Type 1 fimbriae are important factors limiting the dissemination and colonization of mice by Salmonella Enteritidis and contribute to the induction of intestinal inflammation during Salmonella invasion. AB - We have recently shown that Salmonella Gallinarum type 1 fimbriae with endogenous mannose-resistant (MR) variant of the FimH protein increase systemic dissemination of S. Gallinarum and colonization of internal organs in comparison to the S. Gallinarum fimH knockout strain or the mutant expressing mannose sensitive (MS) FimH variant from S. Enteritidis. Elaborating from these studies, we proposed that MS variants of FimH are advantageous in gastrointestinal infections, in contrast to MR FimH variants which decrease intestinal colonization and promote their systemic spreading. To support our hypothesis, we carried out in vivo studies using mice infected with wild-type S. Enteritidis and its fimH knockout strain (S. Enteritidis), which was characterized by significantly lower adhesion and invasiveness of murine ICE-1 intestinal cells. Using bioluminescence imaging, we observed that the loss of MS FimH adhesin correlates well with the highly increased colonization of mice by these bacteria. The appearance of the mutant strain was observed much earlier than wild-type Salmonella, and mice infected with 10(4)-10(7) S. Enteritidis fimH::kan CFUs had significantly (P < 0.05) shorter infection-free time than animals inoculated with wild-type S. Enteritidis. Infections caused by non-typhoid Salmonella, such as S. Enteritidis, are associated with massive inflammation of the lamina propria and lymph nodes in the intestinal tract. Therefore, we evaluated the role of MS type 1 fimbriae in the induction of cytokine expression and secretion, using murine ICE-1 intestinal cells. We showed that the expression, as well as secretion, of Il-1b, Il-6, Il-10, and Il-12b was significantly higher in cells infected with wild-type S. Enteritidis compared to cells infected with the mutant strain. Based on our results, we propose that type 1 fimbriae may play an important role in the pathogenicity of S. Enteritidis and may contribute to an intestinal inflammatory response. PMID- 25914683 TI - The heat shock protein 90 inhibitor BIIB021 suppresses the growth of T and natural killer cell lymphomas. AB - Epstein-Barr virus (EBV), which infects not only B cells but also T and natural killer (NK) cells, is associated with a variety of lymphoid malignancies. Because EBV-associated T and NK cell lymphomas are refractory and resistant to conventional chemotherapy, there is a continuing need for new effective therapies. EBV-encoded "latent membrane protein 1" (LMP1) is a major oncogene that activates nuclear factor kappa B (NF-kappaB), c-Jun N-terminal kinase (JNK), and phosphatidylinositol 3-kinase signaling pathways, thus promoting cell growth and inhibiting apoptosis. Recently, we screened a library of small-molecule inhibitors and isolated heat shock protein 90 (Hsp90) inhibitors as candidate suppressors of LMP1 expression. In this study, we evaluated the effects of BIIB021, a synthetic Hsp90 inhibitor, against EBV-positive and -negative T and NK lymphoma cell lines. BIIB021 decreased the expression of LMP1 and its downstream signaling proteins, NF-kappaB, JNK, and Akt, in EBV-positive cell lines. Treatment with BIIB021 suppressed proliferation in multiple cell lines, although there was no difference between the EBV-positive and -negative lines. BIIB021 also induced apoptosis and arrested the cell cycle at G1 or G2. Further, it down regulated the protein levels of CDK1, CDK2, and cyclin D3. Finally, we evaluated the in vivo effects of the drug; BIIB021 inhibited the growth of EBV-positive NK cell lymphomas in a murine xenograft model. These results suggest that BIIB021 has suppressive effects against T and NK lymphoma cells through the induction of apoptosis or a cell cycle arrest. Moreover, BIIB021 might help to suppress EBV positive T or NK cell lymphomas via the down-regulation of LMP1 expression. PMID- 25914684 TI - A taxonomic framework for emerging groups of ecologically important marine gammaproteobacteria based on the reconstruction of evolutionary relationships using genome-scale data. AB - In recent years a large number of isolates were obtained from saline environments that are phylogenetically related to distinct clades of oligotrophic marine gammaproteobacteria, which were originally identified in seawater samples using cultivation independent methods and are characterized by high seasonal abundances in coastal environments. To date a sound taxonomic framework for the classification of these ecologically important isolates and related species in accordance with their evolutionary relationships is missing. In this study we demonstrate that a reliable allocation of members of the oligotrophic marine gammaproteobacteria (OMG) group and related species to higher taxonomic ranks is possible by phylogenetic analyses of whole proteomes but also of the RNA polymerase beta subunit, whereas phylogenetic reconstructions based on 16S rRNA genes alone resulted in unstable tree topologies with only insignificant bootstrap support. The identified clades could be correlated with distinct phenotypic traits illustrating an adaptation to common environmental factors in their evolutionary history. Genome wide gene-content analyses revealed the existence of two distinct ecological guilds within the analyzed lineage of marine gammaproteobacteria which can be distinguished by their trophic strategies. Based on our results a novel order within the class Gammaproteobacteria is proposed, which is designated Cellvibrionales ord. nov. and comprises the five novel families Cellvibrionaceae fam. nov., Halieaceae fam. nov., Microbulbiferaceae fam. nov., Porticoccaceae fam. nov., and Spongiibacteraceae fam. nov. PMID- 25914685 TI - Drug repurposing as an alternative for the treatment of recalcitrant bacterial infections. AB - Bacterial infection remains one of the leading causes of death worldwide, and the options for treating such infections are decreasing, due the rise of antibiotic resistant bacteria. The pharmaceutical industry has produced few new types of antibiotics in more than a decade. Researchers are taking several approaches toward developing new classes of antibiotics, including (1) focusing on new targets and processes, such as bacterial cell-cell communication that upregulates virulence; (2) designing inhibitors of bacterial resistance, such as blockers of multidrug efflux pumps; and (3) using alternative antimicrobials such as bacteriophages. In addition, the strategy of finding new uses for existing drugs is beginning to produce results: antibacterial properties have been discovered for existing anticancer, antifungal, anthelmintic, and anti-inflammatory drugs. In this review, we discuss the antimicrobial properties of gallium compounds, 5 fluorouracil, ciclopirox, diflunisal, and some other FDA-approved drugs and argue that their repurposing for the treatment of bacterial infections, including those that are multidrug resistant, is a feasible strategy. PMID- 25914686 TI - Chloroquine neither eliminates liver stage parasites nor delays their development in a murine Chemoprophylaxis Vaccination model. AB - Chemoprophylaxis Vaccination (CVac) confers long lasting sterile protection against homologous parasite strains in humans, and involves inoculation of infectious sporozoites (SPZ) under drug cover. CVac using the drug chloroquine (CQ) induces pre-erythrocytic immunity in humans that includes antibody to SPZ and T-cell responses to liver stage (LS) parasites. The mechanism by which CVac with CQ induces strong protective immunity is not understood as untreated infections do not confer protection. CQ kills blood stage parasites, but its effect on LS parasites is poorly studied. Here we hypothesized that CQ may prolong or perturb LS development of Plasmodium, as a potential explanation for enhanced pre-erythrocytic immune responses. Balb/c mice with or without CQ prophylaxis were infected with sporozoite forms of a luciferase-expressing rodent parasite, Plasmodium yoelii-Luc (Py-Luc). Mice that received primaquine, a drug that kills LS parasites, served as a positive control of drug effect. Parasite burden in liver was measured both by bioluminescence and by qRT-PCR quantification of parasite transcript. Time to appearance of parasites in the blood was monitored by microscopic analysis of Giemsa-stained thick and thin blood smears. The parasite load in livers of CQ-treated and untreated mice did not significantly differ at any of the time points studied. Parasites appeared in the blood smears of both CQ-treated and untreated mice 3 days after infection. Taken together, our findings confirm that CQ neither eliminates LS parasites nor delays their development. Further investigations into the mechanism of CQ-induced protection after CVac are required, and may give insights relevant to drug and vaccine development. PMID- 25914687 TI - Engineering mediator-based electroactivity in the obligate aerobic bacterium Pseudomonas putida KT2440. AB - Pseudomonas putida strains are being developed as microbial production hosts for production of a range of amphiphilic and hydrophobic biochemicals. P. putida's obligate aerobic growth thereby can be an economical and technical challenge because it requires constant rigorous aeration and often causes reactor foaming. Here, we engineered a strain of P. putida KT2440 that can produce phenazine redox mediators from Pseudomonas aeruginosa to allow partial redox balancing with an electrode under oxygen-limited conditions. P. aeruginosa is known to employ its phenazine-type redox mediators for electron exchange with an anode in bioelectrochemical systems (BES). We transferred the seven core phenazine biosynthesis genes phzA-G and the two specific genes phzM and phzS required for pyocyanin synthesis from P. aeruginosa on two inducible plasmids into P. putida KT2440. The best clone, P. putida pPhz, produced 45 mg/L pyocyanin over 25 h of growth, which was visible as blue color formation and is comparable to the pyocyanin production of P. aeruginosa. This new strain was then characterized under different oxygen-limited conditions with electrochemical redox control and changes in central energy metabolism were evaluated in comparison to the unmodified P. putida KT2440. In the new strain, phenazine synthesis with supernatant concentrations up to 33 MUg/mL correlated linearly with the ability to discharge electrons to an anode, whereby phenazine-1-carboxylic acid served as the dominating redox mediator. P. putida pPhz sustained strongly oxygen-limited metabolism for up to 2 weeks at up to 12 MUA/cm(2) anodic current density. Together, this work lays a foundation for future oxygen-limited biocatalysis with P. putida strains. PMID- 25914688 TI - An antioxidant response is involved in resistance of Giardia duodenalis to albendazole. AB - Albendazole (ABZ) is a therapeutic benzimidazole used to treat giardiasis that targets beta-tubulin. However, the molecular bases of ABZ resistance in Giardia duodenalis are not understood because beta-tubulin in ABZ-resistant clones lacks mutations explaining drug resistance. In previous work we compared ABZ-resistant (1.35, 8, and 250 MUM) and ABZ-susceptible clones by proteomic analysis and eight proteins involved in energy metabolism, cytoskeleton dynamics, and antioxidant response were found as differentially expressed among the clones. Since ABZ is converted into sulphoxide (ABZ-SO) and sulphone (ABZ-SOO) metabolites we measured the levels of these metabolites, the antioxidant enzymes and free thiols in the susceptible and resistant clones. Production of reactive oxygen species (ROS) and levels of ABZ-SO/ABZ-SOO induced by ABZ were determined by fluorescein diacetate based fluorescence and liquid chromatography respectively. The mRNA and protein levels of antioxidant enzymes (NADH oxidase, peroxiredoxin 1a, superoxide dismutase and flavodiiron protein) in these clones were determined by RT-PCR and proteomic analysis. The intracellular sulfhydryl (R-SH) pool was quantified using dinitrobenzoic acid. The results showed that ABZ induced ROS accumulation in the ABZ-susceptible Giardia cultures but not in the resistant ones whilst the accumulation of ABZ-SO and ABZ-SOO was lower in all ABZ-resistant cultures. Consistent with these findings, all the antioxidant enzymes detected and analyzed were upregulated in ABZ-resistant clones. Likewise the R-SH pool increased concomitantly to the degree of ABZ-resistance. These results indicate an association between accumulation of ABZ metabolites and a pro-oxidant effect of ABZ in Giardia-susceptible clones. Furthermore the antioxidant response involving ROS-metabolizing enzymes and intracellular free thiols in ABZ-resistant parasites suggest that this response may contribute to overcome the pro-oxidant cytotoxicity of ABZ. PMID- 25914689 TI - Exopolysaccharides enriched in rare sugars: bacterial sources, production, and applications. AB - Microbial extracellular polysaccharides (EPS), produced by a wide range of bacteria, are high molecular weight biopolymers, presenting an extreme diversity in terms of chemical structure and composition. They may be used in many applications, depending on their chemical and physical properties. A rather unexplored aspect is the presence of rare sugars in the composition of some EPS. Rare sugars, such as rhamnose or fucose, may provide EPS with additional biological properties compared to those composed of more common sugar monomers. This review gives a brief overview of these specific EPS and their producing bacteria. Cultivation conditions are summarized, demonstrating their impact on the EPS composition, together with downstream processing. Finally, their use in different areas, including cosmetics, food products, pharmaceuticals, and biomedical applications, are discussed. PMID- 25914690 TI - Curcumin rescues Caenorhabditis elegans from a Burkholderia pseudomallei infection. AB - The tropical pathogen Burkholderia pseudomallei requires long-term parenteral antimicrobial treatment to eradicate the pathogen from an infected patient. However, the development of antibiotic resistance is emerging as a threat to this form of treatment. To meet the need for alternative therapeutics, we proposed a screen of natural products for compounds that do not kill the pathogen, but in turn, abrogate bacterial virulence. We suggest that the use of molecules or compounds that are non-bactericidal (bacteriostatic) will reduce or abolish the development of resistance by the pathogen. In this study, we adopted the established Caenorhabditis elegans-B. pseudomallei infection model to screen a collection of natural products for any that are able to extend the survival of B. pseudomallei infected worms. Of the 42 natural products screened, only curcumin significantly improved worm survival following infection whilst not affecting bacterial growth. This suggested that curcumin promoted B. pseudomallei-infected worm survival independent of pathogen killing. To validate that the protective effect of curcumin was directed toward the pathogen, bacteria were treated with curcumin prior to infection. Worms fed with curcumin-treated bacteria survived with a significantly extended mean-time-to-death (p < 0.0001) compared to the untreated control. In in vitro assays, curcumin reduced the activity of known virulence factors (lipase and protease) and biofilm formation. To determine if other bacterial genes were also regulated in the presence of curcumin, a genome wide transcriptome analysis was performed on curcumin-treated pathogen. A number of genes involved in iron acquisition and transport as well as genes encoding hypothetical proteins were induced in the presence of curcumin. Thus, we propose that curcumin may attenuate B. pseudomallei by modulating the expression of a number of bacterial proteins including lipase and protease as well as biofilm formation whilst concomitantly regulating iron transport and other proteins of unknown function. PMID- 25914691 TI - Prevalence and genetic diversity of clinical Vibrio parahaemolyticus isolates from China, revealed by multilocus sequence typing scheme. AB - The population structure of clinical Vibrio parahaemolyticus isolates spreading in China remains undefined. We brought 218 clinical isolates from the pubMLST database originating from different regions of China collected since the year of 1990, analyzed by multilocus sequence typing (MLST), to elucidate the prevalence and genetic diversity of V. parahaemolyticus circulating in Chinese population. The MLST scheme produced 137 sequence types (STs). These STs were clustered into six clonal complexes (CCs), six doublets, and 91 singletons, exhibiting a high level of genetic diversity. However, less diversity was displayed on the peptide level: only 46 different peptide sequence type (pST) were generated, with pST2 (44.0%, 96/218) and pST1 (15.1%, 33/218) the predominant. Further analysis confirmed all the pSTs belong to a single complex founded by pST1, pST2, pST3, and pST4. recA presented the highest degree of nucleotide diversity (0.026) and the largest number of variable sites (176) on the nucleotide level. pyrC was the most diverse locus on the peptide level, possessing the highest percentage of variable sites (9.2%, 15/163). Significant linkage disequilibrium with the alleles was detected when the Standardized Index of Association (I(S) A ) was calculated both for the entire isolates collection (0.7169, P < 0.01) and for the 137 STs (I(S) A = 0.2648, P < 0.01). In conclusion, we provide an overview of prevalence and genetic diversity of clinical V. parahaemolyticus spreading in Chinese population using MLST analysis. The results would offer genetic evidences for uncovering the microevolution relationship of V. parahaemolyticus populations. PMID- 25914692 TI - Impact of oxidative stress defense on bacterial survival and morphological change in Campylobacter jejuni under aerobic conditions. AB - Campylobacter jejuni, a microaerophilic foodborne pathogen, inescapably faces high oxygen tension during its transmission to humans. Thus, the ability of C. jejuni to survive under oxygen-rich conditions may significantly impact C. jejuni viability in food and food safety as well. In this study, we investigated the impact of oxidative stress resistance on the survival of C. jejuni under aerobic conditions by examining three mutants defective in key antioxidant genes, including ahpC, katA, and sodB. All the three mutants exhibited growth reduction under aerobic conditions compared to the wild-type (WT), and the ahpC mutant showed the most significant growth defect. The CFU reduction in the mutants was recovered to the WT level by complementation. Higher levels of reactive oxygen species were accumulated in C. jejuni under aerobic conditions than microaerobic conditions, and supplementation of culture media with an antioxidant recovered the growth of C. jejuni. The levels of lipid peroxidation and protein oxidation were significantly increased in the mutants compared to WT. Additionally, the mutants exhibited different morphological changes under aerobic conditions. The ahpC and katA mutants developed coccoid morphology by aeration, whereas the sodB mutant established elongated cellular morphology. Compared to microaerobic conditions, interestingly, aerobic culture conditions substantially induced the formation of coccoidal cells, and antioxidant treatment reduced the emergence of coccoid forms under aerobic conditions. The ATP concentrations and PMA-qPCR analysis supported that oxidative stress is a factor that induces the development of a viable-but-non-culturable state in C. jejuni. The findings in this study clearly demonstrated that oxidative stress resistance plays an important role in the survival and morphological changes of C. jejuni under aerobic conditions. PMID- 25914694 TI - Essential oils affect populations of some rumen bacteria in vitro as revealed by microarray (RumenBactArray) analysis. AB - In a previous study origanum oil (ORO), garlic oil (GAO), and peppermint oil (PEO) were shown to effectively lower methane production, decrease abundance of methanogens, and change abundances of several bacterial populations important to feed digestion in vitro. In this study, the impact of these essential oils (EOs, at 0.50 g/L) on the rumen bacterial community composition and population was further examined using the recently developed RumenBactArray. Species richness (expressed as number of operational taxonomic units, OTUs) in the phylum Firmicutes, especially those in the class Clostridia, was decreased by ORO and GAO, but increased by PEO, while that in the phylum Bacteroidetes was increased by ORO and PEO. Species richness in the genus Butyrivibrio was lowered by all the EOs. Increases of Bacteroidetes OTUs mainly resulted from increases of Prevotella OTUs. Overall, 67 individual OTUs showed significant differences (P <= 0.05) in relative abundance across the EO treatments. The predominant OTUs affected by EOs were diverse, including those related to Syntrophococcus sucromutans, Succiniclasticum ruminis, and Lachnobacterium bovis, and those classified to Prevotella, Clostridium, Roseburia, Pseudobutyrivibrio, Lachnospiraceae, Ruminococcaceae, Prevotellaceae, Bacteroidales, and Clostridiales. In total, 60 OTUs were found significantly (P <= 0.05) correlated with feed degradability, ammonia concentration, and molar percentage of volatile fatty acids. Taken together, this study demonstrated extensive impact of EOs on rumen bacterial communities in an EO type-dependent manner, especially those in the predominant families Prevotellaceae, Lachnospiraceae, and Ruminococcaceae. The information from this study may aid in understanding the effect of EOs on feed digestion and fermentation by rumen bacteria. PMID- 25914693 TI - Redundancy, resilience, and host specificity of the ruminal microbiota: implications for engineering improved ruminal fermentations. AB - The ruminal microbial community is remarkably diverse, containing 100s of different bacterial and archaeal species, plus many species of fungi and protozoa. Molecular studies have identified a "core microbiome" dominated by phyla Firmicutes and Bacteroidetes, but also containing many other taxa. The rumen provides an ideal laboratory for studies on microbial ecology and the demonstration of ecological principles. In particular, the microbial community demonstrates both redundancy (overlap of function among multiple species) and resilience (resistance to, and capacity to recover from, perturbation). These twin properties provide remarkable stability that maintains digestive function for the host across a range of feeding and management conditions, but they also provide a challenge to engineering the rumen for improved function (e.g., improved fiber utilization or decreased methane production). Direct ruminal dosing or feeding of probiotic strains often fails to establish the added strains, due to intensive competition and amensalism from the indigenous residents that are well-adapted to the historical conditions within each rumen. Known exceptions include introduced strains that can fill otherwise unoccupied niches, as in the case of specialist bacteria that degrade phytotoxins such as mimosine or fluoroacetate. An additional complicating factor in manipulating the ruminal fermentation is the individuality or host specificity of the microbiota, in which individual animals contain a particular community whose species composition is capable of reconstituting itself, even following a near-total exchange of ruminal contents from another herd mate maintained on the same diet. Elucidation of the interactions between the microbial community and the individual host that establish and maintain this specificity may provide insights into why individual hosts vary in production metrics (e.g., feed efficiency or milk fat synthesis), and how to improve herd performance. PMID- 25914695 TI - Importance of adhesins in virulence of Paracoccidioides spp. AB - Members of the Paracoccidioides genus are the etiologic agents of paracoccidioidomycosis (PCM). This genus is composed of two species: Paracoccidioides brasiliensis and Paracoccidioides lutzii. The correct molecular taxonomic classification of these fungi has created new opportunities for studying and understanding their relationships with their hosts. Paracoccidioides spp. have features that permit their growth under adverse conditions, enable them to adhere to and invade host tissues and may contribute to disease development. Cell wall proteins called adhesins facilitate adhesion and are capable of mediating fungi-host interactions during infection. This study aimed to evaluate the adhesion profile of two species of the genus Paracoccidioides, to analyze the expression of adhesin-encoding genes by real-time PCR and to relate these results to the virulence of the species, as assessed using a survival curve in mice and in Galleria mellonella after blocking the adhesins. A high level of heterogeneity was observed in adhesion and adhesin expression, showing that the 14-3-3 and enolase molecules are the most highly expressed adhesins during pathogen-host interaction. Additionally, a survival curve revealed a correlation between the adhesion rate and survival, with P. brasiliensis showing higher adhesion and adhesin expression levels and greater virulence when compared with P. lutzii. After blocking 14-3-3 and enolase adhesins, we observed modifications in the virulence of these two species, revealing the importance of these molecules during the pathogenesis of members of the Paracoccidioides genus. These results revealed new insights into the host-pathogen interaction of this genus and may enhance our understanding of different isolates that could be useful for the treatment of this mycosis. PMID- 25914696 TI - The relationship between leaf area growth and biomass accumulation in Arabidopsis thaliana. AB - Leaf area growth determines the light interception capacity of a crop and is often used as a surrogate for plant growth in high-throughput phenotyping systems. The relationship between leaf area growth and growth in terms of mass will depend on how carbon is partitioned among new leaf area, leaf mass, root mass, reproduction, and respiration. A model of leaf area growth in terms of photosynthetic rate and carbon partitioning to different plant organs was developed and tested with Arabidopsis thaliana L. Heynh. ecotype Columbia (Col-0) and a mutant line, gigantea-2 (gi-2), which develops very large rosettes. Data obtained from growth analysis and gas exchange measurements was used to train a genetic programming algorithm to parameterize and test the above model. The relationship between leaf area and plant biomass was found to be non-linear and variable depending on carbon partitioning. The model output was sensitive to the rate of photosynthesis but more sensitive to the amount of carbon partitioned to growing thicker leaves. The large rosette size of gi-2 relative to that of Col-0 resulted from relatively small differences in partitioning to new leaf area vs. leaf thickness. PMID- 25914697 TI - Tall fescue cultivar and fungal endophyte combinations influence plant growth and root exudate composition. AB - Tall fescue [Lolium arundinaceum (Schreb.)] is a cool-season perennial grass used in pastures throughout the Southeastern United States. The grass can harbor a shoot-specific fungal endophyte (Epichloe coenophiala) thought to provide the plant with enhanced resistance to biotic and abiotic stresses. Because alkaloids produced by the common variety of the endophyte cause severe animal health issues, focus has been on replacing the common-toxic strain with novel varieties that do not produce the mammal-toxic alkaloids but maintain abiotic and biotic stress tolerance benefits. Little attention has been given to the influence of the plant-fungal symbiosis on rhizosphere processes. Therefore, our objective was to study the influence of this relationship on plant biomass production and root exudate composition in tall fescue cultivars PDF and 97TF1, which were either not infected with the endophyte (E-), infected with the common toxic endophyte (CTE+) strain or with one of two novel endophytes (AR542E+, AR584E+). Plants were grown sterile for 3 weeks after which plant biomass, total organic carbon, total phenolic content and detailed chemical composition of root exudates were determined. Plant biomass production and exudate phenolic and organic carbon content were influenced by endophyte status, tall fescue cultivar, and their interaction. GC-TOF MS identified 132 compounds, including lipids, carbohydrates and carboxylic acids. Cluster analysis showed that the interaction between endophyte and cultivar resulted in unique exudate profiles. This is the first detailed study to assess how endophyte infection, notably with novel endophytes, and tall fescue cultivar interact to influence root exudate composition. Our results illustrate that tall fescue cultivar and endophyte status can influence plant growth and root exudate composition, which may help explain the observed influence of this symbiosis on rhizosphere biogeochemical processes. PMID- 25914698 TI - Involvement of nitric oxide in the jasmonate-dependent basal defense against root knot nematode in tomato plants. AB - Jasmonic acid (JA) and nitric oxide (NO) are well-characterized signaling molecules in plant defense responses. However, their roles in plant defense against root-knot nematode (RKN, Meloidogyne incognita) infection are largely unknown. In this study, we found that the transcript levels of the JA- and NO related biosynthetic and signaling component genes were induced after RKN infection. Application of exogenous JA and sodium nitroprusside (SNP; a NO donor) significantly decreased the number of egg masses in tomato roots after RKN infection and partially alleviated RKN-induced decreases in plant fresh weight and net photosynthetic rate. These molecules also alleviated RKN-induced increases in root electrolyte leakage and membrane peroxidation. Importantly, NO scavenger partially inhibited JA-induced RKN defense. The pharmacological inhibition of JA biosynthesis significantly increased the plants' susceptibility to RKNs, which was effectively alleviated by SNP application, showing that NO may be involved in the JA-dependent RKN defense pathway. Furthermore, both JA and SNP induced increases in protease inhibitor 2 (PI2) gene expression after RKN infestation. Silencing of PI2 compromised both JA- and SNP-induced RKN defense responses, suggesting that the PI2 gene mediates JA- and NO-induced defense against RKNs. This work will be important for deepening the understanding of the mechanisms involved in basal defense against RKN attack in plants. PMID- 25914699 TI - Influence of bacterial N-acyl-homoserine lactones on growth parameters, pigments, antioxidative capacities and the xenobiotic phase II detoxification enzymes in barley and yam bean. AB - Bacteria are able to communicate with each other and sense their environment in a population density dependent mechanism known as quorum sensing (QS). N-acyl homoserine lactones (AHLs) are the QS signaling compounds of Gram-negative bacteria which are frequent colonizers of rhizospheres. While cross-kingdom signaling and AHL-dependent gene expression in plants has been confirmed, the responses of enzyme activities in the eukaryotic host upon AHLs are unknown. Since AHL are thought to be used as so-called plant boosters or strengthening agents, which might change their resistance toward radiation and/or xenobiotic stress, we have examined the plants' pigment status and their antioxidative and detoxifying capacities upon AHL treatment. Because the yield of a crop plant should not be negatively influenced, we have also checked for growth and root parameters. We investigated the influence of three different AHLs, namely N hexanoyl- (C6-HSL), N-octanoyl- (C8-HSL), and N-decanoyl- homoserine lactone (C10 HSL) on two agricultural crop plants. The AHL-effects on Hordeum vulgare (L.) as an example of a monocotyledonous crop and on the tropical leguminous crop plant Pachyrhizus erosus (L.) were compared. While plant growth and pigment contents in both plants showed only small responses to the applied AHLs, AHL treatment triggered tissue- and compound-specific changes in the activity of important detoxification enzymes. The activity of dehydroascorbate reductase in barley shoots after C10-HSL treatment for instance increased up to 384% of control plant levels, whereas superoxide dismutase activity in barley roots was decreased down to 23% of control levels upon C6-HSL treatment. Other detoxification enzymes reacted similarly within this range, with interesting clusters of positive or negative answers toward AHL treatment. In general the changes on the enzyme level were more severe in barley than in yam bean which might be due to the different abilities of the plants to degrade AHLs to metabolites such as the hydroxy- or keto-form of the original compound. PMID- 25914700 TI - Genetic control of flowering time in legumes. AB - The timing of flowering, and in particular the degree to which it is responsive to the environment, is a key factor in the adaptation of a given species to various eco-geographic locations and agricultural practices. Flowering time variation has been documented in many crop legumes, and selection for specific variants has permitted significant expansion and improvement in cultivation, from prehistoric times to the present day. Recent advances in legume genomics have accelerated the process of gene identification and functional analysis, and opened up new prospects for a molecular understanding of flowering time adaptation in this important crop group. Within the legumes, two species have been prominent in flowering time studies; the vernalization-responsive long-day species pea (Pisum sativum) and the warm-season short-day plant soybean (Glycine max). Analysis of flowering in these species is now being complemented by reverse genetics capabilities in the model legumes Medicago truncatula and Lotus japonicus, and the emergence of genome-scale resources in a range of other legumes. This review will outline the insights gained from detailed forward genetic analysis of flowering time in pea and soybean, highlighting the importance of light perception, the circadian clock and the FT family of flowering integrators. It discusses the current state of knowledge on genetic mechanisms for photoperiod and vernalization response, and concludes with a broader discussion of flowering time adaptation across legumes generally. PMID- 25914701 TI - An improved method for the visualization of conductive vessels in Arabidopsis thaliana inflorescence stems. AB - Dye perfusion is commonly used for the identification of conductive elements important for the study of xylem development as well as precise hydraulic estimations. The tiny size of inflorescence stems, the small amount of vessels in close arrangement, and high hydraulic resistivity delimit the use of the method for quantification of the water conductivity of Arabidopsis thaliana, one of the recently most extensively used plant models. Here, we present an extensive adjustment to the method in order to reliably identify individual functional (conductive) vessels. Segments of inflorescence stems were sealed in silicone tubes to prevent damage and perfused with a dye solution. Our results showed that dyes often used for staining functional xylem elements (safranin, fuchsine, toluidine blue) failed with Arabidopsis. In contrast, Fluorescent Brightener 28 dye solution perfused through segments stained secondary cell walls of functional vessels, which were clearly distinguishable in native cross sections. When compared to identification based on the degree of development of secondary cell walls, identification with the help of dye perfusion revealed a significantly lower number of functional vessels and values of theoretical hydraulic conductivity. We found that lignified but not yet functional vessels form a substantial portion of the xylem in apical and basal segments of Arabidopsis and, thus, significantly affect the analyzed functional parameters of xylem. The presented methodology enables reliable identification of individual functional vessels, allowing thus estimations of hydraulic conductivities to be improved, size distributions and vessel diameters to be refined, and data variability generally to be reduced. PMID- 25914702 TI - Heat stress during seed filling interferes with sulfur restriction on grain composition and seed germination in oilseed rape (Brassica napus L.). AB - In coming decades, increasing temperatures are expected to impact crop yield and seed quality. To develop low input systems, the effects of temperature and sulfur (S) nutrition in oilseed rape, a high S demanding crop, need to be jointly considered. In this study, we investigated the effects of temperatures [High Temperature (HT), 33 degrees C/day, 19 degrees C/night vs. Control Temperature (Ctrl T), 20 degrees C/day, 15 degrees C/day] and S supply [High S (HS), 500 MUm SO(2-) 4 vs. Low S (LS), 8.7 MUM SO(2-) 4] during seed filling on (i) yield components [seed number, seed dry weight (SDW) and seed yield], (ii) grain composition [nitrogen (N) and S contents] and quality [fatty acid (FA) composition and seed storage protein (SSP) accumulation] and (iii) germination characteristics (pre-harvest sprouting, germination rates and abnormal seedlings). Abscisic acid (ABA), soluble sugar contents and seed conductivity were also measured. HT and LS decreased the number of seeds per plant. SDW was less affected due to compensatory effects since the number of seeds decreased under stress conditions. While LS had negative effects on seed composition by reducing the FA contents and increasing the ratio S-poor SSPs (12S globulins)/S rich SSPs (2S albumins) ratio, HT had positive effects by increasing S and FA contents and decreasing the C18:2/C18:3 ratio and the 12S/2S protein ratio. Seeds produced under HT showed high pre-harvest sprouting rates along with decreased ABA contents and high rates of abnormal seedlings. HT and LS restriction significantly accelerated germination times. High conductivity, which indicates poor seed storage capacity, was higher in HT seeds. Consistently, the lower ratio of (raffinose + stachyose)/sucrose in HT seeds indicated low seed storage capacity. We demonstrated the effects of HT and LS on grain and on germination characteristics. These results suggest that hormonal changes might control several seed characteristics simultaneously. PMID- 25914703 TI - De novo assembly of a genome-wide transcriptome map of Vicia faba (L.) for transfer cell research. AB - Vicia faba (L.) is an important cool-season grain legume species used widely in agriculture but also in plant physiology research, particularly as an experimental model to study transfer cell (TC) development. TCs are specialized nutrient transport cells in plants, characterized by invaginated wall ingrowths with amplified plasma membrane surface area enriched with transporter proteins that facilitate nutrient transfer. Many TCs are formed by trans-differentiation from differentiated cells at apoplasmic/symplasmic boundaries in nutrient transport. Adaxial epidermal cells of isolated cotyledons can be induced to form functional TCs, thus providing a valuable experimental system to investigate genetic regulation of TC trans-differentiation. The genome of V. faba is exceedingly large (ca. 13 Gb), however, and limited genomic information is available for this species. To provide a resource for future transcript profiling of epidermal TC differentiation, we have undertaken de novo assembly of a genome wide transcriptome map for V. faba. Illumina paired-end sequencing of total RNA pooled from different tissues and different stages, including isolated cotyledons induced to form epidermal TCs, generated 69.5 M reads, of which 65.8 M were used for assembly following trimming and quality control. Assembly using a De-Bruijn graph-based approach generated 21,297 contigs, of which 80.6% were successfully annotated against GO terms. The assembly was validated against known V. faba cDNAs held in GenBank, including transcripts previously identified as being specifically expressed in epidermal cells across TC trans-differentiation. This genome-wide transcriptome map therefore provides a valuable tool for future transcript profiling of epidermal TC trans-differentiation, and also enriches the genetic resources available for this important legume crop species. PMID- 25914704 TI - Genome-wide association mapping unravels the genetic control of seed germination and vigor in Brassica napus. AB - Rapid and uniform seed germination is a crucial prerequisite for crop establishment and high yield levels in crop production. A disclosure of genetic factors contributing to adequate seed vigor would help to further increase yield potential and stability. Here we carried out a genome-wide association study in order to define genomic regions influencing seed germination and early seedling growth in oilseed rape (Brassica napus L.). A population of 248 genetically diverse winter-type B. napus accessions was genotyped with the Brassica 60k SNP Illumina genotyping array. Automated high-throughput in vitro phenotyping provided extensive data for multiple traits related to germination and early vigor, such as germination speed, absolute germination rate and radicle elongation. The data obtained indicate that seed germination and radicle growth are strongly environmentally dependent, but could nevertheless be substantially improved by genomic-based breeding. Conditions during seed production and storage were shown to have a profound effect on seed vigor, and a variable manifestation of seed dormancy appears to contribute to differences in germination performance in B. napus. Several promising positional and functional candidate genes could be identified within the genomic regions associated with germination speed, absolute germination rate, radicle growth and thousand seed weight. These include B. napus orthologs of the Arabidopsis thaliana genes SNOWY COTYLEDON 1 (SCO1), ARABIDOPSIS TWO-COMPONENT RESPONSE REGULATOR (ARR4), and ARGINYL-t-RNA PROTEIN TRANSFERASE 1 (ATE1), which have been shown previously to play a role in seed germination and seedling growth in A. thaliana. PMID- 25914705 TI - Phosphoproteomics-based peptide ligand-receptor kinase pairing. Commentary on: "A peptide hormone and its receptor protein kinase regulate plant cell expansion". PMID- 25914706 TI - Contrasting photosynthesis and photoinhibition in tetraploid and its autodiploid honeysuckle (Lonicera japonica Thunb.) under salt stress. AB - Honeysuckle (Lonicera japonica Thunb.) is a popular landscape plant. This study was to explore leaf photosynthetic characterization with emphasis on the coordination between photosystem II (PSII) and photosystem I (PSI) in tetraploid and its autodiploid honeysuckle (TH and DH) upon salt stress (300 mM NaCl). Leaf photosynthetic rate and carboxylation efficiency in DH and TH were significantly decreased under salt stress, and the decrease was greater in DH. PSII photoinhibition was induced in DH under salt stress, as the maximum quantum yield of PSII (Fv/Fm) was significantly decreased. PSII photoinhibition declined electron flow to PSI, but did not prevent PSI photoinhibition, as the maximal photochemical capacity of PSI (MR/MR0) was significantly decreased by salt stress. According to the significant decrease in PSI oxidation amplitude in the first 1 s red illumination, PSI photoinhibition was more severe than PSII photoinhibition. As a result, PSII and PSI coordination was destroyed. Comparatively, salt-induced photoinhibition did not occur in TH, as no significant change was observed in Fv/Fm and MR/MR0. Consequently, PSII and PSI coordination was not significantly affected by salt stress. In conclusion, TH maintained normal coordination between PSII and PSI by preventing photoinhibition and exhibited higher leaf photosynthetic activity than DH under salt stress. Compared with DH, lower leaf ionic toxicity due to greater root Na(+) extrusion and restriction of Na(+) transport to leaf might be responsible for maintaining higher leaf photosynthetic capacity in TH under salt stress. PMID- 25914707 TI - (15)N in tree rings as a bio-indicator of changing nitrogen cycling in tropical forests: an evaluation at three sites using two sampling methods. AB - Anthropogenic nitrogen deposition is currently causing a more than twofold increase of reactive nitrogen input over large areas in the tropics. Elevated (15)N abundance (delta(15)N) in the growth rings of some tropical trees has been hypothesized to reflect an increased leaching of (15)N-depleted nitrate from the soil, following anthropogenic nitrogen deposition over the last decades. To find further evidence for altered nitrogen cycling in tropical forests, we measured long-term delta(15)N values in trees from Bolivia, Cameroon, and Thailand. We used two different sampling methods. In the first, wood samples were taken in a conventional way: from the pith to the bark across the stem of 28 large trees (the "radial" method). In the second, delta(15)N values were compared across a fixed diameter (the "fixed-diameter" method). We sampled 400 trees that differed widely in size, but measured delta(15)N in the stem around the same diameter (20 cm dbh) in all trees. As a result, the growth rings formed around this diameter differed in age and allowed a comparison of delta(15)N values over time with an explicit control for potential size-effects on delta(15)N values. We found a significant increase of tree-ring delta(15)N across the stem radius of large trees from Bolivia and Cameroon, but no change in tree-ring delta(15)N values over time was found in any of the study sites when controlling for tree size. This suggests that radial trends of delta(15)N values within trees reflect tree ontogeny (size development). However, for the trees from Cameroon and Thailand, a low statistical power in the fixed-diameter method prevents to conclude this with high certainty. For the trees from Bolivia, statistical power in the fixed diameter method was high, showing that the temporal trend in tree-ring delta(15)N values in the radial method is primarily caused by tree ontogeny and unlikely by a change in nitrogen cycling. We therefore stress to account for tree size before tree-ring delta(15)N values can be properly interpreted. PMID- 25914709 TI - miRNA regulation of nutrient homeostasis in plants. AB - Small RNAs including micro RNAs (miRNA) play an indispensable role in cell signaling mechanisms. Generally, miRNAs that are 20-24 nucleotides long bind to specific complementary transcripts, attenuating gene expression at the post transcriptional level or via translational inhibition. In plants, miRNAs have emerged as the principal regulator of various stress responses, including low nutrient availability. It has been reported that miRNAs are vital for maintaining nutrient homeostasis in plants by regulating the expression of transporters that are involved in nutrient uptake and mobilization. The present review highlights the role of various miRNAs in several macro- or micronutrient deficiencies in plants. Understanding the regulation of different transporters by miRNAs will aid in elucidating the underlying molecular signal transduction mechanisms during nutritional stress. Recent findings regarding nutrient related-miRNAs and their gene regulation machinery may delineate a novel platform for improving the nutritional status of cereal grains or crop biofortification programs in the future. PMID- 25914708 TI - Biodiversity of genes encoding anti-microbial traits within plant associated microbes. AB - The plant is an attractive versatile home for diverse associated microbes. A subset of these microbes produces a diversity of anti-microbial natural products including polyketides, non-ribosomal peptides, terpenoids, heterocylic nitrogenous compounds, volatile compounds, bacteriocins, and lytic enzymes. In recent years, detailed molecular analysis has led to a better understanding of the underlying genetic mechanisms. New genomic and bioinformatic tools have permitted comparisons of orthologous genes between species, leading to predictions of the associated evolutionary mechanisms responsible for diversification at the genetic and corresponding biochemical levels. The purpose of this review is to describe the biodiversity of biosynthetic genes of plant associated bacteria and fungi that encode selected examples of antimicrobial natural products. For each compound, the target pathogen and biochemical mode of action are described, in order to draw attention to the complexity of these phenomena. We review recent information of the underlying molecular diversity and draw lessons through comparative genomic analysis of the orthologous coding sequences (CDS). We conclude by discussing emerging themes and gaps, discuss the metabolic pathways in the context of the phylogeny and ecology of their microbial hosts, and discuss potential evolutionary mechanisms that led to the diversification of biosynthetic gene clusters. PMID- 25914712 TI - Integrating data on the Arabidopsis NPR1/NPR3/NPR4 salicylic acid receptors; a differentiating argument. AB - Salicylic acid (SA) is a mandatory plant metabolite in the deployment of systemic acquired resistance (SAR), a broad-spectrum systemic immune response induced by local inoculation with avirulent pathogens. The NPR1 transcription co-activator is the central node positively regulating SAR. SA was the last of the major hormones to be without a known receptor. Recently, NPR1 was shown to be the direct link between SA and gene activation. This discovery seems to be controversial. NPR1 being an SA-receptor is reminiscent of the mammalian steroid receptors, which are transcription factors whose binding to DNA is dependent on the interaction with a ligand. Unlike steroid receptors, NPR1 does not bind directly to DNA, but is recruited to promoters by the TGA family of transcription factors to form an enhanceosome. In Arabidopsis, NPR1 is part of a multigene family in which two other members, NPR3 and NPR4, have also been shown to interact with SA. NPR3/NPR4 are negative regulators of immunity and act as substrate adaptors for the recruitment of NPR1 to an E3-ubiquitin ligase, leading to its subsequent degradation by the proteasome. In this perspective, we will stress-test in a friendly way the current NPR1/NPR3/NPR4 model. PMID- 25914711 TI - Vacuolar processing enzyme in plant programmed cell death. AB - Vacuolar processing enzyme (VPE) is a cysteine proteinase originally identified as the proteinase responsible for the maturation and activation of vacuolar proteins in plants, and it is known to be an ortholog of animal asparaginyl endopeptidase (AEP/VPE/legumain). VPE has been shown to exhibit enzymatic properties similar to that of caspase 1, which is a cysteine protease that mediates the programmed cell death (PCD) pathway in animals. Although there is limited sequence identity between VPE and caspase 1, their predicted three dimensional structures revealed that the essential amino-acid residues for these enzymes form similar pockets for the substrate peptide YVAD. In contrast to the cytosolic localization of caspases, VPE is localized in vacuoles. VPE provokes vacuolar rupture, initiating the proteolytic cascade leading to PCD in the plant immune response. It has become apparent that the VPE-dependent PCD pathway is involved not only in the immune response, but also in the responses to a variety of stress inducers and in the development of various tissues. This review summarizes the current knowledge on the contribution of VPE to plant PCD and its role in vacuole-mediated cell death, and it also compares VPE with the animal cell death executor caspase 1. PMID- 25914713 TI - An improved protocol to study the plant cell wall proteome. AB - Cell wall proteins were extracted from alfalfa stems according to a three-steps extraction procedure using sequentially CaCl2, EGTA, and LiCl-complemented buffers. The efficiency of this protocol for extracting cell wall proteins was compared with the two previously published methods optimized for alfalfa stem cell wall protein analysis. Following LC-MS/MS analysis the three-steps extraction procedure resulted in the identification of the highest number of cell wall proteins (242 NCBInr identifiers) and gave the lowest percentage of non-cell wall proteins (about 30%). However, the three protocols are rather complementary than substitutive since 43% of the identified proteins were specific to one protocol. This three-step protocol was therefore selected for a more detailed proteomic characterization using 2D-gel electrophoresis. With this technique, 75% of the identified proteins were shown to be fraction-specific and 72.7% were predicted as belonging to the cell wall compartment. Although, being less sensitive than LC-MS/MS approaches in detecting and identifying low-abundant proteins, gel-based approaches are valuable tools for the differentiation and relative quantification of protein isoforms and/or modified proteins. In particular isoforms, having variations in their amino-acid sequence and/or carrying different N-linked glycan chains were detected and characterized. This study highlights how the extracting protocols as well as the analytical techniques devoted to the study of the plant cell wall proteome are complementary and how they may be combined to elucidate the dynamism of the plant cell wall proteome in biological studies. Data are available via ProteomeXchange with identifier PXD001927. PMID- 25914710 TI - Shaping plant architecture. AB - Plants exhibit phenotypical plasticity. Their general body plan is genetically determined, but plant architecture and branching patterns are variable and can be adjusted to the prevailing environmental conditions. The modular design of the plant facilitates such morphological adaptations. The prerequisite for the formation of a branch is the initiation of an axillary meristem. Here, we review the current knowledge about this process. After its establishment, the meristem can develop into a bud which can either become dormant or grow out and form a branch. Many endogenous factors, such as photoassimilate availability, and exogenous factors like nutrient availability or shading, have to be integrated in the decision whether a branch is formed. The underlying regulatory network is complex and involves phytohormones and transcription factors. The hormone auxin is derived from the shoot apex and inhibits bud outgrowth indirectly in a process termed apical dominance. Strigolactones appear to modulate apical dominance by modification of auxin fluxes. Furthermore, the transcription factor BRANCHED1 plays a central role. The exact interplay of all these factors still remains obscure and there are alternative models. We discuss recent findings in the field along with the major models. Plant architecture is economically significant because it affects important traits of crop and ornamental plants, as well as trees cultivated in forestry or on short rotation coppices. As a consequence, plant architecture has been modified during plant domestication. Research revealed that only few key genes have been the target of selection during plant domestication and in breeding programs. Here, we discuss such findings on the basis of various examples. Architectural ideotypes that provide advantages for crop plant management and yield are described. We also outline the potential of breeding and biotechnological approaches to further modify and improve plant architecture for economic needs. PMID- 25914714 TI - Molecular characterization of genes encoding leucoanthocyanidin reductase involved in proanthocyanidin biosynthesis in apple. AB - Proanthocyanidins (PAs) are the major component of phenolics in apple, but mechanisms involved in PA biosynthesis remain unclear. Here, the relationship between the PA biosynthesis and the expression of genes encoding leucoanthocyanidin reductase (LAR) and anthocyanidin reductase (ANR) was investigated in fruit skin of one apple cultivar and three crabapples. Transcript levels of LAR1 and ANR2 genes were significantly correlated with the contents of catechin and epicatechin, respectively, which suggests their active roles in PA synthesis. Surprisingly, transcript levels for both LAR1 and LAR2 genes were almost undetectable in two crabapples that accumulated both flavan-3-ols and PAs. This contradicts the previous finding that LAR1 gene is a strong candidate regulating the accumulation of metabolites such as epicatechin and PAs in apple. Ectopic expression of apple MdLAR1 gene in tobacco suppresses expression of the late genes in anthocyanin biosynthetic pathway, resulting in loss of anthocyanin in flowers. Interestingly, a decrease in PA biosynthesis was also observed in flowers of transgenic tobacco plants overexpressing the MdLAR1 gene, which could be attributed to decreased expression of both the NtANR1 and NtANR2 genes. Our study not only confirms the in vivo function of apple LAR1 gene, but it is also helpful for understanding the mechanism of PA biosynthesis. PMID- 25914715 TI - Interactions between circadian clocks and photosynthesis for the temporal and spatial coordination of metabolism. AB - All plant productivity, including the food that we eat, arises from the capture of solar energy by plants. At most latitudes sunlight is available for only part of the 24 h day due to the rotation of the planet. This rhythmic and predictable alteration in the environment has driven the evolution of the circadian clock, which has an extremely pervasive influence upon plant molecular biology, physiology and phenology. A number of recent studies have demonstrated that the circadian clock is integrated very closely with photosynthesis and its metabolic products. We consider the coupling of the circadian oscillator with carbohydrate biochemistry and the connections between the nuclear-encoded circadian clock and processes within chloroplasts. We describe how this might provide adaptations to optimize plant performance in an environment that varies both predictably upon a daily and seasonal basis, and unpredictably due to the weather. PMID- 25914716 TI - Circulatory contributors to the phenotype in hereditary hemorrhagic telangiectasia. AB - Hereditary hemorrhagic telangiectasia (HHT) is mechanistically and therapeutically challenging, not only because of the molecular and cellular perturbations that generate vascular abnormalities, but also the modifications to circulatory physiology that result, and are likely to exacerbate vascular injury. First, most HHT patients have visceral arteriovenous malformations (AVMs). Significant visceral AVMs reduce the systemic vascular resistance: supra-normal cardiac outputs are required to maintain arterial blood pressure, and may result in significant pulmonary venous hypertension. Secondly, bleeding from nasal and gastrointestinal telangiectasia leads to iron losses of such magnitude that in most cases, diet is insufficient to meet the 'hemorrhage adjusted iron requirement.' Resultant iron deficiency restricts erythropoiesis, leading to anemia and further increases in cardiac output. Low iron levels are also associated with venous and arterial thromboses, elevated Factor VIII, and increased platelet aggregation to circulating 5HT (serotonin). Third, recent data highlight that reduced oxygenation of blood due to pulmonary AVMs results in a graded erythrocytotic response to maintain arterial oxygen content, and higher stroke volumes and/or heart rates to maintain oxygen delivery. Finally, HHT independent factors such as diet, pregnancy, sepsis, and other intercurrent illnesses also influence vascular structures, hemorrhage, and iron handling in HHT patients. These considerations emphasize the complexity of mechanisms that impact on vascular structures in HHT, and also offer opportunities for targeted therapeutic approaches. PMID- 25914717 TI - The evolutionary dynamics of major regulators for sexual development among Hymenoptera species. AB - All hymenopteran species, such as bees, wasps and ants, are characterized by the common principle of haplodiploid sex determination in which haploid males arise from unfertilized eggs and females from fertilized eggs. The underlying molecular mechanism has been studied in detail in the western honey bee Apis mellifera, in which the gene complementary sex determiner (csd) acts as primary signal of the sex determining pathway, initiating female development by csd-heterozygotes. Csd arose from gene duplication of the feminizer (fem) gene, a transformer (tra) ortholog, and mediates in conjunction with transformer2 (tra2) sex-specific splicing of fem. Comparative molecular analyses identified fem/tra and its downstream target doublesex (dsx) as conserved unit within the sex determining pathway of holometabolous insects. In this study, we aim to examine evolutionary differences among these key regulators. Our main hypothesis is that sex determining key regulators in Hymenoptera species show signs of coevolution within single phylogenetic lineages. We take advantage of several newly sequenced genomes of bee species to test this hypothesis using bioinformatic approaches. We found evidences that duplications of fem are restricted to certain bee lineages and notable amino acid differences of tra2 between Apis and non-Apis species propose structural changes in Tra2 protein affecting co-regulatory function on target genes. These findings may help to gain deeper insights into the ancestral mode of hymenopteran sex determination and support the common view of the remarkable evolutionary flexibility in this regulatory pathway. PMID- 25914718 TI - Nuclear gene mutations as the cause of mitochondrial complex III deficiency. AB - Complex III (CIII) deficiency is one of the least common oxidative phosphorylation defects associated to mitochondrial disease. CIII constitutes the center of the mitochondrial respiratory chain, as well as a crossroad for several other metabolic pathways. For more than 10 years, of all the potential candidate genes encoding structural subunits and assembly factors, only three were known to be associated to CIII defects in human pathology. Thus, leaving many of these cases unresolved. These first identified genes were MT-CYB, the only CIII subunit encoded in the mitochondrial DNA; BCS1L, encoding an assembly factor, and UQCRB, a nuclear-encoded structural subunit. Nowadays, thanks to the fast progress that has taken place in the last 3-4 years, pathological changes in seven more genes are known to be associated to these conditions. This review will focus on the strategies that have permitted the latest discovery of mutations in factors that are necessary for a correct CIII assembly and activity, in relation with their function. In addition, new data further establishing the molecular role of LYRM7/MZM1L as a chaperone involved in CIII biogenesis are provided. PMID- 25914719 TI - Alpers disease mutations in human DNA polymerase gamma cause catalytic defects in mitochondrial DNA replication by distinct mechanisms. AB - The human mitochondrial DNA polymerase gamma (Pol-gamma) is nuclearly encoded and is responsible for the replication and repair of the mitochondrial genome. Mutations S305R and P1073L in the POLG gene have been reported to be associated with early childhood Alpers syndrome. One patient harboring both mutations as compound heterozygous died at 2 years of age after disease onset at 9 months. Quantitative kinetic analysis on purified enzyme showed that the S305R mutation reduces the DNA binding affinity by 10-fold, and reduces the specificity constant (k cat /K m) for correct nucleotide incorporation by fourfold. It also causes a ~threefold reduction in the excision rate to remove mismatched nucleotides. Compared to the wild-type Pol-gamma, the S305R mutant showed no product formation in a reconstituted rolling circle replisome assay. Interestingly, the P1073L mutant exhibited wild-type activity in single turnover kinetics to quantify changes in k cat /K m, k cat, k exo, or processivity, and showed a twofold decrease in the net polymerization rate in the reconstituted replisome assay, while in yeast, P1073L caused a 60-70% mtDNA reduction in haploid cells. The heterozygous diploid yeast cells carrying S305R and P1073L mutations in trans showed ~75% reduction of mtDNA content, relative to homozygous diploid cells with two wild-type alleles. Taken together, we show clearly in both the rolling circle and the humanized yeast system that the P1073L mutation caused significant defects in mtDNA replication, and our results suggest a role for P1073 in the functioning of the Pol-gamma with the mitochondrial DNA helicase, and provide a rationale for understanding the physiological consequences of the S305R/P1073L compound heterozygote in humans. PMID- 25914720 TI - Transposon insertion mapping with PIMMS - Pragmatic Insertional Mutation Mapping System. AB - The PIMMS (Pragmatic Insertional Mutation Mapping System) pipeline has been developed for simple conditionally essential genome discovery experiments in bacteria. Capable of using raw sequence data files alongside a FASTA sequence of the reference genome and GFF file, PIMMS will generate a tabulated output of each coding sequence with corresponding mapped insertions accompanied with normalized results enabling streamlined analysis. This allows for a quick assay of the genome to identify conditionally essential genes on a standard desktop computer prioritizing results for further investigation. AVAILABILITY: The PIMMS script, manual and accompanying test data is freely available at https://github.com/ADAC UoN/PIMMS. PMID- 25914721 TI - Discovering Che-1/AATF: a new attractive target for cancer therapy. AB - The transcriptional cofactor Che-1/AATF is currently emerging as an important component of the DNA damage response (DDR) machinery, the complex signaling network that maintains genome integrity and prevents tumorigenesis. Moreover this protein is involved in a wide range of cellular pathways, regulating proliferation and survival in both physiological and pathological conditions. Notably, some evidence indicates that dysregulation of Che-1/AATF levels are associated with the transformation process and elevated levels of Che-1/AATF are required for tumor cell survival. It is for these reasons that Che-1/AATF has been regarded as an attractive, still theoretical, therapeutic target for cancer treatments. In this review, we will provide an updated overview of Che-1/AATF activities, from transcriptional regulation to DDR. PMID- 25914722 TI - Grey Literature Searching for Health Sciences Systematic Reviews: A Prospective Study of Time Spent and Resources Utilized. AB - OBJECTIVE: To identify estimates of time taken to search grey literature in support of health sciences systematic reviews and to identify searcher or systematic review characteristics that may impact resource selection or time spent searching. METHODS: A survey was electronically distributed to searchers embarking on a new systematic review. Characteristics of the searcher and systematic review were collected along with time spent searching and what resources were searched. Time and resources were tabulated and resources were categorized as grey or non-grey. Data was analyzed using Kruskal-Wallis tests. RESULTS: Out of 81 original respondents, 21% followed through with completion of the surveys in their entirety. The median time spent searching all resources was 471 minutes, and of those a median of 85 minutes were spent searching grey literature. The median number of resources used in a systematic review search was four and the median number of grey literature sources searched was two. The amount of time spent searching was influenced by whether the systematic review was grant funded. Additionally, the number of resources searched was impacted by institution type and whether systematic review training was received. CONCLUSIONS: This study characterized the amount of time for conducting systematic review searches including searching the grey literature, in addition to the number and types of resources used. This may aid searchers in planning their time, along with providing benchmark information for future studies. This paper contributes by quantifying current grey literature search patterns and associating them with searcher and review characteristics. Further discussion and research into the search approach for grey literature in support of systematic reviews is encouraged. PMID- 25914723 TI - Ethnicity, sex, FADS genetic variation, and hormonal contraceptive use influence delta-5- and delta-6-desaturase indices and plasma docosahexaenoic acid concentration in young Canadian adults: a cross-sectional study. AB - BACKGROUND: There is great interest in the relationship between polyunsaturated fatty acids and health. Yet, the combinatory effect of factors such as sex, ethnicity, genetic polymorphisms and hormonal contraceptives (HC) on the concentrations of these fatty acids is unknown. Therefore, we sought to determine the effects of FADS polymorphisms, and HC use in females, on aggregate desaturase indices (ADI), and plasma docosahexaenoic acid (DHA) concentrations in Caucasian and East Asian males and females. METHODS: Fasting plasma samples were collected from subjects (Caucasian males: 113 and females: 298; East Asian males: 98 and females: 277) from the Toronto Nutrigenomics and Health Study. Fatty acid concentrations were measured by gas chromatography. ADI were estimated by dividing concentrations of arachidonic acid by linoleic acid (n-6 ADI) and eicosapentaenoic acid (EPA) by alpha-linolenic acid (n-3 ADI). [DHA/EPA] desaturase index was used to determine effects of FADS2 polymorphisms and HC use on EPA conversion to DHA. RESULTS: In Caucasians, associations between n-6 ADI and multiple SNP (FADS1 rs174547, FADS2 rs174576, and rs174611 in males; FADS1 rs174547, FADS2 rs174570, rs174576, rs174679, rs174611, rs174593, rs174626, rs2072114, rs2845573, and rs2851682 in females) withstood multiple testing. In East Asian females, 5 SNP-n-6 ADI associations (FADS2 rs174602, rs174626, rs2072114, rs2845573, and rs2851682) withstood multiple testing. One FADS2 SNP was associated with altered [DHA/EPA] desaturase index in Caucasian females only (rs174576, p < 0.0001). HC use had a significant effect on DHA concentrations in Caucasian females only (P < 0.0001). CONCLUSIONS: We demonstrate ethnic- and sex specific effects of FADS polymorphisms on desaturase indices, and ethnic-specific effect of HC use on plasma DHA concentrations. PMID- 25914724 TI - Spotlight on the diagnosis of extrinsic allergic alveolitis (hypersensitivity pneumonitis). AB - Repeated inhalative exposures to antigenic material from a variety of sources, mainly from moulds, thermophilic Actinomycetes, and avians, respectively, can induce immune responses with the clinical picture of extrinsic allergic alveolitis (EAA) or hypersensitivity pneumonitis. Delays of years or even decades till the diagnosis is made are not uncommon; frequent misdiagnoses include allergic asthma, COPD, recurrent flue and other infections. We provide here the state of the art references, a detailed case description and recommend a current diagnostics schema. PMID- 25914725 TI - Photoacoustically guided wavefront shaping for enhanced optical focusing in scattering media. AB - Non-invasively focusing light into strongly scattering media, such as biological tissue, is highly desirable but challenging. Recently, ultrasonically guided wavefront shaping technologies have been developed to address this limitation. So far, the focusing resolution of most implementations has been limited by acoustic diffraction. Here, we introduce nonlinear photoacoustically guided wavefront shaping (PAWS), which achieves optical diffraction-limited focusing in scattering media. We develop an efficient dual-pulse excitation approach to generate strong nonlinear photoacoustic (PA) signals based on the Grueneisen relaxation effect. These nonlinear PA signals are used as feedback to guide iterative wavefront optimization. As a result, light is effectively focused to a single optical speckle grain on the scale of 5-7 um, which is ~10 times smaller than the acoustic focus with an enhancement factor of ~6,000 in peak fluence. This technology has the potential to benefit many applications that desire highly confined strong optical focus in tissue. PMID- 25914726 TI - Synthetic Strategy for Preparing Chiral Double-semicrystalline Polyether Block Copolymers. AB - We report an effective strategy for the synthesis of semi-crystalline block copolyethers with well-defined architecture and stereochemistry. As an exemplary system, triblock copolymers containing either atactic (racemic) or isotactic (R or S) poly(propylene oxide) end blocks with a central poly(ethylene oxide) mid block were prepared by anionic ring-opening procedures. Stereochemical control was achieved by an initial hydrolytic kinetic resolution of racemic terminal epoxides followed by anionic ring-opening polymerization of the enantiopure monomer feedstock. The resultant triblock copolymers were highly isotactic (meso triads [mm]% ~ 90%) with optical microscopy, differential scanning calorimetry, wide angle x-ray scattering and small angle x-ray scattering being used to probe the impact of the isotacticity on the resultant polymer and hydrogel properties. PMID- 25914727 TI - Mefenamic acid taste-masked oral disintegrating tablets with enhanced solubility via molecular interaction produced by hot melt extrusion technology. AB - The objective of this study was to enhance the solubility as well as to mask the intensely bitter taste of the poorly soluble drug, Mefenamic acid (MA). The taste masking and solubility of the drug was improved by using Eudragit(r) E PO in different ratios via hot melt extrusion (HME), solid dispersion technology. Differential scanning calorimetry (DSC) studies demonstrated that MA and E PO were completely miscible up to 40% drug loads. Powder X-ray diffraction analysis indicated that MA was converted to its amorphous phase in all of the formulations. Additionally, FT-IR analysis indicated hydrogen bonding between the drug and the carrier up to 25% of drug loading. SEM images indicated aggregation of MA at over 30% of drug loading. Based on the FT-IR, SEM and dissolution results for the extrudates, two optimized formulations (20% and 25% drug loads) were selected to formulate the orally disintegrating tablets (ODTs). ODTs were successfully prepared with excellent friability and rapid disintegration time in addition to having the desired taste-masking effect. All of the extruded formulations and the ODTs were found to be physically and chemically stable over a period of 6 months at 40 degrees C/75% RH and 12 months at 25 degrees C/60% RH, respectively. PMID- 25914728 TI - The evaluation of progress in the treatment of traumatic brain injury. PMID- 25914729 TI - Clinical use of Bevacizumab in treating refractory glaucoma. AB - Bevacizumab is a recombinant humanized monoclonal antibody directed against vascular endothelial growth factor (VEGF). Though other VEGF inhibitors are being approved for the treatment of ophthalmological conditions, bevacizumab found its way into ophthalmology and clinical practice all around the world. The objective of this review is to present the ophthalmic dosage and administration pathways of bevacizumab in treating refractory glaucoma patients. ABBREVIATIONS: VEGF = vascular endothelial growth factor, FDA = Food and Drug Administration, AMD = age related macular degeneration. PMID- 25914730 TI - Analysis of cases of acute occlusive abdomen in elderly patients. AB - Mechanisms of acute abdomen in the elderly patient are not different from the ones of young adults. What differs is the large number of associated diseases and specific geriatric pathology, ischemic disorders, diverticular disease. The diagnosis of acute abdomen in the elderly patient is difficult due to unclear symptoms, laboratory samples less modified and low cooperation. The article analyzed two groups of patients over 65 years, hospitalized in surgery in the last three years, with the diagnosis of acute surgical abdomen, from the point of view of the appearance of complications depending on the days of delay until surgery. PMID- 25914731 TI - The clinical and epidemiological evolution of varicella in Romania during 2004 and 2013. AB - INTRODUCTION: Varicella, a vaccine preventable disease (VPD) is one of the most common communicable diseases in Romania. The objectives of our study were to describe the epidemiological evolution of varicella in Romania between 2004 and 2013 and the clinical characteristics of the cases admitted to NIID between 2011 and 2013. MATERIALS AND METHODS: An epidemiological retrospective study was conducted by using the information reported quarterly by general practitioners and hospitals at the national level. There is no system for the surveillance of severe cases in Romania, so, to describe the clinical characteristics of varicella cases, a second retrospective study was developed, in which the patients hospitalized in the NIID, within the period 2011-2013, were included. Questionnaires were completed by using data from the clinical observation forms. Collected information included demographic, clinical and laboratory data, complications, date of onset and admission, length of stay, admission and discharge diagnosis. Data were processed and analyzed by using Microsoft Excel program. RESULTS: A total of 504,844 cases were reported of at the national level between 2004 and 2013, with a mean incidence of 238.2/ 100,000 inhabitants. The most affected age group was 5-9 years old (incidence 1362.7/ 100,000 inhabitants). The study conducted in NIID, registered 353 patients hospitalized with varicella between 2011 and 2013. Most of the hospitalized cases (88.8%) were under 10 years old and many (72.6 %) attended a community. The majority of cases had rash (98.6%) and fever (79.9%). The main complications were pneumonia (46.2%), bacterial infection (16.1%) and encephalitis (2.5%). DISCUSSIONS: Varicella is a very common disease in Romania, which may develop complications. A specific surveillance system should be introduced in order to provide accurate epidemiological, clinical and laboratory information to assess whether varicella is a public health problem in Romania and if the introduction of vaccination in NIP is recommended. However, given the large number of current cases in Romania, a solution may be a sentinel surveillance system type. PMID- 25914732 TI - Odonto-sinusal influences. AB - There is a wide documentary material regarding the upper dental disease influencing the state of the maxillary sinus. This article tries to show that the relation is a two-way one. PMID- 25914733 TI - Mesenchymal stem cells in multiple sclerosis - translation to clinical trials. AB - Multiple sclerosis is a chronic inflammatory disease of the central nervous system, characterized by an aberrant activation of the immune system and combining demyelination with neurodegeneration. Studies on experimental models of multiple sclerosis revealed immunomodulatory and immunosuppressive properties of mesenchymal stem cells. Clinical trials using mesenchymal stem cells therapy in multiple sclerosis patients showed tolerability, safety on short term, some immunomodulatory properties reducing the Th1 proinflammatory response and the inflammatory MRI parameters. The author reviews the data about experimental studies and clinical trials using mesenchymal stem cells for the treatment of multiple sclerosis. PMID- 25914734 TI - Biochemical changes and treatment in glaucoma. AB - Glaucoma is the second cause of blindness worldwide. This disease is a neurodegenerative disorder characterized by high intraocular pressure, loss of retinal ganglion cells (apoptosis). Even though there is much research done in this field, the results have not yet managed to stop the progression of glaucoma or to heal this pathology. Free oxygen radicals play a major role; they are formed in the aqueous humor and in the vitreous and they produce apoptosis of the neurons in the optic nerve head, degradation of the trabecular meshwork cells. The purpose of the article is to help in trying to understand the physiopathology of glaucoma and the efficacy of its treatments. PMID- 25914735 TI - Pain-associated biomarkers in breast cancer. AB - Breast cancer represents a major public health problem, being the highest incidence neoplasia in females in Romania. The most important step in the treatment of this neoplasia is the surgical procedure; the biggest problem associated with this form of treatment in these patients is pain-related. Pain is a complex symptom with an impact on quality of life and psychology of cancer patient and can only be monitored verbally and subjectively. Consequently, the purpose of our work is to identify some biochemical parameters involved in the events cascade associated with inflammation and pain in breast cancer female patients, monitored in dynamics of anesthesia and surgical procedure. Measurements of lipid peroxides, ceruloplasmin and immune circulating complexes in mentioned dynamics have been performed. The recorded values are in concordance with the inflammatory processes and pain intensity, thus we can allege that these measurements can complete the pain-associated clinical picture in female breast cancer patients. PMID- 25914736 TI - Ups and downs in physician - cancer patient relationship. AB - INTRODUCTION: Over the past years, there has been an increasing interest in involving the cancer patients in the decision making regarding the therapy management due to several factors. The most important aspect to be taken into consideration is the principle of patient autonomy. More and more patients have become interested in making informed decisions regarding their therapy options and physicians need to be able to provide data on the aspect. Some patient physician models have been proposed and used for 40 years now. Still, the debate is very important for most of the physicians due to the shifts in the approach. MATERIALS AND METHODS: To really express the concerns that the authors address, the case of a head and neck cancer patient and the possible dialogues with the physician were presented. Each type of communication model with the patient is very important because nowadays, intrications between the four are likely to occur. There are legal aspects that need to be taken into consideration such as the informed consent, the ethical and moral aspects. CONCLUSIONS: The possibility of individualized oncological therapy for the cancer patient leads to different decisions for both the patient and the physician. The decision making process involves the patient at different levels. Legal implications tend to affect the healthiness of the dialogue between the physician and the cancer patient and might be a key-point in the further development of the ethical aspects. PMID- 25914737 TI - Biomaterials for orbital fractures repair. AB - The unique and complex anatomy of the orbit requires significant contouring of the implants to restore the proper anatomy. Fractures of the orbital region have an incidence of 10-25% from the total facial fractures and the most common age group was the third decade of life. The majority of cases required reconstruction of the orbital floor to support the globe position and restore the shape of the orbit. The reason for this was that the bony walls were comminuted and/ or bone fragments were missing. Therefore, the reconstruction of the missing bone was important rather than reducing the bone fragments. This could be accomplished by using various materials. There is hardly any anatomic region in the human body that is so controversial in terms of appropriate material used for fracture repair: non resorbable versus resorbable, autogenous/ allogeneic/ xenogenous versus alloplastic material, non-prebent versus preformed (anatomical) plates, standard versus custom-made plates, nonporous versus porous material, non-coated versus coated plates. Thus, the importance of the material used for reconstruction becomes more challenging for the ophthalmologist and the oral and maxillofacial surgeon. PMID- 25914738 TI - Proposal for future diagnosis and management of vascular tumors by using automatic software for image processing and statistic prediction. AB - RATIONALE: Infantile Hemangiomas (IH) are the most frequent tumors of vascular origin, and the differential diagnosis from vascular malformations is difficult to establish. Specific types of IH due to the location, dimensions and fast evolution, can determine important functional and esthetic sequels. To avoid these unfortunate consequences it is necessary to establish the exact appropriate moment to begin the treatment and decide which the most adequate therapeutic procedure is. OBJECTIVE: Based on clinical data collected by a serial clinical observations correlated with imaging data, and processed by a computer-aided diagnosis system (CAD), the study intended to develop a treatment algorithm to accurately predict the best final results, from the esthetical and functional point of view, for a certain type of lesion. METHODS AND RESULTS: The preliminary database was composed of 75 patients divided into 4 groups according to the treatment management they received: medical therapy, sclerotherapy, surgical excision and no treatment. The serial clinical observation was performed each month and all the data was processed by using CAD. DISCUSSIONS: The project goal was to create a software that incorporated advanced methods to accurately measure the specific IH lesions, integrated medical information, statistical methods and computational methods to correlate this information with that obtained from the processing of images. Based on these correlations, a prediction mechanism of the evolution of hemangioma, which helped determine the best method of therapeutic intervention to minimize further complications, was established. PMID- 25914739 TI - Abdominal pregnancy - Case presentation. AB - INTRODUCTION: Abdominal pregnancy, a rare diagnosis, belongs to the ectopic pregnancy group, the leading cause of pregnancy related exitus. The positive diagnosis is very difficult to establish most often in an acute setting, leading to a staggering percent of feto-maternal morbidity and mortality. CASE REPORT: We present the case of 26-weeks-old abdominal pregnancy with partial feto-placental detachment in a patient, after hysteroscopy and in vitro fertilization, which until the acute symptoms that led to emergency laparotomy went unrecognized. The patient recovered completely and satisfactorily after surgery and, due to the high risk of uterine rupture with regard to a second pregnancy, opted for a surrogate mother. CONCLUSION: Abdominal pregnancy can be regarded as a difficult to establish diagnosis, with a greater chance in case of increased awareness. It is compulsory to be well informed in order not to be surprised by the diagnosis and to apply the correct treatment immediately as the morbidity and mortality rate is elevated. PMID- 25914740 TI - The simultaneous occurrence of multiple myeloma and JAK2 positive myeloproliferative neoplasms - Report on two cases. AB - Multiple myeloma and JAK2 positive chronic myeloproliferative neoplasms are hematologic malignancies with a completely different cellular origin. Two cases of simultaneous occurrence of multiple myeloma, one with primary myelofibrosis and another one with essential thrombocythemia are reported in this article. In such cases, an accurate diagnosis requires a molecular testing, including gene sequencing and differential diagnosis of pancytosis associated with splenic amyloidosis. In general, in such cases, of two coexisting malignant hematologic diseases, the treatment of the most aggressive one is recommended. For our two cases, it was decided to start a Velcade based therapy. The main concern was the medullar toxicity, especially when a multiple myeloma was associated with a primary myelofibrosis. PMID- 25914741 TI - Incidence of Herpes Simplex Virus Keratitis in HIV/AIDS patients compared with the general population. AB - Acquired immune deficiency syndrome (AIDS) is associated with a wide spectrum of systemic and ocular infectious diseases. Little information is known about Herpes Simplex Virus type 1 (HSV-1) keratoconjunctivitis in association with AIDS. Because HSV-1 is becoming, day by day, a common eye disease (nearly 100% patients of over 60 years old harbor HSV in their trigeminal ganglia at autopsy), this article discussing a worldwide public health problem. AIM: The purpose of this paper is to compare the incidence and clinical aspects of HSV-1 Keratitis in HIV/ AIDS patients compared with the general population who develops HSV- 1 Keratitis. METHOD: The study is retrospective and comparative. Each patient was examined thoroughly at the biomicroscope ocular slit after corneal staining with fluorescein or rose bengal. Visual acuity, intraocular pressure and corneal sensitivity were also examined. RESULTS: From 170 patients with HIV and ocular anterior segment disorders, 47 patients had viral etiology. 58 patients had keratitis; 14 of them were HSV-1 keratitis. CONCLUSION: Doctors should be aware of the existence of the ocular damage in HIV/ AIDS and emphasize the importance of regular ophthalmologic examination of patients with HIV/ AIDS as HSV infection is common nowadays among the general population. PMID- 25914742 TI - Ablation of advanced tongue cancer and mobile tongue reconstruction by using a sensitive anterolateral thigh and vastus lateralis muscle free flap. AB - BACKGROUND: Successful tongue reconstruction after total glossectomy for advanced tongue or base of tongue cancer should restore swallowing, speech function, and cosmesis. METHODS: The anterior lateral thigh flap sensitive myocutaneous (ALTF) with vastus lateralis muscle was used to reconstruct the oral defect in a patient undergoing total glossectomy with laryngeal preservation for T4 tongue cancer. RESULTS: Good functional outcomes, measured by independent feeding, speech and swallowing, were achieved. CONCLUSIONS: The anterolateral thigh myocutaneous flap for total tongue reconstruction creates a free neotongue tip with an adequate volume, producing acceptable swallowing function and cosmesis. The reconstruction with free flaps is a feasible method of restoring the functional outcomes in speech and deglutition among patients who undergo total glossectomy with laryngeal preservation. PMID- 25914743 TI - Ruptured liver cavernous hemangioma - rare cause of hemoperitoneum. AB - We present the case of a 70-year-old patient admitted with strong abdominal pains and operated in our service for hemorrhagic acute abdomen. Intraoperative hepatic cavernous hemangioma was found with capsular rupture and hemoperitoneum. Due to liver cirrhosis, and no proper technical equipment we chose to perform simple hemostasis. Postoperative evolution was favorable. PMID- 25914744 TI - Measuring the hepatic venous pressure gradient in the upper digestive hemorrhages. AB - The upper digestive hemorrhage is one of the main causes of mortality from liver cirrhosis (CH). The measurement of the hepatic venous pressure gradient (HVPG) by angiographic way can be used for the determination of the risk of hemorrhage. The aim of this study is to verify the influence of the HVPG measurement upon the survival in patients with CH and upper digestive hemorrhage. A retrospective pilot study on 33 patients with upper digestive hemorrhage divided into two groups according to the therapeutic attitude followed, was carried out. One group was classically treated, with variceal band ligation, non-elective beta-blockers and in emergency Octreotide. The other group was treated depending on the value of HVPG. From the moment of the first episode of digestive hemorrhage, the survival period was in average of 8.1 months for the patients with viral etiology and for those with alcoholic etiology it was of 19.7 months. In patients treated after HVPG measurement, the average survival period was of 34.2 months and in patients "classically" treated, the average survival period was of 15.5 months (significant difference). In conclusion, the measurement of HVPG allowed the selection of a high-risk group of patients. This permitted the making of a therapeutical decision with a significant prolongation of life in these patients. PMID- 25914745 TI - The efficiency of biologic therapy in a group of patients with rheumatoid arthritis. AB - OBJECTIVES: The following study aims to evaluate the monotherapy with biologic agents: Infliximab (IFX), Etanercept (ETA), Adalimumab (ADA) and Rituximab (RTX) in patients diagnosed with rheumatoid arthritis (RA). METHODS: To achieve these objectives, the database of "Dr. I. Cantacuzino" Clinical Hospital, Department of Internal Medicine and Rheumatology, was used. The study was retrospective and descriptive, covering 168 patients with RA, followed for 12 months, from January 2012 to January 2013. Admission criteria for the study were the following: patients diagnosed with RA according to ACR 1987/ EULAR 2010 criteria, disease activity score (DAS 28)> 5.1, positive inflammation tests, presence of RA refractory to classic remitting treatment administered at least 6 months prior to the initiation of biological therapy, on patients treated with RTX. They were considered non-responders after 6 months of treatment with anti tumor necrosis factor alpha (anti-TNF) and decided to switch agents with anti CD-20. RESULTS: Comparing values between any two points in time (baseline - 6 months -12 months) for any type of therapy, there were significant decreases in the values of erythrocyte sedimentation rate (ESR), reactive C protein (CRP) and disease activity score (DAS 28). There were no significant differences between therapies regarding ESR at 6 months (p = 0.070, ANOVA) and 12 months (p = 0.375, Kruskal Wallis), significant differences were regarding CRP at 6 and 12 months (p = 0.000, Kruskal-Wallis) and DAS 28 at 6 months (p = 0.000, Kruskal- Wallis) and 12 months (p = 0.018, Kruskal-Wallis). CONCLUSION: All 4 therapies have proven efficient, prognostic markers decreasing gradually at 6 and 12 months. PMID- 25914746 TI - Detection of EWS/FLI-1 fusion in non-Ewing soft tissue tumors. AB - OBJECTIVES: EWS/FLI-1 fusion mainly appears in Ewing's sarcoma or the primitive neuroectodermal tumors and represents a genomic marker for these tumors. However, it can appear with lower frequency in other soft tissue tumors. The paper investigates the presence of EWS/FLI-1 fusion in clinically diagnosed sarcoma belonging to different non-Ewing connective tissue tumors in order to search for a possible new biomarker valuable for investigators. METHODOLOGY: 20 patients with soft tissue tumors, who underwent surgery, were tested. Intra-operative samples of normal and tumor tissue were collected for histopathological diagnosis and genetics determinations. The patients' RNA from tumor and normal peritumoral tissue was extracted and EWS/FLI-1 fusion screened by quantitative real-time PCR. The relative expression of the fusion in the tumor sample was compared to the similar expression in normal tissue. RESULTS: The amplification in the threshold zone was shown by 5 samples (25%): 2 clear cell sarcoma, 1 fibrosarcoma, 1 malignant tumor of nerve sheath, 1 metastatic adenocarcinoma. We differentiated between the unspecific amplification and concluded that these are weak positive results. CONCLUSIONS: Genomic investigation may establish the tumor malignancy and its possible affiliation earlier than histopathology. It can support the screening of EWS/FLI-1 fusion in a larger variety of clinically diagnosed soft tissue tumors. PMID- 25914747 TI - Hydroxyapatite ocular implant and non-integrated implants in eviscerated patients. AB - INTRODUCTION: This study compares the outcomes and complications of hydroxyapatite ocular implant and non-integrated ocular implants following evisceration. MATERIALS AND METHODS: This is a retrospective study of 90 patients who underwent evisceration for different ocular affections, in the Ophthalmology Department of the University Emergency Hospital Bucharest, between January 2009 and December 2013. The outcomes measured were conjunctival dehiscence, socket infection, implant exposure and extrusion rate. RESULTS: Forty-three patients had the hydroxyapatite implant (coralline-Integrated Ocular Implants, USA or synthetic-FCI, France) and forty-seven received non-integrated ocular implants (24 acrylic and 23 silicone). Five cases of socket infection, thirteen cases of extrusion and two cases of conjunctival dehiscence were encountered. CONCLUSIONS: There was a higher rate of conjunctival dehiscence with hydroxyapatite ocular implant, but implant extrusion and socket infection were found in non-integrated ocular implants. PMID- 25914748 TI - Correlations between eyelid tumors and tear lipocalin, lysozyme and lactoferrin concentrations in postmenopausal women. AB - RATIONALE: Common ophthalmological problems are found in patients with eyelid tumors and include ocular surface diseases, such as dry eyes, eyelid disorders, excessive tearing and ocular inflammation. OBJECTIVE: The potential correlation between the symptomatology, tear break-up time (TBUT) and lipocalin, lactoferrin and lysozyme concentrations in the tear film were investigated in a group of symptomatic dry-eyed postmenopausal (PM) women compared to age-matched controls, considering the patients with eyelid tumors. METHODS AND RESULTS: 66 females were divided into two groups of 33 females each, one group having dry eye (DE) and one asymptomatic group (non-dry eye) (NDE), based on their responses to the OSDI questionnaire, TBUT and Schirmer test evaluation. Tears were collected via capillary tubes. Tear lysozyme, lactoferrin and lipocalin concentrations were determined via electrophoresis and the results for patients with or without eyelid tumors were compared. The results revealed significant differences in lysozyme concentration between patients with or without eyelid tumors in the DE group (p = 0.004). Lower levels for TBUT and lactoferrin in the DE group were also found, compared to the NDE group for eyelid tumors patients. Tear lipocalins were in the same range in both groups. DISCUSSION: Within a PM population, some components of the tear film were found to be at lower levels in patients with eyelid tumors, compared to patients without this pathology, which resulted in the development of DE or in the enhancement of the symptoms of an existing DE. PMID- 25914749 TI - Computer Tomograph (CT) imaging of mandibular anatomical substrate in animal model restored with nanostructured hydroxyapatite compounds. AB - INTRODUCTION: This study was meant to test a new type of bone graft on an animal model. This material was a nanostructured hydroxyapatite. MATERIALS AND METHODS: the study was conducted according to Ethic Committee Regulation on animal model (Oryctolagus cuniculus - rabbit) between August and November 2014, at "Carol Davila" University of Medicine and Pharmacy, Bucharest. The animals were tested by using a CT at the level of the mandible before and after using the nanostructured hydroxyapatite. RESULTS: The animals were CT scanned at 1, 2 and respectively 3 months, noticing a growth of the mandibular bone density. After 3 months, a bone density equal with the density of the healthy bone was noticed. CONCLUSIONS: The use of the bone graft could be a viable alternative to available materials. The advantage was that bone recovery had a density similar to the density of the healthy bone and the cost of production was low because it was made out of Calcium azotate and monobasic ammonium phosphate. PMID- 25914750 TI - The efficiency of subconjunctival bevacizumab in refractory glaucoma - case report. AB - Anti-vascular endothelial growth factor (anti-VEGF) therapy used as adjunctive to glaucoma filtration surgery may help filtering bleb survival because vascular endothelial growth factor has an important role in the angiogenesis of new vessels and in the fibrogenesis, which lead to scar formation and bleb failure. Bevacizumab is a non-selective monoclonal antibody against all isoforms of VEGF A. We present the case of an inflammatory glaucoma of a 67-year-old female, with uncontrolled intraocular pressure on maximal tolerable medical treatment, who underwent trabeculectomy and received 1.25 mg/0.05 ml of bevacizumab (Avastin) subconjunctivally at the end of the surgery and an additional injection one month later. Right eye intraocular pressure (IOP) was 26 mm Hg at preoperative visit and after surgery, it decreased and remained normal at each postoperative examination with no additional IOP-lowering medication. A localized avascular bleb with moderate elevation was observed six months postoperatively. PMID- 25914751 TI - Spleen preservation in a caudal pancreatic serous cystadenoma - case report. AB - Cystic lesions of the pancreas are relatively rare entities but have been increasingly diagnosed in recent years due to advanced imaging techniques. This category encompasses pancreatic pseudocyst as well as a wide range of pancreatic tumors with benign behavior, borderline or primary malignant. Serous cystadenoma of the pancreas represents the most common benign pancreatic tumor, with a very low but well recognized malignant potential. The clinical presentation varies according to its size; small tumors may be asymptomatic and discovered incidentally, while large tumors are more likely symptomatic. We report the case of a female patient presenting with non-specific left abdominal pain, who was diagnosed through a CT scan with a caudal pancreatic tumor. The patient underwent spleen-preserving distal pancreatectomy. The result of the histopathological examination revealed a serous cystadenoma. PMID- 25914752 TI - Surgical attitude in premalignant lesions and malignant tumors of the lower lip. AB - INTRODUCTION: Malignant tumors of the lower lip may have a variety of histopathology forms. The diagnosis and treatment of premalignant lesions are extremely important to avoid their malignant evolution. The lower lip tumor diagnosis is based on a series of correlations: anamnestic, clinical, laboratory and histopathological (the latter giving the certain diagnose). MATERIAL AND METHODS: This study was carried out by selecting the cases with lower lip tumors operated between January 2012 and July 2014, in the Plastic Surgery and Reconstructive Microsurgery Clinic of Bucharest Clinical Emergency Hospital. The variables considered in the study were the following: age, gender, exposure to risk factors, diagnosis, and histopathology. RESULTS: The histopathological examination revealed 63% squamous cell carcinoma, 30% basal cell carcinomas, 5% keratoacanthoma and 2% actinic keratosis. Men were the predominantly affected genre, with a percentage of 70%. In the group of patients studied, 66% were smokers. DISCUSSIONS: The rate of the malignant transformation of premalignant lesion was 32.6% for keratoacanthoma, 16.9% for actinic cheilitis, 10% for actinic keratoses. CONCLUSIONS: There were no clinical or laboratory features to plead for the pre-malignant or malignant character of the of a lower lip tumor, consequently histopathological examination was used for the diagnosis of the lesion. Due to the high percentage of malignant transformation of precancerous lesions, particularly in the form of squamous cell carcinoma, the surgical attitude intending to eradicate a lower lip tumor from an oncological point of view was the excision with oncologic safety margins followed by a lip reconstruction. PMID- 25914753 TI - Surgical management in a rare case of basaloid squamous cell carcinoma of the maxilla. AB - Basaloid squamous cell carcinoma (BSCC) is a rare and aggressive version of squamous cell carcinoma (SCC) that preferentially occurs in the upper aerodigestive tract. Since the first description by Wain SL et al., in 1986, only 21 cases with BSCC in the nasal cavity or in the paranasal cavity have been reported in the English literature. We present a case of BSCC arising in a paranasal sinus, a 51-year-old male patient with four months history of right cheek swelling and unilateral nasal obstruction, who underwent an operation and postoperative radiotherapy. Clinical, pathological and surgical findings in this case are presented along with a brief discussion of literature. PMID- 25914754 TI - A strategic vision in Neurology. PMID- 25914755 TI - Endothelial Cell Senescence Increases Traction Forces due to Age-Associated Changes in the Glycocalyx and SIRT1. AB - Endothelial cell (EC) aging and senescence are key events in atherogenesis and cardiovascular disease development. Age-associated changes in the local mechanical environment of blood vessels have also been linked to atherosclerosis. However, the extent to which cell senescence affects mechanical forces generated by the cell is unclear. In this study, we sought to determine whether EC senescence increases traction forces through age-associated changes in the glycocalyx and antioxidant regulator deacetylase Sirtuin1 (SIRT1), which is downregulated during aging. Traction forces were higher in cells that had undergone more population doublings and changes in traction force were associated with altered actin localization. Older cells also had increased actin filament thickness. Depletion of heparan sulfate in young ECs elevated traction forces and actin filament thickness, while addition of heparan sulfate to the surface of aged ECs by treatment with angiopoietin-1 had the opposite effect. While inhibition of SIRT1 had no significant effect on traction forces or actin organization for young cells, activation of SIRT1 did reduce traction forces and increase peripheral actin in aged ECs. These results show that EC senescence increases traction forces and alters actin localization through changes to SIRT1 and the glycocalyx. PMID- 25914756 TI - Fluorescent Photo-conversion: A second chance to label unique cells. AB - Not all cells behave uniformly after treatment in tissue engineering studies. In fact, some treated cells display no signs of treatment or show unique characteristics not consistent with other treated cells. What if the "unique" cells could be isolated from a treated population, and further studied? Photo convertible reporter proteins, such as Dendra2, allow for the ability to selectively identify unique cells with a secondary label within a primary labeled treated population. In the current study, select cells were identified and labeled through photo-conversion of Dendra2-transfected human Wharton's Jelly cells (hWJCs) for the first time. Robust photo-conversion of green-to-red fluorescence was achieved consistently in arbitrarily selected cells, allowing for precise cell identification of select hWJCs. The current study demonstrates a method that offers investigators the opportunity to selectively label and identify unique cells within a treated population for further study or isolation from the treatment population. Photo-convertible reporter proteins, such as Dendra2, offer the ability over non-photo-convertible reporter proteins, such as green fluorescent protein, to analyze unique individual cells within a treated population, which allows investigators to gain more meaningful information on how a treatment affects all cells within a target population. PMID- 25914758 TI - Differential Outcomes by Race and Ethnicity in Patients with Coronary Heart Disease: A Contemporary Review. AB - Coronary heart disease (CHD) is a leading cause of death for people of most ethnicities in the USA. However, several racial and ethnic minority groups are disproportionately burdened by CHD and experience higher mortality rates and rehospitalization rates compared with whites. Contemporary CHD research has been dedicated in part to broadening our understanding of the root causes of racial and ethnic disparities in CHD outcomes. Several factors contribute, including socioeconomic and comorbid conditions. These factors may be amenable to change, and targets for initiatives to reduce disparities and improve CHD outcomes. In this article, we review the recently published research related to the distribution and determinants of racial and ethnic differences in CHD outcomes in the USA. PMID- 25914757 TI - Learning by observation and learning by doing in Prader-Willi syndrome. AB - BACKGROUND: New competencies may be learned through active experience (learning by doing) or observation of others' experience (learning by observation). Observing another person performing a complex action accelerates the observer's acquisition of the same action, limiting the time-consuming process of learning by doing. Here, we compared learning by observation and learning by doing in individuals with Prader-Willi syndrome (PWS). It is hypothesized that PWS individuals could show more difficulties with learning by observation than learning by doing because of their specific difficulty in interpreting and using social information. METHODS: The performance of 24 PWS individuals was compared with that of 28 mental age (MA)- and gender-matched typically developing (TD) children in tasks of learning a visuo-motor sequence by observation or by doing. To determine whether the performance pattern exhibited by PWS participants was specific to this population or whether it was a nonspecific intellectual disability effect, we compared the PWS performances with those of a third MA- and gender-matched group of individuals with Williams syndrome (WS). RESULTS: PWS individuals were severely impaired in detecting a sequence by observation, were able to detect a sequence by doing, and became as efficient as TD children in reproducing an observed sequence after a task of learning by doing. The learning pattern of PWS children was reversed compared with that of WS individuals. CONCLUSIONS: The observational learning deficit in PWS individuals may be rooted, at least partially, in their incapacity to understand and/or use social information. PMID- 25914759 TI - Spherical Hamiltonian Monte Carlo for Constrained Target Distributions. AB - Statistical models with constrained probability distributions are abundant in machine learning. Some examples include regression models with norm constraints (e.g., Lasso), probit models, many copula models, and Latent Dirichlet Allocation (LDA) models. Bayesian inference involving probability distributions confined to constrained domains could be quite challenging for commonly used sampling algorithms. For such problems, we propose a novel Markov Chain Monte Carlo (MCMC) method that provides a general and computationally efficient framework for handling boundary conditions. Our method first maps the D-dimensional constrained domain of parameters to the unit ball [Formula: see text], then augments it to a D-dimensional sphere SD such that the original boundary corresponds to the equator of SD . This way, our method handles the constraints implicitly by moving freely on the sphere generating proposals that remain within boundaries when mapped back to the original space. To improve the computational efficiency of our algorithm, we divide the dynamics into several parts such that the resulting split dynamics has a partial analytical solution as a geodesic flow on the sphere. We apply our method to several examples including truncated Gaussian, Bayesian Lasso, Bayesian bridge regression, and a copula model for identifying synchrony among multiple neurons. Our results show that the proposed method can provide a natural and efficient framework for handling several types of constraints on target distributions. PMID- 25914760 TI - Origin of cells and network information. AB - All cells are derived from one cell, and the origin of different cell types is a subject of curiosity. Cells construct life through appropriately timed networks at each stage of development. Communication among cells and intracellular signaling are essential for cell differentiation and for life processes. Cellular molecular networks establish cell diversity and life. The investigation of the regulation of each gene in the genome within the cellular network is therefore of interest. Stem cells produce various cells that are suitable for specific purposes. The dynamics of the information in the cellular network changes as the status of cells is altered. The components of each cell are subject to investigation. PMID- 25914761 TI - Repressors of reprogramming. AB - Induced pluripotent stem cells (iPSCs) have been the focal point of ever increasing interest and scrutiny as they hold the promise of personalized regenerative medicine. However, creation of iPSCs is an inefficient process that requires forced expression of potentially oncogenic proteins. In order to unlock the full potential of iPSCs, both for basic and clinical research, we must broaden our search for more reliable ways of inducing pluripotency in somatic cells. This review surveys an area of reprogramming that does not receive as much focus, barriers to reprogramming, in the hope of stimulating new ideas and approaches towards developing safer and more efficient methods of reprogramming. Better methods of iPSC creation will allow for more reliable disease modeling, better basic research into the pluripotent state and safer iPSCs that can be used in a clinical setting. PMID- 25914762 TI - New insights into pancreatic cancer stem cells. AB - Pancreatic cancer (PC) has been one of the deadliest of all cancers, with almost uniform lethality despite aggressive treatment. Recently, there have been important advances in the molecular, pathological and biological understanding of pancreatic cancer. Even after the emergence of recent new targeted agents and the use of multiple therapeutic combinations, no treatment option is viable in patients with advanced cancer. Developing novel strategies to target progression of PC is of intense interest. A small population of pancreatic cancer stem cells (CSCs) has been found to be resistant to chemotherapy and radiation therapy. CSCs are believed to be responsible for tumor initiation, progression and metastasis. The CSC research has recently achieved much progress in a variety of solid tumors, including pancreatic cancer to some extent. This leads to focus on understanding the role of pancreatic CSCs. The focus on CSCs may offer new targets for prevention and treatment of this deadly cancer. We review the most salient developments in important areas of pancreatic CSCs. Here, we provide a review of current updates and new insights on the role of CSCs in pancreatic tumor progression with special emphasis on DclK1 and Lgr5, signaling pathways altered by CSCs, and the role of CSCs in prevention and treatment of PC. PMID- 25914763 TI - Mesenchymal stem cells in the treatment of inflammatory and autoimmune diseases in experimental animal models. AB - Multipotent mesenchymal stromal cells [also known as mesenchymal stem cells (MSCs)] are currently being studied as a cell-based treatment for inflammatory disorders. Experimental animal models of human immune-mediated diseases have been instrumental in establishing their immunosuppressive properties. In this review, we summarize recent studies examining the effectiveness of MSCs as immunotherapy in several widely-studied animal models, including type 1 diabetes, experimental autoimmune arthritis, experimental autoimmune encephalomyelitis, inflammatory bowel disease, graft-vs-host disease, and systemic lupus erythematosus. In addition, we discuss mechanisms identified by which MSCs mediate immune suppression in specific disease models, and potential sources of functional variability of MSCs between studies. PMID- 25914764 TI - Vibration stimuli and the differentiation of musculoskeletal progenitor cells: Review of results in vitro and in vivo. AB - Due to the increasing burden on healthcare budgets of musculoskeletal system disease and injury, there is a growing need for safe, effective and simple therapies. Conditions such as osteoporosis severely impact on quality of life and result in hundreds of hours of hospital time and resources. There is growing interest in the use of low magnitude, high frequency vibration (LMHFV) to improve bone structure and muscle performance in a variety of different patient groups. The technique has shown promise in a number of different diseases, but is poorly understood in terms of the mechanism of action. Scientific papers concerning both the in vivo and in vitro use of LMHFV are growing fast, but they cover a wide range of study types, outcomes measured and regimens tested. This paper aims to provide an overview of some effects of LMHFV found during in vivo studies. Furthermore we will review research concerning the effects of vibration on the cellular responses, in particular for cells within the musculoskeletal system. This includes both osteogenesis and adipogenesis, as well as the interaction between MSCs and other cell types within bone tissue. PMID- 25914765 TI - Role of Hox genes in stem cell differentiation. AB - Hox genes are an evolutionary highly conserved gene family. They determine the anterior-posterior body axis in bilateral organisms and influence the developmental fate of cells. Embryonic stem cells are usually devoid of any Hox gene expression, but these transcription factors are activated in varying spatial and temporal patterns defining the development of various body regions. In the adult body, Hox genes are among others responsible for driving the differentiation of tissue stem cells towards their respective lineages in order to repair and maintain the correct function of tissues and organs. Due to their involvement in the embryonic and adult body, they have been suggested to be useable for improving stem cell differentiations in vitro and in vivo. In many studies Hox genes have been found as driving factors in stem cell differentiation towards adipogenesis, in lineages involved in bone and joint formation, mainly chondrogenesis and osteogenesis, in cardiovascular lineages including endothelial and smooth muscle cell differentiations, and in neurogenesis. As life expectancy is rising, the demand for tissue reconstruction continues to increase. Stem cells have become an increasingly popular choice for creating therapies in regenerative medicine due to their self-renewal and differentiation potential. Especially mesenchymal stem cells are used more and more frequently due to their easy handling and accessibility, combined with a low tumorgenicity and little ethical concerns. This review therefore intends to summarize to date known correlations between natural Hox gene expression patterns in body tissues and during the differentiation of various stem cells towards their respective lineages with a major focus on mesenchymal stem cell differentiations. This overview shall help to understand the complex interactions of Hox genes and differentiation processes all over the body as well as in vitro for further improvement of stem cell treatments in future regenerative medicine approaches. PMID- 25914766 TI - Use of human pluripotent stem cells to study and treat retinopathies. AB - Human cell types affected by retinal diseases (such as age-related macular degeneration or retinitis pimentosa) are limited in cell number and of reduced accessibility. As a consequence, their isolation for in vitro studies of disease mechanisms or for drug screening efforts is fastidious. Human pluripotent stem cells (hPSCs), either of embryonic origin or through reprogramming of adult somatic cells, represent a new promising way to generate models of human retinopathies, explore the physiopathological mechanisms and develop novel therapeutic strategies. Disease-specific human embryonic stem cells were the first source of material to be used to study certain disease states. The recent demonstration that human somatic cells, such as fibroblasts or blood cells, can be genetically converted to induce pluripotent stem cells together with the continuous improvement of methods to differentiate these cells into disease affected cellular subtypes opens new perspectives to model and understand a large number of human pathologies, including retinopathies. This review focuses on the added value of hPSCs for the disease modeling of human retinopathies and the study of their molecular pathological mechanisms. We also discuss the recent use of these cells for establishing the validation studies for therapeutic intervention and for the screening of large compound libraries to identify candidate drugs. PMID- 25914767 TI - Role of nitric oxide in the maintenance of pluripotency and regulation of the hypoxia response in stem cells. AB - Stem cell pluripotency and differentiation are global processes regulated by several pathways that have been studied intensively over recent years. Nitric oxide (NO) is an important molecule that affects gene expression at the level of transcription and translation and regulates cell survival and proliferation in diverse cell types. In embryonic stem cells NO has a dual role, controlling differentiation and survival, but the molecular mechanisms by which it modulates these functions are not completely defined. NO is a physiological regulator of cell respiration through the inhibition of cytochrome c oxidase. Many researchers have been examining the role that NO plays in other aspects of metabolism such as the cellular bioenergetics state, the hypoxia response and the relationship of these areas to stem cell stemness. PMID- 25914768 TI - Stem cell therapy in intracerebral hemorrhage rat model. AB - Intracerebral hemorrhage (ICH) is a very complex pathology, with many different not fully elucidated etiologies and prognostics. It is the most severe subtype of stroke, with high mortality and morbidity rates. Unfortunately, despite the numerous promising preclinical assays including neuroprotective, anti hypertensive, and anti-inflammatory drugs, to this moment only symptomatic treatments are available, motivating the search for new alternatives. In this context, stem cell therapy emerged as a promising tool. However, more than a decade has passed, and there is still much to be learned not only about stem cells, but also about ICH itself, and how these two pieces come together. To date, rats have been the most widely used animal model in this research field, and there is much more to be learned from and about them. In this review, we first summarize ICH epidemiology, risk factors, and pathophysiology. We then present different methods utilized to induce ICH in rats, and examine how accurately they represent the human disease. Next, we discuss the different types of stem cells used in previous ICH studies, also taking into account the tested transplantation sites. Finally, we summarize what has been achieved in assays with stem cells in rat models of ICH, and point out some relevant issues where attention must be given in future efforts. PMID- 25914770 TI - Current focus of stem cell application in retinal repair. AB - The relevance of retinal diseases, both in society's economy and in the quality of people's life who suffer with them, has made stem cell therapy an interesting topic for research. Embryonic stem cells (ESCs), induced pluripotent stem cells (iPSCs) and adipose derived mesenchymal stem cells (ADMSCs) are the focus in current endeavors as a source of different retinal cells, such as photoreceptors and retinal pigment epithelial cells. The aim is to apply them for cell replacement as an option for treating retinal diseases which so far are untreatable in their advanced stage. ESCs, despite the great potential for differentiation, have the dangerous risk of teratoma formation as well as ethical issues, which must be resolved before starting a clinical trial. iPSCs, like ESCs, are able to differentiate in to several types of retinal cells. However, the process to get them for personalized cell therapy has a high cost in terms of time and money. Researchers are working to resolve this since iPSCs seem to be a realistic option for treating retinal diseases. ADMSCs have the advantage that the procedures to obtain them are easier. Despite advancements in stem cell application, there are still several challenges that need to be overcome before transferring the research results to clinical application. This paper reviews recent research achievements of the applications of these three types of stem cells as well as clinical trials currently based on them. PMID- 25914769 TI - Recent advances in bone regeneration using adult stem cells. AB - Bone is a highly vascularized tissue reliant on the close spatial and temporal association between blood vessels and bone cells. Therefore, cells that participate in vasculogenesis and osteogenesis play a pivotal role in bone formation during prenatal and postnatal periods. Nevertheless, spontaneous healing of bone fracture is occasionally impaired due to insufficient blood and cellular supply to the site of injury. In these cases, bone regeneration process is interrupted, which might result in delayed union or even nonunion of the fracture. Nonunion fracture is difficult to treat and have a high financial impact. In the last decade, numerous technological advancements in bone tissue engineering and cell-therapy opened new horizon in the field of bone regeneration. This review starts with presentation of the biological processes involved in bone development, bone remodeling, fracture healing process and the microenvironment at bone healing sites. Then, we discuss the rationale for using adult stem cells and listed the characteristics of the available cells for bone regeneration. The mechanism of action and epigenetic regulations for osteogenic differentiation are also described. Finally, we review the literature for translational and clinical trials that investigated the use of adult stem cells (mesenchymal stem cells, endothelial progenitor cells and CD34(+) blood progenitors) for bone regeneration. PMID- 25914771 TI - Searching for naive human pluripotent stem cells. AB - Normal mouse pluripotent stem cells were originally derived from the inner cell mass (ICM) of blastocysts and shown to be the in vitro equivalent of those pre implantation embryonic cells, and thus were called embryonic stem cells (ESCs). More than a decade later, pluripotent cells were isolated from the ICM of human blastocysts. Despite being called human ESCs, these cells differ significantly from mouse ESCs, including different morphology and mechanisms of control of pluripotency, suggesting distinct embryonic origins of ESCs from the two species. Subsequently, mouse pluripotent stem cells were established from the ICM-derived epiblast of post-implantation embryos. These mouse epiblast stem cells (EpiSCs) are morphological and epigenetically more similar to human ESCs. This raised the question of whether cells from the human ICM are in a more advanced differentiation stage than their murine counterpart, or whether the available culture conditions were not adequate to maintain those human cells in their in vivo state, leading to a transition into EpiSC-like cells in vitro. More recently, novel culture conditions allowed the conversion of human ESCs into mouse ESC-like cells called naive (or ground state) human ESCs, and the derivation of naive human ESCs from blastocysts. Here we will review the characteristics of each type of pluripotent stem cells, how (and whether) these relate to different stages of embryonic development, and discuss the potential implications of naive human ESCs in research and therapy. PMID- 25914772 TI - Smart scaffolds in bone tissue engineering: A systematic review of literature. AB - AIM: To improve osteogenic differentiation and attachment of cells. METHODS: An electronic search was conducted in PubMed from January 2004 to December 2013. Studies which performed smart modifications on conventional bone scaffold materials were included. Scaffolds with controlled release or encapsulation of bioactive molecules were not included. Experiments which did not investigate response of cells toward the scaffold (cell attachment, proliferation or osteoblastic differentiation) were excluded. RESULTS: Among 1458 studies, 38 met the inclusion and exclusion criteria. The main scaffold varied extensively among the included studies. Smart modifications included addition of growth factors (group I-11 studies), extracellular matrix-like molecules (group II-13 studies) and nanoparticles (nano-HA) (group III-17 studies). In all groups, surface coating was the most commonly applied approach for smart modification of scaffolds. In group I, bone morphogenetic proteins were mainly used as growth factor stabilized on polycaprolactone (PCL). In group II, collagen 1 in combination with PCL, hydroxyapatite (HA) and tricalcium phosphate were the most frequent scaffolds used. In the third group, nano-HA with PCL and chitosan were used the most. As variable methods were used, a thorough and comprehensible compare between the results and approaches was unattainable. CONCLUSION: Regarding the variability in methodology of these in vitro studies it was demonstrated that smart modification of scaffolds can improve tissue properties. PMID- 25914773 TI - Hepatitis C virus: Is it time to say goodbye yet? Perspectives and challenges for the next decade. AB - The majority of individuals exposed to hepatitis C virus (HCV) establish a persistent infection, which is a leading cause of chronic liver disease, cirrhosis and hepatocellular carcinoma. Major progress has been made during the past twenty-five years in understanding the HCV life cycle and immune responses against HCV infection. Increasing evidence indicates that host genetic factors can significantly influence the outcome of HCV infection and the response to interferon alpha-based antiviral therapy. The arrival of highly effective and convenient treatment regimens for patients chronically infected with HCV has improved prospects for the eradication of HCV worldwide. Clinical trials are evaluating the best anti-viral drug combination, treatment doses and duration. The new treatments are better-tolerated and have shown success rates of more than 95%. However, the recent breakthrough in HCV treatment raises new questions and challenges, including the identification of HCV-infected patients and to link them to appropriate health care, the high pricing of HCV drugs, the emergence of drug resistance or naturally occurring polymorphism in HCV sequences which can compromise HCV treatment response. Finally, we still do not have a vaccine against HCV. In this concise review, we will highlight the progress made in understanding HCV infection and therapy. We will focus on the most significant unsolved problems and the key future challenges in the management of HCV infection. PMID- 25914774 TI - Radioembolization with Yttrium-90 microspheres in hepatocellular carcinoma: Role and perspectives. AB - Transarterial radioembolization (TARE) is a form of brachytherapy in which intra arterially injected yttrium-90-loaded microspheres serve as a source for internal radiation purposes. On the average, it produces disease control rates exceeding 80% and it is a consolidated therapy for hepatocellular carcinoma (HCC); however, current data are all based on retrospective series or non-controlled prospective studies since randomized controlled trials comparing it with the other liver directed therapies for intermediate and locally advanced stage HCC are still underway. The data available show that TARE provides similar or even better survival rates when compared to transarterial chemoembolization (TACE). First line TARE is best indicated for both intermediate-stage patients (staged according to the barcelona clinic liver cancer staging classification) who have lesions which respond poorly to TACE due to multiple tumors or a large tumor burden, and for locally advanced-stage patients with solitary tumors, and segmental or lobar portal vein tumor thrombosis. In addition, emerging data have suggested the use of TARE in patients who are classified slightly beyond the Milan criteria regarding radical treatment for downstaging purposes. As a second line treatment, TARE can also be applied in patients progressing to TACE or sorafenib; a large number of phase II/III trials are ongoing with the purpose of evaluating the best association with systemic therapies. Transarterial radioembolization is very well tolerated and has a low rate of complications which are mainly related to unintended non-target tissue irradiation, including the surrounding liver parenchyma. The complications can be additionally reduced by accurate patient selection and a strict pre-treatment evaluation including dosimetry and assessment of the vascular anatomy. Since a correct treatment algorithm for potential TARE candidates is not clear and standardized, this comprehensive review analyzes the best selection criteria for patients who really benefit from TARE and also the new advances of this therapy, which can be a very important weapon against HCC. PMID- 25914775 TI - Influence of cirrhosis in cardiac surgery outcomes. AB - Liver cirrhosis has evolved an important risk factor for cardiac surgery due to the higher morbidity and mortality that these patients may suffer compared with general cardiac surgery population. The presence of contributing factors for a poor outcome, such as coagulopathy, a poor nutritional status, an adaptive immune dysfunction, a degree of cirrhotic cardiomyopathy, and a degree of renal and pulmonary dysfunction, have to be taken into account for surgical evaluation when cardiac surgery is needed, together with the degree of liver disease and its primary complications. The associated pathophysiological characteristics that liver cirrhosis represents have a great influence in the development of complications during cardiac surgery and the postoperative course. Despite the population of cirrhotic patients who are referred for cardiac surgery is small and recommendations come from small series, since liver cirrhotic patients have increased their chance of survival in the last 20 years due to the advances in their medical care, which includes liver transplantation, they have been increasingly considered for cardiac surgery. Indeed, there is an expected rise of cirrhotic patients within the cardiac surgical population due to the increasing rates of non-alcoholic fatty liver disease and non-alcoholic steatohepatitis, especially in western countries. In consequence, a more specific approach is needed in the assessment of care of these patients if we want to improve their management. In this article, we review the pathophysiology and outcome prediction of cirrhotic patients who underwent cardiac surgery. PMID- 25914776 TI - Is hemodialysis a reason for unresponsiveness to hepatitis B vaccine? Hepatitis B virus and dialysis therapy. AB - Impaired renal function is associated with a high risk of chronicity of hepatitis B virus (HBV) infection. Patients on hemodialysis (HD) or peritoneal dialysis are at an increased risk of viral transmission due to frequent necessity of blood product transfer as well as use of contaminated dialysate or dialysis materials. Additionally, health professionals may cause viral spread via contaminated hands and carelessness against hygiene rules. The frequency of chronic HBV infection may be as high as 80% in patients on renal replacement therapies. This is because HBV vaccination is essential to eliminate chronic HBV infection. However, response rates of HD patients to HBV vaccination vary between 10%-50%. Dialysis adequacy and early vaccination before the onset of dialysis therapy seem to be major determinants of high seroconversion rates. Older age, male gender, duration of dialysis therapy and nutritional status are other well-known factors associated with seroconversion rate. There are controversial reports regarding the role of the presence of diabetes mellitus, HCV positivity, erythropoietin resistance, hyperparathyroidism, and vitamin D inadequacy. The role of genetic alteration in the functions or production of cytokines still needs to be elucidated. PMID- 25914777 TI - Importance of imaging and recent developments in diagnosis of nonalcoholic fatty liver disease. AB - Nonalcoholic fatty liver disease (NAFLD) is one of the most common causes of chronic liver disease and is a major public health problem worldwide. It is a spectrum that includes simple steatosis, nonalcoholic steatohepatitis (NASH), fibrosis and cirrhosis. Recently, NAFLD prevalence in children and adolescents has increased too. The increasing prevalence has resulted in NASH-related chronic liver disease. Therefore, early diagnosis and treatment is quite important. Although liver biopsy is still the gold standard for diagnosis and staging of NAFLD, particularly for the diagnosis of NASH, imaging methods such as ultrasonography, computed tomography, magnetic resonance imaging with chemical shift imaging and especially magnetic resonance spectroscopy and elastography have been increasingly approved as noninvasive alternative methods. The aim of this review is to analyze the diagnostic accuracy and limitations of the imaging methods and recent developments in the diagnosis of NAFLD. PMID- 25914778 TI - Hepatitis D and hepatocellular carcinoma. AB - Hepatitis D virus (HDV) is a defective circular shape single stranded HDV RNA virus with two types of viral proteins, small and large hepatitis D antigens, surrounded by hepatitis B surface antigen. Superinfection with HDV in chronic hepatitis B is associated with a more threatening form of liver disease leading to rapid progression to cirrhosis. In spite of some controversy in the epidemiological studies, HDV infection does increase the risk of hepatocellular carcinoma (HCC) compared to hepatitis B virus (HBV) monoinfection. Hepatic decompensation, rather than development of HCC, is the first usual clinical endpoint during the course of HDV infection. Oxidative stress as a result of severe necroinflammation may progress to HCC. The large hepatitis D antigen is a regulator of various cellular functions and an activator of signal transducer and activator of transcription (STAT)3 and the nuclear factor kappa B pathway. Another proposed epigenetic mechanism by which HCC may form is the aberrant silencing of tumor suppressor genes by DNA Methyltransferases. HDV antigens have also been associated with increased histone H3 acetylation of the clusterin promoter. This enhances the expression of clusterin in infected cells, increasing cell survival potential. Any contribution of HBV DNA integration with chromosomes of infected hepatocytes is not clear at this stage. The targeted inhibition of STAT3 and cyclophilin, and augmentation of peroxisome proliferator-activated receptor gamma have a potential therapeutic role in HCC. PMID- 25914779 TI - Chemotherapy and target therapy for hepatocellular carcinoma: New advances and challenges. AB - Primary liver cancer is one of the commonest causes of death. Hepatocellular carcinoma (HCC) accounts for 90% of primary liver cancers. For patients with unresectable or metastatic HCC, conventional chemotherapy is of limited or no benefit. Sorafenib is the only systemic treatment to demonstrate a statistically significant but modest overall survival benefit, leading to an era of targeted agents. Many clinical trials of targeted drugs have been carried out with many more in progress. Some drugs like PTK787 showed potential benefits in the treatment of HCC. Despite these promising breakthroughs, patients with HCC still have a dismal prognosis. Recently, both a phase III trial of everolimus and a phase II clinical trial of trebananib failed to demonstrate effective antitumor activity in advanced HCC. Sorafenib still plays a pivotal role in advanced HCC, leading to further explorations to exert its maximum efficacy. Combinations targeted with chemotherapy or transarterial chemoembolization is now being tested and might bring about advances. New targeted agents such as mammalian target of rapamycin inhibitors are under investigation, as well as further exploration of the mechanism of hepatocarcinogenesis. PMID- 25914781 TI - Impact of all oral anti-hepatitis C virus therapy: A meta-analysis. AB - AIM: To investigate the efficacy, safety, and cost of treatment of direct acting antivirals (DAAs) with and without peg interferon alfa2a (P), and/or ribavirin (R) in treating hepatitis C virus (HCV) genotype 1 patients. METHODS: MEDLINE was searched for randomized controlled trials (RCT) using DAAs for HCV treatment. Phase 1 trials and studies with investigational drugs on genotype 2 or 3, and on human immunodeficiency virus patients were excluded. Data were pooled for sustained virologic response (SVR), serious adverse effects, and drug discontinuation rate on various treatment arms in trials: P + R; 1(st) generation DAA (telaprevir or boceprevir) + P + R; 2(nd) generation DAA (sofosbuvir or simeprevir) + P + R; 2(nd) generation DAA + R; two 2(nd) generation DAA + R; and two 2(nd) gen DAA. Data were analyzed separately for each arm for treatment naive and non-responders (NR) to previous treatment. The cost of treatment with each regimen for achieving one SVR was also compared. RESULTS: Twenty three RCTs (n = 9354, 62% male, 11% cirrhosis) were analyzed. All oral (P free) regimens with combination of 2 DAA achieved SVR above 95%. The cost of treatment to achieve an SVR with DAA based regimens was lower for NR compared to P+R regimen. However, the cost per SVR remained higher for treatment naive patients. CONCLUSION: Second generation and emerging DAAs are promising agents in HCV treatment, with a very high level of safety and efficacy. An important drawback is their high cost. However, the present meta-analysis shows that the cost per SVR for non responders (but not for naive patients) was lower compared to P + R. This finding together with the superior safety profile and better compliance makes these drugs highly attractive. It is possible that further reduction in treatment duration may make them even more cost effective. PMID- 25914780 TI - Diagnosis and management of primary sclerosing cholangitis-perspectives from a therapeutic endoscopist. AB - Primary sclerosing cholangitis (PSC) is a chronic, cholestatic liver condition characterized by inflammation, fibrosis, and destruction of the intra- and extrahepatic bile ducts. The therapeutic endoscopist plays a key role in the diagnosis and management of PSC. In patients presenting with a cholestatic profile, endoscopic retrograde cholangiopancreatography (ERCP) is warranted for a definite diagnosis of PSC. Dominant strictures of the bile duct occur in 36%-57% of PSC patients. Endoscopic balloon dilatation with or without stenting have been employed in the management of dominant strictures. In addition, PSC patients are at increased risk of developing cholangiocarcinoma with a 20% lifetime risk. Brush cytology obtained during ERCP and use of fluorescence in situ hybridization forms the initial diagnostic step in the investigation of patients with dominant biliary strictures. Our review aims to summarize the current evidence supporting the role of a therapeutic endoscopist in the management of PSC patients. PMID- 25914782 TI - Unusual case of B cell lymphoma after immunosuppressive treatment for psoriasis. AB - Lymphomas may be induced by the systemic immunosuppressive therapies used to treat psoriasis, such as ciclosporin, methotrexate and tumour necrosis factor (TNF)-alpha blockers. The biologic agents currently used in psoriasis include alefacept, efalizumab, and the TNF-alpha antagonists etanercept, infliximab, and adalimumab. Infections and cancer are the main possible consequences of intended or unexpected immunosuppression. We report a 59-year-old man with a history of severe psoriasis vulgaris treated with traditional immunosuppressant drugs followed by anti-TNF-alpha therapy; the patient was firstly hospitalized for an acute cholestatic toxic hepatitis, which we supposed to be related to adalimumab. The first liver biopsy showed active disease with severe hepatocellular damage caused by heavy lymphocytes infiltrate in portal tracts at in the interface with a not conclusive diagnosis of lymphoproliferative disease. The correct diagnosis of T cell/histiocyte- rich large B cell lymphoma (T/HRBCL) was only reached through a gastric biopsy and a second liver biopsy. T/HRBCL is an uncommon morphologic variant of diffuse large B-cell lymphoma not described until now in psoriatic patients receiving immunosuppressive biologic agents. In psoriatic patients, treated with biologic immunosuppressive agents, the suspect of abdominal lymphoma should always be included as differential diagnosis. Abdominal ultrasound evaluation need therefore to be included in the pre-treatment screening as in the follow-up surveillance. PMID- 25914783 TI - Endoscopic ultrasound guided radiofrequency ablation, for pancreatic cystic neoplasms and neuroendocrine tumors. AB - AIM: To outline the feasibility, safety, adverse events and early results of endoscopic ultrasound (EUS)-radiofrequency ablation (RFA) in pancreatic neoplasms using a novel probe. METHODS: This is a multi-center, pilot safety feasibility study. The intervention described was radiofrequency ablation (RF) which was applied with an innovative monopolar RF probe (1.2 mm Habib EUS-RFA catheter) placed through a 19 or 22 gauge fine needle aspiration (FNA) needle once FNA was performed in patients with a tumor in the head of the pancreas. The HabibTM EUS RFA is a 1 Fr wire (0.33 mm, 0.013") with a working length of 190 cm, which can be inserted through the biopsy channel of an echoendoscope. RF power is applied to the electrode at the end of the wire to coagulate tissue in the liver and pancreas. RESULTS: Eight patients [median age of 65 (range 27-82) years; 7 female and 1 male] were recruited in a prospective multicenter trial. Six had a pancreatic cystic neoplasm (four a mucinous cyst, one had intraductal papillary mucinous neoplasm and one a microcystic adenoma) and two had a neuroendocrine tumors (NET) in the head of pancreas. The mean size of the cystic neoplasm and NET were 36.5 mm (SD +/- 17.9 mm) and 27.5 mm (SD +/- 17.7 mm) respectively. The EUS-RFA was successfully completed in all cases. Among the 6 patients with a cystic neoplasm, post procedure imaging in 3-6 mo showed complete resolution of the cysts in 2 cases, whilst in three more there was a 48.4% reduction [mean pre RF 38.8 mm (SD +/- 21.7 mm) vs mean post RF 20 mm (SD +/- 17.1 mm)] in size. In regards to the NET patients, there was a change in vascularity and central necrosis after EUS-RFA. No major complications were observed within 48 h of the procedure. Two patients had mild abdominal pain that resolved within 3 d. CONCLUSION: EUS-RFA of pancreatic neoplasms with a novel monopolar RF probe was well tolerated in all cases. Our preliminary data suggest that the procedure is straightforward and safe. The response ranged from complete resolution to a 50% reduction in size. PMID- 25914784 TI - Glucagon receptor gene mutations with hyperglucagonemia but without the glucagonoma syndrome. AB - Pancreatic neoplasms producing exclusively glucagon associated with glucagon cell hyperplasia of the islets and not related to hereditary endocrine syndromes have been recently described. They represent a novel entity within the panel of non syndromic disorders associated with hyperglucagonemia. This case report describes a 36-year-old female with a 10 years history of non-specific abdominal pain. No underlying cause was evident despite extensive diagnostic work-up. More recently she was diagnosed with gall bladder stones. Abdominal ultrasound, computerised tomography and magnetic resonance imaging revealed no pathologic findings apart from cholelithiasis. Endoscopic ultrasound revealed a 5.5 mm pancreatic lesion. Fine needle aspiration showed cells focally expressing chromogranin, suggestive but not diagnostic of a low grade neuroendocrine tumor. OctreoScan((r)) was negative. Serum glucagon was elevated to 66 pmol/L (normal: 0-50 pmol/L). Other gut hormones, chromogranin A and chromogranin B were normal. Cholecystectomy and enucleation of the pancreatic lesion were undertaken. Postoperatively, abdominal symptoms resolved and serum glucagon dropped to 7 pmol/L. Although H and E staining confirmed normal pancreatic tissue, immunohistochemistry was initially thought to be suggestive of alpha cell hyperplasia. A count of glucagon positive cells from 5 islets, compared to 5 islets from 5 normal pancreata indicated that islet size and glucagon cell ratios were increased, however still within the wide range of normal physiological findings. Glucagon receptor gene (GCGR) sequencing revealed a heterozygous deletion, K349_G359del and 4 missense mutations. This case may potentially represent a progenitor stage of glucagon cell adenomatosis with hyperglucagonemia in the absence of glucagonoma syndrome. The identification of novel GCGR mutations suggests that these may represent the underlying cause of this condition. PMID- 25914785 TI - Appendiceal tie syndrome: A very rare complication of a common disease. AB - Acute appendicitis is the most common surgical emergency that we encounter. Adynamic Intestinal obstruction due to appendicitis or its complication may be seen time and often. Mechanical obstruction because of appendicitis is uncommon and even rarer for a closed loop obstruction to occur. Although it was described as early as 1901, very few cases have been reported. We report the case of a 20 years male who presented with generalized colicky pain abdomen, abdominal distension, vomiting and obstipation for three to four days. Vital signs were stable. His abdomen was distended and peritonitic, especially in the right iliac fossa. Rest of the physical examination was unremarkable. Blood tests were normal except for leucocytosis with neutrophilia. An abdominal X-ray finding was indicating a small bowel obstruction. A midline laparotomy was performed. On intraoperative examination, distended loops of small bowel from the jejunum to the distal ileum was observed, and a constricting ring around the terminal ileum created by a phlegmonous appendicitis with its tip adherent to the root of mesentery was found, obstructing an edematous loop of small bowel without signs of ischemia. As the bowel was viable simple appendectomy was done. Postoperatively, he had an uneventful recovery and was discharged after 3 d. PMID- 25914786 TI - Percutaneous pulmonary and tricuspid valve implantations: An update. AB - The field of percutaneous valvular interventions is one of the most exciting and rapidly developing within interventional cardiology. Percutaneous procedures focusing on aortic and mitral valve replacement or interventional treatment as well as techniques of percutaneous pulmonary valve implantation have already reached worldwide clinical acceptance and routine interventional procedure status. Although techniques of percutaneous pulmonary valve implantation have been described just a decade ago, two stent-mounted complementary devices were successfully introduced and more than 3000 of these procedures have been performed worldwide. In contrast, percutaneous treatment of tricuspid valve dysfunction is still evolving on a much earlier level and has so far not reached routine interventional procedure status. Taking into account that an "interdisciplinary challenging", heterogeneous population of patients previously treated by corrective, semi-corrective or palliative surgical procedures is growing inexorably, there is a rapidly increasing need of treatment options besides redo-surgery. Therefore, the review intends to reflect on clinical expansion of percutaneous pulmonary and tricuspid valve procedures, to update on current devices, to discuss indications and patient selection criteria, to report on clinical results and finally to consider future directions. PMID- 25914787 TI - Practical update on imaging and transcatheter aortic valve implantation. AB - After very rapid advances in the development of the technique and devices, transcatheter aortic valve implantation (named TAVI or TAVR), is today a reality that is here to stay. It has become the minimally-invasive treatment option for high-risk and non-surgical patients with severe symptomatic aortic stenosis. Requiring the participation of a multidisciplinary team for its implementation, cardiac imaging plays an important role. From pre-assessment to determine the suitability of the patient, the access site, the type of device, to the guidance during the procedure, and ultimately the long term monitoring of the patient. Correct selection of the patient and device, correct placement of the stent-valve and early detection of complications are of paramount importance for procedural success and for patient outcome. Each technique has advantages and disadvantages, being the cardiologist who will determine the best approach according to the type of patient and the expertise of the center in each one of them. This article summarizes the last contributions of the most common used imaging techniques, in each step of the procedure. PMID- 25914789 TI - Autonomic and endocrine control of cardiovascular function. AB - The function of the heart is to contract and pump oxygenated blood to the body and deoxygenated blood to the lungs. To achieve this goal, a normal human heart must beat regularly and continuously for one's entire life. Heartbeats originate from the rhythmic pacing discharge from the sinoatrial (SA) node within the heart itself. In the absence of extrinsic neural or hormonal influences, the SA node pacing rate would be about 100 beats per minute. Heart rate and cardiac output, however, must vary in response to the needs of the body's cells for oxygen and nutrients under varying conditions. In order to respond rapidly to the changing requirements of the body's tissues, the heart rate and contractility are regulated by the nervous system, hormones, and other factors. Here we review how the cardiovascular system is controlled and influenced by not only a unique intrinsic system, but is also heavily influenced by the autonomic nervous system as well as the endocrine system. PMID- 25914790 TI - Effective treatment of depression improves post-myocardial infarction survival. AB - AIM: To examine the contribution of treatment resistant depression (TRD) to mortality in depressed post-myocardial infarction (MI) patients independent of biological and social predictors. METHODS: This secondary analysis study utilizes the Enhancing Recovery in Coronary Heart Disease (ENRICHD) clinical trial data. From 1834 depressed patients in the ENRICHD study, there were 770 depressed post MI patients who were treated for depression. In this study, TRD is defined as having a less than 50% reduction in Hamilton Depression (HAM-D) score from baseline and a HAM-D score of greater than 10 in 6 mo after depression treatment began. Cox regression analysis was used to examine the independent contributions of TRD to mortality after controlling for the biological and social predictors. RESULTS: TRD occurred in 13.4% (n = 103) of the 770 patients treated for depression. Patients with TRD were significantly younger in age (P = 0.04) (mean = 57.0 years, SD = 11.7) than those without TRD (mean = 59.2 years, SD = 12.0). There was a significantly higher percentage of females with TRD (57.3%) compared to females without TRD (47.4%) [chi(2) (1) = 4.65, P = 0.031]. There were significantly more current smokers with TRD (44.7%) than without TRD (33.0%) [chi(2) (1) = 7.34, P = 0.007]. There were no significant differences in diabetes (P = 0.120), history of heart failure (P = 0.258), prior MI (P = 0.524), and prior stroke (P = 0.180) between patients with TRD and those without TRD. Mortality was 13% (n = 13) in patients with TRD and 7% (n = 49) in patients without TRD, with a mean follow-up of 29 mo (18 mo minimum and maximum of 4.5 years). TRD was a significant independent predictor of mortality (HR = 1.995; 95%CI: 1.011-3.938, P = 0.046) after controlling for age (HR = 1.036; 95%CI: 1.011-1.061, P = 0.004), diabetes (HR = 2.912; 95%CI: 1.638-5.180, P < 0.001), heart failure (HR = 2.736; 95%CI: 1.551-4.827, P = 0.001), and smoking (HR = 0.502; 95%CI: 0.228-1.105, P = 0.087). CONCLUSION: The analysis of TRD in the ENRICHD study shows that the effective treatment of depression reduced mortality in depressed post-MI patients. It is important to monitor the effectiveness of depression treatment and change treatments if necessary to reduce depression and improve cardiac outcomes in depressed post-MI patients. PMID- 25914788 TI - Helicobacter pylori vs coronary heart disease - searching for connections. AB - In this review, we discussed the findings and concepts underlying the potential role of Helicobacter pylori (H. pylori) infections in the initiation, development or persistence of atherosclerosis and coronary heart disease (CHD). This Gram negative bacterium was described by Marshall and Warren in 1984. The majority of infected subjects carries and transmits H. pylori with no symptoms; however, in some individuals these bacteria may cause peptic ulcers, and even gastric cancers. The widespread prevalence of H. pylori infections and the fact that frequently they remain asymptomatic may suggest that, similarly to intestinal microflora, H. pylori may deliver antigens that stimulate not only local, but also systemic inflammatory response. Recently, possible association between H. pylori infection and extragastric disorders has been suggested. Knowledge on the etiology of atherosclerosis together with current findings in the area of H. pylori infections constitute the background for the newly proposed hypothesis that those two processes may be related. Many research studies confirm the indirect association between the prevalence of H. pylori and the occurrence of CHD. According to majority of findings the involvement of H. pylori in this process is based on the chronic inflammation which might facilitate the CHD related pathologies. It needs to be elucidated, if the infection initiate or just accelerate the formation of atheromatous plaque. PMID- 25914791 TI - Limitations of multimodality imaging in the diagnosis of pannus formation in prosthetic aortic valve and review of the literature. AB - Pannus formation is a rare complication and occurs almost exclusively in mechanical prosthetic valves. It consists of fibrous tissue that covers the surface of the prosthesis either concentrically or eccentrically, resulting in valve dysfunction. The pathophysiology seems to be associated to a chronic inflammatory process that explains the late and insidious clinical presentation. This diagnosis should be considered in patients with high transvalvular gradients on transthoracic echo, and workup should be completed with fluoroscopy and transesophageal echocardiography. Treatment is always surgical and recurrence is rare. We present a case of pannus formation in a prosthetic aortic valve and a review of the literature regarding this disorder. PMID- 25914792 TI - In-vivo Light dosimetry for pleural PDT. AB - In-vivo light dosimetry for patients undergoing photodynamic therapy (PDT) is one of the critical dosimetry quantities for predicting PDT outcome. This study examines the relationship between the PDT treatment time and thoracic treatment volume and surface area for patients undergoing pleural PDT. In addition, the mean light fluence (rate) and its accuracy were quantified. The patients studied here were enrolled in Phase II clinical trial of Photofrin-mediated PDT for the treatment of non-small cell lung cancer with pleural effusion. The ages of the patients studied varied from 34 to 69 years old. All patients were administered 2mg per kg body weight Photoprin 24 hours before the surgery. Patients undergoing photodynamic therapy (PDT) are treated with laser light with a light fluence of 60 J/cm2 at 630nm. Fluence rate (mW/cm2) and cumulative fluence (J/cm2) was monitored at 7 different sites during the entire light treatment delivery. Isotropic detectors were used for in-vivo light dosimetry. The anisotropy of each isotropic detector was found to be within 30%. The mean fluence rate deliver varied from 37.84 to 94.05 mW/cm2 and treatment time varied from 1762 to 5232s. We found a linear correlation between the total treatment time and the treatment area: t (sec) = 4.80 A (cm2). A similar correlation exists between the treatment time and the treatment volume: t (sec) = 2.33 V (cm3). The results can be explained using an integrating sphere theory and the measured tissue optical properties assuming that the saline liquid has a mean absorption coefficient of 0.05 cm-1. Our long term accuracy studies confirmed light fluence rate measurement accuracy of +/-10%. The results can be used as a clinical guideline for future pleural PDT treatment. PMID- 25914793 TI - A heterogeneous algorithm for PDT dose optimization for prostate. AB - The object of this study is to develop optimization procedures that account for both the optical heterogeneity as well as photosensitizer (PS) drug distribution of the patient prostate and thereby enable delivery of uniform photodynamic dose to that gland. We use the heterogeneous optical properties measured for a patient prostate to calculate a light fluence kernel (table). PS distribution is then multiplied with the light fluence kernel to form the PDT dose kernel. The Cimmino feasibility algorithm, which is fast, linear, and always converges reliably, is applied as a search tool to choose the weights of the light sources to optimize PDT dose. Maximum and minimum PDT dose limits chosen for sample points in the prostate constrain the solution for the source strengths of the cylindrical diffuser fibers (CDF). We tested the Cimmino optimization procedures using the light fluence kernel generated for heterogeneous optical properties, and compared the optimized treatment plans with those obtained using homogeneous optical properties. To study how different photosensitizer distributions in the prostate affect optimization, comparisons of light fluence rate and PDT dose distributions were made with three distributions of photosensitizer: uniform, linear spatial distribution, and the measured PS distribution. The study shows that optimization of individual light source positions and intensities are feasible for the heterogeneous prostate during PDT. PMID- 25914794 TI - A robotic multi-channel platform for interstitial photodynamic therapy. AB - A custom-made robotic multichannel platform for interstitial photodynamic therapy (PDT) and diffuse optical tomography (DOT) was developed and tested in a phantom experiment. The system, which was compatible with the operating room (OR) environment, had 16 channels for independent positioning of light sources and/or isotropic detectors in separate catheters. Each channel's motor had an optical encoder for position feedback, with resolution of 1.5 mm, and a maximum speed of 5 cm/s. Automatic calibration of detector positions was implemented using an optical diode beam that defined the starting position of each motor, and by means of feedback algorithms controlling individual channels. As a result, the accuracy of zero position of 0.1 mm for all channels was achieved. We have also employed scanning procedures where detectors automatically covered the appropriate range around source positions. Thus, total scan time for a typical optical properties (OP) measurement throughout the phantom was about 1.5 minutes with point sources. The OP were determined based on the measured light fluence rates. These enhancements allow a tremendous improvement of treatment quality for a bulk tumor compared to the systems employed in previous clinical trials. PMID- 25914795 TI - Macroscopic singlet oxygen model incorporating photobleaching as an input parameter. AB - A macroscopic singlet oxygen model for photodynamic therapy (PDT) has been used extensively to calculate the reacted singlet oxygen concentration for various photosensitizers. The four photophysical parameters (xi, sigma, beta, delta) and threshold singlet oxygen dose ([1O2]r,sh) can be found for various drugs and drug light intervals using a fitting algorithm. The input parameters for this model include the fluence, photosensitizer concentration, optical properties, and necrosis radius. An additional input variable of photobleaching was implemented in this study to optimize the results. Photobleaching was measured by using the pre-PDT and post-PDT sensitizer concentrations. Using the RIF model of murine fibrosarcoma, mice were treated with a linear source with fluence rates from 12 - 150 mW/cm and total fluences from 24 - 135 J/cm. The two main drugs investigated were benzoporphyrin derivative monoacid ring A (BPD) and 2-[1-hexyloxyethyl]-2 devinyl pyropheophorbide-a (HPPH). Previously published photophysical parameters were fine-tuned and verified using photobleaching as the additional fitting parameter. Furthermore, photobleaching can be used as an indicator of the robustness of the model for the particular mouse experiment by comparing the experimental and model-calculated photobleaching ratio. PMID- 25914796 TI - A Transformation Similarity Constraint for Groupwise Nonlinear Registration in Longitudinal Neuro Imaging Studies. AB - Patients with Alzheimer's disease and other brain disorders often show a similar spatial distribution of volume change throughout the brain over time,1,2 but this information is not yet used in registration algorithms to refine the quantification of change. Here, we develop a mathematical basis to incorporate that prior information into a longitudinal structural neuroimaging study. We modify the canonical minimization problem for non-linear registration to include a term that couples a collection of registrations together to enforce group similarity. More specifically, throughout the computation we maintain a group level representation of the transformations and constrain updates to individual transformations to be similar to this representation. The derivations necessary to produce the Euler-Lagrange equations for the coupling term are presented and a gradient descent algorithm based on the formulation was implemented. We demonstrate using 57 longitudinal image pairs from the Alzheimer's Disease Neuroimaging Initiative (ADNI) that longitudinal registration with such a groupwise coupling prior is more robust to noise in estimating change, suggesting such change maps may have several important applications. PMID- 25914797 TI - The Prevalence of fungal infections in children with hematologic malignancy in Ali-Asghar Children Hospital between 2005 and 2010. AB - BACKGROUND: A fungal infection represents a growing problem in children with hematologic malignancies, during chemotherapy induced neutropenia. Fungal colonization is considered a major risk factor for subsequent fungal infections. The aim of this retrospective study was to evaluate prevalence of fungal infection among children admitted to hospital between 2005 and 2010 in Tehran, Iran. MATERIALS AND METHODS: 617 hematological patients in the age range of neoteric to 19 years old were enrolled and 87 cases with invasive fungal infections were extracted from patients' files and documented. Diagnosis of fungal infections was based on the local biopsy and pathology for mucormycosis, blood culture, urine culture and clinical examination for candidasis and galactomannan for aspergillus. RESULTS: the mean age of cancer diagnosis was 6.33 years old and the mean age of fungal infection was 7.95 years old. The majority of the infections was caused by candidia spp (74.7%), followed by aspergillus spp (17.2%) and zygomycetes (11.5%). Among candidiasis patients, oral infection had the highest manifestation (92.3%) whereas in 10 of 15 patients with aspergillus, the infectious site was the lung. There was a significant association between mortality and the type of fungal infection (p <0.0001). CONCLUSION: Our finding suggests that there is a high rate of fungal infections in children receiving remission therapy for onco-hematology. These results help improve the management of these patients, however Further studies are needed. PMID- 25914798 TI - The Correlation between Serum Level of Leptin and Troponin in Children with Major Beta-Thalassemia. AB - BACKGROUND: Polypeptide hormone Leptin suppresses inflammation in the heart muscle and protects heart from diseases. The purpose of this study is to evaluate the relationship between leptin and troponin serum levels with cardiac involvement in patients with major beta thalassemia. MATERIALS AND METHODS: In this cross-sectional study, 70 children with major thalassemia were selected. Two ml blood was taken as sample from all children and after separating serum; the samples were maintained in -20 degrees C temperature. Then, regarding cold chain conditions, the sample were sent to the Biochemistry Lab. Afterwards, leptin and troponin serum levels with the relevant kits and BMI were measured in all children, and information about age and gender was recorded. Collected data were analyzed with SPSS. RESULTS: The mean of leptin in girls and boys were 2.47 +/- 3.13 and 0.96 +/- 1.08 respectively which showed a significant difference (t=2.74, p =0.009). A significant correlation was also observed between BMI and leptin (r = 0.374, P = 0.002). Another significant association was found between leptin and age (r = 0.248, P = 0.041). However, a significant inverse correlation between serum ferritin and age (r = - 0.607, P = 0.0001) was discovered. No correlation was found between leptin, troponin, and ferritin. CONCLUSION: Since Leptin increases with the advent of cardiac involvement and independent from troponin T, it can be a predictive marker of cardiac involvement in patients with major beta thalassemia. PMID- 25914799 TI - The Effectiveness of self management program on quality of life in patients with sickle cell disease. AB - BACKGROUND: Sickle cell patients suffer from many physical, psychological, and social problems that can affect their quality of life. To deal with this chronic condition and manage their disease and prevent complications associated with the disease, they must learn skills and behaviours. The aim of this study was to determine the effectiveness of self-management programs on quality of life in these patients. MATERIAL AND METHODS: Samples of this quasi-experimental study, which included 69 patients with sickle cell disease referring to the Thalassemia Clinic of Shafa Hospital, were entered into the study by census method. Patients received a self-management program using the 5A model for 12 weeks, while their quality of life before the intervention were assessed at the twelfth week and thirty-sixth week using SF-36 questionnaire. Data were analyzed by descriptive statistics, paired t-test, Wilcoxon test, Hotelling's T2, and repeated measures test. RESULTS: The eight dimensions and the total QoL score after intervention were significantly increased compared to those before the intervention (P<0.001). Repeated measures test showed that the mean score of eight QoL dimensions and the total QoL score decreased in the thirty-sixth week, compared to twelfth week. However, it was significantly enhanced in comparison with the intervention baseline (P<0.05). CONCLUSIONS: Current study revealed the efficacy of self management interventions on the quality of life in patients with sickle cell disease. Therefore, application of this supportive method could be useful to empower the patients and help them to manage the disease. PMID- 25914800 TI - Expression profiling of microarray gene signatures in acute and chronic myeloid leukaemia in human bone marrow. AB - BACKGROUND: Classification of cancer subtypes by means of microarray signatures is becoming increasingly difficult to ignore as a potential to transform pathological diagnosis; nonetheless, measurement of Indicator genes in routine practice appears to be arduous. In a preceding published study, we utilized real time PCR measurement of Indicator genes in acute lymphoid leukaemia (ALL) and acute myeloid leukaemia (AML) as a way of application of microarray gene signatures. More to the point, the specificity of such genes for this distinction was investigated by their measurement in cases afflicted with chronic myeloid leukaemia (CML) and with normal bone marrow (BM). MATERIAL AND METHOD: Mononuclear cells were sorted into unselected (total), CD34+ve, and CD34-ve fractions, mRNA globally amplified by using PolyA PCR. Moreover, the level of expression of 17 Indicator genes was identified by using real-time PCR. RESULTS: No statistically significant difference was observed in expression for any gene among CML cases. Cyclin D3 (p<=0.04) was exclusively upregulated in CML in the CD34+ fraction, notwithstanding upregulation of HkrT-1 (p<=0.02) and fumarylacetoacetate (p<=0.03) in AML. HOXA9 experienced a non-significant upregulation in AML; however, in combination with proteoglycan 1 distinguished between AML and normal samples in the CD34- fraction in unsupervised clustering. Unsupervised clustering distinguished among AML and the other diagnostic groups. CONCLUSION: The evidence from the present study suggests that the genes discriminatory between ALL and AML are uninformative in the context of CML and normal BM, excepting for distinction with AML. PMID- 25914801 TI - Low frequency of c-MPL gene mutations in Iranian patients with Philadelphia negative myeloproliferative disorders. AB - BACKGROUND: Myeloproliferative disorders are a group of diseases characterized by increased proliferation of myeloid lineage. In addition to JAK2V617F mutation, several mutations in the c-MPL gene have been reported in patients with philadelphia-negative chronic myeloproliferative disorders that could be important in the pathogenesis of diseases. The aim of the present study was to investigate the frequency of c-MPL and JAK2V617F mutations in Iranian patients with Philadelphia-negativemyeloproliferative disorders. MATERIAL AND METHODS: Peripheral blood samples were collected from 60 patients with Philadelphia negative MPD) Subgroups ET and PMF) and 25 healthy subjects as control group. The mutation status of c-MPL and Jak2V617F were investigated by using Amplification refractory mutation system (ARMS) and Allele-Specific PCR (AS-PCR), respectively. The results were confirmed by sequencing. RESULTS: Among 60 patients, 34 (56.6%) and 1(1.7%) had Jak2V617F and c-MPL mutation, respectively. Patients with Jak2V617F mutation had higher WBC counts and hemoglobin concentration than those without the mutation (p= 0.005, p=0.003). In addition, for all healthy subjects in control group, mutations were negative. CONCLUSIONS: The present study revealed that the c-MPL mutations unlike the Jak2V617F mutations are rare in Iranian patients with Ph-negative MPNs and the low mutation rate should be considered in the design of screening strategies of MPD patients. PMID- 25914803 TI - Autoimmune Hemolytic Anemia preceding the Diagnosis of Primary Central Nervous System Lymphoma. AB - In this study, a 2.5-year-old boy suffering from a febrile seizure with normal laboratory tests and a history of immune hemolytic anemia was examined. Brain MRI demonstrated some tumors in the frontal, parietal, and occipital lobe that corroborated the pathology results of primary central nervous system lymphoma for the patient. The patient was treated with high-dose of Methotrexate. Our result suggested regular and careful monitoring of patients with autoimmune hemolytic anemia in order to control the manifestations of concomitant disease such as lymphoma that may develop later. PMID- 25914802 TI - Refractory iron deficiency anemia and Helicobacter Pylori Infection in pediatrics: A review. AB - BACKGROUND: Since the discovery of Helicobacter pylori, several clinical reports have demonstrated that H. Pylori infection has emerged as a new cause of refractory iron stores in children. We carried out a systematic literature review to primarily evaluate the existing evidence on the association between childhood H. Pylori infection and iron deficiency anemia (IDA) and secondly, to investigate the beneficial effects of bacterium elimination. MATERIAL AND METHODS: This review concerns important pediatric studies published from January 1991 to October 2014. Fourteen case reports and series of cases, 24 observational epidemiologic studies, seven uncontrolled trials, and 16 randomized clinical trials were included in the review. RESULTS: Although there are a few observational epidemiologic studies and some randomized trials mostly due to the potential confounders, most studies reported a positive association linking between H. Pylori infection and iron deficiency or iron deficiency anemia among children. In addition, it seems that elimination of H. Pylori infection induces beneficial effects on iron deficiency. CONCLUSIONS: Since the evidence for the association of H. pylori eradication therapy and refractory childhood IDA is not enough and there are contrasting data about such association, future high quality and cohort researches are needed to determine the causal association. PMID- 25914804 TI - Discovery of novel 5-fluoro-N2,N4-diphenylpyrimidine-2,4-diamines as potent inhibitors against CDK2 and CDK9. AB - Based on a 3D-QSAR pharmacophore derived from a diverse set of known cyclin dependent kinase 9 (CDK9) inhibitors and a composite pharmacophore extracted from the complex structure of flavopiridol (FVP)-CDK9, thirty novel 5-fluoro-N2,N4 diphenylpyrimidine-2,4-diamine derivatives were designed and synthesized. Initial tests against four tumor cell lines with the sulforhodamine B (SRB) assay identified a series of potent compounds with GI50 values at lower micromolar or submicromolar level. Most of the highly cytotoxic compounds exhibited potent inhibitory activities against both CDK2/cyclin E1 and CDK9/cyclin T1. Notably, inhibitions against the two enzymes were generally correlated well with the cytotoxicity of these compounds. Appreciable inhibition was also observed for selected compounds in the anti-HIV-1 assay. Docking studies on compounds 6d and 9g provided conducive clues to further structural optimization. PMID- 25914805 TI - Delta-like 4 mRNA is regulated by adjacent natural antisense transcripts. AB - BACKGROUND: Recent evidence suggests that a majority of RNAs in the genome do not code for proteins. They are located in the sense (S) or antisense (AS) orientation and, to date, the functional significance of these non-coding RNAs (ncRNAs) is poorly understood. Here, we examined the relationship between S and AS transcripts in the regulation of a key angiogenesis gene, Delta-like 4 (Dll4). METHODS: Rapid Amplification of cDNA Ends (RACE) method was used to identify natural antisense transcripts in the Dll4 gene locus in murine and human endothelial cells, referred to as Dll4 Anti-Sense (Dll4-AS). Messenger RNA (mRNA) levels of Dll4 and Dll4-AS were quantified by real-time PCR. The function of Dll4 AS was investigated by overexpression and knocking down of Dll4-AS. RESULTS: Dll4 AS comprises of three isoforms that map proximal to the Dll4 promoter region. Expression patterns of Dll4-AS isoforms vary among different endothelial cell lines, but are always congruent with those of Dll4. A dual promoter element in the Dll4 locus has been identified that controls the expression of both transcripts. Both Dll4-AS and Dll4 are sensitive to cellular density in that higher cellular density favors their expression. Exogenous Dll4 stimuli such as VEGF, FGF and Notch signaling inhibitor altered both DLL4-AS and DLL4 expression suggesting co-regulation of the transcripts. Also, knocking down of Dll4-AS results in down-regulation of Dll4 expression. As a consequence, endothelial cell proliferation and migration increases in vitro, and sprout formation increases. The regulation of Dll4 by Dll4-AS was also conserved in vivo. CONCLUSION: A novel form of non-coding RNA-mediated regulation at the Dll4 locus contributes to vascular developmental processes such as cell proliferation, migration and sprouting. PMID- 25878773 TI - Malignant pleural effusions and the role of talc poudrage and talc slurry: a systematic review and meta-analysis. AB - BACKGROUND: Malignant Pleural Effusion (MPE) is common with advanced malignancy. Palliative care with minimal adverse events is the cornerstone of management. Although talc pleurodesis plays an important role in treatment, the best modality of talc application remains controversial. OBJECTIVE: To compare rates of successful pleurodesis, rates of respiratory and non-respiratory complications between thoracoscopic talc insufflation/poudrage (TTI) and talc slurry (TS). DATA SOURCES AND STUDY SELECTION: MEDLINE (PubMed, OVID), EBM Reviews (Cochrane database of Systematic Reviews, ACP Journal Club, DARE, Cochrane Central Register of Controlled Trials, Cochrane Methodology Register, Health Technology Assessment and NHS Economic Evaluation Database), EMBASE and Scopus. Randomized controlled trials published between 01/01/1980 - 10/1/2014 and comparing the two strategies were selected. RESULTS: Twenty-eight potential studies were identified of which 24 studies were further excluded, leaving four studies. No statistically significant difference in the probability of successful pleurodesis was observed between TS and TTI groups (RR 1.06; 95 % CI 0.99-1.14; Q statistic, 4.84). There was a higher risk of post procedural respiratory complications in the TTI group compared to the TS group (RR 1.91, 95% CI= 1.24-2.93, Q statistic 3.15). No statistically significant difference in the incidence of non-respiratory complications between the TTI group and the TS group was observed (RR 0.88, 95% CI= 0.72-1.07, Q statistic 4.61). CONCLUSIONS: There is no difference in success rates of pleurodesis based on patient centered outcomes between talc poudrage and talc slurry treatments. Respiratory complications are more common with talc poudrage via thoracoscopy. PMID- 25914807 TI - Acid-responsive nanospheres from an asparagine-derived amphiphile. AB - We describe the synthesis and self-assembly of an asparagine-derived amphiphile. The self-assembled systems formulated with the inclusion of cholesterol (0-50 mol%) show encapsulation for a hydrophobic model drug and rapidly disintegrate in response to mild acidic conditions. PMID- 25914808 TI - Knowledge, perception and practices about malaria, climate change, livelihoods and food security among rural communities of central Tanzania. AB - BACKGROUND: Understanding the interactions between malaria and agriculture in Tanzania is of particular significance when considering that they are the major sources of illness and livelihoods. The objective of this study was to determine knowledge, perceptions and practices as regards to malaria, climate change, livelihoods and food insecurity in a rural farming community in central Tanzania. METHODS: Using a cross-sectional design, heads of households were interviewed on their knowledge and perceptions on malaria transmission, symptoms and prevention and knowledge and practices as regards to climate change and food security. RESULTS: A total of 399 individuals (mean age = 39.8 +/- 15.5 years) were interviewed. Most (62.41%) of them had attained primary school education and majority (91.23%) were involved in crop farming activities. Nearly all (94.7%) knew that malaria is acquired through a mosquito bite. Three quarters (73%) reported that most people get sick from malaria during the rainy season. About 50% of the respondents felt that malaria had decreased during the last 10 years. The household coverage of insecticide treated mosquito nets (ITN) was high (95.5%). Ninety-six percent reported to have slept under a mosquito net the previous night. Only one in four understood the official Kiswahili term (Mabadiliko ya Tabia Nchi) for climate change. However, there was a general understanding that the rain patterns have changed in the past 10 years. Sixty-two percent believed that the temperature has increased during the same period. Three quarters of the respondents reported that they had no sufficient production from their own farms to guarantee food security in their household for the year. Three quarters (73.0%) reported to having food shortages in the past five years. About half said they most often experienced severe food shortage during the rainy season. CONCLUSION: Farming communities in Kilosa District have little knowledge on climate change and its impact on malaria burden. Food insecurity is common and community-based strategies to mitigate this need to be established. The findings call for an integrated control of malaria and food insecurity interventions. PMID- 25914809 TI - Childhood-onset schizophrenia case with 2.2 Mb deletion at chromosome 3p12.2 p12.1 and two large chromosomal abnormalities at 16q22.3-q24.3 and Xq23-q28. AB - Childhood-onset schizophrenia is rare, comprising 1% of known schizophrenia cases. Here, we report a patient with childhood-onset schizophrenia who has three large chromosomal abnormalities: an inherited 2.2 Mb deletion of chromosome 3p12.2-p12.1, a de novo 16.7 Mb duplication of 16q22.3-24.3, and a de novo 43 Mb deletion of Xq23-q28. PMID- 25914810 TI - STEC:O111-HUS complicated by acute encephalopathy in a young girl was successfully treated with a set of hemodiafiltration, steroid pulse, and soluble thrombomodulin under plasma exchange. AB - We report a 14-year-old girl, who developed shigatoxin-producing E. coli (STEC) HUS complicated by encephalopathy. She was successfully treated with hemodiafiltration, high-dose methylprednisolone pulse therapy, and soluble recombinant thrombomodulin under plasma exchange. von Willebrand factor multimers analysis provides potential insights into how the administered therapies might facilitate successful treatment of STEC-HUS. PMID- 25914811 TI - Protein S deficiency present in a pregnant woman with dyspnea, abdominal pains, restlessness, agitation and hypofibrinogenemia. AB - Hypofibrinogenemia is rare in pulmonary thromboembolism. A pregnant woman with dyspnea, abdominal pain, restlessness, agitation and protein S deficiency exhibited normal blood oxygenation and high D-dimer (370 MUg/mL) and undetectable fibrinogen levels in the blood. The pathogenesis responsible for present findings may have some features similar to amniotic fluid embolism. PMID- 25914812 TI - Polyclonal hyperviscosity syndrome in IgG4-related disease and associated conditions. AB - Polyclonal hyperviscosity syndrome (HVS) is rare and has been reported in various disorders of immune dysregulation and lymphoid hyperplasia. IgG4-Related Disease (IgG4-RD) is an emerging disorder often associated with exuberant hypergammaglobulinemia, and this review of seven cases establishes IgG4-RD as an important cause of polyclonal HVS. PMID- 25914813 TI - Finding the elusive and causative autoantibody: An atypical case of autoimmune hemolytic anemia. AB - An isolated IgA-mediated autoimmune hemolytic anemia can present a diagnostic challenge. When a routine direct antiglobulin test (DAT) is negative but clinical suspicion remains high, further testing with monospecific antisera should be performed. As with IgG-mediated WAIHA, steroids are first-line treatment, though splenectomy is often required to achieve a durable treatment response. PMID- 25914814 TI - Successful treatment of immediate allogeneic myeloablative hematopoietic stem cell transplantation from a HLA-mismatched sibling donor for active systemic epstein-barr virus-positive T-cell lymphoproliferative disease of childhood following primary acute epstein-barr virus infection. AB - A 22-year-old female was admitted for sustained high fever and diagnosed with systemic Epstein-Barr virus-positive T-cell lymphoproliferative disease. As her clinical course was so aggressive, she immediately underwent allogeneic myeloablative bone marrow transplantation from an HLA-mismatched sibling donor on hospital day 46. The patient has remained in complete remission for 3 years. PMID- 25914815 TI - Nonspecific phenotype of Noonan syndrome diagnosed by whole exome sequencing. AB - Noonan syndrome is a genetically heterogeneous condition primarily due to missense mutations in PTPN11. Prenatal diagnosis is typically made in a fetus with increased nuchal translucency and normal karyotype. We demonstrate the ability of whole exome sequencing to make prenatal diagnoses that would not have been made from phenotype alone. PMID- 25914816 TI - Expulsion of a uterine myoma in a patient treated with ulipristal acetate. AB - Description of a spontaneous expulsion of a submucosal myoma in a patient treated with ulipristal acetate. PMID- 25914817 TI - A safe and simpler diagnosis of gastric schwannomas. AB - Although gastric schwannomas usually are nonmalignant, these tumors can undergo malignant transformation. For diagnosis, endoluminal routes are believed to decrease the chance of cancerous cell dissemination. We present a case where a percutaneous route was utilized with supporting evidence for the safe use of this method for diagnosis. PMID- 25914818 TI - Late onset hemopericardium with cardiac tamponade from minor blunt chest trauma - a case report. AB - Hemopericardium with cardiac tamponade following minor blunt trauma is a rare, life-threatening condition in children. Without high index of suspicion, diagnosis and intervention may be delayed as the link between the trauma and illness may be missed. We present a 12-year-old female in Nigeria, and highlight challenges in diagnosis. PMID- 25914819 TI - Moyamoya disease and pregnancy: case reports and criteria for successful vaginal delivery. AB - Based on our experience with seven deliveries (five cesarean and two vaginal deliveries) in five women with Moyamoya disease, we discussed the appropriate method of delivery and anesthesia for patients with Moyamoya disease. In certain conditions, women with Moyamoya disease can successfully undergo vaginal delivery. PMID- 25914820 TI - Pneumocystis jiroveci prophylaxis in patients undergoing Bendamustine treatment: the need for a standardized protocol. AB - The decision for PJP prophylaxis depends on a physician's evaluation of multiple variables. The high rate of PJP infection described in this article combined with the known impaired T-cell function post Bendamustine treatment justifies considering all patients for PJP prophylaxis when they receive Bendamustine treatment. PMID- 25914821 TI - A case of conjoined twins after a transfer of a multinuclear embryo. AB - A pregnancy with conjoined twins was observed after transfer of a multinuclear embryo. As nuclear mechanisms have a role in cellular differentiation, association between multinucleation and fetal malformations is possible. Follow up studies on children born after transfer of embryos with bi/multinuclear blastomeres are needed. PMID- 25914822 TI - Posterior reversible encephalopathy syndrome postpartum. AB - Preeclampsia (PE) should be considered in women with headache who are in gestational week 20 or more, are in labor, or have recently given birth. Early diagnosis is essential to arrest disease progression and further prognosis in PE. PMID- 25914823 TI - Quadricuspid aortic valve and anomalous origin of the left circumflex coronary artery in a young man with Down syndrome. AB - The Authors present the case of an asymptomatic 36-year-old man, affected by Down syndrome, with an unexpected quadricuspid aortic valve coupled with the anomalous origin of the left circumflex coronary artery from the proximal right coronary artery. This is the first report of the concomitant presence of these three conditions. PMID- 25914824 TI - Second-degree atrioventricular block type II and third-degree atrioventricular block requiring cardiac pacing after tooth extraction. AB - Because atrioventricular block can cause cardiovascular collapse, the rapid management of this condition is necessary. An 82-year-old man complained of discomfort after tooth extraction, and electrocardiography showed second- and third-degree atrioventricular blocks. Dentists should monitor patients who report discomfort using electrocardiography because of the possibility of life threatening arrhythmia. PMID- 25914826 TI - Prevalence and sociodemographic correlates of DSM-5 eating disorders in the Australian population. AB - BACKGROUND: New DSM-5 diagnostic criteria for eating disorders were published in 2013. Adolescent cohort studies in the Australian community indicate that the point prevalence of DSM-5 eating disorders may be as high as 15% in females and 3% in males. The goal of the current study was to determine the 3-month prevalence of DSM-5 disorders in a representative sample of Australian older adolescents and adults. A secondary aim was to explore the demographic correlates of these disorders, specifically, age, gender, income, and educational attainment and presence of obesity. METHODS: We conducted and merged sequential cross sectional population survey data of adults (aged over 15 years) collected in 2008 and in 2009 (n = 6041). Demographic information and the occurrence of regular (at least weekly over the past 3 months) objective and subjective binge eating, extreme dietary restriction, purging behaviors, and overvaluation of weight and/or shape, were assessed. RESULTS: The 3-month prevalence of anorexia nervosa and bulimia nervosa were both under 1% whereas the prevalence of binge eating disorder (BED) and sub-threshold BED were 5.6-6.9%. The prevalence of BED including overvaluation of weight/shape was 3%. Other specified and unspecified eating disorders including purging disorder were less common, under 1% to 1.4%. While people with eating disorders were generally younger than others, the mean age was in the fourth decade for anorexia nervosa and bulimia nervosa and in the fourth or fifth decade for all other disorders. Most people with eating disorders had similar household incomes and educational attainments to the general population. People with bulimia nervosa, BED and sub-threshold bulimia nervosa were more likely to be obese than people without an eating disorder. CONCLUSIONS: The findings support the expanded demographic distribution of eating disorders. There is a relatively high prevalence of BED compared to anorexia nervosa and bulimia nervosa. As it is in BED, obesity is a very common co-morbidity in bulimia nervosa. PMID- 25914827 TI - Mental health first aid training for Australian medical and nursing students: an evaluation study. AB - BACKGROUND: The role and demands of studying nursing and medicine involve specific stressors that may contribute to an increased risk for mental health problems. Stigma is a barrier to help-seeking for mental health problems in nursing and medical students, making these students vulnerable to negative outcomes including higher failure rates and discontinuation of study. Mental Health First Aid (MHFA) is a potential intervention to increase the likelihood that medical and nursing students will support their peers to seek help for mental health problems. This study aimed to evaluate the effectiveness of a tailored MHFA course for nursing and medical students. METHODS: Nursing and medical students self-selected into either a face-to-face or online tailored MHFA course. Four hundred and thirty-four nursing and medical students completed pre- and post-course surveys measuring mental health first aid intentions, mental health literacy, confidence in providing help, stigmatising attitudes and satisfaction with the course. RESULTS: The results of the study showed that both the online and face-to-face courses improved the quality of first aid intentions towards a person experiencing depression, and increased mental health literacy and confidence in providing help. The training also decreased stigmatizing attitudes and desire for social distance from a person with depression. CONCLUSION: Both online and face-to-face tailored MHFA courses have the potential to improve outcomes for students with mental health problems, and may benefit the students in their future professional careers. PMID- 25914828 TI - Epidemiology, prevention, and treatment of new-onset atrial fibrillation in critically ill: a systematic review. AB - BACKGROUND: Atrial fibrillation (AF) is a common arrhythmia in the ICU. The aim of this review is to summarize relevant information on new-onset AF in non cardiac critical illness with respect to epidemiology, prevention, and treatment. METHODS: We conducted a PubMed search in June 2014 and included studies describing the epidemiology, prevention, and treatment of new-onset AF and atrial flutter during ICU stay in non-cardiac adult patients. Selected studies were divided into the three categories according to the extracted information. The methodological quality of selected studies was described according to the Grading of Recommendations Assessment, Development and Evaluation system. RESULTS: We identified 1,132 citations, and after full-text-level selection, we included 10 studies on etiology/outcome and five studies on treatment. There was no study related to prevention. Overall quality of evidence was mostly low or very low due to their observational study designs, small sample sizes, flawed diagnosis of new onset AF, and the absence of mortality evaluation. The incidence of new-onset AF varied from 4.5% to 15.0%, excluding exceptional cases (e.g., septic shock). Severity scores of patients with new-onset AF were higher than those without new onset AF in eight studies, in four of which the difference was statistically significant. Five studies reported risk factors for new-onset AF, all of which used multivariate analyses to extract risk factors. Multiple risk factors are reported, e.g., advanced age, the white race, severity scores, organ failures, and sepsis. Hospital mortality in new-onset AF patients was higher than that of patients without AF in all studies, four of which found statistical significance. Among the five studies on treatment, only one study was randomized controlled, and various interventions were studied. CONCLUSIONS: New-onset AF occurred in 5% 15% of the non-cardiac critically ill patients. Patients with new-onset AF had poor outcomes compared with those without AF. Despite the high incidence of new onset AF in the general ICU population, currently available information for AF, especially for management (prevention, treatment, and anticoagulation), is quite limited. Further research is needed to improve our understanding of new-onset AF in critically ill patients. PMID- 25914829 TI - Assessment of a revolving drug fund for essential asthma medicines in Benin. AB - OBJECTIVES: Benin established a revolving drug fund (RDF) for essential asthma medicines in 2008. We evaluated the operation of the RDF and assessed whether there was interruption of supply of asthma medicine from 2008 to 2013. METHODS: We reviewed the process in establishing the RDF. We assessed cost and sale price of asthma medicines, expenditure of the RDF in procuring asthma medicines and other tools, revenue generated by sales of medicines to patients, and balance of capital as of 31 January 2013. We investigated whether there was interruption of supply of essential asthma medicines from 2008-2013. RESULTS: The total amount of grants initially injected into the RDF was 24,101?. As of 31 January 2013, the capital of the RDF, including the deposit in the RDF bank account (8,114?) and the value of inhalers in stock (12,172?), was equivalent to 20,586?, slightly less than the initial capital (24,101?). The decrease of capital was mainly because a number of inhalers were expired or provided free-of-charge (6,091?) and because part of the fund was used to procure other elements required for the management of asthma (4,338?). Thanks to a RDF, Benin maintained an uninterrupted supply of essential asthma medicines in asthma pilot sites from 2008-2013. CONCLUSION: The Benin experience demonstrated that in countries where universal health coverage was not yet in place, establishment of a RDF may help maintain an uninterrupted supply of essential medicines. PMID- 25914830 TI - The Ebola epidemic is ongoing in West Africa and responses from China are positive. AB - The ongoing Ebola outbreak poses an alarming risk to the countries of West Africa and beyond. On August 8, 2014, the World Health Organization (WHO) declared the cross-country Ebola outbreak a Public Emergency of International Concern. China has had no confirmed cases of Ebola. In this paper, virologic characteristics, pathogenesis, clinical manifestations, laboratory examination and prophylactic vaccines and therapeutic drugs of Ebola are summarized. Importantly, active responses and actions from China are introduced. Moreover, the key issues in the future prevention and control of Ebola were also addressed. PMID- 25914831 TI - Optimized management in patients with bladder cancer. PMID- 25914832 TI - Author'S reply. PMID- 25914833 TI - Robot-assisted radical cystectomy and intracorporeal urinary diversion - safe and reproducible? AB - INTRODUCTION: Robot-assisted radical cystectomy (RARC) plus intracorporeal urinary diversion is feasible. Few centers worldwide demonstrated comparable functional and oncologic outcomes. We reported a large series of RARC and intracorporeal diversion to assess its feasibility and reproducibility. MATERIAL AND METHODS: We identified 101 RARCs in 82 men and 19 women (mean age 68.3 years) from October 2009 to October 2014. The patients underwent RARC and pelvic lymphadenectomy followed by intracorporeal urinary diversion (ileal conduit/ neobladder). Out of the 101 patients, 28 (27.7%) received intracorporeal ileal conduits and 73 (72.3%) intracorporeal neobladders. Studer pouch was performed in all the patients who underwent intracorporeal neobladder formation. Perioperative, functional and oncologic results including CSS and OS are reported. RESULTS: Mean operative time was 402.3 minutes (205-690) and blood loss was 345.3 ml (50-1000). The mean hospital stay was 17.1 days (5-62). All the surgeries were completed with no open conversion. Minor complications (Grade I and II) were reported in 27.7% of patients while major complications (grade III and above) were reported in 36.6% of patients. The mean nodal yield was 20.6 (0 46). Positive ureteric margins were found in 8.9% of patients. The average follow up was 27.5 months (1-52). Daytime continence could be achieved in 89.2% of patients who underwent intracorporeal neobladder. The 3-year cancer specific survival (CSS) and overall survival (OS) was 80.2% and 69.8% respectively. CONCLUSIONS: RARC with intracorporeal diversion is safe and reproducible in 'non pioneer' tertiary centers with robotic expertise having acceptable operative time and complications as well as comparable functional and oncologic outcomes. PMID- 25914834 TI - Perioperative and survival outcomes of laparoscopic radical cystectomy for bladder cancer in patients over 70 years. AB - INTRODUCTION: Radical cystectomy in elderly patients is a controversial issue that has noticed an increase in importance overtime because of the lengthening average life span. Our objective was to determine if there were significant differences in the perioperative outcomes of patients over 70 years with bladder cancer treated with laparoscopic radical cystectomy (LRC) compared to those of younger patients. MATERIAL AND METHODS: We selected 180 patients who underwent LRC in our department in the period between 2005-2012. We divided them into 2 groups: 57% <70 years and 43% >70 years, and we compared the different parameters such as: comorbidities, intraoperative and post-operative complications, TNM stage and overall survival. RESULTS: The group <70 years had less comorbidities when compared with the group >70 years. Heterotopic urinary diversion was the diversion of choice in the elderly patients (97.4%). Paralytic ileus and the worsening of renal function were the only complications with statistical differences between the groups. Mean hospital length of stay was not significantly different between the groups. Younger and older patients had similar pathological staging : pT1 or less: 26,2 vs. 18.2%, pT2: 19.4 vs. 16.9%, pT3 38.8 vs. 37.7% and pT4 15.6 vs. 17.2%. Kaplan-Meier curves did not show significant differences in survival. CONCLUSIONS: Laparoscopic radical cystectomy in the elderly patient has similar rates of perioperative morbidity when compared with the younger patient and may be offered as a treatment option in selected elderly patients. PMID- 25914835 TI - Clinical, demographic and histopathological prognostic factors for urothelial carcinoma of the bladder. AB - INTRODUCTION: Our aim is to evaluate the influence of clinical and histopathological parameters, including age, gender, tumor stage, grade, tumor differentiation, necrosis, lymphovascular/perineural invasion (LVI/PNI) and concomitant carcinoma in situ (CIS), on outcomes of patients with urothelial carcinoma of the bladder (UCB). MATERIAL AND METHODS: A total of 84 patients who underwent radical cystectomy (RC) (n = 11) and radical cystoprostatectomy (n = 73) for muscle-invasive bladder cancer at our hospital between 2007-2013, were included in the study. RESULTS: The mean age of patients at diagnosis was 66.1, of whom 75 were males and 9 were females. Of the 84 patients, 38 were <=65 years and 46 were >65 years. Mean tumor diameter was 3.66 cm. There were 38 cases which showed divergent differentiations. Concomitant CIS was observed in 30 tumors, 41 cases showed tumor necrosis, 44 PNI and 61 LVI. The rate of overall survival (OS) in patients aged <=65 years was statistically significantly higher than in those aged >65 years. A negative statistical relationship was found between OS with lymph node metastasis (LNM) and tumor differentiation. On the other hand, necrosis did not remain significant on multivariate analysis. No statistically significant relationship was found between smoking, tumor stage, PNI, LVI and concomitant CIS and OS. CONCLUSIONS: In this study, advanced age, LNM, tumor differentiation were found to be independent prognostic risk factors associated with OS after RC. These additional factors, which may explain the different clinical course in patients with similar tumor stage and lymph node status, should be taken into consideration in treatment planning. PMID- 25914836 TI - Role of morphometry and proliferative parameters in grading of urothelial neoplasms. AB - INTRODUCTION: Mean nuclear area of 10 nuclei (MNA-10), mitotic activity index (MAI) and Ki-67 are highly reproducible and can be routinely used as adjuncts to histopathological grading in classifying tumors. Assays of these biomarkers are non-invasive, rapid, easy to perform, more objective and accurate, with high sensitivity and specificity, and correlate well with tumor grade. MATERIAL AND METHODS: This study was conducted at the Department of Pathology PGIMS, Rohtak on 50 cases, of which 25 cases were high-grade, 15 low-grade, 6 Papillary Urothelial Neoplasm of Low Malignant Potentialand 4 reactive lesions as per the 2004 ISUP/WHO classification. MNA-10, MAI and Ki-67 immunoquantitation were performed on stained sections. RESULTS: The age of the patients varied from 35 to 87 years. Male: female ratio was 3.5:1. The mean MNA-10 (MUm(2)) for High Grade Malignant Potential was 104.52 +/-25.64 MUm(2), which was significantly higher than in PUNLMP (47.64 +/-10.23) and LMP (51.57 +/-15.66). MAI (/10 HPF) showed an increasing trend from reactive lesions to HMP, with a mean of (3 +/-1.16)/10 HPF to (21.36 +/-5.31)/10 HPF respectively. Ki-67 labelling index, a proliferative marker, revealed increasing trend lowest with reactive lesions (10 +/-2.83%) and highest in high grade tumors (65.96 +/-14.44). Spearman's correlation showed maximum correlation between MAI and Ki-67 and the increasing grade of tumor. CONCLUSIONS: MNA-10 in combination with Ki-67 and MAI was found to be stronger than MNA-10 alone. MAI has high reproducibility in differentiating low and high grade, with simple assessment in paraffin embedded sections allowing adequate histopathological analysis and visualization of proliferating cells simultaneously. This multivariate grading model should be applied in routine grading to overcome interobserver variability and to increase reproducibility of grading. PMID- 25914837 TI - Association of metallothionein expression and clinical response to cisplatin based chemotherapy in testicular germ cell tumors. AB - INTRODUCTION: The protective roles of metallothioneins (MT) against metal toxicity suggest that MT may have a functional role in cisplatin resistance. The aim of this study was to investigate the expression of MT in specimens of germ cell tumors and compare it with clinical sensitivity to cisplatin based chemotherapy. MATERIAL AND METHODS: Tissue blocks of primary GCT specimens obtained from 39 patients were examined immunohistochemically for MT expression. Staining intensity was evaluated according to the percentage of MT positive cells and graded as [-], [+] and [++]. The staining characteristics were compared with the clinical response to chemotherapy. RESULTS: Of the 39 tumors, 3 evidenced no MT expression while 26 and 10 specimens showed [+] and [++] staining, respectively. Although seminomas tend to stain weaker than non-seminomas, the difference of staining between them was not significant (p = 0.19). Of the 39 patients, 23 underwent cisplatin based chemotherapy. Of those, 6 progressed and 17 achieved complete remission. Of the non-responders, 5 showed [+] and 1 showed [++] staining. Six of the responders showed [+], 10 had [++] and 1 showed no staining. No association was found between MT staining and chemo-sensitivity (p = 0.53). CONCLUSIONS: MT expression in primary germ cell tumors did not differ between responding and non-responding patients and therefore may not be useful in predicting response to chemotherapy. PMID- 25914838 TI - The cardiovascular and gastrointestinal adverse effects of cyclooxygenase inhibitors seems to be a major concern that restricts their use in the treatment of urinary bladder dysfunction. PMID- 25914839 TI - Author'S reply. PMID- 25914840 TI - Quality of life related to urinary continence in adult spina bifida patients. AB - INTRODUCTION: To analyze the correlations of bladder management technique, ambulatory status and urologic reconstruction on quality of life (QOL) as affected by urinary symptoms in adult spina bifida (SB) patients. MATERIAL AND METHODS: Sixty-six adult SB patients completed the RAND 36-Item Health Survey (mSF-36) and Incontinence Quality of Life (I-QOL). Demographic information, history of urinary reconstruction, and bladder management techniques were reviewed and analyzed with respect to survey scores. RESULTS: Mean age of patients was 32.3 (SD +/-7.2) years and 44 patients (66.7%) were female. Forty five patients (68.2%) were mainly ambulatory, 21 (31.8%) use a wheelchair and 10 (15.2%) had urologic reconstruction, while 56 (83.3%) did not. Twelve patients (18.2%) void, 42 (63.6%) perform clean intermittent catheterization (CIC), 4 (6.1%) use an indwelling catheter, 3 (4.5%) have an ileal conduit (IC) and 5 (7.6%) mainly use diapers. Mean mSF-36 General Health score was 56.5 (SD +/-22.9) and mean I-QOL Sum score was 50.9 (SD +/-21.7), where lower scores reflect lower QOL. mSF-36 and I-QOL scores did not significantly correlate with bladder management technique, ambulatory status or urologic reconstruction. A correlation was noted between I-QOL scales and most mSF-36 scales (all p <0.02). CONCLUSIONS: In our cohort study of adult SB patients, bladder management technique and urologic reconstruction did not correlate with urinary (I-QOL) or general health (mSF-36) domains, although I-QOL and mSF-36 scores correlated closely, suggesting urinary continence is significantly related to general QOL. However, we are unable to identify a single factor that improves either urinary or general QOL. PMID- 25914841 TI - Mini-slings - an option in stress urinary incontinence treatment. Case studies. AB - INTRODUCTION: Stress urinary incontinence (SUI) is a social disease caused by numerous contributing factors such as natural childbirth, obesity, hormonal deficiencies and changes in collagen fibers, to name a few. Currently, mini slings, among all the surgical treatment methods, have gained significance. The aim of this study was to establish the effectiveness of this method. MATERIAL AND METHODS: From 2008 to 2012, one hundred sixty women suffering from SUI underwent surgical procedures to implant mini-slings under the middle part of the urethra and 140 (87.5%) of them remained under observation. In 65 cases, Johnson & Johnson's TVT-Secur was used; in 70 cases, BARD's Adjust mini-sling was used; and in 5 cases, AMS Mini-Arc mini-sling was used. The average period of hospitalization was 3 days per admission, operation and discharge day. RESULTS: In 82 cases, patients urinated well after the removal of the catheter, and had full urine continence. Fourteen patients showed great improvement, and in four cases temporary urine retention was observed. In two cases vaginal bleeding was observed, yet there was no need for wound revision. Evaluation of the 'quality of life improvement' was done using the Visual Analog Scale (VAS). CONCLUSIONS: The obtained results allowed the conclusion that the implantation of mini-slings is a low invasive, relatively safe and effective procedure for the treatment of SUI even in cases of recurrence. Almost full recovery was achieved in all the cases of this study. The mini-sling has become an important element in modern urogynecology. PMID- 25914842 TI - The histomorphological findings of kidneys after application of high dose and high-energy shock wave lithotripsy. AB - INTRODUCTION: In this animal study, we reviewed the histomorphological findings in rabbit kidneys after a high number of high-energy shock wave applications and observed if there were any cumulative effects after repeated sessions. MATERIAL AND METHODS: We formed 2 groups, each consisting of 8 rabbits. Group 1 received 1 session and group 2 received 3 sessions of ESWL with a 7 day interval between sessions, consisting of 3500 beats to the left kidney and 5500 beats to the right kidney per session. The specimens of kidneys were examined histomorphologically after bilateral nephrectomy was performed. For statistical analysis, 4 groups of specimens were formed. The first and second groups received 1 session, 3500 and 5500 beats, respectively. The third and fourth groups received 3 sessions, at 3500 and 5500 beats per each session, respectively. The sections were evaluated under a light microscope to determine subcapsular thickening; subcapsular, intratubular and parenchymal hemorrhage; subcapsular, intersitital, perivascular and proximal ureteral fibrosis; paranchymal necrosis; tubular epithelial vacuolization; tubular atrophy; glomerular destruction and calcification. RESULTS: In histopathological examinations capsular thickening, subcapsular hematoma, tubuloepithelial vacuolisation, glomerular destruction, parenchymal hemorrhage, interstitial fibrosis, and perivascular fibrosis were observed in all groups. In statistical analysis, on the basis of perivascular fibrosis and tubular atrophy, there was a beats per session dependent increase of both. CONCLUSIONS: The detrimental effects from ESWL are dose dependent but not cumulative for up to 3 sessions. Histopathological experimental animal studies will aid in understanding local and maybe, by means of these local effects, systemic effects. PMID- 25914843 TI - Mechanisms linking obesity to male infertility. AB - INTRODUCTION: Obesity in men is associated with infertility in numerous studies. The current trend for decline in semen parameters parallels the increasing prevalence of obesity worldwide. In addition to impaired semen quality, fertility among obese men may be affected by sexual dysfunction, endocrinopathy, aromatization activity, psychological and thermal effects, sleep apnea, leptin and minor toxins, and possibly the inflammatory and obstructive elements of epididymitis pathology. The variable degrees of certainty associated with these causes parallel the levels of supporting evidence. This search aims to shed lights on different conditions that obese men suffer from; as that makes the treatment of infertility more categorized. MATERIAL AND METHODS: A PubMed search was conducted to identify clinical and pathological mechanisms linking obesity to male infertility. RESULTS: Among the myriad of publications reviewed in this paper, impaired spermatogenesis and sexual dysfunction have been shown to drive other variables towards poor fertility potentials. The paper presented a new, detailed flow chart showing more factors and further interactions among conditions leading to infertility. CONCLUSIONS: The prime hormonal defect in obese men is hypotestosteronaemia, which results in impaired spermatogenesis leading to poor fecundability. Studies have shown that most mechanisms accounting for reduced fertility potentials in overweight men are reversible. PMID- 25914844 TI - Association between pre-biopsy white blood cell count and prostate biopsy - related sepsis. AB - INTRODUCTION: Despite all preventive measures and improved biopsy techniques, serious, life-threatening complications of prostate biopsy, including sepsis, still exist. In the present study, in order to identify the risk factors that may be associated with sepsis development after prostate-biopsy, we aimed to analyze retrospectively the data of our patients who underwent transrectal ultrasound guided prostate biopsy. MATERIAL AND METHODS: We retrospectively reviewed the data of 889 patients who underwent prostate biopsy at our clinic. We compared pre biopsy parameters (age, prostate volume, white blood cell (WBC) count, fasting blood glucose, free and total prostate specific antigen levels) between patients who developed sepsis and those who were sepsis-free following prostate biopsy. RESULTS: 28 patients (3.1%) developed sepsis. Among the risk factors evaluated, only pre-biopsy WBC count was found to be a significant risk factor for biopsy related sepsis. A 5.1 fold increase was detected in the risk for sepsis development, when the cut-off value of WBC was accepted as 11.165/MUL, OR: 5.1 (95% CI: 2.3-11.5). The post-biopsy sepsis development rate in patients with pre biopsy WBC count greater and less than 11.165/MUL was 13.7% (n = 10) and 3% (n = 18) respectively. CONCLUSIONS: Patients with a pre-biopsy WBC count greater than 11.165/MUL should be informed of the increased risk of developing post-biopsy sepsis. PMID- 25914845 TI - The comparison of the influence between two different bowel preparation methods on sepsis after prostate biopsies. AB - INTRODUCTION: Transrectal ultrasonography (TRUS) guided prostate needle biopsy has been performed to diagnose and stage prostate cancer for many years. There are many different bowel preparation protocols to diminish the infectious complications, but there is no standardized consensus among urologists. Therefore, we aimed to assess two different bowel preparation methods on the rate of infectious complications in patients who underwent TRUS-guided prostate biopsy. MATERIAL AND METHODS: A total of 387 cases of TRUS-guided prostate biopsy were included in this retrospective study. All patients received antibiotic prophylaxis with ciprofloxacin (500 mg) twice a day orally for 7 days starting on the day before the biopsy. The patients were divided into two groups according to the bowel preparation method used. Patients (Group 1, n = 164) only received self administrated phosphate enema) on the morning of the prostate biopsy. Other patients (Group 2, n = 223) received sennasoid a-b laxatives the night before the prostate biopsy. Infectious complications were classified as sepsis, fever (greater than 38 degrees C) without sepsis, and other clinical infections. RESULTS: Major complications developed in 14 cases (3.8%), including 3 cases (0.8%) of urinary retention, and 11 (3%) infectious complications, all of which were sepsis. There were 3 and 8 cases of urosepsis in Group 1 and Group 2, respectively. There were no statistically significant differences between both Groups regarding to the rates of urosepsis (p = 0.358). CONCLUSIONS: Despite both methods of bowel preparation, sodium phosphate enema or sennasoid a-b calcium laxatives, before TRUS-guided prostate biopsy have similar effect on the rate of urosepsis, so both methods of bowel preparation can be safely used. PMID- 25914846 TI - Firing at a fly with a shotgun. PMID- 25914847 TI - Urinary tract infections and Candida albicans. AB - INTRODUCTION: Urinary tract candidiasis is known as the most frequent nosocomial fungal infection worldwide. Candida albicans is the most common cause of nosocomial fungal urinary tract infections; however, a rapid change in the distribution of Candida species is undergoing. Simultaneously, the increase of urinary tract candidiasis has led to the appearance of antifungal resistant Candida species. In this review, we have an in depth look into Candida albicans uropathogenesis and distribution of the three most frequent Candida species contributing to urinary tract candidiasis in different countries around the world. MATERIAL AND METHODS: For writing this review, Google Scholar -a scholarly search engine- (http://scholar.google.com/) and PubMed database (http://www.ncbi.nlm.nih.gov/pubmed/) were used. The most recently published original articles and reviews of literature relating to the first three Candida species causing urinary tract infections in different countries and the pathogenicity of Candida albicans were selected and studied. RESULTS: Although some studies show rapid changes in the uropathogenesis of Candida species causing urinary tract infections in some countries, Candida albicans is still the most important cause of candidal urinary tract infections. CONCLUSIONS: Despite the ranking of Candida albicans as the dominant species for urinary tract candidiasis, specific changes have occurred in some countries. At this time, it is important to continue the surveillance related to Candida species causing urinary tract infections to prevent, control and treat urinary tract candidiasis in future. PMID- 25914848 TI - A new corporoplasty based on stratified structure of tunica albuginea for the treatment of congenital penile curvature - long-term results. AB - INTRODUCTION: The aim of the study was to report long-term results of treatment of patients with congenital penile curvature (CPC) with a new corporoplasty based on stratified structure of tunica albuginea, in which corporal bodies are not opened. MATERIAL AND METHODS: From October 2006 to September 2013, the authors operated on 111 adult men with CPC. Ventral curvature was detected in 65 patients, lateral in 34, and dorsal in 12. Skin was incised longitudinally on convex surface of curvature. In ventral curvature, dorsal neuro-vascular bundles (NVBs) were separated from tunica albuginea and elliptical fragments of external (longitudinal) layer of tunica were excised. The tunica was sutured with absorbable sutures, which invaginated the internal (transversal) layer of tunica. In dorsal curvature, excisions were performed on both sides of the urethra, in lateral curvature - on the convex penile surface. RESULTS: Follow-up period was from 12 to 84 months. The penis was completely straight in 109 out of 111 patients. In 2 patients (1.8%) recurrent curvature of up to 20 degrees was detected. Redo surgery was done in one individual (0.9%) at patient's request. Glandular sensation loss or erectile dysfunction was not detected in any patient during the period of observation. CONCLUSIONS: A new operation for correction of CPC, which consists of excision of an elliptical fragment of the external layer of the tunica albuginea and plication of the internal layer gives good short and long-term results. Surgery done without penetrating the corpora cavernosa is minimally invasive, which diminishes the potential risk of complications, especially intra- and postoperative bleeding. PMID- 25914849 TI - Artificial urinary conduit construction using tissue engineering methods. AB - INTRODUCTION: Incontinent urinary diversion using an ileal conduit is the most popular method used by urologists after bladder cystectomy resulting from muscle invasive bladder cancer. The use of gastrointestinal tissue is related to a series of complications with the necessity of surgical procedure extension which increases the time of surgery. Regenerative medicine together with tissue engineering techniques gives hope for artificial urinary conduit construction de novo without affecting the ileum. MATERIAL AND METHODS: In this review we analyzed history of urinary diversion together with current attempts in urinary conduit construction using tissue engineering methods. Based on literature and our own experience we presented future perspectives related to the artificial urinary conduit construction. RESULTS: A small number of papers in the field of tissue engineered urinary conduit construction indicates that this topic requires more attention. Three main factors can be distinguished to resolve this topic: proper scaffold construction along with proper regeneration of both the urothelium and smooth muscle layers. CONCLUSIONS: Artificial urinary conduit has a great chance to become the first commercially available product in urology constructed by regenerative medicine methods. PMID- 25914850 TI - Bone marrow derived cells facilitate urinary bladder regeneration by attenuating tissue inflammatory responses. AB - INTRODUCTION: Inflammatory responses following tissue injury are essential for proper tissue regeneration. However, dysfunctional or repetitive inflammatory tissue assaults can lead to poor tissue regeneration and ultimate tissue failure via fibrosis. Previous attempts at urinary bladder tissue regeneration utilizing polymeric and biologic scaffolding materials tended to elicit these responses leading to poor tissue regeneration. Recent advances in bladder regeneration utilizing bone marrow derived mesenchymal stem cells (MSCs) and CD34(+) hematopoietic stem/progenitor cells (HSPCs) with biocompatible citric acid based scaffolds have provided an environment that not only promotes the growth of architecturally germane and physiologically functional tissue, but also modulates aspects of the innate immune response. MATERIAL AND METHODS: Within this study MSCs, CD34(+) HSPCs, or MSC/CD34(+) HSPC seeded POC [poly (1,8-octanediol-co citrate)] scaffolds were utilized in an established rodent bladder augmentation model to evaluate inflammation as it pertains to bladder tissue regeneration. RESULTS: Quantified data from post-augmentation regenerated tissue samples at the 4 week time-point demonstrated that POC/MSC and POC/MSC + CD34(+) HSPC grafts markedly reduced the presence of pro-inflammatory CD68(+) macrophages and MPO(+) neutrophils compared to unseeded POC or POC/CD34(+) HSPC-only seeded grafts. Pro inflammatory cytokines TNFalpha and IL-1b were also significantly down-regulated with a concomitant increase in the anti-inflammatory cytokines IL-10 and IL-13 in the aforementioned POC/MSC and POC/MSC + CD34(+) HSPC composites. Furthermore, this led to fewer instances of bladder tissue granuloma formation combined with greater muscle content and tissue angiogenic events as previous data has demonstrated. CONCLUSIONS: Data indicates that POC/MSC and POC/MSC + CD34(+) HSPC grafts attenuate the innate inflammatory response and promote bladder tissue regeneration. PMID- 25914851 TI - Intermittent hyperammonemic encephalopathy after ureterosigmoidostomy: spontaneous onset in the absence of hepatic failure. AB - Intermittent hyperammonemic encephalopathy after ureterosigmoidostomy is a rare, but if unrecognized, potentially lethal condition. Ureterosigmoidostomy was performed in a male patient with bladder extrophy. After 35 years, he developed hyperammonemic encephalopathy. Diagnostic procedures did not reveal hepatic nor metabolic disorders. Despite administration of preventive medical treatment, several episodes recurred. A durable prevention was finally achieved by conversion into an ileal conduit. Intermittent hyperammonemic encephalopathy can occur decades after ureterosigmoidostomy. In the case of absence of metabolic disorders and resistance to medical treatment, conversion into a urinary diversion using an ileal segment constitutes an effective ultima ratio. PMID- 25914852 TI - AUTONOMY AND RELATEDNESS IN MOTHER-TEEN INTERACTIONS AS PREDICTORS OF INVOLVEMENT IN ADOLESCENT DATING AGGRESSION. AB - OBJECTIVE: This multi-method, longitudinal study examines the negotiation of autonomy and relatedness between teens and their mothers as etiologic predictors of perpetration and victimization of dating aggression two years later. METHOD: Observations of 88 mid-adolescents and their mothers discussing a topic of disagreement were coded for each individual's demonstrations of autonomy and relatedness using a validated coding system. Adolescents self-reported on perpetration and victimization of physical and psychological dating aggression two years later. We hypothesized that mother's and adolescents' behaviors supporting autonomy and relatedness would longitudinally predict lower reporting of dating aggression, and that their behaviors inhibiting autonomy and relatedness would predict higher reporting of dating aggression. RESULTS: Hypotheses were not supported; main findings were characterized by interactions of sex and risk status with autonomy. Maternal behaviors supporting autonomy predicted higher reports of perpetration and victimization of physical dating aggression for girls, but not for boys. Adolescent behaviors supporting autonomy predicted higher reports of perpetration of physical dating aggression for high risk adolescents, but not for low-risk adolescents. CONCLUSIONS: Results indicate that autonomy is a dynamic developmental process, operating differently as a function of social contexts in predicting dating aggression. Examination of these and other developmental processes within parent-child relationships is important in predicting dating aggression, but may depend on social context. PMID- 25914853 TI - Why the Shift? Taking a Closer Look at the Growing Interest in Niche Markets and Personalized Medicine. AB - Pharmaceutical research and development is increasingly focused on niche markets, most notably treatments for rare diseases and "personalized" medicine. Drawing on the results of a qualitative study of 34 key Canadian stakeholders (including drug regulators, funders, scientists, policy experts, pharmaceutical industry representatives, and patient advocates), we explore the major trends that are reportedly contributing to the growing interest of the pharmaceutical industry in niche markets. Informed by both these key informant interviews and a review of the relevant literature, our paper provides a critical analysis of the many different-and sometimes conflicting-views on the reasons for and extent of the shift toward niche markets. We consider some of the potential advantages to industry, as well the important implications and risks that arise from the increasing pursuit of niche markets and pharmacogenomics. While there are many potential benefits associated with targeted therapies and drug development for historically neglected rare diseases, niche market therapies also present evidentiary challenges (e.g., smaller clinical trials and enrichment strategies) that can make approval decisions difficult, and uncertainties remain around the true benefits of many therapies. PMID- 25914854 TI - Who Provides Primary Care? An Assessment of HIV Patient and Provider Practices and Preferences. AB - BACKGROUND: Non-AIDS co-morbidities are emerging as the main health problems for those living with HIV, and primary care for this population is an evolving challenge. Recent studies have raised the question of whether specialists or generalists are best suited to provide HIV primary care, but patients' actual usage patterns and the preferences of patients and providers have not been well studied. METHODS: We anonymously surveyed 98 patients and eight HIV-specialized providers regarding primary care usage patterns and preferences at an academic HIV clinic in Los Angeles that serves insured patients. RESULTS: Fifty-nine percent of patients use their HIV physician as their primary care provider, and 84% would prefer this model. Physicians were divided on their preferred role, with five out of eight desiring to provide both primary care and HIV care. All eight physicians rated their comfort with antiretroviral therapy and opportunistic infections greater than for non-AIDS co-morbidities. Eighty-one percent of patients and seven of eight providers were supportive of having a co located primary care physician at the HIV clinic. CONCLUSIONS: We conclude that patients prefer integration of HIV and primary care, but providers have variable desire to serve as primary care physicians and may be uncomfortable with non-AIDS co-morbidities. This raises the need for improved patient-provider communication about primary care needs, and calls for novel ways of systematically providing primary care to HIV-infected patients. PMID- 25914855 TI - Marital Processes around Depression: A Gendered and Relational Perspective. AB - Despite extensive evidence of the importance of marriage and marital processes for mental health, little is known about the interpersonal processes around depression within marriage and the extent to which these processes are gendered. We use a mixed methods approach to explore the importance of gender in shaping processes around depression within marriage; we approach this in two ways. First, using quantitative longitudinal analysis of 2,601 couples from the Health and Retirement Study (HRS), we address whether depressive symptoms in one spouse shape the other spouse's depressive symptoms and whether men or women are more influential in this process. We find that a wife's depressive symptoms influence her husband's future depressive symptoms but a husband's depressive symptoms do not influence his wife's future symptoms. Second, we conduct a qualitative analysis of in-depth interviews with 29 couples wherein one or both spouses experienced depression to provide additional insight into how gender impacts depression and reactions to depression within marriage. Our study points to the importance of cultural scripts of masculinity and femininity in shaping depression and emotional processes within marriage and highlights the importance of applying a gendered couple-level approach to better understand the mental health effects of marital processes. PMID- 25914856 TI - The Ratio of Emergency Department Visits for ILI to Seroprevalence of 2009 Pandemic Influenza A (H1N1) Virus Infection, Florida, 2009. AB - BACKGROUND: A seroprevalence survey carried out in four counties in the Tampa Bay area of Florida provided an estimate of cumulative incidence of infection due to the 2009 influenza A (H1N1) as of the end of that year's pandemic in the four counties from which seroprevalence data were obtained Methods. Excess emergency department (ED) visits for influenza-like illness (ILI) during the pandemic period (compared to four non-pandemic years) were estimated using the ESSENCE-FL syndromic surveillance system for the four-county area. RESULTS: There were an estimated 44 infections for every ILI ED visit. Age-specific ratios rose from 19.7 to 1 for children aged <5 years to 143.8 to 1 for persons aged >64 years. CONCLUSIONS: These ratios provide a way to estimate cumulative incidence. These estimated ratios can be used in real time for planning and forecasting, when carrying out timely seroprevalence surveys is not practical. Syndromic surveillance data allow age and geographic breakdowns, including for children. PMID- 25914857 TI - Towards an early warning system for forecasting human west nile virus incidence. AB - We have identified environmental and demographic variables, available in January, that predict the relative magnitude and spatial distribution of West Nile virus (WNV) for the following summer. The yearly magnitude and spatial distribution for WNV incidence in humans in the United States (US) have varied wildly in the past decade. Mosquito control measures are expensive and having better estimates of the expected relative size of a future WNV outbreak can help in planning for the mitigation efforts and costs. West Nile virus is spread primarily between mosquitoes and birds; humans are an incidental host. Previous efforts have demonstrated a strong correlation between environmental factors and the incidence of WNV. A predictive model for human cases must include both the environmental factors for the mosquito-bird epidemic and an anthropological model for the risk of humans being bitten by a mosquito. Using weather data and demographic data available in January for every county in the US, we use logistic regression analysis to predict the probability that the county will have at least one WNV case the following summer. We validate our approach and the spatial and temporal WNV incidence in the US from 2005 to 2013. The methodology was applied to forecast the 2014 WNV incidence in late January 2014. We find the most significant predictors for a county to have a case of WNV to be the mean minimum temperature in January, the deviation of this minimum temperature from the expected minimum temperature, the total population of the county, publicly available samples of local bird populations, and if the county had a case of WNV the previous year. PMID- 25914858 TI - Phylodynamic analysis of ebola virus in the 2014 sierra leone epidemic. AB - BACKGROUND: The Ebola virus (EBOV) epidemic in Western Africa is the largest in recorded history and control efforts have so far failed to stem the rapid growth in the number of infections. Mathematical models serve a key role in estimating epidemic growth rates and the reproduction number (R0) from surveillance data and, recently, molecular sequence data. Phylodynamic analysis of existing EBOV time-stamped sequence data may provide independent estimates of the unobserved number of infections, reveal recent epidemiological history, and provide insight into selective pressures acting upon viral genes. METHODS: We fit a series mathematical models of infectious disease dynamics to phylogenies estimated from 78 whole EBOV genomes collected from distinct patients in May and June of 2014 in Sierra Leone, and perform evolutionary analysis on these genomes combined with closely related EBOV genomes from previous outbreaks. Two analyses are conducted with values of the latent period that have been used in recent modelling efforts. We also examined the EBOV sequences for evidence of possible episodic adaptive molecular evolution during the 2014 outbreak. RESULTS: We find evidence for adaptive evolution affecting L and GP protein coding regions of the EBOV genome, which is unlikely to bias molecular clock and phylodynamic analyses. We estimate R0=2.40 (95% HPD:1.54-3.87 ) if the mean latent period is 5.3 days, and R0=3.81, (95% HPD:2.47-6.3) if the mean latent period is 12.7 days. The estimated coefficient of variation (CV) of the number of transmissions per infected host is very high, and a large proportion of infections yield no transmissions. CONCLUSIONS: Estimates of R0 are sensitive to the unknown latent infectious period which can not be reliably estimated from genetic data alone. EBOV phylogenies show significant evidence for superspreading and extreme variance in the number of transmissions per infected individual during the early epidemic in Sierra Leone. PMID- 25914859 TI - Modeling the impact of interventions on an epidemic of ebola in sierra leone and liberia. AB - BACKGROUND: An Ebola outbreak of unparalleled size is currently affecting several countries in West Africa, and international efforts to control the outbreak are underway. However, the efficacy of these interventions, and their likely impact on an Ebola epidemic of this size, is unknown. Forecasting and simulation of these interventions may inform public health efforts. METHODS: We use existing data from Liberia and Sierra Leone to parameterize a mathematical model of Ebola and use this model to forecast the progression of the epidemic, as well as the efficacy of several interventions, including increased contact tracing, improved infection control practices, the use of a hypothetical pharmaceutical intervention to improve survival in hospitalized patients. FINDINGS: Model forecasts until Dec. 31, 2014 show an increasingly severe epidemic with no sign of having reached a peak. Modeling results suggest that increased contact tracing, improved infection control, or a combination of the two can have a substantial impact on the number of Ebola cases, but these interventions are not sufficient to halt the progress of the epidemic. The hypothetical pharmaceutical intervention, while impacting mortality, had a smaller effect on the forecasted trajectory of the epidemic. INTERPRETATION: Near-term, practical interventions to address the ongoing Ebola epidemic may have a beneficial impact on public health, but they will not result in the immediate halting, or even obvious slowing of the epidemic. A long-term commitment of resources and support will be necessary to address the outbreak. PMID- 25914860 TI - Public knowledge, perception and source of information on ebola virus disease - lagos, Nigeria; september, 2014. AB - BACKGROUND: The first ever outbreak of Ebola virus disease (EVD) in Nigeria was declared in July, 2014. Level of public knowledge, perception and adequacy of information on EVD were unknown. We assessed the public preparedness level to adopt disease preventive behavior which is premised on appropriate knowledge, perception and adequate information. METHODS: We enrolled 5,322 respondents in a community-based cross-sectional study. We used interviewer-administered questionnaire to collect data on socio-demographic characteristics, EVD-related knowledge, perception and source of information. We performed univariate and bivariate data analysis using Epi-Info software setting p-value of 0.05 as cut off for statistical significance. RESULTS: Mean age of respondents was 34 years (+/- 11.4 years), 52.3% were males. Forty one percent possessed satisfactory general knowledge; 44% and 43.1% possessed satisfactory knowledge on mode of spread and preventive measures, respectively. Residing in EVD cases districts, male respondents and possessing at least secondary education were positively associated with satisfactory general knowledge (p-value: 0.01, 0.001 and 0.000004, respectively). Seventy one percent perceived EVD as a public health problem while 61% believed they cannot contract the disease. Sixty two percent and 64% of respondents will not shake hands and hug a successfully treated EVD patient respectively. Only 2.2% of respondents practice good hand-washing practice. Television (68.8%) and radio (55.0%) are the most common sources of information on EVD. CONCLUSIONS: Gaps in EVD-related knowledge and perception exist. Targeted public health messages to raise knowledge level, correct misconception and discourage stigmatization should be widely disseminated, with television and radio as media of choice. PMID- 25914861 TI - APPLYING MACHINE LEARNING TECHNIQUES IN DETECTING BACTERIAL VAGINOSIS. AB - There are several diseases which arise because of changes in the microbial communities in the body. Scientists continue to conduct research in a quest to find the catalysts that provoke these changes in the naturally occurring microbiota. Bacterial Vaginosis (BV) is a disease that fits the above criteria. BV afflicts approximately 29% of women in child bearing age. Unfortunately, its causes are unknown. This paper seeks to uncover the most important features for diagnosis and in turn employ classification algorithms on those features. In order to fulfill our purpose, we conducted two experiments on the data. We isolated the clinical and medical features from the full set of raw data, we compared the accuracy, precision, recall and F-measure and time elapsed for each feature selection and classification grouping. We noticed that classification results were as good or better after performing feature selection although there was a wide range in the number of features produced from the feature selection process. After comparing the experiments, the algorithms performed best on the medical dataset. PMID- 25914862 TI - Unleashing the immune system: PD-1 and PD-Ls in the pre-treatment tumor microenvironment and correlation with response to PD-1/PD-L1 blockade. AB - Focal tumor cell PD-L1 expression adjacent to TIL can be used as a surrogate marker of an ongoing antitumor host response, which may be unleashed by PD-1 blockade. Tumor cell PD-L1 expression is superior to TIL PD-1 expression and the presence of TIL alone, when predicting response to anti-PD-1 therapy. PMID- 25914863 TI - Child disaster mental health interventions, part I: Techniques, outcomes, and methodological considerations. AB - This review of child disaster mental health intervention studies describes the techniques used in the interventions and the outcomes addressed, and it provides a preliminary evaluation of the field. The interventions reviewed here used a variety of strategies such as cognitive behavioral approaches, exposure and narrative techniques, relaxation, coping skill development, social support, psychoeducation, eye movement desensitization and reprocessing, and debriefing. A diagnosis of posttraumatic stress disorder (PTSD) and/or posttraumatic stress reactions were the most commonly addressed outcomes although other reactions such as depression, anxiety, behavior problems, fear, and/or traumatic grief also were examined. Recommendations for future research are outlined. PMID- 25914864 TI - Near Real-Time Computer Assisted Surgery for Brain Shift Correction Using Biomechanical Models. AB - Conventional image-guided neurosurgery relies on preoperative images to provide surgical navigational information and visualization. However, these images are no longer accurate once the skull has been opened and brain shift occurs. To account for changes in the shape of the brain caused by mechanical (e.g., gravity-induced deformations) and physiological effects (e.g., hyperosmotic drug-induced shrinking, or edema-induced swelling), updated images of the brain must be provided to the neuronavigation system in a timely manner for practical use in the operating room. In this paper, a novel preoperative and intraoperative computational processing pipeline for near real-time brain shift correction in the operating room was developed to automate and simplify the processing steps. Preoperatively, a computer model of the patient's brain with a subsequent atlas of potential deformations due to surgery is generated from diagnostic image volumes. In the case of interim gross changes between diagnosis, and surgery when reimaging is necessary, our preoperative pipeline can be generated within one day of surgery. Intraoperatively, sparse data measuring the cortical brain surface is collected using an optically tracked portable laser range scanner. These data are then used to guide an inverse modeling framework whereby full volumetric brain deformations are reconstructed from precomputed atlas solutions to rapidly match intraoperative cortical surface shift measurements. Once complete, the volumetric displacement field is used to update, i.e., deform, preoperative brain images to their intraoperative shifted state. In this paper, five surgical cases were analyzed with respect to the computational pipeline and workflow timing. With respect to postcortical surface data acquisition, the approximate execution time was 4.5 min. The total update process which included positioning the scanner, data acquisition, inverse model processing, and image deforming was ~11-13 min. In addition, easily implemented hardware, software, and workflow processes were identified for improved performance in the near future. PMID- 25914865 TI - Judgments of Learning are Influenced by Multiple Cues In Addition to Memory for Past Test Accuracy. AB - When people try to learn new information (e.g., in a school setting), they often have multiple opportunities to study the material. One of the most important things to know is whether people adjust their study behavior on the basis of past success so as to increase their overall level of learning (for example, by emphasizing information they have not yet learned). Monitoring their learning is a key part of being able to make those kinds of adjustments. We used a recognition memory task to replicate prior research showing that memory for past test outcomes influences later monitoring, as measured by judgments of learning (JOLs; confidence that the material has been learned), but also to show that subjective confidence in whether the test answer and the amount of time taken to restudy the items also have independent effects on JOLs. We also show that there are individual differences in the effects of test accuracy and test confidence on JOLs, showing that some but not all people use past test experiences to guide monitoring of their new learning. Monitoring learning is therefore a complex process of considering multiple cues, and some people attend to those cues more effectively than others. Improving the quality of monitoring performance and learning could lead to better study behaviors and better learning. An individual's memory of past test performance (MPT) is often cited as the primary cue for judgments of learning (JOLs) following test experience during multi-trial learning tasks (Finn & Metcalfe, 2007; 2008). We used an associative recognition task to evaluate MPT-related phenomena, because performance monitoring, as measured by recognition test confidence judgments (CJs), is fallible and varies in accuracy across persons. The current study used multilevel regression models to show the simultaneous and independent influences of multiple cues on Trial 2 JOLs, in addition to performance accuracy (the typical measure of MPT in cued recall experiments). These cues include recognition CJs, perceived recognition fluency, and Trial 2 study time allocation (an index of reprocessing fluency). Our results expand the scope of MPT-related phenomena in recognition memory testing to show independent effects of recognition test accuracy and CJs on second-trial JOLs, while also demonstrating individual differences in the effects of these cues on JOLs (as manifested in significant random effects for those regression effects in the model). The effect of study time on second-trial JOLs controlling on other variables, including Trial 1 recognition memory accuracy, also demonstrates that second-trial encoding behavior influence JOLs in addition to MPT. PMID- 25914867 TI - A note on the control function approach with an instrumental variable and a binary outcome. AB - Unobserved confounding is a well known threat to causal inference in non experimental studies. The instrumental variable design can under certain conditions be used to recover an unbiased estimator of a treatment effect even if unobserved confounding cannot be ruled out with certainty. For continuous outcomes, two stage least squares is the most common instrumental variable estimator used in epidemiologic applications. For a rare binary outcome, an analogous linear-logistic two-stage procedure can be used. Alternatively, a control function approach is sometimes used which entails entering the residual from the first stage linear model as a covariate in a second stage logistic regression of the outcome on the treatment. Both strategies for binary response have previously formally been justified only for continuous exposure, which has impeded widespread use of the approach outside of this setting. In this note, we consider the important setting of binary exposure in the context of a binary outcome. We provide an alternative motivation for the control function approach which is appropriate for binary exposure, thus establishing simple conditions under which the approach may be used for instrumental variable estimation when the outcome is rare. In the proposed approach, the first stage regression involves a logistic model of the exposure conditional on the instrumental variable, and the second stage regression is a logistic regression of the outcome on the exposure adjusting for the first stage residual. In the event of a non rare outcome, we recommend replacing the second stage logistic model with a risk ratio regression. PMID- 25914866 TI - Cognitive impairment in first-episode mania: a systematic review of the evidence in the acute and remission phases of the illness. AB - There is evidence of cognitive impairment that persists in the remission phase of bipolar disorder; however, the extent of the deficits that occur from the first onset of the disorder remains unclear. This is the first systematic review on cognitive functioning in the early stages of bipolar I disorder. The aim of the study was to identify the patterns and degree of cognitive impairment that exists from first-episode mania. Three electronic databases (MEDLINE, PsycINFO and PubMed) were systematically searched for studies published from January 1980 to June 2014. Eligible studies were separated into two groups: acute and remission. The Newcastle-Ottawa quality assessment scale was utilised to measure the quality of the included studies. A total of seven studies (three acute and four remission), including 230 first-episode mania and 345 healthy control participants, were eligible for the review. The studies in the acute phase only examined aspects of executive functioning, with impairments identified in cognitive flexibility, though not in response inhibition and verbal fluency relative to healthy controls. The most consistent finding during the remission phase was a deficit in working memory, whereas in the other domains, the findings were equivocal. Non-verbal memory and verbal fluency were not impacted in remission from first-episode mania. In conclusion, deficits are present in some but not all areas of cognitive functioning during the early stages of bipolar I disorder. Further research is warranted to understand the longitudinal trajectory of change from first-episode mania. PMID- 25914868 TI - Quantitative detection of Staphylococcus aureus, Streptococcus pneumoniae and Haemophilus influenzae in patients with new influenza A (H1N1)/2009 and influenza A/2010 virus infection. AB - INTRODUCTION: Viral influenza is a seasonal infection associated with significant morbidity and mortality. In the United States more than 35,000 deaths and 200,000 hospitalizations are recorded annually due to influenza. Secondary bacterial infections or co-infections associated with cases of influenza are a leading cause of severe morbidity and mortality, especially among high-risk groups such as the elderly and young children. AIM: The aim of the present study was the quantitative detection of S. aureus, S. pneumoniae and H. influenzae in a group of patients with seasonal influenza A, influenza A (H1N1) pandemic 2009, and patients with symptoms of respiratory infection, but the negative for H1N1 serving as control group. METHOD: In total, 625 patients suspected respiratory infection from April 2009 to April 2010 were studied. There were 58 patients with influenza A H1N1 and 567 patients negative for influenza A H1N1. From November 2010 to February 2011, 158 patients with respiratory symptoms were analyzed for seasonal influenza A. There were 25 patients with seasonal influenza A. To check the colonization status among the healthy individuals 62 healthy persons were further investigated. Individual were screened in parallel. The choices of special genes were amplified from clinical specimens using real-time PCR with a cutoff of 10(4) CFU/mL to differentiate colonization from infection in respiratory tract. RESULTS: S. aureus, S. pneumoniae and H. influenzae were detected in 12%, 26% and 33% of patients with H1N1, while the corresponding figures were 9%, 19%, and 31% for H1N1 negative patients. Among patients with seasonal influenza A 12% S. aureus, 24% S. pneumoniae, and 32% H. influenzae co infections were detected, while influenza negative control group yielded 5% S. aureus, 11% S. pneumoniae, and 10% H. influenzae, respectively. CONCLUSION: The results of this study indicated that the serotype of pandemic H1N1 2009 did not increase incidence of secondary infection with S. aureus, S. pneumoniae and H. influenzae. Quantitative detection of secondary bacterial infection by QR-PCR can help us for distinguishing colonization from infection and controlling misuse of antibiotics and bacterial drug resistances. PMID- 25914869 TI - Substituent Effects in pi-Stacking of Histidine on Functionalized-SWNT and Graphene. AB - Adsorptions of histidine on the functionalized (10,0) single-walled carbon nanotube (SWNT) and graphene were investigated using density function theory methods, M05-2x and DFT-D. The results show that the binding of the histidine ring to the functionalized SWNT is weaker than that to the pristine SWNT for both singlet and triplet complexes, regardless of the electron-donating (-OH, -NH2) or electron-withdrawing (-COOH) character and their attached sites. The present decreased binding is opposite to the well-known enhanced binding in the substituted benzene dimers. Since the atoms of the histidine are distant from the substituent atoms by over 6A, there would be no direct interaction between histidine and the substituent as in the case of the substituted benzene systems. The decreased binding can be mainly driven by the aromaticity of the functionalized SWNT. The nucleus-independent chemical shift (NICS) index analysis for the functionalized SWNTs in deed shows that local aromaticity of SWNT is decreased because of the electron redistribution induced by functional groups, and the pi-pi stacking between the histidine ring and functionalized-SWNT is therefore decreased as compared to the pristine SWNT. However, the above trend does not remain for the binding between the histidine and graphene. The binding of the histidine to the functionalized graphene with -OH and -NH2 is just slightly weaker than that to the pristine graphene, while its binding to COOH SWNT becomes a little bit stronger. PMID- 25914870 TI - Favorable Levels of All Major Cardiovascular Risk Factors at Younger Ages and High-Sensitivity C-Reactive Protein 39 Years Later -The Chicago Healthy Aging Study. AB - OBJECTIVES: Examine associations of favorable levels of all cardiovascular disease (CVD) risk factors (RFs) [i.e., low risk (LR)] at younger ages with high sensitivity C-reactive protein (hs-CRP) at older ages. METHODS: There were 1,324 participants ages 65-84 years with hs-CRP <= 10mg/l from the Chicago Healthy Aging Study (2007-2010), CVD RFs assessed at baseline (1967-73) and 39 years later. LR was defined as untreated blood pressure (BP) <=120/<=80 mmHg, untreated serum total cholesterol <200 mg/dL, body mass index (BMI) <25 kg/m2, not smoking, no diabetes. Hs-CRP was natural log-transformed or dichotomized as elevated (>=3 mg/l or >=2 mg/l) vs. otherwise. RESULTS: With multivariable adjustment, the odds ratios (95% confidence intervals) for follow-up hs-CRP >=3 mg/ in participants with baseline 0RF, 1RF and 2+RFs compared to those with baseline LR were 1.35 (0.89-2.03), 1.61(1.08-2.40) and 1.69(1.04-2.75), respectively. There was also a graded, direct association across four categories of RF groups with follow-up hs CRP levels (beta coefficient/P-trend = 0.18/0.014). Associations were mainly due to baseline smoking and BMI, independent of 39-year change in BMI levels. Similar trends were observed in gender-specific analyses. CONCLUSIONS: Favorable levels of all CVD RFs in younger age are associated with lower hs-CRP level in older age. PMID- 25914871 TI - Stabilization of bone marrow infiltration by metastatic breast cancer with continuous doxorubicin. AB - Complete bone marrow infiltration with profound pancytopenia is very uncommon in breast cancer. Bone marrow metastasis can frequently occur following development of metastatic breast cancer. However, bone marrow failure as the herald of this disease is not typically seen. Very limited data exists as to the safest and most efficacious manner to treat patients with profound pancytopenia due to metastatic solid tumor involvement. In this case, the patient's thrombocytopenia was particularly worrisome, requiring daily platelet transfusions. There was also concern that cytotoxic chemotherapy would exacerbate the patient's thrombocytopenia and increase bleeding risk. The patient's dramatic response to chemotherapy with full platelet recovery is also highly unusual. For our patient, continuous doxorubicin successfully "unpacked" the bone marrow despite a low baseline platelet level, and without increasing the need for more frequent platelet transfusion or risk of catastrophic bleeding. Given the rarity of this presentation, it is currently unknown if the majority of similar patients experience near full recovery of hematopoietic function after initiation of appropriate systemic treatment for metastatic disease. PMID- 25914872 TI - Randomized Controlled Trial of the Combined Effects of Web and Quitline Interventions for Smokeless Tobacco Cessation. AB - BACKGROUND: Use of smokeless tobacco (moist snuff and chewing tobacco) is a significant public health problem but smokeless tobacco users have few resources to help them quit. Web programs and telephone-based programs (Quitlines) have been shown to be effective for smoking cessation. We evaluate the effectiveness of a Web program, a Quitline, and the combination of the two for smokeless users recruited via the Web. OBJECTIVES: To test whether offering both a Web and Quitline intervention for smokeless tobacco users results in significantly better long-term tobacco abstinence outcomes than offering either intervention alone; to test whether the offer of Web or Quitline results in better outcome than a self help manual only Control condition; and to report the usage and satisfaction of the interventions when offered alone or combined. METHODS: Smokeless tobacco users (N= 1,683) wanting to quit were recruited online and randomly offered one of four treatment conditions in a 2*2 design: Web Only, Quitline Only, Web + Quitline, and Control (printed self-help guide). Point-prevalence all tobacco abstinence was assessed at 3- and 6-months post enrollment. RESULTS: 69% of participants completed both the 3- and 6-month assessments. There was no significant additive or synergistic effect of combining the two interventions for Complete Case or the more rigorous Intent To Treat (ITT) analyses. Significant simple effects were detected, individually the interventions were more efficacious than the control in achieving repeated 7-day point prevalence all tobacco abstinence: Web (ITT, OR = 1.41, 95% CI = 1.03, 1.94, p = .033) and Quitline (ITT: OR = 1.54, 95% CI = 1.13, 2.11, p = .007). Participants were more likely to complete a Quitline call when offered only the Quitline intervention (OR = 0.71, 95% CI = .054, .093, p = .013), the number of website visits and duration did not differ when offered alone or in combination with Quitline. Rates of program helpfulness (p <.05) and satisfaction (p <.05) were higher for those offered both interventions versus offered only quitline. CONCLUSION: Combining Web and Quitline interventions did not result in additive or synergistic effects, as have been found for smoking. Both interventions were more effective than a self-help control condition in helping motivated smokeless tobacco users quit tobacco. Intervention usage and satisfaction were related to the amount intervention content offered. Usage of the Quitline intervention decreased when offered in combination, though rates of helpfulness and recommendations were higher when offered in combination. TRIAL REGISTRATION: Clinicaltrials.gov NCT00820495; http://clinicaltrials.gov/ct2/show/NCT00820495. PMID- 25914873 TI - Use of fluorescent ANTS to examine the BBB-permeability of polysaccharide. AB - Recently, some polysaccharides showed therapeutic potentials for the treatment of neurodegenerative diseases while the most important property, their permeability to the blood brain barrier (BBB) that sheathes the brain and spinal cord, is not yet determined. The determination has been delayed by the difficulty in tracking a target polysaccharide among endogenous polysaccharides in animal. We developed an easy way to examine the BBB-permeability and, possibly, tissue distribution of a target polysaccharide in animal. We tagged a polysaccharide with fluorescent 8 aminonaphthalene-1,3,6-trisulfonic acid disodium salt (ANTS) for tracking. We also developed a simple method to separate ANTS-tagged polysaccharide from unconjugated free ANTS using 75% ethanol. After ANTS-polysaccharide was intra nasally administered into animals, we could quantify the amounts of ANTS polysaccharide in the brain and the serum by fluorocytometry. We could also separate free ANTS-polysaccharide from serum proteins using trichloroacetic acid (TCA) and 75% ethanol. Our method will help to track a polysaccharide in animal easily. ANTS-labeling is less tedious than but as powerful as radiolabeling for tracking a target polysaccharide in animal.Our simple method can separate structurally intact ANTS-polysaccharide from animal serum and tissues.This method is good for the fluorometry-based measurement of ANTS-conjugated macromolecules in tissues. PMID- 25914874 TI - Dendritic Cell-Based Cancer Immunotherapy against Multiple Myeloma: From Bench to Clinic. AB - Although the introduction of stem cell transplantation and novel agents has improved survival, multiple myeloma (MM) is still difficult to cure. Alternative approaches are clearly needed to prolong the survival of patients with MM. Dendritic cell (DC) therapy is a very promising tool immunologically in MM. We developed a method to generate potent DCs with increased Th1 polarization and migration ability for inducing strong myeloma-specific cytotoxic T lymphocytes. In this review, we discuss how the efficacy of cancer immunotherapy using DCs can be improved in MM. PMID- 25914876 TI - Nine-Month Follow-up Results of Treatment for Nasolacrimal Duct Obstruction by Probing with Adjunctive Mitomycin C in Adults: A Prospective Randomized Placebo Controlled Trial. AB - The current study aimed to determine the efficacy of probing with adjunctive mitomycin C (MMC) as a treatment for nasolacrimal duct obstruction (NLDO) in adults and to study the association of probing success with demographic and obstruction characteristics. This was a prospective, randomized, double-blind, placebo-controlled trial including 140 patients (each with a unilateral NLDO) scheduled for nasolacrimal probing who were randomly assigned to receive MMC (0.2 mg/ml, 70 patients; group A) or placebo (normal saline, 70 patients; group B). Irrigation was carried out with 0.5 cc of MMC (0.2 mg/mL) in the duct with a nasal pack for 10 minutes in group A. Patients' postprobing epiphora was evaluated at 2 weeks and 1, 3, 6, and 9 months postoperatively. Probing was judged to be a success if there was no or mild watering for at least 9 months after the procedure. There were no significant differences between the two study groups in demographic characteristics or duration of the operation (p=0.062). The overall success rate of probing with MMC was 47/70 (67.1%), which was significantly higher than the success rate of the procedure with placebo (p=0.0027). When the sex of the patients was controlled for by logistic regression, a significant association between the failure rate of probing and increasing age was found in cases and controls (p=0.004 vs. p=0.006, respectively). No significant side effects of probing with MMC were noted after 9 months of follow-up. Administering MMC in a dosage of 0.2 mg/mL during nasolacrimal probing significantly increased the success rate of probing. The failure rate of probing increased with age. A low dose of MMC is cheap, safe, and easily accessible; thus, it is recommended during nasolacrimal probing, especially in patients who refuse dacryocystorhinostomy surgery. PMID- 25914875 TI - Comorbidity of depression with physical disorders: research and clinical implications. AB - Depression is prevalent in patients with physical disorders, particularly in those with severe disorders such as cancer, stroke, and acute coronary syndrome. Depression has an adverse impact on the courses of these diseases that includes poor quality of life, more functional impairments, and a higher mortality rate. Patients with physical disorders are at higher risk of depression. This is particularly true for patients with genetic and epigenetic predictors, environmental vulnerabilities such as past depression, higher disability, and stressful life events. Such patients should be monitored closely. To appropriately manage depression in these patients, comprehensive and integrative care that includes antidepressant treatment (with considerations for adverse effects and drug interactions), treatment of the physical disorder, and collaborative care that consists of disease education, cognitive reframing, and modification of coping style should be provided. The objective of the present review was to present and summarize the prevalence, risk factors, clinical correlates, current pathophysiological aspects including genetics, and treatments for depression comorbid with physical disorders. In particular, we tried to focus on severe physical disorders with high mortality rates, such as cancer, stroke, and acute coronary syndrome, which are highly comorbid with depression. This review will enhance our current understanding of the association between depression and serious medical conditions, which will allow clinicians to develop more advanced and personalized treatment options for these patients in routine clinical practice. PMID- 25914877 TI - Long-Term Outcome of Treatment with Topical Corticosteroids for Severe Dry Eye Associated with Sjogren's Syndrome. AB - This retrospective study was performed to analyze the long-term outcome of topical corticosteroid treatment for severe dry eye associated with Sjogren's syndrome (SS). Patients who had severe dry eye associated with SS were topically treated with loteprednol etabonate 0.5% (group A, n=66) or fluorometholone 0.1% (group B, n=67) twice daily and were followed up for 2 years. Visual acuity (VA), intraocular pressure (IOP), Schirmer test, tear film breakup time (BUT), keratoepitheliopathy, and symptom scores were measured at baseline and 6, 12, 18, and 24 months after treatment. VA and IOP were not changed significantly during follow-up in either group. Schirmer test results, keratoepitheliopathy, and symptom scores at 6, 12, 18, and 24 months (p<0.05) and tear film BUT at 12, 18, and 24 months (p<0.05) significantly improved after treatment compared with baseline in both groups. No significant differences between the groups were found in any parameter during follow-up. At 24 months, the number of patients with IOP elevation of more than 2 mmHg compared with baseline was 4 in group A (6.1%) and 9 in group B (13.4%). The mean IOP in these patients was lower in group A than in group B (15.00+/-0.82 mmHg versus 16.50+/-1.12 mmHg; p=0.04). Long-term application of low-dose topical corticosteroids is effective for controlling signs and symptoms of chronic, severe dry eye associated with SS. Loteprednol etabonate 0.5% may have a lower risk for IOP elevation than fluorometholone 0.1%. PMID- 25914878 TI - Growth hormone responses to provocative tests in children with short stature. AB - Growth hormone deficiency (GHD) is defined as a serum peak GH concentration <10 ng/mL with provocation as tested by a combination of at least two separate tests. The aim of this study was to compare two standard tests, insulin and levodopa (L dopa), with a primary focus on specificity and accuracy. Clinical data were collected retrospectively from a review of 120 children who visited the pediatric endocrine clinic at Chonnam National University Hospital for the evaluation of short stature between January 2006 and April 2014. Subjects underwent GH provocation tests with insulin and L-dopa. Blood samples were obtained at 0, 15, 30, 45, 60, 90, and 120 min after administration, and GH levels were measured. In the insulin test, serial glucose levels were also checked, closely monitoring hypoglycemia. A total of 83 children (69.2%) were diagnosed with GHD and 37 children (30.8%) were diagnosed with idiopathic short stature (ISS). Peak GH levels were achieved an average of 45 min after the administration of insulin and L-dopa for both groups. The specificity and accuracy were 78.4% and 93.6% for the insulin test and 29.7% and 79.2% for L-dopa test, respectively. In the ISS group, the cumulative frequency of a GH cutoff value of >10 ng/mL at 120 min was 75.6% after insulin stimulation compared with 35.1% after L-dopa stimulation. Considering these results, we recommend performing the insulin test first to exclude ISS and then the L-dopa test for the diagnosis of GHD. This way, ISS patients are diagnosed after a single test, thus reducing hospital days and the burden of undergoing two serial tests. PMID- 25914879 TI - IgG4-Related Systemic Disease Can Be Easily Mistaken as a Uroepithelial Tumor. AB - Immunoglobulin G4-related disease (IgG4-RD) is a newly recognized systemic syndrome characterized by elevated serum IgG4 concentrations and tumefaction or tissue infiltration by IgG4-positive plasma cells. We experienced a case of IgG4 RD involving multiple organs in a 64-year-old female who was referred for a suspected uroepithelial tumor. A mass biopsy confirmed dense lymphoplasmacytic infiltration with an increased number of IgG4-positive plasma cells. We discuss this case and review the literature to bring IgG4-RD to the attention to clinicians because it responds dramatically well to steroid therapy and should be kept in mind as a differential diagnosis to avoid unnecessary surgery. PMID- 25914880 TI - Totally occluded grafted right internal mammary artery to anomalously originated right coronary artery. AB - An anomalous aortic origin of a coronary artery is rare and surgical intervention is recommended when the patient is symptomatic. We performed coronary artery bypass graft surgery in a 21-year-old male patient with a right coronary artery anomalously originating from the left coronary sinus. The artery was significantly stenosed by external compression between the aorta and the pulmonary artery. However, the graft became occluded 1 year after the operation. In such cases, the dynamic nature of the stenosis can cause relatively intact antegrade competitive flow from the native coronary artery and lead to an occlusion of the grafted artery. Methods for evaluating flow rates or intraluminal pressures of native arteries could be helpful in decision-making in similar cases. PMID- 25914881 TI - Successful Delivery Following Staphylococcus aureus Bacteremia after In Vitro Fertilization and Embryo Transfer. AB - A 30-year-old, 16-week primipara woman visited with complaints of lower back pain over the past 3 weeks. She had a history of ultrasound-guided transvaginal oocyte retrieval for in vitro fertilization (IVF) 14 weeks earlier. Lumbar spine magnetic resonance imaging showed infectious spondylitis and the results of blood and spinal biopsy cultures showed Staphylococcus aureus. Intravenous cefazolin was continued for 6 weeks, and 4 months later, she delivered a healthy girl. This is the first reported case of successful term delivery following S. aureus bacteremia with vertebral osteomyelitis after IVF and embryo transfer. It should be considered that S. aureus bacteremia can be a serious complication of IVF. PMID- 25914882 TI - Targeting the innate immune system as immunotherapy for acute myeloid leukemia. AB - Because of its disseminated nature and lack of tumor-draining lymph nodes, acute myeloid leukemia (AML) likely employs unique immune evasion strategies as compared to solid malignancies. Targeting these unique mechanisms may result in improved immunotherapeutic approaches. Emerging data suggest that a specific dendritic cell (DC) subset, CD8alpha DCs, may be responsible for mediating tolerance in AML and thus targeting the innate immune system may be of benefit in this disease. Promising immune targets include the toll-like receptors, calreticulin/CD47, the stimulator of interferon genes pathway, and signal transducer and activator of transcription 3 (STAT3). However, it is becoming clear that compensatory mechanisms may limit the efficacy of these agents alone and thus rationale combinations of immunotherapies are warranted. This review discusses the potential immune evasion strategies in AML, as well as discussion of the promising innate immune targets, both alone and in combination, for this disease. PMID- 25914883 TI - One-year monitoring of an oligonucleotide fluorescence in situ hybridization probe panel laboratory-developed test for bladder cancer detection. AB - BACKGROUND: Previously, we had developed and manufactured an oligonucleotide fluorescence in situ hybridization (OligoFISH) probe panel based on the most clinically sensitive chromosomes found in a reference set of bladder carcinoma cases. The panel was clinically validated for use as a diagnostic and monitoring assay for bladder cancer, reaching 100% correlation with the results of the UroVysion test. After 1 year of using this probe panel, we present here the comparison of cytology, cystoscopy, and pathology findings to the OligoFISH probe panel results to calculate its clinical performance. MATERIALS AND METHODS: In order to calculate clinical performance, we compared the OligoFISH results to the cytology and cystoscopy/pathology findings for 147 initial diagnoses and 399 recurrence monitorings. Finally, we compared clinical performance to published values for the UroVysion test, including both low- and high-grade tumors. RESULTS: Chromosomes 3, 6, 7, and 20 were highly involved in bladder carcinoma aneuploidy. At the initial diagnosis, we obtained 90.5% (95% confidence interval [CI]: 84.5%-94.7%) accuracy, 96.8% sensitivity (95% CI: 91.0%-99.3%), 79.2% specificity (95% CI: 65.9%-87.8%), 89.2% positive predictive value (PPV; 95% CI: 81.5%-94.5%), and 93.3% negative predictive value (NPV; 95% CI: 81.7%-97.3%). When monitoring for recurrence, we obtained 85.2% accuracy (95% CI: 81.3%-88.5%), 82.0% sensitivity (95% CI: 76.0%-87.1%), 88.4% specificity (95% CI: 83.2%-92.5%), 87.7% PPV (95% CI: 82.1%-92.0%), and 83.0% NPV (95% CI: 77.3%-87.8%). When looking at low- and high-grade tumors, the test showed 100% sensitivity for high grade tumors (95% CI: 92.5%-100%) and 87.5% sensitivity (95% CI: 68.8%-95.5%) for low-grade tumors. All the clinical parameters for the OligoFISH panel were higher than the UroVysion test's published performance. We found significantly higher clinical sensitivity and NPV at initial diagnosis and significantly higher specificity and PPV for recurrence. CONCLUSION: The OligoFISH probe panel is a fast, easy, and reproducible test for bladder cancer diagnosis and monitoring, with excellent clinical performance and utility. PMID- 25914886 TI - A Forgiveness Intervention for Women With Fibromyalgia Who Were Abused in Childhood: A Pilot Study. AB - This pilot study compared the efficacy of a forgiveness intervention with a fibromyalgia (FM) health intervention on women with FM who have experienced emotional, physical, or sexual abuse, and emotional or physical neglect, in childhood by one of their parents. Eleven women with FM between the ages of 21 and 68 were randomized to the forgiveness intervention (n = 5) or the FM health intervention (n = 6), and completed the once-weekly individualized program for 24 weeks. The participants completed measures assessing forgiveness, overall FM health, depression, anger, anxiety, self-esteem, and coping strategies at the pretest, the posttest, and the 12-week follow-up test. They also completed the forgiveness intervention and FM health intervention final tests at the posttest, which assessed their knowledge on forgiveness and FM health. The forgiveness intervention participants had greater improvements in forgiveness (p < .001) and overall FM health (p = .046) from the pretest to the posttest, and in forgiveness (p = .018) and state anger (p = .027) from the pretest to the follow-up test than the FM health intervention participants. Moreover, the forgiveness intervention participants scored higher on the forgiveness final test than the FM health intervention participants (p < .001), and the FM health intervention participants scored higher on the FM health final test than the forgiveness intervention participants (p < .001). The results indicate that the forgiveness intervention was potentially helpful in improving forgiveness and overall FM health, and in decreasing state anger of this particular sample of women with FM. PMID- 25914885 TI - Evidence of Aortopathy in Mice with Haploinsufficiency of Notch1 in Nos3-Null Background. AB - Thoracic aortic aneurysms (TAA) are a significant cause of morbidity and mortality in humans. While the exact etiology is unknown, genetic factors play an important role. Mutations in NOTCH1 have been linked to bicuspid aortic valve (BAV) and aortopathy in humans. The aim of this study was to determine if haploinsufficiency of Notch1 contributes to aortopathy using Notch1+/-; Nos3-/- mice. Echocardiographic analysis of Notch1+/-; Nos3-/- mice reveals effacement of the sinotubular junction and a trend toward dilation of the aortic sinus. Furthermore, examination of the proximal aorta of Notch1+/-; Nos3-/- mice reveals elastic fiber degradation, a trend toward increased matrix metalloproteinase 2 expression, and increased smooth muscle cell apoptosis, features characteristic of aneurysmal disease. Although at a lower penetrance, we also found features consistent with aortopathic changes in Notch1 heterozygote mice and in Nos3-null mice. Our findings implicate a novel role for Notch1 in aortopathy of the proximal aorta. PMID- 25914887 TI - Multiset Statistics for Gene Set Analysis. AB - An important data analysis task in statistical genomics involves the integration of genome-wide gene-level measurements with preexisting data on the same genes. A wide variety of statistical methodologies and computational tools have been developed for this general task. We emphasize one particular distinction among methodologies, namely whether they process gene sets one at a time (uniset) or simultaneously via some multiset technique. Owing to the complexity of collections of gene sets, the multiset approach offers some advantages, as it naturally accommodates set-size variations and among-set overlaps. However, this approach presents both computational and inferential challenges. After reviewing some statistical issues that arise in uniset analysis, we examine two model-based multiset methods for gene list data. PMID- 25914888 TI - Towards a computational(ist) neurobiology of language: Correlational, integrated, and explanatory neurolinguistics. AB - We outline what an integrated approach to language research that connects experimental, theoretical, and neurobiological domains of inquiry would look like, and ask to what extent unification is possible across domains. At the center of the program is the idea that computational/representational (CR) theories of language must be used to investigate its neurobiological (NB) foundations. We consider different ways in which CR and NB might be connected. These are (1) A Correlational way, in which NB computation is correlated with the CR theory; (2) An Integrated way, in which NB data provide crucial evidence for choosing among CR theories; and (3) an Explanatory way, in which properties of NB explain why a CR theory is the way it is. We examine various questions concerning the prospects for Explanatory connections in particular, including to what extent it makes sense to say that NB could be specialized for particular computations. PMID- 25914884 TI - Targeting cell cycle regulators in hematologic malignancies. AB - Hematologic malignancies represent the fourth most frequently diagnosed cancer in economically developed countries. In hematologic malignancies normal hematopoiesis is interrupted by uncontrolled growth of a genetically altered stem or progenitor cell (HSPC) that maintains its ability of self-renewal. Cyclin dependent kinases (CDKs) not only regulate the mammalian cell cycle, but also influence other vital cellular processes, such as stem cell renewal, differentiation, transcription, epigenetic regulation, apoptosis, and DNA repair. Chromosomal translocations, amplification, overexpression and altered CDK activities have been described in different types of human cancer, which have made them attractive targets for pharmacological inhibition. Mouse models deficient for one or more CDKs have significantly contributed to our current understanding of the physiological functions of CDKs, as well as their roles in human cancer. The present review focuses on selected cell cycle kinases with recent emerging key functions in hematopoiesis and in hematopoietic malignancies, such as CDK6 and its role in MLL-rearranged leukemia and acute lymphocytic leukemia, CDK1 and its regulator WEE-1 in acute myeloid leukemia (AML), and cyclin C/CDK8/CDK19 complexes in T-cell acute lymphocytic leukemia. The knowledge gained from gene knockout experiments in mice of these kinases is also summarized. An overview of compounds targeting these kinases, which are currently in clinical development in various solid tumors and hematopoietic malignances, is presented. These include the CDK4/CDK6 inhibitors (palbociclib, LEE011, LY2835219), pan-CDK inhibitors that target CDK1 (dinaciclib, flavopiridol, AT7519, TG02, P276-00, terampeprocol and RGB 286638) as well as the WEE-1 kinase inhibitor, MK-1775. The advantage of combination therapy of cell cycle inhibitors with conventional chemotherapeutic agents used in the treatment of AML, such as cytarabine, is discussed. PMID- 25914889 TI - What is embodied about cognition? AB - It is currently debated whether the meanings of words and objects are represented, in whole or in part, in a modality-specific format-the embodied cognition hypothesis. I argue that the embodied/disembodied cognition debate is either largely resolved in favor of the view that concepts are represented in an amodal format, or at a point where the embodied and disembodied approaches are no longer coherently distinct theories. This merits reconsideration of what the available evidence can tell us about the structure of the conceptual system. We know that the conceptual system engages, online, with sensory and motor content. This frames a new question: How is it that the human conceptual system is able to disengage from the sensorimotor system? Answering this question would say something about how the human mind is able to detach from the present and extrapolate from finite experience to hypothetical states of how the world could be. It is the independence of thought from perception and action that makes human cognition special-and that independence is guaranteed by the representational distinction between concepts and sensorimotor representations. PMID- 25914890 TI - The Neural Computation of Scalar Implicature. AB - Language comprehension involves not only constructing the literal meaning of a sentence but also going beyond the literal meaning to infer what was meant but not said. One widely-studied test case is scalar implicature: The inference that, e.g., Sally ate some of the cookies implies she did not eat all of them. Research is mixed on whether this is due to a rote, grammaticalized procedure or instead a complex, contextualized inference. We find that in sentences like If Sally ate some of the cookies, then the rest are on the counter, that the rest triggers a late, sustained positivity relative to Sally ate some of the cookies, and the rest are on the counter. This is consistent with behavioral results and linguistic theory suggesting that the former sentence does not trigger a scalar implicature. This motivates a view on which scalar implicature is contextualized but dependent on grammatical structure. PMID- 25914891 TI - Reversing expectations during discourse comprehension. AB - In two ERP experiments, we asked whether comprehenders used the concessive connective, even so, to predict upcoming events. Participants read coherent and incoherent scenarios, with and without even so, e.g. "Elizabeth had a history exam on Monday. She took the test and aced/failed it. (Even so), she went home and celebrated wildly.", as they rated coherence (Experiment 1) or simply answered intermittent comprehension questions (Experiment 2). The semantic function of even so was used to reverse real-world knowledge predictions, leading to an attenuated N400 to coherent versus incoherent target words ("celebrated"). Moreover, its pragmatic communicative function enhanced predictive processing, leading to more N400 attenuation to coherent targets in scenarios with than without even so. This benefit however, did not come for free: the detection of failed event predictions triggered a later posterior positivity and/or an anterior negativity effect, and costs of maintaining alternative likelihood relations manifest as a sustained negativity effect on sentence-final words. PMID- 25914892 TI - Human T-Lymphotrophic Virus Type-I: A Unique Association with Myelopathy in Sjogren's Syndrome. PMID- 25914893 TI - FGF10 Signaling Enhances Epicardial Cell Expansion during Neonatal Mouse Heart Repair. AB - Unlike zebrafish and newt hearts, mammalian hearts have limited capacity to regenerate. Upon injury or disease, the adult mammalian hearts form a fibrotic scar. Recently, it was shown that neonatal mouse hearts can regenerate similarly to adult zebrafish hearts. However, this capacity quickly decreases after postnatal day 7 (P7). Understanding the molecular mechanisms underlying neonatal heart regeneration might lead to therapeutic approaches for regenerating adult mammalian hearts. In this study, we utilized an inducible transgenic mouse model to determine the effects of FGF10 growth factor over expression on neonatal mouse heart regeneration/repair. Over expression of FGF10 in myocardium enhanced the expansion of Wt1 positive epicardial cells at 21 days after heart injury through increased proliferation. However, this expansion of epicardial cells did not lead to increased epithelial-to-mesenchymal transition or affect fibroblast formation or fibrosis, as seen by vimentin expression, after heart injury. Furthermore, neither continuous nor transient expression of FGF10 did not affect scar thickness or length after heart injury in neonatal hearts. Our results suggest that FGF10 can regulate epicardial cell expansion of neonatal mouse hearts after injury; however, FGF10 alone is not sufficient to cause beneficial effects on heart repair. PMID- 25914894 TI - Circulating Tumor Cells in Metastatic Breast Cancer: A Prognostic and Predictive Marker. AB - The role of circulating tumor cells (CTCs) as a marker for disease progression in metastatic cancer is controversial. The current review will serve to summarize the evidence on CTCs as a marker of disease progression in patients with metastatic breast cancer. The immunohistochemistry(IHC)-based CellSearch(r) is the only FDA-approved isolation technique for quantifying CTCs in patients with metastatic breast cancer. We searched PubMed and Web of Knowledge for clinical studies that assessed the prognostic and predictive value of CTCs using IHC-based isolation. The patient outcomes reported include median and Cox-proportional hazard ratios for overall-survival (OS) and progression-free-survival (PFS). All studies reported shorter OS for CTC-positive patients versus CTC-negative. A subset of the selected trials reported significant lower median PFS for CTC positive patients. The reported trials support the utility of CTC enumeration for patient prognosis. But further studies are required to determine the utility of CTC enumeration for guiding patient therapy. There are three clinical trials ongoing to test this hypothesis. These studies, and others, will further establish the role of CTCs in clinical practice. PMID- 25914895 TI - Vulnerability to Stress-Related Sleep Disturbance and Insomnia: Investigating the Link with Comorbid Depressive Symptoms. AB - Greater sleep difficulty following a challenging event, or a vulnerability to stress-related sleep disturbance (i.e., sleep reactivity), is characteristic of insomnia. However, insomnia is rarely observed in isolation; rather it is frequently seen in combination with other problems, such as depression. Despite the link between depression and increased sensitivity to stress, relatively little is known about the role sleep reactivity has in explaining variability in depressive symptoms. Therefore, the current study examined whether sleep reactivity was associated with depressive symptoms, and whether this relationship was mediated by insomnia. We assessed sleep reactivity, insomnia, and depressive symptoms among 2250 young adults (1244 female; Mage = 23.1, SDage = 2.97) from the Colorado Longitudinal Twin Study and Community Twin Study. Results indicated that greater sleep reactivity was significantly associated with elevated depressive symptoms, and that this link was partially mediated by insomnia. This is one of the first studies to demonstrate an independent association between sleep reactivity and depressive symptomatology. These findings suggest that a greater sensitivity to stress-related sleep disturbance may also be a predisposing factor to depression, and highlight the need for a better understanding of sleep reactivity, as it may represent a more global vulnerability construct. PMID- 25914896 TI - "Universal" vitrification of cells by ultra-fast cooling. AB - Long-term preservation of live cells is critical for a broad range of clinical and research applications. With the increasing diversity of cells that need to be preserved (e.g. oocytes, stem and other primary cells, genetically modified cells), careful optimization of preservation protocols becomes tedious and poses significant limitations for all but the most expert users. To address the challenge of long-term storage of critical, heterogeneous cell types, we propose a universal protocol for cell vitrification that is independent of cell phenotype and uses only low concentrations of cryoprotectant (1.5 M PROH and 0.5 M trehalose). We employed industrial grade microcapillaries made of highly conductive fused silica, which are commonly used for analytical chemistry applications. The minimal mass and thermal inertia of the microcapillaries enabled us to achieve ultrafast cooling rates up to 4,000 K/s. Using the same low, non-toxic concentration of cryoprotectant, we demonstrate high recovery and viability rates after vitrification for human mammary epithelial cells, rat hepatocytes, tumor cells from pleural effusions, and multiple cancer cell lines. PMID- 25914897 TI - Selectivity as an Emotion Regulation Strategy: Lessons from Older Adults. AB - Findings based on studies of daily life consistently associate older ages with relatively positive emotional experience, suggesting that older adults may regulate emotions more effectively than younger adults. Findings from laboratory studies are equivocal, however, with mixed evidence for age-related improvements in use of emotion regulatory strategies. In the current paper, we propose that findings may reflect a failure of laboratory-based experiments to capture the regulatory strategies that older people use in their everyday lives. We argue that the advantages older people have are likely due to antecedent emotion regulation as opposed to response-focused strategies. Understanding the regulatory approaches that older people actually use may inform developmental models of emotion regulation throughout adulthood as well as interventions for improving emotional experience across the life span. PMID- 25914898 TI - Abdominal Visceral Adipose Tissue is Associated with Myocardial Infarction in Patients with COPD. AB - BACKGROUND: Cardiovascular diseases are frequent and a major cause of death in patients with chronic obstructive pulmonary disease (COPD). In the general population, various fat depots including abdominal visceral adipose tissue (VAT), subcutaneous adipose tissue (SAT), and liver fat have been linked to increased risk of cardiovascular diseases. We hypothesize that these adipose tissue compartments are associated with myocardial infarction (MI) in patients with COPD. METHODS: We collected measures of VAT and SAT areas and liver attenuation on the computed tomography scan of the chest from 1267 patients with COPD. MI was a self-reported physician-diagnosed outcome. The association between fat depots and self-reported history of MI was assessed by logistic regression analysis in which the patients within the 2 lowest tertiles of VAT and SAT areas were the reference group. RESULTS: Eighty three patients (6.6%) reported a history of MI at the time of enrollment. Compared to patients who did not have an MI episode, those who had a prior MI had a higher VAT area (mean +/- SD, 303.4 +/- 208.5 vs. 226.8 +/- 172.6 cm2; P=0.002) with no differences in SAT area and liver fat. After adjustment for age, gender, obesity, pack years of smoking, hypertension, high cholesterol, and diabetes, patients within the upper tertile (vs. those in the lower tertiles) of VAT area had increased odds of MI (odds ratio [OR] 1.86, 95% confidence interval [CI] 1.02 - 3.41). CONCLUSION: Increased abdominal visceral fat is independently associated with a history of MI in individuals with COPD. PMID- 25914899 TI - QUANTITATIVE REEVALUATION OF THE EFFECTS OF SHORT- AND LONG-TERM REMOVAL OF DESCENDING MODULATORY INPUTS ON THE PYLORIC RHYTHM OF THE CRAB, CANCER BOREALIS. AB - The crustacean stomatogastric ganglion (STG) receives descending neuromodulatory inputs from three anterior ganglia, the paired commissural ganglia (CoGs) and the single esophageal ganglion (OG). In this paper we provide the first detailed and quantitative analyses of the short- and long-term effects of removal of these descending inputs (decentralization) on the pyloric rhythm of the STG. Thirty minutes after decentralization, the mean frequency of the pyloric rhythm dropped from 1.20 Hz in control to 0.52 Hz. Whereas the relative phase of pyloric neuron activity was approximately constant across frequency in the controls, after decentralization this changed markedly. Nine control preparations kept for 5-6 days in vitro maintained pyloric rhythm frequencies close to their control values. Nineteen decentralized preparations kept for 5-6 days dropped slightly in frequency from those seen at 30 minutes after decentralization, but then displayed stable activity over 6 days. Bouts of higher frequency activity were intermittently seen in both control and decentralized preparations, but the bouts began earlier and were more frequent in the decentralized preparations. Although the bouts may indicate that the removal of the modulatory inputs triggered changes in neuronal excitability, these changes did not produce obvious long lasting changes in the frequency of the decentralized preparations. PMID- 25914900 TI - Colon Cancer Staging in Vulnerable Older Adults: Adherence to National Guidelines and Impact on Survival. AB - BACKGROUND: There is concern that elders are not adequately evaluated prior to colon cancer surgery. We sought to determine adherence with ACOVE-3 (Assessing Care of Vulnerable Elders) quality indicators for pre-operative staging prior to colectomy for colon cancer utilizing the Surveillance, Epidemiology and End Results (SEER)-Medicare linked database (1992-2005). METHODS: We determined the proportion of patients aged 75 and older who had preoperative staging prior to colectomy for colon adenocarcinoma. Preoperative staging was defined as abdominopelvic computed tomography or magnetic resonance imaging scan (SCAN) and colonoscopy or flexible sigmoidoscopy (SCOPE). Multivariate logistic regression identified predictors of adherence. Odds ratios were adjusted for comorbidity, socioeconomic status, and disease severity. The association of adherence to ACOVE 3 and survival was quantified. RESULTS: Of the 37,862 patients, the majority were 75-84 years, 28% of the patients were >=85 years. Regarding preoperative staging in the 6-month interval prior to surgical resection, 8% had neither SCAN nor SCOPE, 6% had only SCAN, 43% had only SCOPE, and 43% had both SCAN and SCOPE. Compared to patients who were not staged, those evaluated with either SCOPE alone or SCAN plus SCOPE had lower odds of 3-year mortality. Patients who were staged with SCAN alone had an increased odds of death compared to those who had neither SCAN or SCOPE. CONCLUSIONS: These data demonstrate that the majority of vulnerable elders with colon cancer did not receive appropriate preoperative staging prior to resection. The findings also confirm that adherence to ACOVE-3 guidelines is associated with improved long-term survival. PMID- 25914901 TI - Depressive symptoms, burnout and the impact of events in non-professional volunteer counselors in Durban, South Africa. PMID- 25914902 TI - Depression and its correlates in South Africa and Ghana among people aged 50 and above: Findings from the WHO Study on global AGEing and adult health. AB - OBJECTIVE: The growth of the older adult population in Africa demands more knowledge about their chronic health problems, such as depression. The aim of this paper is to estimate depression prevalence and identify correlates of depression among older adults in Ghana and South Africa. METHOD: The WHO Study on global AGEing and adult health (SAGE study) was conducted in Ghana and South Africa from 2007 to 2009 by the World Health Organization, using a standardized questionnaire among an adult population. Our analyses included 4289 adults aged 50 and above in Ghana and 3668 in South Africa. Depression was measured using self-reported symptoms over the last 12 months according to ICD-10 criteria. RESULTS: The prevalence of mild depression was 6.7% and 2.7% in Ghana and South Africa, respectively (p<.001), with a gender difference only in Ghana. Factors independently associated with depression among women in Ghana were migration and lack of current work.. Similarly, higher age, lack of current work and lower quality of life were independently associated with depression among women in South Africa, whereas higher age and lower quality of life were associated with depression among men in South Africa. CONCLUSIONS: Ghana had a higher depression rate than South Africa and we identified different factors associated with depression among men and women in these two countries. Our finding underscores the need for culture- and gender-sensitive approaches for the prevention and management of depression among the older adult population in Ghana and South Africa. PMID- 25914903 TI - Abdominal drainage to prevent intra-peritoneal abscess after open appendectomy for complicated appendicitis. AB - BACKGROUND: Appendectomy, the surgical removal of the appendix, is performed primarily for acute appendicitis. Patients who undergo appendectomy for complicated appendicitis, defined as gangrenous or perforated appendicitis, are more likely to suffer from postoperative complications. The routine use of abdominal drainage to reduce postoperative complications after appendectomy for complicated appendicitis is controversial. OBJECTIVES: To assess the safety and efficacy of abdominal drainage to prevent intra-peritoneal abscess after open appendectomy for complicated appendicitis. SEARCH METHODS: We searched The Cochrane Library (Issue 1, 2014), MEDLINE (1950 to February 2014), EMBASE (1974 to February 2014), Science Citation Index Expanded (1900 to February 2014), and Chinese Biomedical Literature Database (CBM) (1978 to February 2014). SELECTION CRITERIA: We included all randomised controlled trials (RCTs) that compared abdominal drainage and no drainage in patients undergoing emergency open appendectomy for complicated appendicitis. DATA COLLECTION AND ANALYSIS: Two review authors identified the trials for inclusion, collected the data, and assessed the risk of bias independently. We performed the meta-analyses using Review Manager 5. We calculated the risk ratio (RR) for dichotomous outcomes (or a Peto odds ratio for very rare outcomes), and the mean difference (MD) for continuous outcomes with 95% confidence intervals (CI). MAIN RESULTS: We included five trials involving 453 patients with complicated appendicitis who were randomised to the drainage group (n = 228) and the no drainage group (n = 225) after emergency open appendectomies. All of the trials were at a high risk of bias. There were no significant differences between the two groups in the rates of intra-peritoneal abscess or wound infection. The hospital stay was longer in the drainage group than in the no drainage group (MD 2.04 days; 95% CI 1.46 to 2.62) (34.4% increase of an 'average' hospital stay). AUTHORS' CONCLUSIONS: The quality of the current evidence is very low. It is not clear whether routine abdominal drainage has any effect on the prevention of intra-peritoneal abscess after open appendectomy for complicated appendicitis. Abdominal drainage after an emergency open appendectomy may be associated with delayed hospital discharge for patients with complicated appendicitis. PMID- 25914904 TI - Chewing gum for postoperative recovery of gastrointestinal function. AB - BACKGROUND: Ileus commonly occurs after abdominal surgery, and is associated with complications and increased length of hospital stay (LOHS). Onset of ileus is considered to be multifactorial, and a variety of preventative methods have been investigated. Chewing gum (CG) is hypothesised to reduce postoperative ileus by stimulating early recovery of gastrointestinal (GI) function, through cephalo vagal stimulation. There is no comprehensive review of this intervention in abdominal surgery. OBJECTIVES: To examine whether chewing gum after surgery hastens the return of gastrointestinal function. SEARCH METHODS: We searched the Cochrane Central Register of Controlled Trials (CENTRAL), MEDLINE (via Ovid), MEDLINE (via PubMed), EMBASE (via Ovid), CINAHL (via EBSCO) and ISI Web of Science (June 2014). We hand-searched reference lists of identified studies and previous reviews and systematic reviews, and contacted CG companies to ask for information on any studies using their products. We identified proposed and ongoing studies from clinicaltrials.gov, World Health Organization (WHO) International Clinical Trials Registry Platform and metaRegister of Controlled Trials. SELECTION CRITERIA: We included completed randomised controlled trials (RCTs) that used postoperative CG as an intervention compared to a control group. DATA COLLECTION AND ANALYSIS: Two authors independently collected data and assessed study quality using an adapted Cochrane risk of bias (ROB) tool, and resolved disagreements by discussion. We assessed overall quality of evidence for each outcome using Grades of Recommendation, Assessment, Development and Evaluation (GRADE). Studies were split into subgroups: colorectal surgery (CRS), caesarean section (CS) and other surgery (OS). We assessed the effect of CG on time to first flatus (TFF), time to bowel movement (TBM), LOHS and time to bowel sounds (TBS) through meta-analyses using a random-effects model. We investigated the influence of study quality, reviewers' methodological estimations and use of Enhanced Recovery After Surgery (ERAS) programmes using sensitivity analyses. We used meta-regression to explore if surgical site or ROB scores predicted the extent of the effect estimate of the intervention on continuous outcomes. We reported frequency of complications, and descriptions of tolerability of gum and cost. MAIN RESULTS: We identified 81 studies that recruited 9072 participants for inclusion in our review. We categorised many studies at high or unclear risk of the bias' assessed. There was statistical evidence that use of CG reduced TFF [overall reduction of 10.4 hours (95% CI: -11.9, -8.9): 12.5 hours (95% CI: 17.2, -7.8) in CRS, 7.9 hours (95% CI: -10.0, -5.8) in CS, 10.6 hours (95% CI: 12.7, -8.5) in OS]. There was also statistical evidence that use of CG reduced TBM [overall reduction of 12.7 hours (95% CI: -14.5, -10.9): 18.1 hours (95% CI: 25.3, -10.9) in CRS, 9.1 hours (95% CI: -11.4, -6.7) in CS, 12.3 hours (95% CI: 14.9, -9.7) in OS]. There was statistical evidence that use of CG slightly reduced LOHS [overall reduction of 0.7 days (95% CI: -0.8, -0.5): 1.0 days in CRS (95% CI: -1.6, -0.4), 0.2 days (95% CI: -0.3, -0.1) in CS, 0.8 days (95% CI: 1.1, -0.5) in OS]. There was statistical evidence that use of CG slightly reduced TBS [overall reduction of 5.0 hours (95% CI: -6.4, -3.7): 3.21 hours (95% CI: 7.0, 0.6) in CRS, 4.4 hours (95% CI: -5.9, -2.8) in CS, 6.3 hours (95% CI: -8.7, 3.8) in OS]. Effect sizes were largest in CRS and smallest in CS. There was statistical evidence of heterogeneity in all analyses other than TBS in CRS.There was little difference in mortality, infection risk and readmission rate between the groups. Some studies reported reduced nausea and vomiting and other complications in the intervention group. CG was generally well-tolerated by participants. There was little difference in cost between the groups in the two studies reporting this outcome.Sensitivity analyses by quality of studies and robustness of review estimates revealed no clinically important differences in effect estimates. Sensitivity analysis of ERAS studies showed a smaller effect size on TFF, larger effect size on TBM, and no difference between groups for LOHS.Meta-regression analyses indicated that surgical site is associated with the extent of the effect size on LOHS (all surgical subgroups), and TFF and TBM (CS and CRS subgroups only). There was no evidence that ROB score predicted the extent of the effect size on any outcome. Neither variable explained the identified heterogeneity between studies. AUTHORS' CONCLUSIONS: This review identified some evidence for the benefit of postoperative CG in improving recovery of GI function. However, the research to date has primarily focussed on CS and CRS, and largely consisted of small, poor quality trials. Many components of the ERAS programme also target ileus, therefore the benefit of CG alongside ERAS may be reduced, as we observed in this review. Therefore larger, better quality RCTS in an ERAS setting in wider surgical disciplines would be needed to improve the evidence base for use of CG after surgery. PMID- 25914905 TI - Proximal contact loss between implant-supported prostheses and adjacent natural teeth: a retrospective study. AB - OBJECTIVES: To determine the prevalence of proximal contact loss between posterior implant-supported prostheses and the adjacent anterior natural tooth and to identify potential contributing factors. MATERIALS AND METHODS: Forty-five consecutive patients, who had received either implant-supported fixed partial denture (FPD) or implant-supported single crown (SC) in the posterior region and were under regular review, were recruited. Interproximal space was assessed by the number of matrix bands that could be placed, and tooth mobility was assessed by Periotest(r). A self-reported questionnaire was administered. Effects of various patient and prosthesis parameters on interproximal space were analyzed by Kruskal-Wallis test or Mann-Whitney U test. Correlations were tested by Spearman's rank correlation coefficient. Differences were considered significant if P < 0.05. RESULTS: Forty-three of 66 (65%) prostheses showed proximal contact loss. Frequent food packing was reported in 40% of the prostheses. The mean interproximal space was 167 (SD = 125) MUm, and it was positively correlated with patients' age (P = 0.031) and time since prostheses delivery (P = 0.002). The interproximal space in the FPD group was significantly larger than the SC group (P = 0.008). CONCLUSION: Proximal contact loss is not uncommon in posterior implant-supported prostheses. In this study, age of the patient, prosthesis type and time since delivery of prosthesis were found to be contributing factors. PMID- 25914906 TI - Chinese herbal medicines for hypothyroidism. AB - BACKGROUND: The reduced production of thyroid hormones is the main feature of the clinical state termed hypothyroidism. In Chinese philosophical and medical theory, it results from Yang deficiency. Chinese herbal medicines (CHM) are thought to restore Yang and have been used in China to treat hypothyroidism for many years. OBJECTIVES: To assess the effects of CHM for hypothyroidism. SEARCH METHODS: We searched The Cochrane Library, MEDLINE, EMBASE, the Chinese Biomedical Literature Database on Disc, and the China National Knowledge Infrastructure for randomised clinical trials (RCTs). The date of the last search was September 2014 for all databases. We also searched for ongoing trials in trial registers. SELECTION CRITERIA: We considered RCTs of CHM alone or combined with thyroid hormone therapy compared with no treatment, placebo or thyroid hormone therapy. We also planned to compare different formulae of CHM with each other, alone or combined with thyroid hormone therapy. Hypothyroid individuals had to be diagnosed by the standard criteria valid at the time of the beginning of the trial regardless of the cause of hypothyroidism. DATA COLLECTION AND ANALYSIS: Data extraction and risk of bias assessment were not performed because no study could be included. MAIN RESULTS: We found no RCTs and therefore could not establish the effects of CHM on hypothyroidism. AUTHORS' CONCLUSIONS: Currently, there is no evidence available from RCTs on CHM for the treatment of hypothyroidism. We also did not find any ongoing registered trial. PMID- 25914908 TI - Diagnostic accuracy of endoscopic ultrasonography (EUS) for the preoperative locoregional staging of primary gastric cancer. AB - BACKGROUND: Endoscopic ultrasound (EUS) is proposed as an accurate diagnostic device for the locoregional staging of gastric cancer, which is crucial to developing a correct therapeutic strategy and ultimately to providing patients with the best chance of cure. However, despite a number of studies addressing this issue, there is no consensus on the role of EUS in routine clinical practice. OBJECTIVES: To provide both a comprehensive overview and a quantitative analysis of the published data regarding the ability of EUS to preoperatively define the locoregional disease spread (i.e., primary tumor depth (T-stage) and regional lymph node status (N-stage)) in people with primary gastric carcinoma. SEARCH METHODS: We performed a systematic search to identify articles that examined the diagnostic accuracy of EUS (the index test) in the evaluation of primary gastric cancer depth of invasion (T-stage, according to the AJCC/UICC TNM staging system categories T1, T2, T3 and T4) and regional lymph node status (N stage, disease-free (N0) versus metastatic (N+)) using histopathology as the reference standard. To this end, we searched the following databases: the Cochrane Library (the Cochrane Central Register of Controlled Trials (CENTRAL)), MEDLINE, EMBASE, NIHR Prospero Register, MEDION, Aggressive Research Intelligence Facility (ARIF), ClinicalTrials.gov, Current Controlled Trials MetaRegister, and World Health Organization International Clinical Trials Registry Platform (WHO ICTRP), from 1988 to January 2015. SELECTION CRITERIA: We included studies that met the following main inclusion criteria: 1) a minimum sample size of 10 patients with histologically-proven primary carcinoma of the stomach (target condition); 2) comparison of EUS (index test) with pathology evaluation (reference standard) in terms of primary tumor (T-stage) and regional lymph nodes (N-stage). We excluded reports with possible overlap with the selected studies. DATA COLLECTION AND ANALYSIS: For each study, two review authors extracted a standard set of data, using a dedicated data extraction form. We assessed data quality using a standard procedure according to the Quality Assessment of Diagnostic Accuracy Studies (QUADAS-2) criteria. We performed diagnostic accuracy meta-analysis using the hierarchical bivariate method. MAIN RESULTS: We identified 66 articles (published between 1988 and 2012) that were eligible according to the inclusion criteria. We collected the data on 7747 patients with gastric cancer who were staged with EUS. Overall the quality of the included studies was good: in particular, only five studies presented a high risk of index test interpretation bias and two studies presented a high risk of selection bias.For primary tumor (T) stage, results were stratified according to the depth of invasion of the gastric wall. The meta-analysis of 50 studies (n = 4397) showed that the summary sensitivity and specificity of EUS in discriminating T1 to T2 (superficial) versus T3 to T4 (advanced) gastric carcinomas were 0.86 (95% confidence interval (CI) 0.81 to 0.90) and 0.90 (95% CI 0.87 to 0.93) respectively. For the diagnostic capacity of EUS to distinguish T1 (early gastric cancer, EGC) versus T2 (muscle-infiltrating) tumors, the meta-analysis of 46 studies (n = 2742) showed that the summary sensitivity and specificity were 0.85 (95% CI 0.78 to 0.91) and 0.90 (95% CI 0.85 to 0.93) respectively. When we addressed the capacity of EUS to distinguish between T1a (mucosal) versus T1b (submucosal) cancers the meta-analysis of 20 studies (n = 3321) showed that the summary sensitivity and specificity were 0.87 (95% CI 0.81 to 0.92) and 0.75 (95% CI 0.62 to 0.84) respectively. Finally, for the metastatic involvement of lymph nodes (N-stage), the meta-analysis of 44 studies (n = 3573) showed that the summary sensitivity and specificity were 0.83 (95% CI 0.79 to 0.87) and 0.67 (95% CI 0.61 to 0.72), respectively.Overall, as demonstrated also by the Bayesian nomograms, which enable readers to calculate post-test probabilities for any target condition prevalence, the EUS accuracy can be considered clinically useful to guide physicians in the locoregional staging of people with gastric cancer. However, it should be noted that between-study heterogeneity was not negligible: unfortunately, we could not identify any consistent source of the observed heterogeneity. Therefore, all accuracy measures reported in the present work and summarizing the available evidence should be interpreted cautiously. Moreover, we must emphasize that the analysis of positive and negative likelihood values revealed that EUS diagnostic performance cannot be considered optimal either for disease confirmation or for exclusion, especially for the ability of EUS to distinguish T1a (mucosal) versus T1b (submucosal) cancers and positive versus negative lymph node status. AUTHORS' CONCLUSIONS: By analyzing the data from the largest series ever considered, we found that the diagnostic accuracy of EUS might be considered clinically useful to guide physicians in the locoregional staging of people with gastric carcinoma. However, the heterogeneity of the results warrants special caution, as well as further investigation for the identification of factors influencing the outcome of this diagnostic tool. Moreover, physicians should be warned that EUS performance is lower in diagnosing superficial tumors (T1a versus T1b) and lymph node status (positive versus negative). Overall, we observed large heterogeneity and its source needs to be understood before any definitive conclusion can be drawn about the use of EUS can be proposed in routine clinical settings. PMID- 25914907 TI - Comparison of routes for achieving parenteral access with a focus on the management of patients with Ebola virus disease. AB - BACKGROUND: Dehydration is an important cause of death in patients with Ebola virus disease (EVD). Parenteral fluids are often required in patients with fluid requirements in excess of their oral intake. The peripheral intravenous route is the most commonly used method of parenteral access, but inserting and maintaining an intravenous line can be challenging in the context of EVD. Therefore it is important to consider the advantages and disadvantages of different routes for achieving parenteral access (e.g. intravenous, intraosseous, subcutaneous and intraperitoneal). OBJECTIVES: To compare the reliability, ease of use and speed of insertion of different parenteral access methods. SEARCH METHODS: We ran the search on 17 November 2014. We searched the Cochrane Injuries Group's Specialised Register, Cochrane Central Register of Controlled Trials (CENTRAL, The Cochrane Library), Ovid MEDLINE(R) In-Process & Other Non-Indexed Citations, Ovid MEDLINE(R) Daily, Ovid MEDLINE(R) and Ovid OLDMEDLINE(R), Embase Classic + Embase (OvidSP), CINAHL (EBSCOhost), clinicaltrials.gov and screened reference lists. SELECTION CRITERIA: Randomised controlled trials comparing different parenteral routes for the infusion of fluids or medication. DATA COLLECTION AND ANALYSIS: Two review authors examined the titles and abstracts of records obtained by searching the electronic databases to determine eligibility. Two review authors extracted data from the included trials and assessed the risk of bias. Outcome measures of interest were success of insertion; time required for insertion; number of insertion attempts; number of dislodgements; time period with functional access; local site reactions; clinicians' perception of ease of administration; needlestick injury to healthcare workers; patients' discomfort; and mortality. For trials involving the administration of fluids we also collected data on the volume of fluid infused, changes in serum electrolytes and markers of renal function. We rated the quality of the evidence as 'high', 'moderate', 'low' or 'very low' according to the GRADE approach for the following outcomes: success of insertion, time required for insertion, number of dislodgements, volume of fluid infused and needlestick injuries. MAIN RESULTS: We included 17 trials involving 885 participants. Parenteral access was used to infuse fluids in 11 trials and medications in six trials. None of the trials involved patients with EVD. Intravenous and intraosseous access was compared in four trials; intravenous and subcutaneous access in 11; peripheral intravenous and intraperitoneal access in one; saphenous vein cutdown and intraosseous access in one; and intraperitoneal with subcutaneous access in one. All of the trials assessing the intravenous method involved peripheral intravenous access.We judged few trials to be at low risk of bias for any of the assessed domains.Compared to the intraosseous group, patients in the intravenous group were more likely to experience an insertion failure (risk ratio (RR) 3.89, 95% confidence interval (CI) 2.39 to 6.33; n = 242; GRADE rating: low). We did not pool data for time to insertion but estimates from the trials suggest that inserting intravenous access takes longer (GRADE rating: moderate). Clinicians judged the intravenous route to be easier to insert (RR 0.15, 95% CI 0.04 to 0.61; n = 182). A larger volume of fluids was infused via the intravenous route (GRADE rating: moderate). There was no evidence of a difference between the two routes for any other outcomes, including adverse events.Compared to the subcutaneous group, patients in the intravenous group were more likely to experience an insertion failure (RR 14.79, 95% CI 2.87 to 76.08; n = 238; GRADE rating: moderate) and dislodgement of the device (RR 3.78, 95% CI 1.16 to 12.34; n = 67; GRADE rating: low). Clinicians also judged the intravenous route as being more difficult to insert and patients were more likely to be agitated in the intravenous group. Patients in the intravenous group were more likely to develop a local infection and phlebitis, but were less likely to develop erythema, oedema or swelling than those in the subcutaneous group. A larger volume of fluids was infused into patients via the intravenous route. There was no evidence of a difference between the two routes for any other outcome.There were insufficient data to reliably determine if the risk of insertion failure differed between the saphenous vein cutdown (SVC) and intraosseous method (RR 4.00, 95% CI 0.51 to 31.13; GRADE rating: low). Insertion using SVC took longer than the intraosseous method (MD 219.60 seconds, 95% CI 135.44 to 303.76; GRADE rating: moderate). There were no data and therefore there was no evidence of a difference between the two routes for any other outcome.There were insufficient data to reliably determine the relative effects of intraperitoneal or central intravenous access relative to any other parenteral access method. AUTHORS' CONCLUSIONS: There are several different ways of achieving parenteral access in patients who are unable meet their fluid requirements with oral intake alone. The quality of the evidence, as assessed using the GRADE criteria, is somewhat limited because of the lack of adequately powered trials at low risk of bias. However, we believe that there is sufficient evidence to draw the following conclusions: if peripheral intravenous access can be achieved easily, this allows infusion of larger volumes of fluid than other routes; but if this is not possible, the intraosseous and subcutaneous routes are viable alternatives. The subcutaneous route may be suitable for patients who are not severely dehydrated but in whom ongoing fluid losses cannot be met by oral intake.A film to accompany this review can be viewed here (http://youtu.be/ArVPzkf93ng). PMID- 25914909 TI - Hydrogel dressings for treating pressure ulcers. AB - BACKGROUND: Pressure ulcers, also known as bedsores, decubitus ulcers and pressure injuries, are localised areas of injury to the skin or the underlying tissue, or both. Dressings are widely used to treat pressure ulcers and there are many different dressing options including hydrogel dressings. A clear and current overview of the current evidence is required to facilitate decision-making regarding dressing use for the treatment of pressure ulcers. OBJECTIVES: To assess the effects of hydrogel dressings on the healing of pressure ulcers in any care setting. SEARCH METHODS: We searched the following databases: the Cochrane Wounds Group Specialised Register (searched 19 June 2014); The Cochrane Central Register of Controlled Trials (CENTRAL; 2014, Issue 5); Ovid MEDLINE (1946 to June Week 2 2014); Ovid MEDLINE (In-Process & Other Non-Indexed Citations, 23 June 2014); Ovid EMBASE (1974 to 20 June 2014); and EBSCO CINAHL (1982 to 18 June 2014). There were no restrictions based on language or date of publication. SELECTION CRITERIA: Published or unpublished randomised controlled trials (RCTs) comparing the effects of hydrogel dressings with alternative wound dressings or no dressing in the treatment of pressure ulcers (stage II or above). DATA COLLECTION AND ANALYSIS: Two review authors independently performed study selection, risk of bias assessment and data extraction. MAIN RESULTS: We included eleven studies (523 participants) in this review. Ten studies had two arms and one had three arms that were all relevant to this review. Three studies compared a hydrogel dressing with a basic wound contact dressing; three studies compared a hydrogel dressing with a hydrocolloid dressing; three studies compared a hydrogel dressing with another hydrogel dressing; one study compared a hydrogel dressing with a foam dressing; one study compared a hydrogel dressing with a dextranomer paste dressing and one study compared a hydrogel dressing with a topical treatment (collagenase). Limited data were available for analyses in this review: we conducted no meta-analyses. Where data were available there was no evidence of a difference between hydrogel and alternative treatments in terms of complete wound healing or adverse events. One small study reported that using hydrogel dressings was, on average, less costly than hydrocolloid dressings, but this estimate was imprecise and its methodology was not clear. All included studies were small, had short follow-up times and were at unclear risk of bias. AUTHORS' CONCLUSIONS: It is not clear if hydrogel dressings are more or less effective than other treatments in healing pressure ulcers or if different hydrogels have different effects, Most trials in this field are very small and poorly reported so that risk of bias is unclear. PMID- 25914910 TI - Interventions to increase adherence to medications for tobacco dependence. AB - BACKGROUND: Pharmacological treatments for tobacco dependence, such as nicotine replacement therapy (NRT), have been shown to be safe and effective interventions for smoking cessation. Higher levels of adherence to these medications increase the likelihood of sustained smoking cessation, but many smokers use them at a lower dose and for less time than is optimal. It is therefore important to determine the effectiveness of interventions designed specifically to increase medication adherence. Such interventions may include further educating individuals about the value of taking medications and providing additional support to overcome problems with maintaining adherence. OBJECTIVES: The primary objective of this review was to assess the effectiveness of interventions to increase adherence to medications for smoking cessation, such as NRT, bupropion, nortriptyline and varenicline (and combination regimens). This was considered in comparison to a control group, typically representing standard care. Secondary objectives were to i) assess which intervention approaches are most effective; ii) determine the impact of interventions on potential precursors of adherence, such as understanding of the treatment and efficacy perceptions; and iii) evaluate key outcomes influenced by prior adherence, principally smoking cessation. SEARCH METHODS: We searched the following databases using keywords and medical subject headings: Cochrane Central Register of Controlled Trials (CENTRAL, The Cochrane Library), MEDLINE (OVID SP) (1946 to July Week 3 2014), EMBASE (OVID SP) (1980 to Week 29 2014), and PsycINFO (OVID SP) (1806 to July Week 4 2014). The Cochrane Tobacco Addiction Group Specialized Register was searched on 9th July 2014. We conducted forward and backward citation searches. SELECTION CRITERIA: Randomised, cluster-randomised or quasi-randomised studies in which participants using active pharmacological treatment for smoking cessation are allocated to an intervention arm or a control arm. Eligible participants were adult (18+) smokers. Eligible interventions comprised any intervention that differed from standard care, and where the intervention content had a clear principal focus on increasing adherence to medications for tobacco dependence. Acceptable comparison groups were those that provided standard care, which depending on setting may comprise minimal support or varying degrees of behavioural support. Included studies used a measure of adherence behaviour that allowed some assessment of the degree of adherence. DATA COLLECTION AND ANALYSIS: Two review authors searched for studies and independently extracted data for included studies. Risk of bias was assessed according to the Cochrane Handbook guidance. For continuous outcome measures, we report effect sizes as standardised mean differences (SMDs). For dichotomous outcome measures, we report effect sizes as relative risks (RRs). We obtained pooled effect sizes with 95% confidence intervals (CIs) using the fixed effects model. MAIN RESULTS: Our search strategy retrieved 3165 unique references and we identified 31 studies as potentially eligible for inclusion. Of these, 23 studies were excluded at full-text screening stage or identified as studies awaiting classification subject to further information. We included eight studies involving 3336 randomised participants. The interventions were all additional to standard behavioural support and typically provided further information on the rationale for, and emphasised the importance of, adherence to medication, and supported the development of strategies to overcome problems with maintaining adherence.Five studies reported on whether or not participants achieved a specified satisfactory level of adherence to medication. There was evidence that adherence interventions led to modest improvements in adherence, with a relative risk (RR) of 1.14 (95% CI, 1.02 to 1.28, P = 0.02, n = 1630). Four studies reported continuous measures of adherence to medication. Although the standardised mean difference (SMD) favoured adherence interventions, the effect was small and not statistically significant (SMD 0.07, 95% CI, -0.03 to 0.17, n = 1529). Applying the GRADE system, the quality of evidence for these results was assessed as moderate and low, respectively.There was evidence that adherence interventions led to modest improvements in rates of cessation. The relative risk for achieving abstinence was similar to that for improved adherence. It was not significant in meta analysis of four studies providing short-term abstinence: RR = 1.07 (95% CI 0.95 to 1.21, n = 1755), but there was statistically significant evidence of improved abstinence at six months or more from a different set of four studies: RR = 1.16 (95% CI, 1.01 to 1.34, P = 0.03, n = 3049). Applying the GRADE system, the quality of evidence for these results was assessed as low for both.As interventions were similar in nature and the number of studies was low, it was not possible to investigate whether different types of intervention approaches were more effective than others. Relevant outcomes other than adherence or cessation were not reported.There was no evidence that interventions to increase adherence to medication led to any adverse events. All included studies were assessed as at high or unclear risk of bias. This was often due to a lack of clarity in reporting - meaning assessments were unclear - rather than clear evidence of failing to sufficiently safeguard against the risk of bias. AUTHORS' CONCLUSIONS: There is some evidence that interventions that devote special attention to improving adherence to smoking cessation medication through providing information and facilitating problem-solving can improve adherence, though the evidence for this is not strong and is limited in both quality and quantity. There is some evidence that such interventions improve the chances of achieving abstinence but again the evidence for this is relatively weak. PMID- 25914911 TI - Giant symptomatic aneurysm of the inferior vena cava. PMID- 25914912 TI - Effectiveness of opioid analgesics in chronic noncancer pain. AB - BACKGROUND: There is general agreement about the need to perform a screening test to assess the risk of opioid misuse prior to starting a long-term opioid treatment for chronic noncancer pain. The evidence supporting the effectiveness of opioid long-term treatment is weak, and no predictors of its usefulness have been assessed. OBJECTIVE: The aim of this study was to assess the effect on pain and quality of life of chronic opioid treatment, and detect the possible predictors of its effectiveness. METHODS: This observational, prospective study was conducted in 2 Italian Pain Relief Units on 77 patients affected by intractable chronic pain. Patients were submitted to psycho-logical tests, investigating the individual pain experience, risk of opioid misuse, mood states, quality of life, and personality characteristics prior to starting treatment and at 2,4, and 6-month follow-up. RESULTS: Both maximum and habitual pain, as measured with VAS, underwent a statistically significant reduction at 2, 4, and 6 month follow-up. In multivariate analysis, lower scores in the Pain Medication Questionnaire (PMQ) were predictive of a major reduction in maximum VAS (P = 0.005). Both low PMQ and MMPI-cynicism scores were predictive of habitual VAS decrease (P = 0.012 and P = 0.028, respectively). CONCLUSION: The results indicate that pain relief significantly improved over a 6-month period of opioid treatment, together with quality of life. The outcome was better in patients with a pretreatment low risk of opioid misuse, low scores in the Cynicism scale of MMPI-2, and no aberrant drug behaviors at follow-up. Therefore, a psychological screening and support is crucial for a good outcome of opioid therapy for chronic noncancer pain patients. PMID- 25914914 TI - Retraction statement: "Depression as a risk factor for dementia and mild cognitive impairment: a meta-analysis of longitudinal studies" by Yuan Gao et al. PMID- 25914913 TI - Reduced effect of percutaneous retrogasserian glycerol rhizolysis in trigeminal neuralgia affecting the third branch. AB - INTRODUCTION: The objective of this study was to determine the long-term efficacy of percutaneous glycerol rhizolysis of the trigeminal ganglion for treating patients with trigeminal neuralgia and search for predictors associated with (long-term) benefit to improve patient selection. METHODS: A retrospective study in 60 consecutive patients treated with percutaneous glycerol rhizolysis of the trigeminal ganglion for trigeminal neuralgia. Charts were reviewed in combination with follow-up by questionnaire (n = 55, 92% response). RESULTS: Initial pain relief was achieved in 92% of the patients. Pain-free survival was 59% of the patients at 12 months and 53% at 24 months. Most common side effects were hypesthesia (15%), dry eye (5%), and meningitis (2%). In patients without involvement of the third branch of the trigeminal nerve, the initial effect was 79%, of which 90% achieved more than 2 years pain-free survival, compared with 97% initial effect and less than 40% pain-free survival of more than 2 years when the third trigeminal branch was involved. DISCUSSION: The present study demonstrates that involvement of the third branch is a negative predictor for long-term outcome in percutaneous glycerol rhizolysis of the trigeminal ganglion in patients with classical trigeminal neuralgia. However, in the absence of third branch involvement, glycerol rhizolysis yields excellent long-term results when initial positive effect is obtained. PMID- 25914915 TI - Prognostic scoring systems for mortality in intensive care units -- the APACHE model. PMID- 25914916 TI - Growth hormone treatment for childhood short stature and risk of stroke in early adulthood. PMID- 25914917 TI - Growth hormone treatment for childhood short stature and risk of stroke in early adulthood--author's response. PMID- 25914918 TI - Viva questions from the IJDVL. PMID- 25914919 TI - Prof. Dr. B. Narasimha Rao. PMID- 25914920 TI - Measure and treat sleep disturbance in breast cancer survivors. PMID- 25914921 TI - Benzobisimidazole cruciform fluorophores. AB - A series of 11 cross-conjugated cruciform fluorophores based on a benzobisimidazole nucleus has been synthesized and characterized. Like in their previously reported benzobisoxazole counterparts, the HOMOs of these new fluorophores are localized along the vertical bisethynylbenzene axes, while their LUMOs remain relatively delocalized across the molecule, except in cruciforms substituted with electron-withdrawing groups along the vertical axis. Benzobisimidazole cruciforms exhibit a pronounced response to deprotonation in their UV/vis absorption and emission spectra, but their response to protonation is significantly attenuated. PMID- 25914922 TI - A critical role of nucleus accumbens dopamine D1-family receptors in renewal of alcohol seeking after punishment-imposed abstinence. AB - In humans, places or contexts previously associated with alcohol use often provoke relapse during abstinence. This phenomenon is modeled in laboratory animals using the ABA renewal procedure, in which extinction training in context (B) suppresses alcohol seeking, and renewal of this seeking occurs when the animal returns to the original training context (A). However, extinction training does not adequately capture the motivation for abstinence in human alcoholics who typically self-initiate abstinence in response to the negative consequences of excessive use. We recently developed a procedure to study renewal in laboratory rats after abstinence imposed by negative consequences (footshock punishment). The mechanisms of renewal of punished alcohol seeking are largely unknown. Here, we used the D1-family receptor antagonist SCH 23390 to examine the role of nucleus accumbens (NAc) shell and core dopamine in renewal of alcohol seeking after punishment-imposed abstinence. We trained alcohol-preferring "P rats" to self-administer 20% alcohol in Context A and subsequently suppressed alcohol taking via response-contingent footshock punishment in Context B. We tested the effects of systemic, NAc shell, or NAc core injections of SCH 23390 on renewal of alcohol seeking after punishment-imposed abstinence. We found that both systemic and NAc shell and core injections of SCH 23390 decreased renewal of punished alcohol seeking. Our results demonstrate a critical role of NAc dopamine in renewal of alcohol seeking after punishment-imposed abstinence. We discuss these results in reference to the brain mechanisms of renewal of alcohol seeking after extinction versus punishment. PMID- 25914923 TI - The impact of motivation on cognitive performance in an animal model of the negative and cognitive symptoms of schizophrenia. AB - Interactions between motivation and cognition are implicated in producing functional impairments and poor quality of life in psychiatric patients. This interaction, however, is not well understood at either the behavioral or neural level. We developed a procedure for mice in which a cognitive measure, sustained attention, is modulated by a motivationally relevant signal that predicts reward probability on a trial-by-trial basis. Using this paradigm, we tested the interaction between motivation and cognition in mice that model the increased striatal D2 receptor activity observed in schizophrenia patients (D2R-OE mice). In control mice, attention was modulated by signaled-reward probability. In D2R OE mice, however, attention was not modulated by reward-related cues. This impairment was not due to any global deficits in attention or maintenance of the trial-specific information in working memory. Turning off the transgene in D2R-OE mice rescued the motivational modulation of attention. These results indicate that deficits in motivation impair the ability to use reward-related cues to recruit attention and that improving motivation improves functional cognitive performance. These results further suggest that addressing motivational impairments in patients is critical to achieving substantive cognitive and functional gains. PMID- 25914924 TI - Interaction of metabolic stress with chronic mild stress in altering brain cytokines and sucrose preference. AB - There is growing evidence that metabolic stressors increase an organism's risk of depression. Chronic mild stress is a popular animal model of depression and several serendipitous findings have suggested that food deprivation prior to sucrose testing in this model is necessary to observe anhedonic behaviors. Here, we directly tested this hypothesis by exposing animals to chronic mild stress and used an overnight 2-bottle sucrose test (food ad libitum) on Day 5 and 10, then food and water deprive animals overnight and tested their sucrose consumption and preference in a 1-hr sucrose test the following morning. Approximately 65% of stressed animals consumed sucrose and showed a sucrose preference similar to nonstressed controls in an overnight sucrose test, and 35% showed a decrease in sucrose intake and preference. Following overnight food and water deprivation the previously "resilient" animals showed a significant decrease in sucrose preference and greatly reduced sucrose intake. In addition, we evaluated whether the onset of anhedonia following food and water deprivation corresponds to alterations in corticosterone, epinephrine, circulating glucose, or interleukin-1 beta (IL-1beta) expression in limbic brain areas. Although all stressed animals showed adrenal hypertrophy and elevated circulating epinephrine, only stressed animals that were food deprived were hypoglycemic compared with food-deprived controls. Additionally, food and water deprivation significantly increased hippocampus IL-1beta while food and water deprivation only increased hypothalamus IL-1beta in stress-susceptible animals. These data demonstrate that metabolic stress of food and water deprivation interacts with chronic stressor exposure to induce physiological and anhedonic responses. PMID- 25914925 TI - Significant reduction of aggression with guanfacine extended release in an adolescent with Prader-Willi syndrome. PMID- 25914926 TI - Size Resolved High Temperature Oxidation Kinetics of Nano-Sized Titanium and Zirconium Particles. AB - While ultrafine metal particles offer the possibility of very high energy density fuels, there is considerable uncertainty in the mechanism by which metal nanoparticles burn, and few studies that have examined the size dependence to their kinetics at the nanoscale. In this work we quantify the size dependence to the burning rate of titanium and zirconium nanoparticles. Nanoparticles in the range of 20-150 nm were produced via pulsed laser ablation, and then in-flight size-selected using differential electrical mobility. The size-selected oxide free metal particles were directly injected into the post flame region of a laminar flame to create a high temperature (1700-2500 K) oxidizing environment. The reaction was monitored using high-speed videography by tracking the emission from individual nanoparticles. We find that sintering occurs prior to significant reaction, and that once sintering is accounted for, the rate of combustion follows a near nearly (diameter)(1) power-law dependence. Additionally, Arrhenius parameters for the combustion of these nanoparticles were evaluated by measuring the burn times at different ambient temperatures. The optical emission from combustion was also used to model the oxidation process, which we find can be reasonably described with a kinetically controlled shrinking core model. PMID- 25914927 TI - The experience of challenging behaviours following severe TBI: A family perspective. AB - PRIMARY OBJECTIVE: Family caregivers play an important role in managing challenging behaviours after TBI. The aims of this study were to understand how family caregivers of individuals with TBI perceive challenging behaviours and their impact on the TBI individual's community integration and family functioning. RESEARCH DESIGN: A qualitative research design was employed to capture the lived experience of family caregivers of individuals with TBI. METHODS AND PROCEDURES: Face-to-face interviews were conducted on six female family caregivers of individuals with severe TBI (sustained an average of 17 years earlier) and long-standing challenging behaviours. MAIN OUTCOMES AND RESULTS: The results revealed that family caregivers adopted a broader definition of challenging behaviour than that used by professionals and these behaviours impacted on the community integration of the individual with TBI, most notably leading to poor social relationships. Challenging behaviours were viewed as a key source of distress and burden for family caregivers and they used many different strategies to manage the behaviours. CONCLUSION: Greater understanding of challenging behaviours from the perspectives of family caregivers may help provide more effective support and interventions to improve quality-of-life for individuals with challenging behaviours after TBI and their families. PMID- 25914928 TI - Does addition of an electrolyte influence the rotational diffusion of nondipolar solutes in a protic ionic liquid? AB - Rotational diffusion of two structurally similar nondipolar solutes, 2,5-dimethyl 1,4-dioxo-3,6-diphenylpyrrolo[3,4-c]pyrrole (DMDPP) and 1,4-dioxo-3,6 diphenylpyrrolo[3,4-c]pyrrole (DPP), has been examined in ethylammonium nitrate lithium nitrate (EAN-LiNO3) mixtures to understand the influence of added electrolyte on the local environment experienced by the solute molecules. The measured reorientation times of both DMDPP and DPP in EAN-LiNO3 mixtures fall within the broad limits set by the hydrodynamic slip and stick boundary conditions. The hydrogen bond accepting DMDPP and the hydrogen bond donating DPP experience specific interactions with the cation and anion of the ionic liquid, respectively. Addition of LiNO3 (0.1 and 0.2 mole fraction) to EAN induces only viscosity related effects on the rotational diffusion of the two nondipolar solutes. These observations suggest that the local environment experienced by DMDPP and DPP in EAN is not altered upon the addition of LiNO3. Our results are consistent with the structural details available in the literature for EAN-LiNO3 mixtures. PMID- 25914929 TI - The Current and Future Landscape of SERCA Gene Therapy for Heart Failure: A Clinical Perspective. AB - Gene therapy has been applied to cardiovascular disease for over 20 years but it is the application to heart failure that has generated recent interest in clinical trials. There is laboratory and early clinical evidence that delivery of sarcoplasmic reticulum calcium ATPase 2a (SERCA2a) gene therapy is beneficial for heart failure and this therapy could become the first positive inotrope with anti arrhythmic properties. In this review we will discuss the rationale for SERCA2a gene therapy as a viable strategy in heart failure, review the published data, and discuss the ongoing clinical trials, before concluding with comments on the future challenges and potential for this therapy. PMID- 25914930 TI - Combined T2w volumetry, DW-MRI and DCE-MRI for response assessment after neo adjuvant chemoradiation in locally advanced rectal cancer. AB - BACKGROUND: To assess the value of combined T2-weighted magnetic resonance imaging (MRI) (T2w) volumetry, diffusion-weighted (DW)-MRI and dynamic contrast enhanced (DCE)-MRI for pathological response prediction after neo-adjuvant chemoradiation (CRT) in locally advanced rectal cancer (LARC). MATERIAL AND METHODS: MRI with DW-MRI and DCE-MRI sequences was performed before start of CRT and before surgery. After surgery, the tumor regression grade (TRG) was obtained based on the score by Mandard et al. Pathological complete responders (pCR, TRG 1), and pathological good responders (GR, TRG 1 + 2) were compared to non-pCR and non-GR patients, respectively. RESULTS: In total 55 patients were analyzed, six had a pCR (10.9%) and 10 a GR (18.2%). Favorable responders had a larger decrease in tumor volume and Ktrans and a larger increase in apparent diffusion coefficient (ADC) values compared to non-responders. ADC change showed the best diagnostic accuracy for pCR. For GR, the model including ADC change and volume change showed the best diagnostic performance. However, this performance was not statistically better compared to the model with ADC change alone. Inclusion of Ktrans change did not increase the diagnostic accuracy for pathological favorable response. CONCLUSIONS: This explorative study showed that ADC change is a promising diagnostic tool for pCR and GR. Volume decrease showed potential limited additional diagnostic value for GR while Ktrans change showed no additional diagnostic value for pCR and GR. PMID- 25914931 TI - Unsustained response to brentuximab as single agent therapy in a patient with CD30 positive angiosarcoma. PMID- 25914932 TI - Immunological characteristics and management considerations in obese patients with asthma. AB - Obesity is associated with severe, poorly controlled asthma that does not respond as well to therapy as asthma in leaner asthmatics. Important insights gained from animal models of obesity and asthma suggests that different forms of obesity may lead to different manifestations of airway disease: obesity is associated with both innate increased airway reactivity and altered responses to aeroallergen and pollutant challenges. In humans, at least two broad groups of obese asthmatics have been recognized: one that is likely unique to obesity and another that is likely lean allergic asthma much complicated by obesity. This article will discuss what we have learned about the immunological and pathophysiological basis of asthma in obesity from animal and human studies, and how this might guide therapy. PMID- 25914935 TI - Neutrophil sensing of cytoplasmic, pathogenic DNA in a cGAS-STING-independent manner. PMID- 25914934 TI - Activation of NLRC4 downregulates TLR5-mediated antibody immune responses against flagellin. AB - Bacterial flagellin is a unique pathogen-associated molecular pattern (PAMP), which can be recognized by surface localized Toll-like receptor 5 (TLR5) and the cytosolic NOD-like receptor (NLR) protein 4 (NLRC4) receptors. Activation of the TLR5 and/or NLRC4 signaling pathways by flagellin and the resulting immune responses play important roles in anti-bacterial immunity. However, it remains unclear how the dual activities of flagellin that activate the TLR5 and/or NLRC4 signaling pathways orchestrate the immune responses. In this study, we assessed the effects of flagellin and its mutants lacking the ability to activate TLR5 and NLRC4 alone or in combination on the adaptive immune responses against flagellin. Flagellin that was unable to activate NLRC4 induced a significantly higher antibody response than did wild-type flagellin. The increased antibody response could be eliminated when macrophages were depleted in vivo. The activation of NLRC4 by flagellin downregulated the flagellin-induced and TLR5-mediated immune responses against flagellin. PMID- 25914937 TI - Influence of self-controlled feedback on learning a serial motor skill. AB - Self-controlled feedback on a variety of tasks are well established as effective means of facilitating motor skill learning. This study assessed the effects of self-controlled feedback on the performance of a serial motor skill. The task was to learn the sequence of 18 movements that make up the Taekwondo Poomsae Taegeuk first, which is the first beginner's practice form learned in this martial art. Twenty-four novice female participants (M age=27.2 yr., SD=1.8) were divided into two groups. All participants performed 16 trials in 4 blocks of the acquisition phase and 20 hr. later, 8 trials in 2 blocks of the retention phase. The self controlled feedback group had significantly higher performance compared to the yoked-feedback group with regard to acquisition and retention. The results of this study may contribute to the literature regarding feedback by extending the usefulness of self-controlled feedback for learning a serial skill. PMID- 25914938 TI - Effect of structural composition and position of occlusion on the legibility of occluded Chinese characters. AB - The study examined the effect of structural composition, position of occlusion, and education background on response time and accuracy rate of adult participants in recognition of occluded Chinese characters used in graphic design. Based on 18 Chinese characters selected from the top 4,000 most commonly used characters, a recognition experiment was conducted. Results indicated that, for the characters with two different composition structures, the right position was the best position of occlusion because the recognition of the radical or feature of a character would be least affected, leading to a shorter response time and more accurate reading comprehension. Educational background did not have a significant influence on response time and recognition accuracy. PMID- 25914936 TI - Lineage relationship of CD8(+) T cell subsets is revealed by progressive changes in the epigenetic landscape. AB - To better elucidate epigenetic mechanisms that correlate with the dynamic gene expression program observed upon T-cell differentiation, we investigated the genomic landscape of histone modifications in naive and memory CD8(+) T cells. Using a ChIP-Seq approach coupled with global gene expression profiling, we generated genome-wide histone H3 lysine 4 (H3K4me3) and H3 lysine 27 (H3K27me3) trimethylation maps in naive, T memory stem cells, central memory cells, and effector memory cells in order to gain insight into how histone architecture is remodeled during T cell differentiation. We show that H3K4me3 histone modifications are associated with activation of genes, while H3K27me3 is negatively correlated with gene expression at canonical loci and enhancers associated with T-cell metabolism, effector function, and memory. Our results also reveal histone modifications and gene expression signatures that distinguish the recently identified T memory stem cells from other CD8(+) T-cell subsets. Taken together, our results suggest that CD8(+) lymphocytes undergo chromatin remodeling in a progressive fashion. These findings have major implications for our understanding of peripheral T-cell ontogeny and the formation of immunological memory. PMID- 25914939 TI - Effects of audio-visual aids on foreign language test anxiety, reading and listening comprehension, and retention in EFL learners. AB - This study examined the effects of audio-visual aids on anxiety, comprehension test scores, and retention in reading and listening to short stories in English as a Foreign Language (EFL) classrooms. Reading and listening tests, general and test anxiety, and retention were measured in English-major college students in an experimental group with audio-visual aids (n=83) and a control group without audio-visual aids (n=94) with similar general English proficiency. Lower reading test anxiety, unchanged reading comprehension scores, and better reading short term and long-term retention after four weeks were evident in the audiovisual group relative to the control group. In addition, lower listening test anxiety, higher listening comprehension scores, and unchanged short-term and long-term retention were found in the audiovisual group relative to the control group after the intervention. Audio-visual aids may help to reduce EFL learners' listening test anxiety and enhance their listening comprehension scores without facilitating retention of such materials. Although audio-visual aids did not increase reading comprehension scores, they helped reduce EFL learners' reading test anxiety and facilitated retention of reading materials. PMID- 25914940 TI - Investigation of the Chemical Interface in the Soybean-Aphid and Rice-Bacteria Interactions Using MALDI-Mass Spectrometry Imaging. AB - Mass spectrometry imaging (MSI) is an emerging technology for high-resolution plant biology. It has been utilized to study plant-pest interactions, but limited to the surface interfaces. Here we expand the technology to explore the chemical interactions occurring inside the plant tissues. Two sample preparation methods, imprinting and fracturing, were developed and applied, for the first time, to visualize internal metabolites of leaves in matrix-assisted laser desorption ionization (MALDI)-MSI. This is also the first time nanoparticle-based ionization was implemented to ionize diterpenoid phytochemicals that were difficult to analyze with traditional organic matrices. The interactions between rice bacterium and soybean-aphid were investigated as two model systems to demonstrate the capability of high-resolution MSI based on MALDI. Localized molecular information on various plant- or pest-derived chemicals provided valuable insight for the molecular processes occurring during the plant-pest interactions. Specifically, salicylic acid and isoflavone based resistance was visualized in the soybean-aphid system and antibiotic diterpenoids in rice-bacterium interactions. PMID- 25914941 TI - Small Molecule Disruptors of the Glucokinase-Glucokinase Regulatory Protein Interaction: 5. A Novel Aryl Sulfone Series, Optimization Through Conformational Analysis. AB - The glucokinase-glucokinase regulatory protein (GK-GKRP) complex plays an important role in controlling glucose homeostasis in the liver. We have recently disclosed a series of arylpiperazines as in vitro and in vivo disruptors of the GK-GKRP complex with efficacy in rodent models of type 2 diabetes mellitus (T2DM). Herein, we describe a new class of aryl sulfones as disruptors of the GK GKRP complex, where the central piperazine scaffold has been replaced by an aromatic group. Conformational analysis and exploration of the structure-activity relationships of this new class of compounds led to the identification of potent GK-GKRP disruptors. Further optimization of this novel series delivered thiazole sulfone 93, which was able to disrupt the GK-GKRP interaction in vitro and in vivo and, by doing so, increases cytoplasmic levels of unbound GK. PMID- 25914942 TI - Characteristics and Prognosis of Never-Smokers and Smokers with Asthma in the Copenhagen General Population Study. A Prospective Cohort Study. AB - RATIONALE: Asthma is associated with complications, cardiovascular comorbidities, and higher mortality in some individuals. OBJECTIVES: To test the hypothesis that, among individuals with asthma, never-smokers have different characteristics and a better prognosis than smokers. METHODS: We recruited 94,079 individuals aged 20-100 years from the Copenhagen General Population Study, a prospective cohort study. Among these individuals, 5,691 (6%) had self-reported asthma (2,304 never-smokers, 2,467 former smokers, and 920 current smokers). We examined respiratory symptoms, lung function, and levels of inflammatory and allergic biomarkers in systemic circulation. Furthermore, we assessed prospectively the risk of asthma or chronic obstructive pulmonary disease (COPD) exacerbations, pneumonias, lung cancer, ischemic heart disease, ischemic stroke, and all-cause mortality during 4.5 years of follow-up. MEASUREMENTS AND MAIN RESULTS: Compared with never-smokers without asthma, individuals with asthma had more respiratory symptoms and airflow limitation and higher levels of inflammatory and allergic biomarkers, which were most pronounced in smokers. Among individuals with asthma compared with never-smokers without asthma, multivariable adjusted hazard ratios for asthma exacerbations were 11 (95% confidence interval: 5.8-22) in never smokers, 13 (6.2-29) in former smokers, and 18 (8.2-39) in current smokers. The corresponding values for other endpoints were, respectively, 8.9 (2.1-38), 23 (8.8-58), and 36 (12-105) for COPD exacerbations; 1.5 (0.9-2.2), 1.6 (1.0-2.4), and 2.4 (1.6-3.7) for pneumonias; 0.6 (0.1-5.1), 4.0 (1.3-12), and 13 (4.3-41) for lung cancer; 1.2 (0.9-1.6), 1.5 (1.2-2.0), and 2.0 (1.4-2.9) for ischemic heart disease; 1.4 (0.9-2.1), 1.2 (0.8-1.9), and 3.0 (1.7-5.3) for ischemic stroke; and 0.9 (0.6-1.3), 1.5 (1.1-2.0), and 2.7 (1.9-3.7) for all-cause mortality. CONCLUSIONS: Never-smokers with asthma had an increased risk of asthma and COPD exacerbations, and possibly pneumonias. Importantly, the risks for lung cancer, cardiovascular comorbidities, and death were restricted to smokers with asthma. Thus, tobacco smoking was the main explanation for poor prognosis in asthma. PMID- 25914943 TI - Prevalence, natural course and predictors of depression 1 year following traumatic brain injury from a population-based study in New Zealand. AB - OBJECTIVE: Depression is common post-TBI, yet has not been studied longitudinally, nor at a population level. This study examined prevalence of depression in a population-based sample across the first year post-TBI. DESIGN AND METHODS: Prospective follow-up of 315 adults (>16 years) with assessments (Hospital Anxiety Depression Scale, DSM-IV criteria) at 1-, 6- and 12-months post TBI. Demographic and injury-related predictors of depression at 1-year post-TBI were also explored. RESULTS: The number of individuals identified as depressed reduced significantly between baseline and 12-months post-TBI from 21-12.4% using the HADS and 49-34% using DSM-IV criteria; with only 10 of the 28 individuals initially meeting criteria on the HADS continuing to do so at 12-month follow-up. Meeting HADS depression criteria was linked to pre-morbid depression and/or anxiety; while those meeting DSM-IV criteria were older, but not significantly so. CONCLUSIONS: The findings suggest depression is common post-TBI and that clinicians/researchers use caution in its diagnosis, as existing criteria have significant overlap with common TBI sequels. PMID- 25914944 TI - Interaction of spirochetes with the host fibrinolytic system and potential roles in pathogenesis. AB - The pathogenic spirochetes Borrelia burgdorferi, B. hermsii, B. recurrentis, Treponema denticola and Leptospira spp. are the etiologic agents of Lyme disease, relapsing fever, periodontitis and leptospirosis, respectively. Lyme borreliosis is a multi-systemic disorder and the most prevalent tick-borne disease in the northern hemisphere. Tick-borne relapsing fever is persistent in endemic areas worldwide, representing a significant burden in some African regions. Periodontal disease, a chronic inflammatory disorder that often leads to tooth loss, is caused by several potential pathogens found in the oral cavity including T. denticola. Leptospirosis is considered the most widespread zoonosis, and the predominant human disease in tropical, undeveloped regions. What these diseases have in common is that they are a significant burden to healthcare costs in the absence of prophylactic measures. This review addresses the interaction of these spirochetes with the fibrinolytic system, plasminogen (Plg) binding to the surface of bacteria and the generation of plasmin (Pla) on their surface. The consequences on host-pathogen interactions when the spirochetes are endowed with this proteolytic activity are discussed on the basis of the results reported in the literature. Spirochetes equipped with Pla activity have been shown to degrade extracellular matrix (ECM) components, in addition to digesting fibrin, facilitating bacterial invasion and dissemination. Pla generation triggers the induction of matrix metalloproteases (MMPs) in a cascade of events that enhances the proteolytic capacity of the spirochetes. These activities in concert with the interference exerted by the Plg/Pla on the complement system - helping the bacteria to evade the immune system - should illuminate our understanding of the mechanisms involved in host infection. PMID- 25914945 TI - Mechanisms of drug release in nanotherapeutic delivery systems. PMID- 25914946 TI - Improved efficiency of hybrid organic photovoltaics by pulsed laser sintering of silver nanowire network transparent electrode. AB - In this Research Article, we demonstrate pulsed laser processing of a silver nanowire network transparent conductor on top of an otherwise complete solar cell. The macroscopic pulsed laser irradiation serves to sinter nanowire-nanowire junctions on the nanoscale, leading to a much more conductive electrode. We fabricate hybrid silicon/organic heterojunction photovoltaic devices, which have ITO-free, solution processed, and laser processed transparent electrodes. Furthermore, devices which have high resistive losses show up to a 35% increase in power conversion efficiency after laser processing. We perform this study over a range of laser fluences, and a range of nanowire area coverage to investigate the sintering mechanism of nanowires inside of a device stack. The increase in device performance is modeled using a simple photovoltaic diode approach and compares favorably to the experimental data. PMID- 25914947 TI - Acute Circulatory Support with ECMO: Great Achievements but Still a Long Road Ahead. PMID- 25914949 TI - Mechanical bridge to long-term device implant: the necessary step for better outcomes. PMID- 25914950 TI - Feasibility and Safety of Early Physical Therapy and Active Mobilization for Patients on Extracorporeal Membrane Oxygenation. AB - Physical therapy (PT) and early mobilization for critically ill patients have been popularized to decrease the length of hospital stay and to improve the quality of life after discharge. We reviewed our experience of PT and active mobilization for patients on extracorporeal membrane oxygenation (ECMO) in terms of its technical feasibility and safety. Study endpoints were safety events during PT and PT interruptions due to unstable vital signs. Of the eight patients, one patient (12.5%) had venoarterial ECMO, seven patients (87.5%) had venovenous ECMO. Among total of 62 sessions including 31 sessions (50%) of passive range of motion and electrical muscle stimulation, 17 sessions (27.4%) were performed for patients who were sitting in bed or on the edge of bed, two sessions (3.2%) were for strengthening in sitting, 11 sessions (18%) were for standing or marching in place, one session (2%) was for walking. Eight sessions (13%) of sitting were supported with invasive mechanical ventilation. Three sessions (5%) were stopped due to tachycardia (n = 1) and tachypnea (n = 2). There was no clinically significant adverse event in patients. Thus, early PT and mobilization for patients on ECMO might be feasible and safe at an experienced ECMO center. PMID- 25914951 TI - First in Man: Sternal Reconstruction with Autologous Stem Cells. AB - Sternal nonunion is associated with high morbidity and treated using rigid plate and screw fixation. This is the first reported example of successful sternal reconstruction using adipose-derived stromal vascular fraction (SVF) stem cells in addition to traditional techniques. Mesenchymal stem cells, one component of the SVF, play an important role in bone healing and were therefore used to promote remedial processes in a patient with sternal nonunion. A 3D printed model of the patient's sternum was used for preoperative planning of the plating. Intraoperatively, SVF was isolated using ultrasonic cavitation and previously planned sternal plating was completed. A total of 300 million cells were delivered via both local injection and intravenously before chest closure. The patient's pain dramatically decreased, commensurate with healed areas of nonunion by 3 months and maintained at 6 months postoperatively, supported by three dimensional computed tomography imaging. Utilizing autologous stem cells from the SVF in conjunction with existing plating techniques may provide an optimal platform to stabilize the sternum and promote bone healing, although additional study is recommended. PMID- 25914953 TI - Robotic Left Ventricular Assist Device Implantation Using Left Thoracotomy Approach in Patients with Previous Sternotomies. AB - Left ventricular assist devices (LVADs) are commonly used as either a bridge-to transplant or a destination therapy. The traditional approach for LVAD implantation is via median sternotomy, but many candidates for this procedure have a history of failed cardiac surgeries and previous sternotomy. Redo sternotomy increases the risk of heart surgery, particularly in the setting of advanced heart failure. Robotics facilitates a less invasive approach to LVAD implantation that circumvents some of the morbidity associated with a redo sternotomy. We compared the outcomes of all patients at our institution who underwent LVAD implantation via either a traditional sternotomy or using robotic assistance. The robotic cohort showed reduced resource utilization including length of hospital stay and use of blood products. As the appropriate candidates become elucidated, robotic assistance may improve the safety and cost effectiveness of reoperative LVAD surgery. PMID- 25914954 TI - Roller and Centrifugal Pumps: A Retrospective Comparison of Bleeding Complications in Extracorporeal Membrane Oxygenation. AB - Centrifugal pumps are increasingly used for extracorporeal membrane oxygenation (ECMO) rather than roller pumps. However, shear forces induced by these types of continuousflow pumps are associated with acquired von Willebrand factor deficiency and bleeding complications. This study was undertaken to compare adverse bleeding complications with the use of centrifugal and roller pumps in patients on prolonged ECMO support. The records of all adult ECMO patients from June 2002 to 2013 were retrospectively reviewed using the University of Michigan Health System database and the Extracorporeal Life Support Organization registry, focusing on patients supported for at least 5 days. Ninety-five ECMO patients met criteria for inclusion (48 roller vs. 47 centrifugal pump). Indications included pulmonary (79%), cardiac (15%), and extracorporeal cardiopulmonary resuscitation (6%), without significant difference between the two groups. Despite lower heparin anticoagulation (10.9 vs. 13.7 IU/kg/hr) with centrifugal pumps, there was a higher incidence of nonsurgical bleeding (gastrointestinal, pulmonary, and neurological) in centrifugal pump patients (26.1 vs. 9.0 events/1,000 patient days, p = 0.024). In conclusion, in our historical comparison, despite reduced anticoagulation, ECMO support using centrifugal pumps was associated with a higher incidence of nonsurgical bleeding. The mechanisms behind this are multifactorial and require further investigation. PMID- 25914955 TI - Minimally Invasive Right Ventricular Assist Device Implantation in a Patient with HeartWare left ventricular Assist Device. AB - Many centers reported positive outcome after left ventricular assist devices (LVADs) implantation using a minimally invasive approach. The main drawback of this minimally invasive approach is the feasibility of right ventricular assist device (RVAD) implantation with direct cannulation of the pulmonary artery in cases of perioperative right ventricular failure (RVF). We report our experience with a 41-year-old male patient who was supported with a temporary RVAD using J sternotomy approach for RVF after LVAD implantation. No technical issue was encountered, and the patient's condition stabilized immediately after RVAD implantation. However, several days later, the patient developed severe septic shock caused by pneumonia and died on the postoperative day 15 after RVAD implantation. PMID- 25914956 TI - Lung Procurement from a Donor on ECMO Support. AB - We report the case of a 50-year-old man with congestive heart failure who became a candidate for organ donation after anoxic brain injury after cardiopulmonary resuscitation (CPR) who was on a venoarterial extracorporeal membrane oxygenation (ECMO) support. On visualization, the donor's lung was acceptable for lung transplantation to a 68-year-old male patient with a chronic history of pulmonary fibrosis. Right single-lung implantation was successfully performed in the recipient. Herein, we report a case that highlights our institution's result suggesting that the use of a lung previously on ECMO support can safely and potentially expand the donor lung pool in carefully selected patients. PMID- 25914957 TI - Use of ECMO in the Management of Severe Acute Respiratory Distress Syndrome: A Survey of Academic Medical Centers in the United States. AB - Mortality of severe acute respiratory distress syndrome (ARDS) remains high. Once conventional mechanical ventilation fails, alternative modes of therapy are used; most of which have limited evidence to support their use. No definitive guidelines exist for the management of these patients with alternate modalities of treatment. We conducted a cross-sectional national survey of 302 adult critical care training programs in the United States to understand the current preferences of intensivists regarding the use of different therapies for severe ARDS, including the use of extracorporeal membrane oxygenation (ECMO). A total of 381 responses were received: 203 critical care faculty and 174 critical care trainees. Airway pressure release ventilation was the initial choice of treatment reported by most when conventional mechanical ventilation strategy failed followed by inhaled nitric oxide and prone positioning. Extracorporeal membrane oxygenation availability was reported by 80% of the respondents at their institutions. Most respondents (83%) would consider ECMO in patients who fail optimal mechanical ventilation strategies, and the majority (60%) believed that ECMO use can facilitate lung protective ventilation, but few favored its use as a first-line modality. The majority of respondents reported limited knowledge of ECMO and desired specific ECMO education during training. PMID- 25914959 TI - Ruthenium-catalyzed silylation of 1,3-butadienes with vinylsilanes. AB - A novel method for the synthesis of 1-silyl-substituted 1,3-butadienes, based on [RuHCl(CO)(PCy3)2]-catalyzed silylative coupling of terminal (E)-1,3-dienes with vinylsilanes, is reported. The reaction provides a facile and straightforward access to (E,E)-dienylsilanes in a highly stereoselective fashion (especially for aryl-substituted dienes) and opens a valuable and general synthetic route for the direct catalytic silylation of conjugated dienes with elimination of ethylene as a single byproduct. Preliminary results on synthetic application of the synthesized silylated 1,3-butadienes in desilylation reactions are described. PMID- 25914958 TI - A reversible and highly selective inhibitor of the proteasomal ubiquitin receptor rpn13 is toxic to multiple myeloma cells. AB - The proteasome is a multisubunit complex responsible for most nonlysosomal turnover of proteins in eukaryotic cells. Proteasome inhibitors are of great interest clinically, particularly for the treatment of multiple myeloma (MM). Unfortunately, resistance arises almost inevitably to these active site-targeted drugs. One strategy to overcome this resistance is to inhibit other steps in the protein turnover cascade mediated by the proteasome. Previously, Anchoori et al. identified Rpn13 as the target of an electrophilic compound (RA-190) that was selectively toxic to MM cells (Cancer Cell 2013, 24, 791-805), suggesting that this subunit of the proteasome is also a viable cancer drug target. Here we describe the discovery of the first highly selective, reversible Rpn13 ligands and show that they are also selectively toxic to MM cells. These data strongly support the hypothesis that Rpn13 is a viable target for the development of drugs to treat MM and other cancers. PMID- 25914960 TI - Trends in Treatment of Uterine Serous Cancer in the Medicare Population. AB - OBJECTIVE: The objectives of this study were to evaluate the rates of chemotherapy and radiotherapy delivery in the treatment of uterine serous carcinoma in the Medicare population and to compare clinical outcomes in treated and untreated patients. METHODS: The linked Surveillance, Epidemiology, and End Results and Medicare databases were queried to identify patients with a diagnosis of uterine serous carcinoma between 1992 and 2009. The impact of chemotherapy on survival was analyzed using the Kaplan-Meier method. Factors predictive of outcome were compared using the Cox proportional hazards model. RESULTS: A total of 2188 patients met study eligibility criteria. Stages I, II, III, and IV diseases accounted for 890 (41%), 174 (8%), 470 (21%), and 654 (30%) of the study population, respectively. Chemotherapy, radiotherapy, both, or none, were administered as adjuvant therapy in 635 (29%), 536 (24%), 308 (14%), and 709 (32%) of the study population, respectively. Use of chemotherapy became more frequent over time. Over the study period, and after adjusting for race, time of diagnosis, SEER registry, marital status, stage, age, surgery, lymph node dissection, socioeconomic status, and comorbidity index, there was an association between receipt of radiotherapy alone (hazard ratio [HR], 1.3; 95% CI, 1.04-1.67) and not receiving any treatment (HR, 1.5; 95% CI, 1.2-2.01) and worst survival. Survival was not improved over time. CONCLUSION: Although adjuvant chemotherapy and combination treatment with chemotherapy and radiation were associated with improved survival in our model, there was no significant improvement in survival over time. PMID- 25914961 TI - An Exercise Intervention During Chemotherapy for Women With Recurrent Ovarian Cancer: A Feasibility Study. AB - OBJECTIVE: The aim of this study was to determine the feasibility of a combined supervised and home-based exercise intervention during chemotherapy for women with recurrent ovarian cancer. Secondary aims were to determine the impact of physical activity on physical and psychological outcomes and on chemotherapy completion rates. METHODS: Women with recurrent ovarian cancer were recruited from 3 oncology outpatient clinics in Sydney and Canberra, Australia. All participants received an individualized exercise program that consisted of 90 minutes or more of low to moderate aerobic, resistance, core stability, and balance exercise per week, for 12 weeks. Feasibility was determined by recruitment rate, retention rate, intervention adherence, and adverse events. Aerobic capacity, muscular strength, fatigue, sleep quality, quality of life, depression, and chemotherapy completion rates were assessed at weeks 0, 12, and 24. RESULTS: Thirty participants were recruited (recruitment rate, 63%), with a retention rate of 70%. Participants averaged 196 +/- 138 min . wk of low to moderate physical activity throughout the intervention, with adherence to the program at 81%. There were no adverse events resulting from the exercise intervention. Participants who completed the study displayed significant improvements in quality of life (P = 0.017), fatigue (P = 0.004), mental health (P = 0.007), muscular strength (P = 0.001), and balance (P = 0.003) after the intervention. Participants completing the intervention had a higher relative dose intensity than noncompleters (P = 0.03). CONCLUSIONS: A program consisting of low to moderate exercise of 90 min . wk was achieved by two-thirds of women with recurrent ovarian cancer in this study, with no adverse events reported. Randomized control studies are required to confirm the benefits of exercise reported in this study. PMID- 25914962 TI - Outcome of Epithelial Ovarian Cancer: Time for Strategy Trials to Resolve the Problem of Optimal Timing of Surgery. AB - INTRODUCTION: The standard treatment of ovarian cancer is the combination of debulking surgery and chemotherapy. There is an ongoing discussion on which treatment is best: primary debulking surgery (PDS) or neoadjuvant chemotherapy with interval debulking (NACT-IDS). Even a large randomized trial has not settled this issue. We examined whether comparing a specified treatment protocol would not be a more logical approach to answer this type of discussions. METHODS: A retrospective study of 142 consecutively treated patients according to a fixed protocol between 2000 and 2012 was conducted. Disease-free survival and overall survival were calculated by univariate and multivariate analyses for the whole group and for advanced stages separately. Specific differences between PDS and NACT-IDS were studied. Comparison of results from large databases was made. RESULTS: Disease-free survival and overall 5-year survival for the whole group were 35% and 50%. For the advanced stages, disease-free survival and overall 5 year survival were 14% and 36%, with a median disease-free and overall survival of 16 and 44 months. Of the 98 women with advanced ovarian carcinoma, 54% of operable patients underwent PDS and 44% underwent NACT-IDS. More patients in the PDS group were optimally (<1 cm) debulked: 80% vs 71%. There was no significant difference in survival between PDS or NACT-IDS. Optimally debulked patients had a significant better overall survival in multivariate analysis with a hazard ratio of 2.1. DISCUSSION: Outcome of treatment according to a fixed protocol with a mixture of PDS and NACT-IDS was similar to results from large databases. We hypothesize that comparison of a specific strategy may yield more useful results than awaiting the perfect randomized trial. PMID- 25914963 TI - Follow the guideline for reducing cardiovascular risk with statins. PMID- 25914964 TI - Leveraging Nanocavity Harmonics for Control of Optical Processes in 2D Semiconductors. AB - Optical cavities with multiple tunable resonances have the potential to provide unique electromagnetic environments at two or more distinct wavelengths--critical for control of optical processes such as nonlinear generation, entangled photon generation, or photoluminescence (PL) enhancement. Here, we show a plasmonic nanocavity based on a nanopatch antenna design that has two tunable resonant modes in the visible spectrum separated by 350 nm and with line widths of ~60 nm. The importance of utilizing two resonances simultaneously is demonstrated by integrating monolayer MoS2, a two-dimensional semiconductor, into the colloidally synthesized nanocavities. We observe a 2000-fold enhancement in the PL intensity of MoS2--which has intrinsically low absorption and small quantum yield--at room temperature, enabled by the combination of tailored absorption enhancement at the first harmonic and PL quantum-yield enhancement at the fundamental resonance. PMID- 25914965 TI - Cell Adhesion Minimization by a Novel Mesh Culture Method Mechanically Directs Trophoblast Differentiation and Self-Assembly Organization of Human Pluripotent Stem Cells. AB - Mechanical methods for inducing differentiation and directing lineage specification will be instrumental in the application of pluripotent stem cells. Here, we demonstrate that minimization of cell-substrate adhesion can initiate and direct the differentiation of human pluripotent stem cells (hiPSCs) into cyst forming trophoblast lineage cells (TLCs) without stimulation with cytokines or small molecules. To precisely control cell-substrate adhesion area, we developed a novel culture method where cells are cultured on microstructured mesh sheets suspended in a culture medium such that cells on mesh are completely out of contact with the culture dish. We used microfabricated mesh sheets that consisted of open meshes (100~200 MUm in pitch) with narrow mesh strands (3-5 MUm in width) to provide support for initial cell attachment and growth. We demonstrate that minimization of cell adhesion area achieved by this culture method can trigger a sequence of morphogenetic transformations that begin with individual hiPSCs attached on the mesh strands proliferating to form cell sheets by self-assembly organization and ultimately differentiating after 10-15 days of mesh culture to generate spherical cysts that secreted human chorionic gonadotropin (hCG) hormone and expressed caudal-related homeobox 2 factor (CDX2), a specific marker of trophoblast lineage. Thus, this study demonstrates a simple and direct mechanical approach to induce trophoblast differentiation and generate cysts for application in the study of early human embryogenesis and drug development and screening. PMID- 25914997 TI - Controllable objects seem closer. AB - More and more we interact with other people across varying amounts of geographical distance. What shapes our categorization of a fixed amount of such distance as near or far? Building upon and expanding prior work on the association between spatial distance perception and reachability, we argue that people judge a given geographical distance as subjectively smaller when they can exert control across that distance. Studies 1-4 demonstrate this effect of control on spatial distance judgment in disparate contexts, including political, work, and family domains, and explore implications of such judgments for the downstream judgment of travel time to a location (Study 2). We do not find that one's desire for control moderates these effects (Study 4). Supporting a cognitive association argument, we find evidence that the association between control and distance is bidirectional, with subjective distance influencing perceived controllability (Study 5). Theoretical and practical implications of these findings are discussed. PMID- 25914996 TI - Delayed Imatinib Treatment for Acute Spinal Cord Injury: Functional Recovery and Serum Biomarkers. AB - With no currently available drug treatment for spinal cord injury, there is a need for additional therapeutic candidates. We took the approach of repositioning existing pharmacological agents to serve as acute treatments for spinal cord injury and previously found imatinib to have positive effects on locomotor and bladder function in experimental spinal cord injury when administered immediately after the injury. However, for imatinib to have translational value, it needs to have sustained beneficial effects with delayed initiation of treatment, as well. Here, we show that imatinib improves hind limb locomotion and bladder recovery when initiation of treatment was delayed until 4 h after injury and that bladder function was improved with a delay of up to 24 h. The treatment did not induce hypersensitivity. Instead, imatinib-treated animals were generally less hypersensitive to either thermal or mechanical stimuli, compared with controls. In an effort to provide potential biomarkers, we found serum levels of three cytokines/chemokines--monocyte chemoattractant protein-1, macrophage inflammatory protein (MIP)-3alpha, and keratinocyte chemoattractant/growth-regulated oncogene (interleukin 8)--to increase over time with imatinib treatment and to be significantly higher in injured imatinib-treated animals than in controls during the early treatment period. This correlated to macrophage activation and autofluorescence in lymphoid organs. At the site of injury in the spinal cord, macrophage activation was instead reduced by imatinib treatment. Our data strengthen the case for clinical trials of imatinib by showing that initiation of treatment can be delayed and by identifying serum cytokines that may serve as candidate markers of effective imatinib doses. PMID- 25914998 TI - Uncertainty and the Diagnostic Leviathan. PMID- 25914999 TI - Quantum chemical and solution phase evaluation of metallocenes as reducing agents for the prospective atomic layer deposition of copper. AB - We propose and evaluate the use of metallocene compounds as reducing agents for the chemical vapour deposition (and specifically atomic layer deposition, ALD) of the transition metal Cu from metalorganic precursors. Ten different transition metal cyclopentadienyl compounds are screened for their utility in the reduction of Cu from five different Cu precursors by evaluating model reaction energies with density functional theory (DFT) and solution phase chemistry. PMID- 25915000 TI - Is evaluative conditioning really uncontrollable? A comparative test of three emotion-focused strategies to prevent the acquisition of conditioned preferences. AB - Evaluative conditioning (EC) is defined as the change in the evaluation of a conditioned stimulus (CS) because of its pairing with a valenced unconditioned stimulus (US). Counter to views that EC is the product of automatic learning processes, recent research has revealed various characteristics of nonautomatic processing in EC. The current research investigated the controllability of EC by testing the effectiveness of 3 emotion-focused strategies in preventing the acquisition of conditioned preferences: (a) suppression of emotional reactions to the US, (b) reappraisal of the valence of the US, and (c) facial blocking of emotional responses. Although all 3 strategies reduced EC effects on self reported evaluations by impairing recollective memory for CS-US pairings, they were ineffective in reducing EC effects on an evaluative priming measure. Regardless of the measure, effective control did not depend on the level of arousal elicited by the US. The results suggest that the 3 strategies can influence deliberate CS evaluations through memory-related processes, but they are ineffective in reducing EC effects on spontaneous evaluative responses. Implications for mental process theories of EC are discussed. PMID- 25915001 TI - Remembering the snake in the grass: Threat enhances recognition but not source memory. AB - Research on the influence of emotion on source memory has yielded inconsistent findings. The object-based framework (Mather, 2007) predicts that negatively arousing stimuli attract attention, resulting in enhanced within-object binding, and, thereby, enhanced source memory for intrinsic context features of emotional stimuli. To test this prediction, we presented pictures of threatening and harmless animals, the color of which had been experimentally manipulated. In a memory test, old-new recognition for the animals and source memory for their color was assessed. In all 3 experiments, old-new recognition was better for the more threatening material, which supports previous reports of an emotional memory enhancement. This recognition advantage was due to the emotional properties of the stimulus material, and not specific for snake stimuli. However, inconsistent with the prediction of the object-based framework, intrinsic source memory was not affected by emotion. PMID- 25915002 TI - Vegetarian Diets in the Prevention and Treatment of Type 2 Diabetes. AB - Observational studies show that prevalence of type 2 diabetes is 1.6 to 2 times lower in vegetarians than in the general population, even after adjustment for differences in body mass index (BMI). Clinical interventional trials demonstrated that vegetarian diets lead to a greater weight loss and greater reduction in fasting plasma glucose, HbA1c, blood lipids, and hypoglycemic medication than a conventional hypocaloric diet in subjects with type 2 diabetes. We found a greater reduction in visceral fat and greater improvements in insulin resistance and oxidative stress markers with a vegetarian compared to a conventional hypocaloric diabetic diet. Vegetarian diets are sustainable in the long term and may elicit desirable improvements not only in physical health but also in mental health. The American Dietetic Association states that well-planned vegetarian diets are healthy and nutritionally adequate and they may be beneficial in prevention and treatment of some illnesses. Larger clinical trials are needed to confirm the effectiveness and promote the inclusion of vegetarian diets in dietary guidelines for prevention and treatment of type 2 diabetes. PMID- 25915003 TI - An Innovative Educational and Mentorship Program for Emergency Medicine Women Residents to Enhance Academic Development and Retention. AB - Given the discrepancy between men and women's equal rates of medical school matriculation and their rates of academic promotion and leadership role acquisition, the need to provide mentorship and education to women in academic medicine is becoming increasingly recognized. Numerous large-scale programs have been developed to provide support and resources for women's enrichment and retention in academic medicine. Analyses of contributory factors to the aforementioned discrepancy commonly cite insufficient mentoring and role modeling as well as challenges with organizational navigation. Since residency training has been shown to be a critical juncture for making the decision to pursue an academic career, there is a need for innovative and tailored educational and mentorship programs targeting residents. Acknowledging residents' competing demands, we designed a program to provide easily accessible mentorship and contact with role models for our trainees at the departmental and institutional levels. We believe that this is an important step towards encouraging women's pursuit of academic careers. Our model may be useful to other emergency medicine residencies looking to provide such opportunities for their women residents. PMID- 25915004 TI - Trends in Status Epilepticus-Related Hospitalizations and Mortality: Redefined in US Practice Over Time. AB - IMPORTANCE: Status epilepticus is a common neurologic emergency with significant associated morbidity, mortality, and health care costs, yet limited data exist detailing trends in status epilepticus-related hospitalizations and mortality. OBJECTIVE: To examine trends in status epilepticus-related hospitalizations and mortality. DESIGN, SETTING, AND PARTICIPANTS: We performed 2 retrospective serial cross-sectional studies including 408 304 status epilepticus-related hospital visits using generalizable national data from January 1, 1999, to December 31, 2010, from the Centers for Disease Control and Prevention and the Nationwide Inpatient Sample. Centers for Disease Control and Prevention death certificate data, using International Statistical Classification of Diseases, Tenth Revision, codes, were used to determine nonstandardized and age-standardized rates of status epilepticus as the underlying cause of death in the United States. Data from the Nationwide Inpatient Sample were used to estimate population standardized status epilepticus-related hospitalization rates using International Statistical Classification of Diseases, Ninth Revision, codes. MAIN OUTCOMES AND MEASURES: Status epilepticus-related hospitalizations were categorized by whether status epilepticus was the principal diagnosis, whether the patient was intubated, and by primary insurance type. Temporal trends were tested using Poisson regression and summarized with quarterly incident rate ratios. RESULTS: In 2010, status epilepticus was the reported underlying cause of death in 613 deaths (approximately 2 per 1 000 000 persons). Age-standardized status epilepticus-related mortality per 1 000 000 persons increased by only 5.6% (incident rate ratio, 1.004; 95% CI, 1.002-1.006) from 1.79 in 1999 to 1.89 in 2010, while population-standardized hospitalizations for status epilepticus per 100 000 persons increased by 56.4% (incident rate ratio, 1.013; 95% CI, 1.012 1.013) from 8.86 in 1999 to 13.86 in 2010. The largest increase (181.6%; incident rate ratio, 1.030; 95% CI, 1.029-1.030) was seen among intubated patients with nonprincipal diagnoses of status epilepticus. Among varied insurance providers, the largest increase (81.3%) was seen in Medicare patients. CONCLUSIONS AND RELEVANCE: A disconnect exists between the relatively stable status epilepticus related mortality and the marked increase in status epilepticus hospitalizations, likely reflecting an increase in status epilepticus diagnoses through improved diagnostic sensitivity and changes in billing and coding. The definition and general approach to status epilepticus, including resource use, should evolve with these changing epidemiologic trends. PMID- 25915005 TI - Conjugated foldamers with unusually high space-charge-limited current hole mobilities. AB - Charge carrier mobility and its optimization play a critical role in the development of cutting-edge organic electronic and optoelectronic devices. Even though space-charge-limited current (SCLC) hole mobilities as high as 1.4 cm(2) V(-1) s(-1) have been reported for microscopically sized highly ordered liquid crystalline conjugated small molecules, the SCLC hole mobility of device-sized thin films of conjugated polymers is still much lower, ranging from 10(-6) to 10( 3) cm(2) V(-1) s(-1). Herein, we report the synthesis, characterizations, and thin-film SCLC mobility of three discotic conjugated polymers, INDT-TT, INDT-BT, and INDT-NDT. Optical studies indicate that polymer INDT-NDT adopts a folded conformation in solutions of good or poor solvents, whereas polymer INDT-TT stays as random monomeric chains in good solvents and interchain aggregates in poor solvents. INDT-BT polymer chains, however, stay as foldamers in dilute solutions of good solvents but interchain aggregates in concentrated solutions or poor solvents. Circular dichroism spectroscopy provides clear evidence for the helical folding of INDT-NDT in solutions. Thin films spin-coated from 1,2-dichlorobenzene solutions of the polymers show SCLC hole mobility of 2.20 * 10(-6), 8.79 * 10( 5), and 2.77 * 10(-2) cm(2) V(-1) s(-1) for INDT-TT, INDT-BT, and INDT-NDT, respectively. HRTEM and powder XRD measurements show that INDT-NDT pristine thin films contain nanocrystalline domains, whereas the INDT-TT and INDT-BT films are amorphous. Thin films of INDT-NDT:PC71BM blends show increased crystallinity and further improved SCLC hole mobility up to 1.29 * 10(-1) cm(2) V(-1) s(-1), one of the highest SCLC mobility values ever recorded on solution-processed organic semiconducting thin films. The persistent folding conformation of INDT-NDT is believed to be responsible for the high crystallinity of its thin films and its high SCLC mobilities. PMID- 25915006 TI - Toxicology Studies for Inhaled and Nasal Delivery. AB - This review examines issues related to the toxicological testing of pharmaceuticals delivered by the inhalation or nasal route. The purpose of the toxicology studies is to conduct studies in animals that will aid the assessment of the safety of these agents delivered to patients. Inhalation toxicology studies present some unique issues because the dosing method differs from more standard administration methods such as oral or injection administration. Also, dose determination issues are more complex, particularly for inhalation administration since it is often difficult to determine the amount of material delivered to the lung both for patients and in animal toxicology studies. PMID- 25915007 TI - Power spectrum of the rectified EMG: when and why is rectification beneficial for identifying neural connectivity? AB - OBJECTIVE: The identification of common oscillatory inputs to motor neurons in the electromyographic (EMG) signal power spectrum is often preceded by EMG rectification for enhancing the low-frequency oscillatory components. However, rectification is a nonlinear operator and its influence on the EMG signal spectrum is not fully understood. In this study, we aim at determining when EMG rectification is beneficial in the study of oscillatory inputs to motor neurons. APPROACH: We provide a full mathematical description of the power spectrum of the rectified EMG signal and the influence of the average shape of the motor unit action potentials on it. We also provide a validation of these theoretical results with both simulated and experimental EMG signals. MAIN RESULTS: Simulations using an advanced computational model and experimental results demonstrated the accuracy of the theoretical derivations on the effect of rectification on the EMG spectrum. These derivations proved that rectification is beneficial when assessing the strength of low-frequency (delta and alpha bands) common synaptic inputs to the motor neurons, when the duration of the action potentials is short, and when the level of cancellation is relatively low. On the other hand, rectification may distort the estimation of common synaptic inputs when studying higher frequencies (beta and gamma), in a way dependent on the duration of the action potentials, and may introduce peaks in the coherence function that do not correspond to physiological shared inputs. SIGNIFICANCE: This study clarifies the conditions when rectifying the surface EMG is appropriate for studying neural connectivity. PMID- 25915008 TI - Single Layer Molybdenum Disulfide under Direct Out-of-Plane Compression: Low Stress Band-Gap Engineering. AB - Tuning the electronic structure of 2D materials is a very powerful asset toward tailoring their properties to suit the demands of future applications in optoelectronics. Strain engineering is one of the most promising methods in this regard. We demonstrate that even very small out-of-plane axial compression readily modifies the electronic structure of monolayer MoS2. As we show through in situ resonant and nonresonant Raman spectroscopy and photoluminescence measurements combined with theoretical calculations, the transition from direct to indirect band gap semiconductor takes place at ~0.5 GPa, and the transition to a semimetal occurs at stress smaller than 3 GPa. PMID- 25915009 TI - Surgical Management of Glaucoma After Congenital Cataract Surgery. AB - PURPOSE: Cataract surgery in children is a difficult entity with possible complications, glaucoma being particularly common. The purpose of this study was to explore the results of surgical intervention for glaucoma after congenital cataract surgery in Alexandria University, Egypt. METHODS: The study was a retrospective chart review of 32 children with glaucoma after congenital cataract surgery between 2005 and 2012. Preoperative, operative, and postoperative data were collected. Complications were noted. Success was studied at the end of follow-up. RESULTS: The study included 41 (36 aphakic, 5 pseudophakic) eyes of 32 children undergoing 57 glaucoma surgical procedures. The mean +/- standard deviation age at the time of surgery was 17.2 +/- 21.6 months (range: 3.0 to 103.5 months) and the mean follow-up period was 39.1 +/- 25.2 months (range: 1 to 75 months). The most common (78%) primary glaucoma surgical procedure was combined trabeculotomy-trabeculectomy with mitomycin C. The mean preoperative intraocular pressure, corneal diameter and thickness, cup-disc ratio, and axial length of the study eyes was 22.3 +/- 6.1 mm Hg (range: 10 to 34 mm Hg), 11.4 +/- 0.9 mm (range: 10 to 13 mm) and 617.6 +/- 66.8 um (range: 538 to 758 um), 0.5 +/- 0.3 mm (range: 0 to 1 mm), and 22.85 +/- 2.75 mm (range: 18.55 to 29.17 mm), respectively, and postoperatively at last follow-up was 11.0 +/- 7.3 mm Hg (range: 1 to 36 mm Hg), 11.5 +/- 0.9 mm (range: 10 to 13 mm) and 576.8 +/- 83.3 um (range: 461 to 736 um), 0.4 +/- 0.3 mm (range: 0 to 1 mm), and 24.62 +/- 2.81 mm (range: 19.70 to 32.81 mm), respectively. Success was reported in 34 (82.9%) eyes. Complications included endophthalmitis, hypotony disc edema, and retinal detachment. CONCLUSIONS: Glaucoma after congenital cataract surgery is a difficult entity, often requiring more than one surgical procedure to control it. Long-term follow-up is mandatory to detect any failure of treatment at any time point and manage accordingly. PMID- 25915010 TI - Prevalence of intestinal helminths, anemia, and malnutrition in Paucartambo, Peru. AB - OBJECTIVE: To evaluate the prevalence of soil-transmitted helminth infections, anemia, and malnutrition among children in the Paucartambo province of Cusco region, Peru, in light of demographic, socio-economic, and epidemiologic contextual factors. METHODS: Children from three to twelve years old from six communities in Huancarani district in the highlands of Peru were evaluated for helminth infections, anemia, and nutritional status. Data collected included demographic variables, socioeconomic status, exposures, complete blood counts, and direct and sedimentation stool tests. RESULTS: Of 240 children analyzed, 113 (47%) were infected with one or more parasites. Giardia (27.5%) and Fasciola (9.6%) were the most commonly identified organisms. Eosinophilia was encountered in 21% of the children. Anemia (48.8%) was associated with age (3-4 vs 5-12 years old; odds ratio (OR): 5.86; 95% confidence interval (CI): 2.81-12.21). Underweight (10%) was associated with male sex (OR: 5.97; CI: 1.12-31.72), higher eosinophil count (OR: 4.67; CI: 1.31-16.68) and education of the mother (OR: 0.6; CI: 0.4-0.9). Stunting (31.3%) was associated with education of the mother (OR: 0.83; CI: 0.72-0.95); wasting (2.7%) was associated with higher eosinophil count (OR: 2.75; CI: 1.04-7.25). CONCLUSIONS: Anemia and malnutrition remain significant problems in the Peruvian highlands. These findings suggest that demographic factors, socio-economic status, and possibly parasitic infections intertwine to cause these health problems. PMID- 25915011 TI - Obstetric emergencies at the United States-Mexico border crossings in El Paso, Texas. AB - OBJECTIVE: To describe the frequency, characteristics, and patient outcomes for women who accessed Emergency Medical Services (EMS) for obstetric emergencies at the ports of entry (POE) between El Paso, Texas, United States of America, and Ciudad Juarez, Chihuahua, Mexico. METHODS: A descriptive study of women 12-49 years of age for whom an EMS ambulance was called to an El Paso POE location from December 2008-April 2011 was conducted. Women were identified through surveillance of EMS records. EMS and emergency department (ED) records were abstracted for all women through December 2009 and for women with an obstetric emergency through April 2011. For obstetric patients admitted to the hospital, additional prenatal and birth characteristics were collected. Frequencies and proportions were estimated for each variable; differences between residents of the United States and Mexico were tested. RESULTS: During December 2008-December 2009, 47.6% (68/143) of women receiving EMS assistance at an El Paso POE had an obstetric emergency, nearly 20 times the proportion for Texas overall. During December 2008-April 2011, 60.1% (66/109) of obstetric patients with ED records were admitted to hospital and 52 gave birth before discharge. Preterm birth (23.1%; No. = 12), low birth weight (9.6%; No. = 5), birth in transit (7.7%; No. = 4), and postpartum hemorrhage (5.8%; No. = 3) were common; fewer than one-half the women (46.2%; No. = 24) had evidence of prenatal care. CONCLUSIONS: The high proportion of obstetric EMS transports and high prevalence of complications in this population suggest a need for binational risk reduction efforts. PMID- 25915012 TI - [Regional differences in cardiovascular mortality transition in Brazil, 1980 to 2012]. AB - OBJECTIVE: To estimate the time trend of cardiovascular mortality from 1980 to 2012. METHODS: We performed an ecological time series study of cardiovascular mortality in Brazil. Data regarding deaths were obtained from the Mortality Information System and divided into two groups: deaths from ischemic heart disease (IHD) and deaths from cerebrovascular disorders (CBVD). RESULTS: A 34.73% variation in IHD standardized mortality rates was recorded for Brazil. Concerning specific regions, an increase was observed in the Northeast (117.98%%) and the Midwest (10.26%). IHD mortality rates fell in the Southeast (-53.08%), South (-44.56%) and North (-4.39%). For CBVD, the overall variation was -48.10%. Mortality rates were reduced in most regions: -61.99% in the Southeast, -55.49% in the South, -26.91% in the Midwest, and -20.78% in the North. Only the Northeast recorded an increase in CBVD mortality (13.77%). CONCLUSIONS: We observed an overall declining trend for IHD and CBVD mortality in Brazil from 1980 to 2012, with strong regional variation. Mortality rates were highest in the Southeast and South for both groups of disorders, and lowest in the North and Northeast. Surveillance efforts should take into account the regional differences in epidemiological profile. PMID- 25915013 TI - An adequacy evaluation of a maternal health intervention in rural Honduras: the impact of engagement of men and empowerment of women. AB - OBJECTIVE: To determine the impact that a 6-year maternal and child health project in rural Honduras had on maternal health services and outcomes, and to test the effect of level of father involvement on maternal health. METHODS: This was a program evaluation conducted through representative household surveys administered at baseline in 2007 and endline in 2011 using 30 cluster samples randomly-selected from the 229 participating communities. Within each cluster, 10 households having at least one mother-child pair were randomly selected to complete a questionnaire, for a total of about 300 respondents answering close to 100 questions each. Changes in key outcome variables from baseline to endline were tested using logistic regression, controlling for mother's education and father's involvement. RESULTS: There were improvements in most maternal health indicators, including an increase in women attending prenatal checkups (84% to 92%, P = 0.05) and institutional births (44% to 63%, P = 0.002). However, the involvement of the fathers decreased as reflected by the percentage of fathers accompanying mothers to prenatal checkups (48% to 41%, P = 0.01); the fathers' reported interest in prenatal care (74% to 52%, P = 0.0001); and fathers attending the birth (66% to 54%, P = 0.05). There was an interaction between the fathers' scores and the maternal outcomes, with a larger increase in institutional births among mothers with the least-involved fathers. CONCLUSIONS: Rather than the father's involvement being key, changes in the mothers may have led to increased institutional births. The project may have empowered women through early identification of pregnancy and stronger social connections encouraged by home visits and pregnancy clubs. This would have enabled even the women with unsupportive fathers to make healthier choices and achieve higher rates of institutional births. PMID- 25915014 TI - Real price and affordability as challenges for effective tobacco control policies: an analysis for Argentina. AB - OBJECTIVE: To describe the evolution of cigarettes' real price and affordability during the last decade in Argentina. METHODS: To analyze the real price of cigarettes, the weighted average monthly price of a pack of 20 cigarettes was divided by the consumer price index (CPI) from 2004 to 2014. The relative income price (RIP) was evaluated for the same period, defining RIP as the percentage of the income required to buy 100 packs of 20-per-pack cigarettes. The RIP was calculated for first-quartile, median, and third-quartile income groups. The lower the RIP, the higher the affordability. RESULTS: The nominal price of a pack of 20 cigarettes sold in Argentina increased from AR$ 2.24 in March 2004 to AR$ 14.36 in June 2014 (nominal price increase of about 19.7% per year). The real price fell from AR$ 2.24 in March 2004 to AR$ 2.11 in June 2014 (real price drop of about 0.6% per year). Between June 2004 and June 2014, the RIP decreased about 39% for the 3rd quartile income group (from 31.3% to 19.2%), about 42% for the median (from 55.7% to 32.0%), and about 50% for the 1st quartile (from 104.4% to 51.8%). CONCLUSIONS: In Argentina, inflation and rising income were greater than growth in cigarette prices. Cigarette affordability increased for each income group, with the highest shifts occurring among the poorest and most vulnerable income earners. The increased affordability of cigarettes might reduce the impact of implemented tobacco control policies. PMID- 25915015 TI - Primary care performance in Dominica. AB - OBJECTIVE: To document the structure and functions of primary care (PC) in the country of Dominica using the Primary Care Assessment Tools (PCAT), a set of questionnaires that evaluate PC functions. METHODS: This cross-sectional study combined data from two surveys. The systems PCAT (S-PCAT) survey gathered national-level data from key informants about health system characteristics and PC performance. The provider version (P-PCAT) survey collected data on PC performance from health providers (nurses and physicians) at all PC facilities in the country. Provider-level data were aggregated to obtain national and district level results for PC domains scored from 0.00 (worst) to 1.00 (best). RESULTS: From the systems perspective, results showed several knowledge gaps in PC policy, financing, and structure. Key informants gave ?Good? (adequate) ratings for ?first-contact? care (0.74), continuity of care (0.77), comprehensive care (0.70), and coordinated care (0.78); middling scores for family-centered care and community-oriented care (0.65); and low scores for access to care (0.57). PC providers assessed access to care (which included ?first-contact? care, in the P PCAT surveys) (0.84), continuity of care (0.86), information systems (0.84), family-centered care (0.92), and community-oriented care (0.85) as ?Very Good?; comprehensive care as ?Good? (0.79); and coordinated care as ?Reasonable? (0.68). Overall, the scores for the country's health districts were good, although the ratings varied by specific PC domain. CONCLUSIONS: The assessments described here were carried out with relatively little expense and have provided important inputs into strategic planning, strategies for improving PC, and identification of priority areas for further investigation. This two-staged approach could be adapted and used in other countries. PMID- 25915016 TI - Relevance of variation in use of terminology to define generic pharmaceutical products. AB - The World Health Organization (WHO) promotes the use of generic drug policies to foster competition in the pharmaceutical sector, reduce drug prices, and increase access to therapeutic drugs. However, little is known about how countries implement these policies. This article describes different terminology adopted by national regulatory authorities to define generic versus proprietary drug products in developing countries, including those in Latin America, and challenges that arise in their application of WHO guidelines, such as labeling issues. The author concludes that variation in generics terminology in these countries is a result of institutional context (i.e., the public sector setting as well as the body of laws and regulations that exists in the country) and policy legacies, such as intellectual property regimes, and highlights the need for further analysis of pharmaceutical regulations to improve understanding of the barriers and political implications of generic drug policies. PMID- 25915017 TI - Trends in research involving human beings in Brazil. AB - Developing countries have experienced a dramatic increase in the number of clinical studies in the last decades. The aim of this study was to describe 1) the number of clinical trials submitted to the Brazilian Health Surveillance Agency (Agencia Nacional de Vigilancia Sanitaria, Anvisa) from 2007 to 2012 and the number of human-subject research projects approved by research ethics committees (RECs) and the National Research Ethics Committee (Comissao Nacional de Etica em Pesquisa, CONEP) in Brazil from 2007 to 2011 and 2) the diseases most frequently studied in Brazilian states in clinical trials approved in the country from 2009 to 2012, based on information from an Anvisa databank. Two databases were used: 1) the National Information System on Research Ethics Involving Human Beings (Sistema Nacional de Informacao Sobre Etica em Pesquisa envolvendo Seres Humanos, SISNEP) and 2) Anvisa's Clinical Research Control System (Sistema de Controle de Pesquisa Clinica, SCPC). Data from the SCPC indicated an increase of 32.7% in the number of clinical trials submitted to Anvisa, and data from the SISNEP showed an increase of 69.9% in those approved by RECs and CONEP (from 18 160 in 2007 to 30 860 in 2011). Type 2 diabetes (26.0%) and breast cancer (20.5%) related to the main causes of mortality in Brazil-were the two most frequently studied diseases. The so-called ?neglected diseases,? such as dengue fever, were among the least studied diseases in approved clinical trials, despite their significant impact on social, economic, and health indicators in Brazil. Overall, the data indicated 1) a clear trend toward more research involving human beings in Brazil, 2) good correspondence between diseases most studied in clinical trials approved by Anvisa and the main causes of death in Brazil, and 3) a low level of attention to neglected diseases, an issue that should be considered in setting future research priorities, given their socioeconomic and health effects. PMID- 25915018 TI - Magnetic metal-organic framework nanocomposites for enrichment and direct detection of small molecules by negative-ion matrix-assisted laser desorption/ionization time-of-flight mass spectrometry. AB - Zeolitic imidazolate framework-8 coated magnetic nanocomposites (Fe3O4@ZIF-8 MNCs) served as an absorbent and a matrix for negative-ion MALDI-TOF MS. The host guest property and interference-free background made them an ideal dual platform for the sensitive analysis of small molecules. PMID- 25915019 TI - Structures of actin-like ParM filaments show architecture of plasmid-segregating spindles. AB - Active segregation of Escherichia coli low-copy-number plasmid R1 involves formation of a bipolar spindle made of left-handed double-helical actin-like ParM filaments. ParR links the filaments with centromeric parC plasmid DNA, while facilitating the addition of subunits to ParM filaments. Growing ParMRC spindles push sister plasmids to the cell poles. Here, using modern electron cryomicroscopy methods, we investigate the structures and arrangements of ParM filaments in vitro and in cells, revealing at near-atomic resolution how subunits and filaments come together to produce the simplest known mitotic machinery. To understand the mechanism of dynamic instability, we determine structures of ParM filaments in different nucleotide states. The structure of filaments bound to the ATP analogue AMPPNP is determined at 4.3 A resolution and refined. The ParM filament structure shows strong longitudinal interfaces and weaker lateral interactions. Also using electron cryomicroscopy, we reconstruct ParM doublets forming antiparallel spindles. Finally, with whole-cell electron cryotomography, we show that doublets are abundant in bacterial cells containing low-copy-number plasmids with the ParMRC locus, leading to an asynchronous model of R1 plasmid segregation. PMID- 25915020 TI - Neurons for hunger and thirst transmit a negative-valence teaching signal. AB - Homeostasis is a biological principle for regulation of essential physiological parameters within a set range. Behavioural responses due to deviation from homeostasis are critical for survival, but motivational processes engaged by physiological need states are incompletely understood. We examined motivational characteristics of two separate neuron populations that regulate energy and fluid homeostasis by using cell-type-specific activity manipulations in mice. We found that starvation-sensitive AGRP neurons exhibit properties consistent with a negative-valence teaching signal. Mice avoided activation of AGRP neurons, indicating that AGRP neuron activity has negative valence. AGRP neuron inhibition conditioned preference for flavours and places. Correspondingly, deep-brain calcium imaging revealed that AGRP neuron activity rapidly reduced in response to food-related cues. Complementary experiments activating thirst-promoting neurons also conditioned avoidance. Therefore, these need-sensing neurons condition preference for environmental cues associated with nutrient or water ingestion, which is learned through reduction of negative-valence signals during restoration of homeostasis. PMID- 25915021 TI - An enigmatic plant-eating theropod from the Late Jurassic period of Chile. AB - Theropod dinosaurs were the dominant predators in most Mesozoic era terrestrial ecosystems. Early theropod evolution is currently interpreted as the diversification of various carnivorous and cursorial taxa, whereas the acquisition of herbivorism, together with the secondary loss of cursorial adaptations, occurred much later among advanced coelurosaurian theropods. A new, bizarre herbivorous basal tetanuran from the Upper Jurassic of Chile challenges this conception. The new dinosaur was discovered at Aysen, a fossil locality in the Upper Jurassic Toqui Formation of southern Chile (General Carrera Lake). The site yielded abundant and exquisitely preserved three-dimensional skeletons of small archosaurs. Several articulated individuals of Chilesaurus at different ontogenetic stages have been collected, as well as less abundant basal crocodyliforms, and fragmentary remains of sauropod dinosaurs (diplodocids and titanosaurians). PMID- 25915022 TI - The Xist lncRNA interacts directly with SHARP to silence transcription through HDAC3. AB - Many long non-coding RNAs (lncRNAs) affect gene expression, but the mechanisms by which they act are still largely unknown. One of the best-studied lncRNAs is Xist, which is required for transcriptional silencing of one X chromosome during development in female mammals. Despite extensive efforts to define the mechanism of Xist-mediated transcriptional silencing, we still do not know any proteins required for this role. The main challenge is that there are currently no methods to comprehensively define the proteins that directly interact with a lncRNA in the cell. Here we develop a method to purify a lncRNA from cells and identify proteins interacting with it directly using quantitative mass spectrometry. We identify ten proteins that specifically associate with Xist, three of these proteins--SHARP, SAF-A and LBR--are required for Xist-mediated transcriptional silencing. We show that SHARP, which interacts with the SMRT co-repressor that activates HDAC3, is not only essential for silencing, but is also required for the exclusion of RNA polymerase II (Pol II) from the inactive X. Both SMRT and HDAC3 are also required for silencing and Pol II exclusion. In addition to silencing transcription, SHARP and HDAC3 are required for Xist-mediated recruitment of the polycomb repressive complex 2 (PRC2) across the X chromosome. Our results suggest that Xist silences transcription by directly interacting with SHARP, recruiting SMRT, activating HDAC3, and deacetylating histones to exclude Pol II across the X chromosome. PMID- 25915024 TI - Chitosan derivatives as important biorefinery intermediates. Quaternary tetraalkylammonium chitosan derivatives utilized in anion exchange chromatography for perchlorate removal. AB - There has recently been great interest in the valorization of biomass waste in the context of the biorefinery. The biopolymer chitosan, derived from chitin, is present in large quantities of crustacean waste. This biomass can be converted into value-added products with applications in energy, fuel, chemicals and materials manufacturing. The many reported applications of this polymer can be attributed to its unique properties, such as biocompatibility, chemical versatility, biodegradability and low toxicity. Cost effective water filters which decontaminate water by removal of specific impurities and microbes are in great demand. To address this need, the development of ion exchange resins using environmentally friendly, renewable materials such as biopolymers as solid supports was evaluated. The identification and remediation of perchlorate contaminated water using an easy, inexpensive method has come under the spotlight recently. Similarly, the use of a low cost perchlorate selective solid phase extraction (SPE) cartridge that can be rapidly employed in the field is desirable. Chitosan based SPE coupled with colorimetric analytical methods showed promise as a renewable anion exchange support for perchlorate analysis or removal. The polymers displayed perchlorate retention comparable to the commercial standard whereby the quaternized iron loaded polymer TMC-Fe(III) displayed the best activity. PMID- 25915023 TI - Overexpressing of OsAMT1-3, a High Affinity Ammonium Transporter Gene, Modifies Rice Growth and Carbon-Nitrogen Metabolic Status. AB - AMT1-3 encodes the high affinity NH4+ transporter in rice roots and is predominantly expressed under nitrogen starvation. In order to evaluate the effect of AMT1-3 gene on rice growth, nitrogen absorption and metabolism, we generated AMT1-3-overexpressing plants and analyzed the growth phenotype, yield, carbon and nitrogen metabolic status, and gene expression profiles. Although AMT1 3 mRNA accumulated in transgenic plants, these plants displayed significant decreases in growth when compared to the wild-type plants. The nitrogen uptake assay using a 15N tracer revealed poor nitrogen uptake ability in AMT1-3 overexpressing plants. We found significant decreases in AMT1-3-overexpressing plant leaf carbon and nitrogen content accompanied with a higher leaf C/N ratio. Significant changes in soluble proteins and carbohydrates were also observed in AMT1-3-overexpressing plants. In addition, metabolite profile analysis demonstrated significant changes in individual sugars, organic acids and free amino acids. Gene expression analysis revealed distinct expression patterns of genes that participate in carbon and nitrogen metabolism. Additionally, the correlation between the metabolites and gene expression patterns was consistent in AMT1-3-overexpressing plants under both low and high nitrogen growth conditions. Therefore, we hypothesized that the carbon and nitrogen metabolic imbalance caused by AMT1-3 overexpressing attributed to the poor growth and yield of transgenic plants. PMID- 25915025 TI - Novel Tertiary Amino Containing Blinding Composite Membranes via Raft Polymerization and Their Preliminary CO2 Permeation Performance. AB - Facile synthesis of poly (N,N-dimethylaminoethyl methacrylate) (PDMAEMA) star polymers on the basis of the prepolymer chains, PDMAEMA as the macro chain transfer agent and divinyl benzene (DVB) as the cross-linking reagent by reversible addition-fragmentation chain transfer (RAFT) polymerization was described. The RAFT polymerizations of DMAEMA at 70 degrees C using four RAFT agents with different R and Z group were investigated. The RAFT agents used in these polymerizations were dibenzyl trithiocarbonate (DBTTC), s-1-dodecyl-s' (alpha,alpha'-dimethyl-alpha-acetic acid) trithiocarbonate (MTTCD), s,s'-bis (2 hydroxyethyl-2'-dimethylacrylate) trithiocarbonate (BDATC) and s-(2-cyanoprop-2 yl)-s-dodecyltrithiocarbonate (CPTCD). The results indicated that the structure of the end-group of RAFT agents had significant effects on the ability to control polymerization. Compared with the above-mentioned RAFT agents, CPTCD provides better control over the molecular weight and molecular weight distribution. The polydispersity index (PDI) was determined to be within the scope of 1.26 to 1.36. The yields, molecular weight, and distribution of the star polymers can be tuned by changing the molar ratio of DVB/PDMAEMA-CPTCD. The chemical composition and structure of the linear and star polymers were characterized by GPC, FTIR, 1H NMR, XRD analysis. For the pure Chitosan membrane, a great improvement was observed for both CO2 permeation rate and ideal selectivity of the blending composite membrane upon increasing the content of SPDMAEMA-8. At a feed gas pressure of 37.5 cmHg and 30 degrees C, the blinding composite membrane (Cs: SPDMAEMA-8 = 4:4) has a CO2 permeation rate of 8.54 * 10-4 cm3 (STP) cm-2?s 1?cm?Hg-1 and a N2 permeation rate of 6.76 * 10-5 cm3 (STP) cm-2?s-1?cm?Hg-1, and an ideal CO2/N2 selectivity of 35.2. PMID- 25915027 TI - Further Study on Chemical Constituents of Parnassia wightiana Wall: Four New Dihydro-beta-agarofuran Sesquiterpene Polyesters. AB - Four new (1-4), along with six known (5-10) dihydro-beta-agarofuran sesquiterpene polyesters were isolated from the whole plants of Parnassia wightiana. The new compounds were structurally elucidated through spectroscopic analysis including UV (Ultraviolet Spectrum), IR (Infrared Spectrum), 1H-NMR (1Hydrogen-Nuclear Magnetic Resonance), 13C-NMR (13Carbon-Nuclear Magnetic Resonance), DEPT (Distortionless Enhancement by Polarization Transfer), 1H-1H COSY (1H-1H Correlation Spectroscopy), HSQC (Heteronuclear Single Quantum Coherence), HMBC (Heteronuclear Multiple Bond Correlation), NOESY (Nuclear Overhauser Enhancement Spectroscopy) and HR-MS (High Resolution Mass Specttrum) and their absolute configurations were proposed by comparison of NOESY spectra and specific optical rotations with those of known compounds and biosynthesis grounds. Compound 2 is the first sesquiterpene alkaloid isolated from this plant. New compounds 1-4 exhibited some cytotoxic activities against NB4, MKN-45 and MCF-7 cells at 20 MUM and of which 4 showed the highest activity against NB4 and MKN-45 cells with inhibition rates of 85.6% and 30.5%, respectively. PMID- 25915026 TI - Identification and Characterization of a PRDM14 Homolog in Japanese Flounder (Paralichthys olivaceus). AB - PRDM14 is a PR (PRDI-BF1-RIZ1 homologous) domain protein with six zinc fingers and essential roles in genome-wide epigenetic reprogramming. This protein is required for the establishment of germ cells and the maintenance of the embryonic stem cell ground state. In this study, we cloned the full-length cDNA and genomic DNA of the Paralichthys olivaceus prdm14 (Po-prdm14) gene and isolated the 5' regulatory region of Po-prdm14 by whole-genome sequencing. Peptide sequence alignment, gene structure analysis, and phylogenetic analysis revealed that Po PRDM14 was homologous to mammalian PRDM14. Results of real-time quantitative polymerase chain reaction amplification (RT-qPCR) and in situ hybridization (ISH) in embryos demonstrated that Po-prdm14 was highly expressed between the morula and late gastrula stages, with its expression peaking in the early gastrula stage. Relatively low expression of Po-prdm14 was observed in the other developmental stages. ISH of gonadal tissues revealed that the transcripts were located in the nucleus of the oocytes in the ovaries but only in the spermatogonia and not the spermatocytes in the testes. We also presume that the Po-prdm14 transcription factor binding sites and their conserved binding region among vertebrates. The combined results suggest that Po-PRDM14 has a conserved function in teleosts and mammals. PMID- 25915028 TI - PRRT2 Mutant Leads to Dysfunction of Glutamate Signaling. AB - Paroxysmal kinesigenic choreoathetosis (PKC) is an inherited disease of the nervous system. We previously identified PRRT2 as the causative gene of PKC. However, as little is known about the function of PRRT2, elucidating its function will benefit not only PKC studies, but also many other related disorders. Here, we reveal higher levels of glutamate in the plasma of PKC patients and the culture medium of neurons following knock-out Prrt2 expression. Using double immunostaining assays we confirm Prrt2 is located at the glutamatergic neurons in accordance with its function. Our co-immunoprecipitation assays reveal mutant PRRT2 interferes with SNAP25 and GRIA1 interactions, respectively. Furthermore, using live-labeling techniques, we confirmed co-transfection with mutant PRRT2 caused an increase in GRIA1 distribution on the cell surface. Therefore, our results suggest that mutant PRRT2, probably through its weakened interaction with SNAP25, affects glutamate signaling and glutamate receptor activity, resulting in the increase of glutamate release and subsequent neuronal hyperexcitability. PMID- 25915029 TI - Expression profiling reveals genes involved in the regulation of wool follicle bulb regression and regeneration in sheep. AB - Wool is an important material in textile manufacturing. In order to investigate the intrinsic factors that regulate wool follicle cycling and wool fiber properties, Illumina sequencing was performed on wool follicle bulb samples from the middle anagen, catagen and late telogen/early anagen phases. In total, 13,898 genes were identified. KRTs and KRTAPs are the most highly expressed gene families in wool follicle bulb. In addition, 438 and 203 genes were identified to be differentially expressed in wool follicle bulb samples from the middle anagen phase compared to the catagen phase and the samples from the catagen phase compared to the late telogen/early anagen phase, respectively. Finally, our data revealed that two groups of genes presenting distinct expression patterns during the phase transformation may have important roles for wool follicle bulb regression and regeneration. In conclusion, our results demonstrated the gene expression patterns in the wool follicle bulb and add new data towards an understanding of the mechanisms involved in wool fiber growth in sheep. PMID- 25915031 TI - A polymer visualization system with accurate heating and cooling control and high speed imaging. AB - A visualization system to observe crystal and bubble formation in polymers under high temperature and pressure has been developed. Using this system, polymer can be subjected to a programmable thermal treatment to simulate the process in high pressure differential scanning calorimetry (HPDSC). With a high-temperature/high pressure view-cell unit, this system enables in situ observation of crystal formation in semi-crystalline polymers to complement thermal analyses with HPDSC. The high-speed recording capability of the camera not only allows detailed recording of crystal formation, it also enables in situ capture of plastic foaming processes with a high temporal resolution. To demonstrate the system's capability, crystal formation and foaming processes of polypropylene/carbon dioxide systems were examined. It was observed that crystals nucleated and grew into spherulites, and they grew at faster rates as temperature decreased. This observation agrees with the crystallinity measurement obtained with the HPDSC. Cell nucleation first occurred at crystals' boundaries due to CO2 exclusion from crystal growth fronts. Subsequently, cells were nucleated around the existing ones due to tensile stresses generated in the constrained amorphous regions between networks of crystals. PMID- 25915030 TI - Proteomic Insights into Sulfur Metabolism in the Hydrogen-Producing Hyperthermophilic Archaeon Thermococcus onnurineus NA1. AB - The hyperthermophilic archaeon Thermococcus onnurineus NA1 has been shown to produce H2 when using CO, formate, or starch as a growth substrate. This strain can also utilize elemental sulfur as a terminal electron acceptor for heterotrophic growth. To gain insight into sulfur metabolism, the proteome of T. onnurineus NA1 cells grown under sulfur culture conditions was quantified and compared with those grown under H2-evolving substrate culture conditions. Using label-free nano-UPLC-MSE-based comparative proteomic analysis, approximately 38.4% of the total identified proteome (589 proteins) was found to be significantly up-regulated (>=1.5-fold) under sulfur culture conditions. Many of these proteins were functionally associated with carbon fixation, Fe-S cluster biogenesis, ATP synthesis, sulfur reduction, protein glycosylation, protein translocation, and formate oxidation. Based on the abundances of the identified proteins in this and other genomic studies, the pathways associated with reductive sulfur metabolism, H2-metabolism, and oxidative stress defense were proposed. The results also revealed markedly lower expression levels of enzymes involved in the sulfur assimilation pathway, as well as cysteine desulfurase, under sulfur culture condition. The present results provide the first global atlas of proteome changes triggered by sulfur, and may facilitate an understanding of how hyperthermophilic archaea adapt to sulfur-rich, extreme environments. PMID- 25915032 TI - Cellular Anti-Melanogenic Effects of a Euryale ferox Seed Extract Ethyl Acetate Fraction via the Lysosomal Degradation Machinery. AB - The aim of this study was to investigate the effect of ethyl acetate fraction of Euryale ferox seed extracts (Efse-EA) on melanogenesis in immortalized mouse melanocyte cell line, melan-a. Efse-EA showed strong dose-dependent mushroom tyrosinase inhibitory activity. Treatment of melan-a cells with 30 MUg/mL Efse-EA produced strong inhibition of cellular tyrosinase and melanin synthesis. Efse-EA significantly reduced the levels of melanogenesis-related proteins, such as tyrosinase, tyrosinase-related proteins 1 and 2, and microphthalmia-associated transcription factor. Because Efse-EA treatment reduced tyrosinase protein levels without changing its mRNA expression, we investigated whether this decrease was related to proteasomal or lysosomal degradation of tyrosinase. We found that chloroquine, a lysosomal proteolysis inhibitor, almost completely abolished both the down-regulation of tyrosinase and the inhibition of melanin synthesis induced by Efse-EA. These results suggested that Efse-EA may contribute to the inhibition of melanogenesis by altering lysosomal degradation of tyrosinase, and that this extract may provide a new cosmetic skin-whitening agent. PMID- 25915033 TI - Spectroscopic evidence for negative electronic compressibility in a quasi-three dimensional spin-orbit correlated metal. AB - Negative compressibility is a sign of thermodynamic instability of open or non equilibrium systems. In quantum materials consisting of multiple mutually coupled subsystems, the compressibility of one subsystem can be negative if it is countered by positive compressibility of the others. Manifestations of this effect have so far been limited to low-dimensional dilute electron systems. Here, we present evidence from angle-resolved photoemission spectroscopy (ARPES) for negative electronic compressibility (NEC) in the quasi-three-dimensional (3D) spin-orbit correlated metal (Sr1-xLax)3Ir2O7. Increased electron filling accompanies an anomalous decrease of the chemical potential, as indicated by the overall movement of the deep valence bands. Such anomaly, suggestive of NEC, is shown to be primarily driven by the lowering in energy of the conduction band as the correlated bandgap reduces. Our finding points to a distinct pathway towards an uncharted territory of NEC featuring bulk correlated metals with unique potential for applications in low-power nanoelectronics and novel metamaterials. PMID- 25915034 TI - In vivo delivery of transcription factors with multifunctional oligonucleotides. AB - Therapeutics based on transcription factors have the potential to revolutionize medicine but have had limited clinical success as a consequence of delivery problems. The delivery of transcription factors is challenging because it requires the development of a delivery vehicle that can complex transcription factors, target cells and stimulate endosomal disruption, with minimal toxicity. Here, we present a multifunctional oligonucleotide, termed DARTs (DNA assembled recombinant transcription factors), which can deliver transcription factors with high efficiency in vivo. DARTs are composed of an oligonucleotide that contains a transcription-factor-binding sequence and hydrophobic membrane-disruptive chains that are masked by acid-cleavable galactose residues. DARTs have a unique molecular architecture, which allows them to bind transcription factors, trigger endocytosis in hepatocytes, and stimulate endosomal disruption. The DARTs have enhanced uptake in hepatocytes as a result of their galactose residues and can disrupt endosomes efficiently with minimal toxicity, because unmasking of their hydrophobic domains selectively occurs in the acidic environment of the endosome. We show that DARTs can deliver the transcription factor nuclear erythroid 2 related factor 2 (Nrf2) to the liver, catalyse the transcription of Nrf2 downstream genes, and rescue mice from acetaminophen-induced liver injury. PMID- 25915036 TI - Correction: Is chronic suppurative otitis media a neglected tropical disease? AB - [This corrects the article DOI: 10.1371/journal.pntd.0003485.]. PMID- 25915037 TI - A Multi-Component Model of Hodgkin's Lymphoma. AB - Hodgkin's lymphoma is an example for a tumor with an extremely tight interaction of tumor cells with cells from the tumor micro-environment. These so-called bystander cells are not inert but interact actively with the tumor cells. Some of these cells support tumor growth by delivery of co-stimulating and anti-apoptotic signals ("helper cells"). Other cells ("killer cells") are involved in the anti tumor immune response which is obviously not efficient enough for tumor elimination. The activity of both helper cells and killer cells is regulated by additional cells in the stroma ("regulatory cells"). The dynamic behavior of such multi-component systems is difficult to predict. In the present paper we propose a model that can be used for simulation of essential features of this system. In this model, tumor growth depends on (i) presence of few cancer stem cells, (ii) co-stimulation of cancer cells by the tumor stroma, (iii) activity of regulatory cells that suppress killer cells without suppression of helper cells. The success of cytotoxic/cytostatic therapy in this model varies depending on the therapy related toxicity for each of the cell populations. The model also allows the analysis of immunotherapeutic interventions. Under certain conditions, paradox enhancement of tumor growth can occur after therapeutic intervention. The model might be useful for the design of new treatment strategies for Hodgkin's lymphoma and other tumors with prominent tumor-stroma interaction. PMID- 25915035 TI - The validity of the multi-informant approach to assessing child and adolescent mental health. AB - Child and adolescent patients may display mental health concerns within some contexts and not others (e.g., home vs. school). Thus, understanding the specific contexts in which patients display concerns may assist mental health professionals in tailoring treatments to patients' needs. Consequently, clinical assessments often include reports from multiple informants who vary in the contexts in which they observe patients' behavior (e.g., patients, parents, teachers). Previous meta-analyses indicate that informants' reports correlate at low-to-moderate magnitudes. However, is it valid to interpret low correspondence among reports as indicating that patients display concerns in some contexts and not others? We meta-analyzed 341 studies published between 1989 and 2014 that reported cross-informant correspondence estimates, and observed low-to-moderate correspondence (mean internalizing: r = .25; mean externalizing: r = .30; mean overall: r = .28). Informant pair, mental health domain, and measurement method moderated magnitudes of correspondence. These robust findings have informed the development of concepts for interpreting multi-informant assessments, allowing researchers to draw specific predictions about the incremental and construct validity of these assessments. In turn, we critically evaluated research on the incremental and construct validity of the multi-informant approach to clinical child and adolescent assessment. In so doing, we identify crucial gaps in knowledge for future research, and provide recommendations for "best practices" in using and interpreting multi-informant assessments in clinical work and research. This article has important implications for developing personalized approaches to clinical assessment, with the goal of informing techniques for tailoring treatments to target the specific contexts where patients display concerns. (PsycINFO Database Record PMID- 25915038 TI - Activating the Wnt/beta-Catenin Pathway for the Treatment of Melanoma- Application of LY2090314, a Novel Selective Inhibitor of Glycogen Synthase Kinase 3. AB - It has previously been observed that a loss of beta-catenin expression occurs with melanoma progression and that nuclear beta-catenin levels are inversely proportional to cellular proliferation, suggesting that activation of the Wnt/beta-catenin pathway may provide benefit for melanoma patients. In order to further probe this concept we tested LY2090314, a potent and selective small molecule inhibitor with activity against GSK3alpha and GSK3beta isoforms. In a panel of melanoma cell lines, nM concentrations of LY2090314 stimulated TCF/LEF TOPFlash reporter activity, stabilized beta-catenin and elevated the expression of Axin2, a Wnt responsive gene and marker of pathway activation. Cytotoxicity assays revealed that melanoma cell lines are very sensitive to LY2090314 in vitro (IC50 ~10 nM after 72hr of treatment) in contrast to other solid tumor cell lines (IC50 >10 uM) as evidenced by caspase activation and PARP cleavage. Cell lines harboring mutant B-RAF or N-RAS were equally sensitive to LY2090314 as were those with acquired resistance to the BRAF inhibitor Vemurafenib. shRNA studies demonstrated that beta-catenin stabilization is required for apoptosis following treatment with the GSK3 inhibitor since the sensitivity of melanoma cell lines to LY290314 could be overcome by beta-catenin knockdown. We further demonstrate that in vivo, LY2090314 elevates Axin2 gene expression after a single dose and produces tumor growth delay in A375 melanoma xenografts with repeat dosing. The activity of LY2090314 in preclinical models suggests that the role of Wnt activators for the treatment of melanoma should be further explored. PMID- 25915039 TI - Characterizing Vocal Repertoires--Hard vs. Soft Classification Approaches. AB - To understand the proximate and ultimate causes that shape acoustic communication in animals, objective characterizations of the vocal repertoire of a given species are critical, as they provide the foundation for comparative analyses among individuals, populations and taxa. Progress in this field has been hampered by a lack of standard in methodology, however. One problem is that researchers may settle on different variables to characterize the calls, which may impact on the classification of calls. More important, there is no agreement how to best characterize the overall structure of the repertoire in terms of the amount of gradation within and between call types. Here, we address these challenges by examining 912 calls recorded from wild chacma baboons (Papio ursinus). We extracted 118 acoustic variables from spectrograms, from which we constructed different sets of acoustic features, containing 9, 38, and 118 variables; as well 19 factors derived from principal component analysis. We compared and validated the resulting classifications of k-means and hierarchical clustering. Datasets with a higher number of acoustic features lead to better clustering results than datasets with only a few features. The use of factors in the cluster analysis resulted in an extremely poor resolution of emerging call types. Another important finding is that none of the applied clustering methods gave strong support to a specific cluster solution. Instead, the cluster analysis revealed that within distinct call types, subtypes may exist. Because hard clustering methods are not well suited to capture such gradation within call types, we applied a fuzzy clustering algorithm. We found that this algorithm provides a detailed and quantitative description of the gradation within and between chacma baboon call types. In conclusion, we suggest that fuzzy clustering should be used in future studies to analyze the graded structure of vocal repertoires. Moreover, the use of factor analyses to reduce the number of acoustic variables should be discouraged. PMID- 25915040 TI - HPLC-DAD-ELSD Combined Pharmacodynamics and Serum Medicinal Chemistry for Quality Assessment of Huangqi Granule. AB - OBJECTIVE: To more scientifically and reasonably control the quality of Huangqi Granules, preliminary studies on the pharmacodynamics and serum pharmacochemistry of this medicine were performed. DPPH and MTT experiments showed that water extracts of Huangqi Granules had good antioxidant activity and increased immunity. Timed blood samples collected 5 min, 15 min, and 30 min after oral administration of a set amount of Huangqi Granules were collected and tested using UPLC-ESI-MS/MS. As a result, calycosin-7-O-beta-D-glucoside, ononin, calycosin, astragaloside IV, and formononetin were found to exist in rat blood after dosing, indicating that the five chemical compounds might have pharmacological activity, and based on this result, they were designated biomarkers for quality control of Huangqi Granules. Consequently, a simple, rapid and efficient method was developed in the present study for the simultaneous determination of the five characteristic compounds in Huangqi Granules using HPLC DAD-ELSD. MATERIALS AND METHODS: The separation was performed using an Agilent Hypersil ODS column (4.6 * 250 mm, 5 MUm) at 30 C. The mobile phase was composed of water (solvent A) and acetonitrile (solvent B) with a flow rate of 1 mL/min. The drift tube temperature of the ELSD system was set to 85 C, and the nitrogen pressure was 3.5 bar. RESULTS: All five characteristic compounds had good linear behavior with r2 values greater than 0.9972. The recoveries varied from 96.31% to 101.22%. Subsequently, the developed method was applied to evaluate the quality of Huangqi Granules from different batches, and hierarchical clustering analysis (HCA) was used to analyze the classification of the samples based on the values of the five compounds. CONCLUSION: The established HPLC method combined with HCA proved to be effective to evaluate the quality of Huangqi Granules. PMID- 25915042 TI - Correction: FOXO4-Knockdown Suppresses Oxidative Stress-Induced Apoptosis of Early Pro-Angiogenic Cells and Augments Their Neovascularization Capacities in Ischemic Limbs. PMID- 25915041 TI - Pachymic acid inhibits growth and induces apoptosis of pancreatic cancer in vitro and in vivo by targeting ER stress. AB - Pachymic acid (PA) is a purified triterpene extracted from medicinal fungus Poria cocos. In this paper, we investigated the anticancer effect of PA on human chemotherapy resistant pancreatic cancer. PA triggered apoptosis in gemcitabine resistant pancreatic cancer cells PANC-1 and MIA PaCa-2. Comparative gene expression array analysis demonstrated that endoplasmic reticulum (ER) stress was induced by PA through activation of heat shock response and unfolded protein response related genes. Induced ER stress was confirmed by increasing expression of XBP-1s, ATF4, Hsp70, CHOP and phospho-eIF2alpha. Moreover, ER stress inhibitor tauroursodeoxycholic acid (TUDCA) blocked PA induced apoptosis. In addition, 25 mg kg-1 of PA significantly suppressed MIA PaCa-2 tumor growth in vivo without toxicity, which correlated with induction of apoptosis and expression of ER stress related proteins in tumor tissues. Taken together, growth inhibition and induction of apoptosis by PA in gemcitabine-resistant pancreatic cancer cells were associated with ER stress activation both in vitro and in vivo. PA may be potentially exploited for the use in treatment of chemotherapy resistant pancreatic cancer. PMID- 25915043 TI - Preclinical Development and In Vivo Efficacy of Ceftiofur-PLGA Microparticles. AB - Drug delivery systems based on polymeric microparticles represent an interesting field of development for the treatment of several infectious diseases for humans and animals. In this work, we developed PLGA microparticles loaded with ceftiofur (PLGA-cef), a third- generation cephalosporin that is used exclusively used in animals. PLGA-cef was prepared by the double emulsion w/o/w method, and exhibited a diameter in the range of 1.5-2.2 MUm, and a negative zeta potential in the range of -35 to -55 mV. The loading yield of PLGA-cef was ~7% and encapsulation efficiency was approximately 40%. The pharmacokinetic study demonstrated a sustained release profile of ceftiofur for 20 days. PLGA-cef administrated in a single dose was more effective than ceftiofur non-encapsulated in rats challenged with S. Typhimurium. The in vivo toxicological evaluation showed that PLGA-cef did not affect the blood biochemical, hematological and hemostasis parameters. Overall, the PLGA-cef showed slow in vivo release profile, high antibacterial efficacy, and low toxicity. The results obtained supports the safe application of PLGA-cef as sustained release platform in the veterinary industry. PMID- 25915044 TI - Prognostic relevance of pretherapeutic gamma-glutamyltransferase in patients with primary metastatic breast cancer. AB - BACKGROUND: Gamma-glutamyltransferase (GGT) is a known marker for apoptotic balance and cell detoxification. Recently, an association of baseline GGT levels and breast cancer incidence, tumor progression and chemotherapy resistance was shown. The purpose of this study was to evaluate the association of pre therapeutic GGT levels, clinical-pathological parameters and survival in patients with primary metastatic breast cancer (PMBC). METHODS: In this multicenter analysis, pre-therapeutic GGT levels and clinical-pathological parameters of 114 patients diagnosed with PMBC between 1996 and 2012 were evaluated. The association between GGT levels and clinical-pathological parameters were analysed. Patients were stratified into four GGT risk-groups (GGT < 18.00 U/L: normal low, 18.00 to 35.99 U/L: normal high, 36.00 to 71.99 U/L: elevated and >= 72.00 U/L: highly elevated) and survival analyses were performed. FINDINGS: Patients in the high risk GGT group had a poorer overall survival, when compared to the low risk group with five-year overall survival rates of 39.5% and 53.7% (p = 0.04), respectively. Patients with larger breast tumors had a trend towards higher GGT levels (p = 0.053). Pre-therapeutic GGT levels were not associated with indicators of aggressive tumor biology such as HER2-status, triple negative histology, or poorly differentiated cancers. CONCLUSION: Pre-therapeutic GGT serum level might serve as a novel prognostic factor for overall-survival in patients with PMBC. PMID- 25915046 TI - Autologous transplantation of oral mucosal epithelial cell sheets cultured on an amniotic membrane substrate for intraoral mucosal defects. AB - The human amniotic membrane (AM) is a thin intrauterine placental membrane that is highly biocompatible and possesses anti-inflammatory and anti-scarring properties. Using AM, we developed a novel method for cultivating oral mucosal epithelial cell sheets. We investigated the autologous transplantation of oral mucosal epithelial cells cultured on AM in patients undergoing oral surgeries. We obtained specimens of AM from women undergoing cesarean sections. This study included five patients without any history of a medical disorder who underwent autologous cultured oral epithelial transplantation following oral surgical procedures. Using oral mucosal biopsy specimens obtained from these patients, we cultured oral epithelial cells on an AM carrier. We transplanted the resultant cell sheets onto the oral mucosal defects. Patients were followed-up for at least 12 months after transplantation. After 2-3 weeks of being cultured on AM, epithelial cells were well differentiated and had stratified into five to seven layers. Immunohistochemistry revealed that the cultured cells expressed highly specific mucosal epithelial cell markers and basement membrane proteins. After the surgical procedures, no infection, bleeding, rejection, or sheet detachment occurred at the reconstructed sites, at which new oral mucous membranes were evident. No recurrence was observed in the long-term follow-up, and the postoperative course was excellent. Our results suggest that AM-cultured oral mucosal epithelial cell sheets represent a useful biomaterial and feasible method for oral mucosal reconstruction. However, our primary clinical study only evaluated their effects on a limited number of small oral mucosal defects. PMID- 25915045 TI - ESAT-6 Targeting to DEC205+ Antigen Presenting Cells Induces Specific-T Cell Responses against ESAT-6 and Reduces Pulmonary Infection with Virulent Mycobacterium tuberculosis. AB - Airways infection with Mycobacterium tuberculosis (Mtb) is contained mostly by T cell responses, however, Mtb has developed evasion mechanisms which affect antigen presenting cell (APC) maturation/recruitment delaying the onset of Ag specific T cell responses. Hypothetically, bypassing the natural infection routes by delivering antigens directly to APCs may overcome the pathogen's naturally evolved evasion mechanisms, thus facilitating the induction of protective immune responses. We generated a murine monoclonal fusion antibody (alpha-DEC-ESAT) to deliver Early Secretory Antigen Target (ESAT)-6 directly to DEC205+ APCs and to assess its in vivo effects on protection associated responses (IFN-gamma production, in vivo CTL killing, and pulmonary mycobacterial load). Treatment with alpha-DEC-ESAT alone induced ESAT-6-specific IFN-gamma producing CD4+ T cells and prime-boost immunization prior to Mtb infection resulted in early influx (d14 post-infection) and increased IFN-gamma+ production by specific T cells in the lungs, compared to scarce IFN-gamma production in control mice. In vivo CTL killing was quantified in relevant tissues upon transferring target cells loaded with mycobacterial antigens. During infection, alpha-DEC-ESAT treated mice showed increased target cell killing in the lungs, where histology revealed cellular infiltrate and considerably reduced bacterial burden. Targeting the mycobacterial antigen ESAT-6 to DEC205+ APCs before infection expands specific T cell clones responsible for early T cell responses (IFN-gamma production and CTL activity) and substantially reduces lung bacterial burden. Delivering mycobacterial antigens directly to APCs provides a unique approach to study in vivo the role of APCs and specific T cell responses to assess their potential anti-mycobacterial functions. PMID- 25915047 TI - Association of oxidative stress biomarkers with gestational diabetes mellitus in pregnant women: a case-control study. AB - OBJECTIVE: The relationship between gestational diabetes mellitus (GDM) and oxidative stress has not been fully elucidated. This study examined the association between biomarkers of oxidative stress and GDM. METHODS: We conducted a case-control study which included 36 women presenting with GDM and 36 asymptomatic matched control subjects who visited Guangzhou Women and Children's Medical Centre, China, from June 2012 to December 2012. Pregnant women were prospectively recruited to the study, and blood samples were collected at the time of a routine oral glucose tolerance test. These samples were then analyzed for levels of endocrine and surrogate markers of oxidative stress. RESULTS: Compared to control subjects, women with GDM exhibited elevated values for plasma glucose, insulin, and insulin resistance (IR), and showed reduced HOMA pancreatic beta-cell function (HOMA-B), insulin sensitivity index (ISI), insulinogenic index, and corrected insulin response at 24-28 weeks gestation. A bivariate logistic regression analysis showed that levels of high-sensitivity C reactive protein (hs-CRP) and high fluorescence reticulocytes at fasting, and hs-CRP in a 1-h OGTT, were significantly associated with GDM. A linear regression analysis showed that levels of hs-CRP (P = 0.003) and reticulocytes (P = 0.029) at fasting were associated with IR, and levels of hs-CRP (P = 0.002) and monocytes (P = 0.006) in a 1-h OGTT were associated with ISI. CONCLUSIONS: Pregnant women with GDM developed a pathological IR and exhibited beta-cell dysfunction. Their decreased ability to compensate for oxidative stress was associated with increased IR and a reduced ISI, which might be important factors in GDM. PMID- 25915048 TI - Helicobacter pylori Eradication on the Prevention of Metachronous Lesions after Endoscopic Resection of Gastric Neoplasm: A Meta-Analysis. AB - BACKGROUND: There is controversy about the effect of Helicobacter pylori (H. pylori) eradication on the prevention of metachronous gastric cancer after endoscopic resection (ER). AIMS: The aim of this study was to systematically evaluate the effect of H. pylori eradication on the prevention of metachronous gastric lesions after ER of gastric neoplasms. METHODS: We performed a systematic search of PubMed, EMBASE, the Cochrane Library, and MEDLINE that encompassed studies through April 2014. Our meta-analysis consisted of 10 studies, which included 5881 patients who underwent ER of gastric neoplasms. RESULTS: When we compared the incidence of metachronous lesions between H. pylori-eradicated and non-eradicated groups, H. pylori eradication significantly lowered the risk of metachronous lesions after ER of gastric neoplasms (five studies, OR = 0.392, 95% CI 0.259 - 0.593, P < 0.001). When we compared H. pylori-eradicated and persistent groups, again, H. pylori eradication significantly lowered the incidence of metachronous lesions after ER of gastric neoplasms (six studies, OR = 0.468, 95% CI 0.326 - 0.673, P < 0.001). There was no obvious heterogeneity across the analyzed studies. CONCLUSIONS: This meta-analysis suggests a preventive role for H. pylori eradication for metachronous gastric lesions after ER of gastric neoplasms. Thus, H. pylori eradication should be considered if H. pylori infection is confirmed during ER. PMID- 25915050 TI - An empirical analysis of primary and secondary pharmaceutical patents in Chile. AB - We analyze the patent filing strategies of foreign pharmaceutical companies in Chile distinguishing between "primary" (active ingredient) and "secondary" patents (patents on modified compounds, formulations, dosages, particular medical uses, etc.). There is prior evidence that secondary patents are used by pharmaceutical originator companies in the U.S. and Europe to extend patent protection on drugs in length and breadth. Using a novel dataset that comprises all drugs registered in Chile between 1991 and 2010 as well as the corresponding patents and trademarks, we find evidence that foreign originator companies pursue similar strategies in Chile. We find a primary to secondary patents ratio of 1:4 at the drug-level, which is comparable to the available evidence for Europe; most secondary patents are filed over several years following the original primary patent and after the protected active ingredient has obtained market approval in Chile. This points toward effective patent term extensions through secondary patents. Secondary patents dominate "older" therapeutic classes like anti-ulcer and anti-depressants. In contrast, newer areas like anti-virals and anti neoplastics (anti-cancer) have a much larger share of primary patents. PMID- 25915049 TI - Contribution to the prediction of the fold code: application to immunoglobulin and flavodoxin cases. AB - BACKGROUND: Folding nucleus of globular proteins formation starts by the mutual interaction of a group of hydrophobic amino acids whose close contacts allow subsequent formation and stability of the 3D structure. These early steps can be predicted by simulation of the folding process through a Monte Carlo (MC) coarse grain model in a discrete space. We previously defined MIRs (Most Interacting Residues), as the set of residues presenting a large number of non-covalent neighbour interactions during such simulation. MIRs are good candidates to define the minimal number of residues giving rise to a given fold instead of another one, although their proportion is rather high, typically [15-20]% of the sequences. Having in mind experiments with two sequences of very high levels of sequence identity (up to 90%) but different folds, we combined the MIR method, which takes sequence as single input, with the "fuzzy oil drop" (FOD) model that requires a 3D structure, in order to estimate the residues coding for the fold. FOD assumes that a globular protein follows an idealised 3D Gaussian distribution of hydrophobicity density, with the maximum in the centre and minima at the surface of the "drop". If the actual local density of hydrophobicity around a given amino acid is as high as the ideal one, then this amino acid is assigned to the core of the globular protein, and it is assumed to follow the FOD model. Therefore one obtains a distribution of the amino acids of a protein according to their agreement or rejection with the FOD model. RESULTS: We compared and combined MIR and FOD methods to define the minimal nucleus, or keystone, of two populated folds: immunoglobulin-like (Ig) and flavodoxins (Flav). The combination of these two approaches defines some positions both predicted as a MIR and assigned as accordant with the FOD model. It is shown here that for these two folds, the intersection of the predicted sets of residues significantly differs from random selection. It reduces the number of selected residues by each individual method and allows a reasonable agreement with experimentally determined key residues coding for the particular fold. In addition, the intersection of the two methods significantly increases the specificity of the prediction, providing a robust set of residues that constitute the folding nucleus. PMID- 25915051 TI - Evaluation of phosphate fertilizers for the immobilization of Cd in contaminated soils. AB - A laboratory investigation was conducted to evaluate the efficiency of four phosphate fertilizers, including diammonium phosphate (DAP), potassium phosphate monobasic (MPP), calcium superphosphateon (SSP), and calcium phosphate tribasic (TCP), in terms of the toxicity and bioavailability of Cd in contaminated soils. The efficiency of immobilization was evaluated on the basis of two criteria: (a) the reduction of extractable Cd concentration below the TCLP regulatory level and (b) the Cd changes associated with specific operational soil fractions on the basis of sequential extraction data. Results showed that after 50 d immobilization, the extractable concentrations of Cd in DAP, MPP, SSP, and TCP treated soils decreased from 42.64 mg/kg (in the control) to 23.86, 21.86, 33.89, and 35.59 mg/kg, respectively, with immobilization efficiency in the order of MPP > DAP > SSP > TCP. Results from the assessment of Cd speciation via the sequential extraction procedure revealed that the soluble exchangeable fraction of Cd in soils treated with phosphate fertilizers, especially TCP, was considerably reduced. In addition, the reduction was correspondingly related to the increase in the more stable forms of Cd, that is, the metal bound to manganese oxides and the metal bound to crystalline iron oxides. Treatment efficiency increased as the phosphate dose (according to the molar ratio of PO4/Cd) increased. Immobilization was the most effective under the molar ratio of PO4/Cd at 4:1. PMID- 25915052 TI - Sex-Biased Temporal Gene Expression in Male and Female Floral Buds of Seabuckthorn (Hippophae rhamnoides). AB - Seabuckthorn is an economically important dioecious plant in which mechanism of sex determination is unknown. The study was conducted to identify seabuckthorn homologous genes involved in floral development which may have role in sex determination. Forty four putative Genes involved in sex determination (GISD) reported in model plants were shortlisted from literature survey, and twenty nine seabuckthorn homologous sequences were identified from available seabuckthorn genomic resources. Of these, 21 genes were found to differentially express in either male or female flower bud stages. HrCRY2 was significantly expressed in female flower buds only while HrCO had significant expression in male flowers only. Among the three male and female floral development stages (FDS), male stage II had significant expression of most of the GISD. Information on these sex specific expressed genes will help in elucidating sex determination mechanism in seabuckthorn. PMID- 25915053 TI - Transcription Factor CREB3L1 Regulates Endoplasmic Reticulum Stress Response Genes in the Osmotically Challenged Rat Hypothalamus. AB - Arginine vasopressin (AVP) is synthesised in magnocellular neurons (MCNs) of supraoptic nucleus (SON) and paraventricular nucleus (PVN) of the hypothalamus. In response to the hyperosmotic stressors of dehydration (complete fluid deprivation, DH) or salt loading (drinking 2% salt solution, SL), AVP synthesis increases in MCNs, which over-burdens the protein folding machinery in the endoplasmic reticulum (ER). ER stress and the unfolded protein response (UPR) are signaling pathways that improve ER function in response to the accumulation of misfold/unfold protein. We asked whether an ER stress response was activated in the SON and PVN of DH and SL rats. We observed increased mRNA expression for the immunoglobulin heavy chain binding protein (BiP), activating transcription factor 4 (Atf4), C/EBP-homologous protein (Chop), and cAMP responsive element binding protein 3 like 1 (Creb3l1) in both SON and PVN of DH and SL rats. Although we found no changes in the splicing pattern of X box-binding protein 1 (Xbp1), an increase in the level of the unspliced form of Xbp1 (Xbp1U) was observed in DH and SL rats. CREB3L1, a novel ER stress inducer, has been shown to be activated by ER stress to regulate the expression of target genes. We have previously shown that CREB3L1 is a transcriptional regulator of the AVP gene; however, a role for CREB3L1 in the response to ER stress has yet to be investigated in MCNs. Here, we used lentiviral vectors to introduce a dominant negative form of CREB3L1 (CREB3L1DN) in the rat SON. Expression of CREB3L1DN in the SON decreased Chop and Xbp1U mRNA levels, but not BiP and Atf4 transcript expression. CREB3L1 is thus implicated as a transcriptional mediator of the ER stress response in the osmotically stimulated SON. PMID- 25915055 TI - Re-defining tigecycline therapy. AB - Tigecycline, the first member of the glycylcyclines, has been approved for complicated skin and soft tissue infections (cSSTIs) and complicated intra abdominal infections (cIAIs). It has a wide range of activity against Gram positive and Gram-negative bacteria, including anaerobes. Since its approval, the worldwide clinical use of tigecycline has been heterogeneous, either as a monotherapy or as a part of combination therapy, almost exclusively at the standard dosage, in patients with community-acquired (CA) infections as well as health-care associated (HCA) or nosocomial infections (HA), including infections caused by multidrug-resistant (MDR) bacteria. In recent years, issues and warnings of an increased mortality in these heterogeneous patients treated with tigecycline have been raised by meta-analyses and by regulatory agencies. Re defining tigecycline therapy is a proposal, based on epidemiological, clinical, microbiological and pharmacological considerations, to distinguish patients who may be treated with monotherapy, according to the official indications and dosages, from those treated with combination treatment, mostly with high dosages in the setting of nosocomial IAIs, possibly caused by MDR bacteria or as a carbapenem-sparing strategy. Whilst available clinical data and guidelines suggest caution with monotherapy in severe infections, experience worldwide indicates that combination treatment with high-dosage tigecycline is increasingly used. PMID- 25915054 TI - A neuron-specific antiviral mechanism prevents lethal flaviviral infection of mosquitoes. AB - Mosquitoes are natural vectors for many etiologic agents of human viral diseases. Mosquito-borne flaviviruses can persistently infect the mosquito central nervous system without causing dramatic pathology or influencing the mosquito behavior and lifespan. The mechanism by which the mosquito nervous system resists flaviviral infection is still largely unknown. Here we report that an Aedes aegypti homologue of the neural factor Hikaru genki (AaHig) efficiently restricts flavivirus infection of the central nervous system. AaHig was predominantly expressed in the mosquito nervous system and localized to the plasma membrane of neural cells. Functional blockade of AaHig enhanced Dengue virus (DENV) and Japanese encephalitis virus (JEV), but not Sindbis virus (SINV), replication in mosquito heads and consequently caused neural apoptosis and a dramatic reduction in the mosquito lifespan. Consistently, delivery of recombinant AaHig to mosquitoes reduced viral infection. Furthermore, the membrane-localized AaHig directly interfaced with a highly conserved motif in the surface envelope proteins of DENV and JEV, and consequently interrupted endocytic viral entry into mosquito cells. Loss of either plasma membrane targeting or virion-binding ability rendered AaHig nonfunctional. Interestingly, Culex pipien pallens Hig also demonstrated a prominent anti-flavivirus activity, suggesting a functionally conserved function for Hig. Our results demonstrate that an evolutionarily conserved antiviral mechanism prevents lethal flaviviral infection of the central nervous system in mosquitoes, and thus may facilitate flaviviral transmission in nature. PMID- 25915056 TI - The impact of viral molecular diversity on the clinical presentation and outcome of acute hepatitis B in Italy. AB - The incidence of acute hepatitis B (AHB) in Italy, mostly sustained by hepatitis B virus (HBV) genotype D, has significantly decreased in the last two decades, but the new HBV strains introduced through immigrant populations from countries with a higher endemicity constitute a new emergency. HBV-genotype D still predominates in AHB, the subgenotype D3 being associated with parenteral transmission, and the recently emerging subgenotype A2 with unsafe sexual intercourse. Genetic, phylogenetic and evolutional analyses are powerful tools for countries with high immigration rates to monitor new viral strains with different aggressiveness and a different response to therapy. PMID- 25915057 TI - Peer education as a strategy for reducing internalized stigma among depressed older adults. AB - OBJECTIVE: This article examines the mechanisms through which peer educator (PE) intervention targets and reduces internalized stigma. There is substantial evidence that internalized stigma negatively impacts the lives of those suffering with mental health concerns, and has been identified as 1 of the most significant barriers to seeking professional mental health services. There has been a push toward identifying interventions and programs that effectively reduce and mitigate the impact of internalized stigma. Research suggests that contact with other individuals who share a stigmatized condition may be a promising approach to targeting and reducing internalized stigma. However, there is a dearth of research that has identified the mechanism through which this contact impacts internalized stigma. METHODS: Study participants (n = 19) completed a 3-month PE intervention. Each participant was matched with an older adult with a history of depression currently in recovery who provided psychoeducation, social support, and motivational interviewing. Participants completed a demographic questionnaire, public stigma (PDD), and internalized stigma (Internalized Stigma of Mental Illness, ISMI) scales pre- and post-PE intervention. They further participated in a brief semistructured qualitative interview to attain in-depth information about their perceptions of stigma and of working with a PE. RESULTS: Overall, internalized stigma scores were significantly reduced after participating in the PE intervention. In addition, participants identified 4 mechanisms through which contact with their PE impacted their stigmatized beliefs: age related concerns, shared understanding, improved mental health literacy, and mutual support. CONCLUSIONS AND IMPLICATIONS FOR PRACTICE: This study suggests that PE is a potentially valuable approach toward reducing internalized stigma among older adults with depression. PMID- 25915058 TI - Subthreshold psychotic symptom distress, self-stigma, and peer social support among college students with mental health concerns. AB - OBJECTIVE: The primary aim of this study was to explore the potential moderating effect of social support on the relation between distress caused by psychosis risk symptoms and self-stigma among college students with mental health diagnoses. METHODS: Participants were young adult college students who endorsed having a past or present mental health diagnosis (n = 63). Self-report data were examined from the Prodromal Questionnaire-Brief, a measure of subthreshold psychosis risk symptoms; the Self-Concurrence/Application subscale of the Self Stigma of Mental Illness Scale, a measure of self-stigma; and the Friendships subscale of the Lubben Social Network Scale-Revised, a measure of social support from peers. RESULTS: There was a modest direct relation between distress associated with psychosis risk symptoms and self-stigma. There was a larger relation between distress from risk symptoms and self-stigma for those with low social support compared to those with mean and high social support. CONCLUSIONS AND IMPLICATIONS FOR PRACTICE: Although causality cannot be determined based on this study, a strong relation between symptom distress and stigma was found among those reporting low peer social support. Interventions that target both self stigma and social support might be relevant for young adults with a history of mental health concerns who currently endorse subthreshold psychotic symptoms. PMID- 25915060 TI - The economic origins of ultrasociality. AB - Ultrasociality refers to the social organization of a few species, including humans and some social insects, having a complex division of labor, city-states, and an almost exclusive dependence on agriculture for subsistence. We argue that the driving forces in the evolution of these ultrasocial societies were economic. With the agricultural transition, species could directly produce their own food and this was such a competitive advantage that those species now dominate the planet. Once underway, this transition was propelled by the selection of within species groups that could best capture the advantages of (1) actively managing the inputs to food production, (2) a more complex division of labor, and (3) increasing returns to larger scale and larger group size. Together these factors reoriented productive life and radically altered the structure of these societies. Once agriculture began, populations expanded as these economic drivers opened up new opportunities for the exploitation of resources and the active management of inputs to food production. With intensified group-level competition, larger populations and intensive resource exploitation became competitive advantages, and the "social conquest of Earth" was underway. Ultrasocial species came to dominate the earth's ecosystems. Ultrasociality also brought a loss of autonomy for individuals within the group. We argue that exploring the common causes and consequences of ultrasociality in humans and the social insects that adopted agriculture can provide fruitful insights into the evolution of complex human society. PMID- 25915059 TI - From local adaptation to ecological speciation in copepod populations from neighboring lakes. AB - Continental copepods have been derived from several independent invasive events from the sea, but the subsequent evolutionary processes that account for the current diversity in lacustrine environments are virtually unknown. Salinity is highly variable among lakes and constitutes a source of divergent selection driving potential reproductive isolation. We studied four populations of the calanoid copepod Leptodiaptomus cf. sicilis inhabiting four neighboring lakes with a common history (since the Late Pleistocene) located in the Oriental Basin, Mexico; one lake is shallow and varies in salinity periodically (1.4-10 g L(-1)), while three are deep and permanent, with constant salinity (0.5, 1.1 and 6.5 g L( 1), respectively). We hypothesized that (1) these populations belong to a different species than L. sicilis sensu stricto and (2) are experiencing ecologically based divergence due to salinity differences. We assessed morphological and molecular (mtDNA) COI variation, as well as fitness differences and tests of reproductive isolation. Although relationships of the Mexican populations with L. sicilis s.s. could not be elucidated, we identified a clear pattern of divergent selection driven by salinity conditions. The four populations can still be considered a single biological species (sexual recognition and hybridization are still possible in laboratory conditions), but they have diverged into at least three different phenotypes: two locally adapted, specialized in the lakes of constant salinity (saline vs. freshwater), and an intermediate generalist phenotype inhabiting the temporary lake with fluctuating salinity. The specialized phenotypes are poorly suited as migrants, so prezygotic isolation due to immigrant inviability is highly probable. This implication was supported by molecular evidence that showed restricted gene flow, persistence of founder events, and a pattern of allopatric fragmentation. This study showed how ecologically based divergent selection may explain diversification patterns in lacustrine copepods. PMID- 25915061 TI - MEVA--An Interactive Visualization Application for Validation of Multifaceted Meteorological Data with Multiple 3D Devices. AB - BACKGROUND: To achieve more realistic simulations, meteorologists develop and use models with increasing spatial and temporal resolution. The analyzing, comparing, and visualizing of resulting simulations becomes more and more challenging due to the growing amounts and multifaceted character of the data. Various data sources, numerous variables and multiple simulations lead to a complex database. Although a variety of software exists suited for the visualization of meteorological data, none of them fulfills all of the typical domain-specific requirements: support for quasi-standard data formats and different grid types, standard visualization techniques for scalar and vector data, visualization of the context (e.g., topography) and other static data, support for multiple presentation devices used in modern sciences (e.g., virtual reality), a user-friendly interface, and suitability for cooperative work. METHODS AND RESULTS: Instead of attempting to develop yet another new visualization system to fulfill all possible needs in this application domain, our approach is to provide a flexible workflow that combines different existing state-of-the-art visualization software components in order to hide the complexity of 3D data visualization tools from the end user. To complete the workflow and to enable the domain scientists to interactively visualize their data without advanced skills in 3D visualization systems, we developed a lightweight custom visualization application (MEVA - multifaceted environmental data visualization application) that supports the most relevant visualization and interaction techniques and can be easily deployed. Specifically, our workflow combines a variety of different data abstraction methods provided by a state-of-the-art 3D visualization application with the interaction and presentation features of a computer-games engine. Our customized application includes solutions for the analysis of multirun data, specifically with respect to data uncertainty and differences between simulation runs. In an iterative development process, our easy-to-use application was developed in close cooperation with meteorologists and visualization experts. The usability of the application has been validated with user tests. We report on how this application supports the users to prove and disprove existing hypotheses and discover new insights. In addition, the application has been used at public events to communicate research results. PMID- 25915062 TI - Extracellular adenosine mediates a systemic metabolic switch during immune response. AB - Immune defense is energetically costly, and thus an effective response requires metabolic adaptation of the organism to reallocate energy from storage, growth, and development towards the immune system. We employ the natural infection of Drosophila with a parasitoid wasp to study energy regulation during immune response. To combat the invasion, the host must produce specialized immune cells (lamellocytes) that destroy the parasitoid egg. We show that a significant portion of nutrients are allocated to differentiating lamellocytes when they would otherwise be used for development. This systemic metabolic switch is mediated by extracellular adenosine released from immune cells. The switch is crucial for an effective immune response. Preventing adenosine transport from immune cells or blocking adenosine receptor precludes the metabolic switch and the deceleration of development, dramatically reducing host resistance. Adenosine thus serves as a signal that the "selfish" immune cells send during infection to secure more energy at the expense of other tissues. PMID- 25915063 TI - The Toluene o-Xylene Monooxygenase Enzymatic Activity for the Biosynthesis of Aromatic Antioxidants. AB - Monocyclic phenols and catechols are important antioxidant compounds for the food and pharmaceutic industries; their production through biotransformation of low added value starting compounds is of major biotechnological interest. The toluene o-xylene monooxygenase (ToMO) from Pseudomonas sp. OX1 is a bacterial multicomponent monooxygenase (BMM) that is able to hydroxylate a wide array of aromatic compounds and has already proven to be a versatile biochemical tool to produce mono- and dihydroxylated derivatives of aromatic compounds. The molecular determinants of its regioselectivity and substrate specificity have been thoroughly investigated, and a computational strategy has been developed which allows designing mutants able to hydroxylate non-natural substrates of this enzyme to obtain high-added value compounds of commercial interest. In this work, we have investigated the use of recombinant ToMO, expressed in cells of Escherichia coli strain JM109, for the biotransformation of non-natural substrates of this enzyme such as 2-phenoxyethanol, phthalan and 2-indanol to produce six hydroxylated derivatives. The hydroxylated products obtained were identified, isolated and their antioxidant potential was assessed both in vitro, using the DPPH assay, and on the rat cardiomyoblast cell line H9c2. Incubation of H9c2 cells with the hydroxylated compounds obtained from ToMO-catalyzed biotransformation induced a differential protective effect towards a mild oxidative stress induced by the presence of sodium arsenite. The results obtained confirm once again the versatility of the ToMO system for oxyfunctionalization reactions of biotechnological importance. Moreover, the hydroxylated derivatives obtained possess an interesting antioxidant potential that encourages the use of the enzyme for further functionalization reactions and their possible use as scaffolds to design novel bioactive molecules. PMID- 25915064 TI - Effects of antiepileptic drug monotherapy on one-carbon metabolism and DNA methylation in patients with epilepsy. AB - PURPOSE: The aim of this study was to compare the serum levels of one-carbon metabolism (OCM) nutrients (e.g., folate, homocysteine and vitamin B12) and peripheral blood DNA methylation in epileptic patients under treatment with antiepileptic drugs (AEDs) and in healthy controls. METHODS: In this cross sectional study, 60 patients with epilepsy who were receiving valproate (VPA) (n = 30) or lamotrigine (LTG) (n = 30) monotherapy were enrolled. Thirty age and sex matched healthy subjects served as the controls. Serum concentrations of OCM nutrients and peripheral blood DNA methylation status were measured. RESULTS: Compared to the control group, the VPA group had higher serum levels of homocysteine (p<0.05). No difference in homocysteine concentration was observed in the LTG group. Patients receiving VPA or LTG had significantly lower serum folate levels in comparison with controls (p<0.001). The level of methylation of long interspersed nucleotide element-1 (LINE-1) in peripheral blood was not significantly different between the AED monotherapy group and healthy controls. A difference in the methylation levels of methylenetetrahydrofolate reductase (MTHFR) amplicon was observed between AED-treated patients with epilepsy and controls (p<0.01). A positive correlation between serum folate levels and peripheral blood MTHFR amplicon methylation status was also observed (r = 0.25, p = 0.023). CONCLUSION: Our findings suggest that the effects of AED monotherapy on OCM may induce specific regions of DNA hypomethylation. PMID- 25915065 TI - Evaluating the SERCA2 and VEGF mRNAs as Potential Molecular Biomarkers of the Onset and Progression in Huntington's Disease. AB - Abnormalities of intracellular Ca2+ homeostasis and signalling as well as the down-regulation of neurotrophic factors in several areas of the central nervous system and in peripheral tissues are hallmarks of Huntington's disease (HD). As there is no therapy for this hereditary, neurodegenerative fatal disease, further effort should be made to slow the progression of neurodegeneration in patients through the definition of early therapeutic interventions. For this purpose, molecular biomarker(s) for monitoring disease onset and/or progression and response to treatment need to be identified. In the attempt to contribute to the research of peripheral candidate biomarkers in HD, we adopted a multiplex real time PCR approach to analyse the mRNA level of targeted genes involved in the control of cellular calcium homeostasis and in neuroprotection. For this purpose we recruited a total of 110 subjects possessing the HD mutation at different clinical stages of the disease and 54 sex- and age-matched controls. This study provides evidence of reduced transcript levels of sarco-endoplasmic reticulum associated ATP2A2 calcium pump (SERCA2) and vascular endothelial growth factor (VEGF) in peripheral blood mononuclear cells (PBMCs) of manifest and pre-manifest HD subjects. Our results provide a potentially new candidate molecular biomarker for monitoring the progression of this disease and contribute to understanding some early events that might have a role in triggering cellular dysfunctions in HD. PMID- 25915067 TI - Total syntheses of murrayamine E, I, and K. AB - We describe efficient synthetic routes to murrayamine A (mukoenine C), O methylmurrayamine A, mahanine, O-methylmahanine, and murrayamine D and the first total syntheses of murrayamine E, I, and K. Key steps are a palladium-catalyzed construction of the carbazole framework and an annulation of the pyran ring, which is either catalyzed by phenylboronic acid or promoted by a Lewis acid. PMID- 25915066 TI - The Timing of the Circadian Clock and Sleep Differ between Napping and Non Napping Toddlers. AB - The timing of the internal circadian clock shows large inter-individual variability across the lifespan. Although the sleep-wakefulness pattern of most toddlers includes an afternoon nap, the association between napping and circadian phase in early childhood remains unexplored. This study examined differences in circadian phase and sleep between napping and non-napping toddlers. Data were collected on 20 toddlers (34.2+/-2.0 months; 12 females; 15 nappers). Children followed their habitual napping and non-napping sleep schedules (monitored with actigraphy) for 5 days before an in-home salivary dim light melatonin onset (DLMO) assessment. On average, napping children fell asleep during their nap opportunities on 3.6+/-1.2 of the 5 days before the DLMO assessment. For these napping children, melatonin onset time was 38 min later (p = 0.044; d = 0.93), actigraphically-estimated bedtime was 43 min later (p = 0.014; d = 1.24), sleep onset time was 59 min later (p = 0.006; d = 1.46), and sleep onset latency was 16 min longer (p = 0.030; d = 1.03) than those not napping. Midsleep and wake time did not differ by napping status. No difference was observed in the bedtime, sleep onset, or midsleep phase relationships with DLMO; however, the wake time phase difference was 47 min smaller for napping toddlers (p = 0.029; d = 1.23). On average, nappers had 69 min shorter nighttime sleep durations (p = 0.006; d = 1.47) and spent 49 min less time in bed (p = 0.019; d = 1.16) than non-nappers. Number of days napping was correlated with melatonin onset time (r = 0.49; p = 0.014). Our findings indicate that napping influences individual variability in melatonin onset time in early childhood. The delayed bedtimes of napping toddlers likely permits light exposure later in the evening, thereby delaying the timing of the clock and sleep. Whether the early developmental trajectory of circadian phase involves an advance associated with the decline in napping is a question necessitating longitudinal data as children transition from a biphasic to monophasic sleep-wakefulness pattern. PMID- 25915068 TI - Recycling acetic acid from polarizing film of waste liquid crystal display panels by sub/supercritical water treatments. AB - Waste liquid crystal display (LCD) panels mainly contain inorganic materials (glass substrate) and organic materials (polarizing film and liquid crystal). The organic materials should be removed first since containing polarizing film and liquid crystal is to the disadvantage of the indium recycling process. In the present study, an efficient and environmentally friendly process to obtain acetic acid from waste LCD panels by sub/supercritical water treatments is investigated. Furthermore, a well-founded reaction mechanism is proposed. Several highlights of this study are summarized as follows: (i) 99.77% of organic matters are removed, which means the present technology is quite efficient to recycle the organic matters; (ii) a yield of 78.23% acetic acid, a quite important fossil energy based chemical product is obtained, which can reduce the consumption of fossil energy for producing acetic acid; (iii) supercritical water acts as an ideal solvent, a requisite reactant as well as an efficient acid-base catalyst, and this is quite significant in accordance with the "Principles of Green Chemistry". In a word, the organic matters of waste LCD panels are recycled without environmental pollution. Meanwhile, this study provides new opportunities for alternating fossil-based chemical products for sustainable development, converting "waste" into "fossil-based chemicals". PMID- 25915069 TI - The body language: The spontaneous influence of congruent bodily arousal on the awareness of emotional words. AB - Nowadays, the idea of a reciprocal influence of physiological and psychological processes seems to be widely accepted. For instance, current theories of embodied emotion suggest that knowledge about an emotion concept involves simulations of bodily experienced emotional states relevant to the concept. In line with this framework, the present study investigated whether actual levels of physiological arousal interact with the processing of emotional words. Participants performed 2 blocks of an attentional blink task, once after a cycling session (increased arousal) and once after a relaxation session (reduced arousal). Concretely, participants were instructed to detect and report 2 target words (T1 and T2) presented among a series of nonword distractors. T1 and T2 were either neutral, high arousal, or low arousal words. Results revealed that increased physiological arousal led to improved reports of high arousal T2 words, whereas reduced physiological arousal led to improved reports of low arousal T2 words. Neutral T2 remained unaffected by the arousing conditions. These findings emphasize that actual levels of physiological arousal modulate the cognitive access to arousal (in-)congruent emotional concepts and suggest a direct grounding of emotion knowledge in our bodily systems of arousal. PMID- 25915070 TI - The role of distractors in object substitution masking. AB - In object substitution masking (OSM) a surrounding mask (typically comprising of 4 dots) onsets with a target but lingers after offset; under such conditions, the ability to perceive the target can be significantly reduced. OSM was originally claimed to occur only when a target was not the focus of attention, for instance, when embedded in an array of distractors (Di Lollo, Enns, & Rensink, 2000). It was argued that the distractors influenced the time taken for focal attention to reach the target. Some recent work, however, failed to find any such distractor influence; the effect of mask duration was found to be independent of set size when steps were taken to avoid ceiling effects in the smallest set size condition (Argyropoulos, Gellatly, Pilling, & Carter, 2013; Filmer, Mattingley, & Dux, 2014). In 3 experiments, we repeatedly found that set size manipulations can interact with mask duration (in which neither ceiling nor floor effects are evident), with the effect of the mask on target perceptibility being amplified according to the number of distractor items. However, a further experiment (Experiment 4) showed that crowding by nearby distractors was actually responsible for this "set size" effect. When decoupled from crowding, set size alone did not interact with masking, though it did influence overall accuracy. Thus, the presence of distractors does influence OSM, but not in the way originally assumed by Di Lollo and colleagues in their model. The Crowding * OSM interaction suggests that the 2 phenomena involve partly overlapping mechanisms. PMID- 25915071 TI - Effects of reward on the accuracy and dynamics of smooth pursuit eye movements. AB - Reward modulates behavioral choices and biases goal-oriented behavior, such as eye or hand movements, toward locations or stimuli associated with higher rewards. We investigated reward effects on the accuracy and timing of smooth pursuit eye movements in 4 experiments. Eye movements were recorded in participants tracking a moving visual target on a computer monitor. Before target motion onset, a monetary reward cue indicated whether participants could earn money by tracking accurately, or whether the trial was unrewarded (Experiments 1 and 2, n = 11 each). Reward significantly improved eye-movement accuracy across different levels of task difficulty. Improvements were seen even in the earliest phase of the eye movement, within 70 ms of tracking onset, indicating that reward impacts visual-motor processing at an early level. We obtained similar findings when reward was not precued but explicitly associated with the pursuit target (Experiment 3, n = 16); critically, these results were not driven by stimulus prevalence or other factors such as preparation or motivation. Numerical cues (Experiment 4, n = 9) were not effective. PMID- 25915072 TI - Form-to-expectation matching effects on first-pass eye movement measures during reading. AB - Recent Electroencephalography/Magnetoencephalography (EEG/MEG) studies suggest that when contextual information is highly predictive of some property of a linguistic signal, expectations generated from context can be translated into surprisingly low-level estimates of the physical form-based properties likely to occur in subsequent portions of the unfolding signal. Whether form-based expectations are generated and assessed during natural reading, however, remains unclear. We monitored eye movements while participants read phonologically typical and atypical nouns in noun-predictive contexts (Experiment 1), demonstrating that when a noun is strongly expected, fixation durations on first pass eye movement measures, including first fixation duration, gaze duration, and go-past times, are shorter for nouns with category typical form-based features. In Experiments 2 and 3, typical and atypical nouns were placed in sentential contexts normed to create expectations of variable strength for a noun. Context and typicality interacted significantly at gaze duration. These results suggest that during reading, form-based expectations that are translated from higher level category-based expectancies can facilitate the processing of a word in context, and that their effect on lexical processing is graded based on the strength of category expectancy. PMID- 25915074 TI - Stochastic or systematic? Seemingly random perceptual switching in bistable events triggered by transient unconscious cues. AB - What we see is a function not only of incoming stimulation, but of unconscious inferences in visual processing. Among the most powerful demonstrations of this are bistable events, but what causes the percepts of such events to switch? Beyond voluntary effort and stochastic processing, we explore the ways in which ongoing dynamic percepts may switch as a function of the content of brief, unconscious, independent cues. We introduced transient disambiguating occlusion cues into the Spinning Dancer silhouette animation. The dancer is bistable in terms of depth and rotation direction, but many observers see extended rotation in the same direction, interrupted only rarely by involuntary switches. Observers failed to notice these occasional disambiguating cues, but their impact was strong and systematic: Cues typically led to seemingly stochastic perceptual switches shortly thereafter, especially when conflicting with the current percept. These results show how the content of incoming information determines and constrains online conscious perception-even when neither the content nor the brute existence of that information ever reaches awareness. Thus, just as phenomenological ease does not imply a corresponding lack of underlying effortful computation, phenomenological randomness should not be taken to imply a corresponding lack of underlying systematicity. PMID- 25915073 TI - Failures of perception in the low-prevalence effect: Evidence from active and passive visual search. AB - In visual search, rare targets are missed disproportionately often. This low prevalence effect (LPE) is a robust problem with demonstrable societal consequences. What is the source of the LPE? Is it a perceptual bias against rare targets or a later process, such as premature search termination or motor response errors? In 4 experiments, we examined the LPE using standard visual search (with eye tracking) and 2 variants of rapid serial visual presentation (RSVP) in which observers made present/absent decisions after sequences ended. In all experiments, observers looked for 2 target categories (teddy bear and butterfly) simultaneously. To minimize simple motor errors, caused by repetitive absent responses, we held overall target prevalence at 50%, with 1 low-prevalence and 1 high-prevalence target type. Across conditions, observers either searched for targets among other real-world objects or searched for specific bears or butterflies among within-category distractors. We report 4 main results: (a) In standard search, high-prevalence targets were found more quickly and accurately than low-prevalence targets. (b) The LPE persisted in RSVP search, even though observers never terminated search on their own. (c) Eye-tracking analyses showed that high-prevalence targets elicited better attentional guidance and faster perceptual decisions. And (d) even when observers looked directly at low prevalence targets, they often (12%-34% of trials) failed to detect them. These results strongly argue that low-prevalence misses represent failures of perception when early search termination or motor errors are controlled. PMID- 25915075 TI - Performance test of multicomponent quantum mechanical calculation with polarizable continuum model for proton chemical shift. AB - Multicomponent quantum mechanical (MC_QM) calculations with polarizable continuum model (PCM) have been tested against liquid (1)H NMR chemical shifts for a test set of 80 molecules. Improvement from conventional quantum mechanical calculations was achieved for MC_QM calculations. The advantage of the multicomponent scheme could be attributed to the geometrical change from the equilibrium geometry by the incorporation of the hydrogen nuclear quantum effect, while that of PCM can be attributed to the change of the electronic structure according to the polarization by solvent effects. PMID- 25915076 TI - GPR120 local regulation might explain the contradictory pro/anti-inflammatory effects of omega-3 PUFA observed in gestational tissue. PMID- 25915077 TI - Role of circulating adipocytokines vaspin, apelin, and visfatin in the loss of appetite in underweight children: a pilot trial. AB - OBJECTIVES: To investigate serum concentrations of vaspin, apelin, and visfatin in underweight children and their association with anthropometric and nutritional markers of malnutrition. SUBJECTS AND METHODS: We recruited 44 underweight prepubertal children (youngest age = 2 years) with thinness grades of 1, 2, and 3, and body weights < 90% of ideal body weight due to loss of appetite and less frequent hunger episodes. Forty-one healthy age- and gender-matched controls were also included in the study. Serum fasting vaspin, apelin, and visfatin concentrations were measured by enzyme immunoassay technique. RESULTS: Mean vaspin and apelin levels were significantly lower in underweight children compared to controls (vaspin: 0.44 +/- 0.18 vs. 0.58 +/- 0.35 pg/mL, p = 0.024; apelin: 483.37 +/- 333.26 vs. 711.71 +/- 616.50 pg/mL, p = 0.041). Visfatin levels were lower in underweight children compared to controls, but the values were not statistically significant (177.81 +/- 158.01 vs. 221.15 +/- 212.94 pg/mL, p = 0.119). CONCLUSIONS: In underweight children, decreased vaspin and apelin levels should be considered in the etiology of anorexia. PMID- 25915078 TI - Protein-induced hyperinsulinaemic hypoglycaemia due to a homozygous HADH mutation in three siblings of a Saudi family. AB - Hyperinsulinaemic hypoglycaemia (HH) is caused by mutations in the key genes involved in regulation of insulin secretion from the pancreatic beta-cells and mutations in ABCC8 and KCNJ11 are the most common causes of HH. Mutations in HADH (which encodes the enzyme 3-hydroxyacyl-CoA dehydrogenase) are a rare cause of HH. We report three siblings (21, 9, and 7 years old) from a consanguineous Saudi family with HH due to a homozygous mutation in HADH. All three siblings presented with HH in the 1st year of life. HH responded well to medical therapy (diazoxide/octreotide) although the 1st sibling suffered neurological damage. The protein load test revealed protein sensitivity in the 21-year-old proband, the oldest reported patient with HH secondary to a HADH mutation. Genetic analysis revealed a homozygous HADH splicing mutation (c.133-1G>A) in all three siblings. HADH mutations can present in later infancy or childhood with severe HH that is usually diazoxide responsive. Severe neurological complications such as epilepsy and developmental delay can be associated with HADH mutations. This is the 1st report of HH due to HADH mutation in an adult suggesting that HH could persist into adulthood possibly becoming milder over the years. PMID- 25915079 TI - Tracking markers of response inhibition in electroencephalographic data: why should we and how can we go beyond the N2 component? AB - Response inhibition is a pivotal component of executive control, which is especially difficult to assess. Indeed, it is a substantial challenge to gauge brain-behavior relationships because this function is precisely intended to suppress overt measurable behaviors. A further complication is that no single neuroimaging method has been found that can disentangle the accurate time-course of concurrent excitatory and inhibitory mechanisms. Here, we argue that this objective can be achieved with electroencephalography (EEG) on some conditions. Based on a systematic review, we emphasize that the standard event-related potential N2 (N200) is not an appropriate marker of prepotent response inhibition. We provide guidelines for assessing the cortical brain dynamics of response inhibition with EEG. This includes the combined use of inseparable data processing steps (source separation, source localization, and single-trial and time-frequency analyses) as well as the amendment of the classical experimental designs to enable the recording of different kinds of electrophysiological activity predicted by different models of response inhibition. We conclude with an illustration based on recent findings of how fruitful this approach can be. PMID- 25915080 TI - The adaptive and maladaptive continuum of stress responses - a hippocampal perspective. AB - Exposure to stressors elicits a spectrum of responses that span from potentially adaptive to maladaptive consequences at the structural, cellular and physiological level. These responses are particularly pronounced in the hippocampus where they also appear to influence hippocampal-dependent cognitive function and emotionality. The factors that influence the nature of stress-evoked consequences include the chronicity, severity, predictability and controllability of the stressors. In addition to adult-onset stress, early life stress also elicits a wide range of structural and functional responses, which often exhibit life-long persistence. However, the outcome of early stress exposure is often contingent on the environment experienced in adulthood, and could either aid in stress coping or could serve to enhance susceptibility to the negative consequences of adult stress. This review comprehensively examines the consequences of adult and early life stressors on the hippocampus, with a focus on their effects on neurogenesis, neuronal survival, structural and synaptic plasticity and hippocampal-dependent behaviors. Further, we discuss potential factors that may tip stress-evoked consequences from being potentially adaptive to largely maladaptive. PMID- 25915081 TI - Cyperus rotundus L. prevents non-steroidal anti-inflammatory drug-induced gastric mucosal damage by inhibiting oxidative stress. AB - BACKGROUND: Since centuries, Cyperus rotundus L. has been used against gastric ailments in traditional Indian medicine, especially in Ayurveda and Siddha. Therefore, it is very obvious that this plant will have a greater potential to treat gastric ulcers. For this reason, in this study, we mainly focused on the ulcer-preventive role of C. rotundus in rats treated with non-steroidal anti inflammatory drugs. METHODS: Seventy percent methanolic extract of the plant was prepared and fed to 36-h fasted rats. Ulcer was induced in these rats by single oral administration of aspirin (400 mg/kg) 1 h after the administration of the plant extract. After 4 h, the rats were sacrificed, ulcer index was calculated, and antioxidant activity of the extract in gastric mucosa was evaluated by determining the levels of superoxide dismutase, glutathione, glutathione peroxidase, and tissue lipid peroxidation. RESULTS: Oral administration of different doses of C. rotundus rhizome methanolic extract (CME; 250 mg/kg and 500 mg/kg) significantly inhibited aspirin-induced gastric ulceration in animals in a dose-dependent manner (49.32% and 53.15%, respectively), which was also comparable with the standard gastric ulcer drug ranitidine. Administration of CME also significantly increased the activity of superoxide dismutase, cellular glutathione and glutathione peroxidase, and inhibited the lipid peroxidation in the gastric mucosa of ulcerated animals in a dose-dependent manner. CONCLUSIONS: Our results showed that C. rotundus extract has the capacity to significantly inhibit aspirin-induced gastric ulcers through an antioxidant defense mechanism. This study warrants further examination of this plant for its gastroprotective activities. PMID- 25915082 TI - Effect of Saraca asoca (Asoka) on estradiol-induced keratinizing metaplasia in rat uterus. AB - BACKGROUND: Estrogen-mediated uterus endometrium instability is considered as one of the etiological factors in dysfunctional uterine bleeding (DUB) and uterine cancer. Saraca asoca (Family: Fabaceae) and its fermented preparation, Asokarishta, are extensively used as uterine tonic to treat gynecological disorders in Ayurveda. The present study evaluated the effect of S. asoca (Asoka) on estrogen-induced endometrial thickening of rat uterus. METHODS: Endometrial thickening was induced by intraperitoneal injection of estradiol (20 MUg/kg b.wt) to 8-day-old immature rats for alternate 5 days. Methanolic extract (200 mg/kg b. wt) from S. asoca bark was given orally along with estradiol. Uterus endometrial thickening was analyzed histopathologically and serum estrogen level by radioimmunoassay (RIA). Cyclooxygenase (COX-2) expression in rat uterus was also estimated by Western blot. Anti-inflammatory activity of the extract was analyzed by formalin- and carrageenan-elicited paw edema models in mouse. RESULTS: Uterus endometrium proliferation and keratinized metaplasia with seven to eight stratified epithelial layers on day 16 was observed in rats administered with estradiol. Treatment with S. asoca reduced the thickening to two to four layers and the serum estrogen level diminished significantly to 82.9+/-12.87 pg/mL compared to rats administered with estrogen alone (111.2+/-10.68 pg/mL). A reduction of formalin- and carrageenan-induced paw edema in mouse by S. asoca extract was observed. Lower level of lipopolysaccharides (LPS)-induced COX-2 enzyme in rat uterus by the extract further confirms its anti-inflammatory activity. CONCLUSIONS: Present study reveals the antiproliferative and antikeratinizing effects of S. asoca in uterus endometrium possibly through its anti-estrogenic and anti-inflammatory properties. PMID- 25915083 TI - Stepping inside the realm of epigenetic modifiers. AB - The ability to regulate gene expression in response to environmental alterations is vital for the endurance of all cells. However, unlike bacteria and unicellular organisms, cells of multicellular eukaryotes have developed this competency in a highly sophisticated manner, which ultimately allows for multiple lineages of differentiated cells. To maintain stability and generate progeny, differentiated cells must remain lineage-committed through numerous cell generations, and therefore their transcriptional modus operandi ought to be memorized and transmittable. To preserve the specialized characteristics of differentiated cells, it is crucial that transcriptional alterations that are triggered by specific external or intrinsic stimuli can last also after stimuli fading and propagate onto daughter cells. The unique composition of DNA and histones, and their ability to acquire a variety of epigenetic modifications, enables eukaryotic chromatin to assimilate cellular plasticity and molecular memory. The most well-studied types of epigenetic modifiers are covalently modifying DNA or histones, mostly in a reversible manner. Additional epigenetic mechanisms include histone variant replacement, energy-utilizing remodeling factors, and noncoding transcripts assembled with modifying complexes. Working with multifunctional complexes including transcription factors, epigenetic modifiers have the potential to dictate a variety of transcriptional programs underlying all cellular lineages, while utilizing in each the same source DNA as their substrates. PMID- 25915084 TI - Chemical Biology of Leucine-Rich Repeat Kinase 2 (LRRK2) Inhibitors. AB - There is an urgent need for the development of Parkinson's disease (PD) treatments that can slow disease progression. The leucine-rich repeat kinase 2 (LRRK2) protein has been genetically and functionally linked to PD, and modulation of LRRK2 enzymatic activity has been proposed as a novel therapeutic strategy. In this review, we describe the bioactivity of selected small molecules that have been used to inhibit LRRK2 kinase activity in vitro or in vivo. These compounds are important tools for understanding the cellular biology of LRRK2 and for evaluating the potential of LRRK2 inhibitors as disease-modifying PD therapies. PMID- 25915085 TI - Test Sample for the Spatially Resolved Quantification of Illicit Drugs on Fingerprints Using Imaging Mass Spectrometry. AB - A novel test sample for the spatially resolved quantification of illicit drugs on the surface of a fingerprint using time-of-flight secondary ion mass spectrometry (ToF-SIMS) and desorption electrospray ionization mass spectrometry (DESI-MS) was demonstrated. Calibration curves relating the signal intensity to the amount of drug deposited on the surface were generated from inkjet-printed arrays of cocaine, methamphetamine, and heroin with a deposited-mass ranging nominally from 10 pg to 50 ng per spot. These curves were used to construct concentration maps that visualized the spatial distribution of the drugs on top of a fingerprint, as well as being able to quantify the amount of drugs in a given area within the map. For the drugs on the fingerprint on silicon, ToF-SIMS showed great success, as it was able to generate concentration maps of all three drugs. On the fingerprint on paper, only the concentration map of cocaine could be constructed using ToF-SIMS and DESI-MS, as the signals of methamphetamine and heroin were completely suppressed by matrix and substrate effects. Spatially resolved quantification of illicit drugs using imaging mass spectrometry is possible, but the choice of substrates could significantly affect the results. PMID- 25915086 TI - Mechanistic Insight into Ketone alpha-Alkylation with Unactivated Olefins via C-H Activation Promoted by Metal-Organic Cooperative Catalysis (MOCC): Enriching the MOCC Chemistry. AB - Metal-organic cooperative catalysis (MOCC) has been successfully applied for hydroacylation of olefins with aldehydes via directed C(sp(2))-H functionalization. Most recently, it was reported that an elaborated MOCC system, containing Rh(I) catalyst and 7-azaindoline (L1) cocatalyst, could even catalyze ketone alpha-alkylation with unactivated olefins via C(sp(3))-H activation. Herein we present a density functional theory study to understand the mechanism of the challenging ketone alpha-alkylation. The transformation uses IMesRh(I)Cl(L1)(CH2?CH2) as an active catalyst and proceeds via sequential seven steps, including ketone condensation with L1, giving enamine 1b; 1b coordination to Rh(I) active catalyst, generating Rh(I)-1b intermediate; C(sp(2))-H oxidative addition, leading to a Rh(III)-H hydride; olefin migratory insertion into Rh(III) H bond; reductive elimination, generating Rh(I)-1c(alkylated 1b) intermediate; decoordination of 1c, liberating 1c and regenerating Rh(I) active catalyst; and hydrolysis of 1c, furnishing the final alpha-alkylation product 1d and regenerating L1. Among the seven steps, reductive elimination is the rate determining step. The C-H bond preactivation via agostic interaction is crucial for the bond activation. The mechanism rationalizes the experimental puzzles: why only L1 among several candidates performed perfectly, whereas others failed, and why Wilkinson's catalyst commonly used in MOCC systems performed poorly. Based on the established mechanism and stimulated by other relevant experimental reactions, we attempted to enrich MOCC chemistry computationally, exemplifying how to develop new organic catalysts and proposing L7 to be an alternative for L1 and demonstrating the great potential of expanding the hitherto exclusive use of Rh(I)/Rh(III) manifold to Co(0)/Co(II) redox cycling in developing MOCC systems. PMID- 25915087 TI - One-Pot Synthesis of Brightly Fluorescent Mes2B-Functionalized Indolizine Derivatives via Cycloaddition Reactions. AB - Four new BMes2-functionalized indolizine derivatives (Mes = mesityl) have been prepared via the cycloaddition reaction between pyrido[2,1-a]isoindole (A) or pyrrolo[1,2-a]pyridine (B) and BMes2-containing alkynes. All four compounds are brightly blue or blue-green fluorescent with lambda(em) = 428-495 nm and Phi = 0.27-0.68, depending on the substitution position of the BMes2 group. Experimental and TD-DFT computational data indicated that the primary electronic transitions responsible for the fluorescence of 1-4 are from HOMO to LUMO (pi -> pi*) rather than charge transfer from N -> B, which is in agreement with previous findings suggesting that the lone-pair on N is delocalized throughout the N heterocycles. PMID- 25915088 TI - Gender-typed attributes and marital satisfaction among Mexican immigrant couples: A latent profile approach. AB - Informed by socioecological and dyadic approaches to understanding marriage, the current study examined the patterning of gender-typed attributes among 120 Mexican immigrant opposite sex couples and the subsequent links with spouses' reports of marital satisfaction. Latent profile analysis (LPA) was used to identify typologies of couples based on spouses' self-reported masculine and feminine attributes. Three couple profiles were identified: (a) Androgynous Couples, (b) Undifferentiated Couples, and (c) Mismatched Couples. Results from a mixed model ANCOVA showed profile differences in couples' marital satisfaction based on profile membership, suggesting that spouses in the Undifferentiated Profile were the least satisfied. Findings illustrate a lack of gender-typing at the individual and couple levels that challenge stereotypical and patriarchal depictions of Latino marital relationships and propose a more complex understanding of Mexican-origin spouses' gender-typed attributes than has yet been portrayed in the literature. The finding that couples with 1 androgynous partner (i.e., wives in the Mismatched Profile) reported similar levels of marital satisfaction to couples in the Androgynous Profile offers additional insights regarding how these qualities operate under the unique socioecological niches that Mexican immigrant couples inhabit-contexts that may place demands on spouses that challenge gendered and culturally bound depictions of marriage. PMID- 25915090 TI - Variation in marital quality in a national sample of divorced women. AB - Previous work has compared marital quality between stably married and divorced individuals. Less work has examined the possibility of variation among divorces in trajectories of marital quality as divorce approaches. This study addressed that hole by first examining whether distinct trajectories of marital quality can be discerned among women whose marriages ended in divorce and, second, the profile of women who experienced each trajectory. Latent class growth analyses with longitudinal data from a nationally representative sample were used to "look backward" from the time of divorce. Although demographic and socioeconomic variables from this national sample did not predict the trajectories well, nearly 66% of divorced women reported relatively high levels of both happiness and communication and either low or moderate levels of conflict. Future research including personality or interactional patterns may lead to theoretical insights about patterns of marital quality in the years leading to divorce. PMID- 25915089 TI - Longitudinal relations between constructive and destructive conflict and couples' sleep. AB - We examined longitudinal relations between interpartner constructive (negotiation) and destructive (psychological and physical aggression) conflict strategies and couples' sleep over 1 year. Toward explicating processes of effects, we assessed the intervening role of internalizing symptoms in associations between conflict tactics and couples' sleep. Participants were 135 cohabiting couples (M age = 37 years for women and 39 years for men). The sample included a large representation of couples exposed to economic adversity. Further, 68% were European American and the remainder were primarily African American. At Time 1 (T1), couples reported on their conflict and their mental health (depression, anxiety). At T1 and Time 2, sleep was examined objectively with actigraphs for 7 nights. Three sleep parameters were derived: efficiency, minutes, and latency. Actor-partner interdependence models indicated that husbands' use of constructive conflict forecasted increases in their own sleep efficiency as well as their own and their wives' sleep duration over time. Actor and partner effects emerged, and husbands' and wives' use of destructive conflict strategies generally predicted worsening of some sleep parameters over time. Several mediation and intervening effects were observed for destructive conflict strategies. Some of these relations reveal that destructive conflict is associated with internalizing symptoms, which in turn are associated with some sleep parameters longitudinally. These findings build on a small, albeit growing, literature linking sleep with marital functioning, and illustrate that consideration of relationship processes including constructive conflict holds promise for gaining a better understanding of factors that influence the sleep of men and women. PMID- 25915091 TI - Different dimensions, different mechanisms? Distinguishing relationship status and quality effects on desistance. AB - This study follows from a long line of research aimed at understanding the effects of romantic relationships on desistance from crime. We expanded this work by testing the differential effects of relationship status (i.e., single, dating, cohabiting, married) and relationship quality on crime and the different mechanisms explaining these effects. We drew upon longitudinal data on African American young adults, and utilized a fixed effects approach to examine intraindividual change in relationship status, relationship quality, and offending. Results suggested that, for men, relationship status was directly associated with crime, in that coresidential unions reduced offending independent of their quality. High-quality relationships, however, were found to deter crime for both men and women no matter their form. The effect of relationship status was largely accounted for by social control processes, whereas the relationship quality effect was explained by cognitive transformation, particularly a change in the "criminogenic knowledge structure." These findings demand greater attention to multiple dimensions of relationships and the unique mechanisms through which they may foster desistance. PMID- 25915092 TI - Surface Transfer Doping of Cubic Boron Nitride Films by MoO3 and Tetrafluoro tetracyanoquinodimethane (F4-TCNQ). AB - Cubic boron nitride (cBN) has strong potential for the applications in high temperature and high-power electronics and deep ultraviolet devices due to its outstanding combined physical and chemical properties. P-type surface transfer doping of heteroepitaxial cBN films was achieved by employing MoO3 and tetrafluoro-tetracyanoquinodimethane (F4-TCNQ) as the surface dopants. The surface conductivities of hydrogenated cBN films increased by 3-6 orders after the deposition of surface dopants. The photoemission spectroscopy (PES) measurements revealed the variation of electronic structures at the interface regions, which suggested that the electron transfer from cBN films to the surface dopants induced hole accumulation at the cBN surface and the increase of surface conductivity. Based on the PES results, the energy level diagrams at MoO3/cBN and F4-TCNQ/cBN interfaces were determined. The achievement provided a potential approach for fabricating cBN-based electronic devices, especially on micrometer and nanometer scales. PMID- 25915093 TI - Visualizing electromagnetic fields at the nanoscale by single molecule localization. AB - Coupling of light to the free electrons at metallic surfaces allows the confinement of electric fields to subwavelength dimensions, far below the optical diffraction limit. While this is routinely used to manipulate light at the nanoscale, in electro-optic devices and enhanced spectroscopic techniques, no characterization technique for imaging the underlying nanoscopic electromagnetic fields exists, which does not perturb the field or employ complex electron beam imaging. Here, we demonstrate the direct visualization of electromagnetic fields on patterned metallic substrates at nanometer resolution, exploiting a strong "autonomous" fluorescence-blinking behavior of single molecules within the confined fields allowing their localization. Use of DNA-constructs for precise positioning of fluorescence dyes on the surface induces this distance-dependent autonomous blinking thus completely obviating the need for exogenous agents or switching methods. Mapping such electromagnetic field distributions at nanometer resolution aids the rational design of nanometals for diverse photonic applications. PMID- 25915094 TI - Tailoring indium oxide nanocrystal synthesis conditions for air-stable high performance solution-processed thin-film transistors. AB - Semiconducting metal oxides (ZnO, SnO2, In2O3, and combinations thereof) are a uniquely interesting family of materials because of their high carrier mobilities in the amorphous and generally disordered states, and solution-processed routes to these materials are of particular interest to the printed electronics community. Colloidal nanocrystal routes to these materials are particularly interesting, because nanocrystals may be formulated with tunable surface properties into stable inks, and printed to form devices in an additive manner. We report our investigation of an In2O3 nanocrystal synthesis for high performance solution-deposited semiconductor layers for thin-film transistors (TFTs). We studied the effects of various synthesis parameters on the nanocrystals themselves, and how those changes ultimately impacted the performance of TFTs. Using a sintered film of solution-deposited In2O3 nanocrystals as the TFT channel material, we fabricated devices that exhibit field effect mobility of 10 cm(2)/(V s) and an on/off current ratio greater than 1 * 10(6). These results outperform previous air-stable nanocrystal TFTs, and demonstrate the suitability of colloidal nanocrystal inks for high-performance printed electronics. PMID- 25915095 TI - Pulmonary Delivery of Vancomycin Dry Powder Aerosol to Intubated Rabbits. AB - Antibiotic multiresistant pneumonia is a risk associated with long-term mechanical ventilation. Vancomycin is commonly prescribed for methicillin resistant Staphylococcus aureus infections; however, current formulations of vancomycin are only given intravenously. High doses of vancomycin have been associated with severe renal toxicity. In this study, we characterized dry powder vancomyin as a potential inhaled therapeutic aerosol and compared pharmacokinetic profiles of iv and pulmonary administered vancomycin in intubated rabbits through an endotracheal tube system. Cascade impaction studies indicated that using an endotracheal tube, which bypasses deposition in the mouth and throat, increased the amount of drug entering the lung. Bypassing the endotracheal tube with a catheter further enhanced drug deposition in the lung. Interestingly, intubated rabbits administered 1 mg/kg vancomycin via inhalation had similar AUC to rabbits that were administered 1 mg/kg vancomycin via a single bolus iv infusion; however, inhalation of vancomycin reduced Cmax and increased Tmax, indicating that inhaled vancomycin resulted in more sustained pulmonary levels of vancomycin. Collectively, these results suggested that dry powder vancomycin can successfully be delivered by pulmonary inhalation in intubated patients. Furthermore, as inhaled vancomycin is delivered locally to the site of pulmonary infection, this delivery route could reduce the total dose required for therapeutic efficacy and simultaneously reduce the risk of renal toxicity by eliminating the high levels of systemic drug exposure required to push the pulmonary dose to therapeutic thresholds during iv administration. PMID- 25915096 TI - Modular synthesis of cell-permeating 2-ketoglutarate esters. AB - Cell-permeating esters of 2-ketoglutarate (2-KG) have been synthesized through a convergent sequence from two modules in two and three steps, respectively. This route provides access to a full series of mono- and disubstituted 2-KG esters, enabling us to define the effect of regioisomeric masking on metabolite release and antihypoxic activity in cell-based assays. In addition to providing insight into the biological activity of cell permeable 2-KG esters, the straightforward and modular nature of this synthetic route may prove useful for the development of next-generation 2-KG analogues for diagnostic and therapeutic applications. PMID- 25915098 TI - How do we value a cure? AB - Future perceptions of the value of curative therapies will likely reflect debates happening today about preferences for funding of preventive versus treatment programs, as well as funding orphan drugs. Little is known about how society will value curative therapies versus standard treatments, and the significant role of a host of psychological factors compared to overarching concerns about opportunity costs will likely lead to significant tension between payers and the public. More research to clarify societal preferences and healthcare goals in regards to curative therapies and in light of the potential for significant opportunity costs will be required. Given what we know about preferences for the funding of prevention and treatment measures, we should expect that cures will not be held to a different measure. PMID- 25915097 TI - Self-awareness and traumatic brain injury outcome. AB - PRIMARY OBJECTIVE: Impaired self-awareness following a traumatic brain injury (TBI) can reduce the effectiveness of rehabilitation, resulting in poorer outcomes. However, little is understood about how the multi-dimensional aspects of self-awareness may differentially change with recovery and impact outcome. Thus, this study examined four self-awareness variables represented in the Dynamic Comprehensive Model of Awareness: metacognitive awareness, anticipatory awareness, error-monitoring and self-regulation. RESEARCH DESIGN: This study evaluated change of the self-awareness measures with recovery from TBI and whether the self-awareness measures predicted community re-integration at follow up. METHODS AND PROCEDURES: Participants were 90 individuals with moderate-to severe TBI who were tested acutely following injury and 90 age-matched controls. Forty-nine of the TBI participants and 49 controls were re-tested after 6 months. MAIN OUTCOME AND RESULTS: Results revealed that the TBI group's error-monitoring performance was significantly poorer than controls at both baseline and follow up. Regression analyses revealed that the self-awareness variables at follow-up were predictive of community re-integration, with error-monitoring being a unique predictor. CONCLUSIONS: The results highlight the importance of error-monitoring and suggest that interventions targeted at improving error-monitoring may be particularly beneficial. Understanding the multi-dimensional nature of self awareness will further improve rehabilitation efforts and understanding of the theoretical basis of self-awareness. PMID- 25915099 TI - Early Metabolic Response to Neoadjuvant Treatment: FDG PET/CT Criteria according to Breast Cancer Subtype. AB - PURPOSE: To investigate parameters based on fluorine 18 fluorodeoxyglucose (FDG) positron emission tomographic (PET) imaging that are best correlated with pathologic complete response (PCR) in human epidermal growth factor receptor type 2 (HER2)-positive cancer and triple-negative breast cancer (TNBC) and with partial or complete response in ER-positive/HER2-negative breast cancer. MATERIALS AND METHODS: This study was approved by institutional review board with waivers of informed written consent and included consecutive patients treated by neoadjuvant chemotherapy. Five PET examination-derived parameters were tested: standard uptake value (SUV) maximum (SUV(max)), peak (SUV(peak)), and mean (SUV(mean)), metabolically active tumor volume, and total lesion glycolysis (TLG). Absolute values at baseline PET, at PET imaging after two cycles of chemotherapy, and variation (ie, change) were measured. Correlations with pathologic response (Wilcoxon rank-sum test) and predictive power assessed (area under the curve [AUC] on the basis of receiver operating characteristic analysis) were examined. RESULTS: Included were 169 consecutive patients (mean age, 50 years). PCR was more frequent in HER2-positive tumors (16 of 33 patients [48.5%]) and TNBCs (20 of 54 patients [37%]) than in ER positive/HER2-negative tumors (four of 82 [4.9%]) (P < .001). Among patients with ER-positive/HER2-negative cancers, 33 patients had partial response. In TNBC, best association with PCR was obtained with change in SUV(max) (AUC, 0.86) or change in TLG (AUC, 0.88). In HER2-positive phenotype, absolute SUV(max) (or SUV(peak)) values at PET imaging after two cycles of chemotherapy (AUC for each cycle, 0.93) were better correlated with PCR than change in SUV(max) (AUC, 0.78; P = .11) or change in TLG (AUC, 0.62; P = .005). Regarding ER-positive/HER2-negative cancers, change in SUV(max) or change in TLG (AUC, 0.75) were parameters best correlated with partial or complete response. Baseline SUV(max) was higher in lymph nodes than in primary tumor in 31 patients. Findings were similar considering the site with highest FDG uptake. CONCLUSION: Quantitative indexes of tumor glucose use that are best correlated with pathologic response vary by phenotype: change in SUV(max) or TLG are most adequate for TNBCs and ER-positive/ HER2-negative cancers and absolute SUV(max) after two cycles of chemotherapy for HER2-positive breast cancers. PMID- 25915100 TI - Breast Cancer Recurrence in Patients with Newly Diagnosed Breast Cancer without and with Preoperative MR Imaging: A Matched Cohort Study. AB - PURPOSE: To compare breast cancer disease-free survival (DFS) outcomes of patients with newly diagnosed breast cancer without and with preoperative magnetic resonance (MR) imaging. MATERIALS AND METHODS This study was approved by an institutional review board, and informed consent was waived. From 2004 to 2009 (unilateral MR imaging from 2004 to 2006 vs bilateral MR imaging from 2007 to 2009), patients with breast cancer without preoperative MR imaging (no MR imaging group) were matched with those with preoperative MR imaging (MR imaging group) according to age, histologic grade, nuclear grade, tumor size, nodal status, stage, hormone receptor status, Ki-67 status, molecular subtype, and lymphovascular invasion. Survival analysis was performed by using Kaplan-Meier estimates. A marginal model was used to evaluate the effect of preoperative MR imaging on DFS. RESULTS: A total of 371 patient pairs from the unilateral imaging period and 97 patient pairs from the bilateral imaging period were matched. During the unilateral imaging period, the MR imaging group had better local regional recurrence DFS (hazard ratio [HR], 0.33; 95% confidence interval [CI]: 0.12, 0.91; P = .032) than did the no MR imaging group; however, no difference was found for contralateral breast (P = .440) or distant recurrence (P = .515) DFS. During the bilateral imaging period, the MR imaging group had better contralateral breast cancer DFS (HR, 0.03; 95% CI: 0.04, 0.21; P < .001) than the no MR imaging group; however, no difference was found for local-regional (P = .180) or distant recurrence (P = .178) DFS. CONCLUSION: Preoperative bilateral breast MR imaging for staging of breast cancer was associated with a reduced risk of contralateral breast recurrence; however, no observed reduction in risk of local-regional or distant recurrence was shown. PMID- 25915101 TI - New muscle for old hearts: engineering tissue from pluripotent stem cells. AB - Stem cell-based therapies are considered to be promising and innovative therapeutic strategies for heart repair. Patient-derived induced pluripotent stem cells (iPSCs) are now available, which combine the advantages of autologous adult stem cells with the unlimited potential of embryonic stem cells for proliferation and differentiation. Intense research has driven dramatic progress in various areas of iPSC technology relevant for clinically applicable iPSC-based cellular therapies. At this point, it is already possible to generate transgene-free autologous iPSCs from small blood samples or hair, to scale up the expansion and differentiation of iPSCs to clinically required dimensions, and to obtain highly enriched cardiomyocyte preparations. On the other hand, critical hurdles such as the targeted specification of distinct cardiomyocyte subpopulations, survival and proper functional integration of cellular transplants after myocardial infarction, and in vitro engineering of prevascularized muscle patches have yet to be overcome. Nevertheless, concepts of cellular cardiomyoplasty seem to have come of age and the first clinical applications of iPSC-based heart repair can be expected within the coming years. PMID- 25915103 TI - Reconfiguring gratings of slanted plasmonic nanocolumns by ion beam irradiation. AB - Gratings with slanted plasmonic nanocolumns of silver (Ag) on top fabricated by physical vapor deposition at large oblique angles on predefined gratings show unique plasmonic properties. These aligned nanocolumns with high-aspect ratios can be uniformly re-oriented to any desired angle of slant by ion beam irradiation. A focused ion beam (FIB) has been used as the ion source here. The plastic deformation of the nanocolumns arises due to defect formation caused by the energetic ions and can enable the complete tuning of the photonic and plasmonic properties of the grating through the slant angle. The reorientation can be uniformly carried over large areas of 0.2 mm(2) with the FIB and the diffraction patterns from the reoriented grating show large changes in the diffraction efficiencies. Electromagnetic simulations of the grating structures reveal large changes in the photonic properties with the slant angle such as diffraction efficiencies and the electromagnetic near fields. PMID- 25915102 TI - Efficacy of Different Treatment Alternatives for Obesity Hypoventilation Syndrome. Pickwick Study. AB - RATIONALE: The incidence of obesity hypoventilation syndrome (OHS) may be increasing in parallel with the present obesity epidemic. Despite extensive noninvasive ventilation (NIV) and continuous positive airway pressure (CPAP) use in patients with OHS, information regarding efficacy is limited. OBJECTIVES: We performed a large, multicenter randomized controlled study to determine the comparative efficacy of NIV, CPAP, and lifestyle modification (control group) using daytime PaCO2 as the main outcome measure. METHODS: Sequentially screened patients with OHS with severe sleep apnea were randomized into the above mentioned groups for a 2-month follow up. Arterial blood gas parameters, clinical symptoms, health-related quality-of-life assessments, polysomnography, spirometry, 6-minute-walk distance, dropouts, compliance, and side effects were evaluated. Statistical analysis was performed using intention-to-treat analysis, although adjustments for CPAP and NIV compliance were also analyzed. MEASUREMENTS AND MAIN RESULTS: In total, 351 patients were selected, and 221 were randomized. NIV yielded the greatest improvement in PaCO2 and bicarbonate, with significant differences relative to the control group but not relative to the CPAP group. In the CPAP group, PaCO2 improvement was significantly different than in the control group only after CPAP compliance adjustment. Additionally, clinical symptoms and polysomnographic parameters improved similarly with NIV and CPAP relative to the control. However, some health-related quality-of-life assessments, the spirometry, and 6-minute-walk distance results improved more with NIV than with CPAP. Dropouts were similar between groups, and compliance and secondary effects were similar between NIV and CPAP. CONCLUSIONS: NIV and CPAP were more effective than lifestyle modification in improving clinical symptoms and polysomnographic parameters, although NIV yielded better respiratory functional improvements than did CPAP. Long-term studies must demonstrate whether this functional improvement has relevant implications. Clinical trial registered with www.clinicaltrials.gov (NCT01405976). PMID- 25915104 TI - Antioxidant, antimicrobial and wound healing properties of Struthanthus vulgaris. AB - CONTEXT: Struthanthus vulgaris (Vell.) Mart. (Loranthaceae) has been widely used in traditional medicine in Brazil to bathe wounds. OBJECTIVE: The objective of this study is to investigate the in vitro wound healing effects, together with the antioxidant and antimicrobial activities of S. vulgaris leaf and branch extracts. MATERIAL AND METHODS: Ethanol leaf and branch extracts of S. vulgaris were investigated at 1-100 ug/ml concentrations in the scratch assay after 14 h. Antioxidant activity was investigated using the 2,2-diphenyl-1-picrylhydrazyl (DPPH) radical-scavenging assay, and the antibacterial activity was tested at concentrations up to 1000 ug/ml against Gram-positive and Gram-negative bacteria by the microdilution test after 24 h. The total phenolic and flavonoid contents were determined by colorimetric methods. RESULTS: Struthanthus vulgaris leaf and branch extracts at 100 ug/ml concentration stimulated migration and proliferation of fibroblasts and enhanced cell numbers by 56.2% and 18.6%, respectively. Antioxidant activity exhibited IC50 values of 24.3 and 18.9 ug/ml for the leaf and branch extracts, respectively. The ethanol leaf extract showed antimicrobial activity against the Gram-positive Staphylococcus mutans and Staphylococcus aureus bacteria, exhibiting minimum inhibitory concentration values of 125 and 500 ug/ml, respectively. An appreciable total phenolic content in the leaves (813.6 +/- 2.7 mg/g) and branches (462.8 +/- 9.6 mg/g), and relatively low concentration of flavonoids in the leaves (13.3 +/- 4.3 mg/g) and branches (1.9 +/- 0.2 mg/g), was detected. DISCUSSION AND CONCLUSION: The antioxidant and antibacterial activities, together with the strong ability to stimulate proliferation and migration of fibroblasts, provide some support for the traditional use of S. vulgaris. PMID- 25915105 TI - Hemodynamic Characterization of a Mouse Model for Investigating the Cellular and Molecular Mechanisms of Neotissue Formation in Tissue-Engineered Heart Valves. AB - Decellularized allograft heart valves have been used as tissue-engineered heart valve (TEHV) scaffolds with promising results; however, little is known about the cellular mechanisms underlying TEHV neotissue formation. To better understand this phenomenon, we developed a murine model of decellularized pulmonary heart valve transplantation using a hemodynamically unloaded heart transplant model. Furthermore, because the hemodynamics of blood flow through a heart valve may influence morphology and subsequent function, we describe a modified loaded heterotopic heart transplant model that led to an increase in blood flow through the pulmonary valve. We report host cell infiltration and endothelialization of implanted decellularized pulmonary valves (dPV) and provide an experimental approach for the study of TEHVs using mouse models. PMID- 25915107 TI - Mathematical Difficulties and White Matter Abnormalities in Subacute Pediatric Mild Traumatic Brain Injury. AB - Mathematical difficulties have been documented following pediatric mild traumatic brain injury (mTBI), yet a precise characterization of these impairments and their neural correlates is currently unavailable. We aimed to characterize these impairments by comparing behavioral and neuroimaging (i.e., diffusion tensor imaging [DTI]) outcomes from children with subacute mTBI to typically-developing controls. Twenty subacute pediatric mTBI patients and 20 well-matched controls underwent cognitive assessment and DTI examination. DTI tractography was used to detect white matter abnormalities in the corpus callosum (CC) and superior and inferior longitudinal fasciculi; these tracts are involved in mathematical performance and they are often damaged after mTBI. Behavioral results revealed that children with mTBI performed significantly more poorly on rapid apprehension of small numbers of objects (or "subitizing"), processing of non-symbolic numerosities, and procedural problem solving. These group differences were explained by differences in visuospatial working memory, which suggests that the observed mathematical difficulties may be a consequence of impairments in visuospatial abilities. DTI analysis revealed subtle group differences in the CC genu and splenium (i.e., higher fractional anisotropy and lower mean and radial diffusivity in children with mTBI) but the observed white matter abnormalities of the CC were not significantly associated with the observed mathematical difficulties in the mTBI patients. PMID- 25915106 TI - Prediction of Android and Gynoid Body Adiposity via a Three-dimensional Stereovision Body Imaging System and Dual-Energy X-ray Absorptiometry. AB - OBJECTIVE: Current methods for measuring regional body fat are expensive and inconvenient compared to the relative cost-effectiveness and ease of use of a stereovision body imaging (SBI) system. The primary goal of this research is to develop prediction models for android and gynoid fat by body measurements assessed via SBI and dual-energy x-ray absorptiometry (DXA). Subsequently, mathematical equations for prediction of total and regional (trunk, leg) body adiposity were established via parameters measured by SBI and DXA. METHODS: A total of 121 participants were randomly assigned into primary and cross validation groups. Body measurements were obtained via traditional anthropometrics, SBI, and DXA. Multiple regression analysis was conducted to develop mathematical equations by demographics and SBI assessed body measurements as independent variables and body adiposity (fat mass and percentage fat) as dependent variables. The validity of the prediction models was evaluated by a split sample method and Bland-Altman analysis. RESULTS: The R(2) of the prediction equations for fat mass and percentage body fat were 93.2% and 76.4% for android and 91.4% and 66.5% for gynoid, respectively. The limits of agreement for the fat mass and percentage fat were -0.06 +/- 0.87 kg and -0.11% +/- 1.97% for android and -0.04 +/- 1.58 kg and -0.19% +/- 4.27% for gynoid. Prediction values for fat mass and percentage fat were 94.6% and 88.9% for total body, 93.9% and 71.0% for trunk, and 92.4% and 64.1% for leg, respectively. CONCLUSIONS: The three-dimensional (3D) SBI produces reliable parameters that can predict android and gynoid as well as total and regional (trunk, leg) fat mass. PMID- 25915108 TI - Role of P-glycoprotein and permeability upon the brain distribution and pharmacodynamics of etamicastat: a comparison with nepicastat. AB - 1. This study explores the impact of permeability and P-glycoprotein (P-gp) efflux, upon brain exposure to etamicastat, a new dopamine-beta-hydroxylase (DBH) inhibitor and consequently brain levels of catecholamines. 2. Brain exposure to etamicastat (10 mg/kg), following intravenous administration to mice, was residual and upon oral administration of the same dose no compound was detected, concurring with the absence of effects upon brain catecholamines. The intravenous co-administration of elacridar (1.0 mg/kg), a known P-gp/BCRP dual modulator, significantly increased brain etamicastat exposure, but the levels attained were very low when compared to those of nepicastat, a centrally active DBH inhibitor. 3. In vitro permeability studies from apical-to-basal direction conducted in Caco 2 cells and MDCK-II cells showed that etamicastat apparent permeability was 1.2 * 10(-5) and 1.1 * 10(-6 )cm/s, respectively, 5- and 50-fold lower as compared to nepicastat. The secretory efflux ratio in MDCK-II cells overexpressing human P-gp showed an efflux ratio greater than 2, for both compounds, which was significantly decreased by elacridar. Despite its lower bioavailability and higher clearance, as compared to nepicastat, etamicastat showed preferential distribution to peripheral tissues and high plasma free fraction (15.5%), which may explain its effects upon peripheral DBH and catecholamine levels. 4. Though P gp-mediated efflux may contribute to the limited brain penetration of etamicastat, the low permeability along with the pharmacokinetic properties of etamicastat may be perceived as the main contributors for its peripheral selectivity, which is advantageous for a cardiovascular drug candidate. PMID- 25915109 TI - Co-administration of paroxetine increased the systemic exposure of pravastatin in diabetic rats due to the decrease in liver distribution. AB - 1. Liver distribution and systemic exposure of pravastatin were the determinant factors of efficacy and toxicity of pravastatin. Aim of the present study was to investigate the effect of paroxetine on the liver distribution and systemic exposure of pravastatin in diabetic rats induced by combining high fat diet (HFD) and low-dose streptozotocin (STZ). 2. Plasma concentrations and liver distribution of pravastatin were measured in the presence of paroxetine. Effect of paroxetine on pravastatin excretion via bile, intestine, feces and urine, as well as pravastatin absorption via intestine was documented. Freshly isolated hepatocytes and Caco-2 cells were used to investigate the effect of paroxetine on pravastatin transport. 3. Paroxetine increased the systemic exposure of pravastatin and decreased hepatic distribution of pravastatin in diabetic rats. In vitro, paroxetine inhibited the hepatic uptake of pravastatin and promoted the efflux of pravastatin in freshly isolated hepatocytes, which may partly explain the decreased hepatic distribution of pravastatin by paroxetine. It was also observed that paroxetine promoted the absorption of pravastatin via jejunum and the uptake of pravastatin in Caco-2 cells. 4. We concluded that paroxetine increased the systemic exposure of pravastatin partly via promoting absorption via jejunum and inhibiting hepatic uptake of pravastatin. PMID- 25915110 TI - Characterization of the M2e antibody response following highly pathogenic H5N1 avian influenza virus infection and reliability of M2e ELISA for identifying infected among vaccinated chickens. AB - A surveillance method able to differentiate between vaccinated and infected poultry is required for those countries that practice vaccination against highly pathogenic avian influenza H5N1. The external domain of the M2 protein (M2e) of influenza virus is a potentially useful differentiating-infected from vaccinated animals (DIVA) antigen but little is known about the M2e antibody response and factors influencing its detection. In this study, the M2e antibody response was characterized in layer birds vaccinated and challenged with an Indonesian H5N1 virus isolate, using a single M2e peptide or four-branched multiple antigenic peptide form of M2e (MAP-M2e) as antigens in two separate ELISAs. Anti-M2e antibodies were absent in chicks with high level of maternal haemagglutination inhibition antibodies and also in all layers vaccinated once, twice or three times with an inactivated commercial H5N1 vaccine. In contrast, anti-M2e antibodies were detected in vaccinated layers challenged with H5N1 virus and their presence was associated with virus isolation and an increase in haemagglutination inhibition titres. The number of birds that developed M2e antibodies, as well as the strength and duration of the M2e antibody response were strongly influenced by the length of the interval between vaccination and challenge. Birds challenged at six weeks after vaccination all developed M2e antibodies by 14 days that lasted until at least 56 days after infection. In birds challenged at two weeks after vaccination, only a proportion of birds developed M2e antibodies by 14 days that lasted only until 28 days post infection. Both single M2e peptide and MAP-M2e ELISAs had high diagnostic specificity but the diagnostic sensitivity of MAP-M2e ELISA was significantly higher and more effective in detecting M2e antibody in immune and infected birds. The results show that MAP-M2e ELISA would be useful for surveillance in countries using vaccination to control highly pathogenic avian influenza H5N1. PMID- 25915111 TI - Association between assisted reproductive technology and cardiac alteration at age 5 years. PMID- 25915112 TI - Sulfation mediates activity of zosteric acid against biofilm formation. AB - Zosteric acid (ZA), a metabolite from the marine sea grass Zostera marina, has attracted much attention due to its attributed antifouling (AF) activity. However, recent results on dynamic transformations of aromatic sulfates in marine phototrophic organisms suggest potential enzymatic desulfation of metabolites like ZA. The activity of ZA was thus re-investigated using biofilm assays and simultaneous analytical monitoring by liquid chromatography/mass spectrometry (LC/MS). Comparison of ZA and its non-sulfated form para-coumaric acid (CA) revealed that the active substance was in all cases the non-sulfated CA while ZA was virtually inactive. CA exhibited a strong biofilm inhibiting activity against Escherichia coli and Vibrio natriegens. The LC/MS data revealed that the apparent biofilm inhibiting effects of ZA on V. natriegens can be entirely attributed to CA released from ZA by sulfatase activity. In the light of various potential applications, the (a)biotic transformation of ZA to CA has thus to be considered in future AF formulations. PMID- 25915113 TI - Subdural hygroma following decompressive craniectomy or non-decompressive craniectomy in patients with traumatic brain injury: Clinical features and risk factors. AB - OBJECTIVE: Subdural hygroma (SDG) is a common complication that can occur after head trauma or secondary to decompressive craniectomy (DC). SDGs can be located not only ipsilateral or contralateral to the side of the DC, but also bilateral or unilateral in patients without DC. This study investigated the incidence and risk factors for different types of SDG in a large cohort of patients with traumatic brain injury (TBI). METHODS: A retrospective study was conducted involving 379 adult patients with TBI who were admitted to Huashan Hospital, Fudan University between January 2009 and December 2013. As the outcome was dichotomous (SDG vs no SDG or hydrocephalus vs no hydrocephalus), multivariate logistic regression analyses were used to identify independent risk factors for the development of SDGs in patients without DC, ipsilateral SDG after unilateral DC, contralateral SDG after unilateral DC or SDG after bilateral DC. Risk factors for the development of hydrocephalus were also evaluated in patients with and without DC. RESULTS: Among the 207 (54.6%) patients without DC, 30 (14.5%) had unilateral SDGs and 34 (16.4%) had bilateral SDGs. Of the 172 patients (45.4%) with DC, 134 (77.9%) underwent unilateral DC and 38 (22.1%) underwent bilateral DC. Of the 134 patients who underwent unilateral DC, 49 developed SDG, including 22 (16.4%) ipsilateral SDG, 19 (14.2%) contralateral SDG and eight (6.0%) both ipsilateral and contralateral SDGs. For patients undergoing bilateral DC, 13 (34.2%) developed a SDG. No significant difference in the incidence of SDG was observed between the patients with and without DC (36.0% vs 30.9%, p = 0.291), but the characteristics of SDGs were different between the two groups. Logistic regression analysis showed that factors independently associated with the development of SDG were male sex (odds ratio [OR] = 3.861; 95% CI = 1.642-9.091; p = 0.002), older age (OR = 1.046; 95% CI = 1.021-1.070; p < 0.001), basal cistern haemorrhage (OR = 4.608; 95% CI = 1.510-14.064; p = 0.007), diffuse injury and swelling (OR = 3.158; 95% CI = 1.341-7.435; p = 0.008) or diffuse injury and shift (OR = 3.826; 95% CI = 1.141-12.830; p = 0.030) in patients without DC. Temporal haematoma or contusion in the non-DC side (OR = 2.623; 95% CI = 1.070-6.428; p = 0.035) and traumatic SAH (OR = 3.751; 95% CI = 1.047 13.438; p = 0.042) were independently associated with the development of ipsilateral SDG in patients who underwent unilateral DC. However, factors independently associated with the development of contralateral SDG were frontal haematoma or contusion on the non-DC side (OR = 3.145; 95% CI = 1.272-7.774; p = 0.013) and SDH on the non-DC side (OR = 7.024; 95% CI = 1.477-33.390; p = 0.014). Only craniectomy area (OR = 1.030; 95% CI = 1.008-1.052; p = 0.008) was independently associated with the development of SDG in patients with bilateral DC. In the multivariate analysis, SDG in patients without DC was not associated with the development of hydrocephalus. However, SDG was significantly associated with the development of hydrocephalus for patients who underwent DC (OR = 2.173; 95% CI = 1.362-3.467; p = 0.001). CONCLUSIONS: This study suggested that the incidence of SDG in patients who have and have not undergone DC was identical; however, the patients' characteristics and risk factors differed. Therefore, the management and prediction of SDG should be performed according to SDG type. PMID- 25915114 TI - Electrochemiluminescence-based detection method of lead(II) ion via dual enhancement of intermolecular and intramolecular co-reaction. AB - A novel analytical method to design a highly selective and sensitive detection technique for lead(II) ions (Pb(2+)) detection was developed based on an electrochemiluminescence (ECL) sensor, taking advantage of the high specificity of the aptamer for Pb(2+) and the use of both intermolecular and intramolecular co-reaction to achieve signal enhancement. For sensing interface construction, L cysteine (Cys) and gold nanostructured layers were electrodeposited on the electrode surface successively, which afforded a large surface area to anchor massive thiol-terminated auxiliary probes (APs) via a thiol-Au interaction. Then, a DNA duplex was generated based on the hybridization of the APs with capture probes (CPs, Pb(2+) specific aptamers). In the presence of Pb(2+), Pb(2+)-induced aptamers were released from the DNA duplex via the formation of a Pb(2+) stabilized G-quadruplex, accompanied by leaving the single CPs on the sensing interface. Herein, the ruthenium(ii) complexes with functional groups of -COOH (Ru-COOH) were covalently bonded on the polyamidoamine dendrimers with amine end groups (PAMAM), which were capped by the high-index-faceted Au nanoparticles (HIFAuNPs) to obtain the ECL signal labels of Ru-PAMAM-HIFAuNPs. Then, the detection probes (DPs) of amino-terminated Pb(2+) specific aptamers were tagged with the Ru-PAMAM-HIFAuNPs. It was demonstrated that the covalent bonding of PAMAM and Ru-COOH could generate a self-enhanced ECL luminophore by an intramolecular co-reaction and the use of a Cys layer modified electrode could enhance the ECL by the intermolecular co-reaction of Cys and Ru-COOH, which lead to a significant enhancement of the ECL response. Based on this analytical method, the ECL signal increased with Pb(2+) concentration which presented a linear relationship in the range 1.0 * 10(-13)-1.0 * 10(-7) M with the detection limit of 4.0 * 10(-14) M. The proposed approach was also successfully utilized for the determination of Pb(2+) in soil samples. PMID- 25915115 TI - Amino Acid Transporters and Release of Hydrophobic Amino Acids in the Heterocyst Forming Cyanobacterium Anabaena sp. Strain PCC 7120. AB - Anabaena sp. strain PCC 7120 is a filamentous cyanobacterium that can use inorganic compounds such as nitrate or ammonium as nitrogen sources. In the absence of combined nitrogen, it can fix N2 in differentiated cells called heterocysts. Anabaena also shows substantial activities of amino acid uptake, and three ABC-type transporters for amino acids have been previously characterized. Seven new loci encoding predicted amino acid transporters were identified in the Anabaena genomic sequence and inactivated. Two of them were involved in amino acid uptake. Locus alr2535-alr2541 encodes the elements of a hydrophobic amino acid ABC-type transporter that is mainly involved in the uptake of glycine. ORF all0342 encodes a putative transporter from the dicarboxylate/amino acid:cation symporter (DAACS) family whose inactivation resulted in an increased uptake of a broad range of amino acids. An assay to study amino acid release from Anabaena filaments to the external medium was set up. Net release of the alanine analogue alpha-aminoisobutyric acid (AIB) was observed when transport system N-I (a hydrophobic amino acid ABC-type transporter) was engaged in the uptake of a specific substrate. The rate of AIB release was directly proportional to the intracellular AIB concentration, suggesting leakage from the cells by diffusion. PMID- 25915116 TI - Developing critical consciousness or justifying the system? A qualitative analysis of attributions for poverty and wealth among low-income racial/ethnic minority and immigrant women. AB - OBJECTIVES: Economic inequality is a growing concern in the United States and globally. The current study uses qualitative techniques to (a) explore the attributions low-income racial/ethnic minority and immigrant women make for poverty and wealth in the U.S., and (b) clarify important links between attributions, critical consciousness development, and system justification theory. METHODS: In-depth interview transcripts from 19 low-income immigrant Dominican and Mexican and native African American mothers in a large Northeastern city were analyzed using open coding techniques. Interview topics included perceptions of current economic inequality and mobility and experiences of daily economic hardships. RESULTS: Almost all respondents attributed economic inequality to individual factors (character flaws, lack of hard work). Structural explanations for poverty and wealth were expressed by fewer than half the sample and almost always paired with individual explanations. Moreover, individual attributions included system-justifying beliefs such as the belief in meritocracy and equality of opportunity and structural attributions represented varying levels of critical consciousness. CONCLUSIONS: Our analysis sheds new light on how and why individuals simultaneously hold individual and structural attributions and highlights key links between system justification and critical consciousness. It shows that critical consciousness and system justification do not represent opposite stances along a single underlying continuum, but are distinct belief systems and motivations. It also suggests that the motive to justify the system is a key psychological process impeding the development of critical consciousness. Implications for scholarship and intervention are discussed. PMID- 25915117 TI - The role of recent thymic emigrant-regulatory T-cell (RTE-Treg) differentiation during pregnancy. AB - During pregnancy, regulatory T cells (Tregs) have a key role in maternal immune tolerance to the semi-allogeneic fetus. Our previous results showed that the naive CD45RA(+)-Treg pool is functionally improved in pregnant women compared with non-pregnant women. Therefore, we examined the thymic output and differentiation of CD45RA(+)CD31(+) recent thymic emigrant (RTE)-Tregs during normal pregnancy and in the presence of preeclampsia. With the onset of pregnancy, the composition of the total CD4(+)CD127(low+/-)FoxP3(+)-Treg pool changed in the way that its percentage of RTE- and CD45RA(-)CD31(+)-memory Tregs decreased strongly, whereas that of the CD45RA(+)CD31(-)-mature naive (MN)-Tregs did not change and that of the CD45RA(-)CD31(-)-memory Tregs increased complementary. Thereby, the ratio of RTE-/MN-Tregs decreased from 1.0 to 0.7 leading to a significant increase in the suppressive activity of the naive CD45RA(+)-Treg pool. This effect was confirmed by re-assembling separated RTE- and MN-Tregs from non-pregnant women in the ratio of pregnant women. The suppressive activity of both separated naive Treg subsets was equally high in non pregnant and pregnant women, but considerably reduced in preeclampsia patients, who showed significantly increased percentages of CD45RA(-)CD31(+)-memory Tregs, but decreased percentages of RTE- and MN-Tregs. Our results suggest a reduced thymic output of RTE-Tregs during pregnancy, which causes a decrease in the ratio of RTE-/MN-Tregs and thus an increase in the differentiation of RTE-Tregs towards CD45RA(-)CD31(-)-memory Tregs. Presumably, this differentiation of RTE-Tregs, which was impaired in preeclampsia patients, ensures the improved suppressive activity of the CD45RA(+)-naive Treg pool and thus retains the maintenance of pregnancy. PMID- 25915118 TI - Injuries in recreational curling include head injuries and may be prevented by using proper footwear. AB - INTRODUCTION: Our study examines a recreational curling population to describe patterns of injury occurrence, estimate risk of injury and to gauge attitudes towards equipment-based prevention strategies. METHODS: In a retrospective case series, we queried the Canadian Hospitals Injury Reporting and Prevention Program (CHIRPP), a national injury surveillance database, for curling injuries entered between 1993 and 2011. Kingston General Hospital and Hotel Dieu Hospital provide the two Kingston, Ontario, sites for emergency department (ED) care and participate in CHIRPP. Each retrieved entry underwent a chart review. A secondary survey was mailed to select individuals who had experienced curling injuries to solicit details on their injury and attitudes towards equipment to prevent injury. We used descriptive statistics for rates and proportions. RESULTS: Over 90% of acute curling injuries resulted from a fall, and 31.7% were head impacts. We found that acute injuries requiring ED presentation occur at a rate of approximately 0.17 per 1000 athlete-exposures (95% CI: 0.12-0.22). The secondary survey was completed by 54% of potential respondents. Of survey respondents, 41.3% attributed their fall to a lack of proper footwear and 73.5% of respondents agreed with mandatory sport-specific footwear as a prevention strategy, but only 8% agreed with mandatory helmet wear. CONCLUSION: Although curling injuries requiring medical care are not common, head injuries make up a large proportion. Mandated use of appropriate footwear appears to be the most effective prevention strategy, as well as the measure deemed most acceptable by players. PMID- 25915119 TI - Status Report--Retracing the history of the early development of national chronic disease surveillance in Canada and the major role of the Laboratory Centre for Disease Control (LCDC) from 1972 to 2000. PMID- 25915120 TI - High-performance probes for light and electron microscopy. AB - We describe an engineered family of highly antigenic molecules based on GFP-like fluorescent proteins. These molecules contain numerous copies of peptide epitopes and simultaneously bind IgG antibodies at each location. These 'spaghetti monster' fluorescent proteins (smFPs) distributed well in neurons, notably into small dendrites, spines and axons. smFP immunolabeling localized weakly expressed proteins not well resolved with traditional epitope tags. By varying epitope and scaffold, we generated a diverse family of mutually orthogonal antigens. In cultured neurons and mouse and fly brains, smFP probes allowed robust, orthogonal multicolor visualization of proteins, cell populations and neuropil. smFP variants complement existing tracers and greatly increase the number of simultaneous imaging channels, and they performed well in advanced preparations such as array tomography, super-resolution fluorescence imaging and electron microscopy. In living cells, the probes improved single-molecule image tracking and increased yield for RNA-seq. These probes facilitate new experiments in connectomics, transcriptomics and protein localization. PMID- 25915121 TI - G&T-seq: parallel sequencing of single-cell genomes and transcriptomes. AB - The simultaneous sequencing of a single cell's genome and transcriptome offers a powerful means to dissect genetic variation and its effect on gene expression. Here we describe G&T-seq, a method for separating and sequencing genomic DNA and full-length mRNA from single cells. By applying G&T-seq to over 220 single cells from mice and humans, we discovered cellular properties that could not be inferred from DNA or RNA sequencing alone. PMID- 25915122 TI - Multispectral labeling technique to map many neighboring axonal projections in the same tissue. AB - We describe a method to map the location of axonal arbors of many individual neurons simultaneously via the spectral properties of retrogradely transported dye-labeled vesicles. We inject overlapping regions of an axon target area with three or more different colored retrograde tracers. On the basis of the combinations and intensities of the colors in the individual vesicles transported to neuronal somata, we calculate the projection sites of each neuron's axon. This neuronal positioning system (NPS) enables mapping of many axons in a simple automated way. In our experiments, NPS combined with spectral (Brainbow) labeling of the input to autonomic ganglion cells showed that the locations of ganglion cell projections to a mouse salivary gland related to the identities of their preganglionic axonal innervation. NPS could also delineate projections of many axons simultaneously in the mouse central nervous system. PMID- 25915123 TI - ATP synthase promotes germ cell differentiation independent of oxidative phosphorylation. AB - The differentiation of stem cells is a tightly regulated process essential for animal development and tissue homeostasis. Through this process, attainment of new identity and function is achieved by marked changes in cellular properties. Intrinsic cellular mechanisms governing stem cell differentiation remain largely unknown, in part because systematic forward genetic approaches to the problem have not been widely used. Analysing genes required for germline stem cell differentiation in the Drosophila ovary, we find that the mitochondrial ATP synthase plays a critical role in this process. Unexpectedly, the ATP synthesizing function of this complex was not necessary for differentiation, as knockdown of other members of the oxidative phosphorylation system did not disrupt the process. Instead, the ATP synthase acted to promote the maturation of mitochondrial cristae during differentiation through dimerization and specific upregulation of the ATP synthase complex. Taken together, our results suggest that ATP synthase-dependent crista maturation is a key developmental process required for differentiation independent of oxidative phosphorylation. PMID- 25915124 TI - The histone deacetylase SIRT6 controls embryonic stem cell fate via TET-mediated production of 5-hydroxymethylcytosine. AB - How embryonic stem cells (ESCs) commit to specific cell lineages and yield all cell types of a fully formed organism remains a major question. ESC differentiation is accompanied by large-scale histone and DNA modifications, but the relations between these epigenetic categories are not understood. Here we demonstrate the interplay between the histone deacetylase sirtuin 6 (SIRT6) and the ten-eleven translocation enzymes (TETs). SIRT6 targets acetylated histone H3 at Lys 9 and 56 (H3K9ac and H3K56ac), while TETs convert 5-methylcytosine into 5 hydroxymethylcytosine (5hmC). ESCs derived from Sirt6 knockout (S6KO) mice are skewed towards neuroectoderm development. This phenotype involves derepression of OCT4, SOX2 and NANOG, which causes an upregulation of TET-dependent production of 5hmC. Genome-wide analysis revealed neural genes marked with 5hmC in S6KO ESCs, thereby implicating TET enzymes in the neuroectoderm-skewed differentiation phenotype. We demonstrate that SIRT6 functions as a chromatin regulator safeguarding the balance between pluripotency and differentiation through Tet mediated production of 5hmC. PMID- 25915125 TI - The ITIM-containing receptor LAIR1 is essential for acute myeloid leukaemia development. AB - Conventional strategies are not particularly successful in the treatment of leukaemia, and identification of signalling pathways crucial to the activity of leukaemia stem cells will provide targets for the development of new therapies. Here we report that certain receptors containing the immunoreceptor tyrosine based inhibition motif (ITIM) are crucial for the development of acute myeloid leukaemia (AML). Inhibition of expression of the ITIM-containing receptor LAIR1 does not affect normal haematopoiesis but abolishes leukaemia development. LAIR1 induces activation of SHP-1, which acts as a phosphatase-independent signalling adaptor to recruit CAMK1 for activation of downstream CREB in AML cells. The LAIR1-SHP-1-CAMK1-CREB pathway sustains the survival and self-renewal of AML stem cells. Intervention in the signalling initiated by ITIM-containing receptors such as LAIR1 may result in successful treatment of AML. PMID- 25915126 TI - TEAD and YAP regulate the enhancer network of human embryonic pancreatic progenitors. AB - The genomic regulatory programmes that underlie human organogenesis are poorly understood. Pancreas development, in particular, has pivotal implications for pancreatic regeneration, cancer and diabetes. We have now characterized the regulatory landscape of embryonic multipotent progenitor cells that give rise to all pancreatic epithelial lineages. Using human embryonic pancreas and embryonic stem-cell-derived progenitors we identify stage-specific transcripts and associated enhancers, many of which are co-occupied by transcription factors that are essential for pancreas development. We further show that TEAD1, a Hippo signalling effector, is an integral component of the transcription factor combinatorial code of pancreatic progenitor enhancers. TEAD and its coactivator YAP activate key pancreatic signalling mediators and transcription factors, and regulate the expansion of pancreatic progenitors. This work therefore uncovers a central role for TEAD and YAP as signal-responsive regulators of multipotent pancreatic progenitors, and provides a resource for the study of embryonic development of the human pancreas. PMID- 25915129 TI - Why bother? Death, failure, and fatalistic withdrawal from life. AB - The current research examines the conditions under which death contemplation will reduce, rather than increase, goal directed activity. By employing a goal regulation perspective on the problem of death, we hypothesized that death awareness precipitates withdrawal from the goal for continued life when life is experienced as dissatisfying and hope for the future appears bleak. In Study 1, participants with low life satisfaction who contemplated goal failure responded to mortality salience with reduced desire for continued life. Studies 2-4 examined general goal motivation. Consistent with the idea that withdrawal from life precipitates a general state of reduced goal motivation, parallel effects were observed on the willingness to delay gratification for future outcomes (Study 2), orientation toward the future (Study 3), and behavioral activation system (BAS) sensitivity (Study 4). Moreover, Study 3 showed that these effects were mediated by a generally pessimistic attitude toward life. Finally, Study 5 assessed felt uncertainty and state depression, revealing that withdrawal from life was associated with reduced uncertainty but increased depression. Discussion is focused on implications for theories of threat and defense, and applications for understanding depression and suicide. PMID- 25915127 TI - Human definitive haemogenic endothelium and arterial vascular endothelium represent distinct lineages. AB - The generation of haematopoietic stem cells (HSCs) from human pluripotent stem cells (hPSCs) will depend on the accurate recapitulation of embryonic haematopoiesis. In the early embryo, HSCs develop from the haemogenic endothelium (HE) and are specified in a Notch-dependent manner through a process named endothelial-to-haematopoietic transition (EHT). As HE is associated with arteries, it is assumed that it represents a subpopulation of arterial vascular endothelium (VE). Here we demonstrate at a clonal level that hPSC-derived HE and VE represent separate lineages. HE is restricted to the CD34(+)CD73(-)CD184(-) fraction of day 8 embryoid bodies and it undergoes a NOTCH-dependent EHT to generate RUNX1C(+) cells with multilineage potential. Arterial and venous VE progenitors, in contrast, segregate to the CD34(+)CD73(med)CD184(+) and CD34(+)CD73(hi)CD184(-) fractions, respectively. Together, these findings identify HE as distinct from VE and provide a platform for defining the signalling pathways that regulate their specification to functional HSCs. PMID- 25915128 TI - Wdr1-mediated cell shape dynamics and cortical tension are essential for epidermal planar cell polarity. AB - During mouse development, core planar cell polarity (PCP) proteins become polarized in the epidermal plane to guide angling/morphogenesis of hair follicles. How PCP is established is poorly understood. Here, we identify a key role for Wdr1 (also known as Aip1), an F-actin-binding protein that enhances cofilin/destrin-mediated F-actin disassembly. We show that cofilin and destrin function redundantly in developing epidermis, but their combined depletion perturbs cell adhesion, cytokinesis, apicobasal polarity and PCP. Although Wdr1 depletion accentuates single-loss-of-cofilin/destrin phenotypes, alone it resembles core PCP mutations. Seeking a mechanism, we find that Wdr1 and cofilin/destrin-mediated actomyosin remodelling are essential for generating or maintaining cortical tension within the developing epidermal sheet and driving the cell shape and planar orientation changes that accompany establishment of PCP in mammalian epidermis. Our findings suggest intriguing evolutionary parallels but mechanistic modifications to the distal wing hinge-mediated mechanical forces that drive cell shape change and orient PCP in the Drosophila wing disc. PMID- 25915130 TI - Low self-esteem prospectively predicts depression in the transition to young adulthood: A replication of Orth, Robins, and Roberts (2008). AB - The present study is a close replication of the work of Orth, Robins, and Roberts (2008). Orth et al. (2008) tested three theoretical models of the relation between self-esteem and depression--the vulnerability model, the scar model, and the common factor model--using longitudinal, cross-lagged panel designs. The authors concluded that depression and self-esteem were not the same construct (contrary to the common-factor model), and furthermore, the results were clearly in line with the vulnerability model and not with the scar model (low self-esteem predicts subsequent levels of depression and not vice versa). In addition, the results held for both men and women. To conduct a very close replication of the work of Orth et al. (2008), we used data from another large longitudinal study (N = 2,512), which is highly similar in study design and that contains the same measures (self-esteem and depression). The present study replicated the results of the Orth et al. (2008) study in a notable manner, in regard to the comparability of the coefficients, and therefore, corroborates the vulnerability model (and not the scar- or the common-factor model). PMID- 25915131 TI - The independent effects of personality and situations on real-time expressions of behavior and emotion. AB - The joint influence of persons and situations on behavior has long been posited by personality and social psychological theory (Funder, 2006; Lewin, 1951). However, a lack of tools for real-time behavioral and situation assessment has left direct investigations of this sort immobilized. This study combines recent advances in situation assessment and experience sampling methodology to examine the simultaneous effects of personality traits and situation characteristics on real-time expressions of behavior and emotion in N = 210 participants. The results support an additive model such that both personality traits and situation characteristics independently predict real-time expressions of behavior and emotion. These results have implications for several prominent theoretical perspectives in personality, including both trait and cognitive theories. PMID- 25915132 TI - The contribution of genetics and early rearing experiences to hierarchical personality dimensions in chimpanzees (Pan troglodytes). AB - A reliable literature finds that traits are related to each other in an organized hierarchy encompassing various conceptualizations of personality (e.g., Big Three, five-factor model). Recent work suggests the potential of a similar organization among our closest nonhuman relative, chimpanzees (Pan troglodytes), with significant links to neurobiology suggesting an evolutionarily and neurobiologically based hierarchical structure of personality. The current study investigated this hierarchical structure, the heritability of the various personality dimensions across levels of the hierarchy, and associations with early social rearing experience in a large sample (N = 238) of socially housed, captive chimpanzees residing in 2 independent colonies of apes. Results provide support for a hierarchical structure of personality in chimpanzees with significant associations with early rearing experiences. Further, heritabilities of the various dimensions varied by early rearing, with affective dimensions found to be significantly heritable among mother-reared apes, whereas personality dimensions were largely independent of relatedness among the nursery-reared apes. Taken together, these findings provide evidence for the influence of both genetic and environmental factors on personality profiles across levels of the hierarchy, supporting the importance of considering environmental variation in models of quantitative trait evolution. PMID- 25915133 TI - Refining the vulnerability model of low self-esteem and depression: Disentangling the effects of genuine self-esteem and narcissism. AB - A growing body of research supports the vulnerability model of low self-esteem and depression, which states that low self-esteem is a risk factor for depression. The goal of the present research was to refine the vulnerability model, by testing whether the self-esteem effect is truly due to a lack of genuine self-esteem or due to a lack of narcissistic self-enhancement. For the analyses, we used data from 6 longitudinal studies consisting of 2,717 individuals. In each study, we tested the prospective effects of self-esteem and narcissism on depression both separately for each construct and mutually controlling the constructs for each other (i.e., a strategy that informs about effects of genuine self-esteem and pure narcissism), and then meta-analytically aggregated the findings. The results indicated that the effect of low self-esteem holds when narcissism is controlled for (uncontrolled effect = -.26, controlled effect = -.27). In contrast, the effect of narcissism was close to zero when self esteem was controlled for (uncontrolled effect = -.06, controlled effect = .01). Moreover, the analyses suggested that the self-esteem effect is linear across the continuum from low to high self-esteem (i.e., the effect was not weaker at very high levels of self-esteem). Finally, self-esteem and narcissism did not interact in their effect on depression; that is, individuals with high self-esteem have a lower risk for developing depression, regardless of whether or not they are narcissistic. The findings have significant theoretical implications because they strengthen the vulnerability model of low self-esteem and depression. PMID- 25915134 TI - Using individual interest and conscientiousness to predict academic effort: Additive, synergistic, or compensatory effects? AB - Although both conscientiousness and domain-specific interest are believed to be major determinants of academic effort, they have rarely been brought together in empirical studies. In the present research, it was hypothesized that both interest and conscientiousness uniquely predict academic effort and statistically interact with each other to predict academic effort. In 4 studies with 2,557, 415, 1,025, and 1,531 students, respectively, conscientiousness and interest meaningfully and uniquely predicted academic effort. In addition, conscientiousness interacted with interest in a compensatory pattern, indicating that conscientiousness is especially important when a student finds a school subject uninteresting and that domain-specific interest plays a particularly important role for students low in conscientiousness. PMID- 25915135 TI - Spontaneous evaluative inferences and their relationship to spontaneous trait inferences. AB - Three experiments are reported that explore affectively based spontaneous evaluative impressions (SEIs) of stimulus persons. Experiments 1 and 2 used modified versions of the savings in relearning paradigm (Carlston & Skowronski, 1994) to confirm the occurrence of SEIs, indicating that they are equivalent whether participants are instructed to form trait impressions, evaluative impressions, or neither. These experiments also show that SEIs occur independently of explicit recall for the trait implications of the stimuli. Experiment 3 provides a single dissociation test to distinguish SEIs from spontaneous trait inferences (STIs), showing that disrupting cognitive processing interferes with a trait-based prediction task that presumably reflects STIs, but not with an affectively based social approach task that presumably reflects SEIs. Implications of these findings for the potential independence of spontaneous trait and evaluative inferences, as well as limitations and important steps for future study are discussed. PMID- 25915136 TI - Attachment insecurity, biased perceptions of romantic partners' negative emotions, and hostile relationship behavior. AB - In the current research, we tested the extent to which attachment insecurity produces inaccurate and biased perceptions of intimate partners' emotions and whether more negative perceptions of partners' emotions elicit the damaging behavior often associated with attachment insecurity. Perceptions of partners' emotions as well as partners' actual emotions were assessed multiple times in couples' conflict discussions (Study 1) and daily during a 3-week period in 2 independent samples (Study 2). Using partners' reports of their own emotional experiences as the accuracy benchmark, we simultaneously tested whether attachment insecurity was associated with the degree to which individuals (a) accurately detected shifts in their partners' negative emotions (tracking accuracy), and (b) perceived their partners were feeling more negative relationship-related emotions than they actually experienced (directional bias). Highly avoidant perceivers were equally accurate at tracking their partners' changing emotions compared to less avoidant individuals (tracking accuracy), but they overestimated the intensity of their partners' negative emotions to a greater extent than less avoidant individuals (directional bias). In addition, more negative perceptions of partners' emotions triggered more hostile and defensive behavior in highly avoidant perceivers both during conflict discussions (Study 1) and in daily life (Study 2). In contrast, attachment anxiety was not associated with tracking accuracy, directional bias, or hostile reactions to perceptions of their partners' negative emotions. These findings demonstrate the importance of assessing biased perceptions in actual relationship interactions and reveal that biased perceptions play an important role in activating the defenses of avoidantly attached people. PMID- 25915137 TI - The burden of responsibility: Interpersonal costs of high self-control. AB - The psychological literature on self-control has illustrated the many benefits experienced by people with high self-control, who are more successful both personally and interpersonally. In the current research, we explore the possibility that having high self-control also may have some interpersonal costs, leading individuals to become burdened by others' reliance. In Studies 1 and 2, we examined the effects of actors' self-control on observers' performance expectations and found that observers had higher performance expectations for actors with high (vs. low) self-control. In Study 3, we tested the effect of actors' self-control on work assigned to actors and found that observers assigned greater workloads to actors with high (vs. low) self-control. In Study 4, we examined how actors and observers differed in their assessments of the effort expended by high and low self-control actors and found that observers (but not actors) reported that high self-control actors expended less effort than low self control actors. Finally, we found that people high (vs. low) in self-control reported greater burden from the reliance of coworkers (Study 5) and romantic partners (Study 6), and this tendency led them to feel less satisfied with their relationships (Study 6). Together, results from these studies provide novel evidence that individuals' self-control affects others' attitudes and behaviors toward them, and suggest that these interpersonal dynamics can have negative consequences for high self-control individuals. PMID- 25915138 TI - Indicators for Cervical Length in Twin Pregnancies. AB - OBJECTIVE: Cervical length (CL) is associated with the risk of preterm birth (PTB) in multiple pregnancies. However, the position of CL within the pathophysiological pathway of PTB is unclear, and it is unknown which factors are predictive for CL. This study aims to investigate whether in twin pregnancies baseline maternal and obstetrical characteristics are potential indicators for CL, to improve insight in the pathophysiological pathway of PTB. STUDY DESIGN: Secondary analysis of data on twin pregnancies and CL measurement between 16 and 22 weeks. A set of 10 potential indicators, known to be associated with an increased risk of PTB and/or which have a plausible mechanism resulting in a change of CL were selected. We used multivariable linear regression with backward selection to identify independent indicators for CL. RESULTS: A total of 1,447 women with twin pregnancies were included. Mean CL was 43.7 (+/-8.9) mm. In multivariable analysis, age (0.27 mm/y; 95% confidence interval [CI] 0.16 to 0.39), use of assisted reproductive technologies (ART) (-1.42 mm, 95% CI -2.6 to 0.25), and having delivered at term in a previous pregnancy (1.32 mm, 95% CI 0.25 to 2.39) were significantly associated with CL. CONCLUSION: This study shows that in twin pregnancies, age, use of ART and having delivered term in a previous pregnancy has an association with CL. PMID- 25915139 TI - Endocannabinoid Levels in Newborns in Relation to the Mode of Delivery. AB - OBJECTIVE: This study aims to examine the endocannabinoid levels in newborns in relation to the mode of delivery. STUDY DESIGN: In this study, the concentrations of the endocannabinoids anandamide (AEA), 2-arachidonylglycerol (2-AG), palmitoylethanolamine (PEA), and the metabolite arachidonic acid (AA) in umbilical cord vein blood of 49 newborns was determined by quantitative mass spectrometry using liquid chromatography multiple reaction monitoring. The newborns were divided by their mode of delivery. Only healthy newborns born after 34(0/7) gestational weeks without birth complications were included. RESULTS: The concentration of AEA, PEA, and AA was significantly higher in vaginal delivered newborns (n=25) in comparison to newborns born by cesarean delivery (n=24). 2-AG exhibited no significant differences between the groups. CONCLUSION: The exposure of the newborn to high endocannabinoid concentrations is a physiological process during vaginal delivery. The endocannabinoids AEA, PEA, and their metabolite AA seem to be part of an endocrine system during labor and birth supporting the fetal transition. PMID- 25915140 TI - Red Blood Cell Transfusions at 21 Days of Age or Older in Previously Transfusion Naive Very Preterm Infants: Association with Neonatal Outcomes. AB - OBJECTIVE: This study aims to assess the association of red blood cell (RBC) transfusion in a cohort of preterm infants with mortality, retinopathy of prematurity (ROP), and chronic lung disease (CLD) transfused at >=21 days of life. STUDY DESIGN AND METHODS: This retrospective cohort study included infants born at <30 weeks' gestation who survived >=21 days, had not received any RBC transfusions before reaching 21 days of age, and were admitted to participating units in the Canadian neonatal network (2003-2009). RESULTS: Out of the 3,799 eligible infants, 3,309 infants did not receive RBC transfusion at >=21 days of age, whereas 490 received transfusion at >=21 days of age. Infants who did not receive RBC transfusion/s at >=21 days of age had higher birth weight (p<0.01) and higher gestational age at the time of birth (p<0.01) as compared with those who received transfusion/s at >=21 days of age. Receipt of RBC transfusion/s at >=21 days of age was not associated with mortality (adjusted odds ratio [AOR] 1.20; 95% confidence interval [CI] 0.33-4.34) or severe ROP (AOR 1.02; 95% CI 0.59-1.77) but was associated with increased odds of CLD (AOR 1.78; 95% CI 1.43 2.22). CONCLUSION: RBC transfusion/s at >=21 days of age in previously transfusion-naive preterm infants was associated with increased odds of CLD but not with ROP or mortality. PMID- 25915141 TI - Maternal methadone treatment and neonatal abstinence syndrome. AB - OBJECTIVE: This article aims to describe neonatal outcomes, clinical correlates, and the rate for neonatal abstinence syndrome (NAS) for women on methadone maintenance therapy. METHODS: This study is a retrospective review, which includes 119 mothers and 120 live newborns. RESULTS: Methadone mothers tends to be white, single, on government insurance, with increased tobacco use (73%) and hepatitis C (11%). Prematurity increased (28%), and the term infant had a higher risk for admission for respiratory symptoms (22, 7%, p < 0.001). Overall, 78% newborns developed NAS, with the onset of symptoms 4.3 +/- 2.9 days, and average length of stay of 36.7 +/- 26.4 days. There was a decreased overall gestational age for those infants who did not have NAS (36, 38 weeks, p = 0.04). Overall, 56% had possible illicit drug supplementation. Self-reporting had a 59% negative predictive value with a positive drug screen. No difference in maternal methadone dosage and newborns with and without NAS. Increasing gestational age will increase the odds for NAS. CONCLUSIONS: Newborns are at higher risk for prematurity and admission for respiratory symptoms. Utilizing a 7-day observation period, 78% of newborns were diagnosed with NAS with a mean onset of symptoms of 4.3 days. There was no difference in methadone dosage between babies with and without NAS. Increasing gestational age increases the risk for NAS. PMID- 25915142 TI - Unplanned extubation and subsequent trial of noninvasive ventilation in the neonatal intensive care unit. AB - OBJECTIVE: Unplanned extubation (UE) occurs as an infrequent complication of mechanical ventilation in the neonatal intensive care unit (NICU). Following UE, a trial of noninvasive ventilation (NIV) may be considered if a neonate is showing adequate respiratory effort. This study investigated the success and failure rate of NIV management of neonates experiencing UE. STUDY DESIGN: Retrospective single-center study of neonates experiencing UE in the NICU over a 9-year period. Reintubation within 12 hours of a trial of NIV following UE was defined as treatment failure. Short-term respiratory outcomes were analyzed for all infants plus the incidence of bronchopulmonary dysplasia for preterm infants born less than 32 weeks' gestation. RESULTS: A total of 43 patients were included. Of those, 30 infants were trialed on NIV following UE. Baseline demographics were similar between both the groups except for the oxygen requirement before UE. The NIV was successful in 20 and failed in 10 infants. Infants who failed a trial of the NIV were reintubated between 0.45 and 5.25 hours following UE. Respiratory outcomes in very preterm infants did not differ between groups. CONCLUSION: A trial of NIV may be considered as a treatment option in preterm and term newborns experiencing UE in the NICU. PMID- 25915143 TI - Kindergarten children can be taught to detect lexical ambiguities. AB - This study investigates the development of metalinguistic skills, particularly ambiguity detection, and whether training accelerates this development for prereaders in kindergarten (5;5-6;6). It is the first to compare homophone detection with lexically ambiguous sentence detection in which the same homophones appear. The experimental group received ambiguity detection training; the control group received vocabulary training. Results showed that there is a spontaneous development of homophone detection abilities at the end of kindergarten, and training may accelerate this trajectory. The development of lexical ambiguity detection is not apparent in kindergarteners. However, explicit training improves this trajectory significantly. The knowledge of both meanings of a homophone is not sufficient to report both meanings of a sentence that contains that homophone. We propose that detecting the dual meanings of an ambiguous sentence involves sentence processing operations and an ability to think flexibly about language that may be enhanced with training. PMID- 25915144 TI - Multiple Self-Reported Concussions Are More Prevalent in Athletes With ADHD and Learning Disability. AB - OBJECTIVE: We evaluated how attention deficit-hyperactivity disorder (ADHD) and learning disability (LD) are associated with concussion history and performance on standard concussion assessment measures. Based on previous reports that developmental disorders are associated with increased injury proneness and poorer cognitive performance, we anticipated that ADHD and LD would be associated with increased history of concussion and poorer baseline performance on assessment measures. DESIGN: Cross-sectional study. SETTING: Clinical research center. PARTICIPANTS: The study sample aggregated data from two separate projects: the National Collegiate Athletic Association Concussion Study and Project Sideline. INTERVENTIONS: We analyzed preseason baseline data from 8056 high school and collegiate athletes (predominantly male football players) enrolled in prior studies of sport-related concussion. MAIN OUTCOME MEASURES: Measures included demographic/health history, symptoms, and cognitive performance. RESULTS: Attention deficit-hyperactivity disorder and LD were associated with 2.93 and 2.08 times the prevalence, respectively, of 3+ historical concussions (for comorbid ADHD/LD the prevalence ratio was 3.38). In players without histories of concussion, individuals with ADHD reported more baseline symptoms, and ADHD and LD were associated with poorer performance on baseline cognitive tests. Interactive effects were present between ADHD/LD status and concussion history for self-reported symptoms. CONCLUSIONS: Neurodevelopmental disorders and concussion history should be jointly considered in evaluating concussed players. CLINICAL RELEVANCE: Clinical judgments of self-reported symptoms and cognitive performance should be adjusted based on athletes' individual preinjury baselines or comparison with appropriate normative samples. PMID- 25915145 TI - Short-Term Effectiveness of Precut Kinesiology Tape Versus an NSAID as Adjuvant Treatment to Exercise for Subacromial Impingement: A Randomized Controlled Trial. AB - OBJECTIVE: To compare the short-term effectiveness of precut kinesiology tape (PCT) to a nonsteroidal anti-inflammatory drug (NSAID) as adjuvant treatment to exercise physiotherapy in improving pain and function in patients with shoulder impingement. DESIGN: Randomized, controlled assessor-blind parallel-design trial with 3 groups. SETTING: Academic-community hospital. PATIENTS: One hundred patients (mean age: 48 +/- 12.3, 61 men, 39 women) with a diagnosis of subacromial impingement (SAI) syndrome were randomized to a treatment group from October 2009 to June 2012. Eighty-one patients completed the study. INTERVENTIONS: Patients were randomized to one of the 3 treatment groups: PCT and Exercise (n = 33), NSAID and Exercise (n = 29), or Exercise only (n = 38) for a 4 session 2-week intervention with a registered physiotherapist. MAIN OUTCOME MEASURES: Numeric pain rating scales for pain at rest and pain with arm elevation, the Simple Shoulder Test (SST), and the Constant Score were assessed pretreatment and post-treatment. RESULTS: A statistically significant reduction in pain at rest and pain with arm elevation, as well as improvement in SST and Constant Score were observed in all 3 treatment groups, with minimal clinically important differences shown on pain with elevation and SST scores. Between-group differences on all outcome measures were not statistically significant or clinically meaningful. CONCLUSIONS: The improvements in pain and function observed with an NSAID or PCT as adjuvant treatments were no greater than with rehabilitation exercise alone. If adjuvant treatment is desired, PCT seems to be better tolerated than an NSAID, although the difference did not reach significance. CLINICAL RELEVANCE: The routine addition of adjuvant treatment is not supported by the results of this study. As adjuvant therapy, PCT seems to be better tolerated than an NSAID. If desired, clinicians may consider incorporating PCT along with an exercise component in the conservative treatment of SAI syndrome. PMID- 25915146 TI - Limitations of Current AHA Guidelines and Proposal of New Guidelines for the Preparticipation Examination of Athletes. AB - OBJECTIVE: To examine the prevalence of athletes who screen positive with the preparticipation examination guidelines from the American Heart Association, the AHA 12-elements, in combination with 3 screening electrocardiogram (ECG) criteria. DESIGN: Observational cross-sectional study. SETTING: Stanford University Sports Medicine Clinic. PARTICIPANTS: Total of 1596 participants, including 297 (167 male; mean age, 16.2 years) high school athletes, 1016 (541 male; mean age, 18.8 years) collegiate athletes, and 283 (mean age, 26.3 years) male professional athletes. MAIN OUTCOME MEASURES: Athletes were screened using the 8 personal and family history questions from the AHA 12-elements. Electrocardiograms were obtained for all participants and interpreted using Seattle criteria, Stanford criteria, and European Society of Cardiology (ESC) recommendations. RESULTS: Approximately one-quarter of all athletes (23.8%) had at least 1 positive response to the AHA personal and family history elements. High school and college athletes had similar rates of having at least 1 positive response (25.9% vs 27.4%), whereas professional athletes had a significantly lower rate of having at least 1 positive response (8.8%, P < 0.05). Females reported more episodes of unexplained syncope (11.4% vs 7.5%, P = 0.017) and excessive exertional dyspnea with exercise (11.1% vs 6.1%, P = 0.001) than males. High school athletes had more positive responses to the family history elements when compared with college athletes (P < 0.05). The percentage of athletes who had an abnormal ECG varied between Seattle criteria (6.0%), Stanford criteria (8.8%), and ESC recommendations (26.8%). CONCLUSIONS: Many athletes screen positive under current screening recommendations, and ECG results vary widely by interpretation criteria. CLINICAL RELEVANCE: In a patient population without any adverse cardiovascular events, the currently recommended AHA 12-elements have an unacceptably high rate of false positives. Newer screening guidelines are needed, with fewer false positives and evidence-based updates. PMID- 25915147 TI - Nociceptive and inflammatory mediator upregulation in a mouse model of chronic prostatitis. AB - Chronic nonbacterial prostatitis, characterized by genitourinary pain in the pelvic region in the absence of an identifiable cause, is common in adult males. Surprisingly, the sensory innervation of the prostate and mediators that sensitize its innervation have received little attention. We thus characterized a mouse model of chronic prostatitis, focusing on the prostate innervation and how organ inflammation affects gene expression of putative nociceptive markers in prostate afferent somata in dorsal root ganglia (DRG) and mediators in the prostate. Retrograde tracing (fast blue) from the prostate revealed that thoracolumbar and lumbosacral DRG are the principal sources of somata of prostate afferents. Nociceptive markers (eg, transient receptor potential, TREK, and P2X channels) were upregulated in fast blue-labeled thoracolumbar and lumbosacral somata for up to four weeks after inflaming the prostate (intraprostate injection of zymosan). Prostatic inflammation was evident histologically, by monocyte infiltration and a significant increase in mast cell tryptase activity 14, 21, and 28 days after zymosan injection. Interleukin 10 and NGF were also significantly upregulated in the prostate throughout the 4 weeks of inflammation. Open-field pain-related behaviors (eg, rearing) were unchanged in prostate inflamed mice, suggesting the absence of ongoing nociception, but withdrawal thresholds to lower abdominal pressure were significantly reduced. The increases in IL-10, mast cell tryptase, and NGF in the inflamed prostate were cotemporaneous with reduced thresholds to probing of the abdomen and upregulation of nociceptive markers in DRG somata innervating the prostate. The results provide insight and direction for the study of mechanisms underlying pain in chronic prostatitis. PMID- 25915148 TI - An omics investigation into chronic widespread musculoskeletal pain reveals epiandrosterone sulfate as a potential biomarker. AB - Chronic widespread musculoskeletal pain (CWP) is common, having a population prevalence of 10%. This study aimed to define the biological basis of the CWP/body mass association by using a systems biology approach. Adult female twins (n = 2444) from the TwinsUK registry who had extensive clinical, anthropometric, and "omic" data were included. Nontargeted metabolomics screening including 324 metabolites was carried out for CWP and body composition using dual-energy X-ray absorptiometry. The biological basis of these associations was explored through a genome-wide association study and replicated in an independent population sample (Cooperative Health Research in the Region of Augsburg [KORA] study, n = 2483). A causal role for the genetic variants identified was sought in CWP using a Mendelian randomisation study design. Fat mass/height2 was the body composition variable most strongly associated with CWP (TwinsUK: P = 2.4 * 10(-15) and KORA: P = 1.59 * 10(-10)). Of 324 metabolites examined, epiandrosterone sulfate (EAS) was highly associated with both CWP (P = 1.05 * 10(-09) in TwinsUK and P = 3.70 * 10(-06) in KORA) and fat mass/height2. Genome-wide association study of EAS identified imputed single nucleotide polymorphism rs1581492 at 7q22.1 to be strikingly associated with EAS levels (P <= 2.49 * 10(-78)), and this result was replicated in KORA (P = 2.12 * 10(-9)). Mendelian randomization by rs1581492 genotype showed that EAS is unlikely to be causally related to CWP. Using an agnostic omics approach to focus on the association of CWP with body mass index, we have confirmed a steroid hormone association and identified a genetic variant upstream of the CYP genes, which likely controls this response. This study suggests that steroid hormone abnormalities result from pain rather than causing it, and EAS may provide a biomarker that identifies subgroups at risk of CWP. PMID- 25915149 TI - Sleep and pain sensitivity in adults. AB - Sleep problems and pain are major public health concerns, but the nature of the association between the 2 conditions is inadequately studied. The aim of this study was to determine whether a range of sleep measures is associated with experimental increased pain sensitivity. A cross-sectional large population-based study from 2007 to 2008, the Tromso 6 study, provided data from 10,412 participants (age: mean [SD], 58 [13] years; 54% women). Self-reported sleep measures provided information on sleep duration, sleep onset latency (SOL), and sleep efficiency, as well as frequency and severity of insomnia. The main outcome measure was pain sensitivity tests, including assessment of cold-pressor pain tolerance. We found that all sleep parameters, except sleep duration, were significantly associated with reduced pain tolerance. Both the frequency and severity of insomnia, in addition to SOL and sleep efficiency, were associated with pain sensitivity in a dose-response manner. Adjusting for demographics and psychological distress reduced the strengths of the hazard ratios, but most associations remained significant in the fully adjusted models. There was also a synergistic interaction effect on pain tolerance when combining insomnia and chronic pain. We conclude that sleep problems significantly increase the risk for reduced pain tolerance. Because comorbid sleep problems and pain have been linked to elevated disability, the need to improve sleep among patients with chronic pain, and vice versa, should be an important agenda for future research. PMID- 25915150 TI - Calcium looping spent sorbent as a limestone replacement in the manufacture of portland and calcium sulfoaluminate cements. AB - The calcium looping (CaL) spent sorbent (i) can be a suitable limestone replacement in the production of both ordinary Portland cement (OPC) and calcium sulfoaluminate (CSA) cement, and (ii) promotes environmental benefits in terms of reduced CO2 emission, increased energy saving and larger utilization of industrial byproducts. A sample of CaL spent sorbent, purged from a 200 kWth pilot facility, was tested as a raw material for the synthesis of two series of OPC and CSA clinkers, obtained from mixes heated in a laboratory electric oven within temperature ranges 1350 degrees -1500 degrees C and 1200 degrees -1350 degrees C, respectively. As OPC clinker-generating mixtures, six clay-containing binary blends were investigated, three with limestone (reference mixes) and three with the CaL spent sorbent. All of them showed similar burnability indexes. Moreover, three CSA clinker-generating blends (termed RM, MA and MB) were explored. They included, in the order: (I) limestone, bauxite and gypsum (reference mix); (II) CaL spent sorbent, bauxite and gypsum; (III) CaL spent sorbent plus anodization mud and a mixture of fluidized bed combustion (FBC) fly and bottom ashes. The maximum conversion toward 4CaO.3Al2O3.SO3, the chief CSA clinker component, was the largest for MB and almost the same for RM and MA. PMID- 25915151 TI - Effects of high progesterone on outcomes of in vitro fertilization-embryo transfer in patients with different ovarian responses. AB - The data of 3,841 cycles undergoing in vitro fertilization-embryo transfer (IVF ET) in our reproductive Center between January 2003 and December 2013 were retrospectively analyzed. According to the number of oocytes retrieved, this study was divided into the high ovarian response group (oocyte retrieval>=20, 842 cycles), the moderate ovarian response group (50.05). The increased level of P on the day of hCG may affect the treatment outcomes of IVF-ET. The cut-off values of serum P seem to be associated with ovarian response. Increased ovarian response causes the cut-off values of serum P to rise. PMID- 25915152 TI - Directional control of pi-conjugation enabled by distortion of the donor plane in diarylaminoanthracenes: a photophysical study. AB - We designed and synthesized a series of diarylaminoanthracenes in which the planarity of the diarylamine moiety is controlled by methylene- or ethylene- bridges. The X-ray crystallographic structures confirm that the methylene- and ethylene bridges gradually decrease the disorder of the diarylamine planes. To quantitatively analyze the photophysical properties and underlying electronic structures of these compounds, we carried out UV-vis and fluorescence spectroscopy, fluorescence quantum yield, and fluorescence lifetime measurements. The results reveal that enhanced planarity of the diarylamine moiety optically forbids the charge-transfer transition between the diarylamine and anthracene moieties. Although it is generally accepted that a planar pi-conjugated system favors electron delocalization, our results indicate that distortion of the donor plane induces interchromophoric conjugation rather than conjugation within the local structure. Density functional theory calculations further illustrate that the frontier orbitals of diarylamine and anthracene interpenetrate as the donor plane is distorted. Additionally, natural bonding orbital analyses reveal that distortion of the donor plane changes the directionality of the pi-conjugation of the nitrogen n-orbital from intrachromophoric to interchromophoric. PMID- 25915153 TI - Dialysis plus do not resuscitate--not a contradiction. PMID- 25915154 TI - Patient Preferences and End-of-Life Care: A Teachable Moment. PMID- 25915155 TI - HER-2 and HER-3 expression in liver metastases of patients with colorectal cancer. AB - OBJECTIVE: In this study, we evaluate the frequency of HER-2 and HER-3 expression in liver metastases from patients with colorectal cancer (CRLM). We analyzed the potential of HER-2 and HER-3 as therapeutic targets and evaluated their prognostic value. PATIENTS AND METHODS: Overall 208 patients with CRLM were enrolled. HER-2 and HER-3 expression were determined in metastatic tissue of diagnostic punch biopsies (n = 29) or resection specimens (n = 179). The results of immunohistochemistry (IHC) scoring and In-situ-hybridization (ISH) amplification were correlated with clinical parameters and for the 179 resected patients with cancer-specific (CSS) and overall survival (OS). The mean follow-up time was 56.7 months. RESULTS: Positivity of HER-2 status (IHC score 2+/ISH+ and IHC 3+) was found in 8.2% of CRLM. High expression of HER-3 (IHC score 2+ and IHC 3+) was detected in 75.0% of liver metastases. CSS after liver surgery was determined and was independent from the HER-2 status (p = 0.963); however HER-3 was prognostic with a favorable course for patients showing an overexpression of HER-3 (p = 0.037). CONCLUSIONS: HER-2 overexpression occurs in only 8% of patients with CRLM but with 75% of cases HER-3 is frequently overexpressed in CRLM. Therefore, HER-2 and particularly HER-3 could serve as novel targets to be addressed within multimodal treatment approaches. PMID- 25915156 TI - Lycorine is a novel inhibitor of the growth and metastasis of hormone-refractory prostate cancer. AB - Lycorine, a natural alkaloid extracted from the Amaryllidaceae plant family, has been reported to exhibit a wide range of physiological effects, including the potential effect against cancer. However, the anti-prostate cancer (PCa) efficacy of Lycorine remains unrevealed. In this context, we figured out Lycorine's anti proliferative and anti-migratory properties for PCa treatment. Lycorine inhibited proliferation of various PCa cell lines, induced cell apoptosis and cell death. Here we showed that Lycorine decreased proliferation, migration, invasion, survival and EMT of prostate cancer cell lines. Subcutaneous and orthotopic xenotransplantations by ectopic implantation of the human hormone-refractory PC 3M-luc cells were used to confirm in vivo anticancer effects of Lycorine. Lycorine inhibited both growth and metastasis in multiple organs (liver, lung, kidney, spleen and bone) in vivo and improved mice survival. Lycorine prevented EGF-induced JAK/STAT signaling. Importantly, anti-cancer effects of Lycorine were dependent on STAT expression. We suggest that Lycorine is a potential therapeutic in prostate cancer. PMID- 25915157 TI - Human bone marrow niche chemoprotection mediated by cytochrome P450 enzymes. AB - Substantial evidence now demonstrates that interactions between the tumor microenvironment and malignant cells are a critical component of clinical drug resistance. However, the mechanisms responsible for microenvironment-mediated chemoprotection remain unclear. We showed that bone marrow (BM) stromal cytochrome P450 (CYP)26 enzymes protect normal hematopoietic stem cells (HSCs) from the pro-differentiation effects of retinoic acid. Here, we investigated if stromal expression of CYPs is a general mechanism of chemoprotection. We found that similar to human hepatocytes, human BM-derived stromal cells expressed a variety of drug-metabolizing enzymes. CYP3A4, the liver's major drug-metabolizing enzyme, was at least partially responsible for BM stroma's ability to protect multiple myeloma (MM) and leukemia cells from bortezomib and etoposide, respectively, both in vitro and in vivo. Moreover, clarithromycin overcame stromal-mediated MM resistance to dexamethasone, suggesting that CYP3A4 inhibition plays a role in its ability to augment the activity of lenalidomide and dexamethasone as part of the BiRd regimen. We uncovered a novel mechanism of microenvironment-mediated drug resistance, whereby the BM niche creates a sanctuary site from drugs. Targeting these sanctuaries holds promise for eliminating minimal residual tumor and improving cancer outcomes. PMID- 25915158 TI - Small-molecule induction of phospho-eIF4E sumoylation and degradation via targeting its phosphorylated serine 209 residue. AB - As phospho-eIF4E (p-eIF4E), unlike total eIF4E (t-eIF4E) essential for normal cells, is specifically required by cancer cells, it is an attractive, yet unrealized, target for anti-tumor intervention. Here we identify a small molecule, homoharringtonine (HHT), that antagonizes p-eIF4E function and eradicates acute myeloid leukemia (AML) expressing high level of p-eIF4E in vitro and in vivo. HHT selectively reduces p-eIF4E levels of leukemia cells without affecting t-eIF4E. HHT targets the phosphorylated serine 209 residue of p-eIF4E and induces p-eIF4E oligomerization, which enhances its interaction with the small ubiquitin-like protein modifier (SUMO)-conjugating enzyme UBC9, resulting in proteasome-dependent degradation of p-eIF4E via SUMO2/3-mediated SUMOylation. These results suggest that the phosphorylated serine 209 residue of p-eIF4E might be a potential target for developing small molecule-based new therapies for leukemia. PMID- 25915160 TI - Effective Recognition of Different Types of Amino Groups: From Aminobenzenesulfonamides to Amino-(N-alkyl)benzenesulfonamides via Iridium Catalyzed N-Alkylation with Alcohols. AB - A simple, highly efficient, and general strategy for the direct synthesis of amino-(N-alkyl)benzenesulfonamides has been accomplished via direct N-alkylation of aminobenzenesulfonamides bearing both different types of amino groups with alcohols as alkylating agents. Notably, this research exhibited the potential for the recognition of different types of amino groups in the N-alkylation of complex molecules with alcohols, facilitating the progress of the transition-metal catalyzed "hydrogen autotransfer (or hydrogen-borrowing) process." PMID- 25915159 TI - NHE9 induces chemoradiotherapy resistance in esophageal squamous cell carcinoma by upregulating the Src/Akt/beta-catenin pathway and Bcl-2 expression. AB - Recently, we found that NHE9 mRNA was upregulated in chemoradiotherapy (CRT) resistant esophageal squamous cell carcinoma (ESCC); however, the underlying mechanisms were unclear. Here, we aimed to clarify the functional contribution of NHE9 to CRT resistance, understand the molecular basis of NHE9-dependent resistance in ESCC, and identify potential therapeutic targets. Our results showed that NHE9 prevented CRT-induced apoptosis. Importantly, we found that RACK1 is a novel binding partner of NHE9 and that NHE9-dependent induction of CRT resistance requires the activation of RACK1-associated Src/Akt/beta-catenin signaling. Moreover, upregulated Bcl-2 protein was also observed in cells exhibiting NHE9-induced CRT resistance. A higher NHE9 level was associated with a poor response to CRT and less decrease in T and N stage in ESCC patients. Furthermore, combining either Dasatinib or ABT-737 with CRT significantly reduced tumor volume, and the response to CRT was restored when these inhibitors were used together with CRT in a xenograft nude mouse model with NHE9 overexpression. Taken together, our findings demonstrate that NHE9 can be an effective predictor of CRT response and may be useful in the development of targeted therapies for CRT-resistant ESCC. PMID- 25915161 TI - Differential mobility separation of leukotrienes and protectins. AB - Differential mobility spectrometry (DMS) is capable of separating stereoisomeric molecular ions based on their mobility in an oscillating electrical field with an asymmetric waveform. Thus, it is an "orthogonal" technique to chromatography and (tandem) mass spectrometry. Bioactive lipids, particularly of the eicosanoid and docosanoid class feature numerous stereoisomers, which exhibit a highly specific structure-activity relationship. Moreover, the geometry of these compounds also reflects their biochemical origin. Therefore, the unambiguous characterization of related isomers of the eicosanoid and docosanoid classes is of fundamental importance to the understanding of their origin and function in many biological processes. Here we show, that SelexION DMS technology coupled to MULC-MS/MS is capable of differentiating at least five closely related leukotrienes partially coeluting and (almost) unresolvable using LC-MS/MS only. We applied the developed method to the separation of LTB4 and its coeluting isomer 5S,12S-diHETE in murine peritoneal exudate cells, showing that LTB4 is present only after zymosan A injection while its isomer 5S,12S-diHETE is produced after saline (PBS) administration. Additionally, we show that the SelexION technology can also be applied to the separation of PD1 and PDX (10S,17S-diHDHA), two isomeric protectins. PMID- 25915162 TI - New Frontiers in Selective Human MAO-B Inhibitors. AB - Accumulating evidence shows a relationship between the human MAO-B (hMAO-B) enzyme and neuropsychiatric/degenerative disorder, personality traits, type II alcoholism, borderline personality disorders, aggressiveness and violence in crime, obsessive-compulsive disorder, depression, suicide, schizophrenia, anorexia nervosa, migraine, dementia, and PD. Thus, MAO-B represents an attractive target for the treatment of a number of human diseases. The discovery, development, and therapeutic use of drugs that inhibit MAO-B are major challenges for future therapy. Various compounds and drugs that selectively target this isoform have been discovered recently. These agents are synthetic compounds or natural products and their analogues, including chalcones, pyrazoles, chromones, coumarins, xanthines, isatin derivatives, thiazolidindiones, (thiazol-2 yl)hydrazones, and analogues of marketed drugs. Despite considerable efforts in understanding the binding interaction with specific substrates or inhibitors, structural information available for the rational design of new hMAO-B inhibitors remains unsatisfactory. Therefore, the quest for novel, potent, and selective hMAO-B inhibitors remains of high interest. PMID- 25915164 TI - Tuning the Magic Size of Atomically Precise Gold Nanoclusters via Isomeric Methylbenzenethiols. AB - Toward controlling the magic sizes of atomically precise gold nanoclusters, herein we have devised a new strategy by exploring the para-, meta-, ortho methylbenzenethiol (MBT) for successful preparation of pure Au130(p-MBT)50, Au104(m-MBT)41 and Au40(o-MBT)24 nanoclusters. The decreasing size sequence is in line with the increasing hindrance of the methyl group to the interfacial Au-S bond. That the subtle change of ligand structure can result in drastically different magic sizes under otherwise similar reaction conditions is indeed for the first time observed in the synthesis of thiolate-protected gold nanoclusters. These nanoclusters are highly stable as they are synthesized under harsh size focusing conditions at 80-90 degrees C in the presence of excess thiol and air (i.e., without exclusion of oxygen). PMID- 25915163 TI - Conformational Switching of a Foldamer in a Multicomponent System by pH-Filtered Selection between Competing Noncovalent Interactions. AB - Biomolecular systems are able to respond to their chemical environment through reversible, selective, noncovalent intermolecular interactions. Typically, these interactions induce conformational changes that initiate a signaling cascade, allowing the regulation of biochemical pathways. In this work, we describe an artificial molecular system that mimics this ability to translate selective noncovalent interactions into reversible conformational changes. An achiral but helical foldamer carrying a basic binding site interacts selectively with the most acidic member of a suite of chiral ligands. As a consequence of this noncovalent interaction, a global absolute screw sense preference, detectable by (13)C NMR, is induced in the foldamer. Addition of base, or acid, to the mixture of ligands competitively modulates their interaction with the binding site, and reversibly switches the foldamer chain between its left and right-handed conformations. As a result, the foldamer-ligand mixture behaves as a biomimetic chemical system with emergent properties, functioning as a "proton-counting" molecular device capable of providing a tunable, pH-dependent conformational response to its environment. PMID- 25915165 TI - Activity-guided chemo toxic profiling of Cassia occidentalis (CO) seeds: detection of toxic compounds in body fluids of CO-exposed patients and experimental rats. AB - Our prior studies have shown an association between the deaths of children and consumption of Cassia occidentalis (CO) seeds. However, the chemicals responsible for the CO poisoning are not known. Therefore, the present study was designed to identify the key moieties in CO seeds and their cytotoxicity in rat primary hepatocytes and HepG2 cells. Activity-guided sequential extraction and fractionation of the seeds followed by GC-MS analysis identified the toxic compounds in the CO seeds. These identified compounds were subsequently detected and quantified in blood and urine samples from CO-exposed rats and CO poisoning human study cases. GC-MS analysis of different fractions of methanol extracts of CO seeds revealed the presence of five anthraquinones (AQs), viz. physcion, emodin, rhein, aloe-emodin, and chrysophanol. Interestingly, these AQs were detected in serum and urine samples from the study cases and CO-exposed rats. Cytotoxicity analysis of the above AQs in rat primary hepatocytes and HepG2 cells revealed that rhein is the most toxic moiety, followed by emodin, aloe-emodin, physcion, and chrysophanol. These studies indicate that AQ aglycones are responsible for producing toxicity, which may be associated with symptoms of hepatomyoencephalopathy in CO poisoning cases. PMID- 25915166 TI - In situ synthesis of Ni(OH)2 nanobelt modified electroactive poly(vinylidene fluoride) thin films: remarkable improvement in dielectric properties. AB - A facile and low cost synthesis of Ni(OH)2 nanobelt (NB) modified electroactive poly(vinylidene fluoride) (PVDF) thin films with excellent dielectric properties has been reported via in situ formation of Ni(OH)2 NBs in the PVDF matrix. The formation and morphology of the NBs are confirmed by UV-visible spectroscopy and field emission scanning electron microscopy respectively. A remarkable improvement in electroactive beta phase nucleation (~82%) and the dielectric constant (epsilon ~ 3.1 * 10(6) at 20 Hz) has been observed in the nanocomposites (NCs). The interface between the NBs and the polymer matrix plays a crucial role in the enhancement of the electroactive beta phase and the dielectric properties of thin films. Strong interaction via hydrogen bonds between Ni(OH)2 NBs and the PVDF matrix is the main reason for enhancement in beta phase crystallization and improved dielectric properties. The NC thin films can be utilized for potential applications as high energy storage devices like supercapacitors, solid electrolyte batteries, self-charging power cells, piezoelectric nanogenerators, and thin film transistors and sensors. PMID- 25915167 TI - Two novel POM-based inorganic-organic hybrid compounds: synthesis, structures, magnetic properties, photodegradation and selective absorption of organic dyes. AB - The hydrothermal reactions of a mixture of (NH4)6Mo7O24.4H2O, Cu(Ac)2.H2O and 3 bpo ligands at different temperatures result in the isolation of two novel inorganic-organic hybrid materials containing different but related isopolymolybdate units, [Cu(3-bpo)(H2O)(Mo4O13)].3H2O () and [Cu2(3 bpo)2(Mo6O20)] (). The {Mo4O13}n chains in and unprecedented [Mo6O20](4-) isopolyhexamolybdate anions in are linked by octahedral Cu(2+) ions into two dimensional hybrid layers. Interestingly, 3-bpo ligands in both and are located on either side of these hybrid layers and serve as arched footbridges to link Cu(ii) ions in the layer via pyridyl N-donors, and at the same time connect these hybrid layers into 3D supramolecular frameworks via weak MoNoxadiazole bonds. Another important point for is that water clusters are filled in the 1D channels surrounded by isopolytetramolybdate units. In addition, dye adsorption and photocatalytic properties of and magnetic properties of have been investigated. The results indicated that complex is not only a good heterogeneous photocatalyst in the degradation of methyl orange (MO) and methylene blue (MB), but also has high absorption capacity of MB at room temperature and can selectively capture MB molecules from binary mixtures of MB/MO or MB/RhB. All MB molecules absorbed on can be completely released and photodegraded in the presence of adequate peroxide. The temperature dependence of magnetic susceptibility revealed that complex exhibits antiferromagnetic ordering at about 5 K, and a spin-flop transition was observed at about 5.8 T at 2 K, indicating metamagnetic-like behaviour from antiferromagnetic to ferromagnetic phases. PMID- 25915169 TI - What do Dutch MSM think of preexposure prophylaxis to prevent HIV-infection? A cross-sectional study. AB - OBJECTIVES: Although preexposure prophylaxis (PrEP) is not registered in Europe, including the Netherlands, its approval and implementation are expected in the near future. We aimed to gain insight into PrEP awareness and the intention to use PrEP among MSM. DESIGN: Cross-sectional study among 448 HIV-negative participants of the Amsterdam Cohort Study who completed a questionnaire concerning behavior and PrEP between 2012 and 2013. METHODS: Characteristics, PrEP awareness, and intention to use PrEP were described and multinomial logistic regression was used to identify determinants of a medium and high intention to use PrEP. RESULTS: PrEP awareness was 54%, but only 13% reported a high intention to use PrEP. High-risk MSM were more likely to have a medium [adjusted odds ratio (aOR): 1.78 (95% confidence interval [CI] 1.07-2.97)] or high [aOR: 3.92 (95% CI 1.68-9.15)] intention to use PrEP than low-risk MSM, as were MSM with higher perceptions of self-efficacy to use PrEP [high intention: aOR: 6.15 (95% CI 2.50 15.09)] and higher perceptions of relief due to PrEP [medium intention: aOR: 2.67 (95% CI 1.32-5.40); high intention: aOR: 14.87 (95% CI 5.98-37.01)] than MSM with lower perceptions. MSM with higher perceptions of shame about using PrEP [medium intention: aOR: 0.35 (95% CI 0.19-0.62); high intention: aOR: 0.22 (95% CI 0.07 0.71)] or with more worries about side-effects were less likely to have a high [aOR: 0.18 (95% CI 0.06-0.54)] or medium [aOR: 0.29 (95% CI 0.12-0.72)] intention to use PrEP. CONCLUSION: The overall intention to use PrEP was relatively low, but higher among high-risk MSM. If PrEP implementation among high-risk MSM in the Netherlands becomes reality, PrEP awareness should be increased and psychosocial determinants that will influence uptake should be addressed. PMID- 25915168 TI - Reduction of soluble CD163, substance P, programmed death 1 and inflammatory markers: phase 1B trial of aprepitant in HIV-1-infected adults. AB - OBJECTIVE: We evaluated safety, antiviral, immunomodulatory and anti-inflammatory properties of aprepitant - a neurokinin 1 receptor antagonist. DESIGN: Phase IB randomized, placebo-controlled, double-blinded study. METHODS: Eighteen patients were randomized (nine to aprepitant and nine to placebo). The patients received once-daily treatment (375 mg aprepitant or placebo by oral administration) for 2 weeks and were followed off drug for 4 weeks. RESULTS: There were no significant changes in the plasma viremia or CD4(+) T cells during the dosing period. Aprepitant treatment was associated with significant decreases of median within patient change in percentages of CD4(+) T cells expressing programmed death 1 ( 4.8%; P = 0.04), plasma substance P (-34.0 pg/ml; P = 0.05) and soluble CD163 ( 563 ng/ml; P = 0.02), with no significant changes in the placebo arm. Mean peak aprepitant plasma concentration on day 14 was 7.6 +/- 3.1 MUg/ml. The use of aprepitant was associated with moderate increases in total cholesterol, low density lipoprotein and high-density lipoprotein (median change = +31 mg/dl, P = 0.01; +26 mg/dl, P = 0.02; +3 mg/dl, P = 0.02, respectively). CONCLUSION: Aprepitant was safe and well tolerated. At the dose used in this proof-of-concept phase IB study, aprepitant did not show a significant antiviral activity. Aprepitant-treated patients had decreased numbers of CD4(+) programmed death 1 positive cells and decreased plasma levels of substance P and soluble CD163, suggesting that blockade of the neurokinin 1 receptor pathway has a role in modulating monocyte activation in HIV infection. Prospective studies in virologically-suppressed individuals are warranted to evaluate the immunomodulatory properties of aprepitant. Exposures exceeding those attained in this trial are more likely to elicit clinical benefit. PMID- 25915171 TI - Parent psychopathology as a mediator of the relationship between anxiety and sleep problems in children. AB - INTRODUCTION: Sleep problems exert a negative impact on youths and their families. Parent and child mental health represent 2 posited, yet understudied, risk factors for sleep problems in youths. As such, this study sought to examine the role that parental psychopathology may play in mediating the relationship between child anxiety and sleep problems utilizing Internet sampling procedures. METHOD: Parents (n = 83; 90.4% female) answered questions about their own mental health, and about their child's (n = 83; 77.1% female) anxiety and sleep. RESULTS: Analyses found that parent anxiety and stress mediated the relationship between child anxiety and sleep problems. DISCUSSION: This is the first study to examine the joint roles of parent psychopathology and child anxiety in explaining sleep problems in youths. Limitations notwithstanding, these results suggest that both parent- and child-level variables are important for developing a more comprehensive understanding of child sleep problems. Future areas of research are discussed. PMID- 25915170 TI - The causal effect of opioid substitution treatment on HAART medication refill adherence. AB - BACKGROUND: People who inject drugs (PWID) account for roughly 13% of the prevalent HIV/AIDS population outside of sub-Saharan Africa, and access to opioid substitution treatment (OST) is limited in many settings globally. OST likely facilitates access to HAART, yet sparse evidence is available to support this hypothesis. Our objective was to determine the causal impact of OST exposure on HAART adherence among HIV-positive PWID in a Canadian setting. METHODS: We executed a retrospective cohort study using linked population-level data for British Columbia, Canada (January 1996-March 2010). We considered HIV-positive PWID after meeting HAART initiation criteria. A marginal structural model was estimated on a monthly timescale using inverse probability of treatment weights. The primary outcome was 95% HAART adherence, according to pharmacy refill compliance. Exposure to OST was defined as 95% of OST receipt, and we controlled for a range of fixed and time-varying covariates. RESULTS: Our study included 1852 (63.3%) HIV-positive PWID with a median follow-up of 5.5 years; 34% were female and 39% had previously accessed OST. The baseline covariate-adjusted odds of HAART adherence following OST exposure was 1.96 (95% confidence interval: 1.72 2.24), although the adjusted odds estimated within the marginal structural model was 1.68 (1.48-1.92). Findings were robust to sensitivity analyses on model specification. CONCLUSION: In a setting characterized by universal healthcare and widespread access to both office-based OST and HAART, OST substantially increased the odds of HAART adherence. This underlines the need to address barriers to OST globally to reduce the disease burden of both opioid dependence and HIV/AIDS. PMID- 25915172 TI - Achieving extremely concentrated aqueous dispersions of graphene flakes and catalytically efficient graphene-metal nanoparticle hybrids with flavin mononucleotide as a high-performance stabilizer. AB - The stable dispersion of graphene flakes in an aqueous medium is highly desirable for the development of materials based on this two-dimensional carbon structure, but current production protocols that make use of a number of surfactants typically suffer from limitations regarding graphene concentration or the amount of surfactant required to colloidally stabilize the sheets. Here, we demonstrate that an innocuous and readily available derivative of vitamin B2, namely the sodium salt of flavin mononucleotide (FMNS), is a highly efficient dispersant in the preparation of aqueous dispersions of defect-free, few-layer graphene flakes. Most notably, graphene concentrations in water as high as ~50 mg mL(-1) using low amounts of FMNS (FMNS/graphene mass ratios of about 0.04) could be attained, which facilitated the formation of free-standing graphene films displaying high electrical conductivity (~52000 S m(-1)) without the need of carrying out thermal annealing or other types of post-treatment. The excellent performance of FMNS as a graphene dispersant could be attributed to the combined effect of strong adsorption on the sheets through the isoalloxazine moiety of the molecule and efficient colloidal stabilization provided by its negatively charged phosphate group. The FMNS-stabilized graphene sheets could be decorated with nanoparticles of several noble metals (Ag, Pd, and Pt), and the resulting hybrids exhibited a high catalytic activity in the reduction of nitroarenes and electroreduction of oxygen. Overall, the present results should expedite the processing and implementation of graphene in, e.g., conductive inks, composites, and hybrid materials with practical utility in a wide range of applications. PMID- 25915173 TI - Atomistic near-field nanoplasmonics: reaching atomic-scale resolution in nanooptics. AB - Electromagnetic field localization in nanoantennas is one of the leitmotivs that drives the development of plasmonics. The near-fields in these plasmonic nanoantennas are commonly addressed theoretically within classical frameworks that neglect atomic-scale features. This approach is often appropriate since the irregularities produced at the atomic scale are typically hidden in far-field optical spectroscopies. However, a variety of physical and chemical processes rely on the fine distribution of the local fields at this ultraconfined scale. We use time-dependent density functional theory and perform atomistic quantum mechanical calculations of the optical response of plasmonic nanoparticles, and their dimers, characterized by the presence of crystallographic planes, facets, vertices, and steps. Using sodium clusters as an example, we show that the atomistic details of the nanoparticles morphologies determine the presence of subnanometric near-field hot spots that are further enhanced by the action of the underlying nanometric plasmonic fields. This situation is analogue to a self similar nanoantenna cascade effect, scaled down to atomic dimensions, and it provides new insights into the limits of field enhancement and confinement, with important implications in the optical resolution of field-enhanced spectroscopies and microscopies. PMID- 25915174 TI - Detecting Liquefied Petroleum Gas (LPG) at Room Temperature Using ZnSnO3/ZnO Nanowire Piezo-Nanogenerator as Self-Powered Gas Sensor. AB - High sensitivity, selectivity, and reliability have been achieved from ZnSnO3/ZnO nanowire (NW) piezo-nanogenerator (NG) as self-powered gas sensor (SPGS) for detecting liquefied petroleum gas (LPG) at room temperature (RT). After being exposed to 8000 ppm LPG, the output piezo-voltage of ZnSnO3/ZnO NW SPGS under compressive deformation is 0.089 V, much smaller than that in air ambience (0.533 V). The sensitivity of the SPGS against 8000 ppm LPG is up to 83.23, and the low limit of detection is 600 ppm. The SPGS has lower sensitivity against H2S, H2, ethanol, methanol and saturated water vapor than LPG, indicating good selectivity for detecting LPG. After two months, the decline of the sensing performance is less than 6%. Such piezo-LPG sensing at RT can be ascribed to the new piezo surface coupling effect of ZnSnO3/ZnO nanocomposites. The practical application of the device driven by human motion has also been simply demonstrated. This work provides a novel approach to fabricate RT-LPG sensors and promotes the development of self-powered sensing system. PMID- 25915175 TI - Multilayered inclusion nanocycles of anionic spiroborates. AB - Multilayered spiroborate nanocycles were prepared from tris- or tetrakis(dihydroxynaphthalene) and tetrahydroxyanthraquinone as pillar and crossbar units via the reversible formation of a spiroborate linkage. The four layered spiroborate nanocycle recognized two cationic aromatic guests simultaneously and exhibited the ability to form a supramolecular one-dimensional array by combining with methyl viologen dimer as the ditopic guest. PMID- 25915176 TI - Improvement of bone marrow fibrosis with ruxolitinib: will this finding change our perception of the drug? AB - Ruxolitinib, a JAK1 and JAK2 inhibitor, has been tested and approved for the treatment of primary and secondary myelofibrosis. Reduction of spleen volume and improvement of constitutional symptoms and quality of life have been reported as the major findings in sponsored randomized clinical trials. Recent data indicated that the drug improves bone marrow fibrosis and that different targets may be involved in this response. These new data, which require confirmation in prospective trials, may change our perspectives and therapeutic strategies for this disease. PMID- 25915178 TI - Low volume-high intensity interval exercise elicits antioxidant and anti inflammatory effects in humans. AB - The purpose of the present study was to compare acute changes in oxidative stress and inflammation in response to steady state and low volume, high intensity interval exercise (LV-HIIE). Untrained healthy males (n = 10, mean +/- s: age 22 +/- 3 years; VO2MAX 42.7 +/- 5.0 ml . kg(-1) . min(-1)) undertook three exercise bouts: a bout of LV-HIIE (10 * 1 min 90% VO2MAX intervals) and two energy-matched steady-state cycling bouts at a moderate (60% VO2MAX; 27 min, MOD) and high (80% VO2MAX; 20 min, HIGH) intensity on separate days. Markers of oxidative stress, inflammation and physiological stress were assessed before, at the end of exercise and 30 min post-exercise (post+30). At the end of all exercise bouts, significant changes in lipid hydroperoxides (LOOH) and protein carbonyls (PCs) (LOOH (nM): MOD +0.36; HIGH +3.09; LV-HIIE +5.51 and PC (nmol . mg(-1) protein): MOD -0.24; HIGH -0.11; LV-HIIE -0.37) were observed. Total antioxidant capacity (TAC) increased post+30, relative to the end of all exercise bouts (TAC (uM): MOD +189; HIGH +135; LV-HIIE +102). Interleukin (IL)-6 and IL-10 increased post+30 in HIGH and LV-HIIE only (P < 0.05). HIGH caused the greatest lymphocytosis, adrenaline and cardiovascular response (P < 0.05). At a reduced energy cost and physiological stress, LV-HIIE elicited similar cytokine and oxidative stress responses to HIGH. PMID- 25915179 TI - Gelucire-stabilized nanoparticles as a potential DNA delivery system. AB - Clinical viability of gene delivery systems has been greatly impacted by potential toxicity of the delivery systems. Recently, we reported the nanoparticle (NP) preparation process that employs biocompatible materials such as Gelucire(r) 44/14 and cetyl alcohol as matrix materials. In the current study, the NP preparation was modified for pDNA loading through: (i) inclusion of cationic lipids (DOTAP or DDAB) with NP matrix materials; or (ii) application of cationic surfactants (CTAB) to generate NPs with desired surface charges for pDNA complexation. Colloidal stability and efficiency of loading pGL3-DR4X2-luciferase plasmid DNA in NPs were verified by gel permeation chromatography. Compared to pDNA alone, all the NPs were effective in preserving pDNA from digestion by DNase. While pDNA loading using CTAB-NPs involved fewer steps compared to DOTAP NPs and DDAB-NPs, CTAB-NPs were greatly impacted by elevated cytotoxicity level which could be ascribed to the concentrations of CTAB in NP formulations. In vitro transfection studies (in HepG2 cells) based on luciferase expression showed the ranking of cell transfection efficiency as DOTAP-NPs > DDAB-NPs > CTAB-NPs. The overall work provided an initial assessment of gelucire-stabilized NPs as a potential platform for gene delivery. PMID- 25915180 TI - Formulation and in vitro characterization of poly(dl-lactide-co glycolide)/Eudragit RLPO or RS30D nanoparticles as an oral carrier of levofloxacin hemihydrate. AB - The main objective of this study was to design positively charged Levofloxacin Hemihydrate (Levo-h)-loaded nanoparticles with improved entrapment efficiency and antibacterial activity. PLGA alone or in combinations with Eudragit(r) RLPO or RS30D with or without positively charged inducing agent; 1,2-dioleoyl-3 trimethylammonium-propane, chloride salt (DOTAP); were used for preparation of nanoparticles. Blending between PLGA and Eudragit(r) RLPO or RS30D with inclusion of DOTAP caused a marked increase in entrapment efficiency and switched zeta potential from negative to positive. Nanoparticle formulations; NR3 (Levo h:PLGA:Eudragit(r) RLPO; 1:1:1 w/w with DOTAP) and NS3 (Levo-h:PLGA:Eudragit(r) RS30D; 1:1:1 w/w with DOTAP) that possess high positive zeta potential (59.3 +/- 7.5 and 55.1 +/- 8.2 mV, respectively) and Efficient Levo-h entrapment (89.54 +/- 1.5 and 77.65 +/- 1.8%, respectively) were selected for further examinations; in vitro release, physical stability and microbiological study. NR3 and NS3 showed significant sustained release of Levo-h. NR3 and NS3 exhibited good stability after storage at room temperature. Microbiological assay showed strengthened antibacterial activity of NR3 against both types of gram-negative bacteria (E. coli, Ps. aeruginosa) and of NS3 against Ps. aeruginosa compared to free Levo-h solution. NR3 and NS3 appear to be promising oral delivery system for Levo-h. PMID- 25915181 TI - Connections between client, clinician and context: Selected articles from the 2014 Speech Pathology Australia Conference. PMID- 25915177 TI - Nontuberculous mycobacterial osteomyelitis. AB - Osteomyelitis caused by nontuberculous mycobacteria (NTM) can have severe consequences and a poor prognosis. Physicians therefore need to be alert to this condition, especially in immunocompromised patients. Although the pathogenesis of NTM osteomyelitis is still unclear, studies in immunodeficient individuals have revealed close relationships between NTM osteomyelitis and defects associated with the interleukin-12-interferon-gamma-tumor necrosis factor-alpha axis, as well as human immunodeficiency virus infection, various immunosuppressive conditions, and diabetes mellitus. Culture and species identification from tissue biopsies or surgical debridement tissue play crucial roles in diagnosing NTM osteomyelitis. Suitable imaging examinations are also important. Adequate surgical debridement and the choice of appropriate, combined antibiotics for long term anti-mycobacterial chemotherapy, based on in vitro drug susceptibility tests, are the main therapies for these bone infections. Bacillus Calmette-Guerin vaccination might have limited prophylactic value. The use of multiple drugs and long duration of treatment mean that the therapeutic process needs to be monitored closely to detect potential side effects. Adequate duration of anti mycobacterial chemotherapy together with regular monitoring with blood and imaging tests are key factors determining the recovery outcome in patients with NTM osteomyelitis. PMID- 25915182 TI - Integration of genetically modified virus-like-particles with an optical resonator for selective bio-detection. AB - A novel virus-like particle (TMV-VLP) receptor layer has been integrated with an optical microdisk resonator transducer for biosensing applications. This bioreceptor layer is functionalized with selective peptides that encode unique recognition affinities. Integration of bioreceptors with sensor platforms is very challenging due their very different compatibility regimes. The TMV-VLP nanoreceptor exhibits integration robustness, including the ability for self assembly along with traditional top-down microfabrication processes. An optical microdisk resonator has been functionalized for antibody binding with this receptor, demonstrating resonant wavelength shifts of (Deltalambdao) of 0.79 nm and 5.95 nm after primary antibody binding and enzyme-linked immunosorbent assay (ELISA), respectively, illustrating label-free sensing of this bonding event. This demonstration of label-free sensing with genetically engineered TMV-VLP shows the flexibility and utility of this receptor coating when considering integration with other existing transducer platforms. PMID- 25915185 TI - Modulation of the Effect of Transforming Growth Factor-beta3 by Low-Intensity Pulsed Ultrasound on Scaffold-Free Dedifferentiated Articular Bovine Chondrocyte Tissues. AB - The aim of this study was to evaluate how low-intensity pulsed ultrasound (LIPUS) modulates the effect of transforming growth factor-beta3 (TGF-beta3) on the differentiation of scaffold-free dedifferentiated bovine articular chondrocyte tissues toward a cartilage-like phenotype. Specifically, the effect of these stimuli on the expression of hypertrophic markers collagen type I, collagen type X, and cartilage-degrading collagenase gene expression for a scaffold-free model was analyzed. A bioreactor that applied LIPUS directly from the transducer through a silicone gel to a six-well plate containing the tissues allowed simple, sterile, and large-scale experiments. Tissues were subjected to LIPUS of 55 mW/cm(2) in a 200 MUs burst sine wave of 1 MHz over a 10-day period with or without TGF-beta3 (10 ng/mL). Tissues exposed to TGF-beta3 had significantly increased glycosaminoglycan and total collagen protein production along with upregulated cartilage-specific gene expression, resulting in tissues with a higher Young's Modulus. However, these tissues had also upregulated gene expression for hypertrophic markers collagen type I, collagen type X, MMP-1, MMP 13, MMP-2, and also an increase in the phosphorylation of p38. The expression of these matrix-degrading enzymes was remediated by hypertrophic development and differentiate dedifferentiated bovine articular chondrocytes towards a chondrogenic lineage allowing it to be a valuable tool in cartilage tissue engineering. PMID- 25915183 TI - Homeodomain Proteins SIX3 and SIX6 Regulate Gonadotrope-specific Genes During Pituitary Development. AB - Sine oculis-related homeobox 3 (SIX3) and SIX6, 2 closely related homeodomain transcription factors, are involved in development of the mammalian neuroendocrine system and mutations of Six6 adversely affect fertility in mice. We show that both small interfering RNA knockdown in gonadotrope cell lines and knockout of Six6 in both embryonic and adult male mice (Six6 knockout) support roles for SIX3 and SIX6 in transcriptional regulation in gonadotrope gene expression and that SIX3 and SIX6 can functionally compensate for each other. Six3 and Six6 expression patterns in gonadotrope cell lines reflect the timing of the expression of pituitary markers they regulate. Six3 is expressed in an immature gonadotrope cell line and represses transcription of the early lineage specific pituitary genes, GnRH receptor (GnRHR) and the common alpha-subunit (Cga), whereas Six6 is expressed in a mature gonadotrope cell line and represses the specific beta-subunits of LH and FSH (LHb and FSHb) that are expressed later in development. We show that SIX6 repression requires interaction with transducin like enhancer of split corepressor proteins and competition for DNA-binding sites with the transcriptional activator pituitary homeobox 1. Our studies also suggest that estradiol and circadian rhythm regulate pituitary expression of Six6 and Six3 in adult females but not in males. In summary, SIX3 and SIX6 play distinct but compensatory roles in regulating transcription of gonadotrope-specific genes as gonadotrope cells differentiate. PMID- 25915184 TI - ACSL1 Is Associated With Fetal Programming of Insulin Sensitivity and Cellular Lipid Content. AB - Individuals who are born small for gestational age (SGA) have a risk to develop various metabolic diseases during their life course. The biological memory of the prenatal state of growth restricted individuals may be reflected in epigenetic alterations in stem cell populations. Mesenchymal stem cells (MSCs) from the Wharton's jelly of umbilical cord tissue are multipotent, and we generated primary umbilical cord MSC isolates from SGA and normal neonates, which were subsequently differentiated into adipocytes. We established chromatin state maps for histone marks H3K27 acetylation and H3K27 trimethylation and tested whether enrichment of these marks was associated with gene expression changes. After validating gene expression levels for 10 significant chromatin immunoprecipitation sequencing candidate genes, we selected acyl-coenzyme A synthetase 1 (ACSL1) for further investigations due to its key roles in lipid metabolism. The ACSL1 gene was found to be highly associated with histone acetylation in adipocytes differentiated from MSCs with SGA background. In SGA derived adipocytes, the ACSL1 expression level was also found to be associated with increased lipid loading as well as higher insulin sensitivity. ACSL1 depletion led to changes in expression of candidate genes such as proinflammatory chemokines and down-regulated both, the amount of cellular lipids and glucose uptake. Increased ACSL1, as well as modulated downstream candidate gene expression, may reflect the obese state, as detected in mice fed a high-fat diet. In summary, we believe that ACSL1 is a programmable mediator of insulin sensitivity and cellular lipid content and adipocytes differentiated from Wharton's jelly MSCs recapitulate important physiological characteristics of SGA individuals. PMID- 25915186 TI - Effect of humic acid in leachate on specific methanogenic activity of anaerobic granular sludge. AB - In order to find out the effects of humic acid (HA) in anaerobic-treated landfill leachate on granular sludge, the anaerobic biodegradability of HA as well as the influences of HA on the total cumulative methane production, the anaerobic methanization process and the specific methanogenic activity (SMA) of granular sludge are studied in this paper. Experimental results show that as a non biodegradable organic pollutant, HA is also difficult to be decomposed by microbes in the anaerobic reaction process. Presence of HA and changes in the concentration have no significant influences on the total cumulative methane production and the anaerobic methanization process of granular sludge. Besides, the total cumulative methane production cannot reflect the inhibition of toxics on the methanogenic activity of granular sludge on the premise of sufficient reaction time. Results also show that HA plays a promoting role on SMA of granular sludge. Without buffering agent the SMA value increased by 19.2% on average due to the buffering and regulating ability of HA, while with buffering agent the SMA value increased by 5.4% on average due to the retaining effect of HA on the morphology of the sludge particles. However, in the presence of leachate the SMA value decreased by 27.6% on average, because the toxic effect of the toxics in the leachate on granular sludge is much larger than the promoting effect of HA. PMID- 25915187 TI - Effect of flecainide on the extension and localization of complex fractionated electrogram during atrial fibrillation. AB - AIMS: Complex fractionated electrogram (CFE) ablation in addition to pulmonary vein isolation is an accepted strategy for the treatment of non-paroxysmal atrial fibrillation (AF). We sought to determine the effect of flecainide on the distribution and extension of CFE areas. METHODS: Twenty-three non-paroxysmal AF patients were enrolled in this prospective study. A first CFE map was obtained under baseline conditions by sampling 5 s of continuous recording from the distal electrodes of the ablation catheter. Intravenous flecainide (1 mg/kg) was administered over 10 min and followed by 30-min observation time. A second CFE map was obtained with the same modalities. CFE-mean values, CFE areas, and atrial electrogram amplitude were retrieved from the electro-anatomical mapping system (Ensite NavX). RESULTS: After flecainide administration, CFE-mean values increased (111.5 +/- 55.3 vs. 132.3 +/- 65.0 ms, p < 0.001) with a decrease of CFE area (32.9%) in all patients. Atrial electrogram amplitude decreased significantly (0.30 +/- 0.31 vs. 0.25 +/- 0.20 mV, p < 0.001). We observed 80.9% preservation of CFE areas. A CFE mean of 78 ms was the best cutoff for predicting stable CFE areas. CONCLUSIONS: Flecainide reduces the extension of CFE areas while preserving their spatial localization. A CFE-mean value <80 ms may be crucial to define and locate stable CFE areas. PMID- 25915188 TI - Whole Grain Consumption and Breast Cancer: A Case-Control Study in Women. AB - OBJECTIVE: Whole grain consumption has long been associated with human health. However, its relationship with breast cancer remains not well understood and appreciated. The aim of this work was to evaluate the association between whole grain consumption and breast cancer in women. METHODS: A case-control study was designed. Two hundred and fifty consecutive, newly diagnosed breast cancer female patients (56 +/- 12 years) and 250 one-to-one age-matched controls were enrolled. A standardized, validated questionnaire assessing various sociodemographic, clinical, lifestyle, and dietary characteristics was applied through face-to-face interviews. Moreover, data on regular consumption of whole grains (i.e., never/rarely, 1-6 times/week, >7 times/week) were recorded. Overall dietary habits were assessed through the level of adherence to the Mediterranean diet using the MedDietScore (theoretical range 0-55). RESULTS: Whole grain consumption of more than 7 times/week was associated with a 0.49-fold (odds ratio = 0.49; 95% confidence interval, 0.29, 0.82) lower likelihood of having breast cancer, after adjustments were made. CONCLUSIONS: This study suggested that whole grain consumption more than 7 times/week was consistently associated with reduced risk of breast cancer. PMID- 25915191 TI - A new emulsion liquid membrane based on a palm oil for the extraction of heavy metals. AB - The extraction efficiency of hexavalent chromium, Cr(VI), from water has been investigated using a vegetable oil based emulsion liquid membrane (ELM) technique. The main purpose of this study was to create a novel ELM formulation by choosing a more environmentally friendly and non-toxic diluent such as palm oil. The membrane phase so formulated includes the mobile carrier tri-n octylmethylammonium chloride (TOMAC), to facilitate the metal transport, and the hydrophilic surfactant Tween 80 to facilitate the dispersion of the ELM phase in the aqueous solution. Span 80 is used as surfactant and butanol as co-surfactant. Our results demonstrate that this novel ELM formulation, using the vegetable palm oil as diluent, is useful for the removal of hexavalent chromium with an efficiency of over 99% and is thus competitive with the already existing, yet less environmentally friendly, ELM formulations. This result was achieved with an optimal concentration of 0.1 M NaOH as stripping agent and an external phase pH of 0.5. Different water qualities have also been investigated showing that the type of water (deionized, distilled, or tap water) does not significantly influence the extraction rate. PMID- 25915192 TI - Tenseness relaxed by vocalizing, illustrated by horses (Equus caballus) whinnying. AB - Animal calls are commonly considered indicators of a sudden change in their arousal state. However, reports evidencing associated internal physiological changes are rare. By homology with human "emotional" vocal productions (e.g., laughter and crying), we predicted that animal vocal productions may result in relaxing tenseness or excitement. In this study, 15 stallions equipped with a heart rate monitor were presented a mare at some distance so as to prevent contact, thereby increasing the males' arousal. Stallions' heart rates increased just before whinnying but returned to baseline rates while vocalizing. We found that sudden changes of a caller's arousal state could be associated with vocalizing, and this opens new lines for noninvasive research concerning the self regulation of emotional via vocal production in humans and animals. PMID- 25915190 TI - Musculoskeletal Pain, Self-reported Physical Function, and Quality of Life in the Teen-Longitudinal Assessment of Bariatric Surgery (Teen-LABS) Cohort. AB - IMPORTANCE: Obesity is associated with chronic musculoskeletal pain and is a risk factor for disability and osteoarthritis. OBJECTIVES: To describe the prevalence, sites, and intensity of musculoskeletal pain in adolescents with severe obesity; to evaluate associations between musculoskeletal pain and self-reported physical function as well as weight-related quality of life; and to evaluate the association between musculoskeletal pain and high-sensitivity C-reactive protein level. DESIGN, SETTING, AND PARTICIPANTS: Teen-Longitudinal Assessment of Bariatric Surgery (Teen-LABS) is a prospective, observational study that collects standardized data on adolescents undergoing weight loss surgery at 5 US centers. We examined baseline data from this cohort between February 28, 2007, and December 30, 2011. We excluded adolescents with Blount disease and slipped capital femoral epiphyses. A total of 233 participants were included in these analyses. MAIN OUTCOMES AND MEASURES: We assessed musculoskeletal pain and pain intensity of the lower back, hips, knees, and ankles/feet using the visual analog scale, categorizing musculoskeletal pain into lower back pain, lower extremity (hips, knees, and feet/ankles combined) pain, and no pain. We assessed self reported physical function status with the Health Assessment Questionnaire Disability Index and assessed weight-related quality of life with the Impact of Weight on Quality of Life-Kids measure. We adjusted for sex, race, age at surgery, body mass index (BMI; calculated as weight in kilograms divided by height in meters squared), and clinical depressive symptoms in regression analyses. RESULTS: Among the 233 participants, the mean (SD) age at surgery was 17.1 (1.56) years and the median BMI was 50.4. Participants were predominantly female (77%), white (73%), and non-Hispanic (93%). Among the participants, 49% had poor functional status and 76% had musculoskeletal pain. Lower back pain was prevalent (63%), followed by ankle/foot (53%), knee (49%), and hip (31%) pain; 26% had pain at all 4 sites. In adjusted analyses, compared with pain-free participants, those reporting lower extremity pain had greater odds of having poor physical function according to scores on the Health Assessment Questionnaire Disability Index (odds ratio = 2.82; 95% CI, 1.35 to 5.88; P < .01). Compared with pain-free participants, those reporting lower extremity pain had significantly lower Impact of Weight on Quality of Life-Kids total scores (beta = -9.42; 95% CI, -14.15 to -4.69; P < .01) and physical comfort scores (beta = 17.29; 95% CI, -23.32 to -11.25; P < .01). After adjustment, no significant relationship was observed between musculoskeletal pain and high-sensitivity C reactive protein level. CONCLUSIONS AND RELEVANCE: Adolescents with severe obesity have musculoskeletal pain that limits their physical function and quality of life. Longitudinal follow-up will reveal whether weight loss surgery reverses pain and physical functional limitations and improves quality of life. PMID- 25915193 TI - Sexual health, alcohol and the university environment: is there a need for sexual health promotion intervention? AB - Background Young university students participate in hazardous drinking and risky sexual health behaviours, however there are few comprehensive interventions targeting this group. METHODS: Undergraduate university students aged 18-24 years (n=2466) were recruited to complete an online survey to investigate the association between levels of alcohol consumption, gender and experienced, second hand and witnessed sexual health behaviours and situations. RESULTS: Male students and hazardous drinkers were most likely to participate in unprotected sex and regretted sex. Female students and hazardous drinkers were most likely to experience an unwanted sexual advance. CONCLUSIONS: Integrated and comprehensive interventions targeting young people in the university setting are needed. PMID- 25915194 TI - Multi-terminal transport measurements of MoS2 using a van der Waals heterostructure device platform. AB - Atomically thin two-dimensional semiconductors such as MoS2 hold great promise for electrical, optical and mechanical devices and display novel physical phenomena. However, the electron mobility of mono- and few-layer MoS2 has so far been substantially below theoretically predicted limits, which has hampered efforts to observe its intrinsic quantum transport behaviours. Potential sources of disorder and scattering include defects such as sulphur vacancies in the MoS2 itself as well as extrinsic sources such as charged impurities and remote optical phonons from oxide dielectrics. To reduce extrinsic scattering, we have developed here a van der Waals heterostructure device platform where MoS2 layers are fully encapsulated within hexagonal boron nitride and electrically contacted in a multi terminal geometry using gate-tunable graphene electrodes. Magneto-transport measurements show dramatic improvements in performance, including a record-high Hall mobility reaching 34,000 cm(2) V(-1) s(-1) for six-layer MoS2 at low temperature, confirming that low-temperature performance in previous studies was limited by extrinsic interfacial impurities rather than bulk defects in the MoS2. We also observed Shubnikov-de Haas oscillations in high-mobility monolayer and few-layer MoS2. Modelling of potential scattering sources and quantum lifetime analysis indicate that a combination of short-range and long-range interfacial scattering limits the low-temperature mobility of MoS2. PMID- 25915195 TI - Highly anisotropic and robust excitons in monolayer black phosphorus. AB - Semi-metallic graphene and semiconducting monolayer transition-metal dichalcogenides are the most intensively studied two-dimensional materials of recent years. Lately, black phosphorus has emerged as a promising new two dimensional material due to its widely tunable and direct bandgap, high carrier mobility and remarkable in-plane anisotropic electrical, optical and phonon properties. However, current progress is primarily limited to its thin-film form. Here, we reveal highly anisotropic and strongly bound excitons in monolayer black phosphorus using polarization-resolved photoluminescence measurements at room temperature. We show that, regardless of the excitation laser polarization, the emitted light from the monolayer is linearly polarized along the light effective mass direction and centres around 1.3 eV, a clear signature of emission from highly anisotropic bright excitons. Moreover, photoluminescence excitation spectroscopy suggests a quasiparticle bandgap of 2.2 eV, from which we estimate an exciton binding energy of ~0.9 eV, consistent with theoretical results based on first principles. The experimental observation of highly anisotropic, bright excitons with large binding energy not only opens avenues for the future explorations of many-electron physics in this unusual two-dimensional material, but also suggests its promising future in optoelectronic devices. PMID- 25915196 TI - Nano Josephson superconducting tunnel junctions in YBa2Cu3O(7-delta) directly patterned with a focused helium ion beam. AB - Since the discovery of the high-transition-temperature superconductors (HTSs), researchers have explored many methods to fabricate superconducting tunnel junctions from these materials for basic science purposes and applications. HTS circuits operating at liquid-nitrogen temperatures (~77 K) would significantly reduce power requirements in comparison with those fabricated from conventional superconductors. The difficulty is that the superconducting coherence length is very short and anisotropic in these materials, typically ~2 nm in the a-b plane and ~0.2 nm along the c axis. The electrical properties of Josephson junctions are therefore sensitive to chemical variations and structural defects on atomic length scales. To make multiple uniform HTS junctions, control at the atomic level is required. In this Letter we demonstrate all-HTS Josephson superconducting tunnel junctions created by using a 500-pm-diameter focused beam of helium ions to directly write tunnel barriers into YBa2Cu3O(7-delta) (YBCO) thin films. We demonstrate the ability to control the barrier properties continuously from conducting to insulating by varying the irradiation dose. This technique could provide a reliable and reproducible pathway for scaling up quantum-mechanical circuits operating at liquid-nitrogen temperatures, as well as an avenue to conduct novel planar superconducting tunnelling studies for basic science. PMID- 25915197 TI - Fourier synthesis of radiofrequency nanomechanical pulses with different shapes. AB - The concept of Fourier synthesis is heavily used in both consumer electronic products and fundamental research. In the latter, pulse shaping is key to dynamically initializing, probing and manipulating the state of classical or quantum systems. In NMR, for instance, shaped pulses have a long-standing tradition and the underlying fundamental concepts have subsequently been successfully extended to optical frequencies and even to the implementation of quantum gate operations. Transferring these paradigms to nanomechanical systems requires tailored nanomechanical waveforms. Here, we report on an additive Fourier synthesizer for nanomechanical waveforms based on monochromatic surface acoustic waves. As a proof of concept, we electrically synthesize four different elementary nanomechanical waveforms from a fundamental surface acoustic wave at f1 ~ 150 MHz using a superposition of up to three discrete harmonics. We use these shaped pulses to interact with an individual sensor quantum dot and detect their deliberately and temporally modulated strain component via the optomechanical quantum dot response. Importantly, and in contrast to direct mechanical actuation by bulk piezoactuators, surface acoustic waves provide much higher frequencies (>20 GHz; ref. 10) to resonantly drive mechanical motion. Thus, our technique uniquely allows coherent mechanical control of localized vibronic modes of optomechanical crystals, even in the quantum limit when cooled to the vibrational ground state. PMID- 25915198 TI - The Bioenergetics of Isolated Mitochondria from Different Animal Models for Diabetes. AB - Diabetes is a metabolic alteration characterized by a higher than normal blood glucose level. For the experimental study of the metabolic changes that occur during this illness, various animal models have been introduced: alloxan- and streptozotocin-injected animals, as well as depancreatized animals, as models for type 1 diabetes, and high-fat fed diabetic animals and laboratory animals with genetic diabetes as models for type 2 diabetes. All these models have been used to investigate specific events on the cellular and organ levels that occur as a consequence of diabetes. In particular, mitochondrial energy metabolism has been extensively studied using these experimental models for diabetes. The experimental results for the bioenergetics of isolated mitochondria harvested from different animal models for diabetes, with the exception of those obtained with high-fat fed diabetic animals, are conflicting; nevertheless, many researchers now consider mitochondrial energy dysfunction as one of the direct causes of the serious complications, in various organs and tissues, that are exhibited as a result of this illness. For this reason, it is important that future research clarify the true energy functional state of these organelles isolated from diabetic animals. In the present paper, the published data on this controversial but important issue of the energetic functioning of the mitochondria isolated from diabetic animals is reviewed. This paper also includes commentary on the status of current research and makes useful suggestions for the future direction of research on this topic. PMID- 25915199 TI - A selective inhibitor of PRMT5 with in vivo and in vitro potency in MCL models. AB - Protein arginine methyltransferase-5 (PRMT5) is reported to have a role in diverse cellular processes, including tumorigenesis, and its overexpression is observed in cell lines and primary patient samples derived from lymphomas, particularly mantle cell lymphoma (MCL). Here we describe the identification and characterization of a potent and selective inhibitor of PRMT5 with antiproliferative effects in both in vitro and in vivo models of MCL. EPZ015666 (GSK3235025) is an orally available inhibitor of PRMT5 enzymatic activity in biochemical assays with a half-maximal inhibitory concentration (IC50) of 22 nM and broad selectivity against a panel of other histone methyltransferases. Treatment of MCL cell lines with EPZ015666 led to inhibition of SmD3 methylation and cell death, with IC50 values in the nanomolar range. Oral dosing with EPZ015666 demonstrated dose-dependent antitumor activity in multiple MCL xenograft models. EPZ015666 represents a validated chemical probe for further study of PRMT5 biology and arginine methylation in cancer and other diseases. PMID- 25915201 TI - Maternal critical care: 'one small step for woman, one giant leap for womankind'. AB - PURPOSE OF REVIEW: The purpose of this study is to outline the challenges of looking after women who either become or are at a risk of becoming critically ill during pregnancy. RECENT FINDINGS: In recent years, there has been an increased demand in the need for maternal critical care. This is partly due to women with complex medical conditions surviving to child-bearing age, coupled with improvements in foetal medicine resulting in more high-risk pregnancies reaching term. SUMMARY: In this review, we identify the need for maternal critical care, explore different models of its provision and outline possible benefits and barriers to its future implementation. PMID- 25915200 TI - HIV gp41-mediated membrane fusion occurs at edges of cholesterol-rich lipid domains. AB - Lipid rafts in plasma membranes have emerged as possible platforms for the entry of HIV and other viruses into cells. However, little is known about how lipid phase heterogeneity contributes to viral entry because of the fine-grained and still poorly understood complexity of biological membranes. We used model systems mimicking HIV envelopes and T cell membranes and found that raft-like liquid ordered (Lo-phase) lipid domains were necessary and sufficient for efficient membrane targeting and fusion. Interestingly, membrane binding and fusion were low in homogeneous liquid-disordered (Ld-phase) and Lo-phase membranes, indicating that lipid phase heterogeneity is essential. The HIV fusion peptide preferentially targeted to Lo-Ld boundary regions and promoted full fusion at the interface between ordered and disordered lipids. Ld-phase vesicles proceeded only to hemifusion. Thus, we propose that edges but not areas of raft-like ordered lipid domains are vital for HIV entry and membrane fusion. PMID- 25915202 TI - Spinal anesthesia in infants: recent developments. AB - PURPOSE OF REVIEW: Spinal anesthesia has long been described as a well-tolerated and effective means of providing anesthesia for infants undergoing lower abdominal surgery. Now, spinal anesthetics are being used for an increasing variety of surgeries previously believed to require a general anesthetic. This, along with increasing concerns over the neurocognitive effects of general anesthetics on developing brains, suggests that further exploration into this technique and its effects is essential. RECENT FINDINGS: Exposure to spinal anesthesia in infancy has not shown the same suggestions of neurocognitive detriment as those resulting from general anesthesia. Ultrasound guidance has enhanced spinal technique by providing real-time guidance into the intrathecal space and confirming medication administration location, as well as helping avoid adverse outcomes by identifying aberrant anatomy. Spinal anesthesia provides benefits over general anesthesia, including cardiorespiratory stability, shorter postoperative recovery, and faster return of gastrointestinal function. SUMMARY: Early findings of spinal anesthesia exposure in infancy have shown it to have no independent effect on neurocognitive delay as well as to provide sound cardiorespiratory stability. With safer means of administering a spinal anesthetic, such as with ultrasound guidance, it is a readily available and desirable tool for those providing anesthesia to infants. PMID- 25915203 TI - The role of cardiac output monitoring in obstetric anesthesia. AB - PURPOSE OF REVIEW: Haemodynamic monitoring in obstetric patients has evolved during the last decade, with the development of minimally invasive and noninvasive continuous cardiac output (CO) monitors. This review focuses on recent articles that improve our understanding of physiology and haemodynamic changes during spinal anaesthesia in healthy pregnant women, and pathophysiology in women with preeclampsia and other cardiovascular disease. RECENT FINDINGS: Recent research findings in healthy women focus on the haemodynamic changes due to aortocaval compression, fluid administration, vasopressor therapy, and oxytocin during spinal anaesthesia for caesarean delivery. In preeclampsia, the haemodynamics of early versus late-onset disease and fluid management have been the subject of considerable investigation. Case reports suggest that invasive monitoring in combination with echocardiography is preferable for clinical management of high-risk obstetrics cases with unstable haemodynamics. SUMMARY: In healthy women, left lateral tilt remains an important clinical intervention during caesarean delivery, and phenylephrine is an essential early adjunct to fluid therapy. Noradrenaline may have a clinical benefit in selected patients. Carbetocin has similar haemodynamic effects to oxytocin. Haemodynamic changes associated with delivery per se may be minor compared with those due to oxytocin. Uncomplicated severe preeclampsia is usually associated with a normal to raised CO. Early-onset preeclampsia may be associated with more vasoconstriction and lower CO than late-onset disease. Passive leg raising may be useful to judge fluid responsiveness, and lung ultrasound may predict pulmonary oedema in preeclampsia. Further research is warranted to study the area of circulatory changes during delivery and the postpartum period, in healthy and preeclamptic women. PMID- 25915204 TI - Update on perioperative care of the cardiac patient for noncardiac surgery. AB - PURPOSE OF REVIEW: The current review will address key topics and recommendations of the recent 2014 update of the American College of Cardiology and American Heart Association clinical practice guideline for the perioperative cardiovascular evaluation and management of patients undergoing noncardiac surgery. RECENT FINDINGS: The completely rewritten guideline provides a stepwise approach for the identification and management of patients at highest risk for major adverse cardiac events and discusses new or updated recommendations. For example, beta-blockers should be continued perioperatively but treatment should not be initiated within 24 h of noncardiac surgery. Angiotensin-converting enzyme inhibitors should be continued, but if held, may be restarted as soon as feasible. Routine aspirin therapy is not recommended without previous coronary stent implantation or risk assessment for myocardial ischemia. Elective noncardiac surgery should not be performed within 30 days of bare metal stent or 12 months of drug-eluting stent implantation because of in-stent thrombosis as well as bleeding risk from dual antiplatelet therapy during surgery. Noncardiac surgery may be considered, however, in patients on antiplatelet agents 180 days after drug-eluting stent placement if risk of surgical delay exceeds risk of stent thrombosis from cessation of antiplatelet therapy. SUMMARY: In conclusion, this review will discuss the important topics from the 2014 American College of Cardiology/American Heart Association guideline in order to provide the perioperative physician with the most recent evidence necessary to minimize major adverse cardiac events in patients undergoing noncardiac surgery. PMID- 25915205 TI - The Impact of Discontinuing Contact Precautions for VRE and MRSA on Device Associated Infections. AB - The impact of discontinuing contact precautions for patients with MRSA and VRE colonization/infection on device-associated hospital-acquired infection rates at an academic medical center was investigated in this before-and-after study. In the setting of a strong horizontal infection prevention platform, discontinuation of contact precautions had no impact on device-associated hospital-acquired infection rates. PMID- 25915206 TI - MeDiA: Mean Distance Association and Its Applications in Nonlinear Gene Set Analysis. AB - Probabilistic association discovery aims at identifying the association between random vectors, regardless of number of variables involved or linear/nonlinear functional forms. Recently, applications in high-dimensional data have generated rising interest in probabilistic association discovery. We developed a framework based on functions on the observation graph, named MeDiA (Mean Distance Association). We generalize its property to a group of functions on the observation graph. The group of functions encapsulates major existing methods in association discovery, e.g. mutual information and Brownian Covariance, and can be expanded to more complicated forms. We conducted numerical comparison of the statistical power of related methods under multiple scenarios. We further demonstrated the application of MeDiA as a method of gene set analysis that captures a broader range of responses than traditional gene set analysis methods. PMID- 25915207 TI - Bmi1 essentially mediates podocalyxin-enhanced Cisplatin chemoresistance in oral tongue squamous cell carcinoma. AB - Oral tongue squamous cell carcinoma (OTSCC) is one of the most common head and neck cancers. Innate or acquired resistance to cisplatin, a standard chemotherapy agent for OTSCC, is common in patients with OTSCC. Understanding the molecular basis for cisplatin chemoresistance in OTSCC cells may serve as a basis for identification of novel therapeutic targets. Podocalyxin (PODXL) has been found critical for malignant progression in a variety of cancers. Bmi1 has recently been found to induce cell apoptosis and cisplatin chemosensitivity in OTSCC cells. In this study, we explored the interaction between PODXL and Bmi1 in OTSCC cells, and assessed its impact on OTSCC cell chemoresistance to cisplatin. PODXL and/or Bmi1 were stably overexpressed or knocked down in SCC-4 and Tca8113 human OTSCC cells. Overexpression of PODXL in both cell lines markedly elevated the expression level of Bmi1 and the half maximal inhibitory concentration (IC50) of cisplain and reduced cisplatin-induced cell apoptosis, which was abolished by knockdown of Bmi1 or a selective focal adhesion kinase (FAK) inhibitor. On the other hand, knockdown of PODXL significantly decreased the Bmi1 expression level and cisplatin IC50 and increased cisplatin-induced cell apoptosis, which was completely reversed by overexpression of Bmi1. While overexpression and knockdown of PODXL respectively increased and decreased the FAK activity, Bmi1 showed no significant effect on the FAK activity in OTSCC cells. In addition, overexpression of PODXL markedly elevated the stability of Bmi1 mRNA, which was abolished by a selective FAK inhibitor. In conclusion, this study provides the first evidence that PODXL up-regulates the expression level of Bmi1 in OTSCC cells by increasing the stability of Bmi1 mRNA through a FAK-dependent mechanism; this effect leads to enhanced cisplatin chemoresistance in OTSCC cells. This study adds new insights into the molecular mechanisms underlying OTSCC chemoresistance. PMID- 25915209 TI - Caring for the adult survivor of Hodgkin lymphoma: highlighting the need for care coordination. PMID- 25915210 TI - Abstracts of the 60th Annual Meeting of the Plastic Surgery Research Council. May 14-16, 2015. Seattle, Washington, USA. PMID- 25915208 TI - Current Efavirenz (EFV) or ritonavir-boosted lopinavir (LPV/r) use correlates with elevate markers of atherosclerosis in HIV-infected subjects in Addis Ababa, Ethiopia. AB - BACKGROUND: HIV patients on antiretroviral therapy have shown elevated incidence of dyslipidemia, lipodystrophy, and cardiovascular disease (CVD). Most studies, however, focus on cohorts from developed countries, with less data available for these co-morbidities in Ethiopia and sub-Saharan Africa. METHODS: Adult HIV negative (n = 36), treatment naive (n = 51), efavirenz (EFV)-treated (n = 91), nevirapine (NVP)-treated (n = 95), or ritonavir-boosted lopinavir (LPV/r)-treated (n=44) subjects were recruited from Black Lion Hospital in Addis Ababa, Ethiopia. Aortic pressure, augmentation pressure, and pulse wave velocity (PWV) were measured via applanation tonometry and carotid intima-media thickness (cIMT) and carotid arterial stiffness, and brachial artery flow-mediated dilation (FMD) were measured via non-invasive ultrasound. Body mass index, waist-to-hip circumference ratio (WHR), skinfold thickness, and self-reported fat redistribution were used to quantify lipodystrophy. CD4+ cell count, plasma HIV RNA levels, fasting glucose, total-, HDL-, and LDL-cholesterol, triglycerides, hsCRP, sVCAM-1, sICAM 1, leptin and complete blood count were measured. RESULTS: PWV and normalized cIMT were elevate and FMD impaired in EFV- and LPV/r-treated subjects compared to NVP-treated subjects; normalized cIMT was also elevated and FMD impaired in the EFV- and LPV/r-treated subjects compared to treatment-naive subjects. cIMT was not statistically different across groups. Treated subjects exhibited elevated markers of dyslipidemia, inflammation, and lipodystrophy. PWV was associated with age, current EFV and LPV/r used, heart rate, blood pressure, triglycerides, LDL, and hsCRP, FMD with age, HIV duration, WHR, and glucose, and cIMT with age, current EFV use, skinfold thickness, and blood pressure. CONCLUSIONS: Current EFV or LPV/r-treatment, but not NVP-treatment, correlated with elevated markers of atherosclerosis, which may involve mechanisms distinct from traditional risk factors. PMID- 25915395 TI - The large variation in acidity of diethyl ether cation induced by internal rotation about a single covalent bond. AB - In the IR spectrum of the diethyl ether cation, an extraordinarily intense band, with an extremely broad bandwidth, was observed at 2700 cm(-1), much lower frequency than normal CH stretch frequencies. This band is assigned to the stretch band of the CH bond, which is hyperconjugated with the singly occupied molecular orbital of the oxygen atom. The hyperconjugation causes the delocalization of the sigma electron of the CH bond so that it enhances the acidity of the CH bond as well as the CH stretch band intensity. Theoretical simulation shows that the strength of hyperconjugation varies greatly with internal rotation of the ethyl group, and this is reflected in the large width of the observed CH stretch band. These results indicate that the DEE cation drastically changes its property from aprotic to highly acidic by the rotational isomerization of the ethyl group. PMID- 25915396 TI - Correction: Synergistic Effects of Concurrent Blockade of PI3K and MEK Pathways in Pancreatic Cancer Preclinical Models. PMID- 25915397 TI - Withdrawal of a novel-design duodenoscope ends outbreak of a VIM-2-producing Pseudomonas aeruginosa. PMID- 25915398 TI - Tumor Necrosis Factor-alpha, Matrix-Metalloproteinases 8 and 9 Levels in the Saliva Are Associated with Increased Hemoglobin A1c in Type 1 Diabetes Subjects. AB - BACKGROUND: Type 1 diabetes (T1D) is an autoimmune disease resulting in the targeted destruction of pancreatic beta-cells and permanent loss of insulin production. Proper glucose management results in better clinical outcomes for T1D and provides a strong rationale to identify non-invasive biomarkers indicative or predictive of glycemic control. Therefore, we investigated the association of salivary inflammation with HbA1c in a T1D cohort. METHODS: Unstimulated saliva was collected from 144 subjects with T1D at the USF Diabetes Center. BMI, duration of diabetes, and HbA1c were recorded during clinical visit. Levels of interleukin (IL)-1beta, -6, -8, -10, IFN-gamma, TNF-alpha, MMP-3, -8, and -9 were measured using multiplexing immunoassay analysis. To account for smoking status, salivary cotinine levels were also determined. RESULTS: Multiple linear (HbA1c) and logistic (self-reported gingival condition) regression analyses were performed to examine the relationships between the Principal Component Analysis (PCA) components and HbA1c and gingival condition (adjusted for age, duration of diabetes, BMI, and sex; model for HbA1c also adjusted for gingival condition and model for gingival condition also adjusted for HbA1c). PCA components 1 (MMP-8 and MMP-9) and 3 (TNF-alpha) were significantly associated with HbA1c (beta = 0.28 +/-0.14, p = 0.045; beta = 0.31 +/-0.14, p = 0.029), while PCA component 2 (IL-6, IL-1beta, and IL-8) was significantly associated with gingival condition (OR 1.60 95% CI 1.09-2.34, p = 0.016). In general, increased salivary inflammatory burden is associated with decreased glycemic control and self reported gingival condition. CONCLUSIONS: The saliva may represent a useful reservoir of novel noninvasive inflammatory biomarkers predictive of the progression and control of T1D. PMID- 25915399 TI - STIM1 Is a Novel Component of ER-Chlamydia trachomatis Inclusion Membrane Contact Sites. AB - Productive developmental cycle of the obligate intracellular bacterial pathogen Chlamydia trachomatis depends on the interaction of the replicative vacuole, named the inclusion, with cellular organelles. We have recently reported the formation of ER-Inclusion membrane contact sites (MCSs), where the endoplasmic reticulum (ER) is in apposition to the inclusion membrane. These platforms contain the C. trachomatis inclusion membrane protein IncD, the mammalian ceramide transfer protein CERT and the ER resident proteins VAPA/B and were proposed to play a role in the non-vesicular trafficking of lipids to the inclusion. Here, we identify STIM1 as a novel component of ER-Inclusion MCSs. STIM1, an ER calcium (Ca2+) sensor that relocate to ER-Plasma Membrane (PM) MCSs upon Ca2+ store depletion, associated with C. trachomatis inclusion. STIM1, but not the general ER markers Rtn3C and Sec61beta, was enriched at the inclusion membrane. Ultra-structural studies demonstrated that STIM1 localized to ER Inclusion MCSs. Time-course experiments showed that STIM1, CERT and VAPB co localized throughout the developmental cycle. By contrast, Orai1, the PM Ca2+ channel that interacts with STIM1 at ER-PM MCSs, did not associate with C. trachomatis inclusion. Upon ER Ca2+ store depletion, a pool of STIM1 relocated to ER-PM MCSs, while the existing ER-Inclusion MCSs remained enriched in STIM1. Finally, we have identified the CAD domain, which mediates STIM1-Orai1 interaction, as the minimal domain required for STIM1 enrichment at ER-Inclusion MCSs. Altogether this study identifies STIM1 as a novel component of ER-C. trachomatis inclusion MCSs. We discuss the potential role(s) of STIM1 during the infection process. PMID- 25915400 TI - Trophic discrimination factors of stable carbon and nitrogen isotopes in hair of corn fed wild boar. AB - Stable isotope measurements are increasingly being used to gain insights into the nutritional ecology of many wildlife species and their role in ecosystem structure and function. Such studies require estimations of trophic discrimination factors (i.e. differences in the isotopic ratio between the consumer and its diet). Although trophic discrimination factors are tissue- and species-specific, researchers often rely on generalized, and fixed trophic discrimination factors that have not been experimentally derived. In this experimental study, captive wild boar (Sus scrofa) were fed a controlled diet of corn (Zea mays), a popular and increasingly dominant food source for wild boar in the Czech Republic and elsewhere in Europe, and trophic discrimination factors for stable carbon (Delta13C) and nitrogen (Delta15N) isotopes were determined from hair samples. The mean Delta13C and Delta15N in wild boar hair were -2.30/00 and +3.50/00, respectively. Also, in order to facilitate future derivations of isotopic measurements along wild boar hair, we calculated the average hair growth rate to be 1.1 mm d(-1). Our results serve as a baseline for interpreting isotopic patterns of free-ranging wild boar in current European agricultural landscapes. However, future research is needed in order to provide a broader understanding of the processes underlying the variation in trophic discrimination factors of carbon and nitrogen across of variety of diet types. PMID- 25915401 TI - A conserved function in phosphatidylinositol metabolism for mammalian Vps13 family proteins. AB - The Vps13 protein family is highly conserved in eukaryotic cells. In humans, mutations in the gene encoding the family member VPS13A lead to the neurodegenerative disorder chorea-acanthocytosis. In the yeast Saccharomyces cerevisiae, there is just a single version of VPS13, thereby simplifying the task of unraveling its molecular function(s). While VPS13 was originally identified in yeast by its role in vacuolar sorting, recent studies have revealed a completely different function for VPS13 in sporulation, where VPS13 regulates phosphatidylinositol-4-phosphate (PtdIns(4)P) levels in the prospore membrane. This discovery raises the possibility that the disease phenotype associated with vps13A mutants in humans is due to misregulation of PtdIns(4)P in membranes. To determine whether VPS13A affects PtdIns(4)P in membranes from mammalian neuronal cells, phosphatidylinositol phosphate pools were compared in PC12 tissue culture cells in the absence or presence of VPS13A. Consistent with the yeast results, the localization of PtdIns(4)P is specifically altered in VPS13A knockdown cells while other phosphatidylinositol phosphates appear unaffected. In addition, VPS13A is necessary to prevent the premature degeneration of neurites that develop in response to Nerve Growth Factor. The regulation of PtdIns(4)P is therefore a conserved function of the Vps13 family and may play a role in the maintenance of neuronal processes in mammals. PMID- 25915402 TI - Interplay between Endometriosis and Pregnancy in a Mouse Model. AB - OBJECTIVES: To evaluate the effect of endometriosis on fertility and the levels of the IL-2 and IFN-gamma in the peritoneal fluid in a mouse model; to evaluate the effect of pregnancy on endometriotic lesion growth, apoptosis and cell proliferation. STUDY DESIGN: Two month old C57BL/6 female mice underwent either a surgical procedure to induce endometriosis or a sham surgery. Four weeks after surgery mice were mated and sacrificed at day 18 of pregnancy. Number of implantation sites, fetuses and fetal weight were recorded. Endometriotic lesions were counted, measured, excised and fixed. Apoptosis and cell proliferation were evaluated in lesions by TUNEL and immunohistochemistry for PCNA respectively. Levels of IL-2 and IFN-gamma were assessed by ELISA in the peritoneal fluid. RESULTS: Pregnancy rate (i.e. pregnant mice/N) decreased in mice with endometriosis. However there were no significant differences in resorption rate, litter size and pup weight between groups. IFN-gamma augmented in endometriosis mice independently of pregnancy outcome. Additionally IFN-gamma increased in pregnant endometriosis mice compared to pregnant sham animals. While IFN-gamma increased in non pregnant versus pregnant mice in the sham group, IL-2 was increased in non pregnant mice in the endometriosis group. The size of endometriotic lesions increased in pregnant mice while apoptosis increased in the stroma and cell proliferation decreased in the epithelium of these lesions. Additionally, leukocyte infiltration, necrosis and decidualization were increased in the same lesions. CONCLUSIONS: Pregnancy rate is reduced in this mouse model of endometriosis. Levels of IL-2 are increased in the peritoneal fluid of mice with endometriosis suggesting a role of this cytokine in infertility related to this disease. The size of endometriotic lesions is increased in pregnant mice; however pregnancy has a beneficial effect on lesions by decreasing cell proliferation and by increasing apoptosis, decidualization and necrosis. PMID- 25915403 TI - Lipopolysaccharide (LPS)-Induced Biliary Epithelial Cell NRas Activation Requires Epidermal Growth Factor Receptor (EGFR). AB - Cholangiocytes (biliary epithelial cells) actively participate in microbe-induced proinflammatory responses in the liver and contribute to inflammatory and infectious cholangiopathies. We previously demonstrated that cholangiocyte TLR dependent NRas activation contributes to proinflammatory/ proliferative responses. We test the hypothesis that LPS-induced activation of NRas requires the EGFR. SV40-transformed human cholangiocytes (H69 cells), or low passage normal human cholangiocytes (NHC), were treated with LPS in the presence or absence of EGFR or ADAM metallopeptidase domain 17 (TACE) inhibitors. Ras activation assays, quantitative RT-PCR, and proliferation assays were performed in cells cultured with or without inhibitors or an siRNA to Grb2. Immunofluorescence for phospho-EGFR was performed on LPS-treated mouse samples and specimens from patients with primary sclerosing cholangitis, primary biliary cirrhosis, hepatitis C, and normal livers. LPS-treatment induced an association between the TLR/MyD88 and EGFR/Grb2 signaling apparatus, NRas activation, and EGFR phosphorylation. NRas activation was sensitive to EGFR and TACE inhibitors and correlated with EGFR phosphorylation. The TACE inhibitor and Grb2 depletion prevented LPS-induced IL6 expression (p<0.05) and proliferation (p<0.01). Additionally, cholangiocytes from LPS-treated mouse livers and human primary sclerosing cholangitis (PSC) livers exhibited increased phospho-EGFR (p<0.01). Moreover, LPS-induced mouse cholangiocyte proliferation was inhibited by concurrent treatment with the EGFR inhibitor, Erlotinib. Our results suggest that EGFR is essential for LPS-induced, TLR4/MyD88-mediated NRas activation and induction of a robust proinflammatory cholangiocyte response. These findings have implications not only for revealing the signaling potential of TLRs, but also implicate EGFR as an integral component of cholangiocyte TLR-induced proinflammatory processes. PMID- 25915404 TI - Prognostic Significance of CREB-Binding Protein and CD81 Expression in Primary High Grade Non-Muscle Invasive Bladder Cancer: Identification of Novel Biomarkers for Bladder Cancer Using Antibody Microarray. AB - High-grade (HG) bladder cancers (BCs) are genetically unstable and have an unpredictable course. The identification of prognostic factors in HG non-muscle invasive BC (NMIBC) is crucial for improving patients' quality of life and preventing BC-specific mortality. Here, we used an antibody microarray (AbM) to identify novel candidate biomarkers in primary HG NMIBC and validated the prognostic significance of the candidate biomarkers. Three pairs of tissue samples from primary HG NMIBC and normal urothelium were analyzed using an AbM kit containing 656 antibodies, and differentially expressed proteins were identified. Among the 42 upregulated and 14 downregulated proteins with statistical significance in BC tissues, CREB-binding protein and CD81 were selected as representative upregulated and downregulated candidate biomarkers, respectively. We then validated the expression of these candidate biomarkers in primary human urothelial cells and BC cell lines by western blotting and immunofluorescence assays, and the results were consistent with the AbM expression profiles. Additionally, Kaplan-Meier survival using immunohistochemical data from an independent primary HG NMIBC cohort comprising 113 patients showed that expression of the 2 biomarkers was significantly associated with recurrence-free and progression-free survival. In multivariate analysis, the 2 biomarkers remained significant predictors for recurrence-free survival. Taken together, our findings suggest that expression of CREB-binding protein and CD81 in BC tissue specimens may have prognostic value in patients with primary HG NMIBC. PMID- 25915407 TI - Use of rhBMP-2/beta-TCP for Interpositional Vertical Grafting Augmentation: 5.5 Year Follow-up Clinically and Histologically. AB - PURPOSE: This case report documented long-term results using rh-BMP-2/beta tricalcium phosphate (TCP) for vertical grafting augmentation. MATERIALS AND METHODS: A 58-year-old patient with extreme atrophy of the left posterior mandible was treated with rh-BMP-2/beta-TCP for vertical bone augmentation. At the time of implant placement, bone biopsy was performed for histological evaluation. RESULTS: Seven months after surgery, CT scan demonstrated approximately 8 mm of bone gain height. The histological results revealed a newly formed vital bone tissue, predominantly lamellar with variable density. Remaining bone ceramic surrounded by newly formed bone tissue or connective tissue was observed. The bone levels remained unchanged during the entire period treatment (5.5 years). CONCLUSION: This technique has demonstrated a potential for reconstruction of atrophic sites when vertical bone gain is desirable. Moreover, the bone gain has shown long-term maintenance without resorption. Future long term prospective clinical trials are needed to confirm these findings. PMID- 25915405 TI - Regulation of L-type Voltage Gated Calcium Channel CACNA1S in Macrophages upon Mycobacterium tuberculosis Infection. AB - We demonstrated earlier the inhibitory role played by Voltage Gated Calcium Channels (VGCCs) in regulating Mycobacterium tuberculosis (M. tb) survival and pathogenesis. In this report, we investigated mechanisms and key players that regulate the surface expression of VGCC-CACNA1S by Rv2463 and M. tb infection in macrophages. Our earlier work identified Rv2463 to be expressed at early times post infection in macrophages that induced suppressor responses to dendritic cells and macrophages. Our results in this study demonstrate a role of MyD88 independent TLR pathway in mediating CACNA1S expression. Dissecting the role for second messengers, we show that calcium homeostasis plays a key role in CACNA1S expression during M. tb infection. Using siRNAs against molecular sensors of calcium regulation, we show an involvement of ER associated Stromal Interaction Molecules 1 and 2 (STIM1 and STIM2), and transcription factor pCREB, towards CACNA1S expression that also involved the MyD88 independent pathway. Interestingly, reactive oxygen species played a negative role in M. tb mediated CACNA1S expression. Further, a cross-regulation of ROS and pCREB was noted that governed CACNA1S expression. Characterizing the mechanisms governing CACNA1S expression would improve our understanding of the regulation of VGCC expression and its role in M. tb pathogenesis during M. tb infection. PMID- 25915406 TI - SIRT3 Overexpression Attenuates Palmitate-Induced Pancreatic beta-Cell Dysfunction. AB - Abnormally high levels of circulating free fatty acids can lead to pancreatic islet beta-cell dysfunction and apoptosis, contributing to beta-cell failure in Type 2 diabetes. The NAD+-dependent protein deacetylase Sirtuin-3 (SIRT3) has been implicated in Type 2 diabetes. In this study, we tested whether SIRT3 overexpression affects palmitate-induced beta-cell dysfunction in cells of line NIT1, which are derived from mouse pancreatic beta-cells. Two different lengths of SIRT3 were overexpressed: full length SIRT3 (SIRT3LF), which was preferentially targeted to mitochondria and partially to the nucleus, and its N terminal truncated form (SIRT3SF), which was located in the nucleus and cytoplasm. Overexpression of SIRT3LF and SIRT3SF using an adenoviral system alleviated palmitate-induced lipotoxicity such as reduction of cell viability and mitogen-activated protein kinase (MAPK) activation. Chronic exposure to low concentrations of palmitate suppressed glucose-stimulated insulin secretion, but the suppression was effectively reversed by overexpression of SIRT3LF or SIRT3SF. The mRNA levels of the endoplasmic reticulum (ER) stress responsive genes ATF4, GRP94 and FKBP11 were increased by palmitate treatment, but the increases were completely inhibited by SIRT3LF overexpression and less effectively inhibited by SIRT3SF overexpression. This result suggests that overexpression of SIRT3 inhibits induction of ER stress by palmitate. Collectively, we conclude that overexpression of SIRT3 alleviates palmitate-induced beta-cell dysfunction. PMID- 25915408 TI - Evaluation of Clinical Soft Tissue Parameters for Extramaxillary Zygomatic Implants and Conventional Implants in All-on-4 Hybrid Rehabilitations: Short-Term Outcome and Proposal of Clinical Recommendations for Intervention in Recall Appointments. AB - PURPOSE: This prospective cohort study aimed to investigate the short-term soft tissue clinical outcomes and recommendation for evaluation and follow-up after a new hybrid All-on-4 rehabilitation. METHODS: Forty consecutively included patients rehabilitated in the complete edentulous atrophic maxillae through a hybrid All-on-4 treatment concept (4 immediate function implants in a combination between zygomatic and conventional implants). Periimplant conditions at zygomatic and conventional implants were compared. Four clinical levels (CLs) were used to classify the presence and severity of periimplant conditions. RESULTS: Four patients withdrew from the study. No significant differences were found for periimplant conditions at zygomatic and conventional implants. The distribution was 28, 2, 1, and 9 patients with CL1, CL2, CL3, and CL4, respectively. CONCLUSIONS: Soft tissue clinical outcomes of extramaxillary zygomatic implants and conventional implants seem to follow a similar distribution. The proposed classification system stratifies patients, supports decision making, and with further validation may elucidate recommendations for frequency of recall appointments and intervention to enhance long-term success. PMID- 25915409 TI - In Vitro Behavior of Primary Human Osteoblasts Onto Microrough Titanium Surface. AB - OBJECTIVE: The aim of this study was to evaluate in vitro the behavior and the biocompatibility of primary human osteoblasts (HOs) grown onto different implant surface. METHODS AND MATERIALS: HOs were cultured onto sandblasted/acid-etched (control group) and sandblasted/acid-etched followed by coating with inorganic ions (test group) experimental titanium discs. At established times, SEM analysis, LDH assay, MTT assay, and enzyme-linked immunosorbent assay for type 1 collagen, interleukin (IL)-6, and PGE2 secretion were performed. RESULTS: Both surfaces promote HOs adhesion and proliferation. After 21 days, cells on test surfaces are well spread, flattened, and attached by cellular extensions, whereas cells on control discs appear mainly elongated. Lower LDH levels and higher values of MTT assay are recorded for cells on test respect to control surfaces at each experimental time. Type 1 collagen release increases until 14 days, significantly decreasing at day 21 in cells grown on both surfaces. IL-6 and PGE2 secretion shows a peak in control group samples at day 7, whereas their levels do not significantly modify in both groups at days 14 and 21. CONCLUSION: Results indicate that the test group surface is more biocompatible, well tolerated, and suitable for supporting osteoblasts growth and proliferation. PMID- 25915410 TI - Modified Proofreading PCR for Detection of Point Mutations, Insertions and Deletions Using a ddNTP-Blocked Primer. AB - The development of simple, accurate, rapid and cost-effective technologies for mutation detection is crucial to the early diagnosis and prevention of numerous genetic diseases, pharmacogenetics, and drug resistance. Proofreading PCR (PR PCR) was developed for mutation detection in 1998 but is rarely applied due to its low efficiency in allele discrimination. Here we developed a modified PR-PCR method using a ddNTP-blocked primer and a mixture of DNA polymerases with and without the 3'-5' proofreading function. The ddNTP-blocked primer exhibited the best blocking efficiency to avoid nonspecific primer extension while the mixture of a tiny amount of high-fidelity DNA polymerase with a routine amount of Taq DNA polymerase provided the best discrimination and amplification effects. The modified PR-PCR method is quite capable of detecting various mutation types, including point mutations and insertions/deletions (indels), and allows discrimination amplification when the mismatch is located within the last eight nucleotides from the 3'-end of the ddNTP-blocked primer. The modified PR-PCR has a sensitivity of 1-5 * 102 copies and a selectivity of 5 * 10-5 mutant among 107 copies of wild-type DNA. It showed a 100% accuracy rate in the detection of P72R germ-line mutation in the TP53 gene among 60 clinical blood samples, and a high potential to detect rifampin-resistant mutations at low frequency in Mycobacterium tuberculosis using an adaptor and a fusion-blocked primer. These results suggest that the modified PR-PCR technique is effective in detection of various mutations or polymorphisms as a simple, sensitive and promising approach. PMID- 25915411 TI - Construction of a BALB/c-Nu Mouse Model of Invasive Bladder Carcinoma and Preliminary Studies on the Treatment of Bladder Tumors through Internal Iliac Arterial Infusion of Albumin-Bound Arsenic Trioxide (As2O3). AB - To establish a BALB/c-nu mouse model of invasive bladder carcinoma and to investigate the feasibility, efficacy, and side effects of treating the mouse xenografts with internal iliac arterial infusion of albumin-bound arsenic trioxide (As2O3). Bladder tumors were established by intravesicular injection. Color Doppler were used to monitor tumor growth. Albumin-bound As2O3 and bovine serum albumin (BSA) nanoparticles were synthesized by cross-linking. BALB/c-nu mice were randomly divided into four treatment groups: 1) normal saline, 2) BSA nanoparticles, 3) As2O3 injections, and 4) albumin-bound As2O3. In an attempt to replicate the treatment of bladder cancer in humans using internal iliac arterial infusion, the drugs were injected into the mouse abdominal aorta. Tumor xenografts were established successfully. Mice treated with As2O3 injections and with albumin-bound As2O3 had significantly smaller bladders (36.59% and 37.82% smaller, respectively) than mice given normal saline injections (P < 0.01). Mice receiving As2O3 injections had lower white blood cell (WBC) and platelet counts compared with mice receiving normal saline injections only (P < 0.05). However, mice treated with albumin-bound As2O3 did not experience a significant decrease in WBC or platelet counts compared with control mice. A model of intra-arterial bladder cancer treatment was successfully established in BALB/c-nu mice. In this model, albumin-bound As2O3 appeared to be an effective method for treating bladder tumors, with less severe hematologic side effects compared with As2O3 alone. The infusion of albumin-bound As2O3 through the internal iliac artery is a promising method of bladder cancer therapy. PMID- 25915412 TI - Spatial Distribution, Air-Water Fugacity Ratios and Source Apportionment of Polychlorinated Biphenyls in the Lower Great Lakes Basin. AB - Polychlorinated biphenyls (PCBs) continue to be contaminants of concern across the Great Lakes. It is unclear whether current concentrations are driven by ongoing primary emissions from their original uses, or whether ambient PCBs are dominated by their environmental cycling. Freely dissolved PCBs in air and water were measured using polyethylene passive samplers across Lakes Erie and Ontario during summer and fall, 2011, to investigate their spatial distribution, determine and apportion their sources and to asses their air-water exchange gradients. Average gaseous and freely dissolved ?29 PCB concentrations ranged from 5.0 to 160 pg/m(3) and 2.0 to 55 pg/L respectively. Gaseous concentrations were significantly correlated (R(2) = 0.80) with the urban area within a 3-20 km radius. Fugacity ratios indicated that the majority of PCBs are volatilizing from the water thus acting as a secondary source for the atmosphere. Dissolved PCBs were probably linked to PCB emissions from contaminated sites and areas of concern. Positive matrix factorization indicated that although volatilized Aroclors (gaseous PCBs) and unaltered Aroclors (dissolved PCBs) dominate in some samples, ongoing non-Aroclor sources such as paints/pigments (PCB 11) and coal/wood combustion showed significant contributions across the lower Great Lakes. Accordingly, control strategies should give further attention to PCBs emitted from current use sources. PMID- 25915413 TI - Platelet mechanosensing of collagen matrices. AB - During vascular injury, platelets adhere to exposed subendothelial proteins, such as collagen, on the blood vessel walls to trigger clot formation. Although the biochemical signalings of platelet-collagen interactions have been well characterized, little is known about the role microenvironmental biomechanical properties, such as vascular wall stiffness, may have on clot formation. To that end, we investigated how substrates of varying stiffness conjugated with the same concentration of Type I collagen affect platelet adhesion, spreading, and activation. Using collagen-conjugated polyacrylamide (PA) gels of different stiffnesses, we observed that platelets do in fact mechanotransduce the stiffness cues of collagen substrates, manifesting in increased platelet spreading on stiffer substrates. In addition, increasing substrate stiffness also increases phosphatidylserine exposure, a key aspect of platelet activation that initiates coagulation on the platelet surface. Mechanistically, these collagen substrate stiffness effects are mediated by extracellular calcium levels and actomyosin pathways driven by myosin light chain kinase but not Rho-associated protein kinase. Overall, our results improve our understanding of how the mechanics of different tissues and stroma affect clot formation, what role the increased vessel wall stiffness in atherosclerosis may directly have on thrombosis leading to heart attacks and strokes, and how age-related increased vessel wall stiffness affects hemostasis and thrombosis. PMID- 25915414 TI - Susceptibility-Weighted Imaging Manifestations in the Brain of Wilson's Disease Patients. AB - PURPOSE: It is well known that patients with Wilson's disease (WD) suffer copper metabolism disorder. However, recent studies point to an additional iron metabolism disorder in WD patients. The purpose of our study was to examine susceptibility-weighted imaging (SWI) manifestations of WD in the brains of WD patients. METHODS: A total of 33 patients with WD and 18 normal controls underwent conventional MRI (Magnetic resonance imaging) and SWI. The phase values were measured on SWI-filtered phase images of the bilateral head of the caudate nuclei, globus pallidus, putamen, thalamus, substantia nigra, and red nucleus. Student's t-tests were used to compare the phase values between WD groups and normal controls. RESULTS: The mean phase values for the bilateral head of the caudate nuclei, globus pallidus, putamen, thalamus, substantia nigra, and red nucleus were significantly lower than those in the control group (P < 0.001), and bilateral putamen was most strongly affected. CONCLUSIONS: There is paramagnetic mineralization deposition in brain gray nuclei of WD patients and SWI is an effective method to evaluate these structures. PMID- 25915415 TI - Relationship between Serum Bilirubin and Left Ventricular Hypertrophy in Patients with Essential Hypertension. AB - BACKGROUND: Prospective studies have found low bilirubin levels were an important predictive factor of cardiovascular events. However, few have yet investigated possible association between serum bilirubin level and LVH in essential hypertension. The aim of the present study was to evaluate the relationship between serum bilirubin levels with LVH in newly diagnosed hypertension patients. METHODS: The present study evaluated the relationship between serum total bilirubin level and left ventricle hypertrophy (LVH) in newly diagnosed hypertensive patients with a sample size of 344. We divided subjects into LVH group (n=138) and non-LVH group (n=206). Physical examination, laboratory tests and echocardiography were conducted. The multivariate logistic regression model was used to verify the independent association between RDW and LVH. RESULTS: Our results found that patients with LVH had lower bilirubin levels than non-LVH ones. Stepwise multiple linear regression analysis showed total bilirubin level (B=-0.017, P=0.008) was negatively associated with left ventricle mass index (LVMI) even adjusting for some confounders. The multiples logistic regression found total bilirubin level was independently related with of LVH, as a protective factors (OR=0.91, P=0.010). CONCLUSION: As a routine and quick laboratory examination index, serum bilirubin may be treated as novel marker for evaluating LVH risk in hypertensive patients. Cohort study with larger sample size are needed. PMID- 25915416 TI - When documentation supersedes patient communication: an example from an endoscopy unit. PMID- 25915417 TI - Oil and gas wells and pipelines on U.S. wildlife refuges: challenges for managers. AB - The increased demand for oil and gas places a burden on lands set aside for natural resource conservation. Oil and gas development alters the environment locally and on a much broader spatial scale depending on the intensity and extent of mineral resource extraction. The current increase in oil and gas exploration and production in the United States prompted an update of the number of pipelines and wells associated with oil and gas production on National Wildlife Refuge System (NWRS) lands. We obtained geospatial data on the location of oil and gas wells and pipelines within and close to the boundaries of NWRS lands (units) acquired as fee simple (i.e. absolute title to the surface land) by the U.S. Fish and Wildlife Service. We found that 5,002 wells are located in 107 NWRS units and 595 pipelines transect 149 of the 599 NWRS units. Almost half of the wells (2,196) were inactive, one-third (1,665) were active, and the remainder of the wells were either plugged and abandoned or the status was unknown. Pipelines crossed a total of 2,155 kilometers (1,339 miles) of NWRS fee simple lands. The high level of oil and gas activity warrants follow up assessments for wells lacking information on production type or well status with emphasis on verifying the well status and identifying abandoned and unplugged wells. NWRS fee simple lands should also be assessed for impacts from brine, oil and other hydrocarbon spills, as well as habitat alteration associated with oil and gas, including the identification of abandoned oil and gas facilities requiring equipment removal and site restoration. PMID- 25915419 TI - Adenosine signaling and the energetic costs of induced immunity. AB - Life history theory predicts that trait evolution should be constrained by competing physiological demands on an organism. Immune defense provides a classic example in which immune responses are presumed to be costly and therefore come at the expense of other traits related to fitness. One strategy for mitigating the costs of expensive traits is to render them inducible, such that the cost is paid only when the trait is utilized. In the current issue of PLOS Biology, Bajgar and colleagues elegantly demonstrate the energetic and life history cost of the immune response that Drosophila melanogaster larvae induce after infection by the parasitoid wasp Leptopilina boulardi. These authors show that infection-induced proliferation of defensive blood cells commands a diversion of dietary carbon away from somatic growth and development, with simple sugars instead being shunted to the hematopoetic organ for rapid conversion into the raw energy required for cell proliferation. This metabolic shift results in a 15% delay in the development of the infected larva and is mediated by adenosine signaling between the hematopoietic organ and the central metabolic control organ of the host fly. The adenosine signal thus allows D. melanogaster to rapidly marshal the energy needed for effective defense and to pay the cost of immunity only when infected. PMID- 25915418 TI - An effector Peptide family required for Drosophila toll-mediated immunity. AB - In Drosophila melanogaster, recognition of an invading pathogen activates the Toll or Imd signaling pathway, triggering robust upregulation of innate immune effectors. Although the mechanisms of pathogen recognition and signaling are now well understood, the functions of the immune-induced transcriptome and proteome remain much less well characterized. Through bioinformatic analysis of effector gene sequences, we have defined a family of twelve genes - the Bomanins (Boms) - that are specifically induced by Toll and that encode small, secreted peptides of unknown biochemical activity. Using targeted genome engineering, we have deleted ten of the twelve Bom genes. Remarkably, inactivating these ten genes decreases survival upon microbial infection to the same extent, and with the same specificity, as does eliminating Toll pathway function. Toll signaling, however, appears unaffected. Assaying bacterial load post-infection in wild-type and mutant flies, we provide evidence that the Boms are required for resistance to, rather than tolerance of, infection. In addition, by generating and assaying a deletion of a smaller subset of the Bom genes, we find that there is overlap in Bom activity toward particular pathogens. Together, these studies deepen our understanding of Toll-mediated immunity and provide a new in vivo model for exploration of the innate immune effector repertoire. PMID- 25915420 TI - The Association of Health Literacy with Illness and Medication Beliefs among Patients with Chronic Obstructive Pulmonary Disease. AB - BACKGROUND: Low health literacy is associated with low adherence to self management in many chronic diseases. Additionally, health beliefs are thought to be determinants of self-management behaviors. In this study we sought to determine the association, if any, of health literacy and health beliefs among elderly individuals with COPD. METHODS: We enrolled a cohort of patients with COPD from two academic urban settings in New York, NY and Chicago, IL. Health literacy was measured using the Short Test of Functional Health Literacy in Adults. Using the framework of the Self-Regulation Model, illness and medication beliefs were measured with the Brief Illness Perception Questionnaire (B-IPQ) and Beliefs about Medications Questionnaire (BMQ). Unadjusted analyses, with corresponding Cohen's d effect sizes, and multiple logistic regression were used to assess the relationships between HL and illness and medication beliefs. RESULTS: We enrolled 235 participants, 29% of whom had low health literacy. Patients with low health literacy were more likely to belong to a racial minority group (p<0.001), not be married (p = 0.006), and to have lower income (p<0.001) or education (p<0.001). In unadjusted analyses, patients with low health literacy were less likely to believe they will always have COPD (p = 0.003, Cohen's d = 0.42), and were more likely to be concerned about their illness ((p = 0.04, Cohen's d = 0.17). In analyses adjusted for sociodemographic factors and other health beliefs, patients with low health literacy were less likely to believe that they will always have COPD (odds ratio [OR]: 0.78, 95% confidence interval [CI]: 0.65-0.94). In addition, the association of low health literacy with expressed concern about medications remained significant (OR: 1.20, 95% CI: 1.05 1.37) though the association of low health literacy with belief in the necessity of medications was no longer significant (OR: 0.92, 95% CI: 0.82-1.04). CONCLUSIONS: In this cohort of urban individuals with COPD, low health literacy was prevalent, and associated with illness beliefs that predict decreased adherence. Our results suggest that targeted strategies to address low health literacy and related illness and medications beliefs might improve COPD medication adherence and other self-management behaviors. PMID- 25915421 TI - Toll-Interacting Protein Suppresses HIV-1 Long-Terminal-Repeat-Driven Gene Expression and Silences the Post-Integrational Transcription of Viral Proviral DNA. AB - Toll-interacting protein (Tollip) is a host adaptor protein for negatively regulating Toll-like receptor 2-, 4-, and IL-1R (interleukin-1 receptor)-mediated signaling. We found that Tollip expression could be induced in MDDCs (monocyte derived dendritic cells) by HIV-1 particles and recombinant gp120 glycoprotein. Hence, we investigated the role of Tollip in modulating HIV-1 infection. We found that Tollip expression suppressed NF-kappaB-dependent HIV-1 long terminal repeat (LTR)-driven transcription and thus inhibited HIV-1 infection. Our protein truncation experiments proved that the intact C-terminus of Tollip was required for inhibition of both NF-kappaB activity and HIV-1 LTR-driven gene expression. Intriguingly, Tollip silenced the post-integrational transcription of HIV-1 proviral DNA, indicating the potential role of Tollip in maintaining viral persistence. Our results reveal the novel role of host factor Tollip in modulating HIV-1 infection, and may suggest the hijacking of Tollip as the negative regulator of the TLR pathway and even the downstream signaling, by HIV-1 for maintaining persistent infection. Further elucidation of the mechanisms by which HIV-1 induces Tollip expression and identification of the role of Tollip in modulating HIV-1 latency will facilitate the understanding of host regulation in viral replication and benefit the exploration of novel strategies for combating HIV-1 infection. PMID- 25915422 TI - Photosynthetic Membranes of Synechocystis or Plants Convert Sunlight to Photocurrent through Different Pathways due to Different Architectures. AB - Thylakoid membranes contain the redox active complexes catalyzing the light dependent reactions of photosynthesis in cyanobacteria, algae and plants. Crude thylakoid membranes or purified photosystems from different organisms have previously been utilized for generation of electrical power and/or fuels. Here we investigate the electron transferability from thylakoid preparations from plants or the cyanobacterium Synechocystis. We show that upon illumination, crude Synechocystis thylakoids can reduce cytochrome c. In addition, this crude preparation can transfer electrons to a graphite electrode, producing an unmediated photocurrent of 15 MUA/cm2. Photocurrent could be obtained in the presence of the PSII inhibitor DCMU, indicating that the source of electrons is QA, the primary Photosystem II acceptor. In contrast, thylakoids purified from plants could not reduce cyt c, nor produced a photocurrent in the photocell in the presence of DCMU. The production of significant photocurrent (100 MUA/cm2) from plant thylakoids required the addition of the soluble electron mediator DCBQ. Furthermore, we demonstrate that use of crude thylakoids from the D1-K238E mutant in Synechocystis resulted in improved electron transferability, increasing the direct photocurrent to 35 MUA/cm2. Applying the analogous mutation to tobacco plants did not achieve an equivalent effect. While electron abstraction from crude thylakoids of cyanobacteria or plants is feasible, we conclude that the site of the abstraction of the electrons from the thylakoids, the architecture of the thylakoid preparations influence the site of the electron abstraction, as well as the transfer pathway to the electrode. This dictates the use of different strategies for production of sustainable electrical current from photosynthetic thylakoid membranes of cyanobacteria or higher plants. PMID- 25915423 TI - Angelica gigas Nakai and Soluplus-Based Solid Formulations Prepared by Hot Melting Extrusion: Oral Absorption Enhancing and Memory Ameliorating Effects. AB - Oral solid formulations based on Angelica gigas Nakai (AGN) and Soluplus were prepared by the hot-melting extrusion (HME) method. AGN was pulverized into coarse and ultrafine particles, and their particle size and morphology were investigated. Ultrafine AGN particles were used in the HME process with high shear to produce AGN-based formulations. In simulated gastrointestinal fluids (pH 1.2 and pH 6.8) and water, significantly higher amounts of the major active components of AGN, decursin (D) and decursinol angelate (DA), were extracted from the HME-processed AGN/Soluplus (F8) group than the AGN EtOH extract (ext) group (p < 0.05). Based on an in vivo pharmacokinetic study in rats, the relative oral bioavailability of decursinol (DOH), a hepatic metabolite of D and DA, in F8 administered mice was 8.75-fold higher than in AGN EtOH ext-treated group. In scopolamine-induced memory-impaired mice, F8 exhibited a more potent cognitive enhancing effect than AGN EtOH ext in both a Morris water maze test and a passive avoidance test. These findings suggest that HME-processed AGN/Soluplus formulation (F8) could be a promising therapeutic candidate for memory impairment. PMID- 25915424 TI - A multi-ingredient containing carbohydrate, proteins L-glutamine and L-carnitine attenuates fatigue perception with no effect on performance, muscle damage or immunity in soccer players. AB - We investigated the effects of ingesting a multi-ingredient (53 g carbohydrate, 14.5 g whey protein, 5 g glutamine, 1.5 g L-carnitine-L-tartrate) supplement, carbohydrate only, or placebo on intermittent performance, perception of fatigue, immunity, and functional and metabolic markers of recovery. Sixteen amateur soccer players ingested their respective treatments before, during and after performing a 90-min intermittent repeated sprint test. Primary outcomes included time for a 90-min intermittent repeated sprint test (IRS) followed by eleven 15 m sprints. Measurements included creatine kinase, myoglobin, interleukine-6, Neutrophil; Lymphocytes and Monocyte before (pre), immediately after (post), 1 h and 24 h after exercise testing period. Overall, time for the IRS and 15 m sprints was not different between treatments. However, the perception of fatigue was attenuated (P<0.001) for the multi-ingredient (15.9+/-1.4) vs. placebo (17.8+/-1.4) but not for the carbohydrate (17.0+/-1.9) condition. Several changes in immune/inflammatory indices were noted as creatine kinase peaked at 24 h while Interleukin-6 and myoglobin increased both immediately after and at 1 h compared with baseline (P<0.05) for all three conditions. However, Myoglobin (P<0.05) was lower 1 h post-exercise for the multi-ingredient (241.8+/-142.6 ng.ml(-1)) and CHO (265.4+/-187.8 ng.ml(-1)) vs. placebo (518.6+/-255.2 ng.ml(-1)). Carbohydrate also elicited lower neutrophil concentrations vs. multi-ingredient (3.9+/-1.5 10(9)/L vs. 4.9+/-1.8 10(9)/L, P = 0.016) and a reduced (P<0.05) monocytes count (0.36+/-0.09 10(9)/L) compared to both multi-ingredient (0.42+/-0.09 10(9)/L) and placebo (0.42+/-0.12 10(9)/L). In conclusion, multi-ingredient and carbohydrate supplements did not improve intermittent performance, inflammatory or immune function. However, both treatments did attenuate serum myoglobin, while only carbohydrate blunted post-exercise leukocytosis. PMID- 25915425 TI - ESPGHAN and NASPGHAN Report on the Assessment of Exocrine Pancreatic Function and Pancreatitis in Children. AB - The purpose of this clinical report is to discuss several recent advances in assessing exocrine pancreatic insufficiency (EPI) and pancreatitis in children, to review the array of pancreatic function tests, to provide an update on the inherited causes of EPI, with special emphasis on newly available genetic testing, and to review newer methods for evaluating pancreatitis. PMID- 25915426 TI - Elevated O-GlcNAcylation promotes colonic inflammation and tumorigenesis by modulating NF-kappaB signaling. AB - O-GlcNAcylation is a reversible post-translational modification. O-GlcNAc addition and removal is catalyzed by O-GlcNAc transferase (OGT) and O-GlcNAcase (OGA), respectively. More recent evidence indicates that regulation of O GlcNAcylation is important for inflammatory diseases and tumorigenesis. In this study, we revealed that O-GlcNAcylation was increased in the colonic tissues of dextran sodium sulfate (DSS)-induced colitis and azoxymethane (AOM)/DSS-induced colitis-associated cancer (CAC) animal models. Moreover, the O-GlcNAcylation level was elevated in human CAC tissues compared with matched normal counterparts. To investigate the functional role of O-GlcNAcylation in colitis, we used OGA heterozygote mice, which have an increased level of O-GlcNAcylation. OGA(+/-) mice have higher susceptibility to DSS-induced colitis than OGA(+/+) mice. OGA(+/-) mice exhibited a higher incidence of colon tumors than OGA(+/+) mice. In molecular studies, elevated O-GlcNAc levels were shown to enhance the activation of NF-kappaB signaling through increasing the binding of RelA/p65 to its target promoters. We also found that Thr-322 and Thr352 in the p65-O GlcNAcylation sites are critical for p65 promoter binding. These results suggest that the elevated O-GlcNAcylation level in colonic tissues contributes to the development of colitis and CAC by disrupting regulation of NF-kappaB-dependent transcriptional activity. PMID- 25915428 TI - A small molecule inhibitor of atypical protein kinase C signaling inhibits pancreatic cancer cell transformed growth and invasion. AB - Pancreatic cancer is highly resistant to current chemotherapies. Identification of the critical signaling pathways that mediate pancreatic cancer transformed growth is necessary for the development of more effective therapeutic treatments. Recently, we demonstrated that protein kinase C iota (PKCiota) and zeta (PKCzeta) promote pancreatic cancer transformed growth and invasion, by activating Rac1 >ERK and STAT3 signaling pathways, respectively. However, a key question is whether PKCiota and PKCzeta play redundant (or non-redundant) roles in pancreatic cancer cell transformed growth. Here we describe the novel observations that 1) PKCiota and PKCzeta are non-redundant in the context of the transformed growth of pancreatic cancer cells; 2) a gold-containing small molecule known to disrupt the PKCiota/Par6 interaction, aurothiomalate, also disrupts PKCzeta/Par6 interaction; 3) aurothiomalate inhibits downstream signaling of both PKCiota and PKCzeta, and blocks transformed growth of pancreatic cancer cells in vitro; and 4) aurothiomalate inhibits pancreatic cancer tumor growth and metastasis in vivo. Taken together, these data provide convincing evidence that an inhibitor of atypical PKC signaling inhibits two key oncogenic signaling pathways, driven non redundantly by PKCiota and PKCzeta, to significantly reduce tumor growth and metastasis. Our results demonstrate that inhibition of atypical PKC signaling is a promising therapeutic strategy to treat pancreatic cancer. PMID- 25915427 TI - MicroRNA-451 regulates stemness of side population cells via PI3K/Akt/mTOR signaling pathway in multiple myeloma. AB - Side population (SP) cells are an enriched source of cancer-initiating cells with stemness characteristics, generated by increased ABC transporter activity, which has served as a unique hallmark for multiple myeloma (MM) stem cell studies. Here we isolated and identified MM SP cells via Hoechst 33342 staining. Furthermore, we demonstrate that SP cells possess abnormal cell cycle, clonogenicity, and high drug efflux characteristics-all of which are features commonly seen in stem cells. Interestingly, we found that bortezomib, As2O3, and melphalan all affected apoptosis and clonogenicity in SP cells. We followed by characterizing the miRNA signature of MM SP cells and validated the specific miR-451 target tuberous sclerosis 1 (TSC1) gene to reveal that it activates the PI3K/Akt/mTOR signaling in MM SP cells. Inhibition of miR-451 enhanced anti-myeloma novel agents' effectiveness, through increasing cells apoptosis, decreasing clonogenicity, and reducing MDR1 mRNA expression. Moreover, the novel specific PI3K/Akt/mTOR signaling inhibitor S14161 displayed its prowess as a potential therapeutic agent by targeting MM SP cells. Our findings offer insights into the mechanisms regulating MM SP cells and provide a novel strategy to overcome resistance to existing therapies against myeloma. PMID- 25915429 TI - Chemotherapy induces the cancer-associated fibroblast phenotype, activating paracrine Hedgehog-GLI signalling in breast cancer cells. AB - Cancer cells recruit normal cells such as fibroblasts to establish reactive microenvironments. Via metabolic stress, catabolism and inflammation, these cancer-associated fibroblasts set up a synergistic relationship with tumour cells, that contributes to their malignancy and resistance to therapy. Given that chemotherapy is a systemic treatment, the possibility that healthy cell damage affects the metastatic risk or the prospect of developing a second malignancy becomes relevant. Here, we demonstrate that standard chemotherapies phenotypically and metabolically transform stromal fibroblasts into cancer associated fibroblasts, leading to the emergence of a highly glycolytic, autophagic and pro-inflammatory microenvironment. This catabolic microenvironment, in turn, activates stemness (Sonic hedgehog/GLI signalling), antioxidant response and interferon-mediated signalling, in adjacent breast cancer cells. Thus, we propose a model by which chemotherapy-induced catabolism in healthy fibroblasts constitutes a source of energy-rich nutrients and inflammatory cytokines that would activate stemness in adjacent epithelial cells, possibly triggering new tumorigenic processes. In this context, immune cell recruitment would be also stimulated to further support malignancy. PMID- 25915431 TI - Lithium Sulfide (Li2S)/Graphene Oxide Nanospheres with Conformal Carbon Coating as a High-Rate, Long-Life Cathode for Li/S Cells. AB - In recent years, lithium/sulfur (Li/S) cells have attracted great attention as a candidate for the next generation of rechargeable batteries due to their high theoretical specific energy of 2600 W.h kg(-1), which is much higher than that of Li ion cells (400-600 W.h kg(-1)). However, problems of the S cathode such as highly soluble intermediate species (polysulfides Li2Sn, n = 4-8) and the insulating nature of S cause poor cycle life and low utilization of S, which prevents the practical use of Li/S cells. Here, a high-rate and long-life Li/S cell is proposed, which has a cathode material with a core-shell nanostructure comprising Li2S nanospheres with an embedded graphene oxide (GO) sheet as a core material and a conformal carbon layer as a shell. The conformal carbon coating is easily obtained by a unique CVD coating process using a lab-designed rotating furnace without any repetitive steps. The Li2S/GO@C cathode exhibits a high initial discharge capacity of 650 mA.h g(-1) of Li2S (corresponding to the 942 mA.h g(-1) of S) and very low capacity decay rate of only 0.046% per cycle with a high Coulombic efficiency of up to 99.7% for 1500 cycles when cycled at the 2 C discharge rate. PMID- 25915430 TI - Reduction of RKIP expression promotes nasopharyngeal carcinoma invasion and metastasis by activating Stat3 signaling. AB - The role and underlying mechanism of Raf kinase inhibitory protein (RKIP) in nasopharyngeal carcinoma (NPC) metastasis remain unclear. Here, we showed that RKIP was downregulated in the NPC with high metastatic potentials, and its decrement correlated with NPC metastasis and poor patient survival, and was an independent predictor for reduced overall survival. With a combination of loss-of function and gain-of-function approaches, we observed that high expression of RKIP reduced invasion, metastasis and epithelial to mesenchymal transition (EMT) marker alternations of NPC cells. We further showed that RKIP overexpression attenuated while RKIP knockdown enhanced Stat3 phosphorylation and activation in NPC cells; RKIP reduced Stat3 phosphorylation through interacting with Stat3; Stattic attenuated NPC cell migration, invasion and EMT marker alternations induced by RKIP knockdown, whereas Stat3 overexpression restored NPC cell migration, invasion and EMT marker alternations reduced by RKIP overexpression. In addition, there was an inverse correlation between RKIP and phospho-Stat3 expression in the NPC tissues and xenograft metastases. Our data demonstrate that RKIP is a metastatic suppressor and predictor for metastasis and prognosis in NPC, and RKIP downregulation promotes NPC invasion, metastasis and EMT by activating Stat3 signaling, suggesting that RKIP/Stat3 signaling could be used as a therapeutic target for NPC metastasis. PMID- 25915432 TI - The association between implicit alcohol attitudes and drinking behavior is moderated by baseline activation in the lateral prefrontal cortex. AB - OBJECTIVE: Intense alcohol consumption is a risk factor for a number of health problems. Dual-process models assume that self-regulatory behavior such as drinking alcohol is guided by both reflective and impulsive processes. Evidence suggests that (a) impulsive processes such as implicit attitudes are more strongly associated with behavior when executive functioning abilities are low, and (b) higher neural baseline activation in the lateral prefrontal cortex (PFC) is associated with better inhibitory control. The present study integrates these 2 strands of research to investigate how individual differences in neural baseline activation in the lateral PFC moderate the association between implicit alcohol attitudes and drinking behavior. METHOD: Baseline cortical activation was measured with resting electroencephalography (EEG) in 89 moderate drinkers. In a subsequent behavioral testing session they completed measures of implicit alcohol attitudes and self-reported drinking behavior. RESULTS: Implicit alcohol attitudes were related to self-reported alcohol consumption. Most centrally, implicit alcohol attitudes were more strongly associated with drinking behavior in individuals with low as compared with high baseline activation in the right lateral PFC. CONCLUSIONS: These findings are in line with predictions made on the basis of dual-process models. They provide further evidence that individual differences in neural baseline activation in the right lateral PFC may contribute to executive functioning abilities such as inhibitory control. Moreover, individuals with strongly positive implicit alcohol attitudes coupled with a low baseline activation in the right lateral PFC may be at greater risk of developing unhealthy drinking patterns than others. (PsycINFO Database Record PMID- 25915433 TI - Acupuncture for treating aromatase inhibitor-related arthralgia in breast cancer: a systematic review and meta-analysis. AB - PURPOSE: Acupuncture has been used as a complementary medical treatment for arthralgia and other types of pain. The objective of this review is to assess the effectiveness of acupuncture in the treatment of arthralgia in patients with breast cancer who were treated with aromatase inhibitors (AIs). METHODS: A literature search was performed, without language restrictions, of 10 databases from their inception through February 2014. The literature reviewed included randomized clinical trials (RCTs) and clinical trials that compared real versus sham acupuncture for the treatment of AI-related musculoskeletal symptoms (AIMSS). The methodologic quality of these trials was assessed by using the modified Jadad Quality Scale. Meta-analytic software (RevMan 5.0) was used to analyze the data. RESULTS: Five To compare the effects of real versus sham acupuncture, five RCTs were assessed by meta-analysis and quality analysis. Three of the RCTs reported favorable effects with regard to use of acupuncture in reducing pain and joint-related symptoms, while the other two RCTs did not. The meta-analysis showed trends toward reduced pain and stiffness in patients given acupuncture compared with those who received sham treatment (n=82; pain, mean difference: -2.07 [95% confidence interval (CI), -4.72 to 0.57]; p=0.12; stiffness, mean difference: -86.10 [95% CI, -249.11 to 76.92]; p=0.30), although these differences were not statistically significant. CONCLUSIONS: Acupuncture has been reported as a safe and promising treatment for AIMSS, but the present analysis indicated that the effects were not statistically significant. Other outcome measurements, such as imaging studies, would be worth including in future studies to further confirm the efficacy of acupuncture in AIMSS. PMID- 25915434 TI - "Job-Sharing" Storage of Hydrogen in Ru/Li2O Nanocomposites. AB - A "job-sharing" hydrogen storage mechanism is proposed and experimentally investigated in Ru/Li2O nanocomposites in which H(+) is accommodated on the Li2O side, while H(-) or e(-) is stored on the side of Ru. Thermal desorption-mass spectroscopy results show that after loading with D2, Ru/Li2O exhibits an extra desorption peak, which is in contrast to Ru nanoparticles or ball-milled Li2O alone, indicating a synergistic hydrogen storage effect due to the presence of both phases. By varying the ratio of the two phases, it is shown that the effect increases monotonically with the area of the heterojunctions, indicating interface related hydrogen storage. X-ray diffraction, Fourier transform infrared spectroscopy, and nuclear magnetic resonance results show that a weak LiO...D bond is formed after loading in Ru/Li2O nanocomposites with D2. The storage pressure curve seems to favor H(+)/H(-) over H(+)/e(-) mechanism. PMID- 25915435 TI - Homopolar dihydrogen bonding in main group hydrides: discovery, consequences, and applications. AB - This perspective describes the recent discovery and investigation of homopolar dihydrogen bonding, and focuses on the identification and characterisation of hydride-hydride interactions in compounds of the main group elements. A highlight of this programme has been an appreciation of the important role played by this interaction in the structural and thermochemical properties of these materials, and in the mechanisms through which they release hydrogen. A fuller understanding of this new class of H???H interactions has also allowed us to explore their role in the supramolecular chemistry of hydrogen-rich compounds. PMID- 25915436 TI - Radical mediated C-H functionalization of 3,6-dichloropyridazine: efficient access to novel tetrahydropyridopyridazines. AB - A radical mediated C-H functionalization of 3,6-dichloropyridazine using primary alcohols, t-BuOOH, and TiCl3 to access alkoxy pyridazines is described. This transformation is conducted open to air and on gram scale. A subsequent cyclization step can then be employed to efficiently access diversely substituted tetrahydropyridopyridazines with multiple functional handles. PMID- 25915437 TI - Hyperspectral deep ultraviolet autofluorescence of muscle fibers is affected by postmortem changes. AB - After slaughter, muscle cells undergo biochemical and physicochemical changes that may affect their autofluorescence characteristics. The autofluorescent response of different rat extensor digitorum longus (EDL) and soleus muscle fiber types was investigated by deep ultraviolet (UV) synchrotron microspectroscopy immediately after animal sacrifice and after 24 h of storage in a moist chamber at 20 degrees C. The glycogen content decreased from 23 to 18 MUmol/g of fresh muscle in 24 h postmortem. Following a 275 nm excitation wavelength, the spectral muscle fiber autofluorescence response showed discrimination depending upon postmortem time (t0 versus t24 h) on both muscles at 346 and 302 nm and, to a lesser extent, at 408 and 325 nm. Taken individually, all fiber types were discriminated but with variable accuracy, with type IIA showing better separation of t0/t24 h than other fiber types. These results suggest the usefulness of the autofluorescent response of muscle cells for rapid meat-aging characterization. PMID- 25915439 TI - Ligand Binding Thermodynamics in Drug Discovery: Still a Hot Tip? AB - The use of ligand binding thermodynamics has been proposed as a potential success factor to accelerate drug discovery. However, despite the intuitive appeal of optimizing binding enthalpy, a number of factors complicate routine use of thermodynamic data. On a macroscopic level, a range of experimental parameters including temperature and buffer choice significantly influence the observed thermodynamic signatures. On a microscopic level, solute effects, structural flexibility, and cooperativity lead to nonlinear changes in enthalpy. This multifactorial character hides essential enthalpy contributions of intermolecular contacts, making them experimentally nonobservable. In this perspective, we present three case studies, reflect on some key factors affecting thermodynamic signatures, and investigate their relation to the hydrophobic effect, enthalpy entropy compensation, lipophilic ligand efficiency, and promiscuity. The studies highlight that enthalpy and entropy cannot be used as direct end points but can together with calculations increase our understanding of ligand binding and identify interesting outliers that do not behave as expected. PMID- 25915438 TI - Factors linked to transitions in adherence to antiretroviral therapy among HIV infected illicit drug users in a Canadian setting. AB - HIV-positive people who use illicit drugs typically achieve lower levels of adherence to antiretroviral therapy and experience higher rates of sub-optimal HIV/AIDS treatment outcomes. Given the dearth of longitudinal research into ART adherence dynamics, we sought to identify factors associated with transitioning into and out of optimal adherence to ART in a longitudinal study of HIV-infected people who use illicit drugs (PWUD) in a setting of universal no-cost HIV/AIDS treatment. Using data from a prospective cohort of community-recruited HIV positive illicit drug users confidentially linked to comprehensive HIV/AIDS treatment records, we estimated longitudinal factors associated with losing or gaining >=95% adherence in the previous six months using two generalized linear mixed-effects models. Among 703 HIV-infected ART-exposed PWUD, becoming non adherent was associated with periods of homelessness (adjusted odds ratio [AOR] = 2.52, 95% confidence interval [95% CI]: 1.56-4.07), active injection drug use (AOR = 1.25, 95% CI: 1.01-1.56) and incarceration (AOR = 1.54, 95% CI: 1.10 2.17). Periods of sex work (AOR = 0.51, 95% CI: 0.34-0.75) and injection drug use (AOR = 0.62, 95% CI: 0.50-0.77) were barriers to becoming optimally adherent. Methadone maintenance therapy was associated with becoming optimally adherent (AOR = 1.87, 95% CI: 1.50-2.33) and was protective against becoming non-adherent (AOR = 0.52, 95% CI: 0.41-0.65). In conclusion, we identified several behavioural, social and structural factors that shape adherence patterns among PWUD. Our findings highlight the need to consider these contextual factors in interventions that support the effective delivery of ART to this population. PMID- 25915440 TI - Medical implications of understanding the functions of human small heat shock proteins. AB - Small heat shock proteins (sHsps) are ubiquitous molecular chaperones that are implicated in a variety of diseases. Upon stress, they stabilize unfolding proteins and prevent them from aggregating. However, under physiological conditions without severe stress, some sHsps interact with other proteins. In a perspective view, their ability to bind specific client proteins might allow them to fine-tune the availability of the client for other, client-dependent cellular processes. Additionally, some sHsps seem to interact with specific co-chaperones. These co-chaperones are usually part of large protein machineries that are functionally modulated upon sHsps interaction. Finally, secreted human sHsps seem to interact with receptor proteins, potentially as signal molecules transmitting the stress status from one cell to another. This review focuses on the mechanistic description of these different binding modes for human sHsps and how this might help to understand and modulate the function of sHsps in the context of disease. PMID- 25915441 TI - Resistance to Downy Mildew in Lettuce 'La Brillante' is Conferred by Dm50 Gene and Multiple QTL. AB - Many cultivars of lettuce (Lactuca sativa L.) are susceptible to downy mildew, a nearly globally ubiquitous disease caused by Bremia lactucae. We previously determined that Batavia type cultivar 'La Brillante' has a high level of field resistance to the disease in California. Testing of a mapping population developed from a cross between 'Salinas 88' and La Brillante in multiple field and laboratory experiments revealed that at least five loci conferred resistance in La Brillante. The presence of a new dominant resistance gene (designated Dm50) that confers complete resistance to specific isolates was detected in laboratory tests of seedlings inoculated with multiple diverse isolates. Dm50 is located in the major resistance cluster on linkage group 2 that contains at least eight major, dominant Dm genes conferring resistance to downy mildew. However, this Dm gene is ineffective against the isolates of B. lactucae prevalent in the field in California and the Netherlands. A quantitative trait locus (QTL) located at the Dm50 chromosomal region (qDM2.2) was detected, though, when the amount of disease was evaluated a month before plants reached harvest maturity. Four additional QTL for resistance to B. lactucae were identified on linkage groups 4 (qDM4.1 and qDM4.2), 7 (qDM7.1), and 9 (qDM9.2). The largest effect was associated with qDM7.1 (up to 32.9% of the total phenotypic variance) that determined resistance in multiple field experiments. Markers identified in the present study will facilitate introduction of these resistance loci into commercial cultivars of lettuce. PMID- 25915442 TI - Synthesis, characterization, and atropisomerism of iron complexes containing the tetrakis(2-chloro-6-fluorophenyl)porphyrinate ligand. AB - Iron complexes of the meso-(tetraaryl)porphyrin, 5,10,15,20-tetrakis(2-chloro-6 fluorophenyl)porphine (H2ClFTPP) are reported. This unique ligand affords the opportunity to study atropisomerism in a porphyrin system containing similar substituents in the 2 and 6 positions of the meso-aryl rings. The atropisomerism displayed by the iron porphyrinates is observed to be a function of both the oxidation state of the metal and the nature of the axial ligand. In the case of iron(iii) porphyrinates, a single atropisomer is favored, whereas with the iron(ii) porphyrinate a statistical distribution of all possible atropisomers is observed. Variable temperature studies with the iron(ii) porphyrinate demonstrate that the distribution of atropisomers is maintained even at elevated temperatures. The results are discussed in the context of atropisomerism with other meso-(tetraaryl)porphyrins. PMID- 25915443 TI - Cellulose Nanocrystals as Chiral Inducers: Enantioselective Catalysis and Transmission Electron Microscopy 3D Characterization. AB - Cellulose nanocrystals (CNCs), derived from cellulose, provide us with an opportunity to devise more sustainable solutions to current technological challenges. Enantioselective catalysis, especially heterogeneous, is the preferred method for the synthesis of pure chiral molecules in the fine chemical industries. Cellulose has been long sought as a chiral inducer in enantioselective catalysis. We report herein an unprecedentedly high enantiomeric excess (ee) for Pd patches deposited onto CNCs used as catalysts for the hydrogenation of prochiral ketones in water at room temperature and 4 bar H2. Our system, where CNCs acted as support and sole chiral source, achieved an ee of 65% with 100% conversions. Cryo-electron microscopy, high-resolution transmission electron microscopy, and tomography were used for the first time to study the 3D structure of a metal functionalized CNC hybrid. It established the presence of sub-nanometer-thick Pd patches at the surface of CNCs and provided insight into the chiral induction mechanism. PMID- 25915444 TI - Confine Clay in an Alternating Multilayered Structure through Injection Molding: A Simple and Efficient Route to Improve Barrier Performance of Polymeric Materials. AB - Various methods have been devoted to trigger the formation of multilayered structure for wide range of applications. These methods are often complicated with low production efficiency or require complex equipment. Herein, we demonstrate a simple and efficient method for the fabrication of polymeric sheets containing multilayered structure with enhanced barrier property through high speed thin-wall injection molding (HSIM). To achieve this, montmorillonite (MMT) is added into PE first, then blended with PP to fabricate PE-MMT/PP ternary composites. It is demonstrated that alternating multilayer structure could be obtained in the ternary composites because of low interfacial tension and good viscosity match between different polymer components. MMT is selectively dispersed in PE phase with partial exfoliated/partial intercalated microstructure. 2D-WAXD analysis indicates that the clay tactoids in PE-MMT/PP exhibits an uniplanar-axial orientation with their surface parallel to the molded part surface, while the tactoids in binary PE-MMT composites with the same overall MMT contents illustrate less orientation. The enhanced orientation of nanoclay in PE-MMT/PP could be attributed to the confinement of alternating multilayer structure, which prohibits the tumbling and rotation of nanoplatelets. Therefore, the oxygen barrier property of PE-MMT/PP is superior to that of PE-MMT because of increased gas permeation pathway. Comparing with the results obtained for PE based composites in literature, outstanding barrier property performance (45.7% and 58.2% improvement with 1.5 and 2.5 wt % MMT content, respectively) is achieved in current study. Two issues are considered responsible for such improvement: enhanced MMT orientation caused by the confinement in layered structure, and higher local density of MMT in layered structure induced denser assembly. Finally, enhancement in barrier property by confining impermeable filler into alternating multilayer structure through such simple and efficient method could provide a novel route toward high-performance packaging materials and other functional materials require layered structure. PMID- 25915445 TI - The Lifekeeper Memory Quilt: evaluation of a suicide postvention program. AB - The Lifekeeper Memory Quilt Project, implemented by the Salvation Army (Suicide Prevention-Bereavement Support Services) in Australia in 2008, aimed to provide support for those bereaved by suicide and to create greater public awareness of suicide. To evaluate participants' satisfaction with this project, 82 bereaved individuals completed surveys and 30 completed an interview. Results indicated that the Quilt was helpful in assisting participants in their bereavement. The Quilt project gave participants an opportunity to reflect on the life of their loved one and provided a space for them to grieve without fear of negative social reactions. PMID- 25915446 TI - Mechanism of rhein-induced apoptosis in rat primary hepatocytes: beneficial effect of cyclosporine A. AB - Past observational and toxicity studies have established an association between the deaths of children and consumption of Cassia occidentalis (CO) seeds. We recently reported chemical evidence of this association following the identification of toxic anthraquinones (AQs), viz. aloe-emodin, chrysophanol, emodin, physcion, and rhein, in CO seeds (Panigrahi, G. K. et al. (2015), Chem. Res. Toxicol. DOI: 10.1021/acs.chemrestox.5b00056 ). Of these five AQs, earlier studies have shown rhein to be the most cytotoxic AQ in hepatocytes. Therefore, the present study was designed to investigate the effect of rhein on rat primary hepatocytes. Results indicated that rhein (50 MUM) causes apoptosis in rat primary hepatocytes by generating reactive oxygen species (ROS), increasing intracellular Ca(2+), decreasing the mitochondrial membrane potential, and depleting intracellular glutathione content. At the molecular level, rhein induced DNA damage results in overexpression of gamma-H2AX protein (2.5-fold), thereby causing enhancement of p53 (4.5-fold) and p21 (3.6-fold), leading to intrinsic pathway-mediated apoptosis involving Bax, bcl2, cytochrome c, caspases 3 and 9, and poly-ADP ribose polymerase. Further, it was observed that rhein induced ROS generation is also involved in the modulation of signaling molecules like MAPK kinases, including ERK1/2, p38, and JNK, and mitochondrial energetics proteins, including complexes II-V, p-AMPK, and Sirt-1. It was shown that 100 nM cyclosporine A was the most effective among the different protective agents at preventing apoptosis in hepatocytes by interfering in various metabolic pathways which were found to be altered by rhein. PMID- 25915447 TI - New Meroterpenoids from Aspergillus terreus with Inhibition of Cyclooxygenase-2 Expression. AB - Two novel meroterpenoids, yaminterritrems A (1) and B (2), were isolated from Aspergillus terreus collected from hot spring zones in Yang-Ming Mountain, Taiwan, and cultured at 40 degrees C. The structures of 1 and 2 were elucidated by NMR, MS spectral and X-ray crystallographic analyses. The biosynthetic route for 1 and 2 involving the conversion of the sesquiterpene with phenyl-alpha pyrone is proposed. Besides, 2 exhibited a dose-dependent inhibitory effect on COX-2 expression in LPS-stimulated RAW264.7 macrophages. PMID- 25915448 TI - A Penny for Our Thoughts. PMID- 25915449 TI - Potential for microbial oxidation of ferrous iron in basaltic glass. AB - Basaltic glass (BG) is an amorphous ferrous iron [Fe(II)]-containing material present in basaltic rocks, which are abundant on rocky planets such as Earth and Mars. Previous research has suggested that Fe(II) in BG can serve as an energy source for chemolithotrophic microbial metabolism, which has important ramifications for potential past and present microbial life on Mars. However, to date there has been no direct demonstration of microbially catalyzed oxidation of Fe(II) in BG. In this study, three different culture systems were used to investigate the potential for microbial oxidation of Fe(II) in BG, including (1) the chemolithoautotrophic Fe(II)-oxidizing, nitrate-reducing "Straub culture"; (2) the mixotrophic Fe(II)-oxidizing, nitrate-reducing organism Desulfitobacterium frappieri strain G2; and (3) indigenous microorganisms from a streambed Fe seep in Wisconsin. The BG employed consisted of clay and silt-sized particles of freshly quenched lava from the TEB flow in Kilauea, Hawaii. Soluble Fe(II) or chemically reduced NAu-2 smectite (RS) were employed as positive controls to verify Fe(II) oxidation activity in the culture systems. All three systems demonstrated oxidation of soluble Fe(II) and/or structural Fe(II) in RS, whereas no oxidation of Fe(II) in BG material was observed. The inability of the Straub culture to oxidize Fe(II) in BG was particularly surprising, as this culture can oxidize other insoluble Fe(II)-bearing minerals such as biotite, magnetite, and siderite. Although the reason for the resistance of the BG toward enzymatic oxidation remains unknown, it seems possible that the absence of distinct crystal faces or edge sites in the amorphous glass renders the material resistant to such attack. These findings have implications with regard to the idea that Fe(II)-Si-rich phases in basalt rocks could provide a basis for chemolithotrophic microbial life on Mars, specifically in neutral-pH environments where acid-promoted mineral dissolution and utilization of dissolved Fe(II) as an energy source is not likely to take place. PMID- 25915450 TI - Synthesis and preliminary in vivo evaluation of well-dispersed biomimetic nanocrystalline apatites labeled with positron emission tomographic imaging agents. AB - In recent years, biomimetic synthetic apatite nanoparticles (AP-NPs), having chemical similarity with the mineral phase of bone, have attracted a great interest in nanomedicine as potential drug carriers. To evaluate the therapeutic perspectives of AP-NPs through the mechanisms of action and organs they interact with, the noninvasive monitoring of their in vivo behavior is of paramount importance. To this aim, here the feasibility to radiolabel AP-NPs ("naked" and surface-modified with citrate to reduce their aggregation) with two positron emission tomographic (PET) imaging agents ([(18)F]NaF and (68)Ga-NO2AP(BP)) was investigated. [(18)F]NaF was used for the direct incorporation of the radioisotope into the crystal lattice, while the labeling by surface functionalization was accomplished by using (68)Ga-NO2AP(BP) (a new radio-metal chelating agent). The labeling results with both tracers were fast, straightforward, and reproducible. AP-NPs demonstrated excellent ability to bind relevant quantities of both radiotracers and good in vitro stability in clinically relevant media after the labeling. In vivo PET studies in healthy Wistar rats established that the radiolabeled AP-NPs gave significant PET signals and they were stable over the investigated time (90 min) since any tracer desorption was detected. These preliminary in vivo studies furthermore showed a clear ability of citrated versus naked AP-NPs to accumulate in different organs. Interestingly, contrary to naked AP-NPs, citrated ones, which unveiled higher colloidal stability in aqueous suspensions, were able to escape the first physiological filter, i.e., the lungs, being then accumulated in the liver and, to a lesser extent, in the spleen. The results of this work, along with the fact that AP-NPs can be also functionalized with targeting ligands, with therapeutic agents, and also with metals for a combination of different imaging modalities, make AP-NPs very encouraging materials for further investigations as theranostic agents in nanomedicine. PMID- 25915451 TI - Dynamics of the nanoneedle probe in trolling mode AFM. AB - Atomic force microscopy (AFM), as an indispensable tool for nanoscale characterization, presents major drawbacks for operation in a liquid environment arising from the large hydrodynamic drag on the vibrating cantilever. The newly introduced 'Trolling mode' (TR-mode) AFM resolves this complication by using a specialized nanoneedle cantilever that keeps the cantilever outside of the liquid. Herein, a mechanical model with a lumped mass was developed to capture the dynamics of such a cantilever with a nanoneedle tip. This new developed model was applied to investigate the effects of the needle-liquid interface on the performance of the AFM, including the imaging capability in liquid. PMID- 25915452 TI - The Combined Action of ENHANCED DISEASE SUSCEPTIBILITY1, PHYTOALEXIN DEFICIENT4, and SENESCENCE-ASSOCIATED101 Promotes Salicylic Acid-Mediated Defenses to Limit Fusarium graminearum Infection in Arabidopsis thaliana. AB - Fusarium graminearum causes Fusarium head blight (FHB) disease in wheat and other cereals. F. graminearum also causes disease in Arabidopsis thaliana. In both Arabidopsis and wheat, F. graminearum infection is limited by salicylic acid (SA) signaling. Here, we show that, in Arabidopsis, the defense regulator EDS1 (ENHANCED DISEASE SUSCEPTIBILITY1) and its interacting partners, PAD4 (PHYTOALEXIN-DEFICIENT4) and SAG101 (SENESCENCE-ASSOCIATED GENE101), promote SA accumulation to curtail F. graminearum infection. Characterization of plants expressing the PAD4 noninteracting eds1(L262P) indicated that interaction between EDS1 and PAD4 is critical for limiting F. graminearum infection. A conserved serine in the predicted acyl hydrolase catalytic triad of PAD4, which is not required for defense against bacterial and oomycete pathogens, is necessary for limiting F. graminearum infection. These results suggest a molecular configuration of PAD4 in Arabidopsis defense against F. graminearum that is different from its defense contribution against other pathogens. We further show that constitutive expression of Arabidopsis PAD4 can enhance FHB resistance in Arabidopsis and wheat. Taken together with previous studies of wheat and Arabidopsis expressing salicylate hydroxylase or the SA-response regulator NPR1 (NON-EXPRESSER OF PR GENES1), our results show that exploring fundamental processes in a model plant provides important leads to manipulating crops for improved disease resistance. PMID- 25915453 TI - Synergistic Action of a Metalloprotease and a Serine Protease from Fusarium oxysporum f. sp. lycopersici Cleaves Chitin-Binding Tomato Chitinases, Reduces Their Antifungal Activity, and Enhances Fungal Virulence. AB - As part of their defense strategy against fungal pathogens, plants secrete chitinases that degrade chitin, the major structural component of fungal cell walls. Some fungi are not sensitive to plant chitinases because they secrete chitin-binding effector proteins that protect their cell wall against these enzymes. However, it is not known how fungal pathogens that lack chitin-binding effectors overcome this plant defense barrier. Here, we investigated the ability of fungal tomato pathogens to cleave chitin-binding domain (CBD)-containing chitinases and its effect on fungal virulence. Four tomato CBD chitinases were produced in Pichia pastoris and were incubated with secreted proteins isolated from seven fungal tomato pathogens. Of these, Fusarium oxysporum f. sp. lycopersici, Verticillium dahliae, and Botrytis cinerea were able to cleave the extracellular tomato chitinases SlChi1 and SlChi13. Cleavage by F. oxysporum removed the CBD from the N-terminus, shown by mass spectrometry, and significantly reduced the chitinase and antifungal activity of both chitinases. Both secreted metalloprotease FoMep1 and serine protease FoSep1 were responsible for this cleavage. Double deletion mutants of FoMep1 and FoSep1 of F. oxysporum lacked chitinase cleavage activity on SlChi1 and SlChi13 and showed reduced virulence on tomato. These results demonstrate the importance of plant chitinase cleavage in fungal virulence. PMID- 25915454 TI - The Efficacy and Safety of Tamsulosin Combined with Extracorporeal Shockwave Lithotripsy for Urolithiasis: A Systematic Review and Meta-Analysis of Randomized Controlled Trials. AB - BACKGROUND AND PURPOSE: Many studies have been conducted to investigate adjunctive tamsulosin therapy after extracorporeal shockwave lithotripsy (SWL) for urolithiasis. The results from those studies, however, are still inconsistent. Therefore, we performed a meta-analysis to provide an update on the clinical efficacy and safety of tamsulosin combined with SWL for urolithiasis. METHODS: A systematic search was performed in PubMed, Cochrane Library, and Embase to identify all relevant randomized controlled trials until January 2015. Two reviewers independently assessed trial quality and extracted data. Meta analysis was conducted with Review Manager (RevMan), version 5.1. RESULTS: Twenty one studies (2093 subjects in total) were identified in the current meta analysis. Compared with a control group, the experimental group (tamsulosin combined with SWL) showed an increased overall benefit for stone expulsion, with pooled risk ratio (RR) of 1.20 (95% confidence interval [CI], 1.15-1.26). With respect to the different geographic regions, European and American had a high possibility of improvement in stone expulsion (RR: 1.33, 95% CI, 1.19-1.49). According to the stone locations (renal, upper and lower ureteral) and sizes (4 10 mm and 11-24 mm), tamsulosin is more useful for lower ureteral stone (RR: 1.28; 95% CI, 1.14-1.43) and larger sized stones (RR: 1.49; 95% CI, 1.28-1.75). The effect estimates did not vary markedly when stratified by follow-up durations but varied by dose of tamsulosin. Furthermore, a shorter expulsion time, reduced occurrence of steinstrasse, fewer incidences of colic, and lower analgesic requirements were observed within the experimental group. In addition, tamsulosin is well tolerated, and its adverse events rarely led to dropouts of patients. CONCLUSIONS: Overall, evidence suggests that tamsulosin combined with SWL is safe and effective in enhancing stone expulsion for patients with urolithiasis. Furthermore, high-quality, randomized and placebo-controlled trials evaluating the efficacy and safety of tamsulosin should be performed. PMID- 25915455 TI - Bioimpedance spectroscopy for the differential diagnosis of hyponatremia. AB - BACKGROUND: Hyponatremia is classified according to volume status with the help of physical examination, biochemical measures, urine and serum osmolalities, and echocardiography. Bioimpedance spectroscopy (BIS) has been getting popularity for revealing tissue compositions of various patient groups. The aim of this observational study was to investigate the role of BIS for the differential diagnosis of hyponatremia (ClinicalTrials.gov Identifier: NCT01838759). PATIENTS AND METHODS: Personal characteristics of age, sex, weight, height, and blood pressure were recorded. Body composition monitor (BCM) was used for hydration status for each individual. Primary outcome was investigated by the accuracy of volume status measured by BIS. STATISTICS: Kappa statistic (K) is a measure of agreement between two sources, which is measured on a binary scale (i.e., condition present/absent). K statistic can take values between 0 and 1: poor agreement: K < 0.20, fair agreement: 0.2.0-0.3.9, moderate agreement: 0.40-0.59, substantial: 0.60-0.79, very good agreement: 0.80-1.00. RESULTS: Fifty-eight hyponatremia-diagnosed patients, 32 (55.2%) of male with the mean age of 65.2 +/- 11 (40-89) years were included. Kappa statistic (K) were very good (K = 0.925) for male (p < 0.00), substantial agreement (K = 0.601) for female (p < 0.002) with the use of BIS for the differential diagnosis of either hypo or hypervolemia in hyponatremic patients compared with gold standard tests which were the combination of echocardiography, serum, and urine osmolality biochemical tests, and physical examination. CONCLUSION: Bioimpedance spectroscopy is a practical and an inexpensive method. This is the first study in the literature showing the role of BIS for the determination of the volume status and differential diagnosis of hyponatremia when compared with echocardiography. PMID- 25915457 TI - Longitudinal effects of dietary sodium and potassium on blood pressure in adolescent girls. AB - IMPORTANCE: Identification of risk factors early in life for the development of high blood pressure is critical to the prevention of cardiovascular disease. OBJECTIVE: To study prospectively the effect of dietary sodium, potassium, and the potassium to sodium ratio on adolescent blood pressure. DESIGN, SETTING, AND PARTICIPANTS: The National Heart, Lung, and Blood Institute's Growth and Health Study is a prospective cohort study with sites in Richmond, California; Cincinnati, Ohio; and Washington, DC. Participants included 2185 black and white girls initially aged 9 to 10 years with complete data for early-adolescent to midadolescent diet and blood pressure who were followed up for 10 years. The first examination visits were from March 1987 through February 1988 and follow-up continued until February 1999. Longitudinal mixed models and analysis of covariance models were used to assess the effect of dietary sodium, potassium, and the potassium to sodium ratio on systolic and diastolic blood pressures throughout adolescence and after 10 years of follow-up, adjusting for race, height, activity, television/video time, energy intake, and other dietary factors. EXPOSURES: Mean dietary sodium and potassium intakes and the mean potassium to sodium ratio in individuals aged 9 to 17 years. To eliminate potential confounding by energy intake, energy-adjusted sodium and potassium residuals were estimated. MAIN OUTCOMES AND MEASURES: Mean systolic and diastolic blood pressures throughout adolescence and at the end of follow-up (individuals aged 17-21 years). RESULTS: Sodium intakes were classified as less than 2500 mg/d (19.4% of participants), 2500 mg/d to less than 3000 mg/d (29.5%), 3000 mg/d to less than 4000 mg/d (41.4%), and 4000 mg/d or more (9.7%). Potassium intakes ranged from less than 1800 mg/d (36.0% of participants) to 1800 mg/d to less than 2100 mg/d (26.2%), 2100 mg/d to less than 2400 mg/d (18.8%), and 2400 mg/d or more (19.0%). There was no evidence that higher sodium intakes (3000 to <4000 mg/d and >=4000 mg/d vs <2500 mg/d) had an adverse effect on adolescent blood pressure and longitudinal mixed models showed that those consuming 3500 mg/d or more had generally lower diastolic blood pressures compared with individuals consuming less than 2500 mg/d (P = .18). However, higher potassium intakes were inversely associated with blood pressure change throughout adolescence (P < .001 for systolic and diastolic) and at the end of follow-up (P = .02 and P = .05 for systolic and diastolic, respectively). While the potassium to sodium ratio was also inversely associated with systolic blood pressure (P = .04), these effects were generally weaker compared with effects for potassium alone. CONCLUSIONS AND RELEVANCE: In this study of adolescent girls, consumption of 3500 mg/d of sodium or more had no adverse effect on blood pressure. The beneficial effects of dietary potassium on both systolic and diastolic blood pressures suggest that consuming more potassium-rich foods during childhood may help suppress the adolescent increase in blood pressure. PMID- 25915458 TI - Combined robotic-aided gait training and physical therapy improve functional abilities and hip kinematics during gait in children and adolescents with acquired brain injury. AB - PURPOSE: To evaluate the combined effect of robotic-aided gait training (RAGT) and physical therapy (PT) on functional abilities and gait pattern in children and adolescents exiting acquired brain injury (ABI), through functional clinical scales and 3D-Gait Analysis (GA). METHODS: A group of 23 patients with ABI underwent 20 sessions of RAGT in addition to traditional manual PT. All the patients were evaluated before and after the training by using the Gross Motor Function Measures (GMFM) and the Functional Assessment Questionnaire. Ambulant children were also evaluated through the 6 Minutes Walk Test (6MinWT) and GA. Finally, results were compared with those obtained from a control group of ABI children who underwent PT only. RESULTS: After the training, the GMFM showed significant improvement in both dimensions 'D' (standing) and 'E' (walking). In ambulant patients the 6MinWT showed significant improvement after training and GA highlighted a significant increase in cadence, velocity and stride length. Moreover, hip kinematics on the sagittal plane revealed a statistically significant increase in range of motion (ROM) during the whole gait cycle, increased hip extension during terminal stance and increased ROM during the swing phase. CONCLUSIONS: The data suggest that the combined programme RAGT + PT induces improvements in functional activities and gait pattern in children and adolescents with ABI and demonstrated it to be an elective tool for the maintenance of the patients' full compliance throughout the rehabilitative programme. PMID- 25915459 TI - High throughput sequencing reveals distinct microbial populations within the mucosal and luminal niches in healthy individuals. AB - BACKGROUND: The intestinal microbiota is associated with human health and diseases. The luminal microbiota (LM) and the mucosal-associated microbiota (MAM) are 2 distinct ecosystems with different metabolic and immunological functions. AIM: To characterize the intestinal LM and MAM in humans using high throughput sequencing of the 16S rRNA gene. METHODS: Fresh fecal samples and distal colonic mucosal biopsies collected from 24 healthy subjects before (fecal) and during (mucosa) a flexible sigmoidoscopy of an un-prepared bowel. High throughput sequencing of the 16S rRNA gene was used to characterize bacterial communities. Sequences were processed using the QIIME pipeline. RESULTS: LM and MAM populations were significantly different (ANOSIM: R = 0.49, P = 0.001). The LM displayed tighter clustering compared to the MAM (average weighted UniFrac distances 0.27 +/- 0.05 vs. 0.43 +/- 0.09, P < 0.001, respectively), and showed higher diversity (Shannon diversity index: 4.96 +/- 0.37 vs 4.14 +/- 0.56, respectively, P < 0.001). The dominant phyla in the LM and MAM were significantly different: Firmicutes (41.4% vs. 29.1%, FDR < 0.0001, respectively), Bacteroidetes (20.2% vs. 26.3%, FDR < 0.05, respectively), Actinobacteria (22% vs. 12.6%, FDR < 0.0001, respectively) and Proteobacteria (9.3% vs. 19.3%, FDR < 0.0001, respectively). The abundance of 56 genera differed significantly (FDR < 0.1) between the 2 niches. All of the genera in the fecal microbiota were present in the MAM while 10 genera were found to be unique to the MAM. CONCLUSION: The LM and MAM are distinct microbial ecosystems that differ significantly from each other in microbial diversity and composition. These two microbial niches should be investigated independently to better understand the role of the intestinal microbiota in health and disease. PMID- 25915460 TI - Cymbopogon species; ethnopharmacology, phytochemistry and the pharmacological importance. AB - Cymbopogon genus is a member of the family of Gramineae which are herbs known worldwide for their high essential oil content. They are widely distributed across all continents where they are used for various purposes. The commercial and medicinal uses of the various species of Cymbopogon are well documented. Ethnopharmacology evidence shows that they possess a wide array of properties that justifies their use for pest control, in cosmetics and as anti-inflammation agents. These plants may also hold promise as potent anti-tumor and chemopreventive drugs. The chemo-types from this genus have been used as biomarkers for their identification and classification. Pharmacological applications of Cymbopogon citratus are well exploited, though studies show that other species may also useful pharmaceutically. Hence this literature review intends to discuss these species and explore their potential economic importance. PMID- 25915461 TI - Flavonoids from Sideritis Species: Human Monoamine Oxidase (hMAO) Inhibitory Activities, Molecular Docking Studies and Crystal Structure of Xanthomicrol. AB - The inhibitory effects of flavonoids on monoamine oxidases (MAOs) have attracted great interest since alterations in monoaminergic transmission are reported to be related to neurodegenerative diseases such as Parkinson's and Alzheimer's diseases and psychiatric disorders such as depression and anxiety, thus MAOs may be considered as targets for the treatment of these multi-factorial diseases. In the present study, four Sideritis flavonoids, xanthomicrol (1), isoscutellarein 7 O-[6'''-O-acetyl-beta-D-allopyranosyl-(1->2)]-beta-D-glucopyranoside (2), isoscutellarein 7-O-[6'''-O-acetyl-beta-D-allopyranosyl-(1->2)]-6''-O-acetyl-beta D-glucopyranoside (3) and salvigenin (4) were docked computationally into the active site of the human monoamine oxidase isoforms (hMAO-A and hMAO-B) and were also investigated for their hMAO inhibitory potencies using recombinant hMAO isoenzymes. The flavonoids inhibited hMAO-A selectively and reversibly in a competitive mode. Salvigenin (4) was found to be the most potent hMAO-A inhibitor, while xanthomicrol (1) appeared as the most selective hMAO-A inhibitor. The computationally obtained results were in good agreement with the corresponding experimental values. In addition, the x-ray structure of xanthomicrol (1) has been shown. The current work warrants further preclinical studies to assess the potential of xanthomicrol (1) and salvigenin (4) as new selective and reversible hMAO-A inhibitors for the treatment of depression and anxiety. PMID- 25915463 TI - Synthesis and 11C-Radiolabelling of 2-Carboranyl Benzothiazoles. AB - Dicarba-closo-dodecaboranes, commonly known as carboranes, possess unique physico chemical properties and can be used as hydrophobic moieties during the design of new drugs or radiotracers. In this work, we report the synthesis of two analogues of 2-(4-aminophenyl)benzothiazole (a compound that was found to elicit pronounced inhibitory effects against certain breast cancer cell lines in vitro) in which the phenyl ring has been substituted by a m-carborane cage. Two different synthetic strategies have been used. For the preparation of 1-(9-amino-1,7 dicarba-closo-dodecaboran-1-yl)-benzo-thiazole, the benzothiazole group was first introduced on one of the cluster carbon atoms of m-carborane and the amine group was further attached in three steps. For the synthesis of 1-(9-amino-1,7-dicarba closo-dodecaboran-1-yl)-6-hydroxybenzothiazole, iodination was performed before introducing the benzothiazole group, and the amino group was subsequently introduced in six steps. Both compounds were radiolabelled with carbon-11 using [11C]CH3OTf as the labelling agent. Radiolabelling yields and radiochemical purities achieved should enable subsequent in vitro and in vivo investigations. PMID- 25915462 TI - Inhibition of Oncogenic Transcription Factor REL by the Natural Product Derivative Calafianin Monomer 101 Induces Proliferation Arrest and Apoptosis in Human B-Lymphoma Cell Lines. AB - Increased activity of transcription factor NF-kappaB has been implicated in many B-cell lymphomas. We investigated effects of synthetic compound calafianin monomer (CM101) on biochemical and biological properties of NF-kappaB. In human 293 cells, CM101 selectively inhibited DNA binding by overexpressed NF-kappaB subunits REL (human c-Rel) and p65 as compared to NF-kappaB p50, and inhibition of REL and p65 DNA binding by CM101 required a conserved cysteine residue. CM101 also inhibited DNA binding by REL in human B-lymphoma cell lines, and the sensitivity of several B-lymphoma cell lines to CM101-induced proliferation arrest and apoptosis correlated with levels of cellular and nuclear REL. CM101 treatment induced both phosphorylation and decreased expression of anti-apoptotic protein Bcl-XL, a REL target gene product, in sensitive B-lymphoma cell lines. Ectopic expression of Bcl-XL protected SUDHL-2 B-lymphoma cells against CM101 induced apoptosis, and overexpression of a transforming mutant of REL decreased the sensitivity of BJAB B-lymphoma cells to CM101-induced apoptosis. Lipopolysaccharide-induced activation of NF-kappaB signaling upstream components occurred in RAW264.7 macrophages at CM101 concentrations that blocked NF-kappaB DNA binding. Direct inhibitors of REL may be useful for treating B-cell lymphomas in which REL is active, and may inhibit B-lymphoma cell growth at doses that do not affect some immune-related responses in normal cells. PMID- 25915464 TI - Assessing measurement invariance of the Personal Growth Initiative Scale-II among Hispanics, African Americans, and European Americans. AB - This study tested the cross-cultural validity of scores on the Personal Growth Initiative Scale-II (PGIS-II; Robitschek et al., 2012) with Hispanic, African American, and European American community samples. Multigroup confirmatory factor analyses were performed on data from 218 Hispanics, 129 African Americans, and 552 European Americans to examine measurement equivalence among these groups. Measurement invariance of the PGIS-II was established with the original 4 factors of readiness for change, planfulness, using resources, and intentional behavior. These findings suggest the PGIS-II can be administered across these groups and provide meaningful comparisons and interpretations. All samples yielded good internal consistency estimates. The African American sample reported higher means than Hispanic and European American samples for all subscale and total mean scores, and Hispanics scored higher in planfulness, readiness for change, and total score than European Americans, indicating potential cultural factors influencing the scores. Implications for research and clinical practice are discussed. PMID- 25915465 TI - Essentialist beliefs, sexual identity uncertainty, internalized homonegativity and psychological wellbeing in gay men. AB - The present study examined essentialist beliefs about sexual orientation and their implications for sexual identity uncertainty, internalized homonegativity and psychological wellbeing in a sample of gay men. A combination of targeted sampling and snowball strategies were used to recruit 639 gay identifying men for a cross-sectional online survey. Participants completed a questionnaire assessing sexual orientation beliefs, sexual identity uncertainty, internalized homonegativity, and psychological wellbeing outcomes. Structural equation modeling was used to test whether essentialist beliefs were associated with psychological wellbeing indirectly via their effect on sexual identity uncertainty and internalized homonegativity. A unique pattern of direct and indirect effects was observed in which facets of essentialism predicted sexual identity uncertainty, internalized homonegativity and psychological wellbeing. Of note, viewing sexual orientation as immutable/biologically based and as existing in discrete categories, were associated with less sexual identity uncertainty. On the other hand, these beliefs had divergent relationships with internalized homonegativity, with immutability/biological beliefs associated with lower, and discreteness beliefs associated with greater internalized homonegativity. Of interest, although sexual identity uncertainty was associated with poorer psychological wellbeing via its contribution to internalized homophobia, there was no direct relationship between identity uncertainty and psychological wellbeing. Findings indicate that essentializing sexual orientation has mixed implications for sexual identity uncertainty and internalized homonegativity and wellbeing in gay men. Those undertaking educational and clinical interventions with gay men should be aware of the benefits and of caveats of essentialist theories of homosexuality for this population. PMID- 25915466 TI - Working through past wrongdoing: Examination of a self-forgiveness counseling intervention. AB - This pilot study examined the effectiveness of a new emotion-focused individual counseling intervention designed to increase self-forgiveness for regretted actions committed against another person. Exactly 26 adult participants (21 completers) who indicated they had unresolved emotions about a past offense enrolled in the study and were randomly assigned to a delayed or immediate treatment condition. Controlling for screening scores, participants who received the treatment had significantly lower self-condemnation and significantly greater self-forgiveness regarding their offense at the end of treatment than did participants who spent time on a waiting list. Again controlling for screening scores, participants who received the treatment had significantly lower general psychological distress and significantly greater trait self-compassion at the end of treatment than did participants who spent time on a waiting list. All treatment gains were maintained at 2-month follow-up. In addition, increases in state self-forgiveness over the course of the intervention predicted lower levels of general psychological distress follow-up. Results of this study demonstrate the utility of this new intervention for helping clients resolve the negative residual effects of unforgiveness toward the self, both for offense-specific and general well-being outcomes. PMID- 25915467 TI - "What should we talk about?" The association between the information exchanged during the mental health intake and the quality of the working alliance. AB - We investigated the association between the content of the information exchanged between clients and therapists during mental health intake and the quality of the therapeutic alliance. Thirty-eight therapists and 107 clients from four mental health clinics in Israel participated in the study. The content of information discussed was coded directly from the recorded intakes by blinded raters. Clients and therapists completed the Working Alliance Inventory immediately following the intake. Therapists spent the majority of intake time in collecting information about their clients' diagnostic symptoms and personal history and sociocultural background. Due to the high negative correlation between these factors, r(107) = .68, p < .001, we created a measure of delta score with higher scores reflecting more discussion of personal history and sociocultural background and less discussion of diagnostic symptoms. We computed three-level hierarchical linear model analysis, with intakes nested within therapists and therapists nested within sites, to examine the association between the delta score and the working alliance, while controlling for intake duration. Results showed significant association between the delta score and clients' rating of the working alliance (gamma200 = 0.014, p = .02), indicating that discussing more personal history and sociocultural background and less diagnostic symptoms was associated with better clients' rating of the working alliance. Therapists' rating of the working alliance was not significantly associated with the content of the information exchanged. The restricted intake time allocated to therapists dictates use of strategies to deal with time trade-offs to complete a thorough diagnostic assessment while allowing clients to tell their personal story. PMID- 25915468 TI - Correction: No turnover in lens lipids for the entire human lifespan. PMID- 25915470 TI - The asymmetric synthesis of CF3-containing spiro[pyrrolidin-3,2'-oxindole] through the organocatalytic 1,3-dipolar cycloaddition reaction. AB - A new strategy for the construction of optically active 5'-CF3 spiro[pyrrolidin 3,2'-oxindole] was described. A series of unprecedented 1,3-dipoles were obtained by condensation of CF3CH2NH2 with isatins. The 1,3-dipolar cycloaddition reactions of these ketimines with enals gave the products bearing four contiguous stereogenic centers in excellent yields, diastereoselectivities and enantioselectivities. PMID- 25915469 TI - History of Depression and Frontostriatal Connectivity During Reward Processing in Late Adolescent Boys. AB - Given that depression in men is associated with risk for seriously adverse consequences, evaluating how putative neural mechanisms of depression-such as reward-related frontostriatal connectivity-may be altered in late adolescent boys with a history of depression is an important research aim. Adolescents and adults with depression have been demonstrated to show blunted striatal response and heightened medial prefrontal cortex (mPFC) activation to winning reward. Function in reward circuits appears to be best understood as coordination of regions within frontostriatal circuitry, and alterations to this circuitry could occur in those with a history of depression. The current study evaluated functional connectivity between the nucleus accumbens and mPFC in a sample of 166 ethnically diverse boys with and without a history of depression. Participants completed an fMRI monetary reward paradigm at age 20. Lifetime history of depression and other psychiatric illnesses was measured prospectively and longitudinally, using structured clinical interviews at 7 time points from ages 8 to 20. Boys with a history of depression showed heightened positive connectivity between the nucleus accumbens and the mPFC relative to boys with no psychiatric history when winning rewards relative to losing rewards. This altered frontostriatal connectivity pattern was also associated with greater number of depressive episodes in the boys' lifetime. History of depression in late adolescent boys may be associated with altered coordination between the nucleus accumbens and mPFC when winning reward. This coordination could reflect oversignaling of the mPFC to dampen typical ventral striatum response or enhance weak ventral striatum response. PMID- 25915471 TI - Relationships between racial/ethnic minority status, therapeutic alliance, and treatment expectancies among veterans with PTSD. AB - Our objective was to examine the relationships between veterans' racial/ethnic minority status, components of therapeutic alliance (bond, tasks, and goals) with former outpatient providers, and expectancies for Department of Veterans Affairs (VA) posttraumatic stress disorder (PTSD) residential treatment. Veterans (N = 819; 37% minority, 63% White) completed surveys at intake into VA PTSD residential treatment programs. As hypothesized, racial/ethnic minority status was related to weaker overall alliance, therapeutic bond, and goal agreement with former outpatient provider. Alliance with former provider was also associated with expectancies for residential treatment. After controlling for other variables, task agreement (not therapeutic bond) and racial/ethnic minority status were linked to higher expectancies. However, effect sizes were small. Thus, we found little evidence of clinically significant differences by racial/ethnic minority status on expectancies of VA PTSD residential treatment. Future research should investigate these relationships among veterans with PTSD not admitted to VA PTSD residential treatment and in other treatment settings, as well as nonveteran racial/ethnic minorities with PTSD. (PsycINFO Database Record PMID- 25915472 TI - The Membrane Proximal Region of AMPA Receptors in Lateral Amygdala is Essential for Fear Memory Formation. AB - The membrane proximal region (MPR) of AMPA receptor (AMPAR) is needed for receptor trafficking and synaptic plasticity. However, its roles in long-term memory formation are not known. To assess the possible roles of AMPAR-MPR in rat lateral amygdala (LA) in short- and long-term fear memory formation, we used glutamate receptors (GluAs)-MPR competitive peptides MPR(DD) and MPR(AA). The MPR(DD) peptide is derived from GluA1 MPR and was previously shown to impair synaptic plasticity and to inhibit GluA1 containing AMPAR insertion into the synapse in an activity-dependent manner. The MPR(AA) peptide is derived from GluA2/4 MPR, and this receptor fragment was shown to be essential for GluA4 protein interaction needed for its insertion into the neuronal membrane and synapse. The peptides were linked to a TAT peptide (TAT-MPR(DD) and TAT-MPR(AA)) to facilitate internalization into LA cells. Infusion of the TAT-MPR(DD) peptide into LA 30 min before fear conditioning led to a significant impairment of long term fear memory formation. Injection of TAT-MPR(DD) peptide into LA 30 min before fear conditioning impaired short-term fear memory formation. The TAT MPR(DD) peptide had no effect on memory retrieval when injected into LA 30 min before fear memory test. Infusion of the TAT-MPR(AA) peptide into LA 30 min before fear conditioning led to a significant impairment of long-term fear memory formation. In contrast, the TAT-MPR(AA) had no effect on short-term fear memory formation. A TAT-control peptide had no effect on short- or long-term fear memory. These results show that the AMPAR-MPR in LA is needed for fear memory formation and that the MPR region of GluA1 is essential for acquisition of memory, whereas the MPR region of GluA4 is essential for long-term fear memory consolidation. PMID- 25915473 TI - Tet3 regulates synaptic transmission and homeostatic plasticity via DNA oxidation and repair. AB - Contrary to the long-held belief that DNA methylation of terminally differentiated cells is permanent and essentially immutable, post-mitotic neurons exhibit extensive DNA demethylation. The cellular function of active DNA demethylation in neurons, however, remains largely unknown. Tet family proteins oxidize 5-methylcytosine to initiate active DNA demethylation through the base excision repair (BER) pathway. We found that synaptic activity bi-directionally regulates neuronal Tet3 expression. Functionally, knockdown of Tet or inhibition of BER in hippocampal neurons elevated excitatory glutamatergic synaptic transmission, whereas overexpressing Tet3 or Tet1 catalytic domain decreased it. Furthermore, dysregulation of Tet3 signaling prevented homeostatic synaptic plasticity. Mechanistically, Tet3 dictated neuronal surface GluR1 levels. RNA-seq analyses further revealed a pivotal role of Tet3 in regulating gene expression in response to global synaptic activity changes. Thus, Tet3 serves as a synaptic activity sensor to epigenetically regulate fundamental properties and meta plasticity of neurons via active DNA demethylation. PMID- 25915474 TI - Dopaminergic control of autophagic-lysosomal function implicates Lmx1b in Parkinson's disease. AB - The role of developmental transcription factors in maintenance of neuronal properties and in disease remains poorly understood. Lmx1a and Lmx1b are key transcription factors required for the early specification of ventral midbrain dopamine (mDA) neurons. Here we show that conditional ablation of Lmx1a and Lmx1b after mDA neuron specification resulted in abnormalities that show striking resemblance to early cellular abnormalities seen in Parkinson's disease. We found that Lmx1b was required for the normal execution of the autophagic-lysosomal pathway and for the integrity of dopaminergic nerve terminals and long-term mDA neuronal survival. Notably, human LMX1B expression was decreased in mDA neurons in brain tissue affected by Parkinson's disease. Thus, these results reveal a sustained and essential requirement of Lmx1b for the function of midbrain mDA neurons and suggest that its dysfunction is associated with Parkinson's disease pathogenesis. PMID- 25915475 TI - Light-regulated translational control of circadian behavior by eIF4E phosphorylation. AB - The circadian (~24 h) clock is continuously entrained (reset) by ambient light so that endogenous rhythms are synchronized with daily changes in the environment. Light-induced gene expression is thought to be the molecular mechanism underlying clock entrainment. mRNA translation is a key step of gene expression, but the manner in which clock entrainment is controlled at the level of mRNA translation is not well understood. We found that a light- and circadian clock-regulated MAPK/MNK pathway led to phosphorylation of the cap-binding protein eIF4E in the mouse suprachiasmatic nucleus of the hypothalamus, the locus of the master circadian clock in mammals. Phosphorylation of eIF4E specifically promoted translation of Period 1 (Per1) and Period 2 (Per2) mRNAs and increased the abundance of basal and inducible PER proteins, which facilitated circadian clock resetting and precise timekeeping. Together, these results highlight a critical role for light-regulated translational control in the physiology of the circadian clock. PMID- 25915478 TI - Do children requiring long-term warfarin therapy present a bleeding risk during routine immunisation? PMID- 25915477 TI - An acetylcholine-activated microcircuit drives temporal dynamics of cortical activity. AB - Cholinergic modulation of cortex powerfully influences information processing and brain states, causing robust desynchronization of local field potentials and strong decorrelation of responses between neurons. We found that intracortical cholinergic inputs to mouse visual cortex specifically and differentially drive a defined cortical microcircuit: they facilitate somatostatin-expressing (SOM) inhibitory neurons that in turn inhibit parvalbumin-expressing inhibitory neurons and pyramidal neurons. Selective optogenetic inhibition of SOM responses blocked desynchronization and decorrelation, demonstrating that direct cholinergic activation of SOM neurons is necessary for this phenomenon. Optogenetic inhibition of vasoactive intestinal peptide-expressing neurons did not block desynchronization, despite these neurons being activated at high levels of cholinergic drive. Direct optogenetic SOM activation, independent of cholinergic modulation, was sufficient to induce desynchronization. Together, these findings demonstrate a mechanistic basis for temporal structure in cortical populations and the crucial role of neuromodulatory drive in specific inhibitory-excitatory circuits in actively shaping the dynamics of neuronal activity. PMID- 25915476 TI - A neural basis for melanocortin-4 receptor-regulated appetite. AB - Pro-opiomelanocortin (POMC)- and agouti-related peptide (AgRP)-expressing neurons of the arcuate nucleus of the hypothalamus (ARC) are oppositely regulated by caloric depletion and coordinately stimulate and inhibit homeostatic satiety, respectively. This bimodality is principally underscored by the antagonistic actions of these ligands at downstream melanocortin-4 receptors (MC4R) in the paraventricular nucleus of the hypothalamus (PVH). Although this population is critical to energy balance, the underlying neural circuitry remains unknown. Using mice expressing Cre recombinase in MC4R neurons, we demonstrate bidirectional control of feeding following real-time activation and inhibition of PVH(MC4R) neurons and further identify these cells as a functional exponent of ARC(AgRP) neuron-driven hunger. Moreover, we reveal this function to be mediated by a PVH(MC4R)->lateral parabrachial nucleus (LPBN) pathway. Activation of this circuit encodes positive valence, but only in calorically depleted mice. Thus, the satiating and appetitive nature of PVH(MC4R)->LPBN neurons supports the principles of drive reduction and highlights this circuit as a promising target for antiobesity drug development. PMID- 25915479 TI - Association Between Opioid Use and Atrial Fibrillation: The Reasons for Geographic and Racial Differences in Stroke (REGARDS) Study. PMID- 25915480 TI - Association between the dopamine transporter gene (DAT1) and attention deficit hyperactivity disorder-related traits in healthy adults. AB - BACKGROUND: The dopamine transporter gene (DAT1) is an established genetic risk factor for attention deficit hyperactivity disorder (ADHD). Therefore, we hypothesized that DAT1 may also influence the manifestation of ADHD-related traits in the normal population. METHODS: A quantitative association study was carried out on 1289 healthy adults. ADHD-related traits were measured using the 25-item Wender Utah Rating Scale (WURS-25). This scale is a self-administered instrument intended to retrospectively measure features of childhood ADHD. Previous studies typically identified three component factors: (i) impulsivity, (ii) inattention, and (iii) mood instability. Our group found that these factors were associated with various diagnoses, such as bipolar disorder and major depression. Six polymorphic markers within the DAT1 gene (rs27072, rs11133767, rs429699, rs27048, rs2937639), including the 3'-untranslated region variable number of tandem repeats, were used as genetic markers. RESULTS: The WURS-25 total score was not associated with any of the markers that we examined. However, the mood instability trait was associated significantly with rs2937639 in male participants (P=0.008); this result was supported by several haplotype-wise findings among the surrounding markers (P=0.00001-0.004). CONCLUSION: Our study results suggest that DAT1 polymorphisms may modulate mood instability traits in the normal population. Considering that mood instability tends to persist through the entire course of ADHD and is highly prevalent in many diseases that are comorbid with ADHD, this trait may be a core endophenotype that defines the role of the DAT1 gene in various psychiatric conditions. PMID- 25915481 TI - Comprehensive study of methylation on the silicon (100)-2 * 1 surface: a density functional approach. AB - A detailed mechanistic investigation of Si-Me formation over the silicon (100)-2 * 1 surface using the Si9H12 cluster model has been performed using various reagents, based on two basic mechanisms: dissociation and substitution. The reagents CH4, CH3Cl for dissociation and CH3Li, CH3MgBr for substitution mechanism are used to explore the methylation process on the silicon surface at the M062X/6-311+G(2d, p) level of theory. The associated potential energy surfaces explored here are aimed to unveil the most favored pathway of methylation with appropriate reagents. Dissociation of methane forms a monomethylated product (D1) through an energetically unfavorable pathway. All the adsorption modes of CH3Cl over the silicon surface are also detected and analyzed. Methyl chloride dissociates to form another monomethylated product D2 and its derivative D3 in the entrance channel, while, in the next step, bridged compounds I1 (Cl-bridged) and I2 (H-bridged) are produced from them, respectively. The C-Cl dissociation leads to the formation of D2 having a lower activation barrier. With a comparably high activation barrier in the C-H dissociation, producing D3, very interestingly carbene intermediate has been detected in the reaction pathway. Detection of energetically unfavored conversions from D2 to I1 and D3 to I2 ensured that the methylation process will not be hampered through these interconversions. For substitution, HCl- and Cl2 passivated Si surfaces are taken, where chlorine is to be substituted by the methyl group of both of the methylating agents. With both substituents, HCl passivated Si9H12 gives D1. The substitution process on Cl2-passivated Si9H12 leads to the formation of D2 in the first step and dimethylated product (S1) in the final step. In all the above substitution processes, methyl lithium proved to be the better substituent for the formations of D1, D2, and S1 on HCl- or Cl2 passivated surfaces. The present work not only demonstrated methyl lithium as one of the best methylating agents but also revealed the interrelation among the dissociative adsorption modes of CH3Cl, reported earlier, in a single potential energy surface with a remarkable detection of carbene intermediate formed in the pathway of C-H dissociation. PMID- 25915483 TI - Emerging molecular targets for treatment of erectile dysfunction: vascular and regenerative therapies on the horizon. AB - INTRODUCTION: Erectile dysfunction (ED) has reached epidemic proportions not expected to abate because of population aging and chronic diseases that accompany advanced age. Vasculopathy is a main cause, but damage to penile innervation also underlies many cases of ED. Phosphodiesterase inhibitor therapies do not help all men with ED, making the search for novel therapeutic drug and treatment targets of utmost importance. AIMS: To review the literature to identify potential new treatment targets to fill a gap in therapeutic options for men with ED, with a focus on treatments for vasculogenic ED, but including novel treatment targets for ED due to penile nerve damage, a frequent consequence of pelvic surgery in men. METHODS: The recent literature was searched for publications on in vitro, in vivo, pre-clinical and observational human studies, when available, that would identify potential new targets for ED therapies not previously, or not extensively reviewed. RESULTS: Literature searches identified microparticles, myeloperoxidase, and heme oxygenase-1 as emerging molecular targets to treat vasculogenic ED. Novel regenerative therapy targets, including sonic hedgehog, galanin, and cell-based treatments were also reviewed as potential future treatments for ED due to damage to penile innervation. CONCLUSION: Novel molecular targets and cell-based therapies offer great hope for advances in ED treatment. Concerns regarding efficacy, toxicity, off target effects, safety, and convenience apply to these targets; much work remains to confirm these as viable targets to pursue for effective ED treatments. To complement targets discussed in this review relevant review papers were cited for the interested reader. To complement targets discussed in this review relevant review papers were cited for the interested reader. PMID- 25915482 TI - Therapeutic Targets in Polycystic Liver Disease. AB - Polycystic liver diseases (PLD) are a group of genetic disorders initiated by mutations in several PLD-related genes and characterized by the presence of multiple cholangiocyte-derived hepatic cysts that progressively replace liver tissue. PLD co-exists with Autosomal Dominant Polycystic Kidney Disease (ADPKD) and Autosomal Recessive PKD as well as occurs alone (i.e., Autosomal Dominant Polycystic Liver Disease [ADPLD]). PLD associated with ADPKD and ARPKD belong to a group of disorders known as cholangiociliopathies since many disease-causative and disease-related proteins are expressed in primary cilia of cholangiocytes. Aberrant expression of these proteins in primary cilia affects their structures and functions promoting cystogenesis. Current medical therapies for PLD include symptomatic management and surgical interventions. To date, the only available drug treatment for PLD patients that halt disease progression and improve quality of life are somatostatin analogs. However, the modest clinical benefits, need for long-term maintenance therapy, and the high cost of treatment justify the necessity for more effective treatment options. Substantial evidence suggests that experimental manipulations with components of the signaling pathways that influence cyst development (e.g., cAMP, intracellular calcium, receptor tyrosine kinase, transient receptor potential cation channel subfamily V member 4 (TRPV4) channel, mechanistic target of rapamycin (mTOR), histone deacetylase (HDAC6), Cdc25A phosphatase, miRNAs and metalloproteinases) attenuate growth of hepatic cysts. Many of these targets have been evaluated in pre-clinical trials suggesting their value as potential new therapies. This review outlines the current clinical and preclinical treatment strategies for PLD. PMID- 25915484 TI - Antioxidant Mechanisms in Nonalcoholic Fatty Liver Disease. AB - Nonalcoholic fatty liver disease (NAFLD) represents a broad spectrum of histological abnormalities with clinical presentations ranging from hepatic steatosis to nonalcoholic steatohepatitis (NASH). Some NAFLD patients may progress to cirrhosis and ultimately hepatocellular carcinoma (HCC). Hepatic steatosis, the hallmark of NAFLD, is defined by the accumulation of triglycerides (TGs) in more than 5% of the hepatocytes. NASH is characterized by inflammation along with variable degrees of fibrosis in addition to steatosis. NAFLD has been considered to be the hepatic manifestation of metabolic syndrome (MS), as it is frequently associated with MS conditions such as insulin resistance (IR) and obesity. Hepatic steatosis mainly results from disrupted homeostasis of lipid metabolism in the setting of IR. Although the mechanism underlying the progression from steatosis to NASH is still not fully elucidated, mounting evidence has suggested oxidative stress (OS) to be a key driving force. Elevated OS has been well documented in NAFLD patients. OS can cause direct damages to lipid, protein, and DNA molecules and trigger the inflammatory and fibrogenesis signaling pathways, which promotes the progression from steatosis to NASH. OS may also have various effects on antioxidant defense mechanisms. Overproduced reactive oxygen species (ROS) may directly deplete antioxidant molecules such as glutathione (GSH) and inhibit the activities of antioxidant enzymes such as superoxide dismutase (SOD). ROS may also induce the expression of antioxidant genes to counteract the OS effects. The aim of this review is to discuss oxidative stress and antioxidant mechanisms in NAFLD. PMID- 25915485 TI - New Advances in the Molecular Mechanisms Driving Biliary Fibrosis and Emerging Molecular Targets. AB - Persistent exposure of biliary epithelial cells (i.e., cholangiocytes) to diverse factors such as disordered immunity, genetic alterations, ischemia, toxic compounds and/or infectious agents leads to a chronic portal inflammatory response which eventually progresses to biliary fibrosis. This stage is characterized by increased production and deposition of scar-forming extracellular matrix proteins (ECM), in particular fibrillar collagen types I and III, but including other ECM constituents such as elastin and fibrillin-1, both components of elastic fibers. The major cellular mediators responsible for collagen deposition are activated hepatic stellate cells (HSCs) and to a lesser extent, portal myofibroblasts, which are activated by soluble inflammatory mediators (i.e., cytokines, growth factors) and extracellular matrix components. Unless the underlying cause of biliary injury can be effectively treated, these processes may ultimately lead to decompensated cirrhosis and can also provide ideal microenvironments for the development and growth of primary tumors. Recent evidence indicates that fibrosis is a dynamic and potentially reversible process. As the curative options for most chronic biliary diseases remain limited to transplantation, there is an urgent need to clarify the molecular pathways involved in the development of biliary fibrosis and identify new therapeutic targets. In this review we describe the cellular and molecular regulators that orchestrate the cholangiocyte /myofibroblast cross-talk and identify the signaling processes that are most promising for therapeutic targeting. PMID- 25915486 TI - Nanoparticles-Based Treatment for Bone Metastasis. AB - Bone is the principal site of metastasis for many carcinomas, including prostate. Once bone metastases are established, the chances of survival dramatically drop. Bone metastases place patients at increased risk of skeletal-related events, including pathologic fractures, bone pain and hypercalcemia. Indeed, skeletal metastases represent the prevalent cause of morbidity and mortality for many tumors. They are the result of interactions among tumour cells, bone marrow environment and bone cells (vicious cycle). In the last few years many efforts were undertaken to identify new therapeutic approaches for bone metastasis. Current therapies target the several players of bone vicious cycle. However many adverse effects are associated with these treatments. This review will focus on the new emerging sector of nanomedicine, that could be important to identify more specific and safe treatments for bone metastasis. PMID- 25915487 TI - Functional Genomics of Cardioprotection by Ischemic Conditioning and the Influence of Comorbid Conditions: Implications in Target Identification. AB - Ischemic heart disease including myocardial infarction develops on the basis of several risk-factors and comorbidities such as obesity, diabetes, hypertension, and hypercholesterolemia. Ischemic heart disease is the leading cause of mortality worldwide, therefore, identification of novel drug targets for cardioprotection is of great importance. Ischemic preconditioning, postconditioning, and remote conditioning trigger endogenous cardioprotective mechanisms that render the heart more resistant to lethal ischemic-reperfusion injury. However, major cardiovascular co-morbidities such as hyperlipidemia, diabetes, and their co-medications interfere with these cardioprotective mechanisms thereby limiting the efficacy of cardioprotective ischemic conditioning maneuvers. Ischemia reperfusion injury and cardioprotection by conditioning have been shown to affect global myocardial gene expression profile at the transcript level. Further understanding and the comprehensive analysis of the cardioprotective gene expression fingerprint in normal, protected, and in comorbid conditions may lead to identification of novel molecular targets for cardioprotection. PMID- 25915488 TI - Caloric restriction decreases orthostatic tolerance independently from 6 degrees head-down bedrest. AB - Astronauts consume fewer calories during spaceflight and return to earth with an increased risk of orthostatic intolerance. Whether a caloric deficiency modifies orthostatic responses is not understood. Thus, we determined the effects of a hypocaloric diet (25% caloric restriction) during 6 degrees head down bedrest (an analog of spaceflight) on autonomic neural control during lower body negative pressure (LBNP). Nine healthy young men completed a randomized crossover bedrest study, consisting of four (2 weeks each) interventions (normocaloric bedrest, normocaloric ambulatory, hypocaloric bedrest, hypocaloric ambulatory), each separated by 5 months. Muscle sympathetic nerve activity (MSNA) was recorded at baseline following normocaloric and hypocaloric interventions. Heart rate (HR) and arterial pressure were recorded before, during, and after 3 consecutive stages (7 min each) of LBNP (-15, -30, -45 mmHg). Caloric and posture effects during LBNP were compared using two-way ANOVA with repeated measures. There was a strong trend toward reduced basal MSNA following caloric restriction alone (normcaloric vs. hypocaloric: 22+/-3 vs. 14+/-4 burst/min, p = 0.06). Compared to the normocaloric ambulatory, both bedrest and caloric restriction were associated with lower systolic blood pressure during LBNP (p<0.01); however, HR responses were directionally opposite (i.e., increase with bedrest, decrease with caloric restriction). Survival analysis revealed a significant reduction in orthostatic tolerance following caloric restriction (normocaloric finishers: 12/16; hypocaloric finishers: 6/16; chi2, p = 0.03). Caloric restriction modifies autonomic responses to LBNP, which may decrease orthostatic tolerance after spaceflight. PMID- 25915489 TI - The role of hydrodynamic processes on anchovy eggs and larvae distribution in the sicily channel (mediterranean sea): a case study for the 2004 data set. AB - Knowledge of the link between ocean hydrodynamics and distribution of small pelagic fish species is fundamental for the sustainable management of fishery resources. Both commercial and scientific communities are indeed seeking to provide services that could "connect the dots" among in situ and remote observations, numerical ocean modelling, and fisheries. In the Mediterranean Sea and, in particular, in the Sicily Channel the reproductive strategy of the European Anchovy (Engraulis encrasicolus) is strongly influenced by the oceanographic patterns, which are often visible in sea surface temperature satellite data. Based on these experimental evidences, we propose here a more general approach where the role of ocean currents, wind effects, and mesoscale activity are tied together. To investigate how these features affect anchovy larvae distribution, we pair ichthyoplankton observations to a wide remote sensing data set, and to Lagrangian numerical simulations for larval transport. Our analysis shows that while the wind-induced coastal current is able to transport anchovy larvae from spawning areas to the recruiting area off the Sicilian south-eastern tip, significant cross-shore transport due to the combination of strong northwesterly mistral winds and topographic effects delivers larvae away from the coastal conveyor belt. We then use a potential vorticity approach to describe the occurrence of larvae cross-shore transport. We conclude that monitoring and quantifying the upwelling on the southern Sicilian coast during the spawning season allows to estimate the cross-shore transport of larvae and the consequent decrease of individuals within the recruiting area. PMID- 25915490 TI - Pectin-lipid self-assembly: influence on the formation of polyhydroxy fatty acids nanoparticles. AB - Nanoparticles, named cutinsomes, have been prepared from aleuritic (9,10,16 trihidroxipalmitic) acid and tomato fruit cutin monomers (a mixture of mainly 9(10),16-dihydroxypalmitic acid (85%, w/w) and 16-hydroxyhexadecanoic acid (7.5%, w/w)) with pectin in aqueous solution. The process of formation of the nanoparticles of aleuritic acid plus pectin has been monitored by UV-Vis spectrophotometry, while their chemical and morphological characterization was analyzed by ATR-FTIR, TEM, and non-contact AFM. The structure of these nanoparticles can be described as a lipid core with a pectin shell. Pectin facilitated the formation of nanoparticles, by inducing their aggregation in branched chains and favoring the condensation between lipid monomers. Also, pectin determined the self-assembly of cutinsomes on highly ordered pyrolytic graphite (HOPG) surfaces, causing their opening and forming interconnected structures. In the case of cutin monomers, the nanoparticles are fused, and the condensation of the hydroxy fatty acids is strongly affected by the presence of the polysaccharide. The interaction of pectin with polyhydroxylated fatty acids could be related to an initial step in the formation of the plant biopolyester cutin. PMID- 25915491 TI - Interventional Laser-assisted Extraction of an Infected Trapped Ventriculoatrial Shunt Based on Techniques for Pacemaker Lead Explantation. AB - We present a case of successful interventional laser-assisted extraction of an endovascularly trapped long-term implanted ventriculoatrial shunt in a patient with shunt-associated septicemia. This approach is based on modified techniques for explantation of pacemaker leads and might be considered an additional option for extraction of otherwise nonremovable trapped endovascular catheters in experienced centers. PMID- 25915492 TI - Delayed Recovery of Visual Acuity after Sphenoorbital Meningioma Surgical Removal: Case Report and Review of the Literature. Is Visual Acuity Recovery Possible after an Initial Decline? AB - BACKGROUND AND STUDY AIMS: To report a case of late recovery of visual acuity after surgical removal of a sphenoorbital meningioma (SOM). MATERIALS AND METHODS: A 42-year-old woman was referred for progressive proptosis of the right eye for 5 years. Her best-corrected visual acuity (BCVA) was 10/10 in her right eye and 10/10 in her left eye, and thyroid function tests were negative. Ophthalmic examination showed slight exophthalmos of her right eye, but eye movements and pupillary light reflexes were normal. Intraocular pressure and fundus examination (FE) in both eyes were normal. Computed tomography scan of the orbits showed hyperostosis and an increase in the thickness of the lateral wall of the orbit, volume reduction of the right orbit, the optic canal, and the sphenoidal fissure, edema, and medial displacement of the lateral rectus muscle. We performed coronal orbitotomy and removed the tumor via a frontotemporal orbitozygomatic approach and lateral orbitotomy. RESULTS: Three hours postoperatively, her right eye was blind with signs of orbital apex syndrome. A high dose of intravenous corticosteroid was then administered. Twenty-four hours postoperatively, BCVA of right eye was motu manu (hand motion), and pupillary light reflexes in the right eye were absent. Five days postoperatively, BCVA allowed counting fingers at 5 m, and ocular motility was partially recovered. Fifteen days postoperatively, BCVA was 1/15, and eye movements were totally recovered. Eight months postoperatively, BCVA was 3/10, pupillary light reflexes were still absent, and FE in the right eye showed a slightly pale temporal half of the optic disc. Twenty months postoperatively, BCVA in the right eye was 7/10. CONCLUSIONS: Late recovery of visual acuity after sphenoorbital meningioma removal may be possible despite an initial decline. PMID- 25915493 TI - First Report of Recurrent Intramuscular Lipoma after Decompression Surgery of the Lumbar Spine. AB - Intramuscular or infiltrating lipomas are rare. We present a 58-year-old man with an intramuscular lipoma developing after decompression surgery for lumbar spinal canal stenosis. One year after macroscopically complete lipoma resection, an even bigger recurrent tumor had to be removed. The lumbar paraspinal musculature is a very uncommon site for an intramuscular lipoma. A relation between surgery and the growth and recurrence of an intramuscular lipoma has not been described previously in the literature. PMID- 25915494 TI - De Novo Aneurysm Formation at the Anastomosis Site Incidentally Detected 2 Years after Single-Barrel STA-MCA Bypass Surgery: Case Report and Review of the Literature. AB - This case report describes the de novo aneurysm formation at the anastomosis site 2 years after single-barrel superficial temporal artery to middle cerebral artery bypass surgery. Correct bypass patency and morphology of the anastomosis site was documented intraoperatively and immediately postoperatively by indocyanine green videoangiography and digital subtraction angiography (DSA). Aneurysmatic dilatation at the anastomosis site was observed 2 years postoperatively upon computed tomography angiographic follow-up examination. After repeat DSA, the patient underwent microsurgical reexploration and clip ligation of the aneurysmatic portion of the donor artery. The possible underlying mechanisms are discussed and the current literature is reviewed. PMID- 25915495 TI - Curative Reconstruction of Giant Fusiform Intracranial Aneurysms with Flow Diverter and Self-expanding Stents. AB - OBJECTIVE AND IMPORTANCE: To demonstrate the curative reconstruction of two giant fusiform aneurysms using a combination of flow-diverter stents and self-expanding stents for intracranial use. CLINICAL PRESENTATION: Two cases that would have been difficult to manage with standard methods: one patient with deficiencies of cranial nerves VI and VII on the left, acute diplopia, and an aneurysm of the vertebrobasilar bifurcation, the other with diplopia, deficiencies of cranial nerves III and VI, and an aneurysm of the intracavernous internal carotid artery. INTERVENTION OR TECHNIQUE: Complete reconstruction was achieved using a combination of flow-diverter and self-expandable stents. Follow-up investigations at 6 months demonstrated the complete reconstruction of the arteries and angiographically determined disappearance of the aneurysms with resolution of the clinical profile. The patients' outcome was excellent (modified Rankin Scale: 0). CONCLUSION: This technique enables safe and definitive treatment of lesions that would be difficult to manage with other methods. The greater metal surface does not seem to interfere with the perforating arteries originating from the segments involved. PMID- 25915496 TI - The Fate of Type II Odontoid Fractures after Posterior Atlantoaxial Fusion: Where Does Healing Occur? AB - BACKGROUND: Anderson and D'Alonzo type II odontoid fractures often require surgical intervention. Our goal was to understand the pattern of healing in patients who had a posterior atlantoaxial fusion for a type II odontoid fracture. METHODS: We conducted a retrospective study of patients who underwent posterior atlantoaxial instrumentation and fusion for a type II odontoid fracture at our institution between 1987 and 2011. Patients who had fusion evaluation by computed tomography (CT) scan >=3 months after surgery were included. Surgical technique included placement of a posterior bone graft with transarticular screws, C1 lateral mass and C2 pars/pedicle screw construct, or a combination of screw fixation techniques. Postoperative CT scans were reviewed to determine the site where fusion occurred. RESULTS: Sixty-four patients underwent posterior atlantoaxial instrumentation and fusion for type II odontoid fractures, 12 of whom had fusion evaluation by CT scan. A total of 11 of 12 patients had fusion across the fracture site, 2 across the C1-C2 joint, and 11 at the posterior graft site. All 12 patients had at least one site of fusion. CONCLUSIONS: There is a high rate of fusion across the fracture site of a type II odontoid fracture after posterior atlantoaxial fixation. In young patients with acute type II fractures who are not candidates for anterior screw fixation, posterior atlantoaxial instrumentation without fusion may be sufficient for fracture healing, thus allowing for the possibility of implant removal and preservation of C1-C2 motion. PMID- 25915497 TI - The Effects of Electrocautery on Peripheral Nerve: An Experimental Study. AB - BACKGROUND The aim of this study was to assess the usability of an electrocautery device as nerve stimulator and to investigate histopathologically the adverse effects of electrocautery at low power on rat sciatic nerves. METHODS A total of 36 female Sprague-Dawley albino rats were divided into six groups according to the power applied to their sciatic nerves (1, 2, 3, 4, 5 and 6 W, respectively). Pathologic changes were studied by microscopic examination and scored (no change = 0, mild = 1, moderate = 2, severe = 3). Multiple comparisons were provided for all groups by the Bonferroni test (one-way analysis of variance). A p value < 0.05 was accepted as statistically significant. RESULTS The average scores were 2.66 +/- 0.51, 3.66 +/- 0.51, 5.83 +/- 1.83, 10.0 +/- 1.78, 11.0 +/- 1.54, and 13.8 +/- 0.89 in groups 1 to 6, respectively. Significant differences were found between all groups (p < 0.01), except between groups 1 and 2, groups 2 and 3, and groups 4 and 5 (p > 0.05) Variable motor responses and foot deformities were observed at the different power levels. CONCLUSION Although electrocautery devices provoke motor responses if getting in contact with peripheral nerves as do nerve stimulators, their use induces histopathologically adverse effects even at the lowest power. Their use around peripheral nerves should be avoided. PMID- 25915498 TI - Percutaneous Pedicle Screw Accuracy with Dynamic Electromyography: The Early Experience of a Traditionally Open Spine Surgeon. AB - BACKGROUND AND STUDY AIMS: The learning curve associated with the adoption of minimally invasive surgery techniques has limited its adoption by many traditionally open surgeons. The use of dynamic electromyography (EMG) to guide the placement of percutaneous pedicle screws (PS) can lessen the learning curve by providing real-time feedback on neural proximity relative to the screw. This study aimed to investigate the safety and accuracy of a single surgeon's experience transitioning from open pedicle screws (OS) to PS using intraoperative fluoroscopy and dynamic EMG. MATERIALS AND METHODS: Forty consecutive patients were treated with EMG and fluoroscopy-guided PS placement by a single surgeon and followed through a prospective registry. This was cross-referenced with a cohort of 53 consecutive patients treated with OS in 2011. Computed tomography was used to check the screw position 1 day after surgery. A misplaced pedicle screw was defined as a breach of the pedicle wall. The accuracy of PS placement in association with dynamic EMG was compared with that of OS. RESULTS: A total of 204 PS were inserted in the study cohort with 97.5% accuracy. Five (2.5%) were misplaced (three medial and two lateral). All three medial screws displayed a caution message (yellow: 8mA) on insertion. No screw caused visceral or neurologic complications postoperatively, and none required revision. In the OS cohort, 254 screws were placed with 94.9% accuracy, 13 (5.1%) were misplaced (8 medial, 3 lateral, and 2 superior), and 3 (1.2%) required revision. CONCLUSIONS: Dynamic EMG combined with intraoperative fluoroscopy and advanced instrumentation provides a safe, real-time, and accurate method for PS placement. PMID- 25915499 TI - Comparative Analysis of Inpatient and Outpatient Interspinous Process Device Placement for Lumbar Spinal Stenosis. AB - PURPOSE: To compare reoperations, health care utilization, and costs in lumbar spinal stenosis (LSS) patients undergoing interspinous process (ISP) device placement in an inpatient versus outpatient setting. METHODS: The MarketScan database (2007-2009) was queried for adults with LSS undergoing ISP device placement as a primary procedure. Reoperations, health care utilization, and costs in patients with at least 18 months of follow-up were analyzed. Chi-square and Student t tests were used to assess the differences in characteristics and outcomes between patients treated in the inpatient and outpatient setting. RESULTS: A total of 411 patients who underwent ISP device placement were identified; the mean age was 72 years, 51% were female, and most patients were insured by Medicare (73.7%). The average postoperative follow-up was 24.9 months. A subset of 182 patients (44.3%) had inpatient procedures; 229 (55.7%) underwent outpatient ISP device placements. The overall reoperation rate was 20.4%. ISP reoperation rates between inpatient and outpatient cohorts were comparable (23.1% versus 18.3%; p = 0.24). Inpatients accrued significantly higher index procedural costs compared with outpatients ($17,432 versus $8854; p = 0.0001), however, the outpatient cohort utilized more postoperative outpatient services (143 versus 112; p = 0.09) and higher outpatient service costs ($25,376 versus $15,481; p = 0.01). Consequently, cumulative overall cost was similar among the two cohorts ($51,059 versus $51,778; p = 0.94). CONCLUSIONS: Long-term reoperation rates following ISP device placement are comparable in the inpatient and outpatient setting. Upfront cost savings may be achieved with outpatient ISP device placement, but this benefit is lost by 18 months following initial surgery. PMID- 25915500 TI - Feasibility of the EORTC/NCIC Trial Protocol in a Neurosurgical Outpatient Unit: The Case for Neurosurgical Neuro-Oncology. AB - OBJECTIVE: With the publication of the European Organization for Research and Treatment of Cancer/National Cancer Information Center (EORTC/NCIC) trial, concomitant radiochemotherapy followed by intermittent chemotherapy became the new treatment standard for patients with primary glioblastoma. Eight years after widespread introduction of this protocol, it is of interest to investigate whether this new standard has been established in daily neuro-oncologic practice. We were particularly interested in its practicality within a neurosurgical neuro oncologic setting. PATIENTS AND METHODS: We analyzed primary glioblastoma patients diagnosed between 2005 and 2013 treated at our center according to the EORTC/NCIC trial. Parameters associated with treatment performance (interruption of radiotherapy, concomitant chemotherapy and intermittent chemotherapy, total number of cycles, and side effects) were retrospectively analyzed and compared with the available data from the EORTC/NCIC trial. RESULTS: In this single-center retrospective study, we identified 189 patients (116 men, 73 women; median age: 62 years) who were treated according to the EORTC/NCIC trial protocol. A total of 176 patients received cytoreductive surgery; 13 patients had stereotactic biopsy only (EORTC/NCIC trial: 239 patients and 48 patients, respectively). Radiotherapy had to be interrupted in 9 patients (5%) (EORTC/NCIC trial: 15 patients [5%]) and concomitant chemotherapy in 26 patients (14%) (EORTC/NCIC trial: 37 patients [13%]). In 156 patients (83%), adjuvant TMZ chemotherapy was initiated (6 median temozolomide [TMZ] cycles; range: 1-30). In the EORTC/NCIC trial, 223 patients (47%) received the intermittent chemotherapy protocol (median: 3 cycles; range: 1 7). Overall, 97 patients (62%) completed 6 TMZ cycles (EORTC/NCIC-trial: 105 patients [47%]); dose escalation to 200 mg/qm at the second cycle was performed in 91 patients (58%) (versus 149 patients [67%]). Intermittent TMZ therapy was discontinued in 59 patients (38%) (versus 118 patients [53%]). Median overall survival in our patient cohort was 19 months (versus 14.6 months); median time to progression was 9 months (versus 6.9 months). CONCLUSION: Comparison between the feasibility of the treatment protocol established by the EORTC/NCIC trial (performed within the setting of a prospective randomized trial) and the daily routine in a dedicated neurosurgical neuro-oncologic department demonstrates that the protocol is suitable for daily practice within a neurosurgical unit. PMID- 25915501 TI - Microneurosurgical Skills Training. AB - Microneurosurgical operations differ from other surgery. Longer operative time, narrow and deep-seated operative corridors, hand-eye coordination, fine manipulation, and physiologic tremor present special problems. Proper understanding of visual feedback, control of physiologic tremor, better instrument design, and development of surgical skills with better precision is important for optimal surgical results. Using the pen-type precision grip with well-supported arm, wrist, hand, and fingers avoids fatigue and improves precision. Proper instrument design, patient positioning, hemostasis techniques, tilting operative table, good operative microscope, an adjustable chair, careful use of suction tube, bipolar forceps, and brain retraction play important roles in microneurosurgery. Sufficient clinical case volume or opportunity during routine operative hours may not be available in the beginning for young neurosurgeons; microsurgical training using various models can enable them to gain experience. Training models using deep-seated and narrow operative corridors, drilling, knot-tying technique, and anastomosis using fine sutures under high magnification can be practiced for skill improvement. Training laboratory and simulation modules can be useful for resident training and skill acquisition. Indigenously made inexpensive models and comparatively less expensive microscopes can be used in resource-constrained situations. The maintenance of microsurgical ability should be preserved by staying active in operative practice. The knowledge of ergonomics, proper training, observing hand movements of skillful surgeons, and the use of operative videos can improve skill. Endoscopic assistance, computer-assisted robot hand technique, and microtechnology can provide access to the smallest areas of the body. PMID- 25915502 TI - An Irrigation Suction System Using a Pressurized Fluid High-Flow Pump System in Comparison with a Standard Cuff Pressure System: Technical Note. AB - OBJECTIVE: In neurosurgical operations, such as clipping of ruptured cerebral aneurysms, irrigation of the operative field is a basic and extremely important surgical technique. Various irrigation-suction (IS) systems have been marketed for irrigation of operative fields in neurosurgery. However, with these devices, we often must increase the cuff pressure to maintain fluid power and change the fluid bag relatively frequently. We report the usefulness of pressurized irrigation fluid with the Niagara high-flow irrigation system (NI). METHOD: Using both the NI system and an IS, we altered pressure and duration to investigate differences in flow rate. RESULTS: There was no change in flow rate 80 minutes after pressurization of the NI system, and flow rates decreased slightly. Additionally, flow rates using NI were sensitive to changes in pressure. CONCLUSION: This system has reduced the workload of assisting nurses and surgeons during surgery. Thus we consider the technique to be very useful for neurosurgical operations that require delicate procedures. PMID- 25915503 TI - Protococcidian Eleutheroschizon duboscqi, an Unusual Apicomplexan Interconnecting Gregarines and Cryptosporidia. AB - This study focused on the attachment strategy, cell structure and the host parasite interactions of the protococcidian Eleutheroschizon duboscqi, parasitising the polychaete Scoloplos armiger. The attached trophozoites and gamonts of E. duboscqi were detected at different development stages. The parasite develops epicellularly, covered by a host cell-derived, two-membrane parasitophorous sac forming a caudal tipped appendage. Staining with Evans blue suggests that this tail is protein-rich, supported by the presence of a fibrous substance in this area. Despite the ultrastructural evidence for long filaments in the tail, it stained only weakly for F-actin, while spectrin seemed to accumulate in this area. The attachment apparatus consists of lobes arranged in one (trophozoites) or two (gamonts) circles, crowned by a ring of filamentous fascicles. During trophozoite maturation, the internal space between the parasitophorous sac and parasite turns translucent, the parasite trilaminar pellicle seems to reorganise and is covered by a dense fibrous glycocalyx. The parasite surface is organised in broad folds with grooves in between. Micropores are situated at the bottom of the grooves. A layer of filaments organised in bands, underlying the folds and ending above the attachment fascicles, was detected just beneath the pellicle. Confocal microscopy, along with the application of cytoskeletal drugs (jasplakinolide, cytochalasin D, oryzalin) confirmed the presence of actin and tubulin polymerised forms in both the parasitophorous sac and the parasite, while myosin labelling was restricted to the sac. Despite positive tubulin labelling, no microtubules were detected in mature stages. The attachment strategy of E. duboscqi shares features with that of cryptosporidia and gregarines, i.e. the parasite itself conspicuously resembles an epicellularly located gregarine, while the parasitophorous sac develops in a similar manner to that in cryptosporidia. This study provides a re evaluation of epicellular development in other apicomplexans and directly compares their niche with that of E. duboscqi. PMID- 25915505 TI - Correction: Health on the web: randomised controlled trial of online screening and brief alcohol intervention delivered in a workplace setting. PMID- 25915504 TI - Analysis of exosome release as a cellular response to MAPK pathway inhibition. AB - Exosome size distributions and numbers of exosomes released per cell are measured by asymmetric flow-field flow fractionation/multi-angle light scattering (A4F/MALS) for three thyroid cancer cell lines as a function of a treatment that inhibits MAPK signaling pathways in the cells. We show that these cell lines release exosomes with well-defined morphological features and size distributions that reflect a common biological process for their formation and release into the extracellular environment. We find that those cell lines with constitutive activation of the MAPK signaling pathway display MEK-dependent exosome release characterized by increased numbers of exosomes released per cell. Analysis of the measured exosome size distributions based on a generalized extreme value distribution model for exosome formation in intracellular multivesicular bodies highlights the importance of this experimental observable for delineating different mechanisms of vesicle formation and predicting how changes in exosome release can be modified by pathway inhibitors in a cell context-dependent manner. PMID- 25915506 TI - Gestational dietary protein is associated with sex specific decrease in blood flow, fetal heart growth and post-natal blood pressure of progeny. AB - STUDY OVERVIEW: The incidence of adverse pregnancy outcomes is higher in pregnancies where the fetus is male. Sex specific differences in feto-placental perfusion indices identified by Doppler assessment have recently been associated with placental insufficiency and fetal growth restriction. This study aims to investigate sex specific differences in placental perfusion and to correlate these changes with fetal growth. It represents the largest comprehensive study under field conditions of uterine hemodynamics in a monotocous species, with a similar long gestation period to the human. Primiparous 14 mo heifers in Australia (n=360) and UK (n=180) were either individually or group fed, respectively, diets with differing protein content (18, 14, 10 or 7% crude protein (CP)) from 60 d prior to 98 days post conception (dpc). Fetuses and placentae were excised at 98 dpc (n = 48). Fetal development an median uterine artery blood flow were assessed monthly from 36 dpc until term using B-mode and Doppler ultrasonography. MUA blood flow to the male feto-placental unit increased in early pregnancy associated with increased fetal growth. Protein restriction before and shortly after conception (-60 d up to 23 dpc) increased MUA diameter and indices of velocity during late pregnancy, reduced fetal heart weight in the female fetus and increased heart rate at birth, but decreased systolic blood pressure at six months of age. CONCLUSION AND SIGNIFICANCE: Sex specific differences both in feto-placental Doppler perfusion indices and response of these indices to dietary perturbations were observed. Further, maternal diet affected development of fetal cardiovascular system associated with altered fetal haemodynamics in utero, with such effects having a sex bias. The results from this study provide further insight into the gender specific circulatory differences present in the fetal period and developing cardiovascular system. PMID- 25915508 TI - Using Social Network Methods to Test for Assortment of Prosociality among Korean High School Students. AB - Assortative interaction among altruistic individuals is a necessary condition for the evolution of cooperation. The requirement for assortment holds regardless of whether a meta-population is subdivided into distinct and isolated subgroups or has ephemeral boundaries with a high migration rate. The assumption, however, is rarely tested directly. In this paper, we develop a method to test for assortment of prosociality in network-structured data. The method is applied to a friendship network collected from 238 Korean students attending the same high school. A mixing matrix was used to explore the presence of assortative friendship among more prosocial individuals. An exponential random graph model of network structure that accounts for additional observed relational propensities (higher than-expected number of people nominating no friends) and sampling constraints (upper bound on friendship nominations) found that individual prosociality predicted friendship propensity, and that individuals with higher prosocial scores had a higher probability of befriending other more prosocial individuals. The results reveal that a considerable level of assortment of prosociality characterizes this population. PMID- 25915507 TI - HbAHP-25, an In-Silico Designed Peptide, Inhibits HIV-1 Entry by Blocking gp120 Binding to CD4 Receptor. AB - Human Immunodeficiency Virus (HIV-1) poses a serious threat to the developing world and sexual transmission continues to be the major source of new infections. Therefore, the development of molecules, which prevent new HIV-1 infections, is highly warranted. In the present study, a panel of human hemoglobin (Hb)-alpha subunit derived peptides and their analogues, with an ability to bind gp120, were designed in-silico and their anti-HIV-1 activity was evaluated. Of these peptides, HbAHP-25, an analogue of Hb-alpha derived peptide, demonstrated significant anti-HIV-1 activity. HbAHP-25 was found to be active against CCR5 tropic HIV-1 strains (ADA5 and BaL) and CXCR4-tropic HIV-1 strains (IIIB and NL4 3). Surface plasmon resonance (SPR) and ELISA revealed direct interaction between HbAHP-25 and HIV-1 envelope protein, gp120. The peptide prevented binding of CD4 to gp120 and blocked subsequent steps leading to entry and/or fusion or both. Anti-HIV activity of HbAHP-25 appeared to be specific as it failed to inhibit the entry of HIV-1 pseudotyped virus (HIV-1 VSV). Further, HbAHP-25 was found to be non-cytotoxic to TZM-bl cells, VK2/E6E7 cells, CEM-GFP cells and PBMCs, even at higher concentrations. Moreover, HbAHP-25 retained its anti-HIV activity in presence of seminal plasma and vaginal fluid. In brief, the study identified HbAHP-25, a novel anti-HIV peptide, which directly interacts with gp120 and thus has a potential to inhibit early stages of HIV-1 infection. PMID- 25915509 TI - Acanthocytosis and the c.680 A>G Mutation in the PANK2 Gene: A Study Enrolling a Cohort of PKAN Patients from the Dominican Republic. AB - Pantothenate Kinase-Associated Neurodegeneration (PKAN) is a form of Neurodegeneration with Brain Iron Accumulation (NBIA) associated with mutations in the pantothenate kinase 2 gene (PANK2). Pantothenate kinases catalyze the rate limiting step of coenzyme A synthesis and Pank2 is the only pantothenate kinase isoform in humans that is localized to mitochondria. Acanthocytosis, the occurrence of spiculated erythrocytes, is observed in about 10% of the PKAN patients. Therefore PKAN is also classified together with other rare neurodegenerative diseases like Chorea Acanthocytosis (ChAc) and McLeod syndrome (MLS) into the Neuroacanthocytosis (NA) syndromes. It has not been investigated yet whether acanthocytosis in PKAN is associated with a specific subset of Pank2 mutations. In this study, we analyzed acanthocytosis of a cohort of 25 PKAN patients from the Dominican Republic that are homozygous for the c.680 A>G mutation in the PANK2 gene as compared to control donors that are heterozygous or wild-type with respect to this mutation. 3D modeling of this mutation indicated that the replacement of a tyrosine by a cysteine at position 227 in Pank2 disrupts a polar interaction within the A domain of the enzyme. Mean acanthocyte count was elevated in the cohort of patients, however, acanthocytosis varied among the patients with nearly half of them showing high (>20%) or elevated acanthocytosis and the rest showing mild (6-10%) or no (<6%) acanthocytosis. Heterozygous control donors revealed a tendency to mild acanthocytosis. Based on the insight that Pank2 is a normal constituent of red blood cells and de novo biosynthesis of coenzyme A is likely to take place in the erythrocyte cytosol we propose a hypothetical model that accounts for the variability in the occurrence of acanthocytic cells in PKAN. PMID- 25915510 TI - Release of Intracoronary Microparticles during Stent Implantation into Stable Atherosclerotic Lesions under Protection with an Aspiration Device. AB - OBJECTIVE: Stent implantation into atherosclerotic coronary vessels impacts on downstream microvascular function and induces the release of particulate debris and soluble substances, which differs qualitatively and quantitatively between native right coronary arteries (RCAs) and saphenous vein grafts on right coronary arteries (SVG-RCAs). We have now quantified the release of microparticles (MPs) during stent implantation into stable atherosclerotic lesions and compared the release between RCAs and SVG-RCAs. METHODS: In symptomatic, male patients with stable angina and a stenosis in their RCA or SVG-RCA, respectively (n = 14/14), plaque volume and composition were analyzed using intravascular ultrasound before stent implantation. Coronary aspirate was retrieved during stent implantation with a distal occlusion/aspiration device and divided into particulate debris and plasma. Particulate debris was weighed. Platelet-derived MPs (PMPs) were distinguished by flow cytometry as CD41+, endothelium-derived MPs (EMPs) as CD144+, CD62E+ and CD31+/CD41-, leukocyte-derived MPs as CD45+, and erythrocyte derived MPs as CD235+. RESULTS: In patients with comparable plaque volume and composition in RCAs and SVG-RCAs, intracoronary PMPs and EMPs were increased after stent implantation into their RCAs and SVG-RCAs (CD41+: 2729.6 +/- 645.6 vs. 4208.7 +/- 679.4 and 2355.9 +/- 503.9 vs. 3285.8 +/- 733.2 nr/uL; CD144+: 451.5 +/- 87.9 vs. 861.7 +/- 147.0 and 444.6 +/- 74.8 vs. 726.5 +/- 136.4 nr/uL; CD62E+: 1404.1 +/- 247.7 vs. 1844.3 +/- 378.6 and 1084.6 +/- 211.0 vs. 1783.8 +/- 384.3 nr/uL, P < 0.05), but not different between RCAs and SVG-RCAs. CONCLUSION: Stenting in stable atherosclerotic lesions is associated with a substantial release not only of PMPs, but also of EMPs in RCAs and SVG-RCAs. Their release does not differ between RCAs and SVG-RCAs. TRIAL REGISTRATION: ClinicalTrials.gov NCT01430884. PMID- 25915511 TI - Pharmacologic Inhibition of the NLRP3 Inflammasome Preserves Cardiac Function After Ischemic and Nonischemic Injury in the Mouse. AB - BACKGROUND: Sterile inflammation resulting from myocardial injury activates the NLRP3 inflammasome and amplifies the inflammatory response mediating further damage. METHODS: We used 2 experimental models of ischemic injury (acute myocardial infarction [AMI] with and without reperfusion) and a model of nonischemic injury due to doxorubicin 10 mg/kg to determine whether the NLRP3 inflammasome preserved cardiac function after injury. RESULTS: Treatment with the NLRP3 inflammasome inhibitor in the reperfused AMI model caused a significant reduction in infarct size measured at pathology or as serum cardiac troponin I level (-56% and -82%, respectively, both P < 0.001) and preserved left ventricular fractional shortening (LVFS, 31 +/- 2 vs. vehicle 26% +/- 1%, P = 0.003). In the non-reperfused AMI model, treatment with the NLRP3 inhibitor significantly limited LV systolic dysfunction at 7 days (LVFS of 20 +/- 2 vs. 14% +/- 1%, P = 0.002), without a significant effect on infarct size. In the doxorubicin model, a significant increase in myocardial interstitial fibrosis and a decline in systolic function were seen in vehicle-treated mice, whereas treatment with the NLRP3 inhibitor significantly reduced fibrosis (-80%, P = 0.001) and preserved systolic function (LVFS 35 +/- 2 vs. vehicle 27% +/- 2%, P = 0.017). CONCLUSIONS: Pharmacological inhibition of the NLRP3 inflammasome limits cell death and LV systolic dysfunction after ischemic and nonischemic injury in the mouse. PMID- 25915512 TI - DJ-1 Mediates the Delayed Cardioprotection of Hypoxic Preconditioning Through Activation of Nrf2 and Subsequent Upregulation of Antioxidative Enzymes. AB - We have recently shown that DJ-1 is implicated in the delayed cardioprotective effect of hypoxic preconditioning (HPC) against hypoxia/reoxygenation (H/R) injury as an endogenous protective protein. This study aims to further investigate the underlying mechanism by which DJ-1 mediates the delayed cardioprotection of HPC against H/R-induced oxidative stress. Using a well characterized cellular model of HPC from rat heart-derived H9c2 cells, we found that HPC promoted nuclear factor erythroid 2-related factor 2 (Nrf2) and its cytoplasmic inhibitor Kelch-like ECH-associated protein-1 (Keap1) dissociation and resulted in increased nuclear translocation, antioxidant response element binding, and transcriptional activity of Nrf2 24 hours after HPC, with subsequent upregulation of manganese superoxide dismutase (MnSOD) and heme oxygenase-1 (HO 1), which provided delayed protection against H/R-induced oxidative stress in normal H9c2 cells. However, the aforementioned effects of HPC were abolished in DJ-1-knockdown H9c2 cells, which were restored by restoration of DJ-1 expression. Importantly, we showed that inhibition of the Nrf2 pathway in H9c2 cells mimicked the effects of DJ-1 knockdown and abolished HPC-derived induction of antioxidative enzymes (MnSOD and HO-1) and the delayed cardioprotection. In addition, inhibition of Nrf2 also reversed the effects of restored DJ-1 expression on induction of antioxidative enzymes and delayed cardioprotection by HPC in DJ-1-knockdown H9c2 cells. Taken together, this work revealed that activation of Nrf2 pathway and subsequent upregulation of antioxidative enzymes could be a critical mechanism by which DJ-1 mediates the delayed cardioprotection of HPC against H/R-induced oxidative stress in H9c2 cells. PMID- 25915513 TI - Isobaric Tags for Relative and Absolute Quantitation-Based Proteomic Analysis of Patent and Constricted Ductus Arteriosus Tissues Confirms the Systemic Regulation of Ductus Arteriosus Closure. AB - We aimed to evaluate global changes in protein expression associated with patency by undertaking proteomic analysis of human constricted and patent ductus arteriosus (DA). Ten constricted and 10 patent human DAs were excised from infants with ductal-dependent heart disease during surgery. Using isobaric tags for relative and absolute quantitation-based quantitative proteomics, 132 differentially expressed proteins were identified. Of 132 proteins, voltage-gated sodium channel 1.3 (SCN3A), myosin 1d (Myo1d), Rho GTPase activating protein 26 (ARHGAP26), and retinitis pigmentosa 1 (RP1) were selected for validation by Western blot and quantitative real-time polymerase chain reaction analyses. Significant upregulation of SCN3A, Myo1d, and RP1 messenger RNA, and protein levels was observed in the patent DA group (all P <= 0.048). ARHGAP26 messenger RNA and protein levels were decreased in patent DA tissue (both P <= 0.018). Immunohistochemistry analysis revealed that Myo1d, ARHGAP26, and RP1 were specifically expressed in the subendothelial region of constricted DAs; however, diffuse expression of these proteins was noted in the patent group. Proteomic analysis revealed global changes in the expression of proteins that regulate oxygen sensing, ion channels, smooth muscle cell migration, nervous system, immune system, and metabolism, suggesting a basis for the systemic regulation of DA patency by diverse signaling pathways, which will be confirmed in further studies. PMID- 25915514 TI - Neutrophil Gelatinase-associated Lipocalin in the Prediction of Contrast-induced Nephropathy: A Systemic Review and Meta-analysis. AB - OBJECTIVE: The aim of this study was to investigate the predictive value of neutrophil gelatinase-associated lipocalin (NGAL) in the early diagnosis of contrast-induced nephropathy (CIN). METHODS: We searched MEDLINE and Embase until December 2014 for articles evaluating the diagnostic accuracy of plasma/serum and urinary NGAL levels to predict CIN. The primary analysis was based on a hierarchical, bivariate, generalized, linear, mixed model. Diagnostic odds ratio (DOR) and sample size-weighted area under the curve for the receiver operating characteristic (AUROC) were calculated. RESULTS: Ten studies involving 1310 patients were analyzed. Overall, the DOR/AUROC for NGAL level to predict CIN was 20.56 [95% confidence interval (CI), 9.67-43.74]/0.87 (95% CI, 0.84-0.90), with sensitivity and specificity of 0.80 (95% CI, 0.74-0.85) and 0.83 (95% CI, 0.73 0.90), respectively. Subgroup analysis showed that the diagnostic performance of the DOR/AUROC of urinary NGAL [29.48 (95% CI, 12.19-71.27)/0.87 (95% CI, 0.84 0.90)] was better than that of plasma/serum NGAL [14.63 (95% CI, 4.51-47.38)/0.85 (95% CI, 0.82-0.88)] (DOR, P = 0.005, and AUROC, P = 0.04, respectively). CONCLUSIONS: Plasma/serum and urinary NGAL levels seem to be useful biomarkers in the early prediction of CIN. Moreover, urinary NGAL levels perform better than plasma/serum NGAL. PMID- 25915515 TI - Allelopathic Potential of Invasive Plantago virginica on Four Lawn Species. AB - Plantago virginica L. has invaded many lawn ecosystems in the Eastern part of China. The invasion has incurred an economic cost to remove them. In order to prevent the invasion, it is critical to understand the invasive mechanisms of this species. However, few studies have been conducted on the allelopathic mechanisms of its invasion. In this study, we examined allelopathic effects of P. virginica on germination of seeds and growth of seedlings of four widely used lawn species. We found extensive allelopathic potential of P. virginica on other lawn species, which varied with species and developmental stage. While most effects of the extracts of P. virginica were inhibitory, some variables in some species were promoted by the addition of the extracts. The extracts of P. virginica significantly inhibited seed germination of Agrostis matsumurae. While the overall differences in seed germination rate of Poa annua were significant among treatments, difference between control and any of the treatments was not significant. The height of seedlings of A. matsumurae and Cynodon dactylon was significantly lower under the treatments of adding extracts of P. virginica. In contrast, growth of seedlings of Festuca elata and P. annua did not show significant differences among treatments. The root length of A. matsumurae, C. dactylon and P. annua was suppressed by the extracts of P. virginica whereas root length of F. elata was not affected. Aboveground biomass of A. matsumurae and F. elata was significantly higher than control, except for F. elata at the concentration of 50mg/mL, whereas aboveground biomass of C. dactylon and P. annua was reduced at higher concentrations of the extracts. Except for A. matsumurae, root biomass of the other three lawn species declined under the treatments with the extracts of P. virginica. Our results revealed that P. virginica had allelopathic potential on four lawn species and supported the theory of "novel weapons hypothesis". Invasion by P. virginica in lawn can be moderated by selecting those species that are not affected or promotionally affected by it. PMID- 25915517 TI - Modulation of Framework and Centricity: Cation Size Effect in New Quaternary Selenites, ASc(SeO3)2 (A = Na, K, Rb, and Cs). AB - Four new stoichiometrically equivalent quaternary scandium selenites, ASc(SeO3)2 (A = Na, K, Rb, and Cs) have been hydrothermally synthesized using A2CO3, Sc(NO3)3.xH2O (or ScO3), and SeO2 as starting materials. All four materials share similar bond networks that are composed of corner-shared distorted ScO6 octahedra and SeO3 trigonal pyramids. However, each material reveals different frameworks and centricities. Detailed structural analysis suggests that the structural variation is attributed to the difference in size and subsequent coordination number for the alkali metal cations. Powder second-harmonic generation (SHG) measurements on noncentrosymmetric (NCS) RbSc(SeO3)2 show that the compound has an SHG efficiency similar to that of (NH4)H2PO4. The observed SHG efficiency is due to the remaining net polarization after cancellation of oppositely aligned moments for SeO3 and ScO6 groups. Thorough characterizations such as spectroscopic, thermal, and elemental analyses for the new materials are presented as are dipole moment and out-of-center distortion calculations. PMID- 25915516 TI - Characterising Non-Structural Protein NS4 of African Horse Sickness Virus. AB - African horse sickness is a serious equid disease caused by the orbivirus African horse sickness virus (AHSV). The virus has ten double-stranded RNA genome segments encoding seven structural and three non-structural proteins. Recently, an additional protein was predicted to be encoded by genome segment 9 (Seg-9), which also encodes VP6, of most orbiviruses. This has since been confirmed in bluetongue virus and Great Island virus, and the non-structural protein was named NS4. In this study, in silico analysis of AHSV Seg-9 sequences revealed the existence of two main types of AHSV NS4, designated NS4-I and NS4-II, with different lengths and amino acid sequences. The AHSV NS4 coding sequences were in the +1 reading frame relative to that of VP6. Both types of AHSV NS4 were expressed in cultured mammalian cells, with sizes close to the predicted 17-20 kDa. Fluorescence microscopy of these cells revealed a dual cytoplasmic and nuclear, but not nucleolar, distribution that was very similar for NS4-I and NS4 II. Immunohistochemistry on heart, spleen, and lung tissues from AHSV-infected horses showed that NS4 occurs in microvascular endothelial cells and mononuclear phagocytes in all of these tissues, localising to the both the cytoplasm and the nucleus. Interestingly, NS4 was also detected in stellate-shaped dendritic macrophage-like cells with long cytoplasmic processes in the red pulp of the spleen. Finally, nucleic acid protection assays using bacterially expressed recombinant AHSV NS4 showed that both types of AHSV NS4 bind dsDNA, but not dsRNA. Further studies will be required to determine the exact function of AHSV NS4 during viral replication. PMID- 25915518 TI - Being "nimble and flexible" is new surgeon general's goal. PMID- 25915519 TI - Electron Transfer Flavoprotein Subunit Beta Is a Candidate Endothelial Cell Autoantigen in Behcet's Disease. AB - Behcet's disease (BD) is a chronic inflammatory disease with multisystem involvement, and it is listed as a rare disease in the United States but is common in the Middle East, China, and Japan. The aim of this study was to identify novel autoantigens in Chinese patients with BD. First, the candidate autoantigens were screened by Western blotting, and the sequences of putative antigens were identified by LC-MALDI-TOF/TOF mass spectrometry. Next, the screened protein was cloned, expressed and purified. Then, an optimized ELISA was developed, and the serological criteria were evaluated using a large number of confirmed patients. One antigen with a molecular weight of approximately 28 kDa was identified as electron transfer flavoprotein subunit beta (ETFB). Positive reactivity was detected in recombinant human ETFB sera from 38 of 92 BD patients (41 %) and 1 of 90 healthy controls (1 %). PMID- 25915521 TI - A framework to explore the knowledge structure of multidisciplinary research fields. AB - Understanding emerging areas of a multidisciplinary research field is crucial for researchers, policymakers and other stakeholders. For them a knowledge structure based on longitudinal bibliographic data can be an effective instrument. But with the vast amount of available online information it is often hard to understand the knowledge structure for data. In this paper, we present a novel approach for retrieving online bibliographic data and propose a framework for exploring knowledge structure. We also present several longitudinal analyses to interpret and visualize the last 20 years of published obesity research data. PMID- 25915520 TI - Exploring the Role of Residue 228 in Substrate and Inhibitor Recognition by VIM Metallo-beta-lactamases. AB - beta-Lactamase inhibitors (BLIs) restore the efficacy of otherwise obsolete beta lactams. However, commercially available BLIs are not effective against metallo beta-lactamases (MBLs), which continue to be disseminated globally. One group of the most clinically important MBLs is the VIM family. The discovery of VIM-24, a natural variant of VIM-2, possessing an R228L substitution and a novel phenotype, compelled us to explore the role of this position and its effects on substrate specificity. We employed mutagenesis, biochemical and biophysical assays, and crystallography. VIM-24 (R228L) confers enhanced resistance to cephems and increases the rate of turnover compared to that of VIM-2 (kcat/KM increased by 6- and 10-fold for ceftazidime and cefepime, respectively). Likely the R -> L substitution relieves steric clashes and accommodates the C3N-methyl pyrrolidine group of cephems. Four novel bisthiazolidine (BTZ) inhibitors were next synthesized and tested against these MBLs. These inhibitors inactivated VIM-2 and VIM-24 equally well (Ki* values of 40-640 nM) through a two-step process in which an initial enzyme (E)-inhibitor (I) complex (EI) undergoes a conformational transition to a more stable species, E*I. As both VIM-2 and VIM-24 were inhibited in a similar manner, the crystal structure of a VIM-2-BTZ complex was determined at 1.25 A and revealed interactions of the inhibitor thiol with the VIM Zn center. Most importantly, BTZs also restored the activity of imipenem against Klebsiella pneumoniae and Pseudomonas aeruginosa in whole cell assays producing VIM-24 and VIM-2, respectively. Our results suggest a role for position 228 in defining the substrate specificity of VIM MBLs and show that BTZ inhibitors are not affected by the R228L substitution. PMID- 25915522 TI - Transferrin receptor levels and polymorphism of its gene in age-related macular degeneration. AB - The aim of the present study was to investigate the association of age related macular degeneration (AMD) risk with some aspects of iron homeostasis: iron concentration in serum, level of soluble transferrin receptor (sTfR), and transferrin receptor (TFRC) genetic variability. Four hundred and ninety one AMD patients and 171 controls were enrolled in the study. Restriction fragment length polymorphism PCR was employed to genotype polymorphisms of the TFRC gene, and colorimetric assays were used to determine the level of iron and sTfR. Multiple logistic regression was applied for all genotype/allele-related analyses and the ANOVA test for iron and sTfR serum level comparison. We found that the genotypes and alleles of the c.-253G > A polymorphism of the TFRC gene were associated with AMD risk and this association was modulated by smoking status, AMD family history, living environment (rural/urban), body mass index and age. The levels of sTfR was higher in AMD patients than controls, whereas concentrations of iron did not differ in these two groups. No association was found between AMD occurrence and the p.Gly142Ser polymorphism of the TRFC gene. The results obtained suggest that transferrin receptor and variability of its gene may influence AMD risk. PMID- 25915523 TI - Eltrombopag modulates reactive oxygen species and decreases acute myeloid leukemia cell survival. AB - Previous studies have demonstrated that the small molecule thrombopoietin (TPO) mimetic, eltrombopag (E), induces apoptosis in acute myeloid leukemia (AML) cells. Here, we sought to define the mechanism of the anti-leukemic effect of eltrombopag. Our studies demonstrate that, at a concentration of 5 MUM E in 2% serum, E induces apoptosis in leukemia cells by triggering PARP cleavage and activation of caspase cascades within 2-6 hours. The induction of apoptotic enzymes is critically dependent on drug concentration and the concentration of serum. This effect is not associated with an alteration in mitochondrial potential but is associated with a rapid decrease in a reactive oxygen species (ROS) in particular hydrogen peroxide (H2O2). Interestingly, E also decreases mitochondrial maximal and spare respiratory capacities suggesting an induced mitochondrial dysfunction that may not be readily apparent under basal conditions but becomes manifest only under stress. Co-treatment of MOLM14 AML cells with E plus Tempol or H2O2 provides a partial rescue of cell toxicity. Ferric ammonioum citrate (FAC) also antagonized the E induced toxicity, by inducing notable increase in ROS level. Overall, we propose that E dramatically decreases ROS levels leading to a disruption of AML intracellular metabolism and rapid cell death. PMID- 25915524 TI - Tracking the Elusive Function of Bacillus subtilis Hfq. AB - RNA-binding protein Hfq is a key component of the adaptive responses of many proteobacterial species including Escherichia coli, Salmonella enterica and Vibrio cholera. In these organisms, the importance of Hfq largely stems from its participation to regulatory mechanisms involving small non-coding RNAs. In contrast, the function of Hfq in Gram-positive bacteria has remained elusive and somewhat controversial. In the present study, we have further addressed this point by comparing growth phenotypes and transcription profiles between wild-type and an hfq deletion mutant of the model Gram-positive bacterium, Bacillus subtilis. The absence of Hfq had no significant consequences on growth rates under nearly two thousand metabolic conditions and chemical treatments. The only phenotypic difference was a survival defect of B. subtilis hfq mutant in rich medium in stationary phase. Transcriptomic analysis correlated this phenotype with a change in the levels of nearly one hundred transcripts. Albeit a significant fraction of these RNAs (36%) encoded sporulation-related functions, analyses in a strain unable to sporulate ruled out sporulation per se as the basis of the hfq mutant's stationary phase fitness defect. When expressed in Salmonella, B. subtilis hfq complemented the sharp loss of viability of a degP hfq double mutant, attenuating the chronic sigmaE-activated phenotype of this strain. However, B. subtilis hfq did not complement other regulatory deficiencies resulting from loss of Hfq-dependent small RNA activity in Salmonella indicating a limited functional overlap between Salmonella and B. subtilis Hfqs. Overall, this study confirmed that, despite structural similarities with other Hfq proteins, B. subtilis Hfq does not play a central role in post-transcriptional regulation but might have a more specialized function connected with stationary phase physiology. This would account for the high degree of conservation of Hfq proteins in all 17 B. subtilis strains whose genomes have been sequenced. PMID- 25915525 TI - Equilibrium molecular thermodynamics from Kirkwood sampling. AB - We present two methods for barrierless equilibrium sampling of molecular systems based on the recently proposed Kirkwood method (J. Chem. Phys. 2009, 130, 134102). Kirkwood sampling employs low-order correlations among internal coordinates of a molecule for random (or non-Markovian) sampling of the high dimensional conformational space. This is a geometrical sampling method independent of the potential energy surface. The first method is a variant of biased Monte Carlo, where Kirkwood sampling is used for generating trial Monte Carlo moves. Using this method, equilibrium distributions corresponding to different temperatures and potential energy functions can be generated from a given set of low-order correlations. Since Kirkwood samples are generated independently, this method is ideally suited for massively parallel distributed computing. The second approach is a variant of reservoir replica exchange, where Kirkwood sampling is used to construct a reservoir of conformations, which exchanges conformations with the replicas performing equilibrium sampling corresponding to different thermodynamic states. Coupling with the Kirkwood reservoir enhances sampling by facilitating global jumps in the conformational space. The efficiency of both methods depends on the overlap of the Kirkwood distribution with the target equilibrium distribution. We present proof-of concept results for a model nine-atom linear molecule and alanine dipeptide. PMID- 25915526 TI - Phosphorylation of transcription factor specificity protein 4 is increased in peripheral blood mononuclear cells of first-episode psychosis. AB - BACKGROUND: Altered expression of transcription factor specificity protein 4 (SP4) has been found in the postmortem brain of patients with psychiatric disorders including schizophrenia and bipolar disorder. Reduced levels of SP4 protein have recently been reported in peripheral blood mononuclear cells in first-episode psychosis. Also, SP4 levels are modulated by lithium treatment in cultured neurons. Phosphorylation of SP4 at S770 is increased in the cerebellum of bipolar disorder subjects and upon inhibition of NMDA receptor signaling in cultured neurons. The aim of this study was to investigate whether SP4 S770 phosphorylation is increased in lymphocytes of first-episode psychosis patients and the effect of lithium treatment on this phosphorylation. METHODS: A cross sectional study of S770 phosphorylation relative to total SP4 immunoreactivity using specific antibodies in peripheral blood mononuclear cells in first-episode psychosis patients (n = 14, treated with lithium or not) and matched healthy controls (n = 14) by immunoblot was designed. We also determined the effects of the prescribed drugs lithium, olanzapine or valproic acid on SP4 phosphorylation in rat primary cultured cerebellar granule neurons. RESULTS: We found that SP4 S770 phosphorylation was significantly increased in lymphocytes in first-episode psychosis compared to controls and decreased in patients treated with lithium compared to patients who did not receive lithium. Moreover, incubation with lithium but not olanzapine or valproic acid reduced SP4 phosphorylation in rat cultured cerebellar granule neurons. CONCLUSIONS: The findings presented here indicate that SP4 S770 phosphorylation is increased in lymphocytes in first episode psychosis which may be reduced by lithium treatment in patients. Moreover, our study shows lithium treatment prevents this phosphorylation in vitro in neurons. This pilot study suggests that S770 SP4 phosphorylation could be a peripheral biomarker of psychosis, and may be regulated by lithium treatment in first-episode psychosis. PMID- 25915527 TI - Exercise, but not acute sleep loss, increases salivary antimicrobial protein secretion. AB - Sleep deficiencies may play a role in depressing immune parameters. Little is known about the impact of exercise after sleep deprivation on mucosal immunity. The purpose of this study was to quantify salivary antimicrobial proteins (AMPs) in response to sleep loss before and after exercise. Four men and 4 women (age: 22.8 +/- 2; : 49.1 +/- 7.1 ml . kg(-1) . min(-1)) completed 2 exercise trials consisting of 45 minutes of running at 75% VO2peak after a normal night of sleep (CON) and after a night without sleep (WS). Exercise trials were separated by 10 +/- 3 days. Saliva was collected before, immediately after, and 1 hour after exercise. LL-37, HNP1-3, Lactoferrin (Lac), and Lysozyme (Lys) were measured. Sleep loss did not affect the concentration or secretion rate of AMPs before or in response to exercise. However, exercise increased the concentration from pre- to post-exercise of LL-37 (pre: 15.5 +/- 8.7; post: 22.3 +/- 16.2 ng . ml(-1)), HNP1-3 (pre: 2.2 +/- 2.3; post: 3.3 +/- 2.5 ug . ml(-1)), Lac (pre: 5,234 +/- 4,202; post: 12,283 +/- 10,995 ng . ml(-1)), and Lys (pre: 5,831 +/- 4,465; post: 12,542 +/- 10,755 ng . ml(-1)), p <= 0.05. The secretion rates were higher immediately after and 1 hour after exercise compared with before exercise for LL 37 (pre: 3.1 +/- 2.1; post: 5.1 +/- 3.7; +1: 6.9 +/- 8.4 ng . min(-1)), HNP1-3 (pre: 0.38 +/- 0.38; post: 0.80 +/- 0.75; +1: 0.84 +/- 0.67 ug . min(-1)), Lac (pre: 1,096 +/- 829; post: 2,948 +/- 2,923; +1: 2,464 +/- 3,785 ng . min(-1)), and Lys (pre: 1,534 +/- 1,790; post: 3,042 +/- 2,773; +1: 1,916 +/- 1,682 ng . min-(1)), p <= 0.05. These data suggest that the major constituents of the mucosal immune system are unaffected by acute sleep loss and by exercise after acute sleep loss. Exercise increased the concentration and secretion rate of each AMP suggesting enhanced immunity and control of inflammation, despite limited sleep. PMID- 25915528 TI - High-performance perovskite photoanode enabled by Ni passivation and catalysis. AB - Lead halide perovskites have achieved phenomenal successes in photovoltaics due to their suitable bandgaps, long diffusion lengths, and balanced charge transport. However, the extreme susceptibility of perovskites to water or air has imposed a seemingly insurmountable barrier for leveraging these unique materials into solar-to-fuel applications such as photoelectrochemical conversion. Here we developed a CH3NH3PbI3-based photoanode with an ultrathin Ni surface layer, which functions as both a physical passivation barrier and a hole-transferring catalyst. Remarkably, a much enhanced photocurrent density, an unassisted photoelectrochemical conversion capability, and a substantially better stability against water have been achieved, which are exceeding most of the previously reported photoanodes as well as a similar CH3NH3PbI3-based device structure but without the Ni surface layer. Our study suggests many exciting opportunities of developing perovskite-based solar-to-fuel conversion. PMID- 25915529 TI - Optimization of a Fluorescence-Based Assay for Large-Scale Drug Screening against Babesia and Theileria Parasites. AB - A rapid and accurate assay for evaluating antibabesial drugs on a large scale is required for the discovery of novel chemotherapeutic agents against Babesia parasites. In the current study, we evaluated the usefulness of a fluorescence based assay for determining the efficacies of antibabesial compounds against bovine and equine hemoparasites in in vitro cultures. Three different hematocrits (HCTs; 2.5%, 5%, and 10%) were used without daily replacement of the medium. The results of a high-throughput screening assay revealed that the best HCT was 2.5% for bovine Babesia parasites and 5% for equine Babesia and Theileria parasites. The IC50 values of diminazene aceturate obtained by fluorescence and microscopy did not differ significantly. Likewise, the IC50 values of luteolin, pyronaridine tetraphosphate, nimbolide, gedunin, and enoxacin did not differ between the two methods. In conclusion, our fluorescence-based assay uses low HCT and does not require daily replacement of culture medium, making it highly suitable for in vitro large-scale drug screening against Babesia and Theileria parasites that infect cattle and horses. PMID- 25915530 TI - Improvement of DC vaccine with ALA-PDT induced immunogenic apoptotic cells for skin squamous cell carcinoma. AB - Dendritic cell (DC) based vaccines have emerged as a promising immunotherapy for cancers. However, most DC vaccines so far have achieved only limited success in cancer treatment. Photodynamic therapy (PDT), an established cancer treatment strategy, can cause immunogenic apoptosis to induce an effective antitumor immune response. In this study, we developed a DC-based cancer vaccine using immunogenic apoptotic tumor cells induced by 5-aminolevulinic acid (ALA) mediated PDT. The maturation of DCs induced by PDT-treated apoptotic cells was evaluated using electron microscopy, FACS, and ELISA. The anti-tumor immunity of ALA-PDT-DC vaccine was tested with a mouse model. We observed the maturations of DCs potentiated by ALA-PDT treated tumor cells, including morphology maturation (enlargement of dendrites and increase of lysosomes), phenotypic maturation (upregulation of surface expression of MHC-II, DC80, and CD86), and functional maturation (enhanced capability to secrete IFN-gamma and IL-12, and to induce T cell proliferation). Most interestingly, PDT-induced apoptotic tumor cells are more capable of potentiating maturation of DCs than PDT-treated or freeze/thaw treated necrotic tumor cells. ALA-PDT-DC vaccine mediated by apoptotic cells provided protection against tumors in mice, far stronger than that of DC vaccine obtained from freeze/thaw treated tumor cells. Our results indicate that immunogenic apoptotic tumor cells can be more effective in enhancing a DC-based cancer vaccine, which could improve the clinical application of PDT-DC vaccines. PMID- 25915532 TI - Development and characterisation of a 3D multi-cellular in vitro model of normal human breast: a tool for cancer initiation studies. AB - Multicellular 3-dimensional (3D) in vitro models of normal human breast tissue to study cancer initiation are required. We present a model incorporating three of the major functional cell types of breast, detail the phenotype and document our breast cancer initiation studies. Myoepithelial cells and fibroblasts were isolated and immortalised from breast reduction mammoplasty samples. Tri-cultures containing non-tumorigenic luminal epithelial cells HB2, or HB2 overexpressing different HER proteins, together with myoepithelial cells and fibroblasts were established in collagen I. Phenotype was assessed morphologically and immunohistochemically and compared to normal breast tissue. When all three cell types were present, polarised epithelial structures with lumens and basement membrane production were observed, akin to normal human breast tissue. Overexpression of HER2 or HER2/3 caused a significant increase in size, while HER2 overexpression resulted in development of a DCIS-like phenotype. In summary, we have developed a 3D tri-cellular model of normal human breast, amenable to comparative analysis after genetic manipulation and with potential to dissect the mechanisms behind the early stages of breast cancer initiation. PMID- 25915533 TI - Targeted sequencing with enrichment PCR: a novel diagnostic method for the detection of EGFR mutations. AB - Epidermal growth factor receptor (EGFR) is an important mediator of tumor cell survival and proliferation. The detection of EGFR mutations can predict prognoses and indicate when treatment with EGFR tyrosine kinase inhibitors should be used. As such, the development of highly sensitive methods for detecting EGFR mutations is important. Targeted next-generation sequencing is an effective method for diagnosing mutations. We compared the abilities of enrichment PCR followed by ultra-deep pyrosequencing (UDP), UDP alone, and PNA-mediated RT-PCR clamping to detect low-frequency EGFR mutations in tumor cell lines and tissue samples. Using enrichment PCR-UDP, we were able to detect the E19del and L858R mutations at minimum frequencies of 0.01% and 0.05%, respectively, in the PC-9 and H197 tumor cell lines. We also confirmed the sensitivity of detecting the E19del mutation by performing a titration analysis in FFPE tumor samples. The lowest mutation frequency detected was 0.0692% in tissue samples. EGFR mutations with frequencies as low as 0.01% were detected using enrichment PCR-UDP, suggesting that this method is a valuable tool for detecting rare mutations, especially in scarce tissue samples or those with small quantities of DNA. PMID- 25915531 TI - The intrinsic stiffness of human trabecular meshwork cells increases with senescence. AB - Dysfunction of the human trabecular meshwork (HTM) plays a central role in the age-associated disease glaucoma, a leading cause of irreversible blindness. The etiology remains poorly understood but cellular senescence, increased stiffness of the tissue, and the expression of Wnt antagonists such as secreted frizzled related protein-1 (SFRP1) have been implicated. However, it is not known if senescence is causally linked to either stiffness or SFRP1 expression. In this study, we utilized in vitro HTM senescence to determine the effect on cellular stiffening and SFRP1 expression. Stiffness of cultured cells was measured using atomic force microscopy and the morphology of the cytoskeleton was determined using immunofluorescent analysis. SFRP1 expression was measured using qPCR and immunofluorescent analysis. Senescent cell stiffness increased 1.88+/-0.14 or 2.57+/-0.14 fold in the presence or absence of serum, respectively. This was accompanied by increased vimentin expression, stress fiber formation, and SFRP1 expression. In aggregate, these data demonstrate that senescence may be a causal factor in HTM stiffening and elevated SFRP1 expression, and contribute towards disease progression. These findings provide insight into the etiology of glaucoma and, more broadly, suggest a causal link between senescence and altered tissue biomechanics in aging-associated diseases. PMID- 25915534 TI - Trametinib modulates cancer multidrug resistance by targeting ABCB1 transporter. AB - Overexpression of adenine triphosphate (ATP)-binding cassette (ABC) transporters is one of the main reasons of multidrug resistance (MDR) in cancer cells. Trametinib, a novel specific small-molecule mitogen-activated extracellular signal-regulated kinase (MEK) inhibitor, is currently used for the treatment of melanoma in clinic. In this study, we investigated the effect of trametinib on MDR mediated by ABC transporters. Trametinib significantly potentiated the effects of two ABCB1 substrates vincristine and doxorubicin on inhibition of growth, arrest of cell cycle and induction of apoptosis in cancer cells overexpressed ABCB1, but not ABCC1 and ABCG2. Furthermore, trametinib did not alter the sensitivity of non-ABCB1 substrate cisplatin. Mechanistically, trametinib potently blocked the drug-efflux activity of ABCB1 to increase the intracellular accumulation of rhodamine 123 and doxorubicin and stimulates the ATPase of ABCB1 without alteration of the expression of ABCB1. Importantly, trametinib remarkably enhanced the effect of vincristine against the xenografts of ABCB1-overexpressing cancer cells in nude mice. The predicted binding mode showed the hydrophobic interactions of trametinib within the large drug binding cavity of ABCB1. Consequently, our findings may have important implications for use of trametinib in combination therapy for cancer treatment. PMID- 25915535 TI - Malignant T cells express lymphotoxin alpha and drive endothelial activation in cutaneous T cell lymphoma. AB - Lymphotoxin alpha (LTalpha) plays a key role in the formation of lymphatic vasculature and secondary lymphoid structures. Cutaneous T cell lymphoma (CTCL) is the most common primary lymphoma of the skin and in advanced stages, malignant T cells spreads through the lymphatic to regional lymph nodes to internal organs and blood. Yet, little is known about the mechanism of the CTCL dissemination. Here, we show that CTCL cells express LTalpha in situ and that LTalpha expression is driven by aberrantly activated JAK3/STAT5 pathway. Importantly, via TNF receptor 2, LTalpha functions as an autocrine factor by stimulating expression of IL-6 in the malignant cells. LTalpha and IL-6, together with VEGF promote angiogenesis by inducing endothelial cell sprouting and tube formation. Thus, we propose that LTalpha plays a role in malignant angiogenesis and disease progression in CTCL and may serve as a therapeutic target in this disease. PMID- 25915536 TI - Highly sensitive and specific novel biomarkers for the diagnosis of transitional bladder carcinoma. AB - Transitional bladder carcinoma (BCa) is prevalent in developed countries, particularly among men. Given that these tumors frequently recur or progress, the early detection and subsequent monitoring of BCa at different stages is critical. Current BCa diagnostic biomarkers are not sufficiently sensitive for substituting or complementing invasive cystoscopy. Here, we sought to identify a robust set of urine biomarkers for BCa detection. Using a high-resolution, mass spectrometry based, quantitative proteomics approach, we measured, compared and validated protein variations in 451 voided urine samples from healthy subjects, non-bladder cancer patients and patients with non-invasive and invasive BCa. We identified five robust biomarkers: Coronin-1A, Apolipoprotein A4, Semenogelin-2, Gamma synuclein and DJ-1/PARK7. In diagnosing Ta/T1 BCa, these biomarkers achieved an AUC of 0.92 and 0.98, respectively, using ELISA and western blot data (sensitivity, 79.2% and 93.9%; specificity, 100% and 96.7%, respectively). In diagnosing T2/T3 BCa, an AUC of 0.94 and 1.0 was attained (sensitivity, 86.4% and 100%; specificity, 100%) using the same methods. Thus, our multiplex biomarker panel offers unprecedented accuracy for the diagnosis of BCa patients and provides the prospect for a non-invasive way to detect bladder cancer. PMID- 25915537 TI - Ubiquitin C-terminal hydrolase-L1 increases cancer cell invasion by modulating hydrogen peroxide generated via NADPH oxidase 4. AB - This study explored the role of ubiquitin C-terminal hydrolase-L1 (UCH-L1) in the production of ROS and tumor invasion. UCH-L1 was found to increase cellular ROS levels and promote cell invasion. Silencing UCH-L1, as well as inhibition of H2O2 generation by catalase or by DPI, a NOX inhibitor, suppressed the migration potential of B16F10 cells, indicating that UCH-L1 promotes cell migration by up regulating H2O2 generation. Silencing NOX4, which generates H2O2, with siRNA eliminated the effect of UCH-L1 on cell migration. On the other hand, NOX4 overexpressed in HeLa cells happens to be ubiquitinated, and NOX4 following deubiquitination by UCH-L1, restored H2O2-generating activity. These in vitro findings are consistent with the results obtained in vivo with catalase (-/-) C57BL/6J mice. When H2O2 and UCH-L1 levels were independently varied in these animals, the former by infecting with H2O2-scavenging adenovirus-catalase, and the latter by overexpressing or silencing UCH-L1, pulmonary metastasis of B16F10 cells overexpressing UCH-L1 increased significantly in catalase (-/-) mice. In contrast, invasion did not increase when UCH-L1 was silenced in the B16F10 cells. These findings indicate that H2O2 levels regulated by UCH-L1 are necessary for cell invasion to occur and demonstrate that UCH-L1 promotes cell invasion by up regulating H2O2 via deubiquitination of NOX4. PMID- 25915539 TI - The impact of outpatient chemotherapy-related adverse events on the quality of life of breast cancer patients. AB - The objective of our study was to clarify the impact of adverse events associated with the initial course of outpatient chemotherapy on the quality of life of breast cancer patients. We conducted a survey to assess the quality of life in 48 breast cancer patients before and after receiving their first course of outpatient chemotherapy at Gifu Municipal Hospital. Patients completed the European Quality of Life 5 Dimensions and Quality of Life Questionnaire for Cancer Patients Treated with Anticancer Drugs before and after 1 course of outpatient chemotherapy. European Quality of Life 5 Dimensions utility value and Quality of Life Questionnaire for Cancer Patients Treated with Anticancer Drugs total score decreased significantly after chemotherapy (p<0.001 and p = 0.018, respectively). The mean scores for the activity, physical condition, and psychological condition subscales of the Quality of Life Questionnaire for Cancer Patients Treated with Anticancer Drugs decreased significantly after chemotherapy (p = 0.003, p<0.001, and p = 0.032, respectively), whereas the social relationships score increased significantly (p<0.001). Furthermore, in the evaluation of quality of life according to individual adverse events, the decrease in quality of life after chemotherapy in terms of the European Quality of Life 5 Dimensions utility value and the Quality of Life Questionnaire for Cancer Patients Treated with Anticancer Drugs total score was greater in anorexic patients than in non-anorexic patients (p = 0.009 and p<0.001, respectively). This suggests that anorexia greatly reduces quality of life. Our findings reveal that anticancer drug-related adverse events, particularly anorexia, reduce overall quality of life following the first course of outpatient chemotherapy in current breast cancer patients. These findings are extremely useful and important in understanding the impact of anticancer drug-related adverse events on quality of life. PMID- 25915538 TI - Plasma genetic and genomic abnormalities predict treatment response and clinical outcome in advanced prostate cancer. AB - Liquid biopsies, examinations of tumor components in body fluids, have shown promise for predicting clinical outcomes. To evaluate tumor-associated genomic and genetic variations in plasma cell-free DNA (cfDNA) and their associations with treatment response and overall survival, we applied whole genome and targeted sequencing to examine the plasma cfDNAs derived from 20 patients with advanced prostate cancer. Sequencing-based genomic abnormality analysis revealed locus-specific gains or losses that were common in prostate cancer, such as 8q gains, AR amplifications, PTEN losses and TMPRSS2-ERG fusions. To estimate tumor burden in cfDNA, we developed a Plasma Genomic Abnormality (PGA) score by summing the most significant copy number variations. Cox regression analysis showed that PGA scores were significantly associated with overall survival (p < 0.04). After androgen deprivation therapy or chemotherapy, targeted sequencing showed significant mutational profile changes in genes involved in androgen biosynthesis, AR activation, DNA repair, and chemotherapy resistance. These changes may reflect the dynamic evolution of heterozygous tumor populations in response to these treatments. These results strongly support the feasibility of using non-invasive liquid biopsies as potential tools to study biological mechanisms underlying therapy-specific resistance and to predict disease progression in advanced prostate cancer. PMID- 25915541 TI - Holographic metalens for switchable focusing of surface plasmons. AB - Surface plasmons polaritons (SPPs) are light-like waves confined to the interface between a metal and a dielectric. Excitation and control of these modes requires components such as couplers and lenses. We present the design of a new lens based on holographic principles. The key feature is the ability to switchably control SPP focusing by changing either the incident wavelength or polarization. Using phase-sensitive near-field imaging of the surface plasmon wavefronts, we have observed their switchable focusing and steering as the wavelength or polarization is changed. PMID- 25915540 TI - The Phosphoinositide 3-Kinase p110alpha Isoform Regulates Leukemia Inhibitory Factor Receptor Expression via c-Myc and miR-125b to Promote Cell Proliferation in Medulloblastoma. AB - Medulloblastoma (MB) is the most common malignant brain tumor in childhood and represents the main cause of cancer-related death in this age group. The phosphoinositide 3-kinase (PI3K) pathway has been shown to play an important role in the regulation of medulloblastoma cell survival and proliferation, but the molecular mechanisms and downstream effectors underlying PI3K signaling still remain elusive. The impact of RNA interference (RNAi)-mediated silencing of PI3K isoforms p110alpha and p110delta on global gene expression was investigated by DNA microarray analysis in medulloblastoma cell lines. A subset of genes with selectively altered expression upon p110alpha silencing in comparison to silencing of the closely related p110delta isoform was revealed. Among these genes, the leukemia inhibitory factor receptor alpha (LIFR alpha) was validated as a novel p110alpha target in medulloblastoma. A network involving c-Myc and miR 125b was shown to be involved in the control of LIFRalpha expression downstream of p110alpha. Targeting the LIFRalpha by RNAi, or by using neutralizing reagents impaired medulloblastoma cell proliferation in vitro and induced a tumor volume reduction in vivo. An analysis of primary tumors revealed that LIFRalpha and p110alpha expression were elevated in the sonic hedgehog (SHH) subgroup of medulloblastoma, indicating its clinical relevance. Together, these data reveal a novel molecular signaling network, in which PI3K isoform p110alpha controls the expression of LIFRalpha via c-Myc and miR-125b to promote MB cell proliferation. PMID- 25915542 TI - I wanted you to know: Breast cancer survivors' control of workplace communication about cancer. AB - Of working women diagnosed with cancer, approximately one-third will have breast cancer. Communicating about their cancer plays an important role in their workplace experience. It is challenging but helpful in eliciting needed social support and accommodations. Fully understanding such communication experiences is important in order to facilitate the well-being and success of such women in their workplaces. A qualitative study permits a richer account of the details of these workplace communications, and a deeper understanding of how women manage the complex and multifaceted communication process. This study used thematic analysis of semistructured interviews from 19 women working full time at the time of their breast cancer diagnosis. We found 3 themes that encapsulated unfolding individual experiences, representing a complex interplay of challenges to maintaining a sense of personal control in workplace responses: challenges to control posed by the experience of sharing information in the workplace about the woman's cancer, women's very individual attempts to control how information about their cancer was shared, and the mixed responses of those who were told. The result was unique individual trajectories in which empathic responses tailored to the individual's needs and preferences were most helpful. These findings can provide guidance on managing cancer communication for survivors, and on how to best support and accommodate women workers with breast cancer, facilitating their ability to control how their cancer impacts their work experience. Our website (http://www.iwantedyoutoknow.ca/) provides a video, tip sheet, and other resources for facilitating supportive communication in the workplace. PMID- 25915543 TI - Correction: Nicotiana small RNA sequences support a host genome origin of Cucumber mosaic virus satellite RNA. AB - [This corrects the article DOI: 10.1371/journal.pgen.1004906.]. PMID- 25915544 TI - First report of Clostridium difficile NAP1/027 in a Mexican hospital. AB - BACKGROUND AND OBJECTIVE: Clostridium difficile NAP1/ribotype 027 is associated with severe disease and high mortality rates. Our aim was to determine the prevalence of NAP1/ribotype 027 among C. difficile isolates in a tertiary care hospital, and review the main clinical data. METHODS: We included 106 stool samples from 106 patients. Samples were tested for A&B toxins and were cultured on CCFA agar. The genes tcdA, tcdB, tcdC, cdtA, and cdtB were amplified using PCR in clinical isolates. The tcdA 3'-end deletion analysis, PCR-ribotyping, and pulsed-field gel electrophoresis (PFGE) were also performed. Stool samples that were positive for culture were tested by the GeneXpert C. difficile assay. Clinical data were collected. RESULTS: Thirty-six patients tested positive for A&B toxins; and 22 patients had positive culture for C. difficile, 14 of which tested positive for the A&B toxins and all 22 patients tested positive by the GeneXpert C. difficile assay. Risk factors included an average hospital stay of 16.1 days prior to toxin detection, average antibiotic use for 16.2 days, and a median of 3 antibiotics used. The 30-day crude mortality rate was 8.4%. Six of the 22 patients died, and 3 of those deaths were directly attributed to C. difficile infection. The majority of isolates, 90.9% (20/22), carried genes tcdB, tcdA, cdtA, and cdtB; and these strains carried the corresponding downregulator gene tcdC, with an 18-bp deletion. PFGE was performed on 17 isolates, and one main pattern was observed. Analysis of the ribotyping data showed similar results. CONCLUSION: The above findings represent the clonal spread of C. difficile in our institution, which mainly includes the NAP1/027 strain. This is the first report of C. difficile ribotype NAP1/027 in Mexico. PMID- 25915546 TI - N-methylation of amines with methanol at room temperature. AB - N-Methylation of amines with methanol proceeds at room temperature in the presence of a silver-loaded titanium dioxide (Ag/TiO2) photocatalyst under UV-vis light irradiation. This method allows facile synthesis/isolation of N methylamines bearing various functional groups including N-benzyl, N-allyl, N Boc, hydroxyl, ether, acetal, carboxamide, formamide, and olefin groups. PMID- 25915545 TI - Cystamine preparations exhibit anticoagulant activity. AB - Transglutaminases are a superfamily of isoenzymes found in cells and plasma. These enzymes catalyze the formation of epsilon-N-(gamma-glutamyl)-lysyl crosslinks between proteins. Cystamine blocks transglutaminase activity and is used in vitro in human samples and in vivo in mice and rats in studies of coagulation, immune dysfunction, and inflammatory disease. These studies have suggested cystamine blocks fibrin crosslinking and has anti-inflammatory effects, implicating transglutaminase activity in the pathogenesis of several diseases. We measured the effects of cystamine on fibrin crosslinking, tissue factor-triggered plasma clot formation and thrombin generation, and coagulation factor enzymatic activity. At concentrations that blocked fibrin crosslinking, cystamine also inhibited plasma clot formation and reduced thrombin generation. Cystamine inhibited the amidolytic activity of coagulation factor XI and thrombin towards chromogenic substrates. These findings demonstrate that cystamine exhibits anticoagulant activity during coagulation. Given the close relationship between coagulation and inflammation, these findings suggest prior studies that used cystamine to implicate transglutaminase activity in disease pathogenesis warrant re-examination. PMID- 25915547 TI - Risk factors for hospital readmission after radical gastrectomy for gastric cancer: a prospective study. AB - BACKGROUND: Hospital readmission is gathering increasing attention as a measure of health care quality and a potential cost-saving target. The purpose of this prospective study was to determine risk factors for readmission within 30 days of discharge after gastrectomy for patients with gastric cancer. METHODS: We conducted a prospective study of patients undergoing radical gastrectomy for gastric cancer from October 2013 to November 2014 in our institution. The incidence, cause and risk factors for 30-day readmission were determined. RESULTS: A total of 376 patients were included in our analysis without loss in follow-up. The 30-day readmission rate after radical gastrectomy for gastric cancer was 7.2% (27of 376). The most common cause for readmission included gastrointestinal complications and postoperative infections. On the basis of multivariate logistic regression analysis, preoperative nutritional risk screening 2002 score >= 3 was an independent risk factor for 30-day readmission. Factors not associated with a higher readmission rate included a history of a major postoperative complication during the index hospitalization, prolonged primary length of hospital stay after surgery, a history of previous abdominal surgery, advanced age, body mass index, pre-existing cardiopulmonary comorbidities, American Society of Anesthesiology grade, type of resection, extent of node dissection and discharge disposition. CONCLUSIONS: Readmission within 30 days of discharge after radical gastrectomy for gastric cancer is common. Patients with nutritional risk preoperatively are at high risk for 30-day readmission. Preoperative optimization of nutritional status of patients at nutritional risk may effectively decrease readmission rates. PMID- 25915548 TI - Use of Pollen Solid-Phase Extraction for the Determination of trans-Resveratrol in Peanut Oils. AB - In this study, a simple and convenient method for the determination of trans resveratrol (TRA) in peanut oils based on pollen grain solid-phase extraction (SPE) was developed. Pollen grains were used as normal-phase SPE sorbent to separate TRA from peanut oils for the first time. As a naturally occurring material, pollen grains exhibited an excellent adsorption capacity for polyphenolic compounds due to their particular functional structures such as hydroxyl groups, saturated and unsaturated aliphatic chains with aromatics. Their stable compositions as well as adequate particle size (30-40 MUm) also make them suitable for SPE. Several parameters influencing extraction performance were investigated. Coupled with high-performance liquid chromatography-ultraviolet detection (HPLC-UV), a green purification method for fast determination of TRA in peanut oils using pollen grain cartridges as sorbents was established. The linearity range of the proposed method was 10-2500 ng . g(-1) with a satisfactory correlation coefficient (r(2)) of 0.9999. The limit of detection (LOD) for TRA in peanut oils was 2.7 ng . g(-1), and the recoveries in spiked oil samples were from 70.2% to 98.4% with the relative standard deviations (RSDs) less than 4.9% (intraday) and 5.2% (interday). This method was successfully applied to the analysis of TRA in several peanut oils with different brands from local market as well as other kinds of vegetable oils. PMID- 25915549 TI - HIV-related stigma in a New York City sample of adults in outpatient care for HIV infection: a short report. AB - This analysis used data from a randomly selected cross-sectional sample of HIV infected outpatient adults in New York City to assess HIV-related stigma and examine gender-specific differences among factors associated with HIV-related stigma. Data was collected by conducting participant interviews and medical records abstraction. HIV-related stigma was assessed using the internalized AIDS related stigma scale (IA-RSS). Exploratory factor analysis of the IA-RSS indicated that the scale consisted of two factors: (1) internalized stigma and (2) anticipated stigma. Of the 447 sampled participants 23.9% had a higher level of internalized stigma and 38.3% had a higher level of anticipated stigma. Multivariate analysis indicated that among females, internalized stigma was associated with being diagnosed HIV positive after the introduction of HAART in 1996 (adjusted prevalence ratio [PR]: 1.9; 95% CI: 1.2, 3.1; P < 0.01) and a diagnosis of depression (adjusted PR: 1.9; 95% CI: 1.2, 2.9; P < 0.01). Among males, anticipated stigma was associated with younger age (18 and 39 years) (adjusted PR: 1.7; 95% CI: 1.3, 2.2; P < 0.001) and use of non-injection drugs (adjusted PR: 0.60; 95% CI: 0.41, 0.86; P < 0.01). Findings suggest that there may be gender-specific differences among factors associated with different dimensions of HIV-related stigma. PMID- 25915550 TI - To punish or to leave: distinct cognitive processes underlie partner control and partner choice behaviors. AB - When a cooperative partner defects, at least two types of response are available: Punishment, aimed at modifying behavior, and ostracism, aimed at avoiding further social interaction with the partner. These options, termed partner control and partner choice, have been distinguished at behavioral and evolutionary levels. However, little work has compared their cognitive bases. Do these disparate behaviors depend on common processes of moral evaluation? Specifically, we assess whether they show identical patterns of dependence on two key dimensions of moral evaluation: A person's intentions, and the outcomes that they cause. We address this issue in a "trembling hand" economic game. In this game, an allocator divides a monetary stake between themselves and a responder based on a stochastic mechanism. This allows for dissociations between the allocator's intent and the actual outcome. Responders were either given the opportunity to punish or reward the allocator (partner control) or to switch to a different partner for a subsequent round of play (partner choice). Our results suggest that partner control and partner choice behaviors are supported by distinct underlying cognitive processes: Partner control exhibits greater sensitivity to the outcomes a partner causes, while partner choice is influenced almost exclusively by a partner's intentions. This cognitive dissociation can be understood in light of the unique adaptive functions of partner control and partner choice. PMID- 25915551 TI - Radiation protection issues on preparedness and response for a severe nuclear accident: experiences of the Fukushima accident. AB - Radiation protection issues on preparedness and response for a severe nuclear accident are discussed in this paper based on the experiences following the accident at Fukushima Daiichi nuclear power plant. The criteria for use in nuclear emergencies in the Japanese emergency preparedness guide were based on the recommendations of International Commission of Radiological Protection (ICRP) Publications 60 and 63. Although the decision-making process for implementing protective actions relied heavily on computer-based predictive models prior to the accident, urgent protective actions, such as evacuation and sheltering, were implemented effectively based on the plant conditions. As there were no recommendations and criteria for long-term protective actions in the emergency preparedness guide, the recommendations of ICRP Publications 103, 109, and 111 were taken into consideration in determining the temporary relocation of inhabitants of heavily contaminated areas. These recommendations were very useful in deciding the emergency protective actions to take in the early stages of the Fukushima accident. However, some suggestions have been made for improving emergency preparedness and response in the early stages of a severe nuclear accident. PMID- 25915552 TI - French policy for managing the post-accident phase of a nuclear accident. AB - In 2005, at the request of the French Government, the Nuclear Safety Authority (ASN) established a Steering Committee for the Management of the Post-Accident Phase of a Nuclear Accident or a Radiological Emergency, with the objective of establishing a policy framework. Under the supervision of ASN, this Committee, involving several tens of experts from different backgrounds (e.g. relevant ministerial offices, expert agencies, local information commissions around nuclear installations, non-governmental organisations, elected officials, licensees, and international experts), developed a number of recommendations over a 7-year period. First published in November 2012, these recommendations cover the immediate post-emergency situation, and the transition and longer-term periods of the post-accident phase in the case of medium-scale nuclear accidents causing short-term radioactive release (less than 24 h) that might occur at French nuclear facilities. They also apply to actions to be undertaken in the event of accidents during the transportation of radioactive materials. These recommendations are an important first step in preparation for the management of a post-accident situation in France in the case of a nuclear accident. PMID- 25915553 TI - Trends in radiation protection of positron emission tomography/computed tomography imaging. AB - Over the past decade, the number of positron emission tomography/computed tomography (PET/CT) imaging procedures has increased substantially. This imaging technique provides accurate functional and anatomical information, particularly for oncological applications. Separately, both PET and CT are considered as high dose imaging modalities. With the increased use of PET/CT, one could expect an increase in radiation doses to staff and patients. As such, major efforts have been made to reduce radiation dose in PET/CT facilities. Variations in working techniques have made it difficult to compare published results. This study aimed to review the literature on proposed methods to reduce patient and staff dose in clinical PET/CT imaging. A brief overview of some published information on staff and patient doses will be analysed and presented. Recent trends regarding radiation protection in PET/CT imaging will be discussed, and practical recommendations for reducing radiation doses to staff and patients will be discussed and summarised. Generally, the CT dose component is often higher in magnitude than the dose from PET alone; as such, focusing on CT dose reduction will decrease the overall patient dose in PET/CT imaging studies. The following factors should be considered in order to reduce the patient's dose from CT alone: proper justification for ordering contrast-enhanced CT; use of automatic exposure control features; use of adaptive statistical iterative reconstruction algorithms; and optimisation of scan parameters, especially scan length. The PET dose component can be reduced by administration of lower activity to the patient, optimisation of the workflow, and appropriate use of protective devices and engineered systems. At the international level, there is wide variation in work practices among institutions. The current observed trends are such that the annual dose limits for radiation workers in PET/CT imaging are unlikely to be exceeded. PMID- 25915554 TI - Referral criteria and clinical decision support: radiological protection aspects for justification. AB - Advanced imaging technology has opened new horizons for medical diagnostics and improved patient care. However, many procedures are unjustified and do not provide a net benefit. An area of particular concern is the unnecessary use of radiation when clinical evaluation or other imaging modalities could provide an accurate diagnosis. Referral criteria for medical imaging are consensus statements based on the best-available evidence to assist the decision-making process when choosing the best imaging procedure for a given patient. Although they are advisory rather than compulsory, physicians should have good reasons for deviation from these criteria. Voluntary use of referral criteria has shown limited success compared with integration into clinical decision support systems. These systems support good medical practice, can improve health service delivery, and foster safer, more efficient, fair, cost-effective care, thus contributing to the strengthening of health systems. Justification of procedures and optimisation of protection, the two pillars of radiological protection in health care, are implicit in the notion of good medical practice. However, some health professionals are not familiar with these principles, and have low awareness of radiological protection aspects of justification. A stronger collaboration between radiation protection and healthcare communities could contribute to improve the radiation protection culture in medical practice. PMID- 25915555 TI - Is the gut microbiome key to modulating vaccine efficacy? AB - A symbiotic relationship with gut microbes is critical for the normal function of human health. Vaccination, however, tips the symbiotic balance slightly in favor of human health. Recent work has shown that gut bacterial residents can have great (positive) influence over vaccine-induced immunity. With an arsenal of modern high-throughput technologies in the hands of microbiologists and immunologists, it is now easier and more cost-effective than ever to characterize and measure the microbiome of vaccinees. Such data will lead to an understanding of how and to what extent gut microbes can impact vaccine efficacy. PMID- 25915556 TI - Hydrogel-driven paper-based microfluidics. AB - Paper-based microfluidics provide an inexpensive, easy to use technology for point-of-care diagnostics in developing countries. Here, we combine paper-based microfluidic devices with responsive hydrogels to add an entire new class of functions to these versatile low-cost fluidic systems. The hydrogels serve as fluid reservoirs. In response to an external stimulus, e.g. an increase in temperature, the hydrogels collapse and release fluid into the structured paper substrate. In this way, chemicals that are either stored on the paper substrate or inside the hydrogel pads can be dissolved, premixed, and brought to reaction to fulfill specific analytic tasks. We demonstrate that multi-step sequences of chemical reactions can be implemented in a paper-based system and operated without the need for external precision pumps. We exemplify this technology by integrating an antibody-based E. coli test on a small and easy to use paper device. PMID- 25915557 TI - Platelet interactions with viruses and parasites. AB - While the interactions between Gram-positive bacteria and platelets have been well characterized, there is a paucity of data on the interaction between other pathogens and platelets. However, thrombocytopenia is a common feature with many infections especially viral hemorrhagic fever. The little available data on these interactions indicate a similarity with bacteria-platelet interactions with receptors such as FcgammaRIIa and Toll-Like Receptors (TLR) playing key roles with many pathogens. This review summarizes the known interactions between platelets and pathogens such as viruses, fungi and parasites. PMID- 25915558 TI - gamma,delta,epsilon-C(sp(3))-H Functionalization through Directed Radical H Abstraction. AB - Aliphatic amides are selectively functionalized at the gamma- and delta-positions through directed radical 1,5 and 1,6 H-abstractions, respectively. The initially formed gamma- or delta-lactams are intercepted by N-iodosuccinimide and trimethylsilyl azide, leading to double and triple C-H functionalizations at the gamma-, delta-, and epsilon-positions. This new reactivity is exploited to convert alkyls into amino alcohols and allylic amines. PMID- 25915559 TI - The Cephalostatins. 23. Conversion of Hecogenin to a Steroidal 1,6 Dioxaspiro[5.5]nonane Analogue for Cephalostatin 11. AB - Cephalostatin 1 (1) has proved to be a remarkably potent cancer cell growth inhibitor. Since this steroidal alkaloid constituent of the marine worm Cephalodiscus gilchristi possesses a complex structure, providing preclinical supplies by total synthesis continues to be challenging. Therefore, syntheses of less complex structural modifications of this important pyrazine have also received substantial attention. Herein are summarized the synthesis of [5.5]spiroketal 5, a simplified right-side steroidal unit of 1, in seven steps from hecogenin acetate (11) with an overall yield of 4.6%. Consistent with other SAR studies, such reduction in structural complexity compared to 1 led to loss of cancer cell growth inhibitory activity against the P388 lymphocytic leukemia cell line. PMID- 25915560 TI - Irradiation-enhanced reactivity of multilayer Al/Ni nanomaterials. AB - We have investigated the effect of accelerated ion beam irradiation on the structure and reactivity of multilayer sputter deposited Al/Ni nanomaterials. Carbon and aluminum ion beams with different charge states and intensities were used to irradiate the multilayer materials. The conditions for the irradiation assisted self-ignition of the reactive materials and corresponding ignition thresholds for the beam intensities were determined. We discovered that relatively short (40 min or less) ion irradiations enhance the reactivity of the Al/Ni nanomaterials, that is, significantly decrease the thermal ignition temperatures (Tig) and ignition delay times (tauig). We also show that irradiation leads to atomic mixing at the Al/Ni interfaces with the formation of an amorphous interlayer, in addition to the nucleation of small (2-3 nm) Al3Ni crystals within the amorphous regions. The amorphous interlayer is thought to enhance the reactivity of the multilayer energetic nanomaterial by increasing the heat of the reaction and by speeding the intermixing of the Ni and the Al. The small Al3Ni crystals may also enhance reactivity by facilitating the growth of this Al-Ni intermetallic phase. In contrast, longer irradiations decrease reactivity with higher ignition temperatures and longer ignition delay times. Such changes are also associated with growth of the Al3Ni intermetallic and decreases in the heat of reaction. Drawing on this data set, we suggest that ion irradiation can be used to fine-tune the structure and reactivity of energetic nanomaterials. PMID- 25915561 TI - Assault on breast cancer. PMID- 25915562 TI - News From the International Council on Women's Health Issues. PMID- 25915563 TI - Effects of trichlorotelluro-dypnones on mitochondrial bioenergetics and their relationship to the reactivity with protein thiols. AB - The effect of four trichlorotelluro-dypnones, named compounds 1, 2, 3, and 4, on the bioenergetics of isolated rat liver mitochondria (RLM) and cells was investigated. In a dose-dependent manner, the studied organotelluranes promoted Ca(2+)-dependent mitochondrial swelling inhibited by cyclosporine A and were associated with a decrease of the total mitochondrial protein thiol content. These effects characterize the opening of the classical mitochondrial permeability transition pore. Despite the reactivity with mitochondrial protein thiol groups, these compounds did not promote significant glutathione depletion. In the absence of Ca(2+), the organotelluranes promoted mitochondrial loss of DeltaPsi in RLM concomitant with respiratory control decrease due to an increase of the state 4 respiration rate. In these conditions, mitochondrial swelling was absent, and thiol content was higher than that in the presence of Ca(2+). The differentiated effects observed in the presence and absence of Ca(2+) are probably related to the effects of that ion on membrane structure, with repercussions for the exposure of specific reactive protein thiol groups. In smooth muscle cells, these compounds promoted the loss of mitochondrial DeltaPsi and apoptosis. The loss of DeltaPsi was not preceded by a decrease of cell viability that is consistent with mitochondria as the primary targets for the action of these organotelluranes. PMID- 25915565 TI - Enantioselective Synthesis of Chromanones via a Peptidic Phosphane Catalyzed Rauhut-Currier Reaction. AB - The enantioselective intramolecular Rauhut-Currier reaction has been developed using a bifunctional dipeptidic phosphane catalyst, providing a direct access to biologically active alpha-methylene-delta-valerolactones in high yields and enantiomeric excesses. The novel catalyst is accessible in only four steps from commercial sources and exhibits unusual binding selectivities for a small molecule, suggesting the possibility for long-range interactions between the catalyst and the substrate. PMID- 25915564 TI - Deubiquitinating enzymes regulate PARK2-mediated mitophagy. AB - The selective degradation of mitochondria by the process of autophagy, termed mitophagy, is one of the major mechanisms of mitochondrial quality control. The best-studied mitophagy pathway is the one mediated by PINK1 and PARK2/Parkin. From recent studies it has become clear that ubiquitin-ligation plays a pivotal role and most of the focus has been on the role of ubiquitination of mitochondrial proteins in mitophagy. Even though ubiquitination is a reversible process, very little is known about the role of deubiquitinating enzymes (DUBs) in mitophagy. Here, we report that 2 mitochondrial DUBs, USP30 and USP35, regulate PARK2-mediated mitophagy. We show that USP30 and USP35 can delay PARK2 mediated mitophagy using a quantitative mitophagy assay. Furthermore, we show that USP30 delays mitophagy by delaying PARK2 recruitment to the mitochondria during mitophagy. USP35 does not delay PARK2 recruitment, suggesting that it regulates mitophagy through an alternative mechanism. Interestingly, USP35 only associates with polarized mitochondria, and rapidly translocates to the cytosol during CCCP-induced mitophagy. It is clear that PARK2-mediated mitophagy is regulated at many steps in this important quality control pathway. Taken together, these findings demonstrate an important role of mitochondrial associated DUBs in mitophagy. Because defects in mitochondria quality control are implicated in many neurodegenerative disorders, our study provides clear rationales for the design and development of drugs for the therapeutic treatment of neurodegenerative diseases such as Parkinson and Alzheimer diseases. PMID- 25915566 TI - Hypoglycemia Observed on Continuous Glucose Monitoring Associated With IGF-2 Producing Solitary Fibrous Tumor. AB - CONTEXT: Tumors producing IGF-2 (IGF-2oma) are a major cause of spontaneous hypoglycemia. The treatment mainstay is surgical resection. Many case reports note resolution of hypoglycemia after IGF-2oma resection; however, outcomes are variable according to tumor type. We report a case of resolving hypoglycemia, observed on continuous glucose monitoring, after resection of an IGF-2-producing solitary fibrous tumor of pleura and review the current literature. CASE REPORT: A 69-year-old woman presented with impaired consciousness because of hypoglycemia. An IGF-2oma was diagnosed as the cause for hypoglycemia because of decreased serum insulin and IGF-1, the presence of a pleural tumor, and a high molecular-weight form of serum IGF-2 detected by Western immunoblot. Surgical resection was performed; pathological examination demonstrated a solitary fibrous tumor with low-grade malignancy. Continuous glucose monitoring showed reversal of hypoglycemia after tumor resection. Approximately 2 years after resection, the patient has no signs of tumor recurrence or hypoglycemia. CONCLUSIONS: An IGF-2 producing solitary fibrous tumor of pleura in this case caused hypoglycemia. From a search of the literature of 2004-2014, 32 cases of IGF-2oma with hypoglycemia that underwent radical surgery were identified; in 19 (59%) patients, hypoglycemia was reversed, and there was no subsequent recurrence. The remaining 13 (41%) patients experienced tumor recurrence or metastasis an average of 43 months after initial tumor resection. The tumor of the present case was a low grade malignancy. Regular follow-up with biomarker monitoring of glucose metabolism and assessment of hypoglycemic symptomatology, in conjunction with imaging tests, is important for detecting possible tumor recurrence and metastasis. PMID- 25915567 TI - The Relationship Between Variation in Size of the Primordial Follicle Pool and Age at Natural Menopause. AB - CONTEXT: Menopause has been hypothesized to occur when the nongrowing follicle (NGF) number falls below a critical threshold. Age at natural menopause can be predicted using NGF numbers and this threshold. These predictions support the use of ovarian reserve tests, reflective of the ovarian follicle pool, in menopause forecasting. OBJECTIVE: The objective of the study was to investigate the hypothesis that age-specific NGF numbers reflect age at natural menopause. DESIGN AND SETTING: Histologically derived NGF numbers obtained from published literature (n = 218) and distribution of menopausal ages derived from the population-based Prospect-European Prospective Investigation into Cancer and Nutrition (Prospect-EPIC) cohort (n = 4037) were combined. PARTICIPANTS: NGF data were from single ovaries that had been obtained postnatally for various reasons, such as elective surgery or autopsy. From the Prospect-EPIC cohort, women aged 58 years and older with a known age at natural menopause were selected. INTERVENTIONS: There were no interventions. MAIN OUTCOME MEASURE(S): Conformity between observed age at menopause in the Prospect-EPIC cohort and NGF-predicted age at menopause from a model for age-related NGF decline constructed using a robust regression analysis. A critical threshold for NGF number was estimated by comparing the probability distribution of the age at which the NGF numbers fall below this threshold with the observed distribution of age at natural menopause from the Prospect-EPIC cohort. RESULTS: The distributions of observed age at natural menopause and predicted age at natural menopause showed close conformity. CONCLUSION: The close conformity observed between NGF-predicted and actual age at natural menopause supports the hypothesis that that the size of the primordial follicle pool is an important determinant for the length of the individual ovarian life span and supports the concept of menopause prediction using ovarian reserve tests, such as anti-Mullerian hormone and antral follicle count, as derivatives of the true ovarian reserve. PMID- 25915568 TI - Hypoglycosylated hFSH Has Greater Bioactivity Than Fully Glycosylated Recombinant hFSH in Human Granulosa Cells. AB - CONTEXT: Previous studies suggest that aging in women is associated with a reduction in hypoglycosylated forms of FSH. OBJECTIVE: Experiments were performed to determine whether glycosylation of the FSHbeta subunit modulates the biological activity of FSH in human granulosa cells. DESIGN AND SETTING: Recombinant human FSH (hFSH) derived from GH3 pituitary cells was purified into fractions containing hypoglycosylated hFSH(21/18) and fully glycosylated hFSH(24). The response to FSH glycoforms was evaluated using the well characterized, FSH-responsive human granulosa cell line, KGN at an academic medical center. INTERVENTIONS: Granulosa cells were treated with increasing concentrations of fully- or hypoglycosylated FSH glycoforms for periods up to 48 hours. MAIN OUTCOME MEASURE(S): The main outcomes were indices of cAMP-dependent cell signaling and estrogen and progesterone synthesis. RESULTS: We observed that hypoglycosylated FSH(21/18) was significantly more effective than fully glycosylated FSH(24) at stimulating cAMP accumulation, protein kinase A (PKA) activity, and cAMP response element binding protein (CREB) (S133) phosphorylation. FSH(21/18) was also much more effective than hFSH(24) on the stimulation CREB-response element-mediated transcription, expression of aromatase and STAR proteins, and synthesis of estrogen and progesterone. Adenoviral mediated expression of the endogenous inhibitor of PKA, inhibited FSH(21/18)- and FSH(24)-stimulated CREB phosphorylation, and steroidogenesis. CONCLUSIONS: Hypoglycosylated FSH(21/18) has greater bioactivity than fully glycosylated hFSH(24), suggesting that age-dependent decreases in hypoglycosylated hFSH contribute to reduced ovarian responsiveness. Hypoglycosylated FSH may be useful in follicle stimulation protocols for older patients using assisted reproduction technologies. PMID- 25915569 TI - LGR5 Activates Noncanonical Wnt Signaling and Inhibits Aldosterone Production in the Human Adrenal. AB - CONTEXT: Aldosterone synthesis and cellularity in the human adrenal zona glomerulosa (ZG) is sparse and patchy, presumably due to salt excess. The frequency of somatic mutations causing aldosterone-producing adenomas (APAs) may be a consequence of protection from cell loss by constitutive aldosterone production. OBJECTIVE: The objective of the study was to delineate a process in human ZG, which may regulate both aldosterone production and cell turnover. DESIGN: This study included a comparison of 20 pairs of ZG and zona fasciculata transcriptomes from adrenals adjacent to an APA (n = 13) or a pheochromocytoma (n = 7). INTERVENTIONS: Interventions included an overexpression of the top ZG gene (LGR5) or stimulation by its ligand (R-spondin-3). MAIN OUTCOME MEASURES: A transcriptome profile of ZG and zona fasciculata and aldosterone production, cell kinetic measurements, and Wnt signaling activity of LGR5 transfected or R-spondin 3-stimulated cells were measured. RESULTS: LGR5 was the top gene up-regulated in ZG (25-fold). The gene for its cognate ligand R-spondin-3, RSPO3, was 5-fold up regulated. In total, 18 genes associated with the Wnt pathway were greater than 2 fold up-regulated. ZG selectivity of LGR5, and its absence in most APAs, were confirmed by quantitative PCR and immunohistochemistry. Both R-spondin-3 stimulation and LGR5 transfection of human adrenal cells suppressed aldosterone production. There was reduced proliferation and increased apoptosis of transfected cells, and the noncanonical activator protein-1/Jun pathway was stimulated more than the canonical Wnt pathway (3-fold vs 1.3-fold). ZG of adrenal sections stained positive for apoptosis markers. CONCLUSION: LGR5 is the most selectively expressed gene in human ZG and reduces aldosterone production and cell number. Such conditions may favor cells whose somatic mutation reverses aldosterone inhibition and cell loss. PMID- 25915570 TI - Treatment with anti-C5aR mAb leads to early-onset clinical and mechanistic effects in the murine delayed-type hypersensitivity arthritis model. AB - Blockade of the complement cascade at the C5a/C5a receptor (C5aR)-axis is believed to be an attractive treatment avenue in rheumatoid arthritis (RA). However, the effects of such interventions during the early phases of arthritis remain to be clarified. In this study we use the murine delayed-type hypersensitivity arthritis (DTHA) model to study the very early effects of a blocking, non-depleting anti-C5aR mAb on joint inflammation with treatment synchronised with disease onset, an approach not previously described. The DTHA model is a single-paw inflammatory arthritis model characterised by synchronised and rapid disease onset driven by T-cells, immune complexes and neutrophils. We show that a reduction in paw swelling, bone erosion, cartilage destruction, synovitis and new bone formation is apparent as little as 60 h after administration of a single dose of a blocking, non-depleting anti-mouse C5aR mAb. Importantly, infiltration of neutrophils into the joint and synovium is also reduced following a single dose, demonstrating that C5aR signalling during the early stage of arthritis regulates neutrophil infiltration and activation. Furthermore, the number of T-cells in circulation and in the draining popliteal lymph node is also reduced following a single dose of anti-C5aR, suggesting that modulation of the C5a/C5aR axis results in effects on the T cell compartment in inflammatory arthritis. In summary, these data demonstrate that blockade of C5aR leads to rapid and significant effects on arthritic disease development in a DTHA model strengthening the rationale of C5aR-blockade as a treatment strategy for RA, especially during the early stages of arthritis flare. PMID- 25915571 TI - Complicating autoimmune diseases in myasthenia gravis: a review. AB - Myasthenia gravis (MG) is a rare autoimmune disease of skeletal muscle endplates. MG subgroup is relevant for comorbidity, but usually not accounted for. MG patients have an increased risk for complicating autoimmune diseases, most commonly autoimmune thyroid disease, systemic lupus erythematosus and rheumatoid arthritis. In this review, we present concomitant autoimmune disorders associated with the different MG subgroups, and show how this influences treatment and prognosis. Concomitant MG should always be considered in patients with an autoimmune disorder and developing new neuromuscular weakness, fatigue or respiratory failure. When a second autoimmune disorder is suspected, MG should be included as a differential diagnosis. PMID- 25915572 TI - Continuing the quest for autoimmunity due to oral metal exposure. AB - AIM: The role of metal exposure in the development of autoimmune disease (AID) is still controversial. Here, we studied the relationship between oral metal exposure, metal allergy and autoimmunity. METHODS: A mixed population (n = 78) of non-allergic volunteers, metal-allergic patients and patients with oral problems putatively due to metal alloys was evaluated for oral Ni, Pd, Au and Hg exposure and skin hypersensitivity. Clinical autoimmune parameters were based on medical histories; additionally, serum levels of the four most common autoantibodies were measured. RESULTS: Skin hypersensitivity, as seen mainly for Ni and/or Pd, was not positively associated with autoimmune parameters. In contrast, metal hypersensitive individuals showed an extremely low frequency of thyroid autoantibodies (3% vs 20% in non-hypersensitive controls). Next, the relation between metal exposure and autoimmunity was evaluated in individuals >35 years (n = 58), since from that age on metal exposure had plateaued and was not correlated with age. In this subgroup, oral Ni exposure was associated (p < 0.01) with self reported AID, irrespective of autoantibody levels. These unexpected findings warrant further confirmation in a larger test group. Of note, oral Pd, Au or Hg contacts were not associated with any of the clinical or serological autoimmune phenomena tested. CONCLUSION: The results of this study support the view that development of metal contact allergies may prevent autoimmune activation, and, second, that oral exposure to Pd, Au or Hg does not facilitate the development of AID. PMID- 25915573 TI - Sustained Reduction in Bloodstream Infections in Infants at a Large Tertiary Care Neonatal Intensive Care Unit. AB - BACKGROUND: Bloodstream infections (BSI) cause significant morbidity and mortality among hospitalized infants. PURPOSE: Reduction of BSIs has emerged as an important patient safety goal. Implementation of central line insertion bundles, standardized line care protocols, and health care provider education programs have reduced BSI in NICUs around the country. The ability of large tertiary care centers to decrease nosocomial infections, including BSI, has been demonstrated. However, long-term BSI reductions in infants are not well documented. We sought to demonstrate that a low incidence of BSI can be maintained over time in a tertiary care NICU. RESULTS: Baseline BSI incidence for infants admitted to the NICU was 5.15 and 6.08 episodes per 1000 infant-days in 2005 and 2006, respectively. After protocol implementation, the incidence of BSI decreased to 2.14/1000 infant-days and 2.44/1000 infant-days in 2008 and 2009, respectively. Yearly incidence remained low over the next 4 years and decreased even further to 0.20 to 0.45 infections per 1000 infant-days. This represents a 92% decrease in BSI over a period of more than 5 years. IMPLICATIONS FOR PRACTICE: Implementation of a nursing-led comprehensive infection control initiative can effectively produce and maintain a reduction in the incidence of BSI in infants at a large tertiary care NICU. IMPLICATIONS FOR RESEARCH: Additional research is needed to effectively expand prevention of central line associated BSIs to BSIs of all etiologies. PMID- 25915574 TI - A National Survey of the Nursing Care of Infants With Prenatal Substance Exposure in Canadian NICUs. AB - BACKGROUND: Many communities are reporting increases in the number of infants requiring NICU care. Practices continue to vary and there is limited available evidence about nursing care. PURPOSE: The purpose of this study was to describe current nursing care practices for infants with prenatal substance exposure in the NICU setting and during transition to the community. Findings from this study were compared with an earlier Canadian survey (by Marcellus in 2002) to identify shifts in clinical nursing practice for this population. METHODS: This was a cross-sectional descriptive survey design. A 68-item survey composed of multiple choice and open-ended questions was administered through FluidSurveys online software. A convenience sample of 62 clinical managers or clinical educators in hospitals with active maternal-infant clinical units with 500 deliveries or more annually and/or pediatric hospitals with a separate designated neonatal service (ie, Level 2 and 3 units) was chosen. RESULTS: A greater number of NICUs are using clinical guidelines to support the standardization of quality care. Improvements in nursing practice were identified and these included the consistent use of a withdrawal scoring tool and provision of education for team members in orientation. A decline in routine discharge planning meetings and routine parent teaching plans was discovered. IMPLICATIONS FOR PRACTICE: This survey has improved understanding of the current state of nursing care for infants with prenatal substance exposure and their families during this critical time of transition. The purpose of the survey was to compare findings with the 2002 study by Marcellus to identify any improved practices and describe current state nursing care practices in the NICU. Practice changes over the last decade have included keeping mothers and infants together, expanding concepts of the team, integrating programs and services across hospital and community settings, and creating opportunities for NICU teams to learn more about substance use, mental health, violence, and trauma. IMPLICATIONS FOR RESEARCH: Focus on discharge planning, parent teaching, and creation and implementation of national/hospital guidelines is essential for consistent evidence-based quality patient care. PMID- 25915575 TI - Toxicity and response to thiopurines in patients with inflammatory bowel disease. AB - The use of thiopurines is well established in the management of inflammatory bowel disease. A wealth of data and experience, amassed over several decades, supporting their efficacy has recently been challenged by trials that failed to show a benefit in Crohn's disease when used early in the disease course, although other trials continue to support their role both as monotherapy and in combination with anti-TNF. Recent reports of previously unrecognized toxicity have also emerged. Fortunately, the absolute incidence of serious toxicity remains low, and an improved understanding of how best to minimize risk and the recognition of groups of patients at higher risk of toxicity from thiopurines means that they remain a relatively safe therapy in the majority of patients. In this paper, we review the literature evaluating the role of thiopurines in inflammatory bowel disease as well as their toxicity. We conclude that education regarding the spectrum of thiopurine side effects and optimal monitoring during therapy may help with optimizing safety and efficacy of these important medications. PMID- 25915576 TI - Life-Long Transgene Expression in Skeletal Muscle Without Transduction of Satellite Cells Following Embryonic Myogenic Progenitor Transduction by Lentivirus Administered in Utero. AB - Embryologic events in mammalian myogenesis remain to be fully defined. Recent evidence supports the presence of a common progenitor arising in the dermomyotome that gives rise to both embryologic and adult muscle and postnatal myogenic stem cells (satellite cells). In this study, we utilize the technique of early intra amniotic gene transfer to target nascent muscle progenitors as they traverse the primitive streak before formation of the dermomyotome. This technique robustly transduced both epaxial and hypaxial muscle groups. Marker gene expression is observed in up to 100% muscle fibers in the lower extremities and is sustained for the lifetime of the mouse. We next analyzed transduced muscle for satellite cell transduction using highly sensitive methodology. Surprisingly, despite high levels of sustained transgene expression in muscle fibers, satellite cells lacked the marker transgene. Our data suggest that dermatomyotome is a heterogeneous structure and that not all myogenic progenitors of dermatomyotome give rise to satellite cells. PMID- 25915577 TI - Adult age differences in memory for schema-consistent and schema-inconsistent objects in a real-world setting. AB - The present study examined age-related differences in the inconsistency effect, in which memory is enhanced for schema-inconsistent information compared to schema-consistent information. Young and older adults studied schema-consistent and schema-inconsistent objects in an academic office under either intentional or incidental encoding instructions, and were given two recognition tests either immediately or after 48 hr: A yes/no item recognition test that included modified remember/know judgments and a token recognition test that required determining whether an original object was replaced with a different object with the same name. Young and older adults showed equivalent inconsistency effects in both item and token recognition tests, although older adults reported phenomenologically less rich memories of schema-inconsistent objects relative to young adults. These findings run counter to previous reports suggesting that aging is associated with processing declines at encoding that impair memory for details of schema inconsistent or distinctive events. The results are consistent with a retrieval based account in which age-related difficulties in retrieving contextual details can be offset by environmental support. PMID- 25915578 TI - The potential of interleukin 12 receptor beta 2 (IL12RB2) and tumor necrosis factor receptor superfamily member 8 (TNFRSF8) gene as diagnostic biomarkers of oral lichen planus (OLP). AB - OBJECTIVE: This study evaluated the potential of interleukin 12 receptor beta 2 and tumor necrosis factor receptor superfamily member 8 as diagnostic biomarkers of oral lichen planus (OLP). MATERIALS AND METHODS: The mRNA expression of IL12RB2 and TNFRSF8 in FFPE OLP samples (OLP group, n = 38) were investigated with quantitative reverse transcriptase-polymerase chain reaction (qRT-PCR) analysis and compared to those of chronic non-specific mucositis (Non-OLP group, n = 25) and normal mucosa (Normal group, n = 18). Predictive modeling of the expression of IL12RB2 and TNFRSF8 was constructed using support vector machine (SVM), random forest (RF), linear discriminant analysis (LDA), neural network (NN) and naive Bayes (NB) methods. RESULTS: Normalized expression of IL12RB2 in the OLP group (3.78 +/- 1.67) was significantly higher than the Normal group (1.97 +/- 1.12), but lower than the Non-OLP group (6.86 +/- 1.67). TNFRSF8 gene expression in the OLP group (7.46 +/- 1.51) was significantly higher than the Normal group (2.90 +/- 1.61), but no significant difference was found between the OLP and Non-OLP groups. The ratio of IL12RB2/TNFRSF8 in the OLP group (0.52 +/- 0.23) was significantly lower than the Normal group (0.74 +/- 0.39) and the Non OLP group (1.07 +/- 0.38). In the predictive modeling, the area under receiver operating characteristic (ROC) curves (AUC) ranged from 0.83-0.92 and their accuracy was higher than 0.75 in all methods. CONCLUSIONS: The IL12RB2/TNFRSF8 ratio can be a useful diagnostic tool for OLP. PMID- 25915579 TI - Decisions regarding resuscitation of extremely premature infants: should social context matter? PMID- 25915580 TI - The role of apolipoprotein E episilon (epsilon)-4 allele on outcome following traumatic brain injury: A systematic review. AB - BACKGROUND: The apolipoprotein E gene (APOE) has emerged as a candidate for prognosticating traumatic brain injury (TBI) recovery, with APOEepsilon4 identified as a susceptibility marker for poor outcome, despite large discrepancy in its reported influence post-TBI. METHODS: A systematic review was conducted, including all primary articles investigating the role of APOEepsilon4 on TBI outcome. A total of 65 studies were included, including 24 predominantly investigating mild (mTBI), seven moderate (modTBI) and 33 severe (sTBI); severity was not reported in one study. RESULTS: In mTBI studies, the association between APOEepsilon4 and post-TBI outcome was concluded as non-contributory in 14 studies (58.3%), hazardous in nine (37.5%) and protective in one (4.2%). In sTBI studies, the role of APOEepsilon4 was hazardous in 21 (63.6%), non-contributory in nine (27.3%) and protective in three (9.1%). Of the seven studies investigating dementia outcomes, four observed a hazardous association with APOEepsilon4, while three reported no association. Six studies examined Alzheimer's dementia pathology, of which three reported a hazardous influence of APOEepsilon4. CONCLUSIONS: The influence of APOEepsilon4 on neuropsychological testing, functional outcome and in paediatric populations was incongruous. This review supports the majority of research indicating APOEepsilon4 adversely influences recovery following TBI, particularly with respect to dementia-related outcomes and outcomes following sTBI. PMID- 25915581 TI - Sexual dimorphism in autoimmunity. AB - Autoimmune diseases occur when the immune system attacks and destroys the organs and tissues of its own host. Autoimmunity is the third most common type of disease in the United States. Because there is no cure for autoimmunity, it is extremely important to study the mechanisms that trigger these diseases. Most autoimmune diseases predominantly affect females, indicating a strong sex bias. Various factors, including sex hormones, the presence or absence of a second X chromosome, and sex-specific gut microbiota can influence gene expression in a sex-specific way. These changes in gene expression may, in turn, lead to susceptibility or protection from autoimmunity, creating a sex bias for autoimmune diseases. In this Review we discuss recent findings in the field of sex-dependent regulation of gene expression and autoimmunity. PMID- 25915582 TI - Albumin-associated free fatty acids induce macropinocytosis in podocytes. AB - Podocytes are specialized epithelial cells in the kidney glomerulus that play important structural and functional roles in maintaining the filtration barrier. Nephrotic syndrome results from a breakdown of the kidney filtration barrier and is associated with proteinuria, hyperlipidemia, and edema. Additionally, podocytes undergo changes in morphology and internalize plasma proteins in response to this disorder. Here, we used fluid-phase tracers in murine models and determined that podocytes actively internalize fluid from the plasma and that the rate of internalization is increased when the filtration barrier is disrupted. In cultured podocytes, the presence of free fatty acids (FFAs) associated with serum albumin stimulated macropinocytosis through a pathway that involves FFA receptors, the Gbeta/Ggamma complex, and RAC1. Moreover, mice with elevated levels of plasma FFAs as the result of a high-fat diet were more susceptible to Adriamycin-induced proteinuria than were animals on standard chow. Together, these results support a model in which podocytes sense the disruption of the filtration barrier via FFAs bound to albumin and respond by enhancing fluid-phase uptake. The response to FFAs may function in the development of nephrotic syndrome by amplifying the effects of proteinuria. PMID- 25915583 TI - Glycosphingolipid synthesis inhibition limits osteoclast activation and myeloma bone disease. AB - Glycosphingolipids (GSLs) are essential constituents of cell membranes and lipid rafts and can modulate signal transduction events. The contribution of GSLs in osteoclast (OC) activation and osteolytic bone diseases in malignancies such as the plasma cell dyscrasia multiple myeloma (MM) is not known. Here, we tested the hypothesis that pathological activation of OCs in MM requires de novo GSL synthesis and is further enhanced by myeloma cell-derived GSLs. Glucosylceramide synthase (GCS) inhibitors, including the clinically approved agent N-butyl deoxynojirimycin (NB-DNJ), prevented OC development and activation by disrupting RANKL-induced localization of TRAF6 and c-SRC into lipid rafts and preventing nuclear accumulation of transcriptional activator NFATc1. GM3 was the prevailing GSL produced by patient-derived myeloma cells and MM cell lines, and exogenous addition of GM3 synergistically enhanced the ability of the pro-osteoclastogenic factors RANKL and insulin-like growth factor 1 (IGF-1) to induce osteoclastogenesis in precursors. In WT mice, administration of GM3 increased OC numbers and activity, an effect that was reversed by treatment with NB-DNJ. In a murine MM model, treatment with NB-DNJ markedly improved osteolytic bone disease symptoms. Together, these data demonstrate that both tumor-derived and de novo synthesized GSLs influence osteoclastogenesis and suggest that NB-DNJ may reduce pathological OC activation and bone destruction associated with MM. PMID- 25915585 TI - Neurovascular crosstalk between interneurons and capillaries is required for vision. AB - Functional interactions between neurons, vasculature, and glia within neurovascular units are critical for maintenance of the retina and other CNS tissues. For example, the architecture of the neurosensory retina is a highly organized structure with alternating layers of neurons and blood vessels that match the metabolic demand of neuronal activity with an appropriate supply of oxygen within perfused blood. Here, using murine genetic models and cell ablation strategies, we have demonstrated that a subset of retinal interneurons, the amacrine and horizontal cells, form neurovascular units with capillaries in 2 of the 3 retinal vascular plexuses. Moreover, we determined that these cells are required for generating and maintaining the intraretinal vasculature through precise regulation of hypoxia-inducible and proangiogenic factors, and that amacrine and horizontal cell dysfunction induces alterations to the intraretinal vasculature and substantial visual deficits. These findings demonstrate that specific retinal interneurons and the intraretinal vasculature are highly interdependent, and loss of either or both elicits profound effects on photoreceptor survival and function. PMID- 25915584 TI - Targeted inhibition of tumor-specific glutaminase diminishes cell-autonomous tumorigenesis. AB - Glutaminase (GLS), which converts glutamine to glutamate, plays a key role in cancer cell metabolism, growth, and proliferation. GLS is being explored as a cancer therapeutic target, but whether GLS inhibitors affect cancer cell autonomous growth or the host microenvironment or have off-target effects is unknown. Here, we report that loss of one copy of Gls blunted tumor progression in an immune-competent MYC-mediated mouse model of hepatocellular carcinoma. Compared with results in untreated animals with MYC-induced hepatocellular carcinoma, administration of the GLS-specific inhibitor bis-2-(5-phenylacetamido 1,3,4-thiadiazol-2-yl)ethyl sulfide (BPTES) prolonged survival without any apparent toxicities. BPTES also inhibited growth of a MYC-dependent human B cell lymphoma cell line (P493) by blocking DNA replication, leading to cell death and fragmentation. In mice harboring P493 tumor xenografts, BPTES treatment inhibited tumor cell growth; however, P493 xenografts expressing a BPTES-resistant GLS mutant (GLS-K325A) or overexpressing GLS were not affected by BPTES treatment. Moreover, a customized Vivo-Morpholino that targets human GLS mRNA markedly inhibited P493 xenograft growth without affecting mouse Gls expression. Conversely, a Vivo-Morpholino directed at mouse Gls had no antitumor activity in vivo. Collectively, our studies demonstrate that GLS is required for tumorigenesis and support small molecule and genetic inhibition of GLS as potential approaches for targeting the tumor cell-autonomous dependence on GLS for cancer therapy. PMID- 25915586 TI - Lineage fate of ductular reactions in liver injury and carcinogenesis. AB - Ductular reactions (DRs) are observed in virtually all forms of human liver disease; however, the histogenesis and function of DRs in liver injury are not entirely understood. It is widely believed that DRs contain bipotential liver progenitor cells (LPCs) that serve as an emergency cell pool to regenerate both cholangiocytes and hepatocytes and may eventually give rise to hepatocellular carcinoma (HCC). Here, we used a murine model that allows highly efficient and specific lineage labeling of the biliary compartment to analyze the histogenesis of DRs and their potential contribution to liver regeneration and carcinogenesis. In multiple experimental and genetic liver injury models, biliary cells were the predominant precursors of DRs but lacked substantial capacity to produce new hepatocytes, even when liver injuries were prolonged up to 12 months. Genetic modulation of NOTCH and/or WNT/beta-catenin signaling within lineage-tagged DRs impaired DR expansion but failed to redirect DRs from biliary differentiation toward the hepatocyte lineage. Further, lineage-labeled DRs did not produce tumors in genetic and chemical HCC mouse models. In summary, we found no evidence in our system to support mouse biliary-derived DRs as an LPC pool to replenish hepatocytes in a quantitatively relevant way in injury or evidence that DRs give rise to HCCs. PMID- 25915587 TI - Mast cells mediate malignant pleural effusion formation. AB - Mast cells (MCs) have been identified in various tumors; however, the role of these cells in tumorigenesis remains controversial. Here, we quantified MCs in human and murine malignant pleural effusions (MPEs) and evaluated the fate and function of these cells in MPE development. Evaluation of murine MPE-competent lung and colon adenocarcinomas revealed that these tumors actively attract and subsequently degranulate MCs in the pleural space by elaborating CCL2 and osteopontin. MCs were required for effusion development, as MPEs did not form in mice lacking MCs, and pleural infusion of MCs with MPE-incompetent cells promoted MPE formation. Once homed to the pleural space, MCs released tryptase AB1 and IL 1beta, which in turn induced pleural vasculature leakiness and triggered NF kappaB activation in pleural tumor cells, thereby fostering pleural fluid accumulation and tumor growth. Evaluation of human effusions revealed that MCs are elevated in MPEs compared with benign effusions. Moreover, MC abundance correlated with MPE formation in a human cancer cell-induced effusion model. Treatment of mice with the c-KIT inhibitor imatinib mesylate limited effusion precipitation by mouse and human adenocarcinoma cells. Together, the results of this study indicate that MCs are required for MPE formation and suggest that MC dependent effusion formation is therapeutically addressable. PMID- 25915588 TI - Comparing the immunogenicity and safety of 3 Japanese encephalitis vaccines in Asia-Pacific area: A systematic review and meta-analysis. AB - Japanese encephalitis virus (JEV), a leading cause of Japanese encephalitis (JE) in children and adults, is a major public health problem in Asian countries. This study reports a meta-analysis of the immunogenicity and safety of vaccines used to protect infants or children from JE. Three types of JE vaccine were examined, namely, Japanese encephalitis live-attenuated vaccine (JEV-L), Japanese encephalitis inactivated vaccine (Vero cell) (JEV-I(Vero)), and Japanese encephalitis inactivated vaccine (primary hamster kidney cell) (JEV-I(PHK)). These vaccines are used to induce fundamental immunity against JE; however, few studies have compared their immunogenicity and safety in infants and young children less than 2 years of age. Data were obtained by searching 5 databases: Web of Science, PubMed, China National Knowledge Infrastructure, the China Wanfang database, and the Cochrane database. Fifteen articles were identified and scored using the Jadad score for inclusion in the meta-analysis. Random effect models were used to calculate the pooled seroconversion rate and adverse reaction rate when tests for heterogeneity were significant. The results showed that the pooled seroconversion rate for JEV-I(PHK) (62.23%) was lower than that for JEV I(Vero) (86.49%) and JEV-L (83.52%), and that the pooled adverse reaction rate for JEV-L (18.09%) was higher than that for JEV-I(PHK) (10.08%) and JEV-I(Vero) (12.49%). The pooled relative risk was then calculated to compare the seroconversion and adverse reaction rates. The results showed that JEV-I(Vero) and JEV-L were more suitable than JEV-I(PHK) for inducing fundamental immunity to JE in infants and children less than 2 years of age. PMID- 25915589 TI - Lower Extremity Joint Angle Tracking with Wireless Ultrasonic Sensors during a Squat Exercise. AB - This paper presents an unrestrained measurement system based on a wearable wireless ultrasonic sensor network to track the lower extremity joint and trunk kinematics during a squat exercise with only one ultrasonic sensor attached to the trunk. The system consists of an ultrasound transmitter (mobile) and multiple receivers (anchors) whose positions are known. The proposed system measures the horizontal and vertical displacement, together with known joint constraints, to estimate joint flexion/extension angles using an inverse kinematic model based on the damped least-squares technique. The performance of the proposed ultrasonic measurement system was validated against a camera-based tracking system on eight healthy subjects performing a planar squat exercise. Joint angles estimated from the ultrasonic system showed a root mean square error (RMSE) of 2.85 degrees +/- 0.57 degrees with the reference system. Statistical analysis indicated great agreements between these two systems with a Pearson's correlation coefficient (PCC) value larger than 0.99 for all joint angles' estimation. These results show that the proposed ultrasonic measurement system is useful for applications, such as rehabilitation and sports. PMID- 25915590 TI - Angular Displacement and Velocity Sensors Based on Coplanar Waveguides (CPWs) Loaded with S-Shaped Split Ring Resonators (S-SRR). AB - In this paper, angular displacement and angular velocity sensors based on coplanar waveguide (CPW) transmission lines and S-shaped split ring resonators (S SRRs) are presented. The sensor consists of two parts, namely a CPW and an S-SRR, both lying on parallel planes. By this means, line-to-resonator magnetic coupling arises, the coupling level being dependent on the line-to-resonator relative angular orientation. The line-to-resonator coupling level is the key parameter responsible for modulating the amplitude of the frequency response seen between the CPW ports in the vicinity of the S-SRR fundamental resonance frequency. Specifically, an amplitude notch that can be visualized in the transmission coefficient is changed by the coupling strength, and it is characterized as the sensing variable. Thus, the relative angular orientation between the two parts is measured, when the S-SRR is attached to a rotating object. It follows that the rotation angle and speed can be inferred either by measuring the frequency response of the S-SRR-loaded line, or the response amplitude at a fixed frequency in the vicinity of resonance. It is in addition shown that the angular velocity can be accurately determined from the time-domain response of a carrier time harmonic signal tuned at the S-SRR resonance frequency. The main advantage of the proposed device is its small size directly related to the small electrical size of the S-SRR, which allows for the design of compact angular displacement and velocity sensors at low frequencies. Despite the small size of the fabricated proof-of-concept prototype (electrically small structures do not usually reject signals efficiently), it exhibits good linearity (on a logarithmic scale), sensitivity and dynamic range. PMID- 25915591 TI - Children draw more affiliative pictures following priming with third-party ostracism. AB - Humans have a strong need to belong. Thus, when signs of ostracism are detected, adults often feel motivated to affiliate with others in order to reestablish their social connections. This study investigated the importance of affiliation to young children following priming with ostracism. Four- and 5-year-old children were primed with either ostracism or control videos and their understanding of, and responses to, the videos were measured. Results showed that children were able to report that there was exclusion in the ostracism videos, and that they recognized that the ostracized individual felt sad. Most interestingly, when subsequently asked to draw a picture of themselves and their friend, children primed with ostracism depicted relationships that were significantly more affiliative. Children drew themselves and their friend standing significantly closer together and adults rated their drawings as more affiliative overall. These findings introduce drawing as a useful new method for measuring social motivations and processes following an experimental manipulation, and demonstrate that affiliation is particularly important to children following even a vicarious experience of social exclusion. PMID- 25915592 TI - Early adversity, elevated stress physiology, accelerated sexual maturation, and poor health in females. AB - Evolutionary-minded developmentalists studying predictive-adaptive-response processes linking childhood adversity with accelerated female reproductive development and health scientists investigating the developmental origins of health and disease (DOoHaD) may be tapping the same process, whereby longer-term health costs are traded off for increased probability of reproducing before dying via a process of accelerated reproductive maturation. Using data from 73 females, we test the following propositions using path analysis: (a) greater exposure to prenatal stress predicts greater maternal depression and negative parenting in infancy, (b) which predicts elevated basal cortisol at 4.5 years, (c) which predicts accelerated adrenarcheal development, (d) which predicts more physical and mental health problems at age 18. Results prove generally consistent with these propositions, including a direct link from cortisol to mental health problems. DOoHaD investigators should consider including early sexual maturation as a core component linking early adversity and stress physiology with poor health later in life in females. PMID- 25915593 TI - Parenting as a Moderator of the Effects of Maternal Depressive Symptoms on Preadolescent Adjustment. AB - The purpose of this study was to examine whether parenting moderated the association between maternal depressive symptoms and initial levels and growth of preadolescent internalizing and externalizing symptoms. This study used a community sample of preadolescent children (N = 214; 8-12 years old at Time 1), measuring maternal depressive symptoms and parenting at Time 1, and preadolescent internalizing and externalizing symptoms at each year for 3 years. After modeling latent growth curves of internalizing and externalizing symptoms, growth factors were conditioned on maternal depressive symptoms, positive (acceptance and consistent discipline) and negative (rejection and physical punishment) parenting, and the interactions of depression and parenting. Maternal rejection moderated the relation of maternal depression with internalizing symptoms, such that high rejection exacerbated the effects of maternal depressive symptoms on initial levels of preadolescent internalizing problems. There were no significant interactions predicting externalizing problems. The findings highlight how specific parenting behaviors may alter the way in which maternal depressive symptoms confer risk for behavior problems. PMID- 25915594 TI - In vivo short-term exposure to residual oil fly ash impairs pulmonary innate immune response against environmental mycobacterium infection. AB - Epidemiological studies have shown that pollution derived from industrial and vehicular transportation induces adverse health effects causing broad ambient respiratory diseases. Therefore, air pollution should be taken into account when microbial diseases are evaluated. Environmental mycobacteria (EM) are opportunist pathogens that can affect a variety of immune compromised patients, which impacts significantly on human morbidity and mortality. The aim of this study was to evaluate the effect of residual oil fly ash (ROFA) pre-exposure on the pulmonary response after challenge with opportunistic mycobacteria by means of an acute short-term in vivo experimental animal model. We exposed BALB/c mice to ROFA and observed a significant reduction on bacterial clearance at 24 h post infection. To study the basis of this impaired response four groups of animals were instilled with (a) saline solution (Control), (b) ROFA (1 mg kg(-1) BW), (c) ROFA and EM-infected (Mycobacterium phlei, 8 * 10(6) CFU), and (d) EM-infected. Animals were sacrificed 24 h postinfection and biomarkers of lung injury and proinflammatory madiators were examined in the bronchoalveolar lavage. Our results indicate that ROFA was able to produce an acute pulmonary injury characterized by an increase in bronchoalveolar polymorphonuclear (PMN) cells influx and a rise in O2 (-) generation. Exposure to ROFA before M. phlei infection reduced total cell number and caused a significant decline in PMN cells recruitment (p < 0.05), O2 (-) generation, TNFalpha (p < 0.001), and IL-6 (p < 0.001) levels. Hence, our results suggest that, in this animal model, the acute short-term pre-exposure to ROFA reduces early lung response to EM infection. PMID- 25915595 TI - A quantum biochemistry investigation of willardiine partial agonism in AMPA receptors. AB - We employ quantum biochemistry methods based on the Density Functional Theory (DFT) approach to unveil the detailed binding energy features of willardiines co crystallized with the AMPA receptor. Our computational results demonstrate that the total binding energies of fluorine-willardiine (FW), hydrogen-willardiine (HW), bromine-willardiine (BrW) and iodine-willardiine (IW) to the iGluR2 ligand pocket correlate with the agonist binding energies, whose experimental sequential data match our computational counterpart, excluding the HW case. We find that the main contributions to the total willardiine-iGluR2 binding energy are due to the amino acid residues in decreasing order Glu705 > Arg485 > Ser654 > Tyr450 > T655. Furthermore, Met708, which is positioned close to the 5-substituent, attracts HW and FW, but repels BrW and IW. Our results contribute significantly to an improved understanding of the willardiine-iGluR2 binding mechanisms. PMID- 25915596 TI - Germline RECQL mutations are associated with breast cancer susceptibility. AB - Several moderate- and high-risk breast cancer susceptibility genes have been discovered, but more are likely to exist. To discover new breast cancer susceptibility genes, we used 2 populations (from Poland and Quebec, Canada) and applied whole-exome sequencing in a discovery phase (n = 195), followed by validation. We identified rare recurrent RECQL mutations in each population. In Quebec, 7 of 1,013 higher-risk breast cancer cases and 1 of 7,136 newborns carried the c.634C>T (p.Arg215*) variant (P = 0.00004). In Poland, 30 of 13,136 unselected breast cancer cases and 2 of 4,702 controls carried the c.1667_1667+3delAGTA (p.K555delinsMYKLIHYSFR) variant (P = 0.008). RECQL is implicated in resolving stalled DNA replication forks to prevent double-stranded DNA (dsDNA) breaks. This function is related to that of other known breast cancer susceptibility genes, many of which are involved in repairing dsDNA breaks. We conclude that RECQL is a breast cancer susceptibility gene. PMID- 25915597 TI - Improved genome inference in the MHC using a population reference graph. AB - Although much is known about human genetic variation, such information is typically ignored in assembling new genomes. Instead, reads are mapped to a single reference, which can lead to poor characterization of regions of high sequence or structural diversity. We introduce a population reference graph, which combines multiple reference sequences and catalogs of variation. The genomes of new samples are reconstructed as paths through the graph using an efficient hidden Markov model, allowing for recombination between different haplotypes and additional variants. By applying the method to the 4.5-Mb extended MHC region on human chromosome 6, combining 8 assembled haplotypes, the sequences of known classical HLA alleles and 87,640 SNP variants from the 1000 Genomes Project, we demonstrate using simulations, SNP genotyping, and short-read and long-read data how the method improves the accuracy of genome inference and identified regions where the current set of reference sequences is substantially incomplete. PMID- 25915598 TI - Mutations in KCNH1 and ATP6V1B2 cause Zimmermann-Laband syndrome. AB - Zimmermann-Laband syndrome (ZLS) is a developmental disorder characterized by facial dysmorphism with gingival enlargement, intellectual disability, hypoplasia or aplasia of nails and terminal phalanges, and hypertrichosis. We report that heterozygous missense mutations in KCNH1 account for a considerable proportion of ZLS. KCNH1 encodes the voltage-gated K(+) channel Eag1 (Kv10.1). Patch-clamp recordings showed strong negative shifts in voltage-dependent activation for all but one KCNH1 channel mutant (Gly469Arg). Coexpression of Gly469Arg with wild type KCNH1 resulted in heterotetrameric channels with reduced conductance at positive potentials but pronounced conductance at negative potentials. These data support a gain-of-function effect for all ZLS-associated KCNH1 mutants. We also identified a recurrent de novo missense change in ATP6V1B2, encoding the B2 subunit of the multimeric vacuolar H(+) ATPase, in two individuals with ZLS. Structural analysis predicts a perturbing effect of the mutation on complex assembly. Our findings demonstrate that KCNH1 mutations cause ZLS and document genetic heterogeneity for this disorder. PMID- 25915599 TI - Analysis of loss-of-function variants and 20 risk factor phenotypes in 8,554 individuals identifies loci influencing chronic disease. AB - A typical human exome harbors dozens of loss-of-function (LOF) variants, which can lower disease risk factor levels and affect drug efficacy. We hypothesized that LOF variants are enriched in genes influencing risk factor levels and the onset of common chronic diseases, such as cardiovascular disease and diabetes. To test this hypothesis, we sequenced the exomes of 8,554 individuals and analyzed the effects of predicted LOF variants on 20 chronic disease risk factor phenotypes. Analysis of this sample as discovery and replication strata of equal size verified two relationships in well-studied genes (PCSK9 and APOC3) and identified eight new loci. Previously unknown relationships included elevated fasting glucose in carriers of heterozygous LOF variation in TXNDC5, which encodes a biomarker for type 1 diabetes progression, and apparent recessive effects of C1QTNF8 on serum magnesium levels. These data demonstrate the utility of functional-variant annotation within a large sample of deeply phenotyped individuals for gene discovery. PMID- 25915601 TI - Distinct phenotype, longitudinal changes of numbers and cell-associated virus in blood dendritic cells in SIV-infected CD8-lymphocyte depleted macaques. AB - Loss of circulating CD123+ plasmacytoid dendritic cells (pDCs) during HIV infection is well established. However, changes of myeloid DCs (mDCs) are ambiguous since they are studied as a homogeneous CD11c+ population despite phenotypic and functional heterogeneity. Heterogeneity of CD11c+ mDCs in primates is poorly described in HIV and SIV infection. Using multiparametric flow cytometry, we monitored longitudinally cell number and cell-associated virus of CD123+ pDCs and non-overlapping subsets of CD1c+ and CD16+ mDCs in SIV-infected CD8-depleted rhesus macaques. The numbers of all three DC subsets were significantly decreased by 8 days post-infection. Whereas CD123+ pDCs were persistently depleted, numbers of CD1c+ and CD16+ mDCs rebounded. Numbers of CD1c+ mDCs significantly increased by 3 weeks post-infection while numbers of CD16+ mDCs remained closer to pre-infection levels. We found similar changes in the numbers of all three DC subsets in CD8 depleted animals as we found in animals that were SIV infected animals that were not CD8 lymphocyte depleted. CD16+ mDCs and CD123+ pDCs but not CD1c+ mDCs were significantly decreased terminally with AIDS. All DC subsets harbored SIV RNA as early as 8 days and then throughout infection. However, SIV DNA was only detected in CD123+ pDCs and only at 40 days post-infection consistent with SIV RNA, at least in mDCs, being surface-bound. Altogether our data demonstrate that SIV infection differently affects CD1c+ and CD16+ mDCs where CD16+ but not CD1c+ mDCs are depleted and might be differentially regulated in terminal AIDS. Finally, our data underline the importance of studying CD1c+ and CD16+ mDCs as discrete populations, and not as total CD11c+ mDCs. PMID- 25915600 TI - Understanding multicellular function and disease with human tissue-specific networks. AB - Tissue and cell-type identity lie at the core of human physiology and disease. Understanding the genetic underpinnings of complex tissues and individual cell lineages is crucial for developing improved diagnostics and therapeutics. We present genome-wide functional interaction networks for 144 human tissues and cell types developed using a data-driven Bayesian methodology that integrates thousands of diverse experiments spanning tissue and disease states. Tissue specific networks predict lineage-specific responses to perturbation, identify the changing functional roles of genes across tissues and illuminate relationships among diseases. We introduce NetWAS, which combines genes with nominally significant genome-wide association study (GWAS) P values and tissue specific networks to identify disease-gene associations more accurately than GWAS alone. Our webserver, GIANT, provides an interface to human tissue networks through multi-gene queries, network visualization, analysis tools including NetWAS and downloadable networks. GIANT enables systematic exploration of the landscape of interacting genes that shape specialized cellular functions across more than a hundred human tissues and cell types. PMID- 25915603 TI - Self-care Decontamination within a Chemical Exposure Mass-casualty Incident. AB - Growing awareness and concern for the increasing frequency of incidents involving hazardous materials (HazMat) across a broad spectrum of contaminants from chemical, biological, radiological, and nuclear (CBRN) sources indicates a clear need to refine the capability to respond successfully to mass-casualty contamination incidents. Best results for decontamination from a chemical agent will be achieved if done within minutes following exposure, and delays in decontamination will increase the length of time a casualty is in contact with the contaminate. The findings presented in this report indicate that casualties involved in a HazMat/CBRN mass-casualty incident (MCI) in a typical community would not receive sufficient on-scene care because of operational delays that are integral to a standard HazMat/CBRN first response. This delay in response will mean that casualty care will shift away from the incident scene into already over tasked health care facilities as casualties seek aid on their own. The self-care decontamination protocols recommended here present a viable option to ensure decontamination is completed in the field, at the incident scene, and that casualties are cared for more quickly and less traumatically than they would be otherwise. Introducing self-care decontamination procedures as a standard first response within the response community will improve the level of care significantly and provide essential, self-care decontamination to casualties. The process involves three distinct stages which should not be delayed; these are summarized by the acronym MADE: Move/Assist, Disrobe/Decontaminate, Evaluate/Evacuate. PMID- 25915602 TI - TNFA Haplotype Genetic Testing Improves HLA in Estimating the Risk of Celiac Disease in Children. AB - BACKGROUND: TNF-alpha and IFN-gamma play a role in the development of mucosal damage in celiac disease (CD). Polymorphisms of TNFA and IFNG genes, as well as of the TNFRSF1A gene, encoding the TNF-alpha receptor 1, might underlie different inter-individual disease susceptibility over a common HLA risk background. The aims of this study were to ascertain whether five SNPs in the TNFA promoter ( 1031T>C,-857C>T,-376G>A,-308G>A,-238G>A), sequence variants of the TNFRSF1A gene and IFNG +874A>T polymorphism are associated with CD in a HLA independent manner. METHODS: 511 children (244 CD, 267 controls) were genotyped for HLA, TNFA and INFG (Real Time PCR). TNFRSF1A variants were studied (DHPLC and sequence). RESULTS: Only the rare TNFA-1031C (OR=0.65, 95% CI:0.44-0.95), -857T (OR=0.42, 95% CI:0.27-0.65), -376A (OR=2.25, 95% CI:1.12-4.51) and -308A (OR=4.76, 95% CI:3.12-7.26) alleles were significantly associated with CD. One TNFRSF1A variant was identified (c.625+10A>G, rs1800693), but not associated with CD. The CD correlated TNFA SNPs resulted in six haplotypes. Two haplotypes were control associated (CCGG and TTGG) and three were CD-associated (CCAG, TCGA and CCGA). The seventeen inferred haplotype combinations were grouped (A to E) based on their frequencies among CD. Binary logistic regression analysis documented a strong association between CD and HLA (OR for intermediate risk haplotypes=178; 95% CI:24-1317; OR for high risk haplotypes=2752; 95% CI:287-26387), but also an HLA-independent correlation between CD and TNFA haplotype combination groups. The CD risk for patients carrying an intermediate risk HLA haplotype could be sub stratified by TNFA haplotype combinations. CONCLUSION: TNFA promoter haplotypes associate with CD independently from HLA. We suggest that their evaluation might enhance the accuracy in estimating the CD genetic risk. PMID- 25915604 TI - Editorial: Heterocycle and Hydrocarbon Compounds from Natural Sources in Medicinal Chemistry: From Synthesis to Computational Design in Pharmacological Applications - Part 1. PMID- 25915605 TI - Bioactive Coumarins from Marine Sources: Origin, Structural Features and Pharmacological Properties. AB - Nature is an ancient pharmacy that is largely used as an inspiring source for drug discovery processes for the early eras. Several drugs used nowadays are of natural product origin or inspired on the basis of natural product structures and approximately half of the 20 best-selling non-protein drugs are related to natural products. However, a largely unexplored marine world that presumably harbors the most biodiversity may be the vastest resource to discover compounds with remarkable biological properties. Marine based drug discovery research has been mainly focused on crude extracts. The purpose of this review is to summarize the findings reported in this area, particularly focuses on marine-derived coumarincontaining compounds. PMID- 25915606 TI - Anxiolytic-Like Effects of 7H-Benzo[e]perimidin-7-One Derivatives through Elevated Plus-Maze Test in Mice. AB - Anxiety is one of the behavior disorders that has been studied more together with depression in the world, and that has enormous interference in the mental health of the affected patients. The states of panic and phobia are a part of the psychological characteristics that some drugs have tried to control though with varied side effects that are proven to be difficult to control. The use of perimidinone derivatives against the effects of anxiety has generated that A5 is the most active and selective anxiolytic compound, differing with regard to diazepam (DZP) used as control reference in elevated plus-maze (EPM) test. This test allows to conclude that it is feasible to differentiate the use selective as anxiolytic or antidepressant of certain perimidinones, because A4 had been characterized by our research group as an important antidepressant respect to A5 studied in previous reports. PMID- 25915607 TI - Molecular Docking Studies of the Antitumoral Activity and Characterization of New Chalcone. AB - Phytochemical investigation of Azorella madreporica led to the isolation of four known compounds and an unknown chalcone. The structure of the new compound was identified by spectroscopy, including two-dimensional NMR techniques and comparison with published spectral data. The antioxidant activity of chalcone (compound 1) was measured using the 1,2-diphenyl-2-picryl-hydrazyl (DPPH) free radical scavenging assay, and the bioactivity was evaluated against five bacteria (Mycobacterium smegmatis ATCC 14468, clinical isolates of Staphylococcus aureus, Klebsiella granulomatis, Morganella morganii and Escherichia coli) and four cancer cell lines. Docking studies with the tested cancer related proteins revealed nearby values of energy between doxorubicin and compound 1. Besides, protein-ligand interactions correlate with these energy values. PMID- 25915608 TI - Cardiovascular Disease: A Target for the Pharmacological Effects of Quercetin. AB - Quercetin, a prominent dietary antioxidant present in vegetables, especially onions, fruits, highlighting apples and berries, wine and tea, belongs to a group of plant derived heterocyclic polyphenols. These compounds could be important mediators of the biological actions attributed to healthy diets. Chemically, quercetin is a type of flavonoid that specifically belongs to the flavonols group. It naturally occurs either as glycoside or aglycone, both of which have biological activity. Many of the natural sources of quercetin are included in the Mediterranean diet, a dietary habit associated with a decrease of cardiovascular diseases. During the last years, several researches have reported effects consistent with pharmacological applications of quercetin in cardiovascular diseases, such as atherosclerosis, ischemia-reperfusion injury, cardiotoxicity, and hypertension, among others. In this review, the pathways and molecules involved in the beneficial effects of quercetin are summarized. In addition, a scope of the new insights concerning quercetin pharmacokinetics, pharmacodynamics and bioavailability are presented. The mechanisms whereby quercetin exerts its effects have not been fully elucidated. However, interesting results have been obtained from early clinical studies involving cardioprotection by quercetin, but much knowledge is still lacking in the field of its bioavailability to improve the clinical application of this flavonol. This study presents evidence supporting the point of view that quercetin should be considered a potential therapeutic agent against cardiovascular diseases, giving rise to novel applications in their prevention and treatment. PMID- 25915609 TI - Piperine and Derivatives: Trends in Structure-Activity Relationships. AB - Piperine is the main constituent of pepper, a commonly used kitchen spice and has been reported to possess various pharmacological activities. The structural features, an aromatic ring with a methylenedioxy bridge, a conjugated dienone system and a piperidine ring constituting an amide bond, possessed by the molecule have been considered important for the molecule to exhibit an array of bioactivities. Several modifications of above structural units have affected the biological properties of piperine, either enhancing or in some cases completely abolishing the activity. The present review emphasizes on the synthetic aspects of piperine along with the structure-activity relationships of its derivatives so as to rationalize the discovery of newer piperine based molecules. PMID- 25915610 TI - Genistein: A Boon for Mitigating Ischemic Stroke. AB - In last decades, diet and dietary components have been regarded as important strategies to prevent the development or mitigate numerous chronic diseases, including inflammation, cardiovascular pathologies, cancer, etc. One of the most common dietary components of Asian population is soy. A plethora of research shows the promising effect of soy soy-based foodstuffs and genistein, which is one of the predominant isoflavone compounds, in the prevention and mitigation of stroke. Growing evidence shows that genistein, which is a selective estrogen receptor modulator, mitigates ischemic stroke-induced damages through the modification of oxidative stress and molecular pathways. The promising pharmacological role of genistein is attributed to its ability to suppress nuclear factor (NF)-kappa B and Akt signaling pathway, direct antioxidant action, and targeting estrogen and androgen-mediated molecular pathways which help to mitigate stroke damages and prolong cell survival. In this work, we systematically review the current reports on the therapeutic role of genistein against ischemic stroke and its molecular mechanism of actions. PMID- 25915611 TI - Cucurbitacin E, An Experimental Lead Triterpenoid with Anticancer, Immunomodulatory and Novel Effects Against Degenerative Diseases. A Mini-Review. AB - A growing number of studies have revealed that natural molecules own interesting antioxidant and anti-apoptotic properties in cell culture as well as in animal models of human diseases such as cancer, inflammatory and neurodegenerative diseases. During the past sixty years, several cucurbitacins have been isolated from a number of cucurbitaceous species, amongst others. Cucurbitacins are triterpenoid compounds originally identify as the bitter components of the Cucurbit family that demonstrated several pro-survival activities in various model of cellular decay. Specifically, Cucurbitacin E (CuE), an oxygenated tetracyclic triterpenoid, has been investigated in a wider array of bioactivities, mainly immunomodulatory. Recently, CuE has been reported to possess anti-inflammatory and anti-tumorigenic properties mediated by its action on the cellular cytoskeleton, on mitotic pathways as well as on cellular autophagy. Few studies also pinpoint the role of CuE in the nervous system as cytostatic for gliomas and neuroprotective in a model of Parkinson's diseases. This review deals with the use of CuE in various experimental models as one of the most promising therapeutic natural molecules against cancer proliferation, as an immunomudulator and for the prevention of neurodegeneration. PMID- 25915612 TI - Neocryptolepine: A Promising Indoloisoquinoline Alkaloid with Interesting Biological Activity. Evaluation of the Drug and its Most Relevant Analogs. AB - Plants are one of the most important resources for the discovery of new drugs. The potential of natural compounds as new drug leads is clearly illustrated by the discovery and development of many modern medicines. This is an encouraging factor that drives natural products research in the vegetable kingdom. Neocryptolepine is a tetracyclic nitrogen heterocycle isolated from the African climber Cryptolepis sanguinolenta, which is widely used in traditional African medicine in many countries of Central and West Africa. The natural product is one of the representative examples of the small family of indolo[2,3-b]quinoline alkaloids, being endowed of multiple biological activities, including DNA-binding and inhibition of the enzyme topoisomerase II. It is also cytotoxic, antibacterial, antifungal and molluscicidal, also displaying antiprotozoal activity, particularly as antitrypanosomal, antileishmanial, antischistosomal and antiplasmodial. Some of these activities have been related to the product's ability to bind to DNA and to inhibit topoisomerase II; however, the exact mechanisms behind all of the observed bioactivities have not been comprehensively clarified. Major research activities regarding neocryptolepine have been focused into two seemingly opposite fields, related to its cytotoxic and antimalarial properties. Optimization of the natural product as a cytotoxic agent implied improvements in its bioavailability and activity, while the need of non-cytotoxic compounds guided the design and optimization of antimalarial agents. Therefore, the aim of the present article is to systematically review the current knowledge about the diversity of the biological activities related to neocryptolepine, its analogs and derivatives. PMID- 25915613 TI - Coumarins: Auspicious Cholinesterase and Monoamine Oxidase Inhibitors. AB - Cholinesterase inhibition is the only current validated target in clinics in the treatment of Alzheimer's disease (AD). Therefore, there is continuous interest in the development and discovery of novel cholinesterase inhibitory molecules. Coumarins, beside their employment in other pharmacological groups, have also attracted attention to be utilized in cholinesterase inhibitory molecule discovery and development. Numerous studies so far indicated the natural and synthetic coumarin analogues that have the potential to inhibit acetylcholinesterase and butyrylcholinesterase enzymes. Since the pathophysiology of AD is highly complex and, in particular, monoamine oxidase (MAO) inhibitors are also utilized in clinic for disease symptoms, coumarin analogues, either natural or synthetic, that have the potential to inhibit cholinesterase or MAO enzymes are summarized within this review. PMID- 25915614 TI - Heterocyclic Curcumin Derivatives of Pharmacological Interest: Recent Progress. AB - Curcumin, a natural yellow polyphenol, is isolated from the herb Curcuma longa L. (turmeric), a member of the ginger family. It has been extensively studied due to their multiple pharmacological properties. Nevertheless, curcumin has disadvantages such as poor water solubility, poor bioavailability and rapid metabolism, which has prompted the search for analogues that overcome these shortcomings while maintaining or improving their good pharmacological properties. Among the main curcumin analogues that have been developed, the heterocyclic curcuminoids show a high interest. In this review, we describe recent progress in the synthesis and pharmacological properties of new heterocyclic curcumin derivatives. The most recent developments in anti-cancer, anti-Alzheimer, anti-bacterial and anti-oxidants heterocyclic curcumin derivatives are covered. PMID- 25915615 TI - Serotonergic 5-HT6 Receptor Antagonists: Heterocyclic Chemistry and Potential Therapeutic Significance. AB - The serotonin 5-HT(6) receptor (5- HT(6)R) is amongst the recently discovered serotonergic receptors with almost exclusive localization in the brain. Hence, this receptor is fast emerging as a promising target for cognition enhancement in central nervous system (CNS) diseases such as Alzheimer's disease (cognitive function), obesity, schizophrenia and anxiety. The last decade has seen a surge of literature reports on the functional role of this receptor in learning and memory processes and investigations related to the chemistry and pharmacology of 5-HT(6) receptor ligands, especially 5- HT(6) receptor antagonists. Studies show the involvement of multiple neurotransmitter systems in cognitive enhancement by 5-HT(6)R antagonists including cholinergic, glutamatergic, and GABAergic systems. Several of the 5-HT(6)R ligands are indole based agents bearing structural similarity to the endogenous neurotransmitter serotonin. Based on the pharmacophoric models proposed for these agents, drug designing has been carried out incorporating various heterocyclic replacements for the indole nucleus. In this review, we have broadly summarized the medicinal chemistry and current status of this fairly recent class of drugs along with their potential therapeutic applications. PMID- 25915616 TI - Economic evaluation of an alternative drug to sulfadoxine-pyrimethamine as intermittent preventive treatment of malaria in pregnancy. AB - BACKGROUND: Intermittent preventive treatment in pregnancy (IPTp) with sulfadoxine-pyrimethamine (SP) is recommended in HIV-negative women to avert malaria, while this relies on cotrimoxazole prophylaxis (CTXp) in HIV-positive women. Alternative antimalarials are required in areas where parasite resistance to antifolate drugs is high. The cost-effectiveness of IPTp with alternative drugs is needed to inform policy. METHODS: The cost-effectiveness of 2-dose IPTp mefloquine (MQ) was compared with IPTp-SP in HIV-negative women (Benin, Gabon, Mozambique and Tanzania). In HIV-positive women the cost-effectiveness of 3-dose IPTp-MQ added to CTXp was compared with CTXp alone (Kenya, Mozambique and Tanzania). The outcomes used were maternal clinical malaria, anaemia at delivery and non-obstetric hospital admissions. The poor tolerability to MQ was included as the value of women's loss of working days. Incremental cost-effectiveness ratios (ICERs) were calculated and threshold analysis undertaken. RESULTS: For HIV-negative women, the ICER for IPTp-MQ versus IPTp-SP was 136.30 US$ (2012 US$) (95%CI 131.41; 141.18) per disability-adjusted life-year (DALY) averted, or 237.78 US$ (95%CI 230.99; 244.57), depending on whether estimates from Gabon were included or not. For HIV-positive women, the ICER per DALY averted for IPTp-MQ added to CTXp, versus CTXp alone was 6.96 US$ (95%CI 4.22; 9.70). In HIV-negative women, moderate shifts of variables such as malaria incidence, drug cost, and IPTp efficacy increased the ICERs above the cost-effectiveness threshold. In HIV positive women the intervention remained cost-effective for a substantial (up to 21 times) increase in cost per tablet. CONCLUSIONS: Addition of IPTp with an effective antimalarial to CTXp was very cost-effective in HIV-positive women. IPTp with an efficacious antimalarial was more cost-effective than IPTp-SP in HIV negative women. However, the poor tolerability of MQ does not favour its use as IPTp. Regardless of HIV status, prevention of malaria in pregnancy with a highly efficacious, well tolerated antimalarial would be cost-effective despite its high price. TRIALS REGISTRATION: ClinicalTrials.gov NCT 00811421; Pan African Trials Registry PACTR2010020001429343 and PACTR2010020001813440. PMID- 25915618 TI - Correction: The transcriptome of equine peripheral blood mononuclear cells. PMID- 25915617 TI - Expression of sirtuin 1 and 2 is associated with poor prognosis in non-small cell lung cancer patients. AB - BACKGROUND: Sirtuin 1 (SIRT1) and sirtuin 2 (SIRT2) are NAD+-dependent protein deacetylases involved in the regulation of key cancer-associated genes. In this study we evaluated the relevance of these deacetylases in lung cancer biology. MATERIAL AND METHODS: Protein levels of SIRT1 and SIRT2 were determined in non small cell lung cancer (NSCLC) cell lines and primary tumors from 105 patients. Changes in proliferation were assessed after SIRT1 and SIRT2 downregulation in lung cancer cell lines using siRNA-mediated technology or tenovin-1, a SIRT1 and SIRT2 inhibitor. RESULTS: High SIRT1 and SIRT2 protein levels were found in NSCLC cell lines compared with non-tumor lung epithelial cells. The expression of SIRT1 and SIRT2 proteins was also significantly higher in lung primary tumors than in normal tissue (P<0.001 for both sirtuins). Stronger nuclear SIRT1 staining was observed in adenocarcinomas than in squamous cell carcinomas (P=0.033). Interestingly, in NSCLC patients, high SIRT1 and SIRT2 expression levels were associated with shorter recurrence-free survival (P=0.04 and P=0.007, respectively). Moreover, the combination of high SIRT1 and SIRT2 expression was an independent prognostic factor for shorter recurrence-free survival (P=0.002) and overall survival (P=0.022). In vitro studies showed that SIRT1 and/or SIRT2 downregulation significantly decreased proliferation of NSCLC. CONCLUSIONS: Our results support the hypothesis that SIRT1 and SIRT2 have a protumorigenic role in lung cancer, promoting cell proliferation. Moreover, the expression of these proteins is associated with poor prognosis in NSCLC patients and may help to identify those NSCLC patients with high risk of recurrence that could benefit from adjuvant therapy after resection. PMID- 25915619 TI - Tight Junction Protein 1a regulates pigment cell organisation during zebrafish colour patterning. AB - Zebrafish display a prominent pattern of alternating dark and light stripes generated by the precise positioning of pigment cells in the skin. This arrangement is the result of coordinated cell movements, cell shape changes, and the organisation of pigment cells during metamorphosis. Iridophores play a crucial part in this process by switching between the dense form of the light stripes and the loose form of the dark stripes. Adult schachbrett (sbr) mutants exhibit delayed changes in iridophore shape and organisation caused by truncations in Tight Junction Protein 1a (ZO-1a). In sbr mutants, the dark stripes are interrupted by dense iridophores invading as coherent sheets. Immuno labelling and chimeric analyses indicate that Tjp1a is expressed in dense iridophores but down-regulated in the loose form. Tjp1a is a novel regulator of cell shape changes during colour pattern formation and the first cytoplasmic protein implicated in this process. PMID- 25915620 TI - Neural tuning matches frequency-dependent time differences between the ears. AB - The time it takes a sound to travel from source to ear differs between the ears and creates an interaural delay. It varies systematically with spatial direction and is generally modeled as a pure time delay, independent of frequency. In acoustical recordings, we found that interaural delay varies with frequency at a fine scale. In physiological recordings of midbrain neurons sensitive to interaural delay, we found that preferred delay also varies with sound frequency. Similar observations reported earlier were not incorporated in a functional framework. We find that the frequency dependence of acoustical and physiological interaural delays are matched in key respects. This suggests that binaural neurons are tuned to acoustical features of ecological environments, rather than to fixed interaural delays. Using recordings from the nerve and brainstem we show that this tuning may emerge from neurons detecting coincidences between input fibers that are mistuned in frequency. PMID- 25915621 TI - The C-terminal region of the motor protein MCAK controls its structure and activity through a conformational switch. AB - The precise regulation of microtubule dynamics is essential during cell division. The kinesin-13 motor protein MCAK is a potent microtubule depolymerase. The divergent non-motor regions flanking the ATPase domain are critical in regulating its targeting and activity. However, the molecular basis for the function of the non-motor regions within the context of full-length MCAK is unknown. Here, we determine the structure of MCAK motor domain bound to its regulatory C-terminus. Our analysis reveals that the MCAK C-terminus binds to two motor domains in solution and is displaced allosterically upon microtubule binding, which allows its robust accumulation at microtubule ends. These results demonstrate that MCAK undergoes long-range conformational changes involving its C-terminus during the soluble to microtubule-bound transition and that the C-terminus-motor interaction represents a structural intermediate in the MCAK catalytic cycle. Together, our work reveals intrinsic molecular mechanisms underlying the regulation of kinesin 13 activity. PMID- 25915622 TI - Visual processing of informative multipoint correlations arises primarily in V2. AB - Using the visual system as a model, we recently showed that the efficient coding principle accounted for the allocation of computational resources in central sensory processing: when sampling an image is the main limitation, resources are devoted to compute the statistical features that are the most variable, and therefore the most informative (eLife 2014;3:e03722. DOI: 10.7554/eLife.03722 Hermundstad et al., 2014). Building on these results, we use single-unit recordings in the macaque monkey to determine where these computations- sensitivity to specific multipoint correlations--occur. We find that these computations take place in visual area V2, primarily in its supragranular layers. The demonstration that V2 neurons are sensitive to the multipoint correlations that are informative about natural images provides a common computational underpinning for diverse but well-recognized aspects of neural processing in V2, including its sensitivity to corners, junctions, illusory contours, figure/ground, and 'naturalness.' PMID- 25915623 TI - Cochlear progenitor number is controlled through mesenchymal FGF receptor signaling. AB - The sensory and supporting cells (SCs) of the organ of Corti are derived from a limited number of progenitors. The mechanisms that regulate the number of sensory progenitors are not known. Here, we show that Fibroblast Growth Factors (FGF) 9 and 20, which are expressed in the non-sensory (Fgf9) and sensory (Fgf20) epithelium during otic development, regulate the number of cochlear progenitors. We further demonstrate that Fgf receptor (Fgfr) 1 signaling within the developing sensory epithelium is required for the differentiation of outer hair cells and SCs, while mesenchymal FGFRs regulate the size of the sensory progenitor population and the overall cochlear length. In addition, ectopic FGFR activation in mesenchyme was sufficient to increase sensory progenitor proliferation and cochlear length. These data define a feedback mechanism, originating from epithelial FGF ligands and mediated through periotic mesenchyme that controls the number of sensory progenitors and the length of the cochlea. PMID- 25915625 TI - Utility of Wood's light in margin determination of melanoma in situ after excisional biopsy. AB - BACKGROUND: Margin evaluation of melanoma in situ (MIS) is difficult because of its ill-defined clinical borders. Wood's light examination is commonly used to help delineate MIS margin before excision. OBJECTIVE: To prospectively study the accuracy of preoperative Wood's light examination for margin assessment of MIS. MATERIALS AND METHODS: The authors evaluated 60 patients before excision of MIS under white light and Wood's light. Staged excision was performed using the square procedure technique. After achieving clear margins, they compared final wound size with expected wound size if surgical margins had been based on Wood's light examination. RESULTS: Seven patients (11.7%) had Wood's light enhancement beyond the visible margin of the biopsy site. In all 7, increased wounding would have occurred if the surgical margins had been based on Wood's light examination. In 1 of the 7, use of the Wood's light examination would have reduced the surgical stages needed by 1 stage but would have increased the wound size by 83.3%. CONCLUSION: Wood's light examination has limited utility if complete excisional biopsy of MIS is performed before treatment. In this study, surgical margin based on the Wood's light examination would have resulted in an increased average wound size and would not have reduced the number of stages needed when performing the square procedure. PMID- 25915624 TI - Posttranslational Modifications and Clearing of alpha-Synuclein Aggregates in Yeast. AB - The budding yeast Saccharomyces cerevisiae represents an established model system to study the molecular mechanisms associated to neurodegenerative disorders. A key-feature of Parkinson's disease is the formation of Lewy bodies, which are cytoplasmic protein inclusions. Misfolded alpha-synuclein is one of their main constituents. Expression of alpha-synuclein protein in yeast leads to protein aggregation and cellular toxicity, which is reminiscent to Lewy body containing human cells. The molecular mechanism involved in clearance of alpha-synuclein aggregates is a central question for elucidating the alpha-synuclein-related toxicity. Cellular clearance mechanisms include ubiquitin mediated 26S proteasome function as well as lysosome/vacuole associated degradative pathways as autophagy. Various modifications change alpha-synuclein posttranslationally and alter its inclusion formation, cytotoxicity and the distribution to different clearance pathways. Several of these modification sites are conserved from yeast to human. In this review, we summarize recent findings on the effect of phosphorylation and sumoylation of alpha-synuclein to the enhanced channeling to either the autophagy or the proteasome degradation pathway in yeast model of Parkinson's disease. PMID- 25915627 TI - Commentary on a Canadian study of the use of poly-L-lactic Acid dermal implant for the treatment of hill and valley acne scarring. PMID- 25915626 TI - A Canadian study of the use of poly-L-lactic acid dermal implant for the treatment of hill and valley acne scarring. AB - BACKGROUND: Hill and valley scarring is 1 of 3 atrophic scar types that occur as a result of acne, becoming more apparent with facial skin aging. Treatment includes resurfacing techniques and the use of injectable fillers. Poly-L-lactic acid is an injectable collagen builder that has been used for the treatment of HIV-associated lipodystrophy and cosmetic enhancement. OBJECTIVE: To determine the degree of correction attainable with poly-L-lactic acid and safety findings for the treatment of hill and valley acne scarring. MATERIALS AND METHODS: Poly-L lactic acid was injected over 3 to 4 serial treatments at 4-week intervals in 22 subjects in this single-arm, unblinded, open-label Phase II study. Efficacy was determined by physician, blinded evaluator, and subject assessment of scar improvement using Likert scales, comparing photographs taken by 3 camera systems at treatment visits 2 to 4 and follow-up to baseline. Subjects also assessed treatment satisfaction. RESULTS: Percentage of patients with much to excellent improvement using the most sensitive camera system (VISIA-CR) ranged from 45.5% to 68.2%. Subject treatment satisfaction scores increased by 44%. One patient experienced a palpable nonvisible nodule. No subjects discontinued treatment. CONCLUSION: Injectable poly-L-lactic acid facilitated improvement in hill and valley acne scarring and was well tolerated. PMID- 25915628 TI - Randomized, blinded, 3-arm clinical trial assessing optimal temperature and duration for treatment with minimally invasive fractional radiofrequency. AB - BACKGROUND: A previous multicenter clinical trial of a needle-based fractional radiofrequency (FRF) treatment for facial and neck rhytides and laxity counterintuitively demonstrated a mean target temperature and treatment duration of 69.5 degrees C and 4.9 seconds for subjects with lesser improvement and 67 degrees C and 4.2 seconds for greater improvement. OBJECTIVE: To determine optimal temperature and duration settings for maximal clinical results in rhytides and laxity from a single FRF treatment of the face and neck. METHODS: A randomized, blinded, 3-arm clinical evaluation of FRF at a series of temperatures from 52-57 degrees C to 67 degrees C. Three blinded plastic surgeons and dermatologists scored rhytides using the Fitzpatrick Wrinkle Assessment Scale and laxity using the Alexiades Laxity Assessment Scale at 1, 3, and 6 months. RESULTS: Blinded grading showed optimal improvement at 67 degrees C and 3 seconds and decreased efficacy below 67 degrees C, with mean rhytide reductions of 40, 29, and 25% and mean laxity reductions of 34, 36, and 25% in Arms 3 (67 degrees C), 2 (62 degrees C), and 1 (52 degrees C-57 degrees C), respectively. A 100% response rate was observed for all subjects treated at 62 degrees C to 67 degrees C target temperature. CONCLUSION: The optimal target dermal temperature for facial and neck rhytide and laxity treatment is 67 degrees C and duration of 3 to 4 seconds with a 100% response rate after a single FRF treatment. PMID- 25915629 TI - Plasmid-Encoded Pgp5 Is a Significant Contributor to Chlamydia muridarum Induction of Hydrosalpinx. AB - We have previously shown that the plasmid-encoded Pgp3 is a major virulence factor for C. muridarum induction of hydrosalpinx. We now report that Pgp5 also plays a significant role in the development of hydrosalpinx following C. muridarum induction. Pgp5 deficiency was introduced via either in-frame deletion (CM-Deltapgp5) or premature stop codon installation (CM-pgp5S). Mice infected with either CM-Deltapgp5 or CM-pgp5S developed hydrosalpinges at significantly reduced levels with an incidence rate of <40% and a mean severity score of 2 or less. In contrast, 80% or more mice developed hydrosalpinx with a severity score of >3 when mice were infected with Pgp5-sufficient C. muridarum (plasmid competent wild type or plasmid-free C. muridarum transformed with a full plasmid or depleted of pgp7 gene). The attenuated pathogenicity of the Pgp5-deficient C. muridarum correlated with a significantly reduced level of ascending infection in the oviduct tissue despite the similar overall shedding courses between mice infected with Pgp5-deficient versus sufficient C. muridarum. Furthermore, in the oviducts of mice infected with Pgp5-deficient C. muridarum, significantly lower levels of inflammatory cell infiltration and cytokine production were detected. Thus, Pgp5 is a significant plasmid-encoded virulence factor for C. muridarum pathogenicity in the upper genital tract. PMID- 25915630 TI - Enhanced Sensitivity for Detection of HIV-1 p24 Antigen by a Novel Nuclease Linked Fluorescence Oligonucleotide Assay. AB - The relatively high detection limit of the Enzyme-linked immunosorbent assay (ELISA) prevents its application for detection of low concentrations of antigens. To increase the sensitivity for detection of HIV-1 p24 antigen, we developed a highly sensitive nuclease-linked fluorescence oligonucleotide assay (NLFOA). Two major improvements were incorporated in NLFOA to amplify antibody-antigen interaction signals and reduce the signal/noise ratio; a large number of nuclease molecules coupled to the gold nanoparticle/streptavidin complex and fluorescent signals generated from fluorescent-labeled oligonucleotides by the nuclease. The detection limit of p24 by NLFOA was 1 pg/mL, which was 10-fold more sensitive than the conventional ELISA (10 pg/mL). The specificity was 100% and the coefficient of variation (CV) was 7.8% at low p24 concentration (1.5 pg/mL) with various concentrations of spiked p24 in HIV-1 negative sera. Thus, NLFOA is highly sensitive, specific, reproducible and user-friendly. The more sensitive detection of low p24 concentrations in HIV-1-infected individuals by NLFOA could allow detection of HIV-1 infections that are missed by the conventional ELISA at the window period during acute infection to further reduce the risk for HIV-1 infection due to the undetected HIV-1 in the blood products. Moreover, NLFOA can be easily applied to more sensitive detection of other antigens. PMID- 25915631 TI - Elevated Muscle-Specific miRNAs in Serum of Myotonic Dystrophy Patients Relate to Muscle Disease Progress. AB - The discovery of reliable and sensitive blood biomarkers is useful for the diagnosis, monitoring and potential future therapy of diseases. Recently, microRNAs (miRNAs) have been identified in blood circulation and might have the potential to be used as biomarkers for several diseases and clinical conditions. Myotonic Dystrophy type 1 (DM1) is the most common form of adult-onset muscular dystrophy primarily characterized by muscle myotonia, weakness and atrophy. Previous studies have shown an association between miRNAs and DM1 in muscle tissue and, recently, in plasma. The aim of this study was to detect and assess muscle-specific miRNAs as potential biomarkers of DM1 muscle wasting, an important parameter in the disease's natural history. Disease stable or progressive DM1 patients with muscle weakness and wasting were recruited and enrolled in the study. RNA isolated from participants' serum was used to assess miRNA levels. Results suggest that the levels of muscle-specific miRNAs are correlated with the progression of muscle wasting and weakness observed in the DM1 patients. Specifically, miR-1, miR-133a, miR133b and miR-206 serum levels were found elevated in DM1 patients with progressive muscle wasting compared to disease stable DM1 patients. Based on these results, we propose that muscle specific miRNAs might be useful molecular biomarkers for monitoring the progress of muscle atrophy in DM1 patients. PMID- 25915632 TI - WDR12, a Member of Nucleolar PeBoW-Complex, Is Up-Regulated in Failing Hearts and Causes Deterioration of Cardiac Function. AB - AIMS: In a recent genome-wide association study, WD-repeat domain 12 (WDR12) was associated with early-onset myocardial infarction (MI). However, the function of WDR12 in the heart is unknown. METHODS AND RESULTS: We characterized cardiac expression of WDR12, used adenovirus-mediated WDR12 gene delivery to examine effects of WDR12 on left ventricular (LV) remodeling, and analyzed relationship between MI associated WDR12 allele and cardiac function in human subjects. LV WDR12 protein levels were increased in patients with dilated cardiomyopathy and rats post-infarction. In normal adult rat hearts, WDR12 gene delivery into the anterior wall of the LV decreased interventricular septum diastolic and systolic thickness and increased the diastolic and systolic diameters of the LV. Moreover, LV ejection fraction (9.1%, P<0.05) and fractional shortening (12.2%, P<0.05) were declined. The adverse effects of WDR12 gene delivery on cardiac function were associated with decreased cellular proliferation, activation of p38 mitogen activated protein kinase (MAPK)/heat shock protein (HSP) 27 pathway, and increased protein levels of Block of proliferation 1 (BOP1), essential for ribosome biogenesis. Post-infarction WDR12 gene delivery decreased E/A ratio (32%, P<0.05) suggesting worsening of diastolic function. In human subjects, MI associated WDR12 allele was associated significantly with diastolic dysfunction and left atrial size. CONCLUSIONS: WDR12 triggers distinct deterioration of cardiac function in adult rat heart and the MI associated WDR12 variant is associated with diastolic dysfunction in human subjects. PMID- 25915634 TI - Parasite physiology: The missing link in artemisinin resistance. PMID- 25915633 TI - HIV-1 and interferons: who's interfering with whom? AB - The ability of interferons (IFNs) to inhibit HIV-1 replication in cell culture models has long been recognized, and the therapeutic administration of IFNalpha to HIV-1-infected patients who are not receiving antiretroviral therapy produces a clear but transient decrease in plasma viral load. Conversely, studies of chronic HIV-1 infection in humans and SIV-infected animal models of AIDS show positive correlations between elevated plasma levels of IFNs, increased expression of IFN-stimulated genes (ISGs), biomarkers of inflammation and disease progression. In this Review, we discuss the evidence that IFNs can control HIV-1 replication in vivo and debate the controversial role of IFNs in promoting the pathological sequelae of chronic HIV-1 infection. PMID- 25915635 TI - Prioritizing risks of antibiotic resistance genes in all metagenomes. PMID- 25915637 TI - Antibiotic resistance genes in the environment: prioritizing risks. PMID- 25915638 TI - Bacterial pathogenesis: Copycat Burkholderia make a move. PMID- 25915636 TI - Sequencing and beyond: integrating molecular 'omics' for microbial community profiling. AB - High-throughput DNA sequencing has proven invaluable for investigating diverse environmental and host-associated microbial communities. In this Review, we discuss emerging strategies for microbial community analysis that complement and expand traditional metagenomic profiling. These include novel DNA sequencing strategies for identifying strain-level microbial variation and community temporal dynamics; measuring multiple 'omic' data types that better capture community functional activity, such as transcriptomics, proteomics and metabolomics; and combining multiple forms of omic data in an integrated framework. We highlight studies in which the 'multi-omics' approach has led to improved mechanistic models of microbial community structure and function. PMID- 25915639 TI - A Diverse Tetrapod Fauna at the Base of 'Romer's Gap'. AB - The lack of fossil tetrapod bearing deposits in the earliest Carboniferous ('Romer's Gap') has provoked some recent discussions regarding the proximal cause, with three explanations being offered: environmental, taphonomic, and collection failure. One of the few, and earliest, windows into this time is the locality of Blue Beach exposed in the Tournaisian deposits at Horton Bluff lying along the Avon River near Hantsport, Nova Scotia, Canada. This locality has long been known but, because the fossils were deposited in high energy settings they are almost always disarticulated, so the fauna has not been described in detail. Recent intensive collection has revealed a diverse assemblage of material, including for the first time associated elements, which permits an evaluation of the faunal constituents at the locality. Although not diagnosable to a fine taxonomic level, sufficient apomorphies are present to identify representatives from numerous clades known from more complete specimens elsewhere. The evidence suggests a diverse fauna was present, including whatcheeriids and embolomeres. A single humerus previously had been attributed to a colosteid, but there is some uncertainty with this identification. Additional elements suggest the presence of taxa otherwise only known from the late Devonian. Depositional biases at the locality favor tetrapod fossils from larger individuals, but indirect evidence from trackways and tantalizing isolated bones evidences the presence of small taxa that remain to be discovered. The fossils from Blue Beach demonstrate that when windows into the fauna of 'Romer's Gap' are found a rich diversity of tetrapods will be shown to be present, contra arguments that suggested this hiatus in the fossil record was due to extrinsic factors such as atmospheric oxygen levels. They also show that the early tetrapod fauna is not easily divisible into Devonian and Carboniferous faunas, suggesting that some tetrapods passed through the end Devonian extinction event unaffected. PMID- 25915640 TI - A Comprehensive Selection of Reference Genes for RT-qPCR Analysis in a Predatory Lady Beetle, Hippodamia convergens (Coleoptera: Coccinellidae). AB - Reverse transcriptase-quantitative polymerase chain reaction (RT-qPCR) is a reliable, rapid, and reproducible technique for measuring and evaluating changes in gene expression. To facilitate gene expression studies and obtain more accurate RT-qPCR data, normalization relative to stable reference genes is required. In this study, expression profiles of seven candidate reference genes, including beta-actin (Actin), elongation factor 1 alpha (EF1A), glyceralde hyde-3 phosphate dehydro-genase (GAPDH), cyclophilins A (CypA), vacuolar-type H+-ATPase (ATPase), 28S ribosomal RNA (28S), and 18S ribosomal RNA (18S) from Hippodamia convergens were investigated. H. convergens is an abundant predatory species in the New World, and has been widely used as a biological control agent against sap sucking insect pests, primarily aphids. A total of four analytical methods, geNorm, Normfinder, BestKeeper, and the DeltaCt method, were employed to evaluate the performance of these seven genes as endogenous controls under diverse experimental conditions. Additionally, RefFinder, a comprehensive evaluation platform integrating the four above mentioned algorithms, ranked the overall stability of these candidate genes. A suite of reference genes were specifically recommended for each experimental condition. Among them, 28S, EF1A, and CypA were the best reference genes across different development stages; GAPDH, 28S, and CypA were most stable in different tissues. GAPDH and CypA were most stable in female and male adults and photoperiod conditions, 28S and EF1A were most stable under a range of temperatures, Actin and CypA were most stable under dietary RNAi condition. This work establishes a standardized RT-qPCR analysis in H. convergens. Additionally, this study lays a foundation for functional genomics research in H. convergens and sheds light on the ecological risk assessment of RNAi-based biopesticides on this non-target biological control agent. PMID- 25915641 TI - The accuracy of a method for printing three-dimensional spinal models. AB - BACKGROUND: To study the morphology of the human spine and new spinal fixation methods, scientists require cadaveric specimens, which are dependent on donation. However, in most countries, the number of people willing to donate their body is low. A 3D printed model could be an alternative method for morphology research, but the accuracy of the morphology of a 3D printed model has not been determined. METHODS: Forty-five computed tomography (CT) scans of cervical, thoracic and lumbar spines were obtained, and 44 parameters of the cervical spine, 120 parameters of the thoracic spine, and 50 parameters of the lumbar spine were measured. The CT scan data in DICOM format were imported into Mimics software v10.01 for 3D reconstruction, and the data were saved in .STL format and imported to Cura software. After a 3D digital model was formed, it was saved in Gcode format and exported to a 3D printer for printing. After the 3D printed models were obtained, the above-referenced parameters were measured again. RESULTS: Paired t-tests were used to determine the significance, set to P<0.05, of all parameter data from the radiographic images and 3D printed models. Furthermore, 88.6% of all parameters of the cervical spine, 90% of all parameters of the thoracic spine, and 94% of all parameters of the lumbar spine had Intraclass Correlation Coefficient (ICC) values >0.800. The other ICC values were <0.800 and >0.600; none were <0.600. CONCLUSION: In this study, we provide a protocol for printing accurate 3D spinal models for surgeons and researchers. The resulting 3D printed model is inexpensive and easily obtained for spinal fixation research. PMID- 25915642 TI - Head Exposure to Cold during Whole-Body Cryostimulation: Influence on Thermal Response and Autonomic Modulation. AB - Recent research on whole-body cryotherapy has hypothesized a major responsibility of head cooling in the physiological changes classically reported after a cryostimulation session. The aim of this experiment was to verify this hypothesis by studying the influence of exposing the head to cold during whole-body cryostimulation sessions, on the thermal response and the autonomic nervous system (ANS). Over five consecutive days, two groups of 10 participants performed one whole-body cryostimulation session daily, in one of two different systems; one exposing the whole-body to cold (whole-body cryostimulation, WBC), and the other exposing the whole-body except the head (partial-body cryostimulation, PBC).10 participants constituted a control group (CON) not receiving any cryostimulation. In order to isolate the head-cooling effect on recorded variables, it was ensured that the WBC and PBC systems induced the same decrease in skin temperature for all body regions (mean decrease over the 5 exposures: 8.6 degrees C +/- 1.3 degrees C and -8.3 +/- 0.7 degrees C for WBC and PBC, respectively), which persisted up to 20-min after the sessions (P20). The WBC sessions caused an almost certain decrease in tympanic temperature from Pre to P20 (-0.28 +/- 0.11 degrees C), while it only decreased at P20 (-0.14 +/- 0.05 degrees C) after PBC sessions. Heart rate almost certainly decreased after PBC ( 8.6%) and WBC (-12.3%) sessions. Resting vagal-related heart rate variability indices (the root-mean square difference of successive normal R-R intervals, RMSSD, and high frequency band, HF) were very likely to almost certainly increased after PBC (RMSSD:+49.1%, HF: +123.3%) and WBC (RMSSD: +38.8%, HF:+70.3%). Plasma norepinephrine concentration was likely increased in similar proportions after PBC and WBC, but only after the first session. Both cryostimulation techniques stimulated the ANS with a predominance of parasympathetic tone activation from the first to the fifth session and in slightly greater proportion with WBC than PBC. The main result of this study indicates that the head exposure to cold during whole-body cryostimulation may not be the main factor responsible for the effects of cryostimulation on the ANS. PMID- 25915644 TI - Adverse childhood experiences, mental health, and quality of life of Chilean girls placed in foster care: An exploratory study. AB - In Latin America, little research has been conducted regarding exposure to adverse childhood experiences (ACEs), mental health, and health-related quality of life (HRQoL) among foster children. This study examined the association between ACEs and mental health, posttraumatic stress disorder (PTSD), and HRQoL in Chilean foster girls relative to age-matched Chilean family girls. Data were obtained from 27 Chilean foster girls and 27 Chilean girls ages 6 to 17 years living in family homes. Standardized self- and proxy-report measures were used. Foster girls reported more ACEs than controls in terms of familial and nonfamilial sexual abuse and both emotional and physical neglect. Girls living in foster care had a significantly higher rate of PTSD, displayed greater behavioral and emotional problems, and reported a lower HRQoL. Analysis confirmed the well known cumulative risk hypothesis by demonstrating a significant positive association between the number of ACEs and PTSD symptom severity and a significant negative association with HRQoL. Chilean foster girls endured more ACEs that impair mental health and HRQoL than age-matched peers living with their families. These findings have implications for out-of-home care services in Latin America, highlighting the need to implement not only appropriate trauma-focused treatments but also appropriate prevention strategies. PMID- 25915643 TI - Regulation by SoxR of mfsA, Which Encodes a Major Facilitator Protein Involved in Paraquat Resistance in Stenotrophomonas maltophilia. AB - Stenotrophomonas maltophilia MfsA (Smlt1083) is an efflux pump in the major facilitator superfamily (MFS). Deletion of mfsA renders the strain more susceptible to paraquat, but no alteration in the susceptibility levels of other oxidants is observed. The expression of mfsA is inducible upon challenge with redox cycling/superoxide-generating drug (paraquat, menadione and plumbagin) treatments and is directly regulated by SoxR, which is a transcription regulator and sensor of superoxide-generating agents. Analysis of mfsA expression patterns in wild-type and a soxR mutant suggests that oxidized SoxR functions as a transcription activator of the gene. soxR (smlt1084) is located in a head-to-head fashion with mfsA, and these genes share the -10 motif of their promoter sequences. Purified SoxR specifically binds to the putative mfsA promoter motifs that contain a region that is highly homologous to the consensus SoxR binding site, and mutation of the SoxR binding site abolishes binding of purified SoxR protein. The SoxR box is located between the putative -35 and -10 promoter motifs of mfsA; and this position is typical for a promoter in which SoxR acts as a transcriptional activator. At the soxR promoter, the SoxR binding site covers the transcription start site of the soxR transcript; thus, binding of SoxR auto represses its own transcription. Taken together, our results reveal for the first time that mfsA is a novel member of the SoxR regulon and that SoxR binds and directly regulates its expression. PMID- 25915645 TI - Predictors of suicidal ideation in treatment-seeking survivors of torture. AB - In this study, we examined sociodemographic, persecutor identity, torture, and postmigration variables associated with suicidal ideation in a clinical sample of 267 immigrant survivors of torture who have resettled in New York City. The purpose of this study was to identify variables associated with increased risk for suicidal ideation in survivors of torture before they receive legal, psychological, or medical services for torture-related needs. Results from a binary logistic regression model identified a combination of 3 variables associated with current suicidal ideation at intake into the program. Being female, having not submitted an application for asylum, and a history of rape or sexual assault were significantly associated with suicidal ideation at intake, when also controlling for several other important variables. The final model explained 21.4% of variation in reported suicidal ideation at intake. The discussion will focus on the importance of conducting a thorough assessment of suicidal ideation in refugees and survivors of torture. PMID- 25915647 TI - Memory and narrative of traumatic events: A literature review. AB - This study presents a literature review of 22 studies published since 2004 that use linguistic procedures to evaluate narratives by persons who had suffered any traumatic event. The aim is to analyze the features of traumatic memories and, thus, how individuals construct and integrate their recall of what happened with other autobiographical memories. It uses cognitive theoretical models of posttraumatic stress disorder (PTSD) and their hypotheses about trauma memories as a framework. Findings reveal that trauma narratives are dominated by sensorial/perceptual and emotional details. The study of other narrative aspects (i.e., fragmentation, length, temporal context, and references to self) provides heterogeneous results. Results are discussed in light of the current state of PTSD research, exploring the principal hypotheses that have been proposed in cognitive theories to explain clinical findings. PMID- 25915646 TI - Mindfulness-based stress reduction to enhance psychological functioning and improve inflammatory biomarkers in trauma-exposed women: A pilot study. AB - This study examined the effects of a mindfulness-based stress reduction (MBSR) program on psychological functioning and inflammatory biomarkers in women with histories of interpersonal trauma. The 8-week MBSR program was conducted at a community-based health center and participants (N = 50) completed several measures of psychological functioning at study entry as well as 4 weeks, 8 weeks, and 12 weeks later. Inflammatory biomarkers were assayed from blood collected at each assessment. A series of linear mixed-model analyses were conducted to measure the effect of attendance and time on the dependent variables. Time was associated with significant decreases in perceived stress, depression, trait and state anxiety, emotion dysregulation, and posttraumatic stress symptoms, as well as increases in mindfulness. Session attendance was associated with significant decreases in interleukin (IL)-6 levels. This pilot study demonstrated the potential beneficial effects of MBSR on psychological functioning and the inflammatory biomarker IL-6 among trauma-exposed and primarily low-income women. Decreases in inflammation have implications for this population, as interpersonal trauma can instigate chronic physiological dysregulation, heightened morbidity, and premature death. This study's preliminary results support efforts to investigate biological remediation with behavioral interventions in vulnerable populations. PMID- 25915648 TI - Veterans' perspectives on initiating evidence-based psychotherapy for posttraumatic stress disorder. AB - Evidence-based psychotherapies (EBP) for posttraumatic stress disorder (PTSD) are effective at reducing symptoms and improving quality of life. Despite their effectiveness, few veterans receive EBP. To examine veterans' experiences initiating EBP for PTSD, we conducted qualitative interviews with those who completed at least 8 sessions of prolonged exposure (PE) or cognitive processing therapy (CPT). Veterans reported learning about EBP from therapists, psychiatrists, and other veterans. Ambivalence and delaying EBP initiation were common. Barriers included fears that EBP would increase symptoms, beliefs that avoidance was helpful, disbelief of the therapy rationale, particularly for PE, and less commonly, lack of knowledge about EBP. Facilitators included feeling a "need to talk about it," prior treatment that increased confidence in the ability to handle EBP, prior knowledge of the EBP therapist, provider behaviors that facilitated buy-in, encouragement from other veterans, and desperation for symptom relief. There were few differences in barriers and facilitators between PE and CPT, although veterans in PE were more likely to express skepticism of the therapy rationale. These results highlight the importance of "word of mouth" about EBP among the veteran community and identifying provider behaviors that may promote EBP initiation. PMID- 25915649 TI - Dihydromyricetin Enhances the Chemo-Sensitivity of Nedaplatin via Regulation of the p53/Bcl-2 Pathway in Hepatocellular Carcinoma Cells. AB - Chemotherapy is an effective weapon in the battle against cancer. Nedaplatin (NDP) is an improved platinum-containing drug with lower cytotoxicity than other similar drugs. However, the repeated use of NDP results in substantial hepatocyte damage as well as drug resistance in hepatocellular carcinoma (HCC) cases. Therefore, the development of effective chemotherapy strategies that enhance tumor sensitivity to chemotherapeutics and reduce the secondary damage to liver cells is urgently needed. Dihydromyricetin (DHM), a natural flavonoid compound, has been shown to have antitumor activity with no obvious toxicity to normal cells in vitro and in vivo. In this study, DHM and NDP were combined to treat liver cancer cells; we found that DHM functions as a protector of normal cells compared with the use of NDP alone. In addition, the synergy of DHM with NDP enhanced the effect of NDP on the induction of HCC cell apoptosis. We found that the combination caused clear changes in the level of reactive oxygen species (ROS). Furthermore, we demonstrated that the combination of DHM and NDP activated the p53/Bcl-2 signaling pathway, which resulted in mitochondrial dysfunction and induced cell death and growth inhibition in HCC cells. PMID- 25915651 TI - Topological ring-current and bond-current properties of the altans of certain K factorizable conjugated systems containing "fixed" single-bonds. AB - The rudimentary Huckel-London-Pople-McWeeny (HLPM) formalism, which frequently mimics the predictions of more-sophisticated ab initio approaches, is used to investigate the pi-electron ring-current and bond-current properties of four novel altan-structures, the parents of three of which are conjugated structures with "fixed" single carbon-carbon bonds: namely, acenaphthylene, fluoranthene, and perylene. Such structures are nowadays sometimes called "K-factorizable". Non K-factorizable peropyrene is also considered, for comparison. The remarkably contrasting sizes of the bond-currents in the unshared bonds situated in the centers of perylene and peropyrene, first noted more than 40 years ago, are preserved in the corresponding bonds of the respective altan-structures. Current patterns in the parent structures frequently remain semiquantitatively intact when the parent is formally converted to the corresponding altan, a finding that largely agrees with the predictions of previous ab initio calculations. The circulations around the [4n]-perimeters of all four of the altans considered here are (as expected) in the clockwise (paramagnetic) direction. PMID- 25915650 TI - Proteomic Investigation of the Response of Enterococcus faecalis V583 when Cultivated in Urine. AB - Enterococcus faecalis is a robust bacterium, which is able to survive in and adapt to hostile environments such as the urinary tract and bladder. In this label-free quantitative proteomic study based on MaxQuant LFQ algorithms, we identified 127 proteins present in the secretome of the clinical vancomycin resistant isolate E. faecalis V583 and we compared proteins secreted in the initial phase of cultivation in urine with the secretome during cultivation in standard laboratory medium, 2xYT. Of the 54 identified proteins predicted to be secreted, six were exclusively found after cultivation in urine including the virulence factor EfaA ("endocarditis specific antigen") and its homologue EF0577 ("adhesion lipoprotein"). These two proteins are both involved in manganese transport, known to be an important determinant of colonization and infection, and may additionally function as adhesins. Other detected urine-specific proteins are involved in peptide transport (EF0063 and EF3106) and protease inhibition (EF3054). In addition, we found an uncharacterized protein (EF0764), which had not previously been linked to the adaptation of V583 to a urine environment, and which is unique to E. faecalis. Proteins found in both environments included a histone-like protein, EF1550, that was up-regulated during cultivation in urine and that has a homologue in streptococci (HlpA) known to be involved in bacterial adhesion to host cells. Up-regulated secreted proteins included autolysins. These results from secretome analyses are largely compatible with previously published data from transcriptomics studies. All in all, the present data indicate that transport, in particular metal transport, adhesion, cell wall remodelling and the unknown function carried out by the unique EF0764 are important for enterococcal adaptation to the urine environment. These results provide a basis for a more targeted exploration of novel proteins involved in the adaptability and pathogenicity of E. faecalis. PMID- 25915654 TI - New donor-acceptor conjugates based on a trifluorenylporphyrin linked to a redox switchable ruthenium unit. AB - Reactions of the 16-electron ruthenium complex [Ru(dppe)2Cl][PF6] with metal-free and zinc ethynylphenyltrifluorenylporphyrins and respectively, gave the new dyads and with ethynylruthenium group as a potential electron donor and the porphyrin as a potential electron acceptor. The redox properties of the porphyrins were investigated by cyclic voltammetry and UV spectroelectrochemistry (SEC), which reveal that the monocation and monoanion of metal-free porphyrin are stable under these conditions whereas the formation of the corresponding radical cation or anion of the zinc porphyrin was accompanied by partial decomplexation of the zinc ion. Oxidations of the dyads and gave stable radical cations as probed using IR, NIR and UV SEC methods. These cations show similar NIR and IR bands to those reported for the known 17-electron [Ru(dppe)2(C[triple bond, length as m dash]CPh)Cl](+) radical cation. Remarkably, the dyad has four stable redox states +2/+1/0/-1 where the second oxidation and first reduction processes take place at the porphyrin unit. Simulated absorption spectra on at optimised geometries obtained by TD-DFT computations with the CAM-B3LYP functional are shown to be in very good agreement with the observed UV absorption spectra of . The spectra of and their oxidised and reduced species were interpreted with the aid of the TD DFT data. Fluorescence measurements reveal that the dyads and are only weakly emitting compared to and , indicative of quenching of the porphyrinic singlet excited state by the ruthenium centre. PMID- 25915652 TI - Intelligence in childhood and atherosclerosis of the carotid and peripheral arteries in later life: the Lothian Birth Cohort 1936. AB - OBJECTIVE: There is some evidence that people who score higher on tests of intelligence in childhood have lower carotid intima-media thickness and higher ankle brachial index in middle age. These findings need replicating in other, older populations. We investigated the prospective relationship between intelligence in childhood and atherosclerosis in the carotid and peripheral arteries at age 73 years. METHODS: Participants were 713 members of the Lothian Birth Cohort 1936 whose intelligence was assessed at age 11 years. At age 73 years, carotid intima-media thickness and degree of stenosis were measured using ultrasound imaging; ankle-brachial index was measured using Doppler ultrasound. RESULTS: There were no significant associations between intelligence at age 11 and measures of atherosclerosis at age 73. In age- and sex-adjusted analyses, for a standard deviation higher score in intelligence, intima-media thickness (x 10) was lower by 0.07 (-0.20, 0.06) mm and ankle brachial index (x 10) was lower by 0.09 (-0.24, 0.07); odds ratios for having carotid stenosis >25% or peripheral arterial disease were 0.98 (0.82, 1.16) and 1.05 (0.81, 1.36) respectively. CONCLUSION: In this study of people aged 73 years, higher childhood intelligence was not associated with reduced risk of atherosclerosis in the carotid or peripheral arteries. PMID- 25915653 TI - In Vivo Volatile Organic Compound Signatures of Mycobacterium avium subsp. paratuberculosis. AB - Mycobacterium avium ssp. paratuberculosis (MAP) is the causative agent of a chronic enteric disease of ruminants. Available diagnostic tests are complex and slow. In vitro, volatile organic compound (VOC) patterns emitted from MAP cultures mirrored bacterial growth and enabled distinction of different strains. This study was intended to determine VOCs in vivo in the controlled setting of an animal model. VOCs were pre-concentrated from breath and feces of 42 goats (16 controls and 26 MAP-inoculated animals) by means of needle trap microextraction (breath) and solid phase microextraction (feces) and analyzed by gas chromatography/ mass spectrometry. Analyses were performed 18, 29, 33, 41 and 48 weeks after inoculation. MAP-specific antibodies and MAP-specific interferon gamma-response were determined from blood. Identities of all marker-VOCs were confirmed through analysis of pure reference substances. Based on detection limits in the high pptV and linear ranges of two orders of magnitude more than 100 VOCs could be detected in breath and in headspace over feces. Twenty eight substances differed between inoculated and non-inoculated animals. Although patterns of most prominent substances such as furans, oxygenated substances and hydrocarbons changed in the course of infection, differences between inoculated and non-inoculated animals remained detectable at any time for 16 substances in feces and 3 VOCs in breath. Differences of VOC concentrations over feces reflected presence of MAP bacteria. Differences in VOC profiles from breath were linked to the host response in terms of interferon-gamma-response. In a perspective in vivo analysis of VOCs may help to overcome limitations of established tests. PMID- 25915655 TI - The Political Alignment of US Physicians: An Update Including Campaign Contributions to the Congressional Midterm Elections in 2014. PMID- 25915656 TI - Loneliness and hypervigilance to social cues in females: an eye-tracking study. AB - The goal of the present study was to examine whether lonely individuals differ from nonlonely individuals in their overt visual attention to social cues. Previous studies showed that loneliness was related to biased post-attentive processing of social cues (e.g., negative interpretation bias), but research on whether lonely and nonlonely individuals also show differences in an earlier information processing stage (gazing behavior) is very limited. A sample of 25 lonely and 25 nonlonely students took part in an eye-tracking study consisting of four tasks. We measured gazing (duration, number of fixations and first fixation) at the eyes, nose and mouth region of faces expressing emotions (Task 1), at emotion quadrants (anger, fear, happiness and neutral expression) (Task 2), at quadrants with positive and negative social and nonsocial images (Task 3), and at the facial area of actors in video clips with positive and negative content (Task 4). In general, participants tended to gaze most often and longest at areas that conveyed most social information, such as the eye region of the face (T1), and social images (T3). Participants gazed most often and longest at happy faces (T2) in still images, and more often and longer at the facial area in negative than in positive video clips (T4). No differences occurred between lonely and nonlonely participants in their gazing times and frequencies, nor at first fixations at social cues in the four different tasks. Based on this study, we found no evidence that overt visual attention to social cues differs between lonely and nonlonely individuals. This implies that biases in social information processing of lonely individuals may be limited to other phases of social information processing. Alternatively, biased overt attention to social cues may only occur under specific conditions, for specific stimuli or for specific lonely individuals. PMID- 25915657 TI - Correction: An AP endonuclease functions in active DNA demethylation and gene imprinting in Arabidopsis. AB - [This corrects the article DOI: 10.1371/journal.pgen.1004905.]. PMID- 25915658 TI - Appendicitis as an early manifestation of subsequent malignancy: an asian population study. AB - BACKGROUND & AIMS: Cancer risk after appendectomy in patients with appendicitis remains unclear. This study examined the role of appendicitis as an early manifestation harbingering the distant malignancy. METHODS: From the insurance claims data of Taiwan, we identified a cohort of 130,374 patients newly received appendectomy from 2000-2009, without cancer diagnosis. A comparison cohort of 260,746 persons without appendectomy and cancer was selected from the same database, frequency matched by age, sex, comorbidity and index year. We monitored subsequent cancers with a12-month follow-up. RESULTS: Over all, 1406 and 616 cancer cases were identified in the appendectomy cohort and comparisons, respectively, with all cancers incidence rate 4.64-fold higher in the appendectomy cohort (9.06 vs. 1.96 per 1000 person-months). Digestive and female genital organs harbored 80.9% of cancer cases in the appendectomy cohort. The Cox model measured site-specific hazard ratio (HR) was the highest for female genital cancers (23.3), followed by cancers of colorectum (14.7), small intestine (10.1), pancreas (7.40), lymphoma (5.89) and urinary system (4.50), all significant at 0.001 level. The HR of all cancers decreased from 13.7 within 3 months after appendectomy to 1.37 in 7-12 months after the surgery. In general, relative to the comparison cohort, younger appendectomy patients tended to have a higher HR than older patients. CONCLUSIONS: The high incident cancers identified soon after appendectomy suggest the acute appendicitis is the early sign of distant metastatic malignancy. The risk of colorectal cancer, female genital cancer and haemopoietic malignancy deserve attention. PMID- 25915659 TI - Rapid assessment of visual impairment in urban population of Delhi, India. AB - PURPOSE: To determine the prevalence, causes and associated demographic factors related to visual impairment amongst the urban population of New Delhi, India. METHODS: A population-based, cross-sectional study was conducted in East Delhi district using cluster random sampling methodology. This Rapid Assessment of Visual Impairment (RAVI) survey involved examination of all individuals aged 40 years and above in 24 randomly selected clusters of the district. Visual acuity (VA) assessment and comprehensive ocular examination were done during the door-to door survey. A questionnaire was used to collect personal and demographic information of the study population. Blindness and Visual Impairment was defined as presenting VA < 3/60 and < 6/18 in the better eye, respectively. Descriptive statistics were computed along with multivariable logistic regression analysis to determine associated factors for visual impairment. RESULTS: Of 2421 subjects enumerated, 2331 (96.3%) were available for ophthalmic examination. Among those examined, 49.3% were males. The prevalence of visual impairment (VI) in the study population, was 11.4% (95% C.I. 10.1, 12.7) and that of blindness was 1.2% (95% C.I. 0.8, 1.6). Uncorrected refractive error was the leading cause of VI accounting for 53.4% of all VI followed by cataract (33.8%). With multivariable logistic regression, the odds of having VI increased with age (OR = 24.6[95% C.I.: 14.9, 40.7]; p < 0.001). Illiterate participants were more likely to have VI [OR = 1.5 (95% C.I.: 1.1,2.1)] when compared to educated participants. CONCLUSIONS: The first implementation of the RAVI methodology in a North Indian population revealed that the burden of visual impairment is considerable in this region despite availability of adequate eye care facilities. Awareness generation and simple interventions like cataract surgery and provision of spectacles will help to eliminate the major causes of blindness and visual impairment in this region. PMID- 25915660 TI - Plasminogen Activator Inhibitor-1 Antagonist TM5484 Attenuates Demyelination and Axonal Degeneration in a Mice Model of Multiple Sclerosis. AB - Multiple sclerosis (MS) is characterized by inflammatory demyelination and deposition of fibrinogen in the central nervous system (CNS). Elevated levels of a critical inhibitor of the mammalian fibrinolitic system, plasminogen activator inhibitor 1 (PAI-1) have been demonstrated in human and animal models of MS. In experimental studies that resemble neuroinflammatory disease, PAI-1 deficient mice display preserved neurological structure and function compared to wild type mice, suggesting a link between the fibrinolytic pathway and MS. We previously identified a series of PAI-1 inhibitors on the basis of the 3-dimensional structure of PAI-1 and on virtual screening. These compounds have been reported to provide a number of in vitro and in vivo benefits but none was tested in CNS disease models because of their limited capacity to penetrate the blood-brain barrier (BBB). The existing candidates were therefore optimized to obtain CNS penetrant compounds. We performed an in vitro screening using a model of BBB and were able to identify a novel, low molecular PAI-1 inhibitor, TM5484, with the highest penetration ratio among all other candidates. Next, we tested the effects on inflammation and demyelination in an experimental allergic encephalomyelitis mice model. Results were compared to either fingolimod or 6alpha methylprednisolone. Oral administration of TM5484 from the onset of signs, ameliorates paralysis, attenuated demyelination, and axonal degeneration in the spinal cord of mice. Furthermore, it modulated the expression of brain-derived neurotrophic factor, which plays a protective role in neurons against various pathological insults, and choline acetyltransferase, a marker of neuronal density. Taken together, these results demonstrate the potential benefits of a novel PAI-1 inhibitor, TM5484, in the treatment of MS. PMID- 25915661 TI - Effects of Proprotein Convertase Subtilisin/Kexin Type 9 Antibodies in Adults With Hypercholesterolemia: A Systematic Review and Meta-analysis. AB - BACKGROUND: Guidelines recommend statins as first-line therapy for dyslipidemia. Monoclonal antibodies targeting proprotein convertase subtilisin/kexin type 9 (PCSK9) is a new lipid-lowering approach. PURPOSE: To assess the efficacy and safety of PCSK9 antibodies in adults with hypercholesterolemia. DATA SOURCES: MEDLINE, PubMed Central, and Google Scholar; conference proceedings; and the ClinicalTrials.gov registry through 4 April 2015. STUDY SELECTION: Phase 2 or 3 randomized, controlled trials (RCTs) comparing treatment using PCSK9 antibodies with no anti-PCSK9 therapy in adults with hypercholesterolemia. DATA EXTRACTION: Two investigators independently extracted data on study characteristics and lipid and clinical outcomes, and rated risk of bias of trials. Prespecified primary end points were all-cause and cardiovascular mortality. DATA SYNTHESIS: Twenty-four RCTs comprising 10 159 patients were included. Compared with no antibody, treatment with PCSK9 antibodies led to marked reductions in low-density lipoprotein cholesterol levels (mean difference, -47.49% [95% CI, -69.64% to 25.35%]; P < 0.001] and other atherogenic lipid fractions, and it reduced all cause mortality (odds ratio [OR], 0.45 [CI, 0.23 to 0.86]; P = 0.015; heterogeneity P = 0.63; I2 = 0%) and cardiovascular mortality (OR, 0.50 [CI, 0.23 to 1.10]; P = 0.084; heterogeneity P = 0.78; I2 = 0%). The rate of myocardial infarction was significantly reduced with use of PCSK9 antibodies (OR, 0.49 [CI, 0.26 to 0.93]; P = 0.030; heterogeneity P = 0.45; I2 = 0%), and increases in the serum creatine kinase level were reduced (OR, 0.72 [CI, 0.54 to 0.96]; P = 0.026; heterogeneity P = 0.65; I2 = 0%). Serious adverse events did not increase with administration of PCSK9 antibodies. LIMITATION: Results were derived from study level data rather than patient-level data, and clinical outcome data are rare. CONCLUSION: PCSK9 antibodies seem to be safe and effective for adults with dyslipidemia. PRIMARY FUNDING SOURCE: CRC 1116 Masterswitches in Myocardial Ischemia, German Research Council DFG. PMID- 25915663 TI - Hysteresis-free nanoplasmonic Pd-Au alloy hydrogen sensors. AB - The recent market introduction of hydrogen fuel cell cars and the prospect of a hydrogen economy have drastically accelerated the need for safe and accurate detection of hydrogen. In this Letter, we investigate the use of arrays of nanofabricated Pd-Au alloy nanoparticles as plasmonic optical hydrogen sensors. By increasing the amount of Au in the alloy nanoparticles up to 25 atom %, we are able to suppress the hysteresis between hydrogen absorption and desorption, thereby increasing the sensor accuracy to below 5% throughout the investigated 1 mbar to 1 bar hydrogen pressure range. Furthermore, we observe an 8-fold absolute sensitivity enhancement at low hydrogen pressures compared to sensors made of pure Pd, and an improved sensor response time to below one second within the 0-40 mbar pressure range, that is, below the flammability limit, by engineering the nanoparticle size. PMID- 25915665 TI - Lower Eyelid Reconstruction for Iatrogenic Eyelid-to-Globe Malposition. AB - An 86-year-old man with iatrogenic eyelid-to-globe malposition had a combination of medial tarsal strip, lateral periosteal sling, and inferior tarsal support with the ear cartilage. An appropriate apposition between the globe and lower eyelid was established postoperatively with good tear meniscus and acceptable cosmetic results. PMID- 25915664 TI - Protein expression profiles characterize distinct features of mouse cerebral cortices at different developmental stages. AB - The proper development of the mammalian cerebral cortex requires precise protein synthesis and accurate regulation of protein expression levels. To reveal signatures of protein expression in developing mouse cortices, we here generate proteomic profiles of cortices at embryonic and postnatal stages using tandem mass spectrometry (MS/MS). We found that protein expression profiles are mostly consistent with biological features of the developing cortex. Gene Ontology (GO) and KEGG pathway analyses demonstrate conserved molecules that maintain cortical development such as proteins involved in metabolism. GO and KEGG pathway analyses further identify differentially expressed proteins that function at specific stages, for example proteins regulating the cell cycle in the embryonic cortex, and proteins controlling axon guidance in the postnatal cortex, suggesting that distinct protein expression profiles determine biological events in the developing cortex. Furthermore, the STRING network analysis has revealed that many proteins control a single biological event, such as the cell cycle regulation, through cohesive interactions, indicating a complex network regulation in the cortex. Our study has identified protein networks that control the cortical development and has provided a protein reference for further investigation of protein interactions in the cortex. PMID- 25915662 TI - Neutralizing S1P inhibits intratumoral hypoxia, induces vascular remodelling and sensitizes to chemotherapy in prostate cancer. AB - Hypoxia promotes neovascularization, increased tumor growth, and therapeutic resistance. The transcription factor, hypoxia-inducible factor 1alpha (HIF 1alpha), has been reported as the master driver of adaptation to hypoxia. We previously identified the sphingosine kinase 1/sphingosine 1-phosphate (SphK1/S1P) pathway as a new modulator of HIF-1alpha under hypoxia. Taking advantage of a monoclonal antibody neutralizing extracellular S1P (sphingomab), we report that inhibition of S1P extracellular signaling blocks HIF-1alpha accumulation and activity in several cancer cell models exposed to hypoxia. In an orthotopic xenograft model of prostate cancer, we show that sphingomab reduces hypoxia and modifies vessel architecture within 5 days of treatment, leading to increased intratumoral blood perfusion. Supporting the notion that a transient vascular normalization of tumor vessels is the mechanism by which sphingomab exerts its effects, we demonstrate that administration of the antibody for 5 days before chemotherapy is more effective at local tumor control and metastatic dissemination than any other treatment scheduling. These findings validate sphingomab as a potential new normalization agent that could contribute to successful sensitization of hypoxic tumors to chemotherapy. PMID- 25915666 TI - A new method of identifying the posterior inferior nasal nerve: implications for posterior nasal neurectomy. AB - INTRODUCTION: Posterior nasal neurectomy is an effective way of treating recalcitrant rhinitis. The aim of this study is to describe the anatomic relationship between the posterior inferior nasal nerve (PINN) and the structures that might be important for posterior nasal neurectomy. MATERIALS AND METHODS: An anatomic study was conducted in a university hospital dissection laboratory with 15 formalin-fixed, sagittally cut adult cadaver heads. The distance between PINN and (1) nasal sill, (2) maxillary sinus ostium, (3) posterior fontanel, (4) torus tubarius, and (5) crista ethmoidalis was measured and the location of PINN with respect to the sphenopalatine artery was assessed to define the exact location of PINN. RESULTS: The mean distance between PINN and nasal sill (56.4 mm), maxillary sinus ostium (27 mm), posterior fontanel (12.5 mm), torus tubarius (13 mm), and crista ethmoidalis (8 mm) was determined. PINN was found consistently posterior to the sphenopalatine artery where the inferior turbinate attaches to the lateral nasal wall. CONCLUSION: Instead of finding PINN around the sphenopalatine foramen, PINN can be located more easily posterior to the sphenopalatine artery where the inferior turbinate attaches to the lateral nasal wall without cauterizing the sphenopalatine artery. PMID- 25915667 TI - Endoscopic modified medial maxillectomy for treatment of inverted papilloma originating from the maxillary sinus. AB - Endoscopic approaches have become an alternative to external approaches in the treatment of sinonasal inverted papillomas (IPs) in recent years. The aim of this study was to analyze the outcomes of endoscopic modified medial maxillectomy preserving the nasolacrimal duct and the inferior turbinate in selected IP cases. Medical charts of patients diagnosed with IP originating from the maxillary sinus between July 2008 and August 2013 were reviewed. Eight patients who had undergone endoscopic modified medial maxillectomy were included in the study. Attachment of IP was located on the medial wall of the maxillary sinus in all cases. The nasolacrimal duct was preserved in all of the patients. The inferior turbinate was completely preserved in 5 patients, and the anterior part of the inferior turbinate was preserved in 3 patients. The mean follow-up period of the patients was 30.8 months (12-60 mo). None of the patients had recurrence or major complications. The postoperative complaints were minor hemorrhagic discharge and crusting for the first few weeks. Endoscopic modified medial maxillectomy preserving the nasolacrimal duct and the inferior turbinate provides good surgical and functional outcomes in selected IP cases. PMID- 25915668 TI - Surgical repair of lacerated anterior cerebral artery presented with massive intracerebral hemorrhage. AB - OBJECTIVE AND IMPORTANCE: Traumatic intracranial aneurysms present diagnostic and therapeutic challenges. Owing to their fragile nature, endovascular intervention has become the first-line treatment; however, direct surgery has an advantage in certain cases. CLINICAL PRESENTATION: A 34-year-old man in coma was admitted after a motor vehicle accident. Brain computed tomographic scans revealed deep bifrontal, left intraventricular, and subarachnoid hemorrhages. Three-dimensional computed tomographic angiography and digital subtraction angiography revealed an aneurysm arising from the left pericallosal artery. INTERVENTION: A massive intracerebral hematoma prompted us to perform emergency surgical intervention. We immediately removed the hematoma and extirpated the aneurysm. After hematoma evacuation via the interhemispheric approach, a pulsating red sphere projecting from the pericallosal artery, with no obvious solid wall or neck, was encountered. While retracting the frontal lobe, it suddenly ruptured. Under temporary trapping of the parent artery, the point of bleeding was identified. No aneurysm wall or fibrous tissue was present, whereas a 1.5-mm laceration was observed at the pericallosal artery close to its branching point. The laceration was sutured with 10-0 nylon. Postoperative digital subtraction angiography confirmed patency of the pericallosal artery. CONCLUSIONS: Although recent technologic advances of intravascular surgery have enabled successful treatment of traumatic pseudoaneurysms, open surgical intervention still has some advantages of providing definitive hemostasis, allowing for parent artery reconstruction, and facilitating mass reduction. The case in the current study was quite unusual in that angiographic aneurysm had disrupted easily, leaving arterial laceration. This finding implies the probability of unavoidable parent artery occlusion when endovascular treatment is applied. PMID- 25915669 TI - Measurements of orbital protrusion from childhood to young adulthood. AB - BACKGROUND: Ocular protrusion is usually measured as the deepest part of the lateral orbital rim to the apex of the cornea. Several studies have been carried out to propose normative data for ocular protrusion according to different age ranges. The protrusion of the eyeball seemed to increase during childhood and adolescence and become stable after the late teens during adulthood. Relationships of ocular protrusion with age are still not completely clarified. The purpose of the current retrospective study was to investigate ocular protrusion on lateral x-rays at different growth stages. METHODS: Ninety-five patients were retrospectively selected and divided into 5 different groups according to ages. Subjects were of both sexes with an age range from 5 to 20 years (mean 12.3 years). The cephalometric analysis proposed in the current study allowed to successfully evaluate sagittal relationships of the orbital-globe and the orbital-cavity in growing patients. All other sagittal and vertical measurements were successfully computed by one trained operator. RESULTS: Analysis of variance results with post hoc corrections showed for the orbital measurements indicating a significant increase of the orbital protrusion from childhood to pubertal stage. CONCLUSIONS: Ocular protrusion measurements showed significant increase from childhood (5-8 years) to teen age (13-15 years) and remained stable after the pubertal growth spurt (17-20 years) in the examined sample of patients. PMID- 25915670 TI - Surgical treatment of denture-induced fibrous hyperplasia with plasma rich in growth factors. AB - Denture-induced fibrous hyperplasia is a fibrous connective tissue lesion that commonly occurs in oral mucosa in patients showing important alveolar ridge atrophy. In this study, we propose Plasma Rich in Growth Factors (PRGF) to overcome constrains of traditional surgical treatment. Herein, we demonstrated that PRGF represents an autologous source of growth factors able to reduce the healing time of the alveolar mucosa and the discomfort of those patients. These properties are the result of PRGF's precise biological features that result in the following: reduction of duration and intensity of postsurgical pain, acceleration of re-epithelialization of the wound, and reduction of bleeding events and of edema. In conclusion, we showed that using PRGF on patients affected by denture-induced fibrous hyperplasia allows a short healing time, thereby reducing complications and overall improving their quality of life. The aims of this study were to evaluate the influence of PRGF-ENDORET on secondary re epithelialization in vestibuloplasty after excision of denture irritation fibrous hyperplasia, with an explorative randomized case control trial with 10 patients, 5 patients treated with PRGF and 5 patients with traditional hemostasis, and to analyze differences with simple surgery, considering postoperative rapidity of re epithelialization, comfort, and discomfort of patients, pain, swelling, and infections. PMID- 25915671 TI - Assessment of orbital volume in frontofacial advancements. AB - OBJECTIVES: The objective of this study was to evaluate the variation of the orbital volume and the correlation with the magnitude of craniofacial advances as well as demonstrate its effectiveness through comparisons with normal levels of orbital volumes. INTRODUCTION: Syndromic craniofacial synostosis is characterized by cranial morphological alterations and hypoplasia of the midface that may result in obstructive sleep apnea and exorbitism; these effects are indications of surgical treatment. The gradual advancement of tissues is the surgical treatment to correct accentuated exorbitisms and jaw retrusions. METHODS: This was a retrospective study by review of medical records and tomographic examinations of 20 patients submitted to distraction osteogenesis between 2001 and 2012, who were divided into 2 groups: groups MB and LF with 11 and 9 patients, who underwent frontofacial or Le Fort III osteotomy. The orbit volume was measured with the InVesalius and Magics software, and facial advancements with Rhinoceros software. Statistical analyses were conducted using Student t test and analysis of variance. RESULTS: Patients' ages ranged from 6 to 29 years. Group MB showed an increase of 8.94 and 9.84 mm(3) in the right and left orbit volume variation, whereas group LF presented 5.70 and 5.77 mm(3). The average advancements in the right and left orbits were 11.36 +/- 3.80 and 11.11 +/- 3.45 mm in group LF, respectively, and 14.22 +/- 4.12 and 14.48 +/- 4.49 mm in group MB. CONCLUSIONS: Exorbitism was satisfactorily treated. The correlation was proportional in group LF and group MB. There was normalization of orbital volume compared with normal levels of orbital volumes. PMID- 25915672 TI - Study on angle of immediate loading of immediate implant placement. AB - OBJECTIVE: To investigate the clinical immediate load at an angle after immediate placement of the implant. METHODS: Select 4 adult dogs; through establishing the angle loading animal experiment model, perform lateral loading on 32 implants respectively at vertical and 0 degrees , 10 degrees , and 20 degrees , with which as a basis for grouping, determine the osseointegration index and new bone growth rate; and observe the peri-implant bone remodeling conditions. RESULTS: The 20 degrees group is found with the most obvious bone absorption, and compared with other groups, its osseointegration index and new bone growth rate are statistically significant (P < 0.01); bone remodeling under 0 degrees load stress is the best, with the formation of new bone and the highest bone contact ratio, which is the most reasonable under this the stress distribution compared with other angles. CONCLUSIONS: The implant stress distribution at 0 degrees against the occlusal force direction is closer to physiologic optimum stress on the implant bone interface, and it is permitted for the long axis of the immediately implanted and immediately loaded implant to be tilted within about 10 degrees against the load angle. PMID- 25915673 TI - Insertion Torque and Pull-Out Strength of Orthodontic Mini-implants Comparing Manual and Motor Insertion Methods. PMID- 25915674 TI - Tooth extractions in high-risk patients under bisphosphonate therapy and previously affected with osteonecrosis of the jaws: surgical protocol supported by low-level laser therapy. AB - Trauma during dental surgery is a predisposing factor for medication-related osteonecrosis of the jaws (MRONJ). There are no specific guidelines for the management of dental extractions in patients under bisphosphonate therapy (BPT). The authors proposed in 2013 a successful protocol for tooth extractions in patients under BPT supported by Nd:YAG low-level laser therapy (LLLT). The aim of this study was to validate the safety and efficacy of this protocol reporting the data related to its application in a particular category of patients under BPT at high risk for MRONJ and who were previously affected with MRONJ. Eighty-two tooth extractions were performed in 36 patients previously affected with MRONJ. Antibiotic treatment was administered 3 days before and 2 weeks after tooth extractions. Patients were additionally treated with Nd:YAG LLLT, 5 applications of 1 minute each. Patients were evaluated 3 days and once a week for 2 months after the extractions and every time they received LLLT. In a total of 82 extractions, minimal bone exposure was observed in 2 cases, treated with Er:YAG laser vaporization and then completely healed. The data confirmed that laser biostimulation is a reliable technique that can be considered in the surgical protocol for patients under BPT. PMID- 25915675 TI - Computer-assisted piezoelectric surgery: a navigated approach toward performance of craniomaxillofacial osteotomies. AB - PURPOSE: The purpose of the current study was to present the clinical applications of a new technique that we term computer-assisted piezoelectric surgery (CAPS). The method marries piezosurgery and navigation to greatly aid the treatment of various maxillofacial problems. METHODS: Preliminary applications in orthognathic surgery, craniofacial procedures, orthodontic surgery, and oncology were analyzed retrospectively. Eighteen patients were treated using the CAPS technique in the interval of 2010 to 2013. RESULTS: The technique emphasizing the features that are not possible without the combination of the 2 systems has been analyzed. The technique is safer than other methods, is minimally invasive, and allows the use of a buried or semiburied approach. CONCLUSIONS: According to our preliminary experience, CAPS seems to be a valuable new technique for craniomaxillofacial osteotomies. PMID- 25915676 TI - Comparative evaluation of cranial base and facial morphology of cleft lip and palate patients with normal individuals in cone beam computed tomography. AB - INTRODUCTION: This study aimed to compare the cranial base and facial morphology of cleft lip and palate (CLP) patients with individuals with no cleft. METHODS: Thirty-two adult individuals including 9 patients without cleft, 14 patients with unilateral CLP, and 9 patients with bilateral CLP participated in the study. The average age of participants was 18.71 +/- 2.1 years. Full skull cone-beam computed tomography of all of the participants was taken. Anatomic landmarks were traced in the midsagittal, coronal, and axial planes, and craniofacial height and width-related parameters were compared among the 3 groups. Analysis of variance and Tukey test were used for comparison. P < 0.05 was considered as significant. RESULTS: SNA (P = 0.048), SNB (P = 0.005), S-N-Pog (P = 0.007), N-ANS (P = 0.013), and the distance between the most superior points of the external auditory meatus (P = 0.01) were significantly decreased in bilateral CLP compared with the control group. Similarly, SNB (P = 0.013) and S-N-Pog (P = 0.008) were significantly smaller in unilateral cases compared with the controls. S-N to the palatal plane was significantly increased in both unilateral (P = 0.013) and bilateral (P = 0.00) cases compared with individuals with no cleft. However, S-N to the palatal plane significantly increased in bilateral cases compared with unilateral clefts (P = 0.028). CONCLUSIONS: Based on the results of the current study, adult patients with CLP showed relatively distinctive morphological features in maxillofacial and cranial base regions. It seems that less dysmorphic characteristics are observed in transverse dimensions of the face and basicranium in both types of cleft. On the other hand, lateral cranial base is more affected by CLP compared with the middle basicranium. PMID- 25915677 TI - Are differences in external noses between whites and Koreans caused by differences in the nasal septum? AB - The nasal septum plays an important role in nose development. East Asians are believed to have inherent hypoplasia of the nasal septum because East Asians have smaller noses than whites do. However, there have been no studies of nasal septum differences between whites and East Asians. We compared the nasal septum and its components in Koreans and whites using computed tomographic scan data. Twenty seven patients of white origin and 64 patients of Korean origin older than 20 years were enrolled in this study between 2008 and 2012. We evaluated a total of 9 measurement items (5 for the nasal bones and septa as well as 4 for the external nose morphology). Sex differences in whites were the same as those in Koreans. Nasal bridge length and cartilaginous nasal bridge length were significantly longer in whites than in Koreans. However, there were no significant differences in nasal height, nasal tip projection, nasal bone length, total septal area, or most components of the nasal septum between the samples. The relative proportions of the cartilaginous septum divided by the total septal area were negatively correlated with the relative proportions of the perpendicular plate in both groups. Differences in the external nasal morphology between whites and Koreans are not caused by differences in the nasal septum. PMID- 25915678 TI - Mandibular distraction for Robin sequence associated with laryngomalacia. AB - INTRODUCTION: Protocols for the treatment of Robin sequence (RS) consider the presence of laryngomalacia as a contraindication to mandibular distraction osteogenesis (MDO). The authors report their institutional experience of MDO applied to infants with RS and associated laryngomalacia. METHODS: An 8-year (2005-2013) retrospective review of all infants with RS and laryngomalacia who underwent MDO at a tertiary care children's hospital was performed. Patients were excluded if they possessed an airway anomaly other than laryngomalacia. Laryngomalacia was identified on laryngoscopy before MDO. Laser supraglottoplasty was performed at the discretion of the otolaryngologist. Recorded variables included preoperative and postoperative AHI, syndromic diagnosis or genetic anomalies, cardiac, central nervous system (CNS), and gastrointestinal (GI) abnormalities. The primary outcomes measured were avoidance or decannulation of tracheostomy and decrease in postoperative AHI. RESULTS: Eleven infants met inclusion criteria. Mean follow-up was 28 months. 18.2% of patients had a syndromic diagnosis, 36.4% cardiac, 9.1% CNS, and 72.7% GI abnormalities. Mean preoperative AHI was 46.1 +/- 31.8 and mean postoperative AHI was 4.1 +/- 3.0 (P = 0.002). All patients without a tracheostomy before intervention avoided tracheostomy after MDO. One patient had a tracheostomy before MDO and was subsequently decannulated. One patient died 1 year after MDO due to complex congenital heart disease. CONCLUSIONS: Infants with RS and laryngomalacia can be successfully treated with MDO to relieve upper airway obstruction. Close cooperation with a pediatric otolaryngologist and treatment of laryngomalacia can significantly enhance tracheostomy avoidance in infants with Robin sequence. PMID- 25915679 TI - A novel method for nasal dorsal reconstruction: permanent fixation using Kirschner wire-guided hidden sutures. AB - BACKGROUND: In this study, we aimed to present a novel application and use of Kirschner wire-guided suturing that is less invasive and allows permanent fixation for nasal dorsal reconstruction. METHODS: A total of 23 patients, who underwent surgery between 2009 and 2013, were included in this study: 19 with saddle nose deformity and 4 patients with keystone area damage, or collapse of the dorsal nasal support during primary septoplasty or rhinoplasty. The patients were asked to fill out a nasal obstruction symptom evaluation (NOSE) scale preoperatively and at the postoperative sixth month to assess breathing quality. The patients were followed up for complications such as nasal dorsal contour irregularity, dorsal collapse, as well as graft malposition and infections. The results of the surgeries were assessed on the basis of preoperative and postoperative examinations, septal support test, NOSE scale results, and photographic comparison. RESULTS: The mean (SD) NOSE scales were 78.91 (10.09) and 30.48 (10.71) in the preoperative and postoperative periods, respectively. The difference of mean NOSE scale was statistically significant (P < 0.001). None of the patients experienced nasal dorsal collapse or graft malposition. Two patients had nasal dorsal irregularity complaints owing to inadequate costal cartilage edge beveling. None of the patients had complications of suture reaction, suture visibility, or suture extrusion. All of the patients stated that they were happy with the cosmetic outcome. CONCLUSIONS: Permanent sutures introduced through channels made with the Kirschner wire provide a less invasive, cosmetically pleasing, and functional solution, promising more reliable results in the long term. PMID- 25915680 TI - Evaluation of bone height of the free fibula flap in mandible reconstruction. AB - BACKGROUND: Use of a vascularized free fibula flap has become a preferred method of mandible reconstruction after oncologic surgical ablation. Despite its many advantages, the low vertical height of the graft is a potential drawback and severe long-term atrophy of fibular bones may cause stress fracture and is disadvantageous for osseointegrated dental implants and facial contours. Therefore, it is important to investigate the degree of resorption based on the fibular height and the factors related to resorption over time. The influence of aspects of the intraoperative surgical procedure, such as preservation of a nutrient artery from the peroneal artery to the fibula bone marrow and the number of segmental osteotomies, has not been examined previously. Therefore, the purpose of this study was to examine the change in fibular height and the factors influencing resorption, including those associated with the surgical procedure. PATIENTS AND METHODS: A retrospective analysis was performed in 19 patients who underwent free vascularized fibular mandibular reconstruction for oncologic surgical defects without radiotherapy. Postoperative Panorex examinations were used to evaluate fibular height, and 7 factors with a potential influence on long term fibular height were evaluated: age, gender, length of the mandible defect, number of segmental osteotomies, preservation of a direct nutrient artery from the peroneal artery to the fibula bone marrow, length of follow-up, and delayed placement of osseointegrated dental implants. RESULTS: Fibular bone height decreased in 13 patients (68%), was unchanged in 2 (11%), and increased in 4 (21%). Segmental osteotomies and female gender were significant factors promoting fibular bone resorption (P < 0.001 and P < 0.001, respectively), and preservation of a nutrient artery to the bone marrow, male gender, and delayed placement of osseointegrated dental implants were significant factors inhibiting bone resorption (P < 0.01, P < 0.001, and P < 0.05, respectively). Age, length of follow-up period, and length of the mandibular defect showed no significant relationship with bone resorption (P = 0.77, P = 0.78, and P = 0.105, respectively). CONCLUSION: The results of this study showed that fibular height in mandibular reconstruction can be maintained by preservation of a direct nutrient artery to bone marrow, avoidance of osteotomies, and delayed placement of osseointegrated dental implants, all of which inhibit fibular bone resorption. PMID- 25915681 TI - How to rehabilitate long-term facial paralysis. AB - OBJECTIVE: To project the surgical resuscitation methods that we apply to the lower part of the face and the eyes with the aim of preventing functional and psychological problems that can occur in patients with facial paralysis. MATERIALS AND METHODS: Twenty-two patients with facial nerve paralysis due to acoustic neuroma, trauma, cholesteatoma, and parotid carcinoma were included in this study. In the lower facial region, the temporal muscle was suspended to the lower lip. In the upper facial region, eyelid gold implantation was performed. The reanimation results of the upper and lower facial regions were graded as excellent, good, fair, and poor in consideration of the symmetry after rest and smile according to May classification in the third month after the surgery. RESULTS: The study group comprised 15 men (68.2%) and 5 women (31.8 %) (mean age, 63.82 +/- 14.18 years; range, 8-78 years). Of the patients, 18.2% (n = 4) had acoustic neuroma, 40.9% (n = 9) had facial trauma, 27.3% (n = 6) had cholesteatoma, and 13.6% (n = 3) had parotid carcinoma.Reanimation techniques were applied to 40.9% (n = 9) of the patients during the first 2-4 years, whereas 59.1% (n = 13) of patients underwent surgery after 4 years.In a total of 17 patients (77.3%) who had lower lip intervention, 4 patients (23.5%) had excellent results, 7 patients (41.2%) had good results, and 6 patients (35.3%) had moderate results.In the 22 patients who underwent the eyelid procedure, 5 patients (22.7 %) had excellent results, 13 patients (59.1 %) had good results, and 3 patients (18.2 %) had moderate results. Poor results were not observed in any patient. CONCLUSION: Facial paralysis is a disease that causes serious functional and psychological problems in patients. Therefore, the choice of treatment method is dependent on the etiology, duration of paralysis, expectations of the patient, and experience of the surgeon. Being less invasive methods, obtaining immediate results, requiring single surgical stage, and having long-lasting results and dynamic muscle transfer and static suspension methods are preferred. PMID- 25915682 TI - Comparative study between partial inferior turbinotomy and microdebrider-assisted inferior turbinoplasty. AB - PURPOSE: The purpose of our study was to compare the inferior turbinotomy and the microdebrider-assisted inferior turbinoplasty in patients with hypertrophy of the inferior turbinate. MATERIAL AND METHODS: We carried out a retrospective review of 205 patients, 96 women and 109 men, with a mean age of 48 years, operated on for hypertrophy of the inferior turbinate between May 2005 and May 2012. Forty seven patients were excluded from our study because in these patients, nasal obstruction was caused by a specific pathologic condition (allergy, tumors or polyps, recurrent rhinosinusitis, etc). The remaining 158 patients were randomly assigned to undergo partial inferior turbinoplasty through the use of microdebrider (group A, n = 79) or partial inferior turbinotomy (group B, n = 79). Surgical outcome was evaluated according to 4 distinct parameters: nasal endoscopic findings, nasal subjective symptoms, anterior rhinomanometry, and nasal mucociliary transport time. These evaluations were made before surgery and 1 week and 3 months after surgery. The follow-up was a minimum of 24 months and a maximum of 60 months, with a mean follow-up of 42 months. RESULTS: Turbinate edema and secretions decreased significantly (P < 0.05) in groups A and B 3 months after surgery. In group A, crusting was not observed after surgery. In group B, crusting had increased significantly (P < 0.005) 1 week after surgery and then decreased significantly at the third month after surgery. Subjective nasal symptoms including nasal obstruction, sneezing, snoring, itchy nose, hyposmia, headache, and dryness were significantly improved in both groups from the third month after surgery (P < 0.05). Rhinomanometric measurements demonstrated a significant nasal flow increase at 3 months (P < 0.05). The mean nasal mucociliary transport time slightly increased in both groups 1 week after surgery, and then restabilized to preoperative values at the third-month follow up in both groups (difference not significant). CONCLUSIONS: Microdebrider assisted inferior turbinoplasty and partial inferior turbinotomy are very effective surgical techniques for solving hypertrophy of the inferior turbinates and therefore related problems of nasal obstruction. Microdebrider-assisted inferior turbinoplasty compared to partial inferior turbinotomy ensures a greater preservation of the nasal mucosa to prevent nasal bleeding. PMID- 25915684 TI - Nasal septum perforation repair using a split septal cartilage graft. PMID- 25915683 TI - Tracheal metastasis. PMID- 25915685 TI - Enzyme-Activatable Cell-Penetrating Peptides through a Minimal Side Chain Modification. AB - Activatable cell-penetrating peptides are of great interest in drug delivery because of their enhanced selectivity which can be controlled by the external stimuli that trigger their activation. The use of a specific enzymatic reaction to trigger uptake of an inert peptide offers a relevant targeting strategy because the activation process takes place in a short time and only in areas where the specific cell surface enzyme is present. To this aim, the lysine side chain of Tat peptides was modified with an enzyme-cleavable domain of minimal size. This yielded blocked Tat-peptides which were inactive but that could be activated by coincubation with the selected enzymes. PMID- 25915686 TI - Maintaining warm, trusting relationships with brands: increased temperature perceptions after thinking of communal brands. AB - Classical theories on interpersonal relations have long suggested that social interactions are influenced by sensation, such as the experience of warmth. Past empirical work now confirms that perceived differences in temperature impact how people form thoughts about relationships. The present work first integrates our knowledge database on brand research with this idea of "grounded social cognition". It then leverages a large sample (total N = 2,552) toward elucidating links between estimates of temperature and positive versus negative evaluations of communal brands. In five studies, the authors have found that thinking about positively (vs. negatively) perceived communal brands leads to heightened temperature estimates. A meta-analysis of the five studies shows a small but consistent effect in this noisy environment, r = .11, 95% CI, .05, .18. Exploratory analyses in Studies 1a and b further suggest that temperature perceptions mediate the (significant) relationship between perceived communality and willingness to purchase from the brand. The authors discuss implications for theory and practice and consider the effects from a Social Baseline Perspective. PMID- 25915687 TI - Experimental design strategy: weak reinforcement leads to increased hit rates and enhanced chemical diversity. AB - High Throughput Screening (HTS) is a common approach in life sciences to discover chemical matter that modulates a biological target or phenotype. However, low assay throughput, reagents cost, or a flowchart that can deal with only a limited number of hits may impair screening large numbers of compounds. In this case, a subset of compounds is assayed, and in silico models are utilized to aid in iterative screening design, usually to expand around the found hits and enrich subsequent rounds for relevant chemical matter. However, this may lead to an overly narrow focus, and the diversity of compounds sampled in subsequent iterations may suffer. Active learning has been recently successfully applied in drug discovery with the goal of sampling diverse chemical space to improve model performance. Here we introduce a robust and straightforward iterative screening protocol based on naive Bayes models. Instead of following up on the compounds with the highest scores in the in silico model, we pursue compounds with very low but positive values. This includes unique chemotypes of weakly active compounds that enhance the applicability domain of the model and increase the cumulative hit rates. We show in a retrospective application to 81 Novartis assays that this protocol leads to consistently higher compound and scaffold hit rates compared to a standard expansion around hits or an active learning approach. We recommend using the weak reinforcement strategy introduced herein for iterative screening workflows. PMID- 25915688 TI - Active magnetoplasmonic ruler. AB - Plasmon rulers are an emerging concept in which the strong near-field coupling of plasmon nanoantenna elements is employed to obtain structural information at the nanoscale. Here, we combine nanoplasmonics and nanomagnetism to conceptualize a magnetoplasmonic dimer nanoantenna that would be able to report nanoscale distances while optimizing its own spatial orientation. The latter constitutes an active operation in which a dynamically optimized optical response per measured unit length allows for the measurement of small and large nanoscale distances with about 2 orders of magnitude higher precision than current state-of-the-art plasmon rulers. We further propose a concept to optically measure the nanoscale response to the controlled application of force with a magnetic field. PMID- 25915690 TI - Motivational pathways from reward sensitivity and punishment sensitivity to gambling frequency and gambling-related problems. AB - Motives for gambling have been shown to have an important role in gambling behavior, consistent with the literature on motives for substance use. While studies have demonstrated that traits related to sensitivity to reward (SR) and sensitivity to punishment (SP) are predictive of substance use motives, little research has examined the role of these traits in gambling motives. This study investigated motivational pathways from SR and SP to gambling frequency and gambling problems via specific gambling motives, while also taking into account history of substance use disorder (SUD). A community sample of gamblers (N = 248) completed self-report questionnaires assessing SR, SP, gambling frequency, gambling-related problems, and motives for gambling (social, negative affect, and enhancement/winning motives). Lifetime SUD was also assessed with a structured clinical interview. The results of a path analysis showed that SR was uniquely associated with all 3 types of gambling motives, whereas SP and SUD were associated with negative affect and enhancement/winning motives but not social motives. Also, both negative affect and enhancement/winning motives were associated with gambling problems, but only enhancement/winning motives were significantly related to gambling frequency. Analyses of indirect associations revealed significant indirect associations from SR, SP, and SUD to gambling frequency mediated through enhancement/winning motives and to gambling problems mediated through both negative affect and enhancement/winning motives. The findings highlight the importance of SR and SP as independent predictors of gambling motives and suggest that specific motivational pathways underlie their associations with gambling outcomes. PMID- 25915689 TI - Coping-motivated marijuana use correlates with DSM-5 cannabis use disorder and psychological distress among emerging adults. AB - Compared to other age cohorts, emerging adults, ages 18-25 years, have the highest rates of marijuana (MJ) use. We examined the relationship of using MJ to cope with negative emotions, relative to using MJ for enhancement or social purposes, to MJ-associated problems and psychological distress among emerging adults. Participants were 288 community-dwelling emerging adults who reported current MJ use as part of a "Health Behaviors" study. Linear and logistic regressions were used to evaluate the adjusted association of coping-motivated MJ use with the fifth edition of the Diagnostic and Statistical Manual of Mental Disorders (DSM-5) cannabis use disorder, MJ-related problem severity, depressive symptoms, and perceived stress. After adjusting for other variables in the regression model, using MJ to cope was positively associated with having DSM-5 cannabis use disorder (OR = 1.85, 95% CI [1.31, 2.62], p < .01), MJ problem severity (b = .41, 95% CI [.24, .57], p < .01), depression (b = .36, 95% CI [.23, .49], p < .01), and perceived stress (b = .37, 95% CI [.22, .51], p < .01). Using MJ for enhancement purposes or for social reasons was not associated significantly with any of the dependent variables. Using MJ to cope with negative emotions in emerging adults is associated with MJ-related problems and psychological distress. Assessment of MJ use motivation may be clinically important among emerging adults. PMID- 25915691 TI - Binge drinking, depression, and electrocortical responses to emotional images. AB - Binge drinking and depression are highly prevalent, associated with cognitive and affective impairments, and frequently co-occur. Yet little research has examined their joint relations with such processing impairment. The current study examines the relation between symptoms of depression, binge drinking, and the magnitude of early (early posterior negativity, EPN) and later (P3 and late positive potential, LPP) visual processing components of affectively negative, positive, and neutral visual stimuli. Participants included 42 undergraduate students recruited on the basis of depressive symptoms. Results of repeated measures analyses of variance (ANOVAs; Depression * Binge * Emotion * Laterality) showed that binge drinkers exhibited lower LPP amplitudes for negative images, compared with nonbinge drinkers, regardless of depression, consistent with motivational models of alcohol abuse. Otherwise, differences across depressed and nondepressed groups were largest among binge drinkers, including a pattern of stronger early attentional engagement (EPN) to negative and neutral images, but decreased later processing (P3 and LPP) across all emotional categories, consistent with a vigilance-avoidance response pattern. PMID- 25915692 TI - Psychological distress among victimized women on probation and parole: A latent class analysis. AB - Latent class analysis was used to identify subgroups of victimized women (N = 406) on probation and parole differentiated by levels of general psychological distress. The 9 primary symptom dimensions from the Brief Symptom Inventory (BSI) were used individually as latent class indicators (Derogatis, 1993). Results identified 3 classes of women characterized by increasing levels of psychological distress; classes were further differentiated by posttraumatic stress disorder symptoms, cumulative victimization, substance use and other domains of psychosocial functioning (i.e., sociodemographic characteristics; informal social support and formal service utilization; perceived life stress; and resource loss). The present research was effective in uncovering important heterogeneity in psychological distress using a highly reliable and easily accessible measure of general psychological distress. Differentiating levels of psychological distress and associated patterns of psychosocial risk can be used to develop intervention strategies targeting the needs of different subgroups of women. Implications for treatment and future research are presented. PMID- 25915693 TI - Constitutive expression of the Poplar FD-like basic leucine zipper transcription factor alters growth and bud development. AB - In poplar, the CO/FT regulatory module mediates seasonal growth cessation. Although FT interacts with the basic leucine zipper transcription factor FD, surprisingly little is known about the possible role of FD in bud development and growth cessation in trees. In this study, we examined the expression and localization of the poplar FD homolog, PtFD1, during short-day (SD)-induced bud development, and the consequences of overexpressing PtFD1 on bud development and shoot growth. PtFD1 was primarily expressed in apical and axillary buds and exhibited a transient increase in expression during the initial stages of SD induced bud development. This transient increase declined with continued SD treatment. When PtFD1 was overexpressed in poplar, SD-induced growth cessation and bud formation were abolished. PTFD1 overexpression also resulted in precocious flowering of juvenile plants in long-day (LD) photoperiods. Because the phenotypes associated with overexpression of PtFD1 are similar to those observe when poplar FT1 is overexpressed (Science, 312, 2006, 1040), the expression and diurnal patterns of expression of both poplar FT1 and FT2 were characterized in PtFD1 overexpression poplars and found to be altered. DNA microarray analysis revealed few differences in gene expression between PtFD1 overexpressing poplars in LD conditions while extensive levels of differential gene expression occur in SD-treated plants. These results enforce the connection between the regulation of flowering and the regulation of growth cessation and bud development in poplar. PMID- 25915694 TI - Electrochemistry and spectroelectrochemistry of bioactive hydroxyquinolines: a mechanistic study. AB - The oxidation mechanism of selected hydroxyquinoline carboxylic acids such as 8 hydroxyquinoline-7-carboxylic acid (1), the two positional isomers 2-methyl-8 hydroxyquinoline-7-carboxylic acid (3) and 2-methyl-5-hydroxyquinoline-6 carboxylic acid (4), as well as other hydroxyquinolines were studied in aprotic environment using cyclic voltammetry, controlled potential electrolysis, in situ UV-vis and IR spectroelectrochemistry, and HPLC-MS/MS techniques. IR spectroelectrochemistry showed that oxidation unexpectedly proceeds together with protonation of the starting compound. We proved that the nitrogen atom in the heterocycle of hydroxyquinolines is protonated during the apparent 0.7 electron oxidation process. This was rationalized by the autodeprotonation reaction by another two starting molecules of hydroxyquinoline, so that the overall oxidation mechanism involves two electrons and three starting molecules. Both the electrochemical and spectroelectrochemical results showed that the oxidation mechanism is not influenced by the presence of the carboxylic group in the chemical structure of hydroxyquinolines, as results from oxidation of 2,7 dimethyl-5-hydroxyquinoline (6). In the presence of a strong proton acceptor such as pyridine, the oxidation ECEC process involves two electrons and two protons per one molecule of the hydroxyquinoline derivative. The electron transfer efficiency of hydroxyquinolines in biosystems may be related to protonation of biocompounds containing nitrogen bases. Molecular orbital calculations support the experimental findings. PMID- 25915695 TI - Structural and Biochemical Characterization of a Ferredoxin:Thioredoxin Reductase-like Enzyme from Methanosarcina acetivorans. AB - Bioinformatics analyses predict the distribution in nature of several classes of diverse disulfide reductases that evolved from an ancestral plant-type ferredoxin:thioredoxin reductase (FTR) catalytic subunit to meet a variety of ecological needs. Methanosarcina acetivorans is a methane-producing species from the domain Archaea predicted to encode an FTR-like enzyme with two domains, one resembling the FTR catalytic subunit and the other containing a rubredoxin-like domain replacing the variable subunit of present-day FTR enzymes. M. acetivorans is of special interest as it was recently proposed to have evolved at the time of the end-Permian extinction and to be largely responsible for the most severe biotic crisis in the fossil record by converting acetate to methane. The crystal structure and biochemical characteristics were determined for the FTR-like enzyme from M. acetivorans, here named FDR (ferredoxin disulfide reductase). The results support a role for the rubredoxin-like center of FDR in transfer of electrons from ferredoxin to the active-site [Fe4S4] cluster adjacent to a pair of redox active cysteines participating in reduction of disulfide substrates. A mechanism is proposed for disulfide reduction similar to one of two mechanisms previously proposed for the plant-type FTR. Overall, the results advance the biochemical and evolutionary understanding of the FTR-like family of enzymes and the conversion of acetate to methane that is an essential link in the global carbon cycle and presently accounts for most of this greenhouse gas that is biologically generated. PMID- 25915696 TI - Relative Efficiency of Field and Online Strategies in the Recruitment of HIV Positive Men Who Have Sex With Men. AB - Efforts to reach HIV-positive men who have sex with men (MSM) and link them to care must be expanded; however, finding and recruiting them remains a challenge. We compared the efficiency of three recruitment sources in reaching self identified HIV-positive MSM with various characteristics. Relative to recruitment online and at clubs and bars, AIDS Service Organizations (ASOs) were significantly more efficient in reaching HIV-positive MSM in general. This was also true for those with specific characteristics of interest such as substance/stimulant use, and HIV-positive MSM who were racial/ethnic minorities. Both ASOs and online recruitment were more efficient than clubs and bars in reaching HIV-positive MSM not taking HIV medication. This was also the case for White HIV-positive MSM in general, and White HIV-positive MSM who used substances and stimulants. Online recruitment was also more efficient than clubs and bars in reaching HIV-positive MSM who were young across the board. PMID- 25915697 TI - Acceptability of PrEP Uptake Among Racially/Ethnically Diverse Young Men Who Have Sex With Men: The P18 Study. AB - Pre-exposure prophylaxis (PrEP) is considered an effective biomedical approach for HIV prevention. However, there is limited understanding of PrEP uptake among racially/ethnically and socioeconomically diverse young men who have sex with men (YMSM). This study examined attitudes and perceptions toward PrEP uptake among YMSM by conducting semistructured interviews with a sample (N = 100) of YMSM in New York City. Thematic analysis was employed to explore key issues related to attitudes and perceptions toward PrEP utilization. Findings suggest that self perceived risk for HIV transmission, enjoying unprotected sex, and being in a romantic relationship were associated with PrEP uptake. The most prominent barriers to PrEP uptake included costs, adherence regimen, and access. In summary, these findings underscore the importance of addressing behavioral and structural factors in maximizing the effectiveness of PrEP. In addition, PrEP implementation programs ought to consider the role of social and structural challenges to PrEP uptake and adherence among YMSM. PMID- 25915698 TI - Heterosexual Partnerships and the Need for HIV Prevention and Testing for Men Who Have Sex With Men and Women in China: A Qualitative Study. AB - Previous studies have reported that approximately 30% of men who have sex with men (MSM) in China have concurrent female partners. Men who have sex with men and women (MSMW) might "bridge" HIV transmission to their female sex partners. This study aimed to explore (a) motivations for why MSMW in China engage in relationships and sexual behaviors with female partners; (b) patterns of sexual behaviors and condom use between MSMW and their female partners; and (c) barriers to and strategies for encouraging MSMW and their female partners to undergo HIV testing. The authors conducted in-depth interviews with 30 MSMW in two urban cities in China, Guangzhou and Chengdu, and used thematic analysis methods to code and interpret the data. MSMW described family, social, and workplace pressures to have a female partner, and expressed futility about their ability to form stable same-sex relationships. Although participants reported concern about the risk of personally acquiring and transmitting HIV or other sexually transmitted infections (STIs) to their female partners, they described the challenges to using condoms with female partners. HIV-positive participants described how stigma restricted their ability to disclose their HIV status to female partners, and HIV-negative participants displayed less immediate concern about the need for female partners to undergo HIV testing. Participants described a range of possible strategies to encourage HIV testing among female partners. These findings highlight the urgent need for HIV risk reduction and testing interventions for Chinese MSMW in the context of heterosexual partnerships, and they also underscore the additional need for privacy and cultural sensitivity when designing future studies. PMID- 25915699 TI - Predictors of Intention to Use HIV Testing Service Among Sexually Experienced Youth in Thailand. AB - This study examined the predictors of intention to use HIV counseling and testing (HCT) services among those who had never used HCT services in a sample of 2,536 Thai youth in Bangkok (ages 15-24). Web-based questionnaires included assessments of HIV knowledge, HIV testing attitude, AIDS stigma, and youth-friendly HCT (YFHCT) service expectation. More than 80% of the sexually experienced youth had never used HCT services but among this group 74.06% reported having intentions to do so. The significant predictors consisted of favorable expectations of YFHCT services (p < .001), positive attitude toward HIV testing (p < .005), perceived high risk for HIV infection (p < .01), having multiple sex partners while also using condoms consistently (p < .01), willingness to pay (p < .001), and being informed about HCT and knowing service locations (p < .001). Policy makers, as well as health promotion program developers and researchers can use these findings to increase intention and use of HCT services among at-risk youth. PMID- 25915700 TI - Informing the scaling up of voluntary medical male circumcision efforts through the use of theory of reasoned action: survey findings among uncircumcised young men in Swaziland. AB - Assessing predictors of intention to circumcise can help to identify effective strategies for increasing uptake of voluntary medical male circumcision (VMMC). Grounded in the theory of reasoned action (TRA), the current study of uncircumcised males ages 13-29 in Swaziland (N = 1,257) employed multivariate logistic regression to determine predictors of VMMC intention. The strongest predictors were strongly disagreeing/disagreeing that sex was more painful for a circumcised man (odds ratio [OR] = 4.37; p = < .007), a Christian man should not get circumcised (OR = 2.47; p < .001), and circumcision makes penetration more painful and difficult (OR = 2.44; p = .007). Several beliefs about enhanced sexual performance, normative beliefs (parents, sexual partner, and friends), and non-TRA-related factors (e.g., importance of plowing season to daily schedule) were also statistically significant predictors. TRA proved a useful theory to explore young men's intention to circumcise and can help inform interventions aimed at increasing uptake of VMMC. PMID- 25915701 TI - Understanding the Effects of Multiple Stigmas Among Formerly Incarcerated HIV Positive African American Men. AB - Race, HIV, and incarceration, as individual and intersecting markers of social identity, have associated stigma. While some research has indicated multiple burdens of stigma can be additive, there remains a lack of investigation relative to the effects of stigma among minorities who experience both HIV and incarceration. Therefore, the current study examines the impact of multiple forms of stigma via a series of ethnographic interviews (n = 46) conducted with 12 African American men over a one-year period. Results suggest that intersecting forms of stigma can have a severe impact on the general health, mental health, and the reintegration process of formerly incarcerated HIV-positive men. Additionally, participants often conceptualized all forms of stigma separately, which resulted in compounded burden of navigation. The experience of multiple forms of stigma was also often internalized as self-stigma whereby HIV-positive individuals with a history of incarceration assumed dominant norms related to both HIV and incarceration. PMID- 25915702 TI - Condom use among female sex workers in Catalonia: why do they use a condom, why don't they use it? AB - The present study, based on social representation theory (Moscovici, 1961), aimed to identify the social representation of condom use (CU) in a collective of female sex workers (FSW) in Catalonia, considering both their work and private life. It involved 124 FSW and combined both qualitative and quantitative methodologies. Results suggest that both CU and non-CU represent strategies that FSW use mainly when confronted by threats to things they consider important. In work life, where CU is widespread, the most important thing is health protection, and the threat is represented by sexually transmitted infections. In private life, where non-CU is widespread, the most important thing is that their relationships adhere to an idealized relationship model, based on love, trust, and sexual gratification; this model lies in contrast to the status of the women as FSW. The threats are represented by both partner infidelity and their FSW status (symbolic threats). PMID- 25915703 TI - Assessing the factor structure of well-being in older adults: findings from the National Health and Aging Trends Study. AB - OBJECTIVES: Well-being has been conceptualized as a two-dimensional construct that includes both hedonic and eudaimonic components. To date, existing measures of well-being may not adequately capture both of these components for older adults, and limited literature has explored whether the two constructs can be integrated into one factor to measure well-being in this population. METHOD: This study examined the factor structure of the 11 well-being items from the National Health and Aging Trends Study (NHATS), a nationally representative panel study of Medicare recipients in the US. Using data from the 2011 wave, we divided the community-dwelling sample into two random subsamples, testing our theory in sample 1 (n = 3305) and examining the replicability of the solution in sample 2 (n = 3297). RESULTS: We conducted confirmatory factor analyses using a correlated uniqueness approach to account for the frequency and negatively worded method effects. The findings from sample 1 indicated that the single factor structure was a superior fit to the data, and the solution was confirmed by sample 2 [chi(2)(33) = 85.002, p < .001, RMSEA = 0.022 (90% CI = 0.016-0.028), CFI = 0.993, TLI = 0.989, WRMR = 0.831]. CONCLUSION: Findings suggest that although the hedonic and eudaimonic components of well-being may be conceptually distinct, they are highly correlated in the NHATS well-being measures and should be measured as a single construct. Implications for future research using the NHATS and research using other data sources and focusing on other populations are discussed. PMID- 25915704 TI - Moving health sovereignty in Africa - disease, governance, climate change. PMID- 25915705 TI - MicroRNA Levels as Prognostic Markers for the Differentiation Potential of Human Mesenchymal Stromal Cell Donors. AB - The ability of human mesenchymal stromal/stem cells (hMSCs) to differentiate into various mesenchymal cell lineages makes them a promising cell source for the use in tissue repair strategies. Since the differentiation potential of hMSCs differs between donors, it is necessary to establish biomarkers for the identification of donors with high differentiation potential. In this study, we show that microRNA (miRNA) expression levels are effective for distinguishing donors with high differentiation potential from low differentiation potential. Twenty hMSC donors were initially tested for marker expression and differentiation potential. In particular, the chondrogenic differentiation potential was evaluated on the basis of histological matrix formation, mRNA expression levels of chondrogenic marker genes, and quantitative glycosaminoglycan deposition. Three donors out of twenty were identified as donors with high chondrogenic potential, whereas nine showed moderate and eight showed low chondrogenic potential. Expression profiles of miRNAs involved in chondrogenesis and cartilage homeostasis were used for the distinction between high-performance hMSCs and low-performance hMSCs. Global mRNA expression profiles of the donors before the onset of chondrogenic differentiation revealed minor differences in gene expression between low and high chondrogenic performers. However, analysis of miRNA expression during a 7 day differentiation period identified miR-210 and miR-630 as positive regulators of chondrogenesis. In contrast, miR-181 and miR-34a, which are negative regulators of chondrogenesis, were upregulated during differentiation in low performing donors. In conclusion, profiling of hMSC donors for a specific panel of miRNAs may have a prognostic value for selecting donors with high differentiation potential to improve hMSC-based strategies for tissue regeneration. PMID- 25915706 TI - ICRP Publication 124: Protection of the Environment under Different Exposure Situations. AB - In this report, the Commission describes its framework for protection of the environment and how it should be applied within the Commission's system of protection. The report expands upon its objectives in relation to protection of the environment, in so far as it relates to the protection of animals and plants (biota) in their natural environment, and how these can be met by the use of Reference Animals and Plants (RAPs); their Derived Consideration Reference Levels (DCRLs), which relate radiation effects to doses over and above their normal local background natural radiation levels; and different potential pathways of exposure. The report explains the different types of exposure situations to which its recommendations apply; the key principles that are relevant to protection of the environment; and hence how reference values based on the use of DCRLs can be used to inform on the appropriate level of effort relevant to different exposure situations. Further recommendations are made with regard to how the Commission's recommendations can be implemented to satisfy different forms of environmental protection objectives, which may require the use of representative organisms specific to a site, and how these may be compared with the reference values. Additional information is also given with regard to, in particular, communication with other interested parties and stakeholders. Issues that may arise in relation to compliance are also discussed, and the final chapter discusses the overall implications of the Commission's work in this area to date. Appendices A and B provide some numerical information relating to the RAPs. Annex C considers various existing types of environmental protection legislation currently in place in relation to large industrial sites and practices, and the various ways in which wildlife are protected from various threats arising from such sites. PMID- 25915707 TI - Engagement, Flow, Self-Efficacy, and Eustress of University Students: A Cross National Comparison Between the Philippines and Argentina. AB - This study examined how self-efficacy, eustress, and flow interact with academic engagement. First, it aimed to test a theoretical model that proposes that self efficacy and eustress promote both flow and engagement and that, in turn, the state of flow promotes academic engagement in undergraduate student. We hypothesized that the theoretical model would be invariant for two countries: the Philippines and Argentina. Secondly, this research aimed to compare the levels of self-efficacy, eustress, study-flow and academic engagement experiences in students from both countries. One hundred seventy-six Filipinos and 171 Argentinean students participated in the study by completing inventories using the Utrecht Student Engagement Scale (Schaufeli, Martinez, et al., 2002), Optimal Experience Survey (Mesurado, 2008), Self-efficacy Scale (O'Sullivan, 2011), and Eustress Scale (O'Sullivan, 2011). Results show that the theoretical model fits the data well in both countries and is invariant across the Philippines and Argentina. Self-efficacy has a positive effect on flow and engagement, whereas eustress has a significant positive relationship with flow but is not directly associated with engagement. However, eustress has an indirect effect, through flow, on student engagement. On the other hand, there are different levels of engagement, flow, self-efficacy, and eustress. Argentinean students scored higher on absorption, dedication, self-efficacy, and flow. Filipino students, meanwhile, scored higher on eustress. PMID- 25915708 TI - Nanofiltration across Defect-Sealed Nanoporous Monolayer Graphene. AB - Monolayer nanoporous graphene represents an ideal membrane for molecular separations, but its practical realization is impeded by leakage through defects in the ultrathin graphene. Here, we report a multiscale leakage-sealing process that exploits the nonpolar nature and impermeability of pristine graphene to selectively block defects, resulting in a centimeter-scale membrane that can separate two fluid reservoirs by an atomically thin layer of graphene. After introducing subnanometer pores in graphene, the membrane exhibited rejection of multivalent ions and small molecules and water flux consistent with prior molecular dynamics simulations. The results indicate the feasibility of constructing defect-tolerant monolayer graphene membranes for nanofiltration, desalination, and other separation processes. PMID- 25915709 TI - Distribution and features of middle cerebral artery atherosclerotic plaques in symptomatic patients: a 3.0 T high-resolution MRI study. AB - OBJECTIVES: To investigate the distribution and features of middle cerebral artery (MCA) atherosclerotic plaques in patients with acute ischaemic strokes using high-resolution magnetic resonance (MR) imaging. METHODS: Forty-six plaques from 44 MCAs (18 right and 26 left) in patients with acute symptomatic ischaemic strokes were studied. High-resolution MR imaging including tb1 weighted imaging (T1WI), tb2 weighted imaging (T2WI), PD weighted imaging (PDWI) and three dimensional magnetization-prepared rapid acquisition gradient-echo (MPRAGE) sequences were used to visualise the plaques. The locations of plaques were classified into ventral, distal, superior and inferior wall of the MCA on oblique sagittal images. The thickness, area and signal intensities of plaques were recorded. The stenosis degree of MCA was calculated. RESULTS: Among all 46 plaques, 26 plaques were located at the ventral wall (56.5%), 6 at the dorsal wall (13.0%), 9 at the superior wall (19.6%), and five at the inferior wall (10.9%). The average thickness and area of plaques were 1.37 +/- 0.53 mm (range: 0.61-3.20 mm) and 3.80 +/- 2.13 mm(2) (range: 1.01-12.2 mm(2)), respectively. No significant differences in plaque thickness (P = 0.464), plaque area (P = 0.107) or stenosis degree (P = 0.563) were noted between different locations. Most of the plaques (44/46) showed iso-intensity on tbl1WI. On tbl2WI and PDWI, 24 plaques showed iso-intensity, 12 plaques showed a slightly high signal intensity (SI), and eight plaques showed a slightly low SI. Intraplaque haemorrhage was found in two plaques, with high SI on tbl1WI and MP-RAGE and high or mixed SI on tbl2WI and PDWI. DISCUSSION: Middle cerebral artery plaques in patients with acute infarction have certain tendency to locate at ventral and superior walls. Distribution and features of plaques revealed some plaque formation characteristics and would help to understand underlying mechanisms of ischaemic events. PMID- 25915710 TI - Formal Synthesis of (+/-)-Tetrodotoxin via the Oxidative Amidation of a Phenol: On the Structure of the Sato Lactone. AB - A formal total synthesis of (+/-)-tetrodotoxin that relies on the bimolecular oxidative amidation of a phenol is described, and a structural correction of the Sato lactone, an important tetrodotoxin intermediate, is provided. This work lays the foundation for an ultimate enantioselective synthesis. PMID- 25915711 TI - Declarative verbal memory impairments in middle-aged women who are caregivers of offspring with autism spectrum disorders: The role of negative affect and testosterone. AB - Caring for offspring diagnosed with a chronic psychological disorder such as autism spectrum disorder (ASD) is used in research as a model of chronic stress. This chronic stress has been reported to have deleterious effects on caregivers' cognition, particularly in verbal declarative memory. Moreover, such cognitive decline may be mediated by testosterone (T) levels and negative affect, understood as depressive mood together with high anxiety and anger. This study aimed to compare declarative memory function in middle-aged women who were caregivers for individuals with ASD (n = 24; mean age = 45) and female controls (n = 22; mean age = 45), using a standardised memory test (Rey's Auditory Verbal Learning Test). It also sought to examine the role of care recipient characteristics, negative mood and T levels in memory impairments. ASD caregivers were highly sensitive to proactive interference and verbal forgetting. In addition, they had higher negative affect and T levels, both of which have been associated with poorer verbal memory performance. Moreover, the number of years of caregiving affected memory performance and negative affect, especially, in terms of anger feelings. On the other hand, T levels in caregivers had a curvilinear relationship with verbal memory performance; that is, increases in T were associated with improvements in verbal memory performance up to a certain point, but subsequently, memory performance decreased with increasing T. Chronic stress may produce disturbances in mood and hormonal levels, which in turn might increase the likelihood of developing declarative memory impairments although caregivers do not show a generalised decline in memory. These findings should be taken into account for understanding the impact of cognitive impairments on the ability to provide optimal caregiving. PMID- 25915712 TI - Effects of an Innovative Psychotherapy Program for Surgical Patients: Bridging Intervention in Anesthesiology--A Randomized Controlled Trial. AB - BACKGROUND: The stepped care program Bridging Intervention in Anesthesiology (BRIA) aims at motivating and supporting surgical patients with comorbid mental disorders to engage in psychosocial mental healthcare options. This study examined the efficacy of BRIA. METHODS: This randomized, parallel-group, open label, controlled trial was conducted in the preoperative anesthesiological assessment clinics and surgical wards of a large university hospital in Germany. A total of 220 surgical patients with comorbid mental disorders were randomized by using the computer-generated lists to one of two intervention groups: BRIA psychotherapy sessions up to 3 months postoperatively (BRIA) versus no psychotherapy/computerized brief written advice (BWA) only. Primary outcome was participation in psychosocial mental healthcare options at month 6. Secondary outcome was change of self-reported general psychological distress (Global Severity Index of the Brief Symptom Inventory) between baseline and month 6. RESULTS: At 6-month follow-up, the rate of patients who engaged in psychosocial mental healthcare options was 30% (33 of 110) in BRIA compared with 11.8% (13 of 110) in BWA (P = 0.001). Number needed to treat and relative risk reduction were 6 (95% CI, 4 to 13) and 0.21 (0.09 to 0.31), respectively. In BRIA, Global Severity Index decreased between baseline and month 6 (P < 0.001), whereas it did not change significantly in BWA (P = 0.197). CONCLUSIONS: Among surgical patients with comorbid mental disorders, BRIA results in an increased engagement in subsequent therapy options and a decrease of general psychological distress. These data suggest that it is reasonable to integrate innovative psychotherapy programs into the context of interdisciplinary surgical care. PMID- 25915713 TI - MEK 1/2 inhibitors in the treatment of hepatocellular carcinoma. AB - Sorafenib is the only approved systemic treatment for advanced hepatocellular carcinoma patients and all the recently published randomized controlled trials on new systemic drugs have been unsuccessful. This is likely due to a lack of understanding of tumor progression, molecular drivers, and liver toxicity, as well as flaws in trial design. An important signaling pathway in hepatocarcinogenesis is the MEK cascade involved in various cellular responses, including adaptation and survival. A key role in this cascade is played by MEK, of which MEK 1/2 represent the prototypes and an interesting target for new oncological drugs. This review analyzes recent developments and future perspectives on the role of MEK inhibitors in hepatocellular carcinoma treatment. PMID- 25915715 TI - Racial disparities in breastfeeding--a continuing shame of our healthcare system. PMID- 25915714 TI - Elucidating the composition and conservation of the autophagy pathway in photosynthetic eukaryotes. AB - Aquatic photosynthetic eukaryotes represent highly diverse groups (green, red, and chromalveolate algae) derived from multiple endosymbiosis events, covering a wide spectrum of the tree of life. They are responsible for about 50% of the global photosynthesis and serve as the foundation for oceanic and fresh water food webs. Although the ecophysiology and molecular ecology of some algal species are extensively studied, some basic aspects of algal cell biology are still underexplored. The recent wealth of genomic resources from algae has opened new frontiers to decipher the role of cell signaling pathways and their function in an ecological and biotechnological context. Here, we took a bioinformatic approach to explore the distribution and conservation of TOR and autophagy related (ATG) proteins (Atg in yeast) in diverse algal groups. Our genomic analysis demonstrates conservation of TOR and ATG proteins in green algae. In contrast, in all 5 available red algal genomes, we could not detect the sequences that encode for any of the 17 core ATG proteins examined, albeit TOR and its interacting proteins are conserved. This intriguing data suggests that the autophagy pathway is not conserved in red algae as it is in the entire eukaryote domain. In contrast, chromalveolates, despite being derived from the red-plastid lineage, retain and express ATG genes, which raises a fundamental question regarding the acquisition of ATG genes during algal evolution. Among chromalveolates, Emiliania huxleyi (Haptophyta), a bloom-forming coccolithophore, possesses the most complete set of ATG genes, and may serve as a model organism to study autophagy in marine protists with great ecological significance. PMID- 25915716 TI - Effect of vitamin C and E supplementation on total antioxidant content of human breastmilk and infant urine. AB - OBJECTIVES: After delivery and birth, mothers and neonates are exposed to oxidative stress. The present study examined the effect of supplementation of the diet of breastfeeding mothers with vitamin C and E to improve the antioxidant content of breastmilk and evidence of antioxidant activity in infant urine. SUBJECTS AND METHODS: The subjects were 60 healthy lactating breastfeeding mothers and their infants 1-6 months of age. They were randomly allocated to a control group (n=30) consuming a free diet or an experimental group (n=30) consuming a free diet supplemented each day with effervescent tablets of vitamin C (500 mg) and chewable tablets of vitamin E (100 IU). After 30 days, the total antioxidant content of the mothers' breastmilk and evidence of antioxidant activity in the infants' urine were measured by the ferric reducing/antioxidant power assay. The free radical scavenging activity of the urine samples was measured by the alpha,alpha-diphenyl-beta-picrylhydrazyl method. Differences pre- and postintervention were compared within and between the groups. RESULTS: Significantly higher levels of antioxidants in the breastmilk (610+/-295.5 to 716+/-237.5 MUmol/L) and infant urine (43.2+/-21.8 to 75.0+/-49.2 MUmol/mg creatinine) were observed in the experimental group over the control group (p<0.05). A significant increase in evidence of free radical scavenging in infant urine was observed in the experimental group after 30 days of supplementation by mothers (p<0.05). CONCLUSIONS: Consumption of vitamin C and E supplements appears to have a positive effect on total antioxidant content of breastmilk and evidence of antioxidant activity in infant urine. PMID- 25915717 TI - Why is breastfeeding in public such a big deal? PMID- 25915718 TI - Enhanced eryptosis following gramicidin exposure. AB - The peptide antibiotic and ionophore gramicidin has previously been shown to trigger apoptosis of nucleated cells. In analogy to apoptosis, the suicidal death of erythrocytes or eryptosis involves cell shrinkage and cell membrane scrambling with phosphatidylserine translocation to the erythrocyte surface. Triggers of eryptosis include oxidative stress, increase of cytosolic Ca2+ activity ([Ca2+]i), and ceramide. The present study explored, whether gramicidin triggers eryptosis. To this end phosphatidylserine exposure at the cell surface was estimated from annexin V binding, cell volume from forward scatter, red blood cell distribution width (RDW) from electronic particle counting, reactive oxidant species (ROS) from 2',7'-dichlorodihydrofluorescein diacetate (DCFDA) fluorescence, [Ca2+]i from Fluo3- and Fluo4 fluorescence, and ceramide abundance from binding of specific antibodies. As a result, a 24 h exposure of human erythrocytes to gramicidin significantly increased the percentage of annexin-V binding cells (>=1 ug/mL), forward scatter (>=0.5 ug/mL) and hemolysis. Gramicidin enhanced ROS activity, [Ca2+]i and ceramide abundance at the erythrocyte surface. The stimulation of annexin-V-binding by gramicidin was significantly blunted but not abolished by removal of extracellular Ca2+. In conclusion, gramicidin stimulates phospholipid scrambling of the erythrocyte cell membrane, an effect at least partially due to induction of oxidative stress, increase of [Ca2+]i and up-regulation of ceramide abundance. Despite increase of [Ca2+]i, gramicidin increases cell volume and slightly reduces RWD. PMID- 25915720 TI - Strong microwave absorption of hydrogenated wide bandgap semiconductor nanoparticles. AB - Electromagnetic interactions in the microelectronvolt (MUeV) or microwave region have numerous important applications in both civil and military fields, such as electronic communications, signal protection, and antireflective coatings on airplanes against microwave detection. Traditionally, nonmagnetic wide-bandgap metal oxide semiconductors lack these MUeV electronic transitions and applications. Here, we demonstrate that these metal oxides can be fabricated as good microwave absorbers using a 2D electron gas plasma resonance at the disorder/order interface generated by a hydrogenation process. Using ZnO and TiO2 nanoparticles as examples, we show that large absorption with reflection loss values as large as -49.0 dB (99.99999%) is obtained in the microwave region. The frequency of absorption can be tuned with the particle size and hydrogenation condition. These results may pave the way for new applications for wide bandgap semiconductors, especially in the MUeV regime. PMID- 25915719 TI - Association between the growth arrest-specific 6 (Gas6) gene polymorphism c.834 + 7G>A and preeclampsia. AB - OBJECTIVE: Preeclampsia (PE) is a hypertensive disease of pregnancy complicating 2-8% of all pregnancies. The exact pathophysiology still remains unknown. Growth arrest-specific 6 (Gas6) is a member of the vitamin K-dependent protein family and it has been suggested as a novel atherothrombotic risk factor with anti angiogenic and pro-atherogenic properties. The goal of the our study was to investigate the relationships between the c.834 + 7G > A polymorphism of GAS6, plasma Gas6 levels and PE. METHODS: A total of 150 women, including 82 preeclamptic pregnant women and 68 normotensive pregnant (NP) women, were recruited in the current study. Blood samples were taken from all participants. Plasma Gas6 levels measured by an enzyme-linked immunosorbent assay. GAS6 polymorphism was determined using a PCR-RFLP method. RESULTS: The plasma Gas6 levels of preeclamptic patients were significantly lower than those of NP women (8.65 +/- 3.70 ng/ml and 10.89 +/- 4.23 ng/ml respectively, p < 0.001). The GG genotype was the most prevalent, and the risk of PE was 3.5-fold higher in pregnant women with GG genotype compared to woman with AA genotype (p < 0.01). The A allele was less frequent in preeclamptic patients than in control subjects (OR = 2.118, 95% CI = 1.330-3.371, p < 0.001). CONCLUSIONS: Our results suggest that GAS6 c.834 + 7G > A polymorphism may have a pivotal role in the pathogenesis of PE suggesting that the A allele has a protective role for PE. PMID- 25915721 TI - Impact of soft splints on upper limb spasticity in chronic patients with disorders of consciousness: A randomized, single-blind, controlled trial. AB - OBJECTIVE: To assess the effectiveness of soft splints on spasticity and hand opening in chronic patients with upper limb spasticity and disorders of consciousness (vegetative state/unresponsive wakefulness syndrome-VS/UWS and minimally conscious state-MCS). METHODS: In this prospective single-blind controlled trial, a blind evaluator assessed spasticity (Modified Ashworth Scale and Modified Tardieu Scale), range of motion (ROM) at the metacarpophalangeal, wrist and elbow joints and the patients' hand opening before and after soft splinting, manual stretching and a control condition (i.e. no treatment), as well as 60 minutes later. SUBJECTS: Seventeen patients with chronic (>3 months) disorders of consciousness were included (five VS/UWS; seven women; mean age = 42 +/- 12 years; time since insult = 35 +/- 31 months). Patients received either passive splinting, manual stretching treatment or no treatment. RESULTS: Thirty minutes of soft splinting or 30 minutes of manual stretching both improved spasticity of the finger flexors. An increase of hand opening ability was observed after 30 minutes of soft splinting. CONCLUSION: Thirty minutes of soft splint application reduces spasticity and improves hand opening of patients with chronic disorders of consciousness. Soft splinting is well tolerated and does not require supervision. PMID- 25915722 TI - MicroRNA-17-5p activates hepatic stellate cells through targeting of Smad7. AB - A considerable amount of research has focused on the roles of microRNAs (miRNA) in the pathophysiology of liver fibrosis in view of their regulatory effects on hepatic stellate cell (HSC) functions, including proliferation, differentiation, and apoptosis. Recently, miR-17-5p was shown to promote cell proliferation and migration in liver. Transforming growth factor-beta1 (TGF-beta1) has been characterized as the master fibrogenic cytokine that stimulates HSC activation and promotes progression of liver fibrosis. The issue of whether miR-17-5p plays a role in TGF-beta1-induced hepatic fibrogenesis remains to be established. In this study, we demonstrated a dose-/time-dependent increase in miR-17-5p expression in TGF-beta1-treated HSCs. Enhanced miR-17-5p expression was additionally observed in CCl4-induced rat liver fibrosis. Inhibition of miR-17-5p led to suppression of HSC proliferation induced by TGF-beta1 without affecting cellular apoptosis. Notably, miR-17-5p was significantly associated with TGF beta1-induced expression of type I collagen and alpha-SMA in HSC. Furthermore, Smad7, a negative regulator of the TGF-beta/Smad pathway, was confirmed as a direct target of miR-17-5p. Serum miR-17-5p levels were significantly higher in patients with cirrhosis, compared to healthy controls. Our results collectively indicate that miR-17-5p promotes HSC proliferation and activation, at least in part, via reduction of Smad7, supporting its potential utility as a novel therapeutic target for liver fibrosis. PMID- 25915724 TI - Receptor role of the annexin A2 in the mesothelial endocytosis of crocidolite fibers. AB - Asbestos-induced mesothelioma is a worldwide problem. Parietal mesothelial cells internalize asbestos fibers that traverse the entire lung parenchyma, an action that is linked to mesothelial carcinogenesis. Thus far, vitronectin purified from serum reportedly enhances the internalization of crocidolite by mesothelial cells via integrin alphavbeta5. To reveal another mechanism by which mesothelial cells endocytose (phagocytose) asbestos, we first evaluated the effects of serum on asbestos uptake, which proved to be nonessential. Thereafter, we undertook a study to identify proteins on the surface of mesothelial cells (MeT5A) that act as receptors for asbestos uptake based on the assumption that receptors bind to asbestos with physical affinity. To this end, we incubated the membrane fraction of MeT5A cells with crocidolite or chrysotile and evaluated the adsorbed proteins using sodium dodecyl sulfate polyacrylamide gel analysis. Next, we extensively identified the proteins using an in-solution or in-gel digestion coupled with mass spectrometry. Among the identified proteins, annexin A2 (ANXA2) and transferrin receptor protein 1 (TFRC) were distinguished because of their high score and presence at the cell surface. Crocidolite uptake by MeT5A cells was significantly decreased by shRNA (short hairpin RNA)-induced knockdown of ANXA2 and direct blockade of cell surface ANXA2 using anti-ANXA2 antibody. In addition, abundant ANXA2 protein was present on the cell membrane of mesothelial cells, particularly facing the somatic cavity. These findings demonstrate that ANXA2 has a role in the mesothelial phagocytosis of crocidolite and may serve as its receptor. PMID- 25915723 TI - Decreased proteasomal function accelerates cigarette smoke-induced pulmonary emphysema in mice. AB - Chronic obstructive pulmonary disease (COPD) is a disease common in elderly people, characterized by progressive destruction of lung parenchyma and chronic inflammation of the airways. The pathogenesis of COPD remains unclear, but recent studies suggest that oxidative stress-induced apoptosis in alveolar cells contributes to emphysematous lung destruction. The proteasome is a multicatalytic enzyme complex that plays a critical role in proteostasis by rapidly destroying misfolded and modified proteins generated by oxidative and other stresses. Proteasome activity decreases with aging in many organs including lungs, and an age-related decline in proteasomal function has been implicated in various age related pathologies. However, the role of the proteasome system in the pathogenesis of COPD has not been investigated. Recently, we have established a transgenic (Tg) mouse model with decreased proteasomal chymotrypsin-like activity, showing age-related phenotypes. Using this model, we demonstrate here that decreased proteasomal function accelerates cigarette smoke (CS)-induced pulmonary emphysema. CS-exposed Tg mice showed remarkable airspace enlargement and increased foci of inflammation compared with wild-type controls. Importantly, apoptotic cells were found in the alveolar walls of the affected lungs. Impaired proteasomal activity also enhanced apoptosis in cigarette smoke extract (CSE) exposed fibroblastic cells derived from mice and humans in vitro. Notably, aggresome formation and prominent nuclear translocation of apoptosis-inducing factor were observed in CSE-exposed fibroblastic cells isolated from Tg mice. Collective evidence suggests that CS exposure and impaired proteasomal activity coordinately enhance apoptotic cell death in the alveolar walls that may be involved in the development and progression of emphysema in susceptible individuals such as the elderly. PMID- 25915725 TI - Circulating Levels of Orexin-A, Nesfatin-1, Agouti-Related Peptide, and Neuropeptide Y in Patients with Hyperthyroidism. AB - BACKGROUND: There is insufficient information about the appetite-related hormones orexin-A, nesfatin-1, agouti-related peptide (AgRP), and neuropeptide Y (NPY) in hyperthyroidism. The aim of the present study was to investigate the effects of hyperthyroidism on the basal metabolic rate (BMR) and energy intake, orexin-A, nesfatin-1, AgRP, NPY, and leptin levels in the circulation, and their relationship with each other and on appetite. METHODS: In this prospective study, patients were evaluated in hyperthyroid and euthyroid states in comparison with healthy subjects. Twenty-one patients with overt hyperthyroidism and 33 healthy controls were included in the study. RESULTS: Daily energy intake in the hyperthyroid state was found to be higher than that in the euthyroid state patient group (p=0.039). BMR was higher in hyperthyroid patients than the control group (p=0.018). Orexin-A was lower and nesfatin-1 was higher in hyperthyroid patients compared to the controls (p<0.001), whereas orexin-A increased and nesfatin-1 decreased after euthyroidism (p=0.003, p<0.001). No differences were found in the AgRP, NPY, and leptin levels between the hyperthyroid and euthyroid states and controls (p>0.05). Orexin-A correlated negatively with nesfatin-1 (p=0.042), BMR (p=0.013), free triiodothyronine (fT3; p<0.001), and free thyroxine (fT4; p<0.001) and positively with thyrotropin (TSH; p<0.001). Nesfatin 1 correlated negatively with orexin-A (p=0.042) and TSH (p<0.001) and positively with fT3 (p=0.005) and fT4 (p=0.001). In the regression analysis, "diagnosis of hyperthyroidism" was the main factor affecting orexin-A (p<0.001). CONCLUSIONS: Although it seems that no relationship exists among orexin-A, nesfatin-1, and increased appetite in hyperthyroidism, the orexin-A and nesfatin-1 levels are markedly affected by hyperthyroidism. PMID- 25915727 TI - Status Epilepticus: Redefined or Increasingly Detected? PMID- 25915726 TI - Resilience in Organ Transplantation: An Application of the Connor-Davidson Resilience Scale (CD-RISC) With Liver Transplant Candidates. AB - End-stage liver disease (ESLD) is a chronic and debilitating condition associated with substantial psychological stress, morbidity, and mortality. The Connor Davidson Resilience Scale (CD-RISC; Connor & Davidson, 2003 ) is a commonly used resilience measure. This research examined the validity of the CD-RISC among ESLD patients (N = 120) using exploratory factor analysis. Results supported a single factor solution after removing poorly loading items. The CD-RISC also was correlated with measures of depression, anxiety, quality of life, social support, age, and cognitive ability, thus providing evidence to support its construct validity. Future research should confirm this factor structure and examine its predictive validity prior to widespread use among ESLD patients. This research represents the first step in this process and proposes an alternative version of the CD-RISC for this population. PMID- 25915728 TI - N-acetyl cysteine alleviates inflammatory reaction of oral epithelial cells to poly (methyl methacrylate) extract. AB - OBJECTIVES: The purpose of this in vitro study was to determine whether the cytotoxicity of self-curing polymethyl methacrylate (PMMA) dental resin to oral epithelial cells was eliminated by mixing the antioxidant amino acid derivative, N-acetyl cysteine (NAC) with the material. MATERIALS AND METHODS: Rat and human oral epithelial cells cultured on polystyrene were incubated in culture medium with or without extract from self-curing PMMA dental resin, with or without pre mixing with NAC. On day 1, the cultures were evaluated for cellular damage, intracellular formaldehyde invasion, cellular redox status and pro-inflammatory cytokine production. Formaldehyde content and the amount of released NAC in the extract were evaluated. RESULTS: Rat epithelial cells cultured with PMMA extract showed marked increases in lactate dehydrogenase (LDH) release, intracellular formaldehyde and lysosomal levels and reductions in attached cell number and the amount of E-cadherin compared with those in the culture without the extract; these adverse biological effects were alleviated or prevented by pre-mixing the resin with NAC. In human oral epithelial cells cultured with PMMA extract, the addition of NAC into the resin prevented the intracellular elevation of reactive oxygen species and the reduction in cellular glutathione levels. Human cell cultures with the extract produced higher levels of various pro-inflammatory cytokines than cultures without the extract; this was prevented by mixing the resin with NAC. The extract from PMMA pre-mixed with NAC contained a lower concentration of formaldehyde and a substantial amount of antioxidants. CONCLUSION: The cytotoxicity of self-curing PMMA dental resin to oral epithelial cells was eliminated by mixing the resin with NAC. PMID- 25915729 TI - X-ray Crystallographic Structures of Oligomers of Peptides Derived from beta2 Microglobulin. AB - Amyloid diseases such as Alzheimer's disease, Parkinson's disease, and type II diabetes share common features of toxic soluble protein oligomers. There are no structures at atomic resolution of oligomers formed by full-length amyloidogenic peptides and proteins, and only a few structures of oligomers formed by peptide fragments. The paucity of structural information provides a fundamental roadblock to understanding the pathology of amyloid diseases and developing preventions or therapies. Here, we present the X-ray crystallographic structures of three families of oligomers formed by macrocyclic peptides containing a heptapeptide sequence derived from the amyloidogenic E chain of beta2-microglobulin (beta2m). Each macrocyclic peptide contains the heptapeptide sequence beta2m63-69 and a second heptapeptide sequence containing an N-methyl amino acid. These peptides form beta-sheets that further associate into hexamers, octamers, and dodecamers: the hexamers are trimers of dimers; the octamers are tetramers of dimers; and the dodecamers contain two trimer subunits surrounded by three pairs of beta-sheets. These structures illustrate a common theme in which dimer and trimer subunits further associate to form a hydrophobic core. The seven X-ray crystallographic structures not only illustrate a range of oligomers that a single amyloidogenic peptide sequence can form, but also how mutation can alter the size and topology of the oligomers. A cocrystallization experiment in which a dodecamer-forming peptide recruits a hexamer-forming peptide to form mixed dodecamers demonstrates that one species can dictate the oligomerization of another. These findings should also be relevant to the formation of oligomers of full-length peptides and proteins in amyloid diseases. PMID- 25915730 TI - Novel Cu(II)-M(II)-Cu(II) (M = Cu or Ni) trinuclear and [NaCu] hexanuclear complexes assembled by bi-compartmental ligands: syntheses, structures, magnetic and catalytic studies. AB - In the present work, two compartmental ligands H2L(1) and H2L(2) were in situ generated during the syntheses of new trinuclear complexes, [Cu2Ni(L(1))(2,2' bpy)2(NO3)2][ClO4]2 (), [Cu3(L(2))(NO3)2][ClO4]2 (), and [Cu3(L(2))(NCS)2(NO3)](+) that co-crystallize in with a [Cu6(L(2))2Na2(NO3)6(NCS)4] unit to give the final molecular formula [Cu6(L(2))2Na2(NO3)6(NCS)4][Cu3(L(2))(NCS)2(NO3)]2(NO3)2.5H2O (). The magnetic property studies of revealed weak Cu(II)-Cu(II) ferromagnetic interactions in compound (JCu-Cu/kB = +1.4(1) K) and (JCu-Cu/kB = +1.6) while in intranuclear Cu(II)-Ni(II)-Cu(II) compound , the magnetic coupling between two Cu(II) ions is switched off by the diamagnetic square planar Ni(II) bridge. The catalytic epoxidation of two olefins, namely styrene and cyclooctene, by tert-BuOOH (TBHP) was also explored in the presence of a catalytic amount of , or in MeCN. For styrene oxidation, exhibited ~57% styrene epoxide selectively (conversion ~37%) with a TON of about 925 along with benzaldehyde (~43%), whereas exhibited conversion up to ~63% (TON ~ 1575) with a good selectivity towards epoxide (~71%). For compound , this conversion is more important (TON ~ 8108) probably due to the presence of more active sites involved in the epoxidation. The concerted path was found to be operative for styrene oxidation while a radical path was suggested for the oxidation of cyclooctene. PMID- 25915731 TI - Eosinophils orchestrate cancer rejection by normalizing tumor vessels and enhancing infiltration of CD8(+) T cells. AB - Tumor-associated eosinophilia is frequently observed in cancer. However, despite numerous studies of patients with cancer and mouse models of cancer, it has remained uncertain if eosinophils contribute to tumor immunity or are mere bystander cells. Here we report that activated eosinophils were essential for tumor rejection in the presence of tumor-specific CD8(+) T cells. Tumor-homing eosinophils secreted chemoattractants that guided T cells into the tumor, which resulted in tumor eradication and survival. Activated eosinophils initiated substantial changes in the tumor microenvironment, including macrophage polarization and normalization of the tumor vasculature, which are known to promote tumor rejection. Thus, our study presents a new concept for eosinophils in cancer that may lead to novel therapeutic strategies. PMID- 25915732 TI - The development of innate lymphoid cells requires TOX-dependent generation of a common innate lymphoid cell progenitor. AB - Diverse innate lymphoid cell (ILC) subtypes have been defined on the basis of effector function and transcription factor expression. ILCs derive from common lymphoid progenitors, although the transcriptional pathways that lead to ILC lineage specification remain poorly characterized. Here we found that the transcriptional regulator TOX was required for the in vivo differentiation of common lymphoid progenitors into ILC lineage-restricted cells. In vitro modeling demonstrated that TOX deficiency resulted in early defects in the survival or proliferation of progenitor cells, as well as ILC differentiation at a later stage. In addition, comparative transcriptome analysis of bone marrow progenitors revealed that TOX-deficient cells failed to upregulate many genes of the ILC program, including genes that are targets of Notch, which indicated that TOX is a key determinant of early specification to the ILC lineage. PMID- 25915735 TI - Crime, violence, and behavioral health: collaborative community strategies for risk mitigation. AB - Criminal conduct is not always violent, and violence does not always lead to criminal charges. Moreover, crime and violence have multifaceted etiologies. Most violence in society is not attributable to mental illness. Where there is a small relationship between violence and mental illness, the risk of violence increases for individuals with substance use histories. Underlying trauma can also play a role. Antisocial attitudes, behaviors, and peer groups further increase the risk that individuals, including those with mental illness, will find themselves at risk of criminal recidivism. Criminal histories among public mental health populations, and mental health and substance use disorders among criminal populations are each higher than general population comparisons. Care within behavioral health settings should therefore target decreased criminal recidivism and decreased violence as part of recovery for those individuals at risk, using trauma-informed approaches and peer supports. Interventions that show promise bring criminal justice and behavioral health systems together, and include police based diversion, specialty courts, court-based alternatives to incarceration, and coordinated re-entry programs. This article reviews these options along with specific risk management strategies, such as using risk, needs, and responsivity factors as a means of improving overall outcomes for persons with mental illness, while minimizing their risk of further criminalization and victimization. PMID- 25915733 TI - Tyrosine phosphatase SHP-2 mediates C-type lectin receptor-induced activation of the kinase Syk and anti-fungal TH17 responses. AB - Fungal infection stimulates the canonical C-type lectin receptor (CLR) signaling pathway via activation of the tyrosine kinase Syk. Here we identify a crucial role for the tyrosine phosphatase SHP-2 in mediating CLR-induced activation of Syk. Ablation of the gene encoding SHP-2 (Ptpn11; called 'Shp-2' here) in dendritic cells (DCs) and macrophages impaired Syk-mediated signaling and abrogated the expression of genes encoding pro-inflammatory molecules following fungal stimulation. Mechanistically, SHP-2 operated as a scaffold, facilitating the recruitment of Syk to the CLR dectin-1 or the adaptor FcRgamma, through its N SH2 domain and a previously unrecognized carboxy-terminal immunoreceptor tyrosine based activation motif (ITAM). We found that DC-derived SHP-2 was crucial for the induction of interleukin 1beta (IL-1beta), IL-6 and IL-23 and anti-fungal responses of the TH17 subset of helper T cells in controlling infection with Candida albicans. Together our data reveal a mechanism by which SHP-2 mediates the activation of Syk in response to fungal infection. PMID- 25915734 TI - Tissue stiffness dictates development, homeostasis, and disease progression. AB - Tissue development is orchestrated by the coordinated activities of both chemical and physical regulators. While much attention has been given to the role that chemical regulators play in driving development, researchers have recently begun to elucidate the important role that the mechanical properties of the extracellular environment play. For instance, the stiffness of the extracellular environment has a role in orienting cell division, maintaining tissue boundaries, directing cell migration, and driving differentiation. In addition, extracellular matrix stiffness is important for maintaining normal tissue homeostasis, and when matrix mechanics become imbalanced, disease progression may ensue. In this article, we will review the important role that matrix stiffness plays in dictating cell behavior during development, tissue homeostasis, and disease progression. PMID- 25915737 TI - How do babies feel pain? AB - Functional MRI studies suggest that healthy full-term newborn babies experience some aspects of pain in a similar way to adults. PMID- 25915738 TI - The changing face of emergency medicine. PMID- 25915736 TI - HDAC Family Members Intertwined in the Regulation of Autophagy: A Druggable Vulnerability in Aggressive Tumor Entities. AB - The exploitation of autophagy by some cancer entities to support survival and dodge death has been well-described. Though its role as a constitutive process is important in normal, healthy cells, in the milieu of malignantly transformed and highly proliferative cells, autophagy is critical for escaping metabolic and genetic stressors. In recent years, the importance of histone deacetylases (HDACs) in cancer biology has been heavily investigated, and the enzyme family has been shown to play a role in autophagy, too. HDAC inhibitors (HDACi) are being integrated into cancer therapy and clinical trials are ongoing. The effect of HDACi on autophagy and, conversely, the effect of autophagy on HDACi efficacy are currently under investigation. With the development of HDACi that are able to selectively target individual HDAC isozymes, there is great potential for specific therapy that has more well-defined effects on cancer biology and also minimizes toxicity. Here, the role of autophagy in the context of cancer and the interplay of this process with HDACs will be summarized. Identification of key HDAC isozymes involved in autophagy and the ability to target specific isozymes yields the potential to cripple and ultimately eliminate malignant cells depending on autophagy as a survival mechanism. PMID- 25915739 TI - A novel criterion for identifying metabolically obese but normal weight individuals using the product of triglycerides and glucose. AB - OBJECTIVES: Metabolically obese but normal weight (MONW) individuals constitute a subgroup of normal weight individuals that display impaired insulin sensitivity with a higher risk of developing diabetes, cardiovascular disease and mortality. We aimed to propose a novel criterion for defining MONW by examining the usefulness and the cutoff value of the TyG index, a product of the levels of triglycerides and glucose, in identifying MONW individuals. In addition, the performance of this criterion in predicting the future incidence of diabetes was assessed. SUBJECTS/METHODS: A total of 7541 non-diabetic, normal weight (body mass index ?18.5 and <25 kg m(-)(2)) subjects were selected from the Korea National Health and Nutrition Examination Survey conducted in 2009-2010. Another 3185 participants with follow-up studies were selected from a prospective community-based cohort study. The TyG index was calculated as ln(fasting triglycerides (mg dl(-1)) * fasting glucose (mg dl(-1))/2). RESULTS: The levels of the TyG index paralleled the prevalence of metabolic syndrome and its components. The cutoff value of the TyG index that reflected MONW based on the receiver operating characteristics analysis was 8.82 for men and 8.73 for women, with the area under the curve values being 0.855 and 0.868, respectively. The sensitivity and the specificity were 84.2 and 77.6% in men and 69.1 and 89.4% in women, respectively. Individuals designated as MONW, who have a normal weight and TyG levels higher than cutoff, displayed a metabolically unhealthy phenotype and an approximately twofold higher risk of developing diabetes compared with metabolically healthy normal weight subjects. CONCLUSIONS: We propose a simple diagnostic criterion of MONW, which might be used to discriminate subjects with a higher risk of metabolic diseases. PMID- 25915740 TI - Role of the endocannabinoid system in obesity induced by neuropeptide Y overexpression in noradrenergic neurons. AB - OBJECTIVE: Endocannabinoids and neuropeptide Y (NPY) promote energy storage via central and peripheral mechanisms. In the hypothalamus, the two systems were suggested to interact. To investigate such interplay also in non-hypothalamic tissues, we evaluated endocannabinoid levels in obese OE-NPY(DbetaH) mice, which overexpress NPY in the noradrenergic neurons in the sympathetic nervous system and the brain. METHODS: The levels of the endocannabinoids anandamide and 2 arachidonoylglycerol (2-AG) were measured in key regulatory tissues, that is, hypothalamus, pancreas, epididymal white adipose tissue (WAT), liver and soleus muscle, over the development of metabolic dysfunctions in OE-NPY(DbetaH) mice. The effects of a 5-week treatment with the CB1 receptor inverse agonist AM251 on adiposity and glucose metabolism were studied. RESULTS: 2-AG levels were increased in the hypothalamus and epididymal WAT of pre-obese and obese OE NPY(DbetaH) mice. Anandamide levels in adipose tissue and pancreas were increased at 4 months concomitantly with higher fat mass and impaired glucose tolerance. CB1 receptor blockage reduced body weight gain and glucose intolerance in OE NPY(DbetaH) to the level of vehicle-treated wild-type mice. CONCLUSIONS: Altered endocannabinoid tone may underlie some of the metabolic dysfunctions in OE NPY(DbetaH) mice, which can be attenuated with CB1 inverse agonism suggesting interactions between endocannabinoids and NPY also in the periphery. CB1 receptors may offer a target for the pharmacological treatment of the metabolic syndrome with altered NPY levels. PMID- 25915741 TI - Body mass index and health status in diabetic and non-diabetic individuals. AB - BACKGROUND/OBJECTIVES: There is controversy regarding the existence of a body mass index (BMI) mortality paradox in diabetes, whereby the optimal BMI category is higher than it is in non-diabetic persons. To explore possible pathways to a mortality paradox, we examined the relationship of BMI with physical and mental health status in diabetic and non-diabetic persons. SUBJECTS/METHODS: We examined adjusted SF-12 Physical and Mental Component Summary (PCS-12 and MCS-12) scores by BMI (kg m(-2)) category (underweight, <20; normal weight, 20 to <25; overweight, 25 to <30; obese, 30 to <35; severely obese ?35) in adult diabetic and non-diabetic respondents to the 2000-2011 United States national Medical Expenditure Panel Surveys (N=119 161). Adjustors were age, sex, race/ethnicity, income, health insurance, education, smoking, comorbidity, urbanicity, geographic region and survey year. RESULTS: In non-diabetic persons the adjusted mean PCS-12 score was highest (that is, most optimal) in the normal-weight category, whereas for diabetic persons the optimal adjusted mean PCS-12 score was in the overweight category (adjusted difference between non-diabetic and diabetic persons in the difference in PCS-12 means for overweight versus normal-weight category=0.8 points, 95% confidence interval; CI 0.1, 1.6; P=0.03). This paradoxical pattern was not evident for the MCS-12, and the adjusted difference between non-diabetic and diabetic persons in the difference in MCS-12 means for overweight versus obese persons was not significant (-0.3 points, 95% CI -0.9, 0.4; P=0.43). The findings were not significantly moderated by smoking status, cancer diagnosis or time period. CONCLUSIONS: The optimal BMI category for physical health status (but not mental health status) was higher among diabetic than non-diabetic persons. The findings are consistent with a BMI physical health status paradox in diabetes and, in turn, a mortality paradox. PMID- 25915742 TI - Comparison of the gut microbiota of people in France and Saudi Arabia. AB - BACKGROUND/OBJECTIVES: The gut microbiota contributes to energy acquisition from food, and changes in the gut microbiome are associated with obesity. The eating habits of Saudis are much different than those of Europeans, and our objective was to compare the fecal microbiota of obese and normal weight Saudis and French. SUBJECTS/METHODS: Illumina MiSeq deep sequencing was used to test the gut microbiota of 9 normal weight and 9 obese individuals from Saudi Arabia and 16 normal weight and 12 obese individuals from France. RESULTS: Obese French possessed significantly more relative Proteobacteria (P=0.002) and Bacteroidetes (P=0.05) and had lower richness and biodiversity at all the operational taxonomic unit (OTU) cutoffs (P<0.05) than normal weight French. Obese Saudis possessed significantly more Firmicutes (P=0.001) without a difference in richness (P=0.2) and biodiversity (P=0.3) compared with normal weight Saudis. We found a common bacterial species core of 23 species existing in ?50% of obese and normal weight Saudis and 29 species in ?50% of obese and normal weight French. Actinomyces odontolyticus, Escherichia coli and Ruminococcus obeum were present in at least 50% of all individuals tested. French individuals had significantly higher richness and biodiversity compared with Saudis at all the OTU cutoffs (P<0.05). CONCLUSION: Microbiota differences between obese and normal weight French were not similar to those between obese and normal weight Saudis. The studies of different populations can result in contrasting data regarding the associations of the gut microbiota and obesity. PMID- 25915743 TI - Effect of multiple binge alcohol on diet-induced liver injury in a mouse model of obesity. AB - BACKGROUND: Alcoholic liver disease (ALD) and non-alcoholic fatty liver disease (NAFLD) are highly prevalent liver diseases that may coexist and contribute significantly to liver disease-related mortality. Obesity is a common underlying risk factor for both disorders. There has been little research investigating the combined effects of high fat diet (HFD) and alcohol. Current mouse models of alcohol- or fat-rich diet alone do not lead to severe liver injury. There is a need to develop animal models recapitulating human settings of drinking and diet to study the mechanisms of liver injury progression. METHODS: C57BL6 male mice were fed either chow or HFD ad libitum for 12 weeks. A sub-set of mice from each group were also given alcohol (2 g kg(-)(1) body weight) twice a week via intra gastric lavage. Animals were monitored progressively for weight gain and blood and livers were harvested at termination. The extent of liver injury was examined by histopathology as well as by liver and serum biochemistry. The expression of lipid metabolism, inflammation and fibrogenesis-related molecules was examined by quantitative reverse transcription PCR (Q-PCR) and immunofluorescence staining. RESULTS: HFD significantly increased total body weight, triglyceride and cholesterol, whereas alcohol increased liver weight. Alcohol+HFD in combination produced maximum hepatic steatosis, increased micro- and macro-vesicular lipid droplets, increased de novo lipogenesis (steroid response-element binding protein 1 (SREBP-1) and stearoyl-CoA desaturase-1 (SCD-1)) and proliferation peroxisome activated receptor alpha (PPARalpha), and decreased fatty acid beta-oxidation (Acyl-CoA oxidase 1 (ACOX1)). Alcohol+HFD treatment also increased the inflammation (CD45+, CD68+, F4/80+ cells; tumour necrosis factor-alpha (TNF alpha), F4/80 mRNAs) and fibrogenesis (vimentin+ activated stellate cells, collagen 1 (Col1) production, transforming growth factor-beta (TGF-beta) and Col 1 mRNAs) in mice livers. CONCLUSIONS: We report a novel mouse model with more severe liver injury than either alcohol or HFD alone recapitulating the human setting of intermittent alcohol drinking and HFD. PMID- 25915744 TI - Surface reconstruction through poisson disk sampling. AB - This paper intends to generate the approximate Voronoi diagram in the geodesic metric for some unbiased samples selected from original points. The mesh model of seeds is then constructed on basis of the Voronoi diagram. Rather than constructing the Voronoi diagram for all original points, the proposed strategy is to run around the obstacle that the geodesic distances among neighboring points are sensitive to nearest neighbor definition. It is obvious that the reconstructed model is the level of detail of original points. Hence, our main motivation is to deal with the redundant scattered points. In implementation, Poisson disk sampling is taken to select seeds and helps to produce the Voronoi diagram. Adaptive reconstructions can be achieved by slightly changing the uniform strategy in selecting seeds. Behaviors of this method are investigated and accuracy evaluations are done. Experimental results show the proposed method is reliable and effective. PMID- 25915745 TI - Impact on Patients' Treatment Outcomes of XpertMTB/RIF Implementation for the Diagnosis of Tuberculosis: Follow-Up of a Stepped-Wedge Randomized Clinical Trial. AB - INTRODUCTION: The impact on treatment outcomes of XpertMTB/RIF, a molecular-based test that provides rapid diagnosis of tuberculosis (TB) and rifampicin resistance with high accuracy, has not been reported despite its adoption in a few countries. We here report treatment outcomes in a step-wedged cluster randomized trial for patients diagnosed with XpertMTB/RIF compared to patients diagnosed with sputum smear examination in public health facilities in Brazil. METHODS: Treatment outcome data were added to the trial database of patients diagnosed from 4 February to 4 October 2012, and crosschecked with data from the national mortality and the drug-resistant TB registers. Treatment outcomes in the intervention (n=2232) and baseline (n=1856) arms were compared using a multilevel regression model. RESULTS: Unfavourable outcomes were frequent in both arms, mainly due to loss to follow-up (16%). Overall unfavourable outcomes were not reduced in the intervention arm (29.6% versus 31.7%, OR=0.93; 95%CI=0.79-1.08). However, the overall TB-attributed death rate was lower in the intervention arm (2.3% vs. 3.8%). Adjusted for HIV status, age group and city, the intervention resulted in a 35% decrease in TB-attributed deaths (OR=0.65, 95%CI=0.44-0.97). CONCLUSIONS: The proportion of patients successfully treated did not increase with Xpert MTB/RIF implementation, with high loss to follow-up rates in both arms. We did observe a 35% reduction in TB-related mortality, which we hypothesize may be explained by less advanced disease among the smear-negative patients diagnosed by Xpert. In conclusion, XpertMTB/RIF introduction did not improve TB treatment outcomes in Brazil. TRIAL REGISTRATION: clinicaltrials.gov NCT01363765. PMID- 25915746 TI - Chemokine-like factor 1-derived C-terminal peptides induce the proliferation of dermal microvascular endothelial cells in psoriasis. AB - Psoriasis is an inflammatory disease characterized by the abnormal proliferation of skin cells, including dermal microvascular endothelial cells. Recently, chemokine-like factor 1 (CKLF1) was found to participate in the local inflammation and cell proliferation. To explore its role in the pathogenesis of psoriasis, the expression of both CKLF1 and its receptor (CCR4) was determined in the psoriatic lesions. Also, the effect of the C-terminal peptides (C19 and C27) of CKLF1 on the proliferation of human umbilical vein endothelial cells was studied in vitro. By immunohistochemistry and immunofluorescence, the expression of both CKLF1 and CCR4 was determined in the psoriatic lesions. The effect of C terminal peptides on human umbilical vein endothelial cells (HUVECs) was studied in vitro by the evaluation of cell proliferation and apoptosis. The in vivo assessment was performed accordingly through the subcutaneous injection peptides on BALB/c mice. The results showed that, by immunohistochemistry, both CKLF1 and CCR4 were increasingly expressed in psoriatic lesions as compared to normal skins. Moreover, the primary umbilical vein endothelial cells exhibited higher proliferation ratio under the C19 or C27 stimulation, which was even enhanced by the addition of psoriatic sera or TNF-alpha. Furthermore, the enhancement of peptide simulation was accompanied with the activation of ERK1/2-MAPKs pathway. In addition, such effect of C19 and C27 was mirrored by the hyperproliferation of cutaneous microvessels in BALB/c mice that were subcutaneously injected with the two peptides. Therefore, we concluded that CKLF1 plays a role in the pathogenesis of psoriasis by promoting the proliferation of microvascular endothelial cells that possibly correlates with ERK1/2-MAPKs activation. PMID- 25915747 TI - Correction: Adverse Events of Anti-Tumor Necrosis Factor alpha Therapy in Ankylosing Spondylitis. PMID- 25915749 TI - When is a choice not a choice? Pigeons fail to inhibit incorrect responses on a go/no-go midsession reversal task. AB - In a 2-stimulus visual discrimination choice task with a reversal in reward contingencies midway through each session, pigeons produce a surprising number of both anticipatory errors (i.e., responding to the second-correct stimulus before the reversal) and perseverative errors (i.e., responding to the first-correct stimulus after the reversal). Here, we used a go/no-go version of the task to examine the degree to which these errors can be attributed to failure to inhibit incorrect responses near the reversal. We presented pigeons with either a green or red stimulus (randomized across trials), with pecks to 1 reinforced with food and pecks to the other stimulus leading to a 10-s time-out; the reward versus time-out contingencies reversed after 40 trials. Pigeons rarely withheld responses when reward was provided for pecking, but produced many incorrect pecks near the reversal. Subsequent experiments examined these errors with longer sessions and multiple reversals, as well as on choice tasks. Our results suggest that pigeons' errors may be due to an inability to inhibit incorrect responses rather than a deliberate choice of the incorrect stimulus on simultaneous discrimination midsession reversal procedures. Results suggest that pigeons learned independent rules about the 2 stimuli, and that training with multiple reversals changed the rules that governed pigeons' responding. (PsycINFO Database Record PMID- 25915748 TI - A Human Anti-M2 Antibody Mediates Antibody-Dependent Cell-Mediated Cytotoxicity (ADCC) and Cytokine Secretion by Resting and Cytokine-Preactivated Natural Killer (NK) Cells. AB - The highly conserved matrix protein 2 (M2) is a good candidate for the development of a broadly protective influenza vaccine that induces long-lasting immunity. In animal models, natural killer (NK) cells have been proposed to play an important role in the protection provided by M2-based vaccines through a mechanism of antibody-dependent cell-mediated cytotoxicity (ADCC). We investigated the ability of the human anti-M2 Ab1-10 monoclonal antibody (mAb) to activate human NK cells. They mediated ADCC against M2-expressing cells in the presence of Ab1-10 mAb. Furthermore, NK cell pro-inflammatory cytokine and chemokine secretion is also enhanced when Ab1-10 mAb is present. We also generated cytokine-preactivated NK cells and showed that they still displayed increased effector functions in the presence of Ab1-10 mAb. Thus, our study has demonstrated that human resting and cytokine-preactivated NK cells may have a very important role in the protection provided by anti-M2 Abs. PMID- 25915750 TI - Changes in the distribution of response rates across the CS-US interval: Evidence that responding switches between two distinct states. AB - Two experiments used the peak procedure to examine timing of conditioned responses in a magazine approach paradigm with rats. A conditioned stimulus (CS) was reinforced with food on 50% of trials. Food was delivered at a fixed time, 20 s, 30 s, or 40 s into the CS presentation. Response rates were recorded during nonreinforced CS presentations that extended well beyond the scheduled time of food delivery. The mean response rate (averaged over many trials) increased during the CS, peaking at the expected time of reinforcement, and decreased again. Detailed analyses of the frequency distribution of response rates showed that responding was described by 2 distinct distributions, consistent with the rat being in a low response state on some trials and in a high response state on others. Modeling of frequency distributions showed that the systematic rise and fall in response rate across a trial was primarily explained by a change in the proportion of time that the rat spent in the low versus high response state. However, the change in responding was also explained in part by a continuous shift in the high response state, such that responding in that state increased and then decreased gradually across the trial. These results support accounts describing response timing as an abrupt change from low to high responding during the CS, but also provide evidence for a continuous change in conditioning strength across the duration of the CS. The implications of these findings for timing and associative theories of conditioning are discussed. (PsycINFO Database Record PMID- 25915751 TI - Extinction of chained instrumental behaviors: Effects of procurement extinction on consumption responding. AB - Instrumental behavior often consists of sequences or chains of responses that minimally include procurement behaviors that enable subsequent consumption behaviors. In such chains, behavioral units are linked by access to one another and eventually to a primary reinforcer, such as food or a drug. The present experiments examined the effects of extinguishing procurement responding on consumption responding after training of a discriminated heterogeneous instrumental chain. Rats learned to make a procurement response (e.g., pressing a lever) in the presence of a distinctive discriminative stimulus; making that response led to the presentation of a second discriminative stimulus that set the occasion for a consumption response (e.g., pulling a chain), which then produced a food-pellet reinforcer. Experiment 1 showed that extinction of either the full procurement-consumption chain or procurement alone weakened the consumption response tested in isolation. Experiment 2 replicated the procurement extinction effect and further demonstrated that the opportunity to make the procurement response, as opposed to simple exposure to the procurement stimulus alone, was required. In Experiment 3, rats learned 2 distinct discriminated heterogeneous chains; extinction of 1 procurement response specifically weakened the consumption response that had been associated with it. The results suggest that learning to inhibit the procurement response may produce extinction of consumption responding through mediated extinction. The experiments suggest the importance of an associative analysis of instrumental behavior chains. (PsycINFO Database Record PMID- 25915752 TI - Rats show molar sensitivity to different aspects of random-interval-with-linear feedback-functions and random-ratio schedules. AB - Three experiments examined the impact of various aspects of reinforcement contingencies on responding maintained by free-operant schedules by food-deprived rats. Experiment 1 demonstrated that random interval (RI) and random-interval with-positive-response-reinforcer-feedback (RI+) schedules maintained similar rates of responding at a variety of reinforcer frequencies. Experiment 2 demonstrated that a random ratio (RR) schedule maintained higher rates than RI or RI+ schedules, except at high rates of reinforcement, where response rates were similar on all schedules. Experiment 3 again demonstrated that RR schedules produced higher response rates than either RI or RI+ schedules, but modification of the RI+ schedule to prevent ratio strain enhanced response rates relative to an RI schedule. Together these results reveal a pattern of interacting factors in schedule controlled behavior: at high rates of reinforcement, this factor overrides the impact of other controlling factors, but as reinforcement rate decreases the joint impact of interresponse times reinforcement, response reinforcer feedback functions, and ratio strain are observed. PMID- 25915753 TI - Pigeons use high spatial frequencies when memorizing pictures. AB - The ability of animals to visually memorize and categorize a large number of pictures is well established. Determining the kinds of information animals use to accomplish these goals has been more difficult. This experiment examined the contribution of spatial frequency information to picture memorization by pigeons. A series of grayscale pictures were notch-filtered to eliminate different portions of the spatial frequency spectrum of memorized pictures. The results indicated that the higher spatial frequencies in the pictures were most important to accurate recognition, suggesting that the detection of fine detail at the high range of pigeon visual acuity was a critical component to their memorized representations. Subsequent tests with band-pass and hybrid conflict stimuli confirmed this conclusion. It is suggested that cognitive and task demands may determine how spatial frequency is used by pigeons, with higher frequencies more important to item memorization, while lower spatial frequencies may contribute to categorization in other types of discrimination tasks. PMID- 25915754 TI - Asymmetrical generalization of length in the rat. AB - Two groups of rats in Experiment 1 were required to escape from a square pool by swimming to 1 of 2 submerged platforms that were situated beside the centers of 2 opposite walls. To help rats find a platform, black panels of equal width were pasted to the middle of the walls that were adjacent to the platforms. The width of the 2 panels was 50 cm for Group 50, and 100 cm for Group 100. Test trials were then conducted in the same pool, but with the platforms removed and with a 50-cm panel on 1 wall and a 100-cm panel on the opposite wall. Group 50 expressed a stronger preference for the 100-cm than the 50-cm panel during the test, whereas Group 100 expressed a similar preference for both panels. Thus the degree of generalization from the short to the long panel was greater than from the long to the short panel. Experiments 2 and 3 pointed to the same conclusion. They were of a similar design to Experiment 1, except that the lengths of the panels for the 2 groups were 25 and 50 cm in Experiment 2, and 25 and 100 cm in Experiment 3. The results are explained by assuming the original training results in the walls without black panels entering into inhibitory associations. This inhibition is then assumed to generalize more to the short than the long test panels and thereby result in an asymmetry in the gradients of generalization between the different lengths. (PsycINFO Database Record PMID- 25915755 TI - Community-Based HIV-1 Early Diagnosis and Risk Behavior Analysis of Men Having Sex with Men in Hong Kong. AB - The increasing prevalence of HIV-1 among men having sex with men (MSM) calls for an investigation of HIV-1 prevalence and incidence in MSM by early diagnosis to assist with early preventive interventions in Hong Kong. The participants were recruited randomly from MSM communities within a one-year period. Rapid HIV Test (RHT) and real-time dried blood spot (DBS)-based quantitative polymerase chain reaction (DBS-qPCR) were used for the early diagnosis of 474 participants. Risk behavior analysis was performed by studying information obtained from the participants during the study period. The HIV-1 prevalence and incident rates in the studied MSM population were 4.01% (19/474) and 1.47% (7/474), respectively. Three infected participants were found at the acute phase of infection by DBS qPCR. Only 46.4% (220/474) MSM were using condoms regularly for anal sex. HIV infection significantly correlated with unprotected receptive anal sex and syphilis infection. An increased number of infections was found among foreign MSM in Hong Kong. This study is the first to use DBS-qPCR to identify acutely infected individuals in a community setting and to provide both the prevalence and incident rates of HIV-1 infection among MSM in Hong Kong. The risk analysis provided evidence that behavior intervention strengthening is necessary to fight against the increasing HIV-1 epidemic among MSM in Hong Kong and surrounding regions in Asia. PMID- 25915757 TI - Local aromaticity in naphtho-annelated fluoranthenes: can the five-membered rings be more aromatic than the six-membered rings? AB - All Kekule-structure-based theories predict that the central five-membered ring in fluoranthene and naphtho-annelated fluoranthenes is nonaromatic. In the present work, a detailed study of the local aromaticity in a series of naphtho annelated fluoranthene derivatives was performed by means of the following aromaticity indices: the energy effect (ef), bond resonance energy (BRE), multicenter delocalization indices (MCI), harmonic oscillator model of aromaticity (HOMA) index, nucleus-independent chemical shifts (NICS), and ring current maps. It was found that, according to the ef, BRE, MCI, and HOMA values, the pentagonal rings in some naphtho-annelated fluoranthenes can be even more aromatic than some hexagonal rings in the respective molecules. The magnetic indices do not support the results obtained by the energetic, electron delocalization, and geometrical aromaticity indices. PMID- 25915756 TI - Estimating bacterial diversity for ecological studies: methods, metrics, and assumptions. AB - Methods to estimate microbial diversity have developed rapidly in an effort to understand the distribution and diversity of microorganisms in natural environments. For bacterial communities, the 16S rRNA gene is the phylogenetic marker gene of choice, but most studies select only a specific region of the 16S rRNA to estimate bacterial diversity. Whereas biases derived from from DNA extraction, primer choice and PCR amplification are well documented, we here address how the choice of variable region can influence a wide range of standard ecological metrics, such as species richness, phylogenetic diversity, beta diversity and rank-abundance distributions. We have used Illumina paired-end sequencing to estimate the bacterial diversity of 20 natural lakes across Switzerland derived from three trimmed variable 16S rRNA regions (V3, V4, V5). Species richness, phylogenetic diversity, community composition, beta-diversity, and rank-abundance distributions differed significantly between 16S rRNA regions. Overall, patterns of diversity quantified by the V3 and V5 regions were more similar to one another than those assessed by the V4 region. Similar results were obtained when analyzing the datasets with different sequence similarity thresholds used during sequences clustering and when the same analysis was used on a reference dataset of sequences from the Greengenes database. In addition we also measured species richness from the same lake samples using ARISA Fingerprinting, but did not find a strong relationship between species richness estimated by Illumina and ARISA. We conclude that the selection of 16S rRNA region significantly influences the estimation of bacterial diversity and species distributions and that caution is warranted when comparing data from different variable regions as well as when using different sequencing techniques. PMID- 25915758 TI - Factors Influencing Intracavitary Electrocardiographic P-Wave Changes during Central Venous Catheter Placement. AB - Amplitude changes in the P-wave of intracavitary electrocardiography have been used to assess the tip placement of central venous catheters. The research assessed the sensitivity and specificity of this sign in comparison with standard radiographic techniques for tip location, focusing on factors influencing its clinical utility. Both intracavitary electrocardiography guided tip location and X-ray positioning were used to verify catheter tip locations in patients undergoing central venous catheter insertion. Intracavitary electrocardiograms from 1119 patients (of a total 1160 subjects) showed specific amplitude changes in the P-wave. As the results show, compared with X-ray positioning, the sensitivity of electrocardiography-guided tip location was 97.3%, with false negative rate of 2.7%; the specificity was 1, with false positive rate of zero. Univariate analyses indicated that features including age, gender, height, body weight, and heart rate have no statistically significant influence on P-wave amplitude changes (P > 0.05). Multivariate logistic regression revealed that catheter insertion routes (OR = 2.280, P = 0.003) and basal P-wave amplitude (OR = 0.553, P = 0.003) have statistically significant impacts on P-wave amplitude changes. As a reliable indicator of tip location, amplitude change in the P-wave has proved of good sensitivity and excellent specificity, and the minor, zero, false positive rate supports the clinical utility of this technique in early recognition of malpositioned tips. A better sensitivity was achieved in placement of centrally inserted central catheters (CICCs) than that of peripherally inserted central catheters (PICCs). In clinical practice, a combination of intracavitary electrocardiography, ultrasonic inspection and the anthropometric measurement method would further improve the accuracy. PMID- 25915759 TI - Passive Smoking and Breast Cancer Risk among Non-Smoking Women: A Case-Control Study in China. AB - BACKGROUND: The role of passive smoking on breast cancer risk was unclear. This study aimed to evaluate the association between passive smoking and breast cancer risk among Chinese women. METHODS/PRINCIPAL FINDINGS: A hospital-based case control study, including 877 breast cancer cases and 890 controls, frequency matched by age and residence, was conducted. A structured questionnaire was used to collect information on passive smoking history through face-to-face interview by trained interviewers. Unconditional logistic regression models were used to estimate the association between passive smoking and breast cancer risk. A positive association between any passive smoking exposure and breast cancer risk was observed. Compared with women who were never exposed to passive smoking, women who were ever exposed had a higher breast cancer risk, with the adjusted odds ratio (OR) and 95% confidence interval (CI) of 1.35 (1.11-1.65). Similar result was found on home passive smoking exposure and breast cancer risk, but not on workplace passive smoking exposure. Women who were ever exposed to tobacco smoke at home had a higher risk of breast cancer compared with never exposed women, with the adjusted OR (95% CI) of 1.30 (1.05-1.61). Home passive smoking exposure showed significant dose-response relationships with breast cancer risk in smoker-years, cigarettes/day and total pack-years (Ptrend=0.003, 0.006 and 0.009, respectively). An increased total smoker-years of any passive exposure significantly elevated the risk of breast cancer (Ptrend<0.001). Positive associations and dose-response relationships were found among postmenopausal women and all subtypes of estrogen receptor (ER) and progesterone receptor (PR) status of breast cancer. CONCLUSIONS: Passive smoking was associated with an increased risk of breast cancer among non-smoking Chinese women. A stronger positive association with breast cancer risk was seen mainly among postmenopausal women. PMID- 25915760 TI - Aldehyde Dehydrogenase 1 (ALDH1) Is a Potential Marker for Cancer Stem Cells in Embryonal Rhabdomyosarcoma. AB - Cancer stem cells (CSCs) are defined as a small population of cancer cells with the properties of high self-renewal, differentiation, and tumor-initiating functions. Recent studies have demonstrated that aldehyde dehydrogenase 1 (ALDH1) is a marker for CSCs in adult cancers. Although CSCs have been identified in some different types of pediatric solid tumors, there have been no studies regarding the efficacy of ALDH1 as a marker for CSCs. Therefore, in order to elucidate whether ALDH1 can be used as a marker for CSCs of pediatric sarcoma, we examined the characteristics of a population of cells with a high ALDH1 activity (ALDH1high cells) in rhabdomyosarcoma (RMS), the most common soft tissue sarcoma in children. We used the human embryonal RMS (eRMS) cell lines RD and KYM-1, and sorted the cells into two subpopulations of ALDH1high cells and cells with a low ALDH1 activity (ALDH1low cells). Consequently, we found that the ALDH1high cells comprised 3.9% and 8.2% of the total cell population, respectively, and showed a higher capacity for self-renewal and tumor formation than the ALDH1low cells. With regard to chemoresistance, the survival rate of the ALDH1high cells was found to be higher than that of the ALDH1low cells following treatment with chemotherapeutic agents for RMS. Furthermore, the ALDH1high cells exhibited a higher degree of pluripotency and gene expression of Sox2, which is one of the stem cell markers. Taken together, the ALDH1high cells possessed characteristics of CSCs, including colony formation, chemoresistance, differentiation and tumor initiation abilities. These results suggest that ALDH1 is a potentially useful marker of CSCs in eRMS. PMID- 25915761 TI - Gp120 on HIV-1 Virions Lacks O-Linked Carbohydrate. AB - As HIV-1-encoded envelope protein traverses the secretory pathway, it may be modified with N- and O-linked carbohydrate. When the gp120s of HIV-1 NL4-3, HIV-1 YU2, HIV-1 Bal, HIV-1 JRFL, and HIV-1 JRCSF were expressed as secreted proteins, the threonine at consensus position 499 was found to be O-glycosylated. For SIVmac239, the corresponding threonine was also glycosylated when gp120 was recombinantly expressed. Similarly-positioned, highly-conserved threonines in the influenza A virus H1N1 HA1 and H5N1 HA1 envelope proteins were also found to carry O-glycans when expressed as secreted proteins. In all cases, the threonines were modified predominantly with disialylated core 1 glycans, together with related core 1 and core 2 structures. Secreted HIV-1 gp140 was modified to a lesser extent with mainly monosialylated core 1 O-glycans, suggesting that the ectodomain of the gp41 transmembrane component may limit the accessibility of Thr499 to glycosyltransferases. In striking contrast to these findings, gp120 on purified virions of HIV-1 Bal and SIV CP-MAC lacked any detectable O glycosylation of the C-terminal threonine. Our results indicate the absence of O linked carbohydrates on Thr499 as it exists on the surface of virions and suggest caution in the interpretation of analyses of post-translational modifications that utilize recombinant forms of envelope protein. PMID- 25915762 TI - Trends in in-hospital cardiopulmonary resuscitation and survival in adults receiving maintenance dialysis. AB - IMPORTANCE: Understanding cardiopulmonary resuscitation (CPR) practices and outcomes can help to support advance care planning in patients receiving maintenance dialysis. OBJECTIVE: To characterize patterns and outcomes of in hospital CPR in US adults receiving maintenance dialysis. DESIGN, SETTING, AND PARTICIPANTS: This national retrospective cohort study studied 663,734 Medicare beneficiaries 18 years or older from a comprehensive national registry for end stage renal disease who initiated maintenance dialysis from January 1, 2000, through December 31, 2010. EXPOSURES: Receipt of in-hospital CPR from 91 days after dialysis initiation through the time of death, first kidney transplantation, or end of follow-up on December 31, 2011. MAIN OUTCOMES AND MEASURES: Incidence of CPR and survival after the first episode of CPR recorded in Medicare claims during follow-up. RESULTS: The annual incidence of CPR for the overall cohort was 1.4 events per 1000 in-hospital days (95% CI, 1.3-1.4). A total of 21.9% CPR recipients (95% CI, 21.4%-22.3%) survived to hospital discharge, with a median postdischarge survival of 5.0 months (interquartile range, 0.7-16.8 months). Among patients who died in the hospital, 14.9% (95% CI, 14.8%-15.1%) received CPR during their terminal admission. From 2000 to 2011, there was an increase in the incidence of CPR (1.0 events per 1000 in-hospital days; 95% CI, 0.9-1.1; to 1.6 events per 1000 in-hospital days; 95% CI, 1.6-1.7; P for trend <.001), the proportion of CPR recipients who survived to discharge (15.2%; 95% CI, 11.1%-20.5%; to 28%; 95% CI, 26.7%-29.4%; P for trend <.001), and the proportion of in-hospital deaths preceded by CPR (9.5%; 95% CI, 8.4%-10.8%; to 19.8%; 95% CI, 19.2%-20.4%; P for trend <.001), with no substantial change in duration of postdischarge survival. CONCLUSIONS AND RELEVANCE: Among a national cohort of patients receiving maintenance dialysis, the incidence of CPR was higher and long-term survival worse than reported for other populations. PMID- 25915763 TI - Simulated sunlight photocatalytic degradation of aqueous p-nitrophenol and bisphenol A in a Pt/BiOBr film-coated quartz fiber photoreactor. AB - Pt/BiOBr film-coated quartz fiber bundles were prepared by dip-coating combined with photodeposition, and their phase and chemical structures, electronic and optical properties, textural properties as well as morphologies were well characterized. The simulated sunlight photocatalytic performance including activity and stability of the as-prepared Pt/BiOBr film was evaluated in a self made quartz fiber photoreactor by selecting two typical light-insensitive organic pollutants, p-nitrophenol (PNP) and bisphenol A (BPA), as the target compounds. Since the quartz fiber bundles served as both the support for Pt/BiOBr films and the medium of light propagation, Pt/BiOBr film-coated quartz fiber bundles exhibited excellent photocatalytic activity due to their enhanced light harvesting ability. In addition, the enhanced photocatalytic activity of the Pt/BiOBr film is explained based on the results of photoelectrochemistry and free radical and hole scavenging experiments. PMID- 25915764 TI - Antigenic Relatedness of Norovirus GII.4 Variants Determined by Human Challenge Sera. AB - The GII.4 noroviruses (NoVs) are a single genotype that is responsible for over 50% of NoV gastroenteritis epidemics worldwide. However, GII.4 NoVs have been found to undergo antigenic drifts, likely selected by host herd immunity, which raises an issue for vaccine strategies against NoVs. We previously characterized GII.4 NoV antigenic variations and found significant levels of antigenic relatedness among different GII.4 variants. Further characterization of the genetic and antigenic relatedness of recent GII.4 variants (2008b and 2010 cluster) was performed in this study. The amino acid sequences of the receptor binding interfaces were highly conserved among all GII.4 variants from the past two decades. Using serum samples from patients enrolled in a GII.4 virus challenge study, significant cross-reactivity between major GII.4 variants from 1998 to 2012 was observed using enzyme-linked immunosorbent assays and HBGA receptor blocking assays. The overall abilities of GII.4 NoVs to bind to the A/B/H HBGAs were maintained while their binding affinities to individual ABH antigens varied. These results highlight the importance of human HBGAs in NoV evolution and how conserved antigenic types impact vaccine development against GII.4 variants. PMID- 25915765 TI - Profiling of viral proteins expressed from the genomic RNA of Japanese encephalitis virus using a panel of 15 region-specific polyclonal rabbit antisera: implications for viral gene expression. AB - Japanese encephalitis virus (JEV), a mosquito-borne flavivirus, is closely related to West Nile (WN), yellow fever (YF), and dengue (DEN) viruses. Its plus strand genomic RNA carries a single open reading frame encoding a polyprotein that is cleaved into three structural (C, prM/M, and E) and at least seven nonstructural (NS1/NS1', NS2A, NS2B, NS3, NS4A, NS4B, and NS5) proteins, based on previous work with WNV, YFV, and DENV. Here, we aimed to profile experimentally all the viral proteins found in JEV-infected cells. We generated a collection of 15 JEV-specific polyclonal antisera covering all parts of the viral protein coding regions, by immunizing rabbits with 14 bacterially expressed glutathione-S transferase fusion proteins (for all nine viral proteins except NS2B) or with a chemically synthesized oligopeptide (for NS2B). In total lysates of JEV-infected BHK-21 cells, immunoblotting with these antisera revealed: (i) three mature structural proteins (~12-kDa C, ~8-kDa M, and ~53-kDa E), a precursor of M (~24 kDa prM) and three other M-related proteins (~10-14 kDa); (ii) the predicted ~45 kDa NS1 and its frameshift product, ~58-kDa NS1', with no evidence of the predicted ~25-kDa NS2A; (iii) the predicted but hardly detectable ~14-kDa NS2B and an unexpected but predominant ~12-kDa NS2B-related protein; (iv) the predicted ~69-kDa NS3 plus two major cleavage products (~34-kDa NS3N-term and ~35 kDa NS3C-term), together with at least nine minor proteins of ~16-52 kDa; (v) the predicted ~14-kDa NS4A; (vi) two NS4B-related proteins (~27-kDa NS4B and ~25-kDa NS4B'); and (vii) the predicted ~103-kDa NS5 plus at least three other NS5 related proteins (~15 kDa, ~27 kDa, and ~90 kDa). Combining these data with confocal microscopic imaging of the proteins' intracellular localization, our study is the first to provide a solid foundation for the study of JEV gene expression, which is crucial for elucidating the regulatory mechanisms of JEV genome replication and pathobiology. PMID- 25915766 TI - Suppression of Human T Cell Proliferation Mediated by the Cathepsin B Inhibitor, z-FA-FMK Is Due to Oxidative Stress. AB - The cathepsin B inhibitor, benzyloxycarbonyl-phenylalanine-alanine-fluoromethyl ketone (z-FA-FMK) readily inhibits anti-CD3-induced human T cell proliferation, whereas the analogue benzyloxycarbonyl-phenylalanine-alanine-diazomethyl ketone (z-FA-DMK) had no effect. In contrast, benzyloxycarbonyl-phenylalanine-alanine chloromethyl ketone (z-FA-CMK) was toxic. The inhibition of T cell proliferation mediated by z-FA-FMK requires not only the FMK moiety, but also the benzyloxycarbonyl group at the N-terminal, suggesting some degree of specificity in z-FA-FMK-induced inhibition of primary T cell proliferation. We showed that z FA-FMK treatment leads to a decrease in intracellular glutathione (GSH) with a concomitant increase in reactive oxygen species (ROS) levels in activated T cells. The inhibition of anti-CD3-induced T cell proliferation mediated by z-FA FMK was abolished by the presence of low molecular weight thiols such as GSH, N acetylcysteine (NAC) and L-cysteine, whereas D-cysteine which cannot be metabolised to GSH has no effect. The inhibition of anti-CD3-induced up regulation of CD25 and CD69 expression mediated by z-FA-FMK was also attenuated in the presence of exogenous GSH. Similar to cell proliferation, GSH, NAC and L cysteine but not D-cysteine, completely restored the processing of caspase-8 and caspase-3 to their respective subunits in z-FA-FMK-treated activated T cells. Our collective results demonstrated that the inhibition of T cell activation and proliferation mediated by z-FA-FMK is due to oxidative stress via the depletion of GSH. PMID- 25915767 TI - Selfie and the city: a world-wide, large, and ecologically valid database reveals a two-pronged side bias in naive self-portraits. AB - Self-portraits are more likely to show the artist's right than left cheek. This phenomenon may have a psychobiological basis: Self-portraitists often copy their subject from mirrors and, if they prefer to present their left cheek (more expressive due to right-lateralization of emotions) to the mirror, this would result in a right-cheek bias in the painting. We tested this hypothesis using SelfieCity (3200 selfies posted on Instagram from December 4 through 12, 2013 from New York, Sao Paulo, Berlin, Moskow, and Bangkok), which includes two selfie taking styles: a "standard" (photograph of selfie-taker) and a "mirror" (photograph of mirror reflection of selfie-taker) style. We show that the first style reveals a left cheek bias, whereas the second reveals a right cheek bias. Thus side biases observed in a world-wide, large, and ecologically valid database of naive self-portraits provide strong support for a role of psychobiological factors in the artistic composition of self-portraits. PMID- 25915768 TI - PCSK9 Inhibitors: A New Era in Lipid-Lowering Treatment? PMID- 25915769 TI - Creating Extremely Asymmetric Lamellar Structures via Fluctuation-Assisted Unbinding of Miktoarm Star Block Copolymer Alloys. AB - We report the creation of highly asymmetric lamellar structures with a well designed miktoarm star block copolymer of the S(IS')3 type, where S and S' are polystyrenes of different lengths and I is poly(isoprene). The domain spacing can be tuned continuously from 37 nm to over 300 nm when the miktoarm star block copolymer is blended with suitable molecular weight polystyrene homopolymers. Beyond the unbinding transition of the lamellar phase, extremely asymmetric lamellar structures were obtained with up to 97 wt % polystyrene, remarkably leaving the poly(isoprene) layers intact at only 3 wt %! PMID- 25915770 TI - Quantifying geographic variation in the climatic drivers of midcontinent wetlands with a spatially varying coefficient model. AB - The wetlands in the Prairie Pothole Region and in the Great Plains are notorious for their sensitivity to weather variability. These wetlands have been the focus of considerable attention because of their ecological importance and because of the expected impact of climate change. Few models in the literature, however, take into account spatial variation in the importance of wetland drivers. This is surprising given the importance spatial heterogeneity in geomorphology and climatic conditions have in the region. In this paper, I use spatially-varying coefficients to assess the variation in ecological drivers in a number of ponds observed over a 50-year period (1961-2012). I included the number of ponds observed the year before on a log scale, the log of total precipitation, and mean maximum temperature during the four previous seasons as explanatory variables. I also included a temporal component to capture change in the number of ponds due to anthropogenic disturbance. Overall, fall and spring precipitation were most important in pond abundance in the west, whereas winter and summer precipitation were the most important drivers in the east. The ponds in the east of the survey area were also more dependent on pond abundance during the previous year than those in the west. Spring temperature during the previous season influenced pond abundance; while the temperature during the other seasons had a limited effect. The ponds in the southwestern part of the survey area have been increasing independently of climatic conditions, whereas the ponds in the northeast have been steadily declining. My results underline the importance of accounting the spatial heterogeneity in environmental drivers, when working at large spatial scales. In light of my results, I also argue that assessing the impacts of climate change on wetland abundance in the spring, without more accurate climatic forecasting, will be difficult. PMID- 25915771 TI - gbpA as a Novel qPCR Target for the Species-Specific Detection of Vibrio cholerae O1, O139, Non-O1/Non-O139 in Environmental, Stool, and Historical Continuous Plankton Recorder Samples. AB - The Vibrio cholerae N-acetyl glucosamine-binding protein A (GbpA) is a chitin binding protein involved in V. cholerae attachment to environmental chitin surfaces and human intestinal cells. We previously investigated the distribution and genetic variations of gbpA in a large collection of V. cholerae strains and found that the gene is consistently present and highly conserved in this species. Primers and probe were designed from the gbpA sequence of V. cholerae and a new Taq-based qPCR protocol was developed for diagnostic detection and quantification of the bacterium in environmental and stool samples. In addition, the positions of primers targeting the gbpA gene region were selected to obtain a short amplified fragment of 206 bp and the protocol was optimized for the analysis of formalin-fixed samples, such as historical Continuous Plankton Recorder (CPR) samples. Overall, the method is sensitive (50 gene copies), highly specific for V. cholerae and failed to amplify strains of the closely-related species Vibrio mimicus. The sensitivity of the assay applied to environmental and stool samples spiked with V. cholerae ATCC 39315 was comparable to that of pure cultures and was of 102 genomic units/l for drinking and seawater samples, 101 genomic units/g for sediment and 102 genomic units/g for bivalve and stool samples. The method also performs well when tested on artificially formalin-fixed and degraded genomic samples and was able to amplify V. cholerae DNA in historical CPR samples, the earliest of which date back to August 1966. The detection of V. cholerae in CPR samples collected in cholera endemic areas such as the Benguela Current Large Marine Ecosystem (BCLME) is of particular significance and represents a proof of concept for the possible use of the CPR technology and the developed qPCR assay in cholera studies. PMID- 25915772 TI - Patient-Reported Outcome Coordinator Did Not Improve Quality of Life Assessment Response Rates: A Report from the Children's Oncology Group. AB - PURPOSE: Health related quality of life (HRQL) assessments during therapy for pediatric cancer provide valuable information to better understand the patient experience. Our objective was to determine the impact of a patient-reported outcome (PRO) coordinator on HRQL questionnaire completion rates during a pediatric acute myeloid leukemia (AML) trial. METHODS: AAML1031 is a multicenter Children's Oncology Group therapeutic trial for de novo AML with a secondary aim to assess HRQL of children and adolescents treated with chemotherapy and hematopoietic stem cell transplantation (HSCT). Parents/guardians are the primary respondents and four questionnaires are administered at eight time points. The questionnaires are the PedsQL 4.0 Generic Core Scales, PedsQL 3.0 Acute Cancer Module, PedsQL Multidimensional Fatigue Scale, and the Pediatric Inventory for Parents. To improve response rates, a central PRO coordinator was instituted and reminded sites about upcoming and delinquent questionnaires. The proportion of HRQL questionnaires completed were compared prior to, and following institution of the PRO coordinator. This analysis evaluated the first five assessment time points. RESULTS: There were231 families who consented to participate in the HRQL aim. Overall response rates for all questionnaires were 73-83%. At time point 1, within 14 days of chemotherapy initiation, post-PRO coordinator completion rates were significantly higher for three of four questionnaires. However, the effect was not sustained and at time point 4, one month following last chemotherapy or HSCT, completion rates were significantly lower post-PRO coordinator for all four questionnaires. CONCLUSION: Addition of a central PRO coordinator did not result in sustained improvement in HRQL questionnaire completion rates. Efforts to improve response rates must consider other strategies. PMID- 25915773 TI - Continuous detection of the self-initiated walking pre-movement state from EEG correlates without session-to-session recalibration. AB - OBJECTIVE: Brain-computer interfaces (BCI) as a rehabilitation tool have been used to restore functions in patients with motor impairments by actively involving the central nervous system and triggering prosthetic devices according to the detected pre-movement state. However, since EEG signals are highly variable between subjects and recording sessions, typically a BCI is calibrated at the beginning of each session. This process is inconvenient especially for patients suffering locomotor disabilities in maintaining a bipedal position for a longer time. This paper presents a continuous EEG decoder of a pre-movement state in self-initiated walking and the usage of this decoder from session to session without recalibrating. APPROACH: Ten healthy subjects performed a self-initiated walking task during three sessions, with an intersession interval of one week. The implementation of our continuous decoder is based on the combination of movement-related cortical potential (MRCP) and event-related desynchronization (ERD) features with sparse classification models. MAIN RESULTS: During intrasession our technique detects the pre-movement state with 70% accuracy. Moreover this decoder can be applied from session to session without recalibration, with a decrease in performance of about 4% on a one- or two-week intersession interval. SIGNIFICANCE: Our detection model operates in a continuous manner, which makes it a straightforward asset for rehabilitation scenarios. By using both temporal and spectral information we attained higher detection rates than the ones obtained with the MRCP and ERD detection models, both during the intrasession and intersession conditions. PMID- 25915774 TI - In Silico Measurements of Twist and Bend Moduli for beta-Solenoid Protein Self Assembly Units. AB - We compute potentials of mean force for bend and twist deformations via force pulling and umbrella sampling experiments for four beta-solenoid proteins (BSPs) that show promise in nanotechnology applications. In all cases, we find quasi Hooke's law behavior until the point of rupture. Bending moduli show modest anisotropy for two-sided and three-sided BSPs, and little anisotropy for a four sided BSP. There is a slight clockwise/counterclockwise asymmetry in the twist potential of mean force, showing greater stiffness when the applied twist follows the intrinsic twist. When we extrapolate to beam theory appropriate for amyloid fibrils of the BSPs, we find bend/twist moduli which are somewhat smaller than those in the literature for other amyloid fibrils. Twist persistence lengths are on the order of a micron, and bend persistence lengths are several microns. Provided the intrinsic twist can be reversed, these results support the usage of BSPs in biomaterials applications. PMID- 25915775 TI - Effect of Embryo Vitrification on Rabbit Foetal Placenta Proteome during Pregnancy. AB - Very limited information on the post-implantatory effects of vitrification has been published till now. We observed in a previous study that the vitrification procedure for the cryopreservation of embryos introduced transcriptomic and proteomic modifications in the rabbit foetal placenta at the middle of gestation. Now, we have conducted a proteomic study to determine whether protein alterations in the foetal placenta induced by the vitrification procedure remain during pregnancy. In this study, we used 2D-DIGE and mass spectrometry (MALDI-TOF-TOF and LC-MS/MS analysis) to identify the protein changes during middle and late stages of gestation (Day 14 and Day 24, respectively) in rabbit foetal placenta. We identified 11 differentially expressed proteins at Day 14 and 13 proteins at Day 24. Data are available via ProteomeXchange with identifiers PXD001840 and PXD001836. In addition, we demonstrate the presence of three proteins, serum albumin, isocitrate dehydrogenase 1 [NADP+], and phosphoglycerate mutase 1, which were altered during pregnancy. We demonstrate the existence of changes in foetal placental protein during pregnancy induced by the vitrification procedure, which brings into question whether vitrification effects observed during foetal development could lead to physiological and metabolic disorders in adulthood. This effect, taken together with other effects reported in the literature, suggests that embryo cryopreservation is not neutral. PMID- 25915776 TI - Neuropsychological outcome and diffusion tensor imaging in complicated versus uncomplicated mild traumatic brain injury. AB - This study examined whether intracranial neuroimaging abnormalities in those with mild traumatic brain injury (MTBI) (i.e., "complicated" MTBIs) are associated with worse subacute outcomes as measured by cognitive testing, symptom ratings, and/or diffusion tensor imaging (DTI). We hypothesized that (i) as a group, participants with complicated MTBIs would report greater symptoms and have worse neurocognitive outcomes than those with uncomplicated MTBI, and (ii) as a group, participants with complicated MTBIs would show more Diffusion Tensor Imaging (DTI) abnormalities. Participants were 62 adults with MTBIs (31 complicated and 31 uncomplicated) who completed neurocognitive testing, symptom ratings, and DTI on a 3T MRI scanner approximately 6-8 weeks post injury. There were no statistically significant differences between groups on symptom ratings or on a broad range of neuropsychological tests. When comparing the groups using tract based spatial statistics for DTI, no significant difference was found for axial diffusivity or mean diffusivity. However, several brain regions demonstrated increased radial diffusivity (purported to measure myelin integrity), and decreased fractional anisotropy in the complicated group compared with the uncomplicated group. Finally, when we extended the DTI analysis, using a multivariate atlas based approach, to 32 orthopedic trauma controls (TC), the findings did not reveal significantly more areas of abnormal DTI signal in the complicated vs. uncomplicated groups, although both MTBI groups had a greater number of areas with increased radial diffusivity compared with the trauma controls. This study illustrates that macrostructural neuroimaging changes following MTBI are associated with measurable changes in DTI signal. Of note, however, the division of MTBI into complicated and uncomplicated subtypes did not predict worse clinical outcome at 6-8 weeks post injury. PMID- 25915778 TI - Correction: Drosophila TIM binds importin alpha1, and acts as an adapter to transport PER to the nucleus. AB - [This corrects the article DOI: 10.1371/journal.pgen.1004974.]. PMID- 25915777 TI - Health-related quality of life in Chinese patients with mild and moderately active ulcerative colitis. AB - BACKGROUND: Ulcerative colitis (UC) impairs the health-related quality of life (HRQOL). The difference in HRQOL between patients with mild and moderately active UC is not well-defined. Few studies have been conducted to explore the factors that influence HRQOL in Chinese patients. Our study aims were to (1) compare HRQOL of mildly active UC patients with moderate patients; (2) explore the factors that influence HRQOL in Chinese patients with UC; and (3) analyze demographic and disease characteristics of UC in China. METHODS: A total of 110 mild and 114 moderate patients with UC were enrolled. The demographic and disease characteristics were recorded. HRQOL was measured by the Chinese version of the inflammatory bowel disease questionnaire (IBDQ) between mild and moderate patients, male and female patients, and different disease distributions. Stepwise regression analysis was used to assess factors influencing the IBDQ score. RESULTS: Patients with moderate UC had significantly lower IBDQ total scores compared to patients with mild UC (P=0.001). The IBDQ total score had a negative correlation with the Mayo score (r=-0.263, P<0.001). Stepwise regression analysis showed that the disease activity index and gender had an influence on the IBDQ total score (P<0.05). The female patients had a lower score than the male patients (P<0.05), especially in the emotional function domain (P=0.002). Different disease distributions were not statistically significant in the IBDQ total score (P=0.183). CONCLUSIONS: UC has a negative influence on HRQOL. HRQOL in patients with moderate UC was lower than HRQOL in patients with mild UC, as measured by the IBDQ. UC disease activity has a negative correlation with HRQOL. Gender and the disease activity index are important factors involved in the impairment of HRQOL in Chinese patients with UC. Chinese females may benefit from increased psychological care as part of UC therapy. PMID- 25915779 TI - Relationships of parental monitoring and emotion regulation with early adolescents' sexual behaviors. AB - OBJECTIVE: The purpose of this study was to examine the moderating influence of parental monitoring (e.g., unsupervised time with opposite sex peers) and adolescent emotional competence on sexual behaviors, among a sample of at-risk early adolescents. METHODS: This study included 376 seventh-grade adolescents (age, 12-14 years) with behavioral or emotional difficulties. Questionnaires were completed on private laptop computers and assessed adolescent Emotional Competence (including Regulation and Negativity/Lability), Unsupervised Time, and a range of Sexual Behaviors. Generalized linear models were used to evaluate the independent and combined influence of Emotional Competency and Unsupervised Time on adolescent report of Sexual Behaviors. Analyses were stratified by gender to account for the notable gender differences in the targeted moderators and outcome variables. RESULTS: Findings indicated that more unsupervised time was a risk factor for all youth but was influenced by an adolescent's ability to regulate their emotions. Specifically, for males and females, poorer Emotion Regulation was associated with having engaged in a greater variety of Sexual Behaviors. However, lower Negativity/Lability and >1* per week Unsupervised Time were associated with a higher number of sexual behaviors among females only. CONCLUSIONS: Based on the findings of this study, a lack of parental supervision seems to be particularly problematic for both male and female adolescents with poor emotion regulation abilities. It may be important to impact both emotion regulation abilities and increase parental knowledge and skills associated with effective monitoring to reduce risk-taking for these youth. PMID- 25915780 TI - Sacituzumab Govitecan (IMMU-132), an Anti-Trop-2/SN-38 Antibody-Drug Conjugate: Characterization and Efficacy in Pancreatic, Gastric, and Other Cancers. AB - Sacituzumab govitecan (IMMU-132) is an antibody-drug conjugate (ADC) made from a humanized anti-Trop-2 monoclonal antibody (hRS7) conjugated with the active metabolite of irinotecan, SN-38. In addition to its further characterization, as the clinical utility of IMMU-132 expands to an ever-widening range of Trop-2 expressing solid tumor types, its efficacy in new disease models needs to be explored in a nonclinical setting. Unlike most ADCs that use ultratoxic drugs and stable linkers, IMMU-132 uses a moderately toxic drug with a moderately stable carbonate bond between SN-38 and the linker. Flow cytometry and immunohistochemistry disclosed that Trop-2 is expressed in a wide range of tumor types, including gastric, pancreatic, triple-negative breast (TNBC), colonic, prostate, and lung. While cell-binding experiments reveal no significant differences between IMMU-132 and parental hRS7 antibody, surface plasmon resonance analysis using a Trop-2 CM5 chip shows a significant binding advantage for IMMU-132 over hRS7. The conjugate retained binding to the neonatal receptor, but it lost greater than 60% of the antibody-dependent cell-mediated cytotoxicity activity compared to that of hRS7. Exposure of tumor cells to either free SN-38 or IMMU-132 demonstrated the same signaling pathways, with pJNK1/2 and p21(WAF1/Cip1) upregulation followed by cleavage of caspases 9, 7, and 3, ultimately leading to poly-ADP-ribose polymerase cleavage and double-stranded DNA breaks. Pharmacokinetics of the intact ADC in mice reveals a mean residence time (MRT) of 15.4 h, while the carrier hRS7 antibody cleared at a similar rate as that of the unconjugated antibody (MRT ~ 300 h). IMMU-132 treatment of mice bearing human gastric cancer xenografts (17.5 mg/kg; twice weekly * 4 weeks) resulted in significant antitumor effects compared to that of mice treated with a nonspecific control. Clinically relevant dosing schemes of IMMU-132 administered either every other week, weekly, or twice weekly in mice bearing human pancreatic or gastric cancer xenografts demonstrate similar, significant antitumor effects in both models. Current Phase I/II clinical trials ( ClinicalTrials.gov , NCT01631552) confirm anticancer activity of IMMU-132 in cancers expressing Trop 2, including gastric and pancreatic cancer patients. PMID- 25915781 TI - First Crystal Structures of Mycobacterium tuberculosis 6-Oxopurine Phosphoribosyltransferase: Complexes with GMP and Pyrophosphate and with Acyclic Nucleoside Phosphonates Whose Prodrugs Have Antituberculosis Activity. AB - Human tuberculosis is a chronic infectious disease affecting millions of lives. Because of emerging resistance to current medications, new therapeutic drugs are needed. One potential new target is hypoxanthine-guanine phosphoribosyltransferase (MtHGPRT), a key enzyme of the purine salvage pathway. Here, newly synthesized acyclic nucleoside phosphonates (ANPs) have been shown to be competitive inhibitors of MtHGPRT with Ki values as low as 0.69 MUM. Prodrugs of these compounds arrest the growth of a virulent strain of M. tuberculosis with MIC50 values as low as 4.5 MUM and possess low cytotoxicity in mammalian cells (CC50 values as high as >300 MUM). In addition, the first crystal structures of MtHGPRT (2.03-2.76 A resolution) have been determined, three of these in complex with novel ANPs and one with GMP and pyrophosphate. These data provide a solid foundation for the further development of ANPs as selective inhibitors of MtHGPRT and as antituberculosis agents. PMID- 25915783 TI - Organizational safety climate and supervisor safety enforcement: Multilevel explorations of the causes of accident underreporting. AB - According to national surveillance statistics, over 3 million employees are injured each year; yet, research indicates that these may be substantial underestimates of the true prevalence. The purpose of the current project was to empirically test the hypothesis that organizational safety climate and transactional supervisor safety leadership would predict the extent to which accidents go unreported by employees. Using hierarchical linear modeling and survey data collected from 1,238 employees in 33 organizations, employee-level supervisor safety enforcement behaviors (and to a less consistent extent, organizational-level safety climate) predicted employee accident underreporting. There was also a significant cross-level interaction, such that the effect of supervisor enforcement on underreporting was attenuated in organizations with a positive safety climate. These results may benefit human resources and safety professionals by pinpointing methods of increasing the accuracy of accident reporting, reducing actual safety incidents, and reducing the costs to individuals and organizations that result from underreporting. PMID- 25915782 TI - Is postoperative imaging mandatory after meningioma removal? Results of a prospective study. AB - BACKGROUND: Routine postoperative imaging (PI) following surgery for intracranial meningiomas is common practice in most neurosurgical departments. The purpose of this study was to determine the role of routine PI and its impact on clinical decision making after resection of meningioma. METHODS: Patient and tumor characteristics, details of radiographic scans, symptoms and alteration of treatment courses were prospectively collected for patients undergoing removal of a supratentorial meningioma of the convexity, falx, tentorium, or lateral sphenoid wing at the authors' institution between January 1st, 2010 and March 31st, 2012. Patients with infratentorial manifestations or meningiomas of the skull base known to be surgically difficult (e.g. olfactory groove, petroclival, medial sphenoid wing) were not included. Maximum tumor diameter was divided into groups of < 3 cm (small), 3 to 6 cm (medium), and > 6 cm (large). RESULTS: 206 patients with meningiomas were operated between January 2010 and March 2012. Of these, 113 patients met the inclusion criteria and were analyzed in this study. 83 patients (73.5%) did not present new neurological deficits, whereas 30 patients (26.5%) became clinically symptomatic. Symptomatic patients had a change in treatment after PI in 21 cases (70%), while PI was without consequence in 9 patients (30%). PI did not result in a change of treatment in all asymptomatic patients (p<0.001) irrespective of tumor size (p<0.001) or localization (p<0.001). CONCLUSIONS: PI is mandatory for clinically symptomatic patients but it is safe to waive it in clinically asymptomatic patients, even if the meningioma was large in size. PMID- 25915784 TI - Who gets credit for input? Demographic and structural status cues in voice recognition. AB - The authors investigate the employee features that, alongside overall voice expression, affect supervisors' voice recognition. Drawing primarily from status characteristics and network position theories, the authors propose and find in a study of 693 employees from 89 different credit union units that supervisors are more likely to credit those reporting the same amount of voice if the employees have higher ascribed or assigned (by the organization) status--cued by demographic variables such as majority ethnicity and full-time work hours. Further, supervisors are more likely to recognize voice from employees who have higher achieved status--cued by their centrality in informal social structures. The authors also find that even when certain groups of lower status employees speak up more, they cannot compensate for the negative effect of their demographic membership on voice recognition by their boss. The authors underscore how recognition of employee voice by supervisors matters for employees. It carries (mediates) the effects of voice expression and status onto performance evaluations 1 year later, which means that demographic differences in the assignment of credit for voice can serve as an implicit pathway for discrimination. PMID- 25915785 TI - Plasmon-induced optical anisotropy in hybrid graphene-metal nanoparticle systems. AB - Hybrid plasmonic metal-graphene systems are emerging as a class of optical metamaterials that facilitate strong light-matter interactions and are of potential importance for hot carrier graphene-based light harvesting and active plasmonic applications. Here we use femtosecond pump-probe measurements to study the near-field interaction between graphene and plasmonic gold nanodisk resonators. By selectively probing the plasmon-induced hot carrier dynamics in samples with tailored graphene-gold interfaces, we show that plasmon-induced hot carrier generation in the graphene is dominated by direct photoexcitation with minimal contribution from charge transfer from the gold. The strong near-field interaction manifests as an unexpected and long-lived extrinsic optical anisotropy. The observations are explained by the action of highly localized plasmon-induced hot carriers in the graphene on the subresonant polarizability of the disk resonator. Because localized hot carrier generation in graphene can be exploited to drive electrical currents, plasmonic metal-graphene nanostructures present opportunities for novel hot carrier device concepts. PMID- 25915786 TI - Correction to Strickland, Watkins, and Caterino (2015). PMID- 25915787 TI - Suicide risk screening: Comparing the Beck Depression Inventory-II, Beck Hopelessness Scale, and Psychache Scale in undergraduates. AB - The current research evaluates the effectiveness and relative merits of 3 screening measures (the Beck Depression Inventory-II, the Beck Hopelessness Scale, and the Psychache Scale) in evaluating preexisting suicide risk factors for a sample of 7,522 undergraduate students. All measures demonstrated significant diagnostic accuracy for indicating suicide ideation, previous single and multiple suicide attempts, and a recent suicide attempt, which are all serious risk factors for subsequent death by suicide in university students. However, the Psychache Scale displayed superior performance in accurately identifying suicide risk compared with both the Beck Depression Inventory-II and the Beck Hopelessness Scale. Identifying students most at risk for suicide requires diagnostically efficient measures, thus preliminary cut-scores for identifying at-risk students are provided. PMID- 25915788 TI - Examining the correlates of the coldheartedness factor of the Psychopathic Personality Inventory-Revised. AB - Coldheartedness is a subscale of the Psychopathic Personality Inventory-Revised (PPI-R) that does not load onto either of the PPI-R's two traditional higher order factors (Fearless Dominance [FD] and Self-Centered Impulsivity [SCI]). As a result, it has been omitted from analyses in many studies. However, owing to Coldheartedness's associations with lack of empathy, guilt, and deep-seated social emotions, this subscale may be highly relevant to the construct of psychopathy. In a sample of 1,158 undergraduates, we attempted to clarify Coldheartedness's correlates within the context of a nomological network of psychopathology and personality; in addition, we examined Coldheartedness's contributions to psychopathy above and beyond FD and SCI. Coldheartedness demonstrated negative correlations with the Big Five personality factors, mixed correlations with indices of impulsivity, and largely negative correlations with measures of depression and anxiety. Regressions suggested that Coldheartedness displays substantial overlap with both FD and SCI but also contains psychologically important unique variance. Although the nature of this variance requires clarification, further research and perhaps an expansion of the Coldheartedness subscale may move the field toward a clearer understanding of the construct assessed by this measure. PMID- 25915789 TI - Factor structure of symptom dimensions in attention-deficit/hyperactivity disorder (ADHD). AB - There is disagreement on whether attention-deficit/hyperactivity disorder (ADHD) symptoms are best characterized along two dimensions consisting of inattention and hyperactivity/impulsivity or three dimensions where hyperactivity and impulsivity are separate. To address this, the current study investigated the underlying symptom dimensions of ADHD by examining two- and three-factor models of ADHD symptom ratings in 400 children and adolescents diagnosed with ADHD. ADHD symptom ratings for each of the 18 DSM-IV Criteria A symptoms were obtained from mothers using a standardized symptom rating scale. Confirmatory factor analysis (CFA) was used to examine whether the 18 symptoms were best explained by two or three latent constructs. Results of the CFA demonstrated that a three-factor model was superior to a two-factor model. Findings support three distinct symptom dimensions that are consistent with previous research demonstrating unique clinical presentations of inattention, hyperactivity, and impulsivity. Differentiating between these three domains may aid in predicting behavioral outcomes in children with ADHD. PMID- 25915790 TI - The laws governing ionic liquid extraction of cations: partition of 1 ethylpyridinium monocation and paraquat dication in ionic liquid/water biphasic systems. AB - To find the laws governing the extraction of cations from aqueous solutions into hydrophobic ionic liquids (ILs), we investigated the partition of 1 ethylpyridinium monocation and paraquat (1,1'-dimethyl-4,4'-bipyridinium) dication in various IL/water biphasic systems. Ten different ILs of 1-butyl-3 methylimidazolium-based or bis(trifluoromethanesulfonyl)amide-based salts were used. The distribution ratio of the target cations (T(n+)) was dependent on the initial concentration in the aqueous phase and also very sensitive to the kind of IL. The behavior was quantitatively explained on the basis of a model in which the extraction goes through both the ion exchange and ion pair transfer processes, while keeping the product of the aqueous concentrations of the IL constituent ions a constant value (solubility product, Ksp). The distribution ratio of T(n+) is expressed as a function of the difference between the initial and equilibrium concentrations of T(n+) in the aqueous phase (Delta[T(n+)]W), the aqueous solubility of IL (Ksp(1/2)), and the cation valence n. The distribution ratio is a nearly constant value (D0) when Delta[T(n+)]W ? Ksp(1/2)/n and decreases inversely proportional to the nth power of Delta[T(n+)]W when Delta[T(n+)]W ? Ksp(1/2)/n. The log D0 versus log Ksp(1/2) plot gives a linear relationship with a slope of +n for the ILs with the same anion but different cations and that with a slope of nearly -n for the ILs with the same cation but different anions. This means that the extractability dependence on the kinds of IL constituent ions is greater for the divalent cation than for the monovalent one. PMID- 25915791 TI - Fluoroquinolone Therapy for the Prevention of Multidrug-Resistant Tuberculosis in Contacts. A Cost-Effectiveness Analysis. AB - RATIONALE: Fluoroquinolone (FQN) therapy of latent tuberculosis infection among contacts of individuals with multidrug-resistant tuberculosis (MDR-TB) is controversial. OBJECTIVES: To determine the potential benefits, risks (including acquired FQN resistance), and cost-effectiveness of FQN therapy to prevent TB in contacts of individuals with MDR-TB. METHODS: We used decision analysis to estimate costs and outcomes associated with no therapy compared with a 6-month course of daily FQN therapy to treat latent TB infection in contacts of individuals with MDR-TB. Outcomes modeled were the incidence of MDR-TB, MDR-TB with FQN resistance, TB-related death, quality-adjusted life years, and health system costs. MEASUREMENTS AND MAIN RESULTS: FQN preventive therapy resulted in health system savings, lower incidence of MDR-TB, and lower mortality than no treatment. We found the incidence of MDR-TB with acquired FQN resistance would also be lower with FQN therapy of infected contacts. CONCLUSIONS: In our model, FQN preventive therapy resulted in substantial health system savings and in reduced mortality, incidence of MDR-TB, and incidence of acquired FQN-resistant disease as well as improved quality of life. FQN therapy remained cost saving with improved outcomes even if the effectiveness of therapy in preventing MDR-TB was as low as 10%. PMID- 25915792 TI - The warrior, military ethics and contemporary warfare: Achilles goes symmetrical. PMID- 25915793 TI - Glycation alters ligand binding, enzymatic, and pharmacological properties of human albumin. AB - Albumin, the major circulating protein in blood plasma, can be subjected to an increased level of glycation in a diabetic context. Albumin exerts crucial pharmacological activities through its drug binding capacity, i.e., ketoprofen, and via its esterase-like activity, allowing the conversion of prodrugs into active drugs. In this study, the impact of the glucose-mediated glycation on the pharmacological and biochemical properties of human albumin was investigated. Aggregation product levels and the redox state were quantified to assess the impact of glycation-mediated changes on the structural properties of albumin. Glucose-mediated changes in ketoprofen binding properties and esterase-like activity were evaluated using fluorescence spectroscopy and p-nitrophenyl acetate hydrolysis assays, respectively. With the exception of oxidative parameters, significant dose-dependent alterations in biochemical and functional properties of in vitro glycated albumin were observed. We also found that the dose-dependent increase in levels of glycation and protein aggregation and average molecular mass changes correlated with a gradual decrease in the affinity of albumin for ketoprofen and its esterase-like property. In parallel, significant alterations in both pharmacological properties were also evidenced in albumin purified from diabetic patients. Partial least-squares regression analyses established a significant correlation between glycation-mediated changes in biochemical and pharmacological properties of albumin, highlighting the important role for glycation in the variability of the drug response in a diabetic situation. PMID- 25915794 TI - Childhood trauma and resilience in old age: applying a context model of resilience to a sample of former indentured child laborers. AB - OBJECTIVES: Psychological resilience has been rarely investigated in elderly populations. We applied a more comprehensive model of trauma-specific coping and resilience, which included Ungar's context model and included decentral factors of resilience (i.e., environments that provide resources to build resilience). METHOD: We assessed resilience in a cohort of former Swiss indentured child laborers (N = 74; 59% males) at two time points; first at the mean age of 80 years and then again 20 months later. At each time point, the following measures of resilience were assessed: resilience indicators of life satisfaction and lack of depression. In addition, resilience predictors of trauma exposure, perceived social support, dysfunctional disclosure of traumatic experiences, social acknowledgment as a victim, and self-efficacy; and decentral resilience factors of education, income, number of children, and physical health were measured. RESULTS: Using path-analysis, we found that life satisfaction and lack of depression were predicted by dysfunctional disclosure, social support, and self efficacy at various significance levels. Change scores of resilience were predicted by higher trauma exposure, social acknowledgment as a victim, and an interaction between the two. The model for decentral factors also fitted, with physical health and income predicting the resilience indicators. CONCLUSION: Applying this comprehensive resilience model in a sample of older adults revealed meaningful findings in predicting resilience at a single time point and over time. Atypical coping strategies, such as perceived social acknowledgment as a victim and disclosure, may be particularly important for former victims who have suffered institutional abuse. PMID- 25915795 TI - Combined use of ion mobility and collision-induced dissociation to investigate the opening of disulfide bridges by electron-transfer dissociation in peptides bearing two disulfide bonds. AB - Disulfide bonds are post-translational modifications (PTMs) often found in peptides and proteins. They increase their stability toward enzymatic degradations and provide the structure and (consequently) the activity of such folded proteins. The characterization of disulfide patterns, i.e., the cysteine connectivity, is crucial to achieve a global picture of the active conformation of the protein of interest. Electron-transfer dissociation (ETD) constitutes a valuable tool to cleave the disulfide bonds in the gas phase, avoiding chemical reduction/alkylation in solution. To characterize the cysteine pairing, the present work proposes (i) to reduce by ETD one of the two disulfide bridges of model peptides, resulting in the opening of the cyclic structures, (ii) to separate the generated species by ion mobility, and (iii) to characterize the species using collision-induced dissociation (CID). Results of this strategy applied to several peptides show different behaviors depending on the connectivity. The loss of SH. radical species, observed for all the peptides, confirms the cleavage of the disulfides during the ETD process. PMID- 25915796 TI - Ultrasoft Alginate Hydrogels Support Long-Term Three-Dimensional Functional Neuronal Networks. AB - Neuron development and function are exquisitely sensitive to the mechanical properties of their surroundings. Three-dimensional (3D) cultures are therefore being explored as they better mimic the features of the native extracellular matrix. Limitations of existing 3D culture models include poorly defined composition, rapid degradation, and suboptimal biocompatibility. Here we show that ionically cross-linked ultrasoft hydrogels made from unmodified alginate can potently promote neuritogenesis. Alginate hydrogels were characterized mechanically and a remarkable range of stiffness (10-4000 Pa) could be produced by varying the macromer content (0.1-0.4% w/v) and CaCl2 concentration. Dissociated rat embryonic cortical neurons encapsulated within the softest of the hydrogels (0.1% w/v, 10 mM CaCl2) showed excellent viability, extensive formation of axons and dendrites, and long-term activity as determined by calcium imaging. In conclusion, alginate is an off-the-shelf, easy to handle, and inexpensive material, which can be used to make ultrasoft hydrogels for the formation of stable and functional 3D neuronal networks. This 3D culture system could have important applications in neuropharmacology, toxicology, and regenerative medicine. PMID- 25915797 TI - Nonlinear elasticity and cavitation of a triblock copolymer gel. AB - Polymer gels are subjected to large-strain deformation during their applications. The gel deformation at large-strain is non-linear and can often lead to failure of the material. Here, we report the large-strain deformation behavior of a physically cross-linked, swollen triblock copolymer gel, which displays unique strain-stiffening response at large-strain. Investigations were performed using large amplitude oscillatory shear (LAOS) and custom developed cavitation rheology techniques. The Gent constitutive equation, which considers finite extensibility of midblock, was fitted with the LAOS data, thereby, linking the estimated parameters from LAOS analysis to the structure of the gel. The pressure responses obtained from the cavitation experiments were modeled using neo-Hookean and Gent constitutive equations. Our results capture the failure behavior of a gel with finite chain extensibility, initiated from a defect within the gel. PMID- 25915798 TI - Viral bimolecular fluorescence complementation: a novel tool to study intracellular vesicular trafficking pathways. AB - The Human Immunodeficiency Virus type 1 (HIV-1) accessory protein Nef interacts with a multitude of cellular proteins, manipulating the host membrane trafficking machinery to evade immune surveillance. Nef interactions have been analyzed using various in vitro assays, co-immunoprecipitation studies, and more recently mass spectrometry. However, these methods do not evaluate Nef interactions in the context of viral infection nor do they define the sub-cellular location of these interactions. In this report, we describe a novel bimolecular fluorescence complementation (BiFC) lentiviral expression tool, termed viral BiFC, to study Nef interactions with host cellular proteins in the context of viral infection. Using the F2A cleavage site from the foot and mouth disease virus we generated a viral BiFC expression vector capable of concurrent expression of Nef and host cellular proteins; PACS-1, MHC-I and SNX18. Our studies confirmed the interaction between Nef and PACS-1, a host membrane trafficking protein involved in Nef mediated immune evasion, and demonstrated co-localization of this complex with LAMP-1 positive endolysosomal vesicles. Furthermore, we utilized viral BiFC to localize the Nef/MHC-I interaction to an AP-1 positive endosomal compartment. Finally, viral BiFC was observed between Nef and the membrane trafficking regulator SNX18. This novel demonstration of an association between Nef and SNX18 was localized to AP-1 positive vesicles. In summary, viral BiFC is a unique tool designed to analyze the interaction between Nef and host cellular proteins by mapping the sub-cellular locations of their interactions during viral infection. PMID- 25915799 TI - Clusters of Low (18)F-Fluorodeoxyglucose Uptake Voxels in Combat Veterans with Traumatic Brain Injury and Post-Traumatic Stress Disorder. AB - Individuals with mild traumatic brain injury (TBI) show diminished metabolic activity when studied with positron emission tomography (PET) with (18)F fluorodeoxyglucose (FDG). Since blast injury may not be localized in the same specific anatomical areas in every patient or may be diffuse, significance probability mapping may be vulnerable to false-negative detection of abnormalities. To address this problem, we used an anatomically independent measure to assess PET scans: increased numbers of contiguous voxels that are 2 standard deviations below values found in an uninjured control group. We examined this in three age-matched groups of male patients: 16 veterans with a history of mild TBI, 17 veterans with both mild TBI and post-traumatic stress disorder (PTSD), and 15 veterans without either condition. After FDG administration, subjects performed a modified version of the California Verbal Learning Task. Clusters of low uptake voxels were identified by computing the mean and standard deviation for each voxel in the healthy combat veteran group and then determining the voxel-based z-score for the patient groups. Abnormal clusters were defined as those that contained contiguous voxels with a z-score <-2. Patients with mild TBI alone and patients with TBI+PTSD had larger clusters of low uptake voxels, and cluster size significantly differentiated the mild TBI groups from combat controls. Clusters were more irregular in shape in patients, and patients also had a larger number of low-activity voxels throughout the brain. In mild TBI and TBI+PTSD patients, but not healthy subjects, cluster volume was significantly correlated with verbal learning during FDG uptake. PMID- 25915800 TI - Gloeophyllins A-J, Cytotoxic Ergosteroids with Various Skeletons from a Chinese Tibet Fungus Gloeophyllum abietinum. AB - Ten new ergosteroids, gloeophyllins A-J (1-10), have been isolated from the solid cultures of Gloeophyllum abietinum. The absolute configurations of 1, 2, and 9 were determined by X-ray crystallographic analysis. Compound 1 has a rare C-nor-D homosteroid skeleton. Compound 9 possesses an unusual ergostane skeleton having a 10-oxabicyclo [4.3.1] decane moiety replacing 6/5 fused C/D rings. Compound 10 represents the first ergosteroid featuring the cleavage of a C8-C14 bond. The cytotoxicity of 1-10 was tested against the human cancer cell lines K562 and HCT116. The biosynthetic pathway for 1-10 is postulated. PMID- 25915801 TI - Current Status of Western Yellow-Billed Cuckoo along the Sacramento and Feather Rivers, California. AB - To evaluate the current status of the western population of the Yellow-billed Cuckoo (Coccyzus americanus) along the Sacramento and Feather rivers in California's Sacramento Valley, we conducted extensive call playback surveys in 2012 and 2013. We also quantified the amount and distribution of potential habitat. Our survey transects were randomly located and spatially balanced to sample representative areas of the potential habitat. We estimated that the total area of potential habitat was 8,134 ha along the Sacramento River and 2,052 ha along the Feather River, for a total of 10,186 ha. Large-scale restoration efforts have created potential habitat along both of these rivers. Despite this increase in the amount of habitat, the number of cuckoos we detected was extremely low. There were 8 detection occasions in 2012 and 10 occasions in 2013 on the Sacramento River, in both restored and remnant habitat. We had no detections on the Feather River in either year. We compared our results to 10 historic studies from as far back as 1972 and found that the Yellow-billed Cuckoo had unprecedentedly low numbers in 2010, 2012, and 2013. The current limiting factor for the Yellow-billed Cuckoo in the Sacramento Valley is likely not the amount of appropriate vegetation, as restoration has created more habitat over the last 30 years. Reasons for the cuckoo decline on the Sacramento and Feather rivers are unclear. PMID- 25915802 TI - Memory and disgust: Effects of appearance-congruent and appearance-incongruent information on source memory for food. AB - The present study was stimulated by previous findings showing that people preferentially remember person descriptions that violate appearance-based first impressions. Given that until now all studies used faces as stimuli, these findings can be explained by referring to a content-specific module for social information processing that facilitates social orientation within groups via stereotyping and counter-stereotyping. The present study tests whether the same results can be obtained with fitness-relevant stimuli from another domain- pictures of disgusting-looking or tasty-looking food, paired with tasty and disgusting descriptions. A multinomial model was used to disentangle item memory, guessing and source memory. There was an old-new recognition advantage for disgusting-looking food. People had a strong tendency towards guessing that disgusting-looking food had been previously associated with a disgusting description. Source memory was enhanced for descriptions that disconfirmed these negative, appearance-based impressions. These findings parallel the results from the social domain. Heuristic processing of stimuli based on visual appearance may be complemented by intensified processing of incongruent information that invalidates these first impressions. PMID- 25915803 TI - Erratum. PMID- 25915804 TI - Functional Screening of the Cronobacter sakazakii BAA-894 Genome reveals a role for ProP (ESA_02131) in carnitine uptake. AB - Cronobacter sakazakii is a neonatal pathogen responsible for up to 80% of fatalities in infected infants. Low birth weight infants and neonates infected with C. sakazakii suffer necrotizing enterocolitis, bacteraemia and meningitis. The mode of transmission most often associated with infection is powdered infant formula (PIF) which, with an aw of ~0.2, is too low to allow most microorganisms to persist. Survival of C. sakazakii in environments subject to extreme hyperosmotic stress has previously been attributed to the uptake of compatible solutes including proline and betaine. Herein, we report the construction and screening of a C. sakazakii genome bank and the identification of ProP (ESA_02131) as a carnitine uptake system. PMID- 25915805 TI - The epidemiology of traumatic brain injury in civilian inpatients of Chinese Military Hospitals, 2001-2007. AB - PRIMARY OBJECTIVE: To investigate the epidemiology of TBI in Chinese inpatients. RESEARCH DESIGN: Civilian inpatients of Chinese military hospitals diagnosed with TBI between 2001-2007 were identified using ICD-9-CM codes. METHODS AND PROCEDURES: Demographic characteristics, admission time, injury cause, injury severity, length of stay and outcomes were compared between ICD-9-CM diagnosis groups. MAIN OUTCOMES AND RESULTS: In total, 203 553 civilian patients with TBI (74.86% male, 25.14% female) were identified from >200 Chinese military hospitals. TBI diagnoses increased by a mean of 4.67% each year. Admission peaked during the third quarter of the year and October annually. The leading causes of TBI were motor vehicle-traffic (51.41%), falls (21.49%) and assaults (15.77%). TBI was categorized by abbreviated injury scale score as mild in 36.64%, serious in 20.13%, severe in 26.81% and critical in 15.68% of inpatients. The mean length of stay was 17.8 +/- 24.1 days. Recovery rate was 93.06% and mortality was 4.14%. CONCLUSIONS: The epidemiological data may contribute to the development of effective, targeted strategies to prevent TBI. PMID- 25915807 TI - Late post-transplant anti-aquaporin-4 Ab-positive optic neuritis in a patient with AML. PMID- 25915806 TI - Allogeneic hematopoietic cell transplant for AML: no impact of pre-transplant extramedullary disease on outcome. AB - The impact of extramedullary disease (EMD) in AML on the outcomes of allogeneic hematopoietic cell transplantation (alloHCT) is unknown. Using data from the Center for International Blood and Marrow Transplant Research, we compared the outcomes of patients who had EMD of AML at any time before transplant, with a cohort of AML patients without EMD. We reviewed data from 9797 AML patients including 814 with EMD from 310 reporting centers and 44 different countries, who underwent alloHCT between and 1995 and 2010. The primary outcome was overall survival (OS) after alloHCT. Secondary outcomes included leukemia-free survival (LFS), relapse rate and treatment-related mortality (TRM). In a multivariate analysis, the presence of EMD did not affect either OS (hazard ratio 1.00, 95% confidence interval (CI) 0.91-1.09), LFS (0.98, 0.89-1.09), TRM (relative risk 0.92, 95% CI 0.80-1.16, P=0.23) or relapse (relative risk=1.03, 95% CI, 0.92 1.16; P=0.62). Furthermore, the outcome of patients with EMD was not influenced by the location, timing of EMD, or intensity of conditioning regimen. The presence of EMD in AML does not affect transplant outcomes and should not be viewed as an independent adverse prognostic feature. PMID- 25915808 TI - Efficacy of plerixafor in children with malignant tumors failing to mobilize a sufficient number of hematopoietic progenitors with G-CSF. AB - Mobilization of suitable amounts of PBSCs with granulocyte-CSF (G-CSF) can be difficult in children. We report the results of using plerixafor in pediatric patients who failed to mobilize progenitors with G-CSF-based regimens. Thirty three patients, median age 9 years (range 1-18 years) and median weight 29 kg (range 10-85 kg) were enrolled into the study. After 4 days of G-CSF stimulation, the median CD34+ cell count in peripheral blood was 10.4 per MUL (range 0.27-23.0 per MUL). Plerixafor was administered subcutaneously (0.24 MUg/kg in 30 patients and 0.3 MUg/kg in 3 patients) 11-12 h before apheresis. At the time of apheresis, CD34+ cell counts increased to a median of 44.1 per MUL (range 8.4-357.0 per MUL), a median 4.4-fold increase. Two patients (6%) failed to mobilize. Thirty one patients underwent apheresis and in 27 >2 * 10(6) CD34+ cells per kg of body weight were collected after one procedure. In total, 31 of 33 patients mobilized successfully and the median number of cryopreserved CD34+ cells was 5.6 * 10(6) /kg body weight (2.7 * 10(6)-27.4 * 10(6)). Twenty-four patients underwent transplantation. Engraftment was achieved in all but one patient, who died on day +9 after hematopoietic stem cell transplantation. The median time of neutrophil and platelet recovery was day +12 and +16, respectively. Our study confirms that plerixafor has impressive efficacy and very modest toxicity in children. PMID- 25915809 TI - Bortezomib-based induction for transplant ineligible AL amyloidosis and feasibility of later transplantation. AB - Recent studies support the use of bortezomib-based therapies in light chain amyloidosis (AL). We performed a retrospective analysis of the safety, efficacy and long-term survival (median follow-up 3 years) after bortezomib-based treatment in 28 consecutive patients with de novo AL deemed ineligible at initial presentation. The first 14 patients received bortezomib and dexamethasone (VD), and the second 14 patients received cyclophosphamide, bortezomib and dexamethasone (CVD; CyBorD). Both regimens were well tolerated with no treatment related mortality. The overall hematological response (HR) rate was 93% in both the groups. Median time to response was shorter in the CVD group (39 days vs 96 days in the VD group; P=0.002). Hematological and organ responses induced with bortezomib-based therapy enabled 8 (33%) of initially transplant ineligible patients to undergo autologous hematopoietic stem cell transplantation (AHCT), including 4 patients with cardiac stage III or IV. Seven of the eight patients (88%) who underwent subsequent AHCT achieved sustained HR at a median of 33 months posttransplant. These data suggest that bortezomib-based induction followed by AHCT is a viable therapeutic strategy for transplant-ineligible AL. Larger, multicenter prospective trials are necessary to confirm our findings. PMID- 25915810 TI - Efficacy and safety of CDX-301, recombinant human Flt3L, at expanding dendritic cells and hematopoietic stem cells in healthy human volunteers. AB - Fms-like tyrosine kinase-3 ligand (Flt3L) uniquely binds the Flt3 (CD135) receptor expressed on hematopoietic stem cells (HSCs), early progenitor cells, immature thymocytes and steady-state dendritic cells (DCs) and induces their proliferation, differentiation, development and mobilization in the bone marrow, peripheral blood and lymphoid organs. CDX-301 has an identical amino-acid sequence and comparable biological activity to the previously tested rhuFlt3L, which ceased clinical development over a decade ago. This Phase 1 trial assessed the safety, pharmacokinetic, pharmacodynamic and immunologic profile of CDX-301, explored alternate dosing regimens and examined the impact of rhuFlt3L on key immune cell subsets. Thirty healthy volunteers received CDX-301 (1-75 MUg/kg/day) over 5-10 days. One event of Grade 3 community-acquired pneumonia occurred. There were no other infections, dose-limiting toxicities or serious adverse events. CDX 301 resulted in effective peripheral expansion of monocytes, hematopoietic stem and progenitor cells and key subsets of myeloid DCs and plasmacytoid DCs, with no clear effect on regulatory T cells. These data from healthy volunteers support the potential for CDX-301, as monotherapy or in combination with other agents, in various indications including allogeneic HSC transplantation and immunotherapy, but the effects of CDX-301 will need to be investigated in each of these patient populations. PMID- 25915811 TI - Human herpesvirus-6 encephalitis after allogeneic hematopoietic cell transplantation: what we do and do not know. AB - Human herpesvirus-6 (HHV-6) encephalitis following allogeneic hematopoietic cell transplantation is a serious and often fatal complication accompanying reactivation of HHV-6B. Incidence varies among studies, but is reportedly 0-11.6% after bone marrow or PBSC transplantation and 4.9-21.4% after umbilical cord blood transplantation, typically around 2-6 weeks post transplant. Symptoms are characterized by memory loss, loss of consciousness and seizures. Magnetic resonance imaging (MRI) typically shows bilateral signal abnormalities in the limbic system. This complication is considered to represent acute encephalitis caused by direct virally induced damage to the central nervous system, but our understanding of the etiologies and pathogenesis is still limited. The mortality rate attributable to this pathology remains high, and survivors are often left with serious sequelae such as impaired memory and epilepsy. Despite the poor prognosis, no validated treatments or preventative measures have been established. Establishment of preventative strategies represents an important challenge. This article reviews the current knowledge of the clinical features, incidence, pathogenesis and treatment of HHV-6 encephalitis, and discusses issues needing clarification in the future to overcome this serious complication. PMID- 25915813 TI - Stereoselective Syntheses of (+)-2-epi-Deoxoprosopinine, (-)-Deoxoprosophylline, (+)-cis-195A, and 2,5-Di-epi-cis-195A from a Common Chiral Nonracemic Building Block. AB - Approaches toward the syntheses of alkaloids belonging to the 2,6-disubstituted 3 hydroxypiperidine and cis-decahydroquinoline (cis-DHQ) classes of alkaloids are developed, starting from a common chiral nonracemic bicyclic lactam lactone (BLL). Two key delta-lactam intermediates, (5S,6S)-5-hydroxy-6-hydroxymethyl- and (5S,6S)-5-hydroxy-6-methylpiperidin-2-ones, are prepared; the latter delta-lactam is obtained via a direct decarbonylation of a bicyclic lactam lactol. The BLL is also used to prepare (4aR,5R,8aS)- and (4aR,5S,8aS)-5-methyloctahydroquinolin-2 ones, which involved a 6-exo-trig free-radical conjugate addition reaction. The stereoselectivity observed in the free-radical cyclization step is found to be governed by allylic 1,2-strain arising from the interaction of the N-(p methoxybenzyl) group and the C6 substituent in the lactam ring of the free radical intermediate. The effectiveness of the developed approaches is demonstrated by the asymmetric syntheses of (+)-2-epi-deoxoprosopinine, (-) deoxoprosophylline, (+)-cis-195A, and 2,5-di-epi-cis-195A. PMID- 25915814 TI - "We all go a little mad sometimes": the problematic depiction of psychotic and psychopathic disorders in cinema. PMID- 25915812 TI - G-CSF-primed bone marrow as a source of stem cells for allografting: revisiting the concept. AB - The source of hematopoietic stem cells (HSCs) for allogeneic transplantation has evolved over the last decades, from the sole use of unstimulated bone marrow (BM) to the use of G-CSF (filgrastim)-mobilized peripheral blood, G-CSF-primed BM (G BM) and cord blood. G-CSF-mobilized PBSC has replaced BM as the most commonly used source of allogeneic stem cells. G-BM is a source of HSCs, with studies demonstrating the safety and feasibility of this strategy with the potential for reducing GvHD, while retaining the speed of engraftment. Although the G-BM had lost its use as the optimal source of stem cells, after the widespread use of haploidentical transplantation, their use has resurfaced in 2010. This source can still be used in today's world of transplantation in aplastic anemia and other benign diseases, as well as in children donors. This study intends to review the evidence for this approach and whether this approach still has merit in the ever evolving field of allogenic HSC transplantation. The merit of G-BM is its ability to offer speed of engraftment with reduced GvHD. PMID- 25915815 TI - Consumer perspectives on the therapeutic value of a psychiatric environment. AB - BACKGROUND: Existing reports of the environmental aspects of recovery from mental illness have been confined to consideration of community spaces and the natural environment. AIMS: This paper aims to extend this literature by assessing the role of psychiatric settings in recovery. METHODS: Nineteen inpatients from the psychiatric unit of a large inner city hospital in Melbourne, Australia, took part in the study, which involved semi-structured interviews and focus groups. RESULTS: Analysis identified three major themes concerning consumers' experience within the unit: the importance of staff; lack of clear architectural identity resulting in confused or confusing space; and limited amenity due to poor architectural design. CONCLUSIONS: These findings have important implications for the delivery of care in psychiatric environments in ways that promote well being within these settings, and align with relevant mental health policy recommendations. PMID- 25915816 TI - "Work is good for me": views of mental health service users seeking work during the UK recession, a qualitative analysis. AB - BACKGROUND: Individual placement and support (IPS) is an effective form of supported employment for people with severe mental illness. Little is known about service users' experiences of these programmes during economic recession. AIMS: Obtain service users' views of an IPS programme implemented in the UK during recession. METHOD: Thirty-one service users enrolled in an IPS programme were interviewed using a semi-structured protocol. The questions covered several areas of their experience, including problems faced in seeking work, perceived barriers in returning to work and what they found helpful in employment support. RESULTS: Unsurprisingly, a large number of service users had problems in finding work due to the number of appropriate jobs available. Nevertheless, many service users felt positively about the support they had received (90% were satisfied with IPS), and would advise others in their position to seek employment. Personal and practical support from employment specialists (ES) was the most useful aspect of the service. CONCLUSIONS: Despite economic recession, an IPS service was implemented and regarded as satisfactory to service users seeking work. Although many found obtaining employment difficult, they would still advise others that work is worthwhile, suggesting that the context of recession has not discouraged them. PMID- 25915817 TI - Home treatment teams: what should they do? A qualitative study of patient opinions. AB - BACKGROUND: Home treatment teams (HTTs) have limited evidence of altering hospital admissions. There is no consensus on what HTTs "do", and a considerable lack of data on whether they deliver patient-relevant meaningful care. The Royal College of Psychiatrists has recently established the Home Treatment Accreditation Scheme (HTAS) to institute a quality standard for HTTs, though it is unclear whether such accreditation could of itself measure effective care. AIMS: To explore opinions of HTT service users on the care they received to guide future research and service provision. METHOD: Ten ex-HTT patients were interviewed on the care they had received, using thematic analysis of semi structured interviews. RESULTS: Positive aspects of HTT intervention included a rapid, accessible and crisis-focused approach, though changing staff and appointment times were considered unhelpful. Proposals were made for greater psycho-and occupational-therapeutic inputs to manage long-term care, and for provision of peer-support within HTTs. CONCLUSIONS: HTTs were valued but service users' focus was on goals notably different to factors generally assayed by existing research. There is a severe lack of longitudinal clinical and patient centred outcome data. HTAS provides a potential vehicle through which this could be addressed. PMID- 25915818 TI - Postsecondary study and mental ill-health: a meta-synthesis of qualitative research exploring students' lived experiences. AB - BACKGROUND: The postsecondary educational experiences of students living with mental health issues are not well understood. Existing studies are generally qualitative, small and context-specific in nature, and individually have limited influence on policy and practice. AIMS: To identify and synthesise the findings of qualitative studies exploring student views of studying while living with mental ill-health. METHOD: A systematic search of six electronic databases including CINAHL, ERIC, PsycINFO and Medline up to March 2013 was conducted. Findings were extracted from included studies and combined using qualitative meta synthesis to identify core processes. FINDINGS: The search identified 16 studies from five countries, with a total of 231 participants. Meta-synthesis of the findings revealed three common core processes: (1) knowing oneself and managing one's mental illness, (2) negotiating the social space, and (3) doing the academic work required for successful postsecondary participation. CONCLUSION: Beyond the learning processes that underpin studying, these findings suggest knowing oneself and negotiating social spaces of educational settings are key processes for students living with mental ill-health seeking to survive and thrive in postsecondary education. With increased awareness of these processes, students and policy makers may conceive new ways to optimise student experiences of postsecondary study. PMID- 25915822 TI - Nanosheets of earth-abundant jarosite as novel anodes for high-rate and long-life lithium-ion batteries. AB - Nanosheets of earth-abundant jarosite were fabricated via a facile template engaged redox coprecipitation strategy at room temperature and employed as novel anode materials for lithium-ion batteries (LIBs) for the first time. These 2D materials exhibit high capacities, excellent rate capability, and prolonged cycling performance. As for KFe3(SO4)2(OH)6 jarosite nanosheets (KNSs), the reversible capacities of above 1300 mAh g(-1) at 100 mA g(-1) and 620 mAh g(-1) after 4000 cycles at a very high current density of 10 A g(-1) were achieved, respectively. Moreover, the resulting 2D nanomaterials retain good structural integrity upon cycling. These results reveal great potential of jarosite nanosheets as low-cost and high-performance anode materials for next-generation LIBs. PMID- 25915823 TI - Troublesome heterotopic ossification and stroke: Features and risk factors. A case control study. AB - PRIMARY OBJECTIVE: To determine the features of stroke-related HO in a large sample of patients and to assess if HO risk is increased by haemorrhagic stroke. RESEARCH DESIGN: A case control study (risk factor of a rare event using retrospective analysis). METHODS AND PROCEDURES: Sixty-one patients with stroke 81 troublesome HOs-were included, each was matched with four controls, i.e. 244 patients with no HO after stroke. Matching criteria were age (+/-3.5 years) and sex. Data recorded were time from stroke to surgery, ischaemic or haemorrhagic stroke and presence of HO risk factors. MAIN OUTCOMES AND RESULTS: Mean age at time of stroke = 46.02 +/- 11.4 years (15.9-76.3) for the case sub-group. Time from stroke to surgery = 23.4 +/- 27.8 months (3.6-150.0). There was a significant relationship between haemorrhagic stroke and HO development (OR = 3.01; 95% CI = 1.14-7.98; p < 0.05), but not for ischaemic stroke. This became non-significant when all matching and risk factors were included in the model (adjusted OR = 1.98; 95% CI = 0.60-6.54; p = 0.26). CONCLUSION: Haemorrhagic stroke appears to increase the risk of HO development. Further studies are required to determine if this risk factor is independent from other comorbid factors. PMID- 25915824 TI - MicroRNA-124 links p53 to the NF-kappaB pathway in B-cell lymphomas. AB - The contribution of microRNAs to lymphoma biology is not fully understood. In particular, it remains untested whether microRNA dysregulation could contribute to the emergence of the aggressive subset of B-cell lymphomas that coexpress MYC and BCL2. Here, we identify microRNA-124 (miR-124) as a negative regulator of MYC and BCL2 expression in B-cell lymphomas. Concordantly, stable or transient ectopic expression of miR-124 suppressed cell proliferation and survival, whereas genetic inhibition of this miRNA enhanced the fitness of these tumors. Mechanistically, the activities of miR-124 towards MYC and BCL2 intersect with both oncogenic and tumor-suppressive pathways. In respect to the former, we show that miR-124 directly targets nuclear factor-kappaB (NF-kappaB) p65, and using genetic approaches, we demonstrate that this interaction accounts for the miR-124 mediated suppression of MYC and BCL2. We also characterized miR-124 promoter region and identified a functional p53 binding site. In agreement with this finding, endogenous or ectopic expression of wild-type, but not mutant, p53 increased miR-124 levels and suppressed p65, MYC and BCL2. Our data unveil an miRNA-dependent regulatory circuitry that links p53 to the NF-kappaB pathway, which when disrupted in B-cell lymphoma may be associated with aberrant coexpression of MYC and BCL2 and poor prognosis. PMID- 25915826 TI - Evaluation of Barley's Beta-glucan Food Fortification through Investigation of Intestinal Permeability in Healthy Adults. AB - OBJECTIVE: Intestinal permeability is an index of the adequate function of the intestinal barrier and its modification is associated with intestinal diseases. The aim of the study is to investigate the hypothesis that barley's beta-glucan can inhibit the alteration of intestinal permeability and maintain intestinal integrity after a period of consumption of a carbohydrate snack (cake) rich in sugars. METHODS AND DESIGN: Volunteers participated in a placebo-controlled intervention study for 1 month. In this double-blind methodology, they were randomly assigned to (1) the intervention group (daily consumption of one portion of cake fortified with barley's beta-glucan) or (2) the placebo group (daily consumption of the same cake without the enrichment). Intestinal permeability was assessed using the lactulose/mannitol test. SETTING: Athens, Greece. SUBJECTS: Twenty-three healthy volunteers (age > 40 years). RESULTS: Intestinal permeability did not differ between the 2 groups, both at the beginning and at the end of the intervention. In addition, the intestinal permeability was not significantly modified at the end of the intervention in each group. CONCLUSIONS: The results of the lactulose/mannitol test for the intervention and placebo groups were comparable. For healthy adults, the daily consumption of a simple cake (placebo) and the consumption of the cake fortified with barley's beta glucan resulted in similar impact for intestinal permeability; thus, beta-glucans did not exert a protective role in intestinal permeability of healthy adults. PMID- 25915825 TI - Versican upregulation in Sezary cells alters growth, motility and resistance to chemotherapy. AB - Sezary syndrome (SeS) represents a leukemic variant of cutaneous T-cell lymphoma, whose etiology is still unknown. To identify dyregulated genes in SeS, we performed transcriptional profiling of Sezary cells (SCs) obtained from peripheral blood of patients with SeS. We identified versican as the highest upregulated gene in SCs. VCAN is an extracellular matrix proteoglycan, which is known to interfere with different cellular processes in cancer. Versican isoform V1 was the most commonly upregulated isoform in SCs. Using a lentiviral plasmid, we overexpressed versican V1 isoform in lymphoid cell lines, which altered their growth behavior by promoting formation of smaller cell clusters and by increasing their migratory capacity towards stromal cell-derived factor 1, thus promoting skin homing. Versican V1 overexpression exerted an inhibitory effect on cell proliferation, partially by promoting activation-induced cell death. Furthermore, V1 overexpression in lymphoid cell lines increased their sensitivity to doxorubicin and gemcitabine. In conclusion, we confirm versican as one of the dysregulated genes in SeS and describe its effects on the biology of SCs. Although versican overexpression confers lymphoid cells with increased migratory capacity, it also makes them more sensitive to activation-induced cell death and some chemotherapeutics, which could be exploited further for therapeutic purposes. PMID- 25915827 TI - Graphene as an anti-corrosion coating layer. AB - Graphene, a single layer of carbon atoms arranged in an aromatic hexagonal lattice, has recently drawn attention as a potential coating material due to its impermeability, thermodynamic stability, transparency and flexibility. Here, the effectiveness of a model system, a graphene covered Pt(100) surface, for studying the anti-corrosion properties of graphene, has been evaluated. Chemical vapour deposition techniques were used to cover the single crystal surface with a complete layer of high-quality graphene and the surface was characterised after exposure to corrosive environments with scanning tunnelling microscopy (STM) and Raman spectroscopy. Graphene covered Pt samples were exposed to: (i) ambient atmosphere for 6 months at room temperature and 60 degrees C for 75 min, (ii) Milli-Q water for 14 hours at room temperature and 60 degrees C for 75 min, and (iii) saltwater (0.513 M NaCl) for 75 min at room temperature and 60 degrees C. STM provides atomic resolution images, which show that the graphene layer and the underlying surface reconstruction on the Pt(100) surface remain intact over the majority of the surface under all conditions, except exposure to saltwater when the sample is kept at 60 degrees C. Raman spectroscopy shows a broadening of all graphene related peaks due to hybridisation between the surface Pt d-orbitals and the graphene pi-bands. This hybridisation also survives exposure to all environments except saltwater on the hot surface, with the latter leading to peaks more representative of a quasi free-standing graphene layer. A mechanism explaining the corrosive effect of hot saltwater is suggested. Based on these experiments, graphene is proposed to offer protection against corrosion in all tested environments, except saltwater on a hot surface, and Raman spectroscopy is proposed as a useful method for indirectly assessing the chemical state of the Pt surface. PMID- 25915828 TI - Basilar Artery Aneurysm in a Woman With Syphilis. PMID- 25915829 TI - Therapeutic potential of using the vascular disrupting agent OXi4503 to enhance mild temperature thermoradiation. AB - PURPOSE: The response of tissues to radiation with mild temperature hyperthermia is dependent on the interval between the two modalities. This study investigated the effect that the vascular disrupting agent OXi4503 had on this time-interval interaction. METHODS: The normal right rear foot of female CDF1 mice or foot implanted C3H mammary carcinomas were locally irradiated (230 kV X-rays) and heated (41.5 degrees C for 60 min) by foot immersion in a water bath. OXi4503 (50 mg/kg) was injected intraperitoneally 1.5 h before irradiating. Irradiation was performed either in the middle of the heating period (simultaneous treatment) or at 1 or 4 h prior to starting the heating (sequential treatments). Response was the percentage of mice showing local tumour control at 90 days or skin moist desquamation between days 11-23. From the radiation dose response curves the dose producing tumour control (TCD(50)) or moist desquamation (MDD50) in 50% of mice was calculated. RESULTS: The TCD(50) and MDD50 values for radiation alone were 54 Gy and 29 Gy, respectively. Simultaneously heating the tissues enhanced radiation response, the respective TCD(50) and MDD50 values being significantly (chi-square test, p < 0.05) reduced to 33 Gy and 14 Gy. A smaller enhancement was obtained with a sequential treatment in both tissues. OXi4503 enhanced the radiation response of tumour and skin. Combined with radiation and heat, the only effect was in tumours where OXi4503 prevented the decrease in sensitisation seen with the sequential treatment. CONCLUSION: Combining OXi4503 with a sequential radiation and heat treatment resulted in a 1.4-fold therapeutic gain. PMID- 25915830 TI - Tunable quantum interference in a 3D integrated circuit. AB - Integrated photonics promises solutions to questions of stability, complexity, and size in quantum optics. Advances in tunable and non-planar integrated platforms, such as laser-inscribed photonics, continue to bring the realisation of quantum advantages in computation and metrology ever closer, perhaps most easily seen in multi-path interferometry. Here we demonstrate control of two photon interference in a chip-scale 3D multi-path interferometer, showing a reduced periodicity and enhanced visibility compared to single photon measurements. Observed non-classical visibilities are widely tunable, and explained well by theoretical predictions based on classical measurements. With these predictions we extract Fisher information approaching a theoretical maximum. Our results open a path to quantum enhanced phase measurements. PMID- 25915831 TI - The serine protease inhibitor SerpinA3N attenuates neuropathic pain by inhibiting T cell-derived leukocyte elastase. AB - Neuropathic pain is a major, intractable clinical problem and its pathophysiology is not well understood. Although recent gene expression profiling studies have enabled the identification of novel targets for pain therapy, classical study designs provide unclear results owing to the differential expression of hundreds of genes across sham and nerve-injured groups, which can be difficult to validate, particularly with respect to the specificity of pain modulation. To circumvent this, we used two outbred lines of rats, which are genetically similar except for being genetically segregated as a result of selective breeding for differences in neuropathic pain hypersensitivity. SerpinA3N, a serine protease inhibitor, was upregulated in the dorsal root ganglia (DRG) after nerve injury, which was further validated for its mouse homolog. Mice lacking SerpinA3N developed more neuropathic mechanical allodynia than wild-type (WT) mice, and exogenous delivery of SerpinA3N attenuated mechanical allodynia in WT mice. T lymphocytes infiltrate the DRG after nerve injury and release leukocyte elastase (LE), which was inhibited by SerpinA3N derived from DRG neurons. Genetic loss of LE or exogenous application of a LE inhibitor (Sivelastat) in WT mice attenuated neuropathic mechanical allodynia. Overall, we reveal a novel and clinically relevant role for a member of the serpin superfamily and a leukocyte elastase and crosstalk between neurons and T cells in the modulation of neuropathic pain. PMID- 25915832 TI - Photovoltaic restoration of sight with high visual acuity. AB - Patients with retinal degeneration lose sight due to the gradual demise of photoreceptors. Electrical stimulation of surviving retinal neurons provides an alternative route for the delivery of visual information. We demonstrate that subretinal implants with 70-MUm-wide photovoltaic pixels provide highly localized stimulation of retinal neurons in rats. The electrical receptive fields recorded in retinal ganglion cells were similar in size to the natural visual receptive fields. Similarly to normal vision, the retinal response to prosthetic stimulation exhibited flicker fusion at high frequencies, adaptation to static images and nonlinear spatial summation. In rats with retinal degeneration, these photovoltaic arrays elicited retinal responses with a spatial resolution of 64 +/ 11 MUm, corresponding to half of the normal visual acuity in healthy rats. The ease of implantation of these wireless and modular arrays, combined with their high resolution, opens the door to the functional restoration of sight in patients blinded by retinal degeneration. PMID- 25915833 TI - The plant cell inhibitor KRP6 is involved in multinucleation and cytokinesis disruption in giant-feeding cells induced by root-knot nematodes. AB - The plant cell cycle inhibitor gene KRP6 has been investigated in roots infected by plant-parasitic root-knot nematodes (Meloidogyne spp.). Unexpectedly, KRP6 overexpressing lines revealed a distinct role for this specific KRP as an activator of the mitotic cell cycle. This function was confirmed in Arabidopsis thaliana suspension cultures ectopically expressing KRP6. A blockage in the mitotic exit was observed in cell suspensions and in giant cells resulted in the appearance of multi-nucleated cells. KRP6 expression during nematode infection and the similarity in phenotypes among KRP6 overexpressing cell cultures and giant-cell morphology strongly suggest that KRP6 is involved in multinucleation and acytokinesis occurring in giant-cells. Once again nematodes have been shown to manipulate the plant cell cycle machinery in order to promote gall establishment. PMID- 25915834 TI - A Phase 2 Exploratory Study of a Novel Interleukin-1 Receptor Inhibitor (EBI-005) in the Treatment of Moderate-to-Severe Allergic Conjunctivitis. AB - OBJECTIVES: Many allergic conjunctivitis (AC) patients are inadequately treated with conventional therapies or require steroids. EBI-005 was developed to address the late phase allergic response. This study's objectives were to evaluate two adapted clinical models for this indication and to assess safety and biological activity of EBI-005 in AC. METHODS: In this randomized, double-masked, vehicle controlled study, 159 subjects with moderate-to-severe AC were randomized to topical EBI-005 (5 mg/mL) or vehicle control given 3 times per day and repeatedly challenged with allergen using an adaptation of 2 clinical models of AC. Subjects were assigned to repetitive aerosolized challenge in an allergy chamber (Environmental Exposure Chamber, EEC), or repetitive challenges with a direct conjunctival allergen challenge (Conjunctival Allergen Provocation Test, CAPT). RESULTS: In the EEC, the prespecified primary endpoint of ocular itching was not met. In the CAPT, EBI-005-treated subjects showed clinically meaningful, statistically significant improvements in ocular itching compared with vehicle control at the final 2 efficacy time points, visit 6 (P=0.033) and visit 7 (P=0.046). EBI-005-treated subjects showed statistically significant improvement compared with vehicle control for ocular tearing (P=0.027 and P=0.044) and nasal symptoms (P=0.004 and P=0.011) at visit 6 and visit 7. EBI-005 was well tolerated. CONCLUSIONS: These results support use of an adapted, multiple challenge, direct conjunctival allergen model to assess efficacy of EBI-005 in late phase AC. In the CAPT, EBI-005 showed statistically significant improvements in clinically meaningful symptoms (ocular itching, tearing, and nasal symptoms) at multiple time points for moderate-to-severe AC subjects. PMID- 25915836 TI - Drug Use and HIV Infection Status of Detainees in Re-Education through Labour Camps in Guangxi Province, China. AB - This study describes HIV disease burden and patterns of drug use before and during incarceration among detainees in Re-education-Through-Labour-Camps (RTLCs) in China. A cross-sectional survey of 576 men and 179 women from three RTLCs was conducted in Guangxi Province, China. Over three-quarters of study participants were detained due to drug-related offences. Over half of the women (n = 313, 54.3%) and two-thirds of men (n = 119, 66.5%) had been previously been incarcerated in a compulsory detoxification treatment centre (CDTC), and around one-third (men n = 159, 27.6%; women n = 50, 27.9%) in a RTLC. Of those surveyed, 49 men (8.5%) and one (0.6%) woman reported ever using drugs while in a CDTC and/or RTLC. Previous incarceration in CDTCs and RTLCs were associated with HIV infection among both male (OR = 2.15 [1.11-4.15]) and female (OR = 3.87 [1.86 9.04]) detainees. Being married/cohabiting with a partner (OR = 0.53, [0.30 0.93]) and being employed (OR = 0.46, [0.22-0.95]) were associated with a reduced odds of HIV infection among male detainees. A significant proportion of RTLC detainees had a history of drug use and a limited number of inmates had used illegal substances whilst in custody. Repeat incarcerations in CDTCs/RTLCs were associated with higher risks of HIV infection. PMID- 25915835 TI - Concentration of lead, mercury, cadmium, aluminum, arsenic and manganese in umbilical cord blood of Jamaican newborns. AB - The objective of this study was to characterize the concentrations of lead, mercury, cadmium, aluminum, and manganese in umbilical cord blood of Jamaican newborns and to explore the possible association between concentrations of these elements and certain birth outcomes. Based on data from 100 pregnant mothers and their 100 newborns who were enrolled from Jamaica in 2011, the arithmetic mean (standard deviation) concentrations of cord blood lead, mercury, aluminum, and manganese were 0.8 (1.3 MUg/dL), 4.4 (2.4 MUg/L), 10.9 (9.2 MUg/L), and 43.7 (17.7 MUg/L), respectively. In univariable General Linear Models, the geometric mean cord blood aluminum concentration was higher for children whose mothers had completed their education up to high school compared to those whose mothers had any education beyond high school (12.2 MUg/L vs. 6.4 MUg/L; p < 0.01). After controlling for maternal education level and socio-economic status (through ownership of a family car), the cord blood lead concentration was significantly associated with head circumference (adjusted p < 0.01). Our results not only provide levels of arsenic and the aforementioned metals in cord blood that could serve as a reference for the Jamaican population, but also replicate previously reported significant associations between cord blood lead concentrations and head circumference at birth in other populations. PMID- 25915837 TI - ICRP Publication 125: Radiological Protection in Security Screening. AB - The use of technologies to provide security screening for individuals and objects has been increasing rapidly, in keeping with the significant increase in security concerns worldwide. Within the spectrum of technologies, the use of ionizing radiation to provide backscatter and transmission screening capabilities has also increased. The Commission has previously made a number of statements related to the general topic of deliberate exposures of individuals in non-medical settings. This report provides advice on how the radiological protection principles recommended by the Commission should be applied within the context of security screening. More specifically, the principles of justification, optimisation of protection, and dose limitation for planned exposure situations are directly applicable to the use of ionising radiation in security screening. In addition, several specific topics are considered in this report, including the situation in which individuals may be exposed because they are concealed ('stowaways') in a cargo container or conveyance that may be subject to screening. The Commission continues to recommend that careful justification of screening should be considered before decisions are made to employ the technology. If a decision is made that its use is justified, the framework for protection as a planned exposure situation should be employed, including optimization of protection with the use of dose constraints and the appropriate provisions for authorisation and inspection. PMID- 25915840 TI - HUS1 regulates in vivo responses to genotoxic chemotherapies. AB - Cells are under constant attack from genotoxins and rely on a multifaceted DNA damage response (DDR) network to maintain genomic integrity. Central to the DDR are the ATM and ATR kinases, which respond primarily to double-strand DNA breaks (DSBs) and replication stress, respectively. Optimal ATR signaling requires the RAD9A-RAD1-HUS1 (9-1-1) complex, a toroidal clamp that is loaded at damage sites and scaffolds signaling and repair factors. Whereas complete ATR pathway inactivation causes embryonic lethality, partial Hus1 impairment has been accomplished in adult mice using hypomorphic (Hus1(neo)) and null (Hus1(Delta1)) Hus1 alleles, and here we use this system to define the tissue- and cell type specific actions of the HUS1-mediated DDR in vivo. Hus1(neo/Delta1) mice showed hypersensitivity to agents that cause replication stress, including the crosslinking agent mitomycin C (MMC) and the replication inhibitor hydroxyurea, but not the DSB inducer ionizing radiation. Analysis of tissue morphology, genomic instability, cell proliferation and apoptosis revealed that MMC treatment caused severe damage in highly replicating tissues of mice with partial Hus1 inactivation. The role of the 9-1-1 complex in responding to MMC was partially ATR-independent, as a HUS1 mutant that was proficient for ATR-induced checkpoint kinase 1 phosphorylation nevertheless conferred MMC hypersensitivity. To assess the interplay between the ATM and ATR pathways in responding to replication stress in vivo, we used Hus1/Atm double mutant mice. Whereas Hus1(neo/neo) and Atm(-/-) single mutant mice survived low-dose MMC similar to wild-type controls, Hus1(neo/neo)Atm(-/-) double mutants showed striking MMC hypersensitivity, consistent with a model in which MMC exposure in the context of Hus1 dysfunction results in DSBs to which the ATM pathway normally responds. This improved understanding of the inter-dependency between two major DDR mechanisms during the response to a conventional chemotherapeutic illustrates how inhibition of checkpoint factors such as HUS1 may be effective for the treatment of ATM deficient and other cancers. PMID- 25915841 TI - A tumor deconstruction platform identifies definitive end points in the evaluation of drug responses. AB - Tumor heterogeneity and the presence of drug-sensitive and refractory populations within the same tumor are almost never assessed in the drug discovery pipeline. Such incomplete assessment of drugs arising from spatial and temporal tumor cell heterogeneity reflects on their failure in the clinic and considerable wasted costs in the drug discovery pipeline. Here we report the derivation of a flow cytometry-based tumor deconstruction platform for resolution of at least 18 discrete tumor cell fractions. This is achieved through concurrent identification, quantification and analysis of components of cancer stem cell hierarchies, genetically instable clones and differentially cycling populations within a tumor. We also demonstrate such resolution of the tumor cytotype to be a potential value addition in drug screening through definitive cell target identification. Additionally, this real-time definition of intra-tumor heterogeneity provides a convenient, incisive and analytical tool for predicting drug efficacies through profiling perturbations within discrete tumor cell subsets in response to different drugs and candidates. Consequently, possible applications in informed therapeutic monitoring and drug repositioning in personalized cancer therapy would complement rational design of new candidates besides achieving a re-evaluation of existing drugs to derive non-obvious combinations that hold better chances of achieving remission. PMID- 25915839 TI - The oncogene ERG: a key factor in prostate cancer. AB - ETS-related gene (ERG) is a member of the E-26 transformation-specific (ETS) family of transcription factors with roles in development that include vasculogenesis, angiogenesis, haematopoiesis and bone development. ERG's oncogenic potential is well known because of its involvement in Ewing's sarcoma and leukaemia. However, in the past decade ERG has become highly associated with prostate cancer development, particularly as a result of a gene fusion with the promoter region of the androgen-induced TMPRRSS2 gene. We review ERG's structure and function, and its role in prostate cancer. We discuss potential new therapies that are based on targeting ERG. PMID- 25915842 TI - Sirtuin 3 inhibits hepatocellular carcinoma growth through the glycogen synthase kinase-3beta/BCL2-associated X protein-dependent apoptotic pathway. AB - SIRT3 is a class III histone deacetylase that has been implicated in a variety of cancers. The role of SIRT3 in hepatocellular carcinoma (HCC) remains elusive. In this study, we found that SIRT3 expression was frequently repressed in HCC and its downregulation was closely associated with tumor grade and size. Ectopic expression of SIRT3 inhibited cell growth and induced apoptosis in HCC cells, whereas depletion of SIRT3 in immortalized hepatocyte promoted cell growth and decreased epirubicin-induced apoptosis. Mechanistic studies revealed that SIRT3 deacetylated and activated glycogen synthase kinase-3beta (GSK-3beta), which subsequently induced expression and mitochondrial translocation of the pro apoptotic protein BCL2-associated X protein (Bax) to promote apoptosis. GSK-3beta inhibitor or gene silencing of BAX reversed SIRT3-induced growth inhibition and apoptosis. Furthermore, SIRT3 overexpression also suppressed tumor growth in vivo. Together, this study reveals a role of SIRT3/GSK-3beta/Bax signaling pathway in the suppression of HCC growth, and also suggests that targeting this pathway may represent a potential therapeutic approach for HCC treatment. PMID- 25915843 TI - An antibody to amphiregulin, an abundant growth factor in patients' fluids, inhibits ovarian tumors. AB - Growth factors of the epidermal growth factor (EGF)/neuregulin family are involved in tumor progression and, accordingly, antibodies that intercept a cognate receptor, epidermal growth factor receptor (EGFR)/ERBB1, or a co receptor, HER2, have been approved for cancer therapy. Although they might improve safety and delay onset of chemoresistance, no anti-ligand antibodies have been clinically approved. To identify suitable ligands, we surveyed fluids from ovarian and lung cancer patients and found that amphiregulin (AREG) is the most abundant and generalized ligand secreted by advanced tumors. AREG is a low affinity EGFR ligand, which is upregulated following treatment with chemotherapeutic drugs. Because AREG depletion retarded growth of xenografted ovarian tumors in mice, we generated a neutralizing monoclonal anti-AREG antibody. The antibody inhibited growth of ovarian cancer xenografts and strongly enhanced chemotherapy efficacy. Taken together, these results raise the possibility that AREG and other low- or high-affinity binders of EGFR might serve as potential targets for cancer therapy. PMID- 25915844 TI - Beyond cytokinesis: the emerging roles of CEP55 in tumorigenesis. AB - CEP55 was initially identified as a pivotal component of abscission, the final stage of cytokinesis, serving to regulate the physical separation of two daughter cells. Over the past 10 years, several studies have illuminated additional roles for CEP55 including regulating the PI3K/AKT pathway and midbody fate. Concurrently, CEP55 has been studied in the context of cancers including those of the breast, lung, colon and liver. CEP55 overexpression has been found to significantly correlate with tumor stage, aggressiveness, metastasis and poor prognosis across multiple tumor types and therefore has been included as part of several prognostic 'gene signatures' for cancer. Here by discussing in depth the functions of CEP55 across different effector pathways, and also its roles as a biomarker and driver of tumorigenesis, we assemble an exhaustive review, thus commemorating a decade of research on CEP55. PMID- 25915846 TI - Mutant versions of von Hippel-Lindau (VHL) can protect HIF1alpha from SART1 mediated degradation in clear-cell renal cell carcinoma. AB - Inactivation of the von Hippel-Lindau (VHL) tumor suppressor drives the development of clear-cell renal cell carcinoma (ccRCC) through hypoxia-inducible factors (HIFs). Although ccRCC cells exhibit constitutive normoxic HIF signaling, the potential role of hypoxia in this setting is not fully understood. We show here that the ccRCC cell lines RCC4 and RCC10, which express mutant versions of VHL, have reduced HIF1alpha expression in hypoxia, whereas HIF2alpha expression is increased or not affected. Similar findings were observed in normoxia after abrogation of prolyl hydroxylase activity by siRNA or pharmacological inhibition, and by siRNA inhibition of mutant VHL. This reduction of HIF1alpha protein is due to proteasome-dependent degradation and is mediated by the E3 ubiquitin ligase SART1. HIF1alpha degradation favors ccRCC proliferation, in line with the previously recognized tumor suppressor capability of HIF1alpha. Our data indicate that mutant VHL can protect HIF1alpha from SART1-dependent degradation in normoxic conditions, but this protection is lost in hypoxic settings, favoring hypoxia-dependent ccRCC proliferation. This mechanism of HIF1alpha degradation might operate in some VHL-related clear-cell renal carcinomas in which the deletion of HIF1alpha locus does not occur. PMID- 25915845 TI - The role of Plk3 in oncogenesis. AB - The polo-like kinases (Plks) encompass a family of five serine/threonine protein kinases that play essential roles in many cellular processes involved in the control of the cell cycle, including entry into mitosis, DNA replication and the response to different types of stress. Plk1, which has been validated as a cancer target, came into the focus of many pharmaceutical companies for the development of small-molecule inhibitors as anticancer agents. Recently, FDA (Food and Drug Administration) has granted a breakthrough therapy designation to the Plk inhibitor BI 6727 (volasertib), which provided a survival benefit for patients suffering from acute myeloid leukemia. However, the various ATP-competitive inhibitors of Plk1 that are currently in clinical development also inhibit the activities of Plk2 and Plk3, which are considered as tumor suppressors. Plk3 contributes to the control and progression of the cell cycle while acting as a mediator of apoptosis and various types of cellular stress. The aberrant expression of Plk3 was found in different types of tumors. Recent progress has improved our understanding of Plk3 in regulating stress signaling and tumorigenesis. When using ATP-competitive Plk1 inhibitors, the biological roles of Plk1-related family members like Plk3 in cancer cells need to be considered carefully to improve treatment strategies against cancer. PMID- 25915847 TI - Induction of the intestinal stem cell signature gene SMOC-2 is required for L1 mediated colon cancer progression. AB - Overactivation of Wnt-beta-catenin signaling, including beta-catenin-TCF target gene expression, is a hallmark of colorectal cancer (CRC) development. We identified the immunoglobulin family of cell-adhesion receptors member L1 as a beta-catenin-TCF target gene preferentially expressed at the invasive edge of human CRC tissue. L1 can confer enhanced motility and liver metastasis when expressed in CRC cells. This ability of L1-mediated metastasis is exerted by a mechanism involving ezrin and the activation of NF-kappaB target genes. In this study, we identified the secreted modular calcium-binding matricellular protein-2 (SMOC-2) as a gene activated by L1-ezrin-NF-kappaB signaling. SMOC-2 is also known as an intestinal stem cell signature gene in mice expressing Lgr5 in cells at the bottom of intestinal crypts. The induction of SMOC-2 expression in L1 expressing CRC cells was necessary for the increase in cell motility, proliferation under stress and liver metastasis conferred by L1. SMOC-2 expression induced a more mesenchymal like phenotype in CRC cells, a decrease in E-cadherin and an increase in Snail by signaling that involves integrin-linked kinase (ILK). SMOC-2 was localized at the bottom of normal human colonic crypts and at increased levels in CRC tissue with preferential expression in invasive areas of the tumor. We found an increase in Lgr5 levels in CRC cells overexpressing L1, p65 or SMOC-2, suggesting that L1-mediated CRC progression involves the acquisition of a stem cell-like phenotype, and that SMOC-2 elevation is necessary for L1-mediated induction of more aggressive/invasive CRC properties. PMID- 25915848 TI - Paxillin confers resistance to tyrosine kinase inhibitors in EGFR-mutant lung cancers via modulating BIM and Mcl-1 protein stability. AB - Tyrosine kinase inhibitors (TKIs) have been documented to have substantial clinical benefits to non-small cell lung cancer with epidermal growth factor receptor (EGFR) mutation. TKI resistance occurs in nearly all patients who receive TKI-targeting therapy, resulting in a modest overall survival benefit. Therefore, establishing a biomarker for early prediction and exploring the mechanism of primary TKI resistance is essential for improving the therapeutic efficacy in non-small cell lung cancer patients. In this study, we provide evidence indicating that paxillin (PXN) overexpression may confer TKI resistance in EGFR-mutant lung cancer cells. Mechanistically, PXN-mediated extracellular signal-regulated kinases (ERK) activation is responsible for TKI resistance via decreased Bcl2-interacting mediator of cell death (BIM) and increased Mcl-1 expression due to modulating their protein stabilities by phosphorylation of BIM at serine 69 and Mcl-1 at threonine 163. The mechanistic action in the cell model was further confirmed by the observation of xenograft tumors in nude mice, revealing that the PXN-mediated TKI resistance was conquered by ERK inhibitor (AZD6244) and Bcl-2 family inhibitor (obatoclax), but the TKI resistance overcome by AZD6244 is more effective than that of obatoclax. Therefore, we suggest that PXN expression may be useful in predicting primary TKI resistance, and combining TKI with ERK inhibitors may clinically benefit EGFR-mutant non-small cell lung cancer patients whose tumors exhibit high PXN expression. PMID- 25915849 TI - Mdm2 overexpression and p73 loss exacerbate genomic instability and dampen apoptosis, resulting in B-cell lymphoma. AB - Many human tumors express high levels of the p53 inhibitor Mdm2, resulting from amplification of the Mdm2 locus or aberrant post-translational regulation of the Mdm2 protein. While the importance of Mdm2 in regulating p53 is clear, Mdm2 also has p53-independent roles. For example, overexpression of Mdm2 results in genomic instability in a p53-independent manner. In addition, Mdm2 has many additional binding partners, some of which, such as the tumor suppressor p73, have also been implicated in genomic instability. In this study, cells and tumors with Mdm2 overexpression and p73 loss exhibit increased genomic instability as compared with either alteration alone and cooperate in development of B-cell lymphomagenesis. Cytogenetic analysis of mouse embryonic fibroblasts and pre malignant B cells demonstrates that loss of p73 exacerbates the chromosome breaks and fusions observed in Mdm2(Tg) cells. B-cell lymphomas from Mdm2(Tg);p73(+/-) mice retain the remaining p73 allele, exhibit elevated levels of the antiapoptotic protein Bcl2 and thus dampen apoptosis. In summary, Mdm2 overexpression and p73 loss cooperate in genomic instability and tumor development, indicating that the oncogenic function of Mdm2 is a combined effect of inhibiting p53 and p73 functions. Given that p73 is lost or silenced in human B-cell lymphomas, the Mdm2(Tg);p73(+/-) mouse serves as a model for human disease and may provide additional insight into the pathways that contribute to B-cell lymphomagenesis. PMID- 25915850 TI - ELAS1-mediated inhibition of the cyclin G1-B'gamma interaction promotes cancer cell apoptosis via stabilization and activation of p53. AB - Radiation therapy (RT) is useful for selectively killing cancer cells. However, because high levels of ionizing radiation (IR) are toxic to normal cells, RT cannot be applied repeatedly to cancer patients. Therefore, novel chemicals that enhance the efficacy of chemoradiotherapy (CRT) would be valuable. Here, we report that ELAS1, a peptide corresponding to the protein phosphatase 2A (PP2A) association domain of cyclin G1 (CycG1), can enhance the efficacy of CRT. ELAS1 interacts with the PP2A B'gamma-subunit and competitively inhibits association with CycG1, thereby preventing the PP2A holoenzyme from dephosphorylating target proteins, Mdm2 (pT218) and p53 (pS46), following DNA double-strand break (DSB) insults. Doxycycline (Dox)-induced overexpression of Myc-ELAS1 caused gamma irradiation to induce apoptosis in human osteosarcoma (U2OS) cells, at 1/10th the effective dosage of gamma-irradiation required for apoptosis in Myc-vector expressing cells; ELAS1 peptide incorporation into U2OS cells also showed similar apoptotic effects. Moreover, administration of DSB-inducing chemicals, camptothecin (CPT) or irinotecan, to Myc-ELAS1-expressing U2OS cells also induced efficient apoptosis with only 1/100th (CPT) or 1/5th (irinotecan) of the amounts of drugs required for this effect in Myc-vector-expressing cells. Taken together, ELAS1 may be important for the design of ELAS1-mimetic compounds to improve CRT efficacy. PMID- 25915852 TI - Ultratrace Detection of Nitroaromatics: Picric Acid Responsive Aggregation/Disaggregation of Self-Assembled p-Terphenylbenzimidazolium-Based Molecular Baskets. AB - 1-(p-Terphenyl)-benzimidazolium (TRIPOD-TP) molecules undergo self-assembly to form rodlike structures in aqueous medium, as shown by field-emission scanning electron microscopy, transmission electron microscopy, and dynamic light scattering studies. Upon gradual addition of picric acid (PA), these aggregates undergo an aggregation/disaggregation process to complex morphological structures (10(-12)-10(-10) M PA) and spherical aggregates (10(-9)-10(-8) M PA). These spherical aggregates undergo further dissolution to well-dispersed spheres between 10(-7)-10(-6) M PA. During fluorescence studies, these aggregates demonstrate superamplified fluorescence quenching (>97%) in the presence of 10( 5) to 0.2 equiv of the probe concentration, an unprecedented process with PA. The lowest detection limits by solution of TRIPOD-TP are 5 * 10(-13) PA, 50 * 10(-12) M 2,4-dinitrophenol, 200 * 10(-12) M 2,4,6-trinitrotoluene, and 1 nM 1-chloro-2,4 dinitrobenzene. Paper strips dipped in the solution of TRIPOD-TP demonstrate quantitative fluorescence quenching between 10(-17) and 10(-6) M PA using front surface steady state studies and can measure as low as 2.29 * 10(-20) g/cm(2) PA. PMID- 25915851 TI - Metabolomic profiling in liver of adiponectin-knockout mice uncovers lysophospholipid metabolism as an important target of adiponectin action. AB - Adiponectin mediates anti-diabetic effects via increasing hepatic insulin sensitivity and direct metabolic effects. In the present study, we conducted a comprehensive and unbiased metabolomic profiling of liver tissue from AdKO (adiponectin-knockout) mice, with and without adiponectin supplementation, fed on an HFD (high-fat diet) to derive insight into the mechanisms and consequences of insulin resistance. Hepatic lipid accumulation and insulin resistance induced by the HFD were reduced by adiponectin. The HFD significantly altered levels of 147 metabolites, and bioinformatic analysis indicated that one of the most striking changes was the profile of increased lysophospholipids. These changes were largely corrected by adiponectin, at least in part via direct regulation of PLA2 (phospholipase A2) as palmitate-induced PLA2 activation was attenuated by adiponectin in primary hepatocytes. Notable decreases in several glycerolipids after the HFD were reversed by adiponectin, which also corrected elevations in several diacyglycerol and ceramide species. Our data also indicate that stimulation of omega-oxidation of fatty acids by the HFD is enhanced by adiponectin. In conclusion, this metabolomic profiling approach in AdKO mice identified important targets of adiponectin action, including PLA2, to regulate lysophospholipid metabolism and omega-oxidation of fatty acids. PMID- 25915853 TI - Suicidal drownings with psychiatric disorders in Shanghai: a retrospective study from 2010.1 to 2014.6. AB - Psychiatric disorders exhibited in 13% suicidal drownings in Southwestern Croatia and 63% in Milan, but in China is unknown. This study is committed to outline the feature of a suicidal drowning with psychiatric disorder, show mental status and reveal key factor to high incidence in China. Immersed corpses were handled by SPSBMPH in its jurisdiction range. Half of immersed corpses were suicidal, and nearly half of suicides had psychiatric disorders. 104 suicidal drownings with psychiatric disorders cases from 2010.1 to 2014.6 were reviewed (21.5% of all immersed corpses, 42.1% of suicides). Most victims clothed normally, and only 2 fastened attached weights. Male victims were more and younger than female. Psycho were prone to commit suicidal drowning in warm and hot season. Psycho were prone to choose familiar area to commit suicide, 45 decedents were found in their familiar areas. Suicidal drowings were occult without suicide attempts, suicide note or abnormal clothing, but showed abnormal mental or behavior changes prior to suicide. The three leading psychiatric disorders were depression (33.7%), depression status (30.8%) and schizophrenia (20.2%). Only 44.2% decedents had visited psychiatric disorder specialist, and merely less than 10% patients could adhere to regular medication. No regular medication on psychiatric disorder was the key factor contributing to high incidence of suicide in psycho. Professional psychiatric and psychological intervention should be taken as soon as possible when they had psychiatric symptoms or suffered misfortune. Guardians should be alert to patients' abnormality to detect their suicidal ideation and intervene, especially in warm season. PMID- 25915854 TI - Simulating carbon stocks and fluxes of an African tropical montane forest with an individual-based forest model. AB - Tropical forests are carbon-dense and highly productive ecosystems. Consequently, they play an important role in the global carbon cycle. In the present study we used an individual-based forest model (FORMIND) to analyze the carbon balances of a tropical forest. The main processes of this model are tree growth, mortality, regeneration, and competition. Model parameters were calibrated using forest inventory data from a tropical forest at Mt. Kilimanjaro. The simulation results showed that the model successfully reproduces important characteristics of tropical forests (aboveground biomass, stem size distribution and leaf area index). The estimated aboveground biomass (385 t/ha) is comparable to biomass values in the Amazon and other tropical forests in Africa. The simulated forest reveals a gross primary production of 24 tcha(-1) yr(-1). Modeling above- and belowground carbon stocks, we analyzed the carbon balance of the investigated tropical forest. The simulated carbon balance of this old-growth forest is zero on average. This study provides an example of how forest models can be used in combination with forest inventory data to investigate forest structure and local carbon balances. PMID- 25915855 TI - Cardiovascular disease after Hodgkin lymphoma treatment: 40-year disease risk. AB - IMPORTANCE: Hodgkin lymphoma (HL) survivors are at increased risk of cardiovascular diseases. It is unclear, however, how long the increased risk persists and what the risk factors are for various cardiovascular diseases. OBJECTIVES: To examine relative and absolute excess risk up to 40 years since HL treatment compared with cardiovascular disease incidence in the general population and to study treatment-related risk factors for different cardiovascular diseases. DESIGN, SETTING, AND PARTICIPANTS: This retrospective cohort study included 2524 Dutch patients diagnosed as having HL at younger than 51 years (median age, 27.3 years) who had been treated from January 1, 1965, through December 31, 1995, and had survived for 5 years since their diagnosis. EXPOSURES: Treatment for HL, including prescribed mediastinal radiotherapy dose and anthracycline dose. MAIN OUTCOMES AND MEASURES: Data were collected from medical records and general practitioners. Cardiovascular events, including coronary heart disease (CHD), valvular heart disease (VHD), and cardiomyopathy and congestive heart failure (HF), were graded according to the Common Terminology Criteria for Adverse Events, version 4.0. RESULTS: After a median follow-up of 20 years, we identified 1713 cardiovascular events in 797 patients. After 35 years or more, patients still had a 4- to 6-fold increased standardized incidence ratio of CHD or HF compared with the general population, corresponding to 857 excess events per 10,000 person-years. Highest relative risks were seen in patients treated before 25 years of age, but substantial absolute excess risks were also observed for patients treated at older ages. Within the cohort, the 40 year cumulative incidence of cardiovascular diseases was 50% (95% CI, 47%-52%). Fifty-one percent of patients with a cardiovascular disease developed multiple events. For patients treated before 25 years of age, cumulative incidences at 60 years or older were 20%, 31%, and 11% for CHD, VHD, and HF as first events, respectively. Mediastinal radiotherapy increased the risks of CHD (hazard ratio [HR], 2.7; 95% CI, 2.0-3.7), VHD (HR, 6.6; 95% CI, 4.0-10.8), and HF (HR, 2.7; 95% CI, 1.6-4.8), and anthracycline-containing chemotherapy increased the risks of VHD (HR, 1.5; 95% CI, 1.1-2.1) and HF (HR, 3.0; 95% CI, 1.9-4.7) as first events compared with patients not treated with mediastinal radiotherapy or anthracyclines, respectively. Joint effects of mediastinal radiotherapy, anthracyclines, and smoking appeared to be additive. CONCLUSIONS AND RELEVANCE: Throughout their lives, HL survivors treated at adolescence or adulthood are at high risk for various cardiovascular diseases. Physicians and patients should be aware of this persistently increased risk. PMID- 25915856 TI - Synthesis and structure of rhodium(i) silyl carbonyl complexes: photochemical C-F and C-H bond activation of fluorinated aromatic compounds. AB - The rhodium(i) silyl carbonyl complexes [Rh{Si(OEt)3}(CO)(dippp)] () and [Rh{Si(OEt)3}(CO)(dippe)] () (dippp = 1,3-bis(diisopropylphosphino)propane, dippe = 1,2-bis-(diisopropylphosphino)ethane) were synthesized on treatment of the methyl compounds [Rh(CH3)(CO)(dippp)] () or [Rh(CH3)(CO)(dippe)] () with HSi(OEt)3 at low temperature. The methyl complexes and were prepared starting from the binuclear complexes [{Rh(MU-Cl)(dippp)}2] () and [{Rh(MU-Cl)(dippe)}2] (), respectively. The silyl complexes and as well as the precursors [{Rh(MU I)(dippp)}2] (), [Rh(X)(CO)(dippp)] (: X = CH3, : X = I) and [Rh(X)(CO)(dippe)] (: X = CH3, : X = Cl) were characterized by NMR and IR spectroscopy and the structures in the solid state were determined by X-ray crystallography. The silyl complex converts into the carbonyl-bridged complex [{Rh(MU-CO)(dippp)}2] () above temperatures of -30 degrees C by loss of the silyl ligand, whereas is more thermally stable and a reaction to the binuclear complex [{Rh(MU-CO)(dippe)}2] () was observed at 50 degrees C. The silyl complex reacted under irradiation with hexafluorobenzene and pentafluoropyridine to give the C-F activation products [Rh(C6F5)(CO)(dippe)] () and [Rh(2-C5F4N)(CO)(dippe)] (), respectively. As additional products the silyl dicarbonyl complex [Rh{Si(OEt)3}(CO)2(dippe)] () and the cationic complex [Rh2(MU-H)(MU-CO)2(dippe)2](+)[SiF5](-) () were identified. Compound was synthesized independently by treatment of with gaseous CO. In a similar manner, the dippp analogue [Rh{Si(OEt)3}(CO)2(dippp)] () was also prepared starting from . Photochemical reaction of with pentafluorobenzene and 2,3,5,6-tetrafluoropyridine resulted selectively in C-H bond activation to afford and [Rh(4-C5F4N)(CO)(dippe)] (), respectively. PMID- 25915858 TI - Correction: 18F-Mefway PET Imaging of Serotonin 1A Receptors in Humans: A Comparison with 18F-FCWAY. PMID- 25915859 TI - Global Tuberculosis Control: Toward the 2015 Targets and Beyond. AB - Since 1990, progress has been made toward global tuberculosis (TB) control, as measured by targets set for 2015. However, TB remains a major threat to health around the world. In 2013, there were an estimated 11 million prevalent cases, and an estimated 9.0 million incident cases occurred globally. Approximately 1.5 million deaths were caused by TB, including 360,000 among people living with HIV. Substantial challenges threaten future control efforts. These include multidrug resistant forms and co-infection with HIV, as well as other factors, such as the increased prominence of noncommunicable diseases and adverse socioeconomic conditions. Beyond 2015, TB control must be seen as both a public health imperative unto itself and a vital component of economic development plans. To that end, control strategies should exploit technical and operational innovations to improve TB control and care and should promote universal health coverage and social protection mechanisms to expand access to essential prevention, diagnostics, and treatment services while avoiding catastrophic costs incurred by patients. PMID- 25915857 TI - Conjugated Linoleic Acid Supplementation under a High-Fat Diet Modulates Stomach Protein Expression and Intestinal Microbiota in Adult Mice. AB - The gastrointestinal tract constitutes a physiological interface integrating nutrient and microbiota-host metabolism. Conjugated linoleic acids (CLA) have been reported to contribute to decreased body weight and fat accretion. The modulation by dietary CLA of stomach proteins related to energy homeostasis or microbiota may be involved, although this has not been previously analysed. This is examined in the present study, which aims to underline the potential mechanisms of CLA which contribute to body weight regulation. Adult mice were fed either a normal fat (NF, 12% kJ content as fat) or a high-fat (HF, 43% kJ content as fat) diet. In the latter case, half of the animals received daily oral supplementation of CLA. Expression and content of stomach proteins and specific bacterial populations from caecum were analysed. CLA supplementation was associated with an increase in stomach protein expression, and exerted a prebiotic action on both Bacteroidetes/Prevotella and Akkermansia muciniphila. However, CLA supplementation was not able to override the negative effects of HF diet on Bifidobacterium spp., which was decreased in both HF and HF+CLA groups. Our data show that CLA are able to modulate stomach protein expression and exert a prebiotic effect on specific gut bacterial species. PMID- 25915860 TI - 12-O-Tetradecanoylphorbol-13-Acetate Induces Up-Regulated Transcription of Variant 1 but Not Variant 2 of VIL2 in Esophageal Squamous Cell Carcinoma Cells via ERK1/2/AP-1/Sp1 Signaling. AB - The membrane-cytoskeleton link organizer ezrin may be the most "dramatic" tumor marker, being strongly over-expressed in nearly one-third of human malignancies. However, the molecular mechanisms of aberrant ezrin expression still need to be clarified. Ezrin, encoded by the VIL2 gene, has two transcript variants that differ in the transcriptional start site (TSS): V1 and V2. Both V1 and V2 encode the same protein. Here, we found that 12-O-tetradecanoylphorbol-13-acetate (TPA) induced over-expression of human VIL2 in esophageal squamous cell carcinoma (ESCC) cells. Furthermore, VIL2 V1 but not V2 was up-regulated after TPA stimulation in a time-dependent manner. AP-1 and Sp1 binding sites within the promoter region of VIL2 V1 acted not only as basal transcriptional elements but also as a composite TPA-responsive element (TRE) for the transcription of VIL2 V1. TPA stimulation enhanced c-Jun and Sp1 binding to the TRE via activation of the ERK1/2 pathway and increased protein levels of c-Jun, c-Fos, and Sp1, resulting in over-expression of VIL2 V1, whereas the MEK1/2 inhibitor U0126 blocked these events. Finally, we showed that TPA promoted the migration of ESCC cells whereas MEK1/2 inhibitor or ezrin silencing could partially inverse this alteration. Taken together, these results suggest that TPA is able to induce VIL2 V1 over-expression in ESCC cells by activating MEK/ERK1/2 signaling and increasing binding of Sp1 and c-Jun to the TRE of the VIL2 V1 promoter, and that VIL2 is an important TPA-induced effector. PMID- 25915862 TI - The Natural Variation of Seed Weight Is Mainly Controlled by Maternal Genotype in Rapeseed (Brassica napus L.). AB - Seed weight is a very important and complex trait in rapeseed (Brassica napus L.). The seed weight of rapeseed shows great variation in its natural germplasm resources; however, the morphological, cytological and genetic causes of this variation have remained unclear. In the present study, nine highly pure inbred rapeseed lines with large seed weight variation and different genetic backgrounds were selected for morphological, cytological and genetic studies on seed weight. The results showed the following: (1) Seed weight showed an extremely significant correlation and coordinated variation with seed size (including seed diameter, seed surface area and seed volume), but it showed no significant correlation with bulk density, which suggests that seed weight is determined by size rather than bulk density. (2) Seed weight showed a higher correlation with the cell numbers of seed coats and cotyledons than the cell sizes of seed coats and cotyledons, which suggests that cell number is more tightly correlated with final seed weight. (3) Seed weight was mainly controlled by the maternal genotype, with little or no xenia and cytoplasmic effects. This is the first report on the morphological and cytological causes of seed weight natural variation in rapeseed. We concluded that the natural variation of seed weight is mainly controlled by maternal genotype. This finding lays a foundation for genetic and breeding studies of seed weight in rapeseed and opens a new field of research on the regulation of seed traits in plants. PMID- 25915861 TI - A Selected Lactobacillus rhamnosus Strain Promotes EGFR-Independent Akt Activation in an Enterotoxigenic Escherichia coli K88-Infected IPEC-J2 Cell Model. AB - Enterotoxigenic Escherichia coli (ETEC) are important intestinal pathogens that cause diarrhea in humans and animals. Although probiotic bacteria may protect against ETEC-induced enteric infections, the underlying mechanisms are unknown. In this study, porcine intestinal epithelial J2 cells (IPEC-J2) were pre incubated with and without Lactobacillus rhamnosus ATCC 7469 and then exposed to F4+ ETEC. Increases in TLR4 and NOD2 mRNA expression were observed at 3 h after F4+ ETEC challenge, but these increases were attenuated by L. rhamnosus treatment. Expression of TLR2 and NOD1 mRNA was up-regulated in cells pre-treated with L. rhamnosus. Pre-treatment with L. rhamnosus counteracted F4+ ETEC-induced increases in TNF-alpha concentration. Increased PGE2. concentrations were observed in cells infected with F4+ ETEC and in cells treated with L. rhamnosus only. A decrease in phosphorylated epidermal growth factor receptor (EGFR) was observed at 3 h after F4+ ETEC challenge in cells treated with L. rhamnosus. Pre treatment with L. rhamnosus enhanced Akt phosphorylation and increased ZO-1 and occludin protein expression. Our findings suggest that L. rhamnosus protects intestinal epithelial cells from F4+ ETEC-induced damage, partly through the anti inflammatory response involving synergism between TLR2 and NOD1. In addition, L. rhamnosus promotes EGFR-independent Akt activation, which may activate intestinal epithelial cells in response to bacterial infection, in turn increasing tight junction integrity and thus enhancing the barrier function and restricting pathogen invasion. Pre-incubation with L. rhamnosus was superior to co-incubation in reducing the adhesion of F4+ ETEC to IPEC-J2 cells and subsequently attenuating F4+ ETEC-induced mucin layer destruction and suppressing apoptosis. Our data indicate that a selected L. rhamnosus strain interacts with porcine intestinal epithelial cells to maintain the epithelial barrier and promote intestinal epithelial cell activation in response to bacterial infection, thus protecting cells from the deleterious effects of F4+ ETEC. PMID- 25915863 TI - What is the role of radionuclide sentinel lymph node biopsy and dissection in papillary thyroid cancer? PMID- 25915864 TI - Association between Mouth Breathing and Atopic Dermatitis in Japanese Children 2 6 years Old: A Population-Based Cross-Sectional Study. AB - As mouth breathing is associated with asthma and otitis media, it may be associated with other diseases. Therefore, this population-based cross-sectional study evaluated the association of mouth breathing with the prevalences of various diseases in children. Preschool children older than 2 years were included. A questionnaire was given to parents/guardians at 13 nurseries in Tokushima City. There were 468 valid responses (45.2%). We defined a subject as a mouth breather in daytime (MBD) if they had 2 or more positive items among the 3 following items: "breathes with mouth ordinarily," "mouth is open ordinarily," and "mouth is open when chewing." We defined subjects as mouth breathers during sleep (MBS) if they had 2 or more positive items among the following 3 items: "snoring," "mouth is open during sleeping," and "mouth is dry when your child gets up." The prevalences of MBD and MBS were 35.5% and 45.9%, respectively. There were significant associations between MBD and atopic dermatitis (odds ratio [OR]: 2.4, 95% confidence interval [CI]: 1.4-4.2), MBS and atopic dermatitis (OR: 2.4, 95% CI: 1.3-4.2), and MBD and asthma (OR: 2.2, 95% CI: 1.2-4.0). After adjusting for history of asthma and allergic rhinitis; family history of atopic dermatitis, asthma, and allergic rhinitis; and nasal congestion; both MBD (OR: 2.6, 95% CI: 1.3-5.4) and MBS (OR: 4.1, 95% CI: 1.8-9.2) were significantly associated with atopic dermatitis. In preschool children older than 2 years, both MBD and MBS may be associated with the onset or development of atopic dermatitis. PMID- 25915865 TI - Towards Fluorescence In Vivo Hybridization (FIVH) Detection of H. pylori in Gastric Mucosa Using Advanced LNA Probes. AB - In recent years, there have been several attempts to improve the diagnosis of infection caused by Helicobacter pylori. Fluorescence in situ hybridization (FISH) is a commonly used technique to detect H. pylori infection but it requires biopsies from the stomach. Thus, the development of an in vivo FISH-based method (FIVH) that directly detects and allows the visualization of the bacterium within the human body would significantly reduce the time of analysis, allowing the diagnosis to be performed during endoscopy. In a previous study we designed and synthesized a phosphorothioate locked nucleic acid (LNA)/ 2' O-methyl RNA (2'OMe) probe using standard phosphoramidite chemistry and FISH hybridization was then successfully performed both on adhered and suspended bacteria at 37 degrees C. In this work we simplified, shortened and adapted FISH to work at gastric pH values, meaning that the hybridization step now takes only 30 minutes and, in addition to the buffer, uses only urea and probe at non-toxic concentrations. Importantly, the sensitivity and specificity of the FISH method was maintained in the range of conditions tested, even at low stringency conditions (e.g., low pH). In conclusion, this methodology is a promising approach that might be used in vivo in the future in combination with a confocal laser endomicroscope for H. pylori visualization. PMID- 25915866 TI - Microbial diversity in a permanently cold and alkaline environment in Greenland. AB - The submarine ikaite columns located in the Ikka Fjord in Southern Greenland represent a unique, permanently cold (less than 6 degrees C) and alkaline (above pH 10) environment and are home to a microbial community adapted to these extreme conditions. The bacterial and archaeal community inhabiting the ikaite columns and surrounding fjord was characterised by high-throughput pyrosequencing of 16S rRNA genes. Analysis of the ikaite community structure revealed the presence of a diverse bacterial community, both in the column interior and at the surface, and very few archaea. A clear difference in overall taxonomic composition was observed between column interior and surface. Whereas the surface, and in particular newly formed ikaite material, was primarily dominated by Cyanobacteria and phototrophic Proteobacteria, the column interior was dominated by Proteobacteria and putative anaerobic representatives of the Firmicutes and Bacteroidetes. The results suggest a stratification of the ikaite columns similar to that of classical soda lakes, with a light-exposed surface inhabited by primary producers and an anoxic subsurface. This was further supported by identification of major taxonomic groups with close relatives in soda lake environments, including members of the genera Rhodobaca, Dethiobacter, Thioalkalivibrio and Tindallia, as well as very abundant groups related to uncharacterised environmental sequences originally isolated from Mono Lake in California. PMID- 25915868 TI - Genetic mechanisms of polygenic hypertension: fundamental insights from experimental models. AB - Essential hypertension is one of the most common disorders that underpin significant morbidity and mortality; however, underlying mechanisms remain elusive that either dictate the actions of individual quantitative trait loci (QTLs) or engineer the overall genetic architecture from them. Recent experimental evidence has unveiled that the genetic architecture determining blood pressure (BP) is assembled from QTL-building blocks by epistasis into regulatory hierarchies. BP, a polygenic and quantitative trait, is homeostasized via pathways participated by Mendelian constituents that operate distantly from end-phase physiological genes. Epistasis genetics performed in the current article has mechanistically unravelled the order and regulatory relationships between certain BP QTLs, and is the first study ever conducted in a mammalian system in analysing a complex trait. The elucidation of the sequence of event and regulatory hierarchies of QTL actions in these pathways will facilitate mechanism based diagnoses and cause-driven treatments for essential hypertension. PMID- 25915869 TI - Losartan treatment for hypertensive patients with hyperuricaemia in Chinese population: a meta-analysis. AB - OBJECTIVES: Many studies have compared losartan with other antihypertensive agents in the management of hypertensive patients with hyperuricaemia in China. However, systematic assessment of efficacy and safety between losartan and other antihypertensive agents is still lacking. This meta-analysis sought to evaluate the available randomized controlled trials (RCTs) regarding losartan treatment for hypertensive patients with hyperuricaemia in China. METHODS: Cochrane Library, PubMed, EMBASE, Chinese National Knowledge Infrastructure, and Wanfang database were searched until December 2013. Only RCTs comparing losartan with other antihypertensive agents for the management of hypertensive patients with hyperuricaemia in Chinese patients were included. RESULTS: Thirty-one RCTs with 2754 patients were identified. Losartan reduced serum uric acid levels (weighted mean differences - 1.57 mg/dl, 95% confidence interval -1.83 to -1.30) compared with other antihypertensive agents. No significant differences in the reduction in SBP or DBP were observed. The incidence of adverse events was comparable between losartan and other agents, so no differences were found in dizziness and headache. Losartan generated a lower incidence than angiotensin-converting enzyme inhibitors of reported dry cough (risk ratio 0.19, 95% confidence interval 0.10 0.36). CONCLUSION: There are no significant differences between losartan and other antihypertensive agents in the reduction of blood pressure. However, losartan is superior to other agents in the reduction of serum uric acid levels; it might be a better choice in hypertensive patients with hyperuricaemia. PMID- 25915867 TI - Sero-epidemiological survey of human cystic echinococcosis in Kashmir, North India. AB - BACKGROUND: Echinococcosis is a human and animal health problem in many endemic areas worldwide. There are numerous reports and hospital-based studies from Kashmir, North India, yet there has been no epidemiological study conducted in Kashmir, the apparently endemic area for human hydatidosis. This study was designed to determine the seroprevalence of hydatid infection in Kashmir Valley and to find out association of risk factors for acquisition of this infection. METHODOLOGY: Fourteen hundred and twenty-nine samples were collected from different districts in the Kashmir region (North India) using systematic random sampling. The 130 control samples included were from apparently healthy blood donors (100), patients with other parasitic infections (20), surgically confirmed hydatidosis patients (5), and apparently healthy subjects excluded for hydatidosis and intestinal parasitic infections (5). Hydatid-specific IgG antibody was detected by enzyme-linked immunosorbent assay, and seropositive samples were analysed further by Western blotting. RESULTS: Out of 1,429 samples, 72 (5.03%) were IgG positive by ELISA. The percentage occurrence of the highly immunoreactive antigenic fractions in IgG ELISA positive samples was 57 kDa (72.2%) followed by 70 kDa (66.7%) and 39 kDa (58.3%) by immunoblotting. Samples with other parasitic infections were reactive with the cluster of 54-59 kDa antigenic fractions. Age <15 years, male gender, contact with dog, and rural residence were the most significant factors associated with the seropositivity. CONCLUSION: The study revealed that 72 (5.03%) out of 1,429 subjects asymptomatic for hydatidosis were seropositve to E.granulosus antigen by ELISA. Western blot analysis of 72 ELISA seropositive samples showed that 66.7% and 58.3% of samples were immunoreactive with 70 and 39 kDa specific antigenic fractions, respectively. The seropositivity was significantly higher (5.79%) in the younger age group (<15 years) as compared to the 16-55 years (4.07%) and > 55 years (3.05%) age groups, suggesting ongoing transmission of this infection in the younger age group. The number of seropositive males was significantly higher as compared to females. The risk factors identified were rural residence and contact with dogs. The study suggests the presence of asymptomatic infection in subjects in Kashmir, North India, and efforts need to be made for implementation of effective prevention measures to reduce the infection burden, which may otherwise lead to symptomatology and complications in the infected subjects. PMID- 25915870 TI - The importance of left ventricular geometry in hypertensive heart disease. PMID- 25915871 TI - The optimal schedule for self-home blood pressure monitoring. PMID- 25915872 TI - Combining -omics in the search for mechanisms in complex trait diseases. PMID- 25915873 TI - Managing hypertension after acute coronary syndrome: missing clinical evidence promote retrospective clues. PMID- 25915874 TI - New threshold and target blood pressures in the hypertension guidelines. Which implications for the hypertensive population? PMID- 25915875 TI - Contrasting effects of prenatal life stress on blood pressure and body mass index in young adults. AB - BACKGROUND: Various environmental stressors in pregnancy have been reported to affect high blood pressure (BP) in adult offspring. However, few studies have examined the effect of prenatal maternal psychological stress on offspring BP and BMI in early adulthood. METHOD: In 957 Raine cohort participants, regression analyses were used to examine the association between the count of maternal life stress events experienced during pregnancy and offspring BP and BMI at age 20. RESULTS: Prenatal life stress associated positively with offspring BMI but inversely with SBP. After adjustment for confounders each additional prenatal life stress event reduced offspring SBP by 0.66 mmHg (P = 0.013) in those with an average BMI and lowered the odds of systolic (pre)hypertension by 17% (odds ratio = 0.83; P = 0.008). The inverse relationship between prenatal life stress and adult SBP was stronger in offspring with higher BMI. On the contrary, each unit increase in prenatal life stress score predicted a BMI increase of 0.37 kg/m (P = 0.022). Longitudinal analysis showed similar effects of prenatal life stress for offspring BMI from age 8 and SBP from age 14. CONCLUSION: This study has shown that maternal stress in pregnancy significantly associated with BMI from early childhood, but contrary to our hypothesis predicted lower resting SBP and lower odds of systolic (pre)hypertension in young adult offspring. The effect of prenatal life stress on BP was accentuated by a higher BMI. Fetal programming events as a result of prenatal stress may underpin some of these relationships. PMID- 25915876 TI - Health-related quality of life and risk of hypertension in the community: prospective results from the Western New York Health Study. AB - OBJECTIVES: Measures of health-related quality of life (HRQL) are strong predictors of health outcomes including cardiovascular disease (CVD). However, prospective evidence on the potential impact of these measures on hypertension risk is scant. We therefore examined the independent role of HRQL on the risk of hypertension in a 6-year longitudinal investigation among 979 women and men (mean age 54.3 years) from the community, who were free of hypertension, CVD and diabetes at the baseline examination. METHODS: Baseline variables included socio demographics, anthropometrics, blood pressure, behavioural risk factors and measures of HRQL, such as the physical and mental health component summaries of the short form-36 questionnaire (SF-36). Incident hypertension was defined as blood pressure at least 140/90 mmHg or on antihypertensive medication at the follow-up visit. RESULTS: The cumulative 6-year incidence of hypertension was 21.9% (214/979). In bivariate analyses, there were several baseline correlates of incident hypertension, including age, abdominal height, BMI and baseline blood pressure levels in both sexes, whereas impaired fasting glucose, family history of hypertension and the SF-36 physical score were all significantly associated with hypertension among women only. After multivariate adjustment, the SF-36 physical scores [odds ratio (OR) 0.97, 0.94-0.99 for unit change] were still significant predictors of hypertension in women only, independent of age, anthropometrics, baseline SBP levels, behavioural risk factors and other covariates. CONCLUSION: Measures of HRQL may represent independent predictors of hypertension risk, at least among women, above and beyond the role of traditional risk factors, such as age, anthropometrics and genetic predisposition. PMID- 25915877 TI - Association of age-dependent height and bone mineral density decline with increased arterial stiffness and rate of fractures in hypertensive individuals. AB - OBJECTIVE: Hypertension and osteoporosis are age-related health risks differentially expressed in men and women. Here we have analysed their prevalence in a randomly selected cross-sectional cohort [CARTaGENE (CaG) of Quebec, Canada and explored their existing relationships along with height, arterial stiffness and bone fractures. METHODS: The principal cohort CaG included 20 007 individuals of age 40-70 years. Participants were subjected to an extensive phenotyping and a questionnaire of medical history and habits. RESULTS: We determined the differences in height of participants and their relation to hypertension status and sex in this cohort and validated it in two other cohorts (The Canadian Heart Health Study and a family cohort from the Saguenay Lac Saint-Jean, a region of Quebec). In all three cohorts, we found that at younger age individuals with hypertension are taller than normotensive individuals, but they have a shorter stature at an older age compared with normotensive individuals. In CaG, we observed that hypertension, low bone mineral density (BMD) and arterial stiffness are strongly associated with height when adjusted for antihypertensive medications (P < 0.0001). Fractures are the net outcome of low BMD, and a significant association is observed (odds ratio = 2.34, confidence interval = 2.12-2.57); this relation was stronger in hypertensive individuals compared with normotensive individuals particularly in younger hypertensive individuals. In addition, we observed that increased arterial stiffness was significantly correlated with a low BMD in both men and women at all ages. CONCLUSION: Shorter stature in elderly, low BMD and fractures correlated with increased arterial stiffness and hypertension. We propose that hypertension and osteoporosis share components of accelerated aging. PMID- 25915878 TI - Antihypertensive treatment is not a risk factor for major cardiovascular events in the Gubbio residential cohort study. AB - BACKGROUND AND OBJECTIVES: Demonstration of antihypertensive beneficial role in population settings is difficult. Relationships of antihypertensive treatment, blood pressure control, risk factors and cardiovascular outcomes were investigated in the Gubbio study. MATERIAL AND METHODS: Among 2248 cardiovascular disease-free men and women aged 35-74 years, individuals were classified as nonhypertensive, controlled hypertensive, uncontrolled hypertensive and untreated hypertensive based on cut-off limits of 140/90 mmHg for SBP/DBP and/or the use of antihypertensive drugs. End-point was the first major coronary, cerebrovascular or peripheral hard event [cardiovascular disease (CVD)] during a 15-year average. Univariate and multivariate analyses were run. RESULTS: Nonhypertensive individuals were about 10 years younger and had lower risk factor levels than the other categories. The relative risk (and 95% confidence interval) for CVD versus nonhypertension was 1.78 (1.02-3.10) for controlled hypertension, 3.76 (2.79-5.06) for uncontrolled hypertension and 3.30 (2.59-4.21) for untreated hypertension (UTH). After adjusting for covariates, such as sex, age, achieved blood pressure and other risk factors, the CVD risk of controlled hypertension was practically equal to that of nonhypertension, and remained unchanged even when blood pressure was excluded from the model (1.03, 0.58-1.82). The higher cardiovascular risk of uncontrolled hypertension and UTH was reduced after adjusting for covariates, but remained significantly higher than in nonhypertension, with no significant differences between uncontrolled hypertension and UTH. CONCLUSIONS: A higher level of baseline risk is not due to treatment per se, the risk being similar in uncontrolled hypertension and UTH. Adjustment for risk factors reduces the risk only in controlled hypertension, suggesting that there may be structural alterations scarcely reversible by antihypertensive treatment. PMID- 25915879 TI - Cardiovascular risk in relation to a new classification of hypertensive left ventricular geometric abnormalities. AB - OBJECTIVES: In 2010, the Dallas Heart Study proposed an upgrade of the left ventricular geometric classification proposed in 1991, by using left ventricular mass combined with end diastolic volumes, and introducing the new categories of dilated left ventricular hypertrophy (LVH). We adopted the new method to test the prognostic impact of the left ventricular geometric patterns from the new classification. METHODS: We evaluated baseline anthropometric, laboratory and echocardiographic parameters of 8848 hypertensive patients from the Campania Salute Network (53 +/- 12 years, 56% male), free of prevalent cardiovascular disease, valve disease and with ejection fraction >=50%. Cut points for left ventricular mass index, relative wall thickness and left ventricular end diastolic dimension (cm/m) were derived from our historical normal reference population. Composite cardiovascular end-points were cardiac death, fatal and nonfatal myocardial infarction and stroke. RESULTS: Independent of confounders, eccentric dilated LVH, concentric nondilated LVH and concentric dilated LVH were associated with higher cardiovascular risk (hazard ratios between 2 and 9, all P < 0.01), mostly depending on the magnitude of LVM index. A volume load was present especially in dilated forms of LVH, the extent of which was important in the determination of harmful types of left ventricular geometry. CONCLUSION: Consideration of left ventricular dilatation in the evaluation of risk related to hypertensive left ventricular geometry reveals the importance of the extent of the volume load coexisting with the typical hypertensive pressure overload. At a given normal ejection fraction, the balance between the two hemodynamic components influences the shape of left ventricular geometric adaptation, the amount of left ventricular mass and the impact on prognosis. PMID- 25915880 TI - Accuracy of self-monitored blood pressure for diagnosing hypertension in primary care. AB - OBJECTIVE: To assess the diagnostic accuracy of recommendations for self monitoring blood pressure (BP) for diagnosing hypertension in primary care. METHODS: Two hundred and forty-seven consecutive participants with raised (>=130 mmHg systolic) BP measured by their general practitioner from four primary care practices in the United Kingdom underwent 28 days of self-monitoring followed by 24-h ambulatory BP monitoring (ABPM). Diagnostic accuracy of the first 7 days of self-monitored BP (minimum 4 days, discarding readings on day 1) in detecting hypertension with ambulatory blood pressure was taken as reference. RESULTS: Two hundred and three participants were included, 109 (53.7%) of whom were diagnosed with hypertension using daytime ambulatory BP. The average of days 2-7 self monitored BP correctly classified 150 of 203 participants [sensitivity 93.6%, 95% confidence interval (CI) 87.2-97.4%; specificity 51.1%, 95% CI 40.5-61.5%). However, the average of days 2-5 self-monitoring correctly classified 152 of 203 participants due to better specificity (53.2%, 95% CI 42.6-63.6%). In sensitivity analysis, diagnostic accuracy was not improved by inclusion of readings beyond day 5, and inclusion of readings taken on day 1 had no impact on diagnostic accuracy. Self-monitoring in the clinic was more accurate than readings taken by the general practitioner, but not self-monitoring outside of the clinic. CONCLUSION: Hypertension can be ruled out in the majority of patients with elevated clinic BP using the average of the first 5 consecutive days of self monitored BP, supporting lower limits for self-monitoring readings in current guidelines. Performing readings beyond day 5 and including readings taken on the first day had no clinical impact on diagnostic accuracy. PMID- 25915881 TI - Swimming training prevents alterations in ecto-NTPDase and adenosine deaminase activities in lymphocytes from Nomega-nitro-L-arginine methyl ester hydrochloride induced hypertension rats. AB - BACKGROUND AND METHOD: Hypertension is accompanied by inflammatory process and purinergic system has been recognized as having an important role in modulating immune functions. Physical training is being considered one of the major lifestyle changes that contributes to the cardiovascular health as well as has an important role in regulating purinergic system. Thus, the aim of this study was to investigate the effect of chronic swimming training on lymphocytic purinergic system enzymes activities related to inflammatory process, as well as in lipid profile and classic inflammatory markers in rats that developed hypertension in response to the oral administration of N-nitro-L-arginine methyl ester hydrochloride (L-NAME). RESULTS: After 6 weeks of training, lymphocytes and serum were separated to be analysed. L-NAME-treated group displayed an increase in SBP as well as in ecto-NTPDase and adenosine deaminase (ADA) activities (P < 0.05). Six weeks of swimming training were able to prevent these alterations and keep the blood pressure and enzymes activities in the same levels of control group. Exercise per se was associated with a decrease in the expression of ecto-NTPDase1 in lymphocytes (-23.4%). Exercise was also efficient in preventing the rise in classic inflammatory markers observed in L-NAME group. CONCLUSION: These findings highlight the link between purinergic signalling and inflammatory process and suggest a novel mechanism in which moderate aerobic exercise possesses the potential to attenuate inflammation caused by hypertension. PMID- 25915882 TI - Decreased proportion of Foxp3+ CD4+ regulatory T cells contributes to the development of hypertension in genetically hypertensive rats. AB - OBJECTIVE: Dysregulation of the sympathetic nervous system and the immune system has been highlighted in the pathogenesis of hypertension. Foxp3 regulatory T (Treg) cells, which maintain immune homeostasis, have potent antihypertensive properties. We systematically explored whether Treg cells proportions are altered in stroke-prone spontaneously hypertensive rats (SHRSP) with increased sympathetic activity. Then, we focused on Treg cells in the spleen and determined whether Treg cells proportion in the spleen could be affected by splenic sympathetic input associated with the progression of hypertension. We also investigated effects of Treg cell induction on hypertension development and cardiac hypertrophy in SHRSP. METHODS AND RESULTS: We evaluated Treg cells in SHRSP. Compared with normotensive Wistar-Kyoto (WKY) rats, SHRSP exhibited decreased proportions of CD4CD25Foxp3 cells (Treg cells) in the spleen before the onset of hypertension. Splenic sympathetic denervation in prehypertensive SHRSP attenuated the reduction of Treg cells at 4 weeks after denervation (P < 0.05) and delayed the development of hypertension in SHRSP. Interleukin (IL)-2 and anti IL-2 mAb complex selectively induced Treg cells in vivo (P < 0.01), delayed the development of hypertension and decreased the heart weight/body weight ratio (4.64 +/- 0.06 vs. 4.25 +/- 0.05 mg/g, P < 0.01) and the cross-sectional area of cardiac myocytes in SHRSP compared with vehicle-treated SHRSP (580 +/- 3.91 vs. 438 +/- 4.43 MUm, P < 0.0001). CONCLUSION: Our findings indicate that a decrease in Treg cell proportion is crucial for the development of hypertension and cardiac hypertrophy in SHRSP, which is involved in sympathetic neural input to the spleen. PMID- 25915883 TI - Protein kinase Cbeta mediates downregulated expression of glucagon-like peptide-1 receptor in hypertensive rat renal arteries. AB - OBJECTIVE: Glucagon-like peptide-1 (GLP-1) exerts its actions via activating GLP 1 receptor (GLP-1R). Our previous study showed a reduced GLP-1R expression in spontaneously hypertensive rat (SHR) renal arteries. The present study investigated the mechanisms underlying GLP-1R downregulation in hypertension. METHODS: Intrarenal arteries of normotensive Wistar-Kyoto rat (WKY) and SHR were suspended in the myograph for force measurement. GLP-1R expression was evaluated by both immunofluorescence and western blotting. Protein kinase Calpha (PKCalpha), PKCbeta, PKCdelta, and total PKC levels were assayed by western blotting. RESULTS: Immunofluorescence revealed reduced GLP-1R level in SHR renal arteries compared with WKY renal arteries. GLP-1R agonist exendin-4 induced concentration-dependent relaxations in WKY arteries, which mainly depended on the presence of endothelium. GLP-1R antagonist exendin 9-39 inhibited this relaxation in WKY arteries, whereas the relaxations were significantly less in SHR arteries. Ex-vivo treatment with PKC inhibitor GFX, PKCalpha and PKCbeta inhibitor Go6976, and PKCbeta inhibitor hispidin but not PKCdelta inhibitor rottlerin improved the impaired relaxations and restored the diminished GLP-1R expression in SHR arteries. Furthermore, PKCbeta level was greater in SHR than WKY arteries, with no difference in PKCalpha, PKCdelta, or total PKC expressions between two rat strains. Treatment with PKC-activating agent phorbol-12-myristate-13-acetate attenuated exendin-4-induced relaxations and reduced GLP-1R expression in WKY arteries, which were reversed by GFX, Go6976, or hispidin. More relevantly, immunofluorescence of human renal arteries also showed a reduced GLP-1R level in hypertensive patients. CONCLUSION: The present results provide novel evidence that the reduced GLP-1R expression in SHR renal arteries is most likely mediated through PKCbeta upregulation; the latter probably contributes to the impaired GLP 1R-mediated vasorelaxations in hypertension. PMID- 25915885 TI - Increased nocturnal heart rate and wave reflection are early markers of cardiovascular disease in Williams-Beuren syndrome children. AB - OBJECTIVE: Williams-Beuren syndrome (WBS) is a genetic disorder that involves elastin gene causing cardiovascular abnormalities and increased risk. However, data on arterial function in these patients are only few and conflicting. Aim of this study was to evaluate dynamic behaviour of central and peripheral blood pressure (BP) and arterial stiffness parameters early in the course of WBS. METHODS: We enrolled 19 WBS paediatric patients (age 13 +/- 4 years) and 23 age, height and BP-matched controls (10 +/- 4 years). We evaluated 24-h ambulatory BP values via an ambulatory blood pressure monitoring (ABPM) system (Mobil-O-Graph) also capable to calculate 24-h central BP and 24-h arterial stiffness parameters. Carotid-femoral PWV (cf-PWV) was assessed in all WBS individuals (Complior). RESULTS: BP values were similar in WBS and control, during the daytime and the night-time. The same behaviour applies to 24-h central BP. However, during the night, WBS showed heart rate values (HR; 78 +/- 10 vs. 71 +/- 9 bpm; P < 0.03), augmentation index (Aix; 24.6 +/- 13.5% vs. 16.5 +/- 8.9%; P = 0.03) and reflection magnitude (68 5.8 vs. 63.5 8.1; P = 0.02) higher than controls. The HR, Aix and reflection magnitude reduction in the day-night shift was lower in WBS than in controls. Cf-PWV in WBS children did not differ when compared with their normalized expected value. CONCLUSION: In WBS children, the higher night time HR, Aix and reflection magnitude and their impaired physiological reduction in the day-night shift suggests an abnormal sympathetic cardiovascular control, an augmented wave reflection and an increase in small arteries resistance. These alterations possibly due to a sympathetic overactivity can be regarded as earlier hallmarks of cardiovascular dysfunction in these patients. PMID- 25915886 TI - Calcified carotid artery plaques predict cardiovascular outcomes in the elderly. AB - BACKGROUND: Identifying plaque composition using ultrasound may aid in stratifying patients at high risk for cardiovascular disease (CVD). Calcification is an integral part of plaque progression and may contribute to plaque vulnerability. We investigated the ability of calcified carotid plaques identified using carotid ultrasound to predict cardiovascular outcomes in older adults. METHODS: Participants included 187 hypertensive and 187 normotensive adults undergoing a duplex scan to identify the presence of calcified carotid plaques. Hypertensive participants received either blood pressure treatment or placebo, and all participants were followed for incident cardiovascular events and death for a maximum of 11 years. RESULTS: The untreated hypertensive group was significantly associated with a higher time-to-any CVD event [relative risk (RR) 2.97, 95% confidence interval (CI) 2.03-4.35, P < 0.0001] and mortality (RR 3.11, 95% CI 1.92-5.04, P < 0.0001) when compared to the normotensive group. Participants with calcified carotid plaques had higher cardiovascular event rates (RR 6.22, 95% CI 1.97-19.6, P = 0.0018) and mortality (RR 6.30, 95% CI 1.55-25.7, P = 0.010) when compared to those without plaque. After controlling for age, male sex, blood pressure status, glucose, and IMT, the presence of calcified carotid plaques remained predictive of CVD events (RR 2.35, 95% CI 1.5-3.8, P = 0.0005) and mortality (RR 2.72, 95% CI 1.4-5.2, P = 0.0021). CONCLUSION: Calcified carotid plaques may predict mortality and cardiovascular outcomes independent of traditional CVD risk factors and may serve as an additional CVD risk assessment in the elderly. PMID- 25915884 TI - Serum carboxymethyl-lysine, an advanced glycation end product, is associated with arterial stiffness in older adults. AB - OBJECTIVE: The objective of this study is to examine the relationship of serum carboxymethyl-lysine (CML), an advanced glycation end product (AGE), with pulse pressure (PP), aortic pulse wave velocity (aPWV) and hypertension in older adults. BACKGROUND: AGEs are bioactive molecules that accumulate in tissues with ageing and can both cross-link collagen and induce inflammation in model systems. The relationship of AGEs with arterial stiffness and hypertension has not been well characterized in community-dwelling older adults. METHODS: We measured serum CML and blood pressure in 3044 adults, aged 70-79 years, who participated in the Health, Aging and Body Composition Study, a population-based study of ageing in Pittsburgh, Pennsylvania and Memphis, Tennessee. aPWV was measured in 2468 participants. RESULTS: Participants in the highest tertile of serum CML had higher PP (highest tertile: beta = 2.85, SE = 0.82, P = 0.0005; middle tertile: beta = 0.60, SE = 0.80, P = 0.45), and higher aPWV (highest tertile: beta = 51.4, SE = 20.1, P = 0.01; middle tertile: beta = 3.2, SE = 19.8, P = 0.87) than those in the lowest tertile in multivariable linear regression models adjusting for age, sex, race, education, BMI, smoking, alcohol use, total cholesterol, high density lipoprotein (HDL) cholesterol, diabetes, cardiovascular disease and chronic kidney disease. Participants in the highest and middle tertiles of serum CML had higher odds of hypertension [odds ratio (OR) 1.32, 95% confidence interval (95% CI) 1.06-1.60, P = 0.005; OR 1.27, 95% CI 1.05-1.53, P = 0.01, respectively] than those in the lowest tertile in a multivariable logistic regression model adjusting for the same covariates. CONCLUSION: Elevated serum CML was associated with arterial stiffness, as reflected by higher PP and aPWV, in older, community-dwelling adults. PMID- 25915888 TI - Correlates of aortic stiffness progression in patients with resistant hypertension: importance of clinic and ambulatory blood pressure changes. AB - OBJECTIVES: Correlates of serial aortic stiffness changes were scarcely evaluated. We aimed to evaluate them in patients with resistant hypertension, with particular attention to the importance of changes in clinic and ambulatory blood pressures (BP). METHODS: In a prospective study, two carotid-femoral pulse wave velocity (cf-PWV) measurements (three measures in each occasion) were performed with the Complior equipment in 442 resistant hypertensive patients over a mean follow-up of 4.6 years. Multivariable regressions assessed the independent correlates of changes in cf-PWV. All analyses were further adjusted for baseline cf-PWV and BP values, and for the time interval between measurements. RESULTS: Carotid-femoral PWV had a median increase of 0.11 m/s per year (1.1% per year). Overall, 224 patients (51%) had an increase or persisted with high cf-PWV, whereas 218 (49%) reduced or persisted with low values. On multivariable regressions, both changes in clinic SBP (partial correlation 0.34, P < 0.001) and in 24-h SBP (partial correlation 0.40, P < 0.001) were correlates of changes in cf-PWV. This means that the white-coat effect, defined as the difference between clinic and daytime BPs, affected cf-PWV changes (partial correlation 0.19, P < 0.001). The other independent correlates of aortic stiffness progression were older age, presence of diabetes, higher waist circumference and worse renal function. CONCLUSION: The exaggerated white-coat effect, by acutely increasing clinic BPs during cf-PWV examination, may partially obscure the beneficial effects of reducing ambulatory BP levels on aortic stiffness attenuation. Arterial stiffness measurements under ambulatory conditions may be needed to correctly assess aortic stiffness changes in resistant hypertensive patients. PMID- 25915887 TI - The role of retinal vessels caliber as a marker of vascular aging in large arteries. AB - OBJECTIVE: To analyze the relationship between retinal vessel caliber and large arterial structure and function in a sample of the general population. METHODS: A cross-sectional study was conducted among 229 participants from the EVIDENT trial (mean age 55.6+/-12.1 years, 61.1% women). Retinal photographs were digitized, temporal vessels were measured in an area of 0.5 to 1 disc diameter from the optic disc and the arterio-venous ratio (AVR) was estimated. Vascular structure and function were assessed by evaluating carotid intima-media thickness (IMT), pulse wave velocity (PWV), augmentation index (AIx), ankle brachial index and ambulatory arterial stiffness index. RESULTS: The mean AVR was 0.792 +/- 0.082, calculated from an arterial caliber of 109.1 +/- 12.5 MUm and a venous caliber of 138.7 +/- 15.4 MUm. A total of 13.1% of the patients presented vascular damage. The AVR was inversely correlated with carotid IMT (r = -0.190, P < 0.01), PWV (r = -0.178, P < 0.01) and AIx (r = -0.187, P < 0.01). In a multiple linear regression analysis, the associations with IMT and with AIx remained after adjusting for possible confounders (beta = -0.152, P = 0.026; and beta = -18.1, P = 0.037, respectively), but the association with PWV was lost when blood pressure was added (beta = -1.520, P = 0.215). In a logistic regression analysis, the odds ratio of the first tertile of mean AVR (<0.76) of having a vascular injury was 7.09 (95% confidence interval 1.78-28.17, P = 0.011) after adjusting for possible confounders. CONCLUSION: In the general population, lower AVR values are associated with increases in carotid IMT, AIx and PWV. AVR may be a good predictor of asymptomatic vascular damage in large arteries. PMID- 25915889 TI - Targeting gamma-secretases protect against angiotensin II-induced cardiac hypertrophy. AB - OBJECTIVE: The Notch pathway has been linked to pulmonary hypertension, but its role in systemic hypertension and, in particular in left ventricular hypertrophy (LVH), remains poorly understood. The main objective of this work was to analyse the effect of inhibiting the Notch pathway on the establishment and maintenance of angiotensin II (Ang-II)-induced arterial hypertension and LVH in adult mice with inducible genetic deletion of gamma-secretase, and to test preclinically the therapeutic efficacy of gamma-secretase inhibitors (GSIs). BASIC METHODS: We analysed Ang-II responses in primary cultures of vascular smooth muscle cells obtained from a novel mouse model with inducible genetic deletion of the gamma secretase complex, and the effects of GSI treatment on a mouse cardiac cell line. We also investigated Ang-II-induced hypertension and LVH in our novel mouse strain lacking the gamma-secretase complex and in GSI-treated wild-type mice. Moreover, we analysed vascular tissue from hypertensive patients with and without LVH. MAIN RESULTS: Vascular smooth muscle cells activate the Notch pathway in response to Ang-II both 'in vitro' and 'in vivo'. Genetic deletion of gamma secretase in adult mice prevented Ang-II-induced hypertension and LVH without causing major adverse effects. Treatment with GSI reduced Ang-II-induced hypertrophy of a cardiac cell line 'in vitro' and LVH in wild-type mice challenged with Ang-II. We also report elevated expression of the Notch target HES5 in vascular tissue from hypertensive patients with LVH compared with those without LVH. CONCLUSION: The Notch pathway is activated in the vasculature of mice with hypertension and LVH, and its inhibition via inducible genetic gamma secretase deletion protects against both conditions. Preliminary observations in hypertensive patients with LVH support the translational potential of these findings. Moreover, GSI treatment protects wild-type mice from Ang-II-induced LVH without affecting blood pressure. Our results unveil the potential use of GSIs in the treatment of hypertensive patients with LVH. PMID- 25915890 TI - Myostatin and insulin-like growth factor-1 in hypertensive heart disease: a prospective study in human heart donors. AB - OBJECTIVE: The physiopathological mechanisms implicated in hypertensive heart disease are multi-factorial, including myocyte hypertrophy, apoptosis and myocardial remodelling. In this process, some hormonal and local growth factors have a regulatory influence. The aim of this study was to evaluate the potential role of myostatin and insulin-like growth factor-1 (IGF-1) myocardial expression in the development of hypertensive-induced cardiac damage. METHODS: Samples of human myocardium tissue from organ donors were prospectively collected and classified according to the presence of hypertension, alcohol consumption, other causes of myocardial damage and the presence of structural cardiomyopathy (CMP). Myocardial samples were studied by immunohistochemistry and myostatin, and IGF-1 myocardial expression was evaluated in all the different groups of donors. Hypertensive donors were compared to other groups. RESULTS: A total of 66 heart samples from human donors were collected: 33 donors had no previous or present history of hypertension and 33 donors presented defined hypertension. Donors with hypertension presented higher myocyte cell and nuclear hypertrophy and showed similar myostatin myocardial expression as controls, but lower IGF-1 myocardial expression. Myostatin expression was significantly higher in hypertensive donors with CMP compared to non-hypertensive healthy donors. The presence of CMP of diverse origin (alcoholic, valve and coronary) also significantly increased myostatin myocardial expression. CONCLUSION: The presence of hypertension significantly decreases IGF-1 myocardial expression. Myostatin myocardial expression increases in the presence of structural CMP either of hypertensive or other origin. These effects open the possibility of modulating hypertensive induced cardiac damage. PMID- 25915891 TI - Impact of hypertension on the outcome of patients admitted with acute coronary syndrome. AB - OBJECTIVE: The role of hypertension and its impact on outcome in patients with acute coronary syndrome (ACS) is still debated. This study aimed to compare the outcomes of hypertensive and nonhypertensive ACS patients. METHODS: Using data of ACS patients enrolled in the Acute Myocardial Infarction in Switzerland Plus Registry from 1997 to 2013, characteristics at presentation and outcomes in hospital and after 1 year were analyzed. Hypertension was defined as previously diagnosed and treated by a physician. The primary endpoint was mortality. Data were analyzed using multiple logistic regressions. RESULTS: Among 41 771 ACS patients, 16 855 (40.4%) were without and 24 916 (59.6%) with preexisting hypertension. Patients with preexisting hypertension had a more favorable in hospital outcome [odds ratio (OR) in-hospital mortality 0.82, 95% confidence interval (CI) 0.73-0.93; P = 0.022]. The independent predictors of in-hospital mortality for patients with preexisting hypertension were age, Killip class greater than 2, Charlson Comorbidity Index greater than 1, no pretreatment with statins and lower admission systemic blood pressure. Preexisting hypertension was not an independent predictor of 1-year mortality in the subgroup of patients (n = 7801) followed: OR 1.07, 95% CI 0.78-1.47; P = 0.68. Independent predictors of mortality 1 year after discharge for the 4796 patients with preexisting hypertension were age, male sex and comorbidities. Angiotensin-converting enzyme inhibitors or angiotensin II receptor antagonists and statins prescribed at discharge improved the outcomes. CONCLUSION: Outcome of ACS patients with preexisting hypertension was associated with an improved in-hospital prognosis after adjustment for their higher baseline risk. However, this effect was not long-lasting and does not necessarily mean a causal relationship exists. Short term and long-term management of patients with hypertension admitted with ACS could be further improved. PMID- 25915892 TI - Eligibility to treatment and economic effect of the implementation of the new U.S. or European Society of Hypertension/European Society of Cardiology hypertension guidelines. AB - OBJECTIVE: To evaluate the population and economic impact of implementing the new Joint National Committee (JNC) or European Society of Hypertension (ESH)/European Society of Cardiology (ESC) hypertension guidelines in the Swiss population. METHODS: Cross-sectional, population-based sample (6708 participants) collected between 2003 and 2006 in the city of Lausanne, Switzerland. Blood pressure categories were defined according to both the JNC (JNC-7 and JNC-8) and the ESH/ESC (2007 and 2013) guidelines. RESULTS: The proportion of participants aged 35-60 years eligible for drug treatment was 25.6% [95% confidence interval (CI) 24.4-26.9%] and 24.8% (95% CI 23.6-26.0%) for the JNC-7 and the JNC-8 guidelines, respectively; for participants aged 60-75 years, the values were 62.3% (95% CI 60.1-64.5%) and 46.8% (95% CI 44.5-49.0%), respectively. Shifting from the JNC-7 to the JNC-8 guidelines would lead to an annual saving of 163.6 million Swiss francs (187.7 million US dollars or 134.5 million European ?). The proportion of participants aged 35-75 years without chronic kidney disease, diabetes mellitus or reported history of cardiovascular disease and eligible for treatment was 30.2% (95% CI 29.0-31.4%) for the ESH/ESC 2007 and 2013 guidelines. For participants with chronic kidney disease, diabetes mellitus or reported history of cardiovascular disease, the values were 73.6% (95% CI 70.8-76.3%) and 55.6% (95% CI 52.5-58.8%), respectively. Shifting from the ESH/ESC 2007 to the ESH/ESC 2013 guidelines would lead to an annual saving of 86.9 million Swiss francs (99.5 million US dollars or 71.4 million European ?). CONCLUSION: In Switzerland, shifting from the JNC-7 to the JNC-8 guidelines or from the ESH/ESC 2007 to the ESH/ESC 2013 guidelines would decrease the prevalence of patients eligible for treatment and increase the percentage of treated patients within blood pressure goals. Both strategies lead to potential savings in antihypertensive drug treatment. PMID- 25915893 TI - Oxidative stress in patients affected by primary aldosteronism. PMID- 25915894 TI - Response to 'Oxidative stress in patients affected by primary aldosteronism'. PMID- 25915895 TI - Estimation of sodium excretion should be made as simple as possible, but not simpler: misleading papers and editorial on spot urines. PMID- 25915896 TI - Response to 'Estimation of sodium excretion should be made as simple as possible, but not simpler: misleading papers and editorial on spot urines'. PMID- 25915897 TI - Influences of different land use spatial control schemes on farmland conversion and urban development. AB - Land use planning is always officially implemented as an effective tool to control urban development and protect farmland. However, its impact on land use change remains untested in China. Using a case study of Hang-Jia-Hu region, the main objective of this paper was to investigate the influence of different land use spatial control schemes on farmland conversion and urban development. Comparisons of farmland conversion and urban development patterns between the urban planning area and the non-urban planning area were characterized by using remote sensing, geographical information systems, and landscape metrics. Results indicated that farmland conversion in the non-urban planning area was more intensive than that in the urban planning area, and that farmland patterns was more fragmented in the non-urban planning area. Built-up land patterns in the non urban planning area showed a trend of aggregation, while those in the urban planning area had a dual trend of fragmentation and aggregation. Existing built up areas had less influence on built-up land sprawl in the non-urban planning area than that in the urban planning area. Built-up land sprawl in the form of continuous development in the urban planning area led to farmland conversion; and in the non-urban planning area, built-up land sprawl in the form of leapfrogging development resulted in farmland areal declines and fragmentation. We argued that it is a basic requirement to integrate land use plans in urban and non-urban planning areas for land use planning and management. PMID- 25915898 TI - The effect of growth-mimicking continuous strain on the early stages of skeletal development in micromass culture. AB - Embryonic skeletogenesis involves proliferation, condensation and subsequent chondrogenic differentiation of mesenchymal precursor cells, and the strains and stresses inherent to these processes have been hypothesized to influence skeletal development. The aim of this study was to determine the effect of growth mimicking strain on the process of early skeletal development in vitro. To this end, we applied continuous uniaxial strain to embryonic skeletal precursor cells in micromass culture. Strain was applied at different times of culture to specifically address the effect of mechanical loading on the sequential stages of cellular proliferation, condensation and differentiation. We found that growth mimicking strain at all three times did not affect proliferation or chondrogenic differentiation under the tested conditions. However, the timing of the applied strain did play a role in the density of mesenchymal condensations. This finding suggests that a mechanically dynamic environment, and specifically strain, can influence skeletal patterning. The growth-mimicking micromass model presented here may be a useful tool for further studies into the role of mechanical loading in early skeletal development. PMID- 25915899 TI - Roles of Spatial Scale and Rarity on the Relationship between Butterfly Species Richness and Human Density in South Africa. AB - Wildlife and humans tend to prefer the same productive environments, yet high human densities often lead to reduced biodiversity. Species richness is often positively correlated with human population density at broad scales, but this correlation could also be caused by unequal sampling effort leading to higher species tallies in areas of dense human activity. We examined the relationships between butterfly species richness and human population density at five spatial resolutions ranging from 2' to 60' across South Africa. We used atlas-type data and spatial interpolation techniques aimed at reducing the effect of unequal spatial sampling. Our results confirm the general positive correlation between total species richness and human population density. Contrary to our expectations, the strength of this positive correlation did not weaken at finer spatial resolutions. The patterns observed using total species richness were driven mostly by common species. The richness of threatened and restricted range species was not correlated to human population density. None of the correlations we examined were particularly strong, with much unexplained variance remaining, suggesting that the overlap between butterflies and humans is not strong compared to other factors not accounted for in our analyses. Special consideration needs to be made regarding conservation goals and variables used when investigating the overlap between species and humans for biodiversity conservation. PMID- 25915900 TI - CD2v Interacts with Adaptor Protein AP-1 during African Swine Fever Infection. AB - African swine fever virus (ASFV) CD2v protein is believed to be involved in virulence enhancement, viral hemadsorption, and pathogenesis, although the molecular mechanisms of the function of this viral protein are still not fully understood. Here we describe that CD2v localized around viral factories during ASFV infection, suggesting a role in the generation and/or dynamics of these viral structures and hence in disturbing cellular traffic. We show that CD2v targeted the regulatory trans-Golgi network (TGN) protein complex AP-1, a key element in cellular traffic. This interaction was disrupted by brefeldin A even though the location of CD2v around the viral factory remained unchanged. CD2v-AP 1 binding was independent of CD2v glycosylation and occurred on the carboxy terminal part of CD2v, where a canonical di-Leu motif previously reported to mediate AP-1 binding in eukaryotic cells, was identified. This motif was shown to be functionally interchangeable with the di-Leu motif present in HIV-Nef protein in an AP-1 binding assay. However, we demonstrated that it was not involved either in CD2v cellular distribution or in CD2v-AP-1 binding. Taken together, these findings shed light on CD2v function during ASFV infection by identifying AP-1 as a cellular factor targeted by CD2v and hence elucidate the cellular pathways used by the virus to enhance infectivity. PMID- 25915901 TI - Retrotransposon-derived promoter of Mammalian Aebp2. AB - Variable DNA methylation in promoter regions has been implicated in altering transcriptional regulation. The current study analyzed the evolutionary origin and DNA methylation pattern of one of the promoters of Aebp2. According to the results, the first promoter of Aebp2 has been derived from retrotransposons independently in the primate and rodent lineages. DNA methylation analyses revealed that this promoter is unmethylated in sperm, methylated in mature oocytes, and partially methylated at embryonic day 10.5 (78.3%) and 14.5 (58.3%). This promoter also shows variable levels of DNA methylation among adult organs, ranging from the highest in spleen (~80%) to the lowest in tail (~50%). The results from the F1 hybrid of interspecific crossing further indicated that both alleles are equally methylated without any allele bias, also supported by its biallelic expression. Therefore, the partial methylation observed among somatic tissues is an outcome of the genome-wide resetting of DNA methylation during the implantation stage, but not of the inherited allelic methylation pattern preset during gametogenesis. Taken together, mammalian Aebp2 has adopted retrotransposons as its promoter, which displays partial DNA methylation pattern of allelic- or non-allelic origin during the different stages of development. PMID- 25915902 TI - G6PD Deficiency and Hemoglobinopathies: Molecular Epidemiological Characteristics and Healthy Effects on Malaria Endemic Bioko Island, Equatorial Guinea. AB - BACKGROUND: Glucose-6-phosphate dehydrogenase (G6PD) deficiency and hemoglobinopathies were the inherited conditions found mostly in African. However, few epidemiological data of these disorders was reported in Equatorial Guinea (EQG). This study aimed to assess the prevalence and healthy effects of G6PD deficiency and hemoglobinopathies among the people on malaria endemic Bioko Island, EQG. MATERIALS AND METHODS: Blood samples from 4,144 unrelated subjects were analyzed for G6PD deficiency by fluorescence spot test (FST), high resolution melting assay and PCR-DNA sequencing. In addition, 1,186 samples were randomly selected from the 4,144 subjects for detection of hemoglobin S (HbS), HbC, and alpha-thalassemia deletion by complete blood count, PCR-DNA sequencing and reverse dot blot (RDB). RESULTS: The prevalence of malaria and anemia was 12.6% (522/4,144) and 32.8% (389/1,186), respectively. Overall, 8.7% subjects (359/4,144) were G6PD-deficient by FST, including 9.0% (249/2,758) males and 7.9% (110/1,386) females. Among the 359 G6PD-deficient individuals molecularly studied, the G6PD A- (G202A/A376G) were detected in 356 cases (99.2%), G6PD Betica (T968C/A376G) in 3 cases. Among the 1,186 subjects, 201 cases were HbS heterozygotes, 35 cases were HbC heterozygotes, and 2 cases were HbCS double heterozygotes; 452 cases showed heterozygous alpha-thalassemia 3.7 kb deletion ( alpha3.7 kb deletion) and 85 homozygous - alpha3.7 kb deletion. The overall allele frequencies were HbS 17.1% (203/1186); HbC, 3.1% (37/1186); and -alpha3.7 kb deletion 52.4% (622/1186), respectively. CONCLUSIONS: High G6PD deficiency in this population indicate that diagnosis and management of G6PD deficiency is necessary on Bioko Island. Obligatory newborn screening, prenatal screening and counseling for these genetic disorders, especially HbS, are needed on the island. PMID- 25915903 TI - Computational Tools for Interpreting Ion Channel pH-Dependence. AB - Activity in many biological systems is mediated by pH, involving proton titratable groups with pKas in the relevant pH range. Experimental analysis of pH dependence in proteins focusses on particular sidechains, often with mutagenesis of histidine, due to its pKa near to neutral pH. The key question for algorithms that predict pKas is whether they are sufficiently accurate to effectively narrow the search for molecular determinants of pH-dependence. Through analysis of inwardly rectifying potassium (Kir) channels and acid-sensing ion channels (ASICs), mutational effects on pH-dependence are probed, distinguishing between groups described as pH-coupled or pH-sensor. Whereas mutation can lead to a shift in transition pH between open and closed forms for either type of group, only for pH-sensor groups does mutation modulate the amplitude of the transition. It is shown that a hybrid Finite Difference Poisson-Boltzmann (FDPB) - Debye-Huckel continuum electrostatic model can filter mutation candidates, providing enrichment for key pH-coupled and pH-sensor residues in both ASICs and Kir channels, in comparison with application of FDPB alone. PMID- 25915907 TI - Cholesterol expels ibuprofen from the hydrophobic membrane core and stabilizes lamellar phases in lipid membranes containing ibuprofen. AB - There is increasing evidence that common drugs, such as aspirin and ibuprofen, interact with lipid membranes. Ibuprofen is one of the most common over the counter drugs in the world, and is used for relief of pain and fever. It interacts with the cyclooxygenase pathway leading to inhibition of prostaglandin synthesis. From X-ray diffraction of highly oriented model membranes containing between 0 and 20 mol% ibuprofen, 20 mol% cholesterol, and dimyristoylphosphatidylcholine (DMPC), we present evidence for a non-specific interaction between ibuprofen and cholesterol in lipid bilayers. At a low ibuprofen concentrations of 2 mol%, three different populations of ibuprofen molecules were found: two in the lipid head group region and one in the hydrophobic membrane core. At higher ibuprofen concentrations of 10 and 20 mol%, the lamellar bilayer structure is disrupted and a lamellar to cubic phase transition was observed. In the presence of 20 mol% cholesterol, ibuprofen (at 5 mol%) was found to be expelled from the membrane core and reside solely in the head group region of the bilayers. 20 mol% cholesterol was found to stabilize lamellar membrane structure and the formation of a cubic phase at 10 and 20 mol% ibuprofen was suppressed. The results demonstrate that ibuprofen interacts with lipid membranes and that the interaction is strongly dependent on the presence of cholesterol. PMID- 25915908 TI - Retraction: Astakine 2--the dark knight linking melatonin to circadian regulation in crustaceans. PMID- 25915905 TI - Acute endovascular reperfusion therapy in ischemic stroke: a systematic review and meta-analysis of randomized controlled trials. AB - BACKGROUND: Randomized controlled trials (RCTs) of endovascular therapy for acute ischemic stroke have had inconsistent results. We evaluated the efficacy and safety of endovascular therapy in published RCTs. METHODS: We performed a systematic review of RCTs of endovascular therapy with thrombolytic or mechanical reperfusion compared with interventions without endovascular therapy. Primary outcome was the frequency of good functional outcome (modified Rankin scale (mRS) of 0-2 at 90 days) and secondary outcomes were mortality at 90 days and symptomatic intracranial hemorrhage (sICH). Random-effects meta-analysis was performed and the Cochrane risk of bias assessment was used to evaluate quality of evidence. RESULTS: Ten studies involving 1,612 subjects were included. Endovascular therapy was not significantly associated with good functional outcome (Relative Risk [RR] =1.17; 95% CI, 0.97 to 1.42; p=0.10 and Absolute Risk Difference [ARD] =7%; 95%CI -0.1% to 14%; p=0.05); heterogeneity was moderate among studies (I2=30%). Mortality was unchanged with endovascular therapy (RR=0.92; 95 % CI, 0.75 to 1.13; p=0.45) and there was no difference in sICH (RR=1.20; 95 % CI, 0.79 to 1.82; p=0.39). The quality of evidence was low for all outcomes and the recommendation is weak for the use of endovascular therapy as per GRADE methodology. CONCLUSIONS: Intra-arterial therapy did not show significant increase in good outcomes and no changes in either mortality or sICH in patients with acute ischemic stroke. We need further RCTs with better design and quality to evaluate the true efficacy of endovascular therapy. PMID- 25915906 TI - Structural brain correlates associated with professional handball playing. AB - BACKGROUND: There is no doubt that good bimanual performance is very important for skilled handball playing. The control of the non-dominant hand is especially demanding since efficient catching and throwing needs both hands. METHODOLOGY/HYPOTHESES: We investigated training-induced structural neuroplasticity in professional handball players using several structural neuroimaging techniques and analytic approaches and also provide a review of the literature about sport-induced structural neuroplastic alterations. Structural brain adaptations were expected in regions relevant for motor and somatosensory processing such as the grey matter (GM) of the primary/secondary motor (MI/supplementary motor area, SMA) and somatosensory cortex (SI/SII), basal ganglia, thalamus, and cerebellum and in the white matter (WM) of the corticospinal tract (CST) and corpus callosum, stronger in brain regions controlling the non-dominant left hand. RESULTS: Increased GM volume in handball players compared with control subjects were found in the right MI/SI, bilateral SMA/cingulate motor area, and left intraparietal sulcus. Fractional anisotropy (FA) and axial diffusivity were increased within the right CST in handball players compared with control women. Age of handball training commencement correlated inversely with GM volume in the right and left MI/SI and years of handball training experience correlated inversely with radial diffusivity in the right CST. Subcortical structures tended to be larger in handball players. The anatomical measures of the brain regions associated with handball playing were positively correlated in handball players, but not interrelated in control women. DISCUSSION/CONCLUSION: Training-induced structural alterations were found in the somatosensory-motor network of handball players, more pronounced in the right hemisphere controlling the non-dominant left hand. Correlations between handball training-related measures and anatomical differences suggest neuroplastic adaptations rather than a genetic predisposition for a ball playing affinity. Investigations of neuroplasticity specifically in sportsmen might help to understand the neural mechanisms of expertise in general. PMID- 25915909 TI - Clinical efficacy and safety of Ezetimibe on major cardiovascular endpoints: systematic review and meta-analysis of randomized controlled trials. AB - BACKGROUND: Randomized clinical trials (RCTs) about Ezetimibe's efficacy on patient-oriented outcomes have given discordant results. The aim of this study was to determine the net effect of Ezetimibe and of the widely marketed combination, Ezetimibe+simvastatin, on mortality and morbidity outcomes. METHODS AND FINDINGS: We searched for RCT on Ezetimibe using MEDLINE, CCTR, EMBASE, ClinicalTrials.gov databases up to December 2013, Merck and Novartis online registers, and personal communications. Two authors independently selected trials fulfilling these criteria: RCTs comparing Ezetimibe+/-statin or another lipid lowering drug against placebo, or against the same lipid-lowering drug at the same dosage, with a follow-up at least 24 weeks and one or more of these outcomes: all-cause mortality, cardiovascular (CV) mortality, stroke, myocardial infarction (MI), cancer, serious adverse events (SAEs); we assessed the risk of bias using the Cochrane checklist. We extracted the data for major clinical events as a dichotomous measure, with the patient the unit of analysis. Pooled analysis was done with random and fixed effect based models. Trials comparing Ezetimibe plus a lipid-lowering drug against the same lipidlowering drug representing the net effect of Ezetimibe, showed a nonsignificant tendency toward damage for cancer, MI, stroke and SAEs. Ezetimibe+simvastatin vs. simvastatin alone showed a stronger tendency towards a higher risk for all-cause death (2.52; 0.65-9.74), CV death (3.04; 0.48-19.21), non-CV death (3.03; 0.12-73.50), MI (1.91; 0.42-8.70), stroke (2.38; 0.46-12.35), cancer (RR 11.11; 0.62-198.29), and SAEs (1.45; 0.95-2.23). Limitations include small numbers of events and inadequate power of the pooling. Trials comparing Ezetimibe+simvastatin vs placebo showed non-significant effects: MI (0.81; 0.66-1.00 p = 0.051), all-cause death (1.02; 0.95-1.09), CV death (0.91; 0.80-1.04), non-CV death (108; 0.99 1.18), stroke (0.86; 0.72-1.04), cancer (1.18; 0.80-1.74), SAEs (1.01; 0.96 1.06). CONCLUSIONS: Ezetimibe+/-simvastatin had inconsistent effects on important outcomes. No firm conclusions are possible, but findings indicative of damage suggest much more selective use of Ezetimibe+/-simvastatin. PMID- 25915910 TI - Histology-based Classification Predicts Pattern of Recurrence and Improves Risk Stratification in Primary Retroperitoneal Sarcoma. AB - OBJECTIVE: To determine the prognostic significance of histologic type/subtype in a large series of patients with primary resected retroperitoneal sarcoma. BACKGROUND: The histologic diversity and rarity of retroperitoneal sarcoma has hampered the ability to predict patient outcome. METHODS: From a single institution, prospective database, 675 patients treated surgically for primary, nonmetastatic retroperitoneal sarcoma during 1982 to 2010 were identified and histologic type/subtype was reviewed. Clinicopathologic variables were analyzed for association with disease-specific death (DSD), local recurrence (LR), and distant recurrence (DR). RESULTS: Median follow-up for survivors was 7.5 years. The predominant histologies were well-differentiated liposarcoma, dedifferentiated liposarcoma, and leiomyosarcoma. Five-year cumulative incidence of DSD was 31%, and factors independently associated with DSD were R2 resection, resection of 3 or more contiguous organs, and histologic type. Five-year cumulative incidence for LR was 39% and for DR was 24%. R1 resection, age, tumor size, and histologic type were independently associated with LR; size, resection of 3 or more organs, and histologic type were independently associated with DR. Liposarcoma and leiomyosarcoma were associated with late recurrence and DSD (as long as 15 years from diagnosis). For solitary fibrous tumor, LR was uncommon (<10%), but early distant recurrence was common (36% at 5 years). Nomograms were developed to predict DSD, LR, and DR. CONCLUSIONS: Histologic type/subtype is the most important independent predictor of DSD, LR, and DR in primary retroperitoneal sarcoma. Histology predicts the pattern and incidence of LR and DR and will aid in more accurate patient counseling and selection of patients for adjuvant therapy trials. PMID- 25915911 TI - Cell Impermeant-based Low-volume Resuscitation in Hemorrhagic Shock: A Biological Basis for Injury Involving Cell Swelling. AB - OBJECTIVE: To determine the role of cell swelling in severe hemorrhagic shock and resuscitation injury. BACKGROUND: Circulatory shock induces the loss of energy dependent volume control mechanisms. As water enters ischemic cells, they swell, die, and compress nearby vascular structures, which further aggravates ischemia by reducing local microcirculatory flow and oxygenation. Loading the interstitial space with cell impermeant molecules prevents water movement into the cell by passive biophysical osmotic effects, which prevents swelling injury and no reflow. METHODS: Adult rats were hemorrhaged to a pressure of 30 to 35 mm Hg, held there until the plasma lactate reached 10 mM, and given a low-volume resuscitation (LVR) (10%-20% blood volume) with saline or various cell impermeants (sorbitol, raffinose, trehalose, gluconate, and polyethylene glycol 20k (PEG-20k). When lactate again reached 10 mM after LVR, full resuscitation was started with crystalloid and red cells. One hour after full resuscitation, the rats were euthanized. Capillary blood flow was measured by the colored microsphere technique. RESULTS: Impermeants prevented ischemia-induced cell swelling in liver tissue and dramatically improved LVR outcomes in shocked rats. Small cell impermeants and PEG-20k in LVR solutions increased tolerance to the low flow state by two and fivefold, respectively, normalized arterial pressure during LVR, and lowered plasma lactate after full resuscitation, relative to saline. This was accompanied by higher capillary blood flow with cell impermeants. CONCLUSIONS: Ischemia-induced lethal cell swelling during hemorrhagic shock is a key mediator of resuscitation injury, which can be prevented by cell impermeants in low-volume resuscitation solutions. PMID- 25915912 TI - Doubling of 30-Day Mortality by 90 Days After Esophagectomy: A Critical Measure of Outcomes for Quality Improvement. AB - OBJECTIVES: Our objectives were to (1) compare 30- and 90-day mortality rates after esophagectomy, (2) compare drivers of 30- and 90-day mortality, and (3) examine whether 90-day mortality affects hospital rankings. BACKGROUND: Operative mortality has traditionally been assessed at 30 days. Ninety-day mortality has been suggested as a more appropriate indicator of quality, particularly after complex cancer surgery. METHODS: Esophagectomies for nonmetastatic esophageal cancer patients diagnosed between 2007 and 2011 were identified in the National Cancer Data Base. Mortality rates were examined by patient demographics, tumor characteristics, and hospital procedural volume. Risk-adjusted hierarchical logistic regression models examined hospital performance for mortality. RESULTS: A total of 15,796 esophagectomy patients at 977 hospitals were available for analysis. Ninety-day overall mortality was more than double the 30-day mortality (8.9% vs 4.2%; P < 0.0001). In multivariate analysis, while both 30- and 90-day mortality were associated with patient factors such as age, comorbidity, and hospital volume, only 90-day mortality was influenced by tumor- and management related variables such as stage, tumor location, and receipt of neoadjuvant therapy. Hospital performance was examined as top 10%, middle 10% to 90%, and lowest 10% as ranked using risk-adjusted odds of mortality. There was moderate correlation between ranking based on 30- and 90-day mortality [weighted kappa = 0.45 (95% confidence interval, 0.39-0.52)]. Compared with 30-day mortality rankings, nearly 20% of hospitals changed their ranking category when 90-day mortality rankings were used. CONCLUSIONS: Examination of 90-day mortality after esophagectomy reflects cancer patient management decisions and may provide actionable targets for quality improvement. PMID- 25915913 TI - Is the Combination of Distal Pancreatectomy and Cytoreductive Surgery With HIPEC Reasonable?: Results of an International Multicenter Study. AB - OBJECTIVE: To report the morbidity and risk factors for overall complications and for pancreatic fistula (PF) after distal pancreatic resection (DP) during cytoreductive surgery and hyperthermic intraperitoneal chemotherapy (CRS/HIPEC). SUMMARY BACKGROUND DATA: The safety of DP in patients with peritoneal surface malignancies treated by CRS and HIPEC has been debated. The risk of PF and its impact on surgical outcomes are not well defined. METHODS: Between 2001 and 2012, 118 patients with peritoneal surface malignancy undergoing CRS/HIPEC required DP at 7 oncological surgical centers. The incidence, clinical impact, and risk factors of PF were analyzed. RESULTS: The indications for DP were tumoral invasion of the pancreatic gland with (n = 24; 20%) or without splenic extension (n = 76; 64%), invasion of the pancreatic capsule (n = 10; 9%), or iatrogenic lesions during CRS (n = 8; 7%). The rate of 90 days postoperative mortality was 7.6%, and the rate of severe morbidity (Clavien-Dindo >=III) was 44%. Pancreatic fistula was observed in 39 cases (33%), with the majority grade B (48.7%) or C (28.2%). In multivariate analysis, the risk factors for PF were a peritoneal cancer index more than 20 (risk ratio: 3.01; P = 0.022) and an operative time more than 550 min (risk ratio: 2.74; P = 0.038). The occurrence of PF was not associated with a higher risk of 90-day mortality (5.1% vs 8.8%, not significant). CONCLUSIONS: With regard to reported morbi-mortality rates, DP associated with CRS/HIPEC may be a reasonable procedure in highly selected patients when done in high-volume centers. Therefore, distal pancreatic involvement should not be considered as a definitive contraindication for CRS/HIPEC in patients with resectable peritoneal surface disease. PMID- 25915914 TI - The Human Colon Is More Resistant to Ischemia-reperfusion-induced Tissue Damage Than the Small Intestine: An Observational Study. AB - OBJECTIVE: Aim of this study was to draw comparisons between human colonic and jejunal ischemia-reperfusion sequelae in a human in vivo experimental model. BACKGROUND: In patients, colonic ischemia-reperfusion generally has a milder course than small intestinal ischemia-reperfusion. It is unclear which pathophysiologic processes are responsible for this difference. METHODS: In 10 patients undergoing colonic surgery and 10 patients undergoing pancreaticoduodenectomy, 6 cm colon or jejunum was isolated and exposed to 60 minutes ischemia followed by various reperfusion periods. Morphology (hematoxylin and eosin), apoptosis (M30), tight junctions (zonula occludens 1), and neutrophil influx (myeloperoxidase) were assessed using immunohistochemistry. Quantitative polymerase chain reaction and enzyme-linked immunosorbent assay were performed for interleukin-6 and tumor necrosis factor-alpha. RESULTS: Hematoxylin and eosin staining revealed intact colonic epithelial lining, but extensive damage in jejunal villus tips after 60 minutes ischemia. After reperfusion, the colonic epithelial lining was not affected, whereas the jejunal epithelium was seriously damaged. Colonic apoptosis was limited to scattered cells in surface epithelium, whereas apoptosis was clearly observed in jejunal villi and crypts, (42 times more M30 positivity compared with colon, P < 0.01). Neutrophil influx and increased tumor necrosis factor-alpha mRNA expression were observed in jejunum after 30 and 120 minutes of reperfusion (P < 0.05). Interleukin-6 mRNA expression was increased in jejunum after 120 minutes of reperfusion (3.6-fold increase, P < 0.05), whereas interleukin-6 protein expression was increased in both colon (1.5 fold increase, P < 0.05) and small intestine (1.5-fold increase, P < 0.05) after 30 and 120 minutes of reperfusion. CONCLUSIONS: Human colon is less susceptible to IR-induced tissue injury than small intestine. PMID- 25915915 TI - Pretreatment Neutrophil to Lymphocyte Ratio Independently Predicts Disease specific Survival in Resectable Gastroesophageal Junction and Gastric Adenocarcinoma. AB - OBJECTIVE: Preoperative methods to estimate disease-specific survival (DSS) for resectable gastroesophageal (GE) junction and gastric adenocarcinoma are limited. We evaluated the relationship between DSS and pretreatment neutrophil to lymphocyte ratio (NLR). BACKGROUND: The patient's inflammatory state is thought to be associated with oncologic outcomes, and NLR has been used as a simple and convenient marker for the systemic inflammatory response. Previous studies have suggested that NLR is associated with cancer-specific outcomes. METHODS: A retrospective review of a prospectively maintained institutional database was undertaken to identify patients who underwent potentially curative resection for GE junction and gastric adenocarcinoma from 1998 to 2013. Clinicopathologic findings, pretreatment leukocyte values, and follow-up status were recorded. The Kaplan-Meier method was used to estimate DSS, and Cox proportional hazards models were used to evaluate the association between variables and DSS. RESULTS: We identified 1498 patients who fulfilled our eligibility criteria. Univariate analysis showed that male sex, Caucasian race, increased T and N stage, GE junction location, moderate/poor differentiation, nonintestinal Lauren histology, and vascular and perineural invasion were associated with worse DSS. Elevated NLR was also associated with worse DSS [hazard ratio (HR) = 1.11; 95% CI: 1.08-1.14; P < 0.01]. On multivariate analysis, pretreatment NLR as a continuous variable was a highly significant independent predictor of DSS. For every unit increase in NLR, the risk of cancer-associated death increases by approximately 10% (HR = 1.10; 95% CI: 1.05-1.13; P < 0.0001). CONCLUSIONS: In patients with resectable GE junction and gastric adenocarcinoma, pretreatment NLR independently predicts DSS. This and other clinical variables can be used in conjunction with cross-sectional imaging and endoscopic ultrasound as part of the preoperative risk stratification process. PMID- 25915922 TI - REGULATOR OF BULB BIOGENESIS1 (RBB1) Is Involved in Vacuole Bulb Formation in Arabidopsis. AB - Vacuoles are dynamic compartments with constant fluctuations and transient structures such as trans-vacuolar strands and bulbs. Bulbs are highly dynamic spherical structures inside vacuoles that are formed by multiple layers of membranes and are continuous with the main tonoplast. We recently carried out a screen for mutants with abnormal trafficking to the vacuole or aberrant vacuole morphology. We characterized regulator of bulb biogenesis1-1 (rbb1-1), a mutant in Arabidopsis that contains increased numbers of bulbs when compared to the parental control. rbb1-1 mutants also contain fewer transvacuolar strands than the parental control, and we propose the hypothesis that the formation of transvacuolar strands and bulbs is functionally related. We propose that the bulbs may function transiently to accommodate membranes and proteins when transvacuolar strands fail to elongate. We show that RBB1 corresponds to a very large protein of unknown function that is specific to plants, is present in the cytosol, and may associate with cellular membranes. RBB1 is involved in the regulation of vacuole morphology and may be involved in the establishment or stability of trans-vacuolar strands and bulbs. PMID- 25915923 TI - Erythropoietin in the general population: reference ranges and clinical, biochemical and genetic correlates. AB - BACKGROUND: Although erythropoietin has been used for decades in the treatment of anemia, data regarding endogenous levels in the general population are scarce. Therefore, we determined erythropoietin reference ranges and its clinical, biochemical and genetic associations in the general population. METHODS: We used data from 6,777 subjects enrolled in the Prevention of REnal and Vascular ENd stage Disease (PREVEND) study. Fasting venous blood samples were obtained in the morning from all participants from 2001-2003. Serum erythropoietin concentrations were measured using a fully automated chemiluminescent enzyme-labeled immunometric assay. A genome-wide association study was performed to identify genetic determinants. RESULTS: Mean age (+/- SD) was 53 +/- 12 years and 50% were female. Median (IQR) erythropoietin concentrations were 7.6 (5.8-9.9) IU/L in men and 7.9 (6.0-10.6) IU/L in women. A strong positive correlation was found between erythropoietin and waist circumference, glucose and systolic blood pressure (all P < 0.05). In subjects with normal renal function there was a strong exponential relation between hemoglobin and erythropoietin, whereas in renal impairment (eGFR < 60 mL/min/1.73m2) this relation was linear (men) or absent (women) (P < 0.001 for interaction). Single-nucleotide polymorphisms at the HBS1L-MYB locus were shown to be related to erythropoietin levels (P < 9x10-21), more significantly than other erythrocyte parameters. CONCLUSION: We provide age-specific reference ranges for endogenous serum erythropoietin. Erythropoietin levels are positively associated with the components of the metabolic syndrome, except cholesterol. We show that even mild renal failure blunts erythropoietin production and propose the HBS1L-MYB locus as a regulator of erythropoietin. PMID- 25915924 TI - Coformulation of a Novel Human alpha-Galactosidase A With the Pharmacological Chaperone AT1001 Leads to Improved Substrate Reduction in Fabry Mice. AB - Fabry disease is an X-linked lysosomal storage disorder caused by mutations in the gene that encodes alpha-galactosidase A and is characterized by pathological accumulation of globotriaosylceramide and globotriaosylsphingosine. Earlier, the authors demonstrated that oral coadministration of the pharmacological chaperone AT1001 (migalastat HCl; 1-deoxygalactonojirimycin HCl) prior to intravenous administration of enzyme replacement therapy improved the pharmacological properties of the enzyme. In this study, the authors investigated the effects of coformulating AT1001 with a proprietary recombinant human alpha-galactosidase A (ATB100) into a single intravenous formulation. AT1001 increased the physical stability and reduced aggregation of ATB100 at neutral pH in vitro, and increased the potency for ATB100-mediated globotriaosylceramide reduction in cultured Fabry fibroblasts. In Fabry mice, AT1001 coformulation increased the total exposure of active enzyme, and increased ATB100 levels in cardiomyocytes, cardiac vascular endothelial cells, renal distal tubular epithelial cells, and glomerular cells, cell types that do not show substantial uptake with enzyme replacement therapy alone. Notably, AT1001 coformulation also leads to greater tissue globotriaosylceramide reduction when compared with ATB100 alone, which was positively correlated with reductions in plasma globotriaosylsphingosine. Collectively, these data indicate that intravenous administration of ATB100 coformulated with AT1001 may provide an improved therapy for Fabry disease and thus warrants further investigation. PMID- 25915925 TI - Cardiac AAV9 Gene Delivery Strategies in Adult Canines: Assessment by Long-term Serial SPECT Imaging of Sodium Iodide Symporter Expression. AB - Heart failure is a leading cause of morbidity and mortality, and cardiac gene delivery has the potential to provide novel therapeutic approaches. Adeno associated virus serotype 9 (AAV9) transduces the rodent heart efficiently, but cardiotropism, immune tolerance, and optimal delivery strategies in large animals are unclear. In this study, an AAV9 vector encoding canine sodium iodide symporter (NIS) was administered to adult immunocompetent dogs via epicardial injection, coronary infusion without and with cardiac recirculation, or endocardial injection via a novel catheter with curved needle and both end- and side-holes. As NIS mediates cellular uptake of clinical radioisotopes, expression was tracked by single-photon emission computerized tomography (SPECT) imaging in addition to Western blot and immunohistochemistry. Direct epicardial or endocardial injection resulted in strong cardiac expression, whereas expression after intracoronary infusion or cardiac recirculation was undetectable. A threshold myocardial injection dose that provides robust nonimmunogenic expression was identified. The extent of transmural myocardial expression was greater with the novel catheter versus straight end-hole needle delivery. Furthermore, the authors demonstrate that cardiac NIS reporter gene expression and duration can be quantified using serial noninvasive SPECT imaging up to 1 year after vector administration. These data are relevant to efforts to develop cardiac gene delivery as heart failure therapy. PMID- 25915926 TI - Using multiscale spatial models to assess potential surrogate habitat for an imperiled reptile. AB - In evaluating conservation and management options for species, practitioners might consider surrogate habitats at multiple scales when estimating available habitat or modeling species' potential distributions based on suitable habitats, especially when native environments are rare. Species' dependence on surrogates likely increases as optimal habitat is degraded and lost due to anthropogenic landscape change, and thus surrogate habitats may be vital for an imperiled species' survival in highly modified landscapes. We used spatial habitat models to examine a potential surrogate habitat for an imperiled ambush predator (eastern diamondback rattlesnake, Crotalus adamanteus; EDB) at two scales. The EDB is an apex predator indigenous to imperiled longleaf pine ecosystems (Pinus palustris) of the southeastern United States. Loss of native open-canopy pine savannas and woodlands has been suggested as the principal cause of the species' extensive decline. We examined EDB habitat selection in the Coastal Plain tidewater region to evaluate the role of marsh as a potential surrogate habitat and to further quantify the species' habitat requirements at two scales: home range (HR) and within the home range (WHR). We studied EDBs using radiotelemetry and employed an information-theoretic approach and logistic regression to model habitat selection as use vs. AVAILABILITY: We failed to detect a positive association with marsh as a surrogate habitat at the HR scale; rather, EDBs exhibited significantly negative associations with all landscape patches except pine savanna. Within home range selection was characterized by a negative association with forest and a positive association with ground cover, which suggests that EDBs may use surrogate habitats of similar structure, including marsh, within their home ranges. While our HR analysis did not support tidal marsh as a surrogate habitat, marsh may still provide resources for EDBs at smaller scales. PMID- 25915927 TI - Evaluation of the contributions of four components of gross domestic product in various regions in China. AB - Four major components influence the growth of the gross domestic product in Chinese provinces: consumption, investment, transnational exports, and inter provincial exports. By splitting a competitive input-output table into a non competitive input-output table, this study used an input-output model to measure the contributions of the four components of gross domestic product in various regions in China. We found that international exports drove the growth of the gross domestic product more strongly in the eastern region than in other regions. Investment and inter-provincial exports were the major impetus for gross domestic product growth in the central and western regions. We also found that consumption played a minimal role in driving the growth of the gross domestic product in all regions in China. According to these findings, although various regions can share much in terms of policies to transform the impetus for economic growth, there should be different foci for different regions. Their shared policy is to increase the role of final consumption in stimulating economic growth. Region specific policies mandate that the eastern region should strengthen the driving force provided by international exports and that the central and western regions should strengthen indigenous growth capabilities by improving scientific innovation, industrial support, and institutional innovation. PMID- 25915928 TI - ICRP Publication 126: Radiological Protection against Radon Exposure. AB - In this report, the Commission provides updated guidance on radiological protection against radon exposure. The report has been developed considering the latest ICRP recommendations for the system of radiological protection, all available scientific knowledge about the risks of radon, and the experience gained by many organisations and countries in the control of radon exposure. The report describes the characteristics of radon exposure, covering sources and transfer mechanisms, the health risks associated with radon, and the challenges of managing radon exposure. The Commission recommends an integrated approach for controlling radon exposure, relying as far as possible on the management of buildings or locations in which radon exposure occurs, whatever the use of the building. This approach is based on the optimisation principle, and is graded reflecting the responsibilities of key stakeholders, notably in workplaces, and the intent of the national authorities to control radon exposure. The report also provides recommendations on managing radon exposure when workers' exposures are considered as occupational, and the appropriate requirements of the Commission should be applied. PMID- 25915930 TI - Correction: New genetic and linguistic analyses show ancient human influence on baobab evolution and distribution in australia. PMID- 25915929 TI - Diagnostic Validity of the Generalized Anxiety Disorder - 7 (GAD-7) among Pregnant Women. AB - OBJECTIVE: Generalized anxiety disorder (GAD) during pregnancy is associated with several adverse maternal and perinatal outcomes. A reliable and valid screening tool for GAD should lead to earlier detection and treatment. Among pregnant Peruvian women, a brief screening tool, the GAD-7, has not been validated. This study aims to evaluate the reliability and validity of the GAD-7. METHODS: Of 2,978 women who attended their first perinatal care visit and had the GAD-7 screening, 946 had a Composite International Diagnostic Interview (CIDI). The Cronbach's alpha was calculated to examine the reliability. We assessed the criterion validity by calculating operating characteristics. The construct validity was evaluated using factor analysis and association with health status on the CIDI. The cross-cultural validity was explored using the Rasch Rating Scale Model (RSM). RESULTS: The reliability of the GAD-7 was good (Cronbach's alpha = 0.89). A cutoff score of 7 or higher, maximizing the Youden Index, yielded a sensitivity of 73.3% and a specificity of 67.3%. One-factor structure of the GAD-7 was confirmed by exploratory and confirmatory factor analysis. Concurrent validity was supported by the evidence that higher GAD-7 scores were associated with poor self-rated physical and mental health. The Rasch RSM further confirmed the cross-cultural validity of the GAD-7. CONCLUSION: The results suggest that the Spanish-language version of the GAD-7 may be used as a screening tool for pregnant Peruvian women. The GAD-7 has good reliability, factorial validity, and concurrent validity. The optimal cutoff score obtained by maximizing the Youden Index should be considered cautiously; women who screened positive may require further investigation to confirm GAD diagnosis. PMID- 25915931 TI - Quantifying discrepancies in opinion spectra from online and offline networks. AB - Online social media such as Twitter are widely used for mining public opinions and sentiments on various issues and topics. The sheer volume of the data generated and the eager adoption by the online-savvy public are helping to raise the profile of online media as a convenient source of news and public opinions on social and political issues as well. Due to the uncontrollable biases in the population who heavily use the media, however, it is often difficult to measure how accurately the online sphere reflects the offline world at large, undermining the usefulness of online media. One way of identifying and overcoming the online offline discrepancies is to apply a common analytical and modeling framework to comparable data sets from online and offline sources and cross-analyzing the patterns found therein. In this paper we study the political spectra constructed from Twitter and from legislators' voting records as an example to demonstrate the potential limits of online media as the source for accurate public opinion mining, and how to overcome the limits by using offline data simultaneously. PMID- 25915932 TI - Catch muscle myorod modulates ATPase activity of Myosin in a phosphorylation dependent way. AB - Myorod is expressed exclusively in molluscan catch muscle and localizes on the surface of thick filaments together with twitchin and myosin. Myorod is an alternatively spliced product of the myosin heavy-chain gene that contains the C terminal rod part of myosin and a unique N-terminal domain. The unique domain is a target for phosphorylation by gizzard smooth myosin light chain kinase (smMLCK) and, perhaps, molluscan twitchin, which contains a MLCK-like domain. To elucidate the role of myorod and its phosphorylation in the catch muscle, the effect of chromatographically purified myorod on the actin-activated Mg2+-ATPase activity of myosin was studied. We found that phosphorylation at the N-terminus of myorod potentiated the actin-activated Mg2+-ATPase activity of mussel and rabbit myosins. This potentiation occurred only if myorod was phosphorylated and introduced into the ATPase assay as a co-filament with myosin. We suggest that myorod could be related to the catch state, a function specific to molluscan muscle. PMID- 25915933 TI - The Phylogeography and Population Demography of the Yunnan Caecilian (Ichthyophis bannanicus): Massive Rivers as Barriers to Gene Flow. AB - Ichthyophis bannanicus is the only caecilian species in China. In this study, the phylogeography and population demography of I. bannanicus were explored, based on the mitochondrial DNA genes (cyt b and ND2) and 15 polymorphic microsatellite loci. Altogether 158 individuals were collected from five populations in Yunnan province, Guangxi province, Guangdong province, and Northern Vietnam. Phylogeographical and population structure analysis identified either two groups (Xishuangbanna, Northern Vietnam-Yulin-Yangchun-Deqing) or three groups (Xishuangbanna, Northern Vietnam-Yulin-Yangchun, and Deqing), indicating that the Red River and Pearl River systems may have acted as gene-flow barriers for I. bannanicus. Historical population expansion that happened 15-17 Ka ago was detected for mtDNA data and was possibly triggered by warmer weather after the Last Glacial Maximum. However, the Bayesian simulations of population history based on microsatellite data pinpointed population decline in all populations since 19,123 to 1,029 years ago, demonstrating a significant influence of anthropogenic habitat alteration on I. bannanicus. PMID- 25915934 TI - Distractor suppression when attention fails: behavioral evidence for a flexible selective attention mechanism. AB - Despite consistent evidence showing that attention is a multifaceted mechanism that can operate at multiple levels of processing depending on the structure and demands of the task, investigations of the attentional blink phenomenon have consistently shown that the impairment in reporting the second of two targets typically occurs at a late, or post-perceptual, stage of processing. This suggests that the attentional blink phenomenon may represent the operation of a unique attentional mechanism that is not as flexible as other attentional mechanisms. To test whether the attentional blink is a fixed or flexible phenomenon, we manipulated first target task demands (i.e., difficulty) and measured the influence this had on processing a subsequently presented distractor and the second target. If the attentional blink represents a mechanism that is fixed and consistently fails at a single stage of processing, then manipulations of task difficulty should not affect distractor processing. However, if the attentional blink represents a more multifaceted and flexible mechanism, then task difficulty should modulate distractor processing. The results revealed that distractor processing during the AB was attenuated under high task difficulty. In addition, unlike previous studies, we failed to find a correlation between distractor processing and the severity of the attentional blink. Using a simulation, we demonstrate that the previously reported correlations may have been spurious and due to using variables that were not independent. Overall, the present results support the conclusion that the selectivity of attention during the AB is flexible and depends on the structure and demands of the task. PMID- 25915935 TI - Genetic polymorphisms of dihydropyrimidinase in a Japanese patient with capecitabine-induced toxicity. AB - Dihydropyrimidinase (DHP) is the second enzyme in the catabolic pathway of uracil, thymine, and chemotherapeutic fluoropyrimidine agents such as 5 fluorouracil (5-FU). Thus, DHP deficiency might be associated with 5-FU toxicity during fluoropyrimidine chemotherapy. We performed genetic analyses of the family of a patient with advanced colon cancer who underwent radical colectomy followed by treatment with 5-FU prodrug capecitabine and developed severe toxicity attributable to a lack of DHP. We measured urinary uracil and dihydrouracil, and genotyped DPYS in the patient and her family. We also measured the allele frequency of DPYS polymorphisms in 391 unrelated Japanese subjects. The patient had compound heterozygous missense and nonsense polymorphisms comprising c.1001A>G (p.Gln334Arg) in exon 6 and c.1393C>T (p.Arg465Ter) in exon 8, which are known to result in a DHP enzyme with little or no activity. The urinary dihydrouracil/uracil ratio in the patient was 17.08, while the mean +/- SD urinary dihydrouracil/uracil ratio in family members who were heterozygous or homozygous for wild-type DPYS was 0.25 +/- 0.06. In unrelated subjects, 8 of 391 individuals were heterozygous for the c.1001A>G mutation, while the c.1393C>T mutation was not identified. This is the first report of a DHP-deficient patient with DPYS compound heterozygous polymorphisms who was treated with a fluoropyrimidine, and our findings suggest that polymorphisms in the DPYS gene are pharmacogenomic markers associated with severe 5-FU toxicity in Japanese patients. PMID- 25915936 TI - Sjogren's Syndrome Antigen B Acts as an Endogenous Danger Molecule to Induce Interleukin-8 Gene Expression in Polymorphonuclear Neutrophils. AB - BACKGROUND: Sjogren's syndrome antigen B is expressed in the nucleus and surface membrane of human polymorphonuclear neutrophils and is released after cell death. However, its biological role is not clear. This study is aimed to investigate the effect of Sjogren's syndrome antigen B on human polymorphonuclear neutrophils. METHODS: Human recombinant Sjogren's syndrome antigen B (rSSB) purified from E. coli was incubated with human polymorphonuclear neutrophils as well as retinoid acid-induced granulocytic differentiated HL-60 cells, HL-60 (RA). Interleukin (IL)-8 protein production and mRNA expressions were measured by enzyme-linked immunosorbent assay and quantitative-polymerase chain reaction, respectively. Uptake of fluorescein isothiocyanate (FITC)-rSSB was assessed by flow cytometry and fluorescence microscopy. Moreover, mitogen-activated protein kinase (MAPK) pathways and nuclear factor-kappaB activation were investigated. RESULTS: Human rSSB stimulated IL-8 production from normal human neutrophils and HL-60 (RA) cells in a time- and dose-dependent manner. This IL-8-stimulated activity was blocked by chloroquine and NH4Cl, indicating that endosomal acidification is important for this effect. We found rSSB activated both MAPK pathway and nuclear factor-kappaB signaling to transcribe the IL-8 gene expression of cells. Furthermore, tumor necrosis factor-alpha exerted an additive effect and rSSB-anti SSB immune complex exhibited a synergistic effect on rSSB-induced IL-8 production. CONCLUSIONS: Sjogren's syndrome antigen B might act as an endogenous danger molecule to enhance IL-8 gene expression in human polymorphonuclear neutrophils. PMID- 25915937 TI - MicroRNA Transcriptome Profile Analysis in Porcine Muscle and the Effect of miR 143 on the MYH7 Gene and Protein. AB - Porcine skeletal muscle fibres are classified based on their different physiological and biochemical properties. Muscle fibre phenotype is regulated by several independent signalling pathways, including the mitogen-activated protein kinase (MAPK), nuclear factor of activated T cells (NFAT), myocyte enhancer factor 2 (MEF2) and peroxisome proliferator-activated receptor (PPAR) signalling pathways. MicroRNAs are non-coding small RNAs that regulate many biological processes. However, their function in muscle fibre type regulation remains unclear. The aim of our study was to identify miRNAs that regulate muscle fibre type during porcine growth to help understand the miRNA regulation mechanism of fibre differentiation. We performed Solexa/Illumina deep sequencing for the microRNAome during 3 muscle growth stages (63, 98 and 161 d). In this study, 271 mature miRNAs and 243 pre-miRNAs were identified. We detected 472 novel miRNAs in the muscle samples. Among the mature miRNAs, there are 23 highest expression miRNAs (over 10,000 RPM), account for 85.3% of the total counts of mature miRNAs., including 10 (43.5%) muscle-related miRNAs (ssc-miR-133a-3p, ssc-miR 486, ssc-miR-1, ssc-miR-143-3p, ssc-miR-30a-5p, ssc-miR-181a, ssc-miR-148a-3p, ssc-miR-92a, ssc-miR-21, ssc-miR-126-5p). Particularly, both ssc-miR-1 and ssc miR-133 belong to the MyomiRs, which control muscle myosin content, myofibre identity and muscle performance. The involvement of these miRNAs in muscle fibre phenotype provides new insight into the mechanism of muscle fibre regulation underlying muscle development. Furthermore, we performed cell transfection experiment. Overexpression/inhibition of ssc-miR-143-3p in porcine skeletal muscle satellite cell induced an/a increase/reduction of the slow muscle fibre gene and protein (MYH7), indicating that miR-143 activity regulated muscle fibre differentiate in skeletal muscle. And it regulate MYH7 through the HDAC4-MEF2 pathway. PMID- 25915938 TI - The impact of smoking on airflow limitation in subjects with history of asthma and inactive tuberculosis. AB - BACKGROUND: Although smoking is the most important and modifiable cause of chronic obstructive pulmonary disease (COPD), other risk factors including asthma and tuberculosis (TB) are also associated. It is common for COPD patients to have more than one of these risk factors. The aims of this study were to determine the prevalence of airflow limitation (FEV1/FVC<0.7) according to the risk factors and to investigate their impact and interaction in airflow limitation. METHODS: From the Korean National Health and Nutrition Examination Survey between 2008 and 2012, we analyzed participants over 40 years of age by spirometry, chest radiograph and questionnaire about asthma and smoking history. RESULTS: Of 12,631 participants, 1,548 (12.3%) had airflow limitation. The prevalence of airflow limitation in smokers (>=10 pack-year), asthmatics, and those with inactive TB was 23.9%, 32.1%, and 33.6%. The prevalence increased with the number of risk factors: 86.1% had airflow limitation if they had all three risk factors. Impacts of inactive TB and asthma on airflow limitation were equivalent to 47 and 69 pack years of smoking, respectively. Airflow limitation resulted from lower levels of smoking in those with inactive TB and asthma. A potential interaction between smoking and inactive tuberculosis in the development of airflow limitation was identified (p = 0.054). CONCLUSIONS: Asthma and inactive TB lesions increase susceptibility to smoking in the development of airflow limitation. People with these risk factors should be seen as a major target population for anti-smoking campaigns to prevent COPD. PMID- 25915939 TI - Ovarian Ecdysteroidogenesis in Both Immature and Mature Stages of an Acari, Ornithodoros moubata. AB - Ecdysteroidogenesis is essential for arthropod development and reproduction. Although the importance of ecdysteroids has been demonstrated, there is little information on the sites and enzymes for synthesis of ecdysteroids from Chelicerates. Ecdysteroid functions have been well studied in the soft tick Ornithodoros moubata, making this species an excellent candidate for elucidating ecdysteroidogenesis in Chelicerates. Results showed that O. moubata has at least two ecdysteroidogenic enzymes, Spook (OmSpo) and Shade (OmShd). RNAi showed both enzymes were required for ecdysteroidogenesis. Enzymatic assays demonstrated OmShd has the conserved functions of ecdysone 20-hydroxylase. OmSpo showed specific expression in the ovaries of final nymphal and adult stages, indicating O. moubata utilizes the ovary as an ecdysteroidogenic tissue instead of specific tissues as seen in other arthropods. On the other hand, OmShd expression was observed in various tissues including the midgut, indicating functional ecdysteroids can be produced in these tissues. In nymphal stages, expression of both OmSpo and OmShd peaked before molting corresponding with high ecdysteroid titers in the hemolymph. In fed adult females, OmSpo expression peaked at 8-10 days after engorgement, while OmShd expression peaked immediately after engorgement. Mated females showed more frequent surges of OmShd than virgin females. These results indicate that the regulation of synthesis of ecdysteroids differs in nymphs and adult females, and mating modifies adult female ecdysteroidogenesis. This is the first report to focus on synthesis of ecdysteroids in ticks and provides essential knowledge for understanding the evolution of ecdysteroidogenesis in arthropods. PMID- 25915940 TI - Leading Causes of Death among Asian American Subgroups (2003-2011). AB - BACKGROUND: Our current understanding of Asian American mortality patterns has been distorted by the historical aggregation of diverse Asian subgroups on death certificates, masking important differences in the leading causes of death across subgroups. In this analysis, we aim to fill an important knowledge gap in Asian American health by reporting leading causes of mortality by disaggregated Asian American subgroups. METHODS AND FINDINGS: We examined national mortality records for the six largest Asian subgroups (Asian Indian, Chinese, Filipino, Japanese, Korean, Vietnamese) and non-Hispanic Whites (NHWs) from 2003-2011, and ranked the leading causes of death. We calculated all-cause and cause-specific age-adjusted rates, temporal trends with annual percent changes, and rate ratios by race/ethnicity and sex. Rankings revealed that as an aggregated group, cancer was the leading cause of death for Asian Americans. When disaggregated, there was notable heterogeneity. Among women, cancer was the leading cause of death for every group except Asian Indians. In men, cancer was the leading cause of death among Chinese, Korean, and Vietnamese men, while heart disease was the leading cause of death among Asian Indians, Filipino and Japanese men. The proportion of death due to heart disease for Asian Indian males was nearly double that of cancer (31% vs. 18%). Temporal trends showed increased mortality of cancer and diabetes in Asian Indians and Vietnamese; increased stroke mortality in Asian Indians; increased suicide mortality in Koreans; and increased mortality from Alzheimer's disease for all racial/ethnic groups from 2003-2011. All-cause rate ratios revealed that overall mortality is lower in Asian Americans compared to NHWs. CONCLUSIONS: Our findings show heterogeneity in the leading causes of death among Asian American subgroups. Additional research should focus on culturally competent and cost-effective approaches to prevent and treat specific diseases among these growing diverse populations. PMID- 25915941 TI - Physical activity and bone health in schoolchildren: the mediating role of fitness and body fat. AB - BACKGROUND: The relationship between physical activity (PA) and bone health is well known, although the role of percent body fat (%BF) and fitness as confounders or mediators in this relationship remains uncertain. OBJECTIVE: To examine whether the association between PA and bone mineral content (BMC) is mediated by %BF and cardiorespiratory fitness (CRF). METHODS: In this cross sectional study, BMC, total %BF (by DXA), vigorous PA (VPA), CRF, age and height were measured in 132 schoolchildren (62 boys, aged 8-11 years). ANCOVA was used to test differences in BMC by %BF, CRF and VPA, controlling for different sets of confounders. Simple mediation analyses and serial multiple mediation analyses were fitted to examine whether the relationship between PA and BMC is mediated by %BF and fitness. RESULTS: Children with high %BF had higher total body BMC than their peers after controlling for all sets of confounders. Children with good CRF or VPA had significantly less total body BMC after controlling for age and sex but in children with good CRF this inverse relation disappeared after adjusting by %BF. %BF and CRF both act as a full mediator in the association between VPA and BMC, after inclusion of the potential confounders in the models. CONCLUSION: Fitness and %BF seem to have a mediator role on the relationship between physical activity and bone mass. PMID- 25915943 TI - Correction: Plant Water Use Efficiency over Geological Time-Evolution of Leaf Stomata Configurations Affecting Plant Gas Exchange. PMID- 25915942 TI - MicroRNA-27a Contributes to Rhabdomyosarcoma Cell Proliferation by Suppressing RARA and RXRA. AB - BACKGROUND: Rhabdomyosarcomas (RMS) are rare but very aggressive childhood tumors that arise as a consequence of a regulatory disruption in the growth and differentiation pathways of myogenic precursor cells. According to morphological criteria, there are two major RMS subtypes: embryonal RMS (ERMS) and alveolar RMS (ARMS) with the latter showing greater aggressiveness and metastatic potential with respect to the former. Efforts to unravel the complex molecular mechanisms underlying RMS pathogenesis and progression have revealed that microRNAs (miRNAs) play a key role in tumorigenesis. METHODOLOGY/PRINCIPAL FINDINGS: The expression profiles of 8 different RMS cell lines were analyzed to investigate the involvement of miRNAs in RMS. The miRNA population from each cell line was compared to a reference sample consisting of a balanced pool of total RNA extracted from those 8 cell lines. Sixteen miRNAs whose expression discriminates between translocation-positive ARMS and negative RMS were identified. Attention was focused on the role of miR-27a that is up-regulated in the more aggressive RMS cell lines (translocation-positive ARMS) in which it probably acts as an oncogene. MiR-27a overexpressing cells showed a significant increase in their proliferation rate that was paralleled by a decrease in the number of cells in the G1 phase of the cell cycle. It was possible to demonstrate that miR-27a is implicated in cell cycle control by targeting the retinoic acid alpha receptor (RARA) and retinoic X receptor alpha (RXRA). CONCLUSIONS: Study results have demonstrated that miRNA expression signature profiling can be used to classify different RMS subtypes and suggest that miR-27a may have a therapeutic potential in RMS by modulating the expression of retinoic acid receptors. PMID- 25915944 TI - A Randomized Pilot Trial Comparing Position Emission Tomography (PET)-Guided Dose Escalation Radiotherapy to Conventional Radiotherapy in Chemoradiotherapy Treatment of Locally Advanced Nasopharyngeal Carcinoma. AB - BACKGROUND: This pilot trial is designed to determine whether PET/CT-guided radiotherapy dose escalation can improve local control while minimizing toxicity for the treatment of locally advanced nasopharyngeal carcinoma. METHODS: 67 patients were randomized into the three treatment arms: conventional chemoradiotherapy (group A), CT-guided dose escalation chemoradiotherapy (group B) and PET/CT-guided dose escalation chemoradiotherapy (group C). Radiotherapy was delivered using the simultaneous modulated accelerated radiation therapy (SMART) technique in the dose-escalation treatment arms. Patients received concurrent and adjuvant chemotherapy. RESULTS: The use of PET/CT significantly changed the treatment volume delineation of the gross tumor volume. 3-year local progression-free (LPF) survival rates of three groups were 83.3%, 90.9% and 100%, respectively. The 3-year regional progression-free survival (RPFS) rates were 95.8%, 95.5% and 100%, respectively. The 3-year disease free survival (DFS) rates were 79.2%, 86.4% and 95.2%, respectively. The 3-year overall survival (OS) rates were 83.3%, 90.9% and 95.2%, respectively. The 3-year disease-free survival (DFS) rates were 79.2%, 86.4% and 95.2%, respectively. No patient had grade 4 late toxicity. CONCLUSIONS: PET/CT-guided dose escalation radiotherapy is well tolerated and appears to be superior to conventional chemoradiotherapy for locally advanced NPC. TRIAL REGISTRATION: ClinicalTrials.gov NCT02089204. PMID- 25915945 TI - Effect of influenza-induced fever on human bioimpedance values. AB - BACKGROUND AND AIMS: Bioelectrical impedance analysis (BIA) is a widely used technique to assess body composition and nutritional status. While bioelectrical values are affected by diverse variables, there has been little research on validation of BIA in acute illness, especially to understand prognostic significance. Here we report the use of BIA in acute febrile states induced by influenza. METHODS: Bioimpedance studies were conducted during an H1N1 influenza A outbreak in Venezuelan Amerindian villages from the Amazonas. Measurements were performed on 52 subjects between 1 and 40 years of age, and 7 children were re examined after starting Oseltamivir treatment. Bioelectrical Impedance Vector Analysis (BIVA) and permutation tests were applied. RESULTS: For the entire sample, febrile individuals showed a tendency toward greater reactance (p=0.058) and phase angle (p=0.037) than afebrile individuals, while resistance and impedance were similar in the two groups. Individuals with repeated measurements showed significant differences in bioimpedance values associated with fever, including increased reactance (p<0.001) and phase angle (p=0.007), and decreased resistance (p=0.007) and impedance (p<0.001). CONCLUSIONS: There are bioelectrical variations induced by influenza that can be related to dehydration, with lower extracellular to intracellular water ratio in febrile individuals, or a direct thermal effect. Caution is recommended when interpreting bioimpedance results in febrile states. PMID- 25915946 TI - Molecular and Functional Characterization of Three Different Postzygotic Mutations in PIK3CA-Related Overgrowth Spectrum (PROS) Patients: Effects on PI3K/AKT/mTOR Signaling and Sensitivity to PIK3 Inhibitors. AB - BACKGROUND: PIK3CA-related overgrowth spectrum (PROS) include a group of disorders that affect only the terminal portion of a limb, such as type I macrodactyly, and conditions like fibroadipose overgrowth (FAO), megalencephaly capillary malformation (MCAP) syndrome, congenital lipomatous asymmetric overgrowth of the trunk, lymphatic, capillary, venous, and combined-type vascular malformations, epidermal nevi, skeletal and spinal anomalies (CLOVES) syndrome and Hemihyperplasia Multiple Lipomatosis (HHML). Heterozygous postzygotic PIK3CA mutations are frequently identified in these syndromes, while timing and tissue specificity of the mutational event are likely responsible for the extreme phenotypic variability observed. METHODS: We carried out a combination of Sanger sequencing and targeted deep sequencing of genes involved in the PI3K/AKT/mTOR pathway in three patients (1 MCAP and 2 FAO) to identify causative mutations, and performed immunoblot analyses to assay the phosphorylation status of AKT and P70S6K in affected dermal fibroblasts. In addition, we evaluated their ability to grow in the absence of serum and their response to the PI3K inhibitors wortmannin and LY294002 in vitro. RESULTS AND CONCLUSION: Our data indicate that patients' cells showed constitutive activation of the PI3K/Akt pathway. Of note, PI3K pharmacological blockade resulted in a significant reduction of the proliferation rate in culture, suggesting that inhibition of PI3K might prove beneficial in future therapies for PROS patients. PMID- 25915947 TI - Serum Immunoglobulin M Concentration Varies with Triglyceride Levels in an Adult Population: Tianjin Chronic Low-Grade Systemic Inflammation and Health (TCLSIHealth) Cohort Study. AB - Persistent low-grade inflammation is thought to underlie the pathogenesis of many chronic diseases, such as cardiovascular diseases and metabolic syndrome. Autoimmunity is correlated with increased levels of chronic low-grade inflammation, and immunoglobulin M (IgM) is reactive to autoantigens and believed to be important for autoimmunity. Triglyceride (TG) is fatty acid carrier and initiator of oxidative stress, and it has been hypothesized that TG stimulates B cells to secrete IgM. However, few studies have investigated the relationship between TG and IgM in human populations. We designed a cross-sectional and prospective cohort study to evaluate how serum TG levels are related to IgM concentration. Participants were recruited from Tianjin Medical University General Hospital-Health Management Centre. Both a baseline cross-sectional (n = 10,808) and a prospective assessment (n = 2,615) were performed. Analysis of covariance was used in the cross-sectional analysis. After multiple adjustments for confounding factors, serum IgM level in the highest quartile of TG in males was significantly higher than levels in lower quartiles (P <0.05). There was no significant difference between the four quartiles in females (P = 0.91). In follow-up analysis, a multiple linear regression model showed a significant and positive correlation between changes in IgM levels and changes of TG concentration in males (P = 0.04, standard beta coefficient = 0.882). This cross sectional and cohort study is the first to show that serum concentration of IgM varies with TG levels in adult male populations. Further research is needed to explore the mechanism by which TG leads to increased IgM concentration. PMID- 25915949 TI - Correction: Validation of serological tests for the detection of antibodies against Treponema pallidum in nonhuman primates. AB - [This corrects the article DOI: 10.1371/journal.pntd.0003637.]. PMID- 25915948 TI - Postoperative Capecitabine with Concurrent Intensity-Modulated Radiotherapy or Three-Dimensional Conformal Radiotherapy for Patients with Stage II and III Rectal Cancer. AB - BACKGROUND: The aim of this study was to evaluate the survival outcomes and toxicity of postoperative chemoradiotherapy with capecitabine and concurrent intensity-modulated radiotherapy (IMRT) or three-dimensional conformal radiotherapy (3D-CRT) in patients with stage II and III rectal cancer. PATIENTS: We recruited 184 patients with pathologically proven, stage II or III rectal cancer. Following total mesorectal excision (TME), the patients were treated with capecitabine and concurrent IMRT/3D-CRT. The treatment regimen consisted of two cycles of oral capecitabine (1600 mg/m2/day), administered twice daily from day 1 14 of radiotherapy, followed by a 7-day rest. The median pelvic dose was 50 Gy in 25 fractions. Oxaliplatin-based adjuvant chemotherapy was administered after the chemoradiotherapy. RESULTS: The 5-year overall survival, disease-free survival and locoregional control (LRC) rates were 85.1%, 80% and 95.4%, respectively. Grade 3 and 4 toxicities were observed in 28.3% of patients during treatment. Grade 3 or 4 late toxicity, including neurotoxicity or gastrointestinal toxicity, was only observed in nine patients (4.9%). CONCLUSIONS: This study demonstrated that capecitabine chemotherapy with concurrent IMRT/3D-CRT following TME is safe, is well tolerated and achieves superior LRC and favorable survival rates, with acceptable toxicity. PMID- 25915950 TI - Increased sensitivity of DNA damage response-deficient cells to stimulated microgravity-induced DNA lesions. AB - Microgravity is a major stress factor that astronauts have to face in space. In the past, the effects of microgravity on genomic DNA damage were studied, and it seems that the effect on genomic DNA depends on cell types and the length of exposure time to microgravity or simulated microgravity (SMG). In this study we used mouse embryonic stem (MES) and mouse embryonic fibroblast (MEF) cells to assess the effects of SMG on DNA lesions. To acquire the insight into potential mechanisms by which cells resist and/or adapt to SMG, we also included Rad9 deleted MES and Mdc1-deleted MEF cells in addition to wild type cells in this study. We observed significant SMG-induced DNA double strand breaks (DSBs) in Rad9-/- MES and Mdc1-/- MEF cells but not in their corresponding wild type cells. A similar pattern of DNA single strand break or modifications was also observed in Rad9-/- MES. As the exposure to SMG was prolonged, Rad9-/- MES cells adapted to the SMG disturbance by reducing the induced DNA lesions. The induced DNA lesions in Rad9-/- MES were due to SMG-induced reactive oxygen species (ROS). Interestingly, Mdc1-/- MEF cells were only partially adapted to the SMG disturbance. That is, the induced DNA lesions were reduced over time, but did not return to the control level while ROS returned to a control level. In addition, ROS was only partially responsible for the induced DNA lesions in Mdc1-/- MEF cells. Taken together, these data suggest that SMG is a weak genomic DNA stress and can aggravate genomic instability in cells with DNA damage response (DDR) defects. PMID- 25915952 TI - ICRP Publication 127: Radiological Protection in Ion Beam Radiotherapy. AB - Abstract -: The goal of external-beam radiotherapy is to provide precise dose localisation in the treatment volume of the target with minimal damage to the surrounding normal tissue. Ion beams, such as protons and carbon ions, provide excellent dose distributions due primarily to their finite range, allowing a significant reduction of undesired exposure of normal tissue. Careful treatment planning is required for the given type and localisation of the tumour to be treated in order to maximise treatment efficiency and minimise the dose to normal tissue. Radiation exposure in out-of-field volumes arises from secondary neutrons and photons, particle fragments, and photons from activated materials. These unavoidable doses should be considered from the standpoint of radiological protection of the patient. Radiological protection of medical staff at ion beam radiotherapy facilities requires special attention. Appropriate management and control are required for the therapeutic equipment and the air in the treatment room that can be activated by the particle beam and its secondaries. Radiological protection and safety management should always conform with regulatory requirements. The current regulations for occupational exposures in photon radiotherapy are applicable to ion beam radiotherapy with protons or carbon ions. However, ion beam radiotherapy requires a more complex treatment system than conventional radiotherapy, and appropriate training of staff and suitable quality assurance programmes are recommended to avoid possible accidental exposure of patients, to minimise unnecessary doses to normal tissue, and to minimise radiation exposure of staff. PMID- 25915951 TI - Increased Short-Term Beat-To-Beat Variability of QT Interval in Patients with Acromegaly. AB - Cardiovascular diseases, including ventricular arrhythmias are responsible for increased mortality in patients with acromegaly. Acromegaly may cause repolarization abnormalities such as QT prolongation and impairment of repolarization reserve enhancing liability to arrhythmia. The aim of this study was to determine the short-term beat-to-beat QT variability in patients with acromegaly. Thirty acromegalic patients (23 women and 7 men, mean age+/-SD: 55.7+/-10.4 years) were compared with age- and sex-matched volunteers (mean age 51.3+/-7.6 years). Cardiac repolarization parameters including frequency corrected QT interval, PQ and QRS intervals, duration of terminal part of T waves (Tpeak-Tend) and short-term variability of QT interval were evaluated. All acromegalic patients and controls underwent transthoracic echocardiographic examination. Autonomic function was assessed by means of five standard cardiovascular reflex tests. Comparison of the two groups revealed no significant differences in the conventional ECG parameters of repolarization (QT: 401.1+/ 30.6 ms vs 389.3+/-16.5 ms, corrected QT interval: 430.1+/-18.6 ms vs 425.6+/ 17.3 ms, QT dispersion: 38.2+/-13.2 ms vs 36.6+/-10.2 ms; acromegaly vs control, respectively). However, short-term beat-to-beat QT variability was significantly increased in acromegalic patients (4.23+/-1.03 ms vs 3.02+/-0.80, P<0.0001). There were significant differences between the two groups in the echocardiographic dimensions (left ventricular end diastolic diameter: 52.6+/-5.4 mm vs 48.0+/-3.9 mm, left ventricular end systolic diameter: 32.3+/-5.2 mm vs 29.1+/-4.4 mm, interventricular septum: 11.1+/-2.2 mm vs 8.8+/-0.7 mm, posterior wall of left ventricle: 10.8+/-1.4 mm vs 8.9+/-0.7 mm, P<0.05, respectively). Short-term beat-to-beat QT variability was elevated in patients with acromegaly in spite of unchanged conventional parameters of ventricular repolarization. This enhanced temporal QT variability may be an early indicator of increased liability to arrhythmia. PMID- 25915954 TI - Fully Automated Renal Tissue Volumetry in MR Volume Data Using Prior-Shape-Based Segmentation in Subject-Specific Probability Maps. AB - Organ segmentation in magnetic resonance (MR) volume data is of increasing interest in epidemiological studies and clinical practice. Especially in large scale population-based studies, organ volumetry is highly relevant requiring exact organ segmentation. Since manual segmentation is time consuming and prone to reader variability, large-scale studies need automatic methods to perform organ segmentation. In this paper, we present an automated framework for renal tissue segmentation that computes renal parenchyma, cortex, and medulla volumetry in native MR volume data without any user interaction. We introduce a novel strategy of subject-specific probability map computation for renal tissue types, which takes inter- and intra-MR-intensity variability into account. Several kinds of tissue-related 2-D and 3-D prior-shape knowledge are incorporated in modularized framework parts to segment renal parenchyma in a final level set segmentation strategy. Subject-specific probabilities for medulla and cortex tissue are applied in a fuzzy clustering technique to delineate cortex and medulla tissue inside segmented parenchyma regions. The novel subject-specific computation approach provides clearly improved tissue probability map quality than existing methods. Comparing to existing methods, the framework provides improved results for parenchyma segmentation. Furthermore, cortex and medulla segmentation qualities are very promising but cannot be compared to existing methods since state-of-the art methods for automated cortex and medulla segmentation in native MR volume data are still missing. PMID- 25915955 TI - Online Calibration of Glucose Sensors From the Measured Current by a Time-Varying Calibration Function and Bayesian Priors. AB - GOAL: Minimally invasive continuous glucose monitoring (CGM) sensors measure in the subcutis a current signal, which is converted into interstitial glucose (IG) concentration by a calibration process periodically updated using fingerstick blood glucose (BG) references. Though important in diabetes management, CGM sensors still suffer from accuracy problems. Here, we propose a new online calibration method improving accuracy of CGM glucose profiles with respect to manufacturer calibration. METHOD: The proposed method fits CGM current signal against the BG references collected twice a day for calibration purposes, by a time-varying calibration function whose parameters are identified in a Bayesian framework using a priori second-order statistical knowledge. The distortion introduced by BG-to-IG kinetics is compensated before parameter identification via nonparametric deconvolution. RESULTS: The method was tested on a database where 108 CGM signals were collected for 7 days by the Dexcom G4 Platinum sensor. Results show the new method drives to a statistically significant accuracy improvement as measured by three commonly used metrics: mean absolute relative difference reduced from 12.73% to 11.47%; percentage of accurate glucose estimates increased from 82.00% to 89.19%; and percentage of values falling in the "A" zone of the Clark error grid increased from 82.22% to 88.86%. CONCLUSION: The new calibration method significantly improves CGM glucose profiles accuracy with respect to manufacturer calibration. SIGNIFICANCE: The proposed algorithm provides a real-time improvement of CGM accuracy, which can be crucial in several CGM-based applications, including the artificial pancreas, thus providing a potential great impact in the diabetes technology research community. PMID- 25915956 TI - Epipolar Consistency in Transmission Imaging. AB - This paper presents the derivation of the Epipolar Consistency Conditions (ECC) between two X-ray images from the Beer-Lambert law of X-ray attenuation and the Epipolar Geometry of two pinhole cameras, using Grangeat's theorem. We motivate the use of Oriented Projective Geometry to express redundant line integrals in projection images and define a consistency metric, which can be used, for instance, to estimate patient motion directly from a set of X-ray images. We describe in detail the mathematical tools to implement an algorithm to compute the Epipolar Consistency Metric and investigate its properties with detailed random studies on both artificial and real FD-CT data. A set of six reference projections of the CT scan of a fish were used to evaluate accuracy and precision of compensating for random disturbances of the ground truth projection matrix using an optimization of the consistency metric. In addition, we use three X-ray images of a pumpkin to prove applicability to real data. We conclude, that the metric might have potential in applications related to the estimation of projection geometry. By expression of redundancy between two arbitrary projection views, we in fact support any device or acquisition trajectory which uses a cone beam geometry. We discuss certain geometric situations, where the ECC provide the ability to correct 3D motion, without the need for 3D reconstruction. PMID- 25915957 TI - A Novel Image Representation via Local Frequency Analysis for Illumination Invariant Stereo Matching. AB - In this paper, we propose a novel image representation approach to tackle illumination variations in stereo matching problems. Images are mapped using their Fourier transforms which are convolved with a set of monogenic filters. Frequency analysis is carried out at different scales to account for most image content. The phase congruency and the local weighted mean phase angle are then computed over all the scales. The original image is transformed into a new representation using these two mappings. This representation is invariant to illumination and contrast variations. More importantly, it is generic and can be used with most sparse as well as dense stereo matching algorithms. In addition, sequential feature matching or tracking can also benefit from our approach in varying radiometric conditions. We demonstrate the improvements introduced with our image mappings on well-established data sets in the literature as well as on our own experimental scenarios that include high dynamic range imagery. The experiments include both dense and sparse stereo and sequential matching algorithms where the latter is considered in the very challenging visual odometry framework. PMID- 25915958 TI - Bayesian estimation of the multifractality parameter for image texture using a whittle approximation. AB - Texture characterization is a central element in many image processing applications. Multifractal analysis is a useful signal and image processing tool, yet, the accurate estimation of multifractal parameters for image texture remains a challenge. This is due in the main to the fact that current estimation procedures consist of performing linear regressions across frequency scales of the 2D dyadic wavelet transform, for which only a few such scales are computable for images. The strongly non-Gaussian nature of multifractal processes, combined with their complicated dependence structure, makes it difficult to develop suitable models for parameter estimation. Here, we propose a Bayesian procedure that addresses the difficulties in the estimation of the multifractality parameter. The originality of the procedure is threefold. The construction of a generic semiparametric statistical model for the logarithm of wavelet leaders; the formulation of Bayesian estimators that are associated with this model and the set of parameter values admitted by multifractal theory; the exploitation of a suitable Whittle approximation within the Bayesian model which enables the otherwise infeasible evaluation of the posterior distribution associated with the model. Performance is assessed numerically for several 2D multifractal processes, for several image sizes and a large range of process parameters. The procedure yields significant benefits over current benchmark estimators in terms of estimation performance and ability to discriminate between the two most commonly used classes of multifractal process models. The gains in performance are particularly pronounced for small image sizes, notably enabling for the first time the analysis of image patches as small as 64 * 64 pixels. PMID- 25915959 TI - Learning compact feature descriptor and adaptive matching framework for face recognition. AB - Dense feature extraction is becoming increasingly popular in face recognition tasks. Systems based on this approach have demonstrated impressive performance in a range of challenging scenarios. However, improvements in discriminative power come at a computational cost and with a risk of over-fitting. In this paper, we propose a new approach to dense feature extraction for face recognition, which consists of two steps. First, an encoding scheme is devised that compresses high dimensional dense features into a compact representation by maximizing the intrauser correlation. Second, we develop an adaptive feature matching algorithm for effective classification. This matching method, in contrast to the previous methods, constructs and chooses a small subset of training samples for adaptive matching, resulting in further performance gains. Experiments using several challenging face databases, including labeled Faces in the Wild data set, Morph Album 2, CUHK optical-infrared, and FERET, demonstrate that the proposed approach consistently outperforms the current state of the art. PMID- 25915960 TI - A feature-enriched completely blind image quality evaluator. AB - Existing blind image quality assessment (BIQA) methods are mostly opinion-aware. They learn regression models from training images with associated human subjective scores to predict the perceptual quality of test images. Such opinion aware methods, however, require a large amount of training samples with associated human subjective scores and of a variety of distortion types. The BIQA models learned by opinion-aware methods often have weak generalization capability, hereby limiting their usability in practice. By comparison, opinion unaware methods do not need human subjective scores for training, and thus have greater potential for good generalization capability. Unfortunately, thus far no opinion-unaware BIQA method has shown consistently better quality prediction accuracy than the opinion-aware methods. Here, we aim to develop an opinion unaware BIQA method that can compete with, and perhaps outperform, the existing opinion-aware methods. By integrating the features of natural image statistics derived from multiple cues, we learn a multivariate Gaussian model of image patches from a collection of pristine natural images. Using the learned multivariate Gaussian model, a Bhattacharyya-like distance is used to measure the quality of each image patch, and then an overall quality score is obtained by average pooling. The proposed BIQA method does not need any distorted sample images nor subjective quality scores for training, yet extensive experiments demonstrate its superior quality-prediction performance to the state-of-the-art opinion-aware BIQA methods. The MATLAB source code of our algorithm is publicly available at www.comp.polyu.edu.hk/~cslzhang/IQA/ILNIQE/ILNIQE.htm. PMID- 25915961 TI - An Approach for the Cooperative Control of FES With a Powered Exoskeleton During Level Walking for Persons With Paraplegia. AB - This paper describes a hybrid system that combines a powered lower limb exoskeleton with functional electrical stimulation (FES) for gait restoration in persons with paraplegia. The general control structure consists of two control loops: a motor control loop, which utilizes joint angle feedback control to control the output of the joint motor to track the desired joint trajectories, and a muscle control loop, which utilizes joint torque profiles from previous steps to shape the muscle stimulation profile for the subsequent step in order to minimize the motor torque contribution required for joint angle trajectory tracking. The implementation described here incorporates stimulation of the hamstrings and quadriceps muscles, such that the hip joints are actuated by the combination of hip motors and the hamstrings, and the knee joints are actuated by the combination of knee motors and the quadriceps. In order to demonstrate efficacy, the control approach was implemented on three paraplegic subjects with motor complete spinal cord injuries ranging from levels T6 to T10. Experimental data indicates that the cooperative control system provided consistent and repeatable gait motions and reduced the torque and power output required from the hip and knee motors of the exoskeleton compared to walking without FES. PMID- 25915963 TI - A New Stochastic Computing Methodology for Efficient Neural Network Implementation. AB - This paper presents a new methodology for the hardware implementation of neural networks (NNs) based on probabilistic laws. The proposed encoding scheme circumvents the limitations of classical stochastic computing (based on unipolar or bipolar encoding) extending the representation range to any real number using the ratio of two bipolar-encoded pulsed signals. Furthermore, the novel approach presents practically a total noise-immunity capability due to its specific codification. We introduce different designs for building the fundamental blocks needed to implement NNs. The validity of the present approach is demonstrated through a regression and a pattern recognition task. The low cost of the methodology in terms of hardware, along with its capacity to implement complex mathematical functions (such as the hyperbolic tangent), allows its use for building highly reliable systems and parallel computing. PMID- 25915962 TI - Utilizing ECG-Based Heartbeat Classification for Hypertrophic Cardiomyopathy Identification. AB - Hypertrophic cardiomyopathy (HCM) is a cardiovascular disease where the heart muscle is partially thickened and blood flow is (potentially fatally) obstructed. A test based on electrocardiograms (ECG) that record the heart electrical activity can help in early detection of HCM patients. This paper presents a cardiovascular-patient classifier we developed to identify HCM patients using standard 10-second, 12-lead ECG signals. Patients are classified as having HCM if the majority of their recorded heartbeats are recognized as characteristic of HCM. Thus, the classifier's underlying task is to recognize individual heartbeats segmented from 12-lead ECG signals as HCM beats, where heartbeats from non-HCM cardiovascular patients are used as controls. We extracted 504 morphological and temporal features-both commonly used and newly-developed ones-from ECG signals for heartbeat classification. To assess classification performance, we trained and tested a random forest classifier and a support vector machine classifier using 5-fold cross validation. We also compared the performance of these two classifiers to that obtained by a logistic regression classifier, and the first two methods performed better than logistic regression. The patient-classification precision of random forests and of support vector machine classifiers is close to 0.85. Recall (sensitivity) and specificity are approximately 0.90. We also conducted feature selection experiments by gradually removing the least informative features; the results show that a relatively small subset of 264 highly informative features can achieve performance measures comparable to those achieved by using the complete set of features. PMID- 25915964 TI - Adaptive Neural Output Feedback Control of Output-Constrained Nonlinear Systems With Unknown Output Nonlinearity. AB - This paper addresses the problem of adaptive neural output-feedback control for a class of special nonlinear systems with the hysteretic output mechanism and the unmeasured states. A modified Bouc-Wen model is first employed to capture the output hysteresis phenomenon in the design procedure. For its fusion with the neural networks and the Nussbaum-type function, two key lemmas are established using some extended properties of this model. To avoid the bad system performance caused by the output nonlinearity, a barrier Lyapunov function technique is introduced to guarantee the prescribed constraint of the tracking error. In addition, a robust filtering method is designed to cancel the restriction that all the system states require to be measured. Based on the Lyapunov synthesis, a new neural adaptive controller is constructed to guarantee the prescribed convergence of the tracking error and the semiglobal uniform ultimate boundedness of all the signals in the closed-loop system. Simulations are implemented to evaluate the performance of the proposed neural control algorithm in this paper. PMID- 25915965 TI - Fall Detection Using Smartphone Audio Features. AB - An automated fall detection system based on smartphone audio features is developed. The spectrogram, mel frequency cepstral coefficents (MFCCs), linear predictive coding (LPC), and matching pursuit (MP) features of different fall and no-fall sound events are extracted from experimental data. Based on the extracted audio features, four different machine learning classifiers: k-nearest neighbor classifier (k-NN), support vector machine (SVM), least squares method (LSM), and artificial neural network (ANN) are investigated for distinguishing between fall and no-fall events. For each audio feature, the performance of each classifier in terms of sensitivity, specificity, accuracy, and computational complexity is evaluated. The best performance is achieved using spectrogram features with ANN classifier with sensitivity, specificity, and accuracy all above 98%. The classifier also has acceptable computational requirement for training and testing. The system is applicable in home environments where the phone is placed in the vicinity of the user. PMID- 25915966 TI - Detecting Subclinical Diabetic Cardiac Autonomic Neuropathy by Analyzing Ventricular Repolarization Dynamics. AB - In this study, a linear parametric modeling technique was applied to model ventricular repolarization (VR) dynamics. Three features were selected from the surface ECG recordings to investigate the changes in VR dynamics in healthy and cardiac autonomic neuropathy (CAN) participants with diabetes including heart rate variability (calculated from RR intervals), repolarization variability (calculated from QT intervals), and respiration [calculated by ECG-derived respiration (EDR)]. Surface ECGs were recorded in a supine resting position from 80 age-matched participants (40 with no cardiac autonomic neuropathy (NCAN) and 40 with CAN). In the CAN group, 25 participants had early/subclinical CAN (ECAN) and 15 participants were identified with definite/clinical CAN (DCAN). Detecting subclinical CAN is crucial for designing an effective treatment plan to prevent further cardiovascular complications. For CAN diagnosis, VR dynamics was analyzed using linear parametric autoregressive bivariate (ARXAR) and trivariate (ARXXAR) models, which were estimated using 250 beats of derived QT, RR, and EDR time series extracted from the first 5 min of the recorded ECG signal. Results showed that the EDR-based models gave a significantly higher fitting value (p < 0.0001) than models without EDR, which indicates that QT-RR dynamics is better explained by respiratory-information-based models. Moreover, the QT-RR-EDR model fitting values gradually decreased from the NCAN group to ECAN and DCAN groups, which indicate a decoupling of QT from RR and the respiration signal with the increase in severity of CAN. In this study, only the EDR-based model significantly distinguished ECAN and DCAN groups from the NCAN group (p < 0.05) with large effect sizes (Cohen's d > 0.75) showing the effectiveness of this modeling technique in detecting subclinical CAN. In conclusion, the EDR-based trivariate QT-RR-EDR model was found to be better in detecting the presence and severity of CAN than the bivariate QT-RR model. This finding also establishes the importance of adding respiratory information for analyzing the gradual deterioration of normal VR dynamics in pathological conditions, such as diabetic CAN. PMID- 25915967 TI - Author's response. PMID- 25915968 TI - Author's response. PMID- 25915969 TI - [In Process Citation]. PMID- 25915970 TI - [Treatment of lingual frenulum]. PMID- 25915972 TI - [Not Available]. PMID- 25915971 TI - [Ventricular septal defect repair]. PMID- 25915973 TI - Innovation waivers: an opportunity for states to pursue their own brand of health reform. AB - States have long been the testing ground for new models of health care and coverage. Section 1332 of the Affordable Care Act, which takes effect in less than two years, throws open the door to innovation by authorizing states to rethink the law's coverage designs. Under State Innovation Waivers, states can modify the rules regarding covered benefits, subsidies, insurance marketplaces, and individual and employer mandates. States may propose broad alternatives or targeted fixes, but all waivers must demonstrate that coverage will remain as accessible, comprehensive, and affordable as before the waiver and that the changes will not add to the federal deficit. This issue brief describes how states may use State Innovation Waivers to reallocate subsidies, expand or streamline their marketplaces, replace or modify the mandates, and otherwise pursue their own brand of reform tailored to local market conditions and political preferences. PMID- 25915974 TI - Editorial from: International Journal of Prisoner Health, Volume 11, Issue 1. PMID- 25915975 TI - Axillary web syndrome, the lost cord, and lingering questions. PMID- 25915976 TI - Characterizing axillary web syndrome: ultrasonographic efficacy. AB - The aim of this study was to determine if ultrasound could successfully characterize axillary web syndrome (AWS) and clarify the pathophysiologic basis of AWS as a vascular or lymphatic abnormality, or an abnormal tissue structure. This prospective study evaluated women who developed AWS following breast cancer surgery. Using an 18 MHz ultrasound transducer, images were taken of the AWS cord and compared to mirror images on the contralateral side. A blinded radiologist assessed the ultrasound characteristics of and structural changes in the skin and subcutaneous tissue and formulated an opinion as to the side in which AWS was located. Seventeen subjects participated in the study. No structure or abnormality consistent with AWS could be identified by ultrasound. There were no statistical differences between the ipsilateral and contralateral side in skin thickness; subcutaneous reflector thickness, number or disorganization; or subcutaneous tissue echodensity (p>0.05). The radiologist correctly identified the side with AWS in 12 of 17 subjects (=0.41). A distinct ultrasonographic structure or abnormality could not be identified in subjects with AWS using 18 MHz ultrasound. The inability to identify a specific structure excludes the possibility that AWS is associated with vein thrombosis or a fascial abnormality, and supports the theory that AWS may be pathology that is not visible with 18 MHz ultrasound, such as microlymphatic stasis or binding of fibrin or other proteins in the interstitial space. PMID- 25915977 TI - Identification and description of the axillary web syndrome (AWS) by clinical signs, MRI and US imaging. AB - The Axillary Web Syndrome (AWS) follows surgery for breast neoplasia and consists of one, or more frequently two or three, cords of subcutaneous tissue. Cords originate from the axilla, spread to the antero-medial surface of the arm down to the elbow and then move into the antero-medial aspect of the forearm and sometimes into the root of the thumb. The purpose of this study was to compare two techniques, ultrasound (US) and Magnetic Resonance Imaging (MRI) for their sensitivity and accuracy in identifying AWS cords and to provide insights to the origin of this pathology. US examinations were performed on fifteen patients using a high frequency probe (17 MHz). We first palpated and marked the cord with location aided by maximum abduction. To identify the cord with MRI (1.5 Tesla), a catheter filled with a gel detectable under MRI was placed on the skin at the site of the cord. We found that in some US cases, the dynamic abduction maneuver was essential to facilitate detection of the cord. This dynamic method on ultrasound confirmed the precise location of the cord even if it was located deeper in the hypodermis fascia junction. US and MRI images revealed features of the cords and surrounding tissues. Imaging the cords was difficult with either of the imaging modalities. However, US seemed to be more efficient than MRI and allowed dynamic evaluation. Overall analysis of our study results supports a lymphatic origin of the AWS cord. PMID- 25915978 TI - Flow cytometry-based isolation of dermal lymphatic endothelial cells from newborn rats. AB - The lymphatic system plays a key role in tissue homeostasis, fatty acid transport, and immune surveillance. Pathologically, dysfunction of the lymphatic system results in edema, and increased lymphangiogenesis can contribute to tumor metastasis. Lymphatic vessels are composed of lymphatic endothelial cells (LECs) that can be identified by distinct marker molecules such as Prox-1, podoplanin, VEGFR-3 and LYVE-1. Primary LECs represent a valuable tool for the study of basic functions of the lymphatic system. However, their isolation remains a challenge, particularly if rodent tissues are used as a source. We developed a method for the isolation of rat dermal LECs from the skin of newborn rats based on sequential enzymatic digestion with trypsin and Liberase followed by flow cytometric sorting using LYVE-1 specific antibodies. Cells isolated according to this protocol expressed the lymphatic markers Prox-1, podoplanin, LYVE-1 and VEGFR-3, and displayed an endothelial-like morphology when taken into culture. These primary cells can be used for studying lymphatic biology in rat models, and the protocol we describe here therefore represents an important extension of the experimental repertoire available for rats and for modeling the human lymphatic system. PMID- 25915979 TI - Pilot study of the impact of sporting compression garments on composition and volume of normal and lymphedema legs. AB - Once clinically manifested as a swollen limb, lymphedema can be difficult to manage. Our focus thus must shift from reactive treatment to proactive management and prevention. On the basis of strong evidence in the literature, lymphedema specialists now encourage exercise as it can improve lymphatic drainage through muscle pump action. However, exercise may increase the lymph load on the vulnerable limb. We aimed to examine whether low level sporting compression is a reasonable recommendation for those with early stage lymphedema by measuring whether sporting compression (SC) tights decrease limb extracellular fluid as measured by Bio-impedance Spectroscopy (BIS) and Perometry in legs following exercise in both healthy controls and those with early stage lymphedema. A group of normal subjects (n=10) and a group of Stage 1 (ISL) lymphedema patients (n=9) were enrolled. Efforts were made to match participants in each group. For those with unilateral lymphedema, the non-affected leg was used as a control. All were measured using BIS, Perometry and Indurometry before and after exercise both with and without sporting compression clothing. The exercise regime was standardized and involved treadmill walking at increasing rates within each person's activity limitation. SC tights were shown to significantly decrease the fluid build up caused by exercise in lymphedema-affected limbs as measured with BIS (p=0.0302). Perometry measurements showed that SC caused a significant decrease in limb volume post exercise of the whole cohort (p=0.0081) and of the control Group B (p=0.0348). Our findings support the notion that SC may provide a socially acceptable and effective means of lymphedema control during exercise for early lymphedema management. PMID- 25915980 TI - Next generation sequencing is here now. AB - The availability of massively parallel DNA sequencers has brought the cost of sequencing genes to affordable levels but the cost of analyzing the huge amount of data has not decreased to the same extent. Thus, only analyzing the sequences of the genes relevant to the patient's condition makes the cost manageable. A panel of genes relevant to lymphedematous conditions is described. PMID- 25915982 TI - [The transition from pediatric care to the doctor and that of the adult, or the importance of "bridging the gap"]. PMID- 25915983 TI - [Transition to adult care: an overview]. AB - Nowadays nearly 90% of children with a chronic condition survive to adulthood and must make the transition from pediatric to adult care. This transition must include not only the continuity of care but also the preparation for adult life so that these young people can develop their full potential. Divided into three phases (preparation, transfer and engagement), the transition process should be adapted to adolescents and ensure access to quality care. PMID- 25915984 TI - [Congenital heart disease: from childhood to adulthood]. AB - With the improvement of congenital heart surgery, most children with congenital heart disease will survive into adulthood with a good quality of life. Regular cardiac follow-up is recommended for all patients. The adolescent period coincides often with medium and long term consequences and complications and repeat surgery or catheter interventions might be needed. It is therefore of prime importance to begin the transition process early and to pursue it well into adulthood. We have elaborated a formal transition program adapted to youngsters with congenital heart disease. PMID- 25915985 TI - [Inborn errors of metabolism: transition from childhood to adulthood]. AB - Inborn errors of metabolism (IEM) are due to mutations of genes coding for enzymes of intermediary metabolism and are classified into 3 broad categories: 1) intoxication, 2) energy defect and 3) cellular organelles synthesis or catabolism defect. Improvements of therapy over these last 20 years has improved prognosis of children with IEM. These children grow up and should have their transition to specialized adult care. Adult patients with IEM are a relatively new phenomenon with currently only limited knowledge. Extrapolated pediatric guidelines are applied to the adult population taking into account adult life stages (social independence, pregnancy, aging process and potential long-term complications). PMID- 25915986 TI - [Transition in diabetology]. AB - For patients with type I diabetes, transition from pediatric to adult care is a challenge due to complex treatment requirements and the physical, psychological and social changes of adolescence. Members of the care team must recognize that while these emerging adults need to develop self-management skills, this may conflict at times with the developmentally appropriate desire for increasing autonomy. The role of nursing in coordinating a successful transition is critical for maintaining continuity of patient-centered care that responds to the specific needs of these young adults. PMID- 25915987 TI - [Transition in kidney transplantation]. AB - Transition from pediatric to adult care in renal transplantation has emerged as a critical step in the life of a young kidney recipient. During this phase, young patients are faced with the physiological and psychological changes associated with adolescence that can lead to non-compliance and potentially graft loss. To date, there is not a unique accepted model of transition, however it has been proved that the presence of a multidisciplinary team including specialists in adolescent management and in the transition from pediatric to adult transplant care is beneficial during this at-risk phase. The goal of this team is to ensure a progressive transition of the patients according to a precise plan and time line. PMID- 25915988 TI - [KidsETransplant--a serious game for children with liver disease or liver transplant]. AB - In Switzerland all children's liver transplants are centralized at the University Hospitals of Geneva (HUG) since 1989. Approximately 150 children have received transplants since then, and their survival rate is higher than 90%--one of the highest in Europe. Maximizing the chances of long-term success requires that patients comply with follow-up treatment, something which mandates a sound understanding of their medical condition. The KidsETransplant project aims to help the child--and his family--to understand better his state of health. To this end, our tool offers secured, unrestricted access to the patient's medical record, with a view to both increase patient autonomy and improve communication with healthcare professionals. This paper describes KidsETransplant, as well as its implemented evaluation process. PMID- 25915990 TI - [Measles in the United States, the political dimension of the controversy about vaccination]. PMID- 25915989 TI - [Misophonia or aversion to human sound: a clinical illustration]. AB - Misophonia, meaning hatred of sound, is a cluster of symptoms which is not completely included in anxiety disorders category as obsessive compulsive or as an impulsivity disorder. It is described as a chronic condition characterized by reactions, aversion to specific sounds that result in subsequent emotional. Indeed, this condition is relatively unknown and few psychiatrists have already faced this disorder causing in some individuals severe impairment. The investigation of a patient suffering of misophonia with severe impairment that we took into care in an outpatient psychiatric clinic in Geneva contributes to a better understanding of this condition and indicates potential factors that may co-occur and influence the clinical presentation. The good response in psychotherapy, has led us to carry out a brief review of the literature in order to better define and identify this disorder. PMID- 25915991 TI - ["It happened near you ..."]. PMID- 25915992 TI - [Treating the habitat to prevent falls and their consequences]. PMID- 25915993 TI - [After the obscene murals, the vaginal taps on anesthetized patients]. PMID- 25915994 TI - [Evaluation of the role of social sciences in the training and practice of health professionals]. PMID- 25915995 TI - [Views on the health status of an aging population in French rural areas]. PMID- 25915996 TI - [Hospital crisis in Neuchatel: "a collective failure" according to Laurent Kurth]. PMID- 25915997 TI - [Vaud: new limits to medical confidentiality in prison]. PMID- 25915998 TI - [Hospital crisis and democratic choice]. PMID- 25916000 TI - Being a good steward of your patients' benefits. PMID- 25915999 TI - CMs should understand financial side as well as clinical side of healthcare, experts recommend. AB - To do their job effectively, case managers must understand the financial side of healthcare and the impact that their actions can have on patient care, the patient's out- of-pocket expenses, and the hospital's bottom line. Recommendations from experts include the following: Communicate and meet regularly with the financial department to identify areas for improvement, and provide input on contracts with payers. Know what benefits each patient's coverage provides and use the information to coordinate care while the patient is in the hospital and to develop a treatment plan. Be aware of payer requirements and be sure that they are followed to avoid denials. PMID- 25916001 TI - Case managers, financial staff work together closely. PMID- 25916002 TI - Post-discharge interventions reduce readmissions by 20%. AB - Phone calls from nurses at Ochsner Health System's Care Coordination Center within 24 to 48 hours after discharge have reduced readmissionsfor at-risk patients who receive calls by 20%. The program was developed as part of Ochsner's accountable care organization and is expanding across the nine-hospital health system. Nurse case managers reinforce discharge education, complete medication reconciliation, and arrange follow-up visits with primary care physicians and specialists. When patients have long-term needs, they are referred to Ochsner's outpatient complex case management program. PMID- 25916003 TI - Primary care-based interventions cut admissions, ED visits. AB - By sending teams of clinicians to work with at-risk patients at primary care practices, Lehigh Valley Health Network has reduced hospital admissions by 49% and emergency department visits by 25%. Teams that include a nurse care manager, a social worker, a behavioral health practitioner, and a pharmacist are assigned to primary care practices and work with the top 5% of high-utilizing, high-cost patients. The care managers call at-risk patients within two days of a hospital admission, conduct a thorough assessment, and refer patients who need assistance to the appropriate team member. The care managers develop a close relationship with patients, who often give them information they wouldn't be comfortable telling their physician. PMID- 25916004 TI - New task force aims to revamp revenue cycle with a 'patient-centric' focus. AB - The Revenue Cycle Management Task Force of the Heathcare Information and Management Systems Society is addressing the next generation of revenue cycle management processes and tools. Payers, providers, vendors, and consultants are involved. Front-end processes such as patient access, business analytics, and point-of-service collections are a key focus. Patient access will need new technology or updated legacy systems. Patients will be able to manage their care with a single portal. PMID- 25916005 TI - Hospital goes high tech, improves hand hygiene. PMID- 25916006 TI - The right question. PMID- 25916007 TI - Marketing claims and genetic tests. PMID- 25916008 TI - Dr. Carney's response. PMID- 25916009 TI - How much is a gored ox worth? PMID- 25916010 TI - Labial veneers: a multidisciplinary approach. PMID- 25916011 TI - Orthodontic management of patients undergoing prosthetic rehabilitation. AB - The successful management of a patient's functional and esthetic dental needs frequently requires a multidisciplinary approach. One such avenue for collaboration is between the orthodontist and the restorative dentist. Orthodontic therapy can also assist the surgeon in preparing a surgical site for implant placement. The practical application of orthodontic therapy in restorative dentistry as well as an approximate time frame for a proposed orthodontic intervention is described in this article. PMID- 25916012 TI - Periodontal considerations in veneer cases. AB - Porcelain veneers are a minimally invasive technique to enhance patients' smiles. A crucial component in these cases is the supporting periodontal apparatus and its interaction with the restorations. This article addresses basic concepts such as biologic width, altered eruption patterns, appropriate gingival contouring and smile design to give practitioners the tools to diagnose, evaluate and treat cases successfully and predictably. PMID- 25916013 TI - Clinical aspects of porcelain laminate veneers: considerations in treatment planning and preparation design. AB - Making the transition from conventional methods to more modern, perhaps more sophisticated, methods in dentistry can be intimidating. Introduction of new techniques and materials into private practice requires understanding of the current scientific literature. Here, a review of the traditional clinical approach to porcelain laminate veneer case planning and intraoral preparation is reviewed. Current research in each of these subjects is also discussed, summarizing some of the literature as well as newer products and technologies. PMID- 25915904 TI - Use of Anticoagulants and Antiplatelet Agents in Stable Outpatients with Coronary Artery Disease and Atrial Fibrillation. International CLARIFY Registry. AB - BACKGROUND: Few data are available regarding the use of antithrombotic strategies in coronary artery disease patients with atrial fibrillation (AF) in everyday practice. We sought to describe the prevalence of AF and its antithrombotic management in a contemporary population of patients with stable coronary artery disease. METHODS AND FINDINGS: CLARIFY is an international, prospective, longitudinal registry of outpatients with stable coronary artery disease, defined as prior (>=12 months) myocardial infarction, revascularization procedure, coronary stenosis >50%, or chest pain associated with evidence of myocardial ischemia. Overall, 33,428 patients were screened, of whom 32,954 had data available for analysis at baseline; of these 2,229 (6.7%) had a history of AF. Median (interquartile range) CHA2DS2-VASc score was 4 (3, 5). Oral anticoagulation alone was used in 25.7%, antiplatelet therapy alone in 52.8% (single 41.8%, dual 11.0%), and both in 21.5%. OAC use was independently associated with permanent AF (p<0.001), CHA2DS2-VASc score (p=0.006), pacemaker (p<0.001), stroke (p=0.04), absence of angina (p=0.004), decreased left ventricular ejection fraction (p<0.001), increased waist circumference (p=0.005), and longer history of coronary artery disease (p=0.008). History of percutaneous coronary intervention (p=0.004) and no/partial reimbursement for cardiovascular medication (p=0.01, p<0.001, respectively) were associated with reduced oral anticoagulant use. CONCLUSIONS: In this contemporary cohort of patients with stable coronary artery disease and AF, most of whom are theoretical candidates for anticoagulation, oral anticoagulants were used in only 47.2%. Half of the patients received antiplatelet therapy alone and one-fifth received both antiplatelets and oral anticoagulants. Efforts are needed to improve adherence to guidelines in these patients. TRIAL REGISTRATION: ISRCTN registry of clinical trials: ISRCTN43070564. PMID- 25916014 TI - Improved communication with the laboratory for the fabrication of labial veneers. AB - Advances in dental materials and adhesive technologies have changed the way we practice dentistry. Consequently, restorative dentistry has seen the adoption and almost exponential increase in usage of materials like zirconia and lithium disilicate. Unlike the incidence of ceramic failure in the past, these newer materials are paving the road to better looking dentistry. This paper focuses on lithium disilicate and predominantly glassy ceramics, as well as improving communication with the laboratory. PMID- 25916015 TI - Precise documentation is a plus in veneer cases. PMID- 25916016 TI - Reasons to read employment posters. PMID- 25916017 TI - [Meningococcus B: control of two outbreaks by vaccination]. AB - The issue of an effective vaccine against Meningococcus B (MenB) has been overcome by identifying, with the "reverse vaccinology" methodology, some antigens able of inducing a response to the majority of MenB strains circulating in the world. The new 4-components MenB vaccine (4CMenB) has been approved in Europe, Australia and Canada, and included in international pediatric immunization schedules: Australia, Canada, UK. In Italy, the first regions that have recommended vaccination against MenB were Basilicata and Puglia. The management of epidemics/outbreaks requires the implementation of a rapid response by health authorities in respect of a medical emergency with a high impact, even emotional, on the population, as recently demonstrated in two American universities. The declaration of outbreak in place has been followed in both contexts by the adoption of a procedure for the use of the 4CMenB vaccine not yet licensed in the USA. It was thus possible to organize interventions of active prophylaxis in the two campuses, establishing the first large-scale use of the new 4CMenB vaccine and achieving, in a relatively short time, high rates of vaccination coverage. With around 14,000 students immunized with at least one dose, no safety issues have been reported following immunization. Besides, to date there have been no cases in subjects who have received the vaccine. As a result of the two outbreaks described, FDA is now evaluating for the extension of the use of the 4CMenB vaccine in adolescents and young adults in USA. PMID- 25916019 TI - Breast self examination and mammography in cancer screening: women health protective behavior. AB - BACKGROUND: Breast cancer (BC) is one of the leading causes of death among women. Secondary prevention may enable early detection, but this is suboptimal among all Iranian women. METHODS: This was a descriptive, analytic cross sectional study on 385 women 35 years old or more with no history of BC. Participants were selected by simple randomized method and were assessed through a two-part self administered questionnaire and a self-examination checklist with content validity and test-re-test reliability. RESULTS: 14.8% of women carried out breast self examination (BSE). Among them 5.7% was done in adequate timing and 9.4% performed it on a regular basis. The average age of BSE onset was 20.1 +/- 7.6 and mean of Score was 6.25 +/- 2.26 (2-11). 2.3% of participants performed BSE poorly, 7.5% fairly and 1.6% performed it well. 25.84% of samples had a history of mammography that 13% of whom received it as a result of prescription. The average age for mammography was 36 +/- 7.2 (20-50) years and the frequency of mammography was 1.8 +/- 1.4 (1-8) of times. Due to the low percentage of breast cancer preventive behaviors, in this study knowledge towards breast cancer was also measured because they are factors that are crucial in performance. CONCLUSION: The results highlight the need to educate Iranian women to recognize the risk factors to promote early detection of breast cancer. Creation of health behavioral by focused educational programs might cause decrease of breast cancer prevalence. PMID- 25916018 TI - Screening for diabetes mellitus and human immunodefiency virus infection in persons with tuberculosis. AB - INTRODUCTION: Nigeria is a country saddled with a high tuberculosis (TB) and human immunodeficiency virus (HIV) burden but the possible combination of these communicable diseases with diabetes mellitus (DM) has been overlooked. We undertook to determine the burden of HIV and DM in persons with TB by documenting the prevalence rates of these disorders. METHODS: This is a cross-sectional Study that was conducted within 54TB/DOT centers in Lagos State. A total of 3,376 persons with TB who were on antiTB drugs were screened for HIV and DM using standardized tests. Statistical analysis was performed using Students t test and chi square. RESULTS: The frequency of occurrence of DM in TB and that of HIV in TB were comparable (4.8% Vs 3.5%). The Study subjects with DM were older, had higher waist circumference measurements and had higher proportions of hypertension compared to the subjects without DM. The combination of HIV and DM in TB was found in (0.3%). We also noted that DM in TB and HIV in TB occurred more frequently in the third and fourth decades of life. CONCLUSION: This study demonstrated the potential co existence of HIV, DM and Tuberculosis. It is therefore important that these two diseases are sought for in patients with TB considering the changing epidemiology of these diseases particularly in developing countries like Nigeria. PMID- 25916020 TI - Molecular identification of Pseudomonas aeruginosa recovered from cystic fibrosis patients. AB - OBJECTIVE: Precise identification of various morphotypes of Pseduomonas aeruginosa which developed during cystic fibrosis (CF) is of prime importance. We aimed to identify the isolates of P. aeruginosa recovered from CF patients at the genus and species level through primers targeting oprI and oprL genes via PCR. METHODS: Sputum samples or throat swabs were taken from 100 CF patients and plated on cetrimide agar. All suspected colonies were primarily screened for P. aeruginosa by a combination of phenotypic tests. Molecular identification of colonies was performed using specific primers for oprI and oprL genes. RESULTS: Based on phenotypic tests, P. aeruginosa isolates were recovered from 40% of CF patients. Forty isolates yielded amplicon of oprI gene using genus-specific primers confirming the identity of fluorescent pseudomonads. However, 37 of 40 isolates yielded amplicon of oprL gene using species-specific primers, verifying the identity of P. aeruginosa. CONCLUSION: This study showed that the species specific PCR targeting oprL gene can be used as accurate test for identification of highly adaptable P. aeruginosa in CF patients. This procedure may provide a simple and reliable method for identification of various morphotypes. PMID- 25916021 TI - Candiduria in children: a first report from an Iranian referral pediatric hospital. AB - Candida spp. especially Candida albicans is considered as one of the most common cause of fungal infections. The aim of our study was to determine epidemiology of candiduria in children who were referred to an Iranian referral hospital. During May 2011 to February 2013, among 4813 urine culture positive, 209 candida spp. isolates (4.3%) was found. Forty-one percent of cadiduria infection was seen in patients between 1 month and 1 year, 24% in neonatant and 24% in patients 1 to 5 years. Cadiduria was mainly found in patients who had received more than 2 or 3 antibiotic during their hospitalization (37% and 24%, respectively). In our study, the highest frequency of cadiduria was seen in patients who had received more than 2 antibiotics and more than 3 antibiotics during their hospitalization; therefore, the strategic goals to optimize antimicrobial use including optimizing choice and duration of empiric therapy as well as monitoring and providing feedback regarding antibiotic resistance are recommended. PMID- 25916022 TI - Ownership and utilisation of insecticide-treated mosquito nets among caregivers of under-five children and pregnant women in a rural community in southwest Nigeria. AB - INTRODUCTION: Malaria still constitutes a serious public health problem in Nigeria despite control efforts. The use of Insecticide Treated Net (ITN) has been proven to be an effective preventive modality in the control of malaria but its utilisation has been shown to be low. This study assessed the ownership and utilisation of ITN in Igbo-Ora, a rural community in Ibarapa Central Local Government Area (LGA) of Oyo State, Southwest Nigeria. METHODS: A descriptive cross-sectional survey among female caregivers of under-five children and pregnant women was conducted using semi-structured interviewer-administered questionnaire. Data were analyzed using SPSS version 16. RESULTS: Among 631 respondents that participated, 84.9% were caregivers of under-five children. Mean age was 27.7 +/- 6.3 years with 53.4% between 20-29 age group. Majority, 91.1% had at least primary education, 60.2% were traders and 69.7% were married. Most respondents, 71.8% had at least one type of mosquito nets. Among those that had, 85.4% had window/door net, 25.2% untreated mosquito net while only 15.5% had ITN. Overall, 11.1% of the respondents had ITN among which 78.6% had ever slept under an ITN. Among those that had ever slept under an ITN, slightly less than half 49.1% slept under an ITN the previous night. Less educated respondents were five times more likely to use ITN (95% CI = 1.24-21.28). CONCLUSIONS: This study revealed very low ownership and utilisation of lTNs. There is need to improve on the knowledge of community members of the relevance of ownership and utilisation of ITN in malaria prevention. PMID- 25916023 TI - Hand hygiene behavior among urban slum children and their care takers in Odisha, India. AB - OBJECTIVE: To study the knowledge and practice of hand washing among mothers and children of shikharchandi slum of Bhubaneswar, Odisha and to recommend possible measures to improve the current practices. METHODOLOGY: Present cross-sectional study was carried out in the Shikharchandi slum located in the Bhubaneswar city of Orissa state in India. 150 women and 80 children were interviewed. Children questionnaire were prepared to suit to their age and according to local context. Components of sanitation like food handling and hand washing were covered in this questionnaire. RESULTS: Hand washing before preparing food is being practiced by 85% of women. Of all women interviewed, 77% wash hands before serving food. Only 15% children said soap was available in their school to wash hands. Out of total children interviewed, 76% told that their teachers tell about sanitation and hand washing in the class. Only 5% children told they were consulted by doctor/health worker during last 3 months. As many as 81% children told that they wash their hands before taking food and 19% children said they take their food without washing hands. Though most of the children told that they wash hands before taking food, but only 17.5% told that they use soap for hand washing. Only 29% children told that their teachers check hand washing in school. When asked about critical timing of hand washing, 44% children told about at least two critical timings and 56% were unaware about the critical timings of hand washing. CONCLUSION: Inadequate knowledge on this among our study participant is a point of concern. Systematic integration of health and hygiene education in schools through curricular modifications could be an appropriate strategy. PMID- 25916024 TI - Seroprotection after hepatitis B vaccination in children aged 1 to 15 years in central province of Iran, Semnan. AB - INTRODUCTION: There are controversies over the long-term persistence of post vaccination immunity to hepatitis B and the need for booster doses of the vaccine. The aim of this study was to verify antibody levels of antibody against hepatitis B virus surface antigen (anti-HBs) in children aged 1 to 15 years who received vaccination against hepatitis B in the central province of Iran, Semnan. MATERIALS AND METHODS: We performed a seroepidemiological survey (n = 210) of anti-HBs in 2011 in the central province of Iran, Semnan using enzyme-linked immunosorbent assay (ELISA). The levels of anti-HBs < 10 mIU/mL were considered to be negative and samples showing an anti-HBs titer >= 10 mIU/mL was considered protective. RESULTS: Protective antibody levels were detected in 88% of the children less than 5 year after vaccination, decreased to 78% between 5 to 10 years after vaccination, and further declined to 74% in 10 years after vaccination, respectively. CONCLUSION: The vaccination program has been proven effective in Semnan and immunological protection against hepatitis B infection was found in the majority of children even more than 10 years after being vaccinated. PMID- 25916025 TI - The colorectal cancer screening program in the local health unit n. 6 of Livorno: evaluation of the screening activity in the period 2000-2011. AB - INTRODUCTION: The colorectal cancer screening program in the Local Health Unit n. 6 of Livorno is running since July 2000 and is meant to residents, aged between 50 and 70, who are invited to perform the test for faecal occult blood every 2 years. The aim of this work is an evaluation of the screening activity in the period 2000-2011. METHODS: The evaluation is based on the analysis of the main quality indicators formulated by GISCoR (Italian Group for Colorectal screening). RESULTS: The screening activity extension reached 93% in 2006 and 100% in 2009. The compliance level was maintained above the acceptable GISCoR value (> 45%) with a maximum of 54.9%. Values around 80% were recorded for the compliance to colonoscopy. The detection rate (DR) for cancer and advanced adenoma showed, as expected, the highest values in the early years and then move on values consistently lower than the regional average. In 2011, the raw DR for cancer was 0.9 x 1000 and the raw DR for advanced adenoma 5.3 x 1000. The distribution by stage at diagnosis of screen-detected carcinomas shows that 58.1% of these were identified at stage I while the proportion of cases in stage III+ is 19.5%. CONCLUSIONS: The overall analysis shows a good performance of the program. The proportion of colonoscopies performed on the total number of positive subjects remains a critical point of the system. The distribution by stage of screen detected cancers shows an excellent diagnostic anticipation of the screening program. PMID- 25916026 TI - Safe meat-handling knowledge, attitudes and practices of private and government meat processing plants' workers: implications for future policy. AB - INTRODUCTION: Food-borne disease outbreaks remain a major global health challenge and cross-contamination from raw meat due to poor handling is a major cause in developing countries. Adequate knowledge of meat handlers is important in limiting these outbreaks. This study evaluated and compared the safe meat handling knowledge, attitudes and practices (KAP) of private (PMPP) and government meat processing plants' (GMPP) workers in south-western Nigeria. METHODS: This cross sectional study comprised 190 meat handlers (PMPP = 55; GMPP = 135). Data concerning their safe meat-handling knowledge, attitudes and practices as well as their socio-demographic characteristics, such as age, gender and work experience were collected. RESULTS: A significant association was observed between the type of meat processing plants and their knowledge (p = 0.000), attitudes (p = 0.000) and practices (p = 0.000) of safe meat-handling. Meat handlers in the GMPP were respectively, about 17 times (OR = 0.060, 95% CI: 0.018-0.203), 57 times (OR = 0.019, 95% CI: 0.007-0.054) and 111 times (OR = 0.009, 95% CI: 0.001- 0.067) less likely to obtain good knowledge, attitude and practice level of safe meat-handling than those from PMPP. Further, KAP levels were significantly associated with age group, education and work experience (p < 0.05). DISCUSSION: Study findings suggest the need for future policy in food industry in developing countries to accommodate increased involvement of private sector for improved food safety and quality delivery. Public health education on safe food handling and hygiene should be on the front burner among food handlers in general. PMID- 25916027 TI - Knowledge of sexually transmitted infections among younger subjects of the city of Messina (Sicily). AB - INTRODUCTION: Sexually transmitted infections (STIs) are considered a serious public health problem worldwide, affecting especially young people. The international monitoring data indicate that 70% of patients with STIs are aged between 15 and 24 years and the World Health Organization estimates that one out of 20 teenagers contracts an STI each year. We wanted to evaluate, through this work, what high school students of Messina know about the STIs. MATERIAL AND METHODS: From February to May 2013 questionnaires were distributed to students of the last three classes of seven high schools, three of which belonging to humanistic area and four to technical area. The completed questionnaires collected were 1588. RESULTS AND DISCUSSION: The investigation carried out showed a better knowledge of the STIs by students of humanistic schools than students of technical-scientific schools, the percentage of correct answers was 74% and 60% respectively; this probably also depends on the family context, in fact, there is a statistically significant correlation between the percentage of correct answers and parents education level. Young people have a limited knowledge on the subject. We concluded our work by stressing the importance and the need to deepen and improve the training and information of the medical staff teachers and families, as it is from their knowledge and their ability to provide complete and accurate information about the risks posed by STIs that can derive knowledge and choices of appropriate lifestyle between the youth population. PMID- 25916028 TI - Antimicrobial susceptibility patterns of the gram-negative bacteria isolated from septicemia in Children's Medical Center, Tehran, Iran. AB - INTRODUCTION: The choice of antimicrobial treatment for septicemia is often empirical and based on the knowledge of local anti-microbial activity patterns of the most common bacteria causing such bloodstream infections. The current study aimed to study the prevalence of bacterial pathogens causing septicemia and their antimicrobial resistant profiles in hospital admitted patients. METHODS: This cross sectional study done at Children's Medical Center, Tehran, Iran. We examined 168 bacterial strains isolated from 186 clinically diagnosed septicemia cases refereed at Children's Medical Center, Tehran, Iran. Over a period of twelve months from July 2010 to 2011 July. 11446 blood samples from patients of clinically suggestive septicemia were evaluated. RESULTS: Bacterial strains were isolated from 910 (7.95%) of blood cultures. Gram-negative bacteria identified were Pseudomonas species (20.5%), Pseudomonas aeruginosa (1.86%), Salmonella spp (1.09%), Acinetobacter naumannii (8.13%), Escherichia coli (4.06%), Klebsiella spp (5.16%). Gram-negative pathogens were more than gram positive in bloodstream infections. Antimicrobial susceptibility testing was done according to Clinical and Laboratory Standards Institute (CLSI, USA) guidelines against: amikacin ampicillin, amoxicillin, amoxiclav, cefuroxime, cefotaxime, ceftazidime, cefoperazone tetracycline, chloramphenicol, ciprofloxacin, gentamicin. Resistanc to different antibiotics in the most important isolated bacteria were: 32.1%, 10.8%, 87.8%, 96%, 39.1%, 35.2, 49.4%, 69%, 80.02%, 22%, 59%, 30.1% respectively, for Pseudomonas spp, 32%, 3.7%, 84.2%, 83.2%, 80.1%, 75.4%, 44.8%, 45.2%, 33.3%, 19%, 34.1, 11.5% respectively for Acinetobacter species. DISCUSSION: Resistant to majority of the antimicrobial agents for several pathogens implicated in bloodstream infections, particularly in Gram-negative bacteria, can make complication in treatment of infection cause by them. PMID- 25916029 TI - Identification and molecular epidemiology of nosocomial outbreaks due to Burkholderia cepacia in cystic fibrosis patients of Masih Daneshvary Hospital, Iran. AB - INTRODUCTION: B. cepacia complex have emerged as an important opportunistic pathogen in hospitalized and immunocompromised patients. Small hospital outbreaks are frequent and are usually due to a single contaminated environmental source. In this study we were going to investigate the role of B.cepacia complex in those patients suspected to involve with cystic fibrosis and evaluate responsible types in Masih Daneshvary Hospital. METHODS: One hundred specimens were collected from all admitted patients who were suspected to cystic fibrosis to Masih Daneshvary hospital during one year April 2011 till end of March 2012. All were culture and identified standard procedure. All samples were checked by API system (API20NE) and by specific PCR method for genus Bulkhorderia and Bcc as well. Identified strains were finally tested by PFGE system to identifying specific involving pulse-types. RESULT: . Isolation and identification methods revealed 5 specimens were B.cepasia, The frequency of the cystic fibrosis detected at this study was lower than other similar study previously reported. All these isolates showed similar pattern by PFGE standard protocol that may have spread from a single source and could not be attributed to cross infections from patient to patients. DISCUSSION: Application of PFGE and identification of pulse-type is a potential tool to enhance the investigation of apparent nosocomial outbreaks of B.cepacia. However it needs to be adjusted with environmental findings. Implementation of educational programs and adherence to infection control policies are obviously the main element for complete elimination of an outbreak. PMID- 25916030 TI - Acute renal failure after influenza vaccination: a case report. AB - A fifty-three years old surgeon had acute renal failure consisting with acute tubulo-interstizial nephropaty twelve days after influenza vaccination; he was on statin therapy since one month. He was given steroidal therapy and fully recovered two weeks apart. This is the fourth case report of acute renal failure after influenza vaccination in patients on statins therapy. The case we describe could account for a underestimated, even if very rare, phenomenon. PMID- 25916031 TI - New measles vaccination schedules in the European countries? AB - Over the last 5 years, a number of outbreaks of measles have occurred in several European Union (EU) countries. Many of these outbreaks continue and/or continued for more than 1 year after the notification of the first case. Curiously in many of measles outbreaks about 10% of the patients were less than 12 months of age. All these patients according to the current EU countries vaccination calendars were not yet vaccinated against measles. Based on the results of measles outbreaks, especially age of affected patients, we should consider changing measles vaccination schedules in all EU countries. Most of mothers between 30 and 40 years of age are not vaccinated against measles, and many of them are not naturally immune against measles. These mothers do not pose antibodies against measles and in turn do not provide vertical protection for their infants. In conclusion, administrating the first dose of measles vaccine in the EU countries should be considered before 12 months of age, most probably at 9 months of age. PMID- 25916032 TI - [Medical support of the Armed Forces of the Russian Federation: the results of the activities and the main tasks for 2015]. AB - Presented the directions of activity of the medical service in the past year, including improving the legal framework, the optimization of medical management software, improving combat and mobilization readiness of units of the army, the optimization of therapeutic and preventive activities, implementation of innovative technologies, increasing mobility of units and subunits, their level of equipping with modern samples of property, training of qualified personnel, intensify research and etc. Analyzed and formulated directions of development of military medicine in 2015, including improvement of combat and mobilization readiness of the management body, military and medical organizations and departments, improving the legal framework of the military health care, holding among the troops interventions for the prevention morbidity of personnel by pneumonia and meningitis, work with commanders at all levels to ensure the preservation and strengthening of health of servicemen, improving of the system of early and active detection of diseases in the military, providing a guaranteed level of care to all contingent Ministry of Defense, improving the quality and accessibility of sanatorium treatment, maintaining constant readiness of medical special forces to carry out tasks for the purpose, improvement of professional training of personnel of the medical service, providing qualitative preparation of government medical service to participate in the training of troops, implementation of unexpected problems, equipping of army medical service with modern medical equipment finishing of the construction and renovation of military medical organizations facilities, improvement of social protection of personnel and many others. PMID- 25916033 TI - [Chemicals as fire damaging factor]. AB - The article provides an overview of published scientific data about toxic chemical compounds formed during thermal degradation of various materials. In case of fire the complex of physical and chemical factors affect the human, along with injuries, thermal burns of the skin and respiratory tract there is a lack of oxygen in the inspired air and the impact of thermal degradation products. The greatest number of deaths in.a fire due to the inhalation by the victims smoke and toxic gases. The impact of the combination of toxic substances leads to the development of various forms of toxic process. The main causes of poisoning at the fires due to the effects of toxic substances and substances which can cause structural and functional disorders of the respiratory organ. Intoxication manifestations by some of them appear already in the fire zone, in other cases, in cases of poisoning by the compounds of the slow motion, there is the latent period of of intoxication. Knowledge of the spectrum of toxic products thermal destruction on the human during the fire, it is necessary to develop approaches to improve medical care and creation of tools of medical protection. PMID- 25916034 TI - [Meningococcal disease: early clinical diagnosis and emergency care]. AB - Late diagnosis of meningococcal disease leads to high mortality. Early diagnosis of its generalized forms plays a crucial role in the pre-hospital phase and mainly based on the clinical picture of the disease. In most cases, pre-hospital typical mistake is late diagnosis of meningococcal disease: We propose an algorithm of early diagnosis of generalized forms of the disease in order to reduce the number of diagnostic errors. Proper and timely diagnosis will enable the physician pre-hospital fully implement measures to provide emergency and urgent care in generalized meningococcal infection, leading to. a more.favourable course and a significant improvement in the outcomes of the disease in the course of further hospital treatment. PMID- 25916035 TI - [Provision of medical care to the wounded with craniocerebral injuries at stages of medical evacuation in mountains and desert areas]. AB - The author shows that surgery with craniocerebral injuries should be fully performed at the stage of specialized medical care. Wounded have to be evacuated not earlier than 5-7 days after surgery with the mandatory use of a special air transport ("Scalpel" or "Spasatel"), accompanied by Anaesthetist. In the absence of the possibility of surgery in 5-7 days at this stage the wounded have to be evacuated by air to the center hospitals. On the stage there are only patients requiring specialized care because of health reasons. Wounded with gunshot wounds of the soft tissues of the head, and those with mild forms of brain damage during the explosive and combat injury (concussion, mild brain contusion) can be evacuated by air transport accompanied by a doctor or paramedic at any period of time after the injury (trauma). PMID- 25916036 TI - [Functional methods of assessment of the blood flow in the lower limbs of the patients with obliterating atherosclerosis during complex conservative treatment]. AB - Have been studied the changes of tissue blood flow in the distal parts of the lower limbs at the capillary level under the influence of the different complexes of rehabilitation. Were obtained the objective results of advantages of the combined use of physical therapy and drug therapy. The study showed that for evaluation of tissue blood flow is preferable to to use the laser flowmetry, and for registration of quantitative indicators of regional blood flow changes- Doppler ultrasound. PMID- 25916037 TI - [Problems of early detection of HIV infection, medical and psychological support of HIV-infected soldiers]. AB - The article contains the analysis of materials about HIV infection and the status of work on its early detection among soldiers. Currently, the figures have a tendency to stabilization, but there is an increase in the persantage of HIV infected persons performing military service under the contract, as well as the actualization sexual way of infection. The insufficient effectiveness of the barrier screening during the laboratory examination of recruits may contribute the increase in the incidence of HIV infection. Have been reviewed the questions medical-diagnostic and medical-psychological support of HIV-infected soldiers. Been analyzed the social consequences of delays in seeking medical help of patients in this group, the opportunities and challenges of their dispensary observation. It was noted that early detection of HIV infection and proper medical and psychological support in the dynamics of pathological process helps to reduce the number of new cases and improve their outcomes and to reduce the period of efficiency recovery of military personnel. PMID- 25916038 TI - [Actual problems of medical care of aviation specialists in the Arctic region]. AB - The article considers the influence of geographic and climatic conditions of the Arctic on a functional condition of aviation professionals. Marked possible effects of aggressive environmental factors on the health of the personnel. Studied the dynamics of the recovery functions of the cardio-respiratory system and of the indicators of general clinical blood test in a period of adaptation to the conditions of the middle latitudes after the return of the personnel from the Arctic. Identified the main activities to preserve the health of aviation specialists, depending on the length of stay in the Arctic region and age. PMID- 25916039 TI - [Medical Service of the Finnish Defence Forces]. AB - Thee article is a brief description of the current state of the Finnish Defence Forces medical service and is based on the study of the open access foreign sources. At the beginning, the general information about Finland, the Finnish Defence Forces, and their medical service is presented. Then some particular features are described with more detail, namely, the organization of the inpatient and outpatient treatment, medical supply, scientific research, combat medicine, medical staff education and training, medical , service personnel income. PMID- 25916040 TI - [Spiritual ties of the Military Medical (Medical and Surgical) Academy]. AB - Before the revolution in its educational, research and clinical potential of Military Medicine (medical and surgical) Academy was on the head position among European institutions. Not less outstanding position among all secular institutions Russian Academy held by the number and wealth of churches, chapels and baptisteries. In the temples of the academy was concentrated a significant number of miracle-working icons and of the particles holy relics, there served some of faith and piety devotees and some of them were canonized. The article presents a brief historical overview of the major Academy shrines--spiritual ties of the different generations. PMID- 25916041 TI - [To the 70th anniversary of the 39th separate medical troop (Airmobile) of Air Force]. AB - On December, 18th, 2014 it is 70 years from the date of creation 39 separate medical troop (aeromobile) of the Air force. The history of troop goes to the Great Patriotic War, when it was organized the 234th separate health battalion, The battalion has passed a fighting way as a part of 106 Guards shooting division from Hungary up to Austria. In the postwar period military personnels of the troop took the active participation in medical maintenance of soldiers-commandos in many local confrontations with the participation of Soviet, and after the Russian Army. During its lifetime the troop was repeatedly reorganized and now it is modern military treatment-and-prophylactic institution, it has in staff 100 beds and does all types of qualified (with elements special-purpose) medical aid to the wounded and sick, carries out the supply to the division of the medical supplies. PMID- 25916042 TI - Expression of vasohibin-2 in pancreatic ductal adenocarcinoma promotes tumor progression and is associated with a poor clinical outcome. AB - This study aimed to assess the expression of vasohibin-2 (VASH2) in pancreatic ductal adenocarcinoma (PDAC) as a marker of tumor aggressiveness and its impact on tumor angiogenesis, proliferation, and clinical outcome. We examined the expression of the VASH2 gene in human pancreatic cell lines PANC-1 and MiaPaCa-2 by quantitative reverse transcription polymerase chain reaction (qRT-PCR) and immunocytochemistry. Fifty samples from patients with PDAC were immunostained with VASH2, CD34, and Ki-67 antibodies. Further, the immunoreactivity of VASH2 correlated with the pathological features, including microvessel density (MVD), tumor cell proliferation (Ki-67 labeling index), and survival. Forty-seven of the 50 samples from PDAC patients showed immunoreactivity for VASH2 along the tumor cell cytoplasm. Among the VASH2-positive samples, 22 were categorized as high VASH2 expression group, and this group had statistical significance with pN stage (p = 0.006), UICC stage (p = 0.033), tumor proliferation (p < 0.001), and MVD (p = 0.017). Moreover, patients with high VASH2 expression showed worse prognosis compared to those showing low VASH2 expression (overall logrank p = 0.003). Thus, our results suggested that overexpression of VASH2 accelerated the pace of tumor development toward a more serious malignant phenotype and was associated with a poor clinical outcome. VASH2 may be an important novel target for the management of PDAC after surgery. PMID- 25916043 TI - Impact of GLP-1 analogue on oxidative damage and hepatic regeneration in experimental 70% hepatectomy model. AB - BACKGROUND/AIMS: The purpose of our study is researching into impact of glucagon like peptide 1 (GLP 1) analogue on liver regeneration after major hepatectomy. METHODOLOGY: 24 wistar albino rats were consecutively divided into 3 groups. Group 1: Control (sham) group day 14 (n = 8), Group 2: Liver resection group day 14 (n = 8); 70% Liver resection was performed, Group 3: Study group day 14 (n = 8); Subsequent to performing 70% liver resection, GLP-1 analogue was administered 2 times a day. (10 MUgr/70 kg x 2 times). After 14 day, rats were sacrificed. Oxi dative stress and antioxidant enzymes and mitochon- drial permeability transition, cytochrome-c, Bax, Bcl- 2, caspase-3, caspase-8 and caspase-3 activity were examined. RESULTS: 70% Liver resection induced oxi- dative stress of liver tissue was ameliorated by GLP-1 induction. Administration of GLP increased Bcl-2 ex- pression. Decreased expression of cytochrome-c was accompanied by a decrease caspase-3, caspase-8, and Bax expression and caspase-3 activity. CONCLUSIONS: Glp 1 induction plays a regenerative role in the major hepatectomy. This effect is dependent on modulation of the antiapoptotic and antioxidative pathways by GLP 1 expression. PMID- 25916044 TI - Sorafenib after RFA in HCC patients: a pilot study. AB - BACKGROUND/AIMS: To investigate the effectiveness and safety of sorafenib after radiofrequency ablation (RFA) in patients with hepatocellular carcinoma (HCC). METHODOLOGY: 44 intermediate or advanced HCC patients received sorafenib treatment after debulking with RFA therapy. Time to progression (TTP), response rate (RR), duration of sorafenib treatment and adverse effects were evaluated. An explorative comparison was performed with patients treated with sorafenib only. RESULTS: At 12 months, TTP was 10.3 months (range: 1-32). RR was 61% with 2 complete responses, and duration of sorafenib therapy was 10.9 months (1-32). No new safety concerns were report-ed. With sorafenib only, TTP was 7.2 months (range: 0-38) and RR was 40%, with one complete response; duration of therapy was 7.3 months (0-38). CONCLUSIONS: The sequence of RFA and sorafenib appears effective and safe in HCC patients. These findings could support the use of a sequential treatment with RFA and sorafenib in HCC patients. PMID- 25916045 TI - Quality of laparoscopic total mesorectal excision: results from a single institution in China. AB - BACKGROUND/AIMS: Incomplete total mesorectal excision (TME) may lead to local recurrence. Factors predicting suboptimal quality of laparoscopic TME have not been well documented. The aim of the prospective observational study was to evaluate factors influencing the quality of laparoscopic TME. METHODOLOGY: Patients undergoing laparoscopic TME for rectal cancer between October 2012 and March 2013 were included. Uni- and multivariate logistic analysis were performed to identify factors independently predicting the suboptimal quality of laparoscopic TME. RESULTS: A total of 52 patients undergoing laparoscopic TME for rectal cancer were included for analysis. Mesorectal resection was complete in 71.2%, nearly complete in 17.3%, and incomplete in 11.5%. Factors found to be significantly related to suboptimal TME in univariate analysis were as follows: BMI >= 25 kg/ cm2 (OR = 11.79, 95% CI: 2.88-48.25; p = 0.003) and advanced tumor stage (pT3/4) (OR = 1.90, 95% CI: 1.41-100.00; p = 0.023). Multivariate analysis identified BMI >= 25 kg/m2 (OR = 21.05, 95%CI: 3.26-136.06; p = 0.010), advanced tumor stage (pT3/4) (OR = 19.03, 95% CI: 1.55-233.88; p = 0.021) and neoadjuvant radiochemotherapy (OR = 29.76, 95% CI: 1.65-537.93; p = 0.022) as factors that were independently related to suboptimal TME. CONCLUSIONS: Laparoscopic TME is feasible with the quality of mesorectal excision which was influenced by patient , tumor-, and treat- ment-related factors. PMID- 25916046 TI - Association between chronic use of proton pump inhibitors and small- intestinal bacterial overgrowth assessed using lactulose hydrogen breath tests. AB - BACKGROUND/AIMS: Several adverse events have been reported in patients who are chronic users of proton pump inhibitors (PPIs); however, the association between PPI use and small-intestinal bacterial overgrowth (SIBO) is controversial. We examined the prevalence of SIBO, as assessed by the lactulose hydrogen breath test (LHBT), based on the use of gastric acid-suppressive drugs in Japanese patients. METH- ODOLOGY: Ninety-four patients who were examined by the LHBT were assessed retrospectively. We used several criteria to define a positive LHBT result. Nine patients received probiotics containing Lactobacillus casei. RESULTS: Fifty patients were PPI users, 14 were histamine-2 receptor antagonist (H2RA) users, and were 30 non-PPI and non-H2RA users (controls). There were no significant differences in prevalence of LHBT-positive cases among the three groups. Multiple-adjusted regression showed no significant association between PPI use and being LHBT-positive. Prevalence of postprandial fullness in PPI users was high (46%), but such symptoms were not related to LHBT results. Four (44%) of 9 cases became LHBT-negative and the maximal peak of H2 production decreased significantly after probiotic treatment. CONCLUSIONS: PPI treatment is not associated with SIBO in Japanese patients. Mechanisms apart from SIBO could cause the high prevalence of postprandial fullness in PPI users. PMID- 25916047 TI - Outcomes of laparoscopic colorectal surgery in patients of previous abdominal surgery: a systemic review and meta-analysis. AB - Previous abdominal surgery (PAS) is an important factor for postoperative adhesion. It is considered to be the most common complication of gastrointestinal and pelvic surgery. Both an Internet based and a manual search were used to acquire relevant studies about this topic. Parameters have been compared such as, Operating time in PAS versus Non PAS, Blood loss, Perioperative blood transfusion, Conversion to open, Anastomotic leakage and overall complications. Results of this study suggest that laparoscopy is too safe and effective in the treatment of colorectal disease for patients with previous abdominal surgery as it is for those without surgical backgrounds. However sufficient large-volume study is necessary to validate the long-term outcomes in previous abdominal surgical patients. PMID- 25916048 TI - Efficacy of non-stented pancreaticojejunostomy demonstrated in the hard pancreas. AB - BACKGROUND/AIMS: The aim of this study was to compare hard and soft pancreas for short-term complications of pancreaticoduodenectomy performed with a duct-to mucosa anastomosis of pancreaticojejunostomy without a stenting tube. METHODOLOGY: We investigated 156 patients with pancreaticojejunostomy who were classified into two groups of hard pancreas (group A: 79) and soft pancreas (group B: 77). Outcomes, including complications and operative procedures, are reported. RESULTS: There were no differences between groups A and B for median age, gender, performance status. Biliary drainage ratio and disease classification of Groups A and B were statistically different. In preoperative status, there were no differences in Body Mass Index, total bilirubin, albumin, hemoglobin, creatinine, and PFD. Group B had lower HbA1C levels than group A. In operative procedures, there were no differences in operative times and blood loss, but group B had longer postoperative hospital days than group A. On operative results, there were no differences in mortality, delayed gastric emptying, biliary fistula, hemorrhage, cholangitis, lymph leakage, and others. There were significant differences between groups A and B in morbidity (12.7% vs. 35.1%), pancreatic fistula (0% vs. 9.1%), intra-abdominal abscess (1.3% vs. 9.1%). CONCLUSION: Efficacy of pancreaticojejunostomy without a stenting tube for hard pancreas was demonstrated. PMID- 25916049 TI - C-reactive protein level as a possible predictor for early postoperative ileus following elective surgery for colorectal cancer. AB - BACKGROUND/AIMS: Inflammatory reactions are par- tially responsible for postoperative ileus (POI). Serum C-reactive protein (CRP) is an acknowledged marker of inflammation. In this study the CRP response with respect to POI in elective colorectal surgery was exam- ined to define the role of serum CRP as an early predic- tor of POI. METHODOLOGY: Three hundred eighty-three patients who underwent elective colorectal resection were identified for inclusion in this study. We defined early POI as that occurring within 30 days following the surgery. Thirty-five patients with POI were com- pared to a subgroup of 348 patients with an unevent- ful postoperative course, and the correlation between postoperative serum CRP levels and POI in colorectal surgery was investigated. RESULTS: In the univariate analysis, length of operation, surgical blood loss, and serum CRP were factors significantly associated with POI following colorectal surgery; however, these fac- tors lost their significance on multivariate analysis. CONCLUSION: Our results suggest that an increase in CRP levels alone is not a predictor for POI following surgery for colorectal surgery. Although inflammatory responses are known to contribute to the ileus, ad- ditional study is required to identify risk factors that would be more useful for prediction of POI. PMID- 25916050 TI - Synchronous and metachronous colorectal cancers: distinct disease entities or different disease courses? AB - BACKGROUND/AIMS: This study aimed to investigate the clinicopathological characteristics of synchronous and metachronous colorectal cancers (CRCs). METHODOLOGY: From January 1, 2001 to December 31, 2010, 5898 patients who underwent surgical resection for CRCs were enrolled. Synchronous CRC was defined as presence of more than one primary CRC within 6 months of resection of the primary tumor; while CRC that occurred at least 6 months later was regarded as metachronous CRC. RESULTS: 5346 patients were eligible for the study and divided into three groups: solitary, synchronous and metachronous CRC. The overall prevalence of the synchronous CRC was 2.2% and the 10-year cumulative incidence of metachronous cancer was 0.84%. 29 (64%) metachronous cancers were diagnosed within 3 years of the index cancer and the mean time interval was 3.2 years. Male gender and presence of associated adenoma were significant risk factors for both synchronous and metachronous CRC. Synchronous and metachronous CRC patients shared similar clinicopathological features except that the former were older than the latter by 3.7 years. The five-year survival rates were not different among the three groups. CONCLUSIONS: Our study indicates that synchronous and metachronous CRC might represent similar disease entity with different courses. PMID- 25916051 TI - Lymph node ratio may predict relapse free survival and overall survival in patients with stage II & III colorectal carcinoma. AB - BACKGROUND/AIMS: Lymph node ratio (LNR) defined as the number of lymph nodes (LNs) involved with metastases divided by number of LNs examined, has been shown to be an independent prognostic factor in breast, stomach and various other solid tumors. Its significance as a prognostic determinant in colorectal cancer (CRC) is still under investigation. This study investigated the prognostic value of LNR in patients with resected CRC. METHODOLOGY: We retrospectively ex- amined 145 patients with stage II & III CRC diagnosed and treated at a single institution during 9 years pe- riod. Patients were grouped according to LNR in three groups. Group 1; LNR < 0.05, Group 2; LNR = 0.05-0.19 & Group 3 > 0.19. Chi square, life table analysis and multivariate Cox regression were used for statistical analysis. RESULTS: On multivariate analysis, number of involved LNs (NILN) (HR = 1.15, 95% CI 1.055-1.245; P = 0.001) and pathological T stage (P = 0.002) were statistically significant predictors of relapse free survival (RFS). LNR as a continuous variable (but not as a categorical variable) was statistically significant predictor of RFS (P = 0.02). LNR was also a statistically significant predictor of overall survival (OS) (P = 0.02). CONCLUSION: LNR may predict RFS and OS in patients with resected stage II & III CRC. Studies with larger cohorts and longer follow up are needed to further examine and validate theprognostic value of LNR. PMID- 25916052 TI - Factors affecting the detection of colorectal cancer and colon polyps on screening abdominal ultrasonography. AB - BACKGROUND/AIMS: The aim of this study was to identify factors affecting the detection of colorectal cancer (CRC) and colon polyps (CPs) using abdominal ultrasonography (US). METHODOLOGY: Patient records were analyzed retrospectively. Those diagnosed as having either CRC or CPs by colonoscopy performed after screening abdominal US were enrolled. The diagnostic criterion for CRC was an irregularly thickened wall or mass. CPs were diagnosed as spherical or ovoid hypoechoic lesions arising within the colonic lumen as seen on abdominal US. RESULTS: Sixteen patients had a total of 16 CRC lesions and 11 patients had a total of 17 CPs. All CRC lesions invaded deeper than the subserosa. Cancer cell invasion limited to the submucosa was noted in the two 1.5-cm CPs. Detection of these lesions was not associated with invasion to lymph or blood vessels. These results suggest that wall thickening might be the consequence of cancer cells invading below the subserosa, thereby resulting in the lesions becoming detectable on abdominal US. CONCLUSIONS: Detection of CRC and CPs on abdominal US was associated with lesion size and depth of invasion. PMID- 25916053 TI - The impact of anesthetic techniques on survival for patients with colorectal cancer: evidence based on six studies. AB - BACKGROUND/AIMS: Epidural-supplemented general anesthesia is perceived as a more beneficial method over general anesthesia since it reduces incidence of side effects, provides better postoperative pain relief and lowers the possibility to use immunosuppressive anesthetics. However, previous prospective and retrospective studies reported conflicting results in the effects of epidural anesthesia on post-operative outcomes of colorectal cancer surgery. Therefore, this study aims to pool available evidence to assess the association between epidural anesthesia and the post- operative outcomes in this group of patients. METHODOLOGY: Relevant studies were searched in databases and a meta-analysis was performed to estimate the association between epidural anesthesia and overall survival and recurrence free survival. RESULTS: Compared with the anesthetic choice without epidural anesthesia, epidural-supplemented anesthesia is associated with significantly longer overall survival (HR: 0.72, 95% CI: 0.55 0.94, p = 0.01) but not with prolonged recurrence free survival (HR: 1.06, 95% CI: 0.96-1.16, p = 0.23). These results showed a highlevel of robustness in sensitive test. CONCLUSION: Although epidural anesthesia might not lead to improved recurrence free survival, it had significant benefit in improving overall survival and reducing all-cause of death. It might be a useful anesthetic technique for colorectal cancer patients undergoing surgery. However, prospective studies are required to confirm whether this benefit is causative with epidural anesthesia. PMID- 25916054 TI - Feasibility Assessment of Modified FOLFOX-6 as adjuvant treatment after resection of liver metastases from colorectal cancer: analyses of a multicenter phase II clinical trial (Miyagi-HBPCOG Trial-001). AB - BACKGROUND/AIMS: This multicenter and single arm phase II clinical trial was performed to examine the safety and efficacy of modified FOLFOX6 (mFOLFOX6) as adjuvant treatment after resection of liver metastases from colorectal cancer. METHODOLOGY: Patients who had undergone R0-1 resection of liver metastases were assigned to 12 cycles of mFOLFOX6. The primary end point was disease-free survival (DFS). RESULTS: We enrolled 49 cases and analyzed adverse events in 48 cases, since in one patient cancer recurred before starting treatment. As to the relative dose intensity, 5-FU was 78.8%, and oxaliplatin was 75.9%. Adverse events of Grade 3 and above includ- ed 18 cases of neutropenia (37.5%), 4 cases of sensory neuropathy (8.3%), 4 cases of thrombocytopenia (8.3%) and 4 cases of allergy (8.3%), and there were no cases of fatality caused by adverse events. The most difference of adverse event compared with MOSAIC trial (Multicenter International Study of Oxaliplatin/5FU-LV in the Adjuvant Treatment of Colon Cancer) was thrombocytopenia. The 2-year DFS was 59.2% (95% CI: 36.7-78.4) in the 49 enrolled cases. CONCLUSION: mFOLFOX6 after hepatectomy was tolerable. And mFOLFOX6 also seemed to improve DFS. mFOLFOX is one of the options for such patients and appears promising as an adjuvant treatment. PMID- 25916055 TI - Anti-TNF-A therapy about infliximab and adalimamab for the effectiveness in ulcerative colitis compared with conventional therapy: a meta-analysis. AB - BACKGROUND/AIMS: TNF-alpha has an important role in the pathogenesis of ulcerative colitis (UC). It seems that anti-TNF-alpha therapy is beneficial in the treatment of UC. The aim was to assess the effectiveness of Infliximab and Adalimamab with UC compared with conventional therapy. METHODOLOGY: The Pubmed and Embase databases were searched for studies investigating the efficacy of infliximab and adalimumab on UC. RESULTS: Infliximab had a statistically significant effects in induction of clinical response (RR = 1.67; 95% CI 1.12 to 2.50) of UC compared with conventional therapy, but those had not a statistically significant effects in clinical remission (RR = 1.63; 95% CI 0.84 to 3.18) and reduction of colectomy rate (RR = 0.54; 95% CI 0.26 to 1.12) of UC. And adalimumab had a statistically significant effects in induction of clinical remission (RR = 1.82; 95% CI 1.24 to 2.67) and clinical response (RR = 1.36; 95% CI 1.13 to 1.64) of UC compared with conventional therapy. CONCLUSION: Our meta analyses suggested that Infliximab had a statistically significant effects in induction of clinical response of UC compared with conventional therapy and adalimumab had a statistically significant effects in induction of clinical remission and clinical response of UC compared with conventional therapy. PMID- 25916056 TI - Percutaneous radiologic gastrostomy via nasopharyngeal intubation for the treatment of patients with complete malignant pharyngoesophageal obstruction. AB - BACKGROUND/AIMS: For patients with complete malignant pharyngoesophageal obstruction (CMPO), percutaneous radiologic gastrostomy (PRG) under ultrasound/CT guidance can complicate it to cause failure due to unsatisfied stomach filling. In this study, we retrospectively investigated whether PRG via nasopharyngeal intubation is feasible and effective for these patients. METHODOLOGY: PRG via nasopharyngeal intubation was attempted in 21 patients with CMPO (mean 70.8 +/- 8.23 years). The technique comprised a dilation of the stomach via nasopharyngeal intubation using a catheter, followed by fluoroscopically guided puncture and gastrostomy tube placement. Complications including hemorrhage, peritonitis, gastrojejunocolic fistula, infection of puncture site, tube blocking and outleakage was observed during and after the procedure. RESULTS: A 5F catheter was successfully inserted to the stomach under fluoroscopical guidance and subsequent PRG was performed in all 21 patients. Minor complications occurred in 14.3% patients including mild infection of the fistula in 1, tube blocking in 1 and unexpected tube drawing out in 1. Follow-up nutrition indexes revealed obvious improved nutrition compared to before PRG (P < 0.05). CONCLUSION: PRG via nasopharyngeal intubation was simple, feasible and effective for patients with CMPO. PMID- 25916057 TI - Esophagojejunostomy reconstruction using a robot-sewing technique during totally robotic total gastrectomy for gastric cancer. AB - BACKGROUND/AIMS: The aim of this study was to report on the feasibility of esophagojejunostomy reconstruction using a robot-sewing technique during a completely robotic total gastrectomy for gastric cancer. METHODOLOGY: Between May 2011 and July 2012, 65 patients in whom gastric adenocarcinoma was diagnosed underwent a completely robotic total gastrectomy, including a robot-sewing esophagojejunal anastomosis. We demonstrated the surgical techniques with analysis of clinicopathologic data and short-term surgical outcomes. RESULTS: All robotic surgeries were successfully performed without conversion. Among the 65 patients, 46 were men and 19 were women. The mean age (+/- SD) was 57.8 +/- 6.5 y. The mean total operative time (+/- SD), EJ anastomosis time (+/- SD), and blood loss (+/- SD) were 245 +/- 53 min, 45 +/- 26 min, and 75 +/- 50 ml, respectively. The mean (+/- SD) post-operative hospital stay was 5.4 +/- 2.5 d. One patient was readmitted for an intestinal obstruction and underwent re operation 14 d post-operatively; he recovered uneventfully and was discharged 10 d post- operatively. During the follow-up, no patients developed an esophgojejunostomy stricture. CONCLUSIONS: A robot-sewing anastomosis for esophagojejunostomy reconstruction during robotic total gastrectomy for gastric cancer is feasible. Indeed, a robot-sewing anastomosis for esophagojejunostomy reconstruction may become a standard surgical technique during completely robotic total gastrectomy for gastric cancer. PMID- 25916058 TI - Serum alpha-fetoprotein may have a significant role in the surveillance of hepatocellular carcinoma in hepatitis B endemic areas. AB - BACKGROUND/AIMS: The role of serum alpha-fetoprotein (AFP) determination in hepatocellular carcinoma (HCC) surveillance is controversial. METHODS: We reviewed a total of 132 patients (mean age 57.8 +/- 9.6, males = 101 (76%); HBsAg positive = 109 (82.6%); cirrhosis = 94 (71.2%)) who were diagnosed with HCC during regular surveillance test with ultrasound (US) and AFP. RESULTS: The primary mode of tumor detection was US only in 51.5%, US and AFP in 22.0%, AFP only in 19.7%, and incidental in 6.8% of patients. US detected 68.5% of tumor diagnosed at early stage, which was significantly lower than tumor beyond-early stage (85.0%, p = 0.048). AFP doubling (an increase in AFP level more than double from a prior surveillance) was more frequently observed in HBV-related HCC (47.7%) than HCV-related HCC (11.8%, p = 0.009). The AFP increased sensitivity by 19.7% for all patients; 28.0% for HBV-related early stage HCC patients. CONCLUSIONS: This result suggest that serum AFP measurements may have a significant role in increasing sensitivity in HCC surveillance, especially for detecting early stage HBV-related HCC. PMID- 25916059 TI - Diagnosis of esophageal varices on liver CT: is thin-section reconstruction necessary? AB - BACKGROUND/AIMS: The aim of this study was to evaluate the effect of 1 mm, 3 mm, and 5 mm section thicknesses of liver CT on the detection and grading of esophageal varices in cirrhotic patients. METHODOLOGY: A total of 219 consecutive cirrhotic patients who had undergone both upper endoscopy and 64-channel liver CT were included. Portal phase images of each CT were reconstructed with a section thickness of 1 mm, 3 mm, and 5 mm. Four radiologists independently reviewed the 3 image sets. The observers evaluated the presence of esophageal varices on a 5 point confidence scale and measured the maximal short diameter of the largest varix identified. Sensitivity, specificity and predictive value calculation and receiver operating characteristic analysis were performed. Correlation between CT measurements and endoscopic grading as the reference standard was assessed. RESULTS: The averaged Az values at 1 mm, 3 mm, and 5 mm image sets were 0.936, 0.946, and 0.935, respectively, and they were not significantly different among the 4 observers. When a 3 mm cut-off criterion for large varices was applied, sensitivity, specificity, and predictive values were comparable among the 3 image datasets. CONCLUSIONS: Routine liver CT protocol is sufficient for evaluation of esophageal varices in cirrhotic patients without adding thin section reconstruction images. PMID- 25916060 TI - Risk factors associated with outcome in liver retransplantation: multicentric study. AB - BACKGROUND/AIMS: To externally validate the predictive mathematical model of survival designed by Linhares et al. (2006). METHODOLOGY: This retrospective study was conducted on 217 individuals submitted to liver retransplantation from January 2000 to December 2008 in four European centers. The following variables were obtained on the recipient: age, creatinine, urgency of retransplantation and time between transplantation and retransplantation. The Kaplan-Meier survival curve and ROC curve were used to validate the mathematical model. RESULTS: The present results showed a similar pattern of survival compared to the study of Linhares et al. (2006) concerning the biological variations, when survival curves were compared for each of the four variables analyzed between both samples. When compared, the areas below the ROC curve (aROC) of derivation (0.733) and validation samples (0.593) presented significant difference (p = 0.005), revealing low relationship of sensitivity and specificity between the two curves. Similarity was observed in Kaplan-Meier survival curves. CONCLUSION: This study allowed external validation by the Kaplan-Meier survival curves of the predictive mathematical model of survival in liver retransplantation proposed by Linhares et al. (2006). However, validation through the ROC curve, the aROC, evidenced weak discrimination ability. PMID- 25916062 TI - Ovarian cancer liver metastases--should we apply the principle of optimal cytoreduction to the liver? A review. AB - Advanced stage ovarian cancer is a common situation at presentation and current medical practice lacks efficient methods of prevention and early diagnosis. Primary maximal cytoreductive surgery followed by adjuvant chemotherapy is currently a generally accepted principle; most patients however undergo recurrence and common therapeutical attitude is secondary cytoreduction based approximately on the same principles as the primary one. Due to the success of liver resections in colorectal metastases and the development of liver surgery in general, different centers worldwide analyzed in the last 20 years liver resections' utility for other primaries, including ovarian tumors. PMID- 25916061 TI - The risk factors for mortality and septic shock in liver transplant recipients with ESKAPE bacteremia. AB - BACKGROUND/AIMS: Although bacteremias due to the six ESKAPE pathogens have recently been identified as a serious emerging problems in solid organ transplant (SOT), no information in liver transplant recipients is available. We sought to investigate the risk factors for mortality and septic shock in liver transplant recipients with ESKAPE bacteremia. METHODOLOGY: A retrospective analysis of bacteremia after liver transplantation was reviewed. Risk factors for mortality and septic shock caused by ESKAPE bacteremia were identified. RESULTS: Forty-nine episodes ofbacteremia in 37 liver transplant recipients were due to ESKAPE strains. The only factor for bacteremia-related mortality independently associated with ESKAPE was septic shock (odds ratio [OR] = 67.500, 95% confidence interval [CI] = 8.464-538.300, P < .001). The factors for septic shock independently associated with ESKAPE were white blood cells count > 15,000/mm3 (OR = 15.205, 95% CI = 2.271-101.799, P = .005) and temperature of 39 degrees C or greater (OR = 10.959, 95% CI = 1.592-75.450, P = .015). CONCLUSIONS: To improve the results of liver transplantation, more effectively therapeutic treatments are of paramount importance when liver transplant recipients with ESKAPE bacteremia present with septic shock, elevated white blood cells count and high body temperature. PMID- 25916063 TI - Comparison of the level of intraoperative nociception between laparoscopic and open hepatic resection. AB - BACKGROUND/AIMS: Sufficient suppression of perioperative nociception is important for ensuring favorable postoperative outcomes. Although the level of nociception during laparoscopic surgery is generally lower than during laparotomy, there is insufficient evidence to support this for hepatic resection. METHODOLOGY: To develop a method to retrospectively evaluate the intraoperative nociceptive level, we collected data of intraoperative averaged values of heart rate, perfusion index, systolic blood pressure during three surgeries with different levels of intraoperative nociception. After we validated the utility of discriminant analysis using these variables for the retrospective evaluation of nociception during surgery, we performed this analysis in patients who underwent either laparoscopic or open hepatic resection. RESULTS: Although there was a significant difference in discriminant score between the open and the laparoscopic hepatic resection groups before propensity score matching, discriminant score showed no significant difference between two groups after matching. CONCLUSIONS: The level of nociception during laparoscopic hepatic resection is likely similar to that during open hepatic resection. An assertive anti-nociceptive strategy might be required for laparoscopic procedures under general anesthesia, as with open procedures. PMID- 25916064 TI - Comparison between anatomical subsegmentectomy and nonanatomical partial resection for hepatocellular carcinoma located within a single subsegment: a single-center retrospective analysis. AB - BACKGROUND/AIMS: For hepatocellular carcinoma (HCC) within a single subsegment, the superiority of anatomical subsegmentectomy over non-anatomical partial resection is still controversial. In this study, we assessed the potential benefit of subsegmentectomy. METHODOLOGY: We selected 44 patients with a single HCC lesion within one subsegment who had undergone anatomical subsegmentectomy or non-anatomical partial resection from among 173 patients who underwent hepatectomy in our hospital from August 2003 to May 2013. We compared the results following anatomical subsegmentectomy (Group A; n = 16) and non-anatomical partial resection (Group N; n = 28). RESULTS: One- and two-year survival rates were 92.5% and 89.3%, respectively; 1- and 2-year recurrence-free survival (RFS) rates were 88.9% and 69.1%, respectively. There was no significant difference in overall survival or RFS between the groups. However, among HBV-positive patients, RFS was significantly better for Group A than Group N (p = 0.008). CONCLUSIONS: For HBV-positive HCC within a single subsegment, we recommend subsegmentectomy. PMID- 25916065 TI - Serum high-sensitivity C-reactive protein are associated with HBV replication, liver damage and fibrosis in patients with chronic hepatitis B. AB - BACKGROUND/AIMS: The aim of this study was to explore the potential role of serum high-sensitivity C-reactive protein (hs-CRP) in the pathogenic process of chronic hepatitis B. METHODOLOGY: A total of 380 patients with chronic hepatitis B were included in this study. All patients received the concentrations of serum hs-CRP, Hepatitis B sero-markers, serum HBV-DNA loads, liver function parameters and liver stiffness were measured, and in which 172 patients undertaken liver biopsy and immunohistochemistry analysis. RESULTS: Serum hs-CRP concentration in patients with the chronic hepatitis B (2.38 +/- 5.52) was significantly higher than healthy controls (0.60 +/- 0.53), P < 0.05. The area under ROC curve in fibrosis S4 and S3 is 0.826 and 0.78. The sensitivity and specificity of hs-CRP for fibrosis S3 and S4 diagnosis were 81.8%, 80% and 73.4%, 76.2% respectively (cut off: 1.01 mg/ml, 1.11 mg/l). CONCLUSIONS: C-reactive Protein are associated with HBV replication, liver damage and fibrosis in patients with chronic hepatitis B, and serum High-sensitivity C-reactive Protein may be a marker for diagnosing significant fibrosis in patients with chronic hepatitis B, and can reflect the severity of liver damage. PMID- 25916066 TI - The effect of radiofrequency ablation vs. liver resection on survival outcome of colorectal liver metastases (CRLM): a meta-analysis. AB - BACKGROUND/AIMS: For patients with solitary colorectal liver metastasis (CRLM), it is still controversial whether radiofrequency ablation (RFA) has the same effect as liver resection (LR). This study aims to pool available evidence and to analyze the effect of RFA versus LR for resectable solitary CRLM in sur- vival indicators. METHODOLOGY: Relevant studies were searched among databases and a meta-analysis was performed to pool the hazard ratio (HR) of RFA versus LR in overall survival (OS) and disease free survival (DFS). RESULTS: A total of 10 studies were included in this meta-analysis. Pooled results showed poorer OS (HR: 1.85, 95% CI: 1.48 to 2.32, p < 0.00001) and DFS (HR: 1.68, 95% CI: 1.14 to 2.48, p = 0.009) among the patient received RFA compared those received LR. Sensitivity analysis confirmed high robustness of the findings. CONCLUSION: In patients with resectable CRLM, LR is superior to RFA in survival outcomes. RFA should be reserved for patients who are not optimal candidates for resection until new supportive evidence is obtained from large RCTs. PMID- 25916067 TI - Identification of MicroRNAs and target genes involvement in hepatocellular carcinoma with microarray data. AB - The aim of the study is to identify the differentially expressed microRNAs (miRNAs) between hepatocellular carcinoma (HCC) samples and controls and provide new diagnostic potential miRNAs for HCC. The miRNAs expression profile data GSE20077 included 7 HCC samples, 1 HeLa sample and 3 controls. Differentially expressed miRNAs (DE-miRNAs) were identified by t-test and wilcox test. The miRNA with significantly differential expression was chosen for further analysis. Target genes for this miRNA were selected using TargetScan and miRbase database. STRING software was applied to construct the target genes interaction network and topology analysis was carried out to identify the hub gene in the network. And we identified the mechanism for affecting miRNA function. A total of 54 differentially expressed miRNAs were identified, in which there were 13 miRNAs published to be related to HCC. The differentially expressed hsa-miR-106b was chosen for further analysis and PTPRT (Receptor-type tyrosine-protein phosphatase T) was its potential target gene. The target genes interaction network was constructed among 33 genes, in which PTPRT was the hub gene. We got the conclusion that the differentially expressed hsa-miR-106b may play an important role in the development of HCC by regulating the expression of its potential target gene PT-PRT. PMID- 25916068 TI - Tumor-to-muscle ratio of 8F-FDG PET for predicting histologic features and recurrence of HCC. AB - BACKGROUND/AIMS: Hepatocellular carcinoma (HCC) recurrence is observed in up to 70-80% of patients despite a curative treatment. Microvascular invasion (MVI) and poor differentiation are strong risk factors for recurrence, but these cannot be known preoperatively. The aim of this study was to investigate the correlation of 18F-FDG PET with MVI and differentiation, and predictive role of tumor-to background ratio of PET for recurrence in HCC. METHODOLOGY: Fifty-four patients had 18F-FDG PET/CT study before surgical resection as a first treatment of HCC between December 2008 and December 2012. We analyzed the predictive role of metabolic parameters of PET for recurrence of HCC. Maximal standardized uptake value, tumor-to-nontumor ratio, tumor-to-muscle ratio (TMR) and tumor-to-blood ratio were tested as metabolic index of 18F-FDG PET. RESULTS: Twenty-seven patients had increased uptake in preoperative PET and 14 (51.9%) of them experienced the recurrence. Increased uptake in PET and TMR were associated with MVI (p = 0.04, p = 0.005) and histologic differentiation (p = 0.018, p = 0.002). MVI was the only predictive factor for re- currence in multivariate analysis although TMR >= 6.36 showed a favorable result despite no statistical significance (p = 0.061). CONCLUSIONS: Increased 18F-FDG uptake of HCC, especially high TMR might be correlated with MVI and poor differentiation, and tends to have a risk for recurrence in HCC. PMID- 25916069 TI - Two-surgeon technique for liver transection using precoagulation by a soft coagulation system and ultrasonic dissection. AB - BACKGROUND/AIMS: A soft-coagulation system (SCS) was introduced as an effective device to reduce blood loss in hepatectomy. Here we evaluated the efficacy of a two-surgeon technique using precoagulation by an SCS and the Cavitron Ultrasonic Surgical Aspirator (CUSA) for liver transection. METHODOLOGY: The 163 patients with liver tumors were divided into two groups (conventional group and two surgeon group). Liver transection was conducted using saline-coupled bipolar electrocautery and CUSA in 102 patients (conventional group). In 61 patients (the two-surgeon group), a two-surgeon technique using precoagulation by an SCS and CUSA for liver resection was performed. RESULTS: The median blood loss was significantly less in the two-surgeon group compared to the conventional group (354.8 mL vs. 557.8 mL, respec tively: p = 0.0011). The postoperative hospital stay was significantly shorter in the two-surgeon group compared to the conventional group (12.7 days vs. 15.5 days, p = 0.0035). CONCLUSIONS: The two surgeon technique using precoagulation by an SCS and CUSA was significantly reduced blood loss during liver transection, and associated with low morbidity and mortality. This technique may be useful for many hepatobiliary surgeons. PMID- 25916070 TI - Red blood cell distribution width as a non-invasive marker for the assessment of inflammation in non-alcoholic steatohepatitis. AB - BACKGROUND/AIMS: The aim of this study was to assess the association between red cell distribution width and inflammation in biopsy proven non-alcoholic steatohepatitis. METHODOLOGY: Fifty four subjects with non-alcoholic steatohepatitis and thirty nine controls were enrolled for the study. Liver biopsy specimens were scored by using non-alcoholic fatty liver disease activity score by a single experienced liver pathologist. RESULTS: Red cell distribution width was higher in the severe inflammation group in non-alcoholic steatohepatitis (p < 0.05). The areas under the receiver operating characteristic curves for the predictive performance of aspartate aminotransferase, alanine aminotransferase, gamma glutamyl transferase and red cell distribution width in identifying inflammation in non-alcoholic steatohepatitis were 0.55 (0.41-0.68), 0.51 (0.37-0.64), 0.53 (0.39-0.67) and 0.73 (0.59-0.84) respectively and the differences of these values between red cell distribution width and other parameters were found to be statistically significant (p < 0.05). To determine the grading of inflammation, the specificity for using the red cell distribution width as an indicator in non-alcoholic steatohepatitis patients was calculated to be 73.3%, with 79.5% sen- sitivity. CONCLUSION: Red cell distribution width was a sensitive and specific method for the assessment of the inflammation in patients with non-alcoholic steatohepatitis. PMID- 25916071 TI - Intrahepatic metastasis is more risky than multiple occurrence in hepatocellular carcinoma patients after curative liver resection. AB - BACKGROUND/AIMS: The characteristics of multiple nudules in hepatocellular carcinomas (HCCs) after curative liver resection remain obscure. We compare the clinicopathologic characteristics and prognoses between patients with hepatic lesions with multicentric occurrence (MO) and intrahepatic metastasis (IM) at the time of surgical resection. METHODOLOGY: The histopathologic features of multiple tumors from 198 patients of HCC were analyzed and divided into MO group (n = 51, 25.8%) for multicentric HCCs and an IM group (n = 147, 74.2%) in cases with intrahepatic metastases. Overall survival rate, disease-free survival and clinicopathologic differences were compared between the two groups. RESULTS: Microvascular invasion and increased tumor size were the most important factors discriminating the IM group from the MO group (P < 0.001 and P = 0.027, respectively). Kaplan-Meier and log rank tests revealed that disease-free survival and overall survival rates in the MO group were significantly higher than those for the IM group (P < 0.001 and P < 0.001, respectively). A multivariate analysis of Cox's proportional hazards model showed that increased alpha-fetoprotein (AFP) and protein induced by vitamin K antagonist-II (PIVKA-II) levels, portal vein invasion and intrahepatic metastases were the most important prognostic factors. CONCLUSIONS: Among HCCs, the prognosis of patients with MO is significantly better than that of patients with IM. PMID- 25916072 TI - Era of liver transplantation: combined anatomic splenectomy and anticoagulant therapy in prevention of portal vein thrombosis after splenectomy. AB - BACKGROUND/AIMS: Portal vein thrombosis (PVT) is a common complication following splenectomy in patients with liver cirrhosis and portal hypertension, which also brings difficulties to future possible liver transplantation. This paper retrospectively analyzes the preventive effect of combined anatomic splenectomy and early anticoagulant therapy on post-splenectomy portal vein thrombosis in patients with portal hypertension. METHODOLOGY: We retrospectively analyzed 136 patients who underwent splenectomy at our hospital between January 2010 and December 2013 due to liver cirrhosis and portal hypertension. Patient conditions, such as coagulation function, splenic and portal vein thrombosis, intra-abdominal hemorrhage, pancreatic leakage and intra-abdominal infections, are observed postoperatively. RESULTS: Despite the presence of liver cirrhosis and portal hypertension in patients, early postoperative anticoagulant therapy has no significant impact on coagulation function and intra-abdominal hemorrhage of these patients (p > 0.05). Anatomic splenectomy can reduce the occurrence of complications such as postoperative bleeding, pancreatic leakage and intra abdominal infections (p < 0.05). CONCLUSION: Combined anatomic splenectomy and early postoperative anticoagulant therapy can reduce post-splenectomy portal vein thrombosis in patients with portal hypertension, and is conducive to the future liver transplantation therapy may be needed by the patients. PMID- 25916073 TI - Management of severe blunt liver injuries by applying the damage control strategies with packing-oriented surgery: experiences at a single institution in Korea. AB - BACKGROUND/AIMS: This study was conducted to investigate effective management strategies for patients with severe blunt liver injuries. METHODOLOGY: Treatment methods and outcomes of 77 patients with grade IV-V damage among patients with liver injury managed between 2009 and 2013 were investigated. RESULTS: Of the 77 patients, 32 were managed surgically. Packing was performed in 29 of these patients, while 26 also underwent liver surgery to maximize the hemostatic effect of packing. All 32 underwent temporary abdominal closure, and the mean amount of blood products used in the first 24 hours after admission included packed red blood cell, 13.3 units; fresh frozen plasma, 12.4 units; and platelets, 12.2 units, very close to 1:1:1. A total of 9 of 77 (11.7%) patients and 8 of 32 who underwent the operation died (operative mortality rate, 25%). Liver-related uncontrolled hemorrhage contributing to death occurred in four patients (12.5%). CONCLUSIONS: Although nonoperative management can first be pursued if the patient's condition allows for it, hemodynamic instability and evidence of peritonitis requires surgical management. Surgical management should abide by the damage control surgery principles that focus on packing to minimize surgical time, followed by aggressive critical care according to damage control resuscitation. PMID- 25916074 TI - Evaluation of antibiotic use to prevent post-endoscopic retrograde cholangiopancreatography pancreatitis and cholangitis. AB - BACKGROUND/AIMS: The purpose of this study was to evaluate the relationship between prophylactic antibiotic use and complications following endoscopic retrograde cholangiopancreatography (ERCP). METHODOLOGY: We retrospectively evaluated 605 consecutive patients who underwent ERCP in our hospital between September 2009 and November 2011. The antibiotic group included patients who underwent their procedure before October 2010, while the control group included patients after October 1, 2010, who did not receive antibiotics. We compared the incidence of postoperative pancreatitis and cholangitis between the groups. RESULTS: There were no significant differences in the backgrounds of the 304 control and the 301 antibiotic-treated patients. The incidence of post-ERCP pancreatitis was 4.9% in the control group and 4.3% in the antibiotic group (p = 0.72). The incidence of postoperative cholangitis was 2.0% in the control group and 1.7% in the antibiotic group (p = 0.99). Choledocholithiasis, pancreatic duct injection, and female gender were detected as significant risk factors for postoperative pancreatitis by multivariate analysis; sclerosing cholangitis and incomplete biliary drainage were significant risk factors for postoperative cholangitis. Even in cases with these risk factors, prophylactic antibiotic use did not influence the incidence of pancreatitis or cholangitis. CONCLUSION: Prophylactic antibiotics do not reduce the incidence of either pancreatitis or cholangitis following ERCP. PMID- 25916075 TI - The effect of no naked pancreatic surface in the cavity of jejunum on pancreaticojejunostomy in 132 consecutive cases. AB - BACKGROUND/AIMS: To prevent the pancreatic fistulas, we designed a technique termed "no naked pancreatic surface in the cavity of jejunum" on pancreaticojejunostomy. METHODOLOGY: We adopted pancreatic exocrine secretions following the pancreatic duct by drainage; there was no naked pancreatic surface in the cavity of jejunum, and entail 2-3 cm sheath of the jejunum to the pancreatic stump. RESULTS: Only 3 (2.27%) cases developed pancreatic fistulas, 1 patient had a grade A leak, and 2 patients had grade B leakage. The overall morbidity was 25.76%. There was no dilatation of pancreatic duct or pancreatic enzyme deficiency shown during followed-up. The duration for accomplishing the anastomosis was 20 minutes averagely. CONCLUSIONS: The technique of no naked pancreatic surface in the cavity of jejunum can be routinely used in any case with pancreaticojejunostomy. It is a safe, simple, and effective technique that avoids the primary complication of anastomotic leakage. PMID- 25916076 TI - Emergent triglyceride-lowering therapy for hypertriglyceridemic pancreatitis. AB - BACKGROUND/AIMS: Hypertriglyceridemia (HTG) is recognized as a main cause of acute pancreatitis. The clinical course of hypertriglyceridemic pancreatitis (HTGP) is usually severe and often associated with complications. Patients with HTGP need therapeutic strategies aimed at rapidly reducing triglyceride (TG) serum levels. Here we review the effects of Emergent triglyceride-lowering therapies as well as their ad vantages and controversies. METHODOLOGY: PubMed and MEDLINE were searched for articles using the keywords hypertriglyceridemia", "hyperlipidemia and "pancreatitis until September 2012. RESULTS: In sulin is a non-invasive, economic and safe treatment but the efficiency of insulin is still limited. Combined use of insulin and heparin, especially low molecular weight heparin (LMWH), remains an acceptable therapeutic option in early stages of HTGP. Therapeutic plasma exchange (TPE) and double-filtration (DF) provides a direct option for the removal of pathogenic substances. However, both of these therapies are expensive and not widely available, and TPE has risks for infection and allergic reactions. Medium chain triglycerides, omega-3-fatty acids, fibrates, niacin, microsomal transport protein inhibitors and gene therapy may be potential adjuvant therapies for achieving per- manent control of HTGP. CONCLUSIONS: Insulin, LMWH combined with insulin, TPE and DF could be used as emergent therapies for HTCP. PMID- 25916077 TI - Correlations between serum trypsinogen-2 and pancreatic cancer. AB - BACKGROUND/AIMS: To investigate associations be- tween serum trypsinogen-2, pancreatitis and pancreatic cancer (PC) and determine cutoff values for PC diagnosis. METHODOLOGY: We recruited 88 patients from Internal Medicine/Surgical Departments of General Military Hospital of Beijing PLA between 12/2009 and 6/2010. Serum samples were collected preoperatively from 23 PC patients, 30 pancreatitis patients and 35 healthy controls. Enzyme-linked immunosorbent assay was used to detect trypsinogen-2 semiquantitatively. RESULTS: Serum trypsinogen-2 levels of PC and pancreatitis patients were significantly higher than those of controls (51.2 +/- 80.3, 107.7 +/- 98.1 vs. 1.0 +/- 0.5, p = 0.03, p < 0.001) and significantly higher in pancreatitis vs. PC patients (107.7 +/- 98.1 vs. 51.2 +/- 80.3, p = 0.01). Higher Balthazar CT grades correlated with higher trypsinogen-2 in pancreatitis group. ROC curves for trypsinogen-2 revealed optimal cutoff value 1.8 as lower PC detection limit with 95.7% sensitivity and 91.4% specificity, and optimal cutoff value 19.9 for upper PC detection limit with 87.0% sensitivity and 97.1% specificity. Trypsinogen-2 levels correlated with pancreatic injury level. An AUC of 0.73 (95% Cl: 0.59-0.84, p = 0.002) distinguished PC from pancreatitis. CONCLUSION: Serum trypsinogen-2 is associated with PC and pancreatitis. Levels between 1.8 MUg/L and 19.9 MUg/L strongly suggest PC. Detection of serum trypsinogen-2 may provide simple, sensitive, specific non-invasive initial screening for early PC diagnosis. PMID- 25916078 TI - Correlation of computed tomography imaging features and pathological features of 41 patients with pancreatic neuroendocrine tumors. AB - BACKGROUND/AIMS: Pancreatic neuroendocrine tumors (PNET) are relatively rare. Here, we present clinical and pathological characteristics of PNETs to show a relationship between computed tomography (CT) imaging and the 2010 World Health Organization (WHO) classification. METHODOLOGY: We retrospectively reviewed the records of 41 PNET patients who were treated between 2002 and 2012. All tumors were classified as neuroendocrine tumor (NET) grade 1 (G1), NET grade 2 (G2), or neuroendocrine carcinoma (NEC) grade 3 (G3) on the basis of the 2010 WHO classification system. RESULTS: Twenty-five tumors were classified as G1, 11 as G2, and five as G3. Mean sizes of the G1, G2 and G3 tumors were 1.84 +/- 0.54, 4.90 +/- 0.84, and 5.62 +/- 1.18 cm, respectively, (P < 0.01). A PNET is typically hypervascular and exhibits contrast enhancement on enhanced CT. Higher percentage of G1 tumors demonstrated typical imaging and showed a significantly greater distinct mass compared with G2 and G3 tumors. CONCLUSIONS: Although PNET has many imaging features that appear on CT, G2 and G3 tumors often show atypical imaging features, particularly with large sizes and/or ill-defined features, when compared with G1 tumors. If a PNET has atypical imaging features, possibility of malignancy should be considered. PMID- 25916079 TI - Results of pancreaticojejunal end-to-side anastomosis using the invagination method without a pancreatic stenting tube. AB - BACKGROUND/AIMS: Perioperative management of pancreaticoduodenectomy (PD) is a constant dilemma and challenging for gastrointestinal surgeons. Postoperative pancreatic fistula (POPF) and delayed gastric emptying (DGE) are of particular concern, and the onset of these conditions indicates a prolonged postoperative stay (POS). The procedure and postoperative outcomes of pancreaticojejunostomy performed at our hospital are reported. METHODOLOGY: POPF, DGE, and POS were investigated in 54 patients who had undergone PD at our hospital since June 2007. Pancreaticojejunal end-to-side anastomosis using the invagination method without a stenting tube and without duct-to-mucosa anastomosis was performed in all patients, regardless of pancreatic duct diameter. RESULTS: There were 26 patients (48.2%) without POPF, 24 (44.4%) with grade A, 4 (7.4%) with grade B, and none with grade C. The mean POS was 28.3 days. DGE was observed in 4 patients (7.4%) who underwent pylorus-preserving PD (PpPD). There were 34 patients with a soft pancreas. None of the patients experienced intraperitoneal bleeding or abscess, and no surgery-related deaths occurred. CONCLUSIONS: The reconstructive pancreaticojejunostomy procedure performed at our hospital appears to be safe and convenient, and we plan to collect additional data, including assessments of the function of the remaining pancreas, in the future. PMID- 25916080 TI - Outcome after pancreaticoduodenectomy for malignancy in elderly patients. AB - BACKGROUND/AIMS: To evaluate short-term outcomes and long-term survival after pancreaticoduodenectomy for malignancy in elderly Chinese patients (aged 70 years or older) compared with younger patients. METHODOLOGY: Between January 2005 and December 2013, 216 consecutive patients who underwent a PD with pancreatic cancer or periampullary cancers in our institution were recruited in this study. Sixty eight patients aged 70 years or older when they underwent PD, while 148 patients younger than 70. RESULTS: There were no significant differences in postoperative mortality (p = 0.104), overall morbidity (p = 0.057) and surgical complications (p = 0.200) between the elderly patients and the younger patients. Elderly patients had a significantly higher incidence of cardiac events (p = 0.008) and pneumonia (p = 0.041) postoperatively. The postoperative hospital stay in the older age group was significantly longer (p = 0.013). The overall survival did not differ between the two age groups both when patients with pancreatic cancer were analyzed (p = 0.836) and when patients with periampullary cancers were analyzed (p = 0.817). CONCLUSIONS: Our results showed that pancreaticoduodenectomy for malignancy in Chinese patients over 70 years old could be performed safely. Age should not be considered as a contraindication to pancreaticoduodenectomy. PMID- 25916081 TI - Detailed analysis of extra-pancreatic nerve plexus invasion in pancreatic body carcinoma analyzed by 50 consecutive series of distal pancreatectomy with en-bloc celiac axis resection. AB - BACKGROUND/AIMS: Advanced pancreatic body carcinoma frequently accompany extra pancreatic nerve plexus (PL) invasion, one of the poor indicator of patient prognosis. The present study aimed to reveal the progress of the PL invasion from cancer of the pancreas body toward the root of the celiac artery (CA) and superior mesenteric artery (SMA) followed by investigation of the relevance of diagnostic accuracy. METHODOLOGY: Resected specimens from 50 consecutive patients who underwent distal pancreatectomy with en bloc celiac axis resection (DP-CAR) were pathologically analyzed for the direction of PL invasion. Diagnostic accuracy on CT imaging were also investigated. RESULTS: Thirty seven of the 50 patients (74%) were positive for PL invasion around the CHA, SPA, CA and SMA. In terms of the diagnostic accuracy, positive predictive values for the PL invasion were 35%, 36%, 43% and 81% for the SPA, CHA, CA and SMA, respectively. Among 21 patients and 23 patients with PL invasion around CHA and SPA, 13 and 6 patients also accompanied PL invasion around CA, respectively. CONCLUSIONS: Carcinoma of the pancreatic body is found to frequently accompany PL invasion around CA. Under the limitation of low diagnostic accuracy, DP-CAR might be feasible operation that increases the possibility of R0 resection. PMID- 25916082 TI - Individualized perfusion of sargent gloryvine decoction for clinical severe acute pancreatitis treatment. AB - BACKGROUND/AIMS: To observe the effects of Sargent gloryvine decoction (SGD) on severe acute pancreatitis (SAP) treatment and to evaluate its clinical value. METHODOLOGY: 112 patients of SAP in our hospital from January, 2005 to December, 2012 were recruited for retrospective analysis. They were divided into two groups, SGD group (62 patients) and control group without treated with SGD (50 patients). Inflammation factor, CT grade and Ranson grade were used to estimate the severity of SAP, and were compared in these two groups. In addition, peripancreatic infection, incidence of pseudo pancreatic cyst, time of anal exsufflation and duration of fever were used to evaluate the effect of SGD treatment. After perfusion of SGD for different time, hospitalization days and cost were recorded to evaluate clinical value of SGD. RESULTS: After perfusion, many indexes in SGD were remarkably superior to those of control group, such as duration of fever, incidence of pseudo pancreatic cyst, peripancreatic infection and Ranson grade. Meanwhile, SGD can sharply down-regulate inflammation reaction levels of SAP patients, so that the hospitalization days and costs can be obviously saved. CONCLUSION: According to comparison, perfusion of SGD is a potential candidate for SAP treatment and is valuable in clinical application. PMID- 25916083 TI - Diffusion-weighted whole body imaging with background body signal suppression/T2 image fusion is negative for patients with intraductal papillary mucinous neoplasm. AB - BACKGROUND/AIMS: One major problem with Intraductal papillary mucinous neoplasm (IPMN) is the appearance of pancreatic duct adenocarcinoma. Diffusion-weighted whole body imaging with background body signal suppression (DWIBS) provides hyperintense signals in cases of cancer. DWIBS and T2 image fusion (DWIBS/T2) provides functional information in anatomical settings, and is useful for the detection of cancer with strong contrast against surrounding tissues. DWIBS/T2 signals were analyzed in patients with IPMN to investigate positive or negative results. METHODOLOGY: Patient records were analyzed retrospectively regarding IPMN. None showed high-risk stigmata or worrisome features. To rule out T2 shine through or differentiate malignant lesions from non-malignant causes of restricted diffusion, positive ADC maps were produced from the recorded ADC values. RESULTS: None of the patients with IPMN had features of malignant progression. No mural nodules were detected by endoscopic ultrasonography. IPMN was hyperintense with DWIBS/T2 and the ADC map. This finding suggested that the hyperintense values of IPMN were T2 shine-through. These results showed that none of the IPMNs were positive with DWIBS/T2. CONCLUSION: DWIBS/T2 was negative for patients with IPMN. DWIBS/T2 might be useful for the evaluation of malignant progression, in addition to observation. PMID- 25916084 TI - Perioperative administration of Daikenchuto (TJ-100) reduces the postoperative paralytic ileus in patients with pancreaticoduodenectomy. AB - BACKGROUND/AIMS: No study has reported whether perioperative administration of Daikenchuto (TJ-100) reduced paralytic ileus after pancreaticoduodenectomy (PD). METHODOLOGY: Forty-five consecutive patients that were scheduled to undergo PD at Wakayama Medical University Hospital between August 2010 and August 2011 were enrolled in this study including the first cohort (n = 15) as the control group and the subsequent cohort (n = 30) as the TJ-100 group. This trial was registered at UMIN-CTR ID# 000005056. RESULTS: Postoperative paralytic ileus occurred more frequently in the control group (73.3% of the control group and 20.0% of the TJ 100 group; p = 0.001). The first passages of flatus significantly improved earlier in the TJ-100 group than in the control group (p = 0.014). A multiple cytokine assay of the drainage and serum showed that IL-9 and IL-10 in the drainage was significantly higher on postoperative day 1 in the TJ-100 group. There were no complications associated with the preoperative administration of TJ 100 before surgery, and no significant differences were observed between the two groups in the incidence of postoperative Gradel-2 diarrhea (CTCAE4.0). CONCLUSIONS: Perioperative administration of TJ-100 was feasible and reduced the incidence of paralytic ileus in PD, and further randomized controlled trials should be conducted. PMID- 25916085 TI - Lymphatic invasion is an independent prognostic factor in pancreatic cancer patients undergoing curative resection followed by adjuvant chemotherapy with gemcitabine or S-1. AB - BACKGROUND/AIMS: The objective of this retrospective study was to clarify prognostic factors in pancreatic cancer patients undergoing curative resection followed by adjuvant chemotherapy with gemcitabine or S-1. METHODOLOGY: Both overall survival (OS) and recurrence-free survival (RFS) were examined in 122 pancreatic cancer patients who underwent curative surgery and received adjuvant gemcitabine or S-1 after surgery between 2005 and 2014. RESULTS: When the length of OS was evaluated according to the log-rank test, significant differences were observed in lymphatic invasion and the T status. Univariate and multivariate Cox's proportional hazard analyses demonstrated that lymphatic invasion was the only significant independent prognostic factor for both OS and RFS. The 5-year OS was 30.1% in the lymphatic invasion-negative group and 12.1% in the lymphatic invasion-positive group (p < 0.001). Moreover, the 5-year RFS was 20.5% in the lymphatic invasion-negative group and 10.4% in the lymphatic invasion- positive group (p = 0.006). CONCLUSIONS: Lymphatic invasion is the most important prognostic factor for OS and RFS in patients with pancreatic cancer who undergo curative resection followed by adjuvant chemotherapy. The present results suggest that adjuvant chemotherapy is not sufficient, especially in patients with risk factors. Such patients should be evaluated as a target group for clinical trials of novel treatments. PMID- 25916086 TI - Practical prognostic index for survival in patients with unresectable pancreatic cancer treated with gemcitabine or S-1. AB - BACKGROUND/AIMS: We performed this retrospective cohort study to identify prognostic factors for unresectable pancreatic cancer treated with current standard therapy using gemcitabine (GEM) or S-1 and to stratify patients prior to treatment using a prognostic index (PI). METHODOLOGY: We analyzed 182 patients with unresectable pancreatic cancer, who had received GEM or S-1 as first-line chemotherapy. Factors that contributed to the prognosis were identified by univariate and multivariate analysis using a Cox proportional hazards model. The PI was constructed using the factors identified in the multivariate analysis. RESULTS: By multivariate analysis, performance status (PS), stage, and absolute neutrophil count (ANC) were identified as factors that independently contributed to the prognosis of unresectable pancreatic cancer (P < 0.05). The hazard ratios were 1.69, 3.33, and 1.18, respectively. In addition, PI was calculated using these three factors. Patients were classified into three groups according to the PI values. A significant difference was observed among the survival curves of these three groups (P < 0.05). CONCLUSIONS: We identified three prognostic factors in the population after the introduction of S-1, and have created a simple and useful PI. This index demonstrates the ability to accurately classify advanced pancreatic cancer patients before the start of treatment. PMID- 25916087 TI - Drain selection reduces pancreatic fistulae risk: a propensity-score matched study. AB - BACKGROUND/AIMS: Appropriate drainage management after pancreaticoduodenectomy (PD) is important to prevent and manage serious complications. This prospective study evaluated postoperative complications with either closed or open drainage placement after PD. METHODOLOGY: The incidence of postoperative complications in patients of PD, assigned to 2 groups of closed- and open-drain systems based on assessment periods, were investigated using propensity scores matching (PSM) after accounting for potential covariates. RESULTS: Baseline characteristics were comparable in both groups of patients [n = 100; open, 36; closed, 64). Pancreatic fistulae requiring clinical treatment, and wound infection, were found in 33.3% and 15.6%, and 22.2% and 0%, of patients in open- and closed-drainage groups, respectively. Drainage fluid culture showed exogenous infection (63.6% of bacteria) in the open-drain group which was absent in the closed-drainage group. PSM cohorts had 26 patients in either group. Following PSM, pancreatic fistulae requiring treatment were found in 12/26 (46.2%) and 3/26 (11.5%) of patients in the open- and closed-drain groups (RR, 0.25, 95% CI, 0.08-0.81), respectively. Intra-abdominal abscess (5/26 [19.2%]) and wound infection (7/26 [26.9%]) were found in the open-drain group only. CONCLUSION: These results indicate postoperative retrograde infections may be prevented, and the incidence of pancreatic fistula reduced, with a closed drainage system. PMID- 25916088 TI - Early effects of oral administration of esomeprazole and omeprazole on the intragastric pH. AB - BACKGROUND/AIMS: The aim of our study was to investigate the inhibitory effects on gastric acid secretion of a single oral dose of a proton pump inhibitor, esomeprazole 20 mg and omeprazole 20 mg. METHODOLOGY: A total of 14 Helicobacter pylori-negative male subjects participated in this study. Intragastric pH was monitored continuously for 6 hours after a single oral dose of omeprazole 20 mg and a single oral dose of esomeprazole 20 mg. Each administration was separated by a 7-day washout period. RESULTS: During the 6-hour study period, the average pH after administration of esomeprazole was higher than that after the administration of omeprazole. Also during the 6-hour study period, each of pH > 2, 3, 3.5, 4, and 5 was maintained for a longer duration after administration of esomeprazole 20 mg than after administration of omeprazole 20 mg (median: 75.4% vs. 53.8%, p = 0.0138; 52.1% vs. 33.4%, p = 0.0188; 45.8% vs. 28.2%, p = 0.0262; 42.5% vs. 20.7%, p = 0.0414; 35.8% vs. 11.6%, p = 0.0262; respectively). CONCLUSIONS: In Helicobacter pylori-negative healthy male subjects, single oral administration of esomeprazole 20 mg increased the intragastric pH more rapidly than single oral administration of omeprazole 20 mg. PMID- 25916089 TI - Effects of AGBL2 on cell proliferation and chemotherapy resistance of gastric cancer. AB - BACKGROUND/AIMS: The present study aimed to investigate the expression status of AGBL2 and its inhibitor latexin, and elucidate their clinical implications in gastric cancer. METHODOLOGY: AGBL2 expression status was examined in gastric cancer cells and 256 gastric cancer specimens by immunohistochemistry staining. The relationship between AGBL2 protein expression and clinicopathological parameters and prognosis was subsequently determined. RESULTS: AGBL2 expression was determined to be related to pathological tumor and nodal stages by Spearman's regression correlation analysis. The Cox regression test identified AGBL2 protein expression as an independent prognostic factor. AGBL2 and latexin were- found to be related to proliferation and chemotherapy resistance. The 2 proteins also formed immune com- plexes in immunoprecipitation experiments. CONCLUSIONS: Our results demonstrate that AGBL2 interacts with latexin, regulating the tubulin tyrosination cycle. It is therefore a potential target for intervention. PMID- 25916090 TI - Protein microarray analysis for detection of serum anti-Helicobacter pylori antibodies after eradication therapy: a clinical follow-up. AB - BACKGROUND/AIMS: We aimed to observe the changes in the anti-Helicobacter pylori (Hp) serum antibodies to Hp virulence factors after eradication therapy and evaluate the potential application value of protein microarray in detecting Hp antibodies after eradication therapy. METHODOLOGY: A total of 107 Hp-positive patients with peptic ulcers (55) and chronic gastritis (52) were recruited. Serum antibodies to Hp urease (Ure), cytotoxin-associated protein (CagA), vacuolating cytotoxin (VacA), heat shock protein 60 (Hsp60), and anti-RdxA nitroreductase were measured. Four weeks after treatment, a 13C-urea breath test (13C- UBT) was applied to assess the Hp eradication state and to analyze correlations between the Hp eradication rate and the five antibodies. Six months after the therapy, protein microarray analysis was used to study the changes in these five serum antibodies. RESULTS: The overall Hp eradication rate was 86.0%There was no significant difference in the rate among the groups that tested positive and negative for the remaining four virulence factors. CONCLUSION: The disease type and serum anti-CagA antibody levels affect the therapeutic outcome of Hp eradication therapy. Protein microarray detection of Hp-related antibodies did not have significant application value for the long-term follow-up of Hp infection after eradication therapy. PMID- 25916091 TI - Metastatic lymph node ratio and prognosis of gastric cancer at different pT stages. AB - BACKGROUND/AIMS: This study aimed to investigate the role of metastatic lymph node ratio (MLR) in the evaluation of prognosis of patients with gastric cancer at different T stages. METHODOLOGY: Clinical information was reviewed retrospectively in a total 535 patients who underwent surgery for gastric cancer. The prognostic value of MLR was compared with that of pN determined according to the UICC/AJCC guidelines (7th Edition), and the characteristics and advantages of MLR were analyzed. Moreover, the role of MLR in the evaluation of prognosis of patients with gastric cancer at different pT stages was investigated. RESULTS: Univariate Kaplan-Meier method was used for the analysis of survival, and the results showed that MLR was closely associated with the prognosis of these patients. Multivariate analysis with Cox proportional hazards regression model showed that MLR was a major independent risk factor in the prognosis of gastric cancer patients. The area under the ROC curve of MLR in predicting the death of gastric cancer patients within 5 years after surgery was not associated with pN stage. MLR was effective in predicting the prognosis of patients with stage pT2 or pT3 gastric cancer (P < 0.05). CONCLUSIONS: MLR is an independent risk factor in the prognosis of gastric cancer. MLR has a prognostic ability comparable to that of pN stage in gastric cancer. Thus, it is more reliable than pN in the evaluation of prognosis of gastric cancer patients, especially those with stage pT2-pT3 gastric cancer. PMID- 25916092 TI - Risk factors associated with multiple and missed gastric neoplastic lesions after endoscopic resection: prospective study at a single institution in south Korea. AB - BACKGROUND/AIMS: Only a small part of visible gas tric mucosal lesion can be removed by endoscopic resection. This study is aimed to identify incidence rate and associated risk factors of multiple and missed gastric lesions, and proper timing of follow-up en doscopy. METHODOLOGY: Endoscopic surveillance was performed on 1 week, and 1, 6, 12 months af ter endoscopic resection. All multiple gastric lesions were divided into main and accessory lesions. The accessory lesions were subdivided into detected and missed lesions. RESULTS: Totally, 250 lesions of 215 patients were analyzed. There were 81 early gastric cancers, 50 high grade dysplasias and 119 low grade dysplasias. Thirty patients (14%) had multiple gastric neoplastic lesions, either adenoma or cancer, within 1 year follow-up after endoscopic resection. Old age, male gender and severe intestinal metaplasia were independent risk factors of multiple gastric lesions. Small size (<= 1 cm) and flat morphology were major risk factors of missed lesion. Among 10 missed lesions, 9 (90%) could be detected within 6 month after resection. CONCLUSIONS: Old age, male gender, severe intestinal metaplasia were risk factors for multiple gastric lesions after endoscopic resection. Follow-up endoscopy is needed at least one time within six months after resection, with careful inspection of entire stomach. PMID- 25916093 TI - Single-incision laparoscopic distal gastrectomy for early gastric cancer through a homemade single port access device. AB - BACKGROUND/AIMS: We presented a series of single-incision laparoscopic distal gastrectomies for early gastric cancer patients through a type of homemade single port access device and some other conventional laparoscopic instruments. METHODOLOGY: A single-incision laparoscopic distal gastrectomy with D1 + alpha lymph node dissection was performed on a 46 years old male patient who had an early gastric cancer. RESULTS: This single port access device has facilitated the conventional laparoscopic instruments to accomplish the surgery and we made in only 6 minutes. Total operating time for this surgery was 240 minutes. During the operation, there were about 100 milliliters of blood loss, and 17 lymph-nodes were retrieved. CONCLUSION: This homemade single port access device shows its superiority in economy and convenience for complex single-incision surgeries. Single-incision laparoscopic distal gastrectomy for early gastric cancer can be conducted by experienced laparoscopic surgeons. Fully take advantage of both SILS and fast track surgery plan can bring to successful surgeries with minimal postoperative pain, quicker mobilization, early recovery of intestinal function, and better cosmesis effect for the patients. PMID- 25916094 TI - Regulatory mechanisms of transcription factors and target genes on gastric cancer by bioinformatics method. AB - BACKGROUND/AIMS: Gastric cancer is one of the most lethal diseases and has caused a global health problem. We aimed to elucidate the major mechanisms involved in the gastric cancer progression. METHODOLOGY: The expression profile GSE13911 was downloaded from GEO database, composing of 31 normal and 38 tumor samples. The transcription factor (TF)--target gene regulatory network and protein-protein interaction (PPI) network related to gastric cancer were obtained from TRED and TRANSFAC databases. After combining the two networks, we constructed an integrated network. RESULTS: In total, 5255 DEGs in tumor samples were identified, which were mainly enriched in 12 pathways including cell cycle. The integrated network of TF--target gene--protein interaction included 7 genes related to cell cycle, in which E2F1 was predicted to mediate the expression of MCM4, MCM5 and CDC6 through regulating the expression of its target gene MCM3. CONCLUSION: In gastric cancer progression, E2F1 may play vital roles in the involvement of cell cycle pathway through regulating its target gene MCM3, which might interact with MCM4, MCM5 and MCM7. Besides, STAT1 was another potentially critical transcription factor which could regulate multiple target genes. PMID- 25916095 TI - Risk, diagnosis and treatment to postoperative delirium in elderly patients with gastrointestinal cancers. AB - In recent years, more elderly patients with gastrointestinal cancers have been undergoing surgery. As one of main postoperative complications, postoperative delirium (POD) is harmful and difficult to prevent and treat. Prevention, diagnosis and treatment to POD properly and ptomptly can promote the patient's overall recovery. However, health care providers still have many problems for POD to face in elderly,with gastrointestinal cancers during the clinical care. In this paper, Etiology, damages, prevention, diagnosis and treatment of POD in elderly with gastrointestinal cancer were reviewed, and the prospect of POD was also discussed. PMID- 25916096 TI - Comparison between early enteral feeding with a transnasal tube and parenteral nutrition after total gastrectomy for gastric cancer. AB - BACKGROUND/AIMS: This retrospective study evaluated 21 patients with early enteral feeding (EEF group) and 22 patients without early enteral feeding (non EEF group) who underwent open total gastrectomy followed by Roux en Y reconstruction and were RO resectable cases. METHDOLOGY: Postoperative complications and course, postoperative/preoperative body weight, whole meal intake, and nutritional, inflammatory, and immunological parameters were recorded and evaluated in both groups. RESULTS: Postoperative meal intake was significantly higher and the first day of defecation was significantly earlier in the EEF group than in the non-EEF group. There were no significant differences between the 2 groups in the blood laboratory data and the rate of complications. In patients with complications, lymphocyte counts and postoperative body weights were compared as indicators of immunostimulation. The lymphocyte counts 7 days after operation and postoperative/preoperative body weight were significantly higher in the EEF group than in the non-EEF group. CONCLUSIONS: Although immunostimulation-like findings were observed in the patients with complications after surgery in the present study, the significance of EEF was not clarified because of the lack of cases whose conditions were severe. EEF should be used especially for patients in whom severe disease is possible and avoidance of TPN is desirable. PMID- 25916097 TI - Junctional adhesion molecule-A promotes proliferation and inhibits apoptosis of gastric cancer. AB - BACKGROUND/AIMS: Junctional adhesion molecules (JAMs) are known as integral constituents of cellular tight junctions. However, the functions of JAMs in cancer tissues are controversial and the function of JAM-A in gastric cancer is unclear. Acordingly, we investigated the function of JAM-A in gastric epithelial and gastric cancer cell proliferation, invasion and apoptosis. METHODOLOGY: A normal rat gastric mucosa-derived cell line (RGM1), a rat gastric cancer-like cell line established from RGM1 (RGK1), and a human gastric cancer cell line (NCI N87) were used in this study. To examine the expression of junctional proteins, immunoblotting and immunofluorescent staining were performed with specific antibodies (JAM-A, claudins, occludin and ZO-1). JAM-A was knocked down by small interfering RNA. RESULTS: RGM1 and RGK1 expressed JAM-A, occludin and ZO-1 but not claudins. RGK1 were significantly more invasive than RGM1. JAM-A knock-down significantly decreased the proliferation and the invasion of RGK1 but not of RGM1. JAM-A knock-down significantly decreased the proliferation of NCI-N87 cells and significantly decreased expression of the anti-apoptotic protein Bcl-xL but not the expression of AKT or Mcl-1. CONCLUSIONS: JAM-A promotes proliferation and inhibits apoptosis of gastric cancer, suggesting that it has a pivotal role in gastric cancer progression. PMID- 25916098 TI - Regulation of neutrophil infiltration into peritoneal cavity by laparoscopic gastrectomy. AB - BACKGROUND/AIMS: Laparoscopic surgery is a minimally invasive operation developed for treating gastrointestinal malignancies. We aimed to characterize the differences in the intra-abdominal environment following open and laparoscopic surgeries. METHODOLOGY: We investigated data of 48 patients who underwent gastrectomy between 2010 and 2012. We analyzed the mRNA expression of chemokines, indoleamine 2, 3-dioxygenase (IDO), and so on in peritoneal lavage fluid with real-time RT-PCR. We also determined the leukocyte population and calculated the granulocyte/lymphocyte (G/L) ratio in peritoneal lavage fluid using flow cytometry. RESULTS: CCL3 mRNA was significantly upregulated, whereas IDO mRNA was significantly downregulated, in the open group compared to the laparoscopic surgery group. Flow cytometry revealed that the G/L ratio was significantly higher in the open group. CONCLUSIONS: We suggest that the production of chemokines and neutrophil infiltration into the abdominal cavity may be suppressed in the laparoscopic surgery. Thus, laparoscopic surgery may be beneficial in preserving local immunity. PMID- 25916099 TI - A new option for intracorporeal circular-stapled esophagojejunostomy in laparoscopic total gastrectomy: Roux-en-Y reconstruction with its efferent loop located at the left side of the patient to prevent twisting of the esophagojejunostomy. AB - BACKGROUND/AIMS: Laparoscopic total gastrectomy (LTG) has not gained widespread acceptance because of the difficult reconstruction technique, especially for esophagojejunostomy. Although various modified procedures using a circular stapler for esophagojejunostomy have been reported, an optimal technique has not yet been established. In addition, in intracorporeal techniques, twisting of the esophagojejunostomy, which might be the cause of stenosis, is often encountered because application of the shaft is restricted. To prevent twisting of the esophagoejunostomy, we underwent LTG with Roux-en-Y reconstruction with its efferent loop located at the left side of the patient. METHODOLOGY: From November 2013 to November 2014, a series of 9 patients underwent LTG with Roux-en-Y reconstruction using the transorally inserted anvil (OrVilTM, Covidien, Mansfield, MA, USA), whose efferent loop was located at the left side of the patient. RESULTS: No twisting of the esophagojejunostomy was encountered in all cases. In addition, no stenosis or leakage of the esophagojejunostomy occurred. CONCLUSIONS: This reconstruction system may be a feasible surgical procedure in LTG. PMID- 25916100 TI - Thomas Say's weevils, with special reference to his Curculionites pamphlet and the extant type material. PMID- 25916101 TI - The tribulations and trials of fetal surgery for spina bifida. PMID- 25916102 TI - The accelerating universe: a Nobel surprise. PMID- 25916103 TI - Sir Christopher Charles Booth 22 June 1924 13 July 2012. PMID- 25916104 TI - Robert Joy Glaser 11 September 1918 - 7 June 2012. PMID- 25916105 TI - Nicholas deB. Katzenbach 17 January 1922 - 8 May 2012. PMID- 25916106 TI - Wolfgang Kurt Hermann Panofsky 24 April 1919 - 24 September 2007. PMID- 25916107 TI - [Research progress on site-oriented and three-dimensional immobilization of proteins]. AB - In today's post-genome era, the goals of research are geared toward understanding the meaning of information in sequenced DNA, namely, understanding the functional characteristics of proteins encoded by genomes of living beings. Protein array technologies, particularly miniaturized high-throughput platforms such as micro- or nano-fluidic chips that allow the parallel detection of thousands of proteins simultaneously, are playing increasing important roles as discovery tools in proteomics. These technologies are based on principles of molecular recognition and consist of a support surface, such as a glass slide, bead, or microtiter plate, to which an array of captured proteins is bound. However, immobilized proteins often lose their immunoactivity and suffer from low surface density, which results in inefficient signal response. In this review, we mainly provide an introduction about the research progress on site-oriented adsorption of protein at solid-liquid interfaces, especially the three-dimensional immobilization of protein, whose objective is to retain immobilized proteins in an active state at great density. PMID- 25916108 TI - [Compartmentalization of the cell nucleus and spatial organization of the genome]. AB - The eukaryotic cell nucleus is one of the most complex cell organelles. Despite the absence of membranes, the nuclear space is divided into numerous compartments where different processes in- volved in the genome activity take place. The most important nuclear compartments include nucleoli, nuclear speckles, PML bodies, Cajal bodies, histone locus bodies, Polycomb bodies, insulator bodies, transcription and replication factories. The structural basis for the nuclear compartmentalization is provided by genomic DNA that occupies most of the nuclear volume. Nuclear compartments, in turn, guide the chromosome folding by providing a platform for the spatial interaction of individual genomic loci. In this review, we discuss fundamental principles of higher order genome organization with a focus on chromosome territories and chromosome domains, as well as consider the structure and function of the key nuclear compartments. We show that the func- tional compartmentalization of the cell nucleus and genome spatial organization are tightly interconnected, and that this form of organization is highly dynamic and is based on stochastic processes. PMID- 25916109 TI - [MiR-128, a key regulator of oncogenic properties]. AB - MicroRNAs (miRNA) are small noncoding RNAs that are critical regulators of gene function. In the recent years, miRNAs have been increasingly noted for their capacity to regulate key malignant properties of tumor cells. MicroRNA-128 (miR 128) is a brain-enriched miRNA that is normally involved in the development of the nervous system and in the maintenance of neural physiological functions. In tumorcells, miR-128 expression is dysregulated through a variety of genetic and epigenetic events. Dysregulation: of miR-128 has profound effects on tumorigenesis and maintenance of tumor cells through alterations in cellular proliferation, differentiation, metabolism, and apoptosis. This article will review the latest advances in our understanding of miR-128, specifically in the context of clinical and fundamental cancer biology. Further characterization of miR-128 will likely identify its new roles in cancer biology. The use of miR-128 as a diagnostic and/or therapeutic tool may result in improvements in diagnosis, prognosis, and treatment of numerous cancers. PMID- 25916110 TI - [Circulating microRNAs in lung cancer: prospects for diagnostics, prognosis and prediction of antitumor treatment efficiency]. AB - The major methods of microRNA extraction from different biological fluids (particularly, serum and plasma), approaches to the analysis of microRNA concentration and composition, normalization methods used in data analysis are outlined in the review. The advantages and disadvantages of the described methodological approaches are being highlighted. Special attention is given to microRNAs, circulating in blood, which could be used as the markers for minimally invasive lung cancer diagnostics, prediction of antitumor treatment efficiency and disease prognosis. Prospects and limitations arising from the evaluation of clinical significance of microRNAs as the potential tumor markers, and emerging as roles of various microRNAs in the pathogenesis of lung cancer become known, are discussed. PMID- 25916111 TI - [The role of Ku antigen in the repair of apurinic/apyrimidinic sites in DNA]. AB - Apurinic/apyrimidinic (AP) sites are some of the most frequent lesions in genomic DNA. It is widely accepted that, irrespective of their origin, AP sites are further processed by the base excision repair (BER) machinery, being the central intermediate of this process. Under special conditions, proteins, which recognize AP sites, are able to form covalent adducts with DNA. By combination of the cross linking technique with mass-spectrometry analysis, Ku antigen (Ku)--the central player in nonhomologous end joining (NHEJ), the pathway of double-strand break (DSB) repair--was identified as a protein reactive to AP sites. Moreover, Ku was shown to be a 5'-dRP/AP lyase that acts near DSBs in NHEJ. The recent studies have demonstrated involvement of Ku in the different stages of BER. Here, Ku roles in NHEJ and BER pathways of DNA repair are overviewed. PMID- 25916112 TI - [DAX1-unusual member of nuclear receptors superfamily with diverse functions]. AB - Nuclear receptors (NRs) are ligand-activated transcription factors that play an important role in metabolism, homeostasis, differentiation and development regulation. NRs are also involved in pathogenesis of various diseases. For most of NRs natural ligands are known. Ligand-activated NRs bind specific nucleotide sequences in target genes and induce their expression. DAX1 protein is an unusual member of NR superfamily that does not have ligand and lacks typical DNA-binding domain. It was established 20 years ago that DAX1 plays a critical role in regulation of adrenal and gonadal development and in biosynthesis of steroid hormones, however the molecular mechanisms of its action remained not fully understood. Further studies have shown that this piotein can interact with many members of NR superfamily and with different co-repressors and co-activators of transcription. Its functions are not restricted to regulation of adrenal and gonadal development and steroidogenesis. Recent studies have elucidated the role of DAX1 in pathogenesis of X-linked adrenal congenital hypoplasia and dose sensitive sex reversal. It was found also that DAX1 is an important component of transcription factors network that maintains the pluripotency of mouse embryonic stem Cells. Here we review the current knowledge on properties, functions and mechanisms of DAX1 action. The role of DAX1 in pathogenesis of inherited diseases is discussed. The specificity of DAX1 interaction with various protein.partners is characterized. The examples of co-repressor and coactivator action of DAX1 on transcription are presented. The potential association of DAX1 with oncoendocrine pathologies and its role in self-renewal of mouse embryonic stem cells are described. PMID- 25916113 TI - [Role of syndecan-2 in amyloid plaque formation]. AB - The famous phrase of F. Engels "Life is the mode of existence of protein bodies", has deeply insinuated itself in our mind. However at a more profound insight, the form of protein bodies is associaited not only with the fact of their existence, but also with the time changes. What unites all of us in our oldage? The answer is clear: it is the change in the way of existence of protein molecules, and more precisely, their uncontrolled aggregation that can take place in any organ and be associated with any protein. In spite of different clinical presentations, all diseases associated with pathological accumulation of aggregated proteins are combined in a general group called amyloisosis. Depen- dent on the place of formation, it is possible to distinguish an infinite number of pathologies from neurodegen- erative and oncologic ones to arthritis and tuberculosis. There is no doubt that provided all clandestine mechanisms are clarified at which an absolutely normal functioning.protein can transform into a pathological aggregated form, it will give us a chance to prevent protein aggregation and create a new form of drugs for prolongation of life. In this review we considered the function of syndecan-2, the structure of syndecan-2 and its role in the formation of amyloid plaques. PMID- 25916114 TI - [Molecular mechanisms of regulaion of transcription by PARP1]. AB - Poly-ADP-ribosylation is a covalent post-translational modification of nuclear proteins that plays a key role in the immediate response of cells to genotoxic stress. Poly(ADP-ribose) polymerase (PARP) synthesizes long and branched polymers of ADP-ribose onto acceptor regulator proteins, and thereby change their activity. Metabolism of poly-ADP regulates DNA repair, cell cycle, replication, aging and death of cells, as well as remodeling of chromatin structure and gene transcription. PARP1 is one of the most common nuclear proteins; it is responsible for production of -90% of the polymers of ADP-ribose in the cell. PARP1 inhibitors are promising antitumor agents. At the same time, the current inhibitors target the catalytic domain of PARP1 that leads to.a number of side effects. Therefore, considering the potential benefits of PARP1 inhibitors for the treatment of multiple diseases, it is necessary to develop new strategies of PARP1 inhibition. PARP1 has a modular structure and has catalytic, transcription and DNA-binding activities. The review focuses primarily on the role of PARP1 in transcriptional regulation; the structure and functional organization of PARP1, as well as multiple ways of regulation of chromatin remodeling, DNA methylation and transcription are covered in detail. Studies of the molecular mechanisms of regulation of transcription factor PARP1 can serve as a basis for search and design of new inhibitors. PMID- 25916115 TI - [Polymorphic variant of MnSOD A16V and risk of diabetic retinopathy]. AB - Dabetic retinopatny Is the most common microvascular complication of diabetes and a leading cause of blindness in industrialized countries. Oxidative stress plays an important role in the development of microangiopathic complications in diabetes. Manganese superoxide dismutase (MnSOD) is a key mitochondrial antioxidant enzyme in the cellular defense against agents that induce oxidative stress. The aim of the present study was to assess whether the MnSODA16V (C47T) polymorphism is associated with Diabetic retinopathy in northern Iran. 140 patients with Diabetic retinopathy and 140 healthy individuals, aged 30 to 75 years old, participated in this study. For genotyping of the MnSOD A16V polymorphism, polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) method was used. The prevalence of genotype frequencies of AA, AV, VW in Diabetic retinopathy subject were 5.71, 71.43 and 22.86%, respectively while in controls were 21.43, 38.57 and 40%, respectively. Significantly increased frequency of AV genotype was observed in patients compared with controls (OR = 6.94, 95% CI = 2.98-16.20, P< 0.0001). In conclusion, it is suggested that the MnSOD A16V polymorphism may be associated with the risk of Diabetic retinopathy in northern Iran. However, larger population-based studies are needed for clarifying the relation between Diabetic retinopathy and MnSOD A16V polymorphism. PMID- 25916116 TI - [Association of the polymorphisms of the FTO, KCNJ11, SLC30A8 and CDKN2B genes with type 2 diabetes]. AB - To study the association with diabetes mellitus type 2 we performed anal- ysis of the distribution of frequencies of alleles and genotypes of polymorphic markers of FTO, KCNJ11, SIC30A8 and CDKN2B genes. The study included groups of T2DM patients and unrelated controls of Russian origin. Analysis of the distribution of frequencies of alleles and genotypes of the polymorphic markers of KCNJ11, SLC30A8 and CDKN2B genes showed the presence of association with T2DM in Russian population, while for the FTO gene was not found statistically significant associations with type 2 diabetes. We can conclude that in Russian population main role in the development of type 2 diabetes play genes, affecting the level of syn- thesis and secretion of the insulin in beta-cells of the pancreas. PMID- 25916117 TI - [Under hypoxia condition contactin-1 regulates migration of MKN45 cells through RhoA pathway]. AB - Recent studies have suggested that contactin-1 has a key role in cancer cell proliferation and migration, however the detailed mechanism of this process is still unclear. Here, human gastric cancer cell line MKN45 was employed. It was found that under hypoxia conditions contactin-1 mRNA and protein levels were both up-regulated by HIF-1alpha expression. Furthermore, although hypoxia increased the migration rate of MKN45 cells, contactin-1 (CNTN1) shRNA reversed this process. Meanwhile, RhoA V14 and RhoA V14N19 mutation constructs were employed, and it was found that constitutively active form of RhoA reversed the cell migration suppression induced by contactin-1 knockdown, while dominant-negative form of RhoA blocked hypoxia induced hypermigration. Apart from this, contactin-1 displayed the ability to phosphorylate the RhoA activator p115 RhoGEF. Thus, under hypoxia conditions, elevated HIF-1alpha seems to up-regulate contactin-1 expression and by this activate RhoA and facilitate migration of cancer cells. PMID- 25916118 TI - [Molecular cloning and expression patterns of two tumor necrosis factor al pha genes in Crucian carp (Carassius carassius)]. AB - Tumor necrosis factor (TNF) is a potent inflammatory cytokine produced during inflammation. In this study, two Crucian carp TNF-alpha genes, TNFalpha-1 and TNFalpha-2 were cloned and sequenced. The TNFalpha-1 was 720 bp and-consisted of a 699 bp opening reading frame encoding 232 amino acids and TNFalpha-2 was 793 bp and contained an open reading frame of 687 bp which encoded 228 amino acids. The genomic structure of both genes consists of4 exons and 3 introns similar to other known TNF-alpha genes. The amino acid sequence ofcrucian carp TNFalpha-1 and TNFalpha-2 shared the highest identity with common carp, goldfish and the lowest with flounder and human. The phylogenetic analysis grouped crucian carp TNFalpha 1 and TNFalpha-2 with other cypriniformes, which are more closely related to the goldfish and common carp TNFEa-1 and TNFalpha-2. Real time PCR analysis showed a con- stitutive expression of crucian carp TNFalpha-1 and TNFalpha-2 in all seven tissues examined. The TNFalpha-1 mRNA was ex- pressed significantly higher in the liver and kidney than those of TNFalpha-2 while TNFalpha-2 was expressed significantly higher in the muscle than that of TNFalpha-1. Aeromonas hydrophila BSK-10 strain upregulated the expression level of TNFalpha-1 and TNFalpha-2 in all tissues tested. At 6 h, the expression level of TNFalpha-1 increased significantly higher in muscle, skin and liver, while the expression level of TNFalpha-2 increased significantly higher in muscle and gill. TNFalpha-1 expressed much stronger than TNFalpha-2. At 12 h the expression level started declining and was more reduced at 24 h. These results imply that both TNFalpha-1 and TNFalpha-2 mRNA are distributed differently in tissues and are implicated in the immune response to bacterial infection. PMID- 25916119 TI - [Dose-dependent effects of dexamethasone on functional activity of T-lymphocytes different grade of differentiation]. AB - Glucocorticoids are anti-inflammatory and immunosuppressive agents which have pleiotropic effects on growth, differentiation and functional activity of T lymphocytes. Under experimental conditions in vitro carried out a comprehensive assessment of the dexamethasone influence on the functional activity of T-cells with different differentiation degrees. It was established that the influence of dexamethasone on the functional activity of CD45RA+ and CD45RO+ T-lymphocytes, in general, has depressing character. It was revealed that in the population of naive (CD45RA+) T-cells dexamethasone exerts a more pronounced inhibitory effect on early (IL-2-dependent, associated with the CD25 expression and IL-2 production) activation stages, whereas in the culture primed memory cells (CD45RO+)--for later (IL-2-independent, associated with the expression of proliferation molecule CD71). Multidirectional effects of dexamethasone on the expression level of telomerase catalytic unit (hTERT) mRNA are associated with the degree of T cells differentiation. It isproposed, that the role of glucocorticoid hormones in immunogenesis is primarily aimed at suppression of excessive T cells growth and on the maintainance of the clonal balance in lymphoid tissue. PMID- 25916120 TI - [Ouabain induces Rho-dependent rock activation and membrane blebbing incultured endothelial cells]. AB - Small G protein Rho and its most studied effectors, ROCK I and ROCK II, are involved in several cellular fuctions including smooth muscle and non-muscle cell contractions, cell migration and apoptosis. Activation of ROCK I by caspase-3 and activation of ROCK II by granzyme B are essential for membrane blebbing in the execution phase of apoptosis. In contrast, it has been demonstrated that Rho signaling is critical for blebbing developed after serum removal. As it was shown by us previously, ouabain induces membrane blebbing and proteolitic cleavage of ROCK I and ROCK II via caspases in human umbilical endothelial cells. However, caspase inhibitors do not prevent ouabain-induced blebs. Ouabain induces concentration-dependent cell death and membrane blebbing in endothelial cells. The aim of this study was to identify the possible role of Rho in ouabain-induced membrane blebbing. Pretreatment of endothelial cells with a Rho inhibitor CT04 did not inhibit the ouabain-induced cell death but prevented the development ofbleb formation. These results indicate that bleb formation is dependent on Rho activity in ouabain-induced cell death in HUVECs. Taken together, these results suggest that the mechanism of membrane bleb formation might be different depending on cell type and cell death-stimuli. PMID- 25916121 TI - [Methylation status of line-1 retrotransposon in chromosomal mosaicism during the early stages of human embryonic development]. AB - Early stages of human embryonic development are characterized by spatio-temporal coincidence of events of total epigenetic genome reprogramming and elevated level of mosaic forms of numerical chromosome abnormalities. It is possible that the abnormal reprogramming of various regions of the genome can lead to violations of local epigenetic chromatin organization and gene expression, affecting the correct chromosome segregation during mitosis. In this study, a comparative analysis of the methylation index of LINE-1 retrotransposon, which is largely reflecting the methylation profile of the genome, is performed in placental tissues of spontaneous abortions with complete and mosaic forms of aneuploidy, and with a normal karyotype, as well as in the control group of induced abortions of the first trimester of pregnancy. It was shown that extraembryonic mesoderm and chorionic cytotrophoblast of spontaneous abortions with chromosomal mosaicism are characterized by the highest index of LINE-1 methylation among all groups studied. At the same time excessive hypomethylation of transposable genetic element recorded in spontaneous abortions with normal karyotype. It is suggested that violations of parental genomes demethylation during epigenetic reprogramming at preimplantation stages of development may be associated with an increased frequency of mitotic errors in chromosome segregation, leading to the formation of a mosaic karyotype. PMID- 25916122 TI - [The ability of cells to adjust to the low oxigen content associated with Na,K ATPase glutationilation]. AB - Decreasing the amount of oxygen in the tissues under hypoxic and ischemic conditions, observed at a number of pathologic processes, inevitably leads to their damage. One of the main causes of cell damage and death is a violation of the systems maintaining ionic balance. Na,K-ATPaseis a basic ion-transporting protein of animal cell plasma membrane and inhibition of the Na,K-ATPase activity at lower concentrations of oxygen is one of the earliest and most critical events for cell viability. Currently there is an active search for modulators of Na,K ATPase activity. For this purpose traditionally used cardiac glycosides but the existence of serious adverse effects forced to look for alternative inhibitors of Na,K-ATPase. Previously we have found that the glutathionylation of Na,K-ATPase catalytic subunit leads to a complete-inhibition of the enzyme. In this paper it is shown that the agents which increase the level of Na,K-ATPase glutathionylation: ethyl glutathione (et-GSH), oxidized glutathione (GSSG) and N acetyl cysteine (NAC), increase cell survival under oxygen deficiency conditions, prevent decline of ATP in the cells and normalize their redox status. Concentration range in which these substances have a maximum protective effect, and does not exhibit cytotoxic properties was defined: for et-GSH 0.2-0.5 mM, for GSSG 0.2-1 mM, for NAC 10 to 15 mM. The results show prospects for development of methods for tissues protection from damage caused by oxygen starvation by varying the degree of Na,K-ATPase glutathionylation. PMID- 25916123 TI - [PIWI protein as a nucleolus visitor in Drosophila melanogaster]. AB - The evolutionarily conserved nuclear Piwi protein of Drosophila melanogaster is a representative of the Argonaute small RNA binding protein family. Guided by small piRNAs, Piwi functions in transposon silencing in somatic and germ cells of the gonad. We found that in ovarian somatic and germ cells, as well as in the established ovarian somatic cell line, Piwi is concentrated predominantly in the nucleolus--the main nuclear compartment, participating not only in rRNA synthesis, but also in various cell stress responses. We demonstrated the colocalization of Piwi with nucleolar marker proteins--fibrillarin and Nopp140. A mutation preventing Piwi transport to the nucleus and disturbing transposon silencing (piwi(Nt)) leads to 6-8-fold upregulation of rRNA genes expression, as evaluated by the level of transcripts of transposon insertions in 28S rRNA genes. RNase treatment of live cultured ovarian somatic cells depletes Piwi from the nucleolus. The same effect is observed upon inhibiting RNA polymerase I which transcribes rRNA, but not RNA polymerase II. In contrast, upon heat shock Piwi is concentrated in the nucleolus and is depleted from the nucleoplasm. These results implicate Piwi in RNA polymerase activity modulation and stress response in the nucleolus. We discuss possible noncanonical Piwi functions along with its canonical role in transposon silencing by piRNAs. PMID- 25916124 TI - [The association between DAZ T > C polymorphism and idiopathic male infertility risk in north of Iran]. PMID- 25916125 TI - [Pancreatitis, pancreatic cancer and obesity: hypothesis and facts]. AB - THE PURPOSE OF THE REVIEW: Analyze the basic data on the role of obesity in the pathogenesis of pancreatic cancer (PC) and the modern mechanisms of this association. RECENT LITERATURE DATA: In the European Union and in Russia incidence of pancreatic diseases increases, such pancreatic cancer (PC) ranks 10th among cancer diseases. Obesity is a risk factor for not only of severe acute pancreatitis, but also PC at that independently of diabetes. In a meta-analysis the PC risk in obese increased by 47%, while the person with a central obesity have a higher PC risk compared to those with a peripheral type of obesity (odds ratio = 1,45, 95% CI: 1,02-2,07), but association between BMI and PC risk in this Japanese population may be different from that in Western populations, sometimes inversely. The link between obesity and PC is explained by insulin resistance and hyperinsulinemia: was proved a direct correlation between the level of circulating C-peptide and PC, low levels of serum adiponektin and leptin increase the PC risk. There are also genetic risk factors for PC: a statistically significant interaction between IVS1-27777C> and IVS1-23525A>T genotypes of the FTO gene with obesity and the PC risk: AA genotype in patients with BMI < 25 kg/m2 reduced PC risk by 22%-28% (p < 0,0001), and with BMI >= 25 kg/m2 was associated with 54%-60% increased PC risk (p < 0,0015). Lifestyle factors (smoking, consumption of saturated fats, etc.) increase the PC risk. PMID- 25916126 TI - [Medico-social characteristics of patients with chronic pancreatitis]. AB - AIM OF STUDY: Comparative analysis of the health status of patients with chronic toxic-metabolic pancreatitis (CTMP) and chronic obstructive pancreatitis (COP). The gender and social factors was analysed. THE MATERIALS AND METHODS: 250 patients with chronic pancreatitis examined. On based of the TIGAR-O classification, two groups of patients choosed: the 1-st group included 142 (56.8%) a patient with CTMP, the 2-nd group--108 (43.2%) patients COP. The social characteristics of patients had produced, including assessment of status social (gender, age, educational level, employment, marital status, bad habits). Quality of life was assessed by using the updated questionnaire SF-36. RESULTS: The average age of patients with CP is 53.2 years, male to female ratio is 3:2. At stake is 56.8% of all CTMP patients with CP, the median age is 42.3 years, the male to female ratio is 4:1. The average age of patients with COP is 54.6 years, male to female ratio is 1:4. Do not work, not married, engaged in an anti-social way of life 43% of people working age with CTMP, have a lower education in comparison with patients with COP. CONCLUSION: Patients with CTMP reduced social significance illustrate reduced social significance as personal (reduction in the level of education, an anti-social way of life), and social (lack of employment, deterioration of demographic indicators). PMID- 25916127 TI - [The association study of the promoter polymorphism -308G>A of tumor necrosis factor gene with the development and severity of acute pancreatitis in Russian population of Kursk region]. AB - The aim of this study was to investigate the relationship between the polymorphism -308G>A of tumor necrosis factor (TNF) gene and the risk and severity of acute pancreatitis (AP) in unrelated Russians from Kursk region. DNA samples were obtained from 190 AP patients and 217 healthy controls for genotyping the polymorphism through a TaqMan allelic discrimination assay. Although -308G>A genotypes did not show a significant association with disease risk, the genotype -308GA was found to be associated only with non-severe type of acute alcohol-related pancreatitis (odds ratio 1.81 (95% CI 1.02-3.23 p=0.04). PMID- 25916128 TI - [Alterations of lymphocyte subsets and indicators of immune suppression in patients with acute pancreatitis]. AB - THE AIM OF STUDY: Assessment of changes in lymphocyte number and some indicators of the immune suppression (frequency of regulatory T cells (Treg), the level of expression of CTLA-4 (cytolytic T lymphocyte-associated antigen 4) and interleukin (IL)-10) in patients with acute pancreatitis (AP). MATERIALS AND METHODS: Peripheral blood samples of 21 patients with AP (including 11 patients with pancreatic necrosis (PN)) were studied for analysis of lymphocyte subsets and 11 blood samples of healthy donors were estimated as control. Evaluation of the expression of molecules of lymphocytes was carried out by flow cytometry. RESULTS: It was found that percentage of CD3+ T cells and their subpopulation of CD4+ T-helper cells in patients with AP were decreased as compared to the control group. Substantial changes were observed in patients with PN: together with decrease in the number of T cells, CD19+ B cells and CD4+ CD25+ activated T helper cells were also reduced, and the percentage of CD8+ T cells was higher. The immunoregulatory index (CD4+/CD8+) was lower in the group of patients, than in control group. The frequency of Treg cells (CD4+ CD25hi and CD4+ CD25+ CD127lo) was higher in patients with AP than in the control. The expression level of the inhibitory molecule CTLA-4 in the subset of CD4+ CD25hi Treg cells in patients with AP was also increased. Moreover, it was found that the expression level of anti-inflammatory cytokine IL-10 was higher in T-helper cells from patients with AP. CONCLUSION: Changes in cellular immunity (especially patients with PN) werefound in patients wish AP. These changes may indicate the possible development of secondary immunodeficiency. This is probably related to the generation of immune suppression, since the values of the investigated parameters (frequency of Treg cells, the expression of CTLA-4 and IL-10) in patients with AP were higher than in controls. PMID- 25916129 TI - [Prevalence of symptoms and risk factors of the gastro esophageal reflux disease at school students of the Republic of Tyva]. AB - For the purpose of the analysis of risk factors of formation of a gastroesophageal reflux disease (GERD) in children's population of the Republic of Tyva examination of school students of Kyzyl is conducted. 2185 pupils (1746 schoolchildren of radical and 439 schoolchildren of the alien population) took part in research. Inspection included an interview by means of the questionnaire developed on the basis of a questionnaire of Mayo Clinic; clinical examination, somatometry and somatometry typing. 203 schoolchildren with complaints to heartburn the fibroesophagogastroduodenoscopy is carried out. Complaints to heartburn showed 11,8% of schoolchildren of radical and 16,6% of pupils of the alien population (p = 0,01). Weekly heartburn was noted by 1,4% of Tuvinians and 2,3% of pupils of the alien population. School students with complaints to heartburn in most cases have no endoscopic signs of damage of a gullet: esophagitis is revealed only at 1% surveyed. The risk of emergence of GERD is higher at the high school age, at the burdened heredity, early artificial feeding, existence of food allergy; the insufficient use of products with the high maintenance of a protein. Risk factors are also disharmonious physical development (high growth and excess body weight), the brahimorphious type of a constitution and accessory to macrosomatotype. PMID- 25916130 TI - [Mucosal immune response to Helicobacter pylori in children with gastroduodenal diseases and allergy]. AB - In children with chronic gastritis/gastroduodenitis, erosions and ulcer of stomach and duodenum and associated allergic diseases (asthma, allergic rhinitis, atopic dermatitis) CagA, sIgA and IgE antibodies to the H. pylori were determined by ELISA in the supernatants of feces. H. pylori infection was determined according to "Maastricht IV". The frequency and contents of CagA did not differ among the groups we studied. However, in children with positive urease test the contents of CagA was significantly higher (p = 0.03) compared with other children. The highest levels of sIgA were found in the feces supernatants from non-allergic children with CG/CGD and were associated with H. pylori infection. The immune response in children with erosions and ulcer of stomach and duodenum and in children with allergy was presented the sIgE to H. pylori. Also, the negative correlation between the level sIgE to H. pylori and content sIgA was found in children with allergy. Thus, increased IgE indicates not only allergy, but also acts as a protective role in the development of anti-infective immunity. PMID- 25916131 TI - [The effect of low-level laser therapy on gastric mucosa microcirculation in patients with gastroesophageal reflux disease]. AB - OBJECTIVE: To study the influence of laser radiation on the parameters of microcirculation in patients with gastroesophageal reflux disease (GERD). MATERIALS AND METHODS: The examined 112 patients with GERD aged 19 to 79 years. 78 patients were given a ten-day course of intravenous laser therapy, which was conducted with the help of the apparatus of laser therapy "matrix-vlok" (produced by "the matrix", Russia) with wavelength 0,405 microns, the radiation power at the output of the main fiber 1-1,5 mW, continuous mode radiation. The studied parameters were determined before and after treatment. RESULTS: The obtained data testify to the improvement of microcirculation in patients with GERD under the influence of laser therapy. PMID- 25916132 TI - [Dynamics of autonomic regulation and daily pH-metry in patients with gastroesophageal reflux disease under the influence of low-intensity laser irradiation of blood]. AB - 102 patients with GERD were examined: 70 female (68%) and 32 men (32%). Age of respondents ranged from 20 to 65 years (average of 45.8 +/-8,2). All patients were randomly divided into 2 groups. In the first (control) group (30 people) traditional drug treatment were used according to the standard therapy of GERD (proton pump inhibitors, antacids, prokinetics), patients in the second (main) group (70 people) along with drug therapy has received a course of intravenous laser therapy according to the methods ILIB-405. For intravenous laser treatment Russian apparatus "Matrix-ILIB" ("Matrix", Russia) was used with wavelength 0,405 MUm, output power at the end of the main optical path of 1-1.5 mW. Laser blood irradiation was carried out for 15 minutes in the CW mode, the course of treatment was 10 daily treatments with a break on Saturday and Sunday. Conclusions: 1. Intravenous laser irradiation of blood in the complex therapy of patients with gastroesophageal reflux disease improved significantly of HRV due to the alignment of parasympathetic regulation circuit and reducing the activity of sympathetic autonomic regulation, 2. the inclusion of intravenous laser irradiation of blood in the complex therapy of patients with GERD was accompanied by reliable normalization of the indicators of the daily pH-metry of the esophagus in patients with GERD. PMID- 25916133 TI - [Interrelation between trophological status and the course of stomach and duodenal ulcer diseases]. AB - There was installed a significant positive relationship between body mass index (BMI) and the velocity of cicatrization of ulcer in patients with ulcer disease (PUD) with trophological violations. Change in the index ratio of lymphocytes and ESR in patients with PUD trophological violations can be used to predict the velocity of cicatrization of ulcer. The general maladjustment more often observed in patients (PUD) underweight. PMID- 25916134 TI - [The role of psycho-autonomic status and the serotonergic system in patients with gastroesophageal reflux disease]. AB - OBJECTIVE: Identify the differences of the autonomic nervous system (ANS), serotonin levels, cognitive, behavioral and emotsinalnoy areas in groups of patients with reflux esophagitis (RE) and non-erosive reflux disease (NERD) and assess the impact on the disease. MATERIALS AND METHODS: The study included 71 patients rith gastroesophageal reflux disease (GERD), including 29 patients with ER, 42--NERD. Diagnosis was based on anamnesis, clinical research, fibrogastrocopy, pH-metry. Tested with a scale situational and personal anxiety Spielberg Hanina, diagnostic techniques and forms of aggression indicators A. Bass and A. Dark, the Toronto aleksitimicheskoy scale method for investigating the level of subjective control, clinical questionnaire for the identification and evaluation of neurotic states, personality questionnaire Bekhterevsky Institute, cardiointervalography, orthoklinostatik and cold test, determined the level of serotonin in the blood. RESULTS: Compared with the group of patients suffering from ER patients with NERD determined by the displacement in the direction of internality measure locus of control personality, and patients with ER, in contrast, had lower locus of control personality, a high level of situational anxiety, irritability, anxiety type of attitude to the situation of the disease associated with impaired autonomic software ANS activity. CONCLUSION: Patients with ER are more pronounced changes in cognitive-emotional sphere may have an impact on the course of disease and requiring psychological, medical correction. PMID- 25916135 TI - [Prevalence of H. pylori CagA strain and characteristics of associated gastritis in schoolchildren with dyspepsia syndrome in Tyva Republic]. AB - AIM: To study the prevalence of H. pylori CagA strain and the activity of associated gastritis in schoolchildren of Tyva Republic (Russia). MATERIALS AND METHODS: The cohorts had been formed out of 1064 native and alien schoolchildren picked up by random in Tyva Republic in the ages from 7 to 17 years. We determined IgG to H. pylori CagA antigen in serum (106 aliens and 112 natives). Out them 59 Tuvins and 72 Europoids with dyspeptic complaints were provided with endoscopic tests including biopsy of mucosa of antrum and stomach body. RESULTS: We had found ethnic peculiarities in the obtained indices in children, namely higher prevalence of the said strain of H. pylori and the absence of meaningful activity in antral sector and body of stomach in CagA-seropositive native children as compared to alien ones, in whom the activity of antral gastritis was higher than the activity in body of stomach. PMID- 25916136 TI - [Endoscopic ultrasonography in determining resectability of the pancreatic adenocarcinoma]. AB - The publication presents the results of the examination and treatment of 82 patients with pancreatic adenocarcinoma. The main objective of the work is the evaluation of endosonography diagnostic significance in identifying tumor vascular invasion and determining resectability of the tumor. The paper describes an EUS methodology, type of echoendoscopes and ultrasound criteria for tumor invasion to the blood vessels. Vessel invasion during endosonography was suspected in 48 (58.5%) cases, according to surgery data, tumor invasion into upper abdomen vessels was detected in 51 patients (62.2%). Sensitivity of endosonography in detecting vessel invasion was 90.2%, specificity--93.5%, accuracy--91.5%. Endosonography being in trend of present day ideas about the criteria of pancreatic cancer resectability is the leading method in the selection of patients to surgery. PMID- 25916137 TI - [Prediction of the acute pancreatitis after surgery on the pancreas]. AB - RESEARCH OBJECTIVE: Study preoperative and intraoperative risk factors for acute postoperative pancreatitis after surgical treatment of the pancreatic diseases. MATERIAL AND METHODS: Predictive value of the probable preoperative and intraoperative risk factors of the acute postoperative pancreatitis after surgical treatment of the proximal and distal pancreatic cancer were explored and evaluated. Patients were divided at the high risk group and mild risk group using a specially developed formula. RESULTS: Preoperative and intraoperative risk factors of the acute postoperative pancreatitis were detected and had predictive value. Much of the identified preoperative risk factors indirectly or objectively showed morphology and function of the pancreas. The importance at the development of the acute postoperative pancreatitis playing the conditions of sur gical intervention, its volume and features of technology, results of the intraoperative research of the pathological focus and status of the pancreatic tissue. Its risk factors have been ranked to intraoperative risk factors. The Identification of the intraoperative risk factors of the acute postoperative pancreatitis allowed to make correction of the risk of complications determined at the preoperative stage. CONCLUSION: The data on the effect of various technological solutions and surgical tactics to the possibility of the development of the acute postoperative pancreatitis should be considered in predicting the development of complications and in develop the most effective and safe technologies of the surgical treatment of the pancreatic diseases, as well as in optimization of the prevention of the acute postoperative pancreatitis and postoperative complications. PMID- 25916138 TI - [Clinical and experimental substantiation of application of composite prosthesis to prosthetic repair of hiatal hernias]. AB - RESEARCH OBJECTIVE: Improve the results of surgical treatment of hiatal hernia through the use of prosthetic techniques hiatal size adjustment. MATERIAL AND METHODS: The pilot study on 24 laboratory animals with use composite and PTFE of prosthesis is executed. Results are used in clinical practice when performing fitting a prosthetic hiatal hernia repair. RESULTS: The composite prosthesis is reliably fixed to a diaphragm by connecting fabric sprouting it and doesn't tend to shift. PTFE implant encapsulated with surrounding implant scar, dosage and do not germinate connective tissue. The use of composite prostheses in the clinic for correction hiatal hernia significantly reduces the rate of recurrence of hernia. CONCLUSION: The most optimum implant for prosthetic repair of hiatal hernia is the composite prosthesis. PMID- 25916139 TI - [Gastroprotective effect of honey and bee pollen]. AB - The effect of honey and pollen for an experimental gastric ulcer in rats by electromyography was investigated Okabe ulcer by applying the 100% acetic acid in the gastric serosa was simulated. Honey and pollen prevent the development of painful gastric motility, which confirms its gastroprotective action. PMID- 25916140 TI - [The problem of autolytic digestion at amniotropic and lactotropic feeding]. AB - The review presented the results of the author, his co-workers and investigators of other laboratories about types of feeding (histotropic, hemotropic, amniotropic, lactotropic, definitive) and digestion (autolytic, native) of a fetus and an infant. The study was based on analysis of enzymes that provided hydrolysis of amniotic fluid and breast milk. The data about probable technology of abovementioned types of digestion in earlier stages of individual human advance and opportunity of hydrolase recretor origin in amniotic fluid and breast milk are shown. PMID- 25916141 TI - [Bronchial spasm as extraesophageal manifestations of gastroesophageal reflux disease]. AB - Gastroesophageal reflux disease is one of the common spread diseases. Its manifestations are diverse and include esophageal and extraesophageal manifestations. One of them is a so-called "respiratory mask". It is very difficult to cure it without realizing therapy of the main disease. A clinical case of a patient with bronchial asthma in combination with a hernia hiatal and GERD is described. Clinical effectiveness of surgical treatment is demonstrated clinically. PMID- 25916142 TI - [Gastroenterology symposium in Bishkek]. PMID- 25916143 TI - [Hydrogen in metabolism of purple bacteria and prospects for practical applications]. AB - Purple bacteria are able to use H2 for photoautotrophic, photomixotrophic, and chemoautotrophic growth, exhibiting high metabolic lability. Depending on the type of metabolism, hydrogen may be consumed with release of energy and/or reductive equivalents. Purple bacteria may also release H2 as a terminal electron acceptor or in the course of dinitrogen fixation. Thus, hydrogen metabolism in purple bacteria is diverse; these bacteria are often used as models for investigation of the metabolic traits and interrelation of the metabolic pathways involving molecular hydrogen. In this review, the present-day state of investigation of hydrogen metabolism in purple bacteria is reflected and its possible practical applications are discussed. Nitrogenase and hydrogenase, the major key enzymes of hydrogen metabolism, are discussed in brief. A generalized scheme of H2 role in the metabolism of purple bacteria is presented. Experimental approaches for investigation of the rates of hydrogen production are discussed. Immobilized systems are noted as the most promising approach for development of model systems for hydrogen production. PMID- 25916144 TI - [Activation of formation of bacterial biofilms by azithromycin and prevention of this effect]. AB - Growth of members of most of the studied genera of gram-positive (Dietzia, Kocuria, and Rhodo- coccus) and gram-negative bacteria (Pseudomonas and Chromobacterium) in biofilms exhibited higher resistance to an translation inhibitor, azithromycin compared to the growth of planktonic cultures of the same strains. Low concentrations of azithromycin were found to stimulate biofilm formation by the studied saprotrophic strains. The rate of synthesis of the polysaccharide matrix component exceeded the rate of cell growth, indicating implementation of the biofilm phenotype under these conditions. It was found that an alkylhydroxybenzene (AHB) compound 4-hexylresorcinol was capable of almost uniform suppression of growth of both planktonic cultures and biofilms of the saprotrophic strains under study. In some cases, combined action ofazithromycin and AHB resulted in an additive inhibitory effect and prevented the stimulation of biofilm growth by subinhibitory azithromycin concentrations. Thus, AHB may be considered a promising antibiofilm agent. PMID- 25916145 TI - [Expression of inulinase genes in the yeasts Saccharomyces cerevisiae and Kluyveromyces marxianus]. AB - Expression of the genes encoding the enzymes involved in inulin, sucrose, and glucose metabolism in the yeasts Saccharomyces cerevisiae and Kluyveromyces marxianus was studied. The exon-intron structure of the relevant genes was identified and the primers for quantitative PCR were optimized. Expression of the genes was found to depend on the carbon source. Glucose was shown to exhibit a repressive effect on inulinase synthesis by K. marxianus, while in S. cerevisiae glucose and sucrose were inulinase inducer and repressor, respectively. PMID- 25916146 TI - [Pigmentation of Serratia marcescens and spectral properties of prodigiosin]. AB - Pigmentation of Serratia marcescens depends on the composition of the cultivation medium. The cultures grown on glycerol-peptone medium and on the medium with acetate are red and yellow (yellowish orange), respectively, with the color depending on the ambient pH. S. marcescens cells growth on glycerol-peptone medium (visually of red color) contain two forms of prodigiosin: the "red" and "yellow" ones with absorption maxima at 535 and 460-470 nm, respectively. The absorption spectrum of prodigiosin in the native pigment-protein complex was different from the spectrum of the pigment dissolved in ethanol and resembled that of the cell suspension in the presence of an additional absorption maximum at 500 nm. PMID- 25916147 TI - [Lipid and fatty acid profiles of Pseudomonas aurantiaca DNA-bound lipids determined by mass spectrometry]. AB - An approach used on investigation of the lipid composition of loosely (fraction 1) and tightly (fraction 2) DNA-bound lipids of Pseudomonas aurantiaca cells by electrospray ionization using mass spectrometry (ESI-LC-MS) was used for determination of the lipidom of a prokaryotic cell. Free fatty acids C16:0, C18:1 (fraction 1), C14:0, C16:0, and C18:2 (fraction 2) were detected. Both fractions of DNA-bound lipids were characterized by the presence of phosphatidylglycerol, phosphatidylserine, and lyso-phosphatidylinositol. The alcohol-soluble fraction 1 could also contain phosphatidylcholine and phosphatidylinositol, while fraction 2 probably contained triacylglycerides. Compared to gas chromatography, ESI-LC-MS provides new possibilities for investigation of the nucleoid lipidome, providing for more detailed investigation of DNA-bound lipids in bacterial cells. PMID- 25916148 TI - [Physiological properties of the vancomycin-resistant strain Staphylococcus epidermidis 33 GISK VAN(R)]. AB - Physiological properties of a selected Staphylococcus epidermidis strain 33 GISK VAN(R) with high resistance to vancomycin, multiple resistance to various antibiotics, as well as decreased sensitivity to lysozyme, lysostaphin, and the low-molecular mass peptide warnerin were studied. The strain was characterized by a thicker cell wall, resulting in considerably decreased rates of vancomycin penetration into the cells and in limited access of the antibiotic to its targets on the bacterial membrane. PMID- 25916149 TI - [Phylogenetic position of the purple sulfur bacterium Lamprobacter modestohalophilus determined based on the data on new strains of the species]. AB - Lamprobacter, the genus of halophilic purple sulfur bacteria (PSB) with the single species Lpb. modestohalophilus was described in 1979. Rod-shaped Lamprobacter cells contained gas vacuoles during the nonmotile growth phase; motile cells without gas vesicles were formed sometimes. Bacteria contained bacteriochlorophyll a and a carotenoid okenone. The names of this genus and species were included in the list of approved microbial names in 1988. Since the type strain Lpb. modestohalophilus ROI(T) has been lost, its 16S rRNA gene sequences have not been obtained. Based on analysis of the 16S rRNA genes, a new genus Halochromatium comprising the motile extremely halophilic Chromatium-like species was proposed in 1998. Members of this genus never contain gas vacuoles. In spite of the phenotypic differences between the genera Lamprobacter and Halochromatium, phylogenetic boundaries between these taxa remained undetermined. Description of a marine bacteria belonging to Lamprobacter according to its morphological andphysiological properties as a new Halochromatium species, Hch. roseum, resulted in additional complication of the taxonomic situation. The present work provides evidence for the preservation of two phenotypically and phylogenetically different genera, Lamprobacter and Halochromatium, Lpb. modestohalophilus is proposed, as the type species of the genus Lamprobacter. Characteristics of two Lpb. modestohalophilus strains were extensively investigated, and one of them (strain Sivash) was proposed as the neotype strain of the species. It was suggested to retain the genus Halochromatium as containing extremely halophilic species Hch. salexigens and Hch. glycolicum, while transfer of the weakly halophilic species Hch. roseum to the genus Lamprobacter is proposed, resulting in a new combination Lamprobacter roseus comb. nov. PMID- 25916150 TI - [Activity and expression of laccase, tyrosinase, glucanase, and chitinase genes during morphogenesis of Lentinus edodes]. AB - Activation of expression of the lcc4 and tir genes encoding laccase and tyrosinase was observed during transition of a xylotrophic basidiomycete Lentinus edodes from the vegetative to the generative growth stages. This was especially pronounced in the brown mycelial mat (the stage preceding formation of the fruiting bodies). Development of this structure was shown to be associated with a sharp increase of laccase and tyrosinase activities, as well as with rearrangements in the phenol oxidase complex. Formation of the tissues with thickened cell walls was associated with enhanced expression of the chi and exg1 genes encoding chitinase and glucanase, respectively. Exogenous treatment of the vegetative mycelium with laccase preparation from the brown mycelial mat promoted formation of this morphological structure. Activation of the lcc4, tir, chi, and exg1 genes may be used as a marker of readiness to fruition in xylotrophic fungi. PMID- 25916151 TI - [Advenella kashmirensis subsp. methylica PK1, a facultative methylotroph from carex rhizosphere]. AB - A strain (PK1) of facultative methylobacteria growing on methanol as a carbon and energy source was isolated from carex rhizosphere (Pamukkale National Park, Turkey). The cells were nonmotile gram-negative rods propagating by binary fission. The organism was a strict anaerobe, oxidase- and catalase-positive. Optimal growth occurred at 29 degrees C, pH 8.0-8.5, and 0.5% NaCl; no growth occurred at 2% NaCl. The organism used the ribulose bisphosphate pathway of C1 assimilation. Predominant fatty acids were 11-octodecenoic (18:1omega7) and cis hexadecenoic (16:1omega7c). Phosphatidylethanolamine and diphosphatidylglycerol were the dominant phospholipids. Q8 was the main ubiquinone. DNA G+C content was 55.4 mol % (mp). Sequencing of the 16S rRNA gene revealed that strain PK1 belonged to the genus Advenella with 98.8 and 99.2% similarity to the type strains A. incenata CCUG 45225T and A. kashmirensis WT001T, respectively. DNA-DNA homology of strain PK1 and A. kashmirensis WT001T was 70%. While MALDI analysis confirmed their close clusterization, RAPD analysis revealed the differences between strain PKI and other Advenella strains. Based on its geno- and phenotypic properties, the isolate PK1 was classified as A. kashmirensis subsp. methylica PK1 (VKM-B 2850 = DSM 27514), the first known methylotroph of the genus Advenella. PMID- 25916152 TI - [Detection of methane in the water column at gas and oil seep sites in central and southern Lake Baikal]. AB - Microbiological and biogeochemical investigation of the water column of oligotrophic Lake Baikal at the sites of the K2 and Bolshoy mud volcanoes and the Gorevoy Utes oil seep was carried out in July 2013. Total microbial numbers (TMN), cell numbers of type I and type II methanotrophs, and methane concentrations were measured; the rate of methane oxidation was determined. Methane concentrations in Lake Baikal water column varied from 0.09 to 1 MUL/L, while methane oxidation rates varied from 0.007 to 0.9 nL/(L day). The highest rates of methane oxidation were revealed in the near-bottom water horizons at the sites of the Bolshoy mud volcano and the Gorevoy Utes oil seep. These were the sites where the most pronounced anomalies in methane concentration were also detected. TMN varied from 0.123 x 10(6) to 1.64 x 10(6) cells/mL. Methanotrophic bacteria were revealed in the water column at all sites, their abundance did not always correlate with methane concentrationsand the rates of methane oxidation. Methanotrophs constituted not more than 1.63% of the total microbial number, with their highest abundance in the upper 200 m of the water column. PMID- 25916153 TI - [Algo-bacterial communities of the Kulunda steppe (Altai region, Russia) soda lakes]. AB - The composition and macroscopic structure of the floating oxygenic phototrophic communities from Kulunda steppe soda lakes (Petukhovskoe sodovoe, Tanatara VI, and Gorchiny 3) was described based on the data of the 2011 and 2012 expeditions (Winogradsky Institute of Microbiology). The algo-bacterial community with a green alga Ctenocladus circinnatus as an edificator was the typical one. Filamentous Geitlerinema sp. and Nodosilinea sp. were the dominant cyanobacteria. Apart from C. circinnatus, the algological component of the community contained unicellular green algae Dunaliella viridis and cf. Chlorella minutissima, as well as diatoms (Anomeoneis sphaerophora, Brchysira brebissonii, Brachysira zellensis, Mastogloia pusilla var. subcapitata, Nitzschia amphibia, Nitzschia communis, and Nitzschia sp.1). The latter have not been previously identified in the lakes under study. In all lakes, a considerable increase in salinity was found to result in changes in the composition and macroscopic structure of algo-bacterial communities. PMID- 25916154 TI - [Identification of cyanobacterial producers of shellfish paralytic toxins in Lake Baikal]. PMID- 25916155 TI - Characteristics of egg parts, chemical composition and nutritive value of Japanese quail eggs--a review. AB - All nutrients including proteins, lipids, vitamins, minerals and growth factors required by the developing embryo, as well as a number of defense factors, can be found in avian eggs. Eggs are also a source of other substances with biological functions and activities inter alia immune proteins and enzymes. Although chicken egg consumption is currently at the highest level, eggs from other species are also becoming popular. Since our knowledge about Japanese quail eggs is still limited, the aim of this review was to shed light on characteristics of egg parts, chemical composition and nutritive value of quail eggs. PMID- 25916156 TI - Age-dependent change in the morphology of nucleoli and methylation of genes of the Nucleolar Organizer Region in Japanese quail Coturnix japonica) model (Temminck and Schlegel, 1849) (Galliformes: Aves). AB - Nucleoli are the product of the activity of nucleolar organizer regions (NOR) in certain chromosomes. Their main functions are the formation of ribosomal subunits from ribosomal protein molecules and the transcription of genes encoding rRNA. The aim of the study was to determine the shape of nucleoli and analyse methylation in the gene RN28S in the spermatocytes of male Japanese quail (Coturnixjaponica) in two age groups. Nucleoli were analysed in cells of the first meiotic prophase. Their number and shape were determined and they were classified as regular, irregular or defragmented. In the cells of the young birds no defragmented nucleoli were observed, with regular and irregular nucleoli accounting for 97% and 3%, respectively. In the cells of older birds no regular nucleoli were observed, while irregular and defragmented nucleoli accounted for 37% and 67%, respectively. MSP (methylation-specific PCR) showed that the gene RN28S is methylated in both 15-week-old and 52-week-old quails. In recent years an association has been established between nucleolus morphology and cellular ageing processes. PMID- 25916157 TI - Expression of leptin, NGF and adiponectin in metabolic syndrome. AB - Adipose tissue secretes a variety of adipokines involved in the regulation of energy metabolism and insulin resistance. Metabolic syndrome corresponds to a clinical condition in which white adipose tissue is characterized by an increased production and secretion of inflammatory molecules which may have local effects on adipose tissue physiology but also systemic effects on other organs. The aim of this study was to assess the expression of leptin, NGF and adiponectin in women with metabolic syndrome compared to healthy controls. Plasma leptin, NGF and adiponectin levels were measured by the ELISA method. Leptin and NGF immunohistochemical expression was analyzed in subcutaneous adipose tissue. The results indicated that in women with metabolic syndrome waist circumference, body mass index, HOMA index, glucose, total cholesterol and triglyceride levels were significantly increased in parallel with overxpressed plasma levels of leptin and NGF and decreased adiponectin. The immunohistochemical expression of leptin and NGF was very strong. In conclusion, this is the first study demonstrating a complex of immunochemical and immunohistochemical expression of the key adipokines including leptin, NGF and adiponectin in women with metabolic syndrome. Locally-produced pro-inflammatory adipokines probably contribute to the ethiopathogenic mechanisms ofmetabolic syndrome. PMID- 25916158 TI - Analysis of genomic instability in primary spermatocytes of interspecific hybrids of the red fox (Vulpes vulpes) and the Arctic fox (Alopex lagopus). AB - The aim of this study was to analyse meiotic cells of male interspecific hybrids of the red fox (Vulpes vulpes) and the arctic fox (Alopex lagopus). To this end we determined stages of meiotic cells as well as carried out FISH analyses with probes specific to heterosomes and a TUNEL assay on synaptonemal complex preparations. The meiotic cell analysis revealed only the presence of stages of the first meiotic division from leptotene to pachytene. Moreover, we observed an increased level of early dissociation of the X-Y bivalent as well as a high percentage of apoptotic cells. These results indicate the disruption of meiotic division in male hybrids manifested through meiotic arrest of the cells. Faulty pairing of the heterosomes can be considered as one of the causes leading to the initiation of the apoptotic process. PMID- 25916159 TI - Effect of growth hormone on basal and LH-stimulated steroid secretion by chicken yellow ovarian follicles. An in vitro study. AB - The aim of the present study was to determine the effect of growth hormone (GH) on basal and LH-regulated steroid secretion by yellow hierarchical follicles before and after maturation, and the granulosa and theca layers of the largest preovulatory follicles during the ovulatory cycle in the chicken. In the first experiment, whole yellow follicles (8-12 mm, 12-18 mm, 18-24 mm and 24-30 mm) isolated from 15 and 17-18 week-old chickens were used. In the second experiment, the granulosa and theca layers of the 3 largest yellow preovulatory follicles (F3 median (uAs p(Wald) = 0.03; bAs p(Wald) = 0.05). This was primarily driven by stronger effects of As exposure on CRP in participants with lower plasma GSH. The effects of As exposure on eGFR were not modified significantly by EhGSH, GSH, or GSSG. These data suggest that participants having lower plasma GSH and a more oxidized plasma EhGSH are at increased risk for As-induced inflammation. Future studies should evaluate whether antioxidant treatment lowers plasma EhGSH and reduces risk for As-induced diseases. PMID- 25916187 TI - Evolution of Spermophagus seed beetles (Coleoptera, Bruchinae, Amblycerini) indicates both synchronous and delayed colonizations of host plants. AB - Seed beetles are a group of specialized chrysomelid beetles, which are mostly associated with plants of the legume family (Fabaceae). In the legume-feeding species, a marked trend of phylogenetic conservatism of host use has been highlighted by several molecular phylogenetics studies. Yet, little is known about the evolutionary patterns of association of species feeding outside the legume family. Here, we investigate the evolution of host use in Spermophagus, a species-rich seed beetle genus that is specialized on two non-legume host-plant groups: morning glories (Convolvulaceae) and mallows (Malvaceae: Malvoideae). Spermophagus species are widespread in the Old World, especially in the Afrotropical, Indomalaya and Palearctic regions. In this study we rely on eight gene regions to provide the first phylogenetic framework for the genus, along with reconstructions of host use evolution, estimates of divergence times and historical biogeography analyses. Like the legume-feeding species, a marked trend toward conservatism of host use is revealed, with one clade specializing on Convolvulaceae and the other on Malvoideae. Comparisons of plants' and insects' estimates of divergence times yield a contrasted pattern: on one hand a quite congruent temporal framework was recovered for morning-glories and their seed predators; on the other hand the diversification of Spermophagus species associated with mallows apparently lagged far behind the diversification of their hosts. We hypothesize that this delayed colonization of Malvoideae can be accounted for by the respective biogeographic histories of the two groups. PMID- 25916188 TI - North or south? Phylogenetic and biogeographic origins of a globally distributed avian clade. AB - Establishing phylogenetic relationships within a clade can help to infer ancestral origins and indicate how widespread species reached their current biogeographic distributions. The small plovers, genus Charadrius, are cosmopolitan shorebirds, distributed across all continents except Antarctica. Here we present a global, species-level molecular phylogeny of this group based on four nuclear (ADH5, FIB7, MYO2 and RAG1) and two mitochondrial (COI and ND3) genes, and use the phylogeny to examine the biogeographic origin of the genus. A Bayesian multispecies coalescent approach identified two major clades (CRD I and CRD II) within the genus. Clade CRD I contains three species (Thinornis novaeseelandiae, Thinornis rubricollis and Eudromias morinellus), and CRD II one species (Anarhynchus frontalis), that were previously placed outside the Charadrius genus. In contrast to earlier work, ancestral area analyses using parsimony and Bayesian methods supported an origin of the Charadrius plovers in the Northern hemisphere. We propose that major radiations in this group were associated with shifts in the range of these ancestral plover species, leading to colonisation of the Southern hemisphere. PMID- 25916189 TI - A new phylogeny of the Cephalaspidea (Gastropoda: Heterobranchia) based on expanded taxon sampling and gene markers. AB - The Cephalaspidea is a diverse marine clade of euthyneuran gastropods with many groups still known largely from shells or scant anatomical data. The definition of the group and the relationships between members has been hampered by the difficulty of establishing sound synapomorphies, but the advent of molecular phylogenetics is helping to change significantly this situation. Yet, because of limited taxon sampling and few genetic markers employed in previous studies, many questions about the sister relationships and monophyletic status of several families remained open. In this study 109 species of Cephalaspidea were included covering 100% of traditional family-level diversity (12 families) and 50% of all genera (33 genera). Bayesian and maximum likelihood phylogenetics analyses based on two mitochondrial (COI, 16S rRNA) and two nuclear gene markers (28S rRNA and Histone-3) were used to infer the relationships of Cephalaspidea. The monophyly of the Cephalaspidea was confirmed. The families Cylichnidae, Diaphanidae, Haminoeidae, Philinidae, and Retusidae were found non-monophyletic. This result suggests that the family level taxonomy of the Cephalaspidea warrants a profound revision and several new family and genus names are required to reflect the new phylogenetic hypothesis presented here. We propose a new classification of the Cephalaspidea including five new families (Alacuppidae, Colinatydidae, Colpodaspididae, Mnestiidae, Philinorbidae) and one new genus (Alacuppa). Two family names (Acteocinidae, Laonidae) and two genera (Laona, Philinorbis) are reinstated as valid. An additional lineage with family rank (Philinidae "Clade 4") was unravelled, but no genus and species names are available to reflect the phylogeny and formal description will take place elsewhere. PMID- 25916190 TI - Phylogenetic analyses provide insights into the historical biogeography and evolution of Brachyrhaphis fishes. AB - The livebearing fish genus Brachyrhaphis (Poeciliidae) has become an increasingly important model in evolution and ecology research, yet the phylogeny of this group is not well understood, nor has it been examined thoroughly using modern phylogenetic methods. Here, we present the first comprehensive phylogenetic analysis of Brachyrhaphis by using four molecular markers (3mtDNA, 1nucDNA) to infer relationships among species in this genus. We tested the validity of this genus as a monophyletic group using extensive outgroup sampling based on recent phylogenetic hypotheses of Poeciliidae. We also tested the validity of recently described species of Brachyrhaphis that are part of the B. episcopi complex in Panama. Finally, we examined the impact of historical events on diversification of Brachyrhaphis, and made predictions regarding the role of different ecological environments on evolutionary diversification where known historical events apparently fail to explain speciation. Based on our results, we reject the monophyly of Brachyrhaphis, and question the validity of two recently described species (B. hessfeldi and B. roswithae). Historical biogeography of Brachyrhaphis generally agrees with patterns found in other freshwater taxa in Lower Central America, which show that geological barriers frequently predict speciation. Specifically, we find evidence in support of an 'island' model of Lower Central American formation, which posits that the nascent isthmus was partitioned by several marine connections before linking North and South America. In some cases where historic events (e.g., vicariance) fail to explain allopatric species breaks in Brachyrhaphis, ecological processes (e.g., divergent predation environments) offer additional insight into our understanding of phylogenetic diversification in this group. PMID- 25916192 TI - Significant CT-angiographic evidence of coexisting abdominal aortoiliac aneurysms with simple renal cysts and abdominal wall hernias. AB - AIM: Aim of the study was to determine and compare the incidence of simple renal cysts (SRCs) and abdominal/inguinal wall hernias (AWHs/IHs) in patients with known abdominal aortoiliac aneurysm (AAA) and aortoiliac occlusive disease (AOD) in order to assess if these comorbidities could be promoted as added high risk factors for AAA development. METHODS: Prospectively collected clinical and radiological data of 236 AAA patients, treated at our institution between June 2009 and June 2012, were retrospectively analyzed regarding the number, location and type of SRCs and AWHs. Two hundred thirty-six randomly chosen patients with aortoiliac occlusive disease (AOD) were recruited as control group. RESULTS: SRCs and AWHs were significantly more frequent in the AAA group than in AOD group (68.6% vs. 37.3%, OR=2.110, 95%-CI 1.325-3.359, P=0.002 and 45.3% vs. 24.2%, OR=1.850, 95%-CI 1.153-2.968, P=0.011). In 30.1% of AAA patients both clinical entities were simultaneously detected (OR=2.441, 95%-CI 1.342-4.437, P=0.003), the comorbidity of SRCs and IHs was related to a 3.6-fold increased risk for a coexisting AAA (OR=3.558, 95%-CI 1.622-7.805, P=0.002). CONCLUSION: The findings of this study contribute to the clinical evidence of a significant coexistence of SRCs and AWH/IHs in AAA patients. However, further clinical screening trials and research are necessary to establish the clinical significance of this observation and to assess a possible common pathogenesis of systemic extracellular matrix degeneration in affected individuals. PMID- 25916191 TI - Scaffold Protein SLP-76 Primes PLCgamma1 for Activation by ITK-Mediated Phosphorylation. AB - Activation of the phospholipase, PLCgamma1, is critical for proper T cell signaling following antigen receptor engagement. In T cells, the Tec family kinase, interleukin-2-induced tyrosine kinase (ITK), phosphorylates PLCgamma1 at tyrosine 783 (Y783) leading to activation of phospholipase function and subsequent production of the second messengers inositol 1,4,5-trisphosphate and diacylglycerol. In this work, we demonstrate that PLCgamma1 can be primed for ITK mediated phosphorylation on Y783 by a specific region of the adaptor protein, SLP 76. The SLP-76 phosphotyrosine-containing sequence, pY(173)IDR, does not conform to the canonical recognition motif for an SH2 domain yet binds with significant affinity to the C-terminal SH2 domain of PLCgamma1 (SH2C). The SLP-76 pY(173) motif competes with the autoinhibited conformation surrounding the SH2C domain of PLCgamma1 leading to exposure of the ITK recognition element on the PLCgamma1 SH2 domain and release of the target tyrosine, Y783. These data contribute to the evolving model for the molecular events occurring early in the T cell activation process. PMID- 25916193 TI - Ductal carcinoma in situ: a disease entity that merits more recognition. AB - Ductal carcinoma in situ (DCIS) is a non-invasive breast carcinoma that remains in the milk ducts. It is a poorly understood disease and its natural history is not well known. This is because once diagnosed, DCIS is usually treated. It is known however that ductal carcinoma is a precursor of invasive breast carcinoma, as 14-53% can become invasive over a period of 10 years, if left untreated. With increasing knowledge about the molecular biology of DCIS, more insight is given in its relation to invasive breast cancer. Diagnosis of ductal carcinoma in situ is increasing in the last few years. This is likely caused by the increased mammographic screening for breast cancer and the higher quality of mammographic images. DCIS represents about one fifth of all mammographically detected breast cancers. Risk factors for the development of ductal carcinoma in situ are: low parity, late age at first birth and menopause, and Body Mass Index. The Van Nuys Prognostic Index is a useful scoring system to grade DCIS. DCIS is graded by scoring four characteristics: patient's age, margin width, tumor size and pathological classification. It allows us to divide DCIS lesions into different groups according to risk of local recurrence: low risk, intermediate risk and high risk. Each group requires a different treatment, respectively: local excision of the tumor; local excision and radiotherapy; and mastectomy. The use of tamoxifen in the treatment of DCIS is still controversial, but research so far has encouraging results. Interesting developments have been made in the use of Her-2 pulsed dendritic cell vaccination before DCIS surgery. PMID- 25916194 TI - Challenges in robotic distal pancreatectomy: systematic review of current practice. AB - Over the last decade, robotics has gained popularity and is increasingly employed to accomplish several abdominal surgical procedures. Nevertheless, pancreatectomies are regarded as demanding procedures for which the application of minimally-invasive surgery is still limited and its effectiveness has not been conclusively established. We aimed to investigate the current role of robot assisted surgery to perform distal pancreatectomy. A systematic review of the English-language literature was conducted for articles dealing with robotic assisted distal pancreatectomies. All relevant papers were evaluated on surgical and oncological outcomes. A total of 10 articles reporting on robotic distal pancreatectomies were finally considered in the analysis, including 259 patients. Mean operative time was 271 minutes (range 181-398); mean blood loss was 210 mL (range 104-361), in 11.6% of cases conversion to laparotomy occurred, spleen preservation was accomplished in 51.4% of procedures, mean time of postoperative hospital stay was 7 days. Overall, postoperative mortality and morbidity were 0% and 23.4% respectively, the mean number of lymph nodes harvested was 12.7. In all included series, no case of R1 resection was reported. Despite its relatively recent introduction in clinical practice, robotic-assisted surgery has been widely employed to perform distal pancreatectomy worldwide and it should be considered a safe and effective procedure. Both surgical and pathologic data support its application in the management of pancreatic lesions of the body and tail. PMID- 25916195 TI - Developments in immunotherapy for gastrointestinal cancer. AB - Gastrointestinal (GI) cancers are the most commonly occurring cancer worldwide. Colorectal cancer (CRC) is the second and third most commonly diagnosed cancer in women and men, respectively. Despite the advent of screening and the declining incidence of CRC overall, most patients are not diagnosed at an early, localized stage. Due to resistance to chemotherapy, recurrence, and metastatic disease, those diagnosed with advanced disease have only a 12% 5-year survival rate. Given the overwhelming global impact of CRC, the need for advanced therapy is crucial. Targeted immunotherapy in addition to surgical resection, traditional chemotherapy, and radiation therapy is on the rise. For the purpose of this review, we focused on the advances of immunotherapy, particularly in CRC, with mention of research pertaining to particular advances in immunotherapy for other aspects of the GI system. We review basic immunology and the microenvironment surrounding colorectal tumors that lead to immune system evasion and poor responses to chemotherapy. We also examined the way these obstacles are proving to be the targets of tumor specific immunotherapy. We will present current FDA approved immunotherapies such as monoclonal antibodies (mAb) targeting tumor specific antigens, as well as vaccines, adoptive cell therapy, cytokines, and check-point inhibitors. A summation of prior research, current clinical trials, and prospective therapies in murine models help delineate our current status and future strategies on CRC immunotherapy. PMID- 25916196 TI - Intertidal Concentrations of Microplastics and Their Influence on Ammonium Cycling as Related to the Shellfish Industry. AB - Microplastics are ubiquitous within the marine environment. The last 10 years have seen research directed at understanding the fate and effect of microplastics within the marine environment; however, no studies have yet addressed how concentrations of these particles could affect sedimentary processes such as nutrient cycling. Herein we first determine the concentration and spatial distribution of microplastics within Baynes Sound, a key shellfish-growing area within coastal British Columbia (BC). We also determined sediment grain size and % organic matter (OM) such that we could relate spatial patterns in sediment microplastic concentrations to sedimentary processes that determine zones of accretion and erosion. Using field-determined concentrations of microplastics, we applied laboratory microcosms studies, which manipulated sediment concentrations of microplastics, OM, and bivalves to determine the influence of sediment microplastics on ammonium cycling within intertidal sediments. Concentrations of microplastics determined within the intertidal sediment varied spatially and were similar to those found in other coastal regions of high urban use. Concentrations were independent of grain size and OM suggesting that physical processes other than those that govern natural sediment components determine the fate of microplastics within sediments. Under laboratory conditions, concentrations of ammonium were significantly greater in the overlying water of treatments with microplastics, clams, and OM compared with treatments without microplastics. These preliminary studies suggest that high concentrations of microplastics have the potential to alter key sedimentary processes such as ammonium flux. This could have serious implications, for example, contributing to eutrophication events in regions of the coast that are highly urbanized. PMID- 25916197 TI - Microplastic in a macro filter feeder: Humpback whale Megaptera novaeangliae. AB - Marine filter feeders are exposed to microplastic because of their selection of small particles as food source. Baleen whales feed by filtering small particles from large water volumes. Macroplastic was found in baleen whales before. This study is the first to show the presence of microplastic in intestines of a baleen whale (Megaptera novaeangliae). Contents of its gastrointestinal tract were sieved, dissolved in 10% potassium hydroxide and washed. From the remaining dried material, potential synthetic polymer particles were selected based on density and appearance, and analysed by Fourier transform infrared (FTIR) spectroscopy. Several polymer types (polyethylene, polypropylene, polyvinylchloride, polyethylene terephthalate, nylon) were found, in varying particle shapes: sheets, fragments and threads with a size of 1mm to 17cm. This diversity in polymer types and particle shapes, can be interpreted as a representation of the varying characteristics of marine plastic and the unselective way of ingestion by M. novaeangliae. PMID- 25916198 TI - Trophic structure in a pilot system for the integrated multi-trophic aquaculture off the east coast of Korean peninsula as determined by stable isotopes. AB - To assess the potential for nutritional exploitation of caged-fish-derived waste through the use of extractive co-cultured species in a pilot system for an integrated multi-trophic aquaculture (IMTA), we compared their C and N stable isotope ratios with those of uncultured macroinvertebrates in and around the system. Black rockfish were co-cultured with sea cucumber, oyster, and two macroalgae as extractive species. Isotope signatures of the co-cultured sea cucumber at the IMTA site differed from those at the control site, indicating their assimilation of aquaculture wastes. In contrast, delta(13)C and delta(15)N of individual taxa of the cultured oyster and uncultured invertebrates were consistent between sites, suggesting a minor contribution of the aquaculture waste to benthic and pelagic food chains in and around the IMTA system. These results provide evidence of the suitability of using sea cucumber as an extractive species to reduce the impact of a monoculture system on the ambient environment. PMID- 25916199 TI - Eight-channel transceiver RF coil array tailored for 1H/19F MR of the human knee and fluorinated drugs at 7.0 T. AB - The purpose of this study was to evaluate the feasibility of an eight-channel dual-tuned transceiver surface RF coil array for combined (1)H/(19)F MR of the human knee at 7.0 T following application of (19)F-containing drugs. The (1)H/(19)F RF coil array includes a posterior module with two (1)H loop elements and two anterior modules, each consisting of one (1)H and two (19)F elements. The decoupling of neighbor elements is achieved by a shared capacitor. Electromagnetic field simulations were performed to afford uniform transmission fields and to be in accordance with RF safety guidelines. Localized (19)F MRS was conducted with 47 and 101 mmol/L of flufenamic acid (FA) - a (19)F-containing non steroidal anti-inflammatory drug - to determine T1 and T2 and to study the (19)F signal-to-dose relationship. The suitability of the proposed approach for (1)H/(19)F MR was examined in healthy subjects. Reflection coefficients of each channel were less than -17 dB and coupling between channels was less than -11 dB. Q(L)/Q(U) was less than 0.5 for all elements. MRS results demonstrated signal stability with 1% variation. T1 and T2 relaxation times changed with concentration of FA: T1 /T2 = 673/31 ms at 101 mmol/L and T1 /T2 = 616/26 ms at 47 mmol/L. A uniform signal and contrast across the patella could be observed in proton imaging. The sensitivity of the RF coil enabled localization of FA ointment administrated to the knee with an in-plane spatial resolution of (1.5 * 1.5) mm(2) achieved in a total scan time of approximately three minutes, which is well suited for translational human studies. This study shows the feasibility of combined (1)H/(19)F MRI of the knee at 7.0 T and proposes T1 and T2 mapping methods for quantifying fluorinated drugs in vivo. Further technological developments are necessary to promote real-time bioavailability studies and quantification of (19)F-containing medicinal compounds in vivo. PMID- 25916201 TI - Anthropological study of ear tubercles in a Spanish sample. AB - The ear has been used since the 19th century as a valuable instrument in personal identification. Its special interest is due to the morphological complexity of the structures involved. The aim of the present investigation is to establish the morphological variability of the helix tubercles in a sample of the Spanish European population (303 individuals between 18 and 72 years old). The frequencies of appearance of each type of tubercle and its degree of expression, as well as the possible relationship with sex, age, and laterality, are determined. Three of the tubercles are relatively frequent in the sample: tubercle of the root of the superior helix (31.7%), tubercle of the anterior helix (27.6%), and the Darwin's tubercle (18.2%). The least frequent helix tubercles are those located on the superior helix (2.7%) and the inferior tubercles at the root of the helix (6%). For all sites, tubercles with the greatest degree of expression are the least frequent. No sexual dimorphism or age differences have been found except for the tubercle of the anterior helix. Overall, tubercles show good symmetry. A relation of dependency among some of the tubercles of the helix has been found. PMID- 25916203 TI - Force-rate characterization of two spiropyran-based molecular force probes. AB - The mechanically accelerated ring-opening reaction of spiropyran to a colored merocyanine provides a useful method by which to image the molecular scale stress/strain distribution within a polymer, but the magnitude of the forces necessary for activation has yet to be quantified. Here, we report single molecule force spectroscopy studies of two spiropyran isomers. Ring opening on the time scale of tens of milliseconds is found to require forces of ~240 pN, well below that of previously characterized covalent mechanophores. The lower threshold force is a combination of a low force-free activation energy and the fact that the change in rate with force (activation length) of each isomer is greater than that inferred in other systems. Finally, regiochemical effects on mechanochemical coupling are characterized, and increasing force reverses the relative ring opening rates of the two isomers. PMID- 25916202 TI - Heterologous expression of NaV1.9 chimeras in various cell systems. AB - SCN11A encodes the voltage-gated sodium channel NaV1.9, which deviates most strongly from the other eight NaV channels expressed in mammals. It is characterized by resistance to the prototypic NaV channel blocker tetrodotoxin and exhibits slow activation and inactivation gating. Its expression in dorsal root ganglia neurons suggests a role in motor or pain signaling functions as also recently demonstrated by the occurrence of various mutations in human SCN11A leading to altered pain sensation syndromes. The systematic investigation of human NaV1.9, however, is severely hampered because of very poor heterologous expression in host cells. Using patch-clamp and two-electrode voltage-clamp methods, we show that this limitation is caused by the C-terminal structure of NaV1.9. A chimera of NaV1.9 harboring the C terminus of NaV1.4 yields functional expression not only in neuronal cells but also in non-excitable cells, such as HEK 293T or Xenopus oocytes. The major functional difference of the chimeric channel with respect to NaV1.9 is an accelerated activation and inactivation. Since the entire transmembrane domain is preserved, it is suited for studying pharmacological properties of the channel and the functional impact of disease causing mutations. Moreover, we demonstrate how mutation S360Y makes NaV1.9 channels sensitive to tetrodotoxin and saxitoxin and that the unusual slow open state inactivation of NaV1.9 is also mediated by the IFM (isoleucine phenylalanine-methionine) inactivation motif located in the linker connecting domains III and IV. PMID- 25916204 TI - Effects of butafosfan with or without cyanocobalamin on the metabolism of early lactating cows with subclinical ketosis. AB - Fifty-one dairy cows with subclinical ketosis were used to investigate the effects of butafosfan alone or in combination with cyanocobalamin on metabolism. Treatments included i.v. injection of 10 ml/100 kg of body weight with butafosfan (BUT) or combined cyanocobalamin with butafosfan (BUTCO) at a similar concentration as in Catosal((r)) . Control cows (CON) received a 0.9% saline solution. Cows were injected on days 1-3 at 22.3 +/- 0.7 days post-partum. Milk production and composition were not affected by the treatments. In plasma, CON cows had a significantly higher plasma NEFA concentration (0.59 +/- 0.03 mm) across the study period than BUTCO cows (p < 0.05; 0.42 +/- 0.03 mm), whereas the plasma NEFA concentration of BUT was intermediate (0.52 +/- 0.03 mm) but not significantly different from CON. Both BUTCO and BUT cows had lower (p < 0.05) plasma BHBA concentrations (1.02 +/- 0.06 mm and 1.21 +/- 0.06 mm, respectively) across the study period than CON (1.34 +/- 0.06 mm). Plasma glucose was not different between treatments, but plasma glucagon concentrations were consistently high in BUT compared to BUTCO and CON. Lowest post-treatment glucagon levels were observed in BUTCO. Hepatic mRNA abundance of liver X receptor alpha, a nuclear receptor protein involved in lipid metabolism, was higher in BUTCO compared to BUT and CON (p < 0.05) on day 7. Furthermore, on day 7, the mRNA abundance of beta-hydroxybutyrate dehydrogenase 2 was higher in BUTCO compared to BUT and CON (p < 0.01). In conclusion, injections of combined cyanocobalamin with butafosfan post-partum in early lactation ketotic dairy cows act on lipid metabolism with effects on plasma metabolites, most likely mediated via modified activity of key factors in the liver. Results indicate that the application of butafosfan only in combination with cyanocobalamin exhibits the expected positive effects on metabolism. PMID- 25916205 TI - Dysregulation of zinc finger protein, X-linked (ZFX) impairs cell proliferation and induces apoptosis in human oral squamous cell carcinorma. AB - Zinc finger protein, X-linked (ZFX) is a transcriptional factor involved in many physiological processes such as embryonic stem cell survival and self-renewal. Though ZFX dysfunctions have been identified in variant human diseases and especially in cancers, its pathological roles have not been fully addressed. Here, we explored the relationship between ZFX expression and squamous cell carcinoma (SCC) of the tongue. We found that ZFX expression was significantly higher in tongue SCC tumors as compared to tumor-adjacent normal tissues. Furthermore, ZFX knockdown impeded cell proliferation, impaired colony formation ability, and lead to cell cycle arrest while induced cell apoptosis in human tongue squamous cell carcinoma cell line Tca-8113. Our results provide evidence suggesting that ZFX overexpression is associated with the development of tongue SCC and ZFX knockdown is a potential treatment for tumor suppression. PMID- 25916206 TI - The roles of ADAMTS in angiogenesis and cancer. AB - Angiogenesis is an indispensable mechanism involved in both physiological processes and various pathological conditions, such as inflammation, aberrant wound healing, tumor progression, and metastasis. Among many angiogenic stimulators and inhibitors, vascular endothelial growth factor (VEGF) is regarded as one of the most important members of the signaling protein family involved in blood vessel formation and maturation. The a disintegrin and metalloproteinase with thrombospondin motifs (ADAMTSs) proteins are a family of multifunctional proteinases. Such proteolytic enzymes are associated with various physiological processes, such as collagen maturation, organogenesis, angiogenesis, and reproduction. Importantly, deficiency or overexpression of certain ADAMTS proteinases has been shown to be directly involved in a number of serious diseases, including tumor progression and metastasis. This review explores in depth the connections between ADAMTS proteinases as positive/negative mediators during angiogenesis and VEGF. PMID- 25916207 TI - Serum calprotectin: a new potential biomarker for thyroid papillary carcinoma. AB - The aim of this study was to evaluate serum calprotectin levels and oxidative stress status in patients with papillary thyroid carcinoma (PTC) and the changes in their levels after total thyroidectomy. The study involved 30 patients with PTC and 30 healthy controls. Blood samples were obtained from the PTC patients before and 1 month after the operation. Preoperative and postoperative serum samples from PTC patients and healthy controls were analysed for calprotectin, total antioxidant status (TAS), total oxidant status (TOS) and lipid hydroperokside (LOOH). The preoperative calprotectin, TOS, OSI and LOOH levels of the patients with PTC were significantly higher compared to those of the control group (p < 0.001, for each). The levels of calprotectin decreased significantly in patients with PTC after the operation (p < 0.001), while TAS, TOS and OSI levels remained unchanged (p = 0.313, p = 0.085 and p = 0.163, respectively). Preoperative serum calprotectin levels were positively correlated with TOS, OSI and LOOH levels and negatively correlated with TAS levels in patients with PTC. In conclusion, serum calprotectin levels is increased in patients with PTC, and calprotectin is positively correlated with TOS and LOOH. Serum calprotectin levels is significantly decreased after total thyroidectomy. PMID- 25916208 TI - Orthotopic inflammation-related pancreatic carcinogenesis in a wild-type mouse induced by combined application of caerulein and dimethylbenzanthracene. AB - Pancreatic ductal adenocarcinoma (PDAC) is one of the most lethal human malignancies, with a poor long-term prognosis, and effective therapeutic options are lacking. Observing the dynamics of the pathogenesis of pancreatic intraepithelial neoplasia (PanIN) and PDAC in tumor models can facilitate understanding of the molecular mechanisms involved in early PDAC. Furthermore, it can compensate for the research limitations associated with analyzing clinical specimens of late-stage PDAC. In this study, we orthotopically treated the pancreas with dimethylbenzanthracene (DMBA) combined with caerulein in wild-type C57BL/6 J mice to induce inflammation-related pancreatic carcinogenesis. We observed that DMBA and caerulein treatment induced a chronic consumptive disease, which caused a decrease in the relative body and pancreas weights, diminishing the health status of the mice and enhancing the inflammation-related histological changes. Moreover, mid-dose and high-frequency treatment with caerulein caused prolonged inflammatory damage to the pancreas and contributed to a permissive environment for the development of PDAC. CXCL12/CXCR4, CCL2/CCR2, and several cytokines, such as interleukin (IL)-1beta, IL-6, and tumor necrosis factor (TNF) alpha were upregulated in the tumor tissue of DMBA and caerulein-induced PDAC mice. This orthotopic mouse pancreatic carcinogenesis model mimic human disease because it reproduces a spectrum of pathological changes observed in human PDAC, ranging from inflammatory lesions to pancreatic intraepithelial neoplasia. Thus, this mouse model may improve the understanding of molecular mechanisms underlying the injury-inflammation-cancer pathway in the early stages of pancreatic carcinogenesis. PMID- 25916209 TI - XPD, APE1, and MUTYH polymorphisms increase head and neck cancer risk: effect of gene-gene and gene-environment interactions. AB - In the present study, we investigated the effect of the DNA repair gene polymorphisms XPD Asp312Asn (G>A), APE1 Asp148Glu (T>G), and MUTYH Tyr165Cys (G>A) on the risk for head and neck cancer (HNC) in association with tobacco use in a population of Northeast India. The study subjects comprised of 80 HNC patients and 92 healthy controls. Genotyping was performed using amplification refractory mutation system-PCR (ARMS-PCR) for XPD Asp312Asn (G>A) and PCR using confronting two-pair primers (PCR-CTPP) for APE1 Asp148Glu (T>G) and MUTYH Tyr165Cys (G>A). The XPD Asp/Asn genotype increased the risk for HNC by 2-fold (odds ratio, OR = 2.072; 95 % CI, 1.025-4.190; p < 0.05). Interaction between APE1 Asp/Asp and XPD Asp/Asn as well as MUTYH Tyr/Tyr and XPD Asp/Asn genotypes further increased the risk by 2.9 (OR = 2.97; 95 % CI, 1.16-7.61; p < 0.05) and 2.3 (OR = 2.37; 95 % CI, 1.11-5.10; p < 0.05) folds, respectively. The risk was further increased in heavy smokers with the XPD Asp/Asn genotype and heavy tobacco chewers with XPD Asn/Asn genotype by 7.7-fold (OR = 7.749; 95 % CI, 2.53 23.70; p < 0.05) and 10-fold (OR = 10; 95 % CI, 1.26-79.13; p < 0.05), respectively. We thus conclude that the XPD Asp312Asn and APE1 Asp148Glu polymorphisms increase the risk for HNC in association with smoking and/or tobacco chewing in the population under study. PMID- 25916210 TI - Induction of cell cycle arrest, DNA damage, and apoptosis by nimbolide in human renal cell carcinoma cells. AB - Nimbolide is a tetranortriterpenoid isolated from the leaves and flowers of Azadirachta indica which has been shown to exhibit anticancer, antioxidant, anti inflammatory, and anti-invasive properties in a variety of cancer cells. However, the anti-tumor effect on human renal cell carcinoma (RCC) cells is unknown. In this study, we found that nimbolide treatment had a cytotoxic effect on 786-O and A-498 RCC cells in a dose-dependent manner. According to flow cytometric analysis, nimbolide treatment resulted in G2/M arrest in 786-O and A-498 cells accompanied with an increase in the phosphorylation status of p53, cdc2, cdc25c, and decreased expressions of cyclin A, cyclin B, cdc2, and cdc25c. Nimbolide also caused DNA damage in a dose-dependent manner as determined by comet assay and measurement of gamma-H2AX. In addition, apoptotic cells were observed in an Annexin V-FITC/propidium iodide double-stained assay. The activities of caspase 3, -9, and poly ADP-ribose polymerase (PARP) were increased, and the expression of pro-caspase-8 was decreased in nimbolide-treated 786-O and A-498 cells. Western blot analysis revealed that the levels of intrinsic-related apoptotic proteins Bax and extrinsic-related proteins (DR5, CHOP) were significantly increased in nimbolide-treated 786-O and A-498 cells. In addition, the expressions of Bcl-2 and Mcl-1 were decreased in 786-O and A-498 cells after nimbolide treatment. We conclude that nimbolide can inhibit the growth of human RCC cells by inducing G2/M phase arrest by modulating cell cycle-related proteins and cell apoptosis by regulating intrinsic and extrinsic caspase signaling pathways. Nimbolide may be a promising therapeutic strategy for the treatment of RCC. PMID- 25916212 TI - The impact of expired and empty quick-relief asthma inhalers: The Asthma and Allergy Foundation of America's Asthma Inhaler Design Survey. AB - BACKGROUND: Despite the available treatments, asthma remains a serious illness, with a considerable socioeconomic burden associated with a high number of unscheduled visits to the emergency department (ED). Poor adherence and inadequate inhaler technique are contributing factors to poor asthma management and control. OBJECTIVE: The Asthma Inhaler Design Survey assessed the behaviors, attitudes, needs, and preferences of patients with asthma and their caregivers with regard to quick-relief inhaler usage and device design. METHODS: The Asthma and Allergy Foundation of America invited 19,157 adult patients and parents of children with asthma to take part in an online survey that focused on previous asthma diagnosis, symptom severity, and quick-relief and controller medication use. Opinions were also collected. RESULTS: Data from 590 respondents (366 adults; 224 children) were included in the final analysis. Relief inhalers were needed and found to be past the expiration date by 284 of 561 (50.6%) and relief inhalers were found to be empty by 270 of 560 (48.2%). Of the empty inhaler group, 28 of 270 (10.4%) had to visit the ED for treatment, 18 of 270 (6.7%) missed work or school for an unscheduled physician office visit, and 54 of 270 (20%) went without treatment. Although 78.5% indicated that they had at least two quick-relief inhalers nearby, these were not always easily accessible. Few respondents (194/578 [33.6%]) indicated that they and/or their child were very confident that they were using their inhaler properly, even though the majority had received some instruction. When asked what they would do to improve satisfaction with their quick-relief inhalers, 173 of 558 (31%) responded that they would add a dose counter. CONCLUSION: Unnecessary health care utilization and avoidable loss of time at work or school were associated with the lack of full availability of properly functioning quick-relief inhalers when needed. Adding a dose counter was the most frequently cited response for improving satisfaction with quick-relief inhalers. Confidence about proper inhaler use was low, despite previous instruction. PMID- 25916211 TI - Serum metabolomic analysis of human upper urinary tract urothelial carcinoma. AB - To find potential serum biomarkers for upper tract urothelial carcinomas (UTUCs) via (1)H nuclear magnetic resonance ((1)H NMR)-based metabolomic analysis. Serum specimens collected from 34 healthy individuals and 39 patients with UTUCs were subjected to (1)H NMR-based metabolomic analysis. Principal component and orthogonal partial least squares discriminant analyses were used to analyse the data. Compared with serum samples from healthy subjects, samples from UTUC patients showed elevated levels of lactate and creatinine as well as decreased levels of glucose, glutamine and taurine. Serum low-density lipoprotein/very low density lipoprotein, valine and glycoprotein levels showed decreasing trends whereas serum polyunsaturated fatty acids and 3,7-dimethyluric acid level presented increasing trends in UTUC patients. (1)H NMR-based metabolomic analysis of serum enhances the current understanding of the mechanisms involved in UTUC development. The present analysis may be a valuable tool for UTUC detection. PMID- 25916214 TI - Glycemic variability in patients with Wolfram syndrome is lower than in type 1 diabetes. AB - AIMS: Wolfram syndrome (WFS) is diagnosed as coexistence of diabetes mellitus and optic atrophy, where pancreatic beta cell destruction is associated with neurodegeneration. Typically, WFS necessitates insulin treatment similar to type 1 diabetes (T1D), but the mechanism of beta cell mass reduction leading to hyperglycemia is different. METHODS: The aim of the study was to assess glycemic variability using the continuous glucose monitoring (CGM) system in seven pediatric patients with genetically confirmed WFS and compare the results with data obtained from 21 propensity score-matched patients with T1D. The "GlyCulator" application was used for the calculation of glycemic variability indices. RESULTS: CGM recordings showed similarities in glycemic variability among WFS patients, but differing from those of the T1D group. Coefficient of variation (%CV), CONGA4h, and GONGA6h were significantly (p < 0.05) lower in WFS patients (28.08 +/- 7.37, 54.96 +/- 11.92, and 55.99 +/- 10.58) than in T1D patients (37.87 +/- 14.24, 74.12 +/- 28.74, p = 0.02, and 80.26 +/- 35.05, respectively). In WFS patients, the percentage of values above 126 mg/dL was 69.79 (52.08-77.43), whereas in patients with T1D, the percentage was significantly lower-47.22 (35.07-62.85, p = 0.018). Curiously, a tendency toward a lower percentage of measurements below 70 mg/dL was noted in the WFS group [0 (0-7.29)] in comparison with the T1D group [6.25 (0-18.06), p = 0.122]. WFS patients had a significantly higher C-peptide level (0.31 +/- 0.2 ng/mL) than T1D patients (0.04 +/- 0.04 ng/mL; p = 0.006). CONCLUSIONS: Patients with WFS show smaller glycemic variability than individuals with T1D, and this may be associated with persistent residual insulin secretion. PMID- 25916213 TI - Association of diabetes and diabetes treatment with incidence of breast cancer. AB - AIMS: The aim of this study was to evaluate the association of diabetes and diabetes treatment with risk of postmenopausal breast cancer. METHODS: Histologically confirmed incident cases of postmenopausal breast (N = 916) cancer were recruited from 23 Spanish public hospitals. Population-based controls (N = 1094) were randomly selected from primary care center lists within the catchment areas of the participant hospitals. ORs (95 % CI) were estimated using mixed effects logistic regression models, using the recruitment center as a random effect term. Breast tumors were classified into hormone receptor positive (ER+ or PR+), HER2+ and triple negative (TN). RESULTS: Diabetes was not associated with the overall risk of breast cancer (OR 1.09; 95 % CI 0.82-1.45), and it was only linked to the risk of developing TN tumors: Among 91 women with TN tumors, 18.7 % were diabetic, while the corresponding figure among controls was 9.9 % (OR 2.25; 95 % CI 1.22-4.15). Regarding treatment, results showed that insulin use was more prevalent among diabetic cases (2.5 %) as compared to diabetic controls (0.7 %); OR 2.98; 95 % CI 1.26-7.01. They also showed that, among diabetics, the risk of developing HR+/HER2- tumors decreased with longer metformin use (ORper year 0.89; 95 % CI 0.81-0.99; based on 24 cases and 43 controls). CONCLUSION: This study reinforces the need to correctly classify breast cancers when studying their association with diabetes. Given the low survival rates in women diagnosed with TN breast tumors and the potential impact of diabetes control on breast cancer prevention, more studies are needed to better characterize this association. PMID- 25916215 TI - Use of capillary blood glucose for screening for gestational diabetes mellitus in resource-constrained settings. AB - AIMS: The aim of the study was to evaluate usefulness of capillary blood glucose (CBG) for diagnosis of gestational diabetes mellitus (GDM) in resource constrained settings where venous plasma glucose (VPG) estimations may be impossible. METHODS: Consecutive pregnant women (n = 1031) attending antenatal clinics in southern India underwent 75-g oral glucose tolerance test (OGTT). Fasting, 1- and 2-h VPG (AU2700 Beckman, Fullerton, CA) and CBG (One Touch Ultra II, LifeScan) were simultaneously measured. Sensitivity and specificity were estimated for different CBG cut points using the International Association of Diabetes in Pregnancy Study Groups (IADPSG) criteria for the diagnosis of GDM as gold standard. Bland-Altman plots were drawn to look at the agreement between CBG and VPG. Correlation and regression equation analysis were also derived for CBG values. RESULTS: Pearson's correlation between VPG and CBG for fasting was r = 0.433 [intraclass correlation coefficient (ICC) = 0.596, p < 0.001], for 1H, it was r = 0.653 (ICC = 0.776, p < 0.001), and for 2H, r = 0.784 (ICC = 0.834, p < 0.001). Comparing a single CBG 2-h cut point of 140 mg/dl (7.8 mmol/l) with the IADPSG criteria, the sensitivity and specificity were 62.3 and 80.7 %, respectively. If CBG cut points of 120 mg/dl (6.6 mmol/l) or 110 mg/dl (6.1 mmol/l) were used, the sensitivity improves to 78.3 and 92.5 %, respectively. CONCLUSIONS: In settings where VPG estimations are not possible, CBG can be used as an initial screening test for GDM, using lower 2H CBG cut points to maximize the sensitivity. Those who screen positive can be referred to higher centers for definitive testing, using VPG. PMID- 25916217 TI - Diagnostic role of 18F-fluorodeoxyglucose positron-emission tomography/computed tomography in restaging renal cell carcinoma. AB - BACKGROUND: The aim of this paper was to review the diagnostic contributions of 18FDG-PET/CT to the restaging of renal cell carcinoma (RCC) retrospectively. METHODS: The current study included 132 patients, who were operated on between July 2007 and April 2013, for renal cell carcinoma (RCC) and received 18FDG PET/CT scans for restaging purposes. Ninety (68.2%) of the patients were male and 42 (31.8%) were female, with a mean age of 60.7 years and standard deviation +/ 11.9 (range min: 28, max: 86). The patients were required to fast for 6 hours prior to scanning, and whole-body PET scanning from the skull base to the upper thighs was performed approximately 1 hour after the intravenous injection of 555 MBq of F-18 FDG. Whole body CT scanning was performed in the cranio-caudal direction. FDG-PET images were reconstructed using CT data for attenuation correction. Suspicious recurrent or metastatic lesions were confirmed by histopathology or clinical follow-up. RESULTS: Sensitivity, specificity, positive predictive value, negative predictive value, and accuracy of 18FDG-PET/CT were 93.8%, 88.2%, 92.6%, 88.2%, and 91.6%, respectively. CONCLUSIONS: 18FDG-PET/CT can detect local and distant metastases with high precision in the restaging of RCC. It can play an important role in the postoperative decision-making for treatment choices, in following treatment response, and can affect decision making. PMID- 25916218 TI - First and second transurethral resections in intermediate-high risk bladder cancer: impact of the surgeon's volume on the recurrence and progression of primary bladder cancer. AB - BACKGROUND: We evaluated the impact of surgeon's volume on recurrence and progression in patients with newly diagnosed transitional cell carcinoma of the bladder after first transurethral resection (TUR) and second-TUR. METHODS: Between March 2005 and December 2012, 209 patients with intermediate-high risk primary bladder cancer who received second TUR within 2 to 6 weeks following the initial resection were prospectively included in a database and retrospectively analyzed. Surgeons were stratified into high-volume (>100 TUR) and low-volume (<100 TUR). Tumor recurrence and progression were analyzed respect to first and second-TUR and surgeon-volume. RESULTS: Of the 209 patients who underwent second TUR, 57 (27.2%) had macroscopic tumors before resection, which correlated to tumors multiplicity. Stage and surgeon category were independent predictors of tumor recurrence, with a 5-year recurrence-free survival rate of 52.7% and 23.1% for high and low-volume surgeon, respectively (P<0.001). Stage and surgeon category at first and second-TUR were independent predictor of tumor progression, with a 5-year progression-free survival rate of 83.8% and 48.0% for high and low volume surgeon, respectively (P<0.001). CONCLUSIONS: As for other major urological procedures, patients undergoing TUR performed by high volume surgeon may have better outcomes than patients operated by low-volume providers. PMID- 25916219 TI - Responses to colour and host odour cues in three cereal pest species, in the context of ecology and control. AB - Many insects show a greater attraction to multimodal cues, e.g. odour and colour combined, than to either cue alone. Despite the potential to apply the knowledge to improve control strategies, studies of multiple stimuli have not been undertaken for stored product pest insects. We tested orientation towards a food odour (crushed white maize) in combination with a colour cue (coloured paper with different surface spectral reflectance properties) in three storage pest beetle species, using motion tracking to monitor their behaviour. While the maize weevil, Sitophilus zeamais (Motsch.), showed attraction to both odour and colour stimuli, particularly to both cues in combination, this was not observed in the bostrichid pests Rhyzopertha dominica (F.) (lesser grain borer) or Prostephanus truncatus (Horn) (larger grain borer). The yellow stimulus was particularly attractive to S. zeamais, and control experiments showed that this was neither a result of the insects moving towards darker-coloured areas of the arena, nor their being repelled by optical brighteners in white paper. Visual stimuli may play a role in location of host material by S. zeamais, and can be used to inform trap design for the control or monitoring of maize weevils. The lack of visual responses by the two grain borers is likely to relate to their different host seeking behaviours and ecological background, which should be taken into account when devising control methods. PMID- 25916220 TI - A randomized, placebo-controlled trial of lubiprostone for opioid-induced constipation in chronic noncancer pain. AB - OBJECTIVES: This multicenter, phase 3 trial evaluated oral lubiprostone for constipation associated with non-methadone opioids in patients with chronic noncancer-related pain. METHODS: Adults with opioid-induced constipation (OIC; <3 spontaneous bowel movements [SBMs] per week) were randomized 1:1 to double-blind lubiprostone 24 MUg or placebo twice daily for 12 weeks. The primary end point was the overall SBM response rate. Responders had at least moderate response (>=1 SBM improvement over baseline frequency) in all treatment weeks with available observed data, as well as full response (>=3 SBMs per week) for at least 9 of the 12 treatment weeks. RESULTS: In total, 431 patients were randomized; 212 each received lubiprostone and placebo, and 7 were not treated. Overall, the SBM response rate was significantly higher for patients treated with lubiprostone vs. placebo (27.1 vs. 18.9%, respectively; P=0.030). Overall mean change from baseline in SBM frequency was significantly greater with lubiprostone vs. placebo (3.2 vs. 2.4, respectively; P=0.001). The median time to first SBM was significantly shorter with lubiprostone vs. placebo (23.5 vs. 37.7 h, respectively; P=0.004). Compared with placebo, the patients treated with lubiprostone exhibited significant improvements in straining (P=0.004), stool consistency (P<0.001), and constipation severity (P=0.010). No significant differences were observed in quality-of-life measures or the use of rescue medication; however, the percentage of patients who used rescue medication was consistently lower in the lubiprostone group than in the placebo group at months 1 (34.9 vs. 37.7%), 2 (23.4 vs. 26.6%), and 3 (20.5 vs. 22.0%). Adverse events (AEs) >5% were diarrhea, nausea, vomiting, and abdominal pain (lubiprostone: 11.3, 9.9, 4.2, and 7.1%, respectively; placebo, 3.8, 4.7, 5.2, and 0%, respectively). None of the serious AEs (lubiprostone, 3.3%; placebo, 2.8%) were related to lubiprostone. CONCLUSIONS: Lubiprostone significantly improved symptoms of OIC and was well tolerated in patients with chronic noncancer pain. PMID- 25916221 TI - Increased risk of microscopic colitis with use of proton pump inhibitors and non steroidal anti-inflammatory drugs. AB - OBJECTIVES: Microscopic colitis (MC) is characterized by chronic watery diarrhea. Recently, several drugs were reported to increase the risk of MC. However, studies lacked a clear exposure definition, did not address duration relationships, and did not take important biases into account. We estimated the risk of MC during drug use. METHODS: This is a population-based nested case control study using a Dutch primary care database (1999-2013). Incident MC cases (aged >=18 years) were matched to community-based and colonoscopy-negative controls on age, sex, and primary care practice. Drug use was assessed within 1 and 2 years before the index date. Adjusted odds ratios (OR) were calculated by conditional logistic regression. RESULTS: From the source population of 1,458,410 subjects, 218 cases were matched to 15,045 community controls and 475 colonoscopy negative controls. Current use (<=3 months) of proton pump inhibitors (PPIs), nonsteroidal anti-inflammatory drugs (NSAIDs), selective serotonin reuptake inhibitors, low-dose aspirin, angiotensin-converting enzyme (ACE) inhibitors and beta-blockers significantly increased the risk of MC compared with never use in community controls. Adjusted ORs ranged from 2.5 (95% confidence interval (CI): 1.5-4.2) for ACE inhibitors to 7.3 (95% CI: 4.5-12.1) for PPIs in the year prior to the index date. After accounting for diagnostic delay, only use of NSAIDs, PPIs, low-dose aspirin, and ACE inhibitors increased the risk of MC. Compared with colonoscopy controls, only use of PPIs (OR-adjusted 10.6; 1.8-64.2) and NSAIDs (OR-adjusted 5.6; 1.2-27.0) increased the risk of MC. CONCLUSIONS: NSAIDs and PPIs are associated with an increased risk of MC. The association of MC with use of the other drugs is probably explained by worsening of diarrhea/symptoms rather than increasing the risk of MC itself. PMID- 25916222 TI - Low Prevalence of Colon Polyps in Chronic Inflammatory Conditions of the Colon. AB - OBJECTIVES: Previous studies have reported a low prevalence of colon polyps in patients with microscopic colitis. The aim of the study was to test whether such inverse associations applied to other inflammatory diseases of the colon. METHODS: In a case-control study among 130,204 patients undergoing colonoscopy for the work-up of diarrhea, we compared the prevalence of colon polyps in a case population of patients with inflammatory bowel disease (IBD), microscopic colitis, histologic signs of active colitis, diverticulitis, or ischemic colitis, and in a control population with normal colon mucosa. Case and control subjects were compared using odds ratios and their 95% confidence intervals adjusted for age and sex. RESULTS: In 11,176 patients with microscopic colitis, the prevalence of hyperplastic polyps, serrated adenomas, and tubular adenomas were all reduced: odds ratios=0.46 (95% confidence intervals=0.43-0.49), 0.24 (0.19-0.30), and 0.35 (0.33-0.38), respectively. In 4,435 patients with IBD, the corresponding values were: 0.18 (0.15-0.21), 0.24 (0.16-0.35), and 0.18 (0.15-0.21), respectively. In 6,501 patients with histologically active colitis, the corresponding values were: 0.58 (0.53-0.63), 0.57 (0.46-0.70), and 0.63 (0.58-0.68), respectively. No such consistent reduction in polyp prevalence was found in patients with diverticulitis or ischemic colitis. CONCLUSIONS: Chronic inflammatory conditions of the colon are associated with a decreased prevalence of colon polyps. PMID- 25916223 TI - Serum Wisteria floribunda Agglutinin-Positive Mac-2-Binding Protein Level Predicts Liver Fibrosis and Prognosis in Primary Biliary Cirrhosis. AB - OBJECTIVES: Noninvasive markers of liver fibrosis in patients with primary biliary cirrhosis (PBC) are needed for predicting disease progression. As the Wisteria floribunda agglutinin-positive Mac-2-binding protein (WFA(+)-M2BP) was recently established as a liver fibrosis glycobiomarker in chronic hepatitis C, we assessed its efficacy in evaluating liver fibrosis stage and disease progression in PBC. METHODS: A total of 137 patients with PBC who underwent liver biopsy and serological tests for WFA(+)-M2BP were enrolled. All patients were treated with ursodeoxycholic acid. Clinical data were compared with those for other noninvasive markers (aspartate aminotransferase-to-platelet ratio, FIB-4 index, aspartate aminotransferase/alanine aminotransferase ratio, Forn's index, and Mayo score) for estimating liver fibrosis using receiver operating characteristic analysis. The association between WFA(+)-M2BP and clinical outcome (liver decompensation, liver transplantation, or death) was evaluated using the Cox proportional hazards model with stepwise method. RESULTS: WFA(+)-M2BP was independently associated with liver fibrosis stage as determined by liver biopsy. The cutoff values of WFA(+)-M2BP for fibrosis stages >=F1, >=F2, >=F3, and F4 were 0.7, 1.0, 1.4, and 2.0, respectively. The area under the receiver operating characteristic curve values for significant fibrosis, severe fibrosis, and cirrhosis were 0.979, 0.933, and 0.965, respectively. WFA(+)-M2BP was significantly superior to the other indices for the determination of significant and severe fibrosis stages. Furthermore, the WFA(+)-M2BP level at enrollment was strongly and independently associated with clinical outcome (hazard ratio 18.59, P=0.021). CONCLUSIONS: Baseline measurements of WFA(+)-M2BP represent a simple and reliable noninvasive surrogate marker of liver fibrosis and prognosis in patients with PBC. PMID- 25916224 TI - Consecutive Monitoring of Fecal Calprotectin and Lactoferrin for the Early Diagnosis and Prediction of Pouchitis after Restorative Proctocolectomy for Ulcerative Colitis. AB - OBJECTIVES: This prospective study was conducted to evaluate the significance of consecutive monitoring of fecal calprotectin and lactoferrin for the early diagnosis and prediction of pouchitis after restorative proctocolectomy for ulcerative colitis (UC). METHODS: Sixty patients who had ileostomy closure following total proctocolectomy and ileal pouch-anal anastomosis for UC were included. Stool samples were collected for the measurement of calprotectin and lactoferrin every 2 months up to 12 months after the ileostomy closure. When patients had symptoms suggestive of pouchitis, endoscopic examination was immediately undertaken. All asymptomatic patients underwent endoscopy at 12 months. Pouchitis was defined as a pouchitis disease activity index score of >=7. RESULTS: During the 12 months, 10 patients (17%) developed pouchitis. In patients with pouchitis, fecal calprotectin and lactoferrin levels were elevated already 2 months before the diagnosis of pouchitis. In contrast, these fecal biomarkers remained at low levels, and they did not change significantly in patients without pouchitis. A cutoff value of 56 MUg/g for calprotectin had a sensitivity of 100% and a specificity of 84% to predict pouchitis, whereas a cutoff value of 50 MUg/g for lactoferrin had a sensitivity of 90% and a specificity of 86%. At the time of endoscopy, the median calprotectin and lactoferrin levels were significantly higher in patients with pouchitis than those without pouchitis. CONCLUSIONS: Elevated fecal calprotectin and lactoferrin levels appeared to be significant predictors of pouchitis after restorative proctocolectomy for UC. Consecutive monitoring of these fecal biomarkers is useful for the early diagnosis of pouchitis. PMID- 25916225 TI - Lack of utility of symptoms and signs at first presentation as predictors of inflammatory bowel disease in secondary care. AB - OBJECTIVES: There are few data concerning the utility of symptoms and signs at first presentation in predicting a diagnosis of ulcerative colitis (UC) or Crohn's disease (CD). We conducted a study to examine this issue in secondary care. METHODS: We collected complete symptom, colonoscopy, and histology data prospectively from 1,981 consecutive adult patients with lower gastrointestinal symptoms at two hospitals in Hamilton, Ontario. Assessors were blinded to symptom status. The reference standard used to define the presence of UC or CD was according to accepted histological criteria. Patients without UC or CD served as controls. Sensitivity, specificity, and positive and negative likelihood ratios (LRs) were calculated for individual items from the clinical history, as well as combinations of these. RESULTS: In identifying 302 patients with inflammatory bowel diseases (IBD), positive LRs for individual items ranged from 1.18 (incomplete emptying) to 2.30 (passage of stools more than four times per day at least most of the time) and negative LRs from 0.70 (bloody stools) to 0.96 (incomplete emptying). Combinations of items had a high specificity, but at the expense of sensitivity. Items that were independent predictors of IBD after logistic regression analysis were family history of IBD, younger age, passage of stools more than four times per day >=75% of the time, urgency most of the time, and anemia. CONCLUSIONS: Individual items from the clinical history are not helpful in predicting a diagnosis of UC or CD. However, this may be because some items lacked sufficient detail. Combinations of symptoms and computer models had a high specificity, but overall were only modestly useful diagnostically. Future studies should evaluate biological markers in combination with symptoms to improve accuracy. PMID- 25916226 TI - Beliefs about GI medications and adherence to pharmacotherapy in functional GI disorder outpatients. AB - OBJECTIVES: Pharmacotherapy is a mainstay in functional gastrointestinal (GI) disorder (FGID) management, but little is known about patient attitudes toward medication regimens. Understanding patient concerns and adherence to pharmacotherapy is particularly important for off-label medication use (e.g., antidepressants) in FGID. METHODS: Consecutive tertiary GI outpatients completed the Beliefs About Medications questionnaire (BMQ). Subjects were categorized as FGID and structural GI disease (SGID) using clinician diagnoses and Rome criteria; GI-specific medications and doses were recorded, and adherence to medication regimens was determined by patient self-report. BMQ domains (overuse, harm, necessity, and concern) were compared between FGID and SGID, with an interest in how these beliefs affected medication adherence. Psychiatric measures (depression, anxiety, and somatization) were assessed to gauge their influence on medication beliefs. RESULTS: A total of 536 subjects (mean age 54.7+/-0.7 years, range 22-100 years; n=406, 75.7% female) were enrolled over a 5.5-year interval: 341 (63.6%) with FGID (IBS, 64.8%; functional dyspepsia, 51.0%, >=2 FGIDs, 38.7%) and 142 (26.5%) with SGID (IBD, 28.9%; GERD, 23.2%). PPIs (n=231, 47.8%), tricyclic antidepressants (TCAs) (n=167, 34.6%), and anxiolytics (n=122, 25.3%) were common medications prescribed. FGID and SGID were similar across all BMQ domains (P>0.05 for overuse, harm, necessity, and concern). SGID subjects had higher necessity-concern framework (NCF) scores compared with FGID subjects (P=0.043). FGID medication adherence correlated negatively with concerns about medication harm (r=-0.24, P<0.001) and overuse (r=-0.15, P=0.001), whereas higher NCF differences predicted medication compliance (P=0.006). Medication concern and overuse scores correlated with psychiatric comorbidity among FGID subjects (P<0.03 for each). FGID patients prescribed TCAs (n=142, 41.6%) expressed a greater medication necessity (17.4+/-0.4 vs. 16.2+/-0.4, P=0.024) and found their GI regimen to be more helpful (P=0.054). FGID subjects not on TCAs expressed a greater apprehension about medication overuse (10.7+/-0.3 vs. 9.7+/-0.2, P=0.002) on the BMQ. CONCLUSIONS: FGID subjects report medication necessity and concern scores comparable to patients with SGID but have negative perceptions about medications, particularly in the presence of psychiatric comorbidity; these factors may affect treatment adherence and willingness to initiate neuromodulator regimens. PMID- 25916228 TI - Data sources for identifying low-income, uninsured populations: application to public health-National Breast and Cervical Cancer Early Detection Program. AB - OBJECTIVE: To provide information on the sources of data for estimating low income, uninsured populations. To recommend uses of these data sources. To demonstrate the application of these data sources in the public health field, using the National Breast and Cervical Cancer Early Detection Program as an example. METHODS: We describe U.S. Census Bureau data sources for identifying low income, uninsured populations using two population surveys: the Annual Social and Economic Supplement to the Current Population Survey (CPS ASEC) and the American Community Survey (ACS), and using one model-based estimation program, the Small Area Health Insurance Estimates (SAHIE). We provide recommendations for use of these data sources, and we use CPS ASEC and SAHIE to estimate the percent of U.S. women eligible for the National Breast and Cervical Cancer Early Detection Program (NBCCEDP). RESULTS: CPS ASEC, ACS, and SAHIE are produced by the U.S. Census Bureau, and they are reliable sources for estimates of the low-income, uninsured populations in the USA. Key characteristics of these three data sources were presented to highlight the strengths of each to meet the needs of various programs at national and local levels. Recommendations are made on the use of the data sources. Based on these three data sources, estimates of NBCCEDP eligibility showed substantial variation over time at the national and state levels, and across states and counties. CONCLUSIONS: Publicly funded programs that are directed toward low-income, uninsured individuals require information on their eligible populations to make decisions about program policy and resource allocation, and to monitor and evaluate the effectiveness of the programs. The U.S. Census Bureau produces three data sources (CPS ASEC, ACS, and SAHIE) for these estimates. The percent of U.S. women eligible for NBCCEDP varies over time and across states and counties. The data sources for these estimates are changing in order to measure key dimensions of the Affordable Care Act (ACA) and can provide helpful information for assessing the legislation's impact. PMID- 25916227 TI - Inter-Observer Agreement among Pathologists Using Wide-Area Transepithelial Sampling With Computer-Assisted Analysis in Patients With Barrett's Esophagus. AB - OBJECTIVES: The histopathological diagnosis of Barrett's esophagus (BE) associated dysplasia has poor inter-observer agreement. The wide-area transepithelial sampling (WATS) procedure uses a minimally invasive brush biopsy technique for acquiring wide-area sampling of BE tissue followed by computer assisted analysis. In this study, our aim was to assess inter-observer agreement among pathologists in the diagnosis of Barrett's-associated dysplasia using the WATS computer-assisted analysis technique. METHODS: WATS slides with varying degrees of BE dysplasia were randomly selected and distributed to four pathologists. Each pathologist graded the slides as nondysplastic, low-grade dysplasia (LGD), or high-grade dysplasia/esophageal adenocarcinoma (HGD/EAC) and completed a standardized case report form (CRF) for each slide. RESULTS: In all, 149 BE slides were evaluated in a blinded manner by 4 pathologists. The slides included the following: no dysplasia (n=109), LGD, and HGD/EAC (n=40). The overall mean kappa value for all 3 diagnoses for the 4 observers was calculated at 0.86 (95% confidence interval (CI) 0.75-0.97). The kappa values (95% CI) for HGD/EAC, IND/LGD, and no dysplasia were 0.95 (0.88-0.99), 0.74 (0.61-0.85), and 0.88 (0.81-0.94), respectively. CONCLUSIONS: The diagnosis of BE and associated dysplasia using the WATS technique has very high inter-observer agreement. This appears to be significantly higher as compared with previously published data using standard histopathology. PMID- 25916229 TI - From producer to consumer: greenhouse tomato quality as affected by variety, maturity stage at harvest, transport conditions, and supermarket storage. AB - Possible causes for differences in quality traits at the time of buying were studied in two widely different red tomato types. Three maturity stages were harvested from commercial greenhouses and transferred immediately to controlled environments simulating different storage, transport, and supermarket conditions. Results show significant differences in development of color, fruit firmness, contents of soluble solids (SSC), titratable acids (TTA), phenolics, and carotenoids from harvest to sale, as related to postharvest conditions. Fruit firmness, SSC, and TTA of vine-ripened red cherry tomatoes was 30, 55 and 11% higher than for those harvested at breakers and ripened to red. Temperature, light, UVC radiation, or ethylene during 4 days transport affected tomato quality traits, and differences persisted during 3 weeks of supermarket storage. Ethylene exposure gave a 3.7-fold increase in lycopene content in cherry tomatoes, whereas UVC hormesis revealed a 6-fold increase compared with the control. Results can be used to update recommendations concerning optimal handling. PMID- 25916230 TI - Contribution to the benchmark for ternary mixtures: Transient analysis in microgravity conditions. AB - We present a transient experimental analysis of the DCMIX1 project conducted onboard the International Space Station for a ternary tetrahydronaphtalene, isobutylbenzene, n-dodecane mixture. Raw images taken in microgravity environment using the SODI (Selectable Optical Diagnostic) apparatus which is equipped with two wavelength diagnostic were processed and the results were analyzed in this work. We measured the concentration profile of the mixture containing 80% THN, 10% IBB and 10% nC12 during the entire experiment using an advanced image processing technique and accordingly we determined the Soret coefficients using an advanced curve-fitting and post-processing technique. It must be noted that the experiment has been repeated five times to ensure the repeatability of the experiment. PMID- 25916231 TI - Contribution to the benchmark for ternary mixtures: Measurement of diffusion and Soret coefficients of ternary system tetrahydronaphtalene-isobutylbenzene-n dodecane with mass fractions 80-10-10 at 25 degrees C. AB - This paper provides the molecular diffusion and Soret coefficients of the ternary system 1,2,3,4-tetrahydronaphtalene, isobutylbenzene, n -dodecane system at mass fractions 0.8-0.1-0.1 and temperature 25 ( degrees )C for implementation into the benchmark presented in this topical issue. The Soret coefficients are determined by digital interferometry using the data of DSC-DCMIX microgravity experiment. The method used takes into account the influence of the thermal field on the Soret separations and the selection of the image processing techniques results in reproducible Soret coefficients.The diffusion coefficients are obtained by the Open Ended Capillary technique The fitting of the data collected through a set of two complementary experimental runs allows retrieving the four Fickian diffusion coefficients. PMID- 25916232 TI - Contribution to the benchmark for ternary mixtures: Measurement of the Soret, diffusion and thermodiffusion coefficients in the ternary mixture THN/IBB/nC12 with 0.8/0.1/0.1 mass fractions in ground and orbital laboratories. AB - We have determined the Soret (ST), diffusion (D, and thermodiffusion (DT) coefficients in a ternary mixture of tetralin-isobutylbenzene-n-dodecane with a composition of 0.80/0.10/0.10 by mass fraction at a temperature of 298K. The Soret coefficients were measured in the microgravity experiment DCMIX1 and on the ground by optical digital interferometry (ODI) using two lasers with different wavelengths. The values of the Soret coefficients were determined from the stationary separation of the components using two- and six-parameter fits. The diffusion coefficients were independently measured using the Taylor Dispersion Technique in the ground laboratory, and the thermodiffusion coefficients were derived from known ST and matrix D. The processing of the data from the DCMIX experiment conducted on the International Space Station is discussed in detail. The multi-user design of the on-board instrument causes perturbations in the component separation. Several recommendations are suggested for improving the quality of the microgravity results. For example, we demonstrated that the tomography reconstruction of the 3-D concentration field allows to restore the underestimated component separation resulting from the spatial non-linearity of the temperature field. Furthermore, to avoid errors in component separation due to mass exchange between the working liquid volume and the expansion volume at the top of the cell, we suggest considering the evolution of the separation only in the lower half of the cell. The results of this study displayed reasonable quantitative agreement between the microgravity and ground experiments. PMID- 25916233 TI - Benchmark values for the Soret, thermodiffusion and molecular diffusion coefficients of the ternary mixture tetralin+isobutylbenzene+n-dodecane with 0.8 0.1-0.1 mass fraction. AB - With the aim of providing reliable benchmark values, we have measured the Soret, thermodiffusion and molecular diffusion coefficients for the ternary mixture formed by 1,2,3,4-tetrahydronaphthalene, isobutylbenzene and n-dodecane for a mass fraction of 0.8-0.1-0.1 and at a temperature of 25 degrees C. The experimental techniques used by the six participating laboratories are Optical Digital Interferometry, Taylor Dispersion technique, Open Ended Capillary, Optical Beam Deflection, Thermogravitational technique and Sliding Symmetric Tubes technique in ground conditions and Selectable Optical Diagnostic Instrument (SODI) in microgravity conditions. The measurements obtained in the SODI installation have been analyzed independently by four laboratories. Benchmark values are proposed for the thermodiffusion and Soret coefficients and for the eigenvalues of the diffusion matrix in ground conditions, and for Soret coefficients in microgravity conditions. PMID- 25916234 TI - Contribution to the benchmark for ternary mixtures: Determination of Soret coefficients by the thermogravitational and the sliding symmetric tubes techniques. AB - This work is part of an international project for the research on the transport properties in ternary mixtures. Six different teams have analysed the same mixture by independent techniques in order to compare the results and validate the techniques. This work is the contribution of the team of Mondragon Unibertsitatea for ground conditions measurements. This team has measured the thermodiffusion coefficients by the thermogravitational techniques and the molecular diffusion coefficients by the Sliding Symmetric Tubes technique. The Soret coefficients have been determined by the combination of the thermodiffusion and molecular diffusion coefficients. The mixture chosen for the study is the one formed by 1,2,3,4-tetrahydronaphtalene, isobutylbenzene and n-dodecane at mass fraction of 80% of THN, 10% of IBB and 10% of n C12, and at 25 degrees C. The good agreement between the results of the different teams shows the validity of the techniques used in this work. PMID- 25916235 TI - Contribution to the benchmark for ternary mixtures: Measurement of diffusion and Soret coefficients in 1,2,3,4-tetrahydronaphthalene, isobutylbenzene, and dodecane onboard the ISS. AB - The paper is devoted to processing the data of DCMIX 1 space experiment. In this experiment, the Optical digital interferometry was used to measure the diffusion and Soret coefficients in the ternary mixture of 1,2,3,4-tetrahydronaphthalene, isobutylbenzene and n-dodecane at mass fractions of 0.8/0.1/0.1 and at 25 degrees C. The raw interferometric images were processed to obtain the temporal and spatial evolution of refractive indices for two laser beams of different wavelengths. The method for extracting the diffusion and thermal diffusion coefficients originally developed for optical beam deflection was extended to optical digital interferometry allowing for the spatial variation of refractive index along the diffusion path. The method was validated and applied to processing the data for Soret and diffusion steps in 5 experimental runs. The obtained results for the Soret coefficients and one of the eigenvalues of diffusion matrix showed acceptable agreement within each step. The second eigenvalue was not determined with sufficient accuracy. PMID- 25916236 TI - Editorial: Thermal non-equilibrium phenomena in multi-component fluids. PMID- 25916237 TI - Analysis of intact cholesteryl esters of furan fatty acids in cod liver. AB - Furan fatty acids (F-acids) are a class of natural antioxidants with a furan moiety in the acyl chain. These minor fatty acids have been reported to occur with high proportions in the cholesteryl ester fraction of fish livers. Here we present a method for the direct analysis of intact cholesteryl esters with F acids and other fatty acids in cod liver lipids. For this purpose, the cholesteryl ester fraction was isolated by solid phase extraction (SPE) and subsequently analyzed by gas chromatography with mass spectrometry (GC/MS) using a cool-on-column inlet. Pentadecanoic acid esterified with cholesterol was used as an internal standard. GC/MS spectra of F-acid cholesteryl esters featured the molecular ion along with characteristic fragment ions for both the cholesterol and the F-acid moiety. All investigated cod liver samples (n = 8) showed cholesteryl esters of F-acids and, to a lower degree, of conventional fatty acids. By means of GC/MS-SIM up to ten F-acid cholesteryl esters could be determined in the samples. The concentrations of cholesteryl esters with conventional fatty acids amounted to 78-140 mg/100 g lipids (mean 97 mg/100 g lipids), while F-acid cholesteryl esters were present at 47-270 mg/100 g lipids (mean 130 mg/100 g lipids). PMID- 25916238 TI - Fatty acid, lipid class, and phospholipid molecular species composition of the soft coral Xenia sp. (Nha Trang Bay, the South China Sea, Vietnam). AB - The soft corals of the genus Xenia are common for Indo-Pacific reef ecosystems. Lipid class, fatty acid (FA), phospho- and phosphonolipid molecular species compositions were identified for the first time in the soft coral Xenia sp. from Vietnam. Total lipids consisted predominantly of waxes, monoalkyl diacylglycerols, triacylglycerols, sterols, and polar lipids (21.4, 7.7, 14.2, 10.5, and 36.7 %, respectively). Sesquiterpene alcohol, valerenenol, was found. Acids 16:0, 18:3n-6, 20:4n-6, and 20:5n-3 dominated in total FA. The markers of zooxanthellae (18:4n-3 and 18:5n-3) and octocorals (24:5n-6 and 24:6n-3) were detected. Acids 18:5n-3, 20:4n-6, 22:4n-6, and 24:5n-6 concentrated in FA of polar lipids, whereas 14:0, 16:0, 16:1n-7, 18:2n-6, and 18:3n-6 were the major FA of neutral lipids. ChoGpl, EtnGpl, SerGpl, CAEP, PtdIns, and lyso ChoGpl constituted 39.5, 20.8, 20.5, 9.7, 4.3, and 5.3 %, respectively, of the sum of phospho- and phosphonolipids. Thirty-two molecular species of phospholipids and ceramide aminoethylphosphonate (CAEP) were determined by high resolution tandem mass spectrometry. Lyso 18:0e PakCho (4.1 %), 18:0e/20:4 PakCho (20.5 %), 18:1e/20:4 PlsEtn (18.0 %), 18:0e/24:5 PakSer (14.0 %), and 16:0 CAEP (9.6 %) were the major molecular species. EtnGpl and PtdIns mainly consisted of alkenyl acyl and diacyl forms, respectively. Alkyl acyl forms predominated in ChoGpl and SerGpl. Acid 24:5n-6 was a principal FA in SerGpl, whereas 20:4n-6 was more abundant in ChoGpl and EtnGpl. PtdIns contained various C20-24 PUFA. In the context of chemotaxonomy of corals, Xenia sp. has the lipid composition typical for soft corals and the FA profile similar to that of alcyonarians with the high level of 18:3n-6. PMID- 25916239 TI - Triacylglycerol estolides, a new class of mammalian lipids, in the paracloacal gland of the brushtail possum (Trichosurus vulpecula). AB - The paracloacal glands are the most prevalent scent glands in marsupials, and previous investigation of their secretions in the brushtail possum (Trichosurus vulpecula) has identified many odorous compounds together with large amounts of neutral lipids. We have examined the lipids by LC-MS, generating ammonium adducts of acylglycerols by electrospray ionisation. Chromatograms showed a complex mixture of coeluting acylglycerols, with m/z from about 404 to 1048. Plots of single [M + NH4](+) ions showed three groups of lipids clearly separated by retention time. MS-MS enabled triacylglycerols and diacylglycerol ethers to be identified from neutral losses and formation of diacylglycerols and other product ions. The earliest-eluting lipids were found to be triacylglycerol estolides, in which a fourth fatty acid forms an ester link with a hydroxy fatty acid attached to the glycerol chain. This is the first report of triacylglycerol estolides in animals. They form a complex mixture with the triacylglycerols and diacylglycerol ethers of lipids with short- and long-chain fatty acids with varying degrees of unsaturation. This complexity suggests a functional role, possibly in social communication. PMID- 25916240 TI - Highly Efficient Oxygen-Storage Material with Intrinsic Coke Resistance for Chemical Looping Combustion-Based CO2 Capture. AB - Chemical looping combustion (CLC) and chemical looping with oxygen uncoupling (CLOU) are emerging thermochemical CO2 capture cycles that allow the capture of CO2 with a small energy penalty. Here, the development of suitable oxygen carrier materials is a key aspect to transfer these promising concepts to practical installations. CuO is an attractive material for CLC and CLOU because of its high oxygen-storage capacity (20 wt %), fast reaction kinetics, and high equilibrium partial pressure of oxygen at typical operating temperatures (850-1000 degrees C). However, despite its promising characteristics, its low Tammann temperature requires the development of new strategies to phase-stabilize CuO-based oxygen carriers. In this work, we report a strategy based on stabilization by co precipitated ceria (CeO2-x ), which allowed us to increase the oxygen capacity, coke resistance, and redox stability of CuO-based oxygen carriers substantially. The performance of the new oxygen carriers was evaluated in detail and compared to the current state-of-the-art materials, that is, Al2 O3 -stabilized CuO with similar CuO loadings. We also demonstrate that the higher intrinsic oxygen uptake, release, and mobility in CeO2-x -stabilized CuO leads to a three times higher carbon deposition resistance compared to that of Al2 O3 -stabilized CuO. Moreover, we report a high cyclic stability without phase intermixing for CeO2-x supported CuO. This was accompanied by a lower reduction temperature compared to state-of-the-art Al2 O3 -supported CuO. As a result of its high resistance towards carbon deposition and fast oxygen uncoupling kinetics, CeO2-x -stabilized CuO is identified as a very promising material for CLC- and CLOU-based CO2 capture architectures. PMID- 25916241 TI - The perceptions of homeless people regarding their healthcare needs and experiences of receiving health care. AB - AIMS: To understand the perspective of the homeless about their healthcare encounters and how their experiences of receiving healthcare influence their health-seeking behaviour. BACKGROUND: A phenomenological study was undertaken because of the increasing levels of homelessness in the United Kingdom. Most of the current literature is American or Canadian. DESIGN: An interpretive phenomenological inquiry. METHOD: An opportunistic sample of fourteen single homeless adults was recruited from one male hostel and one non-residential day centre. Data collection was done in 2013. Semi-structured audio-recorded interviews were conducted one-to-one. Colaizzi's method for data analysis was used. FINDINGS: Three major themes were identified. Expressed Health Need, Healthcare Experiences and Attitudes to health care. Health problems are recognized by the homeless but the need for intervention is not always prioritised. Obstacles in access to health care in the UK are both perceived (attitudes towards the homeless; previous bad experience) and actual (difficulty in registering with a general practitioner, difficulty travelling to services, being forced to move to new area). Some homeless people feel that they are treated with prejudice and receive substandard care. Positive healthcare experiences were also reported. CONCLUSIONS: Positive and negative healthcare encounters can profoundly affect the homeless. RECOMMENDATIONS: Address apparent inconsistency of care; promote greater interdisciplinary communication and referrals to homeless services from prisons and hospitals; increase the availability of intermediate services; reduce obligation of homeless to move area; research experiences of homeless families. PMID- 25916242 TI - Pharmacokinetics of Carboplatin in a One-Year-Old Anuric Boy Undergoing Hemodialysis and a Review of the Literature. AB - There have been few reports of carboplatin-based chemotherapy for anuric infants. As we had a chance to treat a one-year-old anuric hepatoblastoma patient with carboplatin, we performed a pharmacokinetic analysis and examined the optimal treatment strategy. A one-year-old anuric boy under peritoneal dialysis was diagnosed with hepatoblastoma. Surgical resection was performed, and administration of carboplatin was scheduled postoperatively aiming at 5 mg.min/mL of the area under the curve from the time of dosing to the time of the last observation (AUC(0-t)). We set the initial dose at 50 mg, higher than that calculated by the Calvert formula (34 mg); the time from the end of carboplatin infusion to the initiation of hemodialysis at 2 h; and the hemodialysis duration at 24 h. The actual AUC0-t was 3.05 mg.min/mL because the elimination half-lives before and during hemodialysis were shorter than expected. The AUC(0-t) after the second dose (100 mg) and the third dose (80 mg) were 7.00 and 4.68 mg.min/mL, respectively. The Calvert formula is not suitable for hemodialysis patients because removal of platinum by hemodialysis is not taken into account. It appears that extrarenal clearance in anuric infants is different from that in adults. We obtained an optimal AUC(0-t) using a dose of 80 mg (200 mg/m(2)), setting the time from the end of carboplatin infusion to the initiation of hemodialysis at 2 h, and performing 8-h hemodialysis. Further accumulation of the pharmacokinetic data of carboplatin is necessary for anuric children. PMID- 25916243 TI - Isolated Left Atrial Mechanical Standstill after Catheter Ablation of Atrial Fibrillation. PMID- 25916244 TI - Characterization of the Supermolecular Structure of Polydatin/6-O-alpha-Maltosyl beta-cyclodextrin Inclusion Complex. AB - Polydatin is the main bioactive ingredient in many medicinal plants, such as Hu zhang (Polygonum cuspidatum), with many bioactivities. However, its poor aqueous solubility restricts its application in functional food. In this work, 6-O-alpha Maltosyl-beta-cyclodextrin (Malt-beta-CD), a new kind of beta-CD derivative was used to enhance the aqueous solubility and stability of polydatin by forming the inclusion complex. The phase solubility study showed that polydatin and Malt-beta CD could form the complex with the stoichiometric ratio of 1:1. The supermolecular structure of the polydatin/Malt-beta-CD complex was characterized by ultraviolet-visible spectroscopy (UV), Fourier transform infrared spectroscopy (FT-IR), X-ray diffractometry (XRD), thermogravimetric/differential scanning calorimetry (TG/DSC), and proton nuclear magnetic resonance ((1) H-NMR) spectroscopy. The changes of the characteristic spectral and thermal properties of polydatin suggested that polydatin could entrap inside the cavity of Malt-beta CD. Furthermore, to reasonably understand the complexation mode, the supermolecular structure of polydatin/Malt-beta-CD inclusion complex was postulated by a molecular docking method based on Autodock 4.2.3. It was clearly observed that the ring B of polydatin oriented toward the narrow rim of Malt-beta CD with ring A and glucosyl group practically exposed to the wide rim by hydrogen bonding, which was in a good agreement with the spectral data. PMID- 25916245 TI - High Prevalence of Anaplasma spp. in Small Ruminants in Morocco. AB - The prevalence of infection by Anaplasma spp. (including Anaplasma phagocytophilum) was determined using blood smear microscopy and PCR through screening of small ruminant blood samples collected from seven regions of Morocco. Co-infections of Anaplasma spp., Babesia spp, Theileria spp. and Mycoplasma spp. were investigated and risk factors for Anaplasma spp. infection assessed. A total of 422 small ruminant blood samples were randomly collected from 70 flocks. Individual animal (breed, age, tick burden and previous treatment) and flock data (GPS coordinate of farm, size of flock and livestock production system) were collected. Upon examination of blood smears, 375 blood samples (88.9%) were found to contain Anaplasma-like erythrocytic inclusion bodies. Upon screening with a large spectrum PCR targeting the Anaplasma 16S rRNA region, 303 (71%) samples were found to be positive. All 303 samples screened with the A. phagocytophilum-specific PCR, which targets the msp2 region, were found to be negative. Differences in prevalence were found to be statistically significant with regard to region, altitude, flock size, livestock production system, grazing system, presence of clinical cases and application of tick and tick-borne diseases prophylactic measures. Kappa analysis revealed a poor concordance between microscopy and PCR (k = 0.14). Agreement with PCR is improved by considering microscopy and packed cell volume (PCV) in parallel. The prevalence of double infections was found to be 1.7, 2.5 and 24% for Anaplasma Babesia, Anaplasma-Mycoplasma and Anaplasma-Theileria, respectively. Co-infection with three or more haemoparasites was found in 1.6% of animals examined. In conclusion, we demonstrate the high burden of anaplasmosis in small ruminants in Morocco and the high prevalence of co-infections of tick-borne diseases. There is an urgent need to improve the control of this neglected group of diseases. PMID- 25916246 TI - Effect of oral administration of probiotics on growth performance, apparent nutrient digestibility and stress-related indicators in Holstein calves. AB - This study aimed to investigate the effect of dietary supplementation with Lactobacillus plantarum and Bacillus subtilis on growth performance, apparent nutrient digestibility and stress-related indicators in dairy calves. Twenty-four neonatal Holstein calves were randomly allocated to three treatments: a basal diet with no supplementation (control), the basal diet supplemented with 1.7 * 10(10) CFU per head per day (CFU/h.d) of L. plantarum GF103 (LB group) or the basal diet supplemented with a mixture of L. plantarum GF103 (1.7 * 10(10) CFU/h.d) and B. subtilis B27 (1.7 * 10(8) CFU/h.d) (LBS group). Dry matter intake (DMI), average daily gain (ADG), feed conversation ratio (FCR), apparent digestibility of nutrients and stress-related indicators were measured in this trail. The result indicated that no significant differences were observed in DMI or ADG (p > 0.05), but the FCR was improved in the LB group over the first 12 weeks (p > 0.05). The apparent digestibility of nutrients was not altered by probiotics in week 6 (p > 0.05), but the apparent digestibility of total phosphorus was significantly greater in the LB and LBS groups in week 8 (p > 0.05); additionally, an increase in the apparent digestibility of crude protein was detected in the LBS group (p > 0.05). Oral administration of L. plantarum alone improved the T-lymphocyte transformation rate on days 58 and 62 (p > 0.05), while adding the mixture of L. plantarum and B. subtilis increased the T lymphocyte transformation rate (p > 0.05) but decreased the content of cortisol on day 58 (p > 0.05). No significant differences were detected between the LB and LBS groups in growth performance, apparent digestibility of nutrients and stress related indicators (p > 0.05). The results suggested that oral administration of L. plantarum improved growth performance, nutrient digestibility and relieved weaning stress in calves, but no additional effect was obtained by supplementation with B. subtilis. PMID- 25916247 TI - Evaluating a counselling strategy for diagnostic WES in paediatric neurology: an exploration of parents' information and communication needs. AB - As whole exome sequencing (WES) is just starting to be used as a diagnostic tool in paediatric neurology for children with a neurological disorder, and patient experiences and preferences with regard to counselling are relatively underexplored. This article explores experiences and preferences of parents with pre-test and post-test counselling in a trial that uses WES for diagnostics. Second, it maps information and communication needs which exceed the counselling protocol, in order to acquire insight into how it can be improved. Data were gathered through in-depth interviews with parents of 15 children who were included in the trial. Information and communication needs of parents differed from the protocol with respect to (i) the type and amount of information provided about WES research, (ii) incidental findings, (iii) communication about progress of the study, and (iv) the communication of the results. Furthermore, parents preferred to have more of a communicative exchange with health care providers about their daily struggles and concerns related to their life with a diseased child and wanted to know how a diagnosis could offer help. There are different ways to meet parental needs, but we suggest that assigning a case manager might be a helpful option that deserves further exploration. PMID- 25916248 TI - Pediatric patients with pheochromocytoma: Experience of a tertiary health center. AB - BACKGROUND: The aim of this retrospective study was to investigate pheochromocytoma (pheo), which is a rare endocrine tumor in the pediatric population. METHODS: The medical records of five children with pheo were studied. The age, gender, clinical presentation, family history, physical findings, coexisting pathology, laboratory evaluation, surgical treatment, and postoperative course were investigated. RESULTS: The patients were four girls and one boy with a mean age of 13.2 years (range, 9.57-15.95 years). None of the patients had paroxysmal hypertension and one had normal blood pressure. No malign pheo was identified. Mean height and weight standard deviation scores (SDS), body mass index (BMI), and BMI SDS were -0.24, 0.04, 20.9 kg/m(2), and 0.20 at the time of diagnosis, and 0.03, 0.43, 23.8 kg/m(2) and 0.49 1 year after operation, respectively. BMI increased significantly after operation. Three patients had normal epinephrine and metanephrine, but elevated norepinephrine and normetanephrine on 24 h urine. Vanillylmandelic acid on 24 h urine sample was elevated in all patients. Ultrasonography failed to visualize tumors in two patients with bilateral pheo. One patient had postoperative severe hypotension. Insulin resistance associated with severe acanthosis nigricans observed in one patient regressed postoperatively. CONCLUSIONS: Pheo in children may present with different symptoms and findings. Decreased catecholamine in the postoperative period may lead to weight gain. PMID- 25916249 TI - Label-free Protein Detection Based on the Heat-Transfer Method--A Case Study with the Peanut Allergen Ara h 1 and Aptamer-Based Synthetic Receptors. AB - Aptamers are an emerging class of molecules that, because of the development of the systematic evolution of ligands by exponential enrichment (SELEX) process, can recognize virtually every target ranging from ions, to proteins, and even whole cells. Although there are many techniques capable of detecting template molecules with aptamer-based systems with high specificity and selectivity, they lack the possibility of integrating them into a compact and portable biosensor setup. Therefore, we will present the heat-transfer method (HTM) as an interesting alternative because this offers detection in a fast and low-cost manner and has the possibility of performing experiments with a fully integrated device. This concept has been demonstrated for a variety of applications including DNA mutation analysis and screening of cancer cells. To the best our knowledge, this is the first report on HTM-based detection of proteins, in this case specifically with aptamer-type receptors. For proof-of-principle purposes, measurements will be performed with the peanut allergen Ara h 1 and results indicate detection limits in the lower nanomolar regime in buffer liquid. As a first proof-of-application, spiked Ara h 1 solutions will be studied in a food matrix of dissolved peanut butter. Reference experiments with the quartz-crystal microbalance will allow for an estimate of the areal density of aptamer molecules on the sensor-chip surface. PMID- 25916250 TI - Verbal emotional memory in a case with left amygdala damage. AB - The amygdala nuclei appear to be critically implicated in emotional memory. However, in most studies, encoding and consolidation processes cannot be analyzed separately. We thus studied the verbal emotional memory in a young woman with a ganglioglioma of the left amygdala and analyzed its impact (1) on each step of the memory process (encoding, retrieval, and recognition) (2) on short- and long term consolidation (1-hour and 1-week delay) and (3) on processing of valence (positive and negative items compared to neutral words). Results showed emotional encoding impairments and, after encoding was controlled for, emotional long-term consolidation. Finally, although the negative words were not acknowledged as emotionally arousing by the patient, these words were specifically poorly encoded, recalled, and consolidated. Our data suggest that separate cerebral networks support the processing of emotional versus neutral stimuli. PMID- 25916251 TI - Relationship between Agronomic Parameters, Phenolic Composition of Grape Skin, and Texture Properties of Vitis vinifera L. cv. Tempranillo. AB - The relationship between the agronomic parameters of grapevine and the phenolic composition of skin of Vitis vinifera L. cv. Tempranillo grapes was assessed. The physical and mechanical properties of berries and their skins were also determined and correlated to the chemical composition. Results showed a significant negative correlation between grapevine vigor-related parameters (such as leaf area and bunch weight) and anthocyanin composition, whereas the percentage (w/w) of seeds was negatively correlated with the amount of flavanols of grape skins. Texture properties of grape skins also showed an important relationship with chemical composition. Berry hardness showed a negative correlation with the coumaroyl-anthocyanin derivatives, but it was positively correlated to skin flavanic composition. Moreover, significant regressions with high coefficients of determination were found between phenolic composition and grapevine vigor-related and texture variables, thus pointing out that these parameters might be useful for estimating the phenolic composition of grape skins. PMID- 25916252 TI - Electrotonic potentials in simulated chronic inflammatory demyelinating polyneuropathy at 20 degrees C-42 degrees C. AB - Threshold electrotonus changes have been studied following warming to 37 degrees C and cooling to 25 degrees C in patients with chronic inflammatory demyelinating polyneuropathy (CIDP). To extend the tracking of these changes also during hypothermia (<= 25 degrees C) and hyperthermia (>= 40 degrees C), and to explain their mechanisms, we investigate the effects of temperature (from 20 degrees C to 42 degrees C) on polarizing nodal and internodal electrotonic potentials and their current kinetics in previously simulated case of 70% CIDP. The computations use our temperature-dependent multi-layered model of the myelinated human motor nerve fiber. While the changes of electrotonic potentials and their current kinetics are largely similar for the physiological range of 28-37 degrees C, they are altered during hypothermia and hyperthermia in the normal and CIDP cases. The normal (at 37 degrees C) resting membrane potential is further depolarized or hyperpolarized during hypothermia or hyperthermia, respectively, and the internodal current types defining these changes are the same for both cases. Unexpectedly, our results show that in the CIDP case, the lowest and highest critical temperatures for blocking of electrotonic potentials are 20 degrees C and 39 degrees C, while in the normal case the highest critical temperature for blocking of these potentials is 42 degrees C. In the temperature range of 20-39 degrees C, the relevant potentials in the CIDP case, except for the lesser value (at 39 degrees C) in hyperpolarized resting membrane potential, are modified: (i) polarizing nodal and depolarizing internodal electrotonic potentials and their defining currents are increased in magnitude; (ii) inward rectifier (I IR ) and leakage (I Lk ) currents, defining the hyperpolarizing internodal electrotonic potential, are gradually increased with the rise of temperature from 20 degrees C to 39 degrees C, and (iii) the accommodation to long-lasting hyperpolarization is greater than to depolarization. The present results suggest that the electrotonic potentials in patients with CIDP are in high risk for blocking not only during hypothermia and hyperthermia, but they are also in risk for worsening at the temperature range of 37-39 degrees C. PMID- 25916253 TI - Withstanding the obstructive sleep apnea syndrome at the expense of arousal instability, altered cerebral autoregulation and neurocognitive decline. AB - The present review attempts to put together the available evidence and potential research paradigms at the interface of obstructive sleep apnea syndrome (OSAS), sleep micro- and macrostructure, cerebral vasoreactivity and cognitive neuroscience. Besides the significant health-related consequences of OSAS including hypertension, increased risk of cardio- and cerebrovascular events, notable neurocognitive lapses and excessive daytime somnolence are considered as potential burdens. The intermittent nocturnal hypoxia and hypercapnia which occur in OSAS are known to affect cerebral circulation and result in brain hypoperfusion. Arousal instability is then resulted from altered cyclic alternating patterns (CAPs) reflected in sleep EEG. In chronic state, some pathological loss of gray matter may be resulted from obstructive sleep apnea. This is proposed to be related to an upregulated proinflammatory state which may potentially result in apoptotic cell loss in the brain. On this basis, a pragmatic framework of the possible neural mechanisms which underpin obstructive sleep apnea-related neurocognitive decline has been discussed in this review. In addition, the impact of OSAS on cerebral autoregulation and sleep microstructure has been articulated. PMID- 25916254 TI - Challenges to student transition in allied health undergraduate education in the Australian rural and remote context: a synthesis of barriers and enablers. AB - INTRODUCTION: The optimum supply of an allied health workforce in rural and remote communities is a persistent challenge. Despite previous indicative research and government investment, the primary focus for rural and remote recruitment has been on the medical profession. The consequent shortage of allied health professionals leaves these communities less able to receive appropriate health care. This comprehensive review incorporates a literature analysis while articulating policy and further research implications. METHODS: The objective was to identify drivers to recruitment and retention of an allied health workforce in rural and remote communities. This issue was observed in two parts: identification of barriers and enablers for students accessing allied health undergraduate tertiary education, and barriers and enablers to clinical placement experience in rural and remote communities. A search of empirical literature was conducted together with review of theoretical publications, including public health strategies and policy documents. Database searches of CINAHL, Medline, ERIC, PsychInfo and Scopus were performed. Selection criteria included Australian research in English, full text online, keywords in title or abstract, year of publication 1990 to 2012 and research inclusive of rural and remote context by application of the Australian Standard Geographical Classication (ASGC) Remoteness Structure. Theoretical publications, or grey literature, were identified by broad Google searches utilising a variety of search terms relevant to the review objective. Allied health professions were defined as including audiology, dietetics, occupational therapy, optometry, orthoptics, orthotics and prosthetics, pharmacy, physiotherapy, podiatry, psychology, radiography, social work, speech pathology and Aboriginal and Torres Strait Islander Health Workers. RESULTS: A total of 28 empirical publications met the selection criteria with a further 22 grey literature texts identified with relevance to the research objective. Patterns of barriers and enablers for rural and remote student transition in the allied health professions were identified in the literature. Recruitment pathways to allied health tertiary studies in rural and remote communities are vague and often interrupted, and the return of graduates is haphazard. Students from rural and remote communities face an assembly of barriers. They often experience secondary education disadvantage with inadequate subject choices, pathways and opportunities. Programs designed to facilitate transition to tertiary study are often limited in their capacity to address cumulative concerns. Students also face financial imposts and are confronted by daunting social isolation, and separation from families and support systems. In regard to clinical placement, the disincentives weigh heavily. The financial burdens of a rural placement offer little inducement. Social isolation associated with a placement far from home is more acutely felt by students when there is inadequate administrative support and consequent disillusionment. Students also lack a frame of reference to pursue a rural placement option, and are often discouraged by the cumulative commitments involved. CONCLUSIONS: Clear and accessible pathways to allied health training for students from rural and remote communities are pivotal to a stronger representation of this cohort among graduates. Similarly, greater representation of rural and remote clinical placements for allied health undergraduate students is an important facilitator. Despite regional coordination and strategies designed to promote a broader range of placement opportunities, the problems remain. This review has consequences for policy and program development for growth of the rural allied health workforce in Australia, as well as identifying knowledge deficits to guide future research endeavours. PMID- 25916255 TI - Dynamic real-time monitoring of chloroform in an indoor swimming pool air using open-path Fourier transform infrared spectroscopy. AB - This study used open-path Fourier transform infrared (OP-FTIR) spectroscopy to continuously assess the variation in chloroform concentrations in the air of an indoor swimming pool. Variables affecting the concentrations of chloroform in air were also monitored. The results showed that chloroform concentrations in air varied significantly during the time of operation of the swimming pool and that there were two peaks in chloroform concentration during the time of operation of the pool. The highest concentration was at 17:30, which is coincident with the time with the highest number of swimmers in the pool in a day. The swimmer load was one of the most important factors influencing the chloroform concentration in the air. When the number of swimmers surpassed 40, the concentrations of chloroform were on average 4.4 times higher than the concentration measured without swimmers in the pool. According to the results of this study, we suggest that those who swim regularly should avoid times with highest number of swimmers, in order to decrease the risk of exposure to high concentrations of chloroform. It is also recommended that an automatic mechanical ventilation system is installed to increase the ventilation rate during times of high swimmer load. PMID- 25916256 TI - Satisfied or not satisfied: pain experiences of patients with sickle cell disease. AB - AIMS: To examine the relationship between pain and satisfaction in patients with sickle cell disease. BACKGROUND: Frequency and severity of unrelieved sickle cell pain are positively associated with mortality. Yet, information is scarce on whether sickle cell patients are satisfied with their pain level. DESIGN: A cross sectional, correlational analysis of baseline data from a randomized clinical trial. METHODS: A randomized sample of adult outpatients was recruited between February 2007-March 2011. Patients completed the PAINReportIt((r)) , containing measures of pain, satisfaction and socio-demographics. We analysed data using Kendall's rank correlations, analysis of variance, Tukey-Kramer post hoc tests, Fisher's tests and proportional odds logistic regression. RESULTS: There were statistically significant correlations between pain outcomes and satisfaction with pain level, but average pain intensity more strongly discriminated groups based on satisfaction with pain level. Among pain variables bivariately associated with patient satisfaction with pain level, only pain expectation maintained its significant relationship with satisfaction with pain level when average pain intensity was controlled. A smaller percentage of our sickle cell patients reported moderate to severe pain intensity (28%) or high composite pain index (39%), while reporting being satisfied with pain their level than reported in earlier studies using different measures and populations (70-94%). CONCLUSION: Satisfaction with pain level was an unambiguous measure of patient satisfaction and a promising indicator of pain that did not show the paradoxical relationship between satisfaction and pain seen with past measures. PMID- 25916257 TI - The Relationship between Epicardial Fat Thickness and Endothelial Dysfunction in Type I Diabetes Mellitus. AB - BACKGROUND AND AIM: Epicardial adipose tissue (EAT) is a new independent marker of coronary artery disease (CAD). The aim of this study was to investigate the relationship between epicardial fat thickness (EFT) and endothelial dysfunction (ED) in patients with type I diabetes mellitus (TIDM). METHODS AND RESULTS: Seventy-six type I diabetic patients (diabetes duration 11.7 +/- 8,1 years, aged 30.6 +/- 10 years; female/male: 38/38) and 36 healthy controls were enrolled into the study. Fasting plasma glucose (FPG), lipid panel, glycosylated hemoglobin (HbA1C), high-sensitive C-reactive protein (hsCRP), and fibrinogen levels were determined. EFT was measured via two-dimensional (2D) M-mode echocardiography. Endothelial function was assessed as flow-mediated dilatation (FMD) at the brachial artery using high-resolution ultrasound. EFT was significantly higher in patients compared to controls (3.56 +/- 0.48 mm vs. 3.03 +/- 0.48 mm, P < 0.001). In addition, significant differences were observed between the patient and control groups in terms of FMD (6.70% +/- 1.63 vs. 9.99% +/- 1.84, respectively, P < 0.001). EFT was shown to be correlated negatively with FMD (r: -0.94, P < 0.001) and positively with hsCRP (r: 0.41, P < 0.001) and fibrinogen (r: 0. 31, P = 0.007). Multiple regression analysis showed EFT to be an independent factor influencing the endothelial function. CONCLUSION: There was inverse relationship between EFT and endothelial function in this study. EFT measured easily by transthoracic echocardiography may be a useful parameter in the assessment of patients with TIDM. PMID- 25916258 TI - Influences of Operating Parameters on the Formation of Furan During Heating Based on Models of Polyunsaturated Fatty Acids. AB - Furan, a possible carcinogen, is commonly produced by thermal processing in a number of heated foods. The existence of furan levels in foods has attracted considerable attention worldwide. Recent research of furan in food has focused on the possible influences of operating parameters on the furan formation during heat processing. The aim of our study was to investigate the impacts of multiple factors (pH, temperature, heating time, ferric, and glutamic acid) on furan formation using linolenic and linoleic acids-based model systems in which furan was analyzed by headspace gas chromatography-mass spectrometry (HS-GC-MS). The results revealed that the content of furan increased rapidly when the heating temperature was elevated, with the highest levels of furan in neutral buffer solutions, the furan levels were also found to be related to heating time in all model systems. Ferric promoted furan formation from polyunsaturated fatty acids, conversely glutamic acid with an optimum concentration suppressed the furan formation. The minimal level of furan in foods during thermal treatment could be achieved via adding furan formation suppressors, and/or avoidance of furan forming promoter. PMID- 25916259 TI - Recurrent 3-day cycles of water deprivation for over a month depress mating behaviour but not semen characteristics of adult rams. AB - This study aimed to investigate the effect of water deprivation (WD) on reproductive traits of rams. Ten mature rams were used and allocated to two groups balanced for body weight. Control (C) rams had free access to drinking water, while water-restricted rams (WD) were deprived from water for 3 consecutive days and early on the morning of day 4, they had ad libitum access to water for 24 h, similar to C animals. The experiment lasted 32 days, that is eight 4-day cycles of water deprivation and subsequent watering. Feed and water intake were significantly affected by water deprivation; in comparison with C rams, WD rams reduced their feed intake by 18%. During the watering day of the deprivation cycle, WD rams consumed more water than C rams on the same day (11.8 (SD = 3.37) and 8.4 (SD = 1.92) l respectively; p < 0.05). Glucose, total protein and creatinine were increased as a result of water deprivation. However, testosterone levels were lowered as a result of water deprivation and average values were 10.9 and 6.2 (SEM 1.23) ng/ml for C and WD rams respectively (p < 0.05). Semen traits were less affected by treatment; WD rams consistently had superior sperm concentrations than C animals; and statistical significances were reached in cycles 5 and 8 of water deprivation. Several mating behaviour traits were modified as a result of water deprivation. When compared to controls, WD rams had a more prolonged time to first mount attempt (p < 0.001), their frequency of mount attempts decreased [6.8 vs. 5.2 (SEM 0.1); p < 0.001] and their flehmen reaction intensity was negatively affected (p < 0.05). Water deprivation may have practical implications reducing the libido and therefore the serving capacity of rams under field conditions. PMID- 25916260 TI - How low does iron go? Chasing the active species in fe-catalyzed cross-coupling reactions. AB - The catalytic cross-coupling reactions of organic halides or related substrates with organometallic nucleophiles form the cornerstone of many carbon-carbon bond forming processes. While palladium-based catalysts typically mediate such reactions, there are increasing concerns about the long-term sustainability of palladium in synthesis. This is due to the high cost of palladium, coupled with its low natural abundance, environmentally deleterious extraction (~6 g of metal are produced per ton of ore), toxicity, and competition for its use from the automotive and consumer electronics sectors. Therefore, there is a growing interest in replacing palladium-based catalysts with those incorporating more earth-abundant elements. With its low cost, high natural abundance, and low toxicity, iron makes a particularly appealing alternative, and accordingly, the development of iron-catalyzed cross-coupling is undergoing explosive growth. However, our understanding of the mechanisms that underpin the iron-based catalytic cycles is still very much in its infancy. Mechanistic insight into catalytic reactions is not only academically important but also allows us to maximize the efficiency of processes or even to develop entirely new transformations. Key to the development of robust mechanistic models for cross coupling is knowing the lowest oxidation state in the cycle. Once this is established, we can explore subsequent redox processes and build the catalytic manifold. Until we know with confidence what the lowest oxidation state is, any cycles proposed are largely just guesswork. To date, Fe(-II), Fe(-I), Fe(0), Fe(I), and Fe(II) have been proposed as contenders for the lowest-oxidation-state species in the cycle in iron-catalyzed cross-coupling; the aim of this Account is to pull together the various pieces of evidence in support, or otherwise, of each of these suggestions in turn. There currently exists no direct evidence that oxidation states below Fe(0) are active in the catalytic cycle. Meanwhile, the reactivity required of the lowest-oxidation-state species has been observed with model compounds in higher oxidation states, implying that there is no need to invoke such low oxidation states. While subzero-valent complexes do indeed act as effective precatalysts, it is important to recognize that this tells us that they are efficiently converted to an active catalyst but says nothing about the oxidation states of the species in the catalytic cycle. Zero-valent heterogeneous iron nanoparticles can be formed under typical catalytic conditions, but there is no evidence to suggest that homogeneous Fe(0) complexes can be produced under comparable conditions. It seems likely that the zero-valent nanoparticles act as a reservoir for soluble higher-oxidation-state species. Fe(II) complexes can certainly be formed under catalytically relevant conditions, and when bulky nucleophilic coupling partners are exploited, potential intermediates can be isolated. However, the bulky reagents act as poor proxies for most nucleophiles used in cross-coupling, as they give Fe(II) organometallic intermediates that are kinetically stabilized with respect to reductive elimination. When more realistic substrates are exploited, reduction or disproportionation to Fe(I) is widely observed, and while it still has not been conclusively proved, this oxidation state currently represents a likely candidate for the lowest one active in many iron-catalyzed cross-coupling processes. PMID- 25916261 TI - Ethanol and xylitol production by fermentation of acid hydrolysate from olive pruning with Candida tropicalis NBRC 0618. AB - Olive tree pruning biomass has been pretreated with pressurized steam, hydrolysed with hydrochloric acid, conditioned and afterwards fermented using the non traditional yeast Candida tropicalis NBRC 0618. The main aim of this study was to analyse the influence of acid concentration on the hydrolysis process and its effect on the subsequent fermentation to produce ethanol and xylitol. From the results, it could be deduced that both total sugars and d-glucose recovery were enhanced by increasing the acid concentration tested; almost the whole hemicellulose fraction was hydrolysed when 3.77% was used. It has been observed a sequential production first of ethanol, from d-glucose, and then xylitol from d xylose. The overall ethanol and xylitol yields ranged from 0.27 to 0.38kgkg(-1), and 0.12 to 0.23kgkg(-1) respectively, reaching the highest values in the fermentation of the hydrolysates obtained with hydrochloric acid 2.61% and 1.11%, respectively. PMID- 25916262 TI - Investigation of the pellets produced from sugarcane bagasse during liquid hot water pretreatment and their impact on the enzymatic hydrolysis. AB - In the process of liquid hot water (LHW) pretreatment, there are numbers of pellets formed on the lignocellulosic surface. The characteristics and effect of pellets on the enzymatic hydrolysis of LHW-treated sugarcane bagasse (SCB) were investigated. After SCB was treated with LHW at 180 degrees C, the pellets deposited on the surface of solid residues were extracted gently with 1% sodium hydroxide (NaOH) solution. They were composed of 81.0% lignin, 7.0% glucan, and 3.2% xylan. The LHW pretreatment solution (PS) was sprayed to the filter paper, and the pellets were observed on its surface. Fourier transform infrared spectroscopy (FTIR) data showed that lignin was also the main component of the PS pellets. The effect of the pellets on enzymatic hydrolysis was chiefly attributed to the steric hindrance, not the cellulase adsorption. The structural characteristics of LHW-treated SCB might play a more important role in influencing the enzymatic hydrolysis than the pellets. PMID- 25916263 TI - Secular trends in seasonal variation in birth weight. AB - BACKGROUND: Many environmental factors have been shown to influence birth weight (BW) and one of these are season of birth. AIM: The aim of the present study was to investigate the seasonal variation in BW in Denmark during 1936-1989, and to see if the variation could be explained by sunshine exposure during pregnancy. METHODS: The study population was selected from the Copenhagen School Health Records Register and included 276 339 children born between 1936 and 1989. Seasonal variation was modeled using a non-stationary sinusoidal model that allowed the underlying trend in BW and the amplitude and phase of the yearly cycles to change. RESULTS: There was a clear seasonal pattern in BW which, however, changed gradually across the study period. The highest BWs were seen during fall (September - October) from 1936 to 1963, but a new peak gradually grew from the early 1940s during early summer (May - June) and became the highest from 1964 to 1989. The amplitude of the fall peak started at 25.5 (95%CI 24.6; 25.9) grams and gradually disappeared. The amplitude of the early summer peak gradually arose from nothing to a peak of 18.6 (95%CI 17.7; 19.6) grams in the mid 1980s where it started to decrease again. Sunshine did not explain the seasonal variation in BW. CONCLUSION: There was a clear seasonal pattern in BW in Denmark 1936-1989, which however changed across the study period. Throughout the study period we observed a peak in BW during the fall, but gradually, starting in the early 1940s, an additional early summer peak emerged and became the highest from 1964 and onwards. PMID- 25916264 TI - Effects of nickel-oxide nanoparticle pre-exposure dispersion status on bioactivity in the mouse lung. AB - Nanotechnology is emerging as one of the world's most promising new technologies. From a toxicology perspective, nanoparticles possess two features that promote their bioactivity. The first involves physical-chemical characteristics of the nanoparticle, which include the surface area of the nanoparticle. The second feature is the ability of the nanoparticle to traverse cell membranes. These two important nanoparticle characteristics are greatly influenced by placing nanoparticles in liquid medium prior to animal exposure. Nanoparticles tend to agglomerate and clump in suspension, making it difficult to reproducibly deliver them for in vivo or in vitro experiments, possibly affecting experimental variability. Thus, we hypothesize that nanoparticle dispersion status will correlate with the in vivo bioactivity/toxicity of the particle. To test our hypothesis, nano-sized nickel oxide was suspended in four different dispersion media (phosphate-buffered saline (PBS), dispersion medium (DM), a combination of dipalmitoyl-phosphatidyl choline (DPPC) and albumin in concentrations that mimic diluted alveolar lining fluid), Survanta(r), or pluronic (Pluronic F-68). Well dispersed and poorly dispersed suspensions were generated in each media by varying sonication time on ice utilizing a Branson Sonifer 450 (25W continuous output, 20 min or 5 min, respectively). Mice (male, C57BL/6J, 7-weeks-old) were given 0-80 ug/mouse of nano-sized nickel oxide in the different states of dispersion via pharyngeal aspiration. At 1 and 7 d post-exposure, mice underwent whole lung lavage to assess pulmonary inflammation and injury as a function of dispersion status, dose and time. The results show that pre-exposure dispersion status correlates with pulmonary inflammation and injury. These results indicate that a greater degree of pre-exposure dispersion increases pulmonary inflammation and cytotoxicity, as well as decreases in the integrity of the blood-gas barrier in the lung. PMID- 25916265 TI - Effects of steep high-frequency hearing loss on speech recognition using temporal fine structure in low-frequency region. AB - The present study examined the effects of steep high-frequency sensorineural hearing loss (SHF-SNHL) on speech recognition using acoustic temporal fine structure (TFS) in the low-frequency region where the absolute thresholds appeared to be normal. In total, 28 participants with SHF-SNHL were assigned to 3 groups according to the cut-off frequency (1, 2, and 4 kHz, respectively) of their pure-tone absolute thresholds. Fourteen age-matched normal-hearing (NH) individuals were enrolled as controls. For each Mandarin sentence, the acoustic TFS in 10 frequency bands (each 3-ERB wide) was extracted using the Hilbert transform and was further lowpass filtered at 1, 2, and 4 kHz. Speech recognition scores were compared among the NH and 1-, 2-, and 4-kHz SHF-SNHL groups using stimuli with varying bandwidths. Results showed that speech recognition with the same TFS-speech stimulus bandwidth differed significantly in groups and filtering conditions. Sentence recognition in quiet conditions was better than that in noise. Compared with the NH participants, nearly all the SHF-SNHL participants showed significantly poorer sentence recognition within their frequency regions with "normal hearing" (defined clinically by normal absolute thresholds) in both quiet and noisy conditions. These may result from disrupted auditory nerve function in the "normal hearing" low-frequency regions. PMID- 25916266 TI - Ribbon synapses in zebrafish hair cells. AB - The basic architecture and functionality of ribbon synapses of mechanosensitive hair cells are well conserved among vertebrates. Forward and reverse genetic methods in zebrafish (Danio rerio) have identified components that are critical for the development and function of ribbon synapses. This review will focus on the findings of these genetic approaches, and discuss some emergent concepts on the role of the ribbon body and calcium in synapse development, and how perturbations in synaptic vesicles lead to a loss of temporal fidelity at ribbon synapses. This article is part of a Special Issue entitled . PMID- 25916269 TI - What Makes a Strong Organic Electron Donor (or Acceptor)? AB - Organic electron donors are of importance for a number of applications. However, the factors that are essential for a directed design of compounds with desired reduction power are not clear. Here, we analyze these factors in detail. The intrinsic reduction power, which neglects the environment, has to be separated from extrinsic (e.g., solvent) effects. This power could be quantified by the gas phase ionization energy. The experimentally obtained redox potentials in solution and the calculated ionization energies in a solvent (modeled with the conductor like screening model (COSMO)) include both intrinsic and extrinsic factors. An increase in the conjugated pi-system of organic electron donors leads to an increase in the intrinsic reduction power, but also decreases the solvent stabilization. Hence, intrinsic and extrinsic effects compete against each other; generally the extrinsic effects dominate. We suggest a simple relationship between the redox potential in solution and the gas-phase ionization energy and the volume of an organic electron donor. We finally arrive at formulas that allow for an estimate of the (gas-phase) ionization energy of an electron donor or the (gas-phase) electron affinity of an electron acceptor from the measured redox potentials in solution. The formulas could be used for neutral organic molecules with no or only small static dipole moment and relatively uniform charge distribution after oxidation/reduction. PMID- 25916270 TI - A single nucleotide replacement in exon 2 produces a novel HLA-C*01:02 variant, HLA-C*01:02:34. AB - HLA-C*01:02:34 differs from HLA-C*01:02:01 by a single nucleotide replacement in codon 43. PMID- 25916271 TI - Psychometrics of the preschool behavioral and emotional rating scale with children from early childhood special education settings. AB - In a previous study with a nationally representative sample, researchers found that the items of the Preschool Behavioral and Emotional Rating Scale can best be described by a four-factor structure model (Emotional Regulation, School Readiness, Social Confidence, and Family Involvement). The findings of this investigation replicate and extend these previous results with a national sample of children (N = 1,075) with disabilities enrolled in early childhood special education programs. Data were analyzed using classical tests theory, Rasch modeling, and confirmatory factor analysis. Results confirmed that for the most part, individual items were internally consistent within a four-factor model and showed consistent item difficulty, discrimination, and fit relative to their respective subscale scores. PMID- 25916272 TI - Regeneration of rabbit calvarial defects using biphasic calcium phosphate and a strontium hydroxyapatite-containing collagen membrane. AB - OBJECTIVES: Biphasic calcium phosphate (BCP) composed of 10% hydroxyapatite (HA) and 90% beta-tricalcium phosphate has been developed. Recently, a strontium hydroxyapatite-containing collagen membrane (Sr) was shown to stimulate early bone formation in rat calvarial defects at 4 weeks postoperatively, as compared with a cross-linked collagen membrane, for guided bone regeneration (GBR). The objective of this study was to evaluate these novel biomaterials for GBR in relation to a non-cross-linked collagen membrane (BG) and deproteinized bovine bone mineral (BO). MATERIALS AND METHODS: Twenty New Zealand rabbits were used in this study. Four defects of 7 mm in diameter were created in each rabbit, and three of the defects were treated with BG/BO, Sr/BO, and Sr/BCP. Ten rabbits were sacrificed at 12 and 24 weeks, respectively. Histological and histomorphometric analyses were conducted. Volumetric densities of mineralized new bone (MNB), bone marrow (BM), residual grafting material (RG), and non-mineralized connective tissue (NCT) were determined for each group. RESULTS: After 12 weeks, Sr/BCP yielded more MNB than BG/BO and Sr/BO with no significant difference among the three groups. After 24 weeks, however, Sr/BCP demonstrated significantly more MNB than BG/BO and Sr/BO. Both after 12 and 24 weeks, Sr/BCP showed significantly less RG than BG/BO and Sr/BO. There was a significant increase in MNB in Sr/BCP from 12 to 24 weeks. CONCLUSIONS: In defects grafted with BCP, more MNB was formed while less RG remained, than in defects grafted with BO. The Sr membrane was as effective as BG when comparing Sr/BO with BG/BO. PMID- 25916273 TI - Interpretation and Construction of Meaning of Bliss-words in Children. AB - Blissymbolics as a graphic symbol system has the potential to represent a large number of vocabulary items using a small number of basic Bliss-characters. The aim of this project was to investigate how children with typical development, aged 3 years to 7 years 11 months, interpreted Bliss-characters and compound Bliss-words and then constructed their own Bliss-words. Children participated in a teaching procedure that included explanations and feedback on the structure and meaning of Bliss-characters. Their spontaneous interpretations of Bliss characters and their ability to construct new Bliss-words were explored. Results suggest that Bliss-characters, although not very transparent, evoked spontaneous linguistic activities and were retained after brief explanations. Children aged 5 years and older appeared to discover the logic of the structure of Bliss-words. Children of all ages used Bliss-characters to represent new ideas. Some chose Bliss-characters resembling adult representations of concepts, others chose Bliss characters representing personal associations. In sum, children retained many of the Bliss-characters after a relatively brief exposure and demonstrated semantic creativity in interpretation and construction of Bliss-words. PMID- 25916268 TI - Bioactive factors in uteroplacental and systemic circulation link placental ischemia to generalized vascular dysfunction in hypertensive pregnancy and preeclampsia. AB - Preeclampsia is a pregnancy-associated disorder characterized by hypertension, and could lead to maternal and fetal morbidity and mortality; however, the pathophysiological mechanisms involved are unclear. Predisposing demographic, genetic and environmental risk factors could cause localized abnormalities in uteroplacental cytoactive factors such as integrins, matrix metalloproteinases, cytokines and major histocompatibility complex molecules leading to decreased vascular remodeling, uteroplacental vasoconstriction, trophoblast cells apoptosis, and abnormal development of the placenta. Defective placentation and decreased trophoblast invasion of the myometrium cause reduction in uteroplacental perfusion pressure (RUPP) and placental ischemia/hypoxia, an important event in preeclampsia. RUPP could stimulate the release of circulating bioactive factors such as the anti-angiogenic factors soluble fms-like tyrosine kinase-1 and soluble endoglin that cause imbalance with the pro-angiogenic factors vascular endothelial growth factor and placental growth factor, or cause the release of inflammatory cytokines, reactive oxygen species, hypoxia-induced factor-1 and AT1 angiotensin receptor agonistic autoantibodies. The circulating bioactive factors target endothelial cells causing generalized endotheliosis, endothelial dysfunction, decreased vasodilators such as nitric oxide and prostacyclin and increased vasoconstrictors such as endothelin-1 and thromboxane A2, leading to increased vasoconstriction. The bioactive factors also stimulate the mechanisms of VSM contraction including Ca(2+), protein kinase C, and Rho kinase and induce extracellular matrix remodeling leading to further vasoconstriction and hypertension. While therapeutic options are currently limited, understanding the underlying mechanisms could help design new interventions for management of preeclampsia. PMID- 25916274 TI - Goethe's "Comparirte Anatomy" as a foundation for the growth of theoretical and applied biomedical sciences in Jena. AB - In this overview, we aim to outline the development of German morphology and comparative anatomy, concentrating on the "Jena school" since it played the crucial role in the growth of these disciplines. We highlight the outstanding role of Johann Wolfgang von Goethe in this process and exemplify the ways he exercised influence on theoretical and applied biosciences. Goethe crucially influenced all methodological currents of comparative anatomy, and laid foundations for both theoretical and applied research programmes. The latter included the whole range of biosciences and medical sciences including veterinary medicine. Goethe's idea to concentrate at a single location both fundamental biological research and practical medical and veterinary studies was crucial for the success of the Jena school. PMID- 25916276 TI - Feasibility of human lung ventilation imaging using highly polarized naturally abundant xenon and optimized three-dimensional steady-state free precession. AB - PURPOSE: To demonstrate the potential for high quality MRI of pulmonary ventilation using naturally abundant xenon (NAXe) gas. METHODS: MRI was performed at 1.5 Tesla (T) and 3 T on one healthy smoker and two healthy never-smokers. 129Xe gas was polarized to ~25% using an in-house spin-exchange optical pumping polarizer fitted with a laser diode array with integrated volume holographic grating and optical train system. Volunteers inhaled 1 L of NAXe for an 8 to 15 s breathhold while MR images were acquired with full-lung coverage using a three dimensional steady-state free precession sequence, optimized for maximum signal to-noise ratio (SNR) at a given spatial resolution. For the purpose of image quality comparison, the MR acquisition was repeated at 1.5 T with 400 mL enriched xenon and 200 mL 3He. RESULTS: All NAXe lung images were of high quality, with mean SNRs of 25-40 (voxel 4.2 * 4.2 * 8/10 mm3) and ~30% improvement at 3 T versus 1.5 T. The high SNR permitted identification of minor ventilation defects in the healthy smoker's lungs. NAXe images were of comparable SNR to those obtained with enriched xenon and 3He. CONCLUSION: Optimization of MR pulse sequences and advances in polarization technology have facilitated high quality pulmonary ventilation imaging with inexpensive NAXe gas. PMID- 25916277 TI - Nitrogen supply modulates the effect of changes in drying-rewetting frequency on soil C and N cycling and greenhouse gas exchange. AB - Climate change and atmospheric nitrogen (N) deposition are two of the most important global change drivers. However, the interactions of these drivers have not been well studied. We aimed to assess how the combined effect of soil N additions and more frequent soil drying-rewetting events affects carbon (C) and N cycling, soil:atmosphere greenhouse gas (GHG) exchange, and functional microbial diversity. We manipulated the frequency of soil drying-rewetting events in soils from ambient and N-treated plots in a temperate forest and calculated the Orwin & Wardle Resistance index to compare the response of the different treatments. Increases in drying-rewetting cycles led to reductions in soil NO3- levels, potential net nitrification rate, and soil : atmosphere GHG exchange, and increases in NH4+ and total soil inorganic N levels. N-treated soils were more resistant to changes in the frequency of drying-rewetting cycles, and this resistance was stronger for C- than for N-related variables. Both the long-term N addition and the drying-rewetting treatment altered the functionality of the soil microbial population and its functional diversity. Our results suggest that increasing the frequency of drying-rewetting cycles can affect the ability of soil to cycle C and N and soil : atmosphere GHG exchange and that the response to this increase is modulated by soil N enrichment. PMID- 25916275 TI - Nontemplate-driven polymers: clues to a minimal form of organization closure at the early stages of living systems. AB - The emergence of the first polymers played an essential role in the transition from the physicochemical to the biological domain, a perception that embodied many different world paradigms relying on only one primal polymer. However, biological complexity would have appeared with an increasing set of associated chemistries and molecular interactions of many different macromolecules. In agreement with this notion, here, the purpose is to focus specific attention on current knowledge of modern biochemistry of a set of widespread polymers likely present in the Last Universal Common Ancestor synthesized by nontemplate-driven reactions with references to their abiotic synthesis. The proposed overview describes the manner in which these polymers could have organized around two polymerization reaction cycles and integrated into a minimal organizational closure at the early stages of living systems, independently of template replication processes. This hypothesis could provide an alternative conceptual framework to evaluate a plausible scenario addressing the transition from nonliving to protocellular systems. PMID- 25916278 TI - Anti-edema effect of melatonin on spinal cord injury in rats. AB - AIM: To determine the anti-edema effects of melatonin on spinal cord injury (SCI) in rats. METHODS: A total of 150 adult male Sprague-Dawley rats were randomly allocated to the following three groups (n=50): a sham group which underwent laminectomy without dural compression; an SCI group, which underwent laminectomy followed by SCI and received saline i.p. immediately after injury and then daily for 2 days; an MT group, which underwent laminectomy followed by SCI and received a 100 mg/kg dose of melatonin i.p. immediately after SCI and then daily for 2 days. The cords were removed at 12, 24, 48 and 72 h after surgery in every group. Spinal cord edema was evaluated by determining the spinal cord water content. Expressions of AQP4 and GFAP positive cells in injured spinal cord were detected by immunohistochemical staining, and protein expressions of AQP4 and GFAP were detected by Western blotting. RESULTS: Spinal cord water content was obviously increased after SCI, which was maintained almost unchanged by melatonin treatment (100 mg/kg) at 12 h after injury but was significantly reduced from 24 h to 72 h. The expressions of AQP4 and GFAP increased in the injured spinal cord segments, which were decreased by melatonin treatment (100 mg/kg) between 24 h and 72 h after SCI. CONCLUSIONS: Melatonin (100 mg/kg) had anti-edema effects after acute SCI probably by down-regulating the expression level of AQP4 protein, and it may eliminate astrocytic swelling after SCI through down-regulating the expression level of GFAP protein. PMID- 25916279 TI - Fetuin-A (AHSG) and its usefulness in clinical practice. Review of the literature. AB - BACKGROUND: Fetuin-A, also called Alpha 2-Heremans Schmid Glycoprotein, is a multifunctional plasma agent what has been proven in animal and human studies. It plays a role as a physiological inhibitor of insulin receptor tyrosine kinase associated with insulin resistance and a negative acute phase reactant. It also regulates bone remodeling and calcium metabolism being an important inhibitor of calcium salt precipitation and vascular calcifications. METHODS: PubMed database was searched for articles from 2002 up to December 2014 to identify the role of fetuin-A in the pathogenesis of selected internal diseases. RESULTS: Due to secretion of fetuin-A mainly by the liver, it may be a marker of liver function and predictor of mortality in patients with cirrhosis and hepatocellular cancer. The associations between high fetuin-A and metabolic syndrome as well as its hepatic manifestation- nonalcoholic fatty liver disease and atherogenic lipid profile have been well proven. However, fetuin-A relation with BMI is not so clear. Contrary to few reports, many authors suggest that fetuin-A may be an independent risk factor for type 2 diabetes and marker of diabetic complications. Close associations of high and low fetuin-A concentrations with cardiovascular diseases and mortality risk have been reported which is explained by differences in analyzed populations, stages of atherosclerosis and calcifications, coexistence of type 2 diabetes or kidney dysfunction and different main pathways of fetuin-A actions in various diseases. CONCLUSIONS: Fetuin-A has a diagnostic potential as a biomarker for liver dysfunction, cardiovascular diseases and disorders associated with metabolic syndrome. PMID- 25916280 TI - Paroxysmal atrial fibrillation in young cryptogenic ischemic stroke: A 3-week ECG Holter monitoring study. AB - BACKGROUND: Atrial fibrillation is known very frequent cause of ischemic stroke. Undetected paroxysmal atrial fibrillation (PAF) is thus often considered a possible cause of cryptogenic ischemic stroke (CIS). The aim of this prospective study was to detect PAF using ECG Holter monitoring and determinate whether prolongation of the Holter monitoring to 3 weeks would increase the detection rates of PAF in young CIS patients <= 50 years. METHODS: The study set consisted of IS patients <= 50 years enrolled in the HISTORY (Heart and Ischemic STrOke Relationship studY) study (NCT01541163). CIS was defined according to the TOAST criteria including the absence of ultrasonographic or angiographic signs of atherosclerosis, vasculitis or dissection. Admission ECG, serum levels of high sensitive Troponin T (hs TnT) and N-terminal pro-brain natriuretic peptide (NT proBNP), markers of thrombophilia, transoesophageal echocardiography (TEE) and 24 hour ECG-Holter monitoring were performed in all patients. In case of negative 24 h ECG Holter, an additional 3-weeks monitoring was done. RESULTS: Of the 105 enrolled patients <= 50 years, 95 (90%) were identified as cryptogenic (49 males, mean age 39.1 +/- 8.2 years). All CIS patients had normal admission ECG. In total, PAF was detected in 9 (9.5%, 95% CI: 3.5% - 17.8%) patients; in two during 24-h ECG Holter and in seven during 3-weeks Holter monitoring. Patients with PAF had more frequently elevated admission hs TnT and NT-proBNP levels (P - 0.0001). CONCLUSIONS: PAF was detected in 9.5% of young CIS patients and 3-weeks ECG Holter monitoring increased the detection rate. PMID- 25916281 TI - The efficacy of ranibizumab treatment in clinical practice in patients with the wet form of age-related macular degeneration. The results of the Czech National Registry. AB - AIMS: The aim of this communication was to evaluate ranibizumab in the treatment of wet age-related macular degeneration. METHODS: Anonymised data on treatment efficacy and safety were consecutively entered into the Czech national database. From 01/09/2008 to 25/10/2011, 671 patients/685 eyes treated with ranibizumab monotherapy were entered in the registry. 454 ranibizumab treated eyes and 444 patients were monitored for 12-months. The dependent variable used to monitor disease progression and treatment results was change in visual acuity in the ETDRS (Early Treatment Diabetic Retinopathy Study) chart over time. RESULTS: After 12 months of treatment, a loss of < 15 letters in the ETDRS chart was found in 81.5% of eyes treated with ranibizumab. A gain of >= 15 letters was found in 9.7% of eyes on ranibizumab. The results for our patients treated in clinical practice with ranibizumab were poorer than those in the SUSTAIN (Ranibizumab in Patients With Subfoveal Choroidal Neovascularization Secondary to Age-Related Macular Degeneration) study. A rationale for this was sought in a sub-analysis. CONCLUSIONS: Sub-analysis demonstrated that treatment naive CNV (choroidal neovascularization), occult CNV and lower height of the macular oedema at the outset of the disease may be positive prognostic factors for final visual acuity in anti-VEGF (vascular endothelial growth factor) treated patients. PMID- 25916283 TI - [Expert consensus on 4 color flow cytometry for immunophenotyping of acute leukemia(2015)]. PMID- 25916282 TI - A practical method for use in epidemiological studies on enamel hypomineralisation. AB - With the development of the European Academy of Paediatric Dentistry (EAPD) judgment criteria, there has been increasing interest worldwide in investigation of the prevalence of demarcated opacities in tooth enamel substance, known as molar-incisor hypomineralisation (MIH). However, the lack of a standardised system for the purpose of recording MIH data in epidemiological surveys has contributed greatly to the wide variations in the reported prevalence between studies. The present publication describes the rationale, development, and content of a scoring method for MIH diagnosis in epidemiological studies as well as clinic- and hospital-based studies. The proposed grading method allows separate classification of demarcated hypomineralisation lesions and other enamel defects identical to MIH. It yields an informative description of the severity of MIH-affected teeth in terms of the stage of visible enamel destruction and the area of tooth surface affected (i.e. lesion clinical status and extent, respectively). In order to preserve the maximum amount of information from a clinical examination consistent with the need to permit direct comparisons between prevalence studies, two forms of the charting are proposed, a short form for simple screening surveys and a long form desirable for prospective, longitudinal observational research where aetiological factors in demarcated lesions are to be investigated in tandem with lesions distribution. Validation of the grading method is required, and its reliability and usefulness need to be tested in different age groups and different populations. PMID- 25916284 TI - [Treatment of Ph-adult acute lymphoblastic leukemia patients with Tongji-96 regimen]. AB - OBJECTIVE: To investigate the efficacy and side effects of the consecutive chemotherapeutic protocol, Tongji-96, for adult patients with Philadelphia chromosome negative acute lymphoblastic leukemia (Ph-aALL). METHODS: A retrospective analysis was conducted on 95 cases of Ph-aALL patients treated between January 2004 and December 2012 with Tongji-96 regimen in Tongji hospital, Shanghai. RESULTS: Among these 95 patients, the overall complete remission (CR) rate was 92.6%, 7-year overall survival (OS) and event-free survival (EFS) rates were (39.3+/-5.9)% and (31.5+/-5.3)%, respectively, with the median survival of 28 months. Based on multivariable COX proportional hazards regression model analysis, patients with the poor karyotype and failed to achieve CR after first course induction therapy had a higher risk of mortality compared to those who had good or normal cytogenetics and achieved CR after 1 course of induction treatment [the risk ratios (RR) were 3.380 (95% CI 1.530-7.463, P=0.003) and 3.005 (95% CI 1.522-5.933, P=0.002),respectively]. By means of Kaplan-Meier analysis and Log rank test,patients aged less than 60 years and successively achieved CR after first induction therapy had more favorable 7-year OS and EFS rates. Patients with normal karyotype and hyperdiploidy had significantly higher 2-year OS and EFS rates compared with those with complex karyotype, t(4;11) translocation and other karyotypes. CONCLUSION: Age (60 years as the cut-off),treatment courses for achieving CR and cytogenetics were predictive factors for the prognosis of Ph aALL from this retrospective study. As a comprehensive and sequential therapy protocol, Tongji-96 regimen was proved to obtain long-term survival, reduce risks for relapse and improve outcomes for part Ph-aALL patients. PMID- 25916285 TI - [Clinical and prognostic analysis of 21 cases of primary breast lymphoma]. AB - OBJECTIVE: To analyze the clinical features, therapeutic methods and prognosis of primary breast lymphoma (PBL). METHODS: Twenty-one PBL patients treated in Ruijin Hospital from January 2003 to December 2013 were included in this study, with 17 diffuse large cell lymphoma (DLBCL), 1 mucosa-associated lymphoid tumor (MALT), 1 follicular lymphoma (FL), 1 Burkitt lymphoma and 1 subcutaneous peniculitis T cell lymphoma according to the WHO 2008 classification. Of 21 patients, only one patient with MALT has bulged tumor mass (>7 cm), other patients had tumor mass <5 cm. Six patients had core needle biopsy of tumor, 2 modified radical operation, and others tumor excision for diagnosis. All the patients received chemotherapy. The impacts of surgery, rituximab and prophylaxis with lumbar puncture on the outcomes of patients were analyzed. Survival was estimated using Kaplan-Meier method and compared by log-rank test. All the results were analyzed by SPSS 10.0. RESULTS: Among 21 PBL patients, 19 achieved complete remission (CR), 1 partial remission (PR) and 1 disease progression (PD). Followed-up till July 2014, with median follow-up of 14 months (6-75 months), only one patient died, with 3-year survival of 92.3%. Compared with chemotherapy alone, the progression-free survival (PFS) of combination therapy (surgery plus chemotherapy) was significant longer (P=0.015), but without statistic differences of CR rate and overall survival (OS) between two groups. Among the 20 patients with CD20-positive tumor cells, 17 received Rituximab. PFS and OS, as well as CR rate of PBL had no difference between the treatment with and without Rituximab. The incidence of central nervous system (CNS) infiltration had no difference between patients with and without CNS prophylaxis through lumber-puncture and intrathecal injection. CONCLUSION: With the common subtype of DLBCL, PBL patients had good outcome. Surgery, as a method to obtain tumor samples for diagnosis, could not prolong OS of patients. Therefore, radical operation shouldn't be recommended. PBL was reported to have high risk of CNS events, but prophylaxis with lumber puncture and intrathecal injection couldn't decrease the incidence of CNS infiltration. PMID- 25916286 TI - [Clinical and prognostic analysis of 30 cases of primary central nervous system lymphoma]. AB - OBJECTIVE: To explore clinical characteristics, treatment and prognosis of primary central nervous system lymphoma(PCNSL). METHODS: Retrospective analysis, Kaplan-Meier analysis and Log-rank test were conducted on 30 PCNSL patients from 2006 to 2014 in our hospital. RESULTS: The median age of this cohort (14 males and 16 females) was 57.4 years old. 18 cases had single tumor, 12 cases multiple. 17 cases presentd with intracranial hypertension and 13 cases focal neurological deficits. 13 cases (62%) were diffuse large B cell lymphoma. About 60% patients received combination therapy including surgery, radiotherapy or chemotherapy. 63.3% complete remission rate (CR) was achieved for all patients. Kaplan-Meier analysis and Log-rank test showed the median overall survival (OS) was 24 months, the rates of 2-year survival, 5-year survival, 6-month progression-free survival(PFS) and 1-year free-progressed survival (PFS) were as of 46.7%, 13.3%, 60.0% and 43.3% respectively. The median OS of 11 patients received whole brain radiotherapy(WBRT)combined with chemotherapy was 48 months. The median OS of 7 patients treated with stereotactic radiosurgery(SRS) combined with chemotherapy had no significant difference when compared to the former (P=0.233). Survive analysis showed that age was prognostic factor for PCNSL patients(P=0.030). CONCLUSION: Diffuse large B cell lymphoma was the main type of PCNSL, single or multiple location, presented with increased intracranial hypertension or focal neurological deficits. Age was the key prognostic factor for patients. Surgery was suitable for patients with supertentorial and superficial tumor or with acute intracranial hypertension syndrome. SRS was a feasible local therapy which alleviated the symptoms and led to less toxicity. PCNSL patients might benefit from multimode therapy. PMID- 25916287 TI - [Prognostic significance of monosomal karyotype in acute myeloid leukemia]. AB - OBJECTIVE: To explore the prognostic significance of monosomal karyotype (MK) in patients with acute myeloid leukemia (AML). METHODS: The clinical data of 498 AML patients were analyzed retrospectively. RESULTS: Of the 498 patients, 233 (46.8%) cases had an abnormal karyotype. 42 patients fulfilled the criteria for MK, which were 8.4% of all cases and 18.0% of patients with abnormal karyotype, respectively. The most frequent autosomal monosomies were -7 and -17. 70 patients had complex karyotype (CK), in all patients and patients with abnormal karyotype accounted for 14.1% and 30.0%, respectively. Patients with MK were associated with significantly older (median age 62.5 vs 52 years, P=0.003), and lower HGB concentrations (62.5 vs 77 g/L, P=0.009) and lower WBC counts (7.0*109/L vs 11.7*109/L, P=0.008). Among MK cases, the most frequent chromosome abnormalities were complex karyotype, -7, -5, 7q-, and 5q-. In univariate analysis, MK patients had worse survival than those without MK (7.3 months vs 26.3 months, P<0.001). CK patients also had poorer outcomes than patients without CK (14.8 months vs 26.3 months, P<0.001). In CK patients, survival was worse in MK patients than patients without MK (7.4 months vs 19.2 months, P=0.007). By COX analysis, MK was an independent prognostic factor, beyond NCCN criteria and CK [HR=2.610 (1.632 4.175), P<0.001]. CONCLUSION: MK was an independent adverse prognostic factor in AML patients. PMID- 25916288 TI - [Clinical and gene involved of one case of 8p11 myeloproliferative syndrome with ins(13;8)(q12;p11p23)]. AB - OBJECTIVE: To improve the understanding of patients with 8p11 myeloproliferative syndrome (EMS) harboring ins(13;8)(q12;p11p23)/ZNF198 -FGFR1. METHODS: We reported here a 8p11 EMS case and provided more details on the clinical and molecular features of ins(13;8)(q12;p11p23)/ZNF198-FGFR1,full length ZNF198-FGFR1 was cloned by overlap extension PCR method,and the literatures on this topic were reviewed. RESULTS: Clinically, the case with ins(13;8)(q12;p11p23)/ZNF198-FGFR1 had distinct hematological and clinical characteristics: hyperleukocytosis, myeloid hyperplasia,widespread adenopathy and lymphoma; Fluorescence in situ hybridization (FISH) disclosed the positive FGFR1 gene rearrangement; Further molecular studies confirmed a mRNA in-frame fusion between exon 17 of the ZNF198 gene and exon 9 of FGFR1 gene ,the full length ZNF198-FGFR1 was composed of a NH2 terminus of ZNF198 including the ZNF and proline-rich domains, whereas the COOH terminus of FGFR1 included 2 tyrosine kinase domains. CONCLUSION: EMS with ins(13;8)(q12;p11p23)/ZNF198 -FGFR1 was a very rare, distinct myeloproliferative neoplasm, the fusion gene and chimeric protein with constitutive activation of the FGFR1 tyrosine kinase. PMID- 25916289 TI - [CLAG regimen in combination with sorafenib in the treatment of refractory acute myeloid leukemia:a case report]. PMID- 25916290 TI - [Analysis of the karyotype abnormalities and its prognostic in 298 patients with myelodysplastic syndrome]. AB - OBJECTIVE: To investigate the relationship between cytogenetic markers with World Health Organization (WHO) classification, disease progress and prognosis in cases with primary myelodysplastic syndromes (MDS). METHODS: 298 patients with de novo MDS from the first affiliated hospital of medical school, Zhejiang University were enrolled in the retrospective analysis of WHO classification, karyotype, and prognosis. Follow-up study was also conducted. RESULTS: The WHO classifications at first diagnosis were as follows: refractory cytopenia with unilineage dysplasia (RCUD), 18 cases; refractory anemia with ring sideroblasts (RARS), 8 cases; refractory cytopenia with multiline dysplasia (RCMD), 104 cases; refractory anemia with excess blasts-1, 76 cases; refractory anemia with excess blasts-2, 85 cases; MDS unclassified (MDS-U), 5 cases involved; and single del (5q), 2 cases. 39.6% of MDS patients carried karyotypic abnormalities. Among them, the frequency of numerical abnormalities, structural abnormalities and the existence of composite abnormalities were 45, 31, and 42, respectively. The composite abnormalities were unbalanced translocations and complex chromosomal abnormalities. The incidence of both karyotypic abnormalities and complex chromosomal abnormalities in RAEB group was higher than that in non-RAEB group (P<0. 05). An analysis based on IPSS-R Scoring System showed that advanced risk stratification (except the low-risk group) gradually enhanced the incidence of karyotypic abnormalities (P<0.05). In addition, the probability of evolution to leukemia increased with the higher IPSS-R score (P<0.05). In RAEB group, the cases with +8 chromosome, accounting for 19.5% of karyotypic abnormalities, had worse prognosis than those with normal chromosomes. CONCLUSION: Karyotype was identified with an independent risk factor in MDS patients. Therefore, the information on cytogenetic analysis was critical for diagnosis, prognosis and individual treatment. MDS patients presenting+8 chromosome, an intermediate risk factor, were associated with a poorer outcome compared to cases with normal chromosomes in RAEB group. PMID- 25916291 TI - [MRI monitoring in diagnosis and follow-up of iron overload]. AB - OBJECTIVE: To use the technique of magnetic resonance imaging (MRI) T2* mapping to diagnose and follow-up of patients with iron overload. METHODS: 107 patients who were suspected to have iron overload between 2011.7-2014.3 in Peking Union Medical Colleague Hospital were analyzed retrospectively. Patients had the document of MRI T2* value of liver, heart and pancreas, serum ferritin (SF), transferrin saturation (TS), transfusion amount and other related laboratory tests. T2* values were compared with SF and transfusion amount. T2* values in different organs and their relationship with SF were also evaluated. 10 patients who had been adequately chelated for more than half a year were followed up for their SF and T2* values. RESULTS: There were 65 males and 42 females with the median age of 51(8-77)-year-old. They were 50 myelodysplastic syndromes (MDS), 36 aplastic anemia, 10 myelofibrosis, 7 hemachromatosis and 4 thalassemia carriers. Liver T2* value was significantly related to SF (r=0.120, P=0.001), but not related to transfusion amount (r=0.019, P=0.175), whereas cardiac MRI T2* was not related either to SF or to transfusion amount. No correlation of the T2* value was found between liver and heart (r=0.015, P=0.235). 70 patients was detected for liver, heart and pancreas T2* simultaneously. Pancreas T2* was compatible to SF (r=0.061,P=0.039) and cardiac T2* (r=0.110, P=0.005), but not correlated to heptic T2* (r=0.047, P= 0.071) or transfusion amount (r=0.000, P=0.960). For the 10 well-chelated patients, during the half year follow-up period, SF changed significantly from (2 566.5+/-1 152.2) MUg/L before chelation to (1 473.4+/ 803.0) MUg/L after chelation(P=0.001), while liver T2* remained the same [(6.0+/ 5.1) ms, (6.3+/-6.0) ms respectively, P=0.629]. CONCLUSION: MRI, although related to SF to some extent, was a valuable additional methods for quantifying iron overload. Iron deposition in different organs might be not related to each other and needed to be evaluated separately. Well-chelation therapy could change SF in half-year follow-up, but T2* change needed longer time to follow-up. PMID- 25916292 TI - [The role of serum hepcidin and ferroportin1 in placenta on iron transfer from mother to fetus]. AB - OBJECTIVE: To detect the concentration of serum hepcidin and the mRNA expression level of ferroportin1 (FPN1) in the placenta membrane from full term pregnant women with different degree of iron deficiency, and explore their roles for iron transport in placental. METHODS: The concentration of HGB, serum iron (SI) and serum ferritin (SF) of mothers and infants were detected in 55 full term pregnant women and neonates. The expression level of FPN1 mRNA in placental was detected by the RT-PCR technique. The concentration of serum hepcidin was detected by double antibody sandwich biotin avidin enzyme-linked immunosorbent assay. The serum hepcidin level and the FPN1 mRNA expression in the full term placenta from different maternal iron status were compared in three groups. RESULTS: There were no significant differences in the cord blood HGB, SI and SF of newborns from pregnant women with different iron status (P>0.05). The concentration of serum hepcidin of pregnant women among normal, iron deficiency and mild iron deficiency anemia were (193.637+/-52.219), (176.523+/-43.875), and (147.623+/-37.768) MUg/L respectively, with statistical significance (F=3.872, P=0.027). The expression levels of FPN1 mRNA among three groups were 0.462+/-0.077, 0.507+/-0.074 and 0.551+/-0.104 respectively, with statistical significance (F=4.767, P=0.013). A negative correlation between maternal serum hepcidin and placental FPN1 mRNA (r= 0.383, P=0.004) was identified. CONCLUSION: There were no significant differences in the iron status of corresponding newborns from pregnant women with different iron status. With the severity of maternal iron deficiency, the concentration of serum hepcidin was down-regulated, while the expression of FPN1 mRNA in placenta was up-regulated. PMID- 25916293 TI - [Clinical analysis of recombinant human thrombopoietin for 92 adults with severe primary immune thrombocytopenia]. AB - OBJECTIVE: To evaluate the efficacy of recombinant human thrombopoietin (rhTPO) and related factors which influencing the therapeutic effect in adults with severe immune thrombocytopenia (ITP). METHODS: The efficacy of rhTPO in 92 hospitalized adult patients [35 males and 57 females, median age as 34 (18-65) years] with severe ITP, including 7 cases of newly diagnosed ITP, 29 cases of persistent ITP and 56 cases of chronic ITP from May 2012 to May 2014 was retrospectively investigated. All patients received subcutaneous rhTPO, the injected dosage was 300 U.kg-1.d-1 for 14 days, platelet counts were recorded and followed-up for a week. RESULTS: The overall response rate of rhTPO treatment was 60.9%. The overall response rates in newly diagnosed, persistent and chronic ITP were 71.4%, 62.1% and 58.9% respectively. The median platelet counts on fourth,seventh, fourteenth days of treatment, and the seventh day of withdrawal were 27(5-49), 65(16-138), 133(28-208) and 67(15-134)*109/L, respectively. The median time was 6(5-7) days when platelet counts reached 100*109/L, the median peak time was 11(5-17) days, the median maximum peak of platelet counts was 194(132-274)*109/L in patients who reached CR after treatment. Related factors which affected therapeutic effect were analyzed in patients who reached CR after treatment, and indicated that sex, age, disease stage, express of platelet membrane glycoprotein (GP) and relative number of CD19+ B, CD3+CD4+ T, CD3+CD8+ T lymphocyte in blood samples did not influence the probability of complete response (P>0.05). A few patients with fever, muscle aches, fatigue or dizziness could be self-recovery without special intervention. CONCLUSION: Severe ITP in adults treated by rhTPO had satisfactory therapeutic effect and safety. PMID- 25916294 TI - [Clinical study on Rituximab in the treatment of idiopathic thrombotic thrombocytopenic purpura]. AB - OBJECTIVE: To study the efficacy and safety of rituximab (RTX) in the treatment of idiopathic thrombotic thrombocytopenic purpura (ITTP). METHODS: Among 17 ITTP patients, nine cases of the RTX group were administrated with RTX plus plasma exchange (PEX) and steroids. Eight cases of the control group received PEX plus steroids+/-other immune inhibitors. Patients received RTX 375 mg/m2, 1 per week for 4 weeks. The laboratory parameters, including hemogram, LDH, ADAMTS13 activities and its inhibitors, and the ratio of B lymphocytes in peripheral blood were monitored. The number of PEX, total plasma volumes, remission time, relapse ratio and adverse effects in both groups were compared. RESULTS: The median number of PEX/median total plasma volumes in the RTX and control group were 5(2 8)/9.6(4.0-15.4) L and 6(4-9)/11.2(7.5-14.6) L, respectively. Patients in the RTX and control group achieved hematologic remission at the median time of 15(5-20) days and 22(7-36) days, respectively. And the median time of immunological remission in the two groups was 2(2-8) and 2(2-4) weeks, respectively. ADAMTS13 activities increased significantly after 2 weeks in both two groups. There was no relapse in the RTX group, while 4 patients relapsed in the control group. The percentage of B lymphocytes in peripheral blood obviously deduced one week after first dose of RTX infusion compared with the level before treatment [(2.19+/ 5.11)% vs (18.39+/-7.15)%, P<0.001], and began to gradually increase 9 months later. Severe adverse events were not observed in RTX group during the therapeutic procedure and follow-up, but one patient, who had sustained immunologic remission, died of severe pneumonia 7 months later. CONCLUSION: In the treatment of ITTP, RTX in conjunction with PEX and steroids appeared to be a safe and effective therapy, with fast and sustained remission in hematology and even in immunology, with lower relapse rate and less adverse effects. But patients needed to be paid attention to prevent and treat infectious events in time. PMID- 25916295 TI - [A case report of micro hematopoietic stem cell transplantation resulting complete chimerism of the second donor]. PMID- 25916296 TI - [Rapamycin decreases irradiation-induced hematopoietic system damage]. AB - OBJECTIVE: To explore the protection function of rapamycin in hematopoietic system damage induced by irradiation. METHODS: Six to eight week old C57BL/6J male mice were used for experiment. Mice received 4 mg/kg rapamycin by i.p.injection every other day for 5 times. The day after the last injection, mice were exposed to a dose (5 Gy) of total body irradiation (TBI). Peripheral blood was measured by a complete blood count at 0.5, 1, 2, 3, 5, 7, 40, 70 days after TBI. The hematoxylin-eosin staining was used to observe the pathologic changes in sternum obtained from mice at day 5 after TBI. CFU-S of spleen was measured by immerging in Tellyesniczky solution for 24 h at day 5 after TBI. RESULTS: Before TBI, WBC and LYM decreased in rapamycin-treated mice compared with control (P<0.01); RBC and HGB increased (P<0.05); there was no difference in PLT; HE staining of bone marrow from rapamcin-treated and control mice before irradiation showed no difference in marrow cellularity. After TBI, WBC and LYM decreased significantly, with no difference at 0.5 d to 7 d between rapamycin-treated and control. The counts of WBC and LYM in rapamycin-treated mice restored to normal at 40 d and 70 d. RBC and HGB decreased at irradiation group at 3 d to 7 d, but rapamycin stimulated them to a higher level, both of them tended to normal at 40 d and 70 d. HE staining of bone marrow after 5 day of 5 Gy irradiation, nucleated cells in control decreased significantly, but restored in rapamycin-treated mice. CFU-S results showed the colony number in rapamycin-treated mice was much higher than control mice after 5 Gy irradiation, with 40.00+/-12.86 and 13.20+/-2.31 (P=0.035), respectively. CONCLUSION: Administration of rapamycin to mice before irradiation protected the mice from hematopoietic damage induced by irradiation by maintaining the bone marrow nucleated cells, slowing down decrease and promoting the restoration of peripheral blood cells and protecting hematopoitic stem/progenitor cells in spleen. PMID- 25916297 TI - [The establishment of Raji drug-resistant cell line and analyses of prohibitin and miR-27a expression]. AB - OBJECTIVE: To establish Raji adriamycin (ADR)-resistant cell lines and analysis the expression of mitochondria Prohibitin (PHB) and microRNA-27a (miR-27a), as well as discuss its clinical significance. METHODS: Built ADR-resistant Raji cells, detected their resistant index and drug-resistant spectrum and stability, observed their morphology and growth characteristics in general; evaluated the expression of phb mRNA and miR-27a in ADR-resistant cells (Raji/A) and sensitive cells (Raji/S) via real-time quantitative polymerase chain reaction (RT-PCR). RESULTS: The ADR-resistant Raji cell lines were built; expression of PHB1 mRNA in Raji/A was evidently higher than in Raji/S (P<0.05), the expressing difference of PHB2 mRNA in Raji/A and Raji/S was statistically meaningless (P>0.05), the expression of miR-27a in Raji/A was much higher than in Raji/S (P<0.05). CONCLUSION: By building the experimental model of Raji ADR-resistant cell lines, high expression level of PHB1 and miR-27a were detected in the cell lines, indicating that PHB1 and miR-27a may be associated with ADR-resistance of Raji cells. PMID- 25916298 TI - [Construction of CD19-CAR retroviral vector and modification of its transduction of human T-lymphocytes]. AB - OBJECTIVE: To improve the MigR1-CD19-CAR (chimeric antigen receptor) that contains a single chain variable region (scFv) which targeted to CD19 through a retroviral vector transduction efficiency of T-lymphocytes. METHODS: Insert the CD19-CAR fragment into the retroviral vector (MigR1) through recombinant DNA technology, after transfecting plat-A packaging cell lines, viral supernatant was collected to transduce K562 cell line and activated human T-lymphocytes. We used flow cytometry to determine the transduction efficiency and RT-PCR to confirm the transcription of CD19-CAR gene. The ability of the transduced T cells to produce IFN-gamma and TNF-alpha in a CD19-specific manner was measured in an enzyme linked immunosorbent (ELISA) assay. RESULTS: (1)Using MigR1-CD19-CAR retroviral vector to produce the high titer retrovirus. (2)MigR1-CD19-CAR transduction efficiency of K562 cell line was significantly higher than human T-lymphocytes (P<0.01). (3)120 min centrifugation could significantly improve transduction efficiency of T-lymphocytes to (54.5+/-14.6)%. (4)Transduction efficiency could be improved by deciding transduce time according to T-lymphocytes proliferation fold in vitro individually, and the highest transduction efficiency in the study was 69.3%. The CD19-CAR gene sequence was transcripted specificly with high efficiency. (5) IFN-gamma and TNF-alpha released by CD19-CAR transduced T lymphocytes significantly increased to (13 230+/-1 543) pg/ml and (4 217+/-211) pg/ml when coculture with CD19-K562 cells. CONCLUSION: We have successfully constructed a second generation CAR which targeted to CD19 through a retroviral vector called MigR1 (MigR1-CD19-CAR). Deciding transduce time according to T lymphocytes proliferation fold in vitro individually and 120 min centrifugation could improve the CAR transduction efficiency of T-lymphocytes. RT-PCR confirmed that the CD19-CAR gene was specificly transcripted with high efficiency. IFN gamma and TNF-alpha released by CD19-CAR transduced T-lymphocytes significantly increased when activated by target cells. PMID- 25916299 TI - [Preliminary study of microRNA expression profiles in HIV related diffuse large B cell lymphoma]. PMID- 25916300 TI - [Retrospective study of the efficacy and safety of treatment with PDD vs PAD in de novo patients with multiple myiloma]. PMID- 25916301 TI - [Allogeneic hematopoietic stem cell transplantation for Epstein-Barr virus associated hemophagocytic syndrome: a case report and literatures review]. PMID- 25916302 TI - [The effects of low polarity ginsenoside Rh4 on proliferation and differentiation in K562 leukemia cells]. PMID- 25916303 TI - [Haploidentical hematopoietic stem cell transplantation for adult acute lymphoblastic leukemia]. PMID- 25916304 TI - [The progress of diagnostic and prognostic molecular markers of lymphoma]. PMID- 25916305 TI - [Hotspot report of the 56th American Society of Hematology Annual Meeting:progress of treatment in chronic lymphocytic leukemia]. PMID- 25916306 TI - Simple suturing of the nasal septum using the Maniceps septum stitch device. AB - OBJECTIVE: To present the utility of the recently introduced Maniceps septum stitch device for suturing of the nasal septum. METHODS: This paper describes nasal septum suturing techniques using the Maniceps septum stitch device following septoplasty to prevent post-operative complications such as haematoma and nasal septum perforation. CONCLUSION: Nasal septum suturing using the Maniceps septum stitch device appears to be a safe and easy surgical procedure to help prevent post-operative complications and may reduce the incidence of nasal septum perforation following septoplasty. PMID- 25916307 TI - Manager Experiences with the Return to Work Process in a Large, Publically Funded, Hospital Setting: Walking a Fine Line. AB - PURPOSE: Previous research on the role of managers in the return to work (RTW) process has primarily been conducted in contexts where the workplace has declared organizational responsibility for the process. While this is a common scenario, in some countries, including Denmark, there is no explicit legal obligation on the workplace to accommodate RTW. The aim of this study was to gain knowledge about the potential roles and contributions of managers in supporting returning employees in a context where they have no legal obligation to actively support RTW. METHODS: Nineteen Danish hospital managers participated in a one-on-one interview or focus group discussions aimed at identifying barriers and facilitators for supporting employees in their RTW. Five individual interviews and two focus group discussions were conducted. Transcripts were analysed using thematic content analysis. RESULTS: Four main themes were identified: (1) 'Coordinator and collaborator'; (2) 'Dilemmas of the RTW policy enforcer'; (3) 'The right to be sick and absent'; and (4) 'Keep the machinery running...'. Our findings indicated that supervisors' capacity to support returning workers was related to individual, communication, organizational, and policy factors. Instances were observed where supervisors faced the dilemma of balancing ethical and managerial principles with requirements of keeping staffing budgets. CONCLUSION: Although it is not their legislative responsibility, Danish managers play a key role in the RTW process. As has been observed in other contexts, Danish supervisors struggle to balance considerations for the returning worker with those of their teams. PMID- 25916308 TI - Suicidal Intent and Method of Self-Harm: A Large-scale Study of Self-Harm Patients Presenting to a General Hospital. AB - Data from the Oxford Monitoring System for Attempted Suicide (2004-2011) were used to study hospital presentations for self-harm in which Suicidal Intent Scale (SIS) scores were obtained (N = 4,840). Regression of medians was used to control for the confounding effect of age and gender. Higher estimated median SIS scores were associated with increasing age, male gender, self-poisoning versus self injury, multiple methods of self-harm versus self-injury alone, use of gas (mainly carbon monoxide), dangerous methods of self-injury (including hanging, gunshot), and use of alcohol as part of the act. For self-poisoning patients, there was a correlation between the number of tablets taken and the total SIS score. Compared with self-poisoning with paracetamol and paracetamol-containing compounds, self-poisoning with antipsychotics was associated with a lower median SIS score while antidepressants had the same estimated median as paracetamol. Use of alcohol within 6 hours of self-harm was associated with lower SIS scores. In conclusion, certain methods of self-harm, particularly dangerous methods of self injury and self-poisoning with gas, were associated with high intent and should alert clinicians to potential higher risk of suicide. However, apart from use of gas, suicidal intent cannot be inferred from type of drugs used for self poisoning. PMID- 25916309 TI - Multiple evolution of flavonoid 3',5'-hydroxylase. AB - MAIN CONCLUSION: Multiple F3'5'H evolution from F3'H has occurred in dicotyledonous plants. Efficient pollinator attraction is probably the driving force behind, as this allowed for the synthesis of delphinidin-based blue anthocyanins. The cytochrome P450-dependent monooxygenases flavonoid 3' hydroxylase (F3'H) and flavonoid 3',5'-hydroxylase (F3'5'H) hydroxylate the B ring of flavonoids at the 3'- and 3'- and 5'-position, respectively. Their divergence took place early in plant evolution. While F3'H is ubiquitously present in higher plants, the distribution of F3'5'H is scattered. Here, we report that F3'5'H has repeatedly evolved from F3'H precursors at least four times in dicotyledonous plants: In the Asteraceae, we identified F3'5'Hs specific for the subfamilies Cichorioideae and Asteroideae, and additionally an F3'5'H that seems to be specific for the genus Echinops of the subfamily Carduoideae; moreover, characterisation of a sequence from Billardiera heterophylla (formerly Sollya heterophylla) (Pittosporaceae) showed that the independent evolution of an F3'5'H has occurred at least once also in another family. The evolution of F3'5'H from an F3'H precursor represents a gain of enzymatic function, probably triggered by an amino acid change at one position of substrate recognition site 6. The gain of F3'5'H activity allows for the synthesis of delphinidin-based anthocyanins which usually provide the basis for lilac to blue flower colours. Therefore, the need for an efficient pollinator attraction is probably the driving force behind the multiple F3'5'H evolution. PMID- 25916310 TI - Small tandem target mimic-mediated blockage of microRNA858 induces anthocyanin accumulation in tomato. AB - MAIN CONCLUSION: Our work strongly suggests that microRNA858 regulates anthocyanin biosynthesis in tomato by modulating the expression of two R2R3 MYB transcription factors, underscoring the importance of microRNAs in the gene regulatory network controlling specialized metabolism in plants. The biological functions of microRNA858 (miR858), a recently identified small RNA, are not well understood. Here, we identified miR858 as a negative regulator of anthocyanin biosynthesis in tomato (Solanum lycopersicum). RNA ligase-mediated 5'RACE cleavage assay showed that miR858 mediates the cleavage of SlMYB7-like and SlMYB48-like transcripts in tomato. Expression analysis revealed an inverse correlation between the accumulation of miR858 and its target SlMYB7-like mRNA, in different tissues of tomato. Subsequently, a small tandem target mimic construct for blocking miR858 (STTM858) was generated and transformed into tomato. The majority of endogenous miR858 was blocked in STTM858 over-expressing tomato plants, whereas SlMYB7-like transcripts increased significantly. Concomitantly, upregulated expression was detected for several anthocyanin biosynthetic genes, including PAL, CHS, DFR, ANS and 3GT. As a result, anthocyanins were highly accumulated in young seedlings, leaves, stems and leaf buds of the transgenic plants under normal growth conditions. In addition, over expression of STTM858 in tomato activated another MYB transcription factor, SlMYB48, implicating the possible involvement of SlMYB48 in anthocyanin biosynthesis. PMID- 25916311 TI - Transcript abundance patterns of Populus C-repeat binding factor2 orthologs and genetic association of PsCBF2 allelic variation with physiological and biochemical traits in response to abiotic stress. AB - MAIN CONCLUSION: We conducted a candidate gene-based approach to search for genetic associations between 10 SNPs in PsCBF2 and 10 abiotic stress-related traits. The increasing incidence of abiotic stresses and the limitations of available treatments, particularly in trees, highlight the need to improve our understanding of the mechanisms of stress responses. In Arabidopsis, C-repeat binding factor 2 (CBF2) plays an important role in freezing tolerance and cold acclimation. Here, we isolated orthologs of CBF2 from five Populus species. Expression profiling revealed that the Populus CBF2s were preferentially induced in response to cold, with CBF2 transcript abundances ranging from 5.4- to 62-fold higher than in unstressed controls of the corresponding species. In addition, we used a candidate gene-based approach in Populus simonii Carr. to identify single nucleotide polymorphisms (SNPs) in PsCBF2 associated with physiological and biochemical traits. PsCBF2 showed high nucleotide diversity (pi T = 0.00549, theta w = 0.01406) and low average linkage disequilibrium (r (2) = 0.061). Association studies in 528 individuals of an association population showed that nine SNPs (false discovery rate Q < 0.10) and one haplotype (Q < 0.10) were significantly associated with differences in four physiological and biochemical traits (P < 0.005), with each marker explaining 1.31-5.87 % of the total variance in the corresponding trait. PsCBF2 transcript levels differed significantly in abundance among genotypic classes for most of the significant SNPs. Identification of these significant associations will help reveal the molecular basis of physiological differences and provide a starting point for marker assisted selection for traits involved in stress tolerance in P. simonii. PMID- 25916312 TI - Examining the response of needle carbohydrates from Siberian larch trees to climate using compound-specific delta(13) C and concentration analyses. AB - Little is known about the dynamics of concentrations and carbon isotope ratios of individual carbohydrates in leaves in response to climatic and physiological factors. Improved knowledge of the isotopic ratio in sugars will enhance our understanding of the tree ring isotope ratio and will help to decipher environmental conditions in retrospect more reliably. Carbohydrate samples from larch (Larix gmelinii) needles of two sites in the continuous permafrost zone of Siberia with differing growth conditions were analysed with the Compound-Specific Isotope Analysis (CSIA). We compared concentrations and carbon isotope values (delta(13) C) of sucrose, fructose, glucose and pinitol combined with phenological data. The results for the variability of the needle carbohydrates show high dynamics with distinct seasonal characteristics between and within the studied years with a clear link to the climatic conditions, particularly vapour pressure deficit. Compound-specific differences in delta(13) C values as a response to climate were detected. The delta(13) C of pinitol, which contributes up to 50% of total soluble carbohydrates, was almost invariant during the whole growing season. Our study provides the first in-depth characterization of compound-specific needle carbohydrate isotope variability, identifies involved mechanisms and shows the potential of such results for linking tree physiological responses to different climatic conditions. PMID- 25916313 TI - A decade in diabetes specialist services, 2000 to 2011, in England: the views of consultant diabetologists and diabetes specialist nurses amidst persistent healthcare delivery change. AB - AIMS: To assess the impact of continual major National Health Service reorganization on commissioning, organizational and delivery arrangements for secondary care diabetes services. To explore how consultant diabetologists and diabetes specialist nurses perceive the issues facing diabetes specialist services in 2011 and how these have changed in the preceding decade. METHODS: We used a longitudinal case study approach that combined quantitative and qualitative methods. Five locations in England were purposively selected to represent the wider diabetes specialist community, and seven semi-structured interviews were conducted. Interviews were recorded, transcribed verbatim and analysed using Framework analysis. Findings were compared with and contrasted to results from national quantitative surveys of diabetes specialist services undertaken in 2000 and 2006. RESULTS: Clinicians viewed positively the expertise and commitment of multidisciplinary teams and their ability to adapt to new situations. Negative perceptions persisted throughout the decade, relating to the continual change that threatens to dismantle relationships and services which had taken many years to establish. Lack of resources, inadequate manpower planning and poor access to psychological support for people with diabetes remained constant themes from 2000 to 2011. CONCLUSIONS: A willingness to innovate and work differently to improve services was identified; however, clinicians must be supported through organizational changes to ensure people with diabetes receive high-quality care. The disruptive nature of organizational change was a recurrent theme throughout the decade. Periods of stability must exist within commissioning to allow relationships, which are key to integration, to be maintained and permit service improvements to develop. PMID- 25916314 TI - Is Clinic Visit Frequency Associated with Weight Gain During the Interstage Period? A Report from the Joint Council on Congenital Heart Disease National Pediatric Cardiology Quality Improvement Collaborative (JCCHD-NPCQIC). AB - Growth problems are prevalent among infants with congenital heart disease. We sought to determine whether frequency of outpatient clinic visits correlated with weight gain in patients with hypoplastic left heart syndrome or variant during the interstage period between discharge from stage I palliation and presentation for stage II palliation (SIIP). Using prospectively collected data from the JCCHD NPC-QIC database from June 2008 to July 2013, we performed a retrospective cohort study assessing the association of days between clinic visits (DBV) with the change in weight-for-age z-score (WAZ) during the interstage period. Eligible subjects were those who survived to a SIIP performed at <270 days of age and had at least two outpatient clinic visits. There were 561 patients from 49 centers who fulfilled inclusion criteria. The average interstage change in WAZ was +0.22. The mean number of DBV was 16.1 days, and the average number of clinic visits was six. There was no correlation of change in WAZ with either DBV (r = 0.02, P = 0.62) or the number of visits (r = 0.03, P = 0.44). Subjects within this cohort are seen about every 2 weeks averaged over the interstage period. There is no correlation between interstage visit frequency and change in WAZ in this patient population. Further research is needed to describe differences in visit frequency as the patient progresses through the interstage period and to elucidate whether patient factors such as growth velocity are influencing visit frequency. The optimal visit frequency remains unknown. PMID- 25916320 TI - A human-centered framework for innovation in conservation incentive programs. AB - The promise of environmental conservation incentive programs that provide direct payments in exchange for conservation outcomes is that they enhance the value of engaging in stewardship behaviors. An insidious but important concern is that a narrow focus on optimizing payment levels can ultimately suppress program participation and subvert participants' internal motivation to engage in long term conservation behaviors. Increasing participation and engendering stewardship can be achieved by recognizing that participation is not simply a function of the payment; it is a function of the overall structure and administration of the program. Key to creating innovative and more sustainable programs is fitting them within the existing needs and values of target participants. By focusing on empathy for participants, co-designing program approaches, and learning from the rapid prototyping of program concepts, a human-centered approach to conservation incentive program design enhances the propensity for discovery of novel and innovative solutions to pressing conservation issues. PMID- 25916315 TI - Immunologic Aging in Adults with Congenital Heart Disease: Does Infant Sternotomy Matter? AB - Thymectomy is performed routinely in infants undergoing cardiothoracic surgery. Children post-sternotomy have decreased numbers of T lymphocytes, although the mechanisms involved and long-term consequences of this have not been defined. We hypothesized that lymphopenia in patients with adult congenital heart disease (ACHD) would be reflective of premature T cell maturation and exhaustion. Adults with ACHD who had sternotomy to repair congenital heart disease as infants (<1 year) and age-matched ACHD patients without prior sternotomy were studied using polychromatic flow cytometry interrogating markers of lymphocyte maturation, exhaustion and senescence. Group differences were analyzed using Mann-Whitney U and Fisher's exact tests. Eighteen ACHD patients aged 21-40 years participated: 10 cases and 8 controls. Median age at sternotomy for cases was 52 days. Cases and controls were matched for age (28.9 vs. 29.1 years; p = 0.83), gender (p = 0.15) and race (p = 0.62) and had similar case complexity. Cases had a lower mean percentage of cytotoxic CD8 lymphocytes compared to controls (26.8 vs. 33.9 %; p = 0.016), with fewer naive, undifferentiated CD8 T cells (31.0 vs. 53.6 %; p = 0.027). CD8 cells expressing PD1, a marker of immune exhaustion, trended higher in cases versus controls (25.6 vs. 19.0 %; p = 0.083). Mean percentage of CD4 cells was higher in cases versus controls (65.6 vs. 59.6 %; p = 0.027), without differences in CD4 T cell maturation subtype. In summary, ACHD patients who undergo sternotomy as infants exhibit differences in T lymphocyte composition compared to ACHD controls, suggesting accelerated immunologic exhaustion. Investigation is warranted to assess the progressive nature and clinical impact of this immune phenotypic change. PMID- 25916322 TI - Erratum to: High throughput phenotyping of left and right ventricular cardiomyopathy in calcineurin transgene mice. PMID- 25916321 TI - Integrated cardiac magnetic resonance imaging with coronary magnetic resonance angiography, stress-perfusion, and delayed-enhancement imaging for the detection of occult coronary artery disease in asymptomatic individuals. AB - To evaluate the feasibility of using coronary magnetic resonance angiography (CMRA) with stress-perfusion and delayed-enhancement MRI as a screening tool for the detection of coronary artery disease (CAD) in asymptomatic subjects. Three hundred and forty-one self-referred asymptomatic subjects were enrolled in this study. Cardiac MR imaging was performed using a 1.5-T scanner with a 32-channel cardiac coil. Coronary artery stenosis, regional wall motion abnormalities, myocardial perfusion abnormalities, and delayed myocardial enhancement were analyzed. The occurrence of new chest pain and cardiac events was assessed in 332 subjects (97.3 %) over an average 29 +/- 6 months (range, 18-39 months) follow-up period. A total of 3296 (82.4 %) of 4000 coronary artery segments examined exhibited diagnostic image quality on combined whole-heart and volume-targeted CMRA. Combined MRI detected significant CADs in 13 (3.8 %) of 341 subjects. Among these, 11 subjects (84.6 %) had both coronary artery stenosis (>=50 % by diameter) on CMRA and stress-perfusion defects in corresponding areas. Five of the 13 subjects showed evidence of old myocardial infarctions on delayed enhancement MRI. Three subjects (0.9 %) underwent percutaneous coronary intervention after CAD was detected on cardiac MRI. There were no cardiac events during the follow-up period in subjects who complied with follow-up. Normal stress-perfusion and delayed-enhancement MRI lead to excellent outcomes when used to predict future cardiac events in asymptomatic subjects. Coronary MRA correlates well with stress-perfusion MRI for detecting significant CAD and helps exclude CAD in asymptomatic individuals. PMID- 25916323 TI - Correlation between plaque vulnerability of aorta and coronary artery: an evaluation of plaque activity by direct visualization with angioscopy. AB - This study investigated the relationship between the degree of atherosclerotic changes in the descending thoracic aorta (TA) and the coronary artery using angioscopy. Twenty-five consecutive patients undergoing angioscopy of the TA and coronary angiography were enrolled in this study. Participants were divided into three groups according to the angioscopic grading of the TA: white plaque group (W-group), yellow plaque group (Y-group) and intensive yellow, ruptured plaque with ulceration and/or thrombus group (RP-group). The maximum plaque grade, plaque score, number of yellow plaques, frequency of yellow-plaque grades by coronary angioscopy, and SYNTAX score by coronary angiography were evaluated. Brachial-artery pulse wave velocity and high-sensitivity C-reactive protein level tended to be higher in the RP-group than in the other groups, although the differences were not statistically significant. The SYNTAX score was significantly higher in the RP-group than in the W-group (W-group 4.0 +/- 3.6 vs. RP-group 17.5 +/- 10.0, P = 0.045). In addition, the angioscopic maximum plaque grade, plaque score, and number of yellow plaques in the RP-group were significantly higher than in the W-group (maximum plaque grade W-group 0.8 +/- 0.4 vs. RP-group 1.8 +/- 0.8, P = 0.026; plaque score W-group 1.0 +/- 1.2 vs. RP group 4.0 +/- 1.4, P = 0.014; and number of yellow plaques W-group 1.0 +/- 1.2 vs. RP-group 2.5 +/- 0.5, P = 0.023). The yellow-plaque grade in the coronary artery was correlated significantly with the plaque grading of TA (P = 0.043). Our study suggests that the angioscopic progression of aortic atherosclerosis is closely associated with vulnerability to and the extent of coronary stenosis, indicating that vulnerability toward atherosclerotic plaque development occurs simultaneously in the coronary tree and systemic arteries. PMID- 25916324 TI - Synthesis and biological evaluation of kojic acid derivatives containing 1,2,4 triazole as potent tyrosinase inhibitors. AB - A series of 5-substituted-3-[5-hydroxy-4-pyrone-2-yl-methymercapto]-4-amino-1,2,4 triazole derivatives were synthesized by nucleophilic substitution reaction of 5 hydroxy-2-chloromethyl -4H-pyran-4-one with 5-substituted-3-mercapto-4-amino 1,2,4-triazole, and their inhibitory effects on mushroom tyrosinase were evaluated. The results indicated that most of the synthesized compounds exhibited significant inhibitory activity. Specifically, 5-(4-chlorophenyl)-3-[5-hydroxy-4 pyrone-2-yl-methymercapto]-4-amino-1,2,4-triazole (6j) exhibited the most potent tyrosinase inhibitory activity with IC50 value of 4.50 +/- 0.34 MUm. The kinetic studies of the compound (6j) demonstrated that the inhibitory effects of the compound on the tyrosinase were belonging to competitive inhibitors. Meanwhile, the structure-activity relationship was also discussed. PMID- 25916325 TI - Gasless transumbilical laparoscopic-assisted appendectomy as a safe and cost effective alternative surgical procedure for mild acute appendicitis. AB - PURPOSE: Several reports have demonstrated the effectiveness and feasibility of single incisional transumbilical laparoscopic-assisted appendectomy (TULAA). We developed a modified TULAA technique, gasless-TULAA, which involves lifting the abdominal wall with a retractor, without pneumoperitoneum or another incision. METHODS: We assessed the surgical outcomes of 257 patients treated for appendicitis in our hospital between 2005 and 2013. In a preoperative comprehensive evaluation, appendicitis without abscess was defined as mild appendicitis (mild appendicitis group: MAG), and appendicitis with abscess was defined as severe appendicitis (severe appendicitis group: SAG). The clinical outcomes were compared with those in other published reports. The cost effectiveness of gasless-TULAA was compared with that of conventional multiport laparoscopic appendectomy (CMLA) in our hospital. RESULTS: In MAG (n = 228), the operation time and postoperative hospital stay were 46.9 +/- 22.7 min and 2.6 +/- 1.2 days, respectively. The gasless-TULAA was completed without trocars in 91.2 % of patients. The surgical outcomes of SAG were significantly worse than those of MAG (p < 0.001). The surgical cost of gasless-TULAA was significantly lower than that of CMLA (p < 0.001). CONCLUSION: Gasless-TULAA is a cost-effective, safe, and readily available surgical technique for mild appendicitis, which can obviate the need for specialized equipment. PMID- 25916326 TI - Monitoring Technology for Gamma-Aminobutyric acid Production in Polished Mochi Barley Grains using a Carbon Dioxide Sensor. AB - Gamma-aminobutyric acid (GABA) has many biological functions, including the inhibition of blood pressure increases and acceleration of growth hormone secretion. In this study, we discovered the utility of measuring the concentration of carbon dioxide (CO2 ) dissolved in the reaction solution, for development of a real-time and convenient technique to estimate GABA production. In addition to mochi barley bran, we examined the polished grains of three species: mochi barley (a variant of hulless barley), barley, and Japanese millet, all soaked in l-glutamic acid (l-Glu) solution at pH 4.5. We found a positive correlation between GABA and CO2 concentrations, and the production of CO2 was suppressed in the absence of l-Glu at pH 4.5. These results suggest that GABA content can be easily predicted by measuring the aqueous CO2 content using a CO2 sensor, during the process of GABA production in polished mochi barley grains and bran. PMID- 25916327 TI - Effect of super dosing of phytase on growth performance, ileal digestibility and bone characteristics in broilers fed corn-soya-based diets. AB - A feeding trial was designed to assess the effect of super dosing of phytase in corn-soya-based diets of broiler chicken. One hundred and sixty-eight day-old broilers were selected and randomly allocated to four dietary treatment groups, with 6 replicates having 7 chicks per treatment group. Two-phased diets were used. The starter and finisher diet was fed from 0 to 3 weeks and 4 to 5 weeks of age respectively. The dietary treatments were consisted of normal phosphorus (NP) group without any phytase enzyme (4.5 g/kg available/non-phytin phosphorus (P) during starter and 4.0 g/kg during finisher phase), three low-phosphorus (LP) groups (3.2 g/kg available/non-phytin P during starter and 2.8 g/kg during finisher phase) supplemented with phytase at 500, 2500, 5000 FTU/kg diet, respectively, to full fill their phosphorus requirements. The results showed that super doses of phytase (at 2500 FTU and 5000 FTU/kg) on low-phosphorus diet improved feed intake, body weight gain, ileal digestibility (serine, aspartic acid, calcium, phosphorus), blood P levels and bone minerals such as calcium (Ca), P, magnesium (Mg) and zinc (Zn) content. It could be concluded that super doses of phytase in low-phosphorus diet were beneficial than the normal standard dose (at 500 FTU/kg) of phytase in diet of broiler chicken. PMID- 25916328 TI - Acknowledgements to referees. AB - The quality of The Journal of Headache and Pain depends on the qualified and regular collaboration of renowned scientists, who devoted their time to constructively review the submitted articles.We are indebted to the following experts who reviewed papers that completed the peer-reviewing process within 2014. PMID- 25916329 TI - Headache, migraine and risk of brain tumors in women: prospective cohort study. AB - BACKGROUND: While headache is a common symptom among brain tumors patients, often patients with common headache have concerns of being at risk for developing brain tumors. We aimed to disprove that migraine or headache in general is associated with increased risk of developing brain tumors. METHODS: Prospective study among 39,534 middle-aged women, free of any cancer, and who provided information on headache history at baseline. We followed participants for occurrence of medical record-confirmed brain tumors. We ran multivariable-adjusted Cox proportional hazards models to evaluate associations between any headache, migraine, and non migraine headache with incident brain tumors. We further evaluated whether migraine frequency and updated headache information during follow-up could be linked with brain tumors. RESULTS: A total of 13,022 (32.9%) women reported headache, of which 5,731 were classified as non-migraine headache and 7,291 as migraine. During a mean follow-up of 15.8 years, 52 brain tumors were confirmed. The multivariable-adjusted hazard ratios (95% confidence interval) for brain tumors were 1.33 (0.76-2.34) for any headache, 1.18 (0.58-2.41) for migraine and 1.53 (0.75-3.12) for non-migraine headache. The association for any headache was further attenuated in time-varying analyses (1.15; 0.58-2.24). Those who experience migraine six times/year were also not at increased risk of brain tumor (0.67; 0.13-3.32). CONCLUSIONS: Results of this large, prospective cohort study in women do not provide evidence that headache in general or migraine in particular are associated with the occurrence of brain tumors. Our data should reassure patients with headache that brain tumor is not a long-term consequence of headache. PMID- 25916330 TI - Diagnostic criteria for temporomandibular disorders: self-instruction or formal training and calibration? AB - BACKGROUND: To investigate the difference in diagnostic reliability between self instructed examiners and examiners taught in a Diagnostic Criteria for Temporomandibular Disorders (DC/TMD) course and if the reliability of self instructed examiners improves after the course. METHODS: Six examiners were divided into three groups: (1) formal two-day training and calibration course at a DC/TMD training center (Course group), (2) self-teaching through documents and movie (Self group) with three examiners on each and the Self group later participated in the course (Self + course group). Each group examined sixteen subjects, total of 48 volunteers (36 patients with TMD and 12 asymptomatic) and the reliabilities in relation to the diagnoses derived by a Reference Standard Examiner were compared by Cohen's Kappa coefficient. RESULTS: The reliability was good to excellent in all three groups of examiners for all DC/TMD diagnoses, except for Myofascial pain with referral in the Self + course group. The course seemed to improve the reliability regarding Myalgia and Arthralgia at the same time as the examiners experienced the course to be valuable for self-perceived ability and confidence. CONCLUSIONS: This study shows that the diagnostic reliability of formal DC/TMD training and calibration and DC/TMD self-instruction are similar, except for subgroups of Myalgia. Thus, self-instruction seems to be possible to use to diagnose the most common TMDs in general dental practice. The course further improves the reliability regarding Myalgia and Arthralgia at the same time as the examiners experienced the course to be valuable for self perceived ability and confidence. PMID- 25916331 TI - Linear interictal pain in Epicrania Fugax. AB - Epicrania Fugax is a paroxysmal, short-lasting, head pain moving across one hemicranium, describing a linear or zag trajectory, starting and ending in territories of different nerves. Between attacks, patients are usually free of symptoms. We describe an Epicrania Fugax patient complaining of interictal pain. The interictal pain was line-shaped and extended across the usual starting and ending points of the typical Epicrania Fugax paroxysms. Although rarely encountered, persistent linear pain may be a feature of Epicrania Fugax. PMID- 25916332 TI - Case-control study of ADARB1 and ADARB2 gene variants in migraine. AB - BACKGROUND: Migraine causes crippling attacks of severe head pain along with associated nausea, vomiting, photophobia and/or phonophobia. The aim of this study was to investigate single nucleotide polymorphisms (SNPs) in the adenosine deaminase, RNA-specific, B1 (ADARB1) and adenosine deaminase, RNA specific, B2 (ADARB2) genes in an Australian case-control Caucasian population for association with migraine. Both candidate genes are highly expressed in the central nervous system and fit criteria for migraine neuropathology. SNPs in the ADARB2 gene were previously found to be positively associated with migraine in a pedigree-based genome wide association study using the genetic isolate of Norfolk Island, Australia. The ADARB1 gene was also chosen for investigation due to its important function in editing neurotransmitter receptor transcripts. METHODS: Four SNPs in ADARB1 and nine in ADARB2 were selected by inspecting blocks of linkage disequilibrium in Haploview for genotyping using either TaqMan or Sequenom assays. These SNPs were genotyped in two-hundred and ninety one patients who satisfied the International Classification of Headache Disorders-II 2004 diagnostic criteria for migraine, and three-hundred and fourteen controls, and PLINK was used for association testing. RESULTS: Chi-square analysis found no significant association between any of the SNPs tested in the ADARB1 and ADARB2 genes in this study and the occurrence of migraine. CONCLUSIONS: In contrast to findings that SNPs in the ADARB2 gene were positively associated with migraine in the Norfolk Island population, we find no evidence to support the involvement of RNA editing genes in migraine susceptibility in an Australian Caucasian population. PMID- 25916333 TI - Efficacy of frovatriptan as compared to other triptans in migraine with aura. AB - BACKGROUND: The treatment of migraine attacks with aura by triptans is difficult since triptans most probably are not efficacious when taken during the aura phase. Moreover, there are insufficient data from randomised studies whether triptans are efficacious in migraine attacks with aura when taken during the headache phase. In this metaanalysis, we aimed to compare the efficacy of frovatriptan versus rizatriptan, zolmitriptan, and almotriptan. METHODS: Five double-blind, randomized, controlled crossover trials were pooled. All trials had an identical design. Patients were asked to treat three consecutive migraine attacks with frovatriptan 2.5 mg and three consecutive migraine attacks with a comparative triptan (rizatriptan 10 mg; zomitriptan 2.5 mg; almotriptan 12.5 mg). RESULTS: In this analysis, 117 migraine attacks with aura could be included (intention-to-treat population). The mean headache intensity after 2 hours was 1.2 +/- 1.0 for frovatriptan and 1.6 +/- 1.0 for the other triptans (p<0.05); all triptans showed significant improvement of headache. Frovatriptan resulted in significantly lower relapse rates at 24 hours and 48 hours when taken in migraine attacks with aura. CONCLUSIONS: Our data suggest that frovatriptan is efficacious and even superior in some endpoints also when taken during the headache phase in migraine attacks with aura. This is of particular importance for those many patients who have migraine attacks both without and with aura. PMID- 25916334 TI - The epidemiology of primary headache disorders in Zambia: a population-based door to-door survey. AB - BACKGROUND: Little is known of the epidemiology of primary headache disorders in sub-Saharan Africa. We performed a population-based survey in Zambia using methods previously tested in multiple other countries. METHODS: This cross sectional survey was conducted by visiting households unannounced, using cluster randomized sampling, in the mostly urban Lusaka Province and mostly rural Southern Province. Within clusters, households were selected randomly, as was one adult member (18-65 years old) of each selected household. A structured questionnaire, translated into the local languages, was administered face-to-face by trained interviewers. Demographic enquiry was followed by diagnostic questions based on ICHD-II criteria. A random sub-sample of participants were invited for subsequent physician-interview to validate the diagnostic part of the questionnaire. RESULTS: Of 1,134 eligible household members contacted, 1,085 (450 male, 887 urban) consented to interview (refusal rate 4.3%). Others who had been selected but remained unavailable on three visits were not counted as refusals since their reasons were unknown, but gave rise to gender biases, being mostly male in urban areas and mostly female in rural areas. Statistical correction was applied. Adjusted for gender and habitation (urban/rural), the 1-year prevalence of any headache was 61.6%, of migraine 22.9%, of tension-type headache (TTH) 22.8%, of headache on >=15 days/month 11.5% and of probable medication-overuse headache (pMOH) 7.1%. The adjusted point-prevalence of any headache (headache yesterday) was 19.1%. There was a small proportion (5.3%) of unclassified headache, some of which may have been secondary. The overwhelmingly strong association was between urban dwelling and pMOH (OR: 8.6; P=0.0001), with an urban prevalence of 14.5% (gender-adjusted). Validation of the questionnaire was limited by participants' reluctance to present for physician review, substantial delays in doing so and major self-selection bias among those who did. These were unavoidable problems in resource-limited Zambia. CONCLUSIONS: Primary headache disorders, common in high-income countries, are at least as prevalent in Zambia, a sub-Saharan African country. The selectively urban problem of pMOH seems likely to reflect ready availability of non-prescription analgesics, without easy access to professional health care for headache or any focused public-health education regarding correct usage of analgesics or the dangers of their overuse. PMID- 25916335 TI - Improvement of migraine symptoms with a proprietary supplement containing riboflavin, magnesium and Q10: a randomized, placebo-controlled, double-blind, multicenter trial. AB - BACKGROUND: Non-medical, non-pharmacological and pharmacological treatments are recommended for the prevention of migraine. The purpose of this randomized double blind placebo controlled, multicenter trial was to evaluate the efficacy of a proprietary nutritional supplement containing a fixed combination of magnesium, riboflavin and Q10 as prophylactic treatment for migraine. METHODS: 130 adult migraineurs (age 18 - 65 years) with >= three migraine attacks per month were randomized into two treatment groups: dietary supplementation or placebo in a double-blind fashion. The treatment period was 3 months following a 4 week baseline period without prophylactic treatment. Patients were assessed before randomization and at the end of the 3-month-treatment-phase for days with migraine, migraine pain, burden of disease (HIT-6) and subjective evaluation of efficacy. RESULTS: Migraine days per month declined from 6.2 days during the baseline period to 4.4 days at the end of the treatment with the supplement and from 6.2.days to 5.2 days in the placebo group (p = 0.23 compared to placebo). The intensity of migraine pain was significantly reduced in the supplement group compared to placebo (p = 0.03). The sum score of the HIT-6 questionnaire was reduced by 4.8 points from 61.9 to 57.1 compared to 2 points in the placebo-group (p = 0.01). The evaluation of efficacy by the patient was better in the supplementation group compared to placebo (p = 0.01). CONCLUSIONS: Treatment with a proprietary supplement containing magnesium, riboflavin and Q10 (Migravent(r) in Germany, Dolovent(r) in USA) had an impact on migraine frequency which showed a trend towards statistical significance. Migraine symptoms and burden of disease, however, were statistically significantly reduced compared to placebo in patients with migraine attacks. PMID- 25916337 TI - Pendular nystagmus, palatal tremor and progressive ataxia in GM2-gangliosidosis. PMID- 25916336 TI - The effects of acupuncture treatment on the right frontoparietal network in migraine without aura patients. AB - BACKGROUND: Functional and structural abnormalities in resting-state brain networks in migraine patients have been confirmed by previous functional magnetic resonance imaging (fMRI) studies. However, few studies focusing on the neural responses of therapeutic treatment on migraine have been conducted. In this study, we tried to examined the treatment-related effects of standard acupuncture treatment on the right frontoparietal network (RFPN) in migraine patients. METHODS: A total of 12 migraine without aura (MWoA) patients were recruited to undergo resting-state fMRI scanning and were rescanned after 4 weeks standard acupuncture treatment. Another 12 matched healthy control (HC) subjects underwent once scanning for comparison. We analyzed the functional connectivity of the RFPN between MWoA patients and HC subjects before treatment and that of the MWoA patients before and after treatment. Diffusion tensor images (DTI) data analyzing was also performed to detect fiber-related treatment responses. RESULTS: We observed significantly decreased FC in the RFPN and that the decreased FC could be reversed by acupuncture treatment. The changes of FC in MWoA patients was negatively correlated with the decrease of visual analogue scale (VAS) scores after treatment. This study indicated that acupuncture treatment for MWoA patients was associated with normalizing effects on the intrinsic decreased FC of the RFPN. CONCLUSIONS: Our study provided new insights into the treatment-related neural responses in MWoA patients and suggested potential functional pathways for the evaluation of treatment in MWoA patients. Future studies are still in need to confirm the current results and to elucidate the complex neural mechanisms of acupuncture treatment. PMID- 25916338 TI - Re: The association between chronic obstructive pulmonary disease and dementia: a population-based retrospective cohort study. PMID- 25916339 TI - Reply: The association between chronic obstructive pulmonary disease and dementia: a population-based retrospective cohort study. PMID- 25916342 TI - A new vaccine to prevent herpes zoster. PMID- 25916341 TI - Efficacy of an adjuvanted herpes zoster subunit vaccine in older adults. AB - BACKGROUND: In previous phase 1-2 clinical trials involving older adults, a subunit vaccine containing varicella-zoster virus glycoprotein E and the AS01B adjuvant system (called HZ/su) had a clinically acceptable safety profile and elicited a robust immune response. METHODS: We conducted a randomized, placebo controlled, phase 3 study in 18 countries to evaluate the efficacy and safety of HZ/su in older adults (>=50 years of age), stratified according to age group (50 to 59, 60 to 69, and >=70 years). Participants received two intramuscular doses of the vaccine or placebo 2 months apart. The primary objective was to assess the efficacy of the vaccine, as compared with placebo, in reducing the risk of herpes zoster in older adults. RESULTS: A total of 15,411 participants who could be evaluated received either the vaccine (7698 participants) or placebo (7713 participants). During a mean follow-up of 3.2 years, herpes zoster was confirmed in 6 participants in the vaccine group and in 210 participants in the placebo group (incidence rate, 0.3 vs. 9.1 per 1000 person-years) in the modified vaccinated cohort. Overall vaccine efficacy against herpes zoster was 97.2% (95% confidence interval [CI], 93.7 to 99.0; P<0.001). Vaccine efficacy was between 96.6% and 97.9% for all age groups. Solicited reports of injection-site and systemic reactions within 7 days after vaccination were more frequent in the vaccine group. There were solicited or unsolicited reports of grade 3 symptoms in 17.0% of vaccine recipients and 3.2% of placebo recipients. The proportions of participants who had serious adverse events or potential immune-mediated diseases or who died were similar in the two groups. CONCLUSIONS: The HZ/su vaccine significantly reduced the risk of herpes zoster in adults who were 50 years of age or older. Vaccine efficacy in adults who were 70 years of age or older was similar to that in the other two age groups. (Funded by GlaxoSmithKline Biologicals; ZOE-50 ClinicalTrials.gov number, NCT01165177.). PMID- 25916344 TI - The role of point-of-care platelet function testing in predicting postoperative bleeding following cardiac surgery: a systematic review and meta-analysis. AB - This systematic review and meta-analysis appraises the utility of point-of-care platelet function tests for predicting blood loss and transfusion requirements in cardiac surgical patients, and analyses whether their use within a transfusion management algorithm is associated with improved patient outcomes. We included 30 observational studies incorporating 3044 patients in the qualitative assessment, and nine randomised controlled trials including 1057 patients in the meta analysis. Platelet function tests demonstrated significant variability in their ability to predict blood loss and transfusion requirements. Their use within a blood transfusion algorithm demonstrated a reduction in blood loss at longest follow-up (mean difference -102.9 ml (95% CI -149.9 to -56.1 ml), p < 0.001), and transfusion of packed red cells (RR 0.86 (95% CI 0.78-0.94), p = 0.001) and fresh frozen plasma (RR 0.42 (95% CI 0.30-0.59), p < 0.001). Viscoelastic methods used in combination with other platelet function tests achieved greater reduction in blood loss (mean difference -111.8 ml (95% CI -174.9 to -49.1 ml), p = 0.0005) compared with their use alone (mean difference -90.6 ml (95% CI 166.1-15.0 ml), p = 0.02). We conclude that incorporation of point-of-care platelet function tests into transfusion management algorithms is associated with a reduction in blood loss and transfusion requirements in cardiac surgery patients. PMID- 25916343 TI - Deletion of Osr2 Partially Rescues Tooth Development in Runx2 Mutant Mice. AB - Tooth organogenesis depends on genetically programmed sequential and reciprocal inductive interactions between the dental epithelium and neural crest-derived mesenchyme. Previous studies showed that the Msx1 and Runx2 transcription factors are required for activation of odontogenic signals, including Bmp4 and Fgf3, in the early tooth mesenchyme to drive tooth morphogenesis through the bud-to-cap transition and that Runx2 acts downstream of Msx1 to activate Fgf3 expression. Recent studies identified Osr2 as a repressor of tooth development and showed that inactivation of Osr2 rescued molar tooth morphogenesis in the Msx1(-/-) mutant mice as well as in mice with neural crest-specific inactivation of Bmp4. Here we show that Runx2 expression is expanded in the tooth bud mesenchyme in Osr2(-/-) mutant mouse embryos and is partially restored in the tooth mesenchyme in Msx1(-/-)Osr2(-/-) mutants in comparison with Msx1(-/-) and wild-type embryos. Whereas mandibular molar development arrested at the bud stage and maxillary molar development arrested at the bud-to-cap transition in Runx2(-/-) mutant mice, both mandibular and maxillary molar tooth germs progressed to the early bell stage, with rescued expression of Msx1 and Bmp4 in the dental papilla as well as expression of Bmp4, p21, and Shh in the primary enamel knot in the Osr2( /-)Runx2(-/-) compound mutants. In contrast to the Msx1(-/-)Osr2(-/-) compound mutants, which exhibit nearly normal first molar morphogenesis, the Osr2(-/ )Runx2(-/-) compound mutant embryos failed to activate the expression of Fgf3 and Fgf10 in the dental papilla and exhibited significant deficit in cell proliferation in both the dental epithelium and mesenchyme in comparison with the control embryos. These data indicate that Runx2 synergizes with Msx1 to drive tooth morphogenesis through the bud-to-cap transition and that Runx2 controls continued tooth growth and morphogenesis beyond the cap stage through activation of Fgf3 and Fgf10 expression in the dental papilla. PMID- 25916345 TI - Predicting healthy and unhealthy behaviors through physical education: A self determination theory-based longitudinal approach. AB - The aim of this study was to evaluate the relations between three dimensions of the structured teaching environment (promotion of theoretical knowledge, physical learning, and health improvement) in physical education (PE) and the adoption of health-related behaviors by students. The study adopted a two-occasion longitudinal design based on self-determination theory (SDT). PE students (N = 654, mean age = 16.13, SD = .77) completed measures of perceived structured teaching environment, satisfaction of basic psychological needs and motivation for PE, and healthy (physical activity, sport participation, and healthy eating) and unhealthy (consumption of tobacco, alcohol, and drugs) behaviors at the beginning and end of the first year of post-compulsory secondary education. Path analysis of the proposed relations among variables supported SDT tenets and showed positive relations between the three dimensions of the structured teaching environment, the satisfaction of basic psychological needs, and autonomous motivation in PE. Autonomous motivation contributed to an explanation of variance in two healthy behaviors, physical activity and sport participation. However, no relation was found among motivation in PE, healthy eating, and consumption of tobacco, alcohol, and drugs. These results show negligible trans-contextual influence of SDT motivational factors in PE on other healthy behaviors beyond physical activity. PMID- 25916346 TI - A further Rasch study confirms that ALSFRS-R does not conform to fundamental measurement requirements. AB - Our objective was to verify and expand previous evidence of psychometric inadequacies in the ALSFRS-R, in a different sample of subjects suffering from ALS. Since 2009, a prospective registry records all incident cases of ALS in Emilia Romagna Region, Italy (4.4 million inhabitants) referred to its 17 neurological departments. For each patient, demographic and clinical information is collected by the physician in charge, including compilation of the ALSFRS-R at each clinical follow-up. Results showed that a confirmatory factor analysis on the three-factor model previously found (bulbar, motor, respiratory function) showed a good fit. Rasch analysis on the whole scale showed the need to collapse some rating categories, confirmed the multidimensionality of the ALSFRS-R, and demonstrated the presence of differential item functioning between patients with spinal versus bulbar onset. Moreover, some items included in the three ALSFRS-R subscales showed a problematic fit to the respective construct they were intended to measure. In conclusion, the interpretation of a total raw score of ALSFRS-R is hampered by ambiguities due to the different metric properties of the three domains the scale aggregates, and their content and structure. This study confirms that a refinement of ALSFRS-R is warranted, pointing to the need to revise its whole structure, and providing detailed guidelines for its revision. PMID- 25916347 TI - The Artistic Infant Directed Performance: A Mycroanalysis of the Adult's Movements and Sounds. AB - Intersubjectivity experiences established between adults and infants are partially determined by the particular ways in which adults are active in front of babies. An important amount of research focuses on the "musicality" of infant directed speech (defined melodic contours, tonal and rhythm variations, etc.) and its role in linguistic enculturation. However, researchers have recently suggested that adults also bring a multimodal performance to infants. According to this, some scholars seem to find indicators of the genesis of the performing arts (mainly music and dance) in such a multimodal stimulation. We analyze the adult performance using analytical categories and methodologies of analysis broadly validated in the fields of music performance and movement analysis in contemporary dance. We present microanalyses of an adult-7 month old infant interaction scene that evidenced structural aspects of infant directed multimodal performance compatible with music and dance structures, and suggest functions of adult performance similar to performing arts functions or related to them. PMID- 25916348 TI - The burden of comorbidity is associated with symptomatic polymicrobial urinary tract infection among institutionalized elderly. AB - BACKGROUND: Urinary tract infections (UTIs), often sustained by polymicrobial flora (p-UTIs), are a common finding among nursing home patients, and associated with adverse outcomes and increased healthcare costs. P-UTIs have been extensively studied with regard to microbiological aspects. However, little is known about the characteristics of the host. AIMS: The aim of this study is to verify to which extent comorbidity characterizes elderly nursing home patients with p-UTIs. METHODS: We enrolled 299 patients with culture-positive UTI consecutively admitted to the nursing home of the "Fondazione San Raffaele Cittadella della Carita", Taranto, Italy. P-UTI was diagnosed when two uropathogens were simultaneously isolated. The burden of comorbidity was quantified using the Charlson comorbidity score index. Logistic regression analysis was used to assess the adjusted association of the variables of interest with the presence of p-UTI. RESULTS: P-UTIs were detected in 118/299 (39%) patients. According to logistic regression, the presence of p-UTIs was independently associated with the Charlson index (OR 1.70; 95% CI 1.06-2.72; P = .026). This association remained also after excluding participants without urinary catheter (OR 1.88; 95% CI 1.13-3.11; P = .015). DISCUSSION: The presence of P-UTIs is associated with the burden of comorbidity, but not with individual diseases. CONCLUSIONS: Older nursing home patients with comorbidity should be screened for the presence of p-UTIs; further studies are needed to evaluate the impact of early detection and treatment of p-UTIs on the development of comorbidity. PMID- 25916349 TI - Young Children's Help-Seeking as Active Information Gathering. AB - Young children's social learning is a topic of great interest. Here, we examined preschoolers' (M = 52.44 months, SD = 9.7 months) help-seeking as a social information gathering activity that may optimize and support children's opportunities for learning. In a toy assembly task, we assessed each child's competency at assembling toys and the difficulty of each step of the task. We hypothesized that children's help-seeking would be a function of both initial competency and task difficulty. The results confirmed this prediction; all children were more likely to seek assistance on difficult steps and less competent children sought assistance more often. Moreover, the magnitude of the help-seeking requests (from asking for verbal confirmation to asking the adult to take over the task) similarly related to both competency and difficulty. The results provide support for viewing children's help-seeking as an information gathering activity, indicating that preschoolers flexibly adjust the level and amount of assistance to optimize their opportunities for learning. PMID- 25916351 TI - [Improve occupational health promotion and promote new situation of occupational health]. PMID- 25916350 TI - HIV-1 subtypes and drug resistance profiles in a cohort of heterosexual patients in Istanbul, Turkey. AB - Turkey is seeing a steady rise in rates of HIV infection in the country. The number of individuals with HIV/AIDS was greater than 7000 in 2014 according to data released by the Ministry of Health, and heterosexual contacts were reported to be the main transmission routes. Istanbul has the highest number of reported cases of HIV infection. The aim of the study was to determine the prevalence of HIV-1 drug resistance in 50 heterosexual patients from Istanbul. The most prevalent subtype was found to be subtype B (56.2 %). Resistance-associated mutations were found in 14 patients with 6/14 patients being therapy-experienced and 8/14 therapy naive at the time point of analysis. With increasing number of patients who require treatment and the rapid up-scaling of the antiretroviral therapy in Turkey, HIV-1 drug resistance testing is recommended before starting treatment in order to achieve better clinical outcomes. PMID- 25916352 TI - [Relationship of personality with job burnout and psychological stress risk in clinicians]. AB - OBJECTIVE: To analyze the job burnout and mental health status of clinicians and the relationship of personality with job burnout and psychological stress, and to investigate the direct or indirect effects of personality on psychological stress. METHODS: Maslach Burnout Inventory-General Survey (MBI-GS), Eysenck Personality Questionnaire-Revised Short Scale (EPQ-RSC), and Kessler 10 Scale were administered to 775 clinicians. RESULTS: Of all clinicians, 29.5% had mild burnout, with a score of 22.7 +/- 8.18 for psychological stress risk. The effect of personality on emotional exhaustion and cynicism was greater than that on personal accomplishment. Clinicians with a personality of introversion, neuroticism, and psychoticism suffered a higher risk of psychological stress. Personality had both direct and indirect effects on psychological stress. Neuroticism had the strongest effect on psychological stress, with an effect size of 0.55. CONCLUSION: Clinicians have a high level of both job burnout and mental psychological stress risk. Personality is significantly correlated with job burnout and psychological stress risk. Measures depending on personality should be taken for effective intervention. PMID- 25916353 TI - [Association between occupational psychological stress and metabolic syndrome]. AB - OBJECTIVE: To investigate the association between occupational psychological stress and metabolic syndrome (MS) in Hui and Han populations in Ningxia, China. METHODS: A 1:1 matched case-control study was performed. A total of 600 unrelated patients aged from 20 to 60 years who were clearly diagnosed with MS in General Hospital of Ningxia Medical University and Wuzhong People's Hospital from October 2011 to October 2012 were collected as the case group (MS group). A total of 600 healthy people who underwent a regular health examination in the same hospital during the same period were selected as the control group with matched gender, nationality, and age (<= +/- 3 years). The self-designed questionnaire was used to investigate the general situations and do the physical examination, and the fasting venous blood samples were collected for laboratory biochemical blood tests. The Occupational Stress Inventory (OSI) was used to investigate the subjects' occupational stress factors and stress levels. RESULTS: With the increase in stress levels, the levels of WC, FPG, TG, AST, and UA were increased, WHR, SBP, and DBP first increased and then decreased, and the level of HDL-C increased. There were statistically significant differences in these parameters between the two groups (P < 0.05 or 0.01). The occupational psychological stress test results showed that the total score of stress factors (t = 6.676, P < 0.05), workload (t = 10.269, P < 0.05), interpersonal relationship (t = 6.569, P < 0.05), family/work balance (t = 2.028, P < 0.05), cognitive load (t = 8.714, P < 0.05), and other scores (t = 2.838, P < 0.05) in the MS group were all significantly higher than those in the control group, but there were no significant differences in the scores of management role, work responsibilities, and organizational climate between the MS group and the control group (P>0.05). There were no significant differences in the total score of stress factors and the score of each factor between Hui and Han groups (P>0.05). The relative risks of MS in the people with moderate stress exposure were 2.325 and 2.331 times those in the people with mild stress exposure before and after adjustment for age, gender, education level, marriage status, smoking, and drinking, and the relative risks for MS in the people with severe stress exposure were 3.000 and 3.126 times those in the people with mild stress exposure. There were significant differences in the detection rates of abdominal obesity, high TG, low HDL-C, hypertension, hyperglycemia, and diabetes between the sub-groups with different stress levels in the MS group (chi2 = 17.636, 8.514, 14.640, 14.280, and 33.323, P < 0.01). The results of multivariate conditional logistic regression analysis showed that the risk factors for MS were SBP, TG, LDL-C, UA, BMI, fasting blood glucose, family history of hypertension, family history of diabetes, and the level of psychological stress in Ningxia, and the protective factor for MS was HDL-C. CONCLUSION: The occupational psychological stress is closely associated with MS, and it is an environmental risk factor for MS. With the increase in the stress level, the detection rates of MS components and the relative risk for MS are significantly increased. And there is no significant difference in the level of occupational psychological stress between the Hui and Han nationality groups. PMID- 25916354 TI - [Effects of mental workload on work ability in primary and secondary school teachers]. AB - OBJECTIVE: To investigate the change pattern of primary and secondary school teachers' work ability with the changes in their mental workload. METHODS: A total of 901 primary and secondary school teachers were selected by random cluster sampling, and then their mental workload and work ability were assessed by National Aeronautics and Space Administration-Task Load Index (NASA-TLX) and Work Ability Index (WAI) questionnaires, whose reliability and validity had been tested. The effects of their mental workload on the work ability were analyzed. RESULTS: Primary and secondary school teachers' work ability reached the highest level at a certain level of mental workload (55.73< mental workload <= 64.10). When their mental workload was lower than the level, their work ability had a positive correlation with the mental workload. Their work ability increased or maintained stable with the increasing mental workload. Moreover, the percentage of teachers with good work ability increased, while that of teachers with moderate work ability decreased. But when their mental workload was higher than the level, their work ability had a negative correlation with the mental workload. Their work ability significantly decreased with the increasing mental workload (P < 0.01). Furthermore, the percentage of teachers with good work ability decreased, while that of teachers with moderate work ability increased (P < 0.001). CONCLUSION: Too high or low mental workload will result in the decline of primary and secondary school teachers' work ability. Moderate mental workload (55.73~64.10) will benefit the maintaining and stabilization of their work ability. PMID- 25916355 TI - [Assessment and analysis of 108 health promotion demonstration enterprises in Jiangsu Province, China]. AB - OBJECTIVE: To investigate the current status of carrying out the workplace health promotion (WHP) in the enterprises, and to provide a basis for formulation of relevant policies. METHODS: The enterprises that declared Jiangsu Provincial Health Promotion Demonstration Enterprise received on-site assessment by the expert group, including organization management and protection measures, health management, workplace, health, and cultural environment. And a questionnaire survey was performed. The data of evaluations were analyzed by SPSS 19.0. RESULTS: In the last four years, 108 enterprises which had achieved the standard of Health Promotion Demonstration Enterprise were mainly distributed in Southern Jiangsu, including 34 (31.48%) large-sized enterprises, 58 (53.70%) medium-sized enterprises, and 16 (14.81%) small-sized enterprises. And there were 49 (45.37%) wholly foreign-owned enterprises. There were significant differences in the scores between different economic types of enterprises (F = 2.820, P = 0.014). The most deducted points were due to unqualified bulletin boards and warning label of occupation hazards, about 78 times (72.22%); 54.55% of the indices whose deduction rates were higher than 20% were related to occupational disease prevention and control. CONCLUSION: Regions and economic types affect carrying out WHP in enterprises. The current priority is to standardize physical work environment in China. The professional technical level should be improved, and the government needs to redouble efforts to promote the WHP. PMID- 25916356 TI - [Analysis of work-related fatigue characteristics and its influencing factors in scientific and technical personnel]. AB - OBJECTIVE: To investigate the current status and characteristics of work-related fatigue among scientific and technical personnel and its associated factors, and to provide a scientific basis for further interventions. METHODS: A cross sectional survey was conducted in the staff from a single scientific institution, using a self-administered questionnaire. Basic information of participants, Fatigue Scale-14, and Job Content Questionnaire were collected. RESULTS: The prevalence of work-related fatigue among the scientific and technical personnel was 54.6%; work-related fatigue was positively correlated with occupational stress (rs = 0.384, P < 0.05). Significant differences in the scores, proportions, and types of fatigue were found between different types of occupational stress. The associated factors of work-related fatigue included occupational stress profiles, social support, and educational status. A higher risk of work-related fatigue was found in the staff under high stress, compared with those under low stress (OR = 8.5, 95%CI = 3.9~18.7). Social support served as a protective factor for work-related fatigue, while a higher level of education was correlated with more severe work-related fatigue. CONCLUSION: Work related fatigue is common and serious among scientific and technical personnel, especially in those under high stress. Effective interventions according to occupational stress are of great importance to reduce work-related fatigue. PMID- 25916357 TI - [Occupational hazards of organic solvents in the workplace in Guangzhou]. PMID- 25916358 TI - [Status of job burnout and work ability in college teachers]. PMID- 25916359 TI - [Association between occupational stress, social support, and occupational unintentional injuries: a case-control study]. AB - OBJECTIVE: To evaluate the association between occupational stress, social support, and occupational unintentional injuries. METHODS: A 1:1 matched case control study was conducted in 151 cases of occupational unintentional injuries who were admitted to 6 occupational injury-admitted hospitals in Zhongshan City from October 2013 to December 2013 and 151 matched controls without unintentional injuries in the last year who had matched age, sex, and occupation. Their demographic characteristics, occupational stress (by the effort-reward imbalance questionnaire), and social support were investigated with a structured questionnaire. RESULTS: Analysis of the data showed that there were significant differences in the score of each dimension of occupational stress, the ratio of effort to reward, and the score of superior support between the case group and the control group (P < 0.05). The Cox regression analysis results showed that more extrinsic efforts (OR = 1.47, 95%CI = 1.20~1.80) and over commitment (OR = 1.30, 95%CI = 1.08~1.55) were the risk factors for occupational unintentional injuries, while more superior supports (OR = 0.64, 95%CI = 0.48~0.84) and higher earnings (>3 000 yuan each month) (OR = 0.67, 95%CI = 0.54~0.84) were protective factors. CONCLUSION: Occupational stress and social support have an influence on the occurrence of occupational injuries. PMID- 25916360 TI - [Correlation between nurse job burnout and salivary lysozyme activity]. AB - OBJECTIVE: To investigate the correlation between nurse job burnout and salivary lysozyme activity. METHODS: The saliva samples of 131 subjects were collected at four time points for two consecutive days with saliva collection tubes. The acquisition time points were 8:00 (baseline concentration), 10:00 (morning), 15:30 (afternoon), and 17:30 (recovery period). At the same time every subjects completed the job burnout questionnaire to investigate their general demographic characteristics and job burnout level. The salivary lysozyme concentration was measured with ELISA. The data were analyzed by partial correlation analysis and multiple stepwise regression analysis. RESULTS: There were significant differences in the salivary lysozyme activity between subjects with different ages, working years, and education levels. The work period vitality and the average energy of <= 30 age group were higher than other two groups and the recovery energy was higher than >35 age group. Working period vitality, the average energy of group >15 years were less than <= 10 years group. The work period energy and the average energy of university (college) and above group were lower than high school (secondary) and the following group. Job burnout and its three dimensions had a significant negative correlation with salivary lysozyme concentration (P < 0.01). Depersonalization and emotional exhaustion were the negative impact factors for salivary lysozyme activity at baseline. Emotional exhaustion and personal fulfillment were the negative impact factors for salivary lysozyme activity during the working period. Personal fulfillment was the negative factor for salivary lysozyme activity during the recovery period and the average salivary lysozyme activity. CONCLUSION: Salivary lysozyme activity is sensitive for nurse job burnout, so it can be used as an objective evaluation index of job burnout. PMID- 25916361 TI - [Quality of life and influencing factors for patients with silicosis: an analysis of 220 cases]. AB - OBJECTIVE: To investigate the quality of life and influencing factors for patients with silicosis and to provide a basis for treatment of silicosis. METHODS: Two hundred and twenty stone workers with silicosis from June 1999 to June 2014 were enrolled into observation group, while healthy stone workers within the same period were used as controls. The quality of life was evaluated using the Chinese version of the World Health Organization Quality of Life Assessment (WHOQOL-100), and the influencing factors were determined using stepwise multivariate regression analysis. RESULTS: The scores for psychological function, physiological, independence, spiritual realm, the overall quality of life, and physical condition in the observation group were significantly lower than those in the control group (t = 7.1168, P < 0.05; t = 3.8165, P < 0.05; t = 5.9230, P < 0.05; t = 2.7764, P < 0.05; t = 3.0761, P < 0.05). The scores for 11 items including pain, discomfort, energy, fatigue, sleep, and rest in the observation group were significantly lower than those in the control group (P < 0.05). Negative emotions, silicosis stage, recreation, age, reliance on health care, pain, discomfort, and spiritual beliefs were all influencing factors for the quality of life, which resulted in 68.3% of variation in the quality of life. CONCLUSION: Besides clinical treatment, health and psychological education and recreation are important for patients with silicosis to improve their quality of life. PMID- 25916362 TI - [Professional chronic benzene poisoning in workers exposed to low-concentration benzene: a report of 5 cases]. PMID- 25916363 TI - [Correlation between nurse occupational stress and salivary alpha-amylase: an analysis of 131 cases]. AB - OBJECTIVE: To explore the relationship between nurse occupational stress and salivary alpha- amylase (SAA). METHODS: Evaluation of occupational stress was conducted in 131 nurses. The activity of SAA was determined using enzyme-linked immunosorbent assay (ELISA). RESULTS: The activity of SAA in nurses varied with age and working years. The baseline, work period, recovery, average activities of >35 age group were less than those of <= 30 age group; work period, recovery, average activities of <= 10 years group were higher than other two groups; there was no statistical difference between SAA vitalities of different degree groups (P>0.05). In nurses with high scores for job demands, the activity of SAA in working period was significantly higher than that in nurses with low scores (P < 0.05). The baseline SAA activity in nurses with high scores for role conflict and ambiguity was significantly higherthan thatin nurses with low scores (P < 0.05). The baseline SAAactivity was positively correlated with workload, role conflict, and role ambiguity (P < 0.05). The activity of SAA in working period was negatively correlated with task control, decision control, and technology utilization (P < 0.05), and was positively correlated with quantitative load, load change, work monotony, and workload (P < 0.05). The activity of SAA in recovery period was negatively correlated with task control, decision control, resource control, and technology utilization (P < 0.01). The average activity of SAA was negatively correlated with task control, decision control, resource control, technology utilization, opportunity for participating in decision making, and promotion (P < 0.05), and was positively correlated with quantitative load, load change, workload, and role ambiguity (P < 0.05). CONCLUSION: The occupational stress in 131 nurses is correlated with the activity of SAA, which can be used as an objective biomarker for identification and evaluation of occupational stress. PMID- 25916364 TI - [Investigation and intervention of nursing staff psychological state after needle stick injury]. PMID- 25916365 TI - [Effects of simulated nitrogen-oxygen saturation exposure at a water depth of 50m on expression of inflammatory mediators in external auditory canal of rabbits]. AB - OBJECTIVE: To investigate the effects of simulated nitrogen-oxygen saturation exposure at a water depth of 50 m on the expression of inflammatory mediators including interleukin-6 (IL-6), interleukin-10 (IL-10), and tumor necrosis factor alpha (TNF-alpha) in the external auditory canal (EAC) of rabbits. METHODS: Two batches of New Zealand rabbits were exposed to nitrogen-oxygen saturated at a water depth of 50 m. After exposure, the epithelial tissue in the EAC was analyzed using hematoxylin-eosin (HE) staining, and the changes in expression of inflammatory mediators including IL-6, IL-10, and TNF-alpha in the EAC of rabbits were determined by real-time polymerase chain reaction (PCR). RESULTS: According to the result of HE staining, more inflammatory cell infiltration, small vascular congestion, and mucosal edema in the EAC of rabbits were observed in the exposure group than in the control group. Additionally, compared with the control group, the exposure group had increased expression of IL-6 and TNF-alpha and reduced expression of IL-10 in the EAC of rabbits according to the result of real-time PCR. CONCLUSION: The nitrogen-oxygen saturation exposure at a water depth of 50 m can cause inflammatory injuries in the EAC of rabbits. The mechanism may be associated with increased expression of IL-6 and TNF-alpha and reduced expression of IL-10. PMID- 25916366 TI - [Analysis of pathogen distribution and drug resistance in coal workers' pneumoconiosis associated with pneumonia]. AB - OBJECTIVE: To investigate the pathogen distribution and drug resistance in coal workers' pneumoconiosis associated with pneumonia and to provide a scientific basis for early guidance for rational clinical application of antibacterial agents. METHODS: Seventy-six patients with coal workers' pneumoconiosis associated with pneumonia who were admitted to our hospital from June 2011 to June 2014 were enrolled as subjects. The sputum specimens were aseptically collected for bacterial culture and drug sensitivity tests. RESULTS: In 245 sputum specimens collected from 76 patients, a total of 218 strains of pathogens, including 163 strains of Gram-negative bacilli (74.77%), 39 strains of Gram positive cocci (17.89%), and 16 strains of fungi (7.34%) were isolated by bacteriological tests. The main Gram-negative bacilli had high rates of resistance to amoxicillin/clavulanic acid, ampicillin, cotrimoxazole, cefotaxime, and aztreonam, and were sensitive to amikacin, imipenem, and meropenem. The main Gram-positive cocci had high rates of resistance to penicillin, erythromycin, amoxicillin/clavulanic acid, ampicillin, cefotaxime, and clindamycin, and were sensitive to vancomycin and teicoplanin. CONCLUSION: The main pathogens in these patients with coal workers' pneumoconiosis associated with pneumonia are Gram negative bacilli, which are highly resistant to common clinically used antibacterial agents. The pathogen distribution and drug resistance should be well understood, and the antibacterial agents should be rationally selected according to the results of drug sensitivity tests. PMID- 25916367 TI - [Clinical features of cervical spondylopathy in surgeons: an analysis of 338 cases]. PMID- 25916368 TI - [Liquid chromatography for determination of disulfiramin workplace atmosphere]. AB - OBJECTIVE: To establish a method for determination of disulfiram in the workplace atmosphere by liquid chromatography. METHODS: Sampling with glass fiber filter, eluting with methanol, separating with C18 column, and determination with liquid chromatography. RESULTS: The bearing capacity of glass fiber filter exceeded 3.45 mg per piece. The elution efficiency was 97.8%~101.0% The relative standard deviation varied from 1.09% to 1.44%. The limit of detection was 0.1 ug/ml. The minimum detectable concentration was 0.011 mg/m3 (with sampled air volume of 45 L). CONCLUSION: The method has high selectivity, accuracy, and precision and strong applicability. PMID- 25916369 TI - [Improvement of the calibration method on the determination of lead in blood with acid deproteinization method]. PMID- 25916370 TI - [Study of GC/MS/AMDIS in identification VOCs in industrial chemicals]. PMID- 25916371 TI - [Solvent desorption gas chromatography for determination of allyl chloride in workplace atmosphere]. AB - OBJECTIVE: To establish a method for determination of allyl chloride in the workplace atmosphere by solvent desorption-capillary column gas chromatography. METHODS: Allyl chloride in the atmosphere was adsorbed by activated charcoal tubes and desorbed using dichloromethane, and was then separated by capillary column gas chromatography and determined by flame ionization detector. RESULTS: The concentration of allyl chloride showed a good linear relationship within the range of 0~200 ug/ml. The linear regression equation was y = 1.27x-0.22 with the correlation coefficient r being 0.999 8. The limit of detection was 0.20 ug /mL. If 7.5 L of air was sampled, the minimum detectable concentration was 0.03 mg/m3. The intra-day and inter-day relative standard deviations (RSD) of repetitive measurement at the high, middle, and low concentration levels were 2.7%~4.8%. The average sampling efficiency was 100%. The overall desorption efficiency was 94.4%. The breakthrough volume was over 0.59 mg (100 mg activated charcoal). CONCLUSION: The method applies to the determination of allyl chloride in the workplace atmosphere. PMID- 25916372 TI - [Gas chromatography for determination of N-isopropylaniline in workplace atmosphere]. AB - OBJECTIVE: To establish a method for determination of N-isopropylaniline in the workplace atmosphere by gas chromatography. METHODS: Air samples were collected by silica gel tube and desorbed by acetone. Then they were separated through DB WAX columns and N-isopropylaniline was determined by flame ionization detector. RESULTS: The concentration of N-isopropylaniline showed a good linear relationship within the range of 1.40~665.0 ug/ml. The sampling efficiency was 100%. The accuracy was 96%~ 99% and the precision was 2.1%~7.0%. The minimum detectable concentration was 0.056 mg/m(3) (with sampled air volume of 7.5 L). CONCLUSION: The method meets the requirements of analysis and applies to the determination of N-isopropylaniline in the workplace atmosphere. PMID- 25916373 TI - [Gas chromatography for determination of N-butylbenzene in workplace atmosphere]. AB - OBJECTIVE: To establish a method for the determination of N-butylbenzene in the workplace atmosphere by gas chromatography. METHODS: N-butylbenzene in the workplace atmosphere was collected by activated charcoal tube, desorbed using carbon disulfide, and determined by capillary column gas chromatography. RESULTS: The method showed a linear relationship within the range of 0~100 ug/ml. The regression equation was y = 0.870x-0.014, with the correlation coefficient r being 0.999 9. The limit of detection was 0.32 ug/ml. The minimum detectable concentration was 0.21 mg/m3 (with sampled air volume of 1.5 L). The average spike recovery rate was 97.8%~102.6%. The within-run precision was 3.06% and the between-run precision was 3.64%. The rate of average desorption was 99.6%. The breakthrough volume was 6.34 mg. The sampling efficiency was 100%. The samples could be stored for at least 7 days at room temperature. CONCLUSION: All parameters of the method meet the requirements of GBZ/T 210.4-2008 "Guide for establishing occupational health standards-Part 4 Determination methods of air chemicals in workplace" and can be applied for the determination of N butylbenzene in workplace atmosphere. PMID- 25916374 TI - [Determination of tebuconazole in serum by gas chromatography]. PMID- 25916375 TI - [Analysis of current status of occupational health examination and occupational disease diagnosis in Guizhou Province, China]. PMID- 25916376 TI - [Introduction of total health promotion in Japan]. PMID- 25916377 TI - [Disaccordance between diagnosis and identification of occupational disease: an analysis of one case]. PMID- 25916378 TI - [Development of radiography auxiliary device for vertical sternumstand of vehicular X-ray apparatus]. PMID- 25916379 TI - [A case of health promotion in an electronic enterprise]. PMID- 25916380 TI - Redox status in acute ischemic stroke: correlation with clinical outcome. AB - Connection between oxidative stress and clinical outcome in acute ischemic stroke (AIS) has been poorly investigated. This study was aimed to assess redox state (through measurement of oxidative stress markers) of patients with acute ischemic stroke during different stages of follow-up period, and to find association between values of mentioned markers and clinical outcome. The investigation was conducted on 60 patients (both sexes, aged 75.90 +/- 7.37 years) who were recruited in intensive care units at the Special Hospital for Cerebrovascular Diseases "Sveti Sava," Belgrade. After verification of AIS, patients were followed up in four interval of time: (1) at admission, (2) within 24 h after AIS, (3) within 72 h after AIS, and (4) 7 days after AIS. At these points of time, blood samples were taken for determination of oxidative stress parameters [index of lipid peroxidation (measured as TBARS), nitric oxide (NO) in the form of nitrite ([Formula: see text]), superoxide anion radical ([Formula: see text]), hydrogen peroxide (H2O2)], and enzymes of antioxidant defense system [superoxide dismutase (SOD) and catalase (CAT)] using spectrophotometer. Present study provides new insights into redox homeostasis during ischemic stroke which may be of interest in elucidation of molecular mechanisms involved in this life threatening condition. Particular contribution of obtained results could be examination of connection between redox disruption and clinical outcome in these patients. In that sense, our finding have pointed out that [Formula: see text] and NO can serve as the most relevant adjuvant biomarkers to monitor disease progression and evaluate therapies. PMID- 25916381 TI - HDAC7 modulates TNF-alpha-mediated suppression of Leydig cell steroidogenesis. AB - The pro-inflammatory cytokine tumor necrosis factor-alpha (TNF-alpha) has an inhibitory role in gonadal functions particularly in the steroidogenesis of Leydig cells. In the present study, we demonstrate that TNF-alpha activates histone deacetylases 7 (HDAC7), which regulates the expression of steroidogenic enzyme genes in Leydig cells. LC-540 Leydig cells were treated with TNF-alpha (10 ng/ml) for different time intervals. TNF-alpha treatment significantly suppressed histone H3 acetylation and methylation and, concomitantly, increased the total histone deacetylases activity in LC-540 Leydig cells. RT-PCR and western blot analysis revealed that HDAC7 was up-regulated in TNF-alpha-treated cells. Our results also demonstrated that an siRNA-mediated knockdown of HDAC7 restores the expression of steroidogenic proteins in TNF-alpha-treated Leydig cells. These findings provide valuable information that TNF-alpha-mediated suppression of steroidogenesis involves HDAC7 in Leydig cells. PMID- 25916382 TI - Lifestyle-related risk factors and trajectories of work disability over 5 years in employees with diabetes: findings from two prospective cohort studies. AB - AIMS: To examine work disability trajectories among employees with and without diabetes and identify lifestyle-related factors associated with these trajectories. METHODS: We assessed work disability using records of sickness absence and disability pension among participants with diabetes and age- sex-, socio-economic status- and marital status-matched controls in the Finnish Public Sector Study (1102 cases; 2204 controls) and the French GAZEL study (500 cases; 1000 controls), followed up for 5 years. Obesity, physical activity, smoking and alcohol consumption were assessed at baseline and the data analysed using group based trajectory modelling. RESULTS: Five trajectories described work disability: 'no/very low disability' (41.1% among cases and 48.0% among controls); 'low steady' (35.4 and 34.7%, respectively); 'high-steady' (13.6 and 12.1%, respectively); and two 'high-increasing' trajectories (10.0 and 5.2%, respectively). Diabetes was associated with a 'high-increasing' trajectory only (odds ratio 1.90, 95% CI 1.47-2.46). Obesity and low physical activity were similarly associated with high work disability in people with and without diabetes. Smoking was associated with 'high-increasing' trajectory in employees with diabetes (odds ratio 1.88, 95% CI 1.21-2.93) but not in those without diabetes (odds ratio 1.32, 95% CI 0.87-2.00). Diabetes was associated with having multiple ( >= 2) risk factors (21.1 vs. 11.4%) but the association between multiple risk factors and the 'high-increasing' trajectory was similar in both groups. CONCLUSIONS: The majority of employees with diabetes have low disability rates, although 10% are on a high and increasing disability trajectory. Lifestyle related risk factors have similar associations with disability among employees with and without diabetes, except smoking which was only associated with poorer prognosis in diabetes. PMID- 25916383 TI - Atypical MRI features in soft-tissue arteriovenous malformation: a novel imaging appearance with radiologic-pathologic correlation. AB - BACKGROUND: The absence of a discrete mass, surrounding signal abnormality and solid enhancement are imaging features that have traditionally been used to differentiate soft-tissue arteriovenous malformations from vascular tumors on MRI. We have observed that these findings are not uncommon in arteriovenous malformations, which may lead to misdiagnosis or inappropriate treatment. OBJECTIVE: To estimate the frequency of atypical MRI features in soft-tissue arteriovenous malformations and assess their relationship to lesion size, location, tissue type involved and vascular architecture. MATERIALS AND METHODS: Medical records, MRI and histopathology were reviewed in consecutive patients with soft-tissue arteriovenous malformations in a multidisciplinary vascular anomalies clinic. Arteriovenous malformations were divided into those with and without atypical MRI findings (perilesional T2 signal abnormality, enhancement and/or a soft-tissue mass). Lesion location, size, tissue involved and vascular architecture were also compared between groups. Tissue stains were reviewed in available biopsy or resection specimens to assess relationships between MRI findings and histopathology. RESULTS: Thirty patients with treatment-naive arteriovenous malformations were included. Fifteen lesions demonstrated atypical MRI. There was no difference in age, gender, lesion size or involved body part between the groups. However, more than half of the atypical lesions demonstrated multicompartmental involvement, and tiny intralesional flow voids were more common in atypical arteriovenous malformations. Histopathology also differed in atypical cases, showing densely packed endothelial cells with connective tissue architectural distortion and edema. CONCLUSION: Arteriovenous malformations may exhibit features of a vascular tumor on MRI, particularly when multicompartmental and/or containing tiny internal vessels. These features are important to consider in suspected fast-flow vascular malformations and may have implications with respect to their treatment. PMID- 25916384 TI - Appendiceal diameter as a predictor of appendicitis in children: improved diagnosis with three diagnostic categories derived from a logistic predictive model. AB - OBJECTIVES: To develop and assess the performance of a diameter-based logistic predictive model and a derived 3-category interpretive scheme for the sonographic diagnosis of paediatric appendicitis. METHODS: Appendiceal diameters were extracted from reports of ultrasound examinations in children and young adults. Data were used to generate a logistic predictive model which was used to define negative, equivocal and positive interpretive categories. Diagnostic performance of the derived 3-category interpretive scheme was compared with simulated binary interpretive schemes. RESULTS: Six hundred forty-one appendix ultrasound reports were reviewed with appendicitis present in 181 (28.2 %). Cut-off diameters based on the logistic predictive model were <=6 mm = normal, >6 mm-8 mm = equivocal and >8 mm = positive with appendicitis present in 2.6 % (11/428), 64.9 % (72/111) and 96.1 % (98/102) of cases in each group. These cut-offs conferred 97.2 % accuracy with 17.3 % (111/641) of cases considered equivocal. Of the binary cut-offs, a 6 mm cut-off performed best with 91.6 % accuracy. AIC analysis favoured the logistic model over the binary model for prediction of appendicitis. CONCLUSIONS: A 3-category interpretive scheme based on a logistic predictive model provides higher accuracy in the diagnosis of appendicitis than traditional binary diameter cut-offs. Inclusion of an equivocal interpretive category more accurately reflects the probability distribution of prediction of appendicitis by ultrasound. KEY POINTS: * Three diameter categories outperform a 6-mm cut-off to diagnose appendicitis * Three categories allow more confident exclusion of appendicitis * Three categories allow more confident diagnosis of appendicitis * Three categories more accurately reflect the probability of appendicitis by ultrasound. PMID- 25916385 TI - Differential diagnosis of pancreatic cancer from other solid tumours arising from the periampullary area on MDCT. AB - PURPOSE: To investigate CT features and differential diagnosis of pancreatic adenocarcinoma compared to other solid tumours arising in the periampullary area. MATERIALS AND METHODS: One hundred and ninety-five patients with pathologically proven, solid periampullary tumours, including pancreatic adenocarcinoma (n = 98), neuroendocrine tumours (n = 52), gastrointestinal stromal tumours (n = 31), and solid pseudopapillary neoplasms (n = 14), underwent preoperative CT. Two radiologists reviewed CT features and rated the possibility of pancreatic adenocarcinoma. RESULTS: Statistically common findings for pancreatic adenocarcinoma included: patient age >50 years; ill-defined margin; completely solid mass; homogeneous enhancement; hypoenhancement on arterial and venous phases; atrophy; and duct dilatation. Statistically common findings for GIST included: heterogeneous enhancement; hyperenhancement on arterial and venous phases; rim enhancement; and prominent feeding arteries. The hyperenhancement on arterial and venous phases is statistically common in NET, and heterogeneous enhancement, hypoenhancement on the arterial and venous phases are statistically common in SPN. Diagnostic performance of CT for differentiating pancreatic adenocarcinomas from other solid periampullary tumours was 0.962 and 0.977 with excellent interobserver agreement (kappa = 0.824). CONCLUSION: CT is useful not only for differentiating pancreatic adenocarcinoma form other solid tumours but also for differentiating between other solid tumours, including NET, SPN, and GIST, arising in the periampullary area. KEY POINTS: * Periampullary tumours arise within 2 cm of major duodenal papilla. * Many mass-forming periampullary tumours can be completely removed by minimal surgery. * Accurate differentiation of pancreatic adenocarcinoma from other solid tumours is important. * CT is useful for differentiating pancreatic adenocarcinoma from other solid tumours. * CT is useful for characterization of periampullary tumours other than adenocarcinomas. PMID- 25916386 TI - Proton density fat-fraction is an accurate biomarker of hepatic steatosis in adolescent girls and young women. AB - OBJECTIVES: To compare complex quantitative magnetic resonance imaging (MRI) with MR spectroscopy (MRS) for quantification of hepatic steatosis (HS) and determine clinically significant MRI-based thresholds of HS in female youths. METHODS: This prospective, cross-sectional study was conducted in 132 healthy females (11-22 years, mean 13.3 +/- 2). Proton density fat-fraction (PDFF) was measured using complex quantitative MRI and MRS. Body mass index (BMI), fasting labs [glucose, insulin, alanine aminotransferase (ALT), and other metabolic markers] were obtained. Outcomes were measured using regression analysis, Spearman-rank correlation, and receiver operator characteristics (ROC) analysis. HS was defined as MRI-PDFF >5.6%. RESULTS: HS was detected by MRI-PDFF in 15% of all subjects. Linear regression demonstrated excellent correlation and agreement [r(2) = 0.96, slope = 0.97 (95 %CI: 0.94-1.00), intercept = 0.78% (95 %CI: 0.58-0.98%)] between MRI-PDFF and MRS-PDFF. MRI-PDFF had a sensitivity of 100% (95 %CI: 0.79-1.00), specificity of 96.6% (95 %CI: 0.91-0.99), and a kappa index of 87% (95 %CI: 0.75 0.99) for identifying HS. In overweight subjects with HS, MRI-PDFF correlated with ALT (r = 0.84, p < 0.0001) and insulin (r = 0.833, p < 0.001), but not with BMI or WC. ROC analysis ascertained an optimal MRI-PDFF threshold of 3.5% for predicting metabolic syndrome (sensitivity = 76 %, specificity = 83 %). CONCLUSION: Complex quantitative MRI demonstrates strong correlation and agreement with MRS to quantify hepatic triglyceride content in adolescent girls and young women. A low PDFF threshold is predictive of metabolic syndrome in this population. KEY POINTS: * Confounder-corrected quantitative MRI (ccqMRI) effectively measures hepatic triglyceride content in adolescent girls. * MRS and ccqMRI strongly correlate in liver proton density fat-fraction (PDFF) detection. * A PDFF threshold of 3.5% may be predictive of paediatric metabolic syndrome. PMID- 25916387 TI - Volume-based quantitative FDG PET/CT metrics and their association with optimal debulking and progression-free survival in patients with recurrent ovarian cancer undergoing secondary cytoreductive surgery. AB - OBJECTIVE: Our aim was to evaluate the associations between quantitative (18)F fluorodeoxyglucose positron-emission tomography (FDG-PET) uptake metrics, optimal debulking (OD) and progression-free survival (PFS) in patients with recurrent ovarian cancer undergoing secondary cytoreductive surgery. METHODS: Fifty-five patients with recurrent ovarian cancer underwent FDG-PET/CT within 90 days prior to surgery. Standardized uptake values (SUVmax), metabolically active tumour volumes (MTV), and total lesion glycolysis (TLG) were measured on PET. Exact logistic regression, Kaplan-Meier curves and the log-rank test were used to assess associations between imaging metrics, OD and PFS. RESULTS: MTV (p = 0.0025) and TLG (p = 0.0043) were associated with OD; however, there was no significant association between SUVmax and debulking status (p = 0.83). Patients with an MTV above 7.52 mL and/or a TLG above 35.94 g had significantly shorter PFS (p = 0.0191 for MTV and p = 0.0069 for TLG). SUVmax was not significantly related to PFS (p = 0.10). PFS estimates at 3.5 years after surgery were 0.42 for patients with an MTV <= 7.52 mL and 0.19 for patients with an MTV > 7.52 mL; 0.46 for patients with a TLG <= 35.94 g and 0.15 for patients with a TLG > 35.94 g. CONCLUSION: FDG-PET metrics that reflect metabolic tumour burden are associated with optimal secondary cytoreductive surgery and progression-free survival in patients with recurrent ovarian cancer. KEY POINTS: * Both TLG and MTV were associated with optimal tumour debulking. * There was no significant association between SUVmax and tumour debulking status. * Patients with higher MTV and/or TLG had significantly shorter PFS. * SUVmax was not significantly related to PFS. PMID- 25916388 TI - Interest of HYPR flow dynamic MRA for characterization of cerebral arteriovenous malformations: comparison with TRICKS MRA and catheter DSA. AB - OBJECTIVE: HYPR flow is a 3D dynamic contrast-enhanced MRA technique providing isotropic sub-millimetre resolution with half-second temporal resolution. We compared HYPR flow and time-resolved imaging of contrast kinetics (TRICKS) MRA for the characterization of cerebral arteriovenous malformations (cAVMs), using catheter DSA as reference. METHODS: Twenty-two patients underwent HYPR flow and TRICKS MRA within 15 days of DSA. HYPR flow and TRICKS datasets were reviewed separately by two readers for image quality, Spetzler-Martin grade, venous ectasia, and deep venous drainage. RESULTS: Image quality was better for HYPR flow than for TRICKS (narrower full width at half maximum; larger arterial diagnostic window; greater number of arterial frames, P <= 0.05). Using HYPR flow, inter-reader agreement was excellent for all cAVM characteristics. The agreement with DSA for the overall Spetzler-Martin grade was excellent for HYPR flow (ICC = 0.96 and 0.98, depending on the reader) and TRICKS (ICC = 0.82 and 0.95). In comparison to TRICKS, HYPR flow showed higher concordance with DSA for the identification of venous ectasia and deep venous drainage. CONCLUSION: Owing to an excellent agreement with DSA with respect to depiction of the vascular architecture of cAVMs, HYPR flow could be useful for the non-invasive characterization of cAVMs. KEY POINTS: * Dynamic MRA is used for cerebral AVM depiction and follow-up * HYPR flow is a new, highly-resolved dynamic MRA sequence * HYPR flow provides whole brain coverage * HYPR flow provides excellent agreement with the Spetzler-Martin grade * Compared to TRICKS MRA, HYPR flow improves cerebral AVM characterization. PMID- 25916389 TI - Diagnostic performance of the automated breast volume scanner: a systematic review of inter-rater reliability/agreement and meta-analysis of diagnostic accuracy for differentiating benign and malignant breast lesions. AB - OBJECTIVES: To investigate the inter-rater reliability and agreement of the automated breast volume scanner (ABVS) and the diagnostic accuracy for differentiating malignant and benign lesions. The overall aim was to find out if the ABVS is applicable to daily clinical practice. METHODS: Qualifying studies were retrieved from Pubmed, EMBASE, Cochrane Library, Biosis Preview, CBM disc and by manual search and reference lists up to 30 September 2014. Pooled sensitivity and specificity of ABVS were calculated and summary receiver operating characteristic curves were drawn. RESULTS: Thirteen studies were included in the meta-analysis of diagnostic accuracy and seven studies were included in the systematic review of inter-rater reliability/agreement of ABVS. For 'diagnostic accuracy', the pooled values of sensitivity, specificity, positive and negative likelihood ratios, and diagnostic odds ratio were 92 % (95 % CI 89.9-93.8), 84.9 % (82.4-87.0), 6.172 (4.364-8.730), 0.101 (0.075-0.136), and 72.226 (39.637-131.61), respectively. For the studies of inter-rater reliability/agreement, the quality was heterogeneous and no evidenced result can be pooled. CONCLUSIONS: Sensitivity and specificity of ABVS for differentiating malignant and benign breast lesions were high. More sound studies focusing on inter-rater reliability/agreement of ABVS, which deeply affect the clinical utilization and generalization of ABVS, are urgently needed. KEY POINTS: * ABVS has high sensitivity and specificity in differentiating malignant and benign breast lesions. * The quality of published inter-rater reliability studies is heterogeneous. * Empirical evidence concerning the inter-rater reliability/agreement for the ABVS is rare. * Comparison studies on ABVS and other medical imaging examinations are warranted. PMID- 25916390 TI - C-Arm Cone-Beam CT Virtual Navigation-Guided Percutaneous Mediastinal Mass Biopsy: Diagnostic Accuracy and Complications. AB - OBJECTIVES: To assess the usefulness of C-arm cone-beam computed tomography (CBCT) virtual navigation-guided percutaneous mediastinal mass biopsy in terms of diagnostic accuracy and complication rates. METHODS: Seventy-eight CBCT virtual navigation-guided percutaneous mediastinal mass biopsies were performed in 75 patients (M:F, 38:37; mean age, 48.55 +/- 18.76 years). The procedural details, diagnostic sensitivity, specificity, accuracy and complication rate were investigated. RESULTS: Mean lesion size was 6.80 +/- 3.08 cm, skin-to-target distance was 3.67 +/- 1.80 cm, core needle biopsy rate was 96.2 % (75/78), needle indwelling time was 9.29 +/- 4.34 min, total procedure time was 13.26 +/- 5.29 min, number of biopsy specimens obtained was 3.13 +/- 1.02, number of CBCTs performed was 3.03 +/- 0.68, rate of lesion border discrimination from abutting mediastinal structures on CBCT was 26.9 % (21/78), technical success rate was 100 % (78/78), estimated effective dose was 5.33 +/- 4.99 mSv, and the dose area product was 12,723.68 +/- 10,665.74 mGy?cm(2). Among the 78 biopsies, 69 were malignant, 7 were benign and 2 were indeterminate. Diagnostic sensitivity, specificity and accuracy for the diagnosis of malignancies were 97.1 % (67/69), 100 % (7/7) and 97.4 % (74/76), respectively, with a complication rate of 3.85 % (3/78), all of which were small pneumothoraces. CONCLUSIONS: CBCT virtual navigation-guided biopsy is a highly accurate and safe procedure for the evaluation of mediastinal lesions. KEY POINTS: * CBCT virtual navigation-guided percutaneous mediastinal biopsy is highly accurate * CBCT virtual navigation guided percutaneous mediastinal biopsy is a safe procedure * Mediastinal vascular injury can be avoided under CBCT virtual navigation guidance. PMID- 25916391 TI - High-resolution 3D-GRE imaging of the abdomen using controlled aliasing acceleration technique - a feasibility study. AB - OBJECTIVES: To assess the feasibility of high-resolution 3D-gradient-recalled echo (GRE) fat-suppressed T1-weighted images using controlled aliasing acceleration technique (CAIPIRINHA-VIBE), and compare image quality and lesion detection to standard-resolution 3D-GRE images using conventional acceleration technique (GRAPPA-VIBE). MATERIALS AND METHODS: Eighty-four patients (41 males, 43 females; age range: 14-90 years, 58.8 +/- 15.6 years) underwent abdominal MRI at 1.5 T with CAIPIRINHA-VIBE [spatial resolution, 0.76 +/- 0.04 mm] and GRAPPA VIBE [spatial resolution, 1.17 +/- 0.14 mm]. Two readers independently reviewed image quality, presence of artefacts, lesion conspicuity, and lesion detection. Kappa statistic was used to assess interobserver agreement. Wilcoxon signed-rank test was used for image qualitative pairwise comparisons. Logistic regression with post-hoc testing was used to evaluate statistical significance of lesions evaluation. RESULTS: Interobserver agreement ranged between 0.45-0.93. Pre contrast CAIPIRINHA-VIBE showed significantly (p < 0.001) sharper images and lesion conspicuity with decreased residual aliasing, but more noise enhancement and inferior image quality. Post-contrast CAIPIRINHA-VIBE showed significantly (p < 0.001) sharper images and higher lesion conspicuity, with less respiratory motion and residual aliasing artefacts. Inferior fat-suppression was noticeable on CAIPIRINHA-VIBE sequences (p < 0.001). CONCLUSION: High in-plane resolution abdominal 3D-GRE fat-suppressed T1-weighted imaging using controlled-aliasing acceleration technique is feasible and yields sharper images compared to standard resolution images using standard acceleration, with higher post-contrast image quality and trend for improved hepatic lesions detection. KEY POINTS: * High resolution imaging of the upper abdomen is clinically feasible using 2D controlled aliasing acceleration technique. * High-resolution imaging yields significantly sharper images and increased hepatic lesions conspicuity. * High resolution imaging yields significantly less respiratory motion and residual aliasing artefacts. * Controlled-aliasing offers substantial acquisition-time reduction in patients with breath-holding difficulties. PMID- 25916392 TI - Optimizing the MRI protocol of the sacroiliac joints in Spondyloarthritis: which para-axial sequence should be used? AB - INTRODUCTION: To assess the diagnostic value of para-axial T2w-TSE (paT2) and fat suppressed proton density (paPD-FS) MRI sequences for the evaluation of the sacroiliac joint (SIJ) of patients with axial Spondylarthritis (SpA). MATERIALS AND METHODS: One hundred and six patients with clinical findings suggestive of SpA underwent an MR protocol of the SIJ with additional paPD-FS (41 patients) and paT2 (105 patients). Acute (bone marrow oedema [BME], enthesitis, capsulitis, synovitis) and chronic findings (erosions, ankylosis) were assessed by paPD-FS and compared with the gold standard post-contrast sequences, whereas chronic features (because of the lack of fat suppression) were evaluated on paT2 and compared with pcT1. RESULTS: paPD-FS demonstrated high sensitivity (98.9 %) and specificity (99.1 %) for BME; sensitivity and specificity for synovitis and enthesitis were 100 %; 85.7 % and 100 %, respectively, for capsulitis. paPD-FS and paT2 showed 100 % sensitivity and specificity for ankylosis; for erosions, paT2 demonstrated 85.3 % sensitivity and 100 % specificity, whereas paPD-FS, respectively, 98 % and 100 %. DISCUSSION: PaT2 and paPD-FS provided precious information enabling an accurate interpretation of the heterogeneous findings of SpA. paPD-FS showed good results in detecting acute and chronic lesions and its inclusion in a routine MR examination of the SIJ could increase the diagnostic performance of a pre-contrast protocol. KEY POINTS: Para-axial sequence should be included in a routine MRI protocol for SpA. Acute and chronic findings can be evaluated on para-axial PD-FS. Para-axial PD-FS is superior to para-axial T2-W in SpA. PMID- 25916393 TI - Fetal cell microchimerism: a protective role in autoimmune thyroid diseases. AB - OBJECTIVE: The physiological persistence of fetal cells in the circulation and tissue of a previously pregnant woman is called fetal cell microchimerism (FCM). It has been hypothesized to play a role in systemic autoimmune disease; however, only limited data are available regarding its role in autoimmune thyroid disease (AITD). DESIGN: Circulating FCM was analyzed in a large series of previously pregnant women with Graves' disease (GD), Hashimoto's thyroiditis (HT), or no disease (healthy controls (HCs)). To exclude the possible bias related to placental factors, the polymorphic pattern of human leukocyte antigen-G (HLA-G) gene, which is known to be involved in the tolerance of fetal cells by the maternal immune system, was investigated. METHODS: FCM was evaluated by PCR in the peripheral blood, and the Y chromosome was identified by fluorescence in situ hybridization in some GD tissues. HLA-G polymorphism typing was assessed by real time PCR. RESULTS: FCM was significantly more frequent in HC (63.6%) than in GD (33.3%) or HT (27.8%) women (P=0.0004 and P=0.001 respectively). A quantitative analysis confirmed that circulating male DNA was more abundant in HC than it was in GD or HT. Microchimeric cells were documented in vessels and in thyroid follicles. In neither GD/HT patients nor HC women was the HLA-G typing different between FCM-positive and FCM-negative cases. CONCLUSION: The higher prevalence of FCM in HC as compared to GD and HT patients suggests that it plays a possible protective role in autoimmune thyroid disorders. Placental factors have been excluded as determinants of the differences found. The vascular and tissue localization of microchimeric cells further highlights the ability of those cells to migrate to damaged tissues. PMID- 25916394 TI - Immunohistochemical expression of stem cell markers in pheochromocytomas/paragangliomas is associated with SDHx mutations. AB - OBJECTIVE: Pheochromocytomas (PCCs) are neuroendocrine tumors that occur in the adrenal medulla, whereas paragangliomas (PGLs) arise from paraganglia in the head, neck, thorax, or abdomen. In a variety of tumors, cancer cells with stem cell-like properties seem to form the basis of tumor initiation because of their ability to self-renew and proliferate. Specifically targeting this small cell population may lay the foundation for more effective therapeutic approaches. In the present study, we intended to identify stem cells in PCCs/PGLs. DESIGN: We examined the immunohistochemical expression of 11 stem cell markers (SOX2, LIN28, NGFR, THY1, PREF1, SOX17, NESTIN, CD117, OCT3/4, NANOG, and CD133) on tissue microarrays containing 208 PCCs/PGLs with different genetic backgrounds from five European centers. RESULTS: SOX2, LIN28, NGFR, and THY1 were expressed in more than 10% of tumors, and PREF1, SOX17, NESTIN, and CD117 were expressed in <10% of the samples. OCT3/4, NANOG, and CD133 were not detectable at all. Double staining for chromogranin A/SOX2 and S100/SOX2 demonstrated SOX2 immunopositivity in both tumor and adjacent sustentacular cells. The expression of SOX2, SOX17, NGFR, LIN28, PREF1, and THY1 was significantly associated with mutations in one of the succinate dehydrogenase (SDH) genes. In addition, NGFR expression was significantly correlated with metastatic disease. CONCLUSION: Immunohistochemical expression of stem cell markers was found in a subset of PCCs/PGLs. Further studies are required to validate whether some stem cell-associated markers, such as SOX2, could serve as targets for therapeutic approaches and whether NGFR expression could be utilized as a predictor of malignancy. PMID- 25916396 TI - Balancing Proliferation and Connectivity in PTEN-associated Autism Spectrum Disorder. AB - Germline mutations in PTEN, which encodes a widely expressed phosphatase, was mapped to 10q23 and identified as the susceptibility gene for Cowden syndrome, characterized by macrocephaly and high risks of breast, thyroid, and other cancers. The phenotypic spectrum of PTEN mutations expanded to include autism with macrocephaly only 10 years ago. Neurological studies of patients with PTEN associated autism spectrum disorder (ASD) show increases in cortical white matter and a distinctive cognitive profile, including delayed language development with poor working memory and processing speed. Once a germline PTEN mutation is found, and a diagnosis of phosphatase and tensin homolog (PTEN) hamartoma tumor syndrome made, the clinical outlook broadens to include higher lifetime risks for multiple cancers, beginning in childhood with thyroid cancer. First described as a tumor suppressor, PTEN is a major negative regulator of the phosphatidylinositol 3 kinase/protein kinase B/mammalian target of rapamycin (mTOR) signaling pathway controlling growth, protein synthesis, and proliferation. This canonical function combines with less well-understood mechanisms to influence synaptic plasticity and neuronal cytoarchitecture. Several excellent mouse models of Pten loss or dysfunction link these neural functions to autism-like behavioral abnormalities, such as altered sociability, repetitive behaviors, and phenotypes like anxiety that are often associated with ASD in humans. These models also show the promise of mTOR inhibitors as therapeutic agents capable of reversing phenotypes ranging from overgrowth to low social behavior. Based on these findings, therapeutic options for patients with PTEN hamartoma tumor syndrome and ASD are coming into view, even as new discoveries in PTEN biology add complexity to our understanding of this master regulator. PMID- 25916398 TI - Macronutrients, Phytochemicals, and Antioxidant Activity of Soybean Sprout Germinated with or without Light Exposure. AB - This study examined the macronutrients, phytochemicals, and antioxidant activities of yellow soybean sprout (YSS) and green soybean sprout (GSS) with different germination days. YSS and GSS were obtained by sprouting soybean in darkness or with light exposure at 21 degrees C. Lipid, protein, carbohydrate, and ash contents were analyzed before and after soybean germination. Phytochemicals (total phenolic compounds, saponin, and isoflavone) were also determined. DPPH, ferric reducing antioxidant power (FRAP), and oxygen radical absorbance capacity (ORAC) were determined to examine the antioxidant activities of soybean sprout. Results showed YSS had a higher yield than GSS. Based on dry mass composition, 7-d germination of GSS decreased 14% protein, 37% lipid, 22% carbohydrate, and 16% ash, whereas 7-d germination of YSS decreased 6% protein and 47% lipid. Carbohydrate did not change and ash significantly increased for the 7-d germinated YSS. Lipid was greatly metabolized in germination, which explained why the protein relative percentage in dried soybean sprout was higher than that in the corresponding soybean. Total phenolic compounds and saponin (mg/g soybean sprout, dry basis) had the same accumulation trend in soybean sprout with the increases in germination days. Aglycone isoflavones (genistein, glycitein, and daidzein) and daidzin showed an increased trend, whereas malonylgenistin and malonylglycitin showed a decreased trend with germination days for both GSS and YSS. The change in other isoflavones did not show definite trends. GSS had 20% more antioxidant activities than YSS (7-d germinated soybean sprout). The increases in ORAC antioxidant activity suggest eating GSS may be more beneficial than GSS for promoting human health. PMID- 25916397 TI - Autism-Like Behavior in BTBR Mice Is Improved by Electroconvulsive Therapy. AB - Autism is a developmental disorder characterized by impairments in social and communication abilities, as well as by restricted and repetitive behaviors. Incidence of autism is higher than earlier estimates, and treatments have limited efficacy and are costly. Limited clinical and experimental evidence suggest that patients with autism may benefit from electroconvulsive therapy (ECT). We examined the therapeutic potential of ECT in BTBR T+ tf/j mice, which represent a validated model of autism. A series of 13 electroconvulsive shocks (ECS) delivered twice a day over 7 days reversed core autism-like behavioral abnormalities-impaired sociability, social novelty, and repetitive behavior-when the animals were tested 24 h after the last ECS. The effect lasted up to 2 weeks after ECT. Neither single ECS nor a series of 6 ECS modified animals' behavior. Chronic infusion into the lateral brain ventricle of a preferential oxytocin receptor blocker (2S)-2-Amino-N-[(1S,2S,4R)-7,7-dimethyl-1-[[[4-(2-methylphenyl) 1-piperazinyl]sulfonyl]methyl]bicyclo[2.2.1]hept-2-yl]-4 (methylsulfonyl)butanamide hydrochloride abolished ECT-induced improvement of sociability and mitigated improvement of social novelty but did not affect ECT induced reversal of repetitive behavior. These proof-of-principle experiments suggest that ECT may, indeed, be useful in the treatment of autism, and that its therapeutic effects may be mediated, in part, by central oxytocin signaling. PMID- 25916399 TI - Assessment of blood flow velocity and pulsatility in cerebral perforating arteries with 7-T quantitative flow MRI. AB - Thus far, blood flow velocity measurements with MRI have only been feasible in large cerebral blood vessels. High-field-strength MRI may now permit velocity measurements in much smaller arteries. The aim of this proof of principle study was to measure the blood flow velocity and pulsatility of cerebral perforating arteries with 7-T MRI. A two-dimensional (2D), single-slice quantitative flow (Qflow) sequence was used to measure blood flow velocities during the cardiac cycle in perforating arteries in the basal ganglia (BG) and semioval centre (CSO), from which a mean normalised pulsatility index (PI) per region was calculated (n = 6 human subjects, aged 23-29 years). The precision of the measurements was determined by repeated imaging and performance of a Bland-Altman analysis, and confounding effects of partial volume and noise on the measurements were simulated. The median number of arteries included was 14 in CSO and 19 in BG. In CSO, the average velocity per volunteer was in the range 0.5-1.0 cm/s and PI was 0.24-0.39. In BG, the average velocity was in the range 3.9-5.1 cm/s and PI was 0.51-0.62. Between repeated scans, the precision of the average, maximum and minimum velocity per vessel decreased with the size of the arteries, and was relatively low in CSO and BG compared with the M1 segment of the middle cerebral artery. The precision of PI per region was comparable with that of M1. The simulations proved that velocities can be measured in vessels with a diameter of more than 80 um, but are underestimated as a result of partial volume effects, whilst pulsatility is overestimated. Blood flow velocity and pulsatility in cerebral perforating arteries have been measured directly in vivo for the first time, with moderate to good precision. This may be an interesting metric for the study of haemodynamic changes in aging and cerebral small vessel disease. (c) 2015 The Authors NMR in Biomedicine Published by John Wiley & Sons Ltd. PMID- 25916400 TI - Longitudinal FDG microPET imaging of neuropathic pain: does cerebellar activity correlate with neuropathic pain development in a rat model? AB - BACKGROUND: We used [F-18] FDG microPET imaging as part of a longitudinal study to investigate changes in the brain. METHODS: Glucose metabolism during the development of neuropathic pain after tibial and sural nerve transection (TST) model rats. MicroPET images were obtained 1 week before operation and then weekly for 8 weeks post-operation. RESULTS: The behavioral test was performed immediately after the every FDG administration. After TST modeling, neuropathic pain rats showed increased mechanical sensitivity of the injured hind paw. The withdrawal response to mechanical pain stimulation by von Frey filaments was observed within the first week (3.8 +/- 0.73), and it rapidly increased in the third week (7.13 +/- 0.82). This response reached a peak in the fourth week after surgery (9.0 +/- 0.53), which persisted until the eighth week. In microPET scan imaging, cerebellum, which initially started from the ansiform lobule, was activated gradually to all part from the third week in all image acquisitions through the eighth week. CONCLUSIONS: The longitudinal microPET scan study of brains from neuropathic pain rat models showed sequential cerebellar activity that was in accordance with results from behavioral test responses, thus supporting a role for the cerebellum in the development of neuropathic pain. PMID- 25916401 TI - Who needs a pancreas donor risk index? PMID- 25916402 TI - Breath Holding Spells in Children with Long QT Syndrome. AB - BACKGROUND: Long QT syndrome (LQTS) is a genetic heart rhythm disorder that may present with syncope, seizures, or sudden cardiac death. Breath holding spells (BHS) occur in 5% of all children and have been noted in children with LQTS anecdotally. The purpose of this study was to determine the frequency of BHS in children diagnosed with LQTS at <=5 years of age. DESIGN: A retrospective review was performed to identify children diagnosed with LQTS who were <=5 years old at initial presentation to our LQTS clinic from August 1999 to November 2013. The mean length of follow-up was 6.4 +/- 2.8 years. The electronic medical records were reviewed for clinical presentation of BHS, as well as LQTS-associated symptoms, diagnostic tests, and treatment. RESULTS: The study cohort consisted of 115 children with LQTS (58% male; median age at diagnosis, 11 months [range, birth to 5 years]; mean corrected QT interval (QTc), 478 +/- 60 milliseconds). At presentation, 80% of patients were asymptomatic. Genetic testing revealed type 1 LQTS (LQT1) in 48%. Overall, 5 of 115 patients (4.3%) had BHS (2 of 5 [40%] male, mean QTc: 492 +/- 14 milliseconds, 4 [80%] with family history of LQTS). BHS were the presenting symptom in 1 of 23 symptomatic patients (4.3%). All BHS occurred in patients with LQT1 (P = .02). CONCLUSIONS: Although BHS among children with LQTS are relatively rare and occur at similar frequency as the general population, they can be the presenting symptom for a heart rhythm disorder. Careful attention to BHS is important to distinguish an innocent BHS from a potential LQTS-triggered cardiac event so that proper treatment is initiated. PMID- 25916403 TI - Unusual iatrogenic cause for renal stone formation following percutaneous nephrolithotomy. PMID- 25916405 TI - Therapeutic outcome after resection of pulmonary metastases from oral and/or head and neck cancers: complete republication of the article published in Jpn J Chest Surg. AB - OBJECTIVE: Thus far, very few studies have assessed the efficacy and outcome of resection of pulmonary metastases originating from primary oral cancer and/or head and neck cancer. METHODS: We retrospectively reviewed 13 cases that had metastases from primary oral cancers and/or head and neck cancers, and had undergone metastasectomy in our hospital from January 2000 through March 2011. RESULTS: Twelve patients were male and one was female. The median disease-free interval from the time of treatment of their primary cancer was 12 (range 1-73) months. Eleven cases underwent partial resection, one underwent segmentectomy, and one underwent lobectomy. The overall 5-year survival rate after last pulmonary metastasectomy was 45.7 %, and the median survival time was 23 months. Factors predicting a poor prognosis according to univariate analysis were a disease-free interval of <12 months and a diagnosis of stage IV primary cancer, but multivariate analysis revealed no significant prognostic factors. CONCLUSIONS: Pulmonary metastasectomy would give a chance for long-term survival in patients with oral and/or head and neck cancers. PMID- 25916404 TI - Frailty in cardiothoracic surgery: systematic review of the literature. AB - A preoperative surgical risk analysis is necessary and important for predicting clinical and surgical outcomes in a clinical setting. Various tools for evaluating the patient characteristics in order to forecast perioperative clinical outcomes have previously been described; however, an objective and precise preoperative risk assessment has not yet been established. In the last decade, the concept of frailty, which is a geriatric assessment that identifies disabilities and weaknesses in patients, has been used in order to predict clinical mortality and morbidity following invasive surgical interventions because the prevalence of elderly patients among those undergoing surgical interventions is increasing. Since there is currently no single generally accepted clinical definition of frailty, many clinical modalities are needed to evaluate the patients' geriatric activity of daily living. Quantifying the quality of frailty is an evolving challenge for predicting surgical risks preoperatively. In recent years, with the development of transcatheter aortic valve implantation (TAVI), this newly definitive preoperative surgical risk assessment tool, frailty, has become more important and is attracting interest in cardiothoracic surgical settings. Thus, this review summarized current consideration on the preoperative risk analysis by frailty as well as future perspectives and the potential of an ideal frailty risk assessment in cardiothoracic surgery, including the management of elderly patients and high risk aortic valve stenosis by TAVI. PMID- 25916406 TI - Update of Clinical Trials of Anti-PCSK9 Antibodies. AB - Hyperlipidemia is a predominant risk factor for cardiovascular disease (CVD). Statins have been successfully used to treat patients with dyslipidemia and decrease the events of CVD in addition to application of various other non-statin lowering cholesterol agents, such as ezetimibe and niacin. However, there are still residual risks in patients with atherosclerotic CVD. Recently, proprotein convertase subtilisin/kexin type 9 (PCSK9), which was first identified in 2003, has been suggested to play an important role in the metabolism of low-density lipoprotein cholesterol (LDL-C). PCSK9 degrades the LDL-receptor, which may be pharmacologically targeted to improve the lipoprotein profile and future cardiovascular outcomes in patients with dyslipidemia. Several approaches to inhibiting PCSK9 activity have been theoretically proposed. Among them, monoclonal antibodies have been considered as the most promising strategy because of their large effect on lowering lipids as monotherapy and in combination with statins or ezetimibe. In this review, we mainly focus on the current status of monoclonal antibodies of PCSK9 and clinical trial results for an update on clinical application of monoclonal antibodies of PCSK9. The particular effects of monoclonal antibodies of PCSK9 on lipid profiles are also discussed. PMID- 25916407 TI - Synthesis, crystal structure and magnetic properties of a novel heterobimetallic rhenium(IV)-dysprosium(III) chain. AB - The use of the mononuclear rhenium(IV) precursor [ReBr5 (H2 pydc)](-) (H2 pydc=3,5-pyridinedicarboxylic acid) as a metalloligand towards dysprosium(III) afforded the first heterobimetallic Re(IV) -Dy(III) complex. Crystal structures and static and dynamic magnetic properties of both rhenium-containing species are reported herein. The 5d-4f compound shows an extended 1D structure and the AC magnetic measurements reveal frequency dependence at low temperature suggesting slow relaxation of the magnetization. PMID- 25916408 TI - Joint design of large-tip-angle parallel RF pulses and blipped gradient trajectories. AB - PURPOSE: To design multichannel large-tip-angle kT-points and spokes radiofrequency (RF) pulses and gradient waveforms for transmit field inhomogeneity compensation in high field magnetic resonance imaging. THEORY AND METHODS: An algorithm to design RF subpulse weights and gradient blip areas is proposed to minimize a magnitude least-squares cost function that measures the difference between realized and desired state parameters in the spin domain, and penalizes integrated RF power. The minimization problem is solved iteratively with interleaved target phase updates, RF subpulse weights updates using the conjugate gradient method with optimal control-based derivatives, and gradient blip area updates using the conjugate gradient method. Two-channel parallel transmit simulations and experiments were conducted in phantoms and human subjects at 7 T to demonstrate the method and compare it to small-tip-angle designed pulses and circularly polarized excitations. RESULTS: The proposed algorithm designed more homogeneous and accurate 180 degrees inversion and refocusing pulses than other methods. It also designed large-tip-angle pulses on multiple frequency bands with independent and joint phase relaxation. Pulses designed by the method improved specificity and contrast-to-noise ratio in a finger-tapping spin echo blood oxygen level dependent functional magnetic resonance imaging study, compared with circularly polarized mode refocusing. CONCLUSION: A joint RF and gradient waveform design algorithm was proposed and validated to improve large-tip-angle inversion and refocusing at ultrahigh field. PMID- 25916409 TI - Correlation between polymorphisms of BRAF gene and papillary thyroid carcinoma. AB - BACKGROUND: Papillary thyroid carcinoma (PTC), which accounts for 80% of all thyroid cancers, has an increasing incidence over these years. Single nucleotide polymorphisms (SNPs) of BRAF were considered to be one of well-established risk factors leading to development of PTC. The aim of this study was to investigate whether the common mutations of BRAF could elevate significantly the risk of PTC in a Chinese population. METHODS: Four SNPs (rs11762469, rs17623204, rs1267636 and rs3748093) of BRAF were selected through our filter by Haploview 4.2 software with HapMap databases. We used the polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) to genotype the four SNPs in blood samples of 618 subjects (206 patients with PTC and 412 healthy controls). The correlation between BRAF polymorphisms and PTC risk was assessed using student t-test and chi square test. RESULTS: The results showed that mutation in rs3748093 was significantly associated with an increased risk of PTC in allele model (A allele vs. T allele, OR = 1.68, 95% CI = 1.16-2.43, P = 0.006), dominant model (TA + AA vs TT, OR = 1.64, 95% CI = 1.08-2.48, P = 0.019) and homozygote model (AA vs. TT, OR = 2.94, 95% CI = 1.00-8.61, P = 0.040). However, the other three SNPs (rs11762469, rs17623204 and rs1267636) were shown to have no association with the risk of PTC. CONCLUSIONS: Our results indicated that polymorphism of rs3748093*A was significantly correlated with an increased risk of PTC in a Chinese population. Further investigation on the aetiological mechanism of PTC is needed to validate our results. PMID- 25916410 TI - Carbon storage capacity of semi-arid grassland soils and sequestration potentials in northern China. AB - Organic carbon (OC) sequestration in degraded semi-arid environments by improved soil management is assumed to contribute substantially to climate change mitigation. However, information about the soil organic carbon (SOC) sequestration potential in steppe soils and their current saturation status remains unknown. In this study, we estimated the OC storage capacity of semi-arid grassland soils on the basis of remote, natural steppe fragments in northern China. Based on the maximum OC saturation of silt and clay particles <20 MUm, OC sequestration potentials of degraded steppe soils (grazing land, arable land, eroded areas) were estimated. The analysis of natural grassland soils revealed a strong linear regression between the proportion of the fine fraction and its OC content, confirming the importance of silt and clay particles for OC stabilization in steppe soils. This relationship was similar to derived regressions in temperate and tropical soils but on a lower level, probably due to a lower C input and different clay mineralogy. In relation to the estimated OC storage capacity, degraded steppe soils showed a high OC saturation of 78-85% despite massive SOC losses due to unsustainable land use. As a result, the potential of degraded grassland soils to sequester additional OC was generally low. This can be related to a relatively high contribution of labile SOC, which is preferentially lost in the course of soil degradation. Moreover, wind erosion leads to substantial loss of silt and clay particles and consequently results in a direct loss of the ability to stabilize additional OC. Our findings indicate that the SOC loss in semi-arid environments induced by intensive land use is largely irreversible. Observed SOC increases after improved land management mainly result in an accumulation of labile SOC prone to land use/climate changes and therefore cannot be regarded as contribution to long-term OC sequestration. PMID- 25916411 TI - A Rational Approach to CO2 Capture by Imidazolium Ionic Liquids: Tuning CO2 Solubility by Cation Alkyl Branching. AB - Branching at the alkyl side chain of the imidazolium cation in ionic liquids (ILs) was evaluated towards its effect on carbon dioxide (CO2 ) solubilization at 10 and 80 bar (1 bar=1*10(5) Pa). By combining high-pressure NMR spectroscopy measurements with molecular dynamics simulations, a full description of the molecular interactions that take place in the IL-CO2 mixtures can be obtained. The introduction of a methyl group has a significant effect on CO2 solubility in comparison with linear or fluorinated analogues. The differences in CO2 solubility arise from differences in liquid organization caused by structural changes in the cation. ILs with branched cations have similar short-range cation anion orientations as those in ILs with linear side chains, but present differences in the long-range order. The introduction of CO2 does not cause perturbations in the former and benefits from the differences in the latter. Branching at the cation results in sponge-like ILs with enhanced capabilities for CO2 capture. PMID- 25916412 TI - A quantitative exploratory evaluation of the circle of security-parenting program with mothers in residential substance-abuse treatment. AB - Maternal substance abuse is a risk factor for child maltreatment, child attachment insecurity, and maladaptive social information processing. The aim of this study was to conduct a quantitative exploratory evaluation of the effectiveness of an attachment-based parent program, Circle of Security-Parenting (COS-P; G. Cooper, K. Hoffman, & B. Powell, 2009), with a community sample of 15 mothers in residential treatment for substance abuse. Participants attended nine weekly group sessions and were given three measures at pretest and posttest: the Emotion Regulation Questionnaire (J.J. Gross & O.P. John, 2003), the Parent Attribution Test (D. Bugental, ), and the Parenting Scale (D.S. Arnold, S.G. O'Leary, L.S. Wolff, & M.M. Acker, 1993). The results indicate that mothers who attended the majority of group sessions showed greater improvements on all three variables. Participants who attended some of the sessions showed some improvements on the measures, but participants who did not attend the group sessions had no improvements, and on some measures, declined significantly. Further analyses of demographic data indicates that participants with more education, no personal history of child maltreatment, less time in the residential program, and lower social desirability scores demonstrated more positive outcomes. These findings suggest that the COS-P may positively impact parental risk factors associated with child maltreatment and maladaptive social information processing in the context of residential substance-abuse treatment. PMID- 25916413 TI - Correlation between Energy and Spatial Distribution of Intragap Trap States in the TiO2 Photoanode of Dye-Sensitized Solar Cells. AB - The energy and spatial distribution of intragap trap states of the TiO2 photoanode of dye-sensitized solar cells and their impact on charge recombination were investigated by means of time-resolved charge extraction (TRCE) and transient photovoltage (TPV). The photoanodes were built from TiO2 nanospheroids with different aspect ratios, and the TRCE results allowed differentiation of two different types of trap states, that is, deep and shallow ones at the surface and in the bulk of the TiO2 particles, respectively. These trap states exhibit distinctly different characteristic energy with only a slight variation in the particle size, as derived from the results of the density of states. Analyses of the size-dependent TPV kinetics revealed that in a moderate photovoltage regime of about 375-625 mV, the dynamics of electron recombination are dominated by shallow trap states in the bulk, which can be well accounted for by the mechanism of multiple-trap-limited charge transport. PMID- 25916414 TI - Severity of malaria in relation to a complement receptor 1 polymorphism: a case control study. AB - BACKGROUND: Studies on the relationship between complement receptor 1 (CR1) polymorphisms in exon 29 encoding the Knops blood group antigens (Swain-Langley (Sl) and McCoy (McC)) and outcome of clinical malaria have produced inconsistent results. METHODS: Blood samples from Ghanaian children (n = 150) aged 1-12 years with complicated and uncomplicated malaria were genotyped for the Sl and McC blood group alleles by polymerase chain reaction and restriction fragment length polymorphism. Effect of Sl and McC genotypes on the clinical outcome of malaria was evaluated using logistic regression. RESULTS: McCa/b genotype was significantly associated with more than two-fold increased susceptibility for severe malaria (OR = 2.31; 95% CI: 1.03-5.20, P = 0.043). However, McCb/b was associated with an 88% reduced risk of severe malaria (OR = 0.12; 95% CI: 0.02 0.64, P = 0.013). In contrast, there was no significant association between severe malaria and Sl1/1, Sl1/2, Sl2/and McCa/a genotypes. There was a trend towards decreased susceptibility to both cerebral malaria (CM) (OR = 0.13; 95% CI: 0.02-1.15, P = 0.07) and severe malarial anaemia (SA) (OR = 0.14; 95% CI: 0.02-1.19, P = 0.07) for McCb/b genotype when compared with the McCa/a genotype. There were no significant associations between Sl1/2 or Sl2/2 genotype and CM or SA when compared with Sl1/1 genotype. CONCLUSIONS: McCa/b was associated with increased susceptibility to severe malaria and McCb/b associated with reduced risk of severe malaria. Further studies with large sample size in other malaria endemic regions in Africa are warranted to confirm these findings. PMID- 25916416 TI - Re-Setting the Gold Standard. PMID- 25916415 TI - Investigation and conformational analysis of fluorinated nucleoside antibiotics targeting siderophore biosynthesis. AB - Antibiotic resistance represents one of the greatest threats to public health. The adenylation inhibitor 5'-O-[N-(salicyl)sulfamoyl]adenosine (SAL-AMS) is the archetype for a new class of nucleoside antibiotics that target iron acquisition in pathogenic microorganisms and is especially effective against Mycobacterium tuberculosis, the causative agent of tuberculosis. Strategic incorporation of fluorine at the 2' and 3' positions of the nucleoside was performed by direct fluorination to enhance activity and improve drug disposition properties. The resulting SAL-AMS analogues were comprehensively assessed for biochemical potency, whole-cell antitubercular activity, and in vivo pharmacokinetic parameters. Conformational analysis suggested a strong preference of fluorinated sugar rings for either a 2'-endo, 3'-exo (South), or a 3'-endo,2'-exo (North) conformation. The structure-activity relationships revealed a strong conformational bias for the C3'-endo conformation to maintain potent biochemical and whole-cell activity, whereas improved pharmacokinetic properties were associated with the C2'-endo conformation. PMID- 25916419 TI - Rapid body mass loss affects erythropoiesis and hemolysis but does not impair aerobic performance in combat athletes. AB - Rapid body mass loss (RBML) before competition was found to decrease hemoglobin mass (Hbmass ) in elite boxers. This study aimed to investigate the underlying mechanisms of this observation. Fourteen well-trained combat athletes who reduced body mass before competitions (weight loss group, WLG) and 14 combat athletes who did not practice RBML (control group, CON) were tested during an ordinary training period (t-1), 1-2 days before an official competition (after 5-7 days RBML in WLG, t-2), and after a post-competition period (t-3). In WLG, body mass ( 5.5%, range: 2.9-6.8 kg) and Hbmass (-4.1%) were significantly (P < 0.001) reduced after RBML and were still decreased by 1.6% (P < 0.05) and 2.6% (P < 0.001) at t-3 compared with t-1. After RBML, erythropoietin, reticulocytes, haptoglobin, triiodothyronine (FT3 ), and free androgen index (FAI) were decreased compared with t-1 and t-3. An increase occurred in ferritin and bilirubin. Peak treadmill-running performance and VO2peak did not change significantly, but performance at 4-mmol lactate threshold was higher after RBML (P < 0.05). In CON, no significant changes were found in any parameter. Apparently, the significant decrease in Hbmass after RBML in combat athletes was caused by impaired erythropoiesis and increased hemolysis without significant impact on aerobic performance capacity. PMID- 25916420 TI - Music-supported therapy (MST) in improving post-stroke patients' upper-limb motor function: a randomised controlled pilot study. AB - OBJECTIVE: Music-supported therapy (MST) is a new approach for motor rehabilitation of stroke patients. Recently, many studies have demonstrated that MST improved the motor functions of post-stroke patients. However, the underlying mechanism for this effect is still unclear. It may result from repeated practice or repeated practice combined with musical stimulation. Currently, few studies have been designed to clarify this discrepancy. In this study, the application of "mute" musical instruments allowed for the study of music as an independent factor. METHODS: Thirty-three post-stroke patients with no substantial previous musical training were included. Participants were assigned to either audible music group (MG) or mute music group (CG), permitting observation of music's independent effect. All subjects received the conventional rehabilitation treatments. Patients in MG (n = 15) received 20 extra sessions of audible musical instrument training over 4 weeks. Patients in CG (n = 18) received "mute" musical instrument training of the same protocol as that of MG. Wolf motor function test (WMFT) and Fugl-Meyer assessment (FMA) for upper limbs were utilised to evaluate motor functions of patients in both groups before and after the treatment. Three patients in CG dropped out. RESULTS: All participants in both groups showed significant improvements in motor functions of upper limbs after 4 weeks' treatment. However, significant differences in the WMFT were found between the two groups (WMFT-quality: P = 0.025; WMFT-time: P = 0.037), but not in the FMA (P = 0.448). In short, all participants showed significant improvement after 4 weeks' treatment, but subjects in MG demonstrated greater improvement than those in CG. DISCUSSION: This study supports that MST, when combined with conventional treatment, is effective for the recovery of motor skills in post-stroke patients. Additionally, it suggests that apart from the repetitive practices of MST, music may play a unique role in improving upper-limb motor function for post-stroke patients. PMID- 25916421 TI - Latent structure of cognition in schizophrenia: a confirmatory factor analysis of the MATRICS Consensus Cognitive Battery (MCCB). AB - BACKGROUND: The number of separable cognitive dimensions in schizophrenia has been debated. Guided by the extant factor analytic literature, the NIMH Measurement and Treatment Research to Improve Cognition in Schizophrenia (MATRICS) initiative selected seven cognitive domains relevant to treatment studies in schizophrenia: speed of processing, attention/vigilance, working memory, verbal learning, visual learning, reasoning and problem solving, and social cognition. These domains are assessed in the MATRICS Consensus Cognitive Battery (MCCB). The aim of this study was to conduct a confirmatory factor analysis (CFA) of the beta battery of the MCCB to compare the fit of the MATRICS consensus seven-domain model to other models in the current literature on cognition in schizophrenia. METHOD: Using data from 281 schizophrenia outpatients, we compared the seven correlated factors model with alternative models. Specifically, we compared the 7-factor model to (a) a single-factor model, (b) a three correlated factors model including speed of processing, working memory, and general cognition, and (c) a hierarchical model in which seven first-order factors loaded onto a second-order general cognitive factor. RESULTS: Multiple fit indices indicated the seven correlated factors model was the best fit for the data and provided significant improvement in model fit beyond the comparison models. CONCLUSIONS: These results support the assessment of these seven cognitive dimensions in clinical trials of interventions to improve cognition in schizophrenia. Because these cognitive factors are separable to some degree, it is plausible that specific interventions may have differential effects on the domains. PMID- 25916422 TI - Serum 25-hydroxyvitamin D increases with NB-UVB and UVA/UVB phototherapy in patients with psoriasis and atopic dermatitis in Western Australia. AB - BACKGROUND/OBJECTIVE: The benefit of NB-UVB phototherapy on serum 25 hydroxyvitamin D [25(OH)D] levels in patients with inflammatory skin conditions has been reported in the northern hemisphere. Vitamin D status is known to differ between geographical latitudes. The objective of this study was to investigate the influence of NB-UVB and UVA/UVB phototherapy on the 25(OH)D serum levels in patients with psoriasis and atopic dermatitis in Western Australia. METHODS: A total of 35 patients with psoriasis or atopic dermatitis requiring phototherapy thrice weekly for a minimum of 4 weeks were enrolled. Of these, 20 patients completed the study. Serum vitamin D levels were measured at baseline and at approximately 6 weeks into phototherapy. Data were adjusted for season, patients' age, sex, skin condition and Fitzpatrick skin phototype. RESULTS: There was a statistically significant increase in serum 25(OH)D from pre- to post-NB-UVB and UVA/UVB phototherapy (P < 0.0001), with a mean raw increase of 34.6 (25) nmol/L; or 45.1 (7.5) nmol/L when adjusted for covariates. This was also true for patients receiving NB-UVB phototherapy with a baseline vitamin D of <80 nmol/L (P < 0.05) and >80 nmol/L (P < 0.004). CONCLUSIONS: NB-UVB and UVA/UVB phototherapy significantly increased 25(OH)D serum level in patients with psoriasis and atopic dermatitis in Western Australia. Our study cohort had a higher baseline vitamin D level and a lower percentage increase of serum 25(OH)D post-phototherapy than the increases reported in the literature from cohorts in the northern hemisphere. PMID- 25916423 TI - Where are the products of nanotechnology? PMID- 25916424 TI - Comment on "Bottom-up graphene-nanoribbon fabrication reveals chiral edges and enantioselectivity". PMID- 25916425 TI - Reply to "Comment on 'Bottom-up graphene-nanoribbon fabrication reveals chiral edges and enantioselectivity'". PMID- 25916427 TI - Prevalence of scars and "mini-scars", and their impact on quality of life in Japanese patients with acne. AB - There have been very few studies on the prevalence and severity of acne scars in Japanese patients. The aim of the present study was to investigate the prevalence of acne scars and their impact on the quality of life (QOL) in Japanese acne patients. Acne scars were classified as mini-scars (atrophic scars of >=0.5 and <2 mm in diameter) atrophic scars (>=2 mm in diameter), and hypertrophic scars. The severity of acne and acne scars were evaluated. The background of patients and their QOL in relation to acne were assessed. Of 240 subjects, 218 (90.8%) had scars. All patients with scars had mini-scars; 61.2% and 14.2% of 240 had atrophic scars and hypertrophic scars, respectively. Severe scarring was found in patients who had experienced severe acne symptoms, although 15.0% of patients with scars had experienced only mild acne symptoms. The total Dermatology Life Quality Index score was significantly higher in patients with scars than in patients without scars (5.9 +/- 4.4 vs 4.2 +/- 4.1). Almost all the patients had small atrophic scars with a diameter of 0.5 or more and less than 2 mm, which we have termed "mini-scars". Acne scars had a negative impact on patient QOL. Early initiation of treatment is recommended to avoid acne scars. PMID- 25916428 TI - Serum creatinine levels during and after long-term treatment with cyclosporine A in patients with severe atopic dermatitis. AB - Safety data with respect to kidney function during long-term treatment with cyclosporine A (CsA) in patients with atopic dermatitis is limited. Data on serum creatinine levels before, during and after CsA treatment were collected in a retrospective cohort of adult patients with atopic dermatitis. The median duration of treatment of 150 patients was 280 days (interquartile range 203-528 days). There was a significant, but not clinically relevant, increase in serum creatinine compared with the baseline level after 3 weeks of treatment with CsA and stabilization during the maintenance phase at the group level. Twenty-two (14.7%) patients had a greater than 30% increase in serum creatinine (cut-off point for clinically relevant change) compared with baseline. These patients were significantly older than the patients without a 30% increase (mean +/- standard deviation age 41.4 +/- 15.6 vs. 33.8 +/- 11.7 years (p = 0.01)). During follow up, all patients had a less than 30% increase in serum creatinine levels compared with baseline levels. At the group level serum creatinine levels during follow-up were not significantly different from baseline. PMID- 25916429 TI - Impaired immune phenotype of circulating endothelial-derived microparticles in patients with metabolic syndrome and diabetes mellitus. AB - INTRODUCTION: Type two diabetes mellitus (T2DM) remains a leading contributor to cardiovascular mortality worldwide. This study was conducted to investigate the pattern of circulating EMPs in T2DM patients in comparison with MetS subjects. METHODS: The study retrospectively included 101 patients (54 subjects with T2DM and 47 patients with MetS) and 35 healthy volunteers. All the patients gave written informed consent for participation in the study. Biomarkers were measured at baseline of the study. RESULTS: There is a significant difference between healthy subjects and patients regarding CD31+/annexin V+ EMPs to CD62E+ EMPs ratio, which reflects impaired phenotype of EMPs. Therefore, CD31+/annexin V+ EMPs to CD62E+ EMPs ratio was found to be higher in the T2DM patients compared to MetS patients. Using multivariate linear regression analyses, independent impact of T2DM (r = 0.40, P = 0.003), OPG (r = 0.37, P = 0.001), hs-CRP (r = 0.347, P = 0.001), and adiponectin (r = 0.33, P = 0.001) on increased CD31+/annexin V+ to CD62E+ ratio of EMPs was determined. Using C-statistics, we found that inflammatory biomarkers (hs-C-reactive protein, osteoprotegerin and adiponectin) added to the base model (T2DM) improved the relative IDI by 12.6 % for increased CD31+/annexin V+ EMPs to CD62E+ EMPs ratio. CONCLUSION: We found that patients with T2DM and MetS may be distinguished by predominantly appearing phenotypes of circulating EMPs associated with pro-inflammatory cytokine overproduction. Elevated CD31+/annexin V+ EMPs to CD62E+ EMPs ratio is an indicator of impaired immune phenotype of EMPs, which allows determining the pattern of EMPs in dysmetabolic disorder patients. PMID- 25916430 TI - Heterogeneous phenotype in children affected by non-autoimmune hypothyroidism: an update. AB - BACKGROUND: In the last decades, a higher incidence of congenital hypothyroidism (CH) has been recorded in Italy (1:1940) and worldwide, mainly due to the shift to lower screening TSH cutoffs. Although CH can also be caused by dysgenetic defects, most CH cases have recently been found to be more frequently associated with functional defects of an in situ thyroid gland. Although the clinical phenotype is milder with high prevalence of transient forms, some cases eventually prove to be permanent. RESULTS: Possible explanations of the raised incidence of CH are ethnic modifications of the screened population and the increasing incidence of preterm birth and multiple pregnancies. These findings are important in terms of public health and standardization of screening programmes for special at-risk categories such as preterms, acutely ill term neonates, low birth weight and very low birth weight infants, and newborns with specific drug exposure. Other environmental factors have contributed to the increased incidence of hypothyroidism, including thyroid disrupting chemicals, iodine supply (excess/deficiency), and drugs interfering with thyroid function. Finally, an increased prevalence of hypothyroidism has been documented in obese children and patients with syndromic forms (Williams, Down, Turner, pseudohypoparathyroidism). The clinical and molecular phenotype of patients with CH will be better defined thanks to novel genetic approach based on the systematic analysis of a panel of genes (TSHR, DUOX2, DUOXA, TPO, PDS, TG, NKX2.1, JAG1, GLIS3, FOXE1, PAX-8). CONCLUSIONS: This review summarizes significant advances in the epidemiology and aetiology of non-autoimmune hypothyroidism, with a focus on thyroid dysfunction in preterm infants. PMID- 25916432 TI - ENDOCRINOLOGY AND ART. The Dwarf Dona Mercedes, 1899 (oil on canvas) : Zuloaga y Zabaleta, Ignacio, Musee d'Orsay, Paris, France. PMID- 25916431 TI - Does pegvisomant treatment expertise improve control of resistant acromegaly? The Italian ACROSTUDY experience. AB - OBJECTIVE: GH receptor antagonist pegvisomant is indicated for treatment of patients with resistant acromegaly. We compared safety and treatment outcomes of pegvisomant therapy in patients managed by Italian centers enrolling less or more than 15 cases in ACROSTUDY, a safety surveillance study of long-term pegvisomant treatment of patients with acromegaly. A noninterventional safety surveillance study in which safety and treatment outcomes of pegvisomant were evaluated on the basis of data collected during a 7-year period. METHODS: A total of 204 acromegaly patients treated by seven centers enrolling 16-49 patients each (group A) and 137 subjects by 18 centers following 3-14 cases ( group B). RESULTS: Patients of group A and B were treated for 4.4 +/- 2.7 and 4.2 +/- 2.2 years, respectively. IGF-1 ULN normalized in 64.4 % (n = 56) and 54.4 % (n = 31) in group A and B, respectively, after 1-year treatment, and in 57.3 % (n = 106) and 72.5 % (n = 87) at last visit. Starting doses were significantly higher in group A. They were progressively increased during treatment in both groups, but were higher in uncontrolled patients than in controlled ones only in group A. Reported adverse events were more frequent, and the prevalence of patients with adverse events was higher in group B. CONCLUSIONS: On the basis of this original study approach, we could speculate that in the centers in which more patients are treated with pegvisomant, less adverse events are reported, but the long-term effectiveness is lower than in centers with less cases, perhaps because of an inadequate patient's selection. PMID- 25916434 TI - PseudoCushing: why a clinical challenge? PMID- 25916433 TI - Bone density assessment in a cohort of pediatric patients affected by 22q11DS. AB - OBJECTIVE: Hypoparathyroidism and hypocalcemia are two of the most frequent clinical characteristics of 22q11-deletion syndrome (22q11DS). The aim of this study was to evaluate bone metabolism and density in a cohort of patients affected by 22q11DS. METHODS: In 8 pediatric patients (mean age 11.5 years; range 7-16.4) affected by 22q11DS, creatinine, albumin, total and ionized calcium, phosphate, 25(OH) vitamin D, parathyroid hormone, osteocalcin, C-terminal telopeptide and interleukin 6 were assessed. Furthermore, bone mineral density (BMD) was determined by dual-energy X-ray absorptiometry procedure. 14 healthy children were considered as controls. RESULTS: Most of the studied subjects were overweight and lacked quality physical activity. 40 % of the subjects had reduced calcium levels in the absence of related clinical symptoms and all patients also had inadequate levels of Vitamin D. The values of L1-L4 BMD were within the reference range in all patients (z score <2). However, after comparing the age matched indexes of bone mineralization of patients with those of controls, the former had lower bone mineralization indexes than the latter. CONCLUSIONS: In pediatric patients with 22q11DS, an initial and slight bone loss is evident. The incidence of hypocalcemia is underestimated because hypocalcemia is asymptomatic. Several factors contribute to bone impairment in children who still have to achieve bone mass peak. Therefore, we suggest strict monitoring of bone metabolism as well as BMD measurement in patients affected by 22q11DS. PMID- 25916435 TI - How Business Cycles Affect the Healthcare Sector: A Cross-country Investigation. AB - The long-term relationship between the general economy and healthcare expenditures has been extensively researched, to explain differences in healthcare spending between countries, but the midterm (i.e., business cycle) perspective has been overlooked. This study explores business cycle sensitivity in both public and private parts of the healthcare sector across 32 countries. Responses to the business cycle vary notably, both across spending sources and across countries. Whereas in some countries, consumers and/or governments cut back, in others, private and/or public healthcare buyers tend to spend more. We also assess long-term consequences of business cycle sensitivity and show that public cost cutting during economic downturns deflates the mortality rates, whereas private cut backs increase the long-term growth in total healthcare expenditures. Finally, multiple factors help explain variability in cyclical sensitivity. Private cost cuts during economic downturns are smaller in countries with a predominantly publicly funded healthcare system and more preventive public activities. Public cut backs during contractions are smaller in countries that rely more on tax-based resources rather than social health insurances. Copyright (c) 2015 John Wiley & Sons, Ltd. PMID- 25916436 TI - Detection of small abnormal B-Lymphoblast populations at diagnosis of chronic myelogenous leukemia, BCR-ABL1+: Incidence, phenotypic features, and clinical implications. AB - BACKGROUND: According to the 2008 World Health Organization (WHO) Classification of Tumors of the Haematopoietic and Lymphoid Tissues, the finding of B lymphoblasts in the blood or bone marrow of a patient with chronic myelogenous leukemia, BCR-ABL1+ (CML) should raise a concern for progression of the disease to B-lymphoblastic blast phase. Data addressing the incidence and phenotypic features of abnormal B lymphoblasts in CML, and whether the detection of B lymphoblasts inexorably heralds blast phase in CML, though, are limited. METHODS: We reviewed a consecutive series of patients with newly diagnosed CML who had undergone bone marrow examination with flow cytometric immunophenotyping. Polychromatic immunophenotyping data were reviewed, and clinical follow-up data were obtained. RESULTS: A precursor B-cell population with an abnormal composite immunophenotype was detected in 4 of 36 (11.1%) diagnostic bone marrow samples, at levels ranging from 0.01% to 0.30% of viable single cells acquired. The most common phenotypic aberrations were abnormally bright expression of CD10 and CD19 (seen in four and three cases, respectively), and abnormally dim expression of CD38 (seen in four cases). All three patients with adequate clinical follow-up have achieved and maintained a deep or major molecular response with a tyrosine kinase inhibitor, and none has progressed to B-lymphoblastic blast phase (follow up duration: 17-46 months). CONCLUSIONS: In chronic-phase CML, a small (<0.5%) abnormal B-lymphoblast population is present in a significant minority of diagnostic bone marrow samples, but does not inevitably herald progression to B lymphoblastic blast phase. (c) 2015 International Clinical Cytometry Society. PMID- 25916437 TI - [Size distribution characteristics of particulate matter in the top areas of coke oven]. AB - OBJECTIVE: To systematically evaluate the environmental exposure information of coke oven workers, we investigated the concentration and size distribution characteristics of the particle matter (PM) in the top working area of coke oven. METHODS: The aerodynamic particle sizer spectrometer was employed to collect the concentration and size distribution information of PM at a top working area. The PM was divided into PM <= 1.0 um, 1.0 um < PM <= 2.5 um, 2.5 um < PM <= 5.0 um, 5.0 um < PM <= 10.0 um and PM>10.0 um based on their aerodynamic diameters. The number concentration, surface area concentration, and mass concentration were analyzed between different groups. We also conducted the correlation analysis on these parameters among groups. RESULTS: We found the number and surface area concentration of top area particulate was negatively correlated with particle size, but mass concentration curve showed bimodal type with higher point at PM = 1.0 um and PM = 5.0 um. The average number concentration of total particulate matter in the top working area was 661.27 number/cm3, surface area concentration was 523.92 um2/cm3, and mass concentration was 0.12 mg/m3. The most number of particulate matter is not more than 1 um (PM(1.0)), and its number concentration and surface area concentration accounted for 96.85% and 67.01% of the total particles respectively. In the correlation analysis, different particle size correlated with the total particulate matter differently. And the characteristic parameters of PM2.5 cannot fully reflect the total information of particles. CONCLUSION: The main particulate matter pollutants in the top working area of coke oven is PM1.0, and it with PM(5.0) can account for a large proportion in the mass concentration of PM. It suggest that PM1.0 and PM(5.0) should be considered for occupational health surveillance on the particulate matter in the top area of coke oven. PMID- 25916438 TI - [Relationship between HSP70 gene polymorphisms and susceptibility to lung function injury of cock-oven workers]. AB - OBJECTIVE: In this study, we investigate the relationship between HSP70 and lung function injury. To study on the feasibility of HSP70 genes polymorphisms as biological marker of the damage of pulmonary dysfunction susceptibility. METHODS: 183 cock-oven workers were selected as exposure groups and 143 workers unexposed workers were selected as control groups. We investigated their general information with uniform questionnaire. Pulmonary dysfunction indicators were determined using portable spirometer. HSP70-1 G190C, HSP70-2 A1267G, HSP70- hom T2437C genotypes were analyzed by using the polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) technique. The haplotypes were calculated using PHASE 2.0 software. RESULTS: VC%, FVC%, MVV%, FEV(1.0%) in exposed group were lower than in non-exposure group, the difference were significantly (P < 0.05). VC%, FVC%, MVV%, FEV1.0% in exposed group with HSP70-1, HSP70-2, HSP70-hom genotypes were lower than in non-exposure group (P < 0.05); FVC% in exposed group with HSP70-hom T/C genotypes were lower than that with HSP70-hom T/T genotypes, MVV% were lower than that with HSP70-hom T/T, C/C genotypes. There's no difference in pulmonary dysfunction index of HSP70-1, HSP70-2 genotypes (P>0.05), but significant difference between the exposed group with HSP70-1, HSP70-hom genotypes; The adjust OR (95%CI) of exposed group with HSP70-1 G/C genotypes and HSP70-homT/C genotypes were 2.516 (1.012 ~6.252) and 2.284 (1.033~5.053). Exposed group with CGT haplotype pulmonary dysfunction were significantly higher than in non-exposure group (P < 0.05). CONCLUSION: Coke oven exposure may increase pulmonary dysfunction injury, Coke oven workers who have the HSP70-1 G/C genotypes, HSP70-hom T/C genotypes and CGT haplotypes may increase the susceptibility of pulmonary dysfunction. There must be some relationship between HSP70-1, HSP70-hom gene polymorphisms and lung function injury of Cock-oven Workers. PMID- 25916439 TI - [Expression of C3aR and C5aR in trichloroethylene-sensitized mouse liver]. AB - OBJECTIVE: To study the expression of C3aR and C5aR in trichloroethylene sensitized mouse liver injury and discuss the pathogenesis of Dermatitis Medicamentosa-like of TCE (DMLT). METHODS: 6~8 w female BALB/c mouse were randomly divided into blank control group, solvent control group and TCE treatment group. TCE was given to the mouse for sensitization at 1th, 4th, 7th, 10th day and challenge at 17th day and 19th day. Before killing mouse, liver weight and body weight were recorded. The livers were separated at 24 h, 48 h, 72 h and 7 d after challenge. And the liver sections were used for immunofluorescence stain and RT-PCR to detect the expression levels of C3aR and C5aR. RESULTS: Microscopic examination showed no significant change in liver structure or organization in TCE non-sensitized group, while liver cell oedema, cell necrosis and inflammatory cell infiltration were clearly observed in TCE sensitized groups. The expression levels of C3aR and C5aR in 24 h, 48 h, 72 h and 7 d TCE-sensitized groups were significant higher than blank control group, solvent control group and related TCE non-sensitized groups (P < 0.05). CONCLUSION: Complement activation was involved in TCE-induced liver injury and C3aR and C5aR might play essential role in the process. PMID- 25916440 TI - [The effect of nickel-smelting fumes on the expression of bcl-2 and bax in NIH/3T3 cells]. AB - OBJECTIVE: To investigate the effect of nickel-smelting fumes on the expression of bcl-2 and bax in mammalian cells. METHODS: Logarithmic growth NIH/3T3 cells were exposed to venom for 24 h, which sample fumes concentration was respectively 0, 6.25, 12.50, 25.00, 50.00, 100.00 ug/ml. Cell viability was assessed by MTT assay and the level of extracellular LDH activity was detected with Lactate Dehydrogenase (LDH) kit. Morphological changes of apoptotic were observed with Hoechst33342, while Western blot was used to measure the expression of bcl-2 and bax. RESULTS: In addition to 7 days of 6.25 ug/ml nickel-smelting fumes group, each time point and dose group's cell viability reduced with significant differences compared with the control group (P < 0.05). the extracellular LDH activity increased with increasing dose of nickel-smelting fumes, and the extracellular LDH activity of 6.25, 12.50, 25.00, 50.00, 100.00 ug/ml nickel smelting fumes group increased as compared with the control group (P < 0.05). Simultaneously, the cells, treated with 100.00 ug/ml nickel-smelting fumes for 24 h, appeared obvious morphological changes of apoptosis, such as chromatin condensation and cell shrinkage. the expression of bcl-2 significantly increased in groups of 6.25, 12.50, 25.00 ug/ml nickel-smelting fumes (0.58 +/- 0.01, 0.6 3+/- 0.01 and 0.57 +/- 0.01) and decreased in groups of 50.00, 100.00 ug/m nickel smelting fume (0.35 +/- 0.01 and 0.27 +/- 0.01) as compared with that of the control group (P < 0.05). And the expression of bax significantly decreased in group of 6.25 ug/ml nickel-smelting fumes (0.58 +/- 0.00) and increased in groups of 50.00, 100.00 ug/m nickel-smelting fumes (0.71 +/- 0.01 and 0.78 +/- 0.02) as compared with that of the control group (P < 0.05). CONCLUSION: Apoptosis was activated in NIH/3T3 cell after 24 h of exposure to Ni-smelting fumes, which may be induced by oxidative stress. PMID- 25916441 TI - [A case report of acute abamectin poisoing]. PMID- 25916442 TI - [Effects of malathion on testicular spermatogenic function in rats]. AB - OBJECTIVE: To investigate the effects of malathion on the testicular spermatogenic function of male rats and its working mechanism. METHODS: Forty specific pathogen-free male Wistar rats were randomly and equally divided into four groups: three exposure groups and a control group. Malathion was administered orally to male rats in the exposure groups at 33.75, 54, and 108 mg/kg (1/32 LD50, 1/20 LD50, and 1/10 LD50) for 60 days. Rats in the control group received an equal volume of water. The body weights of rats were measured after exposure. The organ weights and coefficients of the testes and epididymes were determined as soon as rats were sacrificed. The sperm motility, counts, and malformation rates were measured in the left epididymis. Histopathological changes, cell apoptosis, and the expression levels of Bcl-2/Bax in the testes of rats were observed using HE staining, terminal deoxynucleotidyl transferase mediated dUPT-biotin nick end labeling, and immunohistochemistry SABC method. RESULTS: The body weights and the testis weights in the exposure groups were significantly lower than those in the control group (P < 0.01). The exposure groups had significantly lower sperm motility and significantly higher sperm malformation rates than the control group (P < 0.01). The sperm counts were significantly lower in the exposure groups than in the control group (P<0.01). The sperm counts and motility were negatively correlated with exposure dose (r = 0.81, P < 0.01; r = -0.51, P < 0.01), while the sperm malformation rate was positively correlated with exposure dose (r = 0.85, P 0.01). The exposure groups had significantly higher spermatogenic cell apoptosis rates than the control group (P<0.01). The expression level of Bax was significantly higher in the exposure groups than in the control group (P<0.01), while the expression level of Bcl-2 was significantly lower in the exposure groups than in the control group (P < 0.01). Histopathological examination of the testes showed degenerative changes in the seminiferous tubules at various doses along with the increase in malathion exposure dose. CONCLUSION: Malathion affects the testicular spermatogenic function of male rats and its working mechanism may involve cell apoptosis induced by down-regulation of Bcl-2 and up-regulation of Bax. PMID- 25916443 TI - [Analyses on relevant factors of the prognosis of patients with acute organophosphate poisoning]. AB - OBJECTIVE: To find out a method which can assess the prognosis of patients with Acute Organophosphate Poisoning objectively and increase the successful ratio of treatment by investigating relevant factors on the prognosis of the patients with Acute Organophosphate Poisoning. METHODS: We retrospected 116 patients with Acute Organophosphate Poisoning who were treated in our hospital's emergency room from April 2006 to March 2014. According to the outcome of patients, we distributed the patients to death group and survival group, compared the clinic data and using multivariate analysis with Logistic regression to prognosis factors. RESULTS: 116 cases of acute organophosphate poisoning patients died in 23 cases, improved in 93 cases. Death group patients' APACHE-II score are higher than whose in the survival group (P < 0.05). Compared with the survival group, patients' body temperature, blood pressure, pH, GCS index were lower in the death group (P < 0.05) and Cr, WBC, ALT, AST, CK-MB, blood glucose, blood lactic acid, heart rate were higher in the death group (P < 0.05), there were significant difference between two groups with statistical.Low blood pressure, lower GCS score, hyperglycemia and high white blood cell count, were independent risk factors of poor prognosis, and hypotension was maximum value of all the factor (OR = 54.22). CONCLUSION: APACHE II prognostic scoring system can be accurately response, vital signs, white blood cell count, pH, serum creatinine, GCS score and serum sodium value which in this system may be associated with prognosis. To evaluate the severity and prognosis of illness Blood glucose, ALT, AST, CK-MB's rising also has certain value. PMID- 25916444 TI - [Dynamic observation of clinical course in patients with subacute 1, 2 dichloroethane poisoning]. AB - OBJECTIVE: To observe the clinical characteristics and regular patterns of subacute 1, 2-dichloroethane poisoning patients for providing evidences to it's diagnosis, treatment and prognosis. METHODS: 51 cases of subacute 1, 2 dichloroethane poisoning analyzed. They were divided into 3 groups according to their main clinical manifestation: group A mainly with intracranial hypertension (n = 25), group B with limbs tremor (n = 18), group C with mental and behavior disorder (n = 8). All cases' clinical symptoms, cranial computer tomography, cerebrospinal pressure (Group A) were observed, the durations of the onset, deterioration, improvement, recovery and whole course of the disease were compared between groups and in each group. RESULTS: In all of 51 cases, only the differences between the deterioration duration of cranial CT and symptom was significantly (t = 2.555, P<0.05), which indicate the deterioration of symptom was earlier than radiological change. The symptom deterioration of group C was the fastest than group A and group B (P<0.00). As to the change of symptom duration, group B's improvement, recovery and whole course was the longest comparing with group A and group C (P<0.05). As to the change of cranial CT duration, group B's recovery duration was the shortest and group A's recovery duration was the longest (P<0.01); group B's whole course was also the shortest and group A's whole course was the longest (P<0.05). The clinical course of symptoms, cranial computer tomography, cerebrospinal pressure (Group A) was compared in each group, in group A, the duration of improvement and whole course of the cranial CT and cerebrospinal pressure change was longer than that of the symptom change (P<0.01), this indicated that group A has longer asymptomatic intracranial hypertension and their cranial radiography recover slowly. In group B, their symptoms (3.94 +/- 4.31 days) deteriorated is earlier than cranial CT changes (P<0.05), the recovery (92.39 +/- 55.04 days) and whole course of symptom was longer than cranial CT change (all P<0.01). In group C, symptom deterioration was earlier than CT deterioration (P< 0.05). CONCLUSION: The clinical characteristic of subacute 1, 2- dichloroethane poisoning is central nervous system damage, it differs according to the different stage of course, the regions and severity of pathology lesions. PMID- 25916445 TI - [Analysis of reports of cases of pesticide poisoning in Jiangsu Province, China, from 2006 to 2013]. AB - OBJECTIVE: To investigate the characteristics of pesticide poisoning in Jiangsu Province, China, and to provide a scientific basis for developing effective intervention measures and prevention strategies. METHODS: The data from report cards of pesticide poisoning in Jiangsu Province from 2006 to 2013 were arranged using EXCEL tables, and assessed. Statistical analysis was applied to the epidemiological data using SPSS. RESULTS: From 2006 to 2013, a total of 32672 cases of pesticide poisoning were reported in Jiangsu Province. Most of the cases were caused by non-occupational poisoning (life poisoning) (72.78%). A majority of patients with pesticide poisoning were 35-54 years old (40.85%) or older than 65 years (15.69%). There were more female patients (58.22%) than male patients (41.78%). Among patients with occupational poisoning, male patients (50.90%) were more than female patients. Among patients with non-occupational poisoning, female patients were more than male patients (38.37%). Pesticide poisoning mainly occurred from July to September. The case-fatality rate of occupational poisoning (0.47%) was lower than that of non-occupational poisoning (7.10%). All 13 cities in Jiangsu Province reported cases of pesticide poisoning. There were more cases in the northern regions than in the southern regions. Pesticide poisoning was mainly caused by organophosphorus insecticides including methamidophos, dichlorvos, dimethoate, omethoate, and parathion, which accounted for 65.58%of all cases. Paraquat had the highest case-fatality rate (10.06%) among all pesticides, followed by tetramine (10.00%), dimethoate or omethoate (7.85%), methamidophos (7.79%), and dimehypo (7.68%). CONCLUSION: Pesticide poisoning cannot be ignored. The management and control should be improved in production and usage of highly toxic pesticides including organophosphorus insecticides, rodenticides, and herbicides. More attention should be paid to the protection of vulnerable groups including women, children, and the elderly. PMID- 25916446 TI - [Survey of urology nurses on occupation protection from intravesical chemotherapy]. AB - OBJECTIVE: To investigate the awareness of self protection and practice of nurses from urology department when giving intravesical chemotherapy to patients with urinary bladder cancer. METHODS: One survey via a self-designed questionnaire and an on-the-spot examination of anticancer drugs preparing were done and compared among 42 nurses from urology department and 48 nurses from oncology department. RESULTS: All nurses from oncology department were trained with anticancer drugs associated knowledge and 83.3% nurses from urology department had received some training (P<0.05). Over 64.6%nurses from department of medical oncology were familiar with all the five parts of chemotherapy drugs protection protocol, while only 40.5%nurses from department of urology were aware of them. During the on-the spot examination, 50.0% and 21.4% nurses respectively from oncology department and urology department could complete seven anticancer drugs preparation procedure correctly (P <0.05) CONCLUSIONS: The nurses from urology department had weak awareness of self protection and were lack of chemotherapy associated training and standard practice when giving intravesical chemotherapy. It is imperative to work out a protection plan to educate the nurses and establish the protocols for preparing anticancer drugs to reduce the occurrence of occupational hazard. PMID- 25916447 TI - [Observation of the inflammatory factors level and the correlation between induced sputum and whole lung lavage fluid for silicosis]. AB - OBJECTIVE: To detect the inflammatory factors of induced sputum (IS) and whole lung lavage fluid in pneumonoconiosis patients and to explore the correlation between the inflammatory factors with pulmonary function. METHODS: The records of 45 cases of pneumonoconiosis patients were observed. All patients underwent lung function examination, sputum induction and massive whole lung lavage (WLL) sequentially through advance. IS and whole lung lavage fluid were collected respectively. Inflammatory factors of the two specimens were detected by using enzyme linked immunosorbent assay. The correlation of inflammatory factors between the two specimens was analyzed. The relationship between the inflammatory factor and lung function index was observed. The statistical analysis is performed with SPSS 17.0 for Windows. P < 0.05 is considered to be statistically significant. RESULTS: Cytokines (MCP-1, TNF-alpha MIP-1alpha, NO(2)(-)/NO(3)(-) and IL-16) were significantly associated between IS and whole lung lavage fluid (P < 0.05), while TNF-alpha, MCP-1, NO(2)(-)/NO(3)(-) and IL-16 were no significantly associated with lung function index (P > 0.05). MIP-1alpha was significantly associated with FEV(1.0)/VCmax and MEF(25), respectively (P < 0.05). CONCLUSIONS: Inflammatory factors were significantly associated between IS and whole lung lavage fluid, which could indicate early lung injury in pneumonoconiosis patients. PMID- 25916448 TI - [The current situation of occupational protection against skin/mucosa contamination among obstetrician and gynecologist]. AB - OBJECTIVE: To investigate the occurrence and protection of skin/mucosa contamination among obstetrician and gynecologist. METHODS: By random, stratified, and clustered sampling, 219 obstetrician and gynecologist were selected. 210 valid questionnaires were collected, efficiency is 95.89%. 110 obstetrician and gynecologist come from tertiary hospitals, 100 come from secondary hospitals. A self-administered questionnaire on skin/mucosa contamination was employed to gauge the implementation of protection, types and working links of skin/mucosa contamination. RESULTS: Of the respondents, only 14.76% (31/210) and 5.24% (11/210) adhered to proper hand washing and wearing protective glasses within nearly 1 year in practical work. Of the respondents, 73.81% (155/210) had experienced the skin/mucosa contamination during their vocation, 50.95% (107/210) occurred sharps injuries, 45.71% (96/210) occurred damaged skin contamination, and 43.33% (91/210) occurred mucosa contamination. Sharps injuries mainly occurred when abdominal operation (45.71%, 96/120), damaged skin contamination mainly occurred when gynecological examination (21.43%, 45/210), and mucosa contamination mainly occurred when midwifery (37.14%, 78/210). CONCLUSION: The implementation of protective measures is inadequate and incidence of skin/mucosa contamination is higher among obstetrician and gynecologist. Therefore, occupational protection education should focus on different types and working links of skin/mucosa contamination. At the same time, strict supervision and management system should be established. PMID- 25916449 TI - [Effects of polygala on the neurogenesis of manganese poisoned mice]. AB - OBJECTIVE: To investigate the effects of polygala on leaning and memory and the expression of Microtubule associated protein on manganese poisoned mice. METHODS: 60 female Kunming mice were randomly and equally divided into 5 group. They are normal control group (CG), manganese poisoned group (MG), manganese poisoned with polygala high dose group (MHG), manganese poisoned with polygala middle dose group (MMG), manganese poisoned with polygala low dose group (MLG). The model of manganese poisoned mice was prepared of the way of intraperitoneal injection of manganese chloride (MnCl2 15 mg/kg), the spatial learning and memory ability was tested by Morris water maze, the Doublecortin (DCX) was tested by the way of immunofluorescent staining in the SVZ and SGZ. RESULT: In the navigation test, compared with MG, the escape latency of MHG, MMG and MLG were significantly decreased (P < 0.05), in space exploration experiments, MHG, MMG, MLG compared with MG, the number increased significantly across platforms (P < 0.05). compared with MG, the DCX expression of MHG, MMG and MLG were significantly increased (P < 0.05). CONCLUTION: The leaning and memory ability of manganese poisoned mice can be improved by the polygala, and the mechanism may be related to promote the expression of DCX and neurogenesis in the brain. PMID- 25916450 TI - [Noninvasive positive pressure ventilation on the treatment of patients with silicosis combined with acute respiratory failure]. PMID- 25916451 TI - [Clinical study on the treatment of acute paraquat poisoning with sequential whole gastric and bowel irrigation]. AB - OBJECTIVE: To explore the clinical efficacy of early application of sequential gastrointestinal lavage in patients with acute paraquat poisoning by analyzing the clinical data of 97 patients. METHODS: A total of 97 eligible patients with acute paraquat poisoning were divided into conventional treatment group (n = 48) and sequential treatment group (n = 49). The conventional treatment group received routine gastric lavage with water. Then 30 g of montmorillonite powder, 30 g of activated charcoal, and mannitol were given to remove intestinal toxins once a day for five days. The sequential treatment group received 60 g of montmorillonite powder for oral administration, followed by small-volume low pressure manual gastric lavage with 2.5%bicarbonate liquid. Then 30 g of activated charcoal, 30 g of montmorillonite powder, and polyethylene glycol electrolyte lavage solution were given one after another for gastrointestinal lavage once a day for five days. Both groups received large doses of corticosteroids, blood perfusion, and anti-oxidation treatment. The levels of serum potassium, serum amylase (AMY) alanine aminotransferase (ALT), total bilirubin (TBIL), blood urea nitrogen (BUN), creatinine (Cr), lactate (Lac), and PaO2of patients were determined at 1, 3, 5, 7, and 10 days. Laxative time, mortality, and survival time of dead cases were evaluated in the two groups. RESULTS: The incidence rates of hypokalemia (<3.5 mmol/L) and AMY (>110 U/L) were significantly lower in the sequential treatment group than in the conventional treatment group (P < 0.05). There were no significant differences in the incidence of ALT (>80 U/L), TBIL (>34.2 umol/L), BUN (>7.2 mmol/L), and Cr (>177 umol/L) between the two groups (P>0.05). However, the highest levels of ALT, TBIL, BUN, Cr, and Lac were significantly lower in the sequential treatment group than in the conventional treatment group (P < 0.05). Moreover, the sequential treatment group had significantly lower incidence of PaO2(<60 mmHg), shorter average laxative time, lower mortality, and longer survival time of dead cases than the conventional treatment group (P < 0.05). CONCLUSION: The early application of sequential gastrointestinal lavage can shorten laxative time, alleviate organ damage in the liver, kidney, lung, and pancreas, reduce mortality, and prolong the survival time of dead cases in patients with acute paraquat poisoning. PMID- 25916452 TI - [Study on compound electrolyte solation for long lavage]. PMID- 25916453 TI - [The significance of monitoring procalcitonin when applying antibiotics to trichlorethylene dermatitis]. AB - OBJECTIVE: To investigate the significance of monitoring procalcitonin (PCT) when applying antibiotics to trichlorethylene (TCE)-induced dermatitis. METHODS: One hundred and two patients who were hospitalized and recovered from TCE-induced dermatitis in our hospital from 2006 to 2013 were enrolled as subjects. Based on whether the PCT level was monitored or not, we divided patients into regular group and PCT group. For the regular group, we applied antibiotic treatment and determined the course of treatment based on clinical symptoms, laboratory test results, medical imaging results, and bacterial culture. For the PCT group, in addition to the above treatments, antibiotic treatment was applied when the PCT level was not lower than 0.25 ng/ml and stopped when the PCT level was lower than 0.25 ng/ml. The distribution of bacterial infection sites, type of bacteria, type of antibiotics, average period of hospitalization, and course of antibiotic treatment were compared between the two groups. RESULTS: There were no significant differences in the distribution of bacterial infection sites, type of bacteria, type of antibiotics, and average period of hospitalization between the two groups (P > 0.05). The course of antibiotic treatment for the PCT group was significantly shorter than that for the regular group (25.37 +/- 11.66 vs 20.58 +/- 7.53 d, P < 0.05). CONCLUSION: Under similar conditions of bacterial infection, antibiotic treatment of TCE-induced dermatitis based on the serum PCT level can significantly shorten the course of treatment and avoid the abuse of antibiotics. PMID- 25916454 TI - [The effect of the tiotropiumbromide treatment of pneumoconiosis compleated with chronic obstructive pulmonary disease]. PMID- 25916455 TI - [Asbestos exposure workers alveolar protein deposition disease]. PMID- 25916456 TI - [A case of oral lime sulfur poisoning]. PMID- 25916457 TI - [Rapid determination of 28 pesticides and tetramine in whole blood by online gel permeation chromatography coupled with gas chromatography-mass spectrometry]. AB - OBJECTIVE: To study the influences of carbon disulfide (CS2) exposureon fatty acid metabolism in apolipoprotein E (ApoE) knockout mice and C57BL/6J mice. METHODS: Twenty-four male ApoE knockout mice were randomly and equally divided into four groups: a CS2-exposed normal diet group, a CS2-unexposed normal diet group, a CS2-exposed high-fat diet group, and a CS2-unexposed high-fat diet group. Twenty-four C57BL/6J male mice were divided into four groups in the same way. The CS2-exposed groups were exposed to CS2 (1 g/m3) by static inhalation for 5 hours a day, 5 days a week. After two weeks, the whole blood of mice was collected. Methyl ester derivatization of fatty acids was performed using an acid catalyzed method. Fatty acid contents before and after exposure were compared by gas chromatography-mass spectroscopy. RESULTS: There were significant differences in fatty acid contents of mice between the four groups. For the C57BL/6J mice, the arachidic acid contents in the CS2-exposed high-fat diet group were significantly lower than those in the CS2-unexposed high-fat diet group (P = 0.0450). For the ApoE knockout mice, the arachidonic acid contents in the CS2 exposed normal diet group were significantly lower than those in the CS2 unexposed control diet group (P = 0.0452). For the ApoE knockout mice, the gamma linolenic acid contents in the CS2-exposed high-fat diet group were significantly higher than those in the unexposed high-fat diet group (P = 0.0447). CONCLUSION: Exposure to CS2 can induce fatty acid metabolism disorder in mice, indicating that CS2 may increase the risk of atherosclerosis and other cardiovascular diseases. PMID- 25916458 TI - [Case fatality rate in patients with pneumoconiosis in China: a meta-analysis]. AB - OBJECTIVE: To evaluate the fatality rate of pneumoconiosis as well as the contributory factors in China in order to provide a foundation for prolonging the patients' lives. METHODS: China National Knowledge Infrastructure (CNKI) and Wanfang Databases were searched to collect observational studies published between Jan, 2000 and Oct, 2013 on pneumoconiosis case fatality rate. Articles meeting the inclusion criteria were reviewed systematically, and analyzed by using Stata/SE 12.0, according to stage and type of pneumoconiosis and whether complicated with tuberculosis. RESULTS: 41 papers were included for meta analysis. The pooled total case fatality rate of pneumoconiosis was 31.2%. The pooled case fatality rate of pneumoconiosis patients of stage 1, 2 and 3 were 25.4%, 39.8%and 57.5%, respectively. The pooled case fatality rate of patients with silicosis, coal worker's pneumoconiosis, foundry worker's pneumoconiosis, asbestosis and cement pneumoconiosis were 35.8%, 32.4%, 24.7%, 35.1%and 5.5%, respectively. The complication with tuberculosis was a risk factor for the death of pneumoconiosis patients and the pooled RR was 1.82 (95%CI: 1.59~2.08). CONCLUSION: There are significant differences in the case fatality rate of pneumoconiosis among different stages and different types of pneumoconiosis and whether complicated with tuberculosis. PMID- 25916459 TI - [Research progress of deposition of metals and their compounds dust lung]. PMID- 25916460 TI - [Advances in diagnosis and treatment of intermediate syndrome of acute organophosphate poisoning]. PMID- 25916461 TI - [Immunomodulatory effects of regulatory T cells in the lung fibrosis]. PMID- 25916462 TI - Predictive value of serial high-resolution computed tomography analyses and concurrent lung function tests in systemic sclerosis. AB - OBJECTIVE: Systemic sclerosis (SSc) carries a high risk of progressive interstitial lung disease (ILD), but tools for stratifying individual risk are scarce. The purpose of this study was to assess detailed data from serial lung fibrosis measurements and paired pulmonary function tests (PFTs) as outcome prediction tools in a prospective cohort of SSc patients. METHODS: Paired PFTs and high-resolution computed tomography (HRCT) scans were obtained at baseline and at followup in 305 SSc patients who met the American College of Rheumatology/European League Against Rheumatism 2013 classification criteria. The extent of fibrosis was scored on 10 sections from every HRCT scan and expressed as the percentage of the total lung volume. RESULTS: Baseline HRCT analyses revealed 3 SSc subgroups: those with >20% lung fibrosis (n = 40), those with 1 20% fibrosis (n = 157), and those with no fibrosis (n = 108). At followup HRCT (mean of 3.1 years later), all 108 group 3 patients were still free of fibrosis. In group 2 patients, 146 continued to have 1-20% fibrosis (group 2a), whereas 11 (marked by short disease duration of 1.3 years) had experienced progression to >20% fibrosis (group 2b). The annual fibrosis progression rate differed across the 4 groups: 0.9% in group 1, 0.7% in group 2a, 5.9% in group 2b, and 0% in group 3. The annual fibrosis progression rate correlated with the total decline in the forced vital capacity (FVC) (7.1%, 5.7%, 8.7%, and 2.9% in groups 1, 2a, 2b, and 3, respectively), but not the diffusing capacity for carbon monoxide (DLco) (8.4%, 7.7%, 7.7%, and 8.6%, respectively). Multivariate analyses identified anticentromere antibodies (odds ratio [OR] 4.7) and baseline DLco (OR 1.04) as predictors of no fibrosis at followup and baseline fibrosis (OR 1.3) and FVC (OR 0.96) as predictors of >20% fibrosis at followup. CONCLUSION: These prospective cohort data suggest that HRCT performed at baseline predicts the development of fibrosis, the rate of progression of fibrosis, and the decline in pulmonary function in SSc. PMID- 25916463 TI - The use of Botulinum toxin-a injection for facial wrinkles: a histological and immunohistochemical evaluation. AB - Botulinum toxin (BTX)-A has been used for years in the reduction of facial wrinkles; however, histological and immunohistochemical changes after its use were not previously investigated. To evaluate histological and immunohistochemical changes after BTX-A injection for facial wrinkles, sixteen volunteers, with wrinkles on the upper third of the face, were subjected to single injection of BTX-A. Skin biopsy specimens were obtained from peri-orbital wrinkle site (crow's feet area) before and after 3 months of BTX-A injection. Using histological and immunohistochemical evaluation coupled with computerized morphometric analysis, measurement of epidermal thickness, wrinkle depth and width as well as quantitative evaluation of collagen types I and III and elastin was performed for skin biopsies. After BTX-A injections, there were significant increase in wrinkle width and granular layer thickness (P < 0.001), while the other histometrical measures as well as the immunohistochemical expression of collagen types I and III and elastin showed no significant difference (P > 0.05). However, collagen fibers showed better organization and orientation after BTX-A injection. The histological changes observed after BTX-A injection for facial wrinkles may help in better understanding of its mechanism of action. PMID- 25916464 TI - Gastric invasion of multiple myeloma presenting as gastrointestinal bleeding. PMID- 25916465 TI - Parasitic nematode communities of the red kangaroo, Macropus rufus: richness and structuring in captive systems. AB - Captive management practices have the potential to drastically alter pre-existing host-parasite relationships. This can have profound implications for the health and productivity of threatened species in captivity, even in the absence of clinical symptoms of disease. Maximising the success of captive breeding programmes requires a detailed knowledge of anthropogenic influences on the structure of parasite assemblages in captive systems. In this study, we employed two high-throughput molecular techniques to characterise the parasitic nematode (suborder Strongylida) communities of the red kangaroo, Macropus rufus, across seven captive sites. The first was terminal restriction fragment length polymorphism (T-RFLP) analysis of a region of rDNA encompassing the internal transcribed spacers 1 (ITS1), the 5.8S rRNA gene and the internal transcribed spacer 2 (ITS2). The second was Illumina MiSeq next-generation sequencing of the ITS2 region. The prevalence, intensity of infection, taxonomic composition and comparative structure of strongylid nematode assemblages was assessed at each location. Prevalence (P = <0.001) and mean infection intensity (df = 6, F = 17.494, P = <0.001) differed significantly between the seven captive sites. Significant levels of parasite community structure were observed (ANOSIM, P = 0.01), with most of the variation being distributed within, rather than between, captive sites. The range of nematode taxa that occurred in captive red kangaroos appeared to differ from that of wild conspecifics, with representatives of the genus Cloacina, a dominant nematode parasite of the macropodid forestomach, being detected at only two of the seven study sites. This study also provides the first evidence for the presence of the genus Trichostrongylus in a macropodid marsupial. Our results demonstrate that contemporary species management practices may exert a profound influence on the structure of parasite communities in captive systems. PMID- 25916466 TI - Stichorchis subtriquetrus (Digenea: Paramphistomatidae) from Eurasian beaver (Castor fiber) in the Czech Republic. AB - Between March 2012 and April 2014, we performed post-mortem parasitological examinations of 11 Eurasian beavers (Castor fiber Linnaeus, 1758) from the basins of four main rivers (Dyje, Labe, Morava, Vltava) in the Czech Republic. The cause of death of five adult animals was unknown, three adult animals died after being hit by cars, while one young and one adult as a result of serious injuries and one juvenile male drowned. The trematode Stichorchis subtriquetrus (Rudolphi, 1814) Luhe, 1909 was only found in the caecum body and caecum apex of nine beavers (82%), with no significant differences in parasite intensity among beavers. The highest number of trematodes (271) occurred in an adult female in July 2013; while a range of 1-57 individuals were found in other positive beavers. S. subtriquetrus size in both parts of the caecum was 11.0-17.0 * 5.5 8.0 mm (mean 14.3 * 6.9 mm). Results demonstrated that for the optimal detection of eggs, it was necessary to examine at least 10 g of faeces with a new modified method of sedimentation. The size range of 30 eggs was 157.1-182.5 * 99.3-109.8 MUm (mean 168.0 * 104.4 MUm). There were no differences in prevalence and seasonal occurrence of S. subtriquetrus between male and female beavers. We did not find any other intestinal endoparasites or tissue parasites (Sarcocystis spp., Trichinella spp.). PMID- 25916468 TI - A systematic review of integrated traditional Chinese and Western medicine for managing irritable bowel syndrome. AB - Traditional Chinese medicine (TCM) has been commonly used by Chinese practitioners to treat irritable bowel syndrome (IBS). However, the effectiveness of combining TCM with Western medicine in managing IBS has not been evaluated systematically. In this study, we evaluated the clinical effectiveness of combining TCM and Western medicine in the treatment of IBS via meta-analyses. We reviewed 72 eligible randomized controlled trials from January 2009 to December 2013 investigating the effectiveness of integrated TCM and Western medicine in the management of IBS. In the meta-analyses, the relative risks (RRs) and 95% confidence interval (95%CI) were calculated using raw data from each study, and low heterogeneity was detected. When compared to the Western medicine treatment alone, our result showed TCM combined with Western interventions significantly improved IBS global symptoms (RR, 1.21; 95%CI: 1.18-1.24). Additionally, there was no significant difference in therapeutic effects of the integrated approach in the meta-analyses involving the various IBS subtypes. Likewise, both Chinese proprietary herbal medicine plus conventional treatment and compound herbal preparations plus conventional treatment showed similar and statistically significant effects on global improvement compared with western treatment alone, with RRs of 1.22 (95%CI: 1.14-1.30) and 1.22 (95%CI: 1.18-1.27), respectively. These results demonstrated that treating IBS with integrated traditional Chinese and Western medicines showed better effectiveness than conventional Western medicine alone. Although due to the quality of the included studies, our results might possess a high risk of bias. TCM, particularly Chinese proprietary medicine, with the benefits of low-cost, easy to use, and good palatability, would be an attractive option to be used in conjunction with conventional Western medicine to manage IBS patients. PMID- 25916467 TI - FGF1 and FGF19 reverse diabetes by suppression of the hypothalamic-pituitary adrenal axis. AB - Fibroblast growth factor-1 (FGF1) and FGF19 have been shown to improve glucose metabolism in diabetic rodents, but how this occurs is unknown. Here to investigate the mechanism of action of these growth factors, we perform intracerebroventricular (i.c.v.) injections of recombinant FGF1 or FGF19 in an awake rat model of type 1 diabetes (T1D) and measure rates of whole-body lipolysis, hepatic acetyl CoA content, pyruvate carboxylase activity and hepatic glucose production. We show that i.c.v. injection of FGF19 or FGF1 leads to a ~60% reduction in hepatic glucose production, hepatic acetyl CoA content and whole-body lipolysis, which results from decreases in plasma ACTH and corticosterone concentrations. These effects are abrogated by an intra-arterial infusion of corticosterone. Taken together these studies identify suppression of the HPA axis and ensuing reductions in hepatic acetyl CoA content as a common mechanism responsible for mediating the acute, insulin-independent, glucose lowering effects of FGF1 and FGF19 in rodents with poorly controlled T1D. PMID- 25916469 TI - Celery Seed Extract Blocks Peroxide Injury in Macrophages via Notch1/NF-kappaB Pathway. AB - Oxidized low-density lipoprotein (ox-LDL)-induced macrophage foam cell formation and injury is one of the major atherogenic factors. This study is aimed to investigate the protective effect of celery seed extract (CSE) on ox-LDL-induced injury of macrophages and the underlying signaling pathway. RAW264.7 macrophages were pre-incubated with CSE for 24 h, followed by stimulation with ox-LDL. Oil red O staining and enzymatic colorimetry indicated CSE significantly lessened lipid droplets and total cholesterol (TC) content in ox-LDL-injured macrophages. ELISA revealed that CSE decreased the secretion of inflammatory cytokine TNF alpha and IL-6 by 12-27% and 5-15% respectively. MTT assay showed CSE promoted cell viability by 16-40%. Cell apoptosis was also analyzed by flow cytometry and laser scanning confocal microscope and the data indicated CSE inhibited ox-LDL induced apoptosis of macrophages. Meanwhile, western blot analysis showed CSE suppressed NF-kappaBp65 and notch1 protein expressions stimulated by ox-LDL in macrophages. These results suggest that CSE inhibits ox-LDL-induced macrophages injury via notch1/NF-kappaB pathway. PMID- 25916470 TI - The mercury levels in crustaceans and cephalopods from Peninsular Malaysia. AB - This study is to determine total mercury in edible tissues of eight species of cephalopods and 12 species of crustaceans purchased from 11 identified major fish landing ports and wet markets throughout Peninsular Malaysia. The concentration of mercury was measured by cold vapor atomic absorption spectrometry (AAS) technique using the Perkin Elmer Flow Injection Mercury System (FIMS-400). In general, the mercury levels were low with concentrations in cephalopods ranging from 0.099 to 2.715 mg/kg dry weight (or 0.0184-0.505 mg/kg wet weight) and in crustaceans ranging from 0.057 to 1.359 mg/kg dry weight (or 0.0111-0.265 mg/kg wet weight). The mercury levels showed no significant differences (P > 0.05) between species for both cephalopods and crustaceans. There was no significant correlation between mercury concentrations and the body size of individual for both groups as well. Comparisons with mercury levels obtained found from other previous studies and/or species noted that they were of the same magnitude or relatively low compared to various locations reported worldwide. PMID- 25916471 TI - The influence of sunlight and oxidative treatment on measured PAH concentrations in biochar. AB - The concentration changes of 18 different polycyclic aromatic hydrocarbons (PAHs) in two different biochars were assessed after (1) chemical oxidative treatment with a solution of H2O2 and Na2S2O8, (2) exposure to sunlight with intermittent wetting, and (3) exposure to sunlight with intermittent wetting after mixing in ZnO and Na2S2O8. Chemical oxidative treatment of biochars derived from gasified wood biochar and a gasified wood/Arundo donax mixture led to decreases in six ring PAHs, but overall significant increases in measured PAH concentration sums for both biochars (from 225 +/- 7 to 312 +/- 18 MUg g(-1) for wood-derived and 165 +/- 3 to 244 +/- 7 MUg g(-1) for mixture-derived). Sunlight exposure of the mixture-derived biochar led to increases in some three- and four-ring PAHs, but overall decreases in summed PAH concentrations (165 +/- 3 to 60 +/- 1 MUg g(-1) with wetting only and 165 +/- 3 to 41 +/- 4 MUg g(-1) when Na2S2O8 and ZnO were included). The mass losses in the sunlight-exposed samples primarily were due to losses of low molar mass (two-ring) PAHs, though high molar mass (five- and six ring) PAH concentrations also decreased. This result implies sun and rain exposure to biochar, prior to agricultural application, will help reduce potential PAH soil contamination from the biochar. PMID- 25916472 TI - Bioavailability of sedimentary phosphorus under repeated sediment resuspension with the addition of algae. AB - The bioavailability of sedimentary P was investigated under repeated sediment resuspension with and without the addition of algae. Results show that the release of P as dissolved total P and dissolved inorganic P depends on the reduction in Fe/Al-P and Ca-P in the sediments. The reduction rates can be attributed to sediment resuspension and algal assimilation. However, under a low algal concentration, the assimilation of algae in P is lower than the readsorption of reoxidized Fe or other P-binding matter, such as clays and CaCO3 particles. This result was confirmed by the increase in algal available P (AAP) under sediment resuspension conditions with and without the addition of algae. Although measuring the formation and reduction rates of AAP is difficult, AAP is a good predictor of the bioavailability of sedimentary P. The bioavailable P in the sediments can be estimated using the sum of NH4Cl-P, AAP, and %Ca-P at certain concentrations of algae given the assimilation of Ca-P under sediment resuspension conditions with the addition of algae. PMID- 25916474 TI - Urinary parabens and polyaromatic hydrocarbons independent of health conditions are associated with adult emotional support needs: USA NHANES, 2005-2008. AB - Everyone needs emotional support at some point in life, but the needs might not always be met. The present study was aimed to investigate the prevalence of unmet needs of emotional support in adults and to identify social, environmental and health attributes in a national and population-based setting in recent years. Data was retrieved from the US National Health and Nutrition Examination Surveys, 2005-2008, including demographics, blood pressure readings, self-reported emotional support needs in the last 12 months, self-reported ever health conditions and urinary environmental chemical concentrations. Statistical analyses included chi-square test, t test, survey-weighted logistic regression modeling and population attributable risk (PAR) estimation. Of 6733 American adults aged 40-80, 1273 (21.0 %) needed more emotional support in the past year. They tended to be aged 40-60, female, Mexican American, other Hispanic, education less than high school, or poverty income ratio 5+. People with higher levels of butyl paraben, ethyl paraben, methyl paraben, 1-hydroxynaphthalene, 2 hydroxynaphthalene, or 9-hydroxyfluorene (but not heavy metals, arsenic, phenols, phthalates, pesticides, or phytoestrogens) or historical diabetes, asthma, arthritis, stroke, thyroid disorder, chronic bronchitis, sleep complaint/disorder, or trouble seeing needed more emotional support. Significant risk associations from environmental chemicals mentioned above have remained after adjusting for historical health conditions as potential mediators. This is the first time examining prevalence of the unmet emotional support in adults and identifying the social, environmental and health attributes. Removal of parabens and polyaromatic hydrocarbons and increasing healthcare for people with health conditions to accommodate emotional support should be considered. PMID- 25916473 TI - Dynamics of chromophoric dissolved organic matter influenced by hydrological conditions in a large, shallow, and eutrophic lake in China. AB - High concentrations of chromophoric dissolved organic matter (CDOM) are terrestrially derived from upstream tributaries to Lake Taihu, China, and are influenced by hydrological conditions of the upstream watershed. To investigate how the dynamics of CDOM in Lake Taihu are influenced by upstream inflow runoff, four sampling cruises, differing in hydrological conditions, were undertaken in the lake and its three major tributaries, rivers Yincun, Dapu, and Changdou. CDOM absorption, fluorescence spectroscopy, chemical oxygen demand (COD), and stable isotope delta(13)C and delta(15)N measurements were conducted to characterize the dynamics of CDOM. The mean absorption coefficient a(350) collected from the three river profiles (5.15 +/- 1.92 m(-1)) was significantly higher than that of the lake (2.95 +/- 1.88 m(-1)), indicating that the upstream rivers carried a substantial load of CDOM to the lake. This finding was substantiated by the exclusively terrestrial signal exhibited by the level of delta(13)C (-26.23 +/- 0.490/00) of CDOM samples collected from the rivers. Mean a(350) and COD in Lake Taihu were significantly higher in the wet season than in the dry season (t test, p < 0.0001), suggesting that the abundance of CDOM in the lake is strongly influenced by hydrological conditions of the watershed. Four components were identified by parallel factor analysis, including two protein-like components (C1 and C2), a terrestrial humic-like component (C3), and a microbial humic-like (C4) component. The contribution percentage of the two humic-like components relative to the summed fluorescence intensity of the four components (C humic) increased significantly from the dry to the wet season. This seasonal difference in contribution further substantiated that an enhanced rainfall followed by an elevated inflow runoff in the lake watershed in the wet season may result in an increase in humic-like substances being discharged into the lake compared to that in the dry season. This finding was further supported by an elevated a(250)/a(365) of CDOM samples collected in the lake in the wet season than in the dry season. Significantly higher mean levels of C3 and a(350) were recorded for CDOM samples collected from River Yincun than those from rivers Dapu and Changdou, differing in seasons, suggesting the significance of terrestrial CDOM input from River Yincun. PMID- 25916475 TI - Biochemical and molecular mechanisms involved in simultaneous phenol and Cr(VI) removal by Acinetobacter guillouiae SFC 500-1A. AB - Bioremediation has emerged as an environmental friendly strategy to deal with environmental pollution. Since the majority of polluted sites contain complex mixtures of inorganic and organic pollutants, it is important to find bacterial strains that can cope with multiple contaminants. In this work, a bacterial strain isolated from tannery sediments was identified as Acinetobacter guillouiae SFC 500-1A. This strain was able to simultaneously remove high phenol and Cr(VI) concentrations, and the mechanisms involved in such process were evaluated. The phenol biodegradation was catalized by a phenol-induced catechol 1,2-dioxygenase through an ortho-cleavage pathway. Also, NADH-dependent chromate reductase activity was measured in the cytosolic fraction. The ability of this strain to reduce Cr(VI) to Cr(III) was corroborated by detection of Cr(III) in cellular biomass after the removal process. While phenol did not affect significantly the chromate reductase activity, Cr(VI) was a major disruptor of catechol dioxygenase activity. Nevertheless, this activity was high even in presence of high Cr(VI) concentrations. Our results suggest the potential application of A. guillouiae SFC 500-1A for wastewaters treatment, and the obtained data provide the insights into the removal mechanisms, dynamics, and possible limitations of the bioremediation. PMID- 25916476 TI - Functions of slags and gravels as substrates in large-scale demonstration constructed wetland systems for polluted river water treatment. AB - The choice of substrates with high adsorption capacity, yet readily available and economical is vital for sustainable pollutants removal in constructed wetlands (CWs). Two identical large-scale demonstration horizontal subsurface flow (HSSF) CWs (surface area, 340 m(2); depth, 0.6 m; HLR, 0.2 m/day) with gravel or slag substrates were evaluated for their potential use in remediating polluted urban river water in the prevailing climate of northwest China. Batch experiments to elucidate phosphorus adsorption mechanisms indicated a higher adsorption capacity of slag (3.15 g/kg) than gravel (0.81 g/kg), whereby circa 20 % more total phosphorus (TP) removal was recorded in HSSF-slag than HSSF-gravel. TP removal occurred predominantly via CaO-slag dissolution followed by Ca phosphate precipitation. Moreover, average removals of chemical oxygen demand and biochemical oxygen demand were approximately 10 % higher in HSSF-slag than HSSF gravel. Nevertheless, TP adsorption by slag seemed to get quickly saturated over the monitoring period, and the removal efficiency of the HSSF-slag approached that of the HSSF-gravel after 1-year continuous operation. In contrast, the two CWs achieved similar nitrogen removal during the 2-year monitoring period. Findings also indicated that gravel provided better support for the development of other wetland components such as biomass, whereby the biomass production and the amount of total nitrogen (TN; 43.1-59.0 g/m(2)) and TP (4.15-5.75 g/m(2)) assimilated by local Phragmites australis in HSSF-gravel were higher than that in HSSF-slag (41.2-52.0 g/m(2) and 3.96-4.07 g/m(2), respectively). Overall, comparable pollutant removal rates could be achieved in large-scale HSSF CWs with either gravel or slag as substrate and provide a possible solution for polluted urban river remediation in northern China. PMID- 25916477 TI - [Basic biochemical processes in glaucoma progression]. AB - The term glaucoma summarizes a group of eye diseases that are accompanied by impairments of the optic nerve and related visual field deficits. An early diagnosis of glaucoma is currently not possible due to a lack of diagnostic tests; therefore, in most cases the disease is diagnosed many years after onset, which prevents an early therapy. The known risk factors for the development and progression of glaucomatous optic neuropathy comprise elevated intraocular pressure and a broad range of pressure fluctuations as well as lipometabolic disorders, genetic factor and diabetes. The consequences include the induction of anti-inflammatory proteins, elevated levels of oxidative stress and the destruction of retinal ganglion cells. Changes in the autoantibody repertoire have also been observed in the course of the disease. Basic ophthalmological research therefore focuses on the investigation of basic biochemical processes in the course of the disease. A better understanding of physiological and biochemical events is sought in order to develop new and more sensitive diagnostic options and to allow more targeted therapeutic measures. The understanding of biochemical processes allows a better insight into glaucoma progression to be gained, which will lead to improvements in diagnosis and therapy. PMID- 25916478 TI - Gastroenterology: Sweet's syndrome in a patient with acutely exacerbated ulcerative colitis. PMID- 25916479 TI - Gastroenterology: Simultaneous practice of narrow band imaging and confocal laser endomicroscopy for a case of early duodenal cancer. PMID- 25916480 TI - Gastrointestinal: Endoscopic findings of collagenous gastroenterocolitis with protein-losing enteropathy. PMID- 25916481 TI - Hepatology: Hepato splenic sarcoidosis presenting as cholestatic jaundice and severe constitutional symptoms mimicking malignancy. PMID- 25916482 TI - Hepatology: Atypical images for multiple focal nodular hyperplasia. PMID- 25916483 TI - Conversion of Uric Acid into Ammonium in Oil-Degrading Marine Microbial Communities: a Possible Role of Halomonads. AB - Uric acid is a promising hydrophobic nitrogen source for biostimulation of microbial activities in oil-impacted marine environments. This study investigated metabolic processes and microbial community changes in a series of microcosms using sediment from the Mediterranean and the Red Sea amended with ammonium and uric acid. Respiration, emulsification, ammonium and protein concentration measurements suggested a rapid production of ammonium from uric acid accompanied by the development of microbial communities containing hydrocarbonoclastic bacteria after 3 weeks of incubation. About 80 % of uric acid was converted to ammonium within the first few days of the experiment. Microbial population dynamics were investigated by Ribosomal Intergenic Spacer Analysis and Illumina sequencing as well as by culture-based techniques. Resulting data indicated that strains related to Halomonas spp. converted uric acid into ammonium, which stimulated growth of microbial consortia dominated by Alcanivorax spp. and Pseudomonas spp. Several strains of Halomonas spp. were isolated on uric acid as the sole carbon source showed location specificity. These results point towards a possible role of halomonads in the conversion of uric acid to ammonium utilized by hydrocarbonoclastic bacteria. PMID- 25916484 TI - Kolaviron was protective against sodium azide (NaN3) induced oxidative stress in the prefrontal cortex. AB - Kolaviron is a phytochemical isolated from Garcina kola (G. kola); a common oral masticatory agent in Nigeria (West Africa). It is a bioflavonoid used--as an antiviral, anti-inflammatory and antioxidant--in relieving the symptoms of several diseases and infections. In this study we have evaluated the neuroprotective and regenerative effect of kolaviron in neurons of the prefrontal cortex (Pfc) before or after exposure to sodium azide (NaN3) induced oxidative stress. Separate groups of animals were treated as follows; kolaviron (200 mg/Kg) for 21 days; kolaviron (200 mg/Kg for 21 days) followed by NaN3 treatment (20 mg/Kg for 5 days); NaN3 treatment (20 mg/Kg for 5 days) followed by kolaviron (200 mg/Kg for 21 days); 1 ml of corn-oil (21 days-vehicle); NaN3 treatment (20 mg/Kg for 5 days). Exploratory activity associated with Pfc function was assessed in the open field test (OFT) following which the microscopic anatomy of the prefrontal cortex was examined in histology (Haematoxylin and Eosin) and antigen retrieval Immunohistochemistry to show astroglia activation (GFAP), neuronal metabolism (NSE), cytoskeleton (NF) and cell cycle dysregulation (p53). Subsequently, we quantified the level of Glucose-6-phosphate dehydrogenase (G6PDH) and lactate dehydrogenase (LDH) in the brain tissue homogenate as a measure of stress-related glucose metabolism. Kolaviron (Kv) and Kolaviron/NaN3 treatment caused no prominent change in astroglia density and size while NaN3 and NaN3/Kv induced astroglia activation and scar formation (astrogliosis) in the Pfc when compared with the control. Similarly, Kolaviron and Kv/NaN3 did not alter NSE expression (glucose metabolism) while NaN3 and NaN3/Kv treatment increased cortical NSE expression; thus indicating stress related metabolism. Further studies on enzymes of glucose metabolism (G6PDH and LDH) showed that NaN3 increased LDH while kolaviron reduced LDH in the brain tissue homogenate (P < 0.001). In addition kolaviron treatment before (P < 0.001) or after (P < 0.05) NaN3 treatment also reduced LDH expression; thus supporting its role in suppression of oxidative stress. Interestingly, NF deposition increased in the Pfc after kolaviron treatment while Kv/NaN3 showed no significant change in NF when compared with the control. In furtherance, NaN3 and NaN3/Kv caused a decrease in NF deposition (degeneration). Ultimately, the protective effect of KV administered prior to NaN3 treatment was confirmed through p53 expression; which was similar to the control. However, NaN3 and NaN3/Kv caused an increase in p53 expression in the Pfc neurons (cell cycle dysregulation). We conclude that kolaviron is not neurotoxic when used at 200 mg/Kg BW. Furthermore, 200 mg/Kg of kolaviron administered prior to NaN3 treatment (Kv/NaN3) was neuroprotective when compared with Kolaviron administered after NaN3 treatment (NaN3/Kv). Some of the observed effects of kolaviron administered before NaN3 treatment includes reduction of astroglia activation, absence of astroglia scars, antioxidation (reduced NSE and LDH), prevention of neurofilament loss and cell cycle regulation. PMID- 25916485 TI - TAT cell-penetrating peptide modulates inflammatory response and apoptosis in human lung epithelial cells. AB - Cell-penetrating peptides (CPPs) are commonly used as delivery vehicles for the introduction of a variety of macromolecules into cells. Trans-activator of transcription (TAT) is the most commonly used CPP and, as a delivery vehicle, is assumed to be biologically inert. In this study, we pretreated human lung epithelial cells with TAT prior to stimulation with phorbol 12,13-dibutyrate (PDBu), a protein kinase C (PKC) activator. Surprisingly, TAT alone inhibited the production of multiple cytokines induced by PKC activation. Furthermore, PKC activation-induced IkappaBalpha degradation was partially reduced by TAT. Moreover, TAT treatment alone induced apoptosis in a dose-dependent manner, influenced expression of several B cell lymphoma 2 (Bcl-2) family members and increased caspase 3 cleavage at a high dose. These findings suggest that TAT as a delivery vehicle should be used cautiously, as it may affect the inflammatory response, as well as signals related to apoptosis. PMID- 25916486 TI - Maternal critical care: what can we learn from patient experience? A qualitative study. AB - OBJECTIVE: For every maternal death, nine women develop severe maternal morbidity. Many of those women will need care in an intensive care unit (ICU) or high dependency unit (HDU). Critical care in the context of pregnancy poses distinct issues for staff and patients, for example, with breastfeeding support and separation from the newborn. This study aimed to understand the experiences of women who experience a maternal near miss and require critical care after childbirth. SETTING: Women and some partners from across the UK were interviewed as part of a study of experiences of near-miss maternal morbidity. DESIGN: A qualitative study, using semistructured interviews. PARTICIPANTS: A maximum variation sample was recruited of 35 women and 11 partners of women who had experienced a severe maternal illness, which without urgent medical attention would have led to her death. 18 of the women were admitted to ICU or HDU. RESULTS: The findings are presented in three themes: being in critical care; being a new mother in critical care; transfer and follow-up after critical care. The study highlights the shock of requiring critical care for new mothers and the gulf between their expectations of birth and what actually happened; the devastation of being separated from their baby, how valuable access to their newborn was, if possible, and the importance of breast feeding; the difficulties of transfer and the need for more support; the value of follow-up and outreach to this population of critical care patients. CONCLUSIONS: While uncommon, critical illness in pregnancy can be devastating for new mothers and presents a challenge for critical care and maternity staff. This study provides insights into these challenges and recommendations for overcoming them drawn from patient experiences. PMID- 25916487 TI - The Tanzanian trauma patients' prehospital experience: a qualitative interview based study. AB - OBJECTIVES: We sought to characterise the prehospital experience of Tanzanian trauma patients, and identify barriers and facilitators to implement community based emergency medical systems (EMS). SETTINGS: Our study was conducted in the emergency department of an urban national referral hospital in Tanzania. PARTICIPANTS: A convenience sample of 34 adult trauma patients, or surrogate family members, presenting or referred to an urban referral emergency department in Tanzania for treatment of injury, participated in the study. INTERVENTIONS: Participation in semistructured, iteratively developed interviews until saturation of responses was reached. OUTCOMES: A grounded theory-based approach to qualitative analysis was used to identify recurrent themes. RESULTS: We characterised numerous deficiencies within the existing clinic-to-hospital referral network, including missed/delayed diagnoses, limited management capabilities at pre-referral facilities and interfacility transfer delays. Potential barriers to EMS implementation include patient financial limitations and lack of insurance, limited public infrastructure and resources, and the credibility of potential first aid responders. Potential facilitators of EMS include communities' tendency to pool resources, individuals' trust of other community members to be first aid responders, and faith in community leaders to organise EMS response. Participants expressed a strong desire to learn first aid. CONCLUSIONS: The composite themes generated by the data suggest that there are myriad structural, financial, institutional and cultural barriers to the implementation of a formal prehospital system. However, our analysis also revealed potential facilitators to a first-responder system that takes advantage of close-knit local communities and the trust of recognised leaders in society. The results suggest favourable acceptability for community-based response by trained lay people. There is significant opportunity for care improvements with short trainings and low-cost supply planning. Further research looking at the effects of delay on outcomes in this population is needed. PMID- 25916488 TI - Health effects of home energy efficiency interventions in England: a modelling study. AB - OBJECTIVE: To assess potential public health impacts of changes to indoor air quality and temperature due to energy efficiency retrofits in English dwellings to meet 2030 carbon reduction targets. DESIGN: Health impact modelling study. SETTING: England. PARTICIPANTS: English household population. INTERVENTION: Three retrofit scenarios were modelled: (1) fabric and ventilation retrofits installed assuming building regulations are met; (2) as with scenario (1) but with additional ventilation for homes at risk of poor ventilation; (3) as with scenario (1) but with no additional ventilation to illustrate the potential risk of weak regulations and non-compliance. MAIN OUTCOME: Primary outcomes were changes in quality adjusted life years (QALYs) over 50 years from cardiorespiratory diseases, lung cancer, asthma and common mental disorders due to changes in indoor air pollutants, including secondhand tobacco smoke, PM2.5 from indoor and outdoor sources, radon, mould, and indoor winter temperatures. RESULTS: The modelling study estimates showed that scenario (1) resulted in positive effects on net mortality and morbidity of 2241 (95% credible intervals (CI) 2085 to 2397) QALYs per 10,000 persons over 50 years follow-up due to improved temperatures and reduced exposure to indoor pollutants, despite an increase in exposure to outdoor-generated particulate matter with a diameter of 2.5 MUm or less (PM2.5). Scenario (2) resulted in a negative impact of -728 (95% CI -864 to -592) QALYs per 10,000 persons over 50 years due to an overall increase in indoor pollutant exposures. Scenario (3) resulted in -539 (95% CI 678 to -399) QALYs per 10,000 persons over 50 years follow-up due to an increase in indoor exposures despite the targeting of pollutants. CONCLUSIONS: If properly implemented alongside ventilation, energy efficiency retrofits in housing can improve health by reducing exposure to cold and air pollutants. Maximising the health benefits requires careful understanding of the balance of changes in pollutant exposures, highlighting the importance of ventilation to mitigate the risk of poor indoor air quality. PMID- 25916491 TI - High-Surface-Area Nitrogen-Doped Reduced Graphene Oxide for Electric Double-Layer Capacitors. AB - A two-step method consisting of solid-state microwave irradiation and heat treatment under NH3 gas was used to prepare nitrogen-doped reduced graphene oxide (N-RGO) with a high specific surface area (1007 m(2) g(-1) ), high electrical conductivity (1532 S m(-1) ), and low oxygen content (1.5 wt %) for electrical double-layer capacitor applications. The specific capacitance of N-RGO was 291 F g(-1) at a current density of 1 A g(-1) , and a capacitance of 261 F g(-1) was retained at 50 A g(-1) , which indicated a very good rate capability. N-RGO also showed excellent cycling stability and preserved 96 % of the initial specific capacitance after 100 000 cycles. Near-edge X-ray absorption fine-structure spectroscopy results provided evidenced for the recovery of pi conjugation in the carbon networks with the removal of oxygenated groups and revealed chemical bonding of the nitrogen atoms in N-RGO. The good electrochemical performance of N RGO is attributed to its high surface area, high electrical conductivity, and low oxygen content. PMID- 25916489 TI - Safe-sex belief and sexual risk behaviours among adolescents from three developing countries: a cross-sectional study. AB - OBJECTIVES: This study intends to evaluate whether the belief that condoms are 100% effective in protecting against HIV infection is associated with sexual risk behaviours among youth. METHODS: A cross-sectional study was performed in representative samples of high-school students in the Philippines, El Salvador and Peru. Participants completed a self-administered questionnaire. Students were asked about the risk of HIV transmission if one has sex using condoms. They were also asked to indicate whether they had ever had sexual relations and whether they used a condom in their first sexual relation. The sample was composed of 8994 students, aged 13-18. RESULTS: One out of seven adolescents believed condoms are 100% effective (safe-sex believers). Those adolescents were 82% more likely to have had sex than those without such belief, after adjusting for confounders (OR=1.82; 95% CI 1.51 to 2.21). On the contrary, no association was found between risk perception and condom use. Subgroup and sensitivity analyses produced similar results. CONCLUSIONS: This is, to the best of our knowledge, the first study conducted specifically to evaluate this phenomenon and that has used the same questionnaire and the same data collection protocol in three different developing countries from Asia, Central and South America. These results reasonably suggest that there could be an association between safe sex beliefs and sexual initiation. Longitudinal studies are needed to better understand this possible association as it could influence how to better promote sexual health. PMID- 25916492 TI - NIH Public Access Policy: How Does Information Get Uploaded to PubMed Central and by Whom? PMID- 25916493 TI - Building the bridge from pediatric to adult diabetes care: making the connection. AB - PURPOSE: The purpose of this study was to evaluate the effectiveness of a structured transition program by measuring clinical and psychometric properties related to transition and adherence to follow-up. Transition of emerging adults with type 1 diabetes can be problematic. This natural progression to adult health care is often delayed, leading to transition at less than optimal times. Implementation of a transition program will improve the transition process for emerging adults with type 1 diabetes. METHODS: Mixed-method, prospective longitudinal study involving collaboration between pediatric and adult providers. Subjects age 18 to 28 years were identified for transition. Transition was facilitated via joint appointment with pediatric and adult health care providers. Participants completed pre- and posttransition surveys measuring diabetes-related distress (Diabetes Distress Scale [DDS]), quality of life (Diabetes Quality of Life Youth-Short Form [DQOLY-SF]), and perceived health care provider autonomy support (Health Care Climate Questionnaire [HCCQ]). Primary outcome was adherence to follow-up. Secondary outcomes evaluated correlations in DDS, DQOLY-SF, HCCQ, and A1C. Chart review assessed acute complications, A1C, and adherence to follow up. RESULTS: Adherence to follow-up was 100%. This study found that correlations between DQOLY-SF and DDS and correlations between DDS and A1C were highly significant during the pretransition phase. This study also indicated that the same correlations were highly significant following transition. Paired t test indicated a statistically significant reduction in diabetes distress from pre- to posttransition evaluations and an increase in HCCQ. Content comparative analysis of open-ended questions further illustrated issues related to transition. CONCLUSION: Use of a structured transition process with joint appointments and transition coordinator improves adherence to follow-up and reduces diabetes related distress. PMID- 25916494 TI - Sentence production after listener and echoic training by prelingual deaf children with cochlear implants. AB - Three children with neurosensory deafness who used cochlear implants were taught to match video clips to dictated sentences. We used matrix training with overlapping components and tested for recombinative generalization. Two 3 * 3 matrices generated 18 sentences. For each matrix, we taught 6 sentences and evaluated generalization with the remaining 3 sentences. We also tested for emergent tacting with all 18 video clips. After training, the participants were able to match untrained video clips to recombined dictated sentences. Tacts of both trained and untrained video clips increased for all participants. PMID- 25916495 TI - The Effectiveness of a Weight Maintenance Intervention for Adults with Intellectual Disabilities and Obesity: A Single Stranded Study. AB - BACKGROUND: The evidence base for weight management programmes incorporating a weight loss and a weight maintenance phase for adults with intellectual disabilities (ID) is limited. This study describes the weight maintenance phase of a multicomponent weight management programme for adults with intellectual disability and obesity (TAKE 5). MATERIALS AND METHODS: Thirty-one participants who had completed the 16 week TAKE five weight loss intervention (Phase I) were invited to participate in a 12 month weight maintenance intervention (Phase II). Content included recommendations of the National Weight Control Registry. RESULTS: Twenty-eight participants completed Phase II with 50.4% maintaining their weight (mean weight change -0.5 kg, SD 2.2), 28.7% gaining weight (mean weight gain 5.4 kg, SD 2.2) and 21.6% losing weight (mean weight loss -8.0 kg, SD 3.0) at 12 months. CONCLUSION: Further research is justified to investigate the efficacy of weight loss maintenance interventions in adults with intellectual disability and obesity, using controlled study designs. PMID- 25916496 TI - A collagen-binding EGFR single-chain Fv antibody fragment for the targeted cancer therapy. AB - Collagen, a primary component of the extracellular matrix (ECM), is highly expressed in a variety of cancers and influences the tumor microenvironment by increasing the recruitment of macrophages and endothelial cells. Therefore, collagen is a highly promising target for cancer therapy. The collagen-binding domain (CBD) can dynamically bind to collagen and achieve the sustained release of CBD-fused protein in the collagen network. Here, we developed a collagen binding epidermal growth factor receptor (EGFR) antibody fragment for targeting the collagen-rich ECM in tumors. The single chain fragment variable (scFv) of cetuximab was fused to CBD (CBD-scFv) and expressed in Pichia pastoris. CBD-scFv preserved the antigen binding domain and anti-tumor activity of cetuximab in vitro. Moreover, CBD-scFv displayed a collagen binding ability due to the function of CBD. In vivo experiments revealed that CBD-scFv bound to collagen and achieved sustained release in tumors. Furthermore, CBD-scFv significantly suppressed the growth of tumors in A431 xenografts. Therefore, CBD-scFv had a potential therapeutic value for the collagen-rich carcinomas. The specific target and sustained release of CBD-scFv in tumors could be a new approach for targeted drug delivery in cancer therapy. PMID- 25916497 TI - The addition of FSH to clomiphene citrate for ovarian stimulation does not affect offspring stature but may alter body composition in childhood. PMID- 25916498 TI - Unambiguous (Z)-geometry and complete 1H and 13C assignments of candidine. PMID- 25916499 TI - Is the Production of Embryos in Small-Scale Farming an Economically Feasible Enterprise? AB - The present assay attempts to evaluate the feasibility of using embryo transfer in small community farmers by in vivo study and by modelling the results obtained. From the total of 59 donor cows, 62.7% responded to treatment, with a significant difference (p = 0.002) in the percentage of the response between breeds, being 90.5% (19/21) in Holstein and 47.4% (18/38) in Brahman. A total of 283 embryos were graded as transferable, while 141 as non-transferable, without difference in the percentage of transferable embryo by breed (p = 0.18). The mean of transferable embryos graded as class I and II was not different between Holstein and Brahman (p = 0.96 and p = 0.92, respectively); besides, no differences were observed in the other grades (non-transferable). The highest difference in costs, regardless of its quality by breed, was seen in the lower levels of probable fertility of the embryo transferred, even reaching several hundred dollars. When modelling the expected costs for embryo produced and transferred, values can reach nearly $2000.00 when the probable fertility is only 10%. However, when the probable fertility was 60%, embryo cost was close to $300.00. This technology seems to be viable on average or high-scale systems, having a superovulatory response between 60 and 80% with 4-6 transferrable embryos. Yet, in small-scale farming, due to the reduced number of donors and/or recipients, the costs surpass the economical feasibility of the technique. PMID- 25916500 TI - Mono-guanidine heterolipid based SMEDDS: A promising tool for cytosolic delivery of antineoplastics. AB - In the present work, we designed and synthesized a novel mono-guanidine heterolipid (MGH) and confirmed its structure by NMR and ESI-MS. The MGH was used as cationic lipid in developing etoposide loaded cationic self-microemulsifying drug delivery system (ECS) intended to be delivered by intratumoral route. The ECS exhibited size <50 nm and zeta potential +32.6 mV on dilution with various isotonic vehicles with no phase separation or drug precipitation. The ECS could be easily sterilized by membrane filtration method and showed excellent stability for 6 months. The ECS demonstrated excellent in vitro antiproliferative activity against B16F10 cells which is attributed to its high transfection efficiency and capability to cause prolonged drug release in cytosolic space. In vivo antitumor activity of ECS was conducted in B16F10 induced melanoma tumor model. ECS at 12 mg/kg dose showed superior tumor suppression ability and exhibited 100% survival compared to other formulations. Mice treated with ECS by intratumoral route, showed neither systemic side effect nor any evidences of hepatotoxicity and nephrotoxicity. In contrast, etoposide administered by intravenous route showed remarkable systemic toxicity, hepatotoxicity and nephrotoxicity. PMID- 25916501 TI - Biomimetic and synthetic esophageal tissue engineering. AB - BACKGROUND/PURPOSE: A tissue-engineered esophagus offers an alternative for the treatment of pediatric patients suffering from severe esophageal malformations, caustic injury, and cancer. Additionally, adult patients suffering from carcinoma or trauma would benefit. METHODS: Donor rat esophageal tissue was physically and enzymatically digested to isolate epithelial and smooth muscle cells, which were cultured in epithelial cell medium or smooth muscle cell medium and characterized by immunofluorescence. Isolated cells were also seeded onto electrospun synthetic PLGA and PCL/PLGA scaffolds in a physiologic hollow organ bioreactor. After 2 weeks of in vitro culture, tissue-engineered constructs were orthotopically transplanted. RESULTS: Isolated cells were shown to give rise to epithelial, smooth muscle, and glial cell types. After 14 days in culture, scaffolds supported epithelial, smooth muscle and glial cell phenotypes. Transplanted constructs integrated into the host's native tissue and recipients of the engineered tissue demonstrated normal feeding habits. Characterization after 14 days of implantation revealed that all three cellular phenotypes were present in varying degrees in seeded and unseeded scaffolds. CONCLUSIONS: We demonstrate that isolated cells from native esophagus can be cultured and seeded onto electrospun scaffolds to create esophageal constructs. These constructs have potential translatable application for tissue engineering of human esophageal tissue. PMID- 25916502 TI - In situ gelling silk-elastinlike protein polymer for transarterial chemoembolization. AB - Hepatocellular carcinoma annually affects over 700,000 people worldwide and trends indicate increasing prevalence. Patients ineligible for surgery undergo loco-regional treatments such as transarterial chemoembolization (TACE) to selectively target tumoral blood supply. Using a microcatheter, chemotherapeutics are infused followed by an embolic agent, or the drug is encapsulated by the embolic moiety; simultaneously inducing stasis while delivering localized chemotherapy. Presently, several products are used, but no universally accepted system is promoted because very disparate limitations exist. The goal of this investigation was to design and develop in situ gelling recombinant silk elastinlike protein polymers (SELPs) for TACE. Two SELP compositions, SELP-47K and SELP-815K, with varying lengths of silk and elastin blocks, were investigated to formulate a new embolic that was injectable through commercially available microcatheters. The goal was to develop a composition providing maximal permeation of tumor vasculature while exhibiting effective embolic activity. The SELPs evaluated remain soluble until reaching 37 degrees C, when irreversible transition ensues forming a solid hydrogel network. SELP-815K formulated at 12% w/w with shear processing demonstrated acceptable rheological properties and clear embolic capability under flow conditions in vitro. A rabbit model showed feasibility of embolization in vivo allowing selective occlusion of lobar hepatic arterial branches. PMID- 25916503 TI - Long-term persistence of immunity induced by OVA-coupled gas-filled microbubble vaccination partially protects mice against infection by OVA-expressing Listeria. AB - Vaccination aims at generating memory immune responses able to protect individuals against pathogenic challenges over long periods of time. Subunit vaccine formulations based on safe, but poorly immunogenic, antigenic entities must be combined with adjuvant molecules to make them efficient against infections. We have previously shown that gas-filled microbubbles (MB) are potent antigen-delivery systems. This study compares the ability of various ovalbumin associated MB (OVA-MB) formulations to induce antigen-specific memory immune responses and evaluates long-term protection toward bacterial infections. When initially testing dendritic cells reactivity to MB constituents, palmitic acid exhibited the highest degree of activation. Subcutaneous immunization of naive wild-type mice with the OVA-MB formulation comprising the highest palmitic acid content and devoid of PEG2000 was found to trigger the more pronounced Th1-type response, as reflected by robust IFN-gamma and IL-2 production. Both T cell and antibody responses persisted for at least 6 months after immunization. At that time, systemic infection with OVA-expressing Listeria monocytgenes was performed. Partial protection of vaccinated mice was demonstrated by reduction of the bacterial load in both the spleen and liver. We conclude that antigen-bound MB exhibit promising properties as a vaccine candidate ensuring prolonged maintenance of protective immunity. PMID- 25916504 TI - Mapping the CXCR4 receptor on breast cancer cells. AB - The CXCR4 receptor triggers cell migration and, in breast cancer, promotes metastasis. To date, the dynamic assembly of CXCR4 on the cell surface as a mediator of receptor binding is not well characterized. The objective of this work is to quantify the density, spatial organization, and magnitude of binding of the CXCR4 receptor on live metastatic breast cancer (MBC) cells. We measured the Young's modulus, the CXCR4 surface density, and CXCR4 unbinding force on MBC cells by atomic force microscopy. We conclude that the CXCR4 density, spatial organization, and matrix stiffness are paramount to achieve strong binding. PMID- 25916505 TI - A novel near-infrared fluorescence imaging probe that preferentially binds to cannabinoid receptors CB2R over CB1R. AB - The type 2 cannabinoid receptors (CB2R) have gained much attention recently due to their important regulatory role in a host of pathophysiological processes. However, the exact biological function of CB2R and how this function might change depending on disease progression remains unclear and could be better studied with highly sensitive and selective imaging tools for identifying the receptors. Here we report the first near infrared fluorescence imaging probe (NIR760-XLP6) that binds preferentially to CB2R over the type 1 cannabinoid receptors (CB1R). The selectivity of the probe was demonstrated by fluorescence microscopy using DBT CB2 and DBT-CB1 cells. Furthermore, in mouse tumor models, NIR760-XLP6 showed significantly higher uptake in DBT-CB2 than that in DBT-CB1 tumors. These findings indicate that NIR760-XLP6 is a promising imaging tool for the study of CB2R regulation. PMID- 25916506 TI - Hesperidin methyl chalcone inhibits oxidative stress and inflammation in a mouse model of ultraviolet B irradiation-induced skin damage. AB - Hesperidin methyl chalcone (HMC) is a safe flavonoid used to treat chronic venous diseases, but its effects and mechanisms on UVB irradiation-induced inflammation and oxidative stress have never been described in vivo. Thus, the purpose of this study was to evaluate the effects of systemic administration of HMC in skin oxidative stress and inflammation induced by UVB irradiation. To induce skin damage, hairless mice were exposed to an acute UVB irradiation dose of 4.14 J/cm(2), and the dorsal skin samples were collected to evaluate oxidative stress and inflammatory response. The intraperitoneal treatment with HMC at the dose of 300 mg/kg inhibited UVB irradiation-induced skin edema, neutrophil recruitment, and matrix metalloproteinase-9 activity. HMC also protected the skin from UVB irradiation-induced oxidative stress by maintaining ferric reducing antioxidant power (FRAP), 2,2'-azino-bis (3-ethylbenzothiazoline-6-sulfonic acid) radical (ABTS) scavenging ability and antioxidant levels (reduced glutathione and catalase). Corroborating, HMC inhibited UVB irradiation-induced superoxide anion generation and gp91phox (NADPH oxidase subunit) mRNA expression. Furthermore, the antioxidant effect of HMC resulted in lower production of inflammatory mediators, including lipid hydroperoxides and a wide range of cytokines. Taken together, these results unveil a novel applicability of HMC in the treatment of UVB irradiation-induced skin inflammation and oxidative stress. PMID- 25916507 TI - Gbeta4gamma1 as a modulator of M3 muscarinic receptor signalling and novel roles of Gbeta1 subunits in the modulation of cellular signalling. AB - Much is known about the how Gbetagamma subunits regulate effectors in response to G protein-coupled receptor stimulation. However, there is still a lot we don't know about how specific combinations of Gbeta and Ggamma are wired into different signalling pathways. Here, using an siRNA screen for different Gbeta and Ggamma subunits, we examined an endogenous M3 muscarinic receptor signalling pathway in HEK 293 cells. We observed that Gbeta(4) subunits were critical for calcium signalling and a downstream surrogate measured as ERK1/2 MAP kinase activity. A number of Ggamma subunits could partner with Gbeta(4) but the best coupling was seen via Gbeta(4)gamma(1). Intriguingly, knocking down Gbeta(1) actually increased signalling through the M3-mAChR most likely via an increase in Gbeta(4) levels. We noted that Gbeta(1) occupies the promoter of Gbeta(4) and may participate in maturation of its mRNA. This highlights a new role for Gbetagamma signalling beyond their canonical roles in cellular signalling. PMID- 25916508 TI - Intermedin ameliorates IgA nephropathy by inhibition of oxidative stress and inflammation. AB - IgA nephropathy (IgAN) is the most frequent form of glomerulonephritis worldwide. The role of oxidative stress and inflammation in the pathogenesis of IgAN has been reported. Intermedin (IMD) is a newly discovered peptide that is closely related to adrenomedullin. We have recently reported that IMD can significantly reduce renal ischemia/reperfusion injury by diminishing oxidative stress and suppressing inflammation. The present study was designed to explore whether IMD ameliorates IgAN via oxidative stress- and inflammation-dependent mechanisms. Our results showed that IMD administration resulted in the prevention of albuminuria and ameliorated renal pathomorphological changes. These findings were associated with (1) decreased renal TGF-beta1 and collagen IV expression, (2) an increased SOD level and reduced MDA level, (3) the inhibition of the renal activation of NF kappaB p65 and (4) the downregulation of the expression of inflammatory factors (TNF-alpha, MCP-1 and MMP-9) in the kidney. These results indicate that IMD in the kidney protects against IgAN by reducing oxidative stress and suppressing inflammation. PMID- 25916509 TI - Rectal cancer concurrent with disseminated superficial porokeratosis in three brothers. PMID- 25916510 TI - Nonparametric discrete survival function estimation with uncertain endpoints using an internal validation subsample. AB - When a true survival endpoint cannot be assessed for some subjects, an alternative endpoint that measures the true endpoint with error may be collected, which often occurs when obtaining the true endpoint is too invasive or costly. We develop an estimated likelihood function for the situation where we have both uncertain endpoints for all participants and true endpoints for only a subset of participants. We propose a nonparametric maximum estimated likelihood estimator of the discrete survival function of time to the true endpoint. We show that the proposed estimator is consistent and asymptotically normal. We demonstrate through extensive simulations that the proposed estimator has little bias compared to the naive Kaplan-Meier survival function estimator, which uses only uncertain endpoints, and more efficient with moderate missingness compared to the complete-case Kaplan-Meier survival function estimator, which uses only available true endpoints. Finally, we apply the proposed method to a data set for estimating the risk of detecting Alzheimer's disease from the Alzheimer's Disease Neuroimaging Initiative. PMID- 25916511 TI - Brettanomyces yeasts--From spoilage organisms to valuable contributors to industrial fermentations. AB - Ever since the introduction of controlled fermentation processes, alcoholic fermentations and Saccharomyces cerevisiae starter cultures proved to be a match made in heaven. The ability of S. cerevisiae to produce and withstand high ethanol concentrations, its pleasant flavour profile and the absence of health threatening toxin production are only a few of the features that make it the ideal alcoholic fermentation organism. However, in certain conditions or for certain specific fermentation processes, the physiological boundaries of this species limit its applicability. Therefore, there is currently a strong interest in non-Saccharomyces (or non-conventional) yeasts with peculiar features able to replace or accompany S. cerevisiae in specific industrial fermentations. Brettanomyces (teleomorph: Dekkera), with Brettanomyces bruxellensis as the most commonly encountered representative, is such a yeast. Whilst currently mainly considered a spoilage organism responsible for off-flavour production in wine, cider or dairy products, an increasing number of authors report that in some cases, these yeasts can add beneficial (or at least interesting) aromas that increase the flavour complexity of fermented beverages, such as specialty beers. Moreover, its intriguing physiology, with its exceptional stress tolerance and peculiar carbon- and nitrogen metabolism, holds great potential for the production of bioethanol in continuous fermentors. This review summarizes the most notable metabolic features of Brettanomyces, briefly highlights recent insights in its genetic and genomic characteristics and discusses its applications in industrial fermentation processes, such as the production of beer, wine and bioethanol. PMID- 25916512 TI - Mechanochemical Sensing: A Biomimetic Sensing Strategy. AB - Existing biosensors employ two major components: analyte recognition and signal transduction. Although specificity is achieved through analyte recognition, sensitivity is usually enhanced through a chemical amplification stage that couples the two main units in a sensor. Although highly sensitive, the extra chemical amplification stage complicates the sensing protocol. In addition, it separates the two elements spatiotemporally, reducing the real-time response of the biosensor. In this review, we discuss the new mechanochemical biosensors that employ mechanochemical coupling strategies to overcome these issues. By monitoring changes in the mechanical properties of a single-molecule template upon analyte binding, single-molecule sensitivity is reached. As chemical amplification becomes unnecessary in this single-molecule mechanochemical sensing (SMMS) strategy, real-time sensing is achieved. PMID- 25916513 TI - Supervisor volume affects oncological outcomes of trainees performing open radical prostatectomy. AB - BACKGROUND: The relationship between biochemical failure (BF) rate and surgeon experience following open radical prostatectomy (ORP) has been well established, but BF when ORP is performed by urology trainees who are supervised by urologists of differing volume has not. We aimed to compare the oncological outcomes from ORP when a urology trainee as primary operator and is supervised by a high- or low-volume consultant urologist. METHODS: Using a centralized whole of population dataset, created through the Victorian Radical Prostatectomy Registry, patients were classified as either those where a consultant was the primary operator, a urology trainee was the primary operator and supervised by a high-volume consultant or those where a urology trainee was supervised by a low-volume consultant. BF- and prostate cancer (PCa)-specific mortality was compared between these latter two groups and the consultant-only group. RESULTS: We found BF- and PCa-specific mortality rate to be poorer when ORP was performed by a urology trainee supervised by a low-volume consultant compared with consultant-led surgery (hazard ratio (HR) = 1.33, P = 0.022; subhazard ratio (SHR) = 2.31, P = 0.010, respectively). When a urology trainee, as primary operator, was supervised by a high-volume consultant, there was no statistical difference in BF- or PCa specific mortality rate following ORP compared with consultant-led surgery (HR = 1.19, P = 0.234; SHR = 1.53, P = 0.346, respectively). There was a trend evident with decreasing supervisor volume leading to worse oncological and mortality outcomes for trainee-led cases. CONCLUSION: This study demonstrates the value of high-volume and fellowship-trained urologists in performing and teaching ORP. As outcomes are increasingly scrutinized with audits, the best strategy for clinicians to maintain standards and optimal patient outcomes is to understand these elements and direct trainees to appropriate centres for training and fellowships. PMID- 25916514 TI - FASTKD2 and human memory: functional pathways and prospects for novel therapeutic target development for Alzheimer's disease and age-associated memory decline. PMID- 25916515 TI - Pharmacogenomics in practice: a case report of personalized inpatient psychiatric care. AB - Given variable response to psychotropic intervention, this case highlights the potential of pharmacogenomics to inform medical decision-making in a male with atypical psychosis and depression with longer-standing attentional difficulties. Likely because of his specific COMT polymorphism and intermediate metabolizing liver enzymes, when the patient's stimulant medications were titrated to affect for attentional needs, he became psychotic secondary to a hyperdopaminergic state. Past prescriptions of dopaminergic antidepressant agents (e.g., bupropion) likely would have exacerbated further the problem. The patient's serotonin transporter polymorphism also potentially was associated with SSRI inefficacy and increased side effects. Knowledge of the patient's genetically influenced departure from average response allowed for personalization of pharmacology with clinical improvement across measures of functioning. PMID- 25916516 TI - Pharmacogenomic assessment of Mexican and Peruvian populations. AB - BACKGROUND: Clinically relevant polymorphisms often demonstrate population specific allele frequencies. Central and South America remain largely uncategorized in the context of pharmacogenomics. MATERIALS & METHODS: We assessed 15 polymorphisms from 12 genes (ABCB1 3435C>T, ABCG2 Q141K, CYP1B1*3, CYP2C19*2, CYP3A4*1B, CYP3A5*3C, ERCC1 N118N, ERCC2 K751Q, GSTP1 I105V, TPMT 238G>C, TPMT 460G>A, TPMT 719A>G, TYMS TSER, UGT1A1*28 and UGT1A1 -3156G>A) in 81 Peruvian and 95 Mexican individuals. RESULTS: Six polymorphism frequencies differed significantly between the two populations: ABCB1 3435C>T, CYP1B1*3, GSTP1 I105V, TPMT 460G>A, UGT1A1*28 and UGT1A1 -3156G>A. The pattern of observed allele frequencies for all polymorphisms could not be accurately estimated from any single previously studied population. CONCLUSION: This highlights the need to expand the scope of geographic data for use in pharmacogenomics studies. PMID- 25916518 TI - Genetic determined low response to thienopyridines is associated with higher systemic inflammation in smokers. AB - AIM: To investigate whether the interactions of CYP2C19*2 and CYP2C19*17 with smoking are associated with the levels of P2Y12 receptor inhibition and CRP, in on-thienopyridine post-stenting patients. METHODS & RESULTS: At 1-month follow up, the interactions of smoking and CYP2C19 polymorphisms on the vasodilator stimulated phosphoprotein - platelet reactivity index (VASP PRI), and CRP were explored in three metabolizing groups (1128 patients) as follow: poor metabolizers (*2 carriers/*17 noncarriers); intermediate metabolizers (*2 carriers/*17 carriers or *2 noncarriers/*17 noncarriers); and ultrarapidmetabolizers (*2 allele noncarriers/*17 carriers). The interactions of metabolizing status and smoking was significant for CRP (p = 0.001) but not for VASP PRI (p = 0.734). CONCLUSION: Interaction between CYP2C19 polymorphisms and smoking modifies on-treatment CRP level of post-stenting, on-thienopyridine patients. This effect seems to be independent to the level of P2Y12 receptor inhibition. PMID- 25916517 TI - SLCO1B1 genetic variants, long-term low-density lipoprotein cholesterol levels and clinical events in patients following cardiac catheterization. AB - AIM: SLCO1B1 variants are associated with intermediate outcomes that may increase risk of death/myocardial infarction (MI) in statin-treated patients. PATIENTS & METHODS: In high-risk Caucasians undergoing cardiac catheterization, we tested the association between rs4149056/625T>C and rs2306283/492A>G with low-density lipoprotein cholesterol (LDL-c) over 3 years (n = 1402) and death/MI over 6 years (n = 2994), accounting for statin use or type during follow-up. RESULTS: Carriers of the rs4149056 C allele had 6.2 +/- 1.7 mg/dl higher LDL-c per C allele (p < 0.001) but were not at higher risk for death/MI (p = 0.9). We found no associations between rs2306283 and LDL-c or death/MI (p > 0.6). CONCLUSION: Functional SLCO1B1 variants are not associated with death/MI in patients commonly treated with statins, despite higher LDL-c in carriers of the rs4149056 C allele. PMID- 25916519 TI - Biomarkers of hippocampal gene expression in a mouse restraint chronic stress model. AB - OBJECTIVE: Acute stress provides many beneficial effects whereas chronic stress contributes to a variety of human health issues including anxiety, depression, gastrointestinal problems, cardiac disease, sleep disorders and obesity. The goal of this work was to identify, using a rodent model, hippocampal gene signatures associated with prolonged chronic stress representing candidate biomarkers and therapeutic targets for early diagnosis and pharmacological intervention for stress induced disease. MATERIALS & METHODS: Mice underwent 'restraint stress' over 7 consecutive days and hippocampal gene-expression changes were analyzed at 3, 12 and 24 h following the final restraint treatment. RESULTS: Data indicated that mice exposed to chronic restraint stress exhibit a differential gene expression profile compared with non-stressed controls. The greatest differences were observed 12 and 24 h following the final stress test. CONCLUSION: Our study indicated that Gpr88, Ttr, Gh and Tac1 mRNAs were modulated in mice exposed to chronic restraint stress. These transcripts represent a panel of biomarkers and druggable targets for further analysis in the context of chronic stress associated disease in humans. PMID- 25916520 TI - Relationship between mRNA expression levels of CYP3A4, CYP3A5 and SXR in peripheral mononuclear blood cells and aging in young kidney transplant recipients under tacrolimus treatment. AB - AIM: The activity of several key enzymes involved in the metabolism of many drugs is subject to change closely related to the age of patients. This possibility must also be considered in the case of tacrolimus, the most important calcineurins inhibitor, which is widely used in pediatric kidney transplantation. As well as in the liver and intestine, some of the enzymes involved in the metabolism of tacrolimus were also isolated in the peripheral blood mononuclear cells (PBMCs), where also appear to play an important regulatory action. Therefore, the influence of some external factors on the expression of specific mRNA can be determined noninvasively. PATIENTS & METHODS: The correlation between the levels of mRNA specific for key enzymes SXR, CYP3A and ABCB1 involved in the metabolism of tacrolimus was evaluated in PBMCs obtained from a selected population of 29 young kidney transplant recipients. A possible correlation between the expression of these specific mRNAs and tacrolimus pharmacokinetics was also investigated. RESULTS: The patients' age and their blood concentrations of SXR mRNA were directly correlated with the expression of CYP3A4, CYP3A5 mRNAs, but not of ABCB1 mRNA in the PBMCs. tacrolimus-normalized daily dose was strongly correlated with patient's age and multivariable regression indicates the CYP3A4 specific mRNA as the sole independent variable influencing tacrolimus concentration-to-dose ratio. CONCLUSION: Aging and SXR mRNA significantly affect the expression of CYP3A4- and CYP3A5-specific mRNA as measured by their concentration in PBMC. PMID- 25916521 TI - Impact of tailored anti-P2Y12 therapies in acute coronary syndromes. AB - Acute coronary syndromes are a major disease burden and the prognosis has improved over the last decades due to improvement of medical and interventional treatments. Novel P2Y12-ADP-receptor antagonists have been introduced into clinical treatment offering more potent and rapid onset of action with the downside of increased bleeding risk. This special report will focus on interindividual variability of antiplatelet drugs in the setting of acute coronary syndromes and the current impact and potential future of point-of-care testing to personalize therapy aiming to improve prognosis in acute coronary syndrome patients. PMID- 25916522 TI - Pharmacogenomics of cyclooxygenases. AB - Cyclooxygenases (COX-1 and COX-2) are key enzymes in several physiopathological processes. Many adverse drugs reactions to NSAIDs are attributable to COX inhibition. The genes coding for these enzymes (PTGS1 and PTGS2) are highly variable, and variations in these genes may underlie the risk of developing, or the clinical evolution of, several diseases and adverse drug reactions. We analyze major variations in the PTGS1 and PTGS2 genes, allele frequencies, functional consequences and population genetics. The most salient clinical associations of PTGS gene variations are related to colorectal cancer and stroke. In many studies, the SNPs interact with NSAIDs use, dietary or environmental factors. We provide an up-to-date catalog of PTGS clinical associations based on case-control studies and genome-wide association studies, and future research suggestions. PMID- 25916523 TI - Genetics and pharmacogenetics of aminergic transmitter pathways in functional gastrointestinal disorders. AB - Functional gastrointestinal disorders (FGIDs) are highly prevalent syndromes, without evident underlying organic causes. Their pathogenesis is multifactorial in nature, with a combination of environmental and genetic factors contributing to their clinical manifestations, for which most of current treatments are not satisfactory. It is acknowledged that amine mediators (noradrenaline, dopamine and serotonin) play pivotal regulatory actions on gut functions and visceral sensation. In addition, drugs of therapeutic interest for FGIDs act on these transmitter pathways. The present article reviews current knowledge on the impact of genetics and pharmacogenetics of aminergic pathways on FGID pathophysiology, clinical presentations, symptom severity and medical management, in an attempt of highlighting the most relevant evidence and point out issues that should be addressed in future investigations. PMID- 25916524 TI - Serotonin pathway polymorphisms and the treatment of major depressive disorder and anxiety disorders. AB - While antidepressants are widely used to treat major depressive disorder and anxiety disorders, only half of the patients will respond to antidepressant treatment and only a third of patients will experience a remission of symptoms. Identification of genetic biomarkers that predict antidepressant treatment response could thus greatly improve current clinical practice by providing guidance on which drug to use for which patient. Most antidepressant drugs for the treatment of depression and anxiety disorders have effects on the serotonergic neurotransmitter system; thus, genetic polymorphisms in the genes involved in this pathway represent logical candidates for investigation. This article reviews recent findings on the pharmacogenetics of antidepressant drugs with a focus on serotonergic pathway polymorphisms and discusses future clinical applications. PMID- 25916525 TI - Genome-wide association studies in pharmacogenomics of antidepressants. AB - Major depressive disorder (MDD) is one of the most common psychiatric disorders worldwide. Doctors must prescribe antidepressants based on educated guesses due to the fact that it is unmanageable to predict the effectiveness of any particular antidepressant in an individual patient. With the recent advent of scientific research, the genome-wide association study (GWAS) is extensively employed to analyze hundreds of thousands of single nucleotide polymorphisms by high-throughput genotyping technologies. In addition to the candidate-gene approach, the GWAS approach has recently been utilized to investigate the determinants of antidepressant response to therapy. In this study, we reviewed GWAS studies, their limitations and future directions with respect to the pharmacogenomics of antidepressants in MDD. PMID- 25916526 TI - [Surgical management of refractory dysphagia and aspiration]. AB - OBJECTIVE: To explore the methods and results of surgical management for refractory dysphagia and aspiration. METHODS: The clinical data of 24 refractory dysphagia and aspiration patients who accepted surgical management were retrospectively analysed. RESULTS: Twenty-four refractory dysphagia and aspiration patients accepted 26 operations between 2001 and 2014. Of the 26 operations, 17 were cricopharyngeal myectomy (CPM), 6 were scarectomy, 3 were laryngeal-tracheal separation. No severe complications occurred. Assessments of dysphagia were completed in 18 operations before and after operation. Aspiration scores of videofluoroscopic swallowing study (VFSS) were 4.50 [4.00;7.00] vs 2.00 [1.00; 3.25], P = 0.000; swallow dysfunction scroes of VFSS were 5.00 [4.00; 12.00] vs 1.00 [1.50; 10.00], P = 0.001; aspiration scores of fibroptic endoscopic evaluation of swallowing (FEES) were 4.00 [5.00; 7.00] vs 2.00 [1.75; 3.00], P = 0.000. But the surgical results for post radiotherapy dysphagia were not successful (n = 5): aspiration scores of VFSS were 7.00 [6.50; 8.00] vs 6.00 [2.00; 7.50], P = 0.109;swallow dysfunction scroes of VFSS were 12.00 [10.50; 12.00] vs 12.00 [7.50; 12.00], P = 0.180;aspiration scores of FEES were 7.00 [6.50; 8.00] vs 6.00 [2.00; 7.50], P = 0.109. CONCLUSION: Surgical management was effective for refractory dysphagia and aspiration, but the surgical indication selection should be strict. PMID- 25916527 TI - [A preliminary study on the assessment of swallowing function after supracricoid partial laryngectomy]. AB - OBJECTIVE: To investigate a reliable and easy assessment method for swallowing function by evaluating objectively the recovery process of swallowing function in patients six months after supracricoid partial laryngectomy. METHODS: The swallowing function of patients who underwent supracricoid partial laryngectomy was evaluated six months after operation in Nanfang Hospital of Southern Medical University between January 2013 and February 2014 with two methods, the modified barium swallow (MBS) and fiberoptic endoscopic evaluation of swallowing (FEES), combined with modified penetration aspiration scale (MPAS). Furthermore, the feasibility, reliability and accuracy of these two methods were compared. RESULTS: Eleven patients were enrolled. MPAS equals score 1 for solid food, semiliquid food, and liquid food was defined as a criteria of normal swallowing function. By MBS evaluation, the numbers of patients with normal swallowing function were two cases at day 16-30 postoperation, two cases at day 31-45 postoperation, five cases at day 46-90 postoperation, and six cases at day 91-180 postoperation, respectively. By FEES evaluation, the above numbers were three cases, four cases, six cases and eight cases, respectively. When the aspiration was minimal and ejected completely and MPAS was less than or equal to score 4 for solid food, semiliquid food, and liquid food, the gastric tube could be removed. According to this standard, the gastric tube was removed in all cases, and the mean time was (21.7 +/- 9.8) days. A good correlation was obtained between these two methods when evaluating solid and semiliquid food, and the Kappa values were 0.802 and 0.844, respectively. However, a little agreement was obtained between these two methods when evaluating liquid food, and the Kappa value was 0.529. CONCLUSIONS: Patients who underwent supracricoid partial laryngectomy could restore good swallowing function in six months after the operation. Both the MBS and FEES are valuable procedures for evaluating objectively the swallowing function in patients after supracricoid partial laryngectomy. The FEES is much better than MBS, because FEES is a simple operation performed alone by otolaryngologists with no radiation. PMID- 25916528 TI - [Comparison of swallowing surface electromyography in globus patients and healthy adults]. AB - OBJECTIVE: To study the surface electromyography (sEMG) changes of globus patients during swallowing and to discuss the cause of the globus. METHODS: The sEMG during swallowing was recorded in 126 healthy volunteers (control group) and 34 globus patients (globus group).Swallow included dry swallow and 20 ml water swallow. The durations and amplitudes of muscle activities during every swallow were recorded. The durations and amplitudes of the sEMG in two groups were compared using t test. RESULTS: The durations of sEMG at dry swallow and 20 ml water swallow were (1.128 +/- 0.191)s and (1.091 +/- 0.208)s, while the amplitudes were (0.313 +/- 0.110) mV and (0.286 +/- 0.106) mV in control group. The durations of sEMG at dry swallow and 20 ml water swallow were (1.178 +/- 0.252)s and (1.127 +/- 0.178)s, while the amplitudes were (0.341 +/- 0.116) mV and (0.316 +/- 0.094) mV in globus group. There were no significant differences between globus patients and healthy volunteers in the durations and amplitudes of sEMG at dry swallow and 20 ml water swallow (P > 0.05).Furthermore, there were also no significant differences in the durations and amplitudes of the sEMG between the two groups in the same gender (P > 0.05). CONCLUSION: The results of swallowing sEMG suggested that the swallowing function in globus patients has not been damaged and psychological intervention should be considered in the treatment. PMID- 25916529 TI - [Comparative study on cluster and conventional immunotherapy in patients with allergic rhinitis]. AB - OBJECTIVE: To compare the efficacy and safety of subcutaneous immunotherapy with dermatophagoides pteronyssinus standardized extract given in conventional and cluster immunotherapy schedules for persistent allergic rhinitis. METHODS: One hundred and ten patients with moderate to severe allergic rhinitis caused by dust mites, in accordance with the immunotherapy inclusion criteria, were allocated to receive conventional immunotherapy as group A (n = 57) or cluster immunotherapy as group B (n = 53). In group A, 7 cases were lost to follow-up, the expulsion rate of group A was 12.28%; in group B, 1 case was lost to follow-up, the expulsion rate of group B was 1.89%. Nasal symptom scores, medicine scores and mini rhinoconjunctivitis quality of life questionnaire (Mini RQLQ) were recorded and compared before and after 7 weeks, 15 weeks, 1.0 year, 1.5 years, 2.0 years. All the scores were assessed to evaluate the clinical efficacy, and also the incidence of local and systemic adverse reactions were registered to evaluate the safety. SPSS 19.0 software was used to analyze the data. RESULTS: Nasal symptom scores, medicine scores and Mini RQLQ of both groups were significant lower than those before the treatment (all P < 0.05). Mini RQLQ and nasal symptom scores in cluster group (0.55 +/- 0.21,0.57 +/- 0.27) were more significantly declined than the conventional group after 7 weeks and 2.0 years of observation (all PMini RQLQ<0.05;nasal symptom scores: 1.41 +/- 0.65, 0.83 +/- 0.30, t value was 11.344, 5.649, both P < 0.05). The clinical efficiency rate in cluster group (86.5%, 94.2%) were more significantly highter than those (60.0%, 80.0%) in the conventional group after 7 weeks and 2 years of observation (chi(2) value was 9.224, 4.642, both P < 0.05). The medicine scores in cluster group (0.11 +/- 0.04) was more significantly declined than conventional group (0.47 +/- 0.11) after 7 weeks (t = 27.665, P < 0.05). The incidence of local and systemic adverse reactions during the incremental-dose phase and maintenance-dose phase compared with conventional immunotherapy were not significantly different (P > 0.05). CONCLUSION: The cluster immunotherapy is a safe treatment method which is more effective and faster than conventional immunotherapy to the dust mites caused allergic rhinitis. PMID- 25916530 TI - [Research on risk factors of depression symptoms in 1 327 patients with obstructive sleep apnea-hypopnea syndrome]. AB - OBJECTIVE: To investigate the comorbidity rate of depression symptoms in patients with obstructive sleep apnea-hypopnea syndrome (OSAHS) in Henan province and to ascertain the risk factors. METHODS: One thousand three hundred and twenty-seven patients with OSAHS determined by overnight polysomnogram (PSG) were enrolled in this study. After screening the Symptom Checklist 90 (SCL-90) and Self-rating Depression Scale (SDS), the patients were divided into two groups: OSAHS (control group, n = 698) and OSAHS+depression (n = 629). The correlation was explored between the depression symptoms in patients with OSAHS and the sociodemographic variables and health status including smoking, drinking, marital status, apnea hyponea index (AHI), anoxicity, Family Burden Scale of Disease (FBS), Family APGAR Index (APGAR), Perceived Social Support Scale (PSSS) and so on. Furthermore, In-depth analyses were carried out between the depression symptoms in patients with OSAHS and the social and family factor items (FBS, APGAR and PSSS). RESULTS: The comorbidity rate of depression symptoms in patients with OSAHS in Henan province was 47.4%, and was correlated with the gender, marital status, FBS, APGAR, AHI, PSSS and anoxicity. Logistic regression analysis indicated that single marital status, APGAR, AHI, PSSS, hypoxemia and heart disease were all independent risk factors for depression in OSAHS patients. The total of the FBS score and three of its subfactors scores (family daily activities, family relationships and mental health of family members) were higher, and the total of the APGAR score and two of its subfactors scores (adaptabilith and affection) were lower in OSAHS with depression compared with the control group (P < 0.05). Besides, the total score for the PSSS AND Scores for its two subfactors (family support and social support) were all lower in OSAHS patients with depression than those of the control group (P < 0.05). CONCLUSION: In patients with OSAHS, depression symptoms are common and are associated with marital status, AHI, anoxicity, concomitant diseases (hypertension, heart disease), concerns and supports from the family and society. PMID- 25916532 TI - [Efficiency of (99)Tc(m)-sestamibi in diagnosis of parathyroid diseases with primary hyperparathyroidism]. AB - OBJECTIVE: To evaluate the efficiency of (99)Tc(m)-sestamibi (MIBI) in the diagnosis of parathyroid diseases with primary hyperparathyroidism. METHODS: One hundred and four cases with primary hyperparathyroidism underwent MIBI and parathyroidectomy between May 2010 to November 2013 were reviewed. With MIBI, single adenoma was found in 91 cases, two adenomas in 5 cases, carcinoma and hyperplasia in 3 cases respectively. Primary hyperparathyroidism was diagnosed based on the associated symptoms and signs in 93 patients, while it was indicated in 11 asymptomatic patients due to the presence of hypercalcemia in health examination. Parathroid hormone levels ranged from 98 to 2 800 ng/L, and serum calcium levels were between 2.56-4.23 mmol/L. RESULTS: The sensitivity of MIBI for total diseased parntyroids was 84.0% (100/119), and that for parathyroid adenoma, parnthyroid carcinoma, atypical adenoma and primary parathyroid hyperplasia was 87.1% (88/101), 3/3, 2/2 and 7/13, respectively. CONCLUSIONS: MIBI is efficient in the diagnosis of parathyroid diseases with primary hyperparathyroidism. The size and cystic degeneration of parathroid disease are two common factors decreasing MIBI reliability, and thyroid nodule is additional source leading to false-positive results. PMID- 25916531 TI - [Analysis of the causes of flap necrosis after head and neck reconstruction]. AB - OBJECTIVE: To analyze the causes of the vascular crisis and necrosis of free flaps used for reconstruction of defects following head and neck cancer resection and the managements of these issues. METHODS: A total of 850 cases with head and neck tumors who underwent free flap reconstruction from October 2010 to April 2014 were studied retrospectively. The risks for vascular crisis and necrosis were analyzed with one-factor analysis and multivariate analysis. RESULTS: The total success rate of 95.1% (808/850) for the free flap reconstruction was obtained. Twelve flaps due to poor blood supply indicated during operation were replaced by other free flaps. Among 73 flaps with vascular crisis, 31 flaps were salvaged by surgical exploration and subcutaneous injection of low molecular heparin calcium. Obesity, smoking, preoperative radiotherapy and surgeon's experience, rather than age, hypertension and diabetes, were the risk factors of skin flap necrosis. Two-vein anastomosis had a higher success rate than one-vein anastomosis. CONCLUSIONS: The necrosis rate of free flaps can be reduced by the choice of suitable flaps, subtly preparation of flaps, carefully vascular anastomosis, and prompt perioperative managements. The two-vein anastomosis is recommended. Diabetes, hypertension and elderly patients are not the contraindications for free flap reconstruction. PMID- 25916533 TI - [Relationship between osteopontin gene genetic polymorphisms and susceptibility of nasopharyngeal carcinoma in Guangxi Zhuang people]. AB - OBJECTIVE: To evaluate the relationship between osteopontin gene genetic polymorphisms and susceptibility of nasopharyngeal carcinoma in Guangxi Zhuang people. METHODS: With a hospital based case-control study, osteopontin gene polymorphisms were compared between patients with nasopharyngeal carcinoma and healthy outpatients as a controls in Zhuang population in Guangxi. The single nucleotide polymorphisms at rs1126772 and rs9138 sites of the osteopontin gene were determined by polymerase chain reaction-single base extension technique (PCR SBE) and DNA sequencing technology. The comparison between genotype and allele frequency distribution differences in case and control group was accomplished by a chi(2) test. The frequencies of haplotypes in osteopontin gene in different groups were analyzed. RESULTS: There were no differences between the patients and controls in the genotype or allele frequencies of osteopontin gene rs1126772 site ( GA/GG: OR = 0.94, 95%CI 0.37-2.37, chi(2) = 0.182, P = 0.891; AA/GG:OR = 0.86, 95%CI 0.35-2.12, chi(2) = 0.834, P = 0.773) or rs9138 site ( CA/CC: OR = 1.42, 95%CI 0.88-2.29, chi(2) = 2.023, P = 0.155; AA/CC:OR = 1.77, 95%CI 0.78-4.01, chi(2) = 1.901, P = 0.168). The frequency of GA haplotype in the patients was significantly higher than that in the controls (P = 0.003), and the GA haplotype was associated with a significantly increased risk of nasopharyngeal carcinoma (OR = 4.84, 95%CI 1.59-14.71). CONCLUSION: The haplotype GA of osteopontin gene rs1126772 and rs9138 sites increases the risk of nasopharyngeal carcinoma in Guangxi Zhuang people. PMID- 25916534 TI - [Clinical features and expressions of p16, p53 protein of human papillomavirus related tonsillar carcinoma]. AB - OBJECTIVE: To analyze the clinical characteristics, prognosis and molecular biological changes of tonsillar squamous cell carcinoma (TSCC). METHODS: Retrospective analysis of 61 TSCC cases treated from January 1999 to December 2012. Demographic data and clinical charts, including histologic grade of tumor, treatment and outcome of the patients, were reviewed.Human papillomavirus (HPV) DNA were detected using SPF10-DNA enzyme immunoassay and LiPA genotyping method. Expressions of p16 and p53 proteins were examinated by immunohistochemistry. Survival rate was calculated with SPSS 19.0 software using the Kaplan-Meier method. RESULTS: There were 55 males and 6 females, with a median age of 57 years. Of the 61 TSCC, 21 were with well differentiation, 19 with moderate differentiation and 21 with poor differentiation, including 7 patients at stage II, 10 at stage III and 44 at stage IV. HPV-positive rate of TSCC was 29.5% (18/61) and high-risk HPV-16 subtype accounted for 72.2% (13/18). The percentage of famel patients in HPV-positive TSCC was higher than HPV-negative TSCC (22.2% vs 4.7%).HPV-positive TSCC was more common in non-smoking patients (50.0% vs 79.1%, chi(2) = 5, 155, P = 0.023) and non-drinking patients (27.8% vs 51.2%, chi(2) = 4.346, P = 0.037). HPV-positive TSCC mostly presented with high expression of p16 protein (88.9% vs 16.3%, chi(2) = 28.481, P = 0.000), and low expression of p53 protein (72.7% vs 46.5%, chi(2) = 5.028, P = 0.025). The prognosis of patients with HPV-associated TSCC was significantly better than non HPV-associated TSCC, and The 3-year and 5-year overall survival rates of patients with HPV-positive TSCC were higher than those of patients with HPV-negative TSCC (87.7% vs 49.5% and 78.9% vs 33.0%, respectively). CONCLUSION: HPV-associated TSCC had unique clinicopathological and molecular biological features, showing better prognosis compared to HPV-negative TSCC. PMID- 25916535 TI - [Expression of hypoxia inducible factor-1alpha in chronic rhinosinusitis and the relationship with mucin secretion]. AB - OBJECTIVE: To investigate the expression of hypoxia inducible factor-1alpha (HIF 1alpha) in chronic rhinosinusitis (CRS) and relationship with mucin MUC5AC, MUC5B secretion. METHODS: The expression of HIF-1alpha, MUC5AC and MUC5B were measured by immunohistochemistry (IHC), Western Blot and reverse transcription polymerase chain reaction (RT-PCR) in CRS with or without nasal polyps (CRSwNP: twenty-three or CRSsNP:twenty) and fifteen normal sinus mucosa without CRS. The relationship between HIF-1alpha and MUC5AC,MUC5B were analyzed by SPSS 16.0 software. RESULTS: PAS and IHC showed that HIF-1alpha, MUC5AC, MUC5B, total mucins were expressed in nuclear of epithelium and gland cells, which were higher than normal control (t values in epithelium cells were 8.650, 9.305, 9.382, 8.524, 7.533, 5.417, 5.507, 5.556, all P < 0.05; t values in gland cells were 8.285, 7.098, 6.798, 7.308, 8.574, 7.933, 6.798, 7.308, all P < 0.05), but there was no significant difference between CRSwNP and CRSsNP (t values in epithelium cells were 0.734, 0.415, 0.572, 0.248, all P > 0.05; t values in gland cells were 0.331, 0.662, 0.249, 0.644, P > 0.05).Western Blot revealed that HIF-1alpha protein in CRSwNP and CRSsNP were higher than in normal contral (t values were 3.522, 3.314, respectively, P < 0.05). The relative expression levels of HIF-1alpha, MUC5AC,MUC5B mRNA in CRSwNP and CRSsNP were 1.35 +/- 0.84, 1.36 +/- 0.94, 0.81 +/ 0.54,0.78 +/- 0.46, 1.13 +/- 1.00, 1.22 +/- 1.02. But the relative expression levels of HIF-1alpha, MUC5AC,MUC5B mRNA in control subjects were 0.43 +/- 0.34, 0.42 +/- 0.36, 0.48 +/- 0.42. There were significant differences between the groups of CRSwNP and control subiects (t values were 4.087, 4.089, 2.519, 2.550, 2.738, 2.955, respectively, all P < 0.05). There was a positive correlation among the expression of HIF-1alpha and MUC5AC, 5B mRNA in CRSwNP (r values were 0.474,0.464, respectively, all P < 0.05). There was a positive correlation among the expression of HIF-1alpha and MUC5AC, 5B mRNA in CRSsNP (r values were 0.477,0.514, respectively, all P < 0.05). CONCLUSIONS: HIF-1alpha, MUC5AC and MUC5B expression were upregulated in CRS with or without nasal polyps, indicating CRS is a disease of mucus hypersecretion and there is a close association between HIF-1alpha with hypersecretion of MUC5AC and MUC5B in mucus. PMID- 25916536 TI - [Expression and significance of NLRP3 inflammasome and its downstream factors IL 1beta/IL-18 in rat model of allergic rhinitis]. AB - OBJECTIVE: To detect the expression and explore the role of the innate immune NLRP3 inflammasome and its downstream factors interleukin-1beta (IL-1beta)/ interleukin-18 (IL-18) in rat model of allergic rhinitis (AR). METHODS: Forty Sprague Dawley (SD) rats were randomly divided into control group (A group), AR model group 1 (B group), AR model group 2(C group), AR model group 3 (D group). Every group contained 10 rats. After the rats in the model group were sensitized by ovalbumin (OVA) and alum, B, C and D groups were separately stimulated with 5% OVA for 10 days, 20 days and 30 days (once a day). The control group did not add OVA in the process of sensitization and excitation. All rats were executed after excitation.Eosinophil granulocyte (EOS) infiltration were observed in nasal mucosa by hematoxylin-eosin (HE) staining, the expression of NLRP3 and cysteinyl aspartate-specific protease-1 (Caspase-1) were observed in nasal mucosa by immunohistochemical staining. The concentrations of ovalbumin specific IgE (OVA sIgE), IL-18 and IL-1beta in peripheral blood and the concentrations of IL-18 and IL-1beta in nasal fluid were tested by enzyme-linked immunosorbent assay (ELISA). The data were processed by SPSS 17.0 software. RESULTS: EOS cell counted, the behavioral score and the concentrations of OVA-sIgE in AR model group were obviously higher than those in control group (P < 0.05), and the difference of which had statistical significance between the AR model groups (P < 0.05). The expression of NLRP3 in AR model group (The expression of NLRP3 in group of B, C and D were 48.80 +/- 10.75, 71.80 +/- 16.98 and 100.32 +/- 13.91, respectively) were obviously higher than those in control group (17.47 +/- 5.59), the difference of which had statistical significance (F = 78.399, P < 0.05). The expression of Caspase-1 in AR model group (The expression of Caspase-1 in group of B, C and D were 36.33 +/- 4.71, 50.87 +/- 11.18 and 73.10 +/- 14.77, respectively) were obviously higher than those in control group (11.48 +/- 2.70), the difference of which had statistical significance (F = 71.727, P < 0.05). The concentrations of IL-1beta in AR model group [The concentrations of IL-1beta in group of B, C and D were (56.46 +/- 10.13), (82.37 +/- 11.93), (112.01 +/- 22.91) pg/ml, respectively] were obviously higher than those in control group [(38.26 +/ 4.66) pg/ml], the difference of which had statistical significance (F = 51.981, P < 0.05). The concentrations of IL-18 in AR model group [The concentrations of IL-18 in group of B, C and D were (177.92 +/- 23.63), (194.33 +/- 20.78), (234.06 +/- 31.70) pg/ml, respectively] were obviously higher than those in control group [(89.71 +/- 5.56) pg/ml], the difference of which had statistical significance (F = 73.295, P < 0.05). And the difference of which had statistical significance between the AR model groups (P < 0.05). The expression of NLRP3 was significantly positively correlated with the behavioral score, the concentrations of OVA-sIgE and EOS cell counted in rat model of allergic rhinitis (r value were 0.833,0.873 and 0.868, respectively, all P < 0.01). CONCLUSION: NLRP3 inflammasome and its downstream factors IL-1beta/IL-18 play a role in the pathogenesis of allergic rhinitis, which may be correlated with the degree of inflammation. PMID- 25916537 TI - [Application of the discharge, inflammation, polyps/edema (DIP) endoscopic scoring system in patients with chronic rhinosinusitis]. AB - OBJECTIVE: To validate the discharge, inflammation, polyps/edema (DIP) scoring system for the assessment of endoscopic sinus surgery (ESS) outcomes in patients with chronic rhinosinusitis (CRS). METHODS: Thirty patients with CRS were included in this prospective study. All patients were evaluated before and 2 months after surgery. Baseline measures and postoperative outcomes were evaluated using sino-nasal outcome test-20 (SNOT-20), visual analogue scale (VAS) symptom score and Lund-Mackay CT score (in baseline only). All endoscopic videos were recorded before surgery and in the end of follow-up. All videos were scored blindly by two rhinologistis using the DIP and Lund-Kennedy system for investigating the inter-rater and test-retest reliability, as well as the correlations with the existing subjective and objective scoring systems.SPSS17.0 software was used to analyze the data. RESULTS: The average scores of VAS, SNOT 20, Lund-Kennedy, and DIP before and after surgery were listed below. Baseline, 29.73 +/- 13.05, 24.43 +/- 13.76, 7.70 +/- 3.25 and 32.67 +/- 13.48. Post surgical, 13.60 +/- 8.67, 10.40 +/- 7.45, 5.03 +/- 2.04 and 16.97 +/- 8.37. All scores were declined significantly from baseline (t value were 7.43, 6.49, 6.88 and 10.93, all P < 0.001). The DIP system showed a higher inter-rater and rest rest reliability than Lund-Kennedy system (interclass coefficient,ICC > 0.75). The Pearson analysis revealed that VAS scores were significantly correlated with SNOT-20 scores both in baseline and post-surgical assessments (r = 0.518 6, P = 0.003, and r = 0.546 7, P = 0.000). Before surgery, Lund-Kennedy scores were significantly correlated with DIP and Lund-Mackay CT scores (r = 0.937 5, P = 0.000 and r = 0.748 0, P = 0.000). DIP scores were significantly correlated with Lund-Mackay CT scores (r = 0.712 2, P = 0.000). After surgery,DIP scores were significantly correlated with Lund-Kennedy scores (r = 0.869 6, P = 0.000). But there were no significant correlations between subjective scores (VAS and SNOT 20) and objective scores (Lund-Kennedy, DIP and Lund-Mackay CT), (all P > 0.05). CONCLUSIONS: The DIP scoring system shows substantial inter-rater and test-retest reliability.It is also significantly correlated with existing objective scoring parameters. It is suitable and reliable to use. PMID- 25916538 TI - [Distribution and drug resistance of the pathogenic bacteria from sputum specimens of 1 125 children with tracheo bronchial foreign bodies]. AB - OBJECTIVE: To analyze the distribution and drug susceptibility of the pathogenic bacteria in the airway secretions in children with tracheobronchial foreign bodies so as to assist physicians in clinical prescription. METHODS: Sputum specimens of 1 125 children with tracheobronchial foreign bodies were collected in removal of the foreign bodies by rigid bronchoscope, and the drug susceptibility test was performed. RESULTS: Pathogenic bacteria were detected in 218 (19.4%) of 1 125 sputum specimens. Among the pathogenic bacteria, 126 (57.79%) strains were gram-negative bacilli, consisting of 76 (34.86%) strains of Haemophilus influenzae, 10 (4.59%) strains of Escherichia coli, 7 (3.21%) strains of Sewer enterobacter, 7 (3.21%) strains of Pseudomonas aeruginosa, and 6 (2.75%) strains of Klebsiella bacillus; and 92 (42.21%) strains were gram-positive bacilli, consisting of 80 (36.69%) strains of Streptococcus pneumonia and 10 (4.59%) strains of Escherichia coli. Most of detected gram-negative bacilli were highly sensitive to cefepime, ceftazidine, imipenem and amikacin, no strains were resistant to meropenem and ciprofloxacin. None of the detected gram-positive bacilli were resistant to cefepime, vancomycin, levofloxacin and teicoplanin. CONCLUSIONS: The Haemophilus influenzae of gram-negative bacilli and the Streptococcus pneumonia of gram-positive bacilli are the main pathogenic bacteria existing in the airway secretions of children with tracheobronchial foreign bodies. The Haemophilus influenzae were highly sensitive to cephalosporin, imipenem and amikacin, and the Streptococcus pneumonia to cefepime, vancomycin, levofloxacin and teicoplanin. PMID- 25916539 TI - [Insomnia after functional endoscopic sinus surgery:a case report]. PMID- 25916540 TI - [Surgical management of dysphagia and dyspnea secondary to esophagus type cervical spondylosis]. PMID- 25916541 TI - [Male breast cancer metastasis to nasal vestibule]. PMID- 25916542 TI - [Primary glottic involvement of extranodal marginal zone B cell lymphoma of mucosa-associated lymphoid tissue: a case report]. PMID- 25916543 TI - [Research progress of monoclonal antibody omalizumab in the treatment of allergic rhinitis]. PMID- 25916544 TI - [Progress of the inner hair cell regeneration and repair]. PMID- 25916545 TI - [Minutes of 2014 China ORL-HNS congress of young and middle-aged scholars]. PMID- 25916546 TI - Fluorescent oligo(p-phenyleneethynylene) contained amphiphiles-encapsulated magnetic nanoparticles for targeted magnetic resonance and two-photon optical imaging in vitro and in vivo. AB - Folate receptor-targeted multifunctional fluorescent magnetic nanoparticles (FMNPs) composed of cores containing iron oxide nanocrystals and amphiphilic oligo(p-phenyleneethynylene) shells with multimodal imaging capability were successfully prepared through a convenient hydrophobic encapsulation approach. The iron oxide nanoparticles in the core provided T2-weighted magnetic resonance imaging (MRI), whereas the amphiphilic oligomers on the surface of the nanoparticles introduced good water-solubility, biocompatibility, excellent fluorescent properties and cancer-targeting. These nanoparticles exhibited superparamagnetic properties with saturation magnetization (Ms) of 23 emu g(-1) and a transverse relaxivity rate of 140.89 mM(-1) s(-1). In vitro studies indicated that the dual-modal FMNPs can serve as an effective two-photon fluorescent and a magnetic probe to achieve the targeted imaging of Hela cells without obvious cytotoxicity. In vivo two-photon fluorescence and MRI results demonstrated that the FMNPs were able to preferentially accumulate in tumor tissues to allow dual-modal detection of tumors in a living body. These studies provided insight in developing novel multifunctional probes for multimodal imaging, which would play an important role for theranostics in biomedical science. PMID- 25916547 TI - Predicting the transition from juvenile delinquency to adult criminality: Gender specific influences in two high-risk samples. AB - BACKGROUND: Most juvenile offenders desist from offending as they become adults, but many continue and ultimately enter the adult corrections system. There has been little prospective examination of which variables may predict the latter transition, particularly for women. AIMS: Our aim was to find out, for men and women separately, what variables identifiable in adolescent offenders predict their continuation of offending into adult life. METHODS: Participants were 61 male and 81 female youths who had been referred from the juvenile justice system for chronic delinquency and recruited into randomised controlled trials comparing Multidimensional Treatment Foster Care with group care ('treatment as usual'). All participants had attained adulthood by the time of our study. We first examined gender differences in childhood risk factors and then used Cox proportional-hazards models to estimate the relationship of potential risk factors to first adult arrest. RESULTS: Results indicated that, for men, juvenile justice referrals alone predicted risk of any first adult arrest as well as arrest for felony arrest specifically. Each additional juvenile referral increased the risk of any adult arrest by 9% and of adult felony arrest by 8%. For women, family violence, parental divorce and cumulative childhood risk factors, but not juvenile justice referrals, were significant predictors of adult arrest. Each additional childhood risk factor increased the risk of adult arrest by 21%. Women who experienced parental divorce were nearly three times more likely to be arrested as an adult, and those who experienced family violence 2.5 times more so than those without such experiences. CONCLUSIONS AND IMPLICATIONS FOR PRACTICE: We found preliminary evidence of gender differences in childhood risk factors for adult offending, and, thus potentially, for the development and use of interventions tailored differently for girls and boys and young men and young women to reduce their risk of becoming adult recidivists. Copyright (c) 2015 John Wiley & Sons, Ltd. PMID- 25916548 TI - Mapping chemical structure-activity information of HAART-drug cocktails over complex networks of AIDS epidemiology and socioeconomic data of U.S. counties. AB - Using computational algorithms to design tailored drug cocktails for highly active antiretroviral therapy (HAART) on specific populations is a goal of major importance for both pharmaceutical industry and public health policy institutions. New combinations of compounds need to be predicted in order to design HAART cocktails. On the one hand, there are the biomolecular factors related to the drugs in the cocktail (experimental measure, chemical structure, drug target, assay organisms, etc.); on the other hand, there are the socioeconomic factors of the specific population (income inequalities, employment levels, fiscal pressure, education, migration, population structure, etc.) to study the relationship between the socioeconomic status and the disease. In this context, machine learning algorithms, able to seek models for problems with multi source data, have to be used. In this work, the first artificial neural network (ANN) model is proposed for the prediction of HAART cocktails, to halt AIDS on epidemic networks of U.S. counties using information indices that codify both biomolecular and several socioeconomic factors. The data was obtained from at least three major sources. The first dataset included assays of anti-HIV chemical compounds released to ChEMBL. The second dataset is the AIDSVu database of Emory University. AIDSVu compiled AIDS prevalence for >2300 U.S. counties. The third data set included socioeconomic data from the U.S. Census Bureau. Three scales or levels were employed to group the counties according to the location or population structure codes: state, rural urban continuum code (RUCC) and urban influence code (UIC). An analysis of >130,000 pairs (network links) was performed, corresponding to AIDS prevalence in 2310 counties in U.S. vs. drug cocktails made up of combinations of ChEMBL results for 21,582 unique drugs, 9 viral or human protein targets, 4856 protocols, and 10 possible experimental measures. The best model found with the original data was a linear neural network (LNN) with AUROC>0.80 and accuracy, specificity, and sensitivity~77% in training and external validation series. The change of the spatial and population structure scale (State, UIC, or RUCC codes) does not affect the quality of the model. Unbalance was detected in all the models found comparing positive/negative cases and linear/non-linear model accuracy ratios. Using synthetic minority over sampling technique (SMOTE), data pre-processing and machine-learning algorithms implemented into the WEKA software, more balanced models were found. In particular, a multilayer perceptron (MLP) with AUROC=97.4% and precision, recall, and F-measure >90% was found. PMID- 25916551 TI - Echocardiographic Parameters of Right Ventricular Diastolic Function in Repaired Tetralogy of Fallot Are Associated with Important Findings on Magnetic Resonance Imaging. AB - BACKGROUND: Right ventricular (RV) dilation, RV dysfunction, RV outflow tract obstruction, and branch pulmonary artery stenosis are risk factors associated with the need for future surgical or catheter-based intervention commonly assessed by cardiac magnetic resonance in patients with tetralogy of Fallot who have undergone initial repair. The ability of echocardiography to predict the presence of these risk factors is limited. OBJECTIVE: We aimed to determine the association between echocardiographic parameters of right ventricular diastolic dysfunction and risk factors for intervention as identified on cardiac magnetic resonance imaging (CMR). DESIGN: We reviewed all echocardiograms and CMRs performed at our institution within 1 year of each other in patients with repaired tetralogy of Fallot. We evaluated patients for the following: RV systolic dysfunction (RV ejection fraction <45%), RV dilation (right ventricular end-diastolic volume >= 160 mL/m(2)), and RV obstruction (RV outflow tract gradient >= 3 m/s by echocardiogram or branch pulmonary artery stenosis assessed by CMR). We evaluated for associations between the above CMR findings and echocardiographic parameters of diastolic function. RESULTS: CMR and echocardiographic images performed between March 2007 and March 2012 were available in 99 patients. RV obstruction was associated with lower E/A ratio (P = .02), E/A reversal (P = .02), and prograde end diastolic pulmonary flow (P < .01). Low tricuspid annular a' and low septal s' were associated with lower RV ejection fraction (P < .01, P < .01). Elevated E/e' was associated with higher RV end diastolic volume (P = .04). In predicting the presence of any of the evaluated risk factors for future intervention, TV E/e' >= 4.7 had positive predictive value (PPV) of 86% and negative predictive value (NPV) of 50%, TV E/A reversal had PPV of 89% and NPV of 34, and prograde end diastolic pulmonary flow on echocardiogram had PPV of 91% and NPV of 38%. CONCLUSIONS: Echocardiographic parameters of diastolic dysfunction have a reasonable PPV but poor NPV for predicting clinically significant risk factors identified by CMR. PMID- 25916550 TI - Epigenetic silencing of microRNA-149 in cancer-associated fibroblasts mediates prostaglandin E2/interleukin-6 signaling in the tumor microenvironment. AB - Tumor initiation and growth depend on its microenvironment in which cancer associated fibroblasts (CAFs) in tumor stroma play an important role. Prostaglandin E2 (PGE2) and interleukin (IL)-6 signal pathways are involved in the crosstalk between tumor and stromal cells. However, how PGE2-mediated signaling modulates this crosstalk remains unclear. Here, we show that microRNA (miR)-149 links PGE2 and IL-6 signaling in mediating the crosstalk between tumor cells and CAFs in gastric cancer (GC). miR-149 inhibited fibroblast activation by targeting IL-6 and miR-149 expression was substantially suppressed in the CAFs of GC. miR-149 negatively regulated CAFs and their effect on GC development both in vitro and in vivo. CAFs enhanced epithelial-to-mesenchymal transition (EMT) and the stem-like properties of GC cells in a miR-149-IL-6-dependent manner. In addition to IL-6, PGE2 receptor 2 (PTGER2/EP2) was revealed as another potential target of miR-149 in fibroblasts. Furthermore, H. pylori infection, a leading cause of human GC, was able to induce cyclooxygenase-2 (COX-2)/PGE2 signaling and to enhance PGE2 production, resulting in the hypermethylation of miR-149 in CAFs and increased IL-6 secretion. Our findings indicate that miR-149 mediates the crosstalk between tumor cells and CAFs in GC and highlight the potential of interfering miRNAs in stromal cells to improve cancer therapy. PMID- 25916549 TI - In-cell infection: a novel pathway for Epstein-Barr virus infection mediated by cell-in-cell structures. AB - Epstein-Barr virus (EBV) can infect both susceptible B lymphocytes and non susceptible epithelial cells (ECs). Viral tropism analyses have revealed two intriguing means of EBV infection, either by a receptor-mediated infection of B cells or by a cell-to-cell contact-mediated infection of non-susceptible ECs. Herein, we report a novel "in-cell infection" mechanism for EBV infection of non susceptible ECs through the formation of cell-in-cell structures. Epithelial CNE 2 cells were invaded by EBV-infected Akata B cells to form cell-in-cell structures in vitro. Such unique cellular structures could be readily observed in the specimens of nasopharyngeal carcinoma. Importantly, the formation of cell-in cell structures led to the autonomous activation of EBV within Akata cells and subsequent viral transmission to CNE-2 cells, as evidenced by the expression of viral genes and the presence of virion particles in CNE-2 cells. Significantly, EBV generated from in-cell infected ECs displayed altered tropism with higher infection efficacy to both B cells and ECs. In addition to CNE-2 tumor cells, cell-in-cell structure formation could also mediate EBV infection of NPEC1-Bmi1 cells, an immortalized nasopharyngeal epithelial cell line. Furthermore, efficient infection by this mechanism involved the activation of the PI3K/AKT signaling pathway. Thus, our study identified "in-cell infection" as a novel mechanism for EBV infection. Given the diversity of virus-infected cells and the prevalence of cell-in-cell structures during chronic infection, we speculate that "in-cell infection" is likely a general mechanism for EBV and other viruses to infect non-susceptible ECs. PMID- 25916552 TI - Comparison between frailty index of deficit accumulation and fracture risk assessment tool (FRAX) in prediction of risk of fractures. AB - A frailty index (FI) of deficit accumulation could quantify and predict the risk of fractures based on the degree of frailty in the elderly. We aimed to compare the predictive powers between the FI and the fracture risk assessment tool (FRAX) in predicting risk of major osteoporotic fracture (hip, upper arm or shoulder, spine, or wrist) and hip fracture, using the data from the Global Longitudinal Study of Osteoporosis in Women (GLOW) 3-year Hamilton cohort. There were 3985 women included in the study, with the mean age of 69.4 years (standard deviation [SD] = 8.89). During the follow-up, there were 149 (3.98%) incident major osteoporotic fractures and 18 (0.48%) hip fractures reported. The FRAX and FI were significantly related to each other. Both FRAX and FI significantly predicted risk of major osteoporotic fracture, with a hazard ratio (HR) of 1.03 (95% confidence interval [CI]: 1.02-1.05) and 1.02 (95% CI: 1.01-1.04) for per 0.01 increment for the FRAX and FI respectively. The HRs were 1.37 (95% CI: 1.19 1.58) and 1.26 (95% CI: 1.12-1.42) for an increase of per-0.10 (approximately one SD) in the FRAX and FI respectively. Similar discriminative ability of the models was found: c-index = 0.62 for the FRAX and c-index = 0.61 for the FI. When cut points were chosen to trichotomize participants into low-risk, medium-risk and high-risk groups, a significant increase in fracture risk was found in the high risk group (HR = 2.04, 95% CI: 1.36-3.07) but not in the medium-risk group (HR = 1.23, 95% CI: 0.82-1.84) compared with the low-risk women for the FI, while for FRAX the medium-risk (HR = 2.00, 95% CI: 1.09-3.68) and high-risk groups (HR = 2.61, 95% CI: 1.48-4.58) predicted risk of major osteoporotic fracture significantly only when survival time exceeded 18months (550 days). Similar findings were observed for hip fracture and in sensitivity analyses. In conclusion, the FI is comparable with FRAX in the prediction of risk of future fractures, indicating that measures of frailty status may aid in fracture risk assessment and fracture prevention in the elderly. Further evidence from randomized controlled trials of osteoporosis medication interventions is needed to support the FI and FRAX as validated measures of fracture risk. PMID- 25916554 TI - Polyaniline-based photothermal paper sensor for sensitive and selective detection of 2,4,6-trinitrotoluene. AB - We report for the first time a photothermal paper sensor for the selective and sensitive detection of 2,4,6-trinitrotoluene (TNT) down to 14 ng/cm(2). In the presence of TNT, a Meisenheimer complex was formed by means of a charge transfer process from an electron-rich group in polyaniline (PANI) to an electron deficient nitro group in TNT, which resulted in the near-infrared absorption around 800 nm. Upon irradiation with an 808 nm diode laser, the photothermal effect of the PANI/TNT complex caused the temperature increase, and the temperature difference (DeltaT) was proportional to the TNT concentration, while the temperature increase was hardly observed for other nitroaromatics including 2,4-dinitrotoluene (DNT), 2,4,6-trinitrophenol (TNP), and nitrobenzene (NB), affording high selectivity toward TNT. All the tests can be conducted both in solution and on paper. Therefore, the proposed photothermal strategy not only offers a fast and convenient protocol for selective detection of TNT but also indicates great potential in practical applications, especially for airport/railway security inspection and prevention of terrorist attacks. PMID- 25916553 TI - Effects of short-term gentle treadmill walking on subchondral bone in a rat model of instability-induced osteoarthritis. AB - OBJECTIVE: Subchondral bone cyst (SBC) growth, caused by osteoclast activity during early knee osteoarthritis (OA) pathogenesis, should be treated to prevent further progressions of OA. In the present study, we evaluated the effects of gentle treadmill walking on subchondral bone and cartilage changes in an experimental rat model of destabilized medial meniscus (DMM). METHOD: Twelve-week old Wistar rats underwent DMM surgery in their right knee and sham surgery in their left knee and were assigned to either the sedentary group or walking group (n = 42/group). Animals in the walking group were subjected to treadmill exercise 2 days after surgery, which included walking for 12 m/min, 30 min/day, 5 days/week for 1, 2, and 4 week(s). Subchondral bone and cartilage changes were evaluated by micro-CT analysis, histological analysis, and biomechanical analysis. RESULTS: Treadmill walking had a tendency to suppress SBC growth, which was confirmed by micro-CT (P = 0.06) and positive staining for tartrate-resistant acid phosphatase (TRAP) activity for the osteoclast number per bone surface (P = 0.09) 4 weeks after surgery. These changes coincide with the prevention of cartilage degeneration as evaluated by the Osteoarthritis Research Society International (OARSI) score (P < 0.05) and biomechanically softening (P < 0.05). Furthermore, treadmill walking could suppressed increasing osteocyte deaths (P < 0.01), which was positively correlated with the OARSI score (r = 0.77; P < 0.01). CONCLUSION: These results indicate biomechanical and biological links exist between cartilage and subchondral bone; preventive effects of treadmill walking on subchondral bone deterioration might be partly explained by the chondroprotective effects. PMID- 25916555 TI - High serum total IgE predicts poor long-term outcome in atopic dermatitis. AB - Most patients with severe atopic dermatitis have elevated serum IgE levels, but there has been little research into IgE as a predictive biomarker in long-term disease outcome. The aim of this study was to evaluate the predictive value of IgE and other factors in patients with atopic dermatitis in a university clinic setting. There were 169 eligible patients (14-78 years) with a mean follow-up of 4.15 years. High baseline IgE (>= 10,000 IU/ml) was the most important patient related factor for a poor long-term outcome, being negatively associated with good treatment response (odds ratio (OR) 0.062, p = 0.002). Only 14.3% of patients with this high baseline IgE achieved a good treatment response in follow up, compared with 79.7% in patients with lower (< 1,000) IgE values (p < 0.001). Serum total IgE may provide an easily measurable way to predict long-term outcome, and to help to select those patients in need of closer follow-up. PMID- 25916557 TI - The impact of environmental toxins on predator-prey dynamics. AB - Predators and prey may be simultaneously exposed to environmental toxins, but one may be more susceptible than the other. To study the effects of environmental toxins on food web dynamics, we develop a toxin-dependent predator-prey model that combines both direct and indirect toxic effects on two trophic levels. The direct effects of toxins typically reduce organism abundance by increasing mortality or reducing fecundity. Such direct effects, therefore, alter both bottom-up food availability and top-down predatory ability. However, the indirect effects, when mediated through predator-prey interactions, may lead to counterintuitive effects. This study investigates how the balance of the classical predator-prey dynamics changes as a function of environmental toxin levels. While high toxin concentrations are shown to be harmful to both species, possibly leading to extirpation of both species, intermediate toxin concentrations may affect predators disproportionately through biomagnification, leading to reduced abundance of predators and increased abundance of the prey. This counterintuitive effect significantly increases biomass at the lower trophic level. Environmental toxins may also reduce population variability by preventing populations from fluctuating around a coexistence equilibrium. Finally, environmental toxins may induce bistable dynamics, in which different initial population levels produce different long-term outcomes. Since our toxin-dependent predator-prey model is general, the theory developed here not only provides a sound foundation for population or community effects of toxicity, but also could be used to help develop management strategies to preserve and restore the integrity of contaminated habitats. PMID- 25916558 TI - How to turn an oscillation in a pink one. PMID- 25916556 TI - A REDD1/TXNIP pro-oxidant complex regulates ATG4B activity to control stress induced autophagy and sustain exercise capacity. AB - Macroautophagy (autophagy) is a critical cellular stress response; however, the signal transduction pathways controlling autophagy induction in response to stress are poorly understood. Here we reveal a new mechanism of autophagy control whose deregulation disrupts mitochondrial integrity and energy homeostasis in vivo. Stress conditions including hypoxia and exercise induce reactive oxygen species (ROS) through upregulation of a protein complex involving REDD1, an mTORC1 inhibitor and the pro-oxidant protein TXNIP. Decreased ROS in cells and tissues lacking either REDD1 or TXNIP increases catalytic activity of the redox sensitive ATG4B cysteine endopeptidase, leading to enhanced LC3B delipidation and failed autophagy. Conversely, REDD1/TXNIP complex expression is sufficient to induce ROS, suppress ATG4B activity and activate autophagy. In Redd1(-/-) mice, deregulated ATG4B activity and disabled autophagic flux cause accumulation of defective mitochondria, leading to impaired oxidative phosphorylation, muscle ATP depletion and poor exercise capacity. Thus, ROS regulation through REDD1/TXNIP is physiological rheostat controlling stress-induced autophagy. PMID- 25916559 TI - Experimental study on the role of intra-articular injection of MSCs on cartilage regeneration in haemophilia. AB - Mesenchymal stem cells (MSCs) therapy is a field in progress in cartilage repair strategies. We tried to investigate the functional properties of the joint and cartilage in experimental haemarthrosis (EH) after MSCs intra-articular (IA) injection. One millilitre of fresh autologous blood was injected twice a week for three consecutive weeks in three groups including control haemophilia 10 days (n = 8), control haemophilia 38 days (n = 8) and MSCs (n = 8) group. In later, 10 days after the end of IA blood injections, MSCs IA injection was performed. Eight animals received no treatment as the normal control group. Thirty-eight days after the end of IA blood injections, animals were sacrificed. Joint friction and stress-relaxation tests were done, inflammatory cytokines of synovial membrane and scanning electron microscopy of the cartilage assessed. Joint friction decreased in MSCs in comparison to other groups and was significant with normal control group, (P = 0.011). The mechanical properties of cartilage showed no significant differences between groups. Tumour necrosis factor alpha and interleukin 1 beta decreased and IL-4 very slightly increased in MSCs in comparison to the time-matched control group. Scanning electron microscopy enabled acquisition of good structural properties of the surface and layers of the cartilage after MSCs injection. The hole induced in the medial plateau of the tibia bones, after inducing haemarthrosis, were covered with cartilage-like structure. The results showed that MSCs IA injection has some beneficial effects on cartilage structure and function in haemarthrosis model and is promising in patients with haemophilia. PMID- 25916560 TI - Characterisation of DWI-MRI confirmed cerebral infarcts in patients with subarachnoid haemorrhage and their association with MMP-9 levels. AB - OBJECTIVES: It has been suggested that metalloproteinase-9 (MMP-9) could predict the onset of cerebral vasospasm after subarachnoidal haemorrhage (SAH). The aim of this study was to analyse, in patients with SAH, the difference between patients with MRI ischaemic infarcts and patients without, and to investigate the role of metalloproteases as a prognostic factor for ischaemic infarcts. METHODS: Sixty eight consecutive patients with SAH and diffusion-weighted magnetic resonance imaging (DWI-MRI) done 3 weeks after SAH. We define two groups, with and without DWI-MRI infarcts. Blood samples were taken at entry, 3 days and 1 week MMP-9 was determined through ELISA method. RESULTS: Forty per cent were male, with a mean age of 54 +/- 14 years. Twenty five patients, 36.8%, had DWI MRI infarcts; in patients with MRI infarcts, SAH was more severe (Fisher = 4 52 vs 25.6%, P = 0.037), with more morbi-mortality (Rankin>3 48 vs 18.6%, P = 0.014), and more symptomatic vasospasm (28 vs 7%, P = 0.031). Levels of MMP-9 were higher than controls, but there were no significant differences between patients with and without infarcts (first determination no infarcts 39.40 ng/ml +/- 35.40 vs infarcts 49.75 ng/ml +/- 34.54, P > 0.005, 3 days no infarcts 72.10 ng/ml +/- 70.95 vs infarcts 62.28 +/- 33.84, P > 0.005, 1 week no infarcts 148.48 ng/ml +/- 142.73 vs infarcts 91.5 ng/ml +/- 1.20, P > 0.005). CONCLUSION: Thirty eight percent in a well-studied series of patients with SAH have DWI-MRI infarcts; the infarcts were associated to SAH severity, SAH outcome and symptomatic vasospasm. Metalloproteinase-9 was higher in SAH patients than in controls, but it could not discriminate the infarct patients. PMID- 25916561 TI - A Missing Pole from a Circular Mapping Catheter Ablation. PMID- 25916562 TI - Alzheimer's disease first symptoms are age dependent: Evidence from the NACC dataset. AB - INTRODUCTION: Determining the relationship between age and Alzheimer's disease (AD) presentation is important to improve understanding and provide better patient services. METHODS: We used AD patient data (N = 7815) from the National Alzheimer Coordinating Center database and multinomial logistic regression to investigate presentation age and first cognitive/behavioral symptoms. RESULTS: The odds of having a nonmemory first cognitive symptom (including impairment in judgment and problem solving, language, and visuospatial function) increased with younger age (P < .001, all tests). Compared with apathy/withdrawal, the odds of having depression and "other" behavioral symptoms increased with younger age (P < .02, both tests), whereas the odds of having psychosis and no behavioral symptom increased with older age (P < .001, both tests). DISCUSSION: There is considerable heterogeneity in the first cognitive/behavioral symptoms experienced by AD patients. Proportions of these symptoms change with age with patients experiencing increasing nonmemory cognitive symptoms and more behavioral symptoms at younger ages. PMID- 25916564 TI - Genetic risk of neurodegenerative diseases is associated with mild cognitive impairment and conversion to dementia. AB - INTRODUCTION: Neurodegenerative diseases are a major cause of cognitive impairment and can ultimately lead to dementia. Genome-wide association studies have uncovered many genetic variants conferring risk of neurodegenerative diseases, but their role in cognitive impairment remains unexplored. METHODS: In the prospective, population-based Rotterdam Study, 3605 nondemented persons aged >=55 years were genotyped, screened for mild cognitive impairment (MCI) in 2002 to 2005 and underwent continuous follow-up for dementia until 2012. Weighted polygenic risk scores of genetic variants for Alzheimer's disease (AD), Parkinson's disease (PD), and the frontotemporal lobar degeneration/amyotrophic lateral sclerosis disease spectrum (FTLD/ALS) were constructed and investigated for association with MCI and the subsequent conversion to dementia. RESULTS: In total, 360 (10.0%) persons had MCI, of whom 147 (4.1%) were amnestic and 213 (5.9%) nonamnestic. The AD risk score was associated with both MCI subtypes (odds ratio for all MCI 1.15 [95% CI, 1.03-1.28]), whereas PD and FTLD/ALS risk scores were associated only with nonamnestic MCI (odds ratios 1.15 [1.00-1.32] and 1.19 [1.03-1.37], respectively). The AD risk score, but not PD and FTLD/ALS risk scores, was associated with an increased risk of dementia (hazard ratio 1.55 [1.37-1.77]). DISCUSSION: Genetic evidence supports the view that multiple neurodegenerative pathways lead to MCI and that the subsequent conversion to dementia, primarily of the AD subtype, is mainly due to the AD pathway(s). PMID- 25916563 TI - Florbetapir positron emission tomography and cerebrospinal fluid biomarkers. AB - BACKGROUND: We evaluated the relationship between florbetapir-F18 positron emission tomography (FBP PET) and cerebrospinal fluid (CSF) biomarkers. METHODS: Alzheimer's Disease Neuroimaging Initiative-Grand Opportunity and Alzheimer's Disease Neuroimaging Initiative 2 (GO/2) healthy control (HC), mild cognitive impairment (MCI), and Alzheimer's disease (AD) dementia subjects with clinical measures and CSF collected +/-90 days of FBP PET data were analyzed using correlation and logistic regression. RESULTS: In HC and MCI subjects, FBP PET anterior and posterior cingulate and composite standard uptake value ratios correlated with CSF amyloid beta (Abeta1-42) and tau/Abeta1-42 ratios. Using logistic regression, Abeta1-42, total tau (t-tau), phosphorylated tau181P (p tau), and FBP PET composite each differentiated HC versus AD. Abeta1-42 and t-tau distinguished MCI versus AD, without additional contribution by FBP PET. Total tau and p-tau added discriminative power to FBP PET when classifying HC versus AD. CONCLUSION: Based on cross-sectional diagnostic groups, both amyloid and tau measures distinguish healthy from demented subjects. Longitudinal analyses are needed. PMID- 25916565 TI - Characterization of ventricular activation pattern and acute hemodynamics during multipoint left ventricular pacing. AB - BACKGROUND: Multipoint left ventricular (LV) pacing (MultiPoint Pacing [MPP], St Jude Medical, Sylmar, CA) in a single coronary sinus branch has been introduced as a novel means of cardiac resynchronization therapy (CRT). It is speculated that MPP improves LV function by capturing a larger LV tissue area, resulting in uniform wavefront propagation throughout the ventricles, in comparison to conventional biventricular pacing (BIV). OBJECTIVE: The purpose of this study was to evaluate MPP by means of contact mapping and hemodynamic measures to understand the underlying mechanisms and effects. METHODS: Ten patients with non ischemic cardiomyopathy (mean age 69 +/- 9 years; 6 men (60%); New York Heart Association heart failure class II or III; QRS duration 173 +/- 20 ms; LV ejection fraction 27% +/- 5%) received a CRT-defibrillator capable of MPP. After the implantation procedure, an acute pacing protocol was implemented, including 2 BIV and up to 9 MPP interventions. In all pacing interventions, LV electrical activation patterns and hemodynamics (dP/dtmax) were evaluated, and for each patient, both the resulting measures were compared between MPP and BIV interventions. RESULTS: Compared with BIV, MPP resulted in an increase in LV dP/dtmax (30% +/- 13% vs. 25% +/- 11%; P = .041), a reduction in QRS duration (22% +/- 11% vs. 11% +/- 11%; P = .01), and a decrease in total endocardial activation time (25% +/- 15% vs. 10% +/- 20%; P = .01). MPP resulted in a larger capture of LV mass during the first 25 ms (35% +/- 22% vs. 16% +/- 8%; P = .005) and during the first 50 ms (78% +/- 27% vs. 60% +/- 23%; P = .03) of pacing, suggesting a quicker wavefront propagation throughout the left ventricle. CONCLUSION: In this acute study, MPP in CRT improved both endocardial and surface electrical parameters and hemodynamics in comparison with BIV. PMID- 25916566 TI - Spatiotemporal organization during ablation of persistent atrial fibrillation. AB - BACKGROUND: Targeting complex fractionated atrial electrograms improves the outcome of ablation of persistent atrial fibrillation (AF); however, the mechanism(s) responsible for the generation of complex fractionated atrial electrogram signals and efficacy of ablation is not clear. OBJECTIVE: The aim of this study was to gain mechanistic insight into ablation of persistent AF by evaluating the spatiotemporal patterns of atrial organization during ablation. METHODS: Intracardiac recordings from 18 ablation procedures were analyzed. Signals recorded by right atrial/coronary sinus catheters were processed. We quantified atrial organization using recurrence maps and recurrence percentage (Rec%) methodology and generated temporally dense time series of cycle lengths and Rec%. RESULTS: A total of 162 intra-atrial recordings were categorized into type I (sudden jump in Rec%), type II (gradual increase), and type III (no increase). Type I was the most common form and was seen in 57% +/- 4% of the recordings. A typical pattern was the initial appearance of local organization, which then expanded to adjacent channels in discrete jumps until eventually an organized atrial flutter emerged. This pattern is consistent with the atrial organization signature expected from ablation of a single spiral wave with fibrillatory conduction to the rest of atria. CONCLUSION: Temporally dense spatiotemporal assessment of atrial organization during the ablation of persistent AF is feasible and provides complementary information to cycle length measurements. Atrial organization starts locally and expands spatially in discrete jumps. The regularization of AF to atrial flutter exhibits characteristics of phase transition in complex systems. PMID- 25916567 TI - P-wave duration and the risk of atrial fibrillation: Results from the Copenhagen ECG Study. AB - BACKGROUND: Results on the association between P-wave duration and the risk of atrial fibrillation (AF) are conflicting. OBJECTIVE: The purpose of this study was to obtain a detailed description of the relationship between P-wave duration and the risk of AF. METHODS: Using computerized analysis of electrocardiograms from a large primary care population, we evaluated the association between P-wave duration and the risk of AF. Secondary end-points were death from cardiovascular causes and putative ischemic stroke. Data on drug use, comorbidity, and outcomes were collected from administrative registries. RESULTS: A total of 285,933 individuals were included. During median follow-up period of 6.7 years, 9550 developed AF, 9371 died of a cardiovascular cause, and 8980 had a stroke. Compared with the reference group (100-105 ms), individuals with very short (<=89 ms; hazard ratio [HR] 1.60, 95% confidence interval [CI] 1.41-1.81), intermediate (112-119 ms; HR 1.22, 95% CI 1.13-1.31), long (120-129 ms; HR 1.50, 95% CI 1.39 1.62), and very long P-wave duration (>=130 ms; HR 2.06, 95% CI 1.89-2.23) had an increased risk of incident AF. With respect to death from cardiovascular causes, we found an increased risk for very short (<=89 ms; HR 1.20, 95% CI 1.06-1.34), long (120-129 ms; HR 1.11, 95% CI 1.04-1.19), and very long P-wave duration (>=130 ms; HR 1.30, 95% CI 1.21-1.40) compared with the reference group (106-111 ms). Similar but weaker associations were found between P-wave duration and the risk of putative ischemic stroke. CONCLUSION: In a large primary care population we found both short and long P-wave duration to be robustly associated with an increased risk of AF. PMID- 25916568 TI - Late gadolinium enhancement of cardiac magnetic resonance imaging indicates abnormalities of time-domain T-wave alternans in hypertrophic cardiomyopathy with ventricular tachycardia. AB - BACKGROUND: The presence of myocardial scar detected by late gadolinium enhancement (LGE) on cardiac magnetic resonance (CMR) imaging has been described as a good independent predictor of mortality in patients with hypertrophic cardiomyopathy (HCM). Time-domain T-wave alternans (TWA) is also a potential predictor of cardiac mortality in patients with left ventricular dysfunction. OBJECTIVE: The purpose of this study was to elucidate the relationship between LGE distribution and TWA in patients with HCM. METHODS: CMR and TWA analyses using Holter monitoring were performed in 42 patients with HCM. The average transmural extent of LGE was scored as 1-4 in each segment, and the sum of the LGE scores (total LGE score) was calculated for each patient. The correlation between the maximal time-domain TWA voltage and LGE findings was analyzed, and the differences in time-domain TWA voltage, total LGE score, and cardiac function assessed by CMR imaging in the presence or absence of ventricular tachycardia (VT) were also compared. RESULTS: The total LGE score was significantly and positively correlated with the maximal time-domain TWA voltage (r = 0.59; P < .001). Furthermore, the total LGE score and maximal time-domain TWA voltage were significantly greater in patients who had episodes of VT (n = 21) than in those without VT (23 +/- 7 vs. 10 +/- 8; P < .001 and 87 +/- 26 MUV vs. 62 +/- 12 MUV; P < .001, respectively). However, the left ventricular ejection fraction did not statistically differ between patients with VT and those without VT (56% +/- 14% vs. 61% +/- 7%; P = .102). CONCLUSION: The magnitude of the localized LGE was significantly correlated with abnormalities in ventricular repolarization as assessed by TWA and QT dispersion. PMID- 25916569 TI - Utilization trends and clinical outcomes in patients implanted with a single- vs a dual-coil implantable cardioverter-defibrillator lead: Insights from the ALTITUDE Study. AB - BACKGROUND: Historically, the most commonly implanted implantable cardioverter defibrillator (ICD) lead is dual coil. Conventional wisdom holds that single-coil leads may be less effective than dual-coil leads, but easier to extract. No contemporary large-scale studies have evaluated the relative epidemiology of these 2 leads or compared their respective clinical outcomes. OBJECTIVE: We sought to evaluate trends in single- vs dual-coil ICD lead implantation and differences in clinical outcomes. METHODS: We evaluated 129,520 ICD recipients enrolled in the LATITUDE remote monitoring system between 2004 and 2014. Kaplan Meier analyses and Cox proportional hazards regression analyses were used for univariate and multivariate survival analysis, respectively. RESULTS: The majority of ICD recipients received a dual-coil lead (n = 110,330 [85.2%]). Single-coil lead implantation increased from 1.9% to 55.2% between 2004 and 2014. After adjusting for age, sex, device type, and year of implant, single-coil lead implantation was associated with a greater odds of induction for defibrillation testing (odds ratio 1.05; 95% confidence interval [CI] 1.01-1.09; P = .0274), a higher rate of lead being taken out of service (hazard ratio 1.19; 95% CI 1.06 1.33; P = .0032), and a decreased mortality rate (hazard ratio 0.91; 95% CI 0.87 0.96; P = .0004). In a 795 patient subset with adjudicated shock outcomes, first shock success was no different (87.0% in single coil vs 86.1% in dual coil; P = .8473). CONCLUSION: In a large real-world US population, single-coil lead implantation rates increased substantially between 2004 and 2014. Single-coil lead implantation was associated with more frequent defibrillation testing and the lead being taken out of service, but was not associated with increased mortality or more frequent defibrillation failure. PMID- 25916570 TI - Low incidence of complications after cephalic vein cutdown for pacemaker lead implantation in children weighing less than 10 kilograms: A single-center experience with long-term follow-up. AB - BACKGROUND: Only a few studies on the cephalic vein cutdown technique for pacemaker lead implantation in children weighing <=10 kg have been reported even though the procedure is widely accepted in adults. OBJECTIVE: The purpose of this study was to prove that cephalic vein cutdown for pacemaker lead implantation is a reliable technique with a low incidence of complications in children weighing <=10 kg. METHODS: The study included 44 children weighing <=10 kg with an endocardial pacemaker. Cephalic, subclavian, and axillary vein diameters were measured by ultrasound before implantation. The measured diameters were used to select either an endocardial or epicardial surgical technique. Regular 6-month follow-up visits included pacemaker interrogation and clinical and ultrasound examinations. RESULTS: Two dual-chamber and 42 single-chamber pacemakers were implanted. Mean weight at implantation was 6.24 kg (range 2.25-10.40 kg), and mean age was 11.4 months (range 1 day-47 months). In 40 children (90.1%), the ventricular leads were implanted using the cephalic vein cutdown technique, and implantation was accomplished via the prepared right external jugular vein in 4 of the children (9.9%). The atrial leads were implanted using axillary vein puncture and external jugular vein preparations. Mean follow-up was 8.9 years (range 0-20.9 years). Only 1 pacemaker-related complication was detected (a lead fracture near the connector that was successfully resolved using a lead repair kit). CONCLUSION: The cephalic vein cutdown technique is feasible and reliable in children weighing <=10 kg, which justifies the application of additional surgical effort in the treatment of these small patients. PMID- 25916571 TI - Formation of contiguous quaternary and tertiary stereocenters by sequential asymmetric conjugate addition of Grignard reagents to 2-substituted enones and Mg enolate trapping. AB - Herein a comprehensive study is provided on the asymmetric conjugate addition (ACA) of Grignard reagents to alpha-substituted cyclic enones. After the elucidation of the optimal experimental conditions, the scope of Grignard reagents and Michael acceptors was examined. Whereas secondary Grignards gave better enantioselectivities with 2-cyclopentenones, both linear and branched Grignard reagents were tolerated for the ACA to 2-methylcyclohexenone. The sequential ACA-enolate trapping, which leads to quaternary stereocenters, was then studied. Thus, many electrophiles have been tested, thereby giving rise to highly functionalized cyclic ketones with contiguous alpha-quaternary and beta tertiary centers. The present technique is believed to bring a new approach to versatile terpenoid-like skeletons of bioactive natural products. Straightforward derivatizations of enantioenriched saturated cyclic ketones further support the potential of the present methodology in synthesis. PMID- 25916572 TI - Equality and diversity in psycho-oncology: sociodemographic inequalities in psychosocial cancer care and outcomes. PMID- 25916575 TI - Fluoride in drinking water and diet: the causative factor of chronic kidney diseases in the North Central Province of Sri Lanka. AB - A significant number of people in the North Central Province of Sri Lanka suffer from chronic kidney diseases (CKD), and the author revisits existing literature related to CKD to find its causative factor. There is a direct connection between high fluoride levels in drinking water and kidney disease, and there are unhealthy levels of fluoride in the groundwater in Sri Lanka's CKD-affected areas. Based on the following observations, the author believes with confidence that excess fluoride in drinking water and in the locally grown food in the affected areas are the culprits of CKD in Sri Lanka. Fluoride excretion rate is considerably lower in children than adults, leading to renal damage of children living in areas with high fluoride. Adults who had renal damage due to fluoride in childhood are vulnerable to CKD with continued consumption of water from the same source. Patients with chronic renal insufficiency are at an increased risk of chronic fluoride toxicity. High content of fluoride in groundwater paves the way to excess fluoride in local food crops, consequently adding more fluoride to the systems of the consumers. People who work outdoors for prolonged periods consume excess water and tea, and are subjected to additional doses of fluoride in their system. In the mid-1980s, the increase in water table levels of the affected areas due to new irrigation projects paved the way to adding more fluorides to their system through drinking water and locally grown foods. PMID- 25916574 TI - An assessment of gene-by-gene interactions as a tool to unfold missing heritability in dyslexia. AB - Even if substantial heritability has been reported and candidate genes have been identified extensively, all known marker associations explain only a small proportion of the phenotypic variance of developmental dyslexia (DD) and related quantitative phenotypes. Gene-by-gene interaction (also known as "epistasis"--G * G) triggers a non-additive effect of genes at different loci and should be taken into account in explaining part of the missing heritability of this complex trait. We assessed potential G * G interactions among five DD candidate genes, i.e., DYX1C1, DCDC2, KIAA0319, ROBO1, and GRIN2B, upon DD-related neuropsychological phenotypes in 493 nuclear families with DD, by implementing two complementary regression-based approaches: (1) a general linear model equation whereby the trait is predicted by the main effect of the number of rare alleles of the two genes and by the effect of the interaction between them, and (2) a family-based association test to detect G * G interactions between two unlinked markers by splitting up the association effect into a between- and a within-family genetic orthogonal components. After applying 500,000 permutations and correcting for multiple testing, both methods show that G * G effects between markers within the DYX1C1, KIAA0319/TTRAP, and GRIN2B genes lower the memory letters composite z-score of on average 0.55 standard deviation. We provided initial evidence that the effects of familial transmission of synergistic interactions between genetic risk variants can be exploited in the study of the etiology of DD, explain part of its missing heritability, and assist in designing customized charts of individualized neurocognitive impairments in complex disorders, such as DD. PMID- 25916576 TI - A critical period for omega-3 nutritional supplementation in the development of the rodent visual system. AB - Retinocollicular connections form precise topographical maps that are normally completed through the selective elimination of misplaced axons and the stabilization of topographically ordered axon terminals during early development. Omega-3 fatty acids, acquired exclusively through the diet, and its main metabolite, docosahexaenoic acid (DHA), are involved in brain development and synaptic maturation. We have previously shown that the nutritional restriction of omega-3/DHA results in abnormal retinocollicular topographical fine-tuning. Therefore, we studied the role of omega-3 fatty acids nutritional supplementation and the developmental time windows during which this postnatal supplementation would restore normal topographical maps in the visual system. Female rats and their litters were chronically fed with either control (soy oil) or restricted omega-3 (coconut oil) diets. Fish oil supplementation was introduced between either postnatal day (PND) 7-13, PND7-28 or PND21-42. At PND13, PND28 or PND42, animals received an anterograde eye injection of a neuronal tracer to visualize retinocollicular axons. Confirming previous observations we found that an omega 3/DHA deficiency resulted in an abnormally high innervation density of retinal axons at the visual layers of the superior colliculus (SC). Although a short-term fish oil supplementation between PND7-13 could not restore normal retinocollicular topography, an extended treatment between PND7-28 completely recovered normal innervation densities of retinotectal axons. However, a late onset supplementation protocol, between PND28-42, was no longer effective in the restoration of the abnormal topographical pattern induced by an early omega-3 nutritional malnutrition. The results suggest a critical period for omega3/DHA dietary intake for the proper development of visual topographical maps. PMID- 25916578 TI - Neuronal tumour necrosis factor-alpha and interleukin-1beta expression in a porcine model of intracerebral haemorrhage: Modulation by U-74389G. AB - Tumour necrosis factor alpha (TNF-alpha) and interleukin 1beta (IL-1beta) are important mediators of intracerebral haemorrhage (ICH) inflammatory response. Lazaroids, established antioxidants and neuroprotectants, have been studied in several brain pathologies. The present study was designed to investigate: a) TNF alpha and IL-1beta changes, in neurons and b) U-74389G effects, 4 and 24h after haematoma induction in a porcine model of intracerebral haemorrhage. In twenty male landrace pigs (swines) aged 135-150 days old, autologous whole blood was injected around the right basal ganglia territory; in ten of the pigs the lazaroid compound U-74389G was administered. Brain TNF-alpha and IL-1beta immunopositive neurons were determined by immunoarray techniques at 4 and 24h timepoints. After the haematoma induction the number of TNF-alpha immunopositive neurons ipsilateral to the haematoma was significantly higher compared to the contralateral site at 4h (p<0.0005), while U-74389G significantly reduced the number of TNF-alpha immunopositive neurons, ipsilateral to the haematoma, at 4h (p=0.002); at 24h, TNF-alpha immunopositive neurons were found significantly lower in the control group ipsilateral to the haematoma in comparison to 4h timepoint(p<0.0005). The number of IL-1beta immunopositive neurons at 4h after the hematoma induction was significantly higher ipsilateral to the haematoma site (p<0.0005). U-74389G had no statistical significant effect. TNF-alpha and IL 1beta, increase in neurons, 4h after the haematoma induction, ipsilateral to the haematoma site. The administration of the antioxidant compound U-74389G, results in early (at 4h) decrease of TNF-alpha immunopositive neurons but shows no statistical significant effect to IL-1beta immunopossitive neurons. PMID- 25916579 TI - Nutrigenomic profiling of transcriptional processes affected in liver and distal intestine in response to a soybean meal-induced nutritional stress in Atlantic salmon (Salmo salar). AB - The aim of the present study was to generate an experimental model to characterize the nutrigenomic profile of a plant-derived nutritional stress. Atlantic salmon (Salmo salar) was used as the model species. The nutritional stress was induced by inclusion of dietary defatted soybean meal (SBM), as this ingredient had been previously demonstrated to induce enteropathy in the distal intestine and reduce growth in salmon. Triplicate groups of Atlantic salmon were fed concentrations of 0, 100, 200 and 300 g kg(-1) SBM for 12 weeks and reduced growth performance was used as the indicator of nutritional stress. The transcriptome was analyzed in two tissues, liver and distal intestine, with the hypothesis being that the liver transcriptome would be characterized by gene expression responses related to overall growth and health performance, whereas intestinal gene expression would be dominated by specific responses to SBM. A set of 133 genes was differentially expressed in liver including 44 genes in common with the intestinal response. The liver-specific response included up-regulation of genes involved in protein digestion, energy metabolism and immune functions, whereas genes in other metabolic pathways were generally anabolic and down regulated. These responses may be more related to general nutritional stress than to SBM per se. The transcriptomic profile in the distal intestine was consistent with the enteritis response as described previously. This study provides a comprehensive report on the profiles of liver and distal intestine transcriptomes, specifically highlighting the role of the liver in fish undergoing SBM-induced nutritional stress. PMID- 25916580 TI - Therapies for inherited skin fragility disorders. AB - Inherited skin fragility comprises disorders characterized by mechanical induced blistering and erosions within the skin and mucosal membranes as a consequence of mutations in genes encoding proteins involved in intra-epidermal or dermal epidermal adhesion. As the molecular pathology is largely known, it is a prototype group of disorders for which numerous experimental treatments have been developed. However, it became clear that single therapeutic strategies will not be able to address all molecular and clinical aspects. Significant progress has been achieved in gene, cell and protein therapies. Although the way towards clinical application seems obvious, major challenges must be addressed before these therapies become largely accessible. Until curative treatments will become available, alternative strategies which aim at increasing protein stability, amending apoptosis, inflammation and scarring may alleviate skin fragility and prevent or delay the onset of complications. PMID- 25916577 TI - Matrix metalloproteinases as therapeutic targets for stroke. AB - Matrix metalloproteinases (MMPs) are important in injury and recovery in ischemic injury. They are proteolytic enzymes that degrade all components of the extracellular matrix (ECM). They are secreted in a latent form, protecting the cell from damage, but once activated induce injury prior to rapid inactivation by four tissue inhibitors to metalloproteinases (TIMPs). Normally the constitutive enzymes, MMP-2 and membrane type MMP (MMP-14), are activated in a spatially specific manner and act close to the site of activation, while the inducible enzymes, MMP-3 and MMP-9, become active through the action of free radicals and other enzymes during neuroinflammation. Because of the complex nature of the interactions with tissues during development, injury and repair, the MMPs have multiple roles, participating in the injury process in the early stages and contributing to recovery during the later stages. This dual role complicates the planning of treatment strategies. This article is part of a Special Issue entitled SI: Cell Interactions In Stroke. PMID- 25916582 TI - Erratum to: Osteoconduction capacity of human deciduous and permanent teeth ash in a rat calvarial bone defect model. PMID- 25916584 TI - Evolutionary genetic bases of longevity and senescence. AB - Senescence, as a time-dependent developmental process, affects all organisms at every stage in their development and growth. During this process, genetic, epigenetic and environmental factors are known to introduce a wide range of variation for longevity among individuals. As an important life-history trait, longevity shows ontogenetic relationships with other complex traits, and hence may be viewed as a composite trait. Factors that influence the origin and maintenance of diversity of life are ultimately governed by Darwinian processes. Here we review evolutionary genetic mechanisms underlying longevity and senescence in humans from a life-history and genotype-epigenetic-phenotype (G-E P) map prospective. We suggest that synergistic and cascading effects of cis ruptive mechanisms in the genome, and epigenetic disruptive processes in relation to environmental factors may lead to sequential slippage in the G-E-P space. These mechanisms accompany age, stage and individual specific senescent processes, influenced by positive pleiotropy of certain genes, superior genome integrity, negative-frequency dependent selection and other factors that universally regulate rarity in nature. Finally we interpret life span as an inherent property of self-organizing systems that, accordingly, maintain species specific limits for the entire complex of fitness traits. We conclude that Darwinian approaches provide unique opportunities to discover the biological bases of longevity as well as devise individual specific medical or other interventions toward improving health span. PMID- 25916583 TI - Internalization of rituximab and the efficiency of B Cell depletion in rheumatoid arthritis and systemic lupus erythematosus. AB - OBJECTIVE: Rituximab, a type I anti-CD20 monoclonal antibody (mAb), induces incomplete B cell depletion in some patients with rheumatoid arthritis (RA) and systemic lupus erythematosus (SLE), thus contributing to a poor clinical response. The mechanisms of this resistance remain elusive. The purpose of this study was to determine whether type II mAb are more efficient than type I mAb at depleting B cells from RA and SLE patients, whether internalization influences the efficiency of depletion, and whether Fcgamma receptor type IIb (FcgammaRIIb) and the B cell receptor regulate this internalization process. METHODS: We used an in vitro whole blood B cell-depletion assay to assess the efficiency of depletion, flow cytometry to study cell surface protein expression, and surface fluorescence-quenching assays to assess rituximab internalization, in samples from patients with RA and patients with SLE. Paired t-test or Mann-Whitney U test was used to compare groups, and Spearman's rank correlation test was used to assess correlation. RESULTS: We found that type II mAb internalized significantly less rituximab than type I mAb and depleted B cells from patients with RA and SLE at least 2-fold more efficiently than type I mAb. Internalization of rituximab was highly variable between patients, was regulated by FcgammaRIIb, and inversely correlated with cytotoxicity in whole blood B cell-depletion assays. The lowest levels of internalization were seen in IgD- B cells, including postswitched (IgD CD27+) memory cells. Internalization of type I anti-CD20 mAb was also partially inhibited by anti-IgM stimulation. CONCLUSION: Variability in internalization of rituximab was observed and was correlated with impaired B cell depletion. Therefore, slower-internalizing type II mAb should be considered as alternative B cell-depleting agents for the treatment of RA and SLE. PMID- 25916585 TI - Candidate genes that affect aging through protein homeostasis. AB - Because aging is a multifactorial, pleiotropic process where many interacting mechanisms contribute to the organismal decline, the candidate gene approach rarely provides a clear message. This chapter discusses some of the inherent complexity, focusing on aspects that impinge upon protein homeostasis and maintain a healthy proteome. We discuss candidate genes that operate in these pathways, and compare their actions in invertebrates, mice and humans. We highlight several themes that emerge from recent research-the interconnections of pathways that regulate aging, the pleiotropic effects of mutations and other manipulations of the candidate proteins and the tissue specificity in these pleiotropic outcomes. This body of knowledge highlights the need for multiple specific readouts of manipulating longevity genes, beyond measuring lifespan, as well as the need to understand the integrated picture, beyond examining the immediate outputs of individual longevity pathways. PMID- 25916587 TI - A genetic view of the mitochondrial role in ageing: killing us softly. AB - In contrast to the nuclear genome, the mitochondrial DNA (mtDNA) is maternally inherited and resides in multiple cellular copies that may vary in sequence (heteroplasmy). Although the interaction between mtDNA and nuclear DNA-encoded factors (mito-nuclear interaction) is vital, the mtDNA accumulates mutations an order of magnitude faster than the nuclear genome both during evolution and during the lifetime of the individual, thus requiring tight mito-nuclear co evolution. These unique features drew the attention of many to suggest a role for the mitochondria in ageing. Although an excess of mtDNA mutations has been found in aged humans and animal models, most of these mutations had minor functional potential. Moreover, there are mtDNA mutations that recur in aged humans, but do not have any clear functionality. Nevertheless, accumulation of recurrent private mutations with minor functionality in the fast-ageing, mtDNA polymerase mutated mice (Pol-gamma), suggested that these very mtDNA alterations participate in ageing. This introduces a paradox: how would either single or recurrent mutations with negligible functionality play a role in a major chronic phenotype such as ageing?Here, we propose a hypothesis to partially resolve this paradox: accumulation of mitochondrial mutations with subtle functionality, which was overlooked by the mechanisms of selection, supplemented by slightly affected fusion-fission cycles, will hamper mitochondrial functional complementation within cells, disrupt mito-nuclear interactions and lead to ageing. Since certain mito-nuclear genotypes are less functionally compatible than others, and since the mtDNA and the nuclear genome segregate independently among generations, mild functionality of mutations will have differential effect on individuals in the population thus explaining the large variability in the ageing phenotype even within ethnic groups. We emphasize the role of recurrent mtDNA mutations with functional potential during evolution and during the lifetime of the individual. PMID- 25916586 TI - Autophagy and aging. AB - Autophagy is a critical quality control pathway that is conserved across diverse systems ranging from simple unicellular organisms like yeast to more complex systems, for instance mammals. Although, the fundamental role of autophagy is to maintain cellular quality control through lysosomal degradation of unwanted proteins and organelles, recent studies have mapped several new functions of this pathway that range from fuel utilization, cellular differentiation to protection against cell death. Given the importance of this pathway in maintaining cellular homeostasis, it has been considered that compromised autophagy could contribute to several of the commonly observed age-associated pathologies including neurodegeneration, reduction of muscle mass, cardiac malfunction, excessive lipid accumulation in tissues and glucose intolerance. The present chapter describes the two best-characterized autophagy pathways-macroautophagy and chaperone mediated autophagy, and discusses how changes in these pathways associate with age-associated disorders. Understanding how to maintain "clean cells" by activation of autophagy could be an attractive strategy to maintain healthspan in aged individuals. PMID- 25916588 TI - GWAS and Meta-Analysis in Aging/Longevity. AB - Longevity is an extremely complex phenotype that is determined by environment, life style and genetics. Genome wide association studies (GWAS) have been a powerful tool to identify the genetic origin of other complex outcome with a similar heritability. In this chapter we discuss the findings all GWAS of longevity conducted to date. Various cut-off to define longevity have been used varying from 85+, 90+ and 100+ years and the impact of these difference are addressed in this chapter. The only consistent association emerging from GWAS to data is the APOE gene that has been already identified as a candidate gene. Although (GWAS) have identified biologically plausible genes and pathways, no new loci for longevity have been conclusively proven. A reason for not finding any replicated associations for longevity could be the complexity of the phenotype, although heterogeneity also underlies many other traits for which GWAS has been successful. One may argue that rare variants explain the high heritability of longevity and the segregation of the trait in families. Yet, whole genome analyses of GWAS data still suggest that over 80 % of the heritability is explained by common variants. Although findings of GWAS to date have been disappointing, there is ample opportunity to improve the statistical power of studies to find common variants with small effects. In the near future, joining of the published studies and new ones emerging may bring to surface new loci. PMID- 25916589 TI - Exome and whole genome sequencing in aging and longevity. AB - Calendar age is the major risk factor for common disease. It is therefore expected that understanding the aging process will eventually lead to promotion of better health conditions in elderly populations. Such insight may be obtained by identifying the genetic determinants of familial and exceptional longevity and age-related disease. Research of these determinants has been performed in candidate gene, genome-wide association and linkage studies. Because exploration of the common variation in the genome did not explain much of the variation in the rate of aging and longevity, researchers in the field have only recently started to investigate the contribution of rare genetic variants to these traits. The increased throughput and decreased costs of next generation sequencing (NGS) have resulted in a great deal of novel applications for sequencing sets of candidate genes, whole exomes, and whole genomes of individuals. Most of the successful NGS applications are as yet those focused on genetic syndromes and cancers for which causal mutations are readily being identified. In this chapter, we discuss the genetic and phenomic aspects of human aging research and the use of NGS data to identify genes relevant for age-related diseases and lifespan regulation, and to investigate the accumulation of somatic genetic variation during the course of life. PMID- 25916590 TI - Models to explore genetics of human aging. AB - Genetic studies have bestowed insight into the biological mechanisms underlying inter-individual differences in susceptibility to (or resistance to) organisms' aging. Recent advances in molecular and genetic epidemiology provide tools to explore the genetic sources of the variability in biological aging in humans. To be successful, the genetic study of a complex condition such as aging requires the clear definition of essential traits that can characterize the aging process phenotypically. Phenotypes of human aging have long relied on mortality rate or exceptional longevity. Genome-wide association studies (GWAS) have been shown to present an unbiased approach to the identification of new candidate genes for human diseases. The GWAS approach can also be used for positive health phenotypes such as longevity or a delay in age-related chronic disease, as well as for other age related changes such as loss of telomere length or lens transparency. Sequencing, either in targeted regions or across the whole genome can further identify rare variation that may contribute to the biological aging mechanisms. To date, the results of the GWAS for longevity are rather disappointing, possibly in part due to the small number of individuals with GWAS data who have reached advanced old age.Human aging phenotypes are needed that can be assessed prior to death, and should be both heritable and validated as predictors of longevity. Potentially, phenotypes that focus on "successful" or "healthy" aging will be more powerful as they can be measured in large numbers of people and also are clinically relevant.We postulate that construction of an integrated phenotype of aging can be achieved capitalizing on multiple traits that may have weak correlations, but a shared underlying genetic architecture. This is based on a hypothesis that convergent results from multiple individual aging-related traits will point out the pleiotropic signals responsible for the overall rate of aging of the organism. An approach would be to investigate traits that are linked to the state of many vital functions, disability, and ultimately survival rates, to identify common biological pathways that govern aging processes in humans. New composite aging phenotypes must be validated by predicting all-cause mortality, major chronic disease and disability late in life. PMID- 25916591 TI - Systems biology of aging. AB - Human aging occurs at rates that vary widely between organisms and cell types. We hypothesize that in both cases, variation is due to differences in heat production, heat management and molecular susceptibility to heat-induced change. Metabolic rates have long been implored for their contributions to the aging process, with a negative correlation observed between basal metabolic rate and lifespan (Savage et al., Proc Natl Acad Sci U S A 104:4718-4723, 2007, Economos, Exp Gerontol 17:145-152, 1982, Keys et al., Metabolism 22:579-587, 1973, O'Connor et al., Comp Biochem Physiol Part A, Molr & Integr Physiol 133:835-842, 2002, Speakman, J Exp Biol 208:1717-1730, 2005, Poehlman, J Am Geriatrics Soc 41:552 559, 1993). Small amounts of heat are the well-known byproduct of metabolism and other biological processes, and despite their magnitude, are sufficient to elicit alterations in biomolecular characteristics (Somero, Ann Rev Physiol 57:43-68, 1995). Existing theories of aging suggest that damage occurs to the conformations or sequences of molecules, which only shifts focus onto the implied failure of repair mechanisms. Contrarily, heat-induced changes affect the behavioral characteristics of molecules and are thus able to persist "under the radar" of heat shock proteins and other canalizing mechanisms, which recognize only physical aberrancies (Rutherford and Lindquist, Nature 396:336-342, 1998, Siegal and Bergman, Proc Natl Acad Sci U S A 99:10528-10532, 2002, Waddington, Nature 150:563-565, 1942). According to our hypothesis, behavioral changes to the binding affinities, kinetics, motilities, and functionalities are dependent on minute energetic fields within and between molecules. Exposure to the thermal byproducts of metabolism cause heritable shifts in molecular interaction schemes and diminish the integrity of genetic and epigenetic networks. Restructured topologies alter the emergent properties of networks and are observed as the increased variation and decreased functionality associated with "aging" (Moorad and Promislow, Proc Royal Soc B Biol Sci 276:2271-2278, 2009, Soltow et al., Integr Comp Biol 50:844-854, 2010, Siegal et al.,Genetica 129:83-103, 2007, Promislow,Proc Biol sci/The Royal Soc 271:1225-1234, 2004, Southworth et al., PLoS Genet 5:e1000776, 2009, Rodwell et al.,PLoS Biol 2:e427, 2004). A major hurdle in the development of this hypothesis was overcome with the discovery of protein moonlighting: the phenomenon by which proteins assume drastically different functions independent of conformational change (Jeffery, Trends Biochem Sci 24:8-11, 1999). This molecular mechanism validates the hypothesis that network and behavioral changes can undergo somatic inheritance, and be accumulated by daughter cells over the course of a lifetime. Once a damage threshold has been surpassed, a system can no longer sustain life, and death results. PMID- 25916592 TI - Epigenetics of aging. AB - The aging phenotype is the result of a complex interaction between genetic, epigenetic and environmental factors, and it is among the most complex phenotypes studied to date. Evidence suggests that epigenetic factors, including DNA methylation, histone modifications and microRNA expression, may affect the aging process and may be one of the central mechanisms by which aging predisposes to many age-related diseases. The total number of altered methylation sites increases with increasing age, such that they could serve as a biomarker for chronological age. This chapter summarizes the mechanisms by which these epigenetic factors contribute to aging and how they may affect the complex physiology of aging, lifespan and age-associated diseases. PMID- 25916593 TI - Sparse conditional logistic regression for analyzing large-scale matched data from epidemiological studies: a simple algorithm. AB - This paper considers the problem of estimation and variable selection for large high-dimensional data (high number of predictors p and large sample size N, without excluding the possibility that N < p) resulting from an individually matched case-control study. We develop a simple algorithm for the adaptation of the Lasso and related methods to the conditional logistic regression model. Our proposal relies on the simplification of the calculations involved in the likelihood function. Then, the proposed algorithm iteratively solves reweighted Lasso problems using cyclical coordinate descent, computed along a regularization path. This method can handle large problems and deal with sparse features efficiently. We discuss benefits and drawbacks with respect to the existing available implementations. We also illustrate the interest and use of these techniques on a pharmacoepidemiological study of medication use and traffic safety. PMID- 25916594 TI - Functional MRI of the placenta--From rodents to humans. AB - The placenta performs a wide range of physiological functions; insufficiencies in these functions may result in a variety of severe prenatal and postnatal syndromes with long-term negative impacts on human adult health. Recent advances in magnetic resonance imaging (MRI) studies of placental function, in both animal models and humans, have contributed significantly to our understanding of placental structure, blood flow, oxygenation status, and metabolic profile, and have provided important insights into pregnancy complications. PMID- 25916595 TI - Environmental heat exposure and cognitive performance in older adults: a controlled trial. AB - Thermal stress has a negative effect on the cognitive performance of military personnel and industry workers exposed to extreme environments. However, no studies have investigated the effects of environmental thermal stress on the cognitive functions of older adults. We carried out a controlled trial with 68 healthy older adults (mean age 73.3 years, 69 % female), each of whom has been assessed twice on the same day with selected tests from the Cambridge Neuropsychological Test Automated Battery (CANTAB). Repeated sessions were conducted with air temperatures set at 24 degrees C and 32 degrees C in a balanced order. Our primary analyses did not show significant differences when comparing the cognitive performance of the total sample under the two experimental temperatures. However, interaction analysis has shown that humidity levels modify the effect of temperature on cognitive outcomes. The subgroup exposed to relative humidity greater than the median value (57.8 %) presented worse cognitive performance in the heat session when compared to the control session. Reported exercising frequency explained individual vulnerability to heat stress. Volunteers with lower levels of physical activity (<4 times per week) were more likely to present worsened cognitive performance under heat stress. In a fully adjusted linear regression model, the performance under heat stress remained associated with relative humidity (beta = -0.21; p = 0.007) and frequency of exercising (beta = 0.18; p = 0.020). Our results indicate that heat stress may have detrimental effects on the cognitive functioning of some subgroups of older adults and under particular circumstances. Further research is needed for exploring a variety of potentially influential factors. PMID- 25916596 TI - Gastroprotective potential of Buddleja scordioides Kunth Scrophulariaceae infusions; effects into the modulation of antioxidant enzymes and inflammation markers in an in vivo model. AB - ETHNOPHARMACOLOGICAL RELEVANCE: A common plant used to treat several gastric disorders is Buddleja scordioides Kunth, commonly known as salvilla. AIM OF THE STUDY: To detect inflammatory markers, in order to evaluate the gastroprotective potential of salvilla infusions, as this could have beneficial impact on the population exposed to gastric ulcers and colitis. MATERIALS AND METHODS: The present work attempted infusions were prepared with B. scordioides (1% w/w) lyophilized and stored. Total phenolic content and GC-MS analysis were performed. Wistar rats were divided into five groups (n=8), a negative vehicle control, an indomethacin group, and three experimental groups, named preventive, curative, and suppressive. All rats were sacrificed under deep ether anesthesia (6h) after the last oral administration of indomethacin/infusion. The rat stomachs were promptly excised, weighed, and chilled in ice-cold and 0.9% NaCl. Histological analysis, nitrites quantification and immunodetection assays were done. RESULTS: B. scordioides infusions markedly reduced the visible hemorrhagic lesions induced by indomethacin in rat stomachs, also showed down-regulation of COX2, IL-8 and TNFalpha and up-regulation of COX-1 with a moderate down-regulation of NFkB and lower amount of nitrites. However, this behavior was dependent on the treatment, showing most down-regulation of COX-2, TNFalpha and IL-8 in the curative treatment; more down-regulation of NF-kB in the preventive treatment; and more up regulation of COX-1 for the suppressor and preventive treatments. CONCLUSION: The anti-inflammatory potential of B. scordioides infusions could be related with the presence of polyphenols as quercetin in the infusion and how this one is consumed. PMID- 25916597 TI - Differentially expressed genes of LPS febrile symptom in rabbits and that treated with Bai-Hu-tang, a classical anti-febrile Chinese herb formula. AB - ETHNOPHARMACOLOGICAL RELEVANCE: Bai-Hu-Tang (BHT) has been traditionally used to clear heat and engender fluids. AIM OF THE STUDY: To reveal the alteration of differentially expressed genes (DEGs) between lipopolysaccharide (LPS) febrile syndrome in rabbits and treatment with BHT which is a classical anti-febrile formula in traditional Chinese medicine. MATERIALS AND METHODS: Febrile model was induced by LPS injection (i.v.) in rabbits, and BHT was gavaged to another group of febrile rabbits. After sacrifice of animals, total RNA of liver tissue was isolated, processed, and hybridized to rabbit cDNA microarrays obtained from Agilent Co. The data of DEGs were obtained by lazer scanning and analyzed with Cluster program 3.0. Then bioinformatic analysis of DEGs was conducted through gene ontology (GO) annotation and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathways. In addition, expression levels of four relative genes were detected by quantitative real time ployenzyme chain reaction (qRT-PCR) to validate the accuracy of microarrays. RESULT: The results demonstrated that genes expression pattern could be clustered into three groups significantly, and there were 606 up regulated genes and 859 down-regulated genes in the model group, and 106 up regulated genes and 429 down-regulated genes in BHT treated group. There were 286 DEGs existed as the common in two experimental groups. Enrichment analysis of GO annotations indicated that DEGs in model and BHT treated animals mainly referred catalytic activity and oxidoreductase activity for metabolic processes located in the membrane system at intracellular part, and binding activities increased significantly in treatment with BHT. Enrichment of KEGG analysis showed that the pathways of phagosome and protein processing in endoplasmic reticulum contained the most altered genes in the LPS group, but the percentage of phagosome pathway almost doubled in BHT group. Most DEGs involved in the LPS signal recognition system was up-regulated in LPS group, but partly decreased in BHT group. RT-PCR results of eight relative genes were consistent with the results of microarrays. CONCLUSION: DEGs of LPS febrile syndrome mainly involved oxidoreductase and catalytic activity of the metabolic processes, and pathways of processing protein for pyrotoxin recognition; BHT mostly regulated the DEGs in the phagosome pathway to clear LPS in the liver, and partly interfered with gene expression in LPS recognition system. The study provided an important pioneering result on gene expression profiling research, and will facilitate the clinical care or further studies of the formula. PMID- 25916598 TI - Supercharging by m-NBA Improves ETD-Based Quantification of Hydroxyl Radical Protein Footprinting. AB - Hydroxyl radical protein footprinting (HRPF) is an MS-based technique for analyzing protein structure based on measuring the oxidation of amino acid side chains by hydroxyl radicals diffusing in solution. Spatial resolution of HRPF is limited by the smallest portion of the protein for which oxidation amounts can be accurately quantitated. Previous work has shown electron transfer dissociation (ETD) to be the most reliable method for quantifying the amount of oxidation of each amino acid side chain in a mixture of peptide oxidation isomers, but efficient ETD requires high peptide charge states, which limits its applicability for HRPF. Supercharging reagents have been used to enhance peptide charge state for ETD analysis, but previous work has shown supercharging reagents to enhance charge state differently for different peptides sequences; it is currently unknown if different oxidation isomers will experience different charge enhancement effects. Here, we report the effect of m-nitrobenzyl alcohol (m-NBA) on the ETD-based quantification of peptide oxidation. The addition of m-NBA to both a defined mixture of synthetic isomeric oxidized peptides and Robo-1 protein subjected to HRPF increased the abundance of higher charge state ions, improving our ability to perform efficient ETD of the mixture. No differences in the reported quantitation by ETD were noted in the presence or absence of m-NBA, indicating that all oxidation isomers were charge-enhanced to a similar extent. These results indicate the utility of m-NBA for residue-level quantification of peptide oxidation in HRPF and other applications. PMID- 25916599 TI - Alternative surfactants for improved efficiency of in situ tryptic proteolysis of fingermarks. AB - Despite recent improvements to in situ proteolysis strategies, a higher efficiency is still needed to increase both the number of peptides detected and the associated ion intensity, leading to a complete and reliable set of biomarkers for diagnostic or prognostic purposes. In the study presented here, an extract of a systematic study is illustrated investigating a range of surfactants assisting trypsin proteolytic activity. Method development was trialled on fingermarks; this specimen results from a transfer of sweat from an individual's fingertip to a surface upon contact. As sweat carries a plethora of biomolecules, including peptides and proteins, fingermarks are, potentially, a very valuable specimen for non-invasive prognostic or diagnostic screening. A recent study has demonstrated the opportunity to quickly detect peptides and small proteins in fingermarks using Matrix Assisted Laser Desorption Ionization Mass Spectrometry Profiling (MALDI MSP). However, intact detection bears low sensitivity and does not allow species identification; therefore, a shotgun proteomic approach was employed involving in situ proteolysis. Data demonstrate that in fingermarks, further improvements to the existing method can be achieved using MEGA-8 as surfactant in higher percentages as well as combinations of different detergents. Also, for the first time, Rapigest SF, normally used in solution digestions, has been shown to successfully work also for in situ proteolysis. PMID- 25916600 TI - Precise Anatomic Localization of Accumulated Lipids in Mfp2 Deficient Murine Brains Through Automated Registration of SIMS Images to the Allen Brain Atlas. AB - Mass spectrometry imaging (MSI) is a powerful tool for the molecular characterization of specific tissue regions. Histochemical staining provides anatomic information complementary to MSI data. The combination of both modalities has been proven to be beneficial. However, direct comparison of histology based and mass spectrometry-based molecular images can become problematic because of potential tissue damages or changes caused by different sample preparation. Curated atlases such as the Allen Brain Atlas (ABA) offer a collection of highly detailed and standardized anatomic information. Direct comparison of MSI brain data to the ABA allows for conclusions to be drawn on precise anatomic localization of the molecular signal. Here we applied secondary ion mass spectrometry imaging at high spatial resolution to study brains of knock out mouse models with impaired peroxisomal beta-oxidation. Murine models were lacking D-multifunctional protein (MFP2), which is involved in degradation of very long chain fatty acids. SIMS imaging revealed deposits of fatty acids within distinct brain regions. Manual comparison of the MSI data with the histologic stains did not allow for an unequivocal anatomic identification of the fatty acids rich regions. We further employed an automated pipeline for co-registration of the SIMS data to the ABA. The registration enabled precise anatomic annotation of the brain structures with the revealed lipid deposits. The precise anatomic localization allowed for a deeper insight into the pathology of Mfp2 deficient mouse models. PMID- 25916601 TI - The effect of calcitriol on endoplasmic reticulum stress response. AB - Calcitriol, the active form of vitamin D, is known for its anticancer properties including induction of apoptosis, inhibition of angiogenesis, and metastasis. Calcitriol also increases intracellular calcium triggering apoptosis in a calpain dependent manner. Since the main storage unit for cellular calcium is endoplasmic reticulum (ER) and a decrease in ER calcium levels might induce ER stress associated cell death, we hypothesized that the cellular actions of calcitriol occur via ER stress. We have evaluated induction of ER stress by assessing BIP expression and XBP-1 splicing in breast cancer cell lines (MCF-7 and MDA-MB-231) and mammary epithelial cell line MCF10A. Our results suggest that cytotoxic concentrations of calcitriol induce an ER stress related response indicated as increased BIP levels and XBP-1 splicing not only in breast cancer cells but also in mammary epithelial cell line. However, vehicle treatment also induced a similar response de-emphasizing the importance of such effect. Calcitriol also failed to activate calpains, further weakening the idea of ER stress as the main mechanism for apoptotic effects of calcitriol. Taken together our results suggest an association between ER stress and vitamin D signaling. However present data indicates that ER stress by itself is not sufficient to explain anticancer properties of calcitriol. PMID- 25916602 TI - Characterizing HIV epidemiology in stable couples in Cambodia, the Dominican Republic, Haiti, and India. AB - Using a set of statistical methods and HIV mathematical models applied on nationally representative Demographic and Health Survey data, we characterized HIV serodiscordancy patterns and HIV transmission dynamics in stable couples (SCs) in four countries: Cambodia, the Dominican Republic, Haiti, and India. The majority of SCs affected by HIV were serodiscordant, and about a third of HIV infected persons had uninfected partners. Overall, nearly two-thirds of HIV infections occurred in individuals in SCs, but only about half of these infections were due to transmissions within serodiscordant couples. The majority of HIV incidence in the population occurred through extra-partner encounters in SCs. There is similarity in HIV epidemiology in SCs between these countries and countries in sub-Saharan Africa, despite the difference in scale of epidemics. It appears that HIV epidemiology in SCs may share similar patterns globally, possibly because it is a natural 'spillover' effect of HIV dynamics in high-risk populations. PMID- 25916603 TI - Colorectal carcinoma in the first decade of life: a systematic review. AB - PURPOSE: The aim of this study is to better understand the main aspects related to colorectal carcinoma diagnosed in the first 10 years of life, through a systematic review. METHODS: We carried out a bibliographic search in PubMed and LILACS, focusing on identifying publications or case reports about colorectal carcinoma in the first 10 years of life. The bibliographical analysis was made in two steps. During the first phase, we excluded those articles whose titles or abstracts did not correspond with the objective settled. Publications without abstract were also included in this phase. During the second phase, we look at the articles and evaluated their content, selecting the cases with colorectal cancer under 10 years old. RESULTS: From 3880 publications, 132 were selected in the first phase and 84 were evaluated in the second phase. Based on these conditions, 33 articles have cases presented which 4 articles were case reviews and 29 were case reports. Duplicated cases were excluded from the analysis. Fifty nine cases were described in English and Latin literature. There is an apparent similar proportion between the sexes, and the mean age was 8.6 years old. The main localization was the rectum and sigmoid (45.8 %). Pathologic findings showed that 86.4 % were adenocarcinoma. These tumors are frequently advanced at diagnosis. The Kaplan-Meier 60-month overall survival was 15.3 %. Dukes classification represents a factor related to survival (p = 0.03). CONCLUSIONS: In children, colorectal carcinoma presents distinctive characteristics, which determines poor survival. PMID- 25916604 TI - The risk of irritable bowel syndrome in patients with endometriosis during a 5 year follow-up: a nationwide population-based cohort study. AB - PURPOSE: Studies have suggested that endometriosis may coexist with irritable bowel syndrome (IBS). Using a population-based cohort study, we followed subjects for a 5-year period to identify the risk of IBS after a diagnosis of endometriosis. METHODS: This cohort study used the Taiwan National Health Insurance Database as a source of subjects. A total of 6076 patients with endometriosis from 2000 to 2005 were identified. Their data were compared with those of 30,380 age-matched controls without endometriosis who were randomly selected from the same database. All subjects were tracked for 5 years from the date of cohort entry to identify the risk of IBS. The Cox model was used to evaluate the 5-year event occurrence of IBS. RESULTS: Nine hundred twenty-six patients were diagnosed with IBS, including 256 in the case cohort (4.2%) and 670 in the control cohort (2.2%). The Kaplan-Meier survival curves demonstrated significantly lower event-free rates in the case cohort than in the control cohort (P = 0.001). After adjusting for urbanization level, monthly income, residential region and comorbidities, the hazard ratio (HR) within 5 years revealed a 1.79-fold (95% confidence interval [CI] 1.55-2.07) greater risk among the cases than the controls. The HR was higher within the first year of follow-up (HR 1.90, 95% CI 1.42-2.55) and in those women aged 25-34 years (HR 2.17, 95% CI 1.61-2.92). CONCLUSIONS: The risk of IBS among endometriosis patients persisted over 5 years of follow-up. The association detected in this study might have proceeded through shared risk and pathogenic factors. PMID- 25916605 TI - Mesenchymal stem cells and platelet-rich plasma in the treatment of patients with perineal Crohn's disease. PMID- 25916606 TI - Epidural analgesia associated with better survival in colon cancer. AB - PURPOSE: Surgery remains the mainstay of treatment for potentially curable colon cancer. Otherwise, the surgical stress response might increase the likelihood of cancer dissemination during and after cancer surgery. There is growing evidence that the type of anaesthesia during cancer surgery plays a role in the metastatic process. Therefore, we assessed if the method of anaesthesia is associated with long-term survival after colon cancer surgery. METHOD: A retrospective single centre study was conducted including 588 patients who underwent colorectal cancer surgery, TNM stage I-IV, in the Jeroen Bosch Hospital between 1995 and 2003. The Cox proportional hazard model was used for statistical analysis. Adjustments were made for age, sex, comorbidity, TNM stage, chemotherapy, emergency surgery status and year of incidence. RESULTS: Of the 588 primary colon cancer patients with a median age of 70 years, 399 (68 %) patients underwent colon surgery with epidural anaesthesia, whilst 189 (32 %) patients were operated without epidural anaesthesia. Five-year survival for patients not receiving epidural analgesia was 42 % versus 51 % for patients receiving epidural analgesia (p = 0.03). This effect remained after adjustment for relevant patient, tumour, and treatment characteristics (hazard ratio (HR) 1.30 (95 % confidence interval (CI) 1.05 1.59), p = 0.01). Subgroup analysis in patients of 80 years and older (n = 100) showed also a better overall survival after receiving epidural analgesia (HR 1.74 (95 % CI 1.11-2.72), p = 0.01). CONCLUSION: Epidural analgesia during colon cancer surgery was associated with a better overall survival. Prospective trials evaluating the effects of locoregional analgesia on colon cancer recurrence are warranted. PMID- 25916607 TI - Child's objection to non-beneficial research: capacity and distress based models. AB - A child's objection, refusal and dissent regarding participation in non beneficial biomedical research must be respected, even when the parents or legal representatives have given their permission. There is, however, no consensus on the definition and criteria of a meaningful and valid child's objection. The aim of this article is to clarify this issue. In the first part we describe the problems of a child's assent in research. In the second part we distinguish and analyze two models of a child's objection to research: the capacity-based model and the distress-based model. In the last part we present arguments for a broader and unified understanding of a child's objection within regulations and practices. This will strengthen children's rights and facilitate the entire process of assessment of research protocols. PMID- 25916609 TI - Analysis of complete genome sequences and a V239A substitution in the helicase domain of swine hepatitis E virus strains isolated in Canada. AB - Among Canadian swine HEV strains, only one complete genome sequence has been published so far, and there are no data on the virulence of these strains. A collection of 28 Canadian swine HEV strains was used in this study. After RNA extraction, a portion of ORF2, the 3' end of the helicase domain, and two complete genomes were amplified and sequenced. These two new Canadian complete genomes belonged to two different subtypes and showed 87.5 and 87.7% sequence identity to the Canadian swine HEV strain Arkell. The V239A substitution within the helicase domain, which is associated with increased virulence of genotype 3 HEV, was detected in one Canadian swine HEV strain. However, no human hepatitis E infections have been associated with this strain. PMID- 25916610 TI - Course and transmission characteristics of oral low-dose infection of domestic pigs and European wild boar with a Caucasian African swine fever virus isolate. AB - In 2007, African swine fever virus (ASFV) was introduced into the Transcaucasian countries and Russia. Since then, it has spread alarmingly and reached the European Union. ASFV strains are highly virulent and lead to almost 100% mortality under experimental conditions. However, the possibility of dose dependent disease courses has been discussed. For this reason, a study was undertaken to assess the risk of chronic disease and the establishment of carriers upon low-dose oronasal infection of domestic pigs and European wild boar. It was demonstrated that very low doses of ASFV are sufficient to infect especially weak or runted animals by the oronasal route. Some of these animals did not show clinical signs indicative of ASF, and they developed almost no fever. However, no changes were observed in individual animal regarding the onset, course and outcome of infection as assessed by diagnostic tests. After amplification of ASFV by these animals, pen- and stablemates became infected and developed acute lethal disease with similar characteristics in all animals. Thus, we found no indication of prolonged or chronic individual courses upon low-dose infection in either species. The scattered onset of clinical signs and pathogen detection within and among groups confirms moderate contagiosity that is strongly linked with blood contact. In conclusion, the prolonged course at the "herd level" together with the exceptionally low dose that proved to be sufficient to infect a runted wild boar could be important for disease dynamics in wild-boar populations and in backyard settings. PMID- 25916611 TI - Full genome sequence of a putative novel mitovirus isolated from Rhizoctonia cerealis. AB - A putative novel mitovirus was found in isolate R1084 of the fungus Rhizoctonia cerealis, the causal agent of sharp eyespot of wheat in China. The full genome sequence of the virus was determined and analyzed. The complete cDNA sequence is 3149 nucleotides long with 59.7% A+T content. Using either the fungal mitochondrial or universal genetic code, the viral genome was found to contain a single large open reading frame that is predicted to encode a protein of 812 amino acids with an RNA-dependent RNA polymerase (RdRp) domain that is conserved in the mitovirus RdRp superfamily. The amino acid sequence of the RdRp domain is only 50% identical to the corresponding domain in Sclerotinia sclerotiorum mitovirus 11, and therefore, this virus is proposed to be a novel mitovirus, designated as Rhizoctonia cerealis mitovirus 1-R1084 (RcMV1-R1084). The distinct codon usage of RcMV1-R1084 hints that this virus is potentially able to replicate not only in mitochondria but also in the cytoplasm. This is the first report of a full-length genomic sequence of a putative mitovirus in R. cerealis. PMID- 25916612 TI - Complete genome sequence of a porcine astrovirus from South Korea. AB - Porcine astrovirus (PAstV) is broadly distributed in pigs in several countries worldwide. PAstVs belong to the genus Mamastrovirus and are divided into five genetically divergent types. This study presents a molecular characterization of PAstV identified in diarrheic piglets in South Korea. The complete genome of the Korean PAstV strain KOR/KNU14-07/2014 was sequenced and analyzed to characterize PAstV circulating in South Korea. The full-length genomic sequence of KNU14-07 was determined to be 6,337 nucleotides in length and consisted of three major open reading frames (5'-ORF1a-ORF1b-ORF2-3'). The overall degree of nucleotide sequence identity was 40.8 to 72.5% between KUN14-07 and other reported PAstVs, indicating high heterogeneity among PAstVs. Genetic and phylogenetic analyses showed that the KNU14-07 strain was most closely related to the PAstV2 lineage, which is the second most common type in South Korea. PMID- 25916613 TI - Is routine single-incision laparoscopic cholecystectomy feasible? A retrospective observational study. AB - BACKGROUND: Single-incision laparoscopic cholecystectomy (SILC) has been shown to be safe for uncomplicated gallbladder diseases. Routinely applying SILC is debatable. METHODS: Two hundred SILCs were performed with single-incision multiple-port longitudinal-array and self-camera techniques. RESULTS: Eighty eight (44%) procedures were scheduled for complicated diseases. The routine group had a higher comorbidity rate, a lower preoperative endoscopic retrograde cholangiopancreatography rate, a higher intraoperative cholangiography rate, a higher proportion of complicated gallbladder diseases, shorter operative time, more intraoperative blood loss, and lower postoperative pethidine dose than the selective group (the first 73 patients). The conversion and complication rates showed no statistical difference. It took fewer cases but longer time to pass the learning phase of SILC for complicated gallbladder diseases. The multivariate analysis showed that male sex and complicated gallbladder diseases were associated with a higher procedure conversion rate, and increased patient age was related to a higher complication rate. CONCLUSIONS: Routine SILC for benign gallbladder diseases is feasible in the experienced phase. Practicing SILC for uncomplicated gallbladder diseases helps to achieve competence in this technique for complicated diseases. PMID- 25916614 TI - Increasing body mass index portends abbreviated survival following pancreatoduodenectomy for pancreatic adenocarcinoma. AB - BACKGROUND: Body mass index (BMI), a common surrogate marker for grading obesity, does not differentiate between metabolically active visceral fat and the relatively inert subcutaneous fat. We aim to determine the utility of BMI as a prognostic marker for the impact of obesity on outcomes and survival following pancreatoduodenectomy for pancreatic adenocarcinoma. METHODS: From a database of over 1,000 patients who had undergone pancreatoduodenectomy, 228 patients with a diagnosis of pancreatic adenocarcinoma were identified. Demographic data including BMI and perioperative parameters-operative time, estimated blood loss, length of stay, survival, nodal status, and American Joint Committee on Cancer stage-were obtained. Data are presented as median. RESULTS: One hundred ninety two patients had a BMI less than or equal to 29 and 36 patients had a BMI greater than or equal to 30 (24 vs. 34, P < .001). Median age was 70 and the majority of the patients (52%) were male and the 2 groups of patients did not differ in this regard. A significantly greater number of obese patients had positive nodes (69% vs. 62%, P < .05) and this was associated with a worse survival (14 vs. 18 months, P < .05). CONCLUSIONS: For patients with pancreatic adenocarcinoma undergoing pancreatoduodenectomy, obesity does not impact operative complexity or length of stay but results in a shortened survival. Therefore, we conclude that BMI is an important prognostic marker that portends an abbreviated survival following pancreatoduodenectomy for pancreatic adenocarcinoma. PMID- 25916615 TI - Phase-change lines, scale breaks, and trend lines using Excel 2013. AB - The development of graphing skills for behavior analysts is an ongoing process. Specialized graphing software is often expensive, is not widely disseminated, and may require specific training. Dixon et al. (2009) provided an updated task analysis for graph making in the widely used platform Excel 2007. Vanselow and Bourret (2012) provided online tutorials that outline some alternate methods also using Office 2007. This article serves as an update to those task analyses and includes some alternative and underutilized methods in Excel 2013. To examine the utility of our recommendations, 12 psychology graduate students were presented with the task analyses, and the experimenters evaluated their performance and noted feedback. The task analyses were rated favorably. PMID- 25916616 TI - Comparison of ADC values in different malignancies of the skeletal musculature: a multicentric analysis. AB - OBJECTIVE: Diffusion-weighted imaging (DWI) provides essential information regarding tumor composition, such as cellularity and/or perfusion. DWI is helpful in distinguishing between malignant and benign lesions. Malignant intramuscular/soft tissue lesions consist of a wide spectrum of tumors that have different cell counts and matrix. It is presumed that these different tumors have different DWI findings and have different apparent diffusion coefficient (ADC) values. The aim of this study was to analyze DWI findings of different intramuscular malignancies in a multicentric study by using a standardized DWI protocol, and to compare the ADC values acquired. MATERIALS AND METHODS: The data banks of four radiology departments were screened retrospectively for malignant intramuscular tumors. Only lesions that were investigated by MRI (with a 1.5-T scanner) using DWI (multishot EPI sequence with b values of 0 and 1,000 s/mm(2)) were included in the study. Overall, 51 patients (28 women, 23 men; mean age 58.8 +/- 16.1 years) with 57 different malignant intramuscular lesions were collected. In every case apparent diffusion constant (ADC) maps were calculated. In 14 patients muscle lymphoma, 11 patients intramuscular metastases from different primary tumors, and in 26 cases several muscle sarcomas were identified. RESULTS: The mean ADC value of the estimated lesions was 1.24 +/- 0.53 * 10(-3) mm(2)s( 1), median value, 1.11 * 10(-3) mm(2)s(-1), range, 0.54-2.9 * 10(-3) mm(2)s(-1). The mean ADC value in muscle metastases was 1.28 +/- 0.24 * 10(-3) mm(2)s(-1), in muscle lymphoma 0.76 +/- 0.14 * 10(-3) mm(2)s(-1), and in muscle sarcomas 1.82 +/ 0.63 * 10(-3) mm(2)s(-1). Muscle lymphoma showed statistically significant lower ADC values in comparison to muscle metastases (p = 0.01) and muscle sarcoma (p = 0.001). There was no significant differences between ADC values in muscle metastases and sarcomas (p = 0.48). ADC values in muscle lymphoma were homogeneous with less inter-patient variability and were within a relatively close range. Muscle sarcomas had a broad range of ADC values. CONCLUSION: Intramuscular malignant lesions had different ADC values on DWI. 22.8% of the tumors analyzed had low ADC values, 26.3% moderate, and 50.9% high ADC values. Muscle lymphoma had statistically significantly lower ADC values in comparison to muscle metastases and sarcomas. Muscle sarcomas presented with a broad range of ADC values. PMID- 25916617 TI - Quantification of proteins by flow cytometry: Quantification of human hepatic transporter P-gp and OATP1B1 using flow cytometry and mass spectrometry. AB - Flow cytometry is a powerful tool for the quantitation of fluorescence and is proven to be able to correlate the fluorescence intensity to the number of protein on cells surface. Mass spectroscopy can also be used to determine the number of proteins per cell. Here we have developed two methods, using flow cytometry and mass spectroscopy to quantify number of transporters in human cells. These two approaches were then used to analyse the same samples so that a direct comparison could be made. Transporters have a major impact on the behaviour of a diverse number of drugs in human systems. While active uptake studies by transmembrane protein transporters using model substrates are routinely undertaken in human cell lines and hepatocytes as part of drug discovery and development, the interpretation of these results is currently limited by the inability to quantify the number of transporters present in the test samples. Here we provide a flow cytometric method for accurate quantification of transporter levels both on the cell surface and within the cell, and compare this to a quantitative mass spectrometric approach. Two transporters were selected for the study: OATP1B1 (also known as SLCO1B1, LST-1, OATP-C, OATP2) due to its important role in hepatic drug uptake and elimination; P-gp (also known as P-glycoprotein, MDR1, ABCB1) as a well characterised system and due to its potential impact on oral bioavailability, biliary and renal clearance, and brain penetration of drugs that are substrates for this transporter. In all cases the mass spectrometric method gave higher levels than the flow cytometry method. However, the two methods showed very similar trends in the relative ratios of both transporters in the hepatocyte samples investigated. The P-gp antibody allowed quantitative discrimination between externally facing transporters located in the cytoplasmic membrane and the total number of transporters on and in the cell. The proportion of externally facing transporter varied considerably in the four hepatocyte samples analysed, ranging from only 6% to 35% of intact and viable cells. The sample with only 6% externally facing transporter was further analysed by confocal microscopy which qualitatively confirmed the low level of transporter in the membrane and the large internal population. Here we prove that flow cytometry is an important tool for future protein analysis as it can not only quantify the number of proteins that a cell express but also identify the number of proteins on the surface and it is easy to apply for routine assays. PMID- 25916618 TI - Integrated systems for exosome investigation. AB - Extracellular vesicles, including exosomes, are currently being investigated to better understand their biogenesis and biological functions. There is also a rapidly growing interest in utilizing exosomes present in patient biofluids for molecular diagnostics in the clinic. Exosomes are natural shuttles of RNA and protein cargo, making them attractive as potential therapeutic delivery vehicles. Here, we describe the methods for using the latest tools and technologies to study exosomes to better understand their roles in cell-to-cell communication, for discovery of clinical biomarkers and to engineer exosomes for therapeutic applications. PMID- 25916619 TI - Correlative light and electron microscopy enables viral replication studies at the ultrastructural level. AB - Electron microscopy (EM) is a powerful tool to study structural changes within cells caused e.g. by ectopic protein expression, gene silencing or virus infection. Correlative light and electron microscopy (CLEM) has proven to be useful in cases when it is problematic to identify a particular cell among a majority of unaffected cells at the EM level. In this technique the cells of interest are first identified by fluorescence microscopy and then further processed for EM. CLEM has become crucial when studying positive-strand RNA virus replication, as it takes place in nanoscale replication sites on specific cellular membranes. Here we have employed CLEM for Semliki Forest virus (SFV) replication studies both by transfecting viral replication components to cells or by infecting different cell types. For the transfection-based system, we developed an RNA template that can be detected in the cells even in the absence of replication and thus allows exploration of lethal mutations in viral proteins. In infected mammalian and mosquito cells, we were able to find replication positive cells by using a fluorescently labeled viral protein even in the cases of low infection efficiency. The fluorescent region within these cells was shown to correspond to an area rich in modified membranes. These results show that CLEM is a valuable technique for studying virus replication and membrane modifications at the ultrastructural level. PMID- 25916620 TI - Detecting monoclonal immunoglobulins in human serum using mass spectrometry. AB - Established guidelines from the International Myeloma Working Group recommend diagnostic screening for patients suspected of plasma cell proliferative disease using protein electrophoresis (PEL), free light chain measurements and immunofixation electrophoresis (IFE) of serum and urine in certain cases. Plasma cell proliferative disorders are generally classified as monoclonal gammopathies given most are associated with the excess secretion of a monoclonal immunoglobulin or M-protein. In clinical practice, the M-protein is detected in a patients' serum by the appearance of a distinct protein band migrating within regions typically occupied by immunoglobulins. Given each M-protein is comprised by a sequence of amino acids pre-defined by somatic recombination unique to each clonal plasma cell, the molecular mass of the M-protein can act as a surrogate marker. We established a mass spectrometry based method to assign molecular mass to the immunoglobulin light chain of the M-protein and used this to detect the presence of M-proteins. Our method first enriches serum for immunoglobulins, followed by reduction to separate light chains from heavy chains, followed by microflow LC-ESI-Q-TOF MS. The multiply charged light chain ions are converted to their molecular mass and reconstructed peak area calculations are used for quantification. Using this method, we term "monoclonal immunoglobulin Rapid Accurate Molecular Mass" or miRAMM, the presence of M-proteins can be reliably detected with superior sensitivity compared to current gel-based PEL and IFE techniques. PMID- 25916621 TI - Organic Light-Emitting Diodes Using a Neutral pi Radical as Emitter: The Emission from a Doublet. AB - Triplet harvesting is a main challenge in organic light-emitting devices (OLEDs), because the radiative decay of the triplet is spin-forbidden. Here, we propose a new kind of OLED, in which an organic open-shell molecule, (4-N-carbazolyl-2,6 dichlorophenyl)bis(2,4,6-trichlorophenyl)methyl (TTM-1Cz) radical, is used as an emitter, to circumvent the transition problem of triplet. For TTM-1Cz, there is only one unpaired electron in the highest singly occupied molecular orbital (SOMO). When this electron is excited to the lowest singly unoccupied molecular orbital (SUMO), the SOMO is empty. Thus, transition back of the excited electron to the SOMO is totally spin-allowed. Spectral analysis showed that electroluminescence of the OLED originated from the electron transition between SUMO and SOMO. The magneto-electroluminescence measurements revealed that the spin configuration of the excited state of TTM-1Cz is a doublet. Our results pave a new way to obtain 100% internal quantum efficiency of OLEDs. PMID- 25916622 TI - Interconnected Co-Entrapped, N-Doped Carbon Nanotube Film as Active Hydrogen Evolution Cathode over the Whole pH Range. AB - The use of electrocatalysts with low metal content (metal-deficient) or metal free for the hydrogen evolution reaction (HER) can prevent or decrease metal ion release, which reduces environmental impact; development of such catalysts with high activity and durability over the whole pH range is thus highly desired but still remains a huge challenge. Herein, we describe the direct growth of a film consisting of interconnected Co-entrapped, N-doped carbon nanotubes on carbon cloth using chemical vapor deposition from dicyanodiamine using a Co3 O4 nanowire array as catalyst. This integrated architecture is used as a flexible 3D electrode for the electrolytic hydrogen evolution with outstanding catalytic activity and durability in acidic media. Moreover, this electrode is also highly efficient under neutral and basic conditions. It offers us an attractive carbon based metal-deficient HER catalyst outperforming most transition-metal and all metal-free/deficient catalysts. PMID- 25916623 TI - The role of appeals to tradition in origin food marketing. A survey among Polish consumers. AB - The frequency of the use of tradition in marketing is growing. Appealing to tradition reflects the need to have reference points, trust and stability. The perceived authenticity of a product is strongly connected with its origin, which is expressed by the factors of time (history), place (area), socialisation (local community) and naturalness (raw materials). The paper aims to examine consumer attitudes, preferences and behaviours regarding origin food in Poland. We carried out a survey in a representative sample of 1000 Polish consumers. According to our respondents, the characteristics differentiating origin food from conventional food include links with tradition as well as sensory and health properties. Referring to the typology proposed by van der Meulen, traditionality and territoriality are the most important characteristics of origin food. The perceived authenticity of origin products depends to the largest extent on such factors as: natural taste, product quality, sale in the region of origin and labelling. The most important determinants of origin food selection include: traditional recipe, taste, and product uniqueness. PMID- 25916624 TI - Consumer clusters in Denmark based on coarse vegetable intake frequency, explained by hedonics, socio-demographic, health and food lifestyle factors. A cross-sectional national survey. AB - Vegetable intake seems to play a protective role against major lifestyle diseases. Despite this, the Danish population usually eats far less than the recommended daily intake. The present study focused on the intake of 17 coarse vegetables and the potential barriers limiting their intake. The present study drew upon a large Danish survey (n = 1079) to study the intake of coarse vegetables among Danish consumers. Four population clusters were identified based on their intake of 17 different coarse vegetables, and profiled according to hedonics, socio-demographic, health, and food lifestyle factors. The four clusters were characterized by a very low intake frequency of coarse vegetables ('low frequency'), a low intake frequency of coarse vegetables; but high intake frequency of carrots ('carrot eaters'), a moderate coarse vegetable intake frequency and high intake frequency of beetroot ('beetroot eaters'), and a high intake frequency of all coarse vegetables ('high frequency'). There was a relationship between reported liking and reported intake frequency for all tested vegetables. Preference for foods with a sweet, salty or bitter taste, in general, was also identified to be decisive for the reported vegetable intake, as these differed across the clusters. Each cluster had distinct socio-demographic, health and food lifestyle profiles. 'Low frequency' was characterized by uninvolved consumers with lack of interest in food, 'carrot eaters' vegetable intake was driven by health aspects, 'beetroot eaters' were characterized as traditional food consumers, and 'high frequency' were individuals with a strong food engagement and high vegetable liking. 'Low frequency' identified more barriers than other consumer clusters and specifically regarded low availability of pre cut/prepared coarse vegetables on the market as a barrier. Across all clusters a low culinary knowledge was identified as the main barrier. PMID- 25916625 TI - Cohabitational effect of grandparents on dietary intake among young Japanese women and their mothers living together. A multicenter cross-sectional study. AB - We examined the cohabitational effect of the grandparents on dietary intakes among young Japanese women and their mothers, using data from a cross-sectional multicenter study conducted in 35 of 47 prefectures in Japan. Among a total of 2032 three-generation families, 1336 female dietetic students (18-20 years), 1336 of their mothers (36-59 years), and 1560 of their paternal or maternal grandmothers (59-94 years) were included. Intake of foods and nutrients was assessed with self-administered diet history questionnaires. The prevalence of students and their mothers living with the grandparents (GP) was 36%. Students living with GP had a higher intake of fruits, vegetables, total dietary fiber, beta-carotene, vitamin C and potassium and lower intake of meats than those living without GP. For mothers, fish and shellfish and vitamin C intakes were higher and meat intake was lower among participants living with GP. The median correlation coefficients of food and nutrient intakes in the students grandmothers living together was higher than in those living apart for both paternal grandmothers (PGM) and maternal grandmothers (MGM) (all P <0.01). The median values of mothers-PGM living together were also significantly higher than in those living apart (P <0.01). However, the values of mothers-MGM did not significantly differ between those living with and without MGM. These results may suggest that family members who live together tend to share similar dietary habits. Further, the mother's dietary habits might affect those of their children even after they live apart. PMID- 25916626 TI - Overexpression of IGF2 mRNA-Binding Protein 2 (IMP2/p62) as a Feature of Basal like Breast Cancer Correlates with Short Survival. PMID- 25916627 TI - Patient Complaints and Adverse Surgical Outcomes. AB - One factor that affects surgical team performance is unprofessional behavior exhibited by the surgeon, which may be observed by patients and families and reported to health care organizations in the form of spontaneous complaints. The objective of this study was to assess the relationship between patient complaints and adverse surgical outcomes. A retrospective cohort study used American College of Surgeons National Surgical Quality Improvement Program data from an academic medical center and included 10 536 patients with surgical procedures performed by 66 general and vascular surgeons. The number of complaints for a surgeon was correlated with surgical occurrences (P < .01). Surgeons with more patient complaints had a greater rate of surgical occurrences if the surgeon's aggregate preoperative risk was higher (beta = .25, P < .05), whereas there was no statistically significant relationship between patient complaints and surgical occurrences for surgeons with lower aggregate perioperative risk (beta = -.20, P = .77). PMID- 25916628 TI - Multimodality imaging in preoperative assessment of left atrial appendage transcatheter occlusion with the Amplatzer Cardiac Plug. AB - AIMS: Percutaneous left atrial appendage occlusion (LAAO) with the Amplatzer Cardiac Plug (ACP) emerged as a valid alternative in patients with a formal contraindication to oral anticoagulant therapy. Transoesophageal echocardiography (TEE), cardiac computed tomography angiography (CCTA), intracardiac echocardiography (ICE), and conventional cardiac angiography (CCA) are used to evaluate LAA diameters. The aim of our study was to compare pre- and intraprocedural imaging techniques in determining the correct selection of the device size, with a retrospective evaluation of the results obtained at post procedural CCTA follow-up. METHODS AND RESULTS: Between September 2009 and July 2013, 66 consecutive patients underwent to LAAO with the ACP at our institution. Preoperative LAA evaluation was realized with TEE, CCTA, ICE, and CCA. Fifty eight (58) patients underwent to post-procedural CCTA to confirm the LAA complete exclusion, the number and extent of the residual leaks, and the positioning of the device. LAA diameters measured by CCTA correlate with the diameters obtained with CCA and ICE, but they are sized slightly larger than the others. TEE has a lower correlation with every other imaging method and a likely tendency to underestimate. The distribution of the leaks and the positioning of the device in post-procedural CCTA show no substantial differences between the devices used greater or equal to the one selected with CCTA in terms of LAA exclusion. CONCLUSION: The sizing of the device decided using CCTA in the phase of maximum LAA expansion reduces the risk of high-flow leaks and device malposition due to undersizing. PMID- 25916630 TI - Environmental NMR. PMID- 25916629 TI - Lessons Learned in the Surgical Treatment of Neurogenic Thoracic Outlet Syndrome Over 10 Years. AB - OBJECTIVE: To evaluate our extensive experience over a decade in the treatment of patients with neurogenic thoracic outlet syndrome (NTOS) who underwent first rib resection and scalenectomy (FRRS). METHODS: Patients treated with FRRS for NTOS from 2003 to 2013 were retrospectively reviewed using a prospectively maintained database. RESULTS: Over 10 years, 286 patients underwent 308 FRRS. During the first 5-year period, 127 FRRS were performed (96 F, 31 M), with an average age of 36.9 years. During the second 5-year period, 181 FRRS were performed (143 F, 38 M), with an average age of 33 years. A total of 24 children (age <=18 years) underwent FRRS, 9 during the first 5 years and 15 during the second 5 years. When comparing the second 5-year period to the first 5-year period, patients were younger (P = .066), reported a significantly shorter length of preoperative symptoms (35.4 vs. 52.1 months, P < .01), prior narcotic use decreased from 31.5% to 23.8% (P < .05), and a history of prior surgical intervention on the ipsilateral side (head, neck, and shoulder) increased from 30.1% to 51.9% (P < .01). Use of lidocaine blocks as a diagnostic tool (57%-35.4%, P = .06) and Botox blocks as a therapeutic tool (29.1%-12.7%, P < .01) decreased in the second 5 years with similar positive results. Improved or fully resolved symptoms following FRRS increased from 89% in the first 5 years to 92.8% in the second 5 years. Average length of follow-up over the 10-year period was 13.4 months. CONCLUSION: Excellent results were seen in this surgical series reported for NTOS. Younger patients with shorter duration of symptoms with less narcotic use led to even better FRRS results in the second 5 years of surgical intervention. An established vascular practice for referrals for NTOS resulted in an increased number of appropriate patients for surgical intervention, requiring fewer lidocaine and/or Botox injections preoperatively. PMID- 25916631 TI - Acetyl Methyl Torsion in N-Ethylacetamide: A Challenge for Microwave Spectroscopy and Quantum Chemistry. AB - The gas-phase structures and parameters describing acetyl methyl torsion of N ethylacetamide are determined with high accuracy, using a combination of molecular beam Fourier-transform microwave spectroscopy and quantum chemical calculations. Conformational studies at the MP2 level of theory yield four minima on the energy surface. The most energetically favorable conformer, which possesses C1 symmetry, is assigned. Due to the torsional barrier of 73.4782(1) cm(-1) of the acetyl methyl group, fine splitting up to 4.9 GHz is found in the spectrum. The conformational structure is not only confirmed by the rotational constants, but also by the orientation of the internal rotor. The (14) N quadrupole hyperfine splittings are analyzed and the deduced coupling constants are compared with the calculated values. PMID- 25916632 TI - Effect of topical vitamin D on chronic kidney disease-associated pruritus: An open-label pilot study. AB - Chronic kidney disease-associated pruritus (CKD-aP) is a troublesome symptom in patients with end-stage renal disease (ESRD). Recently, vitamin D deficiency has been known to be one of the possible etiologic factors in CKD-aP. However, limited data is available on whether topical vitamin D treatment is effective for relieving CKD-aP. Therefore, the purpose of this study is to evaluate the effectiveness of topically vitamin D for CKD-aP. Twenty-three patients with CKD aP were enrolled in a single center, open-label study. Patients were instructed to apply a topical vitamin D (calcipotriol) agent (Daivonex solution; LEO Pharma) or vehicle solution twice daily for a month. We assessed the efficacy and safety of topical vitamin D on CKD-aP using clinical and dermoscopic photographs, and questionnaires including the validated modified pruritus assessment score (VMPAS) and visual analog scale (VAS) every 2 weeks. Dry dermoscopic findings showed significant improvement of scale (dryness) on the skin of topical vitamin D treated patients compared with those of the vehicle group. Both VMPAS and VAS were significantly decreased after 2 and 4 weeks of the topical vitamin D treatment compared with the vehicle, respectively (P < 0.05). No significant side effects were observed. Topical vitamin D may be one of the safe and effective therapeutic candidates for CKD-aP. PMID- 25916633 TI - Orthostatic responses to anticholinesterase inhibition in spinal cord injury. AB - INTRODUCTION: Acetylcholine (Ach) is the pre-synaptic neurotransmitter of the sympathetic nervous system. Increased pre-synaptic Ach may augment post-synaptic release of norepinephrine, thereby increasing systemic blood pressure (BP). OBJECTIVES: The primary objective of this investigation was to determine the hemodynamic effect of pyridostigmine bromide (PYRIDO: 60 mg), an Ach inhibitor (AchI), compared to no-drug (NO-D) during head-up tilt (HUT) in individuals with spinal cord injury (SCI). Secondarily, we aimed to determine the effects of PYRIDO compared to NO-D on symptoms of orthostatic intolerance (OI) and adverse event reporting (AE). METHODS: Ten individuals with SCI (C4-C7) were studied on two occasions: visit (1) NO-D and visit (2) PYRIDO. On each visit subjects underwent a progressive HUT maneuver to 15 degrees , 25 degrees , 35 degrees for 5 min at each angle and 45 min at 45 degrees . Supine and orthostatic heart rate (HR), systolic and diastolic BP (SBP and DBP), as well as monitored and symptoms of OI and AE were monitored and recorded. RESULTS: Supine hemodynamics did not differ between the trials. The significant fall in SBP during the NO-D trial was diminished with PYRIDO, and five subjects had an increased DBP during HUT with PYRIDO compared to the NO-D trial. Individuals that responded to PYRIDO with an increase in orthostatic BP had significantly lower resting HR than non-responders (p < 0.01), which suggests increased levels of pre-synaptic Ach. Subjective symptoms of OI and AE reporting did not differ between the two trials. CONCLUSIONS: These preliminary data suggest that PYRIDO is safe and may be effective at ameliorating the orthostatic fall in BP in select individuals with SCI. PMID- 25916634 TI - scaRNAs regulate splicing and vertebrate heart development. AB - Alternative splicing (AS) plays an important role in regulating mammalian heart development, but a link between misregulated splicing and congenital heart defects (CHDs) has not been shown. We reported that more than 50% of genes associated with heart development were alternatively spliced in the right ventricle (RV) of infants with tetralogy of Fallot (TOF). Moreover, there was a significant decrease in the level of 12 small cajal body-specific RNAs (scaRNAs) that direct the biochemical modification of specific nucleotides in spliceosomal RNAs. We sought to determine if scaRNA levels influence patterns of AS and heart development. We used primary cells derived from the RV of infants with TOF to show a direct link between scaRNA levels and splice isoforms of several genes that regulate heart development (e.g., GATA4, NOTCH2, DAAM1, DICER1, MBNL1 and MBNL2). In addition, we used antisense morpholinos to knock down the expression of two scaRNAs (scarna1 and snord94) in zebrafish and saw a corresponding disruption of heart development with an accompanying alteration in splice isoforms of cardiac regulatory genes. Based on these combined results, we hypothesize that scaRNA modification of spliceosomal RNAs assists in fine tuning the spliceosome for dynamic selection of mRNA splice isoforms. Our results are consistent with disruption of splicing patterns during early embryonic development leading to insufficient communication between the first and second heart fields, resulting in conotruncal misalignment and TOF. Our findings represent a new paradigm for determining the mechanisms underlying congenital cardiac malformations. PMID- 25916636 TI - [Diagnostic features of myeloproliferative neoplasms]. PMID- 25916635 TI - Carbon monoxide protects against hepatic ischemia/reperfusion injury by modulating the miR-34a/SIRT1 pathway. AB - Hepatic ischemia/reperfusion (I/R) injury can arise as a complication of liver surgery and transplantation. Sirtuin 1 (SIRT1), an NAD+-dependent deacetylase, modulates inflammation and apoptosis in response to oxidative stress. SIRT1, which is regulated by p53 and microRNA-34a (miR-34a), can modulate non-alcoholic fatty liver disease, fibrosis and cirrhosis. Since carbon monoxide (CO) inhalation can protect against hepatic I/R, we hypothesized that CO could ameliorate hepatic I/R injury by regulating the miR-34a/SIRT1 pathway. Livers from mice pretreated with CO, or PFT, a p53 inhibitor, displayed reduced production of pro-inflammatory mediators, including TNF-alpha, iNOS, interleukin (IL)-6, and IL-1beta after hepatic I/R injury. SIRT1 expression was increased by CO or PFT in the liver after I/R, whereas acetylated p65, p53 levels, and miR-34a expression were decreased. CO increased SIRT1 expression by inhibiting miR-34a. Both CO and PFT diminished pro-inflammatory cytokines production in vitro. Knockdown of SIRT1 in LPS-stimulated macrophages increased NF-kappaB acetylation, and increased pro-inflammatory cytokines. CO treatment reduced miR-34a expression and increased SIRT1 expression in oxidant-challenged hepatocytes; and rescued SIRT1 expression in p53-expressing or miR-34a transfected cells. In response to CO, enhanced SIRT1 expression mediated by miR-34a inhibition protects against liver damage through p65/p53 deacetylation, which may mediate inflammatory responses and hepatocellular apoptosis. The miR-34a/SIRT1 pathway may represent a therapeutic target for hepatic injury. PMID- 25916637 TI - [Clinicopathologic features and association with Epstein-Barr virus infection in 235 cases of Hodgkin lymphoma from northern China]. AB - OBJECTIVE: To study the clinicopathologic features of Hodgkin lymphoma (HL) occurring in northern China, association with Epstein-Barr virus (EBV) infection and concordance between EBV protein immunohistochemistry (IHC) and in-situ hybridization (ISH). METHODS: Two hundred and thirty-five cases were collected and their HE and IHC slides were reviewed to confirm the diagnosis and sort of HLs. All cases were performed with IHC staining for LMP-1 protein and ISH of EBV encoded RNAs (EBER) was done in 101 cases to detect the existence of EBV. RESULTS: The incidence peak was between age 25 and 35 years, followed by another peak between age 56 to 60 years. There were 135 males and 100 females. The tumor involved lymph nodes in 217 cases, and extranodal sites in 18 cases. There were 3 cases of nodular lymphocyte predominant Hodgkin lymphoma (NLPHL) and 232 cases of classical Hodgkin lymphoma. All tumors were stained for CD30, CD20, CD3. CD30 was expressed in 227 cases (96.6%), CD20 was expressed in 53 cases (22.5%) with different level of intensity. CD3 was expressed only in 1 case (0.4%). CD15 staining was performed in 224 cases and 117 (52.2%) cases were positive. PAX-5 were performed in 213 cases and 160 (75.1%) cases showed weak to moderate expressions. Two hundred and thirty-five cases were immunohistochemically stained with LMP1 and 72 (30.6%) cases were positive. Meanwhile, EBER ISH were applied in 101 cases, and 40 cases (39.6%) were found positive. LMP1 was expressed in 30 cases among those EBER-positive cases, while LMP1 was only detected in 5 cases of the EBER-negative cases. There was no statistically significantce between LMP1 IHC and EBER ISH by pared chi-square test (P = 0.3), the overall concordance rate was 85.2%. CONCLUSIONS: There was a bimodal age distribution in our group of HL cases from the northern part of China, with slight male predominance and mainly nodal involvement. Nodular sclerosis (NS) and mixed cellularity (MC) were major histologic subtypes. When it was compared with the EBER ISH method in detection EBV infection of HL, the more economical and convenient LMP1 IHC showed both high degree of consistency and overall concordance rate. PMID- 25916638 TI - [Correlation of immunoglobulin variable heavy chain gene mutation status with prognosis in patients with mantle cell lymphoma]. AB - OBJECTIVE: To study the relationship between immunoglobulin variable heavy chain (IgVH) gene mutation status and clinical features, pathologic findings and biologic behavior of mantle cell lymphoma (MCL). METHODS: IgVH gene was amplified in 60 cases of MCL with FR1-JH and FR2-JH primers in BIOMED-2. The sequence was determined by cloning. The IgVH somatic mutational status was analyzed using NCBI's Ig-Blast tool. The relationship between IgVH gene mutation status and clinicopathologic features was also analyzed. RESULTS: Forty percent (24 cases, 28 functional Ig genes) of the MCL cases displayed somatically mutated VH genes (defined as > 2% mutated), whereas 60.0% (36 cases, 40 functional Ig genes) showed unmutated VH genes. The most widely used genes were VH3-21 (27.9%) and VH4 34 (19.1%). The former were mainly used by unmutated cases, while the later mainly by mutated cases.Intraclonal heterogeneity was noted in 19 cases. There was no correlation of VH mutation status and specific VH gene with survival (P > 0.05). CONCLUSIONS: MCL comprises at least two subsets that do not correlate with morphology: one with unmutated VH genes and one with mutated VH genes. The biased use of VH3-21 and VH4-34 is noted. The nonrandom usage of IgVH segments suggests specific antigens may play a role in the pathogenesis and progression of MCL subsets. There is no correlation of IgVH mutation status and specific VH gene with survival. PMID- 25916639 TI - [Pathological diagnosis of pediatric Burkitt lymphoma involving bone marrow]. AB - OBJECTIVE: To investigate pathologic and differential diagnostic features of pediatric Burkitt lymphoma (BL). METHODS: A total of 20 cases of pediatric BL were retrospectively reviewed for their clinical and pathologic profiles. Bone marrow aspiration specimens were available in all cases and bone marrow biopsies were available for immunohistochemical study in 18 cases. Flow cytometry study was available in 16 cases. MYC translocation by FISH method was performed in 11 cases. RESULTS: Atypical lymphocytes with cytoplasmic vacuoles were found in bone marrow smears in all 20 cases and peripheral blood films in all 19 available cases. The bone marrow biopsies showed infiltration by uniform medium-sized atypical lymphocytes with multiple small nucleoli but without the starry-sky pattern in all 18 cases. Immunohistochemistry showed the following results in all 18 cases: positive for CD20, PAX-5, CD10, CD34 and TdT, but negative for bcl-2 and CD3 with Ki-67 > 95%.Flow cytometry showed CD19+CD20+CD10+FMC7+CD22+TdT-CD3- in 16 cases, including kappa+ in 8 cases, lambda+ in 7 cases, and kappa-lambda- in 1 case. MYC gene rearrangement by FISH was observed in 10 of the 11 cases. CONCLUSIONS: The histopathology of BL is distinct, including atypical lymphocytes with cytoplasmic vacuoles in bone marrow aspirate, lack of starry-sky patternin bone marrow biopsy. Generally, the diagnosis should be made with a combined immunophenotype and FISH approach. Pediatric BL must be distinguished from DLBCL and B-cell lymphoma, unclassifiable, which has intermediate features between DLBCL and Burkitt lymphoma. PMID- 25916640 TI - [Primary cutaneous diffuse large B-cell lymphoma, leg type: a study of clinicopathology, immunophenotype and gene rearrangement]. AB - OBJECTIVE: To study the clinicopathologic features, immunophenotype and gene rearrangement of primary cutaneous diffuse large B-cell lymphoma, leg type (PCLBCL). METHODS: Seven cases of PCLBCL were enrolled into the study. Clinicopathologic analysis, immunohistochemical staining and gene rearrangement for IgH and Igkappa were undertaken in the study. RESULTS: All the seven cases were male, and the median age was 72 years. Patients usually presented with multiple purple tumors, nodules, papules and infiltrative plaques. Two patients had a history of leg injury before onset, and one had mosquito bites. Histologically, the tumor involved the dermis and subcutis with dense and diffuse infiltrative pattern composing of centroblasts and/or immunoblasts. Immunohistochemical staining showed that seven cases (7/7) expressed CD20, six (6/6) expressed bcl-2, four (4/4) expressed MUM-1, four (4/5) expressed CD79a, four (4/5) expressed PAX-5 and four (4/6) expressed bcl-6, respectively. All cases did not express CD3epsilon, CD45RO, CD10 and CD30. IgH gene rearranged bands were detected in three (3/6) cases and Igkappa was detected in one (1/5) case. Six of the seven cases died and the remaining patient, who was 44-year-old, was alive after 22 months of follow-up. CONCLUSIONS: PCLBCL is rare, predominantly affects elderly male patients. PCLBCL has poor prognosis and high mortality, but younger patients seem to have better prognosis. Some cases had a history of trauma or mosquito bites. The relationship between the history and the onset of PCLBCL needs further evaluation. PMID- 25916641 TI - [Presence of B-cell clones in angioimmunoblastic T cell lymphoma]. AB - OBJECTIVE: To study the significance of B-cell clones in angioimmunoblastic T cell lymphoma (AITL) and the correlation with Epstein-Barr virus (EBV) and prognosis. METHOD: The histopathologic features, T cell clonality and EBV positivity in 33 cases of AITL and 10 cases of peripheral T-cell lymphoma, not otherwise specified (PTCL-NOS) collected from May 2010 to February 2014 were analyzed by immunohistochemistry, PCR gene rearrangement and in situ hybridization. Follow-up data were also collected. RESULTS: Of the 33 cases with AITL, seven cases (21.2%) exhibited clonal rearrangement of Ig genes; 21 cases (63.6%) were EBV positive. Seven cases had B-cell clones and all (7/7) were EBV positive; 14 of the 26 (53.8%) cases without B-cell clones were EBV positive. The difference between the two groups was statistically significant (P = 0.032). Four levels were made according to the number of EBV-labeled cells, Ig gene rearrangements, but there was no significant difference among levels 1, 2 and 3. There was no correlation between B-cell clones and prognosis (P = 0.263). CONCLUSION: Clonal rearrangement of Ig genes is a common finding in AITL, and it is highly associated with EBV positivity, but not with the number of EBV-labeled cells. The clinical significance remains unclear; further study with more samples is warranted. PMID- 25916642 TI - [Prognostic significance of MYCN amplification in children neuroblastic tumors]. AB - OBJECTIVE: To summarize the clinicopathologic features of neuroblastic tumors (NT), and to explore the prognostic significance of MYCN amplification in NT. METHODS: The clinicopathologic data of 267 NT were reviewed. MYCN gene amplification was detected by fluorescence in situ hybridization (FISH) in 119 cases and the relationship with pathological characteristics and prognostic significance were analyzed. RESULTS: The study included 267 cases of children NT from patients aged from 1 day to 13 years (median 27 months). The male to female ratio was 1.43. There were 38 cases (14.2%), 43 cases (16.1%), 71 cases (26.6%), and 115 cases (43.1%) of INSS stages I, II, III and IV respectively.Favorable histology group had 157 cases (59.9%); unfavorable histology group had 110 cases (40.1%).Of the 119 NT cases with MYCN FISH performed, 18 cases (15.1%) showed amplification and the signal ratio of MYCN to CEP2 was 4.08-43.29. One hundred and one cases of non-amplified MYCN included MYCN gain in 79 cases (66.3%) and MYCN negative in 22 cases (18.5%). MYCN expression showed significant difference (P = 0.000) between ages, gender, NT type and MKI, but not INPC and clinical stage (P > 0.05).Of the 18 cases with MYCN amplification, 3 were undifferentiated, and 15 poorly differentiated; 17 had high MKI and one moderate MKI. All 18 cases were in unfavorable histology group; the overall survival rate was 3/18, with an average survival time of (17.9 +/- 2.4) months.Of the 101 MYCN non-amplification cases, the overall survival rate was 68.3% (69/101), with an average survival time of (29.8 +/- 1.3) months. Survival analysis showed the cases with MYCN amplification had worse prognosis (P < 0.05). CONCLUSIONS: NT were commonly diagnosed in early ages and easily to metastasize. Most of cases with favorable histology. The cases of MYCN amplification showed unfavorable histology, and the majority cases with high MKI; The patients with MYCN gene amplification had poor prognosis. PMID- 25916643 TI - [Clinicopathologic features observation of ovarian transitional cell tumors]. AB - OBJECTIVE: To assess clinical and pathological features of ovarian transitional cell tumors. METHODS: Fourteen cases of ovarian transitional cell carcinoma (TCC) were selected and investigated for their clinical and pathological features. Their immunohistochemical profiles were compared with 12 cases of serous adenocarcinoma (SC) admixed with TCC and 4 cases of EC admixed with TCC 20 cases of pure high-grade serous adenocarcinoma (HG-SC), 15 cases of endometrioid adenocarcinoma (EC), 6 cases of Brenner tumor (BT, 2 cases of malignant BT and 4 cases of benign BT). RESULTS: The patients' age ranged from 36-63 years (mean, 56 years). All cases underwent surgery and postoperative chemotherapy with TP or CAP program. Clinical follow-up was available in 9 cases, of which 2 patients died. Histologically, all cases showed features of transitional cell carcinoma without BT component. Immunohistochemically, 13 of 14 TCCs were positive for WT-1 and all were positive for CK7, ER, PR and CA125, but negative for Uroplakin III and CK20.Similar immunohistochemical staining patterns were seen in SC admixed with TCC and pure HG-SC. Percentage of the 14 TCC cases were also diffusely positive for BRCA1. All SCs admixed with TCC and pure HG-SCs were diffusely or heterogeneously positive for WT-1, with a sharp contrast and mottled distribution pattern in the heterogeneous cases. All TCCs were diffusely and strongly positive for p53, while 16 of 20 cases of pure HG-SC were positive. The positive ratio of p53 in SCs admixed with TCC cases was 11/12.WT-1 expression in TCCs was significantly higher than BTs, ECs and ECs admixed with TCC (P < 0.01), while no obvious difference was seen when compared with SCs admixed with TCC and pure HG SCs.SCs admixed with TCC, TCCs and EC were positive for BRCA1 except pure ECs and BTs. The positive rate of Ki-67 of BTs was low, while it was higher in TCCs, SCs admixed with TCC and pure HG-SCs. Only BTs expressed Uroplakin III. CONCLUSIONS: Ovarian TCC has characteristic morphological and immunohistochemical features, similar to SC but different from BT. Therefore, TCC should be considered as a morphological variant of HG-SC. PMID- 25916644 TI - [Histological and ultrastructural features of giant cell myocarditis: report of 3 cases]. AB - OBJECTIVE: To identify clinical and pathological features of giant cell myocarditis. METHODS: Clinical presentation and follow-up data of three patients with giant cell myocarditis were collected.Gross, histopathological, immunohistological and ultrastructural findings of extransplantated hearts of the patients were documented. RESULTS: Grossly, multifocal involvement of the myocardium with variably dilated cardiac chambers were observed in all 3 cases.Histological examination revealed pronounced focal inflammatory infiltrates with multinucleated giant cells. Multinucleated giant cells were positive for CD68 and CD11b immunostains but were negative for CD163 in all cases. Transmission electron microscopy showed that the multinucleated giant cells derived from fusion of several macrophages with adherent lymphocytes and secretary cells. Clinically, the overall patient condition improved in all three cases after heart transplantation.One patient experienced acute cellular rejection (2R level) 4 months after transplantation, but recovered after treatment. One patient developed multinucleated giant cells observed in heart biopsy two weeks after transplantation. CONCLUSIONS: Giant-cell myocarditis is a rare disease of adult, and cardiac transplantation could improve the clinical outcome. Multinucleated giant cell in the myocarditis lesions were derived from macrophages, likely participating in the immune response. Endomyocardial biopsy is important for the diagnosis of giant cell myocarditis. PMID- 25916645 TI - [Significance of NAD (P) H: quinone oxidoreductase 1 overexpression in prognostic evaluation of thyroid medullary carcinoma]. PMID- 25916646 TI - [Intraduct papilloma of salivary gland: a case report]. PMID- 25916647 TI - [Menetrier's disease: a case report]. PMID- 25916648 TI - [Anastomosing hemangioma: a case report]. PMID- 25916649 TI - [Updates on Epstein-Barr virus-positive diffuse large B-cell lymphoma of the elderly]. PMID- 25916650 TI - [Soft tissue tumors with EWSR1 gene rearrangements]. PMID- 25916651 TI - [Diabetic cardiomyopathy and autophagy]. PMID- 25916652 TI - [Research progress on ubiquitination degradation mechanism of hypoxia inducible factor-1alpha]. PMID- 25916653 TI - A novel role for an RCAN3-derived peptide as a tumor suppressor in breast cancer. AB - The members of the human regulators of calcineurin (RCAN) protein family are endogenous regulators of the calcineurin (CN)-cytosolic nuclear factor of activated T-cells (NFATc) pathway activation. This function is explained by the presence of a highly conserved calcipressin inhibitor of calcineurin (CIC) motif in RCAN proteins, which has been shown to compete with NFATc for the binding to CN and therefore are able to inhibit NFATc dephosphorylation and activation by CN. Very recently, emerging roles for NFATc proteins in transformation, tumor angiogenesis and metastasis have been described in different cancer cell types. In this work, we report that the overexpression of RCAN3 dramatically inhibits tumor growth and tumor angiogenesis in an orthotopic human breast cancer model. We suggest that RCAN3 exerts these effects in a CN-dependent manner, as mutation of the CIC motif in RCAN3 abolishes the tumor suppressor effect. Moreover, the expression of the EGFP-R3(178-210) peptide, spanning the CIC motif of RCAN3, is able to reproduce all the antitumor effects of RCAN3 full-length protein. Finally, we show that RCAN3 and the EGFP-R3(178-210) peptide inhibit the CN-NFATc signaling pathway and the induction of the NFATc-dependent gene cyclooxygenase-2. Our work suggests that the EGFP-R3(178-210) peptide possess potent tumor suppressor properties and therefore constitutes a novel lead for the development of potent and specific antitumoral agents. Moreover, we propose the targeting of the CN-NFATc pathway in the tumor cells constitutes an effective way to hamper tumor progression by impairing the paracrine network among tumor, endothelial and polymorphonucleated cells. PMID- 25916654 TI - ERBB4 is over-expressed in human colon cancer and enhances cellular transformation. AB - The ERBB4 receptor tyrosine kinase promotes colonocyte survival. Herein, we tested whether ERBB4's antiapoptotic signaling promotes transformation and colorectal tumorigenesis. ERBB4 alterations in a The Cancer Genome Atlas colorectal cancer (CRC) data set stratified survival, and in a combined Moffitt Cancer Center and Vanderbilt Medical Center CRC expression data set, ERBB4 message levels were increased at all tumor stages. Similarly, western blot and immunohistochemistry on additional CRC tissue banks showed elevated ERBB4 protein in tumors. ERBB4 was highly expressed in aggressive, dedifferentiated CRC cell lines, and its knockdown in LIM2405 cells reduced anchorage-independent colony formation. In nude mouse xenograft studies, ERBB4 alone was insufficient to induce tumor establishment of non-transformed mouse colonocytes, but its over expression in cells harboring Apc(min) and v-Ha-Ras caused a doubling of tumor size. ERBB4-expressing xenografts displayed increased activation of survival pathways, including epidermal growth factor receptor and Akt phosphorylation and COX-2 expression, and decreased apoptotic signals. Finally, ERBB4 deletion from mouse intestinal epithelium impaired stem cell replication and in vitro enteroid establishment. In summary, we report that ERBB4 is over-expressed in human CRC, and in experimental systems enhances the survival and growth of cells driven by Ras and/or WNT signaling. Chronic ERBB4 over-expression in the context of, for example, inflammation may contribute to colorectal carcinogenesis. Tumors with high receptor levels are likely to have enhanced cell survival signaling through epidermal growth factor receptor, PI3K and COX-2. These results suggest ERBB4 as a novel therapeutic target in a subset of CRC. PMID- 25916655 TI - Pigmented nodular melanoma: the predictive value of dermoscopic features using multivariate analysis. AB - BACKGROUND: Nodular melanoma (NM), representing 10-30% of all melanomas, plays a major role in global mortality related to melanoma. Nonetheless, the literature on dermoscopy of NM is scanty. OBJECTIVES: To assess odds ratios (ORs) to quantify dermoscopic features of pigmented NM vs. pigmented superficial spreading melanoma (SSM), and pigmented nodular nonmelanocytic and benign melanocytic lesions. METHODS: To assess the presence or absence of global patterns and dermoscopic criteria, digitized images of 457 pigmented skin lesions from patients with a histopathological diagnosis of NM (n = 75), SSM (n = 93), and nodular nonmelanocytic and benign melanocytic lesions (n = 289; namely, 39 basal cell carcinomas, 85 seborrhoeic keratoses, 81 blue naevi, and 84 compound/dermal naevi) were retrospectively collected and blindly evaluated by three observers. RESULTS: Multivariate analysis showed that ulceration (OR 4.07), homogeneous disorganized pattern (OR 10.76), and homogeneous blue pigmented structureless areas (OR 2.37) were significantly independent prognostic factors for NM vs. SSM. Multivariate analysis of dermoscopic features of NM vs. nonmelanocytic and benign melanocytic lesions showed that the positive correlating features leading to a significantly increased risk of NM were asymmetric pigmentation (OR 6.70), blue black pigmented areas (OR 7.15), homogeneous disorganized pattern (OR 9.62), a combination of polymorphous vessels and milky-red globules/areas (OR 23.65), and polymorphous vessels combined with homogeneous red areas (OR 33.88). CONCLUSIONS: Dermoscopy may be helpful in improving the recognition of pigmented NM by revealing asymmetric pigmentation, blue-black pigmented areas, homogeneous disorganized pattern and abnormal vascular structures, including polymorphous vessels, milky-red globules/areas and homogeneous red areas. PMID- 25916656 TI - AHNS Series--Do you know your guidelines? Guideline recommended follow-up and surveillance of head and neck cancer survivors. AB - In this first article of the "Do You Know Your Guidelines" series, we review National Comprehensive Cancer Network (NCCN) recommendations and underlying evidence for the follow-up and surveillance of head and neck cancer survivors. The goals of follow-up and surveillance care are (1) to maximize long-term oncologic outcomes of therapy with appropriate evaluation for recurrence, (2) to maximize functional and quality of life outcomes, and (3) minimizing unnecessary and harmful low-value care. Finding the right balance of testing and surveillance is a challenge for providers and patients. Herein, we review all NCCN recommendations for head and neck cancer survivors. We pay particular attention to an area of controversy: the use of ongoing surveillance imaging, in particular, PET/CT scans. PMID- 25916657 TI - The Impact of Obesity on Postoperative Outcomes in Adults with Congenital Heart Disease Undergoing Pulmonary Valve Replacement. AB - OBJECTIVE: The impact of obesity on surgical morbidity in adults with congenital heart disease is currently unknown. The aim of our study was to investigate the impact of obesity on postoperative outcomes in adults with congenital heart disease undergoing reoperation for pulmonary valve replacement. METHODS: A retrospective analysis was performed assessing the influence of obesity on surgical outcomes. Obesity was defined as a body mass index >=30 kg/m2. RESULTS: The mean body mass index of the cohort was 25.9 +/- 6.9 kg/m2 . The cohort included 71 patients with 17 patients (24%) being obese. There was no postoperative mortality. Obese patients had a longer hospital length of stay (6.6 vs. 4.7 days; P < .001) and increased incidence of postoperative arrhythmias (29% vs. 5.6%; P = .003) compared with nonobese patients. Multivariable analysis performed using logistic regression with backwards elimination demonstrated obesity was independently associated with hospital length of stay >5 days (odds ratio [OR] = 5.2; 95% confidence interval [CI]: 1.5-18.2, P = .01) and with increased postoperative arrhythmias (OR = 4.2; 95% CI: 1.7-40, P < .01). CONCLUSIONS: Obesity is associated with increased morbidity in adults with congenital heart disease undergoing pulmonary valve replacement, including longer hospitalization and higher risk for postoperative arrhythmias. PMID- 25916658 TI - Oxytocin influences intuitions about the relationship between belief in free will and moral responsibility. AB - Philosophers have proposed that laypeople can have deterministic or indeterministic intuitions about the relationship between free will and moral responsibility. However, the psychophysiological mechanisms that generate these extreme intuitions are still underexplored. Exogenous oxytocin offers a unique opportunity to gain a deeper understanding of these underlying mechanisms, since this neuropeptide influences a wide range of outcomes related to social cognition and prosociality. This study investigated the effects of intranasal oxytocin on intuitions about the relationship between free will and moral responsibility by applying a randomized, double-blind, placebo-controlled, between-subject design. Healthy male participants rated the moral responsibility of a hypothetical offender, who committed crimes in either a primed deterministic or an indeterministic universe. Under placebo, participants held the offender more morally responsible when acting in an indeterministic compared to a deterministic universe, which could be accredited to recognition of the offender's freely chosen action to commit the crimes. Under oxytocin, participants rated the offender's actions with greater leniency and similarly assigned lower moral responsibility in both universes. These findings strengthen the assumption that a person can have different intuitions about the relationship between free will and moral responsibility, which can be presumably dependent on motivational states associated with affiliation. PMID- 25916659 TI - Genotoxic effects of zinc oxide nanoparticles. AB - The potential toxicity of nanoparticles has currently provoked public and scientific discussions, and attempts to develop generally accepted handling procedures for nanoparticles are under way. The investigation of the impact of nanoparticles on human health is overdue and reliable test systems accounting for the special properties of nanomaterials must be developed. Nanoparticular zinc oxide (ZnO) may be internalised through ambient air or the topical application of cosmetics, only to name a few, with unpredictable health effects. Therefore, we analysed the determinants of ZnO nanoparticle (NP) genotoxicity. ZnO NPs (15-18 nm in diameter) were investigated at concentrations of 0.1, 10 and 100 MUg mL(-1) using the cell line A549. Internalised NPs were only infrequently detectable by TEM, but strongly increased Zn(2+) levels in the cytoplasm and even more in the nuclear fraction, as measured by atom absorption spectroscopy, indicative of an internalised zinc and nuclear accumulation. We observed a time and dosage dependent reduction of cellular viability after ZnO NP exposure. ZnCl2 exposure to cells induced similar impairments of cellular viability. Complexation of Zn(2+) with diethylene triamine pentaacetic acid (DTPA) resulted in the loss of toxicity of NPs, indicating the relevant role of Zn(2+) for ZnO NP toxicity. Foci analyses showed the induction of DNA double strand breaks (DSBs) by ZnO NPs and increased intracellular reactive oxygen species (ROS) levels. Treatment of the cells with the ROS scavenger N-acetyl-l-cysteine (NAC) resulted in strongly decreased intracellular ROS levels and reduced DNA damage. However, a slow increase of ROS after ZnO NP exposure and reduced but not quashed DSBs after NAC treatment suggest that Zn(2+) may exert genotoxic activities without the necessity of preceding ROS-induction. Our data indicate that ZnO NP toxicity is a result of cellular Zn(2+) intake. Subsequently increased ROS-levels cause DNA damage. However, we found evidence for the assumption that DNA-DSBs could be caused by Zn(2+) without the involvement of ROS. PMID- 25916660 TI - A randomised controlled trial to evaluate the efficacy of a 6-month dietary and physical activity intervention for patients receiving androgen deprivation therapy for prostate cancer. AB - PURPOSE: Treatment of prostate cancer with androgen deprivation therapy (ADT) is associated with an increased fat mass, decreased lean mass, increased fatigue and a reduction in quality of life (QoL). The aim of this study was to evaluate the efficacy of a 6-month dietary and physical activity intervention for prostate cancer patients receiving ADT, to help minimise these side effects. METHODS: Patients (n = 94) were recruited to this study if they were planned to receive ADT for prostate cancer for at least 6 months. Men randomised to the intervention arm received a dietary and exercise intervention, commensurate with UK healthy eating and physical activity recommendations. The primary outcome of interest was body composition; secondary outcomes included fatigue, QoL, functional capacity, stress and dietary change. RESULTS: The intervention group had a significant (p < 0.001) reduction in weight, body mass index and percentage fat mass compared to the control group at 6 months; the between-group differences were -3.3 kg (95% confidence interval (95% CI) -4.5, -2.1), -1.1 kg/m(2) (95% CI -1.5, -0.7) and 2.1% (95% CI -2.8, -1.4), respectively, after adjustment for baseline values. The intervention resulted in improvements in functional capacity (p < 0.001) and dietary intakes but did not significantly impact fatigue, QoL or stress scores at endpoint. CONCLUSIONS: A 6-month diet and physical activity intervention can minimise the adverse body composition changes associated with ADT. IMPLICATIONS FOR CANCER SURVIVORS: This study shows that a pragmatic lifestyle intervention is feasible and can have a positive impact on health behaviours and other key outcomes in men with prostate cancer receiving ADT. PMID- 25916661 TI - Emergency neurosurgery in Darwin: still the generalist surgeons' responsibility. AB - BACKGROUND: Royal Darwin Hospital (RDH) is the only major hospital for the 'Top End' of Northern Territory and Western Australia. As retrieval distances exceed 2600 km, resident generalist surgeons undertake all emergency neurosurgery. METHODS: Retrospective clinical study from RDH records and review of prospectively collected datasets from RDH Intensive Care Unit and National Critical Care Trauma Response Centre for all emergency neurosurgery patients between 2008 and 2013. RESULTS: Data were obtained from 161 patients with 167 admissions (73% male, 39% indigenous) who underwent 195 procedures (33 per year), including burr hole, craniotomy, cerebral and posterior fossa craniectomy, elevation fracture and ventricular drain. Trauma accounted for 68%, with alcohol as a known factor in 57%. Subdural haematoma (SDH) accounted for 53%. Severity of head injury at presentation correlated with outcome (R(2) = 0.12, P < 0.001). Factors associated with death included injury at remote location (P = 0.022), time injury to operation >24 h (P = 0.023) and specific diagnoses of acute SDH (P = 0.006), acute-on-chronic SDH (P = 0.053) and infection (P = 0.052). Indigenous patients were younger (40 versus 55 years, P < 0.001) and more likely to have alcohol as a factor in trauma cases (71% versus 49%, P = 0.027). Time from injury to hospital was high for accidents at a remote location (12.9 versus 1.3 h, P < 0.001); however, Glasgow Outcome Scales (P = 0.13) were no different to accident at metropolitan Darwin. CONCLUSION: General surgeons at RDH perform a wide range of emergency neurosurgical procedures primarily for trauma. Factors contributing to poor outcomes included remote location of trauma and delay in reaching the hospital. Outcomes at 3 months appear acceptable. PMID- 25916662 TI - Critical older driver errors in a national sample of serious U.S. crashes. AB - OBJECTIVE: Older drivers are at increased risk of crash involvement per mile traveled. The purpose of this study was to examine older driver errors in serious crashes to determine which errors are most prevalent. METHODS: The National Highway Traffic Safety Administration's National Motor Vehicle Crash Causation Survey collected in-depth, on-scene data for a nationally representative sample of 5470 U.S. police-reported passenger vehicle crashes during 2005-2007 for which emergency medical services were dispatched. There were 620 crashes involving 647 drivers aged 70 and older, representing 250,504 crash-involved older drivers. The proportion of various critical errors made by drivers aged 70 and older were compared with those made by drivers aged 35-54. RESULTS: Driver error was the critical reason for 97% of crashes involving older drivers. Among older drivers who made critical errors, the most common were inadequate surveillance (33%) and misjudgment of the length of a gap between vehicles or of another vehicle's speed, illegal maneuvers, medical events, and daydreaming (6% each). Inadequate surveillance (33% vs. 22%) and gap or speed misjudgment errors (6% vs. 3%) were more prevalent among older drivers than middle-aged drivers. Seventy-one percent of older drivers' inadequate surveillance errors were due to looking and not seeing another vehicle or failing to see a traffic control rather than failing to look, compared with 40% of inadequate surveillance errors among middle-aged drivers. About two-thirds (66%) of older drivers' inadequate surveillance errors and 77% of their gap or speed misjudgment errors were made when turning left at intersections. When older drivers traveled off the edge of the road or traveled over the lane line, this was most commonly due to non-performance errors such as medical events (51% and 44%, respectively), whereas middle-aged drivers were involved in these crash types for other reasons. Gap or speed misjudgment errors and inadequate surveillance errors were significantly more prevalent among female older drivers than among female middle-aged drivers, but the prevalence of these errors did not differ significantly between older and middle-aged male drivers. These errors comprised 51% of errors among older female drivers but only 31% among older male drivers. CONCLUSIONS: Efforts to reduce older driver crash involvements should focus on diminishing the likelihood of the most common driver errors. Countermeasures that simplify or remove the need to make left turns across traffic such as roundabouts, protected left turn signals, and diverging diamond intersection designs could decrease the frequency of inadequate surveillance and gap or speed misjudgment errors. In the future, vehicle-to vehicle and vehicle-to-infrastructure communications may also help protect older drivers from these errors. PMID- 25916663 TI - Illegal road crossing behavior of pedestrians at overpass locations: Factors affecting gap acceptance, crossing times and overpass use. AB - The aim of designing overpasses is to provide safe road crossings for pedestrians by helping them to avoid conflicts with motor vehicles. However, the number of pedestrians who do not use overpasses to cross the road is very high. An observational survey of illegal road crossings was conducted at four overpass locations in Izmir, Turkey to determine the crossing time, crossing speed of the pedestrians and their distance and time gap perception for safe road-crossing within 25 m of the overpasses in both directions. Crossing time is the time needed for a pedestrian to cross a particular road. Time gap is strongly related with safety margin. If a pedestrian chooses a larger time gap, then the arrival time of the oncoming vehicle to the crossing point of the pedestrian increases thus, the possibility of a collision decreases. Each overpass was observed on weekdays during peak afternoon (12.30-13.30) and evening hours (17.00-18.00). At all overpass locations 454 illegal crossings were observed. ANOVA results revealed that age had a significant effect both on safety margin and crossing time. During the observations a survey was conducted among pedestrians who completed their crossings either using the overpass or at street level within 25 m of the overpass (n=231). Factors affecting the crossing choice of pedestrians were specified in the surveys. The major part of the respondents (71.7%) indicated that time saving was the main reason for crossing at street level. Pedestrians' crossing speeds were extracted from the video recordings to observe the effect of speed limit on pedestrian behavior. As a result, at locations where the speed limit was 70 km/h, pedestrians' average crossing speed was found to be 1.60 m/s and 1.73 m/s while at locations where the speed limit was 50 km/h, pedestrians' average crossing speed was found to be 1.04 m/s and 0.97 m/s. This shows that pedestrians feel safer while crossing when the vehicle speed is low. PMID- 25916664 TI - Bevacizumab-associated diverticulitis: results of disproportionality analysis. PMID- 25916665 TI - Immunomodulatory therapies for relapsing-remitting multiple sclerosis: monoclonal antibodies, currently approved and in testing. AB - Relapsing-remitting multiple sclerosis (RRMS), a CNS inflammatory demyelinating disease, is one of the most prevalent causes of chronic disability in young adults. Studies of the disease pathogenesis have identified multiple therapeutic targets. The number of approved disease modifying therapies has almost doubled within the past 5 years, which creates a challenge for medical professionals to stay abreast of their use in everyday practice. This manuscript provides an overview of available injectable, oral, and intravenous therapies for RRMS, and offers guidance in selecting an appropriate therapy. Focus is on the recently approved and emerging monoclonal antibody therapies, because they offer more selective and superior therapeutic efficacy compared with injectable and oral disease modifying therapies. We discuss the outlook for monoclonal antibodies and their role in RRMS treatment in the future. PMID- 25916667 TI - Glutamatergic agents for schizophrenia: current evidence and perspectives. AB - Suboptimal outcomes in schizophrenia are a consequence of lacking insight into the etiology, biomarkers and treatment-relevant subgroups, the therapeutic restriction to dopaminergic-modulating antipsychotics that fail to significantly improve negative and cognitive symptoms, non-adherence, and, in the case of treatment-resistance, the underutilization of clozapine. Evidence suggests additional, extra-dopaminergic abnormalities in amino acid neurotransmission, particularly the glutamatergic system. Antidopaminergic antipsychotics modulate this system on several levels, as do mood stabilizers, including lamotrigine, topiramate and pregabaline. Recently, agonists at metabotropic glutamate receptors and glycine uptake inhibitors failed in large placebo-controlled trials for schizophrenia. Problems to overcome for successfully leveraging glutamatergic agents for schizophrenia are patient selection, focus on positive symptoms and late disease stages, and dose-response relationships. Because glutamate guides processes of brain development and maturation, clinical research should focus on the at-risk mental state or first-episode psychosis, address cognition and negative symptoms and use monotherapy designs in parallel to augmentation strategies. PMID- 25916666 TI - Pharmacologic and clinical evaluation of posaconazole. AB - Posaconazole, a broad-spectrum triazole antifungal agent, is approved for the prevention of invasive aspergillosis and candidiasis in addition to the treatment of oropharyngeal candidiasis. There is evidence of efficacy in the treatment and prevention of rarer, more difficult-to-treat fungal infections. Posaconazole oral suspension solution has shown limitations with respect to fasting state absorption, elevated gastrointestinal pH and increased motility. The newly approved delayed-release oral tablet and intravenous solution formulations provide an attractive treatment option by reducing interpatient variability and providing flexibility in critically ill patients. On the basis of clinical experience and further clinical studies, posaconazole was found to be a valuable pharmaceutical agent for the treatment of life-threatening fungal infections. This review will examine the development history of posaconazole and highlight the most recent advances. PMID- 25916668 TI - Functional basis of associative learning and its relationships with long-term potentiation evoked in the involved neural circuits: Lessons from studies in behaving mammals. AB - While contemporary neuroscience is paying increasing attention to subcellular and molecular events and other intracellular phenomena underlying the acquisition, storage, and retrieval of newly acquired motor and cognitive abilities, parallel attention should be paid to the study of the electrophysiological phenomena taking place at selected cortical and subcortical neuronal and synaptic sites during the precise moment of learning acquisition, extinction, and recall. These in vivo approaches to the study of learning and memory processes will allow the proper integration of the important information collected from in vitro and delayed molecular studies. Here, we summarize studies in behaving mammals carried out in our laboratory during the past ten years on the relationships between experimentally evoked long-term potentiation (LTP) and activity-dependent changes in synaptic strength taking place in hippocampal, prefrontal and related cortical and subcortical circuits during the acquisition of classical eyeblink conditioning or operant learning tasks. These studies suggest that different hippocampal synapses are selectively modified in strength during the acquisition of classical, but not instrumental, learning tasks. In contrast, selected prefrontal and striatum synapses are more directly modified by operant conditioning. These studies also show that besides N-methyl-D-aspartate (NMDA) receptors, many other neurotransmitter, intracellular mediating, and transcription factors participate in these two types of associative learning. Although experimentally evoked LTP seems to prevent the acquisition of classical eyeblink conditioning when induced at selected hippocampal synapses, it proved to be ineffective in preventing the acquisition of operant conditioned tasks when induced at numerous hippocampal, prefrontal, and striatal sites. The differential roles of these cortical structures during these two types of associative learning are discussed, and a diagrammatic representation of their respective functions is presented. PMID- 25916669 TI - Risk of surgical site infection in 401 consecutive patients with glioblastoma with and without carmustine wafer implantation. AB - OBJECTIVES: Patients with glioblastoma (GBM) have an inherently shortened survival because of their disease. It has been recently shown that carmustine wafers in addition to other therapies (surgery, temozolomide, and radiation) can further extend survival. There is concern, however, that these therapies may increase infection risk. The goals of this study were to calculate the incidence of postoperative infection, evaluate if carmustine wafers changes the risk of infection and identify factors independently associated with an infection following GBM surgery. METHODS: All patients who underwent non-biopsy, surgical resection of an intracranial GBM from 2007 to 2011 at a single institution were retrospectively reviewed. Stepwise multivariate proportional hazards regression analysis was used to identify factors associated with infection, including the use of carmustine wafers. Variables with P < 0.05 were considered statistically significant. RESULTS: Four hundred and one patients underwent resection of an intracranial GBM during the reviewed period, and 21 (5%) patients developed an infection at a median time of 40 [28-286] days following surgery. The incidence of infection was not higher in patients who had carmustine wafers, and this remained true in multivariate analyses to account for differences in treatment cohorts. The factors that remained significantly associated with an increased risk of infection were prior surgery [RR (95% CI); 2.026 (1.473-4.428), P = 0.01], diabetes mellitus [RR (95% CI); 6.090 (1.380-9.354)], P = 0.02], and increasing duration of hospital stay [RR (95% CI); 1.048 (1.006-1.078); P = 0.02], where the greatest risk occurred with hospital stays > 5 days [RR (95% CI); 3.904 (1.003-11.620), P = 0.05]. DISCUSSION: These findings may help guide treatment regimens aimed at minimizing infection for patients with GBM. PMID- 25916670 TI - Serum reactivity against herpes simplex virus type 1 UL48 protein in Behcet's disease patients and a Behcet's disease-like mouse model. AB - Herpes simplex virus (HSV) infection is a possible pathogenic factor in Behcet's disease (BD). Using proteomics analysis, this study detected a target HSV protein. Serum IgA and IgG reactivities against the identified protein were evaluated in patients with BD and in BD-like mice. A total of 4 protein bands generated by immunoprecipitation were analysed by proteomics, and HSV UL48 was commonly found in both IgA- and IgG-reactive protein bands. Compared with controls, patients with BD and BD-like mice exhibited higher titres of IgA reacting with recombinant HSV UL48 protein. Further proteomics analysis revealed that human heat shock cognate 71 kDa protein (Hsc71) is a cross-reacting target antigen against anti-HSV UL48 antibody. In addition, our data demonstrated a very strong association between serum IgG reactivity against recombinant human Hsc71 and recombinant HSV UL48 in patients with BD. We suggest that HSV infection and impaired human Hsc71 activity may be associated with the activation of autoreactive lymphocytes. PMID- 25916671 TI - Three-dimensional trajectory design for horizontal well based on optimal switching algorithms. AB - This paper considers a three-dimensional trajectory design problem for horizontal well. The problem is formulated as an optimal control problem of switched systems with continuous state inequality constraints. Since the complexity of such constraints and the switching instants is unknown, it is difficult to solve the problem by standard optimization techniques. To overcome the difficulty, by a time-scaling transformation, a smoothing technique and a penalty function method, an efficient computational method is proposed for solving this problem. Convergence results show that, for a sufficiently large penalty parameter, any local optimal solution of the approximate problem is also a local optimal solution of the original problem. Two numerical examples are presented to illustrate the efficiency of the approach proposed. PMID- 25916672 TI - Transcriptional activation by the thyroid hormone receptor through ligand dependent receptor recruitment and chromatin remodelling. AB - A bimodal switch model is widely used to describe transcriptional regulation by the thyroid hormone receptor (TR). In this model, the unliganded TR forms stable, chromatin-bound complexes with transcriptional co-repressors to repress transcription. Binding of hormone dissociates co-repressors and facilitates recruitment of co-activators to activate transcription. Here we show that in addition to hormone-independent TR occupancy, ChIP-seq against endogenous TR in mouse liver tissue demonstrates considerable hormone-induced TR recruitment to chromatin associated with chromatin remodelling and activated gene transcription. Genome-wide footprinting analysis using DNase-seq provides little evidence for TR footprints both in the absence and presence of hormone, suggesting that unliganded TR engagement with repressive complexes on chromatin is, similar to activating receptor complexes, a highly dynamic process. This dynamic and ligand dependent interaction with chromatin is likely shared by all steroid hormone receptors regardless of their capacity to repress transcription in the absence of ligand. PMID- 25916673 TI - Age and Obesity Promote Methylation and Suppression of 5alpha-Reductase 2: Implications for Personalized Therapy of Benign Prostatic Hyperplasia. AB - PURPOSE: In men with symptomatic benign prostatic hyperplasia 5alpha-reductase inhibitors are a main modality of treatment. More than 30% of men do not respond to the therapeutic effects of 5alpha-reductase inhibitors. We have found that a third of adult prostate samples do not express 5alpha-reductase type 2 secondary to epigenetic modifications. We evaluated whether 5alpha-reductase type 2 expression in benign prostatic hyperplasia specimens from symptomatic men was linked to methylation of the 5alpha-reductase type 2 gene promoter. We also identified associations with age, obesity, cardiac risk factors and prostate specific antigen. MATERIALS AND METHODS: Prostate samples from men undergoing transurethral prostate resection were used. We determined 5alpha-reductase type 2 protein expression and gene promoter methylation status by common assays. Clinical variables included age, body mass index, hypertension, hyperlipidemia, diabetes, prostate specific antigen and prostate volume. Univariate and multivariate statistical analyses were performed followed by stepwise logistic regression modeling. RESULTS: Body mass index and age significantly correlated with methylation of the 5alpha-reductase type 2 gene promoter (p <0.05) whereas prostate volume, prostate specific antigen or benign prostatic hyperplasia medication did not correlate. Methylation highly correlated with 5alpha-reductase protein expression (p <0.0001). In a predictive model increasing age and body mass index significantly predicted methylation status and protein expression (p <0.01). CONCLUSIONS: Increasing age and body mass index correlate with increased 5alpha-reductase type 2 gene promoter methylation and decreased protein expression in men with symptomatic benign prostatic hyperplasia. These results highlight the interplay among age, obesity and gene regulation. Our findings suggest an individualized epigenetic signature for symptomatic benign prostatic hyperplasia, which may be important to choose appropriate personalized treatment options. PMID- 25916674 TI - Transarterial Embolization of Angiomyolipoma: A Systematic Review. AB - INTRODUCTION: Transarterial embolization is increasingly used in the management of renal angiomyolipoma. The level of evidence establishing the safety and efficacy of transarterial embolization has not increased in parallel. MATERIALS AND METHODS: Using the MOOSE (Meta-analysis Of Observational Studies in Epidemiology) criteria a systematic review of transarterial embolization of angiomyolipoma was performed to establish procedural safety and efficacy. A MEDLINE(r) PubMed(r) search revealed 1,739 publications, of which 31 studies met eligibility criteria. RESULTS: A total of 524 cases of transarterial embolization of angiomyolipoma were included in analysis. Self-limiting post-embolization syndrome developed following 35.9% of embolizations and further morbidity developed in 6.9%. No procedural mortality was reported. At a mean followup of 39 months the mean size reduction was 3.4 cm (-38.3% of angiomyolipoma diameter). Unplanned repeat embolization or surgery was required in 20.9% of cases during this period. The most frequent indications for repeat procedures included angiomyolipoma revascularization in 30.0% of cases, unchanged or increasing size in 22.6%, refractory or recurring symptoms in 16.7% and representation with acute retroperitoneal hemorrhage in 14.3%. Treatment included a combination of 2 or more embolic agents in 46.8% of cases, ethanol monotherapy in 41.7%, coil monotherapy in 6.2% and foam or microparticle monotherapy in 5.2%. CONCLUSIONS: Transarterial embolization of angiomyolipoma demonstrates low rates of mortality and serious complications. Re-treatment rates and size reduction at a mean followup of 39 months are presented. Longitudinal data assessing long-term size reduction and re-treatment rates are lacking. Recommendations guiding the indications for transarterial embolization and clear followup require further longitudinal data. PMID- 25916675 TI - Neutrophil Gelatinase Associated Lipocalin is an Independent Predictor of Poor Prognosis in Cases of Papillary Renal Cell Carcinoma. AB - PURPOSE: Neutrophil gelatinase associated lipocalin, also known as lipocalin-2, is a 25 kDa protein now considered the biochemical gold standard for the early diagnosis of acute kidney injury. Recently lipocalin-2 was suggested to have an important role in several human neoplasias. In this study we assess lipocalin-2 expression in 2 renal tumor types and analyze its association with clinicopathological parameters and prognosis. MATERIALS AND METHODS: The study group included 189 patients who underwent surgery for renal lesions between 2003 and 2013. Of these patients 105 had clear cell renal cell carcinoma and 84 had papillary renal cell carcinoma. The association of lipocalin-2 immunoexpression and clinicopathological characteristics was evaluated. Cox proportional hazard regression was performed to estimate the prognostic significance of potential confounders in predicting overall and disease-free survival. RESULTS: Lipocalin-2 expression in different histotypes of analyzed tumors was highly and significantly associated with papillary renal cell carcinoma (p <0.001). In papillary renal cell carcinoma high lipocalin-2 expression was associated with high Fuhrman grade (p <0.001), tumor size greater than 7 cm (p = 0.007), increased TNM stage (p <0.001) and lymph node metastasis (p = 0.009). On univariable and multivariable Cox survival analyses of papillary renal cell carcinoma, after a median followup of 49.1 months (range 7 to 136) lipocalin-2 expression was associated with reduced overall survival (HR 4.10, 95% CI 1.19 14.14, p = 0.026) and disease-free survival (HR 2.56, 95% CI 1.01-6.48, p = 0.047). CONCLUSIONS: Lipocalin-2 over expression may be a prognostic factor in decreased overall and disease-free survival in papillary renal cell carcinoma. The association of lipocalin-2 over expression and poor prognosis with papillary renal cell carcinoma may have potential diagnostic and therapeutic utility. PMID- 25916676 TI - Sexual Health Outcomes in Adults with Complete Male Epispadias. AB - PURPOSE: Complete male epispadias is a rare congenital anomaly characterized by failed closure of the entire penopubic dorsal urethra. Epispadias repair is typically performed during infancy, and resultant genitourinary abnormalities can have a marked impact on adult life. We assess long-term post-reconstruction sexual health and fertility outcomes in adults with complete male epispadias. MATERIALS AND METHODS: A total of 132 patients 18 years or older with complete male epispadias who had undergone reconstruction were identified from a prospectively maintained, institutionally approved database. Patients who could be contacted were asked to complete a telephone survey regarding sexual function. Reconstructive history and clinical details were obtained by chart/database review. RESULTS: Of 132 patients with complete male epispadias 74 met inclusion criteria and 15 (20%) completed the questionnaire. Seven patients (47%) reported currently being in a relationship. Although 12 patients (80%) reported overall satisfactory sexual intercourse, 11 (73%) admitted to 1 or more problems with sexual function, including abnormal ejaculation (53%), diminished sensation (20%) and difficulty maintaining an erection (20%). When questioned regarding the importance of fertility on a scale of 0 to 5 using a Likert-type item the response of 10 patients (67%) was 4 points or greater. Five patients (33%) reported having impregnated a sexual partner. Although 4 patients (27%) had suspicion of fertility problems, only 2 (13%) reported having abnormal semen analyses. CONCLUSIONS: This is one of few studies examining post-reconstruction sexual health and function in adults with complete male epispadias. Although small, our study demonstrates that patients are able to engage in relationships, participate in sexual intercourse and impregnate their partners. These results highlight sexual concerns and outcomes that may be of use when counselling patients with complete male epispadias and their families. PMID- 25916677 TI - In vitro evaluation of the biological effect of SOFAT on osteoblasts. AB - Osteoclastogenesis is regulated by osteoblasts especially through the production of receptor activator of nuclear factor kappa-B ligand (RANKL). Immune cells present in inflamed tissues markedly increase this process by upregulating RANKL directly or by secreting proinflammatory cytokines, which stimulate RANKL expression by osteoblasts. A novel T-cell-secreted cytokine, termed secreted osteoclastogenic factor of activated T cells (SOFAT) was recently described. To better understand how SOFAT affects bone metabolism, we investigated its effect on osteoblastic cells. We demonstrate here that SOFAT did not influence MC3T3 cells viability and proliferation, evaluated by trypan blue exclusion and MTT tests, respectively. SOFAT stimulated the secretion of IL-6, IL-10 and GM-CSF in MC3T3 cells, as shown by the analysis of an inflammatory cytokines ELISA array. The upregulation of the corresponding genes was checked by qPCR. Both RANKL mRNA and protein levels did not significantly change in the presence of SOFAT, evaluated by qPCR and western blotting, respectively. In addition, analysis of a PCR array for IL6/STAT3 pathway demonstrated that SOFAT induced the expression of BCL2, IL1B, IL10, IL22, IL2RA, IL4, IL6, TNFSF10 and PIAS3, while IL2, IL21, CD4, CSF3R and TNF were repressed. Our results confirm that the SOFAT mechanism of action is RANKL-independent and indicate that, by co-opting osteoblasts to increase the production of osteoclastogenic cytokines, SOFAT may exacerbate inflammation and support osteoclast formation and bone destruction. PMID- 25916678 TI - Gastroprotective effect of andrographolide sodium bisulfite against indomethacin induced gastric ulceration in rats. AB - Andrographolide sodium bisulfite (ASB), a water-soluble sulfonate of andrographolide has been shown to possess anti-inflammatory, antipyretic and analgesic activities. However, there is no report on the gastroprotective effect of ASB against indomethacin-induced gastric ulcer. Here we investigated the possible anti-ulcerogenic potential of ASB and the underlying mechanism against indomethacin-induced gastric ulcer in rats. The ulcer area, histopathological assessment, contents of gastric mucosal glutathione (GSH), catalase (CAT), superoxide dismutase (SOD), malonaldehyde (MDA) and prostaglandin E2 (PGE2) were examined. In addition, cyclooxygenase-1 (COX-1), cyclooxygenase-2 (COX-2) mRNA expression and immunohistochemical evaluation of HSP70, Bcl-2 and Bax proteins were also investigated. Results indicated that ASB pre-treatment significantly reduced the ulcer areas induced by indomethacin compared with the vehicle group. The gastric levels of GSH, CAT and SOD were markedly increased by ASB while the level of MDA was decreased. In addition, ASB pretreatment significantly promoted the gastric PGE2 levels and up-regulated the COX-1 and COX-2 mRNA expression in comparison with the vehicle group. Immunohistochemistry analysis showed obvious up-regulation of HSP70 and Bcl-2 protein expression while suppression of Bax protein in the gastric tissue of ASB-pretreated group. Taken together, these findings indicated that the gastroprotective effect of ASB might be associated with the improvement of antioxidative status, activation of COX-mediated PGE2 synthesis, down-regulation of Bax proteins and up-regulation of Bcl-2 and HSP70 proteins. ASB might have the potential for further development as a promising alternative for antiulcer treatment. PMID- 25916679 TI - Dihydroquercetin (DHQ) ameliorated concanavalin A-induced mouse experimental fulminant hepatitis and enhanced HO-1 expression through MAPK/Nrf2 antioxidant pathway in RAW cells. AB - Autoimmune hepatitis represents a ubiquitous human health problem and has a poor prognosis. Dihydroquercetin (DHQ), a well-known antioxidant, significantly inhibits fulminant hepatitis through anti-oxidant and anti-inflammation mechanisms. In this study, we show that administration of DHQ ameliorated concanavalin A (ConA)-induced mouse liver injury by increasing the survival rate, reducing the serum ALT and AST level, preventing histopathological injuries and decreasing pro-inflammatory cytokine mRNA expression in hepatic tissue. As macrophages/Kupffer cells in oxidative stress and pro-inflammatory mediators play an important role in the pathogenesis of immune-mediated hepatitis, we further exposed mouse RAW264 macrophage cell lines to ConA in vitro and found that DHQ significantly inhibited mRNA expression and secretion of IFN-gamma and TNF-alpha in cell culture supernatant. In addition, DHQ significantly enhanced heme oxygenase-1 (HO-1) expression in a dose- and time-dependent manner via increased Nrf2 expression in cytoplasm and nuclear translocation. Furthermore, DHQ enhanced phosphorylation of three members of the mitogen-activated protein kinase (MAPK) family, and cell treatment with MEK/ERK (PD98059), p38 (SB203580) and JNK (SP600125) inhibitors reduced DHQ-induced HO-1 expression. These results indicate that DHQ possesses hepatoprotective properties against ConA-induced liver injury, which are attributed to its ability to scavenge oxidative stress and to inhibit the release of inflammatory mediators via upregulation of HO-1 activity through the MAPK/Nrf2 signaling pathway in macrophages/Kupffer cells. PMID- 25916680 TI - Microtubule-targetable fluorescent probe: site-specific detection and super resolution imaging of ultratrace tubulin in microtubules of living cancer cells. AB - Tubulins in microtubules have been recognized as potential targets in cancer chemotherapy for several years. However, their detection and imaging in living cells, especially following exposure to anticancer drugs, remains difficult to achieve. This difficulty is due to the very small cross section of microtubules and the very small changes in tubulin concentration involved. Photoswitchable fluorescent probes combined with the "super-resolution" fluorescence imaging technique present an exciting opportunity for site-specific detection and super resolution imaging of specific microscopic populations, such as tubulin. In this study, a tubulin specific photoswitchable fluorescent probe (Tu-SP), that labels and detects ultratrace levels of tubulin in microtubules of living biosystems, was designed and evaluated. To realize super-resolution fluorescence imaging, the spiropyran derivative (SP), a classic photoswitch, was introduced to Tu-SP as a fluorophore. To detect ultratrace tubulin, Tu-SP employed the tubulin inhibitor, alkaloid colchicine (Tu), as a recognition unit. Tu-SP exhibited nearly nonintrinsic fluorescence before binding to tubulin, even if there were divalent metal ions and 375 nm lasers, respectively. After binding to tubulin, a dramatic increase in fluorescence was detected within milliseconds when irradiated at 375 nm, this increase is a result of the transformation of Tu-SP into a colored merocyanine (Tu-SP-1) with fluorescence. Tu-SP was successfully used for site specific imaging of tubulin at a resolution of 20 +/- 5 nm in microtubules of living cancer cells. More importantly, the probe was suitable for site-specific and quantitative detection of trace tubulin in microtubules of living biological samples. PMID- 25916681 TI - Irisin physiology, oxidative stress, and thyroid dysfunction: What next? PMID- 25916682 TI - nMARQ Ablation for Atrial Fibrillation: Results from a Multicenter Study. AB - BACKGROUND: nMARQ is a multipolar catheter designed to simultaneously ablate at multiple sites around the pulmonary vein (PV) circumference with a single radiofrequency application. We sought to define the safety and efficacy of atrial fibrillation (AF) ablation with the nMARQ catheter. METHODS: In a multicenter study, patients with drug-refractory AF were included. Procedural outcomes were documented at 1 year. RESULTS: 374 patients underwent PV isolation using nMARQ (age 60 +/- 10 years, 264 male), of whom 263 patients had paroxysmal AF (PAF), while 111 patients had persistent AF. A total of 1,468 of 1,474 veins (99.6%) were isolated with the nMARQ catheter alone. Thirty-five (13%) PAF patients and 30 (27%) persistent AF patients underwent additional ablation at non-PV sites (2.4 +/- 1.4 non-PV sites). Procedure time for PV isolation only was 1.9 +/- 0.7 hours (fluoroscopy 24 +/- 14 minutes). Procedure time for PV isolation and non-PV ablation was 2.4 +/- 1.0 hours (fluoroscopy 30 +/- 23 minutes). Major adverse events occurred in two patients (0.5%); one esophago-pericardial fistula and a second, mortality due to sepsis of unknown cause. One-year follow-up data were available in 65 (25%) PAF and 20 (18%) persistent AF patients. Forty-two (65%) PAF and 13 (65%) persistent AF patients were free of arrhythmia at 1 year. In patients undergoing repeat procedures (n = 17) the most frequent points of PV reconnection were: anterior RSPV, inferior RIPV, and superior LSPV. CONCLUSIONS: AF ablation with nMARQ is associated with short procedure times and high acute success rates. Further research is necessary to more clearly define long-term outcome. PMID- 25916684 TI - Ruthenium-Catalyzed Oxidative Coupling of Primary Amines with Internal Alkynes through C-H Bond Activation: Scope and Mechanistic Studies. AB - The oxidative coupling of primary amines with internal alkynes catalyzed by Ru complexes is presented as a general atom-economy methodology with a broad scope of applications in the synthesis of N-heterocycles. Reactions proceed through regioselective C-H bond activation in 15 minutes under microwave irradiation or in 24 hours with conventional heating. The synthesis of 2,3,5-substituted pyridines, benzo[h]isoquinolines, benzo[g]isoquinolines, 8,9-dihydro benzo[de]quinoline, 5,6,7,8-tetrahydroisoquinolines, pyrido[3,4g]isoquinolines, and pyrido[4,3g]isoquinolines is achievable depending on the starting primary amine used. DFT calculations on a benzylamine substrate support a reaction mechanism that consists of acetate-assisted C-H bond activation, migratory insertion, and C-N bond formation steps that involve 28-30 kcal mol(-1) . The computational study is extended to additional substrates, namely, 1 naphthylmethyl-, 2-methylallyl-, and 2-thiophenemethylamines. PMID- 25916685 TI - Feline intestinal mast cell tumours: clinicopathological characterisation and KIT mutation analysis. AB - OBJECTIVES: Feline intestinal mast cell tumours (FIMCTs) are rare and reportedly characterised by poor differentiation, aggressive biological behaviour and lack of reliable therapeutic aids. KIT proto-oncogene-activating mutations have never been investigated in these tumours. This study describes the main clinicopathological and microscopic features observed in 17 FIMCTs. METHODS: Tumour degree of differentiation, proliferative activity, Kit protein expression and KIT mutations were evaluated and correlated with survival to assess their prognostic relevance. RESULTS: Ten tumours were located in the small intestine, two in the ileocaecocolic junction, and five in the large intestine. Survival times ranged from 3-538 days. Fifteen tumours were evaluated histologically, and there were six well-differentiated, six moderately differentiated and three poorly differentiated FIMCTs. The last showed a medium-to-large deposition of collagen tissue (P <0.001), and significantly higher mitotic and Ki67 indexes compared with more differentiated tumours (P = 0.011). On survival analysis, tumour degree of differentiation (P <0.001) and a mitotic index >2 (P = 0.022) were significantly associated with decreased survival times. Twelve cases showed Kit protein immunoexpression. The Kit pattern was membranous in five cases (33.3%), focal paranuclear in five (33.3%) and diffuse cytoplasmic in two (13.3%). Cytoplasmic Kit patterns were associated with a lesser differentiation (P = 0.015). Mutation analysis was successfully performed on 12 primary tumours and four lymph node metastases; however, no encoding mutation was detected. CONCLUSIONS AND RELEVANCE: Contrary to reports in the literature, FIMCTs seem to have an extremely variable biological behaviour. We propose a classification based on tumour degree of differentiation and proliferative activity. These findings need to be confirmed in larger series, and exploration of further genomic regions of KIT is warranted to clarify its role in the development and progression of these neoplasms. PMID- 25916683 TI - Homer2 regulates alcohol and stress cross-sensitization. AB - An interaction exists between stress and alcohol in the etiology and chronicity of alcohol use disorders, yet a knowledge gap exists regarding the neurobiological underpinnings of this interaction. In this regard, we employed an 11-day unpredictable, chronic, mild stress (UCMS) procedure to examine for stress alcohol cross-sensitization of motor activity as well as alcohol consumption/preference and intoxication. We also employed immunoblotting to relate the expression of glutamate receptor-related proteins within subregions of the nucleus accumbens (NAC) to the manifestation of behavioral cross sensitization. UCMS mice exhibited a greater locomotor response to an acute injection of 2 g/kg alcohol than unstressed controls and this cross-sensitization extended to alcohol intake (0-20 percent), as well as to the intoxicating and sedative properties of 3 and 5 g/kg alcohol, respectively. Regardless of prior alcohol injection (2 g/kg), UCMS mice exhibited elevated NAC shell levels of mGlu1alpha, GluN2b and Homer2, as well as lower phospholipase Cbeta within this subregion. GluN2b levels were also lower within the NAC core of UCMS mice. The expression of stress-alcohol locomotor cross-sensitization was associated with lower mGlu1alpha within the NAC core and lower extracellular signal-regulated kinase activity within both NAC subregions. As Homer2 regulates alcohol sensitization, we assayed also for locomotor cross-sensitization in Homer2 wild type (WT) and knock-out (KO) mice. WT mice exhibited a very robust cross sensitization that was absent in KO animals. These results indicate that a history of mild stress renders an animal more sensitive to the psychomotor and rewarding properties of alcohol, which may depend on neuroplasticity within NAC glutamate transmission. PMID- 25916686 TI - Pharmacokinetics and bioavailability of itraconazole oral solution in cats. AB - OBJECTIVES: The aim of this study was to describe the pharmacokinetics and bioavailability of itraconazole (ITR) oral solution in healthy cats. METHODS: The pharmacokinetics of ITR were studied in eight healthy, fasted cats after a single intravenous (IV) and oral (PO) administration at a dose of 5 mg/kg, in a two period crossover design study. Blood was obtained at predetermined intervals for the determination of ITR concentrations with high-performance liquid chromatography. Pharmacokinetic characterisation was performed by a non compartmental method using WinNonlin 5.2.1. RESULTS: After IV administration, the major pharmacokinetic parameters were as follows (mean +/- SD): terminal elimination half-life (T1/2lambdaz ) 15.8 +/- 1.88 h; area under the curve from time zero to infinity (AUC0-infinity ) 13.9 +/- 3.17 h.MUg/ml; total body clearance 0.37 +/- 0.08 l/h/kg; apparent volume of distribution 8.51 +/- 1.92 l/kg; mean residence time 20.6 +/- 3.95 h. After PO administration, the principal pharmacokinetic parameters were as follows (mean +/- SD): T1/2lambdaz 15.6 +/- 3.20 h; AUC0-infinity 7.94 +/- 2.83 h.MUg/ml; peak concentration 0.70 +/- 0.14 MUg/ml; time of peak 1.43 +/- 0.53 h. The absolute bioavailability of ITR oral solution after oral administration was 52.1 +/- 11.6%. CONCLUSIONS AND RELEVANCE: The disposition of ITR oral solution in cats is characterised by a long terminal half-life, a short peak time and moderate bioavailability. PMID- 25916688 TI - The horse pinworm (Oxyuris equi) in archaeology during the Holocene: Review of past records and new data. AB - This paper focuses on the horse pinworm, Oxyuris equi, in archaeology during the Holocene period, and presents an overview of past published occurrences, early mentions in texts, and new data from our paleoparasitology research. This original compilation shows that the most ancient record of the horse pinworm dates to ca. 2500 years before present (ybp) in Central Asia and to ca. 2020 ybp in Western Europe. It also shows that the parasite is not detected on the American continent until contemporary periods. The role of European migrations from 1492 (Christopher Columbus) is discussed to explain the transfer of the horse pinworm from the Old World to the Americas. The absence of any record of this parasite before ca. 2500 ybp in Eurasia could be explained by parasite ecology, unfavorable sampling and scarcity of horse archeological remains. For the Americas, the absence of horse for long periods can be an additional explanation for the absence of the parasite. PMID- 25916687 TI - Audiogenic reflex seizures in cats. AB - OBJECTIVES: This study aimed to characterise feline audiogenic reflex seizures (FARS). METHODS: An online questionnaire was developed to capture information from owners with cats suffering from FARS. This was collated with the medical records from the primary veterinarian. Ninety-six cats were included. RESULTS: Myoclonic seizures were one of the cardinal signs of this syndrome (90/96), frequently occurring prior to generalised tonic-clonic seizures (GTCSs) in this population. Other features include a late onset (median 15 years) and absence seizures (6/96), with most seizures triggered by high-frequency sounds amid occasional spontaneous seizures (up to 20%). Half the population (48/96) had hearing impairment or were deaf. One-third of cats (35/96) had concurrent diseases, most likely reflecting the age distribution. Birmans were strongly represented (30/96). Levetiracetam gave good seizure control. The course of the epilepsy was non-progressive in the majority (68/96), with an improvement over time in some (23/96). Only 33/96 and 11/90 owners, respectively, felt the GTCSs and myoclonic seizures affected their cat's quality of life (QoL). Despite this, many owners (50/96) reported a slow decline in their cat's health, becoming less responsive (43/50), not jumping (41/50), becoming uncoordinated or weak in the pelvic limbs (24/50) and exhibiting dramatic weight loss (39/50). These signs were exclusively reported in cats experiencing seizures for >2 years, with 42/50 owners stating these signs affected their cat's QoL. CONCLUSIONS AND RELEVANCE: In gathering data on audiogenic seizures in cats, we have identified a new epilepsy syndrome named FARS with a geriatric onset. Further studies are warranted to investigate potential genetic predispositions to this condition. PMID- 25916689 TI - Sexual functioning in breast cancer survivors experiencing body image disturbance. AB - BACKGROUND: Breast cancer treatments and the traumatic nature of the cancer experience frequently elicit considerable sexual difficulties. Breast cancer survivors (BCS) experiencing body image (BI) issues may represent a vulnerable group for developing sexual dysfunction posttreatment. The current study explores sexual functioning (SF) in this unique clinical group. METHODS: A descriptive study assessed 127 BCS who were engaged in sexual activity. Standardized baseline measures included the following: BI Scale, BI after Breast Cancer Questionnaire, Female Sexual Function Index (FSFI), Kansas Marital Satisfaction Scale, and Functional Assessment of Cancer Therapy - Breast. Levels of SF were compared with BCS, heterogeneous cancer, and healthy female populations. Correlational analyses were conducted between SF, BI, relationship, and health-related quality of life variables. Guided by a conceptual framework, regression analyses were conducted to determine significant demographic, clinical, and psychosocial predictors of sexual desire, satisfaction, and overall SF. RESULTS: Eighty-three per cent of BCS met the FSFI clinical cutoff score for a sexual dysfunction. Participants exhibited poorer SF when compared with other female cancer and healthy groups. No significant correlations were found between BI questionnaire total scores and SF. BI after Breast Cancer Questionnaire - Body Stigma subscale showed significant associations with FSFI Arousal, Orgasm, Satisfaction (average r = -0.23), and overall SF (r = -0.25). Vaginal dryness (beta = -0.50), body stigma (beta = 0.24), and relationship satisfaction (beta = 0.27) were significant predictors of overall SF. CONCLUSION: Difficulties in SF appear to be highly prevalent in BCS experiencing BI disturbance posttreatment. Brief screening tools assessing SF should adopt a biopsychosocial model, which includes questions regarding vaginal dryness, relationship satisfaction, and body stigma issues. PMID- 25916690 TI - Comparative study between amniotic-fluid mesenchymal stem cells and retinal pigmented epithelium (RPE) stem cells ability to differentiate towards RPE cells. AB - Dysfunction of the retinal pigmented epithelium (RPE) is one of the first effects of dry age-related macular degeneration (AMD) with consequent blindness. Hence, patients affected by this retinal disorder could benefit from a cell-based transplantation strategy for RPE. Actually, an effective protocol to approach this problem is lacking, though recently, it has been postulated the existence of a subpopulation of RPE stem cells (RPESCs) derived from adult RPE and able to reconstitute a functional RPE. On the other hand, the evidence related to the differentiative potential of human mesenchymal stem cells (MSCs) is continuously increasing. Among others, amniotic fluid-derived MSCs (AF-MSCs) may be a promising candidate, since these cells are characterized by high proliferation and differentiative potential. In this study, AF-MSCs and RPESCs were isolated, characterized to assay their stemness and induced to neuronal/retinal differentiation; specific RPE markers were then analyzed. Our results indicate that RPESCs are more suitable candidates for RPE replacement than AF-MSCs. PMID- 25916691 TI - Applying Biopharmaceutical Classification System (BCS) Criteria to Predict Oral Absorption of Drugs in Dogs: Challenges and Pitfalls. AB - The Biopharmaceutical Classification System (BCS) has been a prognostic tool for assessing the potential effects of formulation on the human drug oral bioavailability. When used in conjunction with in vitro dissolution tests, the BCS can support the prediction of in vivo product performance and the development of mechanistic models that support formulation assessments through the generation of "what if" scenarios. To date, the applicability of existing human BCS criteria has not been evaluated in dogs, thereby limiting its use in canine drug development. Therefore, we examined 50 drugs for which absolute bioavailability (F) was available both in dogs and humans. The drugs were also evaluated for any potential association between solubility (calculated from the dose number, Do) or lipophilicity (LogP) and F in dogs. In humans, solubility is determined in 250 mL of fluid. However, the appropriate volume for classifying drug solubility in dogs has not been established. In this analysis, the estimated volume of a water flush administered to fasted dogs (6 mL) and a volume of 250 mL scaled to a Beagle dog (35 mL) were examined. In addition, in humans, a Do value greater than 1.0 is used to define a compound as highly soluble and a LogP value greater than 1.72 as high permeability. These same criteria were applied for defining highly soluble and highly permeable in dogs. Whether using 35 or 6 mL to determine Do, the canine solubility classification remained unchanged for all but seven compounds. There were no clear associations between a drug's F in dogs and humans or between the canine value of F and either its human BCS classification, its LogP value, or the canine Do estimate. There was a tendency for those drugs with canine values of F equal to or greater than 80% to have LogP values equal to or greater than 1.0. Exceptions to this observation tended to be those compounds known to be absorbed via mechanisms other than passive diffusion (e.g., via transporters or paracellular transporters). Although there are limitations to the approach used in this study, the results of our assessment strongly suggest that the human BCS classification system requires substantial modification before it can be reliably applied to dogs. PMID- 25916692 TI - Point-of-care haemostasis monitoring during liver transplantation reduces transfusion requirements and improves patient outcome. AB - BACKGROUND: Optimal haemostasis management can improve patient outcomes and reduce blood loss and transfusion volume in orthotopic-liver-transplant (OLT). METHODS: We performed a prospective study including 200 consecutive OLTs. The first 100 patients were treated according to the clinic's standards and the next 100 patients were treated using the new point-of-care (POC)-based haemostasis management strategy. Transfusion parameters and other outcomes were compared between groups. RESULTS: Transfusion requirements were reduced in the POC group. The median and IQR of red-blood-cells (RBC) transfusion units were reduced from 5 [2-8] to 3 [0-5] (p < 0.001), plasma from 2 [0-4] to 0 (p < 0.001), and platelets from 1 [0-4] to 0 [0-1] (p < 0.001), into the POC group only four patients received tranexamic acid and fibrinogen transfusion rate was 1.13 +/- 1.44 g (p = 0.001). We also improved the incidence of transfusion avoidance, 5% vs. 24% (p < 0.001) and reduced the incidence of massive transfusion (defined as the transfusion of more than 10 RBC units), 13% vs. 2% (p = 0.005). We also observed a relationship between RBC transfusion requirements and preoperative haemoglobin, and between platelet transfusion and preoperative fibrinogen levels. The incidence of postoperative complications, such as, reoperation for bleeding, acute-kidney-failure or haemodynamic instability was significantly lower (13.0% vs. 5%, p = 0.048, 17% vs. 2%, p < 0.001, and 29% vs. 16%, p = 0.028). Overall, blood product transfusion was associated with increased risk of postoperative complications. CONCLUSIONS: A haemostatic therapy algorithm based on POC monitoring reduced transfusion and improved outcome in OLT. PMID- 25916693 TI - Gas chromatography-mass spectrometry microanalysis of alpha- and gamma-tocopherol in plasma and whole blood. AB - BACKGROUND: Assessing vitamin E status in humans is critical for nutritional evaluation and verification of clinical and biological compliance of supplemented subjects. An accurate analytical method for measuring the two main vitamin E isoforms, i.e. alpha- and gamma-tocopherol (alpha- and gamma-TOH) in small volumes of plasma can facilitate the application of this analysis to clinical trials and in situations where a limited amount of sample is available. METHODS: We have developed a micro method, which uses only 5 MUL plasma, based on isotope dilution, trimethylsilation and GC-MS. The method was validated according to the guidelines of the International Conference on Harmonization of analytical procedures. The method was also applied to 5 MUL of whole blood for the potential use in conditions were the availability of specimens is limited. RESULTS: Accurate quantitation of alpha-TOH and gamma-TOH was achieved at levels >= 0.417 MUM and >= 0.007 MUM, respectively. Within-day coefficient of variation was 1.31% and 4.70% for alpha-TOH and gamma-TOH, respectively. Between-day coefficient of variation was 1.32% and 2.88% for alpha-TOH and gamma-TOH, respectively. Recovery, assessed at three concentration levels, ranged 98-103% and 100-102% for alpha-TOH and gamma-TOH, respectively. The method allowed the detection of alpha TOH and gamma-TOH in 5 MUL whole blood and in membranes of red blood cells washed from 5 MUL of blood as well. The analytical performance was assessed in plasma from a cohort of Italian healthy subjects (n = 205). The mean plasma concentrations were 28.01 +/- 6.31 and 0.68 +/- 0.48 MUM (mean +/- SD) for alpha TOH and gamma-TOH, respectively. Alpha-TOH correlated with total cholesterol (r = 0.617, p < 0.0001) and triglycerides (r = 0.420, p < 0.0001) while gamma-TOH correlated modestly with total cholesterol (r = 0.213, p < 0.0001) but not with triglycerides. gamma-TOH, but not alpha-TOH, was significantly lower in smokers than in non-smokers (0.72 +/- 0.50 vs. 0.56 +/- 0.37, MUM, mean +/- SD, p = 0.017). Given the high sensitivity, the method allowed to be applied to 5 MUM whole blood without specific modification. CONCLUSIONS: This micro-method represents an analytical advancement in alpha- and gamma-TOH assay that is available to accurately verify the nutritional status and compliance after supplementation in large-scale settings, and to measure the two vitamers in conditions where sample availability is limited. PMID- 25916694 TI - Melatonin and male reproduction. AB - Melatonin is a neurohormone secreted by the pineal gland whose concentrations in the body are regulated by both the dark-light and seasonal cycles. The reproductive function of seasonal breeding animals is clearly influenced by the circadian variation in melatonin levels. Moreover, a growing body of evidence indicates that melatonin has important effects in the reproduction of some non seasonal breeding animals. In males, melatonin affects reproductive regulation in three main ways. First, it regulates the secretion of two key neurohormones, GnRH and LH. Second, it regulates testosterone synthesis and testicular maturation. Third, as a potent free radical scavenger that is both lipophilic and hydrophilic, it prevents testicular damage caused by environmental toxins or inflammation. This review summarizes the existing data on the possible biological roles of melatonin in male reproduction. Overall, the literature data indicate that melatonin affects the secretion of both gonadotropins and testosterone while also improving sperm quality. This implies that it has important effects on the regulation of testicular development and male reproduction. PMID- 25916695 TI - Individualized fortification of breast milk in 41 Extremely Low Birth Weight (ELBW) preterm infants. AB - BACKGROUND: The use of breast milk presents numerous early and long-term advantages for ELBW preterms. However, breast milk without fortification does not cover the high nutritional needs of such patients. The aim of our study was to assess the effect of individualized fortification of breast milk on the growth of ELBWs hospitalized in a neonatal intensive care unit (NICU). METHODS: Retrospective single-center observational study. RESULTS: We assessed the growth of 41 consecutive ELBWs (21 females, 20 males) with gestational ages between 23 and 30 weeks (mean GA 26.31+/-1.8) fed with breast milk in an individualized way. The rate of growth as the mean weight increase with breast milk fortification was 16.04+/-3.13 g/kg/day, more than the growth of the fetus in the uterus (~15 g/kg/day). This result was confirmed also among the ELBWs of lower GA. However, only 24.4% of all the ELBWs at the time of discharge from the NICU presented an appropriate weight for their gestational age. No cases of Necrotizing Enterocolitis (NEC) were observed. CONCLUSIONS: Despite high growth velocity, the ELBWs failed to remain in the same percentiles of birth and, at discharge, only 27.7% had a weight of >10 centiles. Further studies are needed to improve growth during early critical phases of development. PMID- 25916696 TI - Analytical performance evaluation of the i-STAT Total beta-human chorionic gonadotropin immunoassay. AB - BACKGROUND: The ability to perform quantitative hCG testing in whole blood at the point-of-care is desirable. The purpose of this study was to perform an analytical validation of the Abbott i-STAT Total beta-hCG test. METHODS: Whole blood, plasma, and serum samples were prepared by the addition of hCG and were used to evaluate precision, linearity, analytical sensitivity, accuracy, the high dose hook effect, and dilution recovery. RESULTS: Imprecision was highest with whole blood (CV = 16.0% and 6.7% at 10 and 1184 IU/l, respectively) and lowest in serum (CV = 8.1% and 4.3% at 11 and 1305 IU/l, respectively). The limits-of quantitation were 8 and <5 IU/l for whole blood and both plasma and serum, respectively. The assay was linear between 5 and 2000 IU/l in all sample types (R(2) >= 0.998). i-STAT results agreed most closely with the Architect Total beta hCG assay and with greater differences observed with Beckman DxI Total betahCG and Roche Cobas e601 hCG+beta assays (mean differences across all sample types were 9.3% and 12.3%, respectively). A high-dose hook effect was observed at concentrations > 400,000 IU/l. Accuracy was achieved in samples diluted with serum but not saline. CONCLUSIONS: The i-STAT Total beta-hCG test demonstrates acceptable performance for quantifying hCG in whole blood, plasma and serum. PMID- 25916697 TI - Reply: To PMID 25692959. PMID- 25916698 TI - Concurrent inhibition of MYC and BCL2 is a potentially effective treatment strategy for double hit and triple hit B-cell lymphomas. AB - Double hit lymphoma or triple hit lymphoma (DHL/THL) is a rare form of aggressive B-Cell Lymphoma. Overexpression of MYC, BCL2 or/and BCL6 due to genomic rearrangements are the key molecular features of DHL/THL. Patients with DHL/THL show very aggressive disease course and poor survival due to the lack of effective treatment modalities. Here, we established new THL cell model and assessed its in vitro growth characteristics along with the DHL cell line in response to potent MYC inhibitors, 10058-F4 and JQ-1, and a BCL2 inhibitor, ABT 199, with or without chemotherapeutic agent vincristine or doxorubicin. We found that 10058-F4, JQ-1 or ABT-199 exposure as a single agent inhibited the growth of DHL/THL cells in a dose-dependent manner. Combined exposure of 10058-F4 or JQ-1 and ABT-199 as well as vincristine or doxorubicin markedly suppressed the growth of DHL/THL cells compared with the single treatment. As assessed by multiple approaches, apoptosis induced by ABT-199, 10058-F4 or JQ-1 was underlying cause of the observed growth suppression. These findings suggest that co-inhibition of MYC and BCL2 signaling is a promising therapeutic strategy for patients with DHL/THL lymphomas. PMID- 25916699 TI - Celecoxib sensitizes imatinib-resistant K562 cells to imatinib by inhibiting MRP1 5, ABCA2 and ABCG2 transporters via Wnt and Ras signaling pathways. AB - Imatinib mesylate, a tyrosine kinase inhibitor, is very effective in the treatment of chronic myeloid leukemia (CML). However, development of resistance to imatinib therapy is also a very common mechanism observed with long-term administration of the drug. Our previous studies have highlighted the role of cyclooxygenase-2 (COX-2) in regulating the expression of multidrug resistant protein-1 (MDR1), P-gp, in imatinib-resistant K562 cells (IR-K562) via PGE2-cAMP PKC-NF-kappaB pathway and inhibition of COX-2 by celecoxib, a COX-2 specific inhibitor, inhibits this pathway and reverses the drug resistance. Studies have identified that not only MDR1 but other ATP-binding cassette transport proteins (ABC transporters) are involved in the development of imatinib resistance. Here, we tried to study the role of COX-2 in the regulation of other ABC transporters such as MRP1, MRP2, MRP3, ABCA2 and ABCG2 that have been already implicated in imatinib resistance development. The results of the study clearly indicated that overexpression of COX-2 lead to upregulation of MRP family proteins in IR-K562 cells and celecoxib down-regulated the ABC transporters through Wnt and MEK signaling pathways. The study signifies that celecoxib in combination with the imatinib can be a good alternate treatment strategy for the reversal of imatinib resistance. PMID- 25916700 TI - Tissue mechanics of piled critical size biomimetic and biominerizable nanocomposites: Formation of bioreactor-induced stem cell gradients under perfusion and compression. AB - BACKGROUND: Perfusion bioreactors are used to solve problems in critical size bone tissue engineering. Biominerizable and biocompatible nanocomposites are suitable scaffold materials for this purpose because they offer mineral components in organic carriers. Human adipose derived stem cells (ASCs) can potentially be used to increase bone healing. MATERIALS AND METHODS: Electrospun nanocomposite disks of poly-lactic-co-glycolic acid and amorphous calcium phosphate nanoparticles (PLGA/a-CaP) were seeded with ASCs and eight disks were stacked in a bioreactor running with normal culture. Under perfusion and uniaxial cyclic compression, load-displacement curves as a function of time were assessed. Stiffness and energy dissipation were recorded. Moreover, stem cell densities in the layers of the piled scaffold were determined as well as their morphologies and differentiation status. RESULTS: While the stiffness of the cell free constructs increased over time based on the transformation of the a-CaP nanoparticles into flake-like apatite, ASC-seeded constructs showed a constant stiffness. Stem cell density gradients had a linear increase from the bottom to the top of the pile (r(2)>0.95). Stem cells were getting more roundish at higher flow rates. Some osteogenesis was found upon osteopontin immunostaining, while no endothelial cell differentiation and no chondrogenesis was triggered. CONCLUSIONS: The fabrication of a critical size bone graft is presented based on a biominerizable bone-biomimetic nanocomposite with preserved stiffness when seeded with ASCs. The cell densities of ASCs inside the piled construct varied with a linear gradient. Beginning osteogenesis was triggered by the dynamic culture conditions including perfusion and compression. PMID- 25916702 TI - A high-throughput confocal fluorescence microscopy platform to study DNA replication stress in yeast cells. AB - High-throughput imaging of yeast cells expressing fluorescent proteins can be used to understand biological pathways in the context of spatial organization. Here we describe a method for imaging yeast cells expressing proteins tagged with green fluorescent protein (GFP) and/or red fluorescent protein (RFP), with or without drug treatment, in a 384-well format, using the PerkinElmer Opera high content confocal imaging microscope. PMID- 25916701 TI - Allopurinol and 5-aminosalicylic acid influence thiopurine-induced hepatotoxicity in vitro. AB - INTRODUCTION: The use of thiopurines is frequently accompanied by hepatotoxicity. Studies on hepatocyte cultures showed a time- and dose-dependent increase of thiopurine toxicity. 5-Aminosalicylic acid (5-ASA) and allopurinol can influence thiopurine metabolism; however, it is unknown whether this affects in vitro cytotoxicity. METHODS: Human hepatoma cells (Huh7, HepG2 and HepaRG) were incubated with increasing concentrations of thiopurines, 5-ASA or allopurinol. Water-soluble tetrazolium salt-1 (WST-1) cytotoxicity assays were used to calculate cell survival curves and half maximal inhibitory concentrations (IC50). Combination experiments with thiopurines with a fixed dose of 200 MUM 5-ASA or 100 MUM allopurinol were conducted in HepaRG cells. Caspase-3/7 activation was evaluated, and single cell electrophoresis analysis was performed. RESULTS: A time- and dose-related cytotoxic effect was seen with azathioprine (AZA) in all hepatoma cells, whereas Huh7 and HepG2 cells did not show toxicity to 6 mercaptopurine (6-MP). HepaRG cells expressed the highest levels of drug metabolising enzymes, and therefore, combination experiments were conducted in HepaRG cells. Addition of a non-toxic dose of allopurinol resulted in a twofold to threefold increased cytotoxicity of all thiopurines, which seemed to be mediated by apoptosis/DNA damage. CONCLUSION: The addition of allopurinol to thiopurines leads to a two-threefold increased cytotoxicity in HepaRG cells. PMID- 25916703 TI - Microscopy techniques to examine DNA replication in fission yeast. AB - Temporal and spatial visualization of replication proteins and associated structures within the narrow confines of a yeast nucleus is technically challenging. Choosing the appropriate method depends upon the parameters of the experiment, the nature of the molecules to be observed, and the hypothesis to be tested. In this chapter, we review three broad types of visualization: whole-cell fluorescence or immunofluorescence, which is useful for questions of timing and chromatin association; nuclear spreads, which provide greater resolution within the chromatin for co-localization and region-specific effects; and chromatin fibers, which allow observation of labeled proteins and newly synthesized DNA on a linear chromosome. We also suggest a mounting procedure for live fission yeast with fluorescent proteins. We discuss applications of these protocols and some considerations for choosing methods and fluorophores. PMID- 25916704 TI - High-resolution analysis of Mammalian DNA replication units. AB - Genomic DNA of a eukaryotic cell is replicated once during the S-phase of the cell cycle to precisely maintain the complete genetic information. In the course of S-phase, semiconservative DNA synthesis is sequentially initiated and performed at thousands of discrete patches of the DNA helix termed replicons. At any given moment of S-phase, multiple replicons are active in parallel in different parts of the genome. In the last decades, tools and methods to visualize DNA synthesis inside cells have been developed. Pulse labeling with nucleotides as well as detecting components of the replication machinery yielded an overall picture of multiple discrete sites of active DNA synthesis termed replication foci (RFi) and forming spatiotemporal patterns within the cell nucleus. Recent advances in fluorescence microscopy and digital imaging in combination with computational image analysis allow a comprehensive quantitative analysis of RFi and provide valuable insights into the organization of the genomic DNA replication process and also of the genome itself. In this chapter, we describe in detail protocols for the visualization and quantification of RFi at different levels of optical and physical resolution. PMID- 25916705 TI - Analyzing the dynamics of DNA replication in Mammalian cells using DNA combing. AB - How cells duplicate their chromosomes is a key determinant of cell identity and genome stability. DNA replication can initiate from more than 100,000 sites distributed along mammalian chromosomes, yet a given cell uses only a subset of these origins due to inefficient origin activation and regulation by developmental or environmental cues. An impractical consequence of cell-to-cell variations in origin firing is that population-based techniques do not accurately describe how chromosomes are replicated in single cells. DNA combing is a biophysical DNA fiber stretching method which permits visualization of ongoing DNA synthesis along Mb-sized single-DNA molecules purified from cells that were previously pulse-labeled with thymidine analogues. This allows quantitative measurements of several salient features of chromosome replication dynamics, such as fork velocity, fork asymmetry, inter-origin distances, and global instant fork density. In this chapter we describe how to obtain this information from asynchronous cultures of mammalian cells. PMID- 25916706 TI - Measuring DNA content by flow cytometry in fission yeast. AB - Flow cytometry is an essential tool to monitor DNA content and determine cell cycle distribution. Its utility in fission yeast reflects the ease of sample preparation, the stochiometric binding of the most popular DNA dyes (propidium iodide and Sytox Green), and ability to monitor cell size. However, the study of DNA replication with multicolour flow analysis has lagged behind its use in mammalian cells. We present basic and advanced protocols for analysis of DNA replication in fission yeast by flow cytometry including whole cell, nuclear "ghosts," two-color imaging with BrdU, and estimates of DNA synthesis using EdU. PMID- 25916707 TI - Incorporation of thymidine analogs for studying replication kinetics in fission yeast. AB - Labeling DNA during in vivo replication by the incorporation of exogenous thymidine and thymidine analogs has been a mainstay of DNA replication and repair studies for decades. Unfortunately, thymidine labeling does not work in fungi, because they lack the thymidine salvage pathway required for uptake of exogenous thymidine. This obstacle to thymidine labeling has been overcome in yeast by engineering a minimal thymidine salvage pathway consisting of a nucleoside transporter to allow uptake of exogenous thymidine from the medium and a thymidine kinase to phosphorylate the thymidine into thymidine monophosphate, which can be used by the cell. This chapter describes the labeling of fission yeast, Schizosaccharomyces pombe, with the thymidine analog BrdU in order to identify sites and determine kinetics of DNA replication. PMID- 25916708 TI - EdU Incorporation for FACS and Microscopy Analysis of DNA Replication in Budding Yeast. AB - DNA replication is a key determinant of chromosome segregation and stability in eukaryotes. The yeast Saccharomyces cerevisiae has been extensively used for cell cycle studies, yet simple but key parameters such as the fraction of cells in S phase in a population or the subnuclear localization of DNA synthesis have been difficult to gather for this organism. 5-ethynyl-2'-deoxyuridine (EdU) is a thymidine analogue that can be incorporated in vivo and later detected using copper-catalyzed azide alkyne cycloaddition (Click reaction) without prior DNA denaturation. This chapter describes a budding yeast strain and conditions that allow rapid EdU incorporation at moderate extracellular concentrations, followed by its efficient detection for the analysis of DNA replication in single cells by flow cytometry and fluorescence microscopy. PMID- 25916709 TI - Determination of deoxyribonucleoside triphosphate concentrations in yeast cells by strong anion-exchange high-performance liquid chromatography coupled with ultraviolet detection. AB - DNA polymerase assays are commonly used for the detection of deoxyribonucleoside triphosphates (dNTPs) in biological samples. For better specificity and accuracy, high-performance liquid chromatography (HPLC) methods have been developed for the analysis of the four dNTPs in complex samples. Here we describe a simple method using isocratic strong anion-exchange (SAX) chromatographic separation coupled with ultraviolet detection (UV) for the analysis of the four dNTPs in budding yeast Saccharomyces cerevisiae. This method can be applied to other species of yeast or bacteria. PMID- 25916710 TI - Measuring ribonucleotide incorporation into DNA in vitro and in vivo. AB - Ribonucleotides are incorporated into genomes by DNA polymerases, they can be removed, and if not removed, they can have deleterious and beneficial consequences. Here, we describe an assay to quantify stable ribonucleotide incorporation by DNA polymerases in vitro, and an assay to probe for ribonucleotides in each of the two DNA strands of the yeast nuclear genome. PMID- 25916711 TI - Detection and Sequencing of Okazaki Fragments in S. cerevisiae. AB - We have previously demonstrated that lagging-strand synthesis in budding yeast is coupled with chromatin assembly on newly synthesized DNA. Using a strain of S. cerevisiae in which DNA ligase I can be conditionally depleted, we can enrich and purify Okazaki fragments. We delineate a method to extract, end label, and visualize Okazaki fragments using denaturing agarose gel electrophoresis. Furthermore, we describe an ion-exchange chromatographic method for purification of fragments and preparation of strand-specific sequencing libraries. Deep sequencing of Okazaki fragments generates a comprehensive, genomic map of DNA synthesis, starting from a single asynchronous culture. Altogether this approach represents a tractable system to investigate key aspects of DNA replication and chromatin assembly. PMID- 25916712 TI - ChIP-Seq to Analyze the Binding of Replication Proteins to Chromatin. AB - Chromatin immunoprecipitation (ChIP) is a widely used method to study interactions between proteins and discrete chromosomal loci in vivo. ChIP was originally developed for in vivo analysis of protein associations with candidate DNA sequences known or suspected to bind the protein of interest. The advent of DNA microarrays enabled the unbiased, genome-scale identification of all DNA sequences enriched by ChIP, providing a genomic map of a protein's chromatin binding. This method, termed ChIP-chip, is broadly applicable and has been particularly valuable in DNA replication studies to map potential replication origins in Saccharomyces cerevisiae and other organisms based on the specific association of certain replication proteins with these chromosomal elements, which are distributed throughout the genome. More recently, high-throughput sequencing (HTS) technologies have replaced microarrays as the preferred method for genomic analysis of ChIP experiments, and this combination is termed ChIP Seq. We present a detailed ChIP-Seq protocol for S. cerevisiae that can be adapted for different HTS platforms and for different organisms. We also outline general schemes for data analysis; however, HTS data analyses usually must be tailored specifically for individual studies, depending on the experimental design, data characteristics, and the genome being analyzed. PMID- 25916713 TI - Chromatin immunoprecipitation to detect DNA replication and repair factors. AB - DNA replication is tightly coupled with DNA repair processes in order to preserve genomic integrity. During DNA replication, the replication fork encounters a variety of obstacles including DNA damage/adducts, secondary structures, and programmed fork-blocking sites, which are all difficult to replicate. The replication fork also collides with the transcription machinery, which shares the template DNA with the replisome complex. Under these conditions, replication forks stall, causing replication stress and/or fork collapse, ultimately leading to genomic instability. The mechanisms to overcome these replication problems remain elusive. Therefore, it is important to investigate how DNA repair and replication factors are recruited and coordinated at chromosomal regions that are difficult to replicate. In this chapter, we describe a chromatin immunoprecipitation method to locate proteins required for DNA repair during DNA replication in the fission yeast Schizosaccharomyces pombe. This method can also easily be adapted to study replisome components or chromatin-associated factors. PMID- 25916714 TI - Molecular Genetic Methods to Study DNA Replication Protein Function in Haloferax volcanii, A Model Archaeal Organism. AB - Successful high-fidelity chromosomal DNA replication is fundamental to all forms of cellular life and requires the complex interplay of a variety of essential and nonessential protein factors in a spatially and temporally coordinated manner. Much of what is known about the enzymes and mechanisms of chromosome replication has come from analysis of simple microbial model systems, such as yeast and archaea. Archaea possess a highly simplified eukaryotic-like replication apparatus, making them an excellent model for gaining novel insights into conserved aspects of protein function at the heart of the replisome. Amongst the thermophilic archaea, a number of species have proved useful for biochemical analysis of protein function, but few of these organisms are suited to genetic analysis. One archaeal organism that is genetically tractable is the mesophilic euryarchaeon Haloferax volcanii, a halophile that grows aerobically in high salt medium at an optimum temperature of 40-45 degrees C and with a doubling time of 2-3 h. The Hfx. volcanii genome has been sequenced and a range of methods have been developed to allow reverse genetic analysis of protein function in vivo, including techniques for gene replacement and gene deletion, transcriptional regulation, point mutation and gene tagging. Here we briefly summarize current knowledge of the chromosomal DNA replication machinery in the haloarchaea before describing in detail the molecular methods available to probe protein structure and function within the Hfx. volcanii replication apparatus. PMID- 25916715 TI - Single-molecule observation of prokaryotic DNA replication. AB - Replication of DNA requires the coordinated activity of a number of proteins within a multiprotein complex, the replisome. Recent advances in single-molecule techniques have enabled the observation of dynamic behavior of individual replisome components and of the replisome as a whole, aspects that previously often have been obscured by ensemble averaging in more classical solution-phase biochemical experiments. To improve robustness and reproducibility of single molecule assays of replication and allow objective analysis and comparison of results obtained from such assays, common practices should be established. Here, we describe the technical details of two assays to study replisome activity. In one, the kinetics of replication are observed as length changes in DNA molecules mechanically stretched by a laminar flow applied to attached beads. In the other, fluorescence imaging is used to determine both the kinetics and stoichiometry of individual replisome components. These in vitro single-molecule methods allow for elucidation of the dynamic behavior of individual replication proteins of prokaryotic replication systems. PMID- 25916716 TI - Analyzing the Response to Dysfunction Replication Forks Using the RTS1 Barrier System in Fission Yeast. AB - The study of how eukaryotic cells overcome problems associated with dysfunctional DNA replication forks is assisted by experimental systems that allow site specific replication fork arrest. Here we provide protocols for the use of the fission yeast RTS1 replication fork barrier. The RTS1 barrier is a directional, or polar, replication fork barrier that evolved to ensure directional replication of the fission yeast mating-type locus. We have moved the 859 bp RTS1 sequence to another locus in the genome and demonstrated that it arrests replication forks in a dysfunctional confirmation and that replication is restarted within ~20 min by the action of homologous recombination. We describe here the barrier constructs currently available, the methods by which we regulate the activity of the barrier, how to synchronize cells for analysis of replication intermediates by 2D gel electrophoresis, and the use of a replication slippage assay to measure fork fidelity. PMID- 25916717 TI - Purification of restriction fragments containing replication intermediates from complex genomes for 2-D gel analysis. AB - In order to perform 2-D gel analyses on restriction fragments from higher eukaryotic genomes, it is necessary to remove most of the linear, nonreplicating, fragments from the starting DNA preparation. This is so because the replication intermediates in a single-copy locus constitute such a minute fraction of all of the restriction fragments in a standard DNA preparation-whether isolated from synchronized or asynchronous cultures. Furthermore, the very long DNA strands that characterize higher eukaryotic genomes are inordinately subject to branch migration and shear. We have developed a method that results in significant enrichment of replicating fragments that largely maintain their branched intermediates. The method depends upon two important factors: (1) replicating fragments in higher eukaryotic nuclei appear to be attached to the nuclear matrix in a supercoiled fashion, and (2) partially single-stranded fragments (e.g., those containing replication forks) are selectively adsorbed to benzoylated naphthoylated DEAE (BND)-cellulose in high salt concentrations. By combining matrix-enrichment and BND-cellulose chromatography, it is possible to obtain preparations that are enriched as much as 200-fold over the starting genomic DNA, and are thus suitable for analysis on 2-D gels. PMID- 25916718 TI - Isolation of restriction fragments containing origins of replication from complex genomes. AB - The identification and isolation of origins of replication from mammalian genomes has been a demanding task owing to the great complexity of these genomes. However, two methods have been refined in recent years each of which allows significant enrichment of recently activated origins of replication from asynchronous cell cultures. In one of these, nascent strands are melted from the long template DNA, and the small, origin-centered strands are isolated on sucrose gradients. The second method involves the selective entrapment of bubble containing fragments in gelling agarose and their subsequent recovery and isolation by molecular cloning. Libraries prepared by this method from Chinese hamster and human cells have been shown to be extremely pure, and provide a renewable resource of origins that can be used as probes on microarrays or sequenced by high-throughput techniques to localize them within the genomic source. The bubble-trapping method is described here for asynchronous mammalian cells that grow with reasonable doubling times and from which nuclear matrices can be reliably prepared. The method for nuclear matrix preparation and enrichment of replication intermediates is described in an accompanying chapter entitled "Purification of restriction fragments containing replication intermediates from mammalian cells for 2-D gel analysis" (Chapter 16 ). PMID- 25916719 TI - Children have type 2 diabetes too: an historical perspective. AB - Prior to 1985, type 2 diabetes was a disease of adults. Simultaneously with the global epidemic of childhood obesity, type 2 diabetes has increased in children. Initially, the presentation of small case series of type 2 diabetes in children was met with skepticism. As the number and size of the case series grew and the first long-term outcomes of end-stage complications in young adults appeared in the literature, the international community took notice with guarded interest. Type 2 diabetes disproportionately affects the children of specific ethnic groups and from disadvantaged socioeconomic environments, especially Indigenous populations. The past decade has seen unprecedented intense global interest in the etiology, treatment, and prevention of type 2 diabetes in children. PMID- 25916720 TI - Effect of advanced maternal age on pregnancy outcomes and vascular function in the rat. AB - Advanced maternal age is becoming increasingly common in Western societies and is associated with increased maternal and fetal morbidity and mortality. We hypothesized that aging results in impaired vascular function in pregnancy because of increased vascular oxidative stress and resultant scavenging of nitric oxide in both uterine and systemic arteries, causing reduced uteroplacental perfusion and poor pregnancy outcomes. Using aged rats (9.5 months), we investigated the effect of a delayed first natural pregnancy on pregnancy outcomes and uterine and mesenteric artery function on gestational day 20. Delayed pregnancy in the rat reduced fertility by 46%, reduced litter size by 36%, caused fetal growth restriction, increased placental weight, and increased maternal systolic blood pressure (by 16 mm Hg). Uterine arteries from aged dams displayed reduced constriction to phenylephrine (young: 14.3+/-0.94 mN/mm versus aged: 11.4+/-0.5 mN/mm, P=0.02) and potassium chloride (124 mmol/L; young: 21.8+/ 1.27 mN/mm versus aged: 14.2+/-1.7 mN/mm; P=0.01). Methacholine-induced vasodilation was similar in uterine arteries from young and aged dams. However, mesenteric arteries from aged dams had a greater nitric oxide and a reduced endothelial-derived hyperpolarization contribution to methacholine-mediated vasodilation compared with young dams. Both uterine and mesenteric arteries from aged dams had greater active myogenic responses, with area under the curve increased by 228% and 151%, in aged uterine and mesenteric arteries, respectively. These results demonstrate that vascular function is altered at an advanced maternal age and provides further insights into the risks of poor pregnancy outcomes observed in women who delay pregnancy. PMID- 25916721 TI - Aortic Blood Flow Reversal Determines Renal Function: Potential Explanation for Renal Dysfunction Caused by Aortic Stiffening in Hypertension. AB - Aortic stiffness determines the glomerular filtration rate (GFR) and predicts the progressive decline of the GFR. However, the underlying pathophysiological mechanism remains obscure. Recent evidence has shown a close link between aortic stiffness and the bidirectional (systolic forward and early diastolic reverse) flow characteristics. We hypothesized that the aortic stiffening-induced renal dysfunction is attributable to altered central flow dynamics. In 222 patients with hypertension, Doppler velocity waveforms were recorded at the proximal descending aorta to calculate the reverse/forward flow ratio. Tonometric waveforms were recorded to measure the carotid-femoral (aortic) and carotid radial (peripheral) pulse wave velocities, to estimate the aortic pressure from the radial waveforms, and to compute the aortic characteristic impedance. In addition, renal hemodynamics was evaluated by duplex ultrasound. The estimated GFR was inversely correlated with the aortic pulse wave velocity, reverse/forward flow ratio, pulse pressure, and characteristic impedance, whereas it was not correlated with the peripheral pulse wave velocity or mean arterial pressure. The association between aortic pulse wave velocity and estimated GFR was independent of age, diabetes mellitus, hypercholesterolemia, and antihypertensive medication. However, further adjustment for the aortic reverse/forward flow ratio and pulse pressure substantially weakened this association, and instead, the reverse/forward flow ratio emerged as the strongest determinant of estimated GFR (P=0.001). A higher aortic reverse/forward flow ratio was also associated with lower intrarenal forward flow velocities. These results suggest that an increase in aortic flow reversal (ie, retrograde flow from the descending thoracic aorta toward the aortic arch), caused by aortic stiffening and impedance mismatch, reduces antegrade flow into the kidney and thereby deteriorates renal function. PMID- 25916722 TI - Efficacy of B-Type Natriuretic Peptide Is Coupled to Phosphodiesterase 2A in Cardiac Sympathetic Neurons. AB - Elevated B-type natriuretic peptide (BNP) regulates cGMP-phosphodiesterase activity. Its elevation is regarded as an early compensatory response to cardiac failure where it can facilitate sympathovagal balance and cardiorenal homeostasis. However, recent reports suggest a paradoxical proadrenergic action of BNP. Because phosphodiesterase activity is altered in cardiovascular disease, we tested the hypothesis that BNP might lose its efficacy by minimizing the action of cGMP on downstream pathways coupled to neurotransmission. BNP decreased norepinephrine release from atrial preparations in response to field stimulation and also significantly reduced the heart rate responses to sympathetic nerve stimulation in vitro. Using electrophysiological recording and fluorescence imaging, BNP also reduced the depolarization evoked calcium current and intracellular calcium transient in isolated cardiac sympathetic neurons. Pharmacological manipulations suggested that the reduction in the calcium transient was regulated by a cGMP/protein kinase G pathway. Fluorescence resonance energy transfer measurements for cAMP, and an immunoassay for cGMP, showed that BNP increased cGMP, but not cAMP. In addition, overexpression of phosphodiesterase 2A after adenoviral gene transfer markedly decreased BNP stimulation of cGMP and abrogated the BNP responses to the calcium current, intracellular calcium transient, and neurotransmitter release. These effects were reversed on inhibition of phosphodiesterase 2A. Moreover, phosphodiesterase 2A activity was significantly elevated in stellate neurons from the prohypertensive rat compared with the normotensive control. Our data suggest that abnormally high levels of phosphodiesterase 2A may provide a brake against the inhibitory action of BNP on sympathetic transmission. PMID- 25916723 TI - Role of epidermal growth factor receptor and endoplasmic reticulum stress in vascular remodeling induced by angiotensin II. AB - The mechanisms by which angiotensin II (AngII) elevates blood pressure and enhances end-organ damage seem to be distinct. However, the signal transduction cascade by which AngII specifically mediates vascular remodeling such as medial hypertrophy and perivascular fibrosis remains incomplete. We have previously shown that AngII-induced epidermal growth factor receptor (EGFR) transactivation is mediated by disintegrin and metalloproteinase domain 17 (ADAM17), and that this signaling is required for vascular smooth muscle cell hypertrophy but not for contractile signaling in response to AngII. Recent studies have implicated endoplasmic reticulum (ER) stress in hypertension. Interestingly, EGFR is capable of inducing ER stress. The aim of this study was to test the hypothesis that activation of EGFR and ER stress are critical components required for vascular remodeling but not hypertension induced by AngII. Mice were infused with AngII for 2 weeks with or without treatment of EGFR inhibitor, erlotinib, or ER chaperone, 4-phenylbutyrate. AngII infusion induced vascular medial hypertrophy in the heart, kidney and aorta, and perivascular fibrosis in heart and kidney, cardiac hypertrophy, and hypertension. Treatment with erlotinib as well as 4 phenylbutyrate attenuated vascular remodeling and cardiac hypertrophy but not hypertension. In addition, AngII infusion enhanced ADAM17 expression, EGFR activation, and ER/oxidative stress in the vasculature, which were diminished in both erlotinib-treated and 4-phenylbutyrate-treated mice. ADAM17 induction and EGFR activation by AngII in vascular cells were also prevented by inhibition of EGFR or ER stress. In conclusion, AngII induces vascular remodeling by EGFR activation and ER stress via a signaling mechanism involving ADAM17 induction independent of hypertension. PMID- 25916725 TI - Aortic Stiffening, Aortic Blood Flow Reversal, and Renal Blood Flow. PMID- 25916726 TI - Emerging Role of Phosphodiesterase 2A in Hypertension. PMID- 25916724 TI - Smooth Muscle Peroxisome Proliferator-Activated Receptor gamma Plays a Critical Role in Formation and Rupture of Cerebral Aneurysms in Mice In Vivo. AB - Vascular inflammation plays a critical role in the pathogenesis of cerebral aneurysms. Peroxisome proliferator-activated receptor gamma (PPARgamma) protects against vascular inflammation and atherosclerosis, whereas dominant-negative mutations in PPARgamma promote atherosclerosis and vascular dysfunction. We tested the role of PPARgamma in aneurysm formation and rupture. Aneurysms were induced with a combination of systemic infusion of angiotensin-II and local injection of elastase in (1) mice that received the PPARgamma antagonist GW9662 or the PPARgamma agonist pioglitazone, (2) mice carrying dominant-negative PPARgamma mutations in endothelial or smooth muscle cells, and (3) mice that received the Cullin inhibitor MLN4924. Incidence of aneurysm formation, rupture, and mortality was quantified. Cerebral arteries were analyzed for expression of Cullin3, Kelch-like ECH-associated protein 1, nuclear factor (erythroid-derived 2)-like 2, NAD(P)H dehydrogenase (quinone)1 (NQO1), and inflammatory marker mRNAs. Neither pioglitazone nor GW9662 altered the incidence of aneurysm formation. GW9662 significantly increased the incidence of aneurysm rupture, whereas pioglitazone tended to decrease the incidence of rupture. Dominant negative endothelial-specific PPARgamma did not alter the incidence of aneurysm formation or rupture. In contrast, dominant-negative smooth muscle-specific PPARgamma resulted in an increase in aneurysm formation (P<0.05) and rupture (P=0.05). Dominant-negative smooth muscle-specific PPARgamma, but not dominant negative endothelial-specific PPARgamma, resulted in significant decreases in expression of genes encoding Cullin3, Kelch-like ECH-associated protein 1, and nuclear factor (erythroid-derived 2)-like 2, along with significant increases in tumor necrosis factor-alpha, monocyte chemoattractant protein-1, chemokine (C-X-C motif) ligand 1, CD68, matrix metalloproteinase-3, -9, and -13. MLN4924 did not alter incidence of aneurysm formation, but increased the incidence of rupture (P<0.05). In summary, endogenous PPARgamma, specifically smooth muscle PPARgamma, plays an important role in protecting from formation and rupture of experimental cerebral aneurysms in mice. PMID- 25916727 TI - Prognosis in relation to blood pressure variability: pro side of the argument. PMID- 25916728 TI - Prognosis in relation to blood pressure variability: con side of the argument. PMID- 25916730 TI - Jaw Bone Samples From Bisphosphonate-Treated Patients: A Pilot Cohort Study. AB - Osteonecrosis of the jaw (ONJ) is a severe complication of bisphosphonate treatment. PURPOSE: A detailed characterization of sampled peri-necrotic jawbone from bisphosphonate-treated patients was performed at tissue and cellular level (histological analyses and gene expression). MATERIALS AND METHODS: Alveolar bone samples were collected from patients with (n = 5) and without ONJ (n = 5). Healthy patients served as controls (n = 10). RESULTS: The histological analysis demonstrated low to moderate inflammation, displaying areas of inflammatory infiltrate in the bone marrow. Multinuclear giant cells and osteoclasts were found in both groups. Markers of bone formation (alkaline phosphatase, Col1a1, and osteocalcin), bone resorption (receptor activator of NF-kappaB ligand [RANKL], osteoprotegerin [OPG], tartrate-resistant acid phosphatase, and cathepsin K), inflammation (tumor necrosis factor-alpha, interleukin [IL]-1beta, and IL-6), angiogenesis (vascular endothelial growth factor A), and apoptosis (Casp3, Casp8, p53, and Smac) were evaluated. Nonparametric statistical tests were used to identify differences between the groups. In patients with ONJ, the expression level of the proinflammatory marker IL-1beta was strongly up-regulated compared with controls (p = .040). CONCLUSIONS: A down-regulated expression of Casp8 compared with controls was observed (p = .014) in patients treated with bisphosphonates. The RANKL/OPG ratios were similar in the three groups. The results indicate a need to further investigate the molecular mechanisms involved in the course of ONJ related to antiresorptive treatment. PMID- 25916729 TI - CAPON modulates neuronal calcium handling and cardiac sympathetic neurotransmission during dysautonomia in hypertension. AB - Genome-wide association studies implicate a variant in the neuronal nitric oxide synthase adaptor protein (CAPON) in electrocardiographic QT variation and sudden cardiac death. Interestingly, nitric oxide generated by neuronal NO synthase-1 reduces norepinephrine release; however, this pathway is downregulated in animal models of cardiovascular disease. Because sympathetic hyperactivity can trigger arrhythmia, is this neural phenotype linked to CAPON dysregulation? We hypothesized that CAPON resides in cardiac sympathetic neurons and is a part of the prediseased neuronal phenotype that modulates calcium handling and neurotransmission in dysautonomia. CAPON expression was significantly reduced in the stellate ganglia of spontaneously hypertensive rats before the development of hypertension compared with age-matched Wistar-Kyoto rats. The neuronal calcium current (ICa; n=8) and intracellular calcium transient ([Ca(2+)]i; n=16) were significantly larger in the spontaneously hypertensive rat than in Wistar-Kyoto rat (P<0.05). A novel noradrenergic specific vector (Ad.PRSx8-mCherry/CAPON) significantly upregulated CAPON expression, NO synthase-1 activity, and cGMP in spontaneously hypertensive rat neurons without altering NO synthase-1 levels. Neuronal ICa and [Ca(2+)]i were significantly reduced after CAPON transduction compared with the empty vector. In addition, Ad.PRSx8-mCherry/CAPON also reduced (3)H-norepinephrine release from spontaneously hypertensive rat atria (n=7). NO synthase-1 inhibition (AAAN, 10 MUmol/L; n=6) reversed these effects compared with the empty virus alone. In conclusion, targeted upregulation of CAPON decreases cardiac sympathetic hyperactivity. Moreover, dysregulation of this adaptor protein in sympathetic neurons might further amplify the negative cardiac electrophysiological properties seen with CAPON mutations. PMID- 25916731 TI - Progressive multifocal leukoencephalopathy in common variable immunodeficiency: mitigated course under mirtazapine and mefloquine. AB - Demonstration of survival and outcome of progressive multifocal leukoencephalopathy (PML) in a 56-year-old patient with common variable immunodeficiency, consisting of severe hypogammaglobulinemia and CD4+ T lymphocytopenia, during continuous treatment with mirtazapine (30 mg/day) and mefloquine (250 mg/week) over 23 months. Regular clinical examinations including Rankin scale and Barthel index, nine-hole peg and box and block tests, Berg balance, 10-m walking tests, and Montreal Cognitive Assessment (MoCA) were done. Laboratory diagnostics included complete blood count and JC virus (JCV) concentration in cerebrospinal fluid (CSF). The noncoding control region (NCCR) of JCV, important for neurotropism and neurovirulence, was sequenced. Repetitive MRI investigated the course of brain lesions. JCV was detected in increasing concentrations (peak 2568 copies/ml CSF), and its NCCR was genetically rearranged. Under treatment, the rearrangement changed toward the archetype sequence, and later JCV DNA became undetectable. Total brain lesion volume decreased (8.54 to 3.97 cm(3)) and atrophy increased. Barthel (60 to 100 to 80 points) and Rankin (4 to 2 to 3) scores, gait stability, and box and block (7, 35, 25 pieces) and nine-hole peg (300, 50, 300 s) test performances first improved but subsequently worsened. Cognition and walking speed remained stable. Despite initial rapid deterioration, the patient survived under continuous treatment with mirtazapine and mefloquine even though he belongs to a PML subgroup that is usually fatal within a few months. This course was paralleled by JCV clones with presumably lower replication capability before JCV became undetectable. Neurological deficits were due to PML lesions and progressive brain atrophy. PMID- 25916732 TI - Neurology of the H1N1 pandemic in Singapore: a nationwide case series of children and adults. AB - Neurologic complications have long been associated with influenza. A novel strain of influenza A (H1N1) first described in humans to have outbreak potential in 2009 in Mexico went on to become the first influenza pandemic of this century. We evaluated the neurologic complications of the novel influenza A (H1N1) 2009 in children and adults admitted to all public hospitals in Singapore during the influenza A (H1N1) 2009 pandemic between May 2009 and March 2010. All patients were positive for novel H1N1 infection and presented with neurologic symptoms prior to oseltamivir treatment. Ninety-eight patients (median age 6.6 years, range 0.4-62.6) were identified; 90 % were younger than 18 years; 32 % suffered from preexisting neurological, respiratory, or cardiac disease; and 66 % presented with seizures. Of those presenting with seizures, new onset seizures were the most common manifestation (n = 40, 61.5 %), followed by breakthrough seizures (n = 18, 27.7 %) and status epilepticus (n = 7, 10.8 %). Influenza associated encephalopathy occurred in 20 %. The majority of children (n = 88) presented with seizures (n = 63, 71.6 %), encephalopathy (n = 19, 21.6 %), and syncope (n = 4, 4.5 %). Among adults, a wider range of neurological conditions were seen, with half of them presenting with an exacerbation of their underlying neurological disease. The neurological symptoms developed at a median of 2 days after the onset of systemic symptoms. The median length of hospital stay was 3 days, and 79 % were monitored in general wards. Neurologic complications associated with the novel influenza A (H1N1) 2009 strain were generally mild and had a good outcome. They occurred more frequently in patients with underlying neurological disorders. Seizures and encephalopathy were the most common manifestations, similar to other influenza virus strains. PMID- 25916733 TI - Chemoprophylaxis and vaccination in preventing subsequent cases of meningococcal disease in household contacts of a case of meningococcal disease: a systematic review. AB - Household contacts of an index case of invasive meningococcal disease (IMD) are at increased risk of acquiring disease. In revising WHO guidance on IMD in sub Saharan Africa, a systematic review was undertaken to assess the effect of chemoprophylaxis and of vaccination in preventing subsequent cases of IMD in household contacts following an index case. A literature search for systematic reviews identified a single suitable review on chemoprophylaxis in 2004 (three studies meta-analysed). A search for primary research papers published since 2004 on chemoprophylaxis and without a date limit on vaccination was therefore undertaken. There were 2381 studies identified of which two additional studies met the inclusion criteria. The summary risk ratio for chemoprophylaxis vs. no chemoprophylaxis (four studies) in the 30-day period after a case was 0.16 [95% confidence interval (CI) 0.04-0.64, P = 0.008]; the number needed to treat to prevent one subsequent case was 200 (95% CI 111-1000). A single quasi-randomized trial assessed the role of vaccination. The risk ratio for vaccination vs. no vaccination at 30 days was 0.11 (95% CI 0.01-2.07, P = 0.14). The results support the use of chemoprophylaxis to prevent subsequent cases of IMD in household contacts of a case. Conclusions about the use of vaccination could not be drawn. PMID- 25916734 TI - Probabilistic topic modeling for the analysis and classification of genomic sequences. AB - BACKGROUND: Studies on genomic sequences for classification and taxonomic identification have a leading role in the biomedical field and in the analysis of biodiversity. These studies are focusing on the so-called barcode genes, representing a well defined region of the whole genome. Recently, alignment-free techniques are gaining more importance because they are able to overcome the drawbacks of sequence alignment techniques. In this paper a new alignment-free method for DNA sequences clustering and classification is proposed. The method is based on k-mers representation and text mining techniques. METHODS: The presented method is based on Probabilistic Topic Modeling, a statistical technique originally proposed for text documents. Probabilistic topic models are able to find in a document corpus the topics (recurrent themes) characterizing classes of documents. This technique, applied on DNA sequences representing the documents, exploits the frequency of fixed-length k-mers and builds a generative model for a training group of sequences. This generative model, obtained through the Latent Dirichlet Allocation (LDA) algorithm, is then used to classify a large set of genomic sequences. RESULTS AND CONCLUSIONS: We performed classification of over 7000 16S DNA barcode sequences taken from Ribosomal Database Project (RDP) repository, training probabilistic topic models. The proposed method is compared to the RDP tool and Support Vector Machine (SVM) classification algorithm in a extensive set of trials using both complete sequences and short sequence snippets (from 400 bp to 25 bp). Our method reaches very similar results to RDP classifier and SVM for complete sequences. The most interesting results are obtained when short sequence snippets are considered. In these conditions the proposed method outperforms RDP and SVM with ultra short sequences and it exhibits a smooth decrease of performance, at every taxonomic level, when the sequence length is decreased. PMID- 25916735 TI - Regioselective alkylation of 1,3,4,5-tetrahydrobenzo[d]azepin-2-one and biological evaluation of the resulting alkylated products as potentially selective 5-HT2c agonists. AB - The benzazepine ring system has offered interesting CNS-active medicinal agents. Taking this privileged structure as the basic scaffold, [Formula: see text] and/or [Formula: see text]-alkylated benzazepin-2-one derivatives and their reduced analogs have been prepared as potential [Formula: see text] receptor agonists. The selective alkylation at the [Formula: see text] and/or [Formula: see text] positions of this seven-membered lactam ring is here reported for the first time under different reaction conditions. The synthesized compounds were evaluated for their biological profile as potential [Formula: see text] agonists using a classic pharmacological approach. Three derivatives (15, 17, and 20) have shown promising [Formula: see text] agonistic activity which can be further optimized as anti-obesity agents for the treatment of male sexual dysfunction. Further, a homology model for [Formula: see text] receptor was generated using MODELLER, and ligand-receptor interactions for these potential molecules were studied. PMID- 25916736 TI - Intrinsic and extrinsic mortality reunited. AB - Intrinsic and extrinsic mortality are often separated in order to understand and measure aging. Intrinsic mortality is assumed to be a result of aging and to increase over age, whereas extrinsic mortality is assumed to be a result of environmental hazards and be constant over age. However, allegedly intrinsic and extrinsic mortality have an exponentially increasing age pattern in common. Theories of aging assert that a combination of intrinsic and extrinsic stressors underlies the increasing risk of death. Epidemiological and biological data support that the control of intrinsic as well as extrinsic stressors can alleviate the aging process. We argue that aging and death can be better explained by the interaction of intrinsic and extrinsic stressors than by classifying mortality itself as being either intrinsic or extrinsic. Recognition of the tight interaction between intrinsic and extrinsic stressors in the causation of aging leads to the recognition that aging is not inevitable, but malleable through the environment. PMID- 25916737 TI - Retinal microperfusion after renal denervation in treatment-resistant hypertensive patients. AB - BACKGROUND: High pulsatile pressure and flow in the arteries causes microvascular damage, and hence increased cardio-, and cerebrovascular complications. With advanced stages of hypertensive disease, an exaggerated pulsatile retinal capillary flow (RCF) has been shown, but data about interventional effect are missing. METHODS: Fifty-one patients with true treatment-resistant hypertension (TRH) underwent renal denervation (RDN) using the Symplicity Flex(TM) catheter and were followed for 12 months. RCF was assessed non-invasively using Scanning laser Doppler flowmetry (SLDF) before, 6 (6 M), and 12 (12 M) months after RDN. RCF was measured in systole and diastole and pulsed RCF (difference of RCF in systole minus diastole) was calculated. In addition, flicker light-induced vasodilation (representing vasodilatory capacity) was assessed. RESULTS: Systolic and diastolic office blood pressure (BP) as well as 24-h ABPM decreased significantly 6 M and 12 M after RDN, compared to baseline values (all p < 0.001). There was a significant reduction of pulsed RCF 6 M (231 +/- 81 versus 208 +/- 68 AU, p = 0.046) and 12 M (194 +/- 72 AU, p = 0.001) after RDN, whereas the mean RCF was unchanged. Moreover, there was a significant increase of flicker light-induced vasodilation after RDN (p = 0.043). CONCLUSION: In hypertensive patients with TRH, we observed a decrease of pulsed RCF 6 M and 12 M after RDN and an increase of vasodilatory capacity, in parallel to decreases in BP and heart rate. The reduction of pulsed RCF after RDN implies a decrease of shear stress on the vascular wall by the pulsed blood flow. This and the increment of vasodilatory capacity suggest an improvement of retinal (and potentially cerebral) microcirculation. PMID- 25916738 TI - A patient with a rare cause of elevated troponin I. PMID- 25916739 TI - The Antitumor Activity of Plant-Derived Non-Psychoactive Cannabinoids. AB - As a therapeutic agent, most people are familiar with the palliative effects of the primary psychoactive constituent of Cannabis sativa (CS), Delta(9) tetrahydrocannabinol (THC), a molecule active at both the cannabinoid 1 (CB1) and cannabinoid 2 (CB2) receptor subtypes. Through the activation primarily of CB1 receptors in the central nervous system, THC can reduce nausea, emesis and pain in cancer patients undergoing chemotherapy. During the last decade, however, several studies have now shown that CB1 and CB2 receptor agonists can act as direct antitumor agents in a variety of aggressive cancers. In addition to THC, there are many other cannabinoids found in CS, and a majority produces little to no psychoactivity due to the inability to activate cannabinoid receptors. For example, the second most abundant cannabinoid in CS is the non-psychoactive cannabidiol (CBD). Using animal models, CBD has been shown to inhibit the progression of many types of cancer including glioblastoma (GBM), breast, lung, prostate and colon cancer. This review will center on mechanisms by which CBD, and other plant-derived cannabinoids inefficient at activating cannabinoid receptors, inhibit tumor cell viability, invasion, metastasis, angiogenesis, and the stem-like potential of cancer cells. We will also discuss the ability of non psychoactive cannabinoids to induce autophagy and apoptotic-mediated cancer cell death, and enhance the activity of first-line agents commonly used in cancer treatment. PMID- 25916740 TI - Fusion dual-tracer SPECT-based hepatic dosimetry predicts outcome after radioembolization for a wide range of tumour cell types. AB - PURPOSE: Fusion dual-tracer SPECT imaging enables physiological rather than morphological voxel-based partitioning and dosimetry for (90)Y hepatic radioembolization (RE). We evaluated its prognostic value in a large heterogeneous cohort of patients with extensive hepatic malignancy. METHODS: A total of 122 patients with primary or secondary liver malignancy (18 different cell types) underwent SPECT imaging after intraarterial injection of (99m)Tc macroaggregated albumin (TcMAA) as a simulation of subsequent (90)Y microsphere distribution, followed by administration of an excess of intravenous (99m)Tc labelled sulphur colloid (TcSC) as a biomarker for functional liver, and a second SPECT scan. TcMAA distribution was used to estimate (90)Y radiation absorbed dose in tumour (D T) and in functional liver. Laboratory and clinical follow-up were recorded for 12 weeks after RE, and radiographic responses according to (m)RECIST were evaluated at 3 and 6 months. Dose-response relationships were determined for efficacy and toxicity. RESULTS: Patients were treated with a median of 1.73 GBq activity of resin microspheres (98 patients) or glass microspheres (24 patients), in a whole-liver approach (97 patients) or a lobar approach (25 patients). The objective response rate was 41% at 3 months and 48% at 6 months. Response was correlated with D T (P < 0.01). Median overall survival was 10.1 months (95% confidence interval 7.4 - 12.8 months). Responders lived for 36.0 months compared to 8.7 months for nonresponders (P < 0.01). Stratified for tumour cell type, D T was independently associated with survival (P < 0.01). Absorbed dose in functional liver was correlated with toxicity grade change (P < 0.05) and RE induced liver disease (P < 0.05). CONCLUSION: Fusion dual-tracer SPECT imaging offers a physiology-based functional imaging tool to predict efficacy and toxicity of RE. This technique can be refined to define dosing thresholds for specific tumour types and treatments, but appears generally predictive even in a heterogeneous cohort. PMID- 25916742 TI - V/P SPECT as a diagnostic tool for pregnant women with suspected pulmonary embolism. AB - PURPOSE: The purpose of the study was to assess the prevalence of pulmonary embolism (PE) and other lung diseases among pregnant women with suspected PE and to calculate the radiation exposure to patient and fetus in this population. As a secondary aim, we evaluated the negative predictive value of a normal ventilation/perfusion single photon emission computed tomography (V/P SPECT) examination in pregnancy. METHODS: We studied all 127 pregnant women who had suspected PE and had undergone V/P SPECT at our institution in the course of a 5 year period. Radiation exposure to patient and fetus and the negative predictive value of a normal V/P SPECT examination were also measured. RESULTS: V/P SPECT identified PE in 11 women (9%). Moreover, in 15 women (12%) the examination revealed pneumonia (in 2 cases in addition to PE) and in 1 woman signs of airway obstruction were revealed. Among the 116/127 women (91%) where PE was ruled out by V/P SPECT, none was diagnosed subsequently with PE or deep venous thrombosis (DVT) during the same pregnancy or puerperal period. For P SPECT, the calculated fetal absorbed dose was < 0.6 mGy,and the calculated breast absorbed dose 0.6 mGy. For V SPECT, the calculated fetal absorbed dose was < 0.014 mGy and the breast absorbed dose 0.25 mGy. CONCLUSION: The prevalence of PE was low (9%) among pregnant women with suspected disease. Pneumonia was diagnosed in 12% of patients. The negative predictive value of V/P SPECT was high, and the radiation exposure from V/P SPECT was low both for fetus and patient. PMID- 25916741 TI - Sentinel lymph node biopsy in oral and oropharyngeal squamous cell carcinoma: current status and unresolved challenges. AB - Because imaging with ultrasound, computed tomography, magnetic resonance imaging or positron emission tomography is unreliable for preoperative lymph node staging of early-stage oral and oropharyngeal squamous cell carcinoma (OSCC), elective neck dissection has been typically performed. The targeted sampling of sentinel lymph nodes (SLN) identified by lymphoscintigraphy and detected by gamma probe has become an effective alternative for the selection of patients for regional nodal resection. With careful consideration to technique, high SLN detection rates have been reported. Advanced techniques including intraoperative handheld gamma camera imaging and freehand single photon emission computed tomography (SPECT) are expected to increase surgical confidence in these procedures. This review gives an update on SLN biopsy in patients with OSCC including clinical standards and controversial aspects. PMID- 25916743 TI - Endotracheal metastasis from colorectal cancer. PMID- 25916744 TI - First evidence of PSMA expression in differentiated thyroid cancer using [68Ga]PSMA-HBED-CC PET/CT. PMID- 25916746 TI - Diagnostic accuracy of ultrasonography in assessing meniscal injury: meta analysis of prospective studies. AB - BACKGROUND: The accuracy of ultrasonography for diagnosing meniscal injury remains controversial. The aim of the present meta-analysis was to establish the role of ultrasonography in the diagnosis of meniscal injury by analyzing the data from prospectively designed studies. METHODS: A systematic review was performed by searching electronic bibliographic databases prior to November 2014. Studies with diagnostic results that fulfilled the inclusion criteria were included. The methodological quality of the studies was assessed. Sensitivity, specificity and other measures of the accuracy of ultrasonography in the diagnosis of meniscal injury were summarized. Summary receiver-operating characteristic (SROC) curves were used to summarize overall test performance. Publication bias was assessed used Deek's funnel plot asymmetry test. RESULTS: Seven prospective studies with 551 patients were eligible for the meta-analysis. The Quality Assessment of Diagnostic Accuracy Studies scores for the included studies ranged from 10-13. The summary estimates of the sensitivity, specificity, positive likelihood ratio, negative likelihood ratio and diagnostic odds ratio of ultrasonography in the diagnosis of meniscal injury were 0.88 (95 % CI 0.84-0.91), 0.90 (95 % CI 0.86 0.93), 7.07 (95 % CI 4.34-11.52), 0.17 (95 % CI 0.10-0.26) and 58.13 (95 % CI 24.38-138.62), respectively. There was moderate to significant heterogeneity across the above measures (P < 0.05). The area under the curve of the SROC was 0.948, indicating a high overall diagnostic accuracy. No publication bias was noted across the studies (P = 0.393), which suggested little influence of publication bias on the overall results. CONCLUSION: Our results suggest that the diagnostic accuracy of ultrasonography for diagnosing meniscal injury is acceptable, with a high specificity but moderate sensitivity. PMID- 25916747 TI - Electrostatic assembly/disassembly of nanoscaled colloidosomes for light triggered cargo release. AB - Colloidosome capsules possess the potential for the encapsulation and release of molecular and macromolecular cargos. However, the stabilization of the colloidosome shell usually requires an additional covalent crosslinking which irreversibly seals the capsules, and greatly limits their applications in large cargos release. Herein we report nanoscaled colloidosomes designed by the electrostatic assembly of organosilica nanoparticles (NPs) with oppositely charged surfaces (rather than covalent bonds), arising from different contents of a bridged nitrophenylene-alkoxysilane [NB; 3-nitro-N-(3-(triethoxysilyl)propyl)-4 (((3-(triethoxysilyl)propyl)-amino)methyl)benzamid] derivative in the silica. The surface charge of the positively charged NPs was reversed by light irradiation because of a photoreaction in the NB moieties, which impacted the electrostatic interactions between NPs and disassembled the colloidosome nanosystems. This design was successfully applied for the encapsulation and light-triggered release of cargos. PMID- 25916748 TI - Online monitoring the isomerization of an azobenzene-based dendritic bolaamphiphile using ion mobility-mass spectrometry. AB - Ion mobility-mass spectrometry was used to obtain detailed information about the kinetics of the light-induced cis/trans isomerization process of a new supramolecular azobenzene-based bolaamphiphile. Further experiments revealed that the investigated light-induced structural transition dramatically influences the aggregation behaviour of the molecule. PMID- 25916749 TI - The value of choice as a reinforcer for typically developing children. AB - Previous research has shown that providing choices may result in an increase in appropriate behavior and a decrease in inappropriate behavior; however, the process by which choice results in a behavior change is unknown. In the current study, we replicated and extended previous research by determining the prevalence of preference for choice in a large number of children and evaluating whether a history of differential outcomes associated with choice and no choice resulted in changes in preference for those conditions. Results from Study 1 showed that the majority of participants preferred choice contexts when child choice and experimenter choice resulted in identical outcomes. In Study 2, participants' preferences were altered when child choice and experimenter choice resulted in differential outcomes, but a history with differential outcomes did not produce a reliable and durable effect on selections. PMID- 25916751 TI - Experimental and theoretical characterization of a novel bis-pyrazoylmethane ligand. PMID- 25916750 TI - Insulin-like growth factor-1 receptor is associated with better prognosis in classical Hodgkin's lymphoma: Correlation with MET expression. AB - The purpose of this study was to examine the prognostic significance of insulin like growth factor-1 receptor (IGF-1R) expression alone and in relation to the expression of the MET- receptor and the MET-homologous receptor RON, in classical Hodgkin's lymphoma (cHL). Tumour samples from patients with cHL (n = 202; median age 37.5 years) were analysed retrospectively for IGF-R1, MET or RON expression by immunohistochemistry using tissue microarrays. The median follow-up time was 3.7 years (range, 0.1-20 years). Twenty-nine patients (14.3%) expressed IGF-1R protein in Hodgkin/Reed-Sternberg (HRS) cells, which was associated with a better overall survival (OS) (P = 0.036). IGF-1R expression was closely associated with MET receptor expression and low level of lactate dehydrogenase. In patients with cHL receiving doxorubicin, bleomycin, vinblastine and dacarbazine, those expressing IGF-1R showed a trend towards better OS and event-free survival than IGF-1R-negative patients (P = 0.129 and P = 0.115 respectively), but statistical significance was not reached. This study suggests that IGF-1R expression could be associated with better clinical outcome in cHL but is significantly associated with the expression of MET receptor. PMID- 25916752 TI - Identity appropriateness and the structure of the theory of planned behaviour. AB - In contrast to the cost-benefit, utility-based approach to decision-making implicit in models such as the theory of planned behaviour (TPB), the logic of appropriateness (March, 1994. A Primer on Decision Making: How decisions happen. New York, NY: The Free Press) describes decision-making in terms of heuristic decision rules that involve matching identities to situations. This research is the first to apply the logic of appropriateness in conjunction with the theoretical structure of the TPB and assessed whether a measure of identity appropriateness might independently predict adults' intentions to engage in binge drinking. In Study 1, participants (N = 197) completed questionnaires assessing attitudes, subjective norm, perceived behavioural control, past behaviour, and identity appropriateness in relation to binge drinking. Path analysis revealed an independent predictive effect of identity appropriateness on intentions in addition to an indirect effect via attitudes. In Study 2 (N = 179), a prospective measure of behaviour was included in a similar study: Identity appropriateness again predicted intentions independently of the extended TPB predictors. It was again also found to be a strong predictor of attitudes. We suggest that the notion of identity appropriateness may assist in explaining the capacity of measures of self-identity to predict people's behavioural intentions. PMID- 25916753 TI - Autoinhibitory mechanism and activity-related structural changes in a mycobacterial adenylyl cyclase. AB - An adenylyl cyclase from Mycobacterium avium, Ma1120, is a functional orthologue of a pseudogene Rv1120c from Mycobacterium tuberculosis. We report the crystal structure of Ma1120 in a monomeric form and its truncated construct as a dimer. Ma1120 exists as a monomer in solution and crystallized as a monomer in the absence of substrate or inhibitor. An additional alpha-helix present at the N terminus of the monomeric structure blocks the active site by interacting with the substrate binding residues and occupying the dimer interface region. However, the enzyme has been found to be active in solution, indicating the movement of the helix away from the interface to facilitate the formation of active dimers in conditions favourable for catalysis. Thus, the N-terminal helix of Ma1120 keeps the enzyme in an autoinhibited state when it is not active. Deletion of this helix enabled us to crystallize the molecule as an active homodimer in the presence of a P-site inhibitor 2',5'-dideoxy-3'-ATP, or pyrophosphate along with metal ions. The substrate specifying lysine residue plays a dual role of interacting with the substrate and stabilizing the dimer. The dimerization loop region harbouring the second substrate specifying residue, an aspartate, shows significant differences in conformation and position between the monomeric and dimeric structures. Thus, this study has not only revealed that significant structural transitions are required for the interconversion of the inactive and the active forms of the enzyme, but also provided precise nature of these transitions. PMID- 25916754 TI - Structure of Halorhodopsin from Halobacterium salinarum in a new crystal form that imposes little restraint on the E-F loop. AB - Halorhodopsin from the halophilic archaeon Halobacterium salinarum is a membrane located light-driven chloride pump. Upon illumination Halorhodopsin undergoes a reversible photocycle initiated by the all-trans to 13-cis isomerization of the covalently bound retinal chromophore. The photocycle consists of several spectroscopically distinct intermediates. The structural basis of the chloride transport mechanism remains elusive, presumably because packing contacts have so far precluded protein conformational changes in the available crystals. With the intention to structurally characterize late photocycle intermediates by X-ray crystallography we crystallized Halorhodopsin in a new crystal form using the vesicle fusion method. In the new crystal form lateral contacts are mediated by helices A and G. Helices E and F that were suggested to perform large movements during the photocycle are almost unrestrained by packing contacts. This feature might permit the displacement of these helices without disrupting the crystal lattice. Therefore, this new crystal form might be an excellent system for the structural characterization of late Halorhodopsin photocycle intermediates by trapping or by time resolved experiments, especially at XFELs. PMID- 25916755 TI - Structural basis for the hydrolysis of ATP by a nucleotide binding subunit of an amino acid ABC transporter from Thermus thermophilus. AB - ATP-binding cassette (ABC) transporters are a major family of small molecule transporter proteins, and their deregulation is associated with several diseases, including cancer. Here, we report the crystal structure of the nucleotide binding domain (NBD) of an amino acid ABC transporter from Thermus thermophilus (TTHA1159) in its apo form and as a complex with ADP along with functional studies. TTHA1159 is a putative arginine ABC transporter. The apo-TTHA1159 was crystallized in dimeric form, a hitherto unreported form of an apo NBD. Structural comparison of the apo and ADP-Mg(2+) complexes revealed that Phe14 of TTHA1159 undergoes a significant conformational change to accommodate ADP, and that the bound ADP interacts with the P-loop (Gly40-Thr45). Modeling of ATP Mg(2+):TTHA1159 complex revealed that Gln86 and Glu164 are involved in water mediated hydrogen bonding contacts and Asp163 in Mg(2+) ion-mediated hydrogen bonding contacts with the gamma-phosphate of ATP, consistent with the findings of other ABC transporters. Mutational studies confirmed the necessity of each of these residues, and a comparison of the apo/ADP Mg(2+):TTHA1159 with its ATP complex model suggests the likelihood of a key conformational change to the Gln86 side chain for ATP hydrolysis. PMID- 25916757 TI - Parathyroid carcinoma: Diagnostic criteria, classification, evaluation. AB - Parathyroid carcinoma is a little-known cancer, difficult to diagnose. We focus this short review on the current diagnostic criteria, the classification and the evaluation tools for this cancer based on latest publications. PMID- 25916756 TI - Treatment of heterotopic ossifications secondary to pseudohypoparathyroid. PMID- 25916758 TI - Monitoring of hypo- and pseudohypoparathyroidism. PMID- 25916759 TI - Primary hyperparathyroidism and vitamin D deficiency. AB - Primary hyperparathyroidism (PHPT) and vitamin D (VD) deficiency are frequent conditions due to the widespread application of assays for calcium and VD. PHPT presentation is dominated by diversity in its expression and the current predominance of asymptomatic forms. VD, which plays a major role in calcium and phosphate homeostasis, is also involved in many physiological processes in this disease, such as lipid and glucose metabolism, and in the signalling pathways and functioning of many cell types. The bone and cardiometabolic complications described in PHPT are exacerbated by vitamin D deficiency, the prevalence of which varies according to many parameters (environment, skin pigmentation, associated chronic diseases, liver and kidney function, assay kit used, etc.). In response to this observation, experts in field from medical societies validated the indication for systematic assay of VD occurring with PHPT and the need for replacement in case of deficiency. Several epidemiological studies have confirmed that replacement with natural vitamin D is well tolerated and safe in subjects with PHPT and VD deficiency. This supplementation reduces hyperparathormonemia, does not have symptomatic effects on calciuria, and especially improves the bone and functional condition of patients. PMID- 25916760 TI - The REPLACE study in adults and calcilytics. PMID- 25916761 TI - Epidemiology, pathogenesis of primary hyperparathyroidism: Current data. PMID- 25916762 TI - Problems with the PTH assays. AB - Even if the first assay for parathyroid hormone (PTH) was published in the early 1960s, its determination remains a challenge even today. Indeed, in the circulation, PTH is present in its active form (PTH 1-84), but many PTH fragments can also be present. These fragments accumulate when renal function declines and are recognized, at different extents, by the 2nd generation ("intact") PTH assays that are widely used in the clinical laboratories. Some assays, called "3rd generation PTH" do not recognize these fragments, but are not available everywhere. Hence, different problems are also linked with PTH determination. Among them, one can cite the lack of a reference method, the lack of standardization of the assays and, sometimes, the lack of consistent reference range. We can also point out stability problems and a large intra-individual variation. A workgroup is working on these problems under the auspices of the IFCC and we hope that some of these problems will be resolved in the next years. In this article, we will discuss all the possible issues of PTH determination. PMID- 25916763 TI - Peculiar Properties of Mesoporous Synthetic Carbon/Graphene Phase Composites and their Effect on Supercapacitive Performance. AB - Composites of mesoporous synthetic carbon and the graphene phase were synthesized in aqueous suspension by employing dispersive interactions of both phases. The resulting carbon-based materials were further heat treated in air at 350 degrees C. The composites and their components were characterized by using adsorption of nitrogen, potentiometric titration, thermal analysis-mass spectrometry, X-ray photoelectron spectroscopy, SEM, high-resolution TEM, and XRD. Then, they were tested as supercapacitors in three-electrode cells and under visible-light irradiation. The composites and the initial carbon share exactly the same pore size distributions, but they exhibit significant differences in their surface chemistry, wettability, and conductivity. This allowed us to determine the extent of their effects on their capacitive/pseudocapacitive performance. The results showed that features other than the textural properties can increase the capacitive performance by more than 100 %. The synergistic properties of the composites and their sulfur functional group related photoactivity were linked to chemical interactions between the nanoporous carbon phase and graphite oxide during the formation of the composite. PMID- 25916764 TI - Extending Gurwitsch's field theory of consciousness. AB - Aron Gurwitsch's theory of the structure and dynamics of consciousness has much to offer contemporary theorizing about consciousness and its basis in the embodied brain. On Gurwitsch's account, as we develop it, the field of consciousness has a variable sized focus or "theme" of attention surrounded by a structured periphery of inattentional contents. As the field evolves, its contents change their status, sometimes smoothly, sometimes abruptly. Inner thoughts, a sense of one's body, and the physical environment are dominant field contents. These ideas can be linked with (and help unify) contemporary theories about the neural correlates of consciousness, inattention, the small world structure of the brain, meta-stable dynamics, embodied cognition, and predictive coding in the brain. PMID- 25916765 TI - The dynamic influence of cells on the formation of stable emulsions in organic aqueous biotransformations. AB - Emulsion stability plays a crucial role for mass transfer and downstream processing in organic-aqueous bioprocesses based on whole microbial cells. In this study, emulsion stability dynamics and the factors determining them during two-liquid phase biotransformation were investigated for stereoselective styrene epoxidation catalyzed by recombinant Escherichia coli. Upon organic phase addition, emulsion stability rapidly increased correlating with a loss of solubilized protein from the aqueous cultivation broth and the emergence of a hydrophobic cell fraction associated with the organic-aqueous interface. A novel phase inversion-based method was developed to isolate and analyze cellular material from the interface. In cell-free experiments, a similar loss of aqueous protein did not correlate with high emulsion stability, indicating that the observed particle-based emulsions arise from a convergence of factors related to cell density, protein adsorption, and bioreactor conditions. During styrene epoxidation, emulsion destabilization occurred correlating with product-induced cell toxification. For biphasic whole-cell biotransformations, this study indicates that control of aqueous protein concentrations and selective toxification of cells enables emulsion destabilization and emphasizes that biological factors and related dynamics must be considered in the design and modeling of respective upstream and especially downstream processes. PMID- 25916769 TI - Impact of ammonia exposure on coagulation in white shrimp, Litopenaeus vannamei. AB - Ammonia (un-ionized plus ionized ammonia as nitrogen), the end product of protein catabolism, is produced by decomposing organic matter. In aquaculture, shrimp are commonly exposed to high concentrations of ammonia that induces immunological and histological changes. The purpose of this study was to evaluate the effects on hemolymph coagulation time, transglutaminase (TG) activity as well as TG and clottable protein (CP) genes expressions in Litopenaeus vannamei when exposed to ambient ammonia-nitrogen (N) at 0, 1, 5, and 10mg/L for 0, 2, and 7 days. The actual concentrations in control and tests solution were 0.001, 1.15, 5.11, and 11.68mg/L for ammonia-N, and 7*10(-5), 0.080, 0.357, and 0.815mg/L for NH3-N (unionized ammonia). Delayed coagulation time following exposure to 5 and 10mg/L of ambient ammonia-N for 7 days, and increased transglutaminase (TG) activity following exposure to 5 and 1mg/L of ambient ammonia-N for 2 and 7 days, respectively, were observed. Downregulated TG expression and upregulated clottable protein (CP) expression in the hemocytes of L. vannamei exposed to 10 and 5mg/L of ambient ammonia-N for 2 and 7 days, respectively, were shown. These results indicated that ambient ammonia-N (>5mg/L) and NH3-N (>0.357mg/L) interrupted coagulation and down-regulated TG gene expression in L. vannamei, which caused ecotoxicity on immune deficiencies and may contribute the increased susceptibility to infection by pathogens. PMID- 25916770 TI - Preventing falls in residential construction: Effectiveness of engaging partners for a national social marketing campaign. AB - BACKGROUND: Falls are the leading cause of fatalities in construction. The Safety Pays, Falls Cost campaign aims to prevent falls in residential construction. A critical component of our social marketing approach was to involve 70 partners in reaching target audiences. METHODS: We assessed partner engagement April 2012 August 2013 through: (1) baseline partnership quality interviews (eight partners); (2) pre-/post-partner "market" readiness in-depth interviews (three partners); (3) a pre-/post- (29/31 partners) online partner engagement survey; and (4) standardized metrics to measure partner activity. RESULTS: We found a high level of interest and engagement that increased with the addition of prompting to action through regular communication and new resources from organizers and formation of local partnerships that were able to tailor their activities to their own communities or regions. CONCLUSION: It is feasible to leverage government-labor-management partnerships that enjoy trust among target audiences to widely disseminate campaign materials and messages. PMID- 25916771 TI - Theoretical Computer-Aided Mutagenic Study on the Triple Green Fluorescent Protein Mutant S65T/H148D/Y145F. AB - Green fluorescent protein (GFP) mutant S65T/H148D has been proposed to host a photocycle that involves an excited-state proton transfer between the chromophore (Cro) and the Asp148 residue and takes place in less than 50 fs without a measurable kinetic isotope effect. It has been suggested that the interaction between the unsuspected Tyr145 residue and the chromophore is needed for the ultrafast sub-50 fs rise in fluorescence. To verify this, we have performed a computer-aided mutagenic study to introduce the additional mutation Y145F, which eliminates this interaction. By means of QM/MM molecular dynamics simulations and time-dependent density functional theory studies, we have assessed the importance of the Cro-Tyr145 interaction and the solvation of Asp148 and shown that in the triple mutant S65T/H148D/Y145F a significant loss in the ultrafast rise of the Stokes-shifted fluorescence should be expected. PMID- 25916772 TI - [Effect of antiviral treatment on improving postoperative prognosis of hepatitis B virus-related hepatocellular carcinoma]. PMID- 25916773 TI - [The use of new oral oral anticoagulants in the treatment of acute pulmonary embolism]. PMID- 25916774 TI - [Expression of TPX2 in hepatocellular carcinoma and its clinical significance]. AB - OBJECTIVE: To explore the expression of TPX2 and its significance in hepatocellular carcinoma (HCC) tissue and examine the relationship between TPX2 and clinicopathological characteristics of HCC. METHODS: Reverse transcription polymerase chain reaction (RT-PCR) and immunohistochemical staining were used to compare the expression of TPX2 in tumor and adjacent non-tumoral tissues. RESULTS: The TPX2 mRNA expression was higher in tumor tissues than that in non tumoral counterparts (30/50) (P < 0.05). The positive rate of TPX2 protein in tumor tissues was significantly higher than that in non-tumoral counterparts (56.0% vs 16.0%) (P < 0.05). The expression of TPX2 mRNA and protein were correlated with metastasis, recurrence and time of recurrence after curative resection (P < 0.05). CONCLUSION: An over-expression of TPX2 may be risk factor of metastasis and recurrence after curative resection so that it is a potential biomarker for early diagnosis and prognosis of HCC. PMID- 25916775 TI - [Application values of computer-assisted preoperative planning of hilar cholangiocarcinoma]. AB - OBJECTIVE: To explore the application value of computer-assisted preoperative planning of hilar cholangiocarcinoma. METHODS: Retrospective analyses were conducted for the clinical data of 47 patients with hilar cholangiocarcinoma undergoing radical resection plus hemihepatectomy from January to December 2013. According to whether computer-assisted preoperative planning was used, they were divided two groups of computer-assisted surgical planning (CASP) and without computer-assisted surgical planning (WCASP). Then we analyzed the data including preoperative examinations, preoperative planning, intraoperative findings and postoperative complications. RESULTS: There were 31 cases of hilar vascular invasion by tumor. Among 29 cases of CASP, left hepatic artery originated from left gastric artery (n = 6), right posterior bile duct drained into left hepatic bile duct (n = 1) and right posterior bile duct run into common hepatic bile duct (n = 2). The mean operative duration of CASP was (6.5 +/- 1.3) h and the mean volume of intraoperative bleeding (672.0 +/- 214.3) ml; while the mean operative duration of WCASP was (7.9 +/- 2.9) h and the mean volume of intraoperative bleeding (870.0 +/- 330.1) ml. By statistical analysis, the inter-group differences of mean operative duration had statistical difference (P = 0.028) and the inter-group differences of mean volume of intraoperative bleeding had statistical difference (P = 0.016). The ratio of first negative test in group CASP was higher than that of group WCASP and the inter-group differences had statistical significance (P = 0.043). But the inter-group rate of postoperative complications had no significant difference (P = 0.419). CONCLUSIONS: The computer-assisted surgical planning system provides accurate information so that an optimal surgical protocol may be designed by surgeons. And it has great application values in preoperative surgical planning for hilar cholangiocarcinoma and enjoys wide prospects in precise liver surgery. PMID- 25916776 TI - [Prevention and treatment of complications for full-covered self-expanding removable metal stents in malignant obstructive jaundice]. AB - OBJECTIVE: To explore the prevention and treatment of complications for full covered self-expanding removable metal stents (FCSERMS) in malignant obstructive jaundice. METHODS: The clinical data were analyzed retrospectively for 45 cases undergoing endoscopic biliary FCSERMS drainage for malignant obstructive jaundice from May 2012 to March 2014. RESULTS: Among them, 45 cases were successful one time. The parameters of liver function improved significantly with a jaundice efficiency of 91.1%. There were 4 dead cases. Among 19 cases of early complications, hyperamylasemia (n = 8), acute mild pancreatitis (n = 4), acute cholecystitis (n = 2) and hemobilia (n = 1) recovered after conservative treatments. Acute suppurative cholecystitis (n = 2) and acute obstructive suppurative cholangitis (n = 2) were cured by percutaneous transhepatic cholangial drainage (PTCD) and percutaneous transhepatic gallbladder drainage (PTGBD). And late complications of obstructive jaundice (n = 3), acute suppurative cholecystitis (n = 4), acute cholangitis (n = 2), hepatophyma (n = 2) and acute pancreatitis (n = 1) were cured by endoscopic retrograde cholangiopancreatography (ERCP), PTCD and PTGBD. CONCLUSION: Various complications are associated with FCSERMS in malignant obstructive jaundice.However, positive and effective prevention and proper treatment reduce the incidence of complications. PMID- 25916777 TI - [Correlation between oxygen uptake efficiency and exercise capacity in pulmonary hypertension patients]. AB - OBJECTIVE: To explore the characteristics of oxygen uptake efficiency (OUE) in patients with pulmonary hypertension (PH) and analyze the correlation between OUE and exercise capacity. METHODS: A total of 76 PH patients and 29 healthy controls at Shanghai Pulmonary Hospital between October 2010 and January 2014 were evaluated. All PH patients were classified into 4 groups according to the World Health Organization functional class (WHO-FC). Pulmonary function and cardiopulmonary exercise tests were performed in all subjects. RESULTS: Compared with health control, the PH patients had lower forced vital capacity (FVC) of expected value (%pre), forced expiratory volume in one second (FEV(1))%pre and FEV(1)/FVC ((81.9 +/- 15.5)% vs (88.6 +/- 14.1)%, (75.0 +/- 16.4)% vs (85.2 +/- 17.2)% and (78.3 +/- 9.3)% vs (88.3 +/- 7.3)%, all P < 0.05). Compared with control group, there were also significant reductions in oxygen uptake efficiency slope (OUES), oxygen uptake efficiency plateau (OUEP) and OUE at the anaerobic threshold ((1.14 +/- 0.42) vs (2.32 +/- 0.34) (L/min)/lg (L/min), (27 +/- 5) vs (37 +/- 4) ml/L, (24 +/- 6) vs (34 +/- 5) ml/L, all P < 0.05). No significant differences existed in OUES, OUEP and OUE at the anaerobic threshold in PH patients between WHO-FC Iand WHO-FC II groups. There were significant differences in OUE among other groups (all P < 0.05). And OUES, OUEP and OUE at the anaerobic threshold were correlated positively with exercise tolerance in PH patients. CONCLUSION: OUE significantly declines in PH patients compared with normal subjects and it is correlated positively with exercise capacity. PMID- 25916778 TI - [Clinicopathological features and outcomes: analysis of 21 cases of lymphoma in pregnancy]. AB - OBJECTIVE: To evaluate the clinicopathological features and outcomes of lymphoma in pregnancy. METHODS: A total of 21 patients with lymphoma in pregnancy were diagnosed and treated at our hospital between January 1999 and January 2012. The clinicopathological data were analyzed retrospectively. RESULTS: There were 11 cases of Hodgkin's lymphoma (HL) and 10 cases of nodular sclerosis classical Hodgkin's lymphoma (NSCHL). And, among 10 cases of non-Hodgkin's lymphomas (NHL), there were diffuse large B cell lymphoma (n = 6),B-cell lymphoma, non classifiable with features intermediate between diffuse large B-cell lymphoma and Burkitt lymphoma (n = 1), small lymphocytic lymphoma (n = 1), anaplastic large cell lymphoma with anaplastic lymphoma kinase (ALK) positive (n = 1) and T-cell lymphoblastic lymphoma (n = 1). The median age was 26(22-35) years.Superficial lymphadenopathy was more common in HL than in NHL (10/11 vs 3/10, P = 0.008). At diagnosis, bulky disease and extranodal involvement were more prevalent in NHL than in HL (8/10 vs 2/11, P = 0.009; 7/10 vs 2/11, P = 0.030). All patients received chemotherapy and those with early stages also had combined radiotherapy. Ten patients with HL and 6 patients with NHL achieved complete remission. During a median follow-up of 90 months for HL, the 5-year progression-free survival (PFS) and overall survival (OS) rates were 87.5% and 100% respectively. And during a median follow-up of 31 months for NHL, the 2-year PFS and OS rates were 66.7% and 77.8% respectively. The values of PFS and OS of NHL were inferior to those of HL (P = 0.073 and P = 0.066 respectively).One case of HL and 1 case of NHL received chemotherapy in the second trimester. The patients and their children experienced good outcomes. CONCLUSIONS: NSCHL is the most prevalent subtype of HL during pregnancy. B cell lymphoma and aggressive subtypes are most common for NHL during pregnancy. The outcomes of NHL are inferior to those of HL during pregnancy. PMID- 25916779 TI - [Analysis of SMN1 gene partial deletion of spinal muscular atrophy based on MLPA]. AB - OBJECTIVE: To explore the diversity of mutations in survival motor neuron gene 1 (SMN1) by analyzing seven cases of partial deletion of SMN1 gene. METHODS: Seven patients suspected spinal muscular atrophy (SMA) were recruited from 2011 to 2013. Multiplex ligation-dependent probe amplification (MLPA) for genetic testing of SMA was based on the commercially available SALSA MLPA kit P021-A2. Then the data were analyzed by the software Coffalyser.Negative control samples were chosen with two copies of SMN1 and SMN2. Positive control samples were chosen with zero copies of SMN1 and two copies of SMN2. According to the product description (www.mlpa.com): for exon 7 and 8 of SMN1 and SMN2: a ratio of <0.7 indicates 1 copy, a ratio of 0.7-1.3 2 copies, a ratio of 1.3-1.7 3 copies and a ratio of 1.7-2.3 4 copies. For exon 1, 4, 6, 8 of SMN gene (SMN1+SMN2): a ratio <0.4 indicates 1 copy, a ratio of 4.0-0.6 2 copies, a ratio of 0.7-0.9 3 copies and a ratio of 0.9-1.1 4 copies. All samples were analyzed in duplicate. RESULTS: Using MLPA for clinical diagnostics, two types of partial deletions of SMN1were identified in 7 patients.Since exon 8 is not translated and has no effect on the function of SMN protein, exons 1, 4, 6, 7 were targeted.One had an isolated deletion of exon 7 while the other ones were caused by the deletions of exon 1, 4 and 7. These mutations were not detected by conventional diagnostic methods. Both types of partial deletions of SMN1 gene contained a deletion of exon 7. CONCLUSIONS: Two types of partial deletions of SMN1 gene indicate that the structure of SMN gene is unstable leading to a variety of mutation forms. But the major cause of SMA lies in a deletion of exon 7 of SMN1 gene. PMID- 25916780 TI - [The application and epidemiological research of xTAG GPP multiplex PCR in the diagnosis of infectious diarrhea]. AB - OBJECTIVE: To investigate the application value of xTAG ((r)) gastrointestinal pathogen panel (xTAG9((r)) GPP) multiplex PCR in the early diagnosis of infectious diarrhea, and understand the epidemiology of intestinal diarrhea pathogens. METHODS: Five hundred and ninety two specimens were collected in outpatient of Tongren Hospital, Capital Medical University, from 1st Oct 2013 to 30th Sep 2014, comparing the xTAG((r)) GPP multiplex PCR assay with the traditional methods (culture, rapid enzyme immunoassay chromatography, microscopic examination, Real-time PCR) and mading the statistical analysis. RESULTS: The positive rate of 592 patients with diarrhea specimens was 47.8% (283/592), the proportion of male and female was 1: 1.02, the average age was 31years. The virus detection rate was 18.1%, Rotavirus A was the most common organism detected (8.8%), concentrated in winter, popular in children.Secondly,Norovirus GI/GII (8.4%),Adenovirus 40/41 was five cases. The positive rate of bacteria was 35.5%, Enterotoxigenic E.coli (8.4%, 50/592) was most frequently detected in summer, common in young adults. The other pathogens were Campylobacter 7.7%, Salmonella 7.0%, Clostridium difficile toxinA/B 3.5%, Shigella 3.3%,E.coli O157 3.3% and Shiga toxin-producing E.coli LT/ST 1.7%.None of Yersinia enterocolitica and Vibrio cholerae was detected. There were ten samples with parasitic (1.7%), five samples were positive for Cryptosporidium, three for Entamoeba histolytica and two for Giardia. All of them did not have obvious distribution followed by season and population. Totally 242(40.8%) infected specimens with single pathogen were detected. There were 41 (6.9%) co infections samples, including two pathogens 36 cases (6.1%), three pathogens in 5 cases (0.8%). CONCLUSIONS: xTAG((r)) GPP multiplex PCR is simple, sensitive, specific and can be used as a quick way to diagnose the infectious diarrhea. Diarrhea pathogen has significant characteristics with the season and crowd. PMID- 25916781 TI - [Long-term outcomes of Ahmed glaucoma valve implantation for treating refractory glaucoma]. AB - OBJECTIVE: To explore the efficacies and complications of Ahmed glaucoma valve implantation for treating refractory glaucoma. METHODS: A retrospective study of case series was conducted for 24 patients (26 eyes) with refractory glaucoma from February 2001 to July 2008 at our hospital. Ahmed glaucoma valve implantation was performed. Pre- and post-operative best spectacle-corrected visual acuity (BSCVA), intraocular pressure (IOP), number of medications and complications were recorded and analyzed. The follow-up period was 58-159 months. RESULTS: The post operative values of IOP were 13.02+/-6.79, 11.43+/-5.24 and 18.56+/-6.43 mmHg at 1 day, 1 month and the last follow-up respectively. There were significant difference when compared with pre-operative IOP (37.59+/-10.76 mmHg, P < 0.01). And 65.38% of eyes maintained or gained >= 1 line of BSCVA. But there was no significant difference with pre-operative BSCVA (P = 0.110). Twenty eyes required anti-glaucoma drugs after glaucoma valve implantation and the average number of medication was 1.72+/-0.98. There was significant difference with the pre operative medication number 2.7 +/- 0.7 (P = 0.001). The surgical success rate was 73.1%. And the causes of failure were endophthalmitis, corneal endothelial decompensation, persistent conjunctival wound non-healing, glaucoma valve exposure and loss of light perception.Early postoperative complications were ocular hypotony, shallow anterior chamber, hyphema, transient high IOP and tube occlusion. And long-term complications included encapsulated cyst formation, tube exposure, corneal endothelial decompensation and endophthalmitis. CONCLUSIONS: Ahmed glaucoma valve implantation is efficacious for refractory glaucoma.However, clinicians should pay attention to the prevention and treatment of complications. PMID- 25916782 TI - [Effects of intra-periaqueductal gray injection of zeta pseudosubstrate inhibitory peptide on sensory and affective components of pain]. AB - OBJECTIVE: To explore the effects of intra-PAG injection of ZIP on sensory and affective components of pain. METHODS: For determining the role of ZIP on pain induced aversion, the effects of intra-PAG injection of ZIP on formalin-induced conditioned place avoidance (F-CPA) was investigated. To determine the role of ZIP on pain perception, formalin-induced inflammatory pain model was established and the effects of intra-PAG injection of ZIP on formalin-induced nociceptive behaviors was investigated. RESULTS: In the NS-treated rats, the time in the pain paired compartment during the test session was significantly shorter than that during the preconditioning session 2 and 24 hours after administration of the drug at both 1 and 7 day post-training (Group NS-1 d-2 h: (465.1 +/- 40.6) vs (133.8 +/- 29.4) s (P < 0.001); Group NS-7 d-2 h: (432.3 +/- 43.7) vs (150.5 +/- 26.6) s (P < 0.01); Group NS-1 d-24 h: (500.5 +/- 20.6) vs (107.0 +/- 15.7) s (P < 0.001); Group NS-7 d-24 h: (450.8 +/- 27.4) vs (129.4 +/- 21.1) s (P < 0.001)). On the contrary, in the ZIP-treated rats, no significant differences were observed in the time in the pain-paired compartment between the post-conditioning and pre-conditioning sessions at the same time-points. CPA scores also showed the attenuation of F-CPA by intra-PAG injection of ZIP in comparison to the saline injected rats (P < 0.05). Compared with the intra-PAG saline-injected group, intra-PAG microinjection of ZIP did not affect the formalin-induced nociceptive behaviors (P > 0.05). CONCLUSION: The study suggests that PAG contributes to pain related aversion in rats, and the mechanism of pain emotion encoding in PAG may attribute to the activation of targets of ZIP. PMID- 25916783 TI - [Effects of soluble programmed death ligand 1 on regulating the proliferation of T lymphocytes and its mechanism]. AB - OBJECTIVE: To explore the effects of soluble programmed death ligand 1 (sPD-L1) on the proliferation of T lymphocytes and its mechanism. METHODS: T lymphocytes were isolated from healthy human peripheral blood and activated by phytohemagglutinin (PHA). The experiment had group A: resting T lymphocytes, group B: activated T lymphocytes, group C: activated T lymphocytes+sPD-L1Ig, group D: activated T lymphocytes+sPD-L1Ig+membrance-bound immunoglobulin (mIgG) and group E: activated T lymphocytes+sPD-L1Ig+anti-PD-L1 antibody (2H11). The absorbance value (A) of T lymphocytes in each group was measured by cell counting kit (CCK-8). The cell cycle and apoptosis of T lymphocytes induced by sPD-L1 were measured by flow cytometry. And the phosphorylation level of programmed death 1 (PD-1) signaling motif tyrosine was measured by Western blot. Furthermore, the amounts of signal adaptor molecule Src homology 2 domain-containing tyrosine phosphatase (SHP)-1 and SHP-2 were quantified by immunoprecipitation. And the exciting mechanism of sPD-L1 was explored for PD-1 inhibitory signals. RESULTS: CCK-8 study showed that A values in each group were 0.42 +/- 0.03, 1.20 +/- 0.06, 0.87 +/- 0.05, 0.78 +/- 0.05 and 1.11 +/- 0.09 respectively when the concentration of sPD-L1Ig was 250 ng/ml. The proliferation of T lymphocytes in group C significantly decreased compared with group B (t = 3.946, P = 0.017) while group E significantly increased compared with group D (t = 3.139, P = 0.035). The percentage of cell number in G1 phase of the above-mentioned 5 groups were (94.49 +/- 0.50)%, (79.22 +/- 0.50)%, (89.62 +/- 0.33)%, (92.89 +/- 0.80)% and (87.94 +/- 0.87)% respectively and group C significantly increased compared with group B (t = 17.310, P < 0.001). The apoptotic rate of the above-mentioned five groups were (35.77 +/- 1.82)%, (35.20 +/- 2.70)%, (62.77 +/- 0.24)%, (64.47 +/- 0.44)% and (36.80 +/- 3.53)% respectively. And apoptotic rate in group C significantly increased compared with group B (t = 10.160, P = 0.001) while group E significantly decreased compared with group D (t = 7.790, P = 0.002). The expressions of SHP-1 and SHP-2 showed no inter-group difference (all P > 0.05). However, the expressions of p-SHP-1 and p-SHP-2 in group C was higher than those in group B (t = 10.790, P < 0.001; t = 13.051, P < 0.001) while the expression of p-SHP-1 decreased in group E compared with group D (t = 3.361, P = 0.028). CONCLUSIONS: Soluble PD-L1 can effectively inhibit the proliferation of T lymphocytes. The phosphorylation of SHP-1 and SHP-2 contributes to the inhibitory signaling of PD-1/sPD-L1 pathway. And anti-PD-L1 blocking antibody may partially restore the proliferation of T lymphocytes through a down-regulated expression of p-SHP-1.. PMID- 25916784 TI - [Screening of specific proteins in ultraviolet-induced acute damage of human fibroblasts using proteinchip with surface enhanced laser desorption/ ionization time-of-flight mass spectrometry]. AB - OBJECTIVE: To investigate specific proteins in ultraviolet (UV)-induced acute damage of human fibroblasts using proteinchip with surface enhanced laser desorption/ionization time-of-flight mass spectrometry (SELDI-TOF-MS). METHODS: CM10 Proteinchip and SELDI-TOF-MS were used for detecting protein samples of non irradiated group, UVA (2.5 J/cm(2))-irradiated group and UVB (100 mJ/cm(2)) irradiated group of normal human fibroblasts. RESULTS: Ten protein peaks were down-regulated and 8 protein peaks up-regulated in fibroblasts after UV irradiation. By searching in SWISS-PROT and TrEMBLE databases, the peaks of 11 320.1 and 8 574.3 accorded with those of caspase-7 precursor and cytochrome C oxidase polypeptide VIc precursor proteins. CONCLUSION: As a quick and convenient high-throughout proteomic analytic method, SELDI-TOF-MS plus proteinchip offers a unique platform for detecting dermal photodamage. PMID- 25916785 TI - [Role of FOXO3a in process of hydrogen-rich saline attenuating global cerebral ischemia-reperfusion injury in rats]. AB - OBJECTIVE: To investigate the role of FOXO3a in process of hydrogen-rich saline attenuating global cerebral ischemia-reperfusion (I/R) injury in rats. METHODS: Seventy-two male Sprague Dawley rats, weighing 280-320 g, were randomly divided into six groups (n = 12 each) : sham operation group (group I), cerebral ischemia reperfusion group (group II), hydrogen-rich saline group (group III), vehicle group (group IV), JNK inhibitor SP600125 group (group V), JNK inhibitor+hydrogen rich saline group (group VI). Global cerebral I/R was produced by transesophageal pacing inducing cardiac arrest (CA) method. Cardiopulmonary resuscitation (CPR) and mechanical ventilation was implemented at the end of 4 min for CA. In groups III and VI, hydrogen-rich saline 5 ml/kg was intraperitoneally immediately and 6 hours after reperfusion, while equel volume of nomal saline was injected in the other four groups. The rats in groups V and VI received intracerebroventricular injection of JNK inhibitor SP600125 10 ul 30 min before ischemia, while group IV received intracerebroventricular injection of equal volume of DMSO. Neuro Deficit Score (NDS) was evaluated at 24 h of reperfusion. Then rats were sacrificed, and the global brain tissues were obtained and stained with HE for examination of the changes in pyramidal cells in the CA1 region of hippocampus. The bilateral hippocampi were romoved for detection of the expression of p-JNK, JNK and FOXO3a using Western Blotting. RESULTS: Compared with group I, the expression of p-JNK, nuclear FOXO3a and the level of NDS were significantly up-regulated, and the number of pyramidal cells and was decreased in group II and IV. Compared with group II, the expression of p-JNK, nuclear FOXO3a and the level of NDS were significantly down-regulated, and the number of pyramidal cells was increased in group III, V and VI. CONCLUSION: Hydrogen-rich saline can attenuate global cerebral I/R injure through inhibiting JNK, reducing the expression of FOXO3a. PMID- 25916786 TI - Successful adalimumab treatment of a psoriasis vulgaris patient with hemodialysis for renal failure: A case report and a review of the previous reports on biologic treatments for psoriasis patients with hemodialysis for renal failure. AB - The efficacy and safety of biologic treatments have been established in patients with moderate to severe psoriasis, but there are few reports on biologic therapy for patients with psoriasis complicated by end-stage renal failure on hemodialysis (HD). In this report, we demonstrated the efficacy and safety of adalimumab for patients with severe psoriasis on HD. A 46-year-old Japanese man with a 14-year history of psoriasis was referred to our clinic in September 2009. He had developed hypertension and renal failure during a 7-year history of cyclosporin treatment. With the infliximab treatment, he achieved 75% improvement of the Psoriasis Area and Severity Index (PASI) score within 3 months from the PASI of 42.3 before the treatment. However, his renal failure gradually deteriorated, and HD was initiated at 1 year after the introduction of infliximab. Because of hydration during the i.v. injection of infliximab, he developed pulmonary edema with every infliximab treatment after starting HD. We switched to ustekinumab treatment, but his psoriasis was not improved. Then, we switched to adalimumab and achieved a PASI-100 response within 2 months. The patient received adalimumab treatment for more than a year without any adverse effects. In addition to our case, five articles reported cases of psoriasis patients with renal failure on HD who were treated with biologics. The psoriatic lesions were improved by biologics in these cases, and no severe adverse effects on the renal function were reported. Thus, biologics are a reasonable treatment option for patients with severe psoriasis with renal failure on HD. PMID- 25916787 TI - Intratympanic therapy in Meniere's syndrome or disease: up to date evidence for clinical practice. AB - BACKGROUND: Meniere's syndrome or disease (MS/D) is typically characterised by episodic vertigo, aural fullness, tinnitus and fluctuating hearing loss. There are multiple options available for treatment with variation in consensus on the best intervention. OBJECTIVE: To evaluate the evidence on the efficacy of intratympanic therapies [steroids, gentamicin, antivirals and other therapies] on the frequency and severity of vertigo and other symptoms of MS/D. SEARCH STRATEGY: A literature search was performed on AMED, EMBASE, HMIC, MEDLINE, PsycINFO, BNI, CINAHL, HEALTH BUSINESS ELITE, CENTRAL and Cochrane Ear, Nose and Throat disorders group trials register using various MeSH. The search was restricted to English and human subjects, and the last date of search was December 2014. SELECTION CRITERIA: Randomised controlled trials of intratympanic therapies [steroids, gentamicin antivirals and latanoprost] versus a placebo or another treatment. RESULTS: We analysed 8 RCT's comparing intratympanic steroids, gentamicin, ganciclovir (antiviral) and latanoprost versus another form of intratympanic treatment or placebo. CONCLUSIONS: On the basis of 6 RCT's (n = 242), there is evidence to support the effectiveness of intratympanic steroids and gentamicin to control symptoms of vertigo in MS/D albeit with a risk of hearing loss with gentamicin. However, there was no consensus found on doses or treatment protocols. There was no evidence to support the use of other forms of intratympanic therapy (antivirals and latanoprost) in MS/D. PMID- 25916788 TI - Measurement of the Postgraduate Educational Environment of Junior Doctors Training in Medicine at an Irish University Teaching Hospital. AB - BACKGROUND: A positive learning environment in which postgraduate doctors are supported, supervised and nurtured, is likely to lead to enhanced professional satisfaction and improved patient care. AIMS: The aims of the current study were to use the PHEEM inventory to determine the aspects of their current learning environment which junior doctors rate most and least positively. METHODS: The PHEEM questionnaire was administered to all junior doctors working in medical subspecialties at Galway University Hospitals in Ireland. A response rate of 60 % (n = 61) was obtained. RESULTS: The mean total PHEEM score was 82.88 +/- 18.99, corresponding to an educational environment with more positive than negative aspects but with room for improvement. The mean total PHEEM score (+/-standard deviation) of registrars (89.65 +/- 20.92) exceeded that of Interns (84.00 +/- 15.26) and SHOs (75.12 +/- 18.09). Over half (55 %) of the individual items were rated by the junior doctors as more positive than negative. Nineteen items (48 %) pointed to areas in need of enhancement, whilst 3 items were rated as satisfactory or better. Analysis of qualitative data confirmed that deficiencies exist in various aspects of the educational climate, including protected educational time, access to suitable learning opportunities, the nature of tasks performed by junior doctors, the hospital bleep protocol, implementation of the European Working Time Directive, feedback and career guidance. CONCLUSIONS: Recommendations stemming from this study should lead to improvements in the quality of the educational environment of junior doctors and may stimulate similar evaluations in other teaching hospitals. PMID- 25916789 TI - Depression and alcohol withdrawal syndrome: is antidepressant therapy associated with lower rates of hospital readmission? AB - BACKGROUND: Alcohol withdrawal syndrome (AWS) is a frequent cause of admission to acute care hospitals and many of these patients have a history of depression. AIM: Our objective was to determine if antidepressant use in patients with a history of depression is associated with lower rates of hospital readmission for AWS. METHODS: A retrospective study was performed of patients admitted with AWS between January 1, 2006 and December 31, 2008 to an academic tertiary referral hospital. RESULTS: Three hundred and twenty-two patients were admitted with AWS during the study period. One hundred and sixty-one patients (50 %) had no history of depression, 111 patients (34 %) had a history of depression and antidepressant use, and 50 patients (16 %) had a history of depression and no antidepressant use. There was no significant difference in the number of hospitalizations for AWS between these three groups. Patients with a history of depression on antidepressant medication were more likely to be retired or work disabled compared to the other two groups (p < 0.05). The antidepressant class most commonly used was SSRI (63 %). CONCLUSION: Our study highlights the high frequency of depression and antidepressant use in patients admitted with AWS to an acute care hospital. As alcohol withdrawal is associated with increased morbidity and mortality and depression is common in those with alcohol use disorder, further research is necessary to clarify the optimal treatment of comorbid depression and alcohol use disorder in reducing these revolving door admissions. PMID- 25916790 TI - Analysis of post-transoral robotic-assisted surgery hemorrhage: Frequency, outcomes, and prevention. AB - BACKGROUND: Transoral robotic-assisted surgery (TORS) carries a small, but not insignificant, risk of life-threatening postsurgical hemorrhage. The purpose of this study was to analyze all post-TORS hemorrhagic events at our institution to establish preventative recommendations. METHODS: We conducted a retrospective review of 224 consecutive patients who underwent TORS for any indication at a single tertiary care institution. RESULTS: Twenty-two patients (n = 22; 9.82%) had varying degrees of postoperative bleeding. An impaired ability to protect the airway at the time of hemorrhage increased the rate of severe complications. Prophylactic transcervical arterial ligation did not significantly decrease overall postoperative bleeding rates (9.1% vs 9.9%; p = 1.00); however, there was a trend toward decreased hemorrhage severity in prophylactically ligated patients (3.0% vs 7.3%; p = .7040). CONCLUSION: Prophylactic transcervical arterial ligation may reduce the incidence of severe bleeding following TORS. Post-TORS patients displaying an inability to protect the airway should be strongly considered for prophylactic tracheostomy to assist airway protection. (c) 2015 Wiley Periodicals, Inc. Head Neck 38: E776-E782, 2016. PMID- 25916791 TI - Gait in drug naive patients with de novo Parkinson's disease--altered but symmetric. AB - BACKGROUND: Motor symptoms in Parkinson's disease (PD) are typically asymmetrical. Early stage of PD is characterised with a predominantly unilateral appearance of tremor, rigidity and bradykinesia, with or without axial involvement. Also, studies have demonstrated gait asymmetry in de novo drug naive PD patients. Aim of this study was to investigate gait pattern, gait symmetry and gait variability in early phases of PD. METHODS: The gait was measured in 40 de novo, drug naive PD patients and 43 healthy control subjects (HC) while performing a simple walking task. Calculated parameters were cycle time (CT), stride length (SL) and swing time (ST), and their coefficients of variation (CV). RESULTS: Considering gait parameters, PD patients and HC differed in terms of all parameters, except for the CV of CT. Analysis of gait symmetry, comparison between the gait patterns of the left and the right leg in PD patients revealed no difference for any of the assessed parameters. The majority of the gait parameters did not differ between left and right legs of HC. CONCLUSIONS: It can be concluded that even gait was already altered in de novo drug naive PD patients, gait symmetry remained preserved. The SL was the most prominent parameter of altered gait in initial stages of PD patients, while the ST heralded postural asymmetry. PMID- 25916792 TI - Thematic issue on drug delivery for specific populations. PMID- 25916793 TI - Simultaneous determination of mushroom toxins alpha-amanitin, beta-amanitin and muscarine in human urine by solid-phase extraction and ultra-high-performance liquid chromatography coupled with ultra-high-resolution TOF mass spectrometry. AB - This paper presents a method for the simultaneous determination of alpha amanitin, beta-amanitin and muscarine in human urine by solid-phase extraction (SPE) and ultra-high-performance liquid chromatography coupled with ultra-high resolution TOF mass spectrometry. The method can be used for a diagnostics of mushroom poisonings. Different SPE cartridges were tested for sample preparation, namely hydrophilic modified reversed-phase (Oasis HLB) and polymeric weak cation phase (Strata X-CW). The latter gave better results and therefore it was chosen for the subsequent method optimization and partial validation. In the course of validation, limits of detection, linearity, intraday and interday precisions and recoveries were evaluated. The obtained LOD values of alpha-amanitin and beta amanitin were 1ng/mL and of muscarine 0.09ng/mL. The intraday and interday precisions of human urine spiked with alpha-amanitin (10ng/mL), beta-amanitin (10ng/mL) and muscarine (1ng/mL) ranged from 6% to 10% and from 7% to 13%, respectively. The developed method was proved to be a relevant tool for the simultaneous determination of the studied mushroom toxins in human urine after mushroom poisoning. PMID- 25916794 TI - A state of the art of metabolic networks of unicellular microalgae and cyanobacteria for biofuel production. AB - The most promising and yet challenging application of microalgae and cyanobacteria is the production of renewable energy: biodiesel from microalgae triacylglycerols and bioethanol from cyanobacteria carbohydrates. A thorough understanding of microalgal and cyanobacterial metabolism is necessary to master and optimize biofuel production yields. To this end, systems biology and metabolic modeling have proven to be very efficient tools if supported by an accurate knowledge of the metabolic network. However, unlike heterotrophic microorganisms that utilize the same substrate for energy and as carbon source, microalgae and cyanobacteria require light for energy and inorganic carbon (CO2 or bicarbonate) as carbon source. This double specificity, together with the complex mechanisms of light capture, makes the representation of metabolic network nonstandard. Here, we review the existing metabolic networks of photoautotrophic microalgae and cyanobacteria. We highlight how these networks have been useful for gaining insight on photoautotrophic metabolism. PMID- 25916796 TI - 50 nm sized spherical TiO2 nanocrystals for highly efficient mesoscopic perovskite solar cells. AB - Single crystalline TiO2 nanoparticles (NPs) with spherical morphology are successfully synthesized by a hydrothermal reaction under basic conditions. TiO2 NPs, selectively controlled to the sizes of 30, 40, 50, and 65 nm, are then applied to a mesoporous photoelectrode of CH3NH3PbI3 perovskite solar cells. In particular, a spherical TiO2 NP of 50 nm size (NP50) offers the highest photovoltaic conversion efficiency (PCE) of 17.19%, with JSC of 21.58 mA cm(-2), VOC of 1049 mV, and FF of 0.759 while the enhancement of PCE mainly arises from the increase of VOC and FF. Furthermore, the fabricated photovoltaic devices exhibit reproducible PCE values and very little hysteresis in their J-V curves. Time-resolved photoluminescence measurement and pulsed light-induced transient measurement of the photocurrent indicate that the device employing NP50 exhibits the longest electron lifetime although the electron injection from perovskite to TiO2 is less efficient than the devices with smaller TiO2 NPs. The extended electron lifetime is attributed to the suppression of electron recombination due to optimized mesopores generated by the spherical NP50. PMID- 25916795 TI - The changing nature of the Brucella-containing vacuole. AB - Bacteria of the genus Brucella are intracellular vacuolar pathogens of mammals that cause the worldwide zoonosis brucellosis, and reside within phagocytes of infected hosts to promote their survival, persistence and proliferation. These traits are essential to the bacterium's ability to cause disease and have been the subject of much investigation to gain an understanding of Brucella pathogenic mechanisms. Although the endoplasmic reticulum-derived nature of the Brucella replicative niche has been long known, major strides have recently been made in deciphering the molecular mechanisms of its biogenesis, including the identification of bacterial determinants and host cellular pathways involved in this process. Here I will review and discuss the most recent advances in our knowledge of Brucella intracellular pathogenesis, with an emphasis on bacterial exploitation of the host endoplasmic reticulum-associated functions, and how autophagy-related processes contribute to the bacterium's intracellular cycle. PMID- 25916797 TI - Surreptitious metformin abuse in anorexia nervosa presenting as periodic hypoglycaemia. PMID- 25916798 TI - The importance of cross-cultural research in addictions. PMID- 25916799 TI - Carcinogenicity of psychotropic drugs: A systematic review of US Food and Drug Administration-required preclinical in vivo studies. AB - OBJECTIVE: The US Food and Drug Administration approval process for psychotropic drugs requires safety studies of carcinogenicity in animals. These studies are consistently conducted and provide a database for assessment of potential biological risk of carcinogenicity in humans. This report is a systematic review of that database for psychotropic drugs. METHOD: US Food and Drug Administration approved registration data ('package inserts') were examined, where available, for all psychotropic drugs in the following classes: antidepressants, antipsychotics, benzodiazepines/sedative-hypnotics, amphetamines and anticonvulsants. RESULTS: Overall, new generation (atypical) antipsychotics (90%, 9/10 agents) and anticonvulsants (85.7%, 6/7 agents) showed the highest evidence of carcinogenicity among psychotropic drugs classes assessed. Antidepressants (63.6%, 7/11) and benzodiazepines/sedative-hypnotics (70%, 7/10) were next, and stimulants (with the exception of methylphenidate) were last (25%, 1/4 agents). Overall, 71.4% of all drugs examined (30/42) showed evidence of carcinogenicity in 43.2% (38/88) of specific experimental studies. CONCLUSIONS: US Food and Drug Administration-based analyses demonstrate that almost all atypical antipsychotics and anticonvulsants are carcinogenic in animals, as are the majority of antidepressants and benzodiazepines and methylphenidate. These animal-based results are not sufficient to draw definitive conclusions in humans, but they provide data that could be acknowledged in the informed consent process of clinical treatment. PMID- 25916800 TI - Recall bias in childhood atopic diseases among adults in the Odense Adolescence Cohort Study. AB - Atopic dermatitis (AD) is a common disease in childhood and an important risk factor for the later development of other atopic diseases. Many publications on childhood AD use questionnaires based on information obtained in adulthood, which introduce the possibility of recall bias. In a prospective cohort study, recall bias was evaluated in 1,501 unselected schoolchildren (mean age 14 years) evaluated for the first time in 1995 with a standardized questionnaire combined with a clinical examination and repeated in 2010. The lifetime prevalence of AD was 34.1% including data obtained both during school age and 15 years later, compared with 23.6% including data only from adulthood. The most important factors for remembering having had AD in childhood were: (i) long duration of dermatitis in childhood; (ii) adult hand eczema; and (iii) concomitant atopic disease. Recall bias for childhood AD affected the results of logistic regression on adult hand eczema and is a significant problem in retrospective epidemiological questionnaire studies evaluating previous AD as a risk factor for development of other diseases. PMID- 25916801 TI - Proliferation of rat cardiac stem cells is induced by 2, 3, 5, 4' tetrahydroxystilbene-2-O-beta-D-glucoside in vitro. AB - AIM: To study the effects of 2, 3, 5, 4'-tetrahydroxystilbene-2-O-beta-d glucoside (THSG) on proliferation of rat cardiac stem cells (CSCs) in vitro. MATERIALS AND METHODS: C-kit(+) cells were isolated from neonatal (1 day old) Sprague-Dawley rats by using flow cytometry. Optimal THSG treatment times and doses for growth of CSCs were analyzed. CSCs were treated with various THSG doses (0, 1, 10, and 100 MUM) for 12h. RESULTS: Sorted c-kit(+) cells exhibited self renewing and clonogenic capabilities. Cell Counting Kit (CCK-8) and Proliferating Cell Nuclear Antigen (PCNA) ELISA test positive cells were significantly increased in THSG-treated groups compared with untreated controls. The percentage of S-phase cells also increased after THSG treatment. Moreover, we show that some c-kit(+) cells spontaneously express vascular endothelial growth factor (VEGF), T box transcription factor (Tbx5), hyperpolarization-activated cyclic nucleotide gated 2 (HCN2), hyperpolarization-activated cyclic nucleotide gated 4 (HCN4), alpha myosin heavy chain (alphaMHC), and beta myosin heavy chain (betaMHC) mRNA, and stem cell antigen 1 (Sca-1), cardiac troponin-I, GATA-4, Nkx2.5, and connexin 43 protein were also assessed in CSCs. However, their expression was significantly increased with THSG treatment when compared to untreated controls. CONCLUSION: THSG can increase proliferation of rat CSCs in vitro and thus, shows promise as a potential treatment strategy for stimulating endogenous stem cells to help repair the injured heart after myocardial infarction in patients. PMID- 25916802 TI - Vibrio vulnificus RtxA1 modulated calcium flux contributes reduced internalization in phagocytes. AB - AIMS: Vibrio vulnificusis an opportunistic pathogen that causes primary septicemia and wound infection with high mortality rate. This pathogen produces an RTX toxin (RtxA1) which can cause host cell rounding, cell death and interference with internalization by host phagocytes. However, the mechanism of RtxA1-induced phagocyte paralysis is not clear. MAIN METHODS: Using the murine macrophage cell line RAW264.7, we measured cytotoxicity and phagocytosis of V. vulnificusin normal and calcium-depleted media. To deplete extracellular and cytosolic Ca(2+), cells were exposed to the calcium chelators ethylene glycol tetraacetic acid (EGTA) and 1,2-bis-(o-aminophenoxy)-ethane-N,N,N',N'-tetraacetic acid, tetraacetoxymethyl esteris (BAPTA-AM), respectively. The cytotoxicity was examined by measuring the activity of lactate dehydrogenase (LDH) released from the damaged cells. The gentamicin protection assay was conducted to determine the number of internalized bacteria, while acridine orange staining was applied to visualize the intracellular bacteria. The fluorescent indicator fura-2 acetoxymethyl ester (fura 2-AM) was used to measure the Ca(2+)signal post infection. KEY FINDINGS: We revealed that extracellular Ca(2+)was essential for phagocytes to internalize V. vulnificus. Meanwhile, cytosolic Ca(2+)flux in RAW264.7 cells induced by an RtxA1 isogenic mutant was repressed by the parent strain. Furthermore, depletion of extracellular Ca(2+)level by EGTA significantly reduced the cytotoxicity but did not affect the antiphagocytic activity of RtxA1 toxin. SIGNIFICANCE: Our results indicated that RtxA1 may interfere with cytosolic Ca(2+)flux of phagocyte to promote bacteria colonization. PMID- 25916803 TI - Ezetimibe and simvastatin modulate gut microbiota and expression of genes related to cholesterol metabolism. AB - AIMS: Hypolipidemic drugs are prescribed in the most of cases for the treatment of cardiovascular diseases. Several studies have showed that the gut microbiota is able to regulate the host cholesterol metabolism. This study aimed to investigate the potential impact of hypolipidemic drugs on the gut microbiota in mice, and to correlate it to the regulation of cholesterol metabolism. MAIN METHODS: Male C57Bl/6J mice were divided into four groups fed either a control diet alone (CT), or supplemented with simvastatin (0.1% w/w, Zocor(r), MSD), or ezetimibe (0.021% w/w, Ezetrol(r), MSD) or a combination of simvastatin and ezetimibe (0.1% and 0.021%, respectively) for one week. KEY FINDINGS: The combination of ezetimibe and simvastatin is required to observe a drop in cholesterolemia, linked to a huge activation of hepatic SREBP-2 and the consequent increased expression of genes involved in LDL cholesterol uptake and cholesterol synthesis. The gut microbiota analysis revealed no change in total bacteria, and in major Gram positive and Gram negative bacteria, but a selective significant increase in Lactobacillus spp. in mice treated with the ezetimibe and a decrease by the combination. The changes in lactobacilli level observed in ezetimibe or combination treated-mice are negatively correlated to expression of genes related to cholesterol metabolism. SIGNIFICANCE: The present study showed that ezetimibe taken alone is able to modify the composition of gut microbiota in favor of Lactobacillus spp. These results suggest that members of the genus Lactobacillus play an important role in cholesterol metabolism, even in normocholesterolemic mouse model. PMID- 25916804 TI - The protective effect of astragaloside IV against benzo[a]pyrene induced endothelial progenitor cell dysfunction. AB - AIMS: Benzo[a]pyrene (BaP), a prominent component of tobacco, has been revealed to induce damage to endothelial progenitor cells (EPCs). Astragaloside IV (AS-IV) is widely used for the treatment of cardiovascular diseases in China. In this study, we evaluated the effects of AS-IV on the function of human EPCs after BaP exposure and explored the underlying mechanism. MATERIALS AND METHODS: Human umbilical cord blood mononuclear cells were isolated using density gradient centrifugation. Cells of the 4th passage were randomly divided into 6 groups. EPCs of experimental groups were pre-treated with different concentrations (2, 10 and 50 MUg/mL) of AS-IV for 2h before exposure to BaP (20 MUM) for 24h. The proliferation, migration, and adhesion of the treated EPCs were evaluated using a cell counting kit-8, Transwell assay and adhesion assay respectively. Interleukin 1beta, tumor necrosis factor-alpha, malondialdehyde and SOD contents in the supernatant were evaluated. The expression of RAGE protein was measured by Western blotting. KEY FINDINGS: The results demonstrated that AS-IV pre-treatment significantly improved BaP-induced dysfunction of EPCs in terms of proliferation, migration and adhesion. Furthermore, AS-IV reduced the production of reactive oxygen species, malondialdehyde, interleukin-1beta and tumor necrosis factor alpha of the BaP-treated EPCs. Finally AS-IV pre-treated EPCs showed an increased SOD activity and decreased RAGE protein expression. SIGNIFICANCE: AS-IV is able to prevent BaP-mediated EPC dysfunction by at least inhibiting oxidative stress through the RAGE pathway. PMID- 25916805 TI - The use of secure anonymised data linkage to determine changes in healthcare utilisation following severe open tibial fractures. AB - Severe open fractures of the lower limbs are complex injuries requiring expert multidisciplinary management in appropriate orthoplastic centres. This study aimed to assess the impact of open fractures on healthcare utilisation and test the null hypotheses that there is no difference in healthcare utilisation between the year before and year after injury, and that there is no difference in healthcare utilisation in the year post-injury between patients admitted directly to an orthoplastic centre in keeping with the joint BOA/BAPRAS standards and those having initial surgery elsewhere. This retrospective cohort study utilising secure anonymised information linkage (SAIL), a novel databank of anonymised nationally pooled health records, recruited patients over 18 years of age sustaining severe open lower limb fractures managed primarily or secondarily at our centre and who had data available in the SAIL databank. 101 patients met inclusion criteria and 90 of these had records in the SAIL databank. The number of days in hospital, number of primary care attendances, number of outpatient attendances and number of emergency department attendances in the years prior and subsequent to injury were recorded. Patients sustaining open fractures had significantly different healthcare utilisation in the year after injury when compared with the year before, in terms of days spent in hospital (23.42 vs. 1.70, p=0.000), outpatient attendances (11.98 vs. 1.05, p=0.000), primary care attendances (29.48 vs. 11.99, p=0.000) and emergency department presentations (0.2 vs. 0.01, p=0.025). Patients admitted directly to orthoplastic centres had significantly fewer operations (1.78 vs. 3.31) and GP attendances (23.6 vs. 33.52) than those transferred in subsequent to initial management in other units. There is a significant increase in healthcare utilisation after open tibial fracture. Adherence to national standards minimises the impact of this on both patients and health services. PMID- 25916806 TI - The double-pulley technique for anatomical double-bundled medial patellofemoral ligament reconstruction. AB - INTRODUCTION: Majority of the current medial patellofemoral ligament (MPFL) reconstruction techniques vary with respect to methods of fixation on the patella. In an effort to maximise the area of patellar footprint coverage and minimise the complication of patellar fracture, we developed a procedure that implemented the double-pulley suture anchors technique. DESIGN: Prospective case series. SETTING: A primary medical centre in Kaohsiung, Taiwan. PATIENTS AND METHODS: Eighteen consecutive patients (18 knees) who met the inclusion criteria underwent the aforementioned operation between January 2010 and March 2012. Patients were evaluated using functional scores (Kujala and Tegner-Lysholm scores), apprehension test, and radiographic examination (congruence angle and patellar tilting angle) preoperatively and at the follow-up. RESULTS: The mean follow-up was 35 months. A firm endpoint to lateral patellar translation was noted in all patients at the last follow-up with a mean lateral translation quadrant of 1.5 (improved from 3.5 preoperatively, p<0.001). Both clinical and radiographic assessment improved significantly (p<0.001); the mean Kujala score improved from 55.3+/-6.8 preoperatively to 95.2+/-3.5 at the last follow-up; TegnerLysholm from 43.6+/-8.1 to 93.6+/-6.8; the mean congruence angle improved from 20.6 degrees +/-2.1 degrees preoperatively to -5.2 degrees +/-2.4 degrees at the last follow-up; and the patellar tilting angle from 23.8 degrees +/-2.3 degrees to 9.6 degrees +/-1.3 degrees . CONCLUSION: The double-pulley patellar fixation technique, by having a result that is comparable with those of other studies that used aperture fixation techniques, can be a promising surgical option for anatomically reconstructing the medial petellofemoral ligament. PMID- 25916807 TI - The sense of biomechanical studies in orthopaedics: a discussion on a recent study published in Injury. PMID- 25916808 TI - Organocatalytic Highly Enantioselective Substitution of 3-(1-Tosylalkyl)indoles with Oxindoles Enables the First Total Synthesis of (+)-Trigolutes B. AB - A highly enantioselective organocatalytic substitution of 3-(1-tosylalkyl)indoles with oxindoles has been established by using chiral bifunctional organocatalysts, providing an efficient entry to multiply functionalized 3,3'-disubstituted oxindoles, and was exploited as the key step to enable the first asymmetric total synthesis of optically pure (+)-trigolutes B to be accomplished in a concise manner, within seven steps with an 18% overall yield. PMID- 25916810 TI - dDsk2 regulates H2Bub1 and RNA polymerase II pausing at dHP1c complex target genes. AB - dDsk2 is a conserved extraproteasomal ubiquitin receptor that targets ubiquitylated proteins for degradation. Here we report that dDsk2 plays a nonproteolytic function in transcription regulation. dDsk2 interacts with the dHP1c complex, localizes at promoters of developmental genes and is required for transcription. Through the ubiquitin-binding domain, dDsk2 interacts with H2Bub1, a modification that occurs at dHP1c complex-binding sites. H2Bub1 is not required for binding of the complex; however, dDsk2 depletion strongly reduces H2Bub1. Co depletion of the H2Bub1 deubiquitylase dUbp8/Nonstop suppresses this reduction and rescues expression of target genes. RNA polymerase II is strongly paused at promoters of dHP1c complex target genes and dDsk2 depletion disrupts pausing. Altogether, these results suggest that dDsk2 prevents dUbp8/Nonstop-dependent H2Bub1 deubiquitylation at promoters of dHP1c complex target genes and regulates RNA polymerase II pausing. These results expand the catalogue of nonproteolytic functions of ubiquitin receptors to the epigenetic regulation of chromatin modifications. PMID- 25916811 TI - ANCA-associated vasculitis in patients with primary Sjogren's syndrome: detailed analysis of 7 new cases and systematic literature review. AB - OBJECTIVES: To describe the clinical presentation, management and prognosis of patients diagnosed with both primary Sjogren's syndrome (pSS) and anti-neutrophil cytoplasmic antibody (ANCA)-associated vasculitis (AAV). METHODS: French nation wide survey completed by a systematic literature review. RESULTS: This work identified 7 new cases of coexisting pSS and AAV: 2 microscopic polyangiitis (MPA), 2 granulomatosis with polyangiitis (GPA), 2 anti-myeloperoxidase (MPO) ANCA renal-limited AAV, and 1 eosinophilic granulomatosis with polyangiitis (EGPA). The systematic literature search identified 15 previously published cases. Among the 22 patients, 19 were females. Mean age at diagnosis of AAV was 63.9+/-9.8years. All individuals with available information experienced at least one extra-glandular manifestation attributable to pSS. p-ANCA with anti-MPO specificity were found in 76.2% (16/21), c-ANCA with anti-PR3 specificity in 14.3% (3/21) and isolated c-ANCA in 13.6% (3/22). Vasculitis involved kidneys (n=13), lungs (n=8), skin (n=6), peripheral nerves (n=5), central nervous system (n=2), small bowel (n=1), muscle (n=1), ear chondritis (n=1) and sinuses (n=1). The mean AAV follow-up was 73.5 (+/-120.0) months. While on treatment, disease remission occurred in 77.3% of cases, and one death was reported in the first 6months after diagnosis. CONCLUSION: This work shows that AAV may occur in patients with pSS. These are most commonly p-ANCA associated vasculitis with anti MPO specificity. AAV may reveal an underlying pSS or arise during its evolution, but did not precede pSS in any of these cases. AAV occurrence appears to be correlated with extra-glandular manifestations of pSS. PMID- 25916813 TI - Associations with smoking and shared epitope differ between IgA- and IgG-class antibodies to cyclic citrullinated peptides in early rheumatoid arthritis. AB - OBJECTIVE: Smoking and HLA-DRB1/shared epitope (SE) alleles are risk factors for rheumatoid arthritis (RA) characterized by seropositivity for antibodies targeting citrullinated proteins (ACPAs)/cyclic citrullinated peptides (anti CCP). Previously, mainly IgG-class antibodies have been studied. IgA-class antibodies are to a great extent related to mucosal immunity. The aim of this study was to explore interrelations between cigarette smoking, presence of SE, and seropositivity for circulating IgA and/or IgG anti-CCP antibodies among patients with early RA, to determine whether ACPAs of the IgA subclass are regulated by different mechanisms than those of the IgG subclass. METHODS: Two cohorts of patients with early RA, from the first Epidemiological Investigations of RA trial (n = 1,663) and the second Early Intervention in RA trial (n = 199), were grouped into 4 subsets based on anti-CCP subclass status (IgG-/IgA-, IgG /IgA+, IgG+/IgA-, and IgG+/IgA+), and each subset was compared with regard to associations with smoking (current and former) and presence of SE. Interaction between smoking and SE was calculated using the attributable proportion (AP) due to interaction (assessing deviation from additivity of effects). RESULTS: Smoking was overrepresented among IgA anti-CCP-positive RA patients, regardless of whether IgG anti-CCP were present, whereas in patients with IgG anti-CCP alone, no association with smoking was found. SE alleles were overrepresented among IgG anti-CCP-positive patients, regardless of IgA anti-CCP status, and was not seen in patients with IgA anti-CCP alone. An interaction between ever smoking and SE was found with regard to the risk of IgG+/IgA+ RA (AP 0.5, 95% confidence interval 0.4, 0.6). No significant interaction was observed with regard to the risk of IgG-/IgA+ RA or IgG+/IgA- RA. CONCLUSION: In patients with RA, a history of ever smoking was associated with seropositivity for IgA anti-CCP antibodies, whereas presence of SE was associated with seropositivity for IgG anti-CCP antibodies. An interaction between ever smoking and the SE was limited to the RA subset characterized by seropositivity for both IgG and IgA anti-CCP. These findings provide novel evidence that anti-CCP-positive RA can be divided into at least 3 serologically distinct subsets associated with different risk factors, indicating different modes of pathogenesis in RA. PMID- 25916814 TI - Shock Reduction With Multiple Bursts of Antitachycardia Pacing Therapies to Treat Fast Ventricular Tachyarrhythmias in Patients With Implantable Cardioverter Defibrillators: A Multicenter Study. AB - INTRODUCTION: An empirical sequence of burst antitachycardia pacing (ATP) is effective in terminating fast ventricular tachycardias (FVT) in patients with implantable cardioverter-defibrillators (ICDs). We aimed to determine whether multiple ATP bursts for termination of FVT results in shock reduction compared to a single ATP burst. METHODS AND RESULTS: We analyzed data from the Umbrella trial, a multicenter prospective observational study of ICD patients followed by the CareLink Monitoring System. We compared the safety and effectiveness of a single ATP burst (Group 1) with a strategy of successive ATP sequences (Group 2) for termination of FVT episodes (cycle lengths 250-320 milliseconds) before shock therapy. Over a mean follow-up of 35 months, a total of 650 FVT episodes were detected in 154 patients (mean cycle length: 299 +/- 18 milliseconds). Effectiveness of the first burst ATP in Group 1 was 73% and shocks were required in 27% of episodes. Effectiveness of the first burst ATP in Group 2 was 77%, and this increased to 91% with the third or successive ATP bursts. Shocks were required in 9% of episodes in group 2, representing a 67% reduction in the need of high-energy shocks. Median duration of FVT episodes and mortality in both groups were similar. Multivariate analysis indicated that programming multiple ATP bursts (OR 3.4, 95%CI 1.7-6.8, P = 0.001) was an independent predictor of ATP effectiveness. CONCLUSION: This study provides first evidence that a strategy of multiple burst ATP sequences for termination of FVT episodes leads to a clinically meaningful reduction in the need for shocks. PMID- 25916815 TI - Cardiac troponin I levels in an elderly population from the community--The implications of sex. AB - OBJECTIVES: The importance of sex on cardiac troponin levels is increasingly recognized. We investigated whether the entities associated with troponin leakage and the prognostic consequences thereof would differ between elderly men and women from the community. DESIGN AND METHODS: Cardiac troponin I (cTnI) levels were measured using a high-sensitivity assay (Abbott Laboratories) in 70-year old men (n = 502) and women (n = 502) from the PIVUS study. All study participants were followed up for 10 years regarding all-cause mortality and incident cardiovascular (CV) disease. RESULTS: Median cTnI levels were 4.1 and 3.0 ng/L in men and women, respectively (p<0.001). By multiple linear regression, the relative contribution of lower left-ventricular ejection fraction and ischemic ECG changes to cTnI levels was greater in men compared to women. For other clinical and echocardiographic variables, similar associations were found. cTnI independently predicted all-cause mortality in men (n = 93 [18.5%]; hazard ratio [HR] 1.38 [1.12-1.70]) and women (n = 62 [12.4%]; HR 1.59 [1.11-2.28]) but not incident CV disease in subjects being CV healthy at baseline (n = 163/857). The interaction terms of sex on the associations of cTnI with both outcomes were non significant. Sex-specific cut-offs did not improve prognostication. Variations in the pattern of entities associated with cTnI leakage had no impact on event rates. CONCLUSIONS: We found some differences in the entities associated with higher cTnI levels in elderly community-dwelling men and women. However, this did not translate into differences in the associations of cTnI with adverse outcome. PMID- 25916816 TI - Evaluation of a semi-quantitative pregnancy device for susceptibility to interference caused by hCGbetacf. AB - OBJECTIVE: Previous work has documented the ability of the Clearblue Advanced Test with Weeks Estimator, a new over-the-counter (OTC) urine hCG device, to accurately estimate weeks since ovulation in early pregnancy. In this study, the performance of this device in more advanced pregnancy was assessed. METHODS: The Clearblue Advanced Test with Weeks Estimator device was used to test solutions containing purified intact hCG and hCGbetacf at concentrations consistent with early, middle and late pregnancy. Urine samples from three normal pregnant patients 9-13 weeks of gestation and from a patient 12 weeks of gestation known to generate false negative results on qualitative urine test devices due to excess hCGbetacf were also evaluated. RESULTS: The Clearblue Weeks Estimator device gave expected results using solutions containing purified intact hCG and hCGbetacf at concentrations observed throughout pregnancy. The device generated expected results using urine from three of four patients tested between 9 and 13 weeks of gestation. However, when urine from a patient with elevated concentrations of hCGbetacf was used, the device correctly indicated pregnancy although the estimate for the date was incorrect. CONCLUSION: This device gave expected "pregnant" results using all samples tested. However, the "Weeks Estimator" should be interpreted with caution when used by patients after seven weeks of pregnancy. PMID- 25916817 TI - Plasma microRNAs serve as potential biomarkers for abdominal aortic aneurysm. AB - OBJECTIVES: Abdominal aortic aneurysm (AAA) is often asymptomatic until rupture occurs. Although ultrasound screening has significantly improved the early diagnosis of AAA, the timely biomarker-based diagnosis of AAA remains a major clinical challenge. In this study, we aimed to assess plasma microRNAs (miRNAs) as promising novel biomarkers in patients with AAA. METHODS: Pooled plasma samples from 10 AAA and 10 healthy controls were profiled by microarray. The differentially expressed miRNAs were evaluated in a separate cohort of 120 subjects, including 60 AAA patients and 60 normal controls. RESULTS: The initial profiling study identified 151 miRNAs that showed more than two-fold change. Among them, three miRNAs, miR-191-3p, miR-455-3p and miR-1281 exhibited the largest increase in the patient group (fold change>5). A subsequent validation study confirmed the elevation of these three miRNAs. Receiver operator characteristic curve analysis using the expression ratio of miR-191-3p, miR-455 3p and miR-1281 showed an area under the curve of 0.9700, 0.9825 and 0.9206, respectively. CONCLUSION: Our results suggest that plasma miR-191-3p, miR-455-3p and miR-1281 may be used as potential diagnosis biomarkers for AAA. PMID- 25916818 TI - Mechanical biocompatibility of highly deformable biomedical materials. AB - Mismatch of mechanical properties between highly deformable biomedical materials and adjacent native tissue might lead to short and long term health impairment. The capability of implants to deform at the right level, i.e. similar to the macroscopic mechanical response of the surrounding biological materials, is often associated with dissimilar microstructural deformation mechanisms. This mismatch on smaller length scales might lead to micro-injuries, cell damage, inflammation, fibrosis or necrosis. Hence, the mechanical biocompatibility of soft implants depends not only on the properties and composition of the implant material, but also on its organization, distribution and motion at one or several length scales. The challenges related to the analysis and attainment of mechanical biocompatibility are illustrated with two examples: prosthetic meshes for hernia and pelvic repair and electrospun scaffolds for tissue engineering. For these material systems we describe existing methods for characterization and analysis of the non-linear response to uniaxial and multiaxial stress states, its time and history dependence, and the changes in deformation behavior associated with tissue in-growth and material resorption. We discuss the multi-scale deformation behavior of biomaterials and adjacent tissue, and indicate major interdisciplinary questions to be addressed in future research. PMID- 25916819 TI - A new design concept for knitted external vein-graft support mesh. AB - Autologous vein-graft failure significantly limits the long-term efficacy of coronary artery bypass procedures. The major cause behind this complication is biomechanical mismatch between the vein and coronary artery. The implanted vein experiences a sudden increase (10-12 fold) in luminal pressures. The resulting vein over-distension or 'ballooning' initiates wall thickening phenomenon and ultimate occlusion. Therefore, a primary goal in improving the longevity of a coronary bypass procedure is to inhibit vein over-distension using mechanical constriction. The idea of using an external vein-graft support mesh has demonstrated sustained benefits and wide acceptance in experimental studies. Nitinol based knitted structures have offered more promising mechanical features than other mesh designs owing to their unique loosely looped construction. However, the conventional plain knit construction still exhibits limitations (radial compliance, deployment ease, flexibility, and bending stresses) which limit this design from proving its real clinical advantage. The new knitted mesh design presented in this study is based on the concept of composite knitting utilising high modulus (nitinol and polyester) and low modulus (polyurethane) material components. The experimental comparison of the new design with a plain knit design demonstrated significant improvement in biomechanical (compliance, flexibility, extensibility, viscoelasticity) and procedural (deployment limit) parameters. The results are indicative of the promising role of new mesh in restoring the lost compliance and pulsatility of vein-graft at high arterial pressures. This way it can assist in controlled vein-graft remodelling and stepwise restoration of vein mechanical homoeostasis. Also, improvement in deployment limit parameter offers more flexibility for a surgeon to use a wide range of vein diameters, which may otherwise be rendered unusable for a plain knit mesh. PMID- 25916820 TI - The role of radiotherapy in the management of penile cancer. PMID- 25916821 TI - Rebranding "community mental health". PMID- 25916822 TI - The interdigital brace and other grips for termite nest perforation by chimpanzees of the Goualougo Triangle, Republic of Congo. AB - Studies of chimpanzee termite foraging enlighten our understanding of early hominin tool use not only by modeling the cognitive ability of our ancestors but also by emphasizing the possible role of social insects in the hominin diet. The chimpanzees of the Goualougo Triangle are known to have one of the largest and most complex tool repertoires reported for wild chimpanzees. One tool set habitually used by this population includes a perforating tool to penetrate the hard outer crust of elevated termite nests before fishing for termite prey with an herbaceous stem. Here, we report the variation present in the grips used on the perforating tool. Our analysis of video recordings of chimpanzee visitation to termite nests over a 3-year period shows that these chimpanzees use a variety of grips to navigate the challenges encountered in opening a termite nest. For situations in which the soil is most hardened, perforating requires force and a power grip is often used. When the soil in the passageway is loose, precision grips are suitable for the task. One of the preferred grips reported here is an interdigital brace, which has previously been described in studies of how some people hold a pencil. In this study, for the first time, the interdigital brace has been thoroughly described for chimpanzees. The various strategies and grips used during perforation emphasize the importance of termites as a nutritional resource that should be considered more strongly as a food used by early hominins. PMID- 25916823 TI - Achieving successful delivery of oligonucleotides--From physico-chemical characterization to in vivo evaluation. AB - RNA interference is one of the most promising fields in modern medicine to treat several diseases, ranging from cancer to cardiac diseases, passing through viral infections and metabolic pathologies. Since the discovery of the potential therapeutic properties of non-self oligonucleotides, it was clear that it is important to develop delivery systems that are able to increase plasma stability and bestow membrane-crossing abilities to the oligonucleotides in order to reach their cytoplasmic targets. Polymer therapeutics, among other systems, are widely investigated as delivery systems for therapeutic agents, such as oligonucleotides. Physico-chemical characterization of the supramolecular polyplexes obtained upon charge interaction or covalent conjugation between the polymeric carrier and the oligonucleotides is critical. Appropriate characterization is fundamental in order to predict and understand the in vivo silencing efficacy and to avoid undesired side effects and toxicity profile. Shedding light on the physico-chemical and in vitro requirements of a polyplex leads to an efficient in vivo delivery system for RNAi therapeutics. In this review, we will present the most common techniques for characterization of obtained polymer/oligonucleotide polyplexes and an up-to-date state of the art in vivo preclinical and clinical studies. This is the first review to deal with the difficulties in appropriate characterization of small interfering RNA (siRNA) or microRNA (miRNA) polyplexes and conjugates which limit the clinical translation of this promising technology. PMID- 25916824 TI - Interplay between troponin T phosphorylation and O-N-acetylglucosaminylation in ischaemic heart failure. AB - AIMS: Previous studies have reported that decreased serine 208 phosphorylation of troponin T (TnTpSer208) is associated with ischaemic heart failure (HF), but the molecular mechanisms and functional consequences of these changes are unknown. The aim of this study was to characterize the balance between serine phosphorylation and O-N-acetylglucosaminylation (O-GlcNAcylation) of TnT in HF, its mechanisms, and the consequences of modulating these post-translational modifications. METHODS AND RESULTS: Decreased TnTpSer208 levels in the left ventricles of HF male Wistar rats were associated with reduced expression of PKCepsilon but not of other cardiac PKC isoforms. In both isolated perfused rat hearts and cultured neonatal cardiomyocytes, the PKCepsilon inhibitor epsilonV1-2 decreased TnTpSer208 and simultaneously decreased cardiac contraction in isolated hearts and beating amplitude in neonatal cardiomyocytes (measured by atomic force microscopy). Down-regulating PKCepsilon by silencing RNA (siRNA) also reduced TnTpSer208 in these cardiomyocytes, and PKCepsilon-/- mice had lower TnTpSer208 levels than the wild-type. In parallel, HF increased TnT O-GlcNAcylation via both increased O-GlcNAc transferase and decreased O-GlcNAcase activity. Increasing O GlcNAcylation (via O-GlcNAcase inhibition with Thiamet G) decreased TnTpSer208 in isolated hearts, while reducing O-GlcNAcylation (O-GlcNAc transferase siRNA) increased TnTpSer208 in neonatal cardiomyocytes. Mass spectrometry and NMR analysis identified O-GlcNAcylation of TnT on Ser190. CONCLUSION: These data demonstrate interplay between Ser208 phosphorylation and Ser190 O-GlcNAcylation of TnT in ischaemic HF, linked to decreased activity of both PKCepsilon and O GlcNAcase and increased O-GlcNAc transferase activity. Modulation of these post translational modifications of TnT may be a new therapeutic strategy in HF. PMID- 25916825 TI - Discrete domains of gene expression in germinal layers distinguish the development of gyrencephaly. AB - Gyrencephalic species develop folds in the cerebral cortex in a stereotypic manner, but the genetic mechanisms underlying this patterning process are unknown. We present a large-scale transcriptomic analysis of individual germinal layers in the developing cortex of the gyrencephalic ferret, comparing between regions prospective of fold and fissure. We find unique transcriptional signatures in each germinal compartment, where thousands of genes are differentially expressed between regions, including ~80% of genes mutated in human cortical malformations. These regional differences emerge from the existence of discrete domains of gene expression, which occur at multiple locations across the developing cortex of ferret and human, but not the lissencephalic mouse. Complex expression patterns emerge late during development and map the eventual location of folds or fissures. Protomaps of gene expression within germinal layers may contribute to define cortical folds or functional areas, but our findings demonstrate that they distinguish the development of gyrencephalic cortices. PMID- 25916826 TI - SHP2: a new target for pro-senescence cancer therapies. PMID- 25916827 TI - Neuropeptide Y regulates the hematopoietic stem cell microenvironment and prevents nerve injury in the bone marrow. AB - Many reports have revealed the importance of the sympathetic nervous system (SNS) in the control of the bone marrow environment. However, the specific role of neuropeptide Y (NPY) in this process has not been systematically studied. Here we show that NPY-deficient mice have significantly reduced hematopoietic stem cell (HSC) numbers and impaired regeneration in bone marrow due to apoptotic destruction of SNS fibers and/or endothelial cells. Furthermore, pharmacological elevation of NPY prevented bone marrow impairments in a mouse model of chemotherapy-induced SNS injury, while NPY injection into conditional knockout mice lacking the Y1 receptor in macrophages did not relieve bone marrow dysfunction. These results indicate that NPY promotes neuroprotection and restores bone marrow dysfunction from chemotherapy-induced SNS injury through the Y1 receptor in macrophages. They also reveal a new role of NPY as a regulator of the bone marrow microenvironment and highlight the potential therapeutic value of this neuropeptide. PMID- 25916828 TI - Focus on induced pluripotency and cellular reprogramming. PMID- 25916829 TI - Talk among yourselves: RNA sponges mediate cross talk between functionally related messenger RNAs. PMID- 25916831 TI - Development testing of mobile health interventions for cancer patient self management: A review. AB - As the vision of mobile health (mHealth) is beginning to be realized, rigorous intervention development protocols are needed in order to draw optimal efficacy and effectiveness to support patient-centered oncology care. The purpose of the current study was to conduct a review of published articles that describe the development process of mHealth interventions for patients' cancer care self management. The review search yielded 11 interventions, reported by 14 manuscripts. The following trends emerged: importance of stakeholder engagement during the development process, addressing the unique needs and experiences of cancer patients and care providers, ensuring user satisfaction with the system, and identifying perceived benefits and limitations of the system. This review provides practical suggestions for mHealth intervention development. Assessments of user perceptions should be both qualitative and quantitative, and researchers should follow an established framework when developing a randomized controlled trial employing mHealth. PMID- 25916830 TI - The transcription factor Cabut coordinates energy metabolism and the circadian clock in response to sugar sensing. AB - Nutrient sensing pathways adjust metabolism and physiological functions in response to food intake. For example, sugar feeding promotes lipogenesis by activating glycolytic and lipogenic genes through the Mondo/ChREBP-Mlx transcription factor complex. Concomitantly, other metabolic routes are inhibited, but the mechanisms of transcriptional repression upon sugar sensing have remained elusive. Here, we characterize cabut (cbt), a transcription factor responsible for the repressive branch of the sugar sensing transcriptional network in Drosophila. We demonstrate that cbt is rapidly induced upon sugar feeding through direct regulation by Mondo-Mlx. We found that CBT represses several metabolic targets in response to sugar feeding, including both isoforms of phosphoenolpyruvate carboxykinase (pepck). Deregulation of pepck1 (CG17725) in mlx mutants underlies imbalance of glycerol and glucose metabolism as well as developmental lethality. Furthermore, we demonstrate that cbt provides a regulatory link between nutrient sensing and the circadian clock. Specifically, we show that a subset of genes regulated by the circadian clock are also targets of CBT. Moreover, perturbation of CBT levels leads to deregulation of the circadian transcriptome and circadian behavioral patterns. PMID- 25916832 TI - Recruitment and retention in an SMS-based health education program: Lessons learned from Text2BHealthy. AB - While text messages or short messaging service programs are increasingly utilized for delivering health education, few studies have explored the unique challenges of recruiting and retaining participants in such programs. This study utilizes survey and focus group data from Text2BHealthy, a short messaging service-based nutrition and physical activity promotion program, to examine barriers to enrollment and facilitators of retention among parents of elementary school students. Results show that participants were hard to reach with recruitment materials, had difficulty with self-enrollment, and were apprehensive about program costs. However, 89-90 percent of participants were retained. Results suggest that providing manual enrollment options, alternative program delivery methods (e.g. email messages), and opportunities to reenroll may facilitate participation in short messaging service-based health education and promotion programs. PMID- 25916833 TI - Users' experiences of an emergency department patient admission predictive tool: A qualitative evaluation. AB - Emergency department overcrowding is an increasing issue impacting patients, staff and quality of care, resulting in poor patient and system outcomes. In order to facilitate better management of emergency department resources, a patient admission predictive tool was developed and implemented. Evaluation of the tool's accuracy and efficacy was complemented with a qualitative component that explicated the experiences of users and its impact upon their management strategies, and is the focus of this article. Semi-structured interviews were conducted with 15 pertinent users, including bed managers, after-hours managers, specialty department heads, nurse unit managers and hospital executives. Analysis realised dynamics of accuracy, facilitating communication and enabling group decision-making Users generally welcomed the enhanced potential to predict and plan following the incorporation of the patient admission predictive tool into their daily and weekly decision-making processes. They offered astute feedback with regard to their responses when faced with issues of capacity and communication. Participants reported an growing confidence in making informed decisions in a cultural context that is continually moving from reactive to proactive. This information will inform further patient admission predictive tool development specifically and implementation processes generally. PMID- 25916834 TI - Is plasma soluble CD36 associated with cardiovascular risk factors in early onset coronary artery disease patients? AB - BACKGROUND AND PURPOSE: This is the first study to investigate the relationship between plasma concentration of soluble CD36 (sCD36) and CD36 gene polymorphisms as well as clinical and echocardiographic parameters in patients with early onset coronary artery disease (CAD). METHODS: sCD36 concentrations were measured by the ELISA kits. CD36 sequence alterations detected by the DHPLC technique comprised single nucleotide substitutions: rs3173798, rs3211892, rs5956 and rs141680676. RESULTS: There were significant negative correlations between sCD36 and red blood cell count, hemoglobin, hematocrit and glucose concentration, ApoB/ApoA1 ratio, patients' weight and waist circumference, BMI, WHR, systolic blood pressure, MAP values, left ventricular end-diastolic diameter and volume, left atrium diameter, right ventricular end-diastolic diameter. There were significant positive correlations between sCD36 and patients' age, mean corpuscular volume of erythrocytes, HDL-cholesterol, ApoA1 concentrations. Significantly higher CD36 plasma levels were found in female subgroup. There was no association between CD36 genotypes and sCD36 concentrations. Multiple linear regression analysis revealed that significant independent predictors of higher plasma sCD36 level were female gender, older age, lower serum glucose and lower RBC. CONCLUSION: The presented data suggest possible protective effects of higher sCD36 concentration in relation to metabolic syndrome components in CAD patients. Higher sCD36 concentration is also associated with lower risk of left ventricular hypertrophy, but on the other hand is a potential risk factor of impaired left ventricle diastolic function. PMID- 25916835 TI - Authors' response to letter: 'proper assessment of leptin results with confounders'. PMID- 25916836 TI - Proper assessment of leptin results with confounders. PMID- 25916837 TI - Exploring the complexity of the childhood trait-psychopathology association: Continuity, pathoplasty, and complication effects. AB - Four different models have been generally proposed as plausible etiological explanations for the relation between personality and psychopathology, namely, the vulnerability, complication, pathoplasty, and spectrum or continuity model. The current study entails a joint investigation of the continuity, pathoplasty, and complication models to explain the nature of the associations between early maladaptive traits and psychopathology over time in 717 referred and community children (54.4% girls), aged from 8 to 14 years. Across a 2-year time span, maladaptive traits and psychopathology were measured at three different time points, thereby relying on comprehensive and age-specific dimensional operationalizations of both personality symptoms and psychopathology. The results demonstrate overall compelling evidence for the continuity model, finding more focused support for pathoplasty and complication effects for particular combinations of personality symptoms and psychopathology dimensions. As expected, the continuity associations were found to be more robust for those personality psychopathology associations that are conceptually closer, such as the emotional instability/introversion-internalizing problems association and the disagreeableness-externalizing problems association. Continuity associations were also stronger when personality was considered from a maladaptive rather than from a general trait perspective. The implication of the findings for the treatment of psychopathology and personality symptoms are briefly discussed. PMID- 25916838 TI - Erratum to: A novel mutation (Cys308Phe) of the LDL receptor gene in families from the South-Eastern part of Poland. PMID- 25916840 TI - Reliability and Validity of the Korean Version of the Dimensions of Tobacco Dependence Scale for Adolescents. AB - This study assessed the reliability and validity of the Korean version of the Dimensions of Tobacco Dependence Scale (DTDS) for adolescents in Korea. The DTDS, Modified Fagerstrom Tolerance Questionnaire (M-FTQ), and urine nicotine test were administered to 360 Korean adolescents. The collected data were analyzed using SPSS 21.0 and AMOS 21.0. The construct validity, criterion validity, test-retest reliability, internal consistency reliability, and the area under the curve (AUC) of the Korean version of the DTDS were evaluated. The 4-subscale model of the DTDS (with social, emotional, physical, and sensory subscales) was validated using confirmatory factor analysis, and criterion validity was demonstrated with the M-FTQ. Furthermore, the AUC of the DTDS was 83.1. The Cronbach's alpha coefficient for internal consistency was .96, demonstrating sufficient test retest reliability. The Korean version of the DTDS is a reliable and valid measure of tobacco dependence among Korean adolescents. PMID- 25916839 TI - Adolescent intermittent alcohol exposure: persistence of structural and functional hippocampal abnormalities into adulthood. AB - BACKGROUND: Human adolescence is a crucial stage of neurological development during which ethanol (EtOH) consumption is often at its highest. Alcohol abuse during adolescence may render individuals at heightened risk for subsequent alcohol abuse disorders, cognitive dysfunction, or other neurological impairments by irreversibly altering long-term brain function. To test this possibility, we modeled adolescent alcohol abuse (i.e., intermittent EtOH exposure during adolescence [AIE]) in rats to determine whether adolescent exposure to alcohol leads to long-term structural and functional changes that are manifested in adult neuronal circuitry. METHODS: We specifically focused on hippocampal area CA1, a brain region associated with learning and memory. Using electrophysiological, immunohistochemical, and neuroanatomical approaches, we measured post-AIE changes in synaptic plasticity, dendritic spine morphology, and synaptic structure in adulthood. RESULTS: We found that AIE-pretreated adult rats manifest robust long term potentiation, induced at stimulus intensities lower than those required in controls, suggesting a state of enhanced synaptic plasticity. Moreover, AIE resulted in an increased number of dendritic spines with characteristics typical of immaturity. Immunohistochemistry-based analysis of synaptic structures indicated a significant decrease in the number of co-localized pre- and postsynaptic puncta. This decrease is driven by an overall decrease in 2 postsynaptic density proteins, PSD-95 and SAP102. CONCLUSIONS: Taken together, these findings reveal that repeated alcohol exposure during adolescence results in enduring structural and functional abnormalities in the hippocampus. These synaptic changes in the hippocampal circuits may help to explain learning-related behavioral changes in adult animals preexposed to AIE. PMID- 25916841 TI - Structure-based functional identification of Helicobacter pylori HP0268 as a nuclease with both DNA nicking and RNase activities. AB - HP0268 is a conserved, uncharacterized protein from Helicobacter pylori. Here, we determined the solution structure of HP0268 using three-dimensional nuclear magnetic resonance (NMR) spectroscopy, revealing that this protein is structurally most similar to a small MutS-related (SMR) domain that exhibits nicking endonuclease activity. We also demonstrated for the first time that HP0268 is a nicking endonuclease and a purine-specific ribonuclease through gel electrophoresis and fluorescence spectroscopy. The nuclease activities for DNA and RNA were maximally increased by Mn(2+) and Mg(2+) ions, respectively, and decreased by Cu(2+) ions. Using NMR chemical shift perturbations, the metal and nucleotide binding sites of HP0268 were determined to be spatially divided but close to each other. The lysine residues (Lys7, Lys11 and Lys43) are clustered and form the nucleotide binding site. Moreover, site-directed mutagenesis was used to define the catalytic active site of HP0268, revealing that this site contains two acidic residues, Asp50 and Glu54, in the metal binding site. The nucleotide binding and active sites are not conserved in the structural homologues of HP0268. This study will contribute to improving our understanding of the structure and functionality of a wide spectrum of nucleases. PMID- 25916842 TI - IslandViewer 3: more flexible, interactive genomic island discovery, visualization and analysis. AB - IslandViewer (http://pathogenomics.sfu.ca/islandviewer) is a widely used web based resource for the prediction and analysis of genomic islands (GIs) in bacterial and archaeal genomes. GIs are clusters of genes of probable horizontal origin, and are of high interest since they disproportionately encode genes involved in medically and environmentally important adaptations, including antimicrobial resistance and virulence. We now report a major new release of IslandViewer, since the last release in 2013. IslandViewer 3 incorporates a completely new genome visualization tool, IslandPlot, enabling for the first time interactive genome analysis and gene search capabilities using synchronized circular, horizontal and vertical genome views. In addition, more curated virulence factors and antimicrobial resistance genes have been incorporated, and homologs of these genes identified in closely related genomes using strict filters. Pathogen-associated genes have been re-calculated for all pre-computed complete genomes. For user-uploaded genomes to be analysed, IslandViewer 3 can also now handle incomplete genomes, with an improved queuing system on compute nodes to handle user demand. Overall, IslandViewer 3 represents a significant new version of this GI analysis software, with features that may make it more broadly useful for general microbial genome analysis and visualization. PMID- 25916843 TI - Ectopic expression of RNF168 and 53BP1 increases mutagenic but not physiological non-homologous end joining. AB - DNA double strand breaks (DSBs) formed during S phase are preferentially repaired by homologous recombination (HR), whereas G1 DSBs, such as those occurring during immunoglobulin class switch recombination (CSR), are repaired by non-homologous end joining (NHEJ). The DNA damage response proteins 53BP1 and BRCA1 regulate the balance between NHEJ and HR. 53BP1 promotes CSR in part by mediating synapsis of distal DNA ends, and in addition, inhibits 5' end resection. BRCA1 antagonizes 53BP1 dependent DNA end-blocking activity during S phase, which would otherwise promote mutagenic NHEJ and genome instability. Recently, it was shown that supra physiological levels of the E3 ubiquitin ligase RNF168 results in the hyper accumulation of 53BP1/BRCA1 which accelerates DSB repair. Here, we ask whether increased expression of RNF168 or 53BP1 impacts physiological versus mutagenic NHEJ. We find that the anti-resection activities of 53BP1 are rate-limiting for mutagenic NHEJ but not for physiological CSR. As heterogeneity in the expression of RNF168 and 53BP1 is found in human tumors, our results suggest that deregulation of the RNF168/53BP1 pathway could alter the chemosensitivity of BRCA1 deficient tumors. PMID- 25916844 TI - TP53 mutations, tetraploidy and homologous recombination repair defects in early stage high-grade serous ovarian cancer. AB - To determine early somatic changes in high-grade serous ovarian cancer (HGSOC), we performed whole genome sequencing on a rare collection of 16 low stage HGSOCs. The majority showed extensive structural alterations (one had an ultramutated profile), exhibited high levels of p53 immunoreactivity, and harboured a TP53 mutation, deletion or inactivation. BRCA1 and BRCA2 mutations were observed in two tumors, with nine showing evidence of a homologous recombination (HR) defect. Combined Analysis with The Cancer Genome Atlas (TCGA) indicated that low and late stage HGSOCs have similar mutation and copy number profiles. We also found evidence that deleterious TP53 mutations are the earliest events, followed by deletions or loss of heterozygosity (LOH) of chromosomes carrying TP53, BRCA1 or BRCA2. Inactivation of HR appears to be an early event, as 62.5% of tumours showed a LOH pattern suggestive of HR defects. Three tumours with the highest ploidy had little genome-wide LOH, yet one of these had a homozygous somatic frame-shift BRCA2 mutation, suggesting that some carcinomas begin as tetraploid then descend into diploidy accompanied by genome-wide LOH. Lastly, we found evidence that structural variants (SV) cluster in HGSOC, but are absent in one ultramutated tumor, providing insights into the pathogenesis of low stage HGSOC. PMID- 25916845 TI - Dynamic signal processing by ribozyme-mediated RNA circuits to control gene expression. AB - Organisms have different circuitries that allow converting signal molecule levels to changes in gene expression. An important challenge in synthetic biology involves the de novo design of RNA modules enabling dynamic signal processing in live cells. This requires a scalable methodology for sensing, transmission, and actuation, which could be assembled into larger signaling networks. Here, we present a biochemical strategy to design RNA-mediated signal transduction cascades able to sense small molecules and small RNAs. We design switchable functional RNA domains by using strand-displacement techniques. We experimentally characterize the molecular mechanism underlying our synthetic RNA signaling cascades, show the ability to regulate gene expression with transduced RNA signals, and describe the signal processing response of our systems to periodic forcing in single live cells. The engineered systems integrate RNA-RNA interaction with available ribozyme and aptamer elements, providing new ways to engineer arbitrary complex gene circuits. PMID- 25916846 TI - Extranucleosomal DNA enhances the activity of the LSD1/CoREST histone demethylase complex. AB - The promoter regions of active genes in the eukaryotic genome typically contain nucleosomes post-translationally modified with a trimethyl mark on histone H3 lysine 4 (H3K4), while transcriptional enhancers are marked with monomethylated H3K4. The flavin-dependent monoamine oxidase LSD1 (lysine-specific demethylase 1, also known as KDM1) demethylates mono- and dimethylated H3K4 in peptide substrates, but requires the corepressor protein, CoREST, to demethylate nucleosome substrates. The molecular basis for how the LSD1/CoREST complex interacts with its physiological nucleosome substrate remains largely unknown. We examine here the role of extranucleosomal DNA beyond the nucleosome core particle for LSD1/CoREST function. Our studies of LSD1/CoREST's enzyme activity and nucleosome binding show that extranucleosomal DNA dramatically enhances the activity of LSD1/CoREST, and that LSD1/CoREST binds to the nucleosome as a 1:1 complex. Our photocrosslinking experiments further indicate both LSD1 and CoREST subunits are in close contact with DNA around the nucleosome dyad as well as extranucleosomal DNA. Our results suggest that the LSD1/CoREST interacts with extranucleosomal DNA when it productively engages its nucleosome substrate. PMID- 25916847 TI - A prophage-encoded actin-like protein required for efficient viral DNA replication in bacteria. AB - In host cells, viral replication is localized at specific subcellular sites. Viruses that infect eukaryotic and prokaryotic cells often use host-derived cytoskeletal structures, such as the actin skeleton, for intracellular positioning. Here, we describe that a prophage, CGP3, integrated into the genome of Corynebacterium glutamicum encodes an actin-like protein, AlpC. Biochemical characterization confirms that AlpC is a bona fide actin-like protein and cell biological analysis shows that AlpC forms filamentous structures upon prophage induction. The co-transcribed adaptor protein, AlpA, binds to a consensus sequence in the upstream promoter region of the alpAC operon and also interacts with AlpC, thus connecting circular phage DNA to the actin-like filaments. Transcriptome analysis revealed that alpA and alpC are among the early induced genes upon excision of the CGP3 prophage. Furthermore, qPCR analysis of mutant strains revealed that both AlpA and AlpC are required for efficient phage replication. Altogether, these data emphasize that AlpAC are crucial for the spatio-temporal organization of efficient viral replication. This is remarkably similar to actin-assisted membrane localization of eukaryotic viruses that use the actin cytoskeleton to concentrate virus particles at the egress sites and provides a link of evolutionary conserved interactions between intracellular virus transport and actin. PMID- 25916848 TI - RPA70 depletion induces hSSB1/2-INTS3 complex to initiate ATR signaling. AB - The primary eukaryotic single-stranded DNA-binding protein, Replication protein A (RPA), binds to single-stranded DNA at the sites of DNA damage and recruits the apical checkpoint kinase, ATR via its partner protein, ATRIP. It has been demonstrated that absence of RPA incapacitates the ATR-mediated checkpoint response. We report that in the absence of RPA, human single-stranded DNA-binding protein 1 (hSSB1) and its partner protein INTS3 form sub-nuclear foci, associate with the ATR-ATRIP complex and recruit it to the sites of genomic stress. The ATRIP foci formed after RPA depletion are abrogated in the absence of INTS3, establishing that hSSB-INTS3 complex recruits the ATR-ATRIP checkpoint complex to the sites of genomic stress. Depletion of homologs hSSB1/2 and INTS3 in RPA deficient cells attenuates Chk1 phosphorylation, indicating that the cells are debilitated in responding to stress. We have identified that TopBP1 and the Rad9 Rad1-Hus1 complex are essential for the alternate mode of ATR activation. In summation, we report that the single-stranded DNA-binding protein complex, hSSB1/2-INTS3 can recruit the checkpoint complex to initiate ATR signaling. PMID- 25916849 TI - A novel RNA binding surface of the TAM domain of TIP5/BAZ2A mediates epigenetic regulation of rRNA genes. AB - The chromatin remodeling complex NoRC, comprising the subunits SNF2h and TIP5/BAZ2A, mediates heterochromatin formation at major clusters of repetitive elements, including rRNA genes, centromeres and telomeres. Association with chromatin requires the interaction of the TAM (TIP5/ARBP/MBD) domain of TIP5 with noncoding RNA, which targets NoRC to specific genomic loci. Here, we show that the NMR structure of the TAM domain of TIP5 resembles the fold of the MBD domain, found in methyl-CpG binding proteins. However, the TAM domain exhibits an extended MBD fold with unique C-terminal extensions that constitute a novel surface for RNA binding. Mutation of critical amino acids within this surface abolishes RNA binding in vitro and in vivo. Our results explain the distinct binding specificities of TAM and MBD domains to RNA and methylated DNA, respectively, and reveal structural features for the interaction of NoRC with non coding RNA. PMID- 25916851 TI - Stereochemical control of nucleosome targeting by platinum-intercalator antitumor agents. AB - Platinum-based anticancer drugs act therapeutically by forming DNA adducts, but suffer from severe toxicity and resistance problems, which have not been overcome in spite of decades of research. And yet defined chromatin targets have generally not been considered in the drug development process. Here we designed novel platinum-intercalator species to target a highly deformed DNA site near the nucleosome center. Between two seemingly similar structural isomers, we find a striking difference in DNA site selectivity in vitro, which comes about from stereochemical constraints that limit the reactivity of the trans isomer to special DNA sequence elements while still allowing the cis isomer to efficiently form adducts at internal sites in the nucleosome core. This gives the potential for controlling nucleosome site targeting in vivo, which would engender sensitivity to epigenetic distinctions and in particular cell type/status dependent differences in nucleosome positioning. Moreover, while both compounds yield very similar DNA-adduct structures and display antitumor cell activity rivalling that of cisplatin, the cis isomer, relative to the trans, has a much more rapid cytotoxic effect and distinct impact on cell function. The novel stereochemical principles for controlling DNA site selectivity we discovered could aid in the design of improved site discriminating agents. PMID- 25916850 TI - Stable complex formation of CENP-B with the CENP-A nucleosome. AB - CENP-A and CENP-B are major components of centromeric chromatin. CENP-A is the histone H3 variant, which forms the centromere-specific nucleosome. CENP-B specifically binds to the CENP-B box DNA sequence on the centromere-specific repetitive DNA. In the present study, we found that the CENP-A nucleosome more stably retains human CENP-B than the H3.1 nucleosome in vitro. Specifically, CENP B forms a stable complex with the CENP-A nucleosome, when the CENP-B box sequence is located at the proximal edge of the nucleosome. Surprisingly, the CENP-B binding was weaker when the CENP-B box sequence was located in the distal linker region of the nucleosome. This difference in CENP-B binding, depending on the CENP-B box location, was not observed with the H3.1 nucleosome. Consistently, we found that the DNA-binding domain of CENP-B specifically interacted with the CENP A-H4 complex, but not with the H3.1-H4 complex, in vitro. These results suggested that CENP-B forms a more stable complex with the CENP-A nucleosome through specific interactions with CENP-A, if the CENP-B box is located proximal to the CENP-A nucleosome. Our in vivo assay also revealed that CENP-B binding in the vicinity of the CENP-A nucleosome substantially stabilizes the CENP-A nucleosome on alphoid DNA in human cells. PMID- 25916852 TI - High levels of TopBP1 induce ATR-dependent shut-down of rRNA transcription and nucleolar segregation. AB - Nucleoli are not only organelles that produce ribosomal subunits. They are also overarching sensors of different stress conditions and they control specific nucleolar stress pathways leading to stabilization of p53. During DNA replication, ATR and its activator TopBP1 initiate DNA damage response upon DNA damage and replication stress. We found that a basal level of TopBP1 protein associates with ribosomal DNA repeat. When upregulated, TopBP1 concentrates at the ribosomal chromatin and initiates segregation of nucleolar components--the hallmark of nucleolar stress response. TopBP1-induced nucleolar segregation is coupled to shut-down of ribosomal RNA transcription in an ATR-dependent manner. Nucleolar segregation induced by TopBP1 leads to a moderate elevation of p53 protein levels and to localization of activated p53 to nucleolar caps containing TopBP1, UBF and RNA polymerase I. Our findings demonstrate that TopBP1 and ATR are able to inhibit the synthesis of rRNA and to activate nucleolar stress pathway; yet the p53-mediated cell cycle arrest is thwarted in cells expressing high levels of TopBP1. We suggest that inhibition of rRNA transcription by different stress regulators is a general mechanism for cells to initiate nucleolar stress pathway. PMID- 25916853 TI - New insights into the regulatory mechanisms of ppGpp and DksA on Escherichia coli RNA polymerase-promoter complex. AB - The stringent response modulators, guanosine tetraphosphate (ppGpp) and protein DksA, bind RNA polymerase (RNAP) and regulate gene expression to adapt bacteria to different environmental conditions. Here, we use Atomic Force Microscopy and in vitro transcription assays to study the effects of these modulators on the conformation and stability of the open promoter complex (RPo) formed at the rrnA P1, rrnB P1, its discriminator (dis) variant and lambda pR promoters. In the absence of modulators, RPo formed at these promoters show different extents of DNA wrapping which correlate with the position of UP elements. Addition of the modulators affects both DNA wrapping and RPo stability in a promoter-dependent manner. Overall, the results obtained under different conditions of ppGpp, DksA and initiating nucleotides (iNTPs) indicate that ppGpp allosterically prevents the conformational changes associated with an extended DNA wrapping that leads to RPo stabilization, while DksA interferes directly with nucleotide positioning into the RNAP active site. At the iNTPs-sensitive rRNA promoters ppGpp and DksA display an independent inhibitory effect, while at the iNTPs-insensitive pR promoter DksA reduces the effect of ppGpp in accordance with their antagonistic role. PMID- 25916854 TI - ChIP-Array 2: integrating multiple omics data to construct gene regulatory networks. AB - Transcription factors (TFs) play an important role in gene regulation. The interconnections among TFs, chromatin interactions, epigenetic marks and cis regulatory elements form a complex gene transcription apparatus. Our previous work, ChIP-Array, combined TF binding and transcriptome data to construct gene regulatory networks (GRNs). Here we present an enhanced version, ChIP-Array 2, to integrate additional types of omics data including long-range chromatin interaction, open chromatin region and histone modification data to dissect more comprehensive GRNs involving diverse regulatory components. Moreover, we substantially extended our motif database for human, mouse, rat, fruit fly, worm, yeast and Arabidopsis, and curated large amount of omics data for users to select as input or backend support. With ChIP-Array 2, we compiled a library containing regulatory networks of 18 TFs/chromatin modifiers in mouse embryonic stem cell (mESC). The web server and the mESC library are publicly free and accessible athttp://jjwanglab.org/chip-array. PMID- 25916855 TI - Inosine modifications in human tRNAs are incorporated at the precursor tRNA level. AB - Transfer RNAs (tRNAs) are key adaptor molecules of the genetic code that are heavily modified post-transcriptionally. Inosine at the first residue of the anticodon (position 34; I34) is an essential widespread tRNA modification that has been poorly studied thus far. The modification in eukaryotes results from a deamination reaction of adenine that is catalyzed by the heterodimeric enzyme adenosine deaminase acting on tRNA (hetADAT), composed of two subunits: ADAT2 and ADAT3. Using high-throughput small RNA sequencing (RNAseq), we show that this modification is incorporated to human tRNAs at the precursor tRNA level and during maturation. We also functionally validated the human genes encoding for hetADAT and show that the subunits of this enzyme co-localize in nucleus in an ADAT2-dependent manner. Finally, by knocking down HsADAT2, we demonstrate that variations in the cellular levels of hetADAT will result in changes in the levels of I34 modification in all its potential substrates. Altogether, we present RNAseq as a powerful tool to study post-transcriptional tRNA modifications at the precursor tRNA level and give the first insights on the biology of I34 tRNA modification in metazoans. PMID- 25916857 TI - Identification of determinants of referral and follow-up body mass index of adolescent patients with anorexia nervosa: evidence for the role of premorbid body weight. PMID- 25916858 TI - Non-invasive in situ dynamic monitoring of elastic properties of composite battery electrodes by EQCM-D. AB - Reversible Li-ion intercalation into composite Li-ion battery (LIB) electrodes is often accompanied by significant dimensional electrode changes (deformation) resulting in significant deterioration of the cycling performance. Viscoelastic properties of polymeric binders affected by intercalation-induced deformation of composite LIB electrodes have never been probed in situ on operating electrochemical cells. Here, we introduce a newly developed noninvasive method, namely electrochemical quartz-crystal microbalance with dissipation monitoring (EQCM-D), for in situ monitoring of elastic properties of polymeric binders during charging of LIB electrodes. As such, we find EQCM-D as a uniquely suitable tool to track the binder's structural rigidity/softness in composite Li insertion electrodes in real-time by the characteristic increase/decrease of the dissipation factor during the charging-discharging process. The binders partially swollen in aprotic solutions demonstrate intermediate viscoelastic charge-rate dependent behavior, revealing rigid/soft behavior at high/low charging rates, respectively. The method can be adjusted for continuous monitoring of elastic properties of the polymeric binders over the entire LIB electrodes cycling life. PMID- 25916856 TI - LKB1 inhibition of NF-kappaB in B cells prevents T follicular helper cell differentiation and germinal center formation. AB - T-cell-dependent antigenic stimulation drives the differentiation of B cells into antibody-secreting plasma cells and memory B cells, but how B cells regulate this process is unclear. We show that LKB1 expression in B cells maintains B-cell quiescence and prevents the premature formation of germinal centers (GCs). Lkb1 deficient B cells (BKO) undergo spontaneous B-cell activation and secretion of multiple inflammatory cytokines, which leads to splenomegaly caused by an unexpected expansion of T cells. Within this cytokine response, increased IL-6 production results from heightened activation of NF-kappaB, which is suppressed by active LKB1. Secreted IL-6 drives T-cell activation and IL-21 production, promoting T follicular helper (TFH ) cell differentiation and expansion to support a ~100-fold increase in steady-state GC B cells. Blockade of IL-6 secretion by BKO B cells inhibits IL-21 expression, a known inducer of TFH -cell differentiation and expansion. Together, these data reveal cell intrinsic and surprising cell extrinsic roles for LKB1 in B cells that control TFH -cell differentiation and GC formation, and place LKB1 as a central regulator of T-cell dependent humoral immunity. PMID- 25916859 TI - Immediate Implant Placement into Extraction Sockets with Labial Plate Dehiscence Defects: A Clinical Case Series. AB - PURPOSE: To measure the buccal plate reconstruction of extraction sockets with labial plate dehiscence defects using a bone allograft in combination with an absorbable collagen membrane and a custom-healing abutment at the time of tooth removal. MATERIALS AND METHODS: Ten patients underwent immediate implant placement and reconstruction of the buccal plate. Cone beam computed tomography (CBCT) was performed preextraction, immediately after bone grafting and implant placement (day 0), and between 6 and 9 months following implant surgery. Measurements were taken at three levels: coronal (L1), middle (L2), and apical (L3) level. RESULTS: Implants placed into sockets with labial plate dehiscence defects demonstrated radiographic reformation of the labial plate dehiscence defect at 6 to 9 months posttreatment. The net gain in labial plate on cone beam computerized tomography (CBCT) in L1 and L2 was 3.0 mm, where 0 mm existed at pretreatment. The minimum amount of labial plate thickness of 2.0 mm was achieved in all treated sites, evaluated radiographically at 6 to 9 months postoperatively, in a single procedure, without flap elevation and maintaining the gingival architecture and satisfactory esthetics. CONCLUSION: Placing an absorbable membrane, bone graft, and custom-healing abutment at the time of flapless anterior tooth extraction and immediate implant placement into a socket with a labial osseous dehiscence is a viable clinical technique to reconstitute the absence of the labial bone plate. PMID- 25916860 TI - Machine-learning scoring functions for identifying native poses of ligands docked to known and novel proteins. AB - BACKGROUND: Molecular docking is a widely-employed method in structure-based drug design. An essential component of molecular docking programs is a scoring function (SF) that can be used to identify the most stable binding pose of a ligand, when bound to a receptor protein, from among a large set of candidate poses. Despite intense efforts in developing conventional SFs, which are either force-field based, knowledge-based, or empirical, their limited docking power (or ability to successfully identify the correct pose) has been a major impediment to cost-effective drug discovery. Therefore, in this work, we explore a range of novel SFs employing different machine-learning (ML) approaches in conjunction with physicochemical and geometrical features characterizing protein-ligand complexes to predict the native or near-native pose of a ligand docked to a receptor protein's binding site. We assess the docking accuracies of these new ML SFs as well as those of conventional SFs in the context of the 2007 PDBbind benchmark dataset on both diverse and homogeneous (protein-family-specific) test sets. Further, we perform a systematic analysis of the performance of the proposed SFs in identifying native poses of ligands that are docked to novel protein targets. RESULTS AND CONCLUSION: We find that the best performing ML SF has a success rate of 80% in identifying poses that are within 1 A root-mean square deviation from the native poses of 65 different protein families. This is in comparison to a success rate of only 70% achieved by the best conventional SF, ASP, employed in the commercial docking software GOLD. In addition, the proposed ML SFs perform better on novel proteins that they were never trained on before. We also observed steady gains in the performance of these scoring functions as the training set size and number of features were increased by considering more protein-ligand complexes and/or more computationally-generated poses for each complex. PMID- 25916861 TI - Increased large unstained cells value in varicella patients: A valuable parameter to aid rapid diagnosis of varicella infection. AB - Varicella is a highly contagious infection caused by varicella zoster virus. Sometimes it is difficult to differentiate between other viral infections such as Kaposi's varicelliform eruption (KVE) and disseminated herpes zoster (HZ). The large unstained cells (LUC) value is a differential count parameter reported by routing hematology analysis. LUC have been studied previously, but never been reported in the context of varicella or in dermatological published work. The aim of this study was to compare the LUC values in varicella patients with that in KVE and disseminated HZ patients. Sixty-nine varicella patients, 30 KVE patients and 11 disseminated HZ patients were included in this retrospective study. All data were analyzed using SPSS version 17.0 or GraphPad Prism version 5.0. The mean percentage of LUC (%LUC) in varicella patients was higher than the upper limit of normal reference range and it was increased compared to %LUC of both KVE (P < 0.0001) and disseminated HZ (P = 0.0051) patients. %LUC of varicella patients significantly decreased with clinical improvements (P = 0.0017). %LUC was significantly increased in varicella patients and corresponded with clinical improvements. Patients with %LUC of 3.55 or more favor the diagnosis of varicella over both KVE and disseminated HZ with 71.01% sensitivity and 84.44% specificity. We suggest that %LUC can assist in making a precise diagnosis of varicella in confusing cases. PMID- 25916862 TI - Anti-hypertensive drug treatment of patients with and the metabolic syndrome and obesity: a review of evidence, meta-analysis, post hoc and guidelines publications. AB - Epidemiological studies have shown an increasing prevalence of obesity and the metabolic syndrome worldwide. Lifestyle modifications that include dietary changes, weight reduction, and exercise are the cornerstones in the treatment of this pathology. However, adherence to this approach often meets with failure in clinical practice; therefore, drug therapy should not be delayed. The ideal pharmacological antihypertensive regimen should target the underlying mechanisms involved in this syndrome, including sympathetic activation, increased renal tubular sodium reabsorption, and overexpression of the renin-angiotensin aldosterone system by the adipocyte. Few prospective trials have been conducted in the search of the ideal antihypertensive regimen in patients with obesity and the metabolic syndrome. We summarize previously published ad hoc studies, prospective studies, and guideline publications regarding the treatment of hypertension in patients with obesity and the metabolic syndrome. We conclude that the optimal antihypertensive drug therapy in these patients has not been defined. Though caution exists regarding the use of thiazide diuretics due to potential metabolic derangements, there is insufficient data to show worsened cardiovascular or renal outcomes in patients treated with these drugs. In regard to beta blockers, the risk of accelerating conversion to diabetes and worsening of inflammatory mediators described in patients treated with traditional beta blockers appears much less pronounced or absent when using the vasodilating beta blockers. Renin-angiotensin-aldosterone system (RAAS) inhibition with an ACE or an ARB and treatment with calcium channel blockers appears safe and well tolerated in obesity-related hypertension and in patients with metabolic syndrome. Future prospective pharmacological studies in this population are needed. PMID- 25916864 TI - Indications for and effects of Nunchaku-style silicone tube intubation for primary acquired lacrimal drainage obstruction. AB - PURPOSE: To study the indications for and effectiveness of Nunchaku-style silicone tube intubation (NSTI) in treating primary acquired lacrimal drainage obstruction (PALDO). METHODS: In this interventional cohort study, 235 consecutive patients in 1 institution who had complete lacrimal obstruction were investigated. Of those, 212 PALDO patients were enrolled, and 156 of the PALDO patients ultimately satisfied our treatment protocol and were then followed up for 12 months postsurgery. Patients without dacryocystitis underwent NSTI, while those with dacryocystitis underwent NSTI or endonasal dacryocystorhinostomy (EN DCR) using the NST as a stent. The tubes were left in place for 8 weeks, and all patients received identical postoperative care. Resolution was deemed as patency assessed by irrigation. Logistic regression analyses were performed to compare the success of NSTI for upper (puncta and canaliculus) and lower (lacrimal sac and nasolacrimal duct) obstruction, NSTI for lower obstruction with and without dacryocystitis, and NSTI and EN-DCR for lower obstruction with dacryocystitis. RESULTS: Comparison of the success rates at 12 months postsurgery showed significance as follows: treatment with NSTI was more successful for upper obstruction (94.6%) than for lower obstruction (71.4%) [odds ratio (OR) 8.23; P < 0.01]; treatment with NSTI was more successful for lower obstruction without dacryocystitis (82.9%) than for dacryocystitis (52.4%) (OR 4.96; P < 0.05); and treatment with EN-DCR (95.5%) was more successful than NSTI (52.4%) for treating lower obstruction with dacryocystitis (OR 16.99; P < 0.001). CONCLUSIONS: NSTI is effective for treating PALDO; however, EN-DCR is more effective for treating PALDO cases complicated by dacryocystitis. PMID- 25916865 TI - Anxiety symptoms in young people with autism spectrum disorder attending special schools: Associations with gender, adaptive functioning and autism symptomatology. AB - Anxiety-related problems are among the most frequently reported mental health difficulties in autism spectrum disorder. As most research has focused on clinical samples or high-functioning children with autism spectrum disorder, less is known about the factors associated with anxiety in community samples across the ability range. This cross-sectional study examined the association of gender, age, adaptive functioning and autism symptom severity with different caregiver reported anxiety symptoms. Participants were caregivers of 241 children (6-18 years old) with autism spectrum disorder attending special schools in Singapore. Measures included the Spence Children's Anxiety Scale and assessments of overall emotional, behavioural and adaptive functioning. Caregivers reported more anxiety symptoms in total, but fewer social anxiety symptoms, than Spence Children's Anxiety Scale Australian/Dutch norms. There were no gender differences. Variance in total anxiety scores was best explained by severity of repetitive speech/stereotyped behaviour symptoms, followed by adaptive functioning. Severity of repetitive speech/behaviour symptoms was a significant predictor of separation anxiety, generalized anxiety, panic/agoraphobia and obsessive-compulsive subscale symptoms, but not of social phobia and physical injury fears. Adaptive functioning and chronological age predicted social phobia and generalized anxiety symptoms only. Severity of social/communication autism symptoms did not explain any anxiety symptoms, when the other variables were controlled for. Findings are discussed in relation to the existing literature. Limitations and possible implications for prevention, assessment and intervention are also discussed. PMID- 25916863 TI - Labrador tea (Rhododendron groenlandicum) attenuates insulin resistance in a diet induced obesity mouse model. AB - PURPOSE: Using a diet-induced obesity (DIO) mouse model, we investigated the antidiabetic effect of Labrador tea [Rhododendron groenlandicum (Oeder) Kron and Judd], a beverage and medicinal tea used by the Cree Nations of northern Quebec. METHODS: C57BL6 mice were divided into five groups and given standard chow (~4 % of lipids) or high-fat diet (~35 % of lipids) for 8 weeks until they became obese and insulin resistant. Treatment began by adding the plant extract at three doses (125, 250 and 500 mg/kg) to the high-fat diet for another 8 weeks. At the end of the study, insulin-sensitive tissues (liver, skeletal muscle, adipose tissue) were collected to investigate the plant's molecular mechanisms. RESULTS: Labrador tea significantly reduced blood glucose (13 %), the response to an oral glucose tolerance test (18.2 %) and plasma insulin (65 %) while preventing hepatic steatosis (42 % reduction in hepatic triglyceride levels) in DIO mice. It stimulated insulin-dependent Akt pathway (55 %) and increased the expression of GLUT4 (53 %) in skeletal muscle. In the liver, Labrador tea stimulated the insulin-dependent Akt and the insulin-independent AMP-activated protein kinase pathways. The improvement in hepatic steatosis observed in DIO-treated mice was associated with a reduction in inflammation (through the IKK alpha/beta) and a decrease in the hepatic content of SREBP-1 (39 %). CONCLUSIONS: Labrador tea exerts potential antidiabetic action by improving insulin sensitivity and mitigating high-fat diet-induced obesity and hyperglycemia. They validate the safety and efficacy of this plant, a promising candidate for culturally relevant complementary treatment in Cree diabetics. PMID- 25916868 TI - Erratum to: automated volumetric analysis for comparison of oral sulfate solution (SUPREP) with established cathartic agents at CT colonography. PMID- 25916866 TI - Use of early intervention for young children with autism spectrum disorder across Europe. AB - Little is known about use of early interventions for autism spectrum disorder in Europe. Parents of children with autism spectrum disorder aged 7 years or younger (N = 1680) were recruited through parent organisations in 18 European countries and completed an online survey about the interventions their child received. There was considerable variation in use of interventions, and in some countries more than 20% of children received no intervention at all. The most frequently reported interventions were speech and language therapy (64%) and behavioural, developmental and relationship-based interventions (55%). In some parts of Europe, use of behavioural, developmental and relationship-based interventions was associated with higher parental educational level and time passed since diagnosis, rather than with child characteristics. These findings highlight the need to monitor use of intervention for children with autism spectrum disorder in Europe in order to contrast inequalities. PMID- 25916869 TI - Posterior subcapsular prostate cancer: identification with mpMRI and MRI/TRUS fusion-guided biopsy. AB - PURPOSE: The posterior subcapsular region of the prostate is often undersampled by transrectal ultrasound (TRUS)-guided biopsy. The close proximity of these lesions to the posterior capsular wall of the prostate makes them difficult to localize while increasing the need for early detection because of their increased risk for extracapsular extension. We retrospectively evaluated the multiparametric MRI (mpMRI) features of subcapsular prostate cancers to make radiologists more aware of this condition. MATERIALS AND METHODS: Between January 2010 and July 2014, all patients referred for 3T mpMRI and subsequent MR-US Fusion-guided biopsy (FgBx) and systematic 12-core sextant biopsy (SBx) under an IRB approved protocol, were reviewed, and imaging confirmed subcapsular prostate cancers were identified. Subcapsular lesions were defined as thin lesions that were just inside the prostate capsule. Matching patient demographics and clinical findings including age, PSA, PSA density, whole prostate volume, history of prostate cancer, Gleason score, and clinical management were tabulated. RESULTS: Of 992 eligible patients, 33 patients had subcapsular lesions in the prostate detected by mpMRI. Mean age, PSA, and prostate volume in this group were 63 years (range: 52-76 years), 8.4 ng/mL (range: 1.22-65.20), and 53 mL (range: 12-125 mL), respectively. The combination biopsy (SBx + FgBx) confirmed prostate cancer in 24 of 33 patients (72.7%) and in 9 patients the biopsy was negative. Of the 24 cancers, 19 were confirmed on both FgBx and conventional biopsy; however, 5 cancers were only detected on FgBx. In 4 of the 19 patients in which both biopsy methods were positive, the FgBx yielded a higher Gleason score. CONCLUSION: Subcapsular lesions on mpMRI are relatively infrequent but are usually malignant. Although the majority are confirmed on conventional 12-core biopsies, about 20% of these lesions require FgBx for diagnosis, and FgBx more accurately grades the lesions in another 20%. Thus, FgBx is of considerable benefit in confirming the diagnosis of subcapsular prostate cancer despite their proximity to the prostatic capsule. PMID- 25916870 TI - Differentiation of small arterial enhancing hepatocellular carcinoma from non tumorous arterioportal shunt with an emphasis on the precontrast CT scan. AB - PURPOSE: To evaluate the value of precontrast phase (PP) of quadriphasic CT for differentiation of small arterial enhancing hepatocellular carcinoma (HCC) from non-tumorous arterioportal (AP) shunt in patients with chronic liver disease. METHODS: Forty-eight patients with 28 HCCs and 28 AP shunts were enrolled. All lesions (5-20 mm) showed arterial hyperenhancement with isoattenuation on portal venous phase or delayed phase without typical features of AP shunt. We evaluated and analyzed the attenuation of the lesions with qualitative and quantitative methods in each phase. The size, location, shape, margin, and coexistent HCC were evaluated. Diagnostic performances were also compared with triphasic CT and quadriphasic CT including PP in prediction of AP shunts from HCCs. RESULTS: The round or oval shape and visually low attenuation on PP were independent predictors for differentiating HCCs from AP shunts in multivariate analysis. Our study also revealed significantly increased diagnostic performances for both observers when PP was added to the triphasic CT. CONCLUSIONS: PP can be helpful in differentiation of small arterial enhancing HCCs from AP shunts. Careful evaluation of PP may lower need for follow-up CT or MRI, and can possibly achieve earlier diagnosis of small HCCs. PMID- 25916871 TI - Vascular calcification in chronic kidney disease: an update. AB - Cardiovascular calcification is both a risk factor and contributor to morbidity and mortality. Patients with chronic kidney disease (and/or diabetes) exhibit accelerated calcification of the intima, media, heart valves and likely the myocardium as well as the rare condition of calcific uraemic arteriolopathy (calciphylaxis). Pathomechanistically, an imbalance of promoters (e.g. calcium and phosphate) and inhibitors (e.g. fetuin-A and matrix Gla protein) is central in the development of calcification. Next to biochemical and proteinacous alterations, cellular processes are also involved in the pathogenesis. Vascular smooth muscle cells undergo osteochondrogenesis, excrete vesicles and show signs of senescence. Therapeutically, measures to prevent the initiation of calcification by correcting the imbalance of promoters and inhibitors appear to be essential. In contrast to prevention, therapeutic regression of cardiovascular calcification in humans has been rarely reported. Measures to enhance secondary prevention in patients with established cardiovascular calcifications are currently being tested in clinical trials. PMID- 25916872 TI - Connective tissue growth factor and the cicatrization of cellular crescents in ANCA-associated glomerulonephritis. AB - BACKGROUND: Outcome in patients with anti-neutrophil cytoplasmic antibodies (ANCA)-associated glomerulonephritis (AGN) is difficult to predict. Scoring of renal biopsies has significant but limited predictive value. We investigated whether analysis of plasma and urine levels, and immunostaining of biopsies for the pro-fibrotic peptide connective tissue growth factor (CTGF), might improve prediction of renal outcome. METHODS: ANCA-positive patients were included. Renal biopsies were classified according to the AGN classification. Biopsies were stained for CTGF protein. CTGF was measured by ELISA at the time of renal biopsy in plasma and urine, and during follow-up in plasma. RESULTS: Eighty-two patients were included. CTGF staining was positive in crescentic lesions. Plasma CTGF at the time of renal biopsy was 2.4 +/- 1.7 pmol/mL when compared with 0.5 +/- 0.0 pmol/mL in healthy controls (P < 0.01). Plasma CTGF was associated with cellular crescents, but not when corrected for renal function. Plasma CTGF at baseline was associated with fibrous crescents in the follow-up biopsy, also after correction for renal function. Plasma CTGF at baseline predicted renal survival more accurately than the AGN classification. CONCLUSION: In AGN patients, CTGF was overexpressed in crescentic glomeruli. Baseline plasma CTGF predicted the percentage of fibrous crescents in later biopsies, and renal survival, suggesting that CTGF is involved in the cicatrization, as opposed to resolution of cellular crescents in AGN. PMID- 25916873 TI - Acute Kidney Injury and Hemodilution During Cardiopulmonary Bypass: A Changing Scenario. AB - BACKGROUND: Severe hemodilution during cardiopulmonary bypass (CPB) is a risk factor for acute kidney injury (AKI) after heart operations. Many improvements to CPB technology have been proposed during the past decade to limit the hemodilution-related AKI risk. The present study is a retrospective analysis of the relationship between hemodilution during CPB and AKI in cardiac operations in the setting of different interventions applied over 14 years. METHODS: We retrospectively analyzed 16,790 consecutive patients undergoing heart operations from 2000 to 2013. Various risk factors for AKI were collected and analyzed, together with a number of interventions as possible modifiers of the relationship between a nadir hematocrit (HCT) value during CPB and AKI. RESULTS: The relationship between the nadir HCT value during CPB and AKI was confirmed in a multivariable analysis, with the relative risk of AKI increasing by 7% per percentage point of decrease of the nadir HCT value during CPB. The relative risk of AKI decreased by 8% per year of observation (p = 0.001) despite a significantly increased risk of AKI (p = 0.001). A sensitivity analysis based on differences before and after different interventions demonstrated a beneficial effect of the application of goal-directed perfusion (aimed at preserving oxygen delivery during CPB), with a reduction in the AKI rate from 5.8% to 3.1% (p = 0.001). A policy restricting angiographic examination on the day of operation was also useful (reduction of AKI rate from 4.8% to 3.7%; p = 0.029). CONCLUSIONS: A bundle of interventions mainly aimed at limiting the renal impact of hemodilution during CPB is effective in reducing the AKI rate. PMID- 25916874 TI - Titanium Implant Failure After Chest Wall Osteosynthesis. AB - BACKGROUND: Our objective was to assess potential contributing factors to implant failure (displacement or rupture) after titanium chest wall osteosynthesis. METHODS: We retrospectively reviewed the clinical data and preoperative and postoperative computed tomographic scans of patients undergoing chest wall osteosynthesis with titanium implants: the Stratos or the Matrix Fixation System in two European departments of thoracic surgery. The indications for titanium chest wall osteosynthesis, the type and number of implants, the topography of the reconstruction, surgical site infection, and role of associated flap and mesh were assessed. RESULTS: Between January 2009 and January 2013, 54 patients underwent osteosynthesis after surgical correction of chest wall deformities (n = 25, 46.2%) or to bridge the defect after tumor removal (n = 29, 53.7%). The topography of osteosynthesis was anterior (n = 20), lateral (n = 3), or posterior (n = 1), an average of 1.9 +/- 0.9 implants (range, 1 to 5 implants) being used. A combined mesh restored continuity of the chest wall in 15 patients, and muscle flap coverage was performed in 20. The mean follow-up time was 20.2 +/- 8.4 months (range, 3 to 48 months). Among these 54 patients, 24 (44%) experienced an implant failure. Seven (29%) were symptomatic. Broken (n = 20, 83.3%) or displaced (n = 4, 16.7%) implants were removed with or without replacement. In patients with broken or displaced implants, the mean duration without implant failure was 6.6 +/- 3.1 months (range, 1 to 12 months). There was a significant relationship between the anterior topography of osteosynthesis and implant failure (p = 0.02). CONCLUSIONS: Long-term follow-up after chest wall osteosynthesis using titanium implants is required, especially in anteriorly placed implants. The high rate of implant failure at 1 year advocates for early removal whenever possible and suggests the need for improvements in design. PMID- 25916875 TI - Increasing Disadvantage of "Watchful Waiting" for Repairing Degenerative Mitral Valve Disease. AB - BACKGROUND: Successful durable repair of severe degenerative mitral regurgitation with low operative mortality encourages intervention in asymptomatic patients rather than "watchful waiting." Our objectives were to assess trends in patient characteristics, timing of intervention, and evolving surgical techniques at a high-volume center, and determine effects of these changes on outcomes after mitral valve (MV) repair over a 25-year period. METHODS: From January 1, 1985, to January 1, 2011, 5,902 patients underwent isolated repair (with or without tricuspid repair for functional regurgitation) for degenerative MV disease at Cleveland Clinic. For illustration, the experience is presented in 3 eras: 1985 to 1997 (era 1, n = 1,184), 1997 to 2005 (era 2, n = 2,400), and 2005 to 2011 (era 3, n = 2,318). RESULTS: In era 3, more patients were asymptomatic on presentation (44% in New York Heart Association [NYHA] class I vs 25% in era 1), with less heart failure (11% vs 29%) and atrial fibrillation (9.9% vs 23%). Full sternotomy decreased from era 1 (n = 1,100/93%) to era 2 (n = 602/25%) (era 3, n = 717/31%), and robotic surgery emerged (n = 577/25%) in era 3. Median length of stay shortened (era 1 = 7 days, era 2 = 5.9 days, era 3 = 5.2 days, p < 0.0001), and in-hospital mortality remained low (era 1 = 5/0.42%, era 2 = 5/0.21%, era 3 = 1/0.043%); 0.73% overall required reoperation on the repaired valve before discharge, and 97% had 0 to 1+ regurgitation at discharge. CONCLUSIONS: Treatment trends over 25 years reveal that rather than watchful waiting, a more aggressive approach to degenerative MV disease, with earlier intervention for severe regurgitation in asymptomatic patients and less invasive operative techniques, is successful, safe, and effective. PMID- 25916876 TI - Does Thoracoscopic Surgery Decrease the Morbidity of Combined Lung and Chest Wall Resection? AB - BACKGROUND: Because the traditional open lung approach with en bloc chest wall resection carries substantial risk for complications and death, we studied our thoracoscopic approach for this operation. METHODS: From 2007 to 2013, all consecutive video-assisted thoracoscopic (VATS) and open chest wall resections at a comprehensive cancer center were tabulated retrospectively. Data were analyzed by approach, type, and cause of early major morbidity and mortality. Lung cancer cases (the largest subset, T3) were analyzed separately. Statistical tests included the Kruskal-Wallis test for continuous variables and the chi(2) for categoric variables. Survival data were analyzed by the Kaplan-Meier method and log-rank tests. RESULTS: Of 47 chest wall resections performed, 17 (36%) were performed by VATS with no conversions. Resections were performed for primary non small cell lung cancer (15 VATS and 16 thoracotomy), sarcoma (11), metastatic disease from a separate primary (2), and benign conditions (3). Patients undergoing a VATS approach were older (76 vs 56 years, p = 0.003), and the operative times, blood loss, and ribs resected were similar between groups. Patients undergoing VATS had shorter intensive care unit and hospital lengths of stay, but both groups had high hospital morbidity and mortality, largely resulting from postoperative pneumonia or respiratory systemic inflammatory response syndrome (n = 5), stroke (n = 2), and postoperative colon ischemia (n = 1). Groups had a 90-day mortality of 26.7% and 25% respectively. Stage-matched survival curves for both approaches were superimposable (p=0.88). CONCLUSIONS: Thoracoscopic chest wall resection was feasible, expanded our case selection, and reduced prosthetic reconstruction. It did not, however, protect frail, elderly patients reliably. Briefer, less traumatic operations may be needed for this cohort. PMID- 25916877 TI - Coordination-Resolved Spectrometrics of Local Bonding and Electronic Dynamics of Au Atomic Clusters, Solid Skins, and Oxidized Foils. AB - By using combination of bond-order-length-strength (BOLS) correlation, the tight binding (TB) approach, and zone-selective photoelectron spectroscopy (ZPS), we were able to resolve local bond relaxation and the associated 4f7/2 core-level shift of Au atomic clusters, Au(100, 110, 111) skins, and Au foils exposed to ozone for different lengths of time. In addition to quantitative information, such as local bond length, bond energy, binding-energy density, and atomic cohesive energy, the results confirm our predictions that bond-order deficiency shortens and stiffens the bond between undercoordinated atoms, which results in local densification and quantum entrapment of bonding electrons. The entrapment perturbs the Hamiltonian, and hence, shifts the core-level energy accordingly. ZPS also confirms that oxidation enhances the effect of atomic undercoordination on the positive 4f7/2 energy shift, with the associated valence electron polarization contributing to the catalytic ability of undercoordinated Au atoms. PMID- 25916878 TI - NOMPC-dependent mechanotransduction shapes the dendrite of proprioceptive neurons. AB - Animal locomotion depends on proprioceptive feedback which is generated by mechanosensory neurons. We recently demonstrated that the evolutionarily conserved stumble (stum) gene is essential for mechanical transduction in a group of proprioceptive neurons in Drosophila leg joints. A specialized dendritic ending of the stum-expressing neurons is stretched by changes in joint position, suggesting that the dendritic site is specifically tuned for joint proprioception. Here, we show that the stum-expressing neurons express the mechanosensory channel NOMPC. In nompC mutants responses to joint position were abolished, indicating that NOMPC is the mechanosensitive channel in stum expressing neurons. The NOMPC protein had a similar subcellular distribution as STUM, being located specifically at the dendritic site that is stretched by joint motions, thus validating that this site is a specialized sensory compartment. In the absence of NOMPC the sensory portion of the dendrite was misshapen, generating membrane protrusions. Thus, we have shown that mechanical responsiveness at a specialized dendritic site is essential for determination of the fine dendritic structure. The abnormal morphology at the sensory compartment of non-active neurons suggests that the dendrite samples for a responsive anchoring site and stabilizes the structure that elicits the effective mechanotransduction. PMID- 25916879 TI - Effects of alpha2-adorenoceptor agonist dexmedetomidine on respiratory rhythm generation of newborn rats. AB - Dexmedetomidine, an alpha2-adrenoceptor agonist which has a slight side effect on breathing, is clinically used as an analgesic and sedative agent. Previous studies have shown depressing or modest effects of alpha2-adorenoceptor agonists on respiratory rhythm generation in newborn rat preparation in vitro. In contrast, it was recently reported that dexmedetomidine induced long-lasting activation of respiratory rhythm in brainstem-spinal cord preparation isolated from neonatal mice. In the present study, we examined whether dexmedetomidine induces any effects on respiratory rhythm in brainstem-spinal cord preparation isolated from newborn rats. We also examined the effects of dexmedetomidine on reflex response in the spinal cord, which is presumed to be an indication of nociceptive response. We found that the administration of dexmedetomidine, at the range of 0.1-10MUM, dose-dependently depressed respiratory rhythm and that the inhibitory effect was reversed by atipamezole, an alpha2-adorenoceptor antagonist. Spinal cord reflex responses were depressed by the application of dexmedetomidine at the range of 0.1-1nM, a lower concentration than that affecting respiratory rhythm. The inhibitory effect was also reversed by atipamezole. Our findings provide neuronal mechanisms that support the clinical use of dexmedetomidine, which shows sedative and antinociceptive effects with minimal side effects on breathing. PMID- 25916880 TI - Human mesenchymal stem cells improve the neurodegeneration of femoral nerve in a diabetic foot ulceration rats. AB - Neuropathy is observed in 50% of diabetic patients with diabetic foot. This study attempted to explore the potential role of human mesenchymal stem cells-umbilical cord blood (hMSCs-UC) in femoral nerve (FN) neuropathy. The model rats were established by one time administration of streptozotocin and empyrosis on the dorsal hind foot. At 3d, 7d, 14d after treatment with hMSCs-UC or saline through left femoral artery, the serum NGF was examined by ELISA; NF-200 expression in FN was evaluated by immunohistochemistry; the diameter and roundness of FN, the ratio of capillary and muscular fiber of gastrocnemius were calculated under light microscope; and neuronal degenerations, such as demyelization, axonal atrophy, and loose arrangement of nerve fibers, were observed by electronic microscope. The results showed that, in hMSCs-UC-treated model rats, serum NGF was increased with higher positive rate of NF-200. Although the difference in FN diameters was not established among groups, improvement of roundness of FN was confirmed with increase in the numbers of capillary in FN-innervated gastrocnemius; additionally, degenerative neuropathy was significantly improved. Importantly, the functional study of electroneurogram (ENG) showed that, slowed conduction of FN in model rats was significantly restored by hMSCs-CU treatment. These data suggested that hMSCs-UC-treatment partially reverse the neuronal degeneration and nerve function of FN, which might be contributed by the upregulation of NGF with dramatic angiogenesis in FN-innervated gastrocnemius, consequently reversing neuronal structure and function, preventing or curing foot ulceration. PMID- 25916881 TI - Galphas regulates asymmetric cell division of cortical progenitors by controlling Numb mediated Notch signaling suppression. AB - Asymmetric cell division, which plays fundamental roles in generating cell diversity during development, requires elaborate interactions between extrinsic cues and intrinsic cues. However, the precise nature of this type of interaction and its involving signaling mechanisms are poorly understood. Here, we demonstrate that Galphas is present in the proliferative region of ventricular zone in mouse developing neocortex and co-localizes with intrinsic cell fate determinant protein Numb in dividing apical progenitors. Targeted ablation of Galphas subunit in the cortical progenitor causes an alteration from asymmetric to symmetric cell division, consequently leading to increased progenitor proliferation. Mechanistically, we show that Galphas deletion significantly reduces Numb expression and activates notch signaling. Therefore, these results reveal a novel role of Galphas in control of neural progenitor asymmetric cell division via suppressing Numb mediated Notch signaling inhibition. PMID- 25916882 TI - A novel mutation in FRMD7 causes X-linked idiopathic congenital nystagmus in a North Indian family. AB - Idiopathic congenital nystagmus (ICN) is the most common form of oculomotor disorder characterized by involuntary bilateral ocular oscillations. Primarily the disease is an ocular anomaly but the pathophysiology is associated with neuronal cytoskeletal dynamics in the brain. In the current study, a three generation North Indian family affected with X-linked idiopathic congenital nystagmus (XLICN) was recruited. Our aim was to identify the causal mutation for ICN in the family by screening the candidate gene, FERM domain containing-7 (FRMD7). This gene has been implicated in XLICN as it regulates neuronal cytoskeletal proteins and neurite outgrowth in the developing brain. Therefore, the entire protein coding region, including splice junctions, 5' UTR and 3' UTR of FRMD7 was screened by PCR-Sanger sequencing. Targeted sequencing revealed a novel A to G transition in the exon seven (c.556A>G), resulting in a conservative substitution of methionine by valine at codon 186 (p.M186V). A cohort of healthy individuals was also checked for presence of the putative causal variant by allele specific PCR. All the affected males and carriers in the family shared this variant; however, this was absent in the unaffected males as well as 100 unrelated healthy individuals. Further, protein homology modeling revealed that the change p.M186V might destabilize the interaction between the FERM-M and FERM C domains. The in silico prediction supports pathogenicity of the mutation; nevertheless it needs in vivo validation in the future. This is the first genetic investigation of XLICN in a North Indian family where we report a novel causal mutation c.556A>G (p.M186V) in the gene FRMD7. PMID- 25916883 TI - Nrf2-signaling and BDNF: A new target for the antidepressant-like activity of chronic fluoxetine treatment in a mouse model of anxiety/depression. AB - Several studies have shown that Nrf2, a major redox-sensitive transcription factor involved in the cellular defense against oxidative stress, increases susceptibility to depressive-like behavior. However, little is known about the influence of antidepressant drugs on Nrf2 signaling and expression of its target genes (GCLC, NQO1, HO-1) in the brain. We found that chronic treatment of a mouse model of anxiety/depression (CORT model) with a selective serotonin reuptake inhibitor (SSRI, fluoxetine, 18mg/kg/day) reversed CORT-induced anxiety/depression-like behavior in mice. Chronic fluoxetine treatment restored CORT-induced decreases in Nrf2 protein levels and its target genes in the cortex and hippocampus. Furthermore, we found that chronic fluoxetine also increased brain derived neurotrophic factor (BDNF) protein levels in cortex and hippocampus of CORT-treated Nrf2 knockout mice (KO, Nrf2(-/-)). Taken together, these data suggest that Nrf2 signaling contributes to fluoxetine-induced neuroprotection via an unexpected mechanism involving 5-HT transporter SERT blockade, and not through enhancement of BDNF expression. PMID- 25916884 TI - Adaptive learning can result in a failure to profit from good conditions: implications for understanding depression. AB - BACKGROUND AND OBJECTIVES: Depression is a major medical problem diagnosed in an increasing proportion of people and for which commonly prescribed psychoactive drugs are frequently ineffective. Development of treatment options may be facilitated by an evolutionary perspective; several adaptive reasons for proneness to depression have been proposed. A common feature of many explanations is that depressive behaviour is a way to avoid costly effort where benefits are small and/or unlikely. However, this viewpoint fails to explain why low mood persists when the situation improves. We investigate whether a behavioural rule that is adapted to a stochastically changing world can cause inactivity which appears similar to the effect of depression, in that it persists after the situation has improved. METHODOLOGY: We develop an adaptive learning model in which an individual has repeated choices of whether to invest costly effort that may result in a net benefit. Investing effort also provides information about the current conditions and rates of change of the conditions. RESULTS: An individual following the optimal behavioural strategy may sometimes remain inactive when conditions are favourable (i.e. when it would be better to invest effort) when it is poorly informed about the current environmental state. Initially benign conditions can predispose an individual to inactivity after a relatively brief period of negative experiences. CONCLUSIONS AND IMPLICATIONS: Our approach suggests that the antecedent factors causing depressed behaviour could go much further back in an individual s history than is currently appreciated. The insights from our approach have implications for the ongoing debate about best treatment options for patients with depressive symptoms. PMID- 25916885 TI - Contingency analysis of caregiver behavior: Implications for parent training and future directions. AB - Parent training is often a required component of effective treatment for a variety of common childhood problems. Although behavior analysts have developed several effective parent-training technologies, we know little about the contingencies that affect parent behavior. Child behavior is one source of control for parent behavior that likely contributes to the development of childhood problems and outcomes of parent training. We reviewed the evidence supporting child behavior as controlling antecedents and consequences for parent behavior. The implications for parent training are discussed, and recommendations for future research are suggested. PMID- 25916886 TI - The competition of Y?O and X?N halogen bonds to enhance the group V sigma-hole interaction in the NCY?O=PH3 ?NCX and O=PH3 ?NCX?NCY (X, Y=F, Cl, and Br) complexes. AB - The positive electrostatic potentials (ESP) outside the sigma-hole along the extension of O?P bond in O?PH3 and the negative ESP outside the nitrogen atom along the extension of the C?N bond in NCX could form the Group V sigma-hole interaction O?PH3 ?NCX. In this work, the complexes NCY?O?PH3 ?NCX and O?PH3 ?NCX?NCY (X, Y?F, Cl, Br) were designed to investigate the enhancing effects of Y?O and X?N halogen bonds on the P?N Group V sigma-hole interaction. With the addition of Y?O halogen bond, the VS, max values outside the sigma-hole region of O?PH3 becomes increasingly positive resulting in a stronger and more polarizable P?N interaction. With the addition of X?N halogen bond, the VS, min values outside the nitrogen atom of NCX becomes increasingly negative, also resulting in a stronger and more polarizable P?N interaction. The Y?O halogen bonds affect the sigma-hole region (decreased density region) outside the phosphorus atom more than the P?N internuclear region (increased density region outside the nitrogen atom), while it is contrary for the X?N halogen bonds. PMID- 25916887 TI - Systematic comparison of MRI findings in pediatric ependymoblastoma with ependymoma and CNS primitive neuroectodermal tumor not otherwise specified. AB - BACKGROUND: Ependymoblastoma (EBL), ependymoma (EP), and primitive neuroectodermal tumors of the central nervous system not otherwise specified (CNS PNET NOS) are pediatric brain tumors that can be differentiated by histopathology in the clinical setting. Recently, we described specific MRI features of EBL. In this study, we compare standardized MRI characteristics of EBL with EP and CNS PNET NOS in a series comprising 22 patients in each group. METHODS: All 66 centrally reviewed cases were obtained from the database of the German multicenter HIT trials. We systematically analyzed the initial MRI scans at diagnosis according to standardized criteria, and paired comparison was performed for EBL and EP, as well as for EBL and CNS-PNET NOS. RESULTS: We found differences between EBL and EP regarding age at diagnosis, MR signal intensity, tumor margin and surrounding edema, presence and size of cysts, and contrast enhancement pattern. Although MRI appearance of EBL shares many features with CNS PNET NOS, we revealed significant differences in terms of age at diagnosis, tumor volume and localization, tumor margins, edema, and contrast enhancement. CONCLUSION: This is the first study that systematically compares multiple parameters of MRI in pediatric EBL with findings in EP and CNS-PNET NOS. Although a definite differentiation by means of MRI alone might not be feasible in the individual case, we identify significant differences between these tumor entities. PMID- 25916888 TI - An MRI-based leg model used to simulate biomechanical phenomena during cuff algometry: a finite element study. AB - Cuff pressure stimulation is applicable for assessing deep-tissue pain sensitivity by exciting a variety of deep-tissue nociceptors. In this study, the relative transfer of biomechanical stresses and strains from the cuff via the skin to the muscle and the somatic tissue layers around bones were investigated. Cuff pressure was applied on the lower leg at three different stimulation intensities (mild pressure to pain). Three-dimensional finite element models including bones and three different layers of deep tissues were developed based on magnetic resonance images (MRI). The skin indentation maps at mild pressure, pain threshold, and intense painful stimulations were extracted from MRI and applied to the model. The mean stress under the cuff position around tibia was 4.6, 4.9 and around fibula 14.8, 16.4 times greater than mean stress of muscle surface in the same section at pain threshold and intense painful stimulations, respectively. At the same stimulation intensities, the mean strains around tibia were 36.4, 42.3 % and around fibula 32.9, 35.0 %, respectively, of mean strain on the muscle surface. Assuming strain as the ideal stimulus for nociceptors the results suggest that cuff algometry is less capable to challenge the nociceptors of tissues around bones as compared to more superficially located muscles. PMID- 25916889 TI - The effect of incidence function in backward bifurcation for malaria model with temporary immunity. AB - This paper addresses the effect of the choice of the incidence function for the occurrence of backward bifurcation in two malaria models, namely, malaria model with standard incidence rate and malaria model with nonlinear incidence rate. Rigorous qualitative analyzes of the models show that the malaria model with standard incidence rate exhibits the phenomenon of backward bifurcation whenever a certain epidemiological threshold, known as the basic reproduction number, is less than unity. The epidemiological consequence of this phenomenon is that the classical epidemiological requirement of making the reproductive number less than unity is no longer sufficient, although necessary, for effectively controlling the spread of malaria in a community. For the malaria model with nonlinear incidence rate, it is shown that this phenomenon does not occur and the disease free equilibrium of the model is globally-asymptotically stable whenever the reproduction number is less than unity. When the associated basic reproduction number is greater than unity, the models have a unique endemic equilibrium which is globally asymptotically stable under certain conditions. The sensitivity analysis based on the mathematical technique has been performed to determine the importance of the epidemic model parameters in making strategies for controlling malaria. PMID- 25916890 TI - A sigmoidal model for biosorption of heavy metal cations from aqueous media. AB - A novel multi-input single output (MISO) black-box sigmoid model is developed to simulate the biosorption of heavy metal cations by the fission yeast from aqueous medium. Validation and verification of the model is done through statistical chi squared hypothesis tests and the model is evaluated by uncertainty and sensitivity analyses. The simulated results are in agreement with the data of the studied system in which Schizosaccharomyces pombe biosorbs Ni(II) cations at various process conditions. Experimental data is obtained originally for this work using dead cells of an adapted variant of S. Pombe and represented by Freundlich isotherms. A process optimization scheme is proposed using the present model to build a novel application of a cost-merit objective function which would be useful to predict optimal operation conditions. PMID- 25916891 TI - Real-time growth rate for general stochastic SIR epidemics on unclustered networks. AB - Networks have become an important tool for infectious disease epidemiology. Most previous theoretical studies of transmission network models have either considered simple Markovian dynamics at the individual level, or have focused on the invasion threshold and final outcome of the epidemic. Here, we provide a general theory for early real-time behaviour of epidemics on large configuration model networks (i.e. static and locally unclustered), in particular focusing on the computation of the Malthusian parameter that describes the early exponential epidemic growth. Analytical, numerical and Monte-Carlo methods under a wide variety of Markovian and non-Markovian assumptions about the infectivity profile are presented. Numerous examples provide explicit quantification of the impact of the network structure on the temporal dynamics of the spread of infection and provide a benchmark for validating results of large scale simulations. PMID- 25916892 TI - Aminorhodamine (ARh): A Bichromophore with Three Emission Bands in Low Temperature Glasses. AB - At first glance, aminorhodamine (ARh) is a typical pH responsive fluorescent, rhodamine-type dye. However, hidden under the typical rhodamine absorption band, ARh has another electronic transition of similar energy, but polarized orthogonal to that of the rhodamine chromophore. This transition-assigned to an arylpyrylium type chromophore contained in the system-is responsible for the sensor action of the dye. ARh is non-fluorescent, while protonation of a donor amino group turn on a strong rhodamine-type emission. At low temperature in frozen solution emission from both electronic subsystems of ARh are observed. In order to achieve more complete understanding of the photophysical mechanisms in this type of fluorescent probes, ARh and its protonated counterpart HARh were studied by absorption and fluorescence spectroscopy, computational chemistry, and at low temperatures in solid solution. Results from fluorescence anisotropy and time resolved fluorescence spectra establish a bichromophore model and suggest that a remarkable weak coupling between the two nearly isoenergetic excited states in ARh enables the dual emission. All the complicated properties observed for ARh was accounted for by a bichromophore model describing the electronic system of ARh as a bichromophore constituted by a rhodamine and an arylpyrylium subsystem. PMID- 25916893 TI - Focal Arrhythmia Ablation Determined by High-Resolution Noninvasive Maps: Multicenter Feasibility Study. AB - INTRODUCTION: A noninvasive 3D mapping technique (ECVUETM, CardioInsight Inc., Cleveland) maps the origin and mechanisms of various arrhythmias without catheterizing the heart. METHODS: Thirty-three patients (3 centers, mean 45.0 +/- 14.6 years,) with symptomatic premature ventricular complexes (24 PVCs), focal atrial tachycardias (2 ATs), and manifest accessory pathways (7 WPW syndromes) were prospectively explored using 3D, noninvasive bedside electrocardiomapping. The location of origin of the focal arrhythmia was first determined using noninvasive mapping. Subsequently, a stimulus artifact was delivered at this site to confirm and evaluate the precise location of the mapped focal origin. The procedural parameters and clinical efficacy were studied. RESULTS: Ablation was successful in 32/33 (97%) patients (PVCs: 13 right, 10 left, 1 septal; WPW: 3 left, 3 right; ATs: 2 left) without complications. The time from catheterization to permanent arrhythmia elimination/termination, RF duration, skin-to-skin procedural duration, and fluoroscopic exposure were median 16, 3.98, 71, and 11.9 minutes (for n = 29), respectively. At mean 24.7 +/- 3.7 months of follow-up, 31 patients remain arrhythmia-free after a single procedure. One patient (right WPW syndrome) required repeat ablation 1 month later. One patient had recurrence of PVCs and is now deceased. The cumulative radiation (CT scan and fluoroscopy) exposure was median 7.57 mSv. CONCLUSION: ECVUE(TM) is a noninvasive tool allowing rapid preprocedural localization of focal arrhythmia and enables the electrophysiologist with highly specific information to direct RF delivery at the source of the arrhythmia with minimal intracardiac mapping. PMID- 25916894 TI - Reciprocal transplant reveals trade-off of resource quality and predation risk in the field. AB - Balancing trade-offs between avoiding predators and acquiring food enables animals to maximize fitness. Quantifying their relative contribution to vital rates in nature is challenging because predator abundance and nutrient enrichment are often confounded. We employed a reciprocal transplant study design to separate these confounded effects on growth and reproduction of snails at wetland sites along a gradient of predator threats and phosphorus (P) enrichment associated with a canal. We held snails in mesh bags that allowed the passage of waterborne predator cues and fed them local or transplanted periphyton. Molluscivores were more abundant near the canal, and snails tethered near the canal suffered 33% greater mortality than those tethered far from it (far sites). The greatest difference in snail growth rates was at the far sites where growth on far periphyton was 48% slower than on P-enriched (near canal) periphyton. Close proximity to the canal reduced growth on near periphyton by 21% compared to growth on the same periphyton far from the canal; there was no difference in growth rate on either periphyton type when snails were raised near the canal. Snails laid 81% more egg masses at far sites than at near sites, regardless of periphyton origin. Top-down and bottom-up processes were elevated near the canal, and their effects canceled on growth, but not reproduction. Phenotypic trade-offs such as these may explain why some taxa show little response to nutrient enrichment, compared to others, or that the effects of nutrient enrichment may be context dependent. PMID- 25916895 TI - Promoting Effect of Sodium Chloride on the Solubilization and Depolymerization of Cellulose from Raw Biomass Materials in Water. AB - The development of a green system to solubilize cellulose from raw biomass is important, yet it is challenging because of the insolubility of cellulose in most solvents. Herein, a green NaCl-H2 O system is developed in which NaCl significantly enhances the dissolution and depolymerisation of cellulose from raw biomass. Nearly all the cellulose in the selected biomass types was dissolved and degraded into oligomers with molecular weights of 200-400 Da under relatively mild conditions. Cl(-) could interact strongly with the end ?OH group of the glucose unit in a 1:1 ratio, which resulted in the enhanced breaking of both inter- and intramolecular hydrogen bonds. In particular, the intermolecular hydrogen bond with an FTIR band at approximately v=3200 cm(-1) was disrupted significantly by Cl(-) . The FTIR band for a hydrogen bond between hemicellulose and lignin might appear at v=1636 cm(-1) , whereas this bond could be almost totally broken under hydrothermal conditions at 220 degrees C. PMID- 25916896 TI - Loss of negative regulators amplifies RAS signaling. AB - A new study identifies SPRY4 as a tumor suppressor in acute myeloid leukemia and shows that loss of SPRY4 acts as an alternative mechanism to drive RAS signaling. In addition, a paradigm of cooperativity in which combined loss of multiple negative regulators of the RAS pathway supplants the need for RAS mutations is suggested. PMID- 25916897 TI - Keeping methylation at bay. AB - A hallmark of CpG islands is their unmethylated state, and determining how DNA methylation can invade these elements is therefore important for understanding developmental gene regulation and disease. A new study shows that FBXL10, a protein commonly altered by mutation in leukemia, is part of a mechanism that blocks methylation of CpG islands. PMID- 25916903 TI - Glucagon-like peptide-1 receptor agonist therapeutics for total diabetes management: assessment of composite end-points. AB - Assessment of the benefits of anti-diabetic drugs for type 2 diabetes requires analysis of composite end-points, taking HbA1c, bodyweight, hypoglycemia and other metabolic parameters into consideration; continuous, optimal glycemic control as well as bodyweight, blood pressure and lipid levels are critical to prevent micro- and macro-vascular complications. Glucagon-like peptide-1 receptor agonists (GLP-1RAs) are now established as an important total treatment strategy for type 2 diabetes, exerting glucose-lowering effects with little hypoglycemia risk and also ameliorating bodyweight, blood pressure and lipid levels, which are therapeutic targets for prevention of complications of the disease. The available data strongly suggest only beneficial effects of GLP-1RAs; however, long-term evaluation of the relevant composite end-points including health-related quality of life and cost-effectiveness remain to be investigated in adequately powered, prospective, controlled clinical trials. In the meantime, healthcare professionals need to be scrupulously attentive for potential, rare adverse events in patients using GLP-1RAs. PMID- 25916904 TI - 'Wax bloom' on beeswax cultural heritage objects: Exploring the causes of the phenomenon. AB - The term 'wax bloom' is used to describe a thin whitish crystalline layer that develops on the surface of beeswax objects under specific conditions. This phenomenon is undesirable, especially in the cases of objects with aesthetic or informational value, such as wax sculptures or historical seals. A combination of solid-state NMR and FTIR measurements allowed to obtain fairly detailed insight into the problem and to suggest a probable mechanism of its development. Secondary crystallization of unsaturated hydrocarbons from beeswax was determined as a primary cause. After the macroscopic solidification of beeswax from the melt, these molecules remain for months in a highly mobile, liquid-like state. This facilitates their diffusion to the surface, where they eventually crystallize, forming the 'wax bloom' effect. Although these results are of particular interest with respect to the conservation of beeswax artifacts, they are relevant to this material in general and help with understanding its unique properties. PMID- 25916905 TI - Antibacterial active compounds from Hypericum ascyron L. induce bacterial cell death through apoptosis pathway. AB - Hypericum ascyron L. has been used as a traditional medicine for the treatment of wounds, swelling, headache, nausea and abscesses in China for thousands of years. However, modern pharmacological studies are still necessary to provide a scientific basis to substantiate their traditional use. In this study, the mechanism underlying the antimicrobial effect of the antibacterial activity compounds from H. ascyron L. was investigated. Bioguided fractionation of the extract from H. ascyron L. afforded antibacterial activity fraction 8. The results of cup plate analysis and MTT assay showed that the MIC and MBC of fraction 8 is 5 mg/mL. Furthermore, using Annexin V-FITC/PI, TUNEL labeling and DNA gel electrophoresis, we found that cell death with apoptosis features similar to those in eucaryon could be induced in bacteria strains after exposure to the antibacterial activity compounds from H. ascyron L. at moderate concentration. In addition, we further found fraction 8 could disrupt the cell membrane potential indicate that fraction 8 exerts pro-apoptotic effects through a membrane-mediated apoptosis pathway. Finally, quercetin and kaempferol 3-O-beta-(2"-acetyl) galactopyranoside, were identified from fraction 8 by means of Mass spectrometry and Nuclear magnetic resonance. To our best knowledge, this study is the first to show that Kaempferol 3-O-beta-(2"-acetyl)-galactopyranoside coupled with quercetin had significant antibacterial activity via apoptosis pathway, and it is also the first report that Kaempferol 3-O-beta-(2"-acetyl)-galactopyranoside was found in clusiacea. Our data might provide a rational base for the use of H. ascyron L. in clinical, and throw light on the development of novel antibacterial drugs. PMID- 25916907 TI - New naphthoquinone derivatives against glioma cells. AB - This work was aimed to the development of a set of new naphtoquinone derivatives that can act against glioma. The compounds were tested in order to find out their ability to inhibit the growth of glioma cells, and the results of these assays were correlated with electrochemical analysis and NMR-based reoxidation kinetic studies, suggesting that a redox mechanism underlies and may explain the observed biological behavior. In addition to a full description of the synthetic pathways, electrochemistry, NMR and single crystal X-ray diffraction data are provided. PMID- 25916906 TI - Prospective performance evaluation of selected common virtual screening tools. Case study: Cyclooxygenase (COX) 1 and 2. AB - Computational methods can be applied in drug development for the identification of novel lead candidates, but also for the prediction of pharmacokinetic properties and potential adverse effects, thereby aiding to prioritize and identify the most promising compounds. In principle, several techniques are available for this purpose, however, which one is the most suitable for a specific research objective still requires further investigation. Within this study, the performance of several programs, representing common virtual screening methods, was compared in a prospective manner. First, we selected top-ranked virtual screening hits from the three methods pharmacophore modeling, shape-based modeling, and docking. For comparison, these hits were then additionally predicted by external pharmacophore- and 2D similarity-based bioactivity profiling tools. Subsequently, the biological activities of the selected hits were assessed in vitro, which allowed for evaluating and comparing the prospective performance of the applied tools. Although all methods performed well, considerable differences were observed concerning hit rates, true positive and true negative hits, and hitlist composition. Our results suggest that a rational selection of the applied method represents a powerful strategy to maximize the success of a research project, tightly linked to its aims. We employed cyclooxygenase as application example, however, the focus of this study lied on highlighting the differences in the virtual screening tool performances and not in the identification of novel COX-inhibitors. PMID- 25916908 TI - Greener neighbourhoods, slimmer children? Evidence from 4423 participants aged 6 to 13 years in the Longitudinal Study of Australian children. AB - OBJECTIVES: There is a growing belief that green space (for example, parks) help prevent obesity. There is evidence of an inverse association between green space and childhood body mass index (BMI); however, the majority of these studies are cross-sectional. Longitudinal studies that track change in BMI across childhood in relation to levels of green space proximity would improve the quality of evidence available for decision making. METHODS: Objectively measured BMI was obtained every 2 years between 2006 and 2012 for 4423 participants initially aged 6-7 years in the Longitudinal Study of Australian Children (LSAC). The LSAC is a nationally representative study on a range of health and socio-demographic measures. Using Australian Bureau of Statistics mesh block data, which classify small scale land areas based on the main usage, each participant was assigned an objective measure of green space availability within their Statistical Area (level 2) of residence. Gender-stratified multilevel linear regression was used to estimate BMI growth curves across childhood in relation to green space availability. Family income, Australian Indigenous status, mothers' education and language spoken were used to adjust for socio-economic confounding. RESULTS: Age was found to be an effect modifier of associations between green space and BMI for boys (P=0.005) and girls (P=0.048). As children grew older, an inverse patterning of BMI by green space availability emerged. These findings held after adjustment for socio-economic circumstances for boys (P=0.009), though were less robust for girls after this adjustment (P=0.056). CONCLUSION: A beneficial effect of green space on BMI emerges as children grow older. However, there was little additional benefit after a modest amount of green space was met. Further research is needed to understand whether the drivers of this effect are from age-specific mechanisms, or whether the benefit of living in a greener neighbourhood is accumulated through childhood. PMID- 25916909 TI - Home environment and psychosocial predictors of obesity status among community residing men and women. AB - BACKGROUND/OBJECTIVES: Prior research indicates that features of the home environment (for example, televisions, exercise equipment) may be associated with obesity, but no prior study has examined objective features of the home food environment (for example, location of food) in combination with behavioral (for example, food purchasing), psychological (for example, self-efficacy) and social factors among obese adults. This study identified factors associated with obesity status from measures of home environment, food purchasing behavior, eating behavior and psychosocial functioning. SUBJECTS/METHODS: One hundred community residing obese (mean body mass index (BMI)=36.8, s.e.=0.60) and nonobese (mean BMI=23.7, s.e.=0.57) adults (mean age=42.7, s.e.=1.50; range=20-78 years) completed an observational study with 2-h home interview/assessment and 2-week follow-up evaluation of food purchases and physical activity. Data were analyzed with analysis of variance and logistic regression, controlling for sex. RESULTS: Univariate analyses revealed that homes of obese individuals had less healthy food available than homes of nonobese (F(1,97)=6.49, P=0.012), with food distributed across a greater number of highly visible locations (F(1,96)=6.20, P=0.01). Although there was no group difference in household income or size, obese individuals reported greater food insecurity (F(1,97)=9.70, P<0.001), more reliance on fast food (F(1,97)=7.63, P=0.01) and more long-term food storage capacity in number of refrigerators (F(1,97)=3.79, P=0.05) and freezers (F(1,97)=5.11, P=0.03). Obese individuals also reported greater depressive symptoms (F(1,97)=10.41, P=0.002) and lower ability to control eating in various situations (F(1,97)=20.62, P<0.001). Multiple logistic regression revealed that obesity status was associated with lower self-esteem (odds ratio (OR) 0.58, P=0.011), less healthy food consumption (OR 0.94, P=0.048) and more food available in the home (OR 1.04, P=0.036). CONCLUSIONS: The overall pattern of results reflected that home food environment and psychosocial functioning of obese individuals differed in meaningful ways from that of nonobese individuals. In particular, lower self-esteem may be an important psychosocial aspect of obesity, especially in the context of greater food consumption and food storage/availability. PMID- 25916911 TI - The health effects of green space: then and now. PMID- 25916910 TI - Salivary composition in obese vs normal-weight subjects: towards a role in postprandial lipid metabolism? AB - In the pathophysiological context of obesity, oral exposure to dietary fat can modulate lipid digestion and absorption, but underlying in-mouth mechanisms have not been clearly identified. Therefore, we tested the hypothesis that salivary components related to dietary fat sensitivity would differ according to body mass index (BMI) and postprandial lipid metabolism in young men. Saliva was collected from nine normal-weight (BMI=22.3+/-0.5 kg m(-2)) and nine non-morbid obese (BMI=31.7+/-0.3 kg m(-2)) men before an 8-h postprandial metabolic exploration test involving the consumption of a 40-g fat meal, in which obese subjects revealed a delayed postprandial lipid metabolism. Nine salivary characteristics (flow, protein content, lipolysis, amylase, proteolysis, total antioxidant status, lysozyme, lipocalin 1 and carbonic anhydrase-VI) were investigated. We show that, under fasting conditions, salivary lipolysis was lower in obese vs normal-weight subjects, whereas proteolysis and carbonic anhydrase VI were higher. We reveal through multivariate and Mann-Whitney analysis that differences in fasting salivary lipolysis and proteolysis between both groups are related to differences in postprandial lipid metabolism including exogenous fatty-acid absorption and beta-oxidation. These results suggest a potential role of salivary composition on postprandial lipid metabolism and bring novel causal hypotheses on the links between salivary composition, sensitivity to dietary fat oral income and postprandial lipid metabolism according to BMI. PMID- 25916912 TI - Transition metal-induced degradation of a pharmaceutical compound in reversed phase liquid chromatographic analysis. AB - Drug degradation that occurs in HPLC analysis, during either sample preparation or chromatographic separation, can greatly impact method robustness and result accuracy. In this work, we report a case study of drug dimerization in HPLC analysis where proximate causes were attributed to either the LC columns or the HPLC instrument. Solution stress studies indicated that the same pseudo-dimeric degradants could also be formed rapidly when the compound was exposed to certain oxidative transition metal ions, such as Cu(II) and Fe(III). Two pseudo-dimeric degradants were isolated from transition metal stressed samples and their structures were elucidated. A degradation pathway was proposed, whereby the degradation was initiated through transition metal-induced single electron transfer oxidation. Further studies confirmed that the dimerization was induced by trace transition metals in the HPLC flow path, which could arise from either the stainless steel frits in the LC column or stainless steel tubing in the HPLC instrument. Various procedures to prevent transition metal-induced drug degradation were explored, and a general strategy to mitigate such risks is briefly discussed. PMID- 25916913 TI - Comparison of ultrasound-enhanced air-assisted liquid-liquid microextraction and low-density solvent-based dispersive liquid-liquid microextraction methods for determination of nonsteroidal anti-inflammatory drugs in human urine samples. AB - Two dispersive-based liquid-liquid microextraction methods including ultrasound enhanced air-assisted liquid-liquid microextraction (USE-AALLME) and low-density solvent-based dispersive liquid-liquid microextraction (LDS-DLLME) were compared for the extraction of salicylic acid (the hydrolysis product of acetylsalicylic acid), diclofenac and ibuprofen, as instances of the most commonly used nonsteroidal anti-inflammatory drugs (NSAIDs), in human urine prior to their determination by gas chromatography with flame ionization detection (GC-FID). The influence of different parameters affecting the USE-AALLME (including type and volume of the extraction solvent, sample pH, ionic strength, and simultaneous sonication and number of extraction cycles) and the LDS-DLLME (including type and volume of the extraction and disperser solvents, sample pH, and ionic strength) were investigated to optimize their extraction efficiencies. Both methods are fast, simple and convenient with organic solvent consumption at MUL level. However, the best results were obtained using the USE-AALLME method, applying 30 MUL of 1-octanol as extraction solvent, 5.0 mL of sample at pH 3.0, without salt addition, and 5 extraction cycles during 20s of sonication. This method was validated based on linearities (r(2) >0 .971), limits of detection (0.1-1.0 MUg L(-1)), linear dynamic ranges (0.4-1000.0 MUg L(-1)), enrichment factors (115 +/- 3-135 +/- 3), consumptive indices (0.043-0.037), inter- and intra-day precisions (4.3-4.8 and 5.6-6.1, respectively), and relative recoveries (94-103%). The USE AALLME in combination with GC-FID, and with no need to derivatization step, was demonstrated to be a simple, inexpensive, sensitive and efficient method to determine NSAIDs in human urine samples. PMID- 25916914 TI - Immortal time bias and reverse causality in retrospective analysis: Comment on "effect of cumulative bortezomib dose on survival in multiple myeloma patients receiving bortezomib-melphalan-prednisone in the phase III VISTA study". PMID- 25916915 TI - Cancer risk assessment: Optimizing human health through linear dose-response models. AB - This paper proposes that generic cancer risk assessments be based on the integration of the Linear Non-Threshold (LNT) and hormetic dose-responses since optimal hormetic beneficial responses are estimated to occur at the dose associated with a 10(-4) risk level based on the use of a LNT model as applied to animal cancer studies. The adoption of the 10(-4) risk estimate provides a theoretical and practical integration of two competing risk assessment models whose predictions cannot be validated in human population studies or with standard chronic animal bioassay data. This model-integration reveals both substantial protection of the population from cancer effects (i.e. functional utility of the LNT model) while offering the possibility of significant reductions in cancer incidence should the hormetic dose-response model predictions be correct. The dose yielding the 10(-4) cancer risk therefore yields the optimized toxicologically based "regulatory sweet spot". PMID- 25916916 TI - Immunomodulatory activity of methanolic extract of Amorphophallus commutatus var. wayanadensis under normal and cyclophosphamide induced immunosuppressive conditions in mice models. AB - The present study investigates the immunomodulatory activity of methanolic extract of Amorphophallus commutatus var. wayanadensis (MEAC) under normal and cyclophosphamide induced immunosuppressive conditions in Swiss albino mice models. The splenocyte proliferation assay was performed to study in-vitro immunomodulatory activity of MEAC, where sheep RBC (SRBC) was used to induce immune responses in the experimental animals. The in-vivo immunomodulatory activity was evaluated by humoral antibody titer, quantification of plaque forming cells, qualitative hemolysis, delayed type hypersensitivity assay, phagocytic index and neutrophil adhesion assays. The chemoprotective effect of MEAC was determined against cyclophosphamide induced immunosuppression in mice models. MEAC exhibited significant mitogenic and co-mitogenic activity on Con-A, PHA and LPS stimulated splenocytes isolated from mouse spleen in a dose dependent manner. Furthermore, MEAC also elicited significant immunomodulatory activity with enhanced activation of humoral immune response along with a suppressive effect on cell mediated immune response. Hematological and histopathological analysis revealed the protective effect of MEAC against CP induced immunosuppression. The significant immunomodulatory activity of MEAC observed in the current study could be due to the fatty acids and phytosterols present in the extract. PMID- 25916917 TI - Feed supplemented with byproducts from olive oil mill wastewater processing increases antioxidant capacity in broiler chickens. AB - In the present study, a ceramic membrane microfiltration method was used for the separation of two liquid products, the downstream permeate and the upstream retentate, from olive mill wastewater (OMWW). These liquid products were examined for their antioxidant activity by incorporating them into broilers' feed. Twenty four broilers 13 d old were divided into two feeding groups receiving supplementation with OMWW retentate or permeate for 37 d. Blood was drawn at 17, 27 and 37 d, while tissues (muscle, heart, liver) were collected at 37 d. The antioxidant effects were assessed by measuring oxidative stress biomarkers in blood and tissues. The results showed that broilers given feed supplemented with OMWW retentate or permeate had significantly lower protein oxidation and lipid peroxidation levels and higher total antioxidant capacity in plasma and tissues compared to control group. In both OMWW groups, catalase activity in erythrocytes and tissues was significantly increased compared to control group. OMWW retentate administration increased significantly GSH in erythrocytes in broilers with low GSH, although both OMWW products significantly reduced GSH in broilers with high GSH. Thus, it has been demonstrated for the first time that supplementation with OMWW processing residues could be used for enhancing broilers' redox status. PMID- 25916918 TI - Fast and Accurate Circuit Design Automation through Hierarchical Model Switching. AB - In computer-aided biological design, the trifecta of characterized part libraries, accurate models and optimal design parameters is crucial for producing reliable designs. As the number of parts and model complexity increase, however, it becomes exponentially more difficult for any optimization method to search the solution space, hence creating a trade-off that hampers efficient design. To address this issue, we present a hierarchical computer-aided design architecture that uses a two-step approach for biological design. First, a simple model of low computational complexity is used to predict circuit behavior and assess candidate circuit branches through branch-and-bound methods. Then, a complex, nonlinear circuit model is used for a fine-grained search of the reduced solution space, thus achieving more accurate results. Evaluation with a benchmark of 11 circuits and a library of 102 experimental designs with known characterization parameters demonstrates a speed-up of 3 orders of magnitude when compared to other design methods that provide optimality guarantees. PMID- 25916919 TI - [Pay attention to researches on pain related to Parkinson's disease]. PMID- 25916920 TI - [Local brain activity in different motor subtypes of Parkinson's disease with fMRI]. AB - OBJECTIVE: To explore the changes of local brain activity in motor subtypes of Parkinson's disease (PD) with functional magnetic resonance imaging (fMRI). METHODS: A total of 60 idiopathic PD and 30 age- and gender-matched normal controls were examined with resting-state fMRI from January 2013 to March 2014. All subjects gave their written informed consent for the study. The amplitude of low-frequency fluctuation (ALFF) was calculated to measure local brain activity. The PD patients were divided into two groups of tremor dominant (TD) and postural instability/gait difficulty (PIGD) (n = 30 each). All subjects gave their written in formed consent for the study.One-way ANOVA and post-hoc t-test were performed to detect the differences of local brain activity between PD and normal subjects. And the correlations were examined between ALFF, scores and levodopa dose. RESULTS: Compared with normal subjects, the TD group showed increased activity in bilateral cerebellums (-37, -47, -38), thalamus (-18, -17,0), pons (-3, -23, -37) and left precentral gyrus (-41, -30, 46) versus decreased activity in bilateral frontal lobes (-13, 69, 6), temporal lobes (-42, 18, -21), left insula (-32, 22, 2) and left anterior cingulated (-7, 32, -5). The PIGD group showed increased activity in right postcentral gyrus (63, -18, 39) and decreased activity in bilateral putamens (-24, 12, 3), pre-supplementary motor area (10, 10, 58), frontal lobes (15, -15, 57), temporal lobes (-39, 18, -3) and left insula (-29, 20, 11). Compared with PIGD, the TD group showed increased activity in temporal lobes, but decreased activity in frontal lobes. Additionally, ALFF in bilateral cerebellums and frontal lobes was positively correlated with TD scores while ALFF in left precentral gyrus, bilateral putamens and temporal lobes negatively correlated with TD scores. ALFF in bilateral frontal lobes and left temporal lobe was positively correlated with PIGD scores.However, in right postcentral gyrus and bilateral putamens, ALFF was negatively correlated with PIGD scores. The levodopa dose was positively correlated with frontal lobes and temporal lobe in TD and cerebellums and inferior parietal lobule in PIGD. CONCLUSION: A specific pattern of intrinsic activity in TD and PIGD may provide insights into neurophysiological mechanisms of PD motor subtypes. The changes of brain activity in TD are caused by the interaction between cerebello-thalamo-cortical circuit and basal ganglia loop while the changes in PIGD result largely from damaged basal ganglia loop. PMID- 25916921 TI - [Correlations between olfactory and cognitive functions in early stage Parkinson's disease]. AB - OBJECTIVE: To explore the general characteristics of olfactory and cognitive functions in early Parkinson's disease (PD) and examine their correlations. METHODS: The olfactory functions were assessed for 63 PD patients and 55 age and gender-matched normal subjects using T&T olfactory assessment. The scales of mini mental state examination (MMSE) and Montreal cognitive assessment (MoCA) were employed. The olfactory and cognitive parameters and their relationship were analyzed. There were five different odors in T&T testing liquid and each odor had 5 concentration gradients. The level had an assigned value of 1 to 5 and number 3 represented the standard threshold of olfactory recognition. The mean value of five odors was overall olfactory detection or cognition threshold. RESULTS: (1) The olfactory detection and recognition thresholds were 4.0 +/- 1.3/4.8 +/- 0.9 in PD group versus 2.5 +/- 0.9/2.9 +/- 0.9 in normal controls. The scores of MoCA and MMSE were lower in PD group than those in controls (23.7 +/- 3.0 vs 25.9 +/- 2.0, t = 4.727, P = 0.000; 27.8 +/- 1.9 vs 28.9 +/- 0.9, t = 4.036, P = 0.000). (2) Linear correlation analysis showed that olfactory recognition threshold was correlated negatively with MoCA scores. The olfactory detection and recognition thresholds were correlated negatively with the score of visual-spatial perception and executive capability (r = -0.365, -0.403, P < 0.05). The olfactory recognition threshold was correlated negatively with the score of delayed memory (r = -0.299, P < 0.05). And this phenomenon was absent in controls. CONCLUSION: Early PD patients have olfactory dysfunction and cognitive impairment. And these two non-motor symptoms are negatively correlated. PMID- 25916922 TI - [Effects of a single dose levodopa on heart rate variability in Parkinson's disease]. AB - OBJECTIVE: To explore the effects of levodopa on heart rate variability (HRV) in Parkinson's disease (PD). METHODS: A total of 48 PD patients (M:F = 35: 13, mean age: 59 +/- 6 years, duration of illness: 4.7 +/- 1.8 years, Hoehn & Yahr stage: 2.2 +/- 0.3) on a stable dose of levodopa were recruited from January 2012 to May 2014.For confirming autonomic dysfunction, the baseline patient data (12 hours off-medication) were compared with a control group consisting of 48 age and gender-matched healthy subjects (M: F = 35: 13, mean age 58 +/- 6 years). Resting lead II electrocardiogram (ECG) was recorded at baseline and continuously after two tablets of 100/10 mg levodopa/carbidopa.However, 5-min segments were selected from every quarter, i.e., Q1 (0-15 min), Q2 (15-30 min), Q3 (30-45 min) and Q4 (45-60 min). Artifact-free 5-min segments of ECG were analyzed offline to acquire the parameters of heart rate variability in time and frequency domains. RESULTS: At baseline, PD patients had a significantly reduced standard deviation of normal to-normal intervals (SDRR) [(24 +/- 4) vs (26 +/- 4) ms, P < 0.01)] and total power (TP) [(569 +/- 180) vs (652 +/- 205) ms2, P < 0.05] when compared to controls. Comparing of HRV in PD patients at baseline and during first hour after drug administration, we observed significant increase in SDRR [(29 +/- 12) vs (24 +/- 8) ms, P < 0.05)], TP [(708 +/- 253) vs (569 +/- 180) ms2, P < 0.01], low frequency power (LF) [(203 +/- 98) vs (168 +/- 60) ms2, P < 0.05) ] and high frequency power (HF) [158 +/- 86) vs (114 +/- 90) ms2, P < 0.05] in Q3. CONCLUSION: The results suggest an improvement in the overall variability of heart rate resulting from an enhanced vagal tone. PMID- 25916923 TI - [Efficacies of fluid resuscitation as guided by lactate clearance rate and central venous oxygen saturation in patients with septic shock]. AB - OBJECTIVE: To estimate the efficacies of fluid resuscitations as guided by lactate clearance rate (LC) and central venous oxygen saturation (ScvO2) in patients with septic shock. METHODS: 100 patients diagnosed with septic shock from June 2012 to June 2014 in department of critical care medicine of sixteen hospitals were enrolled. They were randomly divided into two groups of study and control (each n = 50). After a diagnosis of sepsis shock, they were treated symptomatically timely and fluid resuscitation was started as early as possible according to the 2008 Guideline for Managing Sepsis & Septic Shock. Central venous pressure (CVP) >= 8 mmHg (1 mmHg = 0.133 kPa), mean arterial pressure (MAP) >= 65 mmHg, urine output >= 0.5 ml * kg-1 * h-1, ScvO2>= 70% and LC >= 10% (or lactate <= 2.0 mmol) served as target values for fluid resuscitation therapy in study group versus CVP >= 8 mmHg, MAP >= 65 mmHg, urine output >= 0.5 ml * kg 1 * h-1 and ScvO2>= 70% in control group. The general conditions and clinical characteristics, changes in CVP, MAP, urine output, ScvO2, lactate level and/or LC before (0 hour) and every hour (1-6 h) after the start of fluid resuscitation and other related outcome indicators were recorded. RESULTS: No significant difference existed in general data. The 28-day mortality was 40% for study group versus 56% for control group. There was no significant inter-group difference (P > 0.05). The time of mechanical ventilation and length of intensive care unit (ICU) stay were lower in study group than those in control group [mechanical ventilation time (11.200 +/- 17.069) vs (15.760 +/- 14.215), P = 0.150; length of ICU stay (13.240 +/- 17.127) vs (23.980 +/- 18.298), P = 0.003]. The 28-day mortality was independently associated with LC and ScvO2reaching target values for fluid resuscitation in study group (chi2 = 10.930, P = 0.001) while the 28 day mortality was independently associated with ScvO2reaching target value for fluid resuscitation in control group (chi2 = 6.395, P = 0.011). Among all patients, the 28-day mortality was independently associated with ScvO2reaching target value for fluid resuscitation (chi2 = 14.530, P = 0.000), but not LC (chi2 = 1.175, P = 0.278). CONCLUSION: A combination of LC and ScvO2may serve an index in confirming the endpoint of fluid resuscitation for patients with septic shock. Fluid resuscitation therapy under the guidance of LC and ScvO2is more accurate and reliable than the guidance of ScvO2alone. PMID- 25916924 TI - [Correlation of AQP4 gene polymorphism with NMO clinical phenotypes and its underlying mechanism]. AB - OBJECTIVE: To explore the correlation between aquaporin-4 (AQP4) gene single nucleotide polymorphism (SNP) and clinical phenotypes of neuromyelitis optica (NMO) and its underlying mechanism. METHODS: Eight SNPs in AQP4 gene regulatory region were selected and genotyped for 208 anti-AQP4 autoantibodies (NMO-IgG) seropositive cases during January 2010 to January 2014 and 204 healthy subjects. Then the correlation was further analysed between genotypes and NMO phenotypes. And the effect of microRNA (miRNA) on the expression of AQP4 gene was examined by dual-luciferase reporter technique. RESULTS: The A/T genotype of rs1058424 (50.61% vs 70.45%, OR = 0.430, 95% CI 0.210-0.880) and C/T (50.00% vs 68.18%, OR = 0.467, 95%CI 0.231-0.994) genotype of rs3763043 in 3'-UTR were correlated with longitudinal extensive transverse myelitis; the A/T genotype of rs1058424 (46.72% vs 66.28%, OR = 0.525, 95% CI 0.276-0.999) and A/C genotype of rs335929 (45.08% vs 58.14%, OR = 0.527, 95% CI 0.281-0.987) in 3'-UTR as well as C/T genotype of rs151244 (50.82% vs 69.77%, OR = 0.450, 95% CI 0.230-0.881) in promoter 0 region were correlated with optic neuritis. The polymorphism of rs6508459 in 3'-UTR and rs3763040 in intron region were correlated with concurrent systemic autoimmune diseases (P = 0.012 and 0.023 respectively).miRNA 323-3p could regulate AQP4 gene expression.However, variation in SNP rs1058424 failed to affect this regulation. CONCLUSION: SNP in 3'-UTR of AQP4 gene may be associated with NMO phenotypes.miRNA 323-3p may participate in the pathogenesis of NMO by binding to certain SNP sites in 3'-UTR of AQP4 gene and regulating its expression. PMID- 25916925 TI - [Functional connectivity of amygdala in refractory epilepsy:a resting-state functional study of magnetic resonance imaging]. AB - OBJECTIVE: To explore the functions of amygdala functional connectivity in the pathogenesis of refractory epilepsy with resting-state functional magnetic resonance imaging (RS-fMRI). METHODS: A total of 19 patients with refractory epilepsy were recruited from August 2013 to June 2014. And 19 healthy persons were selected as the controls.No obvious epileptogenic lesions of intracranial structures were found on multi-modal neuroimaging.Ictal and interictal epileptic activities on long-term video electroencephalogram (EEG) showed spine spread spike and wave in bilateral cerebral hemispheres. All fMRI data were preprocessed after RS-fMRI scanning. Then left and right amygdalas were selected as regions of interest (ROIs) for calculating the linear correlation between amygdala and whole brain. As relative to the control group, the changes of brain areas in functional connectivity were examined for the intractable epilepsy group. RESULTS: Compared with the controls, left amygdala in refractory epilepsy group showed increased functional connectivity with bilateral fusiform gyrus, bilateral calcarine gyrus and right lingual, on the contrary decreased functional connectivity with bilateral cuneus, bilateral precuneus, bilateral caudatas and left thalamus.However, right amygdala demonstrated increased functional connectivity with bilateral calcarine gyrus and bilateral linguals, but decreased functional connectivity with bilateral caudatas and left putamen (P < 0.05). CONCLUSION: Altered functional connectivity of amygdala reflects its dysfunction in refractory epilepsy patients. It suggested that amygdala is an important component of "epileptic network" participating in the occurrence and development of refractory epilepsy. PMID- 25916926 TI - [Analysis of treating prolactinoma patients with bromocriptine during pregnancy]. AB - OBJECTIVE: To explore the therapeutic efficacies and the timing of taking bromocriptine during pregnancy in patients with pituitary prolactinoma. METHODS: The clinical data were analyzed retrospectively for 230 women with pituitary prolactinoma at our hospital from January 2001 to May 2014. During January 2001 to December 2007, 120 cases were selected as control group. During January 2008 to May 2014, 110 cases were recruited into treatment group.When found pregnant, the control group immediately withdrew while the treatment group continued the original dose of bromocriptine. RESULTS: The rate of embryo stopping was 16.7% (20/120) in control group. As compared with the rate of natural population, the difference was statistically significant (P < 0.05); the rate was 0.91% (1/110) in treatment group. As compared with natural population, the difference had no significance (P > 0.05).No significant inter-group difference existed in embryonic malformation rate (P > 0.05). CONCLUSION: Pituitary prolactinoma patients should continue the original dose of bromocriptine for at least 4 months instead of immediate withdrawal during pregnancy. For those with large adenoma, bromocriptine should be taken throughout pregnancy. Blood levels of prolactin, progesterone, human chorionic gonadotropin (HCG) and visual dysfunction should be monitored every 2 weeks. If the levels of progesterone and HCG are low, they should be timely supplemented.If prolactin rises too rapidly and visual dysfunction worsens, the dose of bromocriptine should be appropriately increased. Taking bromocriptine during pregnancy can significantly reduce the rate of embryo stopping without improving the rate of embryo deformity. Thus use of bromocriptine is both safe and necessary. PMID- 25916927 TI - [Application of Navosure impedance controlled endometrial ablation system in treating the intrauterine disease]. AB - OBJECTIVE: To explore the feasibility, safety and effectiveness of treatment by Novasure system in abnormal uterine bleeding caused by endometrial polyps (AUB-P) or uterine leiomyomas up to 3 cm (AUB-LSM). METHODS: From June 2011 to June 2012, 30 women with abnormal uterine bleeding caused by AUB-P and AUB-LSM were treated by NoveSure system. The clinical efficacies and complications were followed up at months 1, 3, 6, 12. RESULTS: All operations were completed successfully. The mean operative duration was (84 +/- 6) (60-120) s. The volume of blood loss was <10 ml. And the follow-up period was 1, 3, 6 and 12 months. The effective rate was 100% (30/30), 96.67% (29/30), 93.33% (28/30) and 96.67% (29/30) respectively. The rate of amenorrhea was 76.67% (23/30), 70% (21/30), 70% (21/30) and 76.67% (23/30) respectively. The degrees of satisfaction were 100% (30/30), 96.67% (29/30), 96.67% (29/30) and 96.67% (29/30).No severe perioperative or postoperative complications occurred. CONCLUSION: Navosure system is both safe and efficacious for abnormal uterine bleeding caused by AUB-P and AUB-LSM. And it is worth wider popularization. PMID- 25916928 TI - [Clinical study of 16 cases of villoglandular adenocarcinoma of uterine cervix]. AB - OBJECTIVE: To explore the clinicopathologic features, managements and outcomes of villoglandular adenocarcinoma (VA) of uterine cervix. METHODS: From June 2009 to January 2014, a total of 16 cases of VA were reviewed retrospectively. RESULTS: Their mean age was 41.4 (30-56) years. The major symptoms were post-coital hemorrhage or abnormal vaginal hemorrhage (10/16). And the International Federation of Gynecology and Obstetrics (FIGO) stages were Ia1 (n = 1),Ib1 (n = 12),Ib2 (n = 2) and IIa1 (n = 1).One patient of Ia1 stage underwent laparoscopic total hysterectomy and bilateral salpingo-oophorectomy (BSO) after conization; one patient of Ib1 stage total abdominal hysterectomy and BSO after radiotherapy and concurrent chemotherapy while another one of Ib1 stage radical vaginal trachelectomy; one pregnancy-associated patient of Ib1 stage was diagnosed at 12 weeks' gestation and underwent cesarean radical hysterectomy plus pelvic lymphadenectomy after four courses of chemotherapy. Aand the remainder underwent radical hysterectomy plus pelvic lymphadenectomy.None of 14 cases with a known status of lymph node status had positive nodes. And 1/13 cases undergoing ovariectomy had pathologically confirmed cervical cancer metastasis of ovarian surface and the remainder and another patient of ovarian biopsy had negative results for lymph nodes. The median follow-up period was 23.3 (5-60) months. All patients survived and there was one recurrent case of vaginal stump mass at 8 months after initial surgery. The overall and disease-free 5-year survival was 100% and 94% (15/16) respectively. CONCLUSION: VA mainly affects younger women and prognosis is generally fair with a lower rate of ovarian metastasis compared to common forms of cervical cancer. Due to a limited sample size and clinical data are studied retrospectively, multi-center prospective studies are warranted for a better understand of this disease. PMID- 25916929 TI - [Association between glucose variability and poor prognosis in critically ill patients]. AB - OBJECTIVE: To explore the association between glucose variability and poor prognosis in critically ill patients. METHODS: This prospective study was undertaken in a 24-bed intensive care unit (ICU). A total of 145 patients staying for over 24 hours in ICU were enrolled. Their arterial levels of blood glucose were measured four times daily routinely. And the mean glucose level (MGL), standard deviation (SD) and coefficient of variation (CV) were calculated. The incidence of moderate hypoglycemia (MH), severe hypoglycemia (SH), total dosage of hormone, average daily dosage of insulin, duration of renal replacement- therapy (RRT), mechanical ventilation and ICU free days were also recorded. They were divided into survival (n = 85) and nonsurvival (n = 60) groups according to survival or not at 28 days. And CV was compared between two groups and the relationship of CV and mortality examined. RESULTS: The nonsurvival group had higher CV value accompanied by higher RRT proportion, higher incidences of MH and SH, shorter free mechanical ventilation time and free ICU stay. The higher CV value was found in surviving nondiabetics. However, no significant difference existed in diabetes group. CONCLUSION: Critically ill patients have higher CV of glucose variability especially in non-diabetic patients. Blood glucose fluctuations denote a worse prognosis. And hypoglycemia should raise a high alert. Frequent blood glucose monitoring is beneficial to detecting the changes of condition and adjusting treatment regimens accordingly. PMID- 25916930 TI - [Application of B-ultrasound monitoring plus gastric insufflation for nasointestinal tube indwelling in critical neurosurgical patients]. AB - OBJECTIVE: To explore the application of B-ultrasound monitoring plus gastric insufflation for nasointestinal tube indwelling in critical neurosurgical patients. METHODS: A total of 96 critical comatose neurosurgical patients indicated for nasointestinal tube indwelling were randomized into three groups of routine (A, n = 32), gastric insufflation (B, n = 31) and B-ultrasound monitoring plus gastric insufflation (C, n = 33). And the position of nasointestinal tube was observed within 24 h and at 72 h in three groups. RESULTS: The general profiles of three groups showed no significant differences (P > 0.05). The proportions of nasointestinal tube passing pylorus within 24 h in three groups were 43.8%, 74.2% and 93.9% respectively. Comparing group C with groups A and B, the differences presented statistical significance. The proportions of nasointestinal tube passing pylorus at 72 h in three groups were 68.8%, 83.9% and 100% respectively. Comparing group C with groups A and B, the differences had statistical significance. CONCLUSION: Refined method of nasointestinal tube indwelling and B-ultrasound monitoring may boost the rate of successful indwelling.It is worth wider promotion and application. PMID- 25916931 TI - [Levels of autoantibodies against AT1-receptor in hypertensive patients with acute coronary syndromes and its role in coronary artery vasoconstriction]. AB - OBJECTIVE: To explore the levels of autoantibodies against AT1-receptor (AT1-AA) in hypertensive patients with acute coronary syndrome (ACS) and observe the in vitro effects of AT1-AA on resting tension of isolated anterior descending artery of vascular ring in male Wistar rats. METHODS: All patients were recruited from June 2007 to August 2008. There were hypertensive patients with ACS (n = 120), those with simple hypertension (n = 253) and those with simple ACS (n = 115). And the outpatients for health examination during the same period were selected as healthy control group (n = 188). The second extracellular loop amino acid sequences of peptides of ATI receptor was synthesized and used as antigen (AT1 Ag) and sialic acid-enzyme-linked immunosorbent assay (SA-ELISA) for detect the serum levels of AT1-AA. Microvascular ring tension technology was used to test the vascular loop resting tension of anterior descending coronary artery from rats induced by a high-fat diet. RESULTS: The positive rates of AT1-AA in patients with simple hypertension (35.2%) and those with simple ACS (30.4%) were significantly higher than those in healthy control group (7.2%, P < 0.01). And the positive rate of AT1-AA in hypertensive patients with ACS (43.3%) was significantly higher than that in those with simple hypertension (35.2%, P < 0.05) and that in healthy control group (7.2%, P < 0.05).Furthermore, AT1-AA increased the vascular loop resting tension of anterior descending coronary artery rings in rats induced by a high-fat diet in a dose-dependant manner. And the vasoconstrictive action of AT1-AA was equal to 46.4% of AngII's action. And such an action was blocked by losartan and antigens. CONCLUSION: The level of AT1 AA increases markedly in hypertensive patients with ACS. And AT1-AA induces vasoconstrictive effects on anterior descending artery rings in rats induced by a high-fat diet. PMID- 25916932 TI - [Comparison study of small peripheral intrahepatic cholangiocarcinoma with computed tomographic and pathological findings]. AB - OBJECTIVE: To explore the computed tomographic (CT) and pathological findings of small intrahepatic cholangiocarcinoma and improve its understanding. METHODS: A total of 20 patients with bile duct non-dilatation peripheral small intrahepatic cholangiocarcinoma were retrospectively analyzed. All of them were examined by plain and enhanced CT and pathological studies. RESULTS: CT plain scan:there were 15 cases of low-density lesions with fibers and necrotic tissue and surviving tumor tissue in peripheral or central portions. There were 4 cases of lesions with mixed high and low densities. Abundant necrotic tissues were found with a rare vascular distribution.Or abundant fibers and connective tissues around tumor were manifested as hardened cholangiocarcinoma.One lesion showed equal density with abundant necrotic tissue and fibrous connective tissue with peripheral tumor tissue; dynamic contrast-enhanced CT: (1) there were 6 cases of lesion with peripheral thin ring-enhanced and tumor margin of viable tumor tissue. And internal tumor was fibrous tissue; (2) there were 7 cases of lesions with peripheral thick ring-enhanced and enhanced portion was surviving tumor tissue, no enhanced central portion was mainly necrotic tissue mixed with little fibrous tissue; (3) there were 2 cases of whole tumors without enhancement. There were significant hemorrhage and necrosis with few surviving tumor cells in tumor and normal liver tissue; (4) there were 5 cases of lesions with heterogeneous enhancement and the heterogeneous enhancement portion was surviving tumor tissue and little fibrous connective tissue. And some necrotic tissue remained; (5) only one case had overall enhancement of same-sized tumor cells without necrosis. CONCLUSION: CT scanning of peripheral small cholangiocarcinoma lacks distinguishing characteristics. However the findings of contrast-enhanced CT have certain characteristics. Due to different pathological types, each attribute has corresponding characteristic with different pathological features. PMID- 25916933 TI - [Magnetic resonance evaluations of correlation of iron overload and osteoporosis in ovariectomized rats]. AB - OBJECTIVE: To explore the correlation between liver T(2)(*) value and bone mineral density (BMD) in ovariectomized (OVX) rats. METHODS: A total of 60 rats, including sham (n = 25) and OVX (n = 35) groups, underwent dual-energy X-ray absorptiometry (DEXA) and liver magnetic resonance (MR)-T(2)(*) mapping for lumbar vertebra BMD and T(2)(*) values before and after operation monthly for 4 timepoints. Also micro-computed tomography (micro-CT) and biochemical measurements were performed. The sensitivity of liver T(2)(*) relaxation time detecting early osteoporosis were estimated and the correlation between liver T(2)(*) values and BMD analyzed. RESULTS: BMD of lumber vertebra in OVX group decreased compared to control group at Month 2 postoperation ((554 +/- 27) mg/cm3 vs (722 +/- 19) mg/cm3, P < 0.05) in synchrony with an elevation of serum ferritin concentration ((521 +/- 41) ng/ml vs (441 +/- 29) ng/ml, P < 0.01) and liver iron concentration ((291 +/- 18) ug/g vs (237 +/- 27) ug/g, P < 0.01). A significant inter-group difference of liver T(2)(*) was detected at Month 1 postoperation ((13.2 +/- 0.7) ms vs (13.9 +/- 0.4) ms, P < 0.01). Liver T(2)(*) was significant positively correlated with BMD in sham group (r = 0.410, P < 0.01) and OVX group (r = 0.434, P < 0.01). CONCLUSION: Liver T(2)(*) relaxation time may a valuable detection tool of assessing pathophysiological changes of osteoporosis in early stage. PMID- 25916934 TI - [Application values of 64-row computed tomographic angiography in diagnosing liver VX2 tumor in rabbits]. AB - OBJECTIVE: To evaluate the diagnostic values of computed tomographic angiography (CTA) for liver VX2 tumor in rabbits. METHODS: A total of 40 New Zealand white rabbits were employed by implanting tumor fragment into left liver by computed tomography (CT)-guided percutaneous puncture. And successful modeling was established in 38 rabbits. Plain and three-phase enhanced CT scan and its CTA reconstruction were performed in different stages (14, 21 and 28 days) after tumor implantation, followed by digital subtraction angiography (DSA) via femoral artery and hepatic artery. Dynamic observations of tumor growth characteristics were recorded by plain and enhanced CT and comparing CTA and DSA images. And comparisons of CTA and DSA were made for identifying the origin, course and blood supply of transplanted tumors. RESULTS: (1) Multi-slice computed tomography (MSCT) could dynamically monitor the growth transfer characteristics. And all tumors became strengthened obviously in arterial phase and washed out in venous and delayed phases. (2) CTA showed that the feeding artery of transplanted tumor was hepatic artery. (3) No obvious differences existed in the display of feeding artery of transplanted tumor between CTA and DSA.However CTA was superior to DSA in displaying three-dimensional structure. CONCLUSION: Liver VX2 tumors are hypervascular in rabbits. CT enhanced scanning may dynamically monitor the growth patterns of tumors and CTA is a better method than DSA in visualizing the feeding arteries of tumors. Before and after interventions, CTA may replace DSA in evaluating liver VX2 tumors in rabbits. PMID- 25916935 TI - The broad diversity of heme-protein cross-links: An overview. AB - Heme proteins perform a large array of biological functions using the same heme cofactor. A primary method of regulating these diverse functions is the heme protein cross-link, an important post-translational modification. This review presents an overview of the broad diversity of heme-protein cross-links, including Cys/SeCys -heme, Met-heme, His-heme, Trp/Tyr-heme, Glu/Asp-heme and Lys heme cross-links, which have been discovered in the last three decades, with bond type ranging from C-S, C-Se, C-N, C-C to C-O. Many advances have been made in revealing the mechanisms of heme-protein cross-link formation, as well as the structural and functional roles. Moreover, most of these cross-links have been successfully recreated in natural or de novo proteins. These tremendous progresses have not only enhanced our knowledge of how cross-links fine-tune the structure and function of natural heme proteins, but also provided us powerful strategies for design of artificial heme proteins with functionalities beyond those of natural heme proteins. PMID- 25916937 TI - Demonstration of ameliorative effect of lacosamide: in a rat model of sepsis induced critical illness polyneuropathy. AB - OBJECTIVES: Critical illness neuropathy (CIN) is a condition that may occur in diseases with severe systemic response, particularly in sepsis. The aim of this study is to investigate the potential anti-inflammatory and lipid-peroxidation inhibiting activities of lacosamide by measuring tumour necrotizing factor-alpha (TNF-alpha), C-reactive protein (CRP), malondialdehyde (MDA) and white blood cells (WBC) using electroneuromyography (ENMG) in rats with sepsis-induced critical illness neuropathy (SICIN). METHODS: Cecal ligation and puncture (CLP) procedure was performed on 39 rats to induce a sepsis model. The study groups were designed as follows: Group 1: normal (nonoperative); Group 2: (sham operated); Group 3: CLP (untreated group); Group 4: CLP and lacosamide 20 mg/kg; Group 5: CLP and lacosamide 40 mg/kg. TNF-alpha, C reactive protein, MDA and WBC levels was measured and compound muscle action potential (CMAP) distal latans, amplitudes were measured by using ENMG in rats with SICIN. RESULTS: When untreated sepsis group was compared with both control and sham groups, CMAP amplitudes and latans were significantly lower (P < 000.1). When CLP, CLP+lacosamide 20 mg/kg and CLP+lacosamide 40 mg/kg groups were compared, plasma levels of TNF-alpha and MDA were significantly higher in the untreated CLP group (F = 12.74, P < 0.0001), (F = 19.43, P < 0.05). In the CLP+lacosamide 40 mg/kg group, CRP levels were significantly lower only compared to the CLP group (P < 0.001). DISCUSSION: We have showed that lacosamide may have beneficial effects on early SICIN by its potential anti-inflammatory and lipid peroxidation inhibiting activities; however, further comprehensive studies are required to clarify these effects. PMID- 25916936 TI - Neurochondrin is an atypical RIIalpha-specific A-kinase anchoring protein. AB - Protein kinase activity is regulated not only by direct strategies affecting activity but also by spatial and temporal regulatory mechanisms. Kinase signaling pathways are coordinated by scaffolding proteins that orchestrate the assembly of multi-protein complexes. One family of such scaffolding proteins are the A-kinase anchoring proteins (AKAPs). AKAPs share the commonality of binding cAMP-dependent protein kinase (PKA). In addition, they bind further signaling proteins and kinase substrates and tether such multi-protein complexes to subcellular locations. The A-kinase binding (AKB) domain of AKAPs typically contains a conserved helical motif that interacts directly with the dimerization/docking (D/D) domain of the regulatory subunits of PKA. Based on a pull-down proteomics approach, we identified neurochondrin (neurite-outgrowth promoting protein) as a previously unidentified AKAP. Here, we show that neurochondrin interacts directly with PKA through a novel mechanism that involves two distinct binding regions. In addition, we demonstrate that neurochondrin has strong isoform selectivity towards the RIIalpha subunit of PKA with nanomolar affinity. This article is part of a Special Issue entitled: Inhibitors of Protein Kinases. PMID- 25916938 TI - MicroRNA-155 aggravates ischemia-reperfusion injury by modulation of inflammatory cell recruitment and the respiratory oxidative burst. AB - The inflammatory sequelae of ischemia-reperfusion injury (IRI) are a major causal factor of tissue injury in various clinical settings. MicroRNAs (miRs) are short, non-coding RNAs, which regulate protein expression. Here, we investigated the role of miR-155 in IR-related tissue injury. Quantifying microRNA-expression levels in a human muscle tissue after IRI, we found miR-155 expression to be significantly increased and to correlate with the increased expression of TNF alpha, IL-1beta, CD105, and Caspase3 as well as with leukocyte infiltration. The direct miR-155 target gene SOCS-1 was downregulated. In a mouse model of myocardial infarction, temporary LAD ligation and reperfusion injury resulted in a smaller area of necrosis in miR-155-/- animals compared to wildtype animals. To investigate the underlying mechanisms, we evaluated the effect of miR-155 on inflammatory cell recruitment by intravital microscopy and on the generation of reactive oxygen species (ROS) of macrophages. Our intravital imaging results demonstrated a decreased recruitment of inflammatory cells in miR-155-/- animals during IRI. The generation of ROS in leukocytic cells of miR-155-/- animals was also reduced. RNA silencing of the direct miR-155 target gene SOCS-1 abrogated this effect. In conclusion, miR-155 aggravates the inflammatory response, leukocyte infiltration and tissue damage in IRI via modulation of SOCS-1 dependent generation of ROS. MiR-155 is thus a potential target for the treatment or prevention of IRI. PMID- 25916939 TI - Phytoestrogens and mycoestrogens in surface waters--Their sources, occurrence, and potential contribution to estrogenic activity. AB - This review discusses the potential contribution of phytoestrogens and mycoestrogens to in vitro estrogenic activities occurring in surface waters and in vivo estrogenic effects in fish. Main types, sources, and pathways of entry into aquatic environment of these detected compounds were summarized. Reviewed concentrations of phyto/mycoestrogens in surface waters were mostly undetectable or in low ng/L ranges, but exceeded tens of MUg/L for the flavonoids biochanin A, daidzein and genistein at some sites. While a few phytosterols were reported to occur at relatively high concentrations in surface waters, information about their potencies in in vitro systems is very limited, and contradictory in some cases. The relative estrogenic activities of compounds (compared to standard estrogen 17beta-estradiol) by various in vitro assays were included, and found to differ by orders of magnitude. These potencies were used to estimate total potential estrogenic activities based on chemical analyses of phyto/mycoestrogens. In vivo effective concentrations of waterborne phyto/mycoestrogens were available only for biochanin A, daidzein, formononetin, genistein, equol, sitosterol, and zearalenone. The lowest observable effect concentrations in vivo were reported for the mycoestrogen zearalenone. This compound and especially its metabolites also elicited the highest in vitro estrogenic potencies. Despite the limited information available, the review documents low contribution of phyto/mycoestrogens to estrogenic activity in vast majority of surface waters, but significant contribution to in vitro responses and potentially also to in vivo effects in areas with high concentrations. PMID- 25916940 TI - Can polychlorinated biphenyl (PCB) signatures and enantiomer fractions be used for source identification and to age date occupational exposure? AB - Detailed polychlorinated biphenyl (PCB) signatures and chiral Enantiomer Fractions (EFs) of CB-95, CB-136 and CB-149 were measured for 30 workers at a transformer dismantling plant. This was undertaken to identify sources of exposure and investigate changes to the PCB signature and EFs over different exposure periods. Approximately 1.5 g of serum was extracted and PCB signatures were created through analysis by comprehensive two-dimensional gas chromatography with time-of-flight mass spectrometry (GC*GC-TOFMS) and EFs calculated following analysis by gas chromatography with high resolution mass spectrometry (GC-HRMS). A total of 84 PCBs were identified in the serum samples with concentrations of the 7 indicator PCBs ranging from 11-350 ng g(-1) of serum (1.2-39 MUg g(-1) lipid). The PCB signatures were interpreted using principal component analysis (PCA) which was able to distinguish workers with background or recent minimal exposure from those with prolonged occupational exposure. Occupationally exposed individuals had a similar PCB profile to Aroclor A1260. However, individuals with prolonged exposure had depleted proportions of several PCB congeners that are susceptible to metabolism (CB-95, CB-101 and CB-151) and elevated proportions of PCBs that are resistant to metabolism (CB-74, CB-153, CB-138 and CB-180). The results also identified a third group of workers with elevated proportions of CB 28, CB-60, CB-66, CB-74, CB-105 and CB-118 who appeared to have been exposed to an additional source of PCBs. The results show near complete removal of the CB-95 E2 enantiomer in some samples, indicating that bioselective metabolism or preferential excretion of one enantiomer occurs in humans. By considering PCB concentrations along with detailed congener specific signatures it was possible to identify different exposure sources, and gain an insight into both the magnitude and duration of exposure. PMID- 25916941 TI - Antitumour action on human glioblastoma A1235 cells through cooperation of bee venom and cisplatin. AB - Cisplatin (cDDP) is one of the most widely used anticancer-drugs in both therapy and research. However, cDDP-resistance is the greatest obstacle for the successful treatment of cancer patients. In the present study, the possible joint anticancer effect of bee venom (BV), as a natural toxin, and cDDP towards human glioblastoma A1235 cells was evaluated. Treatment with BV alone in concentrations of 2.5-30 MUg/ml displayed dose-dependent cytotoxicity towards A1235 cells, as evaluated with different cytotoxicity assays (MTT, Cristal violet and Trypan blue exclusion assay), with an IC50 value of 22.57 MUg/ml based on the MTT results. Furthermore, BV treatment induced necrosis, which was confirmed by typical morphological features and fast staining with ethidium-bromide dye. Pre-treatment with BV induced cell sensitization to cDDP, indicating that BV could improve the killing effect of selected cells when combined with cDDP. The isobologram method used to determine the extent of synergism in combining two agents to examine their possible therapeutic effect showed that combined treatment induced an additive and/or synergistic effect towards selected cells depending on the concentration of both. Hence, a greater anticancer effect could be triggered if BV was used in the course of chemotherapy. The obtained results indicate that joint treatment with BV could be useful from the point of minimizing the cDDP concentration during chemotherapy, thus reducing and/or postponing the development of drug resistance. Our data, in accordance with previously reported results, suggests that BV could be used in the development of a new strategy for cancer treatment. PMID- 25916942 TI - The antioxidant and chemical properties of Berberis vulgaris and its cytotoxic effect on human breast carcinoma cells. AB - In this study we evaluated the biological activity of alcoholic and aqueous extracts from the fruit of Berberis vulgaris. The total antioxidant capacity of Berberis was characterized by FRAP, DPPH, Folin-Ciocalteu while the anthocyanins content was measured by pH differential method. Cell viability and apoptotic property were determined by MTT and DNA fragmentation assays, respectively. Alcoholic extract of Berberis was richer in antioxidants and anthocyanins compared to aqueous extract. Although both extracts significantly inhibited proliferation of breast cancer cells (MCF-7); these changes were not observed in normal human breast epithelial cells (MCF10-A). The alcoholic extract was more effective in inducing apoptosis as detected by DNA fragmentation in treated cancer cells. Our results suggest that Berberis has potent antioxidant properties and cytotoxic effects that can induce apoptosis. Therefore, Berberis can potentially be exploited for the development of therapeutics to fight against human breast cancer. PMID- 25916943 TI - Gradual-order enhanced stability: a frozen section of electrospun nanofibers for energy storage. AB - A combination of electrospinning and a frozen section has been used to gradually lower the scale of the active materials, thus effectively avoiding nano-reunion, to a certain extent, during electrode fabrication. The as-fabricated electrode based supercapacitor possesses high electrochemical capacitance and good stability. Our results demonstrate a universal top-down route for the controllable fabrication of homodisperse nanoparticle electrodes for use in high performance electrochemical devices. PMID- 25916944 TI - Moving epithelia: Tracking the fate of mammalian limbal epithelial stem cells. AB - Lineage tracing allows the destiny of a stem cell (SC) and its progeny to be followed through time. In order to track their long-term fate, SC must be permanently marked to discern their distribution, division, displacement and differentiation. This information is essential for unravelling the mysteries that govern their replenishing activity while they remain anchored within their niche microenvironment. Modern-day lineage tracing uses inducible genetic recombination to illuminate cells within embryonic, newborn and adult tissues, and the advent of powerful high-resolution microscopy has enabled the behaviour of labelled cells to be monitored in real-time in a living organism. The simple structural organization of the mammalian cornea, including its accessibility and transparency, renders it the ideal tissue to study SC fate using lineage tracing assisted by non-invasive intravital microscopy. Despite more than a century of research devoted to understanding how this tissue is maintained and repaired, many limitations and controversies continue to plague the field, including uncertainties about the specificity of current SC markers, the number of SC within the cornea, their mode of division, their location, and importantly the signals that dictate cell migration. This communication will highlight historical discoveries as well as recent developments in the corneal SC field; more specifically how the progeny of these cells are mobilised to replenish this dynamic tissue during steady-state, disease and transplantation. Also discussed is how insights gleaned from animal studies can be used to advance our knowledge of the fundamental mechanisms that govern modelling and remodelling of the human cornea in health and disease. PMID- 25916945 TI - Inhibition of Bcl-2 or IAP proteins does not provoke mutations in surviving cells. AB - Chemotherapy and radiotherapy can cause permanent damage to the genomes of surviving cells, provoking severe side effects such as second malignancies in some cancer survivors. Drugs that mimic the activity of death ligands, or antagonise pro-survival proteins of the Bcl-2 or IAP families have yielded encouraging results in animal experiments and early phase clinical trials. Because these agents directly engage apoptosis pathways, rather than damaging DNA to indirectly provoke tumour cell death, we reasoned that they may offer another important advantage over conventional therapies: minimisation or elimination of side effects such as second cancers that result from mutation of surviving normal cells. Disappointingly, however, we previously found that concentrations of death receptor agonists like TRAIL that would be present in vivo in clinical settings provoked DNA damage in surviving cells. In this study, we used cell line model systems to investigate the mutagenic capacity of drugs from two other classes of direct apoptosis-inducing agents: the BH3-mimetic ABT-737 and the IAP antagonists LCL161 and AT-406. Encouragingly, our data suggest that IAP antagonists possess negligible genotoxic activity. Doses of ABT-737 that were required to damage DNA stimulated Bax/Bak-independent signalling and exceeded concentrations detected in the plasma of animals treated with this drug. These findings provide hope that cancer patients treated by BH3-mimetics or IAP antagonists may avoid mutation related illnesses that afflict some cancer survivors treated with conventional DNA-damaging anti-cancer therapies. PMID- 25916946 TI - Bringing light into the dark triplet space of molecular systems. AB - A molecule or a molecular system always consists of excited states of different spin multiplicities. With conventional optical excitations, only the (bright) states with the same spin multiplicity of the ground state could be directly reached. How to reveal the dynamics of excited (dark) states remains the grand challenge in the topical fields of photochemistry, photophysics, and photobiology. For a singlet-triplet coupled molecular system, the (bright) singlet dynamics can be routinely examined by conventional femtosecond pump-probe spectroscopy. However, owing to the involvement of intrinsically fast decay channels such as intramolecular vibrational redistribution and internal conversion, it is very difficult, if not impossible, to single out the (dark) triplet dynamics. Herein, we develop a novel strategy that uses an ultrafast broadband white-light continuum as a excitation light source to enhance the probability of intersystem crossing, thus facilitating the population flow from the singlet space to the triplet space. With a set of femtosecond time-reversed pump-probe experiments, we report on a proof-of-concept molecular system (i.e., the malachite green molecule) that the pure triplet dynamics can be mapped out in real time through monitoring the modulated emission that occurs solely in the triplet space. Significant differences in excited-state dynamics between the singlet and triplet spaces have been observed. This newly developed approach may provide a useful tool for examining the elusive dark-state dynamics of molecular systems and also for exploring the mechanisms underlying molecular luminescence/photonics and solar light harvesting. PMID- 25916947 TI - Salivary duct carcinoma: Treatment, outcomes, and patterns of failure. AB - BACKGROUND: Salivary duct carcinoma is rare, with distinct morphology and behavior. We reviewed our institutional experience with salivary duct carcinoma, aiming to characterize clinical behavior and treatment outcomes. METHODS: All salivary duct carcinomas treated curatively between 1999 and 2010 were reviewed. Overall survival (OS), locoregional control, distant control, and patterns of failure were analyzed. Multivariate analysis identified predictors of OS. RESULTS: Fifty-four patients with salivary duct carcinoma (parotid gland = 49; submandibular gland = 5) were included in the analysis. Fifty-three patients underwent primary surgery, and 48 (89%) received postoperative radiotherapy (RT; median dose = 60 Gy). Median follow-up was 5.7 years. The 5-year OS, locoregional control, and distant control were 43%, 70%, and 48%, respectively. Nine local (6 involving facial nerve), 10 regional, and 28 distant failures were identified. Multiple pathologic involved lymph nodes (pN2b/N2c) predicted reduced OS (hazard ratio [HR] = 3.6; p = .02). CONCLUSION: Distant recurrence is common. Presence of pN2b/N2c disease is associated with reduced OS. Local recurrence frequently involves the facial nerves. (c) 2015 Wiley Periodicals, Inc. Head Neck 38: E820 E826, 2016. PMID- 25916948 TI - The better of two evils? Evidence that children exhibiting continuous conduct problems high or low on callous-unemotional traits score on opposite directions on physiological and behavioral measures of fear. AB - The present study examines whether heterogeneous groups of children identified based on their longitudinal scores on conduct problems (CP) and callous unemotional (CU) traits differ on physiological and behavioral measures of fear. Specifically, it aims to test the hypothesis that children with high/stable CP differentiated on CU traits score on opposite directions on a fear-fearless continuum. Seventy-three participants (M age = 11.21; 45.2% female) were selected from a sample of 1,200 children. Children and their parents completed a battery of questionnaires assessing fearfulness, sensitivity to punishment, and behavioral inhibition. Children also participated in an experiment assessing their startle reactivity to fearful mental imagery, a well-established index of defensive motivation. The pattern of results verifies the hypothesis that fearlessness, assessed with physiological and behavioral measures, is a core characteristic of children high on both CP and CU traits (i.e., receiving the DSM 5 specifier of limited prosocial emotions). To the contrary, children with high/stable CP and low CU traits demonstrated high responsiveness to fear, high behavioral inhibition, and high sensitivity to punishment. The study is in accord with the principle of equifinality, in that different developmental mechanisms (i.e., extremes of high and low fear) may have the same behavioral outcome manifested as phenotypic antisocial behavior. PMID- 25916949 TI - Disordered eating in male athletes: a meta-analysis. AB - We examined the propensity for male athletes to exhibit symptoms of disordered eating. Using meta-analytic techniques, we examined overall effect size, individual effect sizes for specific sport types, standard of athletic competition and diagnostic tools from 31 studies. When all studies were considered as a homogeneous group, male athletes did not have symptoms of disordered eating that were significantly different from non-athletic controls. However, significant moderator effects emerged for sport type and measurement: (a) wrestling reported a greater incidence of disordered eating; and (b) studies that reported data from the Eating Attitudes Test yielded a significantly greater incidence of disordered eating in male athletes compared to non-athletes. Although some sports seem to present a higher risk of disordered eating compared to others, the effects are weak and heterogeneous. We make suggestions for the development of the research area, which has been severely hampered by the diagnostic tools that have been available for the study of men. PMID- 25916950 TI - Computational algorithms to predict Gene Ontology annotations. AB - BACKGROUND: Gene function annotations, which are associations between a gene and a term of a controlled vocabulary describing gene functional features, are of paramount importance in modern biology. Datasets of these annotations, such as the ones provided by the Gene Ontology Consortium, are used to design novel biological experiments and interpret their results. Despite their importance, these sources of information have some known issues. They are incomplete, since biological knowledge is far from being definitive and it rapidly evolves, and some erroneous annotations may be present. Since the curation process of novel annotations is a costly procedure, both in economical and time terms, computational tools that can reliably predict likely annotations, and thus quicken the discovery of new gene annotations, are very useful. METHODS: We used a set of computational algorithms and weighting schemes to infer novel gene annotations from a set of known ones. We used the latent semantic analysis approach, implementing two popular algorithms (Latent Semantic Indexing and Probabilistic Latent Semantic Analysis) and propose a novel method, the Semantic IMproved Latent Semantic Analysis, which adds a clustering step on the set of considered genes. Furthermore, we propose the improvement of these algorithms by weighting the annotations in the input set. RESULTS: We tested our methods and their weighted variants on the Gene Ontology annotation sets of three model organism genes (Bos taurus, Danio rerio and Drosophila melanogaster ). The methods showed their ability in predicting novel gene annotations and the weighting procedures demonstrated to lead to a valuable improvement, although the obtained results vary according to the dimension of the input annotation set and the considered algorithm. CONCLUSIONS: Out of the three considered methods, the Semantic IMproved Latent Semantic Analysis is the one that provides better results. In particular, when coupled with a proper weighting policy, it is able to predict a significant number of novel annotations, demonstrating to actually be a helpful tool in supporting scientists in the curation process of gene functional annotations. PMID- 25916951 TI - Chloroma--an uncommon cause of arthritis. PMID- 25916952 TI - Confounding Factors Should be Considered in Determining the Utility of Platelet Indices for Prediction of Recurrent Pregnancy Loss. PMID- 25916953 TI - Assessment of the Diagnostic Value of Plasma Levels, Activities, and Their Ratios of von Willebrand Factor and ADAMTS13 in Patients with Cerebral Infarction. AB - BACKGROUND AND OBJECTIVES: Raised levels of von Willebrand factor (VWF) and reduced levels of a disintegrin and a metalloproteinase with a thrombospondin type I motif, member 13 (ADAMTS13) activity are associated with thrombosis. We aimed to investigate the relationships between plasma levels of VWF and ADAMTS13, their ratios, and the occurrence of cerebral infarction and to understand the roles of VWF and ADAMTS13 in cerebral infarction. METHODS: Ninety-four patients with cerebral infarction and 103 controls were analyzed. Plasma levels of VWF antigen (VWF: Ag), VWF ristocetin cofactor activity (VWF: Rcof), and VWF collagen binding activity (VWF: CB) were measured by enzyme-linked immunosorbent assay (ELISA). The ADAMTS13 activity (ADAMTS13) was measured with FRETS-VWF73. The relationship between plasma levels and ratios of VWF and ADAMTS13 and the occurrence of cerebral infarction were analyzed. RESULTS: Patients with cerebral infarction displayed higher VWF: Ag and VWF: Rcof levels and lower ADAMTS13, VWF: CB/VWF: Ag, ADAMTS13/VWF: Ag, and ADAMTS13/VWF: Rcof levels compared to controls (P < .01). The highest quartiles of VWF: Ag (odds ratio [OR] = 5.11, 95% confidence interval [CI], 1.49-17.50) and VWF: Rcof (OR = 5.04, 95% CI, 1.62 15.66) and the lowest quartiles of VWF: CB/VWF: Ag (OR = 5.91, 95% CI, 1.95 17.93), ADAMTS13/VWF: Ag (OR = 9.11, 95% CI, 2.49-33.33), and ADAMTS13/VWF: Rcof (OR = 3.73, 95% CI, 1.39-10.03) are associated with cerebral infarction. CONCLUSIONS: An association was found between reduced levels of VWF: CB/VWF: Ag, ADAMTS13/VWF: Ag, and ADAMTS13/VWF: Rcof ratios and cerebral infarction. Our data suggest that increased levels of VWF and reduced levels of ADAMTS13 activity may contribute to the pathogenesis of cerebral infarction. PMID- 25916954 TI - A prospective randomized clinical trial of prescription of full-time versus as desired splint wear for de Quervain tendinopathy. AB - PURPOSE: There is no consensus on the best protocol for splint wear in the non operative management of de Quervain tendinopathy. This study aimed to determine if there is a difference between prescription of strict splint wear compared to selective splint wear in patients with de Quervain tendinopathy. We tested the primary null hypothesis that there is no difference in upper-extremity disability eight weeks after initiating splinting between patients prescribed full-time or as-desired splint wear. Secondary study questions addressed differences in grip strength, pain intensity, and treatment satisfaction. Additionally, we evaluated the influence of psychological factors on disability. METHODS: Eighty-three patients diagnosed with de Quervain tendinopathy were randomly allocated into two different splint-wearing instructions: full-time wear (N = 43) or as-desired wear (N = 40). At enrollment, patients had grip strength measured and completed measures of upper-extremity disability, pain intensity, and psychological distress. An average of 7.5 weeks later, patients returned for a second visit. Analysis was by intention-to-treat and with use of mean imputation for missing data. RESULTS: Fifty-eight patients (70 %; 26 in the full-time cohort and 32 in the as-desired cohort) completed the study. There were no statistically significant differences in disability (p = 0.77), grip strength (p = 0.82), pain intensity (p = 0.36), and treatment satisfaction (p = 0.91) between patients instructed to wear the splint full-time and those instructed to use it as desired. Disability at final evaluation correlated significantly with baseline levels of pain anxiety (p = 0.008), catastrophic thinking (p = 0.001), and symptoms of depression (p < 0.001). The best multivariable linear regression model included symptoms of depression alone and accounted for 32 % of the variability in disability (p < 0.001). CONCLUSION: There is no difference in patient-reported outcomes and grip strength with prescription of full-time or as desired splinting, and patients can wear the splint as they prefer. These results suggest that splinting for de Quervain tendinopathy is palliative at best and strict rest is not disease modifying. PMID- 25916955 TI - Clinical experience with arthroscopically-assisted repair of peripheral triangular fibrocartilage complex tears in adolescents--technique and results. AB - PURPOSE: The purpose of this study was to report our preliminary results after arthroscopically-assisted repair of peripheral triangular fibrocartilage complex (TFCC) tears in adolescent patients. METHODS: All children and adolescents who underwent arthroscopically-assisted repair of a Palmer 1B tear were identified and prospectively evaluated after a mean follow-up of 1.3 years. The postoperative assessment included documentation of clinical parameters, pain score (visual analogue scale, VAS), grip strength and completion of validated outcome scores (Modified Mayo Wrist Score, MMWS; Disabilities of the Arm, Shoulder and Hand Inventory, DASH). A total of 12 patients (four males, eight females) with a mean age of 16.3 years at the time of surgery were evaluated. RESULTS: The mean VAS decreased significantly from 7.0 to 1.7 after the procedure. We observed a significant increase of the MMWS after surgery; however, MMWS was still significantly lower at final follow-up when compared to the contralateral side. A mean postoperative DASH score of 16 indicated an excellent outcome after the procedure. DASH Sports and Work Modules showed fair and good overall outcomes in the short-term, respectively. Grip strength averaged 86 % of the contralateral side at final follow-up, with no significant difference being found between both sides. CONCLUSIONS: Arthroscopically-assisted repair of peripheral TFCC tears in adolescents provided predictable pain relief and markedly improved functional outcome scores. Concomitant pathologies may have to be addressed at the same time to eventually achieve a satisfactory outcome. Sports participation, however, may be compromised in the short-term and should therefore be resumed six months postoperatively. PMID- 25916956 TI - Role of the mevalonate pathway in specific CpG site demethylation on AGEs-induced MMP9 expression and activation in keratinocytes. AB - BACKGROUND: Advanced glycation end products (AGEs) played an important role for the development of diabetic foot. In the present study we tried to show the mevalonate pathway and the key demethylation site(s) in the MMP-9 cis-promoter to the component of MMP-9 by AGEs in keratinocyte. METHOD: Human keratinocyte cell line (HaCaT) cells were exposed to AGE-BSA. The plasmid construction and site directed mutagenesis, dual-luciferase reporter assays, immunoblot, zymography, pull down, bisulfite sequencing PCR analysis and Western blotting were applied. RESULTS: The AGE-BSA could increase and more activate the MMP9 in keratinocyte. The RhoA and ROCK1 also could be activated. These affects were blocked by the simvastatin. Meanwhile, the CpG site at -562 site was largely demethylated with AGE-BSA treatment. The cis-promoter sequences with -562 bp site methylated had a lower activity change, which had a highest expression activity and was decreased by simvastatin. Moreover, site-directed mutagenesis of CpG site (-562 bp) in the recombinant plasmid pCpGL-571 brought more reduction in activity, and the activity of methylated mutation pCpGL-571 remains decreased. CONCLUSION: The cis promoter regions of MMP9 would be methylated by AGE-BSA in keratinocyte through the mevalonate pathway, especially the -562 bp site. PMID- 25916957 TI - microRNA expression in autonomous thyroid adenomas: Correlation with mRNA regulation. AB - The objective of the study was to identify the deregulated miRNA in autonomous adenoma and to correlate the data with mRNA regulation. Seven autonomous adenoma with adjacent healthy thyroid tissues were investigated. Twelve miRNAs were downregulated and one was upregulated in the tumors. Combining bioinformatic mRNA target prediction and microarray data on mRNA regulations allowed to identify mRNA targets of our deregulated miRNAs. A large enrichment in mRNA encoding proteins involved in extracellular matrix organization and different phosphodiesterases were identified among these putative targets. The direct interaction between miR-101-3p and miR-144-3p and PDE4D mRNA was experimentally validated. The global miRNA profiles were not greatly modified, confirming the definition of these tumors as minimal deviation tumors. These results support a role for miRNA in the regulation of extracellular matrix proteins and tissue remodeling occurring during tumor development, and in the important negative feedback of the cAMP pathway, which limits the consequences of its constitutive activation in these tumors. PMID- 25916958 TI - Regulation of NUCB2/nesfatin-1 production in rat's stomach and adipose tissue is dependent on age, testosterone levels and lactating status. AB - Nesfatin-1, which is derived from the NEFA/nucleobindin 2 (NUCB2) precursor, was recently identified as an anorexigenic peptide that is produced in several tissues including the hypothalamus. Currently, no data exist regarding the regulation of NUCB2/nesfatin-1 production in peripheral tissues, such as gastric mucosa and adipose tissue, through different periods of development. The aim of the present work was to study the variations on circulating levels, mRNA expression and tissue content in gastric mucosa and adipose tissue of NUCB2/nesfatin-1 with age and specially in two clue periods of maturation, weaning and puberty. The weaning period affected NUCB2/nesfatin-1 production in gastric tissue. The testosterone changes associated with the initiation of puberty regulated NUCB2/nesfatin-1 production via adipose tissue and gastric NUCB2/nesfatin-1 production. In conclusion, the production of NUCB2/nesfatin-1 by the stomach and adipose tissue fluctuates with age to regulate energy homeostasis during different states of development. PMID- 25916959 TI - A double-blinded randomized multicentre study to investigate the effect of changes in stimulation parameters on sacral nerve stimulation for constipation. AB - AIM: Sacral nerve stimulation (SNS) may be offered to patients with constipation who have failed to improve with conservative treatment. The response to SNS is variable, with a significant loss of efficacy in some patients. An increased frequency of stimulation may improve the efficacy of SNS for faecal incontinence. This study aimed to see if alteration of the pulse width or frequency improved the outcome for those with constipation. METHOD: Eleven patients with constipation currently being treated by SNS were recruited from three centres. They were randomized to five different protocols of stimulation each applied for 5 weeks. Group 1 used standard settings (pulse width 210 MUs, frequency 14 Hz); in the other four groups (Groups 2-5) the pulse width and/or frequency were halved or doubled. Patients and investigators were blinded to the group allocation. RESULTS: The Cleveland Clinic constipation score varied significantly between the five groups. Group 1 achieved the lowest score mean (+/- SD) 13.4 (+/ 4.4) (P = 0.03). The number of digitations per defaecation was the lowest in Group 4, 90 MUs and 14 Hz (P < 0.01). No other variable changed significantly. Standard settings were the most preferred by the recruited patients. CONCLUSION: Alteration of pulse width or frequency of stimulation had no significant effect on the outcome of SNS for constipation. PMID- 25916960 TI - Four lanostane-type triterpenes from the fruiting bodies of mushroom Laetiporus sulphureus var. miniatus. AB - Two new 3,4-seco-lanostane-type triterpenes, named as 15alpha-hydroxy-3,4-seco lanosta-4(28),8,24-triene-3,21-dioic acid (1), 5alpha-hydroxy-3,4-seco-lanosta 4(28),8,24-triene-3,21-dioic acid 3-methyl ester (2), and one new lanostane triterpene 15alpha-acetoxylhydroxytrametenolic acid (3) together with a known one versisponic acid D (4) were isolated from the fruiting bodies of Laetiporus sulphureus var. miniatus. Their structures were determined on the basis of extensive spectroscopic methods and comparison with reported data. All four compounds were evaluated for their cytotoxicities against five human cancer cell lines; however, none exhibited inhibitory effects. PMID- 25916961 TI - Safety and caregiver satisfaction associated with laparoscopic hysterectomy among young patients with intellectual disability. AB - OBJECTIVE: To evaluate the safety of laparoscopic hysterectomy for young patients with intellectual disability and the postoperative satisfaction levels of their caregivers. METHODS: A retrospective analysis was conducted of all patients with intellectual disability who underwent laparoscopic hysterectomy at a center in Thailand between January 5, 2004, and August 31, 2010. Information was retrieved about preoperative, intraoperative, and postoperative characteristics. Caregiver satisfaction levels were assessed 3 months after surgery using a Likert-type scale. RESULTS: The mean age of the 74 included patients was 14.9+/-4.2 years. The cause of intellectual disability was unknown for 30 patients (41%); 22 (30%) had Down syndrome. Total laparoscopic hysterectomy was performed among 66 (89%) patients. No major operative complications were noted. Overall, 72 (97%) caregivers were extremely satisfied with the surgical outcome; the remaining 2 (3%) reported being very satisfied. CONCLUSION: Laparoscopic hysterectomy was safe and had good outcomes among patients with intellectual disability. This procedure might be a feasible option to induce therapeutic amenorrhea among young patients with intellectual disability, especially in countries with limited resources. PMID- 25916962 TI - Polypoid adenocarcinoma of the cervix during pregnancy managed with conservative treatment. PMID- 25916963 TI - Regret following female sterilization in Slovenia. AB - OBJECTIVE: To estimate the regret rate and risk factors for regret among women who have undergone sterilization. METHODS: A retrospective study was conducted among all women who underwent a sterilization procedure at the University Medical Center Maribor, Maribor, Slovenia, in 2008-2012. Identified women were contacted and asked to complete an online questionnaire assessing regret and symptoms associated with depression. RESULTS: Among 714 identified women, 308 (43.1%) completed the questionnaire. Four (1.3%) participants reported regret, and 9 (2.9%) reported that they would not opt for sterilization again, all of whom had post-sterilization problems. Such problems were significantly associated with participants reporting that they would not opt for sterilization again (P=0.003). Additionally, women who would not choose sterilization again had significantly higher scores on the depressive scale used than did those who would undergo sterilization again (P=0.028). CONCLUSION: Few women report regret after tubal sterilization in Slovenia. However, an additional consultation on post sterilization problems and depressive disorder before sterilization might minimize the risk of regret. PMID- 25916964 TI - The increasing trend in preterm birth in public hospitals in northern Argentina. AB - OBJECTIVE: To identify factors associated with the increasing incidence of preterm birth in northern Argentina. METHODS: In an observational study, data were reviewed from a prospective, population-based registry of pregnancy outcomes in six cities in 2009-2012. The primary outcome was preterm birth (at 20-37 weeks). Bivariate tests and generalized estimating equations were used within a conceptual hierarchical framework to estimate the cluster-corrected annual trend in odds of preterm birth. RESULTS: The study reviewed data from 11 433 live births. There were 484 (4.2%) preterm births. The incidence of preterm births increased by 38% between 2009 and 2012, from 37.5 to 51.7 per 1000 live births. Unadjusted risk factors for preterm birth included young or advanced maternal age, normal body mass index, nulliparity, no prenatal care, no vitamins or supplements during pregnancy, multiple gestation, and maternal hypertension or prepartum hemorrhage. The prevalence of many risk factors increased over the study period, but variations in these factors explained less than 1% of the increasing trend in preterm birth. CONCLUSION: The incidence of preterm births in six small cities in northern Argentina increased greatly between 2009 and 2012. This trend was unexplained by the risk factors measured. Other factors should be assessed in future studies. PMID- 25916965 TI - Fertility after ectopic pregnancy in a district hospital in Cameroon. AB - OBJECTIVE: To assess spontaneous conception after an ectopic pregnancy (EP) in a rural area of a low-resource country. METHODS: The present prospective cohort study enrolled patients aged 15-45 years who were treated for EP at Sangmelima District Hospital, Cameroon, between January 2006 and December 2008. All patients who wished to become pregnant in the future were included and followed up from treatment for EP either until termination of a subsequent pregnancy or for 3 years if they did not become pregnant, whichever came first. Patients who were followed up for less than 18 months without a pregnancy were excluded from analysis. RESULTS: The final analysis included 56 women, of whom 23 (41%) became pregnant (21 [38%] had intrauterine pregnancies, 2 [4%] EPs). The mean interval between treatment for EP and first conception was 11.82+/-7.46 months. In multivariate analysis, absence of contralateral adnexal pathology was significantly associated with higher fertility (hazard ratio 9.00, 95% confidence interval 1.48-54.67; P=0.017). CONCLUSION: Fertility after EP in a rural area of Cameroon was found to be low, but recurrence of EP was rare. PMID- 25916966 TI - Metalloproteinases: A parade of functions in matrix biology and an outlook for the future. AB - This issue of Matrix Biology is devoted to exploring how metalloproteinases - here inclusive of related families of extracellular proteinases - act on extracellular matrix (ECM) proteins to influence an astonishing diversity of biological systems and diseases. Since their discovery in the 1960's, matrix metalloproteinases (MMPs) have oft and widely been considered as the principal mediators of ECM destruction. However, as becomes clear from several articles in this issue, MMPs affect processes that both promote and limit ECM assembly, structure, and quantity. Furthermore, it has become increasingly apparent that ECM proteolysis is neither the exclusive function of MMPs nor their only sphere of influence. Thus, other enzymes may be important participants in ECM proteolysis, and indeed they are. The ADAMTS (a disintegrin-like and metalloproteinase domain with thrombospondin type 1 repeat) proteinases, BMP/tolloid proteases, and meprins have all emerged as major mechanisms of ECM proteolysis. An aggregate view of proteolysis as an exquisitely specific and crucial post-translational modification of secreted proteins emerges from these reviews. The cumulative evidence strongly suggests that although some MMPs can and do cleave ECM components, notably fibrillar collagens, the majority of these proteinases are not key physiological participants in morphogenesis nor in control of matrix metabolism in homeostasis or disease. In contrast, deficiency of ADAMTS proteases leads to a remarkable array of morphogenetic defects and connective tissue disorders consistent with a specialized role in turnover of the embryonic provisional ECM and in ECM assembly. Astacin-related proteases emerge into crucial positions in ECM assembly and turnover, although they also have numerous roles related to morphogen and growth factor regulation. To further turn the traditional view on its head, it is clear that many MMPs are key participants in many, diverse immune and inflammation processes rather than ECM proteolysis. The overlap in the activities within and between these families leads to the view that ECM proteolysis, which is indispensable for life, was over-engineered to an extraordinary extent during vertebrate evolution. That these proteinases, which likely evolved within networks regulating morphogenesis, immunity and regeneration, also participate in diseases is a side effect of human longevity. Attempts to inhibit metalloproteinases in human diseases thus require continuing appraisal of their biological roles and cautious evaluation of potential new therapeutic opportunities. PMID- 25916967 TI - Hepatocellular carcinoma first presenting as a tumor of the oral cavity. AB - Hepatocellular carcinoma (HCC) is the sixth most common neoplasm worldwide; HCC metastasis is common affecting 50% of cases. However, metastasis to the oral cavity is extremely infrequent. We present a case of hepatocellular cancer first presenting as a mass lesion at the upper alveolus and review metastatic hepatocellular carcinoma to the oral cavity in 73-year-old male patient. PMID- 25916968 TI - DFT study of zinc, cadmium, mercury, copper, silver, and gold complexes of 21,23 dioxaporphyrin and one-dimensional arrays of those complexes. AB - Complexes of 21,23-dioxaporphyrin with neutral Zn, Cd, Hg, Cu, Ag, and Au atoms as well as some one-dimensional arrays of those complexes containing up to ten repeat units were modeled at the PBE/def2-TZVPP level of theory with D3 empirical dispersion correction. The binding energy between the metal atom and the macrocycle was found to vary from 90 kcal/mol for Cu to -14 kcal/mol for Hg. Strong charge transfer from the metal to the macrocycle accompanied complex formation. The complexes were able to form dimers and nanoarrays that were held together mostly by dispersion forces. Different types of dimers were studied: face-to-face (F) and two types of parallel-displaced ones. F dimers were calculated to be the lowest-energy structures for Cu and Ag systems. Nanoarray formation was studied for these complexes. The band gaps (Eg) of the nanoarrays were found to be smaller than 1 eV, and decreased slightly as the number of repeat units in the nanoaggregates increased. The ionization potentials and electron affinities were greatly affected by the number of repeat units due to the delocalization of polarons over the entire nanoarray. The polaron delocalization and the related reorganization energies depended to a considerable extent on the metal present in the complex. For the studied nanoarrays, the reorganization energies for hole and electron transport decreased linearly with 1/n, where n is the number of repeat units in the nanoaggregate; for an infinitely long chain, the reorganization energy was zero for electron transport and 0.03-0.04 eV for hole transport. PMID- 25916969 TI - Retention Forces between Titanium and Zirconia Components of Two-Part Implant Abutments with Different Techniques of Surface Modification. AB - BACKGROUND: The adhesive connection between titanium base and zirconia coping of two-part abutments may be responsible for the failure rate. A high mechanical stability between both components is essential for the long-term success. PURPOSE: The aim of the present in-vitro study was to evaluate the influence of different surface modification techniques and resin-based luting agents on the retention forces between titanium and zirconia components in two-part implant abutments. MATERIALS AND METHODS: A total of 120 abutments with a titanium base bonded to a zirconia coping were investigated. Two different resin-based luting agents (Panavia F 2.0 and RelyX Unicem) and six different surface modifications were used to fix these components, resulting in 12 test groups (n = 10). The surface of the test specimens was mechanically pretreated with aluminium oxide blasting in combination with application of two surface activating primers (Alloy Primer, Clearfil Ceramic Primer) or a tribological conditioning (Rocatec), respectively. All specimens underwent 10,000 thermal cycles between 5 degrees C and 55 degrees C in a moist environment. A pull-off test was then conducted to determine retention forces between the titanium and zirconia components, and statistical analysis was performed (two-way anova). Finally, fracture surfaces were analyzed by light and scanning electron microscopy. RESULTS: No significant differences were found between Panavia F 2.0 and RelyX Unicem. However, the retention forces were significantly influenced by the surface modification technique used (p < 0.001). For both luting agents, the highest retention forces were found when adhesion surfaces of both the titanium bases and the zirconia copings were pretreated with aluminium oxide blasting, and with the application of Clearfil Ceramic Primer. CONCLUSION: Surface modification techniques crucially influence the retention forces between titanium and zirconia components in two part implant abutments. All adhesion surfaces should be pretreated by sandblasting. Moreover, a phosphate-based primer serves to enhance long-term retention of the components. PMID- 25916970 TI - Prognostic factors for second recurrence after surgical resection of recurrent desmoid-type fibromatosis. AB - The optimal management of recurrent desmoid-type fibromatosis is undefined. This study was performed to determine what factors, if any, predict second recurrence after surgical resection of recurrent desmoid tumors. Of 41 patients with recurrent desmoid-type fibromatosis, 29 underwent surgical resection and 8 were followed by observation. Four others received adjuvant chemo/pharmacotherapy. Clinicopathologic features were assessed as prognostic factors for second recurrence after surgical resection of recurrent desmoid tumors by Cox proportional hazards regression. Nine of 29 patients who underwent surgical resection of recurrent desmoid tumor developed a second recurrence. Larger size of recurrent tumor was associated with increased risk of second recurrence (hazard ratio, 1.09; P = 0.006). Treatment of the primary tumor with adjuvant radiation therapy also increased risk of re-recurrence (3.41; P = 0.032). Second recurrence of desmoid-type fibromatosis after surgical resection is, much like recurrence of primary desmoid tumor, difficult to predict with current prognostic indicators. PMID- 25916971 TI - The Association, the Journal and the Publisher: a symbiotic relationship. PMID- 25916972 TI - Systemic physiology and neuroapoptotic profiles in young and adult rats exposed to surgery: A randomized controlled study comprising four different anaesthetic techniques. AB - BACKGROUND: Experimental evidence indicates that general anaesthetics can induce apoptotic neurodegeneration in the developing brain. The majority of these studies have been performed in the absence of surgery and it currently remains unclear how the presence of surgical stimuli would influence neuroapoptosis as well as systemic homeostasis. Here we explored this possibility by performing dorsal skin flap surgery in young and adult rats under four distinct currently used anaesthesia regimens. METHODS: Young (21-days) and adult (2 months) male Sprague-Dawley rats were randomized to 150 min exposure to one of four anaesthetics regimens: (i) sevoflurane/dexmedetomidine, (ii) sevoflurane/fentanyl; (iii) propofol/dexmedetomidine, and (iv) propofol/fentanyl. Animals underwent a dorsal skin flap procedure while physiologic, metabolic and biochemical parameters were closely monitored. Neuroapoptotic profiles were evaluated in the cortex, thalamus and hippocampus (CA1 and CA3) at the end of the procedure in each experimental group. RESULTS: Significant perturbations of systemic homeostasis were found under all anaesthetic regimens. Hyperglycemia and decreased heart rate were particularly relevant in experimental groups receiving dexmedetomidine, while propofol administration was associated with increased systemic lactate levels and metabolic acidosis. A substantial difference in anaesthesia/surgery-induced neuroapoptosis was found between young and adult rats in several brain regions. Combination of sevoflurane and dexmedetomidine resulted in the highest number of caspase-3 positive cells, although the extent of cell death remained relatively low in all experimental groups. CONCLUSION: Combination of anaesthesia and surgery induces significant perturbations of physiological parameters in both young and adult spontaneously breathing rats undergoing surgery. These observations further enlighten the need for detailed physiological monitoring under these experimental conditions. Although some statistically significant differences in activated caspase-3 profiles were detected between experimental groups, the overall extent of neuronal cell death remained very low under all conditions questioning, thereby, the physiological significance of apoptotic neurodegeneration in the context of anaesthesia and surgery. PMID- 25916973 TI - Study of the serum levels of polyunsaturated fatty acids and the expression of related liver metabolic enzymes in a rat valproate-induced autism model. AB - To investigate whether the decreased level of serum polyunsaturated fatty acids (PUFAs) in patients with autism is associated with the expression of related liver metabolic enzymes, we selected rats that were exposed to valproic acid (VPA) on embryonic day 12.5 (E12.5) as a model of autism. We observed the serum levels of PUFAs and the expression of related liver metabolic enzymes, including Delta5-desaturase, Delta6-desaturase and elongase (Elovl2), in VPA-exposed and control rats on postnatal day 35 (PND35) and conducted sex dimorphic analysis. We found that the levels of serum PUFAs and related liver metabolic enzymes in the VPA rats were significantly reduced, in association with autism-like behavioral changes, the abnormal expression of apoptosis-related proteins and hippocampal neuronal injury, compared to the control rats and showed sex difference in VPA group. This finding indicated that rats exposed to VPA at the embryonic stage may exhibit reduced synthesis of serum PUFAs due to the down-regulation of liver metabolic enzymes, thereby inducing nervous system injury and behavioral changes, which is affected by sex in the meantime. PMID- 25916974 TI - Crown-shaped tungstogermanates as solvent-controlled dual systems in the formation of vesicle-like assemblies. AB - Reaction of early lanthanides, GeO2 , and Na2 WO4 in a NaOAc buffer results in large crown-shaped polyoxometalates based on [Ln2 GeW10 O38 ](6-) subunits. By using Ni(2+) as a crystallizing agent, [Na?Ln12 Ge6 W60 O228 (H2 O)24 ](35-) (Na?Ln12 ) hexamers formed by alternating beta(1,5)/beta(1,8) subunits were obtained for Ln=Pr, Nd. The addition of K(+) led to a similar anion for Ln=Sm, namely, [K?Sm12 Ge6 W60 O228 (H2 O)22 ](35-) (K?Sm12 ) and [K?K7 Ln24 Ge12 W120 O444 (OH)12 (H2 O)64 ](52-) (K?Ln24 ) dodecamers that consist of a central core identical to K?Sm12 decorated with six external gamma(3,4) subunits for Ln=Pr, Nd. These anions dissociate in water into hexameric cores and monomeric entities, as shown by ESI mass spectrometry. The former self-assemble into spherical, hollow, and single-layered blackberry-type structures with radii of approximately 75 nm, as monitored by laser light scattering (LLS) and TEM techniques. Analogous studies performed for K?Nd24 in water/acetone mixtures show that the dodecamers remain stable and form in turn their own type of blackberries with sizes that increase from approximately 20 to 50 nm with increasing acetone content. This control over both the composition and size of the vesicle-like assemblies is achieved for the first time by modifying the architecture of the species that undergoes supramolecular association through the solvent polarity. PMID- 25916975 TI - Early medical abortion without prior ultrasound. AB - OBJECTIVE: To explore the potential for using last menstrual period (LMP) rather than ultrasound to establish gestational age (GA) eligibility for medical abortion. STUDY DESIGN: We used the results of a recently published systematic review to identify studies with data on the number of abortion patients with GA more than 63 or 70 days by ultrasound but less than those or other specific limits by LMP. We analyzed data from these studies to estimate the proportion of women with GAs greater than 63 or 70 days by ultrasound in various subgroups of women defined by LMP. RESULTS: We found three studies with relevant data. One enrolled 4257 medical abortion patients of whom 4% had GAs of >70 days by ultrasound. Of the 2681 who were certain that their LMPs began no more than 56 days prior, only 16 (0.6%) were >70 days by ultrasound. In a second much smaller study of surgical abortion patients, of whom 19% were >70 days by ultrasound, 90 women were certain that their LMPs started more than 56 days prior, and of those, 7 (7.8%) had GAs of >70 days by ultrasound. In the third study, which included surgical abortion patients with a mean GA of 61 days, at least 12% of the 138 patients with LMPs <63 days prior were >70 days by ultrasound. CONCLUSION: The possibility that access to medical abortion can be enhanced for selected women by omitting the requirement for a screening ultrasound is promising and should be further investigated. IMPLICATIONS: Gestational dating using LMP rather than ultrasound may be reasonable for selected patients before medical abortion. PMID- 25916976 TI - Efficient and equitable design of marine protected areas in Fiji through inclusion of stakeholder-specific objectives in conservation planning. AB - The efficacy of protected areas varies, partly because socioeconomic factors are not sufficiently considered in planning and management. Although integrating socioeconomic factors into systematic conservation planning is increasingly advocated, research is needed to progress from recognition of these factors to incorporating them effectively in spatial prioritization of protected areas. We evaluated 2 key aspects of incorporating socioeconomic factors into spatial prioritization: treatment of socioeconomic factors as costs or objectives and treatment of stakeholders as a single group or multiple groups. Using as a case study the design of a system of no-take marine protected areas (MPAs) in Kubulau, Fiji, we assessed how these aspects affected the configuration of no-take MPAs in terms of trade-offs between biodiversity objectives, fisheries objectives, and equity in catch losses among fisher stakeholder groups. The achievement of fisheries objectives and equity tended to trade-off concavely with increasing biodiversity objectives, indicating that it is possible to achieve low to mid range biodiversity objectives with relatively small losses to fisheries and equity. Importantly, the extent of trade-offs depended on the method used to incorporate socioeconomic data and was least severe when objectives were set for each fisher stakeholder group explicitly. We found that using different methods to incorporate socioeconomic factors that require similar data and expertise can result in plans with very different impacts on local stakeholders. PMID- 25916977 TI - Body height of mummified pharaohs supports historical suggestions of sibling marriages. AB - Body height is an important factor in reconstructing health conditions and it serves as an indicator of socio-economic status. Researchers rely on ancient data to analyze evolutionary aspects of human health and its interrelation with environmental influences. This study presents body height estimates from all periods of ancient Egyptian history and compares the general population with the existing mummies of the members of royal families. A sample of 259 adult Egyptian mummies originating from various collections and published sources with body lengths (long bone measures or/and overall measurements, CT data) were analyzed, and royal mummies were scored with respect to the level of consanguinity. Male royals were taller than males in the general ancient Egyptian population, while female royals were shorter than females in the general population. The body height variation of the royals is significantly reduced when compared with a pool of non-royal mummies. This provides evidence for inbreeding resulting from consanguineous marriages. However, there appears to be no correlation between the level of inbreeding and individual body height. The random sample of general population does not show signs of inbreeding. Due to the present lack of larger, technically and ethically challenging genetic studies, the selected non-invasive approach of body height is the most reliable indicator of sibling marriages of pharaohs based on direct physical evidence. PMID- 25916978 TI - Cumulene rotaxanes: stabilization and study of [9]cumulenes. AB - The stabilization of long [n]cumulenes has traditionally been achieved by placing sterically bulky "protecting groups" at the termini, which shield the reactive carbon chain from unwanted reactions. Herein, we present an alternative strategy: stabilization through threading the sp-hybridized carbon chain through a phenanthroline-based macrocycle. The result is stable [9]cumulene rotaxanes that enable the study of properties as a function of length for [n]cumulenes in unprecedented detail, including by quantitative UV/Vis spectroscopy, cyclic voltammetry, and differential scanning calorimetry. The experimental results are supported by DFT calculations. PMID- 25916979 TI - Aldehyde Dehydrogenase 1 Expression Predicts Chemoresistance and Poor Clinical Outcomes in Patients with Locally Advanced Cervical Cancer Treated with Neoadjuvant Chemotherapy Prior to Radical Hysterectomy. AB - BACKGROUND: Neoadjuvant chemotherapy (NAC) is an important treatment strategy for cervical cancer; however, few predictive markers of the response to NAC exist. Aldehyde dehydrogenase 1 (ALDH1), a cancer stem cell marker, is associated with chemoresistance in a variety of cancers. This study attempted to investigate the value of ALDH1 as a predictive marker of chemosensitivity and its prognostic value in cervical cancer patients treated with NAC. METHODS: Immunohistochemistry was used to evaluate ALDH1 expression in matched pre- and post-NAC tumor samples from 52 patients with cervical cancer. Kaplan-Meier analysis and a Cox proportional hazards regression model were applied to determine overall survival (OS) and disease-free survival (DFS). RESULTS: Fourteen patients (26.9 %) had ALDH1-positive tumors pre-NAC, and ALDH1 expression pre-NAC was significantly associated with a low clinical chemotherapy response rate and clinical non response. Twenty-two patients (42.3 %) had ALDH1-positive tumors post-NAC, and ALDH1 expression post-NAC was associated with poor DFS and OS (both p = 0.004). Multivariate analysis revealed that ALDH1 expression post-NAC was an independent prognostic factor for OS (hazard ratio 3.513; p = 0.033). Moreover, we observed that ALDH1 expression was increased after NAC in 18 patients (36.7 %). Increased levels of ALDH1 expression after NAC predicted poor DFS and OS (p = 0.013 and p = 0.08, respectively). CONCLUSIONS: Our findings suggest that ALDH1 expression pre NAC may be a predictive marker for response to NAC, and ALDH1 expression post-NAC could be a prognostic marker for cervical cancer. PMID- 25916980 TI - Outcomes of Breast Cancer Patients Treated with Accelerated Partial Breast Irradiation Via Multicatheter Interstitial Brachytherapy: The Pooled Registry of Multicatheter Interstitial Sites (PROMIS) Experience. AB - PURPOSE: To report outcomes for breast-conserving therapy using adjuvant accelerated partial breast irradiation with interstitial multicatheter brachytherapy by a cooperative group of institutions. METHODS: From 1992 to 2013, a total of 1356 patients were treated with breast-conserving surgery and adjuvant accelerated partial breast irradiation using interstitial multicatheter brachytherapy. A total of 1131 patients had >1 year of data available to assess oncologic and cosmesis outcomes. Median age was 59 years old (range 22-90 years). Histologies treated included 1005 (73 %) invasive ductal carcinoma and 240 (18 %) ductal carcinoma-in situ. T stages were 18 % Tis, 75 % T1, and 8 % >=T2. Nodal status was 73 % N0 and 6 % N1a. Estrogen receptor, progesterone receptor, and human epidermal growth factor receptor 2 was positive in 83, 70, and 6 %, respectively. Cox multivariate analysis for local control was performed using histology, age, estrogen receptor status, tumor size, grade, margin, and nodal status. RESULTS: The mean (SD) follow-up was 6.9 years (4.3). The 10-year actuarial risk (95 % confidence interval) of an ipsilateral breast tumor recurrence was 7.6 % (5.6-10.1). Other 10-year actuarial risks (95 % confidence interval) were regional failure 2.3 % (1.4-3.7), distant metastasis 3.8 % (2.5 5.7), cause-specific survival 96.3 % (94.2-97.6), overall survival 86.5 (83.0 89.3), and new contralateral cancers 4.6 % (3.0-6.9). On multivariate analysis, high grade (hazard ratio 2.81) and positive margin status (hazard ratio 18.42) were the only two significant variables associated with an increased risk of local recurrence. Physician-reported cosmesis was excellent/good in 84 % (98 of 116) of patients with >5 years of follow-up. CONCLUSIONS: This is the largest report of outcomes with interstitial breast brachytherapy. This treatment resulted in excellent long-term local control and cosmesis outcomes. PMID- 25916981 TI - An informational diversity framework, illustrated with sexually deceptive orchids in early stages of speciation. AB - Reconstructing evolutionary history for emerging species complexes is notoriously difficult, with newly isolated taxa often morphologically cryptic and the signature of reproductive isolation often restricted to a few genes. Evidence from multiple loci and genomes is highly desirable, but multiple inputs require 'common currency' translation. Here we deploy a Shannon information framework, converting into diversity analogue, which provides a common currency analysis for maternally inherited haploid and bi-parentally inherited diploid nuclear markers, and then extend that analysis to construction of minimum-spanning networks for both genomes. The new approach is illustrated with a quartet of cryptic congeners from the sexually deceptive Australian orchid genus Chiloglottis, still in the early stages of speciation. Divergence is more rapid for haploid plastids than for nuclear markers, consistent with the effective population size differential (N(ep) < (N(en)), but divergence patterns are broadly correlated for the two genomes. There are nevertheless intriguing discrepancies between the emerging plastid and nuclear signals of early phylogenetic radiation of these taxa, and neither pattern is entirely consistent with the available information on the sexual cues used by the orchids to lure the pollinators enforcing reproductive isolation. We describe possible extensions of this methodology to multiple ploidy levels and other types of markers, which should increase the range of application to any taxonomic assemblage in the very early stages of reproductive isolation and speciation. PMID- 25916982 TI - Validating trial-based functional analyses in mainstream primary school classrooms. AB - There is growing evidence to support the use of trial-based functional analyses, particularly in classroom settings. However, there currently are no evaluations of this procedure with typically developing children. Furthermore, it is possible that refinements may be needed to adapt trial-based analyses to mainstream classrooms. This study was designed to expand the trial-based functional analysis literature by implementing the procedure in 2 mainstream primary school classrooms and validating the analysis through comparison of multiple treatment options, including some that were not indicated by the functional analysis. We also extended the procedure by including a peer-attention condition and obtaining data from teachers regarding the feasibility of the procedures. For all participants, functional analysis results helped to identify effective treatments. Furthermore, relative effects among treatments were accurately predicted by the functional analysis outcomes. Teachers reported that they understood the logic of functional analysis and found both analysis and treatment procedures to be easy and effective. PMID- 25916983 TI - Enterococcus faecalis Gelatinase Mediates Intestinal Permeability via Protease Activated Receptor 2. AB - Microbial protease-mediated disruption of the intestinal epithelium is a potential mechanism whereby a dysbiotic enteric microbiota can lead to disease. This mechanism was investigated using the colitogenic, protease-secreting enteric microbe Enterococcus faecalis. Caco-2 and T-84 epithelial cell monolayers and the mouse colonic epithelium were exposed to concentrated conditioned media (CCM) from E. faecalis V583 and E. faecalis lacking the gelatinase gene (gelE). The flux of fluorescein isothiocyanate (FITC)-labeled dextran across monolayers or the mouse epithelium following exposure to CCM from parental or mutant E. faecalis strains indicated paracellular permeability. A protease-activated receptor 2 (PAR2) antagonist and PAR2-deficient (PAR2(-/-)) mice were used to investigate the role of this receptor in E. faecalis-induced permeability. Gelatinase (GelE) purified from E. faecalis V583 was used to confirm the ability of this protease to induce epithelial cell permeability and activate PAR2. The protease-mediated permeability of colonic epithelia from wild-type (WT) and PAR2( /-) mice by fecal supernatants from ulcerative colitis patients was assessed. Secreted E. faecalis proteins induced permeability in epithelial cell monolayers, which was reduced in the absence of gelE or by blocking PAR2 activity. Secreted E. faecalis proteins induced permeability in the colonic epithelia of WT mice that was absent in tissues from PAR2(-/-) mice. Purified GelE confirmed the ability of this protease to induce epithelial cell permeability via PAR2 activation. Fecal supernatants from ulcerative colitis patients induced permeability in the colonic epithelia of WT mice that was reduced in tissues from PAR2(-/-) mice. Our investigations demonstrate that GelE from E. faecalis can regulate enteric epithelial permeability via PAR2. PMID- 25916984 TI - Simultaneous Identification of Potential Pathogenicity Factors of Mycoplasma agalactiae in the Natural Ovine Host by Negative Selection. AB - Mycoplasmas possess complex pathogenicity determinants that are largely unknown at the molecular level. Mycoplasma agalactiae serves as a useful model to study the molecular basis of mycoplasma pathogenicity. The generation and in vivo screening of a transposon mutant library of M. agalactiae were employed to unravel its host colonization factors. Tn4001mod mutants were sequenced using a novel sequencing method, and functionally heterogeneous pools containing 15 to 19 selected mutants were screened simultaneously through two successive cycles of sheep intramammary infections. A PCR-based negative selection method was employed to identify mutants that failed to colonize the udders and draining lymph nodes in the animals. A total of 14 different mutants found to be absent from >= 95% of samples were identified and subsequently verified via a second round of stringent confirmatory screening where 100% absence was considered attenuation. Using this criterion, seven mutants with insertions in genes MAG1050, MAG2540, MAG3390, uhpT, eutD, adhT, and MAG4460 were not recovered from any of the infected animals. Among the attenuated mutants, many contain disruptions in hypothetical genes, implying their previously unknown role in M. agalactiae pathogenicity. These data indicate the putative role of functionally different genes, including hypothetical ones, in the pathogenesis of M. agalactiae. Defining the precise functions of the identified genes is anticipated to increase our understanding of M. agalactiae infections and to develop successful intervention strategies against it. PMID- 25916985 TI - Disruption of Parasite hmgb2 Gene Attenuates Plasmodium berghei ANKA Pathogenicity. AB - Eukaryotic high-mobility-group-box (HMGB) proteins are nuclear factors involved in chromatin remodeling and transcription regulation. When released into the extracellular milieu, HMGB1 acts as a proinflammatory cytokine that plays a central role in the pathogenesis of several immune-mediated inflammatory diseases. We found that the Plasmodium genome encodes two genuine HMGB factors, Plasmodium HMGB1 and HMGB2, that encompass, like their human counterparts, a proinflammatory domain. Given that these proteins are released from parasitized red blood cells, we then hypothesized that Plasmodium HMGB might contribute to the pathogenesis of experimental cerebral malaria (ECM), a lethal neuroinflammatory syndrome that develops in C57BL/6 (susceptible) mice infected with Plasmodium berghei ANKA and that in many aspects resembles human cerebral malaria elicited by P. falciparum infection. The pathogenesis of experimental cerebral malaria was suppressed in C57BL/6 mice infected with P. berghei ANKA lacking the hmgb2 gene (Deltahmgb2 ANKA), an effect associated with a reduction of histological brain lesions and with lower expression levels of several proinflammatory genes. The incidence of ECM in pbhmgb2-deficient mice was restored by the administration of recombinant PbHMGB2. Protection from experimental cerebral malaria in Deltahmgb2 ANKA-infected mice was associated with reduced sequestration in the brain of CD4(+) and CD8(+) T cells, including CD8(+) granzyme B(+) and CD8(+) IFN-gamma(+) cells, and, to some extent, neutrophils. This was consistent with a reduced parasite sequestration in the brain, lungs, and spleen, though to a lesser extent than in wild-type P. berghei ANKA-infected mice. In summary, Plasmodium HMGB2 acts as an alarmin that contributes to the pathogenesis of cerebral malaria. PMID- 25916987 TI - A Neutralizing Monoclonal IgG1 Antibody of Platelet-Activating Factor Acetylhydrolase SsE Protects Mice against Lethal Subcutaneous Group A Streptococcus Infection. AB - Group A Streptococcus (GAS) can cause life-threatening invasive infections, including necrotizing fasciitis. There are no effective treatments for severe invasive GAS infections. The platelet-activating factor (PAF) acetylhydrolase SsE produced by GAS is required for invasive GAS to evade innate immune responses and to invade soft tissues. This study determined whether the enzymatic activity of SsE is critical for its function in GAS skin invasion and inhibition of neutrophil recruitment and whether SsE is a viable target for immunotherapy for severe invasive GAS infections. An isogenic derivative of M1T1 strain MGAS5005 producing SsE with an S178A substitution (SsE(S178A)), an enzymatically inactive SsE mutant protein, was generated. This strain induced higher levels of neutrophil infiltration and caused smaller lesions than MGAS5005 in subcutaneous infections of mice. This phenotype is similar to that of MGAS5005 sse deletion mutants, indicating that the enzymatic activity of SsE is critical for its function. An anti-SsE IgG1 monoclonal antibody (MAb), 2B11, neutralized the PAF acetylhydrolase activity of SsE. Passive immunization with 2B11 increased neutrophil infiltration, reduced skin invasion, and protected mice against MGAS5005 infection. However, 2B11 did not protect mice when it was administered after MGAS5005 inoculation. MGAS5005 induced vascular effusion at infection sites at early hours after GAS inoculation, suggesting that 2B11 did not always have access to infection sites. Thus, the enzymatic activity of SsE mediates its function, and SsE has the potential to be included in a vaccine but is not a therapeutic target. An effective MAb-based immunotherapy for severe invasive GAS infections may need to target virulence factors that are critical for systemic survival of GAS. PMID- 25916988 TI - Dynamic Virus-Bacterium Interactions in a Porcine Precision-Cut Lung Slice Coinfection Model: Swine Influenza Virus Paves the Way for Streptococcus suis Infection in a Two-Step Process. AB - Swine influenza virus (SIV) and Streptococcus suis are common pathogens of the respiratory tract in pigs, with both being associated with pneumonia. The interactions of both pathogens and their contribution to copathogenesis are only poorly understood. In the present study, we established a porcine precision-cut lung slice (PCLS) coinfection model and analyzed the effects of a primary SIV infection on secondary infection by S. suis at different time points. We found that SIV promoted adherence, colonization, and invasion of S. suis in a two-step process. First, in the initial stages, these effects were dependent on bacterial encapsulation, as shown by selective adherence of encapsulated, but not unencapsulated, S. suis to SIV-infected cells. Second, at a later stage of infection, SIV promoted S. suis adherence and invasion of deeper tissues by damaging ciliated epithelial cells. This effect was seen with a highly virulent SIV subtype H3N2 strain but not with a low-virulence subtype H1N1 strain, and it was independent of the bacterial capsule, since an unencapsulated S. suis mutant behaved in a way similar to that of the encapsulated wild-type strain. In conclusion, the PCLS coinfection model established here revealed novel insights into the dynamic interactions between SIV and S. suis during infection of the respiratory tract. It showed that at least two different mechanisms contribute to the beneficial effects of SIV for S. suis, including capsule-mediated bacterial attachment to SIV-infected cells and capsule-independent effects involving virus mediated damage of ciliated epithelial cells. PMID- 25916986 TI - H-NS Silencing of the Salmonella Pathogenicity Island 6-Encoded Type VI Secretion System Limits Salmonella enterica Serovar Typhimurium Interbacterial Killing. AB - The secretion of bacterial toxin proteins is achieved by dedicated machineries called secretion systems. The type VI secretion system (T6SS) is a widespread versatile machine used for the delivery of protein toxins to both prokaryotic and eukaryotic cells. In Salmonella enterica serovar Typhimurium, the expression of the T6SS genes is activated during macrophage or mouse infection. Here, we show that the T6SS gene cluster is silenced by the histone-like nucleoid structuring H NS protein using a combination of reporter fusions, electrophoretic mobility shift assays, DNase footprinting, and fluorescence microscopy. We further demonstrate that derepression of the S. Typhimurium T6SS genes induces T6SS dependent intoxication of competing bacteria. Our results suggest that relieving T6SS H-NS silencing may be used as a sense-and-kill mechanism that will help S. Typhimurium to homogenize and synchronize the microbial population to gain efficiency during infection. PMID- 25916989 TI - Distinct Contributions of CD4+ and CD8+ T Cells to Pathogenesis of Trypanosoma brucei Infection in the Context of Gamma Interferon and Interleukin-10. AB - Although gamma interferon (IFN-gamma) and interleukin-10 (IL-10) have been shown to be critically involved in the pathogenesis of African trypanosomiasis, the contributions to this disease of CD4(+) and CD8(+) T cells, the major potential producers of the two cytokines, are incompletely understood. Here we show that, in contrast to previous findings, IFN-gamma was produced by CD4(+), but not CD8(+), T cells in mice infected with Trypanosoma brucei. Without any impairment in the secretion of IFN-gamma, infected CD8(-/-) mice survived significantly longer than infected wild-type mice, suggesting that CD8(+) T cells mediated mortality in an IFN-gamma-independent manner. The increased survival of infected CD8(-/-) mice was significantly reduced in the absence of IL-10 signaling. Interestingly, IL-10 was also secreted mainly by CD4(+) T cells. Strikingly, depletion of CD4(+) T cells abrogated the prolonged survival of infected CD8(-/-) mice, demonstrating that CD4(+) T cells mediated protection. Infected wild-type mice and CD8(-/-) mice depleted of CD4(+) T cells had equal survival times, suggesting that the protection mediated by CD4(+) T cells was counteracted by the detrimental effects of CD8(+) T cells in infected wild-type mice. Interestingly, CD4(+) T cells also mediated the mortality of infected mice in the absence of IL 10 signaling, probably via excessive secretion of IFN-gamma. Finally, CD4(+), but not CD8(+), T cells were critically involved in the synthesis of IgG antibodies during T. brucei infections. Collectively, these results highlight distinct roles of CD4(+) and CD8(+) T cells in the context of IFN-gamma and IL-10 during T. brucei infections. PMID- 25916990 TI - Attenuated Mutants of Ehrlichia chaffeensis Induce Protection against Wild-Type Infection Challenge in the Reservoir Host and in an Incidental Host. AB - Ehrlichia chaffeensis, a tick-borne rickettsial organism, causes the disease human monocytic ehrlichiosis. The pathogen also causes disease in several other vertebrates, including dogs and deer. In this study, we assessed two clonally purified E. chaffeensis mutants with insertions within the genes Ech_0379 and Ech_0660 as vaccine candidates in deer and dogs. Infection with the Ech_0379 mutant and challenge with wild-type E. chaffeensis 1 month following inoculation with the mutant resulted in the reduced presence of the organism in blood compared to the presence of wild-type infection in both deer and dogs. The Ech_0660 mutant infection resulted in its rapid clearance from the bloodstream. The wild-type infection challenge following Ech_0660 mutant inoculation also caused the pathogen's clearance from blood and tissue samples as assessed at the end of the study. The Ech_0379 mutant-infected and -challenged animals also remained positive for the organism in tissue samples in deer but not in dogs. This is the first study that documents that insertion mutations in E. chaffeensis that cause attenuated growth confer protection against wild-type infection challenge. This study is important in developing vaccines to protect animals and people against Ehrlichia species infections. PMID- 25916993 TI - A comparison of the efficacy of brief interventions to reduce hazardous and harmful alcohol consumption between European and non-European countries: a systematic review and meta-analysis of randomized controlled trials. AB - AIMS: The extent of variation attributable to regional differences for the efficacy of brief intervention (BI) to reduce hazardous and harmful alcohol consumption is unclear. The primary aim of this study was to determine overall efficacy of BI at 6- and 12-month follow-up in primary health care (PHC) and emergency department (ED) studies. The secondary aim was to examine whether variance in study outcome can be explained by the geographical region in which trials have taken place (European versus non-European). METHODS: A systematic review and meta-analysis of randomized controlled trials (RCTs) published before August 2014 was undertaken. Twenty RCTs conducted in PHC settings with a total of 8226 participants (European = 4564/non-European = 3662) and eight RCTs conducted in ED settings with a total of 4799 participants (European = 2465/non-European = 2334) were eligible. Primary outcome measure was reduction in grams of alcohol consumed per week for BI and control groups at 6- and 12-month follow-up. An inverse variance model was applied to measure the effect of treatment in mean differences for BI and control groups at 6- and 12-month follow-up. Variance between study outcomes was explored using subgroup analysis of European versus non-European countries. RESULTS: For PHC trials at 6-month follow-up, statistically significant benefits of BI were indicated [mean difference (MD) = 21.98 g/week; 95% confidence interval (CI) = -37.40 to -6.57; P = 0.005]. At 12 month follow-up, statistically significant benefit of BI was evident (MD = -30.86 g/week; 95% CI = -46.49 to -15.23; P = 0.0001). For ED trials at 6-month follow up, statistically significant benefits of BI were indicated (MD = -17.97 g/week; 95% CI = -29.69 to -6.24; P = .003). At 12-month follow-up, statistically significant benefit in favour of BI was evident (MD = -18.21 g/week; 95% CI = 26.71 to -9.70; P < 0.0001). No statistically significant differences were detected in subgroup analyses of outcomes for European versus non-European studies. CONCLUSIONS: Brief intervention (BI) to reduce alcohol consumption is associated with reducing grams of alcohol consumed per week among hazardous and harmful drinkers at 6- and 12-month follow-up in primary health care and emergency department trials. The geographical region in which trials are undertaken does not appear to explain the variance in trial outcomes for reducing alcohol consumption. PMID- 25916991 TI - Evidence for Proinflammatory beta-1,6 Glucans in the Pneumocystis carinii Cell Wall. AB - Inflammation is a major cause of respiratory impairment during Pneumocystis pneumonia. Studies support a significant role for cell wall beta-glucans in stimulating inflammatory responses. Fungal beta-glucans are comprised of d glucose homopolymers containing beta-1,3-linked glucose backbones with beta-1,6 linked glucose side chains. Prior studies in Pneumocystis carinii have characterized beta-1,3 glucan components of the organism. However, recent investigations in other organisms support important roles for beta-1,6 glucans, predominantly in mediating host cellular activation. Accordingly, we sought to characterize beta-1,6 glucans in the cell wall of Pneumocystis and to establish their activity in lung cell inflammation. Immune staining revealed specific beta 1,6 localization in P. carinii cyst walls. Homology-based cloning facilitated characterization of a functional P. carinii kre6 (Pckre6) beta-1,6 glucan synthase in Pneumocystis that, when expressed in kre6-deficient Saccharomyces cerevisiae, restored cell wall stability. Recently synthesized beta-1,6 glucan synthase inhibitors decreased the ability of isolated P. carinii preparations to generate beta-1,6 carbohydrate. In addition, isolated beta-1,6 glucan fractions from Pneumocystis elicited vigorous tumor necrosis factor alpha (TNF-alpha) responses from macrophages. These inflammatory responses were significantly dampened by inhibition of host cell plasma membrane microdomain function. Together, these studies indicate that beta-1,6 glucans are present in the P. carinii cell wall and contribute to lung cell inflammatory activation during infection. PMID- 25916992 TI - Overexpression of Porcine Beta-Defensin 2 Enhances Resistance to Actinobacillus pleuropneumoniae Infection in Pigs. AB - To reduce the need for antibiotics in animal production, alternative approaches are needed to control infection. We hypothesized that overexpression of native defensin genes will provide food animals with enhanced resistance to bacterial infections. In this study, recombinant porcine beta-defensin 2 (PBD-2) was overexpressed in stably transfected PK-15 porcine kidney cells. PBD-2 antibacterial activities against Actinobacillus pleuropneumoniae, an important respiratory pathogen causing porcine contagious pleuropneumonia, were evaluated on agar plates. Transgenic pigs constitutively overexpressing PBD-2 were produced by a somatic cell cloning method, and their resistance to bacterial infection was evaluated by direct or cohabitation infection with A. pleuropneumoniae. Recombinant PBD-2 peptide that was overexpressed in the PK-15 cells showed antibacterial activity against A. pleuropneumoniae. PBD-2 was overexpressed in the heart, liver, spleen, lungs, kidneys, and jejunum of the transgenic pigs, which showed significantly lower bacterial loads in the lungs and reduced lung lesions after direct or cohabitation infection with A. pleuropneumoniae. The results demonstrate that transgenic overexpression of PBD-2 in pigs confers enhanced resistance against A. pleuropneumoniae infection. PMID- 25916994 TI - Vulvovaginal candidiasis in pregnancy. AB - Prevalence studies indicate that Candida species colonize the vagina in at least 20 % of all women, rising to 30 % in pregnancy. Although, some studies concluded that pregnant women were more likely to have symptomatic vaginal infections caused by Candida, yet other studies found a high prevalence of asymptomatic infection only during pregnancy. Most episodes of symptomatic vulvovaginal candidiasis (VVC) occur during the second and third trimesters. The increased risk of VVC in pregnancy is likely sustained by pregnancy-related factors, such as immunologic alterations, increased estrogen levels, and increased vaginal glycogen production. Although evidence is incomplete, there is some emerging data which suggests that candidiasis in pregnancy may be associated with increased risk of pregnancy complications, such as premature rupture of membranes, preterm labor, chorioamnionitis, and congenital cutaneous candidiasis. In contrast to nonpregnant women, there are no formal studies, evaluating the use of long-term suppressive maintenance oral azoles in the treatment of recurrent VVC (RVVC) in pregnancy. Most clinicians do not offer suppressive therapy in pregnancy and prefer to treat individual symptomatic episodes only utilizing a topical imidazole vaginally for 7 days to minimize systemic exposure to medications. PMID- 25916995 TI - The pros, cons, and unknowns of search and destroy for carbapenem-resistant enterobacteriaceae. AB - Antibiotic drug discovery has not kept pace with the development of microbial resistance to these agents. There are ever increasing reports where the causative agents of serious infections are multi-drug resistant and in some cases resistant to all known antibiotics. The emergence and spread of carbapenemase-producing Enterobacteriaceae has heightened awareness regarding antibiotic stewardship programs and infection prevention and control measures. There has been much controversy regarding the utility of the "search and destroy" strategy to prevent the spread of carbapenem-resistant Enterobacteriaceae. These controversies center on screening and management of carriers, including decontamination and isolation. It is however clear that a functional infection prevention and control program is fundamental to any strategy that serves to address the spread of microbes within a healthcare facility. PMID- 25916996 TI - HIV-associated Neurocognitive Disorders and Antiretroviral Therapy: Current Concepts and Controversies. AB - Antiretroviral drugs may help prevent neurological decline in individuals with HIV infection by suppressing viral replication and associated chronic immune activation in the central nervous system. However, HIV control in the brain may come at the price of drug-induced neurotoxicity. Herein, we review recent advances in the balance between adequate viral suppression in the nervous system and adverse effects of the medications used in HIV treatment. PMID- 25916997 TI - The swiss transplant cohort study: lessons from the first 6 years. AB - Prospective cohort studies significantly contribute to answering specific research questions in a defined population. Since 2008, the Swiss Transplant Cohort Study (STCS) systematically enrolled >95 % of all transplant recipients in Switzerland, collecting predefined data at determined time points. Designed as an open cohort, the STCS has included >3900 patients to date, with a median follow up of 2.96 years (IQR 1.44-4.73). This review highlights some relevant findings in the field of transplant-associated infections gained by the STCS so far. Three key general aspects have crystallized: (i) Well-run cohort studies are a powerful tool to conduct genetic studies, which are crucially dependent on a meticulously described phenotype. (ii) Long-term real-life observations are adding a distinct layer of information that cannot be obtained during randomized studies. (iii) The systemic collection of data, close interdisciplinary collaboration, and continuous analysis of some key outcome data such as infectious diseases endpoints can improve patient care. PMID- 25916998 TI - The origin and evolution of social insect queen pheromones: Novel hypotheses and outstanding problems. AB - Queen pheromones, which signal the presence of a fertile queen and induce daughter workers to remain sterile, are considered to play a key role in regulating the reproductive division of labor of insect societies. Although queen pheromones were long thought to be highly taxon-specific, recent studies have shown that structurally related long-chain hydrocarbons act as conserved queen signals across several independently evolved lineages of social insects. These results imply that social insect queen pheromones are very ancient and likely derived from an ancestral signalling system that was already present in their common solitary ancestors. Based on these new insights, we here review the literature and speculate on what signal precursors social insect queen pheromones may have evolved from. Furthermore, we provide compelling evidence that these pheromones should best be seen as honest signals of fertility as opposed to suppressive agents that chemically sterilize the workers against their own best interests. PMID- 25917001 TI - Preparation of Cyclodextrin-Iron Species in Water by Laser Ablation: Secondary Ion Mass Spectrometry. AB - Supramolecular complexes between cyclodextrin and iron species are studied by using secondary ion mass spectrometry. The iron species are prepared by pulsed laser ablation of bulk iron in water; this gives Fe(+) (56 m/z) and Fex Oy (+) (x, y=1-7) species. Cyclodextrin is added to the water either before or after the laser ablation. When it is added before laser ablation, molecular fragments of cyclodextrin are detected as dehydrated glucopyranose units (C6 H8 O4 (+) ) associated with Fe(+) , FeO(+) , and Fe2 O(+) species. The focus is to observe supramolecular host-guest complexes or adducts between intact molecules of cyclodextrin and iron species. When cyclodextrin is added after laser ablation, the relevant peak at 1210 m/z is observed and assigned as C42 H67 O35 FeNa(+) , which corresponds to a cyclodextrin molecule minus three H atoms. Two possible explanations of this finding are the presence of the host-guest C42 H67 O35 Na-Fe complex, in which Fe is in the cavity, or the presence of the adduct C42 H67 O34 Na-FeO with FeO on the outer surface; the formation of these complexes are supported by the hydrophobicity of Fe and hydrophilicity of FeO, respectively. Due to the presence of 12 % of intact C42 H70 O35 Na-Fe complex and an estimated Fe/FeO ratio of approximately 10(2) , host-guest formation is assumed to be more significant. PMID- 25916999 TI - A combination of the telomerase inhibitor, BIBR1532, and paclitaxel synergistically inhibit cell proliferation in breast cancer cell lines. AB - Breast cancer is one of the most significant causes of female cancer death worldwide. Paclitaxel, an extensively used breast cancer chemotherapeutic has limited success due to drug resistance. 2-[(E)-3-naphtalen-2-yl-but-2-enoylamino] benzoic acid (BIBR1532), a small molecule pharmacological inhibitor of telomerase activity, can inhibit human cancer cell proliferation as well. Thus, to enhance breast cancer treatment efficacy, we studied the combination of BIBR1532 and paclitaxel in breast cancer cell lines. Cell viability assays revealed that BIBR1532 or paclitaxel alone inhibited proliferation in a dose-dependent manner, and combining the drugs synergistically induced growth inhibition in all breast cell lines tested independent of their p53, ER, and HER2 status. The drug combination also synergistically inhibited colony formation of MCF-7 cells in a dose-dependent manner. Annexin V-PI staining and Western blot assays on PARP cleavage and caspase-8 and caspase-3 revealed that BIBR1532 in combination with paclitaxel was more potent than either agent alone in promoting MCF-7 cell apoptosis. Cell cycle analysis indicated that BIBR1532 induced a G1 phase arrest and paclitaxel arrested cells at the G2/M phase. The drug combination dramatically blocked S cells from entering the G2/M phase. Our results suggest the potential of telomerase inhibition as an effective breast cancer treatment and that used in conjunction with paclitaxel; it may potentiate tumor cytotoxicity. PMID- 25917000 TI - Learning the opportunity cost of time in a patch-foraging task. AB - Although most decision research concerns choice between simultaneously presented options, in many situations options are encountered serially, and the decision is whether to exploit an option or search for a better one. Such problems have a rich history in animal foraging, but we know little about the psychological processes involved. In particular, it is unknown whether learning in these problems is supported by the well-studied neurocomputational mechanisms involved in more conventional tasks. We investigated how humans learn in a foraging task, which requires deciding whether to harvest a depleting resource or switch to a replenished one. The optimal choice (given by the marginal value theorem; MVT) requires comparing the immediate return from harvesting to the opportunity cost of time, which is given by the long-run average reward. In two experiments, we varied opportunity cost across blocks, and subjects adjusted their behavior to blockwise changes in environmental characteristics. We examined how subjects learned their choice strategies by comparing choice adjustments to a learning rule suggested by the MVT (in which the opportunity cost threshold is estimated as an average over previous rewards) and to the predominant incremental-learning theory in neuroscience, temporal-difference learning (TD). Trial-by-trial decisions were explained better by the MVT threshold-learning rule. These findings expand on the foraging literature, which has focused on steady-state behavior, by elucidating a computational mechanism for learning in switching tasks that is distinct from those used in traditional tasks, and suggest connections to research on average reward rates in other domains of neuroscience. PMID- 25917002 TI - Recent progress in studies of miRNA and skin diseases. AB - miRNA is a family of small non-coding RNA that consists of 22 nucleotides on average. miRNA are implicated in various cellular activities such as cell proliferation or migration via the modulation of gene expression, and also are linked to the pathogenesis of human diseases. This paper reviews recent research progress about the contribution of miRNA to the pathogenesis of various skin diseases, and possible application of miRNA as the disease markers in each disease. For example, downregulated miR-424-5p in psoriatic skin causes the overexpression of MEK1 and cyclin E1 in psoriatic keratinocytes, resulting in the keratinocyte overgrowth and hyperproliferation seen in the disease. Although there was no significant difference in the serum miR-424-5p levels between psoriasis patients and healthy controls, serum miR-1266-5p levels were significantly upregulated in psoriasis patients, and showed weak and inverse correlation with disease activity. Furthermore, combination of serum levels of miR-146a-5p and -203a-3p was more reliable to distinguish psoriasis patients and normal subjects, than each miRNA alone. Hair shaft miR-424-5p levels were significantly higher in psoriasis patients than normal subjects, while hair root miR-19a-3p levels in psoriasis patients were inversely correlated with the duration between symptom onset and the first visit to the hospital. Future researches of miRNA will enable the advances of their clinical applications including the clarification of pathogenesis, disease markers and novel treatments. PMID- 25917003 TI - Relational conceptions of paternalism: a way to rebut nanny-state accusations and evaluate public health interventions. AB - OBJECTIVES: 'Nanny-state' accusations can function as powerful rhetorical weapons against interventions intended to promote public health. Public health advocates often lack effective rebuttals to these criticisms. Nanny-state accusations are largely accusations of paternalism. They conjure up emotive concern about undue governmental interference undermining peoples' autonomy. But autonomy can be understood in various ways. We outline three main conceptions of autonomy, argue that these that can underpin three different conceptions of paternalism, and consider implications for responses to nanny-state accusations and the assessment of public health interventions. STUDY DESIGN AND METHODS: Detailed conceptual analysis. RESULTS: The conceptions of paternalism implicit in nanny-state accusations generally depend on libertarian conceptions of autonomy. These reflect unrealistic views of personal independence and do not discriminate sufficiently between trivial and important freedoms. Decisional conceptions of paternalism, like their underlying decisional conceptions of autonomy, have limited applicability in public health contexts. Relational conceptions of paternalism incorporate relational conceptions of autonomy, so recognize that personal autonomy depends on socially shaped skills, self-identities and self evaluations as well as externally structured opportunities. They encourage attention to the various ways that social interactions and relationships, including disrespect, stigmatization and oppression, can undermine potential for autonomy. While nanny-state accusations target any interference with negative freedom, however trivial, relational conceptions direct concerns to those infringements of negative freedom, or absences of positive freedom, serious enough to undermine self-determination, self-governance and/or self authorization. CONCLUSION: Relational conceptions of autonomy and paternalism offer public health policymakers and practitioners a means for rebutting nanny state accusations, and can support more nuanced and more appropriately demanding appraisals of public health interventions. PMID- 25917004 TI - The Impact of Disclosure of Intimate Partner Violence on Friends. AB - : Intimate partner violence (IPV) affects people connected to survivors as well as survivors themselves. Despite this, we do not have measures assessing IPV's impact on others. The Impact on Friends measure was developed to understand the impact of disclosure of sexual assault (SA) on friends of survivors. In the present study, the Impact on Friends measure was modified to apply to IPV and administered to two separate online samples. Exploratory factor analysis in one sample (U.S.-based participants) revealed a very similar factor structure to the original Impact on Friends measure, consisting of Emotional Distress, Validation, and Confusion. This factor solution was then applied to the next sample (mostly Indian participants), resulting in an adequate model fit. The Impact on Friends IPV measure has adequate reliability. One of its factors, Emotional Distress, is related to increased depression and post-traumatic distress disorder symptoms of friends, but only in the U.S. SAMPLE: These findings suggest that even though the same dimensions have been found in both a U.S. and an Indian sample, how disclosure of IPV on friends relates to psychological symptoms may differ. This study suggest that there is at least some overlap in the experiences of friends of IPV and SA survivors, but that certain dimensions of the measure may have different relationships to other phenomena in different cultures. PMID- 25917005 TI - Family Violence and Other Potentially Traumatic Interpersonal Events Among 9- to 17-Year-Old Children Attending an Outpatient Psychiatric Clinic. AB - Among children visiting child and adolescent mental health care (CAM), the prevalence of exposure to family violence (FV) is reported to exceed prevalence in community samples, as are potentially traumatic interpersonal events (IPE) outside the family. The aim of the study was to relate CAM patients' self reported experiences of violence exposure to their current psychiatric symptoms and to compare patients exposed to violence with patients who reported no exposure. We asked 305 consecutive 9- to 17-year-old patients in CAM about their current and previous exposure to violence in and outside of the family. Prevalence of exposure to any kind of violence was 67%. Reported exposures were 19% to IPE, 21% to FV, and 27% to both. Children exposed to both FV and IPE were more negatively affected by the events than children exposed to FV or IPE only. Children in the FV + IPE group reported more mental health symptoms than those in the no violence (33%) group. In general, IPE was related to the outcome measures only in combination with FV. Degree of violence exposure seemed to have a dose response relationship with the diagnosis of post-traumatic stress disorder. PMID- 25917006 TI - The Goals of IPV Survivors Receiving Orders of Protection: An Application of the Empowerment Process Model. AB - Protection orders (POs) are a widely recommended and commonly used intervention for intimate partner violence (IPV), but evidence for their effectiveness is mixed. This mixed methods study used the framework of empowerment to explore the goals of petitioners who seek POs, and the extent to which one group of experts considers these goals to be a good fit with the court's intent. We collected data in three phases: (a) We conducted a qualitative study to generate a list of goals (n = 10); (b) we administered the list to a sample of IPV survivors (n = 157); and (c) we surveyed a group of attorneys (n = 10). Results showed that petitioners endorse many goals for seeking POs and that while their highest priority goals relate to safety, other nearly universally endorsed goals are more psychological in nature, such as moving on with one's life. Petitioners also use the orders to navigate complex relationships, helping themselves to set boundaries in addition to sending a clear message to respondents. Our group of lawyers viewed petitioners' highest priority goals as a relatively good fit with the system, but was fairly pessimistic about the likelihood of success. Petitioners' ratings of progress toward their goals, at the time of the PO hearing, differed markedly from lawyers' perceptions. Implications for research and practice are discussed. PMID- 25917007 TI - Mass spectrometry-based proteomic analysis of formalin-fixed paraffin-embedded extrahepatic cholangiocarcinoma. AB - BACKGROUND: Extrahepatic cholangiocarcinoma is very difficult to diagnose at an early stage, and has a poor prognosis. Novel markers for diagnosis and optimal treatment selection are needed. However, there has been very limited data on the proteome profile of extrahepatic cholangiocarcinoma. This study was designed to unravel the proteome profile of this disease and to identify overexpressed proteins using mass spectrometry-based proteomic approaches. METHODS: We analyzed a discovery set of formalin-fixed paraffin-embedded tissues of 14 extrahepatic cholangiocarcinomas using shotgun mass spectrometry, and compared proteome profiles with those of seven controls. Then, selected candidates were verified by quantitative analysis using scheduled selected reaction monitoring-based mass spectrometry. Furthermore, immunohistochemical staining used a validation set of 165 cases. RESULTS: In total, 1,992 proteins were identified and 136 proteins were overexpressed. Verification of 58 selected proteins by quantitative analysis revealed 11 overexpressed proteins. Immunohistochemical validation for 10 proteins showed positive rates of S100P (84%), CEAM5 (75%), MUC5A (62%), OLFM4 (60%), OAT (42%), CAD17 (41%), FABPL (38%), AOFA (30%), K1C20 (25%) and CPSM (22%) in extrahepatic cholangiocarcinomas, which were rarely positive in controls. CONCLUSIONS: We identified 10 proteins associated with extrahepatic cholangiocarcinoma using proteomic approaches. These proteins are potential targets for future diagnostic biomarkers and therapy. PMID- 25917008 TI - Cognitive versus exposure therapy for problem gambling: Randomised controlled trial. AB - BACKGROUND: Problem gambling-specific cognitive therapy (CT) and behavioural (exposure-based) therapy (ET) are two core cognitive-behavioural techniques to treating the disorder, but no studies have directly compared them using a randomised trial. AIMS: To evaluate differential efficacy of CT and ET for adult problem gamblers at a South Australian gambling therapy service. METHODS: Two group randomised, parallel design. Primary outcome was rated by participants using the Victorian Gambling Screen (VGS) at baseline, treatment-end, 1, 3, and 6 month follow-up. FINDINGS: Of eighty-seven participants who were randomised and started intervention (CT = 44; ET = 43), 51 (59%) completed intervention (CT = 30; ET = 21). Both groups experienced comparable reductions (improvement) in VGS scores at 12 weeks (mean difference -0.18, 95% CI: -4.48-4.11) and 6 month follow up (mean difference 1.47, 95% CI: -4.46-7.39). CONCLUSIONS: Cognitive and exposure therapies are both viable and effective treatments for problem gambling. Large-scale trials are needed to compare them individually and combined to enhance retention rates and reduce drop-out. PMID- 25917009 TI - Cognitive-behavioral treatment of insomnia and depression in adolescents: A pilot randomized trial. AB - We tested whether augmenting conventional depression treatment in youth by treating sleep issues with cognitive behavioral therapy for insomnia (CBT-I) improved depression outcomes. We randomized youth 12-20 years of age to 10 weekly sessions of a sleep hygiene control condition (SH) combined with CBT for depression (CBT-D) (n = 20), or an experimental condition consisting of CBT-I combined with CBT-D (n = 21). We assessed outcomes through 26 weeks of follow-up and found medium-large effects favoring the experimental CBT-I arm on some sleep outcomes (actigraphy total sleep time and Insomnia Severity Index "caseness") and depression outcomes (higher percentage recovered, faster time to recovery), but little effect on other measures. Total sleep time improved by 99 min from baseline to week 12 in the CBT-I arm, but not in the SH arm. In addition, our pilot yielded important products to facilitate future studies: the youth-adapted CBT-I program; the study protocol; estimates of recruitment, retention, and attrition; and performance and parameters of candidate outcome measures. ClinicalTrials.gov Identifier NCT00949689. PMID- 25917011 TI - An adjustable stabilizing device for imaging the cutaneous microcirculation with Sidestream Dark Field imaging. AB - The recent development of hand-held videomicroscopy systems, such as the MicroScan, has provided a useful alternative to traditional capillaroscopy for direct in vivo imaging of the cutaneous microcirculation. Their small size and portability provide greater potential for imaging different areas of the skin under a variety of clinical and experimental conditions. To counteract the issues of movement and pressure artifacts associated with these systems, we developed an adaptable stabilization device for use in conjunction with the MicroScan imaging unit. The design presented here is simple yet effective, and the basic platform can be replicated by others or modified to suit particular clinical or experimental needs or for use with other hand-held microscopy systems. PMID- 25917010 TI - Feasibility of assessment of conjunctival microvascular hemodynamics in unilateral ischemic stroke. AB - Since the internal carotid artery supplies blood to both the eye and the brain, ocular microvascular hemodynamics can be altered due to ischemic stroke. The purpose of the current study was to establish the feasibility of conjunctival microcirculation imaging for detection of inter-ocular differences in microvascular hemodynamics in subjects with unilateral ischemic stroke. Conjunctival microcirculation imaging was performed in both eyes of 15 healthy control subjects and 12 subjects following unilateral ischemic stroke. Diameter and axial blood velocity were measured in multiple conjunctival venules of each eye. A two-way repeated measures analysis of variance was performed to determine the effects of stroke (control vs. stroke) and side of stroke (ipsilateral vs. contralateral) on conjunctival diameter and axial blood velocity. There was no significant main effect of stroke on conjunctival diameter (P=0.7) or conjunctival axial blood velocity (P=0.9). There was no significant main effect of side of stroke on conjunctival diameter (P=0.8), but there was a significant main effect of side of stroke on conjunctival axial blood velocity (P=0.02). There was a significant interaction effect between stroke and side of stroke (P=0.04), indicating that conjunctival axial blood velocity was lower in ipsilateral eyes than in contralateral eyes of stroke subjects. Conjunctival axial blood velocity and internal carotid artery blood velocity were correlated in stroke subjects (r=0.75, P=0.01, N=10). Conjunctival microcirculation imaging is a feasible method to detect inter-ocular differences in microvascular hemodynamics in subjects with unilateral ischemic stroke. PMID- 25917012 TI - In vivo optical imaging of human retinal capillary networks using speckle variance optical coherence tomography with quantitative clinico-histological correlation. AB - Retinal capillary networks are critically linked to neuronal health and disease. The ability to perform accurate in vivo examination of human retinal capillary networks is therefore valuable for studying mechanisms that govern retinal homeostasis and retinal vascular diseases. Speckle variance optical coherence tomography (svOCT) is a non-invasive imaging technique that has the capacity to provide angiographic information about the retinal circulation. The application of this technology for studying human retinal capillary networks however has not been validated in a quantifiable manner. We use a custom-built svOCT device to qualitatively and quantitatively study the various capillary networks in the human perifovea. Capillary networks corresponding to the nerve fibre layer (NFL), the retinal ganglion cell/superficial inner plexiform layer (RGC/sIPL), the deep inner plexiform layer/superficial inner nuclear layer (dIPL/sINL) and the deep inner nuclear layer (dINL) are imaged in 9 normal human subjects. Measurements of capillary diameter and capillary density are made from each of these networks and results are compared to post-mortem histological data acquired with confocal scanning laser microscopy. Additionally, retinal capillary measurements from high resolution fundus fluorescein angiogram (FA) are directly compared with svOCT images from 6 eyes. We demonstrate that svOCT images of capillary networks are morphologically comparable to microscopic images of histological specimens. Similar to histological images in svOCT images, the capillaries in the NFL network run parallel to the direction of RGC axons while capillaries in the dINL network comprise a planar configuration with multiple closed loops. Capillaries in remaining networks are convoluted with a complex three-dimensional architecture. We demonstrate that there is no significant difference in capillary density measurements between svOCT and histology images for all networks. Capillary diameter was significantly greater in svOCT images compared to histology for all networks. Capillary density measurements were also higher in svOCT compared to FA. The results of this study suggest that in vivo svOCT imaging allows accurate morphometric assessment of capillary networks in the human perifovea and may provide an improved ability to render microvascular detail compared to FA. Therefore, svOCT may have broad clinical applications in the study of human retinal physiology and disease. The difference in quantitative measurements between svOCT and histology may reflect dynamic variations in the retinal microcirculation and warrants further investigation. PMID- 25917014 TI - Priming with DNA Enhances Considerably the Immunogenicity of hCG beta-LTB Vaccine. AB - PROBLEM: Necessity to elicit antibody response above the protective threshold titres by sexually active women immunized to prevent pregnancy. METHOD OF STUDY: Recombinant hCGbeta-LTB vaccine expressed as both DNA and protein. Balb C mice employed for testing immunogenicity. RESULTS: Necessity to give three primary injections of the vaccine to elicit proper antibody response. Immunization twice with DNA form of the vaccine at fortnightly interval followed by the protein elicits a distinctly higher antibody response than proteinic vaccine alone. Antibodies generated are bio-effective against hCG. CONCLUSION: Immunization with the DNA form of the recombinant hCGbeta-LTB vaccine twice at fortnightly interval followed by the proteinic form of the vaccine induces distinctly higher antibody response. PMID- 25917015 TI - High-Throughput Microbore UPLC-MS Metabolic Phenotyping of Urine for Large-Scale Epidemiology Studies. AB - A new generation of metabolic phenotyping centers are being created to meet the increasing demands of personalized healthcare, and this has resulted in a major requirement for economical, high-throughput metabonomic analysis by liquid chromatography-mass spectrometry (LC-MS). Meeting these new demands represents an emerging bioanalytical problem that must be solved if metabolic phenotyping is to be successfully applied to large clinical and epidemiological sample sets. Ultraperformance (UP)LC-MS-based metabolic phenotyping, based on 2.1 mm i.d. LC columns, enables comprehensive metabolic phenotyping but, when employed for the analysis of thousands of samples, results in high solvent usage. The use of UPLC MS employing 1 mm i.d. columns for metabolic phenotyping rather than the conventional 2.1 mm i.d. methodology shows that the resulting optimized microbore method provided equivalent or superior performance in terms of peak capacity, sensitivity, and robustness. On average, we also observed, when using the microbore scale separation, an increase in response of 2-3 fold over that obtained with the standard 2.1 mm scale method. When applied to the analysis of human urine, the 1 mm scale method showed no decline in performance over the course of 1000 analyses, illustrating that microbore UPLC-MS represents a viable alternative to conventional 2.1 mm i.d. formats for routine large-scale metabolic profiling studies while also resulting in a 75% reduction in solvent usage. The modest increase in sensitivity provided by this methodology also offers the potential to either reduce sample consumption or increase the number of metabolite features detected with confidence due to the increased signal-to-noise ratios obtained. Implementation of this miniaturized UPLC-MS method of metabolic phenotyping results in clear analytical, economic, and environmental benefits for large-scale metabolic profiling studies with similar or improved analytical performance compared to conventional UPLC-MS. PMID- 25917013 TI - The effect of aging on the cutaneous microvasculature. AB - Aging is associated with a progressive loss of function in all organs. Under normal conditions the physiologic compensation for age-related deficits is sufficient, but during times of stress the limitations of this reserve become evident. Explanations for this reduction in reserve include the changes in the microcirculation that occur during the normal aging process. The microcirculation is defined as the blood flow through arterioles, capillaries and venules, which are the smallest vessels in the vasculature and are embedded within organs and tissues. Optimal strategies to maintain the microvasculature following surgery and other stressors must use multifactorial approaches. Using skin as the model organ, we will review the anatomical and functional changes in the microcirculation with aging, and some of the available clinical strategies to potentially mitigate the effect of these changes on important clinical outcomes. PMID- 25917017 TI - Effect of Electrical Stimulation of the Suprahyoid Muscles in Brain-Injured Patients with Dysphagia. AB - The purpose of this study is to determine whether neuromuscular electrical stimulation of the suprahyoid muscle is effective compared to that of the infrahyoid muscle in brain-injured patients with dysphagia. A total of 132 patients with stroke, traumatic brain injury, or brain tumor in 2 university hospitals were allocated to 2 groups: those who received electrical stimulation therapy (EST) on the suprahyoid muscles (SM group, n = 66) and those who received EST with one pair of electrodes on the suprahyoid muscle and the other pair on the infrahyoid muscle (SI group, n = 66). Patients received 11.2 +/- 3.4 sessions of electrical stimulation in the SM group and 11.9 +/- 3.4 sessions in the SI group. The functional dysphagia scale (FDS), swallow function score (SFS), supraglottic penetration, and subglottic aspiration were measured using videofluoroscopic swallowing study. FDS scores decreased from 42.0 +/- 19.1 to 32.3 +/- 17.8 in the SM group and from 44.8 +/- 17.4 to 32.9 +/- 18.8 in the SI group by per-protocol (PP) analysis, and those decreased from 41.2 +/- 20.9 to 34.5 +/- 20.3 in the SM group and from 44.3 +/- 19.1 to 35.7 +/- 20.5 in the SI group by intention-to-treat (ITT) analysis, after electrical stimulation (p < 0.001 for each). SFSs increased from 3.3 +/- 1.8 to 4.2 +/- 1.6 in the SM group and from 2.8 +/- 1.8 to 4.0 +/- 1.8 in the SI group by PP analysis, and those increased from 3.3 +/- 1.6 to 3.9 +/- 1.6 in the SM group and from 2.8 +/- 1.9 to 3.6 +/- 2.0 in the SI group by ITT analysis, after electrical stimulation (p < 0.001, respectively). However, changes in FDS scores, SFSs, penetration, and aspiration were comparable between the SM and the SI groups. The results suggest that both SM and SI therapies induced similar improvements in swallowing function in brain-injured patients. PMID- 25917018 TI - Effectiveness of Non-invasive Brain Stimulation in Dysphagia Subsequent to Stroke: A Systemic Review and Meta-analysis. AB - The objective of this study is to assess the efficacy and safety of non-invasive brain stimulation (NIBS) in patients with dysphagia subsequent to stroke. A systematic search of the literature published by Medline (January 1, 1976 through June 21, 2013), EMBASE (January 1, 1985 through June 21, 2013), and the Cochrane Library (January 1, 1987 through June 21, 2013) was conducted for all relevant articles related to NIBS, dysphagia, and cerebrovascular disorders (CVD). Two reviewers (S.N.Y and S.B.P) independently evaluated the eligibility of retrieved data according to the selection criteria and assessed methodological quality of the studies using the 'assessing risk of bias' table recommended in the Cochrane Handbook for Systematic Reviews of Interventions (version 5.0.2). Six randomized controlled trials (59 intervention groups and 55 placebo groups) were identified as addressing the use of NIBS for dysphagia after CVD and were included in the meta-analysis. The function scale score improvement of dysphagia in patients treated with NIBS was statistically significant compared with that of patients who underwent sham stimulation (standardized mean difference = 1.08, 95 % confidence intervals = 0.29-1.88, p = 0.008; I (2) = 72 %). A subgroup analysis based on the type of intervention (three repetitive transcranial magnetic stimulation (rTMS) studies and three transcranial direct current stimulation (tDCS) studies) revealed a statistically significant beneficial effect of NIBS compared with sham stimulation in the rTMS group, but not in the tDCS group. When the results were examined based on intervention site (ipsilesional vs. contralesional site stimulation), no statistically significant difference was noted between two groups. No complications of NIBS were reported in this analysis. PMID- 25917016 TI - Nf1 Haploinsufficiency Alters Myeloid Lineage Commitment and Function, Leading to Deranged Skeletal Homeostasis. AB - Although nullizygous loss of NF1 leads to myeloid malignancies, haploinsufficient loss of NF1 (Nf1) has been shown to contribute to osteopenia and osteoporosis which occurs in approximately 50% of neurofibromatosis type 1 (NF1) patients. Bone marrow mononuclear cells of haploinsufficient NF1 patients and Nf1(+/-) mice exhibit increased osteoclastogenesis and accelerated bone turnover; however, the culprit hematopoietic lineages responsible for perpetuating these osteolytic manifestations have yet to be elucidated. Here we demonstrate that conditional inactivation of a single Nf1 allele within the myeloid progenitor cell population (Nf1-LysM) is necessary and sufficient to promote multiple osteoclast gains-in function, resulting in enhanced osteoclastogenesis and accelerated osteoclast bone lytic activity in response to proresorptive challenge in vivo. Surprisingly, mice conditionally Nf1 heterozygous in mature, terminally differentiated osteoclasts (Nf1-Ctsk) do not exhibit any of these skeletal phenotypes, indicating a critical requirement for Nf1 haploinsufficiency at a more primitive/progenitor stage of myeloid development in perpetuating osteolytic activity. We further identified p21Ras-dependent hyperphosphorylation of Pu.1 within the nucleus of Nf1 haploinsufficient myelomonocytic osteoclast precursors, providing a novel therapeutic target for the potential treatment of NF1 associated osteolytic manifestations. PMID- 25917020 TI - Why quality matters. PMID- 25917021 TI - Congenital chylothorax treated with oral sildenafil: a case report and review of the literature. AB - Congenital chylothorax (CC) can result from a congenital malformation or an acquired obstruction or disruption of the thoracic duct. Recently, oral administration of the phosphodiesterase-5 inhibitor, sildenafil, was reported to be effective in resolving non-pulmonary lymphatic malformations in infants and young children. We report a case of CC in a late preterm infant with congenital pulmonary lymphangiectasia where octreotide was not effective, but management with oral sildenafil was successful. PMID- 25917023 TI - Monitoring risk for oesophageal thermal injury during radiofrequency catheter ablation for atrial fibrillation: does the characteristic of the temperature probe matter? PMID- 25917022 TI - Radiocarbon concentration in modern tree rings from Fukushima, Japan. AB - A 30-year-old Japanese cedar (Cryptomeria japonica), collected from Iwaki, Fukushima in 2014, was analyzed for the long-lived radionuclide (14)C. Values of Delta(14)C varied from 211.70/00 in 1984 to 16.90/00 in 2013. The temporal Delta(14)C variation can be described as an exponential decline, indistinguishable from the general Northern Hemisphere Zone 2 (NH Zone 2) values in the atmosphere, until at least 1994. Values of Delta(14)C for 1999 and 2004 are slightly depleted compared with NH Zone 2 values, while from 1999 to 2013 the data suggest a clear depletion with a 2-8 ppmV additional CO2 contribution from a (14)C-free (i.e. fossil carbon) source. This change coincides with local traffic increases since two nearby expressways were opened in the 1990's. In addition, the small but visible (14)C pulse observed in the 2011 tree-ring might be caused by release from the damaged reactors during the Fukushima nuclear accident. PMID- 25917024 TI - Preoperative skin antiseptics for prevention of cardiac implantable electronic device infections: a historical-controlled interventional trial comparing aqueous against alcoholic povidone-iodine solutions. AB - AIMS: Local skin antiseptic prevention against cardiac implantable electronic device (CIED) infections is not yet fully understood. This monocentre historical controlled study sought to (i) conduct a prospective observational analysis comparing two antiseptic skin preparations over two similar consecutive periods of time, one conducted over a 1-year period using an aqueous povidone-iodine solution (Group I) and the other over the following with an alcoholic povidone iodine solution (Group II); (ii) determine the predictive factors of CIED infection. METHODS AND RESULTS: Cardiac implantable electronic device implantation was performed in 1326 patients (pts). A total of 32 pts (2.4%) developed a CIED infection. Long-term follow-up (26 +/- 3 months) revealed no significant difference between the groups: infections were observed in 14 of the 648 pts (2.2%) in Group I vs. 18 of the 678 pts (2.7%) in Group II (P = 0.9). Single- and multiple-variable logistic regression analyses were performed to identify risk factors; adjusted odds ratios (aORs) and 95% confidence intervals (CIs) were calculated. The occurrence of infection was positively correlated with re-intervention (aOR, 7.16; 95% CI, 2.56-19.99; P < 0.0001), number of generator replacements, mean (aOR, 3.47; 95% CI, 2.22-5.44; P < 0.001), and haematoma (aOR, 48.4; 95% CI, 13.45-174.25; P < 0.0001). CONCLUSION: This study found that aqueous and alcoholic povidone-iodine solutions displayed similar antiseptic effects regarding CIED infection prevention. Independent predictive factors of CIED infection were re-intervention, haematoma, and number of generator replacements. PMID- 25917025 TI - Ventricular tachycardia ablation after post-infarction ventricular septal defect occluder placement. PMID- 25917026 TI - Neuroprotective or neurotoxic effects of 4-aminopyridine mediated by KChIP1 regulation through adjustment of Kv 4.3 potassium channels expression and GABA mediated transmission in primary hippocampal cells. AB - 4-Aminopyridine (4-AP) is a potassium channel blocker used for the treatment of neuromuscular disorders. Otherwise, it has been described to produce a large number of adverse effects among them cell death mediated mainly by blockage of K(+) channels. However, a protective effect against cell death has also been described. On the other hand, Kv channel interacting protein 1 (KChIP1) is a neuronal calcium sensor protein that is predominantly expressed at GABAergic synapses and it has been related with modulation of K(+) channels, GABAergic transmission and cell death. According to this KChIP1 could play a key role in the protective or toxic effects induced by 4-AP. We evaluated, in wild type and KChIP1 silenced primary hippocampal neurons, the effect of 4-AP (0.25MUM to 2mM) with or without semicarbazide (0.3M) co-treatment after 24h and after 14 days 4 AP alone exposure on cell viability, the effect of 4-AP (0.25MUM to 2mM) on KChIP1 and Kv 4.3 potassium channels gene expression and GABAergic transmission after 24h treatment or after 14 days exposure to 4-AP (0.25MUM to1MUM). 4-AP induced cell death after 24h (from 1mM) and after 14 days treatment. We observed that 4-AP modulates KChIP1 which regulate Kv 4.3 channels expression and GABAergic transmission. Our study suggests that KChIP1 is a key gene that has a protective effect up to certain concentration after short-term treatment with 4 AP against induced cell injury; but this protection is erased after long term exposure, due to KChIP1 down-regulation predisposing cell to 4-AP induced damages. These data might help to explain protective and toxic effects observed after overdose and long term exposure. PMID- 25917028 TI - [New comprehension of markers in outcomes and disease assessment of chronic obstructive pulmonary disease]. PMID- 25917027 TI - The Gene bldA, a regulator of morphological differentiation and antibiotic production in streptomyces. AB - Streptomyces species are well known for their particular features of morphological differentiation. On solid agar, a mold-like aerial mycelium is formed and spores are produced, in which the bld genes play a crucial role. In S. coelicolor, mutations in one specific bld gene called bldA led to a "naked" phenotype lacking aerial hyphae and spores. This peculiar behavior became a major interest for scientific research in the past and it was revealed that bldA is coding for a unique tRNA able to translate a UUA codon into the amino acid leucine. UUA codons are a very rare property of G + C-rich Streptomyces genomes. The impact of bldA on morphology can in parts be attributed to the regulatory effect of bldA on the translational level, because TTA-containing genes can only be translated into their corresponding protein in the presence of a fully functioning bldA gene. In addition to the visible effect of bldA expression on the phenotype of S. coelicolor, bldA mutants were also deficient in antibiotic production. This led to the assumption that the role of bldA must exceed translational control. Many TTA-containing genes are coding for transcriptional regulators which are activating or repressing the transcription of many more genes. Proteomics and transcriptomics are two powerful methods for identifying bldA target genes and it was possible to assign also post-translational regulation to bldA. This review wants to give a short overview on the importance of bldA as a regulator of morphological differentiation and antibiotic production by switching on "silent" gene clusters in Streptomyces. PMID- 25917029 TI - [Molecular targeted therapy of non-small cell lung cancer in China: the first 10 years]. PMID- 25917030 TI - [Present status of medical treatment for patients with chronic obstructive pulmonary disease based upon different severity classifications]. AB - OBJECTIVE: To survey the present status of medical treatment for Chinese outpatients with chronic obstructive pulmonary disease (COPD) based upon the guidelines for diagnosing and treating COPD (2007 Revised Edition and 2013 Revised Edition) and explore the impact of new guideline on treatment regimens. METHODS: A retrospective study was conducted at 11 participating hospitals. Stable COPD patients were consecutively recruited from outpatient clinics in China between September 2007 and December 2008 and categorized into the Global Initiative for Chronic Obstructive Lung Disease (GOLD) I-IV classification and A D groups according to the Chinese guidelines for diagnosing and treating COPD (2007 Revised Edition and 2013 Revised Edition). The authors compared the present status of medical treatment of two guidelines and analyze the impact of new guideline on treatment regimens. RESULTS: Among a total of 749 patients, 79.2% (593/749) patients received medical treatment. The distribution of classification GOLD I-IV was 34 (4.5%), 211 (28.2%), 309 (41.3%) and 195 (26.0%). According to the guideline 2007, the patients on medical under-treatment based upon the guidelines in GOLD I-IV classification were 32.4% (11/34), 53.6% (113/211), 57.6% (178/309) and 55.4% (108/195); those on medical treatment: 23.5% (8/34), 3.8% (8/211), 28.8% (89/309) and 33.3% (65/195); those on medical over-treatment: 44.1% (15/34), 42.7% (90/211), 13.6% (42/309), 11.3% (22/195). The distribution of categories A-D was 93 (12.4%), 45 (6.0%), 196 (26.2%), and 415 (55.4%). According to guideline 2013, the patients on medical under-treatment were 34.4% (32/93), 62.2% (28/45), 67.9% (133/196) and 60.7% (252/415); those on medical treatment: 24.7% (23/93), 4.4% (2/45), 32.1% (63 /196) and 39.3% (163/415); those on medical over-treatment: 40.9% (38/93), 33.3% (15/45), 0 and 0. The concordance analysis comparing the judgments of treatment regimens by these two guideline yielded a weighted Kappa coefficient of 0.534 (P < 0.001), indicating that there was a moderate degree of judgments between two guidelines. Medical treatment regimens recommended by new guideline was different from old guideline in 143 COPD patients. Among them, 24 patients (16.8%) required a step-down therapy while 119 patients (83.2%) a step-up therapy. CONCLUSIONS: There are more outpatients with COPD on medical treatment, but few of them have received standardized treatment. Compared with the old GOLD classification, more patients are recommended for a step-up therapy by new stratification. PMID- 25917031 TI - [Desmosine plasma levels and exacerbation risk assessment of chronic obstructive pulmonary disease]. AB - OBJECTIVE: To explore the relationship between desmosine plasma levels and exacerbation risk in patients with chronic obstructive pulmonary disease (COPD). METHODS: COPD patients and normal subjects were recruited from Beijing Hospital during March 2013 to March 2014. COPD patients were divided into COPD low risk and COPD high risk groups according to the criteria of Global Initiative for Chronic Obstructive Lung Disease (GOLD) strategy. The plasma concentrations of desmosine were measured by enzyme-linked immunosorbent assay (ELISA) for exploring the inter-group difference in desmosine levels. RESULTS: Sixty-three COPD patients (COPD low risk group, n = 30; COPD high risk group, n = 33) and 50 normal subjects (24 healthy non-smokers, 26 healthy smokers) were recruited. The plasma desmosine concentrations in healthy non-smokers, healthy smokers, low risk and high risk COPD patients were (200 +/- 159), (191 +/- 105), (197 +/- 118) and (131 +/- 47) ng/L respectively. The plasma concentration of desmosine was significantly lower in COPD high risk group than healthy non-smokers (mean difference -70, 95%CI: -128--11, P = 0.021), healthy smokers (mean difference 60, 95%CI: -118--3, P = 0.039) and COPD low risk group (mean difference -67, 95%CI: -122--12, P = 0.018). The plasma concentration of desmosine was negatively correlated with exacerbation frequency (r = -0.409, P = 0.002), mMRC scores (r = 0.447, P = 0.010) and emphysema severity (r = -0.386, P = 0.047) in COPD patients. No significant correlation existed between desmosine plasma levels and forced expiratory volume in one second (FEV1%pred) in COPD patients (r = 0.225, P = 0.084). CONCLUSIONS: The plasma levels of desmosine are lower in high risk COPD patients than those in normal subjects or low risk COPD patients. And it is negatively correlated with exacerbation frequency in COPD patients. PMID- 25917032 TI - [Role and mechanism of heat shock protein 70 in airway hypersecretion]. AB - OBJECTIVE: To explore the role and mechanism of heat shock protein 70 (HSP70) in airway hypersecretion. METHODS: After a stimulation of 8% cigarette smoke extract (CSE), airway cells A549 were treated with HSP70 antibody and c-Jun N-terminal kinase (JNK) specific inhibitor SP600125 respectively. And the cells were divided into 4 groups of blank contrast (serum-free medium), CSE stimulation (8% CSE for 24 h), HSP70 antibody (30-min pre-treatment of HSP70 antibody and culturing in 8% CSE for 24 h) and SP600125 (30-min pre-treatment of SP600125 30 umol/L and culturing in 8% CSE for 24 h). The relative expression levels of MUC5AC protein in various groups were determined by enzyme-linked immunosorbent assay (ELISA). And the relative transcription level of MUC5AC mRNA was detected by reverse transcription-polymerase chain reaction (PCR) while the synthesized levels of HS70 as well as the phosphorylation levels of JNK and activated protein-1 (mostly c-Jun) were measured by Western blot. RESULTS: As compared with those in blank contrast group (0.26 +/- 0.10, 0.28 +/- 0.06, 0.30 +/- 0.05, 0.30 +/- 0.08, 0.36 +/- 0.08), HSP70 antibody group (0.30 +/- 0.12, 0.29 +/- 0.09, 0.34 +/- 0.06, 0.47 +/- 0.19, 0.39 +/- 0.13) and SP600125 group (0.38 +/- 0.06, 0.31 +/- 0.14, 0.39 +/- 0.04, 0.44 +/- 0.12, 0.48 +/- 0.11), the relative expression levels of MUC5AC protein and mRNA, phosphorylation JNK (p-JNK), c-Jun and p-c-Jun (0.52 +/- 0.07, 0.64 +/- 0.11, 0.73 +/- 0.06, 0.67 +/- 0.10, 0.67 +/- 0.09) significantly increased in CSE stimulation group (all P < 0.05). And the synthesis levels of HSP70 (0.75 +/- 0.09) in CSE stimulation group increased than blank contrast group (0.29 +/- 0.03) and HSP70 antibody group (0.40 +/- 0.11) (all P < 0.05). CONCLUSION: HSP70 may enhance the expression of MUC5AC in bronchial epithelial A549 cells via a signaling pathway of JNK/AP-1.. PMID- 25917033 TI - [Clinical characteristics and molecular epidemiology of carbapenem- resistant Acinetobacter baumannii infections at Shenzhen People's Hospital during an 8-year period]. AB - OBJECTIVE: To investigate the clinical features, mechanism of resistance and molecular epidemiology of carbapenem-resistant Acinetobacter baumannii (CRAB) infections at Shenzhen People's Hospital during an 8-year period. METHODS: A. baumannii isolates were recovered from nosocomial infections patients at this hospital from 2002 to 2009. The minimum inhibitory concentrations (MICs) of antimicrobial agents against A. baumannii isolates were detected by agar dilution method. Polymerase chain reaction (PCR) and DNA sequencing were used to examine the carbapenemase genotype among CRAB. All isolates were typed by pulse field gel electrophoresis (PFGE). Clinical cases of CRAB infections were retrospectively analyzed according to Chinese experts' consensus on diagnosis, treatments, preventions and controls of Acinetobacter baumannii infections in China. RESULTS: A total of 87 cases of CRAB nosocomial infections were diagnosed in this study. The most prominent infections caused by CRAB was lung infections, followed by bloodstream infections, wound infections and abdominal infections, accounting for 69.0%, 8.0%, 8.0% and 6.9% of 87 cases, respectively. Approximately 80.5% (70/87) of CRAB isolated from intensive care unit (ICU). A sharp increase of CRAB infections (42/87) occurred in 2009, with the majority of pulmonary infections (34/42). Genotyping by PFGE found eight distinct PFGE patterns among 87 isolates of CRAB. The prominent CRAB clone A, carrying a blaOXA-58-like carbapenemase gene, had been prevalent from 2002 to 2006 at this hospital. The CRAB clone C, harboring a blaOXA-23-like carbapenemase gene, as well as clone A became the prominent clones during 2007 to 2008. The CRAB clone D, carrying a blaOXA-23-like carbapenemase gene, replaced clone A and C, and became the dominant clone in 2009. CONCLUSION: The spread of the CRAB clone D harboring a blaOXA-23-like gene causes a rapid increase of CRAB infections at this hospital during 2009. PMID- 25917034 TI - [Risk factors for primary patency of occlusive femoral artery after subintimal angioplasty in diabetics]. AB - OBJECTIVE: To retrospectively explore the status of primary patency after subintimal angioplasty (SIA) and identify the risk factors affecting for primary patency of occlusive lesions in femoral arteries after SIA in patients with diabeticses mellitus. METHODS: From January 2009 to May 2011, 43 diabetics patients with 43 occlusive femoral arteries were successfully underwent subintimal angioplasty successfully with or without stenting.Recurrent stenosis was defined as an arterial diameter reduction of over 50%. And arterial occlusion was confirmed by an absence of color or power signal in the arterial lumen measured on color Doppler. The Kaplan-Meier method was employed to determine the primary patency. A multivariate analysis was performed with Cox's proportional hazard regression model to determine the independent factors for effects on primary patency. RESULTS: A total of 17 morphologic abnormalities occurred during a median follow-up period of 21 (14-32) months. The median follow time of the successful 43 patients was 21 months (from 14 to 32 month). Minor complications occurred in 4 patents. There was no early mortality. A total of 17 morphologic abnormalities occurred during follow-up. The cumulative primary patency at 6, 12, 12 and 24 months were (86 +/- 5)%, (75% +/- 7)% and (43 +/- 12)% respectively. Primary patency was affected negatively by the number of occlusive run-off vessels (B = -4.417, SX- = 1.627, P = 0.007) and the severity degree according to the Inter-society consensus for the management of peripheral arterial disease (TASC II) classification (B = -2.502, SX- = 0.955, P = 0.009), and positively by the a history of smoking (B = 3.115, SX- = 1.523, P = 0.041). CONCLUSIONS: Subintimal angioplasty is a less invasive procedure with a lower rate of morbidity and adequate cceptable patency. And the number of occlusive run-off vessels, lesion typing degree of severity according to the TASC II classification negatively and smoking positively have significant influence effects on the primary patency in diabetics patients. PMID- 25917035 TI - [Value of FOXP3 Tregs predicting the effectiveness of neoadjuvant chemotherapy in patients with breast cancer]. AB - OBJECTIVE: To explore the predictive significance of FOXP3 Tregs in patients with breast cancer on neoadjuvant chemotherapy (NACT). METHODS: A total of 78 newly diagnosed and untreated patients with invasive breast cancer were recruited for this retrospective study.FOXP3 Tregs were assessed by immunohistochemistry. The relationship between clinicopathological factors, FOXP3+ Tregs and pathological complete response (pCR) rate was analyzed. RESULTS: Among 78 patients with TAC neoadjuvant chemotherapy, the pCR rate was 19.2%. The pCR rate of patients with high expressions of FOXP3+ Tregs was significantly lower than that of those with low expressions of FOXP3+ Tregs (9.5% vs 30.5%, P = 0.023). FOXP3+ Tregs expression in breast cancer and efficacy of NACT were negatively correlated. CONCLUSION: FOXP3+ Tregs may serve as a predictor for assessing the efficacy of NACT. PMID- 25917036 TI - [Functions of inflammatory factor in non-tumor deep venous thrombosis of lower extremity]. AB - OBJECTIVE: To explore the functions of inflammatory cytokine, tissue factor (TF) and cancer procoagulant (CP) in non-tumor deep venous thrombosis (NT-DVT). METHODS: A total of 17 NT-DVT patients (5 males and 12 females) were selected for NT-DVT group while 20 voluntary (10 males and 10 females) blood donors for control group from May 2012 to March 2013. The levels of inflammatory cytokines interleukin 1beta (IL-1 beta), IL-18, tumor necrosis factor alpha (TNF-alpha), TF and CP were tested by enzyme-linked immunosorbent assay (ELISA) before and after treatment. Also the correlations of inflammatory cytokines and TF were determined. RESULTS: The levels of inflammatory cytokines and TF were higher in NT-DVT than those in control group pre-treatment ((153.13 +/- 2.30) vs (59.26 +/- 1.57) ng/L, (364.27 +/- 1.46) vs (67.46 +/- 1.48) ng/L, (363.51 +/- 1.85) vs (216.42 +/- 1.55) ug/L, (66.90 +/- 1.44) vs (14.55 +/- 1.52) ng/L, all P < 0.05). And after anticoagulant therapy, the levels decreased (all P < 0.05). Also the levels of IL-1beta,IL-18 and TNF-alpha were positively correlated with TF pre treatment. And the correlation coefficients were 0.492 (P = 0.045), 0.652 (P = 0.005) and 0.511(P = 0.036) respectively. Compared with control group, the plasma level of CP had no obvious change before and after treatment (both P > 0.05). CONCLUSION: A high level of inflammatory cytokines is an important risk factor for NT-DVT. PMID- 25917037 TI - [Effects of denervation on angiogenesis and skeletal muscle fiber remodeling of ischemic limbs]. AB - OBJECTIVE: To establish a murine model of hindlimb ischemia and denervation and evaluate the effects of neural factors on angiogenesis and skeletal muscle fiber remodeling. METHODS: A total of 54 mice were randomly allocated into three groups of control (n = 6), hindlimb ischemia (n = 24), hindlimb ischemia and denervation (n = 24). The model of hindlimb ischemia was established by ligating femoral artery. And the model of hindlimb ischemia and denervation was established by transecting sciatic nerve on the basis of hindlimb ischemia modeling. Gastrocnemius of ischemic hindlimbs were harvested under the condition of peritoneal cavity anesthesia at Days 7, 14, 21 and 28 postoperation. And then the mice were sacrificed. The gastrocnemius of three groups were tested by hematoxylin-eosin staining, CD31 and PCNA immunohistochemical staining and myosin ATPase staining. The protein expressions of nerve growth factor (NGF) and vascular endothelial growth factor (VEGF) were detected by enzyme-linked immunosorbent assay. RESULTS: At Day 7 postoperation, hindlimbs of two intervention groups showed ischemic manifestations as compared with controls. And semiquantitative assessment of ischemic damage showed the proportion level I-IV of hindlimb ischemia and denervation group was significantly higher than that of hindlimb ischemia group (33.4% vs. 16.6%, chi(2) = 7.94, P = 0.047). At Day 28 postoperation, the values of endothelial cell proliferation index [(2.4 +/- 0.4)% vs. (5.7 +/- 1.0)%, P = 0.000], capillary density [(0.44 +/- 0.05) vs. (0.61 +/- 0.07), P = 0.000], NGF protein expression [(6.71 +/- 0.94) vs. (8.36 +/- 0.77) pg/ml, P = 0.008] and VEGF protein expression [(11.32 +/- 1.56) vs. (15.13 +/- 2.93) pg/ml, P = 0.018] of hindlimb ischemia and denervation group significantly decreased as compared with hindlimb ischemia group. At Day 28 postoperation, the proportion of type II muscle fiber in gastrocnemius was significantly higher than that of hindlimb ischemia group [(84.9 +/- 3.8)% vs. (78.8 +/- 1.8)%, P = 0.008]. CONCLUSION: Neural factors play important roles in promoting angiogenesis and maintaining muscle fiber types in ischemic limbs. But its molecular regulatory mechanism requires further studies. PMID- 25917038 TI - [Biological roles of somatostatin in intestinal macaque Peyer's patch B cells]. AB - OBJECTIVE: To explore the effects of somatostatin (SST) on macaque intestinal Peyer's patches (PP) in immune B cells and explore its mechanism. METHODS: A total of 15 healthy adult macaques were randomized into control,MODS and MODS+SST groups.Surgical procedures of MODS in macaques: For MODS group, anesthesia was maintained with diazepam (0.16 +/- 0.09) mg*kg(-1)*h(-1), i.v.). A catheter was inserted into a peripheral vein for infusing 0.9% saline and 20 g glucose (0.1 0.2 ml*kg(-1)*min(-1), i.v.gtt) for 24 h. Midline laparotomy was performed. Then superior mesenteric artery (SMA) was isolated and occluded with a microsurgical clip. After a 1-hour occlusion, clip was removed and intestinal perfusion reestablished.In MODS+SST group, SST was infused intravenously with a syringe pump at a dosage of 5 ug*kg(-1)*h(-1) for 5 min before an occlusion of SMA until the end of experiment.Venous blood samples were redrawn and the animals sacrificed at 24 h post-IIR for harvesting vital organs. The changes of organs and the morphological changes of PP were detected by hematoxylin and eosin. And the expressions of TLR4, TLR2, CD20, CD5, alpha4beta7 and MadCAM-1 were evaluated by immunohistochemical staining.Semiquantitative immunohistochemical analysis of raw data was performed with Image Pro Plus 4.0 software. RESULTS: All animals in MODS group presented with small intestines PP increased both in number and size compared with control group (4.8 +/- 2.3 vs 1.2 +/- 0.9, P < 0.05). After prophylactic to SST, compared with MODS group, the number of PP in small intestines in MODS+SST group decreased (2.7 +/- 1.5 vs 4.8 +/- 2.3, P < 0.05), but there was no significant difference in morphological of PP. The expression of CD20(+) of B-cells in MODS group was significantly lower than in normal group (integrated optical density (IOD), 64.22 +/- 42.45 vs 100.00 +/- 86.67, P < 0.05).Interestingly, after prophylactic dosing of SST, the expression level of CD20(+) of B-cells elevated significantly in MODS+SST group compared with that in MODS group (129.02 +/- 75.04 vs 64.22 +/- 42.45, P < 0.05). There was no alpha4beta7 expression of B-cells in PP of macaques in three groups. And the expression level of MadCAM-1 was strongly up-regulated after prophylactic dosing of STT compared with MODS. After prophylactic dosing of STT, the expressions of TLR4 and TLR2 declined significantly compared with MODS (56.60 +/- 6.83 vs 93.26 +/- 10.40, 35.56 +/- 4.71 vs 62.06 +/- 9.90, P < 0.05). Plasma cells within normal intestinal mucosa were predominantly located in lamina propria. During MODS, plasma cells almost disappeared. After prophylactic dosing of STT, compared to MODS group, there was a rebound of plasma cells. CONCLUSIONS: Endogenous SST controls the switch of B-cells in PP between natural and acquired immunities. The prophylactic dosing of SST could convert excessive natural immunity into beneficial acquired humoral immunity. And SST may facilitate the prevention of multiple organ dysfunction syndromes. PMID- 25917039 TI - [Effects of transcription factor sterol regulatory element binding protein-1c in palmitate acid-induced L6 cells insulin resistance and its mechanism]. AB - OBJECTIVE: Sterol regulatory element binding protein-1c (SREBP-1c) is a master regulator of fatty acid synthase and controls lipogenesis. And insulin receptor substrate-1 (IRS-1) is a key insulin signaling mediator in skeletal muscle. The present study was conducted to explore the mechanism of SREBP-1c in the regulation of IRS-1 in skeletal muscle cells and elucidate the role of SREBP-1c in high fat-induced skeletal muscle insulin resistance. METHODS: L6 cells differentiated into myotubes in differentiation medium with 2%FBS. An in vitro insulin resistant model in L6 myotubes was established by 500 umol/L of palmitate acid (PA). SREBP-1c, p-IRS-1(Tyr608/612), IRS-1, p-AKT (Ser473) and AKT were detected by Western blot after incubating L6 myobutes with 500 umol/L of PA for 0.5, 1, 3, 6, 12, 18 or 24 h.SREBP-1c, FAS and molecules related to insulin signaling pathway were detected by Western blot when L6 myotubes over-expressed SREBP-1c or after a treatment of liver X receptor (LXR) agonist (TO901317, 5 umol/L). The regulatory effects of transcription factor SREBP-1c on promoter region of IRS-1 were assessed by dual-luciferase reporter assay. RESULTS: SREBP 1c protein expression increased significantly after 1-hour exposure to PA. The protein levels of p-IRS-1(Tyr608/612),IRS-1 and p-AKt (Ser473) decreased significantly after a 6-hour incubation of PA. However AKT protein levels were unaffected. The protein expressions of SREBP-1c and FAS were up-regulated by LXR agonist treatment versus controls. By contrast, LXR agonist treatment led to decreased expressions of IRS-1, p-IRS-1(Tyr608/612) and p-AKt (Ser473)/AKT proteins versus controls. The expressions of related proteins were similar to the observations made with LXR agonist intervention. The results of dual-luciferase reporter assay indicated that IRS-1 promoter activity was repressed significantly by SREBP-1c over-expression or TO901317 treatment whereas the dominant negative form of SREBP-1c (a mutant of Tyr320Ala lacking the ability of binding DNA) had no effect. CONCLUSION: SREBP-1c may suppress IRS-1 expression and the subsequent insulin signaling pathway. And it plays a key role in PA-induced insulin resistance of skeletal muscle. PMID- 25917040 TI - [Prevalence, awareness, treatment and control of hypertension in rural areas in North China in 2013]. AB - OBJECTIVE: To investigate the percentages of awareness, treatment and control and the prevalence of hypertension in north rural China. METHODS: An epidemiological study was conducted by stratified cluster random sampling in March 2013 within 4 out of 20 regions in north China. At least 1 250 residents aged over 35 years were recruited and there were 625 males and 625 females from 4 villages randomly selected from each region. The risk factors for hypertension such as blood pressure (BP), height, weight and past history of illness were collected.From 4 575 valid samples, there were 2 062 males and 2 513 females.Hypertension was defined as any subject with mean systolic blood pressure >= 140 mmHg, diastolic blood pressure >= 90 mmHg or use of antihypertensive medication. All the relevant rates were standardized by gender and age group according to the figures of Third National Population Census. RESULTS: The standardized rates of hypertension in population aged over 35 years were 41.2% in Shunyi District, Beijing, 26.0% in Yuzhong County, Gansu Province, 25.2% in Jingyu County, Jilin Province and 22.8% in Dongfeng County, Jilin Province respectively. And significant differences existed among different regions (P < 0.001). The prevalence of hypertension in males was higher than that in females. The overall rates of awareness, treatment, control and control under treatment were 46.9%, 30.5%, 12.8% and 41.5% respectively in males versus 64.2%, 48.9%, 20.4% and 38.4% respectively in females. These rates were significantly higher in people with a family history of hypertension than those without one (P < 0.05). The prevalence of hypertension and the rates of awareness, treatment increased with the increase of BMI (P < 0.05) other than the rates of control and control with drugs. CONCLUSION: The prevalence of hypertension was of great difference between different rural areas in north China. The rates of awareness, treatment and control have remained at a low level. PMID- 25917041 TI - [A systematic evaluation on the quality of Meta-analysis in articles published in National Medical Journal of China from 1998 to 2014]. AB - OBJECTIVE: To assess qualities on methodologies and reporting on Meta-analysis used in papers being published in National Medical Journal of China. METHODS: Computerized literature searching was performed in Wangfang Medical Online to collect articles that Meta-analysis was used in the National Medical Journal of China since January 1998 until October 2014. Manual retrieval was also conducted.Qualities on methodologies and reporting were evaluated by both Assessment of Multiple Systematic Reviews (AMSTAR) and Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) scales. RESULTS: A total of 74 papers were included. The results on the qualities of methodology evaluation in these papers were 3 to 10 (median 7) scores, 10 articles (13.5%) were rated as high, 61 articles (82.4%) as moderate and 3 articles (4.1%) as low. No statistically significant difference existed in each year of AMSTAR score (chi(2) = 10.205, P = 0.423). The titles of AMSTAR scales with a lower coincidence rate were "Was a list of studies (included and excluded) provided?", "Was the conflict of interest stated?", "Was the status of publication (i.e.grey literature) used as an inclusion criterion?" and "Was the likelihood of publication bias assessed?". The results on the qualities of reporting evaluation in these papers were 5.5 to 26 (median 20) scores, 9 articles (12.2%) scored <15 points, 39 articles (52.7%) 15.5-21 points and 26 articles (35.1%) 21.5-27 points. There was statistically significant difference in each year of PRISMA score (F = 4.301, P = 0.000). And the year 2010 was the highest one. The titles of PRISMA scales with a lack of comprehensive reports were "Structured summary", "Objectives of introduction", "Protocol & registration", "Data collection process", "Data items", "Risk of bias in individual studies", "Risk of bias across studies", "Additional analyses", "Study selection","Risk of bias within studies", "Conclusion limitations", "Conclusions" and "Funding support" etc. CONCLUSIONS: Articles of Meta-analysis published in National Medical Journal of China have a high quality so as to provide rationales for clinical decision-making. However, both of qualities on methodology and reports sill call for continual improvements. PMID- 25917042 TI - Photodynamic therapy as salvage therapy for patients with nasopharyngeal carcinoma experiencing local failures following definitive radiotherapy. AB - BACKGROUND: Treating local failures of nasopharyngeal carcinoma (NPC) is a challenge. This study evaluates photodynamic therapy (PDT) in the treatment of residual and recurrent NPC. METHOD: In this phase II study, patients with local recurrent or residual NPC after curative intent (chemo-) radiation could be included. Exclusion criterion was a tumour depth more than 10mm. Foscan(r) 0.15mg/kg was administered intravenously. After 96h, the illumination was performed under local anaesthesia with a nasopharyngeal light applicator. Tumour response was measured 10 weeks after illumination by endoscopy, biopsy and CT scan. Kaplan-Meier method was used for survival analysis. RESULTS: Twenty-one patients were included. Fourteen patients were treated for residual disease (67%), and two for recurrent (10%). For five patients this distinction could not be made, due to uncertainty about complete response after initial treatment. The median follow-up time was 32 months. Twenty patients (95%) had a complete response 10 weeks post-treatment. Two patients had recurrent local disease at 5 and 7 months post-PDT. They received another course of PDT, one with success. The 2-year local control rate was 75%, progression free survival was 49% and overall survival was 65%. Nine patients (43%) had no evidence of disease and were in a good clinical condition (ECOG Performance Scale 0) at the end of the study period. No serious adverse events were observed. CONCLUSION: This study showed that PDT is effective in treating local failures of NPC with a depth of less than 10mm. The treatment was easy to perform under local anaesthesia. Especially in regions were other modalities like radiation and surgery are limited PDT can be a good alternative treatment. PMID- 25917044 TI - Wogonin suppresses inflammatory response and maintains intestinal barrier function via TLR4-MyD88-TAK1-mediated NF-kappaB pathway in vitro. AB - AIMS AND OBJECTIVE: Wogonin has multiple pharmacological effects, including anti inflammatory effects. Here, we hypothesize that wogonin can protect intestinal barrier function in lipopolysaccharide (LPS)-induced Caco-2 cells, which is an in vitro model of intestinal inflammation. METHODS: We measured intestinal barrier function in LPS-induced Caco-2 cells by using transepithelial electrical resistance (TEER) and transport of fluorescent markers. A quantitative (q) RT-PCR and immunofluorescent staining analysis was used to detect the expression of tight junction proteins (claudin-1 and ZO-1) in LPS-induced Caco-2 cells. We measured inflammatory molecules in LPS-induced Caco-2 cells using ELISA and qRT PCR. In addition, the expression of TLR4, MyD88 and TAK1 and their interaction, and NF-kappaB activity in LPS-induced Caco-2 cells were investigated by western blot analysis and immune-precipitation. RESULTS: We found that exposing Caco-2 cells to wogonin (10 and 50 MUM for 24 h) attenuated the LPS-induced changes in TEER and transport of fluorescent markers. In addition, wogonin suppressed LPS induced down-regulation of tight junction proteins (claudin-1 and ZO-1). Furthermore, LPS-induced up-regulation of inflammatory mediators, including interleukin (IL)-1beta, IL-6 and IL-8, cyclooxygenase-2 (COX-2), inducible nitric oxide synthases (iNOS) were reduced after being pre-treated with wogonin. Moreover, wogonin not only inhibited the expression of TLR4, MyD88 and TAK1 and the interaction between these molecules, but also reduced NF-kappaB translocation to nucleus and its DNA-binding activity in LPS-induced Caco-2 cells. CONCLUSION: Our results suggested that pre-treatment with wogonin could attenuate the TLR4 mediated inflammatory response and maintain intestinal barrier function in LPS induced Caco-2 cells, thus might be a potential therapy for treating IBD. PMID- 25917043 TI - Effect of polyphenolic phytochemicals on ectopic oxidative phosphorylation in rod outer segments of bovine retina. AB - BACKGROUND AND PURPOSE: The rod outer segments (OS) of the retina are specialized organelles where phototransduction takes place. The mitochondrial electron transport complexes I-IV, cytochrome c and Fo F1 -ATP synthase are functionally expressed in the OS disks. Here, we have studied the effect of some polyphenolic compounds acting as inhibitors of mitochondrial ATPase/synthase activity on the OS ectopic Fo F1 - ATP synthase. The mechanism of apoptosis in the OS was also investigated studying the expression of cytochrome c, caspase 9 and 3 and Apaf-1. EXPERIMENTAL APPROACH: We prepared OS from fresh bovine retinae. Semi quantitative Western blotting, confocal and electron microscopy, and cytofluorimetry were used along with biochemical analyses such as oximetry, ATP synthesis and hydrolysis. KEY RESULTS: Resveratrol and curcumin plus piperine inhibited ATP synthesis and oxygen consumption in the OS. Epigallocatechin gallate and quercetin inhibited ATP hydrolysis and oxygen consumption in the OS. Malondialdehyde and hydrogen peroxide were produced in respiring OS in the presence of substrates. Cytochrome c was located inside the disk membranes. Procaspase 9 and 3, as well as Apaf-1 were expressed in the OS. CONCLUSIONS AND IMPLICATIONS: These polyphenolic phytochemicals modulated the Fo F1 -ATP synthase activity of the the OS reducing production of reactive oxygen intermediates by the OS ectopic electron transport chain. Polyphenols decrease membrane peroxidation and cytochrome c release from disks, preventing the induction of caspase-dependent apoptosis in the OS Such effects are relevant in the design of protection against functional impairment of the OS following oxidative stress from exposure to intense illumination. PMID- 25917046 TI - Predictors of survival in patients with spinal ependymoma. AB - OBJECTIVES: We aimed to examine the impact of demographic and treatment factors on overall survival among spinal ependymoma patients. METHODS: Using data from Surveillance, Epidemiology, and End Results (SEER) from 1990-2008, we evaluated subjects with histologically confirmed spinal cord ependymoma. RESULTS: We identified 1,353 patients with spinal ependymoma (mean age 43.5 years). Among these, 26 had anaplastic ependymoma (AE), 374 had myxopapillary ependymoma (MPE), and 953 had other low-grade ependymoma (non-MPE). Median follow-up was 61 months. Overall survival at 5 years was 97% for MPE, 92% for low-grade non-MPE, and 73% for AE. Gross total resection (GTR) was achieved in 58% of subjects with MPE, 51% with low-grade non-MPE, and 50% with AE. Radiation occurred more often after subtotal resection (STR) than after GTR, and more often among those with anaplastic histology. Histology and extent of surgical resection were significant prognostic factors in multivariate analyses. Compared to MPE, subjects with low grade non-MPE had a higher risk of mortality at 5 years (HR 2.35, P = 0.03), as did subjects with AE (HR 8.63, P < 0.01). Compared to GTR, STR was associated with an increased risk of mortality at 5 years (HR 2.2, P = 0.01), as was biopsy only (HR 2.05, P = 0.03) and no surgery (HR 4.97, P < 0.01). Among patients with either STR or GTR, adjuvant radiotherapy did not confer a survival benefit at 5 years (STR: HR 2.29, P = 0.07, and GTR: HR 2.2, P = 0.12). DISCUSSION: We found that lower grade histology and higher extent of surgical resection were significant prognostic factors for more favourable survival outcomes for spinal ependymoma patients. PMID- 25917045 TI - Role of IL-6 -174(G/C) promoter polymorphism in the etiology of early-onset preeclampsia. AB - OBJECTIVE: To investigate the relationship between IL-6 -174G/C promoter polymorphism and preeclampsia. METHODS: A total of 140 preeclamptic women and 135 women with normal pregnancy were considered for the present study. A standard amplification refractory mutation system PCR was carried out for genotyping of IL 6 G-174C promoter polymorphism. Genotypic distribution was compared with values predicted by Hardy-Weinberg equilibrium using chi (2) test. Odds ratios and their respective 95 % confidence intervals were used to measure the strength of association. RESULTS: The frequencies observed, CC, GC and GG, were 53.5, 26.6 and 20 % in patients and 26.6, 23.7 and 49.6 % in the controls. There is a significant difference in the distribution of genotypes and alleles of IL-6 G-174 C between the two groups. CONCLUSION: The present study suggests that the IL-6 174 promoter polymorphism is a major genetic regulator in the etiology of early onset preeclampsia. PMID- 25917047 TI - A truncating SOD1 mutation, p.Gly141X, is associated with clinical and pathologic heterogeneity, including frontotemporal lobar degeneration. AB - Amyotrophic lateral sclerosis (ALS) is a degenerative disorder affecting upper and lower motor neurons, but it is increasingly recognized to affect other systems, with cognitive impairment resembling frontotemporal dementia (FTD) in some patients. We report clinical and pathologic findings of a family with ALS due to a truncating mutation, p.Gly141X, in copper/zinc superoxide dismutase (SOD1). The proband presented clinically with FTD and later showed progressive motor neuron disease, while all other family members had early-onset and rapidly progressive ALS without significant cognitive deficits. Pathologic examination of both the proband and her daughter revealed degeneration of corticospinal tracts and motor neurons in brain and spinal cord compatible with ALS. On the other hand, the proband also had neocortical and limbic system degeneration with pleomorphic neuronal cytoplasmic inclusions. Extramotor pathology in her daughter was relatively restricted to the hypothalamus and extrapyramidal system, but not the neocortex. The inclusions in the proband and her daughter were immunoreactive for SOD1, but negative for TAR DNA-binding protein of 43 kDa (TDP-43). In the proband, a number of the neocortical inclusions were immunopositive for alpha internexin, initially suggesting a diagnosis of atypical FTLD, but there was no evidence of fused in sarcoma (FUS) immunoreactivity, which is often detected in atypical FTLD. Analogous to atypical FTLD, neuronal inclusions had variable co localization of SOD1 and alpha-internexin. The current classification of FTLD is based on the major constituent protein: FTLD-tau, FTLD-TDP-43, and FTLD-FUS. The proband in this family indicates that SOD1, while rare, can also be the substrate of FTLD, in addition to the more common presentation of ALS. The explanation for clinical and pathologic heterogeneity of SOD1 mutations, including the p.Gly141X mutation, remains unresolved. PMID- 25917049 TI - Consideration of endoclips to help cannulate an ampulla hidden in a duodenal diverticulum at ERCP. PMID- 25917048 TI - The Effect of Ischemia and Reperfusion on Enteric Glial Cells and Contractile Activity in the Ileum. AB - BACKGROUND: We investigated the effects of ischemia followed by different periods of reperfusion (I/R) on immunoreactive S100beta-positive glial and Hu immunoreactive neurons co-expressing the P2X2 receptor in the myenteric plexus of the rat ileum. METHODS: The ileal artery was occluded for 35 min with an atraumatic vascular clamp. The animals were killed 24 h, 72 h, and 1 week after ischemia. Sham animals were not submitted to ileal artery occlusion. The relative density, size, and co-localization of P2X2 receptor-expressing cells in relation to S100beta-immunoreactive glial and Hu-immunoreactive neuronal cells were evaluated. Additionally, we analyzed the effects of I/R on gastrointestinal transit and ileum contractile activity. RESULTS: The cellular density of P2X2 receptor and neuronal Hu immunoreactivity/cm(2) decreased after I/R, whereas glial S100beta immunoreactivity/cm(2) increased. No significant differences between sham and I/R groups were observed regarding the perikarya area of Hu positive neurons. The area of S100beta-immunoreactive glial cells increased by 24.1 % 1 week after I/R compared with the 24 h group. Methylene blue progression along the small intestine decreased (P < 0.05) from 24.5 +/- 2.3 % in the sham group to 17.2 +/- 2.0 % 1 week post-ischemia. We noted a significant (P < 0.05) decrease in the maximal contraction amplitude triggered by electrical field stimulation in the presence of ATP in preparations submitted to 24 h of I/R. CONCLUSIONS: Changes in the P2X2 receptor density parallel myenteric neuronal loss following I/R of the rat ileum. This, together with the increase in the activated (oversized) glial cells, may contribute to decreased GI motility after I/R. PMID- 25917050 TI - Preemptive Dose Optimization Using Therapeutic Drug Monitoring for Biologic Therapy of Crohn's Disease: Avoiding Failure While Lowering Costs? PMID- 25917052 TI - The influence of hydrogen peroxide and hydrogen on the corrosion of simulated spent nuclear fuel. AB - The synergistic influence between H(2)O(2) and H(2) on the corrosion of SIMFUEL (simulated spent nuclear fuel) has been studied in solutions with and without added HCO(3)(-)/CO(3)(2-). The response of the surface to increasing concentrations of added H(2)O(2) was monitored by measuring the corrosion potential in either Ar or Ar/H(2)-purged solutions. Using X-ray photoelectron spectroscopy it was shown that the extent of surface oxidation (U(V) + U(VI) content) was directly related to the corrosion potential. Variations in corrosion potential with time, redox conditions, HCO(3)(-)/CO(3)(2-) concentration, and convective conditions showed that surface oxidation induced by H(2)O(2) could be reversed by reaction with H(2), the latter reaction occurring dominantly on the noble metal particles in the SIMFUEL. For sufficiently large H(2)O(2) concentrations, the influence of H(2) was overwhelmed and irreversible oxidation of the surface to U(VI) occurred. Subsequently, corrosion was controlled by the chemical dissolution rate of this U(VI) layer. PMID- 25917053 TI - Copper-catalyzed aerobic oxidative amination of C(sp(3))-H bonds: synthesis of imidazo[1,5-a]pyridines. AB - Copper-catalyzed synthesis of imidazo[1,5-a]pyridine-1-carboxylates through oxidative amination of C(sp(3))-H bonds under mild aerobic conditions with broad substrate scope is described. Use of naturally abundant air as the sole oxidant was found to be efficient and selective. The present protocol is also applicable for direct synthesis of functionalized imidazo[1,5-a]pyridines from amino acid derivatives. PMID- 25917051 TI - Oral Lichen Planus in IBD Patients: A Paradoxical Adverse Effect of Anti-TNF alpha Therapy. AB - INTRODUCTION AND AIMS: The efficacy of tumor necrosis factor alpha (TNF-alpha) inhibitors in the treatment of Inflammatory Bowel Disease (IBD) is well established. Many cutaneous and mucosal lesions have been described under anti TNF-alpha therapy, some of them being considered as paradoxical. In this series we aimed to review the cases of oral lichen planus (OLP) in IBD patients under treatment with anti-TNF-alpha agents. METHODS: Histologic findings from oral lesions of IBD patients treated with anti-TNF were revised. RESULTS: Three female patients with IBD developed oral lichen planus (OLP) after starting anti-TNF alpha therapy. Other etiologies were excluded. CONCLUSIONS: In light of the increasing use of TNF-alpha inhibitors the occurrence of OLP is a potentially emerging side effect, thus we recommend a careful monitoring for oral manifestations in IBD patients treated with anti-TNF-alpha agents. PMID- 25917054 TI - Comparison of quality of life between open and endoscopic thyroidectomy for papillary thyroid cancer. AB - BACKGROUND: Recently, various endoscopic thyroidectomy techniques have been introduced for cosmetic purposes. However, few reports have compared the quality of life (QOL) between post-endoscopic thyroidectomy and post-conventional open thyroidectomy. In this study, we investigated whether endoscopic thyroidectomy was comparable to conventional open thyroidectomy with respect to QOL. METHODS: Between January 2010 and September 2011, 75 patients underwent endoscopic thyroid lobectomy and 233 patients underwent conventional open thyroid lobectomy. The QOL was assessed preoperatively and at 1, 3, and 6 months postoperatively by using the European Organization for Research and Treatment of Cancer Quality of Life Questionnaire-Core 30-question (EORTC-QLQ-C30) instruments. RESULTS: Both groups showed similar changes over time in most of the QOL scales. However, patients who underwent endoscopic thyroidectomy showed significantly greater improvement in emotional function at 1 month (p = .039) and physical function at 3 months (p = .032). However, the pain increased more in the patients who underwent endoscopic thyroidectomy at 1 month (p = .042). CONCLUSION: Current findings suggest that endoscopic thyroidectomy may offer more rapid recovery of emotional and physical function than open thyroidectomy. (c) 2015 Wiley Periodicals, Inc. Head Neck 38: E827-E831, 2016. PMID- 25917056 TI - Security and privacy issues in implantable medical devices: A comprehensive survey. AB - Bioengineering is a field in expansion. New technologies are appearing to provide a more efficient treatment of diseases or human deficiencies. Implantable Medical Devices (IMDs) constitute one example, these being devices with more computing, decision making and communication capabilities. Several research works in the computer security field have identified serious security and privacy risks in IMDs that could compromise the implant and even the health of the patient who carries it. This article surveys the main security goals for the next generation of IMDs and analyzes the most relevant protection mechanisms proposed so far. On the one hand, the security proposals must have into consideration the inherent constraints of these small and implanted devices: energy, storage and computing power. On the other hand, proposed solutions must achieve an adequate balance between the safety of the patient and the security level offered, with the battery lifetime being another critical parameter in the design phase. PMID- 25917055 TI - Toward a complete dataset of drug-drug interaction information from publicly available sources. AB - Although potential drug-drug interactions (PDDIs) are a significant source of preventable drug-related harm, there is currently no single complete source of PDDI information. In the current study, all publically available sources of PDDI information that could be identified using a comprehensive and broad search were combined into a single dataset. The combined dataset merged fourteen different sources including 5 clinically-oriented information sources, 4 Natural Language Processing (NLP) Corpora, and 5 Bioinformatics/Pharmacovigilance information sources. As a comprehensive PDDI source, the merged dataset might benefit the pharmacovigilance text mining community by making it possible to compare the representativeness of NLP corpora for PDDI text extraction tasks, and specifying elements that can be useful for future PDDI extraction purposes. An analysis of the overlap between and across the data sources showed that there was little overlap. Even comprehensive PDDI lists such as DrugBank, KEGG, and the NDF-RT had less than 50% overlap with each other. Moreover, all of the comprehensive lists had incomplete coverage of two data sources that focus on PDDIs of interest in most clinical settings. Based on this information, we think that systems that provide access to the comprehensive lists, such as APIs into RxNorm, should be careful to inform users that the lists may be incomplete with respect to PDDIs that drug experts suggest clinicians be aware of. In spite of the low degree of overlap, several dozen cases were identified where PDDI information provided in drug product labeling might be augmented by the merged dataset. Moreover, the combined dataset was also shown to improve the performance of an existing PDDI NLP pipeline and a recently published PDDI pharmacovigilance protocol. Future work will focus on improvement of the methods for mapping between PDDI information sources, identifying methods to improve the use of the merged dataset in PDDI NLP algorithms, integrating high-quality PDDI information from the merged dataset into Wikidata, and making the combined dataset accessible as Semantic Web Linked Data. PMID- 25917057 TI - Automated misspelling detection and correction in clinical free-text records. AB - Accurate electronic health records are important for clinical care and research as well as ensuring patient safety. It is crucial for misspelled words to be corrected in order to ensure that medical records are interpreted correctly. This paper describes the development of a spelling correction system for medical text. Our spell checker is based on Shannon's noisy channel model, and uses an extensive dictionary compiled from many sources. We also use named entity recognition, so that names are not wrongly corrected as misspellings. We apply our spell checker to three different types of free-text data: clinical notes, allergy entries, and medication orders; and evaluate its performance on both misspelling detection and correction. Our spell checker achieves detection performance of up to 94.4% and correction accuracy of up to 88.2%. We show that high-performance spelling correction is possible on a variety of clinical documents. PMID- 25917058 TI - Nonstoichiometry of nanocrystalline monoclinic silver sulfide. AB - Powders of silver sulfide have been synthesized by chemical bath deposition from aqueous solutions of silver nitrate and sodium sulfide in the presence of sodium citrate or EDTA-H2Na2. Colloid solutions have been prepared by a chemical condensation method from the same aqueous solutions. Synthesized silver sulfide nanopowders have a monoclinic (space group P21/c) acanthite-type structure but the occupancy of the metal sublattice sites by Ag atoms is smaller than 1. Unlike coarse-crystalline silver sulfide Ag2S, silver sulfide nanopowders with particles sizes of less than ~50 nm are nonstoichiometric, contain vacant sites in the metal sublattice and have a composition of ~Ag1.93S. PMID- 25917059 TI - Influence of 1p19q status and Ki67 index to predict extent of resection in WHO grade II gliomas: a virtual patient model. PMID- 25917060 TI - Effect of steroids on inflammatory markers and clinical parameters in congenital open heart surgery: a randomised controlled trial. AB - BACKGROUND: Cardiopulmonary bypass is associated with systemic inflammatory response. Steroids suppress this response, although the therapeutic evidence remains controversial. We hypothesised that intravenous steroids in children undergoing open-heart surgery would decrease inflammation leading to better early post-operative outcomes. We conducted a randomised controlled trial to evaluate the trends in the levels of immunomodulators and their effects on clinical parameters. OBJECTIVE: To assess the effects of intravenous steroids on early post-operative inflammatory markers and clinical parameters in children undergoing open-heart surgery. MATERIALS AND METHODS: A randomised controlled trial involving 152 patients, from one month up to 18 years of age, who underwent open-heart surgery for congenital heart disease from April 2010-2012 was carried out. Patients were randomised and administered either three scheduled intravenous pulse doses of dexamethasone (1 mg/kg) or placebo. Blood samples were drawn at four time intervals and serum levels of inflammatory cytokines - Interleukin-6, 8, 10, 18, and tumour necrosis factor-alpha - were measured. Clinical parameters were also assessed. RESULTS: Blood cytokine levels were compared between the dexamethasone (n=65) and placebo (n=64) groups. Interleukin-6 levels were lower at 6 and 24 hours post-operatively (p<0.001), and Interleukin-10 levels were higher 6 hours post-operatively (p<0.001) in the steroid group. Interleukin-8, 18, and tumour necrosis factor-alpha levels did not differ between the groups at any time intervals. The clinical parameters were similar in both the groups. CONCLUSION: Dexamethasone caused quantitative suppression of Interleukin-6 and increased Interleukin-10 activation, contributing to reduced immunopathology, but it did not translate into clinical benefit in the short term. PMID- 25917061 TI - Perceptual training effects on anticipation of direct and deceptive 7-m throws in handball. AB - We examined the effectiveness of perceptual training on the performance of handball goalkeepers when anticipating the direction of both direct and deceptive 7-m throws. Skilled goalkeepers were assigned equally to three matched-ability groups based on their pre-test performance: a perceptual training group (n = 14) received video-based perceptual training, a placebo training group (n = 14) received video-based regular training and a control group received no training. Participants in the perceptual training group significantly improved their performance compared to both placebo and control groups; however, anticipation of deceptive throws improved less than for direct throws. The results confirm that although anticipating deception in handball is a challenging task for goalkeepers, task-specific perceptual training can minimise its effect and improve performance. PMID- 25917062 TI - Inferring slowly-changing dynamic gene-regulatory networks. AB - Dynamic gene-regulatory networks are complex since the interaction patterns between their components mean that it is impossible to study parts of the network in separation. This holistic character of gene-regulatory networks poses a real challenge to any type of modelling. Graphical models are a class of models that connect the network with a conditional independence relationships between random variables. By interpreting these random variables as gene activities and the conditional independence relationships as functional non-relatedness, graphical models have been used to describe gene-regulatory networks. Whereas the literature has been focused on static networks, most time-course experiments are designed in order to tease out temporal changes in the underlying network. It is typically reasonable to assume that changes in genomic networks are few, because biological systems tend to be stable. We introduce a new model for estimating slow changes in dynamic gene-regulatory networks, which is suitable for high dimensional data, e.g. time-course microarray data. Our aim is to estimate a dynamically changing genomic network based on temporal activity measurements of the genes in the network. Our method is based on the penalized likelihood with l1 norm, that penalizes conditional dependencies between genes as well as differences between conditional independence elements across time points. We also present a heuristic search strategy to find optimal tuning parameters. We re write the penalized maximum likelihood problem into a standard convex optimization problem subject to linear equality constraints. We show that our method performs well in simulation studies. Finally, we apply the proposed model to a time-course T-cell dataset. PMID- 25917064 TI - Invited commentary for "preoperative magnetic resonance imaging-based breast volumetry for immediate breast reconstruction". PMID- 25917063 TI - MicroRNA-9 promotion of interleukin-6 expression by inhibiting monocyte chemoattractant protein-induced protein 1 expression in interleukin-1beta stimulated human chondrocytes. AB - OBJECTIVE: Enhanced expression of interleukin-6 (IL-6) plays an important role in the pathogenesis of osteoarthritis (OA). Monocyte chemoattractant protein-induced protein 1 (MCPIP-1) is a novel posttranscriptional regulator of IL-6 expression and is targeted by microRNA-9 (miR-9). We investigated the expression of MCPIP-1 in OA cartilage and explored whether targeting of MCPIP-1 by miR-9 contributes to enhanced IL-6 expression in OA. METHODS: Gene and protein expression in IL-1beta stimulated human OA chondrocytes/cartilage was determined by TaqMan assay and immunoblotting, respectively. Messenger RNA (mRNA) for MCPIP-1 and IL-6 expression at the single-cell level was analyzed using RNAscope. MCPIP-1 protein interaction with IL-6 mRNA was investigated using RNA immunoprecipitation. Transient transfections were used for the small interfering RNA (siRNA)-mediated knockdown and overexpression of MCPIP-1, its RNase-defective mutant miR-9, or antagomir. The role of signaling pathways was evaluated using small-molecule inhibitors. Binding of miR-9 with the "seed sequence" in the 3'-untranslated region of MCPIP-1 mRNA was investigated using a luciferase reporter assay. RESULTS: MCPIP-1 mRNA expression was low, but expression of miR-9 and IL-6 was high, in damaged OA cartilage. In IL-1beta-stimulated OA chondrocytes, the expression of miR-9 and MCPIP-1 was mutually exclusive, and increased expression of miR-9 correlated with reduced MCPIP-1 expression and enhanced IL-6 expression. MCPIP-1 protein directly binds with IL-6 mRNA, and overexpression of wild-type MCPIP-1 destabilized the IL-6 mRNA. MCPIP-1 expression was altered by overexpression or inhibition of miR-9. Transfection with miR-9 mimics inhibited the reporter activity, and mutation of the "seed sequence" abolished the repression of reporter activity. CONCLUSION: These findings implicate miR-9 mediated suppression of MCPIP-1 in the pathogenesis of OA via up-regulation of IL 6 expression in IL-1beta-stimulated human OA chondrocytes. PMID- 25917065 TI - Nurse-led clinics can manage faecal incontinence effectively: results from a tertiary referral centre. AB - AIM: In May 2010, a specialist nurse-initiated assessment and treatment algorithm for faecal incontinence (FI) was introduced at the department of Anal Physiology, Aarhus University Hospital, Denmark. This study aimed to evaluate the effectiveness of and patient satisfaction with the program. METHOD: A medical file audit was preformed on patients evaluated and treated for FI and discharged after September 2010. Patients were invited to participate in a structured telephone interview. This study aimed to enrol 100 patients. Patients were asked if they were satisfied with their current level of continence status (yes/no), and a numerical satisfaction score and Wexner score were recorded. These results were compared to baseline and at time of discharge. RESULTS: One-hundred patients completed the telephone interview; 73 of these patients were satisfied after a median of 420 (range: 114-586) days following discharge from the program. A median of one outpatient consultation followed by one telephone follow-up was required before the patients were discharged. The Wexner score was significantly reduced by 3.9 (+/-4.4) (P < 0.001) points among the satisfied and non significantly reduced by 0.52 (+/- 3.3) (P = 0.42) points among the dissatisfied patients at follow-up compared to baseline. The satisfied and dissatisfied patients at follow-up did not differ in baseline characteristics including Wexner score. CONCLUSIONS: FI can successively be evaluated and conservatively managed by specialist nurses, and these nurses achived high satisfaction rates among their patients. The concept of specialist nurse-led clinics will reduce waiting lists, and descrease the number of patients needing to be evaluated by a surgeon. PMID- 25917066 TI - Non-operative management of a complete anterior cruciate ligament injury in an English Premier League football player with return to play in less than 8 weeks: applying common sense in the absence of evidence. AB - This case report illustrates and discusses the non-operative management of a complete anterior cruciate ligament (ACL) injury in an English Premier League football player, his return to play within 8 weeks and problem-free follow-up at 18 months post injury. When non-operative verses surgical ACL reconstruction is considered there are many fundamental gaps in our knowledge and currently, at elite level, there are no cases in cutting sports within the literature to guide these decisions. When the norm is for all professional footballers to be recommended surgery, it will be very challenging when circumstances and patient autonomy dictate a conservative approach, where prognosis, end points and risk are unclear and assumed to be high. This case challenges current dogma and provides a starting point for much needed debate about best practice, treatment options, research direction and not just at the elite level of sport. PMID- 25917067 TI - Early cavernous sinus thrombosis following unilateral pansinusitis in a child. AB - Cavernous sinus thrombosis (CST) is a life-threatening entity with a high rate of mortality and lifelong morbidity. A strong clinical suspicion of the complication, early radiological detection and institution of timely, aggressive treatment are required to prevent permanent neurological disability. We present a 12-year-old girl with bilateral CST following unilateral pansinusitis. Clinical symptoms of headache and retro-orbital pain out of proportion to clinical signs on presentation prompted a suspicion of something beyond sinusitis and raised the clinical suspicion of cavernous sinus involvement. In spite of institution of an early medical treatment, she progressed to develop bilateral cranial nerve paresis. However, with the persistence of antibiotics and anticoagulation therapy, she was successfully managed with no residual neurological sequelae. The aim of this presentation is to highlight the grave consequences of cavernous sinus involvement following infections of paranasal sinus and the rare complete recovery from disability in this case. PMID- 25917068 TI - Periventricular white matter lesion and incomplete MRZ reaction in a male patient with anti-N-methyl-D-aspartate receptor encephalitis presenting with dysphoric mania. AB - Several findings suggest that there may be an overlap of anti-N-methyl-d aspartate receptor (NMDAR) antibody encephalitis with neuromyelitis optica spectrum disorders or acute demyelinating encephalomyelitis (ADEM)-like demyelination. We present a case of a patient with anti-NMDAR antibody encephalitis, who on MRI featured a single prominent T2-hyperintensive white matter lesion in the periventricular region, adjacent to the anterior horn of the left lateral ventricle. In view of the lesion location and the cerebrospinal fluid (CSF) findings (incomplete MRZ (measles, rubella and varicella zoster) reaction, lymphocytic pleocytosis, intrathecal IgG and IgM synthesis; absence of aquaporin-4 (AQP4) and myelin oligodendrocyte glycoprotein (MOG) antibodies), the presence of a multiple sclerosis-like immune response was discussed. This case appears to add evidence to the hypothesis of an overlap between anti-NMDAR antibody encephalitis and other inflammatory central nervous system diseases. PMID- 25917069 TI - Acquired Wharton's duct stenosis after dental radiographs treated with sialendoscopy. AB - Salivary gland trauma may result in ductal stenosis and chronic sialadenitis. We describe a case of an 81-year-old woman with a history of intermittent left submandibular swelling that began after recent dental examination and radiographs. Diagnostic sialendoscopy was performed and demonstrated a near complete distal stenosis. It was determined that trauma experienced during dental radiography may have resulted in the patient's ductal obstruction and subsequent sialadenitis. This case illustrates an unusual presentation of non-sialolith related ductal obstruction in the submandibular gland, treated with sialendoscopic-assisted sialodochoplasty. PMID- 25917070 TI - Does this case hold the answer to one of the worse types of pain in medicine- that of loin pain haematuria syndrome (LPHS). AB - A patient with loin pain haematuria syndrome suffering chronic throbbing pulsing pain overlaid with prolonged periods of incapacitating colic and overnight vomiting was presented 10 months following diagnosis. Ultrasound was normal. No renal or ureteral stones, or filling defects were seen on CT. At cytoscopy, bladder and urethra were normal, and bloody urine effluxed from the left ureteric orifice. The ureters were normal at diagnosis, and developed new abutting non penetrating calcifications by 8 months. Pain episodes of complete incapacitating intensity of 2-4 h duration were reduced to 10 min with 5 mg crushed tadalafil administered at onset. If tadalafil was delayed to after onset, the original course of agony resulted. Daily tadalafil reduced loin pain intensity, but not the exacerbations. Tadalafil efficacy may indicate that the pain exacerbations are due to spasm of ureter smooth muscle. 5 mg tadalafil taken at onset alleviated severe loin pain exacerbations in this case of loin pain haematuria syndrome. PMID- 25917071 TI - Late onset iatrogenic limb ischaemia after deployment of an Angio-Seal vascular closure device. AB - It is common practice to deploy a vascular closure device for access site closure after percutaneous angiography or cardiovascular interventions for immediate haemostasis and to facilitate early discharge. We encountered two octogenarian women who underwent and had subsequent vascular access site closure with Angio Seal (St Jude) and who later presented with limb ischaemia needing surgical revascularisation. Our patients had undergone uneventful deployment of the Angio Seal vascular closure device (VCD) at the right common femoral artery (CFA) access site with successful haemostasis. About 3 weeks later they presented with features of limb ischaemia needing further diagnostic work-up including repeat angiography, which revealed subtotal occlusion of right common femoral artery at the level of prior access and Angio-Seal deployment site. Both the patients underwent successful surgical repair with restoration of distal flow and resolution of symptoms. These cases illustrate the late presentation of VCD related complications with limb ischaemia, needing surgical revascularisation. PMID- 25917072 TI - Fibroadenoma in axilla: another manifestation of ectopic breast. AB - Fibroadenoma of an accessory breast is a rare disease. The clinical significance lies in the fact that a number of cystic, inflammatory, neoplastic diseases similar to those of a normal breast have been reported in accessory breasts as well. Vigilant self-assessment and complete clinical examination are always encouraged to detect earliest malignancy in the axilla. We report two cases of ectopic breast fibroadenoma with the relevant literature. PMID- 25917073 TI - A rare manifestation of a multisystemic disease: a case of vocal cord palsy secondary to sarcoidosis. AB - We describe a rare case of recurrent laryngeal nerve neuritis secondary to sarcoidosis. A 40-year-old woman presented with persistent dysphonia. This was her first episode of dysphonia with no reports of laryngeal trauma. Fibre-optic laryngoscopy revealed a normal nasal passage, nasopharynx and pharynx. The supraglottic structures were all unremarkable; however, inspection of the true vocal cords revealed a left vocal cord palsy that was identified as being in a paramedian position. Radiological investigation showed mediastinal adenopathy that measured up to 20 mm in the short axis diameter. Histological examination showed granulomatous lymphadenitis of the lymph node with a central area of sclerosis surrounded by discrete, non-caseating granuloma. Stains for acid-fast bacilli were negative. The morphological features were suggestive of sarcoidosis. The lymphadenopathy distribution and size did not suggest left recurrent laryngeal nerve compression, giving a subsequent diagnosis of recurrent laryngeal nerve neuritis secondary to sarcoidosis. PMID- 25917074 TI - Three new iridoids from leaves of Cornus officinalis. AB - Three new iridoids, cornifins A-C (1-3), together with a known iridoid, were obtained from EtOAc layer of leaves of Cornus officinalis. The structures of new compounds were elucidated on the basis of extensive spectroscopic analyses. Compound 2 showed weak inhibitory activity against lung cancer cell line A-549 with IC50 value of 29.1 MUM. PMID- 25917075 TI - LIM-only protein FHL2 critically determines survival and radioresistance of pancreatic cancer cells. AB - Numerous factors determine the current poor prognosis of pancreatic ductal adenocarcinoma (PDAC). One of the greatest challenges to overcome is treatment resistance. Among a large repertoire of intrinsic resistance mechanisms, integrin mediated cell adhesion to extracellular matrix (ECM) has been identified to be fundamental. Coalesced in focal adhesion complexes, integrins, receptor tyrosine kinases, protein kinases and adapter proteins mediate prosurvival signaling. Four and a half LIM domains protein 2 (FHL2) is one of these adapter proteins, which operates through protein-protein interactions and shows tumor-specific expression. Based on this, we investigated FHL2 expression in PDAC specimens and three-dimensionally grown cell lines and how FHL2 mechanistically contributes to cell survival, cell cycling and radiation resistance. PDAC exhibited a significantly increased and heterogeneous FHL2 expression. Upon FHL2 depletion, pancreatic cancer cell lines showed significantly decreased cell survival, proliferation and radioresistance as well as enhanced apoptosis and MEK/ERK signaling and cyclin D1, E, A and B1 expression were strongly induced. Targeting of FHL2 and MEK1 was similarly effective than FHL2 depletion alone, suggesting MEK1 as a downstream signaling mediator of FHL2. Taken together, our results provide evidence for the importance of the focal adhesion protein FHL2 in pancreatic cancer cell survival, proliferation and radiosensitivity. PMID- 25917076 TI - Targeting arginine metabolism pathway to treat arginine-dependent cancers. AB - The significant disparities in metabolism between tumor and normal cells have inspired the development of metabolism-based anti-tumor therapeutics. Arginine is a semi-essential amino acid because normal cells can not only synthesize arginine de novo but also take up extracellular arginine. Several types of tumors have abnormalities in arginine metabolism enzymes and completely rely on extracellular arginine to support necessary biological processes. This property is referred to as arginine auxotrophy. Taking advantage of characteristic arginine auxotrophy in tumors, arginine deprivation, which is generally induced by the use of arginine deiminase (ADI) and arginase I, has been investigated as a novel strategy for cancer therapy. Arginine deprivation demonstrated promising efficacy against arginine-auxotrophic tumors. By integrating perspectives from both clinical oncologists and laboratory scientists, this article reviews the important aspects of arginine deprivation as a promising anticancer therapy. PMID- 25917077 TI - Mesenchymal stem cells derived from low risk acute lymphoblastic leukemia patients promote NK cell antitumor activity. AB - Mesenchymal stem cells (MSCs) are key components of the bone marrow microenvironment which contribute to the maintenance of the hematopoietic stem cell niche and exert immunoregulatory functions in innate and adaptive immunity. We analyze the immunobiology of MSCs derived from acute lymphoblastic leukemia (ALL) patients and their impact on NK cell function. In contrast to the inhibitory effects on the immune response exerted by MSCs from healthy donors (Healthy-MSCs), we demonstrate that MSCs derived from low/intermediate risk ALL patients at diagnosis (ALL-MSCs) promote an efficient NK cell response including cytokine production, phenotypic activation and most importantly, cytotoxicity. Longitudinal studies indicate that these immunostimulatory effects of ALL-MSCs are progressively attenuated. Healthy-MSCs adopt ALL-MSC-like immunomodulatory features when exposed to leukemia cells, acquiring the ability to stimulate NK cell antitumor function. The mechanisms underlying to these functional changes of ALL-MSCs include reduced production of soluble inhibitory factors, differential expression of costimulatory and coinhibitory molecules, increased expression of specific TLRs and Notch pathway activation. Collectively our findings indicate that, in response to leukemia cells, ALL-MSCs could mediate a host beneficial immunomodulatory effect by stimulating the antitumor innate immune response. PMID- 25917078 TI - Smac mimetic and oleanolic acid synergize to induce cell death in human hepatocellular carcinoma cells. AB - Chemotherapy resistance of hepatocellular carcinoma (HCC) is still a major unsolved problem highlighting the need to develop novel therapeutic strategies. Here, we identify a novel synergistic induction of cell death by the combination of the Smac mimetic BV6, which antagonizes Inhibitor of apoptosis (IAP) proteins, and the triterpenoid oleanolic acid (OA) in human HCC cells. Importantly, BV6 and OA also cooperate to suppress long-term clonogenic survival as well as tumor growth in a preclinical in vivo model of HCC underscoring the clinical relevance of our findings. In contrast, BV6/OA cotreatment does not exert cytotoxic effects against normal primary hepatocytes, pointing to some tumor selectivity. Mechanistic studies show that BV6/OA cotreatment leads to DNA fragmentation and caspase-3 cleavage, while supply of the pan-caspase inhibitor N-benzyloxycarbonyl Val-Ala-Asp-fluoromethylketone (zVAD.fmk) revealed a cell type-dependent requirement of caspases for BV6/OA-induced cell death. The receptor interacting protein (RIP)1 kinase Inhibitor Necrostatin-1 (Nec-1) or genetic knockdown of RIP1 fails to rescue BV6/OA-mediated cell death, indicating that BV6/OA cotreatment does not primarily engage necroptotic cell death. Notably, the addition of several reactive oxygen species (ROS) scavengers significantly decreases BV6/OA-triggered cell death, indicating that ROS production contributes to BV6/OA-induced cell death. In conclusion, cotreatment of Smac mimetic and OA represents a novel approach for the induction of cell death in HCC and implicates further studies. PMID- 25917079 TI - Eribulin synergizes with Polo-like kinase 1 inhibitors to induce apoptosis in rhabdomyosarcoma. AB - Eribulin, a novel microtubule-interfering drug, was recently shown to exhibit high antitumor activity in vivo against various pediatric cancers. Here, we identify a novel synthetic lethal interaction of Eribulin together with Polo-like kinase 1 (PLK1) inhibitors against rhabdomyosarcoma (RMS) in vitro and in vivo. Eribulin and the PLK1 inhibitor BI 2536 at subtoxic concentrations synergize to induce apoptosis in RMS cells as confirmed by calculation of combination index (CI). Also, Eribulin/BI 2536 co-treatment is significantly more effective than monotherapy to reduce cell viability and inhibit colony formation of RMS cells. Similarly, Eribulin and BI 2536 act in concert to trigger apoptosis in a primary, patient-derived ARMS culture, underscoring the clinical relevance of this combination. Importantly, Eribulin and BI 2536 cooperate to suppress tumor growth in an in vivo model of RMS. On molecular grounds, Eribulin/BI 2536 co-treatment causes profound mitotic arrest, which is critically required for synergism, since inhibition of mitotic arrest by CDK1 inhibitor RO-3306 abolishes Eribulin/BI 2536 mediated apoptosis. Eribulin and BI 2536 cooperate to activate caspase-9, -3 and 8, which is necessary for apoptosis induction, since the broad-range caspase inhibitor N-benzyloxycarbonyl-Val-Ala-Asp-fluoromethylketone (zVAD.fmk) reduces Eribulin/BI 2536-induced apoptosis significantly, yet partially. Intriguingly, knockdown of endonuclease G (ENDOG) also significantly inhibits Eribulin/BI 2536 triggered apoptosis, demonstrating the involvement of both caspase-dependent and independent effector pathways. Synergistic induction of apoptosis is similarly found for Eribulin/BI 2536 co-treatment in neuroblastoma cells and for the combination of vincristine (another antimicrotubule chemotherapeutic) with Poloxin (another PLK1 inhibitor), thus pointing to a broader significance of this concomitant microtubule- and PLK1-targeting strategy for pediatric oncology. In conclusion, the identification of a novel synthetic lethality by dual targeting of mitosis using microtubule-interfering and PLK1-targeted drugs, i.e. Eribulin and BI 2536, has important implications for the development of more effective treatment strategies for RMS. PMID- 25917080 TI - Impact of retrograde shear rate on brachial and superficial femoral artery flow mediated dilation in older subjects. AB - An inverse, dose-dependent relationship between retrograde shear rate and brachial artery endothelial function exists in young subjects. This relationship has not been investigated in older adults, who have been related to lower endothelial function, higher resting retrograde shear rate and higher risk of cardiovascular disease. AIM: To investigate the impact of a step-wise increase in retrograde shear stress on flow-mediated dilation in older males in the upper and lower limbs. METHODS: Fifteen older (68 +/- 9 years) men reported to the laboratory 3 times. We examined brachial artery flow-mediated dilation before and after 30-min exposure to cuff inflation around the forearm at 0, 30 and 60 mmHg, to manipulate retrograde shear rate. Subsequently, the 30-min intervention was repeated in the superficial femoral artery. Order of testing (vessel and intervention) was randomised. RESULTS: Increases in cuff pressure resulted in dose-dependent increases in retrograde shear in both the brachial and superficial femoral artery in older subjects. In both the brachial and the superficial femoral artery, no change in endothelial function in response to increased retrograde shear was observed in older males ('time' P = 0.274, 'cuff*time P = 0.791', 'cuff*artery*time P = 0.774'). CONCLUSION: In contrast with young subjects, we found that acute elevation in retrograde shear rate does not impair endothelial function in older humans. This may suggest that subjects with a priori endothelial dysfunction are less responsive or requires a larger shear rate stimulus to alter endothelial function. PMID- 25917082 TI - IL-17A, IL-22, and IL-23 as Markers of Psoriasis Activity: A Cross-sectional, Hospital-based Study. AB - INTRODUCTION: T-helper 1 (Th1), Th17 cells, and their related cytokines are implicated in psoriasis pathogenesis although the contribution of each group of cytokines in psoriasis activity has not been fully clarified. OBJECTIVES: To investigate whether Th17-related cytokines are associated with psoriasis activity. METHODS: The serum levels of interleukin (IL)-1beta, 6, 8, 17Alpha, 22, 23, and tumor necrosis factor-alpha (TNFalpha) were measured with flow cytometry in 35 patients with plaque psoriasis (21 with stable and 14 with active disease) and in 20 healthy controls. RESULTS: Interleukin-6, 8, 17A, 22, 23, and TNFalpha were significantly elevated in psoriasis patients compared with controls. In the sensitivity analyses, patients with active disease showed significantly increased levels of IL-17A, IL-23, and IL-22 as compared to the group of patients with stable psoriasis. CONCLUSIONS: Our study highlights a possible crucial role of IL 17A, IL-22, and IL-23 in the activity of psoriasis and the early stages of the disease. PMID- 25917083 TI - Glucocorticoids and Metabolic Control. AB - In response to stress, the central nervous system initiates a signaling cascade, which leads to the production of glucocorticoids (GCs). GCs act through the glucocorticoid receptor (GR) to coordinate the appropriate cellular response with the primary goal of mobilizing the storage forms of carbon precursors to generate a continuous glucose supply for the brain. Although GCs are critical for maintaining energy homeostasis, excessive GC stimulation leads to a number of undesirable side effects, including hyperglycemia, insulin resistance, fatty liver, obesity, and muscle wasting leading to severe metabolic dysfunction. Summarized below are the diverse metabolic roles of glucocorticoids in energy homeostasis and dysregulation, focusing specifically on glucose, lipid, and protein metabolism. PMID- 25917081 TI - Nuclear receptor 4A (NR4A) family - orphans no more. AB - The orphan nuclear receptors NR4A1, NR4A2 and NR4A3 are immediate early genes induced by multiple stressors, and the NR4A receptors play an important role in maintaining cellular homeostasis and disease. There is increasing evidence for the role of these receptors in metabolic, cardiovascular and neurological functions and also in inflammation and inflammatory diseases and in immune functions and cancer. Despite the similarities of NR4A1, NR4A2 and NR4A3 and their interactions with common cis-genomic elements, they exhibit unique activities and cell-/tissue-specific functions. Although endogenous ligands for NR4A receptors have not been identified, there is increasing evidence that structurally-diverse synthetic molecules can directly interact with the ligand binding domain of NR4A1 and act as agonists or antagonists, and ligands for NR4A2 and NR4A3 have also been identified. Since NR4A receptors are key factors in multiple diseases, there are opportunities for the future development of NR4A ligands for clinical applications in treating multiple health problems including metabolic, neurologic and cardiovascular diseases, other inflammatory conditions, and cancer. PMID- 25917084 TI - Endoplasmic Protein Nogo-B (RTN4-B) Interacts with GRAMD4 and Regulates TLR9 Mediated Innate Immune Responses. AB - TLRs are distributed in their characteristic cellular or subcellular compartments to efficiently recognize specific ligands and to initiate intracellular signaling. Whereas TLRs recognizing pathogen-associated lipids or proteins are localized to the cell surface, nucleic acid-sensing TLRs are expressed in endosomes and lysosomes. Several endoplasmic reticulum (ER)-resident proteins are known to regulate the trafficking of TLRs to the specific cellular compartments, thus playing important roles in the initiation of innate immune responses. In this study, we show that an ER-resident protein, Nogo-B (or RTN4-B), is necessary for immune responses triggered by nucleic acid-sensing TLRs, and that a newly identified Nogo-B-binding protein (glucosyltransferases, Rab-like GTPase activators and myotubularins [GRAM] domain containing 4 [GRAMD4]) negatively regulates the responses. Production of inflammatory cytokines in vitro by macrophages stimulated with CpG-B oligonucleotides or polyinosinic:polycytidylic acid was attenuated in the absence of Nogo-B, which was also confirmed in serum samples from Nogo-deficient mice injected with polyinosinic:polycytidylic acid. Although a deficiency of Nogo-B did not change the incorporation or delivery of CpG to endosomes, the localization of TLR9 to endolysosomes was found to be impaired. We identified GRAMD4 as a downmodulator for TLR9 response with a Nogo-B binding ability in ER, because our knockdown and overexpression experiments indicated that GRAMD4 suppresses the TLR9 response and knockdown of Gramd4 strongly enhanced the response in the absence of Nogo-B. Our findings indicate a critical role of Nogo-B and GRAMD4 in trafficking of TLR9. PMID- 25917085 TI - Differential activation of inflammatory pathways in testicular macrophages provides a rationale for their subdued inflammatory capacity. AB - Spermatogenic cells express cell-specific molecules with the potential to be seen as "foreign" by the immune system. Owing to the time difference between their appearance in puberty and the editing of the lymphocyte repertoire around birth, local adaptations of the immune system coined immune privilege are required to confer protection from autoattack. Testicular macrophages (TM) play an important role in maintaining testicular immune privilege and display reduced proinflammatory capacity compared with other macrophages. However, the molecular mechanism underlying this macrophage phenotype remained elusive. We demonstrate that TM have a lower constitutive expression of TLR pathway-specific genes compared with peritoneal macrophages. Moreover, in TM stimulated with LPS, the NF kappaB signaling pathway is blocked due to lack of IkappaBalpha ubiquitination and, hence, degradation. Instead, challenge of TM with LPS or polyinosinic polycytidylic acid induces MAPK, AP-1, and CREB signaling pathways, which leads to production of proinflammatory cytokines such as TNF-alpha, although at much lower levels than in peritoneal macrophages. Pretreatment of TM with inhibitors for MAPKs p38 and ERK1/2 suppresses activation of AP-1 and CREB signaling pathways and attenuates LPS-induced TNF-alpha and IL-10 secretion. High levels of IL-10 production and activation of STAT3 by LPS stimulation in TM indicate a regulatory macrophage phenotype. Our results suggest that TM maintain testicular immune privilege by inhibiting NF-kappaB signaling through impairment of IkappaBalpha ubiquitination and a general reduction of TLR cascade gene expression. However, TM do maintain some capacity for innate immune responses through AP-1 and CREB signaling pathways. PMID- 25917086 TI - The Processed Amino-Terminal Fragment of Human TLR7 Acts as a Chaperone To Direct Human TLR7 into Endosomes. AB - TLR7 mediates innate immune responses to viral RNA in endocytic compartments. Mouse and human (h)TLR7 undergo proteolytic cleavage, resulting in the generation of a C-terminal fragment that accumulates in endosomes and associates with the signaling adaptor MyD88 upon receptor triggering by TLR7 agonists. Although mouse TLR7 is cleaved in endosomes by acidic proteases, hTLR7 processing can occur at neutral pH throughout the secretory pathway through the activity of furin-like proprotein convertases. However, the mechanisms by which cleaved hTLR7 reaches the endosomal compartment remain unclear. In this study, we demonstrate that, after hTLR7 proteolytic processing, the liberated amino (N)-terminal fragment remains bound to the C terminus through disulfide bonds and provides key trafficking information that ensures correct delivery of the complex to endosomal compartments. In the absence of the N-terminal fragment, the C-terminal fragment is redirected to the cell surface, where it is functionally inactive. Our data reveal a novel role for the N terminus of hTLR7 as a molecular chaperone that provides processed hTLR7 with the correct targeting instructions to reach the endosomal compartment, hence ensuring its biological activity and preventing inadvertent cell surface responses to self-RNA. PMID- 25917087 TI - CXCL12 Regulates through JAK1 and JAK2 Formation of Productive Immunological Synapses. AB - The adaptive immune response requires interaction between T cells and APC to form a specialized structure termed the immune synapse (IS). Although the TCR is essential for IS organization, other factors such as chemokines participate in this process. In this study, we show that the chemokine CXCL12-mediated signaling contributes to correct IS organization and therefore influences T cell activation. CXCR4 downregulation or blockade on T cells caused defective actin polymerization at the contact site with APC, altered microtubule-organizing center polarization and the IS structure, and reduced T cell/APC contact duration. T cell activation was thus inhibited, as shown by reduced expression of CD25 and CD69 markers and of IL-2 mRNA levels. The results indicate that, through Gi and JAK1 and 2 kinases activation, CXCL12 signaling cooperates to build the IS and to maintain adhesive contacts between APC and T cells, required for continuous TCR signaling. PMID- 25917088 TI - Peripheral blood-derived virus-specific memory stem T cells mature to functional effector memory subsets with self-renewal potency. AB - Memory T cells expressing stem cell-like properties have been described recently. The capacity of self-renewal and differentiation into various memory/effector subsets make them attractive for adoptive T cell therapy to combat severe virus infections and tumors. The very few reports on human memory stem T cells (T(SCM)) are restricted to analyses on polyclonal T cells, but extensive data on Ag specific T(SCM )are missing. This might be due to their very low frequency limiting their enrichment and characterization. In this article, we provide functional and phenotypic data on human viral-specific T(SCM), defined as CD8(+)CD45RA(+)CCR7(+)CD127(+)CD95(+). Whereas <1% of total T cells express the T(SCM) phenotype, human CMV-specific T(SCM) can be detected at frequencies similar to those seen in other subsets, resulting in ~ 1 /10,000 human CMV specific T(SCM). A new virus-specific expansion protocol of sort-purified T(SCM) reveals both upregulation of various T cell subset markers and preservation of their stem cell phenotype in a significant proportion, indicating both self renewal and differentiation potency of virus-specific T cells sharing their TCR repertoire. Furthermore, we describe a simplified culture protocol that allows fast expansion of virus-specific T(SCM) starting from a mixed naive T/T(SCM) pool of PBLs. Due to the clinical-grade compatibility, this might be the basis for novel cell therapeutic options in life-threatening courses of viral and tumor disease. PMID- 25917089 TI - Upregulation of the N-formyl Peptide receptors in scleroderma fibroblasts fosters the switch to myofibroblasts. AB - Systemic sclerosis (SSc) is characterized by chronic inflammation and fibrosis. N Formyl peptide (fMLF) receptors (FPRs) are chemotactic receptors involved in inflammation. Three FPRs have been identified: FPR1, FPR2, and FPR3. We have examined, by RT-PCR, Western blot and immunohistochemistry, FPRs expression in skin fibroblasts from 10 normal subjects and 10 SSc patients, showing increased expression in SSc fibroblasts. Several functions of FPRs occur through the interaction with a region of the urokinase-type plasminogen activator receptor (uPAR88-92), able to interact with FPRs and to mediate urokinase (uPA) or fMLF dependent cell migration. Soluble uPAR84-95 peptide can act as a direct ligand of FPRs. Furthermore, uPA or its aminoterminal fragment (ATF) can promote the exposure of the uPAR88-92 region. The WKYMVm peptide is a FPRs pan-agonist. We investigated the functional effects of these agonists on normal and SSc fibroblasts. ATF, uPAR84-95, and WKYMVm regulated adhesion, migration, and proliferation of normal fibroblasts. Despite FPR overexpression, the response of SSc fibroblasts to the same agonists was greatly reduced, except for the proliferative response to ATF. SSc fibroblasts showed increased alpha-smooth muscle actin expression and improved capability to induce wound closure. Indeed, they overexpressed a cleaved uPAR form, exposing the uPAR88-92 region, and vitronectin, both involved in fibrosis and in the fibroblast-to-myofibroblast transition. FPR stimulation promoted alpha-smooth muscle actin expression in normal fibroblasts as well as motility, matrix deposition, alphavbeta5 integrin expression, and radical oxygen species generation in normal and SSc fibroblasts. This study provides evidence that FPRs may play a role in fibrosis and in the fibroblast-to-myofibroblast transition. PMID- 25917090 TI - The tolerogenic function of annexins on apoptotic cells is mediated by the annexin core domain. AB - Immunological tolerance is constantly being maintained in the periphery by dendritic cells processing material from apoptotic cells (ACs) in the steady state. Although research has focused on the uptake of ACs by phagocytes, tolerogenic signals exposed by the ACs are much less well defined. In this article, we show that the annexin (Anx) family members AnxA5 and AnxA13 translocate to the surface of ACs to function as redundant tolerogenic signals in vitro and in vivo. Exposure of bone marrow-derived dendritic cells to AnxA5 or AnxA13 in vitro resulted in the inhibition of both proinflammatory cytokine secretion and the upregulation of costimulatory molecules upon TLR stimulation. The highly conserved Anx core domain was sufficient to mediate these effects, whereas recognition by N-formyl peptide receptor family members was dispensable. In vivo, coinjection of OVA-expressing and Anx-expressing ACs prevented induction of Ag-specific CD8(+) T cells. Moreover, mice immunized with Anx-expressing ACs became refractory to an antigenic challenge. These results suggest that several Anxs contribute to AC-induced suppression of dendritic cell activation. Therefore, manipulating Anx-mediated immunosuppression may prove beneficial for patients with cancer or autoimmune diseases and chronic inflammatory disorders. PMID- 25917092 TI - Allogeneic Mature Human Dendritic Cells Generate Superior Alloreactive Regulatory T Cells in the Presence of IL-15. AB - Expansion of Ag-specific naturally occurring regulatory T cells (nTregs) is required to obtain sufficient numbers of cells for cellular immunotherapy. In this study, different allogeneic stimuli were studied for their capacity to generate functional alloantigen-specific nTregs. A highly enriched nTreg fraction (CD4(+)CD25(bright)CD127(-) T cells) was alloantigen-specific expanded using HLA mismatched immature, mature monocyte-derived dendritic cells (moDCs), or PBMCs. The allogeneic mature moDC-expanded nTregs were fully characterized by analysis of the demethylation status within the Treg-specific demethylation region of the FOXP3 gene and the expression of both protein and mRNA of FOXP3, HELIOS, CTLA4, and cytokines. In addition, the Ag-specific suppressive capacity of these expanded nTregs was tested. Allogeneic mature moDCs and skin-derived DCs were superior in inducing nTreg expansion compared with immature moDCs or PBMCs in an HLA-DR- and CD80/CD86-dependent way. Remarkably, the presence of exogenous IL-15 without IL-2 could facilitate optimal mature moDC-induced nTreg expansion. Allogeneic mature moDC-expanded nTregs were at low ratios (<1:320), potent suppressors of alloantigen-induced proliferation without significant suppression of completely HLA-mismatched, Ag-induced proliferation. Mature moDC-expanded nTregs were highly demethylated at the Treg-specific demethylation region within the FOXP3 gene and highly expressed of FOXP3, HELIOS, and CTLA4. A minority of the expanded nTregs produced IL-10, IL-2, IFN-gamma, and TNF-alpha, but few IL-17 producing nTregs were found. Next-generation sequencing of mRNA of moDC-expanded nTregs revealed a strong induction of Treg-associated mRNAs. Human allogeneic mature moDCs are highly efficient stimulator cells, in the presence of exogenous IL-15, for expansion of stable alloantigen-specific nTregs with superior suppressive function. PMID- 25917091 TI - Tumor-associated and disease-associated autoantibody repertoires in healthy colostrum and maternal and newborn cord sera. AB - In this work, we studied autoantibody repertoires and Ig isotypes in 71 mothers and their 104 healthy newborns (including twins and triplets delivered term or premature). Newborns receive maternal IgG Abs via the placenta before birth, but developing infants must produce their own IgM and IgA Abs. We used an Ag microarray analysis to detect binding to a selection of 295 self-Ags, compared with 27 standard foreign Ags. The magnitude of binding to specific self-Ags was found to be not less than that to the foreign Ags. As expected, each newborn shared with its mother a similar IgG repertoire-manifest as early as the 24th week of gestation. IgM and IgA autoantibody repertoires in cord sera were highly correlated among the newborns and differed from their mothers' repertoires; the latter differed in sera and milk. The autoantibodies bound to self-Ags known to be associated with tumors and to autoimmune diseases. Thus, autoantibody repertoires in healthy humans--the immunological homunculus--arise congenitally, differ in maternal milk and sera, and mark the potential of the immune system to attack tumors, beneficially, or healthy tissues, harmfully; regulation of the tissue site, the dynamics, and the response phenotype of homuncular autoimmunity very likely affects health. PMID- 25917093 TI - Anti-factor H autoantibodies in C3 glomerulopathies and in atypical hemolytic uremic syndrome: one target, two diseases. AB - Autoantibodies targeting factor H (FH), which is a main alternative complement pathway regulatory protein, have been well characterized in atypical hemolytic uremic syndrome (aHUS) but have been less well described in association with alternative pathway-mediated glomerulopathies (GP). In this study, we studied 17 patients presenting with GP who were positive for anti-FH IgG. Clinical data were collected and biological characteristics were compared with those of patients presenting with anti-FH Ab-associated aHUS. In contrast to the aHUS patients, the GP patients had no circulating FH-containing immune complexes, and their anti-FH IgG had a weaker affinity for FH. Functional studies demonstrated that these Abs induced no perturbations in FH cell surface protection or the binding of FH to its ligand. However, anti-FH IgG samples isolated from three patients were able to affect the factor I cofactor activity of FH. Epitope mapping identified the N terminal domain of FH as the major binding site for GP patient IgG. No homozygous deletions of the CFHR1 and CFHR3 genes, which are frequently associated with the anti-FH Ab in aHUS patients, were found in the GP patients. Finally, anti-FH Abs were frequently associated with the presence of C3 nephritic factor in child GP patients and with monoclonal gammopathy in adult GP patients, who frequently showed Ig Lchain restriction during reactivity against factor H. These data provide deeper insights into the pathophysiological differences between aHUS and GP, demonstrating heterogeneity of anti-FH IgG. PMID- 25917094 TI - High mitochondrial respiration and glycolytic capacity represent a metabolic phenotype of human tolerogenic dendritic cells. AB - Human dendritic cells (DCs) regulate the balance between immunity and tolerance through selective activation by environmental and pathogen-derived triggers. To characterize the rapid changes that occur during this process, we analyzed the underlying metabolic activity across a spectrum of functional DC activation states, from immunogenic to tolerogenic. We found that in contrast to the pronounced proinflammatory program of mature DCs, tolerogenic DCs displayed a markedly augmented catabolic pathway, related to oxidative phosphorylation, fatty acid metabolism, and glycolysis. Functionally, tolerogenic DCs demonstrated the highest mitochondrial oxidative activity, production of reactive oxygen species, superoxide, and increased spare respiratory capacity. Furthermore, assembled, electron transport chain complexes were significantly more abundant in tolerogenic DCs. At the level of glycolysis, tolerogenic and mature DCs showed similar glycolytic rates, but glycolytic capacity and reserve were more pronounced in tolerogenic DCs. The enhanced glycolytic reserve and respiratory capacity observed in these DCs were reflected in a higher metabolic plasticity to maintain intracellular ATP content. Interestingly, tolerogenic and mature DCs manifested substantially different expression of proteins involved in the fatty acid oxidation (FAO) pathway, and FAO activity was significantly higher in tolerogenic DCs. Inhibition of FAO prevented the function of tolerogenic DCs and partially restored T cell stimulatory capacity, demonstrating their dependence on this pathway. Overall, tolerogenic DCs show metabolic signatures of increased oxidative phosphorylation programing, a shift in redox state, and high plasticity for metabolic adaptation. These observations point to a mechanism for rapid genome-wide reprograming by modulation of underlying cellular metabolism during DC differentiation. PMID- 25917095 TI - MicroRNA-125a Inhibits Autophagy Activation and Antimicrobial Responses during Mycobacterial Infection. AB - MicroRNAs (miRNAs) are small noncoding nucleotides that play critical roles in the regulation of diverse biological functions, including the response of host immune cells. Autophagy plays a key role in activating the antimicrobial host defense against Mycobacterium tuberculosis. Although the pathways associated with autophagy must be tightly regulated at a posttranscriptional level, the contribution of miRNAs and whether they specifically influence the activation of macrophage autophagy during M. tuberculosis infection are largely unknown. In this study, we demonstrate that M. tuberculosis infection of macrophages leads to increased expression of miRNA-125a-3p (miR-125a), which targets UV radiation resistance-associated gene (UVRAG), to inhibit autophagy activation and antimicrobial responses to M. tuberculosis. Forced expression of miR-125a significantly blocked M. tuberculosis-induced activation of autophagy and phagosomal maturation in macrophages, and inhibitors of miR-125a counteracted these effects. Both TLR2 and MyD88 were required for biogenesis of miR-125a during M. tuberculosis infection. Notably, activation of the AMP-activated protein kinase significantly inhibited the expression of miR-125a in M. tuberculosis-infected macrophages. Moreover, either overexpression of miR-125a or silencing of UVRAG significantly attenuated the antimicrobial effects of macrophages against M. tuberculosis. Taken together, these data indicate that miR 125a regulates the innate host defense by inhibiting the activation of autophagy and antimicrobial effects against M. tuberculosis through targeting UVRAG. PMID- 25917096 TI - Collecting lymphatic vessel permeability facilitates adipose tissue inflammation and distribution of antigen to lymph node-homing adipose tissue dendritic cells. AB - Collecting lymphatic vessels (CLVs), surrounded by fat and endowed with contractile muscle and valves, transport lymph from tissues after it is absorbed into lymphatic capillaries. CLVs are not known to participate in immune responses. In this study, we observed that the inherent permeability of CLVs allowed broad distribution of lymph components within surrounding fat for uptake by adjacent macrophages and dendritic cells (DCs) that actively interacted with CLVs. Endocytosis of lymph-derived Ags by these cells supported recall T cell responses in the fat and also generated Ag-bearing DCs for emigration into adjacent lymph nodes (LNs). Enhanced recruitment of DCs to inflammation-reactive LNs significantly relied on adipose tissue DCs to maintain sufficient numbers of Ag-bearing DCs as the LN expanded. Thus, CLVs coordinate inflammation and immunity within adipose depots and foster the generation of an unexpected pool of APCs for Ag transport into the adjacent LN. PMID- 25917097 TI - Expression of GM-CSF in T Cells Is Increased in Multiple Sclerosis and Suppressed by IFN-beta Therapy. AB - Multiple sclerosis (MS) is an autoimmune disease of the CNS. Studies in animal models of MS have shown that GM-CSF produced by T cells is necessary for the development of autoimmune CNS inflammation. This suggests that GM-CSF may have a pathogenic role in MS as well, and a clinical trial testing its blockade is ongoing. However, there have been few reports on GM-CSF production by T cells in MS. The objective of this study was to characterize GM-CSF production by T cells of MS patients and to determine the effect of IFN-beta therapy on its production. GM-CSF production by peripheral blood (PB) T cells and the effects of IFN-beta were characterized in samples of untreated and IFN-beta-treated MS patients versus healthy subjects. GM-CSF production by T cells in MS brain lesions was analyzed by immunofluorescence. Untreated MS patients had significantly greater numbers of GM-CSF(+)CD4(+) and CD8(+) T cells in PB compared with healthy controls and IFN-beta-treated MS patients. IFN-beta significantly suppressed GM CSF production by T cells in vitro. A number of CD4(+) and CD8(+) T cells in MS brain lesions expressed GM-CSF. Elevated GM-CSF production by PB T cells in MS is indicative of aberrant hyperactivation of the immune system. Given its essential role in animal models, abundant GM-CSF production at the sites of CNS inflammation suggests that GM-CSF contributes to MS pathogenesis. Our findings also reveal a potential mechanism of IFN-beta therapy, namely suppression of GM CSF production. PMID- 25917099 TI - T follicular helper, but not Th1, cell differentiation in the absence of conventional dendritic cells. AB - Development of long-lived humoral immunity is dependent on CXCR5-expressing T follicular helper (Tfh) cells, which develop concomitantly to effector Th cells that support cellular immunity. Conventional dendritic cells (cDCs) are critical APCs for initial priming of naive CD4(+) T cells but, importantly, also provide accessory signals that govern effector Th cell commitment. To define the accessory role of cDCs during the concurrent development of Tfh and effector Th1 cells, we performed high-dose Ag immunization in conjunction with the Th1-biased adjuvant polyinosinic:polycytidylic acid (pI:C). In the absence of cDCs, pI:C failed to induce Th1 cell commitment and IgG2c production. However, cDC depletion did not impair Tfh cell differentiation or germinal center formation, and long lived IgG1 responses of unaltered affinity developed in mice lacking cDCs at the time point for immunization. Thus, cDCs are required for the pI:C-driven Th1 cell fate commitment but have no crucial accessory function in relation to Tfh cell differentiation. PMID- 25917098 TI - Prostaglandin E2 Inhibits NLRP3 Inflammasome Activation through EP4 Receptor and Intracellular Cyclic AMP in Human Macrophages. AB - PGE2 is a potent lipid mediator involved in maintaining homeostasis but also promotion of acute inflammation or immune suppression in chronic inflammation and cancer. Nucleotide-binding domain, leucine-rich repeat-containing protein (NLR)P3 inflammasome plays an important role in host defense. Uncontrolled activation of the NLRP3 inflammasome, owing to mutations in the NLRP3 gene, causes cryopyrin associated periodic syndromes. In this study, we showed that NLRP3 inflammasome activation is inhibited by PGE2 in human primary monocyte-derived macrophages. This effect was mediated through PGE2 receptor subtype 4 (EP4) and an increase in intracellular cAMP, independently of protein kinase A or exchange protein directly activated by cAMP. A specific agonist of EP4 mimicked, whereas its antagonist or EP4 knockdown reversed, PGE2-mediated NLRP3 inhibition. PGE2 caused an increase in intracellular cAMP. Blockade of adenylate cyclase by its inhibitor reversed PGE2-mediated NLRP3 inhibition. Increase of intracellular cAMP by an activator of adenylate cyclase or an analog of cAMP, or a blockade of cAMP degradation by phosphodiesterase inhibitor decreased NLRP3 activation. Protein kinase A or exchange protein directly activated by cAMP agonists did not mimic, and their antagonists did not reverse, PGE2-mediated NLRP3 inhibition. Additionally, constitutive IL-1beta secretion from LPS-primed PBMCs of cryopyrin associated periodic fever syndromes patients was substantially reduced by high doses of PGE2. Moreover, blocking cytosolic phospholipase A2alpha by its inhibitor or small interfering RNA or inhibiting cyclooxygenase 2, resulting in inhibition of endogenous PGE2 production, caused an increase in NLRP3 inflammasome activation. Our results suggest that PGE2 might play a role in maintaining homeostasis during the resolution phase of inflammation and might serve as an autocrine and paracrine regulator. PMID- 25917100 TI - C-reactive protein directly suppresses Th1 cell differentiation and alleviates experimental autoimmune encephalomyelitis. AB - Human C-reactive protein (CRP) is a serum-soluble pattern recognition receptor that serves as a marker of inflammation and directly contributes to innate immunity. In this study, we show that human CRP also directly contributes to adaptive immunity, that is, native CRP binds specifically to human Jurkat T cells and to mouse naive CD4(+) T cells and modulates their Th1 and Th2 responses. In vitro both exogenously added (purified) and endogenously expressed (via transfection) human CRP inhibited Th1 differentiation and augmented Th2 differentiation of naive CD4(+) T cells. In vivo for human CRP transgenic compared with wild-type mice, a lesser proportion of the T cells recovered from the spleens of healthy animals were Th1 cells. Moreover, in both CRP transgenic mice and in wild-type mice treated with human CRP, during myelin oligodendrocyte glycoprotein peptide-induced experimental autoimmune encephalomyelitis both the Th1 cell response and disease severity were inhibited. These pattern recognition independent actions of CRP directly on T cells highlights the potential for this soluble pattern recognition receptor to act as a tonic regulator of immunity, shaping global adaptive immune responses during both homeostasis and disease. PMID- 25917101 TI - Mechanistic Assessment of PD-1H Coinhibitory Receptor-Induced T Cell Tolerance to Allogeneic Antigens. AB - PD-1H is a recently identified cell surface coinhibitory molecule of the B7/CD28 immune modulatory gene family. We showed previously that single injection of a PD 1H agonistic mAb protected mice from graft-versus-host disease (GVHD). In this study, we report two distinct mechanisms operate in PD-1H-induced T cell tolerance. First, signaling via PD-1H coinhibitory receptor potently arrests alloreactive donor T cells from activation and expansion in the initiation phase. Second, donor regulatory T cells are subsequently expanded to maintain long-term tolerance and GVHD suppression. Our study reveals the crucial function of PD-1H as a coinhibitory receptor on alloreactive T cells and its function in the regulation of T cell tolerance. Therefore, PD-1H may be a target for the modulation of alloreactive T cells in GVHD and transplantation. PMID- 25917102 TI - Leptin receptor signaling in T cells is required for Th17 differentiation. AB - The hormone leptin plays a key role in energy homeostasis, and the absence of either leptin or its receptor (LepR) leads to severe obesity and metabolic disorders. To avoid indirect effects and to address the cell-intrinsic role of leptin signaling in the immune system, we conditionally targeted LepR in T cells. In contrast with pleiotropic immune disorders reported in obese mice with leptin or LepR deficiency, we found that LepR deficiency in CD4(+) T cells resulted in a selective defect in both autoimmune and protective Th17 responses. Reduced capacity for differentiation toward a Th17 phenotype by lepr-deficient T cells was attributed to reduced activation of the STAT3 and its downstream targets. This study establishes cell-intrinsic roles for LepR signaling in the immune system and suggests that leptin signaling during T cell differentiation plays a crucial role in T cell peripheral effector function. PMID- 25917104 TI - A New Approach for the Treatment of Arthritis in Mice with a Novel Conjugate of an Anti-C5aR1 Antibody and C5 Small Interfering RNA. AB - Rheumatoid arthritis (RA) is an inflammatory autoimmune joint disease in which the complement system plays an important role. Of the several components of complement, current evidence points to C5 as the most important inducer of inflammation. Several groups generated Abs or small interfering RNAs (siRNAs) or small molecule inhibitors against C5 and C5aR1 (CD88) that have showed some efficacy in RA in animal models. However, none of these candidate therapeutics has moved from bench to bedside. In this study, we test in collagen Ab-induced arthritis (CAIA) a new therapeutic strategy using a novel anti-C5ab-C5 siRNA conjugate. We first demonstrate that although C5aR2 or C5L2 (GPR77) plays no role in CAIA, C5aR1 contributes to pathogenesis. We demonstrate that injection of siRNAs blocking C5, C5aR1, or the combination decreased clinical disease activity in mice with CAIA by 45%, 51%, and 58%, respectively. Anti-C5 Ab (BB5.1) has only limited efficacy, but significantly reduced arthritis up to 66%. We then generated a novel anti-C5aR1 Ab-protamine-C5 siRNA conjugate. To our knowledge, we show for the first time that whereas unconjugated Ab plus siRNAs reduce arthritis by 19%, our anti-C5aR1 Ab-protamine-C5 siRNA conjugate was effective in reducing arthritis by 83% along with a parallel decrease in histopathology, C3 deposition, neutrophils, and macrophages in the joints of mice with CAIA. These data suggest that by targeting anti-C5 siRNAs to the receptor for its C5a activation fragment (C5aR1), a striking clinical effect can be realized. PMID- 25917105 TI - A haptotaxis assay for leukocytes based on surface-bound chemokine gradients. AB - The migration of leukocytes in response to chemokine gradients is an important process in the homeostasis of the human immune system and inflammation. In vivo the migration takes place on the surface of the endothelium to which the chemokine gradient is immobilized via interaction with glycosaminoglycans. To study leukocyte migration in response to surface-bound chemokines, we generated chemokine gradients by a simple stamping method: agarose stamps were soaked with chemokine solution to form continuous chemokine gradients by diffusion. These gradients could be easily transferred to a petri dish surface by stamping. We show that neutrophil granulocytes recognize these gradients and migrate toward increasing chemokine concentrations dependent on the slope of the gradient. Single-cell responses were recorded, and statistical analyses of cell behavior and migration were performed. For analysis of chemotaxis/haptotaxis, we propose a chemotactic precision index that is broadly applicable, valid, and allows for a straightforward and rapid quantification of the precision by which cells follow the direction of a given gradient. The presented technique is very simple, cost efficient, and can be broadly applied for generating defined and reproducible immobilized gradients of almost any protein on surfaces, and it is a valuable tool to study haptotaxis. PMID- 25917103 TI - Critical Role of Mast Cells and Peroxisome Proliferator-Activated Receptor gamma in the Induction of Myeloid-Derived Suppressor Cells by Marijuana Cannabidiol In Vivo. AB - Cannabidiol (CBD) is a natural nonpsychotropic cannabinoid from marijuana (Cannabis sativa) with anti-epileptic and anti-inflammatory properties. Effect of CBD on naive immune system is not precisely understood. In this study, we observed that administering CBD into naive mice triggers robust induction of CD11b(+)Gr-1(+) myeloid-derived suppressor cells (MDSC) in the peritoneum, which expressed functional arginase 1, and potently suppressed T cell proliferation ex vivo. Furthermore, CBD-MDSC suppressed LPS-induced acute inflammatory response upon adoptive transfer in vivo. CBD-induced suppressor cells were comprised of CD11b(+)Ly6-G(+)Ly6-C(+) granulocytic and CD11b(+)Ly6-G(-)Ly6-C(+) monocytic subtypes, with monocytic MDSC exhibiting higher T cell-suppressive function. Induction of MDSC by CBD was markedly attenuated in Kit-mutant (Kit(W/W-v)) mast cell-deficient mice. MDSC response was reconstituted upon transfer of wild-type bone marrow-derived mast cells in Kit(W/W-v) mice, suggesting the key role of cKit (CD117) as well as mast cells. Moreover, mast cell activator compound 48/80 induced significant levels of MDSC in vivo. CBD administration in mice induced G CSF, CXCL1, and M-CSF, but not GM-CSF. G-CSF was found to play a key role in MDSC mobilization inasmuch as neutralizing G-CSF caused a significant decrease in MDSC. Lastly, CBD enhanced the transcriptional activity of peroxisome proliferator-activated receptor gamma in luciferase reporter assay, and PPAR gamma selective antagonist completely inhibited MDSC induction in vivo, suggesting its critical role. Together, the results suggest that CBD may induce activation of PPAR-gamma in mast cells leading to secretion of G-CSF and consequent MDSC mobilization. CBD being a major component of Cannabis, our study indicates that marijuana may modulate or dysregulate the immune system by mobilizing MDSC. PMID- 25917106 TI - IL-37 Alleviates Rheumatoid Arthritis by Suppressing IL-17 and IL-17-Triggering Cytokine Production and Limiting Th17 Cell Proliferation. AB - IL-37, a new member of the IL-1 cytokine family, is a natural inhibitor of innate immunity associated with autoimmune diseases. This study was undertaken to evaluate whether IL-37 has antiarthritic effects in patients with rheumatoid arthritis (RA) and in mice with collagen-induced arthritis (CIA). In this study, we analyzed the expression of IL-37 in PBMCs, serum, and lymphocytes from RA patients as well as CD4(+) T cells polarized under Th1/Th2/Th17 conditions. The role of IL-37 was assessed by investigating the effects of recombinant human (rh)IL-37 and an adenovirus encoding human IL-37 (Ad-IL-37) on Th17 cells and Th17-related cytokines in RA patients and CIA mice. We found that active RA patients showed higher IL-37 levels compared with patients with inactive RA and healthy controls. Upregulated IL-37 expression also was found in CD3(+) T cells and CD4(+) T cells from RA patients and in Th1/Th17-differentiation conditions. rhIL-37 markedly decreased IL-17 expression and Th17 cell frequency in PBMCs and CD4(+) T cells from RA patients. Furthermore, IL-37 exerted a more suppressive effect on Th17 cell proliferation, whereas it had little or no effect on Th17 cell differentiation. IL-17 and IL-17-driving cytokine production were significantly reduced in synovium and joint cells from CIA mice receiving injections of Ad-IL-37. Our findings indicate that IL-37 plays a potent immunosuppressive role in the pathogenesis of human RA and CIA models via the downregulation of IL-17 and IL-17-triggering cytokine production and the curbing of Th17 cell proliferation. PMID- 25917107 TI - Arterial Stiffness as a Predictor of Clinical Hypertension. AB - The association between vascular stiffening and blood pressure is likely bidirectional. The present study was designed to examine temporal relationships among vascular stiffness, blood pressure progression, and hypertension. The Asymptomatic Polyvascular Abnormalities Community study is a community-based, prospective, long-term follow-up observational study. The present investigation is based on the baseline examinations (2010-2011) and the first follow-up measurements (2012-2013) included in the study. A total of 4025 participants were followed for an average of 27 months. Of 2153 participants free of hypertension at the baseline examination, 432 (20.07%) had incident hypertension. The authors observed that brachial-ankle pulse wave velocity (baPWV) was an independent predictor of incident hypertension. baPWV during baseline examination was positively associated with higher systolic blood pressure, diastolic blood pressure, pulse pressure, and mean arterial pressure during the first follow-up examination. baPWV but not blood pressure during baseline examination was associated with baPWV during the first follow-up examination. This study not only provides evidence that baPWV is an independent predictor of blood pressure progression and incident hypertension, but also provides evidence that blood pressure is not associated with baPWV after adjusting for baseline baPWV. PMID- 25917108 TI - Molecular imaging using PET for breast cancer. AB - Molecular imaging can visualize the biological processes at the molecular and cellular levels in vivo using certain tracers for specific molecular targets. Molecular imaging of breast cancer can be performed with various imaging modalities, however, positron emission tomography (PET) is a sensitive and non invasive molecular imaging technology and this review will focus on PET molecular imaging of breast cancer, such as FDG-PET, FLT-PET, hormone receptor PET, and anti-HER2 PET. PMID- 25917110 TI - Measurement of oxyhemoglobin concentration changes in interstitial cystitis female patients: A near-infrared spectroscopy study. AB - OBJECTIVES: To investigate brain activity related to bladder sensation in interstitial cystitis patients. METHODS: A total of 10 interstitial cystitis patients (all women; mean age 68 years) and 10 healthy controls (all women; mean age 64 years) participated in the present study. Frontal lobe blood flow was measured non-invasively by using multichannel near-infrared spectroscopy with large and small bladder volumes (created by infusing water) up to the first desire to void. RESULTS: The frontal cortex of the right and left hemisphere was activated, and the activation was detected as an increase in oxyhemoglobin concentration. The increase during the first desire to void in the interstitial cystitis group was greater than that in the control group. In addition, this difference was particularly observed in Brodmann's areas 9, 44, 45 and 46, reportedly associated with micturition and sensory modulation. CONCLUSIONS: The present study shows that the frontal area is largely activated during bladder filling in interstitial cystitis patients. Our findings suggest that the major change in cerebral blood flow is related to the characteristic urinary symptoms of interstitial cystitis patients. PMID- 25917111 TI - The 6,6-dicyanopentafulvene core: a template for the design of electron-acceptor compounds. AB - The electron-accepting ability of 6,6-dicyanopentafulvenes (DCFs) can be varied extensively through substitution on the five-membered ring. The reduction potentials for a set of 2,3,4,5-tetraphenyl-substituted DCFs, with varying substituents at the para-position of the phenyl rings, strongly correlate with their Hammett sigmap-parameters. By combining cyclic voltammetry with DFT calculations ((U)B3LYP/6-311+G(d)), using the conductor-like polarizable continuum model (CPCM) for implicit solvation, the absolute reduction potentials of a set of twenty DCFs were reproduced with a mean absolute deviation of 0.10 eV and a maximum deviation of 0.19 eV. Our experimentally investigated DCFs have reduction potentials within 3.67-4.41 eV, however, the computations reveal that DCFs with experimental reduction potentials as high as 5.3 eV could be achieved, higher than that of F4-TCNQ (5.02 eV). Thus, the DCF core is a template that allows variation in the reduction potentials by about 1.6 eV. PMID- 25917109 TI - Combining modelling and experimental approaches to explain how calcium signatures are decoded by calmodulin-binding transcription activators (CAMTAs) to produce specific gene expression responses. AB - Experimental data show that Arabidopsis thaliana is able to decode different calcium signatures to produce specific gene expression responses. It is also known that calmodulin-binding transcription activators (CAMTAs) have calmodulin (CaM)-binding domains. Therefore, the gene expression responses regulated by CAMTAs respond to calcium signals. However, little is known about how different calcium signatures are decoded by CAMTAs to produce specific gene expression responses. A dynamic model of Ca(2+) -CaM-CAMTA binding and gene expression responses is developed following thermodynamic and kinetic principles. The model is parameterized using experimental data. Then it is used to analyse how different calcium signatures are decoded by CAMTAs to produce specific gene expression responses. Modelling analysis reveals that: calcium signals in the form of cytosolic calcium concentration elevations are nonlinearly amplified by binding of Ca(2+) , CaM and CAMTAs; amplification of Ca(2+) signals enables calcium signatures to be decoded to give specific CAMTA-regulated gene expression responses; gene expression responses to a calcium signature depend upon its history and accumulate all the information during the lifetime of the calcium signature. Information flow from calcium signatures to CAMTA-regulated gene expression responses has been established by combining experimental data with mathematical modelling. PMID- 25917112 TI - Prediction of medication non-adherence and associated outcomes in pediatric kidney transplant recipients. AB - Studies have continued to evaluate risk factors associated with post-transplant non-adherence in pediatric patients. However, many of these studies fail to evaluate how risk factors can be utilized to predict MNA. The aims of this study were to (i) determine salient risk factors associated with MNA to develop an adequate predictive risk model and (ii) assess transplant outcomes based on the presence of MNA in a large, diverse cohort of pediatric KTX recipients. One hundred and seventy-five solitary pediatric KTX recipients transplanted from 1999 to 2013 were included. AA, males, older patients, those who lived in urban environments, had legal issues, and lived shorter distances from the transplant center were more likely to have MNA. Using logistic regression, a parsimonious model applying nine risk factors together was developed for predicting MNA, demonstrating a PPV of 69% and a NPV of 81%. Patients with MNA had more than twice the risk of biopsy proven acute rejection, 1.6 times the risk of hospitalization, and 1.8 times the risk of graft loss. Utilization of a predictive model to determine risk of MNA after pediatric KTX may offer clinicians the ability to efficiently and effectively monitor MNA following transplant. PMID- 25917113 TI - Vitrification of kidney precursors as a new source for organ transplantation. AB - Kidney transplantation from deceased or living human donors has been limited by donor availability as opposed to the increasing demand, and by the risk of allograft loss rejection and immunosuppressive therapy toxicity. In recent years, xenotransplantation of developed kidney precursor cells has offered a novel solution for the unlimited supply of human donor organs. Specifically, transplantation of kidney precursors in adult hosts showed that intact embryonic kidneys underwent maturation, exhibiting functional properties, and averted humoural rejection post-transplantation from non-immunosuppressed hosts. Even if supply and demand could be balanced using xenotransplants or lab-grown organs from regenerative medicine, the future of these treatments would still be compromised by the ability to physically distribute the organs to patients in need and to produce these products in a way that allows adequate inventory control and quality assurance. Kidney precursors originating from fifteen-day old rabbit embryos were vitrified using Cryotop(r) as a device and VM3 as vitrification solution. After 3 months of storage in liquid nitrogen, 18 kidney precursors were transplanted into non-immunosuppressed adult hosts by laparoscopy surgery. Twenty-one days after allotransplantation, 9 new kidneys were recovered. All the new kidneys recovered exhibited significant growth and mature glomeruli. Having achieved these encouraging results, we report, for the first time, that it is possible to create a long-term biobank of kidney precursors as an unlimited source of organs for transplantation, facilitating the inventory control and distribution of organs. PMID- 25917114 TI - The difference conservation makes to extinction risk of the world's ungulates. AB - Previous studies show that conservation actions have prevented extinctions, recovered populations, and reduced declining trends in global biodiversity. However, all studies to date have substantially underestimated the difference conservation action makes because they failed to account fully for what would have happened in the absence thereof. We undertook a scenario-based thought experiment to better quantify the effect conservation actions have had on the extinction risk of the world's 235 recognized ungulate species. We did so by comparing species' observed conservation status in 2008 with their estimated status under counterfactual scenarios in which conservation efforts ceased in 1996. We estimated that without conservation at least 148 species would have deteriorated by one International Union for Conservation of Nature (IUCN) Red List category, including 6 species that now would be listed as extinct or extinct in the wild. The overall decline in the conservation status of ungulates would have been nearly 8 times worse than observed. This trend would have been greater still if not for conservation on private lands. While some species have benefited from highly targeted interventions, such as reintroduction, most benefited collaterally from conservation such as habitat protection. We found that the difference conservation action makes to the conservation status of the world's ungulate species is likely to be higher than previously estimated. Increased, and sustained, investment could help achieve further improvements. PMID- 25917121 TI - Oxygen reduction mediated by single nanodroplets containing attomoles of vitamin B12: electrocatalytic nano-impacts method. AB - We report the use of single Vitamin B12 nanodroplets to mediate the reduction of oxygen in neutral buffer. Electron transfer to single Vitamin B12 nanodroplets is observed using the nano-impacts method and shown to be quantitative. The mechanism of mediated oxygen reduction by single VB12 droplets is revealed as via both Co(II) and Co(I) reduced from Co(III) in VB12 through one or two electron transfer followed by the four-electron reduction of oxygen. PMID- 25917123 TI - Node-based measures of connectivity in genetic networks. AB - At-site environmental conditions can have strong influences on genetic connectivity, and in particular on the immigration and settlement phases of dispersal. However, at-site processes are rarely explored in landscape genetic analyses. Networks can facilitate the study of at-site processes, where network nodes are used to model site-level effects. We used simulated genetic networks to compare and contrast the performance of 7 node-based (as opposed to edge-based) genetic connectivity metrics. We simulated increasing node connectivity by varying migration in two ways: we increased the number of migrants moving between a focal node and a set number of recipient nodes, and we increased the number of recipient nodes receiving a set number of migrants. We found that two metrics in particular, the average edge weight and the average inverse edge weight, varied linearly with simulated connectivity. Conversely, node degree was not a good measure of connectivity. We demonstrated the use of average inverse edge weight to describe the influence of at-site habitat characteristics on genetic connectivity of 653 American martens (Martes americana) in Ontario, Canada. We found that highly connected nodes had high habitat quality for marten (deep snow and high proportions of coniferous and mature forest) and were farther from the range edge. We recommend the use of node-based genetic connectivity metrics, in particular, average edge weight or average inverse edge weight, to model the influences of at-site habitat conditions on the immigration and settlement phases of dispersal. PMID- 25917124 TI - Teaching generatively: Learning about disorders and disabilities. AB - Stimulus equivalence procedures have been used to teach course material in higher education in the laboratory and in the classroom. The current study was a systematic replication of Walker, Rehfeldt, and Ninness (2010), who used a stimulus equivalence procedure to train information pertaining to 12 disorders. Specifically, we conducted (a) a written posttest immediately after each training unit and (b) booster training sessions for poor performers. Results showed immediate improvement from pretest to posttest scores after training, but problems with maintenance were noted in the final examination. Implications of poor maintenance are discussed in the context of the current study and stimulus equivalence research in higher education generally. PMID- 25917122 TI - Prediction and Validation of Load-Dependent Behavior of the Tibiofemoral and Patellofemoral Joints During Movement. AB - The study objective was to construct and validate a subject-specific knee model that can simulate full six degree of freedom tibiofemoral and patellofemoral joint behavior in the context of full body movement. Segmented MR images were used to reconstruct the geometry of 14 ligament bundles and articular cartilage surfaces. The knee was incorporated into a lower extremity musculoskeletal model, which was then used to simulate laxity tests, passive knee flexion, active knee flexion, and human walking. Simulated passive and active knee kinematics were shown to be consistent with subject-specific measures obtained via dynamic MRI. Anterior tibial translation and internal tibial rotation exhibited the greatest variability when uncertainties in ligament properties were considered. When used to simulate walking, the model predicted knee kinematic patterns that differed substantially from passive joint behavior. Predictions of ean knee cartilage contact pressures during normal gait reached 6.2 and 2.8 Pa on the medial tibial plateau and patellar facets, respectively. Thus, the dynamic modeling framework can be used to simulate the interaction of soft tissue loads and cartilage contact during locomotion activities, and therefore provides a basis to simulate the effects of soft tissue injury and surgical treatment on functional knee mechanics. PMID- 25917125 TI - Predictors of participant engagement and naloxone utilization in a community based naloxone distribution program. AB - AIMS: To describe characteristics of participants and overdose reversals associated with a community-based naloxone distribution program and identify predictors of obtaining naloxone refills and using naloxone for overdose reversal. DESIGN: Bivariate statistical tests were used to compare characteristics of participants who obtained refills and reported overdose reversals versus those who did not. We fitted multiple logistic regression models to identify predictors of refills and reversals; zero-inflated multiple Poisson regression models were used to identify predictors of number of refills and reversals. SETTING: San Francisco, California, USA. PARTICIPANTS: Naloxone program participants registered and reversals reported from 2010 to 2013. MEASUREMENTS: Baseline characteristics of participants and reported characteristics of reversals. FINDINGS: A total of 2500 participants were registered and 702 reversals were reported from 2010 to 2013. Participants who had witnessed an overdose [adjusted odds ratio (AOR)=2.02, 95% confidence interval (CI)= 1.53-2.66; AOR = 2.73, 95% CI = 1.73-4.30] or used heroin (AOR = 1.85, 95% CI = 1.44-2.37; AOR = 2.19, 95% CI = 1.54-3.13) or methamphetamine (AOR=1.71, 95% CI=1.37-2.15; AOR=1.61, 95% CI=1.18-2.19) had higher odds of obtaining a refill and reporting a reversal, respectively. African American (AOR = 0.63, 95% CI = 0.45-0.88) and Latino (AOR = 0.65, 95% CI = 0.43-1.00) participants had lower odds of obtaining a naloxone refill, whereas Latino participants who obtained at least one refill reported a higher number of refills [incidence rate ratio (IRR) = 1.33 (1.05-1.69)]. CONCLUSIONS: Community naloxone distribution programs are capable of reaching sizeable populations of high-risk individuals and facilitating large numbers of overdose reversals. Community members most likely to engage with a naloxone program and use naloxone to reverse an overdose are active drug users. PMID- 25917126 TI - Adipocyte-derived monocyte chemotactic protein-1 (MCP-1) promotes prostate cancer progression through the induction of MMP-2 activity. AB - BACKGROUND: Obesity is known to be associated with prostate cancer development and progression, but the detailed mechanism is not clear. Monocyte chemotactic protein-1 (MCP-1) is secreted from cancer cells, stromal cells, and adipocytes, and it is involved in prostate cancer progression. Here we investigated the biological role of MCP-1 secreted from adipocytes for prostate cancer cells. METHODS: Human pre-adipocytes (HPAds) were cultured and differentiated to mature adipocytes. Conditioned medium (CM) from HPAd cells was obtained using phenol red free RPMI1640 medium. We performed a cytokine membrane array analysis to detect cytokines in the CM. To characterize the physiological function of MCP-1 in the CM, we performed an MTT-assay, a wound-healing and invasion assay with anti-MCP-1 antibody using three prostate cancer cell lines: DU145, LNCaP, and PC-3. Matrix metalloproteinase (MMP)-2 and MMP-9 activities were evaluated by gelatin zymography. A qPCR and Western blotting were used to examine the mRNA and protein expression levels of MMP-2. RESULTS: The cytokine membrane array of the CM showed a strong signal of MCP-1compared to the control medium, and we thus focused our attention on MCP-1 in the CM. The CM up-regulated the cancer cell proliferation, and the neutralization by anti-MCP-1 antibody inhibited the proliferative effect of the prostate cancer cell lines. The CM greatly increased the invasive activity in the prostate cancer cell lines, and anti-MCP-1 antibody decreased the invasiveness. Gelatin zymography revealed that the CM markedly enhanced the enzymatic activity of MMP-2, and anti-MCP-1 antibody down-regulated its effect. MMP-2 mRNA expression was undetected and the MMP-2 protein level was unchanged between the control medium and CM in DU145 cells. CONCLUSIONS: MCP-1 from adipocytes enhances the growth and invasion activity of prostate cancer cells. The inhibition of MCP-1 derived from adipocytes might be an effective treatment for prostate cancer. PMID- 25917127 TI - Methods to determine effects of cranberry proanthocyanidins on extraintestinal infections: Relevance for urinary tract health. AB - Urinary tract infections (UTI) are one of the most frequent extraintestinal infections caused by Escherichia coli (ExPEC). Cranberry juice has been used for decades to alleviate symptoms and prevent recurrent UTI. The putative compounds in cranberries are proanthocyanidins (PAC), specifically PAC with "A-type" bonds. Since PAC are not absorbed, their health benefits in UTI may occur through interactions at the mucosal surface in the gastrointestinal tract. Recent research showed that higher agglutination of ExPEC and reduced bacterial invasion are correlated with higher number of "A-type" bonds and higher degree of polymerization of PAC. An understanding of PAC structure-activity relationship is becoming feasible due to advancements, not only in obtaining purified PAC fractions that allow accurate estimation, but also in high-resolution MS methodologies, specifically, MALDI-TOF MS. A recent MALDI-TOF MS deconvolution method allows quantification of the ratios of "A-type" to "B-type" bonds enabling characteristic fingerprints. Moreover, the generation of fluorescently labeled PAC allows visualization of the interaction between ExPEC and PAC with microscopy. These tools can be used to establish structure-activity relationships between PAC and UTI and give insight on the mechanism of action of these compounds in the gut without being absorbed. PMID- 25917128 TI - Solventless Formation of G-Quartet Complexes Based on Alkali and Alkaline Earth Salts on Au(111). AB - Template cations have been extensively employed in the formation, stabilization and regulation of structural polymorphism of G-quadruplex structures in vitro. However, the direct addition of salts onto solid surfaces, especially under ultra high-vacuum (UHV) conditions, to explore the feasibility and universality of the formation of G-quartet complexes in a solventless environment has not been reported. By combining UHV-STM imaging and DFT calculations, we have shown that three different G-quartet-M (M: Na/K/Ca) complexes can be obtained on Au(111) using alkali and alkaline earth salts as reactants. We have also identified the driving forces (intra-quartet hydrogen bonding and electrostatic ionic bonding) for the formation of these complexes and quantified the interactions involved. Our results demonstrate a novel route to fabricate G-quartet-related complexes on solid surfaces, providing an alternative feasible way to bring metal elements to surfaces for constructing metal-organic systems. PMID- 25917129 TI - Stucco keratosis in a patient with esophageal cancer. PMID- 25917130 TI - The O-specific polysaccharides from Phyllobacterium trifolii PETP02(T) LPS contain 3-C-methyl-D-rhamnose. AB - The O-specific polysaccharides of Phyllobacterium trifolii PETP02(T), a microsymbiont of Trifolium pratense, were obtained by mild acid hydrolysis of the lipopolysaccharide and studied by chemical analyses, mass spectrometry, and (1)H and (13)C NMR spectroscopy, including homonuclear ((1)H,(1)H DQF-COSY, TOCSY, NOESY) and heteronuclear ((1)H,(13)C HSQC, HMQC, HMBC) experiments. It was revealed that alpha-D-rhamnose and beta-3-C-methyl-D-rhamnose (evalose) were the only components of two identified O-polysaccharides. The major O-polysaccharide was found to consist of linear hexasaccharide repeating units, while the other minor one, is composed of disaccharide repeats. The following structures of two O polysaccharides were established: -> 2)-beta-D-Rhap3CMe-(1 -> 3)-alpha-D-Rhap-(1 > 3)-alpha-D-Rhap-(1 -> 2)-beta-D-Rhap3CMe-(1 -> 3)-alpha-D-Rhap-(1 -> 2)-alpha-D Rhap-(1 -> and -> 2)-beta-D-Rhap3CMe-(1 -> 3)-alpha-D-Rhap-(1 ->. PMID- 25917131 TI - Structure of the K6 capsular polysaccharide from Acinetobacter baumannii isolate RBH4. AB - The structure of the capsular polysaccharide (CPS) from an Acinetobacter baumannii global clone 2 (GC2) clinical isolate RBH4 that carries the KL6 gene cluster was elucidated by means of chemical and spectroscopical methods. The repeating unit of K6 CPS is linear and contains N-acetyl-D-galactosamine (D GalpNAc), two D-galactose (D-Galp) residues and 5,7-di-N-acetylpseudaminic acid (Pse5Ac7Ac). The synthesis of these sugars could be attributed to genes in the KL6 capsule biosynthesis gene cluster, and the formation of the linkages between the sugars were assigned to glycosyltransferases or the Wzy polymerase encoded in KL6. PMID- 25917133 TI - EMR studies of the internal motion of Mn(4+) ions in the Sr overdoped (La(1 x)Sr(x))(Ga(1-y)Mn(y))O3 (x/y up to 8) supplemented by magnetic and optical spectroscopy measurements. AB - The effect of the Sr doping on electronic structure in single crystals of (La(1 x)Sr(x))(Ga(1-y)Mn(y))O3 solid solutions (LSGM) is investigated by means of electron magnetic resonance (EMR). The EMR results are supplemented by magnetic susceptibility and optical spectroscopy measurements. The compositions with small concentration of Mn doping (y<1%) and overdoped content of Sr (the ratio x(Sr)/y(Mn) up to 8) are used to maximally enhance the role of divalent doping. The experimental results provide evidence of the holes delocalization in the overdoped compound (x(Sr)/y(Mn)>1). This delocalization is accompanied by appearance of the new charge transfer transitions in the optical spectrum and dynamical valence change of manganese atoms. Additionally we observe the thermally activated narrowing of resonance EMR lines due to the internal motion, which is characterized by the energy barrier depending strongly on the ratio x(Sr)/y(Mn). The energy barrier is found to be associated with the charge carrier (hole) self-trapped energy. Fitting the EMR spectra in three orthogonal planes to an orthorhombic spin Hamiltonian enables extracting the zero-field splitting (ZFS) parameters and the Zeeman g-factors for Mn(4+) (S=3/2) ions in LSGM. The experimental ZFS parameters are modeled using superposition model analysis based on an orthorhombic symmetry approximation. PMID- 25917132 TI - Spin-label CW microwave power saturation and rapid passage with triangular non adiabatic rapid sweep (NARS) and adiabatic rapid passage (ARP) EPR spectroscopy. AB - Non-adiabatic rapid passage (NARS) electron paramagnetic resonance (EPR) spectroscopy was introduced by Kittell et al. (2011) as a general purpose technique to collect the pure absorption response. The technique has been used to improve sensitivity relative to sinusoidal magnetic field modulation, increase the range of inter-spin distances that can be measured under near physiological conditions (Kittell et al., 2012), and enhance spectral resolution in copper (II) spectra (Hyde et al., 2013). In the present work, the method is extended to CW microwave power saturation of spin-labeled T4 Lysozyme (T4L). As in the cited papers, rapid triangular sweep of the polarizing magnetic field was superimposed on slow sweep across the spectrum. Adiabatic rapid passage (ARP) effects were encountered in samples undergoing very slow rotational diffusion as the triangular magnetic field sweep rate was increased. The paper reports results of variation of experimental parameters at the interface of adiabatic and non adiabatic rapid sweep conditions. Comparison of the forward (up) and reverse (down) triangular sweeps is shown to be a good indicator of the presence of rapid passage effects. Spectral turning points can be distinguished from spectral regions between turning points in two ways: differential microwave power saturation and differential passage effects. Oxygen accessibility data are shown under NARS conditions that appear similar to conventional field modulation data. However, the sensitivity is much higher, permitting, in principle, experiments at substantially lower protein concentrations. Spectral displays were obtained that appear sensitive to rotational diffusion in the range of rotational correlation times of 10(-3) to 10(-7) s in a manner that is analogous to saturation transfer spectroscopy. PMID- 25917134 TI - Efficient 2D MRI relaxometry using compressed sensing. AB - Potential applications of 2D relaxation spectrum NMR and MRI to characterize complex water dynamics (e.g., compartmental exchange) in biology and other disciplines have increased in recent years. However, the large amount of data and long MR acquisition times required for conventional 2D MR relaxometry limits its applicability for in vivo preclinical and clinical MRI. We present a new MR pipeline for 2D relaxometry that incorporates compressed sensing (CS) as a means to vastly reduce the amount of 2D relaxation data needed for material and tissue characterization without compromising data quality. Unlike the conventional CS reconstruction in the Fourier space (k-space), the proposed CS algorithm is directly applied onto the Laplace space (the joint 2D relaxation data) without compressing k-space to reduce the amount of data required for 2D relaxation spectra. This framework is validated using synthetic data, with NMR data acquired in a well-characterized urea/water phantom, and on fixed porcine spinal cord tissue. The quality of the CS-reconstructed spectra was comparable to that of the conventional 2D relaxation spectra, as assessed using global correlation, local contrast between peaks, peak amplitude and relaxation parameters, etc. This result brings this important type of contrast closer to being realized in preclinical, clinical, and other applications. PMID- 25917135 TI - No association between polygenic risk for schizophrenia and brain volume in the general population. PMID- 25917136 TI - Establishing biomechanical mechanisms in mouse models: practical guidelines for systematically evaluating phenotypic changes in the diaphyses of long bones. AB - Mice are widely used in studies of skeletal biology, and assessment of their bones by mechanical testing is a critical step when evaluating the functional effects of an experimental perturbation. For example, a gene knockout may target a pathway important in bone formation and result in a "low bone mass" phenotype. But how well does the skeleton bear functional loads; eg, how much do bones deform during loading and how resistant are bones to fracture? By systematic evaluation of bone morphological, densitometric, and mechanical properties, investigators can establish the "biomechanical mechanisms" whereby an experimental perturbation alters whole-bone mechanical function. The goal of this review is to clarify these biomechanical mechanisms and to make recommendations for systematically evaluating phenotypic changes in mouse bones, with a focus on long-bone diaphyses and cortical bone. Further, minimum reportable standards for testing conditions and outcome variables are suggested that will improve the comparison of data across studies. Basic biomechanical principles are reviewed, followed by a description of the cross-sectional morphological properties that best inform the net cellular effects of a given experimental perturbation and are most relevant to biomechanical function. Although morphology is critical, whole bone mechanical properties can only be determined accurately by a mechanical test. The functional importance of stiffness, maximum load, postyield displacement, and work-to-fracture are reviewed. Because bone and body size are often strongly related, strategies to adjust whole-bone properties for body mass are detailed. Finally, a comprehensive framework is presented using real data, and several examples from the literature are reviewed to illustrate how to synthesize morphological, tissue-level, and whole-bone mechanical properties of mouse long bones. PMID- 25917137 TI - Concussion under-reporting and pressure from coaches, teammates, fans, and parents. AB - Concussions from sport present a substantial public health burden given the number of youth, adolescent and emerging adult athletes that participate in contact or collision sports. Athletes who fail to report symptoms of a suspected concussion and continue play are at risk of worsened symptomatology and potentially catastrophic neurologic consequences if another impact is sustained during this vulnerable period. Understanding why athletes do or do not report their symptoms is critical for developing efficacious strategies for risk reduction. Psychosocial theories and frameworks that explicitly incorporate context, as a source of expectations about the outcomes of reporting and as a source of behavioral reinforcement, are useful in framing this problem. The present study quantifies the pressure that athletes experience to continue playing after a head impact--from coaches, teammates, parents, and fans--and assesses how this pressure, both independently and as a system, is related to future concussion reporting intention. Participants in the study were 328 male and female athletes from 19 teams competing in one of seven sports (soccer, lacrosse, basketball, softball, baseball, volleyball, field hockey) at four colleges in the northeast region of the United States. Results found that more than one-quarter of the sample had experienced pressure from at least one source to continue playing after a head impact during the previous year. Results of a latent profile mixture model indicated that athletes who experienced pressure from all four of the measured sources were significantly more likely to intend to continue playing in the future than were athletes who had not experienced pressure from all sources, or only pressure from coaches and teammates. These findings underscore the importance of designing interventions that address the system in which athletes make decisions about concussion reporting, including athletes' parents, rather than focusing solely on modifying the individual's reporting cognitions. PMID- 25917138 TI - Decomposing socio-economic inequality in colorectal cancer screening uptake in England. AB - Colorectal cancer (CRC) is the second largest cause of cancer death in the UK. Since 2010, CRC screening based on Faecal Occult Blood testing has been offered by the NHS in England biennially to all persons age 60-69 years. Several studies have demonstrated a gradient in uptake using area-level markers of socio-economic status (SES), but few have examined the individual-level contributors to the gradient. We aimed to quantify the extent of SES inequality in CRC screening uptake in England using individual-level data, and to identify individual factors associated with this inequality. We used data from 1833 participants (aged 61-69) in Wave 5 (collected in years 2010/11) of the English Longitudinal Study of Ageing (ELSA) eligible for having been sent at least one CRC screening invitation. Uptake was defined by self-report of ever having been screened as part of the National Screening Programme. We assessed socio-economic inequality using the corrected concentration index of uptake against SES rank, which was derived by regressing a range of SES markers against net non-pension household wealth. Other demographic and health-related variables were included in the analysis. Factors associated with inequality were measured using concentration index decomposition. There was a significant pro-rich gradient in screening uptake (concentration index: 0.16, 95% CI:0.11-0.22), mostly explained within our model by differences in non-pension wealth (38.7%), partner screening status (15.9%), sickness/disability (13.5%), and health literacy (8.5%). Interventions aimed at reducing inequalities in CRC screening uptake should focus on improving acceptability of screening in populations with low levels of education and literacy barriers. PMID- 25917139 TI - Seasonal variation in vitamin D status of beef cattle reared in the central United States. AB - The objective was to retrospectively measure seasonal sunlight-associated variation in serum concentrations of 25-hydroxyvitamin D (25OHD) in beef cattle. The concentration of 25OHD was measured in crossbred animals born from March to May in 2011 and 2012. Vitamin D status 2 to 3 mo after birth (period 1) was only available for 2012 calves and was measured in June 2012. Period 1 animals had serum 25OHD concentrations of 26.3 +/- 1.5 ng/mL. The 25OHD concentrations for late summer (period 2) were 46.6 +/- 1.4 and 51.0 +/- 1.5 ng/mL for 2011 and 2012, respectively. Serum concentration of 25OHD in early fall (period 3) were 63.8 +/- 1.4 and 55.2 +/- 1.5 ng/mL for calves in 2011 and 2012, respectively. Values observed for both late summer and early fall indicated vitamin D sufficiency (P < 0.001) compared with period 1. With diminishing exposure to ultraviolet B and consuming ~800 IU or 1800 IU (2011 and 2012, respectively) of supplemental vitamin D, the calves' midwinter (period 4) 25OHD concentrations fell to 15.2 +/- 1.6 and 16.7 +/- 1.5 ng/mL for 2011 and 2012, respectively, after 4 to 5 mo on a finishing diet (P < 0.0001). This is considered vitamin D insufficiency in most species. Results indicate that calves are marginally sufficient to insufficient for vitamin D based on serum 25OHD concentrations soon after birth and during winter. Some individual animals would be classified vitamin D deficient. In the absence of sufficient UVB exposure, the dietary vitamin D requirements for rapidly growing beef cattle may need to be increased. PMID- 25917140 TI - Maternal serum progesterone concentration and early conceptus development of bovine embryos produced in vivo or in vitro. AB - The hormone progesterone is essential for proper embryonic development. The objective of this study was to examine the relationship between recipient serum concentrations of progesterone, at the time of embryo transfer and at conceptus recovery, on conceptus development from in vivo- or in vitro-produced embryos. Embryos were produced in vivo by superovulation of Holstein cows (IVO; n = 17) or in vitro with either serum-containing (IVPS; n = 27) or serum-restricted medium (IVPSR; n = 34). Single grade I blastocysts from each embryo production system were transferred into heifers on day 7 of development. Conceptuses were recovered on day 17 of gestation and classified as complete, degenerated, or no conceptus. Compared with the IVO group, in vitro-produced embryos had more (P = 0.055) degenerated conceptuses (IVO, 0%; IVPS, 18.5%; and IVPSR, 20.6%). There were no differences in progesterone concentrations at the time of transfer when recipients received either male or female embryos (P > 0.05). Progesterone concentrations in recipients receiving in vivo-produced embryos were higher (P < 0.05; 3.74 +/- 0.4 ng/mL; least-squares mean +/- standard error of the mean) on day 7 compared with those receiving in vitro-produced embryos (IVPS, 2.4 +/- 0.2; IVPSR, 2.58 +/- 0.3 ng/mL). However, there was no difference in progesterone concentration on day 7 between treatment groups for heifers from which short conceptuses (<=194 mm) were recovered on day 17. In contrast, when longer (>194 mm) conceptuses were recovered on day 17, heifers receiving in vitro-produced embryos had lower (P = 0.05) serum concentrations of progesterone on day 7 compared with those receiving in vivo-produced embryos (IVPS, 2.2 +/- 0.5; IVPSR, 2.3 +/- 0.5; IVO, 3.9 +/- 0.5 ng/mL). In conclusion, differences in autonomy may exist between in vitro- and in vivo-produced embryos during the period of conceptus elongation with in vitro-produced embryos relying more on intrinsic factors to influence elongation. PMID- 25917141 TI - Multiple stages of learning in perceptual categorization: evidence and neurocomputational theory. AB - Virtually all current theories of category learning assume that humans learn new categories by gradually forming associations directly between stimuli and responses. In information-integration category-learning tasks, this purported process is thought to depend on procedural learning implemented via dopamine dependent cortical-striatal synaptic plasticity. This article proposes a new, neurobiologically detailed model of procedural category learning that, unlike previous models, does not assume associations are made directly from stimulus to response. Rather, the traditional stimulus-response (S-R) models are replaced with a two-stage learning process. Multiple streams of evidence (behavioral, as well as anatomical and fMRI) are used as inspiration for the new model, which synthesizes evidence of multiple distinct cortical-striatal loops into a neurocomputational theory. An experiment is reported to test a priori predictions of the new model that: (1) recovery from a full reversal should be easier than learning new categories equated for difficulty, and (2) reversal learning in procedural tasks is mediated within the striatum via dopamine-dependent synaptic plasticity. The results confirm the predictions of the new two-stage model and are incompatible with existing S-R models. PMID- 25917142 TI - A review of control processes and their locus in language switching. AB - Language switching has been one of the main tasks to investigate language control, a process that restricts bilingual language processing to the target language. In the current review, we discuss the How (i.e., mechanisms) and Where (i.e., locus of these mechanisms) of language control in language switching. As regards the mechanisms of language control, we describe several empirical markers of language switching and their relation to inhibition, as a potentially important mechanism of language control. From this overview it becomes apparent that some, but not all, markers indicate the occurrence of inhibition during language switching and, thus, language control. In a second part, we turn to the potential locus of language control and the role of different processing stages (concept level, lemma level, phonology, orthography, and outside language processing). Previous studies provide evidence for the employment of several of these processing stages during language control so that either a complex control mechanism involving different processing stages and/or multiple loci of language control have to be assumed. Based on the discussed results, several established and new theoretical avenues are considered. PMID- 25917143 TI - Relationship between individual differences in speech processing and cognitive functions. AB - A growing body of research has suggested that cognitive abilities may play a role in individual differences in speech processing. The present study took advantage of a widespread linguistic phenomenon of sound change to systematically assess the relationships between speech processing and various components of attention and working memory in the auditory and visual modalities among typically developed Cantonese-speaking individuals. The individual variations in speech processing are captured in an ongoing sound change-tone merging in Hong Kong Cantonese, in which typically developed native speakers are reported to lose the distinctions between some tonal contrasts in perception and/or production. Three groups of participants were recruited, with a first group of good perception and production, a second group of good perception but poor production, and a third group of good production but poor perception. Our findings revealed that modality independent abilities of attentional switching/control and working memory might contribute to individual differences in patterns of speech perception and production as well as discrimination latencies among typically developed speakers. The findings not only have the potential to generalize to speech processing in other languages, but also broaden our understanding of the omnipresent phenomenon of language change in all languages. PMID- 25917148 TI - Acute coronary syndromes: Acute MI in women--the fountain of youth has run dry. PMID- 25917149 TI - Genetics: Alzheimer disease and dyslipidaemia. PMID- 25917144 TI - The negative priming paradigm: An update and implications for selective attention. AB - Negative Priming (NP) is an influential paradigm in cognitive psychology that was originally developed to measure attentional selection. Yet, up to the mid-1990s, a large number of experimental reports questioned whether the NP effect is based on attentional inhibition and/or episodic retrieval processes. In this review, we summarize findings since the mid-1990s and discuss new and old theoretical approaches to Negative Priming. We conclude that more than one process contributes to NP and that future research should analyze the conditions under which a particular process contributes to NP. Moreover, we argue that the paradigm--although it does not measure a single cognitive process alone--is still a useful tool for understanding selection in cognition. In fact, it might be a virtue of the paradigm that several cognitive processes work here together as selection in nonexperimental contexts is surely a multidimensional process. From this perspective, research on NP is relevant for all research fields analyzing selection. We therefore close our review by discussing the implications of the new evidence on NP for theories of selective attention. PMID- 25917150 TI - Integrating traditional Chinese medicine into Western cardiovascular medicine: an evidence-based approach. PMID- 25917152 TI - Risk factors: Link between low vitamin D and heart failure. PMID- 25917153 TI - Assessment of atrial appendage stasis and thrombosis using MDCT. PMID- 25917151 TI - Principles of transthoracic echocardiographic evaluation. AB - Transthoracic echocardiography is the most widely used imaging test in cardiology. Although completely noninvasive, transthoracic echocardiography has a well-established role in the diagnosis of numerous cardiovascular diseases, and also provides critical qualitative and quantitative information on their prognosis and pathophysiological processes. The aim of this Review is to outline the broad principles of transthoracic echocardiography, including the traditional techniques of two-dimensional, colour, and spectral Doppler echocardiography, and newly developed advances including tissue Doppler, myocardial deformation imaging, torsion, stress echocardiography, contrast and three-dimensional echocardiography. The advantages and disadvantages, clinical application, prognostic value, and salient research findings of each modality are described. Advances in complex imaging techniques are expected to continue unabated, and this Review highlights technical improvements that will influence the diagnosis and improve our understanding of cardiovascular function and disease. PMID- 25917155 TI - Evidence for traditional Chinese medication to treat cardiovascular disease. PMID- 25917154 TI - Gene therapy to treat cardiac arrhythmias. AB - Gene therapy to treat electrical dysfunction of the heart is an appealing strategy because of the limited therapeutic options available to manage the most severe cardiac arrhythmias, such as ventricular tachycardia, ventricular fibrillation, and asystole. However, cardiac genetic manipulation is challenging, given the complex mechanisms underlying arrhythmias. Nevertheless, the growing understanding of the molecular basis of these diseases, and the development of sophisticated vectors and delivery strategies, are providing researchers with adequate means to target specific genes and pathways involved in disorders of heart rhythm. Data from preclinical studies have demonstrated that gene therapy can be successfully used to modify the arrhythmogenic substrate and prevent life threatening arrhythmias. Therefore, gene therapy might plausibly become a treatment option for patients with difficult-to-manage acquired arrhythmias and for those with inherited arrhythmias. In this Review, we summarize the preclinical studies into gene therapy for acquired and inherited arrhythmias of the atria or ventricles. We also provide an overview of the technical advances in the design of constructs and viral vectors to increase the efficiency and safety of gene therapy and to improve selective delivery to target organs. PMID- 25917157 TI - Factors affecting urinary excretion of testosterone metabolites conjugated with cysteine. AB - The implementation of the athlete steroidal passport in doping control analysis aims to detect intra-individual changes in the steroid profile related to the abuse of anabolic steroids. In this context, the study of intrinsic variations associated with each marker is of utmost importance. In the present work, the influence of several factors in the excretion of the recently reported testosterone metabolites conjugated with cysteine (Delta(1) -AED; 1,4 androstadien-3,17-dione, Delta(6) -AED; 4,6-androstadien-3,17-dione, Delta(6) -T; 4,6-androstadien-17beta-ol-3-one, and Delta(15) -AD; 15-androsten-3,17-dione) is evaluated for the first time. Degradation experiments at 37 degrees C proved that, although the cysteinyl moiety is released, the variation for urinary Delta(1) -AED/Delta(6) -AED, Delta(1) -AED/Delta(6) -T ratios is less than 30%. Moreover, freeze/thaw cycle testing resulted in RSDs values below 15% for all the analytes. Regarding infradian variability, moderate variations (below 40%) were observed. Additionally, notable alterations in the excretion of these compounds have been observed in the earliest stages of pregnancy. UGT2B17 polymorphism, responsible for the low T/E ratio found in some population, does not influence the excretion of cysteinyl compounds whereas the intake of exogenous substances (alcohol or 5alpha-reductase inhibitors) dramatically affects their excretion. The urinary concentrations of Delta(1) -AED, Delta(6) -AED, and Delta(15) -AD decreased (<50 %) after the ethanol intake, whereas after the administration of dutasteride, an important increase was observed for the concentrations of Delta(6) -AED, Delta(6) -T and Delta(15) -AD. Overall, the presented data describes the stability of the urinary cysteinyl steroids under the influence of many factors, proving their potential as suitable parameters to be included in the steroidal module of the athlete's biological passport. PMID- 25917158 TI - Organ-specific analysis of mahonia using gel-free/label-free proteomic technique. AB - Mahonia is an important medicinal plant used for the treatment of human diseases. To explore the molecular mechanisms underlying the different pharmacological functions of Mahonia, organ-specific proteomics was performed. Protein profiles of leaves, stems, and roots from 2-year-old Mahonia plants were determined using gel-free/label-free proteomic technique, and totals of 304, 314, and 182 proteins were identified, respectively, and included 36 common proteins. In leaves, the most abundant proteins related to photosynthesis. Furthermore, polyethylene glycol fractionation was used to identify low-abundance proteins in leaves. With this approach, oxidative pentose phosphate-related proteins were identified in leaves. In stems, the main functional categories of proteins were protein synthesis and redox ascorbate/glutathione metabolism. In roots, proteins were mainly related to protein synthesis, stress, and amino acid metabolism. Of the proteins identified, the abundance of calreticulin was markedly higher in roots than that detected in stems and leaves. Many roots-specific proteins, including S adenosylmethionine synthetase and (S)-tetrahydroprotoberberine oxidase, involved in the biosynthesis of alkaloids, were identified. Consistent with this finding, levels of the alkaloids, which were columbamine, jatrorrhizine, palmatine, tetrandrine, and berberine, were markedly higher in roots compared to those detected in stems and leaves. Taken together, these results suggest that alkaloid biosynthesis is an important function in Mahonia roots. PMID- 25917159 TI - [Mixed histiocytosis, a rare cause of stroke]. PMID- 25917160 TI - Parkinsonism in a patient with Leber hereditary optic neuropathy (LHON). PMID- 25917161 TI - Welcome to the thrombectomy era. PMID- 25917162 TI - Repeated Solitaire mechanical thrombectomy in an acute anterior stroke patient. PMID- 25917163 TI - [LAST-Q: Adaptation and normalisation in Quebec of the Language Screening Test]. AB - The goal of the present study was to adapt and to establish normative data for the recently developed Language Screening Test (LAST; Flamand-Roze et al., 2011) in the French-Canadian population according to age and level of education. After an adaptation process, 100 French-Canadian speakers were evaluated with the LAST Q. As expected, a perfect score of 15/15 was obtained for all high level education participants, and a score of 14/15 was obtained for all participants with a lowest level of education or aged 80 years or more. Thanks to this adaptation, LAST-Q can be used in acute patients in stroke unit in Quebec. PMID- 25917164 TI - Uptake routes and toxicokinetics of silver nanoparticles and silver ions in the earthworm Lumbricus rubellus. AB - Current bioavailability models, such as the free ion activity model and biotic ligand model, explicitly consider that metal exposure will be mainly to the dissolved metal in ionic form. With the rise of nanotechnology products and the increasing release of metal-based nanoparticles (NPs) to the environment, such models may increasingly be applied to support risk assessment. It is not immediately clear, however, whether the assumption of metal ion exposure will be relevant for NPs. Using an established approach of oral gluing, a toxicokinetics study was conducted to investigate the routes of silver nanoparticles (AgNPs) and Ag(+) ion uptake in the soil-dwelling earthworm Lumbricus rubellus. The results indicated that a significant part of the Ag uptake in the earthworms is through oral/gut uptake for both Ag(+) ions and NPs. Thus, sealing the mouth reduced Ag uptake by between 40% and 75%. An X-ray analysis of the internal distribution of Ag in transverse sections confirmed the presence of increased Ag concentrations in exposed earthworm tissues. For the AgNPs but not the Ag(+) ions, high concentrations were associated with the gut wall, liver-like chloragogenous tissue, and nephridia, which suggest a pathway for AgNP uptake, detoxification, and excretion via these organs. Overall, the results indicate that Ag in the ionic and NP forms is assimilated and internally distributed in earthworms and that this uptake occurs predominantly via the gut epithelium and less so via the body wall. The importance of oral exposure questions the application of current metal bioavailability models, which implicitly consider that the dominant route of exposure is via the soil solution, for bioavailability assessment and modeling of metal-based NPs. PMID- 25917165 TI - Endoscopic laryngo-pharyngeal surgery for superficial laryngo-pharyngeal cancer. AB - BACKGROUND AND STUDY AIMS: Narrow band imaging (NBI) combined with magnifying endoscopy enables us to detect superficial laryngo-pharyngeal cancers, which are difficult to detect by standard endoscopy. Endoscopic laryngo-pharyngeal surgery (ELPS) is a technique developed to treat such lesions and the purpose of this study is to evaluate the usefulness of ELPS for superficial laryngo-pharyngeal cancer. PATIENTS AND METHODS: Seventy five consecutive patients with 104 fresh superficial laryngo-pharyngeal cancers are included in this study. Under general anesthesia, a specially-designed curved laryngoscope was inserted to create a working space in the pharyngeal lumen. A magnifying endoscope was inserted transorally to visualize the field and a head & neck surgeon dissected the lesion using the combination of the orally-inserted curved grasping forceps and electrosurgical needle knife in both hands. The safely, functional outcomes, and oncologic outcomes of ELPS were evaluated retrospectively. RESULTS: Median operation time per lesion was 35 min. Post-operative bleeding occurred in 3 cases and temporal subcutaneous emphysema occurred in 10 cases. No vocal fold impairment occurred after surgery. The median fasting period was 2 days and all patients except one have a normal diet with no limitations. Local recurrence occurred in 1 case, and the 3-year overall survival rate and the 3-year disease specific survival rate was 90% and 100%, respectively. CONCLUSIONS: ELPS is a hybrid of head and neck surgery and gastrointestinal endoscopic treatment, and enjoys the merit of both procedures. ELPS makes it possible to perform minimally invasive surgery, preserving both the swallowing and phonation functions. PMID- 25917166 TI - Wall-lesion development in gaps: The role of the adhesive bonding material. AB - OBJECTIVES: This study evaluated the caries wall lesion development in different composite-dentin interfaces to investigate if the presence and location of two bonding materials in the gaps influence wall caries lesion development. METHODS: Fourteen volunteers wore a modified occlusal splint containing samples with four different interfaces: perfect bonding/no gap, or with a fixed gap (234+/-30 MUm) with either no bonding material, bonding material (Clearfil Protect Bond-PB and Clearfil SE Bond-SE) on dentin or on composite. Eight times a day, the samples were dipped in 20% sucrose solution for 10 min, during 3 weeks. The samples were imaged with microradiography (T-WIM), and lesion depth (LD) and mineral loss (ML) were measured. The data were analysed with paired t-test. RESULTS: The perfect bonding group did not show any caries wall lesion development, whereas all other interfaces did. The interface with bonding on dentin did not show significantly different wall lesion development from the interface with no material. However, when bonding was present on composite, both LD and ML were significantly higher than both other gap conditions (p-values<0.05). A difference between the bonding material was only seen when applied on composite: PB showed less ML than SE (p=0.01). CONCLUSIONS: The presence of bonding on the composite side of a composite-dentin gap increased wall lesion development in situ. CLINICAL SIGNIFICANCE: The presence and location of an adhesive bonding material in the composite-dentin gaps plays a role on the wall caries lesion development. PMID- 25917167 TI - Impact of FDA Black Box Warning on Psychotropic Drug Use in Noninstitutionalized Elderly Patients Diagnosed With Dementia: A Retrospective Study. AB - BACKGROUND: The study seeks to investigate the impact of Food and Drug Administration's black box warning (BBW) on the use of atypical antipsychotics (AAP) and nonantipsychotic psychotropic alternatives in noninstitutionalized elderly population diagnosed with dementia. METHOD: The Medical Expenditure Panel Survey (2004 through 2007) was utilized as the data source. Medication use in elderly patients (>=65 years) was defined as taking at least 1 medication for dementia. We performed a statistical comparison of prewarning (2004-2005) and postwarning (2006-2007) periods with respect to AAP and nonantipsychotic psychotropic use to examine the impact of labeling changes. RESULTS: A bivariate analysis did not yield statistically significant change in either the AAP or nonantipsychotic psychotropic use, pre- versus postwarning. However, multivariate logistic-regression analyses revealed greater odds for antidementia (odds ratio [OR] = 1.976, P = .0195) and benzodiazepine (OR = 3.046, P = .0227) medication use in postwarning period compared to the prewarning period. CONCLUSION: The regulatory warnings and labeling changes regarding off-label use of AAPs in dementia treatment showed minimal impact on their actual use in noninstitutionalized populations. A corresponding increase in the use of nonantipsychotic psychotropics explains that BBW might have resulted in a compensatory shift in favor of benzodiazepines and antidementia medications. Additional research should be conducted to examine the long-term impact of BBW on antipsychotic prescribing changes. PMID- 25917168 TI - What Can a Urine Drug Screening Immunoassay Really Tell Us? AB - Urine drug screening has become standard of care in many medical practice settings to assess compliance, detect misuse, and/or to provide basis for medical or legal action. The antibody-based enzymatic immunoassays used for qualitative analysis of urine have significant drawbacks that clinicians are often not aware of. Recent literature suggests that there is a lack of understanding of the shortcomings of these assays by clinicians who are ordering and/or interpreting them. This article addresses the state of each of the individual immunoassays that are most commonly used today in order to help the reader become proficient in the interpretation and application of the results. Some literature already exists regarding sources of "false positives" and "false negatives," but none seem to present the material with the practicing clinician in mind. This review aims to avoid overwhelming the reader with structures and analytical chemistry. The reader will be presented relevant clinical knowledge that will facilitate appropriate interpretation of immunoassays regardless of practice settings. Using this review as a learning tool and a reference, clinicians will be able to interpret the results of commonly used immunoassays in an evidence-based, informed manner and minimize the negative impact that misinterpretation has on patient care. PMID- 25917169 TI - Guidelines and training initiatives that support communication in cross-cultural primary-care settings: appraising their implementability using Normalization Process Theory. AB - BACKGROUND: Guidelines and training initiatives (G/TIs) available to support communication in cross-cultural primary health care consultations are not routinely used. We need to understand more about levers and barriers to their implementation and identify G/TIs likely to be successfully implemented in practice. OBJECTIVE: To report a mapping process used to identify G/TIs and to prospectively appraise their implementability, using Normalization Process Theory (NPT). METHODS: RESTORE is a 4-year EU FP-7 project. We used purposeful and network sampling to identify experts in statutory and non-statutory agencies across Austria, England, Greece, Ireland, Scotland and the Netherlands who recommended G/TI data from the grey literature. In addition, a peer review of literature was conducted in each country. Resulting data were collated using a standardized Protocol Mapping Document. G/TIs were identified for inclusion by (i) initial elimination of incomplete G/TI material; (ii) application of filtering criteria; and (iii) application of NPT. RESULTS: 20 G/TIs met selection criteria: 8 guidelines and 12 training initiatives. Most G/TIs were identified in the Netherlands (n = 7), followed by Ireland (n = 6) and England (n = 5). Fewer were identified in Scotland (n = 2), and none in Greece or Austria. The majority (n = 13) were generated without the inclusion of migrant service users. All 20 were prospectively appraised for potential implementability by applying NPT. CONCLUSIONS: NPT is useful as a means of prospectively testing G/TIs for implementability. Results indicate a need to initiate meaningful engagement of migrants in the development of G/TIs. A European-based professional standard for development and assessment of cross-cultural communication resources is advised. PMID- 25917170 TI - Drug disposition and modelling before and after gastric bypass: immediate and controlled-release metoprolol formulations. AB - AIMS: The aim of the present study was to evaluate the disposition of metoprolol after oral administration of an immediate and controlled-release formulation before and after Roux-en-Y gastric bypass (RYGB) surgery in the same individuals and to validate a physiologically based pharmacokinetic (PBPK) model for predicting oral bioavailability following RYGB. METHODS: A single-dose pharmacokinetic study of metoprolol tartrate 200 mg immediate release and controlled release was performed in 14 volunteers before and 6-8 months after RYGB. The observed data were compared with predicted results from the PBPK modelling and simulation of metoprolol tartrate immediate and controlled-release formulation before and after RYGB. RESULTS: After administration of metoprolol immediate and controlled release, no statistically significant difference in the observed area under the curve (AUC(0-24 h)) was shown, although a tendency towards an increased oral exposure could be observed as the AUC(0-24 h) was 32.4% [95% confidence interval (CI) 1.36, 63.5] and 55.9% (95% CI 5.73, 106) higher following RYGB for the immediate and controlled-release formulation, respectively. This could be explained by surgery-related weight loss and a reduced presystemic biotransformation in the proximal gastrointestinal tract. The PBPK values predicted by modelling and simulation were similar to the observed data, confirming its validity. CONCLUSIONS: The disposition of metoprolol from an immediate-release and a controlled-release formulation was not significantly altered after RYGB; there was a tendency to an increase, which was also predicted by PBPK modelling and simulation. PMID- 25917171 TI - Receptors involved in the modulation of guinea pig urinary bladder motility by prostaglandin D2. AB - BACKGROUND AND PURPOSE: We have described a urothelium-dependent release of PGD2 like activity which had inhibitory effects on the motility of guinea pig urinary bladder. Here, we have pharmacologically characterized the receptors involved and localized the sites of PGD2 formation and of its receptors. EXPERIMENTAL APPROACH: In the presence of selective DP and TP receptor antagonists alone or combined, PGD2 was applied to urothelium-denuded diclofenac-treated urinary bladder strips mounted in organ baths. Antibodies against PGD2 synthase and DP1 receptors were used with Western blots and for histochemistry. KEY RESULTS: PGD2 inhibited nerve stimulation -induced contractions in strips of guinea pig urinary bladder with estimated pIC50 of 7.55 +/- 0.15 (n = 13), an effect blocked by the DP1 receptor antagonist BW-A868C. After blockade of DP1 receptors, PGD2 enhanced the contractions, an effect abolished by the TP receptor antagonist SQ-29548. Histochemistry revealed strong immunoreactivity for PGD synthase in the urothelium/suburothelium with strongest reaction in the suburothelium. Immunoreactive DP1 receptors were found in the smooth muscle of the bladder wall with a dominant localization to smooth muscle membranes. CONCLUSIONS AND IMPLICATIONS: In guinea pig urinary bladder, the main effect of PGD2 is an inhibitory action via DP1 receptors localized to the smooth muscle, but an excitatory effect via TP receptors can also be evoked. The urothelium with its suburothelium might signal to the smooth muscle which is rich in PGD2 receptors of the DP1 type. The results are important for our understanding of regulation of bladder motility. PMID- 25917172 TI - A Robust CRISPR/Cas9 System for Convenient, High-Efficiency Multiplex Genome Editing in Monocot and Dicot Plants. AB - CRISPR/Cas9 genome targeting systems have been applied to a variety of species. However, most CRISPR/Cas9 systems reported for plants can only modify one or a few target sites. Here, we report a robust CRISPR/Cas9 vector system, utilizing a plant codon optimized Cas9 gene, for convenient and high-efficiency multiplex genome editing in monocot and dicot plants. We designed PCR-based procedures to rapidly generate multiple sgRNA expression cassettes, which can be assembled into the binary CRISPR/Cas9 vectors in one round of cloning by Golden Gate ligation or Gibson Assembly. With this system, we edited 46 target sites in rice with an average 85.4% rate of mutation, mostly in biallelic and homozygous status. We reasoned that about 16% of the homozygous mutations in rice were generated through the non-homologous end-joining mechanism followed by homologous recombination-based repair. We also obtained uniform biallelic, heterozygous, homozygous, and chimeric mutations in Arabidopsis T1 plants. The targeted mutations in both rice and Arabidopsis were heritable. We provide examples of loss-of-function gene mutations in T0 rice and T1 Arabidopsis plants by simultaneous targeting of multiple (up to eight) members of a gene family, multiple genes in a biosynthetic pathway, or multiple sites in a single gene. This system has provided a versatile toolbox for studying functions of multiple genes and gene families in plants for basic research and genetic improvement. PMID- 25917173 TI - Loss of GSNOR1 Function Leads to Compromised Auxin Signaling and Polar Auxin Transport. AB - Cross talk between phytohormones, nitric oxide (NO), and auxin has been implicated in the control of plant growth and development. Two recent reports indicate that NO promoted auxin signaling but inhibited auxin transport probably through S-nitrosylation. However, genetic evidence for the effect of S nitrosylation on auxin physiology has been lacking. In this study, we used a genetic approach to understand the broader role of S-nitrosylation in auxin physiology in Arabidopsis. We compared auxin signaling and transport in Col-0 and gsnor1-3, a loss-of-function GSNOR1 mutant defective in protein de-nitrosylation. Our results showed that auxin signaling was impaired in the gsnor1-3 mutant as revealed by significantly reduced DR5-GUS/DR5-GFP accumulation and compromised degradation of AXR3NT-GUS, a useful reporter in interrogating auxin-mediated degradation of Aux/IAA by auxin receptors. In addition, polar auxin transport was compromised in gsnor1-3, which was correlated with universally reduced levels of PIN or GFP-PIN proteins in the roots of the mutant in a manner independent of transcription and 26S proteasome degradation. Our results suggest that S nitrosylation and GSNOR1-mediated de-nitrosylation contribute to auxin physiology, and impaired auxin signaling and compromised auxin transport are responsible for the auxin-related morphological phenotypes displayed by the gsnor1-3 mutant. PMID- 25917174 TI - Does a corporate worksite physical activity program reach those who are inactive? Findings from an evaluation of the Global Corporate Challenge. AB - ISSUE ADDRESSED: Workplace physical activity programs can motivate inactive target groups to increase daily activity levels, but it is important to determine their reach and impact. METHODS: The Global Corporate Challenge (GCC) is a team based program promoting pedometer-based self-monitoring to reach 10000 steps per day. Participants (n = 587) from an Australian university were recruited and recorded their daily step counts. Demographic, anthropometric, behavioural, self reported physical activity and sitting time data were collected at baseline and following the 16-week program. RESULTS: On average, participants self-estimated 11 638 daily steps in Week 1, increasing to measured estimates of 13 787 daily steps in Week 16 (P < 0.001). At baseline, 92% of survey completers were already meeting the physical activity recommendations, increasing to 98% (P = 0.059) at follow-up. Four month improvements in objectively assessed anthropometric measures showed small, non-significant reductions in weight (-0.12 kg; P = 0.416), body mass index (-0.06 kg/m2; P = 0.314) and waist circumference (-0.43 cm; P = 0.082). Sitting time during work decreased significantly by 21 min per day (P < 0.001) and participants with initially low levels of sitting time at work were more likely to increase their step counts during the GCC (adjusted odds ratio 1.90, 95% confidence interval 1.03-3.50). CONCLUSIONS: Although this pedometer-based program resulted in increases in physical activity and reductions in occupational sedentary behaviour, most participants were already meeting physical activity recommendations at baseline. SO WHAT? Workplace interventions need to be better targeted to reach inactive employees to have population-level impacts on chronic disease risk factors. PMID- 25917175 TI - Old man gallbladder syndrome: Gangrenous cholecystitis in the unsuspected patient population. AB - INTRODUCTION: Acute cholecystitis is a common surgical condition, but not many are aware of the serious complication of gangrenous cholecystitis (GC). Presence of GC increases patients' postoperative complications, morbidity and mortality. Predictive factors for GC include age >45, male gender, white blood cell count >13,000/mm3 and ultrasound findings of a negative Murphy's sign. CASE PRESENTATION: (1) GW, 83 male with dull right upper quadrant pain and a negative Murphy's sign with further imaging showing a thickened septated gallbladder suggestive of GC. Patient's surgery was difficult and he received a cholecystostomy tube for drainage. (2) PH, 75 male with minimal right upper quadrant pain, equivocal ultrasound with a negative Murphy's sign and computer tomography (CT) showing acute cholecystitis. Patient was taken to the operating room for cholecystectomy, with pathology consistent with gangrenous cholecystitis. DISCUSSION: Multiple laboratory findings and imaging patterns have been found to be highly predictive of GC. Along with age and WBC, thickened gallbladder wall and lack of mucosal enhancement have been predictive of GC. On physical examination, lack of Murphy's sign secondary to denervation from gangrenous changes also increases the index of suspicion for GC. CONCLUSION: GC is a serious complication of acute cholecystitis with increased morbidity and mortality. There should be a high index of suspicion for GC if the above unique physical and laboratory findings are present. PMID- 25917176 TI - Gold-catalyzed cascade C-H/C-H cross-coupling/cyclization/alkynylation: an efficient access to 3-alkynylpyrroles. AB - An efficient approach to 3-alkynylpyrroles has been developed through the gold catalyzed reaction of beta-enamino derivatives with terminal alkynes, which features complete regiocontrol, relatively wide substrate scope, and high functional group tolerance. Mechanistic studies show that the reaction proceeds through the gold-catalyzed cascade oxidative C-H/C-H cross-coupling, cyclization and alkynylation. PMID- 25917177 TI - Syncope in a patient with myotonic dystrophy. PMID- 25917178 TI - Young woman with palpitations and preexcitation. PMID- 25917179 TI - Irregular wide complex tachycardia in a young man. PMID- 25917181 TI - [Does intensive care medicine have a future with Generation Y?]. PMID- 25917180 TI - [Near-infrared spectroscopy during cardiopulmonary resuscitation and mechanical circulatory support: From the operating room to the intensive care unit]. AB - BACKGROUND: Near infrared spectroscopy (NIRS) allows continuous measurement of cerebral regional oxygen saturation (rSO2). It is a weighted saturation value derived from approximately 70-75 % venous, 20-25 % arterial and 2.5-5 % capillary blood. In contrast to pulse oximetry, NIRS is independent of pulsatile flow. Therefore, it is also applicable during extracorporeal circulation, cardiopulmonary resuscitation (CPR), and hypothermia. OBJECTIVES: The purpose of this work is to describe the application of cerebral and somatic NIRS in cardiology and cardiac surgery patients in the operation room, during and after CPR, and during the intensive care unit stay. MATERIALS AND METHODS: This article is based on peer-reviewed literature from PubMed. RESULTS: Interventions based on decline of cerebral NIRS values during on-pump cardiac surgery can reduce major organ morbidity and mortality; however, the appearance of a postoperative cognitive dysfunction is scarcely influenced. Persisting of low cerebral oximetry values during resuscitation is a marker for not achieving return of spontaneous circulation under normothermia. NIRS is an additional method for monitoring that can be used during extracorporeal circulation. CONCLUSION: NIRS is a rapidly available, user-friendly, and noninvasive method for continuous measurement of rSO2. NIRS provides additional information about tissue oxygenation especially during resuscitation and extracorporeal circulatory assist support. Recommendations concerning the use of NIRS for standard monitoring during resuscitation and mechanical circulatory support are not currently available. Further studies are required to show if use of NIRS can reduce pulse control and hands-off times during resuscitation and if use of NIRS can improve outcome after CPR and mechanical circulatory support. PMID- 25917182 TI - [Acute kidney injury: choice of the initial modality for renal replacement therapy]. AB - Continuous and intermittent renal replacement therapies are thought to be equally adequate approaches for the treatment of patients with acute kidney injury. Accordingly, current guidelines advocate the use of different modalities in a complementary fashion, i.e., to tailor therapy to the specific clinical situation. In patients with hemodynamic instability or at risk of cerebral edema, continuous renal replacement therapy or prolonged intermittent renal replacement therapy should, however, be preferred. Intermittent hemodialysis, on the other hand, remains the therapy of choice for the rapid correction of life-threatening electrolyte abnormalities or metabolic acidosis. During the further course of treatment, an individualized approach should be continued which may include a switch between modalities based on current therapeutic goals and potential risks for side effects of renal replacement therapy. PMID- 25917183 TI - [Economy in intensive care medicine--a contradiction?]. AB - BACKGROUND: Medical progress and demographic changes will lead to increasing budgetary constraints in the health care system in the coming years. With respect to economic, medical, and ethical aspects, intensive care medicine has a particular role within the health system. Nonetheless, financial restriction will be inevitable in the near future. MATERIALS AND METHODS: A literature review was performed. RESULTS: In an era of economic decline accompanied by widespread recognition that healthcare costs are on a consistent upward spiral, rationalization and rationing are unavoidable. Priorization models will play a pivotal role in allocation of resources. Individual ethics (respect for autonomy, nonmaleficence, beneficence) as well as justice are essential in daily practice. CONCLUSIONS: Economic thinking and acting as well as being ethically responsible are not mutually exclusive. On the contrary, acting in an ethically responsible manner will be of considerable significance given the pressure of increasing costs in intensive care medicine. PMID- 25917184 TI - Effect of dehydrogenase, phosphatase and urease activity in cotton soil after applying thiamethoxam as seed treatment. AB - Soil enzymes are indicators of microbial activities in soil and are often considered as an indicator of soil health and fertility. They are very sensitive to the agricultural practices, pH of the soil, nutrients, inhibitors and weather conditions. To understand the effect of an insecticide, thiamethoxam, on different soil enzyme activities, the experiments were conducted at cotton experimental fields of Punjab Agricultural University, Ludhiana. The results here were presented to understand the impact of thiamethoxam on soil enzyme activities. Thiamethoxam was applied as seed treatment to control the pest. Soil from three localities, i.e. soil in which seed was treated with recommended dose at 2.1 g a.i. kg(-1), soil in which seed was treated with four times recommended dose at 8.4 g a.i. kg(-1) and from the control field, were tested for different enzyme activities. Phosphatase and dehydrogenase activities were high in control soil in comparison to control soil while no effect of this insecticide on urease activity. Thiamethoxam had inhibitory effects on dehydrogenase and phosphatase activities. Therefore, it can be attributed that agricultural practices, weather conditions and use of thiamethoxam might be responsible for the different level of enzyme activities in soil. PMID- 25917185 TI - Probability-based classifications for spatially characterizing the water temperatures and discharge rates of hot springs in the Tatun Volcanic Region, Taiwan. AB - Accurately classifying the spatial features of the water temperatures and discharge rates of hot springs is crucial for environmental resources use and management. This study spatially characterized classifications of the water temperatures and discharge rates of hot springs in the Tatun Volcanic Region of Northern Taiwan by using indicator kriging (IK). The water temperatures and discharge rates of the springs were first assigned to high, moderate, and low categories according to the two thresholds of the proposed spring classification criteria. IK was then used to model the occurrence probabilities of the water temperatures and discharge rates of the springs and probabilistically determine their categories. Finally, nine combinations were acquired from the probability based classifications for the spatial features of the water temperatures and discharge rates of the springs. Moreover, various combinations of spring water features were examined according to seven subzones of spring use in the study region. The research results reveal that probability-based classifications using IK provide practicable insights related to propagating the uncertainty of classifications according to the spatial features of the water temperatures and discharge rates of the springs. The springs in the Beitou (BT), Xingyi Road (XYR), Zhongshanlou (ZSL), and Lengshuikeng (LSK) subzones are suitable for supplying tourism hotels with a sufficient quantity of spring water because they have high or moderate discharge rates. Furthermore, natural hot springs in riverbeds and valleys should be developed in the Dingbeitou (DBT), ZSL, Xiayoukeng (XYK), and Macao (MC) subzones because of low discharge rates and low or moderate water temperatures. PMID- 25917186 TI - Persistence and effect of processing on reduction of chlorantraniliprole residues on brinjal and okra fruits. AB - Dissipation and decontamination of chlorantraniliprole (Coragen 18.5 SC) in brinjal and okra fruits were studied following field application at single and double doses of 30 and 60 g ai ha(-1), and the residues of the insecticide was estimated using LC-MS/MS. Initial residues of chlorantraniliprole at single and double doses on the fruits of brinjal were 0.72 and 1.48 mg kg(-1), while on okra fruits, the residues were 0.48 and 0.91 mg kg(-1), respectively. The residues reached below detectable level of 0.01 mg kg(-1) on the 10th day. Half-life of chlorantraniliprole at 30 and 60 g ai ha(-1) on brinjal was 1.58 and 1.80 days with the calculated waiting period of 0.69 and 2.38 days, whereas on okra, the values were 1.60 and 1.70 and 0 and 1.20 days, respectively. The extent of removal of chlorantraniliprole using simple decontaminating techniques at 2 h and 3 days after spraying was 40.99-91.37% and 29.85-89.12%, respectively, from brinjal fruits and 47.78-86.10% and 41.77-86.48%, respectively, from okra fruits. PMID- 25917187 TI - Thiamethoxam degradation by Pseudomonas and Bacillus strains isolated from agricultural soils. AB - Twelve bacterial species were evaluated to know the degradation pattern of thiamethoxam in liquid medium. All the bacterial species could actively degrade phorate in a mineral salt medium containing phorate (50 MUg ml(-1)) as sole carbon source. As these species have ability to degrade, we used these for the degradation of thiamethoxam--a neonicoitinoids. Screening of 12 active phorate metabolizing bacterial species resulted in selection of Bacillus aeromonas strain IMBL 4.1 and Pseudomonas putida strain IMBL 5.2 causing 45.28 and 38.23 % thiamethoxam (50 MUg ml(-1)) reduction, respectively, in 15 days as potential thiamethoxam degrading species. These two bacterial species grew optimally at 37 degrees C under shake culture conditions in MSMT medium raised with initial pH of 6.0-6.5 and use of these optimum cultural conditions resulted in improved thiamethoxam degradation by these bacterial species. These species caused maximum thiamethoxam degradation only in the presence of thiamethoxam as sole source of carbon and energy and the same was reduced in the presence of easily metabolize able carbon (C0 and C1) and nitrogen ((N0, N1 and N2) sources. This could be attributed to involvement of repressible metabolic pathways, reactions of which are inhibited by the presence of easily available nutrients for growth. Besides above, qualitative analysis of thiamethoxam residues by gas liquid chromatography revealed complete metabolization of thiamethoxam without detectable accumulation of any known thiamethoxam metabolites. PMID- 25917188 TI - Intraoral lining with the fibular osteomyofascial flap without a skin paddle during maxillary and mandibular reconstruction. AB - BACKGROUND: To achieve an ideal intraoral lining, we harvest the fibular osteomyofascial flap to avoid the common embarrassment caused by the fibular osteomyocutaneous flap, and we report on our experience with this technique in this article. METHODS: Twenty-eight patients underwent reconstruction of the maxilla and mandible using an osteomyofascial free fibula flap after oncologic ablation. Data, including the size of the fascial flaps, the number of debulking operations, the complications at both the donor and recipient sites, and the dental rehabilitation, were collected. RESULTS: All fascial flaps survived and were remucosalized, except one with partial necrosis. None of the patients in the osteomyofascial group required an additional debulking operation, and 82% of the patients (23 of 28) had conventional dentures and showed good chewing function and cosmetic results. CONCLUSION: The fibular osteomyofascial flap yielded a more anatomic solution for oral mucosal defects, obviating the need for additional debulking and potentially reducing donor-site wound problems. (c) 2015 Wiley Periodicals, Inc. Head Neck 38: E832-E836, 2016. PMID- 25917189 TI - Erratum to: Abiogenic Photophosphorylation of ADP to ATP Sensitized by Flavoproteinoid Microspheres. PMID- 25917190 TI - Trioctylphosphine as self-assembly inducer. AB - Nickel nanoparticles (NPs) of different shapes and sizes in polydispersed as well as monodispersed forms were synthesized using trioctylphosphine (TOP), triphenylphosphine (TPP), oleylamine (OA) and their combinations as surfactants to study their self-assembly inducing capabilities. Randomly agglomerated polydispersed NPs were found for TPP and OA, and TPP or OA separately. However, in consolidation with the earlier report of Singh et al., J. Mater. Chem. C, 2014, 2, 8918, NPs formed using TOP only and a combination of TOP with OA naturally exhibited monodispersed NPs associated with natural nanolattice formation without any other external force or surfactants, demonstrating clearly the self-inducing capacity of TOP into monodispersed NPs and their self-assembled nanolattices. Fourier-transformed infra-red (FTIR) data clearly indicated the capping of these surfactants along with acetylacetonate ligands from nickel acetylacetonate precursor on the surface of the NPs. Remarkably, the narrowest zeta potential (zeta) base-widths were observed for samples possessing a self assembled nanolattice, compared to the broader ones for randomly agglomerated particles. PMID- 25917191 TI - Empirically derived dietary patterns and incident type 2 diabetes mellitus: a systematic review and meta-analysis on prospective observational studies. AB - OBJECTIVE: To systematically review prospective cohort studies about the association between dietary patterns and type 2 diabetes mellitus (T2DM) incidence, and to quantify the effects using a meta-analysis. DESIGN: Databases such as PubMed, ISI Web of Science, SCOPUS and Google Scholar were searched up to 15 January 2015. Cohort studies which tried to examine the association between empirically derived dietary patterns and incident T2DM were selected. The relative risks (RR) and their 95 % confidence intervals for diabetes among participants with highest v. lowest adherence to derived dietary patterns were incorporated into meta-analysis using random-effects models. RESULTS: Ten studies (n 404 528) were enrolled in the systematic review and meta-analysis; our analysis revealed that adherence to the 'healthy' dietary patterns significantly reduced the risk of T2DM (RR=0.86; 95 % CI 0.82, 0.90), while the 'unhealthy' dietary patterns adversely affected diabetes risk (RR=1.30; 95 % CI 1.18, 1.43). Subgroup analysis showed that unhealthy dietary patterns in which foods with high phytochemical content were also loaded did not significantly increase T2DM risk (RR=1.06; 95 % CI 0.87, 1.30). CONCLUSIONS: 'Healthy' dietary patterns containing vegetables, fruits and whole grains can lower diabetes risk by 14 %. Consuming higher amounts of red and processed meats, high-fat dairy and refined grains in the context of 'unhealthy' dietary patterns will increase diabetes risk by 30 %; while including foods with high phytochemical content in these patterns can modify this effect. PMID- 25917192 TI - Bleeding in TKA: posterior stabilized vs. cruciate retaining. AB - INTRODUCTION: Posterior-stabilized (PS) and cruciate-retaining (CR) total knee arthroplasties (TKA) are both successfully used for treatment of end-stage osteoarthritis. The choice of constraint depends on knee deformity and stability as well as most importantly surgeon preference. The aim of this study was to compare the amount of blood loss and required transfusions following TKA with the two different designs. MATERIALS AND METHODS: In a retrospective approach, 473 patients undergoing TKA were included (240 CR and 233 PS from a single manufacturer). Demographics at base line were comparable between both groups. Blood loss [red blood cell (RBC) loss] was calculated after documentation of pre- and postoperative hematocrit levels at discharge. Transfusion requirements were recorded. Statistical analysis was done using Mann-Whitney U test. RESULTS: The calculated blood loss (RBC loss) at discharge was 548 +/- 216 ml in the PS group compared with 502 +/- 186 ml in the CR group (p = 0.032). There were no differences in the transfusion requirements between both groups (PS 0.41 vs. CR 0.37, p = 0.39). DISCUSSION: The blood loss was significantly higher in the PS group. This may be due to the box preparation that exposes more cancellous femoral bone, which may add to postoperative bleeding. The differences remain, however, small, as they did not lead to a significantly higher transfusion rate with PS TKA. PMID- 25917193 TI - Relative age and birthplace effect in Japanese professional sports: a quantitative evaluation using a Bayesian hierarchical Poisson model. AB - Relative age effect (RAE) in sports has been well documented. Recent studies investigate the effect of birthplace in addition to the RAE. The first objective of this study was to show the magnitude of the RAE in two major professional sports in Japan, baseball and soccer. Second, we examined the birthplace effect and compared its magnitude with that of the RAE. The effect sizes were estimated using a Bayesian hierarchical Poisson model with the number of players as dependent variable. The RAEs were 9.0% and 7.7% per month for soccer and baseball, respectively. These estimates imply that children born in the first month of a school year have about three times greater chance of becoming a professional player than those born in the last month of the year. Over half of the difference in likelihoods of becoming a professional player between birthplaces was accounted for by weather conditions, with the likelihood decreasing by 1% per snow day. An effect of population size was not detected in the data. By investigating different samples, we demonstrated that using quarterly data leads to underestimation and that the age range of sampled athletes should be set carefully. PMID- 25917194 TI - Automatic Mode Switch outside Tachycardia in DDDR Pacemaker. PMID- 25917195 TI - Parameter optimization for constructing competing endogenous RNA regulatory network in glioblastoma multiforme and other cancers. AB - BACKGROUND: In addition to direct targeting and repressing mRNAs, recent studies reported that microRNAs (miRNAs) can bridge up an alternative layer of post transcriptional gene regulatory networks. The competing endogenous RNA (ceRNA) regulation depicts the scenario where pairs of genes (ceRNAs) sharing, fully or partially, common binding miRNAs (miRNA program) can establish coexpression through competition for a limited pool of the miRNA program. While the dynamics of ceRNA regulation among cellular conditions have been verified based on in silico and in vitro experiments, comprehensive investigation into the strength of ceRNA regulation in human datasets remains largely unexplored. Furthermore, pan cancer analysis of ceRNA regulation, to our knowledge, has not been systematically investigated. RESULTS: In the present study we explored optimal conditions for ceRNA regulation, investigated functions governed by ceRNA regulation, and evaluated pan-cancer effects. We started by investigating how essential factors, such as the size of miRNA programs, the number of miRNA program binding sites, and expression levels of miRNA programs and ceRNAs affect the ceRNA regulation capacity in tumors derived from glioblastoma multiforme patients captured by The Cancer Genome Atlas (TCGA). We demonstrated that increased numbers of common targeting miRNAs as well as the abundance of binding sites enhance ceRNA regulation and strengthen coexpression of ceRNA pairs. Also, our investigation revealed that the strength of ceRNA regulation is dependent on expression levels of both miRNA programs and ceRNAs. Through functional annotation analysis, our results indicated that ceRNA regulation is highly associated with essential cellular functions and diseases including cancer. Furthermore, the highly intertwined ceRNA regulatory relationship enables constitutive and effective intra-function regulation of genes in diverse types of cancer. CONCLUSIONS: Using gene and microRNA expression datasets from TCGA, we successfully quantified the optimal conditions for ceRNA regulation, which hinge on four essential parameters of ceRNAs. Our analysis suggests optimized ceRNA regulation is related to disease pathways and essential cellular functions. Furthermore, although the strength of ceRNA regulation is dynamic among cancers, its governing functions are stably maintained. The findings of this report contribute to better understanding of ceRNA dynamics and its crucial roles in cancers. PMID- 25917196 TI - Down-regulation of Rac GTPase-activating protein OCRL1 causes aberrant activation of Rac1 in osteoarthritis development. AB - OBJECTIVE: Chondrocyte hypertrophy and mineralization are considered to be important pathologic factors in osteoarthritis (OA). We previously reported that Rac1 was aberrantly activated to promote chondrocyte hypertrophy, mineralization, and expression of matrix metalloproteinase 13 and ADAMTS in OA. However, the underlying mechanism of aberrant Rac1 activation in OA is unclear. The present study was undertaken to identify the specific molecular regulator controlling Rac1 activity in OA, as well as to investigate its function in chondrocyte hypertrophy, mineralization, and OA development. METHODS: Expression levels of 28 upstream regulators of Rac1 activity, including 8 GTPase-activating proteins (GAPs) and 20 guanine nucleotide exchange factors, in OA and normal cartilage were assessed by quantitative polymerase chain reaction. Chondrocytes were transduced with lentiviral vectors encoding OCRL1, GAP, non-GAP, CA-Rac1, and DN Rac1, either alone or in combination. Alkaline phosphatase staining was used as a marker of chondrocyte hypertrophy. Rac1 activity was analyzed by pulldown assay. Finally, OA was established in mice by surgical transection of the anterior cruciate ligament and cutting of the medial meniscus. The mice were injected intraarticularly with OCRL1-encoding lentivirus, and whole joints were assessed histologically 6 weeks after surgery. RESULTS: OCRL1 was abundantly expressed in normal cartilage and was the only significantly down-regulated RacGAP in OA cartilage. Overexpression of OCRL1 inhibited interleukin-1beta-induced Rac1 activity, chondrocyte hypertrophy, and expression of hypertrophy-related genes. Conversely, knockdown of OCRL1 elevated Rac1 activity and promoted chondrocyte hypertrophy and mineralization. Further, OCRL1 modulated Rac1 activity via its GAP domain. Finally, intraarticular injection of OCRL1-encoding lentivirus protected against destruction and degeneration of cartilage in the mouse OA model. CONCLUSION: OCRL1 acts as a RacGAP in cartilage to impede chondrocyte hypertrophy and OA development through modulating Rac1 activity. This regulatory pathway might provide potential targets for the development of new therapies for OA. PMID- 25917197 TI - Effect of Visceral Obesity on Surgical Outcomes of Patients Undergoing Laparoscopic Colorectal Surgery. AB - BACKGROUND: Visceral obesity has been known to be more pathogenic than body mass index (BMI). There have been a few reports about the association between visceral obesity and surgical outcomes in laparoscopic surgery. The aim of this study was to evaluate the effect of visceral obesity on surgical outcomes undergoing laparoscopic colorectal surgery. METHODS: Between January 2005 and December 2012, a total of 543 patients who underwent laparoscopic resection for colorectal cancer and had available computed tomography (CT) scans were included in this retrospective study. Visceral fat volumes (VFVs) were measured in preoperative CT scans from S1 to 12.5 cm above. Patients were divided into an obese group and a non-obese group according to VFV and BMI. Obesity was defined by VFV >=1.92 dm(3) (75% value of VFV) or BMI >=25 kg/m(2). RESULTS: There were 136 (25.0%) and 150 (27.6%) obese patients according to VFV and BMI, respectively. The high VFV group had a longer operative times (165.2 +/- 84.4 vs. 146.1 +/- 58.9 min; P = 0.016), higher blood loss during surgery (132.5 +/- 144.8 vs. 98.3 +/- 109.6 ml; P = 0.012), more frequent conversion to laparotomy (5.9 vs. 1.5%; P = 0.010), and more frequent major complications (Dindo score >=3; 11.0 vs. 4.7%; P = 0.008), whereas there was no significant difference between the high and low BMI groups. High VFV was a significant independent risk factor for open conversion (odds ratio 4.964, 95% confidence interval 1.336-18.438, P = 0.017). CONCLUSIONS: Visceral obesity can be a more clinically useful predictor than BMI in predicting surgical outcomes for laparoscopic colorectal cancer surgery. PMID- 25917198 TI - Quality of Life After Living Donor Hepatectomy for Liver Transplantation. AB - BACKGROUND: Living donor liver transplantation (LDLT) involves healthy individuals undergoing voluntary major hepatic resection. LDLT program only started in 2012 in Pakistan and its impact on donor's quality of life (QOL) post resection is not known. The objective of this study was to determine health related QOL in donors who underwent hepatectomy in country's first liver transplant program. METHODS: A total of 60 donors who underwent hepatectomy between 2012 and 2014 with a minimum follow-up of 6 months were included in the study. Short form (SF-36) and Profile of mood states (POMS-65) was used to assess QOL. In addition scores were compared between patients who did and did not develop complications. RESULT: Mean time duration between hepatectomy and administration of questionnaire was 15 +/- 5.1 months. Median age was 28 (19-45) years. Mean BMI was 24.4 +/- 3.7. A total of 7 (11.6%) Grade 3 and above complications were observed in donors. Donors exceeded a score of 90 in 6 out of 8 evaluated categories on SF-36. The highest mean score was recorded for emotional role limitation 95.5 +/- 17.1 and lowest for energy 84.8 +/- 17.5. The mean score for anger was 6.6 +/- 7.5. Donors also did well on the POMS vigor score with a mean of 22.7 +/- 5. No significant difference in scores was observed between donors with and without complications for any of the categories except tension. Donors who developed complications post-operatively had a significantly low mean tension score of 1.5 versus 3.8 for donors without complications. CONCLUSION: Acceptable post donation QOL was achieved and surgical complications did not adversely affect SF-36 and POMS scores. PMID- 25917200 TI - Giant conductivity enhancement of ferrite insulators induced by atomic hydrogen. AB - Hydrogen behavior in oxides has triggered much interest for its scientific and technological importance in a wide range of research fields from novel ion conductors to astrochemistry. Here, we report a giant conductivity enhancement in ZnFe2O4 ferrite insulators to the metallic state by over eleven orders of magnitude induced by electrochemically generated atomic hydrogen at room temperature. The conductivity and the amount of incorporated hydrogen increased in an exponential function with time. An activation energy for the atomic hydrogen chemisorption was measured to be 8.23 kJ mol(-1). Quantitative kinetics correlations among the adsorption of atomic hydrogen, hydrogen incorporation and conductivity enhancement are established, based on which hydrogen incorporation process is clarified herein. We demonstrate that the hydrogen incorporation in oxides can be adjusted by manipulating the kinetic factors. These findings have implications for research into hydrogen behavior in oxides in environments containing hydrogen atoms and offer possibilities for utilizing and controlling the modifications of oxide materials induced by atomic hydrogen. PMID- 25917199 TI - Preoperative Platelet-Lymphocyte Ratio Augments CA 19-9 as a Predictor of Malignancy in Chronic Calcific Pancreatitis. AB - INTRODUCTION: Differentiating inflammatory from malignant head mass in the background of chronic calcific pancreatitis (CCP) is difficult, and there is no investigation which can reliably solve this dilemma. An accurate diagnosis is crucial as the treatment is different for the two cases and a failure to identify malignancy before surgery can be disastrous. We aimed to assess the accuracy of platelet-lymphocyte ratio (PLR) and to compare it with CA 19-9 in determining the nature of pancreatic head mass (PHM). MATERIALS AND METHODS: Eighty-three patients, who presented with CCP and PHM between 2005 and 2011, were included in the study. Patients identified to have malignancy underwent pancreaticoduodenectomy, while those deemed to have a benign lesion underwent Frey's procedure. Clinical features of both the groups were compared. CA 19-9 and PLR individually and in combination were compared in both groups. Receiver operating characteristic curves were used to analyze the predictive values of CA 19-9 and PLR individually and together. RESULTS: Histologically, 66.3% had an inflammatory head mass and 33.7% had a malignant head mass. Significant clinical features which predicted a malignancy included the presence of a head mass in CCP of tropics, older age, jaundice, sudden worsening abdominal pain, gastric outlet obstruction, and significant weight loss. Sensitivity and specificity of CA 19-9 and PLR in diagnosing malignancy were similar (85.5 vs. 81.2 and 96.4 vs. 92.8%, respectively), on combining CA 19-9 and PLR, there was an improvement in sensitivity (94.5%). CONCLUSION: PLR is at least as good as CA 19-9 as a diagnostic marker to differentiate between malignant and inflammatory head mass in CCP. When used together, PLR improves the predictive value of serum CA 19-9. PMID- 25917201 TI - Effect of anticoagulant treatment in deep vein thrombosis: A patient-specific computational fluid dynamics study. AB - A methodology that might help physicians to establish a diagnostic and treatment tailored for each specific patient with a pathological thrombus is presented. A realistic model for the geometry of a popliteal vein with a thrombus just above the knee was reconstructed from in vivo computed tomography images acquired from one specific patient and then it was used to perform computational fluid dynamics (CFD) simulations. The wall shear stress (WSS) response to the administration of anticoagulant drugs and the influence of viscosity on the shape of the velocity distribution were investigated. Both a Newtonian and a non-Newtonian viscosity model were implemented for different blood flow rates in the range 3-7 cm(3)/s. The effect of anticoagulants on the blood was simulated by setting three different levels of viscosity in the Newtonian model (MU/MUinfinity=0.60, 0.80 and 1 with MUinfinity=3.45*10(-3) Pas). A reduction of MU by a given amount always led to a more modest reduction, typically by a factor of two, of the resulting WSS levels. Moreover, for a given flow rate the calculation with the non-Newtonian viscosity model yielded WSS levels between 20% and 40% larger than those obtained in the corresponding Newtonian fluid simulation. It was also found that blood moves slowly in the region between the thrombus and the vein wall, a fact that will favor the growth of the thrombotic mass. Both the mean WSS levels and the degree of sluggishness of the blood flow can be described by functions of the Reynolds number. PMID- 25917202 TI - Surgical approach for tumours of the third and fourth part of the duodenum. Distal pancreas-sparing duodenectomy. AB - The anatomic complexity of the duodenum makes surgical resection challenging. We describe our experience with distal pancreas-sparing duodenectomy (PSD) for tumours that arise in the third and fourth parts of the duodenum. Between July 2008 and January 2012 eight patients underwent surgical resection for tumours in the distal parts of the duodenum. Short and long-term outcomes of treatment are retrospectively analyzed. We used the Cattell and Braash surgical approach in six patients. Seven patients underwent a segmental resection of the distal duodenum with a duodenojejunal anastomosis and in one case we performed a wedge local excision with primary closure. There were 5 gastrointestinal stromal tumours (GIST), 1 primary duodenal adenocarcinoma, 1 metastasis of a lung adenocarcinoma and 1 patient with malignant duodenocolic fistula caused by advanced sigmoid colon carcinoma. Median operating time was 200 min and median intraoperatory blood loss 162 mL. Three patients showed postoperative complications and one of them died. There was no reoperation. Median hospital stay was 10 days (range, 7 28 days). The patient with primary adenocarcinoma died after 12 months due to hepatic metastases. All of five patients with GIST are alive without recurrence (mean follow up of 65.6 months), as well as the patient with metastatic duodenal infiltration (45 months after surgery). Segmental resection of the third and fourth portions of the duodenum is reliable and feasible. The Cattell and Braash manoeuvre provides a good exposure and makes this kind of resection easier. PMID- 25917203 TI - Initial learning curve of single-incision transaxillary robotic hemi- and total thyroidectomy--A single team experience from Europe. AB - INTRODUCTION: The primary advantage of robotic thyroidectomy is to avoid a neck scar. On the other hand, this sophisticated technique implies some potential risks otherwise not associated with conventional thyroidectomy, increased costs, and prolonged operating times. With all these factors being an important issue, we analysed the data of our initial European series in order to understand the nature of the learning curve for this technique. METHODS: Ten patients underwent transaxillary robotic thyroidectomy for benign disease, performed consistently by the same surgeon with the same team, within a timeframe of 12 months. There were four total thyroidectomies and six hemithyroidectomies. Operating times broken down into creating the working space, docking the robot, and console work (including wound closure), were prospectively recorded and evaluated. RESULTS: By the end of the initial learning curve comprising ten patients, the total operating time for a robotic hemithyroidectomy and for a total thyroidectomy has decreased by 49% to 190 min, and by 31% to 229 min, respectively. Intraoperative complications were successfully managed without conversion to open access surgery. CONCLUSION: The learning curve for transaxillary robotic thyroidectomy is rather steep; reasonable progress in terms of operating times can be achieved within the first ten cases. Consistency in the team and careful patient selection are paramount factors for success. PMID- 25917204 TI - Electrochemotherapy in locally advanced pancreatic cancer: Preliminary results. AB - OBJECTIVE: Report the preliminary results on electrochemotherapy (ECT) in the treatment of locally advanced pancreatic cancer of a phase I/II study and described the new functional imaging tools to assess ECT response in Magnetic Resonance (MR) imaging compared to morphological Computer Tomography (CT), ultrasound (US) without and with contrast enhancement (CEUS) and MR Imaging. MATERIALS AND METHODS: Thirteen patients were enrolled in an ongoing clinical phase I/II study approved by Ethical Committee of National Cancer Institute G. Pascale Foundation - IRCCS of Naples. ECT with bleomycin was performed during open surgery. All patients underwent US and CT scan, before and after ECT treatment; 7 patients were evaluated using morphological and functional (dynamic contrast enhancement-DCE and diffusion weighted- DW) parameters in MR; 5 patients underwent CEUS. RECIST criteria were used to evaluate ECT response on US, CT and MR images. Functional parameters were also used to evaluate ECT response on MR images. RESULTS: No acute (intraoperative) and/or postoperative serious adverse events related to electrochemotherapy were observed; no clinically significant electrocardiographic, hemodynamic, or serum biologic changes were noted. No clinically relevant elevation of amylase or lipase levels was observed and no bleeding or damage to surrounding viscera occurred. In three patients had seen splenic infarction without thrombosis of the splenic vessels. CONCLUSION: Electrochemotherapy is feasible and safe treatment modality in patients with locally advanced pancreatic adenocarcinoma. Dynamic and diffusion MR imaging in comparison to MR morphological sequence alone and to UC and CT imaging is more suitable to assess ECT treatment response. CEUS is not indicated in follow up after ECT. PMID- 25917205 TI - Tourniquet use during total knee arthroplasty does not offer significant benefit: A retrospective cohort study. AB - INTRODUCTION: Tourniquets are routinely employed during total knee arthroplasty; however, their use remains controversial. METHODS: This study investigates the efficacy and safety of this practice. A retrospective analysis of 186 patients was performed to assess benefits and/or risks associated with tourniquet use during knee arthroplasty. Total knee arthroplasty was performed using the Biomet Vanguard((r)) PCL Prosthesis (Biomet, Warsaw, IN, USA). In total, 126 patients who had undergone total knee arthroplasty were included in our final analysis. RESULTS: Patients with tourniquets had significantly less intraoperative blood loss than patients without (P < .001); patients without tourniquets required more blood transfusions (P = .551), and had significantly longer surgical times (P = .011). However, patients with tourniquets had more postoperative blood loss (P < .001), longer hospital stays (P = .013), and more frequent complications (P = .571). Blood transfusion requirement was significantly associated with complications (P < .001). CONCLUSIONS: Tourniquet use provided no overall benefit. PMID- 25917206 TI - Dynamic surface deformation of silicone elastomers for management of marine biofouling: laboratory and field studies using pneumatic actuation. AB - Many strategies have been developed to improve the fouling release (FR) performance of silicone coatings. However, biofilms inevitably build on these surfaces over time. Previous studies have shown that intentional deformation of silicone elastomers can be employed to detach biofouling species. In this study, inspired by the methods used in soft-robotic systems, controlled deformation of silicone elastomers via pneumatic actuation was employed to detach adherent biofilms. Using programmed surface deformation, it was possible to release > 90% of biofilm from surfaces in both laboratory and field environments. A higher substratum strain was required to remove biofilms accumulated in the field environment as compared with laboratory-grown biofilms. Further, the study indicated that substratum modulus influences the strain needed to de-bond biofilms. Surface deformation-based approaches have potential for use in the management of biofouling in a number of technological areas, including in niche applications where pneumatic actuation of surface deformation is feasible. PMID- 25917207 TI - Controlled and Impaired Mitochondrial Quality in Neurons: Molecular Physiology and Prospective Pharmacology. AB - Tuned mitochondrial physiology is fundamental for qualitative cellular function. This is particularly relevant for neurons, whose pathology is frequently associated with mitochondrial deficiencies. Defects in mitochondria are indeed key features in most neurodegenerative diseases such as Alzheimer's Disease (AD), Parkinson's Disease (PD), Huntington's Disease (HD) and Amyotrophic Lateral Sclerosis (ALS). When mitochondrial coupling impairs, so does cell metabolism, trafficking and the signaling depending on the homeostasis of the mitochondrial network. Moreover, the quality control of mitochondria - via the process of mitochondrial autophagy - results biased in neurodegeneration stemming major interest on the molecular determinants of this process among neuroscientists. In this review, we highlight the most notable and acknowledged deficiencies of mitochondrial function and their relationship with diseases occurring in neurons and their transmission. The physiological aspects of mitochondrial biology in relation to bio-energy, dynamics and quality control will be discussed with the finality to form a comprehensive picture of the mitochondrial contribution to the pathophysiology of neurodegenerative syndromes. In this way we aim to set the scene to conceive novel strategies to better diagnose and target these debilitative conditions. PMID- 25917208 TI - A new therapeutic association to manage relapsing experimental colitis: Doxycycline plus Saccharomyces boulardii. AB - Immunomodulatory antibiotics have been proposed for the treatment of multifactorial conditions such as inflammatory bowel disease. Probiotics are able to attenuate intestinal inflammation, being considered as safe when chronically administered. The aim of the study was to evaluate the anti-inflammatory effects of doxycycline, a tetracycline with immunomodulatory properties, alone and in association with the probiotic Saccharomyces boulardii CNCMI-745. Doxycycline was assayed both in vitro (Caco-2 epithelial cells and RAW 264.7 macrophages) and in vivo, in the trinitrobenzenesulfonic acid (TNBS) model of rat colitis and the dextran sodium sulfate (DSS) model of mouse colitis. In addition, the anti inflammatory effect of the association of doxycycline and the probiotic was evaluated in vitro and in vivo in a DSS model of reactivated colitis in mice. Doxycycline displayed immunomodulatory activity in vitro, reducing IL-8 production by intestinal epithelial cells and nitric oxide by macrophages. Doxycycline administration to TNBS-colitic rats (5, 10 and 25 mg/kg) ameliorated the intestinal inflammatory process, being its efficacy comparable to that previously showed by minocycline. Doxycycline treatment was also effective in reducing acute intestinal inflammation in the DSS model of mouse colitis. The association of doxycycline and S. boulardii helped managing colitis in a reactivated model of colitis, by reducing intestinal inflammation and accelerating the recovery and attenuating the relapse. This was evidenced by a reduced disease activity index, colonic tissue damage and expression of inflammatory mediators. This study confirms the intestinal anti-inflammatory activity of doxycycline and supports the potential use of its therapeutic association with S. boulardii for the treatment of inflammatory bowel diseases, in which doxycycline is used to induce remission and long term probiotic administration helps to prevent the relapses. PMID- 25917209 TI - Ginkgo biloba extract promotes osteogenic differentiation of human bone marrow mesenchymal stem cells in a pathway involving Wnt/beta-catenin signaling. AB - Human bone marrow derived mesenchymal stem cells (BM-MSCs) are a novel cell source used in stem cell therapy to treat bone diseases owing to their high potential to differentiate into osteoblasts. Effective induction of osteogenic differentiation from human BM-MSCs is critical to fulfill their therapeutic potential. In this study, Ginkgo biloba extract (GBE), a traditional herbal medicine, was used to stimulate the proliferation and osteogenic differentiation of human BM-MSCs. The present study revealed that GBE improved the proliferation and osteogenesis of human BM-MSCs in a dose-dependent manner in the range 25-75 mg/l, as indicated by alkaline phosphatase (ALP) activity and calcium content. However, such effect was decreased or inhibited at 100mg/l or higher. The dose dependent improvement in osteogenesis of human BM-MSCs by GBE was further confirmed by the dose-dependent upregulation of marker genes, osteopontin (OPN) and Collagen I. The increased osteoprotegerin (OPG) expression and minimal expression of receptor activator of nuclear factor-kappaB ligand (RANKL) suggested that GBE also inhibited osteoclastogenesis of human BM-MSCs. Further mechanistic study demonstrated that the transcriptional levels of bone morphogenetic protein 4 (BMP4) and runt-related transcription factor 2 (RUNX2) in the BMP signaling, beta-catenin and Cyclin D1 in the Wnt/beta-catenin signaling, increased significantly during GBE-promoted osteogenesis. Meanwhile, loss-of function assay with the signaling inhibitor(s) confirmed that the BMP and Wnt/beta-catenin signaling pathways were indispensable during the GBE-promoted osteogenesis, suggesting that GBE improved osteogenesis via upregulation of the BMP and Wnt/beta-catenin signaling. The present study proposed GBE to be used to upregulate the osteogenic differentiation of human BM-MSCs for new bone formation in BM-MSC-based cell therapy, which could provide an attractive and promising treatment for bone disorders. PMID- 25917210 TI - Geraniin exerts cytoprotective effect against cellular oxidative stress by upregulation of Nrf2-mediated antioxidant enzyme expression via PI3K/AKT and ERK1/2 pathway. AB - BACKGROUND: Geraniin, an active compound with remarkable antioxidant activity, was isolated from Geranium sibiricum. The present study aimed to investigate whether geraniin has the ability to activate Nrf2, induce antioxidant enzyme expression and protect cells from oxidative damage. METHODS: The cells were pretreated with geraniin for 24h and exposed to hydrogen peroxide (H2O2) for 4h. Intracellular reactive oxygen species (ROS) levels, mitochondrial membrane potential and apoptosis were measured. We also investigated intracellular glutathione (GSH) levels and changes in nuclear factor erythroid 2-related factor 2 (Nrf2)-mediated signaling cascade in cells treated with geraniin. RESULTS: We investigated the protective effects of geraniin against H2O2-induced apoptosis in HepG2 cells. Geraniin significantly reduced H2O2-induced oxidative damage in a dose dependent manner. Further, geraniin induced the expression of heme oxygenase 1 (HO-1), NAD(P)H quinone oxidoreductase-1 (NQO1) and level of glutathione (GSH) in a concentration- and time-dependent manner, and increased Nrf2 nuclear translocation. The Nrf2-related cytoprotective effects of geraniin were PI3K/AKT and extracellular signal-regulated protein kinase1/2 (ERK1/2) pathway-dependent. However, inhibitors of PI3K/AKT and ERK1/2 (LY294002 or U0126) not only suppressed geraniin-induced nuclear translocation of Nrf2 but also abolished the expression of HO-1, NQO1 and GSH. CONCLUSIONS: These results demonstrated that geraniin induced Nrf2-mediated expression of antioxidant enzymes HO-1 and NQO1, presumably via PI3K/AKT and ERK1/2 signaling pathways, thereby protecting cells from H2O2-induced oxidative cell death. GENERAL SIGNIFICANCE: Geraniin, at least in part, offers an antioxidant defense capacity to protect cells from the oxidative stress-related diseases. PMID- 25917211 TI - Foot orthoses in the treatment of symptomatic midfoot osteoarthritis using clinical and biomechanical outcomes: a randomised feasibility study. AB - This randomised feasibility study aimed to examine the clinical and biomechanical effects of functional foot orthoses (FFOs) in the treatment of midfoot osteoarthritis (OA) and the feasibility of conducting a full randomised controlled trial. Participants with painful, radiographically confirmed midfoot OA were recruited and randomised to receive either FFOs or a sham control orthosis. Feasibility measures included recruitment and attrition rates, practicality of blinding and adherence rates. Clinical outcome measures were: change from baseline to 12 weeks for severity of pain (numerical rating scale), foot function (Manchester Foot Pain and Disability Index) and patient global impression of change scale. To investigate the biomechanical effect of foot orthoses, in-shoe foot kinematics and plantar pressures were evaluated at 12 weeks. Of the 119 participants screened, 37 were randomised and 33 completed the study (FFO = 18, sham = 15). Compliance with foot orthoses and blinding of the intervention was achieved in three quarters of the group. Both groups reported improvements in pain, function and global impression of change; the FFO group reporting greater improvements compared to the sham group. The biomechanical outcomes indicated the FFO group inverted the hindfoot and increased midfoot maximum plantar force compared to the sham group. The present findings suggest FFOs worn over 12 weeks may provide detectable clinical and biomechanical benefits compared to sham orthoses. This feasibility study provides useful clinical, biomechanical and statistical information for the design and implementation of a definitive randomised controlled trial to evaluate the effectiveness of FFOs in treating painful midfoot OA. PMID- 25917212 TI - Arterial Stiffness and Incidence of Systolic Hypertension: The End to the "Chicken-Egg" Question? PMID- 25917214 TI - Comparison of three methods for measuring psoriasis severity in clinical studies (Part 2 of 2): use of quality of life to assess construct validity of the Lattice System Physician's Global Assessment, Psoriasis Area and Severity Index and Static Physician's Global Assessment. AB - BACKGROUND: Systems for determining psoriasis severity in clinical trials have not been sufficiently validated against patients' perceived quality of life. OBJECTIVE: To validate three systems of physician-determined psoriasis severity (the Lattice System Physician's Global Assessment [LS-PGA], Psoriasis Area and Severity Index [PASI] and static Physician's Global Assessment [sPGA]). METHODS: Data were from a 24-week randomized, double-blind, placebo-controlled, multicenter trial of therapy with oral calcineurin inhibitors in 445 patients. Construct validity was measured by correlations of the three severity scores with patients' self-reported quality of life (QoL) from the Dermatology Life Quality Index (DLQI) and a DLQI item about psoriasis symptoms. RESULTS: All severity systems were moderately and positively correlated with QoL, indicating construct validity. QoL was most consistently related to physicians' assessments of body surface area involved with psoriasis (iBSA) followed by, in the order of consistency, plaque elevation, erythema and scale. CONCLUSIONS: The LS-PGA weights iBSA and aspects of plaque morphology in concert with their relative effects on QoL. The LS-PGA, sPGA and PASI are validated by their relationship to QoL in a clinical trial. PMID- 25917213 TI - alpha-Synuclein expression in the mouse cerebellum is restricted to VGluT1 excitatory terminals and is enriched in unipolar brush cells. AB - alpha-Synuclein has a crucial role in synaptic vesicle release and synaptic membrane recycling. Although its general expression pattern has been described in the cerebellum, the precise cerebellar structures where alpha-synuclein is localized are poorly understood. To address this question, we used alpha synuclein immunohistochemistry in adult mice cerebellar sections. We found that alpha-synuclein labels glutamatergic but not glycinergic and GABAergic synaptic terminals in the molecular and granule cell layers. alpha-Synuclein was preferentially expressed in parallel and mossy fiber synaptic terminals that also express vesicular glutamate transporter 1 (VGluT1), while it was not detected in VGluT2-positive climbing fibers. alpha-Synuclein was particularly enriched in lobules IX and X, a region known to contain a high density of unipolar brush cells (UBCs). To elucidate whether the alpha-synuclein-positive mossy fibers belong to UBCs, we double-labeled cerebellar sections with antibodies to alpha synuclein and UBC-type-specific markers (calretinin for type I and metabotropic glutamate receptor 1alpha (mGluR1alpha) for type II UBCs) and took advantage of organotypic cerebellar cultures (in which all mossy fibers are UBC axons) and moonwalker mice (in which almost all UBCs are ablated) and found that both type I and type II UBCs express alpha-synuclein. In moonwalker mutant cerebella, the alpha-synuclein/VGluT1 immunolabeling showed a dramatic decrease in the vestibulocerebellum that correlated with the absence of UBC. alpha-Synuclein appears to be an excellent marker for intrinsic mossy fibers of the VGluT1 subset in conjunction with UBCs of both subtypes. PMID- 25917215 TI - Rat precision-cut intestinal slices to study P-gp activity and the potency of its inhibitors ex vivo. AB - Rat Precision-Cut Intestinal Slices (PCIS) were evaluated as ex vivo model to study the regional gradient of P-gp activity, and to investigate whether the rank order of inhibitory potency of P-gp inhibitors can be correctly reproduced in this model with more accurate IC50 values than with current in vitro models. PCIS were prepared from small intestine (duodenum, jejunum, ileum) and colon. Rhodamine 123 (R123) was used as P-gp substrate, while verapamil, cyclosporine A, quinidine, ketoconazole, PSC833 and CP100356 were employed as P-gp inhibitors. Increase in tissue accumulation of R123 in the presence of the inhibitors was considered as an indication of the inhibitory effect. The P-gp inhibitors increased the tissue accumulation of R123 in a concentration dependent manner. Fluorescence microscopy elucidated that this increase occurred predominantly in the enterocytes. The rank order of the corresponding IC50 values agreed well with reported values from cell lines expressing rat P-gp. The activity of and inhibitory effects on P-gp were significantly higher in ileum compared to the other regions. These data suggest that rat PCIS are a reliable ex vivo model to study the activity of intestinal P-gp and the inhibitory effect of drugs. PCIS have potential as ex vivo model for the prediction of transporter-mediated drug drug interactions. PMID- 25917216 TI - An electrical conductivity based method of determining the particle deposition rate in air-liquid interface devices. AB - A new in-situ method of determining the particle deposition rate onto cell cultures inside air-liquid interface devices is described. It is based on depositing a surrogate aerosol of salt particles onto the water filled wells of a culture plate while measuring the resulting change in electrical conductivity of the solution in situ, in order to derive the accumulated particle mass. For evaluation purposes, the wells of a six-well cell culture plate were equipped with custom designed electrodes and calibrated with a series of commercially available standard solutions. After the necessary corrections prescribed by theory, the calibration resulted in an accuracy and comparability between cells of +/-3% in terms of measured conductivity. The method was then applied to a specific ALI device consisting essentially of the calibrated six-well culture plate inside an electrostatic cross-flow precipitator, and tested with submicron NaCl aerosol of defined size distribution produced by nebulization of a salt solution. 2h of particle accumulation were sufficient to accumulate between 30 and 10 MUg of salt per well, depending on the location in the precipitator. Resulting deposition rates varied narrowly between the wells by about 2 ng min( 1) cm(-2). Factors affecting the overall accuracy and reproducibility are discussed. PMID- 25917217 TI - Looking at the hand modulates the brain responses to nociceptive and non nociceptive somatosensory stimuli but does not necessarily modulate their perception. AB - Previous studies have suggested that looking at the hand can reduce the perception of pain and the magnitude of the ERPs elicited by nociceptive stimuli delivered onto the hand. In contrast, other studies have suggested that looking at the hand can increase tactile sensory discrimination performance, and enhance the magnitude of the ERPs elicited by tactile stimulation. These opposite effects could be related to differences in the crossmodal effects between vision, nociception, and touch. However, these differences could also be related to the use of different experimental designs. Importantly, most studies on the effects of vision on pain have relied on a mirror to create the illusion that the reflected hand is a direct view of the stimulated hand. Here, we compared the effects of direct versus mirror vision of the hand versus an object on the perception and ERPs elicited by non-nociceptive and nociceptive stimuli. We did not observe any significant effect of vision on the perceived intensity. However, vision of the hand did reduce the magnitude of the nociceptive N240 wave, and enhanced the magnitude of the non-nociceptive P200. Our results confirm that vision of the body differentially affects nociceptive and non-nociceptive processing, but question the robustness of visual analgesia. PMID- 25917220 TI - Non-Native species as conservation priorities: response to Diez-Leon et al. PMID- 25917218 TI - Micelle-Triggered beta-Hairpin to alpha-Helix Transition in a 14-Residue Peptide from a Choline-Binding Repeat of the Pneumococcal Autolysin LytA. AB - Choline-binding modules (CBMs) have a betabeta-solenoid structure composed of choline-binding repeats (CBR), which consist of a beta-hairpin followed by a short linker. To find minimal peptides that are able to maintain the CBR native structure and to evaluate their remaining choline-binding ability, we have analysed the third beta-hairpin of the CBM from the pneumococcal LytA autolysin. Circular dichroism and NMR data reveal that this peptide forms a highly stable native-like beta-hairpin both in aqueous solution and in the presence of trifluoroethanol, but, strikingly, the peptide structure is a stable amphipathic alpha-helix in both zwitterionic (dodecylphosphocholine) and anionic (sodium dodecylsulfate) detergent micelles, as well as in small unilamellar vesicles. This beta-hairpin to alpha-helix conversion is reversible. Given that the beta hairpin and alpha-helix differ greatly in the distribution of hydrophobic and hydrophilic side chains, we propose that the amphipathicity is a requirement for a peptide structure to interact and to be stable in micelles or lipid vesicles. To our knowledge, this "chameleonic" behaviour is the only described case of a micelle-induced structural transition between two ordered peptide structures. PMID- 25917219 TI - Autonomous and nonautonomous regulation of Wnt-mediated neuronal polarity by the C. elegans Ror kinase CAM-1. AB - Wnts are a conserved family of secreted glycoproteins that regulate various developmental processes in metazoans. Three of the five Caenorhabditis elegans Wnts, CWN-1, CWN-2 and EGL-20, and the sole Wnt receptor of the Ror kinase family, CAM-1, are known to regulate the anterior polarization of the mechanosensory neuron ALM. Here we show that CAM-1 and the Frizzled receptor MOM 5 act in parallel pathways to control ALM polarity. We also show that CAM-1 has two functions in this process: an autonomous signaling function that promotes anterior polarization and a nonautonomous Wnt-antagonistic function that inhibits anterior polarization. These antagonistic activities can account for the weak ALM phenotypes displayed by cam-1 mutants. Our observations suggest that CAM-1 could function as a Wnt receptor in many developmental processes, but the analysis of cam-1 mutants may fail to reveal CAM-1's role as a receptor in these processes because of its Wnt-antagonistic activity. In this model, loss of CAM-1 results in increased levels of Wnts that act through other Wnt receptors, masking CAM-1's autonomous role as a Wnt receptor. PMID- 25917221 TI - Socioeconomic status and cardiovascular risk in urban South Asia: The CARRS Study. AB - BACKGROUND: Although South Asians experience cardiovascular disease (CVD) and risk factors at an early age, the distribution of CVD risks across the socioeconomic spectrum remains unclear. METHODS: We analysed the 2011 Centre for Cardiometabolic Risk Reduction in South Asia survey data including 16,288 non pregnant adults (>=20 years) that are representative of Chennai and Delhi, India, and Karachi, Pakistan. Socioeconomic status (SES) was defined by highest education (primary schooling, high/secondary schooling, college graduate or greater); wealth tertiles (low, middle, high household assets) and occupation (not working outside home, semi/unskilled, skilled, white-collar work). We estimated age and sex-standardized prevalence of behavioural (daily fruit/vegetables; tobacco use), weight (body mass index; waist-to-height ratio) and metabolic risk factors (diabetes, hypertension, hypercholesterolaemia; hypo HDL; and hypertriglyceridaemia) by each SES category. RESULTS: Across cities, 61.2% and 16.1% completed secondary and college educations, respectively; 52.8% reported not working, 22.9% were unskilled; 21.3% were skilled and 3.1% were white-collar workers. For behavioural risk factors, low fruit/vegetable intake, smoked and smokeless tobacco use were more prevalent in lowest education, wealthy and occupation (for men only) groups compared to higher SES counterparts, while weight-related risks (body mass index 25.0-29.9 and >=30 kg/m(2); waist-to-height ratio >=0.5) were more common in higher educated and wealthy groups, and technical/professional men. For metabolic risks, a higher prevalence of diabetes, hypertension and dyslipidaemias was observed in more educated and affluent groups, with unclear patterns across occupation groups. CONCLUSIONS: SES-CVD patterns are heterogeneous, suggesting customized interventions for different SES groups may be warranted. Different behavioural, weight, and metabolic risk factor prevalence patterns across SES indicators may signal on-going epidemiological transition in South Asia. PMID- 25917223 TI - Rhodium(III)-Catalyzed ortho C-H Heteroarylation of (Hetero)aromatic Carboxylic Acids: A Rapid and Concise Access to pi-Conjugated Poly-heterocycles. AB - Rh(III)-catalyzed oxidative C-H/C-H cross-coupling between (hetero)aromatic carboxylic acids and various heteroarenes has been accomplished to construct highly functionalized ortho-carboxy-substituted bi(hetero)aryls. The use of a carboxy group as the directing group obviates tedious steps for installation and removal of extra directing groups, and enables a facile one-step synthesis of ortho-carboxy bi(hetero)aryls. The method provides opportunities for rapid assembly of a library of important fluorene and coumarin-type poly-heterocycles through intramolecular electrophilic substitution or oxidative lactonization. As illustrative examples, the strategy developed herein greatly streamlines accesses to a variety of appealing polyheterocycles such as DTPO (5H-dithieno[3,2-b:2',3' d]pyran-5-one), CPDTO (cyclopentadithiophen-4-one), and indenothiophenes. PMID- 25917222 TI - Variation in insurance status by patient demographics and tumor site among nonelderly adult patients with cancer. AB - BACKGROUND: In the United States, an estimated 48 million individuals live without health insurance. The purpose of the current study was to explore the Variation in insurance status by patient demographics and tumor site among nonelderly adult patients with cancer. METHODS: A total of 688,794 patients aged 18 to 64 years who were diagnosed with one of the top 25 incident cancers (representing 95% of all cancer diagnoses) between 2007 and 2010 in the Surveillance, Epidemiology, and End Results (SEER) database were analyzed. Patient characteristics included age, race, sex, marital status, and rural or urban residence. County-level demographics included percent poverty level. Insurance status was defined as having non-Medicaid insurance, Medicaid coverage, or no insurance. RESULTS: On multivariate logistic regression analyses, younger age, male sex, nonwhite race, being unmarried, residence in counties with higher levels of poverty, and rural residence were associated with being uninsured versus having non-Medicaid insurance (all P <.001). The highest rates of non Medicaid insurance were noted among patients with prostate cancer (92.3%), melanoma of the skin (92.5%), and thyroid cancer (89.5%), whereas the lowest rates of non-Medicaid insurance were observed among patients with cervical cancer (64.2%), liver cancer (67.9%), and stomach cancer (70.9%) (P <.001). Among uninsured individuals, the most prevalent cancers were lung cancer (14.9%), colorectal cancer (12.1%), and breast cancer (10.2%) (P <.001). Lung cancer caused the majority of cancer mortality in all insurance groups. CONCLUSIONS: Rates of insurance coverage vary greatly by demographics and by cancer type. The expansion of health insurance coverage would be expected to disproportionally benefit certain demographic populations and cancer types. PMID- 25917224 TI - Patient Activation and Mental Health Care Experiences Among Women Veterans. AB - We utilized a nationally representative survey of women veteran primary care users to examine associations between patient activation and mental health care experiences. A dose-response relationship was observed, with odds of high quality ratings significantly greater at each successive level of patient activation. Higher activation levels were also significantly associated with preference concordant care for gender-related preferences (use of female providers, women only settings, and women-only groups as often as desired). Results add to the growing literature documenting better health care experiences among more activated patients, and suggest that patient activation may play an important role in promoting engagement with mental health care. PMID- 25917225 TI - Clobazam: A Safe, Efficacious, and Newly Rediscovered Therapeutic for Epilepsy. AB - Clobazam is an oral 1,5-benzodiazepine used worldwide for the treatment of many types of epilepsies, although it is currently only approved for Lennox-Gastaut syndrome in the USA. This anticonvulsant and anxiolytic therapeutic has repeatedly demonstrated great efficacy and a high safety profile in refractory epilepsy as well as in a few monotherapy trials in both children and adults. Clobazam allosterically activates the GABAA receptor, and it binds less to subunits that mediate sedative effects than other benzodiazepines. It acts quickly, maintaining a therapeutic effect for a long duration due to its active metabolite, N-desmethylclobazam. Dosage is between 5 mg and 40 mg a day, depending on patient weight, efficacy, and tolerability. Efficacy tolerance has not been a problem in the best studies. Clobazam has provided many benefits to epileptic patients. It should be used by clinicians early as an adjuvant therapy in the treatment of refractory epilepsy and even considered as monotherapy in a broad spectrum of epilepsy syndromes. PMID- 25917231 TI - Practical tips for safe and efficient robotic cystectomy. AB - Robotic-assisted radical cystectomy (RARC) is a challenging procedure that potentially offers the patient decreased perioperative morbidity. With careful patient selection and attention to surgical detail, one can learn to efficiently and safely perform RARC with extracorporeal diversion. As one develops further expertise with RARC, patient selection criteria can be liberalized and intracorporeal diversion can be performed. The accumulated experience of our institution and other high-volume institutions are reviewed with attention to the technical details that yield a safe and efficient robotic cystectomy. PMID- 25917230 TI - The association between speed of transition from initiation to subsequent use of cannabis and later problematic cannabis use, abuse and dependence. AB - AIMS: To test whether speed of transition from initiation use to subsequent use of cannabis is associated with likelihood of later cannabis dependence and other outcomes, and whether transition speed is attributable to genetic or environmental factors. DESIGN: Cross-sectional interview study. SETTING: Australia. PARTICIPANTS: A total of 2239 twins and siblings who reported using cannabis at least twice [mean age at time of survey = 32.0, 95% confidence interval (CI) = 31.9 - 32.1, range = 22-45]. MEASUREMENTS: Time between initiation and subsequent cannabis use (within 1 week; within 3 months; between 3 and 12 months; more than 1 year later), later use of cannabis and symptoms of DSM IV cannabis abuse/dependence. Multinomial regression analyses (comparison group: more than 1 year later) adjusted the association between speed of transition and the outcomes of cannabis daily use, abuse/dependence and treatment-seeking after controlling for socio-demographic, childhood, mental health, peer and licit drug factors. Twin modelling estimated the proportion of variance in transition speed attributable to genetic (A), common environment (C) and unique environmental (E) factors. FINDINGS: Subsequent use of cannabis within 1 week of initiation was associated with daily use [odds ratio (OR) = 2.64, 95% CI = 1.75-3.99], abuse and/or dependence (OR = 3.25, 95% CI = 2.31-4.56) and treatment-seeking for cannabis problems (OR = 1.89, 95% CI = 1.03-3.46). Subsequent use within 3 months was associated with abuse and/or dependence (OR = 1.61, 95% CI = 1.18-2.19). The majority of the variation of the speed of transition was accounted for by unique environment factors (0.75). CONCLUSIONS: Rapid transition from initiation to subsequent use of cannabis is associated with increased likelihood of subsequent daily cannabis use and abuse/dependence. PMID- 25917232 TI - Intraepithelial lymphocytes in relation to NIH category IV prostatitis in autopsy prostate. AB - BACKGROUND: Quantitative analysis of the number, normal and pathologic ratios between lymphocytes and epithelial cells (ECs), and the significance of intraepithelial lymphocytes (IELs) in normal prostatic epithelium, benign prostatic hyperplasia (BPH), and high grade prostatic intraepithelial neoplasia (PIN) in relation to NIH category IV prostatitis (histologic prostatitis: HP) was studied in autopsy prostate. METHODS: IELs were analysed in 59 autopsy prostates, which was routinely embedded in paraffin and immunohistochemically stained for CD3. An average of 300-500 ECs were counted per case. The number of IELs was calculated as the mean/100 ECs. Category IV prostatitis was evaluated using NIH consensus grading system in terms of anatomical localization and grade. RESULTS: In healthy individuals the mean number of IELs/100 ECs was 0.61 +/- 0.34% or <=1 lymphocyte/100 ECs, which is considered as the normal basal level of prostate IELs. In category IV prostatitis, the mean number of IELs/100 ECs was 8.53 +/- 3.25% or 5-11 lymphocytes/100 ECs. The number of IELs in both around and inside inflammation areas correlated to the grade and location of HP (P < 0.0001 and P < 0.0003), the presence of acute glandular inflammation (P < 0.0001), the scattered stromal lymphocytes (P = 0.029), and BPH and PIN associated prostatic inflammation (P < 0.0001). CONCLUSION: The study presents the first attempt to examine and score the basic quantitative values of prostatic IELs in normal prostate and in relation to category IV prostatitis. The detected normal upper limit of CD3+ IELs is 1 lymphocyte/100 ECs in the normal prostate epithelium. This is considered as an organ specific characteristic of the prostate-associated lymphoid tissue (PALT). Values >5 IELs/100 ECs indicate the presence of category IV prostatitis. The severity of inflammation correlates to the number of IELs. There is an intimate link between the quantity of the IELs, the degree of the severity and the localization of category IV prostatitis. HP is a chronic and dynamic inflammatory process affecting the whole prostate gland. The increased number of IELs suggests the immune or autoimmune character of category IV prostatitis, BPH and inflammatory preneoplastic (PIN) lesions in the prostatic tumor environment. PMID- 25917233 TI - Oral administration of apple condensed tannins delays rheumatoid arthritis development in mice via downregulation of T helper 17 (Th17) cell responses. AB - Apples are known to contain high concentrations of phenolic compounds such as condensed tannins. Consumption of condensed tannins has been reported to reduce the risk of many types of chronic diseases including allergies. However, their therapeutic effectiveness and potential in treating autoimmune disease remain controversial. Here, the effect of oral administration of apple condensed tannins (ACT) prepared from apples (Malus pumila cv. Fuji) on bovine type II collagen (CII)-induced arthritis in DBA1/J mice, a well-established murine model of human rheumatoid arthritis (RA), was evaluated. As compared to the control (without ACT administration) group, RA development was delayed and a significant reduction in the RA clinical score was observed in the ACT-administered group. Using cultured splenocytes isolated from CII-immunized mice, ACT-administration was shown to decrease the CII-induced increases in IL-17 expression and production in vitro. We propose that downregulation of T helper (Th) 17 cells is responsible for the ACT-induced RA suppression. PMID- 25917234 TI - Selective Formation of Indene through the Reaction of Benzyl Radicals with Acetylene. AB - The combustion of fossil fuels forms polycyclic aromatic hydrocarbons (PAHs) composed of five- and six- membered aromatic rings, such as indene (C9 H8 ), which are carcinogenic, mutagenic, and deleterious to the environment. Indene, the simplest PAH with single five- and six-membered rings, has been predicted theoretically to be formed through the reaction of benzyl radicals with acetylene. Benzyl radicals are found in significant concentrations in combustion flames, owing to their highly stable aromatic and resonantly stabilized free radical character. We provide compelling experimental evidence that indene is synthesized through the reaction of the benzyl radical (C7 H7 ) with acetylene (C2 H2 ) under combustion-like conditions at 600 K. The mechanism involves an initial addition step followed by cyclization and aromatization through atomic hydrogen loss. This reaction was found to form the indene isomer exclusively, which, in conjunction with the high concentrations of benzyl and acetylene in combustion environments, indicates that this pathway is the predominant route to synthesize the prototypical five- and six-membered PAH. PMID- 25917235 TI - Paralytic ileus in the orthopaedic patient. AB - Paralytic ileus is marked by the cessation of bowel motility. This condition is a major clinical concern that may lead to severe patient morbidity in orthopaedic surgery and trauma patients. Ileus most commonly occurs following spinal surgery, traumatic injury, or lower extremity joint reconstruction, but it may also occur following minor orthopaedic procedures. Possible consequences of ileus include abdominal pain, malnutrition, prolonged hospital stay, hospital readmission, bowel perforation, and death. Therapies used in the treatment of ileus include minimization of opioids, early patient mobilization, pharmacologic intervention, and multidisciplinary care. Orthopaedic surgeons should be aware of the clinical signs and symptoms of paralytic ileus and should understand treatment principles of this relatively common adverse event. PMID- 25917237 TI - Detection of autoantibodies against the calcium-dependent epitopes of desmoglein 3 by ethylenediaminetetraacetic acid-treated enzyme-linked immunosorbent assay with mammalian cell expression system. PMID- 25917236 TI - Loss of Gi G-Protein-Coupled Receptor Signaling in Osteoblasts Accelerates Bone Fracture Healing. AB - G-protein-coupled receptors (GPCRs) are key regulators of skeletal homeostasis and are likely important in fracture healing. Because GPCRs can activate multiple signaling pathways simultaneously, we used targeted disruption of G(i) -GPCR or activation of G(s) -GPCR pathways to test how each pathway functions in the skeleton. We previously demonstrated that blockade of G(i) signaling by pertussis toxin (PTX) transgene expression in maturing osteoblastic cells enhanced cortical and trabecular bone formation and prevented age-related bone loss in female mice. In addition, activation of G(s) signaling by expressing the G(s) -coupled engineered receptor Rs1 in maturing osteoblastic cells induced massive trabecular bone formation but cortical bone loss. Here, we test our hypothesis that the G(i) and G(s) pathways also have distinct functions in fracture repair. We applied closed, nonstabilized tibial fractures to mice in which endogenous G(i) signaling was inhibited by PTX, or to mice with activated G(s) signaling mediated by Rs1. Blockade of endogenous G(i) resulted in a smaller callus but increased bone formation in both young and old mice. PTX treatment decreased expression of Dkk1 and increased Lef1 mRNAs during fracture healing, suggesting a role for endogenous G(i) signaling in maintaining Dkk1 expression and suppressing Wnt signaling. In contrast, adult mice with activated Gs signaling showed a slight increase in the initial callus size with increased callus bone formation. These results show that G(i) blockade and G(s) activation of the same osteoblastic lineage cell can induce different biological responses during fracture healing. Our findings also show that manipulating the GPCR/cAMP signaling pathway by selective timing of G(s) and G(i) -GPCR activation may be important for optimizing fracture repair. PMID- 25917238 TI - A cognitive architecture account of the visual local advantage phenomenon in autism spectrum disorders. AB - Ideally, a cognitive architecture is a neurally plausible model that unifies mental representations and cognitive processes. Here, I apply such a model to re evaluate the local advantage phenomenon in autism spectrum disorders (ASD), that is, the better than typical performance on visual tasks in which local stimulus features are to be discerned. The model takes (a) perceptual organization as a predominantly stimulus-driven process yielding hierarchical stimulus organizations, and (b) attention as predominantly scrutinizing the hierarchical structure of established percepts in a task-driven top-down fashion. This accounts for a dominance of wholes over parts and implies that perceived global structures mask incompatible local features. The model also substantiates that impairments in neuronal synchronization - as found in ASD - reduce the emergence of global structures and, thereby, their masking effect on incompatible features. I argue that this explains the local advantage phenomenon and I discuss implications and suggestions for future research. PMID- 25917241 TI - Advanced care planning: policy and real-life decision-making? PMID- 25917242 TI - A survey of older peoples' attitudes towards advance care planning. AB - BACKGROUND: advance care planning (ACP) is a process to establish an individual's preference for care in the future; few UK studies have been conducted to ascertain public attitudes towards ACP. OBJECTIVE: the aim of this study was to assess the attitudes of older people in East Midlands through the development and administration of a survey. DESIGN: the survey questionnaire was developed on the basis of a literature review, exploratory focus groups with older adults and expert advisor input. The final questions were then re-tested with lay volunteers. SETTING: thirteen general practices were enrolled to send out surveys to potential participants aged 65 or older. There were no additional inclusion or exclusion criteria for participants. METHODS: simple descriptive statistics were used to describe the responses and regression analyses were used to evaluate which items predicted responses to key outcomes. RESULTS: of the 5,375 (34%) community-dwelling older peoples, 1,823 returned questionnaires. Seventeen per cent of respondents had prepared an ACP document; of whom, 4% had completed an Advance Decision to Refuse Treatment (ADRT). Five per cent of respondents stated that they had been offered an opportunity to talk about ACP. Predictors of completing an ACP document included: being offered the opportunity to discuss ACP, older age, better physical function and male gender. Levels of trust were higher for families than for professionals. One-third of the respondents would be interested in talking about ACP if sessions were available. CONCLUSION: although a third of the respondents were in favour of discussing ACP if the opportunity was available with their GP, only a relative minority (17%) had actively engaged. Preferences were for informal discussions with family rather than professionals. PMID- 25917243 TI - Reciting the months of the year backwards: what is a 'normal' score? PMID- 25917239 TI - A dichoptic custom-made action video game as a treatment for adult amblyopia. AB - Previous studies have employed different experimental approaches to enhance visual function in adults with amblyopia including perceptual learning, videogame play, and dichoptic training. Here, we evaluated the efficacy of a novel dichoptic action videogame combining all three approaches. This experimental intervention was compared to a conventional, yet unstudied method of supervised occlusion while watching movies. Adults with unilateral amblyopia were assigned to either play the dichoptic action game (n=23; 'game' group), or to watch movies monocularly while the fellow eye was patched (n=15; 'movies' group) for a total of 40hours. Following training, visual acuity (VA) improved on average by ~0.14logMAR (~28%) in the game group, with improvements noted in both anisometropic and strabismic patients. This improvement is similar to that obtained following perceptual learning, video game play or dichoptic training. Surprisingly, patients with anisometropic amblyopia in the movies group showed similar improvement, revealing a greater impact of supervised occlusion in adults than typically thought. Stereoacuity, reading speed, and contrast sensitivity improved more for game group participants compared with movies group participants. Most improvements were largely retained following a 2-month no contact period. This novel video game, which combines action gaming, perceptual learning and dichoptic presentation, results in VA improvements equivalent to those previously documented with each of these techniques alone. Our game intervention led to greater improvement than control training in a variety of visual functions, thus suggesting that this approach has promise for the treatment of adult amblyopia. PMID- 25917244 TI - Trainee Therapists' Experiences of Supervision During Training: A Meta-synthesis. AB - PURPOSE: Supervision is typically mandatory for therapists in training and plays an important role in their professional development. A number of qualitative studies have considered specific aspects of supervision. This systematic review aimed to synthesize these studies' findings and explore the experience and impact of supervision for trainee therapists. METHODS: A systematic search of the literature was conducted, and inclusion/exclusion criteria were applied. This led to a sample of 15 qualitative studies, with which a meta-synthesis was conducted. RESULTS: The meta-synthesis led to four key concepts: supervision as a learning opportunity, the supervisory relationship, power in supervision and the impact of supervision. These themes explored helpful and unhelpful aspects of supervision, including some concerns regarding the evaluation of supervision. CONCLUSIONS: Supervision can effectively support trainee therapists in their personal and professional development. However, it can also lead to feelings of distress and self-doubt. Supervisors need to consider the power differential within supervision and attend to different factors within the supervisory relationship. Copyright (c) 2015 John Wiley & Sons, Ltd. Key Practitioner Message Supervision can encourage personal and professional development, but it can also have a detrimental impact on trainee therapists' well-being, and consequently their clinical work and clients' experiences. Supervisees may not disclose unhelpful events or impacts from supervision, for fear of negative evaluation. Evaluation of supervisors should be facilitated and encouraged, to maintain good practice. PMID- 25917245 TI - Erratum to: Development of an auditory emotion recognition function using psychoacoustic parameters based on the International Affective Digitized Sounds. PMID- 25917246 TI - Theoretical investigation of self-assembled donor-acceptor phthalocyanine complexes and their application in dye-sensitized solar cells. AB - A theoretical investigation of self-assembled donor-acceptor dyads (ZnPca, ZnPcb and ZnPcc) formed by axial coordination of zinc phthalocyanines appended with 4 carboxyl pyridine has been conducted with the density functional theory (DFT) method and time-dependent DFT (TD-DFT) calculations. A comparison between the molecular structures, atomic charges, molecular orbitals, UV-vis spectra and infrared (IR) spectra has been studied. Further, as sensitizers for the TiO2 based dye-sensitized solar cells, the photovoltaic performances have been investigated. The ZnPcc-sensitized solar cell exhibits a higher conversion efficiency than the ZnPcb and ZnPca-sensitized ones under AM 1.5G solar irradiation, while the ZnPca-sensitized cell performs the poorest due to the lack of peripheral substituents (n-butyoxyl groups) which can be confirmed by the result of the theoretical research. It shows that the directionality of charge transfer in the self-assembled donor-acceptor dyads is important and benefit for the efficiency of the DSSC. PMID- 25917247 TI - Functional characteristics of control adaptation in intermodal sensory processing. AB - The present work investigated functional characteristics of control adjustments in intermodal sensory processing. Subjects performed an interference task that involved simultaneously presented visual and auditory stimuli which were either congruent or incongruent with respect to their response mappings. In two experiments, trial-by-trial sequential congruency effects were analysed for specific conditions that allowed ruling out "non-executive" contributions of stimulus or response priming to the respective RT fluctuations. In Experiment 1, conflict adaptation was observed in an oddball condition in which interference emanates from a task-irrelevant and response-neutral low-frequency stimulus. This finding characterizes intermodal control adjustments to be based - at least partly - on increased sensory selectivity, which is able to improve performance in any kind of interference condition which shares the same or overlapping attentional requirements. In order to further specify this attentional mechanism, Experiment 2 defined analogous conflict adaptation effects in non-interference unimodal trials in which just one of the two stimulus modalities was presented. Conflict adaptation effects in unimodal trials exclusively occurred for unimodal task-switch trials but not for otherwise equivalent task repetition trials, which suggests that the observed conflict-triggered control adjustments mainly consist of increased distractor inhibition (i.e., down-regulation of task-irrelevant information), while attributing a negligible role to target amplification (i.e., enhancement of task-relevant information) in this setup. This behavioral study yields a promising operational basis for subsequent neuroimaging investigations to define brain activations and connectivities which underlie the adaptive control of attentional selection. PMID- 25917248 TI - Coordinating Upper and Lower Body During FES-Assisted Transfers in Persons With Spinal Cord Injury in Order to Reduce Arm Support. AB - OBJECTIVE: The goal of this study is to minimize arm forces applied during sit-to stand (STS) transfers in persons with spinal cord injury (SCI) by using functional electrical stimulation (FES) applied to lower limbs muscles. MATERIALS AND METHODS: A new FES system has been used to automatically trigger muscle stimulation of the lower limbs, at the desired moment in regards to trunk motion. The objective was to decrease arm participation during STS motion of a person with complete paraplegia and low-level tetraplegia. Six participants with chronic SCI participated in the study. Participants with SCI were recruited to complete STS movement using a new system for FES-assisted STS transfer. All participants attended one muscle mapping session to test their muscles condition, two training sessions to become familiarized with the experimental setup, and two measurement sessions using the proposed system for FES-assisted STS movement. The applied arm forces during STS movement were recorded and analyzed for different stimulation onset values with respect to the maximal trunk acceleration signal using one-way ANOVA statistical test. Post-hoc analysis was performed using Tukey's method. RESULTS: The results of this study showed that the moment of the stimulation onset has an influence on the arm forces applied during the STS motion. The lowest values of arm forces were obtained for STS movements where the electrical stimulation was triggered before and around the time corresponding to the maximal value of the trunk acceleration signal. CONCLUSION: Lowest arm forces values were obtained for STS motions that were similar to those of healthy persons in terms of trunk movements and beginning of lower limb movements in regards to maximal trunk acceleration signal. The FES system was able to mimic the rising motion of a healthy individual by triggering the FES at the appropriate moment. This method could prove useful for pivot transfer, therapeutic or functional verticalization. PMID- 25917250 TI - The need for post-mastectomy radiotherapy in patients with IBC. PMID- 25917253 TI - Urological cancer: Is docetaxel the 'black widow' of mCRPC drugs? PMID- 25917256 TI - The need for post-mastectomy radiotherapy in patients with IBC. PMID- 25917257 TI - Wind tunnel investigation of sound attenuation in turbulent flow. AB - Wind tunnel investigation of the sound wave attenuation by grid-generated turbulence is performed. The most influential parameters, such as the propagation distance, intensity of turbulent fluctuations and integral scale of the fluctuations are studied using an ultrasonic technique. The results are compared to the theoretical predictions available on the wave statistics. Theoretical predictions are well confirmed and partly extended. It is demonstrated that the ultrasonic technique provides the possibility of reproducing the main effects of atmospheric turbulence on sound propagation while benefiting from isolating the role of various parameters therefore sets of experimental data can be generated under laboratory conditions to benchmark further extensions of theoretical models and numerical simulations. PMID- 25917254 TI - PET in the management of locally advanced and metastatic NSCLC. AB - Despite considerable improvements in the treatment options for advanced-stage non small-cell lung cancer (NSCLC), disease-specific survival remains poor. With the aim of improving patient outcome, the treatment paradigm of locally advanced NSCLC has shifted from solely radiotherapy towards combined and intensified treatment approaches. Also, treatment for patients with stage IV (oligo)metastatic NSCLC has evolved rapidly, with therapeutic options that include a number of targeted agents, surgery, and stereotactic ablative radiotherapy. However, personalizing treatment to the individual patient remains difficult and requires monitoring of biological parameters responsible for treatment resistance to facilitate treatment selection, guidance, and adaptation. PET is a well-established molecular imaging platform that enables non-invasive quantification of many biological parameters that are relevant to both local and systemic therapy. With increasing clinical evidence, PET has gradually evolved from a purely diagnostic tool to a multifunctional imaging modality that can be utilized for treatment selection, adaptation, early response monitoring, and follow up in patients with NSCLC. Herein, we provide a comprehensive overview of the available clinical data on the use of this modality in this setting, and discuss future perspectives of PET imaging for the clinical management of patients with locally advanced and metastatic NSCLC. PMID- 25917258 TI - Salts affect the interaction of ZnO or CuO nanoparticles with wheat. AB - Exposure to nanoparticles (NPs) that release metals with potential phytotoxicity could pose problems in agriculture. The authors of the present study used growth in a model growth matrix, sand, to examine the influence of 5 mmol/kg of Na, K, or Ca (added as Cl salts) and root exudates on transformation and changes to the bioactivity of copper(II) oxide (CuO) and zinc oxide (ZnO) NPs on wheat. These salt levels are found in saline agricultural soils. After 14 d of seedling growth, particles with crystallinity typical of CuO or ZnO remained in the aqueous fraction from the sand; particles had negative surface charges that differed with NP type and salt, but salt did not alter particle agglomeration. Reduction in shoot and root elongation and lateral root induction by ZnO NPs were mitigated by all salts. However, whereas Na and K promoted Zn loading into shoots, Ca reduced loading, suggesting that competition with Zn ions for uptake occurred. With CuO NPs, plant growth and loading was modified equally by all salts, consistent with major interaction with the plant with CuO rather than Cu ions. Thus, for both NPs, loading into plant tissues was not solely dependent on ion solubility. These findings indicated that salts in agricultural soils could modify the phytotoxicity of NPs. PMID- 25917259 TI - Safety of extravasated sodium bicarbonate. PMID- 25917260 TI - What is the outcome of cancer patients admitted to the ICU after cardiac arrest? Results from a multicenter study. AB - AIM: Low survival rate was previously described after cardiac arrest in cancer patients and may challenge the appropriateness of intensive care unit (ICU) admission after return of spontaneous circulation (ROSC). Objectives of this study were to report outcome and characteristics of cancer patients admitted to the ICU after cardiac arrest. METHODS: A retrospective chart review in seven medical ICUs in France, in 2002-2012. We studied consecutive patients with malignancies admitted after out-of-hospital cardiac arrest (OHCA) or in-hospital cardiac arrest (IHCA). RESULTS: Of 133 included patients of whom 61% had solid tumors, 48 (36%) experienced OHCA and 85 (64%) IHCA. Cardiac arrest was related to the malignancy or its treatment in 47% of patients. Therapeutic hypothermia was used in 51 (41%) patients. The ICU mortality rate was 98/133 (74%). Main causes of ICU death were refractory shock or multiple organ failure (n = 64, 48%) and neurological injury (n = 27, 20%); 42 (32%) patients died in ICU after treatment-limitation decisions. Twenty-four (18%) patients were discharged alive from the hospital. Overall 6-month survival rate was 14% (18/133, 95% confidence interval, 8-21%). Survival rates at ICU discharge and after 6 months did not differ significantly across type of malignancy or between the OHCA and IHCA groups, and neither were they significantly different from those in matched controls who had cardiac arrest but no malignancy. CONCLUSIONS: Even if low, the 6-month survival rate of 14% observed in cancer patients admitted to the ICU after cardiac arrest and ROSC may support the admission of these patients to the ICU and may warrant an initial full-code ICU management. PMID- 25917261 TI - Knowledge of fresh-graduated medical students for advanced cardiovascular life support in China. PMID- 25917262 TI - A quantitative analysis of out-of-hospital pediatric and adolescent resuscitation quality--A report from the ROC epistry-cardiac arrest. AB - AIM: High-quality cardiopulmonary resuscitation (CPR) may improve survival. The quality of CPR performed during pediatric out-of-hospital cardiac arrest (p-OHCA) is largely unknown. The main objective of this study was to describe the quality of CPR performed during p-OHCA resuscitation attempts. METHODS: Prospective observational multi-center cohort study of p-OHCA patients >= 1 and < 19 years of age registered in the Resuscitation Outcomes Consortium (ROC) Epistry database. The primary outcome was an a priori composite variable of compliance with American Heart Association (AHA) guidelines for both chest compression (CC) rate and CC fraction (CCF). Event compliance was defined as a case with 60% or more of its minute epochs compliant with AHA targets (rate 100-120 min(-1); depth >= 38 mm; and CCF >= 0.80). In a secondary analysis, multivariable logistic regression was used to evaluate the association between guideline compliance and return of spontaneous circulation (ROSC). RESULTS: Between December 2005 and December 2012, 2564 pediatric events were treated by EMS providers, 390 of which were included in the final cohort. Of these events, 22% achieved AHA compliance for both rate and CCF, 36% for rate alone, 53% for CCF alone, and 58% for depth alone. Over time, there was a significant increase in CCF (p < 0.001) and depth (p = 0.03). After controlling for potential confounders, there was no significant association between AHA guideline compliance and ROSC. CONCLUSIONS: In this multi-center study, we have established that there are opportunities for professional rescuers to improve prehospital CPR quality. Encouragingly, CCF and depth both increased significantly over time. PMID- 25917263 TI - Association between hospital post-resuscitative performance and clinical outcomes after out-of-hospital cardiac arrest. AB - BACKGROUND: Survival varies among those resuscitated from out-of-hospital cardiac arrest (OHCA). Evidence-based performance measures have been used to describe hospital quality of care in conditions such as acute coronary syndrome and major trauma. It remains unclear if adherence to performance measures is associated with better outcome in patients hospitalized after OHCA. OBJECTIVES: To assess whether a composite performance score based on evidence-based guidelines for care of patients resuscitated from OHCA was independently associated with clinical outcomes. METHODS: Included were 3252 patients with OHCA who received care at 111 U.S. and Canadian hospitals participating in the Resuscitation Outcomes Consortium (ROC-PRIMED) study between June 2007 and October 2009. We calculated composite performance scores for all patients, aggregated these at the hospital level, then associated them with patient mortality and favorable neurological status at discharge. RESULTS: Composite performance scores varied widely (median [IQR] scores from lowest to highest hospital quartiles, 21% [20%, 25%] vs. 59% [55%, 64%]. Adjusted survival to discharge increased with each quartile of performance score (from lowest to highest: 16.2%, 20.8%, 28.5%, 34.8%, P<0.01), with similar findings for adjusted rates of good neurologic status. Hospital score was significantly associated with outcome after risk adjustment for established baseline factors (highest vs. lowest adherence quartile: adjusted OR of survival 1.64; 95% CI 1.13, 2.38). CONCLUSIONS: Greater survival and favorable neurologic status at discharge were associated with greater adherence to recommended hospital based post-resuscitative care guidelines. Consideration should be given to measuring, reporting and improving hospital adherence to guideline-based performance measures, which could improve outcomes following OHCA. PMID- 25917264 TI - Overestimated electrical exposure risk associated with hands-on defibrillation? PMID- 25917265 TI - Does addition of 'mud-pack and hot pool treatment' to patient education make a difference in fibromyalgia patients? A randomized controlled single blind study. AB - The aim of this randomized controlled single-blind study is to explore whether addition of mud-pack and hot pool treatments to patient education make a significant difference in short and mild term outcomes of the patients with fibromyalgia. Seventy women with fibromyalgia syndrome were randomly assigned to either balneotherapy with mud-pack and hot pool treatments (35) or control (35) groups. After randomization, five patients from balneotherapy group and five patients from control group were dropped out from the study with different excuses. All patients had 6-h patient education programme about fibromyalgia syndrome and were given a home exercise programme. The patients in balneotherapy group had heated pool treatment at 38 degrees C for 20 min a day, and mud-pack treatment afterwards on back region at 45 degrees C. Balneotherapy was applied on weekdays for 2 weeks. All patients continued to take their medical treatment. An investigator who was blinded to the intervention assessed all the patients before and after the treatment, at the first and the third months of follow-up. Outcome measures were FIQ, BDI and both patient's and physician's global assessments. Balneotherapy group was significantly better than control group at after the treatment and at the end of the first month follow-up assessments in terms of patient's and physician's global assessment, total FIQ score, and pain intensity, fatigue, non-refreshed awaking, stiffness, anxiety and depression subscales of FIQ. No significant difference was found between the groups in terms of BDI scores. It is concluded that patient education combined with 2 weeks balneotherapy application has more beneficial effects in patients with fibromyalgia syndrome as compared to patient education alone. PMID- 25917266 TI - KRAS and CREBBP mutations: a relapse-linked malicious liaison in childhood high hyperdiploid acute lymphoblastic leukemia. AB - High hyperdiploidy defines the largest genetic entity of childhood acute lymphoblastic leukemia (ALL). Despite its relatively low recurrence risk, this subgroup generates a high proportion of relapses. The cause and origin of these relapses remains obscure. We therefore explored the mutational landscape in high hyperdiploid (HD) ALL with whole-exome (n=19) and subsequent targeted deep sequencing of 60 genes in 100 relapsing and 51 non-relapsing cases. We identified multiple clones at diagnosis that were primarily defined by a variety of mutations in receptor tyrosine kinase (RTK)/Ras pathway and chromatin-modifying genes. The relapse clones consisted of reappearing as well as new mutations, and overall contained more mutations. Although RTK/Ras pathway mutations were similarly frequent between diagnosis and relapse, both intergenic and intragenic heterogeneity was essentially lost at relapse. CREBBP mutations, however, increased from initially 18-30% at relapse, then commonly co-occurred with KRAS mutations (P<0.001) and these relapses appeared primarily early (P=0.012). Our results confirm the exceptional susceptibility of HD ALL to RTK/Ras pathway and CREBBP mutations, but, more importantly, suggest that mutant KRAS and CREBBP might cooperate and equip cells with the necessary capacity to evolve into a relapse-generating clone. PMID- 25917267 TI - The phosphoinositide-3-kinase (PI3K)-delta and gamma inhibitor, IPI-145 (Duvelisib), overcomes signals from the PI3K/AKT/S6 pathway and promotes apoptosis in CLL. AB - The functional relevance of the B-cell receptor (BCR) and the evolution of protein kinases as therapeutic targets have recently shifted the paradigm for treatment of B-cell malignancies. Inhibition of p110delta with idelalisib has shown clinical activity in chronic lymphocytic leukemia (CLL). The dynamic interplay of isoforms p110delta and p110gamma in leukocytes support the hypothesis that dual blockade may provide a therapeutic benefit. IPI-145, an oral inhibitor of p110delta and p110gamma isoforms, sensitizes BCR-stimulated and/or stromal co-cultured primary CLL cells to apoptosis (median 20%, n=57; P<0.0001) including samples with poor prognostic markers, unmutated IgVH (n=28) and prior treatment (n=15; P<0.0001). IPI-145 potently inhibits the CD40L/IL-2/IL-10 induced proliferation of CLL cells with an IC50 in sub-nanomolar range. A corresponding dose-responsive inhibition of pAKT(Ser473) is observed with an IC50 of 0.36 nM. IPI-145 diminishes the BCR-induced chemokines CCL3 and CCL4 secretion to 17% and 37%, respectively. Pre-treatment with 1 MUM IPI-145 inhibits the chemotaxis toward CXCL12; reduces pseudoemperipolesis to median 50%, inferring its ability to interfere with homing capabilities of CLL cells. BCR-activated signaling proteins AKT(Ser473), BAD(Ser112), ERK(Thr202/Tyr204) and S6(Ser235/236) are mitigated by IPI-145. Importantly, for clinical development in hematological malignancies, IPI-145 is selective to CLL B cells, sparing normal B and T-lymphocytes. PMID- 25917269 TI - Facial angiolymphoid hyperplasia with eosinophilia: sustained remission following treatment with carbon dioxide laser. PMID- 25917270 TI - Mucocoele and mucinous tumours of the appendix: A review of the literature. AB - INTRODUCTION: Mucocoele of the appendix is rarely encountered but consultant general surgical and trainees must be aware of it as a differential diagnosis, due to the nuances associated with its management. We aimed to provide a comprehensive review of the current literature concerning this rare surgical pathology. METHODS: Search terms "appendi*", "tumour", "malignancy", "mucino*" and "cystadenoma" were used in combination to identify papers from PubMed. Abstracts and full text were manually reviewed to identify suitable papers. RESULTS: Full search results included 311 articles. Review of titles and abstracts led to further full text review of 46 articles. Of these 30 were selected for inclusion based on relevance, adequate sample size and recent publication date. DISCUSSION: Mucocoele of the appendix describes dilatation with associated luminal mucin and can result from benign and malignant processes. It contributes 0.2-0.7% of all appendiceal pathologies. The most common presenting symptoms are abdominal pain and a palpable mass in the right iliac fossa. Computed tomography of the abdomen and pelvis is key in facilitating diagnosis, although CEA and CA19-9 also have a role. The major complication of malignant causes of mucocoele is progression to pseudomyxoma peritonei. Treatment is surgical with or without chemotherapy depending on the underlying cause. Prognosis depends on aetiology. CONCLUSION: Mucocoele of the appendix is a rare diagnosis. However, given the possibility of neoplastic peritoneal dissemination, it should be considered as a diagnosis, especially in older females with non specific symptoms similar to appendicitis. PMID- 25917268 TI - Immunoinflammatory diseases of the central nervous system - the tale of two cytokines. AB - Cytokines are potent mediators of cellular communication that have crucial roles in the regulation of innate and adaptive immunoinflammatory responses. Clear evidence has emerged in recent years that the dysregulated production of cytokines may in itself be causative in the pathogenesis of certain immunoinflammatory disorders. Here we review current evidence for the involvement of two different cytokines, IFN-alpha and IL-6, as principal mediators of specific immunoinflammatory disorders of the CNS. IFN-alpha belongs to the type I IFN family and is causally linked to the development of inflammatory encephalopathy exemplified by the genetic disorder, Aicardi-Goutieres syndrome. IL-6 belongs to the gp130 family of cytokines and is causally linked to a number of immunoinflammatory disorders of the CNS including neuromyelitis optica, idiopathic transverse myelitis and genetically linked autoinflammatory neurological disease. In addition to clinical evidence, experimental studies, particularly in genetically engineered mouse models with astrocyte-targeted, CNS restricted production of IFN-alpha or IL-6 replicate many of the cardinal neuropathological features of these human cytokine-linked immunoinflammatory neurological disorders giving crucial evidence for a direct causative role of these cytokines and providing further rationale for the therapeutic targeting of these cytokines in neurological diseases where indicated. PMID- 25917271 TI - Cerebral critical closing pressure in hydrocephalus patients undertaking infusion tests. AB - OBJECTIVES: Links between cerebrospinal fluid (CSF) compensation and cerebral blood flow (CBF) have been studied in many clinical scenarios. In hydrocephalus, disturbed CSF circulation seems to be a primary problem, having been linked to CBF disturbances, particularly in white matter close to surface of dilated ventricles. We studied possible correlations between cerebral haemodynamic indices using transcranial Doppler (TCD) ultrasonography and CSF compensatory dynamics assessed during infusion tests. METHODS: We analysed clinical data from infusion tests performed in 34 patients suspected to suffer from normal pressure hydrocephalus, with signals including intracranial pressure (ICP), arterial blood pressure (ABP) and TCD blood flow velocity (FV). Cerebrospinal fluid compensatory parameters (including elasticity) were calculated according to a hydrodynamic model of the CSF circulation. Critical closing pressure (CrCP) was calculated with the cerebrovascular impedance methodology, while wall tension (WT) was estimated as CrCP-ICP. Closing margin (CM) was expressed as the difference between ABP and CrCP. RESULTS: Intracranial pressure increased during infusion from 6.7 +/- 4.6 to 25.0 +/- 10.5 mmHg (mean +/- SD; P < 0.001), resulting in CrCP rising by 22.9% (P < 0.001) and WT decreasing by 11.3% (P = 0.005). Closing margin showed a tendency to decrease, albeit not significantly (P = 0.070) due to rising ABP (9.1%; P = 0.005). Closing margin at baseline ICP was inversely correlated to brain elasticity (R = (0.358; P = 0.038), while being significantly different from zero for the whole duration of the tests (52.8 +/- 22.8 mmHg; P < 0.001). Neither CrCP nor WT was correlated with CSF compensatory parameters. DISCUSSION: Critical closing pressure increases and WT decreases during infusion tests. Closing margin at baseline pressure may act as an indicator of the cerebrospinal compensatory reserve. PMID- 25917272 TI - How big is a food portion? A pilot study in Australian families. AB - ISSUES ADDRESSED: It is not known whether individuals can accurately estimate the portion size of foods usually consumed relative to standard serving sizes in national food selection guides. The aim of the present cross-sectional pilot study was to quantify what adults and children deem a typical portion for a variety of foods and compare these with the serving sizes specified in the Australian Guide to Healthy Eating (AGHE). METHODS: Adults and children were independently asked to serve out their typical portion of 10 common foods (rice, pasta, breakfast cereal, chocolate, confectionary, ice cream, meat, vegetables, soft drink and milk). They were also asked to serve what they perceived a small, medium and large portion of each food to be. Each portion was weighed and recorded by an assessor and compared with the standard AGHE serving sizes. RESULTS: Twenty-one individuals (nine mothers, one father, 11 children) participated in the study. There was a large degree of variability in portion sizes measured out by both parents and children, with means exceeding the standard AGHE serving size for all items, except for soft drink and milk, where mean portion sizes were less than the AGHE serving size. The greatest mean overestimations were for pasta (155%; mean 116 g; range 94-139 g) and chocolate (151%; mean 38 g; range 25-50 g), each of which represented approximately 1.5 standard AGHE servings. CONCLUSION: The findings of the present study indicate that there is variability between parents' and children's estimation of typical portion sizes compared with national recommendations. SO WHAT? Dietary interventions to improve individuals' dietary patterns should target education regarding portion size. PMID- 25917274 TI - Palladium-catalyzed asymmetric allylic amination of racemic butadiene monoxide with isatin derivatives. AB - Isatins and their derivatives are important functional moities and building blocks in pharmaceutical and synthetic chemistry. Numerous enantioselective transformations at the C-3 carbonyl group have been well developed. However, the asymmetric substitution reaction with isatins and their derivatives as nucleophiles based on the free N-H groups has been less studied due to the relatively weaker nucleophilicity resulting from the two electron-withdrawing carbonyl groups. In this paper, a palladium-catalyzed asymmetric allylic amination of racemic butadiene monoxide with isatin derivatives using a chiral phosphoramidite olefin hybrid ligand has been successfully developed under mild conditions. A variety of chiral amino alcohols were afforded in 55-87% yields with 10/1->20/1 regioselectivity ratios and 80-97% ees. PMID- 25917273 TI - Neuron specific reduction in CuZnSOD is not sufficient to initiate a full sarcopenia phenotype. AB - Our previous studies showed that adult (8 month) mice lacking CuZn-superoxide dismutase (CuZnSOD, Sod1KO mice) have neuromuscular changes resulting in dramatic accelerated muscle atrophy and weakness that mimics age-related sarcopenia. We have further shown that loss of CuZnSOD targeted to skeletal muscle alone results in only mild weakness and no muscle atrophy. In this study, we targeted deletion of CuZnSOD specifically to neurons (nSod1KO mice) and determined the effect on muscle mass and weakness. The nSod1KO mice show a significant loss of CuZnSOD activity and protein level in brain and spinal cord but not in muscle tissue. The masses of the gastrocnemius, tibialis anterior and extensor digitorum longus (EDL) muscles were not reduced in nSod1KO compared to wild type mice, even at 20 months of age, although the quadriceps and soleus muscles showed small but statistically significant reductions in mass in the nSod1KO mice. Maximum isometric specific force was reduced by 8-10% in the gastrocnemius and EDL muscle of nSod1KO mice, while soleus was not affected. Muscle mitochondrial ROS generation and oxidative stress measured by levels of reactive oxygen/nitrogen species (RONS) regulatory enzymes, protein nitration and F2-isoprostane levels were not increased in muscle from the nSod1KO mice. Although we did not find evidence of denervation in the nSod1KO mice, neuromuscular junction morphology was altered and the expression of genes associated with denervation acetylcholine receptor subunit alpha (AChRalpha), the transcription factor, Runx1 and GADD45alpha) was increased, supporting a role for neuronal loss of CuZnSOD initiating alterations at the neuromuscular junction. These results and our previous studies support the concept that CuZnSOD deficits in either the motor neuron or muscle alone are not sufficient to initiate a full sarcopenic phenotype and that deficits in both tissues are required to recapitulate the loss of muscle observed in Sod1KO mice. PMID- 25917275 TI - Local Area Unemployment and the Demand for Inpatient Care Among Veterans Affairs Enrollees. AB - Prior research examining the relationship between economic conditions and health service demand has focused primarily on outpatient use. This study examines whether local area unemployment, as an indicator of economic conditions, was associated with use of inpatient care, which is theoretically less subject to discretionary use. Using a random sample of 131,603 patients dually enrolled in the Veterans Affairs (VA) Health System and fee-for-service Medicare, we measured VA, Medicare, and total (VA and Medicare) hospitalizations. Overall, local unemployment was not associated with VA, Medicare, or total hospitalization probability. Among low-income veterans exempt from VA copayments, higher local unemployment was moderately associated with a lower probability of hospitalization through Medicare. For veterans subject to VA copayments, higher local unemployment was moderately associated with a higher likelihood of VA hospitalization. These results suggest inpatient use is less sensitive to the economy, although worse economic conditions slightly affected inpatient demand for select veterans. PMID- 25917276 TI - Surgical Excision of Advanced Endometriosis: Perioperative Outcomes and Impacting Factors. AB - OBJECTIVE: To determine perioperative outcomes and factors impacting operating time, length of hospital stay, and complications of patients undergoing surgery for stage 3 or 4 endometriosis. DESIGN: Retrospective review of medical records (Canadian Task Force classification II-2). SETTING: Mayo Clinic Hospital, Phoenix, Arizona. PATIENTS: Women (n = 493) with endometriosis stage 3 and 4 undergoing surgical excision between March 15, 2005, and December 31, 2011. INTERVENTIONS: Robotic-assisted (n = 331) or laparoscopic (n = 162) excision. MEASUREMENTS: Age, body mass index, comorbidities, number and type of procedures per patient, type of surgical approach, operating time, blood loss, intraoperative and postoperative complications (within 42 days), and length of hospital stay. MAIN RESULTS: The mean patient age was 39.5 years; body mass index, 25.9; number of procedures, 3.3; operating time, 130.4 minutes; blood loss, 88.5 mL; and hospital stay, 1.0 days. Major complications occurred in 5 patients (1.5%). Fifty-nine patients (12.0%) underwent modified radical hysterectomy, 90 (18.3%) underwent ureteral and/or intestinal resection, and 3 (0.6%) underwent diaphragm resection. Factors significantly associated with operating time included age (p = .008) and blood loss, number of procedures per patient, and robotics (all p < .001). Length of stay was affected by age, operating time, and blood loss (all p < .001). Operating time was the only significant factor associated with postoperative complications (p < .001). CONCLUSION: Operating time is an independent and significant factor for postoperative complications and hospital stay. PMID- 25917277 TI - Vaginal Morcellation Inside Protective Pouch: A Safe Strategy for Uterine Extration in Cases of Bulky Endometrial Cancers: Operative and Oncological Safety of the Method. AB - OBJECTIVE: To evaluate the operative and oncologic outcomes of an innovative technique for organ morcellation in patients scheduled for laparoscopic treatment of uterine malignancies. BACKGROUND: Endoscopy is currently considered the standard of care for the operative treatment of endometrial cancer; however, the use of minimal invasive surgery (MIS) is restricted in patients with a bulky uterus or narrow vagina. Conventional unprotected intraperitoneal uterine fragmentation is indeed contraindicated in these cases. Consequently, oncologically safe methods to render these patients eligible for MIS are urgently needed. INTERVENTION: Prospective study of women with histologically proven endometrial cancer in which uterus removal was a realistic concern owing to both organ size and proportionality. The patients underwent laparoscopic staging, including retroperitoneal lymphadenectomy, total hysterectomy, and bilateral salpingo-oophorectomy, followed by vaginal morcellation of the uterus inside a protective pouch (LapSac). RESULTS: In our series of 30 cases, we achieved successful completion in all patients, without conversion to laparotomy. No surgery-related casualty or intraoperative morbidity was observed. The mean organ size was 246 g (range, 148-420 g), and the average additional operative time related to vaginal morcellation was 16 minutes (range, 9-28 minutes). Proper histopathological staging according to 2009 FIGO staging guidelines could be performed in all specimens. Two patients (6%) presented with significant postoperative complications, 1 each with vesicovaginal fistula and vaginal vault dehiscence. Fourteen patients (46%) needed adjuvant therapy. After a median follow-up of 20 months (range, 6-38 months), the 12-month and 24-month overall survival was 100% and 73.4% (95% confidence interval, 51%-96%), respectively. Four patients with positive lymph nodes died of distant metastasis. No case of pelvic or local relapse was observed. CONCLUSION: Vaginal morcellation following oncologic principles is a feasible method that permits rapid uterine extraction and potentially avoids unnecessary laparotomies. This series suggests that the technique may be oncologically safe and also can be used in cases of uterine pathology of uncertain malignancy. PMID- 25917278 TI - Hysteroscopic Essure Inserts for Permanent Contraception: Extended Follow-Up Results of a Phase III Multicenter International Study. AB - OBJECTIVE: To describe safety, tolerability, and effectiveness results through 5 years of follow-up of a Phase III trial with Essure inserts. DESIGN: Multicenter, nonrandomized, single-arm international study (Canadian Task Force classification II-3). SETTING: Thirteen clinical study centers in the United States, Europe, and Australia. PATIENTS: A total of 518 previously fertile women seeking permanent contraception. INTERVENTION: The objective of the hysteroscopic sterilization procedure was bilateral Essure insert placement (ESS205 model) and tubal occlusion. Women with satisfactory device location and tube occlusion (based on modified hysterosalpingography [HSG]) were instructed to discontinue alternative contraception and to rely on Essure inserts for permanent contraception. MEASUREMENTS AND MAIN RESULTS: The primary endpoint for the Phase III study was the rate of pregnancies occurring during the first year of relying (i.e., HSG confirmed occlusion) on the Essure inserts for permanent contraception (i.e., 12 months after HSG). For the full 5 years of follow-up (5 years total of relying on the Essure inserts for contraception), the endpoints of interest were safety, prevention of pregnancy, and satisfaction. No pregnancies were reported among women relying on the Essure inserts who completed the full 5 years of follow-up. As of December 5, 2007, 449 women with successful bilateral placement relying on the Essure inserts contributed a total 24 942 woman-months of follow-up for assessing effectiveness. Overall, the Essure inserts were generally well tolerated, with participant comfort rated as "good" to "excellent" by 99% of women (382 of 385) after 5 years of use. Similarly, overall satisfaction was rated as "somewhat" to "very satisfied" by 98% of women (376 of 384) after 5 years of use. The majority of adverse events reported during the 5 years of follow-up were rated as either "mild" or "moderate" in severity. Three severe events (abdominal pain with very heavy periods and irregular menstrual bleeding) were reported in 2 subjects during follow-up as being "possibly" related to the procedure or the inserts. CONCLUSION: The findings from extended follow-up of this Phase III trial with Essure inserts further support the effectiveness, tolerability, and satisfaction of this nonhormonal, nonincisional option for permanent contraception. PMID- 25917279 TI - Effect of Methotrexate or Salpingectomy for Ectopic Pregnancy on Subsequent In Vitro Fertilization-Embryo Transfer Outcomes. AB - OBJECTIVE: To investigate the effect of methotrexate (MTX) or salpingectomy for ectopic pregnancy on the outcomes of subsequent in vitro fertilization (IVF) embryo transfer (ET) cycles. DESIGN: Retrospective cohort study (Canadian Task Force Classification II-3). SETTING: Academic center. PATIENTS: All patients undergoing fresh IVF-ET between January 2004 and July 2013 after treatment of an ectopic pregnancy with MTX or salpingectomy in the preceding IVF-ET cycle were analyzed for potential inclusion. INTERVENTION: MTX or laparoscopic salpingectomy for an ectopic pregnancy followed by a subsequent IVF-ET cycle. MEASUREMENTS AND MAIN RESULTS: A total of 144 patients with sonographically confirmed ectopic pregnancies were identified during the study period. Of these, 107 (74.3%) patients were treated with MTX and 37 (25.7%) were treated with laparoscopic salpingectomy. Eighty-eight patients (82.2%) in the MTX group and 22 patients (59.4%) patients in the salpingectomy group underwent a subsequent IVF-ET cycle. There were no significant differences in demographic data or baseline cycle characteristics between the 2 groups. No difference was observed in basal follicle-stimulating hormone (FSH) level before and after MTX or salpingectomy treatment. Indicators of ovarian responsiveness, including total days of stimulation, total dosage of gonadotropins, and number of mature oocytes before and after either treatment, were comparable in the 2 groups. The number of doses of MTX (1 vs > 1) did not correlate with changes in ovarian response. The pregnancy outcomes, specifically live birth, were equivalent in the 2 groups. Comparing post-MTX cycles and post-salpingectomy cycles, patients in the latter group required higher doses of gonadotropins (+705 IU vs +221.5 IU; p < .01), although the number of mature oocytes remained similar in the 2 groups. CONCLUSION: Treatment of ectopic pregnancies with MTX or salpingectomy might not adversely affect ovarian reserve, ovarian responsiveness, or subsequent IVF cycle outcomes. However, in our study cohort, patients treated with MTX, those s treated with laparoscopic salpingectomy required higher gonadotropin doses in a subsequent cycle to attain the same number of mature oocytes. PMID- 25917280 TI - Electro-acupuncture effectiveness on labor pain management. PMID- 25917281 TI - Response to: "Electro-acupuncture effectiveness on labor pain management". PMID- 25917282 TI - [Confocal laser scanning microscopy]. AB - Reflectance confocal microscopy (RCM) allows the in vivo evaluation of melanocytic and nonmelanocytic skin tumours with high sensitivity and specificity. RCM represents an optical imaging technique, which enables us to examine the skin at high resolution. Today, RCM represents not only an interesting tool for dermatologic research but has also been introduced as a diagnostic tool in every day clinical practice. As such, RCM is applied for improvement of skin cancer diagnosis adjunct to clinical and dermatoscopic examination. In combination with dermatoscopy RCM has shown an increased specificity with similar sensitivity. In this regard RCM helps to decrease the rate of unnecessary biopsies of benign lesions. Despite its use in dermatooncology RCM may also be used for diagnosis and monitoring of inflammatory diseases. Future developments include technical improvements, teledermatology solutions and the application of ex vivo RCM in Moh's micrographic surgery. PMID- 25917283 TI - [Dermatology on international missions: Globalization of a medical specialty]. PMID- 25917284 TI - Translational treatment paradigm for managing non-unions secondary to radiation injury utilizing adipose derived stem cells and angiogenic therapy. AB - BACKGROUND: Bony non-unions arising in the aftermath of collateral radiation injury are commonly managed with vascularized free tissue transfers. Unfortunately, these procedures are invasive and fraught with attendant morbidities. This study investigated a novel, alternative treatment paradigm utilizing adipose-derived stem cells (ASCs) combined with angiogenic deferoxamine (DFO) in the rat mandible. METHODS: Rats were exposed to a bioequivalent dose of radiation and mandibular osteotomy. Those exhibiting non-unions were subsequently treated with surgical debridement alone or debridement plus combination therapy. Radiographic and biomechanical outcomes were assessed after healing. RESULTS: Significant increases in biomechanical strength and radiographic metrics were observed in response to combination therapy (p < .05). Importantly, combined therapy enabled a 65% reduction in persisting non-unions when compared to debridement alone. CONCLUSION: We support the continued investigation of this promising combination therapy in its potential translation for the management of radiation-induced bony pathology. (c) 2015 Wiley Periodicals, Inc. Head Neck 38: E837-E843, 2016. PMID- 25917286 TI - Facile synthesis of electrospun MFe2O4 (M = Co, Ni, Cu, Mn) spinel nanofibers with excellent electrocatalytic properties for oxygen evolution and hydrogen peroxide reduction. AB - Designing and preparing porous transition metal ferrites without using any template, shape-directing agent, and surfactant is a challenge. Herein, heterojunction MFe2O4 (M = Co, Ni, Cu, Mn) nanofiber (NF) based films with three dimensional configurations were synthesized by electrospinning and the subsequent thermal treatment processes. Characterization results indeed show the 3D net-like textural structures of the electrospun spinel-type MFe2O4 NFs. In particular, the resulting MFe2O4 NFs have lengths up to several dozens of micrometers with an average diameter size of about 150 nm and possess abundant micro/meso/macropores on both the surface and within the films. The hierarchically porous structures and high surface areas of these MFe2O4 NFs (for example, the CoFe2O4 NFs possess a larger BET specific surface area (61.48 m(2) g(-1)) than those of the CoFe2O4 NPs (5.93 m(2) g(-1))) can afford accessible transport channels for effectively decreasing the mass transport resistances, enhancing the electrical conductivity, and increasing the density and reactivity of the exposed catalytic active sites. All these advantages will be responsible for the better electrocatalytic performances of these MFe2O4 NFs compared with their structural isomers (i.e. the MFe2O4 NPs) for the oxygen evolution reaction (OER) and H2O2 reduction in alkaline solution. Meanwhile, both the OER and H2O2 reduction catalytic activities for these MFe2O4 NFs obey the order of CoFe2O4 NFs > CuFe2O4 NFs > NiFe2O4 NFs > MnFe2O4 NFs > Fe2O3 NFs. The CoFe2O4 NFs represent a new class of highly efficient non-noble-metal catalysts for both OER and H2O2 reduction/detection in alkaline media. PMID- 25917285 TI - Population structure and effective/census population size ratio in threatened three-spined stickleback populations from an isolated river basin in northwest Spain. AB - Variability at 20 microsatellite loci was examined to assess the population genetic structure, gene flow, and effective population size (N(e)) in three populations of three-spined stickleback (Gasterosteus aculeatus) from the upper basin of the Mino River in Galicia, NW Spain, where this species is threatened. The three populations showed similar levels of genetic diversity. There is a significant genetic differentiation between the three populations, but also significant gene flow. N(e) estimates based on linkage disequilibrium yielded values of 355 for the Mino River population and 241 and 311 for the Rato and Guisande Rivers, respectively, although we expect that these are overestimates. N(e) estimates based on temporal methods, considering gene flow or not, for the tributaries yielded values of 30-56 and 47-56 for the Rato and Guisande Rivers, respectively. Estimated census size (N(c)) for the Rato River was 880 individuals. This yielded a N(e)/N(c) estimate of 3-6 % for temporal estimation of N(e), which is within the empirical range observed in freshwater fishes. We suggest that the three populations analyzed have a sufficient level of genetic diversity with some genetic structure. Additionally, the absence of physical barriers suggests that conservation efforts and monitoring should focus in the whole basin as a unit. PMID- 25917287 TI - Nutrition among men and household food security in an internally displaced persons camp in Kenya. AB - OBJECTIVE: To determine the nutritional status of men and the food security status of their households in an internally displaced persons (IDP) camp in Kenya. DESIGN: A descriptive, cross-sectional study using a questionnaire and biometric measurements was completed in June 2013. SETTING: IDP camp, Rongai, Kenya. SUBJECTS: A total of 267 men aged >=18 years residing within the camp were recruited via respondent-driven sampling. Statistical associations between categorical variables were analysed using Pearson's chi 2 tests, while independent t tests were used for continuous variables. RESULTS: Among the men surveyed, we found a mean BMI of 20.3 (sd 2.5) kg/m2, with 23.9% of participants in the underweight category (BMI<18.5 kg/m2). The mean Individual Dietary Diversity Score was 6 out of a maximum score of 9. The mean Household Food Insecurity Access Scale score was 11.6 (sd 6.8), with 180 participants (71.7%) residing in households categorised as severely food insecure. Low monthly household income (<2000 Kenyan Shillings, or $US 25) was associated with a higher food insecurity score (P<0.001), greater likelihood of residing in a severely food-insecure household (P<0.001), low dietary diversity score (P<0.05) and being underweight (P<0.01). CONCLUSIONS: While the nutritional status of men in the IDP camp is comparable to non-displaced men in Kenya, household food insecurity is relatively high. Efforts to improve food security for the future are essential to minimise the impact of severe food insecurity on mental health, disease profiles and family well-being reported in other IDP settings. PMID- 25917289 TI - Inhibition of SN-38 glucuronidation by gefitinib and its metabolite. AB - Drug combinations including irinotecan and gefitinib have been evaluated in clinical trials. SN-38 is the active metabolite of irinotecan, and the increase in its concentration due to drug interactions will result in increased clinical toxicity. We aimed to investigate the effects of gefitinib and its predominant metabolite observed in human plasma, O-desmethyl-gefitinib (DMG), on SN-38 glucuronidation. Our data indicated that both gefitinib and DMG are potent inhibitors of SN-38 glucuronidation via UGT1A1 inhibition. It is predicted from in vitro data that gefitinib administered at 700 mg/day may result in about 149 % increase in SN-38 AUC, but there is no significant effects on SN-38 AUC at lower concentrations. Our prediction study provides a basis for design of clinical studies for the development and optimization of this combination. PMID- 25917288 TI - Methylthioadenosine phosphorylase (MTAP)-deficient T-cell ALL xenografts are sensitive to pralatrexate and 6-thioguanine alone and in combination. AB - PURPOSE: To investigate the effectiveness of a combination of 6-thioguanine (6 TG) and pralatrexate (PDX) in methylthioadenosine phosphorylase (MTAP)-deficient T-cell acute lymphoblastic leukemia (T-cell ALL). METHODS: CCRF-CEM (MTAP(-/-)) and Molt4 (MTAP(+/+)) T-cell ALL cell lines were treated with 6-TG or PDX and evaluated for efficacy 72 h later. NOD/SCID gamma mice bearing CEM or Molt4 xenografts were treated with 6-TG and PDX alone or in combination to evaluate antitumor effects. RESULTS: CEM cells were more sensitive to 6-TG and PDX in vitro than Molt4. In vivo, CEM cells were very sensitive to PDX and 6-TG, whereas Molt4 cells were highly resistant to 6-TG. A well-tolerated combination of PDX and 6-TG achieved significant tumor regression in CEM xenografts. CONCLUSIONS: The loss of MTAP expression may be therapeutically exploited in T-cell ALL. The combination of 6-TG and PDX, with the inclusion of leucovorin rescue, allows for a safe and effective regimen in MTAP-deficient T-cell ALL. PMID- 25917290 TI - Dissolved effluent organic matter: Characteristics and potential implications in wastewater treatment and reuse applications. AB - Wastewater reuse is currently considered globally as the most critical element of sustainable water management. The dissolved effluent organic matter (dEfOM) present in biologically treated urban wastewater, consists of a heterogeneous mixture of refractory organic compounds with diverse structures and varying origin, including dissolved natural organic matter, soluble microbial products, endocrine disrupting compounds, pharmaceuticals and personal care products residues, disinfection by-products, metabolites/transformation products and others, which can reach the aquatic environment through discharge and reuse applications. dEfOM constitutes the major fraction of the effluent organic matter (EfOM) and due to its chemical complexity, it is necessary to utilize a battery of complementary techniques to adequately describe its structural and functional character. dEfOM has been shown to exhibit contrasting effects towards various aquatic organisms. It decreases metal uptake, thus potentially reducing their bioavailability to exposed organisms. On the other hand, dEfOM can be adsorbed on cell membranes inducing toxic effects. This review paper evaluates the performance of various advanced treatment processes (i.e., membrane filtration and separation processes, activated carbon adsorption, ion-exchange resin process, and advanced chemical oxidation processes) in removing dEfOM from wastewater effluents. In general, the literature findings reveal that dEfOM removal by advanced treatment processes depends on the type and the amount of organic compounds present in the aqueous matrix, as well as the operational parameters and the removal mechanisms taking place during the application of each treatment technology. PMID- 25917291 TI - Predictors of short- and long-term avoidance in completers of inpatient group interventions for agoraphobia. AB - BACKGROUND: Little is currently known about predictors of follow-up outcome of psychological treatment of agoraphobia. In this study, we wished to examine predictors of short- and long-term avoidance after inpatient group interventions for agoraphobia. METHODS: Ninety-six (68%) of 141 agoraphobic patients (74% women) who had completed treatment in two open and one randomized controlled trial (RCT) were followed up 13 to 21 years after start of treatment. RESULTS: Major depression at pre-treatment predicted less short-term (up to one year after end of treatment) improvement in agoraphobic avoidance. Working and being married/cohabiting at pre-treatment predicted greater long-term (across one-year, two-year, and 13-21 years follow-up) improvement. In contrast, the duration of agoraphobia, amount of Axis I and II co-morbidity, being diagnosed with avoidant, dependent, and obsessive-compulsive personality disorder, and the use of antidepressants and benzodiazepines the month before intake to treatment, were unrelated to short-term as well as long-term outcome. LIMITATIONS: As many as 31.9% of the included patients did not attend long-term follow-up and the power of the study was limited. The long time period between the two and 13-21 year follow-ups is a limitation, in which it is difficult to assess what actually happened. Although all the patients received some form of CBT, there was variability among the treatments. CONCLUSIONS: The only short-term predictor identified represented a clinical feature, whereas the long-term predictors represented features of the patients' life situation. The limited power of the study precludes the inference that non-significant predictors are unrelated to follow-up outcome. PMID- 25917292 TI - Mental health self-management questionnaire: Development and psychometric properties. AB - BACKGROUND: Through self-management, people living with depression, anxiety or bipolar disorders can play an active role in their recovery. However, absence of a validated questionnaire limits empirical research on self-management. The study aimed to develop a French instrument, the Mental Health Self-Management Questionnaire (MHSQ), and to investigate its psychometric properties METHODS: A pool of 86 items was created based on a qualitative study with 50 people in recovery from depression, anxiety or bipolar disorders. The 64 most pertinent items were identified following ratings from 14 experts. A sample of 149 people in recovery completed these items and criterion-related measures (specific aspects of self-management, clinical and personal recovery, social desirability), and 93 participants also completed MHSQ two weeks later RESULTS: Exploratory and confirmatory factor analyses show that MHSQ is composed of three subscales: Clinical (getting help and using resources), Empowerment (building upon strengths and positive self-concept to gain control) and Vitality (active and healthy lifestyle). These subscales had satisfying consistency and test-retest reliability, and were mostly unrelated to social desirability. Correlations with criterion variables support convergent and concurrent validity, especially for Empowerment and Vitality. Comparison of structural models provides evidence of the distinct nature of MHSQ in comparison to the constructs of clinical and personal recovery LIMITATIONS: Longitudinal studies with larger samples are needed to explore the validity of MHSQ for predicting recovery over time CONCLUSION: MHSQ is a psychometrically-sound instrument, useful for establishing the role of self-management in recovery and monitoring the efficacy of self management support programs. PMID- 25917293 TI - Moderation of antidepressant and placebo outcomes by baseline severity in late life depression: A systematic review and meta-analysis. AB - BACKGROUND: Baseline severity is a crucial moderator of trial outcomes in adult depression, with the advantage of antidepressants over placebo increasing as severity increases. However, this relationship has not been examined in late-life depression. METHODS: PubMed, Embase, Web of Science, PsycINFO, and Cochrane were searched for studies published through September 2014. Randomized, acute phase, and double-blind studies comparing an antidepressant group with a placebo group in depressed elderly patients were included. RESULTS: Nineteen studies met all inclusion criteria. Within-group effect sizes revealed significant improvement in antidepressant groups (g=1.35, p<.000), as well as in placebo groups (g=.96, p<.000). Change in depressive symptoms assessed by Hamilton Depression Rating Scale (HDRS) was moderated by baseline severity in antidepressant groups (Z=2.67, p=.008) and placebo groups (Z=4.46, p<.000). However, this would be expected as a result of regression toward the mean, and mean differences between groups did not increase (r=.19, p=.469) as a function of baseline severity. LIMITATIONS: Limited to published data and information was only analyzed at the level of treatment groups. CONCLUSION: Baseline severity was not associated with an antidepressant placebo difference and placebo responses are large in the treatment of depressed elderly people. We propose a stepwise approach, i.e., to initially offer elderly depressed patients psychosocial interventions and only consider antidepressants if patients do not respond. PMID- 25917294 TI - Posttraumatic and depressive symptoms in beta-endorphin dynamics. AB - A disturbed beta-endorphin system can be a part of the post-traumatic stress disorder (PTSD) and depression allostasis. Study subjects (N=392) included those with PTSD and/or (stress-induced) depression, and healthy controls with and without traumas. The aim of the study was to examine the network of relations centered around plasma beta-endorphin. The network included anxiety (as a personality trait), traumatic events, pain, aggressiveness, depressive symptoms, and three clusters of PTSD symptoms: intrusions, avoidance, and hyperarousal. Beta-endorphin was represented by individual mean from 13 time points (BEmean), reflecting the total amount of the peripherally secreted hormone, and the coefficient of variation (BEvar), calculated as the ratio of standard deviation to the mean, reflecting the hormone's dynamics. BEvar correlated with all other variables, BEmean had no correlations. Structural equation modeling (SEM) was used to examine all interrelations (including their directions) of BEvar and the state/trait variables in the context of their entirety. The model revealed that hyperarousal and anxiety were the only direct agents of peripheral beta-endorphin fluctuations, mediating the effects of other variables. Traumatic events and intrusions act on BEvar via hyperarousal, while depressive symptoms, avoidance, and pain act via anxiety. Hyperarousal should be emphasized as the main agent not only because its effect on BEvar is larger than that of anxiety, but also because it increases anxiety itself (via avoidance and pain). All influences on BEvar are positive and they indicate long-term (sensitizing) effects (as opposed to direct stimulation, for example, by acute pain, anger, etc.). Relations apart from beta endorphin are also discussed. PMID- 25917295 TI - Intensive short-term dynamic residential treatment program for patients with treatment-resistant disorders. AB - BACKGROUND: The study investigated the effectiveness of an Intensive Short-Term Dynamic (ISTDP) residential treatment program for patients with treatment resistant anxiety- and/or depressive disorders, with and without comorbid personality disorders. METHOD: A non-randomized controlled trial examined the effects of an eight week intensive residential treatment program based on principles from ISTDP. Patients (N=60), who had repeated prior treatment failure for current mental disorder, sufficient dysfunction to warrant hospitalization, and evidencing capacity to take an intrapsychic perspective on own problems, were included. Outcome variables included measures of target complaints (depression/anxiety, social role dysfunction, and interpersonal distress), general symptom distress, and interpersonal functioning. Measures were administered throughout and after treatment. Change was assessed by multilevel growth curve modeling. Changes during and after treatment were compared to those reported by a sub-sample of wait-list controls taking treatment as usual (N=30). RESULTS: The treatment group evidenced significant improvements on all measures. By contrast, receiving treatment as usual while on the wait-list did not yield significant changes. Effect sizes in the treatment group were consistently large at both termination and follow-up. Fourteen months after treatment 50.0% of patients had recovered in terms of target complaints. Approximately 53.3% and 48.3%, respectively, had recovered in terms of general symptom distress and interpersonal functioning. LIMITATIONS: Limitations included a relatively small sample size, inability to discern the effectiveness of separate components of the treatment program, and lack of randomization of patients to wait-list and treatment. CONCLUSION: ISTDP-based residential treatment with an eight-week time limit appears to be effective for alleviating common and severe, treatment resistant mental disorders. The treatment program was superior to receiving treatment as usual while on the wait-list. Participation in the program quickly reduced target complaints, symptoms and interpersonal problems for patients who, based on previous treatment experiences, were expected to fare poorly in treatment. Gains were consistently maintained or improved further at follow-up. Results are promising for patients with chronic debilitating problems who often do not profit from traditional psychiatric treatment. PMID- 25917296 TI - HEPeak: an HMM-based exome peak-finding package for RNA epigenome sequencing data. AB - BACKGROUND: Methylated RNA Immunoprecipatation combined with RNA sequencing (MeRIP-seq) is revolutionizing the de novo study of RNA epigenomics at a higher resolution. However, this new technology poses unique bioinformatics problems that call for novel and sophisticated statistical computational solutions, aiming at identifying and characterizing transcriptome-wide methyltranscriptome. RESULTS: We developed HEP, a Hidden Markov Model (HMM)-based Exome Peak-finding algorithm for predicting transcriptome methylation sites using MeRIP-seq data. In contrast to exomePeak, our previously developed MeRIP-seq peak calling algorithm, HEPeak models the correlation between continuous bins in an m6A peak region and it is a model-based approach, which admits rigorous statistical inference. HEPeak was evaluated on a simulated MeRIP-seq dataset and achieved higher sensitivity and specificity than exomePeak. HEPeak was also applied to real MeRIP-seq datasets from human HEK293T cell line and mouse midbrain cells and was shown to be able to recapitulate known m6A distribution in transcripts and identify novel m6A sites in long non-coding RNAs. CONCLUSIONS: In this paper, a novel HMM-based peak calling algorithm, HEPeak, was developed for peak calling for MeRIP-seq data. HEPeak is written in R and is publicly available. PMID- 25917298 TI - Carbonylative coupling of allylic acetates with aryl boronic acids. AB - The first allylic carbonylation reaction of allylic acetates with aryl boronic acids under carbon monoxide has been developed. Using Pd-PCy3 as a catalyst, a wide spectrum of allylic acetates was carbonylated in the presence of various aryl boronic acids, affording alpha,beta-unsaturated aryl ketones in good to excellent yields. Preliminary studies indicate that carbon monoxide always inserts at the least substituted terminal allylic carbon and the resulting beta,gamma-unsaturated aryl ketones generally isomerise to the ketones obtained. PMID- 25917297 TI - Exhaled breath temperature measurement and asthma control in children prescribed inhaled corticosteroids: A cross sectional study. AB - BACKGROUND: Exhaled breath temperature (EBT) reflects airways (both eosinophilic and neutrophilic) inflammation in asthma and thus may aid the management of children with asthma that are treated with anti-inflammatory drugs. A new EBT monitor has become available that is cheap and easy to use and may be a suitable monitoring device for airways inflammation. Little is known about how EBT relates to asthma treatment decisions, disease control, lung function, or other non invasive measures of airways inflammation, such as exhaled nitric oxide (ENO). OBJECTIVE: To determine the relationships between EBT and asthma treatment decision, current control, pulmonary function, and ENO. METHODS: Cross-sectional prospective study on 159 children aged 5-16 years attending a pediatric respiratory clinic. EBT was compared with the clinician's decision regarding treatment (decrease, no change, increase), asthma control assessment (controlled, partial, uncontrolled), level of current treatment (according to British Thoracic Society guideline, BTS step), ENO, and spirometry. RESULTS: EBT measurement was feasible in the majority of children (25 of 159 could not perform the test) and correlated weakly with age (R = 0.33, P = <0.01). EBT did not differ significantly between the three clinician decision groups (P = 0.42), the three asthma control assessment groups (P = 0.9), or the current asthma treatment BTS step (P = 0.57). CONCLUSIONS & CLINICAL IMPLICATIONS: EBT measurement was not related to measures of asthma control determined at the clinic. The routine intermittent monitoring of EBT in children prescribed inhaled corticosteroids who attend asthma clinics cannot be recommended for adjusting anti-inflammatory asthma therapy. PMID- 25917299 TI - Comparison of gene expression of Toll-like receptors and antimicrobial peptides in immune organs and tissues between Yorkshire and Tibetan pigs. AB - Toll-like receptors (TLRs), an important family of pattern-recognition receptors, and antimicrobial peptides (AMPs) contribute to the first line of innate protection of mammals against microbes. To compare characteristics of innate immunity between Tibetan and Yorkshire pigs, we investigated the mRNA abundance of TLR genes (TLR1-TLR9) and two AMP-encoding genes (PBD-1 and PR-39) in thymus, spleen, blood, palatine tonsils, and mesenteric and pulmonary hilar lymph nodes of the two breeds at ages of 6, 12 and 24 weeks using quantitative real-time PCR. Results showed that all mRNAs were detected in all tissues. Transcript levels of the major TLR genes of Tibetan pigs were significantly higher than those of Yorkshires in most tissues of the immune system, with a higher abundance of porcine (PBD-1) (beta-defensin-1) and PR-39 mRNA in lymphoid organs and tissues, especially blood, palatine tonsils, and mesenteric and pulmonary hilar lymph nodes. Our data suggest that Tibetan pigs have stronger innate immunity for triggering local and/or systemic immune responses to eliminate infections with pathogenic microorganisms. PMID- 25917300 TI - Genome-wide methylation study of diploid and triploid brown trout (Salmo trutta L.). AB - The induction of triploidization in fish is a very common practice in aquaculture. Although triploidization has been applied successfully in many salmonid species, little is known about the epigenetic mechanisms implicated in the maintenance of the normal functions of the new polyploid genome. By means of methylation-sensitive amplified polymorphism (MSAP) techniques, genome-wide methylation changes associated with triploidization were assessed in DNA samples obtained from diploid and triploid siblings of brown trout (Salmo trutta). Simple comparative body measurements showed that the triploid trout used in the study were statistically bigger, however, not heavier than their diploid counterparts. The statistical analysis of the MSAP data showed no significant differences between diploid and triploid brown trout in respect to brain, gill, heart, liver, kidney or muscle samples. Nonetheless, local analysis pointed to the possibility of differences in connection with concrete loci. This is the first study that has investigated DNA methylation alterations associated with triploidization in brown trout. Our results set the basis for new studies to be undertaken and provide a new approach concerning triploidization effects of the salmonid genome while also contributing to the better understanding of the genome-wide methylation processes. PMID- 25917301 TI - A genome-wide scan for copy number variations using high-density single nucleotide polymorphism array in Simmental cattle. AB - Copy number variations (CNVs) have recently been identified as promising sources of genetic variation, complementary to single nucleotide polymorphisms (SNPs). As a result, detection of CNVs has attracted a great deal of attention. In this study, we performed genome-wide CNV detection using Illumina Bovine HD BeadChip (770k) data on 792 Simmental cattle. A total of 263 CNV regions (CNVRs) were identified, which included 137 losses, 102 gains and 24 regions classified as both loss and gain, covering 35.48 Mb (1.41%) of the bovine genome. The length of these CNVRs ranged from 10.18 kb to 1.76 Mb, with an average length of 134.78 kb and a median length of 61.95 kb. In 136 of these regions, a total of 313 genes were identified related to biological functions such as transmembrane activity and olfactory transduction activity. To validate the results, we performed quantitative PCR to detect nine randomly selected CNVRs and successfully confirmed seven (77.6%) of them. Our results present a map of cattle CNVs derived from high-density SNP data, which expands the current CNV map of the cattle genome and provides useful information for investigation of genomic structural variation in cattle. PMID- 25917302 TI - Transcriptome analysis of adiposity in domestic ducks by transcriptomic comparison with their wild counterparts. AB - Excessive adiposity is a major problem in the duck industry, but its molecular mechanisms remain unknown. Genetic comparisons between domestic and wild animals have contributed to the exploration of genetic mechanisms responsible for many phenotypic traits. Significant differences in body fat mass have been detected between domestic and wild ducks. In this study, we used the Peking duck and Anas platyrhynchos as the domestic breed and wild counterpart respectively and performed a transcriptomic comparison of abdominal fat between the two breeds to comprehensively analyze the transcriptome basis of adiposity in ducks. We obtained approximately 350 million clean reads; assembled 61 250 transcripts, including 23 699 novel ones; and identified alternative 5' splice sites, alternative 3' splice sites, skipped exons and retained intron as the main alternative splicing events. A differential expression analysis between the two breeds showed that 753 genes exhibited differential expression. In Peking ducks, some lipid metabolism-related genes (IGF2, FABP5, BMP7, etc.) and oncogenes (RRM2, AURKA, CYR61, etc.) were upregulated, whereas genes related to tumor suppression and immunity (TNFRSF19, TNFAIP6, IGSF21, NCF1, etc.) were downregulated, suggesting adiposity might closely associate with tumorigenesis in ducks. Furthermore, 280 576 single-nucleotide variations were found differentiated between the two breeds, including 8641 non-synonymous ones, and some of the non-synonymous ones were found enriched in genes involved in lipid associated and immune-associated pathways, suggesting abdominal fat of the duck undertakes both a metabolic function and immune-related function. These datasets enlarge our genetic information of ducks and provide valuable resources for analyzing mechanisms underlying adiposity in ducks. PMID- 25917303 TI - Mitochondrial DNA analysis of medieval sheep (Ovis aries) in central Italy reveals the predominance of haplogroup B already in the Middle Ages. AB - We retrieved 34 medieval ovicaprine remains, from three archaeological sites of central Italy dating to about 1000 years old, and analyzed them using mitochondrial DNA. We compared the reconstructed haplogroups with modern sheep samples from Europe and the Middle East and sequences from the literature. In modern sheep, haplogroup HA is present in countries with access to the Mediterranean and close to the domestication center, whereas it is very rare or absent in the rest of Europe. The haplogroup HB was predominant in ancient samples (90%), whereas haplogroup HA was found at 10%. Ancient haplogroups match the present distribution in modern sheep in Italy, indicating that the current proportion of HA/HB was already established in the Middle Ages and is not the result of subsequent events such as selective breeding practices. PMID- 25917304 TI - An ancient interlocus recombination increases class II MHC DQA diversity in sheep and other Bovidae. AB - Animals with fully characterised major histocompatibility complex (MHC) regions are often used to explore the molecular interactions that control the induction of adaptive immunity. The ovine MHC includes two DQA loci, termed DQA1 and DQA2. However, in a minority of haplotypes the DQA1 locus appears absent (DQA1 null) and is replaced by a second locus termed, DQA2-like. This raises a number of questions regarding the origins and function of the DQA2-like sequences. To address this, we have analysed DQA diversity associated with 10 MHC haplotypes, including two classified as DQA1 null. Pair-wise comparison between full-length DQA transcripts from each haplotype identified unique diversity throughout the DQA2-like sequences. Conserved orthologues of the DQA2-like sequences were identified in cattle and goat, and phylogenetic analysis clustered exons 1 and 2 with DQA2 whereas the remainder of the sequence clustered with DQA1. The DQA2 like allelic lineage appears functional and to have arisen from an ancient interlocus recombination between DQA1 and DQA2 loci which predates Bovidae speciation. PMID- 25917305 TI - Paternal phylogeography and genetic diversity of East Asian goats. AB - This study was a first analysis of paternal genetic diversity for extensive Asian domestic goats using SRY gene sequences. Sequencing comparison of the SRY 3' untranslated region among 210 Asian goats revealed four haplotypes (Y1A, Y1B, Y2A and Y2B) derived from four variable sites including a novel substitution detected in this study. In Asian goats, the predominant haplotype was Y1A (62%) and second most common was Y2B (30%). Interestingly, the Y2B was a unique East Asian Y chromosomal variant, which differentiates eastern and western Eurasian goats. The SRY geographic distribution in Myanmar and Cambodia indicated predominant the haplotype Y1A in plains areas and a high frequency of Y2B in mountain areas. The results suggest recent genetic infiltration of modern breeds into South-East Asian goats and an ancestral SRY Y2B haplotype in Asian native goats. PMID- 25917306 TI - The DMRT3 gene mutation in Chinese horse breeds. PMID- 25917307 TI - Role of the PRNP S127 allele in experimental infection of goats with classical caprine scrapie. PMID- 25917308 TI - Tuning the magnetic properties of Co-ferrite nanoparticles through the 1,2 hexadecanediol concentration in the reaction mixture. AB - This work reports on the effect of the 1,2-hexadecanediol content on the structural and magnetic properties of CoFe2O4 nanoparticles synthesized by thermal decomposition of metal-organic precursors in 1-octadecene. Although pseudo-spherical particles having an average size of about 8 nm and similar stoichiometry have been observed in all studied samples, a high level of variability in the crystal quality and, in turn, in the magnetic properties has been found as a function of the amount of 1,2-hexadecanediol added to the reaction mixture. The magnetic study reveals that samples progress from glassy magnetic behavior to bulk-like, ferrimagnetic order as the crystal quality improves. The analysis of the reaction mixtures by Fourier transform infrared spectroscopy at various stages of the reaction shows the key role of the 1,2 hexadecanediol in favoring the decomposition of the metal-organic precursor, formation of an intermediate Co(2+)Fe(3+)-oleate complex and, finally, the nucleation of nanoparticles at lower temperatures. PMID- 25917309 TI - Core-shell polydopamine magnetic nanoparticles as sorbent in micro-dispersive solid-phase extraction for the determination of estrogenic compounds in water samples prior to high-performance liquid chromatography-mass spectrometry analysis. AB - In this work, core-shell Fe3O4@poly(dopamine) magnetic nanoparticles (m-NPs) were prepared and characterized in our laboratory and applied as sorbents for the magnetic-micro solid phase extraction (m-MUSPE) of twelve estrogenic compounds of interest (i.e. 17alpha-estradiol, 17beta-estradiol, estrone, hexestrol, 17alpha ethynylestradiol, diethylstibestrol, dienestrol, zearalenone, alpha-zearalanol, beta-zearalanol, alpha-zearalenol and beta-zearalenol) from different water samples. Separation, determination and quantification were achieved by high performance liquid chromatography coupled to ion trap mass spectrometry with electrospray ionization. NPs@poly(dopamine) were synthesized by a chemical coprecipitation procedure and characterized by different surface characterization techniques (X-ray diffraction, X-ray photoelectron spectroscopy, thermogravimetric analysis, transmission and scanning electron microscopy, infrared and Raman spectroscopy, vibrating sample magnetometry, microelectrophoresis and adsorption/desorption isotherms). Parameters affecting the extraction efficiency of m-MUSPE (i.e. polymerization time, pH of the sample, extraction and elution conditions) were studied and optimized. The methodology was validated for Milli-Q, mineral, tap and wastewater using 2-methoxyestradiol as internal standard, obtaining recoveries ranging from 70 to 119% with relative standard deviation values lower than 20% and limits of quantification in the range 0.02-1.1 MUg/L. PMID- 25917310 TI - Treadmill exercise enhances synaptic plasticity, but does not alter beta-amyloid deposition in hippocampi of aged APP/PS1 transgenic mice. AB - Several studies reveal that the beneficial effects of exercise interventions are dependent on the progression of Alzheimer's disease (AD). We have previously shown that long-term treadmill exercise begun before the onset of beta-amyloid (Abeta) pathology prevents the deficits of cognition and long-term potentiation (LTP) in amyloid precursor protein (APP)/presenilin 1 (PS1) transgenic mice (8 months of age) paralleled by the reduction of soluble Abeta levels and Abeta deposition in the hippocampus. In the present study, treadmill exercise was initiated at a developed Abeta deposition stage in order to further investigate whether or not treadmill exercise in this phase can delay the progression of AD in aged APP/PS1 mice (17 months of age). Our results show that 5-month treadmill exercise ameliorates the impairment of spatial learning and memory with age paralleled by synaptic plasticity enhancement in aged APP/PS1 mice. In addition, exercise-induced enhancement of synaptic plasticity was accompanied by a significant reduction of soluble Abeta levels rather than Abeta plaque deposition. Therefore, the investigation demonstrates that long-term treadmill exercise has beneficial effects on cognition and synaptic plasticity even when the brain has developed Abeta deposition, and changes in soluble Abeta levels rather than Abeta plaque deposition may contribute to exercise-induced benefits. PMID- 25917311 TI - Chromatographic behavior of small organic compounds in low-temperature high performance liquid chromatography using liquid carbon dioxide as the mobile phase. AB - Low-temperature high-performance liquid chromatography, in which a loop injector, column, and detection cell were refrigerated at -35oC, using liquid carbon dioxide as the mobile phase was developed. Small organic compounds (polyaromatic hydrocarbons, alkylbenzenes, and quinones) were separated by low-temperature high performance liquid chromatography at temperatures from -35 to -5oC. The combination of liquid carbon dioxide mobile phase with an octadecyl-silica (C18 ) column provided reversed phase mode separation, and a bare silica-gel column resulted in normal phase mode separation. In both the cases, nonlinear behavior at approximately -15oC was found in the relationship between the temperature and the retention factors of the analytes (van't Hoff plots). In contrast to general trends in high-performance liquid chromatography, the decrease in temperature enhanced the separation efficiency of both the columns. PMID- 25917312 TI - A temporal context repetition effect in rats during a novel object recognition memory task. AB - Recent research in humans has used formal models of temporal context, broadly defined as a lingering representation of recent experience, to explain a wide array of recall and recognition memory phenomena. One difficulty in extending this work to studies of experimental animals has been the challenge of developing a task to test temporal context effects on performance in rodents. The current study presents results from a novel object recognition memory paradigm that was adapted from a task used in humans and demonstrates a temporal context repetition effect in rats. Specifically, the findings indicate that repeating the first two objects from a once-encountered sequence of three objects incidentally cues memory for the third object, even in its absence. These results reveal that temporal context influences item memory in rats similar to the manner in which it influences memory in humans and also highlight a new task for future studies of temporal context in experimental animals. PMID- 25917313 TI - Defining, Treating, and Understanding Chronic Kidney Disease--A Complex Disorder. AB - Chronic kidney disease (CKD) is prevalent in more than 20 million people in the United States. The majority of care provided to patients with this disease comes from primary care physicians, although it is often poorly understood. After an extensive literature review, it is clear that it can be difficult to classify and there are many barriers to care. Risk factors for both incident CKD and disease progression include hypertension, poor glycemic control, sociodemographic factors, acute kidney injury, metabolic acidosis, and possibly hyperuricemia and dietary factors. Treatment of patients with CKD should focus on mitigating risk factors, as well as common comorbidities such as cardiovascular disease, anemia, and bone mineral disease. Novel therapies such as pirfenidone, pentoxifylline, and endothelin-1 antagonists are being investigated with promising results. PMID- 25917314 TI - Human Adenovirus Diversity in Water Samples Using a Next-Generation Amplicon Sequencing Approach. AB - This study aims to establish a straightforward and original workflow for high throughput typing of human adenoviruses (HAdVs) in environmental samples. Occurrence of HAdVs in water is well documented worldwide, but data on diversity of HAdV types circulating in water are scarcely available. Here, the characterisation of viral particles was performed by determination of amplicon sequences using a next-generation sequencing (NGS) approach. Adenoviral DNA was either directly isolated from wastewater or river water concentrates or after a cell culture passage. Genome amplification targeted a hyper variable region of the hexon gene, allowing the discrimination of the 54 human adenoviral types described until now. After read generation on the benchtop MiSeq platform (Illumina), data were analysed using the Mothur software for identification of all HAdV species and types simultaneously present in a unique sample. NGS results showed a relatively wide HAdV diversity of up to six types in one sample, whereas Sanger sequencing always only retrieved the dominant one. Detected types included HAdV-1, HAdV-2, HAdV-3, HAdV-6, HAdV-12, HAdV-31, HAdV-40 and HAdV-41, HAdV-41 being the most abundant in tested samples. In addition, the influence of the cell line (A549 vs 293A cells) on the infectious HAdV typing results was clearly determined. The 293A appeared to be the most suitable cell line allowing the detection of a larger diversity of infectious HAdVs and reflecting a more realistic initial species distribution than using the A549 cells. These findings demonstrated the feasibility of amplicon sequencing NGS approach to identify viruses in complex environmental water samples. PMID- 25917315 TI - Comparison of three methods for measuring psoriasis severity in clinical studies (Part 1 of 2): change during therapy in Psoriasis Area and Severity Index, Static Physician's Global Assessment and Lattice System Physician's Global Assessment. AB - BACKGROUND: Accurate and reliable assessment of changes in psoriasis severity is critical in clinical trials of therapies. OBJECTIVE: To compare Psoriasis Area and Severity Index (PASI), static Physician's Global Assessment (sPGA), and the Lattice System Physician's Global Assessment (LS-PGA) in a trial of systemic treatments for plaque psoriasis vulgaris and to assess whether they measure change in psoriasis induced by therapy. METHODS: Patients were randomized to voclosporin or cyclosporine for 24 weeks (the '24-week-treatment' group, n = 366), or placebo for 12 weeks followed by voclosporin for 12 weeks (the 'initial placebo' group, n = 89). RESULTS: All scoring systems changed in concert and were sensitive enough to detect reductions in severity during placebo therapy as well as with active therapy (P < 0.01 for each measurement). At study onset, there were poorer correlations of sPGA with PASI (r = 0.45) and LS-PGA (r = 0.39) than between PASI and LS-PGA (r = 0.68). After therapy, all correlations were stronger, but sPGA continued to be less well correlated (with PASI, r = 0.85; with LS-PGA, r = 0.79) than LS-PGA with PASI (r = 0.90). Two- or three-step improvements in LS-PGA showed very good to excellent accuracy in corresponding to PASI-50 and PASI-75, respectively, and were more accurate than comparable changes in sPGA. CONCLUSION: PASI, sPGA and LS-PGA are responsive to the varying degrees of improvement in psoriasis induced by either placebo or active therapy. While the three systems capture similar information, each has different reasons for use in a clinical trial. PMID- 25917316 TI - New role of irisin in hepatocytes: The protective effect of hepatic steatosis in vitro. AB - Irisin is a newly identified myokine related to exercise and the browning of white fat. Recently, it was reported that irisin serum levels are associated with intrahepatic triglyceride content, suggesting that it might have an important role in the liver. The aim of this study was to determine the role of irisin in hepatocytes. Specifically, the effect of recombinant irisin on palmitic acid (PA) induced lipogenesis and its related signal pathways were examined in AML12 cells and mouse primary hepatocytes. In the present study, we observed the presence of irisin inside the cells in response to the treatment of recombinant irisin by flow cytometry and cell imaging technique. Recombinant irisin significantly inhibited the PA-induced increase in lipogenic markers ACC and FAS at the mRNA and protein levels, and prevented the PA-induced lipid accumulation in hepatocytes. Additionally, irisin inhibited the PA-induced increase in the expression, nuclear localization, and transcriptional activities of the master regulators of lipogenesis (LXRalpha and SREBP-1c). Moreover, irisin attenuated PA induced oxidative stress, which was confirmed by measuring the expression of inflammatory markers (NFkappaB, COX-2, p38 MAPK, TNF, IL-6) and superoxide indicator (dihydroethidium). The preventive effects of irisin against lipogenesis and oxidative stress were mediated by the inhibition of protein arginine methyltransferase-3 (PRMT3). These findings suggested that irisin might have a beneficial role in the prevention of hepatic steatosis by altering the expression of lipogenic genes and attenuating oxidative stress in a PRMT3 dependent manner. PMID- 25917317 TI - MiR-205 and miR-218 expression is associated with carboplatin chemoresistance and regulation of apoptosis via Mcl-1 and Survivin in lung cancer cells. AB - Lung cancer chemoresistance is the most frequent barrier in lung cancer therapy. Recent studies have indicated that microRNAs play a significant role in this mechanism and can function as either tumor suppressor or tumor promoters. However the effect of miRNA in lung cancer chemoresistance is poorly understood. Therefore, in the present study we investigated the role of two distinct miR members, the miR-205 and the tumor suppressor miR-218 in the proliferation, invasion and induction of apoptosis in lung cancer cells after carboplatin treatment. The results showed that miR-205 overexpression in A549 and H1975 lung cancer cells is concurrent with the down regulation of miR-218 and in linked with carboplatin sensitivity and chemoresistance. Interestingly, ectopic miR-218 overexpression reduced cell proliferation, invasion and migration of lung cancer cells, whereas miR-205 rescued the suppressive effect of miR-218 by altering the expression levels of the pro-apoptotic proteins PARP, Caspase 3, Bax and upregulating the anti-apoptotic markers Mcl-1 and Survivin. Taken together our findings imply that the miRNAs miR-205 and miR-218 play a key role in the development of lung cancer acquired chemoresistance and the tumor suppressor role of miR-218 in inhibiting lung cancer cell tumorigenesis and overcoming platinum chemoresistance is significant for future cancer therapeutic approaches. PMID- 25917318 TI - Enhancer of zeste homolog-2 (EZH2) methyltransferase regulates transgelin/smooth muscle-22alpha expression in endothelial cells in response to interleukin-1beta and transforming growth factor-beta2. AB - Smooth muscle-22alpha (SM22alpha), encoded by transgelin (TAGLN), is expressed in mesenchymal lineage cells, including myofibroblasts and smooth muscle cells. It is an F-actin binding protein that regulates the organization of actin cytoskeleton, cellular contractility and motility. SM22alpha is crucial for the maintenance of smooth muscle cell phenotype and its function. SM22alpha is also expressed in the processes of mesenchymal transition of epithelial (EMT) or endothelial cells (EndMT). The expression of TAGLN/SM22alpha is induced by transforming growth factor-beta (TGFbeta) signaling and enhanced by concomitant interleukin-1beta (IL-1beta) signaling. We investigated the epigenetic regulation of TAGLN expression by enhancer of zeste homolog-2 (EZH2), the methyltransferase of Polycomb, in the context of TGFbeta and IL-1beta signaling in endothelial cells. We demonstrate that the expression of EZH2 in endothelial cells was regulated by the inflammatory cytokine IL-1beta. A decrease in both expression and activity of EZH2 led to an increase in TAGLN expression. Inhibition of EZH2 augmented TGFbeta2-induced SM22alpha expression. The decrease of EZH2 levels in endothelial cells co-stimulated with IL-1beta and TGFbeta2 correlated with decreased H3K27me3 levels at the TAGLN proximal promoter. Moreover, the SM22alpha expression increased. Taken together, this suggests that EZH2 regulates the chromatin structure at the TAGLN promoter through tri-methylation of H3K27. EZH2 therefore acts as an epigenetic integrator of IL-1beta and TGFbeta2 signaling, providing an example of how cellular signaling can be resolved at the level of epigenetic regulation. Since IL-1beta and TGFbeta2 represent the pro-inflammatory and pro-fibrotic conditions during vascular fibroproliferative disease, we surmise that EZH2, as the molecule that integrates their signaling, could also be a promising target for development of future therapy. PMID- 25917319 TI - Individual differences in resting heart rate variability moderate thought suppression success. AB - Individual differences in heart rate variability (HRV) at rest are thought to represent an individual's capacity for self-regulation, but it remains unclear whether HRV predicts control over unwanted thoughts. The current study used a thought suppression paradigm in which participants recorded occurrences of a personally relevant intrusive thought over three monitoring periods. Among those instructed to suppress, higher levels of HRV were associated with greater declines in intrusions across the monitoring periods; no such relationship was found among those assigned to a control condition. Resting HRV also interacted with spontaneous thought suppression effort to predict intrusive thought frequency. In both cases, these HRV-related differences in thought suppression success predicted the generalized distress symptoms common to depression and anxiety. These findings enhance understanding of the relationships between HRV and cognitive control and highlight how individual differences in self-regulatory capacity impact thought suppression success and emotion regulation. PMID- 25917320 TI - A new simple chromo-fluorogenic probe for NO2 detection in air. AB - A new chromo-fluorogenic probe, consisting of a biphenyl derivative containing both a silylbenzyl ether and a N,N-dimethylamino group, for NO2 detection in the gas phase has been developed. A clear colour change from colourless to yellow together with an emission quenching was observed when the probe reacted with NO2 . A limit of detection to the naked eye of about 0.1 ppm was determined and the system was successfully applied to the detection of NO2 in realistic atmospheric conditions. PMID- 25917321 TI - Comparative effects of Aliskiren and Telmisartan in high fructose diet-induced metabolic syndrome in rats. AB - Fructose is a commonly used sweetener associated with diets that increase the prevalence of metabolic syndrome (MS). Inhibition of the renin-angiotensin system (RAS) has been consistently demonstrated to reduce MS. However, there has been no direct comparison among different pharmacological modes of inhibiting the RAS concerning their effects on MS. This study investigated the effect of aliskiren, a direct renin inhibitor, versus telmisartan, an angiotensin II-receptor blocker, in the treatment of fructose-induced MS in rats. MS was induced by high fructose (FRC) diet feeding for 12 weeks. Oral administrations of telmisartan (TEL, 5 mg/kg), aliskiren (ALS, 30 mg/kg) or vehicle were started in the last 4 weeks. Results showed that administration of either TEL or ALS with FRC diet equally ameliorated the metabolic parameters (glucose level, oral glucose tolerance test, insulin resistance and serum lipids profile), systolic blood pressure and oxidative stress markers (malondialdehyde, nitric oxide, reduced glutathione levels and catalase activity). Additionally, the effects of TEL and ALS were associated with a decrease in body composition index and attenuation of liver index, serum liver enzyme activities and hepatic expressions of inflammatory and fibrotic markers (tumor necrosis factor-alpha, nuclear factor kappa-B and transforming growth factor-beta) with a significant increase in hepatic glucose transporter-2 and peroxisome proliferator-activated receptors-alpha and gamma expressions. The results suggested that, at indicated dosage, ALS has ameliorative effect equal to that of TEL against FRC-induced metabolic and hepatic disorders; implying that drugs which inhibit the RAS, by different mode of inhibition, profoundly affect fructose-induced MS in rats. PMID- 25917322 TI - The critical role of spinal 5-HT7 receptors in opioid and non-opioid type stress induced analgesia. AB - The opioid and non-opioid types of stress-induced analgesia have been well defined. One of the non-opioid type involve the endocannabinoid system. We previously reported that the spinal serotonin 7 receptor (5-HT7) blockers inhibit both morphine and cannabinoid-induced analgesia, thus we hypothesized that descending serotonergic pathways-spinal 5-HT7 receptor loop might contribute to stress-induced analgesia. Stress-induced analgesia was induced with warm (32 degrees C) or cold (20 degrees C) water swim stress in male Balb-C mice. The effects of intrathecal injection of a selective 5-HT7 receptor antagonist, SB 269970, of the denervation of serotonergic neurons by intrathecal administration of 5,7-dihydroxytryptamine (5,7-DHT) and of lesions of the dorsolateral funiculus on opioid and non-opioid type stress-induced analgesia were evaluated with the tail-flick and hot plate tests. The expression of 5-HT7 receptors mRNA in the dorsal lumbar region of spinal cord were analyzed by RT-PCR following spinal serotonin depletion or dorsolateral funiculus lesion. The effects of the selective 5-HT7 receptor agonists LP 44 and AS 19 were tested on nociception. Intrathecal SB 269970 blocked both opioid and non-opioid type stress-induced analgesia. Dorsolateral funiculus lesion or denervation of the spinal serotonergic neurons resulted in a marked decrease in 5-HT7 receptor expression in the dorsal lumbar spinal cord, accompanied by inhibition of opioid and non opioid type stress-induced analgesia. However, the systemic or intrathecal LP 44 and AS 19 alone did not produce analgesia in unstressed mice. These results indicate that descending serotonergic pathways and the spinal 5-HT7 receptor loop play a crucial role in mediating both opioid and non-opioid type stress-induced analgesia. PMID- 25917323 TI - Anti-glycation and anti-angiogenic activities of 5'-methoxybiphenyl-3,4,3'-triol, a novel phytochemical component of Osteomeles schwerinae. AB - Advanced glycation end products (AGEs) are involved in the development of diabetic complications such as diabetic retinopathy. 5'-methoxybiphenyl-3,4,3' triol (referred to as K24) was isolated using bioactivity-guided fractionation of Osteomeles schwerinae C. K. Schneid. and identified as a potent AGE inhibitor. To identify the protective effect of K24 on disruption of the blood-retinal barrier, AGE-RSA was intravitreally injected into rat eyes. K24 had an inhibitory effect on AGE-RSA-induced retinal vascular leakage by suppressing the expression of vascular endothelial growth factor (VEGF) and decreasing the loss of occludin. In addition, we examined whether K24 has a preventive effect against retinal pathogenic angiogenesis in an oxygen-induced retinopathy (OIR) mouse model. K24 significantly reduced the retinal non-perfused area and neovascular tufts in the OIR mice. These data indicate that K24 could serve as an innovative pharmaceutical agent to prevent blood-retinal barrier breakage and retinal pathogenic angiogenesis through an anti-VEGF mechanism. PMID- 25917324 TI - A natural compound macelignan protects midbrain dopaminergic neurons from inflammatory degeneration via microglial arginase-1 expression. AB - Inflammatory events involving activated microglia have been recognized to play an important role in pathogenesis of various neurodegenerative disorders including Parkinson disease. Compounds regulating activation profiles of microglia may provide therapeutic benefits for Parkinson disease characterized by degeneration of midbrain dopaminergic neurons. Here we examined the effect of macelignan, a compound derived from nutmeg, on inflammatory degeneration of midbrain dopaminergic neurons. Treatment of midbrain slice cultures with interferon (IFN) gamma and lipopolysaccharide (LPS) caused a substantial decrease in viable dopaminergic neurons and an increase in nitric oxide (NO) production indicated by extracellular nitrite accumulation. Application of macelignan (10 MUM) concomitantly with LPS prevented the loss of dopaminergic neurons. Besides nitrite accumulation, up-regulation of inducible NO synthase protein expression in response to IFN-gamma/LPS was confirmed by Western blotting, and immunohistochemical examination revealed expression of inducible NO synthase in a subpopulation of Iba-1-poitive microglia. However, macelignan did not affect any of these NO-related parameters. On the other hand, macelignan promoted expression of arginase-1 in midbrain slice cultures irrespective of the presence or the absence of IFN-gamma/LPS treatment. Arginase-1 expression was mainly localized in a subpopulation of Iba-1-positive cells. Importantly, the neuroprotective effect of macelignan was antagonized by N(omega)-hydroxy-nor-L-arginine, a specific arginase inhibitor. The neuroprotective effect of macelignan was also prevented by GW9662, a peroxisome proliferator-activated receptor gamma (PPARgamma) antagonist. Overall, these results indicate that macelignan, a compound with PPARgamma agonist activity, can provide neuroprotective effect on dopaminergic neurons in an arginase-dependent but NO-independent manner. PMID- 25917325 TI - Mast cells as therapeutic target in cancer. AB - Mast cells promote tumorigenesis and tumor progression, and have functions that favor the host. Increased mast cell number correlates with a poor prognosis in several human tumors. In different vascular tumors, as well as a number of hematological and solid tumors, mast cell accumulation correlate with increased neovascularization, tumor aggressiveness, and metastatic spread. Mast cells might act as a new target for the adjuvant treatment of tumors through the selective inhibition of angiogenesis, tissue remodeling and tumor-promoting molecules, permitting the secretion of cytotoxic cytokines and preventing mast cell-mediated immune suppression. PMID- 25917327 TI - Rhodium-Catalyzed Hydroformylation of 1,1-Disubstituted Allenes Employing the Self-Assembling 6-DPPon System. AB - A rhodium-catalyzed hydroformylation of 1,1-disubstituted allenes is reported. Using a Rh(I)/6-DPPon catalyst system, one can obtain beta,gamma-unsaturated aldehydes in high regio- and chemoselectivity. The Z-configured product is formed with up to >95% selectivity when unsymmetrically 1,1-disubstituted allenes are submitted to the reaction conditions. This is the first time that these interesting building blocks are accessible by hydroformylation of allenes. The utility of this methodology is demonstrated by further transformations of one of the obtained products. PMID- 25917326 TI - Changes in systolic blood pressure over time in healthy cats and cats with chronic kidney disease. AB - BACKGROUND: Hypertension is a common problem in older cats, most often associated with chronic kidney disease (CKD). Cross-sectional studies have suggested that blood pressure in cats increases with age. HYPOTHESIS/OBJECTIVES: To determine whether blood pressure in cats increases with age and whether this occurs independently of the presence of CKD. To investigate risk factors for developing hypertension. ANIMALS/SUBJECTS: Two hundred and sixty-five cats with CKD and 133 healthy cats >=9 years were retrospectively identified. METHODS: Four groups were created according to status at initial evaluation (CKD or healthy) and blood pressure at the last included visit (normotensive [NT] or developed hypertension [DH]): Healthy-NT, Healthy-DH, CKD-NT and CKD-DH. Systolic blood pressure (SBP) over time slopes were compared with 0 and between groups. Risk factors for the development of hypertension were investigated, and associations of biochemical and clinical variables with SBP were examined. RESULTS: Cats that were hypertensive at CKD diagnosis (n = 105) were not included in further analyses. Twenty-seven cats with CKD and 9 healthy cats developed hypertension >=3 months after diagnosis of CKD or their first visit. Systolic blood pressure significantly increased with age in all cats (P < .001). Healthy cats were at less risk than cats with CKD to become hypertensive (hazard ratio 0.2, P < .001), with creatinine being an independent risk factor for the development of hypertension. CONCLUSIONS AND CLINICAL IMPORTANCE: The high prevalence of hypertension in azotemic cats in this study shows the importance of monitoring of SBP in elderly cats, and in particular in cats with CKD. PMID- 25917328 TI - Parasitism of Trombidium brevimanum larvae on agrobiont linyphiid spiders from Germany. AB - An experiment on three differently-managed agricultural fields in Ahlum, Germany, which aimed at establishing the impact of different management systems on the biodiversity of predators and decomposers, yielded a significant number of spiders parasitized by larvae of Trombidium brevimanum (Actinotrichida, Parasitengona, Trombidiidae). Spider data from the whole sampling period (September 2010-July 2012), indicated that ectoparasitic larvae were recorded only on spiders in pitfall traps in the period of June-July 2011. In this period, only eight species of Linyphiidae--out of 42 species assigned to nine spider families recorded from the study area--were parasitized by mites; considerable levels of parasitism were recorded on Erigone atra, E. dentipalpis, and Oedothorax apicatus. The highest prevalence of parasitism was recorded on the organic field for E. atra (29%), while on the integrated and conventional fields significantly fewer parasitized spiders were observed. The preferred attachment sites on the spider host were regions with softer cuticle, especially regions on the carapace and on the abdomen, adjacent to the pedicel. PMID- 25917329 TI - Nonalcoholic fatty liver disease induced by noncanonical Wnt and its rescue by Wnt3a. AB - Nonalcoholic fatty liver disease (NAFLD) is the most common cause of chronic liver disease, which begins with isolated steatosis and advances to nonalcoholic steatohepatitis (NASH), steatofibrosis, and cirrhosis. The pathways involved in disease progression are not understood. Loss-of-function mutations in Wnt coreceptor LDL receptor-related protein 6 (LRP6) underlie early-onset atherosclerosis, metabolic risk factors, and NAFLD in humans by unknown mechanisms. We generated mice with the human disease-associated LRP6(R611C) mutation and phenotypically characterized their liver. Homozygote LRP6(R611C) (LRP6(mut/mut)) mice exhibited both steatohepatitis and steatofibrosis. These traits were associated with increased activity of the noncanonical Wnt/Ras homolog family member A, Rho-associated protein kinase 2, and PKC-alpha/-MU pathways. Accordingly, there was increased TGF-beta1 activity, coupled with enhanced expression of smooth muscle alpha-actin and vimentin that colocalized with albumin in LRP6(mut/mut) mouse liver. LRP6 knockdown reprogramed HepG2 cells to express both these markers, linking impaired Wnt signaling with hepatocyte transdifferentiation. The causal link between altered Wnt signaling and NASH was established by normalization of the disease pathways and rescue of the liver traits by Wnt3a administration to LRP6(mut/mut) mice. Thus, this study identifies diverse disease pathways that underlie a spectrum of NASH-related liver diseases and are linked by a single human genetic variant. LRP6 and noncanonical Wnt pathways are important potential therapeutic targets against NASH. PMID- 25917330 TI - Ssb2/Nabp1 is dispensable for thymic maturation, male fertility, and DNA repair in mice. AB - SSB1 and SSB2 are newly identified single-stranded (ss) DNA binding proteins that play a crucial role in genome maintenance in humans. We recently generated a knockout mouse model of Ssb1 and revealed its essential role for neonatal survival. Notably, we found compensatory up-regulation of Ssb2 protein levels in multiple tissues of conditional Ssb1(-/-) mice, suggesting functional compensation between these 2 proteins. We report here the first description of Ssb2(-/-) knockout mice. Surprisingly, unlike Ssb1 knockout mice, Ssb2(-/-) mice are viable and fertile and do not exhibit marked phenotypic changes when compared with their Ssb2(+/+) and Ssb2(+/-) littermates. Notably, we did not detect any pathologic changes in the thymus, spleen, or testes, tissues with the most abundant expression of Ssb2. Moreover, Ssb2(-/-) mouse embryonic fibroblasts (MEFs) did not show any sensitivity to DNA-damaging agents, or defects in DNA repair capacity. However, we observed modest up-regulation of Ssb1 levels in Ssb2(-/-) MEFs as well as in Ssb2(-/-) thymus and spleen, suggesting that Ssb1 is likely able to compensate for the loss of Ssb2 in mice. Altogether, our results show that Ssb2 is dispensable for embryogenesis and adult tissue homeostasis, including thymopoiesis, splenic development, male fertility, and DNA repair in mice. PMID- 25917331 TI - Exacerbation of autoimmune neuroinflammation by dietary sodium is genetically controlled and sex specific. AB - Multiple sclerosis (MS) is a debilitating autoimmune neuroinflammatory disease influenced by genetics and the environment. MS incidence in female subjects has approximately tripled in the last century, suggesting a sex-specific environmental influence. Recent animal and human studies have implicated dietary sodium as a risk factor in MS, whereby high sodium augmented the generation of T helper (Th) 17 cells and exacerbated experimental autoimmune encephalomyelitis (EAE), the principal model of MS. However, whether dietary sodium interacts with sex or genetics remains unknown. Here, we show that high dietary sodium exacerbates EAE in a strain- and sex-specific fashion. In C57BL6/J mice, exposure to a high-salt diet exacerbated disease in both sexes, while in SJL/JCrHsd mice, it did so only in females. In further support of a genetic component, we found that sodium failed to modify EAE course in C57BL6/J mice carrying a 129/Sv derived interval on chromosome 17. Furthermore, we found that the high-sodium diet did not augment Th17 or Th1 responses, but it did result in increased blood brain barrier permeability and brain pathology. Our results demonstrate that the effects of dietary sodium on autoimmune neuroinflammation are sex specific, genetically controlled, and CNS mediated. PMID- 25917332 TI - High Blood Pressure Increases the Risk of Poor Outcome at Discharge and 12-month Follow-up in Patients with Symptomatic Intracranial Large Artery Stenosis and Occlusions: Subgroup analysis of the CICAS Study. AB - AIMS: The purpose of this study was to discuss the relationship between blood pressure and prognosis of patients with symptomatic intracranial arterial stenosis. METHODS: Data on 2426 patients with symptomatic intracranial large artery stenosis and occlusion who participated in the Chinese Intracranial Atherosclerosis (CICAS) study were analyzed. According to the JNC 7 criteria, blood pressure of all patients was classified into one of the four subgroups: normal, prehypertension, hypertension stage I, and hypertension stage II. Poor outcomes were defined as death and functional dependency (mRS 3-5) at discharge or at 1 year. RESULTS: For patients with intracranial stenosis of 70% to 99%, the rate of poor outcome at discharge was 19.3%, 23.5%, 26.8%, and 39.8% (P = 0.001) for each blood pressure subgroup. For patients with intracranial large artery occlusion, the rates were 17.6%, 22.1%, 29.5%, and 49.8%, respectively (P < 0.0001). The rate of poor outcome at 12-month follow-up was 12.6%, 15.3%, 28.5%, and 27.9% (P = 0.0038) in patients with stenosis of 70% to 99% for each blood pressure subgroup and 11.6%, 21.5%, 23.9%, 35.1% (P < 0.0001) in patients with occlusion. CONCLUSIONS: For patients with severe intracranial arterial stenosis or occlusion, higher hypertension stages are associated with an increased risk of poor outcome at discharge and 12-month follow-up. PMID- 25917333 TI - Application of film-casting technique to investigate drug-polymer miscibility in solid dispersion and hot-melt extrudate. AB - Determination of drug-polymer miscibility is critical for successful development of solid dispersions. This report details a practical method to predict miscibility and physical stability of drug with various polymers in solid dispersion and, especially, in melt extrudates by applying a film-casting technique. Mixtures of itraconazole (ITZ) with hydroxypropylmethylcellulose phthalate (HPMCP), Kollidon((r)) VA 64, Eudragit((r)) E PO, and Soluplus((r)) were film-casted, exposed to 40 degrees C/75% RH for 1 month and then analyzed using differential scanning calorimetry (DSC), powder X-ray diffractometry, and polarized light microscopy (PLM). ITZ had the highest miscibility with HPMCP, being miscible at drug to polymer ratio of 6:4 (w/w). There was a downward trend of lower miscibility with Soluplus((r)) (miscible at 3:7, w/w, and a few microcrystals present at 4:6, w/w), Kollidon((r)) VA 64 (2:8, w/w) and Eudragit((r)) E PO (<1:9, w/w). PLM was found more sensitive to detect drug crystallization than DSC and powder X-ray diffractometry. There was general correlation between results of film casting and hot-melt extrusion (HME) using a twin screw extruder. For ITZ-Soluplus((r)) mixtures, HME at 4:6 (w/w) resulted in a single phase, whereas drug crystallization was observed at higher drug load. HME of ITZ-Kollidon((r)) VA 64 mixtures also correlated well with the miscibility predicted by film casting. PMID- 25917334 TI - Kaempferol, a dietary flavonoid, ameliorates acute inflammatory and nociceptive symptoms in gastritis, pancreatitis, and abdominal pain. AB - Kaempferol (KF) is the most abundant polyphenol in tea, fruits, vegetables, and beans. However, little is known about its in vivo anti-inflammatory efficacy and mechanisms of action. To study these, several acute mouse inflammatory and nociceptive models, including gastritis, pancreatitis, and abdominal pain were employed. Kaempferol was shown to attenuate the expansion of inflammatory lesions seen in ethanol (EtOH)/HCl- and aspirin-induced gastritis, LPS/caerulein (CA) triggered pancreatitis, and acetic acid-induced writhing. PMID- 25917336 TI - Analysis: The Accuracy and Efficacy of the Dexcom G4 Platinum Continuous Glucose Monitoring System. AB - In this issue of Journal of Diabetes Science and Technology, Nakamura and Balo report on accuracy and efficacy of the Dexcom G4 Platinum Continuous Glucose Monitoring System. The authors demonstrate good overall performance of this real time continuous glucose monitoring (RT-CGM) system, although accuracy data of the next generation RT-CGM system, the G4AP, is already available. Also, now that MARDs seem to move to single-digit numbers, the question comes up how low we need to go with accuracy. Results of the study also showed a reduction in time spent in hypoglycemia, although the clinical relevance should be questioned. To date, few trials have demonstrated a reduction of severe hypoglycemia. Conventional RT CGM, without threshold suspension or closing the loop, might be insufficient in preventing severe hypoglycemia. PMID- 25917335 TI - Hypoglycemia in Type 2 Diabetes--More Common Than You Think: A Continuous Glucose Monitoring Study. AB - BACKGROUND: Hypoglycemia is often the limiting factor for intensive glucose control in diabetes management, however its actual prevalence in type 2 diabetes (T2DM) is not well documented. METHODOLOGY: A total of 108 patients with T2DM wore a continuous glucose monitoring system (CGMS) for 5 days. Rates and patterns of hypoglycemia and glycemic variability (GV) were calculated. Patient and medication factors were correlated with rates, timing, and severity of hypoglycemia. RESULTS: Of the patients, 49.1% had at least 1 hypoglycemic episode (mean 1.74 episodes/patient/ 5 days of CGMS) and 75% of those patients experienced at least 1 asymptomatic hypoglycemic episode. There was no significant difference in the frequency of daytime versus nocturnal hypoglycemia. Hypoglycemia was more frequent in individuals on insulin (alone or in combination) (P = .02) and those on oral hypoglycemic agents (P < .001) compared to noninsulin secretagogues. CGMS analysis resulted in treatment modifications in 64% of the patients. T2DM patients on insulin exhibited higher glycemic variability (GV) scores (2.3 +/- 0.6) as compared to those on oral medications (1.8 +/- 0.7, P = .017). CONCLUSIONS: CGMS can provide rich data that show glucose excursions in diabetes patients throughout the day. Consequently, unwarranted onset of hypo- and hyperglycemic events can be detected, intervened, and prevented by using CGMS. Hypoglycemia was frequently unrecognized by the patients in this study (75%), which increases their potential risk of significant adverse events. Incorporation of CGMS into the routine management of T2DM would increase the detection and self-awareness of hypoglycemia resulting in safer and potentially better overall control. PMID- 25917338 TI - The presence and clinical implication of intraductal carcinoma of prostate in metastatic castration resistant prostate cancer. AB - BACKGROUND: Intraductal carcinoma of prostate (IDC-P) is always underestimated pathological pattern in prostate cancer and its role is still unclear in castration resistant prostate cancer (CRPC). This study was conducted to investigate the presence and the roles of IDC-P in patients with metastatic CRPC. METHODS: 45 patients with initially diagnosed metastatic prostate cancer and then progressed to CRPC, were included. All of them were received twice transperineal biopsies at the time of initial diagnosis and the time of CRPC. All samples were retrieved to detect the presence of IDC-P. PSA doubling time (PSADT) was considered as a parameter presenting the progression of CRPC. The relationships between IDC-P and other clinicopathological variables were analyzed. RESULTS: IDC P was found only in 20% (9/45) cases at initial diagnosis, whereas, it increased to 62.5% (28/45) at the time of CRPC (chi(2) = 16.568, P = 0.000). Compared to acinar adenocarcinoma components in tumor tissues, IDC-P components, especially solid subtype, had obviously poor/no response to androgen deprivation therapy (ADT). In addition, among patients treated with docetaxel-based chemotherapy (n = 24), patients with IDC-P also showed more unfavorable response than those without IDC-P (20% vs. 66.7%, P = 0.022). The presence of IDC-P and serum testosterone at the time of CRPC, were significantly associated with rapid disease progression. 13/28 (46.4%) CRPC with IDC-P had PSADT less than 30 days, while, only 1/17 (5.9%) patient without IDC-P had a less than 30 days PSADT (chi(2) = 8.114, P = 0.004). Limitations included the relative short follow-up time and a relative small cohort. CONCLUSIONS: The presence of IDC-P was significantly associated with rapid progression of CRPC. And its presence could suggest the poor response to initial ADT and sequential docetaxel-based chemotherapy. Detection of IDC-P should be of importance in CRPC, and re-biopsy at the time of CRPC might be one of practical solutions. The mechanism of the ADT and docetaxel resistance to IDC P needed to be further investigated. PMID- 25917337 TI - Reduction in Inappropriate ICD Therapy in MADIT-RIT Patients Without History of Atrial Tachyarrhythmia. AB - BACKGROUND: There are limited data whether history of atrial tachyarrhythmia (AT) modifies the risk of inappropriate ICD therapy, or the efficacy of novel ICD programming to reduce inappropriate ICD therapy events. METHODS: In MADIT-RIT, we investigated the effects of novel ICD programming with high-rate cut-off VT zone >= 200 bpm (arm B), or 60-second delayed therapy in the VT zone 170-199 bpm (arm C), compared to conventional programming VT zone>170 bpm (arm A) on first inappropriate ICD therapy in those with or those without AT prior to enrollment. RESULTS: In patients with prior AT (n = 203, 14%) there was a higher risk of inappropriate ICD therapy (HR = 2.10, 95% CI: 1.38-3.20, P < 0.001), and inappropriate ICD shock (HR = 2.56, 95% CI: 1.38-4.74, P = 0.003) compared to those with no prior AT. The effects of innovative programming to reduce inappropriate ICD therapy with either high-rate cut-off or delayed VT therapy were similar in patients with prior AT (arm B vs. A HR = 0.11, P < 0.001, arm C vs. A HR = 0.17, P < 0.001), and also in patients without prior AT before enrollment (arm B vs. A HR = 0.15, P < 0.001, arm C vs. A HR = 0.24, P < 0.001, interaction P-values >0.10 for all). CONCLUSIONS: Novel ICD programming with a high-rate cut-off or delayed therapy is equally beneficial to reduce inappropriate ICD therapy in patients with or without prior AT, despite the lower risk of inappropriate ICD therapy in patients without prior AT. PMID- 25917339 TI - The treatment of patients with 1-3 brain metastases: is there a place for whole brain radiotherapy alone, yet? A retrospective analysis. AB - AIM: To evaluate the efficacy of whole brain radiotherapy (WBRT) with or without other treatments in patients (pts) with 1-3 brain metastases (BM). MATERIALS AND METHODS: Toxicities and survival of 134 pts treated between 2009 and 2013 with WBRT alone (58 pts), WBRT plus surgery (SUR-WBRT: 42 pts) or WBRT followed by stereotactic or integrated boost radiotherapy (SRT-WBRT: 34 pts) were analyzed. Differences in toxicity (acute and late) incidence and in overall (OS), disease free (DFS) and disease-specific survival (DSS) were evaluated (chi(2)-test, uni- and multivariate analysis). RESULTS: Pts given intensified treatments (SUR- and SBRT-WBRT) had better 3-month local response compared to WBRT alone group (p < 0.045). Better 1-year local control was evident only in SRT-WBRT pts (p < 0.035). Univariate OS analysis confirmed, as favorable prognostic factors, RPA class I (p < 0.001), GPA class III and IV (p < 0.001), single metastasis (p = 0.045), stable primary disease (p = 0.03), intensified treatment (p = 0.000), systemic therapy after radiotherapy (p = 0.04) and response of metastatic lesions (p = 0.002). At multivariate analysis, OS was better in RPA class I pts (p = 0.002), who had more aggressive radiotherapy treatments (p = 0.001), chemotherapy after radiotherapy (p < 0.001) and response to RT (p = 0.003). Response to radiotherapy (p = 0.002) and BM number (p < 0.001) resulted independently prognostic for DFS. About 60 % of patients had mild acute toxicity (G1), especially headache (51 %) and fatigue (34 %); only 2 patients (2 %) had severe (G3) headache and 5 patients (4 %) severe fatigue (G3) reversible with oral steroids. No differences were evident between the different treatment groups. Among 80 pts followed up with MRI, 12 (15 %) had leukoencephalopathy (equally distributed across subgroups) and 5 (6 %) radionecroses, 4/5 asymptomatic, 5/5 in pts given intensified treatments. CONCLUSIONS: This analysis confirms the known prognostic factors for BM, emphasizing the importance of intensified treatments in a population with favorable features. PMID- 25917341 TI - Special Issue to mark the career and retirement of Professor Gerry Brooks as the Editor-in-Chief of Pest Management Science. PMID- 25917340 TI - Treatment of neurofibromatosis type 1. AB - OPINION STATEMENT: Neurofibromatosis type 1 (NF1) is a genetic multisystemic disorder involving the skin, the central and peripheral nervous systems, bones, and the cardiovascular and endocrine systems. This condition is caused by inherited or de novo mutations of the NF1 gene at the 17q11.2 chromosomal region, a gene that codes for the protein neurofibromin. Neurofibromin is particularly expressed in neural cells and inhibits the RAS pathway, which regulates cellular proliferation and differentiation. The typically age-dependent emergence of diagnostic signs and the risk for severe complications in the first years of life simultaneously makes a precocious diagnosis crucial and makes the management of children with suspected NF1 challenging. Currently, no standardized specific treatments for NF1 and its complications are available. However, in recent years, increasing knowledge of the pathogenetic mechanisms has motivated the scientific search behind targeted biological agents that might change the course of the disease. Numerous clinical trials for the treatment of the most typical NF1 complications, such as plexiform neurofibromas (Ns) and NF1-related tumors, have been conducted. Consequently, encouraging in vitro and in vivo results are emerging. Insufficient efficacy and safety in in vivo data do not permit the routine use of these drugs in clinical practice. Radiotherapy appears to be indicated only for high-grade soft-tissue sarcomas, whereas surgical approaches should be considered for malignant peripheral nerve sheath tumors (MPNSTs) and Ns, optic pathway gliomas, and bone dystrophic changes because they might improve quality of life. Further prospective studies, however, are needed to confirm the efficacy, safety, and cost/benefit ratio of new therapeutic approaches and the optimal timing for their use in patients with NF1. PMID- 25917342 TI - Successful treatment with long-term use of minocycline for Morbihan disease showing mast cell infiltration: A second case report. PMID- 25917343 TI - Strengthening or Weakening? The Impact of Universal Health Insurance on Intergenerational Coresidence in Taiwan. AB - In this article, we exploit a unique natural experiment-the implementation of National Health Insurance (NHI) in Taiwan in 1995-to examine how the introduction of universal health insurance increases or decreases the likelihood of intergenerational coresidence. Five waves of surveys from the Survey of Health and Living Status of the Elderly in Taiwan between 1989 and 2003 are employed, and models with various specifications are estimated. Our results indicate a mixed relationship between the likelihood of intergenerational coresidence and the enactment of NHI. Although NHI on average reduces the probability that elderly parents live with their adult children by approximately 6.6 %, the likelihood of intergenerational coresidence increases among families benefiting most from NHI, such as those with unhealthy elderly mothers and fewer children. PMID- 25917344 TI - Pro-Insulin-Like Growth Factor-II Ameliorates Age-Related Inefficient Regenerative Response by Orchestrating Self-Reinforcement Mechanism of Muscle Regeneration. AB - Sarcopenia, age-related muscle weakness, increases the frequency of falls and fractures in elderly people, which can trigger severe muscle injury. Rapid and successful recovery from muscle injury is essential not to cause further frailty and loss of independence. In fact, we showed insufficient muscle regeneration in aged mice. Although the number of satellite cells, muscle stem cells, decreases with age, the remaining satellite cells maintain the myogenic capacity equivalent to young mice. Transplantation of young green fluorescent protein (GFP)-Tg mice derived satellite cells into young and aged mice revealed that age-related deterioration of the muscle environment contributes to the decline in regenerative capacity of satellite cells. Thus, extrinsic changes rather than intrinsic changes in satellite cells appear to be a major determinant of inefficient muscle regeneration with age. Comprehensive protein expression analysis identified a decrease in insulin-like growth factor-II (IGF-II) level in regenerating muscle of aged mice. We found that pro- and big-IGF-II but not mature IGF-II specifically express during muscle regeneration and the expressions are not only delayed but also decreased in absolute quantity with age. Supplementation of pro-IGF-II in aged mice ameliorated the inefficient regenerative response by promoting proliferation of satellite cells, angiogenesis, and suppressing adipogenic differentiation of platelet derived growth factor receptor (PDGFR)alpha(+) mesenchymal progenitors. We further revealed that pro-IGF-II but not mature IGF-II specifically inhibits the pathological adipogenesis of PDGFRalpha(+) cells. Together, these results uncovered a distinctive pro-IGF-II-mediated self-reinforcement mechanism of muscle regeneration and suggest that supplementation of pro-IGF-II could be one of the most effective therapeutic approaches for muscle injury in elderly people. PMID- 25917345 TI - [Pregnancy after cancer: for whom and when?]. AB - Planning a pregnancy for patients with a history of cancer, including breast cancer, is a clinical situation that becomes more and more common. Several specific items are to be discussed: decrease of fertility after cancer treatment, fertility preservation options, impact of pregnancy on cancer recurrence risk and appropriate interval between cancer and pregnancy. Programming pregnancy after cancer is doable in a multidisciplinary setting, and begins at cancer diagnosis to anticipate the various specific pitfalls. Favor adequate oncologic care remains the leading rule. PMID- 25917346 TI - [Educational and social outcome after childhood cancer]. AB - The survival rate improvement of childhood cancer survivors lead to question about their educational and social outcome. Authors suggest an international review in order to find risk factors of school or social failure after cancer experience. Principal cohort is studied in USA (the Children Cancer Survivor Study). Nevertheless, European studies are also published. The results vary, depending on subpopulation studied and on control choice (siblings or general population). Treatment improvement and supportive care make difficult to compare studies with current situations. Moreover, there are not international standard of education or social outcome. School and social behaviour are influenced by: types of tumor (cerebral tumor but also sometimes hemopathy and osteosarcoma), age at diagnosis (very young children and adolescent), treatments (neurotoxical treatments, hematopoietic stem cell transplant), and social or educational status of the parents. PMID- 25917347 TI - Blockage of Src by Specific siRNA as a Novel Therapeutic Strategy to Prevent Destructive Repair in Steroid-Associated Osteonecrosis in Rabbits. AB - Vascular hyperpermeability and highly upregulated bone resorption in the destructive repair progress of steroid-associated osteonecrosis (SAON) are associated with a high expression of VEGF and high Src activity (Src is encoded by the cellular sarcoma [c-src] gene). This study was designed to prove our hypothesis that blocking the VEGF-Src signaling pathway by specific Src siRNA is able to prevent destructive repair in a SAON rabbit model. Destructive repair in SAON was induced in rabbits. At 2, 4, and 6 weeks after SAON induction, VEGF, anti-VEGF, Src siRNA, Src siRNA+VEGF, control siRNA, and saline were introduced via intramedullary injection into proximal femora for each group, respectively. Vascularization and permeability were quantified by dynamic contrast-enhanced (DCE) MRI. At week 6 after SAON induction, proximal femurs were dissected for micro-computed tomography (MUCT)-based trabecular architecture with finite element analysis (FEA), MUCT-based angiography, and histological analysis. Histological evaluation revealed that VEGF enhanced destructive repair, whereas anti-VEGF prevented destructive repair and Src siRNA and Src siRNA+VEGF prevented destructive repair and enhanced reparative osteogenesis. Findings of angiography and histomorphometry were consistent with those determined by DCE MRI. Src siRNA inhibited VEGF-mediated vascular hyperpermeability but preserved VEGF-induced neovascularization. Bone resorption was enhanced in the VEGF group and inhibited in the anti-VEGF, Src siRNA, Src siRNA+VEGF groups as determined by both 3D MUCT and 2D histomorphometry. FEA showed higher estimated failure load in the Src siRNA and Src siRNA+VEGF groups when compared to the vehicle control group. Blockage of VEGF-Src signaling pathway by specific Src siRNA was able to prevent steroid-associated destructive repair while improving reconstructive repair in SAON, which might become a novel therapeutic strategy. PMID- 25917350 TI - News from the pediatric anesthesia societies: the association of paediatric anaesthetists of Great Britain and Ireland (APAGBI). PMID- 25917351 TI - Does it matter how you get from D (drug dose) to E (clinical effect)? PMID- 25917348 TI - Plasma concentrations of maraviroc and raltegravir after dual therapy in patients with long-term suppressed viraemia: ROCnRAL ANRS 157 study. PMID- 25917352 TI - An effective and reproducible approach for improving face mask ventilation in individuals with craniofacial clefts. PMID- 25917353 TI - Ventilation of severe bronchiolitis in interhospital transport: a place for high frequency oscillatory ventilation? PMID- 25917354 TI - Blood loss assessment in pediatric surgery: visual versus gravimetric methods: an experimental study. PMID- 25917355 TI - Reply to Faraoni D, Fenger-Eriksen C, Gillard S et al. Evaluation of dynamic parameters of thrombus formation measured on whole blood using rotational thromboelastometry in children undergoing cardiac surgery: a descriptive study. PMID- 25917356 TI - New pediatric airway devices, friends or foes? PMID- 25917357 TI - The effect of prophylactic methylprednisolone need more evidences on postoperative outcomes. PMID- 25917358 TI - MiR-501-5p regulates CYLD expression and promotes cell proliferation in human hepatocellular carcinoma. AB - OBJECTIVE: Previous studies have shown that the micro-ribonucleic acid miR-501-5p is upregulated in hepatocellular carcinoma cells and tissues with high hepatitis B virus replication, and that miR-501 overexpression significantly promotes hepatitis B virus replication. We further analysed a published microarray-based high-throughput dataset (NCBI/GEO/GSE36915) and found that miR-501-5p was upregulated in hepatocellular carcinoma tumour tissues. We therefore investigated the possible function of miR-501-5p during the development of hepatocellular carcinoma. METHODS: Expression of miR-501-5p in human hepatocellular carcinoma specimens and cell lines was assessed, using real-time polymerase chain reaction. Luciferase reporter assays were used to confirm CYLD as a target of miR-501-5p. The effect of miR-501-5p on cell proliferation was confirmed, using tetrazolium and colony formation assays. Gene and protein expression were examined, using real-time polymerase chain reaction and western blotting, respectively. RESULTS: MiR-501-5p was upregulated in hepatocellular carcinoma specimens and cell lines, and directly targeted the 3' untranslated region of CYLD. MiR-501-5p upregulation corresponded with a downregulation of CYLD in the same tissues and cell lines, and overexpression of MiR-501-5p decreased CYLD expression, increased expression of cyclin D1 and c-myc and promoted the proliferation of hepatocellular carcinoma cells in vitro. CONCLUSIONS: This study suggests that miR-501-5p may play an important role in the development of hepatocellular carcinoma by promoting cell proliferation, and indicates that miR-501-5p may represent a novel therapeutic target for hepatocellular carcinoma. PMID- 25917359 TI - Real-world use of sunitinib in Japanese patients with advanced renal cell carcinoma: efficacy, safety and biomarker analyses in 1689 consecutive patients. AB - OBJECTIVE: This prospective, post-marketing study collected sunitinib safety and efficacy data in Japanese patients with unresectable/metastatic renal cell carcinoma. Retrospective analysis investigated adverse events as potential sunitinib efficacy biomarkers. METHODS: Patients administered sunitinib, after its release, were registered until reaching a pre-specified number of cases. Primary starting dose was 50 mg/day orally on a 4-weeks-on and 2-weeks-off schedule. Physicians completed investigation forms at 6-week intervals for 24 weeks. Associations between baseline characteristics and adverse events were analyzed by Cox proportional hazards model and compared by chi(2) test. The log rank test compared survival in subpopulations based on selected factors. RESULTS: Of note, 1689 patients receiving sunitinib were registered between June 2008 and November 2009. Most of them were males (75%), aged <65 years (56%), and had Eastern Cooperative Oncology Group performance status 0/1 (90%), metastatic disease (88%) and previous systemic therapy (66%). Grade >= 3 adverse events occurred in 70%, with reduced platelet count the most common (34%). Characteristics significantly associated with Grade >= 3 adverse events were female sex, age >= 55 years, Eastern Cooperative Oncology Group performance status >= 2, history of several medical conditions and prior treatment. Objective response rate was 22%. Median progression-free survival was 22.7 weeks. Median overall survival was not reached; however, 24-week overall survival rate was 84%. Improved overall survival was associated with higher relative dose intensity during the first 6 weeks and specific adverse events: hypertension, hand-foot syndrome, hypothyroidism, leukopenia and thrombocytopenia. CONCLUSIONS: Sunitinib demonstrated acceptable safety and useful efficacy in Japanese patients with unresectable/metastatic renal cell carcinoma. Potential biomarkers associated with greater efficacy were relative dose intensity and specific adverse events. PMID- 25917360 TI - Diabetes: Helminths improve insulin sensitivity and enhance M2 macrophage numbers in WAT of obese mice. PMID- 25917361 TI - Paediatric endocrinology: Treatment of girls with central precocious puberty. PMID- 25917362 TI - Neurodegenerative disease: Balancing BMI--rethinking the relationships between obesity, ageing and risk of dementia. PMID- 25917363 TI - Functional characterization of two single nucleotide polymorphisms of acyl coenzyme A:cholesterol acyltransferase 2. AB - BACKGROUND: Acyl-coenzyme A:cholesterol acyltransferase 2 (ACAT2) plays a critical role in the formation of cholesteryl esters from cholesterol and fatty acids, and is a potential target for treating hypercholesterolemia. We recently reported the significant effects of two human ACAT2 gene polymorphisms, 41A>G (Glu(14)Gly, rs9658625) and 734C>T (Thr(254)Ile, rs2272296), on plasma lipid levels and coronary artery disease susceptibility in a case-control association study. In the present study, we evaluated the possible biological influence of the two polymorphism using two approaches. METHODS: In the first approach, the functional impact of the two polymorphisms was predicted in-silico using available web-based software, and in the second approach, the varying functions of the two polymorphisms were characterized in in vitro experiments, using ACAT2 deficient AC-29 cells. RESULTS: Our results show that the enzymatic activity of mutant Glu(14)Gly is approximately two times higher than wildtype, and that this increase is primarily due to the increased expression and/or stability of the mutant ACAT2 protein. CONCLUSIONS: These results suggest that the genetic variation at Glu(14)Gly is functionally important and may contribute to ACAT2 protein expression and stability. PMID- 25917364 TI - Size, edge, and stage of NSCLC determine the release of CYFRA 21-1 in bloodstream. AB - BACKGROUND: The computed tomography (CT) is the "golden standard" for the assessment of lung cancer progression due to its ability to clearly display the radiomorphologic characteristics. As lung cancer mortality is very high, more comprehensive approaches may be needed for its earlier diagnosis. The research hypothesis was to investigate the relation between the CT morphologic characteristics (size, stage, and edges) of pulmonary lesion and the extent of release of a soluble fragment of cytokeratin 19 being a part of the cytoskeleton of lung epithelial cells. METHODS: This is a retrospective study including 246 pulmonary lesions being diagnosed and subsequently treated at the University Hospital Centre Zagreb, Croatia. The information about the relevant clinical, radiological, and laboratory facts was collected at the time of diagnosis in 164 NSCLC patients, 52 patients with pulmonary metastases, and 30 benign cysts. CYFRA 21-1 was determined by electrochemiluminescence immunoassay. The nonparametric statistical methods were applied. RESULTS: There was a positive correlation between the size and CYFRA 21-1 in NSCLC unlike metastases or cysts (p = 0.0001). The highest values of CYFRA 21-1 were seen in advanced stages of NSCLC and lesions with spiculated edges. CONCLUSIONS: The level of CYFRA 21-1 positively correlates with the greatest size of NSCLC measured by CT. The differences in CYFRA 21-1 according to TNM classification are significant (p = 0.0001): higher values were observed in advanced stages and with tumors having spiculated, lobulated, and poorly defined edges. The combination of CYFRA 21-1 and CT may help articulate the malignancy of pulmonary lesions. PMID- 25917365 TI - Variables determining the development of colistin-associated renal impairment. AB - AIM: The aim of this study was to identify the predictors of acute renal injury associated with colistin treatment. METHODS: The patients who received treatment with colistin for more than 3 days were included in this retrospective cohort study. Acute renal injury was defined by the RIFLE (Risk Injury Failure Loss End stage renal disease) criteria. Patients whose serum creatinine levels increased at least 1.5-fold compared with baseline value were considered as cases with renal injury. The independent variables determining the development of acute renal injury were investigated by survival analysis. RESULTS: A total of 112 cases [67 (59.8 %) were male, median age 64 (range: 18-93) years] were included in the study. Acute renal injury occurred in 66 (58.9 %) patients. Renal injury developed in first 7 days of the colistin therapy in 52 (78.8 %) cases and at day 8-23 in 14 (21.2 %) cases. On the day with highest levels of creatinine, 25 (22.3 %), 17 (15.2 %), and 33 (29.5 %) cases were in 'Risk', 'Injury', and 'Failure' group, respectively, according to RIFLE criteria. We identified three independent risk factors predicting acute colistin-induced renal injury: advanced age, low serum albumin levels, and high serum total bilirubin levels [odds ratio (confidence interval) = 1.022 (1.006-1.037), 0.643 (0.415-0.994), and 1.129 (1.014-1.257), respectively]. CONCLUSIONS: The advanced age, low serum albumin levels, and high serum total bilirubin levels are independent risk factors for colistin-induced nephrotoxicity. PMID- 25917366 TI - HCN channels are a novel therapeutic target for cognitive dysfunction in Neurofibromatosis type 1. AB - Cognitive impairments are a major clinical feature of the common neurogenetic disease neurofibromatosis type 1 (NF1). Previous studies have demonstrated that increased neuronal inhibition underlies the learning deficits in NF1, however, the molecular mechanism underlying this cell-type specificity has remained unknown. Here, we identify an interneuron-specific attenuation of hyperpolarization-activated cyclic nucleotide-gated (HCN) current as the cause for increased inhibition in Nf1 mutants. Mechanistically, we demonstrate that HCN1 is a novel NF1-interacting protein for which loss of NF1 results in a concomitant increase of interneuron excitability. Furthermore, the HCN channel agonist lamotrigine rescued the electrophysiological and cognitive deficits in two independent Nf1 mouse models, thereby establishing the importance of HCN channel dysfunction in NF1. Together, our results provide detailed mechanistic insights into the pathophysiology of NF1-associated cognitive defects, and identify a novel target for clinical drug development. PMID- 25917367 TI - p75NTR ectodomain is a physiological neuroprotective molecule against amyloid beta toxicity in the brain of Alzheimer's disease. AB - In Alzheimer's disease (AD), neurodegenerative signals such as amyloid-beta (Abeta) and the precursors of neurotrophins, outbalance neurotrophic signals, causing synaptic dysfunction and neurodegeneration. The neurotrophin receptor p75 (p75NTR) is a receptor of Abeta and mediates Abeta-induced neurodegenerative signals. The shedding of its ectodomain from the cell surface is physiologically regulated; however, the function of the diffusible p75NTR ectodomain (p75ECD) after shedding remains largely not known. Here, we show that p75ECD levels in cerebrospinal fluid and in the brains of Alzheimer's patients and amyloid-beta precursor protein (APP)/PS1 transgenic mice were significantly reduced, due to inhibition of the sheddase-tumor necrosis factor-alpha-converting enzyme by Abeta. Restoration of p75ECD to the normal level by brain delivery of the gene encoding human p75ECD before or after Abeta deposition in the brain of APP/PS1 mice reversed the behavioral deficits and AD-type pathologies, such as Abeta deposit, apoptotic events, neuroinflammation, Tau phosphorylation and loss of dendritic spine, neuronal structures and synaptic proteins. Furthermore, p75ECD can also reduce amyloidogenesis by suppressing beta-secretase expression and activities. Our data demonstrate that p75ECD is a physiologically neuroprotective molecule against Abeta toxicity and would be a novel therapeutic target and biomarker for AD. PMID- 25917369 TI - Consistent superiority of selective serotonin reuptake inhibitors over placebo in reducing depressed mood in patients with major depression. AB - The recent questioning of the antidepressant effect of selective serotonin reuptake inhibitors (SSRIs) is partly based on the observation that approximately half of company-sponsored trials have failed to reveal a significant difference between active drug and placebo. Most of these have applied the Hamilton depression rating scale to assess symptom severity, the sum score for its 17 items (HDRS-17-sum) serving as effect parameter. In this study, we examined whether the negative outcomes of many SSRI trials may be partly caused by the use of this frequently questioned measure of response. We undertook patient-level post-hoc analyses of 18 industry-sponsored placebo-controlled trials regarding paroxetine, citalopram, sertraline or fluoxetine, and including in total 6669 adults with major depression, the aim being to assess what the outcome would have been if the single item depressed mood (rated 0-4) had been used as a measure of efficacy. In total, 32 drug-placebo comparisons were reassessed. While 18 out of 32 comparisons (56%) failed to separate active drug from placebo at week 6 with respect to reduction in HDRS-17-sum, only 3 out of 32 comparisons (9%) were negative when depressed mood was used as an effect parameter (P<0.001). The observation that 29 out of 32 comparisons detected an antidepressant signal from the tested SSRI suggests the effect of these drugs to be more consistent across trials than previously assumed. Further, the frequent use of the HDRS-17-sum as an effect parameter may have distorted the current view on the usefulness of SSRIs and hampered the development of novel antidepressants. PMID- 25917371 TI - Atypical hidradenitis suppurativa. AB - Hidradenitis suppurativa (HS) is a chronic relapsing inflammatory disease resulting in subcutaneous abscesses, sinus tracts and scarring, arising predominantly in apocrine gland-bearing skin. The sites affected, in order of frequency, are the axillae, groins, perianal and perineal region, mammary and submammary skin, buttocks, and pubic region. Other sites that may be affected more rarely include the chest, eyelids, scalp, retroauricular and preauricular skin, thighs, and abdomen. Research has suggested that mechanical friction and follicular occlusion is the primary cause of HS. HS is one of the conditions of the 'follicular occlusion tetrad', which share a similar pathogenesis. HS at atypical sites may mimic other conditions both clinically and pathologically, so misdiagnosis is possible. We present a case series that illustrates a range of atypical sites affected. Our patients all had severe disease. Satisfactory control has not been achieved despite years of medical and surgical interventions. PMID- 25917370 TI - Pharmacological inhibition of caspase-8 limits lung tumour outgrowth. AB - BACKGROUND AND PURPOSE: Lung cancer is one of the leading causes of cancer death worldwide. Despite advances in therapy, conventional therapy is still the main treatment and has a high risk of chemotherapy resistance. Caspase-8 is involved in cell death and is a recognized marker for poor patient prognosis. EXPERIMENTAL APPROACH: To elucidate the role of caspase-8 in lung carcinoma, we used human samples of non-small cell lung cancer (NSCLC) and a mouse model of carcinogen induced lung cancer. KEY RESULTS: Healthy and cancerous NSCLC samples had similar levels of the active form of caspase-8. Similarly, lung tumour-bearing mice had high levels of the active form of caspase-8. Pharmacological inhibition of caspase-8 by z-IETD-FMK robustly reduced tumour outgrowth and this was closely associated with a reduction in the release of pro-inflammatory cytokines, IL-6, TNF-alpha, IL-18, IL-1alpha, IL-33, but not IL-1beta. Furthermore, inhibition of caspase-8 reduced the recruitment of innate suppressive cells, such as myeloid derived suppressor cells, but not of regulatory T cells to lungs of tumour bearing mice. However, despite the well-known role of caspase-8 in cell death, the apoptotic cascade (caspase-3, caspase-9 and Bcl-2 dependent) was not active in lungs of z-IETD-treated tumour-bearing mice, but instead higher levels of the short segment of c-FLIP (c-FLIPs) were detected. Similarly, human healthy lung samples had higher levels of c-FLIPs than cancerous samples. CONCLUSIONS AND IMPLICATIONS: Our data suggest that caspase-8 is an important orchestrator of cancer-associated inflammation and the presence of short segment of c-FLIP determines whether caspase-8 induces tumour proliferation or tumour arrest/regression in the lung. PMID- 25917372 TI - Culturally appropriate flipcharts improve the knowledge of common respiratory conditions among Northern Territory Indigenous families. AB - ISSUE ADDRESSED: Flipcharts are widely used as education tools in Indigenous health but there is no published quantitative data on their use. As respiratory illness is the most frequent reason for hospitalisation of young children, we developed culturally sensitive flipcharts to educate carers of children on the 3 most common serious respiratory illness (bronchiolitis, pneumonia and bronchiectasis) affecting Indigenous children in the Northern Territory. In this study, we aimed to determine if use of these flipcharts improved the knowledge of these respiratory conditions among carers of Indigenous children admitted to the Royal Darwin Hospital. METHODS: We assessed the knowledge of 60 carers pre- and post-flipchart education using a questionnaire. Pre- and post-flipchart education scores for the three illnesses were combined and were compared using non parametric analyses. RESULTS: Most carers were mothers (n = 43, 72%) aged between 20-40 years (n = 54, 90%) and lived in a remote community (n = 53, 88%). Knowledge of all respiratory conditions improved post education: median scores pre = 8 (Interquartile range 6, 10); post = 12 (10, 14), P = < 0.0001. CONCLUSIONS: The use of culturally appropriate educational flipcharts improves the knowledge of respiratory conditions among carers of Indigenous children hospitalised with common serious respiratory illness. SO WHAT? In the first paediatric quantitative study on the use of flipcharts as a means of providing health education to Indigenous Australians, we have shown that the use of culturally-appropriate flipcharts is an effective method of providing health education. PMID- 25917373 TI - Contractile characteristics of gastrocnemius-soleus muscle in the SOD1G93A ALS mouse model. AB - OBJECTIVES: In the SOD1G93A mouse model of amyotrophic lateral sclerosis (ALS), a selective degeneration of fast-fatigable motor units and consequently an early decline of contractile force in individual fast-twitch muscles have been observed in the preclinical stage. However, most human muscles include fast and slow motor units. Gastrocnemius-soleus group (GS) contains such a mixture of units. METHODS: We have investigated changes in the mechanical properties of GS at different SOD1G93A stages in mice. For this purpose, the tibial nerve was repetitively stimulated with rectangular pulses and the force of GS twitches was recorded using a strain gauge fixed to the Achilles tendon. RESULTS: Isometric and tetanic force were attenuated but not before the first clinical signs developed. However, already at preclinical stages, single twitches showed a slower decay compared to control. Consequently, fusion of GS twitches occurred at lower stimulus rates. Furthermore, already preclinically, the temporal course of successive twitch amplitudes changed during repetitive stimulation at increasing rates. The peak amplitudes as well as the potentiation following decay (fatigue) were lower in preclinical mice than in control. DISCUSSION: The time-lapse analysis of the contractile pattern as well as of the twitch configuration of the mixed muscle GS have revealed distinctive differences between wild-type controls and preclinical SOD1G93A mice. It would be of interest to know whether these preclinical changes are also detectable in ALS patients. PMID- 25917375 TI - A lactone-fused cyclohexadiene as a versatile platform for diversified synthesis of 5,6,5-tricyclic scaffolds. AB - A lactone-fused cyclohexadiene, which can be readily prepared by ruthenium(III) catalyzed [2 + 2 + 2] cyclization of an enediyne, functioned as a versatile platform for the stereoselective synthesis of differently functionalized 5,6,5 tricyclic scaffolds. PMID- 25917374 TI - Xp21 deletion in female patients with intellectual disability: Two new cases and a review of the literature. AB - Xp21 continuous gene deletion syndrome is characterized by complex glycerol kinase deficiency (GK), adrenal hypoplasia congenital (NROB1), intellectual disability and/or Duchenne muscular dystrophy (DMD). The clinical features depend on the size of the deletion, as well as on the number and the nature of the encompassed genes. More than 100 male patients have been reported so far, while only a few cases of symptomatic female carriers have been described. We report here detailed clinical features and X chromosome inactivation analysis in two unrelated female patients with overlapping Xp21 deletions presenting with intellectual disability and inconstant muscular symptoms. PMID- 25917376 TI - Pharmaceutical care of adolescents with diabetes mellitus type 1: the DIADEMA study, a randomized controlled trial. AB - BACKGROUND: Physiological and psychological changes during puberty and a low adherence to complex treatment regimens often result in poor glycemic control in adolescents with type 1 diabetes mellitus (T1DM). The benefit of pharmaceutical care in adults with diabetes mellitus type 2 has been explored; however, evidence in adolescents with T1DM is scarce. OBJECTIVE: To evaluate the impact of pharmaceutical care in adolescents with T1DM provided by pharmacists, in collaboration with physicians and diabetes educators on important clinical outcomes (e.g., HbA1c and severe hypoglycemia) SETTING: At the outpatient Helios Paediatric Clinic and at the 12 regular community pharmacies of the study patients with 14 pharmacists in the Krefeld area, Germany, and at the University Pediatric Clinic with one clinical pharmacist on-site in Sarajevo, Bosnia Herzegovina. METHODS: A randomized, controlled, prospective, multicenter study in 68 adolescents with T1DM. The intervention group received monthly structured pharmaceutical care visits delivered by pharmacists plus supplementary visits and phone calls on an as needed basis, for 6 months. The control group received usual diabetic care. Data were collected at baseline and after 3 and 6 months. MAIN OUTCOME MEASURES: The between-group difference in the change from baseline in glycosylated hemoglobin (HbA1c) and the number of severe hypoglycemic events in both groups. RESULTS: The improvement from baseline in HbA1c was significantly greater in the intervention group than in the control group after 6 months (change from baseline -0.54 vs. +0.32%, p = 0.0075), even after adjustment for country-specific variables (p = 0.0078). However, the effect was more pronounced after only 3 months (-1.09 vs. +0.23%, p = 0.00002). There was no significant between-group difference in the number of severe hypoglycemia events. (p = 0.1276). CONCLUSION: This study suggests that multidisciplinary PhC may add value in the management of T1DM in adolescents with inadequate glycemic control. However, the optimal methods on how to achieve sustained, long-term improvements in this challenging population require further study. PMID- 25917368 TI - The association between lower educational attainment and depression owing to shared genetic effects? Results in ~25,000 subjects. AB - An association between lower educational attainment (EA) and an increased risk for depression has been confirmed in various western countries. This study examines whether pleiotropic genetic effects contribute to this association. Therefore, data were analyzed from a total of 9662 major depressive disorder (MDD) cases and 14,949 controls (with no lifetime MDD diagnosis) from the Psychiatric Genomics Consortium with additional Dutch and Estonian data. The association of EA and MDD was assessed with logistic regression in 15,138 individuals indicating a significantly negative association in our sample with an odds ratio for MDD 0.78 (0.75-0.82) per standard deviation increase in EA. With data of 884,105 autosomal common single-nucleotide polymorphisms (SNPs), three methods were applied to test for pleiotropy between MDD and EA: (i) genetic profile risk scores (GPRS) derived from training data for EA (independent meta analysis on ~120,000 subjects) and MDD (using a 10-fold leave-one-out procedure in the current sample), (ii) bivariate genomic-relationship-matrix restricted maximum likelihood (GREML) and (iii) SNP effect concordance analysis (SECA). With these methods, we found (i) that the EA-GPRS did not predict MDD status, and MDD GPRS did not predict EA, (ii) a weak negative genetic correlation with bivariate GREML analyses, but this correlation was not consistently significant, (iii) no evidence for concordance of MDD and EA SNP effects with SECA analysis. To conclude, our study confirms an association of lower EA and MDD risk, but this association was not because of measurable pleiotropic genetic effects, which suggests that environmental factors could be involved, for example, socioeconomic status. PMID- 25917377 TI - Analysis of the conserved neurotrophic factor MANF in the Drosophila adult brain. AB - Mesencephalic astrocyte-derived neurotrophic factor (MANF) is an evolutionarily conserved neurotrophic factor that supports and protects dopaminergic neurons. The Drosophila MANF (DmMANF) null mutant animals die during early development, and DmMANF is required for the maintenance of dopamine positive neurites. The aim of this study was to investigate the role of DmMANF during later developmental stages. Here we report that DmMANF expression in the adult brain is much wider than in the embryonic and larval stages. It is expressed in both glia and neurons including dopaminergic neurons. Clonal analysis showed that DmMANF is not required cell-autonomously for the differentiation of either glia or dopaminergic neurons. In addition, DmMANF overexpression resulted in no apparent abnormal dopaminergic phenotype while DmMANF silencing in glia resulted in prolonged larval stage. PMID- 25917378 TI - The expression patterns of DNA methylation reprogramming related genes are associated with the developmental competence of cloned embryos after zygotic genome activation in pigs. AB - DNA methylation reprogramming, regulated by DNA methylation and demethylation related genes, is essential for early embryo development; however, it is incomplete in cloned embryos, leading to poor cloning efficiency. Previous studies have shown that DNA methylation inhibitor, 5-aza-2'-deoxycytidine (5-aza dC), could enhance the development of cloned embryos, thus, the genes regulating DNA methylation reprogramming should appropriately express in these embryos. To examine whether there is a correlation between embryo development and the expression patterns of DNA methylation reprogramming related genes, we investigated the developmental progress and transcription levels of candidate genes containing DNA methyltransferases (Dnmt1 and Dnmt3a), ten eleven translocation (Tet) dioxygenases (Tet1, Tet2 and Tet3) and base excision repair related genes including activation induced deamination (Aid), thymine DNA glycosylase (Tdg) and AP endonuclease 1 (Apex1) in porcine early embryos. In this study, our results demonstrated that compared with in vitro fertilized embryos, delayed and reduced development and downregulated transcripts of DNA methylation reprogramming related genes after the 4-cell stage were observed in cloned embryos, showing the significantly (P < 0.05) lower proportions of embryos at the 8-cell, morula and blastocyst stages (19.69% vs 32.64% at 72 h, 16.67% vs 25.49% at 120 h and 19.82% vs 26.29% at 156 h, respectively) and transcription levels of Dnmt3a, Tet1, Tet2, Tet3, Aid, Tdg and Apex1. When cloned embryos were treated with 5-aza-dC, the developmental progress and transcription levels of DNA methylation reprogramming related genes were improved, more similar to those detected in fertilized counterparts. Furthermore, we found that the transcripts of zygotic genome activation and blastocyst quality related genes were also effectively promoted in porcine cloned embryos after 5-aza-dC treatment. In conclusion, our results demonstrated that the disturbed transcripts of DNA methylation reprogramming related genes were observed in porcine cloned embryos, while the enhanced development of porcine cloned embryos induced by 5-aza-dC was accompanied with the improved expression of DNA methylation reprogramming related genes after the 4-cell stage, providing a positive correlation between the expression patterns of DNA methylation reprogramming related genes and the developmental competence of porcine cloned embryos after zygotic genome activation. PMID- 25917379 TI - Tip of the clade on the top of the World--the first fossil Lophopidae (Hemiptera: Fulgoromorpha) from the Palaeocene of Tibet. AB - Lophopidae is a family of planthoppers (Hemiptera: Fulgoromorpha) present today in tropical and subtropical zones of the Old World. The most recent taxonomic studies and phylogeny of these insects do not include the extinct representatives. Therefore, each new discovery of a fossil lophopid is of high interest, giving new insights to their evolutionary history and enabling to test the proposed relationships. The recent findings of extinct Lophopidae in Europe, in various Palaeogene deposits, put in doubts their proposed evolutionary and biogeographic scenario. The new fossil from the Palaeocene of Northern Tibet is related to one of the Lophopidae clades, Apia(+) group, believed to be the most advanced one, and recently distributed in the recent Sundaland-New Guinea Queensland area. A new genus and species Gesaris gnapo gen. et sp. n. provide information on early lophopids diversity and relationships and demonstrates the necessity for a revision of the existing hypotheses for the initial diversification and distributional pattern of the Lophopidae. PMID- 25917380 TI - A universal model of ontogenetic growth. AB - The assumption that a single growth equation can be used to describe all biological objects on different organizational levels and a dimensional analysis are applied in order to substantiate universal model of ontogenetic growth. This model (the mass of a growing organism is a power function of time) is valid only in the initial period of growth. For the whole period of growth, a generalization of the model is advanced; it provides the same accuracy as previously known models of quantitative description of kinetic curves. Within the scope of the developed model, a number of interesting results related to allometry and biological time are obtained. PMID- 25917381 TI - Historical revisionism and the inheritance theories of Darwin and Weismann. PMID- 25917382 TI - Significance of mammalian target of rapamycin in patients with locally advanced stage IV head and neck squamous cell carcinoma receiving induction chemotherapy with docetaxel, cisplatin, and fluorouracil. AB - BACKGROUND: This study evaluated the significance of mammalian target of rapamycin (mTOR) activation on the prognosis of patients with locally advanced head and neck squamous cell carcinoma (HNSCC) receiving induction chemotherapy with docetaxel, cisplatin, and fluorouracil (TPF). METHODS: Immunohistochemistry (IHC) for phosphorylated-mTOR and phosphorylated-p70 ribosomal S6 protein kinase (p70S6K) examined in 107 patients with locally advanced HNSCC receiving TPF was correlated with treatment outcome. The effect of mTOR inhibition on HNSCC cell lines was investigated in vitro and in vivo. RESULTS: Phosphorylated-mTOR expression was independently significantly associated with response to TPF, progression-free survival (PFS), and overall survival (OS). In cell lines and xenograft models, mTOR inhibitor, everolimus, enhanced the effect of docetaxel. CONCLUSION: In patients with locally advanced HNSCC treated with TPF, phosphorylated-mTOR expression was independently associated with prognosis. In vitro and in vivo, concomitant inhibition of mTOR enhanced the effect of docetaxel. Our findings suggest the potential of mTOR as a therapeutic target for locally advanced HNSCC. (c) 2015 Wiley Periodicals, Inc. Head Neck 38: E844-E852, 2016. PMID- 25917383 TI - Investigation of Individual Factors Associated with Anxiety in Youth with Autism Spectrum Disorders. AB - As youth with autism spectrum disorder (ASD) are more likely to experience anxiety than youth in the general population, investigation of associated factors is important for diagnosis and treatment. The present study extended prior research by examining factors associated with caregiver-reported anxiety in 2662 youth (mean age = 8.82 years) with ASD. Logistic regression analyses indicated increases in age, social problems, and cognitive functioning predicted high anxiety group membership. Cognitive functioning moderated the relation of adaptive social behaviors and anxiety. Results from the present study provide support for previously identified factors associated with anxiety; however, further investigation is necessary to uncover additional factors and to explore their relation to anxiety across individuals with ASD with varying levels of cognitive functioning. PMID- 25917384 TI - Ketoprofen as a photoinitiator for anionic polymerization. AB - A new photoinitiating system for anionic polymerization of acrylates based on the efficient photodecarboxylation of Ketoprofen (1) and the related derivatives 3 and 4 that generate the corresponding carbanion intermediates is presented. Carbanion intermediates are confirmed by deuterium incorporation in the trapped Michael adducts and by spectroscopic detection using laser flash photolysis (LFP). This novel anionic initiating system features excitation in the near UV and visible regions, potential characteristics of photocontrolled living polymerization, and metal-free photoinitiators generated from photoexcitation, different from typical anionic polymerization where the polymerizations are initiated by heat and strong base containing alkali metals. PMID- 25917385 TI - The synthesis map is a multidimensional educational tool that provides insight into students' mental models and promotes students' synthetic knowledge generation. AB - Concept mapping was developed as a method of displaying and organizing hierarchical knowledge structures. Using the new, multidimensional presentation software Prezi, we have developed a new teaching technique designed to engage higher-level skills in the cognitive domain. This tool, synthesis mapping, is a natural evolution of concept mapping, which utilizes embedding to layer information within concepts. Prezi's zooming user interface lets the author of the presentation use both depth as well as distance to show connections between data, ideas, and concepts. Students in the class Biology of Cancer created synthesis maps to illustrate their knowledge of tumorigenesis. Students used multiple organizational schemes to build their maps. We present an analysis of student work, placing special emphasis on organization within student maps and how the organization of knowledge structures in student maps can reveal strengths and weaknesses in student understanding or instruction. We also provide a discussion of best practices for instructors who would like to implement synthesis mapping in their classrooms. PMID- 25917386 TI - Twins less frequent than expected among male births in risk averse populations. AB - Male twin gestations exhibit higher incidence of fetal morbidity and mortality than singleton gestations. From an evolutionary perspective, the relatively high rates of infant and child mortality among male twins born into threatening environments reduce the fitness of these gestations, making them more vulnerable to fetal loss. Women do not perceive choosing to spontaneously abort gestations although the outcome may result from estimates, made without awareness, of the risks of continuing a pregnancy. Here, we examine whether the non-conscious decisional biology of gestation can be linked to conscious risk aversion. We test this speculation by measuring the association between household surveys in Sweden that gauge financial risk aversion in the population and the frequency of twins among live male births. We used time-series regression methods to estimate our suspected associations and Box-Jenkins modeling to ensure that autocorrelation did not confound the estimation or reduce its efficiency. We found, consistent with theory, that financial risk aversion in the population correlates inversely with the odds of a twin among Swedish males born two months later. The odds of a twin among males fell by approximately 3.5% two months after unexpectedly great risk aversion in the population. This work implies that shocks that affect population risk aversion carry implications for fetal loss in vulnerable twin pregnancies. PMID- 25917387 TI - From the draining lymph node to the liver: the induction and effector mechanisms of malaria-specific CD8+ T cells. AB - Parasitic protozoa cause considerable disease in humans and, due to their intracellular life cycle, induce robust CD8(+) T cell responses. A greater understanding of the factors that promote and maintain CD8(+) T cell-mediated immunity against these pathogens is likely needed for the development of effective vaccines. Immunization with radiation-attenuated sporozoites, the infectious stage of the malaria parasite transmitted by mosquitoes, is an excellent model to study these questions as CD8(+) T cells specific for a single epitope can completely eliminate parasite infection in the liver. Furthermore, live, radiation-attenuated parasites represent the "gold standard" for malaria vaccination. Here, we will highlight recent studies aimed at understanding the factors required for the induction, recruitment, and maintenance of effector and memory CD8(+) T cells against malaria liver stages. PMID- 25917389 TI - Interval cancer rates in the Irish national breast screening programme. AB - OBJECTIVE: To compare interval cancer rates from the Irish breast screening programme, BreastCheck, for the period 2000-2007 with those from other European countries. METHODS: Data from BreastCheck was linked to National Cancer Registry breast cancer registrations, to calculate numbers of women screened, screen detected cancers, and interval cancers, by year of screening, in the first and second years after screening, and by initial or subsequent screen. Estimated underlying cancer incidence from the period 1996-1999 inclusive was used to calculate proportionate incidence. We calculated the interval cancer ratio as an alternative measure of the burden of interval cancers. RESULTS: There were 372,658 screening records for 178,147 women in the period 2000-2007. The overall interval rate was 9.6 per 10,000 screens. In the first year after screening, the interval cancer rate was 5.8 per 10,000 screens and this increased to 13.4 in the second year after screening. The screen detection rate for the period was 53.6 per 10,000 screened for all screens combined. Initial screens produced a higher detection rate at 66.9 per 10,000 screened compared with subsequent screens with a screen-detected rate of 41.4 per 10,000 screens. CONCLUSION: Interval breast cancer rates for the first years of the programme are within acceptable limits and are comparable with those in other European programmes. Nationwide roll-out together with the adoption of digital mammography may have an impact on interval cancer rates in future years. PMID- 25917390 TI - Does chlorination of seawater reverse osmosis membranes control biofouling? AB - Biofouling is the major problem of reverse osmosis (RO) membranes used for desalting seawater (SW). The use of chlorine is a conventional and common practice to control/prevent biofouling. Unlike polyamide RO membranes, cellulose triacetate (CTA) RO membranes display a high chlorine tolerance. Due to this characteristic, CTA membranes are used in most of the RO plants located in the Middle East region where the elevated seawater temperature and water quality promote the risk of membrane biofouling. However, there is no detailed study on the investigation/characterization of CTA-RO membrane fouling. In this investigation, the fouling profile of a full-scale SWRO desalination plant operating with not only continuous chlorination of raw seawater but also intermittent chlorination of CTA-RO membranes was studied. Detailed water quality and membrane fouling analyses were conducted. Profiles of microbiological, inorganic, and organic constituents of analysed fouling layers were extensively discussed. Our results clearly identified biofilm development on these membranes. The incapability of chlorination on preventing biofilm formation on SWRO membranes could be assigned to its failure in effectively reaching throughout the different regions of the permeators. This failure could have occurred due to three main factors: plugging of membrane fibers, chlorine consumption by organics accumulated on the front side fibers, or chlorine adaptation of certain bacterial populations. PMID- 25917388 TI - CD8 T cells and Mycobacterium tuberculosis infection. AB - Tuberculosis is primarily a respiratory disease that is caused by Mycobacterium tuberculosis. M. tuberculosis can persist and replicate in macrophages in vivo, usually in organized cellular structures called granulomas. There is substantial evidence for the importance of CD4 T cells in control of tuberculosis, but the evidence for a requirement for CD8 T cells in this infection has not been proven in humans. However, animal model data support a non-redundant role for CD8 T cells in control of M. tuberculosis infection. In humans, infection with this pathogen leads to generation of specific CD8 T cell responses. These responses include classical (MHC Class I restricted) and non-classical CD8 T cells. Here, we discuss the potential roles of CD8 T cells in defense against tuberculosis, and our current understanding of the wide range of CD8 T cell types seen in M. tuberculosis infection. PMID- 25917391 TI - Long-term investigation of a novel electrochemical membrane bioreactor for low strength municipal wastewater treatment. AB - A novel and cost-effective electrochemical membrane bioreactor (EMBR) was proposed for low-strength wastewater treatment. In this system, influent organic matter could act as electron donor in the anode chamber and then denitrification was driven on the cathodes. During 270 days of operation, a positive and time-lag correlation was found between temperature and exoelectrogenesis process. At lower temperatures (<10~15 degrees C), power production in the EMBR was negligible and therefore the integration did not improve the reactor performance. With the rebound of water temperatures over 15~20 degrees C, efficient redox reactions were achieved in the EMBR, which subsequently resulted in sludge reduction (27.3% lower than the control MBR) and membrane fouling alleviation. Due to the capture of electrons that were then used at the cathode to drive the denitrification process, the total nitrogen removal efficiency of the EMBR averaged 78.2% at high temperatures, despite the decrease of organic loading rate of the feed for heterotrophic denitrification. Pyrosequencing revealed that the denitrifiers of Denitratisoma, Ottowia, Sulfuritalea and Thiobacillus were notably enriched in the cathode biofilm of the EMBR at high temperatures, and 6.05% of the sequences in the activated sludge were assigned into the denitrification related phylotypes, which was 65% higher compared to that of the control MBR. The enrichment of versatile nitrate/nitrite reducers could be conducive to the autotrophic and heterotrophic denitrification processes. Energy balance analysis also indicated that the total energy consumption of the EMBR was decreased by 20% compared to that of the CMBR (0.386 kWh/m(3) wastewater). Overall, the obtained results clearly demonstrate that this novel EMBR is capable of providing superior effluent quality, alleviating membrane fouling and incorporating into existing treatment facilities for improving the sustainability of wastewater treatment. PMID- 25917392 TI - A structure-based Multiple-Instance Learning approach to predicting in vitro transcription factor-DNA interaction. AB - BACKGROUND: Understanding the mechanism of transcriptional regulation remains an inspiring stage of molecular biology. Recently, in vitro protein-binding microarray experiments have greatly improved the understanding of transcription factor-DNA interaction. We present a method - MIL3D - which predicts in vitro transcription factor binding by multiple-instance learning with structural properties of DNA. RESULTS: Evaluation on in vitro data of twenty mouse transcription factors shows that our method outperforms a method based on simple instance learning with DNA structural properties, and the widely used k-mer counting method, for nineteen out of twenty of the transcription factors. Our analysis showed that the MIL3D approach can utilize subtle structural similarities when a strong sequence consensus is not available. CONCLUSION: Combining multiple-instance learning and structural properties of DNA has promising potential for studying biological regulatory networks. PMID- 25917393 TI - Evidence of monolayer formation via diazonium grafting with a radical scavenger: electrochemical, AFM and XPS monitoring. AB - This paper analyzes the impact of the use of a radical scavenger on organic films generated by aryldiazonium electrografting in terms of thickness, morphology and chemical composition. Glassy carbon (GC) and pyrolyzed photoresist films (PPFs) were modified by electrochemical reduction of 4-nitrobenzenediazonium salt in the presence of various amounts of 2,2-diphenyl-1-picrylhydrazyl (DPPH). The thicknesses of the organic films have been measured by atomic force microscopy (AFM) and the lower threshold values confirm that it is possible to reach a monolayer by radical trapping. X-ray photoelectron spectroscopy (XPS) highlights a decrease in the proportion of nitrophenyl groups grafted via azo bridges as the DPPH concentration decreases and the film thickness increases. A correlation of electrochemical, XPS and AFM data confirms that not all nitrophenyl groups are electroactive in films greater than 2 nm thick. PMID- 25917394 TI - Review article: non-malignant oral manifestations in inflammatory bowel diseases. AB - BACKGROUND: Patients with inflammatory bowel diseases (IBD) may present with lesions in their oral cavity. Lesions may be associated with the disease itself representing an extraintestinal manifestation, with nutritional deficiencies or with complications from therapy. AIM: To review and describe the spectrum of oral nonmalignant manifestations in patients with inflammatory bowel diseases [ulcerative colitis (UC), Crohn's disease (CD)] and to critically review all relevant data. METHODS: A literature search using the terms and variants of all nonmalignant oral manifestations of inflammatory bowel diseases (UC, CD) was performed in November 2014 within Pubmed, Embase and Scopus and restricted to human studies. RESULTS: Oral lesions in IBD can be divided into three categories: (i) lesions highly specific for IBD, (ii) lesions highly suspicious of IBD and (iii) nonspecific lesions. Oral lesions are more common in CD compared to UC, and more prevalent in children. In adult CD patients, the prevalence rate of oral lesions is higher in CD patients with proximal gastrointestinal tract and/or perianal involvement, and estimated to range between 20% and 50%. Oral lesions can also occur in UC, with aphthous ulcers being the most frequent type. Oral manifestations in paediatric UC may be present in up to one-third of patients and are usually nonspecific. CONCLUSIONS: Oral manifestations in IBD can be a diagnostic challenge. Treatment generally involves managing the underlying intestinal disease. In cases presenting with local disabling symptoms and impaired quality of life, local and systemic medical therapy must be considered and/or oral surgery may be required. PMID- 25917395 TI - Conserved V-ATPase c subunit plays a role in plant growth by influencing V-ATPase dependent endosomal trafficking. AB - In plant cells, the vacuolar-type H(+)-ATPases (V-ATPase) are localized in the tonoplast, Golgi, trans-Golgi network and endosome. However, little is known about how V-ATPase influences plant growth, particularly with regard to the V ATPase c subunit (VHA-c). Here, we characterized the function of a VHA-c gene from Puccinellia tenuiflora (PutVHA-c) in plant growth. Compared to the wild type, transgenic plants overexpressing PutVHA-c in Arabidopsis thaliana exhibit better growth phenotypes in root length, fresh weight, plant height and silique number under the normal and salt stress conditions due to noticeably higher V ATPase activity. Consistently, the Arabidopsis atvha-c5 mutant shows reduced V ATPase activity and retarded plant growth. Furthermore, confocal and immunogold electron microscopy assays demonstrate that PutVHA-c is mainly localized to endosomal compartments. The treatment of concanamycin A (ConcA), a specific inhibitor of V-ATPases, leads to obvious aggregation of the endosomal compartments labelled with PutVHA-c-GFP. Moreover, ConcA treatment results in the abnormal localization of two plasma membrane (PM) marker proteins Pinformed 1 (AtPIN1) and regulator of G protein signalling-1 (AtRGS1). These findings suggest that the decrease in V-ATPase activity blocks endosomal trafficking. Taken together, our results strongly suggest that the PutVHA-c plays an important role in plant growth by influencing V-ATPase-dependent endosomal trafficking. PMID- 25917396 TI - Investigation of the GPR39 zinc receptor following inhibition of monoaminergic neurotransmission and potentialization of glutamatergic neurotransmission. AB - Zinc can regulate neural function in the brain via the GPR39 receptor. In the present study we investigated whether inhibition of serotonin, noradrenaline and dopamine synthesis and potentialization of glutamate, via administration of p chlorophenylalanine (pCPA), alpha-methyl-p-tyrosine (alphaMT) and N-methyl-D aspartatic acid (NMDA), respectively, would cause changes in GPR39 levels. Western blot analysis showed GPR39 up-regulation following 3-day administration of alphaMT and NMDA in the frontal cortex, and GPR39 down-regulation following 10 day administration of pCPA, alphaMT, and NMDA in the hippocampus of CD-1 mice. There were no changes in serum zinc levels. Additionally, we investigated tryptophan, tyrosine and glutamate concentrations in the hippocampus and frontal cortex of GPR39 knockout (GPR39 KO) mice. Liquid chromatography-mass spectrometry (LC-MS) showed a significant decrease in tryptophan and tyrosine, but not in glutamate concentrations in the hippocampus of GPR39 KO mice. There were no changes in the frontal cortex between GPR39 KO and wild type. These results indicate a possible role of the GPR39 receptor in monoaminergic and glutamatergic neurotransmission, which plays an important role in the pathophysiology of depression. PMID- 25917397 TI - Histological, ultrastructural and heat shock protein 70 (HSP70) responses to heat stress in the sea cucumber Apostichopus japonicus. AB - The aquaculture industry for Apostichopus japonicus has suffered severe economic and resource losses due to high temperature in recent summers. There is increasing concern about the effect of high temperature on this species. Histological, ultrastructural and HSP70 responses to heat stress were investigated in the intestine of A. japonicus. Tissue degradation was observed in muscular, submucosal and mucosal layers, with significant decrease in plicae circulares of the mucosal layer. Ultrastructural damage intensified with increasing stress time, and indicators of cell apoptosis were evident after 192 h heat stress. Immunostaining showed HSP70 mainly in mucosa and serosa, with faint staining in non-stressed individuals (the control group) and denser staining under stress (the 6, 48 and 192 h groups). Western blot detection confirmed ocurrence of HSP70 in all groups and significant up-regulation under stress. The rapid and persistent response of HSP70 implies its critical role in the heat shock response of A. japonicus. PMID- 25917398 TI - Angiotensin II receptor blockers: a new possible treatment for chronic migraine? AB - The objective is to suggest a possible role of different angiotensin receptor blockers in the treatment of chronic migraine, especially in hypertensive subjects. Chronic migraine is a highly disabling disorder affecting between 1.4 and 2.2 % of the general population. Despite many pharmacological and non pharmacological treatments proposed, the results are rather discouraging. Therefore, we believe that should be highlighted all the possible therapies that may lead to an improvement of the symptomatology. Particularly, data available on efficacy of ARBs in preventing chronic migraine are poor. Methods include case reports, literature review and discussion. We report three cases recently treated with angiotensin II receptor blockers that showed a significant improvement, never previously presented with more conventional treatments, including beta blockers. In all three cases, we obtained the reversibility from a chronic migraine to an episodic. Taking a cue from this observation, we consider desirable large controlled, randomized trials to assess the effectiveness of ARBs both in CM hypertensive patients and in patients who do not require anti hypertensive therapy; furthermore are desirable comparative studies between the various ARB inhibitors to assay any intermolecular differences in efficacy. PMID- 25917399 TI - Corticobasal degeneration: clinical characteristics and multidisciplinary therapeutic approach in 26 patients. AB - Corticobasal syndrome (CBS) is a sporadic tauopathy that manifests by a various combination of motor and cognitive deficits, which makes its diagnosis challenging. Treatment of CBS is symptomatic and based on evidence from other similar disorders due to the lack of studies on CBS. The aim of the study was to investigate low-frequency repetitive transcranial magnetic stimulation (rTMS) as a therapeutic tool in CBS. Twenty-six patients with clinically evident CBS according to Cambridge criteria were followed for 12-18 months while receiving low-frequency rTMS combined with pharmacological, rehabilitation treatment and botulinum toxin injection. The majority of patients are manifested with akinetic rigid syndrome and cognitive dysfunction. There was improvement of the UPDRS and quality of life after 3 months of therapeutic interventions (P < 0.001 and <0.05, respectively). No significant deterioration in cognitive functions was detected over the study period. There was a significant reduction of caregiver burden after 3 months of interventions (P < 0.01); this improvement was maintained up to 18 months. Cognitive dysfunction is a frequent manifestation of CBS. CBS patients can benefit from multidisciplinary therapeutic approach employing low-frequency rTMS. PMID- 25917400 TI - Syndrome of inappropriate antidiuretic hormone secretion due to excessive intake of memantine. PMID- 25917401 TI - Cost-Effectiveness of Therapeutic Drug Monitoring in Diagnosing Primary Aldosteronism in Patients With Resistant Hypertension. AB - Primary aldosteronism (PA) is present in up to 20% of patients with treatment resistant hypertension (TRH). Investigation for PA in patients with TRH is recommended by current guidelines after medication nonadherence is excluded. Studies using therapeutic drug monitoring (TDM) have shown that >50% of patients with TRH are nonadherent to their prescribed antihypertensive medications. However, the relationship between the prevalence of PA and medication adherence as confirmed by TDM has not been previously assessed. A retrospective analysis from a hypertension referral clinic showed that prevalence of PA in adherent patients with TRH by TDM was significantly higher than in nonadherent patients (28% vs 8%, P<.05). Furthermore, cost analysis showed that TDM-guided PA screening was $590.69 less expensive per patient, with minimal impact on the diagnostic accuracy. These data support a TDM-guided PA screening approach as a cost-saving strategy compared with routine PA screening for TRH. PMID- 25917403 TI - Effective treatment with Dabrafenib and Trametinib for a BRAF-mutated metastatic dedifferentiated malignant spindle cell neoplasm. PMID- 25917402 TI - A Moonlighting Enolase from Lactobacillus gasseri does not Require Enzymatic Activity to Inhibit Neisseria gonorrhoeae Adherence to Epithelial Cells. AB - Enolases are generally thought of as cytoplasmic enzymes involved in glycolysis and gluconeogenesis. However, several bacteria have active forms of enolase associated with the cell surface and these proteins are utilized for functions other than central metabolism. Recently, a surface-associated protein produced by Lactobacillus gasseri ATCC 33323 with homology to enolase was found to inhibit the adherence of the sexually transmitted pathogen, Neisseria gonorrhoeae, to epithelial cells in culture. Here, we show that the protein is an active enolase in vitro. A recombinantly expressed, C-terminal His-tagged version of the protein, His6-Eno3, inhibited gonococcal adherence. Assays utilizing inhibitors of enolase enzymatic activity showed that this inhibitory activity required the substrate-binding site to be in an open conformation; however, the enolase enzymatic activity of the protein was not necessary for inhibition of gonococcal adherence. An L. gasseri strain carrying an insertional mutation in eno3 was viable, indicating that eno3 is not an essential gene in L. gasseri 33323. This observation, along with the results of the enzyme assays, is consistent with reports that this strain encodes more than one enolase. Here we show that the three L. gasseri genes annotated as encoding an enolase are expressed. The L. gasseri eno3 mutant exhibited reduced, but not abolished, inhibition of gonococcal adherence, which supports the hypothesis that L. gasseri inhibition of gonococcal adherence is a multifactorial process. PMID- 25917404 TI - Clusterin gene is predominantly regulated by histone modifications in human colon cancer and ectopic expression of the nuclear isoform induces cell death. AB - Clusterin (CLU) is an important glycoprotein involved in various cellular functions. Different reports have mentioned that the two isoforms of CLU; secretary (sCLU) and nuclear (nCLU) have opposite (paradoxical) roles in cancer development. sCLU provides pro-survival signal, whereas nCLU is involved in pro apoptotic signaling. However, the molecular mechanism of CLU gene regulation is not clear as of yet. We hypothesize that CLU gene is regulated by DNA methylation and histone modifications and clusterin plays an important role in colon cancer. To evaluate the hypothesis, we investigated CLU expression in colon cancer tissues and DNA methylation and histone modification status of CLU gene promoter. It is apparent from immonohistology data that both benign and cancerous (primary and metastasis) formalin fixed paraffin embedded (FFPE) tissue samples exhibit CLU expression. However and interestingly only noncancerous tissue samples show nCLU expression. Ectopic expression of nCLU either by epigenetic modulators or by nCLU transfection is responsible for colon cancer cell death. To clarify the molecular mechanisms for regulation of expression of CLU isoforms, we have analyzed DNA methylation and histone modifications, such as histone H3K9me3, H3K27me3, H3K4me3, and H3K9AcS10P patterns around the CLU promoter. There is no remarkable change in the DNA methylation status upon treatment of the cells by AZA, TSA and SAM. Our findings clearly show that promoter histone H3K9me3 and H3K27me3 marks are elevated in comparison to H3K4me3 and H3K9AcS10P marks in colon cancer cell lines. PMID- 25917406 TI - A visible light photocatalytic cross-dehydrogenative coupling/dehydrogenation/6pi cyclization/oxidation cascade: synthesis of 12-nitroindoloisoquinolines from 2 aryltetrahydroisoquinolines. AB - A visible light-induced photocatalytic dehydrogenation/6pi-cyclization/oxidation cascade converts 1-(nitromethyl)-2-aryl-1,2,3,4-tetrahydroisoquinolines into novel 12-nitro-substituted tetracyclic indolo[2,1-a]isoquinoline derivatives. Various photocatalysts promote the reaction in the presence of air and a base, the most efficient being 1-aminoanthraquinone in combination with K3 PO4 . Further, the 12-nitroindoloisoquinoline products can be accessed directly from C1 unfunctionalized 2-aryl-1,2,3,4-tetrahydroisoquinolines by extending the one-pot protocol with a foregoing photocatalytic cross-dehydrogenative coupling reaction, resulting in a quadruple cascade transformation. PMID- 25917405 TI - Resting-state glutamatergic neurotransmission is related to the peak latency of the auditory mismatch negativity (MMN) for duration deviants: An (1)H-MRS-EEG study. AB - Mismatch negativity (MMN), an ERP elicited by a deviant stimulus in a train of standard stimuli, has been suggested to be associated to glutamatergic neurotransmission, mediated by glutamatergic NMDA receptors. In this study, we examined the relationship between interindividual variation of (1)H-MRS-measured glutamate+glutamine (Glx) in the superior temporal gyrus and MMN for duration and frequency deviants in 19 healthy young adults (9 male). We found a significant relationship between the peak latency of the duration-MMN peak and creatine scaled Glx (p = .0003, eta(2) = .43), with increased Glx level being associated to earlier peak of the duration-MMN (r = -.63). In contrast, the amplitude of the duration-MMN was not related to Glx. There was no significant relationship between Glx and the frequency-MMN. The present study is the first to demonstrate that interindividual variation in the glutamatergic neurotransmission affects the MMN response in healthy individuals. PMID- 25917407 TI - Key components of financial-analysis education for clinical nurses. AB - In this study, we identified key components of financial-analysis education for clinical nurses. We used a literature review, focus group discussions, and a content validity index survey to develop key components of financial-analysis education. First, a wide range of references were reviewed, and 55 financial analysis education components were gathered. Second, two focus group discussions were performed; the participants were 11 nurses who had worked for more than 3 years in a hospital, and nine components were agreed upon. Third, 12 professionals, including professors, nurse executive, nurse managers, and an accountant, participated in the content validity index. Finally, six key components of financial-analysis education were selected. These key components were as follows: understanding the need for financial analysis, introduction to financial analysis, reading and implementing balance sheets, reading and implementing income statements, understanding the concepts of financial ratios, and interpretation and practice of financial ratio analysis. The results of this study will be used to develop an education program to increase financial management competency among clinical nurses. PMID- 25917408 TI - ER sheet-tubule balance is regulated by an array of actin filaments and microtubules. PMID- 25917410 TI - Sustainable chemistry for energizing the planet. PMID- 25917409 TI - Risk factors for recurrence of atrial fibrillation in horses after cardioversion to sinus rhythm. AB - BACKGROUND: Although atrial fibrillation (AF) can be successfully treated in horses, recurrence occurs frequently. In humans, atrial function after cardioversion can predict recurrence. OBJECTIVES: To examine the prognostic value of atrial mechanical function at 24 hours after cardioversion and other potential predictor variables for AF recurrence in horses. ANIMALS: 117 horses treated for AF at 4 referral centers. METHODS: Retrospective study. Inclusion criteria were successful cardioversion, echocardiography at 24 hours after cardioversion and >=4 months follow-up. To determine factors associated with AF recurrence, a multivariable survival model was built. RESULTS: 133 AF episodes in 117 horses were included. AF recurred in 36/100 horses with a first AF episode and in 57/133 AF episodes overall. Factors associated with recurrence in horses with a first episode were previous unsuccessful treatment attempt (hazard ratio HR 2.36, 95% confidence interval CI 1.11-4.99, P = .025) and mild or moderate mitral regurgitation (HR 2.70, 95% CI 1.23-5.91, P = .013). When the last AF episode of all horses was included, previous AF (HR 2.53, 1.33-4.82, P = .005) and active left atrial fractional area change <=9.6% (HR 3.43, 1.22-9.67, P = .020) were significant predictors. CONCLUSIONS AND CLINICAL IMPORTANCE: The only echocardiographic variable of left atrial function with significant prognostic value for recurrence was low active left atrial fractional area change. Further research is necessary to evaluate whether echocardiography at a later timepoint could provide more prognostic information. PMID- 25917412 TI - Contextual Influences on Men's Perceptions of Women's Sexual Interest. AB - The current study evaluated whether the sexual relevance of the social environment potentiated men's judgments of women's sexual interest, particularly among men reporting more frequent misperception of a potential partner's sexual interest. Twenty-eight scenes were constructed depicting social environments that were either lower or higher in sexual relevance (e.g., office vs. bar). A full body photograph of one of 14 college-aged women was inserted into each scene; the women all expressed neutral-to-positive affect and varied in provocativeness of dress and attractiveness. A total of 237 undergraduate males viewed each scene and judged how sexually interested and friendly each woman felt. Sexually relevant social environments potentiated men's judgments of women's sexual interest far more than their friendliness. This effect was stronger among more conservatively dressed women and among men reporting more frequent experiences of misperceiving a woman's sexual interest. The findings highlight the contextualized nature of emotional perception, whereby perception of emotion is potentiated in congruent, relative to incongruent, contexts. PMID- 25917411 TI - Assessing the role of masculinity in the transmission of HIV: a systematic review to inform HIV risk reduction counseling interventions for men who have sex with men. AB - HIV affects over 1.2 million people in the United States; a substantial number are men who have sex with men (MSM). Despite an abundance of literature evaluating numerous social/structural and individual risk factors associated with HIV for this population, relatively little is known regarding the individual level role of masculinity in community-level HIV transmission risk. To address this gap, the current analysis systematically reviewed the masculinity and HIV literature for MSM. The findings of 31 sources were included. Seven themes were identified: (1) number of partners, (2) attitudes toward condoms, (3) drug use, (4) sexual positioning, (5) condom decision-making, (6) attitudes toward testing, and (7) treatment compliance. These factors, representing the enactment of masculine norms, potentiate the spread of HIV. The current article aligns these factors into a masculinity model of community HIV transmission. Opportunities for counseling interventions include identifying how masculinity informs a client's cognitions, emotions, and behaviors as well as adapting gender-transformative interventions to help create new conceptualizations of masculinity for MSM clients. This approach could reduce community-level HIV incidence. PMID- 25917413 TI - Multifunctional Metal-Organic Frameworks for Photocatalysis. AB - Metal-organic frameworks (MOFs) have attracted significant research attention in diverse areas due to their unique physical and chemical characteristics that allow their innovative application in various research fields. Recently, the application of MOFs in heterogeneous photocatalysis for water splitting, CO2 reduction, and organic transformation have emerged, aiming at providing alternative solutions to address the world-wide energy and environmental problems by taking advantage of the unique porous structure together with ample physicochemical properties of the metal centers and organic ligands in MOFs. In this review, the latest progress in MOF-involved solar-to-chemical energy conversion reactions are summarized according to their different roles in the photoredox chemical systems, e.g., photocatalysts, co-catalysts, and hosts. The achieved progress and existing problems are evaluated and proposed, and the opportunities and challenges of MOFs and their related materials for their advanced development in photocatalysis are discussed and anticipated. PMID- 25917414 TI - Metamodels to Bridge the Gap Between Modeling and Decision Support. PMID- 25917415 TI - Robust Neuritogenesis-Promoting Activity by Bis(heptyl)-Cognitin Through the Activation of alpha7-Nicotinic Acetylcholine Receptor/ERK Pathway. AB - AIMS: Neurodegenerative disorders are caused by progressive neuronal loss in the brain, and hence, compounds that could promote neuritogenesis may have therapeutic values. In this study, the effects of bis(heptyl)-cognitin (B7C), a multifunctional dimer, on neurite outgrowth were investigated in both PC12 cells and primary cortical neurons. METHODS: Immunocytochemical staining was used to evaluate the proneuritogenesis effects, and Western blot and short hairpin RNA assays were applied to explore the underlying mechanisms. RESULTS: B7C (0.1-0.5 MUM) induced robust neurite outgrowth in PC12 cells, as evidenced by the neurite bearing morphology and upregulation of growth-associated protein-43 expression. In addition, B7C markedly promoted neurite outgrowth in primary cortical neurons as shown by the increase in the length of beta-III-tubulin-positive neurites. Furthermore, B7C rapidly increased ERK phosphorylation. Specific inhibitors of alpha7-nicotinic acetylcholine receptor (alpha7-nAChR) and MEK, but not those of p38 or JNK, blocked the neurite outgrowth as well as ERK phosphorylation induced by B7C. Most importantly, genetic depletion of alpha7-nAChR significantly abolished B7C-induced neurite outgrowth in PC12 cells. CONCLUSION: B7C promoted neurite outgrowth through the activation of alpha7-nAChR/ERK pathway, which offers novel insight into the potential application of B7C in the treatment of neurodegenerative disorders. PMID- 25917416 TI - Electrophysiological Characteristics and Radiofrequency Catheter Ablation of Accessory Pathway Connecting the Right Atrial Appendage and the Right Ventricle. AB - BACKGROUND: The accessory pathway (AP) connecting the right atrial appendage (RAA) and the right ventricle (RV) is rare. OBJECTIVE: We sought to investigate the feature of the AP connecting the RAA and the RV and the efficacy of radiofrequency catheter ablation via the endocardial access. METHODS: We retrospectively analyzed 14 consecutive patients with 14 APs connecting the RAA and the RV managed by 15 procedures between January 2003 and December 2014. RESULTS: Ten patients presented as preexcitation during sinus rhythm. All APs had retrograde conduction. None had either antegrade or retrograde decremental conduction property. Ablation targeting the sites at the tricuspid annulus failed in all patients. They were successfully managed by ablating the atrial insertion sites with a median of 10.5 (range 5-28) radiofrequency applications. Electrograms at the successful target showed high amplitude atrial electrogram and low amplitude or no ventricular electrogram. The atrial insertion sites were at the floor of the RAA in 10 patients and inside the lower lobe of the RAA in the remaining 4 patients. The shortest distance between the successful target and the tricuspid annulus in the right anterior oblique projection was 19.7 +/- 4.0 mm. There were no complications or recurrences during a median follow-up period of 4.3 (range 0.2-11.8) years. CONCLUSION: The APs connecting the RAA and the RV had typical conduction properties. The atrial insertion site favored the floor and the lower lobe of the RAA. Ablation targeting the atrial insertion sites was effective and safe, albeit multiple radiofrequency applications were needed. PMID- 25917417 TI - Environmental Epigenetics and a Unified Theory of the Molecular Aspects of Evolution: A Neo-Lamarckian Concept that Facilitates Neo-Darwinian Evolution. AB - Environment has a critical role in the natural selection process for Darwinian evolution. The primary molecular component currently considered for neo-Darwinian evolution involves genetic alterations and random mutations that generate the phenotypic variation required for natural selection to act. The vast majority of environmental factors cannot directly alter DNA sequence. Epigenetic mechanisms directly regulate genetic processes and can be dramatically altered by environmental factors. Therefore, environmental epigenetics provides a molecular mechanism to directly alter phenotypic variation generationally. Lamarck proposed in 1802 the concept that environment can directly alter phenotype in a heritable manner. Environmental epigenetics and epigenetic transgenerational inheritance provide molecular mechanisms for this process. Therefore, environment can on a molecular level influence the phenotypic variation directly. The ability of environmental epigenetics to alter phenotypic and genotypic variation directly can significantly impact natural selection. Neo-Lamarckian concept can facilitate neo-Darwinian evolution. A unified theory of evolution is presented to describe the integration of environmental epigenetic and genetic aspects of evolution. PMID- 25917419 TI - Successful treatment of neutrophilic dermatosis in patient with Crohn's disease with granulocyte and monocyte adsorption apheresis. PMID- 25917418 TI - Carboplatin in the treatment of Ewing sarcoma: Results of the first Brazilian collaborative study group for Ewing sarcoma family tumors-EWING1. AB - BACKGROUND: Large cooperative group studies have shown the efficacy of risk adapted treatment for Ewing sarcoma. However, validation and local adaptation by National cooperative groups is needed. A multicenter protocol to determine the efficacy and safety of a risk-adapted intensive regimen was developed by the Brazilian cooperative group. PROCEDURE: Patients <30 years old with Ewing sarcoma were eligible. Induction chemotherapy consisted of two cycles of ICE (ifosfamide, carboplatin, and etoposide) followed by two cycles of VDC (vincristine, doxorubicin, and cyclophosphamide), followed by local control. Patients with low risk (LR) disease (localized resectable with normal LDH) received 10 additional alternating courses of IE with VDC. For patients with high-risk (HR) disease (unresectable, pelvic, metastatic, or high LDH), two additional cycles of ICE were given. RESULTS: One-hundred seventy five patients (39% metastatic) were enrolled. Fifty-two patients (29.7%) were LR and 123 (70.3%) were HR. Overall response rate at end of induction was 27.4%. Five-year event-free survival (EFS) and overall survival (OS) estimates were 51.4% and 54.4%, respectively. Patients with localized disease had better outcomes than patients with metastases (5-year EFS 67.9% vs. 25.5%, and 5-year OS 70.3% vs. 29.1%, respectively). On multivariate analysis, the presence of metastatic disease was the only prognostic factor (P < 0.01). CONCLUSION: The VDC/ICE protocol was feasible, and considering the high tumor burden in our population, resulted in comparable results to those reported by cooperative groups in high-income countries. Further adaptation to maximize efficacy and minimize toxicity will be required. PMID- 25917420 TI - Preventing Heterotopic Ossification in Combat Casualties-Which Models Are Best Suited for Clinical Use? AB - BACKGROUND: To prevent symptomatic heterotopic ossification (HO) and guide primary prophylaxis in patients with combat wounds, physicians require risk stratification methods that can be used early in the postinjury period. There are no validated models to help guide clinicians in the treatment for this common and potentially disabling condition. QUESTIONS/PURPOSES: We developed three prognostic models designed to estimate the likelihood of wound-specific HO formation and compared them using receiver operating characteristic (ROC) curve analysis and decision curve analysis (DCA) to determine (1) which model is most accurate; and (2) which technique is best suited for clinical use. METHODS: We obtained muscle biopsies from 87 combat wounds during the first debridement in the United States, all of which were evaluated radiographically for development of HO at a minimum of 2 months postinjury. The criterion for determining the presence of HO was the ability to see radiographic evidence of ectopic bone formation within the zone of injury. We then quantified relative gene expression from 190 wound healing, osteogenic, and vascular genes. Using these data, we developed an Artificial Neural Network, Random Forest, and a Least Absolute Shrinkage and Selection Operator (LASSO) Logistic Regression model designed to estimate the likelihood of eventual wound-specific HO formation. HO was defined as any HO visible on the plain film within the zone of injury. We compared the models accuracy using area under the ROC curve (area under the curve [AUC]) as well as DCA to determine which model, if any, was better suited for clinical use. In general, the AUC compares models based solely on accuracy, whereas DCA compares their clinical utility after weighing the consequences of under- or overtreatment of a particular disorder. RESULTS: Both the Artificial Neural Network and the LASSO logistic regression models were relatively accurate with AUCs of 0.78 (95% confidence interval [CI], 0.72-0.83) and 0.75 (95% CI, 0.71 0.78), respectively. The Random Forest model returned an AUC of only 0.53 (95% CI, 0.48-0.59), marginally better than chance alone. Using DCA, the Artificial Neural Network model demonstrated the highest net benefit over the broadest range of threshold probabilities, indicating that it is perhaps better suited for clinical use than the LASSO logistic regression model. Specifically, if only patients with greater than 25% risk of developing HO received prophylaxis, for every 100 patients, use of the Artificial Network Model would result in six fewer patients who unnecessarily receive prophylaxis compared with using the LASSO regression model while not missing any patients who might benefit from it. CONCLUSIONS: Our findings suggest that it is possible to risk-stratify combat wounds with regard to eventual HO formation early in the debridement process. Using these data, the Artificial Neural Network model may lead to better patient selection when compared with the LASSO logistic regression approach. Future prospective studies are necessary to validate these findings while focusing on symptomatic HO as the endpoint of interest. LEVEL OF EVIDENCE: Level III, prognostic study. PMID- 25917421 TI - Subchondral Calcium Phosphate is Ineffective for Bone Marrow Edema Lesions in Adults With Advanced Osteoarthritis. AB - BACKGROUND: Injury to subchondral bone is associated with knee pain and osteoarthritis (OA). A percutaneous calcium phosphate injection is a novel approach in which subchondral bone marrow edema lesions are percutaneously injected with calcium phosphate. In theory, calcium phosphate provides structural support while it is gradually replaced by bone. However, little clinical evidence supports the efficacy of percutaneous calcium phosphate injections. QUESTIONS/PURPOSES: We asked: (1) Does percutaneous calcium phosphate injection improve validated patient-reported outcome measures? (2) What proportion of patients experience failure of treatment (defined as a low score on the Tegner Lysholm Knee Scoring Scale)? (3) Is there a relationship between outcome and age, sex, BMI, and preoperative grade of OA? METHODS: Between September 2012 and January 2014, we treated 33 patients with percutaneous calcium phosphate injections. Twenty-five satisfied our study inclusion criteria; of those, three patients were lost to followup and 22 (88%; 13 men, nine women) with a median age of 53.5 years (range, 38-70 years) were available for retrospective chart review and telephone evaluation at a minimum of 6 months (median, 12 months; range, 6-24 months). Our general indications for this procedure were the presence of subchondral bone marrow edema lesions observed on MR images involving weightbearing regions of the knee associated with localized pain on weightbearing and palpation and failure to respond to conservative therapy (> 3 months). Patients with pain secondary to extensive nondegenerative meniscal tears with a flipped displaced component at the level of bone marrow edema lesions, or with mechanical axis deviation greater than 8 degrees were excluded. All patients had Grades III or IV chondral lesions (modified Outerbridge grading system for chondromalacia) overlying MRI-identified subchondral bone marrow edema lesions. Percutaneous calcium phosphate injection was performed on the medial tibial condyle (15 patients), the medial femoral condyle (five patients), and the lateral femoral condyle (two patients). Concomitant partial meniscectomy was performed in 18 patients. Preoperative and postoperative scores from the Knee Injury and Arthritis Outcome Score (KOOS) and the Tegner Lysholm Knee Scoring Scale were analyzed. RESULTS: For patients available for followup, the outcome scores improved after treatment. The KOOS improved from a mean of 39.5 +/- 21.8 to 71.3 +/- 23 (95% CI, 18.6-45.2; p < 0.001) and the Tegner and Lysholm score from 48 +/- 15.1 to 77.5 +/- 20.6 (95% CI, 18.8-40.2; p < 0.001). However, seven of the 22 patients had poor clinical outcomes as assessed by the Tegner Lysholm Knee Scoring Scale, whereas three had fair results, five had good results, and seven had excellent results. The postoperative Tegner Lysholm score was inversely related to the preoperative Kellgren-Lawrence OA grade (R(2) = 0.292; F (1.20) = 9.645; p = 0.006). We found no relationship between outcome scores and age, sex, or BMI. CONCLUSIONS: In a study that would have been expected to present a best case analysis (short-term followup, loss to followup of patients with potentially unsatisfactory results, and use of invasive cotreatments including arthroscopic debridements), we found that percutaneous calcium phosphate injection in patients with symptomatic bone marrow edema lesions of the knee and advanced OA yielded poor results in a concerning proportion of our patients. Based on these results, we advise against the use of percutaneous calcium phosphate injections for patients with advanced osteoarthritic changes. LEVEL OF EVIDENCE: Level IV, therapeutic study. PMID- 25917422 TI - Hydrogel-based Delivery of rhBMP-2 Improves Healing of Large Bone Defects Compared With Autograft. AB - BACKGROUND: Autologous bone grafting remains the gold standard in the treatment of large bone defects but is limited by tissue availability and donor site morbidity. Recombinant human bone morphogenetic protein-2 (rhBMP-2), delivered with a collagen sponge, is clinically used to treat large bone defects and complications such as delayed healing or nonunion. For the same dose of rhBMP-2, we have shown that a hybrid nanofiber mesh-alginate (NMA-rhBMP-2) delivery system provides longer-term release and increases functional bone regeneration in critically sized rat femoral bone defects compared with a collagen sponge. However, no comparisons of healing efficiencies have been made thus far between this hybrid delivery system and the gold standard of using autograft. QUESTIONS/PURPOSES: We compared the efficacy of the NMA-rhBMP-2 hybrid delivery system to morselized autograft and hypothesized that the functional regeneration of large bone defects observed with sustained BMP delivery would be at least comparable to autograft treatment as measured by total bone volume and ex vivo mechanical properties. METHODS: Bilateral critically sized femoral bone defects in rats were treated with either live autograft or with the NMA-rhBMP-2 hybrid delivery system such that each animal received one treatment per leg. Healing was monitored by radiography and histology at 2, 4, 8, and 12 weeks. Defects were evaluated for bone formation by longitudinal micro-CT scans over 12 weeks (n = 14 per group). The bone volume, bone density, and the total new bone formed beyond 2 weeks within the defect were calculated from micro-CT reconstructions and values compared for the 2-, 4-, 8-, and 12-week scans within and across the two treatment groups. Two animals were used for bone labeling with subcutaneously injected dyes at 4, 8, and 12 weeks followed by histology at 12 weeks to identify incremental new bone formation. Functional recovery was measured by ex vivo biomechanical testing (n = 9 per group). Maximum torque and torsional stiffness calculated from torsion testing of the femurs at 12 weeks were compared between the two groups. RESULTS: The NMA-rhBMP-2 hybrid delivery system resulted in greater bone formation and improved biomechanical properties compared with autograft at 12 weeks. Comparing new bone volume within each group, the NMA-rhBMP 2-treated group had higher volume (p < 0.001) at 12 weeks (72.59 +/- 18.34 mm(3)) compared with 8 weeks (54.90 +/- 16.14) and 4 weeks (14.22 +/- 9.59). The new bone volume was also higher at 8 weeks compared with 4 weeks (p < 0.001). The autograft group showed higher (p <0.05) new bone volume at 8 weeks (11.19 +/- 8.59 mm(3)) and 12 weeks (14.64 +/- 10.36) compared with 4 weeks (5.15 +/- 4.90). Between groups, the NMA-rhBMP-2-treated group had higher (p < 0.001) new bone volume than the autograft group at both 8 and 12 weeks. Local mineralized matrix density in the NMA-rhBMP-2-treated group was lower than that of the autograft group at all time points (p < 0.001). Presence of nuclei within the lacunae of the autograft and early appositional bone formation seen in representative histology sections suggested that the bone grafts remained viable and were functionally engrafted within the defect. The bone label distribution from representative sections also revealed more diffuse mineralization in the defect in the NMA-rhBMP-2-treated group, whereas more localized distribution of new mineral was seen at the edges of the graft pieces in the autograft group. The NMA rhBMP-2-treated group also revealed higher torsional stiffness (0.042 +/- 0.019 versus 0.020 +/- 0.022 N-m/ degrees ; p = 0.037) and higher maximum torque (0.270 +/- 0.108 versus 0.125 +/- 0.137 N-m; p = 0.024) compared with autograft. CONCLUSIONS: The NMA-rhBMP-2 hybrid delivery system improved bone formation and restoration of biomechanical function of rat segmental bone defects compared with autograft treatment. CLINICAL RELEVANCE: Delivery systems that allow prolonged availability of BMP may provide an effective clinical alternative to autograft treatment for repair of segmental bone defects. Future studies in a large animal model comparing mixed cortical-trabecular autograft and the NMA-rhBMP-2 hybrid delivery system are the next step toward clinical translation of this approach. PMID- 25917423 TI - Whole-body Vibration at Thoracic Resonance Induces Sustained Pain and Widespread Cervical Neuroinflammation in the Rat. AB - BACKGROUND: Whole-body vibration (WBV) is associated with back and neck pain in military personnel and civilians. However, the role of vibration frequency and the physiological mechanisms involved in pain symptoms are unknown. QUESTIONS/PURPOSES: This study asked the following questions: (1) What is the resonance frequency of the rat spine for WBV along the spinal axis, and how does frequency of WBV alter the extent of spinal compression/extension? (2) Does a single WBV exposure at resonance induce pain that is sustained? (3) Does WBV at resonance alter the protein kinase C epsilon (PKCepsilon) response in the dorsal root ganglia (DRG)? (4) Does WBV at resonance alter expression of calcitonin gene related peptide (CGRP) in the spinal dorsal horn? (5) Does WBV at resonance alter the spinal neuroimmune responses that regulate pain? METHODS: Resonance of the rat (410 +/- 34 g, n = 9) was measured by imposing WBV at frequencies from 3 to 15 Hz. Separate groups (317 +/- 20 g, n = 10/treatment) underwent WBV at resonance (8 Hz) or at a nonresonant frequency (15 Hz). Behavioral sensitivity was assessed throughout to measure pain, and PKCepsilon in the DRG was quantified as well as spinal CGRP, glial activation, and cytokine levels at Day 14. RESULTS: Accelerometer-based thoracic transmissibility peaks at 8 Hz (1.86 +/- 0.19) and 9 Hz (1.95 +/- 0.19, mean difference [MD] 0.290 +/- 0.266, p < 0.03), whereas the video-based thoracic transmissibility peaks at 8 Hz (1.90 +/- 0.27), 9 Hz (2.07 +/- 0.20), and 10 Hz (1.80 +/- 0.25, MD 0.359 +/- 0.284, p < 0.01). WBV at 8 Hz produces more cervical extension (0.745 +/- 0.582 mm, MD 0.242 +/- 0.214, p < 0.03) and compression (0.870 +/- 0.676 mm, MD 0.326 +/- 0.261, p < 0.02) than 15 Hz (extension, 0.503 +/- 0.279 mm; compression, 0.544 +/- 0.400 mm). Pain is longer lasting (through Day 14) and more robust (p < 0.01) after WBV at the resonant frequency (8 Hz) compared with 15 Hz WBV. PKCepsilon in the nociceptors of the DRG increases according to the severity of WBV with greatest increases after 8 Hz WBV (p < 0.03). However, spinal CGRP, cytokines, and glial activation are only evident after painful WBV at resonance. CONCLUSIONS: WBV at resonance produces long-lasting pain and widespread activation of a host of nociceptive and neuroimmune responses as compared with WBV at a nonresonance condition. Based on this work, future investigations into the temporal and regional neuroimmune response to resonant WBV in both genders would be useful. CLINICAL RELEVANCE: Although WBV is a major issue affecting the military population, there is little insight about its mechanisms of injury and pain. The neuroimmune responses produced by WBV are similar to other pain states, suggesting that pain from WBV may be mediated by similar mechanisms as other neuropathic pain conditions. This mechanistic insight suggests WBV-induced injury and pain may be tempered by antiinflammatory intervention. PMID- 25917424 TI - Does Blast Medium Affect Heterotopic Ossification in a Blast-amputation Model? AB - BACKGROUND: Heterotopic ossification (HO) develops after nearly 2/3 of traumatic blast amputations in the contemporary battlefield. This phenomenon has potentially devastating consequences for servicemen and women and its pathophysiology warrants further investigation using a previously developed animal blast model. QUESTIONS/PURPOSES: We asked, what is the (1) severity (quantity) and (2) type (location) of HO bone formation after a hindlimb blast amputation with two distinct blast media. We hypothesized that a more "war relevant" blast medium could be a more accurate model and potentially intensify the development of HO. METHODS: Using a Sprague-Dawley rat model, the pathophysiology of ectopic bone formation in a traumatic hindlimb blast amputation was evaluated. Twenty-four animals underwent blast amputations and closure based on a previously established experimental model. Half the amputations were subjected to blasted sand and the other 1/2 to blasted water. Serial orthogonal radiography was performed on each animal until euthanasia at 24 weeks to track the development of HO. Heterotopic bone severity and type were assessed by three independent graders at each time using a novel grading scale to assess quantity and quality of HO. RESULTS: All animals had radiographic evidence of HO develop. No differences were observed in ectopic bone development between sand and water blasting regarding severity or type at any time. Animals that received water and sand blasting had moderate HO develop at 24 weeks (median, 2.0 and 2.5 weeks, respectively; range, 1-3 weeks; difference of medians, 0.5; p=0.67). At the time of euthanasia, 10 animals that were water blasted had Type 3 HO compared with 11 in the sand-blasted group (p=1.00). CONCLUSIONS: Our study showed a clear development of HO after hindlimb blast amputation in a Sprague Dawley rat model; however, no difference was observed in HO development based on the type of blast media. This suggests it is the blast mechanism that induces ectopic bone development, regardless of the blasted medium. The grading scale we developed for our animal-model study provided a reliable means of assessing HO severity and type. CLINICAL RELEVANCE: We anticipate that future investigations will elucidate similarities between service members' wartime extremity injuries and the animal model used in our study, and with focused future research this model may have beneficial therapeutic implications as the pathophysiology of HO development is further understood. PMID- 25917425 TI - Orthopaedic Trainees Retain Knowledge After a Partner Abuse Course: An Education Study. AB - INTRODUCTION: Intimate partner violence (IPV) is a serious global issue that results in a large number of injuries and deaths among women. Educating clinicians about IPV can help providers identify, prevent, and treat victims, and, ultimately, improve care for victims of abuse. We sought to determine the effect of a half-day educational course on IPV for orthopaedic surgical trainees on knowledge and attitudes. QUESTIONS/PURPOSES: We asked (1) whether a half-day educational course on IPV can improve orthopaedic surgical trainees' knowledge and (2) attitudes regarding IPV; and (3) whether a course on IPV can be accepted and viewed as valuable by trainees? METHODS: Using published research on IPV in patients with musculoskeletal injuries, we developed a half-day educational course. The curriculum included lectures and discussion regarding the basics of IPV, the current state of IPV research, what to do when a patient is a victim or perpetrator, and the orthopaedic surgeon's role in recognizing, preventing, and assisting with IPV. All 33 course participants (30 men and three women), all orthopaedic surgical trainees, completed a questionnaire that included general true or false or agree or disagree statements regarding their knowledge, attitudes, and practices of IPV in the musculoskeletal setting; the questionnaire also included a knowledge test of 25 true or false statements. The questionnaire was administered immediately before, immediately after, and 3 months after the course; 76% (25 of 33) took the test immediately after the course and 82% (27 of 33) completed the test at 3 months. Participant knowledge scores were compared across the three different times to determine the effect of the course. RESULTS: Participants increased their knowledge after the course, and the increased knowledge was retained at retesting at 3 months; the mean percentage of correct answers before the course was 57%, which increased to 73% after the course, and was 68% 3 months later (F = 9.505; p = 0.001). Before the course, most of the course participants (30 of 32; 94%) agreed that IPV is an important issue; agreement increased to 100% immediately after the course. The largest change in attitude was in response to the statement: "I am skeptical that the health care system has the resources to screen for IPV." Before the course, 53% (17 of 32) of trainees endorsed this statement, but the percent decreased to 36% (nine of 25) after the course and remained low at 33% (nine of 27), at the 3-month test. CONCLUSIONS: Our findings show that a short course on IPV in patients with musculoskeletal injuries led to an improvement and retention of knowledge 3 months after the course. Based on our findings, we recommend that IPV education be integrated in training programs for orthopaedic surgeons. Future projects should focus on developing and implementing a sustainable education program that can affect practice for healthcare professionals and trainees in multiple clinical settings. PMID- 25917426 TI - Editorial: "Pencil and Paper" Research? Network Meta-analysis and Other Study Designs That Do Not Enroll Patients. PMID- 25917427 TI - A neuroimaging case of chronic arachnoiditis. PMID- 25917429 TI - Kinetics of lymphocyte subpopulations in allogeneic grafted scales of ginbuna crucian carp. AB - In mammals the rejection of allografts is primarily accomplished by cell-mediated immunity including T cells. Recently, considerable studies reveal the existence of helper and cytotoxic T cell subsets in fish. Here we investigate the kinetics of CD4(+) and CD8alpha(+) T cells along with sIgM(+) cells and phagocytic cells in an allogeneic scale graft model using ginbuna crucian carp for understanding the mechanisms of cell-mediated immune response. The results showed that CD4(+) T cells first infiltrated into allogeneic scales followed by CD8alpha(+) and sIgM(+) cells, and finally phagocytic cells appeared in the graft. Furthermore, most of the CD8alpha(+) T cells appeared on the border of the allografted scales at the time of rejection. These results suggest that T cells play crucial roles and work together with other cell types for completion of allograft rejection. PMID- 25917428 TI - Glutamine Regulates Cardiac Progenitor Cell Metabolism and Proliferation. AB - Autologous transplantation of cardiac progenitor cells (CPCs) alleviates myocardial dysfunction in the damaged heart; however, the mechanisms that contribute to their reparative qualities remain poorly understood. In this study, we examined CPC metabolism to elucidate the metabolic pathways that regulate their proliferative capacity. In complete growth medium, undifferentiated CPCs isolated from adult mouse heart proliferated rapidly (Td = 13.8 hours). CPCs expressed the Glut1 transporter and their glycolytic rate was increased by high extracellular glucose (Glc) concentration, in the absence of insulin. Although high Glc concentrations did not stimulate proliferation, glutamine (Gln) increased CPC doubling time and promoted survival under conditions of oxidative stress. In comparison with Glc, pyruvate (Pyr) or BSA-palmitate, Gln, when provided as the sole metabolic substrate, increased ATP-linked and uncoupled respiration. Although fatty acids were not used as respiratory substrates when present as a sole carbon source, Gln-induced respiration was doubled in the presence of BSA-palmitate, suggesting that Gln stimulates fatty acid oxidation. Additionally, Gln promoted rapid phosphorylation of the mTORC1 substrate, p70S6k, as well as retinoblastoma protein, followed by induction of cyclin D1 and cdk4. Inhibition of either mTORC1 or glutaminolysis was sufficient to diminish CPC proliferation, and provision of cell permeable alpha-ketoglutarate in the absence of Gln increased both respiration and cell proliferation, indicating a key role of Gln anaplerosis in cell growth. These findings suggest that Gln, by enhancing mitochondrial function and stimulating mTORC1, increases CPC proliferation, and that interventions to increase Gln uptake or oxidation may improve CPC therapy. PMID- 25917430 TI - The p27 Pathway Modulates the Regulation of Skeletal Growth and Osteoblastic Bone Formation by Parathyroid Hormone-Related Peptide. AB - Parathyroid hormone-related peptide (PTHrP) 1-84 knock-in mice (Pthrp KI) develop skeletal growth retardation and defective osteoblastic bone formation. To further examine the mechanisms underlying this phenotype, microarray analyses of differential gene expression profiles were performed in long bone extracts from Pthrp KI mice and their wild-type (WT) littermates. We found that the expression levels of p27, p16, and p53 were significantly upregulated in Pthrp KI mice relative to WT littermates. To determine whether p27 was involved in the regulation by PTHrP of skeletal growth and development in vivo, we generated compound mutant mice, which were homozygous for both p27 deletion and the Pthrp KI mutation (p27(-/-) Pthrp KI). We then compared p27(-/-) Pthrp KI mice with p27(-/-), Pthrp KI, and WT littermates. Deletion of p27 in Pthrp KI mice resulted in a longer lifespan, increased body weight, and improvement in skeletal growth. At 2 weeks of age, skeletal parameters, including length of long bones, size of epiphyses, numbers of proliferating cell nuclear antigen (PCNA)-positive chondrocytes, bone mineral density, trabecular bone volume, osteoblast numbers, and alkaline phosphatase (ALP)-, type I collagen-, and osteocalcin-positive bone areas were increased in p27(-/-) mice and reduced in both Pthrp KI and p27(-/-) Pthrp KI mice compared with WT mice; however, these parameters were increased in p27(-/-) Pthrp KI mice compared with Pthrp KI mice. As well, protein expression levels of PTHR, IGF-1, and Bmi-1, and the numbers of total colony-forming unit fibroblastic (CFU-f) and ALP-positive CFU-f were similarly increased in p27(-/-) Pthrp KI mice compared with Pthrp KI mice. Our results demonstrate that deletion of p27 in Pthrp KI mice can partially rescue defects in skeletal growth and osteoblastic bone formation by enhancing endochondral bone formation and osteogenesis. These studies, therefore, indicate that the p27 pathway may function downstream in the action of PTHrP to regulate skeletal growth and development. PMID- 25917431 TI - On the road to somewhere: Brain potentials reflect language effects on motion event perception. AB - Recent studies have identified neural correlates of language effects on perception in static domains of experience such as colour and objects. The generalization of such effects to dynamic domains like motion events remains elusive. Here, we focus on grammatical differences between languages relevant for the description of motion events and their impact on visual scene perception. Two groups of native speakers of German or English were presented with animated videos featuring a dot travelling along a trajectory towards a geometrical shape (endpoint). English is a language with grammatical aspect in which attention is drawn to trajectory and endpoint of motion events equally. German, in contrast, is a non-aspect language which highlights endpoints. We tested the comparative perceptual saliency of trajectory and endpoint of motion events by presenting motion event animations (primes) followed by a picture symbolising the event (target): In 75% of trials, the animation was followed by a mismatching picture (both trajectory and endpoint were different); in 10% of trials, only the trajectory depicted in the picture matched the prime; in 10% of trials, only the endpoint matched the prime; and in 5% of trials both trajectory and endpoint were matching, which was the condition requiring a response from the participant. In Experiment 1 we recorded event-related brain potentials elicited by the picture in native speakers of German and native speakers of English. German participants exhibited a larger P3 wave in the endpoint match than the trajectory match condition, whereas English speakers showed no P3 amplitude difference between conditions. In Experiment 2 participants performed a behavioural motion matching task using the same stimuli as those used in Experiment 1. German and English participants did not differ in response times showing that motion event verbalisation cannot readily account for the difference in P3 amplitude found in the first experiment. We argue that, even in a non-verbal context, the grammatical properties of the native language and associated sentence-level patterns of event encoding influence motion event perception, such that attention is automatically drawn towards aspects highlighted by the grammar. PMID- 25917432 TI - High dietborne Cu and Cd induced genotoxicity of Nile tilapia (Oreochromis niloticus). AB - In this study, the effects of fish diet contaminated with Cu, Cd and Cu+Cd on Nile tilapia, was demonstrated by evaluating its bioaccumulation in the muscle and by testing the cytogenetic profile. Fish exposed to diet contaminated with Cu, Cd or their mixture had a significant increase in the number of chromosomal abnormalities and an inhibition of the mitotic index. Our study revealed high muscle Cu or Cd content in fish fed with diet contaminated with high dietborne Cu, Cd, Cu and Cd. It also revealed that the chromosomal abnormalities were higher for fish fed diet Cd contaminated and Cu+Cd contaminated diets than those fed diet Cu contaminated diet. Thus, maybe fish diets contaminated with Cu, Cd, Cu+Cd induced genotoxicity and mutation. Also, maybe high concentrations of Cu and Cd in fish tissue resulted from feeding on Cu and Cd contaminated diets, are dangerous for human consumption. PMID- 25917433 TI - Are red gourami (Colisa labiosa) low xenobiotic metabolizers? Elucidation of in vivo pharmacokinetics of pyrene as a model substrate. AB - Red gourami (Colisa labiosa) have previously been shown to have low levels of pyrene-metabolizing activity. In this study, other pharmacokinetic factors of pyrene in C. labiosa were compared to those in Japanese medaka (Oryzias latipes). Results indicated that the two species labiosa absorbed pyrene in similar amounts. However, excretion of pyrene metabolites from C. labiosa over an 8-day period was lower than those from O. latipes. These findings show that C. labiosa has low ability to metabolize pyrene and to excrete pyrene and its metabolites from the body, and is therefore considered an accumulator of these chemicals. C. labiosa has unique characteristics with regard to pyrene pharmacokinetics. Knowledge about interspecies differences in pharmacokinetics is crucial in determining the endangered species to xenobiotic exposure. PMID- 25917434 TI - Comparison of air-Q and Ambu Aura-i for controlled ventilation in infants: a randomized controlled trial. AB - BACKGROUND: The air-Q is a new supraglottic airway device (SAD) and has been increasingly used as a primary airway device and as a conduit for tracheal intubation in children as well as in adults. This device has either performed equally or better than other SADs in children. The Ambu Aura-i is a commonly used SAD in children undergoing various short surgical procedures. However, limited literature is available evaluating the safety and efficacy of the air-Q and the Ambu Aura-i in small children. We, therefore, conducted this study to compare the clinical performance of these two airway devices in infants weighing up to 10 kg. Our hypothesis is that air-Q, due to its improved and larger cuff design will yield better airway seal pressures as compared with the Ambu Aura-i. METHODS: Sixty-four ASA I-II infants weighing <10 kg undergoing elective ophthalmic surgery were randomly assigned to receive either an air-Q or the Ambu Aura-i. After induction of general anesthesia (GA) and muscle relaxation, we measured oropharyngeal leak pressure (OLP) as the primary outcome. The secondary end points measured were time to insert, first insertion success rate, fiberoptic grade (FO) of laryngeal view and any other airway complications like trauma, laryngospasm, and desaturation. RESULTS: The air-Q ILA provided significantly higher OLP as compared with the Ambu Aura-i [20.2 +/- 4.6 cm H2 O, CI 18.55 21.88; vs 16.2 +/- 5.6 cmH2 O, CI 14.27-18.25, P = 0.003; mean difference 4 +/- 1.29 cm H2 O, CI 1.41-6.58]. However, the Ambu Aura-i required significantly less time for its insertion (14.6 +/- 2.8 s, CI 13.66-15.70; vs 16.3 +/- 1.5 s, CI 15.75-16.86, P = 0.005; mean difference 1.625 +/- 0.56 s, CI 0.48-2.76). There were no differences in first insertion success rate, FO view, and postoperative complications. CONCLUSION: We conclude that air-Q may be considered superior to Ambu Aura-i in infants for controlled ventilation as it provides higher airway sealing pressures. PMID- 25917435 TI - Expert review--identification of intra-partum fetal compromise. AB - Whilst most cases of cerebral palsy occur as a consequence of an ante-natal insult, a significant proportion, particularly in the term fetus, are attributable to intra-partum hypoxia. Intra-partum monitoring using continuous fetal heart rate assessment has led to an increased incidence of operative delivery without a concurrent reduction in the incidence of cerebral palsy. Despite this, birth asphyxia remains the strongest and most consistent risk factor for cerebral palsy in term infants. This review evaluates current intra partum monitoring techniques as well as alternative approaches aimed at better identification of the fetus at risk of compromise in labour. PMID- 25917436 TI - Computerized fetal heart rate analysis in the prediction of myocardial damage in pregnancies with placental insufficiency. AB - OBJECTIVE: To evaluate the reliability of fetal heart rate (FHR) parameters analyzed by computerized cardiotocography (cCTG) in predicting myocardial damage in pregnancies with placental insufficiency. STUDY DESIGN: We evaluated 38 patients with placental insufficiency detected before 34 weeks of gestation. All patients underwent 30 min of cCTG (Sonicaid Fetal Care, version 2.2) and Doppler of umbilical artery, middle cerebral artery, and ductus venosus. Umbilical vein blood samples were collected at birth to determine fetal cardiac Troponin T, and a >=0.09ng/ml value was deemed a sign of myocardial damage. RESULTS: The fetuses with myocardial damage (39%) showed significantly increased values of umbilical artery pulsatility index z-score (P=0.003), ductus venosus pulsatility index z score (P=0.007), basal FHR (P=0.033) and periods of low episodes (P=0.038). The number of small accelerations and the short-term variation (STV) were significantly reduced in the group with myocardial damage (P=0.013 and P=0.003, respectively). Logistic regression analysis identified STV and gestational age at delivery as independent predictors for fetal myocardial damage, with area under ROC curve of 0.91. CONCLUSIONS: Computerized cardiotocography parameters may be useful in the management of early onset placental insufficiency, and the association of STV with gestational age could play a role in detecting myocardial injury in pregnancies with placental insufficiency. PMID- 25917437 TI - Association between maternal tumor necrosis factor-alpha G308A polymorphism and interferon-gamma A874T polymorphism and risk of preterm birth: a meta-analysis. AB - OBJECTIVE(S): This article was undertaken to investigate the association between tumor necrosis factor-alpha (TNF-alpha) G308A polymorphism and interferon-gamma (INF-gamma) A874T polymorphism and risk of preterm birth (PTB) by performing a meta-analysis of available studies. STUDY DESIGN: Articles were chosen based on PubMed, EMBASE, Web of science, and China Biology Medicine (CBM) databases with no language restriction from their inceptions to 1 March, 2014. Specific inclusion criteria were used to evaluate articles. Meta-analysis was performed by using a random or fixed effect model with STATA 11.0 software. We estimated the summary odds ratios (ORs) with its corresponding 95% confidence interval (95%CI) to assess the association. RESULTS: 21 eligible case-control studies with a total of 2103 cases and 5070 controls were finally included into this meta-analysis. Pooled analysis showed that A allele of TNF-alpha G308A was not associated with increased PTB risk (OR=0.84, 95%CI: 0.65-1.07, p=0.167 for G vs. A). Stratifying analysis for ethnicity and different definition of PTB also indicated that A allele was not associated with increased PTB risk. However, the meta-analysis showed that INF-gamma A874T polymorphism was associated with the increased risk of PTB (OR=1.14, 95%CI: 1.11-1.73, p=0.004 for A vs. T). Stratifying analysis was not performed due to the small sample size. CONCLUSION(S): TNF-alpha G308A polymorphism was not associated with an increased risk of PTB, but INF-gamma A874T polymorphism may contribute to increasing susceptibility to PTB. Detection of polymorphism of INF-gamma A874T might be a promising biomarker for the diagnosis and prognosis of preterm delivery. PMID- 25917438 TI - Gastric cancer. Breathing a sigh of relief for noninvasive cancer detection. PMID- 25917439 TI - Gut microbiota. Host-microbe interactions and the enteric nervous system: a new connection? PMID- 25917440 TI - Hepatitis. Can antihistamines treat HCV? PMID- 25917441 TI - Quantitative tissue-tracking cardiac magnetic resonance (CMR) of left atrial deformation and the risk of stroke in patients with atrial fibrillation. AB - BACKGROUND: Recent evidence suggests that left atrial (LA) dysfunction may be mechanistically contributing to cerebrovascular events in patients with atrial fibrillation (AF). We investigated the association between regional LA function and a prior history of stroke during sinus rhythm in patients referred for catheter ablation of AF. METHODS AND RESULTS: A total of 169 patients (59 +/- 10 years, 74% male, 29% persistent AF) with a history of AF in sinus rhythm at the time of pre-ablation cardiac magnetic resonance (CMR) were analyzed. The LA volume, emptying fraction, strain (S), and strain rate (SR) were assessed by tissue-tracking cardiac magnetic resonance. The patients with a history of stroke or transient ischemic attack (n=18) had greater LA volumes (Vmax and Vmin; P=0.02 and P<0.001, respectively), lower LA total emptying fraction (P<0.001), lower LA maximum and pre-atrial contraction strains (Smax and SpreA; P<0.001 and P=0.01, respectively), and lower absolute values of LA SR during left ventricular (LV) systole and early diastole (SRs and SRe; P=0.005 and 0.03, respectively) than those without stroke/transient ischemic attack (n=151). Multivariable analysis demonstrated that the LA reservoir function, including total emptying fraction, Smax, and SRs, was associated with stroke/transient ischemic attack (odds ratio 0.94, 0.91, and 0.17; P=0.03, 0.02, and 0.04, respectively) after adjusting for the CHA2DS2-VASc score and LA Vmin. CONCLUSIONS: Depressed LA reservoir function assessed by tissue-tracking cardiac magnetic resonance is significantly associated with a prior history of stroke/transient ischemic attack in patients with AF. Our findings suggest that assessment of LA reservoir function can improve the risk stratification of cerebrovascular events in AF patients. PMID- 25917443 TI - The early stage of the atrial electroanatomic remodeling as substrates for atrial fibrillation in hypertensive patients. PMID- 25917442 TI - Efficacy and safety of vorapaxar as approved for clinical use in the United States. PMID- 25917444 TI - Variability of antithrombotic dosing among veterans presenting with acute coronary syndrome. AB - BACKGROUND: Antithrombotic therapy for acute coronary syndrome (ACS) patients is recommended by clinical practice guidelines. Appropriate dosing of antithrombotic therapy is necessary to ensure effectiveness and safety and is an American College of Cardiology/American Heart Association ST elevated myocardial infarction/non-ST elevated myocardial infarction performance measure. This study describes the variability in dosing of unfractionated heparin (UH) and low molecular-weight heparin (LMWH) in an integrated health care system with electronic medical records and computerized physician order entry (CPOE). METHODS AND RESULTS: This was a mixed-methods study of veterans presenting with ACS at 135 Veterans Health Administration hospitals from 2009 to 2011. Patients hospitalized with ACS and received antithrombotic therapy were included (n=36 682). The cohort was 98% male with an average age of 66 years and median body mass index (BMI) of 28.6. The average percentage of patients by hospital who received an above-recommended dose of either antithrombotic was 7.5% and ranged 0% to 32.0%. By individual therapy, the average percentage of patients by hospital who received an above-recommended dose of UH was 1.2% and LMWH was 12.9%. Risk-adjusted analyses demonstrated that older age and higher BMI were associated with lower risk for receiving a dose above recommended levels. Additionally, there was an association between antithrombotic ordered by a resident and higher risk of the patient receiving an above-recommended dose. Qualitative interviews supported the quantitative findings by highlighting the need to use current patient weight and the need to adequately train providers on the use of CPOE to improve antithrombotic dosing. CONCLUSION: This study found wide hospital variability in dosing of antithrombotics above the recommended level for patients treated for ACS. PMID- 25917445 TI - Unravelling complexity in seagrass systems for management: Australia as a microcosm. AB - Environmental decision-making applies transdisciplinary knowledge to deliver optimal outcomes. Here we synthesise various aspects of seagrass ecology to aid environmental decision-making, management and policy. Managers often mediate conflicting values and opinions held by different stakeholders. Critical to this role is understanding the drivers for change, effects of management actions and societal benefits. We use the diversity of seagrass habitats in Australia to demonstrate that knowledge from numerous fields is required to understand seagrass condition and resilience. Managers are often time poor and need access to synthesised assessments, commonly referred to as narratives. However, there is no single narrative for management of seagrass habitats in Australia, due to the diversity of seagrass meadows and dominant pressures. To assist the manager, we developed a classification structure based on attributes of seagrass life history, habitat and meadow form. Seagrass communities are formed from species whose life history strategies can be described as colonising, opportunistic or persistent. They occupy habitats defined by the range and variability of their abiotic environment. This results in seagrass meadows that are either transitory or enduring. Transitory meadows may come and go and able to re-establish from complete loss through sexual reproduction. Enduring meadows may fluctuate in biomass but maintain a presence by resisting pressures across multiple scales. This contrast reflects the interaction between the spatial and temporal aspects of species life history and habitat variability. Most management and monitoring strategies in place today favour enduring seagrasses. We adopt a functional classification of seagrass habitats based on modes of resilience to inform management for all seagrass communities. These concepts have world-wide relevance as the Australian case-studies have many analogues throughout the world. Additionally, the approach used to classify primary scientific knowledge into synthesised categories to aid management has value for many other disciplines interfacing with environmental decision-making. PMID- 25917446 TI - Human effects on ecological connectivity in aquatic ecosystems: Integrating scientific approaches to support management and mitigation. AB - Understanding the drivers and implications of anthropogenic disturbance of ecological connectivity is a key concern for the conservation of biodiversity and ecosystem processes. Here, we review human activities that affect the movements and dispersal of aquatic organisms, including damming of rivers, river regulation, habitat loss and alteration, human-assisted dispersal of organisms and climate change. Using a series of case studies, we show that the insight needed to understand the nature and implications of connectivity, and to underpin conservation and management, is best achieved via data synthesis from multiple analytical approaches. We identify four key knowledge requirements for progressing our understanding of the effects of anthropogenic impacts on ecological connectivity: autecology; population structure; movement characteristics; and environmental tolerance/phenotypic plasticity. Structuring empirical research around these four broad data requirements, and using this information to parameterise appropriate models and develop management approaches, will allow for mitigation of the effects of anthropogenic disturbance on ecological connectivity in aquatic ecosystems. PMID- 25917447 TI - An Acute Acetyl Fentanyl Fatality: A Case Report With Postmortem Concentrations. AB - In this case report, we present an evaluation of the distribution of postmortem concentrations of acetyl fentanyl in a fatality attributed to the drug. A young man who had a history of heroin abuse was found deceased at his parents' home. Toxicology testing, which initially screened positive for fentanyl by ELISA, subsequently confirmed acetyl fentanyl by gas chromatography-mass spectrometry specific ion monitoring (GC-MS SIM) analysis following liquid-liquid extraction. No other drugs or medications, including fentanyl, were detected. The acetyl fentanyl peripheral blood concentration was quantified at 260 ng/mL compared with the central blood concentration of 250 ng/mL. The liver concentration was 1,000 ng/kg, the vitreous was 240 ng/mL and the urine was 2,600 ng/mL. The cause of death was certified due to acute acetyl fentanyl intoxication, and the manner of death was certified as an accident. PMID- 25917448 TI - In vitro cytotoxicity evaluation of HDAC inhibitor Apicidin in pancreatic carcinoma cells subsequent time and dose dependent treatment. AB - Apicidin is a potent histone deacetylase inhibitor (HDACI) that selectively binds to histone deacetylases (HDACs) class I and interferes with the deacetylation process, which results in modification of acetylation level of cellular proteins. The aim of the study was to investigate the potential time and dose dependent cytotoxicity of the test compound, Apicidin, in pancreatic cancer cells Capan-1 and Panc-1 as well as estimate maximal tolerable dose (MTD) of the test agent and determine EC50 using four complementary colorimetric cytotoxicity or viability assays. The cells were treated with increasing concentrations of Apicidin (0 5000nM) for 2, 4 and 6h (short term exposure) or 24, 48 and 72h (long term exposure) before conducting cytotoxic analyses with lactate dehydrogenase assay or viability analyses with sulforhodamine B (SRB), methyl tetrazolium (MTT) and crystal violet (CV) assays. In order to investigate whether Apicidin irreversibly affects the cells already during the short term exposure, the medium containing Apicidin was removed and replaced with fresh culturing medium after 6h of treatment. The cells were then incubated for additional 24, 48 or 72h before carrying out the analysis. The results obtained from cytotoxicity and viability assays indicated, that Apicidin was well tolerated by both cell lines at concentrations below 100nM at any given time point and at all applied concentrations during the short term (6h or less) treatment. Continuous prolonged term exposures (48h or greater) of the cells to Apicidin with concentration exceeding 100nM resulted in significantly increasing cytotoxicity and sustained significant loss of cell viability. Moreover, long term exposure of pancreatic cancer cells Capan-1 and Panc-1 to Apicidin concentrations exceeding 100nM showed an initial anti-proliferative effect before cytotoxicity onset. In summary, MTD was exposure time dependent and estimated to 100nM for long term treatment and to at least 5000nM for treatment not greater than 6h. EC50 concentration of Apicidin was established after long term treatment, however with some variation when comparing the different assays and cell lines. Results from this study may encourage reinvestigating the capacity of potent HDACI Apicidin as an attractive agent for interfering with the deacetylation process catalyzed by HDACs for potential pancreatic cancer intervention. PMID- 25917449 TI - Structurally dynamic hydrogels derived from 1,2-dithiolanes. AB - The design and generation of adaptable materials derived from structurally dynamic polymers provides a strategy for generating smart materials that can respond to environmental stimuli or exhibit self-healing behavior. Herein we report an expedient organocatalytic ring-opening polymerization of cyclic carbonates containing pendant dithiolanes (trimethylene carbonate/dithiolane, TMCDT) from poly(ethylene oxide) diols to generate water-soluble triblock (ABA) copolymers containing a central poly(ethylene oxide) block and terminal dithiolane blocks. Hydrogels generated from the triblock copolymers and a cross linking dithiol exhibited dynamic behavior as a result of the reversible ring opening of the pendant 1,2-dithiolanes. These materials exhibit self-healing behavior, can be injected through a syringe, and rapidly recover their mechanical properties after a severe strain deformation. The dynamic properties of these gels can be modulated with the number of dithiolane units, pH, and temperature. PMID- 25917450 TI - Siblings of children with cancer--the price they pay to function. PMID- 25917451 TI - Addressing psychosocial needs of partners of breast cancer patients: a pilot program using social workers to improve communication and psychosocial support. AB - INTRODUCTION: Psychosocial (PsySoc) distress in caregivers is a well-described entity, with some caregivers experiencing more distress than patients themselves. The American College of Surgeons' Commission on Cancer mandates that psychosocial services be provided to all cancer patients and their caregivers, through the entire continuum of cancer care. METHODS: We developed a program for newly diagnosed breast cancer patients and their partners. Both were screened for biopsychosocial stressors. The couple was then paired with two clinican-educators trained in communication and gender differences, who educated the couple in communication-based problem solving and provided referrals to supportive services. RESULTS: Eighty-six patients and 82 partners returned surveys. Compared to partners, patients were more likely to report feeling anxious or fearful (59 vs. 38%, p = 0.014), report difficulty in managing their emotions (46 vs. 11%, p = 0.003), and experience distress over being unable to take care of themselves (37 vs. 6%, p = 0.000). Interestingly, there was no difference between patients and partners in feeling unsupported by their partner (6 vs. 5%, p = 0.85) or in feeling down or depressed (29 vs. 30%, p = 0.96). DISCUSSION: Both patients and partners experience significant distress after a breast cancer diagnosis. We found that partners are equally likely to feel unsupported by their partner (patient) and feel down or depressed. Further study is needed to learn about both patients' and partners' significant distress over lack of support. Partner focused PsySoc interventions should be initiated in all cancer centers to address the emotional needs of both breast cancer patients and their partners. PMID- 25917452 TI - A novel Anxa2-interacting protein Ebp1 inhibits cancer proliferation and invasion by suppressing Anxa2 protein level. AB - Anxa2 is dysregulated in many types of carcinomas and implicated in several pivotal biological functions, such as angiogenesis, cell proliferation, invasion, and metastasis. We previously demonstrated that upregulation of Anxa2 enhances the proliferation and invasion of breast cancer cells. However, the detailed mechanism remains unclear. In this study, co-immunoprecipitation and LC-MS/MS based interactome approach were employed to screen potential Anxa2 binding proteins. A total of 312 proteins were identified as candidate Anxa2 interacting partners. Using Gene Ontology, pathway annotation, and protein-protein interaction analyses, we constructed a connected network for Anxa2 interacting proteins, and Ebp1 may function as a "hub" in the Anxa2 interaction network. Moreover, Ebp1 knockdown resulted in enhanced cell proliferation and invasion, as well as increased expression of Anxa2. Furthermore, the abundance of cyclin D1 and the phosphorylation of Erk1/2 were increased in Ebp1 inhibited cells. This finding is consistent with a previous study, in which upregulation of Anxa2 results in an increased cyclin D1 expression and Erk1/2 activation. Our results suggest a novel function of Ebp1 as a binding protein and negative regulator of Anxa2. The functional association between Anxa2 and EBP1 may also participate in regulating cancer cell proliferation and invasion, thereby contributing to cancer progression. PMID- 25917453 TI - Estrogen receptor alpha-36 (ER-alpha36): A new player in human breast cancer. AB - Prevailing wisdom is that estrogen receptor (ER)-alpha mediated genomic estrogen signaling is responsible for estrogen-stimulated cell proliferation and development of ER-positive breast cancer. However, accumulating evidence indicates that another estrogen signaling pathway, non-genomic or rapid estrogen signaling, also plays an important role in mitogenic estrogen signaling. Previously, our laboratory cloned a 36 kDa variant of ER-alpha, ER-alpha36, and found that ER-alpha36 is mainly expressed in the cytoplasm and at the plasma membrane. ER-alpha36 mediates rapid estrogen signaling and inhibits genomic estrogen signaling. In this review, we review and update the biological function of ER-alpha36 in ER-positive and -negative breast cancer, breast cancer stem/progenitor cells and tamoxifen resistance, potential interaction and cross talk of ER-alpha36 with other ERs and growth factor receptors, and intracellular pathways of ER-alpha36-mediated rapid estrogen signaling. The potential function and underlying mechanism of ER-alpha in development of ER-positive breast cancer will also be discussed. PMID- 25917454 TI - Peroxisome proliferator-activated receptor gamma enhances adiponectin secretion via up-regulating DsbA-L expression. AB - Disulfide-bond A oxidoreductase like-protein (DsbA-L) was identified as a molecular chaperone facilitating the assembly and secretion of adiponectin, an adipokine with multiple beneficial effects. In obesity the level of DsbA-L is reduced with a concomitant decrease of the circulating adiponectin level, especially of the high molecular weight form (HMW). Both rodent and human studies have shown that the nuclear receptor peroxisome proliferator-activated receptor (PPAR)-gamma agonists increase adiponectin levels in serum by activating PPARgamma, which up-regulates critical endoplasmic reticulum (ER) chaperones thus facilitating protein folding. As shown in the present study, overexpression of PPARgamma in human embryonic kidney (HEK) 293 cells elicited the cellular release of HMW adiponectin. PPARgamma enhanced expression of DsbA-L by binding directly to peroxisome proliferator response element (PPRE) site within the DsbA-L promoter. Conversely, in differentiated 3T3-L1 cells, PPARgamma knockdown resulted in decreased expression of Adiponectin, DsbA-L and ERp44. DsbA-L expression increased after PPARgamma agonist treatment and decreased upon treatment with PPARgamma antagonist in 3T3-L1 adipocytes. DsbA-L deficiency in differentiated 3T3-L1 cells impaired the secretion of adiponectin. We therefore propose that DsbA-L plays an important role in facilitating HMW adiponectin formation and release from cells under the regulation of PPARgamma. PMID- 25917455 TI - Molecular characterization of a disintegrin and metalloprotease-17 (ADAM17) in granulosa cells of bovine preovulatory follicles. AB - A disintegrin and metalloprotease-17 (ADAM17) is thought to play a key role in the release of soluble and active epiregulin (EREG) and amphiregulin (AREG) in ovarian follicles but its transcriptional regulation in follicular cells remains largely unknown. The objectives of this study were to characterize the regulation of ADAM17 transcripts in bovine follicles prior to ovulation and to investigate its transcriptional control in bovine granulosa cells. To study the regulation of ADAM17 transcripts, RT-PCR analyses were performed using total RNA extracted from bovine follicles collected between 0 h and 24 h post-hCG. Results showed that levels of ADAM17 mRNA were low prior to hCG (0 h), markedly and transiently increased 6-12 h post-hCG (P <0.05), and returned to low baseline levels at 24 h post-hCG in granulosa and theca interna cells of preovulatory follicles. To determine the transcriptional control of ADAM17 expression, primary cultures of bovine granulosa cells were used. Forskolin (FSK) stimulation induced a pattern of ADAM17 mRNA up-regulation in vitro similar to that observed by hCG in vivo. 5' Deletion mutagenesis studies identified a minimal region of the bovine ADAM17 promoter containing basal and FSK-inducible activities, which were dependent on the presence of a consensus AP1 cis-element. Electrophoretic mobility shift assays revealed an interaction between AP1 and the trans-acting factor Fra2. Chromatin immunoprecipitation assays confirmed an endogenous interaction between Fra2 and the ADAM17 promoter in granulosa cell cultures. FSK-inducible ADAM17 promoter activity and mRNA expression were suppressed by PKA and ERK1/2 inhibitors but not by a p38MAPK inhibitor, pointing to the importance of PKA and ERK1/2 signaling pathways in the up-regulation of bovine ADAM17 mRNA. Collectively, these findings describe the gonadotropin/FSK-dependent up regulation of ADAM17 transcripts in bovine preovulatory follicles and unravel for the first time some of the molecular mechanisms involved in ADAM17 gene expression in granulosa cells of a monoovulatory species. PMID- 25917457 TI - Notes From the Field: Are Rural Medical Practitioners in India Competent? AB - In India, rural medical practitioners (RMPs) practice allopathic, homeopathic, and other modern systems of medicine without formal medical training. However, the quality of treatment offered remains questionable. The present study systematically examines the knowledge, practices, and competencies of the RMPs. While about 80% of RMPs can diagnose common diseases and treat them, 25% are involved in inappropriate practices like unsafe abortion and unsafe childbirth. Hence, there is an urgent need for appropriate intervention to reduce potential harm and improve care provided. PMID- 25917456 TI - Gata3 cooperates with Gcm2 and MafB to activate parathyroid hormone gene expression by interacting with SP1. AB - Haploinsufficiency of the Gata3 gene, which encodes a zinc-finger transcription factor, is associated with the disorder hypoparathyroidism, deafness, and renal dysplasia (HDR) syndrome in humans. However, the roles of Gata3 in transcriptional regulation in the parathyroid glands are not well-understood. In this study, we show that Gata3 activates transcription of parathyroid hormone (PTH), which is secreted from parathyroid glands and is critical for regulating serum calcium and phosphate homeostasis. Gata3 interacted with Gcm2 and MafB, two known transcriptional regulators of parathyroid development, and synergistically stimulated the PTH promoter. An SP1-binding element (GC box) located within the PTH-promoter proximal region was critical for activating transcription by Gata3. In addition, the ubiquitous transcription factor SP1 also interacted with Gata3 as well as MafB and Gcm2, and HDR syndrome-associated Gata3 mutants were defective in activating the PTH promoter. These results suggest that Gata3 is a critical regulator of PTH gene expression. PMID- 25917458 TI - Clinical Outcomes, Utilization, and Charges in Persons With Neck Pain Receiving Guideline Adherent Physical Therapy. AB - In efforts to decrease practice variation, clinical practice guidelines for neck pain have been published. The purpose of this study was to determine the effect of receiving guideline adherent physical therapy (PT) on clinical outcomes, health care utilization, and charges for health care services in patients with neck pain. A retrospective review of 298 patients with neck pain receiving PT from 2008 to 2011 was performed. Clinical outcomes, utilization, and charges were compared between patients who received guideline adherent care and nonadherent care. Patients in the adherent care group experienced a lower percentage improvement in pain score compared to nonadherent care group (p = .01), but groups did not significantly differ on percentage improvement in disability (p = .32). However, patients receiving adherent care had an average 3.6 fewer PT visits (p < .001) and less charges for PT (p < .001). Additionally, patients receiving adherent care had 7.3 fewer visits to other health care providers (p < .001), one less prescription medication (p = .02) and 43% fewer diagnostic images (p = .02) but did not differ in their charges to other health care providers (p = .68) during the calendar year of undergoing PT. Although receiving guideline adherent care demonstrated positive effects on health care utilization and financial outcomes, there appears to be a trade-off with clinical outcomes. PMID- 25917459 TI - Pilot Trial of FANG Immunotherapy in Ewing's Sarcoma. AB - We report on 12 consecutive patients with advanced/metastatic Ewing's sarcoma who were treated as a separate cohort of a phase 1 trial of FANG autologous immunotherapy (1 * 10(6)-2.5 * 10(7) cells/intradermal injection each month for minimum 4 months). Safety and clinical response were monitored. Patient immune response to unmodified autologous tumor cells was assessed by gamma interferon enzyme-linked immunospot (gammaIFN-ELISPOT) assay using peripheral blood mononuclear cells from baseline (pretreatment) and multiple postvaccination time points. None of the 12 patients (47 vaccinations) developed grade 2/3/4 drug related toxicity. Median product release granulocyte-macrophage colony stimulating factor expression was 1,941 pg/10(6) cells, and TGFbeta1and TGFbeta2 knockdown were 99 and 100%, respectively. Eight patients were assessed for ELISPOT response to autologous tumor cells at baseline and all (100%) were negative. In contrast, follow-up ELISPOT response at month 1 or month 4 (one patient) after FANG was positive in all eight patients. One patient achieved a partial tumor response (38% tumor reduction, RECIST 1.1). The Kaplan-Meier estimated survival of these 12 patients at 1 year was 75%. In this phase 1 study in patients with Ewing's sarcoma, FANG immunotherapy was well tolerated, elicited a tumor-specific systemic immune response in all patients, and was associated with favorable 1-year survival. Further clinical testing is indicated. PMID- 25917461 TI - In vitro toxicity of propolis in comparison with other primary teeth pulpotomy agents on human fibroblasts. AB - AIM: The aim of this study was to assess and compare the in vitro toxicity of propolis with other primary teeth pulpotomy medicaments. METHODS: Human periodontal ligament (PDL) cells were subjected to different concentrations of propolis, formocresol, ferric sulfate, and gray mineral trioxide aggregate (MTA) (0.05, 0.5, 5, 50, and 100 MUg/mL) for 24 h at 37 degrees C. Cells that were not exposed to the tested materials served as the negative control. In vitro toxicity was assessed using 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide assay. Statistical analysis of the data was accomplished using anova and Tukey statistical tests (P < 0.05). RESULTS: Only propolis and gray MTA had comparable cell viability to the negative control group. Almost all remaining concentrations of tested materials were significantly inferior to the negative control after 24 h of exposure (P < 0.05). CONCLUSION: Propolis and MTA are more biocompatible than formocresol and ferric sulfate since they were both able to preserve PDL fibroblasts for up to 24 h. PMID- 25917460 TI - The inhibitory effect of secretory leukocyte protease inhibitor (SLPI) on formation of neutrophil extracellular traps. AB - Neutrophil extracellular traps (NETs), web-like DNA structures, provide efficient means of eliminating invading microorganisms but can also present a potential threat to its host because it is a likely source of autoantigens or by promoting bystander tissue damage. Therefore, it is important to identify mechanisms that inhibit NET formation. Neutrophil elastase (NE)-dependent chromatin decondensation is a key event in the release of NETs release. We hypothesized that inhibitors of NE, secretory leukocyte protease inhibitor (SLPI) and alpha(1) proteinase inhibitor (alpha(1)-PI), has a role in restricting NET generation. Here, we demonstrate that exogenous human SLPI, but not alpha(1)-PI markedly inhibited NET formation in human neutrophils. The ability of exogenous SLPI to attenuate NET formation correlated with an inhibition of a core histone, histone 4 (H4), cleavage, and partial dependence on SLPI-inhibitory activity against NE. Moreover, neutrophils from SLPI(-/-) mice were more efficient at generating NETs than were neutrophils from wild-type mice in vitro, and in experimental psoriasis in vivo. Finally, endogenous SLPI colocalized with NE in the nucleus of human neutrophils in vitro, as well as in vivo in inflamed skin of patients with psoriasis. Together, these findings support a controlling role for SLPI in NET generation, which is of potential relevance to infectious and autoinflammatory diseases. PMID- 25917464 TI - Predictors of neurological deterioration during hospitalization: results from the Chinese Intracranial Atherosclerosis (CICAS) Study. AB - OBJECTIVES: Neurological deterioration (ND) after ischaemic stroke has been indicated as an independent risk factor for poor outcome. Previous studies have focussed on ND within the first few days after symptom onset, but many patients are likely to experience deterioration outside of this time frame. We aimed to investigate the predictors of ND during hospitalisation. METHODS: Data were obtained from the Chinese Intracranial Atherosclerosis (CICAS) Study, and patients who were diagnosed with ischaemic stroke and arrived at the hospital within 72 hours after symptom onset were included in the present study. Neurological deterioration was defined as an increase in the National Institutes of Health Stroke Scale (NIHSS) score of >= 2 points at discharge compared with admission. MR angiography (MRA) and duplex colour Doppler ultrasound were used to document the presence of intracranial or extracranial artery stenosis. Intracranial artery stenosis was defined as a reduction in the artery diameter of >= 50% on MRA. Multivariate analyses were conducted to determine the potential predictors of ND during hospitalisation. RESULTS: Of the 1996 patients included in this study, 84 (4.21%) developed ND during hospitalisation. Compared with non ND patients, ND patients showed higher rates of pneumonia (25.0 vs 9.5%, P < 0.001), urinary infection (7.1 vs 1.2%, P < 0.01), stroke recurrence (14.3 vs 1.9%, P < 0.001), watershed infarct (15.5 vs 5.4%, P = 0.002), intracranial internal carotid artery (ICA) stenosis (11.9 vs 6.0%, P = 0.041), middle cerebral artery (MCA) stenosis (39.3 vs 22.0%, P < 0.001) and basilar artery (BA) stenosis (16.7 vs 7.1%, P = 0.011). Multivariate analysis indicated that watershed infarcts (OR, 2.85; 95% CI, 1.04-7.81), MCA (OR, 2.23; 95% CI, 1.17-4.25) and BA (OR, 2.86; 95% CI, 1.19-6.87) stenosis or occlusion were independent risk factors for ND, as was pneumonia (OR, 3.4; 95% CI, 1.46-7.9). DISCUSSION: Patients with watershed infarcts and MCA or BA stenosis or occlusion should be monitored closely, and various therapeutic strategies should be administered simultaneously to prevent pneumonia during hospitalisation. PMID- 25917463 TI - Analysis of KIT mutations and c-KIT expression in Chinese Uyghur and Han patients with melanoma. AB - BACKGROUND: The KIT gene plays an important role in the pathogenesis of malignant melanoma (MM). In recent years, activating mutations in KIT have been recognized as oncogenic. A number of therapies have been established, which provide significant clinical benefits for patients with MM with KIT mutations. Thus, detection of KIT mutations can have profound therapeutic implications. AIM: To investigate KIT gene expression in MMs in Chinese Uyghur and Han patients with mutations in KIT, and to identify the clinical features associated with KIT mutations and c-KIT expression. METHODS: In total, 105 MMs (56 from Uyghur and 49 from Han patients) were selected from patients in the Uyghur Autonomous region. Formalin-fixed, paraffin wax-embedded tumour sections were analysed for c-KIT expression using immunohistochemistry. Exons 11 and 13 of KIT were analysed for the presence of mutations using PCR amplification and DNA sequencing. RESULTS: Of the 105 MMs, 13 (10 Han and 3 Uyghur) were found to have mutations in KIT. Thus, the frequency of KIT mutations in Han patients was significantly higher than that in Uyghur patients (P = 0.02). We detected c-KIT expression in 71.4% and 42.9% of the tumour tissue samples collected from the Uyghur and Han patients, respectively. CONCLUSION: In the Xinjiang Uyghur Autonomous Region in China, chronic sun-induced damage MM is the most prevalent MM among Chinese Uyghur patients, whereas acral and mucosal MMs are the most prevalent in Uyghur patients. Mutations in the KIT gene do not correlate with c-KIT expression. PMID- 25917462 TI - Imidazole-based alkaloid derivative LCB54-0009 suppresses ocular angiogenesis and lymphangiogenesis in models of experimental retinopathy and corneal neovascularization. AB - BACKGROUND AND PURPOSE: Abnormally induced angiogenesis and lymphangiogenesis are associated with human diseases, including neovascular eye disease. Substances that inhibit these processes may have potential as an attractive therapeutic strategy for these diseases. EXPERIMENTAL APPROACH: In vitro and in vivo angiogenesis and/or lymphangiogenesis were assessed in VEGF- or hypoxia stimulated endothelial and retinal cells and in animal models of oxygen-induced retinopathy (OIR), streptozotocin-induced diabetic retinopathy (SIDR), suture induced inflammatory corneal neovascularization (SICNV) and silver nitrate induced corneal neovascularization. HUVECs and retinal cells were cultured under hypoxic conditions or incubated with VEGF to identify the molecular mechanisms involved. KEY RESULTS: The imidazole-based alkaloid derivative LCB54-0009 inhibited capillary-like tube formation in VEGF-induced HUVECs without inducing cytotoxic effects. Intravitreal injection of LCB54-0009 into retinas suppressed the formation of the pathological neovascular tufts and increased vascular permeability in both OIR of mice and SIDR of rats. Furthermore, subconjunctival injection of LCB54-0009 into the cornea suppressed corneal inflammation and inflammation-associated angiogenesis and lymphangiogenesis in SICNV of mice and silver nitrate cauterization of rats. These pharmacological activities were associated with effects on HIF-1alpha protein stability and HIF-1alpha/NF-kappaB redox sensitivity through its antioxidant activities. LCB54-0009 also inhibited the hypoxia-induced expression of angiopoietin-2, and VEGF-induced VEGFR-2 activation and downstream signalling, resulting in the down-regulation of the expression of pro-angiogenic factors and pro-inflammatory mediators and an up regulation of the expression of anti-angiogenic factors. CONCLUSIONS AND IMPLICATIONS: LCB54-0009 is a potential candidate molecule for blocking pathological angiogenesis and lymphangiogenesis mediated by HIF-1alpha- angiopoietin-2 expression and VEGFR-2 activation. PMID- 25917465 TI - Predicting genetic engineering targets with Elementary Flux Mode Analysis: a review of four current methods. AB - Elementary flux modes (EFMs) are a well-established tool in metabolic modeling. EFMs are minimal, feasible, steady state pathways through a metabolic network. They are used in various approaches to predict targets for genetic interventions in order to increase production of a molecule of interest via a host cell. Here we give an introduction to the concept of EFMs, present an overview of four methods which use EFMs in order to predict engineering targets and lastly use a toy model and a small-scale metabolic model to demonstrate and compare the capabilities of these methods. PMID- 25917466 TI - Febrile seizures and genetic epilepsy with febrile seizures plus (GEFS+). AB - To review the literature about febrile seizures and GEFS plus with special emphasis on management and outcome. Selected literature review. Febrile seizures are the most common convulsive event in humans, occurring in 2-6% of the population. The aetiology is complex with strong evidence for a heterogeneous genetic predisposition interacting with fever of any cause, with certain viral infections having a greater effect. A large amount of literature has established that febrile seizures have no long-term consequences on cognition or behaviour. Unfortunately, about 40% of children with a first febrile seizure will have a recurrence. The strongest predictor of recurrence is age <14-16 months at the time of the first febrile seizure. Epilepsy follows febrile seizures in ~3% cases, with the concepts of simple and complex febrile seizures providing relatively weak prediction. Very prolonged febrile seizures may lead to mesial temporal sclerosis and temporal lobe epilepsy although the degree of risk remains uncertain. Investigations beyond establishing the cause of the provoking fever are nearly always unnecessary. Treatment is mainly reassurance and there is some evidence that parents eventually "come to grips" with the fear that their children are dying during a febrile seizure. Antipyretic medications are remarkably ineffective to prevent recurrences. Daily and intermittent prophylactic medications are ineffective or have unacceptable side effects or risks. "Rescue" benzodiazepines may prevent prolonged recurrences for selected patients with a first prolonged febrile seizure although this has not been proven. Genetic epilepsy with febrile seizures plus (GEFS+) is a complex autosomal dominant disorder usually caused by mutations in SCN1A (a voltage-gated sodium channel). One third of patients have febrile seizures only; two thirds have a variety of epilepsy syndromes, both focal and generalized. Febrile seizures may distress parents but rarely have any long-term consequences. Reassurance is the only treatment for the vast majority. Identifying patients with GEFS plus may lead to further investigations and counselling. PMID- 25917467 TI - Maintenance of certification: the price of medical professionalism is $10,108.05, two weeks leave and five white hairs. PMID- 25917469 TI - Does this patient really have chronic obstructive pulmonary disease? AB - Chronic obstructive pulmonary disease (COPD) is a condition commonly encountered by primary care practitioners. The disease should be detected in its early stages to prevent disease progression and to reduce the burden of symptoms. Early treatment also results in improved mortality and reduced morbidity. COPD should be differentiated from other similar conditions such as asthma, as the basis of treatment differs in these conditions, and misdiagnosis can lead to poorer patient outcomes. Non-pharmacological treatment such as smoking cessation and vaccinations are important in the management of COPD, while pharmacotherapy such as bronchodilators and antimuscarinics are the mainstay of therapy in COPD. Referral to a specialist is recommended when there is progression of the disease or uncertainty regarding the diagnosis. PMID- 25917468 TI - Renal-related adverse effects of intravenous contrast media in computed tomography. AB - Renal-related adverse effects of intravascular contrast media (CM) include contrast-induced nephropathy in computed tomography and angiography. While large retrospective studies have been published, the exact pathogenesis of this condition is still unknown. We review the main international guidelines, including the American College of Radiology white paper and the guidelines of European Society of Urogenital Radiology, Royal College of Radiologists and Canadian Association of Radiologists, as well as their references, regarding this subject. We present a simplified, concise approach to renal-related adverse effects of CM, taking into consideration the basis for each recommendation in these published guidelines. This will allow the reader to better understand the rationale behind appropriate patient preparation for cross-sectional imaging. PMID- 25917470 TI - Clinics in diagnostic imaging (160). Levocardia with abdominal situs inversus. AB - Levocardia (left-sided cardiac apex) with abdominal situs inversus is extremely rare. This is also known as isolated levocardia and is almost always associated with severe forms of congenital heart defects with poor prognosis. We report isolated levocardia in a 13-year-old symptomatic male patient. The purpose of this paper is to outline the imaging features of isolated levocardia and to highlight the role of cardiovascular magnetic resonance imaging (CMR) in the diagnosis and management of such cases. Other forms of cardiac malposition, including dextrocardia, mesocardia and criss-cross heart, with chest radiograph and CMR correlation, are also discussed. PMID- 25917471 TI - Distribution of branchial anomalies in a paediatric Asian population. AB - INTRODUCTION: The objective of the present study was to review the distribution and incidence of branchial anomalies in an Asian paediatric population and highlight the challenges involved in the diagnosis of branchial anomalies. METHODS: This was a retrospective chart review of all paediatric patients who underwent surgery for branchial anomalies in a tertiary paediatric hospital from August 2007 to November 2012. The clinical notes were correlated with preoperative radiological investigations, intraoperative findings and histology results. Branchial anomalies were classified based on the results of the review. RESULTS: A total of 28 children underwent surgery for 30 branchial anomalies during the review period. Two children had bilateral branchial anomalies requiring excision. Of the 30 branchial anomalies, 7 (23.3%) were first branchial anomalies, 5 (16.7%) were second branchial anomalies, 3 (10.0%) were third branchial anomalies, and 4 (13.3%) were fourth branchial anomalies (one of the four patients with fourth branchial anomalies had bilateral branchial anomalies). In addition, seven children had 8 (26.7%) branchial anomalies that were thought to originate from the pyriform sinus; however, we were unable to determine if these anomalies were from the third or fourth branchial arches. There was inadequate information on the remaining 3 (10.0%) branchial anomalies for classification. CONCLUSION: The incidence of second branchial anomalies appears to be lower in our Asian paediatric population, while that of third and fourth branchial anomalies was higher. Knowledge of embryology and the related anatomy of the branchial apparatus is crucial in the identification of the type of branchial anomaly. PMID- 25917472 TI - Clinical outcomes of single-level lumbar artificial disc replacement compared with transforaminal lumbar interbody fusion in an Asian population. AB - INTRODUCTION: The objective of this study was to examine the clinical outcome of single-level lumbar artificial disc replacement (ADR) compared to that of transforaminal lumbar interbody fusion (TLIF) for the treatment of symptomatic degenerative disc disease (DDD) in an Asian population. METHODS: This was a retrospective review of 74 patients who had surgery performed for discogenic lower backs that involved only the L4/5 and L5/S1 levels. All the patients had lumbar DDD without radiculopathy or spondylolithesis, and concordant pain with discogram at the pathological level. The patients were divided into two groups- those who underwent ADR and those who underwent TLIF. RESULTS: A trend suggesting that the ADR group had better perioperative outcomes (less blood loss, shorter operating time, shorter hospital stay and shorter time to ambulation) than the TLIF group was observed. However, a trend indicating that surgical-approach related complications occurred more frequently in the ADR group than the TLIF group was also observed. The rate of revision surgery was comparable between the two groups. CONCLUSION: Our findings suggest that for the treatment of discogenic lower back pain, lumbar ADR has better perioperative outcomes and a similar revision rate when compared with TLIF. However, the use of ADR was associated with a higher incidence of surgical-approach-related complications. More studies with bigger cohort sizes and longer follow-up periods are needed to determine the long-term efficacy and safety of ADR in lumbar DDD. PMID- 25917473 TI - High STOP-BANG questionnaire scores predict intraoperative and early postoperative adverse events. AB - INTRODUCTION: Obstructive sleep apnoea (OSA) is the most common sleep-related breathing disorder associated with multisystemic organ involvement. The STOP-BANG questionnaire is a concise, validated questionnaire that is used to screen for OSA. This study aimed to establish the use of the STOP-BANG questionnaire for perioperative patient risk stratification. METHODS: In this retrospective cohort study, we extracted the demographic, medical and perioperative outcome data of all patients who underwent elective surgery, excluding ophthalmic surgeries, from January to December 2011. Multivariate regression analysis was used to predict independent risk factors for intraoperative and early postoperative adverse events. RESULTS: Of the 5,432 patients analysed, 7.4% had unexpected intraoperative and early postoperative adverse events. We found that the risk of unexpected intraoperative and early postoperative adverse events was greater in patients with STOP-BANG scores >= 3 compared to those with a STOP-BANG score of 0 (score 3: odds ratio [OR] 3.6, 95% confidence interval [CI] 2.1-6.3, p < 0.001; score 4: OR 3.4, 95% CI 1.8-6.5, p < 0.001; score 5: OR 6.4, 95% CI 2.7-15.0, p < 0.001; score >= 6: OR 5.6, 95% CI 2.1-15.4, p < 0.001). Patients with STOP-BANG scores >= 5 had a fivefold increased risk of unexpected intraoperative and early postoperative adverse events, while patients with STOP-BANG scores >= 3 had a 'one in four' chance of having an adverse event. Other independent predictors included older age (p < 0.001), American Society of Anesthesiologists class >= 2 (p < 0.003) and uncontrolled hypertension (p = 0.028). CONCLUSION: STOP-BANG score may be used as a preoperative risk stratification tool to predict the risk of intraoperative and early postoperative adverse events. PMID- 25917474 TI - Impact of dengue-induced thrombocytopenia on mandatory anticoagulation for patients with prosthetic heart valves on warfarin. PMID- 25917475 TI - Rene Leriche (1879-1955): Innovator of vascular surgery. PMID- 25917476 TI - Large bowel obstruction complicating a posttraumatic diaphragmatic hernia. AB - Posttraumatic diaphragmatic hernia is a rare cause of large bowel obstruction, and can present weeks or years after the initial trauma. Herein, we report the case of a 28-year-old man who presented with signs and symptoms of bowel obstruction nine months after he had a stab wound to his left chest. Chest radiography showed multiple air-fluid levels in the right upper quadrant, an air fluid level in the left thoracic cavity and significant free air under the diaphragm. Exploratory laparotomy revealed a contaminated abdomen with perforations in the caecum and proximal transverse colon, and a 4 cm * 4 cm defect in the left posterolateral (septal) aspect of the diaphragm, which was closed with a nonabsorbable suture. Posttraumatic diaphragmatic hernias should be part of the differential diagnosis for patients with bowel obstruction, especially if there is a history of trauma. Radiography is useful in facilitating a quick diagnosis. PMID- 25917477 TI - Simultaneous bilateral ganglion cysts of the anterior cruciate ligaments. AB - Intra-articular ganglion cysts of the anterior cruciate ligament (ACL) are rare, and bilateral ganglion cysts are even rarer. These cysts may cause intermittent or chronic nonspecific knee discomfort. Although three cases of bilateral ganglion cysts have been reported in the literature, the knees were not simultaneously affected in those cases. Herein, we report the case of a 56-year old woman who presented with simultaneous bilateral ganglion cysts of the ACL that were symptomatic. She was successfully treated with arthroscopic resection and debridement. We also present a brief review of the literature, highlighting the aetiology, diagnosis and management of ganglion cysts of the ACL. To the best of our knowledge, this is the first report of simultaneous bilateral intra articular ganglion cysts of the ACL. PMID- 25917478 TI - An unusual cause of haemorrhagic shock from a subcutaneous haematoma: a Morel Lavallee lesion. AB - 20-year-old man presented to our emergency department after he was hit by a forklift. He developed haemorrhagic shock from a subcutaneous haematoma in his left thigh and required monitoring in the surgical intensive care unit. He stabilised with aggressive fluid resuscitation with crystalloids and blood transfusion. The recovery was complicated by an infection of the subcutaneous haematoma. Following open drainage of the infected subcutaneous haematoma, he improved and was discharged. To the best of our knowledge, this is the first reported case of a subcutaneous haematoma causing haemorrhagic shock. PMID- 25917479 TI - Successful treatment of solitary intraosseous haemangioma of the femoral neck. AB - Intraosseous haemangiomas (IOHs) are benign vascular bone tumours that account for 1% of all primary bone tumours. They are most frequently seen in the vertebrae and skull, and are rarely found in long bones. Herein, we present an uncommon case of a 25-year-old woman with a solitary IOH that occupied the left femoral neck. We describe the clinical, radiological and histological details of the case, as well as the three-year outcome of the surgical treatment, which successfully preserved the femoral head. We also conducted a review of the literature on this uncommon entity. PMID- 25917480 TI - Central pontine myelinolysis: a rare presentation secondary to hyperglycaemia. AB - Central pontine myelinolysis (CPM) is classically described as a demyelinating condition that results from the rapid correction of hyponatraemia. CPM has also been reported to arise from hyperglycaemia in association with concomitant acidosis, hypernatraemia and hyperosmolar syndrome. Herein, we report a rare presentation of CPM, which was purely secondary to hyperosmolar hyperglycaemia. The patient presented with ataxia and pseudobulbar affect, which evolved subacutely over a duration of two weeks. It is important to note that, in addition to acute changes in osmolality, a subacute shift secondary to hyperglycaemia may also lead to CPM. PMID- 25917481 TI - A Semiconductor Chip-Based Next Generation Sequencing Procedure for the Main Pulmonary Hypertension Genes. AB - The aim of this study was to characterize the mutational spectrum of pulmonary hypertension (PH) patients through a next generation sequencing platform. In a total of 22 patients, the BMPR2, SMAD9, CAV1, KCNK3, and EIF2AK4 genes were sequenced with semiconductor chips and the ion torrent personal genome machine. We found six putative mutations in SMAD (p.R263Q), BMPR2 (p.S301P, p.T493I), CAV1 (p.V155I), and EIF2AK4 (p.L489P, p.P1115L) in five patients. One patient was compound heterozygous for BMPR2 + SMAD mutations, and one patient was homozygous for EIF2AK4 p.P1115L. The reported procedure would facilitate the rapid mutational screening of large cohorts of PH patients. PMID- 25917482 TI - A resting-state functional MRI study on central control of storage: brain response provoked by strong desire to void. AB - AIMS: In order to observe central responses during naturally occurring urinary bladder storage in healthy subjects, we examined brain areas that control strong bladder sensation by resting-state functional magnetic resonance imaging (rs fMRI). METHODS: All subjects were right-handed and scanned twice under the following two conditions: empty bladder and full bladder ('strong desire to void') without the use of filling with a catheter. Brain imaging software (DPARSF and REST) was adopted to analyze the difference in brain-blood perfusion between the two conditions. Voxel-based analysis of the regional homogeneity (Reho) maps between empty and full bladder was performed with a paired t test. Statistical maps were set at P value <0.05 and were corrected for multiple comparisons. RESULTS: The rs-fMRI scans of 30 healthy subjects (8 men and 22 women, between 24 and 49 years of age) were analyzed. The responses became stronger in the state of strong desire to void (P < 0.05). Increased activity during strong desire to void was observed in the prefrontal cortex (PFC), anterior cingulate cortex (ACC), hypothalamus, temporal lobes and left caudate nucleus, which are involved in bladder perception related to large volumes in adults. CONCLUSIONS: There are significant changes in the brain's Reho during the strong sensation to void. The results suggest that the PFC, the ACC, hypothalamus, temporal lobes and left caudate nucleus play a role in the cerebral control of bladder storage without artificial bladder filling in healthy people. PMID- 25917483 TI - The association of ApE1 -656T>G and 1349T>G polymorphisms and idiopathic male infertility risk. AB - PURPOSE: In spite of variety studies in understanding of human reproductive and fertility, the underlying causes of male infertility remains undefined in about 50 % of cases. The polymorphism studies have a crucial role in diseases recognizing. Human apurinic/apyrimidinic endonuclease 1 (ApE1) is a multifunctional protein that has an important role in the base excision repair pathway. The present study was aimed to evaluate whether two polymorphisms 656T>G and 1349T>G ApE1 are related with the susceptibility to idiopathic male infertility. METHODS: Samples were collected from 180 patients diagnosed with idiopathic male infertility and 120 control subjects and genotyped by tetra primer amplification refractory mutation system PCR. RESULTS: We observed a significant difference in genotype distributions of -656T>G ApE1 polymorphism between infertile patients and controls (P = 0.0001). Our findings indicated individuals with the variant TG genotypes had a significant increased risk of idiopathic male infertility (OR 1.84, 95 % CI 1.09-3.11, P = 0.021), whereas the significant association between the 1349T>G polymorphism and idiopathic male infertility risk was not observed (P = 0.2). CONCLUSIONS: Our data suggest that the -656T>G ApE1 polymorphism may be associated with increased risk of idiopathic male infertility. Larger studies with more patients and controls are needed to confirm the results. PMID- 25917484 TI - High blood glucose independent of pre-existing diabetic status predicts mortality in patients initiating peritoneal dialysis therapy. AB - PURPOSE: Poor glycemic control associates with increased mortality in diabetic (DM) dialysis patients, but it is less well established whether high blood glucose (BG) independent of pre-existing diabetic status associates with mortality in dialysis patients. We assessed factors affecting BG at the start of peritoneal dialysis (PD) and its mortality-predictive impact in Korean PD patients. METHODS: In 174 PD patients (55 % males, 56 % DM), BG, nutritional status, comorbidity (CMD), and residual renal function (RRF) were assessed in conjunction with dialysis initiation. Determinants of BG and its association with mortality after a mean follow-up period of 30 +/- 24 months were analyzed. RESULTS: On Cox proportional hazards analysis comprising all patients, old age, high CMD score, presence of protein energy wasting, and low serum albumin (Salb) concentration were independent predictors of mortality but not a high-BG level, while in patients without pre-existing diabetic status, high BG, together with old age and high CMD score, was an independent predictor of mortality. After adjustment for age, CMD score, and Salb, the risk ratio for mortality increased by 12 % per 1 mg/dL increase in BG in the non-DM patients. Patient survival in patients without pre-existing diabetic status with high BG did not differ from DM patients, but the survival of patients with high BG was significantly lower than in patients with low BG. In patients without pre-existing diabetic status, in multiple regression analysis, high BG at initiation of PD associated with high age, high body mass index, and low RRF. CONCLUSIONS: High blood glucose at initiation of PD associated with an increased mortality risk in PD patients without pre-existing diabetic status suggesting that blood glucose monitoring and surveillance of factors contributing to poor glycemic control are warranted in patients initiating PD therapy. PMID- 25917485 TI - History of neurology in Taiwan. PMID- 25917486 TI - A refractory lower extremity variceal ulcer associated with perimedullary arteriovenous fistula. PMID- 25917487 TI - Epilepsy-related clinical characteristics and mortality: a systematic review and meta-analysis. PMID- 25917488 TI - Mystery Case: Cholesterol granuloma of the petrous apex in Gradenigo syndrome. PMID- 25917489 TI - Pearls & Oy-sters: Tonic eye deviation in stiff-person syndrome. PMID- 25917490 TI - Teaching NeuroImages: A rare cause of trigeminal neuralgia: dysplastic venous aneurysm of dural arteriovenous fistula. PMID- 25917491 TI - Suicide after stroke. PMID- 25917492 TI - Emergence of novel clade 2.3.4 influenza A (H5N1) virus subgroups in Yunnan Province, China. AB - From December 2013 to March 2014, a major wave of highly pathogenic avian influenza outbreak occurred in poultry in Yunnan Province, China. We isolated and characterized eight highly pathogenic avian influenza A (H5N1) viruses from poultry. Full genome influenza sequences and analyses have been performed. Sequence analyses revealed that they belonged to clade 2.3.4 but did not fit within the three defined subclades. The isolated viruses were provisional subclade 2.3.4.4e. The provisional subclade 2.3.4.4e viruses with six internal genes from avian influenza A (H5N2) viruses in 2013 were the novel reassortant influenza A (H5N1) viruses which were associated with the outbreak of H5N1 occurred in egg chicken farms in Yunnan Province. The HA genes were similar to subtype H5 viruses isolated from January to March of 2014 in Asia including H5N6 and H5N8. The NA genes were most closely related to A/chicken/Vietnam/NCVD KA423/2013 (H5N1) from the subclade 2.3.2. The HI assay demonstrated a lack of antigenic relatedness between clades 2.3.4.4e and 2.3.4.1 (RE-5 vaccine strain) or 2.3.2.2 (RE-6 vaccine strain). PMID- 25917493 TI - Characterising temporal trends in asymptomatic Plasmodium infections and transporter polymorphisms during transition from high to low transmission in Zanzibar, 2005-2013. AB - BACKGROUND: Improved understanding of the asymptomatic malaria parasite reservoir is a prerequisite to pursue malaria elimination efforts. We therefore characterised temporal trends and transporter polymorphisms in asymptomatic Plasmodium infections during the transition from high to low transmission in Zanzibar. METHODS: Healthy individuals participating in cross-sectional surveys conducted 2005-2013 were screened for asymptomatic malaria by PCR. Complexity/diversity of infection and transporter polymorphisms were assessed in Plasmodium falciparum positive samples. Symptomatic samples were included for comparison of polymorphisms in 2013. RESULTS: PCR-determined parasite prevalence declined from 21.1% (CI95% 17.4-24.9) to 2.3% (CI95% 1.7-2.9) from 2005 to 2013. P. falciparum remained the predominant species; prevalence was highest in children and young adults aged 5-25 years. Parasite densities and complexity of infection, but not population genetic diversity of P. falciparum, decreased from 2005-2009. pfcrt 76T (99.2-64.7%, p < 0.001) and pfmdr1 86Y frequencies (89.4 66.7%, p = 0.03) decreased over time. Pfmdr1 (a.a.86,184,1246) YYY and YYD haplotypes were more frequent in asymptomatic than symptomatic infections in 2013 (p < 0.001). CONCLUSIONS: There is a declining, albeit persistent, reservoir of parasites present at low-densities in asymptomatic individuals in Zanzibar. This study revealed important characteristics of the remaining parasite population, including intriguing temporal trends in molecular markers associated with antimalarial resistance, which need to be further investigated. PMID- 25917494 TI - Chromosomal characteristics and distribution of constitutive heterochromatin in the Matogrossensis and Rubrovaria subcomplexes. AB - Since 1966 the triatomines were grouped in complexes and specific subcomplexes. Although the complex and subcomplexes not have taxonomic importance, should be monophyletic groups and cytogenetic tools have proved to be of great importance to characterize these species groupings. Based on this, this paper aims to describe the chromosomal characteristics and heterochromatic pattern of Matogrossensis and Rubrovaria subcomplexes, in order to contribute to the taxonomic and evolutionary relationships of these vectors. In this study, at least three males from each species (Triatoma baratai, Triatoma costalimai, Triatoma guazu, Triatoma jurbergi, Triatoma matogrossensis, Triatoma vandae, Triatoma williami, Triatoma carcavalloi, Triatoma circummaculata, Triatoma klugi, Triatoma pintodiasi and Triatoma rubrovaria) were analyzed by means analyzed by means of cytogenetic techniques of C-banding. All species showed the same cytogenetic characteristics: 22 chromosomes, low variation in the size of autosomes, sex chromosome Y larger than X, initial prophase composed of only one heterochromatic chromocenter formed by the sex chromosomes X and Y (except for T. pintodiasi that presented the sex chromosomes individualized during all stages of prophase) and presence of constitutive heterochromatin restricted to sex chromosome Y. These characteristics, although common to Matogrossensis and Rubrovaria subcomplexes allow to distinguish these species of species grouped in most of South America subcomplexes, as Brasiliensis, Maculata, Sordida and Insfestans. Thus, the cytogenetic analysis was of extreme importance to differentiate both subcomplexes of the other subcomplexes of South America. However, probably due to evolutionary proximity existing between these subcomplexes was not possible to observar species differences that make up the Matogrossensis subcomplex of the Rubrovaria subcomplex. Therefore, we emphasize that new comparative analyzes, as experimental hybrid crosses and molecular cytogenetic analysis are necessary to clarify the evolutionary relationship between these important subcomplexes of vectors. PMID- 25917495 TI - Effect of sampling methods, effective population size and migration rate estimation in Glossina palpalis palpalis from Cameroon. AB - Human and animal trypanosomiases are two major constraints to development in Africa. These diseases are mainly transmitted by tsetse flies in particular by Glossina palpalis palpalis in Western and Central Africa. To set up an effective vector control campaign, prior population genetics studies have proved useful. Previous studies on population genetics of G. p. palpalis using microsatellite loci showed high heterozygote deficits, as compared to Hardy-Weinberg expectations, mainly explained by the presence of null alleles and/or the mixing of individuals belonging to several reproductive units (Wahlund effect). In this study we implemented a system of trapping, consisting of a central trap and two to four satellite traps around the central one to evaluate a possible role of the Wahlund effect in tsetse flies from three Cameroon human and animal African trypanosomiases foci (Campo, Bipindi and Fontem). We also estimated effective population sizes and dispersal. No difference was observed between the values of allelic richness, genetic diversity and Wright's FIS, in the samples from central and from satellite traps, suggesting an absence of Wahlund effect. Partitioning of the samples with Bayesian methods showed numerous clusters of 2-3 individuals as expected from a population at demographic equilibrium with two expected offspring per reproducing female. As previously shown, null alleles appeared as the most probable factor inducing these heterozygote deficits in these populations. Effective population sizes varied from 80 to 450 individuals while immigration rates were between 0.05 and 0.43, showing substantial genetic exchanges between different villages within a focus. These results suggest that the "suppression" with establishment of physical barriers may be the best strategy for a vector control campaign in this forest context. PMID- 25917496 TI - A molecular phylogenetics-based approach for identifying recent hepatitis C virus transmission events. AB - Improved surveillance methods are needed to better understand the current hepatitis C virus (HCV) disease burden and to monitor the impact of prevention and treatment interventions on HCV transmission dynamics. Sanger sequencing (HCV NS5B, HVR1 and Core-E1-HVR1) and phylogenetics were applied to samples from individuals diagnosed with HCV in British Columbia, Canada in 2011. This included individuals with two or three sequential samples collected <1 year apart. Patristic distances between sequential samples were used to set cutoffs to identify recent transmission clusters. Factors associated with transmission clustering were analyzed using logistic regression. From 618 individuals, 646 sequences were obtained. Depending on the cutoff used, 63 (10%) to 92 (15%) unique individuals were identified within transmission clusters of predicted recent origin. Clustered individuals were more likely to be <40 years old (Adjusted Odds Ratio (AOR) 2.12, 95% CI 1.21-3.73), infected with genotype 1a (AOR 6.60, 95% CI 1.98-41.0), and to be seroconverters with estimated infection duration of <1 year (AOR 3.13, 95% CI 1.29-7.36) or >1 year (AOR 2.19, 95% CI 1.22-3.97). CONCLUSION: Systematic application of molecular phylogenetics may be used to enhance traditional surveillance methods through identification of recent transmission clusters. PMID- 25917497 TI - [Ambiguous loss. Psychopathological and psychosocial consequences in the context of violent conflicts]. AB - BACKGROUND: Disappearances are a frequent phenomenon in the context of violent conflicts. Although it is widely assumed that relatives of missing people face particularly complex adaptation difficulties due to the uncertainty regarding the fate of their loved ones, little is known about the psychological and social consequences for those left behind. OBJECTIVES: The aim of this article is to provide an empirical overview on studies addressing ambiguous loss in violent conflicts as well as to highlight potential risk factors for negative mental health outcomes relevant in this group. RESULTS: Due to the limited number of studies, only preliminary conclusions can be drawn. Studies show that the disappearance of a loved one can adversely affect mental health in a substantial number of those left behind. Studies indicate that relatives of missing persons suffer from higher psychological distress than bereaved persons with confirmed losses, particularly in terms of symptom severity of depression and prolonged grief reactions. Research on factors contributing to these mental health outcomes suggests an elevated risk for exposure to traumatic events and lack of social support among relatives of missing persons. The extent of hope regarding the fate of the missing loved one might prevent relatives from achieving closure and facilitate prolonged grief reactions. Lack of grief rituals and complex family dynamics may furthermore exacerbate coping with the loss. CONCLUSION: Future research should focus on the verification of these findings and evaluate the impact of resilience factors that can protect relatives from maladaptive mental health consequences. Research in this regard can help identify persons at high risk and allow the development of adequate and effective interventions. PMID- 25917498 TI - Dysfunction in gap junction intercellular communication induces aberrant behavior of the inner cell mass and frequent collapses of expanded blastocysts in mouse embryos. AB - PURPOSE: We investigated the role of gap junctions (GJs) in embryological differentiation, and observed the morphological behavior of the inner cell mass (ICM) by time-lapse movie observation (TLM) with gap junction inhibitors (GJis). METHODS: ICR mouse embryos were exposed to two types of GJis in CZB medium: oleamide (0 to 50 MUM) and 1-heptanol (0 to 10 mM). We compared the rate of blastocyst formation at embryonic day 4.5 (E4.5) with E5.5. We also observed and evaluated the times from the second cleavage to each embryonic developing stage by TLM. We investigated embryonic distribution of DNA, Nanog protein, and Connexin 43 protein with immunofluorescent staining. RESULTS: In the comparison of E4.5 with E5.5, inhibition of gap junction intercellular communication (GJIC) delayed embryonic blastocyst formation. The times from the second cleavage to blastocyst formation were significantly extended in the GJi-treated embryos (control vs with oleamide, 2224 +/- 179 min vs 2354 +/- 278 min, p = 0.013). Morphological differences were traced in control versus GJi-treated embryos until the hatching stage. Oleamide induced frequent severe collapses of expanded blastocysts (77.4 % versus 26.3 %, p = 0.0001) and aberrant ICM divisions connected to sticky strands (74.3 % versus 5.3 %, p = 0.0001). Immunofluorescent staining indicated Nanog-positive cells were distributed in each divided ICM. CONCLUSIONS: GJIC plays an important role in blastocyst formation, collapses of expanded blastocysts, and the ICM construction in mouse embryos. PMID- 25917499 TI - Optimal timing of first posttreatment FDG PET/CT in head and neck squamous cell carcinoma. AB - BACKGROUND: The optimal timing for the initial posttreatment fluorodeoxyglucose (FDG) positron emission tomography (PET)/CT scan after definitive treatment of head and neck squamous cell carcinoma (HNSCC) is unclear. METHODS: We conducted a retrospective review of 247 patients with definitively treated nonmetastatic HNSCC. First posttreatment PET/CT scans were grouped into: <7 weeks, 7 to 10 weeks, 11 to 14 weeks, and >=15 weeks. Scans were categorized as positive or negative and accuracy of scans was calculated for each group using biopsy, subsequent imaging, or clinical follow-up for 1 year after treatment as a reference standard. RESULTS: Sixty-seven of the 247 patients (27.1%) had treatment failure. Scans performed at <7 weeks were less accurate than all other time intervals (p < .05). Scans performed at all other intervals were similar in accuracy. CONCLUSION: First posttreatment PET/CT can be obtained as early as 2 months after therapy. Scans performed earlier than 2 months have lower accuracy. (c) 2015 Wiley Periodicals, Inc. Head Neck 38: E853-E858, 2016. PMID- 25917500 TI - A national Swedish longitudinal twin-sibling study of criminal convictions from adolescence through early adulthood. AB - BACKGROUND: Prior twin and adoption studies have demonstrated the importance of both genetic and shared environmental factors in the etiology of criminal behavior (CB). However, despite substantial interest in life-course theories of CB, few genetically informative studies have examined CB in a developmental context. METHOD: In 69,767 male-male twin pairs and full-sibling pairs with <= 2 years' difference in age, born 1958-1976 and ascertained from the Swedish Twin and Population Registries, we obtained information on all criminal convictions from 1973 to 2011 from the Swedish Crime Register. We fitted a Cholesky structural model, using the OpenMx package, to CB in these pairs over three age periods: 15-19, 20-24, and 25-29. RESULTS: The Cholesky model had two main genetic factors. The first began at ages 15-19 and declined in importance over development. The second started at ages 20-24 and was stable over time. Only one major shared environmental factor was seen, beginning at ages 15-19. Heritability for CB declined from ages 15-29, as did shared environmental effects, although at a slower rate. CONCLUSIONS: Genetic risk factors for CB in males are developmentally dynamic, demonstrating both innovation and attenuation. These results are consistent with theories of adolescent-limited and life-course persistent CB subtypes. Heritability for CB did not increase over time as might be predicted from active gene-environmental correlation. However, consistent with expectation, the proportion of variability explained by shared environmental effects declined slightly as individuals aged and moved away from their original homes and neighborhoods. PMID- 25917501 TI - Characterization of the release profile of doxycycline by PLGA microspheres adjunct to non-surgical periodontal therapy. AB - The aim of this pilot study was to assess the release of locally delivered doxycycline by poly (l-lactide-co-glycolide) (PLGA) microspheres in the periodontal pocket of patients with chronic periodontitis, treated by non surgical periodontal therapy. Nineteen sites of non-adjacent teeth of four different patients were evaluated. Five milligram of PLGA microspheres loaded with 16 doxycycline hyclate (DOX) was administered per periodontal site. To quantify DOX released into the periodontal pocket, gingival crevicular fluid (GCF) was collected from the sites on days 2, 5, 7, 10, 15, and 20 after DOX application, and high-performance liquid chromatography was performed. Data were statistically assessed by ANOVA/Tukey test. At days 2, 5, and 7, the DOX concentration was stably sustained (23.33 +/- 1.38, 23.4 +/- 1.82, and 22.75 +/- 1.33 MUg/mL, respectively), with no significant differences over these assessment times (p > 0.05). At days 10 and 15, a tendency was observed toward a decrease in DOX concentration (21.74 +/- 0.91 and 20.53 +/- 4.88 MUg/mL, respectively), but a significant decrease in GCF drug concentration (19.69 +/- 4.70 MUg/mL) was observed only on day 20. The DOX delivery system developed demonstrated a successful sustained release after local administration, as an adjunct to non surgical periodontal therapy. PMID- 25917502 TI - Comparison of Enrichment Broths for Supporting Growth of Shiga Toxin-Producing Escherichia coli. AB - Detection of Shiga toxin-producing Escherichia coli (STEC) in complex sample matrices remains challenging. In an attempt to improve detection, nonselective and selective enrichment broths were compared as follows: (1) trypticase soy broth (TSB) was compared with TSB plus novobiocin, vancomycin, rifampicin, bile salts, and potassium tellurite (TSB-NVRBT) for supporting growth of STEC in pure culture; (2) E. coli broth (EC), TSB, and TSB plus bile salts (mTSB) were compared for enrichment of STEC O26, O45, O103, O104, O111, O121, O145, and O157 (STEC-8) in inoculated cattle fecal samples; (3) EC, TSB, and mTSB were compared for the detection of STEC-8 in inoculated cattle fecal samples. Fecal samples were inoculated with wild-type STEC-8 or nalidixic acid- or rifampicin-resistant derivatives of the same strains at 100, 1000, or 10,000 colony-forming units per gram (CFU/g) of feces. In pure culture, the mean STEC CFU/mL following enrichment in TSB was 1.17 log10 greater than that in TSB-NVRBT (P < 0.05). In inoculated fecal samples, EC enrichment yielded growth of STEC-8 (6.42 log10 CFU/g) that was significantly greater than in TSB (6.23 log10 CFU/g; P < 0.05), and numerically but not significantly greater than in mTSB (6.37 log10 CFU/g; P = 0.60). Wild type STEC strains were detected in 43.8 % (21/48) of the samples enriched in EC and mTSB compared to 27.1 % (13/48) of the samples enriched in TSB (P = 0.15). Overall, STEC grew significantly better when enriched in EC compared to TSB. Modification of TSB by the addition of bile salts improved the growth and detection of STEC compared to TSB alone. PMID- 25917503 TI - Marine Oil-Degrading Microorganisms and Biodegradation Process of Petroleum Hydrocarbon in Marine Environments: A Review. AB - Due to the toxicity of petroleum compounds, the increasing accidents of marine oil spills/leakages have had a significant impact on our environment. Recently, different remedial techniques for the treatment of marine petroleum pollution have been proposed, such as bioremediation, controlled burning, skimming, and solidifying. (Hedlund and Staley in Int J Syst Evol Microbiol 51:61-66, 2001). This review introduces an important remedial method for marine oil pollution treatment-bioremediation technique-which is considered as a reliable, efficient, cost-effective, and eco-friendly method. First, the necessity of bioremediation for marine oil pollution was discussed. Second, this paper discussed the species of oil-degrading microorganisms, degradation pathways and mechanisms, the degradation rate and reaction model, and the factors affecting the degradation. Last, several suggestions for the further research in the field of marine oil spill bioremediation were proposed. PMID- 25917504 TI - Accumulation of Pyrimidine Intermediate Orotate Decreases Virulence Factor Production in Pseudomonas aeruginosa. AB - The impact of orotate accumulation in the medically important bacterium Pseudomonas aeruginosa was studied by deleting pyrE, the gene encoding orotate phosphoribosyltransferase and responsible for converting orotate into orotate monophosphate within the de novo pyrimidine synthesis pathway. The pyrE mutant accumulated orotate and exhibited decreased production of hemolysin, casein protease, and elastase. Feeding orotate at a concentration of 51.25 MUM to the wild type, PAO1, likewise decreased production of these factors except for hemolysin, which was not affected. A significant increase in the pigments pyocyanin and pyoverdin was also observed. Pyocyanin increase in the pyrE mutant was heightened when the mutant was supplemented with orotate. Although pyoverdin production in the wild-type PAO1 was unaffected by orotate supplementation, a decrease in the mutant's production was observed when supplemented with orotate. These results indicate a significant reduction in virulence factor production in the pyrE mutant and reduction in some virulence factors in the wild type when supplemented with orotate. PMID- 25917505 TI - Experimental investigation on the soil sorption properties and hydrophobicity of polymethoxylated, polyhydroxylated diphenyl ethers and methoxylated-, hydroxylated-polychlorinated diphenyl ethers. AB - In the present study, twenty-six types of polymethoxylated diphenyl ethers (PMeODEs), twenty types of polyhydroxylated diphenyl ethers (PHODEs), seven types of methoxylated-polychlorinated diphenyl ethers (MeO-PCDEs) and seven types of hydroxylated-polychlorinated diphenyl ethers (HO-PCDEs) were synthesized. The logKow and logKoc values of all of the synthesized compounds were then determined using HPLC. The soil sorption properties of five types of selected substituted diphenyl ethers (DEs) were investigated. Sorption behavior studies suggested that rapid sorption played a primary role in the sorption process of the selected DEs and their sorption isotherms were fitted the Freundlich logarithmic model. For PMeODEs and PHODEs, with the increase in the number of substituents, both logKow and logKoc values exhibited linearly decreasing trends. Unlike PMeODEs and PHODEs, both logKow and logKoc values of MeO/HO-PCDEs were decreased linearly with the increasing number of chlorine atoms. The reason maybe that both methoxy and hydroxyl are hydrophilic groups, whereas the chlorine atom is hydrophobic group. Linear relationships were observed for the logKow and logKoc of all studied DEs. Moreover, the logKow of PMeODEs, PHODEs, MeO- and HO-PCDEs and their corresponding PCDEs showed good linearity. PMID- 25917506 TI - Distribution of heavy metals and polycyclic aromatic hydrocarbons in holm oak plant-soil system evaluated along urbanization gradients. AB - Heavy metals (HMs) and polycyclic aromatic hydrocarbons (PAHs) were analysed in topsoil and in Quercus ilex L. leaves from holm oak woodlands located along urbanization gradients (urban, periurban and extraurban sites) in two Italian regions (Campania and Tuscany). In each sampling site, the metal bioavailability factors (MBFs) and the pollutant bioaccumulation factors (BAFs) were calculated to estimate the fraction of each total metal concentration in soil potentially available to root uptake and to know the fate of both HMs and PAHs in the plant soil system. In general, the results indicated a low atmospheric deposition of pollutants and, in some cases, leaves and soils accumulated higher HM and PAH concentrations in the most urbanized areas. Correlation analyses showed that in each sampling site topsoil and leaves were exposed to the same atmospheric inputs of HMs and PAHs, although to a different extent. Notwithstanding the MBFs and BAFs differed between the two regions for the most HMs, they did not show a clear pattern in relation to the urbanization gradient. However, some information could be deduced by these ratios: the high BAF calculated for Mn shows that the foliar uptake plays an important role in accumulation of this metal. Moreover, for PAHs the different values of BAFs among low and high molecular weight compounds suggest their different fate, the first accumulated in leaves by stomata and the latter preferentially deposited on topsoil. PMID- 25917507 TI - Designing greener plasticizers: Effects of alkyl chain length and branching on the biodegradation of maleate based plasticizers. AB - The ubiquitous presence of the plasticizer di (2-ethylhexyl) phthalate (DEHP) in the environment is of concern due to negative biological effects associated with it and its metabolites. In particular, the metabolite mono (2-ethylhexyl) phthalate (MEHP) is a potential endocrine disruptor. Earlier work had identified the diester di (2-ethylhexyl) maleate (DEHM) as a potential greener candidate plasticizer to replace DEHP, yet its biodegradation rate was reported to be slow. In this study, we modified the side chains of maleate diesters to be linear (i.e., unbranched) alkyl chains that varied in length from ethyl to n-octyl. The plasticization efficiency of these compounds blended into PVC at 29 wt.% increased with the overall length of the molecule, but all compounds performed as well as or better than comparable samples with DEHP. Tests conducted with the equally long DEHM and dihexyl maleate (DHM) showed that branching has no effect on glass transition temperature (Tg) reduction efficiency. Biodegradation experiments with the common soil bacterium Rhodococcus rhodocrous in the presence of the plasticizer showed acceptable hydrolysis rates of maleates with unbranched side chains, while the branched DEHM showed almost no degradation. The addition of hexadecane as auxiliary carbon source improved hydrolysis rates. Temporary buildup of the respective monoester of the compounds were observed, but only in the case of the longest molecule, dioctyl maleate (DOM), did this buildup lead to growth inhibition of the bacteria. Maleates with linear side chains, if designed and tested properly, show promise as potential candidate plasticizers as replacements for DEHP. PMID- 25917508 TI - Transcriptome-wide analysis of the MADS-box gene family in the orchid Erycina pusilla. AB - Orchids exhibit a range of unique flower shapes and are a valuable ornamental crop. MADS-box transcription factors are key regulatory components in flower initiation and development. Changing the flower shape and flowering time can increase the value of the orchid in the ornamental horticulture industry. In this study, 28 MADS-box genes were identified from the transcriptome database of the model orchid Erycina pusilla. The full-length genomic sequences of these MADS-box genes were obtained from BAC clones. Of these, 27 were MIKC-type EpMADS (two truncated forms) and one was a type I EpMADS. Eleven EpMADS genes contained introns longer than 10 kb. Phylogenetic analysis classified the 24 MIKC(c) genes into nine subfamilies. Three specific protein motifs, AG, FUL and SVP, were identified and used to classify three subfamilies. The expression profile of each EpMADS gene correlated with its putative function. The phylogenetic analysis was highly correlated with the protein domain identification and gene expression results. Spatial expression of EpMADS6, EpMADS12 and EpMADS15 was strongly detected in the inflorescence meristem, floral bud and seed via in situ hybridization. The subcellular localization of the 28 EpMADS proteins was also investigated. Although EpMADS27 lacks a complete MADS-box domain, EpMADS27-YFP was localized in the nucleus. This characterization of the orchid MADS-box family genes provides useful information for both orchid breeding and studies of flowering and evolution. PMID- 25917510 TI - Single-step preparation of two-dimensionally organized gold particles via ionic liquid/metal sputter deposition. AB - Sputtering of noble metals, such as Au, Ag, Pd, and Pt, onto room-temperature ionic liquids (RTILs) enabled the formation of monoparticle films composed of spherical noble metal nanoparticles on the liquid surface only when the RTILs used contained hydroxyl-functionalized cations as a component. Sputter deposition of these metals under the same conditions simply produced well-dispersed metal particles without the formation of any films on the solution surface when pure RTILs with non-functionalized cations were employed. Anionic species, even those containing a hydroxyl group, did not significantly affect the formation of the particle film on the RTIL surface or dispersion of particles in the solution. The size of Au particles could be controlled by varying the sputtering condition regardless of the two-dimensional particle density, which was determined by the composition of RTILs used. An Au monoparticle film on the RTIL surface was easily transferred onto various solid substrates via the horizontal liftoff method without large aggregation even when the substrate surface was highly curved. PMID- 25917509 TI - Fragile X mental retardation protein regulates olfactory sensitivity but not odorant discrimination. AB - Fragile X syndrome (FXS) is the most common cause of inherited intellectual disability and is characterized by cognitive impairments and altered sensory function. It is caused by absence of fragile X mental retardation protein (FMRP), an RNA-binding protein essential for normal synaptic plasticity and function. Animal models have provided important insights into mechanisms through which loss of FMRP impacts cognitive and sensory development and function. While FMRP is highly enriched in the developing and adult olfactory bulb (OB), its role in olfactory sensory function remains poorly understood. Here, we used a mouse model of FXS, the fmr1 (-/y) mouse, to test whether loss of FMRP impacts olfactory discrimination, habituation, or sensitivity using a spontaneous olfactory cross habituation task at a range of odorant concentrations. We demonstrated that fmr1 (-/y) mice have a significant decrease in olfactory sensitivity compared with wild type controls. When we controlled for differences in sensitivity, we found no effect of loss of FMRP on the ability to habituate to or spontaneously discriminate between odorants. These data indicate that loss of FMRP significantly alters olfactory sensitivity, but not other facets of basal olfactory function. These findings have important implications for future studies aimed at understanding the role of FMRP on sensory functioning. PMID- 25917511 TI - What is your diagnosis? Abdominal fluid from a dog. PMID- 25917512 TI - Elemanolide dimers from seeds of Vernonia anthelmintica. AB - The seeds of Vernonia anthelmintica afforded three new elemanolide dimers, vernodalidimers C, D, and E, and four known elemanolides. Their structures were elucidated based on extensive spectroscopic analysis (IR, HR-ESIMS, 1D- and 2D NMR), and the absolute configurations of the new dimers were determined by comparison of the experimental and calculated electronic circular dichroism spectra. Cytotoxicity of the isolated compounds against four human tumor cell lines was assayed. Vernodalidimers C, D, and E exhibited strong cytotoxicity against T47D cell line with IC50 values of 5.58, 0.95, and 12.75MUM, respectively. PMID- 25917513 TI - Insights into drug discovery from natural products through structural modification. AB - Natural products (NPs) have played a key role in drug discovery and are still a prolific source of novel lead compounds or pharmacophores for medicinal chemistry. Pharmacological activity and druggability are two indispensable components advancing NPs from leads to drugs. Although naturally active substances are usually good lead compounds, most of them can hardly satisfy the demands for druggability. Hence, these structural phenotypes have to be modified and optimized to overcome existing deficiencies and shortcomings. This review illustrates druggability optimization of NPs through structural modification with some successful examples. PMID- 25917514 TI - Evaluation of gene expression SAP5, LIP9, and PLB2 of Candida albicans biofilms after photodynamic inactivation. AB - With the increasing number of strains of Candida ssp. resistant to antifungal agents, the accomplishment of researches that evaluate the effects of new therapeutic methods, like photodynamic inactivation (PDI), becomes important and necessary. Thus, the objective of this study was to verify the effects of the PDI on Candida albicans biofilms, evaluating their effects on the expression of the gene hydrolytic enzymes aspartyl proteinase (SAP5), lipase (LIP9), and phospholipase (PLB2). Clinical strains of C. albicans (n = 9) isolated from patient bearers of the virus HIV and a pattern strain ATCC 18804 were used. The quantification of gene expression was related to the production of hydrolytic enzymes using the quantitative polymerase chain reaction (qPCR) assay. For PDI, we used laser-aluminum-gallium arsenide low power (red visible, 660 nm) as a light source and the methylene blue at 300 MUM as a photosensitizer. We assessed two experimental groups for each strain: (a) PDI: sensitization with methylene blue and laser irradiation and (b) control: without sensitization with methylene blue and light absence. The PDI decreased gene expression in 60 % of samples for gene SAP5 and 50 % of the samples decreased expression of LIP9 and PLB2. When we compared the expression profile for of each gene between the treated and control group, a decrease in all gene expression was observed, however no statistically significant difference (Tukey's test/p = 0.12). It could be concluded that PDI (photosensitization with methylene blue followed by low-level laser irradiation) showed a slight reduction on the expression of hydrolytic enzymes of C. albicans, without statistical significance. PMID- 25917515 TI - Effects of photodynamic therapy on Enterococcus faecalis biofilms. AB - Microbial biofilms are involved in almost all infectious pathologies of the oral cavity. This has led to the search for novel therapies specifically aimed at biofilm elimination. In this study, we used atomic force microscopy (AFM) to visualize injuries and to determine surface roughness, as well as confocal laser scanning microscopy (CLSM) to enumerate live and dead bacterial cells, to determine the effects of photodynamic therapy (PDT) on Enterococcus faecalis biofilms. The AFM images showed that PDT consisting of methylene blue and a 670 nm diode laser (output power 280 mW during 30 s) or toluidine blue and a 628-nm LED light (output power 1000 mW during 30 s) induced severe damage, including cell lysis, to E. faecalis biofilms, with the former also causing an important increase in surface roughness. These observations were confirmed by the increase in dead cells determined using CLSM. Our results highlight the potential of PDT as a promising method to achieve successful oral disinfection. PMID- 25917516 TI - A jackknife approach to quantifying single-trial correlation between covariance based metrics undefined on a single-trial basis. AB - The quantification of covariance between neuronal activities (functional connectivity) requires the observation of correlated changes and therefore multiple observations. The strength of such neuronal correlations may itself undergo moment-by-moment fluctuations, which might e.g. lead to fluctuations in single-trial metrics such as reaction time (RT), or may co-fluctuate with the correlation between activity in other brain areas. Yet, quantifying the relation between moment-by-moment co-fluctuations in neuronal correlations is precluded by the fact that neuronal correlations are not defined per single observation. The proposed solution quantifies this relation by first calculating neuronal correlations for all leave-one-out subsamples (i.e. the jackknife replications of all observations) and then correlating these values. Because the correlation is calculated between jackknife replications, we address this approach as jackknife correlation (JC). First, we demonstrate the equivalence of JC to conventional correlation for simulated paired data that are defined per observation and therefore allow the calculation of conventional correlation. While the JC recovers the conventional correlation precisely, alternative approaches, like sorting-and-binning, result in detrimental effects of the analysis parameters. We then explore the case of relating two spectral correlation metrics, like coherence, that require multiple observation epochs, where the only viable alternative analysis approaches are based on some form of epoch subdivision, which results in reduced spectral resolution and poor spectral estimators. We show that JC outperforms these approaches, particularly for short epoch lengths, without sacrificing any spectral resolution. Finally, we note that the JC can be applied to relate fluctuations in any smooth metric that is not defined on single observations. PMID- 25917518 TI - The Incidence and Severity of Postoperative Pain following Inpatient Surgery. AB - OBJECTIVE: In recent years, there has been increased attention to pain management after surgery in the hospital setting along with financial enticement from the US government. The aim of this study is to evaluate the current efficacy of postoperative pain management. METHODS: In a prospective study, patients in an academic private nonprofit medical center were asked the same questions about their postoperative pain as in a previously published 2003 survey. Questionnaires on 1) pain intensity on a verbal categorical scale and 2) patient satisfaction with pain medication were completed in the patient's room before hospital discharge, and followed-up by telephone interviews at 1 and 2 weeks later. Numerical Pain Scale (NRS) pain scores were obtained at the same time points. Hospital Consumer Assessment of Healthcare Providers and Systems (HCAHPS) results for pain management were obtained at bedside interview along with standard mailed HCAHPS survey obtained by Press Ganey. RESULTS: Based on 441 surgical inpatients (Orthopedic, General, Neurosurgery, Gynecological) 12% of patients had "Severe-to Extreme" pain and 54% had "Moderate-to-Extreme" pain at discharge. During the first 2 weeks after discharge, 13% of patients had "Severe-to-Extreme" pain and 46% had "Moderate-to-Extreme" pain. Pain scores at discharge and after discharge were negatively correlated with patient satisfaction with pain medication (P < 0.0001), indicating that increased pain intensity was associated with decreased patient satisfaction. For the HCAHPS question "how often was your pain well controlled?," 66% answered "Always" in the Press Ganey report versus 51% at bedside (P < 0.0001). CONCLUSIONS: The incidence of severe-to-extreme pain in patients before and after discharge following inpatient surgery is 12-13%, and this is a reduction from 10 years ago. PMID- 25917517 TI - Vascular risk factors, cerebrovascular reactivity, and the default-mode brain network. AB - Cumulating evidence from epidemiologic studies implicates cardiovascular health and cerebrovascular function in several brain diseases in late life. We examined vascular risk factors with respect to a cerebrovascular measure of brain functioning in subjects in mid-life, which could represent a marker of brain changes in later life. Breath-hold functional MRI (fMRI) was performed in 541 women and men (mean age 50.4 years) from the Coronary Artery Risk Development in Young Adults (CARDIA) Brain MRI sub-study. Cerebrovascular reactivity (CVR) was quantified as percentage change in blood-oxygen level dependent (BOLD) signal in activated voxels, which was mapped to a common brain template and log transformed. Mean CVR was calculated for anatomic regions underlying the default mode network (DMN) - a network implicated in AD and other brain disorders - in addition to areas considered to be relatively spared in the disease (e.g. occipital lobe), which were utilized as reference regions. Mean CVR was significantly reduced in the posterior cingulate/precuneus (beta=-0.063, 95% CI: 0.106, -0.020), anterior cingulate (beta=-0.055, 95% CI: -0.101, -0.010), and medial frontal lobe (beta=-0.050, 95% CI: -0.092, -0.008) relative to mean CVR in the occipital lobe, after adjustment for age, sex, race, education, and smoking status, in subjects with pre-hypertension/hypertension compared to normotensive subjects. By contrast, mean CVR was lower, but not significantly, in the inferior parietal lobe (beta=-0.024, 95% CI: -0.062, 0.014) and the hippocampus (beta= 0.006, 95% CI: -0.062, 0.050) relative to mean CVR in the occipital lobe. Similar results were observed in subjects with diabetes and dyslipidemia compared to those without these conditions, though the differences were non-significant. Reduced CVR may represent diminished vascular functionality for the DMN for individuals with prehypertension/hypertension in mid-life, and may serve as a preclinical marker for brain dysfunction in later life. PMID- 25917519 TI - Is an online skin cancer toolkit an effective way to educate primary care physicians about skin cancer diagnosis and referral? AB - BACKGROUND: Skin disorders account for over 20% of GP consultations. Half of dermatology referrals to secondary care are for skin lesions, but only 12% of urgent skin cancer referrals are deemed appropriate. Suitably designed online learning resources may positively impact GP confidence in the recognition of skin cancer and improve patient outcomes. OBJECTIVE: This study evaluated the impact of a national, online, skin cancer recognition toolkit on GP confidence and knowledge in diagnosing skin cancers and referral behaviour to secondary care. METHODS: The toolkit, consisting of a referral decision aid, lesion recognition resource, clinical cases and a quiz, was launched in March 2012. Website usage statistics and online focus groups were used to assess the usability of the website and perceived changes in behaviour. The impact of the toolkit was assessed using national skin cancer referral data, cross-sectional questionnaires and urgent skin cancer referral data to two NHS trusts. RESULTS: The toolkit was accessed by 20% of GPs in England from 20th March to 31st October 2012; spending a mean of over 5 minutes each, with over 33% return users. A survey revealed that the toolkit improved perceptions of skin cancer training and self-reported knowledge about skin cancer referral pathways. Analysis of referral patterns did not identify an impact of the toolkit on number or appropriateness of urgent skin cancer referrals in the eight months following the launch of the website. Online focus groups confirmed the usefulness of the resource and suggested a positive influence on knowledge and referral behaviour. CONCLUSION: The skin cancer toolkit is an accessible online learning resource for improving confidence with skin cancer referral amongst GPs. Although we were unable to identify any immediate changes in skin cancer diagnoses or appropriate referral behaviours, research is required to evaluate its longer term effects on outcomes. PMID- 25917520 TI - Gut microbiome, gut function, and probiotics: Implications for health. AB - New insights from a rapidly developing field of research have ushered in a new era of understanding of the complexity of host-microbe interactions within the human body. The paradigm shift from culturing to metagenomics has provided an insight into the complex diversity of the microbial species that we harbor, revealing the fact that we are in fact more microbes than human cells. The largest consortium of these microbes resides in the gut and is called the gut microbiota. This new science has expanded the ability to document shifts in microbial populations to an unparalleled degree. It is now understood that signals from the microbiota provide trophic, nutritional, metabolic, and protective effects for the development and maintenance of the host digestive, immune, and neuroendocrine system. Evidence linking changes in the gut microbiota to gastrointestinal and extraintestinal disorders like irritable bowel syndrome, inflammatory bowel disease, obesity, diabetes, and celiac disease have begun to emerge recently. Probiotics act through diverse mechanisms positively affecting the composition and/or function of the commensal microbiota and alter host immunological responses. Well-controlled intervention trials, systematic reviews, and meta-analysis provide convincing evidence for the benefit of probiotics in prevention and treatment of gastrointestinal as well as extraintestinal disorders. PMID- 25917522 TI - A survey of procedural sedation for pediatric gastrointestinal endoscopy in India. AB - BACKGROUND: Sedation practices for pediatric gastrointestinal endoscopic procedures (PGEP) vary based on infrastructure, availability of trained personnel, and local protocols. Data on prevalent sedation practices is lacking from India. This study aimed to survey the sedation practices for PGEP in India. METHODS: A mailing list was constituted with the e-mail addresses of the members of the Indian Society of Pediatric Gastroenterology, Hepatology and Nutrition, Indian Academy of Pediatrics, Association of Surgeons of India, Indian Association of Pediatric Surgeons, and Indian Society of Gastroenterology. The web-based survey was sent by e-mail. RESULTS: Of the 498 recipients, who responded through the survey link, 91 did not complete the survey. Among those who completed the survey, 91 performed PGEP. Among these 91, 12.1 % performed PGEP without sedation or general anesthesia. Anesthetist involvement was associated with use of propofol based-sedation. Of the respondents, 70.3 % found non-anesthetist administered propofol sedation unacceptable while 38.5 % of the centers had a policy against it. Two-thirds of the respondents were assisted by an anesthetist for most PGEP. An operating room (OR) was used for PGEPs by 23.1 %. PGEP in a non-teaching hospital, non-availability of pediatrician in the endoscopy room, use of an OR for PGEP, and the easy availability of an anesthetist were strongly associated with the involvement of an anesthetist. CONCLUSIONS: The survey indicates a high frequency of involvement of anesthetists and use of OR. This survey should serve as an impetus to evaluate the cost of PGEP in India and the training accorded to non-anesthetists for procedural sedation. PMID- 25917521 TI - B cell non-Hodgkin's lymphoma in chronic hepatitis C virus patients: An interesting relationship. AB - BACKGROUND: An association exists between hepatitis C virus (HCV) infection and non-Hodgkin's lymphoma (NHL), but a causal relationship is not fully established. HCV is a lymphotropic virus that represents a major etiologic agent of mixed cryoglobulinemia (MC) type II which is characterized by a low-grade B cell clonal lymphoproliferative disorder that usually progresses to a more aggressive malignant lymphoma. This study assessed the role of cryoglobulin and B lymphocyte stimulator (BLys) in the pathogenesis of NHL in chronic HCV patients. METHODS: Sixty HCV patients, 30 free of B cell NHL (group I) and 30 with B cell NHL (group II), and 30 healthy controls (group III) were studied. Qualitative cryoglobulin assessment and a quantitative assay for BLys were done. RESULTS: In group II, BLyS positivity rate was 1.5-fold higher than of group I (p <= 0.01). A positive association was found between positivity rate of MC and the level of BLyS (p <= 0.01). CONCLUSION: High BLyS levels were associated with HCV-associated lymphoproliferative disorder coupled with positive MC. PMID- 25917523 TI - Sessile serrated adenomas versus conventional adenomas. Different polyps in different populations? AB - PURPOSE: The aim of this study was to determine risk factors for the development of sessile serrated adenomas (SSA/Ps) as well as to study differences between groups with SSA/Ps and conventional adenomas (tubular, tubulovillus and villus) in the general population. METHODS: One hundred patients with normal colonoscopies, 27 patients with 53 SSA/Ps and 69 patients with 156 conventional adenomas were studied, epidemiological data were collected and calculations of body mass index and waist-to-hip ratio were performed prior to endoscopy. A univariate and a multivariate logistic regression analysis were performed using Stata 9.0. RESULTS: SSA/Ps had a positive association with increasing age (p = 0.01), heavy smoking (>=20 packet years) (p = 0.001) and past history of polyps (p = 0.004) in comparison to normal population. SSA/Ps showed an inverse association with conventional adenomas for diabetes mellitus (p < 0.001) and arterial hypertension (p = 0.001). Meanwhile, female sex was positively associated with SSA/P development in comparison to conventional adenomas (p = 0.031). CONCLUSIONS: Heavy smoking as a significant risk factor for developing SSA/Ps was confirmed from this study. It also seemed that patients with diabetes mellitus and/or hypertension developed conventional adenomas more frequently than SSA/Ps; on the contrary, females were at higher risk of developing SSA/Ps than conventional adenomas. PMID- 25917524 TI - A folate modified pH sensitive targeted polymeric micelle alleviated systemic toxicity of doxorubicin (DOX) in multi-drug resistant tumor bearing mice. AB - PURPOSE: The purpose of this work was to demonstrate the advantages of a folate modified pH sensitive micelle system (HPPF) on reducing the systemic toxicity of antitumor drug doxorubicin (DOX) as well as increasing the antitumor efficacy on multi-drug resistant tumor. METHODS: The micelle HPPF was fabricated by PHIS-PEG and Fol-PEG-PLA using dialysis method. Multi-drug resistant human breast-cancer cell (MCF-7Adr) was used to test the therapeutic effect of DOX loaded HPPF micelles (HPPF/DOX). Nude mice bearing MCF-7Adr tumor was used to evaluate the systemic toxicity of HPPF/DOX. RESULTS: The micelle HPPF was successfully prepared with good size uniformity and pH sensitivity. The in vitro experiments showed that HPPF significantly increased the intracellular level and cytotoxicity of DOX. The in vivo experiments demonstrated that HPPF had largely reduced the mortality and body weight loss, improved the animal status and decreased damages on heart and lung tissues comparing to free DOX. CONCLUSIONS: The HPPF/DOX could significantly increase the antitumor efficacy of DOX and largely alleviate the systemic side effects induced by high dose DOX in the treatment of multi-drug resistant tumor. PMID- 25917525 TI - An in situ gelling liquid crystalline system based on monoglycerides and polyethylenimine for local delivery of siRNAs. AB - The development of delivery systems able to complex and release siRNA into the cytosol is essential for therapeutic use of siRNA. Among the delivery systems, local delivery has advantages over systemic administration. In this study, we developed and characterized non-viral carriers to deliver siRNA locally, based on polyethylenimine (PEI) as gene carrier, and a self-assembling drug delivery system that forms a gel in situ. Liquid crystalline formulations composed of monoglycerides (MO), PEI, propylene glycol (PG) and 0.1M Tris buffer pH 6.5 were developed and characterized by polarized light microscopy, Small Angle X-ray Scattering (SAXS), for their ability to form inverted type liquid crystalline phases (LC2) in contact with excess water, water absorption capacity, ability to complex with siRNA and siRNA release. In addition, gel formation in vivo was determined by subcutaneous injection of the formulations in mice. In water excess, precursor fluid formulations rapidly transformed into a viscous liquid crystalline phase. The presence of PEI influences the liquid crystalline structure of the LC2 formed and was crucial for complexing siRNA. The siRNA was released from the crystalline phase complexed with PEI. The release rate was dependent on the rate of water uptake. The formulation containing MO/PEI/PG/Tris buffer at 7.85:0.65:76.5:15 (w/w/w/w) complexed with 10 MUM of siRNA, characterized as a mixture of cubic phase (diamond-type) and inverted hexagonal phase (after contact with excess water), showed sustained release for 7 days in vitro. In mice, in situ gel formation occurred after subcutaneous injection of the formulations, and the gels were degraded in 30 days. Initially a mild inflammatory process occurred in the tissue surrounding the gel; but after 14 days the tissue appeared normal. Taken together, this work demonstrates the rational development of an in situ gelling formulation for local release of siRNA. PMID- 25917526 TI - Preclinical evaluation of dual action intranasal formulation intended for postoperative/cancer associated therapies. AB - Granisetron hydrochloride is a potent antiemetic yet experiencing first pass metabolism. Ketorolac tromethamine is a potent analgesic NSAID that is known to cause gastrointestinal complications. The purpose of this study is to prepare combined in situ nasal copolymer thermal gel combining both drugs for the management of postoperative and cancer associated nausea, vomiting and pain while avoiding the problems associated with their therapy. In situ gelling nasal formulations with/without different mucoadhesive polymers were prepared and evaluated. Viscosity of different formulations was measured and correlated to in vitro drug release. Selected formulae were evaluated for in-vivo mucociliary transit time. Based on in-vitro release pattern and mucociliary transit time, the selected formula F4 was evaluated for chemical and thermal anti-nociception activity in rats following intranasal or intraperitoneal administration. Only the intra-nasal administration of the selected formulation F4 showed significant analgesia against chemical nociception during both the early and late phases. Also, intranasal administration of the selected formulation F4 showed significant analgesia against thermal nociception. F4 intranasal formulation may offer higher therapeutic value than oral administration as it may not only avoid granisetron first pass metabolism but may also minimize ketorolac gastrointestinal adverse effects as well. PMID- 25917527 TI - Nematode parasites infecting the starry batfish Halieutaea stellata (Vahl) (Lophiiformes: Ogcocephalidae) from the East and South China Sea. AB - The starry batfish Halieutaea stellata (Vahl) is a small, benthic fish found in Indo-West Pacific Oceans. However, our present knowledge of the helminth parasites of this fish is still fragmentary. In this study, a total of 29 fish collected from the East and South China Sea were examined to determine the prevalence, intensity and species composition of helminth parasites in H. stellata. Using morphological and molecular approaches, four species of nematodes were found parasitic in this fish host, including the adults and fourth-stage larvae of Raphidascaroides nipponensis Yamaguti 1941; adults and third-stage larvae of Raphidascaris lophii (Wu 1949), third- and fourth-stage larvae of Hysterothylacium larval type IV-A of Shamsi, Gasser & Beveridge 2013 and third stage larvae of Hysterothylacium amoyense (Hsu 1993). Halieutaea stellata represents a new host record for the three last-named nematodes. Raphidascaroides nipponensis with the highest prevalence (82.5%) and intensity (mean = 13.5) of infection was considered as the dominant parasite species in H. stellata. The detailed morphology of the different developmental stages of the four nematode species was studied using light and scanning electron microscopy. All nematode species were also genetically characterized by sequencing and analysing the internal transcribed spacer (ITS) of the ribosomal DNA. This study provides further data on the occurrence of nematode parasites in H. stellata and also contributes to facilitate an accurate and rapid diagnosis of the infection by these little-known nematodes. PMID- 25917528 TI - Substituent effects on the photochromic properties of benzothiophene-based derivatives. AB - Five diarylethene photochromic derivatives, the structures of which incorporate a central benzothiophene unit, a left-hand thiazole group, and a right-hand benzothiophene group, have been prepared. The compound with a thiazole unit with no substituent on the reaction-center carbon atom reveals an unprecedented transformation upon light irradiation. When the 4-position of thiazole is protected by a methyl group, the compounds show high photosensitivity and photochromic properties. In this case, light irradiation affords new compounds with [5]helicene structures featuring the highest redshifted absorption maxima reported to date. PMID- 25917529 TI - The microRNAs Let7c and miR21 are recognized by neuronal Toll-like receptor 7 to restrict dendritic growth of neurons. AB - Inflammatory responses are known to play critical roles in the regulation of neurodevelopment and neurodegeneration. Although microglial cells are recognized as professional immune cells in brains, recent evidence suggests that neurons also express important receptors and regulators of innate immunity, including Toll-like receptor 7 (TLR7), which is a receptor for single-stranded RNAs (ssRNAs). Here, we report that neuronal TLR7 recognizes endogenous ligands such as the miRNAs Let7c and miR21 and plays a negative role in controlling neuronal growth in a cell-autonomous manner. We show here that hippocampal CA1 neurons in Tlr7(-/Y) mice had more complex dendritic arbors compared with those of wild-type littermates at postnatal (P) day 7, but not at P21. This observation strengthens a role of TLR7 in restricting neuronal growth during development. In cultured neurons, transient knockdown of Tlr7 promoted axonal and dendritic growth, supporting the cell-autonomous effect of TLR7 on neuronal growth. We observed perceptible levels of Let7c and miR21 in the exosomes of the neuronal cultures as well as in developing brains. Treatment with Let7c and miR21 restricted dendritic growth of wild-type neurons but not Tlr7(-/-) neurons. Our study suggests that neuronal TLR7 is activated by endogenous ligands and thus regulates neuronal morphology. Neuronal innate immune responses may influence neurodevelopment and neurodegeneration through the regulation of neuronal morphology. PMID- 25917530 TI - Five-membered cyclic metal carbyne: synthesis of osmapentalynes by the reactions of osmapentalene with allene, alkyne, and alkene. AB - The synthesis of small cyclic metal carbynes is challenging due to the large angle strain associated with the highly distorted nonlinear triple bonds. Herein, we report a general route for the synthesis of five-membered cyclic metal carbyne complexes, osmapentalynes, by the reactions of an osmapentalene derivative with allene, alkyne, and alkene. Experimental observations and theoretical calculations document the aromaticity in the fused five-membered rings of osmapentalynes. The realization of transforming osmapentalene to osmapentalyne through this general route would not only allow further exploration of metallapentalyne chemistry but also show promising applications of this novel aromatic system with broad absorption band and high molar absorption coefficient. PMID- 25917531 TI - Old Friends in New Places: Exploring the Role of Extraintestinal E. coli in Intestinal Disease and Foodborne Illness. AB - The emergence of new antibiotic-resistant Escherichia coli pathotypes associated with human disease has led to an investigation in terms of the origins of these pathogens. According to the Centers for Disease Control and Prevention, unspecified agents are responsible for 38.4 million of the 48 million (80%) cases of foodborne illnesses each year in the United States. It is hypothesized that environmental E. coli not typically associated with the ability to cause disease in humans could potentially be responsible for some of these cases. In order for an environmental E. coli isolate to have the ability to cause foodborne illness, it must be able to utilize the same attachment and virulence mechanisms utilized by other human pathogenic E. coli. Recent research has shown that many avian pathogenic E. coli (APEC) isolated from poultry harbour attachment and virulence genes also currently found in human pathogenic E. coli isolates. Research also suggests that, in addition to the ability to cause gastrointestinal illnesses, APEC may also be an etiological agent of foodborne urinary tract infections (FUTIs). The purpose of this article was to evaluate the evidence pertaining to the ability of APEC to cause disease in humans, their potential for zoonotic transfer along with discussion on the types of illnesses that may be associated with these pathogens. PMID- 25917532 TI - Electrodeposition-based 3D Printing of Metallic Microarchitectures with Controlled Internal Structures. AB - 3D printing of metallic microarchitectures with controlled internal structures is realized at room temperature in ambient air conditions by the manipulation of metal ion concentration and pulsed electric potentials in the electrolyte meniscus during the meniscus-guided electrodeposition. Precise control of the printing nozzle enables the drawing of complex 3D microarchitectures with well defined geometries and positions. PMID- 25917534 TI - Acute Mesenteric Ischemia Is a More Common Cause than Expected of Acute Abdomen in the Elderly. AB - BACKGROUND: The incidence of acute mesenteric ischemia (AMI) increases exponentially with age. The significance of AMI as a differential diagnosis in elderly patients with acute abdomen may be underestimated. METHODS: Consecutive patients hospitalized for AMI between 2009 and 2013 were retrospectively identified in a well-defined population. Acute appendicitis, ruptured abdominal aortic aneurysm, acute pancreatitis, and acute cholecystitis were used as reference diagnoses, and the age-specific incidence rates were calculated. In addition, long-term mortality risk was assessed for AMI survivors. RESULTS: The in-hospital incidence rates of AMI, acute obstructive mesenteric ischemia, and non-obstructive mesenteric ischemia were 7.3, 4.5, and 2.0/100,000/year, respectively. AMI was more common than ruptured abdominal aortic aneurysm, and the age-specific incidence of AMI was higher than the incidence of acute appendicitis in patients over age 75 years with acute abdomen. During the follow up, the age-adjusted risk of death was 1.8 times higher in AMI survivors than in survivors of acute cholecystitis. CONCLUSION: AMI may be a more common cause of acute abdomen in elderly patients than is generally thought, emphasizing the importance of performing urgent computed tomography with contrast enhancement preferably in arterial and venous phases in these patients. PMID- 25917533 TI - Clostridium Difficile Infection from a Surgical Perspective. AB - BACKGROUND: The incidence and the severity of Clostridium difficile infection (CDI) have increased significantly over the last decade, especially in high-risk populations such as patients with inflammatory bowel disease (IBD). Surgeons must be able to both identify and minimize the risk of CDI in their own surgical patients and determine which CDI patients will benefit from surgery. PURPOSE: We sought to define the risk factors, compare the treatment options, define the surgical indications, and identify factors that affect surgical outcomes for CDI based on the currently available literature. RESULTS: Antibiotic use, exposure to the C. difficile bacteria, IBD, and higher levels of co-morbidity are all risk factors for CDI. The majority of CDI can be treated with antibiotics. Severe or fulminant colitis, however, has a high potential for poor outcome, but experience and some data suggest a lower mortality rate with colectomy rather than with continued medical treatment. Open total abdominal colectomy with end ileostomy is typically the preferred surgical strategy. It is often difficult to determine which patients will fail medical management as some may not manifest clinical signs of severe infection. Surrogate parameters of failure of medical therapy include respiratory and/or renal insufficiency, age greater than 60 years, peripheral vascular disease, congestive heart failure, and coagulopathy, all of which have been associated with worse surgical outcomes. Evidence suggests that in appropriately selected patients, colectomy performed before the development of shock requiring vasopressors, respiratory failure, renal failure, multi-organ dysfunction, and mental status changes may reduce mortality of the most severe forms of colitis. For less severe or recurrent presentations, creation of a loop ileostomy with intra-operative colonic lavage, fecal microbiota transfer, and C. difficile vaccinations are being discussed but have only been studied in small case-controlled series. CONCLUSIONS: Prevention, containment, and non-surgical treatment are the cornerstone of management for CDI. However, the most severe forms with toxic colitis benefit from involvement of a surgical team. Swift open total abdominal colectomy with end ileostomy in patients with severe or fulminant C. difficile colitis has the best chance to reduce mortality if it is not delayed until shock, end organ damage, vasopressor requirement, mental status changes develop. Less aggressive approaches may be appropriate for milder and refractory forms but require further study before their applicability can be determined. PMID- 25917537 TI - Facts Are Stubborn Things, but Statistics Are More Pliable*: Should We Use the Antimicrobial Envelope for Every Device Implant? PMID- 25917535 TI - Donor Hepatic Steatosis and Outcome After Liver Transplantation: a Systematic Review. AB - BACKGROUND: There is increasing need to expand availability of donor liver grafts, including steatotic livers. Steatotic liver is associated with poor outcome post-transplantation but with conflicting results in the literature. The aim of this systematic review was to evaluate the impact of steatotic livers on liver transplantation outcomes. METHODS: An electronic search of OVID Medline and Embase databases was performed to identify clinical studies that reported outcomes of steatotic livers in liver transplantation. Data were extracted, and basic descriptive statistics were used to summarise data pooled from individual clinical studies. RESULTS: Ninety-two articles were identified, of which 34 met the inclusion criteria, and stratified analysis were performed. There was a lack of standardised definition of primary non-function or impaired primary function amongst the studies and description of type of steatosis. Severely (>60%) steatotic grafts are associated with increased risk of poor graft function, whilst moderate-severe (>30%) steatotic grafts are associated with decreased graft survival. CONCLUSIONS: Available evidence showed increased risk of poor graft outcome in moderate-severe steatotic livers. A large prospective multi centred trial will be required to identify the true risks of steatotic livers. Consistent definition of primary non-function/impaired primary function and description of type of steatosis is also required. PMID- 25917536 TI - Radiological Morphology of Colorectal Liver Metastases after Preoperative Chemotherapy Predicts Tumor Viability and Postoperative Outcomes. AB - INTRODUCTION: The computed tomography (CT) morphology after chemotherapy is reportedly correlated with the histopathologic response to chemotherapy and a better surgical outcome in patients with colorectal liver metastases (CLM). However, the true prognostic advantage of CT morphology remains uncertain. METHODS: The prognostic advantage of CT morphology was validated in 86 patients who underwent surgical resection for CLM after undergoing a 5-fluorouracil-based chemotherapy regimen with or without bevacizumab. RESULTS: An optimal morphologic response was observed in 18 (22.8%) patients, and a strong correlation between the CT morphology and tumor viability was confirmed (P < 0.001). A multivariate analysis revealed that bevacizumab (odds ratio [OR], 6.8; P = 0.03) and chemotherapy cycles >=6 (OR, 3.6; P = 0.04) were associated with an optimal morphologic response. Overall survival (OS) and recurrence-free survival (RFS) were also predicted by CT morphology with a higher sensitivity. Particularly, a group 1 morphology was associated with a higher OS rate (3-year OS 100%) and RFS rate (3-year RFS, 57.0%), and a multivariate analysis confirmed that group 2 and group 3 tumor morphology was a significant predictive factor for tumor recurrence (hazard ratio [HR], 2.5; P = 0.03 and HR, 3.2; P < 0.01, respectively). CONCLUSION: The CT morphology of CLM predicts tumor viability and long-term surgical outcomes after chemotherapy. PMID- 25917538 TI - Gold nanoparticles and/or N-acetylcysteine mediate carrageenan-induced inflammation and oxidative stress in a concentration-dependent manner. AB - We report the effect of gold nanoparticles (AuNP) in an acute inflammation model induced by carrageenan (CG) and compared this effect with those induced by the antioxidant N-acetylcysteine (NAC) alone and by the synergistic effect of NAC and AuNP together. Male Wistar rats received saline or saline containing CG administered into the pleural cavity, and some rats also received NAC (20 mg/kg) subcutaneously and/or AuNP administered into the pleural cavity immediately after surgery. Four hours later, the rats were sacrificed and pleural exudates obtained for evaluation of cytokine levels and myeloperoxidase activities. Oxidative stress parameters were also evaluated in the lungs. The results demonstrated that the inflammatory process caused by the administration of CG into the pleural cavity resulted in a substantial increase in the levels of tumor necrosis factor alpha, interleukin-1beta, and myeloperoxidase and a reduction in interleukin-10 levels. These levels seem to be reversed after different treatments in animals. Antioxidant enzymes exhibited positive responses after treatment of NAC + AuNP, and all treatments were effective at reducing lipid peroxidation and oxidation of thiol groups induced by CG. These findings suggest that small compounds, such as NAC plus AuNP, may be useful in the treatment of conditions associated with local inflammation. PMID- 25917539 TI - Betapapillomavirus in multiple non-melanoma skin cancers of Netherton syndrome: Case report and published work review. AB - Netherton syndrome (NS) is a rare genetic disease presenting with ichthyosiform erythroderma, hair alterations and atopy. NS is due to SPINK5 gene mutations, which cause absent or decreased expression of the encoded protein lymphoepithelial Kazal-type-related inhibitor (LEKTI) in all stratified epithelia. We report a 43-year-old man affected with NS, who developed several squamous and basal cell carcinomas on the face, ears and scalp and papillomatous lesions of hips, groin and genitoanal area. Molecular analysis of the SPINK5 gene revealed homozygosity for the recurrent mutation c.238dupG. Human papillomavirus (HPV) DNA detection and genotyping on patient skin carcinomas and hyperplastic lesions found betapapillomavirus DNA in 10 of 12 (83%) carcinomas and in a hip papilloma, with multiple betapapillomavirus types being identified. Immunohistochemistry showed upregulated expression of p16(INK4a) protein in nine of 12 (75%) patient carcinomas, in line with findings reported in HPV-related cancers. LEKTI and filaggrin immunostaining was strongly decreased in patient skin. A published work search for NS cases with skin cancers and HPV infection identified 15 NS patients, five of them showing mucosal or cutaneous HPV infection. Overall, our results confirm the increased susceptibility to skin carcinomas of some NS patients and provide further evidence of an association between HPV and non-melanoma skin cancers in NS. The highly impaired skin barrier function, hallmark of NS, could facilitate HPV infection, in turn increasing the risk for cancer development. PMID- 25917540 TI - Psychiatric illness and length of stay in general hospitals: do case finding methods matter? AB - OBJECTIVE: Several prior studies have investigated whether patients with "non cognitive" mental disorders (i.e., organic disorders, substance abuse, delirium, and psychotic disorders excluded) have longer Length Of Stay (LOS) than mentally healthy individuals in nonpsychiatric hospital settings. These studies yielded contrasting results. The present paper aims to examine whether methods of psychiatric case finding can explain these differences. METHODS: Using the Clinical Interview Schedule (CIS) and the General Health Questionnaire (GHQ), 462 in-patients of medical, surgical, gynecological, and rehabilitation departments were assessed for the presence of psychiatric disorders. RESULTS: In multiple regression analysis, all CIS-cases together did not show an association with LOS. Of the diagnostic groups assessed by CIS only major depression showed a significantly prolonged LOS. Using the GHQ sum-score as a continuous variable, LOS was significantly increased while using the GHQ as a dichotomous variable did not show such an association. After removing those suffering from multiple psychiatric diagnoses (such as major depression co-morbid with organic mental illness), none of the case definitions showed a significant association with LOS. CONCLUSIONS: It seems that different case finding methods yield different results concerning the association of psychiatric disorders with LOS. When interpreting these results the small size of some subsamples must be taken into consideration. PMID- 25917541 TI - [Feasibility of consultation - liaison psychiatry in a large general hospital: quantitative description of services and personnel expenditure]. AB - BACKGROUND: The integration of psychiatric departments in general hospitals lead to an increasing demand of psychiatric consultation, which often overstrains personnel resources of short staffed psychiatric services. To provide consulting service, as it is demanded by guidelines, a multidisciplinary consulting team could be a possible solution. METHODS: A retrospective descriptive analysis of all consultations made by the psychosocial consultation and liaison service at the general hospital Wels-Grieskirchen in the years 2012 and 2013. RESULTS: There was an increase in referrals overall of 22 % from 2012 to 2013. The largest increase was observed in the group of psychiatrists, who carried out 33.1 % of all consultations. Most consultations, 39.5 %, were done by the group of clinical psychologists, partly substituting medical attendance. Taking together both occupational groups, the expected number of consultations of at least 3 % of all admissions could be achieved. CONCLUSION: A multidisciplinary consulting team consisting of psychiatrists, psychologists, psychosomatic physicians and social workers staffed with 5.11-6.79 full-time personnel is able to provide psychosocial consultation service at a quantitative level required by international guidelines. PMID- 25917543 TI - FDG PET/CT in infection and inflammation--current and emerging clinical applications. AB - Integrated positron emission tomography/computed tomography (PET/CT) with the glucose analogue, 2-[(18)F]-fluoro-2-deoxy-d-glucose (FDG), is an evolving hybrid imaging technique in the evaluation of an important and diverse group of pathological conditions, which are characterised by infection and aseptic inflammation. With a rapidly expanding body of evidence, it is being increasingly recognised that, in addition to its established role in oncological imaging, FDG PET/CT also has clinical utility in suspected infection and inflammation. The technique can identify the source of infection or inflammation in a timely fashion ahead of morphological changes on conventional anatomical imaging techniques, such as computed tomography (CT) and magnetic resonance imaging (MRI), map the extent and severity of disease, identify sites for tissue sampling, and assess therapy response. FDG PET/CT exhibits distinct advantages over traditional radionuclide imaging techniques in terms of shorter duration of examination, higher spatial resolution, non-invasive nature of acquisition, ability to perform quantitative analyses, and the provision of a synergistic combination of functional and anatomical imaging. With the use of illustrative clinico-radiological cases, this article discusses the current and emerging evidence for the use of FDG PET/CT in a broad spectrum of disorders, such as fever of unknown origin, sarcoidosis, large vessel vasculitis, musculoskeletal infections, joint prosthesis or implant-related complications, human immunodeficiency virus (HIV)-related infections, and miscellaneous indications, such as IgG4-related systemic disease. It will also briefly summarise the role of more novel tracers such as FDG-labelled leukocytes and gallium-68 PET tracers in this arena. PMID- 25917544 TI - Adding MRI to ultrasound and ultrasound-guided fine-needle aspiration reduces the false-negative rate of axillary lymph node metastasis diagnosis in breast cancer patients. AB - AIM: To evaluate whether adding magnetic resonance imaging (MRI) to ultrasound (US) and US-guided fine-needle aspiration (US-FNA) can reduce the false-negative rate (FNR) in the diagnosis of axillary lymph node metastasis (ALNM) in breast cancer patients, and to assess false-negative diagnosis of N2 and N3 disease when adding MRI to US and US-FNA. MATERIALS AND METHODS: From March 2012 to February 2013, 497 breast cancer patients were included in the study. ALNM was evaluated according to US and US-FNA prior to MRI. Second-look US was performed when MRI showed positive findings of ALNM. If second-look US also revealed a positive finding, US-FNA was performed. Diagnostic performance, including FNR, was calculated for US and US-FNA with and without MRI. The negative predictive value (NPV) of N2 and N3 disease was evaluated in negative cases based on US and US-FNA with MRI. RESULTS: A total of 159 of 497 (32.0%) patients were found to have ALNM. Among them, 92 patients were diagnosed with metastasis on US and US-FNA. When adding MRI to US and US-FNA, an additional six patients were diagnosed with metastasis. The FNR of diagnosis of ALNM was improved by the addition of MRI (42.1% versus 38.4%, p = 0.0143). The NPV for N2 and N3 disease was 98% (391/399) based on US and US-FNA with MRI. CONCLUSION: Adding MRI to US and US-FNA could reduce the FNR of the diagnosis of ALNM. Furthermore, US and US-FNA with MRI may exclude 98% of N2 and N3 disease. PMID- 25917542 TI - Imaging of cardiovascular risk in patients with Turner's syndrome. AB - Turner's syndrome is a disorder defined by an absent or structurally abnormal second X chromosome and affects around 1 in 2000 newborn females. The standardised mortality ratio in Turner's syndrome is around three-times higher than in the general female population, mainly as a result of cardiovascular disorders. Most striking is the early age at which Turner's syndrome patients develop the life-threatening complications of cardiovascular disorders compared to the general population. The cardiovascular risk stratification in Turner's syndrome is challenging and imaging is not systematically used. The aim of this article is to review cardiovascular risks in this group of patients and discuss a systematic imaging approach for early identification of cardiovascular disorders in these patients. PMID- 25917545 TI - Callus Growth Kinetics of Physic Nut (Jatropha curcas L.) and Content of Fatty Acids from Crude Oil Obtained In Vitro. AB - The callus growth kinetics allows identifying the appropriate moment for callus pealing and monitoring the accumulation of primary and secondary metabolites. The physic nut (Jatropha curcas L.) is a plant species used for biofuel production due to its high oil content; however, this plant presents a great amount of bioactive compounds which can be useful for industry. The aim of this research was to establish a calli growth curve and to evaluate the fatty acid profile of crude oil extracted from callus. The callus growth kinetics presented a sigmoid standard curve with six distinct phases: lag, exponential, linear, deceleration, stationary, and decline. Total soluble sugars were higher at the inoculation day. Reducing sugars were higher at the inoculation day and at the 80th day. The highest percentage of ethereal extract (oil content) was obtained at the 120th day of culture, reaching 18 % of crude oil from the callus. The calli produced medium-chain and long-chain fatty acids (from 10 to 18 carbon atoms). The palmitic acid was the fatty acid with the highest proportion in oil (55.4 %). The lipid profile obtained in callus oil was different from the seed oil profile. PMID- 25917546 TI - Loss of Faap20 Causes Hematopoietic Stem and Progenitor Cell Depletion in Mice Under Genotoxic Stress. AB - 20-kDa FANCA-associated protein (FAAP20) is a recently identified protein that associates with the Fanconi anemia (FA) core complex component, FANCA. FAAP20 contains a conserved ubiquitin-binding zinc-finger domain and plays critical roles in the FA-BRCA pathway of DNA repair and genome maintenance. The function of FAAP20 in animals has not been explored. Here, we report that deletion of Faap20 in mice led to a mild FA-like phenotype with defects in the reproductive and hematopoietic systems. Specifically, hematopoietic stem and progenitor cells (HSPCs) from Faap20(-) (/) (-) mice showed defects in long-term multilineage reconstitution in lethally irradiated recipient mice, with milder phenotype as compared to HSPCs from Fanca(-) (/) (-) or Fancc(-) (/) (-) mice. Faap20(-) (/) ( ) mice are susceptible to mitomycin C (MMC)-induced pancytopenia. That is, acute MMC stress induced a significant progenitor loss especially the erythroid progenitors and megakaryocyte-erythrocyte progenitors in Faap20(-) (/) (-) mice. Furthermore, Faap20(-) (/) (-) HSPCs displayed aberrant cell cycle pattern during chronic MMC treatment. Finally, using Faap20(-) (/) (-) Fanca(-) (/) (-) double knockout mice, we demonstrated a possible dominant effect of FANCA in the interaction between FAAP20 and FANCA. This novel Faap20 mouse model may be valuable in studying the regulation of the FA pathway during bone marrow failure progress in FA patients. PMID- 25917547 TI - Tn6026 and Tn6029 are found in complex resistance regions mobilised by diverse plasmids and chromosomal islands in multiple antibiotic resistant Enterobacteriaceae. AB - Transposons flanked by direct copies of IS26 are important contributors to the evolution of multiple antibiotic resistance. Tn6029 and Tn6026 are examples of composite transposons that have become widely disseminated on small and large plasmids with different incompatibility markers in pathogenic and commensal Escherichia coli and various serovars of Salmonella enterica. Some of the plasmids that harbour these transposons also carry combinations of virulence genes. Recently, Tn6029 and Tn6026 and derivatives thereof have been found on chromosomal islands in both established and recently emerged pathogens. While Tn6029 and Tn6026 carry genes encoding resistance to older generation antibiotics, they also provide a scaffold for the introduction of genes encoding resistance to a wide variety of clinically relevant antibiotics that are mobilised by IS26. As a consequence, Tn6029 and Tn6026 or variants are likely to increasingly feature in complex resistance regions in multiple antibiotic resistant Enterobacteriaceae that threaten the health of humans and food production animals. PMID- 25917549 TI - Structural mechanisms of DREAM complex assembly and regulation. AB - The DREAM complex represses cell cycle genes during quiescence through scaffolding MuvB proteins with E2F4/5 and the Rb tumor suppressor paralog p107 or p130. Upon cell cycle entry, MuvB dissociates from p107/p130 and recruits B-Myb and FoxM1 for up-regulating mitotic gene expression. To understand the biochemical mechanisms underpinning DREAM function and regulation, we investigated the structural basis for DREAM assembly. We identified a sequence in the MuvB component LIN52 that binds directly to the pocket domains of p107 and p130 when phosphorylated on the DYRK1A kinase site S28. A crystal structure of the LIN52-p107 complex reveals that LIN52 uses a suboptimal LxSxExL sequence together with the phosphate at nearby S28 to bind the LxCxE cleft of the pocket domain with high affinity. The structure explains the specificity for p107/p130 over Rb in the DREAM complex and how the complex is disrupted by viral oncoproteins. Based on insights from the structure, we addressed how DREAM is disassembled upon cell cycle entry. We found that p130 and B-Myb can both bind the core MuvB complex simultaneously but that cyclin-dependent kinase phosphorylation of p130 weakens its association. Together, our data inform a novel target interface for studying MuvB and p130 function and the design of inhibitors that prevent tumor escape in quiescence. PMID- 25917550 TI - Single-word predictions of upcoming language during comprehension: Evidence from the cumulative semantic interference task. AB - Comprehenders predict upcoming speech and text on the basis of linguistic input. How many predictions do comprehenders make for an upcoming word? If a listener strongly expects to hear the word "sock", is the word "shirt" partially expected as well, is it actively inhibited, or is it ignored? The present research addressed these questions by measuring the "downstream" effects of prediction on the processing of subsequently presented stimuli using the cumulative semantic interference paradigm. In three experiments, subjects named pictures (sock) that were presented either in isolation or after strongly constraining sentence frames ("After doing his laundry, Mark always seemed to be missing one..."). Naming sock slowed the subsequent naming of the picture shirt - the standard cumulative semantic interference effect. However, although picture naming was much faster after sentence frames, the interference effect was not modulated by the context (bare vs. sentence) in which either picture was presented. According to the only model of cumulative semantic interference that can account for such a pattern of data, this indicates that comprehenders pre-activated and maintained the pre activation of best sentence completions (sock) but did not maintain the pre activation of less likely completions (shirt). Thus, comprehenders predicted only the most probable completion for each sentence. PMID- 25917548 TI - Manual classification strategies in the ECOD database. AB - ECOD (Evolutionary Classification Of protein Domains) is a comprehensive and up to-date protein structure classification database. The majority of new structures released from the PDB (Protein Data Bank) each week already have close homologs in the ECOD hierarchy and thus can be reliably partitioned into domains and classified by software without manual intervention. However, those proteins that lack confidently detectable homologs require careful analysis by experts. Although many bioinformatics resources rely on expert curation to some degree, specific examples of how this curation occurs and in what cases it is necessary are not always described. Here, we illustrate the manual classification strategy in ECOD by example, focusing on two major issues in protein classification: domain partitioning and the relationship between homology and similarity scores. Most examples show recently released and manually classified PDB structures. We discuss multi-domain proteins, discordance between sequence and structural similarities, difficulties with assessing homology with scores, and integral membrane proteins homologous to soluble proteins. By timely assimilation of newly available structures into its hierarchy, ECOD strives to provide a most accurate and updated view of the protein structure world as a result of combined computational and expert-driven analysis. PMID- 25917551 TI - Incretins and bone: friend or foe? AB - To adapt to its various functions, the bone tissue is remodeled permanently and is under the influence of hormonal, local, mechanical and nervous signals. Among them, a role for gut hormones in controlling bone mass and quality has emerged in the recent years. The aim of this review is to provide the reader with a summary of recent developments in the interaction between incretin hormones and bone physiology. PMID- 25917552 TI - A randomized multi-institutional crossover comparison of the GlideScope(r) Cobalt Video laryngoscope to the flexible fiberoptic bronchoscope in a Pierre Robin manikin. AB - BACKGROUND: The GlideScope Cobalt Video laryngoscope is being used more often in children with challenging laryngoscopy. There are, however, no pediatric trials comparing it to flexible fiberoptic bronchoscopy, the current accepted gold standard. This preliminary manikin study compares the first-attempt intubation success of the GlideScope Cobalt video laryngoscope to the flexible fiberoptic bronchoscope when performed by attending pediatric anesthesiologists at two major pediatric centers. METHODS: This prospective randomized, crossover study evaluated 120 attempts (60 with each study device) to intubate the AirSim Pierre Robin manikin (PRM) with fiberoptic bronchoscopy and video laryngoscopy (VL). Attending pediatric anesthesiologists from two quaternary pediatric centers were eligible to participate. Each attending anesthesiologist randomly performed a single tracheal intubation attempt with one of the study devices followed by the alternate method. The primary outcome was the first-attempt success rate of tracheal intubation. Blinding was not feasible. We hypothesized that first attempt success would be higher with fiberoptic bronchoscopy. RESULTS: Thirty anesthesiologists from each center were randomized to use one of the study devices followed by the alternate method. We analyzed all participants' data. There was no overall difference in first-attempt success between VL and fiberoptic bronchoscopy (88.3% vs 85% respectively, P = 0.59). There were significant institutional differences in first-attempt success using VL (76.7% vs 100%). CONCLUSIONS: There was no difference in first-attempt success of tracheal intubation using VL vs fiberoptic bronchoscopy when performed by attending anesthesiologists at two large pediatric centers. However, institutional differences exist in success rates with VL across the two centers. Results from single-center device evaluations should be verified by multi-center evaluations. A significant proportion of attending anesthesiologists lack experience with advanced airway devices; targeted education may enhance intubation success and patient safety. PMID- 25917554 TI - Lupus nephritis: MAINTAINing perspective in lupus nephritis trials. PMID- 25917553 TI - Emerging treatments for post-transplantation diabetes mellitus. AB - Post-transplantation diabetes mellitus (PTDM), also known as new-onset diabetes mellitus (NODM), occurs in 10-15% of renal transplant recipients and is associated with cardiovascular disease and reduced lifespan. In the majority of cases, PTDM is characterized by beta-cell dysfunction, as well as reduced insulin sensitivity in liver, muscle and adipose tissue. Glucose-lowering therapy must be compatible with immunosuppressant agents, reduced glomerular filtration rate (GFR) and severe arteriosclerosis. Such therapy should not place the patient at risk by inducing hypoglycaemic episodes or exacerbating renal function owing to adverse gastrointestinal effects with hypovolaemia. First-generation and second generation sulphonylureas are generally avoided, and caution is currently advocated for the use of metformin in patients with GFR <60 ml/min/1.73 m(2). DPP 4 inhibitors do not interact with immunosuppressant drugs and have demonstrated safety in small clinical trials. Other therapeutic options include glinides and glitazones. Evidence-based treatment regimens used in patients with type 2 diabetes mellitus cannot be directly implemented in patients with PTDM. Studies investigating the latest drugs are required to direct the development of improved treatment strategies for patients with PTDM. This Review outlines the modern principles of glucose-lowering treatment in PTDM with specific reference to renal transplant recipients. PMID- 25917556 TI - Sepsis: Revising definitions of sepsis. PMID- 25917555 TI - Primary disease recurrence-effects on paediatric renal transplantation outcomes. AB - Primary disease recurrence after renal transplantation is mainly diagnosed by examination of biopsy samples, but can also be associated with clinical symptoms. In some patients, recurrence can lead to graft loss (7-8% of all graft losses). Primary disease recurrence is generally associated with a high risk of graft loss in patients with focal segmental glomerulosclerosis, membranous proliferative glomerulonephritis, primary hyperoxaluria or atypical haemolytic uraemic syndrome. By contrast, disease recurrence is associated with a limited risk of graft loss in patients with IgA nephropathy, renal involvement associated with Henoch-Schonlein purpura, antineutrophil cytoplasmic antibody-associated glomerulonephritis or lupus nephritis. The presence of systemic diseases that affect the kidneys, such as sickle cell anaemia and diabetes mellitus, also increases the risk of delayed graft loss. This Review provides an overview of the epidemiology, pathophysiology and management of primary disease recurrence in paediatric renal graft recipients, and describes the overall effect on graft survival of each of the primary diseases listed above. With appropriate management, few paediatric patients should be excluded from renal transplantation programmes because of an increased risk of recurrence. PMID- 25917557 TI - Hypertension: Vascular type 1A angiotensin II receptors regulate renal blood flow and natriuresis. PMID- 25917558 TI - Genetics: Hidden intronic mutations in DGKE are causative of aHUS. PMID- 25917559 TI - Enhancing oil removal from water by immobilizing multi-wall carbon nanotubes on the surface of polyurethane foam. AB - A surface modification method was carried out to enhance the light crude oil sorption capacity of polyurethane foam (PUF) through immobilization of multi walled carbon nanotube (MWCNT) on the foam surface at various concentrations. The developed sorbent was characterized using scanning electron microscopy, Fourier transform infrared spectroscopy, thermogravimetric analysis, and tensile elongation test. The results obtained from thermogravimetric and tensile elongation tests showed the improvement of thermal and mechanical resistance of surface-modified foam. The experimental data also revealed that the immobilization of MWCNT on PUF surface enhanced the sorption capacity of light crude oil and reduced water sorption. The highest oil removal capacity was obtained for 1 wt% MWCNT on PUF surface which was 21.44% enhancement in light crude oil sorption compared to the blank PUF. The reusability of surface modified PUF was determined through four cycles of chemical regeneration using petroleum ether. The adsorption of light crude oil with 30 g initial mass showed that 85.45% of the initial oil sorption capacity of this modified sorbent was remained after four regeneration cycles. Equilibrium isotherms for adsorption of oil were analyzed by the Freundlich, Langmuir, Temkin, and Redlich-Peterson models through linear and non-linear regression methods. Results of equilibrium revealed that Langmuir isotherm is the best fitting model and non-linear method is a more accurate way to predict the parameters involved in the isotherms. The overall findings suggested the promising potentials of the developed sorbent in order to be efficiently used in large-scale oil spill cleanup. PMID- 25917560 TI - Mechanism for the oxidation of phenol by sulfatoferrate(VI): Comparison with various oxidants. AB - The oxidative action of a solid and stable potassium sulfatoferrate(VI) material on phenol was studied in aqueous solution under different stoichiometries. The performance towards phenol and the total organic carbon is compared to that of potassium permanganate and calcium hypochlorite. The total mineralization of phenol is not completely achieved by the studied chemical oxidants, and some oxidation products have been identified by gas chromatography-mass spectrometry and gas chromatography-flame ionization detector analysis. A radical reaction pathway, involving the formation of oxidation intermediates or by-products such as benzoquinone, phenoxyphenol and ring opening products, is proposed for the decomposition of phenol by ferrate(VI). Phenoxyphenol is also involved in the oxidation mechanism for permanganate whereas chlorinated phenols are produced by hypochlorite. The role of the chloride anion impurity of the potassium sulfatoferrate(VI) material has been highlighted in this study; no negative impact on the removal of phenol and its mineralization is observed compared to the use of a pure commercial ferrate(VI). The efficiency of sulfatoferrate(VI) for the oxidative removal of phenol from industrial wastewater is also confirmed. PMID- 25917561 TI - Selection of P2Y12 antagonist, treatment initiation, and predictors of high on treatment platelet reactivity in a "Real World" registry. AB - OBJECTIVE: The present study aimed to compare characteristics related to selection of a P2Y12 antagonist, investigate initiation of therapy with new generation drugs, and identify predictors of high on-treatment platelet reactivity (HTPR) in patients with acute coronary syndrome treated with stent percutaneous coronary intervention (PCI). METHODS AND RESULTS: Data from 589 patients in the LAPCOR (Laboratory AntiPlatelet efficacy and Clinical Outcome Registry; ClinicalTrials.gov Identifier: NCT02264912) registry was analyzed. P2Y12 receptor antagonist efficacy was measured by VASP phosphorylation 24 +/- 4 hours after a loading dose of clopidogrel (600 mg, N=407), prasugrel (60 mg, N=106), or ticagrelor (180 mg, N=76) and expressed by platelet reactivity index (PRI). HTPR was defined as PRI >=50%. Patients treated with prasugrel were significantly younger and had significantly higher hemoglobin levels than those who received clopidogrel or ticagrelor, while chronic kidney disease was significantly more prevalent in the ticagrelor group. Almost all invasively managed patients given new-generation drugs received a loading dose after coronary angiography. Mean residual PRI and HTPR were significantly higher after clopidogrel (44.2 +/- 23.1% and 42.2%, respectively) vs. prasugrel (17.7 +/- 18.0% and 9.4%, respectively) or ticagrelor (18.8 +/- 17.0% and 7.9%, respectively; all p<0.001). Among multiple variables tested, HTPR in patients treated with the new agents significantly related only to platelet count (p=0.014) and mean platelet volume (p=0.03). CONCLUSION: Safety is the most important aspect under consideration in choosing new agents for an individual patient. Other than platelet count and mean platelet volume, factors known as predictors of higher platelet reactivity, did not influence the efficacy of new generation P2Y12 receptor antagonists. PMID- 25917562 TI - Multilevel Associations of Neighborhood Poverty, Crime, and Satisfaction With Blood Pressure in African-American Adults. AB - BACKGROUND: African-American adults experience the highest rates of elevated blood pressure (BP), and this disparity may be linked to socioeconomic and neighborhood-related disadvantage. Based on a bioecological stress-buffering framework, relations of poverty and neighborhood environmental perceptions with BP were assessed using multilevel regression in at-risk African-American adults. METHODS: This cross-sectional study used baseline data that were collected in 2008 as part of the Positive Action for Today's Health (PATH) trial (N = 409), a community-based intervention to increase walking in low-income, high-crime neighborhoods. BP and perceived neighborhood crime and satisfaction were investigated as individual-level indicators of health and neighborhood environment. Census block groups (N = 22) served as geographic proxies for neighborhoods, and poverty was obtained using 2010 U.S. Census data, to characterize the neighborhood-level socioeconomic environment. RESULTS: There were no individual-level direct associations. Significant cross-product interactions demonstrated that with higher perceived crime, high satisfaction was associated with lower systolic (gamma = 3.34) and diastolic (gamma = -1.37) BP, but low satisfaction was associated with higher systolic (gamma = 15.12) and diastolic (gamma = 7.57) BP. Neighborhood-level poverty was associated with diastolic (gamma = 11.48, SE = 4.08, P = 0.008) and systolic BP (gamma = 12.79, SE = 6.33, P = 0.052). Variance in BP across block groups was low (intraclass correlation coefficients = 0.002-0.014) and there were no significant random effects. CONCLUSIONS: Results supported hypotheses, with greater neighborhood satisfaction linked to lower systolic and diastolic BP when perceived crime was high. Neighborhood poverty was also linked to higher systolic and diastolic BP. Prevention efforts should further investigate whether attending to issues of poverty and related neighborhood perceptions reduces high BP in at-risk African American communities. PMID- 25917563 TI - Therapeutic strategies for functional dyspepsia and irritable bowel syndrome based on pathophysiology. AB - Functional gastrointestinal disorders (FGIDs) are common and distressing. They are so named because a defined pathophysiology in terms of structural or biochemical pathways is lacking. Traditionally FGIDs have been conceptualized as brain-gut disorders, with subgroups of patients demonstrating visceral hypersensitivity and motility abnormalities as well as psychological distress. However, it is becoming apparent that there are certain structural or biochemical gut alterations among subsets with the common FGIDs, most notably functional dyspepsia (FD) and irritable bowel syndrome (IBS). For example, a sodium channel mutation has been identified in IBS that may account for 2 % of cases, and subtle intestinal inflammation has been observed in both IBS and FD. Other research has implicated early life events and stress, autoimmune disorders and atopy and infections, the gut microbiome and disordered mucosal immune activation in patients with IBS or FD. Understanding the origin of symptoms in FGIDs will allow therapy to be targeted at the pathophysiological changes, not at merely alleviating symptoms, and holds hope for eventual cure in some cases. For example, there are promising developments in manipulating the microbiome through diet, prebiotics and antibiotics in IBS, and testing and treating patients for Helicobacter pylori infection remains a mainstay of therapy in patients with dyspepsia and this infection. Locally acting drugs such as linaclotide have been an advance in treating the symptoms of constipation-predominant IBS, but do not alter the natural history of the disease. A role for a holistic approach to patients with FGIDs is warranted, as brain-to-gut and gut-to-brain pathways appear to be activated. PMID- 25917564 TI - Gut microbiota and the development of pediatric diseases. AB - The human gut harbors a huge number of microbes, which are collectively named "microbiota." The dynamic composition of the human gut microbiota is determined by multiple factors, including mode of delivery, diet, environment, and antibiotics. A healthy gut microbiota is helpful to the host in many aspects, including providing nutrients, protection from pathogens, and maturation of immune responses. Dysbiosis plays important roles in various diseases in infancy and later life: necrotizing enterocolitis, inflammatory bowel disease, obesity, and atopic diseases are some examples. Studies of functional metagenomics by newly developed techniques, such as next-generation sequencing, will not only elucidate the molecular mechanisms underlying gut microbiota-host interactions but will also provide new possibilities for disease prevention and treatment. PMID- 25917565 TI - Computational prediction of Escherichia coli proteins host subcellular targeting and their implications in colorectal cancer etiology. AB - Recent evidences indicate potential Escherichia coli involvement in colorectal cancer etiology. Colorectal cancer cells are exclusively colonized by enteroinvasive E. coli, which regulates several factors that can affect colorectal cancer progression in susceptible individuals. Earlier, we predicted nuclear targeting of E. coli proteins and their role in colorectal cancer etiology. In this study, we predict targeting of E. coli proteins in host cell mitochondria and cytoplasm and their role in colorectal cancer. Several important biological processes are regulated in the cell cytoplasm and mitochondria, where the targeting of E. coli proteins may have several possible implications. A total of 87/561 and 315/561 E. coli proteins were found to target host cell mitochondria and cytoplasm respectively. These include several proteins with the ability to influence normal growth behavior. The current article provides an outline for E. coli protein targeting in host cells and suggests that these proteins can contribute to the colorectal cancer etiology through a variety of strategies. PMID- 25917566 TI - Incidence, mortality and survival of childhood cancer in China during 2000-2010 period: A population-based study. AB - The objective of this study is to assess Chinese nationwide incidence, mortality and survival of childhood cancers, which has not been reported. Data from 145 Chinese Cancer Registries, which covered 158,403,248 populations, were pooled for analyses. Cancer patients were diagnosed during 2000-2010 at age 0-14 years. Age standardized incidence and mortality rates and relative survival rates were calculated. Survival was estimated by the classic cohort approach. New cancer cases were projected using a Bayesian age-period-cohort model. Overall age standardized incidence was 87.1 per million and age-standardized mortality was 36.3 per million. We found a statistically significant increase in incidence rate annually with 2.8% (95% CI: 1.1-4.6%, p < 0.05), a non-significant decreased mortality, and overall 5-year relative survival reaching 71.9% (95% CI: 69.4 77.1%). Projected new cases in 2015 are 22,875. We provide, for the first time, Chinese nationwide incidence, mortality and their temporal trends, and relative survival rates during the period of 2003-2005 for childhood cancer, which will contribute to a better understanding of the etiology and prevention of childhood cancers. The increasing trend of incidence rate and low 5-year relative survival rate suggest that more efforts for prevention and control of childhood cancers shall be invested in China. PMID- 25917568 TI - Epithelial-mesenchymal transition induces similar metabolic alterations in two independent breast cancer cell lines. AB - Epithelial-mesenchymal transition (EMT) induces invasive properties in epithelial tumors and promotes metastasis. Although EMT-mediated cellular and molecular changes are well understood, very little is known about EMT-induced metabolic changes. HER2-positive BT-474 breast cancer cells were induced to undergo a stable EMT using mammosphere culture, as previously described by us for the ERalpha-positive MCF-7 breast cancer cells. Two epithelial breast cancer cell lines (BT-474 and MCF-7) were compared to their respective EMT-derived mesenchymal progeny (BT-474(EMT) and MCF-7(EMT)) for changes in metabolic pathways including glycolysis, glycogen metabolism, anabolic pathways and gluconeogenesis. Both EMT-derived cells displayed enhanced aerobic glycolysis along with the overexpression of specific glucose transporters, lactate dehydrogenase isoforms, monocarboxylate transporters and glycogen phosphorylase isoform. In contrast, both EMT-derived cells suppressed the expression of crucial enzymes in anabolic pathways and gluconeogenesis. STAT3, a transcription factor involved in tumor initiation and progression, plays a role in the EMT-related changes in the expression of specific enzymes and transporters. This study provides a broad overview of similar metabolic changes induced by EMT in two independent breast cancer cell lines. These metabolic changes may provide novel therapeutic targets for metastatic breast cancer. PMID- 25917567 TI - FLLL12 induces apoptosis in lung cancer cells through a p53/p73-independent but death receptor 5-dependent pathway. AB - Unlike chemotherapy drugs, the safety of natural compounds such as curcumin has been well established. However, the potential use of curcumin in cancer has been compromised by its low bioavailability, limited tissue distribution and rapid biotransformation leading to low in vivo efficacy. To circumvent these problems, more potent and bioavailable analogs have been synthesized. In the current study, we investigated the mechanism of anti-tumor effect of one such analog, FLLL12, in lung cancers. IC50 values measured by sulforhodamine B (SRB) assay at 72 h and apoptosis assays (annexin V staining, cleavage of PARP and caspase-3) suggest that FLLL12 is 5-10-fold more potent than curcumin against a panel of premalignant and malignant lung cancer cell lines, depending on the cell line. Moreover, FLLL12 induced the expression of death receptor-5 (DR5). Ablation of the expression of the components of the extrinsic apoptotic pathway (DR5, caspase 8 and Bid) by siRNA significantly protected cells from FLLL12-induced apoptosis (p < 0.05). Analysis of mRNA expression revealed that FLLL-12 had no significant effect on the expression of DR5 mRNA expression. Interestingly, inhibition of global phosphatase activity as well as protein tyrosine phosphatases (PTPs), but not of alkaline phosphatases, strongly inhibited DR5 expression and significantly inhibited apoptosis (p < 0.05), suggesting the involvement of PTPs in the regulation of DR5 expression and apoptosis. We further showed that the apoptosis is independent of p53 and p73. Taken together, our results strongly suggest that FLLL12 induces apoptosis of lung cancer cell lines by posttranscriptional regulation of DR5 through activation of protein tyrosine phosphatase(s). PMID- 25917570 TI - Sex differences in the association between body mass index and hypertension - a cross-sectional study in 717 812 adolescents. AB - In order to examine sex-specific differences in the association of body mass index (BMI) and hypertension, we conducted a retrospective, cross-sectional study of 717 812 (402 914 men and 314 898 women) Israeli Jewish adolescents aged 16.0 19.99 years medically screened for military service. A diagnosis of hypertension was established per history or if a mean of 10 separate blood pressure measurements exceeded 140/90, following an initial measurement higher than 140/90. Weight and height were measured. Prevalence of hypertension was 0.42% in men and 0.05% in women. In men, BMI was significantly associated with hypertension from the third decile (odds ratio [OR] 1.67, 1.06-2.65) up to the 10th decile (OR 30.17, 20.83-43.69). In women, we observed a significantly increased risk for hypertension in the ninth decile (OR 3.82, 1.42-10.22) and in the 10th decile (OR 18.92, 7.7-46.51), with no visible trend in lower deciles. BMI effects on hypertension prevalence are different in male and female adolescents. PMID- 25917569 TI - Galanin modulates the neural niche to favour perineural invasion in head and neck cancer. AB - Perineural invasion (PNI) is an indicator of poor survival in multiple cancers. Unfortunately, there is no targeted treatment for PNI since the molecular mechanisms are largely unknown. PNI is an active process, suggesting that cancer cells communicate with nerves. However, nerve-tumour crosstalk is understudied due to the lack of in vivo models to investigate the mechanisms. Here we developed an in vivo model of PNI to characterize this interaction. We show that the neuropeptide galanin (GAL) initiates nerve-tumour crosstalk via activation of its G protein-coupled receptor, GALR2. Our data reveal a novel mechanism by which GAL from nerves stimulates GALR2 on cancer cells to induce NFATC2-mediated transcription of cyclooxygenase-2 and GAL. Prostaglandin E2 promotes cancer invasion, and in a feedback mechanism, GAL released by cancer induces neuritogenesis, facilitating PNI. This study describes a novel in vivo model for PNI and reveals the dynamic interaction between nerve and cancer. PMID- 25917572 TI - The tumour necrosis factor-alpha 308G>A genetic polymorphism may contribute to the pathogenesis of acne: a meta-analysis. AB - BACKGROUND: Tumour necrosis factor (TNF)-alpha is considered to play a central role in the pathogenesis of acne. AIM: To estimate the association between the TNF-alpha 308G>A polymorphism and the pathogenesis of acne. METHODS: A literature search of the PubMed and CNKI databases from inception to December 2013 was conducted. Meta-analyses were performed, and the OR and 95% CI calculated. The strength of association was assessed under five genetic models: allele (A vs. G), dominant (AA+AG vs. GG), recessive (AA vs. GG+AG), homozygous (AA vs. GG), and heterozygous (AA vs. AG). RESULTS: Seven case-control studies were included, with a total of 987 patients with acne and 1078 healthy controls. The meta-analysis result showed a significant association between TNF-alpha 308G>A and the pathogenesis of acne under the recessive (OR = 3.13, 95% CI 1.67-5.86, P < 0.001), homozygous (OR = 3.03, 95% CI 1.63-5.63, P < 0.001) and heterozygous (OR = 3.16, 95% CI 1.61-6.20, P < 0.001) models. The subgroup analysis showed a significant association with male sex (recessive: OR = 3.77, 95% CI 1.26-11.25, P = 0.02, homozygous: OR = 3.25, 95% CI 1.03-10.22, P = 0.04) and severe acne (recessive: OR = 4.62, 95% CI 1.73-12.34, P < 0.01; homozygous: OR = 3.41, 95% CI 1.18-9.89, P = 0.02). CONCLUSION: Our findings indicate that genotype AA of TNF alpha 308G>A may contribute to the pathogenesis of acne. Thus, detection of the TNF-alpha 308G>A polymorphism may be a promising biomarker for the early detection of acne. PMID- 25917573 TI - Predictors of major improvement after intravenous thrombolysis in acute ischemic stroke. AB - BACKGROUND: Intravenous thrombolysis improves outcomes of stroke patients. The immediate response to thrombolysis is variable and few studies attempted to identify predictors of major neurological improvement (MNI) 24 h following thrombolysis. Our objective is to determine predictors of MNI 24 h following thrombolysis. METHODS: We reviewed the prospective database of patients treated through our telestroke network and at our institution between November 2008 and June 2012. We included all patients who received IV t-PA and had a 24-h NIHSS score available. Similar to previous studies, we defined MNI as a reduction in NIHSS score by >=8 points, or a score of 0 or 1 at 24 h. Demographics, risk factors, time to treatment, and clinical and laboratory data, were compared between MNI present or absent. Baseline predictors were compared using t- and Fisher's exact tests, and outcomes using multivariate logistic regression analysis. RESULTS: Out of 316 patients, 306 had 24-h NIHSS scores and 38% of them experienced MNI. Patients with MNI were less likely to be older than 80 years (16% vs. 29%, p = 0.008) and to have atrial fibrillation (9% vs. 24%, p = 0.001) compared to those without; we found no other predictors of MNI. After adjusting for baseline demographics and risk factors, age less than 80 years (OR = 1.9, 95% CI 1.1-3.6) and absence of atrial fibrillation (OR = 3.0, 95% CI: 1.4-6.2) predicted MNI. CONCLUSION: Major neurological improvement within 24 h after thrombolysis is more likely in younger patients and those without atrial fibrillation. PMID- 25917571 TI - A novel snake venom-derived GPIb antagonist, anfibatide, protects mice from acute experimental ischaemic stroke and reperfusion injury. AB - BACKGROUND AND PURPOSE: Ischaemic stroke is a serious disease with limited therapy options. Glycoprotein (GP)Ib binding to von Willebrand factor (vWF) exposed at vascular injury initiates platelet adhesion and contributes to platelet aggregation. GPIb has been suggested as an effective target for antithrombotic therapy in stroke. Anfibatide is a GPIb antagonist derived from snake venom and we investigated its protective effect on experimental brain ischaemia in mice. EXPERIMENTAL APPROACH: Focal cerebral ischaemia was induced by 90 min of transient middle cerebral artery occlusion (MCAO). These mice were then treated with anfibatide (4, 2, 1 MUg.kg(-1) ), injected i.v., after 90 min of MCAO, followed by 1 h of reperfusion. Tirofiban, a GPIIb/IIIalpha antagonist, was used as a positive control. KEY RESULTS: Twenty-four hours after MCAO, anfibatide treated mice showed significantly improved ischaemic lesions in a dose-dependent manner. The mice had smaller infarct volumes, less severe neurological deficits and histopathology of cerebrum tissues compared with the untreated MCAO mice. Moreover, anfibatide decreased the amount of GPIbalpha, vWF and accumulation of fibrin(ogen) in the vasculature of the ischaemic hemisphere. Tirofiban had similar effects on infarct size and fibrin(ogen) deposition compared with the MCAO group. Importantly, the anfibatide-treated mice showed a lower incidence of intracerebral haemorrhage and shorter tail bleeding time compared with the tirofiban-treated mice. CONCLUSIONS AND IMPLICATIONS: Our data indicate anfibatide is a safe GPIb antagonist that exerts a protective effect on cerebral ischaemia and reperfusion injury. Anfibatide is a promising candidate that could be beneficial for the treatment of ischaemic stroke. PMID- 25917574 TI - The effects of bazedoxifene on bone structural strength evaluated by hip structure analysis. AB - Bazedoxifene (BZA) is a selective estrogen receptor modulator that has been shown to prevent and treat postmenopausal osteoporosis. Hip structure analysis (HSA) can be used to extract bone structural properties related to strength from hip bone mineral density (BMD) scans. This exploratory analysis used HSA to evaluate changes in hip structural geometry in postmenopausal women enrolled in a phase 3 osteoporosis treatment study who were treated with BZA 20mg or placebo for 2 years. This analysis cohort included women at increased fracture risk based on known skeletal risk factors (n = 521); 1 or more moderate or severe fractures or 2 or more mild vertebral fractures and/or femoral neck BMD T-score <= -3.0 at baseline combined with additional women from the overall study population (n = 475); a subgroup analysis included just those women at increased fracture risk. HSA was applied to duplicate hip dual-energy X-ray absorptiometry (DXA) scans acquired at screening and 24 months. Percent change from baseline was evaluated using an analysis of covariance for BMD and geometric parameters including section modulus (SM), cross-sectional area (CSA), outer diameter (OD), and buckling ratio (BR). In all regions, BZA was associated with increased BMD and improvements in hip structural geometry. In the narrow neck, BZA 20mg significantly increased SM, CSA, OD, and BMD compared with placebo (P < 0.05 for all). In the intertrochanter region, BZA 20mg significantly increased CSA and BMD and decreased BR compared with placebo (P < 0.05 for all). Other than BMD (P < 0.05), effects of BZA 20mg at the shaft did not reach statistical significance. Similar trends toward improvement in structural geometry with BZA 20mg were observed in all three regions of the hip for the subgroup of women at increased fracture risk. Overall, BZA was associated with geometry-related improvements in bone strength with regard to resistance to bending and compressive forces and to local buckling. These improvements were evident at common fracture locations such as the femoral neck and intertrochanter regions, and are consistent with the significant treatment effect reported for BZA on nonvertebral fractures in higher risk postmenopausal women with osteoporosis. PMID- 25917575 TI - [Evaluation of Malaria Cases that Were Detected in Kocaeli Province During 2008 Through 2013]. AB - OBJECTIVE: Malaria is still a serious public health problem around the world and in our country. In this study, we examined the epidemiology of malaria cases retrorespectively by using the surveillance data provided by the Malaria Control Unit of the Infectious Disease Division of Kocaeli Health Directory, from the years of 2008 to 2013. Our aim was to compare our findings with the findings of the past studies and provide support to the future surveillance studies. METHODS: A total of 10008 periferic blood samples were examined in this surveillance based study. The cases were evaluated according to age groups, gender, month during which the infection was detected and the origin of district. RESULTS: The species of malaria parasites were detected in 27 samples of which 51.9 % (n=14) was Plasmodium vivax and 48.1% (n=13) was Plasmodium falciparum. Among 27 cases 77.8% (n=21) of the cases were male and 22.2% (n=6) were female. 96.3% of the cases were above the age of 15. All cases of Plasmodium vivax were consisted of the workers who came to Kocaeli from Southeastern Anatolia Region. CONCLUSION: Malaria cases detected in our region have displayed a relatively meaningful decrease in comparison to past. While Plasmodium vivax was dominating infecting agent in the past, in recent years Plasmodium falciparum appeared to be infecting nearly half of the cases. These cases were imported cases coming to Kocaeli from other countries. It is important to take the necessary precautions for timely diagnosis of imported cases and to prevent its spread in the area. PMID- 25917576 TI - [Evaluating of Plasmodium species isolated from peripheral blood samples in a non endemic region]. AB - OBJECTIVE: Malaria is a parasitic disease, caused by Plasmodium species, which transmitted to humans through genus Anopheles mosquitoes. This disease widely spreaded in tropical and subtropical areas. The aim of our study is to evaluate malaria cases diagnosed by peripheral blood examination. METHODS: Peripheral blood samples sent to Parasitology Laboratory between 2001 and 2013 years, were examined using thick and thin blood smear techniques. RESULTS: A total of 102 blood samples obtained from suspected patients were examined and eight of them were found to be positive. All cases were male and Plasmodium falciparum and Plasmodium vivax was detected in seven (87.5%) and one (12.5%) of them, respectively. Blood samples were mainly sent from Departments of Infectious Diseases. All P. falciparum cases had a history about work or travel to different African countries. CONCLUSION: We think that patients who has fever and travel history to endemic countries especially in Africa, blood examination for malaria parasites should be taken into account in differential diagnosis. PMID- 25917577 TI - [The Evaluation of Toxoplasma gondii (T.gondii) Serology Results Among Cases Who Admitted to the Serology Laboratory of a Hospital in Afyon City]. AB - OBJECTIVE: The aim of this study is to evaluate Toxoplasma gondii (T. gondii) serology results in different age groups among cases who admitted to the Medical Serology Laboratory of a secondary level hospital in Afyon. METHODS: The patients who has positive result for Toxoplasma gondii IgG and IgM by electrochemiluminescence method (Cobas e-170 Analyzer, Roche Diagnostics) between January and December 2013 were included the study. RESULTS: Patients included the study were aged 1-68 years (mean age: 24 +/- 9). Of the total 1887 sera tested for T. gondii IgG and IgM, 452 were found to be positive (24%) in a period of 12 months. Seropositivity was found to be 4%, 11,1%, 20,2%, 25,3%, 33,3% and 46,6% in 1-8, 9-18, 19-23, 24-28, 29-35 and 36-68 age groups, respectively. CONCLUSION: Because of the high seroprevalence in our country, the knowledge about the values of anti-Toxoplasma gondii antibodies in pre-pregnancy period has an importance for evaluation and follow-up during the pregnancy. In this study, it was determined that there is a relationship between seroprevalence and age. All people should be educated about ways to minimize exposure to T. gondii. PMID- 25917578 TI - [The Assesment of Cutaneous Leishmaniasis Patients Admiting to Gaziantep University of Medicine Faculty Leishmaniasis Diagnosis and Treatment Center]. AB - OBJECTIVE: Cutaneous Leishmaniasis (CL) is a curable clinical condition characterized by atrophic scars caused by the Leishmania species of protozoan parasites. In the period following the beginning of the Syrian Civil War, there has been a dramatic increase in number of CL cases in Gaziantep. The aim of this study was to evaluate the epidemiological characteristics of CL patients admitted to Gaziantep University of Medicine Faculty Leishmaniasis diagnosis and treatment center in Gaziantep. METHODS: Within the context of this study, a total of 635 CL patients admitted between 01 April 2013 and 01 April 2014 to the Leishmaniasis diagnosis and treatment center of the Gaziantep were evaluated retrospectively. Patient data regarding age, sex, the location of lesions, the number of lesions, the duration of the lesions, and the months in which the lesions appeared were recorded and statistically analyzed. RESULTS: Of these patients, 67 (10.6%) were Turkish citizens, while 568 (89.4%) were Syrian citizens. In addition, 299 (47.1%) of the patients were female, while 336 (52.9%) were male. The large majority of the cases were between 5-9 (n=140, 22%) and 10-19 (n=168, 26.5%) years of age; 66% of all cases were below 20 years of age. An evaluation of the distribution of cases according to the months revealed that the lowest number of cases occurred in the months of July (n=14, 2.2%) and August (n=13, 2.0%), while the highest number of cases occurred in the months of January (n=122, 19.2%) and February (n=106, 16.7%). CONCLUSION: Cutaneous Leishmaniasis is a condition that affects individuals of all ages and genders. It is thus necessary to conduct regular health screenings for Cutaneous Leishmaniasis, and to inform and educate vulnerable communities and the society in general regarding this condition. PMID- 25917579 TI - [Evaluation of Cystic Echinococcosis Suspected Patients Applied to National Parasitology Reference Laboratory of Public Health Institution of Turkey Between 2009-2013]. AB - OBJECTIVE: Cystic echinococcosis (CE) caused by the metacestode form of Echinococcus granulosus is an important public health problem common in our country. In this study, anti-E. granulosus antibodies were aimed to investigate in the serum samples of CE suspected patients who applied to the National Parasitology Reference Laboratory of Public Health Institution of Turkey. METHODS: In the study, serum samples of 2921 patients which were sent to our laboratories from different hospitals between 1 January 2009 and 31 December 2013 were evaluated with at least one of the following tests: Enzyme-Linked Immunosorbent Assay (ELISA), Indirect Hemaglutination Assay (IHA) and Western Blot (WB) techniques. RESULTS: Four hundred thirty nine (15.03%) of inspected 2921 samples were determined seropositive with at least one of the methods. When the results analyzed by gender, 13% of males and 16.40% of females were found positive. Examined the distribution of the results by years, with a maximum of 25% positivity was observed in 2009. Compatibility was determined at the rate of 91.4% among ELISA and IHA results; also 89.7% among WB and the other tests results. CONCLUSION: Despite the gradual decreases the CE in Ankara and its surroundings, it is still continues to be a major public health problem. Essential prevention and control measures should be taken to reduce the prevalence of the disease. Also in the diagnosis of the disease, more reliable results can obtained with applying two tests (ELISA/IHA) together and confirm the positivity with WB. PMID- 25917580 TI - Identification of Six Introns in a Partial Sequence of Echinococcus granulosus Paramyosin Gene. AB - OBJECTIVE: Paramyosin is a major protein produced by the metacestode cyst of Echinococcus granulosus, the causative agent of cystic hydatid disease. This protein has been shown to play an important role in modulating host immune responses. In this study, we attempted to characterize the noncoding sequence of the paramyosin gene. METHODS: Genomic DNA was isolated from G1 Iranian hydatid cysts. A DNA fragment of 3200 bp in length was amplified from the paramyosin gene. The polymerase chain reaction (PCR) product was cloned to the pTZ57T vector and sequenced by M13 primers and then compared with unique cDNA coding sequences of E. granulosus (Z21787) and Taenia solium (AY034087). RESULTS: Six introns I (107 bp), II (75 bp), III (47 bp), IV (921 bp), V (19 bp), and VI (456 bp) were identified in the partial sequence of the paramyosin gene. Some nucleotide changes were observed in three exons I, IV, and VI. CONCLUSION: This data could help scientists in better understanding the possible alternative splicing and designing a real-time PCR technique for the evaluation of the transcription levels of paramyosin in the stages of the Echinococcus sp. life cycle. PMID- 25917581 TI - [The Distribution of Pediculus humanus capitis Among Primary School Pupils of the Turkish Chamber of Commerce and Stock Exchange Organisation in Van]. AB - OBJECTIVE: This study was performed in order to study the prevalence of Pediculus humanus capitis (P. h. capitis). METHODS: The study was carried out on pupils between 5-15 years old in a school and kindergarden belonging to the Turkish Chamber of Commerce and Stock Exchange Organization in Van City between November December 2007. The hair of 863 pupils (especially the neck and the back of head areas), 385 girls and 478 boys, were examined for eggs, nymphs and adults of P. h. capitis. A questionnaire was given to the pupils, which was collected the following day. Lice and their eggs/nits, which were removed from the head of children were transferred to a bottle containing 5% glycerin in 70% ethyl alcohol. Later they were sent to the Parasitology Laboratory of the Health Research and Training Hospital of Yuzuncu Yil University. RESULTS: Eggs/nits were found in 164 (42.6%) of the girls and in 34 (7.1%) of the boys (overall 198 (22.9%) infested pupils). The prevalence of P. h. capitis was high, especially in girls. CONCLUSION: The infestation rates observed and the evaluation of the questionnaire showed that there is a statistically significant relationships between pediculosis capitis and sex, level of family income, education level of the mother, number of baths taken per weekly, number of family members living in the same home, room number per capita, and hair length (p<0.001). However, there was no significant relationship between pediculosis capitis and cleaning materials used to wash the head (p>0.05). PMID- 25917582 TI - [The Molecular Classification Of Blackfly (Diptera: Simuliidae) Species Which Pose a Problem in Nevsehir Part of Central Kizilirmak Basin]. AB - OBJECTIVE: This study was carried out to determine the molecular characterization of simuliid species which cause a problem in the part of Kizilirmak passes from Urgup and Gulsehir districts of Nevsehir. METHODS: Between May and September 2011, totally 150 simuliid larvae were sampled. Morphological identifications of the collected larvae specimens were done before the molecular analyses. Genomic DNA extractions were utilized on 7 larvae specimens which were selected from morphologically identified samples and the sequence and phylogenetic analyses were performed after the amplification of the partial mitochondrial cytochrome oxidase subunit 1 (mt-COI) and ribosomal complete internal transcript spacer 2 and partial 28S (ITS-2/28S) gene regions. RESULTS: Eighty-five, 46 and 19 out of 150 morphologically examined specimens were identified as Simulium (S.) Wilhelmia sp., S. Wilhelmia lineatum and S. Wilhelmia balcanicum, respectively. Among the amplified samples with respect to mt-COI and ITS-2/28S gene regions, sequence analyses were performed on 3 and 2 isolates from S. Wilhelmia sp. and both S. lineatum and S. balcanicum. The isolates were found to be clustered together depending on the species for both gene regions phylogenetically and the sequence heterogeneity was found to be higher in S. lineatum. When comparing with the other species under the Wilhelmia subgenus, S. lineatum and S. balcanicum were determined to be more close to each other. CONCLUSION: Scientific data on the molecular characterization and phylogeny of blackfly species under the S. Wilhelima subgenus which pose a problem in the Central Kizilirmak Basin were provided with this study. PMID- 25917583 TI - Demodex Mite, Rosacea and Skin Melanoma; Coincidence or Association? AB - OBJECTIVE: To examine the possible associations between Demodex folliculorum and a number of skin diseases. METHODS: Standardized skin surface biopsy samples were obtained from the cheeks of 144 patients with histopathologically proven basal cell carcinoma (BCC, n = 27), squamous cell carcinoma (SCC, n = 28), melanoma (n = 23), discoid lupus erythematosus (DLE, n = 32), and rosacea (n = 34). Thirty four sex- and age-matched healthy volunteers served as controls. Mite density (per cm2) and infestation (density >= 5) were compared between the controls and patients. RESULTS: Mite infestation rates (%) did not differ significantly between the controls (20.6) and patients with BCC (22.2, p = 0.88), SCC (17.9, p = 0.79), melanoma (4.3, p = 0.08), and DLE (21.9, p = 0.90). Compared with the controls, the mite infestation rate was significantly higher in patients with rosacea (47.1, p = 0.02, odds ratio: 3.43, 95% confidence interval: 1.18-9.99). The mean mite density did not differ significantly between the controls (4.11 +/- 2.17) and patients with BCC (5.34 +/- 2.35, p = 0.75), SCC (3.57 +/- 2.01, p = 0.38), and DLE (3.56 +/- 1.34, p = 0.83), whereas it was significantly higher in patients with rosacea (8.78 +/- 3.58, p = 0.02) and lower in patients with melanoma (1.89 +/- 0.69, p = 0.02). CONCLUSIONS: D. folliculorum may be associated with rosacea and melanoma but not with BCC, SCC, or DLE. PMID- 25917584 TI - [Presence of Nosemosis in Honeybees (Apis mellifera) in Ordu Province]. AB - OBJECTIVE: The aim of this study is to study occurrence of nosemosis in honey bees in Ordu Province and compare disease factors morphologicaly. METHODS: Totally 200 adult bees were collected from ten localities in Ordu Province and examined for nosemosis. Spores of the disease factors were measured and photographed using an Olympus BX51 microscope with a DP-25 digital camera and a DP2-BSW Soft Imaging System. RESULTS: Nosemosis was observed in all examined localities. The infection rate varied from 25 to 85%. The disease was observed with the lowest rate (25%) in Mesudiye and with the highest rate (85%) in Fatsa. An average infection rate was found as 44%. Infection level reached to 85% in Unye. Significant differences were detected between spore morphology of the disease factors. CONCLUSION: Presence of nosemosis in Ordu province has been studied extensively. The disease is very common and very high in the region where it occurs. According to spore morphology is determined that the disease can be caused by two factors. PMID- 25917585 TI - [Morphological and Ultrastructural Features in the Characterization of Microsporidia]. AB - The members of the Microsporidia are single-celled, eukaryotic, obligate intracellular parasites. They infect a wide range of invertebrate and vertebrate hosts. The studies on Microsporidia are of considerable interest because of that they cause desirable and undesirable infections in different animals. That situation requires identification of these organisms correctly. The identification of Microsporidia needs relatively more complex studies. Morphological and ultrastructural studies play important role in the identification of these organisms. In the present study, a working knowledge on the morphological and ultrastructural features of Microsporidia are given. PMID- 25917586 TI - [A Splenic Infarct Developing After Plasmodium falciparum Infection]. AB - Plasmodium vivax malaria is usually seen in our country. Plasmodium falciparum malaria is also detected in the patients who have travelled abroad. A 33 year old male patient applied to our hospital for control. One month ago our patient had travelled to Angola where P. falciparum malaria is endemic. He had been diagnosed with malaria in Iran and successfully treated with quinine, doxycycline, and clindamycin. This time in our patient without any complaints, splenomegaly and splenic infarction were found. In our patient follow-ups it was observed that splenic infarction shrank. Therefore, in this article we present this rare complication. PMID- 25917587 TI - [Successful treatment of cutaneous leishmaniasis with amphotericin B; a case of unresponsive to pentavalent antimony therapy]. AB - Cutaneous Leishmaniasis (CL) is a skin infection caused by various species of Leishmania parasites, which is transmitted by infected Phlebotomus sandfly bites. Pentavalent antimonials (meglumine antimoniate and sodium stibogluconate) are used for the treatment of adult CL patients as an effective and safe method. Liposomal amphotericin B is an alternative for the treatment of choice in cutaneous leishmaniasis cases which pentavalan antimony contraindicated or unresponsive to pentavalent antimony therapy. In this study, successful treatment with systemic liposomal amphotericin B of a cutaneous leishmaniasis case developing local side effects related both systemic and intralesional meglumine antimonate treatment was presented. PMID- 25917588 TI - [Pneumocystis jirovecii Pneumonia in a Patient with Interstitial Lung Disease]. AB - Pneumocystis pneumonia (PCP) caused by Pneumocystis jirovecii (P. jirovecii) is an opportunistic pulmonary infection that occurs in immunocompromised patients. Here, a 49-year-old female patient who was admitted to our hospital with respiratuary distress and whose bronchoalveolar lavage (BAL) fluid specimens had P. jirovecii and Aspegillus fumigatus was presented. She had been treated with corticosteroids because of interstisial lung disease and she was also diabetic. It is important to define the coinfection developed in the presence of immunosuppression. PMID- 25917589 TI - [Amoebic liver abscess in a patient initially diagnosed with pneumonia: case report and discussion of relevant literature]. AB - In one-third of the patients with amoebiasis, amoebic liver abscess (ALA) may occur after the penetration of amoebic trophozoites through the intestinal wall. ALA is seen mostly among men aged 20-45 years with a serious clinical outcome, with fever and abdominal pain on the right upper quadrant. Most patients have no recent history of amoebic colitis; indeed, they have neither gastrointestinal complaints nor Entamoeba histolytica (E. histolytica) cysts/trophozoites in their stools. Therefore, ultrasonography and serology are primary in ALA diagnosis, while searching for E. histolytica DNA in abscess fluid using PCR has been preferred as an effective and reliable method, lately. Early antimicrobial therapy is effective; however, for cases irresponsive to therapy after 72 hours and with large abscess, drainage or surgical intervention is indicated. If left untreated, ALA may disseminate to other organs and cause death. The data concerning the extra-intestinal manifestations of amebiasis in Turkey are limited. Here, a rare case of a young man with an initial diagnosis of pneumonia followed by the identification of ALA after radiological interventions and laboratory tests is presented and the relevant literature is discussed. PMID- 25917590 TI - Incidental isolated pancreatic hydatid cyst. AB - Isolated pancreatic hydatid cysts are a rare parasitic disease even in endemic areas. It is difficult to discriminate primary pancreatic hydatid cysts from other cystic and solid lesions of the pancreas. This is a case report of an incidental isolated pancreatic hydatid cyst. A heterogeneous cystic lesion in the body of the pancreas was identified on magnetic resonance imaging of a patient previously diagnosed patient with cholelithiasis, and because of the malignant possibility of the lesion, splenectomy with distal pancreatectomy and cholecystectomy was performed. The histopathologic diagnosis was reported as a hydatid cyst. Pancreatic hydatid cysts should be kept in mind in the differential diagnosis of pancreatic pseudocysts and cystic malignancies. PMID- 25917591 TI - Hydatid disease involving some rare sites in the body. AB - A hydatid cyst is an endemic disease in our country. Clinical manifestation includes cyst formation, most commonly in the liver and lungs. Renal, brain, and subcuteneous localizations are rare. Here we report four cases: two cases of primary renal hydatid disease, one of intracranial hydatid cyst, and one of subcutaneous hydatid cyst. We discuss the prevalence, diagnostic workup, and management of echinococcosis. PMID- 25917592 TI - Recurrent toxocariasis due to chronic urticaria and successful treatment with prolonged albendazole therapy. AB - Toxocariasis is a worldwide human helminthiasis, especially seen in temperate and tropical climate regions around the world. The diagnosis of this disease is performed on the basis of clinical symptoms and laboratory findings. Albendazole is one of the treatment choices for toxocariasis, with a currently recommended regimen of 10 mg/kg/day in two doses (400 mg twice daily) for 5 days. However, there is no precise consensus about the duration of the treatment. In this article, we report a case of toxocariasis; the patient visited our infectious disease polyclinic with complaints of long-term itching and urticarial skin lesions that were resistant to routine treatment and that recurred. Then, recurrent disease was resolved and skin lesions were diminished after prolonged albendazole therapy. PMID- 25917593 TI - Therapy for Gonococcal and Non-gonococcal Genital Infections is a Major Problem for Clinicians. PMID- 25917594 TI - Continuous intravenous infusion of ATP in humans yields large expansions of erythrocyte ATP pools but extracellular ATP pools are elevated only at the start followed by rapid declines. AB - The pharmacokinetics of adenosine 5'-triphosphate (ATP) was investigated in a clinical trial that included 15 patients with advanced malignancies (solid tumors). ATP was administered by continuous intravenous infusions of 8 h once weekly for 8 weeks. Three values of blood ATP levels were determined. These were total blood (erythrocyte) and blood plasma (extracellular) ATP pools along with the initial rate of release of ATP into the blood plasma. We found that values related to erythrocyte ATP pools showed great variability (diversity) among individuals (standard deviation of about 30-40% of mean at baseline). It was discovered that erythrocyte baseline ATP pool sizes are unique to each individual and that they fall within a narrow range in each individual. At the end of an 8 h continuous intravenous infusion of ATP, intracellular erythrocyte ATP pools were increased in the range of 40-60% and extracellular ATP declined from elevated levels achieved at the beginning and middle of the infusion, to baseline levels. The ability of erythrocytes to sequester exogenously administered ATP to this degree, after its initial conversion to adenosine in the blood plasma is unexpected, considering that some of the adenosine is likely to have been degraded by in vivo catabolic activities or taken up by organs. The data suggest that administration of ATP by short-term intravenous infusions, of up to 4 h, may be a favorable way for elevating extracellular ATP pools. A large fraction of the total exogenously administered ATP is sequestered into the intracellular compartments of the erythrocytes after an 8 h intravenous infusion. Erythrocytes loaded with ATP are known to release their ATP pools by the application of previously established agents or conditions applied locally or globally to circulating erythrocytes. Rapid degradation of intravenously administered ATP to adenosine and subsequent accumulation of ATP inside erythrocytes indicate the existence of very effective mechanisms for uptake of adenosine from blood plasma. These in vivo studies offer an understanding as to how both adenosine and ATP can act as purinergic transmission signals. ATP levels in blood are always accompanied by adenosine formed by catabolism of ATP. The continuous uptake of adenosine enables both to act in transmission of sometimes opposite functions. PMID- 25917596 TI - Effects of solvent concentration and composition on protein dynamics: 13C MAS NMR studies of elastin in glycerol-water mixtures. AB - We use (13)C CP MAS NMR to investigate the dependence of elastin dynamics on the concentration and composition of the solvent at various temperatures. For elastin in pure glycerol, line-shape analysis shows that larger-scale fluctuations of the protein backbone require a minimum glycerol concentration of ~0.6 g/g at ambient temperature, while smaller-scale fluctuations are activated at lower solvation levels of ~0.2 g/g. Immersing elastin in various glycerol-water mixtures, we observe at room temperature that the protein mobility is higher for lower glycerol fractions in the solvent and, thus, lower solvent viscosity. When decreasing the temperature, the elastin spectra approach the line shape for the rigid protein at 245 K for all studied samples, indicating that the protein ceases to be mobile on the experimental time scale of ~10(-5) s. Our findings yield evidence for a strong coupling between elastin fluctuations and solvent dynamics and, hence, such interaction is not restricted to the case of protein water mixtures. Spectral resolution of different carbon species reveals that the protein-solvent couplings can, however, be different for side chain and backbone units. We discuss these results against the background of the slaving model for protein dynamics. PMID- 25917597 TI - Diagnosing phenotypes of single-sample individuals by edge biomarkers. AB - Network or edge biomarkers are a reliable form to characterize phenotypes or diseases. However, obtaining edges or correlations between molecules for an individual requires measurement of multiple samples of that individual, which are generally unavailable in clinical practice. Thus, it is strongly demanded to diagnose a disease by edge or network biomarkers in one-sample-for-one-individual context. Here, we developed a new computational framework, EdgeBiomarker, to integrate edge and node biomarkers to diagnose phenotype of each single test sample. By applying the method to datasets of lung and breast cancer, it reveals new marker genes/gene-pairs and related sub-networks for distinguishing earlier and advanced cancer stages. Our method shows advantages over traditional methods: (i) edge biomarkers extracted from non-differentially expressed genes achieve better cross-validation accuracy of diagnosis than molecule or node biomarkers from differentially expressed genes, suggesting that certain pathogenic information is only present at the level of network and under-estimated by traditional methods; (ii) edge biomarkers categorize patients into low/high survival rate in a more reliable manner; (iii) edge biomarkers are significantly enriched in relevant biological functions or pathways, implying that the association changes in a network, rather than expression changes in individual molecules, tend to be causally related to cancer development. The new framework of edge biomarkers paves the way for diagnosing diseases and analyzing their molecular mechanisms by edges or networks in one-sample-for-one-individual basis. This also provides a powerful tool for precision medicine or big-data medicine. PMID- 25917595 TI - Connecting the microtubule attachment status of each kinetochore to cell cycle arrest through the spindle assembly checkpoint. AB - Kinetochores generate a signal that inhibits anaphase progression until every kinetochore makes proper attachments to spindle microtubules. This spindle assembly checkpoint (SAC) increases the fidelity of chromosome segregation. We will review the molecular mechanisms by which kinetochores generate the SAC and extinguish the signal after making proper attachments, with the goal of identifying unanswered questions and new research directions. We will emphasize recent breakthroughs in how phosphorylation changes drive the activation and inhibition of the signal. We will also emphasize the dramatic changes in kinetochore structure that occur after attaching to microtubules and how these coordinate SAC function with microtubule attachment status. Finally, we will review the emerging cross talk between the DNA damage response and the SAC. PMID- 25917598 TI - Marker-assisted breeding of a LOX-3-null rice line with improved storability and resistance to preharvest sprouting. AB - KEY MESSAGE: Breakage of the tight linkage between rice seed lipoxygenase - 3 and easy preharvest sprouting trait led to breeding of lines with few stale flavors after long storage and desirable preharvest sprouting resistance. Lipoxygenase-3 (LOX-3) is involved in the production of volatile constituents in stored rice, and the development of stale flavor is delayed in LOX-3 null rice. In the process of breeding new LOX-3-null lines with long storability, we found a close association between LOX-3 and preharvest sprouting resistance. To determine whether this relationship was due to the tight linkage of two genes or the pleiotropic effect of LOX-3, we performed marker-assisted selection using a BC3F3 population derived from crosses between LOX-3-present/preharvest sprouting resistant lines and LOX-3-null/preharvest susceptible lines. In one individual, a recombination event occurred 13 kb downstream of LOX-3 (RM15750) and a significant quantitative trait locus, namely qPHS3, for easy preharvest sprouting trait (LOD = 10.4) was detected in an 842-kb region between RM15711 and RM15768. Using BC3F4 and BC3F5 populations, we succeeded in selecting LOX-3-absent and preharvest sprouting-resistant lines with only a 393-kb introgressed chromosome segment from the donor line for LOX-3-null at the LOX-3 locus on chromosome 3. This result indicated that the LOX-3 gene and the locus affecting preharvest sprouting are distinct. The selected line was named 'Hokuriku 244'. Sensory testing of rice grains with and without LOX-3 confirmed that stale flavor production in LOX-3-null rice during storage was lower than in normal LOX-3 rice. These results indicated that rice varieties with little stale flavor after long storage and preharvest sprouting resistance had been selected. PMID- 25917599 TI - Infection processes of xylem-colonizing pathogenic bacteria: possible explanations for the scarcity of qualitative disease resistance genes against them in crops. AB - KEY MESSAGE: Disease resistance against xylem-colonizing pathogenic bacteria in crops. Plant pathogenic bacteria cause destructive diseases in many commercially important crops. Among these bacteria, eight pathogens, Ralstonia solanacearum, Xanthomonas oryzae pv. oryzae, X. campestris pv. campestris, Erwinia amylovora, Pantoea stewartii subsp. stewartii, Clavibacter michiganensis subsp. michiganensis, Pseudomonas syringae pv. actinidiae, and Xylella fastidiosa, infect their host plants through different infection sites and paths and eventually colonize the xylem tissues of their host plants, resulting in wilting symptoms by blocking water flow or necrosis of xylem tissues. Noticeably, only a relatively small number of resistant cultivars in major crops against these vascular bacterial pathogens except X. oryzae pv. oryzae have been found or generated so far, although these pathogens threaten productivity of major crops. In this review, we summarize the lifestyles of major xylem-colonizing bacterial pathogens and then discuss the progress of current research on disease resistance controlled by qualitative disease resistance genes or quantitative trait loci against them. Finally, we propose infection processes of xylem-colonizing bacterial pathogens as one of possible reasons for why so few qualitative disease resistance genes against these pathogens have been developed or identified so far in crops. PMID- 25917600 TI - Falls, falls prevention and the role of physiotherapy and exercise: perceptions and interpretations of Italian-born and Australian-born older persons living in Australia. AB - Exercise programmes are effective in reducing falls but few older people consider doing an exercise programme for falls prevention. This paper examines older people's perceptions and experiences of falls, physiotherapy and exercise. Individual interviews were conducted with Australian-born and Italian-born older persons who had >=1 fall in the past 12 months and completed a community-based physiotherapy programme. Although preventing further falls was considered important, participants were unsure whether falls were preventable. Few described evidence-based approaches such as exercise or medication reviews as strategies to prevent falls. Most participants thought that physiotherapy and exercise were beneficial in improving physical function. A clear explanation on the role of exercise for falls prevention, that many falls are preventable, and understanding of personal motivating and de-motivating factors for exercise for falls prevention are important for clinicians to consider in engaging this group of older people. PMID- 25917601 TI - Prognostic significance of lymph node density in squamous cell carcinoma of the tongue. AB - BACKGROUND: The prognostic significance of lymph node density in oral squamous cell carcinoma (OSCC) has been well recognized. However, its use in a specific subsite of the tongue has not been evaluated. The purpose of this study was to determine the prognostic significance of lymph node density in tongue squamous cell carcinoma (SCC). METHODS: A retrospective analysis of 99 patients with tongue SCC who underwent primary curative resection and neck dissection was conducted. Overall survival (OS) and disease-specific survival (DSS) was used to evaluate the prognostic significance of lymph node density. RESULTS: Lymph node density (using a cutoff of 0.06) was shown to be an independent predictor of OS and DSS. The impact of lymph node density on OS and DSS remained significant on multivariate analysis, whereas conventional nodal staging was not. An alternative staging strategy incorporating depth of invasion and lymph node density performs better than conventional TNM staging in predicting survival. CONCLUSION: Our data suggest that lymph node density is a reliable and applicable predictor of prognosis in patients with tongue SCC. (c) 2015 Wiley Periodicals, Inc. Head Neck 38: E859-E866, 2016. PMID- 25917602 TI - Modelling the Age Dynamics of Chronic Health Conditions: Life-Table-Consistent Transition Probabilities and their Application. AB - Surveys of chronic health conditions provide information about prevalence but not incidence and the process of change within the population. Our study shows how "age dynamics" of chronic conditions - the probabilities of contracting conditions at different ages, of moving from one chronic condition state to another, and of dying - can be inferred from prevalence data for those conditions that can be viewed as irreversible. Transition probability matrices are constructed for successive age groups, with the sequence representing the age dynamics of the health conditions for a stationary population. We simulate the life path of a cohort under the initial probabilities, and again under altered probabilities, to explore the effects of reducing the incidence or mortality rate associated with a particular condition. We show that such surveys of chronic conditions can be made even more valuable by allowing the calculation of the transition probabilities that define the chronic conditions aging process. PMID- 25917603 TI - Predictors of adherence in a community-based tai chi program. AB - This study examined factors affecting adherence in a 16-week tai chi program among multi-ethnic middle-aged and older adults living in a low socioeconomic environment in Toronto. Analysis was based on data collected from three tai chi program cohorts that took place from August 2009 to March 2012. The main outcome variable, adherence, was measured by the total number of sessions attended by each of the participants. Total sample size was 210 participants with a mean age of 68.1 +/- 8.6. Based on the regression model, greater adherence was significantly associated with older age, greater perceived stress, higher education, and higher mental and physical scores of Short Form-36 components. Conversely, lower adherence was significantly associated with higher baseline weekly physical activity. Our findings suggest that we target less-educated individuals with poor mental and physical health to optimize adherence for future community-based tai chi programs. PMID- 25917604 TI - Fixation in large populations: a continuous view of a discrete problem. AB - We study fixation in large, but finite, populations with two types, and dynamics governed by birth-death processes. By considering a restricted class of such processes, which includes many of the evolutionary processes usually discussed in the literature, we derive a continuous approximation for the probability of fixation that is valid beyond the weak-selection (WS) limit. Indeed, in the derivation three regimes naturally appear: selection-driven, balanced, and quasi neutral--the latter two require WS, while the former can appear with or without WS. From the continuous approximations, we then obtain asymptotic approximations for evolutionary dynamics with at most one equilibrium, in the selection-driven regime, that does not preclude a weak-selection regime. As an application, we study the fixation pattern when the infinite population limit has an interior evolutionary stable strategy (ESS): (1) we show that the fixation pattern for the Hawk and Dove game satisfies what we term the one-half law: if the ESS is outside a small interval around 1/2, the fixation is of dominance type; (2) we also show that, outside of the weak-selection regime, the long-term dynamics of large populations can have very little resemblance to the infinite population case; in addition, we also present results for the case of two equilibria, and show that even when there is weak-selection the long-term dynamics can be dramatically different from the one predicted by the replicator dynamics. Finally, we present continuous restatements valid for large populations of two classical concepts naturally defined in the discrete case: (1) the definition of an ESSN strategy; (2) the definition of a risk-dominant strategy. We then present three applications of these restatements: (1) we obtain an asymptotic definition valid in the quasi-neutral regime that recovers both the one-third law under linear fitness and the generalised one-third law for d-player games; (2) we extend the ideas behind the (generalised) one-third law outside the quasi-neutral regime and, as a generalisation, we introduce the concept of critical-frequency; (3) we recover the classification of risk-dominant strategies for d-player games. PMID- 25917605 TI - Comparative toxicities of bismuth oxybromide and titanium dioxide exposure on human skin keratinocyte cells. AB - Nano-sized bismuth oxybromide (BiOBr) particles are being considered for applications within the semiconductor industry. However, little is known about their potential impact on human health. In this study, we comparatively investigated the cytotoxicity of BiOBr and titanium dioxide (TiO2) nanoparticles (NPs) using human skin keratinocyte cell line (HaCaT) as a research model. Results indicate that lamellar-shaped BiOBr (length: 200 nm, width: 150 nm, and an average thickness: around 15 nm) has less toxic effects on cell viability and intracellular organelles than TiO2 (P25) NPs. BiOBr mainly induced late cell apoptosis, while for TiO2, both early apoptosis and late apoptosis were involved. Cell cycle arrest was found in cells on both NPs exposure, and more prominent in TiO2-treated cells. More cellular uptake was achieved after TiO2 exposure, particularly at 10 MUg mL(-1), presence of TiO2 resulted in more than 2-fold increase in cellular granularity compared with BiOBr. Furthermore, TiO2 had a high potential to generate intracellular reactive oxygen species (ROS) in cells, where a 2.7-fold increase in TiO2 group and 2.0-fold increase in BiOBr group at the same concentration of 25 MUg mL(-1). Higher cellular uptake and ROS stimulation should contribute to the more hazards of TiO2 than BiOBr NPs. This knowledge is a crucial component in the environmental and human hazard assessment of BiOBr and TiO2 NPs. PMID- 25917606 TI - Energy reserves mobilization in the yellow eel as herbicide exposure effect. AB - Thiobencarb and propanil are two of the most extensive used herbicides worldwide in rice cultivation. Especially scanty is the available information regarding the effect of herbicides on fish energy resources. In the present study, the effect of sublethal exposure to these herbicides on the energy reserves of juvenile eel Anguilla anguilla was compared. Eels were exposed to 72 h to the herbicide thiobencarb (0.22 mg L(-1)) or Propanil (0.63 mg L(-1)), and allowed to recover in clean water (144 h). Caloric content was determined in liver and skeletal muscle. Fish exposed to thiobencarb rapidly mobilized energy. Reserves from liver were depleted (21%) compared to control values (2.50 kcal g(-1)) at 2 h, whereas in muscle diminished between 12 and 72 h (35%) (control value 0.89 kcal g(-1)). Energy reserves from liver normalized after 144 h in water while in the skeletal muscle were still depleted (24%). Major harmful effects were induced by propanil. Caloric content in liver diminished from the first hours (depletion of 70% at 48h exposure) and in skeletal muscle a 60% (72 h). At the end of the recovery period, energy reserves in pre-exposed eels represented less than 50% compared to control animals. The study indicated that thiobencarb and propanil would constitute a great risk to animals inhabiting freshwater bodies nearby fields of application. Judging from the results, herbicides resulted toxic enough to mobilize fish energy stores. On the other hand, a period of six days in herbicide-free water was not enough time to allow fish to restore energy budgets. PMID- 25917607 TI - Changes in mutagenicity and acute toxicity of solutions of iodinated X-ray contrast media during chlorination. AB - In the present study, the effects of chlorination on the mutagenicity (assessed via the Ames assay) and acute toxicity (assessed via a bioluminescence inhibition assay) of solutions containing one of five commonly used iodinated X-ray contrast media (ICM) (iopamidol, iohexol, iopromide, iomeprol, and diatrizoate) were investigated. Of the five ICM tested, only iopamidol was degraded by chlorine. Chlorination of the iopamidol-containing solution induced both mutagenicity and acute toxicity, which increased with chlorination time (up to 96 h). The areas of five out of 54 peaks detected on the LC/MS total ion chromatogram had good correlation (r(2)>0.90) between peak area and observed mutagenicity. To identify possible contributors to the observed mutagenicity, the Ames assay and LC/MS analysis were conducted on samples collected at 48-h chlorination time and extracted under different pH conditions. Of the five peaks, one peak was detected in the sample extracted at pH 7, but this sample was not mutagenic, indicating that the peak was not related to the observed mutagenicity. MS/MS analysis with an orbitrap mass spectrometer of the remaining four peaks revealed that two of the peaks represented the same TP (detected in negative and positive ion modes). Finally, three TPs were identified as suspected contributors to the mutagenicity induced by the iopamidol-containing solution after chlorination: 5-[(1,3 dihydroxypropan-2-yl)carbamoyl]-3-[(3-hydroxypropanoyl)oxy]-2,4-diiodobenzoic acid; N-(1,3-dihydroxypropan-2-yl)-3-(2,3-dioxopropyl)-2,4,6-triiodobenzamide; and 3-[(1,3-dihydroxypropan-2-yl)carbamoyl]-5-[(3-hydroxybutanoyl)oxy]-2,4,6 triiodobenzoic acid. Prediction of the mutagenicity potential of these three TPs with a battery of four quantitative structure-activity relationship models did not contradict our conclusion that these TPs contributed to the observed mutagenicity. PMID- 25917608 TI - Omics Approaches Toward Defining the Comprehensive Abscisic Acid Signaling Network in Plants. AB - ABA is a plant hormone that plays crucial roles in controlling cellular and physiological responses to osmotic stress and in developmental processes. Endogenous ABA levels are increased in response to a decrease in water availability in cells, and ABA sensing and signaling are thought to be mediated according to the current model established in Arabidopsis thaliana, which involves pyrabactin resistance 1 (PYR)/PYR1-like (PYL)/regulatory components of ABA receptor (RCAR), protein phosphatase 2C (PP2C) and sucrose non-fermenting-1 (SNF1)-related protein kinase 2 (SnRK2). These core components of ABA signaling have a pivotal role in stress-responsive gene expression and stomatal regulation. However, because a limited number of their upstream and downstream factors have been characterized, it is still difficult to define the comprehensive network of ABA signaling in plants. This review focuses on current progress in the study of PYR/PYL/RCARs, PP2Cs and SnRK2s, with particular emphasis on omics approaches, such as interactome and phosphoproteome studies. Moreover, the role of ABA in plant growth and development is discussed based on recent metabolomic profiling studies. PMID- 25917609 TI - In situ trace metal analysis of Neoarchaean--Ordovician shallow-marine microbial carbonate-hosted pyrites. AB - Pre-Cambrian atmospheric and oceanic redox evolutions are expressed in the inventory of redox-sensitive trace metals in marine sedimentary rocks. Most of the currently available information was derived from deep-water sedimentary rocks (black shale/banded iron formation). Many of the studied trace metals (e.g. Mo, U, Ni and Co) are sensitive to the composition of the exposed land surface and prevailing weathering style, and their oceanic inventory ultimately depends on the terrestrial flux. The validity of claims for increased/decreased terrestrial fluxes has remained untested as far as the shallow-marine environment is concerned. Here, the first systematic study of trace metal inventories of the shallow-marine environment by analysis of microbial carbonate-hosted pyrite, from ca. 2.65-0.52 Ga, is presented. A petrographic survey revealed a first-order difference in preservation of early diagenetic pyrite. Microbial carbonates formed before the 2.4 Ga great oxygenation event (GOE) are much richer in pyrite and contain pyrite grains of greater morphological variability but lesser chemical substitution than samples deposited after the GOE. This disparity in pyrite abundance and morphology is mirrored by the qualitative degree of preservation of organic matter (largely as kerogen). Thus, it seems that in microbial carbonates, pyrite formation and preservation were related to presence and preservation of organic C. Several redox-sensitive trace metals show interpretable temporal trends supporting earlier proposals derived from deep water sedimentary rocks. Most notably, the shallow-water pyrite confirms a rise in the oceanic Mo inventory across the pre-Cambrian-Cambrian boundary, implying the establishment of efficient deep-ocean ventilation. The carbonate-hosted pyrite also confirms the Neoarchaean and early Palaeoproterozoic ocean had higher Ni concentration, which can now more firmly be attributed to a greater proportion of magnesian volcanic rock on land rather than a stronger hydrothermal flux of Ni. Additionally, systematic trends are reported for Co, As, and Zn, relating to terrestrial flux and oceanic productivity. PMID- 25917610 TI - A Behavioral Intervention for Reducing Postcompletion Errors in a Safety-Critical System. AB - OBJECTIVE: We investigated the effectiveness of a theoretically motivated intervention at reducing procedural errors in train yard operations, where making these errors could be costly or life-threatening. BACKGROUND: A widespread and persistent memory error that people commit on a daily basis is the postcompletion error (PCE), that is, forgetting to complete the final step of a procedural task in which the final step occurs after completion of the task goal. PCEs occur in the railroad industry when a locomotive conductor changes the direction of a rail switch but fails to report this change. This particular error could contribute to unsafe conditions as another train traveling on the same track could derail. Although training can help reduce some of the factors leading to unsafe conditions on the rail, research has demonstrated that PCEs are different from other errors of omission in that they cannot be eliminated through training, which makes them a difficult problem to address. METHOD: Twenty-eight undergraduates completed train yard tasks within a mid-fidelity simulator used in commercial rail operations for training. Each participant received the behavioral intervention in one block and no intervention in another. Specifically, participants were required to perform an additional task designed to remind participants of the postcompletion step. RESULTS: Our intervention significantly reduced PCE rates in the context of train yard operations, on average by 65%. CONCLUSION: We discuss implications of the effectiveness of our intervention at reducing train yard accidents and how this outcome can contribute to the literature on the cause of PCEs. APPLICATION: In cases such as the railroad industry, where redesigning technology is prohibitive, our behavioral intervention is an effective alternative for significantly reducing PCEs. PMID- 25917611 TI - The Role of Trust as a Mediator Between System Characteristics and Response Behaviors. AB - OBJECTIVE: The purpose of the current work was to clarify how subjective trust determines response behavior when interacting with a signaling system. BACKGROUND: In multiple theoretical frameworks, trust is acknowledged as a prime mediator between system error characteristics and automation dependence. Some researchers have operationally defined trust as the behavior exhibited. Other researchers have suggested that although trust may guide operator responses, trust does not completely determine the behavior. METHOD: Forty-four participants interacted with a primary flight simulation task and a secondary signaling system task. The signaling system varied in reliability (90%, 60%) and error bias (false alarm, miss prone). Trust was measured halfway through the experimental session to address the criterion of temporal precedence in determining the effect of trust on behavior. RESULTS: Analyses indicated that trust partially mediated the relationship between reliability and agreement rate. Trust did not mediate the relationship between reliability and reaction time. Trust also did not mediate the relationships between error bias and reaction time or agreement rate. Analyses of variance generally supported specific behavioral and trust hypotheses, indicating that the paradigm employed produced similar effects on response behaviors and subjective estimates of trust observed in other studies. CONCLUSION: These results indicate that strong assumptions of trust acting as the prime mediator between system error characteristics and response behaviors should be viewed with caution. APPLICATION: Practitioners should consider assessing factors other than trust to determine potential operator response behaviors, which may be more predictive. PMID- 25917612 TI - Using lithium carbonate-based electron injection structures in high-performance inverted organic light-emitting diodes. AB - A lithium carbonate-based bi-layered electron injection layer was introduced into inverted organic light-emitting diodes (OLEDs) to reduce operation voltages and achieve carrier balance. Ultraviolet photoemission spectroscopy was used to confirm the existence of an interfacial dipole between the organic and lithium carbonate layers, which is a dominating factor related to the device performance. The respective maximum efficiencies of 15.9%, 16.9%, and 8.4% were achieved for blue, green, and red phosphorescent inverted OLEDs with identical architectures, indicating that carrier balance was easily obtained. Moreover, adoption of this sophisticated electron injection layer design resulted in respective turn on voltages of only 3.4 V, 3.2 V, and 3.2 V. Furthermore, the inverted OLEDs equipped with silicon dioxide nanoparticle based light-extraction films achieved an approximately 1.3 fold efficiency improvement over pristine devices due to the low refractive index of the silicon dioxide nanoparticles along with an effective scattering function. The blue, green, and red inverted OLEDs with the nanocomposite layer achieved respective peak efficiencies of 20.9%, 21.3%, and 10.1%. PMID- 25917613 TI - NFKB1 common variants and PPP1R13L and CD3EAP in relation to lung cancer risk in a Chinese population. AB - Genetic variations in NFKB1 have been associated with cancer risk. This investigation intended to evaluate the possible association between common variants in NFKB1 and lung cancer risk and gene-gene and gene-environment interactions. A study containing 384 Chinese lung cancer cases and 387 cancer free controls was conducted. 5 htSNPs (rs3774934, rs13117745, rs230541, rs1801, rs3774965) in NFKB1 and interaction with common variants in NFKB1 and PPP1R13L and CD3EAP and smoking-duration were assessed. No association with lung cancer risk was detected for individual htSNP in four genetic models, but the haplotype consisting of the wild-type alleles of rs3774934(G), rs13117745(C), rs230541(A), and rs1801(G) was associated with lowered lung cancer risk after adjustment for smoking duration [OR (95% CI) = 0.71 (0.51-0.98), P = 0.036]. There was no interaction between NFKB1 polymorphisms and PPP1R13L and CD3EAP and smoking status in relation to lung cancer risk. Two significant models: smoking duration as main effect (P < 0.0010) and smoking duration-PPP1R13L rs1970764 combination (P = 0.0040-0.0050) were tested. The results suggest that NFKB1 common variants and smoking duration and smoking duration-PPP1R13L rs1970764 interaction could be concerned with the lung cancer development in a Chinese population. The present findings add to the evidence implicating inflammation in lung cancer etiology. PMID- 25917614 TI - Effect of polymorphism within miRNA-1606 gene on growth and carcass traits in chicken. AB - Genetic variations in microRNAs (miRNAs) including primary miRNAs, precursor miRNAs and mature miRNAs can lead to phenotypic variation by altering the biogenesis of miRNAs and/or their binding to target mRNAs. Increasing functional studies suggest that polymorphisms occurring in miRNAs can lead to phenotypic variation in farm animal. Here, we identified a single nucleotide polymorphism (SNP) located in the precursor of chicken miRNA-1606 gene. The association study on body indexes, body weight at different growth stages, and carcass traits was performed in a Gushi-Anka F2 population resource. The SNP was not only significantly associated with body weight at 10 and 12 weeks, respectively, but also with chicken shank length, chest depth and body slanting length at 8 weeks; shank length, pectoral angle, body slanting length and pelvis breadth at 12 weeks, respectively. And the polymorphism was also significantly associated with carcass traits including semi-evisceration weight, evisceration weight, breast muscle weight, leg weight and carcass weight as well. The observed values of individuals with CA genotype were significantly higher than CC genotype both in body weight at different stages and carcass traits. This SNP altered the predicted second structure of pre-mir-1606, with the altering of the free energy values. And the relative expression level of mature miRNA between CA and AA was significantly changed in leg muscle. Our data suggested that miRNA-1606 may be a candidate gene associated with chicken growth traits. PMID- 25917615 TI - The association between three promoter polymorphisms of IL-1 and stroke: a meta analysis. AB - AIM: The association between Interleukin-1 (IL-1) gene polymorphism and stroke remains controversial. The present study was designed to clarify this relationship through a pooled analysis of the numerous epidemiological studies focusing on this association. METHODS: Published data addressing the association between polymorphism of the IL-1 gene and stroke were selected from electronic databases. A total of 21 studies from 19 publications including 5280 stroke patients and 5699 controls were included in this meta-analysis which detect whether IL-1alpha-889C/T, IL-1beta-511C/T and IL-1 RN polymorphism were associated with stroke susceptibility. RESULT: The combined results of overall analysis revealed that there was a significant association between IL-1alpha 889C/T polymorphism and stroke (allele model: OR = 1.39, 95% CI = 1.14-1.68, P < 0.001; recessive model: OR = 1.56, 95% CI = 1.27-1.90, P < 0.001; dominant model: OR = 1.45, 95% CI = 1.13-1.87, P = 0.004; additive model: OR = 1.70, 95% CI = 1.37-2.10, P < 0.001). On a subgroup analysis by ethnicity of study population, significant association was found in Asians (allele model: OR = 1.25 95% CI = 1.12-1.39, P < 0.001; recessive model: OR = 1.36, 95% CI = 1.09-1.69, P = 0.007; dominant model: OR = 1.29, 95% CI = 1.12-1.48, P < 0.001; additive model: OR = 1.42, 95% CI = 1.13-1.80, P = 0.003). There are no associations of IL-1beta 511C/T and IL-RN polymorphisms on stroke risk were identified. CONCLUSION: In conclusion, our results suggested that IL-1alpha-889C/T polymorphism is associated with stroke risk, especially in Asians. However, no associations of IL 1beta-511C/T and IL-RN polymorphisms on stroke risk in overall analysis or subgroup analysis. PMID- 25917616 TI - CYP17A1 and CYP2E1 variants associated with high altitude polycythemia in Tibetans at the Qinghai-Tibetan Plateau. AB - Tibetans adapt to high altitude environments through low blood hemoglobin concentrations. Previous work has identified that CYP17A1 and CYP2E1 genes exhibit evidence of local positive selection for this Tibetan high-altitude adaptation. Nevertheless, despite this apparent genetic advantage, some Tibetans still develop high altitude polycythemia (HAPC) yet the reasons for this remain unknown. We sought to determine if polymorphisms in CYP17A1 and CYP2E1 genes were associated with susceptibility to HAPC in Tibetans at the Qinghai-Tibetan Plateau in China. We enrolled 63 Tibetan HAPC patients and 131 healthy, age- and gender matched control Tibetans. All subjects are from the Yushu area of Qinghai where the altitude is over 3500 m. Three SNPs of the CYP17A1 including rs3781287, rs11191548 and rs1004467, and four SNPs of CYP2E1 gene, including rs1536836, rs3813865, rs3813867 and rs743535, were genotyped by the Sequenom MassARRAY SNP assays. We discovered that SNP rs1004467 of the CYP17A1 gene and SNP rs3813865 of the CYP2E1 gene were significantly associated with HAPC risk. Furthermore, we identified a positive correlation between these two SNPs and plasma hemoglobin levels. Thus, taken together, our study is the first to our knowledge to show that polymorphisms in the rs1004467 SNP of CYP17A1 and rs3813865 SNP of CYP2E1 correlate with susceptibility to HAPC. PMID- 25917617 TI - Cloning, expression and localization of the Daphnia carinata transformer gene DcarTra during different reproductive stages. AB - In this study, the full-length cDNA of the Transformer (Tra) gene from the common freshwater species Daphnia carinata (DcarTra; GenBank accession no. KJ735445) was cloned using primers based on homologous sequences and rapid amplification of cDNA ends (RACE). The relative expression and localization of DcarTra and the cellular abundance of the DcarTra protein during different sexual phases were subsequently investigated. The full-length DcarTra cDNA was 1620 bp with an ORF of 1143 bp encoding a 380 amino acid polypeptide. Phylogenetic analysis identified closely related genes in Daphnia magna and Daphnia pulex, and more distantly related genes in other insects. Quantitative PCR showed that DcarTra expression was highest in males, followed by sexual females, and lowest in parthenogenetic females. Whole-mount in situ hybridization showed that DcarTra was mainly expressed in the thoracic limbs, ovaries and rectum in parthenogenetic females, and in the joints of second antennae, ovaries, rectum and ventral processes in sexual females. Western blotting showed two differently phosphorylated forms of the Tra protein. When Tra is phosphorylated, DcarTra protein levels were much higher in males than in two females. Otherwise, when Tra is dephosphorylated, the highest Tra protein levels were in sexual females, which revealed that D. carinata can control the sexual transition via these two forms. Together these results suggest that DcarTra plays significant roles in the reproductive transformation of D. carinata and dephosphorylation of DcarTra may be the trigger for females to transform into males. PMID- 25917618 TI - Differential recognition of the ORF2 region in a complete genome sequence of porcine circovirus type 2 (PCV2) isolated from boar bone marrow in Korea. AB - Porcine circovirus type 2 (PCV2) is the causative agent of post-weaning multisystemic wasting syndrome (PMWS) in swine. Here, a phylogenetic tree was constructed using PCV2 nucleotide sequences derived from the bone marrow of Korean boar and previously reported PCV2 sequences isolated from various countries. PCV2 from Korean boar bone marrow (KC188796) was classified into the group containing PCV2a-Canada and other PCV2 strain from Korea. While the ORF1 region of the PCV2 genome was highly conserved, ORF2 (the capsid protein coding region) was relatively variable. The nucleotide sequences for bone marrow-derived PCV2 were 93.4-99.0% homologous to the other reference sequences. The deduced amino acid sequences for the ORF1 and ORF2 coding regions were 97.4-99.3% and 84.5-97.4% homologous with the other reference strains, respectively, indicating that KC188796 did not differ markedly from the other PCV2 strains. Phylogenetic analysis demonstrated that bone marrow-derived PCV2 was highly similar to PCV2a from Canada and may be related to persistent PCV2 infections in swine. PMID- 25917619 TI - Bichir microRNA repertoire suggests a ray-finned fish affinity of Polypteriforme. AB - The phylogenetic position of Polypteriforme (bichirs) remains elusive, despite extensive research both on morphological and molecular datasets. Unfortunately morphological cladistic analyses and molecular phylogenetic analyses had reached conflicting conclusions, as Polypteriformes were either grouped with lobe-finned fishes (Sarcopterygii) or ray-finned fishes (Actinopterygii), or even classified as their own group, the Brachiopterygii. In this study, we applied a third independent source of datasets, the presence versus absence of microRNAs, to re investigate the phylogenetic relationship of bichirs. Through deep sequencing of small RNA library, we showed that bichirs should be grouped into ray-finned fishes rather than lobe-finned fishes. Phylogenetic analysis confirmed that bichirs were placed as the most basal member of the ray-finned fishes. Bichirs shared five unique microRNA families with teleostei, which were not found in any other species investigated to date. Bichirs have also retained three of five microRNAs that were previously deemed to be lost exclusively in teleostei. Furthermore, we report more than one hundred novel microRNAs that are unique to bichir. The identification of microRNAs in bichir provides overwhelming evidence for their affinity of ray-finned fishes. The sarcopterygian-like characteristics such as lobed fins, paired ventral lungs, and external gills in juveniles should not be considered as derived traits shared with those of sarcopterygians. PMID- 25917620 TI - Patients' decisional control over care: a cross-national comparison from both the patients' and nurses' points of view. AB - BACKGROUND: Patients' decisional control over care is the ability or power for patients to decide what their involvement will be in healthcare decisions. There is evidence of limited agreement between the perceptions of patients and the perceptions of nurses and/or caregivers with regard to the degree of patient involvement in the planning and performance of their care. AIM: To analyse and compare patients' and nurses' perceptions of patients' decisional control over their own care. METHOD: A multisite cross-sectional comparative survey design was employed. Data were collected from hospitalised surgical inpatients (n = 1315) and their caregivers (n = 960 nurses) in five European countries. The Individualised Care Scale part B was used for collecting data from both the patients and nurses. Ethical standards were followed throughout the study. RESULTS: Significant between-country differences were found between patients and nurses. In all countries, both patients and nurses regarded that decisional control over care had been actualised (ICS-B: M = 3.75-4.47 and 3.48-4.33, respectively), but there were significant differences in their perceptions regarding four of the six items of the decisional control factor of the ICS-B. CONCLUSIONS: The results show that there are disparities between patients' and nurses' perceptions of patient involvement in care, probably due to cultural issues that need further exploration. CLINICAL RELEVANCE: The disparities between patients' and nurses' perceptions on patients' decisional control over their care should be taken into consideration as a potential cause of patient dissatisfaction with nursing care. PMID- 25917621 TI - The influence of topical mitomycin-C on total fibroblasts, epithelialization, and collagenization in anoplasty wound healing in Wistar rats. AB - PURPOSE: The purpose of this study is to analyze the influence of topical mitomycin-C on total fibroblasts, epithelialization, and collagenization in anoplasty wound healing in Wistar rats. METHODS: In this experimental study, anoplasty procedures were performed on twelve Wistar rats that were subsequently randomly placed into two groups; i.e., control and treated groups. In the treated group, topical mitomycin-C was applied to the wound following the anoplasty procedure. All rats were sacrificed on the seventh day, and tissue samples of the wounds were obtained for histopathological evaluations. The total fibroblasts, epithelialization, and collagenization were evaluated by scoring methods. The Mann-Whitney test was used to analyze the statistical significance of differences, and p values below 0.05 were considered to be significant. RESULTS: The mean fibroblast scores for the treated and control groups were 1.5 and 3.0. The mean epithelialization scores for the treated and control groups were 5 and 3.33. The mean collagenization scores for the treated and control groups were 5 and 3.5. Statistical evaluations revealed significant differences between the groups in total fibroblasts (p=0.006), epithelialization (p=0.022), and collagenization (p=0.022). CONCLUSIONS: Topical mitomycin-C reduced the fibroblasts; however, the treatment did not suppress epithelialization or collagenization during anoplasty wound healing in Wistar rats. PMID- 25917622 TI - Conditional probability of survival in patients with biliary atresia after Kasai portoenterostomy: a Chinese population-based study. AB - Survival estimates are commonly reported for the outcomes of patients. Conditional probability, which offers more relevant information regarding the prognosis for patients once they have survived for some time, are lacking for patients with biliary atresia. The aim of this study is to calculate the conditional probability of survival in patients with biliary atresia after Kasai portoenterostomy. Clinical data from 244 consecutive patients who underwent Kasai portoenterostomy were reviewed and the actuarial survival estimated. Conditional survival probabilities and 95% CIs were calculated. Of the 244 patients, the overall median NLS was 41.2 months (95% CI:30.8-51.6 months), and the 1-year, 3 year, and 5-year NLS rates were 85.4%, 61.1%, and 43.3%, respectively. The probabilities of surviving at the time point of 5 years given survival to 1, 2, 3, and 4 years were 50%, 56%, 73%, and 93%, respectively. For conditional survival for 1 additional year, patients with age >90 days and cholangitis had significantly predictive values(both P<0.05). Cox proportional hazards model showed that age > 90 days(HR: 2.519, P=0.001), and postoperative cholangitis(HR:2.568, P<0.001) were associated with an adverse NLS in the multivariable adjusted analysis. our findings showed that conditional survival of patients with BA is not linear over time after Kasai operation. Information derived from conditional survival can be used to better manage patients with BA, including the potential subsequent treatment decisions, the chance of listing for transplantation, or even the end-of-life planning. PMID- 25917623 TI - Obesity and cancer immunotherapy toxicity. PMID- 25917624 TI - Use of brodalumab for the treatment of psoriasis and psoriatic arthritis. AB - Psoriasis is a chronic immune-mediated disease that affects 2-3% of the population worldwide. Over the past two decades new data on the physiopathology of psoriasis have opened the door for novel therapeutic options. The IL-23-Th17 axis has been shown to play a key role in the inflammatory cascade central to this disease. IL-17 inhibitors are a new group of drugs that have shown excellent clinical effectiveness for the treatment of moderate-to-severe psoriasis in current clinical trials. Brodalumab is an antibody against IL-17 receptor subunit A (IL-17RA). This article reviews the available published data on brodalumab for the treatment of moderate-to-severe psoriasis and psoriatic arthritis. PMID- 25917625 TI - Cellular immunotherapy with ex vivo expanded cord blood T cells in a humanized mouse model of EBV-associated lymphoproliferative disease. AB - BACKGROUND: Donor lymphocyte infusion is not feasible in recipients of cord blood transplantation. AIM: We investigated whether infusion of T cells expanded from cord blood is effective in the treatment of model mice of Epstein-Barr virus (EBV)-associated lymphoproliferative disease (LPD). MATERIALS & METHODS: Humanized mice with reconstituted human immune system were prepared and LPD was induced by inoculating EBV intravenously. T cells were expanded from the same sample of cord blood as used for generation of humanized mice and infused to EBV infected humanized mice. RESULTS: Mice treated with expanded cord blood T cells lived significantly longer than control mice (p = 0.036). CONCLUSION: Infusion of T cells expanded from cord blood was effective in the treatment of model mice for EBV-associated LPD. PMID- 25917626 TI - A Phase I clinical trial with subcutaneous immunotherapy vaccine of Timothy grass pollen extract according to EMA guidelines. AB - AIM: A double-blind placebo-controlled study was conducted according to EMA guidelines, to evaluate safety, tolerability and short-term treatment effects of three up-dosing regimens of Phleum pratense subcutaneous immunotherapy. MATERIALS & METHODS: Forty-two patients were randomized to groups: A (6 weekly doses), B (8 weekly doses) or C (eight doses, two clustered increasing doses over 3 weeks). RESULTS: The most frequent adverse events were local reactions. No serious adverse events were found. Higher number and more severe systemic reactions were reported in group C. A decrease in cutaneous responses and an increase of specific antibodies was shown in all active groups even at very short-term. CONCLUSION: Phleum pratense subcutaneous immunotherapy in depot presentation exhibited good safety and tolerability. Group A seemed to show the best profile. PMID- 25917627 TI - Investigating the potential side effects of anti-TNF therapy for rheumatoid arthritis: cause for concern? AB - There are now five anti-TNF drugs available for clinical use, and it will not be long before they are joined by biosimilar drugs. Some patients treated with selective TNF drugs may develop adverse events such as infections, malignancies, acute infusion and injection reactions, autoimmunity and cardiovascular effects. Registry data consistently show that, particularly during the first 6 months, anti-TNF drugs slightly increase the risk of serious infections of the skin, soft tissues and joints, but it does not seem to increase the risk of cancer other than nonmelanoma skin cancers. A number of studies have shown that the administration of biological agents can lead to the formation of neutralizing and nonneutralizing antibodies. Lipid levels increase, but the atherogenic index remains stable and qualitative changes to lipid particles may reduce the risk of cardiovascular diseases. Patients treated with anti-TNF drugs therefore need to be monitored regularly. PMID- 25917628 TI - Strategies to relieve immunosuppression in pancreatic cancer. AB - Despite continuous progress in the understanding of deregulated pathways in pancreatic cancer cells and development of targeted therapies, therapeutic advances with clinical benefit have been scarce over the last decades. The recent success of immunotherapy for some solid cancers has fueled optimism that this approach might also work for pancreatic cancer. However, a highly immunosuppressive microenvironment mediated by tumor, stromal and immune cells creates a major hurdle for immunotherapy. Mouse models have helped to unravel critical immunosuppressive mechanisms that could serve as novel therapeutic targets. Here we review new promising strategies that alone or in combination with other modalities, such as chemotherapy or irradiation, have the potential to lead to tumor immune control and finally better clinical outcome. PMID- 25917629 TI - Achieving incompatible transplantation through desensitization: current perspectives and future directions. AB - The application of life-saving transplantation is severely limited by the shortage of organs, and histoincompatibility. To increase transplant rates in sensitized patients, new protocols for HLA and blood type incompatible (ABOi) desensitization have emerged. These approaches require significant desensitization using intravenous immunoglobulin, rituximab and plasma exchange. In addition, the development of donor-specific antibody responses post transplant is the major cause of allograft failure with return to dialysis. This increases patient morbidity/mortality and cost. Immunotherapeutic agents used for desensitization evolved from drug development in oncology and autoimmune diseases. Currently, there is a renaissance in development of novel drugs likely to improve antibody reduction in transplantation. These include agents that inactivate IgG molecules, anticytokine antibodies, costimulatory molecule blockade, anticomplement agents and therapies aimed at the plasma cell. PMID- 25917631 TI - New York esophageal squamous cell carcinoma-1 and cancer immunotherapy. AB - New York esophageal squamous cell carcinoma 1 (NY-ESO-1) is a known cancer testis gene with exceptional immunogenicity and prevalent expression in many cancer types. These characteristics have made it an appropriate vaccine candidate with the potential application against various malignancies. This article reviews recent knowledge about the NY-ESO-1 biology, function, immunogenicity and expression in cancers as well as and the results of clinical trials with this antigen. PMID- 25917632 TI - IL-11 signaling as a therapeutic target for cancer. AB - IL-11 is a member of the IL-6 family of cytokines. While it was discovered over 20 years ago, we have very little understanding of the role of IL-11 during normal homeostasis and disease. Recently, IL-11 has gained interest for its newly recognized role in the pathogenesis of diseases that are attributed to deregulated mucosal homeostasis, including gastrointestinal cancers. IL-11 can increase the tumorigenic capacity of cells, including survival of the cell or origin, proliferation of cancerous cells and survival of metastatic cells at distant organs. Here we outline our current understanding of IL-11 biology and recent advances in our understanding of its role in cancer. We advocate that inhibition of IL-11 signaling may represent an emerging therapeutic opportunity for numerous cancers. PMID- 25917630 TI - Novel insights into anti-CD40/CD154 immunotherapy in transplant tolerance. AB - Since the discovery of the CD40-CD154 costimulatory pathway and its critical role in the adaptive immune response, there has been considerable interest in therapeutically targeting this interaction with monoclonal antibodies in transplantation. Unfortunately, initial promise in animal models gave way to disappointment in clinical trials following a number of thromboembolic complications. However, recent mechanistic studies have identified the mechanism of these adverse events, as well as detailed a myriad of interactions between CD40 and CD154 on a wide variety of immune cell types and the critical role of this pathway in generating both humoral and cell-mediated alloreactive responses. This has led to resurgence in interest and the potential resurrection of anti CD154 and anti-CD40 antibodies as clinically viable therapeutic options. PMID- 25917633 TI - An update on current and prospective immunotherapies for chronic lymphocytic leukemia. AB - Chronic lymphocytic leukemia (CLL) is the most common leukemia. Combined agent chemotherapy is the current standard front-line treatment for physically fit patients with CLL. Use of chemotherapy can be complicated by significant toxicity, especially in patients with advanced age or comorbid conditions. Moreover, patients may relapse and become refractory to further chemotherapy. Immunotherapy targets the aberrant immunological processes in CLL without the toxicity of chemotherapy. Immunotherapeutic strategies can also be combined with chemotherapy to improve response rates in this incurable disease. In this review, we evaluate current and future immune-based options in the treatment of CLL. PMID- 25917634 TI - CrossFit-related cervical internal carotid artery dissection. AB - CrossFit is a high-intensity strength and conditioning program that has gained popularity over the past decade. Potential injuries associated with CrossFit training have been suggested in past reports. We report three cases of cervical carotid dissection that are associated with CrossFit workouts. Patient 1 suffered a distal cervical internal carotid artery (ICA) dissection near the skull base and a small infarct in Wernicke's area. He was placed on anticoagulation and on follow-up has near complete recovery. Patient 2 suffered a proximal cervical ICA dissection that led to arterial occlusion and recurrent middle cerebral artery territory infarcts and significant neurological sequelae. Patient 3 had a skull base ICA dissection that led to a partial Horner's syndrome but no cerebral infarct. While direct causality cannot be proven, intense CrossFit workouts may have led to the ICA dissections in these patients. PMID- 25917635 TI - Pitfalls in diagnosis: skeletal holes, clefts, and notches. AB - Radiographs often depict unusually appearing variations in the skeleton that have the appearance of holes, clefts, and prominent notches. Although certain variants are recognizable, others may not be as familiar. Knowledge of characteristic locations of nutrient foramina is also important. The aim of this pictorial essay are to review the anatomic variants in the trunk of the skeleton that manifest as holes, cleft, or notches in the bone and to specify the differentiating features of these variants from those that constitute true pathologic conditions. PMID- 25917636 TI - Nevirapine extended-release formulation tablets in HIV-1-infected children--long term follow-up. AB - In the optional extension of clinical trial 1100.1518 39/40, human immunodeficiency virus-infected patients (aged 3 to <18 years) received >=48 weeks of treatment with extended-release nevirapine. By last visit, all patients had undetectable viral loads and no new safety signals, demonstrating the safety and efficacy of a once-daily antiretroviral regimen. PMID- 25917637 TI - NOD2 pathway via RIPK2 and TBK1 is involved in the aberrant catabolism induced by T-2 toxin in chondrocytes. AB - OBJECTIVE: This study aimed to identify the key intracellular pattern recognition receptor (PRR) and its role in the unbalanced extracellular matrix gene expressions of chondrocytes treated by T-2 toxin, a potential etiological factor for cartilage damages. DESIGN: Differential expressions of intracellular PRRs after T-2 toxin treatment were screened by RT-qPCR in chondrocytes. RNAi was used to knockdown the expression of NOD2 and its two downstream signal molecules, RIPK2, and TBK1, for observing the effects of NOD2 pathway on regulation of metabolism gene expressions by RT-qPCR. The matrix metalloproteinases (MMP) activity was determined by gelatin zymography. The inhibitor of NF-kappaB and ROS scavenger were exploited to analyze the mechanism of NOD2 up-regulation in chondrocytes treated with T-2 toxin. RESULTS: In chondrocytes treated with T-2 toxin, anabolism genes were down-regulated whereas catabolism genes were up regulated, and NOD2 was identified as a significantly up-regulated gene. Intervening NOD2 expression via RNAi could ameliorate the down-regulation of anabolism genes, while inhibit the up-regulation of catablolism genes induced by T-2 toxin in chondrocytes. RNAi of RIPK2 and TBK1 in chondrocytes could obtain the similar outcome. Furthermore, up-regulation of NOD2 expression induced by T-2 toxin could be abrogated by pretreating the cells with inhibitors of NF-kappaB and scavenger of ROS. CONCLUSION: T-2 toxin could up-regulate NOD2 expression via ROS/NF-kappaB pathway and activate NOD2 signaling pathway. The up-regulated NOD2 would affect the metabolism gene expressions and MMP activity in chondrocytes via RIPK2 and TBK1. The findings add new insights into understanding NOD2 effects on chondrocytes treated with T-2 toxin. PMID- 25917639 TI - Smoking Status and Pain Intensity Among OEF/OIF/OND Veterans. AB - OBJECTIVE: Pain and smoking are highly prevalent among Veterans. Studies in non Veteran populations have reported higher pain intensity among current smokers compared with nonsmokers and former smokers. We examined the association of smoking status with reported pain intensity among Veterans of Operations Enduring Freedom, Iraqi Freedom, and New Dawn (OEF/OIF/OND). DESIGN: The sample consisted of OEF/OIF/OND Veterans who had at least one visit to Veterans Affairs (2001 2012) with information in the electronic medical record for concurrent smoking status and pain intensity. The primary outcome measure was current pain intensity, categorized as none to mild (0-3); moderate (4-6); or severe (>=7); based on a self-reported 11-point pain numerical rating scale. Multivariable logistic regression analyses were used to assess the association of current smoking status with moderate to severe (>=4) pain intensity, controlling for potential confounders. RESULTS: Overall, 50,988 women and 355,966 men Veterans were examined. The sample mean age was 30 years; 66.3% reported none to mild pain; 19.8% moderate pain; and 13.9% severe pain; 37% were current smokers and 16% former smokers. Results indicated that current smoking [odds ratio (OR) = 1.29 (95% confidence intervals (CI) = 1.27-1.31)] and former smoking [OR = 1.02 (95% CI = 1.01-1.05)] were associated with moderate to severe pain intensity, controlling for age, service-connected disability, gender, obesity, substance abuse, mood disorders, and Post Traumatic Stress Disorder. CONCLUSIONS: We found an association between current smoking and pain intensity. This effect was attenuated in former smokers. Our study highlights the importance of understanding reported pain intensity in OEF/OIF/OND Veterans who continue to smoke. PMID- 25917638 TI - Meniscus is more susceptible than cartilage to catabolic and anti-anabolic effects of adipokines. AB - OBJECTIVE: This study compared the effects on cartilage and meniscus matrix catabolism and biosynthesis of several adipokines implicated in osteoarthritis (OA). DESIGN: Bovine cartilage and meniscus explants were cultured for 1 or 9 days in serum-free medium alone or with 0.02, 0.2, or 2 MUg/ml of leptin, visfatin, adiponectin, or resistin. Media were supplemented with (3)H-proline or (35)S-sodium sulfate to evaluate protein and sulfated glycosaminoglycan (sGAG) accumulation on the last day of culture. Explants were assayed for radiolabel, sGAG, and DNA contents. Cultured media were assayed for sGAG, nitrite and lactate dehydrogenase. RESULTS: Cartilage tissue was minimally affected by adipokines, with only the highest resistin dose increasing sGAG release and nitrite production compared to controls. In sharp contrast, meniscus tissue was responsive to several adipokines, with elevated sGAG and nitrite release following treatment with resistin, leptin, or visfatin. Cartilage sGAG content was unaltered by adipokine treatment whereas meniscal sGAG content significantly decreased with resistin dosage. Protein ((3)H) incorporation was unaffected by adipokine treatment in both tissues. sGAG ((35)S) incorporation did not significantly vary with adipokine treatment in cartilage but was inhibited by treatment with leptin, visfatin, and resistin in meniscus. CONCLUSION: Our results indicate that meniscal tissue is more susceptible to adipokine-stimulated catabolism than is cartilage. Resistin had the strongest effect of the adipokines tested, inducing sGAG release in both tissues and depleting sGAG content in meniscus. These results suggest that increased adipokine levels due to obesity or joint injury may alter the mechanical integrity of the knee joint through biological pathways. PMID- 25917640 TI - Near-infrared chemical imaging (NIR-CI) as a process monitoring solution for a production line of roll compaction and tableting. AB - In the present study the application of near-infrared chemical imaging (NIR-CI) supported by chemometric modeling as non-destructive tool for monitoring and assessing the roller compaction and tableting processes was investigated. Based on preliminary risk-assessment, discussion with experts and current work from the literature the critical process parameter (roll pressure and roll speed) and critical quality attributes (ribbon porosity, granule size, amount of fines, tablet tensile strength) were identified and a design space was established. Five experimental runs with different process settings were carried out which revealed intermediates (ribbons, granules) and final products (tablets) with different properties. Principal component analysis (PCA) based model of NIR images was applied to map the ribbon porosity distribution. The ribbon porosity distribution gained from the PCA based NIR-CI was used to develop predictive models for granule size fractions. Predictive methods with acceptable R(2) values could be used to predict the granule particle size. Partial least squares regression (PLS R) based model of the NIR-CI was used to map and predict the chemical distribution and content of active compound for both roller compacted ribbons and corresponding tablets. In order to select the optimal process, setting the standard deviation of tablet tensile strength and tablet weight for each tablet batch was considered. Strong linear correlation between tablet tensile strength and amount of fines and granule size was established, respectively. These approaches are considered to have a potentially large impact on quality monitoring and control of continuously operating manufacturing lines, such as roller compaction and tableting processes. PMID- 25917641 TI - Glucose cryoprotectant affects glutathione-responsive antitumor drug release from polysaccharide nanoparticles. AB - The aim of this work was to prepare polysaccharide-based nanoparticles (NPs) sensitive to glutathione (GSH), and to elucidate the effect of the concentration of glucose used as cryoprotectant during freeze-drying on the GSH-responsiveness. NPs were obtained via ionic interaction between negatively charged polysaccharides, chondroitin sulfate and dermatan sulfate, and the positively charged thiolated chitosan (CSSH), and crosslinking of CSSH before or after the nanoparticles formation with a disulfide-bond containing crosslinker, N,N' bis(acryloyl)cystamine (BAC). NPs were freeze-dried with glucose at two different concentrations (0.5 and 5.0%w/w) and then characterized as methotrexate delivery systems, studying the effect of GSH concentration on drug release, efficacy against tumor cells and cellular internalization. Non-loaded NPs were highly compatible with murine fibroblasts and showed a suitable size for being used in anticancer therapy. When methotrexate-loaded NPs were freeze-dried with the highest glucose concentration, they lost their responsiveness to GSH concentration in vitro. Drug-loaded NPs were shown to inhibit the growth of tumor cells (HeLa and CHO-K1) with greater efficiency than free methotrexate, disregarding the concentration of glucose used for freeze-drying. Nevertheless, confocal microscopy studies revealed that cellular internalization of NPs freeze dried with 5.0% glucose is more difficult than for NPs freeze-dried with lower glucose concentration. Thus, concentration of glucose cryoprotectant should be taken into account during development of NPs intended to release the drug as a function of GSH levels, due to the specific interactions of glucose with GSH. PMID- 25917642 TI - Two little-known metazoan parasites potentially pathogenic to smooth-hounds, Mustelus spp., in captivity. PMID- 25917643 TI - Dyshidrosis is a risk factor for herpes zoster. AB - BACKGROUND: Endogenous factors such as stress-induced immune system reactivity were also associated with dyshidrosis. Herpes zoster (HZ) incidence has been demonstrated to increase with immune deficiencies. Therefore, a relationship between dyshidrosis and HZ may exist. OBJECTIVE: This study investigated whether there is an association between dyshidrosis and HZ. METHODS: We conducted a population-based cohort study by using Taiwan's Longitudinal Health Insurance Database (LHID2000) records from 1996 to 2011. The dyshidrosis group comprised 8488 patients with newly identified dyshidrosis and no history of HZ prior to diagnosis of dyshidrosis. For the non-dyshidrosis group, each dyshidrosis patient frequency matched according to age (5-year intervals), sex and index date year with four controls selected randomly from the LHID2000. RESULTS: After adjustments for confounding risk factors, the hazard ratio for HZ in the dyshidrosis group was 1.31 compared with the non-dyshidrosis group. Regardless of comorbidities, patients with dyshidrosis had a higher risk of HZ than did controls without dyshidrosis. Patients with more hospital visits that were due to dyshidrosis had a higher risk of HZ. CONCLUSION: Dyshidrosis is strongly associated with HZ. Patients treated for dyshidrosis should be warned of HZ risk. PMID- 25917645 TI - Ultrastructural changes in the tegument and gut of adult Fasciola hepatica following in vivo treatment with artesunate. AB - An in vivo study in the laboratory rat model has been carried out to monitor changes to the tegument and gut of adult Fasciola hepatica following treatment with artesunate. Rats infected with the triclabendazole-resistant Oberon isolate were dosed orally with artesunate at a concentration of 200 mg/kg and flukes recovered 24, 48, 72 and 96 h post-treatment (pt). The flukes were processed for scanning and transmission electron microscope examination. Changes to the external surface were limited to swelling and blebbing of the interspinal tegument. There was one exception, a specimen recovered 72 h pt, which had completely lost the syncytium over the posterior region of the fluke. Internal changes to the tegumental syncytium and cell bodies were more severe and were apparent from 48 h pt onwards. Increased numbers of secretory bodies were present in the apical region of the syncytium, the basal infolds were swollen and sloughing of the apical plasma membrane was seen at 96 h pt. In the cell bodies, there was swelling and vesiculation of the cisternae of the granular endoplasmic reticulum (ger), swelling of the mitochondria and a decrease in secretory body production. Changes to the gastrodermal cells were evident from 24 h onwards. They comprised swelling and vesiculation of the ger cisternae, swelling and lysis of the mitochondria and accumulation of autophagic vacuoles and lipid droplets. The nuclei of the cells were karyopyknotic by 96 h pt. The gut was consistently more severely affected than the tegument at all time points pt, pointing to an oral route of uptake for artesunate. This study has provided information on the primary subcellular targets for drug action in the fluke. PMID- 25917644 TI - Eimeria collieie n. sp. (Apicomplexa:Eimeriidae) from the western long-necked turtle (Chelodina colliei). AB - A new species, Eimeria collieie n. sp., is described from the western long-necked turtle (Chelodina colliei). Sporulated oocysts (n = 35) are spherical to subspherical, with colourless single layer oocyst wall, 0.6 +/- 0.2 (0.4-0.7) um thick. Oocyst with elongated ellipsoid sporocysts. Oocyst length, 29.8 +/- 0.4 (28.2-31.0) um; oocyst width, 29.4 +/- 0.3 (28.0-30.8) um; oocyst length/width (L/W) ratio, 1.0 +/- 0.03 (1.0-1.05). Micropyle, oocyst residuum and polar granule were absent. Sporocysts with sporocyst residuum and 2 sporozoites. Sporocyst length, 21.6 +/- 0.4 (21.2-22.0) um; sporocyst width, 6.0 +/- 0.3 (5.7 6.3) um; sporocyst L/W ratio, 3.6 +/- 0.2 (3.4-3.8). Stieda, parastieda and substieda bodies were absent. Sporozoite length, 14.0 +/- 0.2 (13.8-14.2) um; sporozoite width, 2.6 +/- 0.2 (2.4-2.8) um; sporozoite L/W ratio, 5.46 +/- 0.10 (5.4-5.6). Molecular analysis was conducted at three loci: the 18S and 28S ribosomal RNA (rRNA), and the mitochondrial cytochrome oxidase gene (COI). At the 18S rRNA locus, E. collieie n. sp. shared 96.4% and 98.3% genetic similarity to E. ranae (GenBank accession number: EU717219) and E. arnyi (AY613853) respectively. At the 28S rRNA locus, E. collieie n. sp. shared 91.6% genetic similarity to E. papillata (GenBank accession number: GU593706) and phylogenetic analysis at this locus placed E. collieie n. sp. in aseparateclade. At the COI locus, E. collieie n. sp. shared 92.7% genetic similarity to Eimeria setonicis (GenBankaccession number: KF225638) from a quokka (Setonix brachyurus) in Western Australia. Reptile-derived sequences were not available for the 28S rRNA and the COI loci. Based on morphological and molecular data, this isolate is a new species of coccidian parasite that, to date, has only been found in western long necked turtles. PMID- 25917646 TI - Immunological, ionic and biochemical responses in blood serum of the marine fish Trachinotus ovatus to poly-infection by Cryptocaryon irritans. AB - To investigate the response of pompano fish (Trachinotus ovatus) to white spot disease, we used the protozoan Cryptocaryon irritans to infect live 450-g specimens at concentrations of 40,000 theronts/fish. We assessed the relative infection intensity (RII), serum immobilizing titer, and immunity-related enzyme activities (ACP, AKP, LZM), and assessed feeding, serum ion concentrations (Na(+), Cl(-), Ca(2+) and K(+)) and blood biochemistry (ALT, AST, LDH) of pompano. The fish were then treated with a lethal dose of C. irritans (70,000 theronts/fish) and the number of deaths was recorded. We found that the relative infection intensities of the control group, group I, and group II were 0, 0.630 +/- 0.179, and 0.014 +/- 0.006. Poly-infection induced a significant increase in the serum immobilizing titer (853.33 +/- 295.60) of group II. In terms of the biochemical assessment, group II had significantly higher alkaline phosphatase and acid phosphatase activities than the other groups, and the lowest lysozyme activity (P < 0.05), compared to higher activity in the control group and the highest level in group I. Only the fishes of group I had stopped feeding after treatment. The concentrations of Na(+), Cl(-), and Ca(2+) in blood serum did not differ significantly among the three groups, but K(+) concentration increased with the increasing infection frequency. Alanine aminotransferase, aspartate aminotransferase, and lactate dehydrogenase activities in fish of group II were significantly higher than those of the other groups. Survival of the fish subjected to the lethal dose of C. irritans was 0, 0, and 100 in groups control, I, and II, respectively. In conclusions, based on the food intake of group II, along with the results of relative infection intensity, serum immobilizing titer, and survival, we speculate that the fish in that group acquired high protective immunity following poly-infection by C. irritans, experiencing limited harm for pompano. PMID- 25917647 TI - Enantiogroup-differentiating biocatalytic reductions of prochiral Cs -symmetrical dicarbonyl compounds to meso compounds. AB - The stereoselective reduction of symmetrical prochiral dicarbonyl compounds bearing enantiotopic carbonyl groups yields several stereogenic centers in one step. In a proof-of-concept study, a new approach is described for the enzymatic desymmetrization of 5-nitrononane-2,8-dione via sequential biocatalytic reduction steps utilizing ketoreductases to yield all possible diastereomers of 5 nitrononane-2,8-diol. PMID- 25917648 TI - Resolving the Differences Between the 1.9 A and 1.95 A Crystal Structures of Photosystem II: A Single Proton Relocation Defines Two Tautomeric Forms of the Water-Oxidizing Complex. AB - Great progress has been made in characterizing the water-oxidizing complex (WOC) in photosystem II (PSII) with the publication of a 1.9 A resolution X-ray diffraction (XRD) and recently a 1.95 A X-ray free-electron laser (XFEL) structure. However, these achievements are under threat because of perceived conflicts with other experimental data. For the earlier 1.9 A structure, lack of agreement with extended X-ray absorption fine structure (EXAFS) data led to the notion that the WOC suffered from X-ray photoreduction. In the recent 1.95 A structure, Mn photoreduction is not an issue, but poor agreement with computational models which adopt the 'high' oxidation state paradigm, has again resulted in criticism of the structure on the basis of contamination with lower S states of the WOC. Here we use DFT modeling to show that the distinct WOC geometries in the 1.9 and 1.95 A structures can be straightforwardly accounted for when the Mn oxidation states are consistent with the 'low' oxidation state paradigm. Remarkably, our calculations show that the two structures are tautomers, related by a single proton relocation. PMID- 25917649 TI - Engineering Pseudomonas putida KT2440 for simultaneous degradation of organophosphates and pyrethroids and its application in bioremediation of soil. AB - Agricultural soils are usually co-contaminated with organophosphate (OP) and pyrethroid pesticides. To develop a stable and marker-free Pseudomonas putida for co-expression of two pesticide-degrading enzymes, we constructed a suicide plasmid with expression cassettes containing a constitutive promoter J23119, an OP-degrading gene (mpd), a pyrethroid-hydrolyzing carboxylesterase gene (pytH) that utilizes the upp gene as a counter-selectable marker for upp-deficient P. putida. By introduction of suicide plasmid and two-step homologous recombination, both mpd and pytH genes were integrated into the chromosome of a robust soil bacterium P. putida KT2440 and no selection marker was left on chromosome. Functional expression of mpd and pytH in P. putida KT2440 was demonstrated by Western blot analysis and enzyme activity assays. Degradation experiments with liquid cultures showed that the mixed pesticides including methyl parathion, fenitrothion, chlorpyrifos, permethrin, fenpropathrin, and cypermethrin (0.2 mM each) were degraded completely within 48 h. The inoculation of engineered strain (10(6) cells/g) to soils treated with the above mixed pesticides resulted in a higher degradation rate than in noninoculated soils. All six pesticides could be degraded completely within 15 days in fumigated and nonfumigated soils with inoculation. Theses results highlight the potential of the engineered strain to be used for in situ bioremediation of soils co-contaminated with OP and pyrethroid pesticides. PMID- 25917650 TI - Antimicrobial Resistance and Multilocus Sequence Types of Finnish Campylobacter jejuni Isolates from Multiple Sources. AB - Antimicrobial susceptibility was determined for 805 domestic Campylobacter jejuni isolates obtained from broilers (n = 459), bovines (n = 120), human patients (n = 95), natural waters (n = 80), wild birds (n = 35) and zoo animals/enclosures (n = 16) with known multilocus sequence types (MLST) for 450 isolates. The minimum inhibitory concentration (MIC) values for erythromycin, tetracycline, streptomycin, gentamicin and the quinolones ciprofloxacin and nalidixic acid were determined with the VetMIC method. MICs were compared with MLST types to find possible associations between sequence type and resistance. The proportions of resistant isolates were 5% (broilers), 6.3% (natural waters), 11.4% (wild birds), 11.6% (human patients), 16.7% (bovines) and 31.3% (zoo). The most common resistance among the human and bovine isolates was quinolone resistance alone while resistance to streptomycin alone was most often detected among the broiler isolates and tetracycline resistance was most commonly observed in the wild bird, water and zoo isolates. No or negligible resistance to erythromycin or gentamicin was detected. In all data, 12/26 of the tetracycline-resistant isolates were also resistant to streptomycin (P < 0.001) and the clonal complex (CC) ST-1034 CC showed a high proportion of 75% (9/12) of tetracycline-resistant isolates, most originating from the zoo and broilers with closely associated MLST types from these sources. No association between quinolone resistance and MLST type was seen. The low percentage of resistant isolates among the domestic Campylobacter infections is most probably due to the long-term controlled use of antimicrobials. However, the higher percentage of tetracycline resistance observed among the zoo isolates could present a risk for zoo visitors of acquisition of resistant C. jejuni. The resistance pattern of tetracycline and streptomycin most often found in ST-1034 CC could indicate a common resistance acquisition mechanism commonly present in this CC. Overall, MLST typing was found to be a useful method in recognition of potential genetic lineages associated with resistance. PMID- 25917651 TI - Letter from Stockholm. AB - Some of the ideas of Sigmund Freud were preceded in a literary form by the Swedish writer August Strindberg in the late 19th century. Psychoanalysis itself was introduced in Sweden about a decade into the 20th century by two rivalling pioneers, the doctors Emanuel af Geijerstam and Poul Bjerre. After a slow start, the Danish-Norwegian Psychoanalytical Society and the Finnish-Swedish Psychoanalytical Society were formed in 1934 in Stockholm. The same year, Ericastiftelsen [The Erica Foundation], a psychotherapeutic clinic for children, was founded by Hanna Bratt. Five years later, in 1939, also in Stockholm, the organization that was to become St. Lukasstiftelsen [The Saint Luke's Foundation] was founded. It has been, and still is, an association that has trained psychodynamic psychotherapists, with a focus on existential, religious and philosophical questions. Today, St. Luke's tries to be up-dated from an academic standpoint. During the Second World War, several important psychoanalysts came to Sweden, for example Rene de Monchy, Lajos and Edith Szekely, and Stefi Pedersen. Ola Andersson's doctoral dissertation ("Studies in the Prehistory of Psychoanalysis", 1962) and the historian Gunnar Brandell's essay ("Freud, a Man of His Century", 1961) have had an international impact. In the last two decades, an authorized and carefully edited translation of Freud's collected works has been published by Natur och Kultur, and the history of psychoanalysis in Sweden has been written at the University of Gothenburg. As a result of a recent interest in the work of Jacques Lacan, and French psychoanalysis, philosophy and literature, the journal Psykoanalytisk Tid/Skrift was founded in 2002, in Gothenburg. Since 2011 the journal is called Arche. The largest organized group of psychoanalysts in Sweden today is the Swedish Psychoanalytical Association (SPAF), which has around 225 members. Since 2008, it no longer has the right to license psychotherapists, a situation which reflects the position of psychoanalysis outside the mainstream of psychiatric health services and academic psychology. Despite the criticism of Freud's thinking from biologically and cognitively oriented theoretical standpoints, the interest in psychoanalysis endures. PMID- 25917652 TI - Death drive, destructive drive and the desobjectalizing function in the analytic process. PMID- 25917653 TI - Classics from the laryngoscope. PMID- 25917654 TI - Free-floating endolymph particles: A new operative finding during posterior semicircular canal occlusion. 1992. PMID- 25917655 TI - Acute and Long-Term Outcomes of Catheter Ablation of Atrial Fibrillation Using the Second-Generation Cryoballoon versus Open-Irrigated Radiofrequency: A Multicenter Experience. AB - INTRODUCTION: There are limited comparative data on catheter ablation of atrial fibrillation (CAAF) using the second-generation cryoballoon (CB-2) versus point by-point radiofrequency (RF). This study examines the acute/long-term CAAF outcomes using these 2 strategies. METHODS AND RESULTS: In this multicenter, retrospective, nonrandomized analysis, procedural and clinical outcomes of 1,196 patients (76% with paroxysmal AF) undergoing CAAF using CB-2 (n = 773) and open irrigated, non-force sensing RF (n = 423) were evaluated. Pulmonary vein isolation was achieved in 98% with CB-2 and 99% with RF (P = 0.168). CB-2 was associated with shorter ablation time (40 +/- 14 min vs. 66 +/- 26 min; P < 0.001) and procedure time (145 +/- 49 minutes vs. 188 +/- 42 minutes; P < 0.001), but greater fluoroscopic utilization (29 +/- 13 minutes vs. 23 +/- 14 minutes; P < 0.001). While transient (7.6% vs. 0%; P < 0.001) and persistent (1.2% vs. 0%; P = 0.026) phrenic nerve palsy occurred exclusively with CB-2, other adverse event rates were similar between CB-2 (1.6%) and RF (2.6%); P = 0.207. However, freedom from AF/atrial flutter/tachycardia at 12 months following a single procedure without antiarrhythmic therapy was greater with CB-2 (76.6%) versus RF (60.4%); P < 0.001. While this difference was evident in patients with paroxysmal AF (P < 0.001), it did not reach significance in those with persistent AF (P = 0.089). Additionally, CB-2 was associated with reduced long-term need for antiarrhythmic therapy (16.7% vs. 22.0%; P = 0.024) and repeat ablations (14.6% vs. 24.1%; P < 0.001). CONCLUSION: In this multicenter, retrospective, nonrandomized study, CAAF using CB-2 coupled with RF as occasionally required was associated with greater freedom from atrial arrhythmias at 12 months following a single procedure without antiarrhythmic therapy when compared to open-irrigated, non-force sensing RF, alone. PMID- 25917656 TI - Different Measures, Different Outcomes? A Systematic Review of Performance-Based versus Self-Reported Measures of Health Literacy and Numeracy. AB - BACKGROUND: Health literacy (HL) and numeracy are measured by one of two methods: performance on objective tests or self-report of one's skills. Whether results from these methods differ in their relationship to health outcomes or use of health services is unknown. METHODS: We performed a systematic review to identify and evaluate articles that measured both performance-based and self-reported HL or numeracy and examined their relationship to health outcomes or health service use. To identify studies, we started with an AHRQ-funded systematic review of HL and health outcomes. We then looked for newer studies by searching MEDLINE from 1 February 2010 to 9 December 2014. We included English language studies meeting pre-specified criteria. Two reviewers independently assessed abstracts and studies for inclusion and graded study quality. One reviewer abstracted information from included studies while a second checked content for accuracy. RESULTS: We identified four "fair" quality studies that met inclusion criteria for our review. Two studies measuring HL found no differences between performance based and self-reported HL for association with self-reported outcomes (including diabetes, stroke, hypertension) or a physician-completed rheumatoid arthritis disease activity score. However, HL measures were differentially related to a patient-completed health assessment questionnaire and to a patient's ability to interpret their prescription medication name and dose from a medication bottle. Only one study measured numeracy and found no difference between performance based and self-reported measures of numeracy and colorectal cancer (CRC) screening utilization. However, in a moderator analysis from the same study, performance-based and self-reported numeracy were differentially related to CRC screening utilization when stratified by certain patient-provider communication behaviors (e.g., the chance to always ask questions and get the support that is needed). DISCUSSION: Most studies found no difference in the relationship between results of performance-based and self-reported measures and outcomes. However, we identified few studies using multiple instruments and/or objective outcomes. PMID- 25917658 TI - Maintaining Competence in General Internal Medicine. PMID- 25917657 TI - Statins and New-Onset Diabetes Mellitus and Diabetic Complications: A Retrospective Cohort Study of US Healthy Adults. AB - BACKGROUND: Statin use is associated with increased incidence of diabetes and possibly with increased body weight and reduced exercise capacity. Data on the long-term effects of these associations in healthy adults, however, are very limited. In addition, the relationship between these effects and diabetic complications has not been adequately studied. OBJECTIVE: To examine the association between statin use and new-onset diabetes, diabetic complications, and overweight/obesity in a cohort of healthy adults. RESEARCH DESIGN: This was a retrospective cohort study. PARTICIPANTS: Subjects were Tricare beneficiaries who were evaluated between October 1, 2003 and March 1, 2012. Patients were divided into statin users and nonusers. INTERVENTION: We excluded patients who, at baseline, had a preexisting disease indicative of cardiovascular diseases, any positive element of the Charlson comorbidity index (including diabetes mellitus), or life-limiting chronic diseases. Using 42 baseline characteristics, we generated a propensity score to match statin users and nonusers. MAIN MEASURES: Outcomes assessed included new-onset diabetes, diabetic complications, and overweight/obesity. KEY RESULTS: A total of 25,970 patients (3982 statin users and 21,988 nonusers) were identified as healthy adults at baseline. Of these, 3351 statins users and 3351 nonusers were propensity score-matched. Statin users had higher odds of new-onset diabetes (odds ratio [OR] 1.87; 95 % confidence interval [95 % CI] 1.67-2.01), diabetes with complications (OR 2.50; 95 % CI 1.88 3.32), and overweight/obesity (OR 1.14; 95 % CI 1.04-1.25). Secondary and sensitivity analyses demonstrated similar findings. CONCLUSIONS: Diabetes, diabetic complications, and overweight/obesity were more commonly diagnosed among statin-users than similar nonusers in a healthy cohort of adults. This study demonstrates that short-term clinical trials might not fully describe the risk/benefit of long-term statin use for primary prevention. PMID- 25917660 TI - Case Report: An Unusual Presentation of an Incomplete Sentence. PMID- 25917659 TI - The Relationship Between Food Insecurity and Depression, Diabetes Distress and Medication Adherence Among Low-Income Patients with Poorly-Controlled Diabetes. AB - BACKGROUND: Food insecurity- lack of dependable access to adequate food-may play a role in poor diabetes control. OBJECTIVE: We aimed to determine the relationship between food security status and depression, diabetes distress, medication adherence and glycemic control. DESIGN: Secondary analysis of baseline data from Peer Support for Achieving Independence in Diabetes, a randomized controlled trial that enrolled patients from November 2011 to October 2013. PARTICIPANTS: Participants had poorly controlled type 2 diabetes (A1c >= 8.0 % on eligibility screen), household income < 250 % of the federal poverty level, were 30-70 years old, and were recruited from a large public hospital, a VA medical center and a community-health center in King County, Washington. MAIN MEASURES: We measured food insecurity determined by the Department of Agriculture's 6-Item Food Security Module. Depression, diabetes distress and medication adherence measured by PHQ-8, Diabetes Distress Scale and Morisky Medication Adherence Scale, respectively. Diet was assessed through Summary of Diabetes Self-Care Activities and Starting the Conversation tool. Incidence of hypoglycemic episodes was by patient report. Glycemic control was assessed with glycosylated hemoglobin (A1c) values from fingerstick blood sample. KEY RESULTS: The prevalence of food insecurity was 47.4 %. Chi-square tests revealed participants with food insecurity were more likely to be depressed (40.7 % vs. 15.4 %, p < 0.001), report diabetes distress (55.2 % vs. 33.8 %, p < 0.001) and have low medication adherence (52.9 % vs. 37.2 %, p = 0.02). Based on linear regression modeling, those with food insecurity had significantly higher mean A1c levels (beta = 0.51; p = 0.02) after adjusting for sex, age, race/ethnicity, language, education, marital status, BMI, insulin use, depression, diabetes distress and low medication adherence. CONCLUSIONS: Almost half of participants had food insecurity. Food insecurity was associated with depression, diabetes distress, low medication adherence and worse glycemic control. Even with adjustment, people with food insecurity had higher mean A1c levels than their food-secure counterparts, suggesting there may be other mediating factors, such as diet, that explain the relationship between food security status and diabetes control. PMID- 25917661 TI - Solving Summer Fever in Early Pregnancy. PMID- 25917662 TI - Don't Believe Everything You Think. PMID- 25917663 TI - Prevalence and Severity of Dysphonia in Patients with Cystic Fibrosis: A Pilot Study. AB - OBJECTIVE: To assess the prevalence and severity of dysphonia in patients with cystic fibrosis sinusitis. We hypothesized that patients with CF sinusitis, compared with 2 control groups, would have higher self-reported prevalence of dysphonia and greater severity of dysphonia, according to patient-reported outcome measures as well as auditory-perceptual evaluation by expert listeners. STUDY DESIGN: Cross-sectional comparative pilot study. SETTING: Academic tertiary care clinic. STUDY PARTICIPANTS AND METHODS: Analysis included 37 study participants: 17 patients with CF sinusitis, 10 healthy individuals, and 10 patients with non-CF sinusitis. All participants completed the 10-item Voice Handicap Index (VHI-10) questionnaire and provided voice samples. On all samples, 6 blinded speech-language pathologists independently performed auditory perceptual evaluation, using Consensus Auditory-Perceptual Evaluation of Voice. To assess severity of sinonasal symptoms, we used the 20-item Sinonasal Outcome Test (SNOT-20). Standard parametric and nonparametric statistical analysis was performed. RESULTS: The differences between the 3 groups in prevalence of abnormal VHI-10 scores were not statistically significant. SNOT-20 scores were similar in the 2 sinusitis patient groups. VHI-10 scores were highest in patients with CF sinusitis, intermediate in patients with non-CF sinusitis, and lowest in healthy individuals (P = .005). Auditory-perceptual evaluation demonstrated greater overall severity of dysphonia in patients with CF sinusitis compared with the 2 control groups (P = .0005). CONCLUSIONS: Cystic fibrosis sinusitis appeared to be associated with worse vocal function as measured by patient self-report as well as auditory-perceptual evaluation of voice compared with patients with non CF sinusitis and healthy controls. Further investigation in this area is warranted. PMID- 25917664 TI - Laryngeal Papillary Squamous Cell Carcinoma: A Population-Based Analysis of Incidence and Survival. AB - OBJECTIVE: Papillary squamous cell carcinoma has emerged as a distinct entity from the more common keratinizing squamous cell carcinoma. The basis behind this distinction relates not only to its histologic variation but also to its overall prognosis and survival. The objective of this study was to demonstrate the incidence, demographics, and long-term survival of laryngeal papillary squamous cell carcinoma (LPSCC) and how it relates to other laryngeal malignancies using a population-based database. STUDY DESIGN: Analysis of a population-based tumor registry. METHODS: The United States National Cancer Institute's Surveillance, Epidemiology, and End Results registry was used to perform a retrospective analysis. Patients diagnosed with LPSCC from 1973 to 2011 were identified. Data endpoints extracted included patient demographics, incidence, and survival. RESULTS: Three-hundred seventy cases of LPSCC were identified, corresponding to 0.5% of all laryngeal tumors. There was a 3:1 male predilection, without a significant racial preference. Most tumors identified were localized (T1) and at stage 1. The 1-year, 5-year, and 10-year disease-specific survival (DSS) for LPSCC was 97.1%, 83.1%, and 73.9%, respectively, compared with 87.9%, 64.5%, and 50.5% for other laryngeal malignancies (P values <.0001). Surgery was associated with a higher overall DSS in both LPSCC (87.4% vs 78.8%) and other laryngeal malignancies (70% vs 59.4%) when compared with other treatment modalities. CONCLUSION: This analysis of the largest sample of LPSCC demonstrates a better prognosis for this pathology compared with other laryngeal malignancies. PMID- 25917665 TI - Oropharyngeal Contamination Predisposes to Complications after Neck Dissection: An Analysis of 9462 Patients. AB - OBJECTIVE: While neck dissection is important in the treatment of head and neck cancer, there is a paucity of studies evaluating outcomes. We sought to compare preoperative variables and outcomes between clean and contaminated neck dissections, using the 2006-2011 American College of Surgeons National Surgical Quality Improvement Program (ACS NSQIP) data sets. STUDY DESIGN: Retrospective review of prospectively maintained database. SETTING: Multicenter (university hospitals; tertiary referral centers). SUBJECTS AND METHODS: A retrospective review was performed of the NSQIP database to identify patients undergoing neck dissection in clean vs oropharyngeal contaminated cases. Clinical factors, comorbidities, epidemiologic factors, and procedural characteristics were analyzed to identify factors associated with 30-day postoperative adverse events, including medical and surgical complications, unplanned reoperation, and mortality. Bivariate and multivariable analyses were performed for the outcome of one or more adverse events. RESULTS: In total, 8890 patients had clean neck dissections, while 572 patients had neck wound contamination with oropharyngeal flora. On multivariable regression analysis, oropharyngeal contamination was a significant risk factor for surgical complications (odds ratio [OR], 3.42; 95% confidence interval [CI], 1.96-5.96; P < .001). However, medical complications and mortality were not significantly different between the 2 cohorts. This finding persisted after subgroup analysis, with removal of all thyroidectomy patients from analysis (OR, 2.33; 95% CI, 1.25-4.36; P = .008). CONCLUSION: Using the ACS-NSQIP data set, this study found an increased risk of surgical complications in the setting of contaminated neck dissections. These data should be used for patient risk stratification, informed consent, and to guide further research. PMID- 25917666 TI - Conventional and 3-Dimensional Computerized Tomography in Eagle's Syndrome, Glossopharyngeal Neuralgia, and Asymptomatic Controls. AB - OBJECTIVE: Eagle's syndrome (ES) is an aggregate of symptoms, including recurrent throat pain, foreign body sensation, dysphagia, or facial pain related to an elongated styloid process (SP). It resembles glossopharyngeal neuralgia and has been linked to irritation of the glossopharyngeal nerve. This study was designed to determine whether computerized tomography (CT) imaging of the stylohyoid chain (SHC) differs between asymptomatic controls (ACs), patients with glossopharyngeal neuralgia (GN), and patients with ES. STUDY DESIGN: Case series with chart review. SETTING: Tertiary otolaryngology practice. SUBJECTS AND METHODS: Conventional and 3-dimensional CT reconstructions of the SHC were reviewed for 10 ES, 17 GN, and 30 AC patients. Demographic and clinical symptom data were recorded. Anatomic data collected from CT scans included length of the ossified SP, anterior-posterior and medial-lateral styloid process angulation, ossification pattern of the SHC, and minimum distances between the SP tip, the internal carotid artery, and the tonsillar fossa. RESULTS: The average distance from the SP tip to the tonsillar fossa was significantly shorter in ES (12.7 mm) compared with GN (21.4 mm; P = .027) or AC (24.8 mm; P < .0005) patients. No other variables were significantly different between groups, including average SP length (ES: 48.0 vs GN: 40.3 vs AC: 40 mm; P > .05). CONCLUSION: The SP was significantly closer to the tonsillar fossa in patients with ES compared with ACs. No significant differences were found in other measures. Distance to the tonsillar fossa may be a more appropriate diagnostic criterion for ES than SP length and may contribute to the pathophysiology of ES. PMID- 25917667 TI - High TPOAb Levels (>1300 IU/mL) Indicate Multifocal PTC in Hashimoto's Thyroiditis Patients and Support Total Thyroidectomy. AB - OBJECTIVE: We aimed to identify whether thyroid peroxidase antibodies (TPOAb) are indicative of multifocal papillary thyroid cancer (PTC) in Hashimoto's thyroiditis (HT) patients and may help to determine necessity for total thyroidectomy. STUDY DESIGN: Retrospective cohort study. SETTING: Teaching hospital. SUBJECTS: A total of 808 consecutive patients with HT alone or with HT and unifocal or multifocal PTC were included. METHODS: Preoperative thyroid function tests, TPOAb determination, preoperative ultrasonography, intraoperative frozen biopsy, and postoperative routine pathologic examination to confirm thyroid nodules were performed for all patients. Patients with nodules or malignancy potential on ultrasound and fine-needle aspiration cytology were included. Patients with hyperthyroidism, concomitant chronic disease, a history of other malignant tumors, or history of major diseases were excluded. All patients underwent surgery, and HT and PTC were confirmed by postoperative pathologic results. RESULTS: No significant differences were found in age and sex between groups (P > .05). TPOAb <=1300 IU/mL were more prevalent in the HT + unifocal PTC group than in the other groups (99.57% vs 15.52% and 60.75%, P < .001). TPOAb >1300 IU/mL were more prevalent in the HT + multifocal PTC group than in the other groups (84.48% vs 0.43% and 39.25%; P < .001). Compared to the other groups, the HT + multifocal PTC group had higher percentages of patients with elevated thyroid-stimulating hormone and positive central lymph node (LN) metastasis (elevated thyroid-stimulating hormone: 8.7% vs 3.2% and 6.5%, P = .008; positive central LN metastasis: 74.57% vs 67.38% and 0%, P < .001). CONCLUSION: High TPOAb levels (>1300 IU/mL) are definitive indicators of multifocal PTC in HT patients, which may support surgical treatment with total thyroidectomy. PMID- 25917668 TI - Jet Fuel Burn of the Ear. PMID- 25917669 TI - Robust Differences in p16-Dependent Oropharyngeal Squamous Cell Carcinoma Distant Metastasis: Implications for Targeted Therapy. AB - OBJECTIVE: Historically, head and neck squamous cell carcinoma (HNSCC) has been earmarked a lymphatic malignancy. Recently, this has been called into question. Our study aims to (1) illustrate the robust differences in distant metastases between p16+ and p16- oropharyngeal squamous cell carcinoma (OPSCC) and (2) provide support that p16+ OPSCC has a predilection toward vasculature invasion and hematogenous spread. STUDY DESIGN: Multi-institutional, case series with chart review. SETTING: Four academic institutions. SUBJECTS AND METHODS: Within a group of 1113 patients with primary OPSCC who received treatment between 1979 and 2013, those who developed distant metastasis (DM) were divided into 2 cohorts based on p16 status. Intergroup and intragroup univariate analysis was performed as well as descriptive analysis of end-organ sites. RESULTS: Of the 1058 patients included, 89 developed DM. Thirty were p16- and 59 were p16+. Of the p16- patients with DM, only 10% had disseminated disease (distant metastases at >=2 sites) compared with 74% of p16+ patients. Distant disease in p16+ patients included brain, abdomen, and a distinct pattern of pulmonary metastases. CONCLUSION: Our large, multi-institutional study supports published reports that p16+ OPSCC metastasizes with a unique phenotype that is hematogenous and widely disseminated with atypical end-organ sites. Our data suggest that p16+ OPSCC has a predilection toward active vasculature invasion as evidenced by the results and illustrative radiologic and pathohistologic examples. These findings may have implications for future targeted therapy when treating p16+ OPSCC. PMID- 25917670 TI - Comparison of Socioeconomic and Demographic Factors in Patients with Chronic Rhinosinusitis and Allergic Fungal Rhinosinusitis. AB - OBJECTIVE: The primary objective of this study is to evaluate the differences in socioeconomic, demographic, and disease severity factors between patients with chronic rhinosinusitis (CRS) and those with allergic fungal rhinosinusitis (AFRS). STUDY DESIGN: A retrospective cohort analysis was performed. SETTING: The study was conducted at the hospital of the University of North Carolina at Chapel Hill. SUBJECTS AND METHODS: A total of 186 patients were included (93 AFRS, 93 CRS with and without nasal polyps). Socio- economic and demographic data were obtained from the North Carolina State Data Center. Indicators of disease severity were measured by Lund-Mackay scores, serum immunoglobulin E (IgE) levels, diagnosis of asthma and/or allergic rhinitis, and the number of surgeries and computed tomography scans performed. Associations were analyzed with Fisher's exact, Wilcoxon rank sum, and Pearson's correlations tests. RESULTS: Compared with patients with AFRS, patients in both CRS groups were predominantly white (P < .0001), were older at the time of diagnosis (P < .0001), had higher county based income per capita (P = .004), had lower quantitative serum IgE level (P < .001), and had lower Lund-Mackay scores (P < .0001). No associations between disease severity, socioeconomic status, and demographic factors were found within the CRS groups. CONCLUSION: Within our cohort of patients residing in North Carolina, those with CRS have higher income, more access to primary care, and lower markers of disease severity than those with AFRS. These data continue to support the notion that AFRS merits classification as a distinct subtype of CRS. PMID- 25917671 TI - KALRN Rare and Common Variants and Susceptibility to Ischemic Stroke in Chinese Han Population. AB - Stroke is the second most common cause of mortality worldwide, and it is a major cause of physical disability. Several genome-wide association studies have yielded numerous common variants which increase the risk of ischemic stroke, including the Kalirin-coding gene, KALRN. KALRN strongly associates with early onset coronary artery disease and atherosclerosis and plays an important role in stroke in the European population. In this study, we analyzed four KALRN gene SNPs in 503 ischemic stroke patients and 493 control subjects, separating the patients into separate research groups based on comorbidity with hypertension or diabetes and stroke type (atherosis or lacunar and combination type). We found a rare variant of KALRN, rs11712619, that associated with lacunar stroke in the northern Chinese Han population with an average-risk allele frequency 0.009 (OR 2.95, 95 % CI 1.08-8.01, p = 0.028). However, after adjusting for relevant factors, including sex, age, body mass index, dyslipidemia, alcohol consumption, and smoking, this association was not evident. Additionally, the KALRN variant rs6438833 was associated with ischemic stroke, ischemic stroke comorbid with diabetes, and lacunar stroke after adjusting for the relevant factors (p = 0.046, p = 0.019 and p = 0.046, respectively), which remained significant after 10,000 permutation procedure test (p' = 0.047, p' = 0.018 and p' = 0.048, respectively). The association of these rare and common variants of KALRN with ischemic stroke in northern Chinese Han population offers insight for potential therapeutic research. PMID- 25917672 TI - Methods and challenges in measuring the impact of national pneumococcal and rotavirus vaccine introduction on morbidity and mortality in Malawi. AB - BACKGROUND: Pneumonia and gastroenteritis are leading causes of vaccine preventable childhood morbidity and mortality. Malawi introduced pneumococcal conjugate and rotavirus vaccines to the immunisation programme in 2011 and 2012, respectively. Evaluating their effectiveness is vital to ensure optimal implementation and justify sustained investment. METHODS/DESIGN: A national evaluation platform was established to determine vaccine effectiveness and impact in Malawi. Impact and effectiveness against vaccine-type invasive pneumococcal disease, radiological pneumonia and rotavirus gastroenteritis are investigated using before-after incidence comparisons and case-control designs, respectively. Mortality is assessed using a prospective population cohort. Cost-effectiveness evaluation is nested within the case-control studies. We describe platform characteristics including strengths and weaknesses for conducting vaccine evaluations. DISCUSSION: Integrating data from individual level and ecological methods across multiple sites provides comprehensive information for policymakers on programme impact and vaccine effectiveness including changes in serotype/genotype distribution over time. Challenges to robust vaccine evaluation in real-world conditions include: vaccination ascertainment; pre-existing rapid decline in mortality and pneumococcal disease in the context of non-vaccine interventions; and the maintenance of completeness and quality of reporting at scale and over time. In observational non-randomised designs ascertainment of vaccine status may be biased particularly in infants with fatal outcomes. In the context of multiple population level interventions targeting study endpoints attribution of reduced incidence to vaccine impact may be flawed. Providing evidence from several independent but complementary studies will provide the greatest confidence in assigning impact. Welcome declines in disease incidence and in child mortality make accrual of required sample sizes difficult, necessitating large studies to detect the relatively small but potentially significant contribution of vaccines to mortality prevention. Careful evaluation of vaccine effectiveness and impact in such settings is critical to sustaining support for vaccine programmes. Our evaluation platform covers a large population with a high prevalence of HIV and malnutrition and its findings will be relevant to other settings in sub-Saharan Africa. PMID- 25917673 TI - Immunogenicity of poliovirus vaccines in chronically malnourished infants: a randomized controlled trial in Pakistan. AB - Reaching high population immunity against polioviruses (PV) is essential to achieving global polio eradication. Efficacy of oral poliovirus vaccine (OPV) varies and is lower among children living in tropical areas with impoverished environments. Malnutrition found as a risk factor for lower serological protection against PV. We compared whether inactivated polio vaccine (IPV) can be used to rapidly close the immunity gap among chronically malnourished (stunted) infants in Pakistan who will not be eligible for the 14 week IPV dose in routine EPI schedule. A phase 3, multicenter 4-arm randomized controlled trial conducted at five Primary Health Care (PHC) centers in Karachi, Pakistan. Infants, 9-12 months were stratified by length for age Z score into chronically malnourished and normally nourished. Infants were randomized to receive one dose of either bivalent OPV (bOPV) alone or bOPV+IPV. Baseline seroprevalence of PV antibodies and serum immune response to study vaccine dose were assessed by neutralization assay. Vaccine PV shedding in stool was evaluated 7 days after a bOPV challenge dose. Sera and stool were analyzed from 852/928 (92%) enrolled children. At baseline, the seroprevalence was 85.6% (n=386), 73.6% (n=332), and 70.7% (n=319) in malnourished children against PV types 1, 2 and 3 respectively; and 94.1% (n=448), 87.0% (n=441) and 83.6% (n=397) in the normally nourished group (p<0.05). Children had previously received 9-10 doses of bOPV (80%) or tOPV (20%). One dose of IPV+bOPV given to malnourished children increased their serological protection (PV1, n=201, 97.6%; PV2, n=198, 96.1% and PV3, n=189, 91.7%) to parity with normally nourished children who had not received IPV (p=<0.001). Seroconversion and boosting for all three serotypes was significantly more frequent in children who received IPV+bOPV than in those with bOPV only (p<0.001) in both strata. Shedding of polioviruses in stool did not differ between study groups and ranged from 2.4% (n=5) to 7.1% (n=15). In malnourished children the shedding was reduced after bOPV+IPV compared to bOPV only. Chronically malnourished infants were more likely to be unprotected against polioviruses than normal infants. bOPV+IPV helped close the immunity gap better than bOPV alone. PMID- 25917674 TI - A randomized trial of rotavirus vaccine versus sucrose solution for vaccine injection pain. AB - OBJECTIVE: Sucrose solutions are analgesic in infants. Oral rotavirus vaccine contains sucrose, however, it is not known if it possesses analgesic properties. The objective was to compare the analgesic effectiveness of rotavirus vaccine to sucrose solution when administered prior to injectable vaccines. METHODS: Infants 2-4 months of age receiving oral rotavirus vaccine and two separate injectable vaccines on the same day were randomized to rotavirus vaccine (Rotarix) first followed by the injectable vaccines and sucrose (Tootsweet) afterwards, or vice versa. Pain was assessed by blinded raters using the Numerical Rating Scale (NRS, range 0-10) (parents, clinicians), or Modified Behavioural Pain Scale (MBPS, range 0-10) and cry duration (observers). Data were analyzed using t-tests or chi(2)-tests; Bonferroni correction was applied to correct for multiple comparisons, as appropriate. RESULTS: Altogether, 120 infants participated: 60 were randomized to rotavirus vaccine first. Groups did not differ in demographics, including; age (p=0.448) and sex (p=0.464). The mean pain score (standard deviation) for both vaccine injections did not differ between infants given rotavirus vaccine first versus sucrose solution first: observer MBPS, parent NRS and clinician NRS scores were 7.4 (1.6) vs. 7.7 (1.6), 4.9 (2.1) vs. 5.8 (2.1), and 4.2 (2.1) vs. 4.6 (2.2), respectively. Similarly, there was no difference between groups in cry duration. CONCLUSION: Rotavirus vaccine did not differ from sucrose solution in reducing injection-induced pain. Based on the findings, it is recommended that rotavirus vaccine be administered prior to injectable vaccines in infants aged 2 and 4 months. PMID- 25917675 TI - Exploring immunological mechanisms of the whole sporozoite vaccination against P. falciparum malaria. AB - Great progress has been made in the development of whole sporozoite vaccines including the manufacturing of cryopreserved Plasmodium falciparum sporozoites (PfSPZ) suitable for clinical application. Such whole sporozoites are being used for clinical studies of controlled human malaria infection (CHMI) as well as for evaluation of candidate vaccine approaches (both attenuated sporozoites and infectious sporozoites administered with chemoprophylaxis) and as reagents for immunology and cell biology assays. CHMI studies with whole sporozoites provide a great opportunity to better understand the intrinsic mechanisms of resistance to P. falciparum (e.g. due to sickle cell trait and other hemoglobinopathies) as well as host responses to an initial P. falciparum infection. High-level protective efficacy has been demonstrated in a small number of volunteers after intravenous (IV) inoculation of radiation-attenuated PfSPZ or in those who were exposed to live PfSPZ while on malaria chemoprophylaxis. These advances and data warrant further investigations of the immunological mechanism(s) whereby whole sporozoite inoculation elicits protective immunity in order to facilitate whole sporozoite vaccine development. The National Institute of Allergy and Infectious Diseases (NIAID) convened a workshop on Sept. 2-3, 2014 involving participation of international experts in the field of malaria vaccine development, and in basic and clinical immunology research. The workshop discussed the current understanding of host immune responses to whole malaria sporozoite inoculation, identified gaps in knowledge, resources to facilitate progress, and applicable new technologies and approaches to accelerate immunologic and vaccinologic studies and biomarker identification. This report summarizes the discussions and major conclusions from the workshop participants. PMID- 25917676 TI - BclA and toxin antigens augment each other to protect NMRI mice from lethal Bacillus anthracis challenge. AB - While proving highly effective in controlling Anthrax in farm animals all over the world currently attenuated live anthrax vaccines employed in a veterinary context suffer from drawbacks such as residual virulence, short term protection, variation in quality and, most importantly, lack of efficacy if administered simultaneously with antibiotics. These limitations have stimulated the development of non-living component vaccines which induce a broad spectrum immune response capable of targeting both toxaemia (as in the case of PA based vaccines) and bacteraemia. To contribute to this several new approaches were tested in outbred NMRI mice for antibody titres and protectiveness. Plasmids encoding a recombinant toxin derived fusion peptide and a spore surface derived peptide were tested as DNA-vaccines in comparison to their protein counterparts utilising two adjuvant approaches and two DNA-vector backbones. The combination of two plasmids encoding LFD1PAD4-mIPS1 and TPA-BclAD1D3-LAMP1, when delivered by GeneGun, protected 90% of the animals against a lethal challenge with 25LD50 spores of the Ames strain of Bacillus anthracis. Single applications of either antigen component showed significantly lower protection rates, indicating the beneficial interaction between anti-spore and anti-toxin components for an acellular vaccine formulation. PMID- 25917677 TI - Efficacy of a high potency O1 Manisa monovalent vaccine against heterologous challenge with a FMDV O Mya98 lineage virus in pigs 4 and 7 days post vaccination. AB - Early protection with a high potency (>6PD50) foot-and-mouth disease (FMD) O1 Manisa (Middle-East South Asia lineage) vaccine against challenge with O/VIT/2010 (O Mya98 lineage) was tested in pigs. Only two pigs that were vaccinated seven days prior to challenge had any demonstrable antibodies as a result of vaccination at the time of challenge. However, 80% and 60% of pigs that were vaccinated seven and four days prior to coronary band challenge were protected. Vaccination significantly reduced the amount of virus excreted in nasal swabs, saliva and faeces compared to unvaccinated and infected controls. Virus and viral RNA could be detected in some pigs until termination of the experiment 14 days after challenge. Antibodies to the non-structural proteins (NSP) were detected in only one pig that was challenged four days post vaccination (dpv) and transiently in two pigs that were challenged sevendpv at only one time point. For each vaccine and control group, a group of unvaccinated pigs were kept in the same room but with no direct contact with the infected pigs to determine whether vaccination prevented transmission. Despite the presence of live virus and viral RNA in these indirect contact pigs, the groups in contact with the vaccinated and infected pigs did not develop clinical signs nor did they sero-convert. Contact pigs in the same room as unvaccinated challenged controls did show signs of disease and virus infection that resulted in sero-conversion to the NSP. A breach of the wall that separated the two groups at nine days post challenge might have contributed to this finding. This study showed that high potency vaccine can provide protection to pigs soon after vaccination and that aerosol transmission within rooms is a rare event. PMID- 25917678 TI - Dynamics of antigen delivery and the functional roles of L121-adjuvant. AB - This study investigates the intracellular transport of protein antigens facilitated by L121-adjuvants and examines the associated cytotoxic T lymphocyte (CTL) effect. EL4 mouse thymoma cells were treated with L121-adjuvant and stained with AnnexinV-propidium iodide (PI) followed by flow cytometric analysis. The intracellular trafficking dynamics of bovine serum albumin (BSA)-FITC in the J774.A.1 macrophages, influenced by the L121-adjuvant, was visualized by confocal microscopy. The antigen-specific cytotoxic T lymphocyte (CTL) effect induced by the L121-adjuvant was determined by the cleavage-specific fluorogenic caspase substrate. The trafficking of BSA-FITC in the J774A.1 cells by confocal microscopy illustrated that the L121-adjuvant facilitated the intracellular transport of proteins to the subcellular compartments, including the lysosome, endoplasmic reticulum (ER), and the cis-Golgi apparatus. The L121-adjuvant also facilitated antigen delivery to the dendritic cells in the lymph nodes. Immunization of mice with the L121-adjuvant resulted in cell-mediated cytotoxic responses in the target cells, as detected by PhiPhiLux, a fluorogenic caspase substrate. Taken together, the L121-adjuvant improved the dynamics of protein delivery to antigen presenting cells, and also induced caspase activation, thereby illustrating the mechanism of antigen-specific CTL effects. PMID- 25917679 TI - Skin vaccination with live virus vectored microneedle arrays induce long lived CD8(+) T cell memory. AB - A simple dissolvable microneedle array (MA) platform has emerged as a promising technology for vaccine delivery, due to needle-free injection with a formulation that preserves the immunogenicity of live viral vectored vaccines dried in the MA matrix. While recent studies have focused largely on design parameters optimized to induce primary CD8(+) T cell responses, the hallmark of a vaccine is synonymous with engendering long-lasting memory. Here, we address the capacity of dried MA vaccination to programme phenotypic markers indicative of effector/memory CD8(+) T cell subsets and also responsiveness to recall antigen benchmarked against conventional intradermal (ID) injection. We show that despite a slightly lower frequency of dividing T cell receptor transgenic CD8(+) T cells in secondary lymphoid tissue at an early time point, the absolute number of CD8(+) T cells expressing an effector memory (CD62L(-)CD127(+)) and central memory (CD62L(+)CD127(+)) phenotype during peak expansion were comparable after MA and ID vaccination with a recombinant human adenovirus type 5 vector (AdHu5) encoding HIV-1 gag. Similarly, both vaccination routes generated CD8(+) memory T cell subsets detected in draining LNs for at least two years post-vaccination capable of responding to secondary antigen. These data suggest that CD8(+) T cell effector/memory generation and long-term memory is largely unaffected by physical differences in vaccine delivery to the skin via dried MA or ID suspension. PMID- 25917680 TI - Safety of Russian-backbone seasonal trivalent, live-attenuated influenza vaccine in a phase II randomized placebo-controlled clinical trial among children in urban Bangladesh. AB - INTRODUCTION: Live-attenuated influenza vaccines (LAIVs) have the potential to be affordable, effective, and logistically feasible for immunization of children in low-resource settings. MATERIAL AND METHODS: We conducted a phase II, randomized, double-blind, parallel group, placebo-controlled trial on the safety of the Russian-backbone, seasonal trivalent LAIV among children aged 24 through 59 months in Dhaka, Bangladesh in 2012. After vaccination, we monitored participants for six months with weekly home visits and study clinic surveillance for solicited and unsolicited adverse events, protocol-defined wheezing illness (PDWI), and serious adverse events (SAEs), including all cause hospitalizations. RESULTS: Three hundred children were randomized and administered LAIV (n=150) or placebo (n=150). No immediate post-vaccination reactions occurred in either group. Solicited reactions were similar between vaccine and placebo groups during the first 7 days post-vaccination and throughout the entire trial. There were no statistically significant differences in participants experiencing PDWI between LAIV and placebo groups throughout the trial (n=13 vs. n=16, p=0.697). Of 131 children with a history of medical treatment or hospitalization for asthma or wheezing at study entry, 65 received LAIV and 66 received placebo. Among this subset, there was no statistical difference in PDWI occurring throughout the trial between the LAIV or placebo groups (7.7% vs. 19.7%, p=0.074). While there were no related SAEs, LAIV recipients had six unrelated SAEs and placebo recipients had none. These SAEs included three due to traumatic injury and bone fracture, and one each due to accidental overdose of paracetamol, abdominal pain, and acute gastroenteritis. None of the participants with SAEs had laboratory confirmed influenza, wheezing illness, or other signs of acute respiratory illness at the time of their events. CONCLUSIONS: In this randomized, controlled trial among 300 children aged 24 through 59 months in urban Bangladesh, Russian backbone LAIV was safe and well tolerated. Further evaluation of LAIV safety and efficacy in a larger cohort is warranted. PMID- 25917681 TI - Focused human gene expression profiling using dual-color reverse transcriptase multiplex ligation-dependent probe amplification. AB - To investigate the human immune response to newly developed or existing vaccines, or during infection/disease on a population scale, we have recently developed a dual-color Reverse Transcriptase Multiplex Ligation-dependent Probe Amplification (dcRT-MLPA) assay, which can rapidly profile mRNA expression of multiple host genes. dcRT-MLPA has a dynamic range and sensitivity comparable to real-time QPCR and RNA-Sequencing. Since this assay is high-throughput, it is an exceptionally suitable technique for monitoring host biomarkers in semi-large scale human cohorts, such as cross sectional studies with multiple groups, or longitudinal studies with multiple time points. Multicomponent host biomarker signatures with excellent predictive values can easily be identified using lasso regression analysis, while exploring additional data adjustment methods like RUV-2 may further optimize the identification of informative host biomarker signatures. dcRT-MLPA also allows comparisons of gene expression patterns across different human populations to explore the impact of geographical diversity on for example vaccine induced responses. The use of dcRT-MLPA is not limited to peripheral blood but can be adapted to analyze host biomarkers derived from any tissue or body fluids, further demonstrating the versatility of the dcRT-MLPA platform. Several examples will be given and discussed. PMID- 25917682 TI - Directional Trans-Synaptic Labeling of Specific Neuronal Connections in Live Animals. AB - Understanding animal behavior and development requires visualization and analysis of their synaptic connectivity, but existing methods are laborious or may not depend on trans-synaptic interactions. Here we describe a transgenic approach for in vivo labeling of specific connections in Caenorhabditis elegans, which we term iBLINC. The method is based on BLINC (Biotin Labeling of INtercellular Contacts) and involves trans-synaptic enzymatic transfer of biotin by the Escherichia coli biotin ligase BirA onto an acceptor peptide. A BirA fusion with the presynaptic cell adhesion molecule NRX-1/neurexin is expressed presynaptically, whereas a fusion between the acceptor peptide and the postsynaptic protein NLG-1/neuroligin is expressed postsynaptically. The biotinylated acceptor peptide::NLG 1/neuroligin fusion is detected by a monomeric streptavidin::fluorescent protein fusion transgenically secreted into the extracellular space. Physical contact between neurons is insufficient to create a fluorescent signal, suggesting that synapse formation is required. The labeling approach appears to capture the directionality of synaptic connections, and quantitative analyses of synapse patterns display excellent concordance with electron micrograph reconstructions. Experiments using photoconvertible fluorescent proteins suggest that the method can be utilized for studies of protein dynamics at the synapse. Applying this technique, we find connectivity patterns of defined connections to vary across a population of wild-type animals. In aging animals, specific segments of synaptic connections are more susceptible to decline than others, consistent with dedicated mechanisms of synaptic maintenance. Collectively, we have developed an enzyme-based, trans-synaptic labeling method that allows high-resolution analyses of synaptic connectivity as well as protein dynamics at specific synapses of live animals. PMID- 25917684 TI - The performance of fine-grained and coarse-grained elastic network models and its dependence on various factors. AB - In a recent work we developed a method for deriving accurate simplified models that capture the essentials of conventional all-atom NMA and identified two best simplified models: ssNMA and eANM, both of which have a significantly higher correlation with NMA in mean square fluctuation calculations than existing elastic network models such as ANM and ANMr2, a variant of ANM that uses the inverse of the squared separation distances as spring constants. Here, we examine closely how the performance of these elastic network models depends on various factors, namely, the presence of hydrogen atoms in the model, the quality of input structures, and the effect of crystal packing. The study reveals the strengths and limitations of these models. Our results indicate that ssNMA and eANM are the best fine-grained elastic network models but their performance is sensitive to the quality of input structures. When the quality of input structures is poor, ANMr2 is a good alternative for computing mean-square fluctuations while ANM model is a good alternative for obtaining normal modes. PMID- 25917683 TI - COGNITION-CHILDHOOD MALTREATMENT INTERACTIONS IN THE PREDICTION OF ANTIDEPRESSANT OUTCOMES IN MAJOR DEPRESSIVE DISORDER PATIENTS: RESULTS FROM THE iSPOT-D TRIAL. AB - BACKGROUND: Childhood maltreatment (CM) history has been associated with poor treatment response in major depressive disorder (MDD), but the mechanisms underlying this relationship remain opaque. Dysfunction in the neural circuits for executive cognition is a putative neurobiological consequence of CM that may contribute importantly to adverse clinical outcomes. We used behavioral and neuroimaging measures of executive functioning to assess their contribution to the relationship between CM and antidepressant response in MDD patients. METHODS: Ninety eight medication-free MDD outpatients participating in the International Study to Predict Optimized Treatment in Depression were assessed at baseline on behavioral neurocognitive measures and functional magnetic resonance imaging during tasks probing working memory (continuous performance task, CPT) and inhibition (Go/No-go). Seventy seven patients completed 8 weeks of antidepressant treatment. Baseline behavioral and neuroimaging measures were assessed in relation to CM (history of childhood physical, sexual, and/or emotional abuse) and posttreatment depression outcomes. RESULTS: Patients with maltreatment exhibited decreased modulation of right dorsolateral prefrontal cortex (DLPFC) activity during working memory updating on the CPT, and a corresponding impairment in CPT behavioral performance outside the scanner. No between-group differences were found for imaging or behavior on the Go/No-go test of inhibition. Greater DLPFC activity during CPT significantly predicted posttreatment symptom improvement in patients without maltreatment, whereas the relationship between DLPFC activity and symptom change was nonsignificant, and in the opposite direction, in patients with maltreatment. CONCLUSIONS: The effect of CM on prefrontal circuitry involved in executive function is a potential predictor of antidepressant outcomes. PMID- 25917686 TI - The Value of Productivity in Health Policy. PMID- 25917685 TI - Clinical Practice Variation Needs to be Considered in Cost-Effectiveness Analyses: A Case Study of Patients with a Recent Transient Ischemic Attack or Minor Ischemic Stroke. AB - BACKGROUND AND OBJECTIVE: The cost-effectiveness of clinical interventions is often assessed using current care as the comparator, with national guidelines as a proxy. However, this comparison is inadequate when clinical practice differs from guidelines, or when clinical practice differs between hospitals. We examined the degree of variation in the way patients with a recent transient ischemic attack (TIA) or minor ischemic stroke are assessed and used the results to illustrate the importance of investigating possible clinical practice variation, and the need to perform hospital-level cost-effectiveness analyses (CEAs) when variation exists. METHODS: Semi-structured interviews were conducted with 16 vascular neurologists in hospitals throughout the Netherlands. Questions were asked about the use of initial and confirmatory diagnostic imaging tests to assess carotid stenosis in patients with a recent TIA or minor ischemic stroke, criteria to perform confirmatory tests, and criteria for treatment. We also performed hospital-level CEAs to illustrate the consequences of the observed diagnostic strategies in which the diagnostic test costs, sensitivity and specified were varied according to the local hospital conditions. RESULTS: 56 % (9/16) of the emergency units and 63 % (10/16) of the outpatient clinics use the initial and confirmatory diagnostic tests to assess carotid stenosis in accordance with the national guidelines. Of the hospitals studied, only one uses the recommended criteria for use of a confirmatory test, 38 % (6/16) follow the guidelines for treatment. The most cost-effective diagnostic test strategy differs between hospitals. CONCLUSIONS: If important practice variation exists, hospital-level CEAs should be performed. These CEAs should include an assessment of the feasibility and costs of switching to a different strategy. PMID- 25917688 TI - Pain with sitting related to injury of the posterior femoral cutaneous nerve. AB - PURPOSE: The ischial tuberosity, referred to as the "sit bone" by patients with pain, is surrounded by critical nerves. This research relates, for the first time, the involvement of the posterior femoral cutaneous nerve (PFCN), including its perineal and inferior cluneal branches to the symptom of "sitting pain." An experience with PFCN resection for treatment of pain with sitting is reported. PATIENTS AND METHODS: The computer records were searched from 2010 through August of 2013, identifying 17 patients who had surgery on PFCN. Fifteen of these 17 were women. Mean age of 17 patients was 54.6 years (range 30-74 years). Each patient had pain with sitting, and spent much of the day standing or lying down. Each had symptoms involving posterior thigh and buttock. Three patients had bilateral problems. Each of 17 patients in this series had resection of PFCN through an incision in the gluteal crease. Resection included inferior cluneal branches and perineal branch. RESULTS: Of 17 patients, at a mean of 19.4 months (range 6 to 42 months) after surgery, the visual analog scale improved from a mean of 9.2 to a mean of 2.1 (P < 0.0001). There were 7 excellent, 6 good, 3 fair, and 1 poor result, for 76% good to excellent result in terms of pain relief and improvement in being able to sit. CONCLUSION: Pain with sitting can be due to injury to PFCN, a previously unreported etiology. Good to excellent results can be expected in 76% of carefully selected patients. PMID- 25917687 TI - Effects of chronic manganese exposure on attention and working memory in non human primates. AB - Manganese (Mn) is essential for a variety of physiological processes, but at elevated levels, can be neurotoxic. While cognitive dysfunction has been recently appreciated to occur as a result of chronic Mn exposures, it is still unclear as to which cognitive domains are most susceptible to disruption by Mn exposure. We previously described early appearing Mn-induced changes in performance on a paired associate learning task in monkeys chronically exposed to Mn and suggested that performance of this task might be a sensitive tool for detecting cognitive dysfunction resulting from Mn exposure. As chronic Mn exposure has been suggested to be associated with attention, working memory and executive function deficits, the present study was conducted to assess the extent to which detrimental effects of chronic Mn exposure could be detected using tasks specifically designed to preferentially assess attention, working memory, and executive function. Six cynomolgus monkeys received Mn exposure over an approximate 12 month period and three served as control animals. All animals were trained to perform a self ordered spatial search (SOSS) task and a five choice serial reaction time (5 CSRT) task. Deficits in performance of the SOSS task began to appear by the fourth month of Mn exposure but only became consistently significantly impaired beginning at the ninth month of Mn exposure. Performance on the 5-CSRT became significantly affected by the third month of Mn exposure. These data suggest that in addition to the paired associate learning task, cognitive processing speed (as measured by the 5-CSRT) may be a sensitive measure of Mn toxicity and that brain circuits involved in performance of the SOSS task may be somewhat less sensitive to disruption by chronic Mn exposure. PMID- 25917689 TI - Does a prophylactic dose of propofol reduce emergence agitation in children receiving anesthesia? A systematic review and meta-analysis. AB - INTRODUCTION: Emergence agitation (EA) is common after sevoflurane anesthesia in children, and can lead to distressing inconsolability, agitation, crying, and injury. Use of a single dose of the short-acting sedative-hypnotic agent propofol at the end of a procedure has shown promise for preventing EA, but evidence evaluating the efficacy and safety of this approach has not been formally summarized. OBJECTIVE: The objective of this review was to assess the effects of a prophylactic dose of propofol vs placebo on the incidence and severity of EA in children age 0-13 years receiving general inhalational anesthesia. SEARCH METHODS: We searched PubMed (1946-2013) via Medline, CENTRAL (1898-2013), and Web of Science (1900-2013) without limits or language restrictions; we also searched ClinicalTrials.gov and reference lists. We reviewed abstracts from the 2012 and 2013 Society for Pediatric Anesthesia meetings and pediatric anesthesia-related abstracts from the 2012 and 2013 International Anesthesia Research Society meetings. SELECTION CRITERIA: We assessed randomized, double-blind trials evaluating the efficacy of a prophylactic dose of propofol (1 mg.kg(-1) ) vs placebo given at the end of inhalational anesthesia to prevent EA in pediatric patients. Studies were required to follow patients through recovery and report at least one prespecified outcome. DATA COLLECTION AND ANALYSIS: Two authors independently assessed trial quality and extracted data from included studies. We contacted study authors regarding any missing data. We used the random effects models to calculate pooled relative risks (RR) and weighted mean differences (WMD). We collected Pediatric Anesthesia Emergence Delirium (PAED) scale scores from included studies. PAED scale scores can range from 0 to 20. MAIN RESULTS: Of 276 studies screened, nine trials involving 997 children met all inclusion criteria. All were considered low risk of bias. For one non-English trial, we obtained a full-text translation and for one non-English trial, we used the English-language abstract, tables, and figures. Based on available evidence, prophylactic propofol was associated with both decreased incidence of EA (29% vs 58%, RR 0.50, 95% confidence intervals [CI] 0.41, 0.61, I(2) = 37%, seven studies), and reduced severity of EA as assessed by mean PAED scale score (WMD 2.08 points, 95% CI -3.20, -0.96, I(2) = 0%, three studies), when compared to placebo. In addition, though prophylactic propofol did lengthen the time to awakening (WMD 4.07 min, 95% CI 2.22, 5.91, I(2) = 82%, six studies), it did not increase recovery time (WMD 2.91 min, 95% CI -0.59, 6.41, I(2) = 82%, six studies) when compared to placebo. No significant adverse events were reported in either arm. CONCLUSION: Based on high quality evidence, prophylactic propofol appears to be effective for reducing the incidence and severity of EA in children emerging from general anesthesia. PMID- 25917690 TI - Methodological accuracy of digital and manual model analysis in orthodontics - A retrospective clinical study. AB - INTRODUCTION: Computer-based digital orthodontic models are available for clinicians, supplemented by dedicated software for performing required diagnostic measurements. The purpose of this study was to evaluate the accuracy of measurements made on three-dimensional digital models obtained with a CBCT scanner (DigiModelTM, OrthoProof((r)), Nieuwegin, The Netherlands). METHODS: 66 orthodontic dental casts of primary and early mixed dentitions were selected. Three-dimensional images were obtained on this CBCT-scanner and analyzed by means of the DigiModelTM software. Measurements were made with a digital caliper directly on the conventional casts and also digitally on the virtual models. 6 anatomic dental points were identified, and a total of 11 measurements were taken from each cast, including midline deviation, overjet, overbite and arch widths. Conformity of digital and manual measurements as well as intra-, inter- and repeated-measurement-reliability were evaluated by Lin's Concordance Correlation Coefficient, ICC and a Bland-Altman-analysis. RESULTS: The agreement and conformity of digital and manual measurements was substantial for all parameters evaluated. Intra-, inter- and repeated-measurement-reliability was excellent. CONCLUSIONS: Measurements on digital models obtained by a CBCT scan of conventional casts (DigiModelTM, OrthoProof((r))) are suited for reliable diagnostic measurements, which compare well to those obtained from plaster casts, the current gold standard. PMID- 25917691 TI - Prediction of blood lead levels in children before and after remediation of soil samples in the upper Meza Valley, Slovenia. AB - The Meza Valley, Slovenia, has been contaminated by Pb smelting, resulting in an epidemic of lead poisoning in childhood. The potential of remediation with EDTA soil washing to mitigate the risk from Pb poisoning was investigated by applying the Integrated Exposure Uptake Bio-kinetic (IEUBK) model. Soils from 79 locations were collected and the total and bio-accessible Pb concentrations were determined before and after extraction with 60 mmol kg(-1) EDTA. Extraction reduced the soil Pb concentration in towns of Mezica, Zerjav and Crna by 53, 67 and 62%, respectively, and the concentration of in vitro bio-accessible Pb in the simulated human gastric phase by 2.6-, 3.2- and 2.9-times, respectively. The predictions of the IEUBK model based on Pb contamination data were verified with data on blood Pb levels in children. The IEUBK model predicted that, after soil remediation, the number of locations at which the expected blood Pb level in children was higher than the stipulated 10 MUg d L(-1) would decrease by 90, 38 and 91% in the towns of Mezica, Zerjav and Crna, respectively. The results confirmed the feasibility of soil washing with EDTA as an efficient remediation measure in Mezica and Crna and advice for soil capping/removal for the most polluted town of Zerjav. PMID- 25917692 TI - Geochemical characteristics and microbial community composition in toxic metal rich sediments contaminated with Au-Ag mine tailings. AB - The effects of extreme geochemical conditions on microbial community composition were investigated for two distinct sets of sediment samples collected near weathered mine tailings. One set (SCH) showed extraordinary geochemical characteristics: As (6.7-11.5%), Pb (1.5-2.1%), Zn (0.1-0.2%), and pH (3.1-3.5). The other set (SCL) had As (0.3-1.2%), Pb (0.02-0.22%), and Zn (0.01-0.02%) at pH 2.5-3.1. The bacterial communities in SCL were clearly different from those in SCH, suggesting that extreme geochemical conditions affected microbial community distribution even on a small spatial scale. The clones identified in SCL were closely related to acidophilic bacteria in the taxa Acidobacterium (18%), Acidomicrobineae (14%), and Leptospirillum (10%). Most clones in SCH were closely related to Methylobacterium (79%) and Ralstonia (19%), both well-known metal resistant bacteria. Although total As was extremely high, over 95% was in the form of scorodite (FeAsO4.2H2O). Acid-extractable As was only ~118 and ~14 mg kg( 1) in SCH and SCL, respectively, below the level known to be toxic to bacteria. Meanwhile, acid-extractable Pb and Zn in SCH were above toxic concentrations. Because As was present in an oxidized, stable form, release of Pb and/or Zn (or a combination of toxic metals in the sediment) from the sediment likely accounts for the differences in microbial community structure. The results also suggest that care should be taken when investigating mine tailings, because large differences in chemical/biological properties can occur over small spatial scales. PMID- 25917694 TI - A comprehensive study of the harmful effects of ZnO nanoparticles using Drosophila melanogaster as an in vivo model. AB - This study planned to determine the range of biological effects associated with ZnO-NP exposure using Drosophila melanogaster as an in vivo model. In addition, ZnCl2 was used to determine the potential role of Zn ions alone. Toxicity, internalization through the intestinal barrier, gene expression changes, ROS production, and genotoxicity were the end-points evaluated. No toxicity or oxidative stress induction was observed in D. melanogaster larvae, whether using ZnO-NPs or ZnCl2. Internalization of ZnO-NPs through the intestinal barrier was observed. No significant changes in the frequency of mutant clones (wing-spot test) or percentage of DNA in tail (comet assay) were observed although significant changes in Hsp70 and p53 gene expression were detected. Our study shows that ZnO-NPs do not induce toxicity or genotoxicity in D. melanogaster, although uptake occurs and altered gene expression is observed. PMID- 25917693 TI - Vanadium bioavailability in soils amended with blast furnace slag. AB - Blast furnace (BF) slags are commonly applied as soil amendments and in road fill material. In Sweden they are also naturally high in vanadium. The aim of this study was to assess the vanadium bioavailability in BF slags when applied to soil. Two soils were amended with up to 29% BF slag (containing 800 mg V kg(-1)) and equilibrated outdoors for 10 months before conducting a barley shoot growth assay. Additional soil samples were spiked with dissolved vanadate(V) for which assays were conducted two weeks (freshly spiked) and 10 months (aged) after spiking. The BF slag vanadium was dominated by vanadium(III) as shown by V K-edge XANES spectroscopy. In contrast, results obtained by HPLC-ICP-MS showed that vanadium(V), the most toxic vanadium species, was predominant in the soil solution. Barley shoot growth was not affected by the BF slag additions. This was likely due to limited dissolution of vanadium from the BF slag, preventing an increase of dissolved vanadium above toxic thresholds. The difference in vanadium bioavailability among treatments was explained by the vanadium concentration in the soil solution. It was concluded that the vanadium in BF slag is sparingly available. These findings should be of importance in environmental risk assessment. PMID- 25917695 TI - Effect of ageing on benzo[a]pyrene extractability in contrasting soils. AB - Changes in benzo[a]pyrene (B[a]P) extractability over 160 days ageing in four contrasting soils varying in organic matter content and clay mineralogy were investigated using dichloromethane: acetone 1:1 (DCM/Ace), 60 mM hydroxypropyl beta-cyclodextrin (HPCD) solution, 1-butanol (BuOH) and Milli-Q water. The B[a]P extractability by the four methods decreased with ageing and a first-order exponential model could be used to describe the kinetics of release. Correlation of the kinetic rate constant with major soil properties showed a significant effect of clay and sand contents and pore volume fraction (<6 nm) on sequestration of the desorbable fraction (by HPCD) and the water-extractable fraction. Analysis of (14)C-B[a]P in soils after ageing showed a limited loss of B[a]P via degradation. Fractionation of B[a]P pools associated with the soil matrix was analysed according to extractability of B[a]P by the different extraction methods. A summary of the different fractions is proposed for the illustration of the effect of ageing on different B[a]P-bound fractions in soils. This study provides a better understanding of the B[a]P ageing process associated with different fractions and also emphasises the extraction capacity of the different methods employed. PMID- 25917696 TI - Molecular binding mechanisms of manganese to the root cell wall of Phytolacca americana L. using multiple spectroscopic techniques. AB - The root cell wall (RCW) of Mn hyperaccumulator Phytolacca americana L. (P. americana) plays an important role in immobilizing and detoxifying excessive Mn, but the molecular binding mechanism of Mn to RCW has been little studied. This study investigated the effect of varied pH on Mn adsorption by the isolated RCW from P. americana in batch experiments, and explored the binding mechanisms of Mn to RCW using Fourier transform infrared spectroscopy (FTIR), synchrotron-based X ray absorption near-edge structure (XANES), and extended X-ray fine structure spectroscopy (EXAFS). Results showed that Mn binding capacity depends on solution pH, with an optimal pH of 5.0-6.0. Experimental isotherm data could be successfully modeled by the Langmuir and Freundlich equations; the estimated maximum Mn adsorption capacity was 5.446 mg g(-1) according to the established Langmuir isotherm. FTIR spectroscopy demonstrated hydroxyl and carboxyl groups were probably involved in the Mn binding process. XANES results showed that Mn remained as Mn(II) after adsorption on RCW, without any change of oxidation state; EXAFS analysis further revealed that Mn was complexed to RCW via bidentate inner-sphere coordination with carboxyl, which provides new structure information of Mn adsorbed on biomaterials and accounted for high Mn accumulation on RCW of P. americana. PMID- 25917698 TI - Epilepsy: Neonatal seizures still lack safe and effective treatment. PMID- 25917697 TI - Chemical characterization and ecotoxicity of three soil foaming agents used in mechanized tunneling. AB - The construction of tunnels and rocks with mechanized drills produces several tons of rocky debris that are today recycled as construction material or as soil replacement for covering rocky areas. The lack of accurate information about the environmental impact of these excavated rocks and foaming agents added during the excavation process has aroused increasing concern for ecosystems and human health. The present study proposes an integrated approach to the assessment of the potential environmental impact of three foaming agents containing different anionic surfactants and other polymers currently on the market and used in tunnel boring machines. The strategy includes chemical characterization with high resolution mass spectrometry techniques to identify the components of each product, the use of in silico tools to perform a similarity comparison among these compounds and some pollutants already listed in regulatory frameworks to identify possible threshold concentrations of contamination, and the application of a battery of ecotoxicological assays to investigate the impact of each foaming mixture on model organisms of soil (higher plants and Eisenia andrei) and water communities (Daphnia magna). The study identified eleven compounds not listed on the material safety data sheets for which we have identified possible concentrations of contamination based on existing regulatory references. The bioassays allowed us to determine the no effect concentrations (NOAECs) of the three mixtures, which were subsequently used as threshold concentration for the product in its entirety. The technical mixtures used in this study have a different degree of toxicity and the predicted environmental concentrations based on the conditions of use are lower than the NOAEC for soils but higher than the NOAEC for water, posing a potential risk to the waters due to the levels of foaming agents in the muck. PMID- 25917703 TI - Motor neuron disease: Can gluten sensitivity mimic amyotrophic lateral sclerosis? PMID- 25917709 TI - In memoriam: Nathan J. Zvaifler, MD, 1927-2015. PMID- 25917706 TI - Vascular parkinsonism--characteristics, pathogenesis and treatment. AB - Parkinson disease is a primary degenerative disease of the brain, but parkinsonism can also result from a variety of vascular disorders. Vascular parkinsonism (VP) most frequently presents as lower body parkinsonism, a condition that is accompanied by the development of white matter lesions (WMLs) and lacunes in the brain. Patients with lower body parkinsonism exhibit gait impairment and go on to develop urinary incontinence, abnormal pyramidal responses and cognitive decline. However, WMLs and lacunes are also common observations among elderly individuals who do not have parkinsonism, which causes difficulty in determining the pathogenetic mechanisms that lead to VP. In addition, imaging studies suggest that many pathological and clinical features are common to VP and Binswanger disease, a type of small vessel vascular dementia. This Review summarizes current understanding of the clinical characteristics of VP, as well as knowledge gained from neuroimaging and nuclear imaging of the pathological features of VP. The lack of current treatment options, and the emergence of new therapies such as cerebrospinal fluid drainage, are also discussed. Finally, consideration is given to whether the overlap between VP and Binswanger disease means that these two disorders should be considered as part of the same disease entity. PMID- 25917711 TI - Translational neurobiology in Shank mutant mice--model systems for neuropsychiatric disorders. AB - The Shank family comprises three core postsynaptic scaffold proteins of excitatory synapses in the mammalian brain: Shank1, Shank2 and Shank3. Since mutations in all three human SHANK genes are linked to neuropsychiatric disorders such as autism and schizophrenia, Shank mutant mice serve as corresponding in vivo model systems. Besides intriguing alterations in behavior, dysfunction of glutamatergic synapses has emerged as a pathological hallmark among several Shank mutant lines. However, there is very limited knowledge of the underlying pathomechanisms. Therefore, precise neurobiological evaluation of morphological, molecular and electrophysiological phenotypes in Shank mutants is crucially needed. In this brief review, I will focus on the Shank mutant mouse lines we have generated so far and discuss how they might help us to develop translational treatment studies in the future. PMID- 25917712 TI - Combined flubendazole-nitazoxanide treatment of cystic echinococcosis: Pharmacokinetic and efficacy assessment in mice. AB - The current chemotherapy of cystic echinococcosis (CE) is mainly based on the use of albendazole, and the results have been shown to be highly variable. Thus, new and more efficient treatment options are urgently needed. The goals of the current study were: a) to compare the ex vivo activity of flubendazole (FLBZ) and nitazoxanide (NTZ), given either separately or co-administered, against Echinococcus granulosus protoscoleces and cysts, b) to characterize the plasma disposition kinetics of FLBZ administered alone or combined with NTZ in mice; (c) to compare the in vivo activity of FLBZ and NTZ (either each alone or as a combined treatment) against secondary CE developed in mice. Ex vivo drug activity study: E. granulosus protoscoleces and cysts were incubated either with FLBZ, NTZ, or the FLBZ-NTZ combination. Protoscoleces and cyst viability was monitored by the methylene blue exclusion test and scanning electron microscopy (SEM). Pharmacokinetic study: Balb/C mice received FLBZ (5 mg/kg) orally either alone or co-administered with NTZ (100 mg/kg). Blood samples were collected up to 12 h post treatment and plasma analyzed for FLBZ/metabolites by HPLC. Clinical Efficacy study: following secondary infection, meaning i.p. injection of 1500 E. granulosus protoscoleces/animal (n=40), the both drugs were administered by intragastric inoculation on a daily basis for a period of 25 days. Balb/C mice received FLBZ (5 mg/kg, twice a day) alone, NTZ (100 mg/kg, once daily) alone or a combination of both molecules (FLBZ, 5mg/kg twice a day and NTZ, 100 mg/kg, once daily). Ten untreated animals were used as a control. All animals were killed and the weight of the cysts collected from each animal was recorded. The presence of NTZ did not markedly affect the FLBZ kinetic parameters in mice. FLBZ alone or combined with NTZ induced a reduction (P<0.05) of cyst weight in comparison to the untreated control and NTZ-treated treated mice. The data obtained here indicate that NTZ did not affect hydatid cyst development in mice. Conversely, FLBZ shows an excellent efficacy against CE. PMID- 25917713 TI - Temporal distribution and behaviour of sand flies (Diptera: Psychodidae) in a cutaneous leishmaniasis focus of the Kani Tribe settlements in the Western Ghats, India. AB - The temporal distribution of sand flies in relation to environmental factors was studied in the Kani tribe settlements located on the southernmost part of the Western Ghats, Kerala, India, between June 2012 and May 2013. This area is known for occurrence of cutaneous leishmaniasis (CL) cases. Employing hand-held aspirator, light trap and sticky-trap collection methods, a total of 7874 sand fly specimens, comprising 19 species was collected. Sergentomyia baghdadis was predominant species, followed by Phlebotomus argentipes. Sand fly abundance was significantly higher indoors (chi(2)=9241.8; p=0.0001) than outdoors. Mean density of P. argentipes in human dwellings, cattle sheds and outdoors was 7.2+/ 2.9, 27.33+/-21.1 and 0.64+/-0.2 females/per man-hour (MHR), respectively. No sand fly species other than P. argentipes was obtained from cattle sheds. Although, sand fly populations were prevalent throughout the year, their abundance fluctuated with seasonal changes. Multiple regression analysis with backward elimination indicated that the increase in precipitation and relative humidity contributed to a significant positive association with the increase in sand fly abundance, while the increase in temperature showed no association. Fully engorged female sand flies tested for blood meal source showed multiple host-blood feeding. Analysis of resting populations of sand flies collected from human shelters indicated that the populations were found maximum on interior walls at 6-8 and >8 ft height, including ceiling during summer (F=83.7, df=6, p=0.001) and at the lower half of the wall at 0 and 0-2 ft height, during monsoon season (F=41.4, df=6, p=0.001). In cooler months, no preference to any height level (F=1.67, df=6, p=0.2) was observed. Proportion of females sand flies with Sella's classification of abdominal stages, namely full-fed, half-gravid and gravid females did not vary significantly (t=1.98, p=0.13827) indoors, confirming their endophilic behaviour. Risk of CL transmission in these tribal settlements is discussed. PMID- 25917714 TI - Optimization of fluoride-containing bioactive glasses as a novel scolicidal agent adjunct to hydatid surgery. AB - We have presented a novel scolicidal agent made from fluoride-containing bioactive glass (FBG). The samples were characterized by XRD and the ion release behavior of the samples was evaluated at 37 degrees C. The scolicidal activity, cellular response and antibacterial activity and biocompatibility of the different concentrations of the FBG (ranging from 0.5 to 2 mg ml(-1)) were evaluated in vitro and in vivo. The results showed an easy diffusion of the fluoride through the glass matrix in an F concentration-dependent manner. The FBG showed an intensive scolicidal property, so that toxicity effect begun from 5 min and the samples with 20, 10, 5 and 0% fluoride showed 98+/-2, 93+/-5.8, 76.2+/-6 and 5.8+/-1.7% scolicidal activity, respectively, after 8h exposing time. Our data revealed that scolicidal activity of the FBG increased with the increase of F ratio and concentrations of the bioactive glass. On the other hand, all the synthesized FBG samples found to be cyto-biocompatible when tested in vitro (MTT and LDH assays) and in vivo (no significant infiltration of inflammatory cells compared with control, p>0.05), and antibacterial against Escherichia coli, Staphylococcus aureus and Pseudomonas aeruginosa. The results demonstrated that the synthesized FBG might have a potential application in prevention of post surgery infections, especially hydatidosis. PMID- 25917715 TI - Epidemiology of canine leishmaniasis in southern Bahia, Brazil. AB - Leishmaniosis is a zoonosis caused by protozoa of the genus Leishmania. American cutaneous leishmaniosis (ACL) is mainly caused by the species L. amazonensis and L. braziliensis, and American visceral leishmaniosis (AVL) is caused by L. infantum chagasi. In addition to their proven roles as reservoirs of AVL, dogs are also suspected by researchers to be reservoirs of ACL due to reports of this infection in domestic environments and of infected dogs in endemic areas. The aim of this study was to detect Leishmania sp. infection in dogs from Vila Operaria, Buerarema, Bahia, using parasitological tests, indirect immunofluorescent assay (IFA) and polymerase chain reaction (PCR). Furthermore, this study also aimed to identify risk factors associated with illness in dogs in this locality by conducting an epidemiological survey. For this purpose, 292 dogs were clinically evaluated for the presence of skin lesions, and the dogs that showed these changes were submitted to scarification injury to enable preparation of slides for microscopic study of amastigotes. Subsequently, the dogs underwent blood sampling for serological (IFA) and molecular (PCR) tests. Additionally, the owners of the dogs answered an epidemiological questionnaire to facilitate the identification of risk factors for exposure of dogs to pathogens of ACL. Of the 292 dogs studied, 13 (4.5%) had lesions suggestive of ACL, but with a negative parasitological examination and 147 (50.3%) were seropositive according to the IFA. Of the 273 dogs studied using PCR test, 10 (3.66%) were positive for L. braziliensis, and all samples were negative for L. infantum chagasi. Wastelands in the peridomicile and the presence of light in the household were risk factors associated with ACL. The results show that Vila Operaria has asymptomatic dogs with ACL and that the detection sensitivity of the IFA was higher than that of PCR for the infected dogs. PMID- 25917716 TI - High selective antileishmanial activity of vanadium complex with stilbene derivative. AB - Leishmaniasis is a group of disease caused by different species of the parasite Leishmania affecting millions of people worldwide. Conventional therapy relies on multiple parenteral injections with pentavalent antimonials which exhibit high toxicity and various side effects have been reported. Hence, the research for an effective and low toxic effect drug is necessary. In the present work, the synthesis, spectroscopic and analytical characterizations of stilbene derivative (H2Salophen) and its vanadium complex (VOSalophen) are reported. Besides the chemical ancillary information, investigation of the leishmanicidal effects of these compounds were provided. The biological assays against promastigote and amastigote forms of L. amazonensis have been shown that VOSalophen exhibited a strong antiparasitic activity (IC50 of 6.65 and 3.51 MUM, respectively). Furthermore, the leishmanicidal activity was concentration and time-dependent. Regarding toxicity and selectivity on mammalian cells, VOSalophen have not caused significant damage to human erythrocytes in all concentrations tested and VOSalophen was almost seven times more destructive for the intracellular parasite than for macrophages. Furthermore, the leishmanicidal activity of VOSalophen in promastigote forms of L. amazonensis could be associated to mitochondrial dysfunction and increase of the reactive oxygen species (ROS) production. In L. amazonensis-infected macrophages, VOSalophen induces ROS production and a microbicidal action NO-dependent. Our biological results indicate the effective and selective action of VOSalophen against L. amazonensis and the leishmanicidal effect can be associated to parasite disorders and immumodulatory effects. PMID- 25917717 TI - First report of Warileya rotundipennis (Psychodidae: Phlebotominae) naturally infected with Leishmania (Viannia) in a focus of cutaneous leishmaniasis in Colombia. AB - The expansion of transmission of cutaneous leishmaniasis from sylvatic ecosystems into peri-urban and domestic settings has occurred as sand flies have adapted to anthropogenic environmental modifications. Assessment of the intradomiciliary presence of sand flies in households of the settlement "La Cabana", in the Department of Risaralda, Colombia, revealed an abundance of Warileya rotundipennis. This unexpected observation motivated further analyses to evaluate the participation of this species in the transmission of cutaneous leishmaniasis. Collections using CDC light traps were conducted during two consecutive nights in May and August 2011.The total of 667 sand flies collected were classified into five species: W. rotundipennis (n=654; 98.05%), Nyssomyia trapidoi (n=7; 1.04%); Lutzomyia (Helcocyrtomyia) hartmanni (n=3; 0.44%); Lutzomyia lichyi (n=2; 0.29%) and Psychodopygus panamensis (n=1; 0.14%). The striking predominance of W. rotundipennis within households during both wet (May) and dry (August) seasons, anthropophilic behavior demonstrated by human blood in 95.23% (60/63) evaluable blood-engorged specimens, and natural infection (5/168-3%) with genetically similar parasites of the Leishmania (Viannia) subgenus observed in a patient in this community, support the involvement of W. rotundipennis in the domestic transmission of cutaneous leishmaniasis in "La Cabana". PMID- 25917718 TI - Economic evaluation of Chagas disease screening in Spain. AB - Although Spain is the European country with the highest Chagas disease burden, the country does not have a national control program of the disease. The purpose of this study is to evaluate the efficiency of several strategies for Chagas disease screening among Latin American residents living in Spain. The following screening strategies were evaluated: (1) non-screening; (2) screening of the Latin American pregnant women and their newborns; (3) screening also the relatives of the positive pregnant women; (4) screening also the relatives of the negative pregnant women. A cost-utility analysis was carried out to compare the four strategies from two perspectives, the societal and the Spanish National Health System (SNHS). A decision tree representing the clinical evolution of Chagas disease throughout patient's life was built. The strategies were compared through the incremental cost-utility ratio, using euros as cost measurement and quality-adjusted life years as utility measurement. A sensitivity analysis was performed to test the model parameters and their influence on the results. We found the "Non-screening" as the most expensive and less effective of the evaluated strategies, from both the societal and the SNHS perspectives. Among the screening evaluated strategies the most efficient was, from both perspectives, to extent the antenatal screening of the Latin American pregnant women and their newborns up to the relatives of the positive women. Several parameters influenced significantly on the sensitivity analyses, particularly the chronic treatment efficacy or the prevalence of Chagas disease. In conclusion, for the general Latin American immigrants living in Spain the most efficient would be to screen the Latin American mothers, their newborns and the close relatives of the mothers with a positive serology. However for higher prevalence immigrant population the most efficient intervention would be to extend the program to the close relatives of the negative mothers. PMID- 25917719 TI - Initial Imaging for Suspected Nephrolithiasis in Emergency Department. Commentary on: Ultrasonography Versus Computed Tomography for Suspected Nephrolithiasis. PMID- 25917721 TI - Editorial comment. PMID- 25917720 TI - The history of microsurgery in urology. PMID- 25917722 TI - Reply: To PMID 25917720. PMID- 25917723 TI - Long-term Adverse Effects of Extracorporeal Shock-wave Lithotripsy for Nephrolithiasis and Ureterolithiasis: A Systematic Review. AB - This study presents a systematic review of the published literature on possible long-term adverse effects after extracorporeal shock wave lithotripsy (ESWL). Although published disagreement exists, this review finds that previous evidence supporting an association between ESWL and long-term adverse effects is weak and that the majority of studies show no evidence for any increase in post-ESWL incidence of arterial hypertension (24 of 30 studies), diabetes mellitus (4 of 6 studies), kidney dysfunction (14 of 14 studies), or infertility (2 of 2 studies). Currently, no strong evidence exists to support the hypothesis that ESWL causes long-term adverse effects. PMID- 25917724 TI - A Comparison of 2 Percutaneous Nephrolithotomy Techniques for the Treatment of Pediatric Kidney Stones of Sizes 10-20 mm: Microperc vs Miniperc. AB - OBJECTIVE: To compare outcomes of micro-percutaneous nephrolithotomy (PNL; microperc) with mini-PNL (miniperc) in the treatment of pediatric renal stones of sizes 10-20 mm. MATERIALS AND METHODS: Patients aged <18 years who underwent PNL for renal stones of sizes 10-20 mm between August 2011 and March 2014 in 3 referral centers were reviewed retrospectively. Patients were evaluated in the following 2 groups: microperc (group 1) and miniperc (group 2). Demographics and perioperative parameters (fluoroscopy and operation time, hemoglobin drop, and stone-free and complication rates) were retrospectively analyzed. RESULTS: A total of 119 patients were evaluated, including group 1 (n = 56) for microperc and group 2 (n = 63) for miniperc. We found mean stone sizes as 13.4 +/- 3.4 and 14.8 +/- 3.7 mm in the groups, respectively (P = .046). Mean operation and fluoroscopy times were 57.1 +/- 31.2 minutes and 132.4 +/- 92.5 seconds in the microperc group and 68.9 +/- 36.7 minutes and 226.2 +/- 166.2 seconds in the miniperc group, respectively (P = .110 and P <.001). Stone-free rates were similar in both groups (82.1% vs 87.3%; P = .433 and 92.8% vs 93.6%; P = 0673) on postoperative day 1 and at first-month follow-up. The mean hemoglobin drop in group 2 differed from that in group 1 significantly (P <.001). The difference of average hospitalization times was statistically significant (43.0 +/- 15.4 vs 68.5 +/- 31.7 hours; P <.001). CONCLUSION: Our outcomes show that microperc may be preferred as an alternative to mini-PNL for the treatment of pediatric kidney stones of sizes 10-20 mm with comparable success and complication rates, as well as shorter hospitalization and fluoroscopy times. PMID- 25917725 TI - Radiation Practice Patterns and Exposure in the High-volume Endourologist. AB - OBJECTIVE: To define radiation exposure among high-volume endourologists and characterize surgeon exposure patterns as previous literature has focused primarily on patient exposure. METHODS: Surveys were obtained from the Research on Calculus Kinetics Society members from 14 different institutions across North America. All surgeons practice at high-volume academic institutions as surgical stone specialists. Protective equipment, fluoroscopy variables, and practice patterns were recorded. Dosimeter readings from the past year were analyzed when available. RESULTS: Fifteen surveys were returned, with a response rate of 94%. Fluoroscopic procedures comprised 87% of surgeon cases. Surgeon mean experience was 12.4 years (range, 1-32 years). Lead aprons were worn in 99.3% of cases, thyroid shields in 98.7%, radiation glasses in 52.7%, and lead gloves in 9.7%. Only 33.3% of surgeons regularly wore dosimeters. Of these surgeons, average deep dose equivalent was 816.6 mrem/y. Lens dose equivalent was 1303.4 mrem/y. Shallow dose equivalent was 1286 mrem/y. CONCLUSION: Endourologists receive moderate radiation exposure, and dosimetry use remains low. As Low As Reasonably Achievable principles should be in place and judiciously followed. Improved monitoring and education should assist with reduction of radiation exposure to both the patient and the endourologist. PMID- 25917726 TI - Editorial comment. PMID- 25917727 TI - Reply: To PMID 25917725. PMID- 25917728 TI - Beyond a Simple Anesthetic Effect: Lidocaine in the Diagnosis and Treatment of Interstitial Cystitis/bladder Pain Syndrome. AB - Intravesical local anesthetics, in a wide variety of combinations, are increasingly used to treat patients with interstitial cystitis-bladder pain syndrome (IC/BPS). Lidocaine has demonstrated properties that block the neuroinflammatory cycle associated with IC/BPS at many of the interactive points in this cycle. Intravesical lidocaine has been shown to assist in identifying the bladder as the source of pain in patients with pelvic pain. An appreciation of these anti-inflammatory effects and of the pharmacokinetics of intravesical lidocaine in patients with IC/BPS could lead to a safe and effective diagnosis and treatment for an as yet unidentified subset of patients in the IC/BPS spectrum. PMID- 25917729 TI - Coital incontinence: what can we learn from urodynamic assessment? AB - OBJECTIVE: To evaluate the association of coital incontinence (CI) with lower urinary tract symptoms (LUTS) and to understand the pathophysiology of CI. METHODS: A database of all women who underwent urodynamic testing in a tertiary referral center in the United Kingdom, from January 1991 to December 2009, was retrospectively analyzed. All women reporting CI were included in the study. Urodynamic testing and interpretation of results were performed in accordance with the recommendations of the International Continence Society. RESULTS: The prevalence of CI in women with LUTS undergoing urodynamics was 11.8%, and they were significantly younger (mean age = 45.3 years; P <.001) than the rest of the group (mean age = 53.4 years). Obesity (body mass index >30 kg/m(2)) and parity were significantly associated with CI (P <.001). Women reporting CI significantly smoked cigarettes and used antidepressants (P <.001). There were fewer postmenopausal women (P <.001) with CI, and previous hysterectomy had a negative association with CI (P = .005). The majority of women had overactive bladder symptoms and stress urinary incontinence (P <.001). CI was significantly associated with urodynamic stress incontinence (UDSI; odds ratio = 2.35) and detrusor overactivity (DO; odds ratio = 1.22) but not DO incontinence (P <.001). Parity, overactive bladder symptoms, and UDSI reached statistical significance when analysis was performed for age-matched controls. CONCLUSION: CI is not uncommon in women with LUTS, and they present earlier than women with LUTS and no CI. CI is significantly associated with risk factors like parity, obesity, cigarette smoking, and antidepressant usage. CI is multifactorial and associated with UDSI and DO but not DO incontinence. PMID- 25917730 TI - Anesthetic Bladder Hydrodistention Is Superior to Superior Hypogastric Plexus Neurolysis in Treatment of Interstitial Cystitis-bladder Pain Syndrome: A Prospective Randomized Trial. AB - OBJECTIVE: To evaluate efficacy and safety of superior hypogastric plexus neurolysis (SHN) for treatment of interstitial cystitis (IC)-bladder pain syndrome (BPS) in comparison with bladder hydrodistention (HD). MATERIALS AND METHODS: In a prospective study, 24 female patients were randomly allocated to receive either SHN or HD. Patients were evaluated by recording the O'Leary-Sant IC symptom indices, IC problem indices, pain visual analog scale (VAS), number of daytime frequency, and nocturia. Pressure flow study was conducted for all patients. Intraoperative and postoperative changes and adverse events were recorded. RESULTS: Basal IC symptom indices, IC problem indices, and VAS scores were comparable between both groups (P = .31, .63, and .94, respectively). There was no statistically significant difference between both groups with respect to urodynamic parameters. Only pain VAS at first week was improved in SHN in comparison with HD (P = .012). Thereafter, all parameters were significantly improved in favor of the HD group at 2- and 4-week visits. Adverse events in both groups were ranked as Grade 1 Clavien-Dindo classification including transient hematuria in the HD group and transient back ache in the SHN group. CONCLUSION: Despite effective pain control in cases with IC-BPS after SHN, it lacks durability. It seems that SHN in its current form is not to be a suitable line of treatment for IC-BPS. Multimodality treatment would be needed for proper control of patients' symptoms. PMID- 25917731 TI - Biochemical hormone parameters in seminal and blood plasma samples correlate with histopathologic properties of testicular biopsy in azoospermic patients. AB - OBJECTIVE: To investigate the relationship between histopathologic patterns of testicular biopsy and biochemical semen and blood plasma parameters, including neutral a-glucosidase (NAG), fructose, follicle-stimulating hormone (FSH), luteinizing hormone (LH), testosterone, and prolactin (PRL) in patients with azoospermia. MATERIALS AND METHODS: A total of 471 azoospermic patients with definitive pathologic diagnosis were enrolled in this study. Six biochemical parameters, including 2 seminal (NAG and fructose) and 4 blood (FSH, LH, testosterone, and PRL) plasma markers, were analyzed. RESULTS: NAG, fructose, FSH, and LH levels were significantly higher in patients with Sertoli-cell-only (SCO) syndrome and severe hypospermatogenesis than in those with normal spermatogenesis or mild hypospermatogenesis (P <.05). In addition, NAG levels positively correlated with fructose amounts in azoospermic patients (P <.05); a significant correlation between FSH and LH levels was also observed in azoospermic patients. Furthermore, PRL levels were higher in SCO syndrome patients compared with subjects showing normal spermatogenesis and the levels positively correlated with NAG, FSH, and LH amounts. However, testosterone levels in SCO syndrome patients were significantly reduced compared with individuals having normal spermatogenesis. CONCLUSION: The levels of biochemical parameters in seminal (NAG and fructose) and blood (FSH, LH, testosterone, and PRL) plasma samples correlate with the histologic diagnosis in azoospermic patients, providing potential benefits in predicting the pathologic diagnosis of male infertility. PMID- 25917732 TI - Interinstitutional variability in testicular volumes and varicocele presence by ultrasound: surprising discrepancies and implications for clinical decision making. AB - OBJECTIVE: To determine the variability of testicular ultrasound (US) volumes and the clinical implications. METHODS: A retrospective review identified 73 patients (62 adult and 11 adolescents) who had testicular US scans performed at both our institution (Urological Institute at Northeastern New York) and at an outside facility (outside hospital study). Testicular volume (TV) was measured using the Lambert formula: length * width * height * 0.71. TV difference (TVD) was calculated as percentage difference = 100 * (right TV - left TV)/left TV and serves as the intrapatient TVD. Patients with clinically palpable varicoceles were correlated to detection on US. Bland-Altman plots were generated to compare the limits of agreement for interinstitutional TVs. Interinstitutional agreement was measured using the Kappa (kappa) coefficient. RESULTS: Although the mean values for TVs were similar between institutions (19.1 vs 19.0 cm(3)), there was a wide range in the limits of agreement with a large standard deviation of difference (8.52 cm(3)). Interinstitutional agreement was poor regarding patients with a >= 20% TVD (kappa = 0.09) and was even worse in patients with both varicoceles and >= 20% TVD (kappa = 0.05). US agreement for verification of clinically detected varicoceles was good (kappa = 0.67). If the variability found in this study was applied to identically sized testicles, an erroneous 20% TVD would be found in 38% of studies. CONCLUSION: Interinstitutional or inter ultrasonographer assessment of TV varies significantly. Clinicians should cautiously interpret the US-determined TV when making surgical decisions. Images, and not just reports, should be reviewed by clinicians. PMID- 25917733 TI - Screening Prostate-specific Antigen Concentration and Prostate Cancer Mortality: The Korean Heart Study. AB - OBJECTIVE: To evaluate the association between serum prostate-specific antigen (PSA) concentration from a screening test and prostate cancer mortality in an Asian population. METHODS: We included 118,665 men in the Korean Heart Study, a large prospective cohort study of participants who voluntarily underwent private health examinations that included PSA-based prostate cancer screening. The baseline visit occurred between January 1994 and December 2004, and follow-up was through December 2011. Deaths from prostate cancer were ascertained from the underlying cause of death from a computerized search of death certificate data from the National Statistical Office in Korea. We used the Cox proportional hazards regression to estimate the association between serum PSA and risk of prostate cancer death adjusting the baseline age, cigarette smoking status, and body mass index. RESULTS: During 1,381,901 person-years of follow-up, 6036 men died of any cause, and of these, 56 men died of prostate cancer. The multivariate adjusted hazard ratio for prostate cancer death statistically significantly increased across PSA concentrations (P trend <.0001). The hazard ratio increased 7% per 1-ng/mL increase in PSA. The association between PSA concentration and death from prostate cancer was stronger in younger than in older men and in heavier than leaner men. CONCLUSION: In conclusion, an increased screening PSA level is associated with an increased risk of prostate cancer death in Korean men. Our findings may have implications for the development of targeted PSA cutpoints for biopsy recommendation. PMID- 25917734 TI - Variation of Prostate-specific Antigen Value in Men and Risk of High-grade Prostate Cancer: Analysis of the Prostate, Lung, Colorectal, and Ovarian Cancer Screening Trial Study. AB - OBJECTIVE: To investigate variations in prostate-specific antigen (PSA) levels among men with an initial normal PSA level in the Prostate, Lung, Colorectal, and Ovarian Cancer Screening Trial study. METHODS: Data were extracted from the Prostate, Lung, Colorectal, and Ovarian Cancer Screening Trial study data set on all men in the interventional arm, with 2 tests performed in a period of < 2 years and with an initial result of the first test <4 ng/mL. The range of variation between first and second tests was computed. Risks of cancer stratified on Gleason score were computed using logistic regression. RESULTS: A total of 31,286 men had 2 PSA tests within 2 years and with an initial value < 4 ng/mL. From the first to the second test, the median variation of PSA levels was 3.4% (interquartile range, -15% to +26%). The variation in PSA value was not associated with the delay between the first and the second test (P = .36), age (P = .16), body mass index (P = .41), and race (P = .12). A total of 2,781 prostate cancers were diagnosed during follow-up. Adjusting for age and initial PSA level, the risk of prostate cancer increased linearly with increasing PSA level at the second test, with an odds ratio of 1.079 (95% confidence interval, 1.058-1.101) for each percent increase in PSA level. However, the variation in PSA was not associated with a higher Gleason score (P = .95 for level variations in cancer of Gleason score < 7 vs >= 7). CONCLUSION: Although an increase in PSA level over time is associated with increased risk of prostate cancer, this association is not related to more aggressive tumors. PMID- 25917735 TI - Surgical anatomy of the penis in hypospadias: magnetic resonance imaging study of the tissue planes, vessels, and collaterals. AB - OBJECTIVE: To report the surgical anatomy of the penis in hypospadias with study of vessels in relation to fascial planes, glans, corpora cavernosa, and corpus spongiosum using magnetic resonance imaging. MATERIALS AND METHODS: Twelve hypospadias presenting at older age (8-20 years) were studied with 1.5-T magnetic resonance imaging scanner and a 3-inch surface coil. Precontrast and postcontrast images were acquired using fast-spin echo sequences in sagittal, coronal, and transverse planes. The findings were processed in Volume Share 4.5, version Workstation, of General Electric Healthcare. Anatomic findings were verified during surgery. With imaging and surgical findings, a 3-dimensional conceptual diagram of surgical anatomy was created. RESULTS: Distinct layers of the skin, dartos fascia, Buck fascia, tunica albuginea, glans urothelium, lamina propria of glans, and corpus spongiosum were delineated with their spatial relationship. Axial pattern vessels of the dartos and its anastomosis with branches of dorsal penile vessels at the coronal sulcus, perforators along the corpus spongiosum, subglanular extension of the fascia, and intraglanular branches of the dorsal penile artery forming an arcade were visualized. CONCLUSION: Dorsomedial and dorsolateral axial pattern vessels are present in penile dartos with relative avascularity at dorsal midline in most cases. Subglanular extension of Buck fascia fused with the basal lamina propria of glans forms a barrier between the tip of corpora and the intraglanular arcade of vessels. Collaterals are present at coronal sulcus, along the bifurcated corpus spongiosum, and the dartos enabling blood flow between the terminal most branches of the external and internal pudendal vessels. PMID- 25917736 TI - Secondary reclosure in classic bladder exstrophy: challenges and outcomes. AB - OBJECTIVE: To analyze the outcomes of failed classic bladder exstrophy (CBE) reclosure with and without pelvic osteotomy. Each failed CBE closure decreases the chance of eventual continence. To minimize secondary failures, most institutions use pelvic osteotomy with reclosure. Reclosure with and without osteotomy can still fail. METHODS: An institutional database of 1210 exstrophy epispadias complex patients was reviewed for CBE patients who had 2 prior failed closures with the third closure at the authors' institution. Patient demographics, closure history, diastasis distance, bladder capacity, and outcomes were examined by chi-square tests comparing osteotomy status with first reclosure. RESULTS: Of 848 CBE patients, 17 met inclusion criteria: 12 with osteotomy at reclosure (group 1) and 5 without (group 2). Median time between initial closure and reclosure in the 2 groups were 6.5 months (range, 0-42 months) and 3 months (range, 0-59 months), respectively. There was no significant difference in the rate of attaining sufficient bladder capacity for bladder neck reconstruction (BNR; 100 cc) between groups 1 and 2 (42% vs 40%; P = .490). Within group 1, patients receiving proper immobilization with external fixation (n = 5) demonstrated a significantly greater rate of attaining sufficient bladder capacity for BNR compared with patients who did not (80% vs 14%; P = .023). There were no differences in the rates of attaining dryness per urethra. CONCLUSION: CBE outcomes worsen with each successive failed closure. Reclosure should be performed with osteotomy and proper immobilization to maximize the chance of sufficient capacity for BNR or augmentation cystoplasty. PMID- 25917737 TI - Robotic excision of recurrent renal cell carcinomas with laparoscopic ultrasound assistance. AB - OBJECTIVE: To report our experience with the first application of minimally invasive robotic resection of solitary recurrences of renal cell carcinoma (RCC) and our use of laparoscopic ultrasound to localize such tumors. PATIENTS AND METHODS: Three patients presented with isolated retroperitoneal recurrences of RCC on surveillance imaging up to 5 years after previous nephrectomy. One patient who originally had caval extension of RCC to the right atrium presented with retrocaval lymphadenopathy consistent with RCC on biopsy. The second patient had a growing lesion in the renal fossa that could not be found during open exploration before referral. The third patient had an enlarging retroaortic mass resected 2 years after left nephrectomy with negative lymphadenectomy. A transperitoneal robotic approach was used in all cases with laparoscopic ultrasound localization. RESULTS: Procedures were completed robotically in 194, 191, and 85 minutes. Recurrent RCC tumors were resected with negative margins. The first patient had 10 benign nodes removed, the second patient underwent robotic mesh repair of a flank hernia, and the third patient had a retroaortic lesion excised despite benign pathology on prior biopsy. Both ambulated and tolerated diet immediately and were discharged on the first postoperative day without complications. Neither patient had recurrence with at least 2 years of follow-up. CONCLUSION: Isolated RCC recurrences are rare with the limited available data advocating surgical resection. We describe the first report of robotic resection of these tumors with excellent surgical and midterm oncologic outcomes. PMID- 25917738 TI - Re: El-Garem et al.: Seminal Helicobacter pylori Treatment Improves Sperm Motility in Infertile Asthenozoospermic Men (Urology 2014;84:1347-1350). PMID- 25917740 TI - Enhanced Sensitivity to Sunitinib by Inhibition of Akt1 Expression in Human Castration-resistant Prostate Cancer PC3 Cells Both In Vitro and In Vivo. AB - OBJECTIVE: To investigate whether antitumor activity of sunitinib is enhanced by silencing Akt1 in a human castration-resistant prostate cancer PC3 model. MATERIALS AND METHODS: We initially established PC3 in which the expression vector containing a short hairpin ribonucleic acid targeting Akt1 was introduced (PC3/sh-Akt1). Changes in various phenotypes of PC3/sh-Akt1 after treatment with sunitinib were compared with those of PC3 transfected with control vector alone (PC3/C) both in vitro and in vivo. RESULTS: When cultured in the standard medium, in vitro growth of PC3/sh-Akt1 was almost similar to that of PC3/C. However, compared with PC3/C, PC3/sh-Akt1 showed a significantly higher sensitivity to sunitinib, accompanying impaired phosphorylation of p44/42 mitogen-activated protein kinase, downregulation of Bcl-2, and upregulation of Bax. In addition, treatment with sunitinib significantly suppressed the migration ability of PC3/sh Akt1 compared with that of PC3/C. In vivo, administration of sunitinib induced the significantly marked growth inhibition of PC3/sh-Akt1 compared with that of PC3/C, and apoptotic index in PC3/sh-Akt1 tumor in mice treated with sunitinib was significantly greater than that in PC3/C tumor. CONCLUSION: Combined treatment with Akt1 inhibitor and sunitinib could be a promising therapeutic approach for men with castration-resistant prostate cancer. PMID- 25917739 TI - Novel agonist of adenosine receptor induces relaxation of corpus cavernosum in guinea pigs: an in vitro and in vivo study. AB - OBJECTIVE: To test the relaxation effect of a new adenosine receptor agonist N acylhydrazone derivative, 3,4-dimethoxyphenyl-N-methyl-benzoylhydrazide (LASSBio 1359), on in vitro and in vivo preparation of corpus cavernosum (CC), and its interaction with type-5 phosphodiesterase enzyme inhibitor, sildenafil. METHODS: For in vitro study, an increasing concentration of LASSBio-1359 was added in the solution at the plateau isometric tension recording of isolated guinea pig CC induced by phenylephrine (30 MUM). Concentration-response curve was repeated in the presence of A2A receptor antagonist, ZM 241385 (10 MUM). Sildenafil-induced CC relaxing effect was compared with that of LASSBio-1359. Isobolographic analysis was performed to identify possible synergistic interaction between LASSBio-1359 and sildenafil. For in vivo study, blood pressure response in the CC of guinea pig was measured after administration of LASSBio-1359 (10 mg/kg intravenously) or sildenafil (10 mg/kg intravenously). RESULTS: LASSBio-1359 caused relaxation of phenylephrine-induced contraction of isolated CC in a concentration-dependent manner (IC50 = 10.1 +/- 1.8 MUM), which was shifted to the right in the presence of ZM 241385 (IC50 = 27.1 +/- 1.4 MUM; P <.05). Isobolographic analysis showed synergistic interaction between LASSBio-1359 and sildenafil. As sildenafil, LASSBio-1359 increased blood pressure oscillation in the CC confirming its systemic efficacy. CONCLUSION: CC relaxing effects induced by the adenosine A2A receptor agonist, LASSBio-1359, demonstrated in vitro and in vivo experimental protocols, represent a promise therapeutic option for the treatment of erectile dysfunction. Synergistic interaction of LASSBio-1359 with sildenafil suggests a combined use to reach a higher population of patients with erectile dysfunction. PMID- 25917741 TI - Compared With Radical Nephrectomy, Nephron-sparing Partial Nephrectomy Protects Apolipoprotein E-deficient Mice From Atherosclerosis Progression. AB - OBJECTIVE: To compare the effect of radical with partial unilateral nephrectomy on the development of atherosclerosis in the apolipoprotein E (apoE(-/-)) deficient mouse model. METHODS: Male apoE(-/-) mice were randomly assigned to the following 3 groups: (1) radical left nephrectomy (RNX, 15 mice), (2) partial left nephrectomy (PNX, 15 mice), and (3) left kidney sham operation (sham-op, 12 mice). The right kidney was left intact in all groups. At 16 weeks after surgery, mice were killed, and atherosclerotic surface area and plaque composition were evaluated in the aortic root and the descending aorta using a quantitative morphologic image processing method. RESULTS: At killing, RNX mice had significantly higher serum urea, total cholesterol, and triglyceride concentrations than PNX and sham-op groups (P <.05, P <.001, and P <.0001, respectively). Atherosclerotic lesions in the aortic root and the descending aorta were significantly increased in the RNX mice compared with those in the PNX and sham-op mice (P <.05 and P <.001, respectively). In addition, aortic plaques of RNX mice showed a significant increase in nitrotyrosine expression (P <.02) and collagen content (P <.05), whereas the degree of macrophage infiltration was comparable between the groups. CONCLUSION: We show for the first time that PNX, as compared with RNX, slows the progression of vascular disease in a mouse model of severe atherosclerosis. This effect was mediated by the prevention of chronic kidney disease-induced increases in oxidative stress and lipid disturbances. Our finding can be interpreted as being in support of an expanded use of nephron sparing techniques in atherosclerosis-prone patients who need to undergo kidney cancer surgery. PMID- 25917742 TI - Eyelid metastasis as the initial presentation of a renal cell carcinoma. AB - Renal cell carcinoma (RCC) often metastasizes to the lungs, liver, brain, and bones. Eyelid metastasis of a distant RCC is an infrequent condition. Breast carcinoma and lung malignancies are responsible of most eyelid metastases, although other malignancies may also metastasize to the eyelid. We report a case with eyelid metastasis as a first presentation of a distant RCC. PMID- 25917743 TI - Heterotopic pancreatic tail appearing as adrenal mass in a patient with left pelvic kidney. AB - A computed tomography scan of a 30-year-old male patient with hematuria incidentally revealed a left pelvic kidney and a lobulated mass in the left adrenal gland concerning for neoplasm. Although laparoscopic adrenalectomy was considered, serial imaging revealed the mass to be the pancreatic tail within the vacant renal fossa. This case demonstrates that ectopia of the kidney can lead to anatomic distortions that may confound the interpretation of radiologic examinations. PMID- 25917744 TI - Seminal vesicle cyst with ipsilateral renal agenesis and ectopic ureter (Zinner syndrome). AB - The symptomatic presentation of seminal vesicle cysts with ipsilateral renal agenesis and ectopic ureter (Zinner syndrome) is rare. Patients are typically diagnosed at the third or the fourth decade of life and often present with infertility. Although the diagnosis can generally be made with magnetic resonance imaging, cystography can also be useful in indeterminate cases. We report on the unusual case of an 18-year-old man who presented with pelvic pain that was intensified by ejaculation. Computed tomography and magnetic resonance imaging revealed a cystic structure in the area of the right seminal vesicle that was successfully excised robotically without complications. PMID- 25917745 TI - Measuring family impact of skin diseases: FDLQI and FROM-16. PMID- 25917746 TI - Reinforcement of hydrogels using three-dimensionally printed microfibres. AB - Despite intensive research, hydrogels currently available for tissue repair in the musculoskeletal system are unable to meet the mechanical, as well as the biological, requirements for successful outcomes. Here we reinforce soft hydrogels with highly organized, high-porosity microfibre networks that are 3D printed with a technique termed as melt electrospinning writing. We show that the stiffness of the gel/scaffold composites increases synergistically (up to 54 fold), compared with hydrogels or microfibre scaffolds alone. Modelling affirms that reinforcement with defined microscale structures is applicable to numerous hydrogels. The stiffness and elasticity of the composites approach that of articular cartilage tissue. Human chondrocytes embedded in the composites are viable, retain their round morphology and are responsive to an in vitro physiological loading regime in terms of gene expression and matrix production. The current approach of reinforcing hydrogels with 3D-printed microfibres offers a fundament for producing tissue constructs with biological and mechanical compatibility. PMID- 25917747 TI - Long-term monitoring of respiratory rate in patients with heart failure: the Multiparametric Heart Failure Evaluation in Implantable Cardioverter Defibrillator Patients (MULTITUDE-HF) study. AB - BACKGROUND: Monitoring respiratory rate (RR) is recommended at the time of hospital presentation for acute decompensation in heart failure (HF). Device based continuous monitoring of RR may be helpful for diagnostic and prognostic stratification after implantable cardioverter-defibrillator (ICD) implantation. This study was undertaken to analyze short- and long-term changes in ICD-measured RR and to relate RR with the patient's clinical status and the occurrence of HF events. METHODS: One hundred twenty-four consecutive HF patients who received ICD endowed with this diagnostic capability (Boston Scientific Inc., Natick, MA, USA) were prospectively enrolled. Patients were followed up for 12 months. RESULTS: At the baseline, the proportion of New York Heart Association (NYHA) class III-IV was higher among patients with daily maximum RR >27 breaths/min (third tertile) than those with <24 breaths/min (first tertile) (43 vs. 23%, p < 0.05). Moreover, the ejection fraction was lower (27 +/- 7 vs. 34 +/- 8%, p < 0.05). In patients with HF hospitalizations (33 events) and urgent visits for HF (15 events), the weekly average of RR calculated over the 7 days preceding hospital accesses did not differ from values recorded at the baseline and before scheduled follow-up visits. However, the weekly variation in RR (i.e., the difference between maximum and minimum values collected over the week) was significantly higher prior to hospitalization (p < 0.05). A weekly variation >3 breaths/min in maximum RR predicted an impending hospital admission for HF with sensitivity of 73 % and specificity of 57%. CONCLUSIONS: In this study, elevated values of ICD-monitored RR identified patients with worse functional status and lower systolic function. The weekly variation in RR increased before HF exacerbation. This monitoring technology may represent a useful tool in the clinical management of patients with HF. PMID- 25917748 TI - Differential expression of mRNA for T-bet and GATA-3 transcription factors in peripheral blood mononuclear cells of patients with vitiligo. AB - BACKGROUND: There is accumulating evidence that aberrant T helper (Th)1 and Th2 cell responses play critical roles in the pathogenesis of autoimmune diseases. However, their importance in the pathobiology of vitiligo have yet to be elucidated. AIM: To evaluate the expression profile of two transcription factors, namely, T-bet, a Th1-specific T box transcription factor and GATA binding protein 3 (GATA-3), a Th2-specific transcription factor, and to measure expression levels of interferon (IFN)-gamma and interleukin (IL)-4 mRNAs as the signature cytokines of Th1 and Th2 cells, respectively. METHODS: Gene expression analysis of peripheral blood mononuclear cells (PBMCs) was performed using real-time reverse transcriptase PCR. RESULTS: In patients with vitiligo compared with controls, mRNA expression was significantly higher for T-bet and IFN-gamma, and significantly lower for GATA-3 and IL-4 mRNAs (P <= 0.05). CONCLUSION: These data suggest additional implications for the role of Th1/Th2 balance in the immunopathogenesis of vitiligo. PMID- 25917749 TI - In Vitro Evaluation of Gd(3+)-Anionic Linear Globular Dendrimer-Monoclonal Antibody: Potential Magnetic Resonance Imaging Contrast Agents for Prostate Cancer Cell Imaging. AB - PURPOSE: Early stage prostate cancer diagnosis is of high global interest. Magnetic resonance imaging (MRI) is a non-invasive modality for early cancer diagnosis, in particular for prostate cancer detection. The research aim is to synthesize a nanodendrimer and its conjugate with C595 monoclonal antibody (mAb C595), against prostate cancer, followed by its chelating with Gd(3+). PROCEDURES: Anti-MUC-1 mAb C595 was conjugated to an anionic linear globular dendrimer (ALGDG2). The polyethylene glycol core and citric acid shell were synthesized followed by loading with Gd(3+) to make novel contrast agents for functional MRI. The in vitro behavior and MRI parameters of the nanoconjugate were investigated performing several studies such as cell toxicity and TNF-alpha evaluations. The investigation of magnetic resonance imaging parameters indicated how well nanoconjugate performs in (1)H-NMR and (17)O-NMR in vitro. RESULTS: Results showed a potential specific MRI activity by improving the swelling responses cell binding. The MTT (2-(4,5-dimethyl-2-thiazolyl)-3,5-diphenyl-2H tetrazolium bromide) assay demonstrated that this contrast agent had significant cytotoxicity on prostate cancer cells. CONCLUSIONS: These results showed that Gd(3+)-ALGDG2-C595 is a potential prostate molecular imaging agent and could be considered as an ideal functional nanoprobe. Additionally, further investigations by clinical trials are in the pipeline. PMID- 25917750 TI - Generation of a Four-Class Attenuation Map for MRI-Based Attenuation Correction of PET Data in the Head Area Using a Novel Combination of STE/Dixon-MRI and FCM Clustering. AB - PURPOSE: The aim of this study is to generate a four-class magnetic resonance imaging (MRI)-based attenuation map (MU-map) for attenuation correction of positron emission tomography (PET) data of the head area using a novel combination of short echo time (STE)/Dixon-MRI and a dedicated image segmentation method. PROCEDURES: MR images of the head area were acquired using STE and two point Dixon sequences. MU-maps were derived from MRI images based on a fuzzy C means (FCM) clustering method along with morphologic operations. Quantitative assessment was performed to evaluate generated MRI-based MU-maps compared to X ray computed tomography (CT)-based MU-maps. RESULTS: The voxel-by-voxel comparison of MR-based and CT-based segmentation results yielded an average of more than 95 % for accuracy and specificity in the cortical bone, soft tissue, and air region. MRI-based MU-maps show a high correlation with those derived from CT scans (R (2) > 0.95). CONCLUSIONS: Results indicate that STE/Dixon-MRI data in combination with FCM-based segmentation yields precise MR-based MU-maps for PET attenuation correction in hybrid PET/MRI systems. PMID- 25917751 TI - Prelimbic Cortical Injections of a GABA Agonist and Antagonist: In Vivo Quantification of the Effect in the Rat Brain Using [(18)F] FDG MicroPET. AB - PURPOSE: We evaluated the glucose metabolism after microinjections of a GABAA antagonist, bicuculline, and a GABAA agonist, muscimol, in the rat prelimbic cortex (PL) by small animal positron emission tomography (MUPET). PROCEDURES: Following a microinjection of either 0.5 MUl bicuculline (0.1 mg/ml), muscimol (1 mg/ml), or saline in the left PL of 11 healthy male Sprague Dawley rats (250-275 g), 2-deoxy-2-[(18)F]fluoro-beta-D-glucose ([(18)F]FDG) PET images were acquired. Volume-of-interest (VOI)-based analysis and voxel-based statistical parametric mapping were performed (n = 9). RESULTS: VOI-based analysis revealed significantly different [(18)F]FDG uptake following bicuculline versus muscimol in PL (p < 0.001), infralimbic cortex (p < 0.01), and cingulate cortex (p < 0.01). Voxel-based analysis showed bicuculline induced widespread significant hypermetabolism throughout the brain while muscimol induced significant localized hypometabolism. CONCLUSIONS: Here, we visualize functional GABAA-mediated correlations of the PL following pharmacological stimulation. This could serve as a reference and shed light on the working and focality of other stimulation paradigms targeting this region. PMID- 25917752 TI - Benchmarking clinical speech recognition and information extraction: new data, methods, and evaluations. AB - BACKGROUND: Over a tenth of preventable adverse events in health care are caused by failures in information flow. These failures are tangible in clinical handover; regardless of good verbal handover, from two-thirds to all of this information is lost after 3-5 shifts if notes are taken by hand, or not at all. Speech recognition and information extraction provide a way to fill out a handover form for clinical proofing and sign-off. OBJECTIVE: The objective of the study was to provide a recorded spoken handover, annotated verbatim transcriptions, and evaluations to support research in spoken and written natural language processing for filling out a clinical handover form. This dataset is based on synthetic patient profiles, thereby avoiding ethical and legal restrictions, while maintaining efficacy for research in speech-to-text conversion and information extraction, based on realistic clinical scenarios. We also introduce a Web app to demonstrate the system design and workflow. METHODS: We experiment with Dragon Medical 11.0 for speech recognition and CRF++ for information extraction. To compute features for information extraction, we also apply CoreNLP, MetaMap, and Ontoserver. Our evaluation uses cross-validation techniques to measure processing correctness. RESULTS: The data provided were a simulation of nursing handover, as recorded using a mobile device, built from simulated patient records and handover scripts, spoken by an Australian registered nurse. Speech recognition recognized 5276 of 7277 words in our 100 test documents correctly. We considered 50 mutually exclusive categories in information extraction and achieved the F1 (ie, the harmonic mean of Precision and Recall) of 0.86 in the category for irrelevant text and the macro-averaged F1 of 0.70 over the remaining 35 nonempty categories of the form in our 101 test documents. CONCLUSIONS: The significance of this study hinges on opening our data, together with the related performance benchmarks and some processing software, to the research and development community for studying clinical documentation and language-processing. The data are used in the CLEFeHealth 2015 evaluation laboratory for a shared task on speech recognition. PMID- 25917754 TI - WORLD BRAIN MEETING The XXII World Congress of Neurology, Santiago, Chile: October 31 - November 5, 2015. PMID- 25917753 TI - Chemosensory perception, symptoms and autonomic responses during chemical exposure in multiple chemical sensitivity. AB - PURPOSE: Multiple chemical sensitivity (MCS) is a prevalent medically unexplained symptom characterized by symptom reactions to everyday chemical exposure below hygienic thresholds. The aim of this study was to investigate the expressions of hyper-reactivity in MCS during whole-body exposure to low concentrations of the odorant n-butanol. METHODS: We exposed 18 participants with MCS and 18 non-ill controls to a low concentration of the odorant n-butanol using an exposure chamber. The first 10 min constituted blank exposure, after which the n-butanol concentration increased and reached a plateau at 11.5 mg/m(3). RESULTS: MCS participants, compared with controls, reported greater perceived odor intensities, more unpleasantness to the exposure and increasing symptoms over time. MCS participants also expressed higher pulse rate and lower pulse rate variability than controls did. No group differences were found for breathing rate or tonic electrodermal activity responses. CONCLUSIONS: We conclude that MCS sufferers differ from healthy controls in terms of autonomic responses, symptoms and chemosensory perception during chemical exposure. PMID- 25917755 TI - Fornix infarction after clipping of anterior communicating artery aneurysm. PMID- 25917756 TI - Relationships between human intestinal absorption and polar interactions drug/phospholipids estimated by IAM-HPLC. AB - Phospholipid affinity indexes (logkW(IAM)) for 15 structurally non-related basic, acidic, ampholytic, and neutral drugs were measured by HPLC on two different phospholipid stationary phases (immobilized artificial membrane - IAM). According to a method we previously proposed, polar and electrostatic forces involved in drug/membrane interactions were quantified both as DeltalogkW(IAM) and as Delta(')logkW(IAM). These values are the differences between the experimental logkW(IAM) and the values expected for a neutral compound having the lipophilicity value equal to either that of the neutral form of the analyte (logP(N)) or that of the mixture of charged and neutral forms of the analyte at jejunum pH 6.5 (logD(6.5)), respectively. Jejunum absorption values, logPeff, measured by the Loc-I-Gut technique, did not relate with logkW(IAM) values. A moderate linear relationship was observed with logP(N) values for all the analytes and a weak parabolic relationship was observed with logD(6.5) values, but only after the exclusion of two analytes. In contrast, a highly significant linear inverse relationship was observed with DeltalogkW(IAM) values. Therefore, differently from the results of our recent studies on blood-brain barrier passage, the intestinal absorption data for not only bases and zwitterions but also for acids relate significantly with DeltalogkW(IAM) and not with Delta(')logkW(IAM) values. The results suggest that membrane passage at jejunum level can be described according to the "flip-flop" model; indeed, the lipophilicity of the neutral forms (logP(N)) appears related to the passage through the non-polar inner moieties of phospholipids whereas DeltalogkW(IAM) parameter appears related to the "trapping" forces at their polar surfaces. The method, easy to perform and at medium throughput, could be of use for preliminary screening of new drugs based on oral absorption potential. PMID- 25917757 TI - Auxin Binding Protein 1: A Red Herring After All? PMID- 25917758 TI - Interactions of OsMADS1 with Floral Homeotic Genes in Rice Flower Development. AB - During reproductive development, rice plants develop unique flower organs which determine the final grain yield. OsMADS1, one of SEPALLATA-like MADS-box genes, has been unraveled to play critical roles in rice floral organ identity specification and floral meristem determinacy. However, the molecular mechanisms underlying interactions of OsMADS1 with other floral homeotic genes in regulating flower development remains largely elusive. In this work, we studied the genetic interactions of OsMADS1 with B-, C-, and D-class genes along with physical interactions among their proteins. We show that the physical and genetic interactions between OsMADS1 and OsMADS3 are essential for floral meristem activity maintenance and organ identity specification; while OsMADS1 physically and genetically interacts with OsMADS58 in regulating floral meristem determinacy and suppressing spikelet meristem reversion. We provided important genetic evidence to support the neofunctionalization of two rice C-class genes (OsMADS3 and OsMADS58) during flower development. Gene expression profiling and quantitative RT-PCR analyses further revealed that OsMADS1 affects the expression of many genes involved in floral identity and hormone signaling, and chromatin immunoprecipitation (ChIP)-PCR assay further demonstrated that OsMADS17 is a direct target gene of OsMADS1. Taken together, these results reveal that OsMADS1 has diversified regulatory functions in specifying rice floral organ and meristem identity, probably through its genetic and physical interactions with different floral homeotic regulators. PMID- 25917760 TI - Lasing in DNA-CTMA doped with Rhodamine 610 in butanol. AB - The light emission properties of the complex formed from deoxyribonucleic acid (DNA)-cetyltrimethylammonium chloride (CTMA) surfactant doped with different concentrations of Rhodamine 610 (Rh610) dye and dissolved in butanol are investigated and discussed. The results are compared to those obtained when only the Rh610 dye is dissolved in butanol, at the same concentrations. The light emission is excited in the investigated samples by the nanosecond pulses of a frequency-doubled Nd:YAG laser, at a wavelength of 532 nm. We have demonstrated the lasing effect in the investigated complex and we have studied its efficiency and coherence properties. The lasing properties of the Rh610 dye are favourably influenced by the presence of the DNA-CTMA complex in the investigated compound. It leads to an increase in the lasing efficiency and in the slope efficiency. Also the temporal coherence of the emitted light is larger and the emission can be tuned to shorter wavelengths. PMID- 25917759 TI - Angiopoietin-like protein 8 (ANGPTL8)/betatrophin overexpression does not increase beta cell proliferation in mice. AB - AIMS/HYPOTHESIS: The identification of novel targets that stimulate endogenous regeneration of beta cells would represent a significant advance in the treatment of patients with diabetes. The betatrophin hypothesis suggests that increased expression of angiopoietin-like protein 8 (ANGPTL8) induces dramatic and specific beta cell proliferation and subsequent beta cell mass expansion with improved glucose tolerance. In light of recent controversy, we further investigated the effects of ANGPTL8 overexpression on beta cell proliferation. METHODS: We performed hydrodynamic tail vein injections of green fluorescent protein (GFP) or Angptl8 (also known as Gm6484) DNA in multiple cohorts of mice of different ages. We employed state-of-the-art methods to comprehensively quantify beta cell mass and proliferation, controlling for mouse age, genetic strain, source of DNA injected, Angptl8 gene expression and proliferation markers. RESULTS: In two young and two aged cohorts of B6.129 mice, no substantial change in beta cell replication, mass or glucose homeostasis was observed following ANGPTL8 overexpression. Even in mice with extremely elevated Angptl8 expression (26-fold increase), beta cell replication was not significantly altered. Finally, we considered mice on the ICR background exactly as studied by Melton and colleagues, and still no beta cell mitogenic effect was detected following ANGPTL8 overexpression. CONCLUSION/INTERPRETATION: ANGPTL8 does not stimulate beta cell replication in young or old mice. PMID- 25917761 TI - Clinical characteristics and treatment outcomes of primary and recurrent malignancy involving the salivary glands in children. AB - BACKGROUND: Malignant salivary gland neoplasms are rare in children. The purpose of this study was to present our experience in the treatment of primary and recurrent salivary gland neoplasm and contribute to the fractional available data. METHODS: All patients <18 years, treated between June 2005 and April 2014 were included in this study. RESULTS: The parotid gland was the most common site for both primary (n = 18) and recurrent (n = 6) tumors and mucoepidermoid carcinoma, low or intermediate grade, main histological type. Surgical excision was performed in all patients, of which 13 patients received radiotherapy. Lymph node metastasis was present in 3 patients with primary tumor, which were assessed accurately on frozen section examination. Local recurrence occurred in 1 patient with primary tumor and all patients are alive. CONCLUSION: Surgery is the prime modality of treatment for malignant salivary gland neoplasm and is associated with excellent outcomes. The role of lymph node sampling and frozen section examination needs further evaluation in identifying lymph node metastasis. (c) 2015 Wiley Periodicals, Inc. Head Neck 38: 852-856, 2016. PMID- 25917762 TI - Antidepressant effects of exercise are produced via suppression of hypocretin/orexin and melanin-concentrating hormone in the basolateral amygdala. AB - Physical exercise is considered beneficial in the treatment of depression, but the underlying mechanism is not clearly understood. In the present study, we investigated the mechanism regulating antidepressant effects of exercise by focusing on the role of the amygdala using a well-defined animal model of depression. C57BL/6 mice treated with repeated restraint showed depression-like behaviors, which was counteracted by post-stress treatment with physical exercise. The two neuropeptides hypocretin/orexin (Hcrt/Orx) and melanin concentrating hormone (MCH) were transcriptionally upregulated in the BLA after repeated stress, and their enhanced expression was downregulated by treatment with exercise, mirroring stress-induced depression-like behaviors and their reversal by exercise. Stereotaxic injection of either Hcrt/Orx peptide or MCH peptide within the BLA commonly increased phospho-CaMKIIalpha level and produced depression-like behaviors, mimicking the neural states in the BLA of mice subjected to repeated stress. In contrast, siRNA-mediated suppression of Hcrt/Orx or MCH in the BLA blocked stress-induced depression-like behaviors. Furthermore, siRNA-mediated inhibition of CaMKIIalpha in the BLA also counteracted stress induced depression-like behaviors. Local injection of Hcrt/Orx peptide or MCH peptide within the BLA in exercise-treated animals blocked antidepressant-like effects of exercise. Together these results suggest that exercise produces antidepressant effects via suppression of Hcrt/Orx and MCH neural systems in the BLA. PMID- 25917763 TI - Endocannabinoids regulate the activity of astrocytic hemichannels and the microglial response against an injury: In vivo studies. AB - Anandamide (AEA) is an endocannabinoid (EC) that modulates multiple functions in the CNS and that is released in areas of injury, exerting putative neuroprotective actions. In the present study, we have used intravital microscopy to analyze the role of the EC system in the glial response against an acute insult. Our data show that AEA modulates astroglial function in vivo by increasing connexin-43 hemichannel (HC) activity. Furthermore, the genetic inactivation of the AEA-degrading enzyme, fatty acid amide hydrolase (FAAH), also increased HC activity and enhanced the microglial response against an acute injury to the brain parenchyma, effects that were mediated by cannabinoid CB1 receptors. The contribution of ATP released through an astrocytic HC was critical for the microglial response, as this was prevented by the use of the HC blocker flufenamic acid and by apyrase. As could be expected, brain concentrations of AEA, palmitoylethanolamide (PEA) and oleoylethanolamide (OEA) were elevated in FAAH-null mice, while 2-arachidonoylglycerol (2-AG) concentrations remained unaltered. In summary, these findings demonstrate that AEA modifies glial functions by promoting an enhanced pro-inflammatory glial response in the brain. PMID- 25917764 TI - Effects of ammonia exposure on apoptosis, oxidative stress and immune response in pufferfish (Takifugu obscurus). AB - Ammonia is one of major environmental pollutants in the freshwater aquatic system that affects the survival and growth of organisms. In the present study, we investigated the effects of ammonia exposure on apoptosis, oxidative stress and immune response in pufferfish (Takifugu obscurus). Fish were exposed to various concentrations of ammonia (0, 1.43, 3.57, 7.14mM) for 72h. The date showed that ammonia exposure could induce intracellular reactive oxygen species (ROS), interrupt intracellular Ca(2+) (cf-Ca(2+)) homeostasis, and subsequently lead to DNA damage and cell apoptosis. To test the apoptotic pathway, the expression patterns of some key apoptotic related genes including P53, Bax Bcl2, Caspase 9, Caspase 8 and Caspase 3 in the liver were examined. The results showed that ammonia stress could change these genes transcription, associated with increasing of cell apoptosis, suggesting that the P53-Bax-Bcl2 pathway and caspase-dependent apoptotic pathway could be involved in cell apoptosis induced by ammonia stress. In addition, ammonia stress could induced up-regulation of inflammatory cytokines (BAFF, TNF-alpha, IL-6 and IL-12) transcription, indicating that innate immune system play important roles in ammonia-induced toxicity in fish. Furthermore, the gene expressions of antioxidant enzymes (Mn-SOD, CAT, GPx, and GR) and heat shock proteins (HSP90 and HSP70) in the liver were induced by ammonia stress, suggesting that antioxidant system and heat shock proteins tried to protect cells from oxidative stress and apoptosis induced by ammonia stress. Our results will be helpful to understand the mechanism of aquatic toxicology induced by ammonia in fish. PMID- 25917766 TI - Diversity of Pediatric Workforce and Education in 2012 in Europe: A Need for Unifying Concepts or Accepting Enjoyable Differences? AB - OBJECTIVE: To evaluate differences in child health care service delivery in Europe based on comparisons across health care systems active in European nations. STUDY DESIGN: A survey involved experts in child health care of 40 national pediatric societies belonging both to European Union and non-European Union member countries. The study investigated which type of health care provider cared for children in 3 different age groups and the pediatric training and education of this workforce. RESULTS: In 24 of 36 countries 70%-100% of children (0-5 years) were cared for by primary care pediatricians. In 12 of 36 of countries, general practitioners (GPs) provided health care to more than 60% of young children. The median percentage of children receiving primary health care by pediatricians was 80% in age group 0-5 years, 50% in age group 6-11, and 25% in children >11 years of age. Postgraduate training in pediatrics ranged from 2 to 6 years. A special primary pediatric care track during general training was offered in 52% of the countries. One-quarter (9/40) of the countries reported a steady state of the numbers of pediatricians, and in one-quarter (11/40) the number of pediatricians was increasing; one-half (20/40) of the countries reported a decreasing number of pediatricians, mostly in those where public health was changing from pediatric to GP systems for primary care. CONCLUSIONS: An assessment on the variations in workforce and pediatric training systems is needed in all European nations, using the best possible evidence to determine the ideal skill mix between pediatricians and GPs. PMID- 25917767 TI - Erythropoiesis Stimulating Agents Demonstrate Safety and Show Promise as Neuroprotective Agents in Neonates. PMID- 25917765 TI - Predictors of Enteral Autonomy in Children with Intestinal Failure: A Multicenter Cohort Study. AB - OBJECTIVES: In a large cohort of children with intestinal failure (IF), we sought to determine the cumulative incidence of achieving enteral autonomy and identify patient and institutional characteristics associated with enteral autonomy. STUDY DESIGN: A multicenter, retrospective cohort analysis from the Pediatric Intestinal Failure Consortium was performed. IF was defined as severe congenital or acquired gastrointestinal diseases during infancy with dependence on parenteral nutrition (PN) >60 days. Enteral autonomy was defined as PN discontinuation >3 months. RESULTS: A total of 272 infants were followed for a median (IQR) of 33.5 (16.2-51.5) months. Enteral autonomy was achieved in 118 (43%); 36 (13%) remained PN dependent and 118 (43%) patients died or underwent transplantation. Multivariable analysis identified necrotizing enterocolitis (NEC; OR 2.42, 95% CI 1.33-4.47), care at an IF site without an associated intestinal transplantation program (OR 2.73, 95% CI 1.56-4.78), and an intact ileocecal valve (OR 2.80, 95% CI 1.63-4.83) as independent risk factors for enteral autonomy. A second model (n = 144) that included only patients with intraoperatively measured residual small bowel length found NEC (OR 3.44, 95% CI 1.36-8.71), care at a nonintestinal transplantation center (OR 6.56, 95% CI 2.53 16.98), and residual small bowel length (OR 1.04 cm, 95% CI 1.02-1.06 cm) to be independently associated with enteral autonomy. CONCLUSIONS: A substantial proportion of infants with IF can achieve enteral autonomy. Underlying NEC, preserved ileocecal valve, and longer bowel length are associated with achieving enteral autonomy. It is likely that variations in institutional practices and referral patterns also affect outcomes in children with IF. PMID- 25917768 TI - Comorbid Conditions Do Not Differ in Children and Young Adults with Functional Disorders with or without Postural Tachycardia Syndrome. AB - OBJECTIVE: To determine if several multisystem comorbid conditions occur more frequently in subjects with tilt-table defined postural tachycardia syndrome (POTS) compared with those without. STUDY DESIGN: Retrospective chart review of 67 subjects aged 6-24 years, referred to a tertiary care neurogastroenterology and autonomic disorders clinic for a constellation of functional gastrointestinal, chronic pain, and autonomic complaints. All patients underwent formal autonomic testing, Beighton scores assessment for joint hypermobility (0 9), and fibromyalgia tender points (0-18) (43 subjects). RESULTS: Twenty-five subjects (37%) met tilt table criteria for POTS. The median age of 16 years (range, 12-24 years) in the POTS group differed from 15 years (range, 6-21 years) in the no-POTS group (P = .03). Comorbidities including chronic fatigue, sleep disturbances, dizziness, syncope, migraines, functional gastrointestinal disorders, chronic nausea, fibromyalgia, and joint hypermobility did not differ between groups. All subjects with fibromyalgia by tender point-examination had a Beighton score >= 4 (P = .002). CONCLUSIONS: Comorbid conditions are equally prevalent in children and young adults with and without tilt-table defined POTS, suggesting that POTS itself is not a cause of the other comorbidities. Instead, POTS likely reflects another comorbid condition in children with functional disorders. Dizziness and syncope, classically associated with POTS, are not predictive of a diagnosis of POTS by tilt table, a test that is still required for formal diagnosis. These results suggest a paradigm shift in the concept of POTS as the physiological basis of many functional symptoms. PMID- 25917769 TI - Hazards Associated with Sitting and Carrying Devices for Children Two Years and Younger. AB - OBJECTIVE: To analyze reported mechanisms of injury and characterize risk factors for infants and young children <= 2 years of age who died in sitting and carrying devices. STUDY DESIGN: A retrospective review of deaths involving sitting and carrying devices (car seats, bouncers, swings, strollers, and slings) reported to the US Consumer Product Safety Commission between 2004 and 2008. RESULTS: Of the 47 deaths analyzed, 31 occurred in car seats, 5 in slings, 4 each in swings and bouncers, and 3 in strollers. The reported elapsed time between the last time a child was seen by a caregiver and found deceased varied greatly, with a mean of 26 minutes in slings; 32 minutes in strollers; 140 minutes in car seats; 150 minutes in bouncers; and 300 minutes in swings. The cause of death was asphyxiation in all cases except one. Fifty-two percent of deaths in car seats were attributed to strangulation from straps; the others were attributed to positional asphyxia. CONCLUSION: Infants and children 2 years of age and younger should be properly restrained and not be left unsupervised in sitting and carrying devices. Car seats should not be used as sleeping areas outside of the vehicle, and children should never be in a car seat with unbuckled or partially buckled straps. Infants in slings should have their faces visible and above the edge of the sling, should not have their faces covered by fabric, and their chins should not be compressed into their chests. PMID- 25917770 TI - Significant Reduction of Central-Line Associated Bloodstream Infections in a Network of Diverse Neonatal Nurseries. AB - OBJECTIVE: To describe a quality improvement (QI) initiative that was associated with a dramatic reduction in neonatal central-line associated bloodstream infection (CLABSI) rate in a diverse group of 8 intensive care nurseries (Neonatal Services). STUDY DESIGN: A quasi-experimental time series QI initiative using the model for improvement and evidenced-based interventions. RESULTS: The aggregate CLABSI rate for Nationwide Children's Hospital-associated Neonatal Services decreased from 6.0 CLABSI per 1000 catheter days to 1.43 CLABSI per 1000 catheter days in less than 2 years and has remained in control at 0.68 per 1000 catheter days for over 5 years. Each of 8 nurseries has had a 1 year or more CLABSI-free period, including the neonatal intensive care unit with the largest patient volume, acuity, and central line usage. Aggregate Neonatal Services has experienced 3 CLABSI-free quarters since 2007. Key success factors included: (1) engagement of senior executive leadership; (2) bedside "huddles" among clinical and epidemiology staffs conducted within 72 hours after a positive blood culture; (3) implementation of chlorhexidine antisepsis and the use of chlorhexidine impregnated catheter site discs; and (4) and establishment of a dedicated team for percutaneously inserted central catheter insertion to serve units in which central lines are placed less frequently. CONCLUSIONS: Using the model for improvement and evidenced-based interventions, this QI project has been associated with reduction in the CLABSI rate by 89%, and over 430 CLABSIs likely have been avoided. PMID- 25917772 TI - Avian rotavirus enteritis - an updated review. AB - Rotaviruses (RVs) are among the leading causes of enteritis and diarrhea in a number of mammalian and avian species, and impose colossal loss to livestock and poultry industry globally. Subsequent to detection of rotavirus in mammalian hosts in 1973, avian rotavirus (AvRV) was first reported in turkey poults in USA during 1977 and since then RVs of group A (RVA), D (RVD), F (RVF) and G (RVG) have been identified around the globe. Besides RVA, other AvRV groups (RVD, RVF and RVG) may also contribute to disease. However, their significance has yet to be unraveled. Under field conditions, co-infection of AvRVs occurs with other infectious agents such as astroviruses, enteroviruses, reoviruses, paramyxovirus, adenovirus, Salmonella, Escherichia coli, cryptosporidium and Eimeria species prospering severity of disease outcome. Birds surviving to RV disease predominantly succumb to secondary bacterial infections, mostly E. coli and Salmonella spp. Recent developments in molecular tools including state-of-the-art diagnostics and vaccine development have led to advances in our understanding towards AvRVs. Development of new generation vaccines using immunogenic antigens of AvRV has to be explored and given due importance. Till now, no effective vaccines are available. Although specific as well as sensitive approaches are available to identify and characterize AvRVs, there is still need to have point of-care detection assays to review disease burden, contemplate new directions for adopting vaccination and follow improvements in public health measures. This review discusses AvRVs, their epidemiology, pathology and pathogenesis, immunity, recent trends in diagnostics, vaccines, therapeutics as well as appropriate prevention and control strategies. PMID- 25917771 TI - Evidence from clinical and animal model studies of the long-term and transgenerational impact of stress on DNA methylation. AB - While it is well-known that stress during development and adulthood can confer long-term neurobiological and behavioral consequences, investigators have only recently begun to assess underlying epigenetic modifications. In this review, we highlight clinical research and work from animal models that provide evidence of the impact of stressful experiences either during the perinatal period or adulthood on DNA methylation and behavior. Additionally, we explore the more controversial concept of transgenerational inheritance, including that associated with preconception stress experienced by the mother or father. Finally, we discuss challenges associated with the idea of transgenerational epigenetics and for the field of epigenetics in general. PMID- 25917774 TI - Maximising image quality in small spaces. AB - A Medical Illustration Department may need to set up a studio in a space that is not designed for that purpose. This joint paper describes the attempts of two separate trusts, University Hospitals Bristol NHS Foundation Trust (UHB) and Norfolk & Norwich University Hospitals (NNUH), to refurbish unusually small studio spaces of 4m * 2m. Each trust had a substantially different project budget and faced separate obstacles, but both had a shared aim; to maximise the limited studio space and enhance the quality of images produced. The outcome at both Trusts is a significant improvement in image quality. PMID- 25917773 TI - [Thyroid C cells and their pathology: Part 2: Medullary thyroid carcinoma]. AB - All tumours with C cell differentiation are designated as medullary carcinomas (MTC). MTC occur sporadically (75-80%) or hereditary (20-25%), the latter being part of the multiple endocrine neoplasia type 2. Familial MTC, which is commonly preceded by "neoplastic" C cell hyperplasia, is caused by autosomal-dominant inherited germ line mutation of the RET-protooncogene; dependent on the codon affected by the mutation, patients show substantially different clinical courses. Due to its morphological heterogeneity, the immunohistochemical demonstration of calcitonin is mandatory for the diagnosis of MTC. For early diagnosis of MTC calcitonin screening has been introduced in Germany and Austria approx. 10 years ago in patients with thyroid nodules; however, an increased calcitonin serum level may also be caused by "non-MEN2-associated" C cell, which is not regarded as a precursor of sporadic MTC. Very rarely tumours may show a mixed C cell follicular cell differentiation. PMID- 25917775 TI - Prospective evaluation of the safety of transrectal ultrasound-guided transperineal prostate biopsy based on adverse events. AB - BACKGROUND: Although transperineal (TP) prostate biopsy is growing in popularity, its safety has not been evaluated based on extensive studies. We prospectively assessed the adverse events associated with transrectal ultrasound (TRUS)-guided TP 16-core prostate biopsy at a single institution. PATIENTS AND METHODS: We enrolled 2,086 males who underwent first-time TRUS-guided TP prostate biopsy under lumbar spinal anesthesia at Chiba Cancer Center between 2009 and 2013. Eight adverse events were assessed prospectively using a purpose-designed questionnaire. The prevalence and duration of all adverse events were evaluated. We performed subgroup analyses for hematuria and urinary retention in relation to clinical factors. RESULTS: Questionnaires were collected from 1,663 cases (79.7 %). The cancer detection rate was 53.5 % in all patients. The prevalence and duration of complications were as follows: hematuria, 73.4 % and 4.51 +/- 2.88 days; perineal bleeding, 7.1 % and 2.20 +/- 2.24 days; hematospermia 14.4 %; dysuria, 15.7 % and 3.12 +/- 2.71 days; urinary tract pain, 49.5 % and 2.43 +/- 2.08 days; perineal pain, 35.5 % and 3.53 +/- 2.59 days; fever >=37 degrees C, 1.7 % and 1.79 +/- 1.72 days; and headache, 22.1 % and 3.40 +/- 2.10 days. Seventeen patients (1.1 %) required indwelling urethral catheterization for grade 2 urinary retention. Pre-biopsy International Prostate Symptom Score (p = 0.014) was an independent related factor for hematuria. Prostate volume (p = 0.001) was an independent related factor for grade 2 urinary retention. CONCLUSIONS: TRUS guided TP prostate biopsy under lumbar spinal anesthesia can be performed safely with only minor adverse events. PMID- 25917776 TI - Clinical characteristics and outcome of pneumothorax after stereotactic body radiotherapy for lung tumors. AB - BACKGOUND: We retrospectively investigated the clinical characteristics and outcome of pneumothorax after stereotactic body radiotherapy (SBRT) for lung tumors. METHODS: Between April 2003 and July 2012, 473 patients with lung tumors were treated with SBRT. We identified 12 patients (2.5 %) with pneumothorax caused by SBRT, and evaluated the clinical features of pneumothorax. RESULTS: All of the tumors were primary lung cancers. The severity of radiation pneumonitis was grade 1 in 10 patients and grade 2 in two patients. Nine patients had emphysema. The planning target volume and pleura overlapped in 11 patients, and the tumors were attached to the pleura in 7 patients. Rib fractures were observed in three patients before or at the same time as the diagnosis of pneumothorax. The median time to onset of pneumothorax after SBRT was 18.5 months (4-84 months). The severity of pneumothorax was grade 1 in 11 patients and grade 3 in one patient. CONCLUSION: Although pneumothorax was a relatively rare late adverse effect after SBRT, some patients demonstrated pneumothorax after SBRT for peripheral lung tumors. Although most pneumothorax was generally tolerable and self-limiting, careful follow-up is needed. PMID- 25917777 TI - Characterization of Missouri surface waters near point sources of pollution reveals potential novel atmospheric route of exposure for bisphenol A and wastewater hormonal activity pattern. AB - Surface water contamination by chemical pollutants increasingly threatens water quality around the world. Among the many contaminants found in surface water, there is growing concern regarding endocrine disrupting chemicals, based on their ability to interfere with some aspect of hormone action in exposed organisms, including humans. This study assessed water quality at several sites across Missouri (near wastewater treatment plants and airborne release sites of bisphenol A) based on hormone receptor activation potencies and chemical concentrations present in the surface water. We hypothesized that bisphenol A and ethinylestradiol would be greater in water near permitted airborne release sites and wastewater treatment plant inputs, respectively, and that these two compounds would be responsible for the majority of activities in receptor-based assays conducted with water collected near these sites. Concentrations of bisphenol A and ethinylestradiol were compared to observed receptor activities using authentic standards to assess contribution to total activities, and quantitation of a comprehensive set of wastewater compounds was performed to better characterize each site. Bisphenol A concentrations were found to be elevated in surface water near permitted airborne release sites, raising questions that airborne releases of BPA may influence nearby surface water contamination and may represent a previously underestimated source to the environment and potential for human exposure. Estrogen and androgen receptor activities of surface water samples were predictive of wastewater input, although the lower sensitivity of the ethinylestradiol ELISA relative to the very high sensitivity of the bioassay approaches did not allow a direct comparison. Wastewater-influenced sites also had elevated anti-estrogenic and anti-androgenic equivalence, while sites without wastewater discharges exhibited no antagonist activities. PMID- 25917778 TI - Intravascular Penetration Following Lumbar Transforaminal Epidural Injections Using the Infraneural Technique. PMID- 25917779 TI - Emergent balloon aortic valvuloplasty as a bridge to transcatheter aortic valve implantation with marked risk reduction of perioperative and postoperative mortality. AB - We report the case of an 87-year-old woman with severe aortic stenosis who presented acutely with cardiogenic shock. Considering her severe condition, we concluded that she would not be able to undergo aortic valve replacement. Life saving emergent balloon aortic valvuloplasty was performed under general anesthesia. There were no postoperative complications, and she was discharged on the 36th hospital day. Shortness of breath with severe aortic stenosis recurred 5 months later. Elective transcatheter aortic valve implantation was performed successfully, and the patient was discharged without complications. Sixteen months on, she is enjoying an active life without disease symptoms. PMID- 25917780 TI - Ruptured saphenous vein graft pseudoaneurysm successfully treated with covered stents. AB - Saphenous vein graft (SVG) pseudoaneurysms are rare complications following coronary bypass graft surgery. A 46-year-old man presented with streptococcal infectious endocarditis and needed sequential operations for aortic root reconstruction. Shortly after the surgeries, a composite SVG on the right coronary artery developed a ruptured pseudoaneurysm, which was successfully treated using covered stents. PMID- 25917781 TI - Letter by Lozano and Vegas Regarding Article, "Temporal Trends in Revascularization Strategy and Outcomes in Left Main Coronary Artery Stenosis: Data From the ASAN Medical Center-Left MAIN Revascularization Registry". PMID- 25917782 TI - A stable chemical SUMO1-Ubc9 conjugate specifically binds as a thioester mimic to the RanBP2-E3 ligase complex. AB - Ubiquitin and ubiquitin-like (Ubl) modifiers such as SUMO are conjugated to substrate proteins by E1, E2, and E3 enzymes. In the presence of an E3 ligase, the E2~Ubl thioester intermediate becomes highly activated and is prone to chemical decomposition, thus making biochemical and structural studies difficult. Here we explored a stable chemical conjugate of the E2 enzyme from the SUMO pathway, Ubc9, with its modifier SUMO1 as a structural analogue of the Ubc9~SUMO1 thioester intermediate, by introducing a triazole linkage by biorthogonal click chemistry. The chemical conjugate proved stable against proteolytic cleavage, in contrast to a Ubc9-SUMO1 isopeptide analogue obtained by auto-SUMOylation. Triazole-linked Ubc9-SUMO1 bound specifically to the preassembled E3 ligase complex RanBP2/RanGAP1*SUMO1/Ubc9, thus suggesting that it is a suitable thioester mimic. We anticipate interesting prospects for its use as a research tool to study protein complexes involving E2 and E3 enzymes. PMID- 25917783 TI - Bariatric Surgery Reduces Features of Nonalcoholic Steatohepatitis in Morbidly Obese Patients. AB - BACKGROUND & AIMS: The effects of bariatric surgery in patients with nonalcoholic fatty liver disease (NASH) are not well established. We performed a prospective study to determine the biological and clinical effects of bariatric surgery in patients with NASH. METHODS: From May 1994 through May 2013, one hundred and nine morbidly obese patients with biopsy-proven NASH underwent bariatric surgery at the University Hospital of Lille, France (the Lille Bariatric Cohort). Clinical, biological, and histologic data were collected before and 1 year after surgery. RESULTS: One year after surgery, NASH had disappeared from 85% of the patients (95% confidence interval [CI]: 75.8%-92.2%). Compared with before surgery, patients had significant reductions in mean +/- SD body mass index (BMI, from 49.3 +/- 8.2 to 37.4 +/- 7) and level of alanine aminotransferase (from 52.1 +/- 25.7 IU/L to 25.1 +/- 20 IU/L); mean levels of gamma-glutamyltransferases were reduced from 51 IU/L before surgery (interquartile range [IQR], 34-87 IU/L) to 23 IU/L afterward (IQR, 14-33 IU/L) and mean insulin resistance index values were reduced from 3.6 +/- 0.5 to 2.9 +/- 0.5 (P < .01 for each comparison). NASH disappeared from a higher proportion of patients with mild NASH before surgery (94%) than severe NASH (70%) (P < .05) according to Brunt score. In histologic analysis, steatosis was detected in 60% of the tissue before surgery (IQR, 40% 80%) but only 10% 1 year after surgery (IQR, 2.5%-21.3%); the mean nonalcoholic fatty liver disease score was reduced from 5 (IQR, 4-5) to 1 (IQR, 1-2) (each P < .001). Hepatocellular ballooning was reduced in 84.2% of samples (n = 69; 95% CI: 74.4-91.3) and lobular inflammation in 67.1% (n = 55; 95% CI: 55.8-77.1). According to Metavir scores, fibrosis was reduced in 33.8% of patients (95% CI: 23.6%-45.2%). Patients whose NASH persisted 1 year after surgery (n = 12) had lost significantly less weight (change in BMI, 9.1 +/- 1.5) than those without NASH (change in BMI, 12.3 +/- 0.6) (P = .005). Patients who underwent laparoscopic gastric banding lost less weight (change in BMI, 6.4 +/- 0.7) than those who underwent gastric bypass (change in BMI, 14.0 +/- 0.5) (P < .0001), and a higher proportion had persistent NASH (30.4% vs 7.6% of those with gastric bypass; P = .015). CONCLUSIONS: Bariatric surgery induced the disappearance of NASH from nearly 85% of patients and reduced the pathologic features of the disease after 1 year of follow-up. It could be a therapeutic option for appropriate morbidly obese patients with NASH who do not respond to lifestyle modifications. More studies are needed to determine the long-term effects of bariatric surgery in morbidly obese patients with NASH. PMID- 25917784 TI - Interleukin 6 Increases Production of Cytokines by Colonic Innate Lymphoid Cells in Mice and Patients With Chronic Intestinal Inflammation. AB - BACKGROUND & AIMS: Innate lymphoid cells (ILCs) are a heterogeneous group of mucosal inflammatory cells that participate in chronic intestinal inflammation. We investigated the role of interleukin 6 (IL6) in inducing activation of ILCs in mice and in human beings with chronic intestinal inflammation. METHODS: ILCs were isolated from colons of Tbx21(-/-) * Rag2(-/-) mice (TRUC), which develop colitis; patients with inflammatory bowel disease (IBD); and patients without colon inflammation (controls). ILCs were characterized by flow cytometry; cytokine production was measured by enzyme-linked immunosorbent assay and cytokine bead arrays. Mice were given intraperitoneal injections of depleting (CD4, CD90), neutralizing (IL6), or control antibodies. Isolated colon tissues were analyzed by histology, explant organ culture, and cell culture. Bacterial DNA was extracted from mouse fecal samples to assess the intestinal microbiota. RESULTS: IL17A- and IL22-producing, natural cytotoxicity receptor-negative, ILC3 were the major subset of ILCs detected in colons of TRUC mice. Combinations of IL23 and IL1alpha induced production of cytokines by these cells, which increased further after administration of IL6. Antibodies against IL6 reduced colitis in TRUC mice without significantly affecting the structure of their intestinal microbiota. Addition of IL6 increased production of IL17A, IL22, and interferon gamma by human intestinal CD3-negative, IL7-receptor-positive cells, in a dose dependent manner. CONCLUSIONS: IL6 contributes to activation of colonic natural cytotoxicity receptor-negative, CD4-negative, ILC3s in mice with chronic intestinal inflammation (TRUC mice) by increasing IL23- and IL1alpha-induced production of IL17A and IL22. This pathway might be targeted to treat patients with IBD because IL6, which is highly produced in colonic tissue by some IBD patients, also increased the production of IL17A, IL22, and interferon-gamma by cultured human colon CD3-negative, IL7-receptor-positive cells. PMID- 25917786 TI - Loss of Infliximab Into Feces Is Associated With Lack of Response to Therapy in Patients With Severe Ulcerative Colitis. AB - BACKGROUND & AIMS: It is not clear why some patients with ulcerative colitis (UC) do not respond to treatment with anti-tumor necrosis factor (TNF) agents, such as infliximab. It could be that some patients have high level of inflammation, with large quantities of TNF to be neutralized by the drug. We investigated whether loss of anti-TNF agents through ulcerated intestinal mucosa reduces the efficacy of these drugs in patients with severe UC. METHODS: We collected fecal samples from 30 consecutive patients with moderate to severely active UC during the first 2 weeks of infliximab therapy at the University of Amsterdam hospital. Infliximab concentrations were measured in serum and supernatants of fecal samples using an enzyme-linked immunosorbent assay (Sanquin Biologicals Laboratory, Amsterdam, The Netherlands). Clinical and endoscopic responses were assessed 2 and 8 weeks and 3 months after treatment began. RESULTS: Infliximab was detected in 129 of 195 fecal samples (66%); the highest concentrations were measured in the first days after the first infusion. Patients that were clinical nonresponders at week 2 had significantly higher fecal concentrations of infliximab after the first day of treatment than patients with clinical responses (median concentration, 5.01 MUg/mL in nonresponders vs 0.54 MUg/mL in responders; P = .0047). We did not observe a correlation between fecal and serum concentrations of infliximab. CONCLUSIONS: Infliximab is lost into stools of patients with UC. High fecal concentrations of infliximab in the first days after therapy begins are associated with primary nonresponse. Additional studies are needed to determine how therapeutic antibodies are lost through the intestinal mucosa and how this process affects treatment response. Clinical trial ID: NL41310.018.12. PMID- 25917785 TI - Radiofrequency Ablation Is Associated With Decreased Neoplastic Progression in Patients With Barrett's Esophagus and Confirmed Low-Grade Dysplasia. AB - BACKGROUND & AIMS: Barrett's esophagus (BE) with low-grade dysplasia (LGD) can progress to high-grade dysplasia (HGD) and esophageal adenocarcinoma (EAC). Radiofrequency ablation (RFA) has been shown to be an effective treatment for LGD in clinical trials, but its effectiveness in clinical practice is unclear. We compared the rate of progression of LGD after RFA with endoscopic surveillance alone in routine clinical practice. METHODS: We performed a retrospective study of patients who either underwent RFA (n = 45) or surveillance endoscopy (n = 125) for LGD, confirmed by at least 1 expert pathologist, from October 1992 through December 2013 at 3 medical centers in the United States. Cox regression analysis was used to assess the association between progression and RFA. RESULTS: Data were collected over median follow-up periods of 889 days (interquartile range, 264-1623 days) after RFA and 848 days (interquartile range, 322-2355 days) after surveillance endoscopy (P = .32). The annual rates of progression to HGD or EAC were 6.6% in the surveillance group and 0.77% in the RFA group. The risk of progression to HGD or EAC was significantly lower among patients who underwent RFA than those who underwent surveillance (adjusted hazard ratio = 0.06; 95% confidence interval: 0.008-0.48). CONCLUSIONS: Among patients with BE and confirmed LGD, rates of progression to a combined end point of HGD and EAC were lower among those treated with RFA than among untreated patients. Although selection bias cannot be excluded, these findings provide additional evidence for the use of endoscopic ablation therapy for LGD. PMID- 25917788 TI - Directed hydrogenations and an Ireland-Claisen rearrangement linked to evans tishchenko chemistry: the highly efficient total synthesis of the marine cyclodepsipeptide doliculide. AB - Two new convergent total syntheses have been developed for the cytotoxic, actin microfilament-stabilizing marine cyclodepsipeptide doliculide (1). A key strategic element of both routes is the establishment of the central stereogenic center of the characteristic polydeoxypropionate stereotriad by means of a hydroxyl-directed catalytic hydrogenation of a trisubstituted double bond. The requisite olefin substrates were obtained through a modified Suzuki-Miyaura coupling or through Ireland-Claisen rearrangement of a propionate ester, respectively; the latter was the direct result of a highly selective Evans Tishchenko reduction of a hydroxy ketone that had been obtained in a stereoselective Paterson aldol reaction. Doliculide (1) was finally obtained in a total number of 17 or 15 (14) linear steps, respectively, which represents a substantial improvement over previous syntheses of this highly bioactive natural product. PMID- 25917787 TI - Inhibitors of ORAI1 Prevent Cytosolic Calcium-Associated Injury of Human Pancreatic Acinar Cells and Acute Pancreatitis in 3 Mouse Models. AB - BACKGROUND & AIMS: Sustained activation of the cytosolic calcium concentration induces injury to pancreatic acinar cells and necrosis. The calcium release activated calcium modulator ORAI1 is the most abundant Ca(2+) entry channel in pancreatic acinar cells; it sustains calcium overload in mice exposed to toxins that induce pancreatitis. We investigated the roles of ORAI1 in pancreatic acinar cell injury and the development of acute pancreatitis in mice. METHODS: Mouse and human acinar cells, as well as HEK 293 cells transfected to express human ORAI1 with human stromal interaction molecule 1, were hyperstimulated or incubated with human bile acid, thapsigargin, or cyclopiazonic acid to induce calcium entry. GSK 7975A or CM_128 were added to some cells, which were analyzed by confocal and video microscopy and patch clamp recordings. Acute pancreatitis was induced in C57BL/6J mice by ductal injection of taurolithocholic acid 3-sulfate or intravenous' administration of cerulein or ethanol and palmitoleic acid. Some mice then were given GSK-7975A or CM_128, which inhibit ORAI1, at different time points to assess local and systemic effects. RESULTS: GSK-7975A and CM_128 each separately inhibited toxin-induced activation of ORAI1 and/or activation of Ca(2+) currents after Ca(2+) release, in a concentration-dependent manner, in mouse and human pancreatic acinar cells (inhibition >90% of the levels observed in control cells). The ORAI1 inhibitors also prevented activation of the necrotic cell death pathway in mouse and human pancreatic acinar cells. GSK-7975A and CM_128 each inhibited all local and systemic features of acute pancreatitis in all 3 models, in dose- and time-dependent manners. The agents were significantly more effective, in a range of parameters, when given at 1 vs 6 hours after induction of pancreatitis. CONCLUSIONS: Cytosolic calcium overload, mediated via ORAI1, contributes to the pathogenesis of acute pancreatitis. ORAI1 inhibitors might be developed for the treatment of patients with pancreatitis. PMID- 25917790 TI - Jurgen Herwig. PMID- 25917789 TI - Clinical and genetic characterisation of infantile liver failure syndrome type 1, due to recessive mutations in LARS. AB - BACKGROUND: Recessive LARS mutations were recently reported to cause a novel syndrome, infantile liver failure syndrome type 1 (ILFS1), in six Irish Travellers. We have since identified four additional patients, including one of Ashkenazi origin, representing the largest ILFS1 cohort to date. Our study aims to define the ILFS1 clinical phenotype to help guide diagnosis and patient management. METHODS: We clinically evaluated and reviewed the medical records of ten ILFS1 patients. Clinical features, histopathology and natural histories were compared and patient management strategies reviewed. RESULTS: Early failure to thrive, recurrent liver dysfunction, anemia, hypoalbuminemia and seizures were present in all patients. Most patients (90 %) had developmental delay. Encephalopathic episodes triggered by febrile illness have occurred in 80 % and were fatal in two children. Two patients are currently >28 years old and clinically well. Leucine supplementation had no appreciable impact on patient well-being. However, we suggest that the traditional management of reducing/stopping protein intake in patients with metabolic hepatopathies may not be appropriate for ILFS1. We currently recommend ensuring sufficient natural protein intake when unwell. CONCLUSIONS: We report the first non-Irish ILFS1 patient, suggesting ILFS1 may be more extensive than anticipated. Low birth weight, early failure to thrive, anemia and hypoalbuminemia are amongst the first presenting features, with liver dysfunction before age 1. Episodic hepatic dysfunction is typically triggered by febrile illness, and becomes less severe with increasing age. While difficult to anticipate, two patients are currently >28 years old, suggesting that survival beyond childhood may be associated with a favourable long-term prognosis. PMID- 25917791 TI - Association of school, family, and mental health characteristics with suicidal ideation among Korean adolescents. AB - In a cross-sectional research design, we investigated factors related to suicidal ideation in adolescents using data from the 2013 Online Survey of Youth Health Behavior in Korea. This self-report questionnaire was administered to 72,435 adolescents aged 13-18 years in middle and high school. School characteristics, family characteristics, and mental health variables were analyzed using descriptive statistics, chi(2) tests, and logistic regression. Both suicidal ideation and behavior were more common in girls. Suicidal ideation was most common in 11th grade for boys and 8th grade for girls. Across the sample, in logistic regression, suicidal ideation was predicted by low socioeconomic status, high stress, inadequate sleep, substance use, alcohol use, and smoking. Living apart from family predicted suicidal ideation in boys but not in girls. Gender- and school-grade-specific intervention programs may be useful for reducing suicidal ideation in students. PMID- 25917793 TI - DNA Functionalized Direct Electro-deposited Gold nanoaggregates for Efficient Detection of Salmonella typhi. AB - Direct electro-deposition of gold nano-aggregates (GNAs) was carried out to fabricate electrochemical DNA biosensor for the detection of Salmonella typhi in urine and blood samples. Size of depositing GNAs was controlled by regulating electro-deposition parameters at physiological pH. This facilitated achieving biocompatible GNAs with desired electrochemical behaviour and enhanced surface area to achieve higher DNA loading. Salmonella typhi (S. typhi) specific 5'amine modified single stranded DNA (ssDNA, NH2-(C6)-5'CGTGCGCGACGCCCGCCGCC3') was covalently immobilized on to GNAs-ITO (indium tin oxide) electrode. Dynamic detection range of 4 aM - 24 fM. using methylene blue (MB) redox indicator at 25 degrees C was achieved using ssDNA-GNAs-ITO bio-electrode to detect the complimentary target sequence (5'GGCGGCGGGCGTCGCGCACG 3') through differential pulse voltammetry (DPV) and electrochemical impedance spectroscopy (EIS). Selectivity of designed electrode was ascertained by response signal for complementary, non-complementary and 1 base mismatch sequences. Furthermore, clear distinction in complementary and non-complimentary targets was obtained by EIS studies for genomic DNA in culture spiked biological fluids 'CSBF' (blood and urine). This study for detection of S. typhi from urine and blood samples using fabricated ssDNA-GNA-ITO bio-electrode showed promising results and have potential to be used as sensor for real patient samples. PMID- 25917792 TI - Effects of panaxadiol saponins component as a new Chinese patent medicine on proliferation, differentiation and corresponding gene expression profile of megakaryocytes. AB - OBJECTIVE: To investigate the effects of panaxadiol saponins component (PDS-C) isolated from total saponins of panax ginseng on proliferation, differentiation and corresponding gene expression profile of megakaryocytes. METHODS: Bone marrow culture of colony forming assay of megakaryocytic progenitor cells (CFU-MK) was observed for the promoting proliferation mediated by PDS-C, and differentiation of megakaryocytic blasts caused by PDS-C was analyzed with flow cytometry in CHRF 288 and Meg-01 cells, as well as proliferation, differentiation-related genes expression profile and protein expression levels were detected by human gene expression microarray and western blot. RESULTS: In response to PDS-C 10, 20 and 50 mg/L, CFU-MK from 10 human bone marrow samples was increased by 28.9%+/-2.7%, 41.0%+/-3.2% and 40.5%+/-2.6% over untreated control, respectively (P <0.01, each). Flow cytometry analysis showed that PDS-C treated CHRF-288 cells and Meg 01 cells significantly increased in CD42b, CD41, TSP and CD36 positive ratio, respectively. PDS-C induced 29 genes up-regulated more than two-fold commonly in both cells detected by human expression microarray representing 4000 known genes. The protein expression levels of ZNF91, c-Fos, BTF3a, GATA-1, RGS2, NDRG2 and RUNX1 were increased with western blot in correspond to microarray results. CONCLUSION: PDS-C as an effective component for hematopoiesis, play the role to enhance proliferation and differentiation of megakaryocytes, also up-regulated expression of proliferation, differentiation-related genes and proteins in vitro. PMID- 25917794 TI - Long-Term Follow-Up and Survivorship After Completing Systematic Surveillance in Stage I-III Colorectal Cancer: Who Is Still at Risk? AB - PURPOSE: In patients with a high life expectancy at the time of surgery for colorectal cancer (CRC), the long-term outcome may be influenced by factors other than their cancer. We aimed to investigate the long-term outcome and cause of death beyond a 5-year surveillance programme. METHODS: We evaluated the overall survival (OS) and cancer-specific survival (CSS) of a population-based cohort of stage I-III CRC patients <75 years old who completed a systematic surveillance programme. RESULTS: In total, 161 patients <75 years old, 111 (69 %) of whom were node negative (pN0), were included. The median follow-up time was 12.1 years. The OS was 54 % at 15 years and differed significantly between the pN0 and pN+ patients (65 vs. 30 %; P < 0.001); CSS (72 %) also differed between the pN0 and pN+ patients (85 vs. 44 %; P < 0.001). For the 5-year survivors (n = 119), 14 (12 %) died of CRC during additional long-term follow-up (7 each for pN0 and pN+), and 6 patients (5 %; all pN0) died of other cancers. Patients aged <65 years exhibited better long-term survival (81 %), but most of the deaths were due to CRC (10/12 deaths). Only two of the 14 cancer-related deaths involved microsatellite instable (MSI) CRC. Females exhibited better OS and CSS beyond 5 years of surveillance. CONCLUSIONS: The long-term survival beyond 5-year survivorship for stage I-III CRC is very good. Nonetheless, cancer-related deaths are encountered in one-third of patients and occur most frequently in patients who are <65 years old at disease onset-pointing to a still persistent risk several years after surgery. PMID- 25917795 TI - Uric Acid Promotes Osteogenic Differentiation and Inhibits Adipogenic Differentiation of Human Bone Mesenchymal Stem Cells. AB - To investigate the effect of uric acid on the osteogenic and adipogenic differentiation of human bone mesenchymal stem cells (hBMSCs). The hBMSCs were isolated from bone marrow of six healthy donors. Cell morphology was observed by microscopy and cell surface markers (CD44 and CD34) of hBMSCs were analyzed by immunofluorescence. Cell morphology and immunofluorescence analysis showed that hBMSCs were successfully isolated from bone marrow. The number of hBMSCs in uric acid groups was higher than that in the control group on day 3, 4, and 5. Alizarin red staining showed that number of calcium nodules in uric acid groups was more than that of the control group. Oil red-O staining showed that the number of red fat vacuoles decreased with the increased concentration of uric acid. In summary, uric acid could promote the proliferation and osteogenic differentiation of hBMSCs while inhibit adipogenic differentiation of hBMSCs. PMID- 25917797 TI - Sepsis guidelines: Suggestions to improve adherence. AB - The context in which a sepsis guideline is to be used is important and to a large extent determines whether it will be implemented successfully. Factors such as lack of time and resources, lack of reimbursement and organizational constraints may also preclude adoption of guidelines. Thus, sepsis guidelines have been adapted to suit the resources in both resource rich and poor regions of the world. However, even when resources are present, physicians' may not follow guidelines due a myriad of reasons including a lack of agreement with the sepsis guideline or with guidelines in general, as well as lack of motivation and expectations of the desired outcomes. A holistic approach is necessary to address all issues that may be impediments to guideline adoption and adherence. This approach would include a rigorous transparent method to craft the guideline, which includes both clinicians and policy makers and addresses cultural and resource issues. PMID- 25917796 TI - UbcH10 expression can predict prognosis and sensitivity to the antineoplastic treatment for colorectal cancer patients. AB - Colorectal cancer (CRC) is one of the most frequent and deadly malignancies worldwide. Despite the progresses made in diagnosis and treatment, the identification of tumor markers is still a strong clinical need, because current treatments are efficacious only in a subgroup of patients. UbcH10 represents a potential candidate biomarker, whose expression levels could be employed to predict response or resistance to chemotherapy or targeted agents. UbcH10 mRNA and protein expression levels have been evaluated in a large group of CRC patients and correlated with clinico-pathological characteristics, including KRAS mutations. Moreover, the endogenous levels of UbcH10 and its role on cell growth have been evaluated in CRC cells. Finally, to investigate the impact of UbcH10 protein expression on the response to irinotecan, its active metabolite SN-38 and cetuximab treatment, UbcH10 silencing experiments were carried-out on two colon carcinoma cell lines, Caco-2, and DLD1. Overexpression of UbcH10 mRNA and protein was observed in the vast majority of patients analyzed. UbcH10 suppression decreased CRC cell growth rate (at least in part through deregulation of Cyclin B and ERK1) and sensitized them to pharmacological treatments with irinotecan, SN 38 and cetuximab (at least in part through a down-regulation of AKT). Taken together, these findings indicate that UbcH10 expression regulates CRC growth and could play an important role in the personalization of the therapy of CRC patients. PMID- 25917798 TI - Group B meningococcal vaccine science and policy. AB - Capsular group B Neisseria meningitidis is one of the leading causes of death in developed countries. A new vaccine (4CMenB) has recently been developed which was found to have an acceptable safety profile in clinical studies and to be immunogenic. This review examines the evidence supporting the licensure of the 4CMenB vaccine and discusses recommendations for its use. PMID- 25917799 TI - Varicella zoster virus immunity: A primer. AB - Varicella zoster (VZV) is among the most prevalent viruses affecting the human race. The majority of us experience primary infection as varicella in childhood and remain latently infected, with occasional reactivation as the infectious entity, shingles. Rarely, VZV causes severe and disseminated disease, which can be fatal despite the availability of highly active antiviral agents. VZV is the only herpesvirus against which effective vaccines have been developed and widely implemented in several countries, further complicating its epidemiology. The immunological correlates of protection against varicella remain incompletely understood. Here we provide a brief overview of evidence from animal models and observational studies that define immunologic risk factors for severe varicella, and thus the most important elements of VZV immunity. Although circulating VZV specific antibody can prevent primary infection, innate and cellular responses appear much more important in limiting its severity and duration. Improved understanding of these protective factors may assist us in developing more effective strategies for the prevention and treatment of severe varicella. PMID- 25917800 TI - Pediatric sepsis in the developing world. AB - Sepsis is the leading killer of children worldwide, but this is not reflected in estimates of global mortality. While it is important to classify deaths according to specific causes such as pneumonia, malaria and diarrheal diseases, we contend that it is a mistake to ignore the unifying feature of all of these deaths--they are due to sepsis. The issue of highlighting sepsis as the end result of severe infections is not merely cosmetic but is important for a provision of care especially in resource limited environments where skilled healthcare workers are in short supply and care is being delivered by teams with limited training and clinical skills. Highlighting sepsis and the few simple emergency therapeutic interventions needed will focus on the actual problems that confront clinicians in regions with limited resources. PMID- 25917801 TI - Febrile neutropenia in children treated for malignancy. AB - Febrile neutropenia (FN) in children treated for malignancy is a common and direct sequela of chemotherapy. Episodes of FN can be life-threatening, and demand prompt recognition, assessment and treatment with broad spectrum antibiotics. While in the majority of episodes no causal infection is identified, 10-20% are secondary to a bloodstream infection (BSI). A reduction in episodes of BSI could be achieved through robust infection prevention strategies, such as CVL care bundles. Alongside good antimicrobial stewardship, these strategies could reduce the risk of emergent, multi-drug resistant (MDR) infections. Emerging bacterial pathogens in BSI include Viridans Group Streptococci (VGS) and Enterobacteriaceae such as Klebsiella spp. which are known for their ability to carry MDR genes. There is also increased recognition of the role of invasive fungal infection (IFI) in FN, in particular with Aspergillus spp. Novel diagnostics, including multiplex blood and respiratory polymerase chain reaction assays can identify infections early in FN, facilitating targeted therapy, and reducing unnecessary antimicrobial exposure. Given appropriate, and sensitive rapid diagnostics, potential also exists to safely inform the risk assessment of patients with FN, identifying those at low risk of complication, who could be treated in the out-patient setting. Several clinical decision rules (CDR) have now been developed and validated in defined populations, for the risk assessment of children being treated for cancer. Future research is needed to develop a universal CDR to improve the management of children with FN. PMID- 25917802 TI - Influenza and humidity--Why a bit more damp may be good for you! AB - Influenza viruses cause much winter-time morbidity and death in temperate regions. We still do not understand why 'flu is more common in winter. Since the 1960s, investigators have studied the role of relative humidity and temperature on viral survival, transmission and infection rates but results have demonstrated only inconclusive trends. Over the past few years however, a series of exciting studies have instead focussed on absolute humidity and demonstrated highly significant correlations with viral survival and transmission rates in both laboratory and epidemiological models. Here we review the evidence for a causal association between absolute humidity and 'flu transmission and outline how this could lead to a new approach to curbing this and perhaps other viral epidemics in the winter months. PMID- 25917803 TI - What the pediatrician should know about non-typeable Haemophilus influenzae. AB - Non-typeable Haemophilus influenzae (NTHi) live exclusively in the pharynges of humans and are increasingly recognized as pathogens that cause both localized infections of the respiratory tract (middle ear spaces, sinuses, and bronchi) and systemic infections such as bacteraemia and pneumonia. Only one vaccine antigen of NTHi, Protein D, has been extensively studied in humans and its efficacy in preventing NTHi otitis media is modest. Recent genetic analyses reveal that NTHi are closely related to Haemophilus haemolyticus (Hh), previously thought to be a non-pathogenic commensal of the pharynx. This review discusses the differences between the pathogenic potential of encapsulated and non-typeable Hi. In addition, information on the lifestyles and bacterial characteristics of NTHi and Hh as they pertain to their pathogenic capacities and the value of the Haemophilus taxonomy to clinicians are presented. Further, the epidemiology and mechanisms of NTHi antibiotic resistance, which include production of beta lactamase and alterations of penicillin-binding protein 3, are reviewed, as are the challenges of vaccine antigen discovery in NTHi. PMID- 25917804 TI - Pediatric intracranial abscesses. AB - Intracranial infections in children are a relatively rare, but potentially severe condition. Because of the potential for rapid deterioration, timely diagnosis and treatment are necessary. These infections are categorized based on their intracranial location: epidural abscess, subdural empyema, and brain abscess. They largely arise from direct extension of adjacent infection, hematogenous seeding, or trauma. Clinical presentations of intracranial infections also vary. However, common signs and symptoms include headache, fever, nausea and vomiting, altered mental status, focal neurologic deficits, and seizures. In general, MRI demonstrates a peripherally enhancing lesion with high signal on diffusion weighted imaging (DWI). Bacterial isolates vary, but most commonly are a single pathogen. Successful treatment requires a multidisciplinary team approach including such modalities as antibiotic therapy and surgical drainage. When possible, open surgical evacuation of the abscess is preferred, however, in cases of deep-seated lesions, or in unstable patients, aspiration has also been performed with good results. PMID- 25917805 TI - Tick-borne diseases of the USA: Ten things clinicians should know. AB - This article highlights critical aspects of the epidemiology, diagnosis, and management of tick-borne infections in children. Principles that apply broadly across the continental United States are emphasized, rather than details of each disease. Tick-borne infections are often confused with other, more common childhood illnesses, in part because of their nonspecific initial clinical findings and because patients are usually unaware of their preceding tick exposures. This is a problem, because delays in starting appropriate antibiotic therapy increase the likelihood of adverse outcomes from these infections, especially Rocky Mountain spotted fever (RMSF). For patients in whom RMSF is a reasonable diagnostic consideration, therapy should be started presumptively, without awaiting the results of confirmatory diagnostic tests. For both adults and children, doxycycline is the drug of choice for RMSF and other American rickettsial infections. Concerns over the potential toxicity of doxycycline in young children are unfounded. Similarly groundless is the belief in "chronic Lyme disease" as an explanation for persistent nonspecific complaints after completing antibiotic therapy for Lyme disease. Prevention of tick-borne infections rests on avoidance of tick-bites and prompt removal of attached ticks. When used appropriately, insect repellents containing DEET are safe and effective for preventing tick exposures. PMID- 25917806 TI - Sore throat: Is it such a big deal anymore? AB - Sore throat remains a common disease of childhood, and a major cost and cause for antibiotic prescriptions. The management of sore throat remains controversial in affluent countries with various guidelines available and overall poor adherence to those guidelines. Group A streptococcus is the commonest bacterial cause with important sequelae including acute rheumatic fever (ARF). The driver for diagnosis and treatment is still questionable. In most affluent populations it is difficult to justify antibiotic treatment on the basis of preventing ARF, whereas this remains the major driver for sore throat management in populations at higher risk of ARF. Reduction in severity and duration of symptoms may be a reasonable basis to consider antibiotic treatment, and thus accurate diagnosis of GAS pharyngitis, particularly in those with more severe symptoms. The potential role of rapid tests in diagnosis appears to be increasing. PMID- 25917807 TI - Recurrent, protracted and persistent lower respiratory tract infection: A neglected clinical entity. AB - Community-acquired pneumonia is a potentially life-threatening disease affecting children worldwide. Recurrent pneumonia episodes can lead to the development of chronic respiratory morbidity. Chronic wet cough, a common pediatric complaint, is defined as a wet cough indicating excessive airway mucus that lasts for a minimum of 4 weeks. Most children with a chronic wet cough do not suffer from underlying debilitating pulmonary disorders. Rather, chronic wet cough is generally associated with neutrophilic airway inflammation and bacterial infections of the conducting airways. Failure to characterize endobronchial infections has led to under-recognition of chronic wet cough as an important clinical entity in children. Under-recognition and under-treatment of protracted bacterial bronchitis (PBB), a diagnosis made by the presence of isolated cough >4 weeks that resolves with appropriate antibiotic treatment, may lead to the development of chronic suppurative lung disease (CSLD) and bronchiectasis. The burden of bronchiectasis is highest in developing countries and in specifically vulnerable populations in developed countries, in particular indigenous children living in remote communities. The incidence, hospitalization rates and risk of long term sequelae of childhood pneumonia in indigenous children are higher than in non-indigenous children residing in the same area. The overlapping clinical and pathophysiological characteristics of PBB, CSLD and bronchiectasis are the presence of a chronic wet cough, impaired mucociliary clearance of the conducting airways, the presence of endobronchial bacterial infection (mainly non-typeable Haemophilus influenzae, Streptococcus pneumoniae and Moraxella catarrhalis) and neutrophilic airway inflammation. The principles of managing PBB, CSLD and bronchiectasis are the same. More research and public health interventions are required to improve the awareness, diagnosis and management of these causes of chronic wet cough in children. PMID- 25917808 TI - Azole-resistant aspergillosis. AB - Azole-resistance in Aspergillus fumigatus is emerging and is becoming an increasing problem in the management of aspergillosis. Two types of development of resistance have been described; resistance acquired during azole treatment in an individual patient and through environmental exposure to fungicides. The main molecular mechanism of azole resistance in A. fumigatus is explained by mutations in the cyp51A-gene. The environmental route of resistance development is particularly worrying and may affect all patients whether azole exposed or naive, and whether suffering from acute or chronic aspergillosis. No management guidelines to assist clinicians confronted with azole-resistant aspergillosis are available and pre-clinical and clinical evidence supporting treatment choices is scarce. PMID- 25917809 TI - Recent advances in the study of Q fever epidemiology, diagnosis and management. AB - Q fever is a worldwide zoonotic infection with an epidemiological pattern consisting of sporadic cases, endemic situations and outbreaks of unsuspected magnitude, as occurred in Holland. This event highlighted the fact that the term "chronic Q fever" is misleading and should be avoided. Here, we review recent advances in the understanding and management of this disease. There have been clonal outbreaks of confirmed "geotypes," such as the outbreaks in French Guiana, where a very high incidence was restricted to one city, with a specific clinical expression, an unusual serological response and a putative common reservoir. The advent of positron emission tomography has improved the diagnosis of endocarditis, vascular and osteoarticular infections. Molecular tests, including fluorescent in situ hybridization, may be included in the diagnostic strategy using the new criteria for endocarditis, vascular and osteoarticular infections. Q fever during pregnancy is challenging because pregnant women are less symptomatic, but infection is associated with a poor fetal outcome, including malformations that are preventable by antibiotics. Male patients over 40 years old with a valvulopathy are at the highest risk for progression to endocarditis. Antibiotic prophylaxis prevents endocarditis in 100% of at-risk patients. Finally, IgG anticardiolipin antibodies, part of the auto-immune response during acute Q fever, were recently added to the risk factors for endocarditis, due to their ability to promote acute valvular lesions and endocarditis. PMID- 25917810 TI - Promoting the rights and responsibilities of children: a South Australian example. AB - In 2014, the Parafield Gardens Children's Centre for Early Childhood Development and Parenting was recognised as a Global Peace School - Early Years (GPSEY). During the recognition process, a project promoting the rights and responsibilities of children and families was facilitated. Partnering with children and families in decision making was a project priority. Young children had an active role in decision making. Through age-appropriate activities and discussions, children and families developed deeper understanding of child rights, peace building, global awareness and social inclusion. Educational staff were supported to enhance this child rights focus. A GPSEY recognition celebration acknowledged child rights and the community's cultural diversity. The outcome of GPSEY recognition is significant but the process that fostered community ownership, participation and social inclusion is worth noting. Involving children in decision making and development promotes their rights and responsibilities; this can make a positive difference for children locally, and globally. PMID- 25917811 TI - GLUTATHIONE S-TRANSFERASE Genes IN THE RICE LEAFFOLDER, Cnaphalocrocis medinalis (LEPIDOPTERA: PYRALIDAE): IDENTIFICATION AND EXPRESSION PROFILES. AB - In insects, glutathione S-transferases (GSTs) play critical roles in the detoxification of various insecticides, resulting in insecticide resistance. The rice leaffolder, Cnaphalocrocis medinalis, is an economically important pest of rice in Asia. GST genes have not been largely identified in this insect species. In the present study, by searching the transcriptome dataset, 25 candidate GST genes were identified in C. medinalis for the first time. Of these, 23 predicted GST proteins fell into five cytosolic classes (delta, epsilon, omega, sigma, and zeta), and two were assigned to the "unclassified" subgroup. Real-time quantitative PCR analysis showed that these GST genes were differentially expressed in various tissues, including the midgut, Malpighian tubules, and fat body of larvae, and the antenna, abdomen, and leg of adults, indicating diversified functions for these genes. Transcription levels of CmGSTd2, CmGSTe6, and CmGSTe7 increased significantly in larvae following exposure to chlorpyrifos, suggesting that these GST genes could be involved in the detoxification of this insecticide. The results of our study pave the way to a better understanding of the detoxification system of C. medinalis. PMID- 25917812 TI - Anaemia management and mortality risk in newly visiting patients with chronic kidney disease in Japan: The CKD-ROUTE study. AB - AIM: To investigate the association between iron deficiency anaemia and mortality risk and assess the changes in anaemia and iron status after primary management by a nephrologist. METHODS: In this prospective cohort study, we stratified 951 non-dialysis chronic kidney disease (CKD) G2-G5 patients newly visiting 16 nephrology centres into four groups according to the presence of anaemia with or without iron deficiency. All-cause mortality, cardiovascular (CV)-related mortality, and a change in anaemia and iron status after specialized primary care were the endpoints evaluated. RESULTS: During a median follow-up time of 19 months, the number of all-cause deaths and CV-related deaths were 56 and 26, respectively. Compared with the control group, the groups with isolated anaemia and iron deficiency anaemia had significantly higher all-cause mortalities (isolated anaemia: hazard ratio (HR), 3.37; 95% confidence intervals (CI), 1.76 6.44; iron deficiency anaemia: HR, 3.11; 95% CI, 1.21-8.01) and CV-related mortalities (isolated anaemia: HR, 3.64; 95% CI, 1.36-9.73; iron deficiency anaemia: HR, 3.86; 95% CI, 1.11-13.41). In the isolated anaemia group, erythropoietin-stimulating agent (ESA) prescriptions significantly increased to approximately 70%. However, in patients with both anaemia and iron deficiency, iron prescriptions only increased to 48.1%. CONCLUSIONS: Iron deficiency anaemia and isolated anaemia were associated with all-cause and CV-related mortality. The absence of relative increase in iron prescriptions suggests that iron deficiency should be accurately assessed and iron supplementation should be appropriately used to manage anaemia in non-dialysis patients with CKD. PMID- 25917813 TI - Functional analysis of naturally occurring DCLRE1C mutations and correlation with the clinical phenotype of ARTEMIS deficiency. AB - BACKGROUND: The endonuclease ARTEMIS, which is encoded by the DCLRE1C gene, is a component of the nonhomologous end-joining pathway and participates in hairpin opening during the V(D)J recombination process and repair of a subset of DNA double-strand breaks. Patients with ARTEMIS deficiency usually present with severe combined immunodeficiency (SCID) and cellular radiosensitivity, but hypomorphic mutations can cause milder phenotypes (leaky SCID). OBJECTIVE: We sought to correlate the functional effect of human DCLRE1C mutations on phenotypic presentation in patients with ARTEMIS deficiency. METHODS: We studied the recombination and DNA repair activity of 41 human DCLRE1C mutations in Dclre1c(-/-) v-abl kinase-transformed pro-B cells retrovirally engineered with a construct that allows quantification of recombination activity by means of flow cytometry. For assessment of DNA repair efficacy, resolution of gammaH2AX accumulation was studied after ionizing radiation. RESULTS: Low or absent activity was detected for mutations causing a typical SCID phenotype. Most of the patients with leaky SCID were compound heterozygous for 1 loss-of-function and 1 hypomorphic allele, with significant residual levels of recombination and DNA repair activity. Deletions disrupting the C-terminus result in truncated but partially functional proteins and are often associated with leaky SCID. Overexpression of hypomorphic mutants might improve the functional defect. CONCLUSIONS: Correlation between the nature and location of DCLRE1C mutations, functional activity, and the clinical phenotype has been observed. Hypomorphic variants that have been reported in the general population can be disease causing if combined in trans with a loss-of-function allele. Therapeutic strategies aimed at inducing overexpression of hypomorphic alleles might be beneficial. PMID- 25917814 TI - Effects of a 15-Month Supervised Exercise Program on Physical and Psychological Outcomes in Prostate Cancer Patients Following Prostatectomy: The ProRehab Study. AB - PURPOSE: Despite advanced medical treatment options, many prostate cancer patients are still confronted with unfavorable physical and psychological burdens. Physical exercise has proven to be beneficial for prostate cancer patients, yet specific exercise offers are rare. The ProRehab Study aimed to evaluate the exercise program offered in rehabilitative prostate cancer sports groups in Germany and determine whether it is beneficial for patients following prostatectomy. METHODS: Eighty-five prostate cancer patients were recruited for a multicenter, 2-armed, nonrandomized controlled trial 6 to 12 weeks after prostatectomy. The intervention group (n = 56) took part in a 15-month supervised multimodal exercise program. Exercise sessions took place once a week for 60 minutes at a moderate intensity (3.84-4.84 MET-hour). The control group (n = 29) received no intervention. Outcomes included aerobic fitness, activity levels, quality of life, disease- and treatment-related adverse effects, such as urinary incontinence and erectile dysfunction, and relapse-relevant blood values. Intention-to-treat analysis was performed. RESULTS: A significant between-group difference was observed in the urinary symptom score (P = .027). Physical fitness, urinary incontinence, physical, role, emotional, and social functioning, as well as further disease- and treatment-related side effects (dyspnea, urinary, and bowel symptoms) significantly improved within the intervention group. Erectile dysfunction and physical activity levels improved similarly in both groups. CONCLUSIONS: The presented data hint at the potential of rehabilitative sports groups for prostate cancer patients. However, according to the current state of the art, exercise intensity and volume may need to be increased to enhance the effects. A number of shorter studies (8-24 weeks) have proven significant between-group differences in quality of life, incontinence, and fitness outcomes when patients exercised 2 to 3 times per week. This is the first exercise intervention study with prostate cancer patients that was conducted over 15 months. Further studies are necessary to investigate whether prostate cancer patients recover sooner when receiving a supervised exercise program. PMID- 25917815 TI - Inhibition of Hepatocellular Carcinoma by Total Alkaloids of Rubus alceifolius Poir Involves Suppression of Hedgehog Signaling. AB - OBJECTIVE: We evaluated the effects of total alkaloids of Rubus alceifolius Poir (TARAP) on the migration and invasion of hepatocellular carcinoma (HCC) and furthermore investigated the possible molecular mechanisms mediating its anticancer activity. METHODS: We implanted nude mice with human HCC HepG2 cells and fed them with vehicle (physiological saline) or 3 g/kg/day dose of TARAP 5 days per week for 21 days. We determined the in vitro effect of TARAP on the migration and invasion of HepG2 cells by transwell assay. We evaluated SHH signaling components' (SHH, PTCH, SMO, and Gli1) expression levels by reverse transcriptase-polymerase chain reaction and immunohistochemistry. Activity of the matrix metalloproteinases (MMPs) in supernatants was analyzed by zymography. The expression of the MMPs and their specific tissue inhibitor (tissue inhibitor of matrix metalloproteinases, TIMP-1, 2) in HCC tissues was detected by immunohistochemistry. RESULTS: We discovered that TARAP inhibited hepatocellular migration and invasion in a dose-dependent manner in vitro. In addition, TARAP decreased the expression of SHH, PTCH, SMO, and Gli1 in HCC mouse tumors at both transcriptional and translational levels. Moreover, TARAP inhibited the activity of MMP2 and MMP9. We found that TARAP reduced the expression of MMP2 and MMP9, as well as the tissue inhibitor of MMPs. CONCLUSION: Our study showed that TARAP inhibits HCC migration and invasion likely through suppression of the hedgehog pathway. This may, in part, explain its anticancer properties. These results suggest that total alkaloids in Rubus alceifolius may have potential as a novel antimetastasis drug in the treatment of HCC. PMID- 25917816 TI - Vivekananda Yoga Program for Patients With Advanced Lung Cancer and Their Family Caregivers. AB - BACKGROUND: The primary purpose of this study was to establish the feasibility of a couple-based Vivekananda Yoga (VKC) intervention in lung cancer patients and caregivers. Secondly, we examined preliminary efficacy regarding quality of life (QOL) outcomes. METHOD: In this single-arm feasibility trial, patients with lung cancer undergoing radiotherapy and their caregivers participated in a 15-session VKC program that focused on the interconnectedness of the dyad. We assessed pre and post-intervention levels of fatigue, sleep disturbances, psychological distress, overall QOL, spirituality, and relational closeness. We tracked feasibility data, and participants completed program evaluations. RESULTS: We approached 28 eligible dyads of which 15 (53%) consented and 9 (60%) completed the intervention. Patients (mean age = 73 years, 63% female, all stage III) and caregivers (mean age = 62 years, 38% female, 63% spouses) completed a mean of 10 sessions and 95.5% of them rated the program as very useful. Paired t tests revealed a significant increase in patients' mental health (d = 0.84; P = .04) and a significant decrease in caregivers' sleep disturbances (d = 1.44; P = .02). Although not statistically significant, for patients, effect sizes for change scores were medium for benefit finding and small for distress (d = 0.65 and 0.37, respectively). For caregivers, medium effects were found for improvement in physical functioning (d = 0.50). CONCLUSION: This novel supportive care program appears to be safe, feasible, acceptable, and subjectively useful for lung cancer patients and their caregivers and lends support for further study. PMID- 25917817 TI - 14-3-3 in Thoracic Aortic Aneurysms: Identification of a Novel Autoantigen in Large Vessel Vasculitis. AB - OBJECTIVE: Large vessel vasculitides (LVV) are a group of autoimmune diseases characterized by injury to and anatomic modifications of large vessels, including the aorta and its branch vessels. Disease etiology is unknown. This study was undertaken to identify antigen targets within affected vessel walls in aortic root, ascending aorta, and aortic arch surgical specimens from patients with LVV, including giant cell arteritis, Takayasu arteritis, and isolated focal aortitis. METHODS: Thoracic aortic aneurysm specimens and autologous blood were acquired from consenting patients who underwent aorta reconstruction procedures. Aorta proteins were extracted from both patients with LVV and age-, race-, and sex matched disease controls with noninflammatory aneurysms. A total of 108 serum samples from patients with LVV, matched controls, and controls with antinuclear antibodies, different forms of vasculitis, or sepsis were tested. RESULTS: Evaluation of 108 serum samples and 22 aortic tissue specimens showed that 78% of patients with LVV produced antibodies to 14-3-3 proteins in the aortic wall (93.7% specificity), whereas controls were less likely to do so (6.7% produced antibodies). LVV patient sera contained autoantibody sufficient to immunoprecipitate 14-3-3 protein(s) from aortic lysates. Three of 7 isoforms of 14-3-3 were found to be up-regulated in aorta specimens from patients with LVV, and 2 isoforms (epsilon and zeta) were found to be antigenic in LVV. CONCLUSION: This is the first study to use sterile, snap-frozen thoracic aorta biopsy specimens to identify autoantigens in LVV. Our findings indicate that 78% of patients with LVV have antibody reactivity to 14-3-3 protein(s). The precise role of these antibodies and 14-3-3 proteins in LVV pathogenesis deserves further study. PMID- 25917819 TI - Health-related profiles of people with lower limb loss. AB - OBJECTIVES: To construct profiles of self-reported health indicators to examine differences and similarities between people with lower limb loss and a normative sample (hereafter called the norm) and to compare health indicators between subgroups based on level and etiology of limb loss. DESIGN: Survey. SETTING: General community. PARTICIPANTS: Adults with unilateral lower limb loss (N=1091) participated in this study. Eligibility criteria included lower limb loss due to trauma or dysvascular complications and regular use of a prosthesis. INTERVENTIONS: Not applicable. MAIN OUTCOME MEASURES: The Patient-Reported Outcomes Measurement Information System 29-item Health Profile version 1.0 measures physical function, pain interference, fatigue, sleep disturbance, anxiety, depression, and satisfaction with participation in social roles. The norm includes 5239 individuals representative of the U.S. general population in sex, age, race, ethnicity, and education. RESULTS: People with lower limb loss reported statistically significantly worse physical function, pain interference, and satisfaction with participation in social roles and significantly less fatigue than did the norm. People with transfemoral (ie, above-knee) amputation significantly differed in physical function from people with transtibial (ie, below-knee) amputation. Similarly, people with amputation due to trauma and dysvascular etiology significantly differed in physical function and satisfaction with social roles after adjusting for relevant clinical characteristics. CONCLUSIONS: People with lower limb loss generally report worse physical function, pain interference, and satisfaction with social roles than do the norm. People with dysvascular amputation reported worse physical function and satisfaction with social roles than did people with traumatic amputation. Health indicator profiles are an efficient way of providing clinically meaningful information about numerous aspects of self-reported health in people with lower limb loss. PMID- 25917818 TI - Exome sequencing reveals pathogenic mutations in 91 strains of mice with Mendelian disorders. AB - Spontaneously arising mouse mutations have served as the foundation for understanding gene function for more than 100 years. We have used exome sequencing in an effort to identify the causative mutations for 172 distinct, spontaneously arising mouse models of Mendelian disorders, including a broad range of clinically relevant phenotypes. To analyze the resulting data, we developed an analytics pipeline that is optimized for mouse exome data and a variation database that allows for reproducible, user-defined data mining as well as nomination of mutation candidates through knowledge-based integration of sample and variant data. Using these new tools, putative pathogenic mutations were identified for 91 (53%) of the strains in our study. Despite the increased power offered by potentially unlimited pedigrees and controlled breeding, about half of our exome cases remained unsolved. Using a combination of manual analyses of exome alignments and whole-genome sequencing, we provide evidence that a large fraction of unsolved exome cases have underlying structural mutations. This result directly informs efforts to investigate the similar proportion of apparently Mendelian human phenotypes that are recalcitrant to exome sequencing. PMID- 25917820 TI - Electrochemiluminescence device for in-situ and accurate determination of CA153 at the MCF-7 cell surface based on graphene quantum dots loaded surface villous Au nanocage. AB - In our work, low potential and sensitive electrochemiluminescence (ECL) detection for CA153 on MCF-7 cell surface was firstly achieved based on a microfluidic paper-based analytical device. Au nanoflowers were grown in paper working electrode (PWE) to construct the ECL platform for primary antibodies immobilizing. After MCF-7 cells were captured in the modified PWE, and subsequently recognized with ECL signal substance labeled secondary antibodies, the sandwich-type cell sensor was fabricated. Graphene quantum dots (GQDs) loaded surface villous Au nanocages were synthesized as the ECL signal substance, and characterized by scanning electron microscope. The specific villous surface structure for Au nanocage permitted more GQDs being carried and electrons transporting, which largely benefited for the ECL performance. As the un negligible impendence for MCF-7 cell would definitely influence the ECL signal, CA153 labeled HMEpic cell was used as the control cell to obtain more accurate determination result. This low-cost and fast strategy showed acceptable biocompatibility and stability, and will be promising for cellular immunochemistry. PMID- 25917821 TI - Smartphone teledermoscopy referrals: comment on the paper by Borve et al. PMID- 25917822 TI - Factors influencing radiographic and clinical outcomes in adult scoliosis surgery: a study of 448 European patients. AB - INTRODUCTION/PURPOSE: In adult scoliosis surgery (AS) delineation of risk factors contributing to failure is important to improve patient care. Treatment goals include deformity correction resulting in a balanced spine and horizontal lowest instrumented vertebra (LIV) in fusions not ending at S1. Therefore, the study objectives were to determine predictors for deformity correction, complications, revision surgery, and outcomes as well as to determine predictors of postoperative evolution of the LIV-take-off angle (LIV-TO) and symptomatic adjacent segment disease (ASD). METHODS: The authors performed a retrospective analysis of 448 patients who had AS surgery. Patients' age averaged 51 years, BMI 26, and follow-up of 40 months. According to the SRS adult scoliosis classification, 51 % of patients had major lumbar curves, 24 % each with single thoracic or double major curves. 54 % of patients had stable vertebra at L5 and 34 % of patients had fusion to S1. The mean number of posterior fusion levels was eight and implant density 73 %. Among standard radiographic measures of deformity the LIV-TO was assessed on neutral and bending/traction-films (bLIV-TO). Clinical outcomes were assessed in 145 patients with degenerative-type AS using validated measures (ODI, COMI and SF-36). Prediction analysis was conducted with stepwise multiple regression analyses. RESULTS: Preoperative thoracic curve (TC) was 53 degrees and 33 degrees at follow-up. Preoperative lumbar curve (LC) was 43 degrees and 24 degrees at follow-up. Curve flexibility was low (TC 34 %/LC 38 %). TC-correction (38 %) was predicted by preoperative TC (r = 0.9) and TC flexibility (r = 0.8). LC-correction (50 %) was predicted by preoperative LC (r = 0.8), LC-flexibility (r = 0.8) and screw density (r = 0.7). Preoperative LIV-TO was 18.2 degrees and at follow-up 9.4 degrees (p < 0.01). 20 % of patients had a non-union (18 % at L5-S1). The risk for non-union at L5-S1 increased with age (p = 0.04), low screw density (p = 0.03), and postoperative sagittal imbalance [(T9-tilt (p = 0.01), C7-SVA (p = 0.01), LL (p = 0.01) and PI-LL mismatch (p = 0.01)]. 32 % of patients had revision surgery. Risk for revision was increased in fusions to S1 (p < 0.01), increased BMI (p < 0.01), sagittal imbalance (C7-SVA, p < 0.01), age (p = 0.02), and disc wedging distal to the LIV (p < 0.01). To a varying extent, clinical outcomes negatively correlated (p < 0.05) with revision, ASD, perioperative complications, age, low postoperative TC- and LC-correction, and sagittal and coronal imbalance at follow-up (C7-SVA, PT, and C7-CSVL). 59 patients had ASD, which correlated with preoperative and postoperative sagittal and coronal parameters of deformity. In a multivariate model, preoperative bLIV TO (p < 0.01) and preoperative LIV-TO (p < 0.01) demonstrated the highest predictive strength for follow-up LIV-TO. CONCLUSION: In the current study, the magnitude of deformity correction in the sagittal and coronal planes was shown to have significant impact on radiographic and clinical outcomes as well as revision rates. Findings indicate that risks for complications might be reduced by restoration of sagittal balance, appropriate deformity correction and advanced lumbosacral fixation. The use of preoperative LIV-TO and LIV-TO on bending/traction-films were shown to be useful for surgical planning, selection of the LIV and prediction of follow-up-TO, respectively. Parameters of sagittal balance rather than coronal deformity predicted ASD. PMID- 25917823 TI - Core Outcome Measure Index for low back patients: do we miss anxiety and depression? AB - PURPOSE: The Core Outcome Measure Index (COMI) is a multidimensional questionnaire that investigates five dimensions in low back pain (LBP) patients, but does not address the psychological dimension. As the biopsychosocial perspective is recognized as important to capture the entire clinical picture of these patients, this multicenter prospective cohort study was designed to investigate the psychometric properties of a modified version of the COMI (COMIAD) which included 2 additional items, exploring anxiety and depression, respectively. METHODS: 168 subacute or chronic LBP patients recruited in spine clinics completed a set of questionnaires before and after treatment (follow-up at 6 months). Construct validity was explored by comparing each item of the COMIAD to validated full-length questionnaires. Thus two additional questionnaires were included to assess the construct validity of the anxiety and depression measures. The psychometric properties of the COMI and COMIAD were then compared. RESULTS: The two new items showed good internal consistency, high correlations with the corresponding full-length questionnaires, no floor or ceiling effect and good reproducibility (test-retest agreement kappa 0.68 for anxiety, 0.62 for depression). The addition of the 2 items did not alter internal validity (Cronbach's alpha = 0.88 and 0.87, respectively). The smallest detectable difference, the Minimal Clinically Important Improvement and the Patient Acceptable Symptom State were only minimally affected by the changes. CONCLUSION: The questions exploring anxiety and depression have good intrinsic and psychometric capacities (i.e., no floor or ceiling effects and high correlations with full-length scales) and did not significantly modify the psychometrics of the original COMI questionnaire. The COMIAD offers the possibility to include the psychological dimension in the multidimensional evaluation without significantly affecting questionnaire length. PMID- 25917824 TI - Reliability and validity of inexpensive and easily administered anthropometric clinical evaluation methods of postural asymmetry measurement in adolescent idiopathic scoliosis: a systematic review. AB - PURPOSE: As accurate and reproducible measurements of spinal curvature are crucial in the examination of patients with adolescent idiopathic scoliosis (AIS), this systematic review aims to report on the reliability and validity of a range of inexpensive and easily administered anthropometric methods of postural asymmetry measurement in an AIS population, to inform practice in a clinical setting. METHODS: A systematic search of health research databases located studies assessing reliability and validity of inexpensive and easily administered anthropometric measures. RESULTS: Fourteen studies satisfied eligibility criteria. The methodological quality of included studies ranged from low to high. Validity studies were of moderate to high quality. In total, nine clinically applicable, inexpensive and easily administered anthropometric methods were identified, for assessing AIS curvature. All methods demonstrated high to very high inter-observer and intra-observer reliability. Reported criterion validity of the scoliometer and 2D photographs, when compared to Cobb angle assessed from radiographs, ranged from low to very high. iPhone measurements correlated well with scoliometer measurements. 2D photography results had a moderate to high correlation with 3D topography results. CONCLUSIONS: Overall, strong levels of evidence exist for iPhone and scoliometer measurements, with a high to very high reliability and moderate to very high validity. Moderate levels of evidence exist for scoliometer with mathematical formula and clinical examination with moderate and low validity, respectively. Limited evidence exists for aesthetic tools TRACE and AI and 2D photography. These results indicate there are accurate and reproducible anthropometric measures that are inexpensive and applicable in therapy settings to assess postural asymmetry; however, these only exist for measurement in the transverse plane, despite 3D characteristics of AIS. Further research is required into an inexpensive and easily administered method that can assess postural asymmetry in all anatomical planes. PMID- 25917825 TI - Range of motion after thoracolumbar corpectomy: evaluation of analogous constructs with a novel low-profile anterior dual-rod system and a traditional dual-rod system. AB - STUDY DESIGN: An in vitro biomechanical study. OBJECTIVES: To compare the biomechanical stability of traditional and low-profile thorocolumbar anterior instrumentation after a corpectomy with cross-connectors. Dual-rod anterior thoracolumbar lateral plates (ATLP) have been used clinically to stabilize the thorocolumbar spine. METHODS: The stability of a low-profile dual-rod system (LP DRS) and a traditional dual-rod system (DRS) was compared using a calf spine model. Two groups of seven specimens were tested intact and then in the following order: (1) ATLP with two cross-connectors and spacer; (2) ATLP with one cross connector and spacer; (3) ATLP with spacer. Data were normalized to intact (100 %) and statistical analysis was used to determine between-group significances. RESULTS: Both constructs reduced motion compared to intact in flexion-extension and lateral bending. Axial rotation motion became unstable after the corpectomy and motion was greater than intact, even with two cross-connectors with both systems. Relative to their respective intact groups, LP DRS significantly reduced motion compared to analogous DRS in flexion-extension. The addition of cross connectors reduced motion in all loading modes. CONCLUSIONS: The LP DRS provides 7.5 mm of reduced height with similar biomechanical performance. The reduced height may be beneficiary by reduced irritation and impingement on adjacent structures. PMID- 25917826 TI - Lineage specification of ovarian theca cells requires multicellular interactions via oocyte and granulosa cells. AB - Organogenesis of the ovary is a highly orchestrated process involving multiple lineage determination of ovarian surface epithelium, granulosa cells and theca cells. Although the sources of ovarian surface epithelium and granulosa cells are known, the origin(s) of theca progenitor cells have not been definitively identified. Here we show that theca cells derive from two sources: Wt1(+) cells indigenous to the ovary and Gli1(+) mesenchymal cells that migrate from the mesonephros. These progenitors acquire theca lineage marker Gli1 in response to paracrine signals Desert hedgehog (Dhh) and Indian hedgehog (Ihh) from granulosa cells. Ovaries lacking Dhh/Ihh exhibit theca layer loss, blunted steroid production, arrested folliculogenesis and failure to form corpora lutea. Production of Dhh/Ihh in granulosa cells requires growth differentiation factor 9 (GDF9) from the oocyte. Our studies provide the first genetic evidence for the origins of theca cells and reveal a multicellular interaction critical for the formation of a functional theca. PMID- 25917827 TI - Nanostructured calcium phosphate coatings on magnesium alloys: characterization and cytocompatibility with mesenchymal stem cells. AB - This article reports the deposition and characterization of nanostructured calcium phosphate (nCaP) on magnesium-yttrium alloy substrates and their cytocompatibility with bone marrow derived mesenchymal stem cells (BMSCs). The nCaP coatings were deposited on magnesium and magnesium-yttrium alloy substrates using proprietary transonic particle acceleration process for the dual purposes of modulating substrate degradation and BMSC adhesion. Surface morphology and feature size were analyzed using scanning electron microscopy and quantitative image analysis tools. Surface elemental compositions and phases were analyzed using energy dispersive X-ray spectroscopy and X-ray diffraction, respectively. The deposited nCaP coatings showed a homogeneous particulate surface with the dominant feature size of 200-500 nm in the long axis and 100-300 nm in the short axis, and a Ca/P atomic ratio of 1.5-1.6. Hydroxyapatite was the major phase identified in the nCaP coatings. The modulatory effects of nCaP coatings on the sample degradation and BMSC behaviors were dependent on the substrate composition and surface conditions. The direct culture of BMSCs in vitro indicated that multiple factors, including surface composition and topography, and the degradation-induced changes in media composition, influenced cell adhesion directly on the sample surface, and indirect adhesion surrounding the sample in the same culture. The alkaline pH, the indicator of Mg degradation, played a role in BMSC adhesion and morphology, but not the sole factor. Additional studies are necessary to elucidate BMSC responses to each contributing factor. PMID- 25917828 TI - Akermanite scaffolds reinforced with boron nitride nanosheets in bone tissue engineering. AB - Akermanite (AKM) is considered to be a promising bioactive material for bone tissue engineering due to the moderate biodegradability and excellent biocompatibility. However, the major disadvantage of AKM is the relatively inadequate fracture toughness, which hinders the further applications. In the study, boron nitride nanosheets (BNNSs) reinforced AKM scaffolds are fabricated by selective laser sintering. The effects of BNNSs on the mechanical properties and microstructure are investigated. The results show that the compressive strength and fracture toughness increase significantly with BNNSs increasing from 0.5 to 1.0 wt%. The remarkable improvement is ascribed to pull out and grain wrapping of BNNSs with AKM matrix. While, overlapping sheets is observed when more BNNSs are added, which results in the decline of mechanical properties. In addition, it is found that the composite scaffolds possess good apatite-formation ability when soaking in simulated body fluids, which have been confirmed by energy dispersed spectroscopy and flourier transform infrared spectroscopy. Moreover, MG63 osteoblast-like cells and human bone marrow stromal cells are seeded on the scaffolds. Scanning electron microscopy analysis confirms that both cells adhere and proliferate well, indicating favorable cytocompatibility. All the facts demonstrate the AKM scaffolds reinforced by BNNSs have potential applications for tissue engineering. PMID- 25917829 TI - The preparation and characterization of micelles from poly(gamma-glutamic acid) graft-poly(L-lactide) and the cellular uptake thereof. AB - Chemotherapy is a traditional therapeutic approach for the treatment of many solid tumors, but the poor solubility and low bioavailability of hydrophobic anti cancer drugs greatly limit their applications. In this article, DOX-loaded micelles were fabricated based on an amphiphilic graft polymer composed of hydrophilic poly(gamma-glutamic acid) (gamma-PGA) and hydrophobic poly (L lactide) (PLLA). The structure of the copolymers and the characteristic of the micelles were studied. The release profiles of doxorubicin as a model drug from the micelles were measured. Due to the protonation of the amino group of DOX and the conformational alteration of gamma-PGA, the release of DOX from gamma-PGA-g PLLA micelle was faster in the acid condition, which is beneficial to tumor therapy. The cellular uptake of the DOX-loaded gamma-PGA-g-PLLA micelle was proved to be a GGT-mediated process. PMID- 25917830 TI - Obstructive sleep apnea syndrome susceptible genes in the Chinese population: a meta-analysis of 21 case-control studies. AB - BACKGROUND: Numbers of single nucleotide polymorphisms (SNPs) were identified as risk factors for obstructive sleep apnea syndrome (OSAS) in the Chinese population; however, published articles drew incompatible or even contradictory results. OBJECTIVE: The aim of this study was to investigate the susceptible SNPs and risk of OSAS in the Chinese population. METHODS: We conducted a meta-analysis of seven polymorphisms and risk of OSAS based on 21 case-control studies. RESULTS: The results of our study showed that tumor necrosis factor-alpha (TNF alpha) -308 G/A (OR = 3.70, 95 % CI = 1.39-9.83), gene-linked polymorphic region (LPR) (OR = 0.57, 95 % CI = 0.41-0.79), and variable number tandem repeat (VNTR) of the 5-hydroxytryptamine transporter gene (5-HTT) (OR = 3.44, 95 % CI = 1.49 7.95) polymorphisms were associated with OSAS risk in the Chinese population, while there was no significant association between 5-hydroxytryptamine 2A receptor (5-HTR2A) 102C/T, 5-HTR2A A1438G, angiotensin-converting enzyme (ACE) insertion (I)/deletion (D), or leptin receptor (LEPR)-Gln 223Arg polymorphism and risk of OSAS in the Chinese population. CONCLUSIONS: Our study demonstrated that TNF-alpha 308 G/A, 5-HTT LPR, and 5-HTT-VNTR polymorphisms were associated with OSAS risk, whereas little association was observed between 5-HTR2A 102C/T, 5 HTR2A A1438G, ACE I/D, or LEPR-Gln 223Arg polymorphism and risk of OSAS in the Chinese population. PMID- 25917831 TI - PRMT4 is involved in insulin secretion via the methylation of histone H3 in pancreatic beta cells. AB - The relationship between protein arginine methyltransferases (PRMTs) and insulin synthesis in beta cells is not yet well understood. In the present study, we showed that PRMT4 expression was increased in INS-1 and HIT-T15 pancreatic beta cells under high-glucose conditions. In addition, asymmetric dimethylation of Arg17 in histone H3 was significantly increased in both cell lines in the presence of glucose. The inhibition or knockdown of PRMT4 suppressed glucose induced insulin gene expression in INS-1 cells by 81.6 and 79% respectively. Additionally, the overexpression of mutant PRMT4 also significantly repressed insulin gene expression. Consistently, insulin secretion induced in response to high levels of glucose was decreased by both PRMT4 inhibition and knockdown. Moreover, the inhibition of PRMT4 blocked high-glucose-induced insulin gene expression and insulin secretion in primary pancreatic islets. These results indicate that PRMT4 might be a key regulator of high-glucose-induced insulin secretion from pancreatic beta cells via H3R17 methylation. PMID- 25917832 TI - The VGF-derived peptide TLQP-62 modulates insulin secretion and glucose homeostasis. AB - Insulin secretion control is critical for glucose homeostasis. Paracrine and autocrine molecules secreted by cells of the islet of Langerhans, as well as by intramural and autonomic neurons, control the release of different hormones that modulate insulin secretion. In pancreatic islets, the abundant presence of the granin protein VGF (nonacronymic; unrelated to VEGF) suggests that some of its proteolytically derived peptides could modulate hormone release. Thus, in the present study, we screened several VGF-derived peptides for their ability to induce insulin secretion, and we identified the VGF C-terminal peptide TLQP-62 as the most effective fragment. TLQP-62 induced a potent increase in basal insulin secretion as well as in glucose-stimulated insulin secretion in several insulinoma cell lines. We found that this peptide stimulated insulin release via increased intracellular calcium mobilization and fast expression of the insulin 1 gene. Moreover, the peripheral injection of TLQP-62 in mice improved glucose tolerance. Together, the present findings suggest that TLQP-62, acting as an endocrine, paracrine, or autocrine factor, can be considered a new, strong insulinotropic peptide that can be targeted for innovative antidiabetic drug discovery programs. PMID- 25917833 TI - Undernutrition and stage of gestation influence fetal adipose tissue gene expression. AB - Low birthweight is a risk factor for neonatal mortality and adverse metabolic health, both of which are associated with inadequate prenatal adipose tissue development. In the present study, we investigated the impact of maternal undernutrition on the expression of genes that regulate fetal perirenal adipose tissue (PAT) development and function at gestation days 89 and 130 (term=145 days). Singleton fetuses were taken from adolescent ewes that were either fed control (C) intake to maintain adiposity throughout pregnancy or were undernourished (UN) to maintain conception weight but deplete maternal reserves (n=7/group). Fetal weight was independent of maternal intake at day 89, but by day 130, fetuses from UN dams were 17% lighter and had lower PAT mass that contained fewer unilocular adipocytes. Relative PAT expression of IGF1, IGF2, IGF2R and peroxisome proliferator-activated receptor gamma (PPARG) mRNA was lower in UN than in controls, predominantly at day 89. Independent of maternal nutrition, PAT gene expression of PPARG, glycerol-3-phosphate dehydrogenase, hormone sensitive lipase, leptin, uncoupling protein 1 and prolactin receptor increased, whereas IGF1, IGF2, IGF1R and IGF2R decreased between days 89 and 130. Fatty acid synthase and lipoprotein lipase (LPL) mRNAs were not influenced by nutrition or stage of pregnancy. Females had greater LPL and leptin mRNA than males, and LPL, leptin and PPARG mRNAs were decreased in UN at day 89 in females only. PAT gene expression correlations with PAT mass were stronger at day 89 than they were at day 130. These data suggest that the key genes that regulate adipose tissue development and function are active beginning in mid-gestation, at which point they are sensitive to maternal undernutrition: this leads to reduced fetal adiposity by late pregnancy. PMID- 25917834 TI - Go protein subunit Goalpha and the secretory process of the natriuretic peptide hormones ANF and BNP. AB - Expression of the G protein subunit Goalpha has been shown to be prominent in the atria of the rat heart and to be significantly associated with atrial natriuretic factor (ANF)-containing atrial-specific secretory granules by immunocytochemistry. In addition, differential expression profile analysis using oligonucleotide arrays has shown that the Goalpha isoform 1 (Goalpha1) is 2.3 fold more abundant in the atria than it is in the ventricles. In the present report, we show protein-protein interaction between Goalpha and ANF by yeast two hybrid and by immunoprecipitation. A cardiac conditional Goalpha knockout model developed for the present study showed a 90% decrease in Goalpha expression and decreased atrial expression and ANF and brain natriuretic peptides (BNP) content. Expression of chromogranin A, a specific atrial granule core constituent, was not affected. Morphometric assessment of atrial tissue showed a very significant decrease in atrial-specific granule density as well as granule core electron density. Atrial electrical activity was not affected. The results obtained are compatible with the suggestion that Goalpha plays a role in ANF sorting during intracellular vectorial transport and with the presence of a mechanism that preserves the molar relationship between cellular ANF and BNP stores in the face of the decreased production of these hormones. PMID- 25917835 TI - Decoding astrocyte heterogeneity: New tools for clonal analysis. AB - The importance of astrocyte heterogeneity came out as a hot topic in neurosciences especially over the last decades, when the development of new methodologies allowed demonstrating the existence of big differences in morphological, neurochemical and physiological features between astrocytes. However, although the knowledge about the biology of astrocytes is increasing rapidly, an important characteristic that remained unexplored, until the last years, has been the relationship between astrocyte lineages and cell heterogeneity. To fill this gap, a new method called StarTrack was recently developed, a powerful genetic tool that allows tracking astrocyte lineages forming cell clones. Using StarTrack, a single astrocyte progenitor and its progeny can be specifically labeled from its generation, during embryonic development, to its final fate in the adult brain. Because of this specific labeling, astrocyte clones, exhibiting heterogeneous morphologies and features, can be easily analyzed in relation to their ontogenetic origin. This review summarizes how astrocyte heterogeneity can be decoded studying the embryonic development of astrocyte lineages and their clonal relationship. Finally, we discuss about some of the challenges and opportunities emerging in this exciting area of investigation. PMID- 25917836 TI - Prefrontal and motor cortex EEG responses and their relationship to ventilatory thresholds during exhaustive incremental exercise. AB - PURPOSE: The purpose of this study was to measure the EEG response in the prefrontal cortex (PFC) and motor cortex (MC) during incremental exercise and align these responses with ventilatory parameters. METHODS: The EEG activity at the motor (MC) and frontal cortices was measured during an incremental exercise test (IET) in 11 cyclists (peak oxygen uptake VO2peak 4.1 +/- 0.74 (SD) L min( 1)). EEG power spectral densities were calculated for alpha slow (alphaS) (8-10 Hz), alpha fast, (alphaF) (10-13 Hz), Beta (beta) (13-30 Hz), and Gamma (gamma) (30-40 Hz). EEG data were calculated as % change from eyes open (EO) baseline and a repeated measures analysis of variance (ANOVA) was performed on regions of interest (ROI), time and bandwidth. RESULTS: All EEG activity increased from 50 % Vo2peak to ventilatory threshold (VT) (P = 0.045) and respiratory compensation point (RCP) (P = 0.019) and decreased from RCP to end of exercise (END) (P = 0.04). Significant differences between regions were found at the VLPFC and MC for both alphaS and alphaF. alphaS and alphaF increased from 50 % VO2peak to RCP (14.9 +/- 10.2 to 23.8 +/- 15.5 and 18.9 +/- 10.6 to 26.12 +/- 12.7, respectively) and then decreased to END (23.8 +/- 15.5 to 14.4 +/- 10.3 and 26.1 +/- 12.7, to 17.7 +/- 8.8, respectively) (P < 0.01) and concomitantly only decreased significantly in MC in alphaF from VT to END (P < 0.05). CONCLUSION: There is a decline in the EEG response to exercise in the PFC following the RCP, whilst alpha activity in the MC is preferentially maintained; therefore, changes within the PFC appear to play a role in exercise termination. PMID- 25917837 TI - Recruiting migrants for health research through social network sites: an online survey among chinese migrants in australia. AB - BACKGROUND: Traditionally, postal surveys or face to face interviews are the main approaches for health researchers to obtain essential research data. However, with the prevalence of information technology and Internet, Web-based surveys are gaining popularity in health research. OBJECTIVE: This study aims to report the process and outcomes of recruiting Chinese migrants through social network sites in Australia and to examine the sample characteristics of online recruitment by comparing the sample which was recruited by an online survey to a sample of Australian Chinese migrants collected by a postal survey. METHODS: Descriptive analyses were performed to describe and compare the process and outcomes of online recruitment with postal survey questionnaires. Chi square tests and t tests were performed to assess the differences between the two samples for categorical and continuous variables respectively. RESULTS: In total, 473 Chinese migrants completed the online health survey from July to October 2013. Out of 426 participants recruited through the three Chinese social network sites in Australia, over 86.6% (369/426) were recruited within six weeks. Participants of the Web-based survey were younger, with a higher education level or had resided in Australia for less time compared to those recruited via a postal survey. However, there was no significant difference in gender, marital status, and professional occupation. CONCLUSIONS: The recruitment of Chinese migrants through social network sites in our online survey was feasible. Compared to a postal survey of Chinese migrants, the online survey attracted different group of Chinese migrants who may have diverse health needs and concerns. Our findings provided insightful information for researchers who are considering employing a Web-based approach to recruit migrants and ethnic minority participants. PMID- 25917838 TI - 15,16-Dihydrotanshinone I suppresses IgE-Ag stimulated mouse bone marrow-derived mast cell activation by inhibiting Syk kinase. AB - ETHNOPHARMACOLOGICAL RELEVANCE: 15,16-Dihydrotanshinone I (DHT-I), isolated from the dried root of Salvia miltiorrhiza Bung, which is traditionally used to treat cardiovascular and inflammatory diseases agent in Chinese medicine. DHT-I has been reported to have a broad range of biological activities, including antibacterial activity, and has been used to treat circulatory disorders, hepatitis, inflammation, cancer, and neurodegenerative diseases. AIM OF THE STUDY: The aim of this study was to evaluate the anti-allergic inflammatory effects of DHT-I on degranulation and on the generation of eicosanoids, such as, prostaglandin D2 (PGD2) and leukotriene C4 (LTC4), in IgE/Ag-stimulated bone marrow-derived mast cells (BMMCs). MATERIALS AND METHODS: The anti-allergic inflammatory activity of DHT-I was evaluated using BMMCs. The effects of DHT-I on mast cell activation were investigated by following degranulation and eicosanoid generation using ELISA and immunoblotting and immunoprecipitation techniques. RESULTS: DHT-I at a concentration of 20MUM markedly inhibited degranulation and the generation of PGD2 and LTC4 in IgE/Ag-stimulated BMMCs (about 90% inhibitions, respectively). Analyses of FcepsilonRI-mediated signaling pathways demonstrated that DHT-I inhibited the phosphorylations of spleen tyrosine kinase (Syk) and linker for activation of T cells (LAT), and inhibited downstream signaling process, including [Ca(2+)]i mobilization induced by the phosphorylation of phospholipase Cgamma1 (PLCgamma1), and the activations of mitogen-activated protein kinases (MAPKs) and the Akt-nuclear factor-kappaB (NF kappaB) pathway. CONCLUSIONS: DHT-1 inhibits the release of allergic inflammatory mediators from IgE/Ag-stimulated mast cells by suppressing a FcepsilonRI-mediated Syk-dependent signal pathway. This result suggests DHT-I offers a novel developmental basis for drugs targeting allergic inflammatory diseases. PMID- 25917839 TI - Ethnoveterinary plants for the treatment of camels in Shiwalik regions of Kathua district of Jammu & Kashmir, India. AB - ETHNOPHARMACOLOGICAL RELEVANCE: Camel is an important mode of transportation in the hot and hilly tracts of Shiwaliks of Kathua districts. The camel owners of the region lack the modern veterinary facilities and therefore depend heavily upon local treatments for the animal. This ethnoveterinary knowledge of plants is acquired by them from their forefathers and generally moves from one generation to another orally. The oral mode of transferring this valuable knowledge is vulnerable to erosion with the passage of time and generations. MATERIAL AND METHODS: Ethnoveterinary information was collected by interviewing 38 camel keepers and traditional healers as per the questionnaire. The data collected was analysed quantitatively using three indices viz. use-value (UV), informant consensus factor (ICF), and fidelity level (Fl %). RESULTS: A total of 41 plants were found to be of ethnoveterinary importance in the present study. Herbs and trees (41.5% each) were the most used life forms. The most used plant part was fruit (27.9%). Rhizome, root and whole plant parts collectively contributed to 18.6%. Most of the ethnoveterinary practices (65.9%) used oral mode of medication. The values of UV and Fl (%) shows that the most important species for curing the ailing camels were Curcuma longa, Trachyspermum ammi, Brassica campestris, Tamarindus indica, Phyllanthus emblica, Cassia fistula, Eruca sativa, Plumbago zeylanica etc. The high values of ICF (0.91-0.99) show that the informants share the knowledge for the treatment of camels amongst themselves on regular basis. CONCLUSION: A good number of plants are utilised by the informants to cure camels. Most of the preparations used fruits and leaves. Only 18.6% of the practices required destructive collection and such species need sustainable use and conservation. Some of the species like Tamarindus indica, Cassia fistula, Eruca sativa, Albizia lebbeck and Citrus medica require further phytochemical and pharmacological studies. PMID- 25917840 TI - Study of pharmacokinetic profiles and characteristics of active components and their metabolites in rat plasma following oral administration of the water extract of Astragali radix using UPLC-MS/MS. AB - ETHNOPHARMACOLOGICAL RELEVANCE: Astragali radix is one of the well-known traditional Chinese herbal medicine, and possesses various biological functions, such as hepatoprotective and anticancer. In present study, to investigate the metabolism and pharmacokinetics of the major constituents of A. radix, a sensitive ultra-performance liquid chromatography-electrospray ionization-mass spectrometry (UPLC-MS/MS) method with shorter chromatographic running time was developed and validated for simultaneous quantification of formononetin, ononin, calycosin, calycosin-7-beta-glucoside, astragaloside IV and their glucuronide metabolites in rat plasma after oral administration of water extract of A. radix at two different doses. MATERIALS AND METHODS: The chromatographic separation was achieved on a C18 column with gradient elution by using a mixture of 0.1% formic acid aqueous solution and acetonitrile as the mobile phase at a flow rate of 0.3mL/min. A tandem mass spectrometric detection was conducted using multiple reaction monitoring (MRM) via electrospray ionization (ESI) source in positive ionization mode. Samples were pre-treated by a single-step protein precipitation with methanol, and erlotinib was used as internal standard (IS). RESULTS: The current UPLC-MS/MS assay was validated for linearity, intra-day and inter-day precisions, accuracy, extraction recovery, matrix effects and stability. The lowest limit of quantifications (LLOQ) were 1ng/mL for all analytes. After oral administration, the plasma concentrations of the glucuronides, especially calycosin-3'-glucuronide, were much higher than the parent compounds. The mean half-life (t1/2) was between 1 and 5h, and the metabolites were eliminated faster than the parent constituents. The median (range) time to reach maximum plasma concentration (Tmax) was between 0.5 and 1h. CONCLUSIONS: This is the first study of the pharmacokinetic study of bioactive compounds and their glucuronides in male rat plasma after oral administration of water extract of A. radix. The results demonstrated the biotransformation between the bioactive isoflavonoids and their glucuronides was extensive in rats and provided a significant basis for better understanding the absorption and metabolism mechanism of A. radix. Furthermore, this study could suggest that future studies should focus on the metabolites and biotransformation between the bioactive constituents when conducting a drug efficacy study. PMID- 25917841 TI - Astragaloside prevents BDL-induced liver fibrosis through inhibition of notch signaling activation. AB - ETHNOPHARMACOLOGICAL RELEVANCE: Huangqi decoction was first described in Prescriptions of the Bureau of Taiping People's Welfare Pharmacy in the Song Dynasty (AD1078). It consists of Radix Astragali (Astragalus membranceus (Fisch.) Bge. Root, Huangqi) and Radix Glycyrrhizae (Glycyrrhiza uralensis Fisch., root and rhizome, Gancao), and it is an effective recipe that is usually used to treat consumptive disease and chronic liver diseases. Astragaloside (AS) is a main component of Radix Astragali had an effect similar to the Huangqi decoction on hepatic fibrosis. AIM OF THE STUDY: Cholestasis is associated with a number of chronic liver diseases and Notch signaling has been demonstrated to be involved in ductular reaction. Previous studies have shown that AS can prevent the progression of cholestatic liver fibrosis, however, whether AS affects the Notch signaling pathway is unclear. MATERIALS AND METHODS: Cholestatic liver fibrosis was established by common bile duct ligation (BDL) in rats. At first weekend, the rats were randomly divided into a model group (BDL), an AS group, and a Sorafenib positive control group (SORA) and treated for 3 weeks. Bile duct proliferation and liver fibrosis were determined by tissue staining. Activation of the Notch signaling pathway was evaluated by analyzing expressions of Notch-1, -2, -3, -4, Jagged 1 (JAG1), Delta-like (DLL)-1, -3, -4, Hes1, Numb and RBP-Jkappa. Activation of the Wnt signaling pathway was evaluated by analyzing expressions of Wnt-4, -5a, -5b, Frizzled (Fzd)-2, -3, -6 and beta-catenin. RESULTS: (1) Compared with the BDL group, AS significantly reduced the deposition of collagen and the Hyp content of liver tissue and inhibited the activation of HSCs. In addition, AS significantly decreased the protein and mRNA expressions of TGF-beta1 and alpha SMA. In contrast, AS significantly enhanced expression of the Smad 7 protein. AS also reduced biliary epithelial cell proliferation, and reduced the mRNA and protein expressions of CK7, CK8, CK18, CK19, OV6, Sox9 and EpCAM. (2) The mRNA and protein expressions of Notch-2, -3, -4 and JAG1 were significantly reduced in the AS compared to the BDL group. In contrast, the mRNA and protein level of Numb was clearly enhanced after AS treatment. CONCLUSION: AS may prevent biliary liver fibrosis via inhibition of the Notch signaling pathway, thereby inhibiting the abnormal proliferation of biliary epithelial cells. Results indicate that AS may be a potential therapeutic drug for cholestatic liver disease. PMID- 25917842 TI - Tradition in treating taboo: Folkloric medicinal wisdom of the aboriginals of Purulia district, West Bengal, India against sexual, gynaecological and related disorders. AB - ETHNOPHARMACOLOGICAL RELEVANCE: In order to explore the traditional medicine practised by the ethnic communities residing in the topographically and climatically challenged Purulia, an underprivileged district of West Bengal, India, a quantitative ethnobiological approach was adopted to document the folkloric use of ethnomedicinals against different sexual, gynaecological and related ailments. MATERIALS AND METHODS: Ethnobiological surveys were conducted during 2012-2015 by interviewing 82 informants or traditional healers with the help of a semi-structured questionnaire. The survey included questions on botanical and non-botanical ingredients and additives mixed with monoherbal and polyherbal formulations, vernacular names of the plants and animals, methods of preparation and administration and restrictions during medications. Additional quantitative indices such as use value, informant's consensus factor and fidelity level were used for data analysis. RESULTS: Twenty eight sexual and gynaecological disorders were found to be treated with 18 monoherbal and 31 polyherbal formulations consisting of a total number of 96 plant species from 86 genera and 47 families and four animal species. A variety of additives, either botanicals or non-botanicals were used with the formulations for higher efficacy and taste enhancement. Fabaceae (16 species) was found to be the most common family of medicinal plants whereas herbs (42.7%) and roots (32%) were the most common habit type and plant part used respectively. Use value, informant's consensus factor and fidelity level indicate frequency and coherence of citations. CONCLUSION: Age old belief on traditional medicine prevails in the studied area due to its efficacy, inexpensive price and the remoteness of tribal villages from conventional medical centres. Traditional healers had detailed knowledge of preparations, doses, methods of administration, restrictions during medications, safety and efficacy of using folkloric therapeutics against sexual and gynaecological disorders. Possible synergistic interactions among phytochemicals and additives were indicated to explain enhanced therapeutic efficacy of mixed herbal formulations. PMID- 25917843 TI - Antimicrobial and antioxidant amphiphilic random copolymers to address medical device-centered infections. AB - Microbial biofilms are known to support a number of human infections, including those related to medical devices. This work is focused on the development of novel dual-function amphiphilic random copolymers to be employed as coatings for medical devices. Particularly, copolymers were obtained by polymerization of an antimicrobial cationic monomer (bearing tertiary amine) and an antioxidant and antimicrobial hydrophobic monomer (containing hydroxytyrosol, HTy). To obtain copolymers with various amphiphilic balance, different molar ratios of the two monomers were used. (1)H NMR and DSC analyses evidenced that HTy aromatic rings are able to interact with each other leading to a supra-macromolecular re arrangement and decrease the copolymer size in water. All copolymers showed good antioxidant activity and Fe(2+) chelating ability. Cytotoxicity and hemolytic tests evidenced that the amphiphilic balance, cationic charge density and polymer size in solution are key determinants for polymer biocompatibility. As for the antimicrobial properties, the lowest minimal inhibitory concentration (MIC = 40 MUg/mL) against Staphylococcus epidermidis was shown by the water-soluble copolymer having the highest HTy molar content (0.3). This copolymer layered onto catheter surfaces was also able to prevent staphylococcal adhesion. This approach permits not only prevention of biofilm infections but also reduction of the risk of emergence of drug-resistant bacteria. Indeed, the combination of two active compounds in the same polymer can provide a synergistic action against biofilms and suppress reactive species oxygen (ROS), known to promote the occurrence of antibiotic resistance. PMID- 25917844 TI - A family of cationic polyamides for in vitro and in vivo gene transfection. AB - The purpose of this study is to develop biodegradable cationic polyamides for non viral gene delivery and elucidate their structural effects on gene transfection activity. To this end, a group of novel cationic polyamides were synthesized by polycondensation reaction between different di-p-nitrophenyl esters and tertiary amine-containing primary diamines. These linear polyamides have flexible alkylene group (ethylene or propylene), protonable amino group and bioreducible disulfide linkage in the polyamide main chain. The alkylene group and disulfide linkage in these polyamides have a distinct effect on their gene delivery properties including buffering capacity, gene binding ability and intracellular gene release profile. Those cationic polyamides containing disulfide linkage and 1,4-bis(3 aminopropyl)piperazine (BAP) residue exhibited high buffering capacity (endosomal escape ability), high gene binding ability, and intracellular gene release ability, thus inducing fast gene nucleus translocation and robust gene transfection in vitro against different cell lines and rat bone marrow mesenchymal stem cells. Moreover, the transfection efficiencies in vitro were comparable or higher than those of 25 kDa branched polyethylenimine and Lipofectamine 2000 transfection agent as positive controls. These cationic polyamides and their polyplexes were of low cytotoxicity when an optimal transfection efficacy was achieved. In vivo transfection tests showed that bioreducible BAP-based polyamides were applicable for intravenous gene delivery in a mouse model, leading to higher level of transgene expression in the liver as compared to 22 kDa linear polyethylenimine as a positive control. These cationic polyamides provide a useful platform to elucidate the relationship between chemical functionalities and gene transfection activity. PMID- 25917845 TI - Hydrosoluble, UV-crosslinkable and injectable chitosan for patterned cell-laden microgel and rapid transdermal curing hydrogel in vivo. AB - Natural and biodegradable chitosan with unique amino groups has found widespread applications in tissue engineering and drug delivery. However, its applications have been limited by the poor solubility of native chitosan in neutral pH solution, which subsequently fails to achieve cell-laden hydrogel at physiological pH. To address this, we incorporated UV crosslinking ability in chitosan, allowing fabrication of patterned cell-laden and rapid transdermal curing hydrogel in vivo. The hydrosoluble, UV crosslinkable and injectable N methacryloyl chitosan (N-MAC) was synthesized via single-step chemoselective N acylation reaction, which simultaneously endowed chitosan with well solubility in neutral pH solution, UV crosslinkable ability and injectability. The solubility of N-MAC in neutral pH solution increased 2.21-fold with substitution degree increasing from 10.9% to 28.4%. The N-MAC allowed fabrication of cell-laden microgels with on-demand patterns via photolithography, and the cell viability in N-MAC hydrogel maintained 96.3 +/- 1.3% N-MAC allowed rapid transdermal curing hydrogel in vivo within 60s through minimally invasive clinical surgery. Histological analysis revealed that low-dose UV irradiation hardly induced skin injury and acute inflammatory response disappeared after 7 days. N-MAC would allow rapid, robust and cost-effective fabrication of patterned cell-laden polysaccharide microgels with unique amino groups serving as building blocks for tissue engineering and rapid transdermal curing hydrogel in vivo for localized and sustained protein delivery. PMID- 25917846 TI - Effect of Soil Aging on the Phytoremediation Potential of Zea mays in Chromium and Benzo[a]Pyrene Contaminated Soils. AB - This study compared the phytoremediation potential of Zea mays in soil either aged or freshly amended with chromium (Cr) and benzo[a]pyrene (B[a]P). Z. mays showed increased shoot biomass in aged soils than in freshly spiked soils. The shoot biomass in contaminated soils increased by over 50% in aged soil when compared to freshly amended soils, and over 29% more Cr was accumulated in the shoot of Z. mays in aged soil than in freshly amended soil. Planting Z. mays in aged soil helped in the dissipation of more than 31% B[a]P than in freshly spiked soil, but in the absence of plants, there seemed to be no difference between the dissipation rates of B[a]P in freshly and aged co-contaminated soil. Z. mays seemed to enhance the simultaneous removal of Cr and B[a]P in aged soil than in freshly spiked soil and hence can be a good plant choice for phytoremediation of co-contaminated soils. PMID- 25917847 TI - Runoff and degradation of aerially applied dinotefuran in paddy fields and river. AB - Variation, run-off and degradation characteristics of the insecticide dinotefuran, (EZ)-(RS)-1-methyl-2-nitro-3-(tetrahydro-3-furyl-methyl)guanidine, in water and soil from two paddy fields after aerial application was investigated as well as in river water. Maximum concentrations of dinotefuran were 290 and 720 ug/L in the two paddy waters, 25 and 28 ug/kg dry in the two paddy soils, and 10 ug/L in the river water. Runoff ratios of dinotefuran from the paddy fields were calculated as 14%-41%. Mean half-lives of dinotefuran were 5.4 days in the paddy water and 12 days in the paddy soil. Results obtained in this study are important for the evaluation of the actual behavior of dinotefuran in paddy fields and rivers. PMID- 25917848 TI - Can the Hyperaccumulating Plant Arabidopsis halleri in Feed Influence a Given Consumer Organism (Rattus norvegicus var. alba)? AB - Zinc and cadmium concentrations in rat (Rattus norvegicus var. alba) tissues were analyzed by inductively coupled plasma optical emission spectrometry. Rats were fed the zinc and cadmium hyperaccumulating plant, Arabidopsis halleri. When compared to the control group, a Cd increase in all tissues (liver, kidneys, small intestine, spleen, testes, muscle), with the exception of bone tissue was observed. In comparison to the control group, the kidneys, liver and small intestine contained 375, 162, and 80 times more Cd, respectively. Differences between zinc concentrations in rats fed with A. halleri and those of the control group were significant only in the small intestine and kidney tissues. Results suggest using the hyperaccumulating plant A. halleri as a feed stresses the consumer organism not through its Zn content, but through its Cd content. PMID- 25917850 TI - Design of Lewis-acid centres in zeolitic matrices for the conversion of renewables. AB - The catalytic conversion of renewable feedstocks into chemicals is pursued as a means to sustainably fulfil future societal needs. Due to the oxygen-rich nature of bio-derived substrates, isomerisation, transfer-hydrogenation and retro-aldol reactions have emerged as relevant transformations to produce commodity chemicals and polymer building blocks. In this context, porous materials containing Lewis acid metals (e.g., Al, Ga, Sn, Ti, Zr) play an important role. Among these, tin containing zeolites have demonstrated superior catalytic properties which have mainly been attributed to their hydrophobicity and crystallinity. This review evaluates the versatility and the scalability of bottom-up and top-down approaches to introduce Lewis-acid functionalities in zeolitic matrices. A precise characterisation is shown to be crucial to determine the structure, acidity and environment of the sites introduced. In this regard, we highlight the limitations of conventional techniques and the advantages of analytical and modelling tools recently applied to gain an improved understanding of these solids. Thereafter, property-performance relations and important aspects for the industrial amenability of new synthetic routes are exemplified through case studies. Finally, we put forward the need for gathering deeper knowledge of the site location, surface properties and stability to aid the design of next generation Lewis-acid catalysts. PMID- 25917849 TI - ERAP2 is associated with ankylosing spondylitis in HLA-B27-positive and HLA-B27 negative patients. PMID- 25917852 TI - Nitric oxide inhibits the pannexin 1 channel through a cGMP-PKG dependent pathway. AB - Nitric oxide (NO), a major gaseous signaling molecule, modulates several ion channels and receptors. Here we show that NO attenuates pannexin 1 (Panx1) mediated currents in HEK-293 cells. NO exerts its effect by activating a cGMP protein kinase G (PKG) dependent pathway. NO donors, sodium nitroprusside (SNP), S-nitroso-N-acetylpenicillamine (SNAP) and S-nitrosoglutathione (GSNO), reduced Panx1 currents by 25-41%. 1H-[1,2,4]oxadiazolo[4,3-a]quinoxalin-1-one (ODQ), an inhibitor of soluble guanylyl cyclase (sGC), blocked the inhibition completely, whereas sGC activator YC-1 mimicked the effect of NO, suggesting the involvement of a cGMP dependent pathway. Supporting this, NO had no effect in the presence of the PKG inhibitor, KT5823. Further, immuno-precipitated Panx1 was recognized by an anti-phosphoserine antibody in Western blot. Phosphorylation was enhanced significantly when cells were treated with SNP. The target for phosphorylation is possibly Ser 206 of Panx1, as its mutation to Ala completely abolished the NO mediated inhibition. PMID- 25917851 TI - Follicular dendritic cell sarcoma of the head and neck: Case report, literature review, and pooled analysis of 97 cases. AB - BACKGROUND: Follicular dendritic cell sarcoma (FDCS) is a rare lymphoid neoplasm presenting in the head and neck. There are no pooled analyses of head and neck FDCS cases in the English language literature. METHODS: A MEDLINE and PubMed review of cases from 1978 to February 2014 was performed. Demographics, clinicopathologic data, and outcomes were summarized. RESULTS: We presented 2 patients and analyzed 97 cases. The mean age was 42.7 years (SD = 16.3 years). Outcomes were available for 76 patients. Tumors <=4 cm had better disease-free survival (63% vs 28% at 5 years; p = .0282). Locoregional recurrence was significantly less likely with surgery and radiation compared to surgery alone (15% vs 45%; p = .019) and in patients receiving a neck dissection (10% vs 43%; p = .046). CONCLUSION: This pooled analysis provides the largest sample size of FDCS of the head and neck to date and suggests that radiation and neck dissection may be beneficial to locoregional oncologic control. (c) 2015 Wiley Periodicals, Inc. Head Neck 38: E2241-E2249, 2016. PMID- 25917853 TI - Endothelial nitric oxide synthase polymorphism and prognosis in systolic heart failure patients. AB - BACKGROUND: The endothelial nitric oxide synthase (eNOS) gene single nucleotide polymorphism G894T is associated with thrombotic vascular diseases. However, its functional significance is controversial and data are scarce concerning its influence in heart failure (HF). METHODS: We studied 215 patients with chronic systolic HF. DNA was analyzed for eNOS gene G894T polymorphism using PCR and DNA sequencing. Evaluation of clinical characteristics and analysis of factors associated with 2-year mortality were performed for the homozygous G-allele G894T variant (GG), relative to the TT and GT variants. RESULTS: The genotype distributions of eNOS G894T alleles were: GG 135 patients (63%) and TT/GT 80 (37%). Two-year mortality was significantly higher in the GG variant (48%) than the combined TT/GT group (32%). The usage of nitrates was associated with increased 2-year mortality (HR 2.0, 95% CI 1.28-3.17; p = 0.003), which was most significant in the GG group treated with nitrates (73.5%) in comparison to the TT/GT group not treated with nitrates (34%); HR 2.75, 95% CI 1.57-4.79, P < 0.001. CONCLUSIONS: Homozygosity for the G allele of the eNOS G894T polymorphism was associated with worse survival in systolic HF patients, especially in those treated with nitrates. ENOS polymorphism may result in different mechanistic interactions in HF than in thrombotic vascular diseases, suggesting that overexpression of NO may be associated with deleterious effects in systolic HF. PMID- 25917854 TI - Gingival displacement: Survey results of dentists' practice procedures. AB - STATEMENT OF PROBLEM: A high percentage of fixed prosthodontic restorations require a subgingival margin placement, which requires the practice of gingival displacement or a deflection procedure to replicate the margins in impression. PURPOSE: The purpose of this study was to learn the different gingival displacement techniques that are currently used by dentists in their practice and to compare the current concepts of gingival displacement with previously published articles. MATERIALS AND METHODS: A survey of questions pertaining to gingival deflection methods was distributed as part of continuing education (CE) course material to dentists attending CE meetings in 7 states in the U.S. and 1 Canadian province. Question topics included initial patient assessment procedures, gingival displacement methods, dentist's knowledge and assessment of systemic manifestations, and brand names of materials used. RESULTS: Ninety-four percent of the participants were general practitioners with 24.11 +/- 12.5 years of experience. Ninety-two percent used gingival displacement cords, while 20.2% used a soft tissue laser and 32% used electrosurgery as an adjunct. Sixty percent of the dentists used displacement cords impregnated with a medicament. Of the preimpregnated cords, 29% were impregnated with epinephrine, 13% with aluminum chloride, and 18% with aluminum potassium sulfate. CONCLUSION: The study showed a steady decrease compared with results of previously published articles in the use of epinephrine as a gingival deflection medicament. PMID- 25917855 TI - Esthetic anterior composite resin restorations using a single shade: Step-by-step technique. AB - Children and young adults often present to a dental practice after accidents that affect their anterior teeth. In many situations, only 1 tooth is affected by the trauma, and choosing the right treatment option can be complex. Esthetic restoration of the maxillary anterior dentition can be accomplished by using direct or indirect techniques. Direct resin composite restoration can be characterized as a life-like definitive restoration and is a predictable, conservative, and reliable chairside procedure. This article describes a straightforward protocol used to restore a patient's appearance with a single shade composite resin after a Class IV fracture received during a sporting event. PMID- 25917857 TI - Is laparoscopic peritoneal lavage for diverticular peritonitis only a "bridge" to elective sigmoidectomy? An alternative hypothesis. PMID- 25917856 TI - Consensus of the Spanish society of pediatric rheumatology for transition management from pediatric to adult care in rheumatic patients with childhood onset. AB - To develop recommendations on the transition from pediatric care to adult care in patients with chronic inflammatory rheumatic diseases with childhood onset based. Recommendations were generated following nominal group methodology and Delphi technique. A panel of 16 experts was established. A systematic literature review (on transitional care) and a narrative review were performed and presented to the panel in the first panel meeting to be discussed. A first draft of recommendations was generated and circulated. Focal groups with adolescents, young adults and parents were organized. In a second meeting, the focus group results along with the input from invited psychologist were used to establish definitive recommendations. Then, a Delphi process (two rounds) was carried out. A group of 72 pediatric and adult rheumatologists took part. Recommendations were voted from 1 (total disagreement) to 10 (total agreement). We defined agreement if at least 70 % voted >=7. The level of evidence and grade or recommendation was assessed using the Oxford center for evidence-based medicine levels of evidence. Transition care was defined as a purposeful, planned process that addresses the medical, psychosocial and educational/vocational needs of adolescents and young adults with chronic inflammatory rheumatic diseases with childhood onset as they move from child-centered to adult-oriented healthcare systems. The consensus covers: transition needs, barriers and facilitators, transitional issues (objectives, participants, content, phases, timing, plans, documentation and responsibilities), physicians' and other health professionals' knowledge and skill requirements, models/programs, and strategies and guideline for implementation. Preliminary recommendations and agreement grade are shown in the Table (first Delphi round). These recommendations are intended to provide health professionals, patients, families and other stakeholders with a consensus on the transition process from pediatric to adult care. PMID- 25917858 TI - Comparison of charged nanoparticle concentrations near busy roads and overhead high-voltage power lines. AB - Overhead high-voltage power lines are known sources of corona ions. These ions rapidly attach to aerosols to form charged particles in the environment. Although the effect of ions and charged particles on human health is largely unknown, much attention has focused on the increasing exposure as a result of the expanding power network in urban residential areas. However, it is not widely known that a large number of charged particles in urban environments originate from motor vehicle emissions. In this study, for the first time, we compare the concentrations of charged nanoparticles near busy roads and overhead power lines. We show that large concentrations of both positive and negative charged nanoparticles are present near busy roadways and that these concentrations commonly exceed those under high-voltage power lines. We estimate that the concentration of charged nanoparticles found near two freeways carrying around 120 vehicles per minute exceeded the corresponding maximum concentrations under two corona-emitting overhead power lines by as much as a factor of 5. The difference was most pronounced when a significant fraction of traffic consisted of heavy-duty diesel vehicles which typically have high particle and charge emission rates. PMID- 25917859 TI - Nanoscale zero-valent iron particles supported on reduced graphene oxides by using a plasma technique and their application for removal of heavy-metal ions. AB - Nanoscale zero-valent iron particles supported on reduced graphene oxides (NZVI/rGOs) from spent graphene oxide (GO)-bound iron ions were developed by using a hydrogen/argon plasma reduction method to improve the reactivity and stability of NZVI. The NZVI/rGOs exhibited excellent water treatment performance with excellent removal capacities of 187.16 and 396.37 mg g(-1) for chromium and lead, respectively. Moreover, the NZVI/rGOs could be regenerated by plasma treatment and maintained high removal ability after four cycles. X-ray photoelectron spectroscopy analysis results implied that the removal mechanisms could be attributed to adsorption/precipitation, reduction, or both. Such multiple removal mechanisms by the NZVI/rGOs were attributed to the reduction ability of the NZVI particles and the role of dispersing and stabilizing abilities of the rGOs. The results indicated that the NZVI/rGOs prepared by a hydrogen/argon plasma reduction method might be an effective composite for heavy metal-ion removal. PMID- 25917860 TI - Predicting Response to Subacromial Injections and Lidocaine/Tetracaine Patch from Pretreatment Pain Quality in Patients with Shoulder Impingement Syndrome. AB - OBJECTIVES: No existing pain treatment is effective for all pain problems, and response to pain treatment is highly variable. Knowledge regarding the patient factors that predict response to different treatments could benefit patients by providing an empirical foundation for patient-treatment matching. This study sought to test the hypothesis that improvements following two treatments thought to operate via similar mechanisms would be predicted by similar baseline pain qualities. DESIGN: Prospective prediction analysis using data from a previously published open label trial comparing a heated lidocaine/tetracaine patch versus subacromial corticosteroid injection for the treatment of pain in individuals with shoulder impingement syndrome. RESULTS: Consistent with the study hypothesis, the response to the two treatments were predicted by similar baseline pain qualities; specifically, higher baseline levels of unpleasant, electric, and sensitive pain predicted subsequent improvements in sleep interference, work/activity interference, and patient global ratings of improvement, respectively. CONCLUSIONS: The findings are consistent with the combined ideas that (1) those who have the most to gain (i.e., those reporting the highest levels of various pain qualities) can expect the best response to effective treatments and (2) different pain qualities may be associated with different types of outcomes. The findings support further research to examine how pain quality measures may be used to improve patient-treatment matching, and therefore, ultimately improve the efficiency, efficacy, and overall benefit-risk of pain treatment. PMID- 25917861 TI - Altering the regioselectivity of a nitroreductase in the synthesis of arylhydroxylamines by structure-based engineering. AB - Nitroreductases have great potential for the highly efficient reduction of aryl nitro compounds to arylhydroxylamines. However, regioselective reduction of the desired nitro group in polynitroarenes is still a challenge. Here, we describe the structure-based engineering of Escherichia coli nitroreductase NfsB to alter its regioselectivity, in order to achieve reduction of a target nitro group. When 2,4-dinitrotoluene was used as the substrate, the wild-type enzyme regioselectively reduced the 4-NO2 group, but the T41L/N71S/F124W mutant primarily reduced the 2-NO2 group, without loss of activity. The crystal structure of T41L/N71S/F124W and docking experiments indicated that the regioselectivity change (from 4-NO2 to 2-NO2 ) might result from the increased hydrophobicity of residues 41 and 124 (proximal to FMN) and conformational changes in residues 70 and 124. PMID- 25917863 TI - Tough decisions: Reproductive timing and output vary with individuals' physiology, behavior and past success in a social opportunistic breeder. AB - This article is part of a Special Issue "SBN 2014". Photoperiod and the hormonal response it triggers are key determinants of reproductive timing in birds. However, other cues and physiological traits may permit flexibility in the timing of breeding and perhaps facilitate adaptation to global change. Opportunistic breeders are excellent models to study the adaptive significance of this flexibility, especially at the individual level. Here, we sought to quantify whether particular male physiological and behavioral traits were linked to reproductive timing and output in wild-derived zebra finches. We repeatedly assessed male stress-induced corticosterone levels (CORT), basal metabolic rate (BMR), and activity before releasing them into outdoor aviaries and quantifying each pair's breeding timing, investment, and output over a seven-month period. Despite unlimited access to food and water, the colony breeding activity occurred in waves, probably due to interpair social stimulations. Pairs adjusted their inter-clutch interval and clutch size to social and temperature cues, respectively, but only after successful breeding attempts, suggesting a facultative response to external cues. When these effects were controlled for statistically or experimentally, breeding intervals were repeatable within individuals across reproductive attempts. In addition, males' first laying date and total offspring production varied with complex interactions between pre breeding CORT, BMR and activity levels. These results suggest that no one trait is under selection but that, instead, correlational selection acts on hormone levels, metabolism, and behavior. Together our results suggest that studying inter-individual variation in breeding strategy and their multiple physiological and behavioral underpinnings may greatly improve our understanding of the mechanisms underlying the evolution of breeding decisions. PMID- 25917862 TI - Long-term consequences of estrogens administered in midlife on female cognitive aging. AB - This article is part of a Special Issue "Estradiol and cognition". Many of the biochemical, structural, and functional changes that occur as the female brain ages are influenced by changes in levels of estrogens. Administration of estrogens begun during a critical window near menopause is hypothesized to prevent or delay age-associated cognitive decline. However, due to potential health risks women often limit use of estrogen therapy to a few years to treat menopausal symptoms. The long-term consequences for the brain of short-term use of estrogens are unknown. Interestingly, there are preliminary data to suggest that short-term use of estrogens during the menopausal transition may afford long term cognitive benefits to women as they age. Thus, there is the intriguing possibility that short-term estrogen therapy may provide lasting benefits to the brain and cognition. The focus of the current review is an examination of the long-term impact for cognition of midlife use of estrogens. We review data from our lab and others indicating that the ability of midlife estrogens to impact estrogen receptors in the hippocampus may contribute to its ability to exert lasting impacts on cognition in aging females. PMID- 25917864 TI - Intra- and interspecific social challenges modulate the levels of an androgen precursor in a seasonally territorial tropical damselfish. AB - Studies on different vertebrate groups have provided evidence that androgen levels in males increase after competitive social interactions during the breeding season, as postulated by the Challenge Hypothesis. However, social modulation of androgen levels may vary with latitude and may differ between species holding seasonal versus year-round territories. Here, we tested the Challenge Hypothesis on a seasonal tropical damselfish, Abudefduf sexfasciatus, where males temporarily defend territory and eggs against both intra- and interspecific individuals. Carrying out simulated territorial intrusions (STIs) in the laboratory, we document for the first time a consistent increase in the plasma level of the androgen precursor 11-ketoandrostenedione (11KA) in fish confronted to either intra- or interspecific challenges. Collecting samples in the field also revealed higher 11KA levels in fish facing frequent territorial interactions than in non-territorial individuals. Levels of 11-ketotestosterone (11KT) were high in territorial males in the field, but were not incremented after simulated territorial intrusions in the laboratory. Plasma levels of cortisol and testosterone were not affected by challenges but were different in wild and captive specimens. Although the endocrine responses to STIs did not differ between intra- and interspecific challenges, agonistic displays expressed by resident fish were more intense towards intraspecific intruders. Taken together, our study emphasizes the need to incorporate androgen precursor concentrations to advance our understanding on the physiology of territorial interactions. PMID- 25917866 TI - Enantiomeric cyclic peptides with different Caco-2 permeability suggest carrier mediated transport. AB - Recently, oral absorption of cyclic hexapeptides was improved by N-methylation of their backbone amides. However, the number and position of N-methylations or of solvent exposed NHs did not correlate to intestinal permeability, measured in a Caco-2 model. In this study, we investigate enantiomeric pairs of three polar and two lipophilic peptides to demonstrate the participation of carrier-mediated transporters. As expected, all the enantiomeric peptides exhibited identical lipophilicity (logD7.4) and passive transcellular permeability determined by the parallel artificial membrane permeability assay (PAMPA). However, the enantiomeric polar peptides exhibited different Caco-2 permeability (Papp) in both directions a-b and b-a. The same trend was observed for one of the lipophilic peptide, whereas the second lipophilic enantiomer pair showed identical Caco-2 permeability (within the errors). These findings provide the first evidence for the involvement of carrier-mediated transport for peptides, especially for those of polar nature. PMID- 25917865 TI - Surprising origins of sex differences in the brain. AB - This article is part of a Special Issue "SBN 2014". Discerning the biologic origins of neuroanatomical sex differences has been of interest since they were first reported in the late 60's and early 70's. The centrality of gonadal hormone exposure during a developmental critical window cannot be denied but hormones are indirect agents of change, acting to induce gene transcription or modulate membrane bound signaling cascades. Sex differences in the brain include regional volume differences due to differential cell death, neuronal and glial genesis, dendritic branching and synaptic patterning. Early emphasis on mechanism therefore focused on neurotransmitters and neural growth factors, but by and large these endpoints failed to explain the origins of neural sex differences. More recently evidence has accumulated in favor of inflammatory mediators and immune cells as principle regulators of brain sexual differentiation and reveal that the establishment of dimorphic circuits is not cell autonomous but instead requires extensive cell-to-cell communication including cells of non-neuronal origin. Despite the multiplicity of cells involved the nature of the sex differences in the neuroanatomical endpoints suggests canalization, a process that explains the robustness of individuals in the face of intrinsic and extrinsic variability. We propose that some neuroanatomical endpoints are canalized to enhance sex differences in the brain by reducing variability within one sex while also preventing the sexes from diverging too greatly. We further propose mechanisms by which such canalization could occur and discuss what relevance this may have to sex differences in behavior. PMID- 25917868 TI - Progesterone receptor A predominance is a discriminator of benefit from endocrine therapy in the ATAC trial. AB - Progesterone receptor (PR) function, while essential in normal human breast, is also implicated in breast cancer risk. The two progesterone receptors, PRA and PRB, are co-expressed at equivalent levels in normal breast, but early in carcinogenesis normal levels of PRA:PRB are frequently disrupted, and predominance of one isoform, usually PRA, results. In model systems, PRA and PRB have different activities, and altering the PRA:PRB ratio in cell lines alters PR signaling. The purpose of this study was to determine whether hormonal or reproductive factors contribute to imbalanced PRA:PRB expression in breast tumors and the impact of PRA:PRB imbalance on disease outcome. The relative expression of PRA and PRB proteins was determined by dual immunofluorescence histochemistry in archival breast tumors and associations with clinical and reproductive history assessed. PRA:PRB expression was not influenced by reproductive factors, whereas exogenous hormone use (menopausal hormone treatment, MHT) favored PRB expression (p < 0.035). The PRA:PRB ratio may be a discriminator of response to endocrine therapy in the TransATAC sample collection, with high PRA:PRB ratio predicting earlier relapse for women on tamoxifen, but not anastrozole (mean lnPRA:PRB ratio; HR (95 % CI) tamoxifen 2.45 (1.20-4.99); p value 0.02; anastrozole 0.80 (0.36-1.78); p value 0.60). The results of this study show that PRA:PRB imbalance in breast cancers is not associated with lifetime endogenous endocrine and reproductive factors, but is associated with MHT use, and that PRA predominance can discriminate those women who will relapse earlier on tamoxifen treatment. These data support a role for imbalanced PRA:PRB expression in breast cancer progression and relative benefit from endocrine treatment. PMID- 25917867 TI - Premenopausal plasma carotenoids, fluorescent oxidation products, and subsequent breast cancer risk in the nurses' health studies. AB - High levels of circulating carotenoids are hypothesized to reduce breast cancer risk, potentially due to their antioxidant properties. However, little is known about the relationship between carotenoid exposure earlier in life and risk. We examined associations of premenopausal plasma carotenoids and markers of oxidative stress and risk of breast cancer among 1179 case-control pairs in the Nurses' Health Study (NHS) and NHSII. Levels of alpha- and beta-carotene, beta cryptoxanthin, lycopene, and lutein/zeaxanthin were quantified by high performance liquid chromatography. Three fluorescent oxidation products (FlOP_360, FlOP_320, FlOP_400) were measured in a subset of participants by spectrofluoroscopy. Multivariate conditional logistic regression was used to estimate odds ratios and 95 % confidence intervals for breast cancer by quartile, as well as P values for tests of linear trend. We additionally examined whether 45 single-nucleotide polymorphisms (SNPs) in five genes involved in oxidative and antioxidative processes or carotenoid availability were associated with risk. Carotenoid measures were not inversely associated with breast cancer risk. No differences by estrogen receptor status were observed, though some inverse associations were observed among women postmenopausal at diagnosis. Plasma FlOP levels were not positively associated with risk, and suggestive inverse associations with FlOP_320 and FlOP_360 were observed. Several SNPs were associated with carotenoid levels, and a small number were suggestively associated with breast cancer risk. We observed evidence of interactions between some SNPs and carotenoid levels on risk. We did not observe consistent associations between circulating levels of premenopausal carotenoids or FlOP levels and breast cancer risk. PMID- 25917869 TI - Adjuvant dose-dense chemotherapy in breast cancer: a systematic review and meta analysis of randomized trials. AB - Dose-dense (DD) chemotherapy (CT) aimed at achieving a higher rate of cancer cell destruction has been adopted as an adjuvant therapy in high-risk breast cancer (BC), with the goal being to improve outcomes. We performed an updated systematic review and meta-analysis of the existing data from randomized phase III trials regarding the efficacy and toxicity of this adjuvant DD-CT strategy in early BC. Randomized-controlled trials that compared a DD with a standard adjuvant CT schedule in adult women with resected BC were identified by searching the databases of Pubmed, the Cochrane Cancer Register of Controlled Trials, SCOPUS, EMBASE, and the Web of Science up to March 2015. Hazard ratios (HRs) of death and recurrence, and the relative risks of adverse events, were estimated and pooled. A total of 8 phase III trials encompassing 17,188 randomized patients met the inclusion criteria. The patients who received DD-CT had better overall survival (OS: HR 0.86, 95 % confidence interval [CI] 0.79-0.93, P = 0.0001) and disease free survival (DFS: HR 0.84, 95 % CI 0.77-0.91, P < 0.0001) than those on the conventional schedule. A statistically significant OS benefit was observed in patients with hormone receptor-negative (ER-) tumors (HR 0.8, P = 0.002), but not in those with ER-positive BC (HR 0.93, 95 % CI 0.82-1.05; P = 0.25). DD-CT leads to better OS and DFS, particularly in women with ER- early BC. These results suggest that the DD strategy should be the standard care offered to high-risk ER- BC patients. PMID- 25917870 TI - Atomic force microscopy force-distance curves with small amplitude ultrasonic modulation. AB - Force-distance curves were acquired on a highly oriented pyrolytic graphite (HOPG) specimen and a gold film specimen under ultrasonic modulation in atomic force microscopy (AFM). Measurements demonstrated that small amplitude ultrasonic oscillation of either the cantilever or the sample has significant impacts on the characteristics of force-distance curves. With the increase of excitation amplitude, the apparent pull-off force decreased gradually and the hysteresis between the approach and retraction curves reduced significantly. Furthermore, the decrease of the pull-off force was determined to be also relevant to the excitation frequency. With the assistance of contact resonance spectra, the pull off force was verified to have a near-linear relationship with the cantilever contact oscillation amplitude. Theoretical analysis and subsequent numerical simulations well interpreted the experimental results. The emergence of large oscillating contact forces under ultrasonic modulation altered the force-distance curves, and such a mechanism was ascertained by further ultrasonic AFM imaging. PMID- 25917871 TI - Functional neuroimaging with default mode network regions distinguishes PTSD from TBI in a military veteran population. AB - PTSD and TBI are two common conditions in veteran populations that can be difficult to distinguish clinically. The default mode network (DMN) is abnormal in a multitude of neurological and psychiatric disorders. We hypothesize that brain perfusion SPECT can be applied to diagnostically separate PTSD from TBI reliably in a veteran cohort using DMN regions. A group of 196 veterans (36 with PTSD, 115 with TBI, 45 with PTSD/TBI) were selected from a large multi-site population cohort of individuals with psychiatric disease. Inclusion criteria were peacetime or wartime veterans regardless of branch of service and included those for whom the traumatic brain injury was not service related. SPECT imaging was performed on this group both at rest and during a concentration task. These measures, as well as the baseline-concentration difference, were then inputted from DMN regions into separate binary logistic regression models controlling for age, gender, race, clinic site, co-morbid psychiatric diseases, TBI severity, whether or not the TBI was service related, and branch of armed service. Predicted probabilities were then inputted into a receiver operating characteristic analysis to compute sensitivity, specificity, and accuracy. Compared to PSTD, persons with TBI were older, male, and had higher rates of bipolar and major depressive disorder (p < 0.05). Baseline quantitative regions with SPECT separated PTSD from TBI in the veterans with 92 % sensitivity, 85 % specificity, and 94 % accuracy. With concentration scans, there was 85 % sensitivity, 83 % specificity and 89 % accuracy. Baseline-concentration (the difference metric between the two scans) scans were 85 % sensitivity, 80 % specificity, and 87 % accuracy. In separating TBI from PTSD/TBI visual readings of baseline scans had 85 % sensitivity, 81 % specificity, and 83 % accuracy. Concentration scans had 80 % sensitivity, 65 % specificity, and 79 % accuracy. Baseline-concentration scans had 82 % sensitivity, 69 % specificity, and 81 % accuracy. For separating PTSD from PTSD/TBI baseline scans had 87 % sensitivity, 83 % specificity, and 92 % accuracy. Concentration scans had 91 % sensitivity, 76 % specificity, and 88 % accuracy. Baseline-concentration scans had 84 % sensitivity, 64 % specificity, and 85 % accuracy. This study demonstrates the ability to separate PTSD and TBI from each other in a veteran population using functional neuroimaging. PMID- 25917872 TI - Specific cerebellar and cortical degeneration correlates with ataxia severity in spinocerebellar ataxia type 7. AB - Spinocerebellar ataxia type 7 (SCA7) is a progressive neurodegenerative disorder that is accompanied by loss of motor control and macular degeneration. Previous studies have shown cerebellar and pons atrophy as well as functional connectivity changes across the whole brain. Although different MRI modalities have been used to study the degenerative process, little is known about the relationship between the motor symptoms and cerebral atrophy. Twenty-four patients with molecular diagnosis of SCA7 where invited to participate in this study. Ataxia severity was evaluated using the scale for the assessment and rating of ataxia (SARA). Structural magnetic resonance imaging (MRI) brain images were used to obtain the grey matter volume of each participant. As expected, we found a significant negative correlation between the SARA score and the grey matter volume in distinct regions of the cerebellum in the patient group. Additionally, we found significant correlations between the ataxia degree and the degeneration of specific cortical areas in these patients. These findings provide a better understanding of the relationship between gray matter atrophy and ataxia related symptoms that result from the SCA7 mutation. PMID- 25917874 TI - Purification and Characterization of a New Serine Protease (VLCII) Isolated from Vipera lebetina Venom: Its Role in Hemostasis. AB - Snake venom serine proteinases (SVSPs) affect various physiological functions including blood coagulation, fibrinolysis, and platelet aggregation. Coagulant serine proteinase (VLCII) was purified from Vipera lebetina venom using three chromatographic steps: gel filtration on SephadexG-75, DEAE-Sephadex A-50, and reversed-phase high-performance liquid chromatography (RP-HPLC) on C8 column. VLCII appeared homogenous (60 kDa) when tested on sodium dodecyl sulfate polyacrylamide gel electrophoresis (SDS-PAGE). VLCII as a thrombin-like enzyme was able to hydrolyze Nalpha-CBZ L-arginine-p-nitroanilide hydrochloride and could be a serine protease because it is inhibited by phenylmethylsulfonyl fluoride. The proteolytic activity of VLCII was not affected by ethylenediaminetetraacetic acid and 1.10-phenanthroline. It showed high coagulant activity against human plasma and cleaved both Aalpha chain and Bbeta chain of bovine fibrinogen. The isolated VLCII displayed proaggregating effect on human platelet in a concentration-dependent manner with an absence of lag time. Clopidogrel P2Y12 adenosine diphosphate (ADP) receptor inhibitor reduced markedly the aggregating effect induced by VLCII than aspirin, indicating the involvement of ADP signaling pathway. PMID- 25917873 TI - Identification of a Novel Rat NR2B Subunit Gene Promoter Region Variant and Its Association with Microwave-Induced Neuron Impairment. AB - Microwave radiation has been implicated in cognitive dysfunction and neuronal injury in animal models and in human investigations; however, the mechanism of these effects is unclear. In this study, single nucleotide polymorphism (SNP) sites in the rat GRIN2B promoter region were screened. The associations of these SNPs with microwave-induced rat brain dysfunction and with rat pheochromocytoma 12 (PC12) cell function were investigated. Wistar rats (n = 160) were exposed to microwave radiation (30 mW/cm(2) for 5 min/day, 5 days/week, over a period of 2 months). Screening of the GRIN2B promoter region revealed a stable C-to-T variant at nucleotide position -217 that was not induced by microwave exposure. The learning and memory ability, amino acid contents in the hippocampus and cerebrospinal fluid, and NR2B expression were then investigated in the different genotypes. Following microwave exposure, NR2B protein expression decreased, while the Glu contents in the hippocampus and CSF increased, and memory impairment was observed in the TT genotype but not the CC and CT genotypes. In PC12 cells, the effects of the T allele were more pronounced than those of the C allele on transcription factor binding ability, transcriptional activity, NR2B mRNA, and protein expression. These effects may be related to the detrimental role of the T allele and the protective role of the C allele in rat brain function and PC12 cells exposed to microwave radiation. PMID- 25917875 TI - Resveratrol activates autophagic cell death in prostate cancer cells via downregulation of STIM1 and the mTOR pathway. AB - Resveratrol (RSV), a natural polyphenol, has been suggested to induce cell cycle arrest and activate apoptosis-mediated cell death in several cancer cells, including prostate cancer. However, several molecular mechanisms have been proposed on its chemopreventive action, the precise mechanisms by which RSV exerts its anti-proliferative effect in androgen-independent prostate cancer cells remain questionable. In the present study, we show that RSV activates autophagic cell death in PC3 and DU145 cells, which was dependent on stromal interaction molecule 1 (STIM1) expression. RSV treatment decreases STIM1 expression in a time-dependent manner and attenuates STIM1 association with TRPC1 and Orai1. Furthermore, RSV treatment also decreases ER calcium storage and store operated calcium entry (SOCE), which induces endoplasmic reticulum (ER) stress, thereby, activating AMPK and inhibiting the AKT/mTOR pathway. Similarly, inhibition of SOCE by SKF-96365 decreases the survival and proliferation of PC3 and DU145 cells and inhibits AKT/mTOR pathway and induces autophagic cell death. Importantly, SOCE inhibition and subsequent autophagic cell death caused by RSV was reversed by STIM1 overexpression. STIM1 overexpression restored SOCE, prevents the loss of mTOR phosphorylation and decreased the expression of CHOP and LC3A in PC3 cells. Taken together, for the first time, our results revealed that RSV induces autophagy-mediated cell death in PC3 and DU145 cells through regulation of SOCE mechanisms, including downregulating STIM1 expression and trigger ER stress by depleting ER calcium pool. PMID- 25917876 TI - Clinical Pharmacokinetic Studies of Enzalutamide. AB - BACKGROUND AND OBJECTIVES: Oral enzalutamide (160 mg once daily) is approved for the treatment of metastatic castration-resistant prostate cancer (mCRPC). This article describes the pharmacokinetics of enzalutamide and its active metabolite N-desmethyl enzalutamide. METHODS: Results are reported from five clinical studies. RESULTS: In a dose-escalation study (n = 140), enzalutamide half-life was 5.8 days, steady state was achieved by day 28, accumulation was 8.3-fold, exposure was approximately dose proportional from 30-360 mg/day, and intersubject variability was <=30 %. In a mass balance study (n = 6), enzalutamide was primarily eliminated by hepatic metabolism. Renal excretion was an insignificant elimination pathway for enzalutamide and N-desmethyl enzalutamide. In a food effect study (n = 60), food did not have a meaningful effect on area under the plasma concentration-time curve (AUC) of enzalutamide or N-desmethyl enzalutamide, and in an hepatic impairment study, AUC of the sum of enzalutamide plus N-desmethyl enzalutamide was similar in men with mild (n = 6) or moderate (n = 8) impairment (Child-Pugh Class A and B) versus men with normal hepatic function (n = 14). In a phase III trial, an exposure-response analysis of steady state predose (trough) concentrations (C trough) versus overall survival (n = 1103) showed that active treatment C trough quartiles for 160 mg/day were uniformly beneficial relative to placebo, and no threshold of C trough was associated with a statistically significant better response. CONCLUSIONS: Enzalutamide has predictable pharmacokinetics, with low intersubject variability. Similar efficacy was observed in patients across the concentration/exposure range associated with a fixed oral dose of enzalutamide 160 mg/day. PMID- 25917877 TI - Performance assessment of the Illumina massively parallel sequencing platform for deep sequencing analysis of viral minority variants. AB - Massively parallel sequencing (MPS) technology has opened new avenues to study viral dynamics and treatment-induced resistance mechanisms of infections such as human immunodeficiency virus (HIV) and hepatitis C virus (HCV). Whereas the Roche/454 platform has been used widely for the detection of low-frequent drug resistant variants, more recently developed short-read MPS technologies have the advantage of delivering a higher sequencing depth at a lower cost per sequenced base. This study assesses the performance characteristics of Illumina MPS technology for the characterization of genetic variability in viral populations by deep sequencing. The reported results from MPS experiments comprising HIV and HCV plasmids demonstrate that a 0.5-1% lower limit of detection can be achieved readily with Illumina MPS while retaining good accuracy also at low frequencies. Deep sequencing of a set of clinical samples (12 HIV and 9 HCV patients), designed at a similar budget for both MPS platforms, reveals a comparable lower limit of detection for Illumina and Roche/454. Finally, this study shows the possibility to apply Illumina's paired-end sequencing as a strategy to assess linkage between different mutations identified in individual viral subspecies. These results support the use of Illumina as another MPS platform of choice for deep sequencing of viral minority species. PMID- 25917878 TI - TRANSCRIPTION FACTOR Bmsage PLAYS A CRUCIAL ROLE IN SILK GLAND GENERATION IN SILKWORM, Bombyx mori. AB - Salivary gland secretion is altered in Drosophila embryos with loss of function of the sage gene. Saliva has a reduced volume and an increased electron density according to transmission electron microscopy, resulting in regions of tube dilation and constriction with intermittent tube closure. However, the precise functions of Bmsage in silkworm (Bombyx mori) are unknown, although its sequence had been deposited in SilkDB. From this, Bmsage is inferred to be a transcription factor that regulates the synthesis of silk fibroin and interacts with another silk gland-specific transcription factor, namely, silk gland factor-1. In this study, we introduced a germline mutation of Bmsage using the Cas9/sgRNA system, a genome-editing technology, resulting in deletion of Bmsage from the genome of B. mori. Of the 15 tested samples, seven displayed alterations at the target site. The mutagenesis efficiency was about 46.7% and there were no obvious off-target effects. In the screened homozygous mutants, silk glands developed poorly and the middle and posterior silk glands (MSG and PSG) were absent, which was significantly different from the wild type. The offspring of G0 mosaic silkworms had indel mutations causing 2- or 9-bp deletions at the target site, but exhibited the same abnormal silk gland structure. Mutant larvae containing different open-reading frames of Bmsage had the same silk gland phenotype. This illustrated that the mutant phenotype was due to Bmsage knockout. We conclude that Bmsage participates in embryonic development of the silk gland. PMID- 25917879 TI - Suboptimal vitamin K status and its risk factors in a population of Chinese chronic haemodialysis patients. AB - AIMS: Vitamin K deficiency is known to be common in haemodialysis patients and associates with adverse outcomes in this population, particularly vascular calcification. We aimed to investigate the vitamin K status in a population of Chinese haemodialysis (HD) patients. METHODS: We collected demographic and biochemical data from a population of maintenance HD (MHD) patients in our unit and a control group composed of healthy subjects from our outpatient clinic. Fasting serum samples from all subjects were collected for the measurement of known vitamin K-dependent proteins i.e. matrix Gla protein (MGP), osteocalcin (OC) and uncarboxylated osteocalcin (ucOC). We also quantified the fraction of ucOC to total OC (%ucOC). Differences of these parameters between groups were analyzed and risk factors of vitamin K deficiency based on the definition as per %ucOC were investigated. RESULTS: We enrolled 93 MHD patients as a test group and 93 healthy subjects as a control group. There was no significant difference in MGP between groups (4.0 +/- 2.8 pg/mL in MHD vs 4.2 +/- 1.2 pg/mL in control; P = 0.676). Mean %ucOC was significantly greater in the MHD patients as compared to control subjects (76.4 +/- 20.0% in MHD vs 48.56 +/- 15.5%; P < 0.001). Time on dialysis and low-density lipoprotein cholesterol level appeared to be indicators of vitamin K deficiency, with the former being an independent risk factor. CONCLUSIONS: Defining Vitamin K deficiency by %ucOC, suboptimal vitamin K levels appear common in Chinese MHD patients. Time on dialysis and LDL cholesterol level predict vitamin K deficiency. PMID- 25917880 TI - Automated and visual measurements of estrous behavior and their sources of variation in Holstein heifers. II: Standing and lying patterns. AB - Lying (LY) and standing (ST) behavior of Holstein heifers (n = 57) was studied from Day -7 to Day +2 relative to estrus (Day 0) using leg-mounted accelerometers. A total of 269 estrus episodes were studied. The objectives were to quantify the effects of estrus on ST and LY patterns, identify sources of variation, and provide insight into new approaches for the use of sensors in estrus detection. The sensors were used to obtain ST bout frequency (bouts per day), total daily ST time, and mean bout duration and duration of the longest bout for ST and LY on a daily basis. Estrus episodes were identified using walking activity peaks and validated by ovarian ultrasonography. Repeated measures ANOVA was used to analyze the effects of estrus order (pubertal vs. second and greater), season, time of estrus onset, category of baseline walking activity, and number of heifers simultaneously in estrus on ST and LY variables. Overall, ST bout frequency was lower, whereas mean ST bout duration, duration of the longest ST bout, and total daily ST time were longer on Day 0 (P < 0.05). The longest ST bout increased from 232 +/- 5 minutes on Day -7 to 488 +/- 16 minutes on Day 0 (P < 0.05), and on Day 0, it started within -2 to 4 hours of time of estrus onset. Measurements of ST bouts varied the most on Day 0 (coefficient of variation = 21.5%-52.8%). The pubertal estrus was characterized by smaller increase in mean ST bout duration, longest ST bout duration, and total daily ST time (P < 0.05) compared to the second and greater episodes. Second and greater episodes had greater longest LY bout on Day +1, but on Day 0 it was not different from other nonestrus days (P < 0.01). The longest ST bout on Day 0 was longer for heifers with high baseline walking activity and for episodes occurring during the cold season (P < 0.05). The effect of estrus on ST variables for morning-onset episodes was observed only on Day 0. Episodes with afternoon and night onset showed the effect of estrus spread over Days -1 and 0, resulting in a smaller change between Day -7 and Day 0. The number of heifers simultaneously in estrus did not affect the studied variables (P > 0.05). Measurements of ST and LY changed during estrus and were correlated to walking activity. The large increase in duration of the longest ST bout and its occurrence in proximity of estrus onset suggest potential for automation. Incorporating measurements of ST and LY corrected for sources of variation could improve estrus detection systems. PMID- 25917882 TI - Diameter of the ovulatory follicle at timed artificial insemination as a predictor of pregnancy status in lactating dairy cows subjected to GnRH-based protocols. AB - Ovulation of an early-stage dominant follicle induced by exogenous GnRH reportedly results in a reduced ovulatory follicle size and fertility in beef and dairy cattle. Objectives were to examine factors associated with ovulatory follicle diameter and the relationship between ovulatory follicle diameter and pregnancy per artificial insemination (P/AI) and pregnancy loss in lactating dairy cows subjected to GnRH-based programs for timed artificial insemination (TAI). A total of 1048 ovulations from 1576 breedings of cows that had or had not been presynchronized and subjected to a 5- or a 7-day GnRH-based protocol with or without progesterone supplementation between initial GnRH and PGF2alpha were analyzed. Ultrasonography was used to determine cyclicity, ovulation, and pregnancy status and to measure diameter of the ovulatory follicle at the time of TAI. Mean (+/-standard error) diameter of the ovulatory follicle was 16.4 +/- 0.1 mm (range, 11-25 mm; n = 1048); the most common diameters were 15 (n = 170), 16 (n = 169), and 17 mm (n = 170). Multiparous cows and those subjected to a 7-day protocol had larger ovulatory follicles (P < 0.05). On average, multiparous cows that did not ovulate after the initial GnRH had the largest ovulatory follicles (17.0 +/- 0.1 mm; n = 290), whereas all cows that ovulated after the initial GnRH and were subjected to a 5-day GnRH-based protocol had the smallest ovulatory follicles (15.6 +/- 0.2 mm; n = 207). The associations between ovulatory follicle diameter and P/AI at 32 and 60 days after TAI were not significant. However, a significant linear relationship between ovulatory follicle diameter and pregnancy loss between 32 and 60 days after TAI was observed, with an increased (P < 0.05) probability of pregnancy loss in cows with an ovulatory follicle greater than 20 mm in diameter. In summary, the diameter of the ovulatory follicle preceding TAI was affected by interactions between ovulatory response to initial GnRH and parity and between ovulatory response to initial GnRH and the length of ovulation synchronization protocol. Ovulatory follicle diameter was not associated with P/AI at 32 or 60 days, but large ovulatory follicle size was identified as a predictor of pregnancy loss in lactating dairy cows subjected to GnRH-based protocols for TAI. PMID- 25917881 TI - Germline transmission in transgenic Huntington's disease monkeys. AB - Transgenic nonhuman primate models are an increasingly popular model for neurologic and neurodegenerative disease because their brain functions and neural anatomies closely resemble those of humans. Transgenic Huntington's disease monkeys (HD monkeys) developed clinical features similar to those seen in HD patients, making the monkeys suitable for a preclinical study of HD. However, until HD monkey colonies can be readily expanded, their use in preclinical studies will be limited. In the present study, we confirmed germline transmission of the mutant huntingtin (mHTT) transgene in both embryonic stem cells generated from three male HD monkey founders (F0) and in second-generation offspring (F1) produced via artificial insemination by using intrauterine insemination technique. A total of five offspring were produced from 15 females that were inseminated by intrauterine insemination using semen collected from the three HD founders (5 of 15, 33%). Thus far, sperm collected from the HD founder (rHD8) has led to two F1 transgenic HD monkeys with germline transmission rate at 100% (2 of 2). mHTT expression was confirmed by quantitative real-time polymerase chain reaction using skin fibroblasts from the F1 HD monkeys and induced pluripotent stem cells established from one of the F1 HD monkeys (rHD8-2). Here, we report the stable germline transmission and expression of the mHTT transgene in HD monkeys, which suggest possible expansion of HD monkey colonies for preclinical and biomedical research studies. PMID- 25917883 TI - Automated and visual measurements of estrous behavior and their sources of variation in Holstein heifers. I: Walking activity and behavior frequency. AB - Holstein heifers (n = 57) were monitored using accelerometers and video observations with the objective of better understanding the behavioral expression of estrus, the variation within and between the heifers, and the possible sources of variation. IceTags recorded walking activity from 7 to 13 months of age. Activity peaks (n = 282) were obtained from a rolling sum of steps within 24-hour periods and validated to be estrus by ovarian ultrasonography. Behavior around activity peak of one estrus for each of 12 heifers was described in detail from video recordings. Baseline behavior was monitored in a corresponding interval 1 week before. Estrus and baseline total steps and steps per hour, estrus relative increase in activity, duration, and interval between episodes were analyzed by descriptive statistics and Spearman rank correlations. Effects of category of baseline walking activity, estrus order (pubertal vs. second and greater episodes), season, hour of estrus onset, and number of heifers simultaneously in estrus were evaluated with proc MIXED. Behavioral changes from baseline to estrus were evaluated by a signed-rank test. Estrus total steps varied greatly (4743 +/- 1740; range: 837-10,070), as well as the relative increase in activity (290 +/- 160%; range: 30%-1190%). Duration of estrus was 14 +/- 4 hours, ranging from 4 to 26 hours. The interval between episodes was the trait that varied the least. Pubertal estrus was shorter and had a smaller relative increase in activity than second and greater episodes (P < 0.05). The number of steps during estrus was greater for heifers of high baseline activity (P < 0.01). Estrus episodes occurring in the winter and starting between 4 PM and 3 AM had the greatest relative increase in activity (P < 0.05). The number of heifers simultaneously in estrus did not influence estrus expression (P > 0.05). The behaviors with greatest change from baseline to estrus were chin rest, sniff, back mount, crossover, accept chin rest, and follow, but variation was large. Overall, estrus was apparent in behavioral changes with large variation within and between the heifers. Estrus order, onset hour, season, and baseline walking activity are important factors affecting estrus activity. Therefore, estrus detection tools should account for potential sources of variation. The visual and automated measurements of estrus expression reported in this study reveal possibilities for improved on-farm estrus detection technologies and potential genetic selection for estrus expression. PMID- 25917884 TI - Effect of single-layer centrifugation or washing on frozen-thawed donkey semen quality: Do they have the same effect regardless of the quality of the sample? AB - The aims of this study were to determine the sperm quality of frozen-thawed donkey sperm samples after single-layer centrifugation (SLC) using Androcoll-E in comparison to sperm washing or no centrifugation and to determine if the effect on the sperm quality after SLC or sperm washing depends on the quality of the sample. Frozen-thawed sperm samples from Andalusian donkeys were divided into three aliquots, and they were processed using three different techniques after thawing: uncentrifuged diluted control (UDC), sperm washing (SW), and SLC. Afterward, sperm quality index was estimated by integrating all parameters (total and progressive sperm motility, membrane integrity, and DNA fragmentation) in a single value. The relationship between the sperm quality of thawed UDC samples and the effect on sperm parameters in SW and SLC-selected samples was assessed. Sperm quality index was significantly higher (P < 0.001) in SLC (0.8 +/- 0.0) samples than that in UDC (0.6 +/- 0.0) and SW (0.6 +/- 0.0) samples, regardless of the sperm quality index after thawing of the sperm sample. In conclusion, SLC of frozen-thawed donkey spermatozoa using Androcoll-E-Small can be a suitable procedure for selecting frozen-thawed donkey sperm with better quality, in particular in those samples where an improvement in motility is needed. PMID- 25917885 TI - Effect of sub-optimal doses of fluoxetine plus estradiol on antidepressant-like behavior and hippocampal neurogenesis in ovariectomized rats. AB - Estrogens and antidepressants synergize to reduce depressive symptoms and stimulate neurogenesis and neuroplastic events. The aim of this study was to explore whether the antidepressant-like effect induced by the combination of low doses of estradiol (E2) and fluoxetine (FLX) involves changes in cell proliferation, early survival, morphology and dendrite complexity of hippocampal new-immature neurons. The antidepressant-like effects of E2 and/or FLX were evaluated by the forced swimming test (FST), cell proliferation was determined with the endogenous marker Ki67, survival of newborn cells was established with bromo-deoxiuridine (BrdU) and immature neurons were ascertained by doublecortin (DCX) labeling while their dendrite complexity was evaluated with Sholl analysis. Ovariectomized Wistar rats were randomly assigned to one of the following groups: Vehicle (saline/14 days+Oil/-8h before FST); E2 (saline/14 days + E2 2.5 or 10 MUg/rat; -8 h before FST); FLX (1.25 or 10 mg/kg for 14 days + oil -8h before FST), and FLX plus E2 (FLX 1.25 mg/kg for 14 days + E2 2.5 MUg/rat -8 h before FST). The combination of sub-threshold doses of FLX plus E2 produced antidepressant-like actions similar to those induced by FLX or E2 given independently at optimal doses. Only FLX at an optimal dose and the combination of FLX plus E2 increased cell proliferation, the number of DCX-labeled immature neurons and the complexity of their dendritic tree, suggesting that these events may be responsible for their antidepressant-like effect. PMID- 25917886 TI - Association of metabolic syndrome with sensory gating deficits in patients with chronic schizophrenia. AB - Metabolic syndrome is more prevalent in schizophrenia than in the general population and is associated with an increased rate of morbidity. It has been associated with cognitive impairments in schizophrenia, which are a core deficit in patients with chronic schizophrenia. Sensory gating deficit is also a core deficit in schizophrenia. The principal objective of this study was to investigate the relationship between sensory gating deficit and metabolic syndrome in patients with schizophrenia, after adjusting for key confounding factors. We hypothesized that patients with metabolic syndrome exhibit a higher rate of sensory gating deficit compared to those without metabolic syndrome. This study investigated sensory gating with the auditory event-related potential method by measuring P50 amplitude changes in a double click conditioning-testing procedure in 51 patients with schizophrenia. Patients with metabolic syndrome (n = 14) had a higher rate of sensory gating deficit (P50 suppression <50%) (p < 0.001) compared to those without metabolic syndrome (n = 37). This result remained significant (B = 2.94, Wald = 8.32, p = 0.004) after taking into account 5 potential confounding factors (age, gender, duration of disorder, Fagerstrom test, presence of clozapine or olanzapine). In patients without metabolic syndrome, sensory gating deficit was linked to a poorer attentional performance (rho = -0.371, p = 0.05). In patients with metabolic syndrome, sensory gating deficit was linked to poorer memory performance (rho = -0.635, p = 0.02). These findings suggest that metabolic syndrome may be linked to sensory gating deficit in patients with schizophrenia and that the relationship between neurocognitive function and sensory gating deficit could be affected by the metabolic status of the patients. Further studies are needed to address the causal relationship between sensory gating deficit related to schizophrenia, cognitive impairments and metabolic syndrome. PMID- 25917887 TI - Prostate cancer: PREVAILing wind blows more good news for enzalutamide. PMID- 25917888 TI - Incontinence: New internally-valved catheter for urinary retention has potential. PMID- 25917889 TI - Prostate cancer: Post-treatment imaging-a desperate need for solid evidence. PMID- 25917890 TI - Urinary incontinence: Novel insights into the mechanism of action of mirabegron on human bladder smooth muscle. PMID- 25917891 TI - Prostate cancer: Under pressure-physical force promotes tumour growth. PMID- 25917892 TI - Leucine-rich alpha2 -glycoprotein as a potential biomarker for joint inflammation during anti-interleukin-6 biologic therapy in rheumatoid arthritis. AB - OBJECTIVE: To investigate whether leucine-rich alpha2 -glycoprotein (LRG) could be a biomarker for disease activity during interleukin-6 (IL-6) blockade treatment of rheumatoid arthritis (RA). METHODS: In 59 RA patients who were treated with tocilizumab for 24 weeks, serum LRG levels were determined by enzyme linked immunosorbent assay. RA disease activity was evaluated by the Clinical Disease Activity Index (CDAI). Receiver operating characteristic (ROC) curve analysis was used to examine the diagnostic performance of LRG and other biomarkers. In monkeys with experimental autoimmune arthritis, swollen joint counts, joint pathologic changes, and blood levels of C-reactive protein (CRP) and LRG were evaluated after treatment with anti-IL-6 receptor antibody. RESULTS: Among tocilizumab-treated RA patients, those with active disease (CDAI >2.8) had significantly higher serum LRG levels compared to those whose disease was in remission. ROC curve analysis suggested that the LRG level was more useful than the CRP or matrix metalloproteinase 3 level or the erythrocyte sedimentation rate in discriminating between remission and active disease during therapy with tocilizumab. In monkeys treated with IL-6 blockade, joint scores were more closely correlated with LRG levels than with CRP levels. Histologic analysis of joints revealed that LRG levels correlated significantly with granulomatous tissue formation, cartilage degeneration, and bone destruction in IL-6 blockade treated monkeys with low levels of CRP. CONCLUSION: Under conditions of IL-6 inhibition, LRG was more useful than other biomarkers in discriminating between active and inactive disease in human RA and in detecting joint inflammation in experimental arthritis. LRG may serve as a convenient biomarker for RA disease activity during IL-6 blockade treatment. PMID- 25917893 TI - Acetylation of human mitochondrial citrate carrier modulates mitochondrial citrate/malate exchange activity to sustain NADPH production during macrophage activation. AB - The mitochondrial citrate-malate exchanger (CIC), a known target of acetylation, is up-regulated in activated immune cells and plays a key role in the production of inflammatory mediators. However, the role of acetylation in CIC activity is elusive. We show that CIC is acetylated in activated primary human macrophages and U937 cells and the level of acetylation is higher in glucose-deprived compared to normal glucose medium. Acetylation enhances CIC transport activity, leading to a higher citrate efflux from mitochondria in exchange with malate. Cytosolic citrate levels do not increase upon activation of cells grown in deprived compared to normal glucose media, indicating that citrate, transported from mitochondria at higher rates from acetylated CIC, is consumed at higher rates. Malate levels in the cytosol are lower in activated cells grown in glucose deprived compared to normal glucose medium, indicating that this TCA intermediate is rapidly recycled back into the cytosol where it is used by the malic enzyme. Additionally, in activated cells CIC inhibition increases the NADP+/NADPH ratio in glucose-deprived cells; this ratio is unchanged in glucose-rich grown cells due to the activity of the pentose phosphate pathway. Consistently, the NADPH producing isocitrate dehydrogenase level is higher in activated glucose-deprived as compared to glucose rich cells. These results demonstrate that, in the absence of glucose, activated macrophages increase CIC acetylation to enhance citrate efflux from mitochondria not only to produce inflammatory mediators but also to meet the NADPH demand through the actions of isocitrate dehydrogenase and malic enzyme. PMID- 25917894 TI - Mitochondria, autophagy and age-associated neurodegenerative diseases: New insights into a complex interplay. AB - Mitochondria represent the major bioenergetic hub coordinating cellular and organismal homeostasis. The underlying causes of many pathologies tormenting humans converge on impaired mitochondrial maintenance. Mitochondria-specific autophagy (mitophagy), a cellular catabolic process targeting mitochondria, holds a prominent role in mitochondrial quality control. In addition to core autophagic machinery components, mitophagy exploits a variety of molecules that identify damaged or superfluous mitochondria and mediate their elimination. Signaling pathways integrating environmental and genetic stimuli interact with key mitophagy effectors to activate cellular stress response mechanisms, ultimately modulating health and lifespan. Here, we review the signaling cascades and molecular mechanisms that govern the process of mitophagy and discuss their involvement in ageing and neurodegeneration. This article is part of a Special Issue entitled: Mitochondrial Dysfunction in Aging. PMID- 25917895 TI - Randomized Clinical Trial: Impact of Oral Administration of Saccharomyces boulardii on Gene Expression of Intestinal Cytokines in Patients Undergoing Colon Resection. AB - BACKGROUND: When intestinal microbiota is imbalanced, a patient becomes more vulnerable to infectious complications; intervention with beneficial probiotics may help lower risk for infection. The aim of this study was to measure levels of inflammatory cytokine messenger RNA (mRNA) in surgical samples of intestinal mucosal tissues from patients who were given the probiotic Saccharomyces boulardii before undergoing colon surgery. METHODS: Thirty-three patients undergoing colon resection were randomly assigned to receive at least 7-day preoperative probiotic treatment (n = 15) or conventional (n = 18) treatment. Probiotic treatment consisted of oral lyophilized S boulardii Cytokine mRNA levels (interleukin [IL]-10, IL-1beta, IL-23A, tumor necrosis factor [TNF]-alpha, IL-12B, interferon-gamma [INF-gamma], and IL-17A) were measured in samples obtained during the operation. Postoperative infections were also assessed. RESULTS: Patients who received probiotics had significantly lower mucosal IL 1beta, IL-10, and IL-23A mRNA levels than the control group (P = .001, P = .04, and P = .03, respectively). However, mRNA expression of other cytokines did not differ between the 2 groups (P > .05). The incidence of postoperative infectious complications was 13.3% and 38.8% in probiotic and control groups, respectively (P > .05). There was no perioperative mortality in either group. The mean total length of hospital stay was similar between the groups (P > .05). CONCLUSIONS: Probiotic treatment with S boulardii downregulates both pro- and anti inflammatory cytokines in the intestinal colonic mucosa with no statistical impact on postoperative infection rates. PMID- 25917896 TI - Repeat DNA in genome organization and stability. AB - Eukaryotic genomes contain millions of copies of repetitive elements (RE). Although the euchromatic parts of most genomes are clearly annotated, the repetitive/heterochromatic parts are poorly defined. It is estimated that between 50 and 70% of the human genome is composed of REs. Despite this, we know surprisingly little about the physiological relevance, molecular regulation and the composition of these regions. This primarily reflects the difficulty that REs pose for PCR-based assays, and their poor map-ability in next generation sequencing experiments. Here we first summarize the nature and classification of REs and then examine how this has been used in the recent years to broaden our understanding of mechanisms that keep the repetitive regions of our genomes silent and stable. PMID- 25917897 TI - Pathogenesis of multiple lentigines in LEOPARD syndrome with PTPN11 gene mutation. AB - LEOPARD syndrome (LS) is an autosomal dominant condition with multiple anomalies, including multiple lentigines. LS is caused by mutations in PTPN11, encoding the protein tyrosine phosphatase, SHP-2. We report here 2 unrelated Japanese cases of LS with different PTPN11 mutations (p.Y279C and p.T468P). To elucidate the pathogenesis of multiple lentigines in LS, ultrastructural and immunohistochemical analyses of lentigines and non-lesional skin were performed. Numerous mature giant melanosomes in melanocytes and keratinocytes were observed in lentigines. In addition, the levels of expression of endothelin-1 (ET-1), phosphorylated Akt, mTOR and STAT3 in the epidermis in lentigines were significantly elevated compared with non-lesional skin. In in vitro assays, melanin synthesis in human melanoma cells expressing SHP-2 with LS-associated mutations was higher than in cells expressing normal SHP-2, suggesting that LS associated SHP-2 mutations might enhance melanin synthesis in melanocytes, and that the activation of Akt/mTOR signalling may contribute to this process. PMID- 25917898 TI - In vivo model with targeted cAMP biosensor reveals changes in receptor microdomain communication in cardiac disease. AB - 3',5'-cyclic adenosine monophosphate (cAMP) is an ubiquitous second messenger that regulates physiological functions by acting in distinct subcellular microdomains. Although several targeted cAMP biosensors are developed and used in single cells, it is unclear whether such biosensors can be successfully applied in vivo, especially in the context of disease. Here, we describe a transgenic mouse model expressing a targeted cAMP sensor and analyse microdomain-specific second messenger dynamics in the vicinity of the sarcoplasmic/endoplasmic reticulum calcium ATPase (SERCA). We demonstrate the biocompatibility of this targeted sensor and its potential for real-time monitoring of compartmentalized cAMP signalling in adult cardiomyocytes isolated from a healthy mouse heart and from an in vivo cardiac disease model. In particular, we uncover the existence of a phosphodiesterase-dependent receptor-microdomain communication, which is affected in hypertrophy, resulting in reduced beta-adrenergic receptor-cAMP signalling to SERCA. PMID- 25917899 TI - CASD-NMR 2: robust and accurate unsupervised analysis of raw NOESY spectra and protein structure determination with UNIO. AB - UNIO is a comprehensive software suite for protein NMR structure determination that enables full automation of all NMR data analysis steps involved--including signal identification in NMR spectra, sequence-specific backbone and side-chain resonance assignment, NOE assignment and structure calculation. Within the framework of the second round of the community-wide stringent blind NMR structure determination challenge (CASD-NMR 2), we participated in two categories of CASD NMR 2, namely using either raw NMR spectra or unrefined NOE peak lists as input. A total of 15 resulting NMR structure bundles were submitted for 9 out of 10 blind protein targets. All submitted UNIO structures accurately coincided with the corresponding blind targets as documented by an average backbone root mean square deviation to the reference proteins of only 1.2 A. Also, the precision of the UNIO structure bundles was virtually identical to the ensemble of reference structures. By assessing the quality of all UNIO structures submitted to the two categories, we find throughout that only the UNIO-ATNOS/CANDID approach using raw NMR spectra consistently yielded structure bundles of high quality for direct deposition in the Protein Data Bank. In conclusion, the results obtained in CASD NMR 2 are another vital proof for robust, accurate and unsupervised NMR data analysis by UNIO for real-world applications. PMID- 25917900 TI - First Delinquent Behavior Among Pre-Pubescent Children: A Development Paradigm Alongside Family SES. AB - The present study investigated what explains and accounts for first pre-pubescent delinquent behaviors among children. This was based on the notion that a developmental paradigm (e.g., self-control) alongside family socio-economic status (SES) can provide a passable explanation for the first and early delinquent behavior. A nationally representative sample of eighth graders (N = 3,449, 50% boys) from the Korea Youth Panel Survey (KYPS) was reviewed in terms of first delinquent behaviors. Results revealed that pre-pubescent boys started to drink at an earlier age than girls, whereas pre-pubescent girls engaged in relational bullying earlier than their male counterparts. Children's onset of delinquency age was inversely associated with family SES, but was positively associated with their degree of self-control. Different types of first delinquency were distinguished by levels of parental education as well as child's self-control. Implications of the findings are discussed. PMID- 25917901 TI - Isolation and quantification of oligomeric and polymeric procyanidins in leaves and flowers of Hawthorn (Crataegus spp.). AB - Proanthocyanidins (PAs) constitute a class of polyphenols with flavan-3-ols as monomeric building blocks. These polyphenols are mostly quantified by colorimetric methods or by chromatographic determination of monomeric flavan-3 ols or low molecular oligomers as lead compounds. No reliable analytical methods are available for unambiguous identification of the homologues series of oligo- and polymeric PAs. For Hawthorn leaf and flower (Crataegi folium cum flore) from Crataegus spp. (Rosaceae) a protocol for preparative isolation of oligomeric and polymeric PAs from an acetone-water extract was developed, yielding procyanidin reference clusters with defined degree of polymerization (DP) from 2 to 10 besides a procyanidin-polymer. Identity and purity of these clusters were proven by HPLC, MS and in part NMR studies. For identification and quantification from Hawthorn an ICH-Q2 validated UHPLC method with fluorimetric detection and less than 10min runtime was developed. The method enabled quantification of procyanidin clusters with DP from 2 to 10 besides the polymer fraction. Batch analysis revealed procyanidin contents of about 20 to 45mg/g from a homologues series of oligomeric PAs and about 50% of polymer fraction. Monitoring of procyanidin distribution during seasonal growth of fresh plants of Crataegus monogyna showed more or less constant contents between 20 and 55mg/g dry weight of oligomeric procyanidins during the growing season in the different plant organs with strong accumulation in the flowers and fruits (55mg/g dry weight). From these data it can be speculated that procyanidins serve as part of the plants defense system in the reproductive organs of the plant. PMID- 25917902 TI - The interaction between Streptococcus spp. and Veillonella tobetsuensis in the early stages of oral biofilm formation. AB - Dental plaque is a multispecies oral biofilm, the development of which is initiated by adherence of the pioneer Streptococcus spp. Oral Veillonella spp., including V. atypica, V. denticariosi, V. dispar, V. parvula, V. rogosae, and V. tobetsuensis, are known as early colonizers in oral biofilm formation. These species have been reported to co-aggregate with Streptococcus spp. in a metabolic cooperation-dependent manner to form biofilms in human oral cavities, especially in the early stages of biofilm formation. However, in our previous study, Streptococcus gordonii showed biofilm formation to the greatest extent in the presence of V. tobetsuensis, without co-aggregation between species. These results suggest that V. tobetsuensis produces signaling molecules that promote the proliferation of S. gordonii in biofilm formation. It is well known in many bacterial species that the quorum-sensing (QS) system regulates diverse functions such as biofilm formation. However, little is known about the QS system with autoinducers (AIs), between Veillonella and Streptococcus. Recently, AI-1 and AI 2 were detected and identified in the culture supernatants of V. tobetsuensis as strong signaling molecules in biofilm formation with S. gordonii. In particular, the supernatant from V. tobetsuensis showed the highest AI-2 activity among 6 oral Veillonella species, indicating that AIs, mainly AI-2, produced by V. tobetsuensis may be important factors and may facilitate biofilm formation of S. gordonii. Clarifying the mechanism that underlies the QS system between S. gordonii and V. tobetsuensis may lead to the development of novel methods for the prevention of oral infectious diseases caused by oral biofilms. PMID- 25917903 TI - The Pseudomonas aeruginosa PA14 ABC Transporter NppA1A2BCD Is Required for Uptake of Peptidyl Nucleoside Antibiotics. AB - Analysis of the genome sequence of Pseudomonas aeruginosa PA14 revealed the presence of an operon encoding an ABC-type transporter (NppA1A2BCD) showing homology to the Yej transporter of Escherichia coli. The Yej transporter is involved in the uptake of the peptide-nucleotide antibiotic microcin C, a translation inhibitor that targets the enzyme aspartyl-tRNA synthetase. Furthermore, it was recently shown that the Opp transporter from P. aeruginosa PAO1, which is identical to Npp, is required for uptake of the uridyl peptide antibiotic pacidamycin, which targets the enzyme translocase I (MraY), which is involved in peptidoglycan synthesis. We used several approaches to further explore the substrate specificity of the Npp transporter. Assays of growth in defined minimal medium containing peptides of various lengths and amino acid compositions as sole nitrogen sources, as well as Biolog Phenotype MicroArrays, showed that the Npp transporter is not required for di-, tri-, and oligopeptide uptake. Overexpression of the npp operon increased susceptibility not just to pacidamycin but also to nickel chloride and the peptidyl nucleoside antibiotic blasticidin S. Furthermore, heterologous expression of the npp operon in a yej deficient mutant of E. coli resulted in increased susceptibility to albomycin, a naturally occurring sideromycin with a peptidyl nucleoside antibiotic. Additionally, heterologous expression showed that microcin C is recognized by the P. aeruginosa Npp system. Overall, these results suggest that the NppA1A2BCD transporter is involved in the uptake of peptidyl nucleoside antibiotics by P. aeruginosa PA14. IMPORTANCE: One of the world's most serious health problems is the rise of antibiotic-resistant bacteria. There is a desperate need to find novel antibiotic therapeutics that either act on new biological targets or are able to bypass known resistance mechanisms. Bacterial ABC transporters play an important role in nutrient uptake from the environment. These uptake systems could also be exploited by a Trojan horse strategy to facilitate the transport of antibiotics into bacterial cells. Several natural antibiotics mimic substrates of peptide uptake routes. In this study, we analyzed an ABC transporter involved in the uptake of nucleoside peptidyl antibiotics. Our data might help to design drug conjugates that may hijack this uptake system to gain access to cells. PMID- 25917904 TI - A Social Medium: ASM's 5th Cell-Cell Communication in Bacteria Meeting in Review. AB - The 5th American Society for Microbiology Conference on Cell-Cell Communication in Bacteria (CCCB-5), which convened from October 18 - 21, 2014 in San Antonio, Texas, highlighted recent advances in our understanding of microbial intercellular signaling. While the CCCB meetings arose from interests in pheromone signaling and quorum sensing, it was evident at CCCB-5 that the cell cell communication field is continuing to mature, expanding into new areas and integrating cutting-edge technologies. In this review, we recap some of the research discussed at CCCB-5 as well as the questions that have arisen from it. PMID- 25917905 TI - NAD-Independent L-Lactate Dehydrogenase Required for L-Lactate Utilization in Pseudomonas stutzeri A1501. AB - NAD-independent L-lactate dehydrogenases (l-iLDHs) play important roles in L lactate utilization of different organisms. All of the previously reported L iLDHs were flavoproteins that catalyze the oxidation of L-lactate by the flavin mononucleotide (FMN)-dependent mechanism. Based on comparative genomic analysis, a gene cluster with three genes (lldA, lldB, and lldC) encoding a novel type of L iLDH was identified in Pseudomonas stutzeri A1501. When the gene cluster was expressed in Escherichia coli, distinctive L-iLDH activity was detected. The expressed L-iLDH was purified by ammonium sulfate precipitation, ion-exchange chromatography, and affinity chromatography. SDS-PAGE and successive matrix assisted laser desorption ionization-time of flight mass spectrometry (MALDI-TOF MS) analysis of the purified L-iLDH indicated that it is a complex of LldA, LldB, and LldC (encoded by lldA, lldB, and lldC, respectively). Purified L-iLDH (LldABC) is a dimer of three subunits (LldA, LldB, and LldC), and the ratio between LldA, LldB, and LldC is 1:1:1. Different from the FMN-containing L-iLDH, absorption spectra and elemental analysis suggested that LldABC might use the iron-sulfur cluster for the L-lactate oxidation. LldABC has narrow substrate specificity, and only L-lactate and DL-2-hydrobutyrate were rapidly oxidized. Mg(2+) could activate L-iLDH activity effectively (6.6-fold). Steady-state kinetics indicated a ping-pong mechanism of LldABC for the L-lactate oxidation. Based on the gene knockout results, LldABC was confirmed to be required for the L lactate metabolism of P. stutzeri A1501. LldABC is the first purified and characterized L-iLDH with different subunits that uses the iron-sulfur cluster as the cofactor. IMPORTANCE: Providing new insights into the diversity of microbial lactate utilization could assist in the production of valuable chemicals and understanding microbial pathogenesis. An NAD-independent L-lactate dehydrogenase (L-iLDH) encoded by the gene cluster lldABC is indispensable for the L-lactate metabolism in Pseudomonas stutzeri A1501. This novel type of enzyme was purified and characterized in this study. Different from the well-characterized FMN containing L-iLDH in other microbes, LldABC in P. stutzeri A1501 is a dimer of three subunits (LldA, LldB, and LldC) and uses the iron-sulfur cluster as a cofactor. PMID- 25917906 TI - Spore Cortex Hydrolysis Precedes Dipicolinic Acid Release during Clostridium difficile Spore Germination. AB - Bacterial spore germination is a process whereby a dormant spore returns to active, vegetative growth, and this process has largely been studied in the model organism Bacillus subtilis. In B. subtilis, the initiation of germinant receptor mediated spore germination is divided into two genetically separable stages. Stage I is characterized by the release of dipicolinic acid (DPA) from the spore core. Stage II is characterized by cortex degradation, and stage II is activated by the DPA released during stage I. Thus, DPA release precedes cortex hydrolysis during B. subtilis spore germination. Here, we investigated the timing of DPA release and cortex hydrolysis during Clostridium difficile spore germination and found that cortex hydrolysis precedes DPA release. Inactivation of either the bile acid germinant receptor, cspC, or the cortex hydrolase, sleC, prevented both cortex hydrolysis and DPA release. Because both cortex hydrolysis and DPA release during C. difficile spore germination are dependent on the presence of the germinant receptor and the cortex hydrolase, the release of DPA from the core may rely on the osmotic swelling of the core upon cortex hydrolysis. These results have implications for the hypothesized glycine receptor and suggest that the initiation of germinant receptor-mediated C. difficile spore germination proceeds through a novel germination pathway. IMPORTANCE: Clostridium difficile infects antibiotic-treated hosts and spreads between hosts as a dormant spore. In a host, spores germinate to the vegetative form that produces the toxins necessary for disease. C. difficile spore germination is stimulated by certain bile acids and glycine. We recently identified the bile acid germinant receptor as the germination-specific, protease-like CspC. CspC is likely cortex localized, where it can transmit the bile acid signal to the cortex hydrolase, SleC. Due to the differences in location of CspC compared to the Bacillus subtilis germinant receptors, we hypothesized that there are fundamental differences in the germination processes between the model organism and C. difficile. We found that C. difficile spore germination proceeds through a novel pathway. PMID- 25917907 TI - S-Inosyl-L-Homocysteine Hydrolase, a Novel Enzyme Involved in S-Adenosyl-L Methionine Recycling. AB - S-Adenosyl-L-homocysteine, the product of S-adenosyl-L-methionine (SAM) methyltransferases, is known to be a strong feedback inhibitor of these enzymes. A hydrolase specific for S-adenosyl-L-homocysteine produces L-homocysteine, which is remethylated to methionine and can be used to regenerate SAM. Here, we show that the annotated S-adenosyl-L-homocysteine hydrolase in Methanocaldococcus jannaschii is specific for the hydrolysis and synthesis of S-inosyl-L homocysteine, not S-adenosyl-L-homocysteine. This is the first report of an enzyme specific for S-inosyl-L-homocysteine. As with S-adenosyl-L-homocysteine hydrolase, which shares greater than 45% sequence identity with the M. jannaschii homologue, the M. jannaschii enzyme was found to copurify with bound NAD(+) and has Km values of 0.64 +/- 0.4 mM, 0.0054 +/- 0.006 mM, and 0.22 +/- 0.11 mM for inosine, L-homocysteine, and S-inosyl-L-homocysteine, respectively. No enzymatic activity was detected with S-adenosyl-L-homocysteine as the substrate in either the synthesis or hydrolysis direction. These results prompted us to redesignate the M. jannaschii enzyme an S-inosyl-L-homocysteine hydrolase (SIHH). Identification of SIHH demonstrates a modified pathway in this methanogen for the regeneration of SAM from S-adenosyl-L-homocysteine that uses the deamination of S adenosyl-L-homocysteine to form S-inosyl-L-homocysteine. IMPORTANCE: In strictly anaerobic methanogenic archaea, such as Methanocaldococcus jannaschii, canonical metabolic pathways are often not present, and instead, unique pathways that are deeply rooted on the phylogenetic tree are utilized by the organisms. Here, we discuss the recycling pathway for S-adenosyl-L-homocysteine, produced from S adenosyl-L-methionine (SAM)-dependent methylation reactions, which uses a hydrolase specific for S-inosyl-L-homocysteine, an uncommon metabolite. Identification of the pathways and the enzymes involved in the unique pathways in the methanogens will provide insight into the biochemical reactions that were occurring when life originated. PMID- 25917908 TI - Elucidation of the Photorhabdus temperata Genome and Generation of a Transposon Mutant Library To Identify Motility Mutants Altered in Pathogenesis. AB - The entomopathogenic nematode Heterorhabditis bacteriophora forms a specific mutualistic association with its bacterial partner Photorhabdus temperata. The microbial symbiont is required for nematode growth and development, and symbiont recognition is strain specific. The aim of this study was to sequence the genome of P. temperata and identify genes that plays a role in the pathogenesis of the Photorhabdus-Heterorhabditis symbiosis. A draft genome sequence of P. temperata strain NC19 was generated. The 5.2-Mb genome was organized into 17 scaffolds and contained 4,808 coding sequences (CDS). A genetic approach was also pursued to identify mutants with altered motility. A bank of 10,000 P. temperata transposon mutants was generated and screened for altered motility patterns. Five classes of motility mutants were identified: (i) nonmotile mutants, (ii) mutants with defective or aberrant swimming motility, (iii) mutant swimmers that do not require NaCl or KCl, (iv) hyperswimmer mutants that swim at an accelerated rate, and (v) hyperswarmer mutants that are able to swarm on the surface of 1.25% agar. The transposon insertion sites for these mutants were identified and used to investigate other physiological properties, including insect pathogenesis. The motility-defective mutant P13-7 had an insertion in the RNase II gene and showed reduced virulence and production of extracellular factors. Genetic complementation of this mutant restored wild-type activity. These results demonstrate a role for RNA turnover in insect pathogenesis and other physiological functions. IMPORTANCE: The relationship between Photorhabdus and entomopathogenic nematode Heterorhabditis represents a well-known mutualistic system that has potential as a biological control agent. The elucidation of the genome of the bacterial partner and role that RNase II plays in its life cycle has provided a greater understanding of Photorhabdus as both an insect pathogen and a nematode symbiont. PMID- 25917909 TI - Activation of Toxin-Antitoxin System Toxins Suppresses Lethality Caused by the Loss of sigmaE in Escherichia coli. AB - sigma(E), an alternative sigma factor that governs a major signaling pathway in envelope stress responses in Gram-negative bacteria, is essential for growth of Escherichia coli not only under stressful conditions, such as elevated temperature, but also under normal laboratory conditions. A mutational inactivation of the hicB gene has been reported to suppress the lethality caused by the loss of sigma(E). hicB encodes the antitoxin of the HicA-HicB toxin antitoxin (TA) system; overexpression of the HicA toxin, which exhibits mRNA interferase activity, causes cleavage of mRNAs and an arrest of cell growth, while simultaneous expression of HicB neutralizes the toxic effects of overproduced HicA. To date, however, how the loss of HicB rescues the cell lethality in the absence of sigma(E) and, more specifically, whether HicA is involved in this process remain unknown. Here we showed that simultaneous disruption of hicA abolished suppression of the sigma(E) essentiality in the absence of hicB, while ectopic expression of wild-type HicA, but not that of its mutant forms without mRNA interferase activity, restored the suppression. Furthermore, HicA and two other mRNA interferase toxins, HigB and YafQ, suppressed the sigma(E) essentiality even in the presence of chromosomally encoded cognate antitoxins when these toxins were overexpressed individually. Interestingly, when the growth media were supplemented with low levels of antibiotics that are known to activate toxins, E. coli cells with no suppressor mutations grew independently of sigma(E). Taken together, our results indicate that the activation of TA system toxins can suppress the sigma(E) essentiality and affect the extracytoplasmic stress responses. IMPORTANCE: sigma(E) is an alternative sigma factor involved in extracytoplasmic stress responses. Unlike other alternative sigma factors, sigma(E) is indispensable for the survival of E. coli even under unstressed conditions, although the exact reason for its essentiality remains unknown. Toxin-antitoxin (TA) systems are widely distributed in prokaryotes and are composed of two adjacent genes, encoding a toxin that exerts harmful effects on the toxin-producing bacterium itself and an antitoxin that neutralizes the cognate toxin. Curiously, it is known that inactivation of an antitoxin rescues the sigma(E) essentiality, suggesting a connection between TA systems and sigma(E) function. We demonstrate here that toxin activation is necessary for this rescue and suggest the possible involvement of TA systems in extracytoplasmic stress responses. PMID- 25917911 TI - Iron Depletion Enhances Production of Antimicrobials by Pseudomonas aeruginosa. AB - Cystic fibrosis (CF) is a heritable disease characterized by chronic, polymicrobial lung infections. While Staphylococcus aureus is the dominant lung pathogen in young CF patients, Pseudomonas aeruginosa becomes predominant by adulthood. P. aeruginosa produces a variety of antimicrobials that likely contribute to this shift in microbial populations. In particular, secretion of 2 alkyl-4(1H)-quinolones (AQs) contributes to lysis of S. aureus in coculture, providing an iron source to P. aeruginosa both in vitro and in vivo. We previously showed that production of one such AQ, the Pseudomonas quinolone signal (PQS), is enhanced by iron depletion and that this induction is dependent upon the iron-responsive PrrF small RNAs (sRNAs). Here, we demonstrate that antimicrobial activity against S. aureus during coculture is also enhanced by iron depletion, and we provide evidence that multiple AQs contribute to this activity. Strikingly, a P. aeruginosa DeltaprrF mutant, which produces very little PQS in monoculture, was capable of mediating iron-regulated growth suppression of S. aureus. We show that the presence of S. aureus suppresses the DeltaprrF1,2 mutant's defect in iron-regulated PQS production, indicating that a PrrF-independent iron regulatory pathway mediates AQ production in coculture. We further demonstrate that iron-regulated antimicrobial production is conserved in multiple P. aeruginosa strains, including clinical isolates from CF patients. These results demonstrate that iron plays a central role in modulating interactions of P. aeruginosa with S. aureus. Moreover, our studies suggest that established iron regulatory pathways of these pathogens are significantly altered during polymicrobial infections. IMPORTANCE: Chronic polymicrobial infections involving Pseudomonas aeruginosa and Staphylococcus aureus are a significant cause of morbidity and mortality, as the interplay between these two organisms exacerbates infection. This is in part due to enhanced production of antimicrobial metabolites by P. aeruginosa when these two species are cocultured. Using both established and newly developed coculture techniques, this report demonstrates that iron depletion increases P. aeruginosa's ability to suppress growth of S. aureus. These findings present a novel role for iron in modulating microbial interaction and provide the basis for understanding how essential nutrients drive polymicrobial infections. PMID- 25917910 TI - Coculture of Staphylococcus aureus with Pseudomonas aeruginosa Drives S. aureus towards Fermentative Metabolism and Reduced Viability in a Cystic Fibrosis Model. AB - The airways of patients with cystic fibrosis are colonized with diverse bacterial communities that change dynamically during pediatric years and early adulthood. Staphylococcus aureus is the most prevalent pathogen during early childhood, but during late teens and early adulthood, a shift in microbial composition occurs leading to Pseudomonas aeruginosa community predominance in ~50% of adults. We developed a robust dual-bacterial in vitro coculture system of P. aeruginosa and S. aureus on monolayers of human bronchial epithelial cells homozygous for the DeltaF508 cystic fibrosis transmembrane conductance regulator (CFTR) mutation to better model the mechanisms of this interaction. We show that P. aeruginosa drives the S. aureus expression profile from that of aerobic respiration to fermentation. This shift is dependent on the production of both 2-heptyl-4 hydroxyquinoline N-oxide (HQNO) and siderophores by P. aeruginosa. Furthermore, S. aureus-produced lactate is a carbon source that P. aeruginosa preferentially consumes over medium-supplied glucose. We find that initially S. aureus and P. aeruginosa coexist; however, over extended coculture P. aeruginosa reduces S. aureus viability, also in an HQNO- and P. aeruginosa siderophore-dependent manner. Interestingly, S. aureus small-colony-variant (SCV) genetic mutant strains, which have defects in their electron transport chain, experience reduced killing by P. aeruginosa compared to their wild-type parent strains; thus, SCVs may provide a mechanism for persistence of S. aureus in the presence of P. aeruginosa. We propose that the mechanism of P. aeruginosa-mediated killing of S. aureus is multifactorial, requiring HQNO and P. aeruginosa siderophores as well as additional genetic, environmental, and nutritional factors. IMPORTANCE: In individuals with cystic fibrosis, Staphylococcus aureus is the primary respiratory pathogen during childhood. During adulthood, Pseudomonas aeruginosa predominates and correlates with worse patient outcome. The mechanism(s) by which P. aeruginosa outcompetes or kills S. aureus is not well understood. We describe an in vitro dual-bacterial species coculture system on cystic fibrosis-derived airway cells, which models interactions relevant to patients with cystic fibrosis. Further, we show that molecules produced by P. aeruginosa additively induce a transition of S. aureus metabolism from aerobic respiration to fermentation and eventually lead to loss of S. aureus viability. Elucidating the molecular mechanisms of P. aeruginosa community predominance can provide new therapeutic targets and approaches to impede this microbial community transition and subsequent patient worsening. PMID- 25917912 TI - Iron-Mediated Control of Pseudomonas aeruginosa-Staphylococcus aureus Interactions in the Cystic Fibrosis Lung. AB - Communication is an important factor for bacterial survival, growth, and persistence. Much work has examined both inter- and intraspecies interactions and their effects on virulence. Now, researchers have begun to explore the ways in which host-modulated factors can impact bacterial interactions and subsequently affect patient outcomes. In this issue, two papers discuss how the host environment alters interactions between the pathogens Pseudomonas aeruginosa and Staphylococcus aureus, largely in the context of cystic fibrosis. PMID- 25917913 TI - Novel Role for PilNO in Type IV Pilus Retraction Revealed by Alignment Subcomplex Mutations. AB - Type IV pili (T4P) are dynamic protein filaments that mediate bacterial adhesion, biofilm formation, and twitching motility. The highly conserved PilMNOP proteins form an inner membrane alignment subcomplex required for function of the T4P system, though their exact roles are unclear. Three potential interaction interfaces for PilNO were identified: core-core, coiled coils (CC), and the transmembrane segments (TMSs). A high-confidence PilNO heterodimer model was used to select key residues for mutation, and the resulting effects on protein-protein interactions were examined both in a bacterial two-hybrid (BTH) system and in their native Pseudomonas aeruginosa context. Mutations in the oppositely charged CC regions or the TMS disrupted PilNO heterodimer formation in the BTH assay, while up to six combined mutations in the core failed to disrupt the interaction. When the mutations were introduced into the P. aeruginosa chromosome at the pilN or pilO locus, specific changes at each of the three interfaces--including core mutations that failed to disrupt interactions in the BTH system--abrogated surface piliation and/or impaired twitching motility. Unexpectedly, specific CC mutants were hyperpiliated but nonmotile, a hallmark of pilus retraction defects. These data suggest that PilNO participate in both the extension and retraction of T4P. Our findings support a model of multiple, precise interaction interfaces between PilNO; emphasize the importance of studying protein function in a minimally perturbed context and stoichiometry; and highlight potential target sites for development of small-molecule inhibitors of the T4P system. IMPORTANCE: Pseudomonas aeruginosa is an opportunistic pathogen that uses type IV pili (T4P) for host attachment. The T4P machinery is composed of four cell envelope-spanning subcomplexes. PilN and PilO heterodimers are part of the alignment subcomplex and essential for T4P function. Three potential PilNO interaction interfaces (the core-core, coiled-coil, and transmembrane segment interfaces) were probed using site-directed mutagenesis followed by functional assays in an Escherichia coli two-hybrid system and in P. aeruginosa. Several mutations blocked T4P assembly and/or motility, including two that revealed a novel role for PilNO in pilus retraction, while other mutations affected extension dynamics. These critical PilNO interaction interfaces represent novel targets for small-molecule inhibitors with the potential to disrupt T4P function. PMID- 25917914 TI - Role and Function of LitR, an Adenosyl B12-Bound Light-Sensitive Regulator of Bacillus megaterium QM B1551, in Regulation of Carotenoid Production. AB - The LitR/CarH family of proteins is a light-sensitive MerR family of transcriptional regulators that contain an adenosyl B12 (coenzyme B12 or AdoB12) binding domain at the C terminus. The genes encoding these proteins are found in phylogenetically diverse bacterial genera; however, the biochemical properties of these proteins from Gram-positive bacteria remain poorly understood. We performed genetic and biochemical analyses of a homolog of the LitR protein from Bacillus megaterium QM B1551, a Gram-positive endospore-forming soil bacterium. Carotenoid production was induced by illumination in this bacterium. In vivo analysis demonstrated that LitR plays a central role in light-inducible carotenoid production and serves as a negative regulator of the light-inducible transcription of crt and litR itself. Biochemical evidence showed that LitR in complex with AdoB12 binds to the promoter regions of litR and the crt operon in a light-sensitive manner. In vitro transcription experiments demonstrated that AdoB12-LitR inhibited the specific transcription of the crt promoter generated by a sigma(A)-containing RNA polymerase holoenzyme under dark conditions. Collectively, these data indicate that the AdoB12-LitR complex serves as a photoreceptor with DNA-binding activity in B. megaterium QM B1551 and that its function as a transcriptional repressor is fundamental to the light-induced carotenoid production. IMPORTANCE: Members of the LitR/CarH family are AdoB12 based photosensors involved in light-inducible carotenoid production in nonphototrophic Gram-negative bacteria. Our study revealed that Bacillus LitR in complex with AdoB12 also serves as a transcriptional regulator with a photosensory function, which indicates that the LitR/CarH family is generally involved in the light-inducible carotenoid production of nonphototrophic bacteria. PMID- 25917915 TI - Role of Spermidine in Overwintering of Cyanobacteria. AB - Polyamines are found in all groups of cyanobacteria, but their role in environmental adaptation has been barely investigated. In Synechocystis sp. strain PCC 6803, inactivation of spermidine synthesis genes significantly reduced the survivability under chill (5 degrees C)-light stress, and the survivability could be restored by addition of spermidine. To analyze the effects of spermidine on gene expression at 5 degrees C, lacZ was expressed from the promoter of carboxy(nor)spermidine decarboxylase gene (CASDC) in Synechocystis. Synechocystis 6803::PCASDC-lacZ pretreated at 15 degrees C showed a high level of LacZ activity for a long period of time at 5 degrees C; without the pretreatment or with protein synthesis inhibited at 5 degrees C, the enzyme activity gradually decreased. In a spermidine-minus mutant harboring PCASDC-lacZ, lacZ showed an expression pattern as if protein synthesis were inhibited at 5 degrees C, even though the stability of its mRNA increased. Four other genes, including rpoA that encodes the alpha subunit of RNA polymerase, showed similar expression patterns. The chill-light stress led to a rapid increase of protein carbonylation in Synechocystis. The protein carbonylation then quickly returned to the background level in the wild type but continued to slowly increase in the spermidine-minus mutant. Our results indicate that spermidine promotes gene expression and replacement of damaged proteins in cyanobacteria under the chill-light stress in winter. IMPORTANCE: Outbreak of cyanobacterial blooms in freshwater lakes is a worldwide environmental problem. In the annual cycle of bloom-forming cyanobacteria, overwintering is the least understood stage. Survival of Synechocystis sp. strain PCC 6803 under long-term chill (5 degrees C)-light stress has been established as a model for molecular studies on overwintering of cyanobacteria. Here, we show that spermidine, the most common polyamine in cyanobacteria, promotes the survivability of Synechocystis under long-term chill light stress and that the physiological function is based on its effects on gene expression and recovery from protein damage. This is the first report on the role of polyamines in survival of overwintering cyanobacteria. We also analyzed spermidine synthesis pathways in cyanobacteria on the basis of bioinformatic and experimental data. PMID- 25917916 TI - Escherichia coli YqjA, a Member of the Conserved DedA/Tvp38 Membrane Protein Family, Is a Putative Osmosensing Transporter Required for Growth at Alkaline pH. AB - The ability to persist and grow under alkaline conditions is an important characteristic of many bacteria. In order to survive at alkaline pH, Escherichia coli must maintain a stable cytoplasmic pH of about 7.6. Membrane cation/proton antiporters play a major role in alkaline pH homeostasis by catalyzing active inward proton transport. The DedA/Tvp38 family is a highly conserved membrane protein family of unknown function present in most sequenced genomes. YqjA and YghB are members of the E. coli DedA family with 62% amino acid identity and partially redundant functions. We have shown that E. coli with DeltayqjA and DeltayghB mutations cannot properly maintain the proton motive force (PMF) and is compromised in PMF-dependent drug efflux and other PMF-dependent functions. Furthermore, the functions of YqjA and YghB are dependent upon membrane-embedded acidic amino acids, a hallmark of several families of proton-dependent transporters. Here, we show that the DeltayqjA mutant (but not DeltayghB) cannot grow under alkaline conditions (ranging from pH 8.5 to 9.5), unlike the parent E. coli. Overexpression of yqjA restores growth at alkaline pH, but only when more than ~100 mM sodium or potassium is present in the growth medium. Increasing the osmotic pressure by the addition of sucrose enhances the ability of YqjA to support growth under alkaline conditions in the presence of low salt concentrations, consistent with YqjA functioning as an osmosensor. We suggest that YqjA possesses proton-dependent transport activity that is stimulated by osmolarity and that it plays a significant role in the survival of E. coli at alkaline pH. IMPORTANCE: The ability to survive under alkaline conditions is important for many species of bacteria. Escherichia coli can grow at pH 5.5 to 9.5 while maintaining a constant cytoplasmic pH of about 7.6. Under alkaline conditions, bacteria rely upon proton-dependent transporters to maintain a constant cytoplasmic pH. The DedA/Tvp38 protein family is a highly conserved but poorly characterized family of membrane proteins. Here, we show that the DedA/Tvp38 protein YqjA is critical for E. coli to survive at pH 8.5 to 9.5. YqjA requires sodium and potassium for this function. At low cation concentrations, osmolytes, including sucrose, can facilitate rescue of E. coli growth by YqjA at high pH. These data are consistent with YqjA functioning as an osmosensing cation dependent proton transporter. PMID- 25917917 TI - Diffusion-MRI in neurodegenerative disorders. AB - The ability to image the whole brain through ever more subtle and specific methods/contrasts has come to play a key role in understanding the basis of brain abnormalities in several diseases. In magnetic resonance imaging (MRI), "diffusion" (i.e. the random, thermally-induced displacements of water molecules over time) represents an extraordinarily sensitive contrast mechanism, and the exquisite structural detail it affords has proven useful in a vast number of clinical as well as research applications. Since diffusion-MRI is a truly quantitative imaging technique, the indices it provides can serve as potential imaging biomarkers which could allow early detection of pathological alterations as well as tracking and possibly predicting subtle changes in follow-up examinations and clinical trials. Accordingly, diffusion-MRI has proven useful in obtaining information to better understand the microstructural changes and neurophysiological mechanisms underlying various neurodegenerative disorders. In this review article, we summarize and explore the main applications, findings, perspectives as well as challenges and future research of diffusion-MRI in various neurodegenerative disorders including Alzheimer's disease, Parkinson's disease, amyotrophic lateral sclerosis, Huntington's disease and degenerative ataxias. PMID- 25917918 TI - RNA-seq-Based Gene Annotation and Comparative Genomics of Four Fungal Grass Pathogens in the Genus Zymoseptoria Identify Novel Orphan Genes and Species Specific Invasions of Transposable Elements. AB - The fungal pathogen Zymoseptoria tritici (synonym Mycosphaerella graminicola) is a prominent pathogen of wheat. The reference genome of the isolate IPO323 is one of the best-assembled eukaryotic genomes and encodes more than 10,000 predicted genes. However, a large proportion of the previously annotated gene models are incomplete, with either no start or no stop codons. The availability of RNA-seq data allows better predictions of gene structure. We here used two different RNA seq datasets, de novo transcriptome assemblies, homology-based comparisons, and trained ab initio gene callers to generate a new gene annotation of Z. tritici IPO323. The annotation pipeline was also applied to re-sequenced genomes of three closely related species of Z. tritici: Z. pseudotritici, Z. ardabiliae, and Z. brevis. Comparative analyses of the predicted gene models using the four Zymoseptoria species revealed sets of species-specific orphan genes enriched with putative pathogenicity-related genes encoding small secreted proteins that may play essential roles in virulence and host specificity. De novo repeat identification allowed us to show that few families of transposable elements are shared between Zymoseptoria species while we observe many species-specific invasions and expansions. The annotation data presented here provide a high quality resource for future studies of Z. tritici and its sister species and provide detailed insight into gene and genome evolution of fungal plant pathogens. PMID- 25917919 TI - Identification of Reproduction-Related Gene Polymorphisms Using Whole Transcriptome Sequencing in the Large White Pig Population. AB - Recent developments in high-throughput sequencing techniques have enabled large scale analysis of genetic variations and gene expression in different tissues and species, but gene expression patterns and genetic variations in livestock are not well-characterized. In this study, we have used high-throughput transcriptomic sequencing of the Finnish Large White to identify gene expression patterns and coding polymorphisms within the breed in the testis and oviduct. The main objective of this study was to identify polymorphisms within genes that are highly and specifically expressed in male and/or female reproductive organs. The differential expression (DE) analysis underlined 1234 genes highly expressed in the testis and 1501 in the oviduct. Furthermore, we used a novel in-house R package hoardeR for the identification of novel genes and their orthologs, which underlined 55 additional DE genes based on orthologs in the human, cow, and sheep. Identification of polymorphisms in the dataset resulted in a total of 29,973 variants, of which 10,704 were known coding variants. Fifty-seven nonsynonymous SNPs were present among genes with high expression in the testis and 67 were present in the oviduct, underlining possible influential genes for reproduction traits. Seven genes (PGR, FRAS1, TCF4, ADAT1, SPAG6, PIWIL2, and DNAH8) with polymorphisms were highlighted as reproduction-related based on their biological function. The expression and SNPs of these genes were confirmed using RT-PCR and Sanger sequencing. The identified nonsynonymous mutations within genes highly expressed in the testis or oviduct provide a list of candidate genes for reproduction traits within the pig population and enable identification of biomarkers for sow and boar fertility. PMID- 25917921 TI - The mechanistic basis of prostacyclin and its stable analogues in pulmonary arterial hypertension: Role of membrane versus nuclear receptors. AB - Pulmonary arterial hypertension (PAH) is a progressive disease of distal pulmonary arteries in which patients suffer from elevated pulmonary arterial pressure, extensive vascular remodelling and right ventricular failure. To date prostacyclin (PGI2) therapy remains the most efficacious treatment for PAH and is the only approved monotherapy to have a positive impact on long-term survival. A key thing to note is that improvement exceeds that predicted from vasodilator testing strongly suggesting that additional mechanisms contribute to the therapeutic benefit of prostacyclins in PAH. Given these agents have potent antiproliferative, anti-inflammatory and endothelial regenerating properties suggests therapeutic benefit might result from a slowing, stabilization or even some reversal of vascular remodelling in vivo. This review discusses evidence that the pharmacology of each prostacyclin (IP) receptor agonist so far developed is distinct, with non-IP receptor targets clearly contributing to the therapeutic and side effect profile of PGI2 (EP3), iloprost (EP1), treprostinil (EP2, DP1) along with a family of nuclear receptors known as peroxisome proliferator activated receptors (PPARs), to which PGI2 and some analogues directly bind. These targets are functionally expressed to varying degrees in arteries, veins, platelets, fibroblasts and inflammatory cells and are likely to be involved in the biological actions of prostacylins. Recently, a highly selective IP agonist, selexipag has been developed for PAH. This agent should prove useful in distinguishing IP from other prostanoid receptors or PPAR binding effects in human tissue. It remains to be determined whether selectivity for the IP receptor gives rise to a superior or inferior clinical benefit in PAH. PMID- 25917920 TI - DPY-17 and MUA-3 Interact for Connective Tissue-Like Tissue Integrity in Caenorhabditis elegans: A Model for Marfan Syndrome. AB - mua-3 is a Caenorhabditis elegans homolog of the mammalian fibrillin1, a monogenic cause of Marfan syndrome. We identified a new mutation of mua-3 that carries an in-frame deletion of 131 amino acids in the extracellular domain, which allows the mutants to survive in a temperature-dependent manner; at the permissive temperature, the mutants grow normally without obvious phenotypes, but at the nonpermissive temperature, more than 90% die during the L4 molt due to internal organ detachment. Using the temperature-sensitive lethality, we performed unbiased genetic screens to isolate suppressors to find genetic interactors of MUA-3. From two independent screens, we isolated mutations in dpy 17 as a suppressor. RNAi of dpy-17 in mua-3 rescued the lethality, confirming dpy 17 is a suppressor. dpy-17 encodes a collagen known to genetically interact with dpy-31, a BMP-1/Tolloid-like metalloprotease required for TGFbeta activation in mammals. Human fibrillin1 mutants fail to sequester TGFbeta2 leading to excess TGFbeta signaling, which in turn contributes to Marfan syndrome or Marfan-related syndrome. Consistent with that, RNAi of dbl-1, a TGFbeta homolog, modestly rescued the lethality of mua-3 mutants, suggesting a potentially conserved interaction between MUA-3 and a TGFbeta pathway in C. elegans. Our work provides genetic evidence of the interaction between TGFbeta and a fibrillin homolog, and thus provides a simple yet powerful genetic model to study TGFbeta function in development of Marfan pathology. PMID- 25917922 TI - CT and MRI findings of the incidental intraosseous lipomatous lesions of the sphenoid bone. AB - BACKGROUND: Intraosseous lipomatous lesions of the sphenoid bone and skull base are increasingly seen and cause a diagnostic challenge. The purpose of this study was to present the imaging findings of 4 patients with incidentally identified intraosseous lipomatous lesions within the sphenoid bone. METHODS: CT scans and MR images of 4 patients are shown. Macroscopic fat content of the lesions were evaluated by fat-saturated sequences on MRI and by measuring fat density in Hounsfield Units on CT. RESULTS: The most striking imaging findings of these well defined lesions were their fat content, preservation of foramina, and absence of cortical destruction. CONCLUSION: Intraosseous lipomatous lesions are asymptomatic, fat containing, non-touch lesions that should be recognized to prevent unnecessary further investigation, such as biopsy. PMID- 25917923 TI - Long non-coding RNAs, a new important regulator of cardiovascular physiology and pathology. AB - LncRNAs were previously considered to be the 'noise' of gene transcription having no biological functions, but now it has become evident that lncRNAs function as modulators of gene expression network. LncRNAs may regulate diverse gene expression levels which were roughly summarized to epigenetic, transcriptional and post-transcriptional levels. It has been clarified that some lncRNAs were expressed differentially in cardiovascular diseases, and aberrant changes of those lncRNAs were involved in the development of heart disorders. The role of lncRNAs in this process transcended the tradition of protein regulatory platform to be the orchestrator of cardiac sophisticated governing system of heart development, adaptation and pathological reaction. This review summarizes recent advances in the study of functions and mechanisms of lncRNAs in cardiovascular physiology and pathology. The regulatory roles of lncRNAs in cardiovascular diseases provide new strategy for interventional therapy of heart diseases. PMID- 25917924 TI - Wavelength-selective cleavage of photoprotecting groups: strategies and applications in dynamic systems. AB - Photocleavable protecting groups (PPGs) are extensively used in chemical and biological sciences. In their application, advantage is taken of using light as an external, non-invasive stimulus, which can be delivered with very high spatiotemporal precision. More recently, orthogonally addressing multiple PPGs, in a single system and with different wavelengths of light, has been explored. This approach allows one to independently control multiple functionalities in an external, non-invasive fashion. In this tutorial review, we discuss the design principles for dynamic systems involving wavelength-selective deprotection, focusing on the choice and optimization of PPGs, synthetic methods for their introduction and strategies for combining multiple PPGs into one system. Finally, we illustrate the design principles with representative examples, aiming at providing the reader with an instructive overview on how the wavelength-selective cleavage of photoprotecting groups can be applied in materials science, organic synthesis and biological systems. PMID- 25917926 TI - Gone with the flow: current velocities mediate parasitic infestation of an aquatic host. AB - Host-parasite interactions are moderated by the environmental conditions of the interaction medium (e.g. air or water). Encounter rate and the time available for a parasite to make physical contact with a host are both influenced by fluid dynamics, yet how they interact is poorly known. Here, we tested whether current velocities altered the initial attachment and post-settlement survival of an ecto parasitic copepod (Lepeophtheirus salmonis) on Atlantic salmon. Current velocities strongly influenced attachment; infestation levels were 2.5 and 1.3 times higher in moderate than high and low velocity currents, respectively, while current velocities did not affect post-settlement survival. An interplay between a reduced host-parasite encounter rate in a low velocity current and reduced contact time in a high velocity current likely explains this result. Initial parasite attachment position was influenced by an interaction between current velocity and swimming behaviour, likely due to different fin positioning by fish in flows of different velocities. Our results imply that rapid swimming by salmon migrating out of coastal waters, usually described as adaptive against predation, could also be adaptive against parasitism. Infestation rates were also highest at the typical swimming speed of farmed salmon in coastal fish farms, which may be a hitherto unrecognised factor contributing to L. salmonis epidemics. PMID- 25917925 TI - Folate status and concentrations of serum folate forms in the US population: National Health and Nutrition Examination Survey 2011-2. AB - Serum and erythrocyte (RBC) total folate are indicators of folate status. No nationally representative population data exist for folate forms. We measured the serum folate forms (5-methyltetrahydrofolate (5-methylTHF), unmetabolised folic acid (UMFA), non-methyl folate (sum of tetrahydrofolate (THF), 5 formyltetrahydrofolate (5-formylTHF), 5,10-methenyltetrahydrofolate (5,10 methenylTHF)) and MeFox (5-methylTHF oxidation product)) by HPLC-MS/MS and RBC total folate by microbiologic assay in US population >= 1 year (n approximately 7500) participating in the National Health and Nutrition Examination Survey 2011 2. Data analysis for serum total folate was conducted including and excluding MeFox. Concentrations (geometric mean; detection rate) of 5-methylTHF (37.5 nmol/l; 100 %), UMFA (1.21 nmol/l; 99.9 %), MeFox (1.53 nmol/l; 98.8 %), and THF (1.01 nmol/l; 85.2 %) were mostly detectable. 5-FormylTHF (3.6 %) and 5,10 methenylTHF (4.4 %) were rarely detected. The biggest contributor to serum total folate was 5-methylTHF (86.7 %); UMFA (4.0 %), non-methyl folate (4.7 %) and MeFox (4.5 %) contributed smaller amounts. Age was positively related to MeFox, but showed a U-shaped pattern for other folates. We generally noted sex and race/ethnic biomarker differences and weak (Spearman's r< 0.4) but significant (P< 0.05) correlations with physiological and lifestyle variables. Fasting, kidney function, smoking and alcohol intake showed negative associations. BMI and body surface area showed positive associations with MeFox but negative associations with other folates. All biomarkers showed significantly higher concentrations with recent folic acid-containing dietary supplement use. These first-time population data for serum folate forms generally show similar associations with demographic, physiological and lifestyle variables as serum total folate. Patterns observed for MeFox may suggest altered folate metabolism dependent on biological characteristics. PMID- 25917927 TI - Extra articular management of knee osteoarthritis pain. PMID- 25917929 TI - Attitude toward preventive counseling and healthy practices among medical students at a Colombian university. AB - Unhealthy behaviors of medical students influence their attitudes toward preventive counseling. The burden of chronic diseases is continually growing in developing countries, emphasizing the need for the increased role of general practitioners in preventive counseling. The objective of this study was to describe the effect of medical training on the risk profiles and attitudes of medical students toward preventive counseling in a Colombian university. Students in their first and fifth years of training were surveyed using the "Healthy Doctor = Healthy Patient" questionnaire to assess counseling attitudes; personal practices, such as risky drinking, smoking, inadequate nutrition, and non compliance with physical activity recommendations; and the university environment. The association among these components was estimated, as well as the effect of the university environment. Risky drinking and smoking decreased from first to fifth year (59.3% vs. 37.1%, P = 0.021 and 31.5% vs. 25.9%, P = 0.51, respectively), whereas inadequate nutrition and non-compliance with physical activity recommendations increased. Physical activity (PA) was associated with positive counseling attitude (ORs: nutrition 7.6; alcohol 5.2; PA 10.6). Areas governed by institutional policies that are emphasized in the curriculum positively affected student practices. PA promoted preventive counseling and healthy lifestyles most effectively. Universities should therefore strengthen their preventive medicine curricula and modify social determinants. PMID- 25917928 TI - Tuning of ZIF-Derived Carbon with High Activity, Nitrogen Functionality, and Yield - A Case for Superior CO2 Capture. AB - A highly effective and facile synthesis route is developed to create and tailor metal-decorated and nitrogen-functionalized active microporous carbon materials from ZIF-8. Clear metal- and pyrrolic-N-induced enhancements of the cyclic CO2 uptake capacities and binding energies are achieved, particularly at a much lower carbonization temperature of 700 degrees C than those often reported (1000 degrees C). The high-temperature carbonization can enhance the porosity but only at the expense of considerable losses of sample yield and metal and N functional sites. The findings are comparatively discussed with carbons derived from metal organic frameworks (MOFs) reported previously. Furthermore, the porosity of the MOF-derived carbon is critically dependent on the structure of the precursor MOF and the crystal growth. The current strategy offers a new and effective route for the creation and tuning of highly active and functionalized carbon structures in high yields and with low energy consumption. PMID- 25917930 TI - Solid polymer substrates and coated fibers containing 2,4,6-trinitrobenzene motifs as smart labels for the visual detection of biogenic amine vapors. AB - Attempts to polymerize trinitrobenzene derivatives (TNB) have been fruitless so far. Accordingly, polymers containing TNB have not been exploited in spite of their envisaged potential applications. Here, we describe two ways for preparing polymers with TNB moieties thus overcoming the previously reported polymerization impairments. We also report on the exploitation of the materials, both obtained as tractable transparent films and coated fibers, as smart labels for the visual detection of amine vapors. More precisely, amines in the atmosphere surrounding the sensory materials diffuse into them reacting with the TNB motifs forming highly colored Meisenheimer complexes, giving rise to development of color and to the naked eye sensing phenomenon. This is the case of highly volatile amines, such as trimethylamine, produced in food spoilage, specifically in the deterioration of fish or meat, for which the color development of the smart labels can be used as a visual test for food freshness. PMID- 25917931 TI - Protective effect of casein phosphopeptide-amorphous calcium phosphate on enamel erosion: Atomic force microscopy studies. AB - The aim of this study was to investigate the in vitro effect of a casein phosphopeptide-amorphous calcium phosphate (CPP-ACP) paste (GC Tooth Mousse- TM, GC Corporation, Tokyo, Japan) on preventing enamel erosion, by using Atomic Force Microscopy (AFM). 30 human incisors, were equally assigned to 6 groups: intact enamel, enamel + soft drink, enamel + TM, enamel + TM + soft drink, enamel + soft drink + TM, enamel + soft drink + TM + soft drink. Specimens were observed through atomic force microscopy (AFM). The most common topographical parameters were determined, such as the surface roughness (Rrms ). The use of soft drink on intact enamel has roughened the surface of the sample. The application of the CPP ACP paste on non-treated enamel made the surface smoother. A significant decrease in roughness was seen after remineralization with CPP-ACP paste. Significant differences were recorded when comparing softened enamel with softened enamel remineralized with CPP-ACP paste. Comparing eroded enamel with demineralized/remineralized specimens, the application of a CPP-ACP paste leads to a significant reduction in roughness values. AFM images of enamel surface treated with CPP-ACP resulted in less morphological changes of the tooth substrate when compared with the only eroded enamel surface morphology; thus, indicating that CPP-ACP paste promoted remineralization. Specimens' surface roughness remained similar regardless that the protective agent is used before or after exposure to coke or between two demineralizing cycles. The results confirmed the effectiveness of the CPP-ACP paste on preventing enamel erosion produced by soft drinks. PMID- 25917932 TI - Adeno-associated virus mediated delivery of an engineered protein that combines the complement inhibitory properties of CD46, CD55 and CD59. AB - BACKGROUND: A variety of disorders are associated with the activation of complement. CD46, CD55 and CD59 are the major membrane associated regulators of complement on human cells. Previously, we have found that independent expression of CD55, CD46 or CD59 through gene transfer protects murine tissues against human complement mediated attack. In the present study, we investigated the potential of combining the complement regulatory properties of CD46, CD55 and CD59 into single gene products expressed from an adeno-associated virus (AAV) vector in a soluble non-membrane anchored form. METHODS: Minigenes encoding the complement regulatory domains from CD46, CD55 and CD59 (SACT) or CD55 and CD59 (DTAC) were cloned into an AAV vector. The specific regulatory activity of each component of SACT and DTAC was measured in vitro. The recombinant AAV vectors were injected into the peritoneum of mice and the efficacy of the transgene products for being able to protect murine liver vasculature against human complement, specifically the membrane attack complex (MAC), was measured. RESULTS: SACT and DTAC exhibited properties similar to CD46, CD55 and CD59 or CD55 and CD59, respectively, in vitro. AAV mediated delivery of SACT or DTAC protected murine liver vasculature from human MAC deposition by 63.2% and 56.7%, respectively. CONCLUSIONS: When delivered to mice in vivo via an AAV vector, SACT and DTAC are capable of limiting human complement mediated damage. SACT and DTAC merit further study as potential therapies for complement mediated disorders when delivered via a gene therapy approach. PMID- 25917933 TI - A genome-wide association study of suicide severity scores in bipolar disorder. AB - BACKGROUND: Suicide claims one million lives worldwide annually, making it a serious public health concern. The risk for suicidal behaviour can be partly explained by genetic factors, as suggested by twin and family studies (reviewed in (Zai et al. 2012)). Recently, genome-wide association studies (GWASs) of suicide attempt on large samples of bipolar disorder (BD) patients from multiple sites have identified a number of novel candidate genes. GWASs of suicide behaviour severity, from suicidal ideation to serious suicide attempt, have not been reported for BD. METHODS: We conducted a GWAS of suicide behaviour severity in three independent BD samples:212 small nuclear families with BD probands from Toronto, Canada, 428 BD cases from Toronto, and 483 BD cases from the UK. We carried out imputation with 1000 Genome Project data as reference using IMPUTE2. Quality control and data analysis was conducted using PLINK and R. We conducted the quantitative analyses of suicide behaviour severity in the three samples separately, and derived an overall significance by a meta-analysis using the METAL software. RESULTS: We did not find genome-wide significant association of any tested markers in any of the BD samples, but we found a number of suggestive associations, including regions on chromosomes 8 and 10 (p < 1e-5). CONCLUSIONS: Our GWAS findings suggest that likely many gene variants of small effects contribute collectively to the risk for suicidal behaviour severity in BD. Larger independent replications are required to strengthen the findings from the GWAS presented here. PMID- 25917934 TI - Beyond PET/CT in Hodgkin lymphoma: a comprehensive review of the role of imaging at initial presentation, during follow-up and for assessment of treatment-related complications. AB - OBJECTIVE: The purpose of this article is to provide a comprehensive review of the role of imaging modalities other than PET/CT in the management of Hodgkin lymphoma (HL). PET/CT is the imaging modality of choice in the management of Hodgkin's lymphoma (HL). However, imaging modalities other than PET/CT such as plain radiographs, ultrasound, CT, MRI and nuclear imaging can help in various stages of clinical management of HL, including the initial workup and post treatment surveillance. Both CT and MRI help in detecting recurrences, treatment related pulmonary, cardiovascular and abdominal complications as well as second malignancies. Familiarity with expected post-treatment changes and complications on surveillance images can help radiologists guide patient management. The purpose of this article is to provide a comprehensive review of the role of imaging modalities other than PET/CT in the management of Hodgkin lymphoma (HL). MAIN MESSAGES: * Surveillance of HL patients is usually performed with plain radiographs and CT. * Follow-up imaging can depict normal post-treatment changes or treatment-related complications. * Imaging is important for the timely detection of second malignancies in HL patients. PMID- 25917935 TI - Near patient CD4 count in a hospitalized HIV patient population. AB - BACKGROUND: Point-of-care (POC) CD4 T-cell counting is increasingly recognized as providing improved linkage-to-care during management of HIV infection, particularly in resource-limited settings where disease burden is highest. This study evaluated prototype POC CD4 T-cell counters from MBio Diagnostics in the context of low CD4 count, hospitalized patients in Mozambique. This study measured system performance when presented with challenging, low count samples from HIV/AIDS patients with acute illnesses resulting in hospitalization. METHODS: Forty whole blood samples were collected from donors on the medical service at Maputo Central Hospital and absolute CD4 counts were generated on the MBio CD4 system and a reference laboratory using flow cytometry. RESULTS: The mean and median CD4 counts by the flow cytometry reference were 173 and 80 cells/uL, respectively. Correlation between the MBio CD4 System and the reference was good. Bland-Altman analysis showed a mean bias of +15 cells/uL (+9 to +21 cells/uL, 95% CI), and limits of agreement of -47 to 77 cells/uL. For samples with counts >100 cells/uL (N = 14), the mean coefficient of variation was 7.3%. For samples with counts <50 cells/uL, mean absolute bias of replicate samples was 4.8 cells/uL. When two MBio readers were compared, Bland-Altman bias was -4 cells/uL (-13 to +6 cells/uL, 95% CI), and limits of agreement of -63 and +55 cells/uL. CONCLUSIONS: The MBio System holds promise as a POC system for quantitation of CD4 T cells in resource-limited settings given system throughput (80-100 cartridges/day), design simplicity, and ease-of-use. (c) 2015 International Clinical Cytometry Society. PMID- 25917937 TI - Biocontainment through reengineered genetic codes. AB - It's only unnatural: Reengineered genetic codes can achieve biocontainment by specifying different meanings for protein sequences in modified versus natural organisms; the synthetic bacterium discussed here is dependent on unnatural amino acids because its reengineered genetic code specifies unnatural amino acids in essential genes. PMID- 25917936 TI - (13)C MRS of human brain at 7 Tesla using [2-(13)C]glucose infusion and low power broadband stochastic proton decoupling. AB - PURPOSE: Carbon-13 ((13)C) MR spectroscopy (MRS) of the human brain at 7 Tesla (T) may pose patient safety issues due to high radiofrequency (RF) power deposition for proton decoupling. The purpose of present work is to study the feasibility of in vivo (13)C MRS of human brain at 7 T using broadband low RF power proton decoupling. METHODS: Carboxylic/amide (13)C MRS of human brain by broadband stochastic proton decoupling was demonstrated on a 7 T scanner. RF safety was evaluated using the finite-difference time-domain method. (13)C signal enhancement by nuclear Overhauser effect (NOE) and proton decoupling was evaluated in both phantoms and in vivo. RESULTS: At 7 T, the peak amplitude of carboxylic/amide (13)C signals was increased by a factor of greater than 4 due to the combined effects of NOE and proton decoupling. The 7 T (13)C MRS technique used decoupling power and average transmit power of less than 35 watts (W) and 3.6 W, respectively. CONCLUSION: In vivo (13)C MRS studies of human brain can be performed at 7 T, well below the RF safety threshold, by detecting carboxylic/amide carbons with broadband stochastic proton decoupling. PMID- 25917938 TI - Widespread telomere instability in prostatic lesions. AB - A critical function of the telomere is to disguise chromosome ends from cellular recognition as double strand breaks, thereby preventing aberrant chromosome fusion events. Such chromosome end-to-end fusions are known to initiate genomic instability via breakage-fusion-bridge cycles. Telomere dysfunction and other forms of genomic assault likely result in misregulation of genes involved in growth control, cell death, and senescence pathways, lowering the threshold to malignancy and likely drive disease progression. Shortened telomeres and anaphase bridges have been reported in a wide variety of early precursor and malignant cancer lesions including those of the prostate. These findings are being extended using methods for the analysis of telomere fusions (decisive genetic markers for telomere dysfunction) specifically within human tissue DNA. Here we report that benign prostatic hyperplasia (BPH), high-grade prostatic intraepithelial neoplasia (PIN), and prostate cancer (PCa) prostate lesions all contain similarly high frequencies of telomere fusions and anaphase bridges. Tumor-adjacent, histologically normal prostate tissue generally did not contain telomere fusions or anaphase bridges as compared to matched PCa tissues. However, we found relatively high levels of telomerase activity in this histologically normal tumor adjacent tissue that was reduced but closely correlated with telomerase levels in corresponding PCa samples. Thus, we present evidence of high levels of telomere dysfunction in BPH, an established early precursor (PIN) and prostate cancer lesions but not generally in tumor adjacent normal tissue. Our results suggest that telomere dysfunction may be a common gateway event leading to genomic instability in prostate tumorigenesis. . PMID- 25917939 TI - The glycosomal-membrane associated phosphoglycerate kinase isoenzyme A plays a role in sustaining the glucose flux in Trypanosoma cruzi epimastigotes. AB - In Trypanosoma cruzi three isoenzymes of phosphoglycerate kinase (PGK) are found which are simultaneously expressed: the cytosolic isoenzyme PGKB as well as two glycosomal enzymes, PGKA and PGKC. In this paper, we show that PGKA in T. cruzi epimastigotes is associated to the glycosomal membrane; it is responsible for about 23% of the glycosomal PGK activity, the fraction that remains in the pellet after osmotic shock treatment of purified organelles, in contrast to the 77% soluble activity that is mainly attributed to PGKC. Antibodies against the unique 80 amino-acid insertion of PGKA blocked almost completely the glucose consumption by epimastigotes that were partially permeabilized with digitonin. These results indicate that PGKA is the predominant isoenzyme for sustaining glycolysis through the glycosomes of these parasites. PMID- 25917940 TI - Evaluation of uraemic pruritus in long-term dialysis patients using a modified Chinese scale. AB - AIM: To examine the reliability and validity of a modified Chinese version of the uraemic pruritus scale for measurement of different degrees of itching, as well as to identify the predictors for the severity of uraemic pruritus among long term dialysis patients. METHODS: Long-term dialysis patients (n = 110) were recruited for a cross-sectional study from a medical centre in Taiwan. A modified Chinese version of the uraemic pruritus scale was used to evaluate sleep disturbance and the severity, frequency and distribution of itching. Reliability was evaluated using item-total correlations, Cronbach's alpha, and intra-class correlation. Validity was evaluated by the content validity index, predictive and discriminative validity. Multiple linear regression was used on the predictors for the severity of uraemic pruritus. RESULTS: After optimization for reliability, the scale retained seven items. The Cronbach's alpha was 0.86, and the results showed that the scale had predictive and discriminative validity. High intact-parathyroid hormone and creatinine clearance rate were important predictors for the severity of uraemic pruritus. The severity of uraemic pruritus was the important predictor for the sleeping disturbance. CONCLUSION: The modified uraemic pruritus scale can discriminate between patients with a total pruritus score of >=11 and those with a score of 0 points. The modified Chinese scale is a useful tool for clinically assessing the various degrees of itching among long-term dialysis patients. Our study validates that it could apply to clinical practice in assessment of uraemic pruritus. PMID- 25917942 TI - [Flexible rehabilitation times after total hip and knee replacement]. AB - BACKGROUND: In the literature, many studies have focussed on the efficacy of individual rehabilitative treatments and therapies, whereas the duration of the rehabilitation after uncomplicated total alloarthoplastic hip and knee replacement in a previously known Cox and gonarthrosis is rarely mentioned. Therefore, the purpose of the present study was to analyze the duration of inpatient medical follow-up treatment. PATIENTS AND METHODS: In the present prospective study, 127 patients with uncomplicated total hip replacement (THR) and 110 patients with total knee replacement (TKR) implantation caused by advanced Cox or gonarthrosis were postoperatively examined. In this study only patients with the health insurance AOK Rheinland/Hamburg were included. To detect the degree of mobility of the patients, the Staffelstein score was used. It was measured at admission of the patient (T1) and afterwards at the weekly follow-ups (T2-T4), and on the day of discharge (T5). For a better assessment of the necessary individual period of rehabilitation, a target number of points was specified in the Staffelstein score whose achievement was defined as a rehabilitation aim. On the day of admission and in the following weeks of rehabilitation, the degree of mobility was recorded and evaluated in order to adapt the rehabilitation period to the individual situation of each patient. RESULTS: The study showed that the highest rehabilitation progress associated with a significant improvement of mobility degree has been achieved in both THR and TKR patients at the end of the second week of rehabilitation (T2-T3). In the Staffelstein score, 45 % of THR patients and 44 % of TKR patients had reached their rehabilitation aim between T2 and T3. The level of mobility could be significantly improved at the end of rehabilitation (t-test: p < 0.001) in both the THR (n = 127) and TKR patients (n = 110). THR patients required an average of 19.1 +/- 4.0 days (range 8-33 days) and the TKR patients on average 19.8 +/- 3.4 days (range 12-29 days). Thus, 58 % (n = 74) of THR patients and 51 % (n = 56) of TKR patients had achieved their rehabilitation goal within 21 days. By adapting the rehabilitation period we had achieved the following economic effects: a saving of 28,469 euros could be achieved for THR patients and 15,574 euros for TKR patients. CONCLUSION: Based on the score-driven detection of degree of mobility at the beginning of inpatient rehabilitation, an individual adaptation of the rehabilitation period based on the progress of the patient is possible. Thus, patients who had achieved their rehabilitation goal within the 21 days could be discharged sooner. As a result, in times of limited financial resources, the saved resources can be used for other rehabilitation groups. PMID- 25917943 TI - Prevalence of Apical Bone Defects and Evaluation of Associated Factors Detected with Cone-beam Computed Tomographic Images. AB - INTRODUCTION: Cone-beam computed tomographic (CBCT) imaging has been shown to be accurate for detecting apical bone defects (ABDs). Medium field of view CBCT imaging may provide apical images of the whole oral cavity at a resolution that is sufficient to allow ABDs to be located and measured. The aim of the work presented was to calculate the prevalence of ABDs from CBCT images as well as to assess some associated factors and their measurement. METHODS: One hundred CBCT data sets with a voxel size of 0.2 mm were analyzed by 2 evaluators according to a standardized reading protocol. The number of maxillary and mandibular teeth, the presence of endodontic treatment, and the presence of ABDs associated with endodontic treatment were identified, and the presence of intraradicular posts was documented. The size of ABDs detected was measured, and they were classified according to the Cone Beam Computed Tomography Periapical Index. RESULTS: A total of 2368 teeth and 100 subjects were analyzed. The prevalence of ABDs in subjects was 78%; in 8.6% of the sample teeth, ABDs were present, and 38.2% of endodontically treated maxillary molars were affected by it. Endodontic treatment was significantly associated with an increased risk for the presence of an ABD (P = .0001); 40.8% of endodontically treated teeth were associated with an ABD. This rate increased to 85.9% in endodontically treated maxillary molars. Placement of a post was significantly associated with the presence of an ABD (P = .003). The most frequent lesions were those with diameters between 2 and 4 mm (39.2%). CONCLUSIONS: There are only few studies on the prevalence of ABDs using CBCT analysis. This study in a French population shows a high prevalence of ABDs, especially on endodontically treated molars. The most effective way to exhaustively detect such defects is with CBCT imaging. Moreover, CBCT images show details of the extent of bone loss, thus providing information valuable for the therapeutic decision and details that could help with the prognosis. PMID- 25917944 TI - Residents' Perceptions of the Graduate Endodontic Application Selection Process and Match. AB - INTRODUCTION: Anecdotal reports suggest that the application process for graduate endodontic programs in the United States and Canada is inefficient and may be perceived by applicants as being unfair. This survey examines residents' perceptions of the graduate endodontic application process and related issues. METHODS: A web-based survey consisting of 24 questions on the residents' perception of the graduate endodontic application process was developed and e mailed to 403 graduate endodontic students in the United States and Canada. RESULTS: Of the 403 invited participants, 218 surveys were completed (53%). The responses were varied. Respondents were not overwhelmingly satisfied with the application/interview/selection process; 45% were satisfied or very satisfied, 25% were neutral, and 30% were dissatisfied or very dissatisfied. Only 39% indicated that they would have preferred a Match process. Eighty-two percent accepted the first program that offered a position, and 79% reported being satisfied or very satisfied with their choice of a program. CONCLUSIONS: Forty five percent of endodontic residents were satisfied with the application/interview/selection process, and most would not have preferred a Match process. PMID- 25917946 TI - Carcass traits and saleable meat yield of alpacas (Vicugna pacos) in Australia. AB - Carcass traits and saleable meat yield (SMY) of female and castrated male alpacas in Australia at 18, 24 and 36 months of age were investigated. Fifty huacaya alpacas, evenly distributed across 14, 20, 32 month ages and two genders, were grazed on coastal summer pastures for four months. Dressing percentage and carcass length were collected at slaughter. At 24h post-mortem the carcasses were prepared into four SMY combinations. Thirty six month animals had heavier hot carcass weights (33.7 +/- 1 kg) and longer carcasses (81.2 +/- 0.7 cm) as expected. The percentage of total carcass bone (17.5 +/- 0.2%), fat trim (1.4 +/- 0.1%) and meat trim (7.8 +/- 0.4%) was assessed as a proportion of cold carcass weight. The proportion of fat increased and bone decreased with age. Females had more trim than males. SMY decreased in females and increased in males with age across all combinations suggesting that males are preferable for meat production. PMID- 25917945 TI - Antimicrobial Effects of Novel Triple Antibiotic Paste-Mimic Scaffolds on Actinomyces naeslundii Biofilm. AB - INTRODUCTION: Actinomyces naeslundii has been recovered from traumatized permanent teeth diagnosed with necrotic pulps. In this work, a triple antibiotic paste (TAP)-mimic scaffold is proposed as a drug-delivery strategy to eliminate A. naeslundii dentin biofilm. METHODS: Metronidazole, ciprofloxacin, and minocycline were added to a polydioxanone (PDS) polymer solution and spun into fibrous scaffolds. Fiber morphology, mechanical properties, and drug release were investigated by using scanning electron microscopy, microtensile testing, and high-performance liquid chromatography, respectively. Human dentin specimens (4 * 4 * 1 mm(3), n = 4/group) were inoculated with A. naeslundii (ATCC 43146) for 7 days for biofilm formation. The infected dentin specimens were exposed to TAP mimic scaffolds, TAP solution (positive control), and pure PDS (drug-free scaffold). Dentin infected (7-day biofilm) specimens were used for comparison (negative control). Confocal laser scanning microscopy was done to determine bacterial viability. RESULTS: Scaffolds displayed a submicron mean fiber diameter (PDS = 689 +/- 312 nm and TAP-mimic = 718 +/- 125 nm). Overall, TAP-mimic scaffolds showed significantly (P <= .040) lower mechanical properties than PDS. Within the first 24 hours, a burst release for all drugs was seen. A sustained maintenance of metronidazole and ciprofloxacin was observed over 4 weeks, but not for minocycline. Confocal laser scanning microscopy demonstrated complete elimination of all viable bacteria exposed to the TAP solution. Meanwhile, TAP mimic scaffolds led to a significant (P < .05) reduction in the percentage of viable bacteria compared with the negative control and PDS. CONCLUSIONS: Our findings suggest that TAP-mimic scaffolds hold significant potential in the eradication/elimination of bacterial biofilm, a critical step in regenerative endodontics. PMID- 25917947 TI - Novel anti-inflammatory therapies for the treatment of atherosclerosis. AB - The underlying role of inflammation in atherosclerosis has been characterized. However, current treatment of coronary artery disease (CAD) predominantly consists of targeted reductions in serum lipoprotein levels rather than combating the deleterious effects of acute and chronic inflammation. Vascular inflammation acts by a number of different molecular and cellular pathways to contribute to atherogenesis. Over the last decades, both basic studies and clinical trials have provided evidence for the potential benefits of treatment of inflammation in CAD. During this period, development of pharmacotherapies directed towards inflammation in atherosclerosis has accelerated quickly. This review will highlight specific therapies targeting interleukin-1beta (IL-1beta), P-selectin and 5-lipoxygenase (5-LO). It will also aim to examine the anti-inflammatory effects of serpin administration, colchicine and intravenous HDL-directed treatment of CAD. We summarize the mechanistic rationale and evidence for these novel anti-inflammatory treatments at both the experimental and clinical levels. PMID- 25917948 TI - The artificial somato-autonomic reflex arch does not improve bowel function in subjects with spinal cord injury. AB - STUDY DESIGN: Prospective cohort study. OBJECTIVE: Although introduced for neurogenic bladder dysfunction, it has been suggested that the artificial somato autonomic reflex arch alleviates neurogenic bowel dysfunction (NBD). We aimed at evaluating the effects of the reflex arch on NBD. SETTING: Denmark. METHODS: Ten subjects with supraconal spinal cord injury (SCI) (nine males, median age 46 years) had an anastomosis created between the ventral part of the fifth lumbar or first sacral nerve root and the ventral part of the second sacral nerve root. Standardized assessment of segmental colorectal transit times with radiopaque markers, evaluation of scintigraphic assessed colorectal emptying upon defecation, scintigraphic assessment of colorectal transport during stimulation of the reflex arch, standard anorectal physiology tests and colorectal symptoms were performed at baseline and 18 months after surgery. RESULTS: No significant change was observed in colorectal emptying upon defecation (median 31% of the rectosigmoid at baseline vs 75% at follow-up, P=0.50), no movement of colorectal contents was observed during stimulation of the reflex arch. Segmental colorectal transit times, anal sphincter pressures and rectal capacity did not change, and no change was seen in NBD score (median 13.5 (baseline) vs 12.5 (follow-up), P=0.51), St Marks fecal incontinence score (4.5 vs 5.0, P=0.36) and Cleveland constipation score (6.0 vs 8.0, P=0.75). CONCLUSIONS: The artificial somato autonomic reflex arch has no effect on bowel function in subjects with supraconal SCI. PMID- 25917949 TI - Study participation rate of patients with acute spinal cord injury early during rehabilitation. AB - STUDY DESIGN: Retrospective observational study. OBJECTIVES: To investigate the study participation rate of patients with acute spinal cord injury (SCI) early during rehabilitation after conveying preliminary study information. SETTING: Single SCI rehabilitation center in Switzerland. METHODS: Newly admitted acute SCI patients receive a flyer to inform them concerning the purpose of clinical research, patient rights and active studies. Upon patient request, detailed study information is given. The rate of patients asking for detailed information (study interest) and the rate of study participation was evaluated from May 2013 to October 2014. Furthermore, the number of patients not withdrawing consent to the utilization of coded health-related data was determined. RESULTS: The flyer was given to 144 of the 183 patients admitted during the observation period. A total of 96 patients (67%) were interested in receiving detailed information, and 71 patients (49%) finally participated in at least one study. The vast majority of patients (that is, 91%) did not withdraw consent for retrospective data analysis. An age over 60 years had a significantly (P?0.023) negative effect on study interest and participation, and the consent rate to retrospective data analysis was significantly (P<0.04) lower in patients older than 75 years. Study interest and participation were reduced more than 5 and 14-fold, respectively, in patients older than 60 years. CONCLUSIONS: The relatively low (approximately 50%) study participation rates of acute SCI patients should be considered when planning clinical trials. The recruitment of patients older than 60 years may be reduced substantially. PMID- 25917950 TI - The effect of preexisting hypertension on early neurologic results of patients with an acute spinal cord injury. AB - STUDY DESIGN: Retrospective case-control. OBJECTIVES: To characterize changes in American Spinal Injury Association Motor Score (AMS) in patients treated with relative hypertension (HTN) (mean arterial pressure (MAP) > 85 mm Hg for 5 days) with and without preexisting HTN. SETTING: A regional spinal cord injury (SCI) center in Pennsylvania, United States. METHODS: All patients with an acute SCI who were treated with induced HTN (MAP goal above 85) in the intensive care unit (ICU) for at least 5 days were identified. Patients were stratified based on the presence of preexisting HTN, and the change in the AMS between admission and day 5 was determined. Predictors of outcome were identified using correlation analysis and multiple linear regression. RESULTS: Ninety-two patients met inclusion criteria of which 22 had a previous history of HTN. HTN was a predictor of poor early outcome. Patients with HTN had an average decline in their AMS of 7.6, compared with an average decrease of only 0.6 in the AMS of patients without HTN (P=0.04). HTN had no effect (P>0.05) on other in-hospital variables including length of stay, length of stay in the ICU, complications or mortality. Additionally, multiple linear regression analysis demonstrated that diabetes, coronary artery disease and pulmonary disease had no effect on the change in AMS. CONCLUSION: Chronic HTN is an independent risk factor for poor early neurologic recovery in patients treated with relative HTN for an acute SCI. This is independent of age and other comorbidities. PMID- 25917951 TI - Long-term outcome of transobturator tape (TOT) for treatment of stress urinary incontinence in females with neuropathic bladders. AB - STUDY DESIGN: Retrospective review of prospectively collected data. OBJECTIVES: Stress urinary incontinence (SUI) is a cause of significant distress in women with neurogenic bladder dysfunction (NBD) due to spinal cord injury (SCI). Transobturator tape (TOT) has not previously been studied in this select group for cure of SUI. We aim to determine the long-term safety and efficacy of TOT in SCI patients with NBD and SUI. SETTING: London, the United Kingdom. METHODS: All patients undergoing TOT between 2005 and 2013 were identified (27 patients). All patients had pre-operative videocystometrogram (VCMG) and all had VCMG-proven SUI. Mean follow-up was 5.2 years. Patient-reported leakage, satisfaction, change in bladder management, complications and de novo overactive bladder (OAB) were recorded. RESULTS: Mean age was 56 years (range 30-82) with complete follow-up. Twenty-two patients (81.5%) reported complete dryness from SUI post surgery. One patient (3.7%) reported SUI only when her bladder was very full but was satisfied. Twenty-three patients (85.2%) were happy. Four patients (14.8%) remained wet. Twenty-five patients (92.6%) had no change in bladder management. Two out of five patients (40%) who voided by straining prior to surgery required clean intermittent self-catheterisation (CISC) post-operatively. Two patients (7.4%) developed de novo OAB. No bladder or vaginal injuries, tape erosions or urethral obstruction were seen. Three patients (11.1%) had transient thigh pain. CONCLUSION: In women with NBD and SUI, TOT should be considered safe and effective with very good medium/long-term outcomes. There may be an increased risk of CISC in women who void by straining pre-operatively. PMID- 25917952 TI - Prevalence of cigarette smoking and attempts to quit in a population-based cohort with spinal cord injury. AB - OBJECTIVE: The purposes of this study were to assess (i) prevalence of smoking in a population-based cohort of persons with spinal cord injury (SCI), (ii) history of quit attempts and (iii) the relationship between access to health care, socioeconomic status (SES), smoking status and history of quit attempts. STUDY DESIGN: Cross-sectional study. SETTING: Population-based SCI cohort. METHODS: A total of 833 adults with SCI of at least 1-year duration were identified through a population-based surveillance system. Current smoking status, attempts to quit smoking in the past year and seeking professional help to quit smoking were assessed. RESULTS: Over one-third (35.3%) of the sample were current smokers, of whom 75.4% had ever tried to quit, and of these, only 27.9% had ever sought professional help. Those with lower SES were more likely to be current smokers, as were those with less access to health care. Access to care was positively related to likelihood of having sought professional help. CONCLUSIONS: We found rates of smoking among persons with SCI to be well above national prevalence rates. We also found poorer access to care related to a greater likelihood of being a current smoker, had no association with trying to quit smoking, but decreased likelihood of using cessation support among those who did attempt to quit. PMID- 25917953 TI - Psychometric properties of the Sexual Adjustment Questionnaire (SAQ) in the Iranian population with spinal cord injury. AB - STUDY DESIGN: This is a cross-sectional study. OBJECTIVES: The objective of this study was to examine the psychometric properties of the Sexual Adjustment Questionnaire (SAQ) for Iranian people with spinal cord injury. SETTING: This study was conducted in the brain and Spinal Cord Injury Research Center, Tehran University of Medical Sciences, Tehran, Iran. METHODS: We assessed the psychometric properties of the SAQ, with 200 participants (men=146, women=54) completing the scale. An evaluation of its test-retest reliability was performed over a 2-weeks period, on a subsample of 30 patients recruited from the overall group. Cronbach's alpha-coefficient was computed for assessment of internal consistency reliability. In addition, content and face validity were examined by an expert committee. Construct validity was assessed by examining convergent and discriminant validity. Finally, exploratory factor analysis was used to extract the factor structure of the questionnaire. RESULTS: The Cronbach's alpha and intraclass correlation coefficient were 0.77 and 0.72 retrospectively. With regard to construct validity, there was a significant (P=0.009) negative correlation (r=-0.28) between the SAQ score and age. Those with lower levels of educations scored significantly lower on the SAQ (P=0.04). The exploratory factor analysis indicated a four-factor structure for the questionnaire, accounting for 68.9% of the observed variance. The expert committee approved the face and content validity of the developed measure. CONCLUSION: The SAQ is a valid measure for assessing sexual adjustment in people with spinal cord injury. The evaluation of sexual well-being may be useful in clinical trials and practical settings. PMID- 25917954 TI - Expression of C5a and its receptor following spinal cord ischemia reperfusion injury in the rat. AB - STUDY DESIGN: Experimental study. OBJECTIVE: To investigate the expression of C5a and its receptor after spinal cord ischemia reperfusion injury (SIRI) in rat. SETTING: Department of Neurosurgery, the Second Affiliated Hospital, Xi'an Jiaotong University, Shaanxi Province, Xi'an, China METHODS: Sprague Dawley rats were subjected to 1 h of infrarenal aorta occlusion to induce spinal cord ischemia. Spinal cord was reperfused for 12, 24, 48 h or 3 days separately after ischemia, respectively. Enzyme-linked immunosorbent assay was used to detect C5a in rat serum. Immunofluorescent staining was performed to detect the expression and cellular localization of C5aR in spinal cord following SIRI. RESULTS: Following SIRI, the motor behavior of the rats was significantly compromised. The serum concentration of C5a in the rat was elevated after SIRI and peaked at 24 h. C5aR was significantly upregulated in the lumbar spinal cord following SIRI and expressed on motor neurons and the microglia, but not astrocyte. There was no significant difference in the expression level of C5aR localized on motor neurons after SIRI. Remarkable upregulation of the C5aR may be associated with increased number of C5aR-positive microglia and elevated cellular expression level. CONCLUSION: This study provides the first evidence of the expression of C5a and its receptors in SIRI and suggests their possible contribution to SIRI in a rat model. PMID- 25917956 TI - Life without limbs: Technology to the rescue. AB - BACKGROUND: This article reports a rare and inspirational case of a four-limb amputee, the range of integrated technology solutions that enable him to be a productive member of his family and the process and pitfalls of seeking technology solutions. CASE DESCRIPTION AND METHODS: A complex case of bilateral transhumeral amputation and bilateral transfemoral amputation with residual upper limbs too short to oppose is presented. The multiple 'high-tech' and 'low-tech' devices used on a daily basis to move around his house and community, control his environment, communicate and feed himself without the use of limbs, prostheses or a second person are outlined. FINDINGS AND OUTCOMES: Recent advances in electronics, computing and telecommunications technologies provide him with capabilities not possible 10 years ago. CONCLUSION: The process and pitfalls in sourcing technology solutions and the innovative solutions to meet the unique functional needs of this individual provide guidance to those with similarly severe and profound limitations to independence. CLINICAL RELEVANCE: Descriptions of technology solutions to improve independent functioning of those with quadruple amputation without prostheses as well as those with high-level spinal cord injury are of value to occupational therapists, patients and families alike. PMID- 25917955 TI - Association between lipid levels and major adverse cardiovascular events in rheumatoid arthritis compared to non-rheumatoid arthritis patients. AB - OBJECTIVE: Lower levels of low-density lipoprotein (LDL) cholesterol may be associated with increased cardiovascular (CV) risk in rheumatoid arthritis (RA). This study was undertaken to determine whether the complex relationship between levels of LDL and high-density lipoprotein (HDL) cholesterol and CV risk is different in RA patients as compared to non-RA controls. METHODS: Using data from a US health insurance plan (2003-2012), we conducted a cohort study that included patients with RA and non-RA control subjects matched with regard to age, sex, and index date. The nonlinearity of associations between lipid levels and incidence of major adverse CV events (MACE) was tested. We used multivariable Cox proportional hazards regression models to examine for an interaction between lipid levels and RA status in relation to the risk of MACE, after adjustment for CV risk factors. RESULTS: In total, 16,085 RA patients and 48,499 non-RA controls were studied. The mean age was 52.6 years and 78.6% were women. The relationship between LDL cholesterol levels and incidence of MACE was nonlinear and similar between RA patients and non-RA controls (P for interaction = 0.72). No significant increase in CV risk was observed between the lowest quintile of LDL cholesterol levels (<=91.0 mg/dl) and the second, third, or fourth quintiles, whereas the highest quintile (>190.0 mg/dl) conveyed a 40% increase in risk of MACE (hazard ratio [HR] 1.40, 95% confidence interval [95% CI] 1.17-1.68). The relationship between HDL cholesterol levels and incidence of MACE was also nonlinear and similar between RA patients and non-RA controls (P for interaction = 0.39). Compared to the lowest quintile of HDL cholesterol levels, each successive quintile was associated with a reduced risk of MACE (HR 0.45, 95% CI 0.48-0.72 for lowest quintile [<=43.0 mg/dl] versus highest quintile [>71.0 mg/dl]). CONCLUSION: The complex relationship between LDL cholesterol levels, HDL cholesterol levels, and risk of MACE was nonlinear in RA patients and also not statistically significantly different from that in an age- and sex-matched non-RA cohort. PMID- 25917958 TI - Executive Function Coaching: Assisting With Transitioning From Secondary to Postsecondary Education. AB - OBJECTIVE: ADHD is defined as impairment to self-regulatory behavior and executive functioning (EF). Many students with other learning disabilities (LD) also experience EF impairments. With the rising number of students with ADHD and LD enrolling in higher education, it is important to recognize the challenges these students face and to provide effective support when transitioning from secondary to postsecondary school. This article examines the challenges of the transition from secondary to postsecondary environments, specifically with the student diagnosed with ADHD and/or other LD. METHOD: Scholarly articles relating to the efficacy of EF coaching as well as students with ADHD and/or other LD transitioning from secondary to postsecondary school were examined and then considered for best practices in EF coaching. RESULTS: Although the literature supports that EF coaching can improve EF skills, there is a paucity of empirical studies that examines the efficacy of EF coaching (Franklin & Franklin, 2012). The literature also supports the use of EF coaching for students with ADHD and/or LD when transitioning from highschool to college, however limited research has been published to date. CONCLUSION: With the finite research available in the field of coaching, recommendations for future consideration and research is included to support the need for evidence-based programs. An EF coaching model at Lynn University's Institute for Achievement and Learning (IAL) is discussed and addresses how students are supported during their first year at the University. PMID- 25917957 TI - C8-glycosphingolipids preferentially insert into tumor cell membranes and promote chemotherapeutic drug uptake. AB - Insufficient drug delivery into tumor cells limits the therapeutic efficacy of chemotherapy. Co-delivery of liposome-encapsulated drug and synthetic short-chain glycosphingolipids (SC-GSLs) significantly improved drug bioavailability by enhancing intracellular drug uptake. Investigating the mechanisms underlying this SC-GSL-mediated drug uptake enhancement is the aim of this study. Fluorescence microscopy was used to visualize the cell membrane lipid transfer intracellular fate of fluorescently labeled C6-NBD-GalCer incorporated in liposomes in tumor and non-tumor cells. Additionally click chemistry was applied to image and quantify native SC-GSLs in tumor and non-tumor cell membranes. SC-GSL-mediated flip-flop was investigated in model membranes to confirm membrane-incorporation of SC-GSL and its effect on membrane remodeling. SC-GSL enriched liposomes containing doxorubicin (Dox) were incubated at 4 degrees C and 37 degrees C and intracellular drug uptake was studied in comparison to standard liposomes and free Dox. SC-GSL transfer to the cell membrane was independent of liposomal uptake and the majority of the transferred lipid remained in the plasma membrane. The transfer of SC-GSL was tumor cell-specific and induced membrane rearrangement as evidenced by a transbilayer flip-flop of pyrene-SM. However, pore formation was measured, as leakage of hydrophilic fluorescent probes was not observed. Moreover, drug uptake appeared to be mediated by SC-GSLs. SC-GSLs enhanced the interaction of doxorubicin (Dox) with the outer leaflet of the plasma membrane of tumor cells at 4 degrees C. Our results demonstrate that SC-GSLs preferentially insert into tumor cell plasma membranes enhancing cell intrinsic capacity to translocate amphiphilic drugs such as Dox across the membrane via a biophysical process. PMID- 25917959 TI - Long-Standing Presternal Plaque. PMID- 25917960 TI - Treatment of Harlequin Ichthyosis With Acitretin. PMID- 25917961 TI - Complicated congenital preauricular fistula: sonographic features. PMID- 25917962 TI - Prevalence of intestinal protozoan infections among individuals living with HIV/AIDS at Felegehiwot Referral Hospital, Bahir Dar, Ethiopia. AB - BACKGROUND: HIV infection continues to pose a serious challenge to global health by predisposing patients to opportunistic infections. A cross-sectional study was conducted from December 2012 to February 2013 to assess the enteric protozoan infection status among individuals living with HIV/AIDS in Felegehiwot Referral Hospital, Bahir Dar, northwest Ethiopia. METHODS: Stool specimens from 399 HIV positive individuals were examined for the presence of trophozoites, cysts, and oocysts using direct wet mount, formol-ether sedimentation and modified Ziehl Neelsen techniques. In addition, CD4+ T-cell counts were measured to evaluate the immune status of the study subjects. RESULTS: An overall prevalence of 30.6% enteric protozoan infections was recorded. Pre-ART (antiretroviral treatment) individuals were more infected than patients on ART, although this was not statistically significant (p>0.05). The highest prevalence of enteric protozoan infection was due to Entamoeba histolytica/E. dispar (19.3%), followed by Cryptosporidium spp (5.8%), Giardia lamblia (4.3%), and Isospora belli (1.3%). A CD4+ T-cell count of <200 cells/MUl and status of being diarrhoeic were significantly associated with the overall prevalence of enteric protozoan infection. CONCLUSIONS: A relatively high prevalence of enteric protozoan infection was observed among individuals living with HIV/AIDS. Routine stool and CD4+ T-cell examinations should be conducted to monitor the status of HIV/AIDS patients. PMID- 25917964 TI - Confident identification of filamentous fungi by matrix-assisted laser desorption/ionization time-of-flight mass spectrometry without subculture-based sample preparation. PMID- 25917963 TI - Susceptibility trends and molecular characterization of Gram-negative bacilli associated with urinary tract and intra-abdominal infections in Jordan and Lebanon: SMART 2011-2013. AB - OBJECTIVES: To investigate phenotypic and genotypic patterns of antimicrobial resistance among Gram-negative bacilli associated with urinary tract infection (UTI) and intra-abdominal infection (IAI) in medical centres of Jordan and Lebanon. METHODS: Gram-negative bacilli from the SMART study, collected between the years 2011 and 2013, were first identified at local laboratories. These isolates were shipped to a central laboratory where re-identification, susceptibility testing, and molecular characterization were performed using standard methods. RESULTS: Among the 523 UTI-associated isolates, Escherichia coli, Klebsiella pneumoniae, and Proteus mirabilis were the most frequent (70%, 14%, and 5%, respectively). E. coli, K. pneumoniae, and Pseudomonas aeruginosa were the most frequent species among the 527 IAI-associated isolates (46%, 14%, and 12%, respectively). Incidence rates of extended-spectrum beta-lactamase (ESBL) producers among UTI-associated E. coli, K. pneumoniae, and P. mirabilis were 43%, 54%, and 4%, respectively. Corresponding rates among IAI-associated isolates were 49%, 56%, and 12%, respectively. Acinetobacter baumannii and P. aeruginosa isolates showed very disturbing low susceptibility patterns. CTX-M-15 was the most prevalent ESBL produced. Seventeen isolates were non-susceptible to carbapenems (estimated prevalence of 1.6%). CONCLUSIONS: The alarmingly high rates of ESBL production and emergence of carbapenemases emphasize the urgent need to develop antimicrobial stewardship initiatives and to maintain antimicrobial resistance surveillance systems. PMID- 25917965 TI - Response to potent anti-HBV agents in chronic hepatitis B and combined effect of HBV reverse transcriptase mutations. AB - BACKGROUND AND AIM: Response to nucleos(t)ide analogue therapy against HBV infection depends on a number of factors. One of them is appearance of drug resistance mutations. The present study aimed to investigate the efficacy of ETV and TDF as anti-HBV agents and to analyze the role of HBV-RT mutations in reducing the efficacy of mentioned drugs. MATERIAL AND METHODS: Sixty nine treatment naive CHB patients (mean age 33.8 +/- 11.9 years) were enrolled and treated with ETV or TDF for one year. Complete virological response (CVR) was defined as undetectable serum HBV DNA after 12 months of therapy. Amino acid and nucleotide sequence analyses of HBV-RT region were performed using Geno2pheno HBV drug resistance tool. The 3D model of HBV-RT protein was built by I-TASSER server and RMSD was calculated between wild type and mutated HBV-RT protein. RESULTS: After 12 months of treatment, four CHB patients did not achieve CVR and all of them were with HBV genotype D. HBeAg seroconversion was achieved in 56% HBeAg positive patients after 12 months of antiviral therapy. The HBV-RT amino acid sequences from these four patients were used for in-silico analysis. It was found that the presence of many mutations in HBV-RT region of HBV isolated from these patients led to a high degree of variation in configuration of atoms of HBV-RT protein and also caused displacement of active site of this protein. CONCLUSION: The efficacy of antiviral drugs in inhibiting HBV replication may be reduced by combined effect of many HBV-RT mutations; however, an in vitro study is needed to validate the findings. PMID- 25917966 TI - Comparative genome analysis of five Pasteurella multocida strains to decipher the diversification in pathogenicity and host specialization. AB - Pasteurella multocida is a Gram-negative bacterial pathogen causing economically important diseases in distinct animal species. Complete genome sequences of five P. multocida strains (Pm70, HB03, HN06, 3480, and 36950) isolated from poultry, swine or bovine, were retrieved from the GenBank database and compared with each other, for the first time. The missense mutations generating a dissimilar amino acid in the peptide chain, nonsense mutations, and insertion/deletions in the nucleotide sequence were identified due to the potential change in the protein function. A total of 500 putative mutant proteins were identified, and categorized into 10 groups including cellular compartments such as outer membrane, capsule and fimbria, and processes such as carbohydrate, energy, nucleic acid and amino acid metabolisms, transport, and drug resistance. The majority of the mutant proteins were associated with the outer compartments of the bacterial cell. Various mutations were also detected in the genes related with biosynthetic pathways. The highest and the lowest numbers of mutant proteins belonged to 36950 vs. HN06 and Pm70 vs. HB03 comparisons, respectively. The major impact on the diversification of P. multocida strains was observed to be conferred by the mutations related with pathogenicity. To exhibit the outcomes of the mutations in the peptide chains, three sample amino acid sequences belonging to AfuA, MetB, and d,d-heptose 1,7-bisphosphate phosphatase were aligned, and their phylogenetic relationships were shown. These comprehensive analyses improve the understanding of molecular pathogenicity and host specialization of P. multocida, and would have a contribution to the recombinant vaccine development against this pathogen. PMID- 25917967 TI - Atrial natriuretic peptide and aldosterone synthase gene in essential hypertension: a case-control study. AB - The renin-angiotensin-aldosterone system (RAAS) and their candidate genes are principally involved in regulation of blood pressure through salt-water homeostasis. Atrial natriuretic peptide (ANP) and Aldosterone synthase (CYP11B2) are the important RAAS mediators, play a major role in hypertension through regulation of cardiorenal homeostasis and water-electrolytes balance, respectively. Present study reports the expression of ANP and CYP11B2 gene at mRNA and proteins levels in patients with essential hypertension in North Indian subjects. Gene expression at mRNA and protein levels was carried out by Real time PCR and Western blot, respectively. We found a significant down regulation in the ANP gene expression at mRNA (85%) and protein (72.6%) levels and significant increase in the CYP11B2 protein expression in patients as compared to controls. A significant increase in Serum creatinine (14.6%), Sodium (1.15%) and decrease in the Blood urea (8.18%) and Potassium (2.32%) levels were also observed among the patients group having higher expression (based on median delta-CT value) in comparison to the lower expression of CYP11B2 gene. Our results suggest that the down-regulation of ANP gene expression at mRNA and protein levels and up regulated CYP11B2 protein expression levels may be correlated with the essential hypertension and could serve as circulating prognostic biomarkers for essential hypertension. PMID- 25917968 TI - Changes in barrier health status of the gill for grass carp (Ctenopharyngodon idella) during valine deficiency: Regulation of tight junction protein transcript, antioxidant status and apoptosis-related gene expression. AB - This study investigated the effects of dietary valine on tight junction protein transcription, antioxidant status and apoptosis on grass carp gills (Ctenopharyngodon idella). Fish were fed six different experimental diets containing graded levels of valine (4.3, 8.0, 10.6, 13.1, 16.7, 19.1 g/kg). The results indicated that valine deficiency decreased Claudin b, Claudin 3, Occludin and ZO-1 transcription and increased Claudin 15 expression in the fish gill (P < 0.05). These effects were partly due to the down-regulation of interleukin 10 (IL 10), transforming growth factor beta1 (TGF-beta1) and IkappaB alpha and the up regulation of relative mRNA expression of interleukin 1beta (IL-1beta), interleukin 8 (IL-8), tumor necrosis factor-alpha (TNF-alpha) and nuclear factor kappaB P65 (NF-kappaB P65) (P < 0.05). However, valine deficiency and valine supplementation did not have a significant effect on Claudin c and Claudin 12 expression in grass carp gills (P > 0.05). Valine deficiency also disrupted antioxidant status in the gill by decreasing anti-superoxide radicals and hydroxyl radical capacity, glutathione contents and the activities and mRNA levels of Cu/Zn superoxide dismutase (SOD1), catalase (CAT), glutathione peroxidase (GPx), glutathione reductase (GR) and glutathione-S-transferase (GST) (P < 0.05). These results may be ascribed to the down-regulation of NF-E2-related factor 2 (Nrf2), target of rapamycin (TOR) and ribosomal protein S6 kinase 1 (S6K1) and the up-regulation of Kelch-like-ECH-associated protein 1 (Keap1) (P < 0.05). Additionally, valine deficiency induced DNA fragmentation via the up regulation of Caspase 3, Caspase 8 and Caspase 9 expressions (P < 0.05). These results may be ascribed to the improvement in ROS levels in the fish gill (P < 0.05). Taken together, the results showed that valine deficiency impaired the structural integrity of fish gill by disrupted fish antioxidant defenses and regulating the expression of tight junction protein, cytokines, antioxidant enzymes, NF-kappaB p65, IkappaBalpha, TOR, Nrf2, Keap1 and apoptosis-related genes in the fish gill. PMID- 25917969 TI - Effects of a recombinant complement component C3b functional fragment alpha2MR (alpha2-macroglobulin receptor) additive on the immune response of juvenile orange-spotted grouper (Epinephelus coioides) after the exposure to cold shock challenge. AB - The effects of Ec-alpha2MR (Epinephelus coiodes-alpha2-macroglobulin receptor) on growth performance, enzymatic activity, respiratory burst, MDA level, total antioxidant capacity, DPPH radical scavenging percentage and immune-related gene expressions of the juvenile orange-spotted grouper were evaluated. The commercial diet supplemented with alpha2MR additive was used to feed the orange-spotted grouper for six weeks. Although a slight increase was observed in the specific growth rate, survival rate and weight gain, no significance was observed among different group. After the feeding trial, the groupers were exposed to cold stress. Respiratory burst activity and MDA level decreased significantly in alpha2MR additive group by comparing with the control and additive control group, while a sharp increase of ACP activity, ALP activity, total antioxidant capacity and DPPH radial scavenging percentage was observed in alpha2MR additive group. qRT-PCR analyses confirmed that the up-regulated mRNA expressions of C3, TNF1, TNF2, IL-6, CTL, LysC, SOD1 and SOD2 were observed in alpha2MR additive group at 20 degrees C. These results showed that alpha2MR additive may moderate the immune response in grouper following cold shock challenge. PMID- 25917970 TI - Acute and subchronic toxic effects of atrazine and chlorpyrifos on common carp (Cyprinus carpio L.): Immunotoxicity assessments. AB - Atrazine (ATR) and chlorpyrifos (CPF) are widely used pesticides in agricultural practices throughout world. It has resulted in a series of toxicological and environmental problems, such as impacts on many non-target aquatic species, including fish. The spleen and head kidney in the bony fish are the major hematopoietic organs, and play a crucial part in immune responses. This study evaluated the subchronic effects of ATR and CPF on the mRNA and protein levels of HSP60, HSP70 and HSP90 in the immune organs of common carp and compared the acute and subchronic effects of ATR and CPF on the swimming speed (SS) of common carp. The results of acute toxicity tests showed that the 96 h-LC50 of ATR and CPF for common carp was determined to be 2.142 and 0.582 mg/L, respectively. Meanwhile, acute and subacute toxicity of ATR and CPF in common carp resulted in hypoactivity. We also found that the mRNA and protein levels of HSP60, HSP70 and HSP90 genes were induced in the spleen and head kidney of common carp exposed to ATR and CPF in the subchronic toxicity test. Our results indicate that ATR and CPF are highly toxic to common carp, and hypoactivity in common carp by acute and subchronic toxicity of ATR and CPF may provide a useful tool for assessing the toxicity of triazine herbicide and organophosphorous pesticides to aquatic organisms. In addition, the results from the subchronic toxicity test exhibited that increasing concentration of ATR and CPF in the environment causes considerable stress for common carp, suggesting that ATR and CPF exposure cause immunotoxicity to common carp. PMID- 25917971 TI - Three novel clade B serine protease inhibitors from disk abalone, Haliotis discus discus: Molecular perspectives and responses to immune challenges and tissue injury. AB - Serine protease inhibitors (SERPINs) control cellular protease activity in order to maintain cellular homeostasis. The immune and inflammatory responses of invertebrate clade B SERPINs have not been widely reported. In the present study, three proteins with high similarity to clade B SERPINs, referred to as AbSERPIN 1, AbSERPIN-2 and AbSERPIN-3, were identified from disk abalone (Haliotis discus discus). While AbSERPIN-1 (399 aa) was of a typical size for this protein class, AbSERPIN-2 (506 aa) and AbSERPIN-3 (532 aa) were relatively larger. Bioinformatic analysis revealed the characteristic SERPIN domain in each AbSERPIN. In addition, the N-terminal region of both AbSERPIN-2 and AbSERPIN-3 contained a predicted low complexity region (LCR) and a signal peptide, suggesting that these proteins are secretory proteins and are, thus, novel peptides. Tertiary structural models of the AbSERPINs highlighted their structural and functional conservation. Ubiquitous expression of AbSERPIN transcripts was evaluated by quantitative real time PCR (qPCR) analysis in seven tissue types. AbSERPIN-1, AbSERPIN-2, and AbSERPIN-3 transcript levels were highest in mantle, hemocytes, and muscles, respectively. Temporal expression analysis revealed that AbSERPINs were significantly (P < 0.05) elevated in hemocytes during the early/middle stages following the injection of a bacterial pathogen (Vibrio parahaemolyticus or Listeria monocytogenes) or an immuno-stimulant (lipopolysaccharide). Moreover, mantle tissue injury led to significant changes in the temporal expression of AbSERPIN mRNA. Specifically, transcription of AbSERPIN-1 and AbSERPIN-3 was considerably up-regulated, while expression of AbSERPIN-2 was suppressed. These results suggest a potential role of AbSERPINs in response to pathogen invasion and tissue injury in disk abalone. PMID- 25917972 TI - Daxx from Pacific white shrimp Litopenaeus vannamei is involved in activation of NF-kappaB pathway. AB - Death domain-associated factor 6 (Daxx) is a Fas-binding protein that mediates the activation of Jun amino-terminal kinase (JNK) pathway and Fas-induced apoptosis. In this study, a crustacean Daxx (LvDaxx) was firstly cloned and identified from Pacific white shrimp Litopenaeus vannamei. The LvDaxx cDNA was 2644 bp in length with an Open Reading Frame (ORF) of 2217 bp. Sequence analysis indicated that LvDaxx contained a single Daxx domain and two nuclear localization signals (NLSs) and shared a similarity with Drosophila melanogaster Daxx. LvDaxx was a nuclear-localized protein that was expressed highest in hemocytes and could be up-regulated in pathogen- and stimulant-challenge shrimps. LvDaxx could activate the artificial promoter containing an NF-kappaB binding site and the promoters of white spot syndrome virus (WSSV) ie1 gene and arthropod antimicrobial peptides (AMPs), suggesting LvDaxx could be involved in the activation of the NF-kappaB pathway. Knock-down of LvDaxx in vivo resulted in down-regulation of shrimp AMPs and reduction of WSSV copies in tissues. Furthermore, suppression of LvDaxx significantly decreased the mortality of WSSV infected shrimps, but increased the mortality of Vibrio Parahaemolyticus-infected shrimps. Thus, these suggested that LvDaxx could play a role in the innate immunity against Vibrio parahaemolyticus in L. vannamei, while in the antiviral response, LvDaxx may be hijacked by WSSV and play a complex role in WSSV pathogenesis. PMID- 25917973 TI - MiR-31 modulates coelomocytes ROS production via targeting p105 in Vibrio splendidus challenged sea cucumber Apostichopus japonicus in vitro and in vivo. AB - MiR-31 is a critical regulator of gene expression in many pathogenic processes in vertebrates. In this study, we identified p105 as a novel target of miR-31 in Apostichopus japonicus and investigated their regulatory roles in vitro and in vivo. The negative expression profiles between miR-31 and Ajp105 were detected in both LPS-exposed primary coelomocytes and Vibrio splendidus-challenged sea cucumber. Co-infection miR-31 mimics significantly depressed the expression of Ajp105 and increased ROS production in vitro. In contrast, miR-31 inhibitor significantly elevated the expression of Ajp105 and decreased ROS level. Consistently, miR-31 over-expression or Ajp105 silencing in vivo both greatly promoted ROS accumulation. Taken together, our findings confirmed that miR-31 could modulate respiratory burst via targeting Ajp105 during sea cucumber pathological development. PMID- 25917974 TI - Isolation of potential probiotic Bacillus spp. and assessment of their subcellular components to induce immune responses in Labeo rohita against Aeromonas hydrophila. AB - Bacillus species isolated from the gut of healthy Labeo rohita (Hamilton) were screened for antibacterial activity against selected fish pathogens. Among the isolates, KADR5 and KADR6 showed antibacterial activity, tolerated low pH and high bile concentrations and were susceptibility to various antibiotics. Based on morphological and biochemical tests and 16S rRNA gene analysis the probiotic strains KADR5 and KADR6 were identified as Bacillus licheniformis and Bacillus pumilus, respectively. The immune stimulatory effect of subcellular components of probiotic Bacillus licheniformis KADR5 and Bacillus pumilus KADR6 in L. rohita against Aeromonas hydrophila infection was studied. Fish were immunized intraperitoneally in case of subcellular components [cell wall proteins (CWPs), extracellular proteins (ECPs), whole cell proteins (WCPs)] and orally in case of live cells (10(8) CFU/g of feed). After 14th day of administration, fishes from each group were challenged intraperitoneally with 0.1 ml of A. hydrophila cell suspension in PBS (10(5) cells ml(-1)). Groups immunized with subcellular components and live cells had significantly lower mortalities of 20-40% and 23 33%, respectively in comparison to control (80% mortality). The non specific immune factors in the cellular components and viable cells of the probiotics increased the expression of lysozyme and respiratory burst. Use of WCPs and CWPs resulted in better protection against A. hydrophila in L. rohita. Our results clearly reflect the potential of cellular components of the probiotics Bacillus species for the protection of fish against A. hydrophila infection by enhancing the immune response. PMID- 25917975 TI - Functional characterisation and expression analysis of recombinant serum amyloid P isoform 1 (RbSAP1) from rock bream (Oplegnathus fasciatus). AB - Lectins are carbohydrate-binding proteins that play important roles in the recognition and elimination of pathogens via the innate immune system. Pentraxins (PTX) are humoral lectins, which are multifunctional proteins in vertebrates. Pentraxins can be divided into two groups based on their primary structure: short (C-reactive protein and serum amyloid P [SAP]) and long pentraxins (PTX3 and neuronal pentraxins). Previously, SAP was shown to have Ca(2+)-dependent binding specificity for various ligands and to be a major acute phase protein. In this study, we identified and characterised the gene encoding SAP isoform 1 in rock bream (Oplegnathus fasciatus) (RbSAP1) and analysed its expression in various tissues after a pathogen challenge. An alignment analysis conducted based on the deduced amino acid sequence of RbSAP1 (1918 bp full-length cDNA with a 699 bp open reading frame encoding 232 amino acids) and SAPs and PTXs isolated from other organisms, revealed that the pentraxin domain and cysteine residues of the deduced protein are conserved. RbSAP1, which was ubiquitously expressed in all tissues examined, was predominantly detected in head kidney, trunk kidney, peripheral blood leukocytes, and gills. RbSAP1 expression was dramatically up regulated in the kidney and liver after infection with Edwardsiella tarda, Streptococcus iniae, or red seabream iridovirus. Purified rRbSAP1 was able to bind Gram-negative bacteria, Gram-positive bacteria, and pathogen-associated molecular patterns. Interestingly, rRbSAP1 aggregated Gram-negative bacteria in the presence of Ca(2+). The anti-pathogen activity of rRbSAP1 suggests that SAP functions in innate immunity in the rock bream. PMID- 25917976 TI - Brown nodule on the lower eyelid: a quiz -- lichenoid keratosis. PMID- 25917978 TI - Biomarker detection of global infectious diseases based on magnetic particles. AB - Infectious diseases affect the daily lives of millions of people all around the world, and are responsible for hundreds of thousands of deaths, mostly in the developing world. Although most of these major infectious diseases are treatable, the early identification of individuals requiring treatment remains a major issue. The incidence of these diseases would be reduced if rapid diagnostic tests were widely available at the community and primary care level in low-resource settings. Strong research efforts are thus being focused on replacing standard clinical diagnostic methods, such as the invasive detection techniques (biopsy or endoscopy) or expensive diagnostic and monitoring methods, by affordable and sensitive tests based on novel biomarkers. The development of new methods that are needed includes solid-phase separation techniques. In this context, the integration of magnetic particles within bioassays and biosensing devices is very promising since they greatly improve the performance of a biological reaction. The diagnosis of clinical samples with magnetic particles can be easily achieved without pre-enrichment, purification or pretreatment steps often required for standard methods, simplifying the analytical procedures. The biomarkers can be specifically isolated and preconcentrated from complex biological matrixes by magnetic actuation, increasing specificity and the sensitivity of the assay. This review addresses these promising features of the magnetic particles for the detection of biomarkers in emerging technologies related with infectious diseases affecting global health, such as malaria, influenza, dengue, tuberculosis or HIV. PMID- 25917977 TI - Normal T2 map profile of the entire femoral cartilage using an angle/layer dependent approach. AB - PURPOSE: To create standard T2 map profiles from the entire femoral cartilage of healthy volunteers in order to assess regional variations using an angular and layer-dependent approach. MATERIALS AND METHODS: Twenty healthy knees were evaluated using 3T sagittal images of a T2 mapping sequence. Manual segmentation of the entire femoral cartilage was performed slice-by-slice by two raters using MatLab. Inter- and intrarater reliabilities were calculated using intraclass correlation coefficient (ICC) and Bland-Altman analysis. T2 values were analyzed with respect to specific locations (medial condyle, trochlea, and lateral condyle), angles to B0 , and layers of cartilage (whole, deep, and superficial). RESULTS: Inter- and intrarater reliability obtained from the entire femoral cartilage was excellent (ICC = 0.84, 0.86, respectively). The ICCs around the trochlea were lower than those of the medial and lateral condyle. Both the inter- and intrarater Bland-Altman plots indicated larger differences in pixel count are seen as the size of the angular segment becomes larger. T2 values were significantly higher in the superficial layer compared to the deep layer at each femoral compartment (P < 0.001). A magic angle effect was clearly observed, especially within the whole and deep layer over the medial and lateral femoral condyles, except for the superficial layer at the medial condyle. CONCLUSION: The normal T2 map profiles of the entire femoral cartilage showed variations in ICCs by location and in T2 values by angles and layers. These profiles can be useful for diagnosis of early cartilage degeneration in a specific angle and layer of each condyle and trochlea. PMID- 25917979 TI - Percutaneous transapical closure of cardiac apex with an ADO-II device after successful transapical transcatheter prosthetic mitral paravalvular leak closure. PMID- 25917980 TI - Discovery of Cushing's Syndrome After Bariatric Surgery: Multicenter Series of 16 Patients. AB - PURPOSE: The aim of this study is to demonstrate the importance of considering Cushing's syndrome (CS) as a potential etiology for weight gain and metabolic complications in patients undergoing bariatric surgery (BS). DESIGN AND METHODS: This is a retrospective chart review case series of patients (n = 16) with CS from five tertiary care centers in the USA who had BS. RESULTS: Median age at BS surgery was 35.5 years (median 2.5 years between BS and CS surgery). CS was not identified in 12 patients prior to BS. Four patients had CS surgery prior to BS, without recognition of recurrent or persistent CS until after BS. Median body mass index (BMI) values before BS, nadir after BS, prior to surgery for CS, and after surgery for CS were 47, 31, 38, and 35 kg/m(2), respectively. Prior to BS, 55 % of patients had hypertension and 55 % had diabetes mellitus. Only 17 % had resolution of hypertension or diabetes mellitus after BS. CONCLUSION: CS may be under-recognized in patients undergoing BS. Testing for CS should be performed prior to BS in patients with features of CS and in post-operative BS patients with persistent hypertension, diabetes mellitus, or excessive weight regain. Studies should be conducted to determine the role of prospective testing for CS in subjects considering BS. PMID- 25917982 TI - RXR/USP and EcR are critical for the regulation of reproduction and the control of JH biosynthesis in Diploptera punctata. AB - During development and reproduction the response to ecdysteroids is mediated by a heterodimeric receptor complex comprising the retinoid X receptor/ultraspiracle (RXR/USP) and the ecdysone receptor (EcR). Here, the role of these receptors in the endocrine control of reproduction is examined in the cockroach Diploptera punctata. We report the sequence of four DpRXR and three DpEcR splice variants, including the first description of a Drosophila EcRB2-like isoform in a hemimetabolous insect. DpRXR and DpEcR are broadly expressed in the tissues of adult females, with relatively high transcript levels in the corpora allata (CA), nervous tissue and ovary. Developmental profiling revealed an inverse correlation between DpRXR and DpEcR expression and the activity of the CA. RNAi-mediated depletion of DpRXR and DpEcR did not affect oocyte growth, but inhibited oviposition and impaired chorion formation. Retained oocytes exhibited a degenerating follicular epithelium and were slowly resorbed. Treated animals showed significantly higher rates of JH biosynthesis and a decrease in ecdysteroid titers at the end of vitellogenesis. Reduction of DpRXR and DpEcR expression resulted in an upregulation of genes involved in JH production and a downregulation of allatostatin receptor mRNA in the CA. Treatment with dsRNA also affected the expression of genes downstream of JH in target tissues including vitellogenin and Kruppel-homolog 1 as well as Broad-Complex, an early ecdysone response gene. Overall, results suggest that DpRXR and DpEcR are not required early in the reproductive cycle when events are JH-dependent, but do mediate critical ecdysteroid feedback to the CA late in the gonadotropic cycle. PMID- 25917981 TI - Bariatric Surgery and Non-Alcoholic Fatty Liver Disease: a Systematic Review of Liver Biochemistry and Histology. AB - BACKGROUND: Non-alcoholic fatty liver disease (NAFLD) is becoming a leading cause of global liver disease that is associated with the rising prevalence of obesity worldwide. There is now increasing clinical and mechanistic evidence reporting on the metabolic and weight loss effects of bariatric surgery on improving NAFLD in obese patients. OBJECTIVES: The aim of this paper was to quantify the effects of bariatric surgery on NAFLD by appraising the modulation between pre- and post operative liver enzyme levels (as markers of liver injury) and liver histology. METHODS: A systematic review of studies reporting pre-operative and post operative liver enzymes or liver histology was done in obese patients with NAFLD undergoing bariatric surgery. Data were meta-analysed using random-effects modelling. Subgroup analysis, quality scoring and risk of bias were assessed. RESULTS: Bariatric surgery is associated with a significant reduction in the weighted incidence of a number of histological features of NAFLD including steatosis (50.2 and 95 %CI of 35.5-65.0), fibrosis (11.9 and 95 %CI of 7.4-16.3 %), hepatocyte ballooning (67.7 and 95 %CI 56.9-78.5) and lobular inflammation (50.7 and 95 %CI 26.6-74.8 %). Surgery is also associated with a reduction in liver enzyme levels, with statistically significant reductions in ALT (11.36 u/l, 95 %CI 8.36-14.39), AST (3.91 u/l, 95 %CI 2.23-5.59), ALP (10.55 u/l, 95 %CI 4.40 16.70) and gamma-GT (18.39 u/l, 95 %CI 12.62-24.16). Heterogeneity in results was high. CONCLUSIONS: Bariatric surgery is associated with a significant improvement in both histological and biochemical markers of NAFLD. Future studies must focus on higher levels of evidence to better identify the benefits of bariatric surgery on liver disease in order to enhance future treatment strategies in the management of NAFLD. PMID- 25917983 TI - Neonatal aortic dilatation secondary to vitamin A deficiency. AB - We report on a term neonate with unexplained respiratory distress, dilatation of the descending aorta, and low serum retinol concentration. The respiratory distress did not respond to conventional medical management and persisted for 22 days requiring an inspired oxygen fraction of 0.4 to 0.5 to maintain adequate arterial oxygen saturation. One week after intramuscular vitamin A therapy, the respiratory distress and requirement for supplementary oxygen resolved. Dilatation of the distal aorta resolved at 7 weeks of age. An association between vitamin A deficiency and aortic dilatation has previously been described in rats, but the association in humans has rarely been reported. We suggest that unexplained neonatal respiratory distress and a dilated aorta should prompt suspicion of vitamin A deficiency. An underlying infective or inflammatory process may give rise to a falsely low serum retinol concentration. Serum retinol and retinol binding protein concentrations in both the mother and infant should be used to guide vitamin A status, treatment, and subsequent response. PMID- 25917984 TI - Heart rates in hospitalized children by age and body temperature. AB - BACKGROUND AND OBJECTIVES: Heart rate (HR) is frequently used by clinicians in the hospital to assess a patient's severity of illness and make treatment decisions. We sought to develop percentiles that characterize the relationship of expected HR by age and body temperature in hospitalized children and to compare these percentiles with published references in both primary care and emergency department (ED) settings. METHODS: Vital sign data were extracted from electronic health records of inpatients <18 years of age at 2 large freestanding children's hospitals from July 2011 to June 2012. We selected up to 10 HR-temperature measurement pairs from each admission. Measurements from 60% of patients were used to derive the percentile curves, with the remainder used for validation. We compared our upper percentiles with published references in primary care and ED settings. RESULTS: We used 60,863 observations to derive the percentiles. Overall, an increase in body temperature of 1 degrees C was associated with an increase of ~ 10 beats per minute in HR, although there were variations across age and temperature ranges. For infants and young children, our upper percentiles were lower than in primary care and ED settings. For school-age children, our upper percentiles were higher. CONCLUSIONS: We characterized expected HR by age and body temperature in hospitalized children. These percentiles differed from references in primary care and ED settings. Additional research is needed to evaluate the performance of these percentiles for the identification of children who would benefit from further evaluation or intervention for tachycardia. PMID- 25917985 TI - Neurodevelopmental outcome in children with congenital heart disease: a work in progress. PMID- 25917986 TI - Head lice. AB - Head lice infestation is associated with limited morbidity but causes a high level of anxiety among parents of school-aged children. Since the 2010 clinical report on head lice was published by the American Academy of Pediatrics, newer medications have been approved for the treatment of head lice. This revised clinical report clarifies current diagnosis and treatment protocols and provides guidance for the management of children with head lice in the school setting. PMID- 25917987 TI - PRES in Children Undergoing Hematopoietic Stem Cell or Solid Organ Transplantation. AB - Posterior reversible encephalopathy syndrome (PRES) is a clinical neuroradiologic entity that is becoming increasingly well known and documented in pediatrics. It is characterized by a variable association of seizures, headache, vomiting, altered mental status, visual disturbances, and seizures, as well as imaging suggesting white-gray matter edema involving the posterior regions of the central nervous system in most cases. The pathophysiology of PRES remains unclear. Although PRES has been associated with a widespread range of clinical conditions, namely infections, adverse drug events, autoimmune diseases, and many others, its onset after hematopoietic stem cell and solid organ transplantation remains the most commonly reported. Historically, PRES has proved to be generally reversible and associated with good clinical outcomes; however, severe complications, sometimes life-threatening, can also occur. Most reported cases of childhood PRES after hematopoietic stem cell or solid organ transplantation have been case reports or series across a broad spectrum of different transplant settings, and no clear consensus exists regarding how best to manage the syndrome. Thus, in this article, we provide a comprehensive review of the pathophysiological, clinical, and diagnostic aspects of PRES in children, with a specific focus on the transplant scenario. Differential diagnoses with other neurologic complications after pediatric transplantation are reviewed, and crucial issues in the management of PRES and the development of future research are ultimately addressed. PMID- 25917988 TI - The evaluation of suspected child physical abuse. AB - Child physical abuse is an important cause of pediatric morbidity and mortality and is associated with major physical and mental health problems that can extend into adulthood. Pediatricians are in a unique position to identify and prevent child abuse, and this clinical report provides guidance to the practitioner regarding indicators and evaluation of suspected physical abuse of children. The role of the physician may include identifying abused children with suspicious injuries who present for care, reporting suspected abuse to the child protection agency for investigation, supporting families who are affected by child abuse, coordinating with other professionals and community agencies to provide immediate and long-term treatment to victimized children, providing court testimony when necessary, providing preventive care and anticipatory guidance in the office, and advocating for policies and programs that support families and protect vulnerable children. PMID- 25917989 TI - Maternal prepregnancy body mass index and child psychosocial development at 6 years of age. AB - BACKGROUND: Both obesity and developmental disabilities have increased in recent decades. Limited studies suggest associations between maternal prepregnancy obesity and child neurodevelopment. METHODS: The Infant Feeding Practices Study II, a US nationally distributed longitudinal study of maternal health and infant health and feeding practices, was conducted from 2005 to 2007. In 2012, mothers were recontacted for information on their children's health and development. We examined associations between maternal prepregnancy BMI and child psychosocial development in 1311 mother-child pairs included in this follow-up study. Children's development was assessed by maternal report of child psychosocial difficulties from the Strengths and Difficulties Questionnaire, past developmental diagnoses, and receipt of special needs services. RESULTS: Adjusting for sociodemographic factors, children of obese class II/III mothers (BMI >35.0) had increased odds of emotional symptoms (adjusted odds ratio [aOR] 2.24; 95% confidence interval [CI], 1.27-3.98), peer problems (aOR 2.07; 95% CI, 1.26-3.40), total psychosocial difficulties (aOR 2.17; 95% CI, 1.24-3.77), attention-deficit/hyperactivity disorder diagnosis (aOR 4.55; 95% CI, 1.80 11.46), autism or developmental delay diagnosis (aOR 3.13; 95% CI, 1.10-8.94), receipt of speech language therapy (aOR 1.93; 95% CI, 1.18-3.15), receipt of psychological services (aOR 2.27; 95% CI, 1.09-4.73), and receipt of any special needs service (aOR 1.99; 95% CI, 1.33-2.97) compared with children of normal weight mothers (BMI 18.5-24.9). Adjustment for potential causal pathway factors including pregnancy weight gain, gestational diabetes, breastfeeding duration, postpartum depression, and child's birth weight did not substantially affect most estimates. CONCLUSIONS: Children whose mothers were severely obese before pregnancy had increased risk for adverse developmental outcomes. PMID- 25917991 TI - The early benefits of human papillomavirus vaccination on cervical dysplasia and anogenital warts. AB - BACKGROUND: Despite widespread promotion of quadrivalent human papillomavirus (qHPV) vaccination for young girls, there is limited information on the vaccine's real-world effectiveness and none on the effectiveness of qHPV vaccination programs. We assessed the impact of the qHPV vaccine and Ontario's grade 8 qHPV vaccination program on cervical dysplasia and anogenital warts (AGW). METHODS: By using administrative health databases of Ontario, Canada, we identified a population-based retrospective cohort of girls in grade 8 before (2005/2006 2006/2007) and after (2007/2008-2008/2009) program implementation. Vaccine exposure was ascertained in grades 8 to 9 and outcomes in grades 10 to 12. A quasi-experimental approach known as regression discontinuity was used to estimate absolute risk differences (RDs), relative risks (RRs), and 95% confidence intervals (CIs) attributable to vaccination and program eligibility (intention-to-treat analysis). RESULTS: The cohort comprised 131,781 ineligible and 128,712 eligible girls (n = 260,493). We identified 2436 cases of dysplasia and 400 cases of AGW. Vaccination significantly reduced the incidence of dysplasia by 5.70 per 1000 girls (95% CI -9.91 to -1.50), corresponding to a relative reduction of 44% (RR 0.56; 95% CI 0.36 to 0.87). Program eligibility also had a significant protective effect on dysplasia: RD -2.32/1000 (95% CI 4.02 to -0.61); RR 0.79 (95% CI 0.66 to 0.94). Results suggested decreases in AGW attributable to vaccination (RD -0.83/1000, 95% CI -2.54 to 0.88; RR 0.57, 95% CI 0.20 to 1.58) and program eligibility (RD -0.34/1000, 95% CI -1.03 to 0.36; RR 0.81, 95% CI 0.52 to 1.25). CONCLUSIONS: This study provides strong evidence of the early benefits of qHPV vaccination among girls aged 14 to 17 years, offering additional justification for not delaying vaccination. PMID- 25917990 TI - First Use of a Serogroup B Meningococcal Vaccine in the US in Response to a University Outbreak. AB - BACKGROUND: In 2013-2014, an outbreak of serogroup B meningococcal disease occurred among persons linked to a New Jersey university (University A). In the absence of a licensed serogroup B meningococcal (MenB) vaccine in the United States, the Food and Drug Administration authorized use of an investigational MenB vaccine to control the outbreak. An investigation of the outbreak and response was undertaken to determine the population at risk and assess vaccination coverage. METHODS: The epidemiologic investigation relied on compilation and review of case and population data, laboratory typing of meningococcal isolates, and unstructured interviews with university staff. Vaccination coverage data were collected during the vaccination campaign held under an expanded-access Investigational New Drug protocol. RESULTS: Between March 25, 2013, and March 10, 2014, 9 cases of serogroup B meningococcal disease occurred in persons linked to University A. Laboratory typing results were identical for all 8 isolates available. Through May 14, 2014, 89.1% coverage with the 2-dose vaccination series was achieved in the target population. From the initiation of MenB vaccination through February 1, 2015, no additional cases of serogroup B meningococcal disease occurred in University A students. However, the ninth case occurred in March 2014 in an unvaccinated close contact of University A students. CONCLUSIONS: No serogroup B meningococcal disease cases occurred in persons who received 1 or more doses of 4CMenB vaccine, suggesting 4CMenB may have protected vaccinated individuals from disease. However, the ninth case demonstrates that carriage of serogroup B Neisseria meningitidis among vaccinated persons was not eliminated. PMID- 25917992 TI - Oseltamivir-warfarin interaction in hypoplastic left heart syndrome: case report and review. AB - An 8-year-old boy with hypoplastic left heart syndrome with a previous history of thrombosis within the inferior vena cava receiving stable warfarin dosing for anticoagulation was diagnosed with influenza B. He was subsequently placed on oseltamivir therapy according to the Centers for Disease Control and Prevention clinical practice guidelines. During the hospitalization, his international normalized ratio steadily increased to supratherapeutic levels and returned to baseline after discontinuation of oseltamivir therapy. This case represents a drug-drug interaction that has not been previously reported in children or adolescents. An extensive review of the pharmacokinetic and pharmacodynamic literature did not uncover a definitive etiology for this interaction. However, several undefined aspects in each drug's disposition pathway need further elucidation. Until this interaction is understood, caution is warranted, and close monitoring of the international normalized ratio should be performed in all patients prescribed oseltamivir concomitantly with warfarin. PMID- 25917993 TI - Hospital stay for healthy term newborn infants. AB - The hospital stay of the mother and her healthy term newborn infant should be long enough to allow identification of problems and to ensure that the mother is sufficiently recovered and prepared to care for herself and her newborn at home. The length of stay should be based on the unique characteristics of each mother infant dyad, including the health of the mother, the health and stability of the newborn, the ability and confidence of the mother to care for herself and her newborn, the adequacy of support systems at home, and access to appropriate follow-up care in a medical home. Input from the mother and her obstetrical care provider should be considered before a decision to discharge a newborn is made, and all efforts should be made to keep a mother and her newborn together to ensure simultaneous discharge. PMID- 25917994 TI - A 2-year-old with 4 weeks of daily fever. AB - A 2-year-old female presents for evaluation of 4 weeks of daily fevers. When the fevers began, she had mild upper respiratory tract symptoms, which quickly resolved. The fevers persisted, however, with a maximum of 40 degrees C. The child's review of symptoms was significant for a 1-kg weight loss over the past month. Ten months before presentation, she had moved from Saudi Arabia with her family. One week before the onset of symptoms, she had visited a petting zoo. During episodes of fever, the patient was ill-appearing and had an elevated heart rate and respiratory rate. On examination, she was found to be thin, febrile, tachycardic, and with scattered lymphadenopathy. Results of laboratory tests were remarkable for an elevated white blood cell count of 16,100 cells per uL with a neutrophilic predominance. Erythrocyte sedimentation rate (ESR) and C-reactive protein (CRP) were elevated at 99 mm/h and 27 mg/dL, respectively. A chest radiograph indicated a small amount of fluid in the interlobar fissures. Our expert panel examines her case, offers a definition of fever of unknown origin, and makes diagnostic considerations. PMID- 25917995 TI - Pediatric appropriate use criteria for echocardiography: implications for clinical practice. PMID- 25917997 TI - No evidence for consistent long-term growth stimulation of 13 tropical tree species: results from tree-ring analysis. AB - The important role of tropical forests in the global carbon cycle makes it imperative to assess changes in their carbon dynamics for accurate projections of future climate-vegetation feedbacks. Forest monitoring studies conducted over the past decades have found evidence for both increasing and decreasing growth rates of tropical forest trees. The limited duration of these studies restrained analyses to decadal scales, and it is still unclear whether growth changes occurred over longer time scales, as would be expected if CO2 -fertilization stimulated tree growth. Furthermore, studies have so far dealt with changes in biomass gain at forest-stand level, but insights into species-specific growth changes - that ultimately determine community-level responses - are lacking. Here, we analyse species-specific growth changes on a centennial scale, using growth data from tree-ring analysis for 13 tree species (~1300 trees), from three sites distributed across the tropics. We used an established (regional curve standardization) and a new (size-class isolation) growth-trend detection method and explicitly assessed the influence of biases on the trend detection. In addition, we assessed whether aggregated trends were present within and across study sites. We found evidence for decreasing growth rates over time for 8-10 species, whereas increases were noted for two species and one showed no trend. Additionally, we found evidence for weak aggregated growth decreases at the site in Thailand and when analysing all sites simultaneously. The observed growth reductions suggest deteriorating growth conditions, perhaps due to warming. However, other causes cannot be excluded, such as recovery from large-scale disturbances or changing forest dynamics. Our findings contrast growth patterns that would be expected if elevated CO2 would stimulate tree growth. These results suggest that commonly assumed growth increases of tropical forests may not occur, which could lead to erroneous predictions of carbon dynamics of tropical forest under climate change. PMID- 25917998 TI - Does levothyroxine administration impact parathyroid localization? AB - BACKGROUND: Proper localization is crucial in performing minimally invasive parathyroidectomy for primary hyperparathyroidism. Ultrasonography (US) and Tc 99m sestamibi (MIBI) scintigraphy are common methods used for localization. As the appearance and activity of the thyroid gland may impact parathyroid localization, the purpose of this study was to determine how exogenous use of the thyroid hormone, levothyroxine (LT), affects parathyroid localization. METHODS: Adult patients with non-familial primary hyperparathyroidism who underwent initial parathyroidectomy from 2000-2014 were retrospectively identified. LT (+LT) and non-LT (-LT) patients were matched 1:3 based on age, gender, goiter status, and preoperative parathyroid hormone levels. Subgroup analysis was performed on patients previously treated with radioactive iodine and patients undergoing single adenoma resection. RESULTS: Of the 1737 patients that met inclusion criteria, 286 were on LT at the time of their parathyroid localization scan. Use of LT did not impact the percentage of correct MIBI localization scans when compared with -LT patients (P = 0.83). Interestingly, use of LT significantly hindered localization by US in comparison with the -LT group (48.4 versus 62.2%, P < 0.01). When examining only patients where a single upper gland was removed, the +LT group was less likely to have a correct US compared with the -LT group (50 versus 72.8%, P < 0.01). However, there was no difference in US accuracy for patients who only had a single lower gland removed (P = 0.51). CONCLUSIONS: Exogenous LT is associated with impaired parathyroid localization with US but not MIBI. Surgeons should be aware of localization efficiency for this subset of patients in the era of personalized medicine and cost effectiveness. PMID- 25917999 TI - Economic impact of bleeding complications after mastectomy. AB - BACKGROUND: We sought to determine the incidence of postmastectomy bleeding, identify bleeding predictors, and evaluate the economic impact. METHODS: Using the 2011 Healthcare Cost and Utilization Project-Nationwide Inpatient Sample, hospital discharges for a primary diagnosis of breast cancer were extracted using International Classification of Diseases, Ninth Revision, Clinical Modification procedure codes 85.34-85.48 for mastectomy and diagnosis codes 174.0-174.9 for breast cancer. Discharges with postoperative bleeding were identified using International Classification of Diseases, Ninth Revision, Clinical Modification diagnosis codes 998.11 and 998.12. Discharges with male gender or a history of coagulation disorders were excluded. Bleeding complication rates and reoperation rates were assessed. Predictors and the impact of bleeding on length of stay and hospital costs were determined using regression analysis and projected to the national level. RESULTS: A total of 7907 discharges met inclusion criteria; 201 had bleeding complications (2.54%), with 42 cases requiring reoperation. On univariate analysis, the presence of congestive heart failure (CHF), obesity, diabetes, chronic pulmonary disease, and the absence of concomitant reconstruction were associated with increased bleeding events. On multivariate analysis, only the presence of CHF remained as a significant predictor of bleeding complications (odds ratio [95% confidence interval], 2.45, [1.25-4.92], P = 0.009). On average, bleeding complications extended the length of stay by 1.3 d (P < 0.0001) while increasing hospital costs by $5495 per admission (P < 0.0001). Projected to a national level, bleeding complications accounted for an additional 1254 d of hospital care at a cost exceeding $5.3 million. CONCLUSIONS: Postmastectomy bleeding complications had an incidence of 2.54%, with CHF the only independent predictor identified. Such bleeding events, although infrequent, are associated with substantial economic costs. PMID- 25917996 TI - Neurodevelopmental outcomes after cardiac surgery in infancy. AB - BACKGROUND: Neurodevelopmental disability is the most common complication for survivors of surgery for congenital heart disease (CHD). METHODS: We analyzed individual participant data from studies of children evaluated with the Bayley Scales of Infant Development, second edition, after cardiac surgery between 1996 and 2009. The primary outcome was Psychomotor Development Index (PDI), and the secondary outcome was Mental Development Index (MDI). RESULTS: Among 1770 subjects from 22 institutions, assessed at age 14.5 +/- 3.7 months, PDIs and MDIs (77.6 +/- 18.8 and 88.2 +/- 16.7, respectively) were lower than normative means (each P < .001). Later calendar year of birth was associated with an increased proportion of high-risk infants (complexity of CHD and prevalence of genetic/extracardiac anomalies). After adjustment for center and type of CHD, later year of birth was not significantly associated with better PDI or MDI. Risk factors for lower PDI were lower birth weight, white race, and presence of a genetic/extracardiac anomaly (all P <= .01). After adjustment for these factors, PDIs improved over time (0.39 points/year, 95% confidence interval 0.01 to 0.78; P = .045). Risk factors for lower MDI were lower birth weight, male gender, less maternal education, and presence of a genetic/extracardiac anomaly (all P < .001). After adjustment for these factors, MDIs improved over time (0.38 points/year, 95% confidence interval 0.05 to 0.71; P = .02). CONCLUSIONS: Early neurodevelopmental outcomes for survivors of cardiac surgery in infancy have improved modestly over time, but only after adjustment for innate patient risk factors. As more high-risk CHD infants undergo cardiac surgery and survive, a growing population will require significant societal resources. PMID- 25918000 TI - Bipedicle-conjoined perforator flaps in breast reconstruction. AB - BACKGROUND: For some patients seeking autologous breast reconstruction, there may be insufficient abdominal skin and soft tissue to reconstruct an adequately sized breast. Perfusion from a single-pedicle deep inferior epigastric perforator artery flap has a high degree of variability across the midline, and this further limits perfusion. We have found that bipedicle-conjoined abdominal perforator flaps are a novel and reliable technique for reconstruction in these women, and this study examines our experience. MATERIALS AND METHODS: A retrospective review was performed over a 2-y period of bipedicle-conjoined abdominal perforator flaps in 28 patients. For each reconstruction, the pedicle of one flap was anastomosed to the anterograde internal mammary artery vessels and the pedicle of the second flap to a side branch of the primary flap or the retrograde internal mammary vessels. RESULTS: Mean age and body mass index were 50.2 y (standard deviation, 8.0) and 25.9 kg/m(2) (standard deviation, 2.8), respectively. In total, 15 patients (53.6%) received radiation therapy before surgery. There were no flap losses; fat necrosis was found in one flap (3.2%). The large contiguous skin island of the bipedicle-conjoined deep inferior epigastric perforator flaps allowed for extensive replacement of damaged or absent breast skin when necessary. Aesthetically satisfactory results were achieved in all patients. CONCLUSIONS: Bipedicle-conjoined abdominal perforator flaps represent a novel technique in select patients seeking breast reconstruction. The added complexity was safe and reliable in this series of patients. Compared to unipedicle flaps, the increased skin and volume allow greater flexibility to achieve the desired shape and projection. PMID- 25918001 TI - Surgical management of bronchopulmonary malformations. AB - BACKGROUND: Bronchopulmonary malformations (BPM) are rare conditions, which typically arise below the carina and can result in significant morbidity (infection and/or hemorrhage) and mortality (respiratory failure). MATERIALS AND METHODS: All children with BPM surgically treated from 2001-2014 at a tertiary care children's hospital were identified. Patient demographics, surgical indications, procedure type, estimated blood loss, pathology, perioperative complications, length of stay, and outcomes were analyzed. RESULTS: A total of 41 BPM patients underwent surgery with 98% overall survival (one abdominal BPM expired) but 100% for thoracic lesions. Resections were performed thoracoscopically (37%), thoracoscopy converted to open (22%), and via thoracotomy (37%). Poor visualization (67%) or inability to tolerate single lung ventilation (33%) led to conversions. No conversions resulted from hemorrhage or received blood transfusions. Patients with prenatally diagnosed BPM were more likely to undergo thoracoscopic surgery (odds ratio [OR], 18.2) versus nonprenatally diagnosed, P = 0.002. Open/converted patients had longer chest tube days (6.2) versus thoracoscopic (2.9), P = 0.048. Additionally, respiratory distress was a more common indication in patients aged <4 mo (OR, 28.0) versus >=4 mo and <6 kg (OR, 40.5) versus >=6 kg, P < 0.001. Open resections were more common in patients aged <4 mo (OR, 26.3) versus >=4 mo, P = 0.002. Operative time was shorter and estimated blood loss (mL/kg) was greater for <6 versus >=6 kg, P < 0.05. CONCLUSIONS: BPM resections have high overall survival. Chest tube days are shorter among thoracoscopic patients, but conversion to thoracotomy can avoid hemorrhage and need for transfusion. Size and respiratory distress limit use of thoracoscopy in young infants with BPM. PMID- 25918002 TI - Mechanism and mortality of pediatric aortic injuries. AB - BACKGROUND: Aortic injuries are rare, but have a high mortality rate in children and adolescents. We sought to investigate mechanisms of injury and predictors of survival. MATERIALS AND METHODS: The Kids' Inpatient Database (1997-2009) was used to identify cases of thoracic and abdominal aortic injury (International Classification of Diseases, ninth Revision, Clinical Modification codes 901.0, 902.0) occurring in children aged <20 y. Bivariate and risk-adjusted multivariate analyses were used to reveal associated diagnoses and procedures and to identify predictors of in-hospital mortality, respectively. Cases were limited to emergent or urgent admissions. RESULTS: A total of 468 cases were identified. Survival was 65% overall, 63% for boys and 68% for girls. The most common mechanism of injury was motor vehicle-related (77%), followed by other penetrating trauma (10%) and firearm injury (8%). On multivariate modeling, boys (odds ratio, 0.15 [95% confidence interval, 0.05, 0.45]) and Hispanic children (0.17 [0.05, 0.60]) had lower associated mortality versus girls and Caucasians, respectively. Self-pay patients (6.47 [1.94, 21.6]) had higher mortality versus privately insured patients. Children in the fourth income quartile had lower mortality versus all income quartile patients. Patients admitted to urban nonteaching hospitals (0.15 [0.04, 0.59]) had lower mortality versus those admitted to urban teaching hospitals. Patients with traumatic shock (47.9 [12.3, 187]) or necessitating exploratory laparotomy (13.7 [2.06, 91.4]) had the highest associated mortality overall. Survival increased over the study period between 1997 and 2009. CONCLUSIONS: Motor vehicle-related injuries are the predominant mechanisms of aortic injury in the pediatric population. Gender, race, payer status, income quartile, and hospital type, along with associated procedures and diagnoses, are significant determinants of mortality on multivariate analysis. PMID- 25918003 TI - Perception does not equal reality for resident vascular trauma skills. AB - BACKGROUND: Experience with the management of vascular trauma by senior surgical residents is increasingly limited. When queried about their understanding of anatomy and ability to perform specific vascular exposures, residents express a moderately high level of confidence. We hypothesized that this perception does not equal reality. METHODS: A total of 42 senior surgical residents participating in an ongoing validation study of the Advanced Surgical Skills for Exposures in Trauma course were asked to self-assess their baseline (precourse) confidence of their understanding of the anatomy required to perform and their ability to perform exposure and control of the axillary, brachial, and femoral arteries, as well as lower extremity fasciotomy using a 5-point Likert scale. Residents then performed the four procedures on a fresh cadaver model and were scored in real time by experts using a global assessment of anatomic knowledge and readiness to perform." The Student t-test was used with alpha set at P < 0.05. RESULTS: Residents consistently rated their understanding of anatomy and their ability to perform the procedures significantly higher than expert evaluator ultimately scored them. Evaluators also deemed that residents would be unable to perform without help 65%-86% of the time. CONCLUSIONS: Senior residents are ill-prepared to perform the procedures studied and have an unwarranted confidence in their knowledge and abilities. Perception clearly does not equal reality in preparing these trainees to perform as advertized. The low global scores for anatomy and performance should be a wake-up call for surgical educators prompting curricular reform and evaluation. PMID- 25918004 TI - Giant omphaloceles: surgical management and perinatal outcomes. AB - BACKGROUND: The purpose of this study was to describe the current management and outcomes of infants with omphalocele. METHODS: The medical records of all patients treated for omphalocele at a large children's hospital from January, 2003-February, 2014 were reviewed. Patients were classified as having an isolated omphalocele or omphalocele with minor or major associated anomalies. Prenatal data collected included fetal magnetic resonance imaging-based observed-to expected total fetal lung volumes. Giant omphalocele (GO) was defined as >50% of liver in the omphalocele sac. RESULTS: Of 95 patients, 59 presented prenatally and had comprehensive fetal center evaluation. Of 82 live-born infants, 21 had chromosomal and 25 had major associated anomalies. No live-born baby with an isolated defect (n = 19) died, whereas mortality was 41% and 17% for those with major and minor anomalies, respectively (P = 0.006). Infants with major anomalies had significantly longer median length of intubation (36 versus 0 versus 0 d; P = 0.04) and hospital stay (157 versus 28.5 versus 18 d; P < 0.001) compared with those with minor or no anomalies. Of 40 infants with GO, the majority (85%) were managed surgically by delayed closure with a median age at repair of 10 mo (range, 3.4-23.6 mo). Six-month survival was 80%. None of the delayed repair patients required a later operative revision, whereas 2 of 5 with early repair did. CONCLUSIONS: The presence of associated anomalies is the strongest predictor of morbidity and mortality in fetuses or neonates with omphalocele. In patients with GO, delayed closure is associated with good outcomes, but larger, prospective studies comparing delayed to early closure are needed to determine the optimal timing of repair. PMID- 25918005 TI - Treatment delays of colon cancer in a safety-net hospital system. AB - BACKGROUND: Disparities in colon cancer survival have been reported to result from advanced stage at diagnosis and delayed therapy. We hypothesized that delays in treatment among medically underserved patients occur as a result of system level barriers in a safety-net hospital system. MATERIALS AND METHODS: Retrospective review and analysis of colon cancer patients treated in a large safety-net hospital system between May 2008 and May 2012. Data were collected on demographics, stage at diagnosis, time to surgery, time to adjuvant chemotherapy, and vital status. Regression analyses were performed to determine predictors of delays and failure to receive therapy. RESULTS: Of 248 patients treated for colon cancer, 56% (n = 140) had advanced disease at the time of presentation; furthermore, 29.1% of all colectomies for colon cancer were performed on an urgent or emergent basis. Thirty-six patients with stage III and IV disease did not receive chemotherapy (26%). Race, age, gender, and hospice care did not predict receipt of chemotherapy or delays to treatment. Patients with stage I colon cancer had a significantly longer interval between diagnosis and elective surgery when compared with patients with stage II, III, and IV colon cancer, with only 10% (n = 3) undergoing resection sooner than 6 wk after diagnosis. CONCLUSIONS: One in three patients diagnosed with colon cancer in a large safety net hospital system require urgent or emergent surgery, and one in two present with advanced disease. Reducing disparities should focus on earlier diagnosis of colon cancer and improving access to surgical specialists. PMID- 25918006 TI - Technical characteristics can make the difference in a surgical linear stapler. Or not? AB - BACKGROUND: Anastomotic leak (AL) after gastrointestinal surgery is a severe complication associated with relevant short- and long-term sequelae. Most of the anastomosis are currently performed with a surgical stapler that is required to have appropriate characteristics to guarantee good performances. The aim of our study was to evaluate, in the laboratory, pressure resistance and tensile strength of anastomosis performed with different surgical linear staplers, available in the market. MATERIALS AND METHODS: We have been studying three linear staplers, with diverse cartridges and staple heights, of three different companies, used for gastrointestinal anastomosis and gastric or intestinal closure. We performed 50 anastomosis for each device, with the pertinent different cartridges, on fresh pig intestine, for a total of 350 anastomosis, then injected saline solution and recorded the pressure that provokes a leak on the staple line. There were no statistically significant differences between the mean pressure necessary to induce an AL in the various instruments (P > 0.05). For studying the tensile strength, we performed a total of 350 anastomosis with the different linear staplers on a special strong paper (Tyvek), then recorded the maximal tensile force that could open the anastomosis. RESULTS: There were no statistically significant differences between the different staplers about the strength necessary to open the staple line (P > 0.05). CONCLUSIONS: we demonstrated that different linear staplers of three companies available in the market give comparable anastomotic pressure resistance and tensile strength. This might suggest that small dissimilarities between different devices are not involved, at least as major parameters, in AL etiology. PMID- 25918007 TI - Response to letter to the editor on the article "Propofol increases preload dependency in septic shock patients". PMID- 25918008 TI - Does obesity affect outcomes of adult burn patients? AB - BACKGROUND: Obesity negatively affects outcomes after trauma and surgery; results after burns are more limited and controversial. The purpose of this study was to determine the effect of obesity on clinical and economic outcomes after thermal injury. METHODS: The National Inpatient Sample was queried for adults from 2005 2009 with International Classification of Diseases-9 codes for burn injury. Demographics and clinical outcomes of obese and nonobese cohorts were compared. Univariate and multivariate analysis using logistic regression models were performed. Data are expressed as median (interquartile range) or mean +/- standard deviation and compared at P < 0.05. RESULTS: In 14,602 patients, 3.3% were obese (body mass index >=30 kg/m(2)). The rate of obesity increased significantly by year (P < 0.001). Univariate analysis revealed significant differences between obese and nonobese patients in incidence of wound infection (7.2% versus 5.0%), urinary tract infection (7.2% versus 4.6%), deep vein thrombosis in total body surface area (TBSA) >=10% (3.1% versus 1.1%), pulmonary embolism in TBSA >=10% (2.3% versus 0.6%), length of stay [6 d (8) versus 5 d (9)], and hospital costs ($10,122.12 [$18,074.72] versus $7892.07 [$17,191.96]) (all P < 0.05). Death occurred less frequently in the obese group (1.9% versus 4%, P = 0.021). Significant predictors of grouped adverse events (urinary tract infection, wound infection, deep vein thrombosis, and pulmonary embolism) on multivariate analysis include obesity, TBSA >=20%, age, and black race (all P <= 0.05). CONCLUSIONS: Obesity is an independent predictor of adverse events after burn injury; however, obesity is associated with decreased mortality. Our findings highlight the potential clinical and economic impact of the obesity epidemic on burn patients nationwide. PMID- 25918009 TI - Difluoromethylation and gem-difluorocyclopropenation with difluorocarbene generated by decarboxylation. AB - Difluoromethylation of the activated X-H bond (X = N, O and S) and aliphatic thiols, and gem-difluorocyclopropenation of alkynes with difluorocarbene generated in situ from difluoromethylene phosphobetaine (Ph3P(+)CF2CO2(-)) by decarboxylation occurred smoothly without the presence of any base or other additives. PMID- 25918010 TI - The HBx oncoprotein of hepatitis B virus engages nucleophosmin to promote rDNA transcription and cellular proliferation. AB - The pleiotropic HBx oncoprotein of hepatitis B virus is well known to promote the expression of ribosomal RNAs and several host proteins that are known to support the development and progression of hepatocellular carcinoma (HCC). While overexpression of the nucleolar phosphoprotein, nucleophosmin (NPM), correlates with HCC progression, its upregulation by viral HBx and the resulting impact on perturbed nucleolar functions remain enigmatic. The present study shows that HBx up-regulates NPM levels and hijacks its functions to promote cellular proliferation. We found that HBx expression stabilizes NPM through post translational modifications. Enhanced CDK2-mediated phosphorylation of NPM at Thr199 upon HBx expression prevented its proteolytic cleavage and provided resistance to apoptosis. Further, HBx directly interacted with the C-terminal domain of NPM and got translocated into the nucleolus where it facilitated the recruitment of RNA polymerase I transcriptional machinery onto the rDNA promoter. Our results indicate that HBx enhances rDNA transcription via a novel regulatory mechanism involving acetylation of NPM and the subsequent depletion of histones from the rDNA promoter. Enhanced production of ribosomal RNA resulting from co expression of HBx and NPM promoted ribosome biogenesis, cellular proliferation and transformation. Taken together, our study strongly suggests an important role of NPM in mediating the oncogenic effects of HBx and the corresponding nucleolar perturbations induced by this viral oncoprotein. PMID- 25918011 TI - Endocytosis of ABCG2 drug transporter caused by binding of 5D3 antibody: trafficking mechanisms and intracellular fate. AB - ABCG2, a metabolite and xenobiotic transporter located at the plasma membrane (predominantly in barrier tissues and progenitor cells), undergoes a direct progressive endocytosis process from plasma membrane to intracellular compartments upon binding of 5D3 monoclonal antibody. This antibody is specific to an external epitope on the protein molecule and locks it in a discrete conformation within its activity cycle, presumably providing a structural trigger for the observed internalization phenomenon. Using routine and novel assays, we show that ABCG2 is endocytosed by a mixed mechanism: partially via a rapid, clathrin-dependent pathway and partially in a cholesterol-dependent, caveolin independent manner. While the internalization process is entirely dynamin dependent and converges initially at the early endosome, subsequent intracellular fate of ABCG2 is again twofold: endocytosis leads to only partial lysosomal degradation, while a significant fraction of the protein is retained in a post endosomal compartment with the possibility of at least partial recycling back to the cell surface. This externally triggered, conformation-related trafficking pathway may serve as a general regulatory paradigm for membrane transporters, and its discovery was made possible thanks to consistent application of quantitative methods. PMID- 25918012 TI - Graves' hyperthyroidism-induced psychosis in a patient with periventricular nodular heterotopia. PMID- 25918013 TI - [Persistence of hepatitis A virus antibodies after primary immunization and response to revaccination in children and adolescents with perinatal HIV exposure]. AB - OBJECTIVE: To assess possible factors associated with the loss of antibodies to hepatitis A 7 years after the primary immunization in children of HIV-infected mothers and the response to revaccination in patients seronegative for hepatitis A. METHODS: Quantification of HAV antibodies by electrochemiluminescence was performed in 39 adolescents followed up at the Pediatric Aids Clinic of Federal University of Sao Paulo (Unifesp): 29 HIV-infected (HIVgroup) (median age: 12.8 years) and 10 HIV-exposed but non-infected (ENI group) (median age: 13.4 years). All of them received two doses of HAV vaccine (Havrix((r))) in 2002. RESULTS: The median age at primary immunization (PI) was 5.4 years for HIV group and 6.5 years for ENI group. All children, from both groups, had antibodies to HAV >20 mIU/mL after PI. Seven years later, the ENI group showed a median concentration of antibodies = 253.5 mIU/mL, while the HIV group = 113.0 mIU/mL (Mann-Whitney test, p=0.085). All ENI group and 23/29 (79.3%) from HIV group mantained HAV antibodies 7 years after PI. The levels of hepatitis A antibodies in the primary vaccination were the only factor independently associated with maintaining these antibodies for 7 years. The group that lost HAV seropositivity was revaccinated and 83.3% (5/6) responded with antibodies >20 mUI/mL. CONCLUSIONS: The antibodies levels acquired in the primary vaccination in the HIV group were the main factor associated with antibodies loss after HAV immunization. PMID- 25918015 TI - Children's beliefs in reciprocation of biases and flexibility. AB - Children display positive and negative biases based on peers' attractiveness, gender, and race, but it is unclear whether children who associate positive attributes with certain peers also believe those peers think positively of them. In each domain (attractiveness, gender, and race), we measured 3- to 11-year olds' (N = 102) biases and flexibility and their beliefs in reciprocity of bias and flexibility by asking who would think positively of them. Children could choose one of two unfamiliar peers (forced choice assessment) or had the additional options of choosing both peers or neither peer (non-forced choice assessment). We found that children often displayed beliefs in reciprocation, with beliefs in positive bias reciprocation from attractive girls showing the largest effect sizes. These beliefs were significantly correlated with and were predictive of children's positive and negative biases and flexibility. The duality of children's beliefs may contribute to strengthening their biases and segregating social groups. PMID- 25918018 TI - A lysine-to-arginine mutation on NEDD8 markedly reduces the activity of cullin RING E3 ligase through the impairment of neddylation cascades. AB - Neural-precursor-cell-expressed developmentally down-regulated 8 (NEDD8) is a ubiquitin-like modifier, which forms covalent conjugates on lysines of its substrates. This post-translational modification, neddylation, plays important roles in tumor cell proliferation and viability. Ubiquitin can form diverse polyubiquitin chains, on its seven lysines, which play important functions in various biological processes. However, the roles of lysines in NEDD8 have not been explored. Here, we generated nine NEDD8 point mutants, each with one lysine replaced by an arginine, to study the putative function of lysines in NEDD8. Our experiments discover that Lys27 in NEDD8 is a critical residue for protein neddylation. Replacement of this residue with arginine almost completely eliminates the conjugation of NEDD8 to its substrates. Furthermore, we find that the K27R mutant impairs NEDD8 conjugation to the E2 enzyme, which normally forms thioester bonds for further transferring NEDD8 to its ligases and substrates. Therefore, this mutation completely inhibits global protein neddylation, including neddylation of cullin family proteins, resulting in decreased activity of cullin-RING E3 ligases. This work sheds new light on the roles of NEDD8 lysines on neddylation cascades and provides a dominant negative mutant for the study of neddylation and its biological functions. PMID- 25918017 TI - HLA-B*59:01: a marker for Stevens-Johnson syndrome/toxic epidermal necrolysis caused by methazolamide in Han Chinese. AB - Methazolamide is an intraocular pressure-lowering drug that is used in the treatment of glaucoma and other ophthalmologic abnormalities. The use of methazolamide has been shown to cause Stevens-Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN) in patients of Asian ancestry. Methazolamide-induced SJS/TEN is associated with the presence of HLA-B59 serotype/HLA-B*59:01 in Korean and Japanese populations. To better understand the genetic risk factors for these adverse reactions in the Han Chinese population, we characterized the HLA class I genotypes of eight Chinese patients with methazolamide-induced SJS/TEN from 2008 to 2014. The frequency of HLA-B*59:01 was 87.5% (7/8) in the case patients, which was significantly different from 0% (0/30) in the methazolamide-tolerant patients (odds ratio (OR)=305.0; P=6.3 * 10(-7)) and 0.35% (1/283) in healthy subjects from the human major histocompatibility complex database (OR=1974.0; P=2.0 * 10( 12)). HLA-C*01:02, which is closely linked to HLA-B*59:01, had a weaker but notable association with methazolamide-induced SJS/TEN compared with the tolerant controls (OR=12.1; P=0.016) and general population (OR=15.5; P=2.0 * 10(-3)). The distribution of the HLA-B*59:01-C*01:02 haplotype was also significantly different in cases and controls. This study demonstrated a strong association between HLA-B*59:01 and methazolamide-induced SJS/TEN in the Han Chinese population for the first time. Pretherapy screening for HLA-B*59:01 would be useful to reduce the risk of methazolamide-induced SJS/TEN. PMID- 25918016 TI - Interleukin 28B polymorphisms as predictors of sustained virological response in chronic hepatitis C: systematic review and meta-analysis. AB - Polymorphism of interleukin 28B gene represents a powerful outcome predictor for interferon-based regimens in hepatitis C virus infection. However, some studies report conflicting results. The predictive value of interleukin 28B genotype over the outcome interferon-alpha/ribavirin treatment was thoroughly evaluated and compared with virological predictors of response. Literature revision was performed on PubMed. Pooled odds ratios (ORs) were calculated by fixed- or random effects models. Heterogeneity and publication bias were also assessed. Sixty-two eligible papers including 20 290 patients were retrieved. Both polymorphisms (rs12979860 and rs8099917) were strongly associated with response (OR=4.09 and 4.00, respectively), however, the association was weaker for subjects infected with viral genotypes 2 and 3 (OR=1.52 and 1.49, respectively). Compared with interleukin 28B genotype, the association with response was lower for baseline viremia (OR=2.15) and higher for rapid virological response (OR=13.86). These results provide a critical evaluation of interleukin 28B genotype as a pharmacogenetic predictor in hepatitis C patients. PMID- 25918020 TI - Effective delivery of recombinant proteins to rod photoreceptors via lipid nanovesicles. AB - The potential of liposomes to deliver functional proteins in retinal photoreceptors and modulate their physiological response was investigated by two experimental approaches. First, we treated isolated mouse retinas with liposomes encapsulating either recoverin, an important endogenous protein operating in visual phototransduction, or antibodies against recoverin. We then intravitrally injected in vivo liposomes encapsulating either rhodamin B or recoverin and we investigated the distribution in retina sections by confocal microscopy. The content of liposomes was found to be released in higher amount in the photoreceptor layer than in the other regions of the retina and the functional effects of the release were in line with the current model of phototransduction. Our study sets the basis for quantitative investigations aimed at assessing the potential of intraocular protein delivery via biocompatible nanovesicles, with promising implications for the treatment of retinal diseases affecting the photoreceptor layer. PMID- 25918021 TI - Conformational change study of dengue virus NS2B-NS3 protease using 19F NMR spectroscopy. AB - The dengue virus NS2B-NS3 protease (NS2B-NS3p), an important antiviral target for drug development, has been reported to adopt an open or closed conformation in crystal structures with different NS2B C-terminus (NS2Bc) positioning. In solution, nevertheless, NS2B-NS3p forms a mixture of open, closed and maybe other intermediate conformations, which is difficult to characterize using conventional biophysical and biochemical techniques. In this study, we developed a new strategy to analyze these conformational changes using (19)F NMR spectroscopy. Low pH or bovine pancreatic trypsin inhibitor (BPTI) binding promote the conformation change from open to closed, showing the importance of charge forces in the interaction between NS2Bc and NS3p. The mutation H51A impairs the charge interaction and the pH dependence of the conformational changes. It stabilizes the open conformation, while the addition of BPTI still converts NS2B-NS3p from open to closed conformation. PMID- 25918019 TI - Overexpression of Pref-1 in pancreatic islet beta-cells in mice causes hyperinsulinemia with increased islet mass and insulin secretion. AB - Preadipocyte factor-1 (Pref-1) is made as a transmembrane protein containing EGF repeats at the extracellular domain that can be cleaved to generate a biologically active soluble form. Pref-1 is found in islet beta-cells and its level has been reported to increase in neonatal rat islets upon growth hormone treatment. We found here that Pref-1 can promote growth of pancreatic tumor derived AR42J cells. To examine Pref-1 function in pancreatic islets in vivo, we generated transgenic mouse lines overexpressing the Pref-1/hFc in islet beta cells using rat insulin II promoter (RIP). These transgenic mice exhibit an increase in islet mass with higher proportion of larger islets in pancreas compared to wild-type littermates. This is in contrast to pancreas from Pref-1 null mice that show higher proportion of smaller islets. Insulin expression and insulin secretion from pancreatic islets from RIP-Pref-1/hFc transgenic mice are increased also. Thus, RIP-Pref-1/hFc transgenic mice show normal glucose levels but with higher plasma insulin levels in both fasting and fed conditions. These mice show improved glucose tolerance. Taken together, we conclude Pref-1 as a positive regulator of islet beta-cells and insulin production. PMID- 25918022 TI - Locomotion of bacteria in liquid flow and the boundary layer effect on bacterial attachment. AB - The formation of biofilm greatly affects the performance of biological reactors, which highly depends on bacterial swimming and attachment that usually takes place in liquid flow. Therefore, bacterial swimming and attachment on flat and circular surfaces with the consideration of flow was studied experimentally. Besides, a mathematical model comprehensively combining bacterial swimming and motion with flow is proposed for the simulation of bacterial locomotion and attachment in flow. Both experimental and theoretical results revealed that attached bacteria density increases with decreasing boundary layer thickness on both flat and circular surfaces, the consequence of which is inherently related to the competition between bacterial swimming and the non-slip motion with flow evaluated by the Peclet number. In the boundary layer, where the Peclet number is relatively higher, bacterial locomotion mainly depends on bacterial swimming. Thinner boundary layer promotes bacterial swimming towards the surface, leading to higher attachment density. To enhance the performance of biofilm reactors, it is effective to reduce the boundary layer thickness on desired surfaces. PMID- 25918023 TI - H2S does not regulate proliferation via T-type Ca2+ channels. AB - T-type Ca(2+) channels (Cav3.1, 3.2 and 3.3) strongly influence proliferation of various cell types, including vascular smooth muscle cells (VSMCs) and certain cancers. We have recently shown that the gasotransmitter carbon monoxide (CO) inhibits T-type Ca(2+) channels and, in so doing, attenuates proliferation of VSMC. We have also shown that the T-type Ca(2+) channel Cav3.2 is selectively inhibited by hydrogen sulfide (H2S) whilst the other channel isoforms (Cav3.1 and Cav3.3) are unaffected. Here, we explored whether inhibition of Cav3.2 by H2S could account for the anti-proliferative effects of this gasotransmitter. H2S suppressed proliferation in HEK293 cells expressing Cav3.2, as predicted by our previous observations. However, H2S was similarly effective in suppressing proliferation in wild type (non-transfected) HEK293 cells and those expressing the H2S insensitive channel, Cav3.1. Further studies demonstrated that T-type Ca(2+) channels in the smooth muscle cell line A7r5 and in human coronary VSMCs strongly influenced proliferation. In both cell types, H2S caused a concentration dependent inhibition of proliferation, yet by far the dominant T-type Ca(2+) channel isoform was the H2S-insensitive channel, Cav3.1. Our data indicate that inhibition of T-type Ca(2+) channel-mediated proliferation by H2S is independent of the channels' sensitivity to H2S. PMID- 25918024 TI - Role of PTEN in TNFalpha induced insulin resistance. AB - AIMS/HYPOTHESIS: PTEN may play a reversible role in TNFalpha induced insulin resistance, which has been linked to obesity-associated insulin resistance (IR). METHODS: Western blots for PTEN and p-Akt were performed on H-411E liver cells incubated with insulin, TNFalpha, and in selected experiments VO-OHpic vanadium complex in the presence and absence of PTEN siRNA. Total PTEN was compared to beta-actin loading control and p-Akt was compared to total Akt. RESULTS: Western blot and Real Time RT-PCR experiments showed increased PTEN after TNFalpha treatment (p = 0.04); slightly decreased PTEN after insulin treatment; and slightly increased PTEN after insulin + TNFalpha treatment. PTEN siRNA markedly inhibited the TNFalpha-induced increase in PTEN (p < 0.01) without significantly changing the p-Akt levels. The vanadium complex, exhibiting insulin-like effects, also significantly prevented the TNFalpha-induced increase in PTEN. Combining insulin and VO-OHpic was additive, providing both proof of concept and insight into mechanism. DISCUSSION: The PTEN increase due to TNFalpha treatment was reversible by both PTEN siRNA knockdown and VO-OHpic treatment. Thus, PTEN is identified as a potential new therapeutic target for reducing IR in Type 2 DM. PMID- 25918025 TI - Simultaneous ternary extension of DNA catalyzed by a trimeric replicase assembled in vivo. AB - According to current models, dimeric DNA Polymerases coordinate the replication of DNA leading and lagging strands. However, it was recently shown that trimeric DNA Polymerases, assembled in vitro, replicate the lagging strand more efficiently than dimeric replicases. Here we show that the tau, alpha, epsilon, and theta subunits of Escherichia coli DNA Polymerase III can be assembled in vivo, yielding the trimeric tau3alpha3epsilon3theta3 complex. Further, we propose a molecular model of this complex, whose catalytic action was investigated using model DNA substrates. Our observations indicate that trimeric DNA replicases reduce the gap between leading and lagging strand synthesis. PMID- 25918026 TI - Relation between dabigatran concentration, as assessed using the direct thrombin inhibitor assay, and activated clotting time/activated partial thromboplastin time in patients with atrial fibrillation. AB - Dabigatran is a direct thrombin inhibitor that has been approved for preventing stroke in patients with atrial fibrillation. In this study, we aimed to assess the associations between the dabigatran concentration (calculated through plasma diluted thrombin time, as assessed using the Hemoclot assay) and the activated partial thromboplastin time (aPTT) and activated clotting time (ACT). We recruited 137 patients with atrial fibrillation who were receiving a normal dose of dabigatran (300 mg/d) or a reduced dose of dabigatran (220 mg/d, usually administered to patients who were elderly, had moderate renal dysfunction, or who were also receiving verapamil). We then assessed the aPTT, ACT, and Hemoclot results of the patients and calculated the plasma dabigatran concentration. The mean plasma concentration of dabigatran was 127 +/- 88 ng/ml, although no significant differences in dabigatran concentration, ACT, or aPTT were observed when we compared the 2 doses of dabigatran (300 or 220 mg/d). The dabigatran concentration was within the therapeutic levels in most patients, although a high value (>300 ng/ml) was observed in several patients, which indicated a high risk of bleeding. The dabigatran concentration was strongly and positively correlated with ACT and aPTT (r = 0.87, p <0.001; and r = 0.76, p <0.001; respectively). Multivariate analysis revealed that verapamil use was independently associated with elevated dabigatran concentrations (p <0.001). Therefore, ACT and aPTT may be useful for bedside assessment of the anticoagulant activity of dabigatran, and verapamil use may be a risk factor for elevated dabigatran concentrations. PMID- 25918027 TI - Improving clinical practice guidelines for practicing cardiologists. AB - Cardiac-related clinical practice guidelines have become an integral part of the practice of cardiology. Unfortunately, these guidelines are often long, complex, and difficult for practicing cardiologists to use. Guidelines should be condensed and their format upgraded, so that the key messages are easier to comprehend and can be applied more readily by those involved in patient care. After presenting the historical background and describing the guideline structure, we make several recommendations to make clinical practice guidelines more user-friendly for clinical cardiologists. Our most important recommendations are that the clinical cardiology guidelines should focus exclusively on (1) class I recommendations with established benefits that are supported by randomized clinical trials and (2) class III recommendations for diagnostic or therapeutic approaches in which quality studies show no benefit or possible harm. Class II recommendations are not evidence based but reflect expert opinions related to published clinical studies, with potential for personal bias by members of the guideline committee. Class II recommendations should be published separately as "Expert Consensus Statements" or "Task Force Committee Opinions," so that both majority and minority expert opinions can be presented in a less dogmatic form than the way these recommendations currently appear in clinical practice guidelines. PMID- 25918028 TI - Myocardial Infarction and Left Ventricular Hypertrophy Seen on an Infant's Electrocardiogram. AB - The clinical and electrocardiographic features of anomalous left coronary artery from the pulmonary trunk, ALCAPA, a frequently fatal congenital cardiac malformation, are described in an 8 1/2-month-old female. PMID- 25918030 TI - A huge spinal ependymoma. PMID- 25918029 TI - Reply: To PMID 25784515. PMID- 25918031 TI - The use of laboratory scale reactors to predict sensitivity to changes in operating conditions for full-scale anaerobic digestion treating municipal sewage sludge. AB - Anaerobic digestion of sewage sludge is highly complex and prone to inhibition, which can cause major issues for digester operators. The result is that there have been numerous investigations into changes in operational conditions, however to date all have focused on the qualitative sensitivities, neglecting the quantitative. This study therefore aimed to determine the quantitative sensitivities by using factorial design of experiments and small semi continuous reactors. Analysis showed total and volatile solids removals are chiefly influenced by retention time, with 79% and 59% of the observed results being attributed to retention time respectively, whereas biogas was mainly influenced by loading rate, 38%, and temperature, 22%. Notably the regression model fitted to the experimental data predicted full-scale performance with a high level of precision, indicating that small reactors are subject to the same sensitivity of full-scale digesters and thus can be used to predict changes loading, retention time, and temperature. PMID- 25918032 TI - Development of a predictive framework to assess the removal of trace organic chemicals by anaerobic membrane bioreactor. AB - This study aims to develop a predictive framework to assess the removal and fate of trace organic chemicals (TrOCs) during wastewater treatment by anaerobic membrane bioreactor (AnMBR). The fate of 27 TrOCs in both the liquid and sludge phases during AnMBR treatment was systematically investigated. The results demonstrate a relationship between hydrophobicity and specific molecular features of TrOCs and their removal efficiency. These molecular features include the presence of electron withdrawing groups (EWGs) or donating groups (EDGs), especially those containing nitrogen and sulphur. All seven hydrophobic contaminants were well removed (>70%) by AnMBR treatment. Most hydrophilic TrOCs containing EDGs were also well removed (>70%). In contrast, hydrophilic TrOCs containing EWGs were mostly poorly removed and could accumulate in the sludge phase. The removal of several nitrogen/sulphur bearing TrOCs (e.g., linuron and caffeine) by AnMBR was higher than that by aerobic treatment, possibly due to nitrogen or sulphur reducing bacteria. PMID- 25918033 TI - Repetitive element signature-based visualization, distance computation, and classification of 1766 microbial genomes. AB - The genomes of living organisms are populated with pleomorphic repetitive elements (REs) of varying densities. Our hypothesis that genomic RE landscapes are species/strain/individual-specific was implemented into the Genome Signature Imaging system to visualize and compute the RE-based signatures of any genome. Following the occurrence profiling of 5-nucleotide REs/words, the information from top-50 frequency words was transformed into a genome-specific signature and visualized as Genome Signature Images (GSIs), using a CMYK scheme. An algorithm for computing distances among GSIs was formulated using the GSIs' variables (word identity, frequency, and frequency order). The utility of the GSI-distance computation system was demonstrated with control genomes. GSI-based computation of genome-relatedness among 1766 microbes (117 archaea and 1649 bacteria) identified their clustering patterns; although the majority paralleled the established classification, some did not. The Genome Signature Imaging system, with its visualization and distance computation functions, enables genome-scale evolutionary studies involving numerous genomes with varying sizes. PMID- 25918034 TI - Cross-validation and hypothesis testing in neuroimaging: An irenic comment on the exchange between Friston and Lindquist et al. AB - The "ten ironic rules for statistical reviewers" presented by Friston (2012) prompted a rebuttal by Lindquist et al. (2013), which was followed by a rejoinder by Friston (2013). A key issue left unresolved in this discussion is the use of cross-validation to test the significance of predictive analyses. This note discusses the role that cross-validation-based and related hypothesis tests have come to play in modern data analyses, in neuroimaging and other fields. It is shown that such tests need not be suboptimal and can fill otherwise-unmet inferential needs. PMID- 25918035 TI - Reassessing the Significance of Intimal Arteritis in Kidney Transplant Biopsy Specimens. AB - Intimal arteritis (the presence of v-lesions) in kidney transplant biopsy specimens is believed to have major prognostic and diagnostic significance. We assessed the relationship of v-lesions to prognosis in 703 indication biopsy specimens and used microarray-based molecular tests to re-examine the relationship of v-lesions to rejection. v-Lesions were noted in 49 specimens (7%) and were usually mild (v1). The presence of v-lesions had no effect on graft survival compared with the absence of v-lesions. Pathologists using current conventions almost always interpreted v-lesions as reflecting T cell-mediated rejection (TCMR), either pure or mixed with antibody-mediated rejection (ABMR). The molecular scores questioned the conventional diagnoses in 29 of 49 specimens (59%), including ten that were conventional TCMR with no molecular rejection and nine that were conventional TCMR mixed with pure ABMR molecularly. The presence of tubulointerstitial inflammation (i-t) meeting TCMR criteria allowed subclassification of v-lesion specimens into 21 i-t-v-lesion specimens and 28 isolated v-lesion specimens. Molecular TCMR scores were positive in 95% of i-t-v lesion specimens but only 21% of isolated v-lesion specimens. Molecular ABMR scores were often positive in isolated v-lesion biopsies (46%). Time of biopsy after transplantation was critical for understanding isolated v-lesions: most early isolated v-lesion specimens had no molecular rejection and were DSA negative, whereas most isolated >1 year after transplantation had positive DSA and ABMR scores. Therefore, v-lesions in indication biopsy specimens do not affect prognosis and can reflect TCMR, ABMR, or no rejection. Time after transplantation, DSA, and accompanying inflammation provide probabilistic basis for interpreting v-lesions. PMID- 25918038 TI - Meltdown: A Tool to Help in the Interpretation of Thermal Melt Curves Acquired by Differential Scanning Fluorimetry. AB - The output of a differential scanning fluorimetry (DSF) assay is a series of melt curves, which need to be interpreted to get value from the assay. An application that translates raw thermal melt curve data into more easily assimilated knowledge is described. This program, called "Meltdown," conducts four main activities--control checks, curve normalization, outlier rejection, and melt temperature (T(m)) estimation--and performs optimally in the presence of triplicate (or higher) sample data. The final output is a report that summarizes the results of a DSF experiment. The goal of Meltdown is not to replace human analysis of the raw fluorescence data but to provide a meaningful and comprehensive interpretation of the data to make this useful experimental technique accessible to inexperienced users, as well as providing a starting point for detailed analyses by more experienced users. PMID- 25918036 TI - Renal Mechanisms of Association between Fibroblast Growth Factor 1 and Blood Pressure. AB - The fibroblast growth factor 1 (FGF1) gene is expressed primarily in the kidney and may contribute to hypertension. However, the biologic mechanisms underlying the association between FGF1 and BP regulation remain unknown. We report that the major allele of FGF1 single nucleotide polymorphism rs152524 was associated in a dose-dependent manner with systolic BP (P = 9.65 * 10(-5)) and diastolic BP (P = 7.61 * 10(-3)) in a meta-analysis of 14,364 individuals and with renal expression of FGF1 mRNA in 126 human kidneys (P=9.0 * 10(-3)). Next-generation RNA sequencing revealed that upregulated renal expression of FGF1 or of each of the three FGF1 mRNA isoforms individually was associated with higher BP. FGF1 stratified coexpression analysis in two separate collections of human kidneys identified 126 FGF1 partner mRNAs, of which 71 and 63 showed at least nominal association with systolic and diastolic BP, respectively. Of those mRNAs, seven mRNAs in five genes (MME, PTPRO, REN, SLC12A3, and WNK1) had strong prior annotation to BP or hypertension. MME, which encodes an enzyme that degrades circulating natriuretic peptides, showed the strongest differential coexpression with FGF1 between hypertensive and normotensive kidneys. Furthermore, higher level of renal FGF1 expression was associated with lower circulating levels of atrial and brain natriuretic peptides. These findings indicate that FGF1 expression in the kidney is at least under partial genetic control and that renal expression of several FGF1 partner genes involved in the natriuretic peptide catabolism pathway, renin-angiotensin cascade, and sodium handling network may explain the association between FGF1 and BP. PMID- 25918037 TI - A Multivariate Computational Method to Analyze High-Content RNAi Screening Data. AB - High-content screening (HCS) using RNA interference (RNAi) in combination with automated microscopy is a powerful investigative tool to explore complex biological processes. However, despite the plethora of data generated from these screens, little progress has been made in analyzing HC data using multivariate methods that exploit the full richness of multidimensional data. We developed a novel multivariate method for HCS, multivariate robust analysis method (M-RAM), integrating image feature selection with ranking of perturbations for hit identification, and applied this method to an HC RNAi screen to discover novel components of the DNA damage response in an osteosarcoma cell line. M-RAM automatically selects the most informative phenotypic readouts and time points to facilitate the more efficient design of follow-up experiments and enhance biological understanding. Our method outperforms univariate hit identification and identifies relevant genes that these approaches would have missed. We found that statistical cell-to-cell variation in phenotypic responses is an important predictor of hits in RNAi-directed image-based screens. Genes that we identified as modulators of DNA damage signaling in U2OS cells include B-Raf, a cancer driver gene in multiple tumor types, whose role in DNA damage signaling we confirm experimentally, and multiple subunits of protein kinase A. PMID- 25918039 TI - Lessons from aviation - the role of checklists in minimally invasive cardiac surgery. AB - We describe an adverse event during minimally invasive cardiac surgery that resulted in a multi-disciplinary review of intra-operative errors and the creation of a procedural checklist. This checklist aims to prevent errors of omission and communication failures that result in increased morbidity and mortality. We discuss the application of the aviation - led "threats and errors model" to medical practice and the role of checklists and other strategies aimed at reducing medical errors. PMID- 25918040 TI - Endovascular occlusion of primary major pelvic arteriovenous fistula using patent ductus arteriosus occluder. AB - The aim of the present study was to investigate the effects and safety of a patent ductus arteriosus occluder (PDAO) in the management of major abdominal arteriovenous fistula. A 56-year-old man was admitted into our hospital, presenting with impeded defecation and claudication. Computed tomographic angiography (CTA) was conducted upon admission, which revealed an aneurysm-like lesion, with the left internal iliac artery as its feeding artery. Super selective embolization treatment was accomplished using a single PDAO. The results of the CTA at follow-up showed no recanalization of the lesion and that a PDAO was at the site. The patient had no pelvic ischemia complications. PMID- 25918041 TI - Public reporting in cardiovascular medicine: accountability, unintended consequences, and promise for improvement. PMID- 25918043 TI - Left atrial mural endocarditis secondary to mitral valve jet lesion. PMID- 25918044 TI - Letter by Rodu and Phillips regarding article, "Discontinuation of smokeless tobacco and mortality risk after myocardial infarction". PMID- 25918045 TI - Response to letter regarding article, "Discontinuation of smokeless tobacco and mortality risk after myocardial infarction". PMID- 25918046 TI - Correction. PMID- 25918047 TI - The N-terminal pro B-type natriuretic peptide, and risk of dementia and cognitive decline: a 10-year follow-up study in the general population. AB - BACKGROUND: The N-terminal pro B-type natriuretic peptide (NT-proBNP) has a well documented prognostic value for cardiovascular disease (CVD) and higher levels are associated with cognitive-dysfunction in patients with CVD. However, how NT proBNP relates to incident dementia and cognitive-decline in community-dwelling persons is unknown. METHODS: Between 1997 and 2001, serum NT-proBNP was measured in 6040 participants (mean age 69 years, 57% women) free of heart-failure and dementia from the Rotterdam Study. Participants were continuously followed-up for incident dementia until 2012, for 56,616 person-years. Cognition was assessed at baseline and reassessed between 2002 and 2006 by Letter-Digit-Substitution-task, Stroop test and Word-Fluency test. Associations of NT-proBNP with dementia (555 cases), Alzheimer's disease (357 cases) and vascular dementia (32 cases) were assessed linearly, and in quartiles using Cox regression. Associations of NT proBNP with cognitive-decline were assessed using multiple linear regression. All analyses were repeated after excluding patients with CVD. RESULTS: Higher NT proBNP was associated with a higher risk of dementia, even after excluding patients with CVD and adjusting for cardiovascular risk factors, HR per SD 1.27 (95% CI 1.13 to 1.44). Associations were particularly strong for vascular dementia, HR per SD 2.04 (95% CI 1.18 to 3.55), but also for Alzheimer's disease when comparing the second and third quartile with first. Higher NT-proBNP was cross-sectionally associated with poorer performance in multiple cognitive tests but longitudinally only in Letter-Digit-Substitution-task. CONCLUSIONS: NT-proBNP reflecting subclinical CVD is associated with dementia, particularly vascular dementia. NT-proBNP can be a useful marker of imminent cognitive-decline and dementia in absence of clinical CVD. PMID- 25918048 TI - Mitochondrial dynamics: Orchestrating the journey to advanced age. AB - Aging is a degenerative process that unfortunately is an inevitable part of life and risk factor for cardiovascular disease including heart failure. Among the several theories purported to explain the effects of age on cardiac dysfunction, the mitochondrion has emerged a central regulator of this process. Hence, it is not surprising that abnormalities in mitochondrial quality control including biogenesis and turnover have such detrimental effects on cardiac function. In fact mitochondria serve as a conduit for biological signals for apoptosis, necrosis and autophagy respectively. The removal of damaged mitochondria by autophagy/mitophagy is essential for mitochondrial quality control and cardiac homeostasis. Defects in mitochondrial dynamism fission/fusion events have been linked to cardiac senescence and heart failure. In this review we discuss the impact of aging on mitochondrial dynamics and senescence on cardiovascular health. This article is part of a Special Issue entitled: CV Aging. PMID- 25918049 TI - The atypical 'b' splice variant of phospholipase Cbeta1 promotes cardiac contractile dysfunction. AB - The activity of the early signaling enzyme, phospholipase Cbeta1b (PLCbeta1b), is selectively elevated in diseased myocardium and activity increases with disease progression. We aimed to establish the contribution of heightened PLCbeta1b activity to cardiac pathology. PLCbeta1b, the alternative splice variant, PLCbeta1a, and a blank virus were expressed in mouse hearts using adeno associated viral vectors (rAAV6-FLAG-PLCbeta1b, rAAV6-FLAG-PLCbeta1a, or rAAV6 blank) delivered intravenously (IV). Following viral delivery, FLAG-PLCbeta1b was expressed in all of the chambers of the mouse heart and was localized to the sarcolemma. Heightened PLCbeta1b expression caused a rapid loss of contractility, 4-6 weeks, that was fully reversed, within 5 days, by inhibition of protein kinase Calpha (PKCalpha). PLCbeta1a did not localize to the sarcolemma and did not affect contractile function. Expression of PLCbeta1b, but not PLCbeta1a, caused downstream dephosphorylation of phospholamban and depletion of the Ca(2+) stores of the sarcoplasmic reticulum. We conclude that heightened PLCbeta1b activity observed in diseased myocardium contributes to pathology by PKCalpha mediated contractile dysfunction. PLCbeta1b is a cardiac-specific signaling system, and thus provides a potential therapeutic target for the development of well-tolerated inotropic agents for use in failing myocardium. PMID- 25918052 TI - Correction. PMID- 25918053 TI - Correction. PMID- 25918050 TI - Regulation of L-type calcium channel by phospholemman in cardiac myocytes. AB - We evaluated whether phospholemman (PLM) regulates L-type Ca(2+) current (ICa) in mouse ventricular myocytes. Expression of alpha1-subunit of L-type Ca(2+) channels between wild-type (WT) and PLM knockout (KO) hearts was similar. Compared to WT myocytes, peak ICa (at -10 mV) from KO myocytes was ~41% larger, the inactivation time constant (tau(inact)) of ICa was ~39% longer, but deactivation time constant (tau(deact)) was similar. In the presence of isoproterenol (1 MUM), peak ICa was ~48% larger and tau(inact) was ~144% higher in KO myocytes. With Ba(2+) as the permeant ion, PLM enhanced voltage-dependent inactivation but had no effect on tau(deact). To dissect the molecular determinants by which PLM regulated ICa, we expressed PLM mutants by adenovirus mediated gene transfer in cultured KO myocytes. After 24h in culture, KO myocytes expressing green fluorescent protein (GFP) had significantly larger peak ICa and longer tau(inact) than KO myocytes expressing WT PLM; thereby independently confirming the observations in freshly isolated myocytes. Compared to KO myocytes expressing GFP, KO myocytes expressing the cytoplasmic domain truncation mutant (TM43), the non-phosphorylatable S68A mutant, the phosphomimetic S68E mutant, and the signature PFXYD to alanine (ALL5) mutant all resulted in lower peak ICa. Expressing PLM mutants did not alter expression of alpha1-subunit of L-type Ca(2+) channels in cultured KO myocytes. Our results suggested that both the extracellular PFXYD motif and the transmembrane domain of PLM but not the cytoplasmic tail were necessary for regulation of peak ICa amplitude. We conclude that PLM limits Ca(2+) influx in cardiac myocytes by reducing maximal ICa and accelerating voltage-dependent inactivation. PMID- 25918054 TI - A novel troponin T peptide in humans: Assay, biochemistry and preliminary findings in acute coronary syndromes. AB - INTRODUCTION: High sensitivity assays for cardiac troponin (cTn) have reduced time to diagnosis of myocardial infarction (MI) but at costs to diagnostic specificity. We hypothesised that measurement of an upstream open reading frame peptide (uORF) from the human cTnT gene (TnTuORF) might improve cTn specificity in MI patients. METHODS: A novel immunoassay to TnTuORF was developed and used to document circulating concentrations in normal healthy volunteers (n=150); assess potential trans-organ secretion in patients undergoing cardiac catheterisation (n=16); characterise temporal TnTuORF concentrations during ST-elevation MI (STEMI, n=4) and assess the potential of TnTuORF to assist the diagnosis and prognosis of MI in patients presenting with chest pain suspicious of ACS (n=502). Plasma immunoreactive TnTuORF was characterised on reverse phase and size exclusion HPLC. RESULTS: In normal volunteers and suspected acute coronary syndrome (ACS) patients, TnTuORF had no relationship with TnI or TnT. Trans-organ venous sampling suggested TnTuORF secretion is not exclusively cardiac based. In STEMI patients, TnTuORF concentrations decreased for up to 12h after onset. In suspected ACS patients, TnTuORF could not diagnose MI (ROC AUC=0.446, P=0.117) but could diagnose cardiac disorders other than MI (AUC=0.79, P<0.001). CONCLUSION: This is the first evidence for a circulating uORF peptide. TnTuORF does not appear to aid the diagnosis of MI but further studies to assess its potential in cardiovascular disease are required. PMID- 25918055 TI - The complex mural cell: pericyte function in health and disease. AB - Pericytes are perivascular cells that can be distinguished from vascular smooth muscle cells by their specific morphology and expression of distinct molecular markers. Found in the microvascular beds distributed throughout the body, they are well known for their regulation of a healthy vasculature. In this review, we examine the mechanism of pericyte support to vasomotion, and the known pathways that regulate pericyte response in angiogenesis and neovascular stabilization. We will also discuss the role of pericytes in vascular basement membrane and endothelial barrier function regulation. In contrast, recent findings have indicated that pericyte dysfunction, characterized by changes in pericyte contractility or pericyte loss of microvascular coverage, plays an important role in onset and progression of vascular-related and fibrogenic diseases. From a therapeutic point of view, pericytes have recently been identified as a putative pool of endogenous mesenchymal stem cells that could be activated in response to tissue injury to contribute to the regenerative process on multiple levels. We will discuss the mechanisms via which pericytes are involved in disease onset and development in a number of pathophysiological conditions, as well as present the evidence that supports a role for multipotent pericytes in tissue regeneration. The emerging field of pericyte research will not only contribute to the identification of new drug targets in pericyte dysfunction associated diseases, but may also boost the use of this cell type in future cell-based regenerative strategies. PMID- 25918057 TI - Treating and healing coronary artery ectasia disease with Bioresorbable Vascular Scaffold. PMID- 25918056 TI - Utility of both carotid intima-media thickness and endothelial function for cardiovascular risk stratification in patients with angina-like symptoms. AB - BACKGROUND: Myocardial perfusion scintigraphy (MPS) is used widely to assess cardiovascular risk in patients with chest pain. The utility of carotid intima media thickness (CIMT) and endothelial function as assessed by reactive hyperemia peripheral arterial tonometry index (RHI) in risk stratifying patients with angina-like symptoms needs to be defined. We investigated whether the addition of CIMT and RHI to Framingham Cardiovascular Risk Score (FCVRS) and MPS improves comprehensive cardiovascular risk prediction in patients presenting with angina like symptoms. METHODS: We enrolled 343 consecutive patients with angina-like symptoms suspected of having stable angina. MPS, CIMT, and RHI were performed and patients were followed for cardiovascular events for a median of 5.3 years (range 4.4-6.2). Patients were stratified by FCVRS and MPS. RESULTS: During the follow up, 57 patients (16.6%) had cardiovascular events. Among patients without perfusion defect, low RHI was significantly associated with cardiovascular events in the intermediate and high FCVRS groups (hazard ratio (HR) [95% confidence interval (CI)] of RHI <= 2.11 was 6.99 [1.34-128] in the intermediate FCVRS group and 6.08 [1.08-114] in the high FCVRS group). Furthermore, although MPS did not predict, only RHI predicted hard cardiovascular events (cardiovascular death, myocardial infarction, and stroke) independent from FCVRS, and adding RHI to FCVRS improved net reclassification index (20.9%, 95% CI 0.8-41.1, p = 0.04). Especially, RHI was significantly associated with hard cardiovascular events in the high FCVRS group (HR [95% CI] of RHI <= 1.93 was 5.66 [1.54-36.4], p = 0.007). CONCLUSIONS: Peripheral endothelial function may improve discrimination in identifying at-risk patients for future cardiovascular events when added to FCVRS-MPS-based risk stratification. PMID- 25918058 TI - Atrial fibrillation is associated with increased risk of erectile dysfunction: A nationwide population-based cohort study. AB - BACKGROUND: Our study aimed to investigate the association between atrial fibrillation (AF) and erectile dysfunction (ED). METHODS: A total of 3853 male patients with AF were identified as the AF cohort, and 15,405 male patients without AF were selected randomly as the control group and matched by age and index years of AF diagnosis. The endpoint of interest in this study was the occurrence of ED. Individuals with prior history of ED, female patients, those with missing information, and those aged 20 years and younger were excluded. RESULTS: The mean follow-up duration was 4.67 +/- 3.20 years for the AF patients and 5.04 +/- 3.30 years for the non-AF patients. During the follow-up period, the incidence of ED in the AF cohort was 1.65-fold higher than the non-AF cohort (20.6 vs 12.5 per 10,000 person-years, P < .001). Stratified by age, the incidence of ED was consistently higher in the AF cohort. After adjustment for patient characteristics, multivariate Cox regression analysis demonstrated that AF and hyperlipidemia remained independent risk factors for ED (hazard ratio [HR] = 1.53, 95% confidence interval [CI] = 1.05-2.24 and HR = 1.96, 95% CI = 1.36 2.81, respectively). Relative to the non-AF cohort without hyperlipidemia, the AF patients with hyperlipidemia were at a higher risk of ED (HR=2.76, 95% CI = 1.52 5.00). CONCLUSION: In a large-scale cohort, the incidence of ED was significantly higher in male patients with AF than those without AF. PMID- 25918059 TI - Myocardial infarction after physical exertion in a healthy young patient with coronary artery ectasia and sickle cell trait. PMID- 25918060 TI - Effects of depression screening on psychiatric outcomes in patients with acute coronary syndrome: Findings from the K-DEPACS and EsDEPACS studies. AB - BACKGROUND: It has been controversial whether routine screening for depression should be recommended in all patients with acute coronary syndrome (ACS) due to lack of evidence for psychiatric as well as for cardiac outcomes. This study aimed to evaluate the result of screening for treatment and subsequent treatment of depression on one-year psychiatric outcomes in ACS. METHODS: At baseline 1152 patients with recently developed ACS were screened with the Beck Depression Inventory (BDI) and depressive disorder diagnoses were applied according to DSM IV criteria. Of the 446 patients with depressive disorder, 300 were randomized to a 24-week double-blind trial of escitalopram or placebo, while the remaining 146 received conventional medical treatment only (MTO) without randomization. Of all baseline participants, 828 were followed up one year later. Psychiatric outcomes included BDI, Hamilton Depression Rating Scale (HAMD), Montgomery Asberg Depression Rating Scale (MADRS), Social and Occupational Functioning Assessment Scale (SOFAS) and the World Health Organization Disability Assessment Schedule-12 (WHODAS-12). RESULTS: BDI screen-positive ACS patients showed worse one-year outcomes on MADRS, SOFAS, and WHODAS scores (p-values<0.01) compared to BDI screen-negative patients. Escitalopram treatment was associated with beneficial effects compared to placebo and MTO on one-year outcomes on HAMD, MADRS and SOFAS (p-values<0.01). Of patients screening positive on the BDI, those with depressive disorder treated with escitalopram had similar outcomes to those without depressive disorder. CONCLUSIONS: Routine screening of depressive symptom in ACS patients is helpful to plan further management. Moreover, successive accurate diagnosis of depressive disorder with appropriated treatment is effective at least for psychiatric outcomes. PMID- 25918061 TI - Left ventricular non-compaction and hypertrabeculation in the athlete: Distinguishing between pathology and physiology. PMID- 25918062 TI - High platelet reactivity and periprocedural myocardial infarction in patients undergoing percutaneous coronary intervention: A significant association beyond definitions. PMID- 25918063 TI - HDAC inhibition: A novel therapeutic target for attenuating myocardial ischemia and reperfusion injury by reversing cardiac remodeling. PMID- 25918064 TI - Effects of captopril, spironolactone, and simvastatin on the cardiovascular system of non-diseased Wistar rats. PMID- 25918065 TI - Heart failure with reduced ejection fraction: Should we submit patients without angina to coronary angiography? PMID- 25918066 TI - Inhaled bronchodilators and the risk of tachyarrhythmias. AB - BACKGROUND/OBJECTIVES: There have been controversies about whether inhaled bronchodilators could increase the risk of clinically important tachyarrhythmias. We investigated the association between inhaled bronchodilators and the development of tachyarrhythmias, including atrial fibrillation and other paroxysmal tachyarrhythmias in real practice. METHODS: We conducted a nested case control study with the use of the nationwide insurance claims database of the Health Insurance Review and Assessment Service (Seoul, Republic of Korea). Overall, 3312 cases with newly developed tachyarrhythmias including atrial fibrillation and other paroxysmal tachyarrhythmias and 9732 matched (up to 1:5) controls were identified from 545,508 subjects without acute major cardiovascular events in the past year between January 1, 2011 and December 31, 2011. Conditional logistic regression analysis adjusted by comorbidities, cardiovascular drugs and healthcare utilization was performed. RESULTS: In various multivariate models, the use of inhaled long-acting muscarinic antagonists (LAMAs) or long-acting inhaled beta2 agonists (LABAs) was significantly associated with tachyarrhythmias. Statistically significant effects of LAMAs on tachyarrhythmias were found only in the non-users of beta-blockers. We did not find a statistically significant difference in the impact of a LABA without a LAMA vs a LAMA without a LABA (aOR, 0.93; 95% CI, 0.74-1.18), or a multiplicative or additive interaction between a LABA and a LAMA. CONCLUSIONS: Inhaled LAMAs and LABAs were significantly and comparably associated with an increased risk of tachyarrhythmias. PMID- 25918067 TI - Ectopic adiposopathy and association with cardiovascular disease risk factors: The Uberlandia Heart Study. PMID- 25918068 TI - Glycosylated hemoglobin levels and clinical outcomes in diabetic patients receiving percutaneous coronary interventions: A meta-analysis of cohort studies. PMID- 25918069 TI - Clinical epidemiology in Italian Registry of Infective Endocarditis (RIEI): Focus on age, intravascular devices and enterococci. AB - INTRODUCTION: The epidemiology of infective endocarditis (IE) is changing due to a number of factors, including aging and health related comorbidities and medical procedures. The aim of this study is to describe the main clinical, epidemiologic and etiologic changes of IE from a large database in Italy. METHODS: We prospectively collected episodes of IE in 17 Italian centers from July 2007 to December 2010. RESULTS: We enrolled 677 patients with definite IE, of which 24% health-care associated. Patients were male (73%) with a median age of 62 years (IQR: 49-74) and 61% had several comorbidities. One hundred and twenty-eight (19%) patients had prosthetic left side IE, 391 (58%) native left side IE, 94 (14%) device-related IE and 54 (8%) right side IE. A predisposing cardiopathy was present in 50%, while odontoiatric and non odontoiatric procedures were reported in 5% and 21% of patients respectively. Symptoms were usually atypical and precocious. The prevalent etiology was represented by Staphylococcus aureus (27%) followed by coagulase-negative staphylococci (CNS, 21%), Streptococcus viridans (15%) and enterococci (14%). CNS and enterococci were relatively more frequent in patients with intravascular devices and prosthesis and S. viridans in left native valve. Diagnosis was made by transthoracic and transesophageal echocardiography in 62% and 94% of cases, respectively. The in-hospital mortality was 14% and 1 year mortality was 21%. CONCLUSION: The epidemiology is changing in Italy, where IE more often affects older patients with comorbidities and intravascular devices, with an acute onset and including a high frequency of enterococci. There were few preceding odontoiatric procedures. PMID- 25918070 TI - The ATLANTIC trial does not support the safety of prehospital ticagrelor treatment for patients with ST-elevation myocardial infarction. PMID- 25918071 TI - Carvedilol use and specific cancer risk in the population with hypertension: Reply. PMID- 25918072 TI - An overview of the applied definitions and diagnostic methods to assess exercise oscillatory ventilation--a systematic review. AB - The variable "exercise oscillatory ventilation" (EOV), assessed during cardiopulmonary exercise test (CPET), recently became a fundamental prognostic parameter in patients with heart failure. In literature, various definitions are suggested, but an uniformly accepted description to identify EOV still lacks. We performed a systematic review of the literature in order to determine the different definitions and diagnostic techniques to assess EOV. A systematic search strategy was established and executed in seven databases (PubMed, Google Scholar, Cochrane Clinical Trials, Science Direct, Pedro, Web Of Science library and Medline (Ovid)) resulting in 605 citations after de-duplication. Full-text articles (n=124) were assessed for eligibility, resulting in 75 citations. The review accounted 17,440 patients of whom 4,638 subjects presented EOV. Seven studies described EOV in a non-heart failure population accounting 168 EOV subjects. The definitions could be categorized in nine subdivisions of which four (n=43) referred to an original description. The other subdivisions were combinations of the original definitions (n=11), quantifications (n=4), computational (n=3), vaguely described (n=8) or not defined (n=6). Symptom limited maximal exercise tests were conducted to assess EOV, however the modes, protocols, software and data sampling were divers. Heterogeneity in the numerous definitions to identify EOV and the vaguely described assessment methods are hindering the evolution to a standardized uniformly accepted definition and technique to identify this abnormal breathing pattern. Unity in definition and international adopted assessment is warranted to strengthen its validity as a prognostic marker and could promote communication. It may facilitate clinical trials on pathophysiology and origin of EOV. PMID- 25918073 TI - Incremental value of copeptin to highly sensitive cardiac Troponin I for rapid rule-out of myocardial infarction. AB - BACKGROUND: The incremental value of copeptin, a novel marker of endogenous stress, for rapid rule-out of non-ST-elevation myocardial infarction (NSTEMI) is unclear when sensitive or even high-sensitivity cardiac troponin cTn (hs-cTn) assays are used. METHODS: In an international multicenter study we evaluated 1929 consecutive patients with symptoms suggestive of acute myocardial infarction (AMI). Measurements of copeptin, three sensitive and three hs-cTn assays were performed at presentation in a blinded fashion. The final diagnosis was adjudicated by two independent cardiologists using all clinical information including coronary angiography and levels of hs-cTnT. The incremental value in the diagnosis of NSTEMI was quantified using four outcome measures: area under the receiver-operating characteristic curve (AUC), integrated discrimination improvement (IDI), sensitivity and negative predictive value (NPV). Early presenters (< 4h since chest pain onset) were a pre-defined subgroup. RESULTS: NSTEMI was the adjudicated final diagnosis in 358 (18.6%) patients. As compared to the use of cTn alone, copeptin significantly increased AUC for two (33%) and IDI (between 0.010 and 0.041 (all p < 0.01)), sensitivity and NPV for all six cTn assays (100%); NPV to 96-99% when the 99 th percentile of the respective cTnI assay was combined with a copeptin level of 9 pmol/l (all p < 0.01). The incremental value in early presenters was similar to that of the overall cohort. CONCLUSION: When used for rapid rule-out of NSTEM in combination with sensitive or hs-cTnI assays, copeptin provides a numerically small, but statistically and likely also clinically significant incremental value. PMID- 25918074 TI - A temperature-sensitive, self-adhesive hydrogel to deliver iPSC-derived cardiomyocytes for heart repair. PMID- 25918075 TI - Predictors of return of spontaneous circulation in patients resuscitated from out of-hospital cardiac arrest. PMID- 25918076 TI - Iatrogenic takotsubo cardiomyopathy. PMID- 25918077 TI - Relationship between the non-motor items of the MDS-UPDRS and Quality of Life in patients with Parkinson's disease. AB - The Movement Disorder Society-Unified Parkinson's Disease Rating Scale (MDS UPDRS) is a newly developed comprehensive tool to assess Parkinson's disease (PD), which covers a wider range of non-motor PD manifestations than the original UPDRS scale. The aim of this study was to assess the relationship between the MDS UPDRS and Quality of Life (QoL) and to analyze the relationship between individual MDS-UPDRS non-motor items and QoL. A total of 291 PD patients were examined in a multicenter Slovak study. Patients were assessed by the MDS-UPDRS, HY scale and PDQ39. Data were analyzed using the multiple regression analyses. The mean participant age was 68.0 +/- 9.0 years, 53.5% were men, mean disease duration was 8.3 +/- 5.3 years and mean HY was 2.7 +/- 1.0. In a multiple regression analysis model the PDQ39 summary index was related to MDS-UPDRS parts II, I and IV respectively, but not to part III. Individual MDS-UPDRS non-motor items related to the PDQ39 summary index in the summary group and in the non fluctuating patients subgroup were pain, fatigue and features of dopamine dysregulation syndrome (DDS). In the fluctuating PD patient subgroup, PDQ39 was related to pain and Depressed mood items. Other MDS-UPDRS non-motor items e.g. Anxious mood, Apathy, Cognitive impairment, Hallucinations and psychosis, Sleep problems, Daytime sleepiness and Urinary problems were related to some PDQ39 domains. The overall burden of NMS in PD is more important in terms of QoL than motor symptoms. Individual MDS-UPDRS non-motor items related to worse QoL are especially pain and other sensations, fatigue and features of DDS. PMID- 25918078 TI - Extraction of tumour embolus following perioperative stroke. PMID- 25918079 TI - [The broad field of urticaria]. PMID- 25918080 TI - Mycology - an update Part 3: Dermatomycoses: topical and systemic therapy. AB - Treatment of dermatophyte infections is based on the clinical picture and mycological detection of the causative pathogen. Based on the appropriate indication, onychomycosis can be treated topically using an antimycotic nail lacquer. Atraumatic nail abrasion with 40 % urea ointment has a beneficial effect on healing. Continuous treatment of onychomycosis with terbinafine represents the most effective systemic therapy. Terbinafine or itraconazole are the safest and most effective antimycotic agents for the treatment of onychomycosis in children. For laser therapy of onychomycosis, only a few studies on clinical efficacy are available. Regarding tinea capitis, targeted species-specific therapy of dermatophytosis of the scalp is currently recommended. Terbinafine, yet also itraconazole and fluconazole, are effective in tinea capitis caused by Trichophyton species. Microsporum infections of the scalp are preferably treated with griseofulvin, alternatively with itraconazole or fluconazole. Terbinafine is less effective. Candidal intertrigo are topically treated with nystatin, but azoles or ciclopirox olamine are also suitable candidates. Systemically, fluconazole or itraconazole are used. Topical and systemic antimycotics are equivalent forms of therapy in acute vulvovaginal mycosis. Fluconazole is the drug of choice in chronic recurrent vulvovaginal mycosis caused by Candida albicans. Ketoconazole shows very good efficacy in tinea versicolor. With respect to systemic treatment of severe and widespread tinea versicolor, itraconazole is the drug of choice. PMID- 25918082 TI - Importance of basic therapy in psoriasis. AB - Basic therapy plays an important role in the management of psoriasis, regardless of disease severity or the therapeutic concept used. It helps reduce symptoms such as pruritus and scaling, decreases exacerbations, and may therefore prolong the remission period after successful antipsoriatic treatment. Accordingly, adequate basic therapy can also have a positive effect on patients' severely impaired quality of life. Unfortunately, the importance of basic therapy in psoriasis is still underestimated. Based on clinical trial data, the present review highlights the efficacy and potential of basic therapy, and focuses on new data and developments in this field. PMID- 25918085 TI - Chronic spontaneous urticaria - a management pathway for patients with chronic spontaneous urticaria. AB - Chronic spontaneous urticaria (CSU) is a common and challenging disease, especially with respect to healthcare provision in the context of the German statutory health insurance system. If treatment with second-generation antihistamines is unsuccessful, current guidelines recommend further therapeutic options. However, most of these are off-label. This discrepancy between treatment according to guidelines and the ability to prescribe drugs at the expense of the statutory health insurance (reimbursability) often leads to uncertainties in everyday clinical practice. In addition, physicians prescribing certain drugs are faced with the difficulty of measuring and documenting therapeutic success/outcome. Respective outcome measurement methods have not yet been established in daily practice. Using a consensus process, a working group composed of dermatologists in private practice and specialized urticaria centers has defined a practical pathway for the implementation of current treatment recommendations based on the 2013 S3 guidelines for urticaria. Here, we present a diagnostic and therapeutic management pathway for CSU. Further, we discuss prescription issues in daily practice, including updosing of antihistamines, with regard to cost-effectiveness and drug approval on the basis of published studies and current legislation. Constituting the highest treatment level, the use of cyclosporine A, montelukast, and omalizumab, which has recently become available as therapeutic option, is reviewed. The urticaria control test (UCT) is presented as a valid outcome measure in routine practice. Our objective was to provide physicians in private practice with a practical guideline-based therapeutic decision tool, taking into account the requirements imposed by the statutory health insurance system. It is not meant to replace individualized history taking or treatment of this heterogeneous disease. Rather, we would like to suggest reference points for clinical diagnosis and treatment of CSU. PMID- 25918087 TI - Efficacy of low-dose 5-fluorouracil/salicylic acid in actinic keratoses in relation to treatment duration. AB - BACKGROUND: In Germany, the number of actinic keratoses (AKs) diagnosed and dermatologically treated has steadily risen in recent years. As AKs represent an early form of squamous cell carcinoma, prompt initiation of treatment is pivotal. The objective of this non-interventional study (NIS) was to determine the efficacy of a low-dose (0.5 %) fluorouracil/10 % salicylic acid (low-dose 5 FU/SA) solution in the treatment of AKs (clinical grade I and II according to Olsen) in relation to treatment duration. PATIENTS AND METHODS: This NIS followed 1,051 AK patients from 212 centers who were treated with low-dose 5-FU/SA. Data were collected at the start of treatment, at an optional follow-up appointment during the treatment period, at the end of treatment, and during the final assessment. RESULTS: During the observation period, there was a decrease in the mean number of lesions by approximately 70 % and in mean size by approximately 80 %. Roughly one-half of the patients were treated for less than six weeks. In the final global assessment, efficacy was rated as very good or good in approximately 89 % of patients; tolerability as very good or good in 87 %. CONCLUSIONS: Under routine clinical conditions, treatment with low-dose 5-FU/SA effectively reduced AK lesions even during short treatment periods, while exhibiting good tolerability. These findings are in keeping with results obtained from a clinical phase III trial. PMID- 25918088 TI - Angiomatoid fibrous histiocytoma - case series with emphasis on a late fibrotic variant. AB - BACKGROUND: Angiomatoid fibrous histiocytoma (AFH) is a rare, low-grade malignant, subcutaneous neoplasm in children or young adults. METHODS: AFHs in different disease stages were studied histologically, in part, also immunohistologically, and by fluorescence in situ hybridization. RESULTS: Depending on the degree of fibrosclerosis, nine AFH were divided into the following categories: classic type (n = 3): well-defined subcutaneous lesions composed of multinodular spindle to epithelioid (histiocytoid) cells surrounding a pseudoangiomatous space filled with blood. Peripherally, there is a fibrous pseudocapsule and an inflammatory infiltrate. Early sclerotic type (n = 4): the fibrous capsule extends more to the inner circle of the lesion, focally replacing the cellular neoplastic component and pseudoangiomatous spaces. Late sclerotic type (n = 2): the architecture of AFH with its zonal arrangement of an outer fibrous and inner cellular component is largely replaced by fibrosis occluding the pseudovascular space in the center of the lesion. Immunohistochemistry was available in 5/9 cases with positivity for EMA (5/5), desmin (3/5), caldesmon (1/2), and CD99 (2/5). One of two cases tested displayed EWSR1 rearrangement. CONCLUSION: Late-stage AFH may present with marked fibrosis obscuring the real nature of the lesion and may easily be misinterpreted by the unwary as a harmless fibrotic condition. PMID- 25918090 TI - Rapidly growing solitary nodule of the ear: a distinctive dermatoscopic pattern. PMID- 25918092 TI - Eczema craquele, an uncommon clinical manifestation of myxedema. PMID- 25918094 TI - Shiitake dermatitis: an impressive case report. PMID- 25918098 TI - Centrifugally spreading erythematous plaques with collarette scaling and pustules. PMID- 25918100 TI - S2k guideline* "Diagnosis and therapy of syphilis"--short version. PMID- 25918105 TI - [Update on BRAF and MEK inhibitors in the treatment of malignant melanoma]. PMID- 25918108 TI - Emergency department management of syncope: need for standardization and improved risk stratification. AB - Variations in emergency department (ED) syncope management have not been well studied. The goals of this study were to assess variations in management, and emergency physicians' risk perception and disposition decision making. We conducted a prospective study of adults with syncope in six EDs in four cities over 32 months. We collected patient characteristics, ED management, disposition, physicians' prediction probabilities at index presentation and followed patients for 30 days for serious outcomes: death, myocardial infarction (MI), arrhythmia, structural heart disease, pulmonary embolism, significant hemorrhage, or procedural interventions. We used descriptive statistics, ROC curves, and regression analyses. We enrolled 3662 patients: mean age 54.3 years, and 12.9 % were hospitalized. Follow-up data were available for 3365 patients (91.9 %) and 345 patients (10.3 %) suffered serious outcomes: 120 (3.6 %) after ED disposition including 48 patients outside the hospital. After accounting for differences in patient case mix, the rates of ED investigations and disposition were significantly different (p < 0.0001) across the four study cities; as were the rates of 30-day serious outcomes (p < 0.0001) and serious outcomes after ED disposition (p = 0.0227). There was poor agreement between physician risk perception and both observed event rates and referral patterns (p < 0.0001). Only 76.7 % (95 % CI 68.1-83.6) of patients with serious outcomes were appropriately referred. There are large and unexplained differences in ED syncope management. Moreover, there is poor agreement between physician risk perception, disposition decision making, and serious outcomes after ED disposition. A valid risk stratification tool might help standardize ED management and improve disposition decision making. PMID- 25918109 TI - Mechanical chest compression: an alternative in helicopter emergency medical services? AB - Mechanical chest compression devices are mentioned in the current guidelines of the European Resuscitation Council (ERC) as an alternative in long-lasting cardiopulmonary resuscitations (CPR) or during transport with ongoing CPR. We compared manual chest compression with mechanical devices in a rescue-helicopter based scenario using a resuscitation manikin. Manual chest compression was compared with the mechanical devices LUCASTM 2, AutoPulseTM and animax mono (10 series each) using the resuscitation manikin AmbuMan MegaCode Wireless, which was intubated endotracheally and controlled ventilated during the entire scenario. The scenario comprised the installation of each device, transport and loading phases, as well as a 10-min phase inside the helicopter (type BK 117). We investigated practicability as well as measured compression quality. All mechanical devices could be used readily in a BK 117 helicopter. The LUCAS 2 group was the only one that fulfilled all recommendations of the ERC (frequency 102 +/- 0.1 min(-1), compression depth 54 +/- 3 mm, hands-off time 2.5 +/- 1.6 %). Performing adequate manual chest compression was barely possible (fraction of correct compressions 21 +/- 15 %). In all four groups, the total hands-off time was <10 %. Performing manual chest compressions during rescue-helicopter transport is barely possible, and only of poor quality. If rescuers are experienced, mechanical chest compression devices could be good alternatives in this situation. We found that the LUCAS 2 system complied with all recommendations of ERC guidelines, and all three tested devices worked consistently during the entire scenario. PMID- 25918110 TI - Determination of the protein expression profiles of breast cancer cell lines by quantitative proteomics using iTRAQ labelling and tandem mass spectrometry. AB - Breast cancer is the principal cancer in women worldwide. Although there are serum tumor markers such as CEA and HER2, they are detected in advanced stages of the disease and used as progression and recurrence markers. Therefore, there is a necessity for the identification of new markers that might lead to an early detection and also provide evidence of an effective treatment. The aim of this work was to determine the differential protein expression profiles of four breast cancer cell lines in comparison to a normal control cell line by iTRAQ labelling and tandem mass spectrometry, in order to identify putative biomarkers of the disease. We identified 1,020 iTRAQ-labelled polypeptides with at least one peptide identified with more than 95% in confidence. Overexpressed polypeptides in all cancer cell lines were 78, whilst the subexpressed were 128. We categorised them with PANTHER program into biological processes, being the metabolic pathways the most affected. We detected six groups of proteins with the STRING program involved in DNA topology, glycolysis, translation initiation, splicing, pentose pathway, and proteasome degradation. The main subexpressed protein network included mitochondrial proteins involved in oxidative phosphorylation. We propose BAG6, DDX39, ANXA8 and COX4 as putative biomarkers in breast cancer. BIOLOGICAL SIGNIFICANCE: We report a set of differentially expressed proteins in the MCF7 and T47D (Luminal A), MDA-MB-231 (Claudin low) and SK-BR-3 (HER2(+)) breast cancer cell lines that have not been previously reported in breast cancer disease. From these proteins, we propose BAG6, DDX39, ANXA8 and COX4 as putative biomarkers in breast cancer. On the other hand, we propose sets of unique polypeptides in each breast cancer cell line that can be useful in the classification of different subtypes of breast cancer. PMID- 25918112 TI - "Protect Your Loved Ones From Fataki": Discouraging Cross-Generational Sex in Tanzania. AB - The Fataki campaign aired in Tanzania via radio from 2008 to 2011 to address cross-generational sex, a major driver of HIV in the region. The campaign sought to incite social disapproval of men who engage in such relationships, generate dialogue around the issue, and encourage community interventions in these relationships through social learning. Using qualitative methods, we explored campaign reactions, use of the term Fataki to describe men in relationships with much younger women, and the nature of discussions spurred by the campaign. We conducted focus group discussions and individual interviews in Iringa and Pwani regions with young women, older men, and community leaders. Results showed that the Fataki term was widely used and had negative connotations reflecting social disapproval of men who participate in such relationships. Dialogue spurred by the campaign, primarily directed toward young women, focused on reasons for avoiding these relationships. We conclude with suggestions for relevant future interventions. PMID- 25918111 TI - Sensitivity of [(11)C]ORM-13070 to increased extracellular noradrenaline in the CNS - a PET study in human subjects. AB - RATIONALE: No validated methods have been available for studying brain noradrenergic neurotransmission in vivo in humans. Positron emission tomography (PET) radiotracers are widely used in clinical drug development targeted to brain receptors and can also in some cases be employed to monitor extracellular (synaptic) neurotransmitter concentrations. OBJECTIVES: The objective of this study is to test the sensitivity of [(11)C]ORM-13070 uptake to increased concentrations of extracellular (synaptic) noradrenaline in the human brain. METHODS: Eight subjects underwent a control PET scan with [(11)C]ORM-13070, a subtype-selective alpha2C-adrenoceptor antagonist radioligand, and two PET scans after two different noradrenaline challenges, i.e. during ketamine infusion and after a dose of atomoxetine combined with cold stimulation. Tracer uptake in the caudate nucleus and putamen was described with AUC values in scan time windows of 10-20 and 5-30 min post injection and quantified with the ratio method. Voxel based analysis was performed with average bound per free (B/F) ratio images. RESULTS: Both noradrenaline challenges were consistently associated with 10-20 % (p < 0.05) reductions in tracer uptake in the dorsal striatum, as determined with region-of-interest-based analysis. Voxel-based analysis revealed significant reductions in B/F ratios in the dorsal striatum, in the brain stem and in several cortical areas. Reductions of 24 and 23 % were detected in the peak putamen clusters with ketamine and atomoxetine + cold, respectively. CONCLUSION: Direct experimental support was gained for the suitability of [(11)C]ORM-13070 for imaging of brain noradrenergic neurotransmission. PMID- 25918113 TI - Enacting Varieties of Subjectivity Through Practices of Care: A Story of Living With Motor Neuron Disease. AB - People living with disability or chronic illness often use practices of care to construct a version of life they are satisfied with. Drawing from a narrative based study with people living with motor neuron disease (MND), I show how one couple tried to be recognized as active agents in their life, although oscillating between positions of less and more power. Through an examination of the practices of care that the couple enacted, I illustrate how their positioning in relation to practices of care helped them create meaning in their life. In their efforts to create a way of living they were satisfied with, they engaged in negotiations between varieties of subjectivity. Their subjectivity was not static but was constructed as they shared power to carry out everyday self-care activities. The findings also underline the importance for health care practices of exploring the experiential knowledge of people living with MND. PMID- 25918114 TI - Decision Making About Gastrostomy and Noninvasive Ventilation in Amyotrophic Lateral Sclerosis. AB - We used thematic analysis to investigate factors affecting decision making about gastrostomy and noninvasive ventilation (NIV) by people with Amyotrophic Lateral Sclerosis (ALS) from the viewpoint of the health care professionals (HCPs) supporting them. We conducted 20 in-depth interviews with 19 HCPs nominated by people with ALS who had made a decision to accept or decline NIV or gastrostomy. We found the main themes influencing decision making were patient-centric, caregiver-related or related to HCPs' own beliefs, perspectives, and actions. HCPs felt patients should be, and were, in control of decision making, although caregivers and HCPs played a role. The patient's evaluation of quality of life, the desirability of prolonging life, and acceptance of the disease and its progression by both patient and caregiver were the most important factors identified by HCPs. HCPs should be aware of the importance of multiprofessional discussions, and the potential influences (identified above) that might require discussion with patients and caregivers. PMID- 25918115 TI - Surgical Considerations in d-Transposition of the Great Arteries. AB - The surgical treatment for d-transposition has evolved dramatically since the inception of cardiac surgery in the 1950s. Today, the arterial switch operation is employed almost exclusively in the management of this disease unless significant left ventricular outflow obstruction is present. Surgical options for these patents are reviewed and an in-depth technical discussion of arterial switch for d-transposition of the great arteries/intact ventricular septum follows. PMID- 25918116 TI - Genome-wide association of carbon and nitrogen metabolism in the maize nested association mapping population. AB - Carbon (C) and nitrogen (N) metabolism are critical to plant growth and development and are at the basis of crop yield and adaptation. We performed high throughput metabolite analyses on over 12,000 samples from the nested association mapping population to identify genetic variation in C and N metabolism in maize (Zea mays ssp. mays). All samples were grown in the same field and used to identify natural variation controlling the levels of 12 key C and N metabolites, namely chlorophyll a, chlorophyll b, fructose, fumarate, glucose, glutamate, malate, nitrate, starch, sucrose, total amino acids, and total protein, along with the first two principal components derived from them. Our genome-wide association results frequently identified hits with single-gene resolution. In addition to expected genes such as invertases, natural variation was identified in key C4 metabolism genes, including carbonic anhydrases and a malate transporter. Unlike several prior maize studies, extensive pleiotropy was found for C and N metabolites. This integration of field-derived metabolite data with powerful mapping and genomics resources allows for the dissection of key metabolic pathways, providing avenues for future genetic improvement. PMID- 25918117 TI - HISTONE DEACETYLASE6 Controls Gene Expression Patterning and DNA Methylation Independent Euchromatic Silencing. AB - To investigate the role of chromatin regulators in patterning gene expression, we employed a unique epigenetically controlled and highly tissue-specific green fluorescent protein reporter line in Arabidopsis (Arabidopsis thaliana). Using a combination of forward and reverse genetic approaches on this line, we show here that distinct epigenetic regulators are involved in silencing the transgene in different tissues. The forward genetic screen led to the identification of a novel HISTONE DEACETYLASE6 (HDA6) mutant allele (epigenetic control1, hda6-8). This allele differs from the previously reported alleles, as it did not affect DNA methylation and only had a very modest effect on the release of transposable elements and other heterochromatic transcripts. Overall, our data shows that HDA6 has at least two clearly separable activities in different genomic regions. In addition, we present an unexpected role for HDA6 in the control of DNA methylation at CG dinucleotides. PMID- 25918118 TI - Association of Attention Deficit Disorder With Bedside Anti-saccades in Survivors of Childhood Leukemia. AB - Impaired attention is well recognized in childhood cancer survivors. We prospectively evaluated 162 long-term survivors of childhood acute lymphoblastic leukemia to study an association between presence of neurologic soft signs as measured by Zurich Neuromotor Scale, bedside evaluation of anti-saccades, and attention deficit disorder. Attention deficit disorder was recognized in 10.5% of the study cohort. We did not find an association of attention deficit with presence of any soft sign. However, there was an association between presence of abnormal anti-saccades and attention deficit (P = .04). These results will require further validation and if confirmed may introduce a quick bedside method of assessing impaired attention in cancer survivors. PMID- 25918119 TI - Peripheral Innervation in Children With Global Developmental Delay: Biomarker for Risk for Self-Injurious Behavior? AB - The relation between somatosensory mechanisms and self-injury among children with neurologic impairments associated with developmental delay is not well understood. We evaluated the feasibility of procuring skin biopsies to examine epidermal nerve fiber density and reported self-injury. Following informed parental consent, epidermal skin biopsies were obtained from a distal leg site with no pre-existing skin damage from 11 children with global developmental delay (55% male; mean age = 36.8 months, 17-63 months). Visual microscopic examination and quantitative analyses showed extremely high epidermal nerve fiber density values for some children. Children with reported self-injury (5/11) had significantly (P < .02) greater density values (138.8, standard deviation = 45.5) than children without self-injury (80.5, standard deviation = 17.5). Results from this novel immunohistologic analysis of skin in very young children with neurodevelopmental delays suggest it may be a useful tool to study peripheral innervation as a possible sensory risk factor for self-injury. PMID- 25918120 TI - Guideline update: The British Thoracic Society Guidelines on home oxygen use in adults. AB - The 2015 British Thoracic Society (BTS) Home Oxygen Guidelines provides detailed evidence-based guidance for the use of oxygen by patients in their own homes or other non-acute hospital settings. PMID- 25918121 TI - Epidemiology of spontaneous pneumothorax: gender-related differences. AB - BACKGROUND: Epidemiology of spontaneous pneumothorax has been scantily studied. We aimed to assess the incidence of spontaneous pneumothorax and describe patients' characteristics with respect to age, sex, seasonal occurrence, primary or secondary character, surgical management and rehospitalisations on a large scale database. METHODS: Data from all patients aged >=14 years and hospitalised with a diagnosis of non-traumatic pneumothorax in France from 2008 to 2011 were retrieved from the National Hospitalisation Database. RESULTS: There were 59 637 hospital stays corresponding to 42 595 patients. Twenty-eight per cent of patients were rehospitalised at least once during the 4-year period. Annual rate of pneumothorax could be estimated at 22.7 (95% CI 22.4 to 23.0) cases for 100 000 habitants. The women to men ratio was 1:3.3. Mean age was significantly higher in women than in men (41+/-19 vs 37+/-19 years, p<0.0001). No seasonal variation was observed. A surgical procedure was performed in 14 352 hospital stays (24%). In the group of patients aged <30 years, there was no statistical difference between men and women with regard to type of pneumothorax (primary or secondary), type of hospitalisation unit (surgery vs medicine), treatment modality (surgery or not), intensive care unit (ICU) admission and hospital stay duration. Rehospitalisation was more frequent in women than in men (56% vs 52%, p<0.0001). In the 30-49 years age group, surgery and rehospitalisation were more frequent in women than in men (each, p<0.001). In the 50-64 years age group, surgical procedures and rehospitalisations were more frequent in men than in women (p=0.002 and p<0.0001, respectively). CONCLUSIONS: Sex and age are determinant factors in the course of spontaneous pneumothorax. PMID- 25918122 TI - c-Kit+ cells isolated from human fetal retinas represent a new population of retinal progenitor cells. AB - Definitive surface markers for retinal progenitor cells (RPCs) are still lacking. Therefore, we sorted c-Kit(+) and stage-specific embryonic antigen-4(-) (SSEA4( )) retinal cells for further biological characterization. RPCs were isolated from human fetal retinas (gestational age of 12-14 weeks). c-Kit(+)/SSEA4(-) RPCs were sorted by fluorescence-activated cell sorting, and their proliferation and differentiation capabilities were evaluated by using immunocytochemistry and flow cytometry. The effectiveness and safety were assessed following injection of c Kit(+)/SSEA4(-) cells into the subretina of Royal College of Surgeons (RCS) rats. c-Kit(+) cells were found in the inner part of the fetal retina. Sorted c Kit(+)/SSEA4(-) cells expressed retinal stem cell markers. Our results clearly demonstrate the proliferative potential of these cells. Moreover, c-Kit(+)/SSEA4( ) cells differentiated into retinal cells that expressed markers of photoreceptor cells, ganglion cells and glial cells. These cells survived for at least 3 months after transplantation into the host subretinal space. Teratomas were not observed in the c-Kit(+)/SSEA4(-)-cell group. Thus, c-Kit can be used as a surface marker for RPCs, and c-Kit(+)/SSEA4(-) RPCs exhibit the ability to self-renew and differentiate into retinal cells. PMID- 25918123 TI - Inner workings and biological impact of phospholipid flippases. AB - The plasma membrane, trans-Golgi network and endosomal system of eukaryotic cells are populated with flippases that hydrolyze ATP to help establish asymmetric phospholipid distributions across the bilayer. Upholding phospholipid asymmetry is vital to a host of cellular processes, including membrane homeostasis, vesicle biogenesis, cell signaling, morphogenesis and migration. Consequently, defining the identity of flippases and their biological impact has been the subject of intense investigations. Recent work has revealed a remarkable degree of kinship between flippases and cation pumps. In this Commentary, we review emerging insights into how flippases work, how their activity is controlled according to cellular demands, and how disrupting flippase activity causes system failure of membrane function, culminating in membrane trafficking defects, aberrant signaling and disease. PMID- 25918125 TI - LigLAP: Encirclement and Ligation of Vessels in Laparoscopic Surgery: A Double Layer Suture Sealing Approach. AB - This article proposes a potential automatic ligation (LigLAP) method to occlude vessels and ducts in several laparoscopic surgical procedures. Currently, stapling devices are widely used for this purpose. However, there are some complications associated with stapling devices, including biliary leak and tissue damage. In this article, we examine the feasibility of an alternative method that uses a double-layer suture to encircle and occlude a vessel. A heating element melts the outer layer of the suture at the cross-point of the suture to create a seal. Several electromechanical mechanisms have been proposed to carry out this ligation process. In addition, some parts have been prototyped for experimental verification and visualization. Several double-layered sutures have been created, and their tensile strength and sealing capabilities have been measured. Moreover, a simple leakage experiment has been performed to verify experimentally the idea of using the double-layer suture. The results show that the new suture and the thermal sealing method provide the required strength to occlude balloons filled with water. Although the results suggest that the proposed method and the double layer suture may be used in surgical ligation processes, much more rigorous testing of leakage is required. PMID- 25918126 TI - The National Physical Activity Plan: a call to action from the American Heart Association: a science advisory from the American Heart Association. PMID- 25918124 TI - Mechanobiology of myofibroblast adhesion in fibrotic cardiac disease. AB - Fibrotic cardiac disease, a leading cause of death worldwide, manifests as substantial loss of function following maladaptive tissue remodeling. Fibrosis can affect both the heart valves and the myocardium and is characterized by the activation of fibroblasts and accumulation of extracellular matrix. Valvular interstitial cells and cardiac fibroblasts, the cell types responsible for maintenance of cardiac extracellular matrix, are sensitive to changing mechanical environments, and their ability to sense and respond to mechanical forces determines both normal development and the progression of disease. Recent studies have uncovered specific adhesion proteins and mechano-sensitive signaling pathways that contribute to the progression of fibrosis. Integrins form adhesions with the extracellular matrix, and respond to changes in substrate stiffness and extracellular matrix composition. Cadherins mechanically link neighboring cells and are likely to contribute to fibrotic disease propagation. Finally, transition to the active myofibroblast phenotype leads to maladaptive tissue remodeling and enhanced mechanotransductive signaling, forming a positive feedback loop that contributes to heart failure. This Commentary summarizes recent findings on the role of mechanotransduction through integrins and cadherins to perpetuate mechanically induced differentiation and fibrosis in the context of cardiac disease. PMID- 25918128 TI - Does myocardial infarction beget atrial fibrillation and atrial fibrillation beget myocardial infarction? PMID- 25918127 TI - Atrial Fibrillation and Risk of ST-Segment-Elevation Versus Non-ST-Segment Elevation Myocardial Infarction: The Atherosclerosis Risk in Communities (ARIC) Study. AB - BACKGROUND: It has recently been reported that atrial fibrillation (AF) is associated with an increased risk of myocardial infarction (MI). However, the mechanism underlying this association is currently unknown. Further study of the relationship of AF with the type of MI (ST-segment-elevation MI [STEMI] versus non-ST-segment-elevation MI [NSTEMI]) might shed light on the potential mechanisms. METHODS AND RESULTS: We examined the association between AF and incident MI in 14 462 participants (mean age, 54 years; 56% women; 26% blacks) from the Atherosclerosis Risk in Communities (ARIC) study who were free of coronary heart disease at baseline (1987-1989) with follow-up through December 31, 2010. AF cases were identified from study visit ECGs and by review of hospital discharge records. Incident MI and its types were ascertained by an independent adjudication committee. Over a median follow-up of 21.6 years, 1374 MI events occurred (829 NSTEMIs, 249 STEMIs, 296 unclassifiable MIs). In a multivariable-adjusted model, AF (n=1545) as a time-varying variable was associated with a 63% increased risk of MI (hazard ratio,1.63; 95% confidence interval, 1.32-2.02). However, AF was associated with NSTEMI (hazard ratio, 1.80; 95% confidence interval, 1.39-2.31) but not STEMI (hazard ratio, 0.49; 95% confidence interval, 0.18-1.34; P for hazard ratio comparison=0.004). Combining the unclassifiable MI group with either STEMI or NSTEMI did not change this conclusion. The association between AF and MI, total and NSTEMI, was stronger in women than in men (P for interaction <0.01 for both). CONCLUSIONS: AF is associated with an increased risk of incident MI, especially in women. However, this association is limited to NSTEMI. PMID- 25918129 TI - Cigarette brands with flavour capsules in the filter: trends in use and brand perceptions among smokers in the USA, Mexico and Australia, 2012-2014. AB - OBJECTIVE: To describe trends, correlates of use and consumer perceptions related to the product design innovation of flavour capsules in cigarette filters. METHODS: Quarterly surveys from 2012 to 2014 were analysed from an online consumer panel of adult smokers aged 18-64, living in the USA (n=6865 observations; 4154 individuals); Mexico (n=5723 observations; 3366 individuals); and Australia (n=5864 observations; 2710 individuals). Preferred brand varieties were classified by price (ie, premium; discount) and flavour (ie, regular; flavoured without capsule; flavoured with capsule). Participants reported their preferred brand variety's appeal (ie, satisfaction; stylishness), taste (ie, smoothness, intensity), and harm relative to other brands and varieties. GEE models were used to determine time trends and correlates of flavour capsule use, as well as associations between preferred brand characteristics (ie, price stratum, flavour) and perceptions of relative appeal, taste and harm. RESULTS: Preference for flavour capsules increased significantly in Mexico (6% to 14%) and Australia (1% to 3%), but not in the USA (4% to 5%). 18-24 year olds were most likely to prefer capsules in the USA (10%) and Australia (4%), but not Mexico. When compared to smokers who preferred regular brands, smokers who preferred brands with capsules viewed their variety of cigarettes as having more positive appeal (all countries), better taste (all countries), and lesser risk (Mexico, USA) than other brand varieties. CONCLUSIONS: Results indicate that use of cigarettes with flavour capsules is growing, is associated with misperceptions of relative harm, and differentiates brands in ways that justify regulatory action. PMID- 25918130 TI - The role of Nrf2 in oxidative stress-induced endothelial injuries. AB - Endothelial dysfunction is an important risk factor for cardiovascular disease, and it represents the initial step in the pathogenesis of atherosclerosis. Failure to protect against oxidative stress-induced cellular damage accounts for endothelial dysfunction in the majority of pathophysiological conditions. Numerous antioxidant pathways are involved in cellular redox homeostasis, among which the nuclear factor-E2-related factor 2 (Nrf2)/Kelch-like ECH-associated protein 1 (Keap1)-antioxidant response element (ARE) signaling pathway is perhaps the most prominent. Nrf2, a transcription factor with a high sensitivity to oxidative stress, binds to AREs in the nucleus and promotes the transcription of a wide variety of antioxidant genes. Nrf2 is located in the cytoskeleton, adjacent to Keap1. Keap1 acts as an adapter for cullin 3/ring-box 1-mediated ubiquitination and degradation of Nrf2, which decreases the activity of Nrf2 under physiological conditions. Oxidative stress causes Nrf2 to dissociate from Keap1 and to subsequently translocate into the nucleus, which results in its binding to ARE and the transcription of downstream target genes. Experimental evidence has established that Nrf2-driven free radical detoxification pathways are important endogenous homeostatic mechanisms that are associated with vasoprotection in the setting of aging, atherosclerosis, hypertension, ischemia, and cardiovascular diseases. The aim of the present review is to briefly summarize the mechanisms that regulate the Nrf2/Keap1-ARE signaling pathway and the latest advances in understanding how Nrf2 protects against oxidative stress induced endothelial injuries. Further studies regarding the precise mechanisms by which Nrf2-regulated endothelial protection occurs are necessary for determining whether Nrf2 can serve as a therapeutic target in the treatment of cardiovascular diseases. PMID- 25918131 TI - Radiotherapy of Hodgkin and Non-Hodgkin Lymphoma: A Nonrigid Image-Based Registration Method for Automatic Localization of Prechemotherapy Gross Tumor Volume. AB - PURPOSE: To improve the contouring of clinical target volume for the radiotherapy of neck Hodgkin/non-Hodgkin lymphoma by localizing the prechemotherapy gross target volume onto the simulation computed tomography using [18F] fluorodeoxyglucose positron emission tomography/computed tomography. MATERIAL AND METHODS: The gross target volume delineated on prechemotherapy [18F] fluorodeoxyglucose positron emission tomography/computed tomography images was warped onto simulation computed tomography using deformable image registration. Fifteen patients with neck Hodgkin/non-Hodgkin lymphoma were analyzed. Quality of image registration was measured by computing the Dice similarity coefficient on warped organs at risk. Five radiation oncologists visually scored the localization of automatic gross target volume, ranking it from 1 (wrong) to 5 (excellent). Deformable registration was compared to rigid registration by computing the overlap index between the automatic gross target volume and the planned clinical target volume and quantifying the V95 coverage. RESULTS: The Dice similarity coefficient was 0.80 +/- 0.07 (median +/- quartiles). The physicians' survey had a median score equal to 4 (good). By comparing the rigid versus deformable registration, the overlap index increased from a factor of about 4 and the V95 (percentage of volume receiving the 95% of the prescribed dose) went from 0.84 +/- 0.38 to 0.99 +/- 0.10 (median +/- quartiles). CONCLUSION: This study demonstrates the impact of using deformable registration between prechemotherapy [18F]-fluorodeoxyglucose positron emission tomography/computed tomography and simulation computed tomography, in order to automatically localize the gross target volume for radiotherapy treatment of patients with Hodgkin/non-Hodgkin lymphoma. PMID- 25918132 TI - Genome-Wide Association Study Identifies Novel Loci Associated With Diisocyanate Induced Occupational Asthma. AB - Diisocyanates, reactive chemicals used to produce polyurethane products, are the most common causes of occupational asthma. The aim of this study is to identify susceptibility gene variants that could contribute to the pathogenesis of diisocyanate asthma (DA) using a Genome-Wide Association Study (GWAS) approach. Genome-wide single nucleotide polymorphism (SNP) genotyping was performed in 74 diisocyanate-exposed workers with DA and 824 healthy controls using Omni-2.5 and Omni-5 SNP microarrays. We identified 11 SNPs that exceeded genome-wide significance; the strongest association was for the rs12913832 SNP located on chromosome 15, which has been mapped to the HERC2 gene (p = 6.94 * 10(-14)). Strong associations were also found for SNPs near the ODZ3 and CDH17 genes on chromosomes 4 and 8 (rs908084, p = 8.59 * 10(-9) and rs2514805, p = 1.22 * 10( 8), respectively). We also prioritized 38 SNPs with suggestive genome-wide significance (p < 1 * 10(-6)). Among them, 17 SNPs map to the PITPNC1, ACMSD, ZBTB16, ODZ3, and CDH17 gene loci. Functional genomics data indicate that 2 of the suggestive SNPs (rs2446823 and rs2446824) are located within putative binding sites for the CCAAT/Enhancer Binding Protein (CEBP) and Hepatocyte Nuclear Factor 4, Alpha transcription factors (TFs), respectively. This study identified SNPs mapping to the HERC2, CDH17, and ODZ3 genes as potential susceptibility loci for DA. Pathway analysis indicated that these genes are associated with antigen processing and presentation, and other immune pathways. Overlap of 2 suggestive SNPs with likely TF binding sites suggests possible roles in disruption of gene regulation. These results provide new insights into the genetic architecture of DA and serve as a basis for future functional and mechanistic studies. PMID- 25918133 TI - Lung cancer and urbanization level in a region of Southern Europe: influence of socio-economic and environmental factors. AB - BACKGROUND: This study analysed the distribution of lung cancer deaths in areas with different urbanization levels in the Madrid Region and whether such differences persisted when deprivation and air pollution were considered. METHODS: This was a population-based cross-sectional study covering lung cancer deaths (2001-07). The exposure indicators were: a deprivation index based on 2001 census data; and the daily mean NO2 measurement (2002-07), both at the census tract level. Analysis was stratified by sex and age group and the Poisson regression models were applied to obtain rate ratios (RRs). RESULTS: After adjustment for age, deprivation index and NO2, mortality was similar in the city and Greater Madrid areas and lower in the rural area for the over-64 age group (RR: 0.84 in men and RR: 0.66 in women, with respect to the city of Madrid), and significantly lower in the Greater Madrid area (RR: 0.84 in men and RR: 0.74 in women) and in the rural area (RR: 0.73 in men and RR: 0.51 in women) with respect to the city of Madrid for the under-65 age group. CONCLUSIONS: The most urbanized areas of the Madrid Region are characterized by higher lung cancer mortality. PMID- 25918135 TI - Interspecies transfer of the penicillin-binding protein 3-encoding gene ftsI between Haemophilus influenzae and Haemophilus haemolyticus can confer reduced susceptibility to beta-lactam antimicrobial agents. AB - Mutations in ftsI, encoding penicillin-binding protein 3, can cause decreased beta-lactam susceptibility in Haemophilus influenzae. Sequencing of ftsI from clinical strains has indicated interspecies recombination of ftsI between H. influenzae and Haemophilus haemolyticus. This study documented apparently unrestricted homologous recombination of ftsI between H. influenzae and H. haemolyticus in vitro. Transfer of ftsI from resistant isolates conferred similar but not identical increases in the MICs of susceptible strains of H. influenzae and H. haemolyticus. PMID- 25918136 TI - Genetic analyses of penicillin binding protein determinants in multidrug resistant Streptococcus pneumoniae serogroup 19 CC320/271 clone with high-level resistance to third-generation cephalosporins. AB - We describe the dissemination of a multidrug-resistant (MDR) serogroup 19 pneumococcal clone of representative multilocus sequence type 271 (ST271) with high-level resistance to cefotaxime in Hong Kong and penicillin binding protein (pbp) genes and its relationships to Taiwan(19F)-14 and the prevalent multidrug resistant 19A clone (MDR19A-ST320). A total of 472 nonduplicate isolates from 2006 and 2011 were analyzed. Significant increases in the rates of nonsusceptibility to penicillin (PEN) (MIC >= 4.0 MUg/ml; 9.9 versus 23.3%; P = 0.0005), cefotaxime (CTX) (MIC >= 2.0 MUg/ml; 12.2 versus 30.3%; P < 0.0001 [meningitis MIC >= 1.0 MUg/ml; 30.2 versus 48.7%; P = 0.0001]), and erythromycin (ERY) (69.2 versus 84.0%; P = 0.0003) were noted when rates from 2006 and 2011 were compared. The CTX-resistant isolates with MICs of 8 MUg/ml in 2011 were of serotype 19F, belonging to ST271. Analyses of the penicillin binding protein 2x (PBP2x) amino acid sequences in relation to the corresponding sequences of the R6 strain revealed M339F, E378A, M400T, and Y595F substitutions found within the ST271 clone but not present in Taiwan(19F)-14 or MDR19A. In addition, PBP2bs of ST271 strains and that of the Taiwan(19F)-14 clone were characterized by a unique amino acid substitution, E369D, while ST320 possessed the unique amino acid substitution K366N, as does that of MDR19A in the United States. We hypothesize that ST271 originated from the Taiwan(19F)-14 lineage, which had disseminated in Hong Kong in the early 2000s, and conferred higher-level beta-lactam and cefotaxime resistance through acquisitions of 19 additional amino acid substitutions in PBP2b (amino acid [aa] positions 538 to 641) and altered PBP2x via recombination events. The serogroup 19 MDR CC320/271 clone warrants close monitoring to evaluate its effect after the switch to expanded conjugate vaccines. PMID- 25918137 TI - Silver oxynitrate, an unexplored silver compound with antimicrobial and antibiofilm activity. AB - Historically it has been accepted, and recent research has established, that silver (Ag) is an efficacious antimicrobial agent. A dwindling pipeline of new antibiotics, combined with an increase in the number of antibiotic-resistant infections, is bringing Ag to the fore as a therapeutic compound to treat infectious diseases. Currently, many formulations of Ag are being deployed for commercial and medical purposes, with various degrees of effectiveness at killing microbial cells. Here, we evaluated the antimicrobial and antibiofilm capacity of our lead compound, silver oxynitrate [Ag(Ag3O4)2NO3 or Ag7NO11], against other metal compounds with documented antimicrobial activity, including Ag2SO4, AgNO3, silver sulfadiazine (AgSD), AgO, Ag2O, and CuSO4. Our findings reveal that Ag7NO11 eradicates biofilm and planktonic populations of Pseudomonas aeruginosa, Escherichia coli, Staphylococcus aureus, uropathogenic Escherichia coli (UPEC), fluoroquinolone-resistant Pseudomonas aeruginosa (FQRP), and methicillin resistant Staphylococcus aureus (MRSA) at lower concentrations than those of the other tested metal salts. Altogether, our results demonstrate that Ag7NO11 has an enhanced efficacy for the treatment of biofilm-forming pathogens. PMID- 25918138 TI - New in vitro model to study the effect of human simulated antibiotic concentrations on bacterial biofilms. AB - A new in vitro pharmacokinetic/pharmacodynamic simulator for bacterial biofilms utilizing flow cell technology and confocal laser scanning microscopy is described. The device has the ability to simulate the changing antibiotic concentrations in humans associated with intravenous dosing on bacterial biofilms grown under continuous culture conditions. The free drug concentrations of a single 2-g meropenem intravenous bolus dose and first-order elimination utilizing a half-life of 0.895 h (elimination rate constant, 0.776 h(-1)) were simulated. The antibacterial activity of meropenem against biofilms of Pseudomonas aeruginosa PAO1 and three clinical strains isolated from patients with cystic fibrosis was investigated. Additionally, the effect of meropenem on PAO1 biofilms cultured for 24 h versus that on biofilms cultured for 72 h was examined. Using confocal laser scanning microscopy, rapid biofilm killing was observed in the first hour of the dosing interval for all biofilms. However, for PAO1 biofilms cultured for 72 h, only bacterial subpopulations at the periphery of the biofilm were affected, with subpopulations at the substratum remaining viable, even at the conclusion of the dosing interval. The described model is a novel method to investigate antimicrobial killing of bacterial biofilms using human simulated concentrations. PMID- 25918139 TI - First description of azole-resistant Aspergillus fumigatus due to TR46/Y121F/T289A mutation in France. AB - Azole resistance in Aspergillus fumigatus is an emerging public health concern. Recently, a novel fungicide-driven mutation in the cyp51A gene and its promoter, TR46/Y121F/T289A, leading to high-level resistance to voriconazole has been identified in The Netherlands, Belgium, Germany, Denmark, Tanzania, and India in both clinical and environmental samples. Here we report the first description of A. fumigatus carrying this mutation in France, in a cystic fibrosis patient, underlining the need for extensive monitoring of Aspergillus resistance. PMID- 25918140 TI - The SmeYZ efflux pump of Stenotrophomonas maltophilia contributes to drug resistance, virulence-related characteristics, and virulence in mice. AB - The resistance-nodulation-division (RND)-type efflux pump is one of the causes of the multidrug resistance of Stenotrophomonas maltophilia. The roles of the RND type efflux pump in physiological functions and virulence, in addition to antibiotic extrusion, have attracted much attention. In this study, the contributions of the constitutively expressed SmeYZ efflux pump to drug resistance, virulence-related characteristics, and virulence were evaluated. S. maltophilia KJ is a clinical isolate of multidrug resistance. The smeYZ isogenic deletion mutant, KJDeltaYZ, was constructed by a gene replacement strategy. The antimicrobial susceptibility, virulence-related physiological characteristics, susceptibility to human serum and neutrophils, and in vivo virulence between KJ and KJDeltaYZ were comparatively assessed. The SmeYZ efflux pump contributed resistance to aminoglycosides and trimethoprim-sulfamethoxazole. Inactivation of smeYZ resulted in attenuation of oxidative stress susceptibility, swimming, flagella formation, biofilm formation, and secreted protease activity. Furthermore, loss of SmeYZ increased susceptibility to human serum and neutrophils and decreased in vivo virulence in a murine model. These findings suggest the possibility of attenuation of the resistance and virulence of S. maltophilia with inhibitors of the SmeYZ efflux pump. PMID- 25918141 TI - Multiple roles for Enterococcus faecalis glycosyltransferases in biofilm associated antibiotic resistance, cell envelope integrity, and conjugative transfer. AB - The emergence of multidrug-resistant bacteria and the limited availability of new antibiotics are of increasing clinical concern. A compounding factor is the ability of microorganisms to form biofilms (communities of cells encased in a protective extracellular matrix) that are intrinsically resistant to antibiotics. Enterococcus faecalis is an opportunistic pathogen that readily forms biofilms and also has the propensity to acquire resistance determinants via horizontal gene transfer. There is intense interest in the genetic basis for intrinsic and acquired antibiotic resistance in E. faecalis, since clinical isolates exhibiting resistance to multiple antibiotics are not uncommon. We performed a genetic screen using a library of transposon (Tn) mutants to identify E. faecalis biofilm associated antibiotic resistance determinants. Five Tn mutants formed wild-type biofilms in the absence of antibiotics but produced decreased biofilm biomass in the presence of antibiotic concentrations that were subinhibitory to the parent strain. Genetic determinants responsible for biofilm-associated antibiotic resistance include components of the quorum-sensing system (fsrA, fsrC, and gelE) and two glycosyltransferase (GTF) genes (epaI and epaOX). We also found that the GTFs play additional roles in E. faecalis resistance to detergent and bile salts, maintenance of cell envelope integrity, determination of cell shape, polysaccharide composition, and conjugative transfer of the pheromone-inducible plasmid pCF10. The epaOX gene is located in a variable extended region of the enterococcal polysaccharide antigen (epa) locus. These data illustrate the importance of GTFs in E. faecalis adaptation to diverse growth conditions and suggest new targets for antimicrobial design. PMID- 25918142 TI - First detection of AmpC beta-lactamase bla(CMY-2) on a conjugative IncA/C plasmid in a Vibrio parahaemolyticus isolate of food origin. AB - Vibrio parahaemolyticus is an important causative agent of gastroenteritis, with the consumption of contaminated seafood being the major transmission route. Resistance to penicillin is common among V. parahaemolyticus strains, whereas cephalosporin resistance remains rare. In an attempt to assess the current prevalence and characteristics of antibiotic resistance of this pathogen in common food samples, a total of 54 (17% of the total samples) V. parahaemolyticus strains were isolated from 318 meat and seafood samples purchased from supermarkets and wet markets in Shenzhen, China, in 2013. These isolates exhibited high-level resistance to ampicillin, yet they were mostly susceptible to other antimicrobials, except for two that were resistant to extended-spectrum cephalosporins. The beta-lactamase gene blaPER-1 was detectable in one strain, V. parahaemolyticus V43, which was resistant to both third- and fourth-generation cephalosporins. Compared to other blaPER-1-positive V. parahaemolyticus strains reported in our previous studies, strain V43 was found to harbor an ~200-kb conjugative plasmid carrying genes that were different from the antimicrobial resistance genes reported from the previous studies. The beta-lactamase gene blaCMY-2 was detectable for the first time in another V. parahaemolyticus isolate, V4, which was resistant to third-generation cephalosporins. This blaCMY 2 gene was shown to be located in an ~150-kb IncA/C-type conjugative plasmid with a genetic structure consisting of traB-traV-traA-ISEcp1-blaCMY-2-blc-sugE-encR orf1-orf2-orf3-orf4-dsbC-traC, which is identical to that of other IncA/C conjugative plasmids in Enterobacteriaceae, albeit with a different size. These findings indicate that the transmission of extended-spectrum-beta-lactamase (ESBL) and AmpC beta-lactamase genes via conjugative plasmids can mediate the development of extended-spectrum cephalosporin resistance in V. parahaemolyticus, thereby posing a potential threat to public health. PMID- 25918143 TI - Cross-protection of influenza A virus infection by a DNA aptamer targeting the PA endonuclease domain. AB - Amino acid residues in the N-terminal of the PA subunit (PAN) of the influenza A virus polymerase play critical roles in endonuclease activity, protein stability, and viral RNA (vRNA) promoter binding. In addition, PAN is highly conserved among different subtypes of influenza virus, which suggests PAN to be a desired target in the development of anti-influenza agents. We selected DNA aptamers targeting the intact PA protein or the PAN domain of an H5N1 virus strain using systematic evolution of ligands by exponential enrichment (SELEX). The binding affinities of selected aptamers were measured, followed by an evaluation of in vitro endonuclease inhibitory activity. Next, the antiviral effects of enriched aptamers against influenza A virus infections were examined. A total of three aptamers targeting PA and six aptamers targeting PAN were selected. Our data demonstrated that all three PA-selected aptamers neither inhibited endonuclease activity nor exhibited antiviral efficacy, whereas four of the six PAN-selected aptamers inhibited both endonuclease activity and H5N1 virus infection. Among the four effective aptamers, one exhibited cross-protection against infections of H1N1, H5N1, H7N7, and H7N9 influenza viruses, with a 50% inhibitory concentration (IC50) of around 10 nM. Notably, this aptamer was identified at the 5th round but disappeared after the 10th round of selection, suggesting that the identification and evaluation of aptamers at early rounds of selection may be highly helpful for screening effective aptamers. Overall, our study provides novel insights for screening and developing effective aptamers for use as anti-influenza drugs. PMID- 25918144 TI - The efflux pump SmeDEF contributes to trimethoprim-sulfamethoxazole resistance in Stenotrophomonas maltophilia. AB - Trimethoprim-sulfamethoxazole (co-trimoxazole) is one of the antimicrobials of choice for the treatment of Stenotrophomonas maltophilia infections. The analysis of mutants either lacking or overexpressing the efflux pump SmeDEF shows that this efflux pump contributes to intrinsic and acquired co-trimoxazole resistance in S. maltophilia. Since SmeDEF can extrude a variety of antibiotics, selection with such antimicrobials, including quinolones, might also select for S. maltophilia co-trimoxazole resistance. PMID- 25918145 TI - Meropenem and chromacef intermediates observed in IMP-25 metallo-beta-lactamase catalyzed hydrolysis. AB - Metallo-beta-lactamases inactivate most beta-lactam antibacterials, and much attention has been paid to their catalytic mechanism. One issue of controversy has been whether beta-lactam hydrolysis generally proceeds through an anionic intermediate bound to the active-site Zn(II) ions or not. The formation of an intermediate has not been shown conclusively in imipenemase (IMP) enzymes to date. Here, we provide evidence that intermediates are formed during the hydrolysis of meropenem and chromacef catalyzed by the variant IMP-25 and, to a lesser degree, IMP-1. PMID- 25918146 TI - Evaluation of moxifloxacin-containing regimens in pathologically distinct murine tuberculosis models. AB - In the recently concluded REMox-TB trial, two 4-month moxifloxacin-containing regimens did not meet the criteria for noninferiority compared to the current 6 month first-line regimen to treat tuberculosis (TB). Despite the disappointing result, this phase 3 clinical trial provides a rare opportunity to gauge the predictive accuracy of the nonclinical models used to support regimen development. In parallel with the REMox-TB trial, we compared the efficacy of the same three regimens against chronic TB infection in the commonly used BALB/c mouse strain and in C3HeB/FeJ mice, which have attracted recent interest as a nonclinical efficacy model because they develop caseous lung lesions which may better resemble human TB. In long-term treatment experiments at two institutions, using low-dose aerosol infection models with 6- to 8-week incubation periods in both mouse strains, control mice received rifampin, isoniazid, pyrazinamide, and ethambutol (RHZE), and test mice received the same regimen with moxifloxacin replacing isoniazid (RMZE) or ethambutol (RHZM). Outcome measures were lung CFU counts during treatment and relapse after various durations of treatment. At both institutions and in both mouse strains, RMZE and RHZM reduced by approximately 1 month and 0 to 1 month, respectively, the treatment duration needed to produce the same relapse rate as RHZE. These results demonstrating generally similar treatment-shortening effects of the moxifloxacin-containing regimens in each mouse strain, with effect sizes consistent with the REMox-TB trial results, reinforce the predictive value of murine models for TB regimen development. PMID- 25918147 TI - Challenges and solutions for clinical development of new antibacterial agents: results of a survey among pharmaceutical industry professionals. AB - As the number of antibacterial medicines in the pipeline remains low, we anonymously surveyed pharmaceutical industry professionals on challenges and solutions for clinical development of these agents. Challenges were reported primarily as financial and regulatory. For multidrug-resistant organisms, there are needs for rapid diagnostic tests, new regulatory guidance, and adaptation of endpoints/trial designs. Regulators and public/private initiatives are addressing these challenges to help ensure that proposed solutions have the support of all involved stakeholders. PMID- 25918148 TI - Two novel Salmonella genomic island 1 variants in Proteus mirabilis isolates from swine farms in China. AB - Four different Salmonella genomic island 1 (SGI1) variants, including two novel variants, were characterized in one Salmonella enterica serovar Rissen sequence type ST1917 isolate and three Proteus mirabilis isolates from swine farms in China. One novel variant was derived from SGI1-B with the backbone gene S021 disrupted by a 12.72-kb IS26 composite transposon containing the dfrA17-aadA5 cassettes and macrolide inactivation gene cluster mphA-mrx-mphR. The other one was an integron-free SGI1 and contained a 183-bp truncated S025 next to IS6100 and S044. PMID- 25918149 TI - Randomized Noninferiority Trial of Dihydroartemisinin-Piperaquine Compared with Sulfadoxine-Pyrimethamine plus Amodiaquine for Seasonal Malaria Chemoprevention in Burkina Faso. AB - The WHO recommends that children living in areas of highly seasonal malaria transmission in the Sahel subregion should receive seasonal malaria chemoprevention (SMC) with sulfadoxine-pyrimethamine plus amodiaquine (SPAQ). We evaluated the use of dihydroartemisinin-piperaquine (DHAPQ) as an alternative drug that could be used if SPAQ starts to lose efficacy. A total of 1,499 children 3 to 59 months old were randomized to receive SMC with SPAQ or DHAPQ over 3 months. The primary outcome measure was the risk of clinical malaria (fever or a history of fever with a parasite density of at least 3,000/MUl). A cohort of 250 children outside the trial was followed up as a control group. Molecular markers of drug resistance were assessed. The risk of a malaria attack was 0.19 in the DHAPQ group and 0.15 in the SPAQ group, an odds ratio of 1.33 (95% confidence interval [CI], 1.02 to 1.72). Efficacy of SMC compared to the control group was 77% (67% to 84%) for DHAPQ and 83% (74% to 89%) for SPAQ. pfdhfr and pfdhps mutations associated with antifolate resistance were more prevalent in parasites from children who received SPAQ than in children who received DHAPQ. Both regimens were highly efficacious and well tolerated. DHAPQ is a potential alternative drug for SMC. (This trial is registered at ClinicalTrials.gov under registration no. NCT00941785.). PMID- 25918150 TI - Stability of the antimalarial drug dihydroartemisinin under physiologically relevant conditions: implications for clinical treatment and pharmacokinetic and in vitro assays. AB - Artemisinins are peroxidic antimalarial drugs known to be very potent but highly chemically unstable; they degrade in the presence of ferrous iron, Fe(II)-heme, or biological reductants. Less documented is how this translates into chemical stability and antimalarial activity across a range of conditions applying to in vitro testing and clinical situations. Dihydroartemisinin (DHA) is studied here because it is an antimalarial drug on its own and the main metabolite of other artemisinins. The behaviors of DHA in phosphate-buffered saline, plasma, or erythrocyte lysate at different temperatures and pH ranges were examined. The antimalarial activity of the residual drug was evaluated using the chemosensitivity assay on Plasmodium falciparum, and the extent of decomposition of DHA was established through use of high-performance liquid chromatography with electrochemical detection analysis. The role of the Fe(II)-heme was investigated by blocking its reactivity using carbon monoxide (CO). A significant reduction in the antimalarial activity of DHA was seen after incubation in plasma and to a lesser extent in erythrocyte lysate. Activity was reduced by half after 3 h and almost completely abolished after 24 h. Serum-enriched media also affected DHA activity. Effects were temperature and pH dependent and paralleled the increased rate of decomposition of DHA from pH 7 upwards and in plasma. These results suggest that particular care should be taken in conducting and interpreting in vitro studies, prone as their results are to experimental and drug storage conditions. Disorders such as fever, hemolysis, or acidosis associated with malaria severity may contribute to artemisinin instability and reduce their clinical efficacy. PMID- 25918151 TI - Emergence of polymyxin B resistance influences pathogenicity in Pseudomonas aeruginosa mutators. AB - The interplay between polymyxin B pharmacodynamics and pathogenicity was examined in Pseudomonas aeruginosa PAO1 and isogenic DNA repair-deficient mutators (mutM and mutS strains). Against mutS mutators, polymyxin B initial killing was concentration dependent, with >99.9% bacterial reduction at 2 h followed by regrowth and resistance. The pre- versus postexposed strains were inoculated real time into Galleria mellonella waxworms, resulting in increased median survival times from 20 h to 23 h (P < 0.001). Emergence of resistance in mutS P. aeruginosa resulted in attenuation of virulence. PMID- 25918152 TI - Saccharomyces cerevisiae-based mutational analysis of the bc1 complex Qo site residue 279 to study the trade-off between atovaquone resistance and function. AB - The bc1 complex is central to mitochondrial bioenergetics and the target of the antimalarial drug atovaquone that binds in the quinol oxidation (Qo) site of the complex. Structural analysis has shown that the Qo site residue Y279 (Y268 in Plasmodium falciparum) is key for atovaquone binding. Consequently, atovaquone resistance can be acquired by mutation of that residue. In addition to the probability of amino acid substitution, the level of atovaquone resistance and the loss of bc1 complex activity that are associated with the novel amino acid would restrict the nature of resistance-driven mutations occurring on atovaquone exposure in native parasite populations. Using the yeast model, we characterized the effect of all the amino acid replacements resulting from a single nucleotide substitution at codon 279: Y279C, Y279D, Y279F, Y279H, Y279N, and Y279S (Y279C, D, F, H, N, and S). Two residue changes that required a double nucleotide substitution, Y279A and W, were added to the series. We found that mutations Y279A, C, and S conferred high atovaquone resistance but decreased the catalytic activity. Y279F had wild-type enzymatic activity and sensitivity to atovaquone, while the other substitutions caused a dramatic respiratory defect. The results obtained with the yeast model were examined in regard to atomic structure and compared to the reported data on the evolution of acquired atovaquone resistance in P. falciparum. PMID- 25918153 TI - Dominance of IMP-4-producing enterobacter cloacae among carbapenemase-producing Enterobacteriaceae in Australia. AB - The prevalence of carbapenemase-producing Enterobacteriaceae (CPE) has been increasing worldwide. blaIMP has been reported to be the predominant carbapenemase-encoding gene within Enterobacteriaceae in Australia. However, there are limited data currently available on CPE from Queensland, Australia. A total of 58 CPE isolates were isolated between July 2009 and March 2014 from Queensland hospitals. The clonality of isolates was determined by Diversilab repetitive sequence-based PCR. The isolates were investigated for the resistance mechanisms carbapenemase, extended-spectrum beta-lactamase, and AmpC beta lactamase and for aminoglycoside resistance and plasmid-mediated quinolone resistance genes by PCR. The plasmid types associated with carbapenemase-encoding genes were characterized. The majority of the CPE were Enterobacter cloacae (n = 29). The majority of Queensland CPE isolates were IMP producers and comprised 11 species (n = 48). Nine NDM-producing Enterobacteriaceae were identified. One NDM producing Klebsiella pneumoniae isolate coproduced OXA-48. One K. pneumoniae isolate was an OXA-181 producer. The incidence of IMP producers increased significantly in 2013. blaIMP-4 was found in all IMP-producing isolates. blaTEM, qnrB, and aacA4 were common among IMP-4 producers. The HI2 (67%) and L/M (21%) replicons were associated with blaIMP-4. All HI2 plasmids were of sequence type 1 (ST1). All but one of the NDM producers possessed blaCTX-M-15. The 16S rRNA methylase genes found among NDM producers were armA, rmtB, rmtC, and rmtF. The substantial increase in the prevalence of CPE in Queensland has been associated mainly with the emergence E. cloacae strains possessing HI2 plasmids carrying blaIMP-4 over the past 2 years. The importation of NDM producers and/or OXA-48 like producers in patients also contributed to the increased emergence of CPE. PMID- 25918154 TI - Role of Apolipoprotein E in beta-Amyloidogenesis: ISOFORM-SPECIFIC EFFECTS ON PROTOFIBRIL TO FIBRIL CONVERSION OF Abeta IN VITRO AND BRAIN Abeta DEPOSITION IN VIVO. AB - Human APOE epsilon4 allele is a strong genetic risk factor of Alzheimer disease. Neuropathological and genetic studies suggested that apolipoprotein E4 (apoE4) protein facilitates deposition of amyloid beta peptide (Abeta) in the brain, although the mechanism whereby apoE4 increases amyloid aggregates remains elusive. Here we show that injection of Abeta protofibrils induced Abeta deposition in the brain of APP transgenic mice, suggesting that Abeta protofibrils acted as a seed for aggregation and deposition of Abeta in vivo. Injection of Abeta protofibrils together with apoE3 significantly attenuated Abeta deposition, whereas apoE4 did not have this effect. In vitro assays revealed that the conversion of Abeta protofibrils to fibrils progressed more slowly upon coincubation with apoE2 or apoE3 compared with that with apoE4. Abeta protofibrils complexed with apoE4 were less stable than those with apoE2 or apoE3. These data suggest that the suppression effect of apoE2 or apoE3 on the structural conversion of Abeta protofibrils to fibrils is stronger than those of apoE4, thereby impeding beta-amyloid deposition. PMID- 25918156 TI - Distinct Agonist Regulation of Muscarinic Acetylcholine M2-M3 Heteromers and Their Corresponding Homomers. AB - Each subtype of the muscarinic receptor family of G protein-coupled receptors is activated by similar concentrations of the neurotransmitter acetylcholine or closely related synthetic analogs such as carbachol. However, pharmacological selectivity can be generated by the introduction of a pair of mutations to produce Receptor Activated Solely by Synthetic Ligand (RASSL) forms of muscarinic receptors. These display loss of potency for acetylcholine/carbachol alongside a concurrent gain in potency for the ligand clozapine N-oxide. Co-expression of a form of wild type human M2 and a RASSL variant of the human M3 receptor resulted in concurrent detection of each of M2-M2 and M3-M3 homomers alongside M2-M3 heteromers at the surface of stably transfected Flp-In(TM) T-REx(TM) 293 cells. In this setting occupancy of the receptors with a muscarinic antagonist was without detectable effect on any of the muscarinic oligomers. However, selective agonist occupancy of the M2 receptor resulted in enhanced M2-M2 homomer interactions but decreased M2-M3 heteromer interactions. By contrast, selective activation of the M3 RASSL receptor did not significantly alter either M3-M3 homomer or M2-M3 heteromer interactions. Selectively targeting closely related receptor oligomers may provide novel therapeutic opportunities. PMID- 25918155 TI - Truncation and Activation of Dual Specificity Tyrosine Phosphorylation-regulated Kinase 1A by Calpain I: A MOLECULAR MECHANISM LINKED TO TAU PATHOLOGY IN ALZHEIMER DISEASE. AB - Hyperphosphorylation and dysregulation of exon 10 splicing of Tau are pivotally involved in pathogenesis of Alzheimer disease (AD) and/or other tauopathies. Alternative splicing of Tau exon 10, which encodes the second microtubule-binding repeat, generates Tau isoforms containing three and four microtubule-binding repeats, termed 3R-Taus and 4R-Taus, respectively. Dual specificity tyrosine phosphorylation-regulated kinase 1A (Dyrk1A) lies at the Down syndrome critical region of chromosome 21. Overexpression of this kinase may contribute to the early Tau pathology in Down syndrome via phosphorylation of Tau and dysregulation of Tau exon 10. Here, we report that Dyrk1A was truncated at the C terminus and was associated with overactivation of calpain I in AD brain. Calpain I proteolyzed Dyrk1A in vitro first at the C terminus and further at the N terminus and enhanced its kinase activity toward Tau via increased Vmax but not Km. C terminal truncation of Dyrk1A resulted in stronger activity than its full-length protein in promotion of exon 10 exclusion and phosphorylation of Tau. Dyrk1A was truncated in kainic acid-induced excitotoxic mouse brains and coincided with an increase in 3R-Tau expression and phosphorylation of Tau via calpain activation. Moreover, truncation of Dyrk1A was correlated with an increase in the ratio of 3R Tau/4R-Tau and Tau hyperphosphorylation in AD brain. Collectively, these findings suggest that truncation/activation of Dyrk1A by Ca(2+)/calpain I might contribute to Tau pathology via promotion of exon 10 exclusion and hyperphosphorylation of Tau in AD brain. PMID- 25918157 TI - The Crystal Structure of Cancer Osaka Thyroid Kinase Reveals an Unexpected Kinase Domain Fold. AB - Macrophages are important cellular effectors in innate immune responses and play a major role in autoimmune diseases such as rheumatoid arthritis. Cancer Osaka thyroid (COT) kinase, also known as mitogen-activated protein kinase kinase kinase 8 (MAP3K8) and tumor progression locus 2 (Tpl-2), is a serine-threonine (ST) kinase and is a key regulator in the production of pro-inflammatory cytokines in macrophages. Due to its pivotal role in immune biology, COT kinase has been identified as an attractive target for pharmaceutical research that is directed at the discovery of orally available, selective, and potent inhibitors for the treatment of autoimmune disorders and cancer. The production of monomeric, recombinant COT kinase has proven to be very difficult, and issues with solubility and stability of the enzyme have hampered the discovery and optimization of potent and selective inhibitors. We developed a protocol for the production of recombinant human COT kinase that yields pure and highly active enzyme in sufficient yields for biochemical and structural studies. The quality of the enzyme allowed us to establish a robust in vitro phosphorylation assay for the efficient biochemical characterization of COT kinase inhibitors and to determine the x-ray co-crystal structures of the COT kinase domain in complex with two ATP-binding site inhibitors. The structures presented in this study reveal two distinct ligand binding modes and a unique kinase domain architecture that has not been observed previously. The structurally versatile active site significantly impacts the design of potent, low molecular weight COT kinase inhibitors. PMID- 25918158 TI - An Iron Reservoir to the Catalytic Metal: THE RUBREDOXIN IRON IN AN EXTRADIOL DIOXYGENASE. AB - The rubredoxin motif is present in over 74,000 protein sequences and 2,000 structures, but few have known functions. A secondary, non-catalytic, rubredoxin like iron site is conserved in 3-hydroxyanthranilate 3,4-dioxygenase (HAO), from single cellular sources but not multicellular sources. Through the population of the two metal binding sites with various metals in bacterial HAO, the structural and functional relationship of the rubredoxin-like site was investigated using kinetic, spectroscopic, crystallographic, and computational approaches. It is shown that the first metal presented preferentially binds to the catalytic site rather than the rubredoxin-like site, which selectively binds iron when the catalytic site is occupied. Furthermore, an iron ion bound to the rubredoxin-like site is readily delivered to an empty catalytic site of metal-free HAO via an intermolecular transfer mechanism. Through the use of metal analysis and catalytic activity measurements, we show that a downstream metabolic intermediate can selectively remove the catalytic iron. As the prokaryotic HAO is often crucial for cell survival, there is a need for ensuring its activity. These results suggest that the rubredoxin-like site is a possible auxiliary iron source to the catalytic center when it is lost during catalysis in a pathway with metabolic intermediates of metal-chelating properties. A spare tire concept is proposed based on this biochemical study, and this concept opens up a potentially new functional paradigm for iron-sulfur centers in iron-dependent enzymes as transient iron binding and shuttling sites to ensure full metal loading of the catalytic site. PMID- 25918159 TI - Structures, Organization, and Function of Reflectin Proteins in Dynamically Tunable Reflective Cells. AB - The reversible assembly of reflectin proteins drives dynamic iridescence in cephalopods. Squid dynamically tune the intensity and colors of iridescence generated by constructive interference from intracellular Bragg reflectors in specialized skin cells called iridocytes. Analysis of the tissue specificity of reflectin subtypes reveals that tunability is correlated with the presence of one specific reflectin sequence. Differential phosphorylation and dephosphorylation of the reflectins in response to activation by acetylcholine, as well as differences in their tissue-specific and subcellular spatial distributions, further support the suggestion of different roles for the different reflectin subtypes. PMID- 25918160 TI - Human NOTCH2 Is Resistant to Ligand-independent Activation by Metalloprotease Adam17. AB - Cell surface receptors of the NOTCH family of proteins are activated by ligand induced intramembrane proteolysis. Unfolding of the extracellular negative regulatory region (NRR), enabling successive proteolysis by the enzymes Adam10 and gamma-secretase, is rate-limiting in NOTCH activation. Mutations in the NOTCH1 NRR are associated with ligand-independent activation and frequently found in human T-cell malignancies. In mammals four NOTCH receptors and five Delta/Jagged ligands exist, but mutations in the NRR are only rarely reported for receptors other than NOTCH1. Using biochemical and functional assays, we compared the molecular mechanisms of ligand-independent signaling in NOTCH1 and the highly related NOTCH2 receptor. Both murine Notch1 and Notch2 require the metalloprotease protease Adam17, but not Adam10 during ligand-independent activation. Interestingly, the human NOTCH2 receptor is resistant to ligand independent activation compared with its human homologs or murine orthologs. Taken together, our data reveal subtle but functionally important differences for the NRR among NOTCH paralogs and homologs. PMID- 25918161 TI - PNAS-4, an Early DNA Damage Response Gene, Induces S Phase Arrest and Apoptosis by Activating Checkpoint Kinases in Lung Cancer Cells. AB - PNAS-4, a novel pro-apoptotic gene, was activated during the early response to DNA damage. Our previous study has shown that PNAS-4 induces S phase arrest and apoptosis when overexpressed in A549 lung cancer cells. However, the underlying action mechanism remains far from clear. In this work, we found that PNAS-4 expression in lung tumor tissues is significantly lower than that in adjacent lung tissues; its expression is significantly increased in A549 cells after exposure to cisplatin, methyl methane sulfonate, and mitomycin; and its overexpression induces S phase arrest and apoptosis in A549 (p53 WT), NCI-H460 (p53 WT), H526 (p53 mutation), and Calu-1 (p53(-/-)) lung cancer cells, leading to proliferation inhibition irrespective of their p53 status. The S phase arrest is associated with up-regulation of p21(Waf1/Cip1) and inhibition of the Cdc25A CDK2-cyclin E/A pathway. Up-regulation of p21(Waf1/Cip1) is p53-independent and correlates with activation of ERK. We further showed that the intra-S phase checkpoint, which occurs via DNA-dependent protein kinase-mediated activation of Chk1 and Chk2, is involved in the S phase arrest and apoptosis. Gene silencing of Chk1/2 rescues, whereas that of ATM or ATR does not affect, S phase arrest and apoptosis. Furthermore, human PNAS-4 induces DNA breaks in comet assays and gamma H2AX staining. Intriguingly, caspase-dependent cleavage of Chk1 has an additional role in enhancing apoptosis. Taken together, our findings suggest a novel mechanism by which elevated PNAS-4 first causes DNA-dependent protein kinase mediated Chk1/2 activation and then results in inhibition of the Cdc25A-CDK2 cyclin E/A pathway, ultimately causing S phase arrest and apoptosis in lung cancer cells. PMID- 25918162 TI - Apolipoprotein D Internalization Is a Basigin-dependent Mechanism. AB - Apolipoprotein D (apoD), a member of the lipocalin family, is a 29-kDa secreted glycoprotein that binds and transports small lipophilic molecules. Expressed in several tissues, apoD is up-regulated under different stress stimuli and in a variety of pathologies. Numerous studies have revealed that overexpression of apoD led to neuroprotection in various mouse models of acute stress and neurodegeneration. This multifunctional protein is internalized in several cells types, but the specific internalization mechanism remains unknown. In this study, we demonstrate that the internalization of apoD involves a specific cell surface receptor in 293T cells, identified as the transmembrane glycoprotein basigin (BSG, CD147); more particularly, its low glycosylated form. Our results show that internalized apoD colocalizes with BSG into vesicular compartments. Down regulation of BSG disrupted the internalization of apoD in cells. In contrast, overexpression of basigin in SH-5YSY cells, which poorly express BSG, restored the uptake of apoD. Cyclophilin A, a known ligand of BSG, competitively reduced apoD internalization, confirming that BSG is a key player in the apoD internalization process. In summary, our results demonstrate that basigin is very likely the apoD receptor and provide additional clues on the mechanisms involved in apoD-mediated functions, including neuroprotection. PMID- 25918163 TI - RWD Domain as an E2 (Ubc9)-Interaction Module. AB - An RWD domain is a well conserved domain found through bioinformatic analysis of the human proteome sequence; however, its function has been unknown. Ubiquitin like modifications require the catalysis of three enzymes generally known as E1, E2, and E3. We solved the crystal structure of the E2 for the small ubiquitin like modifiers (SUMO) in complex with an RWD domain and confirmed the structure using solution NMR analysis. The binding surface of RWD on Ubc9 is located near the N terminus of Ubc9 that is known to be involved in noncovalent binding of the proteins in the conjugation machinery, including a domain of E1, SUMO, and an E3 ligase. NMR data indicate that the RWD domain does not bind to SUMO and E1. The interaction between RWD and Ubc9 has a Kd of 32 +/- 4 MUM. Consistent with the structure and binding affinity and in contrast to a previous report, the RWD domain and RWDD3 have minimal effects on global SUMOylation. The structural and biochemical information presented here forms the basis for further investigation of the functions of RWD-containing proteins. PMID- 25918164 TI - Endoplasmic Reticulum Exit of Golgi-resident Defective for SREBP Cleavage (Dsc) E3 Ligase Complex Requires Its Activity. AB - Layers of quality control ensure proper protein folding and complex formation prior to exit from the endoplasmic reticulum. The fission yeast Dsc E3 ligase is a Golgi-localized complex required for sterol regulatory element-binding protein (SREBP) transcription factor activation that shows architectural similarity to endoplasmic reticulum-associated degradation E3 ligases. The Dsc E3 ligase consists of five integral membrane proteins (Dsc1-Dsc5) and functionally interacts with the conserved AAA-ATPase Cdc48. Utilizing an in vitro ubiquitination assay, we demonstrated that Dsc1 has ubiquitin E3 ligase activity that requires the E2 ubiquitin-conjugating enzyme Ubc4. Mutations that specifically block Dsc1-Ubc4 interaction prevent SREBP cleavage, indicating that SREBP activation requires Dsc E3 ligase activity. Surprisingly, Golgi localization of the Dsc E3 ligase complex also requires Dsc1 E3 ligase activity. Analysis of Dsc E3 ligase complex formation, glycosylation, and localization indicated that Dsc1 E3 ligase activity is specifically required for endoplasmic reticulum exit of the complex. These results define enzyme activity-dependent sorting as an autoregulatory mechanism for protein trafficking. PMID- 25918165 TI - Regulation of Structural Dynamics within a Signal Recognition Particle Promotes Binding of Protein Targeting Substrates. AB - Protein targeting is critical in all living organisms and involves a signal recognition particle (SRP), an SRP receptor, and a translocase. In co translational targeting, interactions among these proteins are mediated by the ribosome. In chloroplasts, the light-harvesting chlorophyll-binding protein (LHCP) in the thylakoid membrane is targeted post-translationally without a ribosome. A multidomain chloroplast-specific subunit of the SRP, cpSRP43, is proposed to take on the role of coordinating the sequence of targeting events. Here, we demonstrate that cpSRP43 exhibits significant interdomain dynamics that are reduced upon binding its SRP binding partner, cpSRP54. We showed that the affinity of cpSRP43 for the binding motif of LHCP (L18) increases when cpSRP43 is complexed to the binding motif of cpSRP54 (cpSRP54pep). These results support the conclusion that substrate binding to the chloroplast SRP is modulated by protein structural dynamics in which a major role of cpSRP54 is to improve substrate binding efficiency to the cpSRP. PMID- 25918166 TI - Cox17 Protein Is an Auxiliary Factor Involved in the Control of the Mitochondrial Contact Site and Cristae Organizing System. AB - The mitochondrial contact site and cristae organizing system (MICOS) is a recently discovered protein complex that is crucial for establishing and maintaining the proper inner membrane architecture and contacts with the outer membrane of mitochondria. The ways in which the MICOS complex is assembled and its integrity is regulated remain elusive. Here, we report a direct link between Cox17, a protein involved in the assembly of cytochrome c oxidase, and the MICOS complex. Cox17 interacts with Mic60, thereby modulating MICOS complex integrity. This interaction does not involve Sco1, a partner of Cox17 in transferring copper ions to cytochrome c oxidase. However, the Cox17-MICOS interaction is regulated by copper ions. We propose that Cox17 is a newly identified factor involved in maintaining the architecture of the MICOS complex. PMID- 25918167 TI - Genomic prediction of complex human traits: relatedness, trait architecture and predictive meta-models. AB - We explore the prediction of individuals' phenotypes for complex traits using genomic data. We compare several widely used prediction models, including Ridge Regression, LASSO and Elastic Nets estimated from cohort data, and polygenic risk scores constructed using published summary statistics from genome-wide association meta-analyses (GWAMA). We evaluate the interplay between relatedness, trait architecture and optimal marker density, by predicting height, body mass index (BMI) and high-density lipoprotein level (HDL) in two data cohorts, originating from Croatia and Scotland. We empirically demonstrate that dense models are better when all genetic effects are small (height and BMI) and target individuals are related to the training samples, while sparse models predict better in unrelated individuals and when some effects have moderate size (HDL). For HDL sparse models achieved good across-cohort prediction, performing similarly to the GWAMA risk score and to models trained within the same cohort, which indicates that, for predicting traits with moderately sized effects, large sample sizes and familial structure become less important, though still potentially useful. Finally, we propose a novel ensemble of whole-genome predictors with GWAMA risk scores and demonstrate that the resulting meta-model achieves higher prediction accuracy than either model on its own. We conclude that although current genomic predictors are not accurate enough for diagnostic purposes, performance can be improved without requiring access to large-scale individual-level data. Our methodologically simple meta-model is a means of performing predictive meta-analysis for optimizing genomic predictions and can be easily extended to incorporate multiple population-level summary statistics or other domain knowledge. PMID- 25918168 TI - Glycerol-3-phosphate Acyltransferase Isoform-4 (GPAT4) Limits Oxidation of Exogenous Fatty Acids in Brown Adipocytes. AB - Glycerol-3-phosphate acyltransferase-4 (GPAT4) null pups grew poorly during the suckling period and, as adults, were protected from high fat diet-induced obesity. To determine why Gpat4(-/-) mice failed to gain weight during these two periods of high fat feeding, we examined energy metabolism. Compared with controls, the metabolic rate of Gpat4(-/-) mice fed a 45% fat diet was 12% higher. Core body temperature was 1 oC higher after high fat feeding. Food intake, fat absorption, and activity were similar in both genotypes. Impaired weight gain in Gpat4(-/-) mice did not result from increased heat loss, because both cold tolerance and response to a beta3-adrenergic agonist were similar in both genotypes. Because GPAT4 comprises 65% of the total GPAT activity in brown adipose tissue (BAT), we characterized BAT function. A 45% fat diet increased the Gpat4(-/-) BAT expression of peroxisome proliferator-activated receptor alpha (PPAR) target genes, Cpt1alpha, Pgc1alpha, and Ucp1, and BAT mitochondria oxidized oleate and pyruvate at higher rates than controls, suggesting that fatty acid signaling and flux through the TCA cycle were enhanced. To assess the role of GPAT4 directly, neonatal BAT preadipocytes were differentiated to adipocytes. Compared with controls, Gpat4(-/-) brown adipocytes incorporated 33% less fatty acid into triacylglycerol and 46% more into the pathway of beta-oxidation. The increased oxidation rate was due solely to an increase in the oxidation of exogenous fatty acids. These data suggest that in the absence of cold exposure, GPAT4 limits excessive fatty acid oxidation and the detrimental induction of a hypermetabolic state. PMID- 25918169 TI - K Domain CR9 of Low Density Lipoprotein (LDL) Receptor-related Protein 1 (LRP1) Is Critical for Aggregated LDL-induced Foam Cell Formation from Human Vascular Smooth Muscle Cells. AB - Low density lipoprotein receptor-related protein (LRP1) mediates the internalization of aggregated LDL (AgLDL), which in turn increases the expression of LRP1 in human vascular smooth muscle cells (hVSMCs). This positive feedback mechanism is thus highly efficient to promote the formation of hVSMC foam cells, a crucial vascular component determining the susceptibility of atherosclerotic plaque to rupture. Here we have determined the LRP1 domains involved in AgLDL recognition with the aim of specifically blocking AgLDL internalization in hVSMCs. The capacity of fluorescently labeled AgLDL to bind to functional LRP1 clusters was tested in a receptor-ligand fluorometric assay made by immobilizing soluble LRP1 "minireceptors" (sLRP1-II, sLRP1-III, and sLRP1-IV) recombinantly expressed in CHO cells. This assay showed that AgLDL binds to cluster II. We predicted three well exposed and potentially immunogenic peptides in the CR7-CR9 domains of this cluster (termed P1 (Cys(1051)-Glu(1066)), P2 (Asp(1090) Cys(1104)), and P3 (Gly(1127)-Cys(1140))). AgLDL, but not native LDL, bound specifically and tightly to P3-coated wells. Rabbit polyclonal antibodies raised against P3 prevented AgLDL uptake by hVSMCs and were almost twice as effective as anti-P1 and anti-P2 Abs in reducing intracellular cholesteryl ester accumulation. Moreover, anti-P3 Abs efficiently prevented AgLDL-induced LRP1 up-regulation and counteracted the down-regulatory effect of AgLDL on hVSMC migration. In conclusion, domain CR9 appears to be critical for LRP1-mediated AgLDL binding and internalization in hVSMCs. Our results open new avenues for an innovative anti VSMC foam cell-based strategy for the treatment of vascular lipid deposition in atherosclerosis. PMID- 25918171 TI - Alcohol-exposed? Next. PMID- 25918172 TI - Better results with HIV clubs in South Africa. PMID- 25918170 TI - Transforming Growth Factor-beta and Interleukin-1beta Signaling Pathways Converge on the Chemokine CCL20 Promoter. AB - CCL20 is the only chemokine ligand for the chemokine receptor CCR6, which is expressed by the critical antigen presenting cells, dendritic cells. Increased expression of CCL20 is likely involved in the increased recruitment of dendritic cells observed in fibroinflammatory diseases such as chronic obstructive pulmonary disease (COPD). CCL20 expression is increased by the proinflammatory cytokine IL-1beta. We have determined that IL-1beta-dependent CCL20 expression is also dependent on the multifunctional cytokine TGF-beta. TGF-beta is expressed in a latent form that must be activated to function, and activation is achieved through binding to the integrin alphavbeta8 (itgb8). Here we confirm correlative increases in alphavbeta8 and IL-1beta with CCL20 protein in lung parenchymal lysates of a large cohort of COPD patients. How IL-1beta- and alphavbeta8 mediated TGF-beta activation conspire to increase fibroblast CCL20 expression remains unknown, because these pathways have not been shown to directly interact. We evaluate the 5'-flanking region of CCL20 to determine that IL-1beta-driven CCL20 expression is dependent on alphavbeta8-mediated activation of TGF-beta. We identify a TGF-beta-responsive element (i.e. SMAD) located on an upstream enhancer of the human CCL20 promoter required for efficient IL-1beta-dependent CCL20 expression. By chromatin immunoprecipitation, this upstream enhancer complexes with the p50 subunit of NF-kappaB on a NF-kappaB-binding element close to the transcriptional start site of CCL20. These interactions are confirmed by electromobility shift assays in nuclear extracts from human lung fibroblasts. These data define a mechanism by which alphavbeta8-dependent activation of TGF beta regulates IL-1beta-dependent CCL20 expression in COPD. PMID- 25918173 TI - Budget emphasizes industry-driven research. PMID- 25918175 TI - Acute calcific retropharyngeal tendonitis. PMID- 25918176 TI - Nonresponding osteomyelitis in a two-year-old boy. PMID- 25918177 TI - Federal budget disappoints seniors' advocates. PMID- 25918178 TI - Kidney function and the use of nitrofurantoin to treat urinary tract infections in older women. AB - BACKGROUND: The antibiotic nitrofurantoin is commonly used to treat uncomplicated urinary tract infections. However, when this drug is used by patients with reduced kidney function, its urine concentration may be subtherapeutic. METHODS: We conducted a population-based study of older women (mean age 79 years) in Ontario, Canada, whose estimated glomerular filtration rate was relatively low (median 38 mL/min per 1.73 m(2)) and for whom 1 of 4 antibiotics had been prescribed for urinary tract infection: nitrofurantoin, ciprofloxacin, norfloxacin or trimethoprim-sulfamethoxazole. We assessed 2 measures of treatment failure in the subsequent 14 days: receipt of a second antibiotic indicated for urinary tract infection and hospital encounter (emergency department visit or hospital admission) with a urinary tract infection. We repeated the analysis for older women with relatively high estimated glomerular filtration rate (median 69 mL/min per 1.73 m(2)). RESULTS: The baseline characteristics of the 4 antibiotic groups were similar. Relative to nitrofurantoin, the other antibiotics (including ciprofloxacin) were associated with a lower rate of treatment failure among women with relatively low estimated glomerular filtration rate (for ciprofloxacin v. nitrofurantoin: second antibiotic prescription, 130/1989 [6.5%] v. 516/3739 [13.8%], odds ratio [OR] 0.44, 95% confidence interval [CI] 0.36-0.53; hospital encounter, 21/1989 [1.1%] v. 95/3739 [2.5%], OR 0.41, 95% CI 0.25-0.66). However, a similar risk of treatment failure with nitrofurantoin was also observed among women with relatively high estimated glomerular filtration rate. The results were consistent in multiple additional analyses. INTERPRETATION: In this study, the presence of mild or moderate reductions in estimated glomerular filtration rate did not justify avoidance of nitrofurantoin. PMID- 25918179 TI - Recovery from severe mental illness. PMID- 25918181 TI - Multidrug-Resistant Tuberculosis and Extensively Drug-Resistant Tuberculosis. AB - The continuing spread of drug-resistant tuberculosis (TB) is one of the most urgent and difficult challenges facing global TB control. Patients who are infected with strains resistant to isoniazid and rifampicin, called multidrug resistant (MDR) TB, are practically incurable by standard first-line treatment. In 2012, there were approximately 450,000 new cases and 170,000 deaths because of MDR-TB. Extensively drug-resistant (XDR) TB refers to MDR-TB strains that are resistant to fluoroquinolones and second-line injectable drugs. The main causes of the spread of resistant TB are weak medical systems, amplification of resistance patterns through incorrect treatment, and transmission in communities and facilities. Although patients harboring MDR and XDR strains present a formidable challenge for treatment, cure is often possible with early identification of resistance and use of a properly designed regimen. Community based programs can improve treatment outcomes by allowing patients to be treated in their homes and addressing socioeconomic barriers to adherence. PMID- 25918182 TI - Impact of America Invents Act on Biotech Intellectual Property. AB - This review introduces the America Invents Act (AIA), a comprehensive reform of U.S. law on patentability and patent enforceability that Congress enacted in 2011. The AIA's most publicized change transforms the United States from a "first to-invent" system to a "first-inventor-to-file" regime, bringing U.S. patent law more in line with the patent systems of nearly every other industrialized country in the world. This new system requires small companies and independent inventors to toe the line against larger competitors in what many have called a "race to the patent office." But a closer look at the AIA reveals several opportunities for smaller entities that may even the playing field, particularly for innovators in the biotech sector. This article addresses changes that the AIA brings to U.S. patent law, keeping an eye toward issues relevant to biotech companies. PMID- 25918183 TI - MicroRNA-125b-5p inhibits proliferation and promotes adipogenic differentiation in 3T3-L1 preadipocytes. AB - Previous evidence has indicated that the microRNA-125b (miR-125b) family plays important roles in the regulation of cancer cell growth, development, differentiation, and apoptosis. However, whether they contribute to the process of adipocyte differentiation remains unclear. In the present study, we revealed that the expression level of miR-125b-5p, a member of miR-125b family, was dramatically up-regulated during differentiation of 3T3-L1 preadipocyte into mature adipocyte. Supplement of miR-125b-5p into 3T3-L1 cells promoted adipogenic differentiation as evidenced by increased lipid droplets and mRNA levels of adipocyte-specific molecular markers, including peroxisome proliferators activated receptor gamma, CCAAT/enhancer-binding protein alpha, fatty acid binding protein 4, and lipoprotein lipase, and by triglyceride accumulation. CCK 8 assay showed that miR-125b-5p supplementation significantly inhibited cell proliferation. Flow cytometry analysis showed that miR-125b-5p impaired G1/S phase transition as well as the mRNA and protein expression of G1/S-related genes, such as Cyclin D2, Cyclin D3, and CDK4. Nevertheless, it had no effect on apoptosis. Additionally, by target gene prediction, we demonstrated that smad4 may be a potential target of miR-125b-5p in mouse 3T3-L1 preadipocytes, accounting for some of miR-125b-5p's functions. Taken together, these data indicated that miR-125b-5p may serve as an important positive regulator in adipocyte differentiation, at least partially through down-regulating smad4. PMID- 25918180 TI - Molecular Regulation of Parturition: The Role of the Decidual Clock. AB - The timing of birth is a critical determinant of perinatal outcome. Despite intensive research, the molecular mechanisms responsible for the onset of labor both at term and preterm remain unclear. It is likely that a "parturition cascade" exists that triggers labor at term, that preterm labor results from mechanisms that either prematurely stimulate or short-circuit this cascade, and that these mechanisms involve the activation of proinflammatory pathways within the uterus. It has long been postulated that the fetoplacental unit is in control of the timing of birth through a "placental clock." We suggest that it is not a placental clock that regulates the timing of birth, but rather a "decidual clock." Here, we review the evidence in support of the endometrium/decidua as the organ primarily responsible for the timing of birth and discuss the molecular mechanisms that prime this decidual clock. PMID- 25918184 TI - Evidence of a cumulative effect of cardiometabolic disorders at midlife and subsequent cognitive function. AB - BACKGROUND: longitudinal data as regards the link between the cumulative effect of cardiometabolic disorders and cognition are relatively scant and heterogeneous. OBJECTIVE: we examined the cross-time associations of MetS status with cognitive performance in ageing adults. DESIGN AND METHODS: using data from the French SU.VI.MAX cohort, we studied 2,788 adults. The presence of abdominal obesity, hyperglycaemia, dyslipidaemia and elevated blood pressure was clinically evaluated in 1994-96. Cognitive performance was assessed after a mean of 13 years via a battery of six validated instruments. The standardised individual test scores were summed up to provide a composite cognitive performance measure; principal component analysis was performed to define performance scores on verbal memory and executive functioning. Associations between MetS and subsequent cognitive performance were examined via ANCOVA, providing estimates of mean difference and corresponding 95% confidence intervals (CI). RESULTS: MetS status at midlife was not associated with subsequent cognitive function. However, a 1 unit increase in the number of cardiometabolic disorders present was associated with a decrease in the composite cognitive score (mean difference = -0.36; 95% CI: -0.68, -0.05). Significant associations were also found with several cardiometabolic disorders (hyperglycaemia, central obesity and dyslipidaemia) and specific cognitive domains. CONCLUSION: this study supports the existence of a cross-time, cumulative effect of cardiometabolic disorders present at midlife and subsequent cognitive performance. Given the worldwide population ageing and the increase in MetS prevalence, there is an urgent need for recommendations as regards cognitive ageing. PMID- 25918185 TI - Mortality rates in community-dwelling Tanzanians with dementia and mild cognitive impairment: a 4-year follow-up study. AB - BACKGROUND: we have previously conducted a community-based prevalence study of dementia in older adults living in the rural Hai district of Tanzania. The aim of this study was to record mortality rates at 4 years post-diagnosis, of those with dementia, mild cognitive impairment (MCI) and no cognitive impairment. METHODS: during Phase I of the prevalence study, 1,198 people aged 70 years and over were screened, and a stratified sample of 296 was assessed for the presence of dementia or MCI in Phase II. Seventy-eight people had dementia and 46 had MCI. Four years after diagnosis, we attempted to follow-up all those seen in Phase II and record all deaths. RESULTS: of the 296, follow-up data were available for 287 (97.0%), including 77 with dementia and 45 with MCI. Of the 172 with no cognitive impairment, 165 (95.9%) were followed up and a sample of 89 people selected as representative of the background population. Forty-eight people with dementia (62.3%), 19 with MCI (42.2%) and 11 with no cognitive impairment (12.4%) had died at 4-year follow-up. After adjusting for the effects of age, gender and education, the hazard ratio was 6.33 (95% CI 3.19-12.58) for dementia and 3.57 (95% CI 1.64-7.79) for MCI relative to people with no cognitive impairment. Mortality rates were highest in those with vascular dementia. CONCLUSION: dementia and MCI were associated with excess mortality relative to those with no cognitive impairment. PMID- 25918186 TI - Comparison of 4th-Generation HIV Antigen/Antibody Combination Assay With 3rd Generation HIV Antibody Assays for the Occurrence of False-Positive and False Negative Results. AB - OBJECTIVE: To assess the false-positive and false-negative rates of a 4th generation human immunodeficiency virus (HIV) assay, the Abbott ARCHITECT, vs 2 HIV 3rd-generation assays, the Siemens Centaur and the Ortho-Clinical Diagnostics Vitros. METHODS: We examined 123 patient specimens. In the first phase of the study, we compared 99 specimens that had a positive screening result via the 3rd generation Vitros assay (10 positive, 82 negative, and 7 indeterminate via confirmatory immunofluorescent assay [IFA]/Western blot [WB] testing). In the second phase, we assessed 24 HIV-1 RNA-positive (positive result via the nuclear acid amplification test [NAAT] and negative/indeterminate results via the WB test) specimens harboring acute HIV infection. RESULTS: The 4th-generation ARCHITECT assay yielded fewer false-positive results (n = 2) than the 3rd generation Centaur (n = 9; P = .02) and Vitros (n = 82; P <.001) assays. One confirmed positive case had a false-negative result via the Centaur assay. When specimens from the 24 patients with acute HIV-1 infection were tested, the ARCHITECT assay yielded fewer false-negative results (n = 5) than the Centaur (n = 10) (P = .13) and the other 3rd-generation tests (n = 16) (P = .002). CONCLUSIONS: This study indicates that the 4th-generation ARCHITECT HIV assay yields fewer false-positive and false-negative results than the 3rd-generation HIV assays we tested. PMID- 25918187 TI - Resistance-Gene Cassettes Associated With Salmonella enterica Genotypes. AB - BACKGROUND: The epidemiology of salmonellosis is complex because of the diversity and different serotypes of Salmonella enterica (S. enterica) that occur in different reservoirs and geographic incidences. OBJECTIVES: To determine the genotype distribution and resistance-gene content of 2 classes of integron among S. enterica isolates. METHODS: Thirty-six S. enterica species were isolated and tested for their serological distribution and the resistance-gene contents of 2 classes of integron, as well as for their genetic diversity, using the pulsed field gel electrophoresis (PFGE) genotyping method. RESULTS: Serogroups E (36.1%) and D (30.5%) were dominant among the isolates. All of the isolates in serogroup D belonged to the serovar enteritidis. The aadA1 gene was found within all resistance-gene cassettes. We observed 4 common and 26 single pulsotypes among the isolates, which indicated a high degree of genetic diversity among the isolates. Using the PulseNet International standard protocol, it was found that these isolates were different from those reported previously in Iran. CONCLUSIONS: The presence of a few common and new pulsotypes among the isolates suggests the emergence and spread of new clones of S. enterica in Iran. PMID- 25918188 TI - Evaluation of test strips for the rapid identification of ethylenediaminetetraacetic acid (EDTA) specimens. AB - BACKGROUND: Identification of specimens that contain ethylenediaminetetraacetic acid (EDTA) is frequently necessary when investigating potentially mislabeled or improperly collected specimens. OBJECTIVE: To evaluate the performance of rapid EDTA detection test strips in clinical specimens. METHODS: We applied specimens to test strips designed to detect EDTA (QUANTOFIX EDTA) using a pipet (drop mode). Reactions were scored visually on a scale from red (no EDTA) to orange (low/indeterminate EDTA) to yellow (contains EDTA). RESULTS: Test strips reliably identified specimens from EDTA-containing tube types. Although test strips did not detect strong reactivity in other specimens, tubes containing NaFl/K-oxalate produced an orange (low/indeterminate EDTA) reaction. Bismuth and citrate levels were higher in specimens after we dipped test strips into solution (dip mode). CONCLUSIONS: Test strips detected the presence of EDTA in concentrations found in EDTA-containing primary tubes. Test strips were less effective in evaluating low level EDTA concentrations expected with intravenous line contamination or backflow. Indeterminate reactions required further investigation. Dip mode can produce analytical problems for assays that measure (or are interfered by) the contents of test strips. PMID- 25918189 TI - Soluble B7-H2 as a novel marker in early evaluation of the severity of acute pancreatitis. AB - The clinical usefulness of soluble B7-H2 (sB7-H2) as an early indicator of acute pancreatitis (AP) remains unclear, so we performed the present study to investigate this issue. For our cohort, we recruited 75 patients with AP, 70 patients with other abdominal sepsis, and 20 healthy control individuals. The sB7 H2 levels of AP patients or healthy control individuals were measured by enzyme linked immunosorbent assay (ELISA). The sB7-H2 levels in patients with AP rather than other patients with abdominal sepsis were significantly higher than those in healthy controls. Hence, we selected AP to study the clinical significance of sB7 H2 in inflammatory conditions. The sB7-H2 level was positively correlated with the white blood cell (WBC) count and the lactate dehydrogenase (LDH), high sensitivity C-reactive protein (hs-CRP), and lipopolysaccharide LPS levels (P <.05 for each). Receiver operating characteristic (ROC) analysis revealed that sB7-H2 can distinguish moderately severe acute pancreatitis (MSAP) and severe acute pancreatitis (SAP) from mildly acute pancreatitis (MAP) with 77.8% sensitivity and 80.0% specificity; and that the levels of sB7-H2 also can distinguish SAP from MSAP and MAP with 92.0% sensitivity and 86.0% specificity. The present results indicate that sB7-H2 might be a useful marker in the clinical diagnosis of AP. PMID- 25918190 TI - Correlation of Increased Expression of MicroRNA-155 in Bladder Cancer and Prognosis. AB - OBJECTIVE: To investigate the expression level and clinical significance of microRNA-155 (miR-155) in bladder cancer. METHODS: We collected 102 pairs of tissue specimens from patients with primary bladder cancer and adjacent normal bladder specimens between March 2008 and May 2013. Quantitative real-time polymerase chain reaction (QRT-PCR) was performed to detect the expression levels of miR-155. We performed univariate survival analyses using the Kaplan-Meier method and assessed statistical significance between survival curves via the log rank test. RESULTS: The mean (SD) level of miR-155 expression in tissues with bladder cancer was 13.78 (4.80), which was significantly higher on average than that in adjacent normal bladder tissues (6.14 [2.26], P <.001). Progression-free survival (PFS) was significantly lower for patients with bladder cancer who had a high expression level of miR-155 (5-year survival rate, 23.0%) than those with a low miR-155 expression level (5-year survival rate, 48.9%; P <.001). CONCLUSIONS: We found that elevated expression of miR-155 is correlated with a poor outcome for patients with bladder cancer; this suggests that miR-155 is a potential biomarker for bladder cancer prognosis. PMID- 25918191 TI - Early detection of high oxidative activity in patients with adenomatous intestinal polyps and colorectal adenocarcinoma: myeloperoxidase and oxidized low density lipoprotein in serum as new markers of oxidative stress in colorectal cancer. AB - OBJECTIVES: To detect whether signs of oxidative stress appear at early stages of colorectal adenocarcinoma (CRC), particularly in the polyp stage. We also aimed to evaluate the specific entities myeloperoxidase (MPO) and oxidized low-density lipoprotein (oxLDL) as novel markers of oxidation in the plasma of patients with CRC and to study the relationship between oxidative status in plasma and patient survival. METHODS: We assayed serum or plasma specimens from healthy control subjects (n = 14), from patients with intestinal polyps (n = 39), and from patients with CRC (n = 128) to calculate the modified oxidative balance score (MOBS) using several serum markers (beta-carotene, lycopene, vitamin A, vitamin E, MPO, and oxLDL). We also assayed the levels of C-reactive protein (CRP) and obtained lipid profiles. Finally, we studied the survival of patients in relationship to oxidative status (antioxidants and pro-oxidants) and inflammation markers, and added theses data to the lipid profile for each patient. RESULTS: Oxidative stress levels increased as disease stage advanced. This increase was detected early in the polyp stage, before polyps progressed to cancer, and could be measured by the increase of such new markers as MPO and oxLDL, the decrease in antioxidants, and the MOBS value. Higher levels of oxidation correlated with lower survival. CONCLUSION: The oxidation process, which can cause mutations leading to CRC, begins development in the polyp stage. This process may be detected early by monitoring serum markers such as MPO and oxLDL. PMID- 25918192 TI - Encrusted Cystitis Secondary to Corynebacterium glucuronolyticum in a 57-Year-Old Man Without Predisposing Factors. AB - Encrusted cystitis is a rare condition characterized by encrustation of the bladder mucosa with associated chronic inflammation induced by urea-splitting bacterial infection--most commonly, Corynebacterium urealyticum. Moreover, it usually occurs in immunocompromised patients, especially recipients of renal transplants or patients with a history of previous urological procedures. Due to the rarity of the entity and the slow growth of Corynebacterium species, appropriate treatment is often delayed due to difficulties in diagnosis and resistance to numerous antibiotics. We report a case of encrusted cystitis caused by Corynebacterium glucuronolyticum, another urea-splitting microbe, in a 57-year old previously healthy Caucasian man with no known predisposing factors. The timely diagnosis and management in this otherwise healthy patient was facilitated by characteristic imaging, cystoscopy, and histologic findings confirmed by results of prolonged urine cultures and 16S ribosomal RNA (rRNA) gene sequencing of the microbe. PMID- 25918193 TI - Thyroid cancer and T lymphoblastic leukemia in Crohn disease: a case report and literature review. AB - The effectiveness of the tumor necrosis-alpha (TNF-alpha) blockade has changed the treatment of several chronic inflammatory diseases, including inflammatory bowel disease; however, this treatment also has disadvantages. The use of immunosuppressants in combination with infliximab has been associated with greater risk of developing malignant neoplasms. Herein, we report the case of a 33-year-old ethnic Korean man with Crohn disease (CD) who developed papillary thyroid carcinoma (PTC) and, subsequently, T-cell acute lymphoblastic leukemia (ALL) after approximately 16.0 years of immunosuppressant therapy and 5.5 years of infliximab therapy. To our knowledge, this is the first case described in the literature of 2 different malignant neoplasms, 1 of hematologic origin and the other involving the solid organs, in a patient with CD. Through a systematic literature review, we found 28 cases of acute leukemia in adult patients with CD, of whom 22 had myeloid leukemia and 6 had lymphoid leukemia. Half of the patients with ALL underwent TNF-alpha-blocker therapy in combination with thiopurines. PMID- 25918194 TI - A nontoxic case of vitamin D toxicity. AB - Vitamin D toxicity also known as hypervitaminosis D was previously believed to be rare. But with an increase in vitamin D supplementation several cases have been reported in literature. Fat soluble vitamins like Vitamin D, due to their ability to accumulate in the body, have a higher potential for toxicity than water soluble vitamins. The main clinical consequence of vitamin D toxicity is hypercalcemia. In this report we describe an adult female patient who developed very high serum Vitamin D levels (746 ng/mL, RI: 20 to 50) as a result of medication error. Inspite of such high serum concentrations the patient was without any clinical symptoms and had normal serum calcium. We critically discuss the mechanism of toxicity and hypothesize the possible molecular/metabolic factors which might have been responsible for this nontoxic presentation. This case study highlights the fact that physicians need to consider the risk of medication errors while prescribing Vitamin D therapy. Clinical trials to study Vitamin D toxicity in humans is not possible ethically. Thus the evidence base regarding the safety profile of Vitamin D supplementation in humans has been build through case reports. This review of the paradoxical clinico-laboratory manifestation of hypervitaminosis D could possibly contribute to existing literature. PMID- 25918195 TI - An unexpected emergency request for glucose-6-phosphate dehydrogenase testing in a 9-year-old African American boy. AB - PATIENT: 9-year-old African American male. CHIEF COMPLAINT: Recently diagnosed with acute lymphoblastic leukemia (ALL) after investigation into a large anterior mediastinal mass causing airway compression. HISTORY OF PRESENT ILLNESS: The day before the unexpected urgent glucose-6-phosphate dehydrogenase (G6PD) request, the patient was diagnosed with an aggressive form of leukemia and a significant tumor mass causing airway compression. A computed tomography (CT) scan indicated potential renal involvement. Based on this information and the size of the mass, the patient was referred for immediate chemotherapy. However, there was a concern that he could develop tumor lysis syndrome (TLS) during treatment. To avoid this condition, the pediatric intensive care unit (ICU) sought to pretreat the child with rasburicase, which led to the emergency G6PD request. PREVIOUS MEDICAL HISTORY: Unknown. FAMILY HISTORY: Largely unknown, but no apparent chronic diseases. PHYSICAL EXAMINATION FINDINGS: Three weeks of progressively worsening lymphadenopathy, coughing, night sweats, mild hepatosplenomegaly, and breathing difficulty when supine. The patient arrived at the medical center for airway management and had a temperature of 36.1 degrees C; blood pressure, 120/87 mmHg; pulse, 115 bpm; respiratory rate, 22 breaths per minute, with labored breathing but normal O(2) saturation while upright and awake, in room air. PRINCIPLE LABORATORY FINDINGS: Table 1. PMID- 25918196 TI - Cytologic features of metanephric adenoma of the kidney: case report and review of the literature. AB - Metanephric adenoma (MA) is a rare, benign renal tumor that can be found in individuals of any age. The histological features of this lesion are well known; however, cytological features of this entity have rarely been described. Herein, we present the case of a 37-year-old white woman with multiple endocrine dysfunctions and a renal mass. The diagnosis of metanephric adenoma was suggested as a differential diagnosis during imprint cytology; this diagnosis was later confirmed by core needle biopsy (CNB) and the results of immunostaining. To our knowledge, this is the first time in the literature that the diagnosis of metanephric adenoma was initially suggested on imprint cytologic testing of a CNB. We review the literature regarding the cytologic features and immunohistochemical reactivity of this tumor to raise awareness of this entity among pathologists and to distinguish it from other lesions, such as renal-cell carcinoma, so physicians can use this information to help them avoid calling for an unnecessary radical nephrectomy. PMID- 25918197 TI - Primary CNS T-cell lymphoma of the spinal cord: case report and literature review. AB - Primary central nervous system lymphoma (PCNSL) accounts for 1% of all lymphoma diagnoses and as many as 6% of all central nervous system (CNS) tumors. Most cases of PCNSL are of B-cell type; few are of T-cell lineage. PCNSL mainly occurs intracranially; primary spinal-cord lymphoma only occurs rarely. Moreover, intramedullary presentation without intracranial lesions is virtually unknown. Herein, we present a case of primary T-cell CNS lymphoma limited to the intramedullary spinal cord in an 82-year-old white man, along with a review of the literature on this condition and similar conditions. PMID- 25918198 TI - Benzodiazepine in a urine specimen without drug metabolites. AB - CLINICAL HISTORY: PATIENT: 41-year-old Hispanic woman. Chief Complaint: Pain in the neck, joints, and shoulders that started in August 2013. History of Present Illness: The patient has a history of psychiatric illness. Her primary care physician from an outside facility had prescribed alprazolam (Xanax) to treat her depression. The patient reported that in 2011 she experienced pain in the right side of her back and was diagnosed with sciatica. In addition, she was diagnosed with systemic lupus erythematosus (SLE) based on a positive finding for antinuclear antibodies (ANA) and double-stranded DNA (ds-DNA). She had not consulted a rheumatologist before this visit, nor had she received any medication for these conditions. Her recent history of symptoms included photosensitivity, painful aphthous ulcers, transient rashes, joint pain, myalgias, and bruising. The results of the most recent evaluation of her SLE serology revealed negative ANA and ds-DNA results. The current medications that the patient has been prescribed at Santa Clara Valley Medical Center include lamotrigine (Lamictal), sertraline (Zoloft), and gabapentin (Neurontin). In April 2014, the patient requested additional pain medication, such as hydrocodone/acetaminophen (Norco), during her physician visit. Consequently, as part of her pain management therapy agreement to ensure compliance,(1) she was subjected to a urine toxicology drug screening. At this time, her urine specimen, from an unwitnessed collection, tested positive for benzodiazepines using the Syva EMIT immunoassay (Siemens AG, Munich, Germany) at the cutoff of 200 ng/mL. However, results of a confirmatory test conducted via gas chromatography-mass spectrometry (GC/MS) did not identify any benzodiazepine metabolites in her urine but instead revealed the presence of a parent drug, alprazolam. Further, the same specimen tested positive for metronidazole. A visual inspection of the specimen revealed crystals on the bottom of the cup. In December 2013, this patient had tested positive for alpha hydroxyalprazolam (an alprazolam metabolite; limit of detection, 10 ng/mL) and methamphetamine. At that time, she explained her positive urine-drug-test result by stating that "somebody had put something in my drink." Family history: Her father has been diagnosed with gout, knee osteoarthritis, and enlarged heart. Her brother has been diagnosed with clinical depression. Social history: Divorced; 3 children in the custody of their father; reported having smoked 0.5 packs of cigarettes per day for 20 years; denied any alcohol intake or illicit drug use. PMID- 25918199 TI - Learning From the Crowd in Terminology Mapping: The LOINC Experience. AB - National policies in the United States require the use of standard terminology for data exchange between clinical information systems. However, most electronic health record systems continue to use local and idiosyncratic ways of representing clinical observations. To improve mappings between local terms and standard vocabularies, we sought to make existing mappings (wisdom) from healt care organizations (the Crowd) available to individuals engaged in mapping processes. We developed new functionality to display counts of local terms and organizations that had previously mapped to a given Logical Observation Identifiers Names and Codes (LOINC) code. Further, we enabled users to view the details of those mappings, including local term names and the organizations that create the mappings. Users also would have the capacity to contribute their local mappings to a shared mapping repository. In this article, we describe the new functionality and its availability to implementers who desire resources to make mapping more efficient and effective. PMID- 25918200 TI - Histoplasmosis in Israeli travelers. AB - Histoplasmosis is a common endemic human mycoses acquired mostly in the Americas. We reviewed 23 cases of histoplasmosis in Israeli travelers; 22 had traveled to Central or South America and one to North America. Fourteen cases had been exposed to bat habitats and were symptomatic, presenting <= 3 months after their return. Asymptomatic patients (N = 9) were diagnosed during the evaluation of incidental radiological findings or because a travel partner had been suspected of Histoplasma infection, 16-120 months after their return. Serological testing was positive in 75% of symptomatic cases but only 22% of asymptomatic cases. Histoplasmosis should be considered in travelers returning from the Americas with respiratory or febrile illness within weeks of return, particularly if exposed to bat habitats. Travel history is essential in patients presenting with pulmonary nodules, even years after travel to endemic countries. PMID- 25918201 TI - Dengue in adults admitted to a referral hospital in Hanoi, Vietnam. AB - Knowledge of adult dengue virus (DENV) infection from Hanoi, Vietnam, is limited. In 2008, we prospectively studied 143 (77 male) confirmed (nonstructural 1 antigen enzyme-linked immunosorbent assay [ELISA], DENV polymerase chain reaction, paired serology) adult dengue patients of median age 23.5 (range 16-72) years. They were admitted to the National Hospital for Tropical Diseases, Hanoi, on median illness day (D) 5 (range 1-8). By D8, 141 (98.6%) were afebrile. Platelet counts and hematocrit (median, interquartile range [IQR]) nadired and peaked on D5 and D4, respectively: 40,000/MUL (10,000-109,000/MUL), 43.4% (34.9 49.7%). Four (2.8%) patients had severe dengue: 1) D10 shock (N = 1) and 2) aspartate aminotransferase (AST) >= 1,000 IU/L (N = 3, D5 and D7). Of 143 patients, 118 (82.5%) had >= 1 warning sign (World Health Organization [WHO] 2009 criteria): mucosal bleeding 66/143 (46.1%), soft tissue edema 54/143 (37.7%), and ultrasound detected plasma leakage (pleural effusions/ascites) 30/129 (23.25%). 138 (96.5%) patients received intravenous (IV) fluids: 3 L (IQR: 0.5-8.5 L). Most patients had non-severe dengue with warning signs. High rates of edema and plasma leakage may be explained partly by liberal use of IV fluids. Studies are needed on optimizing fluid management in non-severe adult dengue. PMID- 25918202 TI - High-throughput multiplex quantitative polymerase chain reaction method for Giardia lamblia and Cryptosporidium species detection in stool samples. AB - Giardia lamblia and Cryptosporidium species belong to a complex group of pathogens that cause diseases hampering development and socioeconomic improvements in the developing countries. Both pathogens are recognized as significant causes of diarrhea and nutritional disorders. However, further studies are needed to clarify the role of parasitic infections, especially asymptomatic infections in malnutrition and stunting. We developed a high throughput multiplex quantitative polymerase chain reaction (qPCR) method for G. lamblia and Cryptosporidium spp. detection in stool samples. The sensitivity and specificity of the method were ensured by analyzing confirmed positive samples acquired from diagnostics laboratories and participating in an external quality control round. Its capability to detect asymptomatic G. lamblia and Cryptosporidium spp. infections was confirmed by analyzing stool samples collected from 44 asymptomatic 6-month-old infants living in an endemic region in Malawi. Of these, five samples were found to be positive for G. lamblia and two for Cryptosporidium spp. In conclusion, the developed method is suitable for large-scale studies evaluating the occurrence of G. lamblia and Cryptosporidium spp. in endemic regions and for clinical diagnostics of these infections. PMID- 25918203 TI - Differential recognition of terminal extracellular Plasmodium falciparum VAR2CSA domains by sera from multigravid, malaria-exposed Malian women. AB - The Plasmodium falciparum erythrocyte membrane protein 1 (PfEMP1) family mediates parasite sequestration in small capillaries through tissue-specific cytoadherence. The best characterized of these proteins is VAR2CSA, which is expressed on the surface of infected erythrocytes that bind to chondroitin sulfate in the placental matrix. Antibodies to VAR2CSA prevent placental cytoadherence and protect against placental malaria. The size and complexity of the VAR2CSA protein pose challenges for vaccine development, but smaller constitutive domains may be suitable for subunit vaccine development. A protein microarray was printed to include five overlapping fragments of the 3D7 VAR2CSA extracellular region. Malian women with a history of at least one pregnancy had antibody recognition of four of these fragments and had stronger reactivity against the two distal fragments than did nulliparous women, children, and men from Mali, suggesting that the C-terminal extracellular VAR2CSA domains are a potential focus of protective immunity. With carefully chosen sera from longitudinal studies of pregnant women, this approach has the potential to identify seroreactive VAR2CSA domains associated with protective immunity against pregnancy-associated malaria. PMID- 25918204 TI - Inhibition of cytochrome bc1 as a strategy for single-dose, multi-stage antimalarial therapy. AB - Single-dose therapies for malaria have been proposed as a way to reduce the cost and increase the effectiveness of antimalarial treatment. However, no compound to date has shown single-dose activity against both the blood-stage Plasmodium parasites that cause disease and the liver-stage parasites that initiate malaria infection. Here, we describe a subset of cytochrome bc1 (cyt bc1) inhibitors, including the novel 4(1H)-quinolone ELQ-400, with single-dose activity against liver, blood, and transmission-stage parasites in mouse models of malaria. Although cyt bc1 inhibitors are generally classified as slow-onset antimalarials, we found that a single dose of ELQ-400 rapidly induced stasis in blood-stage parasites, which was associated with a rapid reduction in parasitemia in vivo. ELQ-400 also exhibited a low propensity for drug resistance and was active against atovaquone-resistant P. falciparum strains with point mutations in cyt bc1. Ultimately, ELQ-400 shows that cyt bc1 inhibitors can function as single dose, blood-stage antimalarials and is the first compound to provide combined treatment, prophylaxis, and transmission blocking activity for malaria after a single oral administration. This remarkable multi-stage efficacy suggests that metabolic therapies, including cyt bc1 inhibitors, may be valuable additions to the collection of single-dose antimalarials in current development. PMID- 25918206 TI - Factors determining water treatment behavior for the prevention of cholera in Chad. AB - Cholera is a well-known and feared disease in developing countries, and is linked to high rates of morbidity and mortality. Contaminated drinking water and the lack of sufficient treatment are two of the key causes of high transmission rates. This article presents a representative health survey performed in Chad to inform future intervention strategies in the prevention and control of cholera. To identify critical psychological factors for behavior change, structured household interviews were administered to N = 1,017 primary caregivers, assessing their thoughts and attitudes toward household water treatment according to the Risk, Attitude, Norm, Ability, and Self-regulation model. The intervention potential for each factor was estimated by analyzing differences in means between groups of current performers and nonperformers of water treatment. Personal risk evaluation for diarrheal diseases and particularly for cholera was very low among the study population. Likewise, the perception of social norms was found to be rather unfavorable for water treatment behaviors. In addition, self-reported ability estimates (self-efficacy) revealed some potential for intervention. A mass radio campaign is proposed, using information and normative behavior change techniques, in combination with community meetings focused on targeting abilities and personal commitment to water treatment. PMID- 25918205 TI - Polymorphisms in the K13-propeller gene in artemisinin-susceptible Plasmodium falciparum parasites from Bougoula-Hameau and Bandiagara, Mali. AB - Artemisinin-resistant Plasmodium falciparum malaria has been documented in southeast Asia and may already be spreading in that region. Molecular markers are important tools for monitoring the spread of antimalarial drug resistance. Recently, single-nucleotide polymorphisms (SNPs) in the PF3D7_1343700 kelch propeller (K13-propeller) domain were shown to be associated with artemisinin resistance in vivo and in vitro. The prevalence and role of K13-propeller mutations are poorly known in sub-Saharan Africa. K13-propeller mutations were genotyped by direct sequencing of nested polymerase chain reaction (PCR) amplicons from dried blood spots of pre-treatment falciparum malaria infections collected before and after the use of artemisinin-based combination therapy (ACT) as first-line therapy in Mali. Although K13-propeller mutations previously associated with delayed parasite clearance in Cambodia were not identified, 26 K13-propeller mutations were identified in both recent samples and pre-ACT infections. Parasite clearance time was comparable between infections with non synonymous K13-propeller mutations and infections with the reference allele. These findings suggest that K13-propeller mutations are present in artemisinin sensitive parasites and that they preceded the wide use of ACTs in Mali. PMID- 25918207 TI - Community prevalence of fever and relationship with malaria among infants and children in low-resource areas. AB - We used Demographic and Health Survey data to describe the 2-week period prevalence of fever, cough, and diarrhea among children aged < 5 years in low resources areas. We then explored the relationship between prevalence of isolated fever and national malaria risk. Fever and isolated fever occurred in 26.7% and 7.0% of children, respectively, and was not fully explained by malaria. PMID- 25918208 TI - Nodding syndrome, western Uganda, 1994. AB - Nodding syndrome (NS) is a poorly understood condition, which was delineated in 2008 as a new epilepsy syndrome. So far, confirmed cases of NS have been observed in three circumscribed African areas: southern Tanzania, southern Sudan, and northern Uganda. Case-control studies have provided evidence of an association between NS and infection with Onchocerca volvulus, but the causation of NS is still not fully clarified. We report a case of a 15-year old boy with head nodding seizures and other characteristic features of NS from an onchocerciasis endemic area in western Uganda, with no contiguity to the hitherto known areas. We suggest that the existence of NS should be systematically investigated in other areas. PMID- 25918209 TI - Age modifies the immunologic response and clinical presentation of American tegumentary leishmaniasis. AB - Leishmania (Viannia) braziliensis is the main causal agent of American tegumentary leishmaniasis (ATL) that may present as cutaneous, mucosal, or disseminated cutaneous leishmaniasis. The disease is highly prevalent in young males and there is a lack of studies of ATL in the elderly. Herein, we compared clinical manifestations, immunologic response, and response to antimony therapy between patients > 60 years of age (N = 58) and patients who were 21-30 years of age (N = 187). The study was performed in Corte de Pedra, Bahia, Brazil, a well known area of L. braziliensis transmission. Cytokine production by cultured peripheral blood mononuclear cells stimulated with soluble Leishmania antigen was performed. Elderly subjects more frequently had a previous history of cutaneous leishmaniasis, large lesions, or mucosal leishmaniasis, and they were less likely to have lymphadenopathy. There was no difference regarding gender and response to therapy. Peripheral blood mononuclear cells from elderly subjects produced a similar amount of tumor necrosis factor than young patients but they produced less interferon-gamma and more interleukin-10 than young subjects. We concluded that elderly patients with cutaneous leishmaniasis should be searched for mucosal or disseminated leishmaniasis. The decreased interferon-gamma production and increase in interleukin-10 observed in elderly patients may contribute to parasite persistence and L. braziliensis infection dissemination. PMID- 25918210 TI - Seasonal transmission of Opisthorchis viverrini sensu lato and a lecithodendriid trematode species in Bithynia siamensis goniomphalos snails in northeast Thailand. AB - Seasonal changes play roles in the transmission success of fish-borne zoonotic trematodes (FZT). This study examined the seasonal transmission patterns of Opisthorchis viverrini sensu lato (s.l.) and a virgulate cercaria (family Lecithodendriidae) in the snail intermediate host, Bithynia siamensis goniomphalos in northeast Thailand. Snail samples were collected monthly during the rainy, cool, and hot seasons during 2012-2013 to determine the prevalence and intensity of larval trematode infections. The prevalence of O. viverrini s.l. varied significantly with season, being 0.31%, 1.05%, and 0.37% in the rainy, cool, and hot seasons, respectively (P < 0.05). Similarly, the prevalence of virgulate cercariae was 3.11%, 6.80%, and 1.64% in the rainy, cool, and hot seasons, respectively (P < 0.05). The intensity of larval trematode infections also varied between seasons and peaked in the hot season (P < 0.05) in both species. The snails infected with O. viverrini s.l. were significantly smaller (P < 0.05) and those infected with virgulate cercariae were significantly larger (P < 0.05) than uninfected snails. Seasonal variation and the different sizes of B. s. goniomphalos parasitized by O. viverrini s.l. and virgulate trematodes indicate complex host-parasite interactions with important implications for the epidemiology of O. viverrini s.l. PMID- 25918211 TI - Diagnosis of Schistosoma haematobium infection with a mobile phone-mounted Foldscope and a reversed-lens CellScope in Ghana. AB - We evaluated two novel, portable microscopes and locally acquired, single-ply, paper towels as filter paper for the diagnosis of Schistosoma haematobium infection. The mobile phone-mounted Foldscope and reversed-lens CellScope had sensitivities of 55.9% and 67.6%, and specificities of 93.3% and 100.0%, respectively, compared with conventional light microscopy for diagnosing S. haematobium infection. With conventional light microscopy, urine filtration using single-ply paper towels as filter paper showed a sensitivity of 67.6% and specificity of 80.0% compared with centrifugation for the diagnosis of S. haematobium infection. With future improvements to diagnostic sensitivity, newer generation handheld and mobile phone microscopes may be valuable tools for global health applications. PMID- 25918212 TI - The first step toward diagnosing female genital schistosomiasis by computer image analysis. AB - Schistosoma haematobium causes female genital schistosomiasis (FGS), which is a poverty-related disease in sub-Saharan Africa. Furthermore, it is co-endemic with human immunodeficiency virus (HIV), and biopsies from genital lesions may expose the individual to increased risk of HIV infection. However, microscopy of urine and hematuria are nonspecific and insensitive predictors of FGS and gynecological investigation requires extensive training. Safe and affordable diagnostic methods are needed. We explore a novel method of diagnosing FGS using computer color analysis of colposcopic images. In a cross-sectional study on young women in an endemic area, we found strong associations between the output from the computer color analysis and both clinical diagnosis (odds ratio [OR] = 5.97, P < 0.001) and urine microscopy for schistosomiasis (OR = 3.52, P = 0.004). Finally, using latent class statistics, we estimate that the computer color analysis yields a sensitivity of 80.5% and a specificity of 66.2% for the diagnosis of FGS. PMID- 25918213 TI - Neurological sequelae of hospitalized Japanese encephalitis cases in Gansu province, China. AB - We conducted a follow-up survey for 55 Japanese encephalitis (JE) cases 1-2 years after hospital discharge in Gansu province, China. Community-, education-, and gender-matched healthy individuals without history of neurologic disease were selected as the comparison group. All subjects received neurological examination, intelligence quotient (IQ) measurement, adaptive behavior measurement, and Wechsler memory scale (WMS) assessment. We found 43.6% JE cases had at least one nervous system sequelae compared with 3.6% healthy individuals. Among JE cases, 22.4% had subnormal IQ, 18.4% subnormal verbal IQ (VIQ), 20.4% subnormal performance IQ (PIQ), and 78.4% had subnormal memory quotient (MQ). Among healthy individuals, 2.0% had subnormal IQ, VIQ, or PIQ and 8.1% had subnormal MQ. Among adult JE cases, 47.8% and 39.1% had adaptive behavior impairments and intellectual disability, respectively, compared with 18.8% and 9.7% among young cases, respectively. The results showed both adult and young surviving JE cases had significant neurological sequelae and mental disability 1-2 years after discharged. PMID- 25918214 TI - Geophagy is associated with environmental enteropathy and stunting in children in rural Bangladesh. AB - There is a growing body of literature indicating an association between stunting and environmental enteropathy (EE), a disorder thought to be caused by repeated exposures to enteric pathogens. To investigate the relationship between exposure to enteric pathogens through geophagy, consumption of soil, EE, and stunting, we conducted a prospective cohort study of 216 children under 5 years of age in rural Bangladesh. Geophagy was assessed at baseline using 5 hour structured observation and caregiver reports. Stool was analyzed for fecal markers of intestinal inflammation: alpha-1-antitrypsin, myeloperoxidase, neopterin (all three combined to form an EE disease activity score), and calprotectin. Eighteen percent of children had observed geophagy events by structured observation and 28% had caregiver reported events in the past week. Nearly all households had Escherichia coli (97%) in soil, and 14% had diarrheagenic E. coli. Children with caregiver-reported geophagy had significantly higher EE scores (0.72 point difference, 95% confidence interval [CI]: 0.01, 1.42) and calprotectin concentrations (237.38 MUg/g, 95% CI: 12.77, 462.00). Furthermore, at the 9-month follow-up the odds of being stunted (height-for-age z-score < -2) was double for children with caregiver-reported geophagy (odds ratio [OR]: 2.27, 95% CI: 1.14, 4.51). These findings suggest that geophagy in young children may be an important unrecognized risk factor for EE and stunting. PMID- 25918215 TI - Failure of ivermectin per rectum to achieve clinically meaningful serum levels in two cases of Strongyloides hyperinfection. AB - Two cases of Strongyloides hyperinfection are presented. Ivermectin was initially administered orally and per rectum pending the availability of subcutaneous (SC) preparations. In neither case did rectal suppositories of ivermectin achieve clinically meaningful serum values. Clinicians should use SC preparations of ivermectin as early as possible in Strongyloides hyperinfection and dissemination. PMID- 25918216 TI - Feasibility of a combined camp approach for vector control together with active case detection of visceral leishmaniasis, post kala-azar dermal leishmaniasis, tuberculosis, leprosy and malaria in Bangladesh, India and Nepal: an exploratory study. AB - BACKGROUND: We assessed the feasibility and results of active case detection (ACD) of visceral leishmaniasis (VL), post kala-azar dermal leishmaniasis (PKDL) and other febrile diseases as well as of bednet impregnation for vector control. METHODS: Fever camps were organized and analyzed in twelve VL endemic villages in Bangladesh, India, and Nepal. VL, PKDL, tuberculosis, malaria and leprosy were screened among the febrile patients attending the camps, and existing bednets were impregnated with a slow release insecticide. RESULTS: Among the camp attendees one new VL case and two PKDL cases were detected in Bangladesh and one VL case in Nepal. Among suspected tuberculosis cases two were positive in India but none in the other countries. In India, two leprosy cases were found. No malaria cases were detected. Bednet impregnation coverage during fever camps was more than 80% in the three countries. Bednet impregnation led to a reduction of sandfly densities after 2 weeks by 86% and 32%, and after 4 weeks by 95% and 12% in India and Nepal respectively. The additional costs for the control programmes seem to be reasonable. CONCLUSION: It is feasible to combine ACD camps for VL and PKDL along with other febrile diseases, and vector control with bednet impregnation. PMID- 25918217 TI - Historical review: does stress provoke Plasmodium falciparum recrudescence? AB - Plasmodium falciparum, unlike P. vivax, must maintain infection in the blood/bone marrow over many months/years in order to bridge periods between transmission periods. Asymptomatic parasitemia at very low concentrations is now known to be quite common due to molecular detection methods. Old tropical medicine texts commonly list many stressful events stated to provoke recrudescent falciparum parasitemia such as fatigue, heat/chill, trauma/surgery, famine/war, transit between areas and other febrile illness. The older literature is reviewed to discover the factual basis of such varied reports since they have not been recently confirmed. It seems likely that human stress sometimes induces falciparum recrudescence of an otherwise asymptomatic infection. Reproducing such observations today has been radically altered as malaria chemotherapy has evolved from suppressive quinine to curative artemisinin combinations. Host stress provoked recrudescence may be part of P. falciparum's survival strategy. PMID- 25918218 TI - Diabetes mellitus prevalence in tuberculosis patients and the background population in Guinea-Bissau: a disease burden study from the capital Bissau. AB - BACKGROUND: Data regarding the association between diabetes mellitus (DM) and tuberculosis (TB) in Africa are scare. We did a DM screening survey among TB patients and non-TB controls in Guinea-Bissau. METHODS: The study was conducted at the Bandim Health Project (BHP) in the capital Bissau. From July 2010 to July 2011, newly diagnosed TB cases were identified through a TB notification system. Concurrently, non-TB controls were selected randomly from the BHP's demographic surveillance database and visited at home. Participants were tested using fasting blood glucose (FBG) measurements. DM was diagnosed as FBG >= 7 mmol/l. Our survey was linked to the patient database at the only existing Diabetes Clinic in Bissau. RESULTS: TB patients (n=110) were older than the controls (n=572) (35 vs 31 years; p=0.02), more often male (55% vs 37%; p<0.001) and had a lower body mass index (18.7 vs 24.2 kg/m(2); p<0.001). The prevalence of DM was 2.8% (3/107) for TB patients and 2.1% (11/531) for controls (p=0.64). Excluding two controls already receiving anti-diabetic treatment, the prevalence of DM was 2.8% (3/107) vs 1.7% (9/529) (p=0.44). CONCLUSIONS: The prevalence of DM was low, also among TB patients. No association between DM and TB was found. PMID- 25918219 TI - Matthew Rasband: Zen and the art of axonal maintenance. PMID- 25918220 TI - Demystifying Aurora B. PMID- 25918221 TI - Reproducibility and cell biology. PMID- 25918222 TI - The source of matrix-degrading enzymes in human cancer: Problems of research reproducibility and possible solutions. AB - Matrix degradation is central to tumor pathogenesis. Enzymes that degrade extracellular matrix are abundant in tumors. But which out of the complex mixture of cells that form a tumor produces them? Surprisingly, several hundred studies devoted to this question have provided confusion rather than clarity. Our analysis of these studies identifies likely reasons as to why this may be the case, which has implications for the broader issue of research reproducibility. PMID- 25918224 TI - TRAMM/TrappC12 plays a role in chromosome congression, kinetochore stability, and CENP-E recruitment. AB - Chromosome congression requires the stable attachment of microtubules to chromosomes mediated by the kinetochore, a large proteinaceous structure whose mechanism of assembly is unknown. In this paper, we present the finding that a protein called TRAMM (formerly known as TrappC12) plays a role in mitosis. Depletion of TRAMM resulted in noncongressed chromosomes and arrested cells in mitosis. Small amounts of TRAMM associated with chromosomes, and its depletion affected the localization of some kinetochore proteins, the strongest effect being seen for CENP-E. TRAMM interacts with CENP-E, and depletion of TRAMM prevented the recruitment of CENP-E to the kinetochore. TRAMM is phosphorylated early in mitosis and dephosphorylated at the onset of anaphase. Interestingly, this phosphorylation/dephosphorylation cycle correlates with its association/disassociation with CENP-E. Finally, we demonstrate that a phosphomimetic form of TRAMM recruited CENP-E to kinetochores more efficiently than did the nonphosphorylatable mutant. Our study identifies a moonlighting function for TRAMM during mitosis and adds a new component that regulates kinetochore stability and CENP-E recruitment. PMID- 25918223 TI - Review series: The cell biology of renal filtration. AB - The function of the kidney, filtering blood and concentrating metabolic waste into urine, takes place in an intricate and functionally elegant structure called the renal glomerulus. Normal glomerular function retains circulating cells and valuable macromolecular components of plasma in blood, resulting in urine with just trace amounts of proteins. Endothelial cells of glomerular capillaries, the podocytes wrapped around them, and the fused extracellular matrix these cells form altogether comprise the glomerular filtration barrier, a dynamic and highly selective filter that sieves on the basis of molecular size and electrical charge. Current understanding of the structural organization and the cellular and molecular basis of renal filtration draws from studies of human glomerular diseases and animal models of glomerular dysfunction. PMID- 25918225 TI - Splicing function of mitotic regulators links R-loop-mediated DNA damage to tumor cell killing. AB - Although studies suggest that perturbing mitotic progression leads to DNA damage and p53 activation, which in turn lead to either cell apoptosis or senescence, it remains unclear how mitotic defects trigger p53 activation. We show that BuGZ and Bub3, which are two mitotic regulators localized in the interphase nucleus, interact with the splicing machinery and are required for pre-mRNA splicing. Similar to inhibition of RNA splicing by pladienolide B, depletion of either BuGZ or Bub3 led to increased formation of RNA-DNA hybrids (R-loops), which led to DNA damage and p53 activation in both human tumor cells and primary cells. Thus, R loop-mediated DNA damage and p53 activation offer a mechanistic explanation for apoptosis of cancer cells and senescence of primary cells upon disruption of the dual-function mitotic regulators. This demonstrates the importance of understanding the full range of functions of mitotic regulators to develop antitumor drugs. PMID- 25918226 TI - The yeast ERAD-C ubiquitin ligase Doa10 recognizes an intramembrane degron. AB - Aberrant endoplasmic reticulum (ER) proteins are eliminated by ER-associated degradation (ERAD). This process involves protein retrotranslocation into the cytosol, ubiquitylation, and proteasomal degradation. ERAD substrates are classified into three categories based on the location of their degradation signal/degron: ERAD-L (lumen), ERAD-M (membrane), and ERAD-C (cytosol) substrates. In Saccharomyces cerevisiae, the membrane proteins Hrd1 and Doa10 are the predominant ERAD ubiquitin-protein ligases (E3s). The current notion is that ERAD-L and ERAD-M substrates are exclusively handled by Hrd1, whereas ERAD-C substrates are recognized by Doa10. In this paper, we identify the transmembrane (TM) protein Sec61 beta-subunit homologue 2 (Sbh2) as a Doa10 substrate. Sbh2 is part of the trimeric Ssh1 complex involved in protein translocation. Unassembled Sbh2 is rapidly degraded in a Doa10-dependent manner. Intriguingly, the degron maps to the Sbh2 TM region. Thus, in contrast to the prevailing view, Doa10 (and presumably its human orthologue) has the capacity for recognizing intramembrane degrons, expanding its spectrum of substrates. PMID- 25918227 TI - Myosin light chain kinase regulates cell polarization independently of membrane tension or Rho kinase. AB - Cells polarize to a single front and rear to achieve rapid actin-based motility, but the mechanisms preventing the formation of multiple fronts are unclear. We developed embryonic zebrafish keratocytes as a model system for investigating establishment of a single axis. We observed that, although keratocytes from 2 d postfertilization (dpf) embryos resembled canonical fan-shaped keratocytes, keratocytes from 4 dpf embryos often formed multiple protrusions despite unchanged membrane tension. Using genomic, genetic, and pharmacological approaches, we determined that the multiple-protrusion phenotype was primarily due to increased myosin light chain kinase (MLCK) expression. MLCK activity influences cell polarity by increasing myosin accumulation in lamellipodia, which locally decreases protrusion lifetime, limiting lamellipodial size and allowing for multiple protrusions to coexist within the context of membrane tension limiting protrusion globally. In contrast, Rho kinase (ROCK) regulates myosin accumulation at the cell rear and does not determine protrusion size. These results suggest a novel MLCK-specific mechanism for controlling cell polarity via regulation of myosin activity in protrusions. PMID- 25918229 TI - TTF-1 positive breast cancer: a cautionary tale. PMID- 25918228 TI - FOXO1 differentially regulates both normal and diabetic wound healing. AB - Healing is delayed in diabetic wounds. We previously demonstrated that lineage specific Foxo1 deletion in keratinocytes interfered with normal wound healing and keratinocyte migration. Surprisingly, the same deletion of Foxo1 in diabetic wounds had the opposite effect, significantly improving the healing response. In normal glucose media, forkhead box O1 (FOXO1) enhanced keratinocyte migration through up-regulating TGFbeta1. In high glucose, FOXO1 nuclear localization was induced but FOXO1 did not bind to the TGFbeta1 promoter or stimulate TGFbeta1 transcription. Instead, in high glucose, FOXO1 enhanced expression of serpin peptidase inhibitor, clade B (ovalbumin), member 2 (SERPINB2), and chemokine (C-C motif) ligand 20 (CCL20). The impact of high glucose on keratinocyte migration was rescued by silencing FOXO1, by reducing SERPINB2 or CCL20, or by insulin treatment. In addition, an advanced glycation end product and tumor necrosis factor had a similar regulatory effect on FOXO1 and its downstream targets and inhibited keratinocyte migration in a FOXO1-dependent manner. Thus, FOXO1 expression can positively or negatively modulate keratinocyte migration and wound healing by its differential effect on downstream targets modulated by factors present in diabetic healing. PMID- 25918230 TI - A Mendelian Randomization Study of Circulating Uric Acid and Type 2 Diabetes. AB - We aimed to investigate the causal effect of circulating uric acid concentrations on type 2 diabetes risk. A Mendelian randomization study was performed using a genetic score with 24 uric acid-associated loci. We used data of the European Prospective Investigation into Cancer and Nutrition (EPIC)-InterAct case-cohort study, comprising 24,265 individuals of European ancestry from eight European countries. During a mean (SD) follow-up of 10 (4) years, 10,576 verified incident case subjects with type 2 diabetes were ascertained. Higher uric acid was associated with a higher diabetes risk after adjustment for confounders, with a hazard ratio (HR) of 1.20 (95% CI 1.11, 1.30) per 59.48 umol/L (1 mg/dL) uric acid. The genetic score raised uric acid by 17 umol/L (95% CI 15, 18) per SD increase and explained 4% of uric acid variation. By using the genetic score to estimate the unconfounded effect, we found that a 59.48 umol/L higher uric acid concentration did not have a causal effect on diabetes (HR 1.01 [95% CI 0.87, 1.16]). Including data from the Diabetes Genetics Replication And Meta-analysis (DIAGRAM) consortium, increasing our dataset to 41,508 case subjects with diabetes, the summary odds ratio estimate was 0.99 (95% CI 0.92, 1.06). In conclusion, our study does not support a causal effect of circulating uric acid on diabetes risk. Uric acid-lowering therapies may therefore not be beneficial in reducing diabetes risk. PMID- 25918231 TI - Toll-Like Receptor 3 Influences Glucose Homeostasis and beta-Cell Insulin Secretion. AB - Toll-like receptors (TLRs) have been implicated in the pathogenesis of type 2 diabetes. We examined the function of TLR3 in glucose metabolism and type 2 diabetes-related phenotypes in animals and humans. TLR3 is highly expressed in the pancreas, suggesting that it can influence metabolism. Using a diet-induced obesity model, we show that TLR3-deficient mice had enhanced glycemic control, facilitated by elevated insulin secretion. Despite having high insulin levels, Tlr3(-/-) mice did not experience disturbances in whole-body insulin sensitivity, suggesting that they have a robust metabolic system that manages increased insulin secretion. Increase in insulin secretion was associated with upregulation of islet glucose phosphorylation as well as exocytotic protein VAMP-2 in Tlr3(-/ ) islets. TLR3 deficiency also modified the plasma lipid profile, decreasing VLDL levels due to decreased triglyceride biosynthesis. Moreover, a meta-analysis of two healthy human populations showed that a missense single nucleotide polymorphism in TLR3 (encoding L412F) was linked to elevated insulin levels, consistent with our experimental findings. In conclusion, our results increase the understanding of the function of innate receptors in metabolic disorders and implicate TLR3 as a key control system in metabolic regulation. PMID- 25918232 TI - Tshz1 Regulates Pancreatic beta-Cell Maturation. AB - The homeodomain transcription factor Pdx1 controls pancreas organogenesis, specification of endocrine pancreas progenitors, and the postnatal growth and function of pancreatic beta-cells. Pdx1 expression in human-derived stem cells is used as a marker for induced pancreatic precursor cells. Unfortunately, the differentiation efficiency of human pancreatic progenitors into functional beta cells is poor. In order to gain insight into the genes that Pdx1 regulates during differentiation, we performed Pdx1 chromatin immunoprecipitation followed by high throughput sequencing of embryonic day (e) 13.5 and 15.5 mouse pancreata. From this, we identified the transcription factor Teashirt zinc finger 1 (Tshz1) as a direct Pdx1 target. Tshz1 is expressed in developing and adult insulin- and glucagon-positive cells. Endocrine cells are properly specified in Tshz1-null embryos, but critical regulators of beta-cell (Pdx1 and Nkx6.1) and alpha-cell (MafB and Arx) formation and function are downregulated. Adult Tshz1(+/-) mice display glucose intolerance due to defects in glucose-stimulated insulin secretion associated with reduced Pdx1 and Clec16a expression in Tshz1(+/-) islets. Lastly, we demonstrate that TSHZ1 levels are reduced in human islets of donors with type 2 diabetes. Thus, we position Tshz1 in the transcriptional network of maturing beta-cells and suggest that its dysregulation could contribute to the islet phenotype of human type 2 diabetes. PMID- 25918233 TI - Materno-Fetal Transfer of Preproinsulin Through the Neonatal Fc Receptor Prevents Autoimmune Diabetes. AB - The first signs of autoimmune activation leading to beta-cell destruction in type 1 diabetes (T1D) appear during the first months of life. Thus, the perinatal period offers a suitable time window for disease prevention. Moreover, thymic selection of autoreactive T cells is most active during this period, providing a therapeutic opportunity not exploited to date. We therefore devised a strategy by which the T1D-triggering antigen preproinsulin fused with the immunoglobulin (Ig)G Fc fragment (PPI-Fc) is delivered to fetuses through the neonatal Fc receptor (FcRn) pathway, which physiologically transfers maternal IgGs through the placenta. PPI-Fc administered to pregnant PPIB15-23 T-cell receptor transgenic mice efficiently accumulated in fetuses through the placental FcRn and protected them from subsequent diabetes development. Protection relied on ferrying of PPI-Fc to the thymus by migratory dendritic cells and resulted in a rise in thymic-derived CD4(+) regulatory T cells expressing transforming growth factor-beta and in increased effector CD8(+) T cells displaying impaired cytotoxicity. Moreover, polyclonal splenocytes from nonobese diabetic (NOD) mice transplacentally treated with PPI-Fc were less diabetogenic upon transfer into NOD.scid recipients. Transplacental antigen vaccination provides a novel strategy for early T1D prevention and, further, is applicable to other immune-mediated conditions. PMID- 25918234 TI - Salt-Inducible Kinase 1 Terminates cAMP Signaling by an Evolutionarily Conserved Negative-Feedback Loop in beta-Cells. AB - Pancreatic beta-cells are critical in the regulation of glucose homeostasis by controlled secretion of insulin in mammals. Activation of protein kinase A by cAMP is shown to be responsible for enhancing this pathway, which is countered by phosphodiesterase (PDE) that converts cAMP to AMP and turns off the signal. Salt inducible kinases (SIKs) were also known to inhibit cAMP signaling, mostly by promoting inhibitory phosphorylation on CREB-regulated transcription coactivators. Here, we showed that SIK1 regulates insulin secretion in beta-cells by modulating PDE4D and cAMP concentrations. Haploinsufficiency of SIK1 led to the improved glucose tolerance due to the increased glucose-stimulated insulin secretion. Depletion of SIK1 promoted higher cAMP concentration and increased insulin secretion from primary islets, suggesting that SIK1 controls insulin secretion through the regulation of cAMP signaling. By using a consensus phosphorylation site of SIK1, we identified PDE4D as a new substrate for this kinase family. In vitro kinase assay as well as mass spectrometry analysis revealed that the predicted Ser(136) and the adjacent Ser(141) of PDE4D are critical in SIK1-mediated phosphorylation. We found that overexpression of either SIK1 or PDE4D in beta-cells reduced insulin secretion, while inhibition of PDE4 activity by rolipram or knockdown of PDE4D restored it, showing indeed that SIK1 dependent phosphorylation of PDE4D is critical in reducing cAMP concentration and insulin secretion from beta-cells. Taken together, we propose that SIK1 serves as a part of a self-regulatory circuit to modulate insulin secretion from pancreatic beta-cells by controlling cAMP concentration through modulation of PDE4D activity. PMID- 25918235 TI - Loss of beta-Cell Identity Occurs in Type 2 Diabetes and Is Associated With Islet Amyloid Deposits. AB - Loss of pancreatic islet beta-cell mass and beta-cell dysfunction are central in the development of type 2 diabetes (T2DM). We recently showed that mature human insulin-containing beta-cells can convert into glucagon-containing alpha-cells ex vivo. This loss of beta-cell identity was characterized by the presence of beta cell transcription factors (Nkx6.1, Pdx1) in glucagon(+) cells. Here, we investigated whether the loss of beta-cell identity also occurs in vivo, and whether it is related to the presence of (pre)diabetes in humans and nonhuman primates. We observed an eight times increased frequency of insulin(+) cells coexpressing glucagon in donors with diabetes. Up to 5% of the cells that were Nkx6.1(+) but insulin(-) coexpressed glucagon, which represents a five times increased frequency compared with the control group. This increase in bihormonal and Nkx6.1(+)glucagon(+)insulin(-) cells was also found in islets of diabetic macaques. The higher proportion of bihormonal cells and Nkx6.1(+)glucagon(+)insulin(-) cells in macaques and humans with diabetes was correlated with the presence and extent of islet amyloidosis. These data indicate that the loss of beta-cell identity occurs in T2DM and could contribute to the decrease of functional beta-cell mass. Maintenance of beta-cell identity is a potential novel strategy to preserve beta-cell function in diabetes. PMID- 25918236 TI - DLK1 Regulates Whole-Body Glucose Metabolism: A Negative Feedback Regulation of the Osteocalcin-Insulin Loop. AB - The endocrine role of the skeleton in regulating energy metabolism is supported by a feed-forward loop between circulating osteoblast (OB)-derived undercarboxylated osteocalcin (Glu-OCN) and pancreatic beta-cell insulin; in turn, insulin favors osteocalcin (OCN) bioactivity. These data suggest the existence of a negative regulation of this cross talk between OCN and insulin. Recently, we identified delta like-1 (DLK1) as an endocrine regulator of bone turnover. Because DLK1 is colocalized with insulin in pancreatic beta-cells, we examined the role of DLK1 in insulin signaling in OBs and energy metabolism. We show that Glu-OCN specifically stimulates Dlk1 expression by the pancreas. Conversely, Dlk1-deficient (Dlk1(-/-) ) mice exhibited increased circulating Glu OCN levels and increased insulin sensitivity, whereas mice overexpressing Dlk1 in OB displayed reduced insulin secretion and sensitivity due to impaired insulin signaling in OB and lowered Glu-OCN serum levels. Furthermore, Dlk1(-/-) mice treated with Glu-OC experienced significantly lower blood glucose levels than Glu OCN-treated wild-type mice. The data suggest that Glu-OCN-controlled production of DLK1 by pancreatic beta-cells acts as a negative feedback mechanism to counteract the stimulatory effects of insulin on OB production of Glu-OCN, a potential mechanism preventing OCN-induced hypoglycemia. PMID- 25918237 TI - CCR5 deficiency predisposes to fatal outcome in influenza virus infection. AB - Influenza epidemics affect all age groups, although children, the elderly and those with underlying medical conditions are the most severely affected. Whereas co-morbidities are present in 50% of fatal cases, 25-50% of deaths are in apparently healthy individuals. This suggests underlying genetic determinants that govern infection severity. Although some viral factors that contribute to influenza disease are known, the role of host genetic factors remains undetermined. Data for small cohorts of influenza-infected patients are contradictory regarding the potential role of chemokine receptor 5 deficiency (CCR5-Delta32 mutation, a 32 bp deletion in the CCR5 gene) in the outcome of influenza virus infection. We tested 171 respiratory samples from influenza patients (2009 pandemic) for CCR5-Delta32 and evaluated its correlation with patient mortality. CCR5-Delta32 patients (17.4%) showed a higher mortality rate than WT individuals (4.7%; P = 0.021), which indicates that CCR5-Delta32 patients are at higher risk than the normal population of a fatal outcome in influenza infection. PMID- 25918238 TI - Characterization of the IFN pathway in the teleost fish gonad against vertically transmitted viral nervous necrosis virus. AB - One of the most powerful innate immune responses against viruses is mediated by type I IFN. In teleost fish, it is known that virus infection triggers the expression of ifn and many IFN-stimulated genes, but the viral RNA sensors and mediators leading to IFN production are scarcely known. Thus, we have searched for the presence of these genes in gilt-head sea bream (Sparus aurata) and European sea bass (Dicentrarchus labrax), and evaluated their expression after infection with viral nervous necrosis virus (VNNV) in the brain, the main viral target tissue, and the gonad, used to transmit the virus vertically. In sea bream, a fish species resistant to the VNNV strain used, we found an upregulation of the genes encoding MDA5 (melanoma differentiation-associated gene 5), TBK1 (TANK-binding kinase 1), IRF3 (IFN regulatory factor 3), IFN, Mx [myxovirus (influenza) resistance protein] and PKR (dsRNA-dependent protein kinase receptor) proteins in the brain, which were unaltered in the gonad and could favour the dissemination by gonad fluids or gametes. Strikingly, in European sea bass, a very susceptible species, we also identified, transcripts coding for LGP2 (Laboratory of Genetics and Physiology 2), MAVS (mitochondrial antiviral signalling), TRAF3 (TNF receptor-associated factor 3), TANK (TRAF family member associated NFkappaB activator) and IRF7 (IFN regulatory factor 7), and found that all the genes analysed were upregulated in the gonad, but only mda5, lgp2, irf3, mx and pkr were upregulated in the brain. These findings supported the notion that the European sea bass brain innate immune response is unable to clear the virus and pointed to the importance of gonad immunity to control the dissemination of VNNV to the progeny--an aspect that is worth investigating in aquatic animals. PMID- 25918239 TI - Discovery of a novel nidovirus in cattle with respiratory disease. AB - The family Coronaviridae represents a diverse group of vertebrate RNA viruses, all with genomes greater than 26,000 nt. Here, we report the discovery and genetic characterization of a novel virus present in cattle with respiratory disease. Phylogenetic characterization of this virus revealed that it clusters within the subfamily Torovirinae, in the family Coronaviridae. The complete genome consists of only 20,261 nt and represents the smallest reported coronavirus genome. We identified seven ORFs, including the canonical nidovirus ORF1a and ORF1b. Analysis of polyprotein 1ab revealed that this virus, tentatively named bovine nidovirus (BoNV), shares the highest homology with the recently described python-borne nidoviruses and contains several conserved nidovirus motifs, but does not encode the NendoU or O-MT domains that are present in other viruses within the family Coronaviridae. In concert with its reduced genome, the atypical domain architecture indicates that this virus represents a unique lineage within the order Nidovirales. PMID- 25918240 TI - Characterization of the Canine Anthracycline-Metabolizing Enzyme Carbonyl Reductase 1 (cbr1) and the Functional Isoform cbr1 V218. AB - The anthracyclines doxorubicin and daunorubicin are used in the treatment of various human and canine cancers, but anthracycline-related cardiotoxicity limits their clinical utility. The formation of anthracycline C-13 alcohol metabolites (e.g., doxorubicinol and daunorubicinol) contributes to the development of anthracycline-related cardiotoxicity. The enzymes responsible for the synthesis of anthracycline C-13 alcohol metabolites in canines remain to be elucidated. We hypothesized that canine carbonyl reductase 1 (cbr1), the homolog of the prominent anthracycline reductase human CBR1, would have anthracycline reductase activity. Recombinant canine cbr1 (molecular weight: 32.8 kDa) was purified from Escherichia coli. The enzyme kinetics of "wild-type" canine cbr1 (cbr1 D218) and a variant isoform (cbr1 V218) were characterized with the substrates daunorubicin and menadione, as well as the flavonoid inhibitor rutin. Canine cbr1 catalyzes the reduction of daunorubicin to daunorubicinol, with cbr1 D218 and cbr1 V218 displaying different kinetic parameters (cbr1 D218 Km: 188 +/- 144 MUM versus cbr1 V218 Km: 527 +/- 136 MUM, P < 0.05, and cbr1 D218 Vmax: 6446 +/- 3615 nmol/min per milligram versus cbr1 V218 Vmax: 15539 +/- 2623 nmol/min per milligram, P < 0.01). Canine cbr1 also metabolized menadione (cbr1 D218 Km: 104 +/- 50 MUM, Vmax: 2034 +/- 307 nmol/min per milligram). Rutin acted as a competitive inhibitor for the reduction of daunorubicin (cbr1 D218 Ki: 1.84 +/- 1.02 MUM, cbr1 V218 Ki: 1.38 +/- 0.47 MUM). These studies show that canine cbr1 metabolizes daunorubicin and provide the necessary foundation to characterize the role of cbr1 in the variable pharmacodynamics of anthracyclines in canine cancer patients. PMID- 25918241 TI - Argonaute 2 Binds Directly to tRNA Genes and Promotes Gene Repression in cis. AB - To further our understanding of the RNAi machinery within the human nucleus, we analyzed the chromatin and RNA binding of Argonaute 2 (AGO2) within human cancer cell lines. Our data indicated that AGO2 binds directly to nascent tRNA and 5S rRNA, and to the genomic loci from which these RNAs are transcribed, in a small RNA- and DICER-independent manner. AGO2 chromatin binding was not observed at non TFIIIC-dependent RNA polymerase III (Pol III) genes or at extra-TFIIIC (ETC) sites, indicating that the interaction is specific for TFIIIC-dependent Pol III genes. A genome-wide analysis indicated that loss of AGO2 caused a global increase in mRNA expression level among genes that flank AGO2-bound tRNA genes. This effect was shown to be distinct from that of the disruption of DICER, DROSHA, or CTCF. We propose that AGO2 binding to tRNA genes has a novel and important regulatory role in human cells. PMID- 25918242 TI - Spt6 Is Essential for rRNA Synthesis by RNA Polymerase I. AB - Spt6 (suppressor of Ty6) has many roles in transcription initiation and elongation by RNA polymerase (Pol) II. These effects are mediated through interactions with histones, transcription factors, and the RNA polymerase. Two lines of evidence suggest that Spt6 also plays a role in rRNA synthesis. First, Spt6 physically associates with a Pol I subunit (Rpa43). Second, Spt6 interacts physically and genetically with Spt4/5, which directly affects Pol I transcription. Utilizing a temperature-sensitive allele, spt6-1004, we show that Spt6 is essential for Pol I occupancy of the ribosomal DNA (rDNA) and rRNA synthesis. Our data demonstrate that protein levels of an essential Pol I initiation factor, Rrn3, are reduced when Spt6 is inactivated, leading to low levels of Pol I-Rrn3 complex. Overexpression of RRN3 rescues Pol I-Rrn3 complex formation; however, rRNA synthesis is not restored. These data suggest that Spt6 is involved in either recruiting the Pol I-Rrn3 complex to the rDNA or stabilizing the preinitiation complex. The findings presented here identify an unexpected, essential role for Spt6 in synthesis of rRNA. PMID- 25918243 TI - NOS1AP Functionally Associates with YAP To Regulate Hippo Signaling. AB - Deregulation of cellular polarity proteins and their associated complexes leads to changes in cell migration and proliferation. The nitric oxide synthase 1 adaptor protein (NOS1AP) associates with the tumor suppressor protein Scribble to control cell migration and oncogenic transformation. However, how NOS1AP is linked to the cell signaling events that curb oncogenic progression has remained elusive. Here we identify several novel NOS1AP isoforms, NOS1APd, NOS1APe, and NOS1APf, with distinct cellular localizations. We show that isoforms with a membrane-interacting phosphotyrosine binding (PTB) domain can associate with Scribble and recognize acidic phospholipids. In a screen to identify novel binding proteins, we have discovered a complex consisting of NOS1AP and the transcriptional coactivator YAP linking NOS1AP to the Hippo signaling pathway. Silencing of NOS1AP reduces the phosphorylation of YAP and of the upstream kinase Lats1. Conversely, expression of NOS1AP promotes YAP and Lats1 phosphorylation, which correlates with reduced TEAD activity and restricted cell proliferation. Together, these data implicate a role for NOS1AP in the regulation of core Hippo signaling and are consistent with the idea that NOS1AP functions as a tumor suppressor. PMID- 25918244 TI - Overexpression of NF90-NF45 Represses Myogenic MicroRNA Biogenesis, Resulting in Development of Skeletal Muscle Atrophy and Centronuclear Muscle Fibers. AB - MicroRNAs (miRNAs) are involved in the progression and suppression of various diseases through translational inhibition of target mRNAs. Therefore, the alteration of miRNA biogenesis induces several diseases. The nuclear factor 90 (NF90)-NF45 complex is known as a negative regulator in miRNA biogenesis. Here, we showed that NF90-NF45 double-transgenic (dbTg) mice develop skeletal muscle atrophy and centronuclear muscle fibers in adulthood. Subsequently, we found that the levels of myogenic miRNAs, including miRNA 133a (miR-133a), which promote muscle maturation, were significantly decreased in the skeletal muscle of NF90 NF45 dbTg mice compared with those in wild-type mice. However, levels of primary transcripts of the miRNAs (pri-miRNAs) were clearly elevated in NF90-NF45 dbTg mice. This result indicated that the NF90-NF45 complex suppressed miRNA production through inhibition of pri-miRNA processing. This finding was supported by the fact that processing of pri-miRNA 133a-1 (pri-miR-133a-1) was inhibited via binding of NF90-NF45 to the pri-miRNA. Finally, the level of dynamin 2, a causative gene of centronuclear myopathy and concomitantly a target of miR-133a, was elevated in the skeletal muscle of NF90-NF45 dbTg mice. Taken together, we conclude that the NF90-NF45 complex induces centronuclear myopathy through increased dynamin 2 expression by an NF90-NF45-induced reduction of miR-133a expression in vivo. PMID- 25918246 TI - mTOR Complex 2 Stabilizes Mcl-1 Protein by Suppressing Its Glycogen Synthase Kinase 3-Dependent and SCF-FBXW7-Mediated Degradation. AB - mTOR complex 2 (mTORC2) regulates cell survival and growth through undefined mechanisms. Mcl-1, a Bcl-2 family protein, functions as an oncogenic protein. The connection between mTORC2 and Mcl-1 stability has not been established and was thus the focus of this study. Mcl-1 levels in cancer cells were decreased by mTOR kinase inhibitors (TORKinibs), which inhibit both mTORCs, by knocking down rictor and by knocking out rictor or Sin1 but not by silencing raptor. TORKinib treatment and rictor knockdown did not alter Mcl-1 mRNA levels but rather decreased its protein stability. Moreover, TORKinib-induced Mcl-1 reduction was rescued by proteasome inhibition. Consistently, TORKinib increased Mcl-1 ubiquitination. Hence, it is clear that inhibition of mTORC2 enhances Mcl-1 degradation, resulting in Mcl-1 reduction. Suppression of glycogen synthase kinase 3 (GSK3) or FBXW7 rescued Mcl-1 reduction induced by TORKinibs or rictor knockdown. Thus, mTORC2 inhibition apparently induces Mcl-1 degradation through a GSK3-dependent and SCF-FBXW7-mediated mechanism. Intriguingly, we detected a direct association between mTORC2 and SCF-FBXW7; this association could be inhibited by TORKinib treatment, suggesting that mTORC2 may directly associate with and inhibit the SCF-FBXW7 complex, resulting in delayed Mcl-1 degradation. Collectively, our findings highlight a novel mechanism by which mTORC2 regulates cell survival and growth by stabilizing Mcl-1. PMID- 25918245 TI - General and MicroRNA-Mediated mRNA Degradation Occurs on Ribosome Complexes in Drosophila Cells. AB - The translation and degradation of mRNAs are two key steps in gene expression that are highly regulated and targeted by many factors, including microRNAs (miRNAs). While it is well established that translation and mRNA degradation are tightly coupled, it is still not entirely clear where in the cell mRNA degradation takes place. In this study, we investigated the possibility of mRNA degradation on the ribosome in Drosophila cells. Using polysome profiles and ribosome affinity purification, we could demonstrate the copurification of various deadenylation and decapping factors with ribosome complexes. Also, AGO1 and GW182, two key factors in the miRNA-mediated mRNA degradation pathway, were associated with ribosome complexes. Their copurification was dependent on intact mRNAs, suggesting the association of these factors with the mRNA rather than the ribosome itself. Furthermore, we isolated decapped mRNA degradation intermediates from ribosome complexes and performed high-throughput sequencing analysis. Interestingly, 93% of the decapped mRNA fragments (approximately 12,000) could be detected at the same relative abundance on ribosome complexes and in cell lysates. In summary, our findings strongly indicate the association of the majority of bulk mRNAs as well as mRNAs targeted by miRNAs with the ribosome during their degradation. PMID- 25918247 TI - Noncanonical Effects of IRF9 in Intestinal Inflammation: More than Type I and Type III Interferons. AB - The interferon (IFN)-stimulated gene factor 3 (ISGF3) transcription factor with its Stat1, Stat2, and interferon regulatory factor 9 (IRF9) subunits is employed for transcriptional responses downstream of receptors for type I interferons (IFN I) that include IFN-alpha and IFN-beta and type III interferons (IFN-III), also called IFN-lambda. Here, we show in a murine model of dextran sodium sulfate (DSS)-induced colitis that IRF9 deficiency protects animals, whereas the combined loss of IFN-I and IFN-III receptors worsens their condition. We explain the different phenotypes by demonstrating a function of IRF9 in a noncanonical transcriptional complex with Stat1, apart from IFN-I and IFN-III signaling. Together, Stat1 and IRF9 produce a proinflammatory activity that overrides the benefits of the IFN-III response on intestinal epithelial cells. Our results further suggest that the CXCL10 chemokine gene is an important mediator of this proinflammatory activity. We thus establish IFN-lambda as a potentially anticolitogenic cytokine and propose an important role for IRF9 as a component of noncanonical Stat complexes in the development of colitis. PMID- 25918248 TI - Inducible Deletion of Protein Kinase Map4k4 in Obese Mice Improves Insulin Sensitivity in Liver and Adipose Tissues. AB - Studies in vitro suggest that mitogen-activated protein kinase kinase kinase kinase 4 (Map4k4) attenuates insulin signaling, but confirmation in vivo is lacking since Map4k4 knockout is lethal during embryogenesis. We thus generated mice with floxed Map4k4 alleles and a tamoxifen-inducible Cre/ERT2 recombinase under the control of the ubiquitin C promoter to induce whole-body Map4k4 deletion after these animals reached maturity. Tamoxifen administration to these mice induced Map4k4 deletion in all tissues examined, causing decreased fasting blood glucose concentrations and enhanced insulin signaling to AKT in adipose tissue and liver but not in skeletal muscle. Surprisingly, however, mice generated with a conditional Map4k4 deletion in adiponectin-positive adipocytes or in albumin-positive hepatocytes displayed no detectable metabolic phenotypes. Instead, mice with Map4k4 deleted in Myf5-positive tissues, including all skeletal muscles tested, were protected from obesity-induced glucose intolerance and insulin resistance. Remarkably, these mice also showed increased insulin sensitivity in adipose tissue but not skeletal muscle, similar to the metabolic phenotypes observed in inducible whole-body knockout mice. Taken together, these results indicate that (i) Map4k4 controls a pathway in Myf5-positive cells that suppresses whole-body insulin sensitivity and (ii) Map4k4 is a potential therapeutic target for improving glucose tolerance and insulin sensitivity in type 2 diabetes. PMID- 25918249 TI - Dietary compound isoliquiritigenin prevents mammary carcinogenesis by inhibiting breast cancer stem cells through WIF1 demethylation. AB - Breast cancer stem cells (CSCs) are considered as the root of mammary tumorigenesis. Previous studies have demonstrated that ISL efficiently limited the activities of breast CSCs. However, the cancer prevention activities of ISL and its precise molecular mechanisms remain largely unknown. Here, we report a novel function of ISL as a natural demethylation agent targeting WIF1 to prevent breast cancer. ISL administration suppressed in vivo breast cancer initiation and progression, accompanied by reduced CSC-like populations. A global gene expression profile assay further identified WIF1 as the main response gene of ISL treatment, accompanied by the simultaneous downregulation of beta-catenin signaling and G0/G1 phase arrest in breast CSCs. In addition, WIF1 inhibition significantly relieved the CSC-limiting effects of ISL and methylation analysis further revealed that ISL enhanced WIF1 gene expression via promoting the demethylation of its promoter, which was closely correlated with the inhibition of DNMT1 methyltransferase. Molecular docking analysis finally revealed that ISL could stably dock into the catalytic domain of DNMT1. Taken together, our findings not only provide preclinical evidence to demonstrate the use of ISL as a dietary supplement to inhibit mammary carcinogenesis but also shed novel light on WIF1 as an epigenetic target for breast cancer prevention. PMID- 25918250 TI - Dual targeting of HER1/EGFR and HER2 with cetuximab and trastuzumab in patients with metastatic pancreatic cancer after gemcitabine failure: results of the "THERAPY"phase 1-2 trial. AB - To improve treatment efficacy, we decided to simultaneously target HER1 and HER2 with trastuzumab and cetuximab. Following promising preclinical results, we conducted a phase 1-2 trial in advanced pancreatic cancer patients after first line gemcitabine-based chemotherapy failure. In this single-arm, non-randomized, multicenter trial, patients received weekly cetuximab (400mg/m2, then 250mg/m2). They were sequentially included in two trastuzumab dose levels: 3.0 or 4.0mg/kg, then 1.5 or 2.0mg/kg/weekly. Endpoints were the objective response rate, safety, progression-free (PFS) and overall survival (OS). During phase 1 (n=10 patients), toxicities were evenly distributed except for skin toxicities that frequently caused compliance issues. The higher dose level was defined as the trastuzumab recommended dose. During phase 2 (n=39 patients), toxicities were mainly cutaneous reactions and asthenia. No objective response was observed. Nine patients were stabilized but arrested treatment due to toxicity. Median PFS was 1.8 months (95%CI: 1.7-2.0 months) and median OS was 4.6 months (95%CI: 2.7-6.6 months). Both were positively correlated with skin toxicity severity (P=0.027 and P=0.001, respectively). Conventional phase 1 dose-escalation schedules are unsuitable for targeted therapies because most cutaneous toxicities are not considered dose-limiting toxicities. The compliance issues caused by skin toxicities were particularly detrimental because of the toxicity-response correlation. PMID- 25918251 TI - Chronic liver inflammation modifies DNA methylation at the precancerous stage of murine hepatocarcinogenesis. AB - Chronic liver inflammation precedes the majority of hepatocellular carcinomas (HCC). Here, we explore the connection between chronic inflammation and DNA methylation in the liver at the late precancerous stages of HCC development in Mdr2(-/-) (Mdr2/Abcb4-knockout) mice, a model of inflammation-mediated HCC. Using methylated DNA immunoprecipitation followed by hybridization with "CpG islands" (CGIs) microarrays, we found specific CGIs in 76 genes which were hypermethylated in the Mdr2(-/-) liver compared to age-matched healthy controls. The observed hypermethylation resulted mainly from an age-dependent decrease of methylation of the specific CGIs in control livers with no decrease in mutant mice. Chronic inflammation did not change global levels of DNA methylation in Mdr2(-/-) liver, but caused a 2-fold decrease of the global 5-hydroxymethylcytosine level in mutants compared to controls. Liver cell fractionation revealed, that the relative hypermethylation of specific CGIs in Mdr2(-/-) livers affected either hepatocyte, or non-hepatocyte, or both fractions without a correlation between changes of gene methylation and expression. Our findings demonstrate that chronic liver inflammation causes hypermethylation of specific CGIs, which may affect both hepatocytes and non-hepatocyte liver cells. These changes may serve as useful markers of an increased regenerative activity and of a late precancerous stage in the chronically inflamed liver. PMID- 25918252 TI - Nimotuzumab increases the anti-tumor effect of photodynamic therapy in an oral tumor model. AB - Oral squamous cell carcinoma (OSCC) represents 90% of all oral cancers and is characterized with poor prognosis and low survival rate. Epidermal growth factor receptor (EGFR) is highly expressed in oral cancer and is a target for cancer therapy and prevention. In this present work, we evaluate the efficacy of photodynamic therapy (PDT) in combination with an EGFR inhibitor, nimotuzumab in oral cancer cell lines and OSCC xenograft tumor model. PDT is a promising and minimally invasive treatment modality that involves the interaction of a photosensitizer, molecular oxygen and light to destroy tumors. We demonstrated that EGFR inhibitors nimotuzumab and cetuximab exhibits anti-angiogenic properties by inhibiting the migration and invasion of oral cancer cell lines and human endothelial cells. The EGFR inhibitors also significantly reduced tube formation of endothelial cells. Chlorin e6-PDT in combination with nimotuzumab and cetuximab reduced cell proliferation in different oral cancer and endothelial cells. Furthermore, our in vivo studies showed that the combination therapy of PDT and nimotuzumab synergistically delayed tumor growth when compared with control and PDT treated tumors. Downregulation of EGFR, Ki-67 and CD31 was observed in the tumors treated with combination therapy. Analysis of the liver and kidney function markers showed no treatment related toxicity. In conclusion, PDT outcome of oral cancer can be improved when combined with EGFR inhibitor nimotuzumab. PMID- 25918253 TI - Role of TGF-beta signaling in uterine carcinosarcoma. AB - Uterine carcinosarcomas (UCS) are rare (3-4%) but highly aggressive, accounting for a disproportionately high (16.4%) mortality among uterine malignancies. Transforming growth factor beta (TGFbeta) is a multifunctional cytokine that regulates important cellular processes including epithelial-mesenchymal transition (EMT). Existence of biphasic elements and a report demonstrating amplification of TGFbeta at 19q13.1 prompted us to investigate the role of TGFbeta signaling in UCS.Here we demonstrated the components of TGFbeta pathway are expressed and functional in UCS. TGFbeta-I induced significant Smad2/3 phosphorylation, migration and EMT responses in UCS cell lines which could be attenuated by the TGFbeta receptor I (TGFbetaR-I) or TGFbeta receptor I/II (TGFbetaR-I/II) inhibitor developed by Eli Lilly and company. Importantly, TGFbeta-I induced proliferation was c-Myc dependent, likely through activation of cell cycle. c-Myc was induced by nuclear translocation of nuclear factor of activated T cells (NFAT-1) in response to TGFbeta-I. Inhibition of NFAT-1 or TGFbetaR-I blocked c-Myc induction, cell cycle progression and proliferation in UCS. In corroboration, mRNA levels of c-Myc were elevated in recurrent versus the non-recurrent UCS patient samples. Interestingly, in the absence of exogenous TGFbeta the TGFbetaR-I/II inhibitor enhanced proliferation likely through non Smad pathways. Thus, inhibition of TGFbetaR-I could be efficacious in treatment of UCS. PMID- 25918254 TI - A plasmid-encoded UmuD homologue regulates expression of Pseudomonas aeruginosa SOS genes. AB - The Pseudomonas aeruginosa plasmid pUM505 contains the umuDC operon that encodes proteins similar to error-prone repair DNA polymerase V. The umuC gene appears to be truncated and its product is probably not functional. The umuD gene, renamed umuDpR, possesses an SOS box overlapped with a Sigma factor 70 type promoter; accordingly, transcriptional fusions revealed that the umuDpR gene promoter is activated by mitomycin C. The predicted sequence of the UmuDpR protein displays 23 % identity with the Ps. aeruginosa SOS-response LexA repressor. The umuDpR gene caused increased MMC sensitivity when transferred to the Ps. aeruginosa PAO1 strain. As expected, PAO1-derived knockout lexA- mutant PW6037 showed resistance to MMC; however, when the umuDpR gene was transferred to PW6037, MMC resistance level was reduced. These data suggested that UmuDpR represses the expression of SOS genes, as LexA does. To test whether UmuDpR exerts regulatory functions, expression of PAO1 SOS genes was evaluated by reverse transcription quantitative PCR assays in the lexA- mutant with or without the pUC_umuD recombinant plasmid. Expression of lexA, imuA and recA genes increased 3.4-5.3 times in the lexA- mutant, relative to transcription of the corresponding genes in the lexA+ strain, but decreased significantly in the lexA- /umuDpR transformant. These results confirmed that the UmuDpR protein is a repressor of Ps. aeruginosa SOS genes controlled by LexA. Electrophoretic mobility shift assays, however, did not show binding of UmuDpR to 5' regions of SOS genes, suggesting an indirect mechanism of regulation. PMID- 25918255 TI - Mucolytics as Adjuvant Agent to Improve Helicobacter pylori Eradication Rate: Still Long and Winding Road to Positive Results. PMID- 25918256 TI - There Is No Reason to Delay Helicobacter pylori Eradication after Treatment for Upper Gastrointestinal Bleeding. PMID- 25918257 TI - Practical suggestions to train better-performing endosonographers. PMID- 25918258 TI - Cross-regulation of innate and adaptive immunity: a new perspective for the pathogenesis of inflammatory bowel disease. PMID- 25918259 TI - Long-term suppression of viral replication in chronic hepatitis B: outcomes and future directions. PMID- 25918263 TI - Concurrent gastric and pulmonary mucosa-associated lymphoid tissue lymphomas with pre-existing intrinsic chronic inflammation: a case report and a review of the literature. PMID- 25918264 TI - Self-assembled plasmonic templates produced by microwave annealing: applications to surface-enhanced Raman scattering. AB - Perhaps the simplest method for creating metal nanoparticles on a substrate is by driving their self-assembly with the thermal annealing of a thin metal film. By properly tuning the annealing parameters one hopes to discover a recipe that allows the pre-determined design of the NP arrangement. However, thermal treatment is known for detrimental effects and is not really the manufacturer's route of choice when it comes to large-scale applications. An alternative method is the use of microwave annealing, a method that has never been applied for metal processing, due to the high reflectance of microwave radiation at the surface of a metal. However, in this work we challenge the widely used nanostructuring methods by proving the microwave's annealing ability to produce plasmonic templates, out of extremely thin metal films, by simply using a domestic microwave oven apparatus. We show that this process is generic and independent of the deposition method used for the metal and we further quantify the suitability of these plasmonic templates for use in surface-enhanced Raman scattering applications. PMID- 25918262 TI - Bile Acid diarrhea: prevalence, pathogenesis, and therapy. AB - Bile acid diarrhea (BAD) is usually seen in patients with ileal Crohn's disease or ileal resection. However, 25% to 50% of patients with functional diarrhea or diarrhea-predominant irritable bowel syndrome (IBS-D) also have evidence of BAD. It is estimated that 1% of the population may have BAD. The causes of BAD include a deficiency in fibroblast growth factor 19 (FGF-19), a hormone produced in enterocytes that regulates hepatic bile acid (BA) synthesis. Other potential causes include genetic variations that affect the proteins involved in BA enterohepatic circulation and synthesis or in the TGR5 receptor that mediates the actions of BA in colonic secretion and motility. BAs enhance mucosal permeability, induce water and electrolyte secretion, and accelerate colonic transit partly by stimulating propulsive high-amplitude colonic contractions. There is an increased proportion of primary BAs in the stool of patients with IBS D, and some changes in the fecal microbiome have been described. There are several methods of diagnosing BAD, such as (75)selenium homotaurocholic acid test retention, serum C4, FGF-19, and fecal BA measurement; presently, therapeutic trials with BA sequestrants are most commonly used for diagnosis. Management involves the use of BA sequestrants including cholestyramine, colestipol, and colesevelam. FXR agonists such as obeticholic acid constitute a promising new approach to treating BAD. PMID- 25918261 TI - Gut microbiota as potential orchestrators of irritable bowel syndrome. AB - Irritable bowel syndrome (IBS) is a multifactorial functional disorder with no clearly defined etiology or pathophysiology. Modern culture-independent techniques have improved the understanding of the gut microbiota's composition and demonstrated that an altered gut microbiota profile might be found in at least some subgroups of IBS patients. Research on IBS from a microbial perspective is gaining momentum and advancing. This review will therefore highlight potential links between the gut microbiota and IBS by discussing the current knowledge of the gut microbiota; it will also illustrate bacterial-host interactions and how alterations to these interactions could exacerbate, induce or even help alleviate IBS. PMID- 25918265 TI - [Pelvic lymph node dissection in robot-assisted laparoscopic radical prostatectomy: safety and adequacy in introductory series]. AB - To evaluate the safety and adequacy of pelvic lymph node dissection (LND) in robot-assisted laparoscopic radical prostatectomy (RALP) in an institutional introductory case series, we retrospectively reviewed the first 135 patients with clinically localized prostate cancer who underwent RALP with no LND (n=78), limited LND (LLND, n=40), or extended LND (ELND, n=17). Data were collected foroperating time itemized by each surgical procedure, estimated blood loss, lymph node yield, total postoperative drainage amount, postoperative days to drainage tube removal and urethral catheter removal, perioperative complication, and postoperative hospital stay. LLND and ELND took a median of 19 (interquartile range 15-22) and 69 (60.5-91) min, respectively. Total operating time was significantly longer (p<0.0001) for those with ELND (median 329 min ; interquartile 272-375) than those with no LND (239 ; 195-292) and LLND (281 ; 230 314). Lymph node yield was 7 (5-9) and 23 (12-30) for LLND and ELND, respectively, which was equivalent to the yield of lymph nodes dissected in open prostatectomy ashistorical and institutional control. Although total drainage amount was significantly greater and drainage tube was placed significantly longer in the ELND group, there were no significant differences in time to urethral catheter removal and postoperative hospital stay among the groups. There were no severe perioperative complications associated with LND except for prolonged lymph fistula in each case of the LLND and ELND groups. In conclusion, LND can be performed safely and adequately in introductory RALP cases. PMID- 25918266 TI - [Vesico-appendiceal fistula caused by appendiceal cancer: a case report]. AB - A case of vesico-appendiceal fistula caused by appendiceal cancer is reported. A 37-year-old male was admitted with the chief complaint of suspended dust in the urine. Under cystoscopy, a tumor (1 cm diameter) was found in the right posterior wall of the bladder. Transurethral resection of the bladder tumor was performed. The pathological outcome was intestinal metaplasia without malignancy. Preoperative abdominal computed tomography suggested vesico-appendiceal fistula, retrospectively. Therefore, appendectomy with partial cystectomy was attempted. However, the appendix was adhered to the sigmoid mesocolon, therefore, appendectomy, partial cystectomy, and sigmoid colectomy were performed. We diagnosed the tumor as mucinous adenocarcinoma. The patient has been receiving adjuvant chemotherapy with tegafur-gimeracil-oteracil potassium for 17 months, because he refused right hemicolectomy. There was no evidence of recurrence after 58 months of follow-up. Vesico-appendiceal fistula caused by appendiceal cancer is very rare. Our case is the 21st case reported in Japan. PMID- 25918267 TI - [Cholesterol crystal embolization following urinary diversion: a case report]. AB - Cholesterol crystal embolization (CCE) is a cardiovascular disorder with poor prognosis, causing multiple organ failure. The primary pathological condition of the disease is embolization of cholesterol crystals in peripheral vessels. We report a case of CCE following urinary diversion. The patient is a 82-year-old male with history of hypertention, pneumonectasia, interstitial pneumonia, and heavy smoking. He was afflicted with advanced bladder cancer. He underwent urinary diversion, and had been scheduled for palliative radiotherapy. The next day, he developed thromboembolism of the left lower leg as acomplication of urinary diversion. Thrombectomy by endovascular catheter procedure was performed immediately, and anticoagulant therapy was started. The day after the thrombectomy, his lower legs showed livedo reticularis and toes showed cyanosis (blue toe). Since the laboratory data showed acute deterioration in renal function, hemodialysis was initiated. Three days after the thrombectomy he died of multiple organ failure. At autopsy, diffuse atherosclerosis of the aorta was observed, and cholesterol crystalemboli were found in the skin of the left foot ; and, the diagnosis of CCE was confirmed. This case suggests that tissue examinations for early diagnosis and stopping anticoagulant therapy are preferred when CCE is suspected. PMID- 25918268 TI - [The efficacy of the use of acetic acid test in a case of local recurrence of penile carcinoma]. AB - A 62-old-year male presented to our hospital with induration of the prepuce and bleeding from the glans penis that occurred during sexual intercourse. Scrape cytology was performed, which showed class V, suspected squamous cell carcinoma. Computed tomography showed no metastases, and magnetic resonance imaging revealed no invasion of the corpus spongiosum. Circumcision and resection of the glanstumor were performed. Histopathological examination revealed squamous cell carcinoma in situ. We diagnosed the case as penile carcinoma in situ (pTisN0M0, UICC stage 0, and Jackson stage I). At 6 months postoperatively, local recurrence of penile carcinoma was detected by visual inspection after 5% acetic acid staining, and tumor resection was performed. At 9 months postoperatively (after the 2nd resection), the patient has remained disease-free, with no evidence of recurrence. PMID- 25918269 TI - [Total penectomy for corpus cavernosum abscess: a case report]. AB - Abscess of corpus cavernosum penis is a rare infection condition. A 69-year-old man was referred toour hospital with gradual development of penis swelling. T2 weighted magnetic resonance imaging of the pelvis showed abscess formation in the corpus cavernosum. There was no apparent cause of his penile abscess from either history or clinical examination. Open drainage improved his clinical symptoms transiently. However, severe penile pain relapsed, and abscess progressively extended in the corpus cavernosum and spongiosum, necessitating total penectomy. The surgical specimen revealed intensive inflammation and his condition improved immediately after penectomy. PMID- 25918260 TI - 2014 KLCSG-NCC Korea Practice Guideline for the Management of Hepatocellular Carcinoma. AB - The guideline for the management of hepatocellular carcinoma (HCC) was first developed in 2003 and revised in 2009 by the Korean Liver Cancer Study Group and the National Cancer Center, Korea. Since then, many studies on HCC have been carried out in Korea and other countries. In particular, a substantial body of knowledge has been accumulated on diagnosis, staging, and treatment specific to Asian characteristics, especially Koreans, prompting the proposal of new strategies. Accordingly, the new guideline presented herein was developed on the basis of recent evidence and expert opinions. The primary targets of this guideline are patients with suspicious or newly diagnosed HCC. This guideline provides recommendations for the initial treatment of patients with newly diagnosed HCC. PMID- 25918270 TI - [A case of abscess of corpus cavernosum as an early symptom of penile pyodermal gangrenosum: we propose the possibility of a new pathogenic finding]. AB - A 76-year-old man with a mass on the penis and a pain during nighttime erection was referred to our institution. T2-weighted magnetic resonance imaging showed a high-intensity area in the dorsal part of corpus cavernosum. We diagnosed him with the abscess of corpus cavernosum. Surgical drainage and chemotherapy had been performed for 3 years. However, it recurred consistently and developed several cutaneous draining fistulae. The abscess culture was sterile. Skin biopsy revealed a diagnosis of penile pyoderma gangrenosum, which was treated successfully with prednisolone and an immunosuppressive drug. Twenty nine cases of the abscess of corpus cavernosum have been reported in the literature. Most of the recurrent cases tend to be idiopathic corpus cavernosum abscess with sterile culture and finally penectomy is performed. Based on this case, we propose a new notion that corpus cavernosum abscess can be an early symptom of pyoderma gangrenosum. PMID- 25918271 TI - [Polyorchidism: a case report and review of the literature]. AB - A 10-year-old boy presented with a painless left scrotal mass that had been present for 2 years. Ultrasound examination revealed 2 left testes measuring 2.4 ml and 1.0 ml with the same echogenicity. Atsurgery, there were 2 similarly sized testes connecting with other spermatic vascular, but the supernumerary testis had no connection with the vas deferens. Histological findings showed immature testicular tissue without malignancy. We report the 26th case of polyorchidism in Japan and discuss this condition. PMID- 25918272 TI - Comment to 'Video-assisted minimally invasive mitral valve surgery: transitioning from sternotomy to mini-thoracotomy'. PMID- 25918273 TI - Reply to Bortolussi et al.: Managing right ventricular dysfunction during minimally invasive mitral valve operations. PMID- 25918274 TI - Remodeling of Kv1.5 channel in right atria from Han Chinese patients with atrial fibrillation. AB - BACKGROUND: The incidence of atrial fibrillation (AF) in rheumatic heart diseases (RHD) is very high and increases with age. Occurrence and maintenance of AF are very complicated process accompanied by many different mechanisms. Ion-channel remodeling, including the voltage-gated potassium channel Kv1.5, plays an important role in the pathophysiology of AF. However, the changes of Kv1.5 channel expression in Han Chinese patients with RHD and AF remain poorly understood. The aim of the present study was to investigate whether the Kv1.5 channels of the right atria may be altered with RHD, age, and sex to contribute to AF. MATERIAL/METHODS: Right atrial appendages were obtained from 20 patients with normal cardiac functions who had undergone surgery, and 26 patients with AF. Subjects were picked from 4 groups: adult and aged patients in normal sinus rhythm (SR) and AF. Patients were divided into non-RHD and RHD groups or men and women groups in normal SR and AF, respectively. The expression of Kv1.5 protein and messenger RNA (mRNA) were measured using Western blotting and polymerase chain reaction (PCR) method, respectively. RESULTS: Compared with the SR group, the expression of Kv1.5 protein decreased significantly in the AF group. However, neither Kv1.5 protein nor KCNA5 mRNA had significant differences in adult and aged groups, non-RHD and RHD group, and men and women group of AF. CONCLUSIONS: The expression of Kv1.5 channel protein changes with AF but not with age, RHD, and sex in AF. PMID- 25918275 TI - Percutaneous dilatational tracheostomy in a patient on antiplatelet therapy with ticagrelor and Aspirin: a case report. PMID- 25918276 TI - Rotem and transfusion protocols: not yet time to give recommendations - Authors' reply. PMID- 25918277 TI - Symptoms and Distress in Children With Advanced Cancer: Prospective Patient Reported Outcomes From the PediQUEST Study. AB - PURPOSE: Thousands of children are living with advanced cancer; yet patient reported outcomes (PROs) have rarely been used to describe their experiences. We aimed to describe symptom distress in 104 children age 2 years or older with advanced cancer enrolled onto the Pediatric Quality of Life and Evaluation of Symptoms Technology (PediQUEST) Study (multisite clinical trial evaluating an electronic PRO system). METHODS: Symptom data were collected using age- and respondent-adapted versions of the PediQUEST Memorial Symptom Assessment Scale (PQ-MSAS) at most once per week. Clinical and treatment data were obtained from medical records. Individual symptom scores were dichotomized into high/low distress. Determinants of PQ-MSAS scores were explored using linear mixed-effects models. RESULTS: During 9 months of follow-up, PQ-MSAS was administered 920 times: 459 times in teens (99% self-report), 249 times in children ages 7 to 12 years (96% child/parent report), and 212 times in those ages 2 to 6 years (parent reports). Common symptoms included pain (48%), fatigue (46%), drowsiness (39%), and irritability (37%); most scores indicated high distress. Among the 73 PQ-MSAS surveys administered in the last 12 weeks of life, pain was highly prevalent (62%; 58% with high distress). Being female, having a brain tumor, experiencing recent disease progression, and receiving moderate- or high-intensity cancer directed therapy in the prior 10 days were associated with worse PQ-MSAS scores. In the final 12 weeks of life, receiving mild cancer-directed therapy was associated with improved psychological PQ-MSAS scores. CONCLUSION: Children with advanced cancer experience high symptom distress. Strategies to promote intensive symptom management are indicated, especially with disease progression or administration of intensive treatments. PMID- 25918279 TI - Approach to patients with pancreatic cancer without detectable metastases. AB - The poors outcomes associated with pancreatic cancer clearly reflect the advanced stage of disease at diagnosis for most patients. Through this lens, it is easy to lose sight of the fact that roughly 50% of patients with pancreatic cancer have no clinically detectable metastases at presentation. Herein, we discuss how patients with localized pancreatic cancer are currently managed. The primary goal of care for patients with resectable and borderline-resectable tumors is cure, facilitated by achieving margin-negative resection of the primary disease and delivering effective adjuvant and/or neoadjuvant therapy. For patients with locally advanced disease, the focus is on limiting local progression and outgrowth of metastatic disease and maintaining quality of life. Although it was once a centerpiece of therapy for localized pancreatic cancer, the value and place of radiation therapy in the treatment algorithm is now under increased scrutiny. In contrast, given its value as demonstrated in multiple prospective trials, chemotherapy is an established part of the treatment paradigm for all patients. With the demonstration that cytotoxic combinations such as fluorouracil, leucovorin, irinotecan, and oxaliplatin as well as gemcitabine/nab paclitaxel are active in the metastatic setting, these agents are now being studied in patients with localized disease. The neoadjuvant setting provides a particularly favorable setting for evaluating new systemic strategies. Given the array of new targets, including immunomodulatory approaches, there is reason for optimism that we can markedly improve survival for all patients with pancreatic cancer and enter an era in which surgery with curative intent actually fulfills this goal on a much more regular basis. PMID- 25918278 TI - Toxicities of Immunotherapy for the Practitioner. AB - The toxicities of immunotherapy for cancer are as diverse as the type of treatments that have been devised. These range from cytokine therapies that induce capillary leakage to vaccines associated with low levels of autoimmunity to cell therapies that can induce damaging cross-reactivity with normal tissue to checkpoint protein inhibitors that induce immune-related adverse events that are autoinflammatory in nature. The thread that ties these toxicities together is their mechanism-based immune nature and the T-cell-mediated adverse events seen. The basis for the majority of these adverse events is a hyperactivated T-cell response with reactivity directed against normal tissue, resulting in the generation of high levels of CD4 T-helper cell cytokines or increased migration of cytolytic CD8 T cells within normal tissues. The T-cell immune response is not tissue specific and may reflect a diffuse expansion of the T-cell repertoire that induces cross-reactivity with normal tissue, effectively breaking tolerance that is active with cytokines, vaccines, and checkpoint protein inhibitors and passive in the case of adoptive cell therapy. Cytokines seem to generate diffuse and nonspecific T-cell reactivity, whereas checkpoint protein inhibition, vaccines, and adoptive cell therapy seem to activate more specific T cells that interact directly with normal tissues, potentially causing specific organ damage. In this review, we summarize the toxicities that are unique to immunotherapies, emphasizing the need to familiarize the oncology practitioner with the spectrum of adverse events seen with newly approved and emerging modalities. PMID- 25918280 TI - Metastatic colorectal cancer: current state and future directions. AB - Substantial improvements have been made in the management of metastatic colorectal cancer over the last two decades. The overall survival of patients diagnosed with unresectable metastatic colorectal cancer has increased from approximately 1 year during the era of fluoropyrimidine monotherapy to more than 30 months with the integration of multiple cytotoxic agents and targeted therapies. More effective therapeutic combinations have increased the rate of curative-intent surgical resections, resulting in median survival in this subgroup that exceed 5 years. Here we review the landscape of systemic therapies for unresectable metastatic colorectal cancer during the current era of targeted therapies, review the effects of RAS and BRAF mutations on clinical decision making, and reflect on future directions for the treatment of metastatic colorectal cancer. PMID- 25918281 TI - Challenges in the Use of DNA Repair Deficiency As a Biomarker in Breast Cancer. PMID- 25918282 TI - Carcinoid and neuroendocrine tumors: building on success. AB - We have come a long way in our understanding and treatment of neuroendocrine tumors since the term "karzinoide" was coined in 1907. Neuroendocrine tumors are a group of biologically and clinically heterogeneous neoplasms that most commonly originate in the lungs, GI tract, and pancreas. The selection of initial and subsequent therapies requires careful consideration of both tumor and treatment characteristics. With recent advances, we now have more tools for the diagnosis and treatment of our patients. This comprehensive review article summarizes recent advances in the field of neuroendocrine tumors and places them into context for best management practices. PMID- 25918283 TI - Screening in GI Cancers: The Role of Genetics. AB - Genetic and epigenetic alterations identified in tumors of different cancer types can provide insights regarding the roles played by different cell signaling pathways in carcinogenesis. Somatic mutation profiles of GI tumors are used to guide choice of chemotherapy and can facilitate identification of individuals whose cancers arise in the setting of genetic predisposition. This review provides a framework for how clinical history, family history of cancer, and tumor genomic phenotype can be used to screen patients with colorectal, gastric, or pancreatic cancer for hereditary cancer syndromes. Early identification of individuals who carry germline mutations can affect clinical care not only for patients with cancer but also for their at-risk relatives. PMID- 25918284 TI - Special Series: Advances in GI Cancer. PMID- 25918285 TI - Genomic Characterization of Non-Small-Cell Lung Cancer in African Americans by Targeted Massively Parallel Sequencing. AB - PURPOSE: Technologic advances have enabled the comprehensive analysis of genetic perturbations in non-small-cell lung cancer (NSCLC); however, African Americans have often been underrepresented in these studies. This ethnic group has higher lung cancer incidence and mortality rates, and some studies have suggested a lower incidence of epidermal growth factor receptor mutations. Herein, we report the most in-depth molecular profile of NSCLC in African Americans to date. METHODS: A custom panel was designed to cover the coding regions of 81 NSCLC related genes and 40 ancestry-informative markers. Clinical samples were sequenced on a massively parallel sequencing instrument, and anaplastic lymphoma kinase translocation was evaluated by fluorescent in situ hybridization. RESULTS: The study cohort included 99 patients (61% males, 94% smokers) comprising 31 squamous and 68 nonsquamous cell carcinomas. We detected 227 nonsilent variants in the coding sequence, including 24 samples with nonoverlapping, classic driver alterations. The frequency of driver mutations was not significantly different from that of whites, and no association was found between genetic ancestry and the presence of somatic mutations. Copy number alteration analysis disclosed distinguishable amplifications in the 3q chromosome arm in squamous cell carcinomas and pointed toward a handful of targetable alterations. We also found frequent SMARCA4 mutations and protein loss, mostly in driver-negative tumors. CONCLUSION: Our data suggest that African American ancestry may not be significantly different from European/white background for the presence of somatic driver mutations in NSCLC. Furthermore, we demonstrated that using a comprehensive genotyping approach could identify numerous targetable alterations, with potential impact on therapeutic decisions. PMID- 25918286 TI - Subtype Classification of Lung Adenocarcinoma Predicts Benefit From Adjuvant Chemotherapy in Patients Undergoing Complete Resection. AB - PURPOSE: The classification for invasive lung adenocarcinoma by the International Association for the Study of Lung Cancer, American Thoracic Society, European Respiratory Society, and WHO is based on the predominant histologic pattern lepidic (LEP), papillary (PAP), acinar (ACN), micropapillary (MIP), or solid (SOL)-present in the tumor. This classification has not been tested in multi institutional cohorts or clinical trials or tested for its predictive value regarding survival from adjuvant chemotherapy (ACT). PATIENTS AND METHODS: Of 1,766 patients in the IALT, JBR.10, CALGB 9633 (Alliance), and ANITA ACT trials included in the LACE-Bio study, 725 had adenocarcinoma. Histologies were reclassified according to the new classification and then collapsed into three groups (LEP, ACN/PAP, and MIP/SOL). Primary end point was overall survival (OS); secondary end points were disease-free survival (DFS) and specific DFS (SDFS). Hazard ratios (HRs) and 95% CIs were estimated through multivariable Cox models stratified by trial. Prognostic value was estimated in the observation arm and predictive value by a treatment effect interaction with histologic subgroups. Significance level was set at .01 for pooled analysis. RESULTS: A total of 575 patients were included in this analysis. OS was not prognostically different between histologic subgroups, but univariable DFS and SDFS were worse for MIP/SOL compared with LEP or ACN/PAP subgroup (P < .01); this remained marginally significant after adjustment. MIP/SOL patients (but not ACN/PAP) derived DFS and SDFS but not OS benefit from ACT (OS: HR, 0.71; 95% CI, 0.51 to 0.99; interaction P = .18; DFS: HR, 0.60; 95% CI, 0.44 to 0.82; interaction P = < .01; and SDFS: HR, 0.59; 95% CI, 0.42 to 0.81; interaction P = .01). CONCLUSION: The new lung adenocarcinoma classification based on predominant histologic pattern was not predictive for ACT benefit for OS, but it seems predictive for disease-specific outcomes. PMID- 25918287 TI - Personalizing colon cancer adjuvant therapy: selecting optimal treatments for individual patients. AB - For more than three decades, postoperative chemotherapy-initially fluoropyrimidines and more recently combinations with oxaliplatin-has reduced the risk of tumor recurrence and improved survival for patients with resected colon cancer. Although universally recommended for patients with stage III disease, there is no consensus about the survival benefit of postoperative chemotherapy in stage II colon cancer. The most recent adjuvant clinical trials have not shown any value for adding targeted agents, namely bevacizumab and cetuximab, to standard chemotherapies in stage III disease, despite improved outcomes in the metastatic setting. However, biomarker analyses of multiple studies strongly support the feasibility of refining risk stratification in colon cancer by factoring in molecular characteristics with pathologic tumor staging. In stage II disease, for example, microsatellite instability supports observation after surgery. Furthermore, the value of BRAF or KRAS mutations as additional risk factors in stage III disease is greater when microsatellite status and tumor location are taken into account. Validated predictive markers of adjuvant chemotherapy benefit for stage II or III colon cancer are lacking, but intensive research is ongoing. Recent advances in understanding the biologic hallmarks and drivers of early-stage disease as well as the micrometastatic environment are expected to translate into therapeutic strategies tailored to select patients. This review focuses on the pathologic, molecular, and gene expression characterizations of early-stage colon cancer; new insights into prognostication; and emerging predictive biomarkers that could ultimately help define the optimal adjuvant treatments for patients in routine clinical practice. PMID- 25918288 TI - Update on metastatic gastric and esophageal cancers. AB - Cancers of the stomach and esophagus are among the most challenging cancers of the GI tract to treat, associated with poor median survivals for metastatic disease and significant, sometimes prolonged, deteriorations in patient performance status as the diseases progress. However, in the past decade, we have begun to better understand disease biology and carcinogenesis, leading to the identification of subtypes of these diseases. There is also an increasing awareness of the global heterogeneity of disease and its impact on drug development. Our improved understanding of the molecular underpinnings of gastric and esophageal cancers has been accompanied with the development of novel therapeutic strategies. Recent actively investigated targets in this disease include human epidermal growth factor receptor 2, angiogenesis, MET, and immune checkpoint inhibition, with approvals of two new targeted agents, trastuzumab and ramucirumab. Improvements in our ability to deliver cytotoxic therapy, which is better tolerated and allows patients an opportunity to benefit from second- and more advanced lines of therapy, have also been observed. In this review, the current state-of-the-art management of advanced and metastatic gastric and esophageal adenocarcinomas, specifically highlighting the development of targeted therapies in these diseases, is described. PMID- 25918289 TI - Localized and systemic approaches to treating hepatocellular carcinoma. PMID- 25918290 TI - Durable Responses With PD-1 Inhibition in Lung and Kidney Cancer and the Ongoing Search for Predictive Biomarkers. PMID- 25918291 TI - Effect of Low-Intensity Physical Activity and Moderate- to High-Intensity Physical Exercise During Adjuvant Chemotherapy on Physical Fitness, Fatigue, and Chemotherapy Completion Rates: Results of the PACES Randomized Clinical Trial. AB - PURPOSE: We evaluated the effectiveness of a low-intensity, home-based physical activity program (Onco-Move) and a moderate- to high-intensity, combined supervised resistance and aerobic exercise program (OnTrack) versus usual care (UC) in maintaining or enhancing physical fitness, minimizing fatigue, enhancing health-related quality of life, and optimizing chemotherapy completion rates in patients undergoing adjuvant chemotherapy for breast cancer. PATIENTS AND METHODS: We randomly assigned patients who were scheduled to undergo adjuvant chemotherapy (N = 230) to Onco-Move, OnTrack, or UC. Performance-based and self reported outcomes were assessed before random assignment, at the end of chemotherapy, and at the 6-month follow-up. We used generalized estimating equations to compare the groups over time. RESULTS: Onco-Move and OnTrack resulted in less decline in cardiorespiratory fitness (P < .001), better physical functioning (P <= .001), less nausea and vomiting (P = .029 and .031, respectively) and less pain (P = .003 and .011, respectively) compared with UC. OnTrack also resulted in better outcomes for muscle strength (P = .002) and physical fatigue (P < .001). At the 6-month follow-up, most outcomes returned to baseline levels for all three groups. A smaller percentage of participants in OnTrack required chemotherapy dose adjustments than those in the UC or Onco-Move groups (P = .002). Both intervention groups returned earlier (P = .012), as well as for more hours per week (P = .014), to work than the control group. CONCLUSION: A supervised, moderate- to high-intensity, combined resistance and aerobic exercise program is most effective for patients with breast cancer undergoing adjuvant chemotherapy. A home-based, low-intensity physical activity program represents a viable alternative for women who are unable or unwilling to follow the higher intensity program. PMID- 25918292 TI - Palliative Oncologists: Specialists in the Science and Art of Patient Care. PMID- 25918293 TI - Role of physical activity and diet after colorectal cancer diagnosis. AB - This review summarizes the evidence regarding physical activity and diet after colorectal cancer diagnosis in relation to quality of life, disease recurrence, and survival. There have been extensive reports on adiposity, inactivity, and certain diets, particularly those high in red and processed meats, and increased risk of colorectal cancer. Only in the past decade have data emerged on how such lifestyle factors are associated with outcomes in colorectal cancer survivors. Prospective observational studies have consistently reported that physical activity after colorectal cancer diagnosis reduces mortality. A meta-analysis estimated that each 15 metabolic equivalent task-hour per week increase in physical activity after colorectal cancer diagnosis was associated with a 38% lower risk of mortality. No randomized controlled trials have been completed to confirm that physical activity lowers risk of mortality among colorectal cancer survivors; however, trials have shown that physical activity, including structured exercise, is safe for colorectal cancer survivors (localized to metastatic stage, during and after treatment) and improves cardiorespiratory fitness and physical function. In addition, prospective observational studies have suggested that a Western dietary pattern, high carbohydrate intake, and consuming sugar-sweetened beverages after diagnosis may increase risk of colorectal cancer recurrence and mortality, but these data are limited to single analyses from one of two US cohorts. Additional data from prospective studies and randomized controlled trials are needed. Nonetheless, on the basis of the available evidence, it is reasonable to counsel colorectal cancer survivors to engage in regular physical activity and limit consumption of refined carbohydrates, red and processed meats, and sugar-sweetened beverages. PMID- 25918294 TI - Biliary tract cancers: understudied and poorly understood. AB - Biliary tract cancers are a heterogeneous group of cancers that arise in either the intra- or extrahepatic bile ducts or the gallbladder. Local therapy with surgical resection and perhaps radiation therapy is used for localized disease. There is no known effective adjuvant therapy, although various combinations have been used clinically without definitive data showing a benefit. The most standard chemotherapy for metastatic disease is gemcitabine plus cisplatin based on a single positive randomized trial. Genetic mutations that may lead to better, targeted therapy choices are being identified, albeit with variable frequency. Early studies of targeted agents have been negative, but these were in unselected patients where it was unknown whether the target was activated in any individual patient. Careful selection of patients enrolling onto trials of targeted agents will make the subsets of biliary tract cancers even smaller but is likely necessary to improve outcomes from these deadly diseases. PMID- 25918295 TI - Immune Therapy in GI Malignancies: A Review. AB - The balance between tumor-promoting and tumor-suppressing immune responses and the difference between them ultimately determine whether a cancer escapes immune recognition mechanisms. Defining the complex relationships between the tumor itself, the tumor environment, and the immune system has been critical in facilitating the development of successful immunotherapies. This review explores the role of oncogenes in inducing cancer-associated inflammation, the local and systemic factors that lead to immune suppression, and immunotherapy approaches to overcome immune privilege. PMID- 25918297 TI - Evidence-Based Diagnostic Algorithm for Glioma: Analysis of the Results of Pathology Panel Review and Molecular Parameters of EORTC 26951 and 26882 Trials. AB - PURPOSE: With the rapid discovery of prognostic and predictive molecular parameters for glioma, the status of histopathology in the diagnostic process should be scrutinized. Our project aimed to construct a diagnostic algorithm for gliomas based on molecular and histologic parameters with independent prognostic values. METHODS: The pathology slides of 636 patients with gliomas who had been included in EORTC 26951 and 26882 trials were reviewed using virtual microscopy by a panel of six neuropathologists who independently scored 18 histologic features and provided an overall diagnosis. The molecular data for IDH1, 1p/19q loss, EGFR amplification, loss of chromosome 10 and chromosome arm 10q, gain of chromosome 7, and hypermethylation of the promoter of MGMT were available for some of the cases. The slides were divided in discovery (n = 426) and validation sets (n = 210). The diagnostic algorithm resulting from analysis of the discovery set was validated in the latter. RESULTS: In 66% of cases, consensus of overall diagnosis was present. A diagnostic algorithm consisting of two molecular markers and one consensus histologic feature was created by conditional inference tree analysis. The order of prognostic significance was: 1p/19q loss, EGFR amplification, and astrocytic morphology, which resulted in the identification of four diagnostic nodes. Validation of the nodes in the validation set confirmed the prognostic value (P < .001). CONCLUSION: We succeeded in the creation of a timely diagnostic algorithm for anaplastic glioma based on multivariable analysis of consensus histopathology and molecular parameters. PMID- 25918298 TI - Role of Radiotherapy and Newer Techniques in the Treatment of GI Cancers. AB - The role of radiotherapy in multidisciplinary treatment of GI malignancies is well established. Recent advances in imaging as well as radiotherapy planning and delivery techniques have made it possible to target tumors more accurately while sparing normal tissues. Intensity-modulated radiotherapy is an advanced method of delivering radiation using cutting-edge technology to manipulate beams of radiation. The role of intensity-modulated radiotherapy is growing for many GI malignancies, such as cancers of the stomach, pancreas, esophagus, liver, and anus. Stereotactic body radiotherapy is an emerging treatment option for some GI tumors such as locally advanced pancreatic cancer and primary or metastatic tumors of the liver. Stereotactic body radiotherapy requires a high degree of confidence in tumor location and subcentimeter accuracy of the delivered dose. New image-guided techniques have been developed to overcome setup uncertainties at the time of treatment, including real-time imaging on the linear accelerator. Modern imaging techniques have also allowed for more accurate pretreatment staging and delineation of the primary tumor and involved sites. In particular, magnetic resonance imaging and positron emission tomography scans can be particularly useful in radiotherapy planning and assessing treatment response. Molecular biomarkers are being investigated as predictors of response to radiotherapy with the intent of ultimately moving toward using genomic and proteomic determinants of therapeutic strategies. The role of all of these new approaches in the radiotherapeutic management of GI cancers and the evolving role of radiotherapy in these tumor sites will be highlighted in this review. PMID- 25918299 TI - Progress in the treatment of metastatic pancreatic cancer and the search for next opportunities. AB - A growing number of therapeutic options are now available for patients with metastatic pancreatic cancer, informed by positive results from recently completed phase III clinical trials. These have led to modest, if not necessarily transformative, improvements in clinical outcomes. Although the standard of care for metastatic disease remains cytotoxic therapy, a variety of novel therapeutic approaches are currently under active investigation, several of which have already demonstrated encouraging results in phase I/II studies. The following three broad categories (with significant overlap among them) are highlighted here: stromal-depleting agents, immunotherapies, and signal transduction inhibitors. The mechanistic rationale, limitations, and promise of each of these strategies specific to pancreatic cancer are discussed, as are the aspects of this disease and this patient population that pose ongoing challenges in terms of both therapeutic management and biomarker-driven trial design. PMID- 25918296 TI - Advances and challenges in treatment of locally advanced rectal cancer. AB - Dramatic improvements in the outcomes of patients with rectal cancer have occurred over the past 30 years. Advances in surgical pathology, refinements in surgical techniques and instrumentation, new imaging modalities, and the widespread use of neoadjuvant therapy have all contributed to these improvements. Several questions emerge as we learn of the benefits or lack thereof for components of the current multimodality treatment in subgroups of patients with nonmetastatic locally advanced rectal cancer (LARC). What is the optimal surgical technique for distal rectal cancers? Do all patients need postoperative chemotherapy? Do all patients need radiation? Do all patients need surgery, or is a nonoperative, organ-preserving approach warranted in selected patients? Answering these questions will lead to more precise treatment regimens, based on patient and tumor characteristics, that will improve outcomes while preserving quality of life. However, the idea of shifting the treatment paradigm (chemoradiotherapy, total mesorectal excision, and adjuvant therapy) currently applied to all patients with LARC to a more individually tailored approach is controversial. The paradigm shift toward organ preservation in highly selected patients whose tumors demonstrate clinical complete response to neoadjuvant treatment is also controversial. Herein, we highlight many of the advances and resultant controversies that are likely to dominate the research agenda for LARC in the modern era. PMID- 25918300 TI - Use of Imaging for GI Cancers. AB - GI cancers are a heterogeneous group of neoplasms that differ in their biologic and physical behaviors depending on the organ of origin, location within the organ, and degree of differentiation. As a result, evaluation of these tumors is complex, requiring integration of information from a patient's clinical history, physical examination, laboratory data, and imaging. With advances in anatomic and functional imaging techniques, we now have tools for assessing patients with these tumors at diagnosis, staging, and treatment assessment. It is difficult for a single imaging modality to provide all the necessary information for a given GI tumor. However, well-chosen combinations of available imaging modalities based on the indications, strength, and limitations of the modalities will provide optimal evaluation of patients with these malignancies. PMID- 25918301 TI - Current Status of Single-Agent Phase I Trials in Japan: Toward Globalization. AB - PURPOSE: In Japan, phase I trials, except first-in-human trials, are usually initiated from approximately 50% of the maximum-tolerated dose (MTD) or maximum administered dose (MAD) determined during the initial phase I trials in North America and Europe (the West). However, the key findings of phase I trials in Japan and the West, such as dose-limiting toxicity (DLT) profiles and MTD or MAD levels, have not been compared. PATIENTS AND METHODS: We retrospectively analyzed data for patients enrolled onto single-agent phase I trials at the National Cancer Center Hospital between 1995 and 2012. DLT profiles, MTDs, and MADs of single-agent phase I trials in Japan were compared with those from trials in the West that were obtained from the literature. RESULTS: A total of 777 patients were enrolled onto 54 single-agent phase I trials, including five first-in-human trials. DLTs were observed in 11.1% of the patients. Importantly, 66.4% of the DLTs were observed within a dose range (80% to 120%) similar to those reported for the trials in the West. The majority of MTDs or MADs could be considered similar between patients, and 80.3% of the drugs had similar MTDs or MADs in the West. CONCLUSION: The toxicity profiles of single-agent phase I agents determined from trials conducted in Japan were comparable to those obtained from trials in the West. We believe that phase I trials in Japan could be conducted over timelines similar to those in the West, allowing for global or parallel phase I clinical trials. PMID- 25918302 TI - Controversies in the treatment of local and locally advanced gastric and esophageal cancers. AB - Despite overall progress in the therapy of local and locally advanced esophageal, gastroesophageal junction, and gastric adenocarcinomas, death as a result of these tumors remains a common outcome. Most randomized phase III trials on which level-one evidence has been built have included the heterogeneous histologies and locations associated with these tumors. However, the different etiologies, molecular biology, and recurrence patterns associated with gastroesophageal malignancies suggest the need to split rather than lump. Biologic and response differences exist between squamous and adenocarcinomas, as well as diffuse and intestinal histologies. This may be a cause behind conflicting outcomes in similar trials. The accepted standard of chemoradiotherapy for locally advanced esophageal and gastroesophageal junction cancers is based on a few positive trials, with the best chemotherapy and total dose of radiation remaining controversial. In the West, the staging evaluations of locally advanced gastric cancer are not uniform. Yet, these evaluations will inform the results of preoperative and perioperative treatments. Although postoperative chemoradiotherapy for gastric cancer has been an accepted treatment option for the last decade, more recent studies have called into question the need for radiotherapy. In perioperative strategies, it has yet to be determined whether histologic or molecular changes in the operative specimen should inform postoperative treatment. An appropriate place for targeted therapy needs to be found in preoperative and postoperative treatment regimens. Finally, because so much is lost when trials are forced to close for lack of accrual, it is imperative to build multidisciplinary consensus before they are launched. PMID- 25918303 TI - GI Stromal Tumors: 15 Years of Lessons From a Rare Cancer. AB - A confluence of factors, most prominently the recognition of GI stromal tumor (GIST) as a specific sarcoma subtype and the availability of imatinib, led to the "Big Bang" of GIST therapy (ie, the successful treatment of the first patient with GIST with imatinib in 2000). The trail blazed by imatinib for chronic myelogenous leukemia and GIST has become a desired route to regulatory approval of an increasing number of oral kinase inhibitors and other novel therapeutics. In this review, the status of GIST management before and after GIST's "Big Bang" and new steps being taken to further improve on therapy are reviewed. PMID- 25918304 TI - Editor's Briefing. PMID- 25918305 TI - Assessing risk and improving survival in lymphoma. PMID- 25918306 TI - Patient safety: the general practice agenda. PMID- 25918307 TI - Physician associates: the challenge facing general practice. PMID- 25918308 TI - Waving not drowning: virtue ethics in general practice. PMID- 25918309 TI - Performance management: can patients' autonomy be protected? PMID- 25918310 TI - GP recruitment and retention. PMID- 25918311 TI - The CQC inspections: not 'outstanding', may be 'good', but 'requires improvement'. PMID- 25918312 TI - CQC intelligent monitoring. PMID- 25918313 TI - How the NCT will bring down the NHS. PMID- 25918314 TI - Always add indication labelling to all repeat prescriptions. PMID- 25918315 TI - Childhood UTI. PMID- 25918316 TI - Are we preparing GP trainees for patient death? PMID- 25918317 TI - Choosing a GP, breast cancer, patient safety, and online dating. PMID- 25918318 TI - International primary care snapshots: Israel and China. PMID- 25918319 TI - Run for the (consultation) hills. PMID- 25918320 TI - Institutional snobbery prevents general practice from being a desirable career choice. PMID- 25918321 TI - The effect of cataracts and cataract surgery on Claude Monet. PMID- 25918322 TI - Are we too busy to be happy? PMID- 25918323 TI - Getting the swagger back into general practice. PMID- 25918324 TI - Mental health and Parkinson's disease: from the cradle to the grave. PMID- 25918327 TI - Writing the hidden curriculum. PMID- 25918328 TI - Clinical pharmacists in general practice: value for patients and the practice of a new role. PMID- 25918329 TI - Following the mixed methods trail: some travel advice. PMID- 25918330 TI - Circinate balanitis as the presenting symptom of sexually-acquired reactive arthritis: a case report. PMID- 25918331 TI - Exercise-induced anaemia: a forgotten cause of iron deficiency anaemia in young adults. PMID- 25918332 TI - Quantifying the risk of non-Hodgkin lymphoma in symptomatic primary care patients aged >=40 years: a large case-control study using electronic records. AB - BACKGROUND: Non-Hodgkin lymphoma (NHL) is the sixth most common cancer in the UK; approximately 35 people are diagnosed and 13 die from the disease daily. AIM: To identify the primary care clinical features of NHL and quantify their risk in symptomatic patients. DESIGN AND SETTING: Matched case-control study using Clinical Practice Research Datalink patient records. METHOD: Putative clinical features of NHL were identified in the year before diagnosis. Results were analysed using conditional logistic regression and positive predictive values (PPVs). RESULTS: A total of 4362 patients aged >=40 years, diagnosed with NHL between 2000 and 2009, and 19 468 age, sex, and general practice-matched controls were studied. Twenty features were independently associated with NHL. The five highest risk symptoms were lymphadenopathy, odds ratio (OR) 263 (95% CI = 133 to 519), head and neck mass not described as lymphadenopathy OR 49 (95% CI = 32 to 74), other mass OR 12 (95% CI = 10 to 16), weight loss OR 3.2 (95% CI = 2.3 to 4.4), and abdominal pain OR 2.5 (95% CI = 2.1 to 2.9). Lymphadenopathy has a PPV of 13% for NHL in patients >=60 years. Weight loss in conjunction with repeated back pain or raised gamma globulin had PPVs >2%. CONCLUSION: Unexplained lymphadenopathy in patients aged >=60 years produces a very high risk of NHL in primary care. These patients warrant urgent investigation, potentially sooner than 6 weeks from initial presentation where the GP is particularly concerned. PMID- 25918333 TI - Quantifying the risk of Hodgkin lymphoma in symptomatic primary care patients aged >=40 years: a case-control study using electronic records. AB - BACKGROUND: In the UK, approximately five people are diagnosed with Hodgkin lymphoma (HL) daily. One-tenth of diagnoses are in those aged >75 years. AIM: To establish a symptom profile of HL and quantify their risk in primary care patients aged >=40 years. DESIGN AND SETTING: Matched case-control study using Clinical Practice Research Datalink patient records. METHOD: Putative clinical features of HL were identified in the year before diagnosis. Results were analysed using conditional logistic regression and positive predictive values (PPVs) calculated for the consulting population. RESULTS: Two-hundred and eighty three patients aged >=40 years, diagnosed with HL between 2000 and 2009, and 1237 age, sex, and general practice-matched participants were studied. Six features were independently associated with HL: lymphadenopathy (OR 280, 95% confidence interval [CI] = 25 to 3100), head and neck mass not described as lymphadenopathy (OR 260, 95% CI = 21 to 3200), other mass (OR 12, 95% CI = 4.4 to 35), thrombocytosis (OR 6.0, 95% CI = 2.6 to 14), raised inflammatory markers (OR 5.2, 95% CI = 3.0 to 9.0), and low full blood count (OR 2.8, 95% CI = 1.6 to 4.8). Lymphadenopathy per se has a positive predictive value (PPV) of 5.6% for HL in patients aged >=60 years. CONCLUSION: Consistent with secondary care findings, lymphadenopathy is the clinical feature with the highest risk of HL in primary care and warrants urgent investigation. PMID- 25918334 TI - Impact of a printed decision aid on patients' intention to undergo prostate cancer screening: a multicentre, pragmatic randomised controlled trial in primary care. AB - BACKGROUND: Despite recommendations against systematic screening for prostate cancer, 70% of patients still request prostate-specific antigen testing. AIM: To assess the impact of a decision aid on patients' intention to undergo prostate cancer screening. DESIGN AND SETTING: Randomised controlled trial with two-arm parallel groups in 86 general practices in urban and rural areas in France. METHOD: Males aged 50-75 years were randomised to receive either the decision aid (intervention group) or usual care (control group). The primary outcome was the proportion of patients' intending to undergo prostate cancer screening, assessed immediately after reading the decision aid. The reasons underlying their choice were elicited and the proportion of patients citing each reason to undergo, or not undergo, prostate cancer screening were compared between the two arms. RESULTS: A total of 1170 patients were randomised (588 in the intervention arm) from November 2012 to February 2013. The proportion of patients who intended to be tested for prostate cancer in the intervention arm (123 patients [20.9%]) was significantly reduced compared with the control arm (57 patients [9.8%]) (difference 11.1%, 95% confidence interval [CI] = 7.0 to 15.2, P<0.0001). In the intervention group, a lower proportion of individuals expressed that cancer screening would protect them from the disease, compared with the control group (P<0.0001), while a greater proportion of individuals stated that prostate cancer screening would not benefit their health (P<0.0001) and may involve procedures with harmful side effects (P = 0.0005). CONCLUSION: The decision aid improved participants' informed decision making and reduced their intent to undergo prostate cancer screening. PMID- 25918335 TI - Patient-doctor continuity and diagnosis of cancer: electronic medical records study in general practice. AB - BACKGROUND: Continuity of care may affect the diagnostic process in cancer but there is little research. AIM: To estimate associations between patient-doctor continuity and time to diagnosis and referral of three common cancers. DESIGN AND SETTING: Retrospective cohort study in general practices in England. METHOD: This study used data from the General Practice Research Database for patients aged >=40 years with a diagnosis of breast, colorectal, or lung cancer. Relevant cancer symptoms or signs were identified up to 12 months before diagnosis. Patient-doctor continuity (fraction-of-care index adjusted for number of consultations) was calculated up to 24 months before diagnosis. Time ratios (TRs) were estimated using accelerated failure time regression models. RESULTS: Patient doctor continuity in the 24 months before diagnosis was associated with a slightly later diagnosis of colorectal (time ratio [TR] 1.01, 95% confidence interval [CI] =1.01 to 1.02) but not breast (TR = 1.00, 0.99 to 1.01) or lung cancer (TR = 1.00, 0.99 to 1.00). Secondary analyses suggested that for colorectal and lung cancer, continuity of doctor before the index consultation was associated with a later diagnosis but continuity after the index consultation was associated with an earlier diagnosis, with no such effects for breast cancer. For all three cancers, most of the delay to diagnosis occurred after referral. CONCLUSION: Any effect for patient-doctor continuity appears to be small. Future studies should compare investigations, referrals, and diagnoses in patients with and without cancer who present with possible cancer symptoms or signs; and focus on 'difficult to diagnose' types of cancer. PMID- 25918336 TI - Patient-reported areas for quality improvement in general practice: a cross sectional survey. AB - BACKGROUND: GPs are often a patient's first point of contact with the health system. The increasing demands imposed on GPs may have an impact on the quality of care delivered. Patients are well placed to make judgements about aspects of care that need to be improved. AIM: To determine whether general practice patients perceive that the care they receive is 'patient-centred' across eight domains of care, and to determine the association between sociodemographic, GP and practice characteristics, detection of preventive health risks, and receipt of patient-centred care. DESIGN AND SETTING: Cross-sectional survey of patients attending Australian general practice clinics. METHOD: Patients completed a touchscreen survey in the waiting room to rate the care received from their GP across eight domains of patient-centred care. Patients also completed the Patient Health Questionnaire (PHQ-9) and self-reported health risk factors. GPs completed a checklist for each patient asking about the presence of health risk factors. RESULTS: In total 1486 patients and 51 GPs participated. Overall, 83% of patients perceived that the care they received was patient-centred across all eight domains. Patients most frequently perceived the 'access to health care when needed' domain as requiring improvement (8.3%). Not having private health insurance and attending a practice located in a disadvantaged area were significantly associated with perceived need for improvements in care (P<0.05). CONCLUSION: Patients in general practice report that accessibility is an aspect of care that could be improved. Further investigation of how indicators of lower socioeconomic status interact with the provision of patient-centred care and health outcomes is required. PMID- 25918337 TI - Effects of patient safety culture interventions on incident reporting in general practice: a cluster randomised trial. AB - BACKGROUND: A constructive safety culture is essential for the successful implementation of patient safety improvements. AIM: To assess the effect of two patient safety culture interventions on incident reporting as a proxy of safety culture. DESIGN AND SETTING: A three-arm cluster randomised trial was conducted in a mixed method study, studying the effect of administering a patient safety culture questionnaire (intervention I), the questionnaire complemented with a practice-based workshop (intervention II) and no intervention (control) in 30 general practices in the Netherlands. METHOD: The primary outcome, the number of reported incidents, was measured with a questionnaire at baseline and a year after. Analysis was performed using a negative binomial model. Secondary outcomes were quality and safety indicators and safety culture. Mixed effects linear regression was used to analyse the culture questionnaires. RESULTS: The number of incidents increased in both intervention groups, to 82 and 224 in intervention I and II respectively. Adjusted for baseline number of incidents, practice size and accreditation status, the study showed that practices that additionally participated in the workshop reported 42 (95% confidence interval [CI] = 9.81 to 177.50) times more incidents compared to the control group. Practices that only completed the questionnaire reported 5 (95% CI = 1.17 to 25.49) times more incidents. There were no statistically significant differences in staff perception of patient safety culture at follow-up between the three study groups. CONCLUSION: Educating staff and facilitating discussion about patient safety culture in their own practice leads to increased reporting of incidents. It is beneficial to invest in a team-wise effort to improve patient safety. PMID- 25918338 TI - Participatory design of a preliminary safety checklist for general practice. AB - BACKGROUND: The use of checklists to minimise errors is well established in high reliability, safety-critical industries. In health care there is growing interest in checklists to standardise checking processes and ensure task completion, and so provide further systemic defences against error and patient harm. However, in UK general practice there is limited experience of safety checklist use. AIM: To identify workplace hazards that impact on safety, health and wellbeing, and performance, and codesign a standardised checklist process. DESIGN AND SETTING: Application of mixed methods to identify system hazards in Scottish general practices and develop a safety checklist based on human factors design principles. METHOD: A multiprofessional 'expert' group (n = 7) and experienced front-line GPs, nurses, and practice managers (n = 18) identified system hazards and developed and validated a preliminary checklist using a combination of literature review, documentation review, consensus building workshops using a mini-Delphi process, and completion of content validity index exercise. RESULTS: A prototype safety checklist was developed and validated consisting of six safety domains (for example, medicines management), 22 sub-categories (for example, emergency drug supplies) and 78 related items (for example, stock balancing, secure drug storage, and cold chain temperature recording). CONCLUSION: Hazards in the general practice work system were prioritised that can potentially impact on the safety, health and wellbeing of patients, GP team members, and practice performance, and a necessary safety checklist prototype was designed. However, checklist efficacy in improving safety processes and outcomes is dependent on user commitment, and support from leaders and promotional champions. Although further usability development and testing is necessary, the concept should be of interest in the UK and internationally. PMID- 25918339 TI - Physician associates and GPs in primary care: a comparison. AB - BACKGROUND: Physician associates [PAs] (also known as physician assistants) are new to the NHS and there is little evidence concerning their contribution in general practice. AIM: This study aimed to compare outcomes and costs of same-day requested consultations by PAs with those of GPs. DESIGN AND SETTING: An observational study of 2086 patient records presenting at same-day appointments in 12 general practices in England. METHOD: PA consultations were compared with those of GPs. Primary outcome was re-consultation within 14 days for the same or linked problem. Secondary outcomes were processes of care. RESULTS: There were no significant differences in the rates of re-consultation (rate ratio 1.24, 95% confidence interval [CI] = 0.86 to 1.79, P = 0.25). There were no differences in rates of diagnostic tests ordered (1.08, 95% CI = 0.89 to 1.30, P = 0.44), referrals (0.95, 95% CI = 0.63 to 1.43, P = 0.80), prescriptions issued (1.16, 95% CI = 0.87 to 1.53, P = 0.31), or patient satisfaction (1.00, 95% CI = 0.42 to 2.36, P = 0.99). Records of initial consultations of 79.2% (n = 145) of PAs and 48.3% (n = 99) of GPs were judged appropriate by independent GPs (P<0.001). The adjusted average PA consultation was 5.8 minutes longer than the GP consultation (95% CI = 2.46 to 7.1; P<0.001); cost per consultation was GBP L6.22, (US$ 10.15) lower (95% CI = -7.61 to -2.46, P<0.001). CONCLUSION: The processes and outcomes of PA and GP consultations for same-day appointment patients are similar at a lower consultation cost. PAs offer a potentially acceptable and efficient addition to the general practice workforce. PMID- 25918340 TI - Modular expression analysis reveals functional conservation between human Langerhans cells and mouse cross-priming dendritic cells. AB - Characterization of functionally distinct dendritic cell (DC) subsets in mice has fueled interest in whether analogous counterparts exist in humans. Transcriptional modules of coordinately expressed genes were used for defining shared functions between the species. Comparing modules derived from four human skin DC subsets and modules derived from the Immunological Genome Project database for all mouse DC subsets revealed that human Langerhans cells (LCs) and the mouse XCR1(+)CD8alpha(+)CD103(+) DCs shared the class I-mediated antigen processing and cross-presentation transcriptional modules that were not seen in mouse LCs. Furthermore, human LCs were enriched in a transcriptional signature specific to the blood cross-presenting CD141/BDCA-3(+) DCs, the proposed equivalent to mouse CD8alpha(+) DCs. Consistent with our analysis, LCs were highly adept at inducing primary CTL responses. Thus, our study suggests that the function of LCs may not be conserved between mouse and human and supports human LCs as an especially relevant therapeutic target. PMID- 25918341 TI - Specific bone cells produce DLL4 to generate thymus-seeding progenitors from bone marrow. AB - Production of the cells that ultimately populate the thymus to generate alpha/beta T cells has been controversial, and their molecular drivers remain undefined. Here, we report that specific deletion of bone-producing osteocalcin (Ocn)-expressing cells in vivo markedly reduces T-competent progenitors and thymus-homing receptor expression among bone marrow hematopoietic cells. Decreased intrathymic T cell precursors and decreased generation of mature T cells occurred despite normal thymic function. The Notch ligand DLL4 is abundantly expressed on bone marrow Ocn(+) cells, and selective depletion of DLL4 from these cells recapitulated the thymopoietic abnormality. These data indicate that specific mesenchymal cells in bone marrow provide key molecular drivers enforcing thymus-seeding progenitor generation and thereby directly link skeletal biology to the production of T cell-based adaptive immunity. PMID- 25918342 TI - Inherited IL-17RC deficiency in patients with chronic mucocutaneous candidiasis. AB - Chronic mucocutaneous candidiasis (CMC) is characterized by recurrent or persistent infections of the skin, nail, oral, and genital mucosae with Candida species, mainly C. albicans. Autosomal-recessive (AR) IL-17RA and ACT1 deficiencies and autosomal-dominant IL-17F deficiency, each reported in a single kindred, underlie CMC in otherwise healthy patients. We report three patients from unrelated kindreds, aged 8, 12, and 37 yr with isolated CMC, who display AR IL-17RC deficiency. The patients are homozygous for different nonsense alleles that prevent the expression of IL-17RC on the cell surface. The defect is complete, abolishing cellular responses to IL-17A and IL-17F homo- and heterodimers. However, in contrast to what is observed for the IL-17RA- and ACT1 deficient patients tested, the response to IL-17E (IL-25) is maintained in these IL-17RC-deficient patients. These experiments of nature indicate that human IL 17RC is essential for mucocutaneous immunity to C. albicans but is otherwise largely redundant. PMID- 25918343 TI - SIRT1 deacetylates RORgammat and enhances Th17 cell generation. AB - The balance of effector and regulatory T cell function, dependent on multiple signals and epigenetic regulators, is critical to immune self-tolerance. Dysregulation of T helper 17 (Th17) effector cells is associated with multiple autoimmune diseases, including multiple sclerosis. Here, we report that Sirtuin 1 (SIRT1), a protein deacetylase previously reported to have an antiinflammatory function, in fact promotes autoimmunity by deacetylating RORgammat, the signature transcription factor of Th17 cells. SIRT1 increases RORgammat transcriptional activity, enhancing Th17 cell generation and function. Both T cell-specific Sirt1 deletion and treatment with pharmacologic SIRT1 inhibitors suppress Th17 differentiation and are protective in a mouse model of multiple sclerosis. Moreover, analysis of infiltrating cell populations during disease induction in mixed hematopoietic chimeras shows a marked bias against Sirt1-deficient Th17 cells. These findings reveal an unexpected proinflammatory role of SIRT1 and, importantly, support the possible therapeutic use of SIRT1 inhibitors against autoimmunity. PMID- 25918344 TI - ICOS and Bcl6-dependent pathways maintain a CD4 T cell population with memory like properties during tuberculosis. AB - Immune control of persistent infection with Mycobacterium tuberculosis (Mtb) requires a sustained pathogen-specific CD4 T cell response; however, the molecular pathways governing the generation and maintenance of Mtb protective CD4 T cells are poorly understood. Using MHCII tetramers, we show that Mtb-specific CD4 T cells are subject to ongoing antigenic stimulation. Despite this chronic stimulation, a subset of PD-1(+) cells is maintained within the lung parenchyma during tuberculosis (TB). When transferred into uninfected animals, these cells persist, mount a robust recall response, and provide superior protection to Mtb rechallenge when compared to terminally differentiated Th1 cells that reside preferentially in the lung-associated vasculature. The PD-1(+) cells share features with memory CD4 T cells in that their generation and maintenance requires intrinsic Bcl6 and intrinsic ICOS expression. Thus, the molecular pathways required to maintain Mtb-specific CD4 T cells during ongoing infection are similar to those that maintain memory CD4 T cells in scenarios of antigen deprivation. These results suggest that vaccination strategies targeting the ICOS and Bcl6 pathways in CD4 T cells may provide new avenues to prevent TB. PMID- 25918345 TI - Long-term survival following autologous and allogeneic stem cell transplantation for blastic plasmacytoid dendritic cell neoplasm. AB - We sought to clarify the role of high-dose chemotherapy followed by autologous hematopoietic stem cell transplantation (auto-HSCT) and allogeneic hematopoietic stem cell transplantation (allo-HSCT) to treat blastic plasmacytoid dendritic cell neoplasm (BPDCN). We retrospectively identified 25 BPDCN patients (allo HSCT, n = 14; auto-HSCT, n = 11) from registry data of the Japan Society for Hematopoietic Cell Transplantation and analyzed clinicopathologic data and clinical outcomes after transplantation. The median age at HSCT was 58 years (range, 17-67 years). All 11 patients who underwent auto-HSCT were in the first complete remission (CR1). With a median follow-up of 53.5 months, the overall survival rates at 4 years for patients who underwent auto-HSCT and allo-HSCT were 82% and 53% (P = .11), respectively, and progression-free survival rates were 73% and 48% (P = .14), respectively. Auto-HSCT for BPDCN in CR1 appears to provide promising results and deserves further evaluation in the setting of prospective trials. PMID- 25918346 TI - Impact of comorbidities on overall survival in patients with chronic myeloid leukemia: results of the randomized CML study IV. AB - We studied the influence of comorbidities on remission rate and overall survival (OS) in patients with chronic myeloid leukemia (CML). Participants of the CML Study IV, a randomized 5-arm trial designed to optimize imatinib therapy, were analyzed for comorbidities at diagnosis using the Charlson Comorbidity Index (CCI); 511 indexed comorbidities were reported in 1519 CML patients. Age was an additional risk factor in 863 patients. Resulting CCI scores were as follows: CCI 2, n = 589; CCI 3 or 4, n = 599; CCI 5 or 6, n = 229; and CCI >= 7, n = 102. No differences in cumulative incidences of accelerated phase, blast crisis, or remission rates were observed between patients in the different CCI groups. Higher CCI was significantly associated with lower OS probabilities. The 8-year OS probabilities were 93.6%, 89.4%, 77.6%, and 46.4% for patients with CCI 2, 3 to 4, 5 to 6, and >=7, respectively. In multivariate analysis, CCI was the most powerful predictor of OS, which was still valid after removal of its age-related components. Comorbidities have no impact on treatment success but do have a negative effect on OS, indicating that survival of patients with CML is determined more by comorbidities than by CML itself. OS may therefore be inappropriate as an outcome measure for specific CML treatments. The trial was registered at www.clinicaltrials.gov as #NCT00055874. PMID- 25918348 TI - Volar locking plates versus K-wire/pin fixation for the treatment of distal radial fractures: a systematic review and quantitative synthesis. AB - INTRODUCTION: Volar locking plate and Kirschner wire/pin fixations are the most commonly used methods for surgical fixation of distal radius fractures. SOURCES OF DATA: A literature search was performed using PubMed, CINAHL, Cochrane Central and Embase Biomedical databases, selecting studies comparing two or more different surgical treatments including Kirschner wire fixation and volar locking plate fixation. This systematic review was conducted following the PRISMA (Preferred Reporting Items for Systematic Reviews and Meta-Analyses) guidelines. Methodological quality of all selected articles was assessed. AREAS OF AGREEMENT: A total of 14 publications (1306 patients) were included in this review, 10 of which were prospectively designed (8 randomized controlled trial). A total of 659 (50.5%) patients underwent volar locking plating (VLP group), while 647 of 1306 (49.5%) were treated with Kirschner wire/pin fixation (KW group). No differences were recorded in terms of ROM, grip strength, radiographic variables and total rate of complications. There is no clear superiority of either fixation method for the surgical management of distal radius fractures. AREAS OF CONTROVERSY: At a pooled analysis, VLP obtained statistically significant better DASH value compared to KW (18.1 +/- 7.8 vs. 12.8 +/- 6.4%, P = 0.026). Costs and surgical times were significantly higher for plate fixation. GROWING POINTS: Both techniques provide excellent clinical and radiographic results, without a clear superiority of either fixation method for the surgical management of distal radius fractures. RESEARCH: There is a need for more randomized trials performing standardized measurements at fixed follow-up, with results divided by subtypes of distal radius fractures. PMID- 25918349 TI - Physician associates are as good as GPs in treating same day patients but cost less, study finds. PMID- 25918347 TI - Idiopathic pneumonia syndrome after hematopoietic cell transplantation: evidence of occult infectious etiologies. AB - Newer diagnostic methods may link more idiopathic pneumonia syndrome (IPS) cases to an infectious agent. Bronchoalveolar lavage (BAL) samples from 69 hematopoietic cell transplant (HCT) recipients with IPS diagnosed between 1992 and 2006 were tested for 28 pathogens (3 bacteria and 25 viruses) by quantitative polymerase chain reaction and for Aspergillus by galactomannan assay. Research BALs from 21 asymptomatic HCT patients served as controls. Among 69 HCT patients with IPS, 39 (56.5%) had a pathogen detected. The most frequent pathogens were human herpesvirus-6 (HHV-6) (N = 20 [29%]) followed by human rhinovirus (HRV), cytomegalovirus (CMV), and Aspergillus (N = 8 [12%] in each). HHV-6 and HRV were rarely detected in controls, whereas CMV and Aspergillus were occasionally detected with low pathogen load. Patients with pathogens had worse day-100 survival than those without (hazard ratio, 1.88; P = .03). Mortality in patients with only pathogens of "uncertain" significance in lung was similar to that in patients with pathogens of "established" significance. Metagenomic next generation sequencing did not reveal additional significant pathogens. Our study demonstrated that approximately half of patients with IPS had pathogens detected in BAL, and pathogen detection was associated with increased mortality. Thus, an expanded infection detection panel can significantly increase the diagnostic precision for idiopathic pneumonia. PMID- 25918350 TI - Measuring the benefit of treatment: number needed to treat. PMID- 25918351 TI - Setting number of decimal places for reporting risk ratios: rule of four. PMID- 25918352 TI - Fresh pair of eyes may speed up cancer diagnosis. PMID- 25918353 TI - Will new Indian growth charts help stem the rise in childhood obesity? PMID- 25918354 TI - Foot drop. PMID- 25918355 TI - Thinking of calcium and fleeing flies. PMID- 25918356 TI - How is SR calcium release in muscle modulated by PIP(4,5)2? PMID- 25918357 TI - New structural insights into the gating movements of CFTR. PMID- 25918358 TI - Targeting the late component of the cardiac L-type Ca2+ current to suppress early afterdepolarizations. AB - Early afterdepolarizations (EADs) associated with prolongation of the cardiac action potential (AP) can create heterogeneity of repolarization and premature extrasystoles, triggering focal and reentrant arrhythmias. Because the L-type Ca(2+) current (ICa,L) plays a key role in both AP prolongation and EAD formation, L-type Ca(2+) channels (LTCCs) represent a promising therapeutic target to normalize AP duration (APD) and suppress EADs and their arrhythmogenic consequences. We used the dynamic-clamp technique to systematically explore how the biophysical properties of LTCCs could be modified to normalize APD and suppress EADs without impairing excitation-contraction coupling. Isolated rabbit ventricular myocytes were first exposed to H2O2 or moderate hypokalemia to induce EADs, after which their endogenous ICa,L was replaced by a virtual ICa,L with tunable parameters, in dynamic-clamp mode. We probed the sensitivity of EADs to changes in the (a) amplitude of the noninactivating pedestal current; (b) slope of voltage-dependent activation; (c) slope of voltage-dependent inactivation; (d) time constant of voltage-dependent activation; and (e) time constant of voltage dependent inactivation. We found that reducing the amplitude of the noninactivating pedestal component of ICa,L effectively suppressed both H2O2- and hypokalemia-induced EADs and restored APD. These results, together with our previous work, demonstrate the potential of this hybrid experimental computational approach to guide drug discovery or gene therapy strategies by identifying and targeting selective properties of LTCC. PMID- 25918359 TI - CaV1.2/CaV3.x channels mediate divergent vasomotor responses in human cerebral arteries. AB - The regulation of arterial tone is critical in the spatial and temporal control of cerebral blood flow. Voltage-gated Ca(2+) (CaV) channels are key regulators of excitation-contraction coupling in arterial smooth muscle, and thereby of arterial tone. Although L- and T-type CaV channels have been identified in rodent smooth muscle, little is known about the expression and function of specific CaV subtypes in human arteries. Here, we determined which CaV subtypes are present in human cerebral arteries and defined their roles in determining arterial tone. Quantitative polymerase chain reaction and Western blot analysis, respectively, identified mRNA and protein for L- and T-type channels in smooth muscle of cerebral arteries harvested from patients undergoing resection surgery. Analogous to rodents, CaV1.2 (L-type) and CaV3.2 (T-type) alpha1 subunits were expressed in human cerebral arterial smooth muscle; intriguingly, the CaV3.1 (T-type) subtype present in rodents was replaced with a different T-type isoform, CaV3.3, in humans. Using established pharmacological and electrophysiological tools, we separated and characterized the unique profiles of Ca(2+) channel subtypes. Pressurized vessel myography identified a key role for CaV1.2 and CaV3.3 channels in mediating cerebral arterial constriction, with the former and latter predominating at higher and lower intraluminal pressures, respectively. In contrast, CaV3.2 antagonized arterial tone through downstream regulation of the large-conductance Ca(2+)-activated K(+) channel. Computational analysis indicated that each Ca(2+) channel subtype will uniquely contribute to the dynamic regulation of cerebral blood flow. In conclusion, this study documents the expression of three distinct Ca(2+) channel subtypes in human cerebral arteries and further shows how they act together to orchestrate arterial tone. PMID- 25918360 TI - Ruling out pyridine dinucleotides as true TRPM2 channel activators reveals novel direct agonist ADP-ribose-2'-phosphate. AB - Transient receptor potential melastatin 2 (TRPM2), a Ca(2+)-permeable cation channel implicated in postischemic neuronal cell death, leukocyte activation, and insulin secretion, is activated by intracellular ADP ribose (ADPR). In addition, the pyridine dinucleotides nicotinamide-adenine-dinucleotide (NAD), nicotinic acid-adenine-dinucleotide (NAAD), and NAAD-2'-phosphate (NAADP) have been shown to activate TRPM2, or to enhance its activation by ADPR, when dialyzed into cells. The precise subset of nucleotides that act directly on the TRPM2 protein, however, is unknown. Here, we use a heterologously expressed, affinity-purified specific ADPR hydrolase to purify commercial preparations of pyridine dinucleotides from substantial contaminations by ADPR or ADPR-2'-phosphate (ADPRP). Direct application of purified NAD, NAAD, or NAADP to the cytosolic face of TRPM2 channels in inside-out patches demonstrated that none of them stimulates gating, or affects channel activation by ADPR, indicating that none of these dinucleotides directly binds to TRPM2. Instead, our experiments identify for the first time ADPRP as a true direct TRPM2 agonist of potential biological interest. PMID- 25918361 TI - Mechanism for phosphoinositide selectivity and activation of TRPV1 ion channels. AB - Although PI(4,5)P2 is believed to play an essential role in regulating the activity of numerous ion channels and transporters, the mechanisms by which it does so are unknown. Here, we used the ability of the TRPV1 ion channel to discriminate between PI(4,5)P2 and PI(4)P to localize the region of TRPV1 sequence that interacts directly with the phosphoinositide. We identified a point mutation in the proximal C-terminal region after the TRP box, R721A, that inverted the selectivity of TRPV1. Although the R721A mutation produced only a 30% increase in the EC50 for activation by PI(4,5)P2, it decreased the EC50 for activation by PI(4)P by more than two orders of magnitude. We used chemically induced and voltage-activated phosphatases to determine that PI(4)P continued to support TRPV1 activity even after depletion of PI(4,5)P2 from the plasma membrane. Our data cannot be explained by a purely electrostatic mechanism for interaction between the phosphoinositide and the protein, similar to that of the MARCKS (myristoylated alanine-rich C kinase substrate) effector domain or the EGF receptor. Rather, conversion of a PI(4,5)P2-selective channel to a PI(4)P selective channel indicates that a structured phosphoinositide-binding site mediates the regulation of TRPV1 activity and that the amino acid at position 721 likely interacts directly with the moiety at the 5' position of the phosphoinositide. PMID- 25918362 TI - A combined coarse-grained and all-atom simulation of TRPV1 channel gating and heat activation. AB - The transient receptor potential (TRP) channels act as key sensors of various chemical and physical stimuli in eukaryotic cells. Despite years of study, the molecular mechanisms of TRP channel activation remain unclear. To elucidate the structural, dynamic, and energetic basis of gating in TRPV1 (a founding member of the TRPV subfamily), we performed coarse-grained modeling and all-atom molecular dynamics (MD) simulation based on the recently solved high resolution structures of the open and closed form of TRPV1. Our coarse-grained normal mode analysis captures two key modes of collective motions involved in the TRPV1 gating transition, featuring a quaternary twist motion of the transmembrane domains (TMDs) relative to the intracellular domains (ICDs). Our transition pathway modeling predicts a sequence of structural movements that propagate from the ICDs to the TMDs via key interface domains (including the membrane proximal domain and the C-terminal domain), leading to sequential opening of the selectivity filter followed by the lower gate in the channel pore (confirmed by modeling conformational changes induced by the activation of ICDs). The above findings of coarse-grained modeling are robust to perturbation by lipids. Finally, our MD simulation of the ICD identifies key residues that contribute differently to the nonpolar energy of the open and closed state, and these residues are predicted to control the temperature sensitivity of TRPV1 gating. These computational predictions offer new insights to the mechanism for heat activation of TRPV1 gating, and will guide our future electrophysiology and mutagenesis studies. PMID- 25918363 TI - Ribosomal protein S6 kinase 1 signaling in prefrontal cortex controls depressive behavior. AB - Current treatments for major depressive disorder (MDD) have a time lag and are ineffective for a large number of patients. Development of novel pharmacological therapies requires a comprehensive understanding of the molecular events that contribute to MDD pathophysiology. Recent evidence points toward aberrant activity of synaptic proteins as a critical contributing factor. In the present studies, we used viral-mediated gene transfer to target a key mediator of activity-dependent synaptic protein synthesis downstream of mechanistic target of rapamycin complex 1 (mTORC1) known as p70 S6 kinase 1 (S6K1). Targeted delivery of two mutants of S6K1, constitutively active or dominant-negative, to the medial prefrontal cortex (mPFC) of rats allowed control of the mTORC1/S6K1 translational pathway. Our results demonstrate that increased expression of S6K1 in the mPFC produces antidepressant effects in the forced swim test without altering locomotor activity. Moreover, expression of active S6K1 in the mPFC blocked the anhedonia caused by chronic stress, resulting in a state of stress resilience. This antidepressant response was associated with increased neuronal complexity caused by enhanced S6K1 activity. Conversely, expression of dominant-negative S6K1 in the mPFC resulted in prodepressive behavior in the forced swim test and was sufficient to cause anhedonia in the absence of chronic stress exposure. Together, these data demonstrate a critical role for S6K1 activity in depressive behaviors, and suggest that pathways downstream of mTORC1 may underlie the pathophysiology and treatment of MDD. PMID- 25918364 TI - Topology, structures, and energy landscapes of human chromosomes. AB - Chromosome conformation capture experiments provide a rich set of data concerning the spatial organization of the genome. We use these data along with a maximum entropy approach to derive a least-biased effective energy landscape for the chromosome. Simulations of the ensemble of chromosome conformations based on the resulting information theoretic landscape not only accurately reproduce experimental contact probabilities, but also provide a picture of chromosome dynamics and topology. The topology of the simulated chromosomes is probed by computing the distribution of their knot invariants. The simulated chromosome structures are largely free of knots. Topologically associating domains are shown to be crucial for establishing these knotless structures. The simulated chromosome conformations exhibit a tendency to form fibril-like structures like those observed via light microscopy. The topologically associating domains of the interphase chromosome exhibit multistability with varying liquid crystalline ordering that may allow discrete unfolding events and the landscape is locally funneled toward "ideal" chromosome structures that represent hierarchical fibrils of fibrils. PMID- 25918365 TI - The ribosome can discriminate the chirality of amino acids within its peptidyl transferase center. AB - The cellular translational machinery (TM) synthesizes proteins using exclusively L- or achiral aminoacyl-tRNAs (aa-tRNAs), despite the presence of D-amino acids in nature and their ability to be aminoacylated onto tRNAs by aa-tRNA synthetases. The ubiquity of L-amino acids in proteins has led to the hypothesis that D-amino acids are not substrates for the TM. Supporting this view, protein engineering efforts to incorporate D-amino acids into proteins using the TM have thus far been unsuccessful. Nonetheless, a mechanistic understanding of why D-aa tRNAs are poor substrates for the TM is lacking. To address this deficiency, we have systematically tested the translation activity of D-aa-tRNAs using a series of biochemical assays. We find that the TM can effectively, albeit slowly, accept D-aa-tRNAs into the ribosomal aa-tRNA binding (A) site, use the A-site D-aa-tRNA as a peptidyl-transfer acceptor, and translocate the resulting peptidyl-D-aa-tRNA into the ribosomal peptidyl-tRNA binding (P) site. During the next round of continuous translation, however, we find that ribosomes carrying a P-site peptidyl-D-aa-tRNA partition into subpopulations that are either translationally arrested or that can continue translating. Consistent with its ability to arrest translation, chemical protection experiments and molecular dynamics simulations show that P site-bound peptidyl-D-aa-tRNA can trap the ribosomal peptidyl transferase center in a conformation in which peptidyl transfer is impaired. Our results reveal a novel mechanism through which D-aa-tRNAs interfere with translation, provide insight into how the TM might be engineered to use D-aa tRNAs, and increase our understanding of the physiological role of a widely distributed enzyme that clears D-aa-tRNAs from cells. PMID- 25918366 TI - Assortative mating without assortative preference. AB - Assortative mating--marriage of a man and a woman with similar social characteristics--is a commonly observed phenomenon. In the existing literature in both sociology and economics, this phenomenon has mainly been attributed to individuals' conscious preferences for assortative mating. In this paper, we show that patterns of assortative mating may arise from another structural source even if individuals do not have assortative preferences or possess complementary attributes: dynamic processes of marriages in a closed system. For a given cohort of youth in a finite population, as the percentage of married persons increases, unmarried persons who newly enter marriage are systematically different from those who married earlier, giving rise to the phenomenon of assortative mating. We use microsimulation methods to illustrate this dynamic process, using first the conventional deterministic Gale-Shapley model, then a probabilistic Gale Shapley model, and then two versions of the encounter mating model. PMID- 25918367 TI - Coral symbiotic algae calcify ex hospite in partnership with bacteria. AB - Dinoflagellates of the genus Symbiodinium are commonly recognized as invertebrate endosymbionts that are of central importance for the functioning of coral reef ecosystems. However, the endosymbiotic phase within Symbiodinium life history is inherently tied to a more cryptic free-living (ex hospite) phase that remains largely unexplored. Here we show that free-living Symbiodinium spp. in culture commonly form calcifying bacterial-algal communities that produce aragonitic spherulites and encase the dinoflagellates as endolithic cells. This process is driven by Symbiodinium photosynthesis but occurs only in partnership with bacteria. Our findings not only place dinoflagellates on the map of microbial algal organomineralization processes but also point toward an endolithic phase in the Symbiodinium life history, a phenomenon that may provide new perspectives on the biology and ecology of Symbiodinium spp. and the evolutionary history of the coral-dinoflagellate symbiosis. PMID- 25918368 TI - Histamine in the basolateral amygdala promotes inhibitory avoidance learning independently of hippocampus. AB - Recent discoveries demonstrated that recruitment of alternative brain circuits permits compensation of memory impairments following damage to brain regions specialized in integrating and/or storing specific memories, including both dorsal hippocampus and basolateral amygdala (BLA). Here, we first report that the integrity of the brain histaminergic system is necessary for long-term, but not for short-term memory of step-down inhibitory avoidance (IA). Second, we found that phosphorylation of cyclic adenosine monophosphate (cAMP) responsive-element binding protein, a crucial mediator in long-term memory formation, correlated anatomically and temporally with histamine-induced memory retrieval, showing the active involvement of histamine function in CA1 and BLA in different phases of memory consolidation. Third, we found that exogenous application of histamine in either hippocampal CA1 or BLA of brain histamine-depleted rats, hence amnesic, restored long-term memory; however, the time frame of memory rescue was different for the two brain structures, short lived (immediately posttraining) for BLA, long lasting (up to 6 h) for the CA1. Moreover, long-term memory was formed immediately after training restoring of histamine transmission only in the BLA. These findings reveal the essential role of histaminergic neurotransmission to provide the brain with the plasticity necessary to ensure memorization of emotionally salient events, through recruitment of alternative circuits. Hence, our findings indicate that the histaminergic system comprises parallel, coordinated pathways that provide compensatory plasticity when one brain structure is compromised. PMID- 25918369 TI - Functional reconstitution of Drosophila melanogaster NMJ glutamate receptors. AB - The Drosophila larval neuromuscular junction (NMJ), at which glutamate acts as the excitatory neurotransmitter, is a widely used model for genetic analysis of synapse function and development. Despite decades of study, the inability to reconstitute NMJ glutamate receptor function using heterologous expression systems has complicated the analysis of receptor function, such that it is difficult to resolve the molecular basis for compound phenotypes observed in mutant flies. We find that Drosophila Neto functions as an essential component required for the function of NMJ glutamate receptors, permitting analysis of glutamate receptor responses in Xenopus oocytes. In combination with a crystallographic analysis of the GluRIIB ligand binding domain, we use this system to characterize the subunit dependence of assembly, channel block, and ligand selectivity for Drosophila NMJ glutamate receptors. PMID- 25918370 TI - Multiple functional variants in long-range enhancer elements contribute to the risk of SNP rs965513 in thyroid cancer. AB - The [A] allele of SNP rs965513 in 9q22 has been consistently shown to be highly associated with increased papillary thyroid cancer (PTC) risk with an odds ratio of ~1.8 as determined by genome-wide association studies, yet the molecular mechanisms remain poorly understood. Previously, we noted that the expression of two genes in the region, forkhead box E1 (FOXE1) and PTC susceptibility candidate 2 (PTCSC2), is regulated by rs965513 in unaffected thyroid tissue, but the underlying mechanisms were not elucidated. Here, we fine-mapped the 9q22 region in PTC and controls and detected an ~33-kb linkage disequilibrium block (containing the lead SNP rs965513) that significantly associates with PTC risk. Chromatin characteristics and regulatory element signatures in this block disclosed at least three regulatory elements functioning as enhancers. These enhancers harbor at least four SNPs (rs7864322, rs12352658, rs7847449, and rs10759944) that serve as functional variants. The variant genotypes are associated with differential enhancer activities and/or transcription factor binding activities. Using the chromosome conformation capture methodology, long range looping interactions of these elements with the promoter region shared by FOXE1 and PTCSC2 in a human papillary thyroid carcinoma cell line (KTC-1) and unaffected thyroid tissue were found. Our results suggest that multiple variants coinherited with the lead SNP and located in long-range enhancers are involved in the transcriptional regulation of FOXE1 and PTCSC2 expression. These results explain the mechanism by which the risk allele of rs965513 predisposes to thyroid cancer. PMID- 25918371 TI - Energy and material flows of megacities. AB - Understanding the drivers of energy and material flows of cities is important for addressing global environmental challenges. Accessing, sharing, and managing energy and material resources is particularly critical for megacities, which face enormous social stresses because of their sheer size and complexity. Here we quantify the energy and material flows through the world's 27 megacities with populations greater than 10 million people as of 2010. Collectively the resource flows through megacities are largely consistent with scaling laws established in the emerging science of cities. Correlations are established for electricity consumption, heating and industrial fuel use, ground transportation energy use, water consumption, waste generation, and steel production in terms of heating degree-days, urban form, economic activity, and population growth. The results help identify megacities exhibiting high and low levels of consumption and those making efficient use of resources. The correlation between per capita electricity use and urbanized area per capita is shown to be a consequence of gross building floor area per capita, which is found to increase for lower-density cities. Many of the megacities are growing rapidly in population but are growing even faster in terms of gross domestic product (GDP) and energy use. In the decade from 2001 2011, electricity use and ground transportation fuel use in megacities grew at approximately half the rate of GDP growth. PMID- 25918372 TI - Operationalizing the social-ecological systems framework to assess sustainability. AB - Environmental governance is more effective when the scales of ecological processes are well matched with the human institutions charged with managing human-environment interactions. The social-ecological systems (SESs) framework provides guidance on how to assess the social and ecological dimensions that contribute to sustainable resource use and management, but rarely if ever has been operationalized for multiple localities in a spatially explicit, quantitative manner. Here, we use the case of small-scale fisheries in Baja California Sur, Mexico, to identify distinct SES regions and test key aspects of coupled SESs theory. Regions that exhibit greater potential for social-ecological sustainability in one dimension do not necessarily exhibit it in others, highlighting the importance of integrative, coupled system analyses when implementing spatial planning and other ecosystem-based strategies. PMID- 25918373 TI - Artemin promotes functional long-distance axonal regeneration to the brainstem after dorsal root crush. AB - Recovery after a spinal cord injury often requires that axons restore synaptic connectivity with denervated targets several centimeters from the site of injury. Here we report that systemic artemin (ARTN) treatment promotes the regeneration of sensory axons to the brainstem after brachial dorsal root crush in adult rats. ARTN not only stimulates robust regeneration of large, myelinated sensory axons to the brainstem, but also promotes functional reinnervation of the appropriate target region, the cuneate nucleus. ARTN signals primarily through the RET tyrosine kinase, an interaction that requires the nonsignaling coreceptor GDNF family receptor (GFRalpha3). Previous studies reported limited GFRalpha3 expression on large sensory neurons, but our findings demonstrate that ARTN promotes robust regeneration of large, myelinated sensory afferents. Using a cell sorting technique, we demonstrate that GFRalpha3 expression is similar in myelinated and unmyelinated adult sensory neurons, suggesting that ARTN likely induces long-distance regeneration by binding GFRalpha3 and RET. Although ARTN is delivered for just 2 wk, regeneration to the brainstem requires more than 3 mo, suggesting that brief trophic support may initiate intrinsic growth programs that remain active until targets are reached. Given its ability to promote targeted functional regeneration to the brainstem, ARTN may represent a promising therapy for restoring sensory function after spinal cord injury. PMID- 25918374 TI - Synaptic abnormalities and cytoplasmic glutamate receptor aggregates in contactin associated protein-like 2/Caspr2 knockout neurons. AB - Central glutamatergic synapses and the molecular pathways that control them are emerging as common substrates in the pathogenesis of mental disorders. Genetic variation in the contactin associated protein-like 2 (CNTNAP2) gene, including copy number variations, exon deletions, truncations, single nucleotide variants, and polymorphisms have been associated with intellectual disability, epilepsy, schizophrenia, language disorders, and autism. CNTNAP2, encoded by Cntnap2, is required for dendritic spine development and its absence causes disease-related phenotypes in mice. However, the mechanisms whereby CNTNAP2 regulates glutamatergic synapses are not known, and cellular phenotypes have not been investigated in Cntnap2 knockout neurons. Here we show that CNTNAP2 is present in dendritic spines, as well as axons and soma. Structured illumination superresolution microscopy reveals closer proximity to excitatory, rather than inhibitory synaptic markers. CNTNAP2 does not promote the formation of synapses and cultured neurons from Cntnap2 knockout mice do not show early defects in axon and dendrite outgrowth, suggesting that CNTNAP2 is not required at this stage. However, mature neurons from knockout mice show reduced spine density and levels of GluA1 subunits of AMPA receptors in spines. Unexpectedly, knockout neurons show large cytoplasmic aggregates of GluA1. Here we characterize, for the first time to our knowledge, synaptic phenotypes in Cntnap2 knockout neurons and reveal a novel role for CNTNAP2 in GluA1 trafficking. Taken together, our findings provide insight into the biological roles of CNTNAP2 and into the pathogenesis of CNTNAP2-associated neuropsychiatric disorders. PMID- 25918375 TI - Biological evidence supports an early and complex emergence of the Isthmus of Panama. AB - The linking of North and South America by the Isthmus of Panama had major impacts on global climate, oceanic and atmospheric currents, and biodiversity, yet the timing of this critical event remains contentious. The Isthmus is traditionally understood to have fully closed by ca. 3.5 million years ago (Ma), and this date has been used as a benchmark for oceanographic, climatic, and evolutionary research, but recent evidence suggests a more complex geological formation. Here, we analyze both molecular and fossil data to evaluate the tempo of biotic exchange across the Americas in light of geological evidence. We demonstrate significant waves of dispersal of terrestrial organisms at approximately ca. 20 and 6 Ma and corresponding events separating marine organisms in the Atlantic and Pacific oceans at ca. 23 and 7 Ma. The direction of dispersal and their rates were symmetrical until the last ca. 6 Ma, when northern migration of South American lineages increased significantly. Variability among taxa in their timing of dispersal or vicariance across the Isthmus is not explained by the ecological factors tested in these analyses, including biome type, dispersal ability, and elevation preference. Migration was therefore not generally regulated by intrinsic traits but more likely reflects the presence of emergent terrain several millions of years earlier than commonly assumed. These results indicate that the dramatic biotic turnover associated with the Great American Biotic Interchange was a long and complex process that began as early as the Oligocene Miocene transition. PMID- 25918376 TI - Homologous trans-editing factors with broad tRNA specificity prevent mistranslation caused by serine/threonine misactivation. AB - Aminoacyl-tRNA synthetases (ARSs) establish the rules of the genetic code, whereby each amino acid is attached to a cognate tRNA. Errors in this process lead to mistranslation, which can be toxic to cells. The selective forces exerted by species-specific requirements and environmental conditions potentially shape quality-control mechanisms that serve to prevent mistranslation. A family of editing factors that are homologous to the editing domain of bacterial prolyl tRNA synthetase includes the previously characterized trans-editing factors ProXp ala and YbaK, which clear Ala-tRNA(Pro) and Cys-tRNA(Pro), respectively, and three additional homologs of unknown function, ProXp-x, ProXp-y, and ProXp-z. We performed an in vivo screen of 230 conditions in which an Escherichia coli proXp y deletion strain was grown in the presence of elevated levels of amino acids and specific ARSs. This screen, together with the results of in vitro deacylation assays, revealed Ser- and Thr-tRNA deacylase function for this homolog. A similar activity was demonstrated for Bordetella parapertussis ProXp-z in vitro. These proteins, now renamed "ProXp-ST1" and "ProXp-ST2," respectively, recognize multiple tRNAs as substrates. Taken together, our data suggest that these free standing editing domains have the ability to prevent mistranslation errors caused by a number of ARSs, including lysyl-tRNA synthetase, threonyl-tRNA synthetase, seryl-tRNA synthetase, and alanyl-tRNA synthetase. The expression of these multifunctional enzymes is likely to provide a selective growth advantage to organisms subjected to environmental stresses and other conditions that alter the amino acid pool. PMID- 25918377 TI - Ligand deconstruction: Why some fragment binding positions are conserved and others are not. AB - Fragment-based drug discovery (FBDD) relies on the premise that the fragment binding mode will be conserved on subsequent expansion to a larger ligand. However, no general condition has been established to explain when fragment binding modes will be conserved. We show that a remarkably simple condition can be developed in terms of how fragments coincide with binding energy hot spots- regions of the protein where interactions with a ligand contribute substantial binding free energy--the locations of which can easily be determined computationally. Because a substantial fraction of the free energy of ligand binding comes from interacting with the residues in the energetically most important hot spot, a ligand moiety that sufficiently overlaps with this region will retain its location even when other parts of the ligand are removed. This hypothesis is supported by eight case studies. The condition helps identify whether a protein is suitable for FBDD, predicts the size of fragments required for screening, and determines whether a fragment hit can be extended into a higher affinity ligand. Our results show that ligand binding sites can usefully be thought of in terms of an anchor site, which is the top-ranked hot spot and dominates the free energy of binding, surrounded by a number of weaker satellite sites that confer improved affinity and selectivity for a particular ligand and that it is the intrinsic binding potential of the protein surface that determines whether it can serve as a robust binding site for a suitably optimized ligand. PMID- 25918378 TI - Enhancing ecosystem restoration efficiency through spatial and temporal coordination. AB - In many large ecosystems, conservation projects are selected by a diverse set of actors operating independently at spatial scales ranging from local to international. Although small-scale decision making can leverage local expert knowledge, it also may be an inefficient means of achieving large-scale objectives if piecemeal efforts are poorly coordinated. Here, we assess the value of coordinating efforts in both space and time to maximize the restoration of aquatic ecosystem connectivity. Habitat fragmentation is a leading driver of declining biodiversity and ecosystem services in rivers worldwide, and we simultaneously evaluate optimal barrier removal strategies for 661 tributary rivers of the Laurentian Great Lakes, which are fragmented by at least 6,692 dams and 232,068 road crossings. We find that coordinating barrier removals across the entire basin is nine times more efficient at reconnecting fish to headwater breeding grounds than optimizing independently for each watershed. Similarly, a one-time pulse of restoration investment is up to 10 times more efficient than annual allocations totaling the same amount. Despite widespread emphasis on dams as key barriers in river networks, improving road culvert passability is also essential for efficiently restoring connectivity to the Great Lakes. Our results highlight the dramatic economic and ecological advantages of coordinating efforts in both space and time during restoration of large ecosystems. PMID- 25918380 TI - Adhesion G protein-coupled receptors are activated by exposure of a cryptic tethered agonist. AB - The large class of adhesion G protein-coupled receptors (aGPCRs) bind extracellular matrix or neighboring cell-surface ligands to regulate organ and tissue development through an unknown activation mechanism. We examined aGPCR activation using two prototypical aGPCRs, GPR56 and GPR110. Active dissociation of the noncovalently bound GPR56 or GPR110 extracellular domains (ECDs) from the respective seven-transmembrane (7TM) domains relieved an inhibitory influence and permitted both receptors to activate defined G protein subtypes. After ECD displacement, the newly revealed short N-terminal stalk regions of the 7TM domains were found to be essential for G protein activation. Synthetic peptides comprising these stalks potently activated GPR56 or GPR110 in vitro or in cells, demonstrating that the stalks comprise a tethered agonist that was encrypted within the ECD. Establishment of an aGPCR activation mechanism provides a rational platform for the development of aGPCR synthetic modulators that could find clinical utility toward aGPCR-directed disease. PMID- 25918379 TI - IL-33 activates tumor stroma to promote intestinal polyposis. AB - Tumor epithelial cells develop within a microenvironment consisting of extracellular matrix, growth factors, and cytokines produced by nonepithelial stromal cells. In response to paracrine signals from tumor epithelia, stromal cells modify the microenvironment to promote tumor growth and metastasis. Here, we identify interleukin 33 (IL-33) as a regulator of tumor stromal cell activation and mediator of intestinal polyposis. In human colorectal cancer, IL 33 expression was induced in the tumor epithelium of adenomas and carcinomas, and expression of the IL-33 receptor, IL1RL1 (also referred to as IL1-R4 or ST2), localized predominantly to the stroma of adenoma and both the stroma and epithelium of carcinoma. Genetic and antibody abrogation of responsiveness to IL 33 in the Apc(Min/+) mouse model of intestinal tumorigenesis inhibited proliferation, induced apoptosis, and suppressed angiogenesis in adenomatous polyps, which reduced both tumor number and size. Similar to human adenomas, IL 33 expression localized to tumor epithelial cells and expression of IL1RL1 associated with two stromal cell types, subepithelial myofibroblasts and mast cells, in Apc(Min/+) polyps. In vitro, IL-33 stimulation of human subepithelial myofibroblasts induced the expression of extracellular matrix components and growth factors associated with intestinal tumor progression. IL-33 deficiency reduced mast cell accumulation in Apc(Min/+) polyps and suppressed the expression of mast cell-derived proteases and cytokines known to promote polyposis. Based on these findings, we propose that IL-33 derived from the tumor epithelium promotes polyposis through the coordinated activation of stromal cells and the formation of a protumorigenic microenvironment. PMID- 25918381 TI - Increasing intracellular trehalose is sufficient to confer desiccation tolerance to Saccharomyces cerevisiae. AB - Diverse organisms capable of surviving desiccation, termed anhydrobiotes, include species from bacteria, yeast, plants, and invertebrates. However, most organisms are sensitive to desiccation, likely due to an assortment of different stresses such as protein misfolding and aggregation, hyperosmotic stress, membrane fracturing, and changes in cell volume and shape leading to an overcrowded cytoplasm and metabolic arrest. The exact stress(es) that cause lethality in desiccation-sensitive organisms and how the lethal stresses are mitigated in desiccation-tolerant organisms remain poorly understood. The presence of trehalose in anhydrobiotes has been strongly correlated with desiccation tolerance. In the yeast Saccharomyces cerevisiae, trehalose is essential for survival after long-term desiccation. Here, we establish that the elevation of intracellular trehalose in dividing yeast by its import from the media converts yeast from extreme desiccation sensitivity to a high level of desiccation tolerance. This trehalose-induced tolerance is independent of utilization of trehalose as an energy source, de novo synthesis of other stress effectors, or the metabolic effects of trehalose biosynthetic intermediates, indicating that a chemical property of trehalose is directly responsible for desiccation tolerance. Finally, we demonstrate that elevated intracellular maltose can also make dividing yeast tolerant to short-term desiccation, indicating that other disaccharides have stress effector activity. However, trehalose is much more effective than maltose at conferring tolerance to long-term desiccation. The effectiveness and sufficiency of trehalose as an antagonizer of desiccation induced damage in yeast emphasizes its potential to confer desiccation tolerance to otherwise sensitive organisms. PMID- 25918382 TI - Characterizing the in vivo role of trehalose in Saccharomyces cerevisiae using the AGT1 transporter. AB - Trehalose is a highly stable, nonreducing disaccharide of glucose. A large body of research exists implicating trehalose in a variety of cellular phenomena, notably response to stresses of various kinds. However, in very few cases has the role of trehalose been examined directly in vivo. Here, we describe the development and characterization of a system in Saccharomyces cerevisiae that allows us to manipulate intracellular trehalose concentrations independently of the biosynthetic enzymes and independently of any applied stress. We found that many physiological roles heretofore ascribed to intracellular trehalose, including heat resistance, are not due to the presence of trehalose per se. We also found that many of the metabolic and growth defects associated with mutations in the trehalose biosynthesis pathway are not abolished by providing abundant intracellular trehalose. Instead, we made the observation that intracellular accumulation of trehalose or maltose (another disaccharide of glucose) is growth-inhibitory in a carbon source-specific manner. We conclude that the physiological role of the trehalose pathway is fundamentally metabolic: i.e., more complex than simply the consequence of increased concentrations of the sugar and its attendant physical properties (with the exception of the companion paper where Tapia et al. [Tapia H, et al. (2015) Proc Natl Acad Sci USA, 10.1073/pnas.1506415112] demonstrate a direct role for trehalose in protecting cells against desiccation). PMID- 25918383 TI - Genetic differences and aberrant methylation in the apelin system predict the risk of high-altitude pulmonary edema. AB - Hypoxia-inducible factor stimulates the expression of apelin, a potent vasodilator, in response to reduced blood arterial oxygen saturation. However, aberrations in the apelin system impair pulmonary vascular function, potentially resulting in the development of high-altitude (HA)-related disorders. This study aimed to elucidate the genetic and epigenetic regulation of apelin, apelin receptor (APLNR), and endothelial nitric oxide synthase (NOS3) in HA adaptation and HA pulmonary edema (HAPE). A genome-wide association study and sequencing identified variants of apelin, APLNR, and NOS3 that were validated in a larger sample size of HAPE-patients (HAPE-p), HAPE-free controls (HAPE-f), and healthy highland natives (HLs). Apelin-13 and nitrite levels and apelin and NOS3 expression were down-regulated in HAPE-p (P < 0.001). Among the several studied polymorphisms, apelin rs3761581, rs2235312, and rs3115757; APLNR rs11544374 and rs2282623; and NOS3 4b/4a, rs1799983, and rs7830 were associated with HAPE (P < 0.03). The risk allele rs3761581G was associated with a 58.6% reduction in gene expression (P = 0.017), and the risk alleles rs3761581G and rs2235312T were associated with low levels of apelin-13 and nitrite (P < 0.05). The latter two levels decreased further when both of these risk alleles were present in the patients (P < 0.05). Methylation of the apelin CpG island was significantly higher in HAPE-p at 11.92% than in HAPE-f and HLs at <= 7.1% (P < 0.05). Moreover, the methylation effect was 9% stronger in the 5' UTR and was associated with decreased apelin expression and apelin-13 levels. The rs3761581 and rs2235312 polymorphisms and methylation of the CpG island influence the expression of apelin in HAPE. PMID- 25918384 TI - Alpha-actinin binding kinetics modulate cellular dynamics and force generation. AB - The actin cytoskeleton is a key element of cell structure and movement whose properties are determined by a host of accessory proteins. Actin cross-linking proteins create a connected network from individual actin filaments, and though the mechanical effects of cross-linker binding affinity on actin networks have been investigated in reconstituted systems, their impact on cellular forces is unknown. Here we show that the binding affinity of the actin cross-linker alpha actinin 4 (ACTN4) in cells modulates cytoplasmic mobility, cellular movement, and traction forces. Using fluorescence recovery after photobleaching, we show that an ACTN4 mutation that causes human kidney disease roughly triples the wild-type binding affinity of ACTN4 to F-actin in cells, increasing the dissociation time from 29 +/- 13 to 86 +/- 29 s. This increased affinity creates a less dynamic cytoplasm, as demonstrated by reduced intracellular microsphere movement, and an approximate halving of cell speed. Surprisingly, these less motile cells generate larger forces. Using traction force microscopy, we show that increased binding affinity of ACTN4 increases the average contractile stress (from 1.8 +/- 0.7 to 4.7 +/- 0.5 kPa), and the average strain energy (0.4 +/- 0.2 to 2.1 +/- 0.4 pJ). We speculate that these changes may be explained by an increased solid-like nature of the cytoskeleton, where myosin activity is more partitioned into tension and less is dissipated through filament sliding. These findings demonstrate the impact of cross-linker point mutations on cell dynamics and forces, and suggest mechanisms by which such physical defects lead to human disease. PMID- 25918385 TI - Microscopic identification of the order parameter governing liquid-liquid transition in a molecular liquid. AB - A liquid-liquid transition (LLT) in a single-component substance is an unconventional phase transition from one liquid to another. LLT has recently attracted considerable attention because of its fundamental importance in our understanding of the liquid state. To access the order parameter governing LLT from a microscopic viewpoint, here we follow the structural evolution during the LLT of an organic molecular liquid, triphenyl phosphite (TPP), by time-resolved small- and wide-angle X-ray scattering measurements. We find that locally favored clusters, whose characteristic size is a few nanometers, are spontaneously formed and their number density monotonically increases during LLT. This strongly suggests that the order parameter of LLT is the number density of locally favored structures and of nonconserved nature. We also show that the locally favored structures are distinct from the crystal structure and these two types of orderings compete with each other. Thus, our study not only experimentally identifies the structural order parameter governing LLT, but also may settle a long-standing debate on the nature of the transition in TPP, i.e., whether the transition is LLT or merely microcrystal formation. PMID- 25918386 TI - Nonsense suppression in archaea. AB - Bacterial strains carrying nonsense suppressor tRNA genes played a crucial role in early work on bacterial and bacterial viral genetics. In eukaryotes as well, suppressor tRNAs have played important roles in the genetic analysis of yeast and worms. Surprisingly, little is known about genetic suppression in archaea, and there has been no characterization of suppressor tRNAs or identification of nonsense mutations in any of the archaeal genes. Here, we show, using the beta gal gene as a reporter, that amber, ochre, and opal suppressors derived from the serine and tyrosine tRNAs of the archaeon Haloferax volcanii are active in suppression of their corresponding stop codons. Using a promoter for tRNA expression regulated by tryptophan, we also show inducible and regulatable suppression of all three stop codons in H. volcanii. Additionally, transformation of a DeltapyrE2 H. volcanii strain with plasmids carrying the genes for a pyrE2 amber mutant and the serine amber suppressor tRNA yielded transformants that grow on agar plates lacking uracil. Thus, an auxotrophic amber mutation in the pyrE2 gene can be complemented by expression of the amber suppressor tRNA. These results pave the way for generating archaeal strains carrying inducible suppressor tRNA genes on the chromosome and their use in archaeal and archaeviral genetics. We also provide possible explanations for why suppressor tRNAs have not been identified in archaea. PMID- 25918387 TI - Reappraisal of hydrocarbon biomarkers in Archean rocks. AB - Hopanes and steranes found in Archean rocks have been presented as key evidence supporting the early rise of oxygenic photosynthesis and eukaryotes, but the syngeneity of these hydrocarbon biomarkers is controversial. To resolve this debate, we performed a multilaboratory study of new cores from the Pilbara Craton, Australia, that were drilled and sampled using unprecedented hydrocarbon clean protocols. Hopanes and steranes in rock extracts and hydropyrolysates from these new cores were typically at or below our femtogram detection limit, but when they were detectable, they had total hopane (<37.9 pg per gram of rock) and total sterane (<32.9 pg per gram of rock) concentrations comparable to those measured in blanks and negative control samples. In contrast, hopanes and steranes measured in the exteriors of conventionally drilled and curated rocks of stratigraphic equivalence reach concentrations of 389.5 pg per gram of rock and 1,039 pg per gram of rock, respectively. Polycyclic aromatic hydrocarbons and diamondoids, which exceed blank concentrations, exhibit individual concentrations up to 80 ng per gram of rock in rock extracts and up to 1,000 ng per gram of rock in hydropyrolysates from the ultraclean cores. These results demonstrate that previously studied Archean samples host mixtures of biomarker contaminants and indigenous overmature hydrocarbons. Therefore, existing lipid biomarker evidence cannot be invoked to support the emergence of oxygenic photosynthesis and eukaryotes by ~ 2.7 billion years ago. Although suitable Proterozoic rocks exist, no currently known Archean strata lie within the appropriate thermal maturity window for syngenetic hydrocarbon biomarker preservation, so future exploration for Archean biomarkers should screen for rocks with milder thermal histories. PMID- 25918388 TI - iRhoms 1 and 2 are essential upstream regulators of ADAM17-dependent EGFR signaling. AB - The metalloproteinase ADAM17 (a disintegrin and metalloprotease 17) controls EGF receptor (EGFR) signaling by liberating EGFR ligands from their membrane anchor. Consequently, a patient lacking ADAM17 has skin and intestinal barrier defects that are likely caused by lack of EGFR signaling, and Adam17(-/-) mice die perinatally with open eyes, like Egfr(-/-) mice. A hallmark feature of ADAM17 dependent EGFR ligand shedding is that it can be rapidly and posttranslationally activated in a manner that requires its transmembrane domain but not its cytoplasmic domain. This suggests that ADAM17 is regulated by other integral membrane proteins, although much remains to be learned about the underlying mechanism. Recently, inactive Rhomboid 2 (iRhom2), which has seven transmembrane domains, emerged as a molecule that controls the maturation and function of ADAM17 in myeloid cells. However, iRhom2(-/-) mice appear normal, raising questions about how ADAM17 is regulated in other tissues. Here we report that iRhom1/2(-/-) double knockout mice resemble Adam17(-/-) and Egfr(-/-) mice in that they die perinatally with open eyes, misshapen heart valves, and growth plate defects. Mechanistically, we show lack of mature ADAM17 and strongly reduced EGFR phosphorylation in iRhom1/2(-/-) tissues. Finally, we demonstrate that iRhom1 is not essential for mouse development but regulates ADAM17 maturation in the brain, except in microglia, where ADAM17 is controlled by iRhom2. These results provide genetic, cell biological, and biochemical evidence that a principal function of iRhoms1/2 during mouse development is to regulate ADAM17-dependent EGFR signaling, suggesting that iRhoms1/2 could emerge as novel targets for treatment of ADAM17/EGFR-dependent pathologies. PMID- 25918389 TI - Solution structure of the PsIAA4 oligomerization domain reveals interaction modes for transcription factors in early auxin response. AB - The plant hormone auxin activates primary response genes by facilitating proteolytic removal of auxin/indole-3-acetic acid (AUX/IAA)-inducible repressors, which directly bind to transcriptional auxin response factors (ARF). Most AUX/IAA and ARF proteins share highly conserved C-termini mediating homotypic and heterotypic interactions within and between both protein families. The high resolution NMR structure of C-terminal domains III and IV of the AUX/IAA protein PsIAA4 from pea (Pisum sativum) revealed a globular ubiquitin-like beta-grasp fold with homologies to the Phox and Bem1p (PB1) domain. The PB1 domain of wild type PsIAA4 features two distinct surface patches of oppositely charged amino acid residues, mediating front-to-back multimerization via electrostatic interactions. Mutations of conserved basic or acidic residues on either face suppressed PsIAA4 PB1 homo-oligomerization in vitro and confirmed directional interaction of full-length PsIAA4 in vivo (yeast two-hybrid system). Mixing of oppositely mutated PsIAA4 PB1 monomers enabled NMR mapping of the negatively charged interface of the reconstituted PsIAA4 PB1 homodimer variant, whose stoichiometry (1:1) and equilibrium binding constant (KD ~ 6.4 MUM) were determined by isothermal titration calorimetry. In silico protein-protein docking studies based on NMR and yeast interaction data derived a model of the PsIAA4 PB1 homodimer, which is comparable with other PB1 domain dimers, but indicated considerable differences between the homodimeric interfaces of AUX/IAA and ARF PB1 domains. Our study provides an impetus for elucidating the molecular determinants that confer specificity to complex protein-protein interaction circuits between members of the two central families of transcription factors important to the regulation of auxin-responsive gene expression. PMID- 25918391 TI - Contribution of air conditioning adoption to future energy use under global warming. AB - As household incomes rise around the world and global temperatures go up, the use of air conditioning is poised to increase dramatically. Air conditioning growth is expected to be particularly strong in middle-income countries, but direct empirical evidence is scarce. In this paper we use high-quality microdata from Mexico to describe the relationship between temperature, income, and air conditioning. We describe both how electricity consumption increases with temperature given current levels of air conditioning, and how climate and income drive air conditioning adoption decisions. We then combine these estimates with predicted end-of-century temperature changes to forecast future energy consumption. Under conservative assumptions about household income, our model predicts near-universal saturation of air conditioning in all warm areas within just a few decades. Temperature increases contribute to this surge in adoption, but income growth by itself explains most of the increase. What this will mean for electricity consumption and carbon dioxide emissions depends on the pace of technological change. Continued advances in energy efficiency or the development of new cooling technologies could reduce the energy consumption impacts. Similarly, growth in low-carbon electricity generation could mitigate the increases in carbon dioxide emissions. However, the paper illustrates the enormous potential impacts in this sector, highlighting the importance of future research on adaptation and underscoring the urgent need for global action on climate change. PMID- 25918390 TI - Ipilimumab-dependent cell-mediated cytotoxicity of regulatory T cells ex vivo by nonclassical monocytes in melanoma patients. AB - Enhancing immune responses with immune-modulatory monoclonal antibodies directed to inhibitory immune receptors is a promising modality in cancer therapy. Clinical efficacy has been demonstrated with antibodies blocking inhibitory immune checkpoints such as cytotoxic T lymphocyte-associated antigen 4 (CTLA-4) or PD-1/PD-L1. Treatment with ipilimumab, a fully human CTLA-4-specific mAb, showed durable clinical efficacy in metastatic melanoma; its mechanism of action is, however, only partially understood. This is a study of 29 patients with advanced cutaneous melanoma treated with ipilimumab. We analyzed peripheral blood mononuclear cells (PBMCs) and matched melanoma metastases from 15 patients responding and 14 not responding to ipilimumab by multicolor flow cytometry, antibody-dependent cell-mediated cytotoxicity (ADCC) assay, and immunohistochemistry. PBMCs and matched tumor biopsies were collected 24 h before (i.e., baseline) and up to 4 wk after ipilimumab. Our findings show, to our knowledge for the first time, that ipilimumab can engage ex vivo FcgammaRIIIA (CD16)-expressing, nonclassical monocytes resulting in ADCC-mediated lysis of regulatory T cells (Tregs). In contrast, classical CD14(++)CD16(-) monocytes are unable to do so. Moreover, we show that patients responding to ipilimumab display significantly higher baseline peripheral frequencies of nonclassical monocytes compared with nonresponder patients. In the tumor microenvironment, responders have higher CD68(+)/CD163(+) macrophage ratios at baseline and show decreased Treg infiltration after treatment. Together, our results suggest that anti-CTLA-4 therapy may target Tregs in vivo. Larger translational studies are, however, warranted to substantiate this mechanism of action of ipilimumab in patients. PMID- 25918392 TI - Crystal structure of the human mitochondrial chaperonin symmetrical football complex. AB - Human mitochondria harbor a single type I chaperonin system that is generally thought to function via a unique single-ring intermediate. To date, no crystal structure has been published for any mammalian type I chaperonin complex. In this study, we describe the crystal structure of a football-shaped, double-ring human mitochondrial chaperonin complex at 3.15 A, which is a novel intermediate, likely representing the complex in an early stage of dissociation. Interestingly, the mitochondrial chaperonin was captured in a state that exhibits subunit asymmetry within the rings and nucleotide symmetry between the rings. Moreover, the chaperonin tetradecamers show a different interring subunit arrangement when compared to GroEL. Our findings suggest that the mitochondrial chaperonins use a mechanism that is distinct from the mechanism of the well-studied Escherichia coli system. PMID- 25918393 TI - Metabolic and trophic interactions modulate methane production by Arctic peat microbiota in response to warming. AB - Arctic permafrost soils store large amounts of soil organic carbon (SOC) that could be released into the atmosphere as methane (CH4) in a future warmer climate. How warming affects the complex microbial network decomposing SOC is not understood. We studied CH4 production of Arctic peat soil microbiota in anoxic microcosms over a temperature gradient from 1 to 30 degrees C, combining metatranscriptomic, metagenomic, and targeted metabolic profiling. The CH4 production rate at 4 degrees C was 25% of that at 25 degrees C and increased rapidly with temperature, driven by fast adaptations of microbial community structure, metabolic network of SOC decomposition, and trophic interactions. Below 7 degrees C, syntrophic propionate oxidation was the rate-limiting step for CH4 production; above this threshold temperature, polysaccharide hydrolysis became rate limiting. This change was associated with a shift within the functional guild for syntrophic propionate oxidation, with Firmicutes being replaced by Bacteroidetes. Correspondingly, there was a shift from the formate- and H2-using Methanobacteriales to Methanomicrobiales and from the acetotrophic Methanosarcinaceae to Methanosaetaceae. Methanogenesis from methylamines, probably stemming from degradation of bacterial cells, became more important with increasing temperature and corresponded with an increased relative abundance of predatory protists of the phylum Cercozoa. We concluded that Arctic peat microbiota responds rapidly to increased temperatures by modulating metabolic and trophic interactions so that CH4 is always highly produced: The microbial community adapts through taxonomic shifts, and cascade effects of substrate availability cause replacement of functional guilds and functional changes within taxa. PMID- 25918394 TI - Missense mutation in immunodeficient patients shows the multifunctional roles of coiled-coil domain 3 (CC3) in STIM1 activation. AB - Store-operated Ca(2+) entry (SOCE) is a universal Ca(2+) influx pathway that is important for the function of many cell types. SOCE occurs upon depletion of endoplasmic reticulum (ER) Ca(2+) stores and relies on a complex molecular interplay between the plasma membrane (PM) Ca(2+) channel ORAI1 and the ER Ca(2+) sensor stromal interaction molecule (STIM) 1. Patients with null mutations in ORAI1 or STIM1 genes present with severe combined immunodeficiency (SCID)-like disease. Here, we describe the molecular mechanisms by which a loss-of-function STIM1 mutation (R429C) in human patients abolishes SOCE. R429 is located in the third coiled-coil (CC3) domain of the cytoplasmic C terminus of STIM1. Mutation of R429 destabilizes the CC3 structure and alters the conformation of the STIM1 C terminus, thereby releasing a polybasic domain that promotes STIM1 recruitment to ER-PM junctions. However, the mutation also impairs cytoplasmic STIM1 oligomerization and abolishes STIM1-ORAI1 interactions. Thus, despite its constitutive localization at ER-PM junctions, mutant STIM1 fails to activate SOCE. Our results demonstrate multifunctional roles of the CC3 domain in regulating intra- and intermolecular STIM1 interactions that control (i) transition of STIM1 from a quiescent to an active conformational state, (ii) cytoplasmic STIM1 oligomerization, and (iii) STIM1-ORAI1 binding required for ORAI1 activation. PMID- 25918395 TI - Direct conversion of human fibroblasts into functional osteoblasts by defined factors. AB - Osteoblasts produce calcified bone matrix and contribute to bone formation and remodeling. In this study, we established a procedure to directly convert human fibroblasts into osteoblasts by transducing some defined factors and culturing in osteogenic medium. Osteoblast-specific transcription factors, Runt-related transcription factor 2 (Runx2), and Osterix, in combination with Octamer-binding transcription factor 3/4 (Oct4) and L-Myc (RXOL) transduction, converted ~ 80% of the fibroblasts into osteocalcin-producing cells. The directly converted osteoblasts (dOBs) induced by RXOL displayed a similar gene expression profile as normal human osteoblasts and contributed to bone repair after transplantation into immunodeficient mice at artificial bone defect lesions. The dOBs expressed endogenous Runx2 and Osterix, and did not require continuous expression of the exogenous genes to maintain their phenotype. Another combination, Oct4 plus L-Myc (OL), also induced fibroblasts to produce bone matrix, but the OL-transduced cells did not express Osterix and exhibited a more distant gene expression profile to osteoblasts compared with RXOL-transduced cells. These findings strongly suggest successful direct reprogramming of fibroblasts into functional osteoblasts by RXOL, a technology that may provide bone regeneration therapy against bone disorders. PMID- 25918396 TI - A OmegaXaV motif in the Rift Valley fever virus NSs protein is essential for degrading p62, forming nuclear filaments and virulence. AB - Rift Valley fever virus (RVFV) is a single-stranded RNA virus capable of inducing fatal hemorrhagic fever in humans. A key component of RVFV virulence is its ability to form nuclear filaments through interactions between the viral nonstructural protein NSs and the host general transcription factor TFIIH. Here, we identify an interaction between a OmegaXaV motif in NSs and the p62 subunit of TFIIH. This motif in NSs is similar to OmegaXaV motifs found in nucleotide excision repair (NER) factors and transcription factors known to interact with p62. Structural and biophysical studies demonstrate that NSs binds to p62 in a similar manner as these other factors. Functional studies in RVFV-infected cells show that the OmegaXaV motif is required for both nuclear filament formation and degradation of p62. Consistent with the fact that the RVFV can be distinguished from other Bunyaviridae-family viruses due to its ability to form nuclear filaments in infected cells, the motif is absent in the NSs proteins of other Bunyaviridae-family viruses. Taken together, our studies demonstrate that p62 binding to NSs through the OmegaXaV motif is essential for degrading p62, forming nuclear filaments and enhancing RVFV virulence. In addition, these results show how the RVFV incorporates a simple motif into the NSs protein that enables it to functionally mimic host cell proteins that bind the p62 subunit of TFIIH. PMID- 25918397 TI - Dose-dependent regulation of microbial activity on sinking particles by polyunsaturated aldehydes: Implications for the carbon cycle. AB - Diatoms and other phytoplankton play a crucial role in the global carbon cycle, fixing CO2 into organic carbon, which may then be exported to depth via sinking particles. The molecular diversity of this organic carbon is vast and many highly bioactive molecules have been identified. Polyunsaturated aldehydes (PUAs) are bioactive on various levels of the marine food web, and yet the potential for these molecules to affect the fate of organic carbon produced by diatoms remains an open question. In this study, the effects of PUAs on the natural microbial assemblages associated with sinking particles were investigated. Sinking particles were collected from 150 m in the water column and exposed to varying concentrations of PUAs in dark incubations over 24 h. PUA doses ranging from 1 to 10 uM stimulated respiration, organic matter hydrolysis, and cell growth by bacteria associated with sinking particles. PUA dosages near 100 uM appeared to be toxic, resulting in decreased bacterial cell abundance and metabolism, as well as pronounced shifts in bacterial community composition. Sinking particles were hot spots for PUA production that contained concentrations within the stimulatory micromolar range in contrast to previously reported picomolar concentrations of these compounds in bulk seawater. This suggests PUAs produced in situ stimulate the remineralization of phytoplankton-derived sinking organic matter, decreasing carbon export efficiency, and shoaling the average depths of nutrient regeneration. Our results are consistent with a "bioactivity hypothesis" for explaining variations in carbon export efficiency in the oceans. PMID- 25918398 TI - Intercellular chaperone transmission via exosomes contributes to maintenance of protein homeostasis at the organismal level. AB - The heat shock response (HSR), a transcriptional response that up-regulates molecular chaperones upon heat shock, is necessary for cell survival in a stressful environment to maintain protein homeostasis (proteostasis). However, there is accumulating evidence that the HSR does not ubiquitously occur under stress conditions, but largely depends on the cell types. Despite such imbalanced HSR among different cells and tissues, molecular mechanisms by which multicellular organisms maintain their global proteostasis have remained poorly understood. Here, we report that proteostasis can be maintained by molecular chaperones not only in a cell-autonomous manner but also in a non-cell-autonomous manner. We found that elevated expression of molecular chaperones, such as Hsp40 and Hsp70, in a group of cells improves proteostasis in other groups of cells, both in cultured cells and in Drosophila expressing aggregation-prone polyglutamine proteins. We also found that Hsp40, as well as Hsp70 and Hsp90, is physiologically secreted from cells via exosomes, and that the J domain at the N terminus is responsible for its exosome-mediated secretion. Addition of Hsp40/Hsp70-containing exosomes to the culture medium of the polyglutamine expressing cells results in efficient suppression of inclusion body formation, indicating that molecular chaperones non-cell autonomously improve the protein folding environment via exosome-mediated transmission. Our study reveals that intercellular chaperone transmission mediated by exosomes is a novel molecular mechanism for non-cell-autonomous maintenance of organismal proteostasis that could functionally compensate for the imbalanced state of the HSR among different cells, and also provides a novel physiological role of exosomes that contributes to maintenance of organismal proteostasis. PMID- 25918399 TI - Targeting beta-arrestin2 in the treatment of L-DOPA-induced dyskinesia in Parkinson's disease. AB - Parkinson's disease (PD) is characterized by severe locomotor deficits and is commonly treated with the dopamine (DA) precursor l-3,4-dihydroxyphenylalanine (L DOPA), but its prolonged use causes dyskinesias referred to as L-DOPA-induced dyskinesias (LIDs). Recent studies in animal models of PD have suggested that dyskinesias are associated with the overactivation of G protein-mediated signaling through DA receptors. beta-Arrestins desensitize G protein signaling at DA receptors (D1R and D2R) in addition to activating their own G protein independent signaling events, which have been shown to mediate locomotion. Therefore, targeting beta-arrestins in PD L-DOPA therapy might prove to be a desirable approach. Here we show in a bilateral DA-depletion mouse model of Parkinson's symptoms that genetic deletion of beta-arrestin2 significantly limits the beneficial locomotor effects while markedly enhancing the dyskinesia-like effects of acute or chronic L-DOPA treatment. Viral rescue or overexpression of beta-arrestin2 in knockout or control mice either reverses or protects against LIDs and its key biochemical markers. In other more conventional animal models of DA neuron loss and PD, such as 6-hydroxydopamine-treated mice or rats and 1 methyl-4-phenyl-1,2,3,6-tetrahydropyridine-treated nonhuman primates, beta arrestin2 overexpression significantly reduced dyskinesias while maintaining the therapeutic effect of L-DOPA. Considerable efforts are being spent in the pharmaceutical industry to identify therapeutic approaches to block LIDs in patients with PD. Our results point to a potential therapeutic approach, whereby development of either a genetic or pharmacological intervention to enhance beta arrestin2- or limit G protein-dependent D1/D2R signaling could represent a more mechanistically informed strategy. PMID- 25918400 TI - Structure-relaxation mechanism for the response of T4 lysozyme cavity mutants to hydrostatic pressure. AB - Application of hydrostatic pressure shifts protein conformational equilibria in a direction to reduce the volume of the system. A current view is that the volume reduction is dominated by elimination of voids or cavities in the protein interior via cavity hydration, although an alternative mechanism wherein cavities are filled with protein side chains resulting from a structure relaxation has been suggested [Lopez CJ, Yang Z, Altenbach C, Hubbell WL (2013) Proc Natl Acad Sci USA 110(46):E4306-E4315]. In the present study, mechanisms for elimination of cavities under high pressure are investigated in the L99A cavity mutant of T4 lysozyme and derivatives thereof using site-directed spin labeling, pressure resolved double electron-electron resonance, and high-pressure circular dichroism spectroscopy. In the L99A mutant, the ground state is in equilibrium with an excited state of only ~ 3% of the population in which the cavity is filled by a protein side chain [Bouvignies et al. (2011) Nature 477(7362):111-114]. The results of the present study show that in L99A the native ground state is the dominant conformation to pressures of 3 kbar, with cavity hydration apparently taking place in the range of 2-3 kbar. However, in the presence of additional mutations that lower the free energy of the excited state, pressure strongly populates the excited state, thereby eliminating the cavity with a native side chain rather than solvent. Thus, both cavity hydration and structure relaxation are mechanisms for cavity elimination under pressure, and which is dominant is determined by details of the energy landscape. PMID- 25918401 TI - Reconciling reported and unreported HFC emissions with atmospheric observations. AB - We infer global and regional emissions of five of the most abundant hydrofluorocarbons (HFCs) using atmospheric measurements from the Advanced Global Atmospheric Gases Experiment and the National Institute for Environmental Studies, Japan, networks. We find that the total CO2-equivalent emissions of the five HFCs from countries that are required to provide detailed, annual reports to the United Nations Framework Convention on Climate Change (UNFCCC) increased from 198 (175-221) Tg-CO2-eq ? y(-1) in 2007 to 275 (246-304) Tg-CO2-eq ? y(-1) in 2012. These global warming potential-weighted aggregated emissions agree well with those reported to the UNFCCC throughout this period and indicate that the gap between reported emissions and global HFC emissions derived from atmospheric trends is almost entirely due to emissions from nonreporting countries. However, our measurement-based estimates of individual HFC species suggest that emissions, from reporting countries, of the most abundant HFC, HFC-134a, were only 79% (63 95%) of the UNFCCC inventory total, while other HFC emissions were significantly greater than the reported values. These results suggest that there are inaccuracies in the reporting methods for individual HFCs, which appear to cancel when aggregated together. PMID- 25918402 TI - EGFR inhibits DNA mismatch repair. PMID- 25918403 TI - Predator lipids induce paralytic shellfish toxins in bloom-forming algae. AB - Interactions among microscopic planktonic organisms underpin the functioning of open ocean ecosystems. With few exceptions, these organisms lack advanced eyes and thus rely largely on chemical sensing to perceive their surroundings. However, few of the signaling molecules involved in interactions among marine plankton have been identified. We report a group of eight small molecules released by copepods, the most abundant zooplankton in the sea, which play a central role in food webs and biogeochemical cycles. The compounds, named copepodamides, are polar lipids connecting taurine via an amide to isoprenoid fatty acid conjugate of varying composition. The bloom-forming dinoflagellate Alexandrium minutum responds to pico- to nanomolar concentrations of copepodamides with up to a 20-fold increase in production of paralytic shellfish toxins. Different copepod species exude distinct copepodamide blends that contribute to the species-specific defensive responses observed in phytoplankton. The signaling system described here has far reaching implications for marine ecosystems by redirecting grazing pressure and facilitating the formation of large scale harmful algal blooms. PMID- 25918404 TI - Surface sum-frequency vibrational spectroscopy of nonpolar media. AB - Sum-frequency generation spectroscopy is surface specific only if the bulk contribution to the signal is negligible. Negligible bulk contribution is, however, not necessarily true, even for media with inversion symmetry. The inevitable challenge is to find the surface spectrum in the presence of bulk contribution, part of which has been believed to be inseparable from the surface contribution. Here, we show that, for nonpolar media, it is possible to separately deduce surface and bulk spectra from combined phase-sensitive sum frequency vibrational spectroscopic measurements in reflection and transmission. The study of benzene interfaces is presented as an example. PMID- 25918405 TI - Hydration water mobility is enhanced around tau amyloid fibers. AB - The paired helical filaments (PHF) formed by the intrinsically disordered human protein tau are one of the pathological hallmarks of Alzheimer disease. PHF are fibers of amyloid nature that are composed of a rigid core and an unstructured fuzzy coat. The mechanisms of fiber formation, in particular the role that hydration water might play, remain poorly understood. We combined protein deuteration, neutron scattering, and all-atom molecular dynamics simulations to study the dynamics of hydration water at the surface of fibers formed by the full length human protein htau40. In comparison with monomeric tau, hydration water on the surface of tau fibers is more mobile, as evidenced by an increased fraction of translationally diffusing water molecules, a higher diffusion coefficient, and increased mean-squared displacements in neutron scattering experiments. Fibers formed by the hexapeptide (306)VQIVYK(311) were taken as a model for the tau fiber core and studied by molecular dynamics simulations, revealing that hydration water dynamics around the core domain is significantly reduced after fiber formation. Thus, an increase in water dynamics around the fuzzy coat is proposed to be at the origin of the experimentally observed increase in hydration water dynamics around the entire tau fiber. The observed increase in hydration water dynamics is suggested to promote fiber formation through entropic effects. Detection of the enhanced hydration water mobility around tau fibers is conjectured to potentially contribute to the early diagnosis of Alzheimer patients by diffusion MRI. PMID- 25918406 TI - Cas9-mediated targeting of viral RNA in eukaryotic cells. AB - Clustered, regularly interspaced, short palindromic repeats-CRISPR associated (CRISPR-Cas) systems are prokaryotic RNA-directed endonuclease machineries that act as an adaptive immune system against foreign genetic elements. Using small CRISPR RNAs that provide specificity, Cas proteins recognize and degrade nucleic acids. Our previous work demonstrated that the Cas9 endonuclease from Francisella novicida (FnCas9) is capable of targeting endogenous bacterial RNA. Here, we show that FnCas9 can be directed by an engineered RNA-targeting guide RNA to target and inhibit a human +ssRNA virus, hepatitis C virus, within eukaryotic cells. This work reveals a versatile and portable RNA-targeting system that can effectively function in eukaryotic cells and be programmed as an antiviral defense. PMID- 25918407 TI - How a well-adapted immune system is organized. AB - The repertoire of lymphocyte receptors in the adaptive immune system protects organisms from diverse pathogens. A well-adapted repertoire should be tuned to the pathogenic environment to reduce the cost of infections. We develop a general framework for predicting the optimal repertoire that minimizes the cost of infections contracted from a given distribution of pathogens. The theory predicts that the immune system will have more receptors for rare antigens than expected from the frequency of encounters; individuals exposed to the same infections will have sparse repertoires that are largely different, but nevertheless exploit cross-reactivity to provide the same coverage of antigens; and the optimal repertoires can be reached via the dynamics of competitive binding of antigens by receptors and selective amplification of stimulated receptors. Our results follow from a tension between the statistics of pathogen detection, which favor a broader receptor distribution, and the effects of cross-reactivity, which tend to concentrate the optimal repertoire onto a few highly abundant clones. Our predictions can be tested in high-throughput surveys of receptor and pathogen diversity. PMID- 25918409 TI - Correction for Chen et al., MeCP2 binds to non-CG methylated DNA as neurons mature, influencing transcription and the timing of onset for Rett syndrome. PMID- 25918408 TI - Diabetes-associated dysregulation of O-GlcNAcylation in rat cardiac mitochondria. AB - Elevated mitochondrial O-GlcNAcylation caused by hyperglycemia, as occurs in diabetes, significantly contributes to mitochondrial dysfunction and to diabetic cardiomyopathy. However, little is known about the enzymology of mitochondrial O GlcNAcylation. Herein, we investigated the enzymes responsible for cycling O GlcNAc on mitochondrial proteins and studied the mitochondrial transport of UDP GlcNAc. Analyses of purified rat heart mitochondria from normal and streptozocin treated diabetic rats show increased mitochondrial O-GlcNAc transferase (OGT) and a concomitant decrease in the mito-specific O-GlcNAcase (OGA). Strikingly, OGT is mislocalized in cardiac mitochondria from diabetic rats. Interaction of OGT and complex IV observed in normal rat heart mitochondria is visibly reduced in diabetic samples, where OGT is mislocalized to the matrix. Live cell OGA activity assays establish the presence of O-GlcNAcase within the mitochondria. Furthermore, we establish that the inner mitochondrial membrane transporter, pyrimidine nucleotide carrier, transports UDP-GlcNAc from the cytosol to the inside of the mitochondria. Knockdown of this transporter substantially lowers mitochondrial O-GlcNAcylation. Inhibition of OGT or OGA activity within neonatal rat cardiomyocytes significantly affects energy production, mitochondrial membrane potential, and mitochondrial oxygen consumption. These data suggest that cardiac mitochondria not only have robust O-GlcNAc cycling, but also that dysregulation of O-GlcNAcylation likely plays a key role in mitochondrial dysfunction associated with diabetes. PMID- 25918411 TI - Correction for Sano et al., Two distinct signaling pathways in hair cycle induction: Stat3-dependent and -independent pathways. PMID- 25918410 TI - Inactivation of EWS reduces PGC-1alpha protein stability and mitochondrial homeostasis. AB - EWS (Ewing sarcoma) encodes an RNA/ssDNA binding protein that is frequently rearranged in a number of different cancers by chromosomal translocations. Physiologically, EWS has diverse and essential roles in various organ development and cellular processes. In this study, we uncovered a new role of EWS in mitochondrial homeostasis and energy metabolism. Loss of EWS leads to a significant decrease in mitochondria abundance and activity, which is caused by a rapid degradation of Peroxisome proliferator-activated receptor gamma Coactivator (PGC-1alpha), a central regulator of mitochondria biogenesis, function, and cellular energy metabolism. EWS inactivation leads to increased ubiquitination and proteolysis of PGC-1alpha via proteasome pathway. Complementation of EWS in Ews-deficient cells restores PGC-1alpha and mitochondrial abundance. We found that expression of E3 ubiquitin ligase, FBXW7 (F-box/WD40 domain protein 7), is increased in the absence of Ews and depletion of Fbxw7 in Ews-null cells restores PGC-1alpha expression and mitochondrial density. Consistent with these findings, mitochondrial abundance and activity are significantly reduced in brown fat and skeletal muscles of Ews-deficient mice. Furthermore, expression of mitochondrial biogenesis, respiration and fatty acid beta-oxidation genes is significantly reduced in the liver of Ews-null mice. These results demonstrate a novel role of EWS in mitochondrial and cellular energy homeostasis by controlling PGC-1alpha protein stability, and further implicate altered mitochondrial and energy metabolism in cancers harboring the EWS translocation. PMID- 25918412 TI - How release of phosphate from mammalian F1-ATPase generates a rotary substep. AB - The rotation of the central stalk of F1-ATPase is driven by energy derived from the sequential binding of an ATP molecule to its three catalytic sites and the release of the products of hydrolysis. In human F1-ATPase, each 360 degrees rotation consists of three 120 degrees steps composed of substeps of about 65 degrees , 25 degrees , and 30 degrees , with intervening ATP binding, phosphate release, and catalytic dwells, respectively. The F1-ATPase inhibitor protein, IF1, halts the rotary cycle at the catalytic dwell. The human and bovine enzymes are essentially identical, and the structure of bovine F1-ATPase inhibited by IF1 represents the catalytic dwell state. Another structure, described here, of bovine F1-ATPase inhibited by an ATP analog and the phosphate analog, thiophosphate, represents the phosphate binding dwell. Thiophosphate is bound to a site in the alpha(E)beta(E)-catalytic interface, whereas in F1-ATPase inhibited with IF1, the equivalent site is changed subtly and the enzyme is incapable of binding thiophosphate. These two structures provide a molecular mechanism of how phosphate release generates a rotary substep as follows. In the active enzyme, phosphate release from the beta(E)-subunit is accompanied by a rearrangement of the structure of its binding site that prevents released phosphate from rebinding. The associated extrusion of a loop in the beta(E)-subunit disrupts interactions in the alpha(E)beta(E-)catalytic interface and opens it to its fullest extent. Other rearrangements disrupt interactions between the gamma subunit and the C-terminal domain of the alpha(E)-subunit. To restore most of these interactions, and to make compensatory new ones, the gamma-subunit rotates through 25 degrees -30 degrees . PMID- 25918413 TI - Strain and the optoelectronic properties of nonplanar phosphorene monolayers. AB - Lattice kirigami, ultralight metamaterials, polydisperse aggregates, ceramic nanolattices, and 2D atomic materials share an inherent structural discreteness, and their material properties evolve with their shape. To exemplify the intimate relation among material properties and the local geometry, we explore the properties of phosphorene--a new 2D atomic material--in a conical structure, and document a decrease of the semiconducting gap that is directly linked to its nonplanar shape. This geometrical effect occurs regardless of phosphorene allotrope considered, and it provides a unique optical vehicle to single out local structural defects on this 2D material. We also classify other 2D atomic materials in terms of their crystalline unit cells, and propose means to obtain the local geometry directly from their diverse 2D structures while bypassing common descriptions of shape that are based from a parametric continuum. PMID- 25918414 TI - Correction for Kim et al., Cortically projecting basal forebrain parvalbumin neurons regulate cortical gamma band oscillations. PMID- 25918415 TI - Molecular blueprint of allosteric binding sites in a homologue of the agonist binding domain of the alpha7 nicotinic acetylcholine receptor. AB - The alpha7 nicotinic acetylcholine receptor (nAChR) belongs to the family of pentameric ligand-gated ion channels and is involved in fast synaptic signaling. In this study, we take advantage of a recently identified chimera of the extracellular domain of the native alpha7 nicotinic acetylcholine receptor and acetylcholine binding protein, termed alpha7-AChBP. This chimeric receptor was used to conduct an innovative fragment-library screening in combination with X ray crystallography to identify allosteric binding sites. One allosteric site is surface-exposed and is located near the N-terminal alpha-helix of the extracellular domain. Ligand binding at this site causes a conformational change of the alpha-helix as the fragment wedges between the alpha-helix and a loop homologous to the main immunogenic region of the muscle alpha1 subunit. A second site is located in the vestibule of the receptor, in a preexisting intrasubunit pocket opposite the agonist binding site and corresponds to a previously identified site involved in positive allosteric modulation of the bacterial homolog ELIC. A third site is located at a pocket right below the agonist binding site. Using electrophysiological recordings on the human alpha7 nAChR we demonstrate that the identified fragments, which bind at these sites, can modulate receptor activation. This work presents a structural framework for different allosteric binding sites in the alpha7 nAChR and paves the way for future development of novel allosteric modulators with therapeutic potential. PMID- 25918416 TI - A site of varicella-zoster virus vulnerability identified by structural studies of neutralizing antibodies bound to the glycoprotein complex gHgL. AB - Varicella-zoster virus (VZV), of the family Alphaherpesvirinae, causes varicella in children and young adults, potentially leading to herpes zoster later in life on reactivation from latency. The conserved herpesvirus glycoprotein gB and the heterodimer gHgL mediate virion envelope fusion with cell membranes during virus entry. Naturally occurring neutralizing antibodies against herpesviruses target these entry proteins. To determine the molecular basis for VZV neutralization, crystal structures of gHgL were determined in complex with fragments of antigen binding (Fabs) from two human monoclonal antibodies, IgG-94 and IgG-RC, isolated from seropositive subjects. These structures reveal that the antibodies target the same site, composed of residues from both gH and gL, distinct from two other neutralizing epitopes identified by negative-stain electron microscopy and mutational analysis. Inhibition of gB/gHgL-mediated membrane fusion and structural comparisons with herpesvirus homologs suggest that the IgG-RC/94 epitope is in proximity to the site on VZV gHgL that activates gB. Immunization studies proved that the anti-gHgL IgG-RC/94 epitope is a critical target for antibodies that neutralize VZV. Thus, the gHgL/Fab structures delineate a site of herpesvirus vulnerability targeted by natural immunity. PMID- 25918417 TI - Charge-mediated influence of the antibody variable domain on FcRn-dependent pharmacokinetics. AB - Here, we investigated the influence of the variable fragment (Fv) of IgG antibodies on the binding to the neonatal Fc receptor (FcRn) as well as on FcRn dependent pharmacokinetics (PK). FcRn plays a key role in IgG homeostasis, and specific manipulation in the crystallizable fragment (Fc) is known to affect FcRn dependent PK. Although the influence of the antigen-binding fragment (Fab) on FcRn interactions has been reported, the underlying mechanism is hitherto only poorly understood. Therefore, we analyzed the two IgG1 antibodies, briakinumab and ustekinumab, that have similar Fc parts but different terminal half-lives in human and systematically engineered variants of them with cross-over exchanges and varied charge distribution. Using FcRn affinity chromatography, molecular dynamics simulation, and in vivo PK studies in human FcRn transgenic mice, we provide evidence that the charge distribution on the Fv domain is involved in excessive FcRn binding. This excessive binding prevents efficient FcRn-IgG dissociation at physiological pH, thereby reducing FcRn-dependent terminal half lives. Furthermore, we observed a linear correlation between FcRn column retention times of the antibody variants and the terminal half-lives in vivo. Taken together, our study contributes to a better understanding of the FcRn-IgG interaction, and it could also provide profound potential in FcRn-dependent antibody engineering of the variable Fab region. PMID- 25918418 TI - Transcriptome dynamics of developing maize leaves and genomewide prediction of cis elements and their cognate transcription factors. AB - Maize is a major crop and a model plant for studying C4 photosynthesis and leaf development. However, a genomewide regulatory network of leaf development is not yet available. This knowledge is useful for developing C3 crops to perform C4 photosynthesis for enhanced yields. Here, using 22 transcriptomes of developing maize leaves from dry seeds to 192 h post imbibition, we studied gene up- and down-regulation and functional transition during leaf development and inferred sets of strongly coexpressed genes. More significantly, we developed a method to predict transcription factor binding sites (TFBSs) and their cognate transcription factors (TFs) using genomic sequence and transcriptomic data. The method requires not only evolutionary conservation of candidate TFBSs and sets of strongly coexpressed genes but also that the genes in a gene set share the same Gene Ontology term so that they are involved in the same biological function. In addition, we developed another method to predict maize TF-TFBS pairs using known TF-TFBS pairs in Arabidopsis or rice. From these efforts, we predicted 1,340 novel TFBSs and 253 new TF-TFBS pairs in the maize genome, far exceeding the 30 TF-TFBS pairs currently known in maize. In most cases studied by both methods, the two methods gave similar predictions. In vitro tests of 12 predicted TF-TFBS interactions showed that our methods perform well. Our study has significantly expanded our knowledge on the regulatory network involved in maize leaf development. PMID- 25918419 TI - Event representations constrain the structure of language: Sign language as a window into universally accessible linguistic biases. AB - According to a theoretical tradition dating back to Aristotle, verbs can be classified into two broad categories. Telic verbs (e.g., "decide," "sell," "die") encode a logical endpoint, whereas atelic verbs (e.g., "think," "negotiate," "run") do not, and the denoted event could therefore logically continue indefinitely. Here we show that sign languages encode telicity in a seemingly universal way and moreover that even nonsigners lacking any prior experience with sign language understand these encodings. In experiments 1-5, nonsigning English speakers accurately distinguished between telic (e.g., "decide") and atelic (e.g., "think") signs from (the historically unrelated) Italian Sign Language, Sign Language of the Netherlands, and Turkish Sign Language. These results were not due to participants' inferring that the sign merely imitated the action in question. In experiment 6, we used pseudosigns to show that the presence of a salient visual boundary at the end of a gesture was sufficient to elicit telic interpretations, whereas repeated movement without salient boundaries elicited atelic interpretations. Experiments 7-10 confirmed that these visual cues were used by all of the sign languages studied here. Together, these results suggest that signers and nonsigners share universally accessible notions of telicity as well as universally accessible "mapping biases" between telicity and visual form. PMID- 25918420 TI - Inverted formin 2 in focal adhesions promotes dorsal stress fiber and fibrillar adhesion formation to drive extracellular matrix assembly. AB - Actin filaments and integrin-based focal adhesions (FAs) form integrated systems that mediate dynamic cell interactions with their environment or other cells during migration, the immune response, and tissue morphogenesis. How adhesion associated actin structures obtain their functional specificity is unclear. Here we show that the formin-family actin nucleator, inverted formin 2 (INF2), localizes specifically to FAs and dorsal stress fibers (SFs) in fibroblasts. High resolution fluorescence microscopy and manipulation of INF2 levels in cells indicate that INF2 plays a critical role at the SF-FA junction by promoting actin polymerization via free barbed end generation and centripetal elongation of an FA associated actin bundle to form dorsal SF. INF2 assembles into FAs during maturation rather than during their initial generation, and once there, acts to promote rapid FA elongation and maturation into tensin-containing fibrillar FAs in the cell center. We show that INF2 is required for fibroblasts to organize fibronectin into matrix fibers and ultimately 3D matrices. Collectively our results indicate an important role for the formin INF2 in specifying the function of fibrillar FAs through its ability to generate dorsal SFs. Thus, dorsal SFs and fibrillar FAs form a specific class of integrated adhesion-associated actin structure in fibroblasts that mediates generation and remodeling of ECM. PMID- 25918421 TI - Structural basis of human gamma-secretase assembly. AB - The four-component intramembrane protease gamma-secretase is intricately linked to the development of Alzheimer's disease. Despite recent structural advances, the transmembrane segments (TMs) of gamma-secretase remain to be specifically assigned. Here we report a 3D structure of human gamma-secretase at 4.32-A resolution, determined by single-particle, electron cryomicroscopy in the presence of digitonin and with a T4 lysozyme fused to the amino terminus of presenilin 1 (PS1). The overall structure of this human gamma-secretase is very similar to that of wild-type gamma-secretase determined in the presence of amphipols. The 20 TMs are unambiguously assigned to the four components, revealing principles of subunit assembly. Within the transmembrane region, PS1 is centrally located, with its amino-terminal fragment (NTF) packing against Pen-2 and its carboxyl-terminal fragment (CTF) interacting with Aph-1. The only TM of nicastrin associates with Aph-1 at the thick end of the TM horseshoe, and the extracellular domain of nicastrin directly binds Pen-2 at the thin end. TM6 and TM7 in PS1, which harbor the catalytic aspartate residues, are located on the convex side of the TM horseshoe. This structure serves as an important framework for understanding the function and mechanism of gamma-secretase. PMID- 25918422 TI - MurJ and a novel lipid II flippase are required for cell wall biogenesis in Bacillus subtilis. AB - Bacterial surface polysaccharides are synthesized from lipid-linked precursors at the inner surface of the cytoplasmic membrane before being translocated across the bilayer for envelope assembly. Transport of the cell wall precursor lipid II in Escherichia coli requires the broadly conserved and essential multidrug/oligosaccharidyl-lipid/polysaccharide (MOP) exporter superfamily member MurJ. Here, we show that Bacillus subtilis cells lacking all 10 MOP superfamily members are viable with only minor morphological defects, arguing for the existence of an alternate lipid II flippase. To identify this factor, we screened for synthetic lethal partners of MOP family members using transposon sequencing. We discovered that an uncharacterized gene amj (alternate to MurJ; ydaH) and B. subtilis MurJ (murJBs; formerly ytgP) are a synthetic lethal pair. Cells defective for both Amj and MurJBs exhibit cell shape defects and lyse. Furthermore, expression of Amj or MurJBs in E. coli supports lipid II flipping and viability in the absence of E. coli MurJ. Amj is present in a subset of gram negative and gram-positive bacteria and is the founding member of a novel family of flippases. Finally, we show that Amj is expressed under the control of the cell envelope stress-response transcription factor sigma(M) and cells lacking MurJBs increase amj transcription. These findings raise the possibility that antagonists of the canonical MurJ flippase trigger expression of an alternate translocase that can resist inhibition. PMID- 25918423 TI - Multiple stiffening effects of nanoscale knobs on human red blood cells infected with Plasmodium falciparum malaria parasite. AB - During its asexual development within the red blood cell (RBC), Plasmodium falciparum (Pf), the most virulent human malaria parasite, exports proteins that modify the host RBC membrane. The attendant increase in cell stiffness and cytoadherence leads to sequestration of infected RBCs in microvasculature, which enables the parasite to evade the spleen, and leads to organ dysfunction in severe cases of malaria. Despite progress in understanding malaria pathogenesis, the molecular mechanisms responsible for the dramatic loss of deformability of Pf infected RBCs have remained elusive. By recourse to a coarse-grained (CG) model that captures the molecular structures of Pf-infected RBC membrane, here we show that nanoscale surface protrusions, known as "knobs," introduce multiple stiffening mechanisms through composite strengthening, strain hardening, and knob density-dependent vertical coupling. On one hand, the knobs act as structural strengtheners for the spectrin network; on the other, the presence of knobs results in strain inhomogeneity in the spectrin network with elevated shear strain in the knob-free regions, which, given its strain-hardening property, effectively stiffens the network. From the trophozoite to the schizont stage that ensues within 24-48 h of parasite invasion into the RBC, the rise in the knob density results in the increased number of vertical constraints between the spectrin network and the lipid bilayer, which further stiffens the membrane. The shear moduli of Pf-infected RBCs predicted by the CG model at different stages of parasite maturation are in agreement with experimental results. In addition to providing a fundamental understanding of the stiffening mechanisms of Pf-infected RBCs, our simulation results suggest potential targets for antimalarial therapies. PMID- 25918424 TI - Completion of the seven-step pathway from tabersonine to the anticancer drug precursor vindoline and its assembly in yeast. AB - Antitumor substances related to vinblastine and vincristine are exclusively found in the Catharanthus roseus (Madagascar periwinkle), a member of the Apocynaceae plant family, and continue to be extensively used in cancer chemotherapy. Although in high demand, these valuable compounds only accumulate in trace amounts in C. roseus leaves. Vinblastine and vincristine are condensed from the monoterpenoid indole alkaloid (MIA) precursors catharanthine and vindoline. Although catharanthine biosynthesis remains poorly characterized, the biosynthesis of vindoline from the MIA precursor tabersonine is well understood at the molecular and biochemical levels. This study uses virus-induced gene silencing (VIGS) to identify a cytochrome P450 [CYP71D1V2; tabersonine 3 oxygenase (T3O)] and an alcohol dehydrogenase [ADHL1; tabersonine 3-reductase (T3R)] as candidate genes involved in the conversion of tabersonine or 16 methoxytabersonine to 3-hydroxy-2,3-dihydrotabersonine or 3-hydroxy-16-methoxy 2,3-dihydrotabersonine, which are intermediates in the vindorosine and vindoline pathways, respectively. Biochemical assays with recombinant enzymes confirm that product formation is only possible by the coupled action of T3O and T3R, as the reaction product of T3O is an epoxide that is not used as a substrate by T3R. The T3O and T3R transcripts were identified in a C. roseus database representing genes preferentially expressed in leaf epidermis and suggest that the subsequent reaction products are transported from the leaf epidermis to specialized leaf mesophyll idioblast and laticifer cells to complete the biosynthesis of these MIAs. With these two genes, the complete seven-gene pathway was engineered in yeast to produce vindoline from tabersonine. PMID- 25918426 TI - Visible photoelectrochemical water splitting into H2 and O2 in a dye-sensitized photoelectrosynthesis cell. AB - A hybrid strategy for solar water splitting is exploited here based on a dye sensitized photoelectrosynthesis cell (DSPEC) with a mesoporous SnO2/TiO2 core/shell nanostructured electrode derivatized with a surface-bound Ru(II) polypyridyl-based chromophore-catalyst assembly. The assembly, [(4,4' (PO3H2)2bpy)2Ru(4-Mebpy-4'-bimpy)Ru(tpy)(OH2)](4+) ([Ru(a) (II)-Ru(b) (II) OH2](4+), combines both a light absorber and a water oxidation catalyst in a single molecule. It was attached to the TiO2 shell by phosphonate-surface oxide binding. The oxide-bound assembly was further stabilized on the surface by atomic layer deposition (ALD) of either Al2O3 or TiO2 overlayers. Illumination of the resulting fluorine-doped tin oxide (FTO)|SnO2/TiO2|-[Ru(a) (II)-Ru(b) (II) OH2](4+)(Al2O3 or TiO2) photoanodes in photoelectrochemical cells with a Pt cathode and a small applied bias resulted in visible-light water splitting as shown by direct measurements of both evolved H2 and O2. The performance of the resulting DSPECs varies with shell thickness and the nature and extent of the oxide overlayer. Use of the SnO2/TiO2 core/shell compared with nanoITO/TiO2 with the same assembly results in photocurrent enhancements of ~ 5. Systematic variations in shell thickness and ALD overlayer lead to photocurrent densities as high as 1.97 mA/cm(2) with 445-nm, ~ 90-mW/cm(2) illumination in a phosphate buffer at pH 7. PMID- 25918425 TI - In vitro selection of a sodium-specific DNAzyme and its application in intracellular sensing. AB - Over the past two decades, enormous progress has been made in designing fluorescent sensors or probes for divalent metal ions. In contrast, the development of fluorescent sensors for monovalent metal ions, such as sodium (Na(+)), has remained underdeveloped, even though Na(+) is one the most abundant metal ions in biological systems and plays a critical role in many biological processes. Here, we report the in vitro selection of the first (to our knowledge) Na(+)-specific, RNA-cleaving deoxyribozyme (DNAzyme) with a fast catalytic rate [observed rate constant (ko(bs)) ~ 0.1 min(-1)], and the transformation of this DNAzyme into a fluorescent sensor for Na(+) by labeling the enzyme strand with a quencher at the 3' end, and the DNA substrate strand with a fluorophore and a quencher at the 5' and 3' ends, respectively. The presence of Na(+) catalyzed cleavage of the substrate strand at an internal ribonucleotide adenosine (rA) site, resulting in release of the fluorophore from its quenchers and thus a significant increase in fluorescence signal. The sensor displays a remarkable selectivity (>10,000-fold) for Na(+) over competing metal ions and has a detection limit of 135 uM (3.1 ppm). Furthermore, we demonstrate that this DNAzyme-based sensor can readily enter cells with the aid of alpha-helical cationic polypeptides. Finally, by protecting the cleavage site of the Na(+) specific DNAzyme with a photolabile o-nitrobenzyl group, we achieved controlled activation of the sensor after DNAzyme delivery into cells. Together, these results demonstrate that such a DNAzyme-based sensor provides a promising platform for detection and quantification of Na(+) in living cells. PMID- 25918428 TI - Metabolic cascades in marine microbial communities. PMID- 25918429 TI - India plans to set up central e-health authority to improve healthcare delivery. PMID- 25918430 TI - Admixture of Eastern and Western European Red Deer Lineages as a Result of Postglacial Recolonization of the Czech Republic (Central Europe). AB - Due to a restriction of the distributional range of European red deer (Cervus elaphus L.) during the Quaternary and subsequent recolonization of Europe from different refugia, a clear phylogeographical pattern in genetic structure has been revealed using mitochondrial DNA markers. In Central Europe, 2 distinct, eastern and western, lineages of European red deer are present; however, admixture between them has not yet been studied in detail. We used mitochondrial DNA (control region and cytochrome b gene) sequences and 22 microsatellite loci from 522 individuals to investigate the genetic diversity of red deer in what might be expected to be an intermediate zone. We discovered a high number of unique mtDNA haplotypes belonging to each lineage and high levels of genetic diversity (cyt b H = 0.867, D-loop H = 0.914). The same structuring of red deer populations was also revealed by microsatellite analysis, with results from both analyses thus suggesting a suture zone between the 2 lineages. Despite the fact that postglacial recolonization of Central Europe by red deer occurred more than 10000 years ago, the degree of admixture between the 2 lineages is relatively small, with only 10.8% admixed individuals detected. Direct translocations of animals by humans have slightly blurred the pattern in this region; however, this blurring was more apparent when using maternally inherited markers than nuclear markers. PMID- 25918427 TI - Functional connectivity arises from a slow rhythmic mechanism. AB - The mechanism underlying temporal correlations among blood oxygen level-dependent signals is unclear. We used oxygen polarography to better characterize oxygen fluctuations and their correlation and to gain insight into the driving mechanism. The power spectrum of local oxygen fluctuations is inversely proportional to frequency raised to a power (1/f) raised to the beta, with an additional positive band-limited component centered at 0.06 Hz. In contrast, the power of the correlated oxygen signal is band limited from ~ 0.01 Hz to 0.4 Hz with a peak at 0.06 Hz. These results suggest that there is a band-limited mechanism (or mechanisms) driving interregional oxygen correlation that is distinct from the mechanism(s) driving local (1/f) oxygen fluctuations. Candidates for driving interregional oxygen correlation include rhythmic or pseudo-oscillatory mechanisms. PMID- 25918431 TI - Stumbling towards a diagnosis. PMID- 25918432 TI - A qualitative study of the variable effects of audit and feedback in the ICU. AB - BACKGROUND: Audit and feedback is integral to performance improvement and behaviour change in the intensive care unit (ICU). However, there remain large gaps in our understanding of the social experience of audit and feedback and the mechanisms whereby it can be optimised as a quality improvement strategy in the ICU setting. METHODS: We conducted a modified grounded theory qualitative study. Seventy-two clinicians from five academic and five community ICUs in Ontario, Canada, were interviewed. Team members reviewed interview transcripts independently. Data analysis used constant comparative methods. RESULTS: Clinicians interviewed experienced audit and feedback as fragmented and variable in its effectiveness. Moreover, clinicians felt disconnected from the process. The audit process was perceived as being insufficiently transparent. Feedback was often untimely, incomplete and not actionable. Specific groups such as respiratory therapists and night-shift clinicians felt marginalised. Suggestions for improvement included improving information sharing about the rationale for change and the audit process, tools and metrics; implementing peer-to-peer quality discussions to avoid a top-down approach (eg, incorporating feedback into discussions at daily rounds); providing effective feedback which contains specific, transparent and actionable information; delivering timely feedback (ie, balancing feedback proximate to events with trends over time) and increasing engagement by senior management. CONCLUSIONS: ICU clinicians experience audit and feedback as fragmented communication with feedback being especially problematic. Attention to improving communication, integration of the process into daily clinical activities and making feedback timely, specific and actionable may increase the effectiveness of audit and feedback to affect desired change. PMID- 25918434 TI - Multiple-embryo transfer for studying very early maternal-embryo interactions in cattle. AB - In the present paper, we highlight the need to study very early maternal-embryo interactions and discuss how these interactions can be addressed. Bovine species normally carry one or, less frequently, two embryos to term; there are very rare cases of triplets or higher-order multiple pregnancies in which all the offspring are born alive. Multiple-embryo transfer (MET) in cattle allows for the detection of endometrial responses in scenarios where single-embryo transfer would not. Although MET is non-physiological, the present study shows that at the very early embryonic stages, a uterus carrying zona-enclosed embryos does not exhibit non physiological reactions. On the contrary, MET should be considered the sum of multiple individual effects triggered by developing embryos. We provide arguments to support our hypothesis that describe a rationale for current work with MET, and we discuss alternative hypotheses. Using cattle as a model, we describe how technical approaches to analyzing zona-enclosed early embryo-maternal interactions (i.e., transcriptomics, proteomics, and endometrial cell culture) can help identify molecular changes that may be difficult to observe when only a single embryo is present. We conclude that MET can be used for studying very early maternal-embryo interactions in vivo in monotocous species. Free Spanish abstract: A Spanish translation of this abstract is freely available at http://www.reproduction-online.org/content/150/2/R35/suppl/DC1. PMID- 25918435 TI - Expression and effect of NAMPT (visfatin) on progesterone secretion in hen granulosa cells. AB - In mammals, nicotinamide phosphoribosyltransferase (NAMPT) is an adipokine produced by adipose tissue that is found in intracellular and extracellular compartments. The intracellular form of NAMPT is a nicotinamide phosphoribosyltransferase, whereas the extracellular form is considered an adipokine. In humans, NAMPT regulates energy metabolism and reproductive functions, such as ovarian steroidogenesis. To date, no study has investigated the role of NAMPT in hen ovaries. We investigated whether NAMPT is present in hen ovarian follicles and its role in granulosa cells. Using RT-PCR, western blotting and immunocytochemistry, we detected mRNA transcripts and proteins related to NAMPT in theca and granulosa cells from pre-ovulatory follicles. Using RT-PCR, we demonstrated that mRNA NAMPT levels were higher in granulosa cells than they were in theca cells and that during follicle development, theca cell levels decreased, whereas levels remained unchanged in granulosa cells. NAMPT protein quantities were significantly higher in theca cells than they were in granulosa cells, but they were unchanged during follicular development. Plasma NAMPT levels, as determined by ELISA and immunoblotting, were significantly lower in adult hens than they were in juveniles. In vitro, treatment with human recombinant NAMPT (100 ng/ml, 48 h) halved basal and IGF1-induced progesterone secretion, and this was associated with a reduction in STAR and HSD3B protein levels and MAPK3/1 phosphorylation levels in granulosa cells. These effects were abolished by the addition of FK866, a specific inhibitor of NAMPT enzymatic activity. Moreover, NAMPT had no effect on granulosa cell proliferation. In conclusion, NAMPT is present in hen ovarian cells and inhibits progesterone production in granulosa cells. PMID- 25918436 TI - Histone methyltransferase Smyd3 regulates early embryonic lineage commitment in mice. AB - SET and MYND domain-containing protein 3 (Smyd3) is a histone H3 lysine 4 (H3K4) di- and tri-methyltransferase that forms a transcriptional complex with RNA polymerase II and activates the transcription of oncogenes and cell cycle genes in human cancer cells. However, the study of Smyd3 in mammalian early embryonic development has not yet been addressed. In the present study, we investigated the expression pattern of Smyd3 in mouse preimplantation embryos and the effects of RNA interference (RNAi)-mediated Smyd3 repression on the development of mouse embryos. We showed that Smyd3 mRNA levels increased after the two-cell stage, peaked at the four-cell stage, and gradually decreased thereafter. Moreover, in two-cell to eight-cell embryos, SMYD3 staining was more intense in the nuclei than it was in the cytoplasm. In Smyd3-knockdown embryos, the percentage of inner cell mass (ICM)-derived colony formation and trophectoderm (TE)-derived cell attachment were significantly decreased, which resulted in a reduction in the number of viable offspring. Furthermore, the expression of Oct4 and Cdx2 during mid-preimplantation gene activation was significantly decreased in Smyd3 knockdown embryos. In addition, the transcription levels of ICM and epiblast markers, such as Oct4, Nanog, and Sox2, the transcription levels of primitive endoderm markers, such as Gata6, and the transcription levels of TE markers, such as Cdx2 and Eomes, were significantly decreased in Smyd3-knockdown blastocysts. These findings indicate that SMYD3 plays an important role in early embryonic lineage commitment and peri-implantation development through the activation of lineage-specific genes. PMID- 25918437 TI - The geometric clutch at 20: stripping gears or gaining traction? AB - It has been 20 years since the geometric clutch (GC) hypothesis was first proposed. The core principle of the GC mechanism is fairly simple. When the axoneme of a eukaryotic flagellum is bent, mechanical stress generates forces transverse to the outer doublets (t-forces). These t-forces can push doublets closer together or pry them apart. The GC hypothesis asserts that changes in the inter-doublet spacing caused by t-forces are responsible for the activation and deactivation of the dynein motors, that creates the beat cycle. A series of computer models utilizing the clutch mechanism has shown that it can simulate ciliary and flagellar beating. The objective of the present review is to assess where things stand with the GC hypothesis in the clarifying light of new information. There is considerable new evidence to support the hypothesis. However, it is also clear that it is necessary to modify some of the original conceptions of the hypothesis so that it can be consistent with the results of recent experimental and ultrastructural studies. In particular, dynein deactivation by t-forces must be able to occur with dyneins that remain attached to the B-subtubule of the adjacent doublet. PMID- 25918438 TI - Ovarian cancer: involvement of the matrix metalloproteinases. AB - Ovarian cancer is the leading cause of death from gynecologic malignancies. One of the reasons for the high mortality rate associated with ovarian cancer is its late diagnosis, which often occurs after the cancer has metastasized throughout the peritoneal cavity. Cancer metastasis is facilitated by the remodeling of the extracellular tumor matrix by a family of proteolytic enzymes known as the matrix metalloproteinases (MMPs). There are 23 members of the MMP family, many of which have been reported to be associated with ovarian cancer. In the current paradigm, ovarian tumor cells and the surrounding stromal cells stimulate the synthesis and/or activation of various MMPs to aid in tumor growth, invasion, and eventual metastasis. The present review sheds light on the different MMPs in the various types of ovarian cancer and on their impact on the progression of this gynecologic malignancy. PMID- 25918439 TI - Surveillance of antibiotic resistance. AB - Surveillance involves the collection and analysis of data for the detection and monitoring of threats to public health. Surveillance should also inform as to the epidemiology of the threat and its burden in the population. A further key component of surveillance is the timely feedback of data to stakeholders with a view to generating action aimed at reducing or preventing the public health threat being monitored. Surveillance of antibiotic resistance involves the collection of antibiotic susceptibility test results undertaken by microbiology laboratories on bacteria isolated from clinical samples sent for investigation. Correlation of these data with demographic and clinical data for the patient populations from whom the pathogens were isolated gives insight into the underlying epidemiology and facilitates the formulation of rational interventions aimed at reducing the burden of resistance. This article describes a range of surveillance activities that have been undertaken in the UK over a number of years, together with current interventions being implemented. These activities are not only of national importance but form part of the international response to the global threat posed by antibiotic resistance. PMID- 25918440 TI - Tackling the threat of antimicrobial resistance: from policy to sustainable action. AB - Antibiotics underpin all of modern medicine, from routine major surgery through to caesarean sections and modern cancer therapies. These drugs have revolutionized how we practice medicine, but we are in a constant evolutionary battle to evade microbial resistance and this has become a major global public health problem. We have overused and misused these essential medicines both in the human and animal health sectors and this threatens the effectiveness of antimicrobials for future generations. We can only address the threat of antimicrobial resistance (AMR) through international collaboration across human and animal health sectors integrating social, economic and behavioural factors. Our global organizations are rising to the challenge with the recent World Health Assembly resolution on AMR and development of the Global Action plan but we must act now to avoid a return to a pre-antibiotic era. PMID- 25918441 TI - Antimicrobial resistance in humans, livestock and the wider environment. AB - Antimicrobial resistance (AMR) in humans is inter-linked with AMR in other populations, especially farm animals, and in the wider environment. The relatively few bacterial species that cause disease in humans, and are the targets of antibiotic treatment, constitute a tiny subset of the overall diversity of bacteria that includes the gut microbiota and vast numbers in the soil. However, resistance can pass between these different populations; and homologous resistance genes have been found in pathogens, normal flora and soil bacteria. Farm animals are an important component of this complex system: they are exposed to enormous quantities of antibiotics (despite attempts at reduction) and act as another reservoir of resistance genes. Whole genome sequencing is revealing and beginning to quantify the two-way traffic of AMR bacteria between the farm and the clinic. Surveillance of bacterial disease, drug usage and resistance in livestock is still relatively poor, though improving, but achieving better antimicrobial stewardship on the farm is challenging: antibiotics are an integral part of industrial agriculture and there are very few alternatives. Human production and use of antibiotics either on the farm or in the clinic is but a recent addition to the natural and ancient process of antibiotic production and resistance evolution that occurs on a global scale in the soil. Viewed in this way, AMR is somewhat analogous to climate change, and that suggests that an intergovernmental panel, akin to the Intergovernmental Panel on Climate Change, could be an appropriate vehicle to actively address the problem. PMID- 25918442 TI - The livestock reservoir for antimicrobial resistance: a personal view on changing patterns of risks, effects of interventions and the way forward. AB - The purpose of this review was to provide an updated overview on the use of antimicrobial agents in livestock, the associated problems for humans and current knowledge on the effects of reducing resistance in the livestock reservoir on both human health and animal production. There is still limiting data on both use of antimicrobial agents, occurrence and spread of resistance as well as impact on human health. However, in recent years, emerging issues related to methicillin resistant Staphylococcus aureus, Clostridium difficile, Escherichia coli and horizontally transferred genes indicates that the livestock reservoir has a more significant impact on human health than was estimated 10 years ago, where the focus was mainly on resistance in Campylobacter and Salmonella. Studies have indicated that there might only be a marginal if any benefit from the regular use of antibiotics and have shown that it is possible to substantially reduce the use of antimicrobial agents in livestock production without compromising animal welfare or health or production. In some cases, this should be done in combination with other measures such as biosecurity and use of vaccines. To enable better studies on both the global burden and the effect of interventions, there is a need for global harmonized integrated and continuous surveillance of antimicrobial usage and antimicrobial resistance, preferably associated with data on production and animal diseases to determine the positive and negative impact of reducing antimicrobial use in livestock. PMID- 25918443 TI - Time for a change: addressing R&D and commercialization challenges for antibacterials. AB - The antibacterial therapeutic area has been described as the perfect storm. Resistance is increasing to the point that our hospitals encounter patients infected with untreatable pathogens, the overall industry pipeline is described as dry and most multinational pharmaceutical companies have withdrawn from the area. Major contributing factors to the declining antibacterial industry pipeline include scientific challenges, clinical/regulatory hurdles and low return on investment. This paper examines these challenges and proposes approaches to address them. There is a need for a broader scientific agenda to explore new approaches to discover and develop antibacterial agents. Additionally, ideas of how industry and academia could be better integrated will be presented. While promising progress in the regulatory environment has been made, more streamlined regulatory paths are still required and the solutions will lie in global harmonization and clearly defined guidance. Creating the right incentives for antibacterial research and development is critical and a new commercial model for antibacterial agents will be proposed. One key solution to help resolve both the problem of antimicrobial resistance (AMR) and lack of new drug development are rapid, cost-effective, accurate point of care diagnostics that will transform antibacterial prescribing and enable more cost-effective and efficient antibacterial clinical trials. The challenges of AMR are too great for any one group to resolve and success will require leadership and partnerships among academia, industry and governments globally. PMID- 25918445 TI - Antimicrobial resistance: addressing the threat to global health. Preface. PMID- 25918444 TI - The human gut resistome. AB - In recent decades, the emergence and spread of antibiotic resistance among bacterial pathogens has become a major threat to public health. Bacteria can acquire antibiotic resistance genes by the mobilization and transfer of resistance genes from a donor strain. The human gut contains a densely populated microbial ecosystem, termed the gut microbiota, which offers ample opportunities for the horizontal transfer of genetic material, including antibiotic resistance genes. Recent technological advances allow microbiota-wide studies into the diversity and dynamics of the antibiotic resistance genes that are harboured by the gut microbiota ('the gut resistome'). Genes conferring resistance to antibiotics are ubiquitously present among the gut microbiota of humans and most resistance genes are harboured by strictly anaerobic gut commensals. The horizontal transfer of genetic material, including antibiotic resistance genes, through conjugation and transduction is a frequent event in the gut microbiota, but mostly involves non-pathogenic gut commensals as these dominate the microbiota of healthy individuals. Resistance gene transfer from commensals to gut-dwelling opportunistic pathogens appears to be a relatively rare event but may contribute to the emergence of multi-drug resistant strains, as is illustrated by the vancomycin resistance determinants that are shared by anaerobic gut commensals and the nosocomial pathogen Enterococcus faecium. PMID- 25918446 TI - How could preventive therapy affect the prevalence of drug resistance? Causes and consequences. AB - Various forms of preventive and prophylactic antimicrobial therapies have been proposed to combat HIV (e.g. pre-exposure prophylaxis), tuberculosis (e.g. isoniazid preventive therapy) and malaria (e.g. intermittent preventive treatment). However, the potential population-level effects of preventative therapy (PT) on the prevalence of drug resistance are not well understood. PT can directly affect the rate at which resistance is acquired among those receiving PT. It can also indirectly affect resistance by altering the rate at which resistance is acquired through treatment for active disease and by modifying the level of competition between transmission of drug-resistant and drug-sensitive pathogens. We propose a general mathematical model to explore the ways in which PT can affect the long-term prevalence of drug resistance. Depending on the relative contributions of these three mechanisms, we find that increasing the level of coverage of PT may result in increases, decreases or non-monotonic changes in the overall prevalence of drug resistance. These results demonstrate the complexity of the relationship between PT and drug resistance in the population. Care should be taken when predicting population-level changes in drug resistance from small pilot studies of PT or estimates based solely on its direct effects. PMID- 25918447 TI - Carriage burden, multiple colonization and antibiotic pressure promote emergence of resistant vaccine escape pneumococci. AB - Pneumococcal conjugate vaccines target the limited subset of the more than 90 known serotypes of Streptococcus pneumoniae responsible for the greatest burden of pneumococcal disease and antibiotic resistance. Following the introduction of these vaccines, serotypes not targeted were able to expand and resistance became more common within these types. Here we use a stochastic dynamic model of pediatric pneumococcal carriage to evaluate potential influences on the emergence of new resistant lineages following the introduction of a vaccine targeting more common resistant types. Antibiotic pressure was the strongest driver, with no emergence at low levels and universal emergence at high levels. At intermediate levels of antibiotic pressure, higher carriage burden and a greater degree of dual carriage promoted emergence. This may have implications for current plans to introduce childhood pneumococcal vaccination in several high-burden countries. PMID- 25918449 TI - Nutrition and Cognitive Achievement: An Evaluation of the School Breakfast Program. AB - This paper investigates the impact of the School Breakfast Program (SBP) on cognitive achievement. The SBP is a federal entitlement program that offers breakfast to any student, including free breakfast for any low-income student, who attends a school that participates in the program. To increase the availability of the SBP, many states mandate that schools participate in the program if the percent of free or reduced-price eligible students in a school exceeds a specific threshold. Using the details of these mandates as a source of identifying variation, I find that the availability of the program increases student achievement. PMID- 25918450 TI - Analysis of liposome model systems by time-of-flight secondary ion mass spectrometry. AB - Time-of-flight secondary ion mass spectrometry (ToF-SIMS) is an important technique for studying chemical composition of micrometer scale objects due to its high spatial resolution imaging capabilities and chemical specificity. In this work we focus on the application of ToF-SIMS to gain insight into the chemistry of micrometer size liposomes as a potential model for neurotransmitter vesicles. Two models of giant liposomes were analyzed: histamine and aqueous two phase system (ATPS)-containing liposomes. Characterization of the internal structure of single fixed liposomes was done both with the Bi3+ and C60+ ion sources. The depth profiling capability of ToF-SIMS was used to investigate the liposome interior. PMID- 25918451 TI - ToF-SIMS imaging of lipids and lipid related compounds in Drosophila brain. AB - Drosophila melanogaster (fruit fly) has a relatively simple nervous system but possesses high order brain functions similar to humans. Therefore, it has been used as a common model system in biological studies, particularly drug addiction. Here, the spatial distribution of biomolecules in the brain of the fly was studied using time-of flight secondary ion mass spectrometry (ToF-SIMS). Fly brains were analyzed frozen to prevent molecular redistribution prior to analysis. Different molecules were found to distribute differently in the tissue, particularly the eye pigments, diacylglycerides, and phospholipids, and this is expected to be driven by their biological functions in the brain. Correlations in the localization of these molecules were also observed using principal components analysis of image data, and this was used to identify peaks for further analysis. Furthermore, consecutive analyses following 10 keV Ar2500+ sputtering showed that different biomolecules respond differently to Ar2500+ sputtering. Significant changes in signal intensities between consecutive analyses were observed for high mass molecules including lipids. PMID- 25918452 TI - ? AB - Recently, the phenomenon of young people not in education, employment or training (NEET) has come to the fore due to the risks associated to this situation. The contribution of this paper is in its analysis of this population's composition, dynamics, poverty patterns, individual and family characteristics, as well as projections for 2030. In addition, we propose a classification for NEET's that could be used for the design of public policies and that was used to identify that this population will tend to decreased due to the proportion of women who study and join the labor force and that, in the future, the unemployed will outnumber other groups. PMID- 25918453 TI - MicroRNA-155 hallmarks promising accuracy for the diagnosis of various carcinomas: results from a meta-analysis. AB - BACKGROUND: Recent studies have shown that microRNAs (miRNAs) have diagnostic values in various cancers. This meta-analysis seeks to summarize the global diagnostic role of miR-155 in patients with a variety of carcinomas. METHODS: Eligible studies were retrieved by searching the online databases, and the bivariate meta-analysis model was employed to generate the summary receiver operator characteristic (SROC) curve. RESULTS: A total of 17 studies dealing with various carcinomas were finally included. The results showed that single miR-155 testing allowed for the discrimination between cancer patients and healthy donors with a sensitivity of 0.82 (95% CI: 0.73-0.88) and specificity of 0.77 (95% CI: 0.70-0.83), corresponding to an area under curve (AUC) of 0.85, while a panel comprising expressions of miR-155 yielded a sensitivity of 0.76 (95% CI: 0.68 0.82) and specificity of 0.82 (95% CI: 0.77-0.86) in diagnosing cancers. The subgroup analysis displayed that serum miR-155 test harvested higher accuracy than plasma-based assay (the AUC, sensitivity, and specificity were, resp., 0.87 versus 0.73, 0.78 versus 0.74, and 0.77 versus 0.70). CONCLUSIONS: Our data suggest that single miR-155 profiling has a potential to be used as a screening test for various carcinomas, and parallel testing of miR-155 confers an improved specificity compared to single miR-155 analysis. PMID- 25918454 TI - Assessment of glomerular filtration rate based on alterations of serum brain derived neurotrophic factor in type 2 diabetic subjects treated with amlodipine/benazepril or valsartan/hydrochlorothiazide. AB - BACKGROUND: Brain-derived neurotrophic factor (BDNF) is associated with sympathetic activation. However, the effects of BDNF on diabetic nephropathy are unknown. The aim of this study was to assess the estimated glomerular filtration rates (eGFRs) and changes in serum BDNF levels in type 2 diabetic subjects treated with antihypertensive medications. METHODS: In this randomized, double blind clinical trial, type 2 diabetic subjects with hypertension were assigned to either the benazepril/amlodipine or valsartan/hydrochlorothiazide treatment groups for a 16-week period. The post hoc analyses were based on increased or decreased serum BDNF levels. RESULTS: Of the 153 enrolled subjects, the changes in eGFR were significantly and inversely correlated with those in BDNF in the 76 subjects treated with valsartan/hydrochlorothiazide (r = -0.264, P = 0.021) but not in the 77 subjects treated with benazepril/amlodipine (r = -0.025, P = 0.862). The 45 subjects with increased BDNF following valsartan/hydrochlorothiazide treatment exhibited a significantly reduced eGFR ( 8.8 +/- 14.9 mL/min/1.73 m(2); P < 0.001). Multivariate regression analysis revealed that increased serum BDNF represents an independent factor for reduced eGFR (95% confidence interval between -0.887 and -0.076, P = 0.020). CONCLUSIONS: Increased serum BDNF is associated with reduced eGFR in type 2 diabetic subjects treated with valsartan/hydrochlorothiazide but not with amlodipine/benazepril. PMID- 25918455 TI - The changing spectrum of surgically treated cystic neoplasms of the pancreas. AB - Introduction. While the incidence of pancreatic cystic lesions has steadily increased, we sought to evaluate the changes in their surgical management. Methods. Patients with pancreatic cystic lesions who underwent surgical resection from 2003 to 2013 were identified. Clinicopathologic factors were analyzed and compared to a similar cohort from 1992 to 2002. Results. There were 134 patients with pancreatic cystic lesions who underwent surgical resection from 2003 to 2013, compared to 73 from 1992 to 2002. The most common preoperative imaging was a CT scan, although 66% underwent EUS and 63% underwent biopsy. Pathology included 18 serous, 47 mucinous, 11 pseudopapillary, and 58 intraductal papillary mucinous neoplasms (IPMN). In comparing cohorts, there were significantly fewer serous lesions and more IPMN. Postoperative complication rates were similar, and perioperative mortality rates were comparable. Conclusion. There has been a dramatic change in surgically treated pancreatic cystic tumors over the past two decades. Our data suggests that the incorporation of new imaging and diagnostic tests has led to greater detection of cystic tumors and a decreased rate of potentially unnecessary resections. Therefore, all patients with cystic pancreatic lesions should undergo a focused CT-pancreas, and an EUS biopsy should be considered, in order to best select those that would benefit from surgical resection. PMID- 25918458 TI - Non-communicable eye diseases: facing the future. PMID- 25918456 TI - "Forget to whom you have told this proverb": directed forgetting of destination memory in Alzheimer's disease. AB - Destination memory is the ability to remember the receiver of transmitted information. By means of a destination memory directed forgetting task, we investigated whether participants with Alzheimer's Disease (AD) were able to suppress irrelevant information in destination memory. Twenty-six AD participants and 30 healthy elderly subjects were asked to tell 10 different proverbs to 10 different celebrities (List 1). Afterwards, half of the participants were instructed to forget the destinations (i.e., the celebrities) whereas the other half were asked to keep them in mind. After telling 10 other proverbs to 10 other celebrities (List 2), participants were asked to read numbers aloud. Subsequently, all the participants were asked to remember the destinations of List 1 and List 2, regardless of the forget or remember instructions. The results show similar destination memory in AD participants who were asked to forget the destinations of List 1 and those who were asked to retain them. These findings are attributed to inhibitory deficits, by which AD participants have difficulties to suppress irrelevant information in destination memory. PMID- 25918457 TI - The motor recovery related with brain lesion in patients with intracranial hemorrhage. AB - Although studies have demonstrated that several specific brain lesions are related to the severity of functional outcomes, the effects of specific brain lesions are not yet clear. This study investigated the effects of hemorrhagic stroke lesions on motor recovery. Eleven subjects with hemorrhagic stroke were assessed. Using the Fugl-Meyer Assessment and functional ambulation category, clinical motor and sensory impairments were tested four times in total: initially within 2 weeks and 1, 3, and 6 months after the onset of stroke. Brain lesions and size were evaluated using MRIcron, SPM8, and Talairach Daemon software. Trunk control, motor function in the lower limbs, and sensory function improved significantly within 3 months, after which the change was no longer significant. Upper limb function and gait were unchanged within 1 month but improved significantly 3 months after onset and continued to improve for 6 months. Involvement of the anterior putamen, internal capsule, thalamus, periventricular white matter, and premotor cortex was related to poor upper limb recovery in patients with hemorrhagic stroke. These results should be useful for planning rehabilitation strategies and understanding the prognosis of hemorrhagic stroke. PMID- 25918459 TI - Anti-VEGF drugs in the prevention of blindness. PMID- 25918460 TI - Use of anti-VEGF drugs at the Instituto de la Vision de Montemorelos. PMID- 25918462 TI - Intravitreal injection technique. PMID- 25918461 TI - Anti-VEGF treatment for acute ROP - not yet recommended! PMID- 25918464 TI - Age-related macular degeneration. PMID- 25918463 TI - Anti-VEGF drugs: evidence for effectiveness. PMID- 25918465 TI - Getting ready to cope with non-communicable eye diseases. PMID- 25918466 TI - 'An ideal service for glaucoma would be...'. PMID- 25918467 TI - Glaucoma care at ATBUTH Eye Clinic, Bauchi. PMID- 25918469 TI - Case study: Monitoring the quality of cataract surgery at the Presbyterian Eye Clinic Acha-Bafoussam. PMID- 25918468 TI - The value of clinical audit to improve cataract quality. PMID- 25918470 TI - How to measure blood glucose. PMID- 25918471 TI - Understanding and caring for a Schiotz tonometer. PMID- 25918472 TI - Training trichiasis surgeons: ensuring quality. PMID- 25918473 TI - Test your knowledge and understanding. PMID- 25918474 TI - Picture quiz. PMID- 25918476 TI - Free DNA in cystic fibrosis airway fluids correlates with airflow obstruction. AB - Chronic obstructive lung disease determines morbidity and mortality of patients with cystic fibrosis (CF). CF airways are characterized by a nonresolving neutrophilic inflammation. After pathogen contact or prolonged activation, neutrophils release DNA fibres decorated with antimicrobial proteins, forming neutrophil extracellular traps (NETs). NETs have been described to act in a beneficial way for innate host defense by bactericidal, fungicidal, and virucidal actions. On the other hand, excessive NET formation has been linked to the pathogenesis of autoinflammatory and autoimmune disease conditions. We quantified free DNA structures characteristic of NETs in airway fluids of CF patients and a mouse model with CF-like lung disease. Free DNA levels correlated with airflow obstruction, fungal colonization, and CXC chemokine levels in CF patients and CF like mice. When viewed in combination, our results demonstrate that neutrophilic inflammation in CF airways is associated with abundant free DNA characteristic for NETosis, and suggest that free DNA may be implicated in lung function decline in patients with CF. PMID- 25918475 TI - Neurotrauma and inflammation: CNS and PNS responses. AB - Traumatic injury to the central nervous system (CNS) or the peripheral nervous system (PNS) triggers a cascade of events which culminate in a robust inflammatory reaction. The role played by inflammation in the course of degeneration and regeneration is not completely elucidated. While, in peripheral nerves, the inflammatory response is assumed to be essential for normal progression of Wallerian degeneration and regeneration, CNS trauma inflammation is often associated with poor recovery. In this review, we discuss key mechanisms that trigger the inflammatory reaction after nervous system trauma, emphasizing how inflammations in both CNS and PNS differ from each other, in terms of magnitude, cell types involved, and effector molecules. Knowledge of the precise mechanisms that elicit and maintain inflammation after CNS and PNS tissue trauma and their effect on axon degeneration and regeneration is crucial for the identification of possible pharmacological drugs that can positively affect the tissue regenerative capacity. PMID- 25918477 TI - Gender-specific association of oxidative stress and inflammation with cardiovascular risk factors in Arab population. AB - BACKGROUND: The impact of gender difference on the association between metabolic stress and cardiovascular disease (CVD) remains unclear. We have investigated, for the first time, the gender effect on the oxidative and inflammatory stress responses and assessed their correlation with classical cardiometabolites in Arab population. METHODS: A total of 378 adult Arab participants (193 females) were enrolled in this cross-sectional study. Plasma levels of CRP, IL-6, IL-8, TNF alpha, ROS, TBARs, and PON1 were measured and correlated with anthropometric and cardiometabolite parameters of the study population. RESULTS: Compared to females, males had significantly higher FBG, HbA1c, TG, and blood pressure but lower BMI, TC, and HDL (P < 0.05). After adjustment for BMI and WC, females had higher levels of ROS, TBARS, and CRP (P < 0.001) whereas males had increased levels of IL-8, IL-6, and TNF-alpha (P < 0.05). Moreover, after adjustment for age, BMI, and gender, the levels of TNF-alpha, IL-6, and ROS were associated with central obesity but not general obesity. CONCLUSION: Inflammation and oxidative stress contribution to CVD risk in Arab population linked to gender and this risk is better reflected by central obesity. Arab females might be at risk of CVD complications due to increased oxidative stress. PMID- 25918480 TI - A comparison of material decomposition techniques for dual-energy CT colonography. AB - In recent years, dual-energy computed tomography (DECT) has been widely used in the clinical routine due to improved diagnostics capability from additional spectral information. One promising application for DECT is CT colonography (CTC) in combination with computer-aided diagnosis (CAD) for detection of lesions and polyps. While CAD has demonstrated in the past that it is able to detect small polyps, its performance is highly dependent on the quality of the input data. The presence of artifacts such as beam-hardening and noise in ultra-low-dose CTC may severely degrade detection performances of small polyps. In this work, we investigate and compare virtual monochromatic images, generated by image-based decomposition and projection-based decomposition, with respect to CAD performance. In the image-based method, reconstructed images are firstly decomposed into water and iodine before the virtual monochromatic images are calculated. On the contrary, in the projection-based method, the projection data are first decomposed before calculation of virtual monochromatic projection and reconstruction. Both material decomposition methods are evaluated with regards to the accuracy of iodine detection. Further, the performance of the virtual monochromatic images is qualitatively and quantitatively assessed. Preliminary results show that the projection-based method does not only have a more accurate detection of iodine, but also delivers virtual monochromatic images with reduced beam hardening artifacts in comparison with the image-based method. With regards to the CAD performance, the projection-based method yields an improved detection performance of polyps in comparison with that of the image-based method. PMID- 25918481 TI - Perinatal outcomes in HIV positive pregnant women with concomitant sexually transmitted infections. AB - OBJECTIVE: To evaluate whether HIV infected pregnant women with concomitant sexually transmitted infection (STIs) are at increased risk of adverse perinatal and neonatal outcomes. METHODS: We conducted a cohort study of HIV positive women who delivered at an inner-city hospital in Atlanta, Georgia, from 2003 to 2013. Demographics, presence of concomitant STIs, prenatal care information, and maternal and neonatal outcomes were collected. The outcomes examined were the association of the presence of concomitant STIs on the risk of preterm birth (PTB), postpartum hemorrhage, chorioamnionitis, preeclampsia, intrauterine growth restriction, small for gestational age, low Apgar scores, and neonatal intensive care admission. Multiple logistic regression was performed to adjust for potential confounders. RESULTS: HIV positive pregnant women with concomitant STIs had an increased risk of spontaneous PTB (odds ratio (OR) 2.11, 95% confidence interval [CI] 1.12-3.97). After adjusting for a history of preterm birth, maternal age, and low CD4+ count at prenatal care entry the association between concomitant STIs and spontaneous PTB persisted (adjusted OR 1.96, 95% CI 1.01 3.78). CONCLUSIONS: HIV infected pregnant women with concomitant STIs relative to HIV positive pregnant women without a concomitant STI are at increased risk of spontaneous PTB. PMID- 25918479 TI - Altered immunoregulation in rheumatoid arthritis: the role of regulatory T cells and proinflammatory Th17 cells and therapeutic implications. AB - In recent years several studies investigated the role of T lymphocyte subpopulations in the pathogenesis of rheumatoid arthritis (RA). Pathogenic Th17 cells mediate pannus growth, osteoclastogenesis, and synovial neoangiogenesis; hence they are key players in the development of the disease. On the other hand, regulatory T (Treg) cells are a T cell subset whose peculiar function is to suppress autoreactive lymphocytes. The imbalance between Th17 and Treg cells has been identified as a crucial event in the pathogenesis of RA. In addition, the effects of currently employed RA therapeutic strategies on these lymphocyte subpopulations have been extensively investigated. This review article aims to discuss current knowledge on Treg and Th17 cells in RA and possible implications of their therapeutic targeting in this disorder. PMID- 25918478 TI - Evasion of early antiviral responses by herpes simplex viruses. AB - Besides overcoming physical constraints, such as extreme temperatures, reduced humidity, elevated pressure, and natural predators, human pathogens further need to overcome an arsenal of antimicrobial components evolved by the host to limit infection, replication and optimally, reinfection. Herpes simplex virus-1 (HSV-1) and herpes simplex virus-2 (HSV-2) infect humans at a high frequency and persist within the host for life by establishing latency in neurons. To gain access to these cells, herpes simplex viruses (HSVs) must replicate and block immediate host antiviral responses elicited by epithelial cells and innate immune components early after infection. During these processes, infected and noninfected neighboring cells, as well as tissue-resident and patrolling immune cells, will sense viral components and cell-associated danger signals and secrete soluble mediators. While type-I interferons aim at limiting virus spread, cytokines and chemokines will modulate resident and incoming immune cells. In this paper, we discuss recent findings relative to the early steps taking place during HSV infection and replication. Further, we discuss how HSVs evade detection by host cells and the molecular mechanisms evolved by these viruses to circumvent early antiviral mechanisms, ultimately leading to neuron infection and the establishment of latency. PMID- 25918483 TI - How to write an original research paper (and get it published). PMID- 25918482 TI - Adipokine gene expression in peripheral blood of adult and juvenile dermatomyositis patients and their relation to clinical parameters and disease activity measures. AB - OBJECTIVE: Recently adipokines have been implicated in the regulation of immune and inflammatory responses in autoimmune disease. To investigate the role of adipokines in adult and pediatric patients with newly diagnosed dermatomyositis (DM), we analyzed peripheral blood and skeletal muscle gene expression of four adipokines: visfatin, leptin, adiponectin and resistin. METHODS: Peripheral blood mononuclear cells (PBMCs) were collected for 21 adult DM, 26 juvenile DM, 5 non disease adult controls, and 6 non-disease pediatric controls at two time points: baseline and 6 months. Muscle biopsies from 5 adult DM patients and 5 non-disease adult controls were collected at baseline. Similarly, muscle biopsies from 7 juvenile DM patients and 5 non-disease pediatric controls were collected at baseline. The gene expression levels of leptin, adiponectin, resistin, visfatin and related inflammatory cytokines, IL-6, TNF- alpha, and housekeeping genes GAPDH, B2M, and ACTB were generated using a custom RT(2) Profiler PCR Array. RESULTS: Visfatin gene expression levels in peripheral blood were significantly higher in newly diagnosed adult DM cases compared to non-disease controls (P = 0.004) and these levels correlated with baseline clinical parameters such as age (r = 0.34, P = 0.020), male sex (r = -0.35, P = 0.017), prednisone use (r = 0.42, P = 0.006), and DMARD use (r = 0.35, P = 0.025). No significant association was found between change in visfatin gene expression levels and change in disease activity measures. While visfatin gene expression was significantly up-regulated in muscle tissue of juvenile DM patients (P = 0.028), in adult DM patients only a trend towards significance was observed (P = 0.08). Also, muscle gene expression levels of resistin were significantly elevated in both adult and juvenile DM patients compared respectively to non-disease adult and pediatric controls. Furthermore, an association between peripheral blood resistin gene expression and DM disease activity, including global, muscle, and extra-skeletal disease activity was also observed. CONCLUSION: Peripheral blood visfatin gene expression and muscle resistin gene expression are significantly increased in newly diagnosed adult DM patients. Further longitudinal studies should explore the possibility of using gene expression levels of adipokines such as visfatin and resistin as novel clinical diagnostic biomarkers in DM. PMID- 25918484 TI - Flipping the classroom to teach systematic reviews: the development of a continuing education course for librarians. AB - OBJECTIVE: The researchers used the flipped classroom model to develop and conduct a systematic review course for librarians. SETTING: The research took place at an academic health sciences library. METHOD: A team of informationists developed and conducted a pilot course. Assessment informed changes to both course components; a second course addressed gaps in the pilot. MAIN RESULTS: Both the pilot and subsequent course received positive reviews. Changes based on assessment data will inform future iterations. CONCLUSION: The flipped classroom model can be successful in developing and implementing a course that is well rated by students. PMID- 25918485 TI - Benchmarking participation of Canadian university health sciences librarians in systematic reviews. AB - This study describes the current state of Canadian university health sciences librarians' knowledge about, training needs for, and barriers to participating in systematic reviews (SRs). A convenience sample of Canadian librarians was surveyed. Over half of the librarians who had participated in SRs acknowledged participating in a traditional librarian role (e.g., search strategy developer); less than half indicated participating in any one nontraditional librarian role (e.g., data extractor). Lack of time and insufficient training were the most frequently reported barriers to participating in SRs. The findings provide a benchmark for tracking changes in Canadian university health sciences librarians' participation in SRs. PMID- 25918486 TI - Lessons learned from ten years of distance learning outreach. AB - OBJECTIVE: The study tested the efficacy of providing distance learning with real time videoconferencing to broaden high school student knowledge of health careers. METHODS: A pilot program was tried out and extended over ten years to include other schools in four different time zones and the National Library of Medicine. Survey results, site visits, and continued school participation were used as effectiveness indicators. Student ratings, site visits, and ongoing discussions were used to evaluate critical factors in the program. RESULTS: Nine program factors contributed to success. CONCLUSIONS: Synchronous communication can be effective for outreach to special populations given appropriate infrastructure, technology, program design, and implementation. PMID- 25918487 TI - Harnessing health information to foster disadvantaged teens' community engagement, leadership skills, and career plans: a qualitative evaluation of the Teen Health Leadership Program. AB - This paper describes a qualitative evaluation of a small-scale program aiming to improve health information literacy, leadership skills, and interest in health careers among high school students in a low-income, primarily minority community. Graduates participated in semi-structured interviews, transcripts of which were coded with a combination of objectives-driven and data-driven categories. The program had a positive impact on the participants' health information competency, leadership skills, academic orientation, and interest in health careers. Program enablers included a supportive network of adults, novel experiences, and strong mentorship. The study suggests that health information can provide a powerful context for enabling disadvantaged students' community engagement and academic success. PMID- 25918488 TI - Health sciences librarians, patient contact, and secondary traumatic stress. AB - OBJECTIVE: The purpose of this study was to determine the prevalence of secondary traumatic stress (STS) in health sciences librarians (HSLs) who have direct contact with traumatized individuals and their families. METHODS: A twenty-five item survey and the Secondary Traumatic Stress Scale (STSS) were distributed via email to three Medical Library Association email discussion lists. RESULTS: A total of fifty-five HSLs responded to the survey. Survey results indicate moderate levels of STS and variability of symptoms among participants. CONCLUSIONS: Library and employee assistance program managers should be aware of the emotional toll of patient and/or family contact for HSLs. PMID- 25918489 TI - Librarian readiness for research partnerships. AB - This study investigated health sciences librarians' knowledge and skill-based readiness to partner on sponsored research involving human participants. The authors developed and deployed, at two time points, a web-based survey on nine indicators of research activities with response choices reflecting the transtheoretical model of stages of behavior change. Librarians with research experience or membership in the Medical Library Association Research Section reported higher levels of having completed indicators. Our results suggest that creating awareness in precontemplation responders could encourage skill development. Mentoring and continuing education could support librarians who are contemplating or preparing to perform indicator activities. PMID- 25918490 TI - Knowledge translation status and barriers. PMID- 25918491 TI - An innovative model of evidence-based practice for other professions. PMID- 25918492 TI - The health sciences librarian as scientific entertainer. PMID- 25918493 TI - A tale of a dentist and his books: classic dental books in the Becker Medical Library. PMID- 25918494 TI - Numerical experiments on evaporation and explosive boiling of ultra-thin liquid argon film on aluminum nanostructure substrate. AB - Evaporation and explosive boiling of ultra-thin liquid film are of great significant fundamental importance for both science and engineering applications. The evaporation and explosive boiling of ultra-thin liquid film absorbed on an aluminum nanostructure solid wall are investigated by means of molecular dynamics simulations. The simulated system consists of three regions: liquid argon, vapor argon, and an aluminum substrate decorated with nanostructures of different heights. Those simulations begin with an initial configuration for the complex liquid-vapor-solid system, followed by an equilibrating system at 90 K, and conclude with two different jump temperatures, including 150 and 310 K which are far beyond the critical temperature. The space and time dependences of temperature, pressure, density number, and net evaporation rate are monitored to investigate the phase transition process on a flat surface with and without nanostructures. The simulation results reveal that the nanostructures are of great help to raise the heat transfer efficiency and that evaporation rate increases with the nanostructures' height in a certain range. PMID- 25918495 TI - Novel hollow alpha-Fe2O3 nanofibers via electrospinning for dye adsorption. AB - Nanomaterials such as iron oxides and ferrites have been intensively investigated for water treatment and environmental remediation applications. In this work, hollow alpha-Fe2O3 nanofibers made of rice-like nanorods were successfully synthesized via a simple hydrothermal reaction on polyvinyl alcohol (PVA) nanofiber template followed by calcination. The crystallographic structure and the morphology of the as-prepared alpha-Fe2O3 nanofibers were characterized by X ray diffraction, energy dispersive X-ray spectrometer, and scanning electron microscope. Batch adsorption experiments were conducted, and ultraviolet-visible spectra were recorded before and after the adsorption to investigate the dye adsorption performance. The results showed that hollow alpha-Fe2O3 fiber assembles exhibited good magnetic responsive performance, as well as efficient adsorption for methyl orange in water. This work provided a versatile strategy for further design and development of functional nanofiber-nanoparticle composites towards various applications. PMID- 25918496 TI - Active site formation mechanism of carbon-based oxygen reduction catalysts derived from a hyperbranched iron phthalocyanine polymer. AB - Carbon-based cathode catalysts derived from a hyperbranched iron phthalocyanine polymer (HB-FePc) were characterized, and their active-site formation mechanism was studied by synchrotron-based spectroscopy. The properties of the HB-FePc catalyst are compared with those of a catalyst with high oxygen reduction reaction (ORR) activity synthesized from a mixture of iron phthalocyanine and phenolic resin (FePc/PhRs). Electrochemical measurements demonstrate that the HB FePc catalyst does not lose its ORR activity up to 900 degrees C, whereas that of the FePc/PhRs catalyst decreases above 700 degrees C. Hard X-ray photoemission spectra reveal that the HB-FePc catalysts retain more nitrogen components than the FePc/PhRs catalysts between pyrolysis temperatures of 600 degrees C and 800 degrees C. This is because the linked structure of the HB-FePc precursor has high thermostability against nitrogen desorption. Consequently, effective doping of active nitrogen species into the sp (2) carbon network of the HB-FePc catalysts may occur up to 900 degrees C. PMID- 25918497 TI - Family members of older persons with multi-morbidity and their experiences of case managers in Sweden: an interpretive phenomenological approach. AB - BACKGROUND: Family members of older persons (75+) with multi-morbidity are likely to benefit from utilising case management services performed by case managers. However, research has not yet explored their experiences of case managers. OBJECTIVES: The aim of the study was to deepen the understanding of the importance of case managers to family members of older persons (75+) with multi morbidity. DESIGN: The study design was based on an interpretive phenomenological approach. METHOD: Data were collected through individual interviews with 16 family members in Sweden. The interviews were analysed by means of an interpretive phenomenological approach. RESULTS: The findings revealed one overarching theme: "Helps to fulfil my unmet needs", based on three sub-themes: (1) "Helps me feel secure - Experiencing a trusting relationship", (2) "Confirms and strengthens me - Challenging my sense of being alone" and (3) "Being my personal guide - Increasing my competence". CONCLUSION AND DISCUSSION: The findings indicate that case managers were able to fulfil unmet needs of family members. The latter recognised the importance of case managers providing them with professional services tailored to their individual needs. The findings can contribute to the improvement of case management models not only for older persons but also for their family members. PMID- 25918498 TI - Energy metabolism and behavior in the corticotropin-releasing factor family of peptides. PMID- 25918499 TI - Acetylcholine release in mouse hippocampal CA1 preferentially activates inhibitory-selective interneurons via alpha4beta2* nicotinic receptor activation. AB - Acetylcholine (ACh) release onto nicotinic receptors directly activates subsets of inhibitory interneurons in hippocampal CA1. However, the specific interneurons activated and their effect on the hippocampal network is not completely understood. Therefore, we investigated subsets of hippocampal CA1 interneurons that respond to ACh release through the activation of nicotinic receptors and the potential downstream effects this may have on hippocampal CA1 network function. ACh was optogenetically released in mouse hippocampal slices by expressing the excitatory optogenetic protein oChIEF-tdTomato in medial septum/diagonal band of Broca cholinergic neurons using Cre recombinase-dependent adeno-associated viral mediated transfection. The actions of optogenetically released ACh were assessed on both pyramidal neurons and different interneuron subtypes via whole cell patch clamp methods. Vasoactive intestinal peptide (VIP)-expressing interneurons that selectively innervate other interneurons (VIP/IS) were excited by ACh through the activation of nicotinic receptors containing alpha4 and beta2 subunits (alpha4beta2*). ACh release onto VIP/IS was presynaptically inhibited by M2 muscarinic autoreceptors. ACh release produced spontaneous inhibitory postsynaptic current (sIPSC) barrages blocked by dihydro-beta-erythroidine in interneurons but not pyramidal neurons. Optogenetic suppression of VIP interneurons did not inhibit these sIPSC barrages suggesting other interneuron selective interneurons were also excited by alpha4beta2* nicotinic receptor activation. In contrast, interneurons that innervate pyramidal neuron perisomatic regions were not activated by ACh release onto nicotinic receptors. Therefore, we propose ACh release in CA1 facilitates disinhibition through activation of alpha4beta2* nicotinic receptors on interneuron-selective interneurons whereas interneurons that innervate pyramidal neurons are less affected by nicotinic receptor activation. PMID- 25918500 TI - Duration of Purkinje cell complex spikes increases with their firing frequency. AB - Climbing fiber (CF) triggered complex spikes (CS) are massive depolarization bursts in the cerebellar Purkinje cell (PC), showing several high frequency spikelet components (+/-600 Hz). Since its early observations, the CS is known to vary in shape. In this study we describe CS waveforms, extracellularly recorded in awake primates (Macaca mulatta) performing saccades. Every PC analyzed showed a range of CS shapes with profoundly different duration and number of spikelets. The initial part of the CS was rather constant but the later part differed greatly, with a pronounced jitter of the last spikelets causing a large variation in total CS duration. Waveforms did not effect the following pause duration in the simple spike (SS) train, nor were SS firing rates predictive of the waveform shapes or vice versa. The waveforms did not differ between experimental conditions nor was there a preferred sequential order of CS shapes throughout the recordings. Instead, part of their variability, the timing jitter of the CS's last spikelets, strongly correlated with interval length to the preceding CS: shorter CS intervals resulted in later appearance of the last spikelets in the CS burst, and vice versa. A similar phenomenon was observed in rat PCs recorded in vitro upon repeated extracellular stimulation of CFs at different frequencies in slice experiments. All together these results strongly suggest that the variability in the timing of the last spikelet is due to CS frequency dependent changes in PC excitability. PMID- 25918502 TI - Blocking NMDA-receptors in the pigeon's "prefrontal" caudal nidopallium impairs appetitive extinction learning in a sign-tracking paradigm. AB - Extinction learning provides the ability to flexibly adapt to new contingencies by learning to inhibit previously acquired associations in a context-dependent manner. The neural networks underlying extinction learning were mostly studied in rodents using fear extinction paradigms. To uncover invariant properties of the neural basis of extinction learning, we employ pigeons as a model system. Since the prefrontal cortex (PFC) of mammals is a key structure for extinction learning, we assessed the role of N-methyl-D-aspartate receptors (NMDARs) in the nidopallium caudolaterale (NCL), the avian functional equivalent of mammalian PFC. Since NMDARs in PFC have been shown to be relevant for extinction learning, we locally antagonized NMDARs through 2-Amino-5-phosphonovalerianacid (APV) during extinction learning in a within-subject sign-tracking ABA-renewal paradigm. APV-injection slowed down extinction learning and in addition also caused a disinhibition of responding to a continuously reinforced control stimulus. In subsequent retrieval sessions, spontaneous recovery was increased while ABA renewal was unaffected. The effect of APV resembles that observed in studies of fear extinction with rodents, suggesting common neural substrates of extinction under both appetitive and aversive conditions and highlighting the similarity of mammalian PFC and the avian caudal nidopallium despite 300 million years of independent evolution. PMID- 25918503 TI - Does predictability matter? Effects of cue predictability on neurocognitive mechanisms underlying prospective memory. AB - Prospective memory (PM) represents the ability to successfully realize intentions when the appropriate moment or cue occurs. In this study, we used event-related potentials (ERPs) to explore the impact of cue predictability on the cognitive and neural mechanisms supporting PM. Participants performed an ongoing task and, simultaneously, had to remember to execute a pre-specified action when they encountered the PM cues. The occurrence of the PM cues was predictable (being signaled by a warning cue) for some participants and was completely unpredictable for others. In the predictable cue condition, the behavioral and ERP correlates of strategic monitoring were observed mainly in the ongoing trials wherein the PM cue was expected. In the unpredictable cue condition they were instead shown throughout the whole PM block. This pattern of results suggests that, in the predictable cue condition, participants engaged monitoring only when subjected to a context wherein the PM cue was expected, and disengaged monitoring when the PM cue was not expected. Conversely, participants in the unpredictable cue condition distributed their resources for strategic monitoring in more continuous manner. The findings of this study support the most recent views-the "Dynamic Multiprocess Framework" and the "Attention to Delayed Intention" (AtoDI) model confirming that strategic monitoring is a flexible mechanism that is recruited mainly when a PM cue is expected and that may interact with bottom-up spontaneous processes. PMID- 25918504 TI - Mishaps, errors, and cognitive experiences: on the conceptualization of perceptual illusions. AB - Although a visual illusion is often viewed as an amusing trick, for the vision scientist it is a question that demands an answer, which leads to even more questioning. All researchers hold their own chain of questions, the links of which depend on the very theory they adhere to. Perceptual theories are devoted to answering questions concerning sensation and perception, but in doing so they shape concepts such as reality and representation, which necessarily affect the concept of illusion. Here we consider the macroscopic aspects of such concepts in vision sciences from three classic viewpoints-Ecological, Cognitive, Gestalt approaches-as we see this a starting point to understand in which terms illusions can become a tool in the hand of the neuroscientist. In fact, illusions can be effective tools in studying the brain in reference to perception and also to cognition in a much broader sense. A theoretical debate is, however, mandatory, in particular with regards to concepts such as veridicality and representation. Whether a perceptual outcome is considered as veridical or illusory (and, consequently, whether a class of phenomena should be classified as perceptual illusions or not) depends on the meaning of such concepts. PMID- 25918506 TI - DSMs and the Brazilian psychiatric reform. PMID- 25918507 TI - Losing track of time through delayed body representations. AB - The ability to keep track of time is perceived as crucial in most human societies. However, to lose track of time may also serve an important social role, associated with recreational purpose. To this end a number of social technologies are employed, some of which may relate to a manipulation of time perception through a modulation of body representation. Here, we investigated an influence of real-time or delayed videos of own-body representations on time perception in an experimental setup with virtual mirrors. Seventy participants were asked to either stay in the installation until they thought that a defined time (90 s) had passed, or they were encouraged to stay in the installation as long as they wanted and after exiting were asked to estimate the duration of their stay. Results show that a modulation of body representation by time-delayed representations of the mirror-video displays influenced time perception. Furthermore, these time-delayed conditions were associated with a greater sense of arousal and intoxication. We suggest that feeding in references to the immediate past into working memory could be the underlying mental mechanism mediating the observed modulation of time perception. We argue that such an influence on time perception would probably not only be achieved visually, but might also work with acoustic references to the immediate past (e.g., with music). PMID- 25918505 TI - Structures and functions of insect arylalkylamine N-acetyltransferase (iaaNAT); a key enzyme for physiological and behavioral switch in arthropods. AB - The evolution of N-acetyltransfeases (NATs) seems complex. Vertebrate arylalkylamine N-acetyltransferase (aaNAT) has been extensively studied since it leads to the synthesis of melatonin, a multifunctional neurohormone prevalent in photoreceptor cells, and is known as a chemical token of the night. Melatonin also serves as a scavenger for reactive oxygen species. This is also true with invertebrates. NAT therefore has distinct functional implications in circadian function, as timezymes (aaNAT), and also xenobiotic reactions (arylamine NAT or simply NAT). NATs belong to a broader enzyme group, the GCN5-related N acetyltransferase superfamily. Due to low sequence homology and a seemingly fast rate of structural differentiation, the nomenclature for NATs can be confusing. The advent of bioinformatics, however, has helped to classify this group of enzymes; vertebrates have two distinct subgroups, the timezyme type and the xenobiotic type, which has a wider substrate range including imidazolamine, pharmacological drugs, environmental toxicants and even histone. Insect aaNAT (iaaNAT) form their own clade in the phylogeny, distinct from vertebrate aaNATs. Arthropods are unique, since the phylum has exoskeleton in which quinones derived from N-acetylated monoamines function in coupling chitin and arthropodins. Monoamine oxidase (MAO) activity is limited in insects, but NAT-mediated degradation prevails. However, unexpectedly iaaNAT occurs not only among arthropods but also among basal deuterostomia, and is therefore more apomorphic. Our analyses illustrate that iaaNATs has unique physiological roles but at the same time it plays a role in a timezyme function, at least in photoperiodism. Photoperiodism has been considered as a function of circadian system but the detailed molecular mechanism is not well understood. We propose a molecular hypothesis for photoperiodism in Antheraea pernyi based on the transcription regulation of NAT interlocked by the circadian system. Therefore, the enzyme plays both unique and universal roles in insects. The unique role of iaaNATs in physiological regulation urges the targeting of this system for integrated pest management (IPM). We indeed showed a successful example of chemical compound screening with reconstituted enzyme and further attempts seem promising. PMID- 25918501 TI - Harnessing the power of theta: natural manipulations of cognitive performance during hippocampal theta-contingent eyeblink conditioning. AB - Neurobiological oscillations are regarded as essential to normal information processing, including coordination and timing of cells and assemblies within structures as well as in long feedback loops of distributed neural systems. The hippocampal theta rhythm is a 3-12 Hz oscillatory potential observed during cognitive processes ranging from spatial navigation to associative learning. The lower range, 3-7 Hz, can occur during immobility and depends upon the integrity of cholinergic forebrain systems. Several studies have shown that the amount of pre-training theta in the rabbit strongly predicts the acquisition rate of classical eyeblink conditioning and that impairment of this system substantially slows the rate of learning. Our lab has used a brain-computer interface (BCI) that delivers eyeblink conditioning trials contingent upon the explicit presence or absence of hippocampal theta. A behavioral benefit of theta-contingent training has been demonstrated in both delay and trace forms of the paradigm with a two- to four-fold increase in learning speed. This behavioral effect is accompanied by enhanced amplitude and synchrony of hippocampal local field potential (LFP)s, multi-unit excitation, and single-unit response patterns that depend on theta state. Additionally, training in the presence of hippocampal theta has led to increases in the salience of tone-induced unit firing patterns in the medial prefrontal cortex, followed by persistent multi-unit activity during the trace interval. In cerebellum, rhythmicity and precise synchrony of stimulus time-locked LFPs with those of hippocampus occur preferentially under the theta condition. Here we review these findings, integrate them into current models of hippocampal-dependent learning and suggest how improvement in our understanding of neurobiological oscillations is critical for theories of medial temporal lobe processes underlying intact and pathological learning. PMID- 25918508 TI - Singing abilities in children with Specific Language Impairment (SLI). AB - Specific Language Impairment (SLI) is a heritable neurodevelopmental disorder diagnosed when a child has difficulties learning to produce and/or understand speech for no apparent reason (Bishop et al., 2012). The verbal difficulties of children with SLI have been largely documented, and a growing number of studies suggest that these children may also have difficulties in processing non-verbal complex auditory stimuli (Corriveau et al., 2007; Brandt et al., 2012). In a recent study, we reported that a large proportion of children with SLI present deficits in music perception (Planchou et al., under revision). Little is known, however, about the singing abilities of children with SLI. In order to investigate whether or not the impairments in expressive language extend to the musical domain, we assessed singing abilities in eight children with SLI and 15 children with Typical Language Development (TLD) matched for age and non-verbal intelligence. To this aim, we designed a ludic activity consisting of two singing tasks: a pitch-matching and a melodic reproduction task. In the pitch-matching task, the children were requested to sing single notes. In the melodic reproduction task, children were asked to sing short melodies that were either familiar (FAM-SONG and FAM-TUNE conditions) or unfamiliar (UNFAM-TUNE condition). The analysis showed that children with SLI were impaired in the pitch-matching task, with a mean pitch error of 250 cents (mean pitch error for children with TLD: 154 cents). In the melodic reproduction task, we asked 30 healthy adults to rate the quality of the sung productions of the children on a continuous rating scale. The results revealed that singing of children with SLI received lower mean ratings than the children with TLD. Our findings thus indicate that children with SLI showed impairments in musical production and are discussed in light of a general auditory-motor dysfunction in children with SLI. PMID- 25918509 TI - Dietary self-control influences top-down guidance of attention to food cues. AB - Motivational objects attract attention due to their rewarding properties, but less is known about the role that top-down cognitive processes play in the attention paid to motivationally relevant objects and how this is affected by relevant behavioral traits. Here we assess how thinking about food affects attentional guidance to food items and how this is modulated by traits relating to dietary self-control. Participants completed two tasks in which they were presented with an initial cue (food or non-food) to either hold in working memory (memory task) or to merely attend to (priming task). Holding food items in working memory strongly affected attention when the memorized cue re-appeared in the search display. Tendency towards disinhibited eating was associated with greater attention to food versus non-food pictures in both the priming and working memory tasks, consistent with greater attention to food cues per se. Successful dieters, defined as those high in dietary restraint and low in tendency to disinhibition, showed reduced attention to food when holding food related information in working memory. These data suggest a strong top-down effect of thinking about food on attention to food items and indicate that the suppression of food items in working memory could be a marker of dieting success. PMID- 25918510 TI - Cross-validation of the reduced form of the Food Craving Questionnaire-Trait using confirmatory factor analysis. AB - OBJECTIVE: The Food Craving Questionnaire-Trait (FCQ-T) is commonly used to assess habitual food cravings among individuals. Previous studies have shown that a brief version of this instrument (FCQ-T-r) has good reliability and validity. This article is the first to use Confirmatory factor analysis to examine the psychometric properties of the FCQ-T-r in a cross-validation study. METHOD: Habitual food cravings, as well as emotion regulation strategies, affective states, and disordered eating behaviors, were investigated in two independent samples of non-clinical adult volunteers (Sample 1: N = 368; Sample 2: N = 246). Confirmatory factor analyses were conducted to simultaneously test model fit statistics and dimensionality of the instrument. FCQ-T-r reliability was assessed by computing the composite reliability coefficient. RESULTS: Analysis supported the unidimensional structure of the scale and fit indices were acceptable for both samples. The FCQ-T-r showed excellent reliability and moderate to high correlations with negative affect and disordered eating. CONCLUSION: Our results indicate that the FCQ-T-r scores can be reliably used to assess habitual cravings in an Italian non-clinical sample of adults. The robustness of these results is tested by a cross-validation of the model using two independent samples. Further research is required to expand on these findings, particularly in children and adolescents. PMID- 25918511 TI - Musical experience modulates categorical perception of lexical tones in native Chinese speakers. AB - Although musical training has been shown to facilitate both native and non-native phonetic perception, it remains unclear whether and how musical experience affects native speakers' categorical perception (CP) of speech at the suprasegmental level. Using both identification and discrimination tasks, this study compared Chinese-speaking musicians and non-musicians in their CP of a lexical tone continuum (from the high level tone, Tone1 to the high falling tone, Tone4). While the identification functions showed similar steepness and boundary location between the two subject groups, the discrimination results revealed superior performance in the musicians for discriminating within-category stimuli pairs but not for between-category stimuli. These findings suggest that musical training can enhance sensitivity to subtle pitch differences between within category sounds in the presence of robust mental representations in service of CP of lexical tonal contrasts. PMID- 25918512 TI - Endogenous digitalis-like factors: an overview of the history. AB - The sodium pump is a ubiquitous cell surface enzyme, a Na, K ATPase, which maintains ion gradients between cells and the extracellular fluid (ECF). The extracellular domain of this enzyme contains a highly conserved binding site, a receptor for a plant derived family of compounds, the digitalis glycosides. These compounds inhibit the enzyme and are used in the treatment of congestive heart failure and certain cardiac arrhythmias. The highly conserved nature of this enzyme and its digitalis receptor led to early suggestions that endogenous regulators might exist. Recent examination of this hypothesis emerged from research in two separate areas: the regulation of ECF volume by a natriuretic hormone (NH), and the regulation of peripheral vascular resistance by a circulating inhibitor of vascular Na, K ATPase. These two areas merged with the hypothesis that NH and the vascular Na, K ATPase inhibitor were in fact the same entity, and that it played a causative role in the pathophysiology of certain types of hypertension. The possibility that multiple endogenous digitalis-like factors (EDLFs) exist emerged from efforts to characterize the circulating enzyme inhibitory activity. In this review, the development of this field from its beginnings is traced, the current status of the structure of EDLFs is briefly discussed, and areas for future development are suggested. PMID- 25918513 TI - Substrate binding accelerates the conformational transitions and substrate dissociation in multidrug efflux transporter AcrB. AB - The tripartite efflux pump assembly AcrAB-TolC is the major multidrug resistance transporter in E. coli. The inner membrane transporter AcrB is a homotrimer, energized by the proton movement down the transmembrane electrochemical gradient. The asymmetric crystal structures of AcrB with three monomers in distinct conformational states [access (A), binding (B) and extrusion (E)] support a functional rotating mechanism, in which each monomer of AcrB cycles among the three states in a concerted way. However, the relationship between the conformational changes during functional rotation and drug translocation has not been totally understood. Here, we explored the conformational changes of the AcrB homotrimer during the ABE to BEA transition in different substrate-binding states using targeted MD simulations. It was found that the dissociation of substrate from the distal binding pocket of B monomer is closely related to the concerted conformational changes in the translocation pathway, especially the side chain reorientation of Phe628 and Tyr327. A second substrate binding at the proximal binding pocket of A monomer evidently accelerates the conformational transitions as well as substrate dissociation in B monomer. The acceleration effect of the multi-substrate binding mode provides a molecular explanation for the positive cooperativity observed in the kinetic studies of substrate efflux and deepens our understanding of the functional rotating mechanism of AcrB. PMID- 25918515 TI - Evolutionary developmental genetics of fruit morphological variation within the Solanaceae. AB - Morphological variations of fruits such as shape and size, and color are a result of adaptive evolution. The evolution of morphological novelties is particularly intriguing. An understanding of these evolutionary processes calls for the elucidation of the developmental and genetic mechanisms that result in particular fruit morphological characteristics, which determine seed dispersal. The genetic and developmental basis for fruit morphological variation was established at a microevolutionary time scale. Here, we summarize the progress on the evolutionary developmental genetics of fruit size, shape and color in the Solanaceae. Studies suggest that the recruitment of a pre-existing gene and subsequent modification of its interaction and regulatory networks are frequently involved in the evolution of morphological diversity. The basic mechanisms underlying changes in plant morphology are alterations in gene expression and/or gene function. We also deliberate on the future direction in evolutionary developmental genetics of fruit morphological variation such as fruit type. These studies will provide insights into plant developmental processes and will help to improve the productivity and fruit quality of crops. PMID- 25918514 TI - Signal regulators of systemic acquired resistance. AB - Salicylic acid (SA) is an important phytohormone that plays a vital role in a number of physiological responses, including plant defense. The last two decades have witnessed a number of breakthroughs related to biosynthesis, transport, perception and signaling mediated by SA. These findings demonstrate that SA plays a crictical role in both local and systemic defense responses. Systemic acquired resistance (SAR) is one such SA-dependent response. SAR is a long distance signaling mechanism that provides broad spectrum and long-lasting resistance to secondary infections throughout the plant. This unique feature makes SAR a highly desirable trait in crop production. This review summarizes the recent advances in the role of SA in SAR and discusses its relationship to other SAR inducers. PMID- 25918516 TI - Arabidopsis thaliana mutants lacking cpFtsY or cpSRP54 exhibit different defects in photosystem II repair. AB - Photosystem II (PS II) is a multi subunit protein complex embedded in the thylakoid membrane of cyanobacteria and chloroplasts. As the PS II reaction center protein D1 is prone to a light induced damage that inhibits PS II function especially at elevated light intensities, a highly ordered repair process including synthesis, targeting and insertion of D1 has evolved. To elucidate the function of the chloroplast signal recognition particle subunits, cpSRP43 and cpSRP54, and the cpSRP-receptor cpFtsY in D1 biogenesis we investigated the efficiency of the PS II repair cycle in the corresponding mutants of Arabidopsis thaliana. Immunological analyses, PAM measurements and in vivo labeling experiments demonstrate an impaired replacement of damaged D1 in the cpftsy mutant, while the chaos and the ffc mutant lacking cpSRP43 and cpSRP54, respectively, were not or hardly affected. The defect in cpftsy was neither caused by an impaired psbA transcript accumulation, D1 translation initiation nor by an enhanced D1 degradation. Further experiments revealed a decreased amount of salt stable, thylakoid membrane-associated translating ribosomes in the cpftsy mutant, while the amount of membrane-associated translating ribosomes is unaltered in the chaos and the ffc mutants. Therefore, our data indicate that the lack of cpFtsY leads to an inefficient PS II repair cycle caused by an impaired binding of translating ribosomes to the thylakoid membrane. PMID- 25918517 TI - Genetics of aging, health, and survival: dynamic regulation of human longevity related traits. AB - BACKGROUND: The roles of genetic factors in human longevity would be better understood if one can use more efficient methods in genetic analyses and investigate pleiotropic effects of genetic variants on aging and health related traits. DATA AND METHODS: We used EMMAX software with modified correction for population stratification to perform genome wide association studies (GWAS) of female lifespan from the original FHS cohort. The male data from the original FHS cohort and male and female data combined from the offspring FHS cohort were used to confirm findings. We evaluated pleiotropic effects of selected genetic variants as well as gene-smoking interactions on health and aging related traits. Then we reviewed current knowledge on functional properties of genes related to detected variants. RESULTS: The eight SNPs with genome-wide significant variants were negatively associated with lifespan in both males and females. After additional QC, two of these variants were selected for further analyses of their associations with major diseases (cancer and CHD) and physiological aging changes. Gene-smoking interactions contributed to these effects. Genes closest to detected variants appear to be involved in similar biological processes and health disorders, as those found in other studies of aging and longevity e.g., in cancer and neurodegeneration. CONCLUSIONS: The impact of genes on longevity may involve trade-off-like effects on different health traits. Genes that influence lifespan represent various molecular functions but may be involved in similar biological processes and health disorders, which could contribute to genetic heterogeneity of longevity and the lack of replication in genetic association studies. PMID- 25918518 TI - Clinical, biochemical, and genetic spectrum of seven patients with NFU1 deficiency. AB - Disorders of the mitochondrial energy metabolism are clinically and genetically heterogeneous. An increasingly recognized subgroup is caused by defective mitochondrial iron-sulfur (Fe-S) cluster biosynthesis, with defects in 13 genes being linked to human disease to date. Mutations in three of them, NFU1, BOLA3, and IBA57, affect the assembly of mitochondrial [4Fe-4S] proteins leading to an impairment of diverse mitochondrial metabolic pathways and ATP production. Patients with defects in these three genes present with lactic acidosis, hyperglycinemia, and reduced activities of respiratory chain complexes I and II, the four lipoic acid-dependent 2-oxoacid dehydrogenases and the glycine cleavage system (GCS). To date, five different NFU1 pathogenic variants have been reported in 15 patients from 12 families. We report on seven new patients from five families carrying compound heterozygous or homozygous pathogenic NFU1 mutations identified by candidate gene screening and exome sequencing. Six out of eight different disease alleles were novel and functional studies were performed to support the pathogenicity of five of them. Characteristic clinical features included fatal infantile encephalopathy and pulmonary hypertension leading to death within the first 6 months of life in six out of seven patients. Laboratory investigations revealed combined defects of pyruvate dehydrogenase complex (five out of five) and respiratory chain complexes I and II+III (four out of five) in skeletal muscle and/or cultured skin fibroblasts as well as increased lactate (five out of six) and glycine concentration (seven out of seven). Our study contributes to a better definition of the phenotypic spectrum associated with NFU1 mutations and to the diagnostic workup of future patients. PMID- 25918519 TI - Whole-genome CNV analysis: advances in computational approaches. AB - Accumulating evidence indicates that DNA copy number variation (CNV) is likely to make a significant contribution to human diversity and also play an important role in disease susceptibility. Recent advances in genome sequencing technologies have enabled the characterization of a variety of genomic features, including CNVs. This has led to the development of several bioinformatics approaches to detect CNVs from next-generation sequencing data. Here, we review recent advances in CNV detection from whole genome sequencing. We discuss the informatics approaches and current computational tools that have been developed as well as their strengths and limitations. This review will assist researchers and analysts in choosing the most suitable tools for CNV analysis as well as provide suggestions for new directions in future development. PMID- 25918520 TI - Circulating Oxidized Low-Density Lipoproteins and Antibodies against Oxidized Low Density Lipoproteins as Potential Biomarkers of Colorectal Cancer. AB - Introduction. The aim of the study was evaluation of the diagnostic utility of serum oxidized low-density lipoproteins (oxLDL), antibodies against oxLDLs (o LAB), and CEA as risk markers of colorectal cancer (CRC). Material and Methods. The serum levels of study factors were measured in 73 patients with CRC and in 35 healthy controls who were gender- and BMI-matched to the study group. Concentrations of oxLDL, o-LAB, and CEA were detected in ELISA tests. Serum lipids, lipoproteins, and glucose levels were also coestimated. Results. Age and o-LAB were significant factors of CRC presence, but results of logistic regression analysis showed that both were weak predictors of CRC risk. Concentration of o-LAB was significantly higher in colon cancer than in rectal cancer, especially when the cancer was located in the right section of colon. Serum CEA levels were significantly elevated in the advanced stage of disease, primary tumor progression, angiolymphatic invasion, and presence of distant metastasis. Conclusions. Obtained results have demonstrated that oxLDL and o-LAB were not satisfactory risk markers of CRC. Although significant relation between o-LAB level and CRC is observed, it may be rather the result of individual differences in the host immune responses against cancer. PMID- 25918521 TI - Hepatic Overexpression of GRP94 in a Rabbit Model of Parenteral Nutrition Associated Liver Disease. AB - Objective. To use a rabbit model of parenteral nutrition-associated liver disease (PNALD) to study changes of the endoplasmic reticulum stress (ERS) marker glucose regulatory protein 94 (GRP94) and determine its role in the pathogenesis of PNALD. Methods. A rabbit PNALD model total parenteral nutrition (TPN) group was established. A corresponding control group received breast-feeding for one week. Serum biochemical parameters were measured and liver histological examinations were performed. The level of GRP94 mRNA and protein were measured. Results. The results showed that the serum TBIL, DBIL, and gamma-GT levels in the TPN group were significantly higher than those in the control group, while levels of serum ALB in TPN group were significantly lower than those in the control group. The immunohistochemistry results showed that the protein expression level of GRP94 in the liver of TPN group was significantly increased compared with the control group. The RT-PCR results showed that the level of GRP94 mRNA in the liver of the TPN group was significantly higher compared with the control group. Conclusions. The mRNA and protein levels of GRP94 in the TPN group were both significantly increased, indicating that ERS may be directly related to the occurrence and development of PNALD. PMID- 25918522 TI - Clinical impact of prophylactic antibiotic treatment for self-expandable metallic stent insertion in patients with malignant colorectal obstruction. AB - Purpose. The aim of this study was to determine the efficacy of prophylactic antibiotics (PA) for reducing the infectious complications and the potential risk factors responsible for the infectious complications after stent insertion for malignant colorectal obstruction. Methods. We performed a retrospective review of 224 patients who underwent self-expandable metallic stent (SEMS) insertion for malignant colorectal obstruction from May 2004 to December 2012. Results. There were 145 patients in the PA group and 79 in non-PA group. The CRP level in PA group was significantly higher than that in non-PA. Abdominal tenderness and mechanical ileus were significantly more frequent in PA group than those in non PA. The frequency of post-SEMS insertion fever, systemic inflammatory response syndrome (SIRS), and bacteremia was not significantly different between PA and non-PA groups. In multivariate analysis, the CRP level was risk factor related to post-SEMS insertion SIRS. However, in propensity score matching analysis, there was no independent risk factor related to post-SEMS insertion fever, SIRS, and bacteremia. Conclusion. The use of PA in patients with malignant colorectal obstruction may be not effective to prevent the development of infectious complications after SEMS insertion. PMID- 25918523 TI - Endoscopic retrieval technique of proximally migrated pancreatic stents: a retrospective study in a tertiary centre. AB - Background. There were scarce trials concerning the treatments and outcomes of proximal pancreatic stent migration. Herein, we did a retrospective study to discuss this problem from an endoscopist's point of view. Patients and Methods. From January 2009 to June 2014, patients with proximally migrated pancreatic duct stents were identified. Their clinical information was viewed. Retrieval techniques, success rates, and adverse events were analyzed. Results. A total of 36 procedures were performed in 34 patients; the median age of the patients was 53 years, with 17 males and 17 females. Eight patients' pancreatic duct stents could still be seen in the major or minor papilla and were pulled out with a snare forceps or a grasping forceps; in the remaining 28 procedures, the management was somewhat thorny; the retrieval called for several devices. Final success was achieved in 31 patients. No adverse event was observed in the process of ERCP procedures, 5 patients developed post-ERCP pancreatitis (PEP), 1 patient got infection, and 1 patient had haemorrhage. Conclusions. Endoscopic retrieval of migrated pancreatic stent is safe and less invasive; nonetheless, attention should be paid so as to reduce the incidence and degree of related adverse events, especially PEP. PMID- 25918524 TI - Increased chromogranin a cell density in the large intestine of patients with irritable bowel syndrome after receiving dietary guidance. AB - The large intestine contains five types of endocrine cells that regulate its functions by sensing its luminal contents and releasing specific hormones. Chromogranin A (CgA) is a common marker for the gastrointestinal endocrine cells, and it is abnormal in irritable bowel syndrome (IBS) patients. Most IBS patients relate their symptoms to certain food elements. The present study investigated the effect of dietary guidance on the total endocrine cells of the large intestine as detected by CgA in 13 IBS patients. Thirteen control subjects were also included. Each patient received three sessions of dietary guidance. Colonoscopies were performed on controls and patients (at baseline and at 3-9 months after receiving guidance). Biopsy samples from the colon and rectum were immunostained for CgA and quantified by computerized image analysis. The densities of CgA cells in the total colon (mean +/- SEM) among the controls and the IBS patients before and after receiving dietary guidance were 83.3 +/- 10.1, 38.6 +/- 3.7, and 64.7 +/- 4.2 cells/mm(2), respectively (P = 0.0004), and were unchanged in the rectum. In conclusion, the increase in CgA cell density after receiving dietary guidance may reflect a change in the densities of the large intestinal endocrine cells causing an improvement in the IBS symptoms. PMID- 25918525 TI - Differential expression of motilin receptor in various parts of gastrointestinal tract in dogs. AB - Objectives. The presence of motilin receptor in the GI tract of different animal species has been verified. However, the quantitation of motilin receptor expression in different regions of the GI tract remains unclear. The aim of this study was to investigate the expression of motilin receptor in the GI tract and semiquantitatively compare the expression difference in different GI regions in dogs. Methods. Antrum, duodenum, jejunum, ileum, proximal colon, middle colon, and distal colon were obtained from various parts of the GI tract of six sacrificed dogs. The distribution of motilin receptor was determined by immunohistochemistry. The expression levels of motilin receptor mRNA in different regions were measured by RT-PCR. Results. Motilin receptor was expressed throughout the GI tract in dogs. Multiple comparisons of the mean motilin receptor mRNA expression among various regions were significant (P < 0.05). Motilin receptor mRNA was extensively expressed in duodenum, followed by ileum, jejunum, proximal colon, antrum, middle colon, and distal colon. Immunohistochemistry revealed that motilin receptor immunoreactivity was observed only in the enteric nervous system. Conclusion. Motilin receptor is expressed differentially along the GI tract in dogs. The significantly high expression of motilin receptor mRNA is found in the duodenum. PMID- 25918526 TI - Prospective analysis of risk for hypothyroidism after hemithyroidectomy. AB - Objectives. To evaluate risk factors and to develop a simple scoring system to grade the risk of postoperative hypothyroidism (PH). Methods. In a controlled prospective study, 109 patients, who underwent hemithyroidectomy for a benign thyroid disease, were followed up for 12 months. The relation between clinical data and PH was analyzed for significance. A risk scoring system based on significant risk factors and clinical implications was developed. Results. The significant risk factors of PH were higher TSH (thyroid-stimulating hormone) level and lower ratio of the remaining thyroid weight to the patient's weight (derived weight index). Based on the log of risk factor, preoperative TSH level greater than 1.4 mU/L was assigned 2 points; 1 point was for 0.8-1.4 mU/L. The derived weight index lower than 0.8 g/kg was assigned 1 point. A risk scoring system was calculated by summing the scores. The incidences of PH were 7.3%, 30.4%, and 69.2% according to the risk scores of 0-1, 2, and 3. Conclusion. Risk factors for PH are higher preoperative TSH level and lower derived weight index. Our developed risk scoring system is a valid and reliable tool to identify patients who are at risk for PH before surgery. PMID- 25918527 TI - Increased serum pigment epithelium-derived factor in women with gestational diabetes is associated with type 2 diabetes. AB - Background. Pigment epithelium-derived factor (PEDF) is demonstrated to be elevated in diabetes patients. However, no reports have emerged in pregnant women with gestational diabetes mellitus (GDM). This study was undertaken to investigate serum PEDF levels in GDM women and to evaluate PEDF as a biomarker to predict diabetes postpartum. Methods. Serum PEDF concentration and clinical characteristics were detected in the pregnant women with GDM (n = 120) and without GDM (control group, n = 120). Results. PEDF levels were elevated in subjects with GDM versus controls. Univariate correlations showed that serum PEDF levels were positively correlated with fasting glucose and fasting insulin levels, respectively, and negatively correlated with adiponectin. Receiver operating characteristic (ROC) analysis demonstrated that the AUC of serum PEDF for diabetes mellitus in women postpartum was 0.893. Conclusion. Serum PEDF was elevated in pregnant women with GDM, which is probably an early detection marker for predicting development of GDM to diabetes mellitus. PMID- 25918528 TI - Methylation of promoter regions of genes of the human intrauterine Renin Angiotensin system and their expression. AB - The intrauterine renin angiotensin system (RAS) is implicated in placentation and labour onset. Here we investigate whether promoter methylation of RAS genes changes with gestation or labour and if it affects gene expression. Early gestation amnion and placenta were studied, as were term amnion, decidua, and placenta collected before labour (at elective caesarean section) or after spontaneous labour and delivery. The expression and degree of methylation of the prorenin receptor (ATP6AP2), angiotensin converting enzyme (ACE), angiotensin II type 1 receptor (AGTR1), and two proteases that can activate prorenin (kallikrein, KLK1, and cathepsin D, CTSD) were measured by qPCR and a DNA methylation array. There was no effect of gestation or labour on the methylation of RAS genes and CTSD. Amnion and decidua displayed strong correlations between the percent hypermethylation of RAS genes and CTSD, suggestive of global methylation. There were no correlations between the degree of methylation and mRNA abundance of any genes studied. KLK1 was the most methylated gene and the proportion of hypermethylated KLK1 alleles was lower in placenta than decidua. The presence of intermediate methylated alleles of KLK1 in early gestation placenta and in amnion after labour suggests that KLK1 methylation is uniquely dynamic in these tissues. PMID- 25918529 TI - Parental Reports of Stigma Associated with Child's Disorder of Sex Development. AB - Disorders of sex development (DSD) are congenital conditions in which chromosomal, gonadal, or anatomic sex development is atypical. DSD-associated stigma is purported to threaten positive psychosocial adaptation. Parental perceptions of DSD-related stigma were assessed in 154 parents of 107 children (newborn-17 years) questionnaire comprising two scales, child-focused and parent focused, and three subscales, perceived stigmatization, future worries, and feelings about the child's condition. Medical chart excerpts identified diagnoses and clinical management details. Stigma scale scores were generally low. Parents of children with DSD reported less stigma than parents of children with epilepsy; however, a notable proportion rated individual items in the moderate to high range. Stigma was unrelated to child's age or the number of DSD-related surgeries. Child-focused stigma scores exceeded parent-focused stigma and mothers reported more stigma than fathers, with a moderate level of agreement. Within 46,XY DSD, reported stigma was higher for children reared as girls. In conclusion, in this first quantitative study of ongoing experiences, DSD-related stigma in childhood and adolescence, while limited in the aggregate, is reported at moderate to high levels in specific areas. Because stigma threatens positive psychosocial adaptation, systematic screening for these concerns should be considered and, when reported, targeted for psychoeducational counseling. PMID- 25918530 TI - A comparative evaluation of static frictional resistance using various methods of ligation at different time intervals: an in vitro study. AB - Aim. To compare and evaluate the static frictional resistance offered by the four different types of ligation methods in both dry and wet conditions and at different durations when immersed in artificial saliva. Material and Methods. Alastik Easy to Tie modules, Super Slick Mini Stix elastomeric modules, Power "O" modules, and 0.009(") Stainless Steel ligatures were used to compare the static friction using maxillary canine and premolar Preadjusted Edgewise brackets with 0.022(") * 0.028(") slot and 0.019(") * 0.025(") stainless steel wires. Results. The mean frictional resistance for Alastik modules was the lowest and that of Stainless Steel ligatures was found to be highest among the four groups compared and the difference among the four groups was statistically significant (P < 0.005). The mean static frictional resistance in all groups under dry conditions was lower than that under wet conditions. No statistical significant differences were found when the groups were compared at different time periods of immersion in artificial saliva. Conclusion. This study concludes that the Alastik modules showed the lowest mean static frictional forces compared to any other ligation method, though no significant difference was found for different time periods of immersion in the artificial saliva. PMID- 25918531 TI - The influence of different drying methods on constituents and antioxidant activity of saffron from china. AB - More and more saffron has been cultivated in China because of the increasing saffron demand, but no paper has studied the influence of drying methods on the quality of Chinese saffron. In this paper, three different dehydration treatments applied in actual production were evaluated: dehydration with electric oven, vacuum oven, and microwave. We determined that the highest quality of saffron will be obtained when fresh saffron is treated at higher temperatures (no more than 70 degrees C) for a long time by electric oven drying and vacuum oven drying. In microwave drying, treatments at lower microwave power and longer time benefit the quality of saffron. In addition, the influence of the drying method on antioxidants in saffron is discussed. The correlation between individual saffron profiles and the antioxidant value was estimated by spectrum-effect relationships analysis. PMID- 25918532 TI - Myotonic dystrophy-1 complicated by factor-v (leiden) mutation. AB - Objectives. Presence of a factor-V Leiden mutation in a patient with myotonic dystrophy type 1 (DM1) has been reported only once. Here we report the second DM1 patient carrying a factor-V mutation who died from long-term complications of this mutation. Case Report. A 66-year-old DM1 patient with multi-organ-disorder syndrome developed a first deep venous thrombosis (DVT) and consecutive pulmonary embolism (PE) at age 50 y. Acetyl-salicylic acid was given. One year later he experienced a second DVT; that is why phenprocoumon was started. Despite anticoagulation, he experienced a third DVT bilaterally and a second PE bilaterally at 61 y; that is why a vena cava filter was additionally deployed. Despite therapeutic anticoagulation, he experienced a vena cava filter thrombosis at age 62 y. Genetic workup revealed a heterozygous factor-V mutation in addition to a CTG-repeat expansion of 500. As a consequence of PE he developed chronic obstructive pulmonary disease and experienced recurrent pulmonary infections, which were lastly responsible for decease at age 66 y despite intensive care measures. Conclusion. The heterozygous Leiden mutation may severely affect DM1 patients to such a degree that they die from its complications. If DM1 patients present with unusual manifestations, search for causes other than a CTG-repeat expansion is indicated. PMID- 25918533 TI - Severe Transient Hyperglycemia in a Prediabetic Patient during Mild Acute Pancreatitis. AB - A 30-year-old obese male patient had been diagnosed with diabetes mellitus due to acute hyperglycemia and ketonuria. He also presented with severe hypertriglyceridemia and high levels of serum lipase. He was initially misdiagnosed with type 1 diabetes and treated with insulin for one month. At two months from first presentation, pancreatic antibodies were negative, and the C peptide level was normal. A1c level was 5.9% without insulin treatment. The association between diabetes mellitus and acute pancreatitis is well established. We reported a case of severe transient hyperglycemia during mild acute pancreatitis in a metabolically ill patient. PMID- 25918535 TI - Supporting patient-centred care / A l'appui des soins centres sur le patient. PMID- 25918534 TI - Targeted Knockdown of RNA-Binding Protein TIAR for Promoting Self-Renewal and Attenuating Differentiation of Mouse Embryonic Stem Cells. AB - RNA-binding protein TIAR has been suggested to mediate the translational silencing of ARE-containing mRNAs. To analyze the functions of TIAR, we established RNAi and genetic rescue assays. We evaluated the expression of neuroectoderm markers Pax6 and nestin, mesoderm markers brachyury and Flk1, and hypoblast and definitive endoderm markers Sox17 and Gata6 during EB differentiation and found that knockdown TIAR expression restrained the differentiation of E14 cells. We assessed gene expression levels of Flk-1 and VE cadherin and observed attenuated differentiation of E14 cells into endothelial cells upon downregulation of TIAR gene expression. As such, we hypothesized an essential role of TIAR related to EB differentiation. As TIAR inhibits the translation of c-myc, we proposed that downregulation of TIAR results in restrained differentiation of E14 cells, due in part to the function of c-myc. We found that TIAR inhibited c-myc expression at the translational level in E14 cells; accordingly, a reduction of TIAR expression promoted self-renewal of pluripotent cells and attenuated differentiation. Additionally, we established that TIAR inhibited TIA-1 expression at the translational level in E14 cells. Taken together, we have contributed to the understanding of the regulatory relationships between TIAR and both c-myc and TIA-1. PMID- 25918536 TI - When to trust health information posted on the Internet. PMID- 25918537 TI - Pharmacist-administered influenza vaccine in a community pharmacy: A patient experience survey. PMID- 25918538 TI - Evidence for the role and impact of pharmacists: Description of a website. PMID- 25918539 TI - A pharmacist's guide to the 2012 update of the Canadian Cardiovascular Society Guidelines for the Use of Antiplatelet Therapy. PMID- 25918541 TI - 2015: The state of pharmacy in Canada. PMID- 25918540 TI - Gonorrhea: Treatment update for an increasingly resistant organism. PMID- 25918542 TI - Comment on "effect of pumpkin seed oil on hair growth in men with androgenetic alopecia: a randomized, double-blind, placebo-controlled trial". PMID- 25918543 TI - 1,2,3,4,6-Penta-O-galloylglucose within Galla Chinensis Inhibits Human LDH-A and Attenuates Cell Proliferation in MDA-MB-231 Breast Cancer Cells. AB - A characteristic feature of aggressive malignancy is the overexpression of lactic acid dehydrogenase- (LDH-) A, concomitant to pericellular accumulation of lactate. In a recent high-throughput screening, we identified Rhus chinensis (Mill.) gallnut (RCG) (also known as Galla Chinensis) extract as a potent (IC50 < 1 ug/mL) inhibitor of human LDH-A (hLDH-A). In this study, through bioactivity guided fractionation of the crude extract, the data demonstrate that penta 1,2,3,4,6-O-galloyl-beta-D-glucose (PGG) was a primary constituent responsible for hLDH-A inhibition, present at ~9.95 +/- 0.34% dry weight. Theoretical molecular docking studies of hLDH-A indicate that PGG acts through competitive binding at the NADH cofactor site, effects confirmed by functional enzyme studies where the IC50 = 27.32 nM was reversed with increasing concentration of NADH. Moreover, we confirm protein expression of hLDH-A in MDA-231 human breast carcinoma cells and show that PGG was toxic (LC50 = 94.18 uM), parallel to attenuated lactic acid production (IC50 = 97.81 uM). In a 72-hour cell proliferation assay, PGG was found to be a potent cytostatic agent with ability to halt cell division (IC50 = 1.2 uM) relative to paclitaxel (IC50 < 100 nM). In summary, these findings demonstrate that PGG is a potent hLDH-A inhibitor with significant capacity to halt proliferation of human breast cancer cells. PMID- 25918544 TI - Antioxidant and hypolipidemic potential of aged garlic extract and its constituent, s-allyl cysteine, in rats. AB - Aged garlic extract (AGE) is one of the unique preparations standardized with 100% bioavailable active ingredients found in the bloodstream. The current research was aimed at exploring the role of AGE and its chief active constituent, s-allyl cysteine (SAC) as antioxidant and hypolipidemic agent in rats. At the end of treatment of AGE and SAC, separated serum and freshly prepared liver tissue homogenate were analyzed for biochemical enzymes and biomarkers to evaluate and compare potencies of investigational agents. Both AGE and SAC significantly declined elevated levels of triglyceride, total cholesterol, ALP, AST, ALT, malondialdehyde, glutathione peroxidase enzyme activity, total glutathione and oxidised glutathione in serum and inclined superoxide dismutase, catalase, ferric reducing/antioxidant power, and total sulfhydryl values in liver tissue with reduction in thiobarbituric acid reactive species. The protective effects were superior with AGE compared with SAC indicating potential implication of other active constituents apart from SAC in AGE for combating hyperlipidemic stress. PMID- 25918545 TI - Ginsenoside Rh1 Improves the Effect of Dexamethasone on Autoantibodies Production and Lymphoproliferation in MRL/lpr Mice. AB - Ginsenoside Rh1 is able to upregulate glucocorticoid receptor (GR) level, suggesting Rh1 may improve glucocorticoid efficacy in hormone-dependent diseases. Therefore, we investigated whether Rh1 could enhance the effect of dexamethasone (Dex) in the treatment of MRL/lpr mice. MRL/lpr mice were treated with vehicle, Dex, Rh1, or Dex + Rh1 for 4 weeks. Dex significantly reduced the proteinuria and anti-dsDNA and anti-ANA autoantibodies. The levels of proteinuria and anti-dsDNA and anti-ANA autoantibodies were further decreased in Dex + Rh1 group. Dex, Rh1, or Dex + Rh1 did not alter the proportion of CD4+ splenic lymphocytes, whereas the proportion of CD8+ splenic lymphocytes was significantly increased in Dex and Dex + Rh1 groups. Dex + Rh1 significantly decreased the ratio of CD4+/CD8+ splenic lymphocytes compared with control. Con A-induced CD4+ splenic lymphocytes proliferation was increased in Dex-treated mice and was inhibited in Dex + Rh1 treated mice. Th1 cytokine IFN-gamma mRNA was suppressed and Th2 cytokine IL-4 mRNA was increased by Dex. The effect of Dex on IFN-gamma and IL-4 mRNA was enhanced by Rh1. In conclusion, our data suggest that Rh1 may enhance the effect of Dex in the treatment of MRL/lpr mice through regulating CD4+ T cells activation and Th1/Th2 balance. PMID- 25918546 TI - Antiproliferative and Apoptosis-Inducing Activities of 4-Isopropyl-2,6-bis(1 phenylethyl)phenol Isolated from Butanol Fraction of Cordyceps bassiana. AB - The Cordyceps species have been widely used for treating various cancer diseases. Although the Cordyceps species have been widely known as an alternative anticancer remedy, which compounds are responsible for their anticancer activity is not fully understood. In this study, therefore, we examined the anticancer activity of 5 isolated compounds derived from the butanol fraction (Cb-BF) of Cordyceps bassiana. For this purpose, several cancer cell lines such as C6 glioma, MDA-MB-231, and A549 cells were employed and details of anticancer mechanism were further investigated. Of 5 compounds isolated by activity-guided fractionation from BF of Cb-EE, KTH-13, and 4-isopropyl-2,6-bis(1 phenylethyl)phenol, Cb-BF was found to be the most potent antiproliferative inhibitor of C6 glioma and MDA-MB-231 cell growth. KTH-13 treatment increased DNA laddering, upregulated the level of Annexin V positive cells, and altered morphological changes of C6 glioma and MDA-MB-231 cells. In addition, KTH-13 increased the levels of caspase 3, caspase 7, and caspase 9 cleaved forms as well as the protein level of Bax but not Bcl-2. It was also found that the phosphorylation of AKT and p85/PI3K was also clearly reduced by KTH-13 exposure. Therefore, our results suggest KTH-13 can act as a potent antiproliferative and apoptosis-inducing component from Cordyceps bassiana, contributing to the anticancer activity of this mushroom. PMID- 25918547 TI - Protective effects of N-acetyl-L-cysteine in human oligodendrocyte progenitor cells and restoration of motor function in neonatal rats with hypoxic-ischemic encephalopathy. AB - Objective. Since oligodendrocyte progenitor cells (OPCs) are the target cells of neonatal hypoxic-ischemic encephalopathy (HIE), the present study was aimed at investigating the protective effects of N-acetyl-l-cysteine (NAC), a well-known antioxidant and precursor of glutathione, in OPCs as well as in neonatal rats. Methods. In in vitro study, protective effects of NAC on KCN cytotoxicity in F3.Olig2 OPCs were investigated via MTT assay and apoptotic signal analysis. In in vivo study, NAC was administered to rats with HIE induced by hypoxia-ischemia surgery at postnatal day 7, and their motor functions and white matter demyelination were analyzed. Results. NAC decreased KCN cytotoxicity in F3.Olig2 cells and especially suppressed apoptosis by regulating Bcl2 and p-ERK. Administration of NAC recovered motor functions such as the using ratio of forelimb contralateral to the injured brain, locomotor activity, and rotarod performance of neonatal HIE animals. It was also confirmed that NAC attenuated demyelination in the corpus callosum, a white matter region vulnerable to HIE. Conclusion. The results indicate that NAC exerts neuroprotective effects in vitro and in vivo by preserving OPCs, via regulation of antiapoptotic signaling, and that F3.Olig2 human OPCs could be a good tool for screening of candidates for demyelinating diseases. PMID- 25918548 TI - Nonpharmacological interventions for pain management in paramedicine and the emergency setting: a review of the literature. AB - Paramedicine and the emergency medical services have been moving in the direction of advancing pharmaceutical intervention for the management of pain in both acute and chronic situations. This coincides with other areas of advanced life support and patient management strategies that have been well researched and continue to benefit from the increasing evidence. Even though paramedic practice is firmly focused on pharmacological interventions to alleviate pain, there is emerging evidence proposing a range of nonpharmacological options that can have an important role in pain management. This review highlights literature that suggests that paramedicine and emergency medical services should be considering the application of complementary and alternative therapies which can enhance current practice and reduce the use of pharmacological interventions. PMID- 25918549 TI - Non-invasive assessment of leaf water status using a dual-mode microwave resonator. AB - The water status in plant leaves is a good indicator for the water status in the whole plant revealing stress if the water supply is reduced. The analysis of dynamic aspects of water availability in plant tissues provides useful information for the understanding of the mechanistic basis of drought stress tolerance, which may lead to improved plant breeding and management practices. The determination of the water content in plant tissues during plant development has been a challenge and is currently feasible based on destructive analysis only. We present here the application of a non-invasive quantitative method to determine the volumetric water content of leaves and the ionic conductivity of the leaf juice from non-invasive microwave measurements at two different frequencies by one sensor device. A semi-open microwave cavity loaded with a ceramic dielectric resonator and a metallic lumped-element capacitor- and inductor structure was employed for non-invasive microwave measurements at 150 MHz and 2.4 Gigahertz on potato, maize, canola and wheat leaves. Three leaves detached from each plant were chosen, representing three developmental stages being representative for tissue of various age. Clear correlations between the leaf- induced resonance frequency shifts and changes of the inverse resonator quality factor at 2.4 GHz to the gravimetrically determined drying status of the leaves were found. Moreover, the ionic conductivity of Maize leaves, as determined from the ratio of the inverse quality factor and frequency shift at 150 MHz by use of cavity perturbation theory, was found to be in good agreement with direct measurements on plant juice. In conjunction with a compact battery- powered circuit board- microwave electronic module and a user-friendly software interface, this method enables rapid in-vivo water amount assessment of plants by a handheld device for potential use in the field. PMID- 25918550 TI - Classification of Parkinsonian syndromes from FDG-PET brain data using decision trees with SSM/PCA features. AB - Medical imaging techniques like fluorodeoxyglucose positron emission tomography (FDG-PET) have been used to aid in the differential diagnosis of neurodegenerative brain diseases. In this study, the objective is to classify FDG PET brain scans of subjects with Parkinsonian syndromes (Parkinson's disease, multiple system atrophy, and progressive supranuclear palsy) compared to healthy controls. The scaled subprofile model/principal component analysis (SSM/PCA) method was applied to FDG-PET brain image data to obtain covariance patterns and corresponding subject scores. The latter were used as features for supervised classification by the C4.5 decision tree method. Leave-one-out cross validation was applied to determine classifier performance. We carried out a comparison with other types of classifiers. The big advantage of decision tree classification is that the results are easy to understand by humans. A visual representation of decision trees strongly supports the interpretation process, which is very important in the context of medical diagnosis. Further improvements are suggested based on enlarging the number of the training data, enhancing the decision tree method by bagging, and adding additional features based on (f)MRI data. PMID- 25918551 TI - Application of phase congruency for discriminating some lung diseases using chest radiograph. AB - A novel procedure using phase congruency is proposed for discriminating some lung disease using chest radiograph. Phase congruency provides information about transitions between adjacent pixels. Abrupt changes of phase congruency values between pixels may suggest a possible boundary or another feature that may be used for discrimination. This property of phase congruency may have potential for deciding between disease present and disease absent where the regions of infection on the images have no obvious shape, size, or configuration. Five texture measures calculated from phase congruency and Gabor were shown to be normally distributed. This gave good indicators of discrimination errors in the form of the probability of Type I Error (delta) and the probability of Type II Error (beta). However, since 1 - delta is the true positive fraction (TPF) and beta is the false positive fraction (FPF), an ROC analysis was used to decide on the choice of texture measures. Given that features are normally distributed, for the discrimination between disease present and disease absent, energy, contrast, and homogeneity from phase congruency gave better results compared to those using Gabor. Similarly, for the more difficult problem of discriminating lobar pneumonia and lung cancer, entropy and homogeneity from phase congruency gave better results relative to Gabor. PMID- 25918552 TI - Tissue-specific regulation of Igf2r/Airn imprinting during gastrulation. AB - BACKGROUND: Appropriate epigenetic regulation of gene expression during lineage allocation and tissue differentiation is required for normal development. One example is genomic imprinting, which is defined as parent-of-origin mono-allelic gene expression. Imprinting is established largely due to epigenetic differences arriving in the zygote from sperm and egg haploid genomes. In the mouse, there are approximately 150 known imprinted genes, many of which occur in imprinted gene clusters that are regulated together. One imprinted cluster includes the maternally expressed Igf2r, Slc22a2, and Slc22a3 genes and the paternally expressed long non-coding RNA (lncRNA) Airn. Although it is known that Igf2r and Airn are reciprocally imprinted, the timing of imprinted expression and accompanying epigenetic changes have not been well characterized in vivo. RESULTS: Here we show lineage- and temporal-specific regulation of DNA methylation and histone modifications at the Igf2r/Airn locus correlating with differential establishment of imprinted expression during gastrulation. Our results show that Igf2r is expressed from both alleles in the E6.5 epiblast. After gastrulation commences, the locus becomes imprinted in the embryonic lineage with the lncRNA Airn expressed from the paternal allele and Igf2r restricted to maternal allele expression. We document differentially enriched allele-specific histone modifications in extraembryonic and embryonic tissues. We also document for the first time allele-specific spreading of DNA methylation during gastrulation concurrent with establishment of imprinted expression of Igf2r. Importantly, we show that imprinted expression does not change in the extraembryonic lineage even though maternal DMR2 methylation spreading does occur, suggesting distinct mechanisms at play in embryonic and extraembryonic lineages. CONCLUSIONS: These results indicate that similar to preimplantation, gastrulation represents a window of dynamic lineage-specific epigenetic regulation in vivo. PMID- 25918553 TI - Functional signatures of oral dysbiosis during periodontitis progression revealed by microbial metatranscriptome analysis. AB - BACKGROUND: Periodontitis is a polymicrobial biofilm-induced inflammatory disease that affects 743 million people worldwide. The current model to explain periodontitis progression proposes that changes in the relative abundance of members of the oral microbiome lead to dysbiosis in the host-microbiome crosstalk and then to inflammation and bone loss. Using combined metagenome/metatranscriptome analysis of the subgingival microbiome in progressing and non-progressing sites, we have characterized the distinct molecular signatures of periodontitis progression. METHODS: Metatranscriptome analysis was conducted on samples from subgingival biofilms from progressing and stable sites from periodontitis patients. Community-wide expression profiles were obtained using Next Generation Sequencing (Illumina). Sequences were aligned using 'bowtie2' against a constructed oral microbiome database. Differential expression analysis was performed using the non-parametric algorithm implemented on the R package 'NOISeqBio'. We summarized global functional activities of the oral microbial community by set enrichment analysis based on the Gene Ontology (GO) orthology. RESULTS: Gene ontology enrichment analysis showed an over representation in the baseline of active sites of terms related to cell motility, lipid A and peptidoglycan biosynthesis, and transport of iron, potassium, and amino acids. Periodontal pathogens (Tannerella forsythia and Porphyromonas gingivalis) upregulated different TonB-dependent receptors, peptidases, proteases, aerotolerance genes, iron transport genes, hemolysins, and CRISPR associated genes. Surprisingly, organisms that have not been usually associated with the disease (Streptococcus oralis, Streptococcus mutans, Streptococcus intermedius, Streptococcus mitis, Veillonella parvula, and Pseudomonas fluorenscens) were highly active transcribing putative virulence factors. We detected patterns of activities associated with progression of clinical traits. Among those we found that the profiles of expression of cobalamin biosynthesis, proteolysis, and potassium transport were associated with the evolution towards disease. CONCLUSIONS: We identified metabolic changes in the microbial community associated with the initial stages of dysbiosis. Regardless of the overall composition of the community, certain metabolic signatures are consistent with disease progression. Our results suggest that the whole community, and not just a handful of oral pathogens, is responsible for an increase in virulence that leads to progression. TRIAL REGISTRATION: NCT01489839, 6 December 2011. PMID- 25918554 TI - Cell-lineage heterogeneity and driver mutation recurrence in pre-invasive breast neoplasia. AB - BACKGROUND: All cells in an individual are related to one another by a bifurcating lineage tree, in which each node is an ancestral cell that divided into two, each branch connects two nodes, and the root is the zygote. When a somatic mutation occurs in an ancestral cell, all its descendants carry the mutation, which can then serve as a lineage marker for the phylogenetic reconstruction of tumor progression. Using this concept, we investigate cell lineage relationships and genetic heterogeneity of pre-invasive neoplasias compared to invasive carcinomas. METHODS: We deeply sequenced over a thousand phylogenetically informative somatic variants in 66 morphologically independent samples from six patients that represent a spectrum of normal, early neoplasia, carcinoma in situ, and invasive carcinoma. For each patient, we obtained a highly resolved lineage tree that establishes the phylogenetic relationships among the pre-invasive lesions and with the invasive carcinoma. RESULTS: The trees reveal lineage heterogeneity of pre-invasive lesions, both within the same lesion, and between histologically similar ones. On the basis of the lineage trees, we identified a large number of independent recurrences of PIK3CA H1047 mutations in separate lesions in four of the six patients, often separate from the diagnostic carcinoma. CONCLUSIONS: Our analyses demonstrate that multi-sample phylogenetic inference provides insights on the origin of driver mutations, lineage heterogeneity of neoplastic proliferations, and the relationship of genomically aberrant neoplasias with the primary tumors. PIK3CA driver mutations may be comparatively benign inducers of cellular proliferation. PMID- 25918555 TI - ClinSeK: a targeted variant characterization framework for clinical sequencing. AB - Applying genomics to patient care demands sensitive, unambiguous and rapid characterization of a known set of clinically relevant variants in patients' samples, an objective substantially different from the standard discovery process, in which every base in every sequenced read must be examined. Further, the approach must be sufficiently robust as to be able to detect multiple and potentially rare variants from heterogeneous samples. To meet this critical objective, we developed a novel variant characterization framework, ClinSeK, which performs targeted analysis of relevant reads from high-throughput sequencing data. ClinSeK is designed for efficient targeted short read alignment and is capable of characterizing a wide spectrum of genetic variants from single nucleotide variation to large-scale genomic rearrangement breakpoints. Applying ClinSeK to over a thousand cancer patients demonstrated substantively better performance, in terms of accuracy, runtime and disk storage, for clinical applications than existing variant discovery tools. ClinSeK is freely available for academic use at http://bioinformatics.mdanderson.org/main/clinsek. PMID- 25918556 TI - Long-term treatment with active Abeta immunotherapy with CAD106 in mild Alzheimer's disease. AB - INTRODUCTION: CAD106 is designed to stimulate amyloid-beta (Abeta)-specific antibody responses while avoiding T-cell autoimmune responses. The CAD106 first in-human study demonstrated a favorable safety profile and promising antibody response. We investigated long-term safety, tolerability and antibody response after repeated CAD106 injections. METHODS: Two phase IIa, 52-week, multicenter, randomized, double-blind, placebo-controlled core studies (2201; 2202) and two 66 week open-label extension studies (2201E; 2202E) were conducted in patients with mild Alzheimer's disease (AD) aged 40 to 85 years. Patients were randomized to receive 150MUg CAD106 or placebo given as three subcutaneous (2201) or subcutaneous/intramuscular (2202) injections, followed by four injections (150 MUg CAD106; subcutaneous, 2201E1; intramuscular, 2202E1). Our primary objective was to evaluate the safety and tolerability of repeated injections, including monitoring cerebral magnetic resonance imaging scans, adverse events (AEs) and serious AEs (SAEs). Further objectives were to assess Abeta-specific antibody response in serum and Abeta-specific T-cell response (core only). Comparable Abeta-immunoglobulin G (IgG) exposure across studies supported pooled immune response assessments. RESULTS: Fifty-eight patients were randomized (CAD106, n = 47; placebo, n = 11). Baseline demographics and characteristics were balanced. Forty-five patients entered extension studies. AEs occurred in 74.5% of CAD106 treated patients versus 63.6% of placebo-treated patients (core), and 82.2% experienced AEs during extension studies. Most AEs were mild to moderate in severity, were not study medication-related and did not require discontinuation. SAEs occurred in 19.1% of CAD106-treated patients and 36.4% of placebo-treated patients (core). One patient (CAD106-treated; 2201) reported a possibly study drug-related SAE of intracerebral hemorrhage. Four patients met criteria for amyloid-related imaging abnormalities (ARIA) corresponding to microhemorrhages: one was CAD106-treated (2201), one placebo-treated (2202) and two open-label CAD106-treated. No ARIA corresponded to vasogenic edema. Two patients discontinued extension studies because of SAEs (rectal neoplasm and rapid AD progression, respectively). Thirty CAD106-treated patients (63.8%) were serological responders. Sustained Abeta-IgG titers and prolonged time to decline were observed in extensions versus core studies. Neither Abeta1-6 nor Abeta1-42 induced specific T-cell responses; however, positive control responses were consistently detected with the CAD106 carrier. CONCLUSIONS: No unexpected safety findings or Abeta-specific T-cell responses support the CAD106 favorable tolerability profile. Long-term treatment-induced Abeta-specific antibody titers and prolonged time to decline indicate antibody exposure may increase with additional injections. CAD106 may be a valuable therapeutic option in AD. TRIAL REGISTRATION: ClinicalTrials.gov identifiers: NCT00733863, registered 8 August 2008; NCT00795418, registered 10 November 2008; NCT00956410, registered 10 August 2009; NCT01023685, registered 1 December 2009. PMID- 25918557 TI - Use of 4-factor prothrombin complex concentrate in the treatment of a gastrointestinal hemorrhage complicated by dabigatran. AB - Target-specific oral anticoagulants (TSOACs) provide patients and healthcare providers with an alternative to vitamin K antagonists (VKA). The TSOACs are of similar or superior efficacy to warfarin, but unlike VKAs, there are no approved 'antidotes' for rapid reversal of life-threatening bleeding on therapy. We report here the case of an 83-year-old gentleman, who presented to the emergency department with severe gastrointestinal hemorrhage and coagulopathy (hemoglobin: 5.3 g/dL and INR: 2.2) while on the direct thrombin inhibitor dabigatran. His coagulopathy reversed rapidly after administration of 4-factor prothrombin complex concentrate (4 F-PCC), and after initial administration of 2 units of packed red blood cells, no further product transfusions were required. He was discharged 4 days later without further complications. PMID- 25918558 TI - A statistical method for single sample analysis of HumanMethylation450 array data: genome-wide methylation analysis of patients with imprinting disorders. AB - BACKGROUND: The Illumina Infinium HumanMethylation450 BeadChip is an array-based technology for analysing DNA methylation at approximately 475,000 differentially methylated cytosines across the human genome. Hitherto, the array has been used for case-control studies, where sample numbers can be sufficient to yield statistically robust data on a genome-wide basis. We recently reported an informatic pipeline capable of yielding statistically and biologically significant results using only five cases, which expanded the use of this technology to rare disease studies. However, the clinical application of these technologies requires the ability to perform robust analysis of individual patients. RESULTS: Here we report a novel informatic approach for methylation array analysis of single samples, using the Crawford-Howell t-test. We tested our approach on patients with ultra-rare imprinting disorders with aberrant DNA methylation at multiple locations across the genome, which was previously detected by targeted testing. However, array analysis outperformed targeted assays in three ways: it detected loci not normally analysed by targeted testing, detected methylation changes too subtle to detect by the targeted testing and reported broad and consistent methylation changes across genetic loci not captured by point testing. CONCLUSIONS: This method has potential clinical utility for human disorders where DNA methylation change may be a biomarker of disease. PMID- 25918559 TI - Assessment of changes in quality of life among patients in the SAVE Study - Sirolimus as therapeutic Approach to uVEitis: a randomized study to assess the safety and bioactivity of intravitreal and subconjunctival injections of sirolimus in patients with non-infectious uveitis. AB - BACKGROUND: The National Eye Institute 39-Question Visual Function Questionnaire (NEI VFQ-39) is an indicator of vision-related quality of life (QoL). The NEI VFQ 39 is used to assess the QoL in patients with non-infectious posterior uveitis, intermediate uveitis, or panuveitis, treated with subconjunctival (SCJ) or intravitreal (IVT) sirolimus as an immunomodulatory therapeutic (IMT) agent, delivered subconjunctivally (SCJ) or intravitreally (IVT) (the SAVE Study). Thirty subjects with non-infectious uveitis were randomized (SCJ:IVT, 1:1) for a prospective clinical trial. The 39-Question Visual Function Questionnaire (VFQ 39) was administered at baseline (BL), month 6 (M6), and month 12 (M12) visits. The survey measures self-reported vision health status for patients with chronic eye disease and assesses the effects of visual impairment on both task-oriented visual function and general health domains. In accordance to the NEI-VFQ Manual, each patient's questionnaire was converted to a scaled score between 0 (worst) and 100 (best), and median scores were calculated for each of the subcategories and overall composite score at BL, M6, and M12. Wilcoxon signed-rank test was performed. RESULTS: Twenty-six patients completed the VFQ-39 at BL and M6, whereas 23 patients completed it at M12. Patients showed a significant improvement in pooled composite scores from BL to M6 and BL to M12. Analysis by treatment groups showed that intravitreal injection of sirolimus is better tolerated. CONCLUSIONS: Sirolimus has demonstrated bioactivity as an IMT and corticosteroid-sparing agent to treat non-infectious uveitis. Patients receiving intravitreal injection of sirolimus showed overall improvement of vision-related health while those receiving subconjunctival injections did not. Larger randomized control trials with sirolimus are indicated to validate these results. TRIAL REGISTRATION: ClinicalTrials.gov: NCT00908466. PMID- 25918560 TI - Curbing Ebola infections among healthcare workers in West Africa: unconventional strategies needed. PMID- 25918561 TI - Primary tuberculoma of the liver: a case report and literature review. AB - We report the case of an immunocompetent patient with an isolated tuberculoma of the liver, which was diagnosed by percutaneous US-guided liver biopsy. The patient received an antitubercular therapy, and there has been no relapse to date. PMID- 25918562 TI - [Severe mesenteric infarction by superior mesenteric artery occlusion in a patient suffering from Buerger's disease]. PMID- 25918563 TI - [Lipoblastoma of the subtemporal fossa]. PMID- 25918564 TI - Spontaneous rupture of the spleen operated in gynecological unit mistaken for ruptured hemorrhagic ovarian cyst: total splenectomy. AB - Spontaneous splenic rupture is always neglected when consulting acute abdominal pains in gynecological emergencies. It constitutes about 1% of all splenic ruptures and can be managed by abstention, surgery or embolization. We present the case of a young lady who was diagnosed of spontaneous rupture during surgery that was mistaken for ruptured hemorrhagic ovarian cyst and finally treated by total splenectomy. The pre-operative work up was absolute for a rupturred hemorrhagic cyst and secondariy for a ruptured ectopic gestation. PMID- 25918565 TI - Open fracture of the acromion associated with a supraspinatus tendon rupture: an exceptional case report. AB - The combination of the acromion Open fracture to a section of the supraspinatus tendon is an exceptional situation. The author reports the case of a young patient with a wound of the posterolateral side of the right shoulder. Screwing was done for the fracture of the acromion after supraspinatus tendon suture with good clinical and radiological outcome after an appropriate rehabilitation. PMID- 25918566 TI - [Basal cell carcinoma of the nose: an historical case]. PMID- 25918567 TI - Association between body fat composition and blood pressure level among secondary school adolescents in Dar es Salaam, Tanzania. AB - INTRODUCTION: Excess body fat and high blood pressure (BP) are important risk factors for increased cardiovascular morbidity and mortality, and both may have their roots of occurrence in childhood and adolescence. The present study aimed at determining the association between body fat composition and BP level among adolescents in Tanzania. METHODS: A cross-sectional study involving 5 randomly selected secondary schools within Dar es Salaam was conducted between June and November 2013. Structured questionnaires were used to collect information on demographic characteristics and other cardiovascular risk factors. BP, height, weight and waist circumference were measured following standard methods. Body fat was assessed by skinfold thickness and categorized as underfat, healthy, overfat or obese according to World Health Organization definitions. Hypertension was defined as BP >= 90(th) percentile for age, height and gender of the adolescent. RESULTS: The study included 582 adolescents (mean age 16.5 +/- 1.8 years, 52.1% boys). The proportion of adolescents with overfat or obesity was 22.2%. Systolic, diastolic and combined hypertension was present in 17.5%, 5.5%, and 4.0% respectively. In the total population mean body fat percent correlated positively with diastolic BP and mean arterial pressure (MAP) but not with systolic BP. In multivariate analysis body mass index (beta=0.21, p=0.008) and waist circumference (beta=0.12, p=0.049), but not body fat percentage (beta=-0.09, p=0.399) independently predicted higher MAP. CONCLUSION: Body mass index predicts BP level better than body fat composition and should be used as a measure of increased risk for hypertension among adolescents. PMID- 25918568 TI - Post traumatic type 1 diabetes mellitus (insulin-dependent): a case report. AB - Most researchers have studied the influence of life stress as precipitating the onset of type 1 diabetes, but as the relationship between severe psychological trauma and diabetes has been a rarely studied subject in paediatric age group. Here, we report the case of a 10-year-old Libyan boy, without personal or familial diabetes mellitus history, which is presented to Moroccan medico surgical field hospital, installed in Tunisia for refugees of the Libyan revolution, for type 1 diabetes appeared immediately after severe psychological trauma. PMID- 25918569 TI - Commonization of HIV/AIDS services in Nigeria: the need, the processes and the prospects. AB - INTRODUCTION: With the first case of Human Immunodeficiency Virus infection/Acquired Immunodeficiency Syndrome (HIV/AIDS) identified in 1986, the management of HIV/AIDS in Nigeria has evolved through the years. The emergency phase of the HIV/AIDS program, aimed at containing the HIV/AIDS epidemic within a short time frame, was carried out by international agencies that built structures separate from hospitals' programs. It is imperative that Nigeria shifts from the previous paradigm to the concept of Commonization of HIV to achieve sustainability. Commonization ensures that HIV/AIDS is seen as a health condition like others. It involves making HIV services available at all levels of healthcare. METHODS: Excellence & Friends Management Consult (EFMC) undertook this process by conducting HIV tests in people's homes and work places, referring infected persons for treatment and follow up, establishing multiple HIV testing points and HIV services in private and public primary healthcare facilities. EFMC integrated HIV services within existing hospital care structures and trained all healthcare workers at all supported sites on HIV/AIDS prevention, care and treatment modalities. RESULTS: Commonization has improved the uptake of HIV testing and counseling and enrolment into HIV care as more people are aware that HIV services are available. It has integrated HIV services into general hospital services and minimized the cost of HIV programming as the existing structures and personnel in healthcare facilities are utilized for HIV services. CONCLUSION: Commonization of HIV services i.e. integrating HIV care into the existing fabric of the healthcare system, is highly recommended for a sustainable and efficient healthcare system as it makes HIV services acceptable by all. PMID- 25918570 TI - Hydatid cyst of the pericardium: a case report. AB - Pericardial hydatid cystis a rare condition; its clinical presentation is variable. It can reveal straightaway at the stage of life threatening complications. We report the case of a 17 years old female Arab patient, who complained of a sudden onset dyspnea, clinical examination was poor; the diagnosis was suspected by echocardiography and confirmed by the CT scan and hydatid serology. Furthermore, no other location was noted. Surgical treatmentwas proposed. The modern cross-sectional imaging especially CT scan and MRI revolutionized the diagnosis of this rare hydatid location. PMID- 25918571 TI - [Dynamic stabilization of a winging scapula (about a case with review of the literature)]. PMID- 25918572 TI - Antimicrobial resistance: capacity and practices among clinical laboratories in Kenya, 2013. AB - INTRODUCTION: Antimicrobial resistance is neglected in developing countries; associated with limited surveillance and unregulated use of antimicrobials. Consequently, delayed patient recoveries, deaths and further antimicrobial resistance occur. Recent gastroenteritis outbreak at a children's home associated with multidrug resistant non-typhoidal Salmonella spp, raised concerns about the magnitude of the problem in Kenya, prompting antimicrobial resistance assessment preceding surveillance system establishment. METHODS: Eight public medical laboratories were conveniently selected. Questionnaires were administered to key informants to evaluate capacity, practice and utilization of antimicrobial susceptibility tests. Retrospective review of laboratory records determined antimicrobial resistance to isolates. Antimicrobial resistance was defined as resistance of a microorganism to an antimicrobial agent to which it was previously sensitive and multidrug resistance as non-susceptibility to at least one agent in three or more antimicrobial categories. RESULTS: The laboratories comprised; 2(25%) national, 4(50%) sub-national and 2(25%) district. Overall, antimicrobial susceptibility testing capacity was inadequate in all. Seven (88%) had basic capacity for stool cultures, 3(38%) had capacity for blood culture. Resistance to enteric organisms was observed with the following and other commonly prescribed antimicrobials, ampicillin: 40(91%) Salmonella spp isolates; Tetracycline: 16(84%) Shigella flexineri isolates; cotrimoxazole: 20(100%) Shigella spp isolates, 24(91%) Salmonella spp isolates. Comparable patterns of multidrug resistance were evident with Shigella flexineri and Salmonella typhimurium. Ten (100%) clinicians reported not using laboratory results for patient management, for various reasons. PMID- 25918573 TI - The future of postgraduate training. AB - Improvements to postgraduate training have included newly designed postgraduate curricula, new forms of delivery of learning, more valid and reliable assessments, and more rigorous evaluation of training programmes. All these changes have been necessary and have now started to settle in. Now therefore is an appropriate time to look to the future of postgraduate training. Predicting the future is difficult in any course of life-however an examination of recent trends is often a good place to start. In this regard the recent trend to start to produce more doctors and healthcare professionals of the type that the population needs is likely to continue for some time to come. Medical education will also need to be more flexible in the future. The more flexible that training programmes are, the more likely that we will have experts that are sufficiently flexible to meet a range of different challenges throughout the rest of their careers. Medical education will also become more seamless in the future (at present there are probably too many major milestones and transitions in medical education). In the future educators will make much more use of technology enhanced learning, e-learning and simulation in postgraduate medical education. There will also be more pressure on postgraduate training programmes to offer value for money and to be able to demonstrate such value for money. Postgraduate medical education of the future will also be a more personalised and adaptive experience. It will be far more based on learners' individual needs and will be more responsive to those needs. Lastly postgraduate education will be much more closely supervised than it has been in the past. A common theme running through these changes will be patient centredness. This will mean safer training programmes that produce the type of doctors that patients and populations need. PMID- 25918574 TI - [Impact of varicocele on testicular volume and sperm parameters]. PMID- 25918575 TI - Factors which predict violence victimization in Uganda. AB - INTRODUCTION: Violence is a major public health issue, globally and on the African continent. This paper looks at Uganda and begins the process of identifying the factors that predict violence in that country. The purpose is to interpret the implications of the study results for violence prevention programs. METHODS: The study includes the responses of 2 399 Ugandans collected in 2011 by the Fifth Round of the Afrobarometer surveys. The study concentrates on 259 respondents who reported either they or someone else in their family had been the victim of violence, defined as being physically attacked, in the last year. RESULTS: Logistical regression analysis identified six factors that predict physical violence in Uganda. In order, these included being the victim of a property crime, age, gender, fear of crime in the home, poverty, and residential crowding. The surprising findings relate to what may be called target hardening, especially for those likely to be re-victimized. Respondents did tend to be re victimized, with about 61 percent of violence victims also property crime victims. Fear of crime in home was another predictor of violence victimization, and many of these respondents had been crime victims. CONCLUSION: These findings imply that target hardening should be the basis to begin to implement violence prevention programs in Uganda. The suggestion is crime prevention personnel/ law enforcement need to respond to reported incidents of property and/or violence victimization and attempt to prepare victims to protect both their premises and their persons in the future. PMID- 25918576 TI - [Perception of breastfeeding and complementary feeding in a Congolese urban area]. PMID- 25918577 TI - Factors associated with uptake of voluntary medical male circumcision, Mazowe District, Zimbabwe, 2014. AB - INTRODUCTION: Voluntary Medical Male Circumcision (VMMC) is the surgical removal of the foreskin by a trained health worker. VMMC was introduced in Zimbabwe in 2009. It is of concern that the programme performance has been below expectations nationally and in Mazowe district. Zimbabwe is unlikely to meet its 2015 target of circumcising 1 200 000 men aged between 15 and 29 years and unlikely to enjoy maximum benefits of VMMC which include prevention of HIV, sexually transmitted infections and cervical cancer. We therefore broadly aimed at identifying factors influencing the level of VMMC uptake in Mazowe district. METHODS: An analytic cross-sectional study was carried out in Mazowe district. A multi-stage probability sampling strategy was used to select 300 men aged between 18 and 49 years. Pretested interviewer administered questionnaires, key informant interviews and focus group discussions were used to collect data. Quantitative data was analysed using Epi info where odds ratios and p-values were calculated. Qualitative data was analysed thematically. RESULTS: Being of Shona origin (AOR= 7.69 (95%CI 1.78-33.20)), fear of pain (AOR= 7.09 (95%CI 2.58-19.47)) and fear of poor wound healing (AOR= 2.68 (95%CI 1.01-7.08)) were independently associated with being uncircumcised while having a circumcised friend and encouragement by a friend or relative were independently associated with being circumcised. CONCLUSION: Fear of pain, fear of poor wound healing and encouragement by a friend or relative were associated with circumcision status. Widening use of surgical devices and third part referrals may assist in scaling up the programme. PMID- 25918578 TI - Corrigendum: Risks, precipitants and clinical presentation of gastro-oesophageal reflux disease at the Kilimanjaro Christian Medical Centre in Tanzania. AB - This corrigendum corrects article "Risks, precipitants and clinical presentation of gastro-oesophageal reflux disease at the Kilimanjaro Christian Medical Centre in Tanzania". Pan Afr Med J. 2014 Oct 1;19:119. doi: 10.11604/pamj.2014.19.119.3575.[This corrects the article DOI: 10.11604/pamj.2014.19.119.3575.]. PMID- 25918579 TI - The mitochondrial translocator protein and arrhythmogenesis in ischemic heart disease. AB - Mitochondrial dysfunction is a hallmark of multiple cardiovascular disorders, including ischemic heart disease. Although mitochondria are well recognized for their role in energy production and cell death, mechanisms by which they control excitation-contraction coupling, excitability, and arrhythmias are less clear. The translocator protein (TSPO) is an outer mitochondrial membrane protein that is expressed in multiple organ systems. The abundant expression of TSPO in macrophages has been leveraged to image the immune response of the heart to inflammatory processes. More recently, the recognition of TSPO as a regulator of energy-dissipating mitochondrial pathways has extended its utility from a diagnostic marker of inflammation to a therapeutic target influencing diverse pathophysiological processes. Here, we provide an overview of the emerging role of TSPO in ischemic heart disease. We highlight the importance of TSPO in the regenerative process of reactive oxygen species (ROS) induced ROS release through its effects on the inner membrane anion channel (IMAC) and the permeability transition pore (PTP). We discuss evidence implicating TSPO in arrhythmogenesis in the settings of acute ischemia-reperfusion injury and myocardial infarction. PMID- 25918580 TI - Traumatic brain injury and NADPH oxidase: a deep relationship. AB - Traumatic brain injury (TBI) represents one of the major causes of mortality and disability in the world. TBI is characterized by primary damage resulting from the mechanical forces applied to the head as a direct result of the trauma and by the subsequent secondary injury due to a complex cascade of biochemical events that eventually lead to neuronal cell death. Oxidative stress plays a pivotal role in the genesis of the delayed harmful effects contributing to permanent damage. NADPH oxidases (Nox), ubiquitary membrane multisubunit enzymes whose unique function is the production of reactive oxygen species (ROS), have been shown to be a major source of ROS in the brain and to be involved in several neurological diseases. Emerging evidence demonstrates that Nox is upregulated after TBI, suggesting Nox critical role in the onset and development of this pathology. In this review, we summarize the current evidence about the role of Nox enzymes in the pathophysiology of TBI. PMID- 25918581 TI - Oxidative stress responses and NRF2 in human leukaemia. AB - Oxidative stress as a result of elevated levels of reactive oxygen species (ROS) has been observed in almost all cancers, including leukaemia, where they contribute to disease development and progression. However, cancer cells also express increased levels of antioxidant proteins which detoxify ROS. This includes glutathione, the major antioxidant in human cells, which has recently been identified to have dysregulated metabolism in human leukaemia. This suggests that critical balance of intracellular ROS levels is required for cancer cell function, growth, and survival. Nuclear factor (erythroid-derived 2)-like 2 (NRF2) transcription factor plays a dual role in cancer. Primarily, NRF2 is a transcription factor functioning to protect nonmalignant cells from malignant transformation and oxidative stress through transcriptional activation of detoxifying and antioxidant enzymes. However, once malignant transformation has occurred within a cell, NRF2 functions to protect the tumour from oxidative stress and chemotherapy-induced cytotoxicity. Moreover, inhibition of the NRF2 oxidative stress pathway in leukaemia cells renders them more sensitive to cytotoxic chemotherapy. Our improved understanding of NRF2 biology in human leukaemia may permit mechanisms by which we could potentially improve future cancer therapies. This review highlights the mechanisms by which leukaemic cells exploit the NRF2/ROS response to promote their growth and survival. PMID- 25918582 TI - In vitro toxicity of epigallocatechin gallate in rat liver mitochondria and hepatocytes. AB - Epigallocatechin-3-gallate (EGCG) is the main compound of green tea with well described antioxidant, anti-inflammatory, and tumor-suppressing properties. However, EGCG at high doses was reported to cause liver injury. In this study, we evaluated the effect of EGCG on primary culture of rat hepatocytes and on rat liver mitochondria in permeabilized hepatocytes. The 24-hour incubation with EGCG in concentrations of 10 MUmol/L and higher led to signs of cellular injury and to a decrease in hepatocyte functions. The effect of EGCG on the formation of reactive oxygen species (ROS) was biphasic. While low doses of EGCG decreased ROS production, the highest tested dose induced a significant increase in ROS formation. Furthermore, we observed a decline in mitochondrial membrane potential in cells exposed to EGCG when compared to control cells. In permeabilized hepatocytes, EGCG caused damage of the outer mitochondrial membrane and an uncoupling of oxidative phosphorylation. EGCG in concentrations lower than 10 MUmol/L was recognized as safe for hepatocytes in vitro. PMID- 25918583 TI - Renal oxidative stress induced by long-term hyperuricemia alters mitochondrial function and maintains systemic hypertension. AB - We addressed if oxidative stress in the renal cortex plays a role in the induction of hypertension and mitochondrial alterations in hyperuricemia. A second objective was to evaluate whether the long-term treatment with the antioxidant Tempol prevents renal oxidative stress, mitochondrial alterations, and systemic hypertension in this model. Long-term (11-12 weeks) and short-term (3 weeks) effects of oxonic acid induced hyperuricemia were studied in rats (OA, 750 mg/kg BW), OA+Allopurinol (AP, 150 mg/L drinking water), OA+Tempol (T, 15 mg/kg BW), or vehicle. Systolic blood pressure, renal blood flow, and vascular resistance were measured. Tubular damage (urine N-acetyl-beta-D-glucosaminidase) and oxidative stress markers (lipid and protein oxidation) along with ATP levels were determined in kidney tissue. Oxygen consumption, aconitase activity, and uric acid were evaluated in isolated mitochondria from renal cortex. Short-term hyperuricemia resulted in hypertension without demonstrable renal oxidative stress or mitochondrial dysfunction. Long-term hyperuricemia induced hypertension, renal vasoconstriction, tubular damage, renal cortex oxidative stress, and mitochondrial dysfunction and decreased ATP levels. Treatments with Tempol and allopurinol prevented these alterations. Renal oxidative stress induced by hyperuricemia promoted mitochondrial functional disturbances and decreased ATP content, which represent an additional pathogenic mechanism induced by chronic hyperuricemia. Hyperuricemia-related hypertension occurs before these changes are evident. PMID- 25918584 TI - Accuracy of magnetic resonance cholangiography compared to operative endoscopy in detecting biliary stones, a single center experience and review of literature. AB - AIM: To compare diagnostic sensitivity, specificity and accuracy of magnetic resonance cholangiopancreatography (MRCP) without contrast medium and endoscopic ultrasound (EUS)/endoscopic retrograde cholangiopancreatography (ERCP) for biliary calculi. METHODS: From January 2012 to December 2013, two-hundred-sixty three patients underwent MRCP at our institution, all MRCP procedure were performed with the same machinery. In two-hundred MRCP was done for pure hepatobiliary symptoms and these patients are the subjects of this study. Among these two-hundred patients, one-hundred-eleven (55.5%) underwent ERCP after MRCP. The retrospective study design consisted in the systematic revision of all images from MRCP and EUS/ERCP performed by two radiologist with a long experience in biliary imaging, an experienced endoscopist and a senior consultant in Hepatobiliopancreatic surgery. A false positive was defined an MRCP showing calculi with no findings at EUS/ERCP; a true positive was defined as a concordance between MRCP and EUS/ERCP findings; a false negative was defined as the absence of images suggesting calculi at MRCP with calculi localization/extraction at EUS/ERCP and a true negative was defined as a patient with no calculi at MRCP ad at least 6 mo of asymptomatic follow-up. Biliary tree dilatation was defined as a common bile duct diameter larger than 6 mm in a patient who had an in situ gallbladder. A third blinded radiologist who examined the MRCP and ERCP data reviewed misdiagnosed cases. Once obtained overall data on sensitivity, specificity, accuracy, positive predictive value (PPV) and negative predictive value (NPV) we divided patients in two groups composed of those having concordant MRCP and EUS/ERCP (Group A, 72 patients) and those having discordant MRCP and EUS/ERCP (Group B, 20 patients). Dataset comparisons had been made by the Student's t-test and chi (2) when appropriate. RESULTS: Two-hundred patients (91 men, 109 women, mean age 67.6 years, and range 25-98 years) underwent MRCP. All patients attended regular follow-up for at least 6 mo. Morbidity and mortality related to MRCP were null. MRCP was the only exam performed in 89 patients because it did show only calculi into the gallbladder with no signs of the presence of calculi into the bile duct and symptoms resolved within a few days or after colecistectomy. The patients remained asymptomatic for at least 6 mo, and we assumed they were true negatives. One hundred eleven (53 men, 58 women, mean age 69 years, range 25-98 years) underwent ERCP following MRCP. We did not find any difference between the two groups in terms of race, age, and sex. The overall median interval between MRCP and ERCP was 9 d. In detecting biliary stones MRCP Sensitivity was 77.4%, Specificity 100% and Accuracy 80.5% with a PPV of 100% and NPV of 85%; EUS showed 95% sensitivity, 100% specificity, 95.5% accuracy with 100% PPV and 57.1% NPV. The association of EUS with ERCP performed at 100% in all the evaluated parameters. When comparing the two groups, we did not find any statistically significant difference regarding age, sex, and race. Similarly, we did not find any differences regarding the number of extracted stones: 116 stones in Group A (median 2, range 1 to 9) and 27 in Group B (median 2, range 1 to 4). When we compared the size of the extracted stones we found that the patients in Group B had significantly smaller stones: 14.16 +/- 8.11 mm in Group A and 5.15 +/- 2.09 mm in Group B; 95% confidence interval = 5.89-12.13, standard error = 1.577; P < 0.05. We also found that in Group B there was a significantly higher incidence of stones smaller than 5 mm: 36 in Group A and 18 in Group B, P < 0.05. CONCLUSION: Major finding of the present study is that choledocholithiasis is still under-diagnosed in MRCP. Smaller stones (< 5 mm diameter) are hardly visualized on MRCP. PMID- 25918585 TI - 100 classic papers of interventional radiology: A citation analysis. AB - AIM: To define the 100 citation classic papers of interventional radiology. METHODS: Using the database of Journal Citation Reports the 40 highest impact factor radiology journals were chosen. From these journals the 100 most cited interventional radiology papers were chosen and analysed. RESULTS: The top paper received 2497 citations and the 100(th) paper 200 citations. The average number of citations was 320. Dates of publication ranged from 1953 - 2005. Most papers originated in the United States (n = 67) followed by Italy (n = 20) and France (n = 10). Harvard University (n = 18) and Osped Civile (n = 11) were the most prolific institutions. Ten journals produced all of the top 100 papers with "Radiology" and "AJR" making up the majority. SN Goldberg and T Livraghi were the most prolific authors. Nearly two thirds of the papers (n = 61) were published after 1990. CONCLUSION: This analysis identifies many of the landmark interventional radiology papers and provides a fascinating insight into the changing discourse within the field. It also identifies topics, authors and institutions which have impacted greatly on the specialty. PMID- 25918586 TI - Comparison of 25-hydroxyvitamin D and Calcium Levels between Polycystic Ovarian Syndrome and Normal Women. AB - BACKGROUND: Given the relationship of vitamin D deficiency with insulin resistance syndrome as the component of polycystic ovary syndrome (PCOS), the main aim of this study was to compare serum level of 25hydroxyvitamin D [25(OH)D] between PCOS patients and normal individuals. MATERIALS AND METHODS: A cross sectional study was conducted to compare 25(OH)D level between117 normal and 125 untreated PCOS cases at our clinic in Arash Hospital, Tehran, Iran, during 2011 2012. The obtained levels of 25(OH)D were classified as follows: lower than 25 nmol/ml as severe deficiency, between 25-49.9 nmol/ml as deficiency, 50-74.9 nmol/ml as insufficiency, and above 75 nmol/ml asnormal. In addition, endocrine and metabolic variables were evaluated. RESULTS: Among PCOS patients, our findings shows 3(2.4%) normal, 7(5.6%) with insufficiency, 33(26.4%) with deficiency and 82(65.6%) with severe deficiency, whereas in normal participants, 5(4.3%) normal, 4(3.4%) with insufficiency, 28(23.9%) with deficiency and 80(68.4%) with severe deficiency. Comparison of 25(OH)D level between two main groups showed no significant differences (p= 0.65). Also, the calcium and 25(OH)D levels had no significant differences in patients with overweight (p=0.22) and insulin resistance (p=0.64). But we also found a relationship between 25(OH)D level and metabolic syndrome (p=0.01). Furthermore, there was a correlation between 25(OH)D and body mass index (BMI) in control group (p=0.01), while the C reactive protein (CRP) level was predominantly higher in PCOS group (p<0.001). CONCLUSION: Although the difference of 25(OH)D level between PCOS and healthy women is not significant, the high prevalence of 25(OH)D deficiency is a real alarm for public health care system and may influence our results. PMID- 25918587 TI - Comparison between Unilateral and Bilateral Ovarian Drilling in Clomiphene Citrate Resistance Polycystic Ovary Syndrome Patients: A Randomized Clinical Trial of Efficacy. AB - BACKGROUND: Laparoscopic ovarian drilling (LOD) is an alternative method to induce ovulation in polycystic ovary syndrome (PCOS) patients with clomiphene citrate (CC) resistant instead of gonadotropins. This study aimed to compare the efficacy of unilateral LOD (ULOD) versus bilateral LOD (BLOD) in CC resistance PCOS patients in terms of ovulation and pregnancy rates. MATERIALS AND METHODS: In a prospective randomized clinical trial study, we included 100 PCOS patients with CC resistance attending to Al-Zahra Hospital in Rasht, Guilan Province, Iran, from June 2011 to July 2012. Patients were randomly divided into two ULOD and BLOD groups with equal numbers. The clinical and biochemical responses on ovulation and pregnancy rates were assessed over a 6-month follow-up period. RESULTS: Differences in baseline characteristics of patients between two groups prior to laparoscopy were not significant (p>0.05). There were no significant differences between the two groups in terms of clinical and biochemical responses, spontaneous menstruation (66.1 vs. 71.1%), spontaneous ovulation rate (60 vs. 64.4%), and pregnancy rate (33.1 vs. 40%) (p>0.05). Following drilling, there was a significant decrease in mean serum concentrations of luteinizing hormone (LH) (p=0.001) and testosterone (p=0.001) in both the groups. Mean decrease in serum LH (p=0.322) and testosterone concentrations (p=0.079) were not statistically significant between two groups. Mean serum level of follicle stimulating hormone (FSH) did not change significantly in two groups after LOD (p>0.05). CONCLUSION: Based on results of this study, ULOD seems to be equally efficacious as BLOD in terms of ovulation and pregnancy rates (Registration Number: IRCT138903291306N2). PMID- 25918588 TI - A Randomized Clinical Trial on Comparing The Cycle Characteristics of Two Different Initiation Days of Letrozole Treatment in Clomiphene Citrate Resistant PCOS Patients in IUI Cycles. AB - BACKGROUND: There are still many questions about the ideal protocol for letrozole (LTZ) as the commonest aromatase inhibitor (AI) used in ovulation induction. The aim of this study is to compare the ultrasonographic and hormonal characteristics of two different initiation times of LTZ in clomiphene citrate (CC) failure patients and to study androgen dynamics during the cycle. MATERIALS AND METHODS: This randomized clinical trial was done from March to November 2010 at the Mashhad IVF Center, a university based IVF center. Seventy infertile polycystic ovarian syndrome (PCOS) patients who were refractory to at least 3 CC treatment cycles were randomly divided into two groups. Group A (n=35) receiving 5 mg LTZ on cycle days 3-7 (CD3), and group B (n=35) receiving the same amount on cycle days 5-9 (CD5). Hormonal profile and ultrasonographic scanning were done on cycle day 3 and three days after completion of LTZ treatment (cycle day 10 or 12). Afterward, 5,000-10,000 IU human chorionic gonadotropin (hCG) was injected if at least one follicle >=18 mm was seen in ultrasonographic scanning. Intrauterine insemination (IUI) has been done 36-40 hours later. The cycle characteristics, the ovulation and pregnancy rate were compared between two groups. The statistical analysis was done using Fisher's exact test, t test, logistic regression, and Mann-Whitney U test. RESULTS: There were no significant differences between two groups considering patient characteristics. The ovulation rate (48.6 vs. 32.4% in group A and B, respectively), the endometrial thickness, the number of mature follicles, and length of follicular phase were not significantly different between the two groups. CONCLUSION: LTZ is an effective treatment in CC failure PCOS patients. There are no significant differences regarding ovulation and pregnancy rates between two different protocols of LTZ starting on days 3 and 5 of menstrual cycle ( REGISTRATION NUMBER: IRCT201307096467N3). PMID- 25918589 TI - Age-specific serum anti-mullerian hormone and follicle stimulating hormone concentrations in infertile Iranian women. AB - BACKGROUND: Anti-Mullerian hormone (AMH) is secreted by the granulosa cells of growing follicles during the primary to large antral follicle stages. Abnormal levels of AMH and follicle stimulating hormone (FSH) may indicate a woman's diminished ability or inability to conceive. Our aim is to investigate the changes in serum AMH and FSH concentrations at different age groups and its correlation with ovarian reserves in infertile women. MATERIALS AND METHODS: This cross-sectional study analyzed serum AMH and FSH levels from 197 infertile women and 176 healthy controls, whose mean ages were 19-47 years. Sample collection was performed by random sampling and analyzed with SPSS version 16 software. RESULTS: There were significantly lower mean serum AMH levels among infertile women compared to the control group. The mean AMH serum levels from different ages of infertile and control group (fertile women) decreased with increasing age. However, this reduction was greater in the infertile group. The mean FSH serum levels of infertile women were significantly higher than the control group. Mean serum FSH levels consistently increased with increasing age in infertile women; however mean luteinizing hormone (LH) levels were not consistent. CONCLUSION: We have observed increased FSH levels and decreased AMH levels with increasing age in women from 19 to 47 years of age. Assessments of AMH and FSH levels in combination with female age can help in predicting ovarian reserve in infertile women. PMID- 25918590 TI - The outcomes of intracytoplasmic sperm injection and laser assisted hatching in women undergoing in vitro fertilization are affected by the cause of infertility. AB - BACKGROUND: We sought to determine the association between factors that affected clini- cal pregnancy and live birth rates in patients who underwent in vitro fertilization (IVF) and received intracytoplasmic sperm injection (ICSI) and/or laser assisted hatching (LAH), or neither. MATERIALS AND METHODS: In this retrospective cohort study, the records of women who underwent IVF with or without ICSI and/or LAH at the Far Eastern Memorial Hospital, Taipei, Taiwan between January 2007 and December 2010 were reviewed. We divided patients into four groups: 1. those that did not receive ICSI or LAH, 2. those that received ICSI only, 3. those that received LAH only and 4. those that received both ICSI and LAH. Univariate and multivariate analyses were performed to determine factors associated with clinical pregnancy rate and live birth rate in each group. RESULTS: A total of 375 women were included in the analysis. Oocyte number (OR=1.07) affected the live birth rate in patients that did not receive either ICSI or LAH. Mater- nal age (OR=0.89) and embryo transfer (ET) number (OR=1.59) affected the rate in those that received ICSI only. Female infertility factors other than tubal affected the rate (OR=5.92) in patients that received both ICSI and LAH. No factors were found to affect the live birth rate in patients that received LAH only. CONCLUSION: Oocyte number, maternal age and ET number and female infertility fac- tors other than tubal affected the live birth rate in patients that did not receive ICSI or LAH, those that received ICSI only, and those that received both ICSI and LAH, respectively. No factors affected the live birth rate in patients that received LAH only. These data might assist in advising patients on the appropriateness of ICSI and LAH after failed IVF. PMID- 25918591 TI - Are uterine and ovarian artery Doppler velocimetry values good pregnancy predictors in clomiphene citrate cycles? AB - BACKGROUND: We conducted this prospective study to evaluate the prognostic significance of uterine and ovarian artery Doppler velocimetry in clomiphene citrate (CC) cycles. MATERIALS AND METHODS: A total of 80 patients with unexplained infertility were given 100 mg/day of CC from day 3 to day 7 of their cycles in this current prospective study. On cycle day 3, before administration of CC, each patient underwent Doppler transvaginal ultrasonography. The Doppler velocimetries of the right and left uterine and ovarian arteries were recorded and analyzed in association with demographic and clinical parameters. RESULTS: TheThere were 6 out of 80 patients who became pregnant, the overall pregnancy rate in this population was 7.5% for the current study. The cases were divided into two groups according to whether they became pregnant or not. Demographic characteristics showed no statistically significant differences between these groups (p>0.05). However, the duration of infertility did show statistically significant differences between the groups. Doppler velocimetry was not statistically significantly different between the two groups. CONCLUSION: Doppler velocimetry of the uterine and ovarian arteries is not a factor in the prognosis for pregnancy in CC cycles. PMID- 25918592 TI - Chromosomal analysis of couples with repeated spontaneous abortions in northeastern iran. AB - BACKGROUND: Cytogenetic study of reproductive wastage is an important aspect in determining the genetic background of early embryogenesis. Approximately 15 to 20% of all pregnancies in humans are terminated as recurrent spontaneous abortions (RSAs). The aim of this study was to detect chromosome abnormalities in couples with RSAs and to compare our results with those reported previously. MATERIALS AND METHODS: In this retrospective study, the pattern of chromosomal aberrations was evaluated during a six-year period from 2005 to 2011. The population under study was 728 couples who attended genetic counseling services for their RSAs at Pardis Clinical and Genetics Laboratory, Mashhad, Iran. RESULTS: In this study, about 11.7% of couples were carriers of chromosomal aberrations. The majority of abnormalities were found in couples with history of abortion, without stillbirth or livebirth. Balanced reciprocal translocations, Robertsonian translocations, inversions and sex chromosome aneuploidy were seen in these cases. Balanced reciprocal translocations were the most frequent chromosomal anomalies (62.7%) detected in current study. CONCLUSION: These findings suggest that chromosomal abnormalities can be one of the important causes of RSAs. In addition, cytogenetic study of families who experienced RSAs may prevent unnecessary treatment if RSA are caused by chromosomal abnormalities. The results of cytogenetic studies of RSA cases will provide a standard protocol for the genetic counselors in order to follow up and to help these families. PMID- 25918593 TI - mRNA expression of VEGF and its receptors in fallopian tubes of women with ectopic pregnancies. AB - BACKGROUND: Establishment of viable pregnancy requires embryo implantation and placentation. Ectopic pregnancy (EP) is a pregnancy complication which occurs when an embryo implants outside of the uterine cavity, most often in a fallopian tube. On the other hand, an important aspect of successful implantation is angiogenesis. Vascular endothelial growth factor (VEGF) is a potent angiogenic factor responsible for vascular development that acts through its receptors, VEGF receptor 1 (VEGFR1) and VEGFR2. This study aims to investigate mRNA expression of VEGF and its receptors in fallopian tubes of women who have EP compared with fallopian tubes of pseudo-pregnant women. We hypothesize that expression of VEGF and its receptors in human fallopian tubes may change during EP. MATERIALS AND METHODS: This was a case-control study. The case group consisted of women who underwent salpingectomy because of EP. The control group consisted of women with normal fallopian tubes that underwent hysterectomy. Prior to tubal sampling, each control subject received an injection of human chorionic gonadotropin (hCG) to produce a state of pseudo-pregnancy. Fallopian tubes from both groups were procured. We investigated VEGF, VEGFR1 and VEGFR2 mRNA expressions in different sections of these tubes (infundibulum, ampulla and isthmus) by reverse transcription polymerase chain reaction (RT-PCR) and quantitative PCR (Q-PCR). RESULTS: RT-PCR showed expressions of these genes in all sections of the fallopian tubes in both groups. Q-PCR analysis revealed that expressions of VEGF, VEGFR1 and VEGFR2 were lower in all sections of the fallopian tubes from the case group compared to the controls. Only VEGFR2 had higher expression in the ampulla of the case group. CONCLUSION: Decreased expressions of VEGF, VEGFR1 and VEGFR2 in the EP group may have a role in the pathogenesis of embryo implantation in fallopian tubes. PMID- 25918594 TI - The Effects of Post-Mating Administration of Anti-IL-10 and Anti-TGFbeta on Conception Rates in Mice. AB - BACKGROUND: In fertility studies, it has been shown that transforming growth factor beta (TGFbeta) and interlukin 10 (IL-10) play very important roles in implantation, maternal immune tolerance, placentation and fetal development, and the release beginning of release for fetal and postnatal death. The present study aims to determine the effects of the postmating administration of neutralizing antibodies against IL-10 and TGFbeta, which significantly impact pregnancy in females and the conception rates in mice via assessments of blood serum and uterine fluid concentrations of IL-2, IL-4, IL-6, IL-10, IL-17, interferon gamma (IFNgamma), Tumor necrosis factor alpha (TNFalpha), and TGFbeta. MATERIALS AND METHODS: In this experimental study, 21 BALB/c strain female mice were mated and randomly divided into three groups. The mice in the first group were selected as the control group. The second group of animals was injected with 0.5 mg of anti IL-10 after mating, while those in the third group were intraperitoneally injected with 0.5 mg of anti-TGFbeta. The animals in all groups were decapitated on the 13thday after mating and their blood samples were taken. The uteri were removed to determine pregnancy. The mice's uterine irrigation fluids were also obtained. We used the multiplex immunoassay technique to determine the cytokine concentrations in uterine fluid and blood serum of the mice. RESULTS: We observed no intergroup difference with respect to conception rates. A comparison of the cytokine concentrations in the uterine fluids of pregnant mice revealed higher TGFbeta concentrations (p<0.01) in the second group injected with the anti-IL-10 antibody compared with the other groups. There was no difference detected in pregnant animals with regards to both uterine fluid and blood serum concentrations of the other cytokines. CONCLUSION: Post-mating administration of anti-IL-10 and anti-TGFbeta antibodies in mice may not have any effect on conception rates. PMID- 25918595 TI - Effect of human umbilical cord mesenchymal stem cells transplantation on nerve fibers of a rat model of endometriosis. AB - BACKGROUND: Endometriosis is a common, benign, oestrogen-dependent, chronic gynaecological disorder associated with pelvic pain and infertility. Some researchers have identified nerve fibers in endometriotic lesions in women with endometriosis. Mesenchymal stem cells (MSCs) have attracted interest for their possible use for both cell and gene therapies because of their capacity for self renewal and multipotentiality of differentiation. We investigated how human umbilical cord-MSCs (hUC-MSCs) could affect nerve fibers density in endometriosis. MATERIALS AND METHODS: In this experimental study, hUC-MSCs were isolated from fresh human umbilical cord, characterized by flow cytometry, and then transplanted into surgically induced endometriosis in a rat model. Ectopic endometrial implants were collected four weeks later. The specimens were sectioned and stained immunohistochemically with antibodies against neurofilament (NF), nerve growth factor (NGF), NGF receptor p75 (NGFRp75), tyrosine kinase receptor-A (Trk-A), calcitonin gene-related peptide (CGRP) and substance P (SP) to compare the presence of different types of nerve fibers between the treatment group with the transplantation of hUC-MSCs and the control group without the transplantation of hUC-MSCs. RESULTS: There were significantly less nerve fibers stained with specific markers we used in the treatment group than in the control group (p<0.05). CONCLUSION: MSC from human umbilical cord reduced nerve fiber density in the treatment group with the transplantation of hUC-MSCs. PMID- 25918596 TI - Exploration of infertile couples' support requirements: a qualitative study. AB - BACKGROUND: Due to high prevalence of infertility, increasing demand for infertility treatment, and provision of high quality of fertility care, it is necessary for healthcare professionals to explore infertile couples' expectations and needs. Identification of these needs can be a prerequisite to plan the effective supportive interventions. The current study was, therefore, conducted in an attempt to explore and to understand infertile couples' experiences and needs. MATERIALS AND METHODS: This is a qualitative study based on a content analysis ap- proach. The participants included 26 infertile couples (17 men and 26 women) and 7 members of medical personnel (3 gynecologists and 4 midwives) as the key informants. The infertile couples were selected from patients attending public and private infertility treatment centers and private offices of infertility specialists in Isfahan and Rasht, Iran, during 2012-2013. They were selected through purposive sampling method with maximum variation. In-depth unstructured interviews and field notes were used for data gathering among infertile couples. The data from medical personnel was collected through semi structured interviews. The interview data were analyzed using conventional content analysis method. RESULTS: Data analysis revealed four main categories of infertile couples' needs, including: i. Infertility and social support, ii. Infertility and financial support, iii. Infertility and spiritual support and iv. Infertility and informational support. The main theme of all these categories was assistance and support. CONCLUSION: The study showed that in addition to treatment and medical needs, infertile couples encounter various challenges in different emotional, psychosocial, communicative, cognitive, spiritual, and economic aspects that can affect various areas of their life and lead to new concerns, problems, and demands. Thus, addressing infertile couples' needs and expectations alongside their medical treatments as well as provision of psychosocial services by development of patient-centered approaches and couple based interventions can improve their quality of life and treatment results and also relieve their negative psychosocial consequences. PMID- 25918597 TI - Effect of phosalone on testicular tissue and in vitro fertilizing potential. AB - BACKGROUND: The current study aimed to evaluate the effects of phosalone (PLN) as an organophosphate (OP) compound on testicular tissue, hormonal alterations and embryo development in rats. MATERIALS AND METHODS: In this experimental study, we divided 18 mature Wistar rats into three groups-control, control-sham and test (n=6 per group). Animals in the test group received one-fourth the lethal dose (LD50) of PLN (150 mg/kg), orally, once per day for 45 days. DNA laddering and epi-fluorescent analyses were performed to evaluate testicular DNA fragmentation and RNA damage, respectively. Serum levels of testosterone and inhibin-B (IN-B) were evaluated. Testicular levels of total antioxidant capacity (TAC), total thiol molecules (TTM) and glutathione peroxidase (GSH-px) were analyzed. Finally, we estimated sperm parameters and effect of PLN on embryo development. Two-way ANOVA was used for statistical analyses. RESULTS: There was severe DNA fragmentation and RNA damage in testicular tissue of animals that received PLN. PLN remarkably (p<0.05) decreased testicular TAC, TTM and GSH-px levels. Animals that received PLN exhibited significantly (p<0.05) decreased serum levels of testosterone and IN-B. Reduced sperm count, viability, motility, chromatin condensation and elevated sperm DNA damage were observed in the test group rats. PLN resulted in significant (p<0.05) reduction of in vitro fertilizing (IVF) potential and elevated embryonic degeneration. CONCLUSION: PLN reduced fertilization potential and embryo development were attributed to a cascade of impacts on the testicles and sperm. PLN promoted its impact by elevating DNA and RNA damages via down-regulation of testicular endocrine activity and antioxidant status. PMID- 25918598 TI - Predictive factors of successful microdissection testicular sperm extraction in patients with presumed sertoli cell-only syndrome. AB - BACKGROUND: To evaluate predictive factors of successful microdissection testicular sperm extraction (MD-TESE) in patients with presumed Sertoli cell-only syndrome (SCOS). MATERIALS AND METHODS: In this retrospective analysis, 874 men with non-obstructive azoospermia (NOA), among whom 148 individuals with diagnosis of SCOS in prior biopsy, underwent MD-TESE at Department of Andrology, Royan Institute, Tehran, Iran. The predictive values of follicle stimulating hormone (FSH), luteinizing hormone (LH), and testosterone (T) levels, testicular volume, as well as male age for retrieving testicular sperm by MD-TESE were analyzed by multiple logistic regression analysis. RESULTS: Testicular sperm were successfully retrieved in 23.6% men with presumed SCOS. Using receiver operating characteristic (ROC) curve analysis, it was shown that sperm retrieval rate in the group of men with FSH values >15.25% was 28.9%. This was higher than the group of men with FSH <=15.25 (11.8%). CONCLUSION: Sperm retrieval rate (SRR) was 23.6% in men with presumed SCOS and FSH level can be a fair predictor for SPR at MD-TESE. MD-TESE appears to be recommendable in such cases (SCOS with high FSH concentration) with reasonable results. PMID- 25918599 TI - Study on the effect of royal jelly on reproductive parameters in streptozotocin induced diabetic rats. AB - BACKGROUND: Diabetes mellitus has a variety of structural and functional effects on the male reproductive system. Diabetes results in reduced sperm parameters and libido. The present study aims to investigate the effects of royal jelly (RJ) on reproductive parameters of testosterone and malondialdehyde (MDA) production in diabetic rats. MATERIALS AND METHODS: This experimental study was conducted on adult male Wistar rats. The animals were divided into four groups (n=8 per group): control, RJ, diabetic and diabetic treated with RJ. Diabetes was induced by intraperitoneal injection of 60 mg/kg body weight (BW) of streptozotocin (STZ). RJ, at a dose of 100 mg/kg BW was given by gavage. The duration of treatment was six weeks. After the treatment period the rats were sacrificed. The testes were weighed and changes in sperm count, motility, viability, deformity, DNA integrity and chromatin quality were analyzed. Serum testosterone and MDA concentrations of testicular tissue were determined. Data were analyzed by oneway ANOVA with p<0.05 as the significant level. RESULTS: STZ-induced diabetes decreased numerous reproductive parameters in rats. Testicular weight, sperm count, motility, viability and serum testosterone levels increased in the diabetic group treated with RJ. There was a significant decrease observed in sperm deformity, DNA integrity, chromatin quality, and tissue MDA levels in diabetic rats treated with RJ compared to the diabetic group (p<0.05). CONCLUSION: RJ improved reproductive parameters such as testicular weight, sperm count, viability, motility, deformity, DNA integrity, chromatin quality, serum testosterone and testicular tissue MDA levels in diabetic rats. PMID- 25918600 TI - Oxidant and antioxidant status in experimental rat testis after testicular torsion/detorsion. AB - BACKGROUND: The aim of this study was to determine oxidative stress (OS) parameters after testicular torsion/detorsion in adult rats. MATERIALS AND METHODS: In this experimental study, male adult Wistar rats were divided into four groups, each consisting of seven animals: group I-one hour right testicular torsion with subsequent orchiectomy, group II-one hour right testicular torsion followed by detorsion, group III-unilateral right-sided orchiectomy without previous torsion and group IV-control. After 30 days, bilateral orchiectomies were performed in rats with both testes and unilateral orchiectomies in rats with single testicles. Parameters of OS were determined in testicular tissue and in plasma. RESULTS: Plasma concentrations of advanced oxidation protein products (AOPP) and thiobarbituric acid reactive substances (TBARS) were higher (p<0.05 and p<0.01, respectively), whilst the plasma concentration of the total sulfhydryl (T-SH)-groups was lower (p<0.05) in group I compared to the control group. Group II had higher plasma concentrations of AOPP compared to group IV (p<0.05), as well as significantly increased TBARS and decreased T-SH-group levels compared to groups III (p<0.05 and p<0.01, respectively) and IV (p<0.01, for both parameters). There were significant differences in OS markers between the ipsilateral and contralateral testis, as well as significant correlations among levels of both plasma and tissue markers of OS. CONCLUSION: The increase in TBARS levels seen throughout the experimental period indicated that OS development was caused by ischemia/reperfusion in the testicular tissue. The oxidant-antioxidant system of the testicular tissue was altered during torsion as well as detorsion. PMID- 25918601 TI - In vitro effect of cell phone radiation on motility, DNA fragmentation and clusterin gene expression in human sperm. AB - BACKGROUND: Use of cellular phones emitting radiofrequency electromagnetic field (RF-EMF) has been increased exponentially and become a part of everyday life. This study aimed to investigate the effects of in vitro RF-EMF exposure emitted from cellular phones on sperm motility index, sperm DNA fragmentation and seminal clusterin (CLU) gene expression. MATERIALS AND METHODS: In this prospective study, a total of 124 semen samples were grouped into the following main categories: i. normozoospermia (N, n=26), ii. asthenozoospermia (A, n=32), iii. asthenoteratozoospermia (AT, n=31) and iv. oligoasthenoteratozoospermia (OAT, n=35). The same semen samples were then divided into two portions non-exposed and exposed samples to cell phone radiation for 1 hour. Before and immediately after exposure, both aliquots were subjected to different assessments for sperm motility, acrosin activity, sperm DNA fragmentation and CLU gene expression. Statistical differences were analyzed using paired t student test for comparisons between two sub-groups where p<0.05 was set as significant. RESULTS: There was a significant decrease in sperm motility, sperm linear velocity, sperm linearity index, and sperm acrosin activity, whereas there was a significant increase in sperm DNA fragmentation percent, CLU gene expression and CLU protein levels in the exposed semen samples to RF-EMF compared with non-exposed samples in OAT>AT>A>N groups, respectively (p<0.05). CONCLUSION: Cell phone emissions have a negative impact on exposed sperm motility index, sperm acrosin activity, sperm DNA fragmentation and seminal CLU gene expression, especially in OAT cases. PMID- 25918602 TI - Microlithiasis of Seminal Vesicles and Severe Oligoasthenospermia in Pulmonary Alveolar Microlithiasis (PAM): Report of An Unusual Sporadic Case. AB - Pulmonary alveolar microlithiasis (PAM) is classified as an elective dysmetabolic thesaurotic pneumoalveolitis and characterized by the presence within the alveoli of the lungs of myriad of tiny calculi. The classic presentation of the chest radiography is unmistakable with multiple small "sand-like" opacities diffusely involving both lung fields. We present a case of male infertility for hypoposia and severe oligoasthenospermia in a young patient with recurrent haematuria and small calcifications in the seminal vesicles similar to pulmonary microliths. PAM was diagnosed on routine chest radiography, com- puter tomography (CT), transbronchial biopsy and bronchoalveolar lavage (BAL). PMID- 25918603 TI - Comparative Outcome of Computed Tomography-guided Percutaneous Radiofrequency Ablation, Partial Nephrectomy or Radical Nephrectomy in the Treatment of Stage T1 Renal Cell Carcinoma. AB - Renal cell carcinoma (RCC) accounts for 3% of all cancers in adults. The indications for Radiofrequency Ablation (RFA) for renal carcinomas include T1a (tumor 4 cm or less, limited to the kidney), elderly patients, renal impairment, comorbidities, poor surgical candidate, and multiple bilateral renal masses. We retrospectively reviewed medical records, specifically investigating the indications, complications and outcomes of RFA and nephrectomy for treatment of RCC in a tertiary medical center with a predominantly Hispanic patient population. Forty-nine patients with RCC were evaluated. Nine patients had RFA, 9 had partial nephrectomy and 31 had radical nephrectomy. All patients among the 3 groups had stage T1N0M0 RCC at diagnosis. Tumor recurrence was observed in 2 (22%) patients that had RFA, one (11%) patient that had partial nephrectomy and no patients that had radical nephrectomy. One patient had recurrence of the tumor at the opposite kidney pole from the initial RFA site 4 years later. This particular patient did not have any tumor recurrence at the site of the initial RFA. A second RFA was performed on the recurrent tumor with no recurrence upon subsequent follow up visits. The second patient had recurrence of the RCC on 1 year follow that was discovered to be sarcomatoid RCC, which is an aggressive type with a poor prognosis. Our results support the clinical utility of RFA in patients with stage T1 RCC who are poor surgical candidates or those with reduced renal function. The clinical utility of RFA as an equally effective approach when compared to partial nephrectomy in patients with stage T1 RCC that meet strict indications for the procedure. The treatment choice should be individualized and based on the characteristics of the renal tumor such as size, location and histological type of RCC. We conclude that RFA presents a safe treatment choice for patients with RCC if long term follow up is maintained. PMID- 25918604 TI - Paraneoplastic autoimmune hemolytic anemia in ovarian cancer: a marker of disease activity. AB - Autoimmune hemolytic anemia (AIHA) is a rare paraneoplastic syndrome associated with ovarian malignancies. We report a case of a 77 year-old female with metastatic ovarian carcinoma who presented with worsening anemia from her baseline, and was found to have a warm autoimmune hemolytic anemia. We performed a literature review and analyzed all 10 cases (including our patient) that have been reported to date, and incorporated the clinical presentation, histology and stage of underlying malignancies, types, treatment, prognosis and mechanisms of AIHA in ovarian carcinoma. PMID- 25918605 TI - Retroperitoneal schwannomas of renal and pararenal origin: presentation of two case reports. AB - Retroperitoneal schwannomas are a rare entity. They originate from the Schwann cells of the nerve sheaths and may be of renal or pararenal origin. We report on two patients with retroperitoneal schwannomas, who received surgery under the suspicion of renal cell carcinoma. PMID- 25918606 TI - Giant cells glioblastoma: case report and pathological analysis from this uncommon subtype of glioma. AB - Glioblastoma multiforme (GBM) is the most common glial tumor of the brain system; nevertheless, the giant cell (GC) subtype is uncommon. Recent reviews report for an incidence of 1% in adults and 3% in children. The GCs usually have a better prognosis than GBM and also an increasing long-term survival rate. It is known that the diagnosis of this tumor is due to its histological findings and patterns, such as the unusual increased number of giant cells. Unfortunately, due to its rarity, the immunohistochemical and cytogenetical analysis of this tumor is not well known. Some authors also suggest that there are few subtypes of GCs and their patterns of aggressiveness could be due to cytogenetical markers. It is recognized that maximum safe resection treatment and adjuvant radiotherapy can improve survival rate (5-13 months) similar to GBM patients. PMID- 25918607 TI - Soft tissue sarcomas of the kidney. AB - Soft tissue sarcomas are rare mesenchymal tumors. Amongst others, primitive neuroectodermal tumors (PNET) of the kidney and synovial sarcoma of the kidney belong to the group of soft tissue sarcomas. Synovial sarcomas can occur almost anywhere in the body, most frequently, however, in the lower (62%) or upper extremities (21%). Metastases occur in 50-70% of cases, and thus the prognosis is poor. PNETs are rare, highly aggressive neoplastic lesions which mainly occur in the torso or axial skeleton in young adults. The prognosis is poor with a 5-year disease-free survival rate of 45-55%. The primary therapeutic approach is surgical resection. Most randomized studies assessing adjuvant chemotherapy for all types of localized soft tissue sarcomas did not show statistically significantly better overall survival times after chemotherapy, although they did show longer progression-free survival. We report on two cases of primary renal synovial sarcoma and one case of PNET of the kidney. PMID- 25918608 TI - Posterior mediastinal capillary hemangioma misdiagnosed as neurofibromas: a rare case report and review of the literature. AB - Capillary hemangioma is a common benign tumor which can occur everywhere in the whole body, however its occurrence in posterior mediastinum is extremely rare, and to the best of our knowledge less than 20 cases have been reported in the English literature so far. Here in we report a 65-year-old lady who presented with prolonged cough and diagnosed to have a posterior mediastinal mass. Before operation, according to the site of tumor, it has been diagnosed as neurofibroma. It is very important to consider hemangioma before operation to reduce surgical complications, and it should be in the differential diagnosis of posterior mediastinal masses. PMID- 25918609 TI - A rare occurrence of neonatal nephroblastoma in sub-saharan Africa: a case report and management in a resource-constrained region. AB - Neonatal nephroblastoma has been rarely reported in African neonate. A premature newborn (a 5-day-old male) was transferred with a history of neonatal abdominal mass. Ultrasonography revealed 75*46 mm, well-defined mass with mixed echogenicity replacing the right kidney. The patient underwent right radical nephrectomy and the tumor was confirmed to be a blastemal predominant Wilms' tumor by the histopathological examination and has an unfavorable prognosis. The child died secondary to multiple organ failure, three days after surgery. Our case report serves to remind us the need to bear in mind the possibility of the diagnosis of neonatal nephroblastoma in neonate with renal mass. PMID- 25918610 TI - Cherubism in sub-saharan Africa: a first case-report in a child. AB - Cherubism is rare disease and has been rarely reported in African pediatric population. We report here the case of a 10-year-old child who was referred to our hospital for bilateral jaws swelling. Physical examination revealed bilateral swelling symmetry of the face. Histopathological examination of the biopsy specimen showed loose fibrous stroma, proliferating fibrous connective with tissue interspersed with multinucleated giant cells, small thin walled blood vessels and scattered sparse mononuclear inflammatory infiltrate. Our patient presented cherubism. Cherubism is rarely described in children living in sub Saharan Africa. Genetic and molecular investigations plays an important role in diagnosis but were not available in poor resources settings in developing countries such as the Democratic Republic of Congo. PMID- 25918611 TI - Primary gastric hemangioblastoma: report of a case. AB - Capillary hemangioblastoma (CHB) is a benign, highly vascularized tumor that generally occurs in central nervous system either in the setting of von Hippel Lindau (VHL) disease or, more often, as a solitary sporadic lesion that is increasingly recognized in extraneural sites. We present the case of a 18 year old man with abdominal pain, nausea and hematemesis, the endoscopy showed polypoid tumor bleeding of 5 cm in gastric antrum. The patients had not signs of VHL disease and was subjected to subtotal gastrectomy and referred to our institution. To our knowledge this is the first reported case of CHB occurring in stomach. PMID- 25918612 TI - Primary gastric melanoma: case report of a rare malignancy. AB - We report the case of a 64-year-old white male who presented to his primary care physician with complaints of fatigue. Physical exam was unremarkable and laboratory studies revealed profound anemia, for which the patient received a transfusion. Esophagogastroduodenoscopy revealed a bleeding mass in the proximal stomach that was histologically determined to be malignant melanoma, with immunohistochemical staining demonstrating positivity for SOX10, S100, MART-1, and HMG-45. After an extensive dermatological exam no other primary lesion was identified. Whole body positron emission tomography (18-FDG-PET/CT) demonstrated pathologic uptake only in the area of the proximal stomach. For this reason, primary gastric melanoma was suspected in this patient. The patient underwent subtotal gastrectomy with mass excision followed by Roux-en-Y reconstruction. Very few cases of primary gastric melanoma have been reported. We report this case and present diagnostic criteria for primary non-cutaneous melanoma and discuss potential non-surgical therapies. PMID- 25918613 TI - Estimation of Daily Proteinuria in Patients with Amyloidosis by Using the Protein To-Creatinine ratio in Random Urine Samples. AB - Measurement of daily proteinuria in patients with amyloidosis is recommended at the time of diagnosis for assessing renal involvement, and for monitoring disease activity. Renal involvement is usually defined by proteinuria >500 mg/day. We evaluated the accuracy of the random urine protein-to-creatinine ratio (Pr/Cr) in predicting 24 hour proteinuria in patient with amyloidosis. We compared results of random urine Pr/Cr ratio and concomitant 24-hour urine collections in 44 patients with amyloidosis. We found a strong correlation (Spearman's rho=0.874) between the Pr/Cr ratio and the 24 hour urine protein excretion. For predicting renal involvement, the optimal cut-off point of the Pr/Cr ratio was 715 mg/g. The sensitivity and specificity for this point were 91.8% and 95.5%, respectively, and the area under the curve value was 97.4%. We conclude that the random urine Pr/Cr ratio could be useful in the screening of renal involvement in patients with amyloidosis. If validated in a prospective study, the random urine Pr/Cr ratio could replace the 24 hour urine collection for the assessment of daily proteinuria and presence of nephrotic syndrome in patients with amyloidosis. PMID- 25918614 TI - A Case of Lymphoepithelioma-like Carcinoma in the Uterine Cervix. AB - Lymphoepithelioma-like carcinoma occurring in the reproductive organs is a rare variant of squamous cell carcinoma, and this tumor of the uterine cervix accounts for 0.7% of all primary cervical uterine neoplasms. Associations with Epstein Barr virus (EBV) and human papilloma virus (HPV) have been demonstrated in some studies. Some investigators suggested that EBV has an important role in the initiation of lymphoepitheliomalike carcinoma in Asian women. Here we report the case of a 45-year-old Japanese woman, gravida 2 and parity 2. She was admitted due to severe atypical genital bleeding caused by uterine cervical cancer. A >60 mm tumor was detected at the uterine cervix, and no distal metastasis or swallowing of lymph nodes was revealed by magnetic resonance imaging and a computed tomography scan. The cervical cancer stage FIGO Ib2 was diagnosed, and a radical hysterectomy was performed for this malignant tumor. The in situ hybridization for EBV was negative. HVP infection was strongly suspected because the squamous cell carcinoma was observed macroscopically in the uterine cervix. The prognosis of uterine lymphoepithelioma-like carcinoma is thought to be better than those of other cervical cancer types, but careful follow-up at fixed intervals is recommended. The patient has been followed up for 4 months since her surgery, and no evidence of recurrence has been detected. PMID- 25918615 TI - Whole exome sequencing of a patient with metastatic hidradenocarcinoma and review of the literature. AB - Hidradenocarcinoma is a rare malignancy of the sweat glands with only a few cases reported in literature. The management of these tumors is based on the extent of disease with local disease managed with surgical resection. These can tumors carry a high potential of lymphatic and vascular spread and local and distant metastases are not uncommon. Given the rarity of the tumor and lack of genetic and clinical data about these tumors, there is no consensus on the proper management of metastatic disease. Here in we report the first case of metastatic hidradenocarcinoma with detailed molecular profiling including whole exome sequencing. We identified mutations in multiple genes including two that are potentially targetable: PTCH1 and TCF7L1. Further work is necessary to not only confirm the presence of these mutations but also to confirm the clinical significance. PMID- 25918616 TI - Onychomycosis by syncephalastrum racemosum: case report from kerala, India. AB - We report a rare case of onychomycosis caused by Syncephalastrum racemosum in a 50-year-old diabetic patient. The patient's nail was surgically excised and thorough debridement was done. The patient was successfully treated with topical nystatin. PMID- 25918617 TI - Efficacy of Intravenous Immunoglobulin Monotherapy in Patients with Cutaneous Lupus Erythematosus: Results of Proof-of-Concept Study. AB - Cutaneous lupus erythematosus (CLE) is a chronic inflammatory autoimmune skin disease. Evidence-based therapy for CLE is lacking in the most part. Intravenous immunoglobulin (IVIg) is being increasingly utilized as off-label therapy for a variety of autoimmune and inflammatory conditions, especially in dermatology. The usefulness of IVIg in CLE is not well established. The goal of the present study was to obtain the proof-of-concept evidence that IVIg can control acute CLE and thus replace current systemic immunosuppressive therapy that causes severe side effects and adverse reactions. Sixteen patients who tried and failed various systemic treatments for CLE were screened and consented to use IVIg as a monotherapy. The IVIg was administered at 500 mg/kg/day on 4 consecutive days up to a total of 2 g/kg/month for 3 months, and the subjects were monitored for additional 6 months off any drug for a possible relapse. The cumulative results revealed an overall improvement, as evinced by a decrease of both objective and subjective measures of disease activity. The most sensitive and specific objective and subjective instruments for assessment of the therapeutic effect of IVIg were CLASI-A (Cutaneous Lupus Erythematosus Disease Area and Severity Index) measuring disease activity and Skindex-29 scores, respectively. The CLASI-A score dropped down from the initial value taken as 100%, and remained in the range of approximately 70% until the last visit. Three patients (18.8%) had a temporary flare of CLE symptoms but recovered within a month from the relapse. No serious side effects and adverse reactions occurred. Thus, IVIg monotherapy in CLE allowed to achieve: i) rapid and persistent decreased in disease activity; ii) steady improvement of patients' quality of life assessed by Skindex-29; iii) low relapse rate; and iv) mild nature and short duration of relapses. Since healing was maintained for months after IVIg treatment, it is possible that the IVIgtriggered molecular events mediating the therapeutic action of IVIg that continued to unfold after the end of therapy. PMID- 25918618 TI - Severe scratcher-reaction: an unknown health hazard? AB - Tattoos are well known to cause skin problems and the number of reported adverse reactions after tattooing has increased. Illegally imported tattoo ink is unrestrained and can contain unknown ingredients and contamination thereby posing a serious health hazard. We present a case illustrating the risk of pronounced phototoxic allergic reaction and other severe complications after using home kit tattoo ink. PMID- 25918619 TI - Delayed immune mediated adverse effects to hyaluronic Acid fillers: report of five cases and review of the literature. AB - Hyaluronic acid (HA) fillers in cosmetic medicine have been considered relatively safe, though fillers used in European countries and throughout the world are not necessarily approved by the Food and Drug Administration. As their use continues to expand worldwide, physicians in a wide range of medical specialties are authorized to perform HA injections, including general medicine practitioners and even dentists. An increasing number of reports have appeared regarding side effects to these products. It is now known that reactions to Hyaluronic acid are related not only to technical faults of the injections, but also to immune responses, including delayed hypersensitivity and granulomatous reactions. Herein, we describe five cases treated by a variety of treatment modalities, all with delayed reactions to different brands of hyaluronic acid fillers. As there is currently no standardization of treatment options of adverse effects, these cases accentuate the debate regarding the approach to the individual patient and the possible need for pre-testing in patients with an atopic tendency. PMID- 25918620 TI - Treatment of primary cutaneous anaplastic large cell lymphoma with superficial x rays. AB - The optimal radiation schedule for primary cutaneous anaplastic lymphoma (PCALCL) has not been investigated. We report here satisfactory outcomes of low-dose (16 20 Gy, 3-5 fractions), superficial X-ray radiation (40-50 kV) in a series of 10 patients with PCALCL. Only 1 patient developed a local relapse during the median observation time of 25 months; complete remission was recorded in the other patients. This observation indicates that superficial, low dose X-ray therapy may provide a cost-effective alternative to the traditional 35-45 Gy schedules. PMID- 25918621 TI - Malignant rhabdoid tumor of the liver: a case report and literature review. AB - Malignant rhabdoid tumor (MRT) is a rare and aggressive malignancy associated with poor outcomes. MRT of the liver is even rarer, and little information has been described. We report the case of an 8-month-old boy with MRT of the liver. The tumor showed aggressive progression despite a multidisciplinary approach, and the patient died due to multiple organ failure 14 days after admission. Autopsy revealed the liver tumor and multiple metastases with negative immunohistochemistry for INI1/BAF47. A review of 53 cases of pediatric MRT of the liver is provided. PMID- 25918622 TI - Determinants of stillbirths in katsina, Nigeria: a hospital-based study. AB - Every year, about 3 million stillbirths occur globally, almost a third occurring during the intra-partum period. Almost all stillbirths (98%) occur in low and middle income countries, with Nigeria having the third largest burden. The aim of this study was to determine the stillbirth rate and its determinants in the Federal Medical Centre Katsina, located in north western Nigeria. This study was a retrospective review of all deliveries conducted between 1(st) March 2010 and 31(st) December 2012 in Federal Medical Centre Katsina. Data were extracted from labor room and theatre records, and patient folders. Cases were matched with controls by booking status. The privacy and confidentiality of information retrieved from cases and controls was also ensured by anonymizing the data retrieved. No conflict of interest was identified. The data was analyzed with SPSS 20. During the period under review, there were 6628 deliveries, out of which 331 of the products were stillborn. The stillbirth rate was 46.9+/-3.6 per 1000 deliveries. Determinants of stillbirths were antepartum hemorrhage, hypertensive disorders of pregnancy, uterine rupture, low birth weight and congenital fetal malformations. The study highlighted the poor perinatal health in the study population. PMID- 25918623 TI - Paternal Age, Paternal Presence and Children's Health: An Observational Study. AB - In an observational study of 31,257 children we investigated the effects of paternal age at the time of the child's birth, paternal absence and non biological fathers on children's health. Results are per 5 year change in paternal age. Older fathers were associated with lower rates of unintentional injuries, odds ratio (OR)=0.966, P=0.0027. There was a quadratic association between paternal age and risk of hospital admission, beta=0.0121, P=0.0109, with minimum risk at paternal age 37.7. Absent fathers were associated with increased risk of hospital admission, OR=1.19, P<10(-3), lower rates of complete immunizations to 9 months, OR=0.562, P<10(-3), higher Strength and Difficulties Questionnaire (SDQ) difficulties scores: beta=0.304, P=0.0024 (3 year olds), beta=0.697, P<10(-3) (5 year olds). Non-biological fathers were associated with increased risk of unintentional injury, OR=1.16, P=0.0319 and hospital admission, OR=1.26, P=0.0166; lower rates of complete immunizations to 9 months, OR=0.343, P=0.0309 and higher SDQ difficulties scores: beta=0.908, P<10(-3). PMID- 25918624 TI - Impact of psychological interventions on reducing anxiety, fear and the need for sedation in children undergoing magnetic resonance imaging. AB - Children undergoing magnetic resonance imaging examination frequently experience anxiety and fear before and during the scanning. The aim of the present study was to assess: i) whether and to what extent psychological interventions might reduce anxiety and fear levels; ii) whether the intervention is related to a decrease in the need for sedation. The interventions consisted of three activities: a clown show, dog interaction and live music. The emotional status (anxiety and fear) of the children was evaluated before and after the activities through a rating scale questionnaire. The results showed that the activities had high effectiveness in reducing the level of anxiety and fear and decreased the need for sedation in the experimental group compared to the control group. This approach proved to be a positive patient experience, helping to alleviate children's anxiety and fear, decreasing the need for sedation, and was cost-effective. PMID- 25918625 TI - Acute respiratory distress syndrome associated with tumor lysis syndrome in a child with acute lymphoblastic leukemia. AB - Tumor lysis syndrome is a serious and dangerous complication usually associated with antiblastic treatment in some malignancies characterized by high cell turn over. Mild or severe electrolyte abnormalities including high serum levels of uric acid, potassium, phosphorus, creatinine, bun and reduction of calcium can be responsible for multi-organ failure, involving mostly kidneys, heart and central nervous system. Renal damage can be followed by acute renal failure, weight gain, progressive liver impairment, overproduction of cytokines, and subsequent maintenance of multi-organ damage. Life-threatening acute respiratory failure associated with tumor lysis syndrome is rare. We describe a child with T-cell acute lymphoblastic leukemia, who developed an unusually dramatic tumor lysis syndrome, after administration of the first low doses of steroid, that was rapidly associated with severe acute respiratory distress syndrome. Subsequent clinical course and treatment modalities that resulted in the gradual and full recovery of the child are also described. PMID- 25918626 TI - Essentials in cardiac arrest during cesarean section. AB - Cardiac arrest during cesarean section is very rare. Obstetrical teams have low exposure to these critical situations necessitating frequent rehearsal and knowledge of its differential diagnosis and treatment. A 40-year-old woman pregnant with triplets underwent cesarean sections because of vaginal bleeding due to a placenta previa at 35.2 weeks of gestation. Spinal anesthesia was performed. Asystole occurred during uterotomy. Immediate resuscitation and delivery of the neonates eventually resulted in good maternal and neonatal outcomes. The differential diagnosis is essential and should include obstetric and non-obstetric causes. We describe the consideration of Bezold Jarisch reflex and amniotic fluid embolism as most appropriate in this case. PMID- 25918627 TI - Till Surgery do us Part: Unexpected Bilateral Kissing Molars. AB - The occurrence impacted teeth, single or multiple is very common. But, phenomenon of kissing molars is an extremely rare phenomenon. Mandibular third molars are the most common impacted teeth. Mandibular first or second molars does not share the same frequency of occurrence. But, there are rare cases in which the occlusal surfaces of impacted molars are united by the same follicular space and the roots point in the opposite direction, and are termed as kissing molars. Sometimes, these teeth will be associated with pathologies. This article reports a rare case of mandibular bilateral kissing molars. PMID- 25918628 TI - A recurrent giant cell tumor of bone treated with denosumab. AB - Although the giant cell tumor of bone is generally classified as a benign tumor it can rarely metastasize and has a potential risk of local recurrence. We want to report about a female patient who suffered from a recurrence of a giant cell tumor of bone after the implantation of a total endoprosthesis of the knee joint. We have treated her with denosumab, which is a receptor activator of nuclear factor kappa-B ligand inhibitor. In this case report we want to present a new option to treat this kind of neoplasm. PMID- 25918629 TI - An important cause of pes planus: the posterior tibial tendon dysfunction. AB - Posterior tibial tendon dysfunction (PTTD) is an important cause of acquired pes planus that frequently observed in adults. Factors that play a role in the development of PTTD such as age-related tendon degeneration, inflammatory arthritis, hypertension, diabetes mellitus, obesity, peritendinous injections and more rarely acute traumatic rupture of the tendon. PTT is the primary dynamic stabilizer of medial arch of the foot. Plantar flexion and inversion of the foot occurs with contraction of tibialis posterior tendon, and arch of the foot becomes elaveted while midtarsal joints are locked and midfoot-hindfoot sets as rigid. Thus, during the walk gastrocnemius muscle works more efficiently. If the PTT does not work in the order, other foot ligaments and joint capsule would be increasingly weak and than pes planus occurs. We present a 10-year-old female patient diagnosed as PTTD and conservative treatment with review of the current literature. PMID- 25918630 TI - Congenital prepubic sinus accompanied by prevesical abscess. AB - Congenital prepubic sinus is an extremely rare anomaly. The etiology is uncertain and the anatomical features often differ from each other. We report a 22-year-old woman with a congenital prepubic sinus accompanied by a prevesical abscess. She was admitted to our hospital with high-grade fever and low abdominal pain. Computed tomography revealed a prevesical abscess. After treatment of the prevesical abscess, we completely excised the congenital prepubic sinus. To our knowledge, this is the first reported case that accompanied by prevesical abscess on a congenital prepubic sinus. Moreover, this case represents the oldest reported age of a patient with a congenital prepubic sinus. PMID- 25918631 TI - Staphylococcus lugdunensis gluteal abscess in a patient with end stage renal disease on hemodialysis. AB - A 57-year-old end stage renal disease patient on hemodialysis (HD) presented with sepsis secondary to right buttock abscess and overlying cellulitis. She was started on broad-spectrum antibiotic therapy and underwent incision and drainage with marked improvement. Her cultures grew methicillin-resistant Staphylococcus lugdunensis. This bacterium is more virulent than other coagulase negative staphylococci and has been implicated in causing a variety of serious infections but it has been underreported as a cause of skin infections in HD patients and possible other patient populations. PMID- 25918632 TI - Bilateral inguinal hernias containing ovaries. AB - Inguinal hernias are rare in females. The authors report a case of bilateral inguinal hernias in a 10-year-old female. On exploration, the patient was found to be having a sliding hernia containing incarcerated ovary as contents on both sides. Peroperatively the contents were reduced, the sac was transfixed at its base and the redundant sac was excised. The repair of this form of hernias is more difficult because of adhesions between the contents and the wall of the sac and risk of damage during dissection. A description of this clinical presentation in the pre operative assessment and operative management are discussed in this report. PMID- 25918633 TI - Helicobacter pylori gastritis, a presequeale to coronary plaque. AB - Helicobacter pylori are considered the most common human pathogen colonizing gastric mucosa. Gastritis with or without H. pylori infection is associated with increase in levels of homocysteine and high-sensitivity C-reactive protein (hs CRP) but a more pronounced increase is noted in gastritis with H. pylori infection. Increasing level of homocysteine, due to decreased absorption of vitamin B12 and folic acid, together with increased CRP levels in gastritis with H. pylori infection may be the earliest event in the process of atherosclerosis and plaque formation. Retrospective study conducted at tertiary care hospital in Mumbai by Department of Biochemistry in association with Department of Surgery. Eighty patients who underwent gastroscopy in view of gastritis were subjected to rapid urease test for diagnosis of H. pylori infection. Vitamin B12, folic acid, homocysteine and hs-CRP were analyzed using chemiluminescence immuno assay. Student's t-test, Pearson's correlation and linear regression used for statistical analysis. Patients with H. pylori gastritis had significantly lower levels of vitamin B12 (271.6+/-101.3 vs 390.6+/-176.7 pg/mL; P=0.0005), as well as higher levels of homocysteine (17.4+/-7.4 vs 13.8+/-7.8 umol/L; P=0.037) and hs-CRP (2.5+/-2.9 vs 1.2+/-1.1 mg/L; P=0.017), than in patients without H. pylori gastritis. However, folic acid showed (8.9+/-3.2 vs 10.0+/-3.6 ng/mL; P=0.171) no significant difference. Elevated homocysteine and hs-CRP in H. pylori gastritis may independently induce endothelial dysfunction, leading to cardiovascular pathology. PMID- 25918634 TI - Primary retroperitoneal mucinous cystic tumors with borderline malignancy: a case report and literature review. AB - Primary retroperitoneal mucinous cystic tumors with borderline malignancy are rarely encountered. To date, only 12 cases have been reported in the literature. In this report, we present an additional case. A 65-year-old nulliparous woman complained of abdominal fullness. Her medical history included a hysterectomy and a single salpingo-oophorectomy performed 25 years prior to the present event. Physical examination revealed a large cystic mass in the abdomen and pelvis. During laparotomy, a cystic tumor measuring 21*14 cm in size was observed in the left retroperitoneal space. The tumor was resected, and the final diagnosis was primary retroperitoneal mucinous cystic cancer with borderline malignancy. PMID- 25918635 TI - An unusual pituitary mass revealing a primary hypothyroidism! AB - Autoimmune hypothyroidism is a common medical condition. Its revelation by thyrotrophic hyperplasia is an unusual and may be misdiagnosed as a pituitary adenoma. A 35-year-old man is referred to us for endocrinological assessment before surgery of a pituitary macroadenoma with bitemporal hemianopsia. Biological data reveal profound primary hypothyroidism. With thyroid hormone substitution, the thyroid function was normalized. Follow-up magnetic resonance imaging, showed the complete shrinkage of the pituitary mass attesting of a thyrotrophic pituitary hyperplasia. This case highlights the importance of a multidisciplinary assessment of pituitary masses to avoid unnecessary surgery and to prevent consequences of sellar masses. PMID- 25918636 TI - Bilateral endoscopic endonasal marsupialization of nasopalatine duct cyst. AB - Nasopalatine duct cysts are the most common non-odontogenic cysts in the maxilla, and are conventionally treated through a sublabial or palatine approach. Recently, the endoscopic approach has been used, but experience is extremely limited. We treated a 29-year-old male with nasopalatine duct cyst by endoscopic marsupialization, but paresthesia of the incisor region occurred after surgery. This paresthesia gradually remitted within 6 months. The nasopalatine nerve, which innervates the upper incisor region, enters two lateral canals separately at the nasal floor and exits the central main canal at the palate. Damage to the bilateral nasopalatine nerves might lead to paresthesia, so we recommend careful examination for nerve fibers during endoscopic surgery, especially if fenestration is performed on both sides. PMID- 25918637 TI - Prospective adherence to specific immunotherapy in Europe (PASTE) survey protocol. AB - BACKGROUND: Adherence to allergen immunotherapy is important for its effectiveness. There is currently limited data available on allergen immunotherapy adherence outside of clinical trials i.e. in real-life clinical practice. As part of a European Academy of Allergy and Clinical Immunology Immunotherapy Interest group initiative, we endeavoured to design a survey in order to prospectively evaluate adherence to subcutaneous and sublingual immunotherapy across different European countries. METHOD/DESIGN: The inclusion criteria for this prospective, multi-country survey were set as: adults, starting clinically indicated allergen immunotherapy for respiratory allergic disorders or Hymenoptera venom allergy. An online survey was designed in order to enrol participants and assess adherence to immunotherapy. Eight countries (Czech Republic, Georgia, Germany, Greece, Italy, Poland, Portugal, Spain) were selected to reflect different parts of Europe and differences in allergens and routes of immunotherapy administration. Each country has an allocated National co-ordinator that has identified local Allergy departments willing to enrol participants in this survey. Each participant will be followed up for a total of three years. In order to assess adherence, a 4-monthly follow-up form detailing any missed doses and reasons will be completed online. In case of a participant discontinuing treatment, reasons for this will be recorded. DISCUSSION: The use of online survey software has enabled us to make this survey a reality and reach clinicians in different countries. Forty-five centres have enrolled a total of over 1,350 participants. It is hoped that this prospective real life survey will enable us to gain a better understanding of reasons that affect adherence to subcutaneous and sublingual immunotherapy and assist in developing ways to improve this. PMID- 25918638 TI - Defining the minimally effective dose and schedule for parenteral hydrogen sulfide: long-term benefits in a rat model of hindlimb ischemia. AB - BACKGROUND: Peripheral arterial disease (PAD) affects millions of Americans and leads to critical limb ischemia (CLI) in the most severe cases. Investigators have demonstrated the utility of hydrogen sulfide for restoring perfusion in rodent models of chronic ischemia. We sought to determine the minimum effective dose (MED) of sulfide necessary to restore perfusion in the rat hindlimb, to assess the persistence of limb perfusion after cessation of treatment, and to compare perfusion measurements between laser doppler and ultrasound methods. METHODS: In 3 separate experiments, sodium sulfide (1.0, 0.5, or 0.25 mg/kg twice daily for 14 days, 0.25 mg/kg twice daily for 7 days, 0.5 mg/kg once daily for 7 days, or 0.25 mg/kg twice daily for 3 days) or vehicle was administered after left femoral artery ligation and transection. Hindlimb perfusion was assessed by laser doppler flowmetry and contrast enhanced ultrasound over the duration of each study, and cellular proliferation and vascular density were assessed by immunohistochemical means in the initial experiment. RESULTS: Intravenous sodium sulfide at 0.25, 0.5, or 1.0 mg/kg twice daily for 2 weeks significantly enhanced the recovery of blood flow to the ischemic hindlimb by 7 days. The enhancement of blood flow with 1.0 mg/kg dosing was coincident with an increase in cellular proliferation and vascular density in the ischemic tissue. In a final experiment, i.v. administration of sodium sulfide at 0.5 mg/kg once daily for 7 days or 0.25 mg/kg twice daily for 7 days significantly elevated blood flow and skeletal muscle perfusion in the ischemic hindlimb, whereas 0.25 mg/kg twice daily for 3 days had no effect. This enhancement of blood flow appeared long lived, as blood flow remained elevated 3 weeks after cessation of treatment. CONCLUSIONS: These data, together with other published observations, demonstrate the efficacy of hydrogen sulfide in restoring perfusion to chronically ischemic tissue and establish a minimum efficacious dose in the rat hindlimb model. PMID- 25918639 TI - VirAmp: a galaxy-based viral genome assembly pipeline. AB - BACKGROUND: Advances in next generation sequencing make it possible to obtain high-coverage sequence data for large numbers of viral strains in a short time. However, since most bioinformatics tools are developed for command line use, the selection and accessibility of computational tools for genome assembly and variation analysis limits the ability of individual labs to perform further bioinformatics analysis. FINDINGS: We have developed a multi-step viral genome assembly pipeline named VirAmp, which combines existing tools and techniques and presents them to end users via a web-enabled Galaxy interface. Our pipeline allows users to assemble, analyze, and interpret high coverage viral sequencing data with an ease and efficiency that was not possible previously. Our software makes a large number of genome assembly and related tools available to life scientists and automates the currently recommended best practices into a single, easy to use interface. We tested our pipeline with three different datasets from human herpes simplex virus (HSV). CONCLUSIONS: VirAmp provides a user-friendly interface and a complete pipeline for viral genome analysis. We make our software available via an Amazon Elastic Cloud disk image that can be easily launched by anyone with an Amazon web service account. A fully functional demonstration instance of our system can be found at http://viramp.com/. We also maintain detailed documentation on each tool and methodology at http://docs.viramp.com. PMID- 25918641 TI - Flurbiprofen alone and in combination with alfuzosin for the management of lower urinary tract symptoms. AB - INTRODUCTION: We aimed to investigate the effectiveness and safety of flurbiprofen, a non-steroidal anti-inflammatory drug with dual cyclooxygenase inhibition, and alpha-blocker alfuzosin, both alone and in combination with each other for lower urinary tract symptoms suggestive of benign prostatic obstruction (LUTS/BPO). MATERIAL AND METHODS: Ninety patients complaining of moderate-to severe LUTS/BPO were randomly assigned into 3 groups (30 patients each) to receive alfuzosin XL 10 mg, or flurbiprofen SR 200 mg, or combination of alfuzosin XL 10 mg and flurbiprofen SR 200 mg, once daily for 4 weeks. Patients were evaluated using the international prostate symptom score (IPSS) (total and IPSSstorage, IPSSempty subscores), uroflow-metry (maximum (Qmax) and average (Qave) flow rates) and postvoid residual urine (PVR) both at baseline and following the drug therapy course. RESULTS: There was no difference among the 3 groups regarding age and baseline values of prostate volume, IPSS, IPSSstorage, IPSSempty, Qmax, Qave and PVR (P >0.05). IPSS, IPSSstorage, IPSSempty, and PVR decreased significantly in all the 3 groups after drug therapies (P <0.01). However, Qmax and Qave significantly improved only in the combination group (P <0.01). CONCLUSIONS: Addition of flurbiprofen increased the therapeutic effectiveness of alfuzosin by further improving symptoms in patients with LUTS/BPO. Combination therapy also improved urine flow compared to baseline. Monotherapy with flurbiprofen was not superior to alfuzosin. PMID- 25918640 TI - Neonatal resuscitation: evolving strategies. AB - Birth asphyxia accounts for about 23% of the approximately 4 million neonatal deaths each year worldwide (Black et al, Lancet, 2010, 375(9730):1969-87). The majority of newborn infants require little assistance to undergo physiologic transition at birth and adapt to extrauterine life. Approximately 10% of infants require some assistance to establish regular respirations at birth. Less than 1% need extensive resuscitative measures such as chest compressions and approximately 0.06% require epinephrine (Wyllie et al, Resuscitation, 2010, 81 Suppl 1:e260-e287). Transition at birth is mediated by significant changes in circulatory and respiratory physiology. Ongoing research in the field of neonatal resuscitation has expanded our understanding of neonatal physiology enabling the implementation of improved recommendations and guidelines on how to best approach newborns in need for intervention at birth. Many of these recommendations are extrapolated from animal models and clinical trials in adults. There are many outstanding controversial issues in neonatal resuscitation that need to be addressed. This article provides a comprehensive and critical literature review on the most relevant and current research pertaining to evolving new strategies in neonatal resuscitation. The key elements to a successful neonatal resuscitation include ventilation of the lungs while minimizing injury, the judicious use of oxygen to improve pulmonary blood flow, circulatory support with chest compressions, and vasopressors and volume that would hasten return of spontaneous circulation. Several exciting new avenues in neonatal resuscitation such as delayed cord clamping, sustained inflation breaths, and alternate vasopressor agents are briefly discussed. Finally, efforts to improve resuscitative efforts in developing countries through education of basic steps of neonatal resuscitation are likely to decrease birth asphyxia and neonatal mortality. PMID- 25918642 TI - Short term outcome of anterior lamellar reposition in treating trachomatous trichiasis. AB - Purpose. To evaluate the outcome of anterior lamellar reposition (ALR) in treating trachomatous trichiasis. Methods. Patients with trachomatous trichiasis or entropion with short tarsus were treated by ALR between February 2009 and November 2013. This included splitting of the lid margin behind the aberrant lash line to separate the lid lamellae. The anterior lamella was recessed and fixated using 4/0 silk sutures. The extra lashes and their routes were excised. Sutures were removed by the 3rd week and patients completed 6 months of follow-up. Recurrence of <=5 lashes was treated by electrolysis. Results. The study included 752 eyelids (445 patients; 58.4% females, 41.6% males), mean age 53.2 +/- 6.9 y. 179 (25.1%) lids had entropion while 287 (64.5%) patients had corneal affection. By the third week, 2.66% lid had trichiasis while 30.8% had no rubbing lashes. By the 6th month, 14.9% of lids showed recurrence while 66.1% were completely cured (CI = 0.63-0.69) and 19% had partial success (CI = 0.16-0.21). Abnormal lid appearance persisted in 2.66% and 12.9% required another surgery. Conclusion. ALR is a good option for treating trachomatous trichiasis especially without cicatricial entropion. Excision of dysplastic lashes is thought to augment the surgical outcome. PMID- 25918643 TI - Brain Angiotensin II Type 1 Receptor Blockade Improves Dairy Blood Pressure Variability via Sympathoinhibition in Hypertensive Rats. AB - Abnormal blood pressure (BP) elevation in early morning is known to cause cardiovascular events. Previous studies have suggested that one of the reasons in abnormal dairy BP variability is sympathoexcitation. We have demonstrated that brain angiotensin II type 1 receptor (AT1R) causes sympathoexcitation. The aim of the present study was to investigate whether central AT1R blockade attenuates the excess BP elevation in rest-to-active phase in hypertensive rats or not. Stroke prone spontaneously hypertensive rats (SHRSP) were treated with intracerebroventricular infusion (ICV) of AT1R receptor blocker (ARB), oral administration of hydralazine (HYD), or ICV of vehicle (VEH). Telemetric averaged mean BP (MBP) was measured at early morning (EM), after morning (AM), and night (NT). At EM, MBP was significantly lower in ARB to a greater extent than in HYD compared to VEH, though MBP at AM was the same in ARB and HYD. At NT, MBP was also significantly lower in ARB than in HYD. These results in MBP were compatible to those in sympathoexcitation and suggest that central AT1R blockade attenuates excess BP elevation in early active phase and continuous BP elevation during rest phase independent of depressor response in hypertensive rats. PMID- 25918644 TI - Long-term weight maintenance after a 17-week weight loss intervention with or without a one-year maintenance program: a randomized controlled trial. AB - BACKGROUND: Weight lost by obese patients is almost always regained over time. Extended treatment may improve maintenance, but solid evidence is lacking. PURPOSE: We determined effectiveness of maintenance therapy after a weight loss program. METHODS: Together 201 patients (mean age 47 years and BMI 42 kg/m(2), 71% women) were randomly assigned to either a 17-week weight loss program followed by a one-year maintenance program or to a weight loss program without subsequent maintenance intervention. The weight loss program included behavior modification and a very-low-calorie diet, and maintenance program behavior modification. The primary outcome measure was percentage of patients with 5% or more weight loss at the end of maintenance (week 69) and one year later (week 121). Secondary outcomes were weight related changes in lifestyle and quality of life. RESULTS: At week 69, 52% of the patients with and 44% of those without maintenance program had lost weight >=5%, P = 0.40, and, at week 121, 33% and 34%, P = 0.77, respectively. At week 121 secondary outcomes did not differ between the groups among those successfully followed up. CONCLUSIONS: This one year maintenance program was not effective in preventing weight regain in severely obese patients. Trial Registration. This trial is registered under clinicaltrials.gov Identifier: NCT00590655. PMID- 25918645 TI - International burden of chronic kidney disease and secondary hyperparathyroidism: a systematic review of the literature and available data. AB - The international burden of secondary hyperparathyroidism (SHPT) is unknown, but it may be estimable through the available chronic kidney disease and SHPT literature. Structured reviews of biomedical literature and online data systems were performed for selected countries to ascertain recent estimates of the incidence, prevalence, and survival of individuals with CKD and SHPT. International societies of nephrology were contacted to seek additional information regarding available data. Estimates were abstracted from 35 sources reporting estimates of CKD in 25 countries. Population prevalence estimates of CKD stages 3-5 in adults ranged from approximately 1 to 9% (China, Mexico, resp.). Estimates of the population prevalence of maintenance dialysis therapy ranged from 79 per million population (pmp; China) to 2385 pmp (Japan); incidence rates ranged from 91 pmp (United Kingdom) to 349 pmp (United States). Prevalence of SHPT among stage 5D populations was highly variable and dependent upon the disease definition used. Among the few nations reporting, approximately 30-50% of stage 5D patients had serum parathyroid hormone levels >300 pg/mL. Reported incidence and prevalence estimates across the individual nations were variable, likely reflecting differing population demographics, risk factors, etiologies, and availability of treatment through all stages of CKD. PMID- 25918646 TI - Primary hyperoxaluria type 1 in 18 children: genotyping and outcome. AB - Background. Primary hyperoxaluria belongs to a group of rare metabolic disorders with autosomal recessive inheritance. It results from genetic mutations of the AGXT gene, which is more common due to higher consanguinity rates in the developing countries. Clinical features at presentation are heterogeneous even in children from the same family; this study was conducted to determine the clinical characteristics, type of AGXT mutation, and outcome in children diagnosed with PH1 at a tertiary referral center in Oman. Method. Retrospective review of children diagnosed with PH1 at a tertiary hospital in Oman from 2000 to 2013. Result. Total of 18 children were identified. Females composed 61% of the children with median presentation age of 7 months. Severe renal failure was initial presentation in 39% and 22% presented with nephrocalcinosis and/or renal calculi. Family screening diagnosed 39% of patients. Fifty percent of the children underwent hemodialysis. 28% of children underwent organ transplantation. The most common mutation found in Omani children was c.33-34insC mutation in the AGXT gene. Conclusion. Due to consanguinity, PH1 is a common cause of ESRD in Omani children. Genetic testing is recommended to help in family counseling and helps in decreasing the incidence and disease burden; it also could be utilized for premarital screening. PMID- 25918647 TI - Establishment of MDCK Stable Cell Lines Expressing TMPRSS2 and MSPL and Their Applications in Propagating Influenza Vaccine Viruses in Absence of Exogenous Trypsin. AB - We established two Madin-Darby canine kidney (MDCK) cell lines stably expressing human airway transmembrane protease: transmembrane protease, serine 2 (TMPRSS2) and mosaic serine protease large form (MSPL) which support multicycle growth of two H5 highly pathogenic avian influenza viruses (HPAIV) recombinant vaccines (Re 5 and Re-6) and an H9 avian influenza virus (AIV) recombinant vaccine (Re-9) in the absence of trypsin. Data showed that the cell lines stably expressed TMPRSS2 and MSPL after 20 serial passages. Both MDCK-TMPRSS2 and MDCK-MSPL could proteolytically cleave the HA of Re-5, Re-6, and Re-9 and supported high-titer growth of the vaccine without exogenous trypsin. Re-5, Re-6, and Re-9 efficiently infected and replicated within MDCK-TMPRSS2 and MDCK-MSPL cells and viral titer were comparable to the virus grown in MDCK cells with TPCK-trypsin. Thus, our results indicate a potential application for these cell lines in cell-based influenza vaccine production and may serve as a useful tool for HA proteolytic cleavage-related studies. PMID- 25918649 TI - Myofibroma of the gingiva: a rare case report and literature review. AB - Myofibromas are benign uncommon fibroblastic tumors of the soft tissue, bone, or internal organs affecting all ages. These lesions histopathologically may mimic many other soft tissue tumors of the oral cavity such as spindle cell tumors of neurogenic and smooth muscle cell origin, thus leading to misdiagnosis and mistreatment. This case report describes a rare benign tumor, which presented as a soft tissue swelling on posterior gingiva. Surgical excision of the lesion was carried out under local anaesthesia. Histopathologic and immunohistochemical examination confirmed the diagnosis of myofibroma. Myofibroma should be included in the clinical differential diagnosis of masses of the oral soft tissues; however immunohistochemical examination is essential to establish an accurate diagnosis. PMID- 25918648 TI - Neuronal BDNF signaling is necessary for the effects of treadmill exercise on synaptic stripping of axotomized motoneurons. AB - The withdrawal of synaptic inputs from the somata and proximal dendrites of spinal motoneurons following peripheral nerve injury could contribute to poor functional recovery. Decreased availability of neurotrophins to afferent terminals on axotomized motoneurons has been implicated as one cause of the withdrawal. No reduction in contacts made by synaptic inputs immunoreactive to the vesicular glutamate transporter 1 and glutamic acid decarboxylase 67 is noted on axotomized motoneurons if modest treadmill exercise, which stimulates the production of neurotrophins by spinal motoneurons, is applied after nerve injury. In conditional, neuron-specific brain-derived neurotrophic factor (BDNF) knockout mice, a reduction in synaptic contacts onto motoneurons was noted in intact animals which was similar in magnitude to that observed after nerve transection in wild-type controls. No further reduction in coverage was found if nerves were cut in knockout mice. Two weeks of moderate daily treadmill exercise following nerve injury in these BDNF knockout mice did not affect synaptic inputs onto motoneurons. Treadmill exercise has a profound effect on synaptic inputs to motoneurons after peripheral nerve injury which requires BDNF production by those postsynaptic cells. PMID- 25918650 TI - Durable Red Blood Cell Transfusion Independence in a Patient with an MDS/MPN Overlap Syndrome Following Discontinuation of Iron Chelation Therapy. AB - Background. Hematologic improvement (HI) occurs in some patients with acquired anemias and transfusional iron overload receiving iron chelation therapy (ICT) but there is little information on transfusion status after stopping chelation. Case Report. A patient with low IPSS risk RARS-T evolved to myelofibrosis developed a regular red blood cell (RBC) transfusion requirement. There was no response to a six-month course of study medication or to erythropoietin for three months. At 27 months of transfusion dependence, she started deferasirox and within 6 weeks became RBC transfusion independent, with the hemoglobin normalizing by 10 weeks of chelation. After 12 months of chelation, deferasirox was stopped; she remains RBC transfusion independent with a normal hemoglobin 17 months later. We report the patient's course in detail and review the literature on HI with chelation. Discussion. There are reports of transfusion independence with ICT, but that transfusion independence may be sustained long term after stopping chelation deserves emphasis. This observation suggests that reduction of iron overload may have a lasting favorable effect on bone marrow failure in at least some patients with acquired anemias. PMID- 25918651 TI - Two cases of primary cold agglutinin disease associated with megaloblastic anemia. AB - We report two cases of primary cold agglutinin disease (CAD) associated with megaloblastic anemia in Japanese elderly patients. Case 1 was a 67-year-old male and Case 2 was a 55-year-old male. Both patients were diagnosed with primary CAD, with continuously high cold agglutinin titers (1 : >8,192 and 1 : 16,834, resp.), monoclonal IgM-kappa light chains, and no underlying disease. In addition, both patients had megaloblastic anemia due to vitamin B12 deficiency. One patient received rituximab and both received vitamin 12 supplementation. To date, no cooccurrence of primary CAD and megaloblastic anemia has been emphasized. Thus, the association of these hematological diseases may be incidental; however, given that CAD is an autoimmune disease which may show antibodies against intrinsic factor and gastric parietal cells, this association was thought to be probably not a coincidence. Clinicians should be aware of the possible simultaneous presence of autoimmune hemolytic/megaloblastic anemia in patients with primary CAD. PMID- 25918652 TI - A case of fatal gastrointestinal anthrax in north eastern iran. AB - Background. Bacillus species are aerobic or facultative anaerobic, gram-positive, or gram-variable spore-forming rods. They are ubiquitous in the environmental sources. Bacillus anthracis may usually cause three forms of anthrax: inhalation, gastrointestinal, and cutaneous. The gastrointestinal (GI) anthrax develops after eating contaminated meat. In this paper we report septic intestinal anthrax. Case Presentation. We report an isolation of Bacillus anthracis from blood culture of patient with intestinal anthrax. Bacillus anthracis was isolated from a blood culture of a 34-year-old man who had a history of severe abdominal pain, bloody diarrhea, nausea, vomiting, fever, sweating, and lethargy within 4 to 5 days after eating the meat of domestic goat. He had evidence of severe infection and septic shock and did not respond to treatments and subsequently expired 9 hours after hospitalization. Conclusion. Gastrointestinal anthrax is characterized by rapid onset, fever, and septicemia. Rapid diagnosis and prompt initiation of antibiotic therapy can help in survival. Most of previous cases of septicemic anthrax were related to injection drug users but, in our case, septicemia occurred after gastrointestinal anthrax. PMID- 25918653 TI - A Novel Technique for Laparoscopic Salvage of CAPD Catheter Malfunction and Migration: The Santosh-PGI Hanging Loop Technique. AB - CAPD catheter malfunction is a common problem. Obstruction due to wrapping by appendices epiploicae of sigmoid colon has been rarely reported in literature. We report a case of CAPD catheter malfunction caused by catheter tip migration and obstruction by appendices epiploicae that was successfully managed by laparoscopic hanging loop technique. This case report highlights the ease with which epiplopexy can be performed and catheter tip migration can be prevented by this innovative laparoscopic procedure. PMID- 25918654 TI - Resolution of internal carotid dissection with middle cerebral artery occlusion in pregnancy. AB - Introduction. Cervical artery dissection (CAD) is a common cause of stroke in younger patients. While the incidence of stroke in pregnancy is increasing, CAD remains a rare cause of ischemic stroke in the pregnant population, with only 30 cases described in the literature, most in the postpartum period. Methods. The case of a pregnant patient at 18 weeks of gestation presenting with CAD and ischemic stroke following intercourse is discussed. Discussion. CAD results from an intimal tear in the carotid artery, allowing accumulation of blood in the vessel wall. Stroke results from embolization of thrombogenic material in the wall. Etiology includes minor trauma, connective tissue disorders, or anatomic variations of the carotid artery. Most patients present with headache and/or neck pain, while ischemic symptoms are seen in at least 50% of patients. In the pregnant population, imaging with MRI or MRA of the head and neck aids in diagnosis. Once the diagnosis is made, patients are treated with either anticoagulation or antiplatelet medications. The optimal treatment in both pregnant and nonpregnant patients has not been well-studied. Conclusion. CAD is an important diagnosis to consider in a pregnant patient with persistent headache, especially if neurological symptoms are present. Imaging should be quickly obtained so treatment can be initiated. PMID- 25918655 TI - Widespread recurrence 7 years after radical abdominal trachelectomy for early cervical adenocarcinoma. AB - Cervical cancer is the third most common female cancer worldwide and the use of routine screening resulted in earlier stage and younger age at diagnosis. Fertility preservation via radical trachelectomy comes up as an option in such patients. Recent literature reviews confirm the safety of this operation with excellent oncologic outcomes in appropriately chosen patients. However, recurrent disease is likely and a strict follow-up is recommended to detect recurrences at an early stage following radical trachelectomy. In this report, a case who underwent radical trachelectomy and developed widespread recurrences 7 years after initial surgery possibly due to the lack of oncologic follow-up is discussed. PMID- 25918656 TI - False Positive Radioiodinated Metaiodobenzylguanidine ((123)I-MIBG) Uptake in Undifferentiated Adrenal Malignant Tumor. AB - (123)I-Metaiodobenzylguanidine ((123)I-MIBG) scintigraphy is a widely used functional imaging tool with a high degree of sensitivity and specificity in diagnosis of pheochromocytoma. However, rare cases of false positive reactions have been reported. A 67-year-old male patient was admitted with epigastric pain. Abdominal computed tomography (CT) revealed a heterogeneous left adrenal mass 6 cm in diameter; following hormone testing, (123)I-MIBG scintigraphy was performed to determine the presence of pheochromocytoma, which confirmed eccentric uptake by a large left adrenal gland mass. Chest CT and PET-CT confirmed metastatic lymphadenopathy; therefore, endobronchial ultrasound transbronchial needle aspiration was performed. Metastatic carcinoma of unknown origin was suspected from a lymph node biopsy, and surgical resection was performed for definitive diagnosis and correction of excess hormonal secretion. A final diagnosis of undifferentiated adrenal malignant tumor was rendered, instead of histologically malignant pheochromocytoma, despite the uptake of (123)I-MIBG demonstrated by scintigraphy. PMID- 25918657 TI - Tolosa-hunt syndrome in double-hit lymphoma. AB - Tolosa-Hunt syndrome (THS) is a painful condition characterized by hemicranial pain, retroorbital pain, loss of vision, oculomotor nerve paralysis, and sensory loss in distribution of ophthalmic and maxillary division of trigeminal nerve. Lymphomas rarely involve cavernous sinus and simulate Tolosa-Hunt syndrome. Here we present a first case of double-hit B cell lymphoma (DHL) relapsing and masquerading as Tolosa-Hunt syndrome. The neurological findings were explained by a lymphomatous infiltration of the right Gasserian ganglion which preceded systemic relapse. As part of this report, the diagnostic criteria for Tolosa-Hunt syndrome and double-hit lymphoma are reviewed and updated treatment recommendations are presented. PMID- 25918658 TI - Late onset ipilimumab-induced pericarditis and pericardial effusion: a rare but life threatening complication. AB - Metastatic cutaneous melanoma has poor prognosis with 2-year survival rate of 10 20%. Melanoma cells express various antigens including gp100, melanoma antigen recognized by T cells 1 (MART-1), and tyrosinase, which can induce immune mediated anticancer response via T cell activation. Cytotoxic T-lymphocyte associated antigen-4 (CTLA-4) is an immune check point molecule that negatively regulates T cell activation and proliferation. Accordingly, recent phase III clinical trials demonstrated significant survival benefit with ipilimumab, a human monoclonal antibody (IgG1) that blocks the interaction of CTLA-4 with its ligands. Since the efficacy of ipilimumab depends on T cell activation, it is associated with substantial risk of immune mediated adverse reactions such as colitis, hepatitis, thyroiditis, and hypophysitis. We report the first case of late onset pericarditis and cardiac tamponade associated with ipilimumab treatment in patient with metastatic cutaneous melanoma. PMID- 25918659 TI - Foreign body granulomas induced by intramuscular leuprorelin acetate injection for prostate cancer: clinical mimics of soft tissue sarcoma. AB - We describe two cases of florid, foreign body granulomatous reaction occurring in the upper arms of males in their eighth decade, who were undergoing treatment with depot injection of leuprorelin acetate for prostatic carcinoma. These patients presented with rapidly enlarging extremity soft tissue masses and were referred to a tertiary sarcoma center with clinical suspicion of a primary soft tissue neoplasm. The occurrence of injection site granulomas secondary to leuprorelin acetate administration is rarely known outside the urological and dermatological communities, and their recognition is important due to the spectrum of clinical differential diagnoses and potential for diagnostic confusion with metastatic prostatic cancer and primary sarcoma and in order to avoid unnecessary stress and clinical intervention for patients. PMID- 25918660 TI - Acute corneal hydrops mimicking infectious keratitis as initial presentation of keratoconus in a 10-year-old child. AB - Purpose. To report a case of acute hydrops in a 10-year-old child with advanced keratoconus. Case Presentation. A ten-year-old boy diagnosed as having right eye (RE) infectious keratitis, not responding to antimicrobial therapy, was referred to our hospital. The diagnosis of infectious keratitis was established one month prior to his presentation following an episode of acute corneal whitening, pain, and drop in visual acuity. Topical fortified antibiotics followed by topical antiviral therapy were used with no improvement. Slit lamp examination showed significant corneal protrusion with edema surrounding a rupture in Descemet's membrane in the RE. The diagnosis of acute corneal hydrops from advanced keratoconus was highly suspected and confirmed with corneal topography. Conclusion. Although a relatively rare disease at the age of 10 years, keratoconus can be rapidly progressive in the pediatric group. Keratoconus should always be considered in the differential diagnosis of progressive vision loss in this age group. PMID- 25918661 TI - Rotationplasty with vascular reconstruction for prosthetic knee joint infection. AB - Rotationplasty is used most often as a function-preserving salvage procedure after resection of sarcomas of the lower extremity; however, it is also used after infection of prosthetic knee joints. Conventional vascular management during rotationplasty is to preserve and coil major vessels, but recently, transection and reanastomosis of the major vessels has been widely performed. However, there has been little discussion regarding the optimal vascular management of rotationplasty after infection of prosthetic knee joints because rotationplasty is rarely performed for this indication. We reviewed four patients who had undergone resection of osteosarcomas of the femur, placement of a prosthetic knee joint, and rotationplasty with vascular reconstruction from 2010 to 2013. The mean interval between prosthetic joint replacement and rotationplasty was 10.4 years and the mean interval between the diagnosis of prosthesis infection and rotationplasty was 7.9 years. Rotationplasty was successful in all patients; however, in one patient, arterial thrombosis developed and necessitated urgent surgical removal and arterial reconstruction. All patients were able to walk independently with a prosthetic limb after rehabilitation. Although there is no consensus regarding the most appropriate method of vascular management during rotationplasty for revision of infected prosthetic joints, vascular transection and reanastomosis is a useful option. PMID- 25918662 TI - Total en bloc spondylectomy for locally aggressive vertebral hemangioma causing neurological deficits. AB - Vertebral hemangiomas are common; however, aggressive vertebral hemangiomas with extraosseous extensions causing neurological deficits are rare. The treatment for this subtype of hemangioma remains controversial, since there are few reports on long-term clinical outcomes or tumor recurrence rates. We describe a case of aggressive vertebral hemangioma treated by total en bloc spondylectomy, with a literature review focusing on long-term recurrence. A 52-year-old male with a two month history of numbness in the bilateral lower extremities was referred to our hospital. Imaging studies showed a tumor originating in the T9 vertebra and extending to the T8 and T10 vertebrae, with extraosseous extension causing spinal cord compression. Ten months after onset, the patient presented with progressive paraparesis and hypalgesia. Total en bloc spondylectomy was performed, and pathology was consistent with cavernous hemangioma. Motor and sensory deficits improved significantly, and no signs of recurrence are seen at 2.5 years after operation. A review of literature revealed a recurrence rate of 12.7% (10/79 cases). The available evidence indicates satisfactory long-term outcomes for total tumor resection without adjuvant radiotherapy. PMID- 25918663 TI - A rare case of adductor longus muscle rupture. AB - An adductor longus muscle rupture is a rare injury. This case report describes a 32-year-old patient with an adductor longus rupture. The trauma mechanism was a hyperabduction movement during a soccer game. Nonoperative treatment was initiated. After a follow-up of 4 years, the patient was without pain but a small swelling was still visible. This report describes the anatomy, pathophysiology, and evidence-based treatment of adductor longus rupture. PMID- 25918664 TI - Cocaine induced pleural and pericardial effusion syndrome. AB - A 42-year-old African American female with chronic cocaine use for 20 years, presented with two-day history of exertional shortness of breath and pleuritic chest pain. She was admitted three years back with acute kidney injury and skin rashes. At that time, skin biopsy was consistent with leukocytoclastic vasculitis and renal biopsy revealed proliferative glomerulonephritis. She responded to oral prednisone and mycophenolate with complete recovery of her kidney functions. Skin rash was waxing and waning over the last two years. On the second admission, patient was found to have large pleural effusion on computerized tomography scan and pericardial effusion on echocardiogram as shown in the figures. Pleural fluid analysis was exudative. Her serology was negative for ANA (antineutrophilic antibody) and anti-dsDNA (double stranded DNA). Complements levels were normal. She had positive low titers of ANCA levels. The patient was started on a course of prednisone for 6 months. Her pleural and pericardial effusion resolved completely on follow-up imaging with computerized tomography scan and echocardiogram. This case is unique since the pericardial and pleural effusions developed without any other etiology in the setting of cocaine; hence, we describe this clinical syndrome as cocaine induced pleural and pericardial effusions syndrome (CIPP). PMID- 25918665 TI - Conservative Management of Large Rectosigmoid Perforation under Peritoneal Reflection: Case Report and Review of the Literature. AB - Colonoscopy is accepted as the best method in diagnosis, treatment, and follow-up of colorectal diseases. As the amount of the usage of diagnostic and therapeutic colonoscopy rises, iatrogenic complications are more likely to be seen. The most important complications are perforations and bleeding. Whereas perforation is a complication that is seen rarely, because of the high ratio of morbidity and mortality, it should be analyzed more carefully. There is not a common view on the optimal treatment of colonoscopic perforation. Most cases require urgent surgery, and in some cases the iatrogenic perforation of colon can be managed by conservative methods. In this report, we present a rectosigmoid perforation under peritoneal reflection and conservative management of this case. PMID- 25918666 TI - Treatment of symptomatic lower pole stones of a kidney with partial nephrectomy using micropercutaneous nephrolithotomy technique. AB - We present the treatment of lower pole stones of a 62-year-old male patient with a history of open partial nephrectomy due to renal angiomyolipoma and renal stones. He was successfully treated with micropercutaneous nephrolithotomy technique under spinal anesthesia in spite of fibrotic and scar tissue due to previous open surgery. The patient was stone-free and was discharged after a 24 hour hospitalization period. There is not any published report of micropercutaneous nephrolithotomy in a partial nephrectomized kidney before. In this report, we suggest that microperc technique may be considered for challenging conditions in case of failed retrograde intrarenal surgery. PMID- 25918667 TI - Endovascular treatment of posttraumatic pseudoaneurysm of the common carotid artery. AB - Carotid artery injuries with pseudoaneurysm are uncommon but associated with central neurologic dysfunction. We present a case of posttraumatic pseudoaneurysm of the right common carotid artery treated by implantation of a covered stent. A 44-year-old woman with multiple injuries after fall from height presents a small dissection flap of the right common carotid artery (RCCA) on the initial computed tomography angiography (CTA). Fifteen days later a 10 mm pseudoaneurysm is observed on control CTA. We decided endovascular treatment. Through right femoral access with a long introducer sheath placed in the innominate artery, we implanted a covered stent Advanta V12 9 * 38 mm in the RCCA. The patient was discharged from the hospital with antiplatelet therapy without any neurological dysfunction and complete exclusion of the pseudoaneurysm. Use of covered stents has emerged as a safe and effective alternative to surgical repair of carotid injuries. PMID- 25918669 TI - Progesterone Exerts a Neuromodulatory Effect on Turning Behavior of Hemiparkinsonian Male Rats: Expression of 3 alpha -Hydroxysteroid Oxidoreductase and Allopregnanolone as Suggestive of GABAA Receptors Involvement. AB - There is a growing amount of evidence for a neuroprotective role of progesterone and its neuroactive metabolite, allopregnanolone, in animal models of neurodegenerative diseases. By using a model of hemiparkinsonism in male rats, injection of the neurotoxic 6-OHDA in left striatum, we studied progesterone's effects on rotational behavior induced by amphetamine or apomorphine. Also, in order to find potential explanatory mechanisms, we studied expression and activity of nigrostriatal 3alpha-hydroxysteroid oxidoreductase, the enzyme that catalyzes progesterone to its active metabolite allopregnanolone. Coherently, we tested allopregnanolone for a possible neuromodulatory effect on rotational behavior. Also, since allopregnanolone is known as a GABAA modulator, we finally examined the action of GABAA antagonist bicuculline. We found that progesterone, in addition to an apparent neuroprotective effect, also increased ipsilateral expression and activity of 3alpha-hydroxysteroid oxidoreductase. It was interesting to note that ipsilateral administration of allopregnanolone reversed a clear sign of motor neurodegeneration, that is, contralateral rotational behavior. A possible GABAA involvement modulated by allopregnanolone was shown by the blocking effect of bicuculline. Our results suggest that early administration of progesterone possibly activates genomic mechanisms that promote neuroprotection subchronically. This, in turn, could be partially mediated by fast, nongenomic, actions of allopregnanolone acting as an acute modulator of GABAergic transmission. PMID- 25918668 TI - Mitochondrial Dysfunction and alpha-Synuclein Synaptic Pathology in Parkinson's Disease: Who's on First? AB - Parkinson's disease (PD) is the most common neurodegenerative movement disorder. Its characteristic neuropathological features encompass the loss of dopaminergic neurons of the nigrostriatal system and the presence of Lewy bodies and Lewy neurites. These are intraneuronal and intraneuritic proteinaceous insoluble aggregates whose main constituent is the synaptic protein alpha-synuclein. Compelling lines of evidence indicate that mitochondrial dysfunction and alpha synuclein synaptic deposition may play a primary role in the onset of this disorder. However, it is not yet clear which of these events may come first in the sequel of processes leading to neurodegeneration. Here, we reviewed data supporting either that alpha-synuclein synaptic deposition precedes and indirectly triggers mitochondrial damage or that mitochondrial deficits lead to neuronal dysfunction and alpha-synuclein synaptic accumulation. The present overview shows that it is still difficult to establish the exact temporal sequence and contribution of these events to PD. PMID- 25918670 TI - Oral lactic acid bacteria related to the occurrence and/or progression of dental caries in Japanese preschool children. AB - Previous studies have demonstrated that the presence of lactic acid bacteria (LAB), especially those classified into the genus Lactobacillus, is associated with the progression of dental caries in preschool children. Nevertheless, the kinds of species of LAB and the characteristics that are important for dental caries have been unclear. The aims of this study were: (1) to investigate the distribution of oral LAB among Japanese preschool children with various prevalence levels of caries; and (2) to reveal the characteristics of these isolated LAB species. Seventy-four Japanese preschool children were examined for caries scores and caries progression, and their dental cavity samples were collected for LAB isolation and identification. The saliva-induced agglutination rate and the resistance to acidic environments of the identified strains were measured. Statistical analysis showed that preschool children carrying Lactobacillus (L.) salivarius or Streptococcus mutans have a significantly higher prevalence of dental caries, the growth ability in acidic environments correlates with the caries scores of individuals with L. salivarius, and the caries scores exhibit positive correlation with saliva-induced agglutination in L. salivarius. These results show that specific Lactobacillus species are associated with dental caries based on the level of carious lesion severity. The present study suggests that these specific Lactobacillus species, especially those with easily agglutinated properties and acid resistance, affect the dental caries scores of preschool children, and that these properties may provide useful information for research into the prevention of dental caries. PMID- 25918671 TI - Continuous consumption of fermented milk containing Bifidobacterium bifidum YIT 10347 improves gastrointestinal and psychological symptoms in patients with functional gastrointestinal disorders. AB - The aim of this study was to investigate whether consumption of probiotic fermented milk containing Bifidobacterium bifidum YIT 10347 improves symptoms in patients with functional gastrointestinal disorders (FGID). Thirty-seven FGID patients (18 male, 19 female) aged 12-80 years (mean +/- SD, 52.6 +/- 17.5 years) whose condition had not improved despite being seen at several medical institutions consumed 100 mL/day of B. bifidum YIT 10347 fermented milk for 4 weeks. Symptoms were evaluated after the enrollment period (BL: baseline), sample consumption period (CP) and 4 weeks after the CP (FP: follow-up period). Gastrointestinal symptoms were evaluated using the Gastrointestinal Symptom Rating Scale (GSRS) and the Frequency Scale for the Symptoms of Gastroesophageal Reflux Disease (FSSG); psychological symptoms were evaluated using the Profile of Mood States (POMS) short form. Concentrations of salivary stress markers and the oxidative stress marker urinary 8-hydroxy-2'-deoxyguanosine (8-OHdG) were measured. GSRS subscale scores for abdominal pain, diarrhea, and constipation significantly improved relative to BL after consumption of the fermented milk, as did FSSG subscale scores for symptoms of acid-related dyspepsia. Some subjective psychological symptoms improved. POMS scores significantly improved, and "Anger Hostility" subscale scores significantly decreased after the consumption period, while "Vigor" subscale scores marginally increased during the consumption period. The concentrations of urinary 8-OHdG and the stress marker salivary cortisol were significantly lower at CP but returned to baseline levels at FP. Continuous consumption of B. bifidum YIT 10347 fermented milk is expected to improve gastrointestinal symptoms and reduce psychological stress in FGID patients. PMID- 25918672 TI - Culture-independent bacterial community analysis of the salty-fermented fish paste products of Thailand and Laos. AB - A bacterial community analysis, using a culture-independent method (polymerase chain reaction-denaturing gradient gel electrophoresis), detected 17 species of bacteria including species of the genera Tetragenococcus, Lactobacillus, Pediococcus, Weissella Halanaerobium, Clostridium, and Sphingomonas in a traditional salty-fermented fish paste known as pla-ra or pa-daek in Thailand and Laos, which is used as a storage-stable multi-purpose seasoning. The representative genus of lactic acid bacteria seemed to vary in the 10 products collected from Thailand and Laos. Tetragenococci were common in products from central Thailand and Vientiane in Laos which had salinities of not less than 11% and pH values ranging from 5.6 to 6.1. However, lactobacilli were common in products from northern Thailand which had the lowest salinities (8.3-8.6%) and pH values (4.5-4.8) of all the samples examined. Two Lactobacillus and one Tetragenococcus species were detected in one product from northeastern Thailand containing 10% salt. These results suggest that salinity in pla-ra/pa-daek is an important determinant of the representative genus of lactic acid bacteria such as, Tetragenococcus or Lactobacillus. Additionally, differences in the acidity between these two groups seemed to be related to the production of d-/l-lactic acid in the lactic acid bacteria in each product. This is the first study to report a correlation between bacterial community structure and taste components in pla-ra/pa-daek products from various regions. This scientific work on a traditional fermented food will be useful in helping local producers meet differing consumer preferences in various regions. PMID- 25918673 TI - Novel (89)Zr cell labeling approach for PET-based cell trafficking studies. AB - BACKGROUND: With the recent growth of interest in cell-based therapies and radiolabeled cell products, there is a need to develop more robust cell labeling and imaging methods for in vivo tracking of living cells. This study describes evaluation of a novel cell labeling approach with the positron emission tomography (PET) isotope (89)Zr (T 1/2 = 78.4 h). (89)Zr may allow PET imaging measurements for several weeks and take advantage of the high sensitivity of PET imaging. METHODS: A novel cell labeling agent, (89)Zr-desferrioxamine-NCS ((89)Zr DBN), was synthesized. Mouse-derived melanoma cells (mMCs), dendritic cells (mDCs), and human mesenchymal stem cells (hMSCs) were covalently labeled with (89)Zr-DBN via the reaction between the NCS group on (89)Zr-DBN and primary amine groups present on cell surface membrane protein. The stability of the label on the cell was tested by cell efflux studies for 7 days. The effect of labeling on cellular viability was tested by proliferation, trypan blue, and cytotoxicity/apoptosis assays. The stability of label was also studied in in vivo mouse models by serial PET scans and ex vivo biodistribution following intravenous and intramyocardial injection of (89)Zr-labeled hMSCs. For comparison, imaging experiments were performed after intravenous injections of (89)Zr hydrogen phosphate ((89)Zr(HPO4)2). RESULTS: The labeling agent, (89)Zr DBN, was prepared in 55% +/- 5% decay-corrected radiochemical yield measured by silica gel iTLC. The cell labeling efficiency was 30% to 50% after 30 min labeling depending on cell type. Radioactivity concentrations of labeled cells of up to 0.5 MBq/10(6) cells were achieved without a negative effect on cellular viability. Cell efflux studies showed high stability of the radiolabel out to 7 days. Myocardially delivered (89)Zr-labeled hMSCs showed retention in the myocardium, as well as redistribution to the lung, liver, and bone. Intravenously administered (89)Zr-labeled hMSCs also distributed primarily to the lung, liver, and bone, whereas intravenous (89)Zr(HPO4)2 distributed to the liver and bone with no activity in the lung. Thus, the in vivo stability of the radiolabel on the hMSCs was evidenced. CONCLUSIONS: We have developed a robust, general, and biostable (89)Zr-DBN-based cell labeling strategy with promise for wide applications of PET-based non-invasive in vivo cell trafficking. PMID- 25918674 TI - FIBT versus florbetaben and PiB: a preclinical comparison study with amyloid-PET in transgenic mice. AB - BACKGROUND: Over the last decade, an increasing number of studies have been published on the use of amyloid-beta (Abeta) PET imaging with different (18)F radiopharmaceuticals for clinical characterization of Alzheimer's disease (AD) in different stages. However, distinct study cohorts and different quantification techniques allow only for an indirect comparison between the different tracers. Thus, the aim of this study was the direct intra-individual in vivo comparison of different Abeta-targeted radiopharmaceuticals for PET imaging, including the newly developed agent [(18)F]FIBT. METHODS: A small group of four animals of a well-characterized APP/PS1 transgenic (tg) mouse model of AD and gender-matched control (ctl) animals underwent a sequential and standardized PET imaging regimen for direct comparison of [(18)F]FIBT, [(18)F]florbetaben, and [(11)C]PiB. The quantitative PET imaging data were cross-validated with the cerebral Abeta plaque load as quantified ex vivo on histological sections. RESULTS: We found that FIBT (2-(p-methylaminophenyl)-7-(2-[(18)F]fluoroethoxy)imidazo[2,1-b]benzothiazole) compares favorably to florbetaben as a high-contrasting PET radiopharmaceutical for imaging Abeta pathology. The excellent pharmacokinetics of FIBT in combination with its high-binding affinity towards Abeta resulted in feasible high-contrast imaging of Abeta with high global cortex to cerebellum standard uptake value ratio (SUVR) in 24-month-old tg mice (tg 1.68 +/- 0.15 vs. ctl 0.95 +/- 0.02). The SUVRs in transgenic versus control animals (SUVRtg/SUVRctl) for FIBT (1.78 +/- 0.16) were similar to the ratios as observed in humans (SUVRAD/SUVRctl) for the established gold standard Pittsburgh compound B (PiB) (1.65 +/- 0.41). CONCLUSIONS: This head-to-head PET tracer comparison study in mice indicated the good imaging properties of [(18)F]FIBT, such as high initial brain uptake, fast clearance of the brain, and high binding affinity towards Abeta as directly compared to the established amyloid tracers. Moreover, the preclinical study design is recommendable for reliable assessment and comparison of novel radiopharmaceuticals. PMID- 25918675 TI - Twins in spirit - episode I: comparative preclinical evaluation of [(68)Ga]DOTATATE and [(68)Ga]HA-DOTATATE. AB - BACKGROUND: Recently, an intra-patient comparison demonstrated that the somatostatin (sst) ligand [(68)Ga]HA-DOTATATE ([(68)Ga]DOTA-3-iodo-Tyr(3) octreotate) provides PET images comparable to or superior to those obtained with [(68)Ga]DOTATATE. To provide a comprehensive basis for nevertheless observed slight differences in tracer biodistribution and dosimetry, the characteristics of [(68)Ga]HA-DOTATATE were investigated in a detailed preclinical study. METHODS: Affinities of (nat)Ga-HA-DOTATATE and (nat)Ga-DOTATATE to sst1-5 were determined using membrane preparations and [(125)I]SST-28 as radioligand. Internalization into AR42J cells was studied in dual-tracer studies with [(125)I]TOC as internal reference. Biodistribution was investigated using AR42J tumor-bearing CD1 mice, and specificity of tracer uptake was confirmed in competition studies by coinjection of 0.8 mg TOC/kg. RESULTS: Sst2 affinities (IC50) of [(nat)Ga]HA-DOTATATE (1.4 +/- 0.8 nM, logP: -3.16) and [(nat)Ga]DOTATATE (1.2 +/- 0.6 nM, logP: -3.69) were nearly identical. Both compounds displayed IC50 > 1 MUM for sst1,3,4, while sst5 affinity was markedly increased for (nat)Ga-HA-DOTATATE (102 +/- 65 nM vs >1 MUM for (nat)Ga-DOTATATE). [(nat)Lu]HA-DOTATATE and [(nat)Lu]DOTATATE showed slightly lower, identical sst2 affinities (2.0 +/- 1.6 and 2.0 +/- 0.8 nM, respectively) and sst3 affinities of 93 +/- 1 and 162 +/- 16 nM. Internalization of [(68)Ga]HA-DOTATATE was tenfold higher than that of [(125)I]TOC but only sixfold higher for [(68)Ga]DOTATATE and [(177)Lu]HA-DOTATATE. While [(68)Ga]HA-DOTATATE and [(68)Ga]DOTATATE had shown similar target- and non-target uptake in patients, biodistribution studies in mice at 1 h post injection (n = 5) revealed slightly increased non-specific uptake of [(68)Ga]HA-DOTATATE in the blood, liver, and intestines (0.7 +/- 0.3, 1.0 +/- 0.2, and 4.0 +/- 0.7 %iD/g vs 0.3 +/- 0.1, 0.5 +/- 0.1, and 2.7 +/- 0.8 %iD/g for [(68)Ga]DOTATATE). However, sst-mediated accumulation of [(68)Ga]HA DOTATATE in the pancreas, adrenals, and tumor was significantly enhanced (36.6 +/ 4.3, 10.8 +/- 3.2, and 33.6 +/- 10.9 %iD/g vs 26.1 +/- 5.0, 5.1 +/- 1.4, and 24.1 +/- 4.9 %iD/g, respectively). Consequently, tumor/background ratios for [(68)Ga]HA-DOTATATE in the AR42J model are comparable or slightly increased compared to [(68)Ga]DOTATATE. CONCLUSIONS: The present preclinical data fully confirm the general biodistribution pattern and excellent in vivo sst-targeting characteristics previously observed for [(68)Ga]HA-DOTATATE in patients. The effect of slightly enhanced lipophilicity on background accumulation and normal organ dose is compensated by the high uptake of [(68)Ga]HA-DOTATATE in tumor. Thus, [(68)Ga]HA-DOTATATE represents a fully adequate, freely available substitute for [(68)Ga]DOTATATE and, given the superb sst-targeting characteristics of [(177)Lu]HA-DOTATATE in vitro, potential applicability for sst targeted PRRT. PMID- 25918676 TI - Whole-body organ-level and kidney micro-dosimetric evaluations of (64)Cu-loaded HER2/ErbB2-targeted liposomal doxorubicin ((64)Cu-MM-302) in rodents and primates. AB - BACKGROUND: Features of the tumor microenvironment influence the efficacy of cancer nanotherapeutics. The ability to directly radiolabel nanotherapeutics offers a valuable translational tool to obtain biodistribution and tumor deposition data, testing the hypothesis that the extent of delivery predicts therapeutic outcome. In support of a first in-human clinical trial with (64)Cu labeled HER2-targeted liposomal doxorubicin ((64)Cu-MM-302), a preclinical dosimetric analysis was performed. METHODS: Whole-body biodistribution and pharmacokinetic data were obtained in mice that received (64)Cu-MM-302 and used to estimate absorbed radiation doses in normal human organs. PET/CT imaging revealed non-uniform distribution of (64)Cu signal in mouse kidneys. Kidney micro dosimetry analysis was performed in mice and squirrel monkeys, using a physiologically based pharmacokinetic model to estimate the full dynamics of the (64)Cu signal in monkeys. RESULTS: Organ-level dosimetric analysis of mice receiving (64)Cu-MM-302 indicated that the heart was the organ receiving the highest radiation absorbed dose, due to extended liposomal circulation. However, PET/CT imaging indicated that (64)Cu-MM-302 administration resulted in heterogeneous exposure in the kidney, with a focus of (64)Cu activity in the renal pelvis. This result was reproduced in primates. Kidney micro-dosimetry analysis illustrated that the renal pelvis was the maximum exposed tissue in mice and squirrel monkeys, due to the highly concentrated signal within the small renal pelvis surface area. CONCLUSIONS: This study was used to select a starting clinical radiation dose of (64)Cu-MM-302 for PET/CT in patients with advanced HER2-positive breast cancer. Organ-level dosimetry and kidney micro-dosimetry results predicted that a radiation dose of 400 MBq of (64)Cu-MM-302 should be acceptable in patients. PMID- 25918677 TI - The fundus slit lamp. AB - Fundus biomicroscopy with the slit lamp as it is practiced widely nowadays was not established until the 1980-es with the introduction of the Volk lenses +90 and +60D. Thereafter little progress has been made in retinal imaging with the slit lamp. It is the aim of this paper to fully exploit the potential of a video slit lamp for fundus documentation by using easily accessible additions. Suitable still images are easily retrieved from videorecordings of slit lamp examinations. The effects of changements in the slit lamp itself (slit beam and apertures) and its examination equipment (converging lenses from +40 to +90D) on quality and spectrum of fundus images are demonstrated. Imaging software is applied for reconstruction of larger fundus areas in a mosaic pattern (Hugin(r)) and to perform the flicker test in order to visualize changes in the same fundus area at different points of time (Power Point(r)). The three lenses +90/+60/+40D are a good choice for imaging the whole spectrum of retinal diseases. Displacement of the oblique slit light can be used to assess changes in the surface profile of the inner retina which occurs e.g. in macular holes or pigment epithelial detachment. The mosaic function in its easiest form (one strip macula adapted to one strip with the optic disc) provides an overview of the posterior pole comparable to a fundus camera's image. A reconstruction of larger fundus areas is feasible for imaging in vitreoretinal surgery or occlusive vessel disease. The flicker test is a fine tool for monitoring progressive glaucoma by changes in the optic disc, and it is also a valuable diagnostic tool in macular disease. Nearly all retinal diseases can be imaged with the slit lamp - irrespective whether they affect the posterior pole, mainly the optic nerve or the macula, the whole retina or only its periphery. Even a basic fundus controlled perimetry is possible. Therefore fundus videography with the slit lamp is a worthwhile approach especially for the many ophthalmologists without access to the most recent diagnostic equipment or a professional photographer at hand. PMID- 25918679 TI - Real-time analysis application for identifying bursty local areas related to emergency topics. AB - Since social media started getting more attention from users on the Internet, social media has been one of the most important information source in the world. Especially, with the increasing popularity of social media, data posted on social media sites are rapidly becoming collective intelligence, which is a term used to refer to new media that is displacing traditional media. In this paper, we focus on geotagged tweets on the Twitter site. These geotagged tweets are referred to as georeferenced documents because they include not only a short text message, but also the documents' posting time and location. Many researchers have been tackling the development of new data mining techniques for georeferenced documents to identify and analyze emergency topics, such as natural disasters, weather, diseases, and other incidents. In particular, the utilization of geotagged tweets to identify and analyze natural disasters has received much attention from administrative agencies recently because some case studies have achieved compelling results. In this paper, we propose a novel real-time analysis application for identifying bursty local areas related to emergency topics. The aim of our new application is to provide new platforms that can identify and analyze the localities of emergency topics. The proposed application is composed of three core computational intelligence techniques: the Naive Bayes classifier technique, the spatiotemporal clustering technique, and the burst detection technique. Moreover, we have implemented two types of application interface: a Web application interface and an android application interface. To evaluate the proposed application, we have implemented a real-time weather observation system embedded the proposed application. we used actual crawling geotagged tweets posted on the Twitter site. The weather observation system successfully detected bursty local areas related to observed emergency weather topics. PMID- 25918678 TI - RAD51, XRCC3, and XRCC2 mutation screening in Finnish breast cancer families. AB - Majority of the known breast cancer susceptibility genes have a role in DNA repair and the most important high-risk genes BRCA1 and BRCA2 are specifically involved in the homologous recombination repair (HRR) of DNA double-strand breaks. A central player in HRR is RAD51 that binds DNA at the damage site. The RAD51 paralogs RAD51B, RAD51C, RAD51D, XRCC2, and XRCC3 facilitate the binding of RAD51 to DNA. While germline mutations in RAD51C and RAD51D are associated with high ovarian cancer risk and RAD51B polymorphisms with breast cancer, the contribution of RAD51, XRCC3, and XRCC2 is more unclear. To investigate the role of RAD51, XRCC3, and XRCC2 in breast cancer predisposition and to identify putative recurrent founder mutations in the Finnish population where such mutations have been observed in most of the currently known susceptibility genes, we screened 182 familial Finnish breast or ovarian cancer patients for germline variation in the RAD51and XRCC3 genes and 342 patients for variation in XRCC2, with a subset of the patients selected on the basis of decreased RAD51 protein expression on tumors. We also performed haplotype analyses for 1516 breast cancer cases and 1234 controls to assess the common variation in these genes. No pathogenic mutations were detected in any of the genes and the distribution of haplotypes was similar between cases and controls. Our results suggest that RAD51, XRCC3, and XRCC2 do not substantially contribute to breast cancer predisposition in the Finnish population. PMID- 25918680 TI - Clean synthesis of biolubricant range esters using novel liquid lipase enzyme in solvent free medium. AB - In view of the rising global problems of environment pollution and degradation, the present process provides a 'green solution' to the synthesis of higher esters of lubricant range, more specifically in the range C12-C36, using different combinations of acids and alcohols, in a single step reaction. The esters produced are biodegradable in nature and have a plethora of uses, such as in additives, as lubricating oils and other hydraulic fluids. The enzymatic esterification was performed using liquid (non-immobilized or free) lipase enzyme, without any additional organic solvent. Soluble lipase proves to be superior to immobilized enzymes as it is more cost effective and provides a faster process for the production of higher esters of lubricant range. An interesting finding was, that the lipase enzyme showed higher conversion rates with increasing carbon number of straight chain alcohols and acids. Reactions were carried out for the optimization of initial water concentration, temperature, pH of the substrate mixture and the chain length of the substrates. Under optimized conditions, the method was suitable to achieve ~ 99% conversion. Thus, the process provides an environment friendly, enzymatic alternative to the chemical route which is currently used in the industrial synthesis of lubricant components. PMID- 25918681 TI - Pretreatment levels of the serum biomarkers CEA, CYFRA 21-1, SCC and the soluble EGFR and its ligands EGF, TGF-alpha, HB-EGF in the prediction of outcome in erlotinib treated non-small-cell lung cancer patients. AB - The aim of this study has been to investigate the potential of serum biomarkers used in clinical practice (CEA, CYFRA 21-1, SCC) together with the serum epidermal growth factor receptor (EGFR) and its associated ligands (EGF, TGF alpha, HB-EGF) as outcome predictors of non-small cell lung cancer (NSCLC) patients treated with the TKI erlotinib. The pretreatment levels of these markers were evaluated through immunoassays carried out in 58 patients. The progression free survival (PFS) and overall survival (OS) were assessed by the Kaplan-Meier method and differences between groups were compared by means of the Log-Rank test. Association of risk factors with survival was evaluated using the univariate and multivariate Cox modelling procedures. Higher CEA (>5 ng/mL) and sEGFR (>56.87 ng/mL) concentrations associated significantly with a higher overall survival. The pre-treatment sEGFR serum levels constituted an independent prognostic factor. The EGFR gene mutational status and the sEGFR level combination was the single to associate significantly with longer progression free survival periods, in circumstances in which the EGFR gene was mutated and increased protein serum levels were detected. The overall survival as assessed through a Cox analysis revealed similar death hazards with respect to low sEGFR levels combined both with non-mutated EGFR genotypes and low CEA serum levels. Our results suggest that the pre-treatment CEA and sEGFR serum levels may provide a comparable source of information to that supplied by the EGFR gene mutational status with respect to the prognosis of erlotinib treated NSCLC patients. A combined sEGFR and CEA level appraisal could be of considerable value to select patients to undergo EGFR-TKI treatments. PMID- 25918682 TI - A case of hypothalamic hypopituitarism accompanied by recurrent severe hypoglycemia. AB - INTRODUCTION: Hypothalamic hypopituitarism is relatively rare cause of secondary adrenal deficiency which is often accompanied by severe hypoglycemia. Hydrocortisone replacement therapy is essential for this condition, but gastrointestinal symptom such as nausea and vomiting is not well-recognized adverse effect of hydrocortisone. CASE DESCRIPTION: A 64-year-old-woman was referred to our hospital because of frequent severe hypoglycemia. She was diagnosed as type 2 diabetes when she was 58 years old but had not been treated since she was 60. We ruled out the possibility of exogenous administration of insulin or other anti-diabetic drugs, insulinoma and insulin autoimmune syndrome. After glucose injection, she once became conscious, but severe hypoglycemia was often observed even after that. In addition, counter-regulatory hormone levels were not increased even at the time of hypoglycemia. We conducted several hormone load tests. In corticotropin-releasing hormone (CRH) load test, excess and delayed reaction of ACTH was observed. In thyrotropin-releasing hormone (TRH) load test, TSH and prolactin were normally secreted in response to TRH. In luteinizing hormone-releasing hormone (LHRH) load test, delayed reaction of LH and FSH was observed. Based on such hormone loading tests, we diagnosed this patient as idiopathic hypothalamic hypopituitarism and consequent adrenal deficiency. We immediately intravenously injected hydrocortisone and started oral hydrocortisone therapy. However, just after taking hydrocortisone, vomiting was often observed which disturbed sufficient steroid hormone replacement, leading to recurrent hypoglycemia. Therefore, we stopped hydrocortisone and instead started an alternative treatment with prednisolone. After that, vomiting and hypoglycemia were not observed at all. DISCUSSION AND EVALUATION: We diagnosed this subject as hypothalamic hypopituitarism mainly by the following two findings: (1) excess and delayed reaction of ACTH in CRH load test, (2) delayed reaction of LH and FSH in LHRH load test. CONCLUSIONS: We should be aware of the possibility of hypothalamic hypopituitarism as a cause of recurrent severe hypoglycemia. Also, we should be aware that hydrocortisone could induce gastrointestinal symptom and that in such a case we should stop hydrocortisone and start prednisolone to sufficiently replace steroid hormone and avoid recurrent hypoglycemia. PMID- 25918684 TI - Leprous lesion presents enrichment of opportunistic pathogenic bacteria. AB - Leprosy is a chronic infectious disease that remains a major challenge to public health in endemic countries. Increasing evidence has highlighted the importance of microbiota for human general health and, as such, the study of skin microbiota is of interest. But while studies are continuously revealing the complexity of human skin microbiota, the microbiota of leprous cutaneous lesions has not yet been characterized. Here we used Sanger and massively parallel small sub-unit rRNA (SSU) rRNA gene sequencing to characterize the microbiota of leprous lesions, and studied how it differs from the bacterial skin composition of healthy individuals previously described in the literature. Taxonomic analysis of leprous lesions revealed main four phyla: Proteobacteria, Firmicutes, Bacteroidetes, and Actinobacteria, with Proteobacteria presenting the highest diversity. There were considerable differences in the distribution of Proteobacteria, Bacteroidetes, Firmicutes, and Actinobacteria, with the first two phyla enriched and the other markedly diminished in the leprous lesions, when compared with healthy skin. Propionibacterium, Corynebacterium and Staphylococcus, resident and abundant in healthy skin, were underrepresented in skin from leprous lesions. Most of the taxa found in skin from leprous lesions are not typical in human skin and potentially pathogenic, with the Burkholderia, Pseudomonas and Bacillus genera being overrepresented. Our data suggest significant shifts of the microbiota with emergence and competitive advantage of potentially pathogenic bacteria over skin resident taxa. PMID- 25918683 TI - Validation of endogenous reference genes in Buglossoides arvensis for normalizing RT-qPCR-based gene expression data. AB - Selection of a stably expressed reference gene (RG) is an important step for generating reliable and reproducible quantitative real-time reverse transcription polymerase chain reaction (RT-qPCR) gene expression data. We, in this study, have sought to validate RGs for Buglossoides arvensis, a high nutraceutical value plant whose refined seed oil is entering the market under the commercial trade name AhiflowerTM. This weed plant has received attention for its natural ability to significantly accumulate the poly-unsaturated fatty acid (PUFA) stearidonic acid (SDA, C18:4n-3) in its seeds, which is uncommon for most plant species. Ten candidate RGs (beta-Act, 18S rRNA, EF-1a, alpha-Tub, UBQ, alpha-actin, CAC, PP2a, RUBISCO, GAPDH) were isolated from B. arvensis and TaqManTM compliant primers/probes were designed for RT-qPCR analysis. Abundance of these gene transcripts was analyzed across different tissues and growth regimes. Two of the most widely used algorithms, geNorm and NormFinder, showed variation in expression levels of these RGs. However, combinatorial analysis of the results clearly identified CAC and alpha-actin as the most stable and unstable RG candidates, respectively. This study has for the first time identified and validated RGs in the non-model system B. arvensis, a weed plant projected to become an important yet sustainable source of dietary omega-3 PUFA. PMID- 25918685 TI - Diversity of putative archaeal RNA viruses in metagenomic datasets of a yellowstone acidic hot spring. AB - Two genomic fragments (5,662 and 1,269 nt in size, GenBank accession no. JQ756122 and JQ756123, respectively) of novel, positive-strand RNA viruses that infect archaea were first discovered in an acidic hot spring in Yellowstone National Park (Bolduc et al., 2012). To investigate the diversity of these newly identified putative archaeal RNA viruses, global metagenomic datasets were searched for sequences that were significantly similar to those of the viruses. A total of 3,757 associated reads were retrieved solely from the Yellowstone datasets and were used to assemble the genomes of the putative archaeal RNA viruses. Nine contigs with lengths ranging from 417 to 5,866 nt were obtained, 4 of which were longer than 2,200 nt; one contig was 204 nt longer than JQ756122, representing the longest genomic sequence of the putative archaeal RNA viruses. These contigs revealed more than 50% sequence similarity to JQ756122 or JQ756123 and may be partial or nearly complete genomes of novel genogroups or genotypes of the putative archaeal RNA viruses. Sequence and phylogenetic analyses indicated that the archaeal RNA viruses are genetically diverse, with at least 3 related viral lineages in the Yellowstone acidic hot spring environment. PMID- 25918686 TI - Comparing the effect of topical anesthesia and retrobulbar block with intravenous sedation on hemodynamic changes and satisfaction in patients undergoing cataract surgery (phaco method). AB - BACKGROUND: Cataract is one of the most common surgical procedures in the elderly. In most cases, the elderly have cardiac ischemia or chronic coronary diseases, which would lead to more ischemic events during general anesthesia. Therefore, surgeons and anesthetists prefer regional aesthesia to the general one owing to its more advantages and less complications. OBJECTIVES: Therefore, this study aimed to compare topical method and retrobulbar block for pain intensity, patient's satisfaction, hemodynamic changes and intra and postoperative complications. PATIENTS AND METHODS: In a single-blinded clinical trial, 114 patients scheduled for cataract surgery, aged 50 to 90 years with ASA physical status of I-III, were randomly assigned to two groups under monitored anesthesia care as topical anesthesia and retrobulbar block. After the injection of intravenous sedation, which was the combination of midazolam 0.5-1 mg with fentanyl 0.5-1 u/kg, patients received retro bulbar block or topical anesthesia. During the operation, heart rate, systolic and diastolic blood pressure, mean arterial blood pressure and arterial saturation of O2were measured every five minutes. In addition, pain (VAS) and satisfaction (ISAS) scores were recorded every 15 minutes, then at recovery and one hour after the ending of operation in the ward. Findings were statistically analyzed using SPSS 16. RESULTS: In this study, no significant association was found between age, gender, education and physical condition of patients in both topical and retro bulbar block groups. Comparison of pain based on VAS, satisfaction based on ISAS score and MAP in the studied periods had no significant differences between the two groups of patients undergoing cataract surgery. However, significant differences were found between the two groups (P = 0.045, 0.02, 0.042 and P < 0.05) regarding heart rate, systolic and diastolic blood pressure and arterial oxygen saturation percentage after 20-30 minutes of the operation. CONCLUSIONS: Both methods, topical and retro bulbar block had similar impression in cataract surgery regarding analgesia and patient satisfaction. However, in non-complicated cataract surgeries with short duration, topical anesthesia may be the preferable method, because of non invasiveness, appropriate analgesia, patient satisfaction and hemodynamic stability. PMID- 25918687 TI - Surveillance epidemiology and end results analysis demonstrates improvement in overall survival for cervical cancer patients treated in the era of concurrent chemoradiotherapy. AB - BACKGROUND: In February 1999, the National Cancer Institute (NCI) issued a clinical alert based on five randomized trials that reported better overall survival (OS) with concurrent chemoradiotherapy (CCRT) than with surgery or radiation alone for locoregional cervical cancer. This study analyzes data from the surveillance epidemiology and end results (SEER) program to evaluate the improvement in survival in the era of CCRT. METHODS: The SEER database was queried for FIGO stages IB2-IVA cervical cancer patients treated with radiotherapy between 1995 and 2002. Patients diagnosed between 1999 and 2002 (CCRT era) were assumed to have received CCRT more frequently than patients diagnosed between 1995 and 1998 (RT era). Cases were stratified by period of diagnosis, age, and SEER region. OS and cause specific survival (CSS) were compared between the two time periods with chi-square log-rank tests. Multivariable Cox models were also used to compare OS and CSS between the two time periods, with adjustment for stratification variables and other covariates. RESULTS: The study included 3517 patients. Unadjusted OS and CSS were significantly improved in 1999-2002 compared with 1995-1998 (OS: p < 0.001, hazard ratio (HR): 0.81; CSS: p < 0.001, HR: 0.79). Significant improvements in OS and CSS were retained after adjustment for multiple variables (multivariable OS HR 0.78; CSS HR 0.76). CONCLUSION: Cervical cancer patients treated with radiotherapy after 1999 had improved OS and CSS compared with patients treated before 1999, likely reflecting increased usage of CCRT. This study adds to the population-level evidence supporting the adoption of CCRT as the standard of care for locoregional cervical cancer. PMID- 25918689 TI - Neurodevelopmental outcome of high risk newborns discharged from special care baby units in a rural district in India. AB - BACKGROUND: High risk newborns are most vulnerable to develop neuro-developmental delay (NDD). Early detection of delay in this group and identification of associated perinatal factors and their prevention can prevent disability in later life. DESIGN AND METHODS: Observational cohort study. Field based tracking and neuro-developmental screening of high risk newborns discharged between January 2010 to June 2012 from a district Hospital in India was conducted by a team of developmental specialists, using standardized tools like Denver Developmental Screening Tool II, Trivandrum Developmental Screening Chart and Amiel-Tison method of tone assessment. Associated perinatal factors were identified. Early intervention was initiated on those detected with NDD. RESULTS: Developmental delay was detected in 31.6% of study population. Prevalence of NDD was significantly higher in low birth weight (LBW, >2 kg), preterm (<36 weeks) and twins. Neonatal sepsis/meningitis and convulsions also showed significant association with NDD. Of the 134 with developmental delay, 61 were preterm, 80 LBW, with h/o sepsis in 52, convulsion in 14, birth asphyxia in 39 and jaundice in 14 neonates. CONCLUSIONS: Incidence of NDD among high risk newborns is significantly high with LBW, prematurity and neonatal illnesses are major contributors. Most NDDs go undetected in the early years of life. Improved perinatal care, early detection and early intervention at the grass root level will bring down incidence of developmental challenges in this vulnerable group. Significance for public healthThe public health significance of this study lies in the fact that a large proportion of high-risk newborns in rural India were detected with developmental delay and some preventable perinatal and neonatal factors like prematurity, low birth weight, sepsis and meningitis were found to be associated with the problem. So, it suggests that prevention of these perinatal factors, timely detection with proper screening methods and early intervention will help curb the burden of disability in the community. Once a disability develops in a child, the magnitude of the problem swells in all aspects: medical, social and economic. But much of this burden can be lessened if we intervene early, as a third of most disabilities are preventable. Moreover, if we can identify the perinatal factors leading to neonatal brain damage and prevent them, much of the neuro-developmental delay can be averted. PMID- 25918688 TI - Human colon-derived soluble factors modulate gut microbiota composition. AB - The commensal microbiota modulates immunological and metabolic aspects of the intestinal mucosa contributing to development of human gut diseases including inflammatory bowel disease. The host/microbiota interaction often referred to as a crosstalk, mainly focuses on the effect of the microbiota on the host neglecting effects that the host could elicit on the commensals. Colonic microenvironments from three human healthy controls (obtained from the proximal and distal colon, both in resting conditions and after immune - IL-15- and microbiota - LPS-in vitro challenges) were used to condition a stable fecal population. Subsequent 16S rRNA gene-based analyses were performed to study the effect induced by the host on the microbiota composition and function. Non supervised principal component analysis (PCA) showed that all microbiotas, which had been conditioned with colonic microenvironments clustered together in terms of relative microbial composition, suggesting that soluble factors were modulating a stable fecal population independently from the treatment or the origin. Our findings confirmed that the host intestinal microenvironment has the capacity to modulate the gut microbiota composition via yet unidentified soluble factors. These findings indicate that an appropriate understanding of the factors of the host mucosal microenvironment affecting microbiota composition and function could improve therapeutic manipulation of the microbiota composition. PMID- 25918690 TI - Dental caries and the associated factors influencing it in tribal, suburban and urban school children of Tamil Nadu, India: a cross sectional study. AB - BACKGROUND: The study was planned to assess the prevalence of dental caries among tribal, suburban and urban children of Tiruchengode and Erode of Tamil Nadu state, India. The objective of the study was to assess the association of dental caries with family background, dental service availability, transportation and knowledge on preventive dental measures among these three groups. DESIGN AND METHODS: Cross-sectional study. A total of 1028 school children in the age range of 9-12 years from various government schools located in Palamalai and Kolli Hills (tribal), Tiruchengode (suburban) and Erode (urban), Tamil Nadu, were included in the study. Decayed, filled, and missing teeth (DMFT), decayed and filled teeth (dft) and Significant Caries Index were recorded. A specially prepared questionnaire was used to record all the data regarding oral hygiene practices, socioeconomic background, dental treatment availability, parent's education level were used for the study. ANOVA t-test and post hoc test were used for comparing quantitative variables between the 3 subgroups. RESULTS: The tribal school children had 89.3% caries prevalence, where as it was 77% in suburban and 55% in urban school children. The mean DMFT score among tribal, suburban and urban school children were statistically significant different (P=0.001) between the three groups. There was a highly significant difference (P=0.001) in the mean DMFT score based on brushing frequency. There was a statistically significant difference (P=0.018) in the mean DMFT scores in the urban group based on the mothers education status. There were no statistically significant differences in the mean DMFT scores based on the presence or absence of television in their house and the parents' income. CONCLUSIONS: Oral hygiene practices, dietary habits and access to dental care services played an important role in prevalence of dental caries. It was observed that the socioeconomic status, parents' educational status and mass media influenced the oral health of these children but without a significant contribution. Significance for public healthIt was observed from the present study that the socioeconomic status, parents' educational status, media and family structure influence the oral health of children in under-privileged communities. Oral hygiene practices, dietary habits and access to dental care services also play an important role in the prevalence of dental caries among children. Children of government schools in Tamil Nadu, India, don't get adequate information on oral health, related diseases and methods of prevention. Oral health education and health promotion should be mandatory for all school children. PMID- 25918692 TI - How can we bring public health in all policies? Strategies for healthy societies. AB - New scenarios are emerging in the European and worldwide context: the ageing of society, the climate changes, the increasing of health inequalities and the financial crisis. In this context, the scientific community and the decision makers agree on the role of health in all policies (HiAP) strategy in improving the population's health. The HiAP takes into account factors not strictly related to health but with important health consequences. To bring public health in all policies a change is needed, but there are some obstacles to overcome: for instance, the lack of evidence regarding the governance tools and frameworks for HiAP, the difficulty of convincing stakeholders and producing a cultural change in the political positioning of decision-makers. Consequently, it is necessary: i) to implement stronger and responsible decision-support approaches, such as health impact assessment and health technology assessment; ii) to encourage and coordinate all relevant sectors in playing their part in reducing health gaps within the European Union; iii) to strengthen cooperation and make better use of existing networks and existing public health and related institutions. The final aim will be to monitor the impact of the health determinants in order to promote the effective implementation of HiAP approach. Significance for public healthThis paper makes public health professionals aware of the pivotal role that they could play in reducing health inequalities and in helping to overcome the crisis of the European health systems. It discusses how, thanks to a systematic approach based on new instruments like health impact assessment and health technology assessment, and thanks also to a stronger cooperation among stakeholders and policy makers, it is possible to monitor the health determinants and consequently to bring health in all policies. PMID- 25918691 TI - Adolescent and parent use of new technologies for health communication: a study in an urban latino community. AB - BACKGROUND: Mobile communication technologies provide novel opportunities to support clinic-based health initiatives. Adoption of technologies for daily use and for health communication can differ between communities, depending upon demographic and cultural characteristics. DESIGN AND METHODS: A survey was administered in adolescent primary care and subspecialty clinics to assess parent adolescent preferences in use of mobile technologies and social media to support provider-patient communication in an urban Latino community. RESULTS: Of 130 respondents (65 parent-adolescent pairs), approximately half frequently sent and received text messages but lacked agreement regarding the other's text messaging use. In contrast, adolescents only rarely used email compared to parents (15.4% versus 37.5%, P=0.006). Of social media, FacebookTM/MySpaceTM was most frequently used by parents and youth (60% and 55.4%, P=0.59); however, most lacked interest in using social media for health communication. Parents reported more interest than adolescents in receiving email (73.4% versus 35.9%, P<0.001) and text messages (58.5% versus 33.9%, P=0.005) for health, but had more concerns about privacy issues (26.2% versus 9.2%, P=0.01). Respondents who were American born (aOR 5.7, 95%CI 1.2-28.5) or regularly used Instant Messaging or FacebookTM/MySpaceTM (aOR 4.6, 95%CI 1.4-14.7) were more likely to be interested in using social media for health communication. CONCLUSIONS: These findings underscore the importance of targeted assessment for planning the utilization of communication technologies and social media in clinical care or research for underserved youth. Significance for public healthCommunication technologies provide novel opportunities to support clinic-based health initiatives for underserved youth. However, adoption of technologies among communities may differ depending upon demographic and cultural characteristics. We surveyed a sample of urban Latino parents and youth regarding their current use of mobile and social media technologies and preferences for use of these technologies for health communication. This is the first study to compare the perspective of underserved parents and their youth regarding use of a wide variety of mobile and social communication technologies, concordance between youth-parent pairs in perceived use of texting and preferences for the purpose of health communication. Our findings differ from those from adults surveyed in other under-served communities, highlighting heterogeneity between communities. Variations in use of communication technologies and social media and preferences between parent-youth pairs suggest that understanding these factors within target populations is crucial for successful use to support health and health services. PMID- 25918693 TI - Medical records confidentiality and public health research: two values at stake? An italian survey focus on individual preferences. AB - In a time when Europe is preparing to introduce new regulations on privacy protection, we conducted a survey among 1700 twins enrolled in the Italian Twin Register about the access and use of their medical records for public health research without explicit informed consent. A great majority of respondents would refuse or are doubtful about the access and use of hospital discharge records or clinical data without their explicit consent. Young and female individuals represent the modal profile of these careful people. As information retrieved from medical records is crucial for progressing knowledge, it is important to promote a better understanding of the value of public health research activities among the general population. Furthermore, public opinions are relevant to policy making, and concerns and preferences about privacy and confidentiality in research can contribute to the design of procedures to exploit medical records effectively and customize the protection of individuals' medical data. Significance for public healthInformation retrieved from medical records is critical for public health research and policy. In particular, large amounts of individual health data are needed in an epidemiological setting, where methodological constraints (e.g. follow-up update) and quality control procedures very often require data to be re-identifiable. Concern about European regulation affecting access to medical records seems to be widespread in the scientific community. Highlighting individuals' concerns and preferences about privacy and informed consent regarding the use of health data can support policy making for public health research. It can contribute to the design of procedures aiming to extract the greatest value from medical records and, more importantly, to create a system for the protection of personal data tailored to the needs of different people. PMID- 25918694 TI - Adherence to physical activity recommendations and its associated factors: an interregional population-based study. AB - BACKGROUND: Though the influence of physical activity in preventing cardiovascular diseases is well documented, only a few comparative studies have determined the degree of adherence to physical activity recommendations among populations and identified the demographic, socioeco-nomic, behavioural and health-related factors associated with good compliance. DESIGN AND METHODS: Cross sectional interregional NESCaV survey of 3133 subjects compared three populations, Luxembourg, Lorraine (France) and Wallonia (Belgium), by using the International Physical Activity Questionnaire. Age and gender prevalence rates of physical activity were standardized to the European population. RESULTS: The likelihood to meet the recommendations was higher in Luxembourg, after adjustment for age, gender, education, employment, weight status, morbidity score, health perception and level of importance attributed to the practice of physical activity (P<0.0001). The odds for meeting the recommendations were significantly higher among those with secondary than tertiary education. Compared to good self health perception, subjects with poor or fair self-perceived health were less likely to meet the recommendations; this also applied to those attributing little or enough importance to physical activity compared with great importance. CONCLUSIONS: Region, education, self-perceived health and perception of importance of physical activity were emerged as independent determinants of meeting the recommendations. Awareness of the positive health effects of physical activity might thus be crucial for motivating the people to become more active. Further research is needed to explore potential region-specific factors which might explain the difference in population behaviours with respect to physical activity. Significance for public healthThis manuscript describes the prevalence of physical activity level of adult population from three European regions, Luxembourg, Wallonia and Lorraine, based on the adherence to the WHO physical activity recommendations. It identifies the potential demographic, socioeconomic, perceptive and behavioural factors associated with meeting physical activity recommendations. This study hence has a significant public health interest; as it constitutes a first step to help decision-makers and health authorities to target at-risk populations and to guide the development of preventive programs. Preventing physical inactivity in the Greater Region, the fourth leading cause of mortality, can reduce cardiovascular disease burden and substantially improve overall health of a big segment of the European population. PMID- 25918695 TI - Childhood Malnutrition is Associated with Maternal Care During Pregnancy and Childbirth: A Cross-Sectional Study in Bauchi and Cross River States, Nigeria. AB - BACKGROUND: Malnutrition remains an important cause of childhood morbidity and mortality; the levels of childhood malnutrition in Nigeria are among the highest in the world. The literature supports many direct and indirect causes of malnutrition, but few studies have examined the link between maternal care during pregnancy and childbirth and childhood malnutrition. This study examines this potential link in Bauchi and Cross River states in Nigeria. DESIGN AND METHODS: In 2011, a household survey collected information about children under four years old and their mothers' last pregnancy. Trained fieldworkers measured mid-upper arm circumference (MUAC) of children aged 6-47 months. We examined associations with childhood malnutrition in bivariate and multivariate analysis. RESULTS: Some 4.4% of 3643 children in Cross River, and 14.7% of 2706 in Bauchi were malnourished (MUAC z-score). In both states, a child whose mother had fewer than four government antenatal care visits was more likely to be malnourished (Cross River: OR 1.85, 95%CIca 1.33-2.55; Bauchi: OR 1.29, 95%CIca 1.02-1.63). In Bauchi, a child whose mother who rarely or never discussed pregnancy and childbirth with her husband (OR 1.34, 95%CIca 1.07-1.68), and who did not have her last delivery attended by a skilled health worker was more likely to be malnourished (OR 1.50, 95%CIca 1.09-2.07). CONCLUSIONS: These findings, if confirmed in other studies, suggest that poor care of women in pregnancy and childbirth could pose a longer term risk to the health of the child, as well as increasing immediate risks for both mother and child. Significance for public healthChildhood malnutrition is a public health priority, accounting for almost 1/5 of global disease burden among children under five years old. Many studies have examined risk factors for childhood malnutrition, but few have examined the link between maternal care during pregnancy and childbirth and childhood malnutrition. This study, albeit a cross-sectional design, provides evidence of a link between poor care during pregnancy and childbirth and childhood malnutrition in two states of Nigeria. This is important for public health because it suggests another benefit of caring for women during pregnancy and childbirth. This could not only reduce maternal and child perinatal mortality, but also have benefits for the longer-term health and development of children. This finding could be useful for paternal advocacy; it may motivate men to support their wives during pregnancy and childbirth since through this support, fathers can also protect the future development of their children. PMID- 25918696 TI - An Examination of Health Inequities among College Students by Sexual Orientation Identity and Sex. AB - BACKGROUND: Lesbian, gay, and bisexual (LGB) college students may have an increased number of health inequities compared to their heterosexual counterparts. However, to date, no research has provided a comprehensive examination of health-related factors by sexual orientation identity and sex among a national sample of college students. Thus, the purpose of this study was to examine physical, sexual, interpersonal relations/safety, and mental health inequities by sexual orientation identity and sex among a national sample of college students. DESIGN AND METHODS: Participants (n=39,767) completed the National College Health Assessment II during the fall 2008/spring 2009 academic year. Hierarchical binary logistic regression analyses were used to examine health inequities by sexual orientation identity and sex. RESULTS: LGB students compared to heterosexual students, experienced multiple health inequities including higher rates of being verbally threatened and lower rates of physical activity and condom use. CONCLUSIONS: An understanding of health inequities experienced by LGB college students is critical as during these years of transition, students engage in protective (e.g., physical activity) and risky (e.g., lack of condom use) health behaviours, establishing habits that could last a lifetime. Future research should be used to design and implement targeted public health strategies and policies to reduce health inequities and improve health-related quality of life among LGB college students. Significance for public healthHealth inequities based on sexual orientation identity and sex among college students is a critical public health concern. Based on the results of the current study, lesbian, gay, and bisexual (LGB) college students experienced multiple physical, sexual, interpersonal relations and safety, and mental health inequities. This understanding of health inequities experienced by LGB college students is critical as during these years of transition, students engage in protective (e.g., physical activity) and risky (e.g., lack of condom use) health behaviours, establishing habits that could last a lifetime. By intervening during the college years, targeted public health strategies and policies can be designed and implemented to reduce health inequities and improve health-related quality of life among LGB individuals during mid-to-later adulthood. PMID- 25918697 TI - Spatial patterns of epilepsy-related emergency department visits in california. AB - BACKGROUND: Socio-demographic factors are associated with increased emergency department (ED) use among patients with epilepsy. However, there has been limited spatial analysis of such visits. DESIGN AND METHODS: California ED visit at the patient ZIP Code level were examined using Kulldorf's spatial scan statistic to identify clusters of increased risk for epilepsy-related visits. Logistic regression was used to examine the relative importance of patient socio demographics, Census-based and hospital measures. RESULTS: During 2009-2011 there were 29,715,009 ED visits at 330 hospitals, of which 139,235 (0.5%) had epilepsy (International Classification of Disease-9 345.xx) as the primary diagnosis. Three large urban clusters of high epilepsy-related ED visits were centred in the cities of Los Angeles, Oakland and Stockton and a large rural cluster centred in Kern County. No consistent pattern by age, race/ethnicity, household structure, and income was observed among all clusters. Regression found only the Los Angeles cluster significant after adjusting for other measures. CONCLUSIONS: Geospatial analysis within a large and geographically diverse region identified a cluster within its most populous city having an increased risk of ED visits for epilepsy independent of selected socio-demographic and hospital measures. Additional research is necessary to determine whether elevated rates of ED visits represent increased prevalence of epilepsy or an inequitable system of epilepsy care. Significance for public healthThere have been few spatial analyses regarding treatment for epilepsy. This paper significantly expands upon previous work by simultaneously considering multiple urban centres and sparsely populated agricultural and desert/mountain areas in a large state. Furthermore, most epilepsy studies involve one system of care or funding source (such as Department of Veterans Affairs, Medicare, Medicaid, or private insurance plans). This paper considers all funding sources at community-based hospitals. Patient socio demographics, area-based summaries of socio-demographics, and basic hospital characteristics explain most of the observed spatial variation in rates of emergency department (ED) visits related to epilepsy. However, preliminary spatial analysis demonstrated that an area within downtown Los Angeles did have a higher rate of epilepsy-related visits compared to the rest of the state. A more comprehensive surveillance approach with ED visit data could be readily applied to other large geographic areas and be useful both for on-going monitoring and public health intervention. PMID- 25918698 TI - Assessment of screening practices for gestational hyperglycaemia in public health facilities: a descriptive study in bangalore, India. AB - BACKGROUND: Screening and timely treatment of gestational hyperglycaemia (GH) is proved to be beneficial and improves maternal and foetal health outcomes. To understand screening practices, we explored the knowledge and perceptions of doctors working in public health facilities in Bangalore, India. We also studied participation factors by examining whether undergoing glucose estimation tests affects morning sickness in pregnant women. DESIGN AND METHODS: We aimed to understand the screening practices and knowledge of doctors. A semi-structured questionnaire was self-administered by the 50 participant doctors, selected from the sampling frame comprising of all the doctors working in public health facilities. We included 105 pregnant women for baseline assessment, in whom a well-structured questionnaire was used. RESULTS: We reported that gestational diabetes mellitus (GDM) screening was done in nearly all the health centres (96%). However, only 12% of the doctors could provide all components of GDM diagnosis and management correctly and 46% would diagnose by using a random blood glucose test. A majority (92%) of the doctors had poor knowledge (68%) about the cut-off values of glucose tests. More than 80% of pregnant women experienced some discomfort mostly due to rapid ingestion glucose in short span of time. CONCLUSIONS: Our study established that screening for GH is done in most public health facilities. Nonetheless, knowledge of doctors on the glucose tests and their interpretation needs improvement. Re-orientation trainings of the doctors can improve their knowledge and thereby can efficiently screen for GH. Further, adequate planning prior to the tests can aid successful completion of them. Significance for public healthRising burden of hyperglycaemia in pregnancy is a cause for concern and is associated with short and long term deleterious consequences for mother and offspring. Hence, there is an urgent need to explore the screening practices for gestational hyperglycaemia (GH). The current study considers patient and doctors' perspectives regarding GH screening. The results from our study indicate several issues during screening of gestational hyperglycaemia in public health facilities in Bangalore, India. These included low awareness levels among doctors, lack of standard operating procedures and lack of adequate care and attention provided to pregnant women. Re-orientation trainings of the doctors within public health facilities can improve their knowledge and thereby can efficiently screen for GH. Further, adequate planning and preparation of the patient prior to the tests can help ensure successful completion of the tests. The findings of the study are comparable with the practices of public health hospitals in India. PMID- 25918699 TI - School-based diabetes interventions and their outcomes: a systematic literature review. AB - Type 1 diabetes is one of the most common chronic childhood diseases, while type 2 diabetes in children is increasing at alarming rates globally. Against this backdrop, the school is a critical environment for children with diabetes. They continue to face barriers to education that may lead to depression, poor academic performance, and poor quality of life. To address these challenges, diabetes interventions have been implemented in school and the goal was to systematically review these interventions and their outcomes between 2000 and 2013. Fifteen studies were included in the narrative synthesis. Education of school personnel was the main focus before 2006. Studies reported gains in knowledge and perceived confidence of school staff. Since 2006, more comprehensive interventions have been developed to promote better care coordination and create a safe school environment. These studies reported improved diabetes management and quality of life of students. Assessment tools varied and study design included randomized controlled trials, quantitative and qualitative methods. Although many of the studies reported a significant difference in the parameters measured, it was not possible to determine optimal ways to improve the health, quality of life and academic performance of children with diabetes, given the disparity in scope, assessment tools and measured outcomes. Experimental designs, longer follow-up studies, larger sample sizes, and a higher number of participating schools are critical issues to consider in future studies. Most of the research was conducted in North America and further research is needed in other parts of the world. Significance for public healthDiabetes is one of the most common chronic childhood diseases; both type 1 and type 2 diabetes are increasing in children globally. Against this backdrop, the school is a critical environment for children with diabetes. This systematic literature review on school-based diabetes interventions and their outcomes demonstrates that increasing efforts are being made to improve diabetes care and create a safe school environment. Studies reported gains in knowledge and confidence of school staff, as well as improved health and quality of life of students. Given the disparity of the assessment tools used, it was not possible to determine optimal ways to improve the health, quality of life and academic performance of children with diabetes. Future evaluations should include experimental designs, longer follow-up studies, and larger sample sizes. School-based diabetes interventions and solid evaluations will contribute to improving diabetes school policies and ensuring children with diabetes have the same educational opportunities as other children. PMID- 25918700 TI - The promise and prospects of argumentation for public health communication. PMID- 25918702 TI - Listeriosis outbreaks in British Columbia, Canada, caused by soft ripened cheese contaminated from environmental sources. AB - Soft ripened cheese (SRC) caused over 130 foodborne illnesses in British Columbia (BC), Canada, during two separate listeriosis outbreaks. Multiple agencies investigated the events that lead to cheese contamination with Listeria monocytogenes (L.m.), an environmentally ubiquitous foodborne pathogen. In both outbreaks pasteurized milk and the pasteurization process were ruled out as sources of contamination. In outbreak A, environmental transmission of L.m. likely occurred from farm animals to personnel to culture solutions used during cheese production. In outbreak B, birds were identified as likely contaminating the dairy plant's water supply and cheese during the curd-washing step. Issues noted during outbreak A included the risks of operating a dairy plant in a farm environment, potential for transfer of L.m. from the farm environment to the plant via shared toilet facilities, failure to clean and sanitize culture spray bottles, and cross-contamination during cheese aging. L.m. contamination in outbreak B was traced to wild swallows defecating in the plant's open cistern water reservoir and a multibarrier failure in the water disinfection system. These outbreaks led to enhanced inspection and surveillance of cheese plants, test and release programs for all SRC manufactured in BC, improvements in plant design and prevention programs, and reduced listeriosis incidence. PMID- 25918701 TI - Nuclear PI3K signaling in cell growth and tumorigenesis. AB - The PI3K/Akt signaling pathway is a major driving force in a variety of cellular functions. Dysregulation of this pathway has been implicated in many human diseases including cancer. While the activity of the cytoplasmic PI3K/Akt pathway has been extensively studied, the functions of these molecules and their effector proteins within the nucleus are poorly understood. Harboring key cellular processes such as DNA replication and repair as well as nascent messenger RNA transcription, the nucleus provides a unique compartmental environment for protein-protein and protein-DNA/RNA interactions required for cell survival, growth, and proliferation. Here we summarize recent advances made toward elucidating the nuclear PI3K/Akt signaling cascade and its key components within the nucleus as they pertain to cell growth and tumorigenesis. This review covers the spatial and temporal localization of the major nuclear kinases having PI3K activities and the counteracting phosphatases as well as the role of nuclear PI3K/Akt signaling in mRNA processing and exportation, DNA replication and repair, ribosome biogenesis, cell survival, and tumorigenesis. PMID- 25918703 TI - Performance of three multipurpose disinfecting solutions with a silicone hydrogel contact lens. AB - PURPOSE: To evaluate the clinical performance of a silicone hydrogel (Si-Hy) soft contact lens (CL) in combination with three different multipurpose disinfecting solutions (MPDSs). METHODS: This was a prospective, randomized, single-masked, crossover, and comparative study in which 31 habitual soft CL wearers were randomly assigned to one of the three MPDSs (Synergi, COMPLETE RevitaLens, and OPTI-FREE PureMoist) for 1 month with a 1-week wash-out period between each exposure. All subjects were successfully refitted with a Si-Hy CL (Biofinity). Subjects were then scheduled for follow-up visits after 1 month of lens wear, being evaluated at 2 and 8 hours after lens insertion. Visual Analogue Scales (VAS) were used to gauge comfort rating. RESULTS: The tarsal conjunctiva showed a significantly different degree of lid redness between the MPDSs at the 2-hour visit (P < 0.05, Kruskal-Wallis test), being lower for COMPLETE RevitaLens compared to the other two MPDSs (Mann-Whitney U test). Furthermore, a significantly different degree of lid roughness at the 8-hour visit was seen (P < 0.05, Kruskal-Wallis test), being higher for Synergi (Mann-Whitney U test). The subjective comfort was similar with the three MPDSs. CONCLUSION: Tarsal conjunctival response should be also considered in the context of the clinical performance of MPDs at the ocular surface. PMID- 25918704 TI - Induced second trimester abortion and associated factors in Amhara region referral hospitals. AB - BACKGROUND: Although the vast majority of abortions are performed in the first trimester, still 10-15% of terminations of pregnancies have taken place in the second trimester period globally. As compared to first trimester, second trimester abortions are disproportionately contribute for maternal morbidity and mortality especially in low-resource countries where access to safe second trimester abortion is limited. The main aim of this study was to assess the prevalence and associated factors of induced second trimester abortion in Amhara region referral hospitals, northwest Ethiopia. METHODS: Institution based cross sectional study was conducted in Amhara region referral hospitals among 416 women who sought abortion services. Participants were selected using systematic sampling technique. Data were collected using pretested structured questionnaire through interviewing. After the data were entered and analyzed; variables which have P value < 0.2 in bivariate analysis, not colinear, were entered into multiple logistic regressions to see the net effect with 95% CI and P value < 0.05. RESULTS: The prevalence of induced second trimester abortion was 19.2%. Being rural (AOR = 1.86 [95% CI = 1.11-3.14]), having irregular menstrual cycle (AOR = 1.76 [95% CI = 1.03-2.98]), not recognizing their pregnancy at early time (AOR = 2.05 [95% CI = 1.21-3.48]), and having logistics related problems (AOR = 2.37 [95% CI = 1.02-5.53]) were found to have statistically significant association with induced second trimester abortion. CONCLUSION: Induced second trimester abortion is high despite the availability of first trimester abortion services. Therefore, increase accessibility and availability of safe second trimester abortion services below referral level, counseling and logistical support are helpful to minimize late abortions. PMID- 25918705 TI - Temporal changes of microarchitectural and mechanical parameters of cancellous bone in the osteoporotic rabbit. AB - This study was aimed at elucidating the temporal changes of microarchitectural and mechanical parameters of cancellous bone in the osteoporotic rabbit model induced by ovariectomy (OVX) combined with glucocorticoid (GC) administration. Osteoporotic (OP) group received bilateral OVX combined with injections of GC, while sham group only received sham operation. Cancellous bone quality in vertebrae and femoral condyles in each group was assessed by DXA, MUCT, nanoindentation, and biomechanical tests at pre-OVX and 4, 6, and 8 weeks after injection. With regard to femoral condyles, nanoindentation test could detect significant decline in tissue modulus and hardness at 4 weeks. However, BMD and microarchitecture of femoral condylar cancellous bone changed significantly at 6 weeks. In vertebrae, BMD, microarchitecture, nanoindentation, and biomechanical tests changed significantly at 4 weeks. Our data demonstrated that temporal changes of microarchitectural and mechanical parameters of cancellous bone in the osteoporotic rabbit were significant. The temporal changes of cancellous bone in different anatomical sites might be different. The nanoindentation method could detect the changes of bone quality at an earlier stage at both femoral condyle and vertebra in the osteoporotic rabbit model than other methods (MUCT, BMD). PMID- 25918706 TI - Haematuria in postrenal transplant patients. AB - Haematuria has a prevalence of 12% in the postrenal transplant patient population. It heralds potentially dangerous causes which could threaten graft loss. It is important to consider causes in light of the unique, urological, and immunological standpoints of these patients. We review the literature on common causes of haematuria in postrenal transplant patients and suggest the salient approach to the evaluation of this condition. A major cause of haematuria is urinary tract infections. There should be a higher index of suspicion for mycobacterial, fungal, and viral infection in this group of immunosuppressed patients. Measures recommended in the prevention of urinary tract infections include early removal of foreign bodies as well as prophylactic antibiotics during the early transplant phase. Another common cause of haematuria is that of malignancies, in particular, renal cell carcinomas. When surgically managing cancer in the setting of a renal transplant, one has to be mindful of the limited retropubic space and the need to protect the anastomoses. Other causes include graft rejections, recurrences of primary disease, and calculus formation. It is important to perform a comprehensive evaluation with the aid of an experienced multidisciplinary transplant team. PMID- 25918707 TI - Radiation oncology and medical physics. PMID- 25918708 TI - A New Double Stranded RNA Suppresses Bladder Cancer Development by Upregulating p21 (Waf1/CIP1) Expression. AB - We have previously demonstrated that miR-1180-5p has potent ability to upregulate p21 expression by targeting promoter and inhibit bladder cancer. This prompted us to conjecture that a candidate dsRNA (dsP21-397) with perfect complementarity to the miR-1180-5p target site of p21 promoter may also trigger p21 expression. Transfection of dsP21-397 into T24 and EJ cells significantly activated p21 expression at 72 h and the activation presented in a time-course and dose dependent manner. Moreover, the p21-activated activities of dsP21-397 and miR 1180-5p are not significantly different. Overexpression of p21 downregulated Cyclin D1, CDK4/6, and Cyclin A2 expression, and thereby induced cell cycle arrest and inhibited proliferation. Moreover, dsP21-397 suppressed bladder cancer largely depended on manipulating p21. In conclusion, our study identifies a pair of miRNA-dsRNA mediating endogenous p21 overexpression. PMID- 25918709 TI - Oxidative/Antioxidative status in obese and sport trained children: a comparative study. AB - The aim of the study was to compare oxidative/antioxidative status in obese and sport trained children and to correlate obtained redox markers with anthropometrical measurements, body composition parameters, and adipokines levels. 78 (44 males) obese (SG) and 80 (40 males) normal weight sport trained (CG) children matched for age and Tanner stage were recruited for the study. Body composition parameters and basal metabolic rate (BMR) were assessed by bioelectrical impedance analysis (BIA). Oxidative/antioxidative status was evaluated in plasma by total oxidative status (PerOX), oxidized-LDL cholesterol (oxLDL), total antioxidative capacity (ImAnOx), and glutathione peroxidase activity (GPx). Leptin and adiponectin levels and adiponectin/leptin ratio (A/L) were also investigated. OxLDL was higher in SG versus CG (P < 0.05), but ImAnOx and GPx were reduced in SG versus CG (P < 0.01). Redox markers correlated significantly with BMI Z-score, WHR, WHtR, body composition parameters, leptin (in boys only), and A/L ratio (in boys only) in SG and in a whole studied population. PerOX significantly correlated with BMR in the CG. Antioxidative/oxidative status in obese children is significantly impaired and related adipose tissue excess and its hormonal activity. Oxidative status assessed by PerOx is also high in sport trained children but antioxidative defense is significantly more efficient with no overproduction of oxidized LDL. PMID- 25918710 TI - Effects of PMA (PHORBOL-12-MYRISTATE-13-ACETATE) on the Developing Rodent Brain. AB - Perinatal infections have a negative impact on brain development. However, the underlying mechanisms leading to neurological impairment are not completely understood and reliable models of inflammation are urgently needed. Using phorbol myristate-acetate as an activator of inflammation, we investigated the effect on the developing rodent brain. Neonatal rats and mice deficient in IL-18 or IRAK-4 were exposed to PMA. Brains were assessed for regulation of pro- and anti inflammatory cytokines and cell death 24 hrs, 7 and 14 days after treatment. PMA induced an inflammatory response and caused widespread neurodegeneration in the brains of 3- and 7-day-old rats. In contrast, 14-day-old rats were resistant to the neurotoxic effect of PMA. Histological evaluation at the age of 14 and 21 days revealed a destruction of the cortical microstructure with decreased numerical density of neuronal cells. Mice deficient in IL-18 or IRAK-4 were protected against PMA induced brain injury. PMA treatment during a vulnerable period can alter brain development. IL-18 and IRAK-4 appear to be important for the development of PMA induced injury. PMID- 25918711 TI - Duck RIG-I CARD Domain Induces the Chicken IFN-beta by Activating NF-kappaB. AB - Retinoic acid-inducible gene I- (RIG-I-) like receptors (RLRs) have recently been identified as cytoplasmic sensors for viral RNA. RIG-I, a member of RLRs family, plays an important role in innate immunity. Although previous investigations have proved that RIG-I is absent in chickens, it remains largely unknown whether the chicken can respond to RIG-I ligand. In this study, the eukaryotic expression vectors encoding duRIG-I full length (duck RIG-I, containing all domains), duRIG I N-terminal (containing the two caspase activation and recruitment domain, CARDs), and duRIG-I C-terminal (containing helicase and regulatory domains) labeled with 6*His tags were constructed successfully and detected by western blotting. Luciferase reporter assay and enzyme-linked immunosorbent assay (ELISA) detected the duRIG-I significantly activated NF-kappaB and induced the expression of IFN-beta when polyinosinic-polycytidylic acid (poly[I:C], synthetic double stranded RNA) challenges chicken embryonic fibroblasts cells (DF1 cells), while the duRIG-I was inactive in the absence of poly[I:C]. Further analysis revealed that the CARDs (duRIG-I-N) induced IFN-beta production regardless of the presence of poly[I:C], while the CARD-lacking duRIG-I (duRIG-I-C) was not capable of activating downstream signals. These results indicate that duRIG-I CARD domain plays an important role in the induction of IFN-beta and provide a basis for further studying the function of RIG-I in avian innate immunity. PMID- 25918712 TI - The Water Cycle, a Potential Source of the Bacterial Pathogen Bacillus cereus. AB - The behaviour of the sporulating soil-dwelling Bacillus cereus sensu lato (B. cereus sl) which includes foodborne pathogenic strains has been extensively studied in relation to its various animal hosts. The aim of this environmental study was to investigate the water compartments (rain and soil water, as well as groundwater) closely linked to the primary B. cereus sl reservoir, for which available data are limited. B. cereus sl was present, primarily as spores, in all of the tested compartments of an agricultural site, including water from rain to groundwater through soil. During rain events, leachates collected after transfer through the soil eventually reached the groundwater and were loaded with B. cereus sl. In groundwater samples, newly introduced spores of a B. cereus model strain were able to germinate, and vegetative cells arising from this event were detected for up to 50 days. This first B. cereus sl investigation in the various types of interrelated environments suggests that the consideration of the aquatic compartment linked to soil and to climatic events should provide a better understanding of B. cereus sl ecology and thus be relevant for a more accurate risk assessment of food poisoning caused by B. cereus sl pathogenic strains. PMID- 25918713 TI - Relationship between Cognitive Performance and Motor Dysfunction in Patients with Parkinson's Disease: A Pilot Cross-Sectional Study. AB - The aim of this pilot cross-sectional study was to extensively investigate the relationships between cognitive performance and motor dysfunction involving balance and gait ability in patients with Parkinson's disease. Twenty subjects with Parkinson's disease underwent a cognitive (outcomes: Frontal Assessment Battery-Italian version, Montreal overall Cognitive Assessment, Trail Making Test, Semantic Verbal Fluency Test, and Memory with Interference Test) and motor (outcomes: Berg Balance Scale, 10-Meter Walking Test, 6-Minute Walking Test, Timed Up and Go Test performed also under dual task condition, and Unified Parkinson's Disease Rating Scale) assessment. Our correlation analyses showed that balance skills are significantly correlated with executive functions, cognitive impairment, and ability to switch attention between two tasks. Furthermore, functional mobility showed a significant correlation with cognitive impairment, verbal fluency, and ability to switch attention between two tasks. In addition, the functional mobility evaluated under the dual task condition showed a significant correlation with cognitive impairment and ability to switch attention between two tasks. These findings might help early identification of cognitive deficits or motor dysfunctions in patients with Parkinson's disease who may benefit from rehabilitative strategies. Future prospective larger-scale studies are needed to strengthen our results. PMID- 25918714 TI - Antibiotic-resistant vibrios in farmed shrimp. AB - Antimicrobial susceptibility pattern was determined in 100 strains of Vibrio isolated from the Litopenaeus vannamei shrimp and identified phenotypically. A high antibiotic-resistance index (75%) was observed, with the following phenotypic profiles: monoresistance (n = 42), cross-resistance to beta-lactams (n = 20) and multiple resistance (n = 13). Plasmid resistance was characterized for penicillin (n = 11), penicillin + ampicillin (n = 1), penicillin + aztreonam (n = 1), and ampicillin (n = 1). Resistance to antimicrobial drugs by the other strains (n = 86) was possibly mediated by chromosomal genes. The findings of this study support the conclusion that the cultured shrimps can be vehicles of vibrios resistant to beta-lactam and tetracycline. PMID- 25918715 TI - Integrative Analysis of CRISPR/Cas9 Target Sites in the Human HBB Gene. AB - Recently, the clustered regularly interspaced short palindromic repeats (CRISPR) system has emerged as a powerful customizable artificial nuclease to facilitate precise genetic correction for tissue regeneration and isogenic disease modeling. However, previous studies reported substantial off-target activities of CRISPR system in human cells, and the enormous putative off-target sites are labor intensive to be validated experimentally, thus motivating bioinformatics methods for rational design of CRISPR system and prediction of its potential off-target effects. Here, we describe an integrative analytical process to identify specific CRISPR target sites in the human beta-globin gene (HBB) and predict their off target effects. Our method includes off-target analysis in both coding and noncoding regions, which was neglected by previous studies. It was found that the CRISPR target sites in the introns have fewer off-target sites in the coding regions than those in the exons. Remarkably, target sites containing certain transcriptional factor motif have enriched binding sites of relevant transcriptional factor in their off-target sets. We also found that the intron sites have fewer SNPs, which leads to less variation of CRISPR efficiency in different individuals during clinical applications. Our studies provide a standard analytical procedure to select specific CRISPR targets for genetic correction. PMID- 25918717 TI - Advances in gene delivery systems. PMID- 25918716 TI - Functional roles of calreticulin in cancer biology. AB - Calreticulin is a highly conserved endoplasmic reticulum chaperone protein which participates in various cellular processes. It was first identified as a Ca(2+) binding protein in 1974. Accumulated evidences indicate that calreticulin has great impacts for the development of different cancers and the effect of calreticulin on tumor formation and progression may depend on cell types and clinical stages. Cell surface calreticulin is considered as an "eat-me" signal and promotes phagocytic uptake of cancer cells by immune system. Moreover, several reports reveal that manipulation of calreticulin levels profoundly affects cancer cell proliferation and angiogenesis as well as differentiation. In addition to immunogenicity and tumorigenesis, interactions between calreticulin and integrins have been described during cell adhesion, which is an essential process for cancer metastasis. Integrins are heterodimeric transmembrane receptors which connect extracellular matrix and intracellular cytoskeleton and trigger inside-out or outside-in signaling transduction. More and more evidences reveal that proteins binding to integrins might affect integrin-cytoskeleton interaction and therefore influence ability of cell adhesion. Here, we reviewed the biological roles of calreticulin and summarized the potential mechanisms of calreticulin in regulating mRNA stability and therefore contributed to cancer metastasis. PMID- 25918718 TI - Does high thoracic epidural analgesia with levobupivacaine preserve myocardium? A prospective randomized study. AB - BACKGROUND: Our study aimed to compare HTEA and intravenous patient-controlled analgesia (PCA) in patients undergoing coronary bypass graft surgery (CABG), based on haemodynamic parameters and myocardial functions. MATERIALS AND METHODS: The study included 34 patients that were scheduled for elective CABG, who were randomly divided into 2 groups. Anesthesia was induced and maintained with total intravenous anesthesia in both groups while intravenous PCA with morphine was administered in Group 1 and infusion of levobupivacaine was administered from the beginning of the anesthesia in Group 2 by thoracic epidural catheter. Blood samples were obtained presurgically, at 6 and 24 hours after surgery for troponin I, creatinine kinase-MB (CK-MB), total antioxidant capacity, and malondialdehyde. Postoperative pain was evaluated every 4 hours until 24 hours via VAS. RESULTS: There were significant differences in troponin I or CK-MB values between the groups at postsurgery 6 h and 24 h. Heart rate and mean arterial pressure in Group 1 were significantly higher than in Group 2 at all measurements. Cardiac index in Group 2 was significantly higher than in Group 1 at all measurements. CONCLUSION: Patients that underwent CABG and received HTEA had better myocardial function and perioperative haemodynamic parameters than those who did not receive HTEA. PMID- 25918720 TI - Optimizing perfusion-decellularization methods of porcine livers for clinical scale whole-organ bioengineering. AB - Aim. To refine the decellularization protocol of whole porcine liver, which holds great promise for liver tissue engineering. Methods. Three decellularization methods for porcine livers (1% sodium dodecyl sulfate (SDS), 1% Triton X-100 + 1% sodium dodecyl sulfate, and 1% sodium deoxycholate + 1% sodium dodecyl sulfate) were studied. The obtained liver scaffolds were processed for histology, residual cellular content analysis, and extracellular matrix (ECM) components evaluation to investigate decellularization efficiency and ECM preservation. Rat primary hepatocytes were seeded into three kinds of scaffold to detect the biocompatibility. Results. The whole liver decellularization was successfully achieved following all three kinds of treatment. SDS combined with Triton had a high efficacy of cellular removal and caused minimal disruption of essential ECM components; it was also the most biocompatible procedure for primary hepatocytes. Conclusion. We have refined a novel, standardized, time-efficient, and reproducible protocol for the decellularization of whole liver which can be further adapted to liver tissue engineering. PMID- 25918719 TI - Emerging roles of focal adhesion kinase in cancer. AB - Focal adhesion kinase (FAK) is a cytoplasmic nonreceptor tyrosine kinase that enables activation by growth factor receptors or integrins in various types of human cancers. The kinase-dependent and kinase-independent scaffolding functions of FAK modulate the authentic signaling and fundamental functions not only in cancer cells but also in tumor microenvironment to facilitate cancer progression and metastasis. The overexpression and activation of FAK are usually investigated in primary or metastatic cancers and correlated with the poor clinical outcome, highlighting FAK as a potential prognostic marker and anticancer target. Small molecule inhibitors targeting FAK kinase activity or FAK-scaffolding functions impair cancer development in preclinical or clinical trials. In this review, we give an overview for FAK signaling in cancer cells as well as tumor microenvironment that provides new strategies for the invention of cancer development and malignancy. PMID- 25918721 TI - Microbiological Quality of Ready-to-Eat Vegetables Collected in Mexico City: Occurrence of Aerobic-Mesophilic Bacteria, Fecal Coliforms, and Potentially Pathogenic Nontuberculous Mycobacteria. AB - The aims of this study were to evaluate the microbiological quality and the occurrence of nontuberculous mycobacteria (NTM) in a variety of salads and sprouts from supermarkets and street vendors in Mexico City. Aerobic-mesophilic bacteria (AMB) were present in 100% of RTE-salads samples; 59% of samples were outside guidelines range (>5.17 log10 CFU per g). Although fecal coliforms (FC) were present in 32% of samples, only 8% of them exceeded the permissible limit (100 MPN/g). Regarding the 100 RTE-sprouts, all samples were also positive for AMB and total coliforms (TC) and 69% for FC. Seven NTM species were recovered from 7 salad samples; they included three M. fortuitum, two M. chelonae, one M. mucogenicum, and one M. sp. Twelve RTE-sprouts samples harbored NTM, which were identified as M. porcinum (five), M. abscessus (two), M. gordonae (two), M. mucogenicum (two), and M. avium complex (one). Most RTE-salads and RTE-sprouts had unsatisfactory microbiological quality and some harbored NTM associated with illness. No correlation between the presence of coliforms and NTM was found. Overall, these results suggest that RTE-salads and RTE-sprouts might function as vehicles for NTM transmission in humans; hence, proper handling and treatment before consumption of such products might be recommendable. PMID- 25918723 TI - Environmental Trigger(s) of Type 1 Diabetes: Why Is It So Difficult to Identify? PMID- 25918722 TI - Hippocampal-prefrontal circuit and disrupted functional connectivity in psychiatric and neurodegenerative disorders. AB - In rodents, the hippocampus has been studied extensively as part of a brain system responsible for learning and memory, and the prefrontal cortex (PFC) participates in numerous cognitive functions including working memory, flexibility, decision making, and rewarding learning. The neuronal projections from the hippocampus, either directly or indirectly, to the PFC, referred to as the hippocampal-prefrontal cortex (Hip-PFC) circuit, play a critical role in cognitive and emotional regulation and memory consolidation. Although in certain psychiatric and neurodegenerative diseases, structural connectivity viewed by imaging techniques has been consistently found to be associated with clinical phenotype and disease severity, the focus has moved towards the investigation of connectivity correlates of molecular pathology and coupling of oscillation. Moreover, functional and structural connectivity measures have been emerging as potential intermediate biomarkers for neuronal disorders. In this review, we summarize progress on the anatomic, molecular, and electrophysiological characters of the Hip-PFC circuit in cognition and emotion processes with an emphasis on oscillation and functional connectivity, revealing a disrupted Hip PFC connectivity and electrical activity in psychiatric and neurodegenerative disorders as a promising candidate of neural marker for neuronal disorders. PMID- 25918724 TI - Oral tori in chronic hemodialysis patients. AB - BACKGROUND: This study investigated the epidemiology of torus palatinus (TP) and torus mandibularis (TM) in hemodialysis patients and analyzed the influences of hyperparathyroidism on the formation of oral tori. METHOD: During 2013, 119 hemodialysis patients were recruited for dental examinations for this study. RESULTS: The prevalence of oral tori in our sample group was high at 33.6% (40 of 119). The most common location of tori was TP (70.0%), followed by TM (20.0%), and then both TP and TM (10.0%). Of the 40 tori cases, most (67.5%) were <2 cm in size; moreover, the majority (52.5%) were flat in shape. In symmetry, most (70.0%) occurred in the midline, followed by bilateral sides (20.0%). Notably, the levels of intact parathyroid hormone did not differ in patients with or without tori (P = 0.611). Furthermore, patients with tori did not differ from patients without tori in inflammatory variables such as log high-sensitivity C reactive protein (P = 1.000) or nutritional variables such as albumin (P = 0.247). Finally, there were no differences between patients with and without tori in adequacy of dialysis (P = 0.577). CONCLUSIONS: Neither hyperparathyroidism nor inflammation malnutrition syndrome was found to contribute to the formation of oral tori in chronic hemodialysis patients. Further studies are warranted. PMID- 25918725 TI - Inhibition of mTOR by Rapamycin Results in Auditory Hair Cell Damage and Decreased Spiral Ganglion Neuron Outgrowth and Neurite Formation In Vitro. AB - Rapamycin is an antifungal agent with immunosuppressive properties. Rapamycin inhibits the mammalian target of rapamycin (mTOR) by blocking the mTOR complex 1 (mTORC1). mTOR is an atypical serine/threonine protein kinase, which controls cell growth, cell proliferation, and cell metabolism. However, less is known about the mTOR pathway in the inner ear. First, we evaluated whether or not the two mTOR complexes (mTORC1 and mTORC2, resp.) are present in the mammalian cochlea. Next, tissue explants of 5-day-old rats were treated with increasing concentrations of rapamycin to explore the effects of rapamycin on auditory hair cells and spiral ganglion neurons. Auditory hair cell survival, spiral ganglion neuron number, length of neurites, and neuronal survival were analyzed in vitro. Our data indicates that both mTOR complexes are expressed in the mammalian cochlea. We observed that inhibition of mTOR by rapamycin results in a dose dependent damage of auditory hair cells. Moreover, spiral ganglion neurite number and length of neurites were significantly decreased in all concentrations used compared to control in a dose dependent manner. Our data indicate that the mTOR may play a role in the survival of hair cells and modulates spiral ganglion neuronal outgrowth and neurite formation. PMID- 25918726 TI - In silico search of energy metabolism inhibitors for alternative leishmaniasis treatments. AB - Leishmaniasis is a complex disease that affects mammals and is caused by approximately 20 distinct protozoa from the genus Leishmania. Leishmaniasis is an endemic disease that exerts a large socioeconomic impact on poor and developing countries. The current treatment for leishmaniasis is complex, expensive, and poorly efficacious. Thus, there is an urgent need to develop more selective, less expensive new drugs. The energy metabolism pathways of Leishmania include several interesting targets for specific inhibitors. In the present study, we sought to establish which energy metabolism enzymes in Leishmania could be targets for inhibitors that have already been approved for the treatment of other diseases. We were able to identify 94 genes and 93 Leishmania energy metabolism targets. Using each gene's designation as a search criterion in the TriTrypDB database, we located the predicted peptide sequences, which in turn were used to interrogate the DrugBank, Therapeutic Target Database (TTD), and PubChem databases. We identified 44 putative targets of which 11 are predicted to be amenable to inhibition by drugs which have already been approved for use in humans for 11 of these targets. We propose that these drugs should be experimentally tested and potentially used in the treatment of leishmaniasis. PMID- 25918727 TI - Effect of sulodexide on urinary biomarkers of kidney injury in normoalbuminuric type 2 diabetes: a randomized controlled trial. AB - Glycosaminoglycans or sulodexide has shown benefits in early experimental diabetic nephropathy (DN) models, but its efficacy in patients with early stage of DN is unknown. Methods. Twenty patients were randomly assigned to the placebo group and another 20 patients were randomly assigned to receive sulodexide 100 mg/day for 14 weeks. Primary outcome was a change of urinary TGF-beta1, albuminuria, and glomerular filtration rate (GFR). All patients had stable metabolic profiles for at least 90 days before randomization. Results. Urinary TGF-beta1 increased significantly in the placebo group but did not change significantly in the sulodexide group. Additionally, the mean change of urine TGF beta1 in the placebo group was significantly higher than that in the sulodexide group (8.44 +/- 9.21 versus 2.17 +/- 6.96 pg/mg Cr, P = 0.02). Mean changes of urinary albumin were 15.05 +/- 30.09 MUg/mg Cr (P = 0.038) in the placebo group and 13.89 +/- 32.25 MUg/mg Cr (P = 0.069) in the sulodexide group. No consistent patterns of side effects were observed. Conclusion. In this 14-week trial, benefits of sulodexide in preventing the increase of urinary TGF-beta1 were observed in patients with normoalbuminuric type 2 diabetes. The study suggests that sulodexide treatment may provide additional renoprotection in early stage DN. This trial is registered with TCTR20140806001. PMID- 25918728 TI - High-intensity interval training as an efficacious alternative to moderate intensity continuous training for adults with prediabetes. AB - AIMS: High-intensity interval training (HIIT) leads to improvements in various markers of cardiometabolic health but adherence to HIIT following a supervised laboratory intervention has yet to be tested. We compared self-report and objective measures of physical activity after one month of independent exercise in individuals with prediabetes who were randomized to HIIT (n = 15) or traditional moderate-intensity continuous training (MICT, n = 17). METHOD: After completing 10 sessions of supervised training participants were asked to perform HIIT or MICT three times per week for four weeks. RESULTS: Individuals in HIIT (89 +/- 11%) adhered to their prescribed protocol to a greater extent than individuals in MICT (71 +/- 31%) as determined by training logs completed over one-month follow-up (P = 0.05, Cohen's d = 0.75). Minutes spent in vigorous physical activity per week measured by accelerometer were higher in HIIT (24 +/- 18) as compared to MICT (11 +/- 10) at one-month follow-up (P = 0.049, Cohen's d = 0.92). Cardiorespiratory fitness and systolic blood pressure assessed at one month follow-up were equally improved (P's < 0.05). CONCLUSIONS: This study provides preliminary evidence that individuals with prediabetes can adhere to HIIT over the short-term and do so at a level that is greater than MICT. PMID- 25918729 TI - Renal kallikrein activation and renoprotection after dual blockade of renin angiotensin system in diet-induced diabetic nephropathy. AB - PURPOSE: The objective of this study is to investigate the effect of dual blockage of renin-angiotensin system (RAS) on renal kallikrein expression and inflammatory response in diabetic nephropathy (DN). METHODS: Rats were randomly divided into 5 groups with 10 rats in each group: normal control; DN model induced by high fat and high sucrose diets; and DN treated with either benazepril 10 mg/kg/d, irbesartan 30 mg/kg/d, or both. After 8-week treatment, we examined changes in the kidney histopathology, function and immunohistochemical stain of kallikrein, macrophage marker CD68, and profibrotic markers transforming growth factor- (TGF-) beta and alpha-smooth muscle action (SMA). RESULTS: DN rats showed enlarged kidneys with glomerulosclerosis, interstitial chronic inflammation and fibrosis, and proteinuria. All the pathological damage and functional impairments were improved after the RAS blockades (all P < 0.05). Compared with monotherapy, combined treatment further alleviated the kidney impairments in parallel to increased tubular immunoreactivity for kallikrein and decreased immunopositive cells for CD68, TGF-beta, and alpha-SMA. CONCLUSION: The renoprotective effects of the dual RAS blockade in diabetic nephropathy may be attributed to improved tubular kallikrein expression and interstitial inflammatory response. PMID- 25918730 TI - Alteration of mevalonate pathway in proliferated vascular smooth muscle from diabetic mice: possible role in high-glucose-induced atherogenic process. AB - The proliferation of vascular smooth muscle cells (VSMCs) is one of the main features of atherosclerosis induced by high glucose. Mevalonate pathway is an important metabolic pathway that plays a key role in multiple cellular processes. The aim of this study was to define whether the enzyme expression in mevalonate pathway is changed in proliferated VSMCs during atherogenic process in diabetic mice. Diabetes was induced in BALB/c mice with streptozotocin (STZ, 50 mg/kg/day for 5 days). Induction of diabetes with STZ was associated with an increase of lesion area and media thickness after 8 and 16 weeks of diabetes. In aorta, there were overexpressions of some enzymes, including 3-hydroxy-3-methylglutaryl coenzyme A reductase (HMGR), farnesyl pyrophosphate synthase (FPPS), geranylgeranyl pyrophosphate synthase (GGPPS), farnesyltransferase (FNT), and geranylgeranyltransferase-1 (GGT-1), and unchanged expression of squalene synthase (SQS) and phosphor-3-hydroxy-3-methylglutaryl-coenzyme A reductase (P HMGR) in 8 and 16 weeks of diabetes. In vitro, VSMCs were cultured and treated with different glucose concentrations for 48 h. High glucose (22.2 mM) induced VSMC proliferation and upregulation of HMGR, FPPS, GGPPS, FNT, and GGT-1 but did not change the expressions of SQS and P-HMGR. In conclusion, altered expression of several key enzymes in the mevalonate pathway may play a potential pathophysiological role in atherogenic process of diabetes macrovascular complication. PMID- 25918731 TI - Nuclear factor of activated T cells is activated in the endothelium of retinal microvessels in diabetic mice. AB - The pathogenesis of diabetic retinopathy (DR) remains unclear but hyperglycemia is an established risk factor. Endothelial dysfunction and changes in Ca2+ signaling have been shown to precede the onset of DR. We recently demonstrated that high extracellular glucose activates the Ca(2+)/calcineurin-dependent transcription factor NFAT in cerebral arteries and aorta, promoting the expression of inflammatory markers. Here we show, using confocal immunofluorescence, that NFAT is expressed in the endothelium of retinal microvessels and is readily activated by high glucose. This was inhibited by the NFAT blocker A-285222 as well as by the ectonucleotidase apyrase, suggesting a mechanism involving the release of extracellular nucleotides. Acute hyperglycemia induced by an IP-GTT (intraperitoneal glucose tolerance test) resulted in increased NFATc3 nuclear accumulation and NFAT-dependent transcriptional activity in retinal vessels of NFAT-luciferase reporter mice. In both Akita (Ins2(+/-) ) and streptozotocin- (STZ-) induced diabetic mice, NFAT transcriptional activity was elevated in retinal vessels. In vivo inhibition of NFAT with A-285222 decreased the expression of OPN and ICAM-1 mRNA in retinal vessels, prevented a diabetes driven downregulation of anti-inflammatory IL-10 in retina, and abrogated the increased vascular permeability observed in diabetic mice. Results identify NFAT signaling as a putative target for treatment of microvascular complications in diabetes. PMID- 25918732 TI - Cardiovascular control during exercise in type 2 diabetes mellitus. AB - Controlled studies of male and female subjects with type 2 diabetes mellitus (DM) of short duration (~3-5 years) show that DM reduces peak VO2 (L.min(-1) and mL.kg(-1).min(-1)) by an average of 12-15% and induces a greater slowing of the dynamic response of pulmonary VO2 during submaximal exercise. These effects occur in individuals less than 60 years of age but are reduced or absent in older males and are consistently associated with significant increases in the exercise pressor response despite normal resting blood pressure. This exaggerated pressor response, evidence of exertional hypertension in DM, is manifest during moderate submaximal exercise and coincides with a more constrained vasodilation in contracting muscles. Maximum vasodilation during contractions involving single muscle groups is reduced by DM, and the dynamic response of vasodilation during submaximal contractions is slowed. Such vascular constraint most likely contributes to exertional hypertension, impairs dynamic and peak VO2 responses, and reduces exercise tolerance. There is a need to establish the effect of DM on dynamic aspects of vascular control in skeletal muscle during whole-body exercise and to clarify contributions of altered cardiovascular control and increased arterial stiffness to exertional hypertension. PMID- 25918734 TI - Mesenchymal stem cells from patients with rheumatoid arthritis display impaired function in inhibiting Th17 cells. AB - Mesenchymal stem cells (MSCs) possess multipotent and immunomodulatory properties and are suggested to be involved in the pathogenesis of immune-related diseases. This study explored the function of bone marrow MSCs from rheumatoid arthritis (RA) patients, focusing on immunomodulatory effects. RA MSCs showed decreased proliferative activity and aberrant migration capacity. No significant differences were observed in cytokine profiles between RA and control MSCs. The effects of RA MSCs on proliferation of peripheral blood mononuclear cells (PBMCs) and distribution of specific CD4(+) T cell subtypes (Th17, Treg, and Tfh cells) were investigated. RA MSCs appeared to be indistinguishable from controls in suppressing PBMC proliferation, decreasing the proportion of Tfh cells, and inducing the polarization of Treg cells. However, the capacity to inhibit Th17 cell polarization was impaired in RA MSCs, which was related to the low expression of CCL2 in RA MSCs after coculture with CD4(+) T cells. These findings indicated that RA MSCs display defects in several important biological activities, especially the capacity to inhibit Th17 cell polarization. These functionally impaired MSCs may contribute to the development of RA disease. PMID- 25918733 TI - Adipokines as drug targets in diabetes and underlying disturbances. AB - Diabetes and obesity are worldwide health problems. White fat dynamically participates in hormonal and inflammatory regulation. White adipose tissue is recognized as a multifactorial organ that secretes several adipose-derived factors that have been collectively termed "adipokines." Adipokines are pleiotropic molecules that gather factors such as leptin, adiponectin, visfatin, apelin, vaspin, hepcidin, RBP4, and inflammatory cytokines, including TNF and IL 1beta, among others. Multiple roles in metabolic and inflammatory responses have been assigned to these molecules. Several adipokines contribute to the self styled "low-grade inflammatory state" of obese and insulin-resistant subjects, inducing the accumulation of metabolic anomalies within these individuals, including autoimmune and inflammatory diseases. Thus, adipokines are an interesting drug target to treat autoimmune diseases, obesity, insulin resistance, and adipose tissue inflammation. The aim of this review is to present an overview of the roles of adipokines in different immune and nonimmune cells, which will contribute to diabetes as well as to adipose tissue inflammation and insulin resistance development. We describe how adipokines regulate inflammation in these diseases and their therapeutic implications. We also survey current attempts to exploit adipokines for clinical applications, which hold potential as novel approaches to drug development in several immune-mediated diseases. PMID- 25918735 TI - Enhanced cysteinyl-leukotriene type 1 receptor expression in T cells from house dust mite-allergic individuals following stimulation with Der p. AB - In order to determine the potential for allergen to modulate T cell expression of the CysLT1 receptor and responsiveness to leukotrienes, peripheral blood mononuclear cells from house dust mite-allergic or nonallergic individuals were incubated with D. pteronyssinus allergen (Der p). Baseline CysLT1 expression was similar in both groups of donors, but Der p significantly enhanced CysLT1 expression in CD4(+) and CD8(+) T cells of only allergic individuals and induced enhanced responsiveness of CD4(+) T cells to LTD4 in terms of calcium mobilisation. This effect was prevented by the CysLT1 antagonist MK571. Der p also induced IL-4 and IL-10 production, and neutralizing antibody to IL-4 prevented both the enhanced CysLT1 expression and the enhanced responsiveness of T cells to LTD4 induced by Der p. In allergic individuals, Der p also induced T cell proliferation and a Th2-biased phenotype. Our data suggest that, in allergen sensitized individuals, exposure to allergen can enhance T cell expression of CysLT1 receptors through a mechanism involving IL-4 production. This, in turn, would induce CD4(+) T cell responsiveness to cysteinyl-leukotrienes and Th2 cell activation. PMID- 25918736 TI - Sleep abnormality in neuromyelitis optica spectrum disorder. AB - OBJECTIVES: We investigated the sleep structure of patients with neuromyelitis optica spectrum disorder (NMOSD) and the association of abnormalities with brain lesions. METHODS: This was a prospective cross-sectional study. Thirty-three patients with NMOSD and 20 matched healthy individuals were enrolled. Demographic and clinical characteristics of patients were collected. Questionnaires were used to assess quality of sleep, daytime sleepiness, fatigue, and depression. Nocturnal polysomnography was performed. RESULTS: Compared with healthy controls, patients with NMOSD had decreases in sleep efficiency (7%; p = 0.0341), non-REM sleep N3 (12%; p < 0.0001), and arousal index (6; p = 0.0138). REM sleep increased by 4% (p = 0.0423). There were correlations between arousal index and REM% or Epworth Sleepiness Scale (r = -0.0145; p = 0.0386, respectively). Six patients with NMOSD (18%, 5 without infratentorial lesions and 1 with infratentorial lesions) had a hypopnea index >5, and all of those with sleep apnea had predominantly the peripheral type. The periodic leg movement (PLM) index was higher in patients with NMOSD than in healthy controls (20 vs 2, p = 0.0457). Surprisingly, 77% of the patients with PLM manifested infratentorial lesions. CONCLUSIONS: Sleep architecture was markedly disrupted in patients with NMOSD. Surveillance of nocturnal symptoms and adequate symptomatic control are expected to improve the quality of life of patients with NMOSD. PMID- 25918737 TI - Cone-beam computed tomography as a diagnostic method for determination of gingival thickness and distance between gingival margin and bone crest. AB - The objective of the present study was to assess cone-beam computed tomography (CBCT) as a diagnostic method for determination of gingival thickness (GT) and distance between gingival margin and vestibular (GMBC-V) and interproximal bone crests (GMBC-I). GT and GMBC-V were measured in 348 teeth and GMBC-I was measured in 377 tooth regions of 29 patients with gummy smile. GT was assessed using transgingival probing (TP), ultrasound (US), and CBCT, whereas GMBC-V and GMBC-I were assessed by transsurgical clinical evaluation (TCE) and CBCT. Statistical analyses used independent t-test, Pearson's correlation coefficient, and simple linear regression. Difference was observed for GT: between TP, CBCT, and US considering all teeth; between TP and CBCT and between TP and US in incisors and canines; between TP and US in premolars and first molars. TP presented the highest means for GT. Positive correlation and linear regression were observed between TP and CBCT, TP and US, and CBCT and US. Difference was observed for GMBC V and GMBC-I using TCE and CBCT, considering all teeth. Correlation and linear regression results were significant for GMBC-V and GMBC-I in incisors, canines, and premolars. CBCT is an effective diagnostic method to visualize and measure GT, GMBC-V, and GMBC-I. PMID- 25918738 TI - Effect of aging treatment on the damping capacity and mechanical properties of Mg 6Al-1Zn alloy. AB - The damping capacity and mechanical properties of Mg-6Al-1Zn alloy after heat treatment were investigated. The damping characteristics of un-heat-treated, solution treated, and aged Mg-6Al-1Zn specimens were determined by measuring the damping ratio and the logarithmic decrement of free vibrations of a bending beam clamped at one side. The microstructural evaluations confirmed that the beta Mg17Al12 phase was reprecipitated after aging and increased with an increase in aging time. The peak level of damping ratio and logarithmic decrement was obtained after 34 hr of aging time, over which the damping capacity declined according to increasing amount of strong pining points. PMID- 25918739 TI - Comment on "effects of scheduled exercise on cancer-related fatigue in women with early breast cancer". PMID- 25918740 TI - Optimization of the Switch Mechanism in a Circuit Breaker Using MBD Based Simulation. AB - A circuit breaker is widely used to protect electric power system from fault currents or system errors; in particular, the opening mechanism in a circuit breaker is important to protect current overflow in the electric system. In this paper, multibody dynamic model of a circuit breaker including switch mechanism was developed including the electromagnetic actuator system. Since the opening mechanism operates sequentially, optimization of the switch mechanism was carried out to improve the current breaking time. In the optimization process, design parameters were selected from length and shape of each latch, which changes pivot points of bearings to shorten the breaking time. To validate optimization results, computational results were compared to physical tests with a high speed camera. Opening time of the optimized mechanism was decreased by 2.3 ms, which was proved by experiments. Switch mechanism design process can be improved including contact-latch system by using this process. PMID- 25918741 TI - Energy aware swarm optimization with intercluster search for wireless sensor network. AB - Wireless sensor networks (WSNs) are emerging as a low cost popular solution for many real-world challenges. The low cost ensures deployment of large sensor arrays to perform military and civilian tasks. Generally, WSNs are power constrained due to their unique deployment method which makes replacement of battery source difficult. Challenges in WSN include a well-organized communication platform for the network with negligible power utilization. In this work, an improved binary particle swarm optimization (PSO) algorithm with modified connected dominating set (CDS) based on residual energy is proposed for discovery of optimal number of clusters and cluster head (CH). Simulations show that the proposed BPSO-T and BPSO-EADS perform better than LEACH- and PSO-based system in terms of energy savings and QOS. PMID- 25918742 TI - Spatial mutual information based hyperspectral band selection for classification. AB - The amount of information involved in hyperspectral imaging is large. Hyperspectral band selection is a popular method for reducing dimensionality. Several information based measures such as mutual information have been proposed to reduce information redundancy among spectral bands. Unfortunately, mutual information does not take into account the spatial dependency between adjacent pixels in images thus reducing its robustness as a similarity measure. In this paper, we propose a new band selection method based on spatial mutual information. As validation criteria, a supervised classification method using support vector machine (SVM) is used. Experimental results of the classification of hyperspectral datasets show that the proposed method can achieve more accurate results. PMID- 25918743 TI - On a modified form of navier-stokes equations for three-dimensional flows. AB - A rephrased form of Navier-Stokes equations is performed for incompressible, three-dimensional, unsteady flows according to Eulerian formalism for the fluid motion. In particular, we propose a geometrical method for the elimination of the nonlinear terms of these fundamental equations, which are expressed in true vector form, and finally arrive at an equivalent system of three semilinear first order PDEs, which hold for a three-dimensional rectangular Cartesian coordinate system. Next, we present the related variational formulation of these modified equations as well as a general type of weak solutions which mainly concern Sobolev spaces. PMID- 25918744 TI - Strategic management advanced service for sustainable computing environment. PMID- 25918745 TI - Due-window assignment scheduling with variable job processing times. AB - We consider a common due-window assignment scheduling problem jobs with variable job processing times on a single machine, where the processing time of a job is a function of its position in a sequence (i.e., learning effect) or its starting time (i.e., deteriorating effect). The problem is to determine the optimal due windows, and the processing sequence simultaneously to minimize a cost function includes earliness, tardiness, the window location, window size, and weighted number of tardy jobs. We prove that the problem can be solved in polynomial time. PMID- 25918747 TI - Dynamic schedule-based assignment model for urban rail transit network with capacity constraints. AB - There is a great need for estimation of passenger flow temporal and spatial distribution in urban rail transit network. The literature review indicates that passenger flow assignment models considering capacity constraints with overload delay factor for in-vehicle crowding are limited in schedule-based network. This paper proposes a stochastic user equilibrium model for solving the assignment problem in a schedule-based rail transit network with considering capacity constraint. As splitting the origin-destination demands into the developed schedule expanded network with time-space paths, the model transformed into a dynamic schedule-based assignment model. The stochastic user equilibrium conditions can be equivalent to the equilibrium passenger overload delay with crowding penalty in the transit network. The proposal model can estimate the path choice probability according to the equilibrium condition when passengers minimize their perceptive cost in a schedule-based network. Numerical example in Beijing urban rail transit (BURT) network is used to demonstrate the performance of the model and estimate the passenger flow temporal and spatial distribution more reasonably and dynamically with train capacity constraints. PMID- 25918746 TI - Innovative targeting strategies in drug therapy for inflammatory diseases: mechanistic approaches. PMID- 25918748 TI - Multiscale Region-Level VHR Image Change Detection via Sparse Change Descriptor and Robust Discriminative Dictionary Learning. AB - Very high resolution (VHR) image change detection is challenging due to the low discriminative ability of change feature and the difficulty of change decision in utilizing the multilevel contextual information. Most change feature extraction techniques put emphasis on the change degree description (i.e., in what degree the changes have happened), while they ignore the change pattern description (i.e., how the changes changed), which is of equal importance in characterizing the change signatures. Moreover, the simultaneous consideration of the classification robust to the registration noise and the multiscale region consistent fusion is often neglected in change decision. To overcome such drawbacks, in this paper, a novel VHR image change detection method is proposed based on sparse change descriptor and robust discriminative dictionary learning. Sparse change descriptor combines the change degree component and the change pattern component, which are encoded by the sparse representation error and the morphological profile feature, respectively. Robust change decision is conducted by multiscale region-consistent fusion, which is implemented by the superpixel level cosparse representation with robust discriminative dictionary and the conditional random field model. Experimental results confirm the effectiveness of the proposed change detection technique. PMID- 25918749 TI - Low-Cost Disposable Cartridge for Performing a White Blood Cell Count and Partial Differential at the Point-of-Care. AB - Being able to perform a white blood cell (WBC) count and differential is a crucial laboratory test for basic diagnostic practices. In this paper, we demonstrate proof of concept results for a disposable cartridge that could be used to perform a WBC count and 3-part differential at the point-of-care. The cartridge is composed of a glass slide, a layer of transfer tape, and a glass cover slip and incorporates acridine orange for cell staining and sub-type differentiation; the stained blood is then imaged, and image analysis techniques return a WBC count and 3-part differential. The cartridge was tested on a laboratory microscope with 3 normal samples, and had promising results with 85.7% of images resulting in a WBC count with +/-15% of the true value. Further, the 3 part differential concentrations determined using the disposable cartridge had strong correlations with the true concentrations (R2 values of 0.9986, 0.9421, and 0.6942 for granulocytes, lymphocytes, and monocytes, respectively). Preliminary designs for a low-cost, portable microscope have been created and are currently being prototyped. PMID- 25918750 TI - Design and Performance of a Low-Cost, Handheld Reader for Diagnosing Anemia in Blantyre, Malawi. AB - Anemia, a condition characterized by insufficient hemoglobin, affects 56.2% of pregnant women and 66.1% of children under five in low-resource countries. Though hemoglobin concentration measurement is the most common laboratory test in the world, the high cost of disposables (>$1.00 per test in Malawi) limits its availability in these settings. We have demonstrated a spectrophotometric method that reduces the per-test cost of anemia diagnosis to under $0.01 by using chromatography paper as the only disposable. Improvements in the hand-held reader, including using laser modules and a reference photodiode, enabled repeatable results within and across devices. We evaluated this method by analyzing capillary blood samples from 70 patients in the pediatric ward of Queen Elizabeth Central Hospital, Blantyre, Malawi. ~90% of these samples were within 2 g/dL of the standard value, with higher accuracy on more anemic samples. Current work aims to improve this accuracy by converting the hemoglobin in the sample to the more stable form methemoglobin. PMID- 25918751 TI - Tongue phlebothrombosis: Pathogenesis and potential risks. AB - Phlebothrombosis is a thrombus which develops within a vein. About 90% of phlebothrombosis takes place in the extremities and constitutes a risk factor for deep venous thrombosis, a lifethreatening disease. The occurrence of this lesion in the oral cavity is rare. To our knowledge, besides this case, there is only one previously reported case of tongue phlebothrombosis. Here, we report the second case in addition to a comprehensive discussion of the pathogenesis and potential risks of this uncommon lesion. PMID- 25918752 TI - Dental implants in the patient with multiple myeloma: Literature review and case report. AB - Multiple myeloma is a blood dyscrasia involving plasma cells in the bone marrow. Much new information and many management strategies exist for these disorders. For dental care, there are a number of issues for the clinician to consider. This review discusses current management of this disease and a case report. PMID- 25918753 TI - Preoperative 3D imaging in maxillary sinus: brief review of the literature and case report. AB - OBJECTIVE: The purpose of the present case report is to document the removal of a radix in antro without a hemorrhagic complication in presence of a posterior superior alveolar artery (PSAA) with a 2.8 mm diameter following a radiographic 3D planning by cone beam computed tomography (CBCT) scan. Furthermore, a brief literature overview on studies describing the existence and the variance of the PSAA is provided. METHOD AND MATERIALS: A foreign body removal in the right maxillary sinus was performed on a 33-year-old healthy man by using the lateral window osteotomy. The preoperative CBCT scan showed three arteries in the lateral maxillary sinus wall at a distance of 24.6 mm, 19.5 mm, and 13.5 mm to the alveolar crest. RESULTS: By removing a foreign body out of the maxillary sinus a vessel with a diameter of nearly 3 mm was exposed. Due to CBCT scan planning and the use of piezosurgery it was possible to avoid any damage to the vessel during the operation. The postoperative healing was uneventful and no complications occurred. CONCLUSION: Although laceration of vessels with a large diameter during lateral window osteotomy is not life-threatening it may compromise visualization and reduces the surgical outcome. Therefore, 3D imaging is recommended for the minimization of intra- and postoperative complications and for the localization of any foreign body in relation to other anatomical structures. This is of special interest in case of anatomical variances of blood vessels. PMID- 25918754 TI - Detection of mandibular condyle pesudocysts in panoramic radiographs: Digital and film-based radiology. AB - OBJECTIVE: To determine the detection rate of mandibular condyle pseudocyst in both digital panoramic radiographs and film-based panoramic radiographs. METHOD AND MATERIALS: All film-based and digital panoramic radiographs of patients treated at our institute during a 4-month period were analyzed by two experienced practitioners. Diagnosis of a condylar pseudocyst was based on the following criteria: appearance of cyst-like radiolucency, partially or completely circumscribed by radiopaque border, located at the anterior aspect of mandibular condyle. RESULTS: 825 radiographs (415 film-based, 410 digital) were included in the study. In 342 (41.5%) radiographs at least one condylar pseudocyst was observed, with no differences between radiograph type, 173 (42.2%) in digital and 169 (40.7%) in film-based radiographs (P = .36). Condylar pseudocyst detection rate was positively associated with older age (P < .001), whereas gender had no influence (P = .93). CONCLUSION: An equally high detection rate of condylar pseudocyst was found in digital and film-based panoramic radiographs. PMID- 25918755 TI - Effect of audiovisual eyeglasses during local anesthesia injections in 5- to 8 year-old children. AB - OBJECTIVE: To evaluate the effectiveness of audiovisual (AV) eyeglasses on pain reduction during local anesthetic injection in children who are 5 to 8 years old. METHOD AND MATERIALS: Forty-nine healthy, cooperative children with bilateral carious molars requiring treatment under local anesthesia were recruited in this crossover study. Treatments were done in two visits, 1 to 4 weeks apart. Subjects were randomly divided into two groups according to the sequence of AV eyeglasses used. Group I received the injection without wearing AV eyeglasses in the first visit and then wearing AV eyeglasses in a second visit. Group II was vice versa. Self-reporting pain using the Faces Pain Scale-Revised (FPS-R), face, legs, activity, crying, and consolability scale (FLACC), and heart rate (HR), were measured to assess the injection pain. RESULTS: No significant differences in sex (P = .132) and treatment arch (P = .779) were observed between the two groups using a chi-square test at P < .05. There were no significant differences in age (P = .341, t test at P <= .05) and previous dental experience (P = .19, Fisher's exact test at P <= .05) between the two groups. Pain scores were lower when the patients had their injection while wearing AV eyeglasses in both groups. No subject reported a maximum score on the pain rating scale when wearing AV eyeglasses, while 14% of the subjects reported so when not wearing the eyeglasses. AV eyeglasses significantly reduced FLACC scores (P = .03) and HR (P = .005) when compared with not wearing the eyeglasses (Mann-Whitney U test at P <= .05). CONCLUSION: AV eyeglasses successfully reduced pain, physical distress, and HR during local anesthesia injection. PMID- 25918756 TI - Perception of pain due to various orthodontic procedures. AB - OBJECTIVE: To investigate five orthodontic procedures, namely separator placement, banding, initial arch wire ligation (0.016 NiTi), T-loop activation, and use of intermaxillary elastics with respect to intensity of peak pain, time of peak pain, need of medication for pain relief, and effect on routine life due to pain. METHOD AND MATERIALS: One hundred patients (52 males, 48 females) selected for comprehensive orthodontic therapy were included in the study. They were divided into five study groups, namely the separator group, banding group, initial NiTi group, T-loop activation group, and intermaxillary elastics group. Each patient was given a previously prepared questionnaire regarding the following: time of peak pain, intensity of peak pain, need for analgesic consumption, and effect on routine life. RESULTS: Consumption of medication for pain relief was found to be highest in the separator and the initial NiTi groups. Routine life was affected most in the intermaxillary elastics and the initial NiTi groups, but it was not statistically significant. Statistically significant differences were found between the T-loop activation and the banding groups and also between the banding and the intermaxillary elastic groups with respect to perception of intensity of peak pain. In the separator group, the time of peak pain was experienced at the 24th hour and in the rest of the groups it was at the 6th hour with most patients, although the values were not statistically significant. CONCLUSION: Peak pain intensity varies from one procedure to another. It was significantly more due to T-loop activation and wear of intermaxillary elastics than banding. PMID- 25918757 TI - The properties of chlorhexidine and undesired effects of its use in endodontics. AB - OBJECTIVE: The purpose of this article was to review the literature on the properties of chlorhexidine (CHX) and the adverse effects that may occur from its use in endodontics. In addition, adverse effects that may result from its use, such as dark staining of teeth, chemical interaction with sodium hypochlorite and formed flocculate, biologic hazards, and interactions with the filling material were evaluated. DATA SOURCES: Relevant publications on the use CHX in endodontics were thoroughly reviewed from the literature published between the years 2007 and 2014. METHOD AND MATERIALS: The authors conducted an electronic search using the English language databases Medline and PubMed. RESULTS: According to the reviewed studies, it was concluded that CHX has proven antimicrobial activity, excellent substantivity, low surface tension, and low cytotoxicity and genotoxicity that depend on the dose and exposed area. There is scientific evidence showing the possibility of tooth staining and formation of brown precipitate when its use is associated with sodium hypochlorite. On the other hand, it is not well established that its use interferes with the quality of endodontic fillings. With respect to the biologic risks, the degradation of CHX may generate para chloroaniline and free radicals, which are harmful to the vital tissues. There is no established consensus on the potential risk of CHX. CONCLUSION: The final considerations of this review will encourage researchers to seek scientific evidence demonstrating the safety of the use and applicability of CHX in endodontic therapy. PMID- 25918758 TI - Trifactorial classification system for osteotome sinus floor elevation based on an observational retrospective analysis of 926 implants followed up to 10 years. AB - OBJECTIVE: A novel osteotome trifactorial classification system is proposed for transcrestal osteotome-mediated sinus floor elevation (OSFE) sites that includes residual bone height (RBH), sinus floor anatomy (contour), and multiple versus single sites OSFE (tenting). METHOD AND MATERIALS: An analysis of RBH, contour, and tenting was retrospectively applied to a cohort of 926 implants placed using OSFE without added bone graft and followed up to 10 years. RBH was divided into three groups: high (RBH > 6 mm), mid (RBH = 4.1 to 6 mm), and low (RBH = 2 to 4 mm). The sinus "contour" was divided into four groups: flat, concave, angle, and septa. For "tenting", single versus multiple adjacent OSFE sites were compared. RESULTS: The prevalence of flat sinus floors increased as RBH decreased. RBH was a significant predictor of failure with rates as follows: low- RBH = 5.1%, mid RBH = 1.5%, and high-RBH = 0.4%. Flat sinus floors and single sites as compared to multiple sites had higher observed failure rates but neither achieved statistical significance; however, the power of the study was limited by low numbers of failures. CONCLUSION: The osteotome trifactorial classification system as proposed can assist planning OSFE cases and may allow better comparison of future OSFE studies. PMID- 25918759 TI - Efficacy of forced eruption/enamel matrix derivative with freeze-dried bone allograft or with demineralized freeze-dried bone allograft in infrabony defects: A randomized trial. AB - OBJECTIVE: To determine the efficacy of enamel matrix derivative (EMD) and forced eruption alone or in combination with freeze-dried bone allograft (FDBA) or demineralized FDBA (DFDBA) when managing infrabony defects. METHOD AND MATERIALS: Seventy-four patients with an inadequate biologic width due to subgingival caries were randomly assigned to one of three intervention groups: Ortho/EMD/FDBA (OEF) (n = 25), Ortho/EMD/DFDBA (OED) (n = 24), and Ortho/EMD alone without graft material as a control (OE) (n = 25). Each patient donated an infrabony defect. The primary outcomes were absolute change in probing depth (PD) reduction and clinical attachment level (CAL) gain from baseline to 1- and 3-year follow-up. Infrabony defects were surgically treated with EMD/FDBA, EMD/DFDBA, or EMD alone 4 weeks before orthodontic extrusive force was applied to reestablish a biologic width of 2 mm. RESULTS: Seventy-four patients (OEF, n = 25; OED, n = 24; OE, n = 25) were analyzed. All groups demonstrated significant improvement in PD reduction and CAL gain from baseline. The changes at 1 year for PD were: OEF (mm, 95% CI), 4.3, 3.7 to 4.7; OED, 4.2, 3.6 to 4.9; and OE, 3.4, 3.1 to 3.7; for CAL, changes were: OEF, 4.3, 3.9 to 4.7; OED, 3.9, 3.5 to 4.4; and OE, 3.3, 3.1 to 3.5. Longer follow-ups showed similar findings. CONCLUSION: This study showed that both forced eruption/EMD/FDBA and forced eruption/EMD/DFDBA combination therapies result in greater soft tissue improvements at 1- and 3-year follow-up in addition to greater hard tissue improvements at 6-month re-entry compared with forced eruption/EMD alone. PMID- 25918760 TI - In vitro studies on CAD/CAM restorations fabricated with Procera technology: an overview. AB - OBJECTIVE: The number of available CAD/CAM systems has dramatically increased in recent years. Consequently, although clinical data for the newer systems are missing, in vitro studies are published frequently. The goal of this review was to provide an overview of in vitro studies conducted with the Procera system. METHOD AND MATERIALS: Repeated online searching in PubMed was done until June 2014 using the search terms Nobel, Procera, dental, implant. Papers reporting clinical studies, evaluating cementation procedures as well as investigations using norm-shaped test specimens were excluded from analysis. Data were then assigned to the following categories: material characterization, scanner technology, single crown and multi-unit restorations, passivity of fit of implant supported restorations, and implant abutments. RESULTS: Relative comparisons within specific studies based on the control specimens used indicate that all Procera restorations meet clinical requirements. Absolute comparisons between studies are not possible due to great variations in study design and outcome measures. CONCLUSION: While the relevance of in vitro data is frequently questioned, practicing clinicians have to rely on such information when judging the applicability of a novel CAD/CAM system. Given that the Procera CAD/CAM system has proven its reliability both in vitro and in clinical use, existing in vitro data for this CAD/CAM system may serve as a useful reference providing benchmark values for future developments. PMID- 25918761 TI - Three-year outcomes of Straumann Bone Level SLActive dental implants in daily dental practice: a prospective non-interventional study. AB - OBJECTIVE: The aim of this investigation was to evaluate the performance of Straumann Bone Level SLActive implants in various clinical situations in daily dental practice for up to 3 years. METHOD AND MATERIALS: This was a prospective, multicenter, non-interventional study in which implants were placed within approved indications in any situation deemed suitable by the treating clinician. No implant placement or loading protocol was specified, and implants were placed according to the routine treatment protocols at each participating center. RESULTS: In this analysis, data were available from 342 implants in 233 patients in three countries (USA, Canada, and Switzerland). One or two implants were placed in the majority of patients (70.8% and 19.3%, respectively), mostly in the maxilla (71.3%); almost half (47.7%) were placed in the esthetic zone. Implant placement after 4 to > 16 weeks of healing was preferred in Switzerland (92.0%), while 42.0% of implants were placed immediately in the USA and Canada. A flapless procedure was performed in 25.2% of cases in the USA and Canada, compared to 0.5% in Switzerland. Cumulative implant survival and success rates after 3 years were 97.5% and 93.5%, respectively. CONCLUSION: Straumann Bone Level Implants can achieve favorable outcomes and high survival rates after 3 years in daily dental practice. The survival and success rates were comparable with those achieved in formal controlled clinical trials. PMID- 25918762 TI - Retrospective analysis of loosening of cement-retained vs screw-retained fixed implant-supported reconstructions. AB - OBJECTIVE: The cementation of fixed dental prostheses (FDPs) on implants involves the risk of undetected excess cement. If a zinc oxide-eugenol cement (ZEC) is used as the luting material, this risk appears to be lower, as the excess cement will dissolve in the peri-implant sulcus. However, using a ZEC on a general basis conflicts with the manufacturers' classification of a ZEC as a temporary luting material. To evaluate the clinical safety of ZECs, the present study investigated whether more ZECretained reconstructions than screw-retained reconstructions loosen over time. METHOD AND MATERIALS: In a retrospective observational study, the frequency of FDP loosening was investigated. For this purpose, data from patients who had been fitted with FDPs on two or more than two posterior implants were investigated. The study compared screw-retained (n = 59) vs cement-retained (n = 40) FDPs on implants over an observation period of 3.5 years after reconstruction incorporation. All cement-retained FDPs had been cemented with a temporary ZEC. RESULTS: The prevalence of reconstruction loosening was significantly lower for cement-retained FDPs when a ZEC (10%) was used than it was for screw-retained FDPs (29%); four screw-retained FDPs and one cementretained FDP developed major complications. The survival rate of the reconstructions within the observation period was 97% for screw-retained FDPs and 100% for cement-retained FDPs (not significant). CONCLUSION: The prevalence of cementretained FDP loosening was significantly lower than that of screw-retained FDPs. Cementing FDPs on implants using a temporary cement does not necessarily lead to a higher number of loosened reconstructions. Permanent cementation with ZEC appears to be justified. PMID- 25918763 TI - Photodynamic therapy in periodontal and peri-implant diseases. AB - OBJECTIVE: In recent years, photodynamic therapy (PDT) using a combination of photosensitizer and laser light source has been used in periodontal therapy. The aim of this review is to provide an overview of the current status and use of PDT. DATA SOURCES: A review of pertinent literature was carried out in PubMED to determine the current position of PDT applications in periodontal and peri implant diseases. CONCLUSIONS: In spite of different results and suggestions from various researchers, the present review showed that use of PDT may help improve periodontal outcomes. Therefore, it could become a new method for antibacterial treatment and may be used as an adjunct to or as conventional therapy for the treatment of periodontal and peri-implant diseases. Based on the results presented herein, there is promising, albeit preliminary, information regarding the benefits of PDT use on periodontal treatment outcomes. However, the conclusions are a reflection of a relatively small sample size and therefore need to be demonstrated in the general population. CLINICAL RELEVANCE: Periodontal diseases and peri-implantitis are among the specific targets where PDT can be applied. PMID- 25918764 TI - The controlled synthesis of plasmonic nanoparticle clusters as efficient surface enhanced Raman scattering platforms. AB - A facile aqueous synthesis method for the preparation of Au nanoparticle clusters by the controlled galvanic replacement of Ag nanoparticles with Au precursors is described. The prepared clusters showed both significantly enhanced surface enhanced Raman scattering activity and stability. PMID- 25918766 TI - Retraction. Effects of thymoquinone (volatile oil of black cumin) on rheumatoid arthritis in rat models. PMID- 25918765 TI - A new diluted magnetic semiconductor based on the expanded phase of ZnS: surmounting the random distribution of magnetic impurities. AB - Because of the strong d-d interactions, the doped transition metal (TM) atoms in the semiconducting host matrix tend to cluster and form a random distribution or a chemical phase separation. Hence it is a long-standing dream to achieve the desired diluted magnetic semiconductor (DMS) with regularly and separately distributed TM impurities and room-temperature ferromagnetism. Here we, for the first time, demonstrate via accurate ab initio calculations that the cage-like building block Zn12S12 of the novel cluster-assembled sodalite phase of ZnS can provide an appropriate potential well to trap a foreign Mn atom, realizing regular distribution of the doped magnetic atoms. Interestingly, the endohedrally doped Mn@SOD-ZnS displays a ferromagnetic (FM) ground state with the encapsulated Mn atoms preserving their highly atom-like magnetic moment. Furthermore, such a framework is predicted to possess room-temperature half-metallicity. A detailed analysis of the electronic structure shows that the FM half-metallicity originates from the competition between the FM double exchange interaction and the anti-ferromagnetic (AFM) super-exchange interaction. The present study highlights a new avenue to achieve the needed DMS with regular distribution of the magnetic impurities. PMID- 25918767 TI - [Nasopharyngeal carcinoma. Brush biopsy with EBV-PCR is suitable as a screening test]. AB - The nasopharyngeal carcinoma (NPC) is closely associated with the Epstein-Barr virus (EBV) infection. Because each tumor cell in a patient regardless of histological subtype contains an identical copy of the viral clone, the virus is easily detectable at early pre-invasive lesions. Nevertheless, the nasopharyngeal carcinoma is still usually diagnosed late, often not until they exhibit infested lymph nodes and / or distant metastases have occurred. Canadian scientists have now discovered and analyzed a new screening method. PMID- 25918768 TI - [Surgery with laryngotracheal stenosis. Rib cartilage interposition for airway reconstruction]. AB - The surgical management of this problem is a major challenge with various optional surgical procedures. The Chinese authors show in their retrospective analysis the success of laryngotracheal reconstruction (LTR) by cartilage interposition and facial cutaneous flap in patients with complex laryngotracheal stenoses and / or anterior cervical defect. PMID- 25918769 TI - Endovascular repair of a complex splenic artery aneurysm using a multilayer stent. PMID- 25918770 TI - International Journal of Prisoner Health. Editorial. PMID- 25918771 TI - David Stanley Precious (1944-2015). PMID- 25918772 TI - Older adults' perceptions of using iPads for improving fruit and vegetable intake: an exploratory study. AB - Fruit and vegetable (FV) consumption can improve older adults' health outcomes, but conventional interventions can be resource demanding and make it difficult to provide just-in-time intervention content. iPad-based interventions may help overcome these limitations, but little is known about how older adults might perceive and use iPads for FV consumption. To address this gap in the literature, we conducted a qualitative study to explore older adults' perceptions and use of iPads for improving FV consumption between February and August of 2012. Five focus group sessions each lasting 120 min were conducted with 22 older adult participants. During each session, participants received guided exposure and instruction on iPad use and then explored three iPad applications targeting FV consumption (MyFood, FiveADay Lite, and Whole Foods Market Recipes). Detailed notes from focus group interviews were analyzed with a grounded theory approach that applied a constant comparative method to enable themes to emerge from the data. Three themes were identified from the data regarding participants' baseline perceptions of iPads. These included (a) limited knowledge on iPad's functions, (b) iPads were intended for younger users, and (c) iPads were too expensive. Themes identified regarding participants' perceptions of iPads after guided exposure included (a) the touchscreen was easier to use than a computer mouse, (b) tapping the interface required practice, (c) portability was an asset in conjunction with functionality, (d) portability and functionality supported personal interests, (e) the difficulty of learning an iPad's functions varied, and (f) practice and instruction helped overcome fear of the iPad. Finally, participants recommended iPad app features that could help them overcome barriers to their FV intake. These included (a) locating inexpensive FV from nearby sources, (b) providing tailored food and recipe suggestions, and (c) tracking and communicating FV intake with a doctor. These findings have important implications for future research on mobile app-based eHealth interventions to improve older adults' FV intake. PMID- 25918773 TI - The high price of obesity in nursing homes. AB - This article provides a commentary on the costs of obese nursing home patients. We conducted a comprehensive literature search, which found 46 relevant articles on obesity in older adults and effects on nursing home facilities. This review indicated obesity is increasing globally for all age groups and older adults are facing increased challenges with chronic diseases associated with obesity more than ever before. With medical advances comes greater life expectancy, but obese adults often experience more disabilities, which require nursing home care. In the United States, the prevalence of obesity in adults aged 60 years and older increased from 9.9 million (23.6%) to 22.2 million (37.0%) in 2010. Obese older adults are twice as likely to be admitted to a nursing home. Many obese adults have comorbidities such as Type 2 diabetes; patients with diabetes incurred 1 in every 4 nursing home days. Besides the costs of early entrance into nursing facilities, caring for obese residents is different than caring for nonobese residents. Obese residents have more care needs for additional equipment, supplies, and staff costs. Unlike emergency rooms and hospitals, nursing homes do not have federal requirements that require them to serve all patients. Currently, some nursing homes are not prepared to deal with very obese patients. This is a public health concern because there are more obese people than ever in history before and the future appears to have even a heavier generation moving forward. Policymakers need to become aware of this serious gap in nursing home care. PMID- 25918774 TI - Community-based case management and health care use in older adults: outcomes of a collaborative multiagency approach. AB - Case management (CM) establishes valuable connections between clients and needed supports. There are, however, mixed results on its prediction of health care use. This quasi-experimental record review (N = 96) of a collaborative CM consortium examined predictors of health care use among older adults (aged older than 60 years) who had received CM for at least 6 months. Descriptive, bivariate, and multivariate models were used to predict differences in outcomes (hospitalization and emergency room [ER] visits) between participants who received CM and those who did not. Hospitalization rates were significantly lower among CM recipients. Living alone, identifying as White/non-Hispanic, and higher numbers of medications were significant copredictors of hospital use. CM was not a significant predictor of ER use. Race/ethnicity, however, remained significant in that White/non-Hispanic participants were 4 times likely to have at least 1 ER visit than persons of color. Implications for future research are discussed to promote better understanding of the effectiveness of CM, particularly within ethnically and racially diverse communities. Further inquiry is needed around the experiences of older adults of color, those who live alone, or who take multiple medications as needed. Further testing of a consortium model is necessary to determine value added through a multiagency approach. PMID- 25918775 TI - Identifying pious and heretical citizens in a permanent supported housing community. AB - This article offers an analysis of the impact of recovery-oriented treatment discourses and practices on tenant-staff relationships in the context of the Pinewood Apartments, a Texas-based permanent supported housing community. Drawing on 6 months of ethnographic research and personal experience of working as a caregiver at Pinewood, I demonstrate how tenant-staff relationships were compromised by service providers' negative evaluations of certain tenants in the context of emotionally charged service interactions. These negative evaluations, I argue, stem from deeply held ideas about valuable citizenship that are embedded in the philosophy and practices of recovery, which emphasizes client choice, self sufficiency, and autonomy. It should be noted, though, that negative evaluations were not necessarily definitive; both tenants and service providers at times exhibited sympathy and forgiveness for each other. PMID- 25918776 TI - The analysis for the causes of surgical cancellations in a Brazilian university hospital. AB - BACKGROUND: The aim of our study is to quantify the occurrence of suspension of scheduled surgeries in a Brazilian university hospital, trying to identify the causes of suspension of these operations and meet the medical specialties that most contributed to the cancellation. METHODS: This study takes the form of an exploratory, descriptive, and quantitative enquiry carried out by analyzing the database from 2008 to 2011 of the operating theater. RESULTS: Of the 29,518 scheduled surgeries, 16.1% were cancelled. The patient was the main reason, accounting for more than 40% of all suspensions. When calculating the rate of surgery suspended from a specialty, dividing the number of cancelled surgeries in a specialty by the number of scheduled surgeries in the same, we found that otolaryngology is the specialty with the highest rate of 21.3%. CONCLUSIONS: One of the main reasons in our sample why surgeries were cancelled is nonappearance of the patient. Improving communication between patient and hospital facilitates the client program and also contributes to avoid cancellations. PMID- 25918777 TI - Outcomes of the Maryland Person-Centered Hospital Discharge Program: a pilot targeting decreasing long-term care use and hospital readmissions. AB - The Person-Centered Hospital Discharge Program (PCHDP) was offered by the Centers for Medicare and Medicaid Services as a way to improve care to Medicare and Medicaid beneficiaries in Maryland. The PCHDP used a care nurse/coordinator to facilitate the successful transition of patients at risk for becoming eligible for Medicaid. The purpose of this study was to examine the outcomes of the PCHDP pilot, explore factors that influenced hospital and long-term care admissions following hospital discharge, and obtain operational data to develop new programs with related objectives. Area Agencies on Aging were provided with a care coordinator who obtained patient data, developed an individualized care plan, and determined visit frequency and length of services. Multivariate analysis of variance was conducted to examine differences between those hospitalized or admitted to a skilled nursing facility during the follow-up period. The sample consisted of 359 at-risk patients, and the mean length of follow-up was approximately two months. Most patients did not go to the emergency room (N = 319, 88%) during the period of follow-up and were not admitted to an acute care setting (N = 301, 84%) or skilled nursing home (N = 322, 86%). Those who were rehospitalized were slightly younger and had more visits from the care coordinator. We anticipate that the care coordinators identified individuals at greatest need for follow-up and support. Future research should explore ways in which these care coordinators can intervene to prevent hospital readmission and long-term nursing home care. PMID- 25918778 TI - The leaf, wood and bark oils of three species of Myodocarpus (Myodocarpaceae) endemic to New Caledonia. AB - The leaf, wood and bark oils of three species of Myodocarpus, M. viellardii Brongn. & Gris, M. fraxinifolius Brongn. & Gris and M. lanceolatus Dubard & R. Viguier have been examined. From the wood oil of M. viellardii the major components were alpha-pinene (22.4%) and a monoterpene methyl ester, methyl myodocarpate (methyl 3,7-dimethylbicyclo [4,1,0]hept-3-ene-7-carboxylate) (61%), based on the delta-3-carene skeleton. Also present in lesser amounts was the corresponding acid, myodocarpic acid (3,7-dimethylbicyclo[4,1,0]hept-3-ene-7 carboxilic acid) and the corresponding alcohol, myodocarpol (3,7- dimethylbicyclo[4,1,0]hept-3-en-7-yl) methanol), in lesser (< 3%) amounts. The bark oil contained beta-caryophyllene (13.8%) and a series of long chain fatty alcohols, dodecanol, tetradecanol, hexadecanol, octadecanol and octadec-9-en-1-ol in amounts of 1.4-15% (all but octadecanol > 11%). The leaf oil of this species produced a sesquiterpenic oil with the principal components being beta caryophyllene (36%), alpha-humulene (11.1%) and bicyclogermacrene (10.6%). In M. fraxinifolius, both the wood and bark oils contained a series of long chain alcohols, tetradecanol (30-38%), hexadecanol (23-29%) and octadec-9-en-1-ol (12%) as principal components. In the leaf oil of this species the principal component was beta-caryophyllene (63%), with lesser amounts of humulene oxide II (2.9%), isocomene (2.8%) and viridiflorol (1.4%). In M. lanceolatus, the leaf oil was dominated by the monoterpene hydrocarbons alpha-pinene (22.9%) and delta-3-carene (32.6%). In the wood oil of this species the principal components were geraniol (7.4%), citronellol (4.7%), germacrene-B (7.1%), zingiberine (6.8%) and linalool (6.7%), while in the bark oil they were geraniol (12.4%), citronellol (2.6%), germacrene-B (5.8%), and linalool (6.5%). PMID- 25918779 TI - Iridoids and a norsesquiterpenoid from the leaves of Villaria odorata. AB - Phytochemical investigation of Villaria odorata, a Philippine endemic Rubiaceae species, led to the identification of three iridoids, morindolide (1), hydrophylin A (2), hydrophylin B (3) and a norsesquiterpenoid, vomifoliol (4). This is the first report of compounds 1-4 from the genus Villaria. These classes of compounds proved to be important chemotaxonomic markers in the Rubiaceae family in combination with morphology and molecular data. PMID- 25918780 TI - Induction, cloning and functional expression of a sesquiterpene biosynthetic enzyme, delta-guaiene synthase, of Aquilaria microcarpa cell cultures. AB - A homology-based cloning strategy yielded a cDNA clone presumably encoding delta guaiene synthase, a sesquiterpene cyclase, from tissue cultures of Aquilaria microcarpa, which were treated with methyl jasmonate. Incubation of cell cultures of the plant with yeast extract also induced transcriptional activation of the sesquiterpene synthase gene. The translated protein of the gene obtained by heterologous expression in Escherichia coli catalyzed the cyclization of farnesyl diphosphate to liberate delta-guaiene with delta-guaiene and germacrene A as the minor products. The results obtained in the present study, together with the previously reported results, suggest that two classes of delta-guaiene synthase occur in Aquilaria; the enzyme proteins from A. microcarpa and A. sinensis liberate germacrene A as a minor product, while the protein from A. crassna generates alpha-humulene instead of germacrene A. PMID- 25918781 TI - Zerumbone induces G2/M cell cycle arrest and apoptosis via mitochondrial pathway in Jurkat cell line. AB - This investigation determined the anticancer properties of zerumbone (ZER) on the human T-cell (Jurkat) line using the MTT assay, microscopic evaluations, flow cytometric analyses, and caspase activity estimations. The results showed that ZER is selectively cytotoxic to Jurkat cells in a dose and time-dependent manner with IC50 of 11.9 +/- 0.2, 8.6 +/- 0.5 and 5.4 +/- 0.4 MUg/mL at 24, 48 and 72 hours of treatment, respectively. ZER did not produce an adverse effect on normal human peripheral blood mononuclear cells (PBMC). ZER is not as cytotoxic as doxorubicin, which imposed an inhibitory effect on Jurkat cells with IC50 of 2.1 +/- 0.2, 1.8 +/- 0.15, 1.5 +/- 0.07 MUg/mL after 24, 48 and 72 hours treatment, respectively. ZER significantly (P < 0.05) arrested Jurkat cells at the G2/M phase of the cell cycle. The antiproliferative effect of ZER on Jurkat cells was through the apoptotic intrinsic pathway via the activation of caspase-3 and -9. The results showed that ZER can be further developed into a safe chemotherapeutic compound for the treatment of cancers, especially leukemia. PMID- 25918782 TI - Diterpenoids from Fagonia mollis. AB - A new acyclic diterpenoid (1) and a new erythroxan diterpenoid (2), together with 4 erythroxan diterpenoids and 3 triterpenoids, have been isolated from the aerial parts of Fagonia mollis. Their structures were elucidated on the basis of 1D and 2D NMR data. The cytotoxic activity of the isolated compounds was investigated against HL-60 cancer cells. PMID- 25918783 TI - Cytotoxicity of the diterpene 14-O-methyl-ryanodanol from Erythroxylum passerinum in an astrocytic cells model. AB - Plant secondary metabolites, such as, specifically, alkaloids and terpenes, may present psychoactive properties that modify the function of the central nervous system (CNS) and induce neurotoxicity. Neurotoxicity involves the response of glial cells, mainly astrocytes, which play a fundamental role in the control of homeostasis of the CNS. Some Erythroxylum species are indigenous to the state of Bahia in Brazil. This study investigated the cytotoxic activity of the diterpene AEP-1, extracted from the fruit of E. passerinum in a GL-15 cell line, astrocytic, glial cells model. The effects on cell viability, analyzed by the MTT assay, demonstrated a dose-dependent cytotoxic effect, with maximum effect at 500 MUg/mL of AEP-1, and with a reduction of about 40 and 47% on cellular viability after 24 h and 72 h treatment, respectively. Evidence for induction of apoptosis by AEP-1 was first obtained when GL-15 glial cells were incubated with 250 MUg/mL AEP-1 causing reniform and/or pyknotic nuclei and apoptotic bodies revealed by chromatin staining with Hoechst 33258. Increase in DNA fragmentation was also observed by comet assays in cells incubated with 500 MUg/mL of AEP-1. Moreover, cells exposed to a sub toxic dose of AEP-1 (250 MUg/mL) showed significant changes in morphology--contraction of the cytoplasm and expansion of cellular projections--signifying the presence of astrocytic cytoskeletal protein and glial fibrillary acidic protein (GFAP). These findings indicated astrocytic cells as the target for terpene AEP-1 and suggest the involvement of glial cells with psychoactive symptoms observed in humans and animals after consumption of fruits of plants of the genus Erythroxylum. PMID- 25918784 TI - Absolute configuration of cembrane diterpenoids from Bursera multijuga. AB - The stems of Bursera multijuga afforded (-)-(1S,3E,7R,8R,11E)-7,8-epoxycembra 3,11-dien-1-ol (1) and its acetate 2, together with cembrene A (3), nephthenol (4), and cembrenol (5). The structures of 1 and 2 were elucidated by 1D and 2D NMR, HRESIMS, and X-ray diffraction. The conformational preference of flexible 1 was studied by molecular modeling at the DFT B3LYP/DGDZVP level of theory. Good agreement between calculated and experimental vibrational circular dichroism curves established the absolute configuration of 1. This is the first time that cembrane derivatives have been isolated from the genus Bursera. PMID- 25918785 TI - Trichostemonoate, a new anticancer tirucallane from the stem bark of Walsura trichostemon. AB - Trichostemonoate (1), a new tirucallane, together with four known compounds, 11alpha,20-dihydroxydammar-24-ene-3-one (2), sapelin E acetate (3), grandifolinolenenone (4) and alpha-mangostin (5), were isolated from the stem bark of Walsura trichostemon. The structural assignment of the new compound was based on spectroscopic methods. All isolated compounds were evaluated for their cytotoxicity against five cancer cell lines. PMID- 25918787 TI - Kolgaosides A and B, two new triterpene glycosides from the Arctic deep water sea cucumber Kolga hyalina (Elasipodida: Elpidiidae). AB - Two novel triterpene holostane nonsulfated pentaosides, kolgaosides A (1) and B (2), and one known, holothurinoside B (3), were isolated from the Arctic sea cucumber Kolga hyalina, the second representative of the family Elpidiidae, order Elasipodida, from which triterpene glycosides have been obtained. The structures of 1 and 2 were elucidated using 1H and 13C NMR and 2D NMR procedures (HSQC, HMBC, COSY, ROESY, TOCSY) and HRESI mass-spectrometry. Kolgaosides A (1) and B (2) demonstrate low cytotoxic activity against the cells of the ascite form of mouse Ehrlich carcinoma and moderate hemolytic activity against mouse erythrocytes, despite the presence of hydroxy groups in the side chains of the aglycones. The glycosides of K. hyalina are similar to those of the Antarctic sea cucumber Rhipidothuria racowitzai Herouard, 1901 (=Achlionice violaescupidata) (Elasipodida: Elpidiidae); this may have chemotaxonomic significance. PMID- 25918786 TI - A new cycloartane glucoside from Rhizophora stylosa. AB - Nine secondary metabolites, including a new cycloartane glucoside, rhizostyloside (1), were isolated from a methanol extract of Rhizophora stylosa leaves through several chromatographic experiments. The structures of the compounds were determined on the basis of NMR spectroscopic (1H and 13C NMR, HSQC, HMBC, 1H-1H COSY, NOESY) and HR-ESI-MS data and by comparison with literature values. Compound 1 exhibited significant cytotoxicity against three human cancer cell lines: KB (epidermoid carcinoma), LU-1 (lung adenocarcinoma), and SK-Mel-2 (melanoma). In addition, 1 strongly activated caspase-3/7 in LU-1 cells. PMID- 25918788 TI - Acaricidal activity against Panonychus citri and active ingredient of the mangrove plant Cerbera manghas. AB - Cerbera manghas is a mangrove plant which possesses comprehensive biological activities. A great deal of research has been undertaken on the chemical constituents and medical functions of C. manghas; insecticidal and antifungal activities have also been reported, but the acaricidal activity has not been studied. In our study, the acaricidal activity and active substances of C. manghas were investigated using a spray method, which showed that the methanol extracts of the fruit, twigs and leaves exhibited contact activity against female adults of Panonychus citri, with LC50 values at 24 h of 3.39 g L(-1), 4.09 g L( 1) and 4.11 g L(-1), respectively. An acaricidal compound was isolated from C. manghas by an activity-guided isolation method, and identified as (-)-17beta neriifolin, which is a cardiac glycoside. (-)-17beta-Neriifolin revealed high contact activity against female adults, nymphae, larvae and eggs of P. citri, with LC50 values at 24 h of 0.28 g L(-1), 0.29 g L(-1), 0.28 g L(-1) and 1.45 g L(-1), respectively. PMID- 25918789 TI - Three new steroid biglycosides, plancisides A, B, and C, from the starfish Acanthaster planci. AB - Three new steroid biglycosides, plancisides A-C (1-3), were isolated from the ethanolic extract of the starfish Acanthaster planci. The structures of 1-3 were determined by extensive NMR and ESI-MS techniques, as (24S)-28-O-[beta-D galactofuranosyl-(1-->5)-alpha-L-arabinofuranosyl]-24-methyl-5alpha-cholestane 3beta, 4beta, 6alpha, 8, 15alpha,16alpha, 28-heptol (1), (24S)-28-O-[alpha-L fucopyranosyl-(1 --> 2)-3-O-methy-beta-D-xylopyranosy]-24-methy-5alpha-cholestane 3beta, 4beta,6alpha,8,15beta,16beta,28- heptol (2) and (24S)-28-O-[2,4-di-O methyl-beta-D-xylopyranosyl-(1 --> 2)-alpha-L-arabinofuranosyl]-24-methyl-5alpha cholestane-3beta,4beta,6alpha,8,15beta,16beta,28-heptol 6-O-sulfate (3), respectively. Compound 2 is the first steroid glycoside containing an alpha fucopyranose unit found from starfish. Compound 1 slightly inhibits cell proliferation of HCT-116, T-47D, and RPMI-7951 cancer cell lines, but has no effect on colony formation of these cells in a soft agar clonogenic assay. PMID- 25918790 TI - Unusual 2(1H)-pyrazinones isolated from a culture of a Brazilian marine-derived Streptomyces sp. AB - Four new secondary metabolites, giovaninones A-D (1-4), were isolated from an ethyl acetate extract of a culture of a marine-derived Streptomyces strain designated SS99BA-2. Chemical analysis was completely conducted in a coupled automated LC-SPE system with the use of a cryogenic NMR probehead and HRMS. The application of this system to identify, purify and elucidate all the structures is described. PMID- 25918791 TI - An HPLC evaluation of cytochalasin D biosynthesis by Xylaria arbuscula cultivated in different media. AB - A quantitative profile of cytochalasin D production by Xylaria arbuscula was followed by growing the fungus in rice, Czapek, Czapek enriched with yeast extract, wheat, and corn. This cytochalasin producer, X. arbuscula, was collected as an endophytic fungus from healthy tissues of Cupressus lusitanica (Cupressaceae). A new HPLC method was developed using a synthetic N-acetyl-L phenylalanine ethyl ester as internal standard, which showed a good correlation coefficient (r2 = 0.9995). The results varied from 6.40 to 39.55 mg per 100 g of culture medium, with wheat being the best medium for cytochalasin D production. The level of any free amino acids in the medium, not necessarily phenylalanine, appeared to be an important factor to enhance cytochalasin D biosynthesis. PMID- 25918792 TI - A simple method for isolation and purification of DIBOA-Glc from Tripsacum dactyloides. AB - Naturally occurring benzoxazinones (Bx) are a highly reactive class of compounds that have received particular attention in the past several decades. Recently, we identified 2-beta-D-glucopyranosyloxy-4-hydroxy-1,4-benzoxazin-3-one (DIBOA-Glc) as the compound present in the roots of Eastern gamagrass {Tripsacum dactyloides (L.)} responsible for atrazine degradation. However, characterization of the DIBOA-Glc/atrazine degradation reaction has been limited due to difficulties in attaining sufficient quantities of purified DIBOA-Glc. The objective of the study was to develop a simple purification and isolation method for obtaining bulk quantities of highly purified DIBOA-Glc. T. dactyloides roots were extracted with 90% aqueous methanol, and the crude extract was fractionated using an HPLC equipped with a C8 semi-prep column and fraction collector. UHPLC-DAD-MS/MS was used to confirm the identity of DIBOA-Glc in the fractions collected. Analysis by 13C and 1H NMR and DAD indicated that 542 mg of DIBOA-Glc with a purity of > 99% was obtained. The reactivity of the DIBOA-Glc was confirmed in a 16 hour assay with atrazine, which resulted in 48.5% +/- 1.2% (SD) atrazine degradation. The method described here offers several advantages over existing extraction and synthesis methods, which are more cumbersome, use hazardous chemicals, and yield only small quantities of purified compound. The newly developed method will facilitate future research characterizing the chemical behavior of DIBOA-Glc and determine its potential as an atrazine mitigation and remediation tool. PMID- 25918793 TI - Antimicrobial metabolites from endophytic Streptomyces sp. YIM61470. AB - Six compounds were isolated from Streptomyces sp. YIM61470, and their structures elucidated by spectral analysis as (R)-1-O-(phenylacetyl)glycerol (1), 4',5 dihydroxy-6-(3,3-dimethylallyl)-7-methoxyflavanone (2), (32R,33R,34S) 32,33,34,35-bacteriohopanetetrol (3), MKN-003C (4), cyclo (L-Pro-L-Gly) (5), and cyclo(L-Pro-L-Tyr) (6). Compound 1, an chiral monoacylglycerol, was isolated from a natural source for the first time. Compound 2 was first found in microorganisms, and compound 3, a bacteriohopanoid, was found first in the genus Streptomyces. Compounds 1-6 showed weak anti-microbial activity. PMID- 25918794 TI - Genkwanin 4'-O-glucosyl-(1 --> 2)-rhamnoside from new chemotype of Asplenium normale in Japan. AB - New flavone glycoside, genkwanin 4'-O-beta-glucopyranosyl-(1 --> 2)-O-alpha rhamnopyranoside was isolated from the fronds of new chemotype of Asplenium normale D. Don, together with two known C-glycosylflavones, vicenin-2 and lucenin 2. The chemical structure of the isolated glycoside was established by UV, LC-MS, characterization of acid hydrolysates, and 1H and 13C NMR spectroscopy. PMID- 25918795 TI - Potent SIRT1 enzyme-stimulating and anti-glycation activities of polymethoxyflavonoids from Kaempferia parviflora. AB - The SIRT1 enzyme-stimulating and anti-glycation activities of Kaempferia parviflora extract and its main polymethoxyflavonoids were evaluated in vitro. K. parviflora extract elevated SIRT1 catalytic activity by eight- and 17-fold at 20 MUg/mL and 100 MUg/mL, respectively, compared with vehicle only. Two major polymethoxyflavonoids, 3,5,7,3',4'-pentamethoxyflavone (4) and 5,7,4' trimethoxyflavone (5), were isolated from this extract and are four- and fivefold more potent than resveratrol, hitherto the strongest known natural SIRT1 activator. In addition, the anti-glycation activity of K. parviflora extract was observed to be seven times more effective than aminoguanidine, a clinical anti diabetes drug. 3,5,7,3',4'-Pentamethoxyflavone (4) and 5,7,4'-trimethoxyflavone (5) showed the strongest anti-glycation activity among the tested polymethoxyflavonoids. Further comparison of the activity of these structurally related polymethoxyflavonoids revealed a possible structure-activity relationship, in particular, for the contribution of methoxy moieties. PMID- 25918796 TI - Protective activity of C-geranylflavonoid analogs from Paulownia tomentosa against DNA damage in 137Cs irradiated AHH-1 cells. AB - Radiotherapy is an important form of treatment for a wide range of cancers, but it can damage DNA and cause adverse effects. We investigated if the diplacone analogs of P. tomentosa were radio-protective in a human lymphoblastoid cell line (AHH-1). Four geranylated flavonoids, diplacone, 3'-O-methyl-5'-hydroxydiplacone, 3'-O-methyl-5'-O-methyldiplacone and 3'-O-methyldiplacol, were tested for their antioxidant and radio-protective effects. Diplacone analogs effectively scavenged free radicals and inhibited radiation-induced DNA strand breaks in vitro. They significantly decreased levels of reactive oxygen species and cellular DNA damage in 2 Gy-irradiated AHH-1 cells. Glutathione levels and superoxide dismutase activity in irradiated AHH-1 cells increased significantly after treatment with these analogs. The enhanced biological anti-oxidant activity and radioprotective activity of diplacone analogs maintained the survival of irradiated AHH-1 cells in a clonogenic assay. These data suggest that diplacone analogs may protect healthy tissue surrounding tumor cells during radiotherapy to ensure better control of radiotherapy and allow higher doses of radiotherapy to be employed. PMID- 25918797 TI - Antibacterial activities of oxyprenylated chalcones and napthtoquinone against Helicobacter pylori. AB - In this study, we synthesized and characterized the antibacterial activity of three naturally occurring oxyprenylated chalcones {xinjiachalcone A (1), (2E)-1 {2,6-dihydroxy-4-[(3-methylbut-2-enyl)oxy]phenyl}-3-(4-hydroxyphenyl)prop-2-en-1 one (2), (2E)-1-{2,6-dihydroxy-4-[(3-methylbut-2-enyl)oxy]phenyl}-3-phenylprop-2 en-1-one (3), and lawsone 2-isopentenyl ether (4)}. Using several strains of Helicobacter pylori, including clinical ones, minimum inhibitory concentration (MIC) values and bactericidal activities of these compounds were determined. Xinjiachalcone A (1), active principle of Glycyrrhiza inflata Batalin, was the most effective compound, showing both a low MIC and a strong bactericidal activity against H. pylori. This study suggests that these compounds represent potential natural molecules for the prevention and treatment of H. pylori associated diseases. PMID- 25918798 TI - Anti-proliferation effect on human breast cancer cells via inhibition of pRb phosphorylation by taiwanin E isolated from Eleutherococcus trifoliatus. AB - Eleutherococcus trifoliatus has been used as a folk medicine since ancient times, especially as refreshing qi medicines. In our current study, taiwanin E, which possesses strong cytotoxicity, was isolated from the branches of E. trifoliatus by using a bioactivity guided fractionation procedure. Taiwanin E presented a potent anti-proliferation activity on the growth of a human breast adenocarcinoma cell line (MCF-7), with an IC50 value for cytotoxicity of 1.47 MUM. Cell cycle analysis revealed that the proportion of cells in the G0/G1 phase increased in a dose-dependent manner (from 79.4% to 90.2%) after 48 h exposure to taiwanin E at a dosage range from 0.5 to 4MUM. After treatment with taiwanin E, phosphorylation of retinoblastoma protein (pRb) in MCF-7 cells was inhibited, accompanied by a decrease in the levels of cyclin D1, cyclin D3 and cyclin-dependent kinase 4 (cdk4) and cdk6; in addition, there was an increase in the expression of cyclin dependent kinase inhibitors p21(WAF-1/Cip) and p27(Kip1). The results suggest that taiwanin E inhibits cell cycle progression of MCF-7 at the G0/G1 transition. PMID- 25918799 TI - New mechanism of magnolol and honokiol from Magnolia officinalis against Staphylococcus aureus. AB - Cell division protein, FtsZ, has been identified as a new potential antimicrobial target against multidrug-resistant (MDR) and methicillin-resistant Staphylococcus aureus (MRSA). By using computer-aided simulation, the phenolic compounds magnolol and honokiol from Magnolia officinalis were shown to have high anchor energies to FtsZ of S. aureus. The calculated binding energies of magnolol and honokiol for this FtsZ (PDB Code: 4DXD) were established to be -7.6 kcal/mol and 8.2 kcal/mol, respectively. Both of them showed polymerization inhibition efficacy for this FtsZ at 100 ppm, which confirmed the simulation results. Their antibacterial activity against S. aureus including multidrug-resistant (MDR) and methicillin-resistant S. aureus (MRSA) with minimum inhibitory concentration (MIC) values in the range of 8-16 ppm. These findings support the use of computer aided simulation to screen natural compounds for this cell division protein, FtsZ, and this method can be a quick and promising approach for the development of antimicrobial agents against multi-drug resistant S. aureus. PMID- 25918800 TI - Molecular cloning and characterization of tyrosine aminotransferase and hydroxyphenylpyruvate reductase, and rosmarinic acid accumulation in Scutellaria baicalensis. AB - Rosmarinic acid (a-O-caffeoyl-3,4-dihydroxyphenylacetic acid, RA) is a caffeoyl ester widely distributed in plants. cDNA clones encoding tyrosine aminotransferase (TAT1 and 2) and hydroxyphenylpyruvate reductase (HPPR) have been isolated from Scutellaria baicalensis. The open reading frames (ORFs) of SbTAT1 and 2 were 1230 and 1272 bp long and encoded 409 and 423 amino acid residues, respectively. HPPR corresponded to a 942-bp ORF and 313 amino acid residues of translated protein. To study the molecular mechanisms of TAT and HPPR and investigate RA accumulation in S. baicalensis, we examined the transcript levels of TAT isoforms and HPPR with quantitative real-time PCR and analyzed the RA content in different organs by using high-performance liquid chromatography. The transcript levels of SbTATI SbTAT2, and SbHPPR in the flowers were higher than those in other organs. RA was also highly accumulated in the flowers and with a trace amount in the roots. No RA was detected in the leaves and stems of S. baicalensis. The amount of accumulated RA in the flowers was 28.7 times higher than that in the roots. Our results will be helpful in elucidating the mechanisms of RA biosynthesis in S. baicalensis. PMID- 25918801 TI - Phenols and antioxidant activity in vitro and in vivo of aqueous extracts obtained by ultrasound-assisted extraction from artichoke by-products. AB - Artichoke by-products are rich in phenolic compounds although they represent a waste for the food industry. This paper examines the application of ultrasound assisted extraction (UAE) for obtaining organic solvent-free extracts rich in nutraceuticals from artichoke scraps. Application of ultrasounds for 60 minutes on test samples, using water as a solvent, improved recovery of phenolic substances compared with untreated samples. Among the phenols detected by high performance liquid chromatography, 5-O-caffeoylquinic and 1,5-di-O-caffeoylquinic acids were identified. In vivo treatments of tobacco BY-2 cells with ultrasonic extracts consistently enhanced their antioxidant power, making the cells more resistant to heat stress. UAE applied to artichoke by-products, using water as a solvent, appears to be a powerful eco-friendly technique that can provide extracts rich in nutraceuticals and turn waste products into resources. The extracts could be advantageously utilized in the food industry to produce functional foods. PMID- 25918802 TI - Bioactive metabolites from Cnidoscolus souzae and Acmella pilosa. AB - The bioassay-guided purification of the ethanol extracts of Acmella pilosa and Cnidoscolus souzae, two plants of the native flora of the Yucatan Peninsula used in traditional medicine to treat inflammation and pain, resulted in the identification of rosmarinic acid (1) and caffeic acid (2) as the bioactive metabolites from A. pilosa, and of 7-deoxynimbidiol (4) as the major bioactive metabolite from C. souzae. Metabolites 1, 2, and 4 proved to be responsible for the antioxidant activity originally detected in the corresponding organic crude extracts; 7-deoxynimbidiol (4) showed good analgesic and anti-inflammatory activities, inhibiting the pain induced by PGE2 and reducing the edema induced by carrageenan, respectively. PMID- 25918803 TI - Dipterostilbenosides A and B, oligostilbene glycosides from Dipterocarpus tuberculatus. AB - From the chemical investigation of the methanolic extract of the roots of the Thai dipterocarp, Dipterocarpus tuberculatus, two new oligostilbene glycosides, dipterostilbenes A (1) and B (2), were isolated together with four known stilbenes. Their structures and relative configurations were determined on the basis of spectroscopic data. From an evaluation of cytotoxic activity against KB and HeLa cell lines, alpha-viniferin (5) and (-)-hopeaphenol (6) showed potent activity, but less than that of doxorubicin. PMID- 25918804 TI - Isolation of beta-indomycinone guided by cytotoxicity tests from Streptomyces sp. IFM11607 and revision of its double bond geometry. AB - The antibiotic beta-indomycinone was isolated from Streptomyces sp. IFM11607 by cytotoxicity-guided fractionation against human gastric adenocarcinoma AGS cells, and the geometry of its delta17,18-double bond was revised from E to Z based on the coupling constant. PMID- 25918805 TI - Daurichromenic acid-producing oxidocyclase in the young leaves of Rhododendron dauricum. AB - Rhododendron dauricum L., a flowering tree popular in Hokkaido, produces daurichromenic acid (DCA), a terpenophenol with a potent anti-HIV activity. The DCA-producing enzyme, named DCA synthase, could be detected in the soluble protein fraction prepared from the young leaves of R. dauricum. DCA synthase catalyzed oxidocyclization of the farnesyl group of grifolic acid to form (+)-DCA as the major reaction product. The DCA synthase reaction proceeds without the need for any cofactors and coenzymes except for molecular oxygen. Interestingly, these catalytic properties of DCA synthase are quite similar to those reported for cannabinoid synthases in the marijuana plant Cannabis sativa L. PMID- 25918806 TI - Synthesis and characterization of 4-aryl-4H-chromenes from H-cardanol. AB - We have synthesized and characterized a variety of fat-soluble, low-melting and medicinally useful 4-aryl-4H-chromenes from H-cardanol (side-chain perhydrogenated cardanol, 3-pentadecylphenol), a renewable and low-cost product from locally grown cashew nut trees (Anacardium occidentale L.). We incorporated H-cardanol into the aromatic rings of either 4H-chromene or phenol, or both. Substitution of C4SMe in N-methyl-4-(methylthio)-3-nitro-4H-chromene-2-amines with H-cardanol was regio-specific at the C6 position. PMID- 25918807 TI - Galactans of Gracilaria pudumadamensis (Gracilariales, Rhodophyta) of Indian waters. AB - Galactans from the Indian agarophyte Gracilaria pudumadamensis were extracted and characterized. The isolated native (GP(Native)) and alkali treated (GP(Alkali)) galactans were characterized by IR, 13C NMR, GC-MS and GPC. It was found that GP(Native) and GP(Alkali) were composed mainly of 3,6-anhydro L-galactose, 6-O methylated D-galactose and galactose in various mole proportions (15.6:69.9:17.5 mole% for GP(Native) and 20.2:69.8:10.0 mole% for GP(Alkali)). The GP(Native) and GP(Alkali) exhibited low gel strengths (< 100 g/cm2) and high melting points (-76 degrees C), which may be due to the presence of high 6-O-Me-galactose contents. The latter, having low sulfate (2.1%), was by far the greatest 6-O-Me-galactose containing polysaccharide in a Gracilaria spp. reported in the literature. This methylated agar contained very low heavy metal ions estimated by inductively coupled plasma spectrophotometry (ICP). The results of this investigation would be useful in bioprospecting of agarophytes, especially those occurring in Indian waters and would be potentially useful in food, personal care and related domains. PMID- 25918808 TI - The effect of Ginkgo biloba and Camellia sinensis extracts on psychological state and glycemic control in patients with type 2 diabetes mellitus. AB - Interest in finding natural antioxidants for use in food or medical materials to prevent free radical imbalance has increased considerably over the past years. The aim of this research was to evaluate changes in glycemic control and psychological state of patients with type 2 diabetes mellitus (T2DM) after use of antioxidant plant preparations. Fifty-six patients with T2DM were randomly allocated to receive standardized Ginkgo biloba L. leaves dry extract, green tea dry extract, or placebo capsules. Diabetes glycemic control measured as glycated hemoglobin (HbA1c) level, antioxidant state and psychological data were evaluated at baseline, after 9 and 18 months of using either antioxidant preparations or placebo. The level of perceived stress lowered significantly after 9 months (p = 0.038) and 18 months (p = 0.030), and the psychological aspect of quality of life significantly improved after 18 months (p = 0.019) of use of G. biloba extrac. No significant differences were detected after using green tea extract. In patients using placebo, significant lowering of HbA1c level was observed after 18 months (p = 0.017). In conclusion, antioxidant G. biloba leaf extract exhibited a mild effect on psychological state and a trend of improving glycemic control in patients with type 2 diabetes mellitus. PMID- 25918809 TI - Comparative anti-inflammatory effects of anti-arthritic herbal medicines and ibuprofen. AB - Non-steroidal anti-inflammatory drugs (NSAIDS), such as ibuprofen, are widely used over-the-counter drugs to treat arthritis, but they are often associated with side effects. Herbal medicines have been used to treat various diseases such as arthritis, but the scientific profiles are not well understood. In this study, we examined, in comparison with ibuprofen, the inhibitory effects on various inflammatory markers of the most commonly used herbal medicines to treat arthritis, boswellia (Boswellia sapindales), licorice (Glycyrrhiza glabra), guggul (Commiphora wightii), and neem (Azadirachta indica). To elicit inflammatory response, we exposed mouse myoblast C2C12 cells to lipopolysaccharide (LPS). Tumor necrosis factor-alpha (TNF-alpha) and monocyte chemotactic protein-1 (MCP-1), which are cytokines activated during an inflammatory response, were determined. The optimal non-toxic concentration was determined by exposing different concentrations of drugs (from 0.01 to 10 mg/mL). Cell death measurement revealed that the drug concentrations lower than 0.05 mg/mL were non-toxic concentrations for each drug, and these doses were used for the main experiments. We found that neem and licorice showed robust anti inflammatory responses compared with ibuprofen. However, boswellia and guggul did not demonstrate significant anti-inflammatory responses. We concluded that neem and licorice are more effective than ibuprofen in suppressing LPS-induced inflammation in C2C12 cells. PMID- 25918810 TI - Quantitative analysis coupled with toxic evaluation to investigate the influence of sulfur-fumigation on the quality of Chrysanthemum morifolium. AB - In the present study, quantitative analysis coupled with toxic evaluation was applied to investigate the influence of sulfur-fumigation on the quality of Chrysanthemum morifolium. The results showed that the average contents of six flavonoids (cynaroside, hyperoside, isoquercitrin, luteolin, apigenin, and diosmetin) in sulfur-fumigated C. morifolium samples decreased by about 6.2%, 3.5%, 22.0%, 33.3%, 26.0%, and 36.9%, respectively, while the average contents of two organic acids (chlorogenic acid and isochlorogenic acid A) in sulfur fumigated C. morifolium samples increased by about 16.8% and 7.6%, respectively. Furthermore, high dosage sulfur-fumigated C. morifolium could induce hydropic degeneration in epithelial cells of the renal tubule and interstitial edema. This indicates that sulfur-fumigated C. morifolium may lead to renal toxicity. PMID- 25918811 TI - Chemical composition of the leaf oil of Actephila excelsa from Vietnam.. AB - Fresh leaves of Actephila excelsa (Dazl.) Muell. from Vietnam were steam distilled to produce an oil in a yield of 0.15% (v/w). The essential oil was analyzed by a combination of capillary gas chromatography-flame ionization detection (GC-FID) and gas chromatography coupled with mass spectrometry (GC/MS). The main constituents of the oil were the sesquiterpenes gamma-elemene (25.7%) and beta-caryophyllene (11.2%). Other significant compounds were methyl salicylate (5.8%), benzyl benzoate (5.2%), (E,E)-farnesylacetone (4.9%), anisole (4.7%), sabinene (4.1%) and menthone (4.0%). This is the first report on the volatile constituents of this plant. PMID- 25918812 TI - Composition and chemical variability of Corsican Pinus halepensis cone oil. AB - The composition of the essential oil isolated from cones of Pinus halepensis grown in Corsica has been investigated by a combination of chromatographic (CC, GC) and spectroscopic (MS, 13C NMR) techniques. In total, 48 compounds that accounted for 95.5% of the whole composition have been identified. alpha-Pinene (47.5%) was the major component followed by myrcene (11.0%), (E)-beta caryophyllene (8.3%) and caryophyllene oxide (5.9%). Various diterpenes have been identified by 13C NMR in the fractions of CC. Fifteen oil samples isolated from cones harvested in three forests have been analyzed and two groups of similar importance have been differentiated within the 15 compositions. Oil samples of the first group contained alpha-pinene (mean 45.0 g/100 g, SD = 5.5) as the major component. The composition of samples of the second group was dominated by myrcene (mean 30.3 g/100g, SD = 9.0) and alpha-pinene (mean 24.6 g/100 g, SD = 3.1). PMID- 25918813 TI - Hawaiian sandalwood: oil composition of Santalum paniculatum and comparison with other sandal species. AB - Four commercial qualities of Hawaiian sandalwood oil produced from wood of Santalum paniculatum originating from the island of Hawaii ("The Big Island") were analyzed using GC and GC-MS. Main constituents of the oils were (Z)-alpha santalol (34.5-40.4%) and (Z)-beta-santalol (11.0-16.2%). An odor evaluation of the oils was carried out against East Indian sandalwood oil. In addition, the chemical composition of Hawaiian sandalwood oil was compared with four different Santalum species originating from East India, New Caledonia, Eastern Polynesia and Australia, respectively. PMID- 25918814 TI - Aroma compounds of mountain tea (Sideritis scardica and S. raeseri) from western Balkan. AB - The composition of the volatile aroma components was defined in the dried and fresh aerial parts of Sideritis scardica Griseb. from R. Macedonia and S. raeseri Boiss. & Heldr. from R. Macedonia, Albania and Greece. Analysis was made by gas chromatography (GC/FID/MS) equipped with a headspace (HS) sampler. Thirty-two components (15 monoterpenes representing 33.2- 62.8% and 17 sesquiterpenes representing 25.2- 51.2% of the entire volatiles) were identified as aroma components of dried plant material of S. scardica. Thirty components {14 monoterpenes (19.3-74.2%), 2 alcohols (6.2- 38.4%) and 14 sesquiterpenes (18.2- 33.5%)} were identified as aroma components in the fresh aerial parts of S. scardica. The predominant components were trans-caryophyllene, beta-pinene, alpha pinene and 1-octen-3-ol, which were found only in the fresh samples. In the aerial parts of S. rteseri, 43 components were identified in the dried samples {22 monoterpenes (65.7-94.3%) and 21 sesquiterpenes (5.4- 27.8%)} and 29 components {15 monoterpenes (77.3-90.7%) and 14 sesquiterpenes (6.3- 18.2%)} in the respective fresh samples. Prevailing components in all tested samples of S. raeseri were beta-pinene, alpha-pinene, alpha-copaene, sabinene and limonene. Only minor differences were revealed in the qualitative composition of the aroma volatiles between the dried and fresh plant material of both species. Furthermore there was almost no difference in the chemical profiles of the aroma compounds between S. scardica and S. raeseri, except for 1- octen-3-ol, which was present only in fresh S. scardica. PMID- 25918815 TI - Chemical composition of the essential oil of the local endemics Centaurea davidovii and C. parilica (Asteraceae, sect. Lepteranthus) from Bulgaria. AB - In the present study the chemical compositions of the essential oils from aerial parts of Centaurea davidovii Urum. and C. parilica Stoj. & Stef., both endemic to Bulgaria, were evaluated by GC and GC-MS. The main components of C. davidovii were beta-eudesmol (13.9%), spathulenol (13.3%), caryophyllene oxide (10.1%) and (Z)-phytol (5.4%). The main components of Cparilica were hexadecanoic acid (39.2%), (Z,Z)-9,12-octadecadienoic acid (11.9%), caryophyllene oxide (6.8%) and spathulenol (6.6%). In order to compare the essential oils composition of these taxa and of related species a PCA analysis was carried out. PMID- 25918816 TI - Compositional analysis and in vitro protective activity against oxidative stress of essential oils from egyptian plants used in traditional medicine. AB - The Sinai desert in Egypt contains great variability in plants extensively used for traditional medicines such as Achillea fragrantissima, Chiliadenus montanus, Mentha longifolia and Haplophyllum tuberculatum. The essential oils extracted by hydrodistillation from the aerial parts have been analyzed. Subsequently, their potential protective activity against oxidative stress has been evaluated, employing H2O2 as oxidant inductor and astrocytes as the cell model. The chemical composition of the essential oils was analyzed by GC/MS. Most of the compounds identified in A. fragrantissima and M. longifolia samples were oxygenated monoterpene derivatives, whereas for H. tuberculatum they were monoterpenes hydrocarbons and oxygenated compounds, and for C. montanus oxygenated monoterpenes and oxygenated sesquiterpenes predominated. The in vitro evaluation of antioxidant properties, using ORAC assay, revealed that M. longifolia essential oil possessed the highest scavenging activity against peroxyl radicals, following by H. tuberculatum, A. fragrantissima and C. montanus. Under oxidative stress conditions, M. longifolia and H. tuberculatum essential oils were the only ones that protected human astrocytoma U373-MG cells against H2O2 damage. Both essential oils prevented cell death and inhibited ROS production caused by H2O2. M. longifolia essential oil was the most active, suggesting an interesting prevention role in those CNS disorders associated with oxidative stress. PMID- 25918817 TI - Chemical composition and antifungal activity of the essential oils of Schinus weinmannifolius collected in the spring and winter. AB - Reports on the chemical and pharmacological profile of the essential oil of Schinus weinmannifolius do not exist, although other Schinus species have been widely investigated for their biological activities. This work aimed to evaluate the chemical composition and antimicrobial activity of the essential oil of S. weinmannifolius collected in the spring and winter. The essential oils were extracted by hydrodistillation, analyzed by GC/MS and submitted to microdilution tests, to determine the minimum inhibitory concentration. The oils displayed different chemical composition and antimicrobial action. Bicyclogermacrene and limonene predominated in the oils extracted in the winter and spring, respectively, whereas only the latter oil exhibited antifungal activity. PMID- 25918818 TI - The essential oil profiles and antibacterial activity of six wild Cinnamomum species. AB - The essential oil composition of six species of wild Cinnamomum found in Borneo was investigated. The oils were obtained from bark by hydrodistillation and the volatile chemical profile was obtained via Gas Chromatography-Mass Spectrometry (GCMS). A total of 65 volatile constituents were identified, where the essential oils of the studied specimens contained high contents of oxygenated monoterpenes. Eucalyptol (1.2-31.1%), terpinen-4-ol (7.9-22.1%), eugenol (0.4-37.9%) and alpha cadinol (0.4-1.8%) were detected consistently in the specimens studied. The oils of C. cuspidatum and C. crassinervium exhibited significant inhibition against Listeria monocytogenes, specifically the latter, which displayed a lower minimum bactericidal concentration (MBC) value against Staphylococcus aereus and L. monocytogenes. This result had highlighted the possible usage of the essential oil derived from wild cinnamom species against food borne pathogens. PMID- 25918819 TI - Dissecting traditional Chinese medicines by omics and bioinformatics. AB - Traditional Chinese medicines (TCM) are a rich source of potential leads for drug development. However, there are fundamental differences between traditional Chinese medical concepts and modern pharmacology, which greatly hinder the modern development of TCM. To address this challenge, new techniques associated with genomics, transcriptomics, proteomics, metabolomics and bioinformatics have been used to dissect the pharmacological mechanisms of TCM. This review article provides an overview of the current research in this area, and illustrates the potential of omic and bioinformatic methods in TCM-based drug discovery. PMID- 25918820 TI - Daily Bathing with Chlorhexidine and Its Effects on Nosocomial Infection Rates in Pediatric Oncology Patients. AB - Infections remain a serious complication in pediatric oncology patients. To determine if daily bathing with Chlorhexidine gluconate can decrease the rate of nosocomial infection in pediatric oncology patients, we reviewed rates of infections in pediatric oncology patients over a 14-month span. Intervention group received daily bath with Chlorhexidine, while the control group did not receive daily bath. The results showed that daily bath with antiseptic chlorhexidine as daily prophylactic antiseptic topical wash leads to decreased infection density amongst the pediatric oncology patients, especially in patients older than 12 years of age. Furthermore, daily chlorhexidine bathing significantly reduced the rate of hospital acquired infection in patients older than 12 years of age. The findings of this study suggest that daily bathing with chlorhexidine may be an effective measure of reducing nosocomial infection in pediatric oncology patients. PMID- 25918821 TI - Cutaneous and pulmonary dirofilariasis due to Dirofilaria repens. AB - Dirofilariasis is a worldwide zoonotic infection that accidentally affects humans. It is caused by filarial nematodes of the genus Dirofilaria, which are transmitted by mosquitoes. Cutaneous dirofilariasis appears as inflammatory lesions that could be consistent with Wells' cellulitis. We present a remarkable case of human infection with Dirofilaria repens, causing both subcutaneous and pulmonary nodules. PMID- 25918822 TI - Stoichiometry, Length, and Wall Thickness Optimization of TiO2 Nanotube Array for Efficient Alcohol Sensing. AB - The present study concerns development of an efficient alcohol sensor by controlling the stoichiometry, length, and wall thickness of electrochemically grown TiO2 nanotube array for its use as the sensing layer. Judicious variation of H2O content (0, 2, 10 and 100% by volume) in the mixed electrolyte comprising ethylene glycol and NH4F resulted into the desired variation of stoichiometry. The sensor study was performed within the temperature range of 27 to 250 degrees C for detecting the alcohols in the concentration range of 10-1000 ppm. The nanotubes grown with the electrolyte containing 2 vol % H2O offered the maximum response magnitude. For this stoichiometry, variation of corresponding length (1.25-2.4 MUm) and wall thickness (19.8-9 nm) of the nanotubes was achieved by varying the anodization time (4-16 h) and temperatures (42-87 degrees C), respectively. While the variation of length influenced the sensing parameters insignificantly, the best response magnitude was achieved for ~13 nm wall thickness. The underlying sensing mechanism was correlated with the experimental findings on the basis of structural parameters of the nanotubes. PMID- 25918823 TI - Solar Ultraviolet Radiation Exposure of South African Marathon Runners During Competition Marathon Runs and Training Sessions: A Feasibility Study. AB - Marathon runners spend considerable time in outdoor training for and participating in marathons. Outdoor runners may experience high solar ultraviolet radiation (UVR) exposure. South Africa, where running is popular, experiences high ambient solar UVR levels that may be associated with adverse health effects. This feasibility study explores the use of personal dosimeters to determine solar UVR exposure patterns and possible related acute health risks of four marathon runners during marathons and training sessions in Cape Town and Pretoria. Runners running marathons that started early in the day, and that did not exceed 4 hours, yielded low total solar UVR exposure doses (mean 0.093 SED per exposure period run, median 0.088 SED, range 0.062-0.136 SED; average of 16.54% of ambient solar UVR). Training sessions run during early morning and late afternoon presented similar results. Several challenges hindered analysis including accounting for anatomical position of personal dosimeter and natural shade. To assess health risks, hazard quotients (HQs) were calculated using a hypothetical runner's schedule. Cumulative, annual solar UVR exposure-calculated acute health risks were low (HQ = 0.024) for training sessions and moderate (HQ = 4.922) for marathon runs. While these data and calculations are based on 18 person-days, one can measure marathon runners' personal solar UVR exposure although several challenges must be overcome. PMID- 25918824 TI - Stronger T-Cell Alloreactivity and Diminished Suppressive Capacity of Peripheral Regulatory T Cells in Infertile Women Undergoing In Vitro Fertilization. AB - PROBLEM: Increasing evidence suggests modulation of the maternal immune response to be essential for successful pregnancy. We studied the immunophenotypic profile and function of peripheral blood T lymphocytes in infertile women undergoing in vitro fertilization (IVF) and fertile control population. METHOD: We collected peripheral blood mononuclear cells (PBMC) from infertile patients with recurrent implantation failure (RIF), infertile patients with successful IVF (IVFs), and normal fertile women. Cells were phenotypically analyzed, and the proliferative response and cytokine production were studied in mixed lymphocyte cultures (MLC), using lymphocytes of the own partner, or a third-party male as stimulators cells. To examine the suppressive capacity of regulatory regulatory T cells (Tregs), we performed MLC studies with a CD45(+) fraction depleted for CD4(+) CD25(bright) T cells. RESULTS: No significant differences in proportions of subsets of circulating T lymphocytes were observed. The proliferative allo-immune response of PBMC of IVF women (RIF and IVFs) was significantly higher, with higher production of T-helper cells (Th1) and Th2 cytokines, compared to the fertile women. This difference in proliferation and cytokine production was associated with a diminished suppressive capacity of Tregs in these women. CONCLUSION: The higher allo-immune response of the IVF women compared to fertile women might be the result of a diminished suppressive capacity of Tregs and emphasizes the important role of Tregs during conception. PMID- 25918825 TI - The Relationship Between Parental Physical Activity and Screen Time Behaviors and the Behaviors of their Young Children. AB - The main purpose of this study was to examine the relationships between parental and children's physical activity and screen time behaviors in a large sample of children in the early years. The results are based on 738 children aged 0-5 years and their parents from the Kingston, Canada area. Parents completed a questionnaire from May to September 2011 that assessed sociodemographic characteristics, their physical activity and screen time, and their child's physical activity and screen time. Logistic regression models, adjusted for potential confounders, were conducted. Parents in the lowest quartile of physical activity were 2.77 (95% confidence interval (CI): 1.68-4.57) times more likely to have a child in the lowest quartile of physical activity compared with parents in the highest quartile of physical activity. Relationships were stronger in two parent homes compared with single-parent homes. Parents in the second (odds ratio = 2.27, 95% CI: 1.36-3.78), third (2.30, 1.32-3.99), and fourth (7.47, 4.53 12.33) screen time quartiles were significantly more likely to have a child in the highest quartile of screen time compared with parents in quartile one. To optimize healthy growth and development in the early years, future family centered interventions targeting both physical activity and screen time appear important. PMID- 25918826 TI - Two promoter polymorphisms in TBX22 are associated with the risk of NSCLP in Indian women. AB - The aetiology of nonsyndromic cleft lip with or without cleft palate (NSCLP) is complex and involves both genetic and environmental risk factors. Classical research has shown that growth and patterning of the developing palatal shelves depend on epithelial-mesenchymal interactions. Expression of several signalling molecules and transcription factors in the anterior palate during early palate development has been documented. TBX22 encodes a T-box containing transcription factor and mutations in this gene are responsible for X-linked cleft palate and ankyloglossia. In the present study, we analysed two TBX22 promoter rs7055763 and rs41307258 single-nucleotide polymorphisms (SNPs) in 173 patients with NSCLP and 176 normal controls of south Indian origin using Kbioscience KASPar chemistry, which is a competitive allele-specific PCR SNP genotyping system. As the SNPs are located on chromosome X, the association analysis was carried out separately in men and women. Significant associations of rs7055763 (P=0.034) and rs41307258 (P=0.022) with NSCLP were found only in women. Both polymorphisms increased the risk for NSCLP in the heterozygous and homozygous variant state, but this was not significant. Both SNPs were not associated with a risk for NSCLP in men. Pair wise linkage disequilibrium between rs7055763 and rs41307258 was strong and significant (D'=0.97 and r2=0.77). Only three haplotypes were observed with an estimated frequency more than 5%. Haplotype AA, which carries both mutant alleles (rs7055763 A - rs41307258 A), was significantly associated with an increased risk of NSCLP in women, but not in men. Our study showed a significant role of TBX22 promoter polymorphisms (rs7055763 and rs41307258) in the pathogenesis of NSCLP and reinforces the previous findings of a strong link between X-linked genes and orofacial clefts. PMID- 25918827 TI - Structure-based predictions of activity cliffs. AB - In drug discovery, it is generally accepted that neighboring molecules in a given descriptor's space display similar activities. However, even in regions that provide strong predictability, structurally similar molecules can occasionally display large differences in potency. In QSAR jargon, these discontinuities in the activity landscape are known as "activity cliffs". In this study, we assessed the reliability of ligand docking and virtual ligand screening schemes in predicting activity cliffs. We performed our calculations on a diverse, independently collected database of cliff-forming cocrystals. Starting from ideal situations, which allowed us to establish our baseline, we progressively moved toward simulating more realistic scenarios. Ensemble- and template-docking achieved a significant level of accuracy, suggesting that, despite the well-known limitations of empirical scoring schemes, activity cliffs can be accurately predicted by advanced structure-based methods. PMID- 25918828 TI - Effects of visual focus and gait speed on walking balance in the frontal plane. AB - We investigated how head position and gait speed influenced frontal plane balance responses to external perturbations during gait. Thirteen healthy participants walked on a treadmill at three different gait speeds. Visual conditions included either focus downward on lower extremities and walking surface only or focus forward on a stationary scene with horizontal and vertical lines. The treadmill was positioned on a platform that was stationary (non-perturbed) or moving in a pattern that appeared random to the subjects (perturbed). In non-perturbed walking, medial-lateral upper body motion was very similar between visual conditions. However, in perturbed walking, there was significantly less body motion when focus was on the stationary visual scene, suggesting visual feedback of stationary vertical and horizontal cues are particularly important when balance is challenged. Sensitivity of body motion to perturbations was significantly decreased by increasing gait speed, suggesting that faster walking was less sensitive to frontal plane perturbations. Finally, our use of external perturbations supported the idea that certain differences in balance control mechanisms can only be detected in more challenging situations, which is an important consideration for approaches to investigating sensory contribution to balance during gait. PMID- 25918829 TI - Lithium ion-water clusters in strong electric fields: a quantum chemical study. AB - We use density functional theory to investigate the impact that strong electric fields have on the structure and energetics of small lithium ion-water clusters, Li(+).nH2O, with n = 4 or 6. We find that electric field strengths of ~0.5 V/A are sufficient to break the symmetry of the n = 4 tetrahedral energy minimum structure, which undergoes a transformation to an asymmetric cluster consisting of three water molecules bound to lithium and one additional molecule in the second solvation shell. Interestingly, this cluster remains the global minimum configuration at field strengths ?0.15 V/A. The 6-coordinated cluster, Li(+).6H2O, features a similar transition to 5- and 4-coordinated clusters at field strengths of ~0.2 and ~0.3 V/A, respectively, with the tetra-coordinated structure being the global minimum even in the absence of the field. Our findings are relevant to understanding the behavior of the Li(+) ion in aqueous environments under strong electric fields and in interfacial regions where field gradients are significant. PMID- 25918830 TI - C- and N-Selective Grignard Addition Reactions of alpha-Aldimino Esters in the Presence or Absence of Zinc(II) Chloride: Synthetic Applications to Optically Active Azacycles. AB - Highly practical synthetic methods were developed for the C- and N-selective Grignard addition reactions of N-4-MeOC6H4-protected alpha-aldimino esters in the presence or absence of zinc(II) chloride. Diastereoselective C-alkyl addition, tandem C-alkyl addition-N-alkylation, and some transformations to synthetically useful optically active azacycles were demonstrated. PMID- 25918831 TI - Metagenomic and network analysis reveal wide distribution and co-occurrence of environmental antibiotic resistance genes. AB - A metagenomic approach and network analysis was used to investigate the wide spectrum profiles of antibiotic resistance genes (ARGs) and their co-occurrence patterns in 50 samples from 10 typical environments. In total, 260 ARG subtypes belonging to 18 ARG types were detected with an abundance range of 5.4 * 10(-6) 2.2 * 10(-1) copy of ARG per copy of 16S-rRNA gene. The trend of the total ARG abundances in environments matched well with the levels of anthropogenic impacts on these environments. From the less impacted environments to the seriously impacted environments, the total ARG abundances increased up to three orders of magnitude, that is, from 3.2 * 10(-3) to 3.1 * 10(0) copy of ARG per copy of 16S rRNA gene. The abundant ARGs were associated with aminoglycoside, bacitracin, beta-lactam, chloramphenicol, macrolide-lincosamide-streptogramin, quinolone, sulphonamide and tetracycline, in agreement with the antibiotics extensively used in human medicine or veterinary medicine/promoters. The widespread occurrences and abundance variation trend of vancomycin resistance genes in different environments might imply the spread of vancomycin resistance genes because of the selective pressure resulting from vancomycin use. The simultaneous enrichment of 12 ARG types in adult chicken faeces suggests the coselection of multiple ARGs in this production system. Non-metric multidimensional scaling analysis revealed that samples belonging to the same environment generally possessed similar ARG compositions. Based on the co-occurrence pattern revealed by network analysis, tetM and aminoglycoside resistance protein, the hubs of the ARG network, are proposed to be indicators to quantitatively estimate the abundance of 23 other co occurring ARG subtypes by power functions. PMID- 25918832 TI - Crustose coralline algal species host distinct bacterial assemblages on their surfaces. AB - Crustose coralline algae (CCA) are important components of many marine ecosystems. They aid in reef accretion and stabilization, create habitat for other organisms, contribute to carbon sequestration and are important settlement substrata for a number of marine invertebrates. Despite their ecological importance, little is known about the bacterial communities associated with CCA or whether differences in bacterial assemblages may have ecological implications. This study examined the bacterial communities on four different species of CCA collected in Belize using bacterial tag-encoded FLX amplicon pyrosequencing of the V1-V3 region of the 16S rDNA. CCA were dominated by Alphaproteobacteria, Gammaproteobacteria and Actinomycetes. At the operational taxonomic unit (OTU) level, each CCA species had a unique bacterial community that was significantly different from all other CCA species. Hydrolithon boergesenii and Titanoderma prototypum, CCA species that facilitate larval settlement in multiple corals, had higher abundances of OTUs related to bacteria that inhibit the growth and/or biofilm formation of coral pathogens. Fewer coral larvae settle on the surfaces of Paragoniolithon solubile and Porolithon pachydermum. These CCA species had higher abundances of OTUs related to known coral pathogens and cyanobacteria. Coral larvae may be able to use the observed differences in bacterial community composition on CCA species to assess the suitability of these substrata for settlement and selectively settle on CCA species that contain beneficial bacteria. PMID- 25918833 TI - Metagenomic and lipid analyses reveal a diel cycle in a hypersaline microbial ecosystem. AB - Marine microbial communities experience daily fluctuations in light and temperature that can have important ramifications for carbon and nutrient cycling. Elucidation of such short time scale community-wide dynamics is hindered by system complexity. Hypersaline aquatic environments have lower species richness than marine environments and can be well-defined spatially, hence they provide a model system for diel cycle analysis. We conducted a 3-day time series experiment in a well-defined pool in hypersaline Lake Tyrrell, Australia. Microbial communities were tracked by combining cultivation-independent lipidomic, metagenomic and microscopy methods. The ratio of total bacterial to archaeal core lipids in the planktonic community increased by up to 58% during daylight hours and decreased by up to 32% overnight. However, total organism abundances remained relatively consistent over 3 days. Metagenomic analysis of the planktonic community composition, resolved at the genome level, showed dominance by Haloquadratum species and six uncultured members of the Halobacteriaceae. The post 0.8 MUm filtrate contained six different nanohaloarchaeal types, three of which have not been identified previously, and cryo-transmission electron microscopy imaging confirmed the presence of small cells. Notably, these nano-sized archaea showed a strong diel cycle, with a pronounced increase in relative abundance over the night periods. We detected no eukaryotic algae or other photosynthetic primary producers, suggesting that carbon resources may derive from patchily distributed microbial mats at the sediment-water interface or from surrounding land. Results show the operation of a strong community-level diel cycle, probably driven by interconnected temperature, light abundance, dissolved oxygen concentration and nutrient flux effects. PMID- 25918835 TI - Preliminary comparison of diffusion-weighted MRI and PET/CT in predicting histological type and malignancy of lung cancer. AB - INTRODUCTION: Emerging evidence shows that diffusion-weighted magnetic resonance imaging (DW MRI) and fluorine 18 fluorodeoxyglucose positron emission tomography/computed tomography (18 F-FDG PET/CT) might be useful in predicting histological type and malignancy of lung cancer, and even in specifically detecting the types of gene mutation. OBJECTIVE: We assessed whether DW MRI is equivalent to PET/CT in lung cancer diagnosis and evaluation. METHODS: The institutional review board approved this study, and written informed consent was obtained from all patients. DW MRI and FDG PET/CT were performed before therapy in 15 lung cancer patients diagnosed by pathological examination. Apparent diffusion coefficient (ADC), ratio of ADC (rADC = ADC in tumor/ADC in spinal cord) and maximal standardized uptake value (SUVmax ) were assessed. RESULTS: ADC, rADC and SUVmax did not reveal significant differences among different types of lung cancer. Sensitivity, specificity and accuracy of ADC, rADC and SUVmax proved to be not significantly different in the detection of adenocarcinoma and squamous cell carcinoma. Difference in the abilities of the sensitivity, specificity and accuracy of ADC, rADC and SUVmax to detect adenocarcinoma and squamous cell carcinoma proved to be insignificant. Although Ki-67 score did not show correlation with ADC, rADC and SUVmax , significant positive correlation was found between ADC and rADC, and ADC and SUVmax . CONCLUSIONS: Both DW MRI and FDG PET/CT had similar limited diagnostic capability of predicting different histological types and malignancy of lung cancer. This study may help provide a novel insight into diagnostic and therapeutic strategies of lung cancer based on DW MRI. PMID- 25918836 TI - Laparoscopic anterior resection with transanal total mesorectal excision for rectal cancer: preliminary experience and impact on postoperative bowel function. AB - AIM: Transanal total mesorectal excision (TME) and the "down-to-up" mobilization concept might be possible alternatives to the standard TME, particularly in cases of narrow pelvis or bulky tumors in obese patients. Our aim was to test the feasibility and safety of transanal TME and to evaluate its impact on short-term functional outcome. SUBJECTS AND METHODS: Six consecutive patients with histologically proven low/middle rectal adenocarcinoma were prospectively enrolled. All patients underwent laparoscopic anterior resection with transanal TME. Intraoperative complications, postoperative morbidity, and oncologic adequacy of the surgical specimen were evaluated in all patients. A bowel function questionnaire using information from the Wexner's score continence grading scale was administered to all patients 1 week before surgery and 6 months following operation. RESULTS: Laparoscopically assisted transanal TME was successful in all patients. Mean operative time was 236 minutes (range, 200-270 minutes). There were no intraoperative complications. The anastomotic leak rate was 16.6%. Clear distal and circumferential margins and proper lymphadenectomy were obtained in all surgical specimens (mean number of nodes harvested, 32; range, 19-68). In no patients was a major incontinence observed; the median (range) Wexner score at 6 months after surgery was 3 (1-7). CONCLUSIONS: Transanal TME is safe and feasible. Preliminary outcomes meet oncologic criteria. Moreover, the transanal approach does not have an adverse impact on functional outcome. Further long-term evaluation of results and clinical trials should be performed. PMID- 25918837 TI - Formation of {Co(dppe)}2{MU2-eta(2):eta(2)-eta(2):eta(2)-[(C60)2]} Dimers Bonded by Single C-C Bonds and Bridging eta(2)-Coordinated Cobalt Atoms. AB - Coordination of two bridging cobalt atoms to fullerenes by the eta(2) type in {Co(dppe)}2{MU2-eta(2):eta(2)-eta(2):eta(2)-[(C60)2]}.3C6H4Cl2 [1; dppe = 1,2 bis(diphenylphosphino)ethane] triggers fullerene dimerization with the formation of two intercage C-C bonds of 1.571(4) A length. Coordination-induced fullerene dimerization opens a path to the design of fullerene structures bonded by both covalent C-C bonds and eta(2)-coordination-bridged metal atoms. PMID- 25918834 TI - Stress and Bronchodilator Response in Children with Asthma. AB - RATIONALE: Stress is associated with asthma morbidity in Puerto Ricans (PRs), who have reduced bronchodilator response (BDR). OBJECTIVES: To examine whether stress and/or a gene regulating anxiety (ADCYAP1R1) is associated with BDR in PR and non PR children with asthma. METHODS: This was a cross-sectional study of stress and BDR (percent change in FEV1 after BD) in 234 PRs ages 9-14 years with asthma. We assessed child stress using the Checklist of Children's Distress Symptoms, and maternal stress using the Perceived Stress Scale. Replication analyses were conducted in two cohorts. Polymorphisms in ADCYAP1R1 were genotyped in our study and six replication studies. Multivariable models of stress and BDR were adjusted for age, sex, income, environmental tobacco smoke, and use of inhaled corticosteroids. MEASUREMENTS AND MAIN RESULTS: High child stress was associated with reduced BDR in three cohorts. PR children who were highly stressed (upper quartile, Checklist of Children's Distress Symptoms) and whose mothers had high stress (upper quartile, Perceived Stress Scale) had a BDR that was 10.2% (95% confidence interval, 6.1-14.2%) lower than children who had neither high stress nor a highly stressed mother. A polymorphism in ADCYAP1R1 (rs34548976) was associated with reduced BDR. This single-nucleotide polymorphism is associated with reduced expression of the gene for the beta2-adrenergic receptor (ADRB2) in CD4(+) lymphocytes of subjects with asthma, and it affects brain connectivity of the amygdala and the insula (a biomarker of anxiety). CONCLUSIONS: High child stress and an ADCYAP1R1 single-nucleotide polymorphism are associated with reduced BDR in children with asthma. This is likely caused by down-regulation of ADRB2 in highly stressed children. PMID- 25918838 TI - Physical activity level is impaired and diet dependent in preterm newborn pigs. AB - BACKGROUND: Preterm infants show delayed development of motor function after birth. This may relate to functional immaturity of many organs, including the gut and brain. Using pigs as model for preterm infants, we hypothesized that early initiation of enteral feeding stimulates both gut growth and neonatal physical activity. METHODS: In experiment 1, preterm and term pigs were fed parenteral nutrition (PN) or PN plus bovine colostrum (BC, 16-64 ml/kg/d enterally) for 5 d. In experiment 2, preterm pigs were fed PN+BC or PN+formula for 5 d. In experiment 3, preterm pigs were fed BC, formula, or human milk (HM) for 10 d. Incubator home cage activity (HCA) was quantified by continuous camera recordings. RESULTS: Preterm birth was associated with reduced intestinal weight and HCA (experiment 1), and BC or formula supplementation increased intestinal weights and HCA (experiments 1+2). Enteral BC and HM feeding increased HCA, intestinal weights, and necrotizing enteritis resistance, relative to formula (experiment 3). CONCLUSION: Preterm pigs show decreased physical activity, and the first enteral feeds diet dependently stimulate both gut growth and physical activity. The effects may arise from maturation of digestive, metabolic, and neurological functions, including gut serotonin production, by the first enteral feeds and milk bioactive factors. PMID- 25918839 TI - Francisella tularensis Subtype A.II Genomic Plasticity in Comparison with Subtype A.I. AB - Although Francisella tularensis is considered a monomorphic intracellular pathogen, molecular genotyping and virulence studies have demonstrated important differences within the tularensis subspecies (type A). To evaluate genetic variation within type A strains, sequencing and assembly of a new subtype A.II genome was achieved for comparison to other completed F. tularensis type A genomes. In contrast with the F. tularensis A.I strains (SCHU S4, FSC198, NE061598, and TI0902), substantial genomic variation was observed between the newly sequenced F. tularensis A.II strain (WY-00W4114) and the only other publically available A.II strain (WY96-3418). Genome differences between WY 00W4114 and WY96-3418 included three major chromosomal translocations, 1580 indels, and 286 nucleotide substitutions of which 159 were observed in predicted open reading frames and 127 were located in intergenic regions. The majority of WY-00W4114 nucleotide deletions occurred in intergenic regions, whereas most of the insertions and substitutions occurred in predicted genes. Of the nucleotide substitutions, 48 (30%) were synonymous and 111 (70%) were nonsynonymous. WY 00W4114 and WY96-3418 nucleotide polymorphisms were predominantly G/C to A/T allelic mutations, with WY-00W4114 having more A+T enrichment. In addition, the A.II genomes contained a considerably higher number of intact genes and longer repetitive sequences, including transposon remnants than the A.I genomes. Together these findings support the premise that F. tularensis A.II may have a fitness advantage compared to the A.I subtype due to the higher abundance of functional genes and repeated chromosomal sequences. A better understanding of the selective forces driving F. tularensis genetic diversity and plasticity is needed. PMID- 25918840 TI - Development of an Efficient Virus Induced Gene Silencing Strategy in the Non Model Wild Ginger-Zingiber zerumbet and Investigation of Associated Proteome Changes. AB - Zingiber zerumbet (Zingiberaceae) is a wild, tropical medicinal herb that shows a high degree of resistance to diseases affecting cultivated ginger. Barley stripe mosaic virus (BSMV) silencing vectors containing an endogenous phytoene desaturase (PDS) gene fragment were agroinfiltrated into young leaves of Z. zerumbet under controlled growth conditions to effect virus-induced gene silencing (VIGS). Infiltrated leaves as well as newly emerged leaves and tillers showed visual signs of PDS silencing after 30 days. Replication and systemic movement of the viral vectors in silenced plants were confirmed by RT-PCR. Real time quantitative PCR analysis verified significant down-regulation of PDS transcripts in the silenced tissues. Label-free proteomic analysis was conducted in leaves with established PDS transcript down regulation and buffer-infiltrated (mock) leaves. A total of 474 proteins were obtained, which were up-regulated, down-regulated or modulated de novo during VIGS. Most of these proteins were localized to the chloroplast, as revealed by UniprotKB analysis, and among the up regulated proteins there were abiotic stress responsive, photosynthetic, metabolic and membrane proteins. Moreover, the demonstration of viral proteins together with host proteins proved successful viral infection. We report for the first time the establishment of a high-throughput gene functional analysis platform using BSMV-mediated VIGS in Z. zerumbet, as well as proteomic changes associated with VIGS. PMID- 25918841 TI - A genome wide association study links glutamate receptor pathway to sporadic Creutzfeldt-Jakob disease risk. AB - We performed a genome-wide association (GWA) study in 434 sporadic Creutzfeldt Jakob disease (sCJD) patients and 1939 controls from the United Kingdom, Germany and The Netherlands. The findings were replicated in an independent sample of 1109 sCJD and 2264 controls provided by a multinational consortium. From the initial GWA analysis we selected 23 SNPs for further genotyping in 1109 sCJD cases from seven different countries. Five SNPs were significantly associated with sCJD after correction for multiple testing. Subsequently these five SNPs were genotyped in 2264 controls. The pooled analysis, including 1543 sCJD cases and 4203 controls, yielded two genome wide significant results: rs6107516 (p value=7.62x10-9) a variant tagging the prion protein gene (PRNP); and rs6951643 (p-value=1.66x10-8) tagging the Glutamate Receptor Metabotropic 8 gene (GRM8). Next we analysed the data stratifying by country of origin combining samples from the pooled analysis with genotypes from the 1000 Genomes Project and imputed genotypes from the Rotterdam Study (Total n=12967). The meta-analysis of the results showed that rs6107516 (p-value=3.00x10-8) and rs6951643 (p-value=3.91x10 5) remained as the two most significantly associated SNPs. Rs6951643 is located in an intronic region of GRM8, a gene that was additionally tagged by a cluster of 12 SNPs within our top100 ranked results. GRM8 encodes for mGluR8, a protein which belongs to the metabotropic glutamate receptor family, recently shown to be involved in the transduction of cellular signals triggered by the prion protein. Pathway enrichment analyses performed with both Ingenuity Pathway Analysis and ALIGATOR postulates glutamate receptor signalling as one of the main pathways associated with sCJD. In summary, we have detected GRM8 as a novel, non-PRNP, genome-wide significant marker associated with heightened disease risk, providing additional evidence supporting a role of glutamate receptors in sCJD pathogenesis. PMID- 25918842 TI - Prolonged exercise in type 1 diabetes: performance of a customizable algorithm to estimate the carbohydrate supplements to minimize glycemic imbalances. AB - Physical activity in patients with type 1 diabetes (T1DM) is hindered because of the high risk of glycemic imbalances. A recently proposed algorithm (named Ecres) estimates well enough the supplemental carbohydrates for exercises lasting one hour, but its performance for prolonged exercise requires validation. Nine T1DM patients (5M/4F; 35-65 years; HbA1c 54 +/- 13 mmol . mol(-1)) performed, under free-life conditions, a 3-h walk at 30% heart rate reserve while insulin concentrations, whole-body carbohydrate oxidation rates (determined by indirect calorimetry) and supplemental carbohydrates (93% sucrose), together with glycemia, were measured every 30 min. Data were subsequently compared with the corresponding values estimated by the algorithm. No significant difference was found between the estimated insulin concentrations and the laboratory-measured values (p = NS). Carbohydrates oxidation rate decreased significantly with time (from 0.84 +/- 0.31 to 0.53 +/- 0.24 g . min(-1), respectively; p < 0.001), being estimated well enough by the algorithm (p = NS). Estimated carbohydrates requirements were practically equal to the corresponding measured values (p = NS), the difference between the two quantities amounting to -1.0 +/- 6.1 g, independent of the elapsed exercise time (time effect, p = NS). Results confirm that Ecres provides a satisfactory estimate of the carbohydrates required to avoid glycemic imbalances during moderate intensity aerobic physical activity, opening the prospect of an intriguing method that could liberate patients from the fear of exercise-induced hypoglycemia. PMID- 25918843 TI - Child and adolescent psychiatrists' reported monitoring behaviors for second generation antipsychotics. AB - OBJECTIVE: The number of children and adolescents (hereafter referred to as "children") who have been prescribed second-generation antipsychotics (SGAs) has increased over the last decade, but little is known about monitoring practices in pediatric patients who are vulnerable to adverse effects. We examined factors associated with psychiatrists' self-reported monitoring of children who were prescribed SGAs. METHODS: A survey was mailed to a national, randomly selected sample of 1600 child and adolescent psychiatrists from the American Medical Association mailing list. Using logistic regression, we tested whether psychiatrist characteristics, attitudes, and practice characteristics were associated with monitoring (baseline and/or periodic) the following: Patient history, height and weight, blood pressure, waist circumference, lipid and glucose levels, and electrocardiogram. RESULTS: Among the analytic sample of 308, at least two thirds reported monitoring patient history, height and weight, blood pressure, and fasting plasma lipids and glucose; 23% reported monitoring waist circumference; and 12% reported conducting an electrocardiogram. More than one third stated that they routinely monitored thyroid levels and more than half reported monitoring complete blood count and electrolytes/blood urea nitrogen. Psychiatrists reporting that they were able to measure vital signs on site were more likely to measure height and weight. Those who reported feeling comfortable conducting a physical examination were more likely to measure blood pressure. Those answering that the risk of metabolic syndrome was low were less likely to measure blood pressure and waist circumference. Being board certified and able to measure vital signs on site were associated with more monitoring of glucose and lipid levels. Conversely, years in practice and feeling that patients were nonadherent with blood work were associated with less monitoring of glucose and lipid levels. CONCLUSIONS: In this sample, inconsistent monitoring patterns of children prescribed SGAs were found. Efforts to communicate guidelines' evidence base and improve office capacity to measure and track adverse effects are needed to increase appropriate adverse effect monitoring in children who have been prescribed SGAs. PMID- 25918844 TI - MICOS coordinates with respiratory complexes and lipids to establish mitochondrial inner membrane architecture. AB - The conserved MICOS complex functions as a primary determinant of mitochondrial inner membrane structure. We address the organization and functional roles of MICOS and identify two independent MICOS subcomplexes: Mic27/Mic10/Mic12, whose assembly is dependent on respiratory complexes and the mitochondrial lipid cardiolipin, and Mic60/Mic19, which assembles independent of these factors. Our data suggest that MICOS subcomplexes independently localize to cristae junctions and are connected via Mic19, which functions to regulate subcomplex distribution, and thus, potentially also cristae junction copy number. MICOS subunits have non redundant functions as the absence of both MICOS subcomplexes results in more severe morphological and respiratory growth defects than deletion of single MICOS subunits or subcomplexes. Mitochondrial defects resulting from MICOS loss are caused by misdistribution of respiratory complexes in the inner membrane. Together, our data are consistent with a model where MICOS, mitochondrial lipids and respiratory complexes coordinately build a functional and correctly shaped mitochondrial inner membrane. PMID- 25918845 TI - Synaptojanin cooperates in vivo with endophilin through an unexpected mechanism. AB - Synaptojanin and endophilin represent a classic pair of endocytic proteins that exhibit coordinated action during rapid synaptic vesicle endocytosis. Current models suggest that synaptojanin activity is tightly associated with endophilin through high-affinity binding between the synaptojanin proline-rich domain (PRD) and the endophilin SH3 domain. Surprisingly, we find that truncated synaptojanin lacking the PRD domain sustains normal synaptic transmission, indicating that synaptojanin's core function in vivo resides in the remaining two domains that contain phosphoinositide-phosphatase activities: an N-terminal Sac1 phosphatase domain and a 5-phosphatase domain. We further show that the Sac1 domain plays an unexpected role in targeting synaptojanin to synapses. The requirement for Sac1 is bypassed by tethering the synaptojanin 5-phophatase to the endophilin membrane bending Bin-Amphiphysin-Rvs (BAR) domain. Together, our results uncover an unexpected role for the Sac1 domain in vivo in supporting coincident action between synaptojanin and endophilin at synapses. PMID- 25918847 TI - Exercise Physiology and Pulmonary Hemodynamic Abnormality in PH Patients with Exercise Induced Venous-To-Systemic Shunt. AB - OBJECTIVES: To identify the pulmonary hypertension (PH) patients who develop an exercise induced venous-to-systemic shunt (EIS) by performing the cardiopulmonary exercise test (CPET), analyse the changes of CPET measurements during exercise and compare the exercise physiology and resting pulmonary hemodynamics between shunt-PH and no-shunt-PH patients. METHODS: Retrospectively, resting pulmonary function test (PFT), right heart catheterization (RHC), and CPET for clinical evaluation of 104 PH patients were studied. RESULTS: Considering all 104 PH patients by three investigators, 37 were early EIS+, 61 were EIS-, 3 were late EIS+, and 3 others were placed in the discordant group. PeakVO2, AT and OUES were all reduced in the shunt-PH patients compared with the no-shunt-PH subjects, whereas VE/VCO2 slope and the lowest VE/VCO2 increased. Besides, the changes and the response characteristics of the key CPET parameters at the beginning of exercise in the shunt group were notably different from those of the no shunt one. At cardiac catheterization, the shunt patients had significantly increased mean pulmonary artery pressure (mPAP), mean right atrial pressure (mRAP) and pulmonary vascular resistance (PVR), reduced cardiac output (CO) and cardiac index (CI) compared with the no shunt ones (P<0.05). Resting CO was significantly correlated with exercise parameters of AT (r = 0.527, P<0.001), OUES (r = 0.410, P<0.001) and Peak VO2 (r = 0.405, P<0.001). PVR was significantly, but weakly, correlated with the above mentioned CPET parameters. IN CONCLUSIONS: CPET may allow a non-invasive method for detecting an EIS and assessing the severity of the disease in PH patients. PMID- 25918848 TI - Muscle activation characteristics of the front leg during baseball swings with timing correction for sudden velocity decrease. AB - This study aimed to clarify the activation characteristics of the vastus lateralis muscle in the front leg during timing correction for a sudden decrease in the velocity of a target during baseball swings. Eleven male collegiate baseball players performed coincident timing tasks that comprised constant velocity of 8 m/s (unchanged) and a sudden decrease in velocity from 8 to 4 m/s (decreased velocity). Electromyography (EMG) revealed that the muscle activation was typically monophasic when responding unchanged conditions. The type of muscle activation during swings in response to decreased velocity condition was both monophasic and biphasic. When biphasic activation appeared in response to decreased velocity, the impact time and the time to peak EMG amplitude were significantly prolonged and the timing error was significantly smaller than that of monophasic activation. However, the EMG onset from the target start was consistent both monophasic and biphasic activation in response to conditions of decreased velocity. In addition, batters with small timing errors in response to decreased velocity were more likely to generate biphasic EMG activation. These findings indicated that timing correction for a sudden decrease in the velocity of an oncoming target is achieved by modifying the muscle activation characteristics of the vastus lateralis muscle of front leg from monophasic to biphasic to delay reaching peak muscle activation and thus prolong impact time. Therefore, the present findings suggests that the extent of timing errors in response to decreased velocity is influenced by the ability to correct muscle activation after its initiation rather than by delaying the initiation timing of muscle activation during baseball swings. PMID- 25918846 TI - TRIP13 is a protein-remodeling AAA+ ATPase that catalyzes MAD2 conformation switching. AB - The AAA+ family ATPase TRIP13 is a key regulator of meiotic recombination and the spindle assembly checkpoint, acting on signaling proteins of the conserved HORMA domain family. Here we present the structure of the Caenorhabditis elegans TRIP13 ortholog PCH-2, revealing a new family of AAA+ ATPase protein remodelers. PCH-2 possesses a substrate-recognition domain related to those of the protein remodelers NSF and p97, while its overall hexameric architecture and likely structural mechanism bear close similarities to the bacterial protein unfoldase ClpX. We find that TRIP13, aided by the adapter protein p31(comet), converts the HORMA-family spindle checkpoint protein MAD2 from a signaling-active 'closed' conformer to an inactive 'open' conformer. We propose that TRIP13 and p31(comet) collaborate to inactivate the spindle assembly checkpoint through MAD2 conformational conversion and disassembly of mitotic checkpoint complexes. A parallel HORMA protein disassembly activity likely underlies TRIP13's critical regulatory functions in meiotic chromosome structure and recombination. PMID- 25918850 TI - Antiphospholipid antibody and risk of retinal vein occlusion: a systematic review and meta-analysis. AB - BACKGROUND: Retinal vein occlusion (RVO) is a common retinal vascular disease and it is one of the most frequently reported causes of visual damage and blindness in the elderly. The current study investigated the potential association between antiphospholipid antibodies (APLA) and RVO risk by conducting a meta-analysis of case-control studies. METHODS: A systematic literature search of Pubmed and Embase databases was conducted in August 1st, 2014. Odds ratios (ORs) were used to evaluate the associations between APLA and the incidence of RVO. A random effects model was obtained for the quantitative synthesis. RESULTS: A total of 11 studies were included in this meta-analysis. A meta-analysis of all studies assessing the risk of RVO revealed that APLA was associated with a statistically increased risk of RVO incidence (OR = 5.18, 95% CI = [3.37, 7.95]). The association between anticardiolipin antibodies (ACA) and the risk of RVO was significant (n =8, OR = 4.59, 95% CI = [2.75, 7.66]). However, the association between lupus anticoagulants (LA) and risk of RVO was non-significant (n = 5, OR = 3.90, 95% CI = [0.99, 15.37]). No significant publication bias was found in the 11 selected studies. CONCLUSION: APLA was significantly associated with the risk of RVO. Advanced analyses showed that ACA rather than LA affected the risk of RVO. Additional well-designed and well-conducted epidemiological studies are required to further our understanding of the relationship between APLA and RVO risk. PMID- 25918851 TI - Does aspirin reduce recurrence after completing anticoagulant treatment for an idiopathic thromboembolic event? AB - Idiopathic thromboembolic disease presents a high risk of recurrence. There is controversy about the effects of aspirin in reducing this risk after the completion of anticoagulant treatment. Searching in Epistemonikos database, which screens 30 databases, we identified four systematic reviews that together include two randomized trials. We combined the evidence using meta-analysis and generated a summary of findings table following the GRADE approach. We concluded that aspirin administered after having completed anticoagulation reduces the risk of recurrence, probably without importantly increasing the risk of hemorrhage. PMID- 25918849 TI - Characterization of tissue-engineered posterior corneas using second- and third harmonic generation microscopy. AB - Three-dimensional tissues, such as the cornea, are now being engineered as substitutes for the rehabilitation of vision in patients with blinding corneal diseases. Engineering of tissues for translational purposes requires a non invasive monitoring to control the quality of the resulting biomaterial. Unfortunately, most current methods still imply invasive steps, such as fixation and staining, to clearly observe the tissue-engineered cornea, a transparent tissue with weak natural contrast. Second- and third-harmonic generation imaging are well known to provide high-contrast, high spatial resolution images of such tissues, by taking advantage of the endogenous contrast agents of the tissue itself. In this article, we imaged tissue-engineered corneal substitutes using both harmonic microscopy and classic histopathology techniques. We demonstrate that second- and third-harmonic imaging can non-invasively provide important information regarding the quality and the integrity of these partial-thickness posterior corneal substitutes (observation of collagen network, fibroblasts and endothelial cells). These two nonlinear imaging modalities offer the new opportunity of monitoring the engineered corneas during the entire process of production. PMID- 25918852 TI - Soil organic carbon across scales. AB - Mechanistic understanding of scale effects is important for interpreting the processes that control the global carbon cycle. Greater attention should be given to scale in soil organic carbon (SOC) science so that we can devise better policy to protect/enhance existing SOC stocks and ensure sustainable use of soils. Global issues such as climate change require consideration of SOC stock changes at the global and biosphere scale, but human interaction occurs at the landscape scale, with consequences at the pedon, aggregate and particle scales. This review evaluates our understanding of SOC across all these scales in the context of the processes involved in SOC cycling at each scale and with emphasis on stabilizing SOC. Current synergy between science and policy is explored at each scale to determine how well each is represented in the management of SOC. An outline of how SOC might be integrated into a framework of soil security is examined. We conclude that SOC processes at the biosphere to biome scales are not well understood. Instead, SOC has come to be viewed as a large-scale pool subjects to carbon flux. Better understanding exists for SOC processes operating at the scales of the pedon, aggregate and particle. At the landscape scale, the influence of large- and small-scale processes has the greatest interaction and is exposed to the greatest modification through agricultural management. Policy implemented at regional or national scale tends to focus at the landscape scale without due consideration of the larger scale factors controlling SOC or the impacts of policy for SOC at the smaller SOC scales. What is required is a framework that can be integrated across a continuum of scales to optimize SOC management. PMID- 25918854 TI - Effect of continuous high cutoff hemodialysis on vascular permeability of septic patients with acute kidney injury. PMID- 25918855 TI - Masking agent-free and channel-switch-mode simultaneous sensing of Fe(3+) and Hg(2+) using dual-excitation graphene quantum dots. AB - A novel channel-switch-mode strategy for simultaneous sensing of Fe(3+) and Hg(2+) is developed with dual-excitation single-emission graphene quantum dots (GQDs). By utilizing the dual-channel fluorescence response performance of GQDs, this strategy achieved a facile, low-cost, masking agent-free, quantitative and selective dual-ion assay even in mixed ion samples and practical water samples. PMID- 25918856 TI - Thromboelastographic assessment of the contribution of platelets and clotting proteases to the hypercoagulable state of dogs with immune-mediated hemolytic anemia. AB - BACKGROUND: Hypercoagulability is a well-known feature of canine immune-mediated hemolytic anemia (IMHA) and is believed to increase the risk of thrombosis. This study was undertaken to differentiate the relative contribution of platelets and clotting proteases to this hypercoagulability using thromboelastography (TEG). STUDY DESIGN: Retrospective observational study. METHODS: Thromboelastograms from 27 dogs with IMHA were retrospectively evaluated. Standard TEG parameters (R, K, alpha, MA), the G value, and the novel parameter delta (Delta) were determined. Hypercoagulability was attributed to the platelet component of hemostasis when there was an increased G value with a normal Delta value. KEY FINDINGS: Nineteen of 27 dogs (70.4%) had >= 2 TEG variables suggestive of hypercoagulability, 18 (66.7%) had a hypercoagulable G value, and 11 (40.7%) had a hypercoagulable Delta value. Ten of 27 (37%) samples met the criteria for platelet hypercoagulability. SIGNIFICANCE: Our report documents the derivation and application of the Delta value to differentiate enzymatic from platelet hypercoagulability. Further studies are required to validate the use of these TEG variables in this manner. The hypercoagulable tendency in dogs with IMHA is complex and multifactorial, and in some dogs this hypercoagulability may be attributed primarily to platelet hyper reactivity. Our findings may support the use of anti-platelet drugs in some dogs with IMHA. PMID- 25918857 TI - Palladium-Catalyzed alpha,beta-Dehydrogenation of Esters and Nitriles. AB - A highly practical and general palladium-catalyzed methodology for the alpha,beta dehydrogenation of esters and nitriles is reported. Generation of a zinc enolate or (cyanoalkyl)zinc species followed by the addition of an allyl oxidant and a palladium catalyst results in synthetically useful yields of alpha,beta unsaturated esters, lactones, and nitriles. Preliminary mechanistic investigations are consistent with reversible beta-hydride elimination and turnover-limiting, propene-forming reductive elimination. PMID- 25918858 TI - A Japanese fairy tale, Urashima Taro, and dementia. PMID- 25918859 TI - Ab initio simulation of elastic and mechanical properties of Zn- and Mg-doped hydroxyapatite (HAP). AB - Hydroxyapatite (HAP) is an important bioceramic which constitutes the mineral components of bones and hard tissues in mammals. It is bioactive and used as bioceramic coatings for metallic implants and bone fillers. HAP readily absorbs a large amount of impurities. Knowledge on the elastic and mechanical properties of impurity-doped HAP is a subject of great importance to its potential for biomedical applications. Zn and Mg are the most common divalent cations HAP absorbs. Using density function theory based ab initio methods, we have carried out a large number of ab initio calculations to obtain the bulk elastic and mechanical properties of HAP with Zn or Mg doped in different concentration at the Ca1 and Ca2 sites using large 352-atom supercells. Detailed information on their dependece on the concetraion of the substitued impurity is obtained. Our results show that Mg enhances overall elastic and bulk mechanical properties whereas Zn tends to degrade except at low concentrations. At a higher concentration, the mechanical properties of Zn and Mg doped HAP also depend significantly on impurity distribution between the Ca1 and Ca2 sites. There is a strong evidence that Zn prefers Ca2 site for substituion whereas Mg has no such preference. These results imply that proper control of dopant concentration and their site preference must carefully considered in using doped HAP for specific biomedical applications. PMID- 25918860 TI - Hemodynamic and energetic aspects of the left ventricle in patients with mitral regurgitation before and after mitral valve surgery. AB - BACKGROUND: The role of intracardiac blood flow behavior within the context of manifestation and interventional success in patients with mitral regurgitation is unknown to date. The present study aims to assess left ventricular blood flow behavior characterized by kinetic energy (KE) in patients with mitral regurgitation before and after mitral valve surgery. METHODS: Patients with mitral regurgitation (mean age 56 +/- 9 years) and the necessity for mitral valve repair (n = 6) or biological valve replacement (n = 4) received cardiac magnetic resonance before and after surgery and were compared with a group of healthy volunteers (n = 7; mean age 27 +/- 7 years). Volumetric data and KE of the left ventricle were obtained for all subjects. KE normalized and nonnormalized to volume was calculated from four-dimensional flow magnetic resonance imaging. Mean KE and KE peaks (systolic, early-diastolic and late diastolic), and end-systolic phase duration were considered. RESULTS: End-diastolic, end-systolic and stroke volume were significantly higher in patients with mitral regurgitation than in healthy volunteers (P = 0.00, 0.01, and 0.00, respectively) and decreased significantly after surgery (P = 0.00, 0.01, and 0.00, respectively). A significant postoperative decrease of mean KE, systolic and early-diastolic KE peaks was observed (P = 0.01, 0.02, and 0.01, respectively). Late-diastolic KE peak remained high in postoperative patients (P = 0.58). CONCLUSION: Intracardiac blood flow as characterized by measurements of KE is altered in patients with mitral regurgitation. Physiological flow conditions appear to not fully be restored with mitral valve surgery. PMID- 25918861 TI - Nitrogen-Doped Carbon Nanotube Aerogels for High-Performance ORR Catalysts. AB - By utilizing the dual roles of the erasable promoter (pyrrole), "clean", highly conductive, and nitrogen-doped CNT aerogels are derived from a promoter-assisted hydrothermal reaction (HTR) coupling with pyrolysis. The resulting materials show an excellent performance towards oxygen reduction reaction (ORR). PMID- 25918862 TI - Ketorolac salt is a newly discovered DDX3 inhibitor to treat oral cancer. AB - DDX3 belongs to DEAD box RNA helicase family and is involved in the progression of several types of cancer. In this work, we employed a High Throughput Virtual screening approach to identify bioactive compounds against DDX3 from ZINC natural database. Ketorolac salt was selected based on its binding free energy less than or equals to -5 Kcal/mol with reference to existing synthetic DDX3 inhibitors and strong hydrogen bond interactions as similar to crystallized DDX3 protein (2I4I). The anti-cancer activity of Ketorolac salt against DDX3 was tested using oral squamous cell carcinoma (OSCC) cell lines. This compound significantly down regulated the expression of DDX3 in human OSCC line (H357) and the half maximal growth inhibitory concentration (IC50) of Ketorolac salt in H357 cell line is 2.6 uM. Ketorolac salt also inhibited the ATP hydrolysis by directly interacting with DDX3. More importantly, we observed decreased number of neoplastic tongue lesions and reduced lesion severity in Ketorolac salt treated groups in a carcinogen induced tongue tumor mouse model. Taken together, our result demonstrates that Ketorolac salt is a newly discovered bioactive compound against DDX3 and this compound can be used as an ideal drug candidate to treat DDX3 associated oral cancer. PMID- 25918863 TI - Every 15-min delay in recanalization by intra-arterial therapy in acute ischemic stroke increases risk of poor outcome. AB - BACKGROUND: Intra-arterial therapy has improved recanalization rates compared with intravenous thrombolysis for acute ischemic stroke; however, superior clinical efficacy has not been convincingly demonstrated. Time to recanalization is postulated as a mechanism hindering the efficacy of intra-arterial therapy. AIM: To investigate the effects of time to recanalization on clinical outcome postintra-arterial therapy for acute ischemic stroke. METHODS: Clinical data were collected prospectively for consecutive patients undergoing intra-arterial therapy for acute ischemic stroke at a single center between 2009 and 2013. Ninety-day functional outcome was assessed by the modified Rankin scale. Univariate analyses identified candidate clinical variables for inclusion in the multivariable model; multivariable logistic regression analyses identified variables independently associated with good outcome, defined as modified Rankin scale 0-2. RESULTS: One hundred and seven patients were included in the analysis. Median (interquartile range) age was 67 (54-77) years, 41 (38%) were female, and median (interquartile range) baseline National Institute of Health Stroke Severity score was 18 (13-22). Median time from symptom onset to recanalization was 330 min (interquartile range 277-397). Fifty-four (50%) patients achieved a favorable modified Rankin scale at 90 days. Age, successful recanalization, and time to recanalization were independently associated with good outcome at 90 days in multivariable logistic regression analysis. For every 15 min delay in recanalization, the odds of good outcome decreased by 10%. CONCLUSIONS: Longer time to recanalization was associated with poorer functional outcome post intra arterial therapy. We recommend that a systematic approach to minimize time delay to treatment is warranted in intra-arterial therapy for acute ischemic stroke. PMID- 25918864 TI - An ultra-low cost NMR device with arbitrary pulse programming. AB - Ultra-low cost, general purpose electronics boards featuring microprocessors or field programmable gate arrays (FPGA) are reaching capabilities sufficient for direct implementation of NMR spectrometers. We demonstrate a spectrometer based on such a board, implemented with a minimal need for the addition of custom electronics and external components. This feature allows such a spectrometer to be readily implemented using typical knowledge present in an NMR laboratory. With FPGA technology, digital tasks are performed with precise timing, without the limitation of predetermined hardware function. In this case, the FPGA is used for programming of arbitrarily timed pulse sequence events, and to digitally generate required frequencies. Data acquired from a 0.53T permanent magnet serves as a demonstration of the flexibility of pulse programming for diverse experiments. Pulse sequences applied include a spin-lattice relaxation measurement using a pulse train with small-flip angle pulses, and a Carr-Purcell-Meiboom-Gill experiment with phase cycle. Mixing of NMR signals with a digitally generated, 4 step phase-cycled reference frequency is further implemented to achieve sequential quadrature detection. The flexibility in hardware implementation permits tailoring this type of spectrometer for applications such as relaxometry, polarimetry, diffusometry or NMR based magnetometry. PMID- 25918865 TI - Factors affecting the ecology of tick-borne encephalitis in Slovenia. AB - Recognition of factors that influence the formation of tick-borne encephalitis (TBE) foci is important for assessing the risk of humans acquiring the viral infection and for establishing what can be done (within reasonable boundaries) to minimize that risk. In Slovenia, the dynamics of the TBE vector, i.e. Ixodes ricinus, was studied over a 4-year period and the prevalence of infection in ticks was established. Two groups of tick hosts were investigated: deer and small mammals. Red deer have been confirmed as having a direct influence on the incidence of TBE and rodents have been recognized as important sentinels for TBE infections, although their role in the enzootic cycle of the virus still remains to be elucidated. Last, forest and agricultural areas, which are influenced by human activity, are suitable habitats for ticks, and important for TBEV transmission and establishment. Human behaviour is also therefore an important factor and should always be considered in studies of TBE ecology. PMID- 25918866 TI - Lessons learnt from comparative species' studies. PMID- 25918867 TI - A mutation-sensitive switch assay to detect five clinically significant epidermal growth factor receptor mutations. AB - Epidermal growth factor receptor (EGFR) mutations can affect the therapeutic efficacy of drugs used to treat nonsmall-cell lung cancer (NSCLC). We aimed to develop methods to detect five common EGFR somatic mutations in tumor tissues from NSCLC patients by using a nanoscale mutation-sensitive switch consisting of a high-fidelity polymerase and phosphorothioate-modified allele-specific primers. The five clinically significant EGFR mutations examined here are S768I, T790M, L858R, and 15- and 18-bp deletion mutations in exon 19. Our assays showed sensitivities of 100 copies and specificities of more than three log scales for matched templates relative to mismatched templates by routine polymerase chain reaction (PCR), real-time PCR, and multiplex PCR. This assay would be superior to DNA sequencing in situations where mutant DNA is not abundant. PMID- 25918868 TI - Ethical challenges in nursing homes--staff's opinions and experiences with systematic ethics meetings with participation of residents' relatives. AB - BACKGROUND: Many ethical problems exist in nursing homes. These include, for example, decision-making in end-of-life care, use of restraints and a lack of resources. AIMS: The aim of the present study was to investigate nursing home staffs' opinions and experiences with ethical challenges and to find out which types of ethical challenges and dilemmas occur and are being discussed in nursing homes. METHODS: The study used a two-tiered approach, using a questionnaire on ethical challenges and systematic ethics work, given to all employees of a Norwegian nursing home including nonmedical personnel, and a registration of systematic ethics discussions from an Austrian model of good clinical practice. RESULTS: Ninety-one per cent of the nursing home staff described ethical problems as a burden. Ninety per cent experienced ethical problems in their daily work. The top three ethical challenges reported by the nursing home staff were as follows: lack of resources (79%), end-of-life issues (39%) and coercion (33%). To improve systematic ethics work, most employees suggested ethics education (86%) and time for ethics discussion (82%). Of 33 documented ethics meetings from Austria during a 1-year period, 29 were prospective resident ethics meetings where decisions for a resident had to be made. Agreement about a solution was reached in all 29 cases, and this consensus was put into practice in all cases. Residents did not participate in the meetings, while relatives participated in a majority of case discussions. In many cases, the main topic was end-of-life care and life-prolonging treatment. CONCLUSIONS: Lack of resources, end-of-life issues and coercion were ethical challenges most often reported by nursing home staff. The staff would appreciate systematic ethics work to aid decision-making. Resident ethics meetings can help to reach consensus in decision-making for nursing home patients. In the future, residents' participation should be encouraged whenever possible. PMID- 25918869 TI - Occipital and trigeminal nerve blocks for migraine. PMID- 25918870 TI - MR elastography for evaluating regeneration of tissue-engineered cartilage in an ectopic mouse model. AB - PURPOSE: The purpose of the present study was to apply noninvasive methods for monitoring regeneration and mechanical properties of tissue-engineered cartilage in vivo at different growth stages using MR elastography (MRE). METHODS: Three types of scaffolds, including silk, collagen, and gelatin seeded by human mesenchymal stem cells, were implanted subcutaneously in mice and imaged at 9.4T where the shear stiffness and transverse MR relaxation time (T2 ) were measured for the regenerating constructs for 8 wk. An MRE phase contrast spin echo-based sequence was used for collecting MRE images. At the conclusion of the in vivo study, constructs were excised and transcript levels of cartilage-specific genes were quantitated using reverse-transcription polymerase chain reaction. RESULTS: Tissue-engineered constructs showed a cartilage-like construct with progressive tissue formation characterized by increase in shear stiffness and decrease in T2 that can be correlated with increased cartilage transcript levels including aggrecan, type II collagen, and cartilage oligomeric matrix protein after 8 wk of in vivo culture. CONCLUSION: Altogether, the outcome of this research demonstrates the feasibility of MRE and MRI for noninvasive monitoring of engineered cartilage construct's growth after implantation and provides noninvasive biomarkers for regeneration, which may be translated into treatment of tissue defects. PMID- 25918871 TI - Effect of the probiotic Saccharomyces cerevisiae on ligature-induced periodontitis in rats. AB - BACKGROUND AND OBJECTIVE: This study assessed the effects of the local use of Saccharomyces cerevisiae as monotherapy and as an adjuvant to the mechanical treatment of ligature-induced periodontitis in rats. MATERIAL AND METHODS: Periodontitis was induced in 72 rats via the installation of a ligature around the mandibular first molar. After 7 d, the ligature was removed and the rats were placed in one of the following groups: no treatment (C; n = 18); scaling and root planing (SRP; n = 18); local irrigation with probiotics (PRO; n = 18); and SRP followed by local irrigation with probiotics (SRP/PRO; n = 18). Six rats from each group were killed at 7, 15 and 30 d. The histological characteristics, alveolar bone loss (ABL) and immunolabeling of tumor necrosis factor alpha (TNF alpha), interleukin-1beta (IL-1beta), interleukin-10 (IL-10) and TRAP on the furcation area of the first molar were assessed. RESULTS: The PRO group showed features of acceleration of the tissue-repair process during the entire experiment. On day 15, there was less ABL in the SRP/PRO group compared with the C group. There were fewer TRAP-positive cells in the SRP and SRP/PRO groups at 30 d. There was less immunostaining for TNF-alpha in the PRO and SRP/PRO groups and less immunostaining for IL-1beta in the PRO group. However, there was more immunostaining for IL-10 in the PRO group on day 15. CONCLUSION: Local use of the probiotic did not result in any adverse effects on periodontal tissues. When used as monotherapy or as an adjuvant, the probiotic was effective at controlling periodontitis in rats. PMID- 25918872 TI - Early and resectable HCC: Definition and validation of a subgroup of patients who could avoid liver transplantation. AB - BACKGROUND: Liver transplantation (LT) remains the best curative option for early hepatocellular carcinoma (HCC) but is limited by the ongoing graft shortage. The present study aimed at defining the population in which primary liver resection (LR) could represent the best alternative to LT. METHODS: An exploration set of 357 HCC patients (LR n = 221 and LT n = 136) operated between 2000-2012 was used in order to identify factors associated with survival following LR and define a good prognosis (GP) group for which LR may challenge the results of upfront LT. These factors were validated in an external validation set of 565 HCC patients operated at another center (LR n = 287 LR and LT n = 278). RESULTS: In the exploration set, factors associated with survival on multivariate analysis were a solitary lesion, a diameter <50 mm, a well-moderately differentiated lesion, the absence of microvascular invasion, and preoperative AST level <2N. Thirty-nine patients (18%) displayed all these criteria and constituted the GP patients. Overall survivals at 1, 3, and 5 years did not significantly differ between GP resected patients, and the in Milan transplanted patients (93, 80.4, and 80.4% vs. 86.9, 82, and 78.8%, P = 0.79). In the validation cohort, patients with GP factors of survival still displayed better overall survivals than those without (P = 0.036) but also displayed better survivals than in Milan HCC transplanted patients (P = 0.005). CONCLUSION: In a group of early HCC patients gathering all factors of GP, primary LR achieves at least similar survival as upfront LT and should be the approach of choice. PMID- 25918873 TI - Child Care Provider Adherence to Infant and Toddler Feeding Recommendations: Findings from the Baby Nutrition and Physical Activity Self-Assessment for Child Care (Baby NAP SACC) Study. AB - BACKGROUND: Identifying characteristics associated with the Institute of Medicine's (IOM) recommended feeding practices among infant and toddler care providers in child care centers could help in preventing childhood obesity. METHODS: In 2009, at baseline in a pilot intervention study of 29 licensed Massachusetts child care centers with at least 50% of enrolled children identified as racial minorities, 57 infant and 109 toddler providers completed feeding questionnaires. To assess provider adherence to six IOM-recommended behaviors, we used cluster-adjusted multivariable logistic regression models including provider type (infant or toddler), race, education, and center Child and Adult Care Food Program (CACFP) participation. RESULTS: In multivariable analysis, CACFP participation was associated with providers sitting with children at meals (odds ratio [OR], 5.2; 95% confidence interval [CI], 1.2-21.7), offering fruits and vegetables (OR, 3.3; 95% CI 1.7-6.2), and limiting fast food (OR, 3.5; 95% CI, 1.8-6.7). Providers at centers serving meals family style were less likely to allow children to leave food unfinished (OR, 0.27; 95% CI, 0.09-0.77). Infant providers were more likely than toddler providers to sit with children at meals (OR, 6.98; 95% CI, 1.51-32.09), allow children to eat when hungry (OR, 3.50; 95% CI, 1.34-9.16), and avoid serving sugary (OR, 8.74; 95% CI, 3.05-25.06) or fast foods (OR, 11.56; 95% CI, 3.20-41.80). CONCLUSIONS: CACFP participation may encourage IOM-recommended feeding practices among infant and toddler providers. Child care providers may benefit from education about how to feed infants and toddlers responsively, especially when offering foods family style. Future research should explore ways to promote child-centered feeding practices, while addressing barriers to providing children with nutrient-rich foods. PMID- 25918874 TI - Smart enrichment and facile separation of oil from emulsions and mixtures by superhydrophobic/superoleophilic particles. AB - The separation and removal of oil or organic pollutants from water is highly imperative. The oil phases in surfactant-free oil-in-water emulsions or in free oil/water mixtures can be smartly enriched and transported by using superhydrophobic/superoleophilic iron particles (SHIPs) under a magnetic field. For water-in-oil emulsion, SHIPs-based composite membranes selectively allow the oil to pass through. Their convenient and scalable preparation, excellent separation performance, and good reusability are of great advantages for practical applications in wastewater treatment, the cleanup of oil spills, emulsion concentration, and fuel purification. PMID- 25918876 TI - Influence of inter-dental tissues and root surface condition on complete root coverage following treatment of gingival recessions: a 1-year retrospective study. AB - AIM: To explore the influence of inter-dental tissues and root surface condition on complete root coverage following surgical treatment of gingival recessions. METHODS: Three hundred and eighty-six single recessions treated over 28 years were assessed. Patient-level and periodontal variables, presence/loss of inter dental tissues, and presence/absence of non-carious cervical lesions (NCCLs) were recorded. Root coverage was assessed 1-year post-surgery. Multilevel analysis was performed to identify predictors of CRC. RESULTS: Based on type of root coverage procedure four patient groups were created: free gingival graft (FGG) (n = 116), coronally advanced flap (CAF) (n = 107), CAF+connective tissue graft (CTG) (n = 131), and guided tissue regeneration (GTR) (n = 32). Percentages of complete root coverage (CRC) were 18.1% for FGG, 35.5% for CAF, 35.1% for CAF+CTG, and 18.8% for GTR. There was an OR = 0.26 (p < 0.0001) of achieving CRC in cases with loss of inter-dental tissue compared with cases with no inter-dental tissue loss. Similarly, cases with presence of NCCL showed an OR = 0.28 (p < 0.0001) of achieving CRC compared with cases without a NCCL. FGG achieved less CRC then CAF+CTG (p = 0.0012; OR = 0.32). CONCLUSIONS: NCCLs, just like inter-dental tissue loss, are significant negative prognostic factors in achieving CRC following root coverage procedures. PMID- 25918877 TI - Full-life chronic toxicity of sodium salts to the mayfly Neocloeon triangulifer in tests with laboratory cultured food. AB - Although insects occur in nearly all freshwater ecosystems, few sensitive insect models exist for use in determining the toxicity of contaminants. The objectives of the present study were to adapt previously developed culturing and toxicity testing methods for the mayfly Neocloeon triangulifer (Ephemeroptera: Baetidae), and to further develop a method for chronic toxicity tests spanning organism ages of less than 24 h post hatch to adult emergence, using a laboratory cultured diatom diet. The authors conducted 96-h fed acute tests and full-life chronic toxicity tests with sodium chloride, sodium nitrate, and sodium sulfate. The authors generated 96-h median lethal concentrations (LC50s) of 1062 mg Cl/L (mean of 3 tests), 179 mg N-NO3 /L, and 1227 mg SO4 /L. Acute to chronic ratios ranged from 2.1 to 6.4 for chloride, 2.5 to 5.1 for nitrate, and 2.3 to 8.5 for sulfate. The endpoints related to survival and development time were consistently the most sensitive in the tests. The chronic values generated for chloride were in the same range as those generated by others using natural foods. Furthermore, our weight-versus-fecundity plots were similar to those previously published using the food culturing method on which the present authors' method was based, indicating good potential for standardization. The authors believe that the continued use of this sensitive mayfly species in laboratory studies will help to close the gap in understanding between standard laboratory toxicity test results and field-based observations of community impairment. PMID- 25918875 TI - Beyond glycolysis: GAPDHs are multi-functional enzymes involved in regulation of ROS, autophagy, and plant immune responses. AB - Glyceraldehyde-3-phosphate dehydrogenase (GAPDH) is an important enzyme in energy metabolism with diverse cellular regulatory roles in vertebrates, but few reports have investigated the importance of plant GAPDH isoforms outside of their role in glycolysis. While animals possess one GAPDH isoform, plants possess multiple isoforms. In this study, cell biological and genetic approaches were used to investigate the role of GAPDHs during plant immune responses. Individual Arabidopsis GAPDH knockouts (KO lines) exhibited enhanced disease resistance phenotypes upon inoculation with the bacterial plant pathogen Pseudomonas syringae pv. tomato. KO lines exhibited accelerated programmed cell death and increased electrolyte leakage in response to effector triggered immunity. Furthermore, KO lines displayed increased basal ROS accumulation as visualized using the fluorescent probe H2DCFDA. The gapa1-2 and gapc1 KOs exhibited constitutive autophagy phenotypes in the absence of nutrient starvation. Due to the high sequence conservation between vertebrate and plant cytosolic GAPDH, our experiments focused on cytosolic GAPC1 cellular dynamics using a complemented GAPC1-GFP line. Confocal imaging coupled with an endocytic membrane marker (FM4 64) and endosomal trafficking inhibitors (BFA, Wortmannin) demonstrated cytosolic GAPC1 is localized to the plasma membrane and the endomembrane system, in addition to the cytosol and nucleus. After perception of bacterial flagellin, GAPC1 dynamically responded with a significant increase in size of fluorescent puncta and enhanced nuclear accumulation. Taken together, these results indicate that plant GAPDHs can affect multiple aspects of plant immunity in diverse sub cellular compartments. PMID- 25918878 TI - Evolution of mitral valve procedural volumes in the advent of endovascular treatment options: Experience at an early-adopting center in Germany. AB - OBJECTIVES: Our objectives were to assess the evolution of surgical and endovascular mitral valve procedural volumes and to study utilization and reimbursement effects of transcatheter mitral valve repair (TMVR) at our center and to put these in perspective with the corresponding data at the national level. BACKGROUND: TMVR using the MitraClip system has been available in Germany since 2008 as a complementary treatment option for high-risk or inoperable patients. METHODS: Relevant procedure codes were identified for 2006-2012 and yearly utilization volumes obtained from our center's databases and from the national statistics office. Volumes were analyzed in total, and stratified by treatment approach. Procedure reimbursement at our center was determined for years 2007-2012. RESULTS: At our center, 378 MitraClip procedures were performed from 2008 to 2012. During this period, surgical volumes grew at an average of 10.6% annually (2008: 262; 2012: 392; 49.6% total growth rate). Total surgical and TMVR reimbursement increased from EUR 3.8 million (2007) to EUR 7.9 million (2012). By comparison, mitral valve procedural volumes grew by 56.1% from 2006 to 2012 at the national level, with TMVR constituting 9.1% of 20,328 procedures in 2012. Since the introduction of MitraClip, nationwide surgical procedural volumes grew at an average of 6.3% annually (2008: 14,477; 2012: 18,478; 27.6% total growth rate). CONCLUSIONS: Growth in procedural volumes during 2006-2012 reflects an increasing supply and subsequent demand for mitral valve procedures. The introduction of TMVR has contributed to overall growth, and has not reduced continued growth in surgical volumes. Our center-specific analysis suggests a "halo effect" of an integrated approach to mitral valve disease contributing to additional growth in surgical and overall reimbursement volumes. PMID- 25918879 TI - Biomechanical properties of Achilles tendon in diabetic vs. non-diabetic patients. AB - BACKGROUND/OBJECTIVES: Structural and functional impairments of the Achilles tendon in diabetic patients has the potential to contribute to ulcer formation through altered foot mechanics. This study aimed to examine the biomechanical and histopathological alterations in Achilles tendon specimens from diabetic vs. non diabetic individuals. MATERIALS AND METHODS: 42 Achilles tendon samples obtained from patients treated with below-knee or above-knee amputation for chronic diabetic foot ulcers (n=21) or for non-diabetic conditions (n=21) were included. A tensile test was performed for each tendon and a stress vs. strain graft was obtained to calculate following biomechanical parameters: elasticity (Young modulus), load, stiffness, toughness, energy, strain, elongation and tenacity. Groups were also compared with regard to histopathological findings (inflammatory cell infiltration, collagen organization, and degeneration). RESULTS: Non diabetic tendons exhibited a superior biomechanical profile over diabetic tendons with regard to the following biochemical parameters: elasticity, maximum load, stiffness, toughness, load, energy, strain and elongation at break point, tenacity, and strain at automatic load drop (p<0.05 for all comparisons). Diabetic tendons had mild impairment of collagen organization and focal collagen degeneration, whereas neither diabetic nor non-diabetic tendons had inflammatory cell infiltration. CONCLUSION: The structural and functional alterations associated with diabetes adversely affect the biomechanical properties of the Achilles tendon, potentially acting together with neuropathy and ischemia in the development of diabetic foot ulcers. PMID- 25918880 TI - Revealing the underlying mechanism of diabetic nephropathy viewed by microarray analysis. AB - To explore the molecular mechanisms of diabetic nephropathy (DN) progression and provide the theoretical basis for treating DN, GSE1009 microarray data were downloaded from Gene Expression Omnibus database. Microarray data were obtained from glomeruli isolated from normal kidneys (n=3) and kidneys from patients with DN (n=3). We first screened the differentially expressed genes (DEGs) in kidneys by the Linear Models for Microarray Data package in R. Then the function of DEGs in DN was explored through Gene Ontology (GO) and KEGG pathway enrichment analyses. Critical DEGs for DN progression were investigated by constructing PPI network and mining significant modules. Afterwards, enriched protein domains of modules were analyzed by Interpro and DAVID. At last, the regulatory miRNAs for DEGs were calculated by WebGestalt, and DEGs-miRNAs network was visualized with Cytoscape. A total of 666 DEGs including 384 up- and 282 down-regulated genes were screened out. The up-regulated DEGs were significantly enriched in plasma membrane and signal transmission, and mainly participated in pathways of cytokine cytokine receptor and neuroactive ligand-receptor interaction. The down-regulated DEGs significantly enriched in extracellular region and cytoskeletal protein binding, and mainly participated in ECM-receptor interaction and dilated cardiomyopathy. 2 PPI networks were constructed with confidence score>0.4. One significant module obtained from PPI network for up-regulated DEGs mainly enriched in protein domain of rhodopsin-like G protein-coupled receptors. The down-regulated DEGs were mainly regulated by 10 miRNAs clusters. Together, we constructed a comprehensive molecular network for DN progression and miR-1 and miR-25 might be theoretical targets for DN. PMID- 25918881 TI - Oxidative stress in hypertension: mechanisms and therapeutic opportunities. AB - Hypertension is a highly prevalent disease worldwide. It is known for being one of the most important risk factors for developing cardiovascular disease, including acute myocardial infarction and stroke. Therefore, during the last decades there have been multiple efforts to fully understand the mechanisms underlying hypertension, and then develop effective therapeutic interventions to attenuate the morbidity and mortality associated with this condition. In this regard, oxidative stress has been proposed as a key mechanistic mediator of hypertension, which is an imbalance between oxidant species and the antioxidant defense systems. A large amount of evidence supports the role of vascular wall as a major source of reactive oxygen species. These include the activation of enzymes, such as NADPH oxidase and xanthine oxidase, the uncoupling eNOS and mitochondrial dysfunction, having as a major product the superoxide anion. Among the stimuli that increase the production of oxidative species can be found the action of some vasoactive peptides, such as angiotensin II, endothelin-1 and urotensin II. The oxidative stress state generated leads to a decrease in the biodisponibility of nitric oxide and prostacyclin, key factors in maintaining the vascular tone. The knowledge of the mechanisms mentioned above has allowed generating some therapeutic strategies using antioxidants as antihypertensives with different results. Further studies are required to position antioxidants as key agents in the treatment of hypertension. The current review summarize evidence of the role of oxidative stress in hypertension, emphasizing in therapeutic targets that can be consider in antioxidant therapy. PMID- 25918882 TI - Diffuse miliary nodules in the bronchial mucosa observed by bronchoscopy: sarcoidosis or tuberculosis? AB - BACKGROUND AND AIMS: Miliary tuberculosis is a form of tuberculosis that is characterized by a wide dissemination into lung fields. So far, no report has shown a miliary tuberculosis case where diffuse miliary nodules can be observed in airways by bronchoscopy. Here we reported a case of military tuberculosis that can easily be misdiagnosed as sarcoidosis. METHODS: Report of one case. RESULTS: Bronchoscopy showed the presence of diffuse miliary nodules in the mucosa of bilateral bronchi. Pathological examination revealed non-caseating necrotic granuloma. Mycobacterium tuberculosis was not detected. Our case was extremely difficult to differentiate sarcoidosis from tuberculosis. With patient's safety in mind, we finally administered anti-tuberculosis therapy and obtained satisfactory results. CONCLUSION: To our knowledge, this is the first report of a miliary tuberculosis case where diffuse miliary nodules were observed by bronchoscopy. Therefore, when diffused miliary nodules are observed during bronchoscopy, all of the patient's test results should be thoroughly analyzed to rule out miliary tuberculosis. If the diagnosis is very difficult, anti tuberculosis therapy should be considered first to ensure patient safety. PMID- 25918883 TI - Diversity in host clone performance within a Chinese hamster ovary cell line. AB - Much effort has been expended to improve the capabilities of individual Chinese hamster ovary (CHO) host cell lines to synthesize recombinant therapeutic proteins (rPs). However, given the increasing variety in rP molecular types and formats it may be advantageous to employ a toolbox of CHO host cell lines in biomanufacturing. Such a toolbox would contain a panel of hosts with specific capabilities to synthesize certain molecular types at high volumetric concentrations and with the correct product quality (PQ). In this work, we examine a panel of clonally derived host cell lines isolated from CHOK1SV for the ability to manufacture two model proteins, an IgG4 monoclonal antibody (Mab) and an Fc-fusion protein (etanercept). We show that these host cell lines vary in their relative ability to synthesize these proteins in transient and stable pool production format. Furthermore, we examined the PQ attributes of the stable pool produced Mab and etanercept (by N-glycan ultra performance liquid chromatography (UPLC) and liquid chromatography - tandem mass spectrometry (LC-MS/MS), respectively), and uncovered substantial variation between the host cell lines in Mab N-glycan micro-heterogeneity and etanercept N and O-linked macro heterogeneity. To further investigate the capabilities of these hosts to act as cell factories, we examined the glycosylation pathway gene expression profiles as well as the levels of endoplasmic reticulum (ER) and mitochondria in the untransfected hosts. We uncovered a moderate correlation between ER mass and the volumetric product concentration in transient and stable pool Mab production. This work demonstrates the utility of leveraging diversity within the CHOK1SV pool to identify new host cell lines with different performance characteristics. PMID- 25918884 TI - Heart re-transplantation combined with kidney transplantation. PMID- 25918885 TI - 'Is it the crime of the century?': factors for psychiatrists and service users that influence the long-term prescription of hypnosedatives. AB - Given the longstanding controversy about hypnosedative use, we aimed to investigate the attitudes of prescribing psychiatrists and service users towards long-term use of hypnosedative medication, and their perceptions of barriers to evidence-based nonmedication alternatives. Qualitative data from focus groups in Aotearoa/NZ were analysed thematically. A novel research design involved a service user researcher contributing throughout the research design and process. Service users and psychiatrists met to discuss each other's views, initially separately, and subsequently together. Analysis of the data identified four key themes: the challenge, for both parties, of sleep disturbance among service users with mental health problems; the conceptual and ethical conflicts for service users and psychiatrists in managing this challenge; the significant barriers to service users accessing evidence-based nonmedication alternatives; and the initial sense of disempowerment, shared by both service users and psychiatrists, which was transformed during the research process. Our results raise questions about the relevance of the existing guidelines for this group of service users, highlight the resource and time pressures that discourage participants from embarking on withdrawal regimes and education programmes on alternatives, highlight the lack of knowledge about alternatives and reflect the complex interaction between sleep and mental health problems, which poses a significant dilemma for service users and psychiatrists. PMID- 25918886 TI - The importance of liver lesions and changes to biochemical and coagulation factors in the pathogenesis of RHD. AB - RHDV (rabbit haemorrhagic disease virus) is an etiologic factor of RHD (rabbit haemorrhagic disease), which is highly morbid and mortal viral infection of an adult European rabbit. Although three decades have passed since the first outbreak of rabbit haemorrhagic disease, the pathogenesis of RHD has still not been fully elucidated. It is known that RHDV replicates in the liver within the first hours following infection, causing necrotic and apoptotic cell death of hepatocytes. Anatomopathological changes are also observed in other organs of infected rabbits, i.e. lungs, spleen, kidneys, heart, as well as central nerve system. These changes leading to animals death are predominantly caused by systemic hemorrhagic diathesis with disseminated intravascular coagulation (DIC), appearing most likely as a consequence of liver cell loss through RHDV-induced apoptosis. In this paper, we presented previously described changes in biochemical and coagulation factors in RHDV infection. PMID- 25918887 TI - Influence of charge density and ionic strength on the aggregation process of cellulose nanocrystals in aqueous suspension, as revealed by small-angle neutron scattering. AB - Aggregation of rodlike colloidal particles is investigated here through the aggregation process by either increasing ionic strength or decreasing surface charge density of cellulose nanocrystals (CNCs). The form factor of the nanoparticles is characterized up to the Guinier plateau using small-angle neutron scattering (SANS) extended to very small scattering vector Q. Ionic strength, above the threshold of screening charges, brings aggregative conditions that induced fractal organizations for both charged and uncharged CNCs. These two structures display respective fractal dimensions of 2.1 for charged CNCs at high ionic strength and 2.3 for desulfated CNCs over more than a decade of the scattering vector Q, irrespective of salinity, revealing a denser structuration for neutral particles. This is discussed in the framework of aggregation of rodlike particles with an aspect ratio higher than 8. Furthermore, dilution of the rod gel led to disentanglement of the network of fractal aggregates with a subsequent macroscopic sedimentation of the suspensions, with a characteristic time that depends upon the ionic strength and surface charge density. It revealed a threshold independent of salt content around 2.5 g/L and the metastable out-of equilibrium character of CNC suspensions. PMID- 25918888 TI - Water resources planning for a river basin with recurrent wildfires. AB - Situated in the north of Portugal, the Beca River basin is subject to recurrent wildfires, which produce serious consequences on soil erosion and nutrient exports, namely by deteriorating the water quality in the basin. In the present study, the ECO Lab tool embedded in the Mike Hydro Basin software was used for the evaluation of river water quality, in particular the dissolved concentration of phosphorus in the period 1990-2013. The phosphorus concentrations are influenced by the burned area and the river flow discharge, but the hydrologic conditions prevail: in a wet year (2000, 16.3 km(2) of burned area) with an average flow of 16.4 m(3).s(-1) the maximum phosphorus concentration was as low as 0.02 mg.L(-1), while in a dry year (2005, 24.4 km(2) of burned area) with an average flow of 2 m(3).s(-1) the maximum concentration was as high as 0.57 mg.L( 1). Phosphorus concentrations in the water bodies exceeded the bounds of good ecological status in 2005 and between 2009 and 2012, water for human consumption in 2009 and water for multiple uses in 2010. The River Covas, a right margin tributary of Beca River, is the most appropriate stream as regards the use of water for human consumption, because it presents the biggest water potential with the best water quality. Since wildfires in the basin result essentially from natural causes and climate change forecasts indicate an increase in their frequency and intensity in the near future, forestry measures are proposed to include as a priority the conversion of stands of maritime pine in mixed stands of conifer and hardwood species. PMID- 25918889 TI - Coastal vegetation invasion increases greenhouse gas emission from wetland soils but also increases soil carbon accumulation. AB - Soil properties and soil-atmosphere fluxes of CO2, CH4 and N2O from four coastal wetlands were studied throughout the year, namely, native Kandelia obovata mangrove forest vs. exotic Sonneratia apetala mangrove forest, and native Cyperus malaccensis salt marsh vs. exotic Spartina alterniflora salt marsh. Soils of the four wetlands were all net sources of greenhouse gases while Sonneratia forest contributed the most with a total soil-atmosphere CO2-equivalent flux of 137.27 mg CO2 m(-2) h(-1), which is 69.23%, 99.75% and 44.56% higher than that of Kandelia, Cyperus and Spartina, respectively. The high underground biomass and distinctive root structure of Sonneratia might be responsible for its high greenhouse gas emission from the soil. Soils in Spartina marsh emitted the second largest amount of total greenhouse gases but it ranked first in emitting trace greenhouse gases. Annual average CH4 and N2O fluxes from Spartina soil were 13.77 and 1.14 MUmol m(-2) h(-1), respectively, which are 2.08 and 1.46 times that of Kandelia, 1.03 and 1.15 times of Sonneratia, and 1.74 and 1.02 times of Cyperus, respectively. Spartina has longer growing season and higher productivity than native marshes which might increase greenhouse gas emission in cold seasons. Exotic wetland soils had higher carbon stock as compared to their respective native counterparts but their carbon stocks were offset by a larger proportion because of their higher greenhouse gas emissions. Annual total soil-atmosphere fluxes of greenhouse gases reduced soil carbon burial benefits by 8.1%, 9.5%, 6.4% and 7.2% for Kandelia, Sonneratia, Cyperus and Spartina, respectively, which narrowed down the gaps in net soil carbon stock between native and exotic wetlands. The results indicated that the invasion of exotic wetland plants might convert local coastal soils into a considerable atmospheric source of greenhouse gases although they at the same time increase soil carbon accumulation. PMID- 25918890 TI - Lysimeter monitoring as assessment of the potential for revegetation to manage former iron industry settling ponds. AB - To assess the impact of metal-rich brownfields on groundwater quality, the fluxes in a Technosol developed on a former iron industry settling pond were studied. Intact soil monoliths (1 m(2) * 2 m) were extracted and placed in lysimeters. Dynamics of fluxes of metals and solutes under varying vegetation cover were monitored over the course of four years. Soil hydraulic properties were also determined. Results showed that the Technosol has a high retention capacity for water and metals, in relation to its mineral components and resulting chemical and physical properties. As a consequence, metal fluxes were limited. However, soluble compounds, such as SO4(2-), were found at significant concentrations in the leachates. The presence of a dense and deeply-rooted vegetation cover limited water- and solute-fluxes by increasing evapotranspiration and water uptake, thereby reducing the risks of transfer of potentially toxic compounds to local groundwater sources. However, vegetation development may induce changes in soil chemical (e.g. pH, redox potential) and physical properties (e.g. structure), favoring metal mobilization and transport. Revegetation is a valuable management solution for former iron industry settling ponds, provided vegetation does not change soil physico-chemical conditions in the long term. Monitored natural attenuation is required. PMID- 25918891 TI - Delivery of unprecedented amounts of perfluoroalkyl substances towards the deep sea. AB - The finding of perfluoroalkyl substances (PFASs) in particles sinking to the deep northwestern Mediterranean Sea confirms the role of the latter as ballast for the transfer of pollutants to the deep sea. The transfer of particulate matter down to the deep is enhanced during atmosphere-driven, high-energy physical oceanographic processes like dense shelf water cascading (DSWC), which is caused by winter surface heat losses and evaporation. Here we present data from samples collected during winter 2012, when dense shelf water formation and subsequent cascading triggered the flushing of large amounts of PFASs through a submarine canyon to depths in excess of 1000 m. The finding of quantifiable concentrations of long-chain PFOA, PFOS and PFNA substances and significantly high concentrations of the short-chain substances PFHxA and PFBA indicates that these compounds, sorbed onto particulate matter, are quickly and directly transferred to the ocean's interior, thus highlighting the role of DSWC in removing those pollutants from the coastal ocean. Eventually, uncertainties about our results arising from the limited number of samples available are counterbalanced by their intrinsic value as intense DSWC events, like the one in 2012, occur only every 5 7 years in the study area, which seriously restricts sampling opportunities. Our results add PFASs to the list of persistent organic pollutants like polychlorinated biphenyls, chlorobenzenes or polycyclic aromatic hydrocarbons known to be conveyed to the deep marine environment. PMID- 25918892 TI - Seasonal variation in the input of atmospheric selenium to northwestern Greenland snow. AB - Oxygen isotope ratio (delta(18)O) and concentrations of Al, Na(+), methanesulfonic acid (MSA), SO4(2-), and selenium (Se) in a continuous series of 70 snow samples from a 3.2-m snow pit at a site in northwestern Greenland were determined using ultraclean procedures. Well-defined depth profiles of delta(18)O, Al, and sea-salt-Na(+) allowed the determination of chronology of the snow pit that spanned approximately 6 years from spring 2003 to summer 2009. Se concentrations were at a low pg/g level, ranging from 7.2 to 45 pg/g, and exhibited high variability with generally higher values during winter and spring and lower values during summer and fall. Very high crustal enrichment factors (EFc) of Se averaging approximately 26,600 for the entire time period indicate a small contribution from crust dust. High Se/MSA ratios are generally observed in the winter and spring snow layers, in which the Se concentrations were relatively high (>20 pg/g). This suggests that a significant component of the Se present in the snow layers is of anthropogenic origin. During the summer season, however, high EFc values are accompanied with low Se/MSA, indicating an increased contribution of marine biogenic sources. Significant correlations between Se, Al, and non-sea-salt SO4(2-) highlight that significant inputs of Se to the snow are likely controlled by the seasonality in the transport efficiency of anthropogenic Se from the source regions to the site. Based on the seasonal changes in Se concentrations, Se/MSA, and Se/S ratios observed in the samples, the input of anthropogenic Se to the site appears to be governed by the long-range transportation of Se emitted from coal combustion in East Asian countries, especially in China. PMID- 25918893 TI - Spatial variability of soil carbon stock in the Urucu river basin, Central Amazon Brazil. AB - The Amazon Forest plays a major role in C sequestration and release. However, few regional estimates of soil organic carbon (SOC) stock in this ecoregion exist. One of the barriers to improve SOC estimates is the lack of recent soil data at high spatial resolution, which hampers the application of new methods for mapping SOC stock. The aims of this work were: (i) to quantify SOC stock under undisturbed vegetation for the 0-30 and the 0-100 cm under Amazon Forest; (ii) to correlate the SOC stock with soil mapping units and relief attributes and (iii) to evaluate three geostatistical techniques to generate maps of SOC stock (ordinary, isotopic and heterotopic cokriging). The study site is located in the Central region of Amazon State, Brazil. The soil survey covered the study site that has an area of 80 km(2) and resulted in a 1:10,000 soil map. It consisted of 315 field observations (96 complete soil profiles and 219 boreholes). SOC stock was calculated by summing C stocks by horizon, determined as a product of BD, SOC and the horizon thickness. For each one of the 315 soil observations, relief attributes were derived from a topographic map to understand SOC dynamics. The SOC stocks across 30 and 100 cm soil depth were 3.28 and 7.32 kg C m(-2), respectively, which is, 34 and 16%, lower than other studies. The SOC stock is higher in soils developed in relief forms exhibiting well-drained soils, which are covered by Upland Dense Tropical Rainforest. Only SOC stock in the upper 100 cm exhibited spatial dependence allowing the generation of spatial variability maps based on spatial (co)-regionalization. The CTI was inversely correlated with SOC stock and was the only auxiliary variable feasible to be used in cokriging interpolation. The heterotopic cokriging presented the best performance for mapping SOC stock. PMID- 25918894 TI - Temporal trends in the levels of polychlorinated dioxins, -furans, -biphenyls and polybrominated diethyl ethers in bank voles in Northern Finland. AB - Dioxin-like chemicals and brominated flame retardants are ubiquitous in the environment, despite the introduction of international prohibitions and restrictions. These chemicals do not remain in the vicinity of their source, instead they can be transported over long distances, in fact even to pristine areas in the northern latitudes. However, there have been rather few time series experiments monitoring the trends in the levels of chlorinated and brominated forms of these chemicals in the environment. In this study, the concentrations of polychlorinated dibenzo-p-dioxins and -furans (PCDDs/Fs), polychlorinated biphenyls (PCBs) and polybrominated diethyl ethers (PBDEs) were measured in the liver and muscle of bank voles (Myodes glareolus) caught in a remote area in Finnish Lapland during 1986-2007. Five time points were selected: years 1986, 1992, 1998, 2003 and 2007. The levels of PCDDs/Fs and PCBs declined from 1986 until 2003 in both females and males, but tended to increase again in 2007. The peak levels of the most abundant PBDE congeners (PBDEs 47, 99, 100 and 153) were measured in 1998 and 2003. These results reveal that the levels of dioxin-like chemicals remain high also in rural areas in Lapland, whereas the concentrations of brominated flame retardants decreased and follow the current restriction prohibitions. PMID- 25918895 TI - Source identification of fine-grained suspended sediment in the Kharaa River basin, northern Mongolia. AB - Fine sediment inputs into river systems can be a major source of nutrients and heavy metals and have a strong impact on water quality and ecosystem functions of rivers and lakes, including those in semiarid regions. However, little is known to date about the spatial distribution of sediment sources in most large scale river basins in Central Asia. Accordingly, a sediment source fingerprinting technique was used to assess the spatial sources of fine-grained (<10 MUm) sediment in the 15 000 km(2) Kharaa River basin in northern Mongolia. Variation in geochemical composition (e.g. in Ti, Sn, Mo, Mn, As, Sr, B, U, Ca and Sb) was used for sediment source discrimination with geochemical composite fingerprints based on Genetic Algorithm (GA)-driven Discriminant Function Analysis, the Kruskal-Wallis H-test and Principal Component Analysis. All composite fingerprints yielded a satisfactory GOF (>0.97) and were subsequently used for numerical mass balance modelling with uncertainty analysis. The contributions of the individual sub-catchment spatial sediment sources varied from 6.4% (the headwater sub-catchment of Sugnugur Gol) to 36.2% (the Kharaa II sub-catchment in the middle reaches of the study basin), generally showing higher contributions from the sub-catchments in the middle, rather than the upstream, portions of the study area. The importance of river bank erosion is shown to increase from upstream to midstream tributaries. The source tracing procedure provides results in reasonable accordance with previous findings in the study region and demonstrates the applicability and associated uncertainties of the approach for fine-grained sediment source investigation in large scale semi-arid catchments. PMID- 25918896 TI - Mitigation strategies in the agro-food sector: The anaerobic digestion of tomato puree by-products. An Italian case study. AB - Tomato processing involves a significant production of residues, mainly constituted by discarded tomatoes, skins, seeds and pulp. Often, these residues are not valorized and represent an added cost for manufacturing companies because of disposal processes, with environmental issues due to the difficult management. The exploitation of these residual materials results complex as their availability is mainly concentrated in few months. A possible solution is the production of biogas employed in a Combine Heat and Power engine for energy production, in line with the 2020 targets of European Union in terms of promotion of energy from renewable resources and greenhouse gas emission reduction. The tomato by-product utilization for energy production as a strategy to reduce the environmental load of tomato puree was evaluated by means of Life Cycle Assessment. Two scenarios were considered: Baseline Scenario - tomato by-products are sent back to the tomato fields as organic fertilizers; Alternative Scenario - tomato by-products are employed in a nearby biogas plant for energy production. Methane production of tomato by-products was assessed by means of specific laboratory tests. The comparison between the two scenarios highlighted reductions for all the impact categories with the Alternative Scenario. The most important reductions are related to particulate matter (-5.3%), climate change (-6.4%) and ozone depletion (-13.4%). Although small, the reduction of the environmental impact cannot be neglected; for example for climate change, the anaerobic digestion of by-products allows a saving of GHG emissions that, over the whole year, is equal to 1.567 tons of CO2 eq. The results of this study could be up scaled to the food industries with high heat demand producing considerable amounts of fermentable by-products employable as feedstock for biogas production. PMID- 25918897 TI - Surface water sewer misconnections in England and Wales: Pollution sources and impacts. AB - In urban areas served by separate sewerage consisting of separate pipe systems it is not uncommon for misconnections to be made either accidentally or deliberately, whereby the wrong effluent is connected to the wrong sewer. The main focus of this problem has been on in-household appliances that are wrongly connected to separate surface water sewers, potentially leading to pollution of receiving waters and non-compliance with statutory water quality standards. This paper examines the available evidence to evaluate the potential scale, severity and cost of the problem in England and Wales in comparison to that reported from investigations in the United States. The particular difficulties associated with distinguishing specific sewage sources in the wastewater "cocktail" discharged at polluted surface water outfalls are reviewed. The deficiencies of existing legislation and enforcing compliance with respect to misconnections are also discussed and the pollution potential resulting from domestic misconnections is explored based on sampled data. PMID- 25918898 TI - Characteristics and oxidative stress on rats and traffic policemen of ambient fine particulate matter from Shenyang. AB - Fine particulate matter (PM2.5) pollution is becoming serious in China. This study aimed to investigate the impact of PM2.5 on DNA damage in Shenyang city. The concentration and composition of PM2.5 in traffic policemen's working sites including fields and indoor offices were obtained. Blood samples of field and office policemen were collected to detect DNA damage by Comet assay. Rats were used to further analyzing the oxidative DNA damage. The average concentration of PM2.5 in exposed group was significantly higher than that in control group. Composition analysis revealed that toxic heavy metal and polycyclic aromatic hydrocarbon substances were main elements of this PM2.5. DNA damage in field policemen was significantly higher than those in non-field group. Moreover, animal studies confirmed the oxidative DNA damage induced by PM2.5. Taken together, high DNA damages are found in the Shenyang traffic policemen and rats exposed to high level of airborne PM2.5. PMID- 25918899 TI - Folic Acid and Trastuzumab Functionalized Redox Responsive Polymersomes for Intracellular Doxorubicin Delivery in Breast Cancer. AB - Redox responsive biodegradable polymersomes comprising of poly(ethylene glycol) polylactic acid-poly(ethylene glycol) [PEG-s-s-PLA-s-s-PLA-s-s-PEG] triblock copolymer with multiple disulfide linkages were developed to improve intracellular delivery and to enhance chemotherapeutic efficacy of doxorubicin in breast cancer with minimal cardiotoxicity. Folic acid and trastuzumab functionalized monodispersed polymersomes of size ~150 nm were prepared by nanoprecipitation method while achieving enhanced doxorubicin loading of ~32% in the polymersomes. Multiple redox responsive disulfide linkages were incorporated in the polymer in order to achieve complete disintegration of polymersomes in redox rich environment of cancer cells resulting in enhanced doxorubicin release as observed in in vitro release studies, where ~90% doxorubicin release was achieved in pH 5.0 in the presence of 10 mM glutathione (GSH) as compared to ~20% drug release in pH 7.4. Folic acid and trastuzumab mediated active targeting resulted in improved cellular uptake and enhanced apoptosis in in vitro studies in breast cancer cell lines. In vivo studies in Ehrlich ascites tumor bearing Swiss albino mice showed enhanced antitumor efficacy and minimal cardiotoxicity of polymersomes with ~90% tumor regression as compared to ~38% tumor regression observed with free doxorubicin. The results highlight therapeutic potential of the polymersomes as doxorubicin delivery nanocarrier in breast cancer therapy with its superior antitumor efficacy and minimal cardiotoxicity. PMID- 25918901 TI - Periodontal disease in a remote Asian population: association between clinical and microbiological parameters. AB - OBJECTIVE: The aim was to clinically and microbiologically describe the periodontal conditions in a remote adult Asian population with poor oral hygiene. METHODS: The subjects were 30-60-year-old adults of Karen Hill tribes with no access to dental care. Eighty-six subjects were selected randomly. Clinical registrations included number of remaining teeth, plaque index (PlI), bleeding on probing (BoP), clinical attachment loss (CAL), and probing pocket depth (PPD). Subgingival plaque samples were collected and analyzed with the checkerboard method. RESULTS: Subjects of the study group had mean number of remaining teeth of 26.5 despite the abundant plaque and a high bleeding score. Severe periodontitis (CAL >= 7 mm) was recorded in 12.9% of the youngest age group (30 39 years) while it was significantly higher (52%) in the middle group (40-49 years) and (60%) in the eldest age group (50-60 years). Pathological pocketing (PPD >= 7 mm) was significantly lower in all age groups. Age, betel chewing, and a microbiological cluster including at least one of Prevotella tannerae, Filifactor alocis and Porphyromonas endodontalis significantly correlated with the severity of periodontal disease. CONCLUSION: Age, betel chewing, and a new bacterial complex other than the "red complex" correlated to periodontal breakdown in this remote adult Asian population. PMID- 25918902 TI - ECD kidney transplantation outcomes are improved when matching donors to recipients using a novel creatinine clearance match ratio (CCMR). AB - Improved outcomes have been associated with various methods of size matching between expanded criteria (ECD) donors and recipients. A novel method for improved functional based matching was developed utilizing manipulation of Cockcroft-Gault estimated creatinine clearances for donor and recipient. We hypothesized that optimal clearance-based matches would have superior outcomes for both immediate graft function and long-term graft survival. For the analysis, recipients of ECD kidneys in the Scientific Registry of Transplant Recipients (SRTR) transplanted between October 1, 1987 and August 31, 2011 were included. Univariate and multivariate analyses predicted the hazard ratio of graft failure and the odds ratio of requiring dialysis within the first week. A total of 25,640 ECD kidney transplants were analyzed. On multivariate analysis, higher creatinine clearance match ratio (CCMR) was associated with increased graft failure and odds of requiring dialysis within the first week (comparing highest ratio quintile versus lowest ratio quintile: HR 1.43, p < 0.001; OR 2.08, p < 0.001). This study suggests that ECD kidneys have improved outcomes when the recipient/donor CCMR is optimized. PMID- 25918903 TI - Hexaphenylbenzene-Based, pi-Conjugated Snowflake-Shaped Luminophores: Tunable Aggregation-Induced Emission Effect and Piezofluorochromism. AB - In this work, two rigid, multiple tetraphenylethene (TPE)-substituted, pi conjugated, snowflake-shaped luminophores BT and BPT were facilely synthesized by using a 6-fold Suzuki coupling reaction. These molecules are constructed based on the nonplanar structure of propeller-shaped hexaphenylbenzene (HPB) or benzene as core groups and TPE as end groups. As a result, they reserve the intrinsic aggregation-induced emission (AIE) property of the TPE moiety. Meanwhile, both fluorescence quantum yield and piezochromic behavior in the solid state can be tuned or switched by inserting the phenyl bridges through changing the twisting conformation. The more extended structure BPT showed a much stronger AIE effect and higher PhiF,f in the solid state in comparison with that of BT. Furthermore, an excellent optical waveguide application of these molecules was achieved. However, the revisable piezofluorochromic behavior has only appeared when BT was ground using a pestle and treated with solvent. PMID- 25918904 TI - Vitreous and aqueous concentrations of brimonidine following topical application of brimonidine tartrate 0.1% ophthalmic solution in humans. AB - PURPOSE: To determine the vitreous and aqueous concentrations of brimonidine after topical application of the ophthalmic solution 0.1%. METHODS: The prospective observational case series included patients with an idiopathic epiretinal membrane or macular hole who were scheduled for a pars plana vitrectomy. Brimonidine tartrate ophthalmic solution 0.1% was topically administered twice daily for 1 week preoperatively. Vitreous and aqueous humor was collected before vitrectomy, and then, the brimonidine concentration was measured with liquid chromatography tandem spectrometry (LC/MS/MS). RESULTS: Twenty-four patients (19 phakic eyes and 5 pseudophakic eyes) were enrolled. The mean concentrations in the aqueous humor and vitreous were 336.0 +/- 276.2 and 4.8 +/- 3.2 nM, respectively. A significant relationship was observed between the vitreous and aqueous samples (P = 0.034, R(2) = 0.22). Nineteen (79%) of the 24 eyes showed more than 2 nM of brimonidine tartrate concentration in the vitreous. In the phakic eyes, the mean concentration of brimonidine in the vitreous was 4.9 +/- 3.3 nM, while the mean concentration in the pseudophakic eyes was 4.1 +/- 2.4 nM, demonstrating no significant difference between pseudophakic and phakic eyes (P = 0.59). CONCLUSIONS: After 1 week of dosing, in most of the patients who topically received brimonidine tartrate 0.1%, the concentration in the vitreous of the molecule was above 2 nM, which is known to activate neuroprotective alpha 2 receptors in animal retina. The drug penetration into the vitreous seems to be independent of lens status. PMID- 25918905 TI - AAFreqCoil: a new classifier to distinguish parallel dimeric and trimeric coiled coils. AB - Coiled coils are characteristic rope-like protein structures, constituted by one or more heptad repeats. Native coiled-coil structures play important roles in various biological processes, while the designed ones are widely employed in medicine and industry. To date, two major oligomeric states (i.e. dimeric and trimeric states) of a coiled-coil structure have been observed, plausibly exerting different biological functions. Therefore, exploration of the relationship between heptad repeat sequences and coiled coil structures is highly important. In this paper, we develop a new method named AAFreqCoil to classify parallel dimeric and trimeric coiled coils. Our method demonstrated its competitive performance when benchmarked based on 10-fold cross validation and jackknife cross validation. Meanwhile, the rules that can explicitly explain the prediction results of the test coiled coil can be extracted from the AAFreqCoil model for a better explanation of user predictions. A web server and stand-alone program implementing the AAFreqCoil algorithm are freely available at . PMID- 25918906 TI - The impact of fatigue on latent print examinations as revealed by behavioral and eye gaze testing. AB - Eye tracking and behavioral methods were used to assess the effects of fatigue on performance in latent print examiners. Eye gaze was measured both before and after a fatiguing exercise involving fine-grained examination decisions. The eye tracking tasks used similar images, often laterally reversed versions of previously viewed prints, which holds image detail constant while minimizing prior recognition. These methods, as well as a within-subject design with fine grained analyses of the eye gaze data, allow fairly strong conclusions despite a relatively small subject population. Consistent with the effects of fatigue on practitioners in other fields such as radiology, behavioral performance declined with fatigue, and the eye gaze statistics suggested a smaller working memory capacity. Participants also terminated the search/examination process sooner when fatigued. However, fatigue did not produce changes in inter-examiner consistency as measured by the Earth Mover Metric. Implications for practice are discussed. PMID- 25918907 TI - Response to "Nasal bone length: prenasal thickness ratio: a strong 2D ultrasound marker for Down syndrome". PMID- 25918908 TI - Why do mothers of young infants choose to formula feed in China? Perceptions of mothers and hospital staff. AB - In China the exclusive breastfeeding rate remains low and infant formula is widely used. This study aimed to elicit and compare mothers' and hospital staff perceptions of the reasons that shaped mothers' decision to formula feed. In depth interviews with 50 mothers, and four focus group discussions with 33 hospital staff, were conducted in Hangzhou and Shenzhen in November 2014. Responses given by the mothers and hospital staff showed a number of commonalities. The perception of "insufficient breast milk" was cited by the majority of women (n = 37, 74%) as the reason for formula feeding. Mothers' confidence in breastfeeding appears to be further reduced by maternal mothers or mothers-in-law's and "confinement ladies" misconceptions about infant feeding. Inadequate breastfeeding facilities and limited flexibility at their workplace was another common reason given for switching to formula feeding. A substantial proportion of mothers (n = 27, 54%) lacked an understanding of the health benefits of breastfeeding. Antenatal education on breastfeeding benefits for expectant mothers and their families is recommended. Moreover, mothers should be provided with breastfeeding support while in hospital and be encouraged to seek professional assistance to deal with breastfeeding problems after discharge. Employers should also make work environments more breastfeeding-friendly. PMID- 25918909 TI - Common features of opportunistic premise plumbing pathogens. AB - Recently it has been estimated that the annual cost of diseases caused by the waterborne pathogens Legionella pneumonia, Mycobacterium avium, and Pseudomonas aeruginosa is $500 million. For the period 2001-2012, the estimated cost of hospital admissions for nontuberculous mycobacterial pulmonary disease, the majority caused by M. avium, was almost $1 billion. These three waterborne opportunistic pathogens are normal inhabitants of drinking water--not contaminants--that share a number of key characteristics that predispose them to survival, persistence, and growth in drinking water distribution systems and premise plumbing. Herein, I list and describe these shared characteristics that include: disinfectant-resistance, biofilm-formation, growth in amoebae, growth at low organic carbon concentrations (oligotrophic), and growth under conditions of stagnation. This review is intended to increase awareness of OPPPs, identify emerging OPPPs, and challenge the drinking water industry to develop novel approaches toward their control. PMID- 25918910 TI - Community, state, and federal approaches to cumulative risk assessment: challenges and opportunities for integration. AB - Community, state, and federal approaches to conventional and cumulative risk assessment (CRA) were described and compared to assess similarities and differences, and develop recommendations for a consistent CRA approach, acceptable across each level as a rigorous scientific methodology, including partnership formation and solution development as necessary practices. Community, state, and federal examples were described and then summarized based on their adherence to CRA principles of: (1) planning, scoping, and problem formulation; (2) risk analysis and ranking, and (3) risk characterization, interpretation, and management. While each application shared the common goal of protecting human health and the environment, they adopted different approaches to achieve this. For a specific project-level analysis of a particular place or instance, this may be acceptable, but to ensure long-term applicability and transferability to other projects, recommendations for developing a consistent approach to CRA are provided. This approach would draw from best practices, risk assessment and decision analysis sciences, and historical lessons learned to provide results in an understandable and accepted manner by all entities. This approach is intended to provide a common ground around which to develop CRA methods and approaches that can be followed at all levels. PMID- 25918911 TI - A comparison of direct and two-stage transportation of patients to hospital in Poland. AB - BACKGROUND: The rapid international expansion of telemedicine reflects the growth of technological innovations. This technological advancement is transforming the way in which patients can receive health care. MATERIALS AND METHODS: The study was conducted in Poland, at the Department of Cardiology of the Regional Hospital of Louis Rydygier in Torun. The researchers analyzed the delay in the treatment of patients with acute coronary syndrome. The study was conducted as a survey and examined 67 consecutively admitted patients treated invasively in a two-stage transport system. Data were analyzed statistically. RESULTS: Two-stage transportation does not meet the timeframe guidelines for the treatment of patients with acute myocardial infarction. Intervals for the analyzed group of patients were statistically significant (p < 0.0001). CONCLUSIONS: Direct transportation of the patient to a reference center with interventional cardiology laboratory has a significant impact on reducing in-hospital delay in case of patients with acute coronary syndrome. PERSPECTIVES: This article presents the results of two-stage transportation of the patient with acute coronary syndrome. This measure could help clinicians who seek to assess time needed for intervention. It also shows how time from the beginning of pain in chest is important and may contribute to patient disability, death or well-being. PMID- 25918912 TI - A concurrent exposure to arsenic and fluoride from drinking water in Chihuahua, Mexico. AB - Inorganic arsenic (iAs) and fluoride (F-) are naturally occurring drinking water contaminants. However, co-exposure to these contaminants and its effects on human health are understudied. The goal of this study was examined exposures to iAs and F- in Chihuahua, Mexico, where exposure to iAs in drinking water has been associated with adverse health effects. All 1119 eligible Chihuahua residents (>18 years) provided a sample of drinking water and spot urine samples. iAs and F concentrations in water samples ranged from 0.1 to 419.8 ug As/L and from 0.05 to 11.8 mg F-/L. Urinary arsenic (U-tAs) and urinary F- (U-F-) levels ranged from 0.5 to 467.9 ng As/mL and from 0.1 to 14.4 ug F-/mL. A strong positive correlation was found between iAs and F- concentrations in drinking water (rs = 0.741). Similarly, U-tAs levels correlated positively with U-F- concentrations (rs = 0.633). These results show that Chihuahua residents exposed to high iAs concentrations in drinking water are also exposed to high levels of F-, raising questions about possible contribution of F- exposure to the adverse effects that have so far been attributed only to iAs exposure. Thus, investigation of possible interactions between iAs and F- exposures and its related health risks deserves immediate attention. PMID- 25918913 TI - Lead isotope characterization of petroleum fuels in Taipei, Taiwan. AB - Leaded gasoline in Taiwan was gradually phased out from 1983 to 2000. However, it is unclear whether unleaded gasoline still contributes to atmospheric lead (Pb) exposure in urban areas. In this study, Pb isotopic compositions of unleaded gasolines, with octane numbers of 92, 95, 98, and diesel from two local suppliers in Taipei were determined by multi-collector inductively coupled plasma mass spectrometry with a two-sigma uncertainty of +/- 0.02 %. Lead isotopic ratios of vehicle exhaust (208Pb/207Pb: 2.427, 206Pb/207Pb: 1.148, as estimated from petroleum fuels) overlap with the reported aerosol data. This agreement indicates that local unleaded petroleum fuels, containing 10-45 ng.Pb.g-1, are merely one contributor among various sources to urban aerosol Pb. Additionally, the distinction between the products of the two companies is statistically significant in their individual 208Pb/206Pb ratios (p-value < 0.001, t test). Lead isotopic characterization appears to be applicable as a "fingerprinting" tool for tracing the sources of Pb pollution. PMID- 25918915 TI - Maternal hypoglycemia on 50 g glucose challenge test: outcomes are influenced by fetal gender. AB - OBJECTIVE: To assess the perinatal outcomes in pregnant women with maternal hypoglycemia following a second trimester oral glucose challenge test (GCT). MATERIALS AND METHODS: This retrospective case control study consisted of 2091 pregnant women with hypoglycemia (glucose levels >88 mg/dL 1 h following a 50 g GCT in the second trimester of pregnancy) and a control group of 2091 pregnant women with a GCT result between 88 and 130 mg/dL. Perinatal and neonatal characteristics obtained from electronic medical records were compared between groups. RESULTS: The rates of pregnancy complications were similar in both groups, with the exception of a lower incidence of polyhydramnios and a higher rate of deliveries before the 34th week of gestation in patients with hypoglycemia (0.5% vs. 1.1%, P=0.016 vs. 2.6% vs. 1.7%, P=0.033); respectively. Neonates born to mothers with hypoglycemia had significantly less birth trauma (0.3% vs. 0.9%, P=0.027) and neonatal hypoglycemia. When the data for male and female infants were analyzed separately, male infants had a 1.5-fold (95% CI: 1.05-2.18) increased chance of being small for gestational age (SGA), whereas the risk for female infants did not increase (OR: 0.79, 95% CI: 0.56-1.11). CONCLUSION: A low maternal plasma glucose level on the GCT is associated with favorable outcomes, such as decreased rates of birth trauma and neonatal hypoglycemia. In addition, male infants have a higher risk of being SGA than female infants when maternal GCT results were <88 mg/dL. PMID- 25918916 TI - Early pregnancy serum neopterin concentrations predict spontaneous preterm birth in asymptomatic pregnant women. AB - OBJECTIVE: To investigate if early pregnancy serum neopterin concentrations (EPSN) could predict spontaneous preterm birth (SPB). METHODS: EPSN was measured in 92 sera collected from 46 pregnant women with birth at term and 40 sera from 20 pregnant women with preterm birth. Two sera were collected for each case: in the first and early second trimester. RESULTS: EPSN concentrations correlate with gestational age (rho=0.275, P=0.001), a correlation which was present in both groups: term and preterm birth. EPSN were higher in pregnancies with SPB compared with normal pregnancies (6.27+/-1.03 vs. 6.04+/-0.15, P=0.039). Patients with SPB showed a considerable increase of EPSN in the second trimester compared with patients with birth at term (7.30+/-1.53 vs. 6.16+/-0.23, P=0.043). A sharper increase was found in the group with SPB before 32 weeks of pregnancy (wp) (9.83+/-4.36 vs. 6.16+/-0.23, P=0.016). Pregnant women with an early second trimester serum neopterin value of above 8 nmol/L are associated with a risk of SPB before 32 wp (odds ratio=14.4, P=0.01) and of SPB before 34 wp (odds ratio=3.6, P=0.05), respectively. CONCLUSIONS: EPSN increases with the gestational age and predicts SPB in asymptomatic pregnant women. PMID- 25918914 TI - Clinical chorioamnionitis at term III: how well do clinical criteria perform in the identification of proven intra-amniotic infection? AB - OBJECTIVE: The diagnosis of clinical chorioamnionitis is based on a combination of signs [fever, maternal or fetal tachycardia, foul-smelling amniotic fluid (AF), uterine tenderness and maternal leukocytosis]. Bacterial infections within the amniotic cavity are considered the most frequent cause of clinical chorioamnionitis and an indication for antibiotic administration to reduce maternal and neonatal morbidity. Recent studies show that only 54% of patients with the diagnosis of clinical chorioamnionitis at term have bacteria in the AF and evidence of intra-amniotic inflammation. The objective of this study was to examine the performance of the clinical criteria for the diagnosis of chorioamnionitis to identify patients with microbial-associated intra-amniotic inflammation (also termed intra-amniotic infection). MATERIALS AND METHODS: This retrospective cross-sectional study included 45 patients with the diagnosis of clinical chorioamnionitis at term, whose AF underwent analysis for: 1) the presence of microorganisms using both cultivation and molecular biologic techniques [polymerase chain reaction (PCR) with broad primers], and 2) interleukin (IL)-6 concentrations by enzyme-linked immunosorbent assay. The diagnostic performance (sensitivity, specificity, accuracy, and likelihood ratios) of each clinical sign and their combination to identify clinical chorioamnionitis were determined using microbial-associated intra-amniotic inflammation [presence of microorganisms in the AF using cultivation or molecular techniques and elevated AF IL-6 concentrations (>=2.6 ng/mL)] as the gold standard. RESULTS: The accuracy of each clinical sign for the identification of microbial-associated intra-amniotic inflammation (intra-amniotic infection) ranged between 46.7% and 57.8%. The combination of fever with three or more clinical criteria did not substantially improve diagnostic accuracy. CONCLUSION: In the presence of a fever during labor at term, signs used to diagnose clinical chorioamnionitis do not accurately identify the patient with proven intra amniotic infection (i.e., those with microorganisms detected by culture or molecular microbiologic techniques and an associated intra-amniotic inflammatory response). PMID- 25918917 TI - Hepatoprotective and antioxidant activity of hydromethanolic extract of Daniella oliveri leaves in carbon tetrachloride-induced hepatotoxicity in rats. AB - BACKGROUND: Daniella oliveri is a deciduous plant that is commonly found in savanna and open grassland. Various parts of the plant is used by herbalist in the management of different ailments. The present study aims at investigating the hepatoprotective and antioxidant activity of the methanolic extract of D. oliveri leaves. METHODS: The hepatoprotective activity was investigated using carbon tetrachloride (CCl4)-induced hepatotoxicity in albino rats. The antioxidant activity was determined using both in vitro (2, 2-diphenyl-1-picrylhydrazine photometric assay) and in vivo (malondialdehyde and catalase level assay) models. RESULTS: The pretreatment with extract (100, 200, and 400 mg/kg) and silymarin (100 mg/kg) produced a significant (p<0.05) dose-dependent increase in hepatoprotective activity when compared with the negative control group. The extract (25-400 MUg/mL concentration) produced a concentration-dependent increase in antioxidant activity in 2, 2-diphenyl-1-picrylhydrazine (DPPH) photometric assay. The IC50 of the extract in DPPH photometric assay was 400 MUg/mL concentrations. The extract and silymarin showed a significant (p<0.05) dose dependent increase in catalase level in treated rats when compared with the negative control group. Also, the extract and silymarin produced a significant (p<0.05) dose-dependent decrease in malondialdehyde level in treated rats when compared with the negative control group. CONCLUSIONS: The results of the study suggest that D. oliveri leaves has a potent hepatoprotective activity that may be linked to its antioxidant activities and validates its use in the traditional management of liver disorders. PMID- 25918918 TI - Protective effects of blackberry and quercetin on sodium fluoride-induced oxidative stress and histological changes in the hepatic, renal, testis and brain tissue of male rat. AB - BACKGROUND: Sodium fluoride (NaF) intoxication is associated with oxidative stress and altered antioxidant defense mechanism. The present study was carried out to evaluate the potential protective role of blackberry and quercetin (Q) against NaF-induced oxidative stress and histological changes in liver, kidney, testis and brain tissues of rats. METHODS: The rats were allocated evenly to seven groups. The first group was maintained as the control, whereas groups 2, 3, 4, 5, 6 and 7 were administered blackberry juice (BBJ), Q, NaF, BBJ+NaF, Q+NaF and BBJ+Q+NaF, respectively, for a period of 30 days. RESULTS AND CONCLUSIONS: NaF caused an elevation in lipid peroxidation level paralleled with significant decline in glutathione peroxidase, glutathione reductase, glutathione S transferase, superoxide dismutase and catalase activities as well as the total antioxidant activity in liver, kidney, testes and brain. Some histopathological changes were detected in all tested tissues of the NaF treated group. Q and BBJ had successfully maintained normal histological architecture and mitigated the induction of oxidative stress caused by NaF. Q effectively reduced the elevation in thiobarbituric acid reactive substances level and restored the activities of antioxidant enzymes in liver, kidney, testis and brain. Less histopathological changes were observed in Q+NaF and BBJ+NaF treated groups. As a result, BBJ and Q significantly reduced NaF-induced oxidative and histological changes in rats. In the combination of BBJ and Q against NaF toxicity, the effects were more severe than from separate exposure, thus indicating that these flavonoids exhibited synergistic effects on all antioxidant and histological parameters. PMID- 25918919 TI - Antibiotic prophylaxis for preventing meningitis in patients with basilar skull fractures. AB - BACKGROUND: Basilar skull fractures predispose patients to meningitis because of the possible direct contact of bacteria in the paranasal sinuses, nasopharynx or middle ear with the central nervous system (CNS). Cerebrospinal fluid (CSF) leakage has been associated with a greater risk of contracting meningitis. Antibiotics are often given prophylactically, although their role in preventing bacterial meningitis has not been established. OBJECTIVES: To evaluate the effectiveness of prophylactic antibiotics for preventing meningitis in patients with basilar skull fractures. SEARCH METHODS: We searched CENTRAL (2014, Issue 5), MEDLINE (1966 to June week 1, 2014), EMBASE (1974 to June 2014) and LILACS (1982 to June 2014). We also performed an electronic search of meeting proceedings from the American Association of Neurological Surgeons (1997 to September 2005) and handsearched the abstracts of meeting proceedings of the European Association of Neurosurgical Societies (1995, 1999 and 2003). SELECTION CRITERIA: Randomised controlled trials (RCTs) comparing any antibiotic versus placebo or no intervention. We also identified non-RCTs to perform a separate meta-analysis in order to compare results. DATA COLLECTION AND ANALYSIS: Three review authors independently screened and selected trials, assessed risk of bias and extracted data. We sought clarification with trial authors when needed. We pooled risk ratios (RRs) for dichotomous data with their 95% confidence intervals (CIs) using a random-effects model. We assessed the overall quality of evidence using the GRADE (Grades of Recommendation, Assessment, Development and Evaluation) approach. MAIN RESULTS: In this update we did not identify any new trials for inclusion. We included five RCTs with 208 participants in the review and meta-analysis. We also identified 17 non-RCTs comparing different types of antibiotic prophylaxis with placebo or no intervention in patients with basilar skull fractures. Most trials presented insufficient methodological detail. All studies included meningitis in their primary outcome. When we evaluated the five included RCTs, there were no significant differences between antibiotic prophylaxis groups and control groups in terms of reduction of the frequency of meningitis, all-cause mortality, meningitis-related mortality and need for surgical correction in patients with CSF leakage. There were no reported adverse effects of antibiotic administration, although one of the five RCTs reported an induced change in the posterior nasopharyngeal flora towards potentially more pathogenic organisms resistant to the antibiotic regimen used in prophylaxis. We performed a subgroup analysis to evaluate the primary outcome in patients with and without CSF leakage. We also completed a meta-analysis of all the identified controlled non-RCTs (enrolling a total of 2168 patients), which produced results consistent with the randomised data from the included studies.Using the GRADE approach, we assessed the quality of trials as moderate. AUTHORS' CONCLUSIONS: Currently available evidence from RCTs does not support prophylactic antibiotic use in patients with basilar skull fractures, whether there is evidence of CSF leakage or not. Until more research is available, the effectiveness of antibiotics in patients with basilar skull fractures cannot be determined because studies published to date are flawed by biases. Large, appropriately designed RCTs are needed. PMID- 25918920 TI - Laetrile treatment for cancer. AB - BACKGROUND: Laetrile is the name for a semi-synthetic compound which is chemically related to amygdalin, a cyanogenic glycoside from the kernels of apricots and various other species of the genus Prunus. Laetrile and amygdalin are promoted under various names for the treatment of cancer although there is no evidence for its efficacy. Due to possible cyanide poisoning, laetrile can be dangerous. OBJECTIVES: To assess the alleged anti-cancer effect and possible adverse effects of laetrile and amygdalin. SEARCH METHODS: We searched the following databases: CENTRAL (2014, Issue 9); MEDLINE (1951-2014); EMBASE (1980 2014); AMED; Scirus; CINAHL (all from 1982-2015); CAMbase (from 1998-2015); the MetaRegister; the National Research Register; and our own files. We examined reference lists of included studies and review articles and we contacted experts in the field for knowledge of additional studies. We did not impose any restrictions of timer or language. SELECTION CRITERIA: Randomized controlled trials (RCTs) and quasi-RCTs. DATA COLLECTION AND ANALYSIS: We searched eight databases and two registers for studies testing laetrile or amygdalin for the treatment of cancer. Two review authors screened and assessed articles for inclusion criteria. MAIN RESULTS: We located over 200 references, 63 were evaluated in the original review, 6 in the 2011 and none in this update. However, we did not identify any studies that met our inclusion criteria. AUTHORS' CONCLUSIONS: The claims that laetrile or amygdalin have beneficial effects for cancer patients are not currently supported by sound clinical data. There is a considerable risk of serious adverse effects from cyanide poisoning after laetrile or amygdalin, especially after oral ingestion. The risk-benefit balance of laetrile or amygdalin as a treatment for cancer is therefore unambiguously negative. PMID- 25918921 TI - Interventions for hirsutism (excluding laser and photoepilation therapy alone). AB - BACKGROUND: Hirsutism occurs in 5% to 10% of women of reproductive age when there is excessive terminal hair growth in androgen-sensitive areas (male pattern). It is a distressing disorder with a major impact on quality of life. The most common cause is polycystic ovary syndrome. There are many treatment options, but it is not clear which are most effective. OBJECTIVES: To assess the effects of interventions (except laser and light-based therapies alone) for hirsutism. SEARCH METHODS: We searched the Cochrane Skin Group Specialised Register, CENTRAL (2014, Issue 6), MEDLINE (from 1946), EMBASE (from 1974), and five trials registers, and checked reference lists of included studies for additional trials. The last search was in June 2014. SELECTION CRITERIA: Randomised controlled trials (RCTs) in hirsute women with polycystic ovary syndrome, idiopathic hirsutism, or idiopathic hyperandrogenism. DATA COLLECTION AND ANALYSIS: Two independent authors carried out study selection, data extraction, 'Risk of bias' assessment, and analyses. MAIN RESULTS: We included 157 studies (sample size 30 to 80) comprising 10,550 women (mean age 25 years). The majority of studies (123/157) were 'high', 30 'unclear', and four 'low' risk of bias. Lack of blinding was the most frequent source of bias. Treatment duration was six to 12 months. Forty-eight studies provided no usable or retrievable data, i.e. lack of separate data for hirsute women, conference proceedings, and losses to follow-up above 40%.Primary outcomes, 'participant-reported improvement of hirsutism' and 'change in health-related quality of life', were addressed in few studies, and adverse events in only half. In most comparisons there was insufficient evidence to determine if the number of reported adverse events differed. These included known adverse events: gastrointestinal discomfort, breast tenderness, reduced libido, dry skin (flutamide and finasteride); irregular bleeding (spironolactone); nausea, diarrhoea, bloating (metformin); hot flushes, decreased libido, vaginal dryness, headaches (gonadotropin-releasing hormone (GnRH) analogues)).Clinician's evaluation of hirsutism and change in androgen levels were addressed in most comparisons, change in body mass index (BMI) and improvement of other clinical signs of hyperandrogenism in one-third of studies.The quality of evidence was moderate to very low for most outcomes.There was low quality evidence for the effect of two oral contraceptive pills (OCPs) (ethinyl estradiol + cyproterone acetate versus ethinyl estradiol + desogestrel) on change from baseline of Ferriman-Gallwey scores. The mean difference (MD) was 1.84 (95% confidence interval (CI) -3.86 to 0.18).There was very low quality evidence that flutamide 250 mg, twice daily, reduced Ferriman-Gallwey scores more effectively than placebo (MD -7.60, 95% CI -10.53 to -4.67 and MD -7.20, 95% CI 10.15 to -4.25). Participants' evaluations in one study with 20 participants confirmed these results (risk ratio (RR) 17.00, 95% CI 1.11 to 259.87).Spironolactone 100 mg daily was more effective than placebo in reducing Ferriman-Gallwey scores (MD -7.69, 95% CI -10.12 to -5.26) (low quality evidence). It showed similar effectiveness to flutamide in two studies (MD -1.90, 95% CI -5.01 to 1.21 and MD 0.49, 95% CI -1.99 to 2.97) (very low quality evidence), as well as to finasteride in two studies (MD 1.49, 95% CI -0.58 to 3.56 and MD 0.40, 95% CI -1.18 to 1.98) (low quality evidence).Although there was very low quality evidence of a difference in reduction of Ferriman-Gallwey scores for finasteride 5 mg to 7.5 mg daily versus placebo (MD -5.73, 95% CI -6.87 to 4.58), it was unlikely it was clinically meaningful. These results were reinforced by participants' assessments (RR 2.06, 95% CI 0.99 to 4.29 and RR 11.00, 95% CI 0.69 to 175.86). However, finasteride showed inconsistent results in comparisons with other treatments, and no firm conclusions could be reached.Metformin demonstrated no benefit over placebo in reduction of Ferriman Gallwey scores (MD 0.05, 95% CI -1.02 to 1.12), but the quality of evidence was low. Results regarding the effectiveness of GnRH analogues were inconsistent, varying from minimal to important improvements.We were unable to pool data for OCPs with cyproterone acetate 20 mg to 100 mg due to clinical and methodological heterogeneity between studies. However, addition of cyproterone acetate to OCPs provided greater reductions in Ferriman-Gallwey scores.Two studies, comparing finasteride 5 mg and spironolactone 100 mg, did not show differences in participant assessments and reduction of Ferriman-Gallwey scores (low quality evidence). Ferriman-Gallwey scores from three studies comparing flutamide versus metformin could not be pooled (I2 = 62%). One study comparing flutamide 250 mg twice daily with metformin 850 mg twice daily for 12 months, which reached a higher cumulative dosage than two other studies evaluating this comparison, showed flutamide to be more effective (MD -6.30, 95% CI -9.83 to -2.77) (very low quality evidence). Data showing reductions in Ferriman-Gallwey scores could not be pooled for four studies comparing finasteride with flutamide as the results were inconsistent (I2 = 67%).Studies examining effects of hypocaloric diets reported reductions in BMI, but which did not result in reductions in Ferriman Gallwey scores. Although certain cosmetic measures are commonly used, we did not identify any relevant RCTs. AUTHORS' CONCLUSIONS: Treatments may need to incorporate pharmacological therapies, cosmetic procedures, and psychological support. For mild hirsutism there is evidence of limited quality that OCPs are effective. Flutamide 250 mg twice daily and spironolactone 100 mg daily appeared to be effective and safe, albeit the evidence was low to very low quality. Finasteride 5 mg daily showed inconsistent results in different comparisons, therefore no firm conclusions can be made. As the side effects of antiandrogens and finasteride are well known, these should be accounted for in any clinical decision-making. There was low quality evidence that metformin was ineffective for hirsutism and although GnRH analogues showed inconsistent results in reducing hirsutism they do have significant side effects.Further research should consist of well-designed, rigorously reported, head-to-head trials examining OCPs combined with antiandrogens or 5alpha-reductase inhibitor against OCP monotherapy, as well as the different antiandrogens and 5alpha-reductase inhibitors against each other. Outcomes should be based on standardised scales of participants' assessment of treatment efficacy, with a greater emphasis on change in quality of life as a result of treatment. PMID- 25918922 TI - Invasive urodynamic studies for the management of lower urinary tract symptoms (LUTS) in men with voiding dysfunction. AB - BACKGROUND: Invasive urodynamic tests are used to investigate men with lower urinary tract symptoms (LUTS) and voiding dysfunction to determine a definitive objective diagnosis. The aim is to help clinicians select the treatment that is most likely to be successful. These investigations are invasive and time consuming. OBJECTIVES: To determine whether performing invasive urodynamic investigation, as opposed to other methods of diagnosis such as non-invasive urodynamics or clinical history and examination alone, reduces the number of men with continuing symptoms of voiding dysfunction. This goal will be achieved by critically appraising and summarising current evidence from randomised controlled trials related to clinical outcomes and cost-effectiveness. This review is not intended to consider whether urodynamic tests are reliable for making clinical diagnoses, nor whether one type of urodynamic test is better than another for this purpose.The following comparisons were made.* Urodynamics versus clinical management.* One type of urodynamics versus another. SEARCH METHODS: We searched the Cochrane Central Register of Controlled Trials (CENTRAL) (2014, issue 10), MEDLINE (1 January 1946 to Week 4 October 2014), MEDLINE In-Process and other non indexed citations (covering 27 November 2014; all searched on 28 November 2014), EMBASE Classic and EMBASE (1 January 2010 to Week 47 2014, searched on 28 November 2014), ClinicalTrials.gov and the World Health Organization International Clinical Trials Registry Platform (WHO ICTRP) (searched on 1 December 2014 and 3 December 2014, respectively), as well as the reference lists of relevant articles. SELECTION CRITERIA: Randomised and quasi-randomised trials comparing clinical outcomes in men who were and were not investigated with the use of invasive urodynamics, or comparing one type of urodynamics against another, were included. Trials were excluded if they did not report clinical outcomes. DATA COLLECTION AND ANALYSIS: Three review authors independently assessed trial quality and extracted data. MAIN RESULTS: We included two trials, but data were available for only 339 men in one trial, of whom 188 underwent invasive urodynamic studies. We found evidence of risk of bias, such as lack of outcome information for 24 men in one arm of the trial.Statistically significant evidence suggests that the tests did change clinical decision making. Men in the invasive urodynamics arm were more likely to have their management changed than men in the control arm (proportion with change in management 24/188 (13%) vs 0/151 (0%), risk ratio (RR) 39.41, 95% confidence interval (CI) 2.42 to 642.74). However, the quality of the evidence was low.Low-quality evidence indicates that men in the invasive urodynamics group were less likely to undergo surgery as treatment for voiding LUTS (164/188 (87%) vs 151/151 (100%), RR 0.87, 95% CI 0.83 to 0.92).Investigators observed no difference in urine flow rates before and after surgery for LUTS (mean percentage increase in urine flow rate, 140% in invasive urodynamic group vs 149% in immediate surgery group, P value = 0.13). Similarly, they found no differences between groups with regards to International Prostate Symptom Score (IPSS) (mean percentage decrease in IPSS score, 58% in invasive urodynamics group vs 59% in immediate surgery group, P value = 0.22).No evidence was available to demonstrate whether differences in management equated to improved health outcomes, such as relief of symptoms of voiding dysfunction or improved quality of life.No evidence from randomised trials revealed the adverse effects associated with invasive urodynamic studies. AUTHORS' CONCLUSIONS: Although invasive urodynamic testing did change clinical decision making, we found no evidence to demonstrate whether this led to reduced symptoms of voiding dysfunction after treatment. Larger definitive trials of better quality are needed, in which men are randomly allocated to management based on invasive urodynamic findings or to management based on findings obtained by other diagnostic means. This research will show whether performance of invasive urodynamics results in reduced symptoms of voiding dysfunction after treatment. PMID- 25918923 TI - Coexistence of Henoch-Schonlein purpura and infective endocarditis in elderly. PMID- 25918924 TI - The reply. PMID- 25918925 TI - Trends in physical inactivity. PMID- 25918926 TI - The reply. PMID- 25918927 TI - Connect the patient to the expert: referral to a registered dietitian nutritionist. PMID- 25918928 TI - The reply. PMID- 25918929 TI - [Hospital Costs of Ambulatory Care-Sensitive Conditions in Germany]. AB - Ambulatory care-sensitive conditions (ACSC) are defined as conditions that lead to a hospital admission of which the onset could have been prevented through a more easily accessible ambulatory sector or one that provides better quality care. They are used by health-care systems as a quality indicator for the ambulatory sector. The definition for ACSC varies internationally. Sets of conditions have been defined and evaluated already in various countries, e. g., USA, England, New Zealand and Canada, but not yet for Germany. Therefore this study aims to evaluate the hospital costs of ACSC in Germany using the National Health Service's set of ACSC. In order to calculate these costs a model has been set up for the time period between 2003 and 2010. It is based on G-DRG browsers issued by the German Institute for the Hospital Remuneration System as required by German law. Within these browsers all relevant DRG-ICD combinations have been extracted. The number of cases per combination was then multiplied by their corresponding cost weights and the average effective base rates. The results were then aggregated into their corresponding ICD groups and then into their respective conditions which lead to the costs per condition and the total costs. The total number of cases and total costs were then compared to another second source. These calculations resulted in 11.7 million cases, of which 10.7% were defined as ambulatory care-sensitive. Within the analysed time period the number of ambulatory care-sensitive cases increased by 6% in total and had a 0.9% CAGR. The corresponding costs amounted to a total of EUR 37.6B and to EUR 3.3B for ACSC. 60% of the costs were caused by three of the 19 ACSC. These results validate that it is worthwhile to further investigate this quality indicator for the ambulatory sector. PMID- 25918930 TI - [Use of Psychotropic Substances and Satisfaction with Vocational Education]. AB - Objective: The aim of this study was to investigate if there is an independent association between substance use and satisfaction in vocational education. Methods: A cross-sectional study of 5 688 first-year apprentices from 49 vocational schools, mean age 19.4 years (SD=3.9 years) was undertaken. Data were analysed using multilevel linear regression analysis. Predictors were use of tobacco, alcohol, cannabis and pharmaceuticals as well as personal characteristics (sex, age, migration background, educational level, financial status, chronic diseases, psychological distress, physical activity, media use, personality) and vocational/firm characteristics (firm size, number of apprentices, perceived quality of mentoring, amount of pay, vocational field, working conditions, over- and underload, housing situation, number of previous apprenticeships, first choice). Vocational satisfaction was used as primary outcome. Results: Satisfaction was most strongly associated with perceived quality of mentoring, judgement that the chosen education was first choice and working climate in the training company. In addition, only problematic alcohol use remained significant in the multivariate analysis. There was no association in the adjusted model between vocational satisfaction and daily tobacco use or problematic use of cannabis and pharmaceuticals. Conclusions: Results suggest that problematic alcohol use could be an independent risk factor for problems in vocational education. PMID- 25918931 TI - [Early Selection of At-risk Patients for Type 2 Diabetes in the GP Surgery by Medical Assistants - A Feasibility Study]. AB - Objective: We investigated whether patients who belong to the high risk group to develop type-2 diabetes can be identified by medical assistants (MFA) in the everyday routine of the general practice by means of a few characteristics. The effectiveness of a diabetes-risk screening could be improved by a selective approach to patients who are at risk. Method: As part of the feasibility study 'SeRiFIN', patients who were between 20 and 50 years old and/or had a positive family history were approached by trained MFA in 6 general practices. To determine the risk of diabetes, the selected patients should complete the FINDRISK questionnaire. In the 5 control practices, patients of the same age group without known type 2 diabetes, were also asked to perform a risk analysis with the help of the FINDRISK questionnaire. Results: 916 FINDRISK questionnaires were evaluated. In the selection group, 62% of surveyed patients indicated that there were cases of diabetes in the family. In 86% of patients the waist circumference was increased. A 30% risk or higher to develop type 2 diabetes in the next ten years was found in 22% of the addressed patients. In the unselected group only 7% of patients had a risk that had to be investigated. In addition there was a significant difference in the eating behaviour and the level of daily exercise between the selection an the control group. The training of MFA as well as the implementation of the intervention were well received and considered feasible to conduct in addition to the routine work of MFA. Furthermore MFA expressed their astonishment at the effectiveness of this pre-selection. Conclusion: After training MFA recognise patients at risk for type 2 diabetes reliably in their everyday practice routine. The targeted approach to patients at risk can be delegated to the MFA. Thus, the time resources of general practitioners can be more effectively used for prevention treatment. Especially cardiovascular risk patients should benefit from the earliest possible identification and intervention. PMID- 25918932 TI - [Minimum Standards for the Spatial Accessibility of Primary Care: A Systematic Review]. AB - BACKGROUND: Regional disparities of access to primary care are substantial in Germany, especially in terms of spatial accessibility. However, there is no legally or generally binding minimum standard for the spatial accessibility effort that is still acceptable. Our objective is to analyse existing minimum standards, the methods used as well as their empirical basis. METHODS: A systematic literature review was undertaken of publications regarding minimum standards for the spatial accessibility of primary care based on a title word and keyword search using PubMed, SSCI/Web of Science, EMBASE and Cochrane Library. RESULTS: 8 minimum standards from the USA, Germany and Austria could be identified. All of them specify the acceptable spatial accessibility effort in terms of travel time; almost half include also distance(s). The travel time maximum, which is acceptable, is 30 min and it tends to be lower in urban areas. Primary care is, according to the identified minimum standards, part of the local area (Nahbereich) of so-called central places (Zentrale Orte) providing basic goods and services. The consideration of means of transport, e. g. public transport, is heterogeneous. The standards are based on empirical studies, consultation with service providers, practical experiences, and regional planning/central place theory as well as on legal or political regulations. CONCLUSIONS: The identified minimum standards provide important insights into the effort that is still acceptable regarding spatial accessibility, i. e. travel time, distance and means of transport. It seems reasonable to complement the current planning system for outpatient care, which is based on provider-to population ratios, by a gravity-model method to identify places as well as populations with insufficient spatial accessibility. Due to a lack of a common minimum standard we propose - subject to further discussion - to begin with a threshold based on the spatial accessibility limit of the local area, i. e. 30 min to the next primary care provider for at least 90% of the regional population. The exceeding of the threshold would necessitate a discussion of a health care deficit and in line with this a potential need for intervention, e. g. in terms of alternative forms of health care provision. PMID- 25918933 TI - The role of curcumin as an inhibitor of oxidative stress caused by ischaemia re perfusion injury in tetralogy of Fallot patients undergoing corrective surgery. AB - BACKGROUND: Cardiopulmonary bypass during tetralogy of Fallot corrective surgery is associated with oxidative stress, and contributes to peri-operative problems. Curcumin has been known as a potent scavenger of reactive oxygen species, which enhances the activity of antioxidants and suppresses phosphorylation of transcription factors involved in inflamation and apoptosis. OBJECTIVES: To evaluate the effects of curcumin as an antioxidant by evaluating the concentrations of malondialdehyde and glutathione, activity of nuclear factor kappa B, c-Jun N-terminal kinase, caspase-3, and post-operative clinical outcomes. METHODS: Tetralogy of Fallot patients for corrective surgery were randomised to receive curcumin (45 mg/day) or placebo orally for 14 days before surgery. Malondialdehyde and glutathione concentrations were evaluated during the pre-ischaemia, ischaemia, re-perfusion phases, and 6 hours after aortic clamping off. Nuclear factor-kappa B, c-Jun N-terminal kinase, and caspase-3, taken from the infundibulum, were assessed during the pre-ischaemia, ischaemia, and re perfusion phases. Haemodynamic parameters were monitored until day 5 after surgery. RESULTS: In all the observation phases, malondialdehyde and glutathione concentrations were similar between groups. There was no significant difference in nuclear factor-kappa B activity between the groups for three observations; however, in the curcumin group, c-Jun N-terminal kinase significantly decreased from the pre-ischaemia to the re-perfusion phases, and caspase-3 expression was lower in the ischaemia phase. Patients in the curcumin group had lower temperature and better ventricular functions, but no significant differences were found in mechanical ventilation day or length of hospital stay in the two groups. CONCLUSION: Cardioprotective effects of curcumin may include inhibition of the c Jun N-terminal kinase pathway and caspase-3 in cardiomyocytes, particularly in the ischaemia phase. PMID- 25918935 TI - Mesenchymal stem cells and induced pluripotent stem cells as therapies for multiple sclerosis. AB - Multiple sclerosis (MS) is a chronic, autoimmune, inflammatory demyelinating disorder of the central nervous system that leads to permanent neurological deficits. Current MS treatment regimens are insufficient to treat the irreversible neurological disabilities. Tremendous progress in the experimental and clinical applications of cell-based therapies has recognized stem cells as potential candidates for regenerative therapy for many neurodegenerative disorders including MS. Mesenchymal stem cells (MSC) and induced pluripotent stem cell (iPSCs) derived precursor cells can modulate the autoimmune response in the central nervous system (CNS) and promote endogenous remyelination and repair process in animal models. This review highlights studies involving the immunomodulatory and regenerative effects of mesenchymal stem cells and iPSCs derived cells in animal models, and their translation into immunomodulatory and neuroregenerative treatment strategies for MS. PMID- 25918934 TI - In vitro and in vivo antitumoral effects of combinations of polyphenols, or polyphenols and anticancer drugs: perspectives on cancer treatment. AB - Carcinogenesis is a multistep process triggered by genetic alterations that activate different signal transduction pathways and cause the progressive transformation of a normal cell into a cancer cell. Polyphenols, compounds ubiquitously expressed in plants, have anti-inflammatory, antimicrobial, antiviral, anticancer, and immunomodulatory properties, all of which are beneficial to human health. Due to their ability to modulate the activity of multiple targets involved in carcinogenesis through direct interaction or modulation of gene expression, polyphenols can be employed to inhibit the growth of cancer cells. However, the main problem related to the use of polyphenols as anticancer agents is their poor bioavailability, which might hinder the in vivo effects of the single compound. In fact, polyphenols have a poor absorption and biodistribution, but also a fast metabolism and excretion in the human body. The poor bioavailability of a polyphenol will affect the effective dose delivered to cancer cells. One way to counteract this drawback could be combination treatment with different polyphenols or with polyphenols and other anti-cancer drugs, which can lead to more effective antitumor effects than treatment using only one of the compounds. This report reviews current knowledge on the anticancer effects of combinations of polyphenols or polyphenols and anticancer drugs, with a focus on their ability to modulate multiple signaling transduction pathways involved in cancer. PMID- 25918936 TI - The Role of Food Peptides in Lipid Metabolism during Dyslipidemia and Associated Health Conditions. AB - Animal and human clinical studies have demonstrated the ability of dietary food proteins to modulate endogenous lipid levels during abnormal lipid metabolism (dyslipidemia). Considering the susceptibility of proteins to gastric proteolytic activities, the hypolipidemic functions of proteins are possibly due, in part, to their peptide fragments. Food-derived peptides may directly modulate abnormal lipid metabolism in cell cultures and animal models of dyslipidemia. The peptides are thought to act by perturbing intestinal absorption of dietary cholesterol and enterohepatic bile acid circulation, and by inhibiting lipogenic enzymatic activities and gene expression in hepatocytes and adipocytes. Recent evidence indicates that the hypolipidemic activities of some peptides are due to activation of hepatic lipogenic transcription factors. However, detailed molecular mechanisms and structural requirements of peptides for these activities are yet to be elucidated. As hypolipidemic peptides can be released during enzymatic food processing, future studies can explore the prospects of combating metabolic syndrome and associated complications using peptide-rich functional food and nutraceutical products. PMID- 25918937 TI - Insights on Structural Characteristics and Ligand Binding Mechanisms of CDK2. AB - Cyclin-dependent kinase 2 (CDK2) is a crucial regulator of the eukaryotic cell cycle. However it is well established that monomeric CDK2 lacks regulatory activity, which needs to be aroused by its positive regulators, cyclins E and A, or be phosphorylated on the catalytic segment. Interestingly, these activation steps bring some dynamic changes on the 3D-structure of the kinase, especially the activation segment. Until now, in the monomeric CDK2 structure, three binding sites have been reported, including the adenosine triphosphate (ATP) binding site (Site I) and two non-competitive binding sites (Site II and III). In addition, when the kinase is subjected to the cyclin binding process, the resulting structural changes give rise to a variation of the ATP binding site, thus generating an allosteric binding site (Site IV). All the four sites are demonstrated as being targeted by corresponding inhibitors, as is illustrated by the allosteric binding one which is targeted by inhibitor ANS (fluorophore 8 anilino-1-naphthalene sulfonate). In the present work, the binding mechanisms and their fluctuations during the activation process attract our attention. Therefore, we carry out corresponding studies on the structural characterization of CDK2, which are expected to facilitate the understanding of the molecular mechanisms of kinase proteins. Besides, the binding mechanisms of CDK2 with its relevant inhibitors, as well as the changes of binding mechanisms following conformational variations of CDK2, are summarized and compared. The summary of the conformational characteristics and ligand binding mechanisms of CDK2 in the present work will improve our understanding of the molecular mechanisms regulating the bioactivities of CDK2. PMID- 25918939 TI - A Moonlighting Human Protein Is Involved in Mitochondrial Import of tRNA. AB - In yeast Saccharomyces cerevisiae, ~3% of the lysine transfer RNA acceptor 1 (tRK1) pool is imported into mitochondria while the second isoacceptor, tRK2, fully remains in the cytosol. The mitochondrial function of tRK1 is suggested to boost mitochondrial translation under stress conditions. Strikingly, yeast tRK1 can also be imported into human mitochondria in vivo, and can thus be potentially used as a vector to address RNAs with therapeutic anti-replicative capacity into mitochondria of sick cells. Better understanding of the targeting mechanism in yeast and human is thus critical. Mitochondrial import of tRK1 in yeast proceeds first through a drastic conformational rearrangement of tRK1 induced by enolase 2, which carries this freight to the mitochondrial pre-lysyl-tRNA synthetase (preMSK). The latter may cross the mitochondrial membranes to reach the matrix where imported tRK1 could be used by the mitochondrial translation apparatus. This work focuses on the characterization of the complex that tRK1 forms with human enolases and their role on the interaction between tRK1 and human pre-lysyl tRNA synthetase (preKARS2). PMID- 25918938 TI - Single cell confocal Raman spectroscopy of human osteoarthritic chondrocytes: a preliminary study. AB - A great deal of effort has been focused on exploring the underlying molecular mechanism of osteoarthritis (OA) especially at the cellular level. We report a confocal Raman spectroscopic investigation on human osteoarthritic chondrocytes. The objective of this investigation is to identify molecular features and the stage of OA based on the spectral signatures corresponding to bio-molecular changes at the cellular level in chondrocytes. In this study, we isolated chondrocytes from human osteoarthritic cartilage and acquired Raman spectra from single cells. Major spectral differences between the cells obtained from different International Cartilage Repair Society (ICRS) grades of osteoarthritic cartilage were identified. During progression of OA, a decrease in protein content and an increase in cell death were observed from the vibrational spectra. Principal component analysis and subsequent cross-validation was able to associate osteoarthritic chondrocytes to ICRS Grade I, II and III with specificity 100.0%, 98.1%, and 90.7% respectively, while, sensitivity was 98.6%, 82.8%, and 97.5% respectively. The overall predictive efficiency was 92.2%. Our pilot study encourages further use of Raman spectroscopy as a noninvasive and label free technique for revealing molecular features associated with osteoarthritic chondrocytes. PMID- 25918940 TI - Different storage conditions influence biocompatibility and physicochemical properties of iron oxide nanoparticles. AB - Superparamagnetic iron oxide nanoparticles (SPIONs) have attracted increasing attention in many biomedical fields. In magnetic drug targeting SPIONs are injected into a tumour supplying artery and accumulated inside the tumour with a magnet. The effectiveness of this therapy is thus dependent on magnetic properties, stability and biocompatibility of the particles. A good knowledge of the effect of storage conditions on those parameters is of utmost importance for the translation of the therapy concept into the clinic and for reproducibility in preclinical studies. Here, core shell SPIONs with a hybrid coating consisting of lauric acid and albumin were stored at different temperatures from 4 to 45 degrees C over twelve weeks and periodically tested for their physicochemical properties over time. Surprisingly, even at the highest storage temperature we did not observe denaturation of the protein or colloidal instability. However, the saturation magnetisation decreased by maximally 28.8% with clear correlation to time and storage temperature. Furthermore, the biocompatibility was clearly affected, as cellular uptake of the SPIONs into human T-lymphoma cells was crucially dependent on the storage conditions. Taken together, the results show that the particle properties undergo significant changes over time depending on the way they are stored. PMID- 25918942 TI - [Latin-American plants as a source of new antineoplastic drugs, current situation and new opportunities against cancer]. AB - Cancer is one of the most relevant pandemics in modern world. There is a clear predominance of this pathology with distinct epidemiological characteristics in developing and developed countries. Effective, low-cost treatment and prophylaxis strategies that also have minimal side effects are needed. The present work is a brief revision of research that show the great therapeutic potential of plants, highlighting those carried out in Latin America with local plants considering that this is a yet incipient field of study. The great pool of organic compounds and other substances such as proteins indicate that they might provide a reliable alternative in the search for new actors in the battle against cancer. PMID- 25918943 TI - Highly selective carboxylative cyclization of allenylmethylamines with carbon dioxide using N-heterocyclic carbene-silver(I) catalysts. AB - Silver(I) carboxylate complexes promote the carboxylative cyclization of allenylmethylamines to afford 5-alkenyl-1,3-oxazolidin-2-ones in 2-propanol. The use of an N-heterocyclic carbene ligand (IPr) under pressurized CO2 is effective in suppressing the intramolecular hydroamination that leads to 2,5 dihydropyrroles. The mechanism involving a nucleophilic attack of the carbamate of the allene moiety and a subsequent protonation was realized on the basis of experimental and theoretical results involving a model intermediate, the alkenylgold(I) complex, which was synthesized from Au(OH)(IPr) and 1-methylamino 2,3-butadiene. PMID- 25918941 TI - New biofuel alternatives: integrating waste management and single cell oil production. AB - Concerns about greenhouse gas emissions have increased research efforts into alternatives in bio-based processes. With regard to transport fuel, bioethanol and biodiesel are still the main biofuels used. It is expected that future production of these biofuels will be based on processes using either non-food competing biomasses, or characterised by low CO2 emissions. Many microorganisms, such as microalgae, yeast, bacteria and fungi, have the ability to accumulate oils under special culture conditions. Microbial oils might become one of the potential feed-stocks for biodiesel production in the near future. The use of these oils is currently under extensive research in order to reduce production costs associated with the fermentation process, which is a crucial factor to increase economic feasibility. An important way to reduce processing costs is the use of wastes as carbon sources. The aim of the present review is to describe the main aspects related to the use of different oleaginous microorganisms for lipid production and their performance when using bio-wastes. The possibilities for combining hydrogen (H2) and lipid production are also explored in an attempt for improving the economic feasibility of the process. PMID- 25918944 TI - How Innocent are Potentially Redox Non-Innocent Ligands? Electronic Structure and Metal Oxidation States in Iron-PNN Complexes as a Representative Case Study. AB - Herein we present a series of new alpha-iminopyridine-based iron-PNN pincer complexes [FeBr2LPNN] (1), [Fe(CO)2LPNN] (2), [Fe(CO)2LPNN](BF4) (3), [Fe(F)(CO)2LPNN](BF4) (4), and [Fe(H)(CO)2LPNN](BF4) (5) with formal oxidation states ranging from Fe(0) to Fe(II) (LPNN = 2-[(di-tert-butylphosphino)methyl]-6 [1-(2,4,6-mesitylimino)ethyl]pyridine). The complexes were characterized by a variety of methods including (1)H, (13)C, (15)N, and (31)P NMR, IR, Mossbauer, and X-ray photoelectron spectroscopy (XPS) as well as electron paramagnetic resonance (EPR) and magnetic circular dichroism (MCD) spectroscopy, SQUID magnetometry, and X-ray crystallography, focusing on the assignment of the metal oxidation states. Ligand structural features suggest that the alpha-iminopyridine ligand behaves as a redox non-innocent ligand in some of these complexes, particularly in [Fe(CO)2LPNN] (2), in which it appears to adopt the monoanionic form. In addition, the NMR spectroscopic features ((13)C, (15)N) indicate the accumulation of charge density on parts of the ligand for 2. However, a combination of spectroscopic measurements that more directly probe the iron oxidation state (e.g., XPS), density functional theory (DFT) calculations, and electronic absorption studies combined with time-dependent DFT calculations support the description of the metal atom in 2 as Fe(0). We conclude from our studies that ligand structural features, while useful in many assignments of ligand redox non-innocence, may not always accurately reflect the ligand charge state and, hence, the metal oxidation state. For complex 2, the ligand structural changes are interpreted in terms of strong back-donation from the metal center to the ligand as opposed to electron transfer. PMID- 25918945 TI - Influence of Exciton Localization on the Emission and Ultraviolet Photoresponse of ZnO/ZnS Core-Shell Nanowires. AB - The structural and optical properties of ZnO and ZnO/ZnS core-shell nanowires grown by a wet chemical method are investigated. The near-bandgap ultraviolet (UV) emission of the ZnO nanowires was enhanced by four times after coating with ZnS. The enhanced emission was attributed to surface passivation of the ZnO nanowires and localized states introduced during ZnS growth. The emission of the ZnO and ZnO/ZnS core-shell nanowires was attributed to neutral donor-bound excitons and localized excitons, respectively. Localized states prevented excitons from diffusing to nonradiative recombination centers, so therefore contributed to the enhanced emission. Emission from the localized exciton was not sensitive to temperature, so emission from the ZnO/ZnS core-shell nanowires was more stable at higher temperature. UV photodetectors based on the ZnO and ZnO/ZnS core-shell nanowires were fabricated. Under UV excitation, the device based on the ZnO/ZnS core-shell nanowires exhibited a photocurrent approximately 40 times higher than that of the device based on the ZnO nanowires. The differing photoresponse of the detectors was consistent with the existence of surface passivation and localized states. This study provides a means for modifying the optical properties of ZnO materials, and demonstrates the potential of ZnO/ZnS core-shell nanowires in UV excitonic emission and detection. PMID- 25918946 TI - Nanoparticle assemblies in supramolecular nanocomposite thin films: concentration dependence. AB - The phase behavior of supramolecular nanocomposite thin films was systematically investigated as a function of nanoparticle (NP) loading from 1 to >50 wt %. The coassembly of NP and supramolecule can be divided into five regimes, from a supramolecule-guided assembly to a NP governing assembly process, depending on the energetic contributions from the surface energy, NP-supramolecule interaction, and the kinetic pathway of the assembly process. A range of morphologies such as 1D NP chains, 2D sheets, 3D NP assemblies, and NP solids can be readily obtained, providing opportunities to meet structural control in nanocomposites for a wide range of applications. PMID- 25918948 TI - A transdiagnostic investigation of emotional distress after traumatic brain injury. AB - Emotional distress after traumatic brain injury (TBI) often presents as a range of neurobehavioural and emotional reactions rather than distinct disorders. This study adopted a transdiagnostic approach with the aim of identifying psychological processes common to depression, anxiety and global distress after TBI. Fifty participants with TBI (aged 19-66 years, 12-65 months post-injury) completed measures of threat appraisals and avoidance behaviour (Appraisal of Threat and Avoidance Questionnaire), self-discrepancy (Head Injury Semantic Differential Scale III), emotion dysregulation (Difficulties in Emotion Regulation Scale), worry (Penn State Worry Questionnaire), negative self-focused attention (Self-Focus Sentence Completion) and emotional distress (Depression Anxiety Stress Scales and Brief Symptom Inventory). Significant correlations were found among the proposed transdiagnostic variables (rs = .29-.82, p < .05). A principal components analysis revealed two underlying factors: (1) Threats to Self, and (2) Emotion Dysregulation. Only the Emotion Dysregulation factor accounted for significant unique variance in levels of depression, anxiety and global distress (sr(2) = .12-.17). Such findings indicate the need for interventions to target difficulties in identifying and regulating emotions after TBI to facilitate emotional adjustment. PMID- 25918947 TI - Cys34-PEGylated Human Serum Albumin for Drug Binding and Delivery. AB - Polyethylene glycol (PEG) derivatives were conjugated onto the Cys-34 residue of human serum albumin (HSA) to determine their effects on the solubilization, permeation, and cytotoxic activity of hydrophobic drugs such as paclitaxel (PTX). PEG(C34)HSA conjugates were prepared on a multigram scale by treating native HSA (n-HSA) with 5- or 20-kDa mPEG-maleimide, resulting in up to 77% conversion of the mono-PEGylated adduct. Nanoparticle tracking analysis of PEG(C34)HSA formulations in phosphate buffer revealed an increase in the number of nanosized aggregates relative to n-HSA, both in the absence and presence of PTX. Cell viability studies conducted with MCF-7 breast cancer cells indicated that PTX cytotoxicity was enhanced by PEG(C34)HSA when mixed at 10:1 mol ratios, up to a 2 fold increase in potency relative to n-HSA. The PEG(C34)HSA conjugates were also evaluated as PTX carriers across monolayers of HUVEC and hCMEC/D3 cells, and found to have permeation profiles nearly identical to those of n-HSA. PMID- 25918949 TI - Type 2 diabetes mellitus: limitations of conventional therapies and intervention with nucleic acid-based therapeutics. PMID- 25918950 TI - Right ventricular wave reflection relate to clinical measures in pulmonary arterial hypertension. AB - OBJECTIVES: When a forward running pressure wave from the right ventricle reaches the narrow vessels in the pulmonary circulation, it is reflected as a backward running wave. We aimed to relate changes in right ventricular waveform reflection (RVWR) to changes in clinical variables in pulmonary arterial hypertension (PAH) patients. DESIGN: Twenty-one PAH patients with RV waveform recordings from two sequential catheterisations at least 6 months apart were included. Six-minute walked distance (6MWD) and brain natriuretic peptide (BNP) level were also available. RVWR was defined as 'the pressure from the inflection point on the upstroke RV pressure wave to RV peak pressure'. Direction of change in RVWR, 6MWD and BNP was classified as (+) if increased and (-) if decreased. Spearman correlations were used to analyse the relation between changes. Pearson's correlation coefficient was used to analyse relation between RVWR and pulmonary vascular resistance (PVR). RESULTS: The correlation between change in RVWR and 6MWD was - 0.67 (p < 0.01) and between RVWR and BNP was - 0.53 (p < 0.05). Actual RVWR and PVR correlated both at first (0.56, p < 0.001) and at second right heart catheterisation (0.45, p < 0.001). CONCLUSION: RVWR might have clinical implications indicating a change in clinical status and disease progression in patients with PAH. PMID- 25918952 TI - The use of porcine acellular dermal matrix for management of gastrocutaneous fistula after laparoscopic sleeve gastrectomy. AB - Sleeve gastrectomy is an effective and single stand-alone surgical procedure for the treatment of morbid obesity. One of the most frequent and serious complications of this procedure is staple-line leak. It can usually be treated with self-expandable stents. If this process results in failure and gastrocutaneous fistula occurs, a challenging period starts for the patient and the surgeon. We describe a new, relatively simple and quick endoscopic technique for closing a chronic gastrocutaneous fistula. A plug prepared with porcine acellular dermal matrix was used for this purpose. Gastrocutaneous fistula following an obesity surgery can be successfully treated endoscopically with this technique. This method can prevent the need for aggressive reconstructive surgery following a gastrocutaneous fistula and can prompt rapid improvement while decreasing the average hospital stay for this condition. PMID- 25918951 TI - Increased Mutagen Sensitivity and DNA Damage in Pulmonary Arterial Hypertension. AB - RATIONALE: Pulmonary arterial hypertension (PAH) is a serious lung condition characterized by vascular remodeling in the precapillary pulmonary arterioles. We and others have demonstrated chromosomal abnormalities and increased DNA damage in PAH lung vascular cells, but their timing and role in disease pathogenesis is unknown. OBJECTIVES: We hypothesized that if DNA damage predates PAH, it might be an intrinsic cell property that is present outside the diseased lung. METHODS: We measured DNA damage, mutagen sensitivity, and reactive oxygen species (ROS) in lung and blood cells from patients with Group 1 PAH, their relatives, and unrelated control subjects. MEASUREMENTS AND MAIN RESULTS: Baseline DNA damage was significantly elevated in PAH, both in pulmonary artery endothelial cells (P < 0.05) and peripheral blood mononuclear cells (PBMC) (P < 0.001). Remarkably, PBMC from unaffected relatives showed similar increases, indicating this is not related to PAH treatments. ROS levels were also higher (P < 0.01). DNA damage correlated with ROS production and was suppressed by antioxidants (P < 0.001). PBMC from patients and relatives also showed markedly increased sensitivity to two chemotherapeutic drugs, bleomycin and etoposide (P < 0.001). Results were consistent across idiopathic, heritable, and associated PAH groups. CONCLUSIONS: Levels of baseline and mutagen-induced DNA damage are intrinsically higher in PAH cells. Similar results in PBMC from unaffected relatives suggest this may be a genetically determined trait that predates disease onset and may act as a risk factor contributing to lung vascular remodeling following endothelial cell injury. Further studies are required to fully characterize mutagen sensitivity, which could have important implications for clinical management. PMID- 25918953 TI - Rattle-type colloidal crystals composed of spherical hollow particles containing an anisotropic, movable core. AB - Controls over the position and orientation of anisotropic particles in their assemblies are intriguing issues for functional colloidal crystals that are switchable with external fields such as electric and magnetic fields. We propose a novel approach for the fabrication of rattle-type colloidal crystals containing an anisotropic, movable core surrounded by a void space that allows rearrangement of the anisotropic core in the assembly. In the fabrication, multilayered core shell particles composed of a titania core, polystyrene shell, and silica shell were prepared and then heated at 500 degrees C for 4 h to selectively remove the middle layer of polystyrene. The heating treatment induced deformation of spherical titania cores in the compartment of silica shells, while the void space required for the orientation and relocation of anisotropic core was generated. The rattle particles fabricated were self-assembled by a simple dip-coating to form an arrangement of the spherical yolk/shell particles incorporating an anisotropic core. Brownian motion of the anisotropic cores observed with an optical microscope showed that the assembly of rattle-type particles had the potential to control location and orientation of the anisotropic cores in the shell compartment by application of external fields. PMID- 25918954 TI - Association of survivin promoter polymorphisms with inflammatory bowel disease and response to antitumor necrosis factor therapy. AB - BACKGROUND/AIM: Recent evidence suggests that survivin, a member of the inhibitors of apoptosis family that prevents cell death and regulates cell division is implicated in the pathogenesis of inflammatory bowel disease (IBD). The aim of the study was to identify a possible association between individual genetic variation, IBD susceptibility, and response to infliximab (IFX). MATERIAL AND METHODS: The expression levels of survivin were detected in pathologic areas of fresh tissues and blood samples by real-time reverse transcriptase - polymerase chain reaction (RT-PCR) from IBD patients. Polymorphisms were identified using the polymerase chain reaction - Restriction Fragment Length Polymorphism (PCR-RFLP) technique. Clinical and endoscopic response to IFX was evaluated by ileocolonoscopy performed at baseline and after 12-20 weeks of therapy with patients classified as either responders or nonresponders. RESULTS: No significant differences were found between survivin mRNA levels between patients and controls. Significant differences in both allele and genotype frequencies between Crohn's disease (CD) and ulcerative colitis (UC) patients and controls were found in -31C/G polymorphism. No association with IBD development was found for the -625G/C and -241T/C polymorphisms, since those polymorphisms were overrepresented in a healthy population. Additionally no significant association was found between -31C/G polymorphism and the clinical response of CD patients to IFX. CONCLUSIONS: Survivin promoter polymorphism -31C/G might influence the susceptibility to IBD in the Greek population, but not the CD patient's response to anti-TNF drugs. PMID- 25918955 TI - Decolonization and decontamination: what's their role in infection control? AB - PURPOSE OF REVIEW: Hospital-acquired infections cause up to 19% of infections in paediatric patients contributing to the spread of antimicrobial resistance. This review evaluates the effect of decolonization and decontamination in hospitalized children and neonates as an adjunct to standard infection control measures. RECENT FINDINGS: Few studies on decolonization and decontamination are available in children. The evidence about the effectiveness of daily chlorhexidine washcloths on bacteraemia in paediatric patients relies on a single randomized controlled trial, in neonates with central venous access in a single retrospective observational study. It is uncertain whether nasal mupirocin reduces methicillin-resistant Staphylococcus aureus carriage and infections in neonates, whereas oral chlorhexidine mouthwashes have not proven effective in children in intensive care settings. Scanty evidence demonstrates a reduction in the rate of ventilation-acquired pneumonia with digestive tract decontamination in paediatric patients and no studies are available in neonates. These strategies have not been extensively tested in resource-poor countries. SUMMARY: Strong evidence about the efficacy of decolonization and decontamination interventions exists in adult medicine but not in paediatric patients. There is an urgent need to understand how these interventions could be adapted to neonates and resource poor settings in which the prevalence of hospital-acquired infections is higher. PMID- 25918956 TI - Respiratory syncytial virus in infants: is maternal vaccination a realistic strategy? AB - PURPOSE OF REVIEW: Respiratory syncytial virus (RSV) remains an important cause of serious and sometimes fatal acute lower respiratory tract disease in infants, yet no effective antiviral treatment or vaccine for the prevention of RSV in early life is available. Vaccination of women during pregnancy is considered to be the most plausible strategy to provide direct RSV antibody protection to young infants during a period of greatest vulnerability. RECENT FINDINGS: Interest in the development of RSV vaccines for immunization of women during pregnancy is high. Numerous studies are underway to better understand the epidemiology and impact of RSV disease in pregnant women and infants, as well as the role of maternal antibodies in the protection of infants against early and severe RSV disease, to identify and measure serologic correlates of protection to RSV in infants and develop well tolerated and immunogenic RSV vaccines for pregnant women. SUMMARY: Studies of RSV vaccination in pregnancy are in progress, making maternal vaccination a realistic intervention for the protection of young infants against RSV disease in the near future. Maternal immunization with an immunogenic vaccine has the potential to substantially impact the morbidity and mortality of RSV-associated lower respiratory tract illness in infants worldwide. PMID- 25918958 TI - Current concepts in pathogenesis of acute and chronic osteomyelitis. AB - PURPOSE OF REVIEW: The term osteomyelitis covers a wide range of inflammatory bone disorders caused by microbial invasion or due to autoinflammatory processes, but furthermore osteomyelitis also occurs at different ages and at preferred localizations in the human skeleton. This article aims to give an overview of the current literature focussing on pathognomonic aspects of osteomyelitis because of microbial invasion. RECENT FINDINGS: Outlining the chronological sequence of osteomyelitis originating from the invasion of microbes finally leading to destruction of bone tissue, the formation and proliferation of biofilm structures play a key role in the development of inflammatory bone disorders. The components of the biofilm on the one hand mediate an immune response leading to an increase of local cytokines and induction of osteoclastogenesis but on the other hand also directly interact with the osteoblasts. As a result, the bone-remodelling process is immensely diminished by induction of proapoptotic pathways, decreased proliferation and differentiation of osteoblasts and an additional promotion of osteoclastogenesis. SUMMARY: Although microbial invasion is responsible to be the cause for inflammatory bone disorders, except for an autoinflammatory origin, the underlying and detailed mechanisms in the pathogenesis of osteomyelitis are not yet fully understood, but represent an absolute precondition for the development of effective causal treatment strategies in the future. PMID- 25918957 TI - The roles of injury and nonsteroidal anti-inflammatory drugs in the development and outcomes of severe group A streptococcal soft tissue infections. AB - PURPOSE OF REVIEW: This review summarizes clinical and basic science evidence linking trauma and nonsteroidal anti-inflammatory drug (NSAID) use to initiation and progression of severe group A streptococcal (GAS) soft tissue infection. RECENT FINDINGS: New evidence includes recent clinical series and controlled studies that lend support to an NSAID/GAS association, basic science studies that demonstrate unique roles for nonpenetrating injury and NSAID administration in initiation of cryptogenic GAS infection and experimental studies showing that nonselective NSAIDs accelerate disease progression and limit antibiotic efficacy in established GAS soft tissue infections. Potential mechanisms for these processes are discussed. SUMMARY: NSAIDs are important anti-inflammatory and analgesic drugs; however, new experimental data suggest that nonselective NSAIDs do more than simply mask the signs and symptoms of developing GAS infection. A more thorough understanding of the triadic interplay of injury-triggered immune signaling, GAS soft tissue infection and NSAIDs is of significant clinical importance and could shift the current paradigm of pain management to avert the consequences of such devastating infections. PMID- 25918960 TI - 19-Norvitamin D analogs for breast cancer therapy. AB - The active form of vitamin D3, 1alpha,25-dihydroxyvitamin D3 (1alpha,25(OH)2D3 or calcitriol), is known to inhibit the proliferation and invasiveness of many types of cancer cells, including breast, colon, pancreatic, prostate, and liver cancer cells. These findings support the use of 1alpha,25(OH)2D3 for the treatment of these types of cancer. However, 1alpha,25(OH)2D3 can cause hypercalcemia, so analogs of 1alpha,25(OH)2D3 that are less calcemic but exhibit more potent anti tumor activity would be good candidates as therapeutic agents. Therefore, a series of 19-norvitamin D analogs, in which the methylidene group on C19 is replaced with 2 hydrogen atoms, have been synthesized by several laboratories. In our laboratory, we have designed and synthesized a series of 2alpha-functional group substituted 19-norvitamin D3 analogs and examined their anti-proliferative activity. Among them, 2alpha- and 2beta-(3-hydroxypropyl)-1alpha,25-dihydroxy-19 norvitamin D3 (MART-10 and MART-11) were found to be the most promising. Here, we review the rationale and approaches for the synthesis of different 19-norvitamin D analogs, and the pre-clinical studies using these analogs in breast cancer cells, in particular, we chose MART-10 for its potential application to the prevention and treatment of breast cancer. PMID- 25918961 TI - Rasch measurement: the Arm Activity measure (ArmA) passive function sub-scale. AB - PURPOSE: To evaluate the conformity of the Arm Activity measure (ArmA) passive function sub-scale to the Rasch model. METHODS: A consecutive cohort of patients (n = 92) undergoing rehabilitation, including upper limb rehabilitation and spasticity management, at two specialist rehabilitation units were included. Rasch analysis was used to examine scaling and conformity to the model. Responses were analysed using Rasch unidimensional measurement models (RUMM 2030). The following aspects were considered: overall model and individual item fit statistics and fit residuals, internal reliability, item response threshold ordering, item bias, local dependency and unidimensionality. RESULTS: ArmA contains both active and passive function sub-scales, but in this analysis only the passive function sub-scale was considered. Four of the seven items in the ArmA passive function sub-scale initially had disordered thresholds. These items were rescored to four response options, which resulted in ordered thresholds for all items. Once the items with disordered thresholds had been rescored, item bias was not identified for age, global disability level or diagnosis, but with a small difference in difficulty between males and females for one item of the scale. Local dependency was not observed and the unidimensionality of the sub scale was supported and good fit to the Rasch model was identified. The person separation index (PSI) was 0.95 indicating that the scale is able to reliably differentiate at least two groups of patients. CONCLUSIONS: The ArmA passive function sub-scale was shown in this evaluation to conform to the Rasch model once disordered thresholds had been addressed. Using the logit scores produced by the Rasch model it was possible to convert this back to the original scale range. Implications for Rehabilitation The ArmA passive function sub-scale was shown, in this evaluation, to conform to the Rasch model once disordered thresholds had been addressed and therefore to be a clinically applicable and potentially useful hierarchical measure. Using Rasch logit scores it has be possible to convert back to the original ordinal scale range and provide an indication of real change to enable evaluation of clinical outcome of importance to patients and clinicians. PMID- 25918962 TI - Validity and reliability of a novel measure of activity performance and participation. AB - PURPOSE: To develop and evaluate an innovative clinician-rated measure, which produces global numerical ratings of activity performance and participation. METHOD: Repeated measures study with 48 community-dwelling participants investigating clinical sensibility, comprehensiveness, practicality, inter-rater reliability, responsiveness, sensitivity and concurrent validity with Barthel Index. RESULTS: Important clinimetric characteristics including comprehensiveness and ease of use were rated >8/10 by clinicians. Inter-rater reliability was excellent on the summary scores (intraclass correlation of 0.95-0.98). There was good evidence that the new outcome measure distinguished between known high and low functional scoring groups, including both responsiveness to change and sensitivity at the same time point in numerous tests. Concurrent validity with the Barthel Index was fair to high (Spearman Rank Order Correlation 0.32-0.85, p > 0.05). The new measure's summary scores were nearly twice as responsive to change compared with the Barthel Index. Other more detailed data could also be generated by the new measure. CONCLUSIONS: The Activity Performance Measure is an innovative outcome instrument that showed good clinimetric qualities in this initial study. Some of the results were strong, given the sample size, and further trial and evaluation is appropriate. Implications for Rehabilitation The Activity Performance Measure is an innovative outcome measure covering activity performance and participation. In an initial evaluation, it showed good clinimetric qualities including responsiveness to change, sensitivity, practicality, clinical sensibility, item coverage, inter-rater reliability and concurrent validity with the Barthel Index. Further trial and evaluation is appropriate. PMID- 25918963 TI - Needs and requests--patients and physicians voices about improving the management of spinal cord injury neuropathic pain. AB - PURPOSE: The present purpose was to explore patients' and involved physicians' needs and requests for improving their management of neuropathic pain following spinal cord injury (SCI). METHODS: Sixteen patients with SCI and neuropathic pain, and nine physicians, were interviewed in focus-groups or individual interviews. An emergent design was used and the interviews and analyses were carried out in parallel, making it possible to use and deepen new emerging knowledge. The interviews were transcribed verbatim and processed according to content analysis. RESULTS: A final model with four themes described the results. Three themes covered the current situation: limitations in structure, lack of knowledge and competence, and frustrations. A fourth theme, needs and requests, described suggestions by patients and physicians for future improvements. Suggestions included increased participation, increased patient involvement in the pain rehabilitation process, support in the process of learning to live with pain, implementation of multi-modal pain rehabilitation, and the use of complementary treatments for neuropathic pain. CONCLUSION: Neuropathic pain following SCI needs to be assessed and treated using a structured, inter disciplinary, multi-modal rehabilitation approach involving patients in planning and decision-making. IMPLICATIONS FOR REHABILITATION: For improving SCI neuropathic pain management, there is a great need for individually-tailored management, planned in a dialogue on equal terms between health care and the patient. Patients desire continuity and regularity and the possibility of receiving complementary treatments for SCI neuropathic pain. Access to structured pain rehabilitation is needed. Support and tools need to be provided in the learning-to-live with pain process. PMID- 25918964 TI - Genetic ancestry as an effect modifier of naltrexone in smoking cessation among African Americans: an analysis of a randomized controlled trial. AB - OBJECTIVES: To determine whether there were differential quit rates between African Americans (AA) and European Americans with the experimental treatment naltrexone, and examine the role of genetic ancestry on these outcomes among AAs. METHODS: Data from a previous randomized trial of 315 smokers to naltrexone versus placebo were reanalyzed using West African (WA) genetic ancestry to define subpopulations. Logistic regression models were used to estimate treatment effects on early and end of treatment quit rates, by race and WA ancestry. RESULTS: Among European Americans (n=136), naltrexone significantly increased quit rates at 4 weeks (62 vs. 43%, P=0.03) with directional, but not statistically significant effects at 12 weeks (30 vs. 18%, P=0.12). In contrast, among the AAs (n=95), quit rates did not differ between naltrexone and placebo groups at either interval (4 weeks: 43 vs. 32%, P=0.27; 12 weeks: 22 vs. 18%, P=0.60). A median split was conducted in AAs for WA ancestry. Among AAs with low WA ancestry, quit rates were significantly higher with naltrexone compared with placebo (60 vs. 27%, P=0.03). There was no advantage in quit rates with naltrexone for the high WA ancestry group. CONCLUSION: Naltrexone efficacy for smoking cessation varies across AA individuals with different levels of WA ancestry. These results suggest that genetic background may partially explain racial differences in drug response. PMID- 25918965 TI - A study comparing standard and transepithelial collagen cross-linking riboflavin solutions: epithelial findings and pain scores. AB - PURPOSE: To evaluate epithelial signs and pain after epithelial-on corneal collagen cross-linking (Epi-on CCL) with new transepithelial riboflavin formulation and epithelial-off corneal collagen cross-linking (Epi-off CCL) with standard riboflavin formulation and to compare pain and duration of epithelial healing between both techniques. METHODS: Thirty-nine eyes of 39 patients undergoing Epi-on CCL and 39 eyes of 39 patients undergoing Epi-off CCL were evaluated. Corneal epithelial signs and durations of corneal epithelial healing and subjective pain scores after the procedures were recorded and compared between 2 groups. RESULTS: Total epithelialization was observed after 2.7 +/- 0.7 days in Epi-on CCL and 2.3 +/- 0.4 days in Epi-off CCL (P = 0.006). The mean pain score on the first day was 3.1 +/- 0.6 in Epi-on CCL and 2.3 +/- 0.4 in Epi-off CCL with a significant difference (P = 0.0001). CONCLUSION: The epithelial damage was observed in both procedures; also, the epithelial healing time was longer in Epi-on CCL and it is of great importance that the patients should have therapeutic contact lenses until the epithelium heals in both procedures. The Epi off CCL group had less pain scores than the Epi-on CCL group and more pain problems after Epi-on CCL still remains. The patient should be informed about pain, even if the Epi-on CCL procedure was performed. PMID- 25918966 TI - Mobile phone use patterns and preferences in safety net office-based buprenorphine patients. AB - BACKGROUND: Integrating mobile phone technologies in addiction treatment is of increasing importance and may optimize patient engagement with their care and enhance the delivery of existing treatment strategies. Few studies have evaluated mobile phone and text message (TM) use patterns in persons enrolled in addiction treatment, and none have assessed the use in safety net, office-based buprenorphine practices. METHODS: A 28-item, quantitative and qualitative semistructured survey was administered to opiate-dependent adults in an urban, publicly funded, office-based buprenorphine program. Survey domains included demographic characteristics, mobile phone and TM use patterns, and preferences pertaining to their recovery. RESULTS: Surveyors approached 73 of the 155 eligible subjects (47%); 71 respondents completed the survey. Nearly all participants reported mobile phone ownership (93%) and TM use (93%), and most reported "very much" or "somewhat" comfort sending TM (79%). Text message contact with 12-step group sponsors, friends, family members, and counselors was also described (32%). Nearly all preferred having their providers' mobile phone number (94%), and alerting the clinic via TM in the event of a potential relapse to receive both supportive TM and a phone call from their buprenorphine provider was also well received (62%). CONCLUSIONS: Mobile phone and TM use patterns and preferences among this sample of office-based buprenorphine participants highlight the potential of adopting patient-centered mobile phone-based interventions in this treatment setting. PMID- 25918967 TI - Patient Awareness of Untoward Effects of Smoking on Fetal and Maternal Well-being During Pregnancy: A Pilot Study. AB - INTRODUCTION: To identify knowledge gaps regarding adverse effects of smoking during pregnancy that could be targeted through antenatal education. METHODS: This was a cross-sectional survey of patients who presented for initial prenatal care from April 6, 2011, through May 25, 2011. Inclusion criteria included fluency in English and completion of at least 75% of the questionnaire. Survey included demographic information and 4 sections that assessed (1) general knowledge about the effects of smoking, (2) cancer risks associated with smoking, (3) maternal and fetal complications resulting from smoking, and (4) long-term effects of smoking on offspring. Participants were grouped as nonsmokers, former smokers, and current smokers. Data from each group were compared using analysis of variance with Tukey-Kramer post-hoc tests. RESULTS: There were 82 participants (54 nonsmokers, 17 former smokers, and 11 smokers). Self-perceived knowledge about the adverse effects of smoking was significantly less in smokers than in nonsmokers (P < 0.05). There was no statistical difference between the knowledge base of smokers when compared with nonsmokers and former smokers. Smokers seemed to be less aware of the long-term respiratory morbidity associated with maternal smoking in their offspring. There was an overall deficit in knowledge among all 3 groups of cancer risks associated with smoking other than lung cancer. CONCLUSIONS: Obstetrician-gynecologists should employ more aggressive approaches in the education of pregnant parturients about the known deleterious maternal and fetal effects of smoking, especially those risks related to cancers other than lung and long-term respiratory morbidity in their children. PMID- 25918969 TI - ABNORMAL IMAGING FINDINGS OF THE FEMORAL THIRD TROCHANTER IN 20 HORSES. AB - Injuries involving the femoral third trochanter are an uncommon but important source of equine lameness; however, clinical localization can be challenging. The purpose of this retrospective study was to describe ultrasonographic and scintigraphic findings in a group of horses with presumed third trochanter injury. Medical records of an equine referral hospital were searched from 2004 2014, and 20 horses met the inclusion criteria. Lesions consistent with third trochanter fracture were identified with ultrasound in 14/20 horses. Onset of lameness was acute (11), insidious (2), or unknown (1). All but one horse was lame at presentation, ranging from Grade 2-4/5. Ultrasound was the primary diagnostic modality in 5/14 horses with fragmentation, while scintigraphic findings of intense (3), moderate (5), and mild (1) increased radiopharmaceutical uptake (IRU) prompted ultrasonographic examinations in 9/14 fractured horses. A nondisplaced fracture was suspected in an additional horse with intense IRU and negative ultrasound findings. In the remaining five horses, imaging findings included only mild IRU. Lameness was localized to other regions in these cases. Six of 12 fractured horses with available outcome data were returned to function after a prolonged rehabilitation of 8-18 months. Scintigraphic findings helped to direct focused ultrasound exams in the majority of fracture cases. Horses with evidence of third trochanter fracture had similar clinical characteristics to that reported for pelvic fractures and authors therefore recommend ultrasonographic examination of both regions, especially when scintigraphy is unavailable. Prognosis for return to function in horses of the current study was less favorable than previously reported. PMID- 25918968 TI - Impaired Decision-Making, Higher Impulsivity, and Drug Severity in Substance Dependence and Pathological Gambling. AB - OBJECTIVES: Substance use disorder is characterized by impaired decision making, impulsivity, and risk taking. Pathological gambling shares many of these characteristics, and having both diagnoses may be associated with greater problems than either diagnosis alone. We investigated whether among substance dependent individuals, comorbid pathological gambling would be associated with worse decision making, greater impulsivity, risk taking, and drug severity. METHODS: Ninety-six substance-dependent individuals were recruited from a residential treatment program and divided into 1 of the 2 groups depending on whether they met Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition, criteria for pathological gambling (SDPG, n = 26) or not (SD, n = 70). Ninety-two controls were recruited from the community. Participants completed a decision-making task (modified Iowa Gambling Task), measures of impulsivity (Barratt Impulsivity Scale and Delay Discounting), and risk taking (Balloon Analog Risk Task). Decision making was analyzed using a computational model. We tested for group differences using analysis of covariance or Kruskal-Wallis and appropriate post-hoc tests. RESULTS: The groups differed in decision-making parameters (P < 0.001) and self-reported impulsivity (P < 0.001). All post-hoc comparisons were significant on these measures, and indicated stepwise changes in controls, followed by SD, followed by SDPG, with SDPG performing worse on decision making and being more impulsive. Compared with SD, SDPG had greater drug severity (P < 0.001). No group differences were observed in delay discounting or risk taking. CONCLUSIONS: Compared with individuals with substance dependence without pathological gambling, those with both disorders demonstrated worse decision making and significantly more drug-related symptoms. When evaluating patients with substance dependence, clinicians should consider diagnostic assessments for gambling, as the co-occurrence of both disorders may impact clinical characteristics. PMID- 25918971 TI - Nail unit squamous cell carcinoma in people with immunosuppression. AB - BACKGROUND: Nail unit squamous cell carcinoma (NUSCC) is uncommon and diagnosis is often initially incorrect or delayed. Immunosuppression appears important in the clinical behaviour of NUSCCs. OBJECTIVES: To highlight the frequency and nature of immunosuppression in a case series of patients with NUSCC, and identify the distinguishing characteristics in this subgroup. MATERIALS AND METHODS: Clinical, photographic and histological details were reviewed for all patients with NUSCC, over a 16-year period in a university dermatology department. RESULTS: Forty-three patients were identified and seven (16%) were immunosuppressed. Patients with immunosuppression presented at a younger age (mean 52 vs. 63 years, P = 0.08) and sooner (mean 9 vs. 65 months, P < 0.001) than immunocompetent patients, and had a higher frequency of polydactylous disease [four of seven (57%) vs. two of 36 (6%), P < 0.001], relapse at the same site [two of seven (29%) vs. 0], and recurrent disease at other sites [four of seven (57%) vs. 0]. CONCLUSIONS: Immunosuppression plays a role in the development and clinical behaviour of NUSCCs. Clinicians should have a low threshold for early biopsy of nail dystrophies, particularly in those with immunosuppression. These patients are at higher risk of relapse and recurrent disease and therefore require prolonged follow-up. PMID- 25918970 TI - Ultraviolet B Inhibits Skin Wound Healing by Affecting Focal Adhesion Dynamics. AB - As the most important interface between human body and external environment, skin acts as an essential barrier preventing various environmental damages, among which DNA-damaging UV radiation from the sun remains the major environmental risk factor causing various skin diseases. It has been well documented that wavelengths in the ultraviolet B (UVB) radiation range (290-320 nm) of the solar spectrum can be absorbed by skin and lead to cutaneous injury and various other deleterious effects. During process such as wound healing, the orchestrated movement of cells in a particular direction is essential and highly regulated, integrating signals controlling adhesion, polarity and the cytoskeleton. Cell adhesion and migration are modulated through both of actin and microtubule cytoskeletons. However, little was known about how UVB affects skin wound healing and migration of epidermal keratinocytes. Here, we demonstrate that UVB can delay the wound healing progress in vivo with a murine model of full-thickness skin wound. In addition, UVB significantly inhibited keratinocyte motility by altering focal adhesion turnover and cytoskeletal dynamics. Our results provide new insights into the etiology of UVB exposure-induced skin damages. PMID- 25918973 TI - Acute renal failure is prevalent in patients with thrombotic thrombocytopenic purpura associated with low plasma ADAMTS13 activity: comment. PMID- 25918972 TI - Effect of ninjin'yoeito, a Kampo (traditional Japanese) medicine, on cognitive impairment and depression in patients with Alzheimer's disease: 2 years of observation. AB - BACKGROUND: Only a few approved drugs are capable of alleviating the cognitive and behavioural symptoms of people living with Alzheimer's disease (AD). In recent years, however, the number of studies examining the clinical effects of herbal medicines on cognitive function in patients with AD has increased considerably. This study evaluated the long-term effects of a traditional Japanese medicine (Kampo medicine) known as ninjin'yoeito (NYT) on cognitive impairment and mood status in patients with AD over a 2-year period. METHODS: Twenty-three patients with mild-to-moderate probable AD according to the National Institute of Neurological and Communicative Disorders and Stroke and Alzheimer's Disease and Related Disorders Association criteria were included. Each participant had exhibited an insufficient response to treatment with donepezil alone before the start of the trial. Eleven patients received treatment with donepezil alone, and the remaining patients received a combined treatment of donepezil and NYT for 2 years. Patients were assessed by the Mini-Mental State Examination and the Alzheimer's Disease Assessment Scale-cognitive component Japanese version for cognitive function, and the Neuropsychiatric Inventory was used to evaluate the patients' mood status at baseline and every 6 months for 2 years. RESULTS: The Mini-Mental State Examination results showed no significant differences between the two groups. Significant improvements were observed on the Alzheimer's Disease Assessment Scale-cognitive component-Japanese version and the Neuropsychiatric Inventory depression scores of patients who received the combined therapy with donepezil and NYT (Alzheimer's Disease Assessment Scale cognitive component-Japanese version, 12 months: P < 0.01, 18 months: P = 0.04, 24 months: P < 0.01; Neuropsychiatric Inventory depression, 6 months: P < 0.05, 24 months: P < 0.05). CONCLUSIONS: A 2-year follow-up of patients receiving donepezil and NYT treatment showed an improved cognitive outcome and alleviation of AD-related depression. PMID- 25918974 TI - Endobronchial ultrasound-guided transbronchial needle aspiration for diagnosing mediastinal lymphadenectasis: a cohort study from a single center. AB - OBJECTIVE: Endobronchial ultrasound-guided transbronchial needle aspiration (EBUS TBNA) is commonly used for clinical diagnosis of mediastinal lymphadenectasis. This study aimed to evaluate the diagnostic significance of EBUS-TBNA for mediastinal lymphadenectasis in a large single center. METHODS: A total of 846 patients who were not definitively diagnosed with mediastinal lymphadenectasis underwent EBUS-TBNA were retrospectively analyzed in this study. RESULTS: In total, 842 patients underwent EBUS-TBNA successfully. There were 589 patients with malignancy, including squamous carcinoma (118 cases; 20.6%), adenocarcinoma (187 cases; 32.7%) and small cell carcinoma (88 cases; 15.4%). A total of 253 patients were diagnosed with benign disease, including tuberculosis (111 cases; 43.9%) and sarcoidosis (93 cases; 36.7%). The diagnostic sensitivity of lung cancer, tuberculosis and sarcoidosis were 94.4%, 81.1% and 51.6%, respectively. The overall sensitivity of EBUS-TBNA was 92.0%. N2 stage in lung cancer patients who were diagnosed by EBUS-TBNA was significantly higher than other stages. The positive rate of targeted puncture is high for the lymph nodes whose short-axis diameters were larger than 1 cm. CONCLUSION: The operation risk of EBUS-TBNA is relatively small. In diseases complicated by mediastinal lymphadenectasis, malignant diseases are most, and benign diseases mainly are granulomatous. EBUS TBNA is a valuable diagnostic technique in patients with mediastinal lymphadenectasis whose diagnosis have not been determined. PMID- 25918975 TI - Pyogranulomatous panophthalmitis with systemic coronavirus disease in a domestic ferret (Mustela putorius furo). AB - A 15-month-old spayed female ferret (Mustela putorius furo) presented for lethargy and weight loss of 2 weeks duration. Upon physical examination, a 2-mm diameter focal area of opacity was noted in the left cornea. In addition, the ferret was quiet, in poor body condition, and dehydrated. A complete blood count and plasma biochemistry revealed a severe nonregenerative anemia, azotemia, hyperproteinemia, hypoalbuminemia, and mild hyperphosphatemia and hyperchloremia. Urinalysis revealed hyposthenuria. Whole body radiographs showed multifocal thoracic nodular disease, splenomegaly, and renomegaly. Abdominal ultrasonography confirmed bilaterally enlarged kidneys, hypoechoic liver and spleen, and a caudal abdominal hypoechoic mobile nodule. The ferret was humanely euthanized, and a postmortem examination with subsequent histopathology showed multifocal necrotizing pyogranulomas in the lung, spleen, kidneys, mesenteric lymph nodes, and serosa of the duodenum. Pyogranulomatous panophthalmitis was diagnosed in the left eye. The multisystemic granulomatous lesions were suggestive of ferret systemic coronavirus (FRSCV). The presence of coronavirus in the left eye was confirmed by positive immunohistochemistry. Reverse transcriptase polymerase chain reaction (RT-PCR) on formalin fixed paraffin embedded tissue from the lung, spleen, and kidney was negative for FRSCV and positive for ferret enteric coronavirus (FRECV). Systemic coronavirus disease in ferrets closely resembles feline infectious peritonitis (FIP) in domestic cats, which can manifest with anterior uveitis, chorioretinitis, optic neuritis, and retinal detachment. To the authors' knowledge, this is the first report of ocular lesions in a ferret with systemic coronavirus disease, suggesting that ferrets presented with similar ocular lesions should also be evaluated for evidence of coronavirus infection. PMID- 25918976 TI - Prediction of intracerebral haemorrhage expansion with clinical, laboratory, pharmacologic, and noncontrast radiographic variables. AB - BACKGROUND: Hematoma expansion confers excess mortality in intracerebral haemorrhage, and is potentially preventable if at-risk patients can be identified. Contrast extravasation on initial computed tomographic angiography strongly predicts hematoma expansion but is not very sensitive, and most centers have not yet integrated computed tomographic angiography into acute intracerebral haemorrhage management. We therefore asked whether other presentation variables can predict hematoma expansion. METHODS: We searched the electronic medical records of a large integrated healthcare delivery system to identify patients with a hospitalization discharge diagnosis of intracerebral haemorrhage between the years 2008 and 2010. Hematoma expansion was defined as radiographic increase by 1/3 or by 12.5 ml within 48 h of presentation. Pre-specified patient demographic and clinical presentation variables were extracted. Stepwise multivariable logistic regression was performed to model hematoma expansion. Because some patients may have died from hematoma expansion without a second head computed tomography, we constructed a separate model including patients that died without a second head computed tomography in 48 h, hematoma expansion or death. RESULTS: Ninety-one of 257 patients (35%) had hematoma expansion. Antithrombotic use (odds ratio = 1.9, P = 0.04) and initial mNIHSS (modified National Institutes of Health Stroke Scale; odds ratio = 1.06, P = 0.001) were significant predictors in the hematoma expansion model (area under the Receiver-Operator Characteristics curve, AUROC = 0.6712, pseudo-r(2) = 0.0641). 163 of 343 patients (48%) had hematoma expansion or death. Age (odds ratio = 1.02, P = 0.02), initial mNIHSS (odds ratio = 1.07, P < 0.001), and initial hematoma volume (odds ratio = 1.01, P = 0.03) were significant predictors of hematoma expansion or death (AUROC = 0.7579, pseudo-r(2) = 0.1722). CONCLUSION: Clinical and noncontrast radiographic variables only weakly predict hematoma expansion. Examination of other indicators, such as computed tomographic angiography contrast extravasation (the 'spot sign'), may prove more valuable in acute intracerebral haemorrhage care. PMID- 25918977 TI - Translation and psychometric evaluation of a Swedish version of the parental stressor scale PSS: NICU. AB - AIM: The aim was to translate the Parental Stressor Scale: Neonatal Intensive Care Unit (PSS: NICU) into the Swedish language and to evaluate the psychometric properties of the Swedish version. METHOD: The PSS: NICU was translated into Swedish using the process of forward-backward translation. Thereafter, an internal panel of neonatal nurses (n = 10) assessed face and content validity and a panel of parents (n = 10) assessed content validity. A sample of 95 parents recruited from three different neonatal units completed the PSS: NICU and answered some open-ended questions in which they could comment on language and wording. There were eight new items in the PSS: NICU, compared with the very first version of the instrument. These had not been psychometrically tested previously. In this study, the subscales and total scale were analysed both with and without the new items to determine whether or not to use them. Psychometric properties including internal consistency, Cronbach's alpha (if item deleted) and corrected item total were evaluated. RESULT: The result indicates that the Swedish version of PSS: NICU, both with and without the nonvalidated items, has acceptable psychometric properties and can be used in clinical practice in NICUs in Sweden. CONCLUSION: In order to meet the psychological needs of parents, healthcare professionals need to identify risk factors in the Neonatal Intensive Care Unit that contribute to stress amongst parents. The Swedish version of the PSS: NICU can be used for this purpose. PMID- 25918978 TI - Solubility of chiral species as function of the enantiomeric excess. AB - The solubility of racemizable and nonracemizable chiral species is discussed in terms of: enantiomeric excess, nature of solvent and the solid phases, which are in equilibrium with a saturated solution. Stable and metastable equilibria are contemplated by an extensive used of phase diagrams. PMID- 25918979 TI - Spirochete immunostaining is not just for syphilis: diagnostic utility in borreliosis. PMID- 25918980 TI - A sarcoidosis-like granuloma reaction in the lymph nodes of a patient with lung squamous cancer: from stasis to the invasive phase with FGFR1 gene amplification. AB - BACKGROUND: Granulomatous inflammation is considered an immune mechanism against infection or certain non-neoplastic conditions. Sarcoidosis-like granuloma reactions (SGRs) in primary tumors or in regional lymph nodes are occasionally observed; however, they are rare in lung cancer. CASE REVIEW: In this study, we reported on a case of squamous lung cancer with swollen mediastinal lymph nodes, similar to sarcoidosis. He was misdiagnosed as benign lymph node SGRs or tuberculosis for 2 years. Reexamination of the lymph node by immunohistochemistry confirmed the malignant disease. The lung cancer appeared to remain in the stasis phase for 2 years and then burst to stage IV with the amplification of the fibroblast growth factor receptor 1 gene. CONCLUSIONS: Although tumor-induced draining lymph node granulomatous reactions are rare, they did exist in some of the patients. In this case, differential diagnoses with malignant granulomas should be performed carefully to avoid the misdiagnosis of a benign disease. The biological significance of such a granulomatous response in inducing tumor remission or in shielding tumor cells from host lymphocytes remains obscure. PMID- 25918981 TI - Research lessons from implementing a national nursing workforce study. AB - BACKGROUND: National nursing workforce studies are important for evidence-based policymaking to improve nursing human resources globally. Survey instrument translation and contextual adaptation along with level of experience of the research team are key factors that will influence study implementation and results in countries new to health workforce studies. AIM: This study's aim was to describe the pre-data collection instrument adaptation challenges when designing the first national nursing workforce study in Poland while participating in the Nurse Forecasting: Human Resources Planning in Nursing project. METHODS: A descriptive analysis of the pre-data collection phase of the study. Instrument adaptation was conducted through a two-phase content validity indexing process and pilot testing from 2009 to September 2010 in preparation for primary study implementation in December 2010. Means of both content validation phases were compared with pilot study results to assess for significant patterns in the data. RESULTS: The initial review demonstrated that the instrument had poor level of cross-cultural relevance and multiple translation issues. After revising the translation and re-evaluating using the same process, instrument scores improved significantly. Pilot study results showed floor and ceiling effects on relevance score correlations in each phase of the study. LIMITATIONS: The cross-cultural adaptation process was developed specifically for this study and is, therefore, new. It may require additional replication to further enhance the method. CONCLUSIONS: The approach used by the Polish team helped identify potential problems early in the study. The critical step improved the rigour of the results and improved comparability for between countries analyses, conserving both money and resources. This approach is advised for cross-cultural adaptation of instruments to be used in national nursing workforce studies. IMPLICATIONS FOR NURSING AND HEALTH POLICY: Countries seeking to conduct national nursing workforce surveys to improve nursing human resources policies may find the insights provided by this paper useful to guide national level nursing workforce study implementation. PMID- 25918982 TI - Der p1 and Der p2-Specific T Cells Display a Th2, Th17, and Th2/Th17 Phenotype in Atopic Dermatitis. PMID- 25918983 TI - Prognostic Significance of Promoter Hypermethylation and Diminished Gene Expression of SYNPO2 in Melanoma. PMID- 25918984 TI - Functional Beta2-Integrins Restrict Skin Inflammation In Vivo. AB - Beta2-integrins and the important integrin regulator kindlin-3 are essential for leukocyte trafficking, but the role of beta2-integrins in regulating inflammation is still incompletely understood. Here, we have investigated skin inflammation in a mouse model where the kindlin-3 binding site in the beta2-integrin has been mutated (TTT/AAA-beta2-integrin knock-in), leading to expressed but dysfunctional integrins. We show that, surprisingly, neutrophil trafficking into the inflamed skin in a contact hypersensitivity model is normal in these mice, although trafficking of T cells and eosinophils into the skin is reduced. Instead, expression of dysfunctional integrins leads to increased mast cell and dendritic cell numbers in the skin, increased inflammatory cytokine production in the inflamed skin in vivo, and in mast cells in vitro. Furthermore, expression of dysfunctional integrins leads to increased dendritic cell activation and migration to lymph nodes and increased Th1 responses in vivo. Therefore, the kindlin-3/integrin interaction is important for trafficking of T cells and eosinophils but not absolutely required for neutrophil trafficking into the inflamed skin. Functional beta2-integrins also have a major role in restricting the immune response in the inflamed skin and lymph nodes in vivo, likely through effects on mast cell and dendritic cell numbers and activation. PMID- 25918985 TI - Factors affecting discharge destination following lung transplantation. AB - BACKGROUND: Lung transplant (LT) recipients requiring additional care may be referred to inpatient rehabilitation prior to discharge home. This study seeks to describe discharge destinations following LT, compare the characteristics of patients discharged to different destinations, and identify the predictors of discharge destination. METHODS: Retrospective study of 243 LT recipients who survived to hospital discharge between 2006 and 2009. LT recipients were compared based on discharge destination on data pertaining to demographics, clinical characteristics, and healthcare utilization. RESULTS: Of the 243 recipients, 197 (81%) were discharged home, 42 (17%) to inpatient rehabilitation, and 4 (2%) to other medical facilities. Age, pulmonary diagnosis, most recent six-minute walk distance (6 MWD) prior to transplant, pre-transplant mechanical ventilation, priority listing status, pre- and post-transplant intensive care unit length of stay (ICU LOS), post-transplant LOS, total LOS, and participation in pre transplant rehabilitation were statistically different between patients that were discharged home versus inpatient rehabilitation. Age, most recent 6 MWD prior to transplant, pre-transplant mechanical ventilation, and total LOS were found to be independent predictors of discharge destination. CONCLUSION: Clinical factors can help identify patients more likely to require inpatient rehabilitation. Identification of these factors has the potential to facilitate early discharge planning and optimize continuity of care. PMID- 25918986 TI - Prognostic value of continuous electroencephalography monitoring in children with severe brain damage. AB - PURPOSE: The purpose of this study is to determine whether there is a relationship between continuous electroencephalography (EEG) monitoring patterns and prognosis for children with severe brain damage. Patients and METHODS: The different patterns of EEG were analyzed for 103 children (Glasgow Coma Scale [GCS] score < 8) who were monitored with continuous video-EEG (CVEEG) within 72 hours after the onset of coma. The clinical outcomes were scored and evaluated at hospital discharge by the modified Pediatric Cerebral and Overall Performance Category Scale (PCOPCS). EEG parameters of the different prognosis groups were compared and risk factors for prognosis were identified. RESULTS: Of the 103 children, 36 were in the good prognosis group (PCOPCS scores 1 and 2) and 67 were in the poor prognosis group (PCOPCS scores 3-6). The poor prognosis group had the lower proportion of events in reactive EEG patterns and sleep architecture, and a higher proportion of low-voltage events. Multivariate analyses showed that the lower GCS score and no sleep architecture were significantly associated with poor prognosis. CONCLUSIONS: Comatose children with higher GCS score and sleep architecture have better clinical outcomes in terms of morbidity and mortality. PMID- 25918987 TI - Sleep in children with neurodevelopmental disabilities. AB - This review describes recent research in pediatric sleep disorders associated with neurodevelopmental disabilities (NDDs) and their treatment. NDDs affect more than 2% of the general population and represent more than 35% of the total cases of children referred to a neuropsychiatric center for sleep problems. Specific clinical and therapeutic aspects of sleep disorders associated with Down syndrome, Fragile X syndrome, Prader-Willi syndrome, Angelman syndrome, Rett syndrome, Smith-Magenis syndrome, cerebral palsy, and autism spectrum disorders are described. Furthermore, the drugs commonly used for sleep disorders in children with NDDs are described. The review clearly highlighted that children with NDDs are often affected by sleep disorders that require appropriate clinical and therapeutic approach to improve quality of life in both patients and families. PMID- 25918989 TI - When the bi-directional Glenn is an unfavourable option: primary extracardiac inferior cavopulmonary connection as an alternative palliation. AB - The superior cavopulmonary anastomosis - bi-directional Glenn - is the standard palliation for single ventricle physiology. When upper body systemic venous anatomic concerns such as superior caval vein stenosis, hypoplasia, or inadequate collateral tributaries are present, a Glenn may be precluded or have a high risk of poor outcome. A primary inferior cavopulmonary connection with an extracardiac conduit is an alternative palliation that provides a generous pathway for pulmonary blood flow, with the additional benefit of including hepatic venous return. We report a case of primary extracardiac inferior cavopulmonary connection in a patient unsuitable for Glenn, with successful post-operative outcome and early follow-up. PMID- 25918988 TI - Dietary intake in the dependent elderly: evaluation of the risk of nutritional deficit. AB - BACKGROUND: Malnutrition is a frequent problem in elderly dependent patients and their prognosis is adversely affected. Assessment of food consumption and adequacy of energy and nutrient intake of dependent elderly is needed to plan any selected actions for this population. METHODS: The study comprised a multicentre cross-sectional study of 190 users (>=65 years) of a home care programme provided by primary care centers in Tarragona (Spain), at nutritional risk (Mini Nutritional Assessment: 17-23.5 points). Food consumption was assessed using a semiquantitative validated food frequency questionnaire. Energy intake was compared with the Spanish dietary reference intake (DRI) and nutritional intakes with the DRI of the American Institute of Medicine. RESULTS: Mean (SD) age was 85.0 (7.2) years (67.5% female). The food items consumed were varied but lower than the recommended portions for cereals, fruits, vegetables and legumes. Energy intake was 7454.2 (1553.9 kJ day(-1)) [1781.6 (371.4) kcal day(-1)] (97.7% of recommended dietary allowance; RDA) and protein intake was 1.0 (0.4) g kg(-1) of weight (121.4% of RDA). Proteins provided 13.3%, carbohydrates provided 39.9% and fats provided 45.8% of energy intake. The intakes of calcium, vitamin D, vitamin E and folates were less than two-thirds of the RDA and their probability of inadequate intake was >85%. CONCLUSIONS: Dietary intakes of elderly dependent patients at nutritional risk were well balanced. In general, energy and protein intakes meet the recommendations. The diet was high in energy density, low in complex carbohydrates, high in simple carbohydrates and excessive in fats. The dependent elderly had inadequate intake of micronutrients often related to fragility, such as calcium, vitamin D, vitamin E and folates. PMID- 25918990 TI - Using magnetic nanoparticles for gene transfer to neural stem cells: stem cell propagation method influences outcomes. AB - Genetically engineered neural stem cell (NSC) transplants offer a key strategy to augment neural repair by releasing therapeutic biomolecules into injury sites. Genetic modification of NSCs is heavily reliant on viral vectors but cytotoxic effects have prompted development of non-viral alternatives, such as magnetic nanoparticle (MNPs). NSCs are propagated in laboratories as either 3-D suspension "neurospheres" or 2-D adherent "monolayers". MNPs deployed with oscillating magnetic fields ("magnetofection technology") mediate effective gene transfer to neurospheres but the efficacy of this approach for monolayers is unknown. It is important to address this issue as oscillating magnetic fields dramatically enhance MNP-based transfection in transplant cells (e.g., astrocytes and oligodendrocyte precursors) propagated as monolayers. We report for the first time that oscillating magnetic fields enhanced MNP-based transfection with reporter and functional (basic fibroblast growth factor; FGF2) genes in monolayer cultures yielding high transfection versus neurospheres. Transfected NSCs showed high viability and could re-form neurospheres, which is important as neurospheres yield higher post-transplantation viability versus monolayer cells. Our results demonstrate that the combination of oscillating magnetic fields and a monolayer format yields the highest efficacy for MNP-mediated gene transfer to NSCs, offering a viable non-viral alternative for genetic modification of this important neural cell transplant population. PMID- 25918991 TI - Diffusivity of the uncinate fasciculus in heroin users relates to their levels of anxiety. AB - Heroin use is closely associated with emotional dysregulation, which may explain its high comorbidity with disorders such as anxiety and depression. However, the understanding of the neurobiological etiology of the association between heroin use and emotional dysregulation is limited. Previous studies have suggested an impact of heroin on diffusivity in white matter involving the emotional regulatory system, but the specificity of this finding remains to be determined. Therefore, this study investigated the association between heroin use and diffusivity of white matter tracts in heroin users and examined whether the tracts were associated with their elevated anxiety and depression levels. A sample of 26 right-handed male abstinent heroin users (25 to 42 years of age) and 32 matched healthy controls (19 to 55 years of age) was recruited for this study. Diffusion tensor imaging data were collected, and their levels of anxiety and depression were assessed using the Hospital Anxiety and Depression Scale. Our findings indicated that heroin users exhibited higher levels of anxiety and depression, but the heroin use-associated left uncinate fasciculus was only related to their anxiety level, suggesting that association between heroin and anxiety has an incremental organic basis but that for depression could be a threshold issue. This finding improves our understanding of heroin addiction and its comorbid affective disorder and facilitates future therapeutic development. PMID- 25918993 TI - Testing the accuracy of an observation-based classifier for rapid detection of autism risk. PMID- 25918992 TI - Neuropsychological and functional outcomes in recent-onset major depression, bipolar disorder and schizophrenia-spectrum disorders: a longitudinal cohort study. AB - Functional disability is the lead contributor to burden of mental illness. Cognitive deficits frequently limit functional recovery, although whether changes in cognition and disability are longitudinally associated in recent-onset individuals remains unclear. Using a prospective, cohort design, 311 patients were recruited and assessed at baseline. One hundred and sixty-seven patients met eligibility criteria (M=21.5 years old, s.d.=4.8) and returned for follow-up (M=20.6 months later, s.d.=7.8). Two-hundred and thirty participants were included in the final analysis, comprising clinically stable patients with major depression (n=71), bipolar disorder (BD; n=61), schizophrenia-spectrum disorders (n=35) and 63 healthy controls. Neuropsychological functioning and self-rated functional disability were examined using mixed-design, repeated-measures analysis, across diagnoses and cognitive clusters, covarying for relevant confounds. Clinical, neuropsychological and functional changes did not differ between diagnoses (all P>0.05). Three reliable neuropsychological subgroups emerged through cluster analysis, characterized by psychomotor slowing, improved sustained attention, and improved verbal memory. Controlling for diagnosis and changes in residual symptoms, clusters with improved neuropsychological functioning observed greater reductions in functional disability than the psychomotor slowing cluster, which instead demonstrated a worsening in disability (P<0.01). Improved sustained attention was independently associated with greater likelihood of follow-up employment (P<0.01). Diagnosis of BD uniquely predicted both follow-up employment and independent living. Neuropsychological course appears to be independently predictive of subjective and objective functional outcomes. Importantly, cognitive phenotypes may reflect distinct pathophysiologies shared across major psychiatric conditions, and be ideal targets for personalized early intervention. PMID- 25918994 TI - Genome-wide methylation study on depression: differential methylation and variable methylation in monozygotic twins. AB - Depressive disorders have been shown to be highly influenced by environmental pathogenic factors, some of which are believed to exert stress on human brain functioning via epigenetic modifications. Previous genome-wide methylomic studies on depression have suggested that, along with differential DNA methylation, affected co-twins of monozygotic (MZ) pairs have increased DNA methylation variability, probably in line with theories of epigenetic stochasticity. Nevertheless, the potential biological roots of this variability remain largely unexplored. The current study aimed to evaluate whether DNA methylation differences within MZ twin pairs were related to differences in their psychopathological status. Data from the Illumina Infinium HumanMethylation450 Beadchip was used to evaluate peripheral blood DNA methylation of 34 twins (17 MZ pairs). Two analytical strategies were used to identify (a) differentially methylated probes (DMPs) and (b) variably methylated probes (VMPs). Most DMPs were located in genes previously related to neuropsychiatric phenotypes. Remarkably, one of these DMPs (cg01122889) was located in the WDR26 gene, the DNA sequence of which has been implicated in major depressive disorder from genome wide association studies. Expression of WDR26 has also been proposed as a biomarker of depression in human blood. Complementarily, VMPs were located in genes such as CACNA1C, IGF2 and the p38 MAP kinase MAPK11, showing enrichment for biological processes such as glucocorticoid signaling. These results expand on previous research to indicate that both differential methylation and differential variability have a role in the etiology and clinical manifestation of depression, and provide clues on specific genomic loci of potential interest in the epigenetics of depression. PMID- 25918996 TI - Ren Shen Yangrong Tang for Fatigue in Cancer Survivors: A Phase I/II Open-Label Study. AB - OBJECTIVES: This open-label, prospective, phase I/II trial was performed to establish the safety and efficacy of Traditional Chinese Medicine (TCM) herbal products for treating non-anemia-related fatigue in patients with cancer. Although this practice is widespread in China, it has not been confirmed in a prospective clinical study. DESIGN: Thirty-three patients who had completed cancer treatment, had stable disease and no anemia, and reported moderate to severe fatigue (rated >=4 on a 0-10 scale) were enrolled in a TCM outpatient clinic. Patients took Ren Shen Yangrong Tang (RSYRT) decoction, a soup containing 12 TCM herbs, twice a day for 6 weeks. RSYRT aims to correct qi deficiency. Fatigue was assessed before and after RSYRT therapy, which all patients completed. RESULTS: No discomfort or toxicity was observed. Before the study, all patients had had fatigue for at least 4 months. Fatigue severity decreased significantly from before therapy to 6 weeks after therapy: from 7.06 to 3.30 on a 0-10 scale (p<0.001). Fatigue category (mild, moderate, severe) shifted significantly (p=0.024): Of 22 patients with severe fatigue (rated >=7) before therapy, 11 had mild fatigue and 11 had moderate fatigue after TCM treatment. The time-to-fatigue-alleviation was 2-3 weeks. CONCLUSION: RSYRT therapy was safe and was associated with fatigue improvement in nonanemic cancer survivors, consistent with historical TCM clinical practice experience. Because of a possible placebo effect in this open-label study, decoction RSYRT warrants further study in randomized clinical trials to confirm its effectiveness for managing moderate to severe fatigue. PMID- 25918995 TI - Genome-wide association data suggest ABCB1 and immune-related gene sets may be involved in adult antisocial behavior. AB - Adult antisocial behavior (AAB) is moderately heritable, relatively common and has adverse consequences for individuals and society. We examined the molecular genetic basis of AAB in 1379 participants from a case-control study in which the cases met criteria for alcohol dependence. We also examined whether genes of interest were expressed in human brain. AAB was measured using a count of the number of Antisocial Personality Disorder criteria endorsed under criterion A from the Diagnostic and Statistical Manual of Mental Disorders, 4th Edition (DSM IV). Participants were genotyped on the Illumina Human 1M BeadChip. In total, all single-nucleotide polymorphisms (SNPs) accounted for 25% of the variance in AAB, although this estimate was not significant (P=0.09). Enrichment tests indicated that more significantly associated genes were over-represented in seven gene sets, and most were immune related. Our most highly associated SNP (rs4728702, P=5.77 * 10(-7)) was located in the protein-coding adenosine triphosphate-binding cassette, sub-family B (MDR/TAP), member 1 (ABCB1). In a gene-based test, ABCB1 was genome-wide significant (q=0.03). Expression analyses indicated that ABCB1 was robustly expressed in the brain. ABCB1 has been implicated in substance use, and in post hoc tests we found that variation in ABCB1 was associated with DSM-IV alcohol and cocaine dependence criterion counts. These results suggest that ABCB1 may confer risk across externalizing behaviors, and are consistent with previous suggestions that immune pathways are associated with externalizing behaviors. The results should be tempered by the fact that we did not replicate the associations for ABCB1 or the gene sets in a less-affected independent sample. PMID- 25918997 TI - Anti-inflammatory Hydrolyzable Tannins from Myricaria bracteata. AB - Twelve hydrolyzable tannins were obtained from the twigs of Myricaria bracteata, including two new hellinoyl-type dimers, bracteatinins D1 (1) and D2 (2); a new hellinoyl-type trimer, bracteatinin T1 (3); two known monomers, nilotinin M4 (4) and 1,3-di-O-galloyl-4,6-O-(aS)-hexahydroxydiphenoyl-beta-d-glucose (5); six known dimers, tamarixinin A (6), nilotinin D8 (7), hirtellins A (10), B (9), and E (8), and isohirtellin C (11); and a known trimer, hirtellin T3 (12). The structures of the tannins were elucidated by spectroscopic data analysis and comparisons to known tannins. All compounds were evaluated as free radical scavengers using 1,1-diphenyl-2-picrylhydrazyl and hydroxy radicals and compared to the activity of BHT and Trolox. Compound 6 showed a significant anti inflammatory effect on croton oil-induced ear edema in mice (200 mg/kg, inhibition rate 69.8%) and on collagen-induced arthritis in DBA/1 mice (20 mg/kg, inhibition rate 46.0% at day 57). PMID- 25918998 TI - Should acetylcysteine be used to prevent contrast induced nephropathy? AB - Diagnostic and therapeutic procedures that require the infusion of iodine containing contrast solutions are associated with the risk of contrast-induced nephropathy, a condition that can cause significant morbidity. Acetylcysteine has been proposed as a measure to prevent this condition. Searching in Epistemonikos database, which is maintained by screening 30 databases, we identified 20 systematic reviews including 64 randomized trials. We combined the evidence using meta-analysis and generated a summary of findings table following the GRADE approach. We concluded that even though acetylcysteine might not cause important adverse effects, it does not decrease need for dialysis, mortality or other important outcomes. PMID- 25918999 TI - Costs and Consequences of Using Interferon-gamma Release Assays for the Diagnosis of Active Tuberculosis in India. AB - BACKGROUND: There is growing concern that interferon-gamma release assays (IGRAs) are being used off-label for the diagnosis of active tuberculosis (TB) disease in many high-burden settings, including India, where the background prevalence of latent TB infection is high. We analyzed the costs and consequences of using IGRAs for the diagnosis of active TB in India from the perspective of the Indian TB control sector. METHODS AND FINDINGS: We constructed a decision analytic model to estimate the incremental cost and effectiveness of IGRAs for the diagnosis of active TB in India. We compared a reference scenario of clinical examination and non-microbiological tests against scenarios in which clinical diagnosis was augmented by the addition of either sputum smear microscopy, IGRA, or Xpert MTB/RIF. We examined costs (in 2013 US dollars) and consequences from the perspective of the Indian healthcare sector. Relative to sputum smear microscopy, use of IGRA for active TB resulted in 23,700 (95% uncertainty range, UR: 3,800 - 38,300) additional true-positive diagnoses, but at the expense of 315,700 (95% UR: 118,300 - 388,400) additional false-positive diagnoses and an incremental cost of US$49.3 million (95% UR: $34.9 - $58.0 million) (2.9 billion Indian Rupees). Relative to Xpert MTB/RIF (including the cost of treatment for drug resistant TB), use of IGRA led to 400 additional TB cases treated (95% UR: [ 8,000] - 16,200), 370,600 (95% UR: 252,200 - 441,700) more false-positive diagnoses, 70,400 (95% UR: [-7,900] - 247,200) fewer disability-adjusted life years averted, and US$14.6 million (95%UR: [-$7.2] - $28.7 million) (854 million Indian Rupees) in additional costs. CONCLUSION: Using IGRAs for diagnosis of active TB in a setting like India results in tremendous overtreatment of people without TB, and substantial incremental cost with little gain in health. These results support the policies by WHO and Standards for TB Care in India, which discourage the use of IGRAs for the diagnosis of active TB in India and similar settings. PMID- 25919000 TI - Acupuncture therapy for sudden sensorineural hearing loss: a systematic review and meta-analysis of randomized controlled trials. AB - OBJECTIVE: Acupuncture has commonly been used in China, either alone or in combination with Western medicine, to treat sudden sensorineural hearing loss (SSHL). The purpose of this systematic review is to assess the efficacy and safety of acupuncture therapy for patients with SSHL. METHODS: We searched PubMed, the Cochrane Library, Embase, China National Knowledge Internet (CNKI), Database for Chinese Technical Periodicals (VIP), and Chinese Biomedical literature service system (SinoMed) to collect randomized controlled trials of acupuncture for SSHL published before July 2014. A meta-analysis was conducted according to the Cochrane systematic review method using RevMan 5.2 software. The evidence level for each outcome was assessed using the GRADE methodology. RESULTS: Twelve trials involving 863 patients were included. A meta-analysis showed that the effect of manual acupuncture combined with Western medicine comprehensive treatment (WMCT) was better than WMCT alone (RR 1.33, 95%CI 1.19 1.49) and the same as the effect of electroacupuncture combined with WMCT (RR 1.33, 95%CI 1.19-1.50). One study showed a better effect of electroacupuncture than of WMCT (RR 1.34, 95%CI 1.24-1.45). For mean changes in hearing over all frequencies, the meta-analysis showed a better effect with the combination of acupuncture and WMCT than with WMCT alone (MD 10.85, 95%CI 6.84-14.86). However, the evidence levels for these interventions were low or very low due to a high risk of bias and small sample sizes in the included studies. CONCLUSION: There was not sufficient evidence showing that acupuncture therapy alone was beneficial for treating SSHL. However, interventions combining acupuncture with WMCT had more efficacious results in the treatment of SSHL than WMCT alone. Electroacupuncture alone might be a viable alternative treatment besides WMCT for SSHL. However, given that there were fewer eligible RCTs and limitations in the included trials, such as methodological drawbacks and small sample sizes, large scale RCTs are required to confirm the current findings regarding acupuncture therapy for SSHL. PMID- 25919002 TI - Synthesis of 3-Iminoindol-2-amines and Cyclic Enaminones via Palladium-Catalyzed Isocyanide Insertion-Cyclization. AB - A palladium-catalyzed isocyanide insertion-cyclization using low-cost and readily accessible 2-haloanilines, 2-iodophenylethanones, and isocyanides for efficient synthesis of 3-iminoindol-2-amine and cyclic enaminone derivatives has been developed. The method features low-cost and readily accessible starting materials, reliable scalability, and bond-forming efficiency as well as simple one-pot operation, which makes this strategy highly attractive. A reasonable mechanism for forming 3-iminoindol-2-amine involved double isocyanide insertion/cyclization process is proposed. PMID- 25919001 TI - Peripheral blood T cell dynamics predict relapse in multiple sclerosis patients on fingolimod. AB - BACKGROUND: Fingolimod efficiently reduces multiple sclerosis (MS) relapse by inhibiting lymphocyte egress from lymph nodes through down-modulation of sphingosine 1-phosphate (S1P) receptors. We aimed to clarify the alterations in peripheral blood T cell subsets associated with MS relapse on fingolimod. METHODS/PRINCIPAL FINDINGS: Blood samples successively collected from 23 relapsing-remitting MS patients before and during fingolimod therapy (0.5 mg/day) for 12 months and 18 healthy controls (HCs) were analysed for T cell subsets by flow cytometry. In MS patients, the percentages of central memory T (CCR7+CD45RO+) cells (TCM) and naive T (CCR7+CD45RO-) cells decreased significantly, while those of effector memory T (CCR7-CD45RA-) and suppressor precursor T (CD28-) cells increased in both CD4+T and CD8+T cells from 2 weeks to 12 months during fingolimod therapy. The percentages of regulatory T (CD4+CD25highCD127low) cells in CD4+T cells and CCR7-CD45RA+T cells in CD8+T cells also increased significantly. Eight relapsed patients demonstrated greater percentages of CD4+TCM than 15 non-relapsed patients at 3 and 6 months (p=0.0051 and p=0.0088, respectively). The IL17-, IL9-, and IL4-producing CD4+T cell percentages were significantly higher at pre-treatment in MS patients compared with HCs (p<0.01 for all), while the IL17-producing CD4+T cell percentages tended to show a transient increase at 2 weeks of fingolimod therapy (pcorr=0.0834). CONCLUSIONS: The CD4+TCM percentages at 2 weeks to 12 months during fingolimod therapy are related to relapse. PMID- 25919003 TI - Preemption versus Entrenchment: Towards a Construction-General Solution to the Problem of the Retreat from Verb Argument Structure Overgeneralization. AB - Participants aged 5;2-6;8, 9;2-10;6 and 18;1-22;2 (72 at each age) rated verb argument structure overgeneralization errors (e.g., *Daddy giggled the baby) using a five-point scale. The study was designed to investigate the feasibility of two proposed construction-general solutions to the question of how children retreat from, or avoid, such errors. No support was found for the prediction of the preemption hypothesis that the greater the frequency of the verb in the single most nearly synonymous construction (for this example, the periphrastic causative; e.g., Daddy made the baby giggle), the lower the acceptability of the error. Support was found, however, for the prediction of the entrenchment hypothesis that the greater the overall frequency of the verb, regardless of construction, the lower the acceptability of the error, at least for the two older groups. Thus while entrenchment appears to be a robust solution to the problem of the retreat from error, and one that generalizes across different error types, we did not find evidence that this is the case for preemption. The implication is that the solution to the retreat from error lies not with specialized mechanisms, but rather in a probabilistic process of construction competition. PMID- 25919004 TI - Strong and electrically conductive graphene-based composite fibers and laminates. AB - Graphene is an ideal candidate for lightweight, high-strength composite materials given its superior mechanical properties (specific strength of 130 GPa and stiffness of 1 TPa). To date, easily scalable graphene-like materials in a form of separated flakes (exfoliated graphene, graphene oxide, and reduced graphene oxide) have been investigated as candidates for large-scale applications such as material reinforcement. These graphene-like materials do not fully exhibit all the capabilities of graphene in composite materials. In the current study, we show that macro (2 inch * 2 inch) graphene laminates and fibers can be produced using large continuous sheets of single-layer graphene grown by chemical vapor deposition. The resulting composite structures have potential to outperform the current state-of-the-art composite materials in both mechanical properties and electrical conductivities (>8 S/cm with only 0.13% volumetric graphene loading and 5 * 10(3) S/cm for pure graphene fibers) with estimated graphene contributions of >10 GPa in strength and 1 TPa in stiffness. PMID- 25919006 TI - IL-17RA Signaling in Airway Inflammation and Bronchial Hyperreactivity in Allergic Asthma. AB - Asthma is a heterogeneous disease characterized by airway inflammation and hyperreactivity. IL-17 receptor A (IL-17RA) is a shared receptor subunit required for activity of IL-17 family cytokines, including IL-17A and IL-25. IL-17A and IL 25 induce different proinflammatory responses, and concentrations are elevated in subjects with asthma. However, the individual contributions of IL-17A and IL-25 to disease pathogenesis are unclear. We explored proinflammatory activities of the IL-17 pathway in models of pulmonary inflammation and assessed its effects on contractility of human bronchial airway smooth muscle. In two mouse models, IL 17RA, IL-17RB, or IL-25 blockade reduced airway inflammation and airway hyperreactivity. Individually, IL-17A and IL-25 enhanced contractility of human bronchial smooth muscle induced by methacholine or carbachol. IL-17A had more pronounced effects on methacholine-induced contractility in bronchial rings from donors with asthma compared with donors without asthma. Blocking the IL-17 pathway via IL-17RA may be a useful therapy for some patients with asthma by reducing pulmonary inflammation and airway hyperreactivity. PMID- 25919005 TI - Cervical Lymph Nodes as a Selective Niche for Brucella during Oral Infections. AB - Cervical lymph nodes (CLN) are the first lymph nodes encountered by material taking the oral route. To study their role in orally acquired infections, we analyzed 307 patients of up to 14 years treated in the university clinic of Skopje, Macedonia, for brucellosis, a zoonotic bacterial disease frequently acquired by ingestion of contaminated dairy products. From these children, 36% had lymphadenopathy. Among orally infected children, lymphadenopathy with CLN being the only lymph nodes affected was significantly more frequent as compared to those infected by contact with animals (83% vs. 63%), suggesting a possible involvement of CLN during orally acquired human brucellosis. Using a murine model where bacteria are delivered into the oral cavity, we show that Brucella quickly and selectively colonize the CLN where they proliferate and persist over long periods of time for up to 50 days post-infection. A similar efficient though less specific drainage to CLN was found for Brucella, Salmonella typhimurium and fluorescent microspheres delivered by gavage, a pathway likely representing a mixed infection mode of intragastric and oral infection, suggesting a central pathway of drained material. Microspheres as well as bacteria drained to CLN predominately reside in cells expressing CD68 and no or low levels of CD11c. Even though no systemic response could be detected, Brucella induced a locally restricted inflammatory reaction with increased expression levels of interferon gamma, interleukin (IL)-6, IL-12, granzyme B and a delayed induction of Nos2. Inflammation led to pronounced lymphadenopathy, infiltration of macrophages/monocytes expressing high levels of major histocompatibility complex II and to formation of epitheloid granulomas. Together, these results highlight the role of CLN in oral infections as both, an initial and efficient trap for bacterial invaders and as possible reservoir for chronic pathogens. They likewise cast a new light on the significance of oral routes for means of vaccination. PMID- 25919007 TI - Self-assembled monolayers on a ferromagnetic permalloy surface. AB - Self-assembled monolayers (SAMs) are nowadays broadly used as surface protectors or modifiers and play a key role in many technological applications. This has motivated the study of their formation in all kind of materials; however, and despite the current interest in molecular spintronics, the study of SAMs on ferromagnetic surfaces remains almost unexplored. In this paper, we report for the first time a methodology for the formation of SAMs of n-alkylphosphonic acids on permalloy in ambient conditions. The formed monolayers have been fully characterized by means of contact angle measurements, atomic force microscopy, X ray photoelectron spectroscopy, matrix assisted laser desorption ionization time of-flight mass spectrometry, infrared reflection absorption spectroscopy, and X ray reflectometry. Additionally, the magnetic stability of the modified permalloy after the solution process required for the SAM formation has been confirmed by magneto-optical Kerr effect magnetometry. Moreover, by means of microcontact printing lithography, very accurate SAM patterns have been transferred onto permalloy surfaces and used as resist mask in a chemical etching process giving rise to submicrometric permalloy surface patterns with potential interest in nanomagnetism, spintronics, and storage technologies. PMID- 25919008 TI - Carbene supported dimer of heavier ketenimine analogue with p and si atoms. AB - A cyclic alkyl(amino) carbene (cAAC) stabilized dimer [(cAAC)Si(P-Tip)]2 (2) (Tip = 2,4,6-triisopropylphenyl) is reported. 2 can be considered as a dimer of the heavier ketenimine (R2C?C?N-R) analogue. The dark-red rod-shaped crystals of 2 were synthesized by reduction of the precursor, cAAC-dichlorosilylene-stabilized phosphinidene (cAAC)SiCl2->P-Tip with sodium napthalenide. The crystals of 2 are storable at room temperature for several months and stable up to 215 degrees C under an inert atmosphere. X-ray single-crystal diffraction revealed that 2 contains a cyclic nonplanar four-membered SiPSiP ring. Magnetic susceptibility measurements confirmed the singlet spin ground state of 2. Cyclic voltammetry of 2 showed a quasi-reversible one-electron reduction indicating the formation of the corresponding radical anion 2(*-), which was further characterized by EPR measurements in solution. The electronic structure and bonding of 2 and 2(*-) were studied by theoretical calculations. The experimentally obtained data are in good agreement with the calculated values. PMID- 25919009 TI - NGAL and ST2 levels in ambulatory patients with chronic heart failure. Clinical and echocardiographic correlates. AB - AIM: Neutrophil gelatinase-associated lipocalin (NGAL) and ST2 receptor, a member of the interleukin-1 receptor family, are novel biomarkers with a potential role in the diagnosis and risk stratification of patients with chronic heart failure (CHF). There is however scarce data on their relation with clinical characteristics and cardiac function in patients with CHF. METHODS: Consecutive ambulatory patients with CHF were studied. All patients underwent clinical and echocardiographic assessment, and blood samples were collected for the estimation of ST2 and NGAL serum levels during the same assessment. RESULTS: A total of 76 patients (79% male, mean age: 63 +/- 14 years), with CHF and left ventricular ejection fraction of 28 +/- 7% were included. Median NGAL was 0.16 (0.09-0.275) mg/L and median ST2 was 0.0125 (0.0071-0.0176) mg/L. No association between NGAL and ST2 was observed. Multivariate analysis revealed tissue Doppler-derived right ventricular systolic velocity as an independent predictor of ST2, and the duration of HF and serum creatinine levels as independent predictors of NGAL. CONCLUSIONS: NGAL levels depend on the renal function and the duration of HF, while ST2 levels are affected by the right but not the left ventricular function and show no association with clinical indices of HF. PMID- 25919010 TI - Intravaginal lactic Acid bacteria modulated local and systemic immune responses and lowered the incidence of uterine infections in periparturient dairy cows. AB - The objective of this investigation was to evaluate whether intravaginal infusion of a lactic acid bacteria (LAB) cocktail around parturition could influence the immune response, incidence rate of uterine infections, and the overall health status of periparturient dairy cows. One hundred pregnant Holstein dairy cows were assigned to 1 of the 3 experimental groups as follows: 1) one dose of LAB on wk -2 and -1, and one dose of carrier (sterile skim milk) on wk +1 relative to the expected day of parturition (TRT1); 2) one dose of LAB on wk -2, -1, and +1 (TRT2), and 3) one dose of carrier on wk -2, -1, and +1 (CTR). The LAB were a lyophilized culture mixture composed of Lactobacillus sakei FUA3089, Pediococcus acidilactici FUA3138, and Pediococcus acidilactici FUA3140 with a cell count of 108-109 cfu/dose. Blood samples and vaginal mucus were collected once a week from wk -2 to +3 and analyzed for content of serum total immunoglobulin G (IgG), lipopolysaccharide-binding protein (LBP), serum amyloid A (SAA), haptoglobin (Hp), tumor necrosis factor (TNF), interleukin (IL)-1, IL-6, and vaginal mucus secretory IgA (sIgA). Clinical observations including rectal temperature, vaginal discharges, retained placenta, displaced abomasum, and laminitis were monitored from wk -2 to +8 relative to calving. Results showed that intravaginal LAB lowered the incidence of metritis and total uterine infections. Intravaginal LAB also were associated with lower concentrations of systemic LBP, an overall tendency for lower SAA, and greater vaginal mucus sIgA. No differences were observed for serum concentrations of Hp, TNF, IL-1, IL-6 and total IgG among the treatment groups. Administration with LAB had no effect on the incidence rates of other transition cow diseases. Overall intravaginal LAB lowered uterine infections and improved local and systemic immune responses in the treated transition dairy cows. PMID- 25919011 TI - Are pain-related fears mediators for reducing disability and pain in patients with complex regional pain syndrome type 1? An explorative analysis on pain exposure physical therapy. AB - OBJECTIVE: To investigate whether pain-related fears are mediators for reducing disability and pain in patients with Complex Regional Pain Syndrome type 1 when treating with Pain Exposure Physical Therapy. DESIGN: An explorative secondary analysis of a randomised controlled trial. PARTICIPANTS: Fifty-six patients with Complex Regional Pain Syndrome type 1. INTERVENTIONS: The experimental group received Pain Exposure Physical Therapy in a maximum of five treatment sessions; the control group received conventional treatment following the Dutch multidisciplinary guideline. OUTCOME MEASURES: Levels of disability, pain, and pain-related fears (fear-avoidance beliefs, pain catastrophizing, and kinesiophobia) were measured at baseline and after 3, 6, and 9 months follow-up. RESULTS: The experimental group had a significantly larger decrease in disability of 7.77 points (95% CI 1.09 to 14.45) and in pain of 1.83 points (95% CI 0.44 to 3.23) over nine months than the control group. The potential mediators pain related fears decreased significantly in both groups, but there were no significant differences between groups, which indicated that there was no mediation. CONCLUSION: The reduction of pain-related fears was comparable in both groups. We found no indication that pain-related fears mediate the larger reduction of disability and pain in patients with Complex Regional Pain Syndrome type 1 treated with Pain Exposure Physical Therapy compared to conventional treatment. TRIAL REGISTRATION: International Clinical Trials Registry NCT00817128. PMID- 25919013 TI - Vascular Endothelial Growth Factor as a Prognostic Parameter in Subjects with "Plateau Red Face". AB - Ma, Lan, Ying Chen, Guoen Jin, Yingzhong Yang, Qin Ga, and Ri-Li Ge. Vascular endothelial growth factor as a prognostic parameter in subjects with "plateau red face." High Alt Med Biol 16:147-153, 2015.--Some individuals living at high altitude on the Qinghai Plateau in China develop a red face called " Plateau Red Face" (PRF). It is characterized by telangiectasia of the cheeks, which become a unique ruddy color. It is more common in young females than males, subjects who have polycythemia are more susceptible to PRF, and its pathogenesis is unknown. The aim of this study was to investigate associations between PRF and levels of vascular endothelial growth factor (VEGF). METHODS: A total of 158 subjects (82 male and 76 female) residing at 4300 m and 140 subjects (73 male and 67 female) residing at 2260 m on the Qinghai Plateau, China, participated in this study. The determination and magnitude of PRF is evaluated by the dilation of veins on the face in the Qinghai chronic mountain sickness(CMS) score, established during the World Congress in 2004. Arterial O(2) saturation (Sao(2)), hemoglobin (Hb) concentration, pulmonary function tests, and serum concentration of VEGF (by ELISA) were measured in all participants. RESULTS: The occurrence of PRF was 32.9% (52/158) among subjects living at 4300 m and 15.7% (22/140) among those living at 2260 m. The levels of VEGF in PRF and non-PRF subjects were 399.9+/ 115.6 pg/mL and 270.7+/-78.1 pg/mL, respectively (p<0.001) at 4300 m, and 244.4+/ 109.0 pg/mL and 135.6+/-65.3 pg/mL, respectively (p<0.01) at 2260 m. However, comparing the levels of VEGF between the genders and ethnic groups at the same altitude, there were no significant differences between male and female both in Xining (p=0.12) and Maduo (p=0.18). There was also no significant difference between Tibetan and Han nationality in Xining (p=0.71), but In Maduo, the levels of VEGF in Han (351.70+/-122.62 pg/mL) were higher than that of Tibetan (300.20+/ 102.89 pg/mL), and there was significant difference (p=0.01). Sao2 levels in PRF subjects (86.58+/-3.49) were lower than those of non-PRF subjects (88.04+/-3.68; p=0.018), while Hb was higher. Areas under receiver operator characteristic curve for diagnosis of PRF were 0.813, 0.679, and 0.373 for VEGF, Hb, and Sao(2), respectively. VEGF levels correlated positively with Hb levels both in Xining (r=0.367, p<0.001) and Maduo (r=0.319, p<0.001), and only negatively with Sao(2) levels in Maduo (r=-0.424, P<0.001) but not in Xining (r=0.125, p=0.141). CONCLUSION: Chronic hypoxemia may stimulate overproduction of angiogenic cytokine (VEGF), and this peptide may lead to formation of abnormal new vessels and development of congestion in mucosa and conjunctiva. Thus, VEGF may, at least in part, serve as a marker of the pathophysiologic trigger for PRF. PMID- 25919012 TI - HIV shedding from male circumcision wounds in HIV-infected men: a prospective cohort study. AB - BACKGROUND: A randomized trial of voluntary medical male circumcision (MC) of HIV infected men reported increased HIV transmission to female partners among men who resumed sexual intercourse prior to wound healing. We conducted a prospective observational study to assess penile HIV shedding after MC. METHODS AND FINDINGS: HIV shedding was evaluated among 223 HIV-infected men (183 self-reported not receiving antiretroviral therapy [ART], 11 self-reported receiving ART and had a detectable plasma viral load [VL], and 29 self-reported receiving ART and had an undetectable plasma VL [<400 copies/ml]) in Rakai, Uganda, between June 2009 and April 2012. Preoperative and weekly penile lavages collected for 6 wk and then at 12 wk were tested for HIV shedding and VL using a real-time quantitative PCR assay. Unadjusted prevalence risk ratios (PRRs) and adjusted PRRs (adjPRRs) of HIV shedding were estimated using modified Poisson regression with robust variance. HIV shedding was detected in 9.3% (17/183) of men not on ART prior to surgery and 39.3% (72/183) of these men during the entire study. Relative to baseline, the proportion shedding was significantly increased after MC at 1 wk (PRR = 1.87, 95% CI = 1.12-3.14, p = 0.012), 2 wk (PRR = 3.16, 95% CI = 1.94 5.13, p < 0.001), and 3 wk (PRR = 1.98, 95% CI = 1.19-3.28, p = 0.008) after MC. However, compared to baseline, HIV shedding was decreased by 6 wk after MC (PRR = 0.27, 95% CI = 0.09-0.83, p = 0.023) and remained suppressed at 12 wk after MC (PRR = 0.19, 95% CI = 0.06-0.64, p = 0.008). Detectable HIV shedding from MC wounds occurred in more study visits among men with an HIV plasma VL > 50,000 copies/ml than among those with an HIV plasma VL < 400 copies/ml (adjPRR = 10.3, 95% CI = 4.25-24.90, p < 0.001). Detectable HIV shedding was less common in visits from men with healed MC wounds compared to visits from men without healed wounds (adjPRR = 0.12, 95% CI = 0.07-0.23, p < 0.001) and in visits from men on ART with undetectable plasma VL compared to men not on ART (PRR = 0.15, 95% CI = 0.05-0.43, p = 0.001). Among men with detectable penile HIV shedding, the median log10 HIV copies/milliliter of lavage fluid was significantly lower in men with ART-induced undetectable plasma VL (1.93, interquartile range [IQR] = 1.83-2.14) than in men not on ART (2.63, IQR = 2.28-3.22, p < 0.001). Limitations of this observational study include significant differences in baseline covariates, lack of confirmed receipt of ART for individuals who reported ART use, and lack of information on potential ART initiation during follow-up for those who were not on ART at enrollment. CONCLUSION: Penile HIV shedding is significantly reduced after healing of MC wounds. Lower plasma VL is associated with decreased frequency and quantity of HIV shedding from MC wounds. Starting ART prior to MC should be considered to reduce male-to-female HIV transmission risk. Research is needed to assess the time on ART required to decrease shedding, and the acceptability and feasibility of initiating ART at the time of MC. PMID- 25919014 TI - Mutational Analysis of the TYR and OCA2 Genes in Four Chinese Families with Oculocutaneous Albinism. AB - BACKGROUND: Oculocutaneous albinism (OCA) is an autosomal recessive disorder. The most common type OCA1 and OCA2 are caused by homozygous or compound heterozygous mutations in the tyrosinase gene (TYR) and OCA2 gene, respectively. OBJECTIVE: The purpose of this study was to evaluate the molecular basis of oculocutaneous albinism in four Chinese families. PATIENTS AND METHODS: Four non-consanguineous OCA families were included in the study. The TYR and OCA2 genes of all individuals were amplified by polymerase chain reaction (PCR), sequenced and compared with a reference database. RESULTS: Four patients with a diagnosis of oculocutaneous albinism, presented with milky skin, white or light brown hair and nystagmus. Genetic analyses demonstrated that patient A was compound heterozygous for c.1037-7T.A, c.1037-10_11delTT and c.1114delG mutations in the TYR gene; patient B was heterozygous for c.593C>T and c.1426A>G mutations in the OCA2 gene, patients C and D were compound heterozygous mutations in the TYR gene (c.549_550delGT and c.896G>A, c.832C>T and c.985T>C, respectively). The heterozygous c.549_550delGT and c.1114delG alleles in the TYR gene were two novel mutations. Interestingly, heterozygous members in these pedigrees who carried c.1114delG mutations in the TYR gene or c.1426A>G mutations in the OCA2 gene presented with blond or brown hair and pale skin, but no ocular disorders when they were born; the skin of these patients accumulated pigment over time and with sun exposure. CONCLUSION: This study expands the mutation spectrum of oculocutaneous albinism. It is the first time, to the best of our knowledge, to report that c.549_550delGT and c.1114delG mutations in the TYR gene were associated with OCA. The two mutations (c.1114delG in the TYR gene and c.1426A>G in the OCA2 gene) may be responsible for partial clinical manifestations of OCA. PMID- 25919015 TI - Difficult behaviors in the emergency department: a cohort study of housed, homeless and alcohol dependent individuals. AB - BACKGROUND: This study contrasted annual rates of difficult behaviours in emergency departments among cohorts of individuals who were homeless and low income housed and examined predictors of these events. METHODS: Interviews in 1999 with men who were chronically homeless with drinking problems (CHDP) (n = 50), men from the general homeless population (GH) (n = 61), and men residing in low-income housing (LIH) (n = 58) were linked to catchment area emergency department records (n = 2817) from 1994 to 1999. Interview and hospital data were linked to measures of difficult behaviours. RESULTS: Among the CHDP group, annual rates of visits with difficult behaviours were 5.46; this was 13.4 (95% CI 10.3 16.5) and 14.3 (95% CI 11.2-17.3) times higher than the GH and LIH groups. Difficult behaviour incidents included physical violence, verbal abuse, uncooperativeness, drug seeking, difficult histories and security involvement. Difficult behaviours made up 57.54% (95% CI 55.43-59.65%), 24% (95% CI 19-29%), and 20% (95% CI 16-24%) of CHDP, GH and LIH visits. Among GH and LIH groups, 87% to 95% were never involved in verbal abuse or violence. Intoxication increased all difficult behaviours while decreasing drug seeking and leaving without being seen. Verbal abuse and violence were less likely among those housed, with odds ratios of 0.24 (0.08, 0.72) and 0.32 (0.15, 0.69), respectively. CONCLUSIONS: Violence and difficult behaviours are much higher among chronically homeless men with drinking problems than general homeless and low-income housed populations. They are concentrated among subgroups of individuals. Intoxication is the strongest predictor of difficult behaviour incidents. PMID- 25919016 TI - Prevalence and Associated Cost and Utilization of Multiple Chronic Conditions in the Outpatient Setting among Adult Members of an Employer-Based Health Plan. AB - Patients with multiple chronic conditions (MCCs) are a significant concern for the US health care system. MCC patients represent an increasing proportion of the US population and are associated with increased health care cost and utilization, and poor quality of care. Research that has been conducted on MCC patients to date has been at the national level using large data sets, such as Medicare and Medicaid claims and the National Inpatient Sample. These studies have produced research evidence that may be of little utility to individual employer-based health plans given the inherent differences in the patient populations they serve. This study analyzed evaluation and management claims for patients ages 18 years and older (n=632,477) from the Beaumont Employee Health Plan (BEHP), a regional health insurance provider serving Beaumont Health System employees and their families across Southeastern Michigan. The study found that individuals with MCCs are associated with increased cost and visits, and decreased time between appointments in the outpatient setting. Despite decreasing prevalence of MCCs over the study period, substantial increases in cost and visits, and a decrease in time between appointments was observed for MCC patients. Asthma and chronic back pain were uniquely identified as additional primary targets for disease management programs for employer-based health plans. These findings speak to the value of studying MCCs at the employer-based health plan level, where population-specific MCCs can be identified for meaningful intervention and management. Significant opportunity exists for employer-based health plans to study, prevent, and manage MCCs among adult patients. PMID- 25919017 TI - [Smoking and spirometric values in third year medical students: cross-sectional study]. AB - OBJECTIVE: The aim of this study is to determine frequency of cigarette smoking and its relationship with indicators of lung function, as well as habits and attitudes towards smoking in third-year medical students of the Health Sciences Institute, Hector A. Barcelo Foundation, Santo Tome, Corrientes, Argentina. METHODS: We performed a cross-sectional and analytic study in third-year medical students, during the first two weeks of October 2014. We divided the study group into smokers and non-smokers and we obtained spirometric values with a computerized Flowmax 2 spirometer following the protocols established by the American Thoracic Society. In addition, we applied a questionnaire to the study group with 36 questions including the Fagerstrom test. RESULTS: We obtained a mean age of 22.5 +/- 3.81 years in 227 students; 52.9% were female and 47.1% male; 26.4% were smokers, predominantly male and with a larger consumption of cigarettes than women; 5% of smokers presented obstructive ventilatory spirometric patterns with a significant association (p = 0.017) with smoking. Twenty-five percent (25%) of male and 8.4% of female showed moderate to high tobacco physical dependence. In the non-smoker group, 18.6% had quit in the previous year or earlier, mostly to improve their health. CONCLUSION: It is important to encourage medical students to quit smoking, as well as to be aware of the harm that second-hand smoke produces. The future physician should be cognizant of the consequences associated with smoking and the importance of preventing and educating patients acting as a role model very early in their studies. PMID- 25919018 TI - Bacterial detection with amphiphilic carbon dots. AB - New bacterial detection and imaging methods are desirable for diagnostics and healthcare applications, as well as in basic scientific research. We present a simple analytical platform for bacterial detection and imaging based upon attachment of amphiphilic carbon dots (CDs) to bacterial cells. We show that CDs functionalized with hydrocarbon chains readily bind to bacterial cells following short incubation and enable detection of bacteria through both fluorescence spectroscopy and microscopy. Importantly, we demonstrate that the intensity and spectral position of the carbon dots' fluorescence depend upon bacterial species, providing a tool for distinguishing among bacteria even in cases of mixed bacterial populations. Moreover, bacterial labelling with the amphiphilic CDs enables visualization of physiological processes such as cell division. PMID- 25919019 TI - The Prevalence of Vancomycin-Intermediate Staphylococcus aureus and Heterogeneous VISA Among Methicillin-Resistant Strains Isolated from Pediatric Population in a Turkish University Hospital. AB - There are limited data regarding the prevalence of vancomycin-intermediate Staphylococcus aureus (VISA)/heterogeneous VISA (hVISA) among pediatric population. Our objective was to determine the distribution of vancomycin and daptomycin minimum inhibitory concentrations (MICs) and explore the phenomenon of vancomycin MIC creep and the VISA/hVISA prevalence among the methicillin resistant Staphylococcus aureus (MRSA) strains belonging to pediatric population by population analysis profile-area under the curve (PAP-AUC) and Etest macromethod. Vancomycin and daptomycin susceptibilities of 94 pediatric isolates of MRSA were tested by broth microdilution (BMD) and Etest methods. To determine the prevalence of VISA/hVISA, Etest macromethod and PAP-AUC was performed on all isolates. All isolates were susceptible to vancomycin and daptomycin by both BMD and Etest methods. Twenty-eight (29.8%) isolates had vancomycin MICs of 2 MUg/ml by BMD. No increase in vancomycin MICs was observed over time. There were no VISA among 94 MRSA tested but 20 (21.3%) hVISA isolates were identified by PAP-AUC. Results of Etest macromethod were compared to PAP-AUC. Etest macromethod was 60.0% sensitive and 90.5% specific. The hVISA isolates represented 53.6% of isolates with vancomycin MICs of 2 MUg/ml. Also, 75% of hVISA isolates had vancomycin MICs of 2 MUg/ml. To our knowledge, this is the first study investigating the prevalence of VISA/hVISA among MRSA isolated from pediatric patients by PAP-AUC method. Based on our findings, MRSA isolates, which have vancomycin MIC of 2 MUg/ml can be investigated for the presence of hVISA. In this study, daptomycin showed potent activity against all isolates and may represent a therapeutic option for MRSA infections. PMID- 25919020 TI - Determination of steroid hormone concentrations. PMID- 25919021 TI - Autotransfusion of a restricted volume of shed mediastinal blood does not affect the haemostatic capacity in patients following cardiac surgery. AB - The aim was to investigate the haemostatic capacity after autotransfusion of shed mediastinal blood in patients following cardiac surgery. Fifteen cardiac surgery patients with a chest tube drainage >= 300 mL blood within the first 6 hours postoperatively were included. The haemostatic capacity was evaluated using whole blood thromboelastometry (ROTEM((r))), impedance aggregometry (Multiplate((r))) and conventional coagulation tests. Measurements were carried out in (1) mediastinal blood, and in blood samples obtained, (2) before autotransfusion, and (3) after autotransfusion of mediastinal blood. In shed mediastinal blood, ROTEM((r)) analyses showed reduced clot firmness in the EXTEM (p < 0.001), INTEM (p < 0.001), and FIBTEM assay (p = 0.002). Platelet function and conventional coagulation parameters were significantly impaired (p < 0.001). However, ROTEM((r)), platelet function and conventional coagulation tests remained unchanged after autotransfusion. CONCLUSION: Shed mediastinal blood has a substantially reduced haemostatic capacity, but autotransfusion of an average of 350 mL did not affect the overall haemostatic capacity. PMID- 25919022 TI - Reduction in glomerular pore size is not restricted to pregnant women. Evidence for a new syndrome: 'Shrunken pore syndrome'. AB - The plasma levels of cystatin C, beta2-microglobulin, beta-trace protein, retinol binding protein (RBP) and creatinine were determined in plasma samples from 111 randomly selected patients with eGFRcystatin C <= 60% of eGFRcreatinine and from 55 control patients with 0.9eGFRcreatinine <= eGFRcystatin C <= 1.1eGFRcreatinine (eGFRcystatin C ~ eGFRcreatinine). The concentration ratios of cystatin C/creatinine, beta2-microglobulin/creatinine, beta-trace protein/creatinine and RBP/creatinine were significantly higher in patients with eGFRcystatin C <= 60% of eGFRcreatinine than in patients with eGFRcystatin C ~ eGFRcreatinine. When the patients were divided into three groups with different estimated GFR intervals (<= 40, 40-60 and >= 60 mL/min/1.73m(2)) the concentration ratios of cystatin C/creatinine, beta2-microglobulin/creatinine, and beta-trace protein/creatinine were significantly higher in patients with eGFRcystatin C <= 60% of eGFRcreatinine than in patients with eGFRcystatin C ~ eGFRcreatinine for all GFR intervals. Similar results were obtained when the population without pregnant women was studied as well as the subpopulations of men or of non-pregnant women. Populations of pre-eclamptic women and pregnant women in the third trimester display similar results. Since the production of these four proteins with sizes similar to that of cystatin C is not co-regulated, the most likely explanation for the simultaneous increase of their creatinine-ratios in patients with eGFRcystatin C <= 60% of eGFRcreatinine is that their elimination by glomerular filtration is decreased. We suggest that this is due to a reduction in pore diameter of the glomerular membrane and propose the designation 'Shrunken pore syndrome' for this pathophysiological state. PMID- 25919023 TI - Functional trait strategies of trees in dry and wet tropical forests are similar but differ in their consequences for succession. AB - Global plant trait studies have revealed fundamental trade-offs in plant resource economics. We evaluated such trait trade-offs during secondary succession in two species-rich tropical ecosystems that contrast in precipitation: dry deciduous and wet evergreen forests of Mexico. Species turnover with succession in dry forest largely relates to increasing water availability and in wet forest to decreasing light availability. We hypothesized that while functional trait trade offs are similar in the two forest systems, the successful plant strategies in these communities will be different, as contrasting filters affect species turnover. Research was carried out in 15 dry secondary forest sites (5-63 years after abandonment) and in 17 wet secondary forest sites (<1-25 years after abandonment). We used 11 functional traits measured on 132 species to make species-trait PCA biplots for dry and wet forest and compare trait trade-offs. We evaluated whether multivariate plant strategies changed during succession, by calculating a 'Community-Weighted Mean' plant strategy, based on species scores on the first two PCA-axes. Trait spectra reflected two main trade-off axes that were similar for dry and wet forest species: acquisitive versus conservative species, and drought avoiding species versus evergreen species with large animal dispersed seeds. These trait associations were consistent when accounting for evolutionary history. Successional changes in the most successful plant strategies reflected different functional trait spectra depending on the forest type. In dry forest the community changed from having drought avoiding strategies early in succession to increased abundance of evergreen strategies with larger seeds late in succession. In wet forest the community changed from species having mainly acquisitive strategies to those with more conservative strategies during succession. These strategy changes were explained by increasing water availability during dry forest succession and increasing light scarcity during wet forest succession. Although similar trait spectra were observed among dry and wet secondary forest species, the consequences for succession were different resulting from contrasting environmental filters. PMID- 25919024 TI - A longitudinal study on early hospitalized airway infections and subsequent childhood asthma. AB - BACKGROUND: Acute airway infections, including bronchiolitis, are common causes of early childhood hospitalization. The development of later asthma may be related to early airway infections in young children. This study is to investigate the relationship between hospitalized airway infections (HAI) in young children (< 3 years old) and later childhood asthma. METHODS: Hospitalized children (< 3 years old) with bronchiolitis or other acute airway infections (other HAI group) from 1997-2000 were retrieved from the National Health Insurance Research Database of Taiwan, and compared to age- and gender-matched subjects with regards to asthma until 10 years of age; and potential comorbidities and medical care conditions. RESULTS: In total, 3,264 children (1,981 with bronchiolitis; 1,283 with other HAIs) were compared to 18,527 controls. The incidence of childhood asthma was higher in the study (16.2%) than the control (11.7%) group, and most cases were diagnosed between 3-5 years old. The hazard ratios were 1.583 (95% CI: 1.414-1.772) and 1.226 (95% CI: 1.053 1.428) for the bronchiolitis and other HAI subgroups, respectively, compared to the control group, and 1.228 (95% CI: 1.075-1.542) in the bronchiolitis subgroup compared to the other HAIs subgroup. A significantly higher odds ratio (1.973, 95% CI: 1.193-3.263) for the children with congenital heart disease (CHD) in the bronchiolitis subgroup was found at an age of 3-5 years compared to the control group. CONCLUSIONS AND CLINICAL RELEVANCE: Young children (< 3 years old) hospitalized due to acute HAIs are at a higher risk of developing childhood asthma at age 3 to 10 years. The parents of children with HAIs at age 0 to 2 years should be informed for the higher risk of developing childhood asthma, especially in children with CHD and bronchiolitis. PMID- 25919025 TI - A prognostic score for patients with intermediate-stage hepatocellular carcinoma treated with transarterial chemoembolization. AB - BACKGROUND: Intermediate-stage hepatocellular carcinoma (HCC), defined according to the Barcelona Clinic Liver Cancer (BCLC) staging system, is a heterogeneous condition with variable clinical benefits from transarterial chemoembolization (TACE). This study aimed to develop a simple validated prognostic score based on the predictive factors for survival in patients with intermediate-stage HCC treated with TACE. METHODS: Three-hundred and fifty patients with intermediate stage HCC undergoing initial TACE at Chiba University Hospital (training cohort; n = 187) and two affiliated hospitals (validation cohort; n = 163) were included. Following variables were entered into univariate and multivariate Cox regression models to develop a points-based clinical scoring system: gender, age, etiology, pretreatment, Child-Pugh score, aspartate aminotransferase, creatinine, C reactive protein, alfa-fetoprotein, size of the largest lesion, and number and location of lesions. RESULTS: The number of lesions and the Child-Pugh score were identified as independent prognostic factors in the training cohort. The development of a 0-7-point prognostic score, named the Chiba HCC in intermediate stage prognostic (CHIP) score, was based on the sum of three subscale scores (Child-Pugh score = 0, 1, 2, or 3, respectively, number of lesions = 0, 2, or 3, respectively, HCV-RNA positivity = 0 or 1, respectively). The generated scores were then differentiated into five groups (0-2 points, 3 points, 4 points, 5 points, and 6-7 points) by the median survival time (65.2, 29.2, 24.3, 13.1, and 8.4 months, respectively; p < 0.0001). These results were confirmed in the external validation cohort (p < 0.0001). CONCLUSIONS: The CHIP score is easy-to use and may assist in finding an appropriate treatment strategy for intermediate stage HCC. PMID- 25919026 TI - Convergent evolution of mechanically optimal locomotion in aquatic invertebrates and vertebrates. AB - Examples of animals evolving similar traits despite the absence of that trait in the last common ancestor, such as the wing and camera-type lens eye in vertebrates and invertebrates, are called cases of convergent evolution. Instances of convergent evolution of locomotory patterns that quantitatively agree with the mechanically optimal solution are very rare. Here, we show that, with respect to a very diverse group of aquatic animals, a mechanically optimal method of swimming with elongated fins has evolved independently at least eight times in both vertebrate and invertebrate swimmers across three different phyla. Specifically, if we take the length of an undulation along an animal's fin during swimming and divide it by the mean amplitude of undulations along the fin length, the result is consistently around twenty. We call this value the optimal specific wavelength (OSW). We show that the OSW maximizes the force generated by the body, which also maximizes swimming speed. We hypothesize a mechanical basis for this optimality and suggest reasons for its repeated emergence through evolution. PMID- 25919027 TI - The predecessors of bitcoin and their implications for the prospect of virtual currencies. AB - To examine whether the recent price patterns and transaction costs of Bitcoin represent a general characteristic of decentralized virtual currencies, we analyze virtual currencies in online games that have been voluntarily managed by individuals since 1990s. We find that matured game currencies have price stability similar to that of small size equities or gold, and their transaction costs are sometimes lower than real currencies. Assuming that virtual currencies with a longer history can provide an estimate for Bitcoin's prospects, we project that Bitcoin will be less influenced by speculative trades and become a low cost alternative to real currencies. PMID- 25919028 TI - A BMP7 Variant Inhibits Tumor Angiogenesis In Vitro and In Vivo through Direct Modulation of Endothelial Cell Biology. AB - Bone morphogenetic proteins (BMPs), members of the TGF-beta superfamily, have numerous biological activities including control of growth, differentiation, and vascular development. Using an in vitro co-culture endothelial cord formation assay, we investigated the role of a BMP7 variant (BMP7v) in VEGF, bFGF, and tumor-driven angiogenesis. BMP7v treatment led to disruption of neo-endothelial cord formation and regression of existing VEGF and bFGF cords in vitro. Using a series of tumor cell models capable of driving angiogenesis in vitro, BMP7v treatment completely blocked cord formation. Pre-treatment of endothelial cells with BMP7v significantly reduced their cord forming ability, indicating a direct effect on endothelial cell function. BMP7v activated the canonical SMAD signaling pathway in endothelial cells but targeted gene knockdown using shRNA directed against SMAD4 suggests this pathway is not required to mediate the anti angiogenic effect. In contrast to SMAD activation, BMP7v selectively decreased ERK and AKT activation, significantly decreased endothelial cell migration and down-regulated expression of critical RTKs involved in VEGF and FGF angiogenic signaling, VEGFR2 and FGFR1 respectively. Importantly, in an in vivo angiogenic plug assay that serves as a measurement of angiogenesis, BMP7v significantly decreased hemoglobin content indicating inhibition of neoangiogenesis. In addition, BMP7v significantly decreased angiogenesis in glioblastoma stem-like cell (GSLC) Matrigel plugs and significantly impaired in vivo growth of a GSLC xenograft with a concomitant reduction in microvessel density. These data support BMP7v as a potent anti-angiogenic molecule that is effective in the context of tumor angiogenesis. PMID- 25919030 TI - Is TCL1 overexpression a good or a bad player in mantle cell lymphoma? PMID- 25919029 TI - Defining the in vivo phenotype of artemisinin-resistant falciparum malaria: a modelling approach. AB - BACKGROUND: Artemisinin-resistant falciparum malaria has emerged in Southeast Asia, posing a major threat to malaria control. It is characterised by delayed asexual-stage parasite clearance, which is the reference comparator for the molecular marker 'Kelch 13' and in vitro sensitivity tests. However, current cut off values denoting slow clearance based on the proportion of individuals remaining parasitaemic on the third day of treatment ('day-3'), or on peripheral blood parasite half-life, are not well supported. We here explore the parasite clearance distributions in an area of artemisinin resistance with the aim refining the in vivo phenotypic definitions. METHODS AND FINDINGS: Data from 1,518 patients on the Thai-Myanmar and Thai-Cambodian borders with parasite half life assessments after artesunate treatment were analysed. Half-lives followed a bimodal distribution. A statistical approach was developed to infer the characteristics of the component distributions and their relative contribution to the composite mixture. A model representing two parasite subpopulations with geometric mean (IQR) parasite half-lives of 3.0 (2.4-3.9) hours and 6.50 (5.7 7.4) hours was consistent with the data. For individual patients, the parasite half-life provided a predicted likelihood of an artemisinin-resistant infection which depends on the population prevalence of resistance in that area. Consequently, a half-life where the probability is 0.5 varied between 3.5 and 5.5 hours. Using this model, the current 'day-3' cut-off value of 10% predicts the potential presence of artemisinin-resistant infections in most but not all scenarios. These findings are relevant to the low-transmission setting of Southeast Asia. Generalisation to a high transmission setting as in regions of Sub-Saharan Africa will need additional evaluation. CONCLUSIONS: Characterisation of overlapping distributions of parasite half-lives provides quantitative insight into the relationship between parasite clearance and artemisinin resistance, as well as the predictive value of the 10% cut-off in 'day-3' parasitaemia. The findings are important for the interpretation of in vitro sensitivity tests and molecular markers for artemisinin resistance and for contextualising the 'day 3' threshold to account for initial parasitaemia and sample size. PMID- 25919031 TI - Human adipose-tissue derived stromal cells in combination with hypoxia effectively support ex vivo expansion of cord blood haematopoietic progenitors. AB - The optimisation of haematopoietic stem and progenitor cell expansion is on demand in modern cell therapy. In this work, haematopoietic stem/progenitor cells (HSPCs) have been selected from unmanipulated cord blood mononuclear cells (cbMNCs) due to adhesion to human adipose-tissue derived stromal cells (ASCs) under standard (20%) and tissue-related (5%) oxygen. ASCs efficiently maintained viability and supported further HSPC expansion at 20% and 5% O2. During co culture with ASCs, a new floating population of differently committed HSPCs (HSPCs-1) grew. This suspension was enriched with SD34+ cells up to 6 (20% O2) and 8 (5% O2) times. Functional analysis of HSPCs-1 revealed cobble-stone area forming cells (CAFCs) and lineage-restricted colony-forming cells (CFCs). The number of CFCs was 1.6 times higher at tissue-related O2, than in standard cultivation (20% O2). This increase was related to a rise in the number of multipotent precursors - BFU-E, CFU-GEMM and CFU-GM. These changes were at least partly ensured by the increased concentration of MCP-1 and IL-8 at 5% O2. In summary, our data demonstrated that human ASCs enables the selection of functionally active HSPCs from unfractionated cbMNCs, the further expansion of which without exogenous cytokines provides enrichment with CD34+ cells. ASCs efficiently support the viability and proliferation of cord blood haematopoietic progenitors of different commitment at standard and tissue-related O2 levels at the expense of direct and paracrine cell-to-cell interactions. PMID- 25919032 TI - Facile synthesis and photocatalytic properties of ZnO core/ZnS-CdS solid solution shell nanorods grown vertically on reductive graphene oxide. AB - In the present study, ZnS-CdS solid solution sensitized ZnO nanorods were anchored on graphene sheets by combining a hydrothermal process and ion exchange technique, and the significant influence of CdS content in the shell on photo absorption and photocatalytic performance were investigated. Electron microscopic images reveal that the as-prepared nanocomposites display a sandwich-like 3D structure, consisting of ZnO nanorods with a ZnxCd1-xS or CdS shell grown vertically on both sides of the graphene sheets. UV/Vis DRS shows that the solid solution sensitized nanocomposites have enhanced visible light absorption and also exhibited a red-shift of the band-edge as compared to RGO/ZnO and RGO/ZnO@ZnS. Fluorescence emission spectra indicate that the deposition of CdS on the shell with an appropriate CdS/ZnS ratio and the incorporation of graphene causes improved charge separation. The photocatalytic experiments demonstrate that the RGO/ZnO@ZnxCd1-xS nanocomposites possess much higher photocatalytic activity for H2 evolution than the RGO/ZnO nanorods and RGO/ZnO@ZnS core/shell nanorods. Under the irradiation of a 300 W Xe lamp, the highest photocatalytic hydrogen production rate of 1865 MUmol h(-1) g(-1) is observed over the RGO/ZnO@Zn0.6Zn0.4S sample, which is about 2.1 and 1.4 times more active than RGO/ZnO and RGO/ZnO@ZnS, respectively. Under the irradiation of visible light (>420 nm), the RGO/ZnO and RGO/ZnO@ZnS nanorods are barely active, whereas RGO/ZnO@Zn0.6Zn0.4S displays a hydrogen production rate of 160 MUmol h(-1) g(-1). The highly improved performance of the composites can be ascribed to the increased light absorption and efficient charge separation. PMID- 25919034 TI - Acceptability, Precision and Accuracy of 3D Photonic Scanning for Measurement of Body Shape in a Multi-Ethnic Sample of Children Aged 5-11 Years: The SLIC Study. AB - BACKGROUND: Information on body size and shape is used to interpret many aspects of physiology, including nutritional status, cardio-metabolic risk and lung function. Such data have traditionally been obtained through manual anthropometry, which becomes time-consuming when many measurements are required. 3D photonic scanning (3D-PS) of body surface topography represents an alternative digital technique, previously applied successfully in large studies of adults. The acceptability, precision and accuracy of 3D-PS in young children have not been assessed. METHODS: We attempted to obtain data on girth, width and depth of the chest and waist, and girth of the knee and calf, manually and by 3D-PS in a multi-ethnic sample of 1484 children aged 5-11 years. The rate of 3D-PS success, and reasons for failure, were documented. Precision and accuracy of 3D-PS were assessed relative to manual measurements using the methods of Bland and Altman. RESULTS: Manual measurements were successful in all cases. Although 97.4% of children agreed to undergo 3D-PS, successful scans were only obtained in 70.7% of these. Unsuccessful scans were primarily due to body movement, or inability of the software to extract shape outputs. The odds of scan failure, and the underlying reason, differed by age, size and ethnicity. 3D-PS measurements tended to be greater than those obtained manually (p < 0.05), however ranking consistency was high (r2 > 0.90 for most outcomes). CONCLUSIONS: 3D-PS is acceptable in children aged >= 5 years, though with current hardware/software, and body movement artefacts, approximately one third of scans may be unsuccessful. The technique had poorer technical success than manual measurements, and had poorer precision when the measurements were viable. Compared to manual measurements, 3D-PS showed modest average biases but acceptable limits of agreement for large surveys, and little evidence that bias varied substantially with size. Most of the issues we identified could be addressed through further technological development. PMID- 25919035 TI - Evaluating the use of plant hormones and biostimulators in forage pastures to enhance shoot dry biomass production by perennial ryegrass (Lolium perenne L.). AB - Fertilisation of established perennial ryegrass forage pastures with nitrogen (N) based fertilisers is currently the most common practice used on farms to increase pasture forage biomass yield. However, over-fertilisation can lead to undesired environmental impacts, including nitrate leaching into waterways and increased gaseous emissions of ammonia and nitrous oxide to the atmosphere. Additionally, there is growing interest from pastoral farmers to adopt methods for increasing pasture dry matter yield which use 'natural', environmentally safe plant growth stimulators, together with N-based fertilisers. Such plant growth stimulators include plant hormones and plant growth promotive microorganisms such as bacteria and fungi ('biostimulators', which may produce plant growth-inducing hormones), as well as extracts of seaweed (marine algae). This review presents examples and discusses current uses of plant hormones and biostimulators, applied alone or together with N-based fertilisers, to enhance shoot dry matter yield of forage pasture species, with an emphasis on perennial ryegrass. PMID- 25919033 TI - Genetic code evolution reveals the neutral emergence of mutational robustness, and information as an evolutionary constraint. AB - The standard genetic code (SGC) is central to molecular biology and its origin and evolution is a fundamental problem in evolutionary biology, the elucidation of which promises to reveal much about the origins of life. In addition, we propose that study of its origin can also reveal some fundamental and generalizable insights into mechanisms of molecular evolution, utilizing concepts from complexity theory. The first is that beneficial traits may arise by non adaptive processes, via a process of "neutral emergence". The structure of the SGC is optimized for the property of error minimization, which reduces the deleterious impact of point mutations. Via simulation, it can be shown that genetic codes with error minimization superior to the SGC can emerge in a neutral fashion simply by a process of genetic code expansion via tRNA and aminoacyl-tRNA synthetase duplication, whereby similar amino acids are added to codons related to that of the parent amino acid. This process of neutral emergence has implications beyond that of the genetic code, as it suggests that not all beneficial traits have arisen by the direct action of natural selection; we term these "pseudaptations", and discuss a range of potential examples. Secondly, consideration of genetic code deviations (codon reassignments) reveals that these are mostly associated with a reduction in proteome size. This code malleability implies the existence of a proteomic constraint on the genetic code, proportional to the size of the proteome (P), and that its reduction in size leads to an "unfreezing" of the codon - amino acid mapping that defines the genetic code, consistent with Crick's Frozen Accident theory. The concept of a proteomic constraint may be extended to propose a general informational constraint on genetic fidelity, which may be used to explain variously, differences in mutation rates in genomes with differing proteome sizes, differences in DNA repair capacity and genome GC content between organisms, a selective pressure in the evolution of sexual reproduction, and differences in translational fidelity. Lastly, the utility of the concept of an informational constraint to other diverse fields of research is explored. PMID- 25919036 TI - Evaluation of noise-induced hearing loss by auditory steady-state and auditory brainstem-evoked responses. AB - OBJECTIVES: Noise-induced hearing loss (NIHL) may result from occupational noise exposures and is considered as an 'Occupational Disease'; therefore, it is compensable. To verify the existence and severity of the work-related hearing loss, there is a need of an objective, reliable auditory measure in cases of arbitration of financial disputes to resolve any medicolegal aspects. The objective of the study was to compare between the ABR and ASSR for predicting the behavioural threshold in subjects with normal hearing or NIHL. DESIGN: The study included 82 subjects regularly exposed to high levels of occupational noise, with normal hearing and NIHL. ABR to clicks and to tone bursts were recorded followed by multiple-frequency ASSR. Physiological and behavioural thresholds were compared for specific frequencies (1000, 2000 Hz) and average of high-frequency range (2000 and 4000 Hz). In addition, Pearson correlations and the specificity and sensitivity of each measure were also calculated using receiver operating characteristic (ROC) curves. RESULTS: In the NIHL group, there was a significantly smaller difference between the behavioural threshold and click-ABR than the ASSR in high-frequency range. Pearson correlations were significantly higher for click-ABR. Analysis of specific frequencies yielded a smaller difference between behavioural and ASSR than tone-burst-ABR thresholds, with a slightly better correlation for ASSR than tone-burst-ABR. Higher sensitivity but lower specificity was suggested for ASSR than ABR. CONCLUSIONS: ASSR is associated with high-frequency specificity, shorter test sessions and good correlations with behavioural thresholds, making it a potentially better measure than ABR for predicting audiograms in subjects with NIHL. These findings have diagnostic implications, especially in cases of workers' compensation when subjects may be uncooperative. PMID- 25919037 TI - Modulation of transcranial focusing thermal deposition in nonlinear HIFU brain surgery by numerical simulation. AB - As the skull induces strong aberrations in phase and amplitude during transcranial treatment of brain surgery, high-intensity focused ultrasound suffers degradation in beam shape and deposits significant heat in the skull which may cause thermal damage to the bone and surrounding tissue. The goal of this study is to optimize the transcranial pressure and thermal fields to reduce thermal damage to the skull and simultaneously concentrate more energy in the focal region and make its size controllable during transcranial brain tumor treatment by modulating the excitation signals of the transducer array (including the phase and amplitude) and superposing the signals used to reduce peak pressure in the skull. A 3D numerical model was developed based on the reconstructed images from high-resolution CT scans of a human skull and a 64-element phased array to simulate acoustic propagation and thermal behavior calculated by the finite-difference time domain method. The simulation showed that more energy was focused at the setting target with little temperature elevation in the skull after correcting phase and amplitude and reducing peak pressure in the skull; through modulating the input intensity of arrays, the volume of focal regions located off-axis could be made equal to the volume achieved with on-axis focusing. PMID- 25919038 TI - Myocardial deformation and total atrial conduction time in the prediction of cardiac involvement in patients with pulmonary sarcoidosis. AB - AIMS: In this study, we aim to evaluate the left atrial global longitudinal strain (LAGLS), total atrial conduction time (TACT) and left ventricle (LV) functions in recently diagnosed pulmonary sarcoidosis (PS) patients. METHOD: Fifty recently diagnosed PS patients (group 1) and a control group of 50 healthy individuals (group 2) were evaluated in the study. Two-dimensional echocardiography images were obtained from LV apical 4-chamber (4C), long-axis (L) and 2-chamber (2C) views. Peak longitudinal strain and strain rate (SR) were obtained from 4C, L and 2C views. Mean values of the three views were calculated. LV global longitudinal strain and LV-SR torsion were determined as the net differences in the mean rotation between the apical and basal levels. LAGLS and TACT values were calculated. RESULTS: The study found that LAGLS was significantly lower in group 1 than in group 2 (P < 0.05). TACT was also significantly longer in group 1 than in group 2 (respectively group 1: 111.6 +/- 15.1 ms; group 2: 103.4 +/- 5.8 ms, P < 0.001). There was a significant moderate negative correlation between LAGLS and TACT (r = -0.36, P < 0.05). Patients with sarcoidosis had significantly lower LV longitudinal strain and SR measurements than the control group. Although LV basal rotation (LVR) values were similar in both groups, LVR-apical and LV-torsion (LVTR) values were significantly higher in the patient group (group 1). CONCLUSION: The identification of left atrial and left ventricular myocardial deformation using speckle tracking echocardiography in patients with PS allows subclinical LV dysfunction and subclinical electrophysiologic changes to be detected earlier. PMID- 25919039 TI - Suspected malignant transformation of B lymphocytes in the equine cornea from immune-mediated keratitis. AB - OBJECTIVE: To describe clinical, in vivo confocal microscopic, histopathologic, polymerase chain reaction assay for antigen receptor rearrangement (PARR) and immunohistochemical features of a horse with suspected malignant transformation of corneal B lymphocytes in immune-mediated keratitis (IMMK) and to also report surgical management and adjunctive treatment including topical and radiation therapies. CASE DESCRIPTION: A 15-year-old Oldenburg gelding was examined for presumptive progressive stromal IMMK of the right eye which became refractory to medical management. Corneal in vivo confocal microscopy revealed a marked infiltration of neovascularization, leukocytes, and dendritic cells. Superficial keratectomy was performed. Histopathologic and immunohistopathologic abnormalities of the cornea were restricted to the anterior and mid-stroma and included sheets of medium-size atypical lymphocytes which stained positively for CD79a and CD20 and also demonstrated clonal rearrangements of immunoglobulin heavy chain 2 (IGH2) and 3 (IGH3) confirming B-cell lymphoma. Complete physical examination, complete blood count, serum chemistry, thoracic radiographs, and thoracic ultrasound were performed. No evidence of systemic metastasis was found. Adjunctive local therapy included topical dexamethasone, mitomycin C, and radiation therapy using electronic surface brachytherapy. Follow-up at 16 months revealed a lack of corneal infiltrate and progressive clearing of corneal fibrosis and superficial pigment. CONCLUSIONS: This case represents a unique presentation of primary corneal lymphoma in the horse. Tumor development was associated with chronic IMMK and chronic topical anti-inflammatory therapy. Surgical excision with adjunctive therapy using mitomycin C and electronic surface brachytherapy was well tolerated and considered curative. Future immunohistochemistry and PARR will be important in characterizing the IMMK syndrome and its variations. PMID- 25919040 TI - Long-term use of steroids protects from the development of symptomatic diverticulitis requiring hospitalization in the Asian population. AB - OBJECTIVE: The pathophysiology of diverticulitis is poorly understood. Factors such as physical inactivity, constipation, obesity, smoking, and the use of nonsteroidal antiinflammatory drugs (NSAIDs) have been associated with an increased risk of diverticular disease. To evaluate whether patients exhibiting long-term steroid use are at increased risk of colonic diverticulitis. METHOD: We conducted a population-based, nested case-control study. Data were retrospectively collected from the National Health Insurance Research Database. The study cohort comprised patients diagnosed with diverticulitis, identified using inpatient discharge records using International Classification of Diseases, Ninth Revision, Clinical Modification (ICD-9-CM) codes (562.11 and 562.13), and those who were administered one or more prescriptions for corticosteroids for systemic use. Control patients were matched to cases by age, sex, NSAID use, laxative drug use, and index date. We enrolled 690 patients with colonic diverticulitis and 2760 in the control group. The adjusted odds ratios (ORs) and 95% confidence intervals (CIs) were estimated using conditional logistic regression. RESULTS: Compared with steroid nonusers, the adjusted ORs were 0.60 (95% CI = 0.35-1.06) and 0.80 (95% CI = 0.64-1.008) in current steroid users and previous steroid users, respectively. In addition, the adjusted ORs were 0.55 (95% CI = 0.31-0.98), 0.57 (95% CI = 0.31-0.98), and 0.44 (95% CI = 0.22-0.86) for steroid use duration more than half time by an exposure period of 90 days, 180 days, and 365 days before the claim date of colonic diverticulitis, respectively. CONCLUSIONS: The results indicated that long-term steroid use within one year is associated with lower risk of colonic diverticulitis. PMID- 25919041 TI - The evaluation of clinical usefulness of transbrochoscopic lung biopsy in undefined interstitial lung diseases: a retrospective study. AB - BACKGROUND AND AIMS: Previous studies mostly focused on the diagnostic accuracy of transbronchoscopic lung biopsy (TBLB) in the diagnosis of interstitial lung diseases (ILDs). We aimed to explore the clinical usefulness of TBLB results in the diagnostic procedure of undefined ILDs. METHODS: The retrospective analysis included patients undergoing TBLB for the diagnosis of undefined ILDs from January 2007 to December 2010. The clinically useful TBLB was defined as that lead to a specific histopathological diagnosis or that was consistent with the working diagnosis based on existing clinical and radiological data. RESULTS: A total of 664 patients were included in the study. TBLB failed to obtain lung parenchyma in 155 cases (23.3%). TBLB was considered clinically helpful in 202 procedures (30.4%), including 114 cases that provided definitive histopathological diagnoses and 88 cases that were consistent with working diagnoses. Among 202 cases of clinically useful TBLBs, the majority were diagnosed as pulmonary alveolar proteinosis (PAP) (67 cases, 33.2%), connective tissue disease-related ILDs (CTD-ILDs) (65, 32.2%) and idiopathic pulmonary fibrosis (IPF) (33, 16.3%). Although TBLB could provide definitive histopathological diagnoses in all cases diagnosed as PAP, only few cases of IPF (7, 21.2% of IPF diagnoses) and CTD-ILDs (9, 13.8% of CTD-ILD diagnoses) could be identified by TBLBs. CONCLUSION: The clinical usefulness of TBLB, in conjunction with thorough clinical and radiological data, in the diagnosis of ILDs may be varied depending on different subtypes. The use of histopathological analysis and the type of biopsy employed should therefore be considered on a case-by-case basis. PMID- 25919044 TI - Metabolomics - the complementary field in systems biology: a review on obesity and type 2 diabetes. AB - Metabolomic studies on obesity and type 2 diabetes mellitus have led to a number of mechanistic insights into biomarker discovery and comprehension of disease progression at metabolic levels. This article reviews a series of metabolomic studies carried out in previous and recent years on obesity and type 2 diabetes, which have shown potential metabolic biomarkers for further evaluation of the diseases. Literature including journals and books from Web of Science, Pubmed and related databases reporting on the metabolomics in these particular disorders are reviewed. We herein discuss the potential of reported metabolic biomarkers for a novel understanding of disease processes. These biomarkers include fatty acids, TCA cycle intermediates, carbohydrates, amino acids, choline and bile acids. The biological activities and aetiological pathways of metabolites of interest in driving these intricate processes are explained. The data from various publications supported metabolomics as an effective strategy in the identification of novel biomarkers for obesity and type 2 diabetes. Accelerating interest in the perspective of metabolomics to complement other fields in systems biology towards the in-depth understanding of the molecular mechanisms underlying the diseases is also well appreciated. In conclusion, metabolomics can be used as one of the alternative approaches in biomarker discovery and the novel understanding of pathophysiological mechanisms in obesity and type 2 diabetes. It can be foreseen that there will be an increasing research interest to combine metabolomics with other omics platforms towards the establishment of detailed mechanistic evidence associated with the disease processes. PMID- 25919042 TI - Effect of carboxylesterase 1 c.428G > A single nucleotide variation on the pharmacokinetics of quinapril and enalapril. AB - AIM: The aim of the present study was to investigate the effects of the carboxylesterase 1 (CES1) c.428G > A (p.G143E, rs71647871) single nucleotide variation (SNV) on the pharmacokinetics of quinapril and enalapril in a prospective genotype panel study in healthy volunteers. METHODS: In a fixed-order crossover study, 10 healthy volunteers with the CES1 c.428G/A genotype and 12 with the c.428G/G genotype ingested a single 10 mg dose of quinapril and enalapril with a washout period of at least 1 week. Plasma concentrations of quinapril and quinaprilat were measured for up to 24 h and those of enalapril and enalaprilat for up to 48 h. Their excretion into the urine was measured from 0 h to 12 h. RESULTS: The area under the plasma concentration-time curve from 0 h to infinity (AUC0-infinity) of active enalaprilat was 20% lower in subjects with the CES1 c.428G/A genotype than in those with the c.428G/G genotype (95% confidence interval of geometric mean ratio 0.64, 1.00; P = 0.049). The amount of enalaprilat excreted into the urine was 35% smaller in subjects with the CES1 c.428G/A genotype than in those with the c.428G/G genotype (P = 0.044). The CES1 genotype had no significant effect on the enalaprilat to enalapril AUC0-infinity ratio or on any other pharmacokinetic or pharmacodynamic parameters of enalapril or enalaprilat. The CES1 genotype had no significant effect on the pharmacokinetic or pharmacodynamic parameters of quinapril. CONCLUSIONS: The CES1 c.428G > A SNV decreased enalaprilat concentrations, probably by reducing the hydrolysis of enalapril, but had no observable effect on the pharmacokinetics of quinapril. PMID- 25919045 TI - The effect of benzodiazepine and nonbenzodiazepine prescriptions for diabetes mellitus type 2 in elderly Taiwanese with depressive symptoms. AB - BACKGROUND: This study examined the relationship between depression, benzodiazepine (BZD)/nonbenzodiazepine hypnotics (non-BZD), and other risk factors in a national sample of Taiwan's elderly diabetic patients. METHODS: Data were drawn from the 2005 Taiwan National Health Interview Survey and adults aged 65 years and older. A total of 1331 subjects were included in this study. The Chinese version of Center for Epidemiologic Studies Depression Scale was used to evaluate patients' depression symptoms. RESULTS: The rates of depression in the diabetes mellitus (DM) and non-DM groups were 13.5% (39/288) and 9.8% (102/1043) and the average ages were 73.7 and 73.4 years, respectively. In multivariate regression, the odds ratio of depression was 1.66-fold higher among BZD/non-BZD users (95% confidence interval: 1.10-2.51, model 2) than among those without BZD/non-BZD use. In addition, hyperlipidaemia, poor physical function, and antidepressant use were associated with a higher risk of depressive symptoms. Meanwhile, a monthly household income of NT$30 000-NT$49 999, exercise, and betel chewing were associated with a lower risk of depression. We performed an additional logistic analysis for which the odds ratio of depression significantly increased to 1.52 in non-DM elderly patients (95% confidence interval: 1.06-2.19) who were prescribed BZD/non-BZD. In contrast, there was no significant difference in the odds ratio of depression in the DM elderly regardless of BZD/non-BZD use, although there was a slight tendency for depression among those who used BZD/non BZD. CONCLUSION: Depression in non-DM Taiwanese elderly patients was found to be associated with BZD/non-BZD use, whereas depression in DM Taiwanese elderly patients was not found to be associated with BZD/non-BZD use. PMID- 25919047 TI - Special issue: signaling. PMID- 25919046 TI - Survival difference between coronary bypass surgery and percutaneous coronary intervention. AB - OBJECTIVES: To assess whether the previously observed lower death rate with coronary artery bypass surgery compared with percutaneous coronary intervention in subsets of patients with coronary artery disease persists in more recent years. DESIGN: Retrospective study from Feiring Heart Clinic database of survival in 17739 patients followed for 5 years after coronary revascularization. The cohorts treated in 1999-2005 and 2006-2011 were compared using Cox regression and propensity score analyses. RESULTS: Cox regression and propensity score analyses revealed no difference in survival in either time period in one- and two-vessel diseases. In three-vessel disease, the hazard ratios between bypass surgery and percutaneous intervention were 0.62 (95% confidence interval [CI]: 0.53-0.71, p < 0.001) and 0.59 (95% CI: 0.47-0.73, p < 0.001), respectively, in the two time periods, indicating persistent higher survival with bypass surgery. CONCLUSIONS: The previously observed lower death rate of coronary artery bypass surgery compared with percutaneous intervention in patients with three-vessel disease is persistent in more recent years and indicates that bypass surgery still should be the standard treatment for these patients. PMID- 25919051 TI - Rapid authentication of Cordyceps by lateral flow dipstick. AB - Cordyceps (Dongchongxiacao), a valuable traditional Chinese medicine, is composed of the fruiting body of Ophiocordyceps sinensis (Family: Ophiocordycipitaceae) on a caterpillar of ghost-moth species (Family: Hepialidae). Owing to its multiple potential functions, Cordyceps are in great demand and represent significant economic value. Adulterants or substitutes named Cordyceps or Chongcao from related fungi have been reported. In this study, polymerase chain reaction (PCR) coupled with a lateral flow dipstick (LFD) system was developed to distinguish genuine herb O. sinensis from its common adulterant Cordyceps gunnii and Cordyceps militaris. Specific primers (EF-CS-F1-Biotin, EF-CG-F1-Biotin and EF-CM F1- Biotin) were designed to differentiate the three Cordyceps species. Internal control (EF-F1-b-DIG and EF-R1-FITC) was included to minimize the false signal due to PCR inhibitors or DNA degradation. LFD was then successfully employed for speedy and accurate detection of the respective PCR products. PMID- 25919050 TI - Circulating TGF-beta1 and VEGF and risk of cancer among liver transplant recipients. AB - Transplant recipients have elevated cancer risk, perhaps partly due to direct carcinogenic effects of immunosuppressive medications. Experimental evidence indicates that calcineurin inhibitors given to transplant recipients increase cellular expression of transforming growth factor beta1 (TGF-beta1) and vascular endothelial growth factor (VEGF), which could promote cancer. To assess the potential role of these pathways in the transplantation setting, we conducted a case-control study nested in a cohort of liver recipients. Cases had nonmelanoma skin cancer (N = 84), cancer of the lung (N = 29), kidney (N = 20), or colorectum (N = 17), or melanoma (N = 3). We selected N = 463 recipients without cancer as controls. TGF-beta1 and VEGF levels were measured in sera obtained, on average, approximately 3 years before case diagnosis/control selection. We also measured platelet factor 4 (PF4), a marker of ex vivo platelet degranulation, because TGF beta1 and VEGF can be released from platelets, and we developed a statistical model to isolate the platelet-derived fraction from the remaining circulating component. Compared with controls, lung cancer cases had higher levels of TGF beta1 (median 22.8 vs. 19.4 ng/mL, P = 0.02) and VEGF (277 vs. 186 pg/mL, P = 0.02). However, lung cancer cases also had higher platelet counts (P = 0.08) and PF4 levels (P = 0.02), while residual serum levels of TGF-beta1 and VEGF, after accounting for PF4, were unassociated with lung cancer (P = 0.40 and P = 0.15, respectively). Associations were not seen for other cancers. In conclusion, TGF beta1 and VEGF levels were increased in association with lung cancer among transplant recipients, which may be explained by increased platelet counts and platelet degranulation in lung cancer cases. PMID- 25919052 TI - Kaempulchraols A-H, Diterpenoids from the Rhizomes of Kaempferia pulchra Collected in Myanmar. AB - Eight new diterpenoids, kaempulchraols A-H (1-8), along with five known analogues were isolated from the CHCl3-soluble extract of rhizomes of Kaempferia pulchra of Myanmar. The structures of these compounds were elucidated using extensive spectroscopic techniques including X-ray diffraction analysis. All the isolates were tested for their antiproliferative activity against a panel of five human cancer cell lines (A549, human lung cancer; HeLa, human cervix cancer; PANC-1 and PSN-1, human pancreatic cancer; MDA-MB-231, human breast cancer) and TIG-3, normal human primary fibroblast cells. Kaempulchraol F (6) exhibited weak activity against the human pancreatic PSN-1 cell line with an IC50 value of 12.3 MUM. PMID- 25919054 TI - Patient-directed therapy during in-patient stroke rehabilitation: stroke survivors' views of feasibility and acceptability. AB - PURPOSE: Patient-led therapy, in which patients work outside therapy sessions without direct supervision, is a possible way to increase the amount of therapy stroke patients' receive without increasing staff demands. Here, we report patients' views of patient-led mirror therapy and lower limb exercises. METHOD: 94 stroke survivors with upper and lower limb limitations at least 1-week post stroke undertook 4 weeks of daily patient-led mirror therapy or lower limb exercise, then completed questionnaires regarding their experience and satisfaction. A convenience random sample of 20 participants also completed a semi-structured telephone interview to consider their experience in more detail and to capture their longer term impressions. RESULTS: Participants were generally positive about patient-led therapy. About 71% found it useful; 68% enjoyed it; 59% felt it "worked" and 88% would recommend it to other patients. Exercise was viewed more positively than the mirror therapy. Difficulties included arranging the equipment and their position, particularly for more severe strokes, loss of motivation and concerns about working unsupervised. CONCLUSIONS: Patient-led mirror therapy and lower limb exercises during in-patient rehabilitation is generally feasible and acceptable to patients but "light touch" supervision to deal with any problems, and strategies to maintain focus and motivation are needed. Implications for Rehabilitation Most stroke patients receive insufficient therapy to maximize recovery during rehabilitation. As increases in staffing are unlikely there is an imperative to find ways for patients to increase the amount of exercise and practice of functional tasks they undertake without increasing demands on staff. Patient-led therapy (also known as patient-directed therapy or independent practice), in which patients undertake exercises or functional tasks practice prescribed by a professional outside formal therapy sessions is one way of achieving this. It is widely used in community-based rehabilitation but is uncommon in hospital-based stroke care. We explored the feasibility and acceptability of two types of patient-led therapy during hospital-based stroke care; mirror therapy for the upper limb and exercises (without a mirror) for the lower limb. Here, we report patients' experiences of undertaking patient-led therapy. Patient-led mirror therapy and lower limb exercises during in-patient stroke rehabilitation is generally feasible and acceptable to patients but "light touch" supervision to deal with any problems, and strategies to maintain focus and motivation are needed. PMID- 25919055 TI - Antazoline for termination of atrial fibrillation during the procedure of pulmonary veins isolation. AB - PURPOSE: Pulmonary vein isolation is a well established method of definite treatment of atrial fibrillation (AF). Periprocedural onset of AF usually terminates spontaneously within minutes, but not in all cases. Antazoline is an antihistaminic agent with antiarrhythmic properties. The aim of our retrospective study was to evaluate the efficacy of antazoline in termination of AF in patients undergoing pulmonary vein isolation. MATERIALS AND METHODS: Consecutive 141 patients who received antazoline to terminate AF during pulmonary vein isolation were analyzed. The antazoline was administered at the rate of 30-50mg/min (max. 500mg) after the circumferential ablation in the ostia of pulmonary veins and before confirmation of isolation. Success was defined as restoration of sinus rhythm within 20min after antazoline infusion. RESULTS: The efficacy of antazoline was 83.6% in paroxysmal and 31.1% in persistent AF patients. Clinical variables that were independently predictive of antazoline ineffectiveness were female (odds ratio [OR]: 4.35; 95% confidence interval [CI]: 1.26-14.3; p=0.018) and AF at the beginning of procedure (OR 28.4; 95% CI 3.89-208.0; p=0.001). Due to antazoline related side effects infusion was discontinued in 7 patients (5%). CONCLUSIONS: Antazoline seems to be safe agent in termination of AF in patients undergoing pulmonary vein isolation. We also observed satisfying efficacy, which needs to be proved in a randomized clinical trial. PMID- 25919056 TI - [Return to Work: A Workplace Focused Module to be Integrated in Cognitive Behavioral Therapy]. AB - Psychiatric disorders, in particular depression and anxiety disorders, are important causes of impaired job performance and increased sick leave. Longer periods of sickness leave lead regularly to difficulties concerning return to work. Furthermore, work is an important factor for psychological health. The central issue of the "return to work" (RTW) module by Lagerveldt and colleagues 5 is remission from psychiatric disorder, and structured support to return to work. The module is based on principles of cognitive-behavioral therapy (CBT), and can be integrated in standard CBT. Existing data from a randomized controlled trial suggest that treatment outcome concerning remission is similar between CBT supplemented with RTW (CBT-W) module and standard CBT. However, time to return to work is reduced in CBT-W. PMID- 25919057 TI - [The ICD-10 Symptom Rating (ISR): validation of the depression scale in a clinical sample]. AB - The ICD-10 Symptom Rating (ISR) 1 measures the severity of psychiatric disorders with 29 items on 5 subscales as comprehensively as possible. The following syndromes are measured: Depressive syndrome, anxiety syndrome, obsessive compulsive syndrome, Somatoform syndrome, eating disorder syndrome as well as additional items that cover various mental syndromes, and an overall score. The study reports findings on the validity and sensitivity to change of the depression subscale (ISR-D). In a clinical sample of N=949 inpatients with depression spectrum disorders the convergent validity was determined by correlation with the Beck Depression Inventory (BDI) 3 and the subscale "depression" of the Symptom-Checklist-90-R (SCL-90-R) 4. The high correlation between the different instruments confirms the validity of the ISR-Depression Scale. The sensitivity to change of the ISR seems higher than that of the BDI and the SCL-90. Because of its economy and the good psychometric properties the ISR is recommended for use in clinical samples. PMID- 25919058 TI - [Self-Medication: A Nationwide Representative Survey on Motives, Reasons and Sources on Consuming Over-the-Counter Medication]. AB - INTRODUCTION: Self-medication, meaning the autonomous treatment of self diagnosed diseases with non-prescription drugs, has become an increasingly relevant topic - not the least because since 2004 most non-prescription drugs were no longer refunded by statutory health insurance, due to the GKV-Modernisierungsgesetz. In light of the above, the central questions that motivate this paper are the following: - Where does the german population obtain information about non prescription drugs? - Which health impairments are treated with non-prescription drugs before seeing a doctor and for what reasons? - Which habits, experiences and estimates concerning self-medication are shared? METHODS: To answer these questions the GfK market research institution in Nurnberg conducted a survey treating different topics from 7(th) to 21(st) December 2012. The sample selected by the quota method is considered to be representative for the population of men and women aged 14 and above in Germany and is based on a total of 1 976 personal interviews. RESULTS: 94.9% of those questioned did treat at least one of the 25 symptoms included in the survey with non-prescription medicine before potentially seeing a doctor. The most common place to obtain information about OTC products is pharmacies. The symptoms most commonly treated by oneself are cold symptoms and headaches. The evidence from this study suggests a variety of factors explaining this behavior. Most of the respondents do not want to see a doctor over minor issues, i. e., think their health problems are not severe enough require consulting a doctor. Furthermore long waiting times and limited opening hours are mentioned. The majority of the respondents had good experiences with self-medication. However, some of the participants keep their OTC use from their treating physicians. CONCLUSION: In conclusion, it becomes evident that both opportunities and risks come with self-medication. Strategies to capitalize those opportunities and mitigate these risks are presented, with the trusted relationship between physician and patient playing critical role. PMID- 25919059 TI - [Validation of the Essen Quality of Life-Index for Eating Disorders (ELI)]. AB - The aim of this study was the validation of a short disease-specific questionnaire (ELI, Essen Quality of Life Index for Eating Disorders) to measure the health-related quality of life in patients with eating disorders. A total of 182 currently ill and former eating disordered patients and 87 healthy controls completed the ELI questionnaire as well as other reliable and valid instruments (EDQOL, SF-12, EDI-2, FKB-20, SEED, BSI, IIP-D and SOC-13). In addition, 46 eating disorder patients completed the same questionnaires at the end of therapy. The ELI proved to have a high internal consistency of alpha=0.96. As expected, one main factor was found with a high declaration of variance of 71.25%. There is also evidence for very good construct validity and good sensitivity for change. Therefore, the ELI is an economic, reliable and valid instrument that assesses disease-specific health-related quality of life of individuals with eating disorders. The questionnaire can be recommended for research as well as clinical care contexts. PMID- 25919060 TI - [Review Model for the Assessment of Psychometric Instruments--Recommendations of the German College of Psychosomatic Medicine (DKPM)]. AB - OBJECTIVES: Psychometric instruments are commonly applied in psychotherapeutic research and care for the baseline assessment of symptoms, the planning of therapeutic interventions, the assessment of the longitudinal course of symptoms and outcomes of therapeutic interventions as well as quality management of care. Psychometric properties as well as economic aspects should be considered in the selection of specific instruments. It is assumed that users of psychometric instruments face a great variety of instruments and related information. For that reason, it seems challenging to absorb the current knowledge and to integrate it into clinical practice and research. Thus, it is likely that well-known, established and easily accessible instruments are commonly used, while new developed instruments might not be disseminated in research and healthcare. METHODS: Based on available international review models, the working group "Psychometrics and Psychodiagnostics" of the German College of Psychosomatic Medicine (DKPM) has developed and tested a review model specifically tailored for psychotherapeutic research and care. RESULTS: The different steps of development, as well as the final review model based on the consensus of the working group are presented. The review model contains 6 generic terms (reliability, validity, objectivity, reference groups and aspects of application) with 21 different criteria to be assessed with 0-3 asterisks (*). The criteria are clearly operationalized and the practical use of the review model is explained and discussed. CONCLUSIONS: With the review model for the assessment of psychometric instruments a well-defined evaluation system is made available for research and clinical practice which has been developed by an expert group. The review model facilitates systematic, transparent and comparative evaluation of psychometric instruments along clearly defined criteria. It also supports the selection of psychometric instruments in research and care. Next, the working group aims at disseminating and implementing the review model as well as the application and publication of reviews for different psychometric instruments based on the review model. PMID- 25919062 TI - Stereoselective Synthesis of 1-Methyl-3',4',5',6'-tetrahydrospiro[indoline-3,2' pyran]-2-one Derivatives via Prins Cyclization. AB - A novel spirocyclization has been developed for the construction of functionalized spirooxindole pyran via Lewis acid promoted Prins cyclization. The reaction proceeds through formation of a single diastereoisomer with high stereoselectivity. This approach can be used to construct biologically important substituted spirooxindole as well as fluorinated pyran scaffolds. PMID- 25919061 TI - Rationale and design of a randomized, double-blind, event-driven, multicentre study comparing the efficacy and safety of oral rivaroxaban with placebo for reducing the risk of death, myocardial infarction or stroke in subjects with heart failure and significant coronary artery disease following an exacerbation of heart failure: the COMMANDER HF trial. AB - AIMS: Thrombin is a critical element of crosstalk between pathways contributing to worsening of established heart failure (HF). The aim of this study is to explore the efficacy and safety of rivaroxaban 2.5 mg bid compared with placebo (with standard care) after an exacerbation of HF in patients with reduced ejection fraction (HF-rEF) and documented coronary artery disease. METHODS: This is an international prospective, multicentre, randomized, double-blind, placebo controlled, event-driven study of approximately 5000 patients for a targeted 984 events. Patients must have a recent symptomatic exacerbation of HF, increased plasma concentrations of natriuretic peptides (B-type natriuretic peptide >=200 pg/mL or N-terminal pro-B-type natriuretic peptide >=800 pg/mL), with left ventricular ejection fraction <=40% and coronary artery disease. Patients requiring anticoagulation for atrial fibrillation or other conditions will be excluded. After an index event (overnight hospitalization, emergency department or observation unit admission, or unscheduled outpatient parenteral treatment for worsening HF), patients will be randomized 1:1 to rivaroxaban or placebo (with standard of care). The primary efficacy outcome event is a composite of all-cause mortality, myocardial infarction or stroke. The principal safety outcome events are the composite of fatal bleeding or bleeding into a critical space with potential permanent disability, bleeding events requiring hospitalization and major bleeding events according to International Society on Thrombosis and Haemostasis bleeding criteria. CONCLUSION: COMMANDER HF is the first prospective study of a target-specific oral antithrombotic agent in HF. It will provide important information regarding rivaroxaban use following an HF event in an HF rEF patient population with coronary artery disease. PMID- 25919063 TI - Enhanced skin delivery of aceclofenac via hydrogel-based solid lipid nanoparticles. AB - The aim of the present study was to develop solid lipid nanoparticles (SLN) and formulate a hydrogel for enhanced topical delivery of aceclofenac (ACF). The SLN were prepared by the ultrasonic emulsification method and optimized on the basis of stirring speed and lipid content. The optimized formulation was characterized for particle size (189 +/- 9.2 nm), polydispersity index (PDI) (0.162 +/- 0.02), zeta potential (-32.51 +/- 0.12 mV), entrapment efficiency (86.51 +/- 2.46%), surface morphology, differential scanning calorimetry (DSC) and X-ray diffraction (XRD). In vivo performance of ACF-loaded SLN hydrogel showed prolonged inhibition of edema, as compared to that observed using plain ACF hydrogel, after 24 h. The results demonstrated that the ACF-SLN formulation for skin targeting could be a promising carrier for topical delivery of ACF. PMID- 25919064 TI - Nanotechnological approaches for the effective management of psoriasis. AB - Psoriasis is a chronic disorder with erythematous scaly patches, which typically affects the exposed surfaces of the body and scalp. Various factors such as bacterial infection, genetic and environmental factors, and immune disorders play an important role in causing psoriasis. Different types of psoriasis can be observed, such as guttate psoriasis, inverse psoriasis, pustular psoriasis, and psoriatic arthritis. Various ancient, topical, and systemic approaches have been used to control the disease, but have failed to achieve a complete reduction of the disease, besides causing toxic effects. Therefore, our main aim in this review article is to introduce the different advanced nanotechnological approaches for effective treatment of psoriasis. PMID- 25919065 TI - Digestive capacity predicts diet diversity in Neotropical frugivorous bats. AB - 1. Predicting the diet diversity of animals is important to basic and applied ecology. Knowledge of diet diversity in animals helps us understand niche partitioning, functional diversity and ecosystem services such as pollination, pest control and seed dispersal. 2. There is a negative relationship between the length of the digestive tract and diet diversity in animals; however, the role of digestive physiology in determining diet diversity has been ignored. This is especially important in vertebrates with powered flight because, unlike non flying vertebrates, they have limitations that may constrain gut size. 3. Here, we evaluate the relationship between digestive capacity and diet diversity in Carollinae and Stenodermatinae frugivorous bats. These bats disperse the seeds of plants that are key to Neotropical forest regeneration. 4. Our results show that digestive capacity is a good predictor of diet diversity in Carollinae and Stenodermatinae frugivorous bats (R(2) = 0.77). 5. Surprisingly, the most phylogenetically closely related species were not similar in their digestive capacity or diet diversity. The lack of a phylogenetic signal for the traits evaluated implies differences in digestive physiology and diet in closely related species. 6. Our results highlight the predictive usefulness of digestive physiology for understanding the feeding ecology of animals. PMID- 25919066 TI - Temperature-dependent and bistable current-voltage measurements in zinc porphyrin molecular junctions. AB - We report bistability in current-voltage curves from di(PEP)PorZn in an electromigrated molecular junction. Bistability was observed at +/-0.3 V at 300 K but did not occur at 4 K. No bistability was identified at 300 K for another porphyrin molecule (di(Xyl)PorZn), where the phenyl-ethnyl-phenyl (PEP) side groups were replaced with a flexible p-xylene. Molecular dynamics simulations show that bistability may be due to conformation changes related to the fluctuation of the dihedral angle surrounding the zinc and/or the rotation of the porphyrin central plane of the molecule. Results suggest that other mechanisms may play a role in the current-voltage characteristics observed. PMID- 25919067 TI - Prediction of adherence to a gluten-free diet using protection motivation theory among adults with coeliac disease. AB - BACKGROUND: Coeliac disease is a chronic autoimmune disease that requires strict adherence to a gluten-free diet. However, strict adherence to a gluten-free diet is difficult, with findings from a recent review suggesting that up to 42% of individuals with coeliac disease do not eat a strict gluten-free diet. METHODS: The present study aimed to examine psychosocial predictors of adherence (purposeful and accidental) to a gluten-free diet among adults with coeliac disease over a 1-month period. In this longitudinal study, 212 North American adults with coeliac disease completed online questionnaires at two time points, baseline and 1 month later. RESULTS: The results revealed that intentions partially mediated the effects of symptom severity, self-regulatory efficacy, planning and knowledge on purposeful gluten consumption. Intentions did not mediate the effects of severity, response cost, self-regulatory efficacy, planning and knowledge for accidental gluten consumption but, interestingly, self regulatory efficacy directly predicted fewer accidental incidents of gluten consumption. CONCLUSIONS: These findings delineate the differential psychological processes in understanding accidental and purposeful gluten consumption among adults with coeliac disease and emphasise the importance of bolstering self regulatory efficacy beliefs to prevent accidental and purposeful consumption of gluten. PMID- 25919068 TI - Editorial. 17th International Workshop on the Enzymology and Molecular Biology of Carbonyl Metabolism. PMID- 25919070 TI - A fear worse than death. PMID- 25919069 TI - Early Endocrine and Metabolic Changes After Bariatric Surgery in Grade III Morbidly Obese Patients: A Randomized Clinical Trial Comparing Sleeve Gastrectomy and Gastric Bypass. AB - BACKGROUND: We compared the early endocrine and metabolic changes associated with sleeve gastrectomy (SG) and gastric bypass (GB) in grade III obese patients. METHODS: Fifty morbidly obese patients were randomized into two groups on the basis of their position in the queue-group A comprised SG and group B was GB. Comparison between the two groups was based on clinical and laboratory variables such as fasting blood glucose, insulin, homeostasis model assessment of insulin resistance (HOMA-IR), glycated hemoglobin (HbA1c), lipids, albumin, and ferritin. Patients were assessed after 7, 14, 30, 60, and 90 days and additional laboratory tests were done on the 90(th) day. RESULTS: The following mean values were recorded for groups A and B, respectively: Age (years), 36.4 and 31.1; weight (kg), 123.2 and 128.3; and body mass index (BMI; kg/m(2)), 45.6 and 47.3. In the first postoperative week, group B showed a greater weight loss (P=0.047) that was not observed after 14, 30, 60, and 90 days (P>0.05). Group A had an average excess weight loss of 31.09 kg compared to 32.69 kg in group B (P=0.222). Glycemic control was better in group B (P=0.023), whereas the control of systemic arterial pressure was better in group A (P=0.026). There were no significant differences in early lipid control and micronutrient deficiencies between the two groups. CONCLUSIONS: SG and GB were equally effective in promoting weight loss after 90 days. However, whereas SG was associated with better early remission rates for hypertension, GB was more effective in fasting blood glucose control but not in HOMA-IR and HbA1c levels. There was no difference in the protein or vitamin deficiencies of the two groups. PMID- 25919071 TI - Is dyad practice in simulation really cost-effective? PMID- 25919072 TI - In reply to Walsh. PMID- 25919073 TI - A proposal for getting "back to the future" of spirituality in medicine. PMID- 25919074 TI - In reply to Cayley. PMID- 25919075 TI - Beyond the medical marriage: attending to the wellness of unmarried physicians. PMID- 25919076 TI - In reply to Chung. PMID- 25919077 TI - Artist's Statement: Tuskegee Men. PMID- 25919078 TI - Baptism by rotation [excerpt]. PMID- 25919079 TI - Commentary on an excerpt from "baptism by rotation". PMID- 25919080 TI - Numbers and narratives. PMID- 25919081 TI - Disappearance of centroacinar cells in the Notch ligand-deficient pancreas. AB - Notch signaling has been shown to contribute to murine pancreatic development at various stages. Delta-like 1 (Dll1) or Jagged1 (Jag1) are the Notch ligands that solely function to trigger this signaling during the pancreatic bud stage (~e9.5) or after birth, respectively. However, it has not been elucidated whether these Notch ligands are required at the later stage (e10.5-18.5) when the particular pancreas structures form. Here, we detected the dual expression of Dll1 and Jag1 in the epithelium after e10.5, which was restricted to the ductal cell lineage, including centroacinar cells expressing Sox9, CD133 and Hes1 but not the ductal cell markers Hnf1beta and DBA, at e18.5. To evaluate the significance of the Notch ligands during this period, we established double-floxed mice of Dll1 and Jag1 genes with Ptf1a-Cre knock-in allele and examined the effects on development. The abrogation of both ligands but not a single one led to the loss of centroacinar cells, which was due to the decrease in cell proliferation and the increase in cell death, as well as to the reduction of Sox9. These results suggested that Dll1 and Jag1 function redundantly and are necessary to maintain the centroacinar cells as an environmental niche in the developing pancreas. PMID- 25919082 TI - Identifying prognostic indicators in staging metastatic sarcomas using hospital episode statistics. AB - Detailed staging data are currently not available for sarcoma patients. This paper uses Hospital Episodes Statistics (HES) data to identify patients with Stage IV disease at diagnosis. Cancer patients with a record of metastasis at diagnosis were identified by combining HES data with National Cancer Data Repository data. The presence of metastases at diagnosis varied with age, sarcoma morphological sub-type, and anatomical location. Survival rates for patients with metastases were significantly lower than for those without metastases. Although not a perfect substitute for detailed staging information, the method described provides a good proxy to identify patients with Stage IV disease. PMID- 25919083 TI - DNA sensor's selectivity enhancement and protection from contaminating nucleases due to a hydrated ionic liquid. AB - The thermodynamic stability of certain mismatched base pairs has made the development of DNA sequence sensing systems challenging. Thus, the stability of fully matched and mismatched DNA oligonucleotides in the hydrated ionic liquid choline dihydrogen phosphate (choline dhp) was investigated. Mismatched base pairs were significantly destabilized in choline dhp relative to those in aqueous buffer. A molecular beacon that forms a triplex with a conserved HIV-1 sequence was then designed and tested in choline dhp. The molecular beacon specifically detected the target duplex via triplex formation at concentrations as low as 1 pmol per 10 MUL with 10,000-fold sequence selectivity. Moreover, the molecular beacon was protected from a contaminating nuclease in choline dhp, and DNAs in aqueous solutions were not sufficiently stable for practical use. PMID- 25919084 TI - Hierarchical Flowerlike Gold Nanoparticles Labeled Immunochromatography Test Strip for Highly Sensitive Detection of Escherichia coli O157:H7. AB - Gold nanoparticles (AuNPs) labeled lateral-flow test strip immunoassay (LFTS) has been widely used in biomedical, feed/food, and environmental analysis fields. Conventional ILFS assay usually uses spherical AuNPs as labeled probes and shows low detection sensitivity, which further limits its widespread practical application. Unlike spherical AuNP used as labeled probe in conventional ILFS, in our present study, a hierarchical flowerlike AuNP specific probe was designed for LFTS and further used to detect Escherichia coli O157:H7 (E. coli O157:H7). Three types of hierarchical flowerlike AuNPs, such as tipped flowerlike, popcornlike, and large-sized flowerlike AuNPs were synthesized in a one-step method. Compared with other two kinds of Au particles, tipped flowerlike AuNPs probes for LFTS particularly exhibited highly sensitive detection of E. coli O157:H7. The remarkable improvement of detection sensitivity of tipped flowerlike AuNPs probes can be achieved even as low as 10(3) colony-forming units (CFU)/mL by taking advantages of its appropriate size and hierarchical structures, which is superior over the detection performance of conventional LFTS. Using this novel tipped flower AuNPs probes, quantitative detection of E. coli O157:H7 can be obtained partially in a wide concentration range with good repeatability. This hierarchical tipped flower-shaped AuNPs probe for LFTS is promising for the practical applications in widespread analysis fields. PMID- 25919085 TI - How communication changes when we cannot mime the world: Experimental evidence for the effect of iconicity on combinatoriality. AB - Communication systems are exposed to two different pressures: a pressure for transmission efficiency, such that messages are simple to produce and perceive, and a pressure for referential efficiency, such that messages are easy to understand with their intended meaning. A solution to the first pressure is combinatoriality--the recombination of a few basic meaningless forms to express an infinite number of meanings. A solution to the second is iconicity--the use of forms that resemble what they refer to. These two solutions appear to be incompatible with each other, as iconic forms are ill-suited for use as meaningless combinatorial units. Furthermore, in the early stages of a communication system, when basic referential forms are in the process of being established, the pressure for referential efficiency is likely to be particularly strong, which may lead it to trump the pressure for transmission efficiency. This means that, where iconicity is available as a strategy, it is likely to impede the emergence of combinatoriality. Although this hypothesis seems consistent with some observations of natural language, it was unclear until recently how it could be soundly tested. This has changed thanks to the development of a line of research, known as Experimental Semiotics, in which participants construct novel communication systems in the laboratory using an unfamiliar medium. We conducted an Experimental Semiotic study in which we manipulated the opportunity for iconicity by varying the kind of referents to be communicated, while keeping the communication medium constant. We then measured the combinatoriality and transmission efficiency of the communication systems. We found that, where iconicity was available, it provided scaffolding for the construction of communication systems and was overwhelmingly adopted. Where it was not available, however, the resulting communication systems were more combinatorial and their forms more efficient to produce. This study enriches our understanding of the fundamental design principles of human communication and contributes tools to enrich it further. PMID- 25919086 TI - Quality of life and stressors in patients with chronic kidney disease depending on treatment. AB - This study evaluated health-related quality of life (HRQOL) in a Spanish sample of chronic kidney disease patients (n = 90) undergoing different renal replacement therapies, considering the influence of treatment stressors, mood, anxiety and quality of sleep. While all patients had worse physical functioning than controls (p < .01), only those undergoing haemodialysis (HD) showed worse physical well-being, occupational functioning, spiritual fulfillment and more health interference with work (p < .05). They also obtained higher depression scores than renal transplant patients (TX) (p = .005). Those TX receiving the immunosuppressor sirolimus exhibited more cardiac/renal, cognitive and physical limitations than the rest (p < .05). Dialysis vintage correlated positively with sleep disturbances and depression scores and negatively with total Quality of Life (QLI) (p < .05). HD patients experienced more psychological distress than peritoneal dialysis patients (PD) (p = .036). Regression models including sleep, anxiety and depression were estimated for subscales of HRQOL. In TX patients, low depressive scores related to an optimal QLI in almost all subscales, while in HD patients they explained part of the variability in psychological well-being, interpersonal functioning and personal fulfillment. HD condition results in a QLI more distant to the standards of controls. PMID- 25919087 TI - Indigenous knowledge of medicinal plants among Dozo hunters: an ethnobotanical survey in Niamberla village, Burkina Faso. AB - OBJECTIVES: This investigation aims to provide a database of Dozo traditional knowledge of medicinal plants used for the treatment of common diseases. DESIGN: The study was conducted through individual interviews using a survey form. Data were recorded in a database allowing statistical analysis. Each plant was recorded and documented with a herbarium specimen. Settings/Location & Subjects: The term Dozo refers to great hunters from Burkina Faso, highly renowned for their knowledge of medicinal plants. Niamberla village was founded by Dozo hunters and is currently the residence of many traditional healers. Unfortunately, their indigenous knowledge is not well recorded and may be lost between two generations. RESULTS: A total of 16 traditional healers were interviewed, giving 89 recipes for the treatment of 37 diseases. The most common diseases are malaria (13%), psychological/spiritual issues (12%), gastric disorders (11%), sexually transmitted diseases (10%), and wounds (8%). A total of 56 medicinal plants have been identified, consisting mostly of trees (44%), shrubs (34%), and herbs (16%). CONCLUSIONS: The results of this research provide a basis for pharmacological and toxicological investigations and are necessary to preserve the indigenous knowledge of traditional medicine among Dozo hunters. PMID- 25919088 TI - Vertical/Planar Growth and Surface Orientation of Bi2Te3 and Bi2Se3 Topological Insulator Nanoplates. AB - Nanostructures are not only attractive for fundamental research but also offer great promise for bottom-up nanofabrications. In the past, the growth of one dimensional vertical/planar nanomaterials such as nanowires has made significant progresses. However, works on two-dimensional nanomaterials are still lacking, especially for those grown out of a substrate. We report here a vertical growth of topological insulator, Bi2Se3 and Bi2Te3, nanoplates on mica. In stark contrast to the general belief, these nanoplates are not prisms exposing (100) lateral surfaces, which are expected to minimize the surface area. Instead, they are frustums, enclosed by (01-4), (015), and (001) facets. First-principles calculations, combined with experiments, suggest the importance of surface oxidation in forming these unexpected surfaces. PMID- 25919089 TI - Aptamer-Mediated Codelivery of Doxorubicin and NF-kappaB Decoy Enhances Chemosensitivity of Pancreatic Tumor Cells. AB - Aptamers able to bind efficiently cell-surface receptors differentially expressed in tumor and in healthy cells are emerging as powerful tools to perform targeted anticancer therapy. Here, we present a novel oligonucleotide chimera, composed by an RNA aptamer and a DNA decoy. Our assembly is able to (i) target tumor cells via an antitransferrin receptor RNA aptamer and (ii) perform selective codelivery of a chemotherapeutic drug (Doxorubicin) and of an inhibitor of a cell-survival factor, the nuclear factor kappaB decoy oligonucleotide. Both payloads are released under conditions found in endolysosomal compartments (low pH and reductive environment). Targeting and cytotoxicity of the oligonucleotidic chimera were assessed by confocal microscopy, cell viability, and Western blot analysis. These data indicated that the nuclear factor kappaB decoy does inhibit nuclear factor kappaB activity and ultimately leads to an increased therapeutic efficacy of Doxorubicin selectively in tumor cells. PMID- 25919090 TI - Targeting the PD-1/PD-L1 Immune Evasion Axis With DNA Aptamers as a Novel Therapeutic Strategy for the Treatment of Disseminated Cancers. AB - Blocking the immunoinhibitory PD-1:PD-L1 pathway using monoclonal antibodies has led to dramatic clinical responses by reversing tumor immune evasion and provoking robust and durable antitumor responses. Anti-PD-1 antibodies have now been approved for the treatment of melanoma, and are being clinically tested in a number of other tumor types as both a monotherapy and as part of combination regimens. Here, we report the development of DNA aptamers as synthetic, nonimmunogenic antibody mimics, which bind specifically to the murine extracellular domain of PD-1 and block the PD-1:PD-L1 interaction. One such aptamer, MP7, functionally inhibits the PD-L1-mediated suppression of IL-2 secretion in primary T-cells. A PEGylated form of MP7 retains the ability to block the PD-1:PD-L1 interaction, and significantly suppresses the growth of PD L1+ colon carcinoma cells in vivo with a potency equivalent to an antagonistic anti-PD-1 antibody. Importantly, the anti-PD-1 DNA aptamer treatment was not associated with off-target TLR-9-related immune responses. Due to the inherent advantages of aptamers including their lack of immunogenicity, low cost, long shelf life, and ease of synthesis, PD-1 antagonistic aptamers may represent an attractive alternative over antibody-based anti PD-1 therapeutics. PMID- 25919091 TI - The Complex Relationship Between Quality and Resource Use Among Medicare Fee-for Service Beneficiaries with Diabetes. AB - This study examines the relationship between Healthcare Effectiveness Data and Information Set-based diabetes quality measures and resource use for evaluation and management (E&M), inpatient facility, and surgical procedure services for a national sample of Medicare fee-for-service beneficiaries in 1685 Hospital Service Areas. Using multivariate regression analyses, the study findings suggest that higher rates of beneficiaries' receipt of HbA1c, low-density lipoprotein cholesterol, and retinal eye exam tests ("composite quality") during the year is inversely related to average inpatient resource use. However, no association is found between composite quality and E&M services, suggesting that quality improvement with respect to increased rates of testing could be achieved without significant increases in resource use. PMID- 25919093 TI - Who is an "Orthodontist"? 1915. PMID- 25919094 TI - Who is an "Orthodontist"? Reprise for 2015. PMID- 25919092 TI - Solution structure of the RNA-binding cold-shock domain of the Chlamydomonas reinhardtii NAB1 protein and insights into RNA recognition. AB - Light-harvesting complex (LHC) proteins are among the most abundant proteins on Earth and play critical roles in photosynthesis, both in light capture and in photoprotective mechanisms. The Chlamydomonas reinhardtii nucleic acid-binding protein 1 (NAB1) is a negative regulator of LHC protein translation. Its N terminal cold-shock domain (CSD) binds to a 13-nt element [CSD consensus sequence (CSDCS)] found in the mRNA of specific LHC proteins associated with Photosystem II (PSII), an interaction which regulates LHC expression and, consequently, PSII associated antenna size, structure and function. In the present study, we elucidated the solution structure of the NAB1 CSD as determined by heteronuclear NMR. The CSD adopts a characteristic five-stranded anti parallel beta-barrel fold. Upon addition of CSDCS RNA, a large number of NMR chemical shift perturbations were observed, corresponding primarily to surface-exposed residues within the highly conserved beta2- and beta3-strands in the canonical RNA-binding region, but also to residues on beta-strand 5 extending the positive surface patch and the overall RNA-binding site. Additional chemical shift perturbations that accompanied RNA binding involved buried residues, suggesting that transcript recognition is accompanied by conformational change. Our results indicate that NAB1 associates with RNA transcripts through a mechanism involving its CSD that is conserved with mechanisms of sequence-specific nucleic acid recognition employed by ancestrally related bacterial cold-shock proteins (CSPs). PMID- 25919095 TI - Charles Virgil Mosby. PMID- 25919096 TI - Dr Angle's private orthodontic practice. PMID- 25919097 TI - Orthodontic profiles: John Valentine Mershon. PMID- 25919099 TI - Postsurgical volumetric airway changes in 2-jaw orthognathic surgery patients. AB - INTRODUCTION: Findings from early cephalometric studies on airway changes after 2 jaw orthognathic surgery have been challenged because the previous anteroposterior interpretation of airway changes can now be evaluated in 3 dimensions. The aims of this study were to use cone-beam computed tomography to quantify the nasopharynx, oropharynx, and total airway volume changes associated with skeletal movements of the maxilla and mandible in a sample of patients undergoing 2-jaw orthognathic surgery for correction of skeletal malocclusion. METHODS: Skeletal movements and airway volumes of 71 postpubertal patients (31 male, 40 female; mean age, 18.8 years) were measured. They were divided into 2 groups based on ANB angle, overjet, and occlusion (Class II: ANB, >2 degrees ; overjet, >1 mm; total, 35 subjects; and Class III: ANB, <1 degrees ; overjet, <1 mm; total, 36 subjects). Presurgical and postsurgical measurements were collected for horizontal, vertical, and transverse movements of the maxilla and the mandible, along with changes in the nasopharynx, oropharynx, and total airways. Associations between the directional movements of skeletal structures and the regional changes in airway volume were quantified. Changes in the most constricted area were also noted. RESULTS: Horizontal movements of D-point were significantly associated with increases in both total airway (403.6 +/- 138.6 mm(3); P <0.01) and oropharynx (383.9 +/- 127.9 mm(3); P <0.01) volumes. Vertical movements of the posterior nasal spine were significantly associated with decreases in total airway volume (-459.2 +/- 219.9 mm(3); P = 0.04) and oropharynx volume (-639.7 +/- 195.3 mm(3); P <0.01), increases in nasopharynx (187.2 +/- 47.1 mm(3); P <0.01) volume, and decreases in the most constricted area (-10.63 +/- 3.69 mm(2); P <0.01). In the Class III patients only, the vertical movement of D-point was significantly associated with decreases in both total airway (-724.0 +/- 284.4 mm(3); P = 0.02) and oropharynx (-648.2 +/- 270.4 mm(3); P = 0.02) volumes. A similar negative association was observed for the most constricted area for the vertical movement of D-point (-15.45 +/- 4.91 mm(2); P <0.01). CONCLUSIONS: Optimal control of airway volume is through management of the mandible in the horizontal direction and the vertical movement of the posterior maxilla for all patients. The surgeon and the orthodontist should optimally plan these movements to control gains or losses in airway volume as a result of orthognathic surgery. PMID- 25919100 TI - Flapless cortical bone damage has no effect on medullary bone mesial to teeth being moved. AB - INTRODUCTION: In this study, we evaluated the effects of bone awl-induced damage to bone surrounding a tooth that was moved. METHODS: A randomized split-mouth design with 7 foxhounds was performed to evaluate protraction of the mandibular third premolars for 56 days with 200 g of orthodontic force. Before initiating tooth movements, a bone awl was used on the experimental side to create 60 buccal and lingual microfracture injuries to the cortical bone without a periosteal flap. Tooth movements were performed on the control and experimental sides. Microcomputed tomography and histology were used to assess bone morphology and modeling. Radiographic and caliper measures were used to assess tooth movements. RESULTS: The awl-induced injuries produced significant damage and microfractures (95 mm(3)). Buccal and lingual cortical bone volume fractions and densities were significantly less and cortical modeling was significantly greater on the experimental sides than on the control sides. Bone volume fractions and densities mesial to the third premolars were the same on the experimental and control sides. Experimental side tooth movements (1.40 +/- 0.25 mm) were statistically the same as the control side tooth movements (1.57 +/- 0.45 mm). CONCLUSIONS: The effects of flapless, bone awl-induced damage were limited to the cortical bone. Because there was no effect on the medullary bone mesial to the tooth being moved, no differences in tooth movements were produced. PMID- 25919101 TI - Follow-up study of dental and skeletal changes in patients with obstructive sleep apnea and hypopnea syndrome with long-term treatment with the Silensor appliance. AB - INTRODUCTION: In this study, we aimed to investigate the dental and skeletal changes associated with long-term use of the Silensor appliance (Erkodent, Cologne, Germany) in patients with obstructive sleep apnea and hypopnea syndrome. METHODS: The sample included 42 patients with mild-to-severe obstructive sleep apnea and hypopnea syndrome (mean apnea-hypopnea index, 27; range, 5-74) who had been treated with the Silensor appliance for an average of 4 years (range, 1-11 years). A questionnaire was used to assess of the side effects subjectively; the cephalometric analysis was conducted to identify the dental and skeletal changes of different treatment times objectively. RESULTS: The Silensor appliance was associated with few subjective side effects. Most subjective side effects decreased after long-term use of the Silensor appliance. Significant changes after long-term use of the Silensor appliance were observed in incisor angulation, overbite, overjet, mandibular plane angle, anterior lower facial height, and anterior facial height. Overbite and skeletal changes at treatment times between 1 year and 3 years were a decrease in overbite and increases in the mandibular plane angle, anterior lower facial height, and anterior facial height. Overjet and other dental changes at treatment times longer than 3 years were a decrease in overjet, retroclination of the maxillary incisors, and proclination of the mandibular incisors. CONCLUSIONS: The Silensor appliance was well tolerated and preferred by most subjects. Common but mild dental and skeletal changes resulted from using the appliance over a long period of time. The changes after 1 to 3 years of use were skeletal changes predominantly. Both dental and skeletal changes were observed simultaneously at treatment times longer than 3 years. PMID- 25919102 TI - Combined maxillary and mandibular distraction osteogenesis in patients with hemifacial microsomia. AB - INTRODUCTION: Hemifacial microsomia is a deformity of variable expressivity with unilateral hypoplasia of the mandible and the ear. In this study, we evaluated skeletal soft tissue changes after bimaxillary unilateral vertical distraction. METHODS: Eight patients (4 preadolescents 4 adolescents) each with a grade II mandibular deformity underwent a LeFort I osteotomy and an ipsilateral horizontal mandibular ramus osteotomy. A semiburied distraction device was placed over the ramus, and intermaxillary fixation was applied. Anteroposterior cephalometric and frontal photographic analyses were conducted before and after distraction. Statistics were used to analyze the preoperative and postoperative changes. RESULTS: Cephalometrically, the nasal floor and the occlusal and gonial plane angles decreased. The ratios of affected-unaffected ramus and gonial angle heights improved by 15% and 20%, respectively. The position of menton moved toward the midline. The photographic analysis showed a decrease of the nasal and commissure plane angles, and the chin moved to the unaffected side. The parallelism between the horizontal skeletal and soft tissue planes improved, with an increase in the affected side ramus height and correction of the chin point toward the midline. CONCLUSIONS: Simultaneous maxillary and mandibular distraction improved facial balance and symmetry. Patients in the permanent dentition with fixed orthodontic appliances and well-aligned dental arches responded well to this intervention. PMID- 25919103 TI - Effect of low-level laser irradiation on the rate and short-term stability of rotational tooth movement in dogs. AB - INTRODUCTION: Low-level laser therapy (LLLT) has many biostimulative effects such as acceleration of mesiodistal orthodontic tooth movement. However, its effects on the extent and short-term stability of rotational tooth movement have not been researched. The purpose of this study was to investigate the effect of low-level laser irradiation during rotational tooth movement on the rate of movement and the amount of relapse in dogs. METHODS: In this interventional study, fixed orthodontic appliances were used to rotate both mandibular lateral incisors in 8 dogs. Sixteen teeth were divided into 2 groups: the experimental group with LLLT during orthodontic force application, and a control group with orthodontic couple force application only. In the first group, the gallium-aluminum-arsenide diode laser (810 nm, 200 mw, 10 seconds, 2 J/session, 32 J/cm(2)/point) was emitted on 2 points at the buccal side of the roots on days 0, 1, 2, 3, 4, 7, 14, 21, and 28 during 4 weeks of movement, and the amount of relapse was then observed for 3 months. The extent of rotational movement was measured on dental casts, and the statistical analysis was carried out with t tests. RESULTS: There was no significant difference between the LLLT group and the control group on the amount of rotational tooth movement (P = 0.66). The mean percentages of relapse after 1 week, 1 month, and 3 months were 33.02%, 53.44%, and 60.64% in the LLLT group and 54.22%, 68.74%, and 73.92% in the control group, respectively. This demonstrates significant differences between these groups at all studied times (P <=0.05). This difference was greatest in the first week and then decreased until the end of the third month. The greatest percentage of relapse in both groups was registered in the first week after tooth movement. CONCLUSIONS: The total energy dose of the laser used in this study could not accelerate rotational tooth movement, but it did effectively reduce the relapse tendency in teeth rotated by orthodontic movements. PMID- 25919104 TI - Impact of malocclusion and common oral diseases on oral health-related quality of life in young adults. AB - INTRODUCTION: The aim of this study was to assess the association between malocclusion and oral health-related quality of life in young adults without orthodontic treatment, controlling for sociodemographic factors and common oral diseases. METHODS: The sample consisted of 429 Korean patients (328 men, 101 women) 18 to 32 years of age. They completed the Korean version of the oral health impact profile-14 questionnaire and had a clinical examination, including an assessment with the index of orthodontic treatment need-dental health component. We collected sociodemographic information (age, sex, and education level) and evaluated other common oral diseases (decayed, missing, and filled teeth; periodontal health status; temporomandibular disorder; and oral soft tissue diseases). RESULTS: Multiple logistic regression analysis showed that patients requiring extensive orthodontic treatment were more than 2.7 times as likely to have poor oral health-related quality of life as the corresponding "no treatment needed" reference group (odds ratio, 2.74; 95% confidence interval, 1.60-4.59; P <0.001). Severe malocclusion is significantly associated with functional limitations, physical pain, and social disability in young adults. CONCLUSIONS: Malocclusion is a key factor associated with poor quality of life caused by limited oral function, pain, and social disability in young adults. PMID- 25919105 TI - Extraction vs no treatment: Long-term facial profile changes. AB - INTRODUCTION: Long-term soft tissue response to extraction orthodontic treatment has been a subject of interest for years. The purposes of this study were to investigate long-term soft tissue profile changes in an extraction sample and to compare them with profile changes in an untreated sample. METHODS: A premolar extraction-treated sample (n = 47) and an untreated control sample (n = 57) were studied. Descriptive statistics were collected, and individual t tests were used for comparison and contrast of the treated and untreated samples. RESULTS: We found that the untreated soft tissue profile changed in the downward and forward direction. The treated soft tissue profile change was similar, but with more of a forward component than in the untreated sample. Most noteworthy was the finding that the soft tissue profiles of both the untreated and the treated samples were similar at the end point. CONCLUSIONS: The following conclusions were derived from the study. (1) There was no substantive difference in the soft tissue profiles of the samples, but there were some differences in the directional changes between them. (2) The changes for the untreated sample were the greatest for the lips and the chin, with the change occurring in the downward and forward direction. (3) The soft tissue profiles of the extraction sample also had the greatest measurable changes in the lips and the chin, but the changes had more of a forward component than they did in the untreated sample. (4) Extraction treatment does not adversely impact soft tissue profile changes over time. PMID- 25919106 TI - Influence of common fixed retainers on the diagnostic quality of cranial magnetic resonance images. AB - INTRODUCTION: Orthodontists are often asked to remove fixed retainers before magnetic resonance imaging (MRI). This study was undertaken to assess the effects of 2 commonly used fixed retainers on MRI distortion and whether they should be removed. METHODS: MRI scans were performed on a dry skull with Twistflex (Dentaurum, Ispringen, Germany) and Ortho Flex Tech (Reliance Orthodontic Products, Itasca, Ill) retainers. Two neuroradiologists independently ranked the distortions. The influence of the fixed retainers' alloys, their distance to the area of diagnosis, location, strength of the magnetic field, and the spin-echo sequence were examined. Statistical analysis included kappa and Pearson chi square tests. RESULTS: Ortho Flex Tech retainers caused no distortion. Twistflex retainers caused distortion in 46% of the tests in areas close to the retainer (tongue and jaws). Maxillary fixed retainers and the combination of maxillary and mandibular fixed retainers further increased the distortion. Greater distortion was observed with 3-T magnetic fields and T1-weighted spin-echo sequences. CONCLUSIONS: Removal of the Ortho Flex Tech retainer is unnecessary before MRI. Removal of the Twistflex should be considered if the MRI scans are performed to diagnose areas close to the fixed retainers, when 3-T magnetic fields and T1 weighted sequences are used, and when both maxillary and mandibular fixed retainers are present. PMID- 25919107 TI - Association of orthodontic force system and root resorption: A systematic review. AB - INTRODUCTION: In this systematic review, we assessed the literature to determine which evidence level supports the association of orthodontic force system and root resorption. METHODS: PubMed, Cochrane, and Embase databases were searched with no restrictions on year, publication status, or language. Selection criteria included human studies conducted with fixed orthodontic appliances or aligners, with at least 10 patients and the force system well described. RESULTS: A total of 259 articles were retrieved in the initial search. After the review process, 21 full-text articles met the inclusion criteria. Sample sizes ranged from 10 to 73 patients. Most articles were classified as having high evidence levels and low risks of bias. CONCLUSIONS: Although a meta-analysis was not performed, from the available literature, it seems that positive correlations exist between increased force levels and increased root resorption, as well as between increased treatment time and increased root resorption. Moreover, a pause in tooth movement seems to be beneficial in reducing root resorption because it allows the resorbed cementum to heal. The absence of a control group, selection criteria of patients, and adequate examinations before and after treatment are the most common methodology flaws. PMID- 25919108 TI - Litigation and Legislation. What record is playing? PMID- 25919109 TI - Statistical inference with confidence intervals. PMID- 25919111 TI - Utilizing Health Information Technology to Support Universal Healthcare Delivery: Experience of a National Healthcare System. AB - Recent discussions have focused on using health information technology (HIT) to support goals related to universal healthcare delivery. These discussions have generally not reflected on the experience of countries with a large amount of experience using HIT to support universal healthcare on a national level. HIT was compared globally by using data from the Ministry of the Interior, Republic of China (Taiwan). Taiwan has been providing universal healthcare since 1995 and began to strategically implement HIT on a national level at that time. Today the national-level HIT system is more extensive in Taiwan than in many other countries and is used to aid administration, clinical care, and public health. The experience of Taiwan thus can provide an illustration of how HIT can be used to support universal healthcare delivery. In this article we present an overview of some key historical developments and successes in the adoption of HIT in Taiwan over a 17-year period, as well as some more recent developments. We use this experience to offer some strategic perspectives on how it can aid in the adoption of large-scale HIT systems and on how HIT can be used to support universal healthcare delivery. PMID- 25919110 TI - A systematic review of pharmacological treatment options used to reduce ischemia reperfusion injury in rat liver transplantation. AB - BACKGROUND: Although animal studies models are frequently used for the purpose of attenuating ischemia reperfusion injury (IRI) in liver transplantation (LT), many of pharmacological agents have not become part of clinical routine. METHODS: A search was performed using the PubMed database to identify agents, from which 58 articles containing 2700 rat LT procedures were selected. The identified pharmacological agents were categorized as follows: I - adenosine agonists, nitric oxide agonists, endothelin antagonists, and prostaglandins, II - Kupffer cell inactivator, III - complement inhibiter, IV - antioxidant, V - neutrophil inactivator, VI -anti-apoptosis agent, VII - heat shock protein and nuclear factor kappa B inducer, VIII - metabolic agent, IX - traditional Chinese medicine, and X - others. Meta-analysis using 7-day-survival rate was also performed with Mantel-Haenszel's Random effects model. RESULTS: The categorization revealed that the rate of donor-treated experiments in each group was highest for agents from Group II (70%) and VII (71%), whereas it was higher for agents from Group V (83%) in the recipient-treated experiments. Furthermore, 90% of the experiments with agents in Group II provided 7-day-survival benefits. The Risk Ratio (RR) of the meta-analysis was 2.43 [95% CI: 1.88-3.14] with moderate heterogeneity. However, the RR of each of the studies was too model dependent to be used in the search for the most promising pharmacological agent. CONCLUSION: With regard to hepatic IRI pathology, the categorization of agents of interest would be a first step in designing suitable multifactorial and pleiotropic approaches to develop pharmacological strategies. PMID- 25919112 TI - Association between TAAR6 polymorphisms and airway responsiveness to inhaled corticosteroids in asthmatic patients. AB - BACKGROUND: Genetic polymorphisms may be responsible for the wide variation in response to inhaled corticosteroids in asthmatic patients. We had previously reported that one polymorphism rs7772821, located on the 3'-UTR of trace amine associated receptor 6 (TAAR6), is significantly associated with percentile changes in the forced expiratory volume in 1 s (%DeltaFEV1) after inhaled corticosteroid treatment in asthmatics using a genome-wide association study. The aim of the present study was to validate the association between 15 single nucleotide polymorphisms (SNPs) on the TAAR6 and airway responsiveness to inhaled corticosteroids in the asthmatics. METHODS: The %DeltaFEV1 induced by 4 weeks' treatment with inhaled fluticasone propionate (1000 MUg daily) was measured in 246 asthmatics. The 15 SNPs of TAAR6 were genotyped using a TaqMan assay. An association analysis between %DeltaFEV1 and TAAR6 polymorphisms was carried out using a linear regression model controlling for age, sex, smoking status, presence of atopy, and baseline FEV1 as covariates. RESULTS: Among the 15 SNPs and seven haplotypes of TAAR6, rs7772821 (T>G) on the 3'-UTR showed the strongest correlation with inhaled corticosteroid-induced %DeltaFEV1 (Pcorr=0.002 in the codominant model, Pcorr=0.03 in the dominant model, Pcorr=0.01 in the recessive model). The %DeltaFEV1 of the rs7772821T>G minor homozygotes (60.77%) was higher than that of patients harboring either the rs7772821 T/G or T/T genotypes (21.32 and 31.60%, respectively). CONCLUSION: The TAAR6 rs7772821 polymorphism may be one of the important genetic factors for predicting the response to treatment with inhaled corticosteroids in asthmatics. PMID- 25919113 TI - Immunomic Screening of Cell Surface Molecules on Undifferentiated Human Dental Pulp Stem Cells. AB - Human adult dental pulp tissue is a source of adult stem cells that have a potential to differentiate into various tissues, although the primary cell suspensions cultured from pulp tissue are mixtures of both stem cell and nonstem cell populations with heterogeneous phenotypes and various differentiation efficiencies. Therefore, cell surface protein markers on dental pulp stem cells are critical for detection and purification of stem cell populations. Yet, little is known about the cell surface molecules that are specifically associated with the undifferentiated and progenitor state of human adult dental pulp stem cells (hDPSCs). Presently, cell surface proteins expressed on hDPSCs were assessed by screening surface molecules specifically expressed on dentinogenic progenitors. Using a decoy immunization strategy, a set of monoclonal antibodies (MAbs) was generated against undifferentiated pulp progenitor cells. Forty-five hybridomas produced MAbs that interacted weakly, if at all, to differentiated pulp cells. Of these, 19 MAbs (18 IgG, 1 IgM) recognized surface molecules on undifferentiated hDPSCs. By multicolor flow cytometric analysis, 40%-60% of newly identified MAb positive cells were demonstrated to be positive for the CD44 and CD90 mesenchymal markers. When MAb-positive cells were sorted from the heterogeneous pulp cell suspension, mineralization efficiency was increased three to five times compared with MAb-negative cells. The results suggest that the decoy immunization is an efficient method for isolation of MAbs against dentinogenic progenitors. These MAbs will be helpful for identification and enrichment of hDPSCs for efficient dentin regeneration. PMID- 25919114 TI - Redox Regulation of Cell Contacts by Tricellulin and Occludin: Redox-Sensitive Cysteine Sites in Tricellulin Regulate Both Tri- and Bicellular Junctions in Tissue Barriers as Shown in Hypoxia and Ischemia. AB - Tight junctions (TJs) seal paracellular clefts in epithelia/endothelia and form tissue barriers for proper organ function. TJ-associated marvel proteins (TAMPs; tricellulin, occludin, marvelD3) are thought to be relevant to regulation. Under normal conditions, tricellulin tightens tricellular junctions against macromolecules. Traces of tricellulin occur in bicellular junctions. AIMS: As pathological disturbances have not been analyzed, the structure and function of human tricellulin, including potentially redox-sensitive Cys sites, were investigated under reducing/oxidizing conditions at 3- and 2-cell contacts. RESULTS: Ischemia, hypoxia, and reductants redistributed tricellulin from 3- to 2 cell contacts. The extracellular loop 2 (ECL2; conserved Cys321, Cys335) trans oligomerized between three opposing cells. Substitutions of these residues caused bicellular localization. Cys362 in transmembrane domain 4 contributed to bicellular heterophilic cis-interactions along the cell membrane with claudin-1 and marvelD3, while Cys395 in the cytosolic C-terminal tail promoted homophilic tricellullar cis-interactions. The Cys sites included in homo-/heterophilic bi /tricellular cis-/trans-interactions contributed to cell barrier tightness for small/large molecules. INNOVATION: Tricellulin forms TJs via trans- and cis association in 3-cell contacts, as demonstrated electron and quantified fluorescence microscopically; it tightens 3- and 2-cell contacts. Tricellulin's ECL2 specifically seals 3-cell contacts redox dependently; a structural model is proposed. CONCLUSIONS: TAMP ECL2 and claudins' ECL1 share functionally and structurally similar features involved in homo-/heterophilic tightening of cell cell contacts. Tricellulin is a specific redox sensor and sealing element at 3 cell contacts and may compensate as a redox mediator for occludin loss at 2-cell contacts in vivo and in vitro. Molecular interaction mechanisms were proposed that contribute to tricellulin's function. In conclusion, tricellulin is a junctional redox regulator for ischemia-related alterations. PMID- 25919115 TI - Standardized uptake value and apparent diffusion coefficient of endometrial cancer evaluated with integrated whole-body PET/MR: Correlation with pathological prognostic factors. AB - PURPOSE: To evaluate the correlation between maximum standardized uptake value (SUVmax ) and minimum apparent diffusion coefficient (ADCmin ) of endometrial cancer derived from an integrated positron emission tomography / magnetic resonance (PET/MR) system and to determine their correlation with pathological prognostic factors. MATERIALS AND METHODS: This prospective study was approved by the Institutional Review Board of the hospital, and informed consent was obtained. Between April and December 2014, 47 consecutive patients with endometrial cancer were enrolled and underwent simultaneous PET/MR examinations before surgery. Thirty-six patients with measurable tumors on PET/MR were included for image analysis. Pearson's correlation coefficient was used to evaluate the correlation between SUVmax and ADCmin of the tumors. The Mann Whitney U-test was utilized to evaluate relationships between these two imaging biomarkers and pathological prognostic factors. RESULTS: The mean SUVmax and ADCmin were 14.7 +/- 7.1 and 0.48 +/- 0.13 * 10(-3) mm(2) /s, respectively. A significant inverse correlation was found between SUVmax and ADCmin (r = -0.53; P = 0.001). SUVmax was significantly higher in tumors with advanced stage, deep myometrial invasion, cervical invasion, lymphovascular space involvement, and lymph node metastasis (P < 0.05). ADCmin was lower in tumors with higher grade, advanced stage, and cervical invasion (P < 0.05). The ratio of SUVmax to ADCmin was higher in tumors with higher grade, advanced stage, deep myometrial invasion, cervical invasion, lymphovascular space involvement, and lymph node metastasis (P < 0.05). CONCLUSION: SUVmax and ADCmin of endometrial cancer derived from integrated PET/MR are inversely correlated and are associated with pathological prognostic factors. PMID- 25919116 TI - Analysis of Binary Multivariate Longitudinal Data via 2-Dimensional Orbits: An Application to the Agincourt Health and Socio-Demographic Surveillance System in South Africa. AB - We analyse demographic longitudinal survey data of South African (SA) and Mozambican (MOZ) rural households from the Agincourt Health and Socio-Demographic Surveillance System in South Africa. In particular, we determine whether absolute poverty status (APS) is associated with selected household variables pertaining to socio-economic determination, namely household head age, household size, cumulative death, adults to minor ratio, and influx. For comparative purposes, households are classified according to household head nationality (SA or MOZ) and APS (rich or poor). The longitudinal data of each of the four subpopulations (SA rich, SA poor, MOZ rich, and MOZ poor) is a five-dimensional space defined by binary variables (questions), subjects, and time. We use the orbit method to represent binary multivariate longitudinal data (BMLD) of each household as a two dimensional orbit and to visualise dynamics and behaviour of the population. At each time step, a point (x, y) from the orbit of a household corresponds to the observation of the household, where x is a binary sequence of responses and y is an ordering of variables. The ordering of variables is dynamically rearranged such that clusters and holes associated to least and frequently changing variables in the state space respectively, are exposed. Analysis of orbits reveals information of change at both individual- and population-level, change patterns in the data, capacity of states in the state space, and density of state transitions in the orbits. Analysis of household orbits of the four subpopulations show association between (i) households headed by older adults and rich households, (ii) large household size and poor households, and (iii) households with more minors than adults and poor households. Our results are compared to other methods of BMLD analysis. PMID- 25919117 TI - Fermentative production of the diamine putrescine: system metabolic engineering of corynebacterium glutamicum. AB - Corynebacterium glutamicum shows great potential for the production of the glutamate-derived diamine putrescine, a monomeric compound of polyamides. A genome-scale stoichiometric model of a C. glutamicum strain with reduced ornithine transcarbamoylase activity, derepressed arginine biosynthesis, and an anabolic plasmid-addiction system for heterologous expression of E. coli ornithine decarboxylase gene speC was investigated by flux balance analysis with respect to its putrescine production potential. Based on these simulations, enhancing glycolysis and anaplerosis by plasmid-borne overexpression of the genes for glyceraldehyde 3-phosphate dehydrogenase and pyruvate carboxylase as well as reducing 2-oxoglutarate dehydrogenase activity were chosen as targets for metabolic engineering. Changing the translational start codon of the chromosomal gene for 2-oxoglutarate dehydrogenase subunit E1o to the less preferred TTG and changing threonine 15 of OdhI to alanine reduced 2-oxoglutarate dehydrogenase activity about five fold and improved putrescine titers by 28%. Additional engineering steps improved further putrescine production with the largest contributions from preventing the formation of the by-product N-acetylputrescine by deletion of spermi(di)ne N-acetyltransferase gene snaA and from overexpression of the gene for a feedback-resistant N-acetylglutamate kinase variant. The resulting C. glutamicum strain NA6 obtained by systems metabolic engineering accumulated two fold more putrescine than the base strain, i.e., 58.1 +/- 0.2 mM, and showed a specific productivity of 0.045 g.g-1.h-1 and a yield on glucose of 0.26 g.g-1. PMID- 25919118 TI - Effect of Levosimendan on Diastolic Function in Patients Undergoing Coronary Artery Bypass Grafting: A Comparative Study. AB - PURPOSE: To compare the efficacy of levosimendan with nitroglycerin in patients with isolated diastolic dysfunction undergoing coronary artery bypass grafting. PROCEDURE: Thirty patients with isolated diastolic dysfunction undergoing on-pump coronary artery bypass grafting were randomized into 2 groups receiving levosimendan or nitroglycerin infusion. The infusion was started before sternotomy and continued in the postoperative period. Perioperatively, diastolic function was serially evaluated at 3 different time points using echocardiography. N-terminal fragment of pro-B-natriuretic peptide (NT-proBNP) levels were measured in both the groups. RESULTS: There was a significant improvement in diastolic function as measured by isovolumic relaxation time (P = 0.0001, P = 0.001) and deceleration time (P = 0.0001, P = 0.0001) in the levosimendan group from the baseline in patients with impaired relaxation. Similarly, tissue Doppler imaging also revealed an improvement from the baseline in patients with a pseudonormal pattern (P = 0.018, P = 0.001). Furthermore, there was a significant improvement in the above parameters when compared with the nitroglycerin group. The NT-proBNP levels also demonstrated a similar pattern between the 2 groups (P = 0.03, P = 0.02) when levosimendan was compared with nitroglycerin in patients with a pseudonormal pattern on echocardiography. CONCLUSIONS: Levosimendan is superior to nitroglycerin in improving diastolic function irrespective of coronary revascularization. PMID- 25919119 TI - Tumor-specific expression and detection of a CEST reporter gene. AB - PURPOSE: To develop an imaging tool that enables the detection of malignant tissue with enhanced specificity using the exquisite spatial resolution of MRI. METHODS: Two mammalian gene expression vectors were created for the expression of the lysine-rich protein (LRP) under the control of the cytomegalovirus (CMV) promoter and the progression elevated gene-3 promoter (PEG-3 promoter) for constitutive and tumor-specific expression of LRP, respectively. Using those vectors, stable cell lines of rat 9L glioma, 9L(CMV-LRP) and 9L(PEG-LRP) , were established and tested for CEST contrast in vitro and in vivo. RESULTS: 9L(PEG LRP) cells showed increased CEST contrast compared with 9L cells in vitro. Both 9L(CMV-LRP) and 9L(PEG-LRP) cells were capable of generating tumors in the brains of mice, with a similar growth rate to tumors derived from wild-type 9L cells. An increase in CEST contrast was clearly visible in tumors derived from both 9L(CMV LRP) and 9L(PEG-LRP) cells at 3.4 ppm. CONCLUSION: The PEG-3 promoter:LRP system can be used as a cancer-specific, molecular-genetic imaging reporter system in vivo. Because of the ubiquity of MR imaging in clinical practice, sensors of this class can be used to translate molecular-genetic imaging rapidly. PMID- 25919120 TI - Effect of combined treatment with immunoadsorption and membrane filtration on plasma coagulation--Results of a randomized controlled crossover study. AB - The combined use of immunoadsorption (IA) and membrane filtration (MF) may markedly enhance removal of IgM and complement component C1q, supporting its use as an element of recipient desensitization in antibody-incompatible transplantation. However, coagulation factor removal may contribute to altered hemostasis, posing a risk of bleeding in the perioperative setting. This secondary endpoint analysis of standard coagulation assays and rotational thromboelastometry (ROTEM(r)) was performed in the context of a randomized controlled crossover study designed to assess the effect of combined IA (GAM-146 peptide) and MF on levels of ABO antigen-specific IgM. Fourteen patients with autoimmune disorders were randomized to a single treatment with IA+MF followed by IA alone, or vice versa. MF was found to markedly enhance fibrinogen depletion (57% vs. 28% median decrease after IA alone, P < 0.001), whereby four patients showed post-treatment fibrinogen concentrations below 100 mg dL(-1). In support of a critical contribution of fibrinogen depletion to impaired coagulation, extrinsically activated ROTEM((r)) analysis revealed a marked reduction in fibrinogen-dependent clot formation upon IA+MF (59% median decrease in FIBTEM mean clot firmness (MCF) as compared to 24% after IA alone, P < 0.001). Moreover, the addition of MF led to a substantial prolongation of activated partial thromboplastin time, possibly due to depletion of macromolecular coagulation factors contributing to intrinsically activated coagulation. Our study demonstrates substantial effects of combined IA+MF on clot formation, which may be mainly attributable to fibrinogen depletion. We suggest that the use of combined apheresis in the setting of transplant surgery may necessitate a careful monitoring of coagulation. PMID- 25919121 TI - CYP2D6 predicted metabolizer status and safety in adult patients with attention deficit hyperactivity disorder participating in a large placebo-controlled atomoxetine maintenance of response clinical trial. AB - Atomoxetine, which is indicated for treatment of attention-deficit hyperactivity disorder (ADHD), is predominantly metabolized by genetically polymorphic cytochrome P450 2D6 (CYP2D6). Based on identified CYP2D6 genotypes, individuals can be categorized into 4 phenotypic metabolizer groups as ultrarapid, extensive, intermediate, and poor. Previous studies have focused on observed differences between poor and extensive metabolizers, but it is not well understood whether the safety profile of intermediate metabolizers differs from that of ultrarapid and extensive metabolizers. This study compared safety and tolerability among the different CYP2D6 metabolizer groups in the 12-week open-label phase of an atomoxetine study in adult patients with ADHD. Genotyping identified 1039 patients as extensive/ultrarapid metabolizers, 780 patients as intermediate metabolizers, and 117 patients as poor metabolizers. Common (>=5% frequency) treatment-emergent adverse events did not significantly differ between extensive/ultrarapid and intermediate metabolizers (odds ratios were <2.0 or >0.5). Poor metabolizers had higher frequencies of dry mouth, erectile dysfunction, hyperhidrosis, insomnia, and urinary retention compared with the other metabolizer groups. There were no significant differences between extensive/ultrarapid and intermediate metabolizers in changes from baseline in vital signs. These results suggest that data from CYP2D6 intermediate and extensive/ultrarapid metabolizers can be combined when considering safety analyses related to atomoxetine. PMID- 25919122 TI - Endoscopic prediction of tumor margin and invasive depth in early gastric cancer. AB - Gastric cancer (GC) is the fifth most common cancer and the third leading cause of cancer-related deaths in the world. The prognosis of GC is clearly associated with the tumor stage, with a 5-year overall survival rate for early gastric cancer (EGC) exceeding 90%, which is significantly higher than that of advanced gastric cancer. Endoscopic resection, including endoscopic mucosal resection and endoscopic submucosal dissection, has been adopted in recent decades as the first treatment option of EGC in many countries for its minimal invasion and high curative rate. However, the horizontal and vertical margins are related to the curative resection of EGC and the prognosis of patients. Thus the accurate prediction of the tumor boundary and its invasive depth before treatment counts for much in planning the most appropriate treatment strategy and promising curative resection. To date, various endoscopic techniques have been identified to play a role in pretreatment evaluation, such as white light endoscopy, chromoendoscopy, narrow band imaging and endoscopic ultrasonography. This article aimed to summarize the diagnostic methods, applications and limitations of these different endoscopic techniques for identifying tumor horizontal and vertical margins in EGC, helping to increase preoperative evaluation of capabilities and to improve the curative resection rate of EGC. PMID- 25919123 TI - Racial Disparities in Hypofractionated Radiotherapy Breast Cancer Clinical Trials. AB - There is a paucity of data regarding factors affecting enrollment onto radiation oncology clinical trials. The purpose of this study was to determine patients and tumor characteristics that influenced enrollment of breast cancer patients onto hypofractionated breast radiotherapy trials (HBRTs) at a single institution. In this retrospective cohort study, patients enrolled on HBRTs at the Rutgers Cancer Institute of New Jersey (n = 132) were compared with a cohort of breast cancer patients eligible for, but not enrolled onto HBRTs treated during the same time period (n = 132). Charts were retrospectively reviewed to determine patients' demographics, clinico-pathologic factors, and treatment characteristics. Statistical analysis was performed to analyze variables affecting enrollment onto HBRTs between the two groups. Over a 42-month time period, 132 patients treated on HBRTs received 2,475-4,995 cGy over 3 to 15 fractions. When compared with patients treated off trial, there was no statistically significant effect of age, family history, lymph node positivity, tumor grade, estrogen or Her-2 receptor status, use of chemotherapy or hormones, use of brachytherapy, or the site of initial consultation on HBRT enrollment. Non-White women were less likely to enroll in HBRT's when compared with White women (25.7% versus 40.1%, p = 0.0129), though this was found to be a nonsignificant trend when taking stage into consideration on multivariate analysis (OR for lower T-stage: 0.281, p = 0.003, OR 1.839 for white race, p = 0.076). Consistent with previous studies, non-White women were less likely to enroll in HBRTs than White women. However, disease stage accounted for these racial disparities. Further studies must be performed to determine if race is an independent factor determining radiation oncology clinical trial enrollment. PMID- 25919124 TI - Multilocus Sequence Typing of Pathogenic Candida albicans Isolates Collected from a Teaching Hospital in Shanghai, China: A Molecular Epidemiology Study. AB - Molecular typing of Candida albicans is important for studying the population structure and epidemiology of this opportunistic yeast, such as population dynamics, nosocomial infections, multiple infections and microevolution. The genetic diversity of C. albicans has been rarely studied in China. In the present study, multilocus sequence typing (MLST) was used to characterize the genetic diversity and population structure of 62 C. albicans isolates collected from 40 patients from Huashan Hospital in Shanghai, China. A total of 50 diploid sequence types (DSTs) were identified in the 62 C. albicans isolates, with 41 newly identified DSTs. Based on cluster analysis, the 62 isolates were classified into nine existing clades and two new clades (namely clades New 1 and New 2). The majority of the isolates were clustered into three clades, clade 6 (37.5%), clade 1 (15.0%) and clade 17 (15.0%). Isolates of clade New 2 were specifically identified in East Asia. We identified three cases of potential nosocomial transmission based on association analysis between patients' clinical data and the genotypes of corresponding isolates. Finally, by analyzing the genotypes of serial isolates we further demonstrated that the microevolution of C. albicans was due to loss of heterozygosity. Our study represents the first molecular typing of C. albicans in eastern China, and we confirmed that MLST is a useful tool for studying the epidemiology and evolution of C. albicans. PMID- 25919125 TI - Large and negative magnetic anisotropy in pentacoordinate mononuclear Ni(ii) Schiff base complexes. AB - A series of pentacoordinate Ni(ii) complexes of the general formula [Ni(L5)] () with various pentadentate Schiff base ligands H2L5 (originating in a condensation of aromatic ortho-hydroxy-aldehydes and aliphatic triamines) was synthesized and characterized by X-ray structure analysis and magnetometry. The alternations of substituents on the H2L parent ligand resulted in the complexes with the geometry varying between the square-pyramid and trigonal-bipyramid. In the compounds whose chromophore geometry is closer to a trigonal-bipyramid, a large and negative uniaxial anisotropy (D = -64 cm(-1)) was identified. Moreover, the simple linear expression for the axial zero-field splitting (ZFS) parameter, D/cm(-1) = 32.7(4.8) - 151(10)tau, was proposed, where tau (in degrees) stands for the Addison parameter. The results of magnetic analysis were also supported by ab initio CASSCF/NEVPT2 calculations of the ZFS splitting parameters D and E, and g tensors. Despite large and negative D-values of the reported compounds, slow relaxation of magnetization was not observed either in zero or non-zero static magnetic field, thus no single-molecule magnetic behaviour was detected. PMID- 25919126 TI - Dynamic Aminal-Based TPA Ligands. AB - The use of dynamic covalent reactions (DCRs) is gaining popularity for the construction of self-assembling architectures. We have recently introduced DCRs that exchange alcohols and aldehydes to create hemiaminal ethers within tri(2 picolyl)amine (TPA) ligands, all of which are templated by Zn(II). To expand the scope of this assembly, aromatic imines derived from pyridine-2-carboxyaldehyde were explored as dynamic covalent receptors for di(2-picolyl)amine in the presence of Zn(II) to create TPA ligands that contain aminal linkages. This represents another metal-templated in situ multicomponent assembly. The stability of the assembly was successfully modulated through substituent effects, and the equilibrium constants from imines to aminals were correlated by a linear free energy relationship (LFER) with sigma(+) values. Dynamic component exchange was investigated as a means of probing multiple equilibriums quantitatively in the system. Further, the mechanism was analyzed with a qualitative kinetics study. NMR spectra reveal the different extents of two competing pathways for assembly depending upon whether the aromatic amine has electron-withdrawing or electron donating groups on the ring. Finally, mass spectral evidence supports the presence and differing extents of dominance of the two pathways as a function of the substituents. PMID- 25919127 TI - Voriconazole N-oxide and its ultraviolet B photoproduct sensitize keratinocytes to ultraviolet A. AB - BACKGROUND: The antifungal agent, voriconazole, is associated with phototoxicity and photocarcinogenicity. Prior work has indicated that voriconazole and its hepatic N-oxide metabolite do not sensitize keratinocytes to ultraviolet B (UVB). Clinical observations have suggested that ultraviolet A (UVA) may be involved. OBJECTIVES: To determine the photochemistry and photobiology of voriconazole and its major hepatic metabolite, voriconazole N-oxide. MATERIALS AND METHODS: Voriconazole and voriconazole N-oxide were spectrophotometrically monitored following various doses of UVB. Cultured human keratinocytes were treated with parental drugs or with their UVB photoproducts, and survival following UVA irradiation was measured by thiazolyl blue metabolism. Reactive oxygen species (ROS) and 8-oxoguanine were monitored by fluorescence microscopy. RESULTS: Voriconazole and voriconazole N-oxide have varying UVB absorption but do not acutely sensitize cultured human keratinocytes following UVB exposure. However, sustained UVB exposures produced notable dose- and solvent-dependent changes in the absorption spectra of voriconazole N-oxide, which in aqueous solution acquires a prominent UVA absorption band, suggesting formation of a discrete photoproduct. Neither the parental drugs nor their photoproducts sensitized cells to UVB although all but voriconazole N-oxide were moderately toxic to cells in the dark. Notably, both voriconazole N-oxide and its UVB photoproduct, but not voriconazole or its photoproduct, additionally sensitized cells to UVA by greater than three-fold relative to controls in association with UVA-induced ROS and 8 oxoguanine levels. CONCLUSIONS: Voriconazole N-oxide and its UVB-photoproduct act as UVA-sensitizers that generate ROS and that produce oxidative DNA damage. These results suggest a mechanism for the phototoxicity and photocarcinogenicity observed with voriconazole treatment. PMID- 25919128 TI - Application of an aqueous two-phase micellar system to extract bromelain from pineapple (Ananas comosus) peel waste and analysis of bromelain stability in cosmetic formulations. AB - Bromelain is a set of proteolytic enzymes found in pineapple (Ananas comosus) tissues such as stem, fruit and leaves. Because of its proteolytic activity, bromelain has potential applications in the cosmetic, pharmaceutical, and food industries. The present study focused on the recovery of bromelain from pineapple peel by liquid-liquid extraction in aqueous two-phase micellar systems (ATPMS), using Triton X-114 (TX-114) and McIlvaine buffer, in the absence and presence of electrolytes CaCl2 and KI; the cloud points of the generated extraction systems were studied by plotting binodal curves. Based on the cloud points, three temperatures were selected for extraction: 30, 33, and 36 degrees C for systems in the absence of salts; 40, 43, and 46 degrees C in the presence of KI; 24, 27, and 30 degrees C in the presence of CaCl2 . Total protein and enzymatic activities were analyzed to monitor bromelain. Employing the ATPMS chosen for extraction (0.5 M KI with 3% TX-114, at pH 6.0, at 40 degrees C), the bromelain extract stability was assessed after incorporation into three cosmetic bases: an anhydrous gel, a cream, and a cream-gel formulation. The cream-gel formulation presented as the most appropriate base to convey bromelain, and its optimal storage conditions were found to be 4.0 +/- 0.5 degrees C. The selected ATPMS enabled the extraction of a biomolecule with high added value from waste lined-up in a cosmetic formulation, allowing for exploration of further cosmetic potential. PMID- 25919129 TI - Use of antiseptic hand rubs in the health and community services industry: an Australian population-based survey. AB - BACKGROUND: The use of antiseptic hand rubs (AHRs), rather than washing with soap and water, is considered to be the gold standard for reducing the frequency of nosocomial infections, as well as being less damaging to the hands than washing with soap and water, but little is known at a population level about usage patterns for AHRs. OBJECTIVES: To describe AHR use patterns among workers in the health and community services industry in Australia. METHODS: Using data from a population-based survey of Australian workers, we focused on health and community services workers' exposure to chemicals at work, including the use of AHRs. Data regarding the frequency of hand-washing were also collected. RESULTS: Nine hundred and fifty-six health and community service workers participated in the Australian National Hazard Exposure Worker Surveillance survey. Of these, 11% reported using AHRs, and 31% reported hand-washing >20 times per shift. According to an adjusted logistic regression model, professional workers [adjusted odds ratio (aOR) 2.29, 95% confidence interval (CI): 1.40-3.72] and frequent hand washers (aOR 3.08, 95%CI: 1.92-4.93) were more likely to use AHRs. CONCLUSIONS: AHR use by health and community service workers was generally lower than expected. AHR use was most likely to be reported by professionals and frequent hand washers, suggesting that AHRs are used as an adjunct to conventional hand washing. PMID- 25919130 TI - Conversations between persons with dementia disease living in nursing homes and nurses--qualitative evaluation of an intervention with the validation method. AB - Living with dementia disease (DD) can include difficulties describing experiences of everyday lives, which can lead to withdrawal, social isolation or existential homelessness. Persons with DD living in nursing homes are mainly dependent on the nurses for establishing and maintaining relationships with those around them. It can be challenging for nurses to understand what a person with DD is trying to express and to make themselves understood in turn. The validation method is intended to facilitate communication with persons with DD, but to our knowledge, there have been no qualitative studies of how this influences persons' communication. This study aimed to illuminate the actions and reactions of persons with DD living in nursing homes in one-to-one conversations with nurses during 1 year of validation method training, as observed in videotapes. Four persons with DD were involved in videotaped conversations with four nurses who were participating in a validation method training programme. Videotapes with at least 5 months between the first and last recording were analysed and compared qualitatively. The findings are presented in four categories that were identified to various degrees in conversations at the beginning and at the end of the programme: being uninterested in or unable to answer questions, talking about more than one topic of conversation at the same time, trying to talk about what is on one's mind and speaking more freely about what is on one's mind. In the videotaped conversations at the end of the programme, the persons had the opportunity to use their remaining communication abilities. This may have been related to the development of the nurses' communication skills during the training programme, and so it is possible that persons with DD could benefit from communicating with nurses trained in the validation method. PMID- 25919131 TI - The metallome of the human placenta in gestational diabetes mellitus. AB - Obtaining the knowledge of the "omics" and therefore of the metallomics of gestational diabetes mellitus (GDM) appears to be a necessary task to obtain information about the molecular causes of this disease. In this study, the metallome of GDM and of other types of diabetes mellitus was first reviewed. The comparative analysis of the published data revealed that no GDM elemental markers could be identified with sufficient reliability in blood or in the other considered samples, with the partial exception of selenium. The placenta was chosen as an alternative target organ for the analysis of the GDM metallome. The full elemental average composition of 19 healthy placentas was obtained by ICP MS. Analyses were then performed on 28 placentas from women affected by GDM. The statistical tests and the principal component analysis evidenced that cadmium was found in lower concentrations and selenium was found in higher concentrations in GDM placentas than in those of the control group. These results were interpreted in light of literature data, and they attract attention on two key elements for understanding the molecular pathways of GDM. PMID- 25919132 TI - Convergence on an optimal way to swim. AB - A study of eight independent instances of evolution of a distinct mode of swimming by animals such as rays and cuttlefish shows repeated arrival at a single optimal solution. PMID- 25919133 TI - Risk-optimized proton therapy to minimize radiogenic second cancers. AB - Proton therapy confers substantially lower predicted risk of second cancer compared with photon therapy. However, no previous studies have used an algorithmic approach to optimize beam angle or fluence-modulation for proton therapy to minimize those risks. The objectives of this study were to demonstrate the feasibility of risk-optimized proton therapy and to determine the combination of beam angles and fluence weights that minimizes the risk of second cancer in the bladder and rectum for a prostate cancer patient. We used 6 risk models to predict excess relative risk of second cancer. Treatment planning utilized a combination of a commercial treatment planning system and an in-house risk optimization algorithm. When normal-tissue dose constraints were incorporated in treatment planning, the risk model that incorporated the effects of fractionation, initiation, inactivation, repopulation and promotion selected a combination of anterior and lateral beams, which lowered the relative risk by 21% for the bladder and 30% for the rectum compared to the lateral-opposed beam arrangement. Other results were found for other risk models. PMID- 25919134 TI - Solvent and Temperature Probes of the Long-Range Electron-Transfer Step in Tyramine beta-Monooxygenase: Demonstration of a Long-Range Proton-Coupled Electron-Transfer Mechanism. AB - Tyramine beta-monooxygenase (TbetaM) belongs to a family of physiologically important dinuclear copper monooxygenases that function with a solvent-exposed active site. To accomplish each enzymatic turnover, an electron transfer (ET) must occur between two solvent-separated copper centers. In wild-type TbetaM, this event is too fast to be rate limiting. However, we have recently shown [Osborne, R. L.; et al. Biochemistry 2013, 52, 1179] that the Tyr216Ala variant of TbetaM leads to rate-limiting ET. In this study, we present a pH-rate profile study of Tyr216Ala, together with deuterium oxide solvent kinetic isotope effects (KIEs). A solvent KIE of 2 on kcat is found in a region where kcat is pH/pD independent. As a control, the variant Tyr216Trp, for which ET is not rate determining, displays a solvent KIE of unity. We conclude, therefore, that the observed solvent KIE arises from the rate-limiting ET step in the Tyr216Ala variant, and show how small solvent KIEs (ca. 2) can be fully accommodated from equilibrium effects within the Marcus equation. To gain insight into the role of the enzyme in the long-range ET step, a temperature dependence study was also pursued. The small enthalpic barrier of ET (Ea = 3.6 kcal/mol) implicates a significant entropic barrier, which is attributed to the requirement for extensive rearrangement of the inter-copper environment during PCET catalyzed by the Tyr216Ala variant. The data lead to the proposal of a distinct inter-domain pathway for PCET in the dinuclear copper monooxygenases. PMID- 25919135 TI - Endothelial dysfunction in patients with pulmonary thromboembolism: neutrophil to lymphocyte ratio and platelet to lymphocyte ratio. AB - BACKGROUND AND AIMS: Pulmonary thromboembolism (PTE) is a common cardiovascular emergency. Activated leukocytes may produce free oxygen radicals and endothelial damage, and, thereby, increased inflammation and thrombogenesis. In this study, we aimed to investigate endothelial dysfunction in patients with PTE. METHODS: Between May 2012 and July 2013, a total of 71 patients with acute PTE (32 males, 39 females; mean age: 64.94 +/- 15.27 years; range: 33 to 87 years) who were admitted to the Emergency and Thoracic Diseases Departments and 56 healthy controls (44 males, 12 females; mean age: 62.52 +/- 9.80 years; range: 46 to 79 years) were included. Brachial artery flow-mediated dilation (BFMD) was performed. Neutrophil to lymphocyte ratio (NLR) and platelet to lymphocyte ratio (PLR) were calculated. RESULTS: Significantly higher BFMD values were observed in patients with PTE (P < 0.05). Patients with PTE also had significantly higher NLR and PLR values, compared with the healthy control group (P < 0.05). CONCLUSION: The results of our study suggest that using non-invasive method such as ultrasonography combined with NLR and PLR in endothelial dysfunction diagnosis in PTE patients are both effective and inexpensive. We believe in PTE patients endothelial dysfunction may play a role in the development of probable cardiovascular events in future. PMID- 25919137 TI - Laboratory investigation and phylogenetic analysis of an imported Middle East respiratory syndrome coronavirus case in Greece. AB - Rapid and reliable laboratory diagnosis of persons suspected of Middle East respiratory syndrome coronavirus (MERS-CoV) infection is important for timely implementation of infection control practices and disease management. In addition, monitoring molecular changes in the virus can help elucidate chains of transmission and identify mutations that might influence virus transmission efficiency. This was illustrated by a recent laboratory investigation we conducted on an imported MERS-CoV case in Greece. Two oropharyngeal swab specimens were collected on the 1st and 2nd day of patient hospitalization and tested using two real-time RT-PCR (rRT-PCR) assays targeting the UpE and Orf-1a regions of the MERS-CoV genome and RT-PCR and partial sequencing of RNA-dependent RNA polymerase and nucleocapsid genes. Serum specimens were also collected and serological test were performed. Results from the first swab sample were inconclusive while the second swab was strongly positive for MERS-CoV RNA by rRT PCR and confirmed positive by RT-PCR and partial gene sequencing. Positive serologic test results further confirmed MERS-CoV infection. Full-length nucleocapsid and spike gene coding sequences were later obtained from the positive swab sample. Phylogenetic analysis revealed that the virus was closely related to recent human-derived MERS-CoV strains obtained in Jeddah and Makkah, Saudi Arabia, in April 2014 and dromedary camels in Saudi Arabia and Qatar. These findings were consistent with the patient's history. We also identified a unique amino acid substitution in the spike receptor binding domain that may have implications for receptor binding efficiency. Our initial inconclusive rRT-PCR results highlight the importance of collecting multiple specimens from suspect MERS-CoV cases and particularly specimens from the lower respiratory tract. PMID- 25919136 TI - Identifying Human Genome-Wide CNV, LOH and UPD by Targeted Sequencing of Selected Regions. AB - Copy-number variations (CNV), loss of heterozygosity (LOH), and uniparental disomy (UPD) are large genomic aberrations leading to many common inherited diseases, cancers, and other complex diseases. An integrated tool to identify these aberrations is essential in understanding diseases and in designing clinical interventions. Previous discovery methods based on whole-genome sequencing (WGS) require very high depth of coverage on the whole genome scale, and are cost-wise inefficient. Another approach, whole exome genome sequencing (WEGS), is limited to discovering variations within exons. Thus, we are lacking efficient methods to detect genomic aberrations on the whole genome scale using next-generation sequencing technology. Here we present a method to identify genome-wide CNV, LOH and UPD for the human genome via selectively sequencing a small portion of genome termed Selected Target Regions (SeTRs). In our experiments, the SeTRs are covered by 99.73%~99.95% with sufficient depth. Our developed bioinformatics pipeline calls genome-wide CNVs with high confidence, revealing 8 credible events of LOH and 3 UPD events larger than 5M from 15 individual samples. We demonstrate that genome-wide CNV, LOH and UPD can be detected using a cost-effective SeTRs sequencing approach, and that LOH and UPD can be identified using just a sample grouping technique, without using a matched sample or familial information. PMID- 25919138 TI - On-Off Kinetics of Engagement of FNI Modules of Soluble Fibronectin by beta Strand Addition. AB - Intrinsically disordered sequences within bacterial adhesins bind to E-strands in the beta-sheets of multiple FNI modules of fibronectin (FN) by anti-parallel beta strand addition, also called tandem beta-zipper formation. The FUD segment of SfbI of Streptococcus pyogenes and Bbk32 segment of BBK32 of Borrelia burgdorferi, despite being imbedded in different adhesins from different bacteria, target the same 2-5,8-9 FNI modules, 2-5,8-9 FNI, in the N-terminal 70 kDa region (FN70K) of FN. To facilitate further comparisons, FUD, Bbk32, two other polypeptides based on SfbI that target 1-5 FNI (HADD) and 2-5 FNI (FRD), and mutant Bbk32 (DeltaBbk32) were produced with fluorochromes placed just outside of the binding sequences. Unlabeled FUD competed ~ 1000-fold better for binding of labeled Bbk32 to FN than unlabeled Bbk32 competed for binding of labeled FUD to FN. Binding kinetics were determined by fluorescence polarization in a stopped-flow apparatus. On-rates for FUD, Bbk32, HADD, and FRD were similar, and all bound more rapidly to FN70K fragment than to full length FN. In stopped flow displacement and size exclusion chromatographic assays, however, k off for FUD or HADD to FN70K or FN was considerably lower compared to k off of FRD or Bbk32. FUD and Bbk32 differ in the spacing between sequences that interact with 3FNI and 4FNI or with 5FNI and 8FNI. DeltaBbk32, in which 2 residues were removed from Bbk32 to make the spacing more like FUD, had a k off intermediate between that of Bbk32 and FUD. These results indicate a "folding-after-binding" process after initial association of certain polypeptide sequences to FN that results in formation of a stable complex and is a function of number of FNI modules engaged by the polypeptide, spacing of engagement sites, and perhaps flexibility within the polypeptide-FN complex. We suggest that contributions of SfbI and BBK32 adhesins to bacterial pathogenicity may be determined in part by stability of adhesin-FN complexes. PMID- 25919139 TI - Tigers of Sundarbans in India: is the population a separate conservation unit? AB - The Sundarbans tiger inhabits a unique mangrove habitat and are morphologically distinct from the recognized tiger subspecies in terms of skull morphometrics and body size. Thus, there is an urgent need to assess their ecological and genetic distinctiveness and determine if Sundarbans tigers should be defined and managed as separate conservation unit. We utilized nine microsatellites and 3 kb from four mitochondrial DNA (mtDNA) genes to estimate genetic variability, population structure, demographic parameters and visualize historic and contemporary connectivity among tiger populations from Sundarbans and mainland India. We also evaluated the traits that determine exchangeability or adaptive differences among tiger populations. Data from both markers suggest that Sundarbans tiger is not a separate tiger subspecies and should be regarded as Bengal tiger (P. t. tigris) subspecies. Maximum likelihood phylogenetic analyses of the mtDNA data revealed reciprocal monophyly. Genetic differentiation was found stronger for mtDNA than nuclear DNA. Microsatellite markers indicated low genetic variation in Sundarbans tigers (He= 0.58) as compared to other mainland populations, such as northern and Peninsular (Hebetween 0.67- 0.70). Molecular data supports migration between mainland and Sundarbans populations until very recent times. We attribute this reduction in gene flow to accelerated fragmentation and habitat alteration in the landscape over the past few centuries. Demographic analyses suggest that Sundarbans tigers have diverged recently from peninsular tiger population within last 2000 years. Sundarbans tigers are the most divergent group of Bengal tigers, and ecologically non-exchangeable with other tiger populations, and thus should be managed as a separate "evolutionarily significant unit" (ESU) following the adaptive evolutionary conservation (AEC) concept. PMID- 25919142 TI - Evidence and the Latin American region--dialogue or diatribe? PMID- 25919141 TI - Phylogeography of a Marine Insular Endemic in the Atlantic Macaronesia: The Azorean Barnacle, Megabalanus azoricus (Pilsbry, 1916). AB - The Azorean barnacle, Megabalanus azoricus (Pilsbry, 1916), is a Macaronesian endemic whose obscure taxonomy and the unknown relationships among forms inhabiting isolated Northern Atlantic oceanic islands is investigated by means of molecular analysis herein. Mitochondrial data from the 16S rRNA and COX1 genes support its current species status, tropical ancestry, and the taxonomic homogeneity throughout its distribution range. In contrast, at the intraspecific level and based on control region sequences, we detected an overall low level of genetic diversity and three divergent lineages. The haplogroups alpha and gamma were sampled in the Azores, Madeira, Canary, and Cabo Verde archipelagos; whereas haplogroup beta was absent from Cabo Verde. Consequently, population analysis suggested a differentiation of the Cabo Verde population with respect to the genetically homogenous northern archipelagos generated by current oceanographic barriers. Furthermore, haplogroup alpha, beta, and gamma demographic expansions occurred during the interglacial periods MIS5 (130 Kya - thousands years ago -), MIS3 (60 Kya), and MIS7 (240 Kya), respectively. The evolutionary origin of these lineages is related to its survival in the stable southern refugia and its demographic expansion dynamics are associated with the glacial-interglacial cycles. This phylogeographic pattern suggests the occurrence of genetic discontinuity informative to the delimitation of an informally defined biogeographic entity, Macaronesia, and its generation by processes that delineate genetic diversity of marine taxa in this area. PMID- 25919140 TI - High EMT Signature Score of Invasive Non-Small Cell Lung Cancer (NSCLC) Cells Correlates with NFkappaB Driven Colony-Stimulating Factor 2 (CSF2/GM-CSF) Secretion by Neighboring Stromal Fibroblasts. AB - We established co-cultures of invasive or non-invasive NSCLC cell lines and various types of fibroblasts (FBs) to more precisely characterize the molecular mechanism of tumor-stroma crosstalk in lung cancer. The HGF-MET-ERK1/2-CREB-axis was shown to contribute to the onset of the invasive phenotype of Calu-1 with HGF being secreted by FBs. Differential expression analysis of the respective mono- and co-cultures revealed an upregulation of NFkappaB-related genes exclusively in co-cultures with Calu-1. Cytokine Array- and ELISA-based characterization of the "cytokine fingerprints" identified CSF2 (GM-CSF), CXCL1, CXCL6, VEGF, IL6, RANTES and IL8 as being specifically upregulated in various co-cultures. Whilst CXCL6 exhibited a strictly FB-type-specific induction profile regardless of the invasiveness of the tumor cell line, CSF2 was only induced in co-cultures of invasive cell lines regardless of the partnered FB type. These cultures revealed a clear link between the induction of CSF2 and the EMT signature of the cancer cell line. The canonical NFkappaB signaling in FBs, but not in tumor cells, was shown to be responsible for the induced and constitutive CSF2 expression. In addition to CSF2, cytokine IL6, IL8 and IL1B, and chemokine CXCL1 and CXCL6 transcripts were also shown to be increased in co-cultured FBs. In contrast, their induction was not strictly dependent on the invasiveness of the co-cultured tumor cell. In a multi-reporter assay, additional signaling pathways (AP-1, HIF1 alpha, KLF4, SP-1 and ELK-1) were found to be induced in FBs co-cultured with Calu-1. Most importantly, no difference was observed in the level of inducibility of these six signaling pathways with regard to the type of FBs used. Finally, upon tumor fibroblast interaction the massive induction of chemokines such as CXCL1 and CXCL6 in FBs might be responsible for increased recruitment of a monocytic cell line (THP-1) in a transwell assay. PMID- 25919143 TI - Low-dose etretinate shows promise in management of punctate palmoplantar keratoderma type 1: Case report and review of the published work. AB - Punctate palmoplantar keratoderma type 1 (PPKP1) is a rare autosomal dominant disorder of keratinization, clinically characterized by punctate keratotic papules affecting the palmoplantar skin. Loss-of-function mutations in AAGAB have recently been reported as a cause of PPKP1. Despite the discovery of the genetic cause of PPKP1, pathogenesis-based therapies are still unavailable. Moreover, little is known about the effectiveness of treatments for PPKP1. In this study, we analyzed a Japanese woman with PPKP1 and identified a novel frame-shift mutation c.195_198del4 (p.Lys66Phefs*43) in AAGAB. Moreover, low-dose etretinate was effective in improving the PPKP1 lesions in our patient. Our published work review identified only eight cases of PPKP1 with successful response to topical or systemic treatments. Notably, six of the cases were successfully treated with systemic retinoids. Thus, this study clearly provides further evidence that PPKP1 is caused by AAGAB mutations and that systemic retinoids are the most promising current treatment for PPKP1. PMID- 25919144 TI - Interventions for rosacea. AB - BACKGROUND: Rosacea is a common chronic skin condition affecting the face, characterised by flushing, redness, pimples, pustules and dilated blood vessels. The eyes are often involved and thickening of the skin with enlargement (phymas), especially of the nose, can occur in some people. A range of treatment options are available but it is unclear which are most effective. OBJECTIVES: To assess the efficacy and safety of treatments for rosacea. SEARCH METHODS: We updated our searches, to July 2014, of: the Cochrane Skin Group Specialised Register, CENTRAL in The Cochrane Library (2014, Issue 6), MEDLINE (from 1946), EMBASE (from 1974) and Science Citation Index (from 1988). We searched five trials registers and checked reference lists for further relevant studies. SELECTION CRITERIA: Randomised controlled trials in people with moderate to severe rosacea. DATA COLLECTION AND ANALYSIS: Study selection, data extraction, risk of bias assessment and analyses were carried out independently by two authors. MAIN RESULTS: We included 106 studies, comprising 13,631 participants. Sample sizes of 30-100 and study duration of two to three months were most common. More women than men were included, mean age of 48.6 years, and the majority had papulopustular rosacea, followed by erythematotelangiectatic rosacea.A wide range of comparisons (67) were evaluated. Topical interventions: metronidazole, azelaic acid, ivermectin, brimonidine or other topical treatments. Systemic interventions: oral antibiotics, combinations with topical treatments or other systemic treatments, i.e. isotretinoin. Several studies evaluated laser or light based treatment.The majority of studies (57/106) were assessed as 'unclear risk of bias', 37 'high risk ' and 12 'low risk'. Twenty-two studies provided no usable or retrievable data i.e. none of our outcomes were addressed, no separate data reported for rosacea or limited data in abstracts.Eleven studies assessed our primary outcome 'change in quality of life', 52 studies participant-assessed changes in rosacea severity and almost all studies addressed adverse events, although often only limited data were provided. In most comparisons there were no statistically significant differences in number of adverse events, most were mild and transient. Physician assessments including investigators' global assessments, lesion counts and erythema were evaluated in three-quarters of the studies, but time needed for improvement and duration of remission were incompletely or not reported.The quality of the body of evidence was rated moderate to high for most outcomes, but for some outcomes low to very low.Data for several outcomes could only be pooled for topical metronidazole and azelaic acid. Both were shown to be more effective than placebo in papulopustular rosacea (moderate quality evidence for metronidazole and high for azelaic acid). Pooled data from physician assessments in three trials demonstrated that metronidazole was more effective compared to placebo (risk ratio (RR) 1.98, 95% confidence interval (CI) 1.29 to 3.02). Four trials provided data on participants' assessments, illustrating that azelaic acid was more effective than placebo (RR 1.46, 95% CI 1.30 to 1.63). The results from three studies were contradictory on which of these two treatments was most effective.Two studies showed a statistically significant and clinically important improvement in favour of topical ivermectin when compared to placebo (high quality evidence). Participants' assessments in these studies showed a RR of 1.78 (95% CI 1.50 to 2.11) and RR of 1.92 (95% CI 1.59 to 2.32),which were supported by physicians' assessments. Topical ivermectin appeared to be slightly more effective than topical metronidazole for papulopustular rosacea, based on one study, for improving quality of life and participant and physician assessed outcomes (high quality evidence for these outcomes).Topical brimonidine in two studies was more effective than vehicle in reducing erythema in rosacea at all time points over 12 hours (high quality evidence). At three hours the participants' assessments had a RR of 2.21 (95% CI 1.52 to 3.22) and RR of 2.00 (95% CI 1.33 to 3.01) in favour of brimonidine. Physicians' assessments confirmed these data. There was no rebound or worsening of erythema after treatment cessation.Topical clindamycin phosphate combined with tretinoin was not considered to be effective compared to placebo (moderate quality evidence).Topical ciclosporin ophthalmic emulsion demonstrated effectiveness and improved quality of life for people with ocular rosacea (low quality evidence).Of the comparisons assessing oral treatments for papulopustular rosacea there was moderate quality evidence that tetracycline was effective but this was based on two old studies of short duration. Physician-based assessments in two trials indicated that doxycycline appeared to be significantly more effective than placebo (RR 1.59, 95% CI 1.02 to 2.47 and RR 2.37, 95% CI 1.12 to 4.99) (high quality evidence). There was no statistically significant difference in effectiveness between 100 mg and 40 mg doxycycline, but there was evidence of fewer adverse effects with the lower dose (RR 0.25, 95% CI 0.11 to 0.54) (low quality evidence). There was very low quality evidence from one study (assessed at high risk of bias) that doxycycline 100 mg was as effective as azithromycin. Low dose minocycline (45 mg) was effective for papulopustular rosacea (low quality evidence).Oral tetracycline was compared with topical metronidazole in four studies and showed no statistically significant difference between the two treatments for any outcome (low to moderate quality evidence).Low dose isotretinoin was considered by both the participants (RR 1.23, 95% CI 1.05 to 1.43) and physicians (RR 1.18, 95% CI 1.03 to 1.36) to be slightly more effective than doxycycline 50-100 mg (high quality evidence).Pulsed dye laser was more effective than yttrium-aluminium-garnet (Nd:YAG) laser based on one study, and it appeared to be as effective as intense pulsed light therapy (both low quality evidence). AUTHORS' CONCLUSIONS: There was high quality evidence to support the effectiveness of topical azelaic acid, topical ivermectin, brimonidine, doxycycline and isotretinoin for rosacea. Moderate quality evidence was available for topical metronidazole and oral tetracycline. There was low quality evidence for low dose minocycline, laser and intense pulsed light therapy and ciclosporin ophthalmic emulsion for ocular rosacea. Time needed to response and response duration should be addressed more completely, with more rigorous reporting of adverse events. Further studies on treatment of ocular rosacea are warranted. PMID- 25919145 TI - Coronary artery calcification detected in lung cancer screening predicts cardiovascular death. AB - OBJECTIVES: It remains unknown whether non-electrocardiogram-gated coronary artery calcium (CAC) score in lung cancer screening provides incremental prognostic value. The aim of this study was to evaluate the prognostic value of CAC in the Danish Lung Cancer Screening Trial (DLCST), in addition to conducting a systematic review and meta-analysis including previously published studies regarding CAC in lung cancer screening. DESIGN: In DLCST, we measured Agatston CAC scores in 1,945 current and former smokers. Causes of death were extracted from the Danish National Death Registry. We used Cox proportional hazards model to determine hazard ratios (HRs) of CAC scores. A weighted fixed-effects model was used for the meta-analysis. RESULTS: Median follow-up in DLCST was 7.1 years, and 55% were men. Overall survival rates associated with CAC scores of 0, 1-400, and > 400 were 98%, 96%, and 92% (p < 0.001), respectively. Adjusted HR of cardiovascular death associated with CAC >400 was 3.8 (1.0-15) (p < 0.05). The meta-analysis included 28,045 asymptomatic participants. A high non-gated CAC score was associated with fatal or non-fatal cardiovascular events (p < 0.0001). CONCLUSION: Assessment of non-electrocardiogram-gated CAC in lung cancer screening programs is a robust prognostic measure of fatal or non-fatal cardiovascular events in current and former smokers independent of traditional cardiovascular risk factors. PMID- 25919146 TI - Secondary mania due to AIDS and cryptococcal meningitis in a 78-year-old patient. AB - We report a 78-year-old man without past psychiatric history who experienced his first manic episode successfully treated with quetiapine and lorazepam, but was ultimately found to have AIDS and Cryptococcus neoformans meningitis. Our presented case highlights the importance of comprehensive differential diagnoses to rule out secondary causes of psychiatric symptoms presenting for the first time in elderly patients. PMID- 25919148 TI - Foreword. PMID- 25919147 TI - Clinical implications of hypoxia biomarker expression in head and neck squamous cell carcinoma: a systematic review. AB - Awareness increases that the tumor biology influences treatment outcome and prognosis in cancer. Tumor hypoxia is thought to decrease sensitivity to radiotherapy and some forms of chemotherapy. Presence of hypoxia may be assessed by investigating expression of endogenous markers of hypoxia (EMH) using immunohistochemistry (IHC). In this systematic review we investigated the effect of EMH expression on local control and survival according to treatment modality in head and neck cancer (head and neck squamous cell carcinoma [HNSCC]). A search was performed in MEDLINE and EMBASE. Studies were eligible for inclusion that described EMH expression in relation to outcome in HNSCC patients. Quality was assessed using the Quality in Prognosis Studies (QUIPS) tool. Hazard ratios for locoregional control and survival were extracted. Forty studies of adequate quality were included. HIF-1a, HIF-2a, CA-IX, GLUT-1, and OPN were identified as the best described EMHs. With exception of HIF-2a, all EMHs were significantly related to adverse outcome in multiple studies, especially in studies where patients underwent single-modality treatment. Positive expression was often correlated with adverse clinical characteristics, including disease stage and differentiation grade. In summary, EMH expression was common in HNSCC patients and negatively influenced their prognosis. Future studies should investigate the effect of hypoxia-modified treatment schedules in patients with high In summary, EMH expression. These may include ARCON, treatment with nimorazole, or novel targeted therapies directed at hypoxic tissue. Also, the feasibility of surgical removal of the hypoxic tumor volume prior to radiotherapy should be investigated. PMID- 25919150 TI - A learning experience from price negotiations for vaccines. PMID- 25919149 TI - Cost-effectiveness of rotavirus vaccination in Kenya and Uganda. AB - INTRODUCTION: Rotavirus vaccines have the potential to prevent a substantial amount of life-threatening gastroenteritis in young African children. This paper presents the results of prospective cost-effectiveness analyses for rotavirus vaccine introduction for Kenya and Uganda. METHODOLOGY: In each country, a national consultant worked with a national technical working group to identify appropriate data and validate study results. Secondary data on demographics, disease burden, health utilization, and costs were used to populate the TRIVAC cost-effectiveness model. The baseline analysis assumed an initial vaccine price of $0.20 per dose, corresponding to Gavi, the Vaccine Alliance stipulated copay for low-income countries. The incremental cost-effectiveness of a 2-dose rotavirus vaccination schedule was evaluated for 20 successive birth cohorts from the government perspective in both countries, and from the societal perspective in Uganda. RESULTS: Between 2014 and 2033, rotavirus vaccination can avert approximately 60,935 and 216,454 undiscounted deaths and hospital admissions respectively in children under 5 years in Kenya. In Uganda, the respective number of undiscounted deaths and hospital admission averted is 70,236 and 329,779 between 2016 and 2035. Over the 20-year period, the discounted vaccine program costs are around US$ 80 million in Kenya and US$ 60 million in Uganda. Discounted government health service costs avoided are US$ 30 million in Kenya and US$ 10 million in Uganda (or US$ 18 million including household costs). The cost per disability-adjusted life-year (DALY) averted from a government perspective is US$ 38 in Kenya and US$ 34 in Uganda (US$ 29 from a societal perspective). CONCLUSIONS: Rotavirus vaccine introduction is highly cost-effective in both countries in a range of plausible 'what-if' scenarios. The involvement of national experts improves the quality of data used, is likely to increase acceptability of the results in decision-making, and can contribute to strengthened national capacity to undertake economic evaluations. PMID- 25919151 TI - Estimated impact and cost-effectiveness of rotavirus vaccination in Senegal: A country-led analysis. AB - INTRODUCTION: Rotavirus is the leading cause of acute severe diarrhea among children under 5 globally and one of the leading causes of death attributable to diarrhea. Among African children hospitalized with diarrhea, 38% of the cases are due to rotavirus. In Senegal, rotavirus deaths are estimated to represent 5.4% of all deaths among children under 5. Along with the substantial disease burden, there is a growing awareness of the economic burden created by diarrheal disease. This analysis aims to provide policymakers with more consistent and reliable economic evidence to support the decision-making process about the introduction and maintenance of a rotavirus vaccine program. METHODS: The study was conducted using the processes and tools first established by the Pan American Health Organization's ProVac Initiative in the Latin American region. TRIVAC version 2.0, an Excel-based model, was used to perform the analysis. The costs and health outcomes were calculated for 20 successive birth cohorts (2014-2033). Model inputs were gathered from local, national, and international sources with the guidance of a Senegalese group of experts including local pediatricians, personnel from the Ministry of Health and the World Health Organization, as well as disease-surveillance and laboratory specialists. RESULTS: The cost per disability-adjusted life-year (DALY) averted, discounted at 3%, is US$ 92 from the health care provider perspective and US$ 73 from the societal perspective. For the 20 cohorts, the vaccine is projected to prevent more than 2 million cases of rotavirus and to avert more than 8500 deaths. The proportion of rotavirus deaths averted is estimated to be 42%. For 20 cohorts, the discounted net costs of the program were estimated to be US$ 17.6 million from the healthcare provider perspective and US$ 13.8 million from the societal perspective. CONCLUSION: From both perspectives, introducing the rotavirus vaccine is highly cost-effective compared to no vaccination. The results are consistent with those found in many African countries. The ProVac process and tools contributed to a collaborative, country-led process in Senegal that provides a platform for gathering and reporting evidence for vaccine decision-making. PMID- 25919152 TI - Cost-effectiveness analysis of rotavirus vaccination in Argentina. AB - BACKGROUND: Rotavirus is a leading cause of severe diarrhea in children under 5. In Argentina, the most affected regions are the Northeast and Northwest, where hospitalizations and deaths are more frequent. This study estimated the cost effectiveness of adding either of the two licensed rotavirus vaccines to the routine immunization schedule. METHODS: The integrated TRIVAC vaccine cost effectiveness model from the Pan American Health Organization's ProVac Initiative (Version 2.0) was used to assess health benefits, costs savings, life-years gained (LYGs), DALYs averted, and cost/DALY averted of vaccinating 10 successive cohorts, from the health care system and societal perspectives. Two doses of monovalent (RV1) rotavirus vaccine and three doses of pentavalent (RV5) rotavirus vaccine were each compared to a scenario assuming no vaccination. The price/dose was US$ 7.50 and US$ 5.15 for RV1 and RV5, respectively. We ran both a national and sub-national analysis, discounting all costs and benefits 3% annually. Our base case results were compared to a range of alternative univariate and multivariate scenarios. RESULTS: The number of LYGs was 5962 and 6440 for RV1 and RV5, respectively. The cost/DALY averted when compared to no vaccination from the health care system and societal perspective was: US$ 3870 and US$ 1802 for RV1, and US$ 2414 and US$ 358 for RV5, respectively. Equivalent figures for the Northeast were US$ 1470 and US$ 636 for RV1, and US$ 913 and US$ 80 for RV5. Therefore, rotavirus vaccination was more cost-effective in the Northeast compared to the whole country; and, in the Northwest, health service's costs saved outweighed the cost of introducing the vaccine. Vaccination with either vaccine compared to no vaccination was highly cost-effective based on WHO guidelines and Argentina's 2011 per capita GDP of US$ 9090. Key variables influencing results were vaccine efficacy, annual loss of efficacy, relative coverage of deaths, vaccine price, and discount rate. CONCLUSION: Compared to no vaccination, routine vaccination against rotavirus in Argentina would be highly cost-effective with either vaccine. Health and economic benefits would be higher in the Northeast and Northwest regions, where the intervention would even be cost saving. PMID- 25919153 TI - Costs and financing of routine immunization: Approach and selected findings of a multi-country study (EPIC). AB - BACKGROUND: Few detailed facility-based costing studies of routine immunization (RI) programs have been conducted in recent years, with planners, managers and donors relying on older information or data from planning tools. To fill gaps and improve quality of information, a multi-country study on costing and financing of routine immunization and new vaccines (EPIC) was conducted in Benin, Ghana, Honduras, Moldova, Uganda and Zambia. METHODS: This paper provides the rationale for the launch of the EPIC study, as well as outlines methods used in a Common Approach on facility sampling, data collection, cost and financial flow estimation for both the routine program and new vaccine introduction. Costing relied on an ingredients-based approach from a government perspective. Estimating incremental economic costs of new vaccine introduction in contexts with excess capacity are highlighted. The use of more disaggregated System of Health Accounts (SHA) coding to evaluate financial flows is presented. RESULTS: The EPIC studies resulted in a sample of 319 primary health care facilities, with 65% of facilities in rural areas. The EPIC studies found wide variation in total and unit costs within each country, as well as between countries. Costs increased with level of scale and socio-economic status of the country. Governments are financing an increasing share of total RI financing. CONCLUSIONS: This study provides a wealth of high quality information on total and unit costs and financing for RI, and demonstrates the value of in-depth facility approaches. The paper discusses the lessons learned from using a standardized approach, as well as proposes further areas of methodology development. The paper discusses how results can be used for resource mobilization and allocation, improved efficiency of services at the country level, and to inform policies at the global level. Efforts at routinizing cost analysis to support sustainability efforts would be beneficial. PMID- 25919154 TI - Cost-effectiveness analysis of introducing universal human papillomavirus vaccination of girls aged 11 years into the National Immunization Program in Brazil. AB - OBJECTIVES: To evaluate the impact and cost-effectiveness of introducing universal human papillomavirus (HPV) vaccination into the National Immunization Program (NIP) in Brazil. METHODS: The Excel-based CERVIVAC decision support model was used to compare two strategies: (1) status quo (with current screening program) and (2) vaccination of a cohort of 11-year-old girls. National parameters for the epidemiology and costs of cervical cancer were estimated in depth. The estimates were based on data from the health information systems of the public health system, the PNAD 2008 national household survey, and relevant scientific literature on Brazil. Costs are expressed in 2008 United States dollars (US$), and a 5% discount rate is applied to both future costs and future health benefits. RESULTS: Introducing the HPV vaccine would reduce the burden of disease. The model estimated there would be 229 deaths avoided and 6677 disability-adjusted life years (DALYs) averted in the vaccinated cohort. The incremental cost-effectiveness ratios (ICERs) per DALY averted from the perspectives of the government (US$ 7663), health system (US$ 7412), and society (US$ 7298) would be considered cost-effective, according to the parameters adopted by the World Health Organization. In the sensitivity analysis, the ICERs were most sensitive to variations in discount rate, disease burden, vaccine efficacy, and proportion of cervical cancer caused by types 16 and 18. However, universal HPV vaccination remained a cost-effective strategy in most variations of the key estimates. CONCLUSIONS: Vaccine introduction could contribute additional benefits in controlling cervical cancer, but it requires large investments by the NIP. Among the essential conditions for attaining the expected favorable results are immunization program sustainability, equity in a population perspective, improvement of the screening program, and development of a surveillance system. PMID- 25919155 TI - Cost-effectiveness analysis of pneumococcal conjugate vaccine introduction in Paraguay. AB - OBJECTIVE: To describe a cost-effectiveness analysis of 10- or 13-valent pneumococcal conjugate vaccine (PCV10 or 13) introduction in Paraguay compared to no vaccination. METHODS: The integrated TRIVAC vaccine cost-effectiveness model (version 2.0) jointly developed by the Pan American Health Organization's ProVac Initiative and the London School of Hygiene & Tropical Medicine was applied from the government and societal perspectives to estimate the cost-effectiveness (CE) of PCV introduction during 2010 and 2011. The cost-effectiveness ratios of PCV10 and PCV13 were separately compared to non-vaccination. The model calculated health and economic benefits of vaccination for 10 birth cohorts of children <5 years of age. A base case scenario with two primary doses at 2 and 4 months and a booster dose at 12 months (2+1 schedule) and alternate scenarios with varying parameters were considered. RESULTS: With PCV10 introduction, the incremental costs of the vaccination program would be approximately US$ 67 million to vaccinate all 10 cohorts of children; with PCV13, US$ 87 million. Health services costs avoided by the government with PCV10 would be US$ 19.5 million; with PCV 13, US$ 17.7 million. From the societal perspective, savings were much greater: with PCV10, US$ 43 million; with PCV13, US$ 35 million. For the higher priced PCV13, the average cost-effectiveness ratio was better than for PCV10 when compared to no vaccination, but regardless both were cost effective for government and society based on a threshold of 3* GDP per capita in Paraguay (2009 US$ 2516). The number of averted meningitis and all-cause pneumonia cases and deaths was greater with PCV13 than with PCV10 when compared to no vaccination. CONCLUSION: The introduction of either PCV10 or PCV13 would be cost effective when compared to no vaccination, and in some scenarios, highly cost effective in Paraguay. The outcomes of these analyses demonstrate that a pneumococcal vaccine could substantially reduce morbidity and mortality in children <5 years in Paraguay. PMID- 25919156 TI - Cost-effectiveness analysis of 10- and 13-valent pneumococcal conjugate vaccines in Peru. AB - OBJECTIVE: To evaluate the cost-effectiveness of introducing the 10-valent pneumococcal conjugate vaccine (PCV10) versus the 13-valent PCV (PCV13) to the National Immunization Schedule in Peru for prevention of pneumococcal disease (PD) in children <5 years of age. METHODS: The integrated TRIVAC vaccine cost effectiveness model from the Pan American Health Organization's ProVac Initiative (version 2.0) was applied from the perspective of the Government of Peru. Twenty successive cohorts of children from birth to 5 years were evaluated. Clinical outcomes were pneumococcal pneumonia (PP), pneumococcal meningitis (PM), pneumococcal sepsis (PS) and acute otitis media from any causes (AOM). Measures included prevention of cases, neurological sequelae (NS), auditory sequelae (AS), deaths and disability adjusted life years (DALYs). A sensitivity analyses was also performed. FINDINGS: For the 20 cohorts, net costs with PCV10 and PCV13 were US$ 363.26 million and US$ 408.26 million, respectively. PCV10 prevented 570,273 AOM; 79,937 PP; 2217 PM; 3049 PS; 282 NS; 173 AS; and 7512 deaths. PCV13 prevented 419,815 AOM; 112,331 PN; 3116 PM; 4285 PS; 404 NS; 248 AS; and 10,386 deaths. Avoided DALYs were 226,370 with PCV10 and 313,119 with PCV13. Saved treatment costs were US$ 37.39 million with PCV10 and US$ 47.22 million with PCV13. Costs per DALY averted were US$ 1605 for PCV10, and US$ 1304 for PCV13. Sensitivity analyses showed similar results. PCV13 has an extended dominance over PCV10. CONCLUSION: Both pneumococcal vaccines are cost effective in the Peruvian context. Although the net cost of vaccination with PCV10 is lower, PCV13 prevented more deaths, pneumococcal complications and sequelae. Costs per each prevented DALY were lower with PCV13. Thus, PCV13 would be the preferred policy; PCV10 would also be reasonable (and cost-saving relative to the status quo) if for some reason 13-valent were not feasible. PMID- 25919157 TI - Cost-effectiveness analysis of the introduction of the human papillomavirus vaccine in Honduras. AB - BACKGROUND: Cervical cancer is the leading cause of cancer deaths in Honduras. With the availability of a vaccine to prevent human papillomavirus (HPV), the causative agent for cervical cancer, the Honduran Secretary of Health undertook a cost-effectiveness analysis of introducing the HPV vaccine to support their national decision-making process. METHODS: A national multidisciplinary team conducted this analysis with the CERVIVAC model, developed by the London School of Hygiene and Tropical Medicine in collaboration with the Pan American Health Organization's ProVac Initiative. The cumulative costs and health benefits of introducing the HPV vaccine were assessed over the lifetime of one single cohort of 11-year-old girls. We assumed a three-dose series with 95% vaccination coverage of the cohort using a mixture of school-based and facility-based delivery. To estimate national cervical cancer cases and deaths, we used United Nations demographic projections and GLOBOCAN estimates based on registry data from El Salvador, Guatemala, and Nicaragua. Based on estimates from the World Health Organization (WHO) and the Division of Intensified Cooperation with Countries (ICO), we assumed that 70% of cervical cancer would be due to vaccine types HPV16 and HPV18. We used a vaccine dose price of US$ 13.45 and evidence from the scientific literature to estimate vaccine effectiveness. National information was used to estimate health service utilization and costs of cervical cancer treatment. All costs and health benefits were discounted at 3%. RESULTS: Upon fully vaccinating 86,906 11-year old girls, 2250 (undiscounted) cervical cancer cases and 1336 (undiscounted) deaths would be prevented over the lifetime of the cohort. After discounting future health benefits at 3% per year, the equivalent cases and deaths prevented were 421 and 170. HPV vaccination is estimated to cost around US$ 5 million per vaccinated cohort, but this would be offset by around US$ 1 million in avoided costs borne by the government to treat cervical cancer. Furthermore, 4349 discounted disability adjusted life years (DALYs) could be avoided at a cost of US$ 926 per DALY avoided, making HPV vaccination in Honduras a highly cost-effective intervention. DISCUSSION: The net cost of HPV vaccination per DALY avoided is less than the WHO threshold for cost effectiveness. However, at a cost of around US$ 5 million per vaccinated cohort, an important element to consider in this discussion is the budgetary implications that the introduction of the HPV vaccine would cause for the country. CONCLUSIONS: When comparing the costs and benefits of HPV vaccine introduction in Honduras, it is clear that this intervention would be highly cost-effective and that the intervention would greatly reduce cervical cancer disease. For these reasons, it is in the country's best interest to explore financing opportunities that could support the vaccine's introduction. PMID- 25919158 TI - Cost-effectiveness of HPV vaccination in Belize. AB - OBJECTIVE: Among women in Belize, cervical cancer is both the leading cancer and the leading cause of cancer deaths. Both the quadrivalent and bivalent human papillomavirus (HPV) vaccines are licensed in Belize. The Ministry of Health of Belize convened a multidisciplinary team to estimate the costs, health benefits, and cost-effectiveness of adding an HPV vaccine to the national immunization schedule. METHODOLOGY: The CERVIVAC cost-effectiveness model (Version 1.123) was used to assess the lifetime health and economic outcomes of vaccinating one cohort of girls aged 10 years against HPV. The comparator was no HPV vaccination. The PAHO Revolving Fund negotiated price of US$ 13.79 per dose was used (for the quadrivalent vaccine) and national data sources were used to define demography, cervical cancer incidence and mortality, cervical cancer treatment costs, and vaccine delivery costs. Estimates from international agencies were used in scenario analysis. RESULTS: In a cohort of ~4000 Belizean girls tracked over a lifetime, HPV vaccination is estimated to prevent 69 new cases of cervical cancer (undiscounted), and 51 cervical cancer deaths (undiscounted). Considering the potential cervical cancer treatment costs and lost wages avoided by households (societal perspective), the cost per disability-adjusted life year (DALY) averted was estimated to be US$ 429. This increased to US$ 1320 when cervical cancer treatment costs and lost wages were excluded from the analysis. Both estimates are far below the gross domestic product (GDP) per capita of Belize (US$ 4795). The lifetime health care costs saved by the women and their families represent more than 60% of the investment cost needed by the Government for the vaccine. CONCLUSION: Routine HPV vaccination would be highly cost-effective in Belize. If affordable, efforts should be made to expedite the introduction of this vaccine into the Belizean national immunization program. PMID- 25919159 TI - Cost-effectiveness analysis of the introduction of the pneumococcal conjugate vaccine (PCV-13) in the Egyptian national immunization program, 2013. AB - INTRODUCTION: Pneumonia is one of the most important causes of morbidity and mortality in children under 5 in Egypt, and the Ministry of Health of Egypt is considering introducing pneumococcal conjugate vaccine (PCV) in its national immunization program. We performed an economic analysis to evaluate the cost effectiveness of this vaccine in Egypt and to provide the decision-makers with needed evidence. METHODS: The analysis was done using the TRIVAC model. Data included demographic characteristics, burden of disease, coverage and efficacy of the vaccine, health resource utilization, and costs of pneumococcal disease vaccination and treatment. Whenever possible, we used national or regional data. Two alternatives were compared: (1) general vaccination of children younger than 5 years with the 13-valent pneumococcal conjugate vaccine (PCV13), using a three dose schedule without booster, and (2) no vaccination. Outcomes of 10 cohorts from birth to 5 years were analyzed. The study was performed from the governmental perspective and selected public health providers. RESULTS: In comparison to no vaccine, the introduction of PCV13 would be cost-effective, with an incremental cost-effectiveness ratio of US$ 3916 per disability-adjusted life year (DALY) averted (government perspective). The total incremental cost of the PCV vaccination program (10 cohorts) would be approximately US$ 1.09 billion. Over the 10 cohorts, the program would avert 8583 pneumococcal deaths - 42% of all pneumococcal-related deaths. CONCLUSION: The introduction of PCV13 would be a good value for money from the government perspective. It would represent a high impact public health intervention for Egypt and respond to the National Immunization Technical Advisory Group (NITAG) resolution on reducing pneumonia burden and overall child mortality. Strengthening surveillance will be critical to generating high-quality national data, improving future economic analyses that support evidence-based decisions for introducing vaccines and public health interventions, and to monitoring their impact. PMID- 25919160 TI - Cost-effectiveness analysis of the introduction of rotavirus vaccine in Iran. AB - BACKGROUND: Although the mortality from diarrheal diseases has been decreasing dramatically in Iran, it still represents an important proportion of disease burden in children <5 years old. Rotavirus vaccines are among the most effective strategies against diarrheal diseases in specific epidemiological conditions. This study aimed to evaluate the cost-effectiveness of the introduction of rotavirus vaccine (3 doses of pentavalent RotaTeq (RV5)) in Iran, from the viewpoints of Iran's health system and society. METHODS: The TRIVAC decision support model was used to calculate total incremental costs, life years (LYs) gained, and disability-adjusted life years (DALYs) averted due to the vaccination program. Necessary input data were collected from the most valid accessible sources as well as a systematic review and meta-analysis on epidemiological studies. We used WHO guidelines to estimate vaccination cost. An annual discount rate of 3% was considered for both health gain and costs. A deterministic sensitivity analysis was performed for testing the robustness of the models results. RESULTS: Our results indicated that total DALYs potentially lost due to rotavirus diarrhea within 10 years would be 138,161, of which 76,591 could be prevented by rotavirus vaccine. The total vaccination cost for 10 cohorts was estimated to be US$ 499.91 million. Also, US$ 470.61 million would be saved because of preventing outpatient visits and inpatient admissions (cost-saving from the society perspective). We estimated a cost per DALY averted of US$ 2868 for RV5 vaccination, which corresponds to a highly cost-effective strategy from the government perspective. In the sensitivity analysis, all scenarios tested were still cost-saving or highly cost-effective from the society perspective, except in the least favorable scenario and low vaccine efficacy and disease incidence scenario. CONCLUSION: Based on the findings, introduction of rotavirus vaccine is a highly cost-effective strategy from the government perspective. Introducing the vaccine to the national immunization program is an efficient use of available funds to reduce child mortality and morbidity in Iran. PMID- 25919161 TI - Perspectives on expanding the evidence base to inform vaccine introduction: Program costing and cost-effectiveness analyses. PMID- 25919162 TI - Cost-effectiveness of rotavirus vaccination in Albania. AB - BACKGROUND: Rotavirus vaccines have been introduced in several European countries but can represent a considerable cost, particularly for countries that do not qualify for any external financial support. This study aimed to evaluate the cost effectiveness of introducing rotavirus vaccination into Albania's national immunization program and to inform national decision-making by improving national capacity to conduct economic evaluations of new vaccines. METHODS: The TRIVAC model was used to assess vaccine impact and cost-effectiveness. The model estimated health and economic outcomes attributed to 10 successive vaccinated birth cohorts (2013-2022) from a government and societal perspective. Epidemiological and economic data used in the model were based on national cost studies, and surveillance data, as well as estimates from the scientific literature. Cost-effectiveness was estimated for both the monovalent (RV1) and pentavalent vaccines (RV5). A multivariate scenario analysis (SA) was performed to evaluate the uncertainty around the incremental cost-effectiveness ratios (ICERs). RESULTS: With 3% discounting of costs and health benefits over the period 2013-2022, rotavirus vaccination in Albania could avert 51,172 outpatient visits, 14,200 hospitalizations, 27 deaths, 950 disability-adjusted life-years (DALYs), and gain 801 life-years. When both vaccines were compared to no vaccination, the discounted cost per DALY averted was US$ 2008 for RV1 and US$ 5047 for RV5 from a government perspective. From the societal perspective the values were US$ 517 and US$ 3556, respectively. CONCLUSION: From both the perspectives, the introduction of rotavirus vaccine to the Albanian immunization schedule is either cost-effective or highly cost-effective for a range of plausible scenarios. In most scenarios, including the base-case scenario, the discounted cost per DALY averted was less than three times the gross domestic product (GDP) per capita. However, rotavirus vaccination was not cost-effective when rotavirus cases and deaths were based on plausible minimum estimates. Introduction of RV1 would yield similar benefits at lower cost. PMID- 25919163 TI - Cost-effectiveness of pneumococcal conjugate vaccination in Croatia. AB - OBJECTIVE: Pneumococcus is a known cause of meningitis, pneumonia, sepsis, and acute otitis media in children and adults globally. Two new vaccines for children have the potential to prevent illness, disability, and death, but these vaccines are expensive. The Croatian Ministry of Health has considered introducing the vaccine in the past, but requires economic evidence to ensure that the limited funds available for health care will be used in the most effective way. METHODOLOGY: Croatia appointed a multidisciplinary team of experts to evaluate the cost-effectiveness of introducing pneumococcal conjugate vaccination (PCV) into the national routine child immunization program. Both 10-valent and 13 valent PCV (PCV10 and PCV13) were compared to a scenario assuming no vaccination. The TRIVAC decision-support model was used to estimate cost-effectiveness over the period 2014-2033. We used national evidence on demographics, pneumococcal disease incidence and mortality, the age distribution of disease in children, health service utilization, vaccine coverage, vaccine timeliness, and serotype coverage. Vaccine effectiveness was based on evidence from the scientific literature. Detailed health care costs were not available from the Croatian Institute for Health Insurance at the time of the analysis so assumptions and World Health Organization (WHO) estimates for Croatia were used. We assumed a three-dose primary vaccination schedule, and an initial price of US$ 30 per dose for PCV10 and US$ 35 per dose for PCV13. We ran univariate sensitivity analyses and multivariate scenario analyses. RESULTS: Either vaccine is estimated to prevent approximately 100 hospital admissions and one death each year in children younger than five in Croatia. Compared to no vaccine, the discounted cost effectiveness of either vaccine is estimated to be around US$ 69,000-77,000 per disability-adjusted life-years (DALYs) averted over the period 2014-2033 (from the government or societal perspective). Only two alternative scenarios were borderline cost-effective (US$ per DALY averted less than 3*GDP per capita of approximately US$ 40,000). The first was a scenario based primarily on the WHO 2008 pneumococcal disease burden estimates for Croatia. The second was a scenario that assumed a fairly dramatic drop in the price of the vaccine over the period. Both vaccines would need to be priced at approximately US$ 20 per dose or less to be considered cost-effective under base-case assumptions. PCV10 would be more cost-effective than PCV13 with base-case assumptions, but this is sensitive to the price of each vaccine. CONCLUSION: Based on estimated health and economic benefits in children alone, PCV is unlikely to be cost-effective in Croatia. Both vaccines would need to be priced at less than US$ 20 per dose to be considered cost-effective for children. Further analyses should be conducted to estimate the health and economic burden of pneumococcal disease in older age groups, and to assess the influence on cost-effectiveness results when short-term and long-term indirect effects are included for older individuals. While there are important uncertainties around the price and effectiveness of both vaccines, our analysis suggests there is insufficient evidence to warrant a significant difference in the price of the two vaccines. PMID- 25919164 TI - ProVac Global Initiative: a vision shaped by ten years of supporting evidence based policy decisions. AB - INTRODUCTION: The Pan American Health Organization (PAHO) created the ProVac Initiative in 2004 with the goal of strengthening national technical capacity to make evidence-based decisions on new vaccine introduction, focusing on economic evaluations. In view of the 10th anniversary of the ProVac Initiative, this article describes its progress and reflects on lessons learned to guide the next phase. METHODS: We quantified the output of the Initiative's capacity-building efforts and critically assess its progress toward achieving the milestones originally proposed in 2004. Additionally, we reviewed how country studies supported by ProVac have directly informed and strengthened the deliberations around new vaccine introduction. RESULTS: Since 2004, ProVac has conducted four regional workshops and supported 24 health economic analyses in 15 Latin American and Caribbean countries. Five Regional Centers of Excellence were funded, resulting in six operational research projects and nine publications. Twenty four decisions on new vaccine introductions were supported with ProVac studies. Enduring products include the TRIVAC and CERVIVAC cost-effectiveness models, the COSTVAC program costing model, methodological guides, workshop training materials and the OLIVES on-line data repository. Ten NITAGs were strengthened through ProVac activities. DISCUSSION: The evidence accumulated suggests that initiatives with emphasis on sustainable training and direct support for countries to generate evidence themselves, can help accelerate the introduction of the most valuable new vaccines. International and Regional Networks of Collaborators are necessary to provide technical support and tools to national teams conducting analyses. Timeliness, integration, quality and country ownership of the process are four necessary guiding principles for national economic evaluations to have an impact on policymaking. It would be an asset to have a model that offers different levels of complexity to choose from depending on the vaccine being evaluated, the availability of data, and the time frame of the decision. CONCLUSION: Decision support for new vaccine introduction in low- and middle income countries is critical to maximizing the efficiency and impact of vaccination programs. Global technical cooperation will be required. In the future, PAHO and WHO have an opportunity to expand the reach of the ProVac philosophy, models, and methods to additional regions and countries requiring real-time support. The ProVac Global Initiative is proposed as an effective mechanism to do so. PMID- 25919165 TI - Cost-effectiveness of pneumococcal conjugate vaccination in Georgia. AB - OBJECTIVE: Financial support from the Global Alliance for Vaccines and Immunization (GAVI) to introduce the 10-valent pneumococcal conjugate vaccine (PCV10) into the routine childhood immunization schedule in Georgia is ending in 2015. As a result, the Interagency Coordination Committee (ICC) decided to carry out a cost-effectiveness analysis to gather additional evidence to advocate for an appropriate evidence-based decision after GAVI support is over. The study also aimed to strengthen national capacity to conduct cost-effectiveness studies, and to introduce economic evaluations into Georgia's decision-making process. METHODOLOGY: A multidisciplinary team of national experts led by a member of the ICC carried out the analysis that compared two scenarios: introducing PCV10 vs no vaccination. The TRIVAC model was used to evaluate 10 cohorts of children over the period 2014-2023. National data was used to inform demographics, disease burden, vaccine coverage, health service utilization, and costs. Evidence from clinical trials and the scientific literature was used to estimate the impact of the vaccine. A 3+0 schedule and a vaccine price increasing to US$ 3.50 per dose was assumed for the base-case scenario. Alternative univariate and multivariate scenarios were evaluated. RESULTS: Over the 10-year period, PCV10 was estimated to prevent 7170 (8288 undiscounted) outpatient visits due to all-cause acute otitis media, 5325 (6154 undiscounted) admissions due to all-cause pneumonia, 87 (100 undiscounted) admissions due to pneumococcal meningitis, and 508 (588 undiscounted) admissions due to pneumococcal non-pneumonia and non-meningitis (NPNM). In addition, the vaccine was estimated to prevent 41 (48 undiscounted) deaths. This is equivalent to approximately 5 deaths and 700 admissions prevented each year in Georgia. Over the 10-year period, PCV10 would cost the government approximately US$ 4.4 million ($440,000 per year). However, about half of this would be offset by the treatment costs prevented. The discounted cost effectiveness ratio was estimated to be US$ 1599 per DALY averted with scenarios ranging from US$ 286 to US$ 7787. DISCUSSION: This study led to better multi sectoral collaboration and improved national capacity to perform economic evaluations. Routine infant vaccination against Streptococcus pneumoniae would be highly cost-effective in Georgia. The decision to introduce PCV10 was already made some time before the study was initiated but it provided important economic evidence in support of that decision. There are several uncertainties around many of the parameters used, but a multivariate scenario analysis with several conservative assumptions (including no herd effect in older individuals) shows that this recommendation is robust. This study supports the decision to introduce PCV10 in Georgia. PMID- 25919166 TI - Economic analysis of the single-dose immunization strategy against hepatitis A in Argentina. AB - BACKGROUND: Vaccination against hepatitis A (HA) was carried out only as part of a limited outbreak control strategy in Argentina until June 2005, when universal immunization in infants was introduced into the national immunization calendar. A single-dose strategy was chosen instead of the standard two-dose schedule used elsewhere. This study aimed to estimate preventive, medical, and non-medical costs related to HA and to compare these costs in the periods before and after mass vaccination. METHODS: A retrospective analysis estimated treatment costs of HA and unspecified hepatitis cases reported to the National Health Surveillance System from 2000 to 2010. Costs related to immunization, fulminant hepatitis (FH), liver transplantation, and death were projected as well. Using a social perspective and a healthcare system perspective, costs in two 5-year periods were compared: 2000-2004 versus 2006-2010. Finally, we evaluated the impact of different discount rates, FH risk, and exclusion of unspecified hepatitis cases in the sensitivity analysis. RESULTS: Total HA and unspecified hepatitis cases decreased from 157,871 in 2000-2004 to 17,784 in 2006-2010. Medical and non medical costs decreased from US$11,811,600 and US$30,118,222 to US$1,252,694 and US$4,995,895 in those periods, respectively. Immunization costs increased from US$6,506,711 to US$40,912,132. Total preventive, medical, and non-medical costs decreased from US$48,436,534 to US$47,160,721, representing a 2.6% reduction in total costs between the two periods. When a healthcare system perspective was considered or unspecified hepatitis cases were excluded, total costs were 130.2% and 30.8% higher in 2006-2010 than in the previous period, respectively. CONCLUSION: After implementation of the universal single-dose vaccination against HA in infants in Argentina, an impressive decline was observed in HA cases, with a decrease in medical and non-medical costs in the first 5 years. The single-dose strategy, which is simpler and less expensive than the standard two-dose scheme, can be a good alternative for future vaccination policies in other countries where HA is endemic. PMID- 25919168 TI - Estimating costs of care for meningitis infections in low- and middle-income countries. AB - Meningitis infections are often associated with high mortality and risk of sequelae. The costs of treatment and care for meningitis are a great burden on health care systems, particularly in resource-limited settings. The objective of this study is to review data on the costs of care for meningitis in low- and middle-income countries, as well as to show how results could be extrapolated to countries without sound data. We conducted a systematic review of the literature from six databases to identify studies examining the cost of care in low- and middle-income countries for all age groups with suspected, probable, or confirmed meningitis. We extracted data on treatment costs and sequelae by infectious agent and/or pathogen, where possible. Using multiple regression analysis, a relationship between hospital costs and associated determinants was investigated in order to predict costs in countries with missing data. This relationship was used to predict treatment costs for all 144 low- and middle-income countries. The methodology of conducting a systematic review, extrapolating, and setting up a standard database can be used as a tool to inform cost-effectiveness analyses in situations where cost of care data are poor. Both acute and long-term costs of meningitis could be extrapolated to countries without reliable data. Although only bacterial causes of meningitis can be vaccine-preventable, a better understanding of the treatment costs for meningitis is crucial for low- and middle-income countries to assess the cost-effectiveness of proposed interventions in their country. This cost information will be important as inputs in future cost-effectiveness studies, particularly for vaccines. PMID- 25919167 TI - Thirty years of vaccination in Vietnam: Impact and cost-effectiveness of the national Expanded Programme on Immunization. AB - INTRODUCTION: Countries like Vietnam transitioning to middle-income status increasingly bear the cost of both existing and new vaccines. However, the impact and cost-effectiveness of the Expanded Programme on Immunization (EPI) as a whole has never been assessed on a country level. METHODS: Data on vaccine-preventable disease incidence and mortality from Vietnam's national surveillance was analysed to estimate the likely impact that vaccination in 1980-2010 may have had. Adjustment for under-reporting was made by examining trends in reported mumps incidence and in case-fatality risks for each disease. The same data were separately analysed using the Lives Saved Tool (LiST) to give an alternative estimate of impact. The financial cost of EPI in 1996-2010 was also estimated from the perspective of service provider. RESULTS: National surveillance data suggests that up to 5.7 million diseases cases and 26,000 deaths may have been prevented by EPI. Analysis using LiST suggests that even more deaths (370,000) may have been prevented by measles and pertussis vaccination alone. The cost effectiveness of EPI is estimated to be around $1000-$27,000 per death prevented. CONCLUSION: Two separate approaches to assessing EPI impact in Vietnam give different quantitative results but a common conclusion: that EPI has made a substantial impact on mortality and represents good value for money. PMID- 25919169 TI - Rotavirus vaccine effectiveness in Latin American and Caribbean countries: A systematic review and meta-analysis. AB - INTRODUCTION: There are two group A rotavirus (RVA) vaccines available worldwide since 2006: monovalent (Rotarix((r)), RV1) and pentavalent (RotaTeq((r)), RV5). Currently, 16 countries and 1 territory in Latin America and the Caribbean (LAC) have introduced RVA vaccines and since their introduction several impact and effectiveness studies have been conducted in different countries. The purpose of this study was to assess RVA vaccine effectiveness in LAC countries. METHODOLOGY: We conducted a systematic review and meta-analysis of studies in children under five who were admitted with laboratory-confirmed RVA diarrhea. We searched Medline, WOS, LILACS, Scopus, and other sources from 2006 to October 2013. Two independent evaluators identified the studies that met predefined selection criteria and extracted relevant information according to a protocol. Pooled estimates were obtained with fixed and random-effects models and stratified according to selected effect modifiers. RESULTS: Of the 806 articles meeting the initial criteria, 8 case-control studies which involved 27,713 participants (6265 cases and 21,448 controls) were included in the final analyses. The pooled estimates were calculated using different types of controls, leading to different degrees of effectiveness. The effectiveness of two doses of RV1 against rotavirus related hospitalizations ranged from 63.5% (95% CI: 39.2-78.0) to 72.2% (95%CI: 60.9-80.2). Effectiveness ranged from 75.4% (95%CI: 64.6-82.9) to 81.8% (CI 95%:72.3-88.1) among infants <12 months for RV1, and from 56.5% (95%CI: 26.2 74.3) to 66.4% (95%CI: 54.1-75.5) for infants >12 months. The RV5 effectiveness for diarrhea with a Vesikari score >11 in infants 6 to 11 months old ranged from 76.1% (95%CI: 57.6-86.6) to 88.8% (95%CI: 78.3-94.3). Also, it showed 63.5% (95%CI: 29.4-82.6) of effectiveness against G2P [4]. CONCLUSION: RVA vaccines consistently showed protection against diarrhea-related hospitalizations in LAC. Results were more robust for RV1. Effectiveness was shown with different types of controls, but appeared somewhat higher with community controls. Effectiveness was higher among infants <12 months and lower in older children. PMID- 25919170 TI - Evidence-based decision-making for vaccine introductions: Overview of the ProVac International Working Group's experience. AB - INTRODUCTION: Pan American Health Organization's (PAHO) ProVac Initiative aims to strengthen countries' technical capacity to make evidence-based immunization policy. With financial support from the Bill and Melinda Gates Foundation, PAHO established the ProVac International Working Group (IWG), a platform created for two years to transfer the ProVac Initiative's tools and methods to support decisions in non-PAHO regions. METHODS: In 2011, WHO Regional Offices and partner agencies established the IWG to transfer the ProVac framework for new vaccine decision support, including tools and trainings to other regions of the world. During the two year period, PAHO served as the coordinating secretariat and partner agencies played implementing or advisory roles. RESULTS: Fifty nine national professionals from 17 countries received training on the use of economic evaluations to aid vaccine policy making through regional workshops. The IWG provided direct technical support to nine countries to develop cost-effectiveness analyses to inform decisions. All nine countries introduced the new vaccine evaluated or their NITAGs have made a recommendation to the Ministry of Health to introduce the new vaccine. DISCUSSION: Developing countries around the world are increasingly interested in weighing the potential health impact due to new vaccine introduction against the investments required. During the two years, the ProVac approach proved valuable and timely to aid the national decision making processes, even despite the different challenges and idiosyncrasies encountered in each region. The results of this work suggest that: (1) there is great need and demand for technical support and for capacity building around economic evaluations; and (2) the ProVac method of supporting country-owned analyses is as effective in other regions as it has been in the PAHO region. CONCLUSION: Decision support for new vaccine introduction in low- and middle-income countries is critical to guiding the efficient use of resources and prioritizing high impact vaccination programs. PMID- 25919171 TI - Strengthening national decision-making on immunization by building capacity for economic evaluation: Implementing ProVac in Europe. AB - BACKGROUND: For many years, low- and middle-income countries have made efforts to strengthen national decision-making on immunization. The Pan American Health Organization (PAHO) ProVac Initiative was established to help expedite the use of evidence-based decision-making around new vaccine introduction. This initiative provides training in user-friendly cost-effectiveness models and supports the development of country-led economic evaluations. Due to the success of the ProVac Initiative in the Americas, and following requests from countries from outside the Americas, the Bill & Melinda Gates Foundation funded a two-year pilot effort to expand the initiative to other world regions. Called the ProVac International Working Group (IWG), this endeavor took place in 2012 and 2013. It was coordinated by PAHO and carried out in collaboration with several international partners, including the Agence de Medecine Preventive (AMP), London School of Hygiene & Tropical Medicine (LSHTM), Program for Appropriate Technology in Health, Sabin Vaccine Institute, United States Centers for Disease Control and Prevention, and the World Health Organization (WHO). In the WHO European Region, technical support was provided by AMP, in close collaboration with the WHO Regional Office for Europe and other ProVac IWG partners. METHODS: In 2012, AMP, the WHO Regional Office for Europe, and other partners held a training workshop in Dubrovnik, Croatia, for 31 participants from four countries of the WHO European Region. The aim was to train health professionals in standard methods of economic evaluation and to assess regional demand for economic studies to support decision-making on immunization. AMP and the other organizations also supported four national cost-effectiveness studies in the WHO European Region. The assistance included country visits and support over a period of six months, the establishment of multidisciplinary teams of experts, ongoing training on the TRIVAC decision-support model for new-vaccine economic analysis, review of local evidence, recommending key data inputs, and support in presenting results to national decision makers. RESULTS: National cost-effectiveness studies were conducted in four countries: Albania (rotavirus vaccine [RV]), Azerbaijan (pneumococcal conjugate vaccine [PCV]), Croatia (PCV), and Georgia (PCV). All four countries improved their estimates of the burden of disease preventable by the new vaccines. National advisory bodies and ministries of health obtained economic evidence that helped Albania and Croatia to make decisions on introducing the new vaccines. Azerbaijan and Georgia used economic evidence to confirm previously made preliminary decisions to introduce PCV and make corresponding financial commitments. The study helped Albania to obtain access to affordable prices for rotavirus vaccines through participation in the UNICEF procurement mechanism for middle-income countries. Croatia was able to define the PCV price that would make its introduction cost-effective, and can use this figure as a basis for price negotiations. DISCUSSION: Despite some challenges due to competing national priorities, tight budgets for immunization, and lack of available national data, the ProVac IWG helped to build capacity of national health professionals, support decision-making for the introduction of new vaccines, and promote utilization of economic evidence for making decisions on immunization. This type of strong collaboration among international partners and countries should be scaled up, given that many other countries in the WHO European Region have expressed interest in receiving assistance from the ProVac IWG. PMID- 25919172 TI - Gavi's balancing act: Accelerating access to vaccines while ensuring robust national decision-making for sustainable programmes. PMID- 25919173 TI - Costs of routine immunization and the introduction of new and underutilized vaccines in Ghana. AB - BACKGROUND: Limited knowledge exists on the full cost of routine immunization in Africa. Ghana was the first African country to simultaneously introduce rotavirus, pneumococcal and measles second-dose vaccines. Given their high price, it would be beneficial to Ghanaian health authorities to know the true cost of their introduction. METHODS: The economic costs of routine immunization for 2011 and the incremental costs of new vaccines were assessed as part of a multi country study on costing and financing of routine immunization known as the Expanded Program on Immunization Costing (EPIC). Immunization delivery costs were evaluated at the local facility, district, regional, and central levels. Stratified random sampling was used for district and facility selection. We calculated the allocation of nationwide costs to the four health-system levels. RESULTS: The total aggregated national costs for routine immunization - including vaccine costs - equaled US$ 53.5 million during 2011 (including central, regional, and district costs); this equated to US$ 60.3 per fully immunized child (FIC) when counting vaccine costs, or US$ 48.1 without. National immunization program delivery costs were allocated as follows: local facility level, 85% of total national cost; district, 11%; central, 2% and regional, 2%. Salaried labor represented 61% of total costs, and vaccines represented 17%. For new vaccine introduction, programmatic start-up costs amounted to US$ 3.9 million, primarily due to salaried labor (66%). The mean facility-level cost per vaccine dose administered in a routine immunization program was US$ 5.1 (with a range of US$ 2.4-7.8 depending on facility characteristics) and US$ 3.7 for delivery costs. DISCUSSION: We identified a high cost per fully immunized child, mostly due to non-vaccine costs at the facility level, which indicates that immunization program financing - whether national or donor-driven - must take a broad viewpoint. This substantial variation in overall costs emphasizes the additional effort associated with reaching children in various settings. PMID- 25919174 TI - Cost analysis of routine immunisation in Zambia. AB - BACKGROUND: This study aimed to inform planning and funding by providing updated, detailed information on total and unit costs of routine immunisation (RI) in Zambia, a GAVI-eligible lower middle-income country with a population of 13 million. METHODS: The exercise was part of a multi-country study on costs and financing of routine immunisation (EPIC) that utilized a common, ingredients based approach to costing. Data on inputs, prices and outputs were collected in a stratified, random sample of 51 facilities in nine districts between December 2012 and March 2013 using a pre-tested questionnaire. Shared inputs were allocated to RI costs on the basis of tracing factors developed for the study. A comprehensive set of costs were analysed to obtain total and unit costs, at facility and above-facility levels. RESULTS: The total annual economic cost of RI was $38.16 million, equivalent to approximately 10% of government health spending. Government contributed 83% of finances. Labour accounted for the lion's share (49%) of total costs followed by vaccines (16%) and travel allowances (12%). Analysis of specific activity costs showed that outreach and facility based services accounted for half of total economic costs. Costs for managing the program at district, provincial and national levels (above-facility costs) represented 24% of total costs. Average unit costs were $7.18 per dose, $59.32 per infant and $65.89 per DPT3 immunised child, with markedly higher unit costs in rural facilities. Analyses suggest that greater efficiency is associated with higher utilisation levels and urban facility type. CONCLUSIONS: Total and unit costs, and government's contribution, were considerably higher than previous Zambian estimates and international benchmarks. These findings have substantial implications for planners, efficiency improvement and sustainable financing, particularly as new vaccines are introduced. Variations in immunisation costs at facility level warrant further statistical analyses. PMID- 25919175 TI - Examining the cost of delivering routine immunization in Honduras. AB - BACKGROUND: Many countries have introduced new vaccines and expanded their immunization programs to protect additional risk groups, thus raising the cost of routine immunization delivery. Honduras recently adopted two new vaccines, and the country continues to broaden the reach of its program to adolescents and adults. In this article, we estimate and examine the economic cost of the Honduran routine immunization program for the year 2011. METHODS: The data were gathered from a probability sample of 71 health facilities delivering routine immunization, as well as 8 regional and 1 central office of the national immunization program. Data were collected on vaccinations delivered, staff time dedicated to the program, cold chain equipment and upkeep, vehicle use, infrastructure, and other recurrent and capital costs at each health facility and administrative office. Annualized economic costs were estimated from a modified societal perspective and reported in 2011 US dollars. RESULTS: With the addition of rotavirus and pneumococcal conjugate vaccines, the total cost for routine immunization delivery in Honduras for 2011 was US$ 32.5 million. Vaccines and related supplies accounted for 23% of the costs. Labor, cold chain, and vehicles represented 54%, 4%, and 1%, respectively. At the facility level, the non-vaccine system costs per dose ranged widely, from US$ 25.55 in facilities delivering fewer than 500 doses per year to US$ 2.84 in facilities with volume exceeding 10,000 doses per year. Cost per dose was higher in rural facilities despite somewhat lower wage rates for health workers in these settings; this appears to be driven by lower demand for services per health worker in sparsely populated areas, rather than increased cost of outreach. CONCLUSIONS: These more-precise estimates of the operational costs to deliver routine immunizations provide program managers with important information for mobilizing resources to help sustain the program and for improving annual planning and budgeting as well as longer-term resource allocation decisions. PMID- 25919176 TI - Perspectives on the development and use of economic evidence for immunization decision-making in a developing country. PMID- 25919177 TI - Costs of routine immunization services in Moldova: Findings of a facility-based costing study. AB - OBJECTIVE: Available estimates on how much it costs to provide routine immunization services are out-dated. This study attempts to address gaps in evidence by evaluating the total economic and unit costs of delivering routine immunization (RI) services in Moldova as part of a multi-country study on the costs and financing of routine immunization (EPIC). METHODS: This cross-sectional study is based on a multistage stratified random sample of fifty primary health care facilities. Data on inputs, prices, and outputs were collected retrospectively for 2011 and analyzed using an ingredient-based costing approach in Excel and SPSS. RESULTS: The average total annual facility cost for RI was $11,943 ranging from $565 to $112,548 and labor cost was the main driver of routine immunization costs contributing 65%, followed by capital costs - 16.3% and the cost of vaccines and injection supplies accounting for 9%. The average cost per dose was $18.3, the cost per child was $316.6 and the cost per fully immunized child was $332.3. The results show considerable variation in the costs of routine immunization services across facility type and depending on a facility scale i.e. annual doses administered. CONCLUSIONS: The study shows that the cost of fully immunizing a child in a middle-income country is much higher than previous estimates. These results will be used by the government for better planning and financing of routine immunization services, leading to greater sustainability. PMID- 25919178 TI - Determinants of routine immunization costing in Benin and Ghana in 2011. AB - BACKGROUND: Existing tools to evaluate costs do not always capture the heterogeneity of costs at the facility level. This study seeks to address this issue through an analysis of determinants of health facility immunization costs. METHODS: A statistical analysis on facility routine delivery and vaccine costs was conducted using ordinary least squares regression. Explanatory variables included the number of doses administered; proportion of time spent by facility staff on immunization; average staff wage; whether the health facility had enough staff; presence of cold chain equipment; distance to a vaccine collection point; and, facility ownership. Data were drawn from representative samples of primary care facilities in Benin and Ghana (46 and 50 facilities, respectively) collected as part of the EPIC studies. RESULTS: Weighted average RI immunization facility cost was US$ 16,459 in Ghana and US$ 14,994 in Benin. The regression found total doses administered to be positively and significantly associated with facility cost in both countries. A 10% increase in doses resulted in a 4% increase in cost in Ghana, and a 7.5% increase in Benin. In Ghana, the proportion of immunization time, presence of cold chain, and sufficiency of staff were positively and significantly associated with total cost. In Benin, facility cost was negatively and significantly related to distance to the vaccine collection point. In the pooled sample, facilities in capital cities were associated with significantly higher costs. CONCLUSIONS: This study provides evidence on the importance of the level of scale in determining facility immunization cost, as well as the role of availability of health workers and time they spend on immunization in Ghana and Benin. This type of analysis can provide insights into the costs of scaling up immunization services, and can assist with development of more efficient immunization strategies. PMID- 25919179 TI - The drivers of facility-based immunization performance and costs. An application to Moldova. AB - OBJECTIVE: This paper identifies factors that affect the cost and performance of the routine immunization program in Moldova through an analysis of facility-based data collected as part of a multi-country costing and financing study of routine immunization (EPIC). METHODS: A nationally representative sample of health care facilities (50) was selected through multi-stage, stratified random sampling. Data on inputs, unit prices and facility outputs were collected during October 3rd 2012-January 14th 2013 using a pre-tested structured questionnaire. Ordinary least square (OLS) regression analysis was performed to determine factors affecting facility outputs (number of doses administered and fully immunized children) and explaining variation in total facility costs. RESULTS: The study found that the number of working hours, vaccine wastage rates, and whether or not a doctor worked at a facility (among other factors) were positively and significantly associated with output levels. In addition, the level of output, price of inputs and share of the population with university education were significantly associated with higher facility costs. A 1% increase in fully immunized child would increase total cost by 0.7%. CONCLUSIONS: Few costing studies of primary health care services in developing countries evaluate the drivers of performance and cost. This exercise attempted to fill this knowledge gap and helped to identify organizational and managerial factors at a primary care district and national level that could be addressed by improved program management aimed at improved performance. PMID- 25919180 TI - Mapping financial flows for immunisation in Uganda 2009/10 and 2010/11: New insights for methodologies and policy. AB - BACKGROUND: The Global Vaccine Action Plan highlights the need for immunisation programmes to have sustainable access to predictable funding. A good understanding of current and future funding needs, commitments, and gaps is required to enhance planning, improve resource allocation and mobilisation, and to avoid funding bottlenecks, as well as to ensure that co-funding arrangements are appropriate. This study aimed to map the resource envelope and flows for immunisation in Uganda in 2009/10 and 2010/11. METHODS: To assess costs and financing of immunisation, the study applied a common methodology as part of the multi-country Expanded Program on Immunisation Costing (EPIC) study (Brenzel et al., 2015). The financial mapping developed a customised extension of the System of Health Accounts (SHA) codes to explore immunisation financing in detail. Data were collected from government and external sources. The mapping was able to assess financing more comprehensively than many studies, and the simultaneous costing of routine immunisation collected detailed data about human resources costs. RESULTS: The Ugandan government contributed 56% and 42% of routine immunisation funds in 2009/10 and 2010/11, respectively, higher than previously estimated, and managed up to 90% of funds. Direct delivery of services used 93% of the immunisation financial resources in 2010/11, while the above service delivery costs were small (7%). Vaccines and supplies (41%) and salaries (38%) absorbed most funding. There were differences in the key cost categories between actual resource flows and the estimates from the comprehensive multi-year plan (cMYP). CONCLUSIONS: Results highlight that governments and partners need to improve systems to routinely track immunisation financing flows for enhanced accountability, performance, and sustainability. The modified SHA coding allowed financing to be mapped to specific immunisation activities, and could be used for standardised, resource tracking compatible with National Health Accounts (NHA). Recommendations are made for refining routine resource mapping approaches. PMID- 25919181 TI - The ProVac initiative and evolving decision support. PMID- 25919182 TI - Tracking financial flows for immunization in Honduras. AB - INTRODUCTION: In Honduras, until 2008, vaccine and injection supplies were financed with domestic resources. With the introduction of rotavirus vaccine in 2009 and pneumococcal conjugate in 2011, the country's Expanded Program on Immunization required an influx of resources to support not only vaccine procurement but also investments in cold chain infrastructure and programmatic strategies. This paper examines the origin, allocation, and use of resources for immunization in 2011 in Honduras, with the aim of identifying gaps in financing. METHODS: An adaptation of the System of Health Accounts (2011) codes was used to specifically track resources for immunization services in Honduras for 2011. All financial flows were entered into an Excel database, and each transfer of resources was coded with a financing source and a financing agent. These coded financing sources were then distributed by provider, health care function (activity), health care provision (line item or resource input), and beneficiary (geographic, population, and antigen). All costs were calculated in 2011 United States dollars. RESULTS: In 2011, financing for routine immunization in Honduras amounted to US$ 49.1 million, which is equal to 3.3% of the total health spending of US$ 1.49 billion and 0.29% of the GDP. Of the total financing, 64% originate from domestic sources. The other 36% is external financing, most importantly Gavi support for introducing new vaccines. This analysis identified potential financing gaps for many immunization-related activities besides procuring vaccines, such as expanding the cold chain, training, social mobilization, information systems, and research. CONCLUSIONS: The funding for Honduras' immunization program is a small share of total public spending on health. However, new vaccines recently added to the schedule with financial support from Gavi have increased the financing requirements by more than 30% in comparison to 2008. The Honduran government and its partners are developing sustainability plans to cover a financing gap that will occur when the country graduates from Gavi support in 2016. Access to lower vaccine prices will make the existing and future program, including the planned introduction of HPV vaccine to adolescent girls, more affordable. PMID- 25919183 TI - What have we learned on costs and financing of routine immunization from the comprehensive multi-year plans in GAVI eligible countries? AB - BACKGROUND: Immunization is one of the most cost-effective health interventions, but as countries introduce new vaccines and scale-up immunization coverage, costs will likely increase. This paper updates estimates of immunization costs and financing based on information from comprehensive multi-year plans (cMYPs) from GAVI-eligible countries during a period when countries planned to introduce a range of new vaccines (2008-2016). METHODS: The analysis database included information from baseline and 5-year projection years for each country cMYP, resulting in a total sample size of 243 observations. Two-thirds were from African countries. Cost data included personnel, vaccine, injection, transport, training, maintenance, cold chain and other capital investments. Financing from government and external sources was evaluated. All estimates were converted to 2010 US Dollars. Statistical analysis was performed using STATA, and results were population-weighted. RESULTS: Results pertain to country planning estimates. Average annual routine immunization cost was $62 million. Vaccines continued to be the major cost driver (51%) followed by immunization-specific personnel costs (22%). Non-vaccine delivery costs accounted for almost half of routine program costs (44%). Routine delivery cost per dose averaged $0.61 and the delivery cost per infant was $10. The cost per DTP3 vaccinated child was $27. Routine program costs increased with each new vaccine introduced. Costs accounted for 5% of government health expenditures. Governments accounted for 67% of financing. CONCLUSION: Total and average costs of routine immunization programs are rising as coverage rates increase and new vaccines are introduced. The cost of delivering vaccines is nearly equivalent to the cost of vaccines. Governments are financing greater proportions of the immunization program but there may be limits in resource scarce countries. Price reductions for new vaccines will help reduce costs and the burden of financing. Strategies to improve efficiency in service delivery should be pursued. PMID- 25919184 TI - Costs of vaccine programs across 94 low- and middle-income countries. AB - While new mechanisms such as advance market commitments and co-financing policies of the GAVI Alliance are allowing low- and middle-income countries to gain access to vaccines faster than ever, understanding the full scope of vaccine program costs is essential to ensure adequate resource mobilization. This costing analysis examines the vaccine costs, supply chain costs, and service delivery costs of immunization programs for routine immunization and for supplemental immunization activities (SIAs) for vaccines related to 18 antigens in 94 countries across the decade, 2011-2020. Vaccine costs were calculated using GAVI price forecasts for GAVI-eligible countries, and assumptions from the PAHO Revolving Fund and UNICEF for middle-income countries not supported by the GAVI Alliance. Vaccine introductions and coverage levels were projected primarily based on GAVI's Adjusted Demand Forecast. Supply chain costs including costs of transportation, storage, and labor were estimated by developing a mechanistic model using data generated by the HERMES discrete event simulation models. Service delivery costs were abstracted from comprehensive multi-year plans for the majority of GAVI-eligible countries and regression analysis was conducted to extrapolate costs to additional countries. The analysis shows that the delivery of the full vaccination program across 94 countries would cost a total of $62 billion (95% uncertainty range: $43-$87 billion) over the decade, including $51 billion ($34-$73 billion) for routine immunization and $11 billion ($7-$17 billion) for SIAs. More than half of these costs stem from service delivery at $34 billion ($21-$51 billion)-with an additional $24 billion ($13-$41 billion) in vaccine costs and $4 billion ($3-$5 billion) in supply chain costs. The findings present the global costs to attain the goals envisioned during the Decade of Vaccines to prevent millions of deaths by 2020 through more equitable access to existing vaccines for people in all communities. By projecting the full costs of immunization programs, our findings may aid to garner greater country and donor commitments toward adequate resource mobilization and efficient allocation. As service delivery costs have increasingly become the main driver of vaccination program costs, it is essential to pay additional consideration to health systems strengthening. PMID- 25919185 TI - Palliative care in cancer: enhancing our view with the science of emotion and decision making. PMID- 25919186 TI - miR-144/451 Promote Cell Proliferation via Targeting PTEN/AKT Pathway in Insulinomas. AB - Insulinoma is the main type of functional pancreatic neuroendocrine tumors. The functional microRNAs (miRNAs) regulating tumor growth and progression in insulinomas are still unknown. We conducted the miRNA expression profile analysis using miRNA quantitative RT-PCR array and identified 114 differentially expressed miRNAs in human insulinomas compared with normal pancreatic islets. Forty-one differentially expressed miRNAs belonged to 7 miRNA families, and 28 miRNAs in 3 of the families localized in the epigenetically regulated imprinted chromosome 14q32 region. We validated the most significant differentially expressed miRNA cluster miR-144/451 in another 8 human normal islet samples and 25 insulinomas. Our data showed that the overexpression of miR-144/451 in mouse pancreatic beta cells promoted cell proliferation by targeting the beta-cell regulator phosphatase and tensin homolog deleted on chromosome ten/v-akt murine thymoma viral oncogene homolog pathway and cyclin-dependent kinase inhibitor 2D. Our findings highlight the importance of functional miRNAs in insulinomas. PMID- 25919187 TI - Role of OAT4 in Uptake of Estriol Precursor 16alpha-Hydroxydehydroepiandrosterone Sulfate Into Human Placental Syncytiotrophoblasts From Fetus. AB - Estriol biosynthesis in human placenta requires the uptake of a fetal liver derived estriol precursor, 16alpha-hydroxydehydroepiandrosterone sulfate (16alpha OH DHEAS), by placental syncytiotrophoblasts at their basal plasma membrane (BM), which faces the fetal circulation. The aim of this work is to identify the transporter(s) mediating 16alpha-OH DHEAS uptake at the fetal side of syncytiotrophoblasts by using human placental BM-enriched vesicles and to examine the contribution of the putative transporter to estriol synthesis at the cellular level, using choriocarcinoma JEG-3 cells. Organic anion transporter (OAT)-4 and organic anion transporting polypeptide 2B1 proteins were enriched in human placental BM vesicles compared with crude membrane fraction. Uptake of [(3)H]16alpha-OH DHEAS by BM vesicles was partially inhibited in the absence of sodium but was significantly increased in the absence of chloride and after preloading glutarate. Uptake of [(3)H]16alpha-OH DHEAS by BM vesicles was significantly inhibited by OAT4 substrates such as dehydroepiandrosterone sulfate, estrone-3-sulfate, and bromosulfophthalein but not by cyclosporin A, tetraethylammonium, p-aminohippuric acid, or cimetidine. These characteristics of vesicular [(3)H]16alpha-OH DHEAS uptake are in good agreement with those of human OAT4-transfected COS-7 cells as well as forskolin-differentiated JEG-3 cells. Estriol secretion from differentiated JEG-3 cells was detected when the cells were incubated with 16alpha-OH DHEAS for 8 hours but was inhibited in the presence of 50 MUM bromosulfophthalein. Our results indicate that OAT4 at the BM of human placental syncytiotrophoblasts plays a predominant role in the uptake of 16alpha-OH DHEAS for placental estriol synthesis. PMID- 25919189 TI - Product environmental footprint in policy and market decisions: Applicability and impact assessment. AB - In April 2013, the European Commission published the Product and Organisation Environmental Footprint (PEF/OEF) methodology--a life cycle-based multicriteria measure of the environmental performance of products, services, and organizations. With its approach of "comparability over flexibility," the PEF/OEF methodology aims at harmonizing existing methods, while decreasing the flexibility provided by the International Organization for Standardization (ISO) standards regarding methodological choices. Currently, a 3-y pilot phase is running, aiming at testing the methodology and developing product category and organization sector rules (PEFCR/OEFSR). Although a harmonized method is in theory a good idea, the PEF/OEF methodology presents challenges, including a risk of confusion and limitations in applicability to practice. The paper discusses the main differences between the PEF and ISO methodologies and highlights challenges regarding PEF applicability, with a focus on impact assessment. Some methodological aspects of the PEF and PEFCR Guides are found to contradict the ISO 14044 (2006) and ISO 14025 (2006). Others, such as prohibition of inventory cutoffs, are impractical. The evaluation of the impact assessment methods proposed in the PEF/OEF Guide showed that the predefined methods for water consumption, land use, and abiotic resources are not adequate because of modeling artefacts, missing inventory data, or incomplete characterization factors. However, the methods for global warming and ozone depletion perform very well. The results of this study are relevant for the PEF (and OEF) pilot phase, which aims at testing the PEF (OEF) methodology (and potentially adapting it) as well as addressing challenges and coping with them. PMID- 25919188 TI - Developmental Programming: Prenatal and Postnatal Androgen Antagonist and Insulin Sensitizer Interventions Prevent Advancement of Puberty and Improve LH Surge Dynamics in Prenatal Testosterone-Treated Sheep. AB - Prenatal T excess induces maternal hyperinsulinemia, early puberty, and reproductive/metabolic defects in the female similar to those seen in women with polycystic ovary syndrome. This study addressed the organizational/activational role of androgens and insulin in programming pubertal advancement and periovulatory LH surge defects. Treatment groups included the following: 1) control; 2) prenatal T; 3) prenatal T plus prenatal androgen antagonist, flutamide; 4) prenatal T plus prenatal insulin sensitizer, rosiglitazone; 5) prenatal T and postnatal flutamide; 6) prenatal T and postnatal rosiglitazone; and 7) prenatal T and postnatal metformin. Prenatal treatments spanned 30-90 days of gestation and postnatal treatments began at approximately 8 weeks of age and continued throughout. Blood samples were taken twice weekly, beginning at approximately 12 weeks of age to time puberty. Two-hour samples after the synchronization with prostaglandin F2alpha were taken for 120 hours to characterize LH surge dynamics at 7 and 19 months of age. Prenatal T females entered puberty earlier than controls, and all interventions prevented this advancement. Prenatal T reduced the percentage of animals having LH surge, and females that presented LH surge exhibited delayed timing and dampened amplitude of the LH surge. Prenatal androgen antagonist, but not other interventions, restored LH surges without normalizing the timing of the surge. Normalization of pubertal timing with prenatal/postnatal androgen antagonist and insulin sensitizer interventions suggests that pubertal advancement is programmed by androgenic actions of T involving insulin as a mediary. Restoration of LH surges by cotreatment with androgen antagonist supports androgenic programming at the organizational level. PMID- 25919190 TI - Ibogan, tacaman, and cytotoxic bisindole alkaloids from tabernaemontana. Cononusine, an iboga alkaloid with unusual incorporation of a pyrrolidone moiety. AB - Six new indole alkaloids, viz., cononusine (1, a rare example of an iboga pyrrolidone conjugate), ervaluteine (2), vincamajicine (3), tacamonidine (4), 6 oxoibogaine (5), and N(4)-chloromethylnorfluorocurarine chloride (6), and two new vobasinyl-iboga bisindole alkaloids, ervatensines A (7) and B (8), in addition to other known alkaloids, were isolated from the stem-bark extract of the Malayan Tabernaemontana corymbosa. The structures of these alkaloids were established on the basis of NMR and MS analyses and, in one instance (7), confirmed by X-ray diffraction analysis. Vincamajicine (3) showed appreciable activity in reversing multidrug resistance in vincristine-resistant KB cells (IC50 2.62 MUM), while ervatensines A (7) and B (8) and two other known bisindoles displayed pronounced in vitro growth inhibitory activity against human KB cells (IC50 < 2 MUM). Compounds 7 and 8 also showed good growth inhibitory activity against A549, MCF 7, MDA-468, HCT-116, and HT-29 cells (IC50 0.70-4.19 MUM). Cell cycle and annexin V-FITC apoptosis assays indicated that compounds 7 and 8 inhibited proliferation of HCT-116 and MDA-468 cells, evoking apoptotic and necrotic cell death. PMID- 25919191 TI - The relationship between consumption of beverages and tooth wear among adults in the United States. AB - OBJECTIVES: To investigate the prevalence and severity of tooth wear (TW) and its relationship with consumption of beverages among adults in the United States. METHODS: The National Health and Nutrition Examinations Survey data for 2003-2004 was analyzed. TW was defined as "wear on at least one surface of at least one examined tooth." Drink/juice consumption was ascertained via a Food Frequency Questionnaire processed with Diet*Calc software to obtain the average daily consumption frequency for all queried drinks and juice categories including milk. Survey-weighted descriptive and multivariable analyses with interaction terms were performed. RESULTS: Our study sample consisted of 3,773 adults (aged 20 and above). Eighty percent of the subjects had evidence of TW, and soft drinks were the most consumed beverage. Significant interactions between the effects of age, gender, and race/ethnicity on TW were found (P < 0.001). After adjustment for demographic factors, consumption of fruit drinks was found to be significantly associated with the severity [odds ratio (OR) = 1.32 and 1.42], but not prevalence of TW. However, this trend was reversed for grape juice consumption (OR = 0.34, 0.41). CONCLUSIONS: This study demonstrates that a substantial proportion of adults had evidence of TW, which was affected by demographic factors in a complex way. Fruit drinks consumption in adults was associated with the severity of TW, but not with the prevalence of TW after adjusting for demographics. These findings are important for the development of appropriate treatment guidelines, public policy, and programs aimed at reducing TW in adults. PMID- 25919192 TI - Organophosphorous biocides reduce tenacity and cellular viability but not esterase activities in a non-target prosobranch (limpet). AB - Detecting impacts of organophosphorus biocides (OP) is facilitated by analysing "biomarkers" - biological responses to environmental insults. Understanding is hampered by studying biomarkers in isolation at different levels of biological response and limited work on ecologically-important species. We tested the relevance of esterases as biomarkers of OP-exposure in limpets (Patella vulgata), abundant prosobranchs that structure the assemblages on rocky shores through their grazing. We characterized esterases in haemolymph and tissue, and quantified their dose-dependent inhibition by chlorfenvinphos (0.1-3.0 mM) in vitro. To determine whether esterases are useful biomarkers we exposed limpets to chlorfenvinphos (0-10 MUg L(-1)). Despite reduced tenacity (ability to stick to a surface) and haemocyte-viability, esterases remained unaffected. Tenacity was reduced by >50% at 5 MUg L(-1) and by 95% at 10 MUg L(-1), whilst haemocyte viability was more sensitive with >40% reductions at concentrations of 0.5 MUg L( 1) and above. We discuss results in relation to linking sub-lethal and ecological impacts at contaminated sites. PMID- 25919193 TI - CTP-Based Tissue Outcome: Promising Tool to Prove the Beneficial Effect of Mechanical Recanalization in Acute Ischemic Stroke. AB - PURPOSE: To prove the tissue-protecting effect of mechanical recanalization, we assessed the CT perfusion-based tissue outcome ("TO") and correlated this imaging parameter with the 3-month clinical outcome ("CO"). MATERIALS AND METHODS: 159 patients with large intracranial artery occlusions revealing mechanical recanalization were investigated by CCT, CT angiography (CTA) and CT perfusion (CTP) upon admission. For the final infarct volume, native CCT was repeated after 24 h. The "TO" ("percentage mismatch loss" = %ML) was defined as the difference between initial penumbral tissue on CTP and final infarct volume on follow-up CCT. We monitored the three-month modified Rankin Scale (mRS), age, bleeding occurrence, time to recanalization, TICI score and collateralization grade, infarct growth and final infarct volume. Spearman's correlation and nominal regression analysis were used to evaluate the impact of these parameters on mRS. RESULTS: Significant correlations were found for %ML and mRS (c = 0.48, p < 0.001), for final infarct volume and mRS (c = 0.52, p < 0.001), for TICI score and mRS (c = - 0.35, p < 0.001), for initial infarct core and mRS (c = 0.14, p = 0.039) as well as for age and mRS (c = 0.37, p < 0.001). According to the regression analysis, %ML predicted the classification of mRS correctly in 38.5 % of cases. The subclasses mRS 1 and 6 could be predicted by %ML with 86.4 % and 60.9 % reliability, respectively. No correlations were found for time to recanalization and mRS, for collateralization grade and mRS, and for post interventional bleeding and mRS. CONCLUSION: Better than the TICI score, CT based TO predicts the clinical success of mechanical recanalization, showing that not recanalization, but reperfusion should be regarded as a surrogate parameter for stroke therapy. KEY POINTS: * %ML as well as the final infarct volume can make a direct point about the immediate effect of successful mechanical recanalization.* The clinical outcomes after mechanical recanalization are reliably predicted by %ML, reflecting the benefit of escalation therapy including interventional reopening of parent vessel occlusions.* Not recanalization but rather reperfusion should be regarded as a surrogate parameter for successful stroke therapy. PMID- 25919194 TI - The Aging Lung: Clinical and Imaging Findings and the Fringe of Physiological State. AB - Since aspects of demographic transition have become an essential part of socioeconomic, medical and health-care research in the last decades, it is vital for the radiologist to discriminate between normal ageing related effects and abnormal imaging findings in the elderly. This article reviews functional and structural aspects of the ageing lung and focuses on typical ageing related radiological patterns. KEY POINTS: * The physiological aging process of the thoracic organs shows typical structural and functional aspects.* Mild interstitial fibrosis and focal parenchymal abnormalities like septal thickening can be diagnosed frequently - whereas a clinical correlate is often lacking.* With increasing patient age, the influence by various intrinsic and extrinsic factors (including comorbidities of the patient, and drug inhalation toxicants) also increases.* A growing spectrum of imaging techniques (including functional cardiopulmonary MRI, MRI spectroscopy, hybrid-techniques) is confronted by rare empiric data in the very old people (aging 80 years and older). PMID- 25919195 TI - Inter-population ovarian fluid variation differentially modulates sperm motility in Atlantic cod Gadus morhua. AB - This study tested the hypothesis that the effects of Atlantic cod Gadus morhua ovarian fluid on sperm motility variables are population specific. Sperm from a northern G. morhua population were activated in the presence of ovarian fluid from either northern or southern G. morhua at different concentrations. Ovarian fluid acted as a filter, in some cases reducing sperm swimming performance compared with seawater. Fluid from females foreign in population (southern) to the males (northern) had a greater inhibiting effect than those from the native population. Follow-up analysis indicated that the ovarian fluids had lower Ca(2+) concentration in northern than southern G. morhua, which could be the causative mechanism. If widespread, such cryptic female choice could reduce the incidence of intraspecific hybridization among diverged populations and contribute to reproductive isolation. PMID- 25919196 TI - Pure shift NMR. AB - Although scalar-coupling provides important structural information, the resulting signal splittings significantly reduce the resolution of NMR spectra. Limited resolution is a particular problem in proton NMR experiments, resulting in part from the limited proton chemical shift range (~10 ppm) but even more from the splittings due to scalar coupling to nearby protons. "Pure shift" NMR spectroscopy (also known as broadband homonuclear decoupling) has been developed for disentangling overlapped proton NMR spectra. The resulting spectra are considerably simplified as they consist of single lines, reminiscent of proton decoupled C-13 spectra at natural abundance, with no multiplet structure. The different approaches to obtaining pure shift spectra are reviewed here and several applications presented. Pure shift spectra are especially useful for highly overlapped proton spectra, as found for example in reaction mixtures, natural products and biomacromolecules. PMID- 25919198 TI - Chaperones and chaperone-substrate complexes: Dynamic playgrounds for NMR spectroscopists. AB - The majority of proteins depend on a well-defined three-dimensional structure to obtain their functionality. In the cellular environment, the process of protein folding is guided by molecular chaperones to avoid misfolding, aggregation, and the generation of toxic species. To this end, living cells contain complex networks of molecular chaperones, which interact with substrate polypeptides by a multitude of different functionalities: transport them towards a target location, help them fold, unfold misfolded species, resolve aggregates, or deliver them towards a proteolysis machinery. Despite the availability of high-resolution crystal structures of many important chaperones in their substrate-free apo forms, structural information about how substrates are bound by chaperones and how they are protected from misfolding and aggregation is very sparse. This lack of information arises from the highly dynamic nature of chaperone-substrate complexes, which so far has largely hindered their crystallization. This highly dynamic nature makes chaperone-substrate complexes good targets for NMR spectroscopy. Here, we review the results achieved by NMR spectroscopy to understand chaperone function in general and details of chaperone-substrate interactions in particular. We assess the information content and applicability of different NMR techniques for the characterization of chaperones and chaperone substrate complexes. Finally, we highlight three recent studies, which have provided structural descriptions of chaperone-substrate complexes at atomic resolution. PMID- 25919199 TI - Proton MRS and MRSI of the brain without water suppression. AB - Water suppression (WS) techniques have played a vital role in the commencement and development of in vivo proton magnetic resonance spectroscopy (MRS, including spectroscopic imaging - MRSI). WS not only made in vivo proton MRS functionally available but also made its applications conveniently accessible, and it has become an indispensable tool in most of the routine applications of in vivo proton MR spectroscopy. On the other hand, WS brought forth some challenges. Therefore, various techniques of proton MRS without WS have been developed since the pioneering work in the late 1990s. After more than one and a half decades of advances in both hardware and software, non-water-suppressed proton MRS is coming to the stage of maturity and seeing increasing application in biomedical research and clinical diagnosis. In this article, we will review progress in the technical development and applications of proton MRS without WS. PMID- 25919200 TI - Efficiency Enhancement of Nanotextured Black Silicon Solar Cells Using Al2O3/TiO2 Dual-Layer Passivation Stack Prepared by Atomic Layer Deposition. AB - In this study, efficient nanotextured black silicon (NBSi) solar cells composed of silicon nanowire arrays and an Al2O3/TiO2 dual-layer passivation stack on the n(+) emitter were fabricated. The highly conformal Al2O3 and TiO2 surface passivation layers were deposited on the high-aspect-ratio surface of the NBSi wafers using atomic layer deposition. Instead of the single Al2O3 passivation layer with a negative oxide charge density, the Al2O3/TiO2 dual-layer passivation stack treated with forming gas annealing provides a high positive oxide charge density and a low interfacial state density, which are essential for the effective field-effect and chemical passivation of the n(+) emitter. In addition, the Al2O3/TiO2 dual-layer passivation stack suppresses the total reflectance over a broad range of wavelengths (400-1000 nm). Therefore, with the Al2O3/TiO2 dual layer passivation stack, the short-circuit current density and efficiency of the NBSi solar cell were increased by 11% and 20%, respectively. In conclusion, a high efficiency of 18.5% was achieved with the NBSi solar cells by using the n(+) emitter/p-base structure passivated with the Al2O3/TiO2 stack. PMID- 25919203 TI - The evolution of evaluation and management of urinary or fecal incontinence and pelvic organ prolapse. PMID- 25919204 TI - Anti-Androgenic Activity of Nardostachys jatamansi DC and Tribulus terrestris L. and Their Beneficial Effects on Polycystic Ovary Syndrome-Induced Rat Models. AB - BACKGROUND: Polycystic ovary syndrome (PCOS) is a major hyperandrogenic disorder. Many drugs prescribed specifically to treat PCOS have side effects; however, previous studies suggest that natural therapeutics including botanicals may be less invasive and equally effective for the management of PCOS. METHODS: In the present study, plants were screened for antiandrogenic activity using the RIKILT yeast Androgen bioAssay (RAA). Selected positive plants were subsequently tested for their efficacy against PCOS induced by estradiol valerate (EV) in rat models. RESULTS: RAA revealed the antiandrogenic property of Nardostachys jatamansi DC (NJ), Tribulus terrestris L. (TT), and Embelia tsjeriam-cottam DC (EJ), whereas Whithania somnifera Dunal (WS), Symplocos racemosa Roxb. (SR), and Helicteres isora L. (HI) exhibited androgenic properties. EJ also exhibited mild androgenic activity and therefore was excluded from further study. EV administration reduced the weight gain and disrupted cyclicity in all rats. NJ and TT extract treatment normalized estrous cyclicity and steroidal hormonal levels and regularized ovarian follicular growth. CONCLUSION: The in vitro antiandrogenic activity of plant extracts and their positive effects on different parameters of PCOS were proved in vivo. PMID- 25919197 TI - Magic angle spinning NMR of viruses. AB - Viruses, relatively simple pathogens, are able to replicate in many living organisms and to adapt to various environments. Conventional atomic-resolution structural biology techniques, X-ray crystallography and solution NMR spectroscopy provided abundant information on the structures of individual proteins and nucleic acids comprising viruses; however, viral assemblies are not amenable to analysis by these techniques because of their large size, insolubility, and inherent lack of long-range order. In this article, we review the recent advances in magic angle spinning NMR spectroscopy that enabled atomic resolution analysis of structure and dynamics of large viral systems and give examples of several exciting case studies. PMID- 25919205 TI - Ultrasmall [(64)Cu]Cu nanoclusters for targeting orthotopic lung tumors using accurate positron emission tomography imaging. AB - Positron emission tomography (PET) imaging has received special attention owing to its higher sensitivity, temporal resolution, and unlimited tissue penetration. The development of tracers that target specific molecules is therefore essential for the development and utility of clinically relevant PET procedures. However, (64)Cu as a PET imaging agent generally has been introduced into biomaterials through macrocyclic chelators, which may lead to the misinterpretation of PET imaging results due to the detachment and transchelation of (64)Cu. In this study, we have developed ultrasmall chelator-free radioactive [(64)Cu]Cu nanoclusters using bovine serum albumin (BSA) as a scaffold for PET imaging in an orthotopic lung cancer model. We preconjugated the tumor target peptide luteinizing hormone releasing hormone (LHRH) to BSA molecules to prepare [(64)Cu]CuNC@BSA-LHRH. The prepared [(64)Cu]Cu nanoclusters showed high radiolabeling stability, ultrasmall size, and rapid deposition and diffusion into tumor, as well as predominantly renal clearance. [(64)Cu]CuNC@BSA-LHRH showed 4 times higher tumor uptake compared with that of [(64)Cu]CuNC@BSA by analyzing the (64)Cu radioactivity of tissues via gamma counting. The PET imaging using [(64)Cu]Cu nanoclusters as tracers showed more sensitive, accurate, and deep penetration imaging of orthotopic lung cancer in vivo compared with near-infrared fluorescence imaging. The nanoclusters provide biomedical research tools for PET molecular imaging. PMID- 25919207 TI - Supportive environments for care of families and children. PMID- 25919208 TI - Should Older Teens and Young Adults With Chronic, Life-Threatening Pediatric Illnesses be Transitioned to Adult Providers and Care Based on Chronologic Age? PMID- 25919209 TI - Improving communication and coordination of complex perinatal patients. AB - Pregnant women with complex medical problems require comprehensive communication among members of their healthcare team. Using the Magnet Hospital model, our Patient and Perinatal Interprofessional Team at Seton Medical Center Austin focused on improving communication and patient satisfaction by initiating Perinatal Patient Care Conferences. Pregnant women with medical or obstetric complications and their families became a part of care plan development prior to admission to promote consistent communication and excellent care. We report our 7 year history of proactive meetings with pregnant women and their families in a nonclinical environment to discuss diagnosis, treatment, and prognosis. A collaborative written plan of care is developed that accommodates the woman's needs and wishes and is then disseminated among the healthcare team. This process has decreased women's and caregivers' anxiety and supported a culture of safety across the continuum of care. PMID- 25919210 TI - Breastfeeding, co-sleeping and dental health advice. AB - PURPOSE: To identify dental health advice offered by healthcare providers (HCPs) to mothers that cosleep and breastfeed at night. STUDY DESIGN AND METHODS: Mothers were recruited via local contacts, e-mail, and support groups. In-person, digitally recorded interviews were conducted with 14 cosleeping, breastfeeding mothers with children from 6 months to 2 years. Interviews included seven open ended questions about cosleeping patterns, night breastfeeding patterns, and dental health advice offered by HCPs. These HCPs included pediatricians, family medicine physicians, midwives, and obstetricians. Interviews were transcribed verbatim and qualitative descriptive analysis was done. RESULTS: The majority of women reported keeping their child in bed with them for most, if not all, of the night. All of the mothers reported breastfeeding on demand. Approximately half of the mothers did not disclose their sleeping patterns to their HCP. Mothers reported few HCPs initiated a discussion on cosleeping or oral hygiene for their child. CLINICAL IMPLICATIONS: Mothers did not readily share their cosleeping, nor did most HCPs initiate a conversation about cosleeping and dental hygiene. This qualitative study identifies the need for education on anticipatory guidance of oral hygiene discussions from HCPs. As HCPs, it is our responsibility to initiate the conversation with the mother because this study demonstrates that mothers will be unlikely to do so. PMID- 25919211 TI - Formaldehyde exposure during pregnancy. AB - BACKGROUND: Pregnancy is a particularly vulnerable time for exposure to indoor air pollutants, such as formaldehyde (FA), which is linked to spontaneous abortion, congenital malformations, and premature birth. PURPOSE: To determine personal exposure to FA during pregnancy, and to identify the relationship between FA exposure levels and potential residential sources of FA. STUDY DESIGN AND METHODS: The study sample consisted of 140 pregnant women recruited from obstetrical clinics in Huntsville, Alabama. Formaldehyde exposure was measured by FA vapor monitor badges. Questionnaires were administered to participants to identify potential residential sources of FA. Urine cotinine, a surrogate for tobacco smoke exposure, was also used as an indicator of a possible source of residential exposure to FA. RESULTS: The mean level of FA exposure by vapor monitor badge was 0.04 parts per million (ppm) (SD = 0.06; range 0.003-0.54 ppm). Minimum risk levels of 0.03 and higher were found in 36.4% of participants. Exposure levels of FA were higher in spring than winter (p < 0.001). Exposure levels of FA were correlated with indoor temperature of dwellings (p < 0.02), installation of new carpet within last 5 years (p < 0.04), and use of nail polish (p < 0.01). No relationship was found between FA exposure and urine cotinine levels. CLINICAL IMPLICATIONS: Formaldehyde exposure may increase at various times in the lives of women; however, it is of particular concern during pregnancy because of perinatal risk to the exposed fetus. PMID- 25919212 TI - Acceptability and initial efficacy of education for teen mothers. AB - PURPOSE: Educational materials used by healthcare agencies frequently do not follow national health guidelines for plain talk. Adolescent mothers are a vulnerable population in need of accurate and accessible health information to promote their own health and that of their baby. The aims of our study were to: Determine acceptability of simple, written educational pamphlets to adolescent mothers; Determine efficacy of simple, written educational pamphlets in improving an adolescent mother's knowledge related to breastfeeding, infant care, postpartum depression, and mother-infant relationship; Determine if higher knowledge scores are maintained after a 2-week period; and Determine general parenting health literacy of adolescent mothers. STUDY DESIGN AND METHODS: Using a prospective, experimental design, students enrolled in a teen parent program (n = 123) completed a pretest and The Parent Health Literacy Activities Test (PHLAT), read the health educational materials, and completed an immediate posttest of knowledge and acceptability. Two weeks later, the same participants completed a second posttest of knowledge. RESULTS: Adolescent mothers found the intervention (simple, written educational materials) to be acceptable. The intervention was initially effective in improving knowledge scores in all four content areas. However, knowledge was not retained and scores were not significantly different from baseline at the 2-week assessment. The mean health literacy of the adolescent mothers was poor. CLINICAL IMPLICATIONS: A booster session may be necessary for knowledge retention. Other methods of education should be studied to evaluate efficacy for adolescent mothers' knowledge retention of important health information. PMID- 25919213 TI - Fetal heart monitoring prior to cesarean birth. PMID- 25919214 TI - Should we diagnose psychopathology in infancy? PMID- 25919215 TI - Helping families understand portion and serving sizes. PMID- 25919216 TI - Downloading electronic health record data with a blue button or green button. PMID- 25919217 TI - Kangaroo mother care for preterm infants globally. PMID- 25919220 TI - The effects of cross-orientation masking on the visual gamma response in humans. AB - Electrophysiological recordings in primates indicate that visual gamma contains distinct broad- and narrowband components that reflect different neuronal processes. Evidence suggests that cross-orientation masking of luminance-defined gratings should differentially modulate these two components. To test this we measured the effect of cross-orientation masking on the gamma response in 12 human participants using magentoencephalography (MEG). Although both the amplitude and the frequency of gamma were modulated by the presence of a cross orientation mask, we failed to find evidence for distinguishable components: both broadband gamma at stimulus onset and sustained narrowband gamma were similarly modulated by mask contrast. However, we could not confirm the presence of masking effects due to mask contrast being confounded with the contrast of the stimulus as a whole. We therefore tested a further 12 participants in a second experiment in which the stimuli were: a plaid stimulus, the two component gratings which formed the plaid and the same two gratings but with Michelson contrast matched to the plaid. We found that gamma amplitude was reduced and gamma frequency increased to the plaid stimulus when compared with the contrast-matched gratings or with the sum of the two component gratings, indicating that visual gamma was indeed modulated by cross-orientation masking. Surprisingly, masking did not affect the pattern-onset evoked response, challenging previous hypotheses that cross-orientation suppression - the phenomenon by which the response to an orientated grating is suppressed by a cross-orientation mask - is driven by feedforward inputs to V1. PMID- 25919221 TI - Response to: lower-dose valganciclovir for prevention of cytomegalovirus after solid organ transplant: an important tradeoff. PMID- 25919222 TI - MnO2 nanosheets based fluorescent sensing platform with organic dyes as a probe with excellent analytical properties. AB - Manganese dioxide (MnO2) nanosheets have recently been demonstrated to be particularly attractive for fluorescent sensing and imaging; however, almost all MnO2 nanosheets-based fluorescent assays have been developed with emissive nanoparticles as the probes. In this study, we developed a novel strategy to use organic dyes, instead of emissive nanoparticles, as the probe to construct a platform for biosensing with excellent analytical properties. With 5 carboxyfluorescein (FAM) as a model organic dye, we firstly investigate the effect of MnO2 nanosheets on the fluorescence of FAM and find that the fluorescence intensity of FAM is considerably suppressed by MnO2 nanosheets based on the inner filter effect (IFE). To demonstrate that the MnO2 nanosheets-based fluorescence sensing platform can easily achieve a high selectivity with organic dyes as the probe, we use single-stranded DNA (ssDNA) oligonucleotide as a typical biorecognition unit, which is labeled with the FAM probe to form FAM ssDNA. The fluorescent intensity of FAM-ssDNA is first suppressed by MnO2 nanosheets through the combination of IFE and Forster resonant energy transfer (FRET), and then recovered with subsequent hybridization with the complementary DNA oligonucleotide. To demonstrate the potential applications of the MnO2 nanosheets-based fluorescence sensing platform with organic dyes as the probes, we developed methods for simple but effective microRNA and thrombin assays. With the platform demonstrated here, the limits of detection for miR124a and thrombin are 0.8 nM and 11 nM, respectively. Moreover, the fluorescent sensing assay for thrombin exhibits high selectivity. This study essentially demonstrates a new 2D nanostructure-based fluorescent sensing platform that is robust, technically simple, and easily manipulated to achieve high selectivity and sensitivity for practical applications. PMID- 25919223 TI - Investigation of epothilone B-induced cell death mechanisms in human epithelial cancer cells -in consideration of combined treatment with ionizing radiation. AB - Epothilone B was shown to have promising chemo- and radiosensitizing effects on cells, but the mechanisms underlying cell death remain ambiguous. The aim of the study was to examine selected cell death pathways on the basis of FaDu and A549 cells. Western blot analyses were used for investigation of specific apoptotic markers. Immunofluorescence imaging and flow cytometry were utilized for examination of cell death mechanisms. DNA-staining was used for studying influence of epothilone B on micronucleus rate. We showed that epothilone B can initiate cell death via apoptosis and mitotic catastrophe, but induction of cell death was cell type specific. PMID- 25919224 TI - Mussel-adhesive-inspired fabrication of multifunctional silver nanoparticle assemblies. AB - The assembly of metal nanoparticles (NPs) has attracted a great deal of attention recently because of their collective properties that could not be exhibited by individual NPs. Here a one-step approach was reported for the fabrication of spherical silver NP assemblies (AgNAs). The formation of AgNAs simply included the stirring of silver ammonia and 3,4-dihydroxy-l-phenylalanine (DOPA) in aqueous solution at room temperature, in which DOPA acted as a reductant for AgNPs first because of its reducing ability and then directed the assembly of AgNPs into AgNAs. The AgNAs exhibited hierarchical structure with controllable sizes ranging from 180 to 610 nm by adjusting the concentrations of reagents. The two individual components, AgNPs and polyDOPA, also allowed AgNAs with multiple functions as demonstrated in this study of durable catalytic activity, high SERS sensitivity, and good antioxidant properties. The thin polyDOPA layer coated on AgNAs further offered the opportunity to modify the surface of AgNAs. The results presented here may provide a green and facile approach to designing multifunctional NP assemblies. PMID- 25919225 TI - Impacts of a farmers' market incentive programme on fruit and vegetable access, purchase and consumption. AB - OBJECTIVE: The present study examines the impact of Health Bucks, a farmers' market incentive programme, on awareness of and access to farmers' markets, and fruit and vegetable purchase and consumption in low-income New York City neighbourhoods. DESIGN: The evaluation used two primary data collection methods: (i) an on-site point-of-purchase survey of farmers' market shoppers; and (ii) a random-digit-dial telephone survey of residents in neighbourhoods where the programme operates. Additionally, we conducted a quasi-experimental analysis examining differential time trends in consumption before and after programme introduction using secondary Community Health Survey (CHS) data. SETTING: New York City farmers' markets and communities. SUBJECTS: Farmers' market shoppers (n 2287) completing point-of-purchase surveys in a representative sample of New York City farmers' markets in 2010; residents (n 1025) completing random-digit-dial telephone survey interviews in 2010; and respondents (n 35 606) completing CHS interviews in 2002, 2004, 2008 and 2009. RESULTS: Greater Health Bucks exposure was associated with: (i) greater awareness of farmers' markets; (ii) increased frequency and amount of farmers' market purchases; and (iii) greater likelihood of a self-reported year-over-year increase in fruit and vegetable consumption. However, our CHS analysis did not detect impacts on consumption. CONCLUSIONS: While our study provides promising evidence that use of farmers' market incentives is associated with increased awareness and use of farmers' markets, additional research is needed to better understand impacts on fruit and vegetable consumption. PMID- 25919226 TI - (211)Astatine-Conjugated Monoclonal CD45 Antibody-Based Nonmyeloablative Conditioning for Stem Cell Gene Therapy. AB - Most hematopoietic stem cell gene therapy studies require host conditioning to allow for efficient engraftment of gene-modified cells. Conditioning regimens with lower treatment-related toxicities are especially relevant for the treatment of nonmalignant blood disorders, such as hemoglobinopathies and immunodeficiencies, and for patients who are otherwise ineligible for conventional high-dose conditioning. Radioimmunotherapy, which employs an alpha- or a beta-emitting radionuclide conjugated to a targeting antibody, is effective for delivering cytotoxic doses of radiation to a cell type of interest while minimizing off-target toxicity. Here, we demonstrate the feasibility of using a nonmyeloablative dose of a monoclonal anti-CD45 antibody conjugated to the alpha emitter Astatine-211 ((211)At) to promote engraftment of an autologous gene modified stem cell graft in the canine model. The doses used provided myelosuppression with rapid autologous recovery and minimal off-target toxicity. Engraftment levels were low in all dogs and reflected the low numbers of gene modified cells infused. Our data suggest that a cell dose exceeding 1*10(6) cells/kg be used with nonmyeloablative doses of (211)At-anti-CD45 monoclonal antibodies for sustained engraftment in the dog model. PMID- 25919227 TI - Fat, fibre and cancer risk in African Americans and rural Africans. AB - Rates of colon cancer are much higher in African Americans (65:100,000) than in rural South Africans (<5:100,000). The higher rates are associated with higher animal protein and fat, and lower fibre consumption, higher colonic secondary bile acids, lower colonic short-chain fatty acid quantities and higher mucosal proliferative biomarkers of cancer risk in otherwise healthy middle-aged volunteers. Here we investigate further the role of fat and fibre in this association. We performed 2-week food exchanges in subjects from the same populations, where African Americans were fed a high-fibre, low-fat African-style diet and rural Africans a high-fat, low-fibre western-style diet, under close supervision. In comparison with their usual diets, the food changes resulted in remarkable reciprocal changes in mucosal biomarkers of cancer risk and in aspects of the microbiota and metabolome known to affect cancer risk, best illustrated by increased saccharolytic fermentation and butyrogenesis, and suppressed secondary bile acid synthesis in the African Americans. PMID- 25919229 TI - Bendable and thin sulfide solid electrolyte film: a new electrolyte opportunity for free-standing and stackable high-energy all-solid-state lithium-ion batteries. AB - Bulk-type all-solid-state lithium batteries (ASLBs) are considered a promising candidate to outperform the conventional lithium-ion batteries. Unfortunately, the current technology level of ASLBs is in a stage of infancy in terms of cell based (not electrode-material-based) energy densities and scalable fabrication. Here, we report on the first ever bendable and thin sulfide solid electrolyte films reinforced with a mechanically compliant poly(paraphenylene terephthalamide) nonwoven (NW) scaffold, which enables the fabrication of free standing and stackable ASLBs with high energy density and high rate capabilities. The ASLB, using a thin (~70 MUm) NW-reinforced SE film, exhibits a 3-fold increase of the cell-energy-density compared to that of a conventional cell without the NW scaffold. PMID- 25919228 TI - Examining Contextual Influences on Fall-Related Injuries Among Older Adults for Population Health Management. AB - The objectives were to assess the associations between fall-related injuries (FRIs) treated in the emergency department (ED) among older adults in California and contextual county-level physical, social, and economic characteristics, and to assess how county-level economic conditions are associated with FRIs when controlling for other county-level factors. Data from 2008 California ED discharge, Medicare Impact File, and County Health Rankings were used. Random effects logistic regression models estimated contextual associations between county-level factors representing economic conditions, the built environment, community safety, access to care, and obesity with patient-level FRI treatment among 1,712,409 older adults, controlling for patient-level and hospital-level characteristics. Patient-level predictors of FRI treatment were consistent with previous studies not accounting for contextual associations. Larger and rural hospitals had higher odds of FRI treatment, while teaching and safety net hospitals had lower odds. Better county economic conditions were associated with greater odds (beta=0.73, P=0.001) and higher county-level obesity were associated with lower odds (beta=-0.37, P=0.004), but safer built environments (beta=-0.31, P=0.38) were not associated with FRI treatment. The magnitude of association between county-level economic conditions and FRI treatment attenuated with the inclusion of county-level obesity rates. FRI treatment was most strongly and consistently related to more favorable county economic conditions, suggesting differences in treatment or preferences for treatment for FRIs among older individuals in communities of varying resource levels. Using population health data on FRIs, policy makers may be able to remove barriers unique to local contexts when implementing falls prevention educational programs and built environment modifications. PMID- 25919230 TI - Molecular cytotoxicity mechanisms of allyl alcohol (acrolein) in budding yeast. AB - Allyl alcohol (AA) is one of the environmental pollutants used as a herbicide and industrial chemical. AA undergoes enzymatic oxidation in vivo to form Acrolein (Acr), a highly reactive and ubiquitous environmental toxicant. The exposure to AA/Acr has detrimental effects on cells and is highly fatal. In corroboration to the current literature describing AA/Acr toxicity, this study aimed to investigate the molecular cytotoxicity mechanisms of AA/Acr using budding yeast as a eukaryotic model organism. Genome-wide transcriptome analysis of cells treated with a sublethal dose of AA (0.4 mM) showed differential regulation of approximately 30% of the yeast genome. Functional enrichment analysis of the AA transcriptome revealed that genes belong to diverse cellular processes including the cell cycle, DNA damage repair, metal homeostasis, stress response genes, ribosomal biogenesis, metabolism, meiosis, ubiquitination, cell morphogenesis, and transport. Moreover, we have identified novel molecular targets of AA/Acr through genetic screening, which belongs to oxidative stress, DNA damage repair, iron homeostasis, and cell wall integrity. This study also demonstrated the epigenetic basis of AA/Acr toxicity mediated through histone tails and chromatin modifiers. Interestingly, our study disclosed the use of pyrazole and ethanol as probable antidotes for AA intoxication. For the first time, this study also demonstrated the reproductive toxicity of AA/Acr using the yeast gametogenesis (spermatogenesis) model. Altogether, this study unravels the molecular mechanisms of AA/Acr cytotoxicity and facilitates the prediction of biomarkers for toxicity assessment and therapeutic approaches. PMID- 25919232 TI - IVF: a short but exciting story. PMID- 25919233 TI - Genetics of premature ovarian failure. AB - PURPOSE OF REVIEW: To provide an overview on the genetic basis of premature ovarian failure (POF) with specific attention to recently published molecular genetic studies. RECENT FINDINGS: POF is an insidious cause of female infertility. Despite enormous efforts to understand the genetic pathogenesis, we know almost nothing but Turner syndrome and Fragile X syndrome. The era of genome wide association studies opened a new window into the understanding of the complex, polygenic nature of ovarian failure by identifying several candidate regions. Most of the genes in these regions are waiting for confirmation in isolated POF cohorts. Recently, molecular evidence on the regulatory role of small noncoding RNAs in folliculogenesis and oocyte development began to emerge. The association between certain microRNA polymorphisms and POF has been reported. SUMMARY: Although there exist numerous candidate genes in the literature, a few of them have comprehensive and consistent molecular workup that showed strong genotype/phenotype association. PMID- 25919234 TI - Ovarian response biomarkers: physiology and performance. AB - PURPOSE OF REVIEW: This review summarizes recent technological developments in the measurement of anti-Mullerian hormone (AMH) and presents an update of the relative performance characteristics of both AMH and antral follicle count (AFC) in predicting the ovarian response to controlled stimulation. RECENT FINDINGS: The introduction of two automated AMH immunoassays appears to have resolved the majority of preanalytical and analytical limitations of the manual assays thereby facilitating the delivery of consistent and accurate results. However, as they exhibit different calibration from preexisting assays, derivation of new reference ranges and clinical thresholds for prediction of ovarian response categories will be required. Randomized controlled trials have highlighted the superiority of AMH to AFC in ovarian response prediction and provide a sound basis for its ongoing assessment for stratification and personalization of treatment. SUMMARY: Trial evidence combined with full automation of AMH assay measurement suggests that the future for ovarian response prediction will be AMH focused. Sonography will continue to be invaluable for the identification of tubal, ovarian and endometrial pathologies, but the days of counting follicles are numbered. PMID- 25919235 TI - Random-start ovarian stimulation in patients with cancer. AB - PURPOSE OF REVIEW: Awaiting menses to start ovarian stimulation for oocyte/embryo cryopreservation in patients with cancer may result in a significant delay of cancer treatment that may lead to patients forgoing fertility preservation. The purpose of this review is to describe the new protocols to facilitate the start of ovarian stimulation, including random-start ovarian stimulation. RECENT FINDINGS: In random-start protocols, the number of total and mature oocytes retrieved, oocyte maturity rate, mature oocyte yield and fertilization rates are similar to those in conventional (early follicular phase start) protocols. Starting ovarian stimulation in the late follicular or luteal phase did not show any superiority against the other. The presence of corpus luteum or luteal phase progesterone levels did not adversely affect synchronized follicular development, number of mature oocytes retrieved, and/or fertilization rates. SUMMARY: Random start ovarian stimulation provides a significant advantage by decreasing total time for the IVF cycle, and in emergent settings, ovarian stimulation can be started at a random cycle date for the purpose of fertility preservation without compromising oocyte yield and maturity. PMID- 25919238 TI - Keep Using My Health Apps: Discover Users' Perception of Health and Fitness Apps with the UTAUT2 Model. AB - BACKGROUND: Health and fitness applications (apps) are one of the major app categories in the current mobile app market. Few studies have examined this area from the users' perspective. This study adopted the Extended Unified Theory of Acceptance and Use of Technology (UTAUT2) Model to examine the predictors of the users' intention to adopt health and fitness apps. MATERIALS AND METHODS: A survey (n=317) was conducted with college-aged smartphone users at a Midwestern university in the United States. RESULTS: Performance expectancy, hedonic motivations, price value, and habit were significant predictors of users' intention of continued usage of health and fitness apps. However, effort expectancy, social influence, and facilitating conditions were not found to predict users' intention of continued usage of health and fitness apps. CONCLUSIONS: This study extends the UTATU2 Model to the mobile apps domain and provides health professions, app designers, and marketers with the insights of user experience in terms of continuously using health and fitness apps. PMID- 25919237 TI - Neural Stem Cells in the Adult Subventricular Zone Oxidize Fatty Acids to Produce Energy and Support Neurogenic Activity. AB - Neural activity is tightly coupled to energy consumption, particularly sugars such as glucose. However, we find that, unlike mature neurons and astrocytes, neural stem/progenitor cells (NSPCs) do not require glucose to sustain aerobic respiration. NSPCs within the adult subventricular zone (SVZ) express enzymes required for fatty acid oxidation and show sustained increases in oxygen consumption upon treatment with a polyunsaturated fatty acid. NSPCs also demonstrate sustained decreases in oxygen consumption upon treatment with etomoxir, an inhibitor of fatty acid oxidation. In addition, etomoxir decreases the proliferation of SVZ NSPCs without affecting cellular survival. Finally, higher levels of neurogenesis can be achieved in aged mice by ectopically expressing proliferator-activated receptor gamma coactivator 1 alpha (PGC1alpha), a factor that increases cellular aerobic capacity by promoting mitochondrial biogenesis and metabolic gene transcription. Regulation of metabolic fuel availability could prove a powerful tool in promoting or limiting cellular proliferation in the central nervous system. Stem Cells 2015;33:2306-2319. PMID- 25919239 TI - Histogram analysis of apparent diffusion coefficient at 3.0t: Correlation with prognostic factors and subtypes of invasive ductal carcinoma. AB - PURPOSE: To evaluate apparent diffusion coefficient (ADC) histogram parameters that show correlations with prognostic factors and subtypes of breast cancer. MATERIALS AND METHODS: At 3.0T, various ADC histogram parameters were calculated including the entire tumor volume in 173 invasive ductal carcinomas: the minimum, 10th percentile, mean, median, 90th percentile, and maximum. ADC parameters were correlated with prognostic factors and subtype. RESULTS: The mean ADCmedian value was significantly higher in the group with lymph node metastasis, HER2 positivity, and a Ki-67 value <14% than in the group with negativity for lymph node metastasis, HER2 negativity, and a Ki-67 value >=14% (0.907, 0.978, and 0.941 vs. 0.735, 0.778, and 0.761 * 10(-3) mm(2) /s, respectively) (P < 0.01). There was no significant correlation between ADCmedian and tumor size, histologic grade, estrogen receptor expression, and progesterone receptor expression (P = 0.272, 0.113, 0.261, and 0.181, respectively). For most ADC parameters except for ADCmin , the mean of variable ADC parameters of HER2-positive, luminal A, luminal B-HER2(+), triple-negative, and luminal B-HER2(-) diseases were arranged in descending order (1.175, 0.936, 0.863, 0.811, and 0.665 * 10(-3) mm(2) /s in ADCmedian , respectively) with statistical significant difference (P < 0.001). In multivariate analysis, histologic grade, the Ki-67 index, and HER2 expression were statistically significant explanatory prognostic factors for ADCmedian and the Ki-67 index had the most robust effects on ADC parameters (standardized coefficient = -0.317). CONCLUSION: Various ADC parameters were correlated with prognostic factors and subtype, except for ADCmin . HER2 positivity showed high ADC values and high Ki-67 index revealed low ADC values. PMID- 25919240 TI - Genetic Evaluation of Copy Number Variations, Loss of Heterozygosity, and Single Nucleotide Variant Levels in Human Embryonic Stem Cells With or Without Skewed X Chromosome Inactivation. AB - Human embryonic stem cells (hESCs) exhibiting skewed X chromosome inactivation (XCI) have been reported. The copy number variations (CNVs), loss of heterozygosity (LOH), or single-nucleotide variant (SNV) events in those epigenetically distinct cells remain unknown, and whether such genetic abnormalities will influence the XCI status of hESCs is unclear. In this study, three hESCs with skewed XCI, three with random XCI, and two male hESC lines at different passages were analyzed for CNVs and LOH levels using a high-resolution genotyping microarray. Whole-exome sequencing was used to investigate the potentially damaging SNVs. On average, 17.6 CNVs and 5.3 cases of LOH were identified in the skewed hESCs, which were similar to the rates observed in random hESCs. Five recurrent CNV regions were uniquely identified in the skewed hESCs, but all of them were considered polymorphisms. With the exception of a nongenic CNV, no additional CNVs were detected on the X chromosome in the skewed hESCs. Although the XCI status in two hESC lines was observed to be changed from random to skewed, no significant CNV difference was identified before and after the XCI change. SNV analysis indicated that normal alleles are maintained for most genes within copy-neutral LOH regions. Three types of expression patterns were observed in heterozygous alleles, and the damaging SNVs in skewed hESCs favored the expression of the wild-type alleles. In conclusion, in the present study, we did not find genetic differences in the CNV and LOH levels between hESCs with and without skewed XCI. Wild-type allele expression in the presence of damaging SNVs on the X chromosome in skewed hESCs might alleviate adverse effects in those hESCs. PMID- 25919241 TI - A case-controlled study of the oncologic safety of fat grafting. AB - BACKGROUND: Currently, there is no clinical evidence of oncologic risk associated with fat grafting, although its safety has been questioned. The authors investigated the risk of relapse associated with fat grafting in women with a history of breast cancer. METHODS: Of 328 women with previously treated malignant breast disease who underwent fat grafting at the Nottingham Breast Institute, complete data were available for 211 (invasive carcinoma, n = 184; ductal carcinoma in situ, n = 27). Mean follow-up was 88 months after primary cancer surgery and 32 months after fat grafting. Control subjects were matched 2:1 for date of primary cancer operation (within 2 years), age (within 5 years), type of surgery, tumor histology, estrogen receptor status, and disease-free status by time equivalent to that of fat grafting. Final endpoints were tumor recurrence and death. Outcome results were compared with a systematic review of all patients undergoing fat grafting with adequate follow-up reported in the literature. RESULTS: No significant excess oncologic events were observed in patients who had fat grafting compared to controls with regard to local (0.95 percent versus 1.90 percent; p = 0.33), regional (0.95 percent versus 0 percent; p = 0.16), and distant recurrences (3.32 percent versus 2.61 percent; p = 0.65). A systematic review identified case series with a total of 1573 women who had fat grafting after primary oncologic breast surgery. The locoregional relapse rate for these patients was 2.92 percent (0.95 percent per year). CONCLUSION: This study has found no evidence of increased oncologic risk associated with fat grafting in women previously treated for breast cancer. CLINICAL QUESTION/LEVEL OF EVIDENCE: Risk, II. PMID- 25919242 TI - Breast reduction in patients with prior breast irradiation: outcomes using a central mound technique. AB - BACKGROUND: Breast reduction in patients with a history of lumpectomy and irradiation is controversial because of a heightened risk of infection and wound healing complications. Persistent macromastia or asymmetry remains a problem in this patient population that is commonly not addressed. The authors studied the safety and efficacy of a central mound technique with minimal dissection for breast reduction or mastopexy in patients with a history of breast irradiation. METHODS: A case-control study of all patients undergoing bilateral breast reduction mammaplasty between 2008 and 2013 at Memorial Sloan Kettering Cancer Center was conducted. Patients who had unilateral breast irradiation and bilateral reduction using the central mound technique were included. Each patient had a control breast and an irradiated breast. Complications and outcomes were analyzed. RESULTS: Thirteen patients were included for analysis. Their average age was 50.23 +/- 9.9 years, and average time from irradiation to breast reduction mammaplasty was 41.3 +/- 48.5 months (range, 9 to 132 months). The average specimen weight of irradiated breasts was less than that of control breasts; however, this failed to reach statistical significance (254.2 +/- 173.5 g versus 386.9 +/- 218.5 g; p = 0.099). One patient developed fat necrosis in the previously irradiated breast and underwent biopsy. There was no incidence of nipple necrosis or breast cancer in either irradiated or nonirradiated breasts. CONCLUSIONS: Breast reduction mammaplasty in patients who have had irradiation is feasible and can be performed safely in select cases. The central mound technique provides reliable and reproducible results and should be considered in patients with macromastia/asymmetry and a history of irradiation. CLINICAL QUESTION/LEVEL OF EVIDENCE: Therapeutic, III. PMID- 25919243 TI - Effect of federal and state policy changes on racial/ethnic variation in immediate postmastectomy breast reconstruction. AB - BACKGROUND: Breast reconstruction after mastectomy has been shown to provide substantial clinical and psychosocial benefits for many patients; however, disparities in the use of immediate postmastectomy breast reconstruction persist. Using the unique dataset from the New York State Inpatient Database, the following developments were studied: (1) trends in immediate postmastectomy breast reconstruction between 1998 and 2006 among white, African American, and Hispanic women; (2) factors associated with its use; and (3) changes in racial/ethnic variation in immediate postmastectomy breast reconstruction before and after implementation of the New York State Medicaid expansion in 2001. METHODS: A step-in multivariable logistic regression model was used to assess the effect of race/ethnicity, age, mastectomy type, number of comorbidities, socioeconomic status, and insurance on the probability of undergoing immediate postmastectomy breast reconstruction. Then, adjusted immediate postmastectomy breast reconstruction rates for before and after Medicaid expansion were predicted, stratified by race/ethnicity. RESULTS: The probability of undergoing immediate postmastectomy breast reconstruction increased (p < 0.001); however, even with Medicaid expansion occurring during the 8 years studied, gaps in use between white and African American women and between white and Hispanic women increased by 6 percent (95% CI, 0.07 to 0.05) and 5 percent (95% CI, 0.07 to 0.04), respectively. Being younger, having greater income and education, and having private health insurance are associated with a greater probability of immediate postmastectomy breast reconstruction. CONCLUSION: These findings indicate that expanding safety-net policies such as Medicaid without providing support such as consultation or health literacy education might not be effective in reducing disparities in health care. CLINICAL QUESTION/LEVEL OF EVIDENCE: Risk, III. PMID- 25919244 TI - Midface rejuvenation: a critical evaluation of a 7-year experience. AB - BACKGROUND: Although "traditional" face-lifting techniques can achieve excellent improvement along the jawline and neck, they often have little impact on the midface area. Thus, many different types of procedures have been developed to provide rejuvenation in this region, usually contemplating various dissection planes, incisions, and suspension vectors. METHODS: A 7-year observational study of 350 patients undergoing midface lift was analyzed. The authors suspended the midface flap, anchoring to the deep temporal aponeurosis with a suspender-like suture (superolateral vector), or directly to the lower orbital rim with a belt like suture (superomedial vector). Subjective and objective methods were used to evaluate the results. The subjective methods included a questionnaire completed by the patients. The objective method involved the evaluation of preoperative and postoperative photographs by a three-member jury instructed to compare the "critical" anatomical areas of the midface region: malar eminence, nasojugal groove, nasolabial fold, and jowls in the lower portion of the cheeks. The average follow-up period was 24 months. RESULTS: High satisfaction was noticeable from the perceptions of both the jury and the patients. Objective evaluation evidenced that midface lift with temporal anchoring was more efficient for the treatment of malar eminence, whereas midface lift with transosseous periorbital anchoring was more efficient for the treatment of nasojugal groove. CONCLUSIONS: The most satisfying aspect of the adopted techniques is a dramatic facial rejuvenation and preservation of the patient's original youthful identity. Furthermore, choosing the most suitable technique respects the patient's needs and enables correction of the specific defects. CLINICAL QUESTION/LEVEL OF EVIDENCE: Therapeutic, IV. PMID- 25919245 TI - Anatomical considerations to prevent facial nerve injury. AB - Injury to the facial nerve during a face lift is a relatively rare but serious complication. A large body of literature has been dedicated toward bettering the understanding of the anatomical course of the facial nerve and the relative danger zones. Most of these prior reports, however, have focused on identifying the location of facial nerve branches based on their trajectory mostly in two dimensions and rarely in three dimensions. Unfortunately, the exact location of the facial nerve relative to palpable or visible facial landmarks is quite variable. Although the precise location of facial nerve branches is variable, its relationship to soft-tissue planes is relatively constant. The focus of this report is to improve understanding of facial soft-tissue anatomy so that safe planes of dissection during surgical undermining may be identified for each branch of the facial nerve. Certain anatomical locations more prone to injury and high-risk patient parameters are further emphasized to help minimize the risk of facial nerve injury during rhytidectomy. PMID- 25919246 TI - A Prospective, Split-Face, Randomized, Double-Blind Study Comparing OnabotulinumtoxinA to IncobotulinumtoxinA for Upper Face Wrinkles. AB - BACKGROUND: The authors sought to compare the newest U.S. Food and Drug Administration-approved botulinum toxin type A product, incobotulinumtoxinA, to onabotulinumtoxinA for upper face wrinkles. This is the first prospective, split face, randomized, double-blind study addressing three types of facial wrinkles using a 1:1 dose ratio. METHODS: The study was designed, institutional review board approval was obtained, and 45 patients were enrolled. A three-judge independent reviewer panel compared photographs of patients to the upper face validated assessment scales, selecting a grade ranging from 0 (no lines) to 4 (very severe) for the degree of glabellar lines, crow's feet, and forehead lines for each side of the face for photographs taken before treatment and 3 days, 2 weeks, 3 months, and 4 months after treatment. For toxin comparison, the difference in the magnitude of the degree of wrinkle scale at each period compared to before treatment was calculated and statistical analysis performed. Individual wrinkle types and all three wrinkle types combined were analyzed. RESULTS: Both products offered significant reduction in individual and combined wrinkles at comparable time points; however, onabotulinumtoxinA had significantly greater combined dynamic wrinkle reduction at 3 days (p < 0.010), 2 weeks (p < 0.008), 3 months (p < 0.013), and 4 months (p < 0.045). CONCLUSIONS: For identical dosage, both onabotulinumtoxinA and incobotulinumtoxinA are safe and effective in reducing dynamic wrinkles in the upper face; however, for the authors' dosages, onabotulinumtoxinA had statistically greater efficacy at 3 days, 2 weeks, 3 months, and 4 months. CLINICAL QUESTION/LEVEL OF EVIDENCE: Therapeutic, II. PMID- 25919247 TI - Desmopressin as a hemostatic agent to provide a dry intraoperative field in rhinoplasty. AB - BACKGROUND: Intraoperative bleeding during rhinoplasty makes it difficult to sculpt cartilages. Residual blood from a wet field can lead to induration, fibrosis, and definition loss. Recent studies with desmopressin (1-deamino-8-D arginine vasopressin) to reduce blood loss in a variety of operations and minimize postoperative bleeding problems suggest using that drug routinely for elective rhinoplasty and not just for patients with coagulation issues. METHOD: Seventy-three consecutive rhinoplasty patients received desmopressin for the purpose of obtaining a dry operative field. The initial dose was 0.1 MUg/kg. If the field was not as dry as desired, a second dose was given; if necessary, a third dose to a maximum of 0.3 MUg/kg was given. All cases exhibited a satisfactorily dry field. There were no adverse effects. A retrospective comparison was made to 300 consecutive cases not receiving desmopressin. RESULTS: Thirty of the 73 patients received a starting dose of 0.1 MUg/kg and nothing more. Fourteen received a second dose of 0.1 MUg/kg because the field was not as dry as desired and 29 received a third dose of 0.1 MUg/kg because the field was not as dry as desired. All 73 patients exhibited a satisfactorily dry field, in contrast to 9 percent in the group not receiving desmopressin. CONCLUSIONS: This study confirms the hemostatic effectiveness of desmopressin at lower than normally used doses in rhinoplasty. It also confirms its safety. It suggests its use in other procedures. A larger, carefully controlled study is indicated. CLINICAL QUESTION/LEVEL OF EVIDENCE: Therapeutic, III. PMID- 25919248 TI - Precision in otoplasty: combining reduction otoplasty with traditional otoplasty. AB - BACKGROUND: Otoplasty for prominent ears is a routine procedure that is generally met with satisfaction by patients and family members. A significant percentage of patients requesting otoplasty, however, have some degree of macrotia in addition to protruding ears. Combining ear reduction with traditional otoplasty allows correction of these deformities. There are few studies in the literature that describe ear reduction, and those that do, describe small subsets of patients. METHODS: A retrospective review was performed of the senior author's (C.H.T.) otoplasty procedures from 2010 to 2013. Charts were reviewed for patient demographics, preoperative assessment, surgical technique used, complications, and need for revision. All otoplasty procedures, primary or secondary, were included in the series. RESULTS: Over a 3-year period, 84 total otoplasty procedures were performed. Of these, 30 patients had some degree of scaphal reduction as a component of the procedure. Five patients (6 percent) also had shortening of the earlobes in addition to the scaphal reduction. Nineteen of the patients (23 percent) had an otoplasty previously (none performed by the senior author) but were not completely satisfied. Complications of reduction otoplasty were limited to a single patient with a suture protrusion behind the ear. None of the patients in this series have required reoperation. CONCLUSIONS: Scaphal reduction to modify the contour of the upper auricle and/or decrease the overall size of the ear can be a valuable adjunct to otoplasty and may be indicated in a larger than expected percentage of patients presenting for otoplasty. CLINICAL QUESTION/LEVEL OF EVIDENCE: Therapeutic, IV. PMID- 25919249 TI - Diagnosis and management of galactorrhea after breast augmentation. AB - BACKGROUND: A known but not fully understood complication of breast augmentation is galactorrhea. To date, all publications on this subject have been case reports. The purpose of this retrospective study was to examine a large group of consecutive patients who had undergone breast augmentation and identify the incidence of galactorrhea and galactocele, and the associated preoperative and intraoperative risk factors. The authors also evaluated the treatment algorithm used. METHODS: A retrospective chart review was performed on patients who underwent primary breast augmentation using silicone implants in a single group practice from 2008 to 2013. Logistic regression for rare events data was applied to evaluate the risk of galactorrhea according to the variables. RESULTS: The study included 832 patients (1664 implants) who had undergone breast augmentation. The follow-up period ranged from 12 to 52 months (mean, 15 months). Eight patients (0.96 percent; 95 percent CI, 0.42 to 1.89) experienced galactorrhea after breast augmentation during the follow-up period. All eight patients had bilateral involvement, and three (0.36 percent of the total and 38 percent of the galactorrhea cases) presented with a galactocele. Use of a periareolar incision, however, statistically significantly increased the incidence of galactorrhea among these patients. The authors' management algorithm proved to be an effective clinical course of action. CONCLUSIONS: Although galactorrhea is rare after breast augmentation, it can be disfiguring and devastating for the patient. This is the first longitudinal retrospective study on the subject. Adequate treatment and patient information are essential. CLINICAL QUESTION/LEVEL OF EVIDENCE: Therapeutic, III. PMID- 25919250 TI - Safely combining abdominoplasty with aggressive abdominal liposuction based on perforator vessels: technique and a review of 300 consecutive cases. AB - BACKGROUND: There continues to be controversy about performing abdominoplasty concurrently with abdominal liposuction. The concern is that liposuction on the already vascularly compromised abdominal flap will lead to increased complications and flap necrosis. The central abdomen is supplied by the epigastric system. If perforator vessels from this system are spared, the blood supply to the abdomen can be spared and liposuction should be able to be safely performed on the elevated abdominal flap. The purpose of this study was to evaluate the safety of abdominoplasty with concurrent abdominal liposuction when a perforator vessel is spared. METHODS: A standard abdominoplasty was performed, sparing one or two perforator vessels from the deep superior epigastric artery system. A retrospective chart review of 300 consecutive patients who underwent abdominoplasty surgery combined with concurrent abdominal liposuction was performed. Complications, total volume of abdominal liposuction, and results were reviewed. RESULTS: The overall complication rate was 17.3 percent (52 patients). Sixteen percent (48 patients) suffered minor complications and 1.3 percent (four patients) suffered major complications. CONCLUSIONS: Abdominoplasty can be combined safely with concurrent abdominal liposuction when a perforator vessel is spared. The combination of concurrent liposuction with abdominoplasty showed no increase in complication rates when a perforator vessel was spared. The perforator vessels are located consistently in a 2-cm radius located 4 cm from the midline and 6 cm from the subcostal margin. The potential advantages of abdominoplasty with concurrent liposuction include a better postoperative cosmetic result. CLINICAL QUESTION/LEVEL OF EVIDENCE: Therapeutic, IV. PMID- 25919251 TI - Laser lipolysis: skin tightening in lipoplasty using a diode laser. AB - BACKGROUND: New devices have been developed for surgical repair of deformities caused by localized fat deposits associated with skin laxity. The use of these devices requires the adoption of safety parameters. The aim of this study was to investigate skin tightening by laser lipolysis, using a dual-wavelength diode laser. METHODS: This prospective, cross-sectional study was conducted between June of 2008 and July of 2010 with 41 consecutive patients who underwent laser lipolysis to correct contour deformities. Laser lipolysis was performed with a diode laser operating at two wavelengths (924 and 975 nm) controlled independently, and using three different tip lengths, allowing treatment of small, medium, and large areas of adipose tissue. The procedure was performed under local anesthesia in a surgical setting. To calculate the optimal cumulative energy, a total energy dose of 5 kJ/10 * 10-cm skin area was used as a safety parameter to prevent treatment complications. The circumferences of body regions were measured preoperatively, immediately after surgery, and 90 days later. Measurements were compared using the Wilcoxon test at a significance level of 0.05 (p < 0.05). RESULTS: A significant skin tightening was observed in all patients, regardless of the body site involved (i.e., face, breast, arms, or waist regions), and no complications occurred. CONCLUSION: Laser lipolysis results in progressive skin tightening over time. CLINICAL QUESTION/LEVEL OF EVIDENCE: Therapeutic, IV. PMID- 25919252 TI - Discussion: laser lipolysis: skin tightening in lipoplasty using a diode laser. PMID- 25919253 TI - Gluteoplasty with autologous fat tissue: experience with 106 consecutive cases. AB - BACKGROUND: The female waist-hip ratio of around 0.7 is reachable through liposuction and gluteal fat grafting. The authors evaluated the reliability of this technique. METHODS: Prospective evaluation was performed of all female patients subjected to gluteoplasty with autologous fat tissue between July of 2010 and July of 2013 without a weight change greater than 10 percent during follow-up. Results were evaluated through photographs. The degree of satisfaction (patient and surgeon) was assessed on a scale of 1 (poor outcome) to 4 (excellent improvement), and agreement was measured by Kappa statistics. The technique involved epidural anesthesia, tumescent infiltration, liposuction around the buttocks, fat decantation, and grafting with retrograde injection in different planes. RESULTS: A total of 106 patients were included. Patient age ranged between 18 and 62 years (mean, 33 years). The preoperative body mass index was between 19 and 31.6 kg/m (mean, 24.8 kg/m). The volume grafted to the buttocks ranged between 180 and 840 cc (mean, 505 cc). There were no medical complications. Five patients (4.7 percent) had seroma in the donor area, 103 patients felt satisfied (97.1 percent), scoring 3 and 4, one patient (0.94 percent) complained of volume resorption 4 months postoperatively, and two patients (1.88 percent) asked to diminish their lateral gluteal volume (score 2) and underwent revision surgery 6 months postoperatively. CONCLUSIONS: This gluteoplasty technique is simple and inexpensive, with minimal morbidity and excellent results. A good result depends on harmoniously combining fat elimination by liposuction and fat grafting for buttocks sculpting, with lasting results. CLINICAL QUESTION/LEVEL OF EVIDENCE: Therapeutic, IV. PMID- 25919254 TI - Discussion: gluteoplasty with autologous fat tissue: experience with 106 consecutive cases. PMID- 25919255 TI - Surgical correction of gynecomastia: a geometric approach. AB - Many techniques are available for surgical correction of gynecomastia. In this article, we describe a technique based on geometrical principles that is simple to execute, effective, highly reproducible, and relies less on intuition of the surgeon. PMID- 25919256 TI - Obesity is associated with increased health care charges in patients undergoing outpatient plastic surgery. AB - BACKGROUND: Obesity is associated with greater rates of surgical complications. To address these complications after outpatient plastic surgery, obese patients may seek care in the emergency department and potentially require admission to the hospital, which could result in greater health care charges. The purpose of this study was to determine the relationship of obesity, postdischarge hospital based acute care, and hospital charges within 30 days of outpatient plastic surgery. METHODS: From state ambulatory surgery center databases in four states, all discharges for adult patients who underwent liposuction, abdominoplasty, breast reduction, and blepharoplasty were identified. Patients were grouped by the presence or absence of obesity. Multivariable regression models were used to compare the frequency of hospital-based acute care, serious adverse events, and hospital charges within 30 days between groups while controlling for confounding variables. RESULTS: The final sample included 47,741 discharges, with 2052 of these discharges (4.3 percent) being obese. Obese patients more frequently had a hospital-based acute care encounter [7.3 percent versus 3.9 percent; adjusted OR, 1.35 (95% CI,1.13 to 1.61)] or serious adverse event [3.2 percent versus 0.9 percent; adjusted OR, 1.73 (95% CI, 1.30 to 2.29)] within 30 days of surgery. Obese patients had adjusted hospital charges that were, on average, $3917, $7412, and $7059 greater (p < 0.01) than those of nonobese patients after liposuction, abdominoplasty, and breast reduction, respectively. CONCLUSION: Obese patients who undergo common outpatient plastic surgery procedures incur substantially greater health care charges, in part attributable to more frequent adverse events and hospital-based health care within 30 days of surgery. CLINICAL QUESTION/LEVEL OF EVIDENCE: Risk, II. PMID- 25919257 TI - Enhanced Contraction of a Normal Breast-Derived Fibroblast-Populated Three Dimensional Collagen Lattice via Contracted Capsule Fibroblast-Derived Paracrine Factors: Functional Significance in Capsular Contracture Formation. AB - BACKGROUND: The authors' aim was to identify morphological, genotypic, and cytokine profiles of normal breast-derived fibroblasts, noncontracted breast implant capsule (Baker grades 1 and 2) fibroblasts, and contracted breast implant capsule (Baker grades 3 and 4) fibroblasts, and to investigate the paracrine effects of contracted breast capsule fibroblast--conditioned media on a breast derived fibroblast-populated three-dimensional collagen lattice. METHODS: Primary breast-derived fibroblasts (n = 5), noncontracted breast capsule fibroblasts (n = 5), and contracted breast capsule fibroblasts (n = 5) were cultured, and conditioned media were obtained from passage 1 cells. Cells were immunostained for alpha smooth muscle actin to identify myofibroblasts. A panel of 16 inflammatory, fibrosis, extracellular matrix, and tissue remodeling-related genes were investigated using quantitative reverse transcriptase polymerase chain reaction and cytokine arrays. Fibroblast-populated collagen lattices were fabricated and treated with conditioned media, and lattice contracture was measured over 5 days. RESULTS: Several inflammatory and fibrotic genes were significantly dysregulated in contracted breast capsule fibroblasts compared with noncontracted breast capsule fibroblasts and breast-derived fibroblasts (p < 0.05). Breast-derived fibroblast-populated collagen lattices treated with contracted breast capsule fibroblast-conditioned media demonstrated increased lattice contraction compared with treatment with normal 10% serum media (control), breast-derived fibroblasts, or noncontracted breast capsule fibroblast conditioned media (p < 0.05). Breast-derived fibroblasts supplemented with contracted breast capsule fibroblast-conditioned media transformed into a contracted breast capsule fibroblast-like cell (p < 0.05). CONCLUSION: The authors show that contracted breast capsule-derived fibroblasts induce normal breast fibroblast transformation and contraction via paracrine signaling, which may contribute to capsular contracture formation. PMID- 25919258 TI - Fat grafting in primary cleft lip repair. AB - The goal of primary cleft lip repair is to unify the lip elements and achieve a nearly normal appearance. Many techniques can confer satisfactory results; however, scarring and contour irregularities may persist. Lipofilling can modulate scar formation and enable soft-tissue augmentation. The authors hypothesize that fat grafting during immediate cleft lip repair may be of benefit. Patients who underwent primary cleft lip repair with and without immediate fat grafting were compared. Postoperative photographs were analyzed by three blinded reviewers. Cronbach statistics and a two-tailed t-test were used. Scar analysis revealed statistically significant (p < 0.05) improvement in scar appearance and contour of the fat-grafted cleft lip repair. Immediate fat grafting may be a promising strategy to improve lip appearance, contour, and scarring during primary cleft lip repair. CLINICAL QUESTION/LEVEL OF EVIDENCE: Therapeutic, III. PMID- 25919259 TI - Craniofacial fellowship training: where are we now? AB - BACKGROUND: The authors sought to evaluate current craniofacial training in the United States to achieve perspective on changes over time and to gain insights into possible process improvements. METHODS: Following a review of the San Francisco Match listings and an Internet search, an anonymous online survey invitation was sent to all fellows finishing in 2013. RESULTS: Thirty-three fellows were identified in 29 listed programs and 30 responded (91 percent). All had completed plastic surgery training. A mean caseload of 380 cases (95 percent CI, 307 to 452) was reported. Case analyses permitted subclassification of fellowships into five areas of relative strengths: cleft/intracranial/midface, 35 percent; cleft/general pediatrics, 20 percent; cleft/adult plastics, 20 percent; cleft/facial trauma, 15 percent; and adult plastics/facial trauma, 10 percent of programs. Eighty-six percent were residency-type programs, whereas only 14 percent remained apprenticeships. Fellows cited confidence in any procedure following participation in more than 12 cases, but 20 percent reported not feeling adequately trained following fellowship. Over half (52 percent) thought training could be improved by establishing core areas of exposure and case category minimums. CONCLUSIONS: Fellowships identified as "craniofacial" are actually fairly heterogeneous, offering diverse clinical experiences. Currently, only a minority emphasize traditional cleft, intracranial, and midfacial procedures, with the majority focused more on cleft care, general pediatric plastic surgery, and trauma. Concomitant with an increase in fellowship-trained surgeons has come a change in program structure from apprenticeships to residency type models. Prospective fellows should consider matching their individual training goals with each program's unique clinical strengths. PMID- 25919260 TI - The foreign body response: at the interface of surgery and bioengineering. AB - BACKGROUND: The surgical implantation of materials and devices has dramatically increased over the past decade. This trend is expected to continue with the broadening application of biomaterials and rapid expansion of aging populations. One major factor that limits the potential of implantable materials and devices is the foreign body response, an immunologic reaction characterized by chronic inflammation, foreign body giant cell formation, and fibrotic capsule formation. METHODS: The English literature on the foreign body response to implanted materials and devices is reviewed. RESULTS: Fibrotic encapsulation can cause device malfunction and dramatically limit the function of an implanted medical device or material. Basic science studies suggest a role for immune and inflammatory pathways at the implant-host interface that drive the foreign body response. Current strategies that aim to modulate the host response and improve construct biocompatibility appear promising. CONCLUSIONS: This review article summarizes recent basic science, preclinical, and clinicopathologic studies examining the mechanisms driving the foreign body response, with particular focus on breast implants and synthetic meshes. Understanding these molecular and cellular mechanisms will be critical for achieving the full potential of implanted biomaterials to restore human tissues and organs. PMID- 25919262 TI - SIEA versus DIEP Arterial Complications: A Cohort Study. AB - BACKGROUND: The authors analyzed arterial complications in patients undergoing breast reconstruction with superficial inferior epigastric artery (SIEA) flaps compared with deep inferior epigastric artery perforator (DIEP) flaps. The variability, caliber, and angiosome of the SIEA are cited as limitations. Experts currently limit SIEA reconstruction to cases with favorable arterial anatomy on preoperative imaging. METHODS: In this retrospective cohort study, consecutive flaps for breast reconstruction from the initial 7 years of a single microsurgeon's practice (2007 to 2013) were reviewed. Preoperative imaging was not used. Consistent intraoperative criteria for SIEA flap selection were used. All complications were abstracted independently in duplicate using a standardized form and a priori criteria. RESULTS: One hundred sixty-nine free flaps (SIEA, n = 44; DIEP, n = 125) were performed on 112 patients for unilateral or bilateral breast reconstruction. Significantly more SIEA flaps required reexploration versus DIEP flaps (20 percent versus 7 percent; p = 0.03). Arterial insufficiency was significantly higher among SIEA flaps (14 percent versus 1 percent; p = 0.001). There was no difference in venous insufficiency (p = 0.92). Significantly more SIEA flaps had necrosis requiring intervention (p = 0.03). Ultimately, significantly more SIEA flaps failed completely (14 percent versus 2 percent; p < 0.01). All SIEA flap failures were attributable to arterial thrombosis. CONCLUSIONS: Compared with DIEP flaps, SIEA flaps had significantly higher proportions of reexploration, arterial complication, necrosis, and failure. No difference in venous complications was found. DIEP outcomes agree with existing literature from specialized centers. Complications and failures in SIEA flaps were attributed to arterial thrombosis. Given the authors' practice setting, SIEA flaps are no longer performed. CLINICAL QUESTION/LEVEL OF EVIDENCE: Therapeutic, III. PMID- 25919263 TI - Pulsed Electromagnetic Fields Reduce Postoperative Interleukin-1beta, Pain, and Inflammation: A Double-Blind, Placebo-Controlled Study in TRAM Flap Breast Reconstruction Patients. AB - BACKGROUND: Pulsed electromagnetic fields have been shown to reduce postoperative pain, inflammation, and narcotic requirements after breast reduction and augmentation surgical procedures. This study examined whether pulsed electromagnetic field therapy could produce similar results in patients undergoing unilateral transverse rectus abdominis myocutaneous (TRAM) flap breast reconstruction, a significantly more complex and painful surgical procedure. METHODS: In this double-blind, placebo-controlled, randomized study, 32 patients undergoing unilateral TRAM flap breast reconstruction received active or sham pulsed electromagnetic field therapy. Pain levels were measured by using a visual analogue scale; narcotic use and wound exudate volume were recorded starting 1 hour postoperatively. Wound exudates were analyzed for interleukin-1beta. RESULTS: Mean visual analogue scale pain scores were 2-fold higher in the sham cohort at 5 hours and 4-fold higher at 72 hours (p < 0.01), along with a concomitant 2-fold increase in narcotic use in sham patients (p < 0.01). Wound exudate volume was 2-fold higher in the sham cohort at 24 hours (p < 0.01), and mean interleukin-1beta concentration in wound exudates of sham patients was 5 fold higher at 24 hours (p < 0.001). CONCLUSIONS: Pulsed electromagnetic field therapy significantly reduced postoperative pain, inflammation, and narcotic use following TRAM flap breast reconstruction, paralleling its effect in breast reduction patients. Both studies also report a significant reduction of interleukin-1beta in the wound exudate, supporting a mechanism involving a pulsed electromagnetic field effect on nitric oxide/cyclic guanosine monophosphate signaling, which modulates the body's antiinflammatory pathways. Adjunctive pulsed electromagnetic field therapy could impact the speed and quality of wound repair in many surgical procedures. CLINICAL QUESTION/LEVEL OF EVIDENCE: Therapeutic, I. PMID- 25919264 TI - Pertinent anatomy and analysis for midface volumizing procedures. AB - BACKGROUND: The study was conducted to construct an anatomically inspired midfacial analysis facilitating safe, accurate, and dynamic nonsurgical rejuvenation. Emphasis is placed on determining injection target areas and adverse event zones. METHODS: Twelve hemifacial fresh cadavers were dissected in a layered fashion. Dimensional measurements between the midfacial fat compartments, prezygomatic space, mimetic muscles, and neurovascular bundles were used to develop a topographic analysis for clinical injections. RESULTS: A longitudinal line from the base of the alar crease to the medial edge of the levator anguli oris muscle (1.9 cm), lateral edge of the levator anguli oris muscle (2.6 cm), and zygomaticus major muscle (4.6 cm) partitions the cheek into two aesthetic regions. A six-step facial analysis outlines three target zones and two adverse event zones and triangulates the point of maximum cheek projection. The lower adverse event zone yields an anatomical explanation to inadvertent jowling during anterior cheek injection. The upper adverse event zone localizes the palpebral branch of the infraorbital artery. The medial malar target area isolates quadrants for anterior cheek projection and tear trough effacement. The middle malar target area addresses lid-cheek blending and superficial compartment turgor. The lateral malar target area highlights lateral cheek projection and locates the prezygomatic space. CONCLUSIONS: This stepwise analysis illustrates target areas and adverse event zones to achieve midfacial support, contour, and profile in the repose position and simultaneous molding of a natural shape during animation. This reproducible method can be used both procedurally and in record keeping for midface volumizing procedures. PMID- 25919265 TI - Assessing Patient-Reported Satisfaction with Appearance and Quality of Life following Rhinoplasty Using the FACE-Q Appraisal Scales. AB - BACKGROUND: Patient satisfaction with appearance and improved quality of life are primary outcomes in cosmetic surgery. The purpose of this study was to assess changes in patient satisfaction with facial and nose appearance, and quality of life following rhinoplasty. METHODS: Patients presenting for rhinoplasty completed the FACE-Q, a new patient-reported outcome instrument composed of scales that measure outcomes in patients undergoing facial cosmetic procedures. The following FACE-Q scales were used: satisfaction with facial appearance overall, satisfaction with nose, psychological well-being, and social function. RESULTS: Fifty-six patients completed the FACE-Q at the time of their preoperative consultation and/or at postoperative follow-up visits. Among all patients presenting for rhinoplasty, FACE-Q scores (range, 0 to 100) increased following the procedure in satisfaction with facial appearance (+26.5; p < 0.01), psychological well-being (+15.7; p < 0.01), and social function (+13.7; p = 0.03). Satisfaction with nose item scores (range, 1 to 4) all increased significantly from before to after rhinoplasty, including in satisfaction with nose appearance in the mirror (+1.4; p < 0.01), size (+1.1; p < 0.01), shape (+1.5; p < 0.01), profile (+1.6; p < 0.01), and in photographs (+1.6; p < 0.01). Similar results were seen among a subgroup of patients who completed the FACE-Q scales both before and after rhinoplasty. CONCLUSIONS: In an objective study using a validated patient-reported outcome instrument, improvements in satisfaction with facial and nose appearance and quality of life were demonstrated among rhinoplasty patients. This model supports the successful outcomes possible in rhinoplasty. CLINICAL QUESTION/LEVEL OF EVIDENCE: Therapeutic, IV. PMID- 25919266 TI - Anatomy and surgical treatment of the depressor septi nasi muscle: a systematic review. AB - BACKGROUND: Although the majority of nasal alterations in rhinoplasty result from either augmentation or reduction of bone and cartilaginous substructure, modifications of influential soft-tissue provide significant contribution to the final result. The depressor septi nasi muscle is a soft-tissue structure well known to influence the final result in rhinoplasty. The objective of this study was to perform a standardized, comprehensive review of relevant data published with regard to the depressor septi nasi muscle. METHODS: A comprehensive search of the terms "depressor septi muscle" and "depressor septi nasi muscle" was performed using the PubMed, MEDLINE, and Cochrane databases. Articles were reviewed for relevancy and included if criteria were met. A secondary review was performed of all articles cited, to maximize diligence. RESULTS: Forty-three articles were identified in the initial search. Thirteen of the 43 were found to meet inclusion criteria. Secondary search revealed additional studies meeting inclusion criteria. Altogether, there were 175 cadaver specimens and 821 surgically treated patients for which data were available. Anatomical reports and nomenclature were found to vary. Surgical approach and muscle treatment diverged, with objective data showing no superior method. CONCLUSIONS: Although variation exists in anatomical reports regarding the depressor septi nasi muscle, the prevailing thought is that it originates from the maxilla and/or orbicularis oris muscle. More importantly, the muscle inserts on the medial crura and adjacent soft tissue. Disruption of this relationship provides the basis for surgical treatment of tip descent on animation. PMID- 25919267 TI - Combined breast surgery and abdominoplasty: strategies for success. AB - Abdominoplasty and breast surgery are frequently appealing to patients as combined procedures. The practice of combining abdominoplasty with other procedures originates from abdominoplasty performed in conjunction with intraabdominal or gynecologic surgery. Initially, the focus of combined surgery was on ensuring safety and minimizing local (e.g., wound healing) complications. As surgeons began combining abdominoplasty with distant procedures such as breast surgery, because the individual procedures have little adverse impact on one another and are not altered because of the combination, concerns with systemic morbidity surpassed the initial focus on avoiding local complications. Prevention of venous thromboembolism became a paramount concern. The authors perform abdominoplasty in conjunction with other procedures more frequently than in isolation, reflecting broader societal demand. Indeed, because of the effects of pregnancy and aging, abdominoplasty is being performed in conjunction with breast surgery with frequency sufficient to have driven the term "mommy makeover" into mainstream parlance. Consideration regarding length of surgery and the other recommendations in this report allows for the safe and successful execution of this common combination. PMID- 25919268 TI - Frequency and risk factors of blood transfusion in abdominoplasty in post bariatric surgery patients: data from the nationwide inpatient sample. AB - BACKGROUND: There are limited data regarding blood transfusion following abdominoplasty, especially in post-bariatric surgery patients. The purpose of this study was to evaluate (1) the frequency and outcomes of blood transfusion in post-bariatric surgery patients undergoing abdominoplasty and (2) the predictive risk factors of blood transfusion in this patient population. METHODS: Using the Nationwide Inpatient Sample database, the authors examined the clinical data of patients with a history of bariatric surgery who underwent abdominoplasty from 2007 to 2011 in the United States. RESULTS: A total of 20,130 post-bariatric surgery patients underwent abdominoplasty during this period. Overall, 1871 patients (9.3 percent) received blood transfusion. Chronic anemia patients had the highest rate of blood transfusion (25.6 percent). Post-bariatric surgery patients who received blood transfusion experienced a significantly higher complication rate (10.1 percent versus 4.8 percent; p < 0.01), longer mean hospital stay (4.0 days versus 2.4 days; p < 0.01), and higher mean total hospital charges ($49,116 versus $33,927; p < 0.01). Multivariate regression analysis showed that deficiency anemia (adjusted OR, 3.8), congestive heart failure (adjusted OR, 2.4), concurrent breast reduction (adjusted OR, 1.5), diabetes mellitus (adjusted OR, 1.4), coronary artery disease (adjusted OR, 1.4), African American race (adjusted OR, 1.4), Hispanic race (adjusted OR, 1.4), and female sex (adjusted OR, 1.3) were all independent risk factors for blood transfusion. CONCLUSIONS: The blood transfusion rate in post-bariatric surgery abdominoplasty patients is not insignificant. Chronic anemia and congestive heart failure are the two major predictors of transfusion. Modifying risk factors such as anemia before abdominoplasty might significantly decrease the possibility of blood transfusion. CLINICAL QUESTION/LEVEL OF EVIDENCE: Risk, III. PMID- 25919269 TI - Digital image correlation: a novel dynamic three-dimensional imaging technique for precise quantification of the dynamic rhytid and botulinum toxin type a efficacy. AB - BACKGROUND: Quantification of facial dynamic motion is paramount for improving cosmetic and reconstructive surgical outcomes. The authors introduce digital image correlation using speckle tracking photogrammetry and Aramis software (GOM mbH, Braunschweig, Germany) to study facial dynamics and demonstrate its application in quantifying botulinum toxin efficacy. METHODS: Fourteen subjects were evaluated using a dual camera system and three-dimensional optical analysis. Using Aramis software, the anatomic regions of the glabella, forehead, and total face were identified and highlighted. Tissue strain, defined as either compression or stretch, was measured within these regions over 36 frames during brow furrowing. Each patient was measured before and 2 weeks after injection of 20 units of onabotulinumtoxinA in the glabella. Average stretch and compression in treated areas were analyzed across all available frames. Results were compared using a Wilcoxon signed rank test. RESULTS: After neurotoxin injection, average vertical stretch of the glabella during brow furrowing decreased from 2.51 percent to 1.15 percent (p < 0.05), and average vertical stretch in the forehead decreased from 6.73 percent to 1.67 percent (p < 0.05). Horizontal compression in the glabella decreased from 9.11 percent to 2.60 percent (p < 0.05) and from 4.83 percent to 0.83 percent (p < 0.05) in the forehead. Total facial major strain decreased from 4.41 percent to 3.05 percent (p < 0.05), and total facial minor strain decreased from 5.01 percent to 3.51 percent (p < 0.05). CONCLUSIONS: The authors introduce digital image correlation as a novel technology for measuring dynamic rhytid and neurotoxin efficacy. This technique allows for advancements in the study of dynamic aging and neuromuscular disorders. CLINICAL QUESTION/LEVEL OF EVIDENCE: Diagnostic, II. PMID- 25919270 TI - Development of chemotactic smart scaffold for use in tissue regeneration. AB - BACKGROUND: Regenerative medicine aims to obviate the need for autologous grafting through the use of bioengineered constructs that combine stem cells, growth factors, and biocompatible vehicles. Human mesenchymal stem cells and vascular endothelial growth factor (VEGF) have both shown promise for use in this context, the former because of their pluripotent capacity and the latter because of its chemotactic activity. The authors harnessed the regenerative potential of human mesenchymal stem cells and VEGF to develop a chemotactic scaffold for use in tissue engineering. METHODS: Human mesenchymal stem cells were transduced with human VEGF via lentivirus particles to secrete VEGF. The chemotactic activity of the VEGF-transduced stem cells was evaluated via a trans-well assay. Migration through semipermeable membranes was significantly greater in chambers filled with medium conditioned by VEGF-transduced cells. VEGF-transduced cells were then seeded on apatite-coated poly(lactic-co-glycolic acid) scaffolds, thereby creating the Smart Scaffold. To determine in vivo angiogenesis, the Smart Scaffolds were implanted into subcutaneous pockets in the backs of nude mice. RESULTS: Significantly larger numbers of capillaries were observed in the Smart Scaffold compared with control implants on immunohistologic studies. For the chemotactic in vivo study, human mesenchymal stem cells tagged with a fluorescent dye (1,1-dioctadecyl-3,3,3,3-tetramethylindotricarbocyanine iodide) were injected intravenously via tail vein after the subcutaneous implantation of the Smart Scaffolds. In vivo fluorescent imaging revealed that fluorescent dye-tagged human mesenchymal stem cells successfully accumulated within the Smart Scaffolds. CONCLUSION: These observations suggest that VEGF may play a vital role in the design of clinically relevant tissue regeneration graft substitutes through its angiogenic effects and ability to chemoattract mesenchymal stem cells. PMID- 25919271 TI - Reduced three-dimensional nasal airway volume in treacher collins syndrome and its association with craniofacial morphology. AB - BACKGROUND: Airway insufficiency decreases quality of life and may be life threatening in patients with Treacher Collins syndrome. The authors calculated the three-dimensional nasal airway volume in patients with Treacher Collins syndrome to identify correlations between nasal airway volume and craniofacial morphology and provide guidance for surgical planning. METHODS: Thirty nonoperated patients with Treacher Collins syndrome were compared with 35 unaffected age- and gender-matched controls. Anatomic variables of the cranial base, the maxilla complex, and internal diameters of nasal airway were compared between patients and control subjects using three-dimensional craniometric analyses. In the Treacher Collins group, the relation of craniofacial morphology to nasal airway volume was assessed separately. Statistical analyses were performed using independent sample t tests and Pearson correlation coefficient analyses. RESULTS: Nasal airway volume was decreased 38.6 percent in patients with Treacher Collins syndrome relative to controls (p = 0.001). A positive correlation of maxillary position and nasal airway volume was shown in Treacher Collins patients (r = +0.463, p = 0.013). Maxillary, nasal bone, and orbitale width were also positively correlated with nasal airway volume (r = +0.582, p = 0.001; r = +0.408, p = 0.035; and r = +0.677, p < 0.001, respectively). Shortened internal diameters of the nasal airway all positively correlated with nasal airway volume. CONCLUSIONS: Nasal airway volume is reduced in patients with Treacher Collins syndrome. Reduced projection of the maxilla and transverse maxillary deficiency are correlated with reduced nasal airway volume and are primarily responsible for obstruction of the nasal airway. CLINICAL QUESTION/LEVEL OF EVIDENCE: Risk, II. PMID- 25919272 TI - Surgical treatment and reconstruction of nonmelanoma facial skin cancers. AB - LEARNING OBJECTIVES: After reading this article, the participant should be able to: (1) Identify the appropriate resection margins for common types of nonmelanoma skin cancer. (2) Discuss indications for secondary intention healing, skin grafting, and local flaps for reconstruction of facial skin cancer defects. (3) Describe at least one local flap for reconstruction of scalp, forehead, temple/cheek, periocular, nose, and lips. SUMMARY: Current evidence for diagnosis and surgical treatment of nonmelanoma facial skin cancers is reviewed. In addition, reconstructive options for facial defects are discussed by anatomic location. PMID- 25919273 TI - Worth the "Likes"? The Use of Facebook among Plastic Surgeons and Its Perceived Impact. AB - BACKGROUND: Facebook is the leading online media platform used by plastic surgeons. This study examined Facebook use among plastic surgeons and its perceived impact. METHODS: A survey on Facebook use was distributed to two groups of plastic surgeons: 500 with professional Facebook pages and 500 without Facebook pages. Responses were stripped of identifying information and analyzed for statistical significance (p < 0.05). RESULTS: One hundred twenty-three total surveys were completed (12.3 percent response rate). No respondents with Facebook reported a negative impact on their practice, whereas 57 percent reported a very positive or positive impact. There was no correlation with perceived impact and number of "likes." Perceived advantages of Facebook included facilitation of patient feedback/communication (77 percent) and increased practice exposure (67 percent). Many surgeons (15 to 36 percent) did not follow the direct impact of Facebook on their practices. Some reported that Facebook was responsible for only one to 50 professional Web site hits and less than 5 percent of their new patient referrals in the past year. Estimated conversion-to-surgery rates were highly variable for Facebook users and nonusers. Most Facebook nonusers (67 percent) expected a "neutral" impact, expressing more concerns about unsolicited advertising (51 percent) and wasting time (47 percent). CONCLUSIONS: Plastic surgeons tend to perceive Facebook's impact on their practices as positive, but most do not track its direct effects on professional Web site hits, new referrals, or conversion-to-surgery rates. Plastic surgeons using Facebook are encouraged to monitor these parameters to determine whether its continued use is actually worthwhile. PMID- 25919274 TI - A systematic review comparing furlow double-opposing z-plasty and straight-line intravelar veloplasty methods of cleft palate repair. PMID- 25919275 TI - Significance of beta-Galactoside alpha2,6 Sialyltranferase 1 in Cancers. AB - Altered glycosylation is a common feature of cancer cells. It takes a variety of forms, which includes loss of expression or excessive expression of some structures, the accumulation of precursors, the appearance of novel structures, etc. Notably, these changes in glycan structure do not occur as a random consequence of disorder biology. Only a limited subset of oligosaccharides is found frequently enriched on the tumor cell surface and implicated in different tumor phenotypes. Among these, altered sialylation has long been associated with metastatic cell behaviors such as invasion and enhanced cell survival and accumulating evidence points to the alteration occurring in the sialic acid linkage to other sugars, which normally exists in three main configurations: alpha2,3, alpha2,6, and alpha2,8, catalyzed by a group of sialyltransferases. The aberrant expression of all three configurations has been described in cancer progression. However, the increased alpha2,6 sialylation catalyzed by beta galactoside alpha2,6 sialyltranferase 1 (ST6Gal I) is frequently observed in many types of the cancers. In this review, we describe the findings on the role of ST6Gal I in cancer progression, and highlight in particular the knowledge of how ST6Gal I-mediated alpha2,6 sialylated glycans or sialylated carrier proteins regulate cell signaling to promote the malignant phenotype of human carcinoma. PMID- 25919276 TI - Recent developments in the Suzuki-Miyaura reaction: 2010-2014. AB - The Suzuki-Miyaura reaction (SMR), involving the coupling of an organoboron reagent and an organic halide or pseudo-halide in the presence of a palladium or nickel catalyst and a base, has arguably become one of most utilized tools for the construction of a C-C bond. This review intends to be general account of all types of catalytic systems, new coupling partners and applications, including the literature between September 2010 and December 2014. PMID- 25919277 TI - Pi-pi Stacking Mediated Cooperative Mechanism for Human Cytochrome P450 3A4. AB - Human Cytochrome P450 3A4 (CYP3A4) is an important member of the cytochrome P450 superfamily with responsibility for metabolizing ~50% of clinical drugs. Experimental evidence showed that CYP3A4 can adopt multiple substrates in its active site to form a cooperative binding model, accelerating substrate metabolism efficiency. In the current study, we constructed both normal and cooperative binding models of human CYP3A4 with antifungal drug ketoconazoles (KLN). Molecular dynamics simulation and free energy calculation were then carried out to study the cooperative binding mechanism. Our simulation showed that the second KLN in the cooperative binding model had a positive impact on the first one binding in the active site by two significant pi-pi stacking interactions. The first one was formed by Phe215, functioning to position the first KLN in a favorable orientation in the active site for further metabolism reactions. The second one was contributed by Phe304. This pi-pi stacking was enhanced in the cooperative binding model by the parallel conformation between the aromatic rings in Phe304 and the dioxolan moiety of the first KLN. These findings can provide an atomic insight into the cooperative binding in CYP3A4, revealing a novel pi-pi stacking mechanism for drug-drug interactions. PMID- 25919278 TI - Nitric Oxide Plays a Central Role in Water Stress-Induced Tanshinone Production in Salvia miltiorrhiza Hairy Roots. AB - Nitric oxide (NO), a well-known signaling molecule plays an important role in abiotic and biotic stress-induced production of plant secondary metabolites. In this study, roles of NO in water stress-induced tanshinone production in Salvia miltiorrhiza hairy roots were investigated. The results showed that accumulations of four tanshinone compounds in S. miltiorrhiza hairy roots were significantly stimulated by sodium nitroprusside (SNP, a NO donor) at 100 MUM. Effects of SNP were just partially arrested by the mevalonate (MVA) pathway inhibitor (mevinolin), but were completely inhibited by the 2-C-methyl-d-erythritol-4 phosphate pathway (MEP) inhibitor (fosmidomycin). The increase of tanshinone accumulation and the up-regulation of HMGR and DXR expression by PEG and ABA treatments were partially inhibited by an inhibitor of NO biosynthesis (Nomega nitro-L-arginine methyl ester (L-NAME)) and a NO scavenger (2-(4-Carboxyphenyl)- 4,4,5,5-tetramethylimidazoline-1-oxyl-3-oxide (c-PTIO)). Simultaneously, NO generation in the hairy roots was triggered by PEG and ABA, and the effects were also arrested by c-PTIO and L-NAME. These results indicated that NO signaling probably plays a central role in water stress-induced tanshinone production in S. miltiorrhiza hairy roots. SNP mainly stimulated the MEP pathway to increase tanshinone accumulation. PMID- 25919279 TI - BMP Signaling Regulates Bone Morphogenesis in Zebrafish through Promoting Osteoblast Function as Assessed by Their Nitric Oxide Production. AB - Bone morphogenetic proteins (BMPs) control many developmental and physiological processes, including skeleton formation and homeostasis. Previous studies in zebrafish revealed the crucial importance of proper BMP signaling before 48 h post-fertilization (hpf) for cartilage formation in the skull. Here, we focus on the involvement of the BMP pathway between 48 and 96 hpf in bone formation after 96 hpf. Using BMP inhibitors and the expression of a dominant-negative BMP receptor, we analyze whether the loss of BMP signaling affects osteoblastogenesis, osteoblast function and bone mineralization. To this end, we used the transgenic zebrafish line Tg(osterix:mCherry), detection of nitric oxide (NO) production, and alizarin red staining, respectively. We observed that inhibition of BMP signaling between 48 and 72 hpf led to a reduction of NO production and bone mineralization. Osteoblast maturation and chondrogenesis, on the other hand, seemed unchanged. Osteoblast function and bone formation were less affected when BMP signaling was inhibited between 72 and 96 hpf. These results suggest that for the onset of bone formation, proper BMP signaling between 48 and 72 hpf is crucial to ensure osteoblast function and ossification. Furthermore, detection of NO in developing zebrafish larvae appears as an early indicator of bone calcification activity. PMID- 25919280 TI - Modulation of the RNA Interference Activity Using Central Mismatched siRNAs and Acyclic Threoninol Nucleic Acids (aTNA) Units. AB - The understanding of the mechanisms behind nucleotide recognition by Argonaute 2, core protein of the RNA-induced silencing complex, is a key aspect in the optimization of small interfering RNAs (siRNAs) activity. To date, great efforts have been focused on the modification of certain regions of siRNA, such as the 3'/5'-termini and the seed region. Only a few reports have described the roles of central positions flanking the cleavage site during the silence process. In this study, we investigate the potential correlations between the thermodynamic and silencing properties of siRNA molecules carrying, at internal positions, an acyclic L-threoninol nucleic acid (aTNA) modification. Depending on position, the silencing is weakened or impaired. Furthermore, we evaluate the contribution of mismatches facing either a natural nucleotide or an aTNA modification to the siRNA potency. The position 11 of the antisense strand is more permissive to mismatches and aTNA modification, in respect to the position 10. Additionally, comparing the ON-/OFF-target silencing of central mismatched siRNAs with 5' terminal modified siRNA, we concluded: (i) central perturbation of duplex pairing features weights more on potency rather than silencing asymmetry; (ii) complete bias for the ON-target silencing can be achieved with single L-threoninol modification near the 5'-end of the sense strand. PMID- 25919281 TI - Effect of coenzyme Q10 on the incidence of atrial fibrillation in patients with heart failure. AB - BACKGROUND: There is mounting evidence to support the influence of inflammation and oxidative stress in the pathogenesis of atrial fibrillation (AF) and heart failure (HF). The efficacy of coenzymeQ10 (CoQ10), an antioxidant used as an adjunct treatment in patients with AF and HF, remains less well established. METHODS: Consecutive patients with HF were randomized and divided into 2 groups: the CoQ10 group (combined administration of common drugs and CoQ10) and the control group (administration of common drugs). Ambulatory electrocardiogram Holter monitoring (24 hours), Doppler echocardiography, and evaluation of inflammatory cytokines were performed before treatment and 6 and 12 months after treatment. RESULTS: One hundred two patients (72 male and 30 female patients), with ages ranging from 45 to 82 years (mean age, 62.3 years), were examined. There was significant reduction in the level of malondialdehyde (3.9 +/- 0.7 vs 2.5 +/- 0.6 ng/mL; 3.9 +/- 0.7 vs 2.3 +/- 0.5 ng/mL, P < 0.05) in the CoQ10 group, whereas there was no significant difference (3.3 +/- 0.8 vs 2.9 +/- 0.8 ng/mL; 3.3 +/- 0.8 vs 2.9 +/- 0.5 ng/mL) in the control group after 6 and 12 months. Three patients (6.3%) in the CoQ10 group and 12 patients (22.2%) in the control group had episodes of AF after 12 months' treatment (P = 0.02). Four patients with AF in the control group went through the third Holter recording. CONCLUSIONS: CoenzymeQ10 as adjuvant treatment in patients with HF may attenuate the incidence of AF. The mechanisms of the effect perhaps have relation with the reduced levels of malondialdehyde. PMID- 25919282 TI - SHP2-Deficiency in Chondrocytes Deforms Orofacial Cartilage and Ciliogenesis in Mice. AB - Congenital orofacial abnormalities are clinically seen in human syndromes with SHP2 germline mutations such as LEOPARD and Noonan syndrome. Recent studies demonstrate that SHP2-deficiency leads to skeletal abnormalities including scoliosis and cartilaginous benign tumor metachondromatosis, suggesting that growth plate cartilage is a key tissue regulated by SHP2. The role and cellular mechanism of SHP2 in the orofacial cartilage, however, remains unknown. Here, we investigated the postnatal craniofacial development by inducible disruption of Shp2 in chondrocytes. Shp2 conditional knockout (cKO) mice displayed severe deformity of the mandibular condyle accompanied by disorganized, expanded cartilage in the trabecular bone region, enhanced type X collagen, and reduced Erk production. Interestingly, the length of primary cilia, an antenna like organelle sensing environmental signaling, was significantly shortened, and the number of primary cilia was reduced in the cKO mice. The expression levels of intraflagellar transports (IFTs), essential molecules in the assembly and function of primary cilia, were significantly decreased. Taken together, lack of Shp2 in orofacial cartilage led to severe defects of ciliogenesis through IFT reduction, resulting in mandibular condyle malformation and cartilaginous expansion. Our study provides new insights into the molecular pathogenesis of SHP2-deficiency in cartilage and helps to understand orofacial and skeletal manifestations seen in patients with SHP2 mutations. PMID- 25919283 TI - Prognostic significance of matrix metalloproteinase-7 in gastric cancer survival: a meta-analysis. AB - The prognostic role of matrix metalloproteinase-7 in gastric cancer survival has been widely evaluated. However, the results are controversial. We aimed to set up a meta-analysis to reach a conclusion on the prognostic significance of metalloproteinase-7 in gastric cancer survival as well as its association with clinicopathological parameters. We searched popular databases from 1988 until October 2014 to gather eligible peer-reviewed papers addressing the prognostic effect of matrix metalloproteinase-7 in gastric cancer patients' survival. The CASP check list was used for quality appraisal. Pooled hazard ratio (HR) for survival and odds ratio (OR) for association with their 95% confidence interval (CI) were considered as summary measurements. Finally, 1208 gastric cancer patients from nine studies were included in the meta-analysis. Pooled HR estimate for survival was 2.01 (95% CI = 1.62 - 2.50, P < 0.001), which indicated a significant poor prognostic effect for matrix metalloproteinase-7. Sensitivity analysis detected no dominancy for any study. No publication bias was detected according to Egger's and Begg's tests. Clinicopathological assessment revealed that higher matrix metalloproteinase-7 expression is associated with deeper invasion (pooled OR = 3.20; 95% CI = 1.14 - 8.96; P = 0.026), higher TNM stage (pooled OR = 3.67; 95% CI = 2.281-5.99; P<0.001), lymph node metastasis (pooled OR = 2.84; 95% CI = 1.89 - 4.25; P<0.001), and distant metastasis (pooled OR = 3.68; 95% CI = 1.85 - 7.29; P<0.001), but not with histological grade. This meta analysis indicated a significant poor prognostic effect of matrix metalloproteinase-7 in gastric cancer survival. Additionally it was associated with aggressive tumor phenotype. PMID- 25919285 TI - The impact of reduced-volume, intensity-modulated radiation therapy on disease control in nasopharyngeal carcinoma. AB - OBJECTIVE: To investigate the feasibility of using intensity-modulated radiotherapy (IMRT) with reduced, high-dose target volumes for nasopharyngeal carcinoma (NPC). METHODS: The first 57 patients (admitted from October 2005 to May 2008) were treated with large-target-volume IMRT (LV-IMRT). For the LV-IMRT group, the CTV at 70 Gy (CTV70) was delineated as the gross target volume (GTV) plus 7mm, with or without the first-echelon lymph-node region. The next 56 patients (admitted from June 2008 to November 2011) were treated with reduced target-volume IMRT (RV-IMRT). For the RV-IMRT group, the CTV70 was delineated as the GTV alone. RESULTS: The 4-year local recurrence-free, regional recurrence free, distant metastasis-free, progression-free, and overall survival rates were 77.2%, 80.1%, 83.2%, 61.2%, and 74.4% for the LV-IMRT group and 83.5%, 92.6%, 89.1%, 78.5, and 91.0% for the RV-IMRT group, respectively. Late toxicity scoring of xerostomia was lesser in the RV-IMRT group than the LV-IMRT group (P < 0.001). CONCLUSIONS: The use of RV-IMRT for the treatment of NPC did not negatively affect survival rates but did reduce the late xerostomia events compared to LV IMRT. PMID- 25919286 TI - Migratory Patterns of Wild Chinook Salmon Oncorhynchus tshawytscha Returning to a Large, Free-Flowing River Basin. AB - Upriver movements were determined for Chinook salmon Oncorhynchus tshawytscha returning to the Yukon River, a large, virtually pristine river basin. These returns have declined dramatically since the late 1990s, and information is needed to better manage the run and facilitate conservation efforts. A total of 2,860 fish were radio tagged during 2002-2004. Most (97.5%) of the fish tracked upriver to spawning areas displayed continual upriver movements and strong fidelity to the terminal tributaries entered. Movement rates were substantially slower for fish spawning in lower river tributaries (28-40 km d-1) compared to upper basin stocks (52-62 km d-1). Three distinct migratory patterns were observed, including a gradual decline, pronounced decline, and substantial increase in movement rate as the fish moved upriver. Stocks destined for the same region exhibited similar migratory patterns. Individual fish within a stock showed substantial variation, but tended to reflect the regional pattern. Differences between consistently faster and slower fish explained 74% of the within-stock variation, whereas relative shifts in sequential movement rates between "hares" (faster fish becoming slower) and "tortoises" (slow but steady fish) explained 22% of the variation. Pulses of fish moving upriver were not cohesive. Fish tagged over a 4-day period took 16 days to pass a site 872 km upriver. Movement rates were substantially faster and the percentage of atypical movements considerably less than reported in more southerly drainages, but may reflect the pristine conditions within the Yukon River, wild origins of the fish, and discrete run timing of the returns. Movement data can provide numerous insights into the status and management of salmon returns, particularly in large river drainages with widely scattered fisheries where management actions in the lower river potentially impact harvests and escapement farther upstream. However, the substantial variation exhibited among individual fish within a stock can complicate these efforts. PMID- 25919284 TI - Rhizobium leguminosarum bv. viciae 3841 Adapts to 2,4-Dichlorophenoxyacetic Acid with "Auxin-Like" Morphological Changes, Cell Envelope Remodeling and Upregulation of Central Metabolic Pathways. AB - There is a growing need to characterize the effects of environmental stressors at the molecular level on model organisms with the ever increasing number and variety of anthropogenic chemical pollutants. The herbicide 2,4 dichlorophenoxyacetic acid (2,4-D), as one of the most widely applied pesticides in the world, is one such example. This herbicide is known to have non-targeted undesirable effects on humans, animals and soil microbes, but specific molecular targets at sublethal levels are unknown. In this study, we have used Rhizobium leguminosarum bv. viciae 3841 (Rlv) as a nitrogen fixing, beneficial model soil organism to characterize the effects of 2,4-D. Using metabolomics and advanced microscopy we determined specific target pathways in the Rlv metabolic network and consequent changes to its phenotype, surface ultrastructure, and physical properties during sublethal 2,4-D exposure. Auxin and 2,4-D, its structural analogue, showed common morphological changes in vitro which were similar to bacteroids isolated from plant nodules, implying that these changes are related to bacteroid differentiation required for nitrogen fixation. Rlv showed remarkable adaptation capabilities in response to the herbicide, with changes to integral pathways of cellular metabolism and the potential to assimilate 2,4-D with consequent changes to its physical and structural properties. This study identifies biomarkers of 2,4-D in Rlv and offers valuable insights into the mode of-action of 2,4-D in soil bacteria. PMID- 25919287 TI - Is there a role for digitalis in chronic heart failure? AB - The main clinical guidelines recommend the use of digitalis for chronic heart failure when moderate to severe symptoms persist after standard therapy, even though there is controversy about its efficacy and security. Searching in Epistemonikos database, which is maintained by screening 30 databases, we identified three systematic reviews including 13 randomized trials. We combined the evidence using meta-analysis and generated a summary of findings table following the GRADE approach. We concluded the use of digitalis for chronic heart failure probably leads to little or no decrease in mortality, but might reduce hospitalizations and clinical deterioration. However, the certainty of the evidence is low. PMID- 25919288 TI - Protective effects of myricetin on acute hypoxia-induced exercise intolerance and mitochondrial impairments in rats. AB - PURPOSE: Exercise tolerance is impaired in hypoxia. The aim of this study was to evaluate the effects of myricetin, a dietary flavonoid compound widely found in fruits and vegetables, on acute hypoxia-induced exercise intolerance in vivo and in vitro. METHODS: Male rats were administered myricetin or vehicle for 7 days and subsequently spent 24 hours at a barometric pressure equivalent to 5000 m. Exercise capacity was then assessed through the run-to-fatigue procedure, and mitochondrial morphology in skeletal muscle cells was observed by transmission electron microscopy (TEM). The enzymatic activities of electron transfer complexes were analyzed using an enzyme-linked immuno-sorbent assay (ELISA). mtDNA was quantified by real-time-PCR. Mitochondrial membrane potential was measured by JC-1 staining. Protein expression was detected through western blotting, immunohistochemistry, and immunofluorescence. RESULTS: Myricetin supplementation significantly prevented the decline of run-to-fatigue time of rats in hypoxia, and attenuated acute hypoxia-induced mitochondrial impairment in skeletal muscle cells in vivo and in vitro by maintaining mitochondrial structure, mtDNA content, mitochondrial membrane potential, and activities of the respiratory chain complexes. Further studies showed that myricetin maintained mitochondrial biogenesis in skeletal muscle cells under hypoxic conditions by up regulating the expressions of mitochondrial biogenesis-related regulators, in addition, AMP-activated protein kinase(AMPK) plays a crucial role in this process. CONCLUSIONS: Myricetin may have important applications for improving physical performance under hypoxic environment, which may be attributed to the protective effect against mitochondrial impairment by maintaining mitochondrial biogenesis. PMID- 25919289 TI - Molecular and Phenotypic Characterization of Aerococcus viridans Associated with Subclinical Bovine Mastitis. AB - Aerococcus viridans is a wide spread bacterium in the environment and clinically this organism is associated with different diseases in animals and humans. However, the geno- and phenotypic characterization of A. viridans associated with bovine mastitis has not yet been reported. The objectives of this study were to investigate the genetic and phenotypic diversity of A. viridans isolates using three different molecular methods including 16S rRNA gene sequencing, pulsed field gel electrophoresis and random amplified polymorphic DNA (RAPD) along with biochemical tests, including antimicrobial susceptibility test. In total, 60 A. viridans strains were cultured from dairy herds presenting with subclinical mastitis. The results of biochemical tests revealed that most of the isolates (75.0%) were accurately identified by API Rapid 20 Strep system and the majority of A. viridans strains (96.7%) were found to be catalase negative, while two (3.3%) isolates were weakly positive. All isolates were resistant to trimethoprim sulfamethoxazole, followed by streptomycin (96.7%), tetracycline (65.0%) and clindamycin (56.7%) by minimum inhibition concentration-determining broth microdilution technique. As compared to the sequence of 16S rRNA gene, both PFGE and RAPD showed their capacities to discriminate the intra-species diversity of A. viridans. Furthermore, most of the isolates obtained from the same herd or region belonged to the same major RAPD group, which indicated that RAPD is an appropriate assay for tracking the origins of isolates and epidemiological studies of A. viridans. This is a novel approach to use three molecular techniques and to compare their efficiency regarding the genetic diversity of A. viridans. The data suggest that A. viridans associated with subclinical mastitis has a considerable phenotypic and genotypic diversity. PMID- 25919290 TI - Phenotype accessibility and noise in random threshold gene regulatory networks. AB - Evolution requires phenotypic variation in a population of organisms for selection to function. Gene regulatory processes involved in organismal development affect the phenotypic diversity of organisms. Since only a fraction of all possible phenotypes are predicted to be accessed by the end of development, organisms may evolve strategies to use environmental cues and noise like fluctuations to produce additional phenotypic diversity, and hence to enhance the speed of adaptation. We used a generic model of organismal development --gene regulatory networks-- to investigate how different levels of noise on gene expression states (i.e. phenotypes) may affect access to new, unique phenotypes, thereby affecting phenotypic diversity. We studied additional strategies that organisms might adopt to attain larger phenotypic diversity: either by augmenting their genome or the number of gene expression states. This was done for different types of gene regulatory networks that allow for distinct levels of regulatory influence on gene expression or are more likely to give rise to stable phenotypes. We found that if gene expression is binary, increasing noise levels generally decreases phenotype accessibility for all network types studied. If more gene expression states are considered, noise can moderately enhance the speed of discovery if three or four gene expression states are allowed, and if there are enough distinct regulatory networks in the population. These results were independent of the network types analyzed, and were robust to different implementations of noise. Hence, for noise to increase the number of accessible phenotypes in gene regulatory networks, very specific conditions need to be satisfied. If the number of distinct regulatory networks involved in organismal development is large enough, and the acquisition of more genes or fine tuning of their expression states proves costly to the organism, noise can be useful in allowing access to more unique phenotypes. PMID- 25919291 TI - Neural computations mediating one-shot learning in the human brain. AB - Incremental learning, in which new knowledge is acquired gradually through trial and error, can be distinguished from one-shot learning, in which the brain learns rapidly from only a single pairing of a stimulus and a consequence. Very little is known about how the brain transitions between these two fundamentally different forms of learning. Here we test a computational hypothesis that uncertainty about the causal relationship between a stimulus and an outcome induces rapid changes in the rate of learning, which in turn mediates the transition between incremental and one-shot learning. By using a novel behavioral task in combination with functional magnetic resonance imaging (fMRI) data from human volunteers, we found evidence implicating the ventrolateral prefrontal cortex and hippocampus in this process. The hippocampus was selectively "switched" on when one-shot learning was predicted to occur, while the ventrolateral prefrontal cortex was found to encode uncertainty about the causal association, exhibiting increased coupling with the hippocampus for high-learning rates, suggesting this region may act as a "switch," turning on and off one-shot learning as required. PMID- 25919292 TI - Enhanced IMP3 Expression Activates NF-kB Pathway and Promotes Renal Cell Carcinoma Progression. AB - BACKGROUND: Insulin-like growth factor 2 mRNA binding protein 3 (IMP3) is expressed in metastatic and a subset of primary renal cell carcinoma (RCC). However, the role of IMP3 in RCC progression was poorly understood. We aim to uncover the mechanism of IMP3 in regulating clear cell RCC (CCRCC) progression and validate the prognostic significance of IMP3 in localized CCRCC. METHODS: Caki-1 cells stably overexpressing IMP3 and Achn cells with knockdown of IMP3 were analyzed for cell migration and invasion by Transwell assay. RNA-seq was used to profile gene expression in IMP3-expressing Caki-1 cells. A cohort of 469 localized CCRCC patients were examined for IMP3 expression by immunohistochemistry using tumor tissue array. RESULTS: IMP3 promoted Caki-1 cell migration and invasion, whereas knockdown of IMP3 by RNAi inhibited Achn cell migration and invasion. Enhanced IMP3 expression activated NF-kB pathway and through which, it functioned in promoting the RCC cell migration. IMP3 expression in localized CCRCC was found to be associated with higher nuclear grade, higher T stage, necrosis and sarcomatoid differentiation (p< 0.001). Enhanced IMP3 expression was correlated with shorter recurrence-free and overall survivals. Multivariable analysis validated IMP3 as an independent prognostic factor for localized CCRCC patients. CONCLUSION: IMP3 promotes RCC cell migration and invasion by activation of NF-kB pathway. IMP3 is validated to be an independent prognostic marker for localized CCRCC. PMID- 25919293 TI - Comparative efficacy and safety of antidiabetic drug regimens added to metformin monotherapy in patients with type 2 diabetes: a network meta-analysis. AB - INTRODUCTION: When first line therapy with metformin is insufficient for patients with type 2 diabetes (T2D), the optimal adjunctive therapy is unclear. We assessed the efficacy and safety of adjunctive antidiabetic agents in patients with inadequately controlled T2D on metformin alone. MATERIALS AND METHODS: A search of MEDLINE and CENTRAL, clinicaltrials.gov, regulatory websites was performed. We included randomized controlled trials of 3-12 months duration, evaluating Food and Drug Administration or European Union approved agents (noninsulin and long acting, once daily basal insulins) in patients experiencing inadequate glycemic control with metformin monotherapy (>= 1500 mg daily or maximally tolerated dose for >= 4 weeks). Random-effects network meta-analyses were used to compare the weighted mean difference for changes from baseline in HbA1c, body weight (BW) and systolic blood pressure (SBP), and the risk of developing hypoglycemia, urinary (UTI) and genital tract infection (GTI). RESULTS: Sixty-two trials evaluating 25 agents were included. All agents significantly reduced HbA1c vs. placebo; albeit not to the same extent (range, 0.43% for miglitol to 1.29% for glibenclamide). Glargine, sulfonylureas (SUs) and nateglinide were associated with increased hypoglycemia risk vs. placebo (range, 4.00-11.67). Sodium glucose cotransporter-2 (SGLT2) inhibitors, glucagon-like peptide-1 analogs, miglitol and empagliflozin/linagliptin significantly reduced BW (range, 1.15-2.26 kg) whereas SUs, thiazolindinediones, glargine and alogliptin/pioglitazone caused weight gain (range, 1.19-2.44 kg). SGLT2 inhibitors, empagliflozin/linagliptin, liraglutide and sitagliptin decreased SBP (range, 1.88-5.43 mmHg). No therapy increased UTI risk vs. placebo; however, SGLT2 inhibitors were associated with an increased risk of GTI (range, 2.16 8.03). CONCLUSIONS: Adding different AHAs to metformin was associated with varying effects on HbA1c, BW, SBP, hypoglycemia, UTI and GTI which should impact clinician choice when selecting adjunctive therapy. PMID- 25919294 TI - Metabolic disease in 10 patients with sudden unexpected death in infancy or acute life-threatening events. AB - In order to determine the associations between sudden unexpected death in infancy (SUDI) or acute life-threatening events (ALTE) and inborn errors of metabolism, particularly organic acidemia and fatty acid oxidation disorders, we evaluated clinical features in patients with SUDI or ALTE. The subjects were infants between the ages of 7 days and 3 years who developed SUDI or ALTE between January 2004 and December 2013. They were then diagnosed as having inborn errors of metabolism on gas chromatography-mass spectrometry (GC/MS) and/or tandem mass spectrometry (MS/MS). The age distribution, onset forms, and clinical findings were evaluated during the acute phase. Inborn errors of metabolism were detected in three of 196 patients with SUDI, and in seven of 167 patients with ALTE. Of these 10 patients, nine had a history of poor feeding and somnolence during the neonatal period, and symptoms of infection such as cough, fever or vomiting during infancy. Routine laboratory tests during an acute phase indicated hyperammonemia, liver dysfunction, increased blood creatine kinase, acidosis, positive ketone bodies in urine or blood, or hypoglycemia. When SUDI or ALTE are encountered in the emergency unit, it is essential that a detailed medical history is taken, particularly with regard to the neonatal period, and that specific abnormalities are investigated on routine laboratory tests. Moreover, samples such as urine, serum, and filter paper blood specimens should be collected for GC/MS and/or MS/MS of organic acids and acylcarnitines, to identify inborn metabolic disorders. PMID- 25919296 TI - ALPPL2 Aptamer-Mediated Targeted Delivery of 5-Fluoro-2'-Deoxyuridine to Pancreatic Cancer. AB - Nucleoside analogues are the most promising drugs for the treatment of pancreatic cancer to date. However, their use is often limited due to toxic side effects. Aptamer-mediated targeted delivery of these drugs to cancer cells could maximize their effectiveness and concomitantly minimize the toxic side effects by reducing uptake into normal cells. Previously, we identified a pancreatic cancer-specific, nuclease-resistant RNA aptamer, SQ2, which binds to alkaline phosphatase placental-like 2 (ALPPL2), a putative biomarker for pancreatic cancer. In this study, we demonstrate that the aptamer can be internalized into pancreatic cancer cells and can thus be used for the targeted delivery of therapeutics. Using the aptamer as a ligand, we established that glycophosphatidylinositol-anchored ALPPL2 is internalized by the cells through clathrin-independent and caveolae dependent or dynamin-mediated cell-type-dependent pathways. Finally, we show that SQ2 can deliver nucleoside drug 5-fluoro-2'-deoxyuridine specifically to ALPPL2 expressing pancreatic cancer cells, inhibiting cell proliferation. PMID- 25919295 TI - Cholesteryl esters are elevated in the lipid fraction of bronchoalveolar lavage fluid collected from pediatric cystic fibrosis patients. AB - BACKGROUND: Host-derived lipids including cholesteryl esters (CEs) such as cholesteryl linoleate have emerged as important antibacterial effectors of innate immunity in the airways and cholesteryl linoleate has been found elevated in the context of inflammation. Cystic fibrosis (CF) patients suffer from chronic infection and severe inflammation in the airways. Here, we identified and quantified CEs in bronchoalveolar lavage fluid (BALF) from CF patients and non-CF disease controls, and tested whether CE concentrations are linked to the disease. MATERIALS AND METHODS: CEs in BALF from 6 pediatric subjects with CF and 7 pediatric subjects with non-CF chronic lung disease were quantified by mass spectral analysis using liquid chromatography coupled with tandem mass spectrometry and multiple reaction monitoring. BALFs were also examined for total lipid, total protein, albumin, and, as a marker for inflammation, human neutrophil peptide (HNP) 1-3 concentrations. Statistical analysis was conducted after log 10 transformation of the data. RESULTS: Total lipid/protein ratio was reduced in CF BALF (p = 0.018) but the concentrations of CEs, including cholesteryl linoleate, were elevated in the total lipid fraction in CF BALF compared to non-CF disease controls (p < 0.050). In addition, the concentrations of CEs and HNP1-3 correlated with one another (p < 0.050). CONCLUSIONS: The data suggests that the lipid composition of BALF is altered in CF with less total lipid relative to protein but with increased CE concentrations in the lipid fraction, likely contributed by inflammation. Future longitudinal studies may reveal the suitability of CEs as a novel biomarker for CF disease activity which may provide new information on the lipid mediated pathophysiology of the disease. PMID- 25919297 TI - 532 nm Low-Power Laser Irradiation Facilitates the Migration of GABAergic Neural Stem/Progenitor Cells in Mouse Neocortex. AB - BACKGROUND AND OBJECTIVE: Accumulating evidence has shown that low-power laser irradiation (LLI) affects cell proliferation and survival, but little is known about LLI effects on neural stem/progenitor cells (NSPCs). Here we investigate whether transcranial 532 nm LLI affects NSPCs in adult murine neocortex and in neurospheres from embryonic mice. STUDY DESIGN/MATERIALS AND METHODS: We applied 532 nm LLI (Nd:YVO4, CW, 60 mW) on neocortical surface via cranium in adult mice and on cultured cells from embryonic mouse brains in vitro to investigate the proliferation and migration of NSPCs and Akt expression using immunohistochemical assays and Western blotting techniques. RESULTS: In vivo experiments demonstrated that 532 nm LLI significantly facilitated the migration of GABAergic NSPCs that were induced to proliferate in layer 1 by mild ischemia. In vitro experiments using GABAergic NSPCs derived from embryonic day 14 ganglionic eminence demonstrated that 532 nm LLI for 60 min promoted the migration of GAD67 immunopositive NSPCs with a significant increase of Akt expression. Meanwhile, the LLI induced proliferation, but not migration, of NSPCs that give rise to excitatory neurons. CONCLUSION: It is concluded that 532 nm LLI promoted the migration of GABAergic NSPCs into deeper layers of the neocortex in vivo by elevating Akt expression. PMID- 25919298 TI - Availability of empty zona pellucida for generating embryonic chimeras. AB - In the present study we used an empty zona pellucida derived from hatched blastocysts as an alternative source for embryo aggregation and compared results with the conventional microwell method. Denuded 4-cell stage porcine embryos were aggregated by introduction into an empty zona or placement within a concave microwell. The present study showed that although the rate of aggregate formation was similar, the blastocyst rates and allocation of more cells to the inner cell mass (ICM) in the resultant aggregates were increased significantly more in the empty zona than in the microwell. Notably, using an empty zona showed no limitations with regards to the increased number of embryos aggregated or embryonic stages for aggregation, while partial or no aggregation frequently occurred in the microwell. The discrepancy may be due to the difference of microenvironments where the embryos were placed namely, the presence/absence of zona pellucida. We hypothesize the success of the empty zona in generating aggregates is due to the physical aggregation of individual embryos allowing closer contact between the blastomeres and/or embryos compared with a concave microwell. These results indicate that aggregation conditions could influence overall production efficiency and developmental potential of aggregates, suggesting physical restraint via empty zona that provide three-dimensional pressures is an important factor for successful embryo aggregation. PMID- 25919299 TI - Single chain variable fragment against abeta expressed in baculovirus inhibits abeta fibril elongation and promotes its disaggregation. AB - Alzheimer's disease (AD) is the most common form of age-related dementia, and the most urgent problem is that it is currently incurable. Amyloid-beta (Abeta) peptide is believed to play a major role in the pathogenesis of AD. We previously reported that an Abeta N-terminal amino acid targeting monoclonal antibody (MAb), A8, inhibits Abeta fibril formation and has potential as an immunotherapy for AD based on a mouse model. To further study the underlying mechanisms, we tested our hypothesis that the single chain fragment variable (scFv) without the Fc fragment is capable of regulating either Abeta aggregation or disaggregation in vitro. Here, a model of cell-free Abeta "on-pathway" aggregation was established and identified using PCR, Western blot, ELISA, transmission electron microscopy (TEM) and thioflavin T (ThT) binding analyses. His-tagged A8 scFvs was cloned and solubly expressed in baculovirus. Our data demonstrated that the Ni-NTA agarose affinity-purified A8 scFv inhibited the forward reaction of "on-pathway" aggregation and Abeta fibril maturation. The effect of A8 scFv on Abeta fibrillogenesis was markedly more significant when administered at the start of the Abeta folding reaction. Furthermore, the results also showed that pre-formed Abeta fibrils could be disaggregated via incubation with purified A8 scFv, which suggested that A8 scFv is involved in the reverse reaction of Abeta aggregation. Therefore, A8 scFv was capable of both inhibiting fibrillogenesis and disaggregating matured fibrils. Our present study provides valuable insight into the regulators of ultrastructural dynamics of cell-free "on-pathway" Abeta aggregation and will assist in the development of therapeutic strategies for AD. PMID- 25919300 TI - Characteristic MRI Findings of upper Limb Muscle Involvement in Myotonic Dystrophy Type 1. AB - The objective of our study was to evaluate the relation between muscle MRI findings and upper limb weakness with grip myotonia in patients with myotonic dystrophy type 1 (DM1). Seventeen patients with DM1 were evaluated by manual muscle strength testing and muscle MRI of the upper limbs. Many DM1 patients presenting with decreased grasping power frequently showed high intensity signals in the flexor digitorum profundus (FDP) muscles on T1-weighted imaging. Patients presenting with upper limb weakness frequently also showed high intensity signals in the flexor pollicis longus, abductor pollicis longus, and extensor pollicis muscles. Disturbances of the distal muscles of the upper limbs were predominant in all DM1 patients. Some DM1 patients with a prolonged disease duration showed involvement of not only distal muscles but also proximal muscles in the upper limbs. Muscle involvement of the upper limbs on MRI strongly correlated positively with the disease duration or the numbers of CTG repeats. To our knowledge, this is the first study to provide a detailed description of the distribution and severity of affected muscles of the upper limbs on MRI in patients with DM1. We conclude that muscle MRI findings are very useful for identifying affected muscles and predicting the risk of muscle weakness in the upper limbs of DM1 patients. PMID- 25919301 TI - Measuring Vital Signs: an IOM report on core metrics for health and health care progress. PMID- 25919303 TI - How one-shot learning unfolds in the brain. AB - Much learning occurs gradually through trial and error, but rare and important experiences require one-shot learning; a new study explores how the brain switches between these two strategies for identifying causal relationships. Read the Research Article. PMID- 25919302 TI - Chromium(VI) release from leather and metals can be detected with a diphenylcarbazide spot test. AB - BACKGROUND: Along with chromium, nickel and cobalt are the clinically most important metal allergens. However, unlike for nickel and cobalt, there is no validated colorimetric spot test that detects chromium. Such a test could help both clinicians and their patients with chromium dermatitis to identify culprit exposures. OBJECTIVES: To evaluate the use of diphenylcarbazide (DPC) as a spot test reagent for the identification of chromium(VI) release. METHODS: A colorimetric chromium(VI) spot test based on DPC was prepared and used on different items from small market surveys. RESULTS: The DPC spot test was able to identify chromium(VI) release at 0.5 ppm without interference from other pure metals, alloys, or leather. A market survey using the test showed no chromium(VI) release from work tools (0/100). However, chromium(VI) release from metal screws (7/60), one earring (1/50), leather shoes (4/100) and leather gloves (6/11) was observed. We found no false-positive test reactions. Confirmatory testing was performed with X-ray fluorescence (XRF) and spectrophotometrically on extraction fluids. CONCLUSIONS: The use of DPC as a colorimetric spot test reagent appears to be a good and valid test method for detecting the release of chromium(VI) ions from leather and metal articles. The spot test has the potential to become a valuable screening tool. PMID- 25919304 TI - Lower-dose valganciclovir for the prevention of cytomegalovirus after solid organ transplantation: an important tradeoff. PMID- 25919305 TI - Soybean development: the impact of a decade of agricultural change on urban and economic growth in Mato Grosso, Brazil. AB - In this research we consider the impact of export-driven, soybean agriculture in Mato Grosso on regional economic growth. Here we argue that the soybean sector has served as a motor to the state's economy by increasing the demand for services, housing, and goods, and by providing a source of investment capital to the non-agricultural sector. Specifically, we show that each square kilometer of soybean production supports 2.5 formal sector jobs outside of agriculture, and the equivalent of approximately 150,000US in annual, non-agricultural GDP. We also show that annual gains in non-agricultural employment and GDP are closely tied to soybean profitability, and thus vary from year to year. However, while this article highlights the potential of the agricultural sector as a driver of regional economic growth, it also acknowledges that this growth has been sustained by profits determined by externally set prices and the rate of exchange, and that future growth trajectories will be susceptible to potential currency of market shocks. We also show that while Mato Grosso's economic growth has come at a significant cost to the environment, value added by the agriculture sector, directly and indirectly, has surpassed the value of the CO2-e emitted through land clearings. PMID- 25919306 TI - Maternal consumption of non-staple food in the first trimester and risk of neural tube defects in offspring. AB - To study the associations between maternal consumption of non-staple food in the first trimester and risk of neural tube defects (NTDs) in offspring. Data collected from a hospital-based case-control study conducted between 2006 and 2008 in Shandong/Shanxi provinces including 459 mothers with NTDs-affected births and 459 mothers without NTDs-affected births. Logistic regression models were used to examine the associations between maternal consumption of non-staple food in the first trimester and risk of NTDs in offspring. The effects were evaluated by odds ratio (OR) and 95% confidence intervals (95% CIs) with SAS9.1.3.software. Maternal consumption of milk, fresh fruits and nuts in the first trimester were protective factors for total NTDs. Compared with consumption frequency of ?1 meal/week, the ORs for milk consumption frequency of 1-2, 3-6, >=7 meals/week were 0.50 (95% CI: 0.28-0.88), 0.56 (0.32-0.99), and 0.59 (0.38-0.90), respectively; the ORs for fresh fruits consumption frequency of 1-2, 3-6, >=7 meals/week were 0.29 (95% CI: 0.12-0.72), 0.22 (0.09-0.53), and 0.32 (0.14-0.71), respectively; the ORs for nuts consumption frequency of 1-2, 3-6, >=7 meals/week were 0.60 (95% CI: 0.38-0.94), 0.49 (0.31-0.79), and 0.63 (0.36-1.08), respectively. Different effects of above factors on NTDs were found for subtypes of anencephaly and spina bifida. Maternal non-staple food consumption of milk, fresh fruits and nuts in the first trimester was associated with reducing NTDs risk in offspring. PMID- 25919307 TI - Lower Protein-to-Carbohydrate Ratio in Maternal Diet is Associated with Higher Childhood Systolic Blood Pressure up to Age Four Years. AB - The prenatal environment can influence development of offspring blood pressure (BP), which tracks into adulthood. This prospective longitudinal study investigated whether maternal pregnancy dietary intake is associated with the development of child BP up to age four years. Data are from 129 mother-child dyads enrolled in the Women and Their Children's Health study. Maternal diet was assessed using a validated 74-item food frequency questionnaire at 18 to 24 weeks and 36 to 40 weeks, with a reference period of the previous three months. Child systolic and diastolic BP were measured at 3, 6, 9, 12, 24, 36 and 48 months, using an automated BP monitor. Using mixed-model regression analyses adjusted for childhood growth indices, pregnancy intakes of percentage of energy (E%) polyunsaturated fat (beta coefficient 0.73; 95% CI 0.003, 1.45; p = 0.045), E% omega-6 fatty acids (beta coefficient 0.89; 95% CI 0.09, 1.69; p = 0.03) and protein-to-carbohydrate (P:C) ratio (beta coefficient -14.14; 95% CI -27.68, 0.60; p = 0.04) were associated with child systolic BP trajectory up to 4 years. Child systolic BP was greatest at low proportions of dietary protein (<16% of energy) and high carbohydrate (>40% of energy) intakes. There may be an ideal maternal macronutrient ratio associated with optimal infant BP. Maternal diet, which is potentially modifiable, may play an important role in influencing offspring risk of future hypertension. PMID- 25919308 TI - Optimization of the cytokine secretion assay for human IL-2 in single and combination assays. AB - The cytokine secretion assay identifies live cytokine-secreting cells by capturing the secreted cytokine on a surface-bound capture antibody in dilute suspension culture, followed by detection with a fluorescent anti-cytokine antibody. However, examining the kinetics of cytokine detection revealed that IL 2 staining reached a maximum at early times and then declined, whereas staining for other cytokines including interferon (IFNgamma) increased for up to 90 min. The decline in IL-2 staining could have been due to rapid cessation of cytokine synthesis, coupled with internalization of cytokine/antibody complexes from the cell surface. Consistent with this model, addition of the anti-IL-2 detection antibody during the cytokine secretion step resulted in higher and more sustained staining. This modified method enhanced staining of IL-2 and IL-4, but not IFNgamma, tumor necrosis factor alpha (TNFalpha), or IL-5. However, the longer secretion times possible in the modified assay also improved detection of other cytokines in multi-cytokine combinations. PMID- 25919309 TI - Leptin Manipulation Reduces Appetite and Causes a Switch in Mating Preference in the Plains Spadefoot Toad (Spea bombifrons). AB - Condition- or context-dependent mate choice occurs when females modify their mate preferences depending on their internal or external environment. While the ecological and evolutionary factors that favor the evolution of such plasticity are emerging, relatively little is known of the mechanisms underlying such choice. Here we evaluated whether leptin, a protein hormone involved in the regulation of appetite, might affect the expression of condition-dependent mate choice decisions. To do so, we administered leptin to spadefoot toads, Spea bombifrons, which exhibit condition-dependent mate choice for males of their own species versus congeneric males of S. multiplicata. In particular, poor-condition S. bombifrons are more likely than are good-condition S. bombifrons to prefer S. multiplicata males, but only in environments where hybridization between the two species is beneficial. We found that our leptin treatment reduced appetite in S. bombifrons adults, as was expected from leptin's known effects on appetite. However, although we predicted that leptin would reduce female preferences for heterospecific males, we found the opposite. In particular, our leptin treatment generated a consistent, repeatable preference for heterospecifics in an environment where females generally prefer conspecifics regardless of condition. These results indicate that leptin has the potential to affect female mate choice, but that it might do so in non-intuitive ways. PMID- 25919310 TI - An extended stable isotope-labeled signature peptide internal standard for tracking immunocapture of human plasma osteopontin for LC-MS/MS quantification. AB - A stable isotope-labeled signature peptide, whose sequence corresponds to the human osteopontin (hOPN) specific antibody epitope, was evaluated as an internal standard to compensate for immunocapture variability during quantification of hOPN by immunoaffinity-coupled LC-MS/MS. Immunocapture variability was induced by varying the antibody amount per well from 150 to 4500 ng and analysis was carried out with internal standards added before and after the immunocapture step. The immunocapture variability ranged from -80.9 to 77.0% when the IS was added after immunocapture and from -37.5 to 20.3% when the internal standard was added before immunocapture. The lower variability demonstrates the ability of stable labeled isotope internal standard peptide to compensate for variation during immunocapture. PMID- 25919311 TI - Relationship between pelvic floor symptoms and POP-Q measurements. AB - AIM: To investigate the relationship between pelvic floor symptoms using the Pelvic Floor Bother Questionnaire (PFBQ) and the Pelvic Organ Prolapse Quantification system (POP-Q) measurements. METHODS: This was a retrospective study. Consecutive women seeking care for pelvic floor symptoms were evaluated. The PFBQ was self-administered by all patients before they were examined by three urogynecologists according to the POP-Q. Pearson's correlation and a receiver operating characteristic (ROC) curve were used to investigate relationship between symptoms and POP-Q findings. RESULTS: Four hundred and sixty-seven patients completed the questionnaire and underwent standardized pelvic examination. Anterior, posterior and apical compartment prolapse were found in 95.5%, 78.8% and 35.9%, respectively. Moderate correlations were found between a feeling of bulging and the increasing severity of prolapse of all compartments. For all 8 pelvic floor symptoms, the area under the curve for a feeling of bulge with point Ba and point C was significantly greater than 0.7, suggesting fair ability to predict symptomatic patients. The sensitivity and specificity of the symptom were 60% and 83% when point Ba was 1 cm below the hymen. Whereas they were 55% and 83% when point C was 3 cm above the hymen. CONCLUSIONS: The feeling of a bulge in the vagina is the only symptom that correlated with prolapse of all compartments. The specific thresholds for the feeling of a bulge appear to be 1 cm below the hymen for anterior vaginal wall prolapse, and 3 cm above the hymen for apical prolapse. Neurourol. Urodynam. 35:724-727, 2016. (c) 2015 Wiley Periodicals, Inc. PMID- 25919312 TI - Downregulation of immune responses in asthmatic humans by ES products of Marshallagia marshalli. AB - BACKGROUND AND AIMS: Helminths and their products are considered to possess therapeutic capability to control or even prevent immune-mediated diseases. Studies suggest that helminths induce a systemic immunomodulatory network, including regulatory T cells and anti-inflammatory interleukin-10 (IL-10), which might play a key role in the protection against the allergic phenotype. Thus, helminthic therapy is becoming of a major interest, and several researchers are enthusiastically tended to explore its role in allergic diseases. METHODS: Peripheral blood mononuclear cells (PBMCs) from 25 asthmatic and 25 healthy human were collected. After isolation of PBMCs, they were stimulated with excretory/secretory (ES) antigen of M. marshalli, in incubator with 5% CO2 , 37 degrees C. Total RNA was isolated from all cells from antigen stimulated and non stimulated control PBMC in asthmatic and healthy human after 6 h. The concentration of Th1 type cytokines [interferon-gamma (IFN-gamma)] and Th2 type cytokines (IL-4) and T-reg cytokines [transforming growth factor-beta (TGF-beta), IL-10] was determined using real-time polymerase chain reaction. RESULTS: Results showed that the IFN-gamma expression was significantly decreased in culture condition with ES Ag of M. marshalli in healthy and asthmatic patients (P < 0.05). Similar data were obtained for IL-4 expression in both healthy individuals (<0.006) and asthmatic patients (<0.001). The increment of regulatory cytokines IL-10 and TGF-beta expression was considerably increased in our investigation. CONCLUSION: To our knowledge, this is the first report to document the suppressive effect that the M. marshalli ES product has on PBMSC cell culture of asthmatic patients. The present study provides new insights into understanding the immune modulation governed by parasite-derived products and the development of new asthma treatment strategies. PMID- 25919313 TI - Finite Element Analysis of the Cingulata Jaw: An Ecomorphological Approach to Armadillo's Diets. AB - Finite element analyses (FEA) were applied to assess the lower jaw biomechanics of cingulate xenarthrans: 14 species of armadillos as well as one Pleistocene pampathere (11 extant taxa and the extinct forms Vassallia, Eutatus and Macroeuphractus). The principal goal of this work is to comparatively assess the biomechanical capabilities of the mandible based on FEA and to relate the obtained stress patterns with diet preferences and variability, in extant and extinct species through an ecomorphology approach. The results of FEA showed that omnivorous species have stronger mandibles than insectivorous species. Moreover, this latter group of species showed high variability, including some similar biomechanical features of the insectivorous Tolypeutes matacus and Chlamyphorus truncatus to those of omnivorous species, in agreement with reported diets that include items other than insects. It remains unclear the reasons behind the stronger than expected lower jaw of Dasypus kappleri. On the other hand, the very strong mandible of the fossil taxon Vassallia maxima agrees well with the proposed herbivorous diet. Moreover, Eutatus seguini yielded a stress pattern similar to Vassalia in the posterior part of the lower jaw, but resembling that of the stoutly built Macroeuphractus outesi in the anterior part. The results highlight the need for more detailed studies on the natural history of extant armadillos. FEA proved a powerful tool for biomechanical studies in a comparative framework. PMID- 25919314 TI - Alcohol-related victimisation: Differences between sexual minorities and heterosexuals in an Australian national sample. AB - INTRODUCTION AND AIMS: Alcohol-related violence and other types of victimisation are prevalent, but unevenly distributed across the population. The study investigated the relationship between alcohol-related victimisation and sexual orientation (heterosexual, homosexual, bisexual, other) in a national sample. DESIGN AND METHODS: The study used cross-sectional data from the 2010 Australian National Drug Strategy Household Survey. Logistic regression was used to assess the association of sexual orientation with three types of victimisation (verbal abuse, physical abuse and feeling threatened by a person intoxicated on alcohol in the last 12 months) and controlled for probable confounding variables. RESULTS: Of 24, 858 eligible respondents aged 14 years or older, 26.8% experienced victimisation. Less than 30% of heterosexual men and women suffered victimisation compared with nearly 50% of gay men and bisexual women. Controlling for alcohol, tobacco and illicit drug use, age group, mental health, Indigenous status and socioeconomic factors, logistic regression, stratified by gender, found that the odds of both verbal [adjusted odds ratio (AOR) = 1.52] and physical abuse (AOR=2.04) were greatest for lesbians, while gay men had the greatest odds (AOR=2.25) of feeling threatened. DISCUSSION AND CONCLUSIONS: Across all types of victimisation, some or all sexual minority groups had increased odds of being victimised in the last 12 months compared with their heterosexual counterparts. The pattern of results shows the importance of disaggregating sexual minority status in considering the impact of alcohol related victimisation and in developing interventions or policies. PMID- 25919315 TI - Tackling 30-Day, All-Cause Readmissions with a Patient-Centered Transitional Care Bundle. AB - In 2008, Kaiser Permanente Northwest identified the transition from hospital to home as a pivotal quality improvement opportunity and used multiple patient centered data collection methods to identify unmet needs contributing to preventable readmissions. A transitional care bundle that crosses care settings and organizational functions was developed to meet needs expressed by patients. It comprises 5 elements: risk stratification, a specialized phone number for discharged patients, timely postdischarge follow-up, standardized patient discharge instructions and same-day discharge summaries, and pharmacist-supported medication reconciliation. The transitional care bundle has been in place for 6 years. Readmission rates decreased from 12.1% to 10.6%, Hospital Consumer Assessment of Healthcare Providers and Systems scores for the discharge instruction composite moved from below the 50(th) to above the 90(th) national percentile, average time to the first postdischarge appointment decreased from 9.7 days to 5.3 days, and error rates on the discharge medication list decreased from 57% to 21% (P<.0001 for all). The program, which continues to evolve to address sustainability challenges and organizational initiatives, suggests the potential of a multicomponent, patient-centered care bundle to address the complex, interrelated drivers of preventable readmissions. PMID- 25919316 TI - Facilitation of visual perception in head direction: visual attention modulation based on head direction. AB - People usually see things using frontal viewing, and avoid lateral viewing (or eccentric gaze) where the directions of the head and eyes are largely different. Lateral viewing interferes with attentive visual search performance, probably because the head is directed away from the target and/or because the head and eyes are misaligned. In this study, we examined which of these factors is the primary one for interference by conducting a visual identification experiment where a target was presented in the peripheral visual field. The critical manipulation was the participants' head direction and fixation position: the head was directed to the fixation location, the target position, or the opposite side of the fixation. The performance was highest when the head was directed to the target position even when there was misalignment of the head and eye, suggesting that visual perception can be influenced by both head direction and fixation position. PMID- 25919317 TI - Regional assessment of LV wall in infarcted heart using tagged MRI and cardiac modelling. AB - A segmental two-parameter empirical deformable model is proposed for evaluating regional motion abnormality of the left ventricle. Short-axis tagged MRI scans were acquired from 10 healthy subjects and 10 postinfarct patients. Two motion parameters, contraction and rotation, were quantified for each cardiac segment by fitting the proposed model using a non-rigid registration algorithm. The accuracy in motion estimation was compared to a global model approach. Motion parameters extracted from patients were correlated to infarct transmurality assessed with delayed-contrast-enhanced MRI. The proposed segmental model allows markedly improved accuracy in regional motion analysis as compared to the global model for both subject groups (1.22-1.40 mm versus 2.31-2.55 mm error). By end-systole, all healthy segments experienced radial displacement by ~25-35% of the epicardial radius, whereas the 3 short-axis planes rotated differently (basal: 3.3 degrees ; mid: -1 degrees and apical: -4.6 degrees ) to create a twisting motion. While systolic contraction showed clear correspondence to infarct transmurality, rotation was nonspecific to either infarct location or transmurality but could indicate the presence of functional abnormality. Regional contraction and rotation derived using this model could potentially aid in the assessment of severity of regional dysfunction of infarcted myocardium. PMID- 25919318 TI - Transport of treosulfan and temozolomide across an in-vitro blood-brain barrier model. AB - In vitro, treosulfan (TREO) has shown high effectiveness against malignant gliomas. However, a first clinical trial for newly diagnosed glioblastoma did not show any positive effect. Even though dosing and timing might have been the reasons for this failure, it might also be that TREO does not reach the brain in sufficient amount. Surprisingly, there are no published data on TREO uptake into the brain of patients, despite extensive research on this compound. An in-vitro blood-brain barrier (BBB) model consisting of primary porcine brain capillary endothelial cells was used to determine the transport of TREO across the cell monolayer. Temozolomide (TMZ), the most widely used cytotoxic drug for malignant gliomas, served as a reference. An HPLC-ESI-MS/MS procedure was developed to detect TREO and TMZ in cell culture medium. Parallel to the experimental approach, the permeability of TREO and the reference substance across the in vitro BBB was estimated on the basis of their physicochemical properties. The detection limit was 30 nmol/l for TREO and 10 nmol/l for TMZ. Drug transport was measured in two directions: influx, apical-to-basolateral (A-to-B), and efflux, basolateral-to-apical (B-to-A). For TREO, the A-to-B permeability was lower (1.6%) than the B-to-A permeability (3.0%). This was in contrast to TMZ, which had higher A-to-B (13.1%) than B-to-A (7.2%) permeability values. The in-vitro BBB model applied simulated the human BBB properly for TMZ. It is, therefore, reasonable to assume that the values for TREO are also meaningful. Considering the lack of noninvasive, significant alternative methods to study transport across the BBB, the porcine brain capillary endothelial cell model was efficient to collect first data for TREO that explain the disappointing clinical results for this drug against cerebral tumors. PMID- 25919319 TI - Effectiveness, toxicity, and economic evaluation of vinflunine for the treatment of patients with transitional cell carcinoma in the Spanish outpatient setting. AB - The aim of this study was to evaluate the effectiveness and toxicity profile of the vinflunine chemotherapy regimen and to examine the cost-effectiveness relation in a real-world sample of patients with transitional cell carcinoma of the bladder. This is a multicenter, observational, retrospective cohort study. To assess the effectiveness and safety of vinflunine treatment, progression-free survival, overall survival, and adverse events were registered. An economic evaluation was performed and cost-effectiveness ratios were calculated. A total of 37 patients were included in the study, with a mean age of 67 (SD=9) years. The median progression-free survival was 2.61 months (95% confidence interval 1.79-4.23) and the median overall survival was 5.72 months (95% confidence interval 3.34-10.35). An objective response was achieved in eight (22%) patients. Statistically significant differences were found between patients treated with vinflunine as a second-line therapy and those treated with vinflunine as a third line therapy (P=0.036). The most commonly reported analytical adverse event was anemia (n=34; 92%), and the most severe was neutropenia (n=19; 51%), with nine patients developing grade 4 neutropenia (9/19; 47%). The total cost of vinflunine treatment was &OV0556;553 873, with a median of &OV0556;8524 (interquartile range, &OV0556;9220) per patient. The median-based cost-effectiveness ratio was &OV0556;44 789 (&OV0556;31 706-58 022) per progression-free year gained and &OV0556;22 750 (&OV0556;14 526-34 085) per life-year gained. The data from this study fill an important need for information on the relative value of this treatment in terms of cost-effectiveness and might help achieve an optimal quality healthcare system. PMID- 25919320 TI - Changes in Achilles tendon mechanical properties following eccentric heel drop exercise are specific to the free tendon. AB - Mechanical loading of the Achilles tendon during isolated eccentric contractions could induce immediate and region-dependent changes in mechanical properties. Three-dimensional ultrasound was used to examine the immediate effect of isolated eccentric exercise on the mechanical properties of the distal (free tendon) and proximal (gastrocnemii) regions of the Achilles tendon. Participants (n = 14) underwent two testing sessions in which tendon measurements were made at rest and during a 30% and 70% isometric plantar flexion contractions immediately before and after either: (a) 3 * 15 eccentric heel drops or (b) 10-min rest. There was a significant time-by-session interaction for free tendon length and strain for all loading conditions (P < 0.05). Pairwise comparisons revealed a significant increase in free tendon length and strain at all contraction intensities after eccentric exercise (P < 0.05). There was no significant time-by-session interaction for the gastrocnemii (medial or lateral) aponeurosis or tendon for any of the measured parameters. Immediate changes in Achilles tendon mechanical properties were specific to the free tendon and consistent with changes due to mechanical creep. These findings suggest that the mechanical properties of the free tendon may be more vulnerable to change with exercise compared with the gastrocnemii aponeurosis or tendon. PMID- 25919321 TI - Meta-analysis of the effect of preoperative breast MRI on the surgical management of ductal carcinoma in situ. AB - BACKGROUND: MRI has been used increasingly in the diagnosis and management of women with invasive breast cancer. However, its usefulness in the preoperative assessment of ductal carcinoma in situ (DCIS) remains questionable. A meta analysis was conducted to examine the effects of MRI on surgical treatment of DCIS by analysing studies comparing preoperative MRI with conventional preoperative assessment. METHODS: Using random-effects modelling, the proportion of women with various outcomes in the MRI versus no-MRI groups was estimated, and the odds ratio (OR) and adjusted OR (adjusted for study-level median age) for each model were calculated. RESULTS: Nine eligible studies were identified that included 1077 women with DCIS who had preoperative MRI and 2175 who did not. MRI significantly increased the odds of having initial mastectomy (OR 1.72, P = 0.012; adjusted OR 1.76, P = 0.010). There were no significant differences in the proportion of women with positive margins following breast-conserving surgery (BCS) in the MRI and no-MRI groups (OR 0.80, P = 0.059; adjusted OR 1.10, P = 0.716), nor in the necessity of reoperation for positive margins after BCS (OR 1.06, P = 0.759; adjusted OR 1.04, P = 0.844). Overall mastectomy rates did not differ significantly according to whether or not MRI was performed (OR 1.23, P = 0.340; adjusted OR 0.97, P = 0.881). CONCLUSION: Preoperative MRI in women with DCIS is not associated with improvement in surgical outcomes. PMID- 25919324 TI - Infliximab and adalimumab, unlike ustekinumab, increase serum KL-6 levels in Japanese patients with psoriasis. PMID- 25919322 TI - Heterogeneity in the properties of mutant secreted lymphocyte antigen 6/urokinase receptor-related protein 1 (SLURP1) in Mal de Meleda. PMID- 25919325 TI - Cytokinin concentrations and CHASE-DOMAIN CONTAINING HIS KINASE 2 (NaCHK2)- and NaCHK3-mediated perception modulate herbivory-induced defense signaling and defenses in Nicotiana attenuata. AB - Herbivore attack elicits changes in cytokinins (CKs), but how these changes influence defense signaling remains poorly described. We investigated the influence of the CK pathway on the well-described inducible defense pathways of Nicotiana attenuata in response to wounding with and without elicitors from the specialist herbivore Manduca sexta. CK pathway manipulation often suffers from substantial side effects on plant growth and development. We therefore used multiple manipulation tools including spray application of CKs, chemically inducible expression of the CK biosynthesis enzyme isopentenyltransferase, and transient and constitutive RNAi-mediated gene silencing of CK receptors to resolve the function of CKs in plant defense. The results demonstrated that CK concentrations in leaves and perception through CHASE-DOMAIN CONTAINING HIS KINASE 2 (NaCHK2) and NaCHK3 were important for the accumulation of jasmonic acid (JA) and phenolamides and proteinase inhibitor activity. By contrast, the CK pathway did not promote the accumulation of the active JA-isoleucine conjugate and negatively regulated the release of specific green leaf volatile esters. Interestingly, CK signaling also promotes the systemic phenolamide accumulation. We conclude that the CK pathway is an important regulator of herbivory-inducible defense signaling and chemistry, which expands its reported participation in adjusting a plant's physiology to abiotic and biotic stress responses. PMID- 25919326 TI - Inclusion complex formation of ternary system: Fluoroscein-p-sulfonato calix[4]arene-Cu(2+) by cooperative binding. AB - The aqueous solution of fluorescein-para sulfonato calix[4]arene-metal ion complex has been studied based on absorption, fluorescence, (1)H NMR and FTIR spectroscopic results. It was found that the fluorescence intensity quenched regularly upon addition of pSCX4 and metal ion. The quenching constants and binding constants were determined for pSCX4-FL and pSCX4-FL-Cu(2+) systems. 1:1 stoichiometry is obtained for pSCX4-Cu(2+) system by continuous variation method. The NMR and IR results indicates the interaction among FL, pSCX4 and Cu(2+). The combined results demonstrate the cooperative binding to design the complex for ternary system. The life time for binary and ternary system has been studied. PMID- 25919327 TI - Quality assessment of the saffron samples using second-order spectrophotometric data assisted by three-way chemometric methods via quantitative analysis of synthetic colorants in adulterated saffron. AB - Saffron is a valuable culinary spice that can be used not only for dyes and cooking, but also for many medical purposes. Due to its high price and restriction of its production, various fraud manners in its production have been growing. Addition of synthetic colorants to saffron is the most common way for adulteration. In this work, chemometric methods are proposed to resolve the three dimensional absorbance spectra-pH data for simultaneous determination of the two colorants Tartrazin and Sunset yellow, in adulterated saffron. The rank deficiency in the concentration mode impaired the system. Therefore, to extirpate the ambiguity, which results from rank deficiency, three-way variation array V was generated by subtracting the first pH spectrum from each spectrum at each pH. This allows the extraction of extent reaction profile and mixture reaction spectral profiles, as well as the relative concentrations of the analytes. PMID- 25919328 TI - FT-IR and FT-Raman spectra of 2-hydroxyethyl methacrylate--A conformational and vibrational analysis. AB - A conformational search of the flexible 2-hedroxyethyl methacrylate molecule by semi-empirical AM1 and B3LYP formalisms leads to six stable conformations. Four of them are in the s-trans conformation. The optimized geometries at DFT using 6 311+G(**) basis set are in good agreement with experimental electron diffraction data of the methyl methacrylate molecule, thereby the s-trans is the most stable form. The harmonic frequencies at the fully optimized geometries of all conformers have been performed at the DFT//B3LYP/6-311+G(**) level of theory. Infrared and Raman intensities and potential energy distributions of the scaled harmonic frequencies are used for the assignment of the observed IR and Raman bands. We noticed a good agreement between the experimental and the computed spectra. The strong band at 1081 cm(-1), in the infrared spectrum, maybe used as a characteristic band of the s-trans conformation. Henceforth, the less stable structure contribute alone for reproducing the Raman bands located at 276 (sh) and 3020 (vw) cm(-1). PMID- 25919329 TI - Colorimetric detection of Bi (III) in water and drug samples using pyridine-2,6 dicarboxylic acid modified silver nanoparticles. AB - A new selective, simple, fast and sensitive method is developed for sensing assay of Bi (III) using pyridine-2,6-dicarboxylic acid or dipicolinic acid (DPA) modified silver nanoparticles (DPA-AgNPs). Silver nanoparticles (AgNPs) were synthesized by reducing silver nitrate (AgNO3) with sodium borohydride (NaBH4) in the presence of DPA. Bismuth detection is based on color change of nanoparticle solution from yellow to red that is induced in the presence of Bi (III). Aggregation of DPA-AgNPs has been confirmed with UV-vis absorption spectra and transmission electron microscopy (TEM) images. Under the optimized conditions, a good linear relationship (correlation coefficient r=0.995) is obtained between the absorbance ratio (A525/A390) and the concentration of Bi (III) in the 0.40 8.00 MUM range. This colorimetric probe allows Bi (III) to be rapidly quantified with a 0.01 MUM limit of detection. The present method successfully applied to determine bismuth in real water and drug samples. Recoveries of water samples were in the range of 91.2-99.6%. PMID- 25919330 TI - Structural and spectral investigation of terbium molybdate nanophosphor. AB - Terbium molybdate nanophosphors were synthesized through a facile sol-gel route. The structure of the phosphors was characterized by X-ray diffraction, Raman spectra and Fourier transform infrared spectroscopy analysis. The X-ray diffraction studies revealed that the structure of the nanophosphor gradually changes from monoclinic to orthorhombic phase as heated from 700 to 900 degrees C. High resolution transmission electron microscopy, SAED and EDS were also employed to characterize the size, crystallinity and composition of the samples. Detailed spectroscopic investigations were carried out by Judd-Ofelt analysis based on UV-Visible-NIR absorption and emission spectra. The luminescence spectra suggest that phosphors with orthorhombic structure have better luminescence properties than the monoclinic structure. The phosphors showed intense green emission under near-UV excitation due to the energy transfer from the host lattice to Tb(3+) ions. The CIE coordinates suggest enhanced color purity for green emission and short fluorescence decay values proposes the suitability for LED applications. These phosphors can be applied as promising candidates for blue and near-UV excited WLEDs. PMID- 25919332 TI - Hypochondriasis as an early manifestation of dementia with Lewy bodies: an autopsied case report. AB - Discrepancies between clinical and pathological diagnoses of dementia with Lewy bodies (DLB) may occur because the full disease progression remains unclear, especially during the early stage. Herein, we report the case of a 78-year-old Japanese man with hypochondriasis who had autopsy-confirmed limbic-type DLB pathology. He exhibited no core clinical features of DLB. We attempted to identify the clinicopathological correlations in the early stages of DLB. At the age of 77, he became hypochondriacal and exhibited progressive cognitive decline after the death of his wife. He was concerned about his poor physical condition, but hospital examinations did not identify any overtly abnormal findings. At 78 years of age, he consulted a neurologist with complaints of facial numbness and irritability. Neurological examination revealed no overt abnormality, and he scored 21 points on the Mini-Mental State Examination. Magnetic resonance imaging of the brain showed mild bilateral ventricular enlargement. The patient was clinically diagnosed as having possible Alzheimer's disease. Approximately 1 month after his consult, he died of acute pneumonia in a psychiatric hospital to which he had been admitted for severe aggressive behaviour. He exhibited no core clinical features pointing towards a clinical diagnosis of DLB. Neuropathological investigation revealed limbic-type Lewy body disease with concurrent minimum Alzheimer-type pathology, which corresponds to high-likelihood DLB pathology based on the Third Consortium DLB pathological criteria. The patient had minimum nigral degeneration, which is consistent with the absence of parkinsonism. This autopsied case suggests that some DLB patients exhibit hypochondriasis in the early stage of the disease, even if they lack the core clinical features of DLB. PMID- 25919333 TI - Versatile (bio)functionalization of bromo-terminated phosphonate-modified porous aluminum oxide. AB - Porous aluminum oxide (PAO) is a nanoporous material used for various (bio)technological applications, and tailoring its surface properties via covalent modification is a way to expand and refine its application. Specific and complex chemical modification of the PAO surface requires a stepwise approach in which a secondary reaction on a stable initial modification is necessary to achieve the desired terminal molecular architecture and reactivity. We here show that the straightforward initial modification of the bare PAO surface with bromo terminated phosphonic acid allows for the subsequent preparation of PAO with a wide scope of terminal reactive groups, making it suitable for (bio)functionalization. Starting from the initial bromo-terminated PAO, we prepared PAO surfaces presenting various terminal functional groups, such as azide, alkyne, alkene, thiol, isothiocyanate, and N-hydroxysuccinimide (NHS). We also show that this wide scope of easily accessible tailored reactive PAO surfaces can be used for subsequent modification with (bio)molecules, including carbohydrate derivatives and fluorescently labeled proteins. PMID- 25919334 TI - [Equipment, Risk Awareness and Safety-Relevant Behaviour of Via Ferrata Climbers]. AB - BACKGROUND: Climbing via ferrata routes is becoming more and more popular. The growing number of via ferrata climbers is associated with an increasing number of accidents. In addition to adequate equipment and its correct handling, knowledge of specific risks and safety-related behaviour play an important role for safety on via ferrata routes. The goal of this study was to collect data on equipment, via ferrata-specific risk knowledge, safety-related behaviour, and general risk taking behaviour of via ferrata climbers. METHODS: In this survey, data of 332 climbers of different via ferrata routes in Tyrol (Austria) were collected using a standardised data entry form including socio-demographic data, the use of via ferrata-specific equipment and first aid equipment. Knowledge of via ferrata specific risks was assayed by a questionnaire including 4 questions. Additionally, safety-related behaviour and general risk-taking behaviour of the via ferrata climbers were evaluated. RESULTS: 92 % of the interviewed persons were wearing a helmet and helmet use was significantly lower in females (86 %) compared to males (96 %). In total, 10 % of the via ferrata climbers used inadequate belaying equipment or no equipment at all. The 4 questions related to via ferrata-specific risks were correctly answered by an average of 46 % of the climbers. A partner check was carried out by 76 % before starting the tour. 96 % of the climbers stated they ask the climber ahead of them for the possibility to overtake and wait for a suitable and safe spot. 64 % reported that they would not pass without self-belay. General risk-taking behaviour was scored at 4.26 +/- 1.75 with significant differences between female and male via ferrata climbers (3.79 +/- 1.37 vs. 4.53 +/- 1.88). CONCLUSION: Although most of the via ferrata climbers use adequate equipment, helmet use could be optimised in females. Via ferrata climbers should be better informed of the risks of climbing via ferrata routes and safety-related behaviour. Preventive measures including information panels at the entrances of the via ferrata routes and broad information campaigns could contribute to reduce the number of accidents. PMID- 25919335 TI - [Interrater Reliability of the Single Leg Pick-Up Test for Evaluating Postural Control and Movement Control of the Lumbar Spine and Lower Extremity]. AB - BACKGROUND: Patellofemoral pain syndrome is not really a diagnosis but rather describes the symptoms of this non-traumatic knee joint disease. Decreased movement control of the entire leg is discussed as a reason for the developing pain. Assessments of movement control include functional performance tests. A test to assess postural control and movement control of the foot, knee, hip and lumbar spine is the "Single Leg Pick-Up Test". The aim of the present study is to evaluate the interrater reliability of this test. Subjects/Material and Methods: 56 healthy subjects and three experienced raters participated in the study to assess the interrater reliability. Live rating and video rating were assessed and compared by pairs. RESULTS: Intraclass correlations of the reached scores ranged from good to excellent (ICCunjust 0.72/0.63/0.85). Kappa and PABAK calculations of the observation criteria reached moderate to good values. The O PABAK for all observation criteria was 0.70/0.69/0.80 for the paired comparison of the raters. The agreement of six of seven observation criteria based on PABAK calculations were good to very good for the pairs of raters. CONCLUSIONS: All motor control deficits present in patellofemoral pain syndrome can be observed by the "Single Leg Pick-Up Test" with substantial reliability. Future studies should confirm reliability and further evaluate discriminative validity of the test. The "Single Leg Pick-Up" can be carried out easily and has the potential to assess patients with patellofemoral pain syndrome and healthy athletes for movement control deficits. PMID- 25919336 TI - Assembly and purification of enzyme-functionalized DNA origami structures. AB - The positioning of enzymes on DNA nanostructures for the study of spatial effects in interacting biomolecular assemblies requires chemically mild immobilization procedures as well as efficient means for separating unbound proteins from the assembled constructs. We herein report the exploitation of free-flow electrophoresis (FFE) for the purification of DNA origami structures decorated with biotechnologically relevant recombinant enzymes: the S-selective NADP(+)/NADPH-dependent oxidoreductase Gre2 from S. Cerevisiae and the reductase domain of the monooxygenase P450 BM3 from B. megaterium. The enzymes were fused with orthogonal tags to facilitate site-selective immobilization. FFE purification yielded enzyme-origami constructs whose specific activity was quantitatively analyzed. All origami-tethered enzymes were significantly more active than the free enzymes, thereby suggesting a protective influence of the large, highly charged DNA nanostructure on the stability of the proteins. PMID- 25919337 TI - Protein transduction domain of transactivating transcriptional activator fused to outer membrane protein K of Vibrio parahaemolyticus to vaccinate marbled eels (Anguilla marmorata) confers protection against mortality caused by V. parahaemolyticus. AB - Although immersion and oral vaccination are the most practical methods for fish farmers, their applications are very limited due to low immune stimulation effect. We used the protein transduction domain (PTD) of transactivating transcriptional factor (TAT) derived from HIV TAT protein to increase the delivery efficiency of aquatic protein vaccines. Vibrio parahaemolyticus outer membrane protein K (ompK), a reported vaccine candidate for the prevention of V. parahaemolyticus infection, was fused with TAT-PTD expressed in Escherichia coli. We found that PTD-ompK fusion protein effectively penetrated into marbled eel bodies. Analysis of ompK antibody titres demonstrated that immersion vaccination with PTD-ompK was superior to ompK alone and induced robust immune stimulation in marbled eels. Both active and passive protection analyses against immersive challenge with V. parahaemolyticus strains demonstrated that marbled eels immunized with PTD-ompK survived significantly longer than those immunized with ompK alone. Our results indicated that TAT-PTD could be served as is an efficient delivery system for aquatic immersion vaccinations against various infectious diseases commonly seen in aquatic farm industry. PMID- 25919338 TI - A threat to our integrity--Meanings of providing nursing care for older patients with cognitive impairment in acute care settings. AB - BACKGROUND: Older people with cognitive impairment represent a large group of patients in acute care settings. Research show that these acute care environments can be unsafe and even unfriendly for frail older patients. Research and clinical experience show that being a nurse in acute/specialised medical facilities means to work in a high-speed, technologically complex and demanding environment. When caring for older patients with cognitive impairment, nurses' workload and responsibilities have been shown to increase. This is largely dependent on how easily it is to connect with and help patients understand what to do, and what is best for them. AIM: This study aimed to illuminate meanings of caring for older patients with cognitive impairment in acute care settings as experienced by nursing staff. METHOD: A purposeful sample of thirteen nurses experienced in caring for older people with cognitive impairment in acute care settings participated in the study. Narrative interviews were conducted during autumn 2012 and interpreted using a phenomenological hermeneutic method. FINDINGS: Caring for older, acutely ill cognitively impaired patients was found to be very complex. The meanings of caring for these older patients seemed to change depending on the nurses' perceptions of the patients and the gap between what they could do (real) and wanted to do (ideal) in providing care for them. The greater this gap was felt to be and the more care was perceived as meaningless, the more serious was the threat to nurses' personal-professional integrity which could be at risk, compromised or harmed. CONCLUSION: The comprehensive understanding indicates that being a nurse and having to care for older patients in acute care settings means providing nursing care in an environment that does not support possibilities to protect and develop nurses' personal-professional integrity. PMID- 25919339 TI - Photochemical Degradation of the Anticancer Drug Bortezomib by V-UV/UV (185/254 nm) Investigated by (1)H NMR Fingerprinting: A Way to Follow Aromaticity Evolution. AB - We have investigated the removal of bortezomib, an anticancer drug prescribed in multiple myeloma, using the photochemical advanced oxidation process of V-UV/UV (185/254 nm). We used two complementary analytical techniques to follow the removal rate of bortezomib. Nuclear magnetic resonance (NMR) is a nonselective method requiring no prior knowledge of the structures of the byproducts and permits us to provide a spectral signature (fingerprinting approach). This untargeted method provides clues to the molecular structure changes and information on the degradation of the parent drug during the irradiation process. This holistic NMR approach could provide information for monitoring aromaticity evolution. We use liquid chromatography, coupled with high-resolution mass spectrometry (LC-MS), to correlate results obtained by (1)H NMR and for accurate identification of the byproducts, in order to understand the mechanistic degradation pathways of bortezomib. The results show that primary byproducts come from photoassisted deboronation of bortezomib at 254 nm. A secondary byproduct of pyrazinecarboxamide was also identified. We obtained a reliable correlation between these two analytical techniques. PMID- 25919341 TI - Heavy metal contents in the sediments of astatic ponds: Influence of geomorphology, hydroperiod, water chemistry and vegetation. AB - The contents of heavy metals (Cd, Cr, Cu, Ni, Pb, Zn) were analysed in the bottom sediments of 30 small, astatic ponds located in the agricultural landscape of Western Poland. The samples were collected from 118 stations located in patches of four vegetation types. Relationships between the contents of particular elements and four groups of factors (geomorphology, hydroperiod, water quality and vegetation) were tested using Redundancy Analysis (RDA). The most important factors influencing the heavy metal contents were the maximum depth and area of the pond, its hydroperiod, water pH and conductivity values. In general, low quantities of heavy metals were recorded in the sediments of kettle-like ponds (small but located in deep depressions) and high in water bodies of the shore bursting type (large but shallow). Moreover, quantities of particular elements were influenced by the structure of the vegetation covering the pond. Based on the results, we show which types of astatic ponds are most exposed to contamination and suggest some conservation practices that may reduce the influx of heavy metals. PMID- 25919340 TI - Objectively measured physical activity and longitudinal changes in adolescent body fatness: an observational cohort study. AB - BACKGROUND: The data regarding prospective associations between physical activity (PA) and adiposity in youth are inconsistent. OBJECTIVE: The objective of this study was to investigate associations between baseline levels of objectively measured PA and changes in adiposity over 2.5 years from mid-to-late adolescence. METHODS: This was an observational cohort study in 728 school students (43% boys) from Cambridgeshire, United Kingdom. Fat mass index (FMI, kg m(-2) ) was estimated at baseline (mean +/- standard deviation age: 15 +/- 0.3 years) and follow-up (17.5 +/- 0.3 years) by anthropometry and bioelectrical impedance. Habitual PA was assessed at baseline by >=3 d combined heart rate and movement sensing. Average daily PA energy expenditure (PAEE) and the time (min d(-1) ) spent in light, moderate and vigorous intensity PA (LPA, MPA and VPA, respectively) was estimated. Multilevel models were used to investigate associations between baseline PA and change in FMI (DeltaFMI). Adjustment for baseline age, sex, follow-up duration, area-level socioeconomic status, season of PA assessment, sedentary time, energy intake and sleep duration was made; baseline FMI was also added in a second model. RESULTS: FMI increased significantly over follow-up (0.6 +/- 1.2 kg m(-2) , P < 0.001). Baseline PAEE and LPA positively predicted DeltaFMI in overfat participants (P <= 0.030), as did VPA in initially normal fat participants (P <= 0.044). There were further positive associations between PAEE and DeltaFMI in normal fat participants, and between MPA and DeltaFMI in both fat groups, when adjusted for baseline FMI (P <= 0.024). CONCLUSIONS: Baseline PAEE and its subcomponents were positively associated with small and unlikely clinically relevant increases in DeltaFMI. These counter-intuitive findings may be explained by behavioural changes during the course of study follow-up. PMID- 25919342 TI - delta(34)S values and S concentrations in native and transplanted Pleurozium schreberi in a heavily industrialised area. AB - Sulphur is an element found in surplus in anthropogenic areas and one of the minerals responsible for the development of acid rains. The analysis of stable S isotopes provides a powerful tool for studying various aspects of the biogeochemical circulation of sulphur. delta(34)S values and S concentrations were determined in a 90-day experiment with the native moss Pleurozium schreberi from rural, urban and industrial sites in Upper Silesia in southern Poland. At the same time P. schreberi from a control site was transplanted to the same rural, urban and industrial sites and the delta(34)S values and S concentrations were determined in the same 90-day experiment. (34)S enrichment (up to 4.70/00) in the mosses tested indicates that these plants responded to environmental pollution stress. Sulphur isotopic composition in the transplanted P. schreberi was related to S concentrations in this species after 90 days of the experiment. Higher delta(34)S values and S concentrations were noted in native mosses than in those transplanted from rural and urban sites while an opposite situation was reported in industrial sites. The transplanted P. schreberi was a better sulphur bioindicator than the native moss in more polluted industrial sites and worse in less polluted rural and urban sites. PMID- 25919343 TI - Health status of tadpoles and metamorphs of Rhinella arenarum (Anura, Bufonidae) that inhabit agroecosystems and its implications for land use. AB - Perturbations of water bodies near agricultural and livestock systems can affect embryonic and larval stages of anurans and negatively impact adult populations and structure of amphibian communities. This study is focused on early development of Rhinella arenarum, for which body growth, abnormalities in the oral disc and genetic damage on erythrocytes were analyzed to establish the impact of agroecosystems on local populations of amphibians. Tadpoles and metamorphs of R. arenarum were collected in three agroecosystems (namely, C1, C2, and C3) and in a site without agricultural and livestock activities (SM) from central Argentina. Egg masses of C1 were extracted for breeding tadpoles under laboratory conditions (Lab). Tadpoles were in small size and lighter in weight in C1 and C2. Metamorphs were shorter and lighter in weight in C1 and C3. In SM and Lab samples, no tadpoles with abnormal LTRF (labial tooth row formula) or without labial teeth were observed. In C1, the highest frequency of abnormal LTRF was recorded and was the only site in which tadpoles without labial teeth were found. In C1 and C2 the tadpoles had highest micronucleus frequencies and nuclear abnormalities. C1 can be considered as the site with the highest anthropogenic perturbation and with less healthy tadpoles. Livestock practices such as alternating cattle between parcel and keeping a buffer between crops and water bodies, would allow a better development of the first aquatic stages that are essential for the conservation of the anuran populations. PMID- 25919344 TI - Comparison of Monoplanar and Biplanar Access Techniques for Percutaneous Nephrolithotomy. AB - PURPOSE: The aim of this study was to compare the positive aspects and complications of monoplanar and biplanar access techniques used in percutaneous nephrolithotomy (PCNL) based on the modified Clavien complication grading system. PATIENTS AND METHODS: The data from patients who underwent PCNL using either monoplanar access (group 1) or biplanar access (group 2) techniques were analyzed retrospectively. For the biplanar technique, puncture is adjusted based on different fluoroscopic projections, including vertical and 30 degree positions. For the monoplanar technique, a C-arm fluoroscope was brought into vertical position, the collecting system was visualized with a contrast agent, and the most appropriate calix was selected to extract the targeted stone. RESULTS: The monoplanar technique was performed for renal access in 310 patients (group 1), and the biplanar technique was used for renal access in 351 patients (group 2). There were no statistically significant differences between the two groups with regard to demographic data. The mean puncture time was significantly lower in group 1 (monoplanar) when compared with that of group 2 (biplanar, P=0.04). The overall success rates of the monoplanar and biplanar groups were 88% and 89% (including clinically insignifican residual fragments in 9% and 7%), respectively (P>0.05), and the complication rates of both groups were similar. CONCLUSION: The monoplanar access technique, which is safe to use, decreases puncture time, minimizes the surgeon's direct exposure time to radiation, and has similar success rates as the biplanar access technique. PMID- 25919345 TI - Behavioural responses in a net restraint test predict interrenal reactivity in Arctic charr Salvelinus alpinus. AB - In this study, a 1 min net restraint test was evaluated as a method to predict stress-coping style in Arctic charr Salvelinus alpinus, by investigating the relationship between behaviour during the test and levels of plasma cortisol sampled after 30 min confinement. In two separate groups of S. alpinus, general linearized model revealed significant correlations between cortisol levels and principal component scores extracted from principal component analysis, combining measures of activity in the tests. With the use of glmulti, the model selection ruled out any effects of size, sex and order of capture on interrenal reactivity. In general, S. alpinus that were more active in the net restraint test also had low levels of circulating cortisol, suggesting a proactive coping style. The results from two repeated runs were not correlated, but both runs, performed eight days apart, show a negative correlation between post-stress cortisol level and activity in the net. The lack of consistency could be explained by different treatments before each run and individual differences in behavioural plasticity. The net restraint test is thus predictive of stress-coping style in S. alpinus, and has the benefit of being less time-consuming than the commonly used confinement stress test. PMID- 25919346 TI - Screening, verification, and optimization of biomarkers for early prediction of cardiotoxicity based on metabolomics. AB - Drug-induced cardiotoxicity seriously affects human health and drug development. However, many conventional detection indicators of cardiotoxicity exhibit significant changes only after the occurrence of severe heart injuries. Therefore, we investigated more sensitive and reliable indicators for the evaluation and prediction of cardiotoxicity. We created rat cardiotoxicity models in which the toxicity was caused by doxorubicin (20 mg/kg), isoproterenol (5 mg/kg), and 5-fluorouracil (125 mg/kg). We collected data from rat plasma samples based on metabolomics using ultra-performance liquid chromatography quadrupole time-of-flight mass spectrometry. Following multivariate statistical and integration analyses, we selected 39 biomarker ions of cardiotoxicity that predict cardiotoxicity earlier than biochemical analysis and histopathological assessment. Because drugs with different toxicities may cause similar metabolic changes compared with other noncardiotoxic models (hepatotoxic and nephrotoxic models), we obtained 10 highly specific biomarkers of cardiotoxicity. We subsequently used a support vector machine (SVM) to develop a predictive model to verify and optimize the exclusive biomarkers. l-Carnitine, 19 hydroxydeoxycorticosterone, LPC (14:0), and LPC (20:2) exhibited the strongest specificities. The prediction rate of the SVM model is as high as 90.0%. This research provides a better understanding of drug-induced cardiotoxicity in drug safety evaluations and secondary development and demonstrates novel ideas for verification and optimization of biomarkers via metabolomics. PMID- 25919347 TI - Characterizing the Three-Dimensional Structure of Block Copolymers via Sequential Infiltration Synthesis and Scanning Transmission Electron Tomography. AB - Understanding and controlling the three-dimensional structure of block copolymer (BCP) thin films is critical for utilizing these materials for sub-20 nm nanopatterning in semiconductor devices, as well as in membranes and solar cell applications. Combining an atomic layer deposition (ALD)-based technique for enhancing the contrast of BCPs in transmission electron microscopy (TEM) together with scanning TEM (STEM) tomography reveals and characterizes the three dimensional structures of poly(styrene-block-methyl methacrylate) (PS-b-PMMA) thin films with great clarity. Sequential infiltration synthesis (SIS), a block selective technique for growing inorganic materials in BCPs films in an ALD tool and an emerging technique for enhancing the etch contrast of BCPs, was harnessed to significantly enhance the high-angle scattering from the polar domains of BCP films in the TEM. The power of combining SIS and STEM tomography for three dimensional (3D) characterization of BCP films was demonstrated with the following cases: self-assembled cylindrical, lamellar, and spherical PS-b-PMMA thin films. In all cases, STEM tomography has revealed 3D structures that were hidden underneath the surface, including (1) the 3D structure of defects in cylindrical and lamellar phases, (2) the nonperpendicular 3D surface of grain boundaries in the cylindrical phase, and (3) the 3D arrangement of spheres in body-centered-cubic (BCC) and hexagonal-closed-pack (HCP) morphologies in the spherical phase. The 3D data of the spherical morphologies was compared to coarse grained simulations and assisted in validating the simulations' parameters. STEM tomography of SIS-treated BCP films enables the characterization of the exact structure used for pattern transfer and can lead to a better understating of the physics that is utilized in BCP lithography. PMID- 25919348 TI - Translating Professional Obligations to Care for Patients With Ebola Virus Disease Into Practice in Nonepidemic Settings. AB - Determining how clinicians should meet their professional obligations to treat patients with Ebola virus disease in nonepidemic settings necessitates considering measures to minimize risks to clinicians, the context of care, and fairness. Minimizing risks includes providing appropriate equipment and training, implementing strategies for reducing exposure to infectious material, identifying a small number of centers to provide care, and determining which risky procedures should be used when they pose minimal likelihood of appreciable clinical benefit. Factors associated with the clinical environment, such as the local prevalence of the disease, the nature of the setting, and the availability of effective treatment, are also relevant to obligations to treat. Fairness demands that the best possible medical care be provided for health care professionals who become infected and that the rights and interests of relevant stakeholders be addressed through policy-making processes. Going forward it will be essential to learn from current approaches and to modify them based on data. PMID- 25919349 TI - Highly photostable zinc selective molecular marker bearing flexible pivotal unit: opto-fluorescence enhancement effect and imaging applications in living systems. AB - Novel molecular probes for imaging zinc in biological systems are gaining interest as they help in understanding the role of zinc in regulating various bio events. In this regard, a new C2-symmetric molecular system has been developed and successfully applied as light-up material for signaling divalent zinc with green emission. The fluorescence enhancement was highly zinc specific and this newly developed probe bears a submicromolar detection capability. While probe and the ensemble -Zn(2+) exhibited remarkably high photostability, light-triggered fluorescence enhancement was observed in the case of -Zn(2+). The nature of the Zn(2+) complex and the associated spectral shift are further supported by theoretical calculations. As the present probe absorbs in the visible region and emits in the green, it was preferred as a potential material for imaging zinc in biological systems including animal and plant cells such as pollen grains and fish egg cells. Such fluorescence imaging of zinc revealed the efficacy of the probe in detection and localization of zinc in various biological systems. PMID- 25919350 TI - Variation of photoautotrophic fatty acid production from a highly CO2 tolerant alga, Chlorococcum littorale, with inorganic carbon over narrow ranges of pH. AB - Photoautotrophic fatty acid production of a highly CO2 -tolerant green alga Chlorococcum littorale in the presence of inorganic carbon at 295 K and light intensity of 170 umol-photon m(-2) s(-1) was investigated. CO2 concentration in the bubbling gas was adjusted by mixing pure gas components of CO2 and N2 to avoid photorespiration and beta-oxidation of fatty acids under O2 surrounding conditions. Maximum content of total fatty acid showed pH-dependence after nitrate depletion of the culture media and increased with the corresponding inorganic carbon ratio. Namely, [HCO3 (-) ]/([CO2 ]+n[ CO32-]) ratio in the culture media was found to be a controlling factor for photoautotrophic fatty acid production after the nitrate limitation. At a CO2 concentration of 5% (vol/vol) and a pH of 6.7, the fatty acid content was 47.8 wt % (dry basis) at its maximum that is comparable with land plant seed oils. PMID- 25919351 TI - Giant Chondroid Syringoma of the Breast. PMID- 25919352 TI - Synthesis and pharmacological evaluation of a novel AT1 angiotensin II receptor antagonist with anti-hypertension and anti-tumor effects. AB - A new compound 2-(4-((2-butyl-5-nitro-1H-benzo[d]imidazol-1-yl)methyl)-1H-indol-1 yl) benzamide (1) was designed, synthesized and evaluated as a novel AT1 receptor antagonist. Compound 1 displayed high affinity to AT1 receptor with an IC50 value of 1.65 +/- 0.2 nM in radio-ligand binding assays. It had an efficient and long lasting effect in reducing blood pressure which could last for more than 12 h at the dose of 10 mg/kg in spontaneously hypertensive rats. Acute toxicity tests suggested that compound 1 was safe with the LD50 value of 2519.81 mg/kg. Besides, in vitro and in vivo tests suggested its anti-proliferative and anti-tumor activities, respectively. So compound 1 could be considered as a novel anti hypertension, anti-tumor candidate and deserved further investigation. PMID- 25919353 TI - The emergence of hyper-altruistic behaviour in conflictual situations. AB - Situations where people have to decide between hurting themselves or another person are at the core of many individual and global conflicts. Yet little is known about how people behave when facing these situations in the lab. Here we report a large (N = 2.379) experiment in which participants could either take x dollars from another anonymous participant or give y dollars to the same participant. Depending on the experimental treatments, participants were also allowed to exit the game without making any decision, but paying a cost c >= 0. Across different protocols and parameter specifications, we found three major results: (i) when exiting is allowed and costless, subjects tend to exit the game; (ii) females are more likely than males to exit the game, but only when the cost of the exit is small; (iii) when exiting is not allowed, altruistic actions are more common than predicted by the dominant economic models. In particular, about one sixth of the subjects show hyper-altruistic tendencies, that is, they prefer giving y rather than taking x > y. In doing so, our findings shed light on human decision-making in conflictual situations and suggest that economic models should be revised in order to take into account hyper-altruistic behaviour. PMID- 25919357 TI - Molecular phylogeny reveals high diversity, geographic structure and limited ranges in neotenic net-winged beetles platerodrilus (coleoptera: lycidae). AB - The neotenic Platerodrilus net-winged beetles have strongly modified development where females do not pupate and retain larval morphology when sexually mature. As a result, dispersal propensity of females is extremely low and the lineage can be used for reconstruction of ancient dispersal and vicariance patterns and identification of centres of diversity. We identified three deep lineages in Platerodrilus occurring predominantly in (1) Borneo and the Philippines, (2) continental Asia, and (3) Sumatra, the Malay Peninsula and Java. We document limited ranges of all species of Platerodrilus and complete species level turnover between the Sunda Islands and even between individual mountain regions in Sumatra. Few dispersal events were recovered among the major geographical regions despite long evolutionary history of occurrence; all of them were dated at the early phase of Platerodrilus diversification up to the end of Miocene and no exchange of island faunas was identified during the Pliocene and Pleistocene despite the frequently exposed Sunda Shelf as sea levels fluctuated with each glacial cycle. We observed high diversity in the regions with persisting humid tropical forests during cool periods. The origins of multiple species were inferred in Sumatra soon after the island emerged and the mountain range uplifted 15 million years ago with the speciation rate lower since then. We suppose that the extremely low dispersal propensity makes Platerodrilus a valuable indicator of uninterrupted persistence of rainforests over a long time span. Additionally, if the diversity of these neotenic lineages is to be protected, a high dense system of protected areas would be necessary. PMID- 25919356 TI - Molecular Dynamics Simulations of the Human Glucose Transporter GLUT1. AB - Glucose transporters (GLUTs) provide a pathway for glucose transport across membranes. Human GLUTs are implicated in devastating diseases such as heart disease, hyper- and hypo-glycemia, type 2 diabetes and cancer. The human GLUT1 has been recently crystalized in the inward-facing open conformation. However, there is no other structural information for other conformations. The X-ray structures of E. coli Xylose permease (XylE), a glucose transporter homolog, are available in multiple conformations with and without the substrates D-xylose and D-glucose. XylE has high sequence homology to human GLUT1 and key residues in the sugar-binding pocket are conserved. Here we construct a homology model for human GLUT1 based on the available XylE crystal structure in the partially occluded outward-facing conformation. A long unbiased all atom molecular dynamics simulation starting from the model can capture a new fully opened outward-facing conformation. Our investigation of molecular interactions at the interface between the transmembrane (TM) domains and the intracellular helices (ICH) domain in the outward- and inward-facing conformation supports that the ICH domain likely stabilizes the outward-facing conformation in GLUT1. Furthermore, inducing a conformational transition, our simulations manifest a global asymmetric rocker switch motion and detailed molecular interactions between the substrate and residues through the water-filled selective pore along a pathway from the extracellular to the intracellular side. The results presented here are consistent with previously published biochemical, mutagenesis and functional studies. Together, this study shed light on the structure and functional relationships of GLUT1 in multiple conformational states. PMID- 25919358 TI - Broadband quantum efficiency enhancement in high index nanowire resonators. AB - Light trapping in subwavelength semiconductor nanowires (NWs) offers a promising approach to simultaneously reducing material consumption and enhancing photovoltaic performance. Nevertheless, the absorption efficiency of a NW, defined by the ratio of optical absorption cross section to the NW diameter, lingers around 1 in existing NW photonic devices, and the absorption enhancement suffers from a narrow spectral width. Here, we show that the absorption efficiency can be significantly improved in NWs with higher refractive indices, by an experimental observation of up to 350% apparent external quantum efficiency in lead sulfide NW resonators, a 3-fold increase compared to Si NWs. Furthermore, broadband absorption enhancement is achieved in single tapered NWs, where light of various wavelengths is absorbed at segments with different diameters. Overall, the single NW Schottky junction solar cells benefit from optical resonance, near bandgap open circuit voltage, and long minority carrier diffusion length, demonstrating power conversion efficiency comparable to Si and III-V single NW coaxial p-n junction cells but with much simpler fabrication processes. PMID- 25919359 TI - New singlet oxygen donors based on naphthalenes: synthesis, physical chemical data, and improved stability. AB - Singlet oxygen donors are of current interest for medical applications, but suffer from a short half-life leading to low singlet oxygen yields and problems with storage. We have synthesized more than 25 new singlet oxygen donors based on differently substituted naphthalenes in only a few steps. The influence of functional groups on the reaction rate of the photooxygenations, thermolysis, half-life, and singlet oxygen yield has been thoroughly studied. We determined various thermodynamic data and compared them with density functional calculations. Interestingly, remarkable stabilities of functional groups during the photooxygenations and stabilizing effects for some endoperoxides during the thermolysis have been found. Furthermore, we give evidence for a partly concerted and partly stepwise thermolysis mechanism leading to singlet and triplet oxygen, respectively. Our results might be interesting for "dark oxygenations" and future applications in medicine. PMID- 25919361 TI - Erratum. PMID- 25919362 TI - Precise implant placement with a computer-assisted surgical guide in cleft lip and palate patients. AB - It is very common for cleft lip and palate patients to have congenitally missing teeth. Insufficient buccopalatal bone volume, a shallow vestibule, and lack of soft tissue resulting from previous surgical scarring render it difficult for clinicians to place implants in the missing area. This report describes guide surgery that represents a treatment option for cases in which implants need to be placed in tight spaces with minimal bone space, to minimize as far as possible manual placement errors. PMID- 25919363 TI - Progressive development in experimental models of transungual drug delivery of anti-fungal agents. AB - Pre-clinical development comprises of different procedures that relate drug discovery in the laboratory for commencement of human clinical trials. Pre clinical studies can be designed to recognize a lead candidate from a list to develop the procedure for scale-up, to choose the unsurpassed formulation, to determine the frequency, and duration of exposure; and eventually make the foundation of the anticipated clinical trial design. The foremost aim in the pharmaceutical research and industry is the claim of drug product quality throughout a drug's life cycle. The particulars of the pre-clinical development process for different candidates may vary; however, all have some common features. Typically in vitro, in vivo or ex vivo studies are elements of pre clinical studies. Human pharmacokinetic in vivo studies are often supposed to serve as the 'gold standard' to assess product performance. On the other hand, when this general assumption is revisited, it appears that in vitro studies are occasionally better than in vivo studies in assessing dosage forms. The present review is compendious of different such models or approaches that can be used for designing and evaluation of formulations for nail delivery with special reference to anti-fungal agents. PMID- 25919364 TI - A Behavioral Economic Model of Alcohol Advertising and Price. AB - This paper presents a new empirical study of the effects of televised alcohol advertising and alcohol price on alcohol consumption. A novel feature of this study is that the empirical work is guided by insights from behavioral economic theory. Unlike the theory used in most prior studies, this theory predicts that restriction on alcohol advertising on TV would be more effective in reducing consumption for individuals with high consumption levels but less effective for individuals with low consumption levels. The estimation work employs data from the National Longitudinal Survey of Youth, and the empirical model is estimated with quantile regressions. The results show that advertising has a small positive effect on consumption and that this effect is relatively larger at high consumption levels. The continuing importance of alcohol taxes is also supported. Education is employed as a proxy for self-regulation, and the results are consistent with this assumption. The key conclusion is that restrictions on alcohol advertising on TV would have a small negative effect on drinking, and this effect would be larger for heavy drinkers. Copyright (c) 2015 John Wiley & Sons, Ltd. PMID- 25919365 TI - Deep groundwater and potential subsurface habitats beneath an Antarctic dry valley. AB - The occurrence of groundwater in Antarctica, particularly in the ice-free regions and along the coastal margins is poorly understood. Here we use an airborne transient electromagnetic (AEM) sensor to produce extensive imagery of resistivity beneath Taylor Valley. Regional-scale zones of low subsurface resistivity were detected that are inconsistent with the high resistivity of glacier ice or dry permafrost in this region. We interpret these results as an indication that liquid, with sufficiently high solute content, exists at temperatures well below freezing and considered within the range suitable for microbial life. These inferred brines are widespread within permafrost and extend below glaciers and lakes. One system emanates from below Taylor Glacier into Lake Bonney and a second system connects the ocean with the eastern 18 km of the valley. A connection between these two basins was not detected to the depth limitation of the AEM survey (~350 m). PMID- 25919366 TI - Proteomic Analysis of Plasma from California Sea Lions (Zalophus californianus) Reveals Apolipoprotein E as a Candidate Biomarker of Chronic Domoic Acid Toxicosis. AB - Domoic acid toxicosis (DAT) in California sea lions (Zalophus californianus) is caused by exposure to the marine biotoxin domoic acid and has been linked to massive stranding events and mortality. Diagnosis is based on clinical signs in addition to the presence of domoic acid in body fluids. Chronic DAT further is characterized by reoccurring seizures progressing to status epilepticus. Diagnosis of chronic DAT is often slow and problematic, and minimally invasive tests for DAT have been the focus of numerous recent biomarker studies. The goal of this study was to retrospectively profile plasma proteins in a population of sea lions with chronic DAT and those without DAT using two dimensional gel electrophoresis to discover whether individual, multiple, or combinations of protein and clinical data could be utilized to identify sea lions with DAT. Using a training set of 32 sea lion sera, 20 proteins and their isoforms were identified that were significantly different between the two groups (p<0.05). Interestingly, 11 apolipoprotein E (ApoE) charge forms were decreased in DAT samples, indicating that ApoE charge form distributions may be important in the progression of DAT. In order to develop a classifier of chronic DAT, an independent blinded test set of 20 sea lions, seven with chronic DAT, was used to validate models utilizing ApoE charge forms and eosinophil counts. The resulting support vector machine had high sensitivity (85.7% with 92.3% negative predictive value) and high specificity (92.3% with 85.7% positive predictive value). These results suggest that ApoE and eosinophil counts along with machine learning can perform as a robust and accurate tool to diagnose chronic DAT. Although this analysis is specifically focused on blood biomarkers and routine clinical data, the results demonstrate promise for future studies combining additional variables in multidimensional space to create robust classifiers. PMID- 25919367 TI - Posttraumatic stress disorder and the risk of respiratory problems in World Trade Center responders: longitudinal test of a pathway. AB - OBJECTIVE: Posttraumatic stress disorder (PTSD) is associated with high medical morbidity, but the nature of this association remains unclear. Among responders to the World Trade Center (WTC) disaster, PTSD is highly comorbid with lower respiratory symptoms (LRS), which cannot be explained by exposure alone. We sought to examine this association longitudinally to establish the direction of the effects and evaluate potential pathways to comorbidity. METHODS: 18,896 responders (8466 police and 10,430 nontraditional responders) participating in the WTC-Health Program were first evaluated between 2002 and 2010 and assessed again 2.5 years later. LRS were ascertained by medical staff, abnormal pulmonary function by spirometry, and probable WTC-related PTSD with a symptom inventory. RESULTS: In both groups of responders, initial PTSD (standardized regression coefficient: beta = 0.20 and 0.23) and abnormal pulmonary function (beta = 0.12 and 0.12) predicted LRS 2.5 years later after controlling for initial LRS and covariates. At follow-up, LRS onset was 2.0 times more likely and remission 1.8 times less likely in responders with initial PTSD than in responders without. Moreover, PTSD mediated, in part, the association between WTC exposures and development of LRS (p < .0001). Initial LRS and abnormal pulmonary function did not consistently predict PTSD onset. CONCLUSIONS: These analyses provide further evidence that PTSD is a risk factor for respiratory symptoms and are consistent with evidence implicating physiological dysregulation associated with PTSD in the development of medical conditions. If these effects are verified experimentally, treatment of PTSD may prove helpful in managing physical and mental health of disaster responders. PMID- 25919368 TI - Accuracy analysis of a multi-view stereo approach for phenotyping of tomato plants at the organ level. AB - Accessing a plant's 3D geometry has become of significant importance for phenotyping during the last few years. Close-up laser scanning is an established method to acquire 3D plant shapes in real time with high detail, but it is stationary and has high investment costs. 3D reconstruction from images using structure from motion (SfM) and multi-view stereo (MVS) is a flexible cost effective method, but requires post-processing procedures. The aim of this study is to evaluate the potential measuring accuracy of an SfM- and MVS-based photogrammetric method for the task of organ-level plant phenotyping. For this, reference data are provided by a high-accuracy close-up laser scanner. Using both methods, point clouds of several tomato plants were reconstructed at six following days. The parameters leaf area, main stem height and convex hull of the complete plant were extracted from the 3D point clouds and compared to the reference data regarding accuracy and correlation. These parameters were chosen regarding the demands of current phenotyping scenarios. The study shows that the photogrammetric approach is highly suitable for the presented monitoring scenario, yielding high correlations to the reference measurements. This cost effective 3D reconstruction method depicts an alternative to an expensive laser scanner in the studied scenarios with potential for automated procedures. PMID- 25919370 TI - Analysis and experimental kinematics of a skid-steering wheeled robot based on a laser scanner sensor. AB - Skid-steering mobile robots are widely used because of their simple mechanism and robustness. However, due to the complex wheel-ground interactions and the kinematic constraints, it is a challenge to understand the kinematics and dynamics of such a robotic platform. In this paper, we develop an analysis and experimental kinematic scheme for a skid-steering wheeled vehicle based-on a laser scanner sensor. The kinematics model is established based on the boundedness of the instantaneous centers of rotation (ICR) of treads on the 2D motion plane. The kinematic parameters (the ICR coefficient , the path curvature variable and robot speed ), including the effect of vehicle dynamics, are introduced to describe the kinematics model. Then, an exact but costly dynamic model is used and the simulation of this model's stationary response for the vehicle shows a qualitative relationship for the specified parameters and . Moreover, the parameters of the kinematic model are determined based-on a laser scanner localization experimental analysis method with a skid-steering robotic platform, Pioneer P3-AT. The relationship between the ICR coefficient and two physical factors is studied, i.e., the radius of the path curvature and the robot speed . An empirical function-based relationship between the ICR coefficient of the robot and the path parameters is derived. To validate the obtained results, it is empirically demonstrated that the proposed kinematics model significantly improves the dead-reckoning performance of this skid-steering robot. PMID- 25919369 TI - Optical fiber nanotips coated with molecular beacons for DNA detection. AB - Optical fiber sensors, thanks to their compactness, fast response and real-time measurements, have a large impact in the fields of life science research, drug discovery and medical diagnostics. In recent years, advances in nanotechnology have resulted in the development of nanotools, capable of entering the single cell, resulting in new nanobiosensors useful for the detection of biomolecules inside living cells. In this paper, we provide an application of a nanotip coupled with molecular beacons (MBs) for the detection of DNA. The MBs were characterized by hybridization studies with a complementary target to prove their functionality both free in solution and immobilized onto a solid support. The solid support chosen as substrate for the immobilization of the MBs was a 30 nm tapered tip of an optical fiber, fabricated by chemical etching. With this set-up promising results were obtained and a limit of detection (LOD) of 0.57 nM was reached, opening up the possibility of using the proposed nanotip to detect mRNAs inside the cytoplasm of living cells. PMID- 25919371 TI - Routing and Scheduling Algorithms for WirelessHARTNetworks: A Survey. AB - Wireless communication is a trend nowadays for the industrial environment. A number of different technologies have emerged as solutions satisfying strict industrial requirements (e.g., WirelessHART, ISA100.11a, WIA-PA). As the industrial environment presents a vast range of applications, adopting an adequate solution for each case is vital to obtain good performance of the system. In this context, the routing and scheduling schemes associated with these technologies have a direct impact on important features, like latency and energy consumption. This situation has led to the development of a vast number of routing and scheduling schemes. In the present paper, we focus on the WirelessHART technology, emphasizing its most important routing and scheduling aspects in order to guide both end users and the developers of new algorithms. Furthermore, we provide a detailed literature review of the newest routing and scheduling techniques forWirelessHART, discussing each of their features. These routing algorithms have been evaluated in terms of their objectives, metrics, the usage of theWirelessHART structures and validation method. In addition, the scheduling algorithms were also evaluated by metrics, validation, objectives and, in addition, by multiple superframe support, as well as by the redundancy method used. Moreover, this paper briefly presents some insights into the main WirelessHART simulation modules available, in order to provide viable test platforms for the routing and scheduling algorithms. Finally, some open issues in WirelessHART routing and scheduling algorithms are discussed. PMID- 25919372 TI - Adaptive control of the packet transmission period with solar energy harvesting prediction in wireless sensor networks. AB - A number of research works has studied packet scheduling policies in energy scavenging wireless sensor networks, based on the predicted amount of harvested energy. Most of them aim to achieve energy neutrality, which means that an embedded system can operate perpetually while meeting application requirements. Unlike other renewable energy sources, solar energy has the feature of distinct periodicity in the amount of harvested energy over a day. Using this feature, this paper proposes a packet transmission control policy that can enhance the network performance while keeping sensor nodes alive. Furthermore, this paper suggests a novel solar energy prediction method that exploits the relation between cloudiness and solar radiation. The experimental results and analyses show that the proposed packet transmission policy outperforms others in terms of the deadline miss rate and data throughput. Furthermore, the proposed solar energy prediction method can predict more accurately than others by 6.92%. PMID- 25919373 TI - [Long-term psychosocial functioning in congenital heart disease children and adolescents and in their parents]. AB - BACKGROUND: This review describes the main findings of two follow-up studies into long-term psychosocial outcomes of in children and adolescents with congenital heart disease (CHD) and their parents. METHODS: For both studies, all consecutive patients, who underwent their first open heart surgery or invasive treatment for congenital heart disease (study 1: between 1968-1980, study 2: between 1990-1995) in the Erasmus Medical Center Rotterdam, the Netherlands, who were younger than 15 years of age at the time of surgery, were eligible. The first study was performed between 1989-1991, the second one between 2003-2005. RESULTS: The first study demonstrated that 10-17 year-old CHD children and adolescents, who underwent surgical "correction" for congenital heart disease before 1980, showed significantly higher levels of behavioural/emotional problems compared to normative groups, both according to parents' reports (N=144) and self-reports (N=179). The second, more recent study was executed in 7-17-year-old patients (N=124). Despite improvements in medical treatment over the years, patients from this more recent study still showed higher levels of behavioural/emotional problems and also a poorer health-related quality of life, compared to reference groups. Parents of patients showed favorable outcomes on psychosocial well-being (N=100 mothers, 61 fathers) and coping styles. In both studies, no clear relationships were found between cardiac diagnoses and psychosocial outcomes. CONCLUSION: Considering the poorer behavioural/emotional functioning and poorer health related quality of life of these children and adolescents with congenital heart disease, we recommend early screening to identify children are at risk. PMID- 25919374 TI - Identification of Two Novel Compound Heterozygous PTPRQ Mutations Associated with Autosomal Recessive Hearing Loss in a Chinese Family. AB - Mutations in PTPRQ are associated with deafness in humans due to defects of stereocilia in hair cells. Using whole exome sequencing, we identified responsible gene of family 1572 with autosomal recessively non-syndromic hearing loss (ARNSHL). We also used DNA from 74 familial patients with ARNSHL and 656 ethnically matched control chromosomes to perform extended variant analysis. We identified two novel compound heterozygous missense mutations, c. 3125 A>G p.D1042G (maternal allele) and c.5981 A>G p.E1994G (paternal allele), in the PTPRQ gene, as the cause of recessively inherited sensorineural hearing loss in family 1572. Both variants co-segregated with hearing loss phenotype in family 1572, but were absent in 74 familial patients. Heterozygosity for c. 3125 A>G was identified in two samples from unaffected Chinese individuals (656 chromosomes). Therefore, the hearing loss in this family was caused by two novel compound heterozygous mutations in PTPRQ. PMID- 25919375 TI - Drinking water turbidity and emergency department visits for gastrointestinal illness in New York City, 2002-2009. AB - BACKGROUND: Studies have examined whether there is a relationship between drinking water turbidity and gastrointestinal (GI) illness indicators, and results have varied possibly due to differences in methods and study settings. OBJECTIVES: As part of a water security improvement project we conducted a retrospective analysis of the relationship between drinking water turbidity and GI illness in New York City (NYC) based on emergency department chief complaint syndromic data that are available in near-real-time. METHODS: We used a Poisson time-series model to estimate the relationship of turbidity measured at distribution system and source water sites to diarrhea emergency department (ED) visits in NYC during 2002-2009. The analysis assessed age groups and was stratified by season and adjusted for sub-seasonal temporal trends, year-to-year variation, ambient temperature, day-of-week, and holidays. RESULTS: Seasonal variation unrelated to turbidity dominated (~90% deviance) the variation of daily diarrhea ED visits, with an additional 0.4% deviance explained with turbidity. Small yet significant multi-day lagged associations were found between NYC turbidity and diarrhea ED visits in the spring only, with approximately 5% excess risk per inter-quartile-range of NYC turbidity peaking at a 6 day lag. This association was strongest among those aged 0-4 years and was explained by the variation in source water turbidity. CONCLUSIONS: Integrated analysis of turbidity and syndromic surveillance data, as part of overall drinking water surveillance, may be useful for enhanced situational awareness of possible risk factors that can contribute to GI illness. Elucidating the causes of turbidity-GI illness associations including seasonal and regional variations would be necessary to further inform surveillance needs. PMID- 25919376 TI - A Browser-Server-Based Tele-audiology System That Supports Multiple Hearing Test Modalities. AB - INTRODUCTION: Millions of global citizens suffering from hearing disorders have limited or no access to much needed hearing healthcare. Although tele-audiology presents a solution to alleviate this problem, existing remote hearing diagnosis systems support only pure-tone tests, leaving speech and other test procedures unsolved, due to the lack of software and hardware to enable communication required between audiologists and their remote patients. This article presents a comprehensive remote hearing test system that integrates the two most needed hearing test procedures: a pure-tone audiogram and a speech test. MATERIALS AND METHODS: This enhanced system is composed of a Web application server, an embedded smart Internet-Bluetooth((r)) (Bluetooth SIG, Kirkland, WA) gateway (or console device), and a Bluetooth-enabled audiometer. Several graphical user interfaces and a relational database are hosted on the application server. The console device has been designed to support the tests and auxiliary communication between the local site and the remote site. RESULTS: The study was conducted at an audiology laboratory. Pure-tone audiogram and speech test results from volunteers tested with this tele-audiology system are comparable with results from the traditional face-to-face approach. CONCLUSIONS: This browser-server based comprehensive tele-audiology offers a flexible platform to expand hearing services to traditionally underserved groups. PMID- 25919379 TI - Early detection and intervention for people with psychosis: getting to the bottom line. PMID- 25919378 TI - Incorporation of Peptides Targeting EGFR and FGFR1 into the Adenoviral Fiber Knob Domain and Their Evaluation as Targeted Cancer Therapies. AB - Oncolytic virotherapies based on adenovirus 5 (Ad5) hold promise as adjunctive cancer therapies; however, their efficacy when delivered systemically is hampered by poor target cell specificity and preexisting anti-Ad5 immunity. Ovarian cancer represents a promising target for virotherapy, since the virus can be delivered locally into the peritoneal cavity. Both epidermal growth factor receptor (EGFR) and fibroblast growth factor receptor 1 (FGFR1) are overexpressed in the majority of human tumors, including ovarian cancer. To generate adenoviral vectors with improved tumor specificity, we generated a panel of Ad5 vectors with altered tropism for EGFR and FGFR, rather than the natural Ad5 receptor, hCAR. We have included mutations within AB loop of the viral fiber knob (KO1 mutation) to preclude interaction with hCAR, combined with insertions in the HI loop to incorporate peptides that bind either EGFR (peptide YHWYGYTPQNVI, GE11) or FGFR1 (peptides MQLPLAT, M*, and LSPPRYP, LS). Viruses were produced to high titers, and the integrity of the fiber protein was validated by Western blotting. The KO1 mutation efficiently ablated hCAR interactions, and significantly increased transduction was observed in hCAR(low)/EGFR(high) cell lines using Ad5.GE11, while transduction levels using Ad5.M* or Ad5.LS were not increased. In the presence of physiological concentrations of human blood clotting factor X (hFX), significantly increased levels of transduction via the hFX-mediated pathway were observed in cell lines, but not in primary tumor cells derived from epithelial ovarian cancer (EOC) ascites samples. Ad5-mediated transduction of EOC cells was completely abolished by the presence of 2.5% serum from patients, while, surprisingly, incorporation of the GE11 peptide resulted in significant evasion of neutralization in the same samples. We thus speculate that incorporation of the YHWYGYTPQNVI dodecapeptide within the fiber knob domain may provide a novel means of circumventing preexisting Ad5 immunity that warrants further investigation. PMID- 25919380 TI - Early intervention in psychosis: obvious, effective, overdue. AB - Early intervention for potentially serious disorder is a fundamental feature of healthcare across the spectrum of physical illness. It has been a major factor in the reductions in morbidity and mortality that have been achieved in some of the non-communicable diseases, notably cancer and cardiovascular disease. Over the past two decades, an international collaborative effort has been mounted to build the evidence and the capacity for early intervention in the psychotic disorders, notably schizophrenia, where for so long deep pessimism had reigned. The origins and rapid development of early intervention in psychosis are described from a personal and Australian perspective. This uniquely evidence-informed, evidence building and cost-effective reform provides a blueprint and launch pad to radically change the wider landscape of mental health care and dissolve many of the barriers that have constrained progress for so long. PMID- 25919381 TI - Predictors of the Onset of Schizophrenia in US Military Personnel. AB - Alterations in immune response may be an important component in the etiopathogenesis of schizophrenia and bipolar disorder. We examined the associations of pentraxin-3 (PTX3) with the onset of schizophrenia or bipolar disorder. We tested preonset serum specimens from 160 US military service members who were later diagnosed with schizophrenia or bipolar disorder and 160 matched controls without psychiatric disorders. Lower serum levels of PTX3 were predictive of schizophrenia but not of bipolar disorder. Subjects with below median PTX3 levels had a 3.0 odds ratio (confidence interval, 1.6-5.7) for schizophrenia onset in the multivariable logistic regression model controlling for demographic and military variables. The test for trends was significant (p = 0.002), with the likelihood increasing as the levels of PTX3 decreased. Crude and adjusted categorized levels were not predictive of bipolar disorder. A lower level of inflammatory response indicated by PTX3 might be implicated in developing schizophrenia. PMID- 25919382 TI - Attenuated psychosis syndrome: a new diagnostic class? AB - Early detection and treatment of illness are fundamental in providing optimal health care. However, this is a major challenge in mental illness, where diagnoses depend on symptom manifestation and the symptoms are often on a continuum with behaviors observed in the non-ill population. During the past 25 years, substantial progress has been made in identifying clinical high risk for psychoses with extensive validation and the beginning of treatment trials for symptom reduction and secondary prevention of psychoses. Attenuated psychosis syndrome is placed in Section 3 of the Diagnostic and Statistical Manual of Mental Disorders, 5th Edition, as a new disorder for further study. But the value and wisdom of creating a new disorder are hotly debated. The author advocates establishing a new disorder class as essential for progress. Key reasons to justify this view are described. Reasons to oppose the creation of a new class are briefly described. PMID- 25919384 TI - Evidence-based early interventions for individuals at clinical high risk for psychosis: a review of treatment components. AB - Youth and young adults at clinical high risk (CHR) for psychosis experience a broad range of difficulties, including attenuated psychotic symptoms, comorbid concerns, functional impairments, and family and interpersonal stress. Given emerging evidence that early interventions may improve functioning and reduce symptomatology while also lowering risk of transition to full-threshold psychosis, several randomized controlled trials have systematically evaluated the efficacy of CHR treatment approaches. This article describes and summarizes psychosocial intervention approaches that have demonstrated efficacy in treating people at CHR, with a focus on distilling individual components of these treatments. On the basis of the existing literature, we propose an empirically based, flexible, and comprehensive modularized approach to early intervention that meets the varying needs of individuals experiencing CHR-related distress and dysfunction, many of whom may be on a trajectory toward psychosis. PMID- 25919383 TI - North American Prodrome Longitudinal Study (NAPLS 2): The Prodromal Symptoms. AB - In studies describing the long-term follow-up up of youth at clinical high risk (CHR) of psychosis, little attention has been given to details of specific prodromal symptoms. In this paper, we describe the prodromal symptoms of 764 CHR participants recruited in the multi-site North American Prodrome Longitudinal Study (NAPLS). Symptoms were rated on the Scale of Prodromal Symptoms (SOPS) at baseline and 6-, 12-, 18-, and 24-month follow-ups. Clinical outcome at the 2 year assessment was categorized as psychotic, prodromal progression, symptomatic or in remission. Most of the CHR sample (92%) met criteria for the attenuated positive symptoms syndrome (APSS). Significant improvements in SOPS symptoms were observed over time. Unusual thought content, disorganized communication, and overall ratings on disorganized symptoms differentiated those who transitioned to psychosis from the other clinical outcome groups. Suspiciousness and total positive symptoms differentiated those in remission from the other clinical outcome groups. PMID- 25919385 TI - Suicidal behavior and mortality in first-episode psychosis. AB - Suicide is a serious public health problem, with more than 800,000 deaths taking place worldwide each year. Mental disorders are associated with increased risk of suicide. In schizophrenia and other psychotic disorders, the lifetime risk of suicide death is estimated to be 5.6%. The risk is particularly high during the first year of the initial contact with mental health services, being almost twice as high as in the later course of the illness. The most consistently reported risk factor for suicide among people with psychotic disorders is a history of attempted suicide and depression. Suicide risk in psychosis in Denmark decreased over time, most likely because of improved quality of inpatient and outpatient services. There is a high proportion of young people with first-episode psychosis who attempted suicide before their first contact with mental health services. This finding suggests that the mortality rates associated with psychotic disorders may be underreported because of suicide deaths taking place before first treatment contact. However, currently, no data exist to confirm or refute this hypothesis. Attempted suicide can be an early warning sign of later psychotic disorder. Data from different studies indicate that the risk of suicide attempt during the first year of treatment is as high as 10%. The most important risk factors for attempted suicide after the first contact are young age, female sex, suicidal plans, and a history of suicide attempt. Early intervention services are helpful in first-episode psychosis, and staff members should, in collaboration with the patients, monitor the risk of suicide and develop and revise crisis plans. PMID- 25919386 TI - The potential of immune biomarkers to advance personalized medicine approaches for schizophrenia. AB - Molecular profiling studies have helped increase the understanding of the immune processes thought to be involved in the etiology and pathophysiology of psychiatric disorders such as schizophrenia. Current therapeutic interventions with first- and second-generation antipsychotics are suboptimal. Poor response rates and debilitating side effects often lead to poor treatment compliance. This highlights the pressing need to identify more effective treatments as well as objective biomarker based tests, which can help predict treatment response and identify diagnostic subpopulations. Such tests could enable early detection of patients who will benefit from particular therapeutic interventions. In this review, we discuss studies relating to dysfunctions of the immune system in patients with schizophrenia and the effects of antipsychotic medication on the molecular components of these systems. Immune system dysfunction may in part be related to genetic risk factors for schizophrenia, but there is substantial evidence that a wide range of environmental factors ranging from exposure to infectious agents such as influenza and Toxoplasma gondii to HPA axis dysfunction play an important role in the etiopathogenesis of schizophrenia. Ongoing research efforts, testing therapeutic efficacy of anti-inflammatory agents used as add-on medications are also discussed. From a therapeutic perspective, these represent the initial steps toward novel treatment approaches and more effective patient care in the field of mental health. PMID- 25919388 TI - Tramadol in palliative care #290. AB - Tramadol has an important position as a Step II agent on the WHO pain ladder, where it is effective for a variety of syndromes in patients with mild to moderate pain intensity. Its recommended dosing adjustments, potential ceiling effect, cost, pertinent drug interactions, and risk for significant adverse drug reactions may limit its chronic use in patients with significant pain. PMID- 25919389 TI - Internal thoracic impedance - a useful method for expedient detection and convenient monitoring of pleural effusion. AB - Measurement of internal thoracic impedance (ITI) is sensitive and accurate in detecting acute pulmonary edema even at its preclinical stage. We evaluated the suitability of the highly sensitive and noninvasive RS-207 monitor for detecting pleural effusion and for demonstrating increased ITI during its resolution. This prospective controlled study was performed in a single department of internal medicine of a university-affiliated hospital between 2012-2013. One-hundred patients aged 25-96 years were included, of whom 50 had bilateral or right pleural effusion of any etiology (study group) and 50 had no pleural effusion (controls). ITI, the main component of which is lung impedance, was continuously measured by the RS-207 monitor. The predictive value of ITI monitoring was determined by 8 measurements taken every 8 hours. Pleural effusion was diagnosed according to well-accepted clinical and roentgenological criteria. During treatment, the ITI of the study group increased from 32.9+/-4.2 ohm to 42.8+/-3.8 ohm (p<0.0001) compared to non-significant changes in the control group (59.6+/ 6.6 ohm, p = 0.24). Prominent changes were observed in the respiratory rate of the study group: there was a decrease from 31.2+/-4.0 to 19.5+/-2.4 ohm (35.2%) compared to no change for the controls, and a mean increase from 83.6+/- 5.3% 92.5+/-1.6% (13.2%) in O2 saturation compared to 94.2+/-1.7% for the controls. Determination of ITI for the detection and monitoring of treatment of patients with pleural effusion enables earlier diagnosis and more effective therapy, and can prevent hospitalization and serious complications, such as respiratory distress, and the need for mechanical ventilation. TRIAL REGISTRATION: The study is registered at ClinicalTrials.gov NCT01601444. PMID- 25919392 TI - Environmental conditions associated with repetitive behavior in a group of African elephants. AB - Repetitive movement patterns are commonly observed in zoo elephants. The extent to which these behaviors constitute a welfare concern varies, as their expression ranges from stereotypies to potentially beneficial anticipatory behaviors. Nevertheless, their occurrence in zoo animals is often viewed negatively. To better identify conditions that prompt their performance, observations were conducted on six African elephants (Loxodonta africana) at the North Carolina Zoo. Individuals spent most of their time engaged in feeding, locomotion, resting, and repetitive behavior. Both generalized estimating equation and zero inflated negative binomial models were used to identify factors associated with increased rates of repetitive behavior. Time of day in conjunction with location on- or off-exhibit best explained patterns of repetitive behavior. Repetitive behaviors occurred at a lower rate in the morning when on-exhibit, as compared to afternoons on-exhibit or at any time of day off-exhibit. Increased repetitive behavior rates observed on-exhibit in the afternoon prior to the evening transfer and feeding were possibly anticipatory responses towards those events. In contrast, consistently elevated frequencies of repetitive behavior off-exhibit at all times of day could be related to differences in exhibit complexity between off-exhibit and on-exhibit areas, as well as a lack of additional foraging opportunities. Our study contributes valuable information on captive elephant behavior and represents a good example of how behavioral research can be employed to improve management of zoo animals. PMID- 25919391 TI - Time to clinical stability among children hospitalized with pneumonia. AB - We evaluated the performance of time to clinical stability (TCS), a longitudinal outcome measure using 4 physiologic parameters (temperature, heart rate, respiratory rate, and use of supplemental oxygen), among children enrolled in a prospective study of pneumonia hospitalizations. We calculated the time from admission to normalization for each of the 4 parameters individually along with various combinations of these parameters (>=2 parameters). We assessed for agreement between the combined TCS measures and both hospital length of stay and an ordinal severity scale (nonsevere, severe, and very severe). Overall, 323 (96.7%) of 334 included children had >=1 parameter abnormal on admission; 70 (21%) children had >=1 parameter abnormal at discharge. For the 4 combined measures, median TCS decreased with increasing age. Increasing TCS was associated with both longer length of stay and increasing disease severity. The simplest combined measure incorporating only respiratory rate and need for supplemental oxygen performed similarly to more complex measures including additional parameters. Our study demonstrates that longitudinal TCS measures may be useful in children with pneumonia, both in clinical settings to assess recovery and readiness for discharge, and as an outcome measure in research and quality assessments. Additional study is needed to further validate our findings. PMID- 25919390 TI - TURAN and EVAN mediate pollen tube reception in Arabidopsis Synergids through protein glycosylation. AB - Pollen tube (PT) reception in flowering plants describes the crosstalk between the male and female gametophytes upon PT arrival at the synergid cells of the ovule. It leads to PT growth arrest, rupture, and sperm cell release, and is thus essential to ensure double fertilization. Here, we describe TURAN (TUN) and EVAN (EVN), two novel members of the PT reception pathway that is mediated by the FERONIA (FER) receptor-like kinase (RLK). Like fer, mutations in these two genes lead to PT overgrowth inside the female gametophyte (FG) without PT rupture. Mapping by next-generation sequencing, cytological analysis of reporter genes, and biochemical assays of glycoproteins in RNAi knockdown mutants revealed both genes to be involved in protein N-glycosylation in the endoplasmic reticulum (ER). TUN encodes a uridine diphosphate (UDP)-glycosyltransferase superfamily protein and EVN a dolichol kinase. In addition to their common role during PT reception in the synergids, both genes have distinct functions in the pollen: whereas EVN is essential for pollen development, TUN is required for PT growth and integrity by affecting the stability of the pollen-specific FER homologs ANXUR1 (ANX1) and ANX2. ANX1- and ANX2-YFP reporters are not expressed in tun pollen grains, but ANX1-YFP is degraded via the ER-associated degradation (ERAD) pathway, likely underlying the anx1/2-like premature PT rupture phenotype of tun mutants. Thus, as in animal sperm-egg interactions, protein glycosylation is essential for the interaction between the female and male gametophytes during PT reception to ensure fertilization and successful reproduction. PMID- 25919393 TI - Newly Exerted T Cell Pressures on Mutated Epitopes following Transmission Help Maintain Consensus HIV-1 Sequences. AB - CD8+ T cells are important for HIV-1 virus control, but are also a major contributing factor that drives HIV-1 virus sequence evolution. Although HIV-1 cytotoxic T cell (CTL) escape mutations are a common aspect during HIV-1 infection, less is known about the importance of T cell pressure in reversing HIV 1 virus back to a consensus sequences. In this study we aimed to assess the frequency with which reversion of transmitted mutations in T cell epitopes were associated with T cell responses to the mutation. This study included 14 HIV-1 transmission pairs consisting of a 'source' (virus-donor) and a 'recipient' (newly infected individual). Non-consensus B sequence amino acids (mutations) in T cell epitopes in HIV-1 gag regions p17, p24, p2 and p7 were identified in each pair and transmission of mutations to the recipient was verified with population viral sequencing. Longitudinal analyses of the recipient's viral sequence were used to identify whether reversion of mutations back to the consensus B sequence occurred. Autologous 12-mer peptides overlapping by 11 were synthesized, representing the sequence region surrounding each reversion and longitudinal analysis of T cell responses to source-derived mutated and reverted epitopes were assessed. We demonstrated that mutations in the source were frequently transmitted to the new host and on an average 17 percent of mutated epitopes reverted to consensus sequence in the recipient. T cell responses to these mutated epitopes were detected in 7 of the 14 recipients in whom reversion occurred. Overall, these findings indicate that transmitted non-consensus B epitopes are frequently immunogenic in HLA-mismatched recipients and new T cell pressures to T cell escape mutations following transmission play a significant role in maintaining consensus HIV-1 sequences. PMID- 25919394 TI - Personality predictors of successful development: toddler temperament and adolescent personality traits predict well-being and career stability in middle adulthood. AB - The aim of the study was to predict both adaptive psychological functioning (well being) and adaptive social functioning (career stability) in middle adulthood based on behaviors observed in toddlerhood and personality traits measured in adolescence. 83 people participated in an ongoing longitudinal study started in 1961 (58% women). Based on children's behavior in toddlerhood, three temperamental dimensions were identified - positive affectivity, negative affectivity and disinhibition. In adolescence, extraversion and neuroticism were measured at the age of 16 years. Various aspects of well-being were used as indicators of adaptive psychological functioning in adulthood: life satisfaction, self-esteem and self-efficacy. Career stability was used as an indicator of adaptive social functioning. Job careers of respondents were characterized as stable, unstable or changeable. Extraversion measured at the age of 16 proved to be the best predictor of well-being indicators; in case of self-efficacy it was also childhood disinhibition. Extraversion in adolescence, childhood disinhibition and negative affectivity predicted career stability. Findings are discussed in the context of a theoretical framework of higher order factors of the Big Five personality constructs, stability and plasticity. PMID- 25919395 TI - European screening for alpha1 -antitrypsin deficiency in subjects with lung disease. AB - BACKGROUND AND AIMS: Alpha1 -antitrypsin deficiency (AATD) predisposes individuals to early-onset emphysema. Despite its prevalence, especially among patients with chronic obstructive pulmonary disease, AATD is still underdiagnosed. The aim of this study is to identify individuals with lung disease and severe AATD in central-eastern Europe. METHODS: Subjects with respiratory symptoms that could be indicative of AATD provided blood samples as dried blood spot. The alpha1 -antitrypsin (AAT) concentration was determined by nephelometry and, if lower than 1.70 mg/dL in dried blood spot (equivalent to 1.04 g/L in serum), polymerase chain reaction was used to detect the PiS and PiZ alleles. Isoelectric focusing was used for confirmation of doubtful genotype results. RESULTS: From 13 countries, 11 648 subjects were included. Genotyping of 1404 samples with AAT levels <1.70 mg/dL revealed 71 (5.06%) PiS, 151 (10.8%) PiZ, 1 (0.071%) PiSS, 8 (0.57%) PiSZ and 32 (2.28%) PiZZ. Phenotyping of 1363 samples negative for the S and Z alleles or with PiS and PiZ genotype showed two (0.147%) PiZ(rare) and two (0.147%) Pi(null)(null). The countries with the highest rate of severe AATD were Croatia, Russia and Slovakia. By regions, the Baltic countries area showed the highest rate of both PiZ and severe AATD (2.45% and 1.20%, respectively) while the lowest rates were observed in the Balkan Peninsula (0.48% and 0.31%, respectively). CONCLUSION: This study confirms the need for targeted testing of symptomatic patients and provides AATD genotype data from countries for which only some estimates of prevalence were available until now. PMID- 25919396 TI - A systematic review of interventions for co-occurring substance use and borderline personality disorders. AB - ISSUES: The aim of this study was to undertake a systematic review on effective treatment options for co-occurring substance use and borderline personality disorders to examine effective treatments for this group. APPROACH: A systematic review using a narrative analysis approach was undertaken as there were too few studies within each intervention type to undertake a meta-analysis. The inclusion criteria comprised of English language studies (between 1999 and 2014) and a sample of >70% borderline personality disorder, with measurable outcomes for substance use and borderline personality disorder. All abstracts were screened (n = 376) resulting in 49 studies assessed for eligibility, with 10 studies, examining three different treatment types, included in the final review. KEY FINDINGS: There were four studies that examined dialectical behaviour therapy (DBT), three studies that examined dynamic deconstructive psychotherapy (DDP) and three studies that examined dual-focused schema therapy (DFST). Both DBT and DDP demonstrated reductions in substance use, suicidal/self-harm behaviours and improved treatment retention. DBT also improved global and social functioning. DFST reduced substance use and both DFST and DPP improved treatment utilisation, but no other significant positive changes were noted. IMPLICATIONS: Overall, there were a small number of studies with small sample sizes, so further research is required. However, in the absence of a strong evidence base, there is a critical need to respond to this group with co-occurring borderline personality disorder and substance use. CONCLUSION: Both DBT and DPP showed some benefit in reducing symptoms, with DBT the preferred option given its superior evidence base with women in particular. PMID- 25919397 TI - From mice to elephants: overturning the 'one size fits all' paradigm in marine plankton food chains. AB - It is widely believed that consumer control is a weak regulator of marine phytoplankton communities. It remains unclear, however, why this should be the case when marine consumers routinely regulate their prey at higher trophic levels. One possibility is that the weak consumer control of phytoplankton communities results from the inability of field researchers to effectively account for consumer-prey trophic relationships operating at the scale of the plankton. We explored this issue by reviewing studies of trophic control in marine plankton. Experimental studies indicate that size is a critical determinant of feeding relationships among plankton. In sharp contrast, of the 51 field studies reviewed, 78% did not distinguish among the sizes or species of phytoplankton and their consumers, but instead assumed a general bulk phytoplankton-zooplankton trophic connection. Such an approach neglects the possibility that several trophic connections may separate the smallest phytoplankton (0.2 MUm) from the larger zooplankton (~ 1000 MUm), a remarkable size differential exceeding that between a mouse (~10 cm) and an elephant (~2500 cm). The size-based approach we propose integrates theory, experiments and field observations and has the potential to greatly enhance our understanding of the causes and consequences of recently documented restructuring of plankton communities. PMID- 25919399 TI - Cross-Continuum Collaboration in Health Care: Unleashing the Potential. PMID- 25919398 TI - Propionibacterium acnes Augments Antitumor, Anti-Angiogenesis and Immunomodulatory Effects of Melatonin on Breast Cancer Implanted in Mice. AB - Breast cancer is one of the most invasive cancers with high mortality. The immune stimulating Propionibacterium acnes is a Gram positive bacterium that has the ability to cause inflammation and activate Th1-type cytokine immune response. Antitumor response was associated with the inflammation induced by P. acnes, but the antitumor effect of this bacterium was not evaluated in combination with other agents. The aim of this study was to test the antitumor potential of a combination of melatonin and P. acnes against breast cancer implanted in mice. Balb/C mice were transplanted with EMT6/P cell line and in vivo antitumor effect was assessed for P. acnes, melatonin, and a combination of melatonin and P. acnes. Tumor and organs sections were examined using hematoxylin/eosin staining protocol, and TUNEL colorimetric assay was used to detect apoptosis. The expression of vascular endothelial growth factor (VEGF) was measured in tumor sections and serum levels of INF-gamma, and IL-4 were measured to evaluate the immune system function. To evaluate the toxicity of our combination, AST and ALT levels were measured in the serum of treated mice. The combination of melatonin and P. acnes has high efficiency in targeting breast cancer in mice. Forty percent of treated mice were completely cured using this combination and the combination inhibited metastasis of cancer cells to other organs. The combination therapy reduced angiogenesis, exhibited no toxicity, induced apoptosis, and stimulates strong Th1-type cytokine antitumor immune response. The combination of melatonin and P. acnes represents a promising option to treat breast cancer. However, carful preclinical and clinical evaluation is needed before considering this combination for human therapy. PMID- 25919400 TI - Symmetries of the 2D magnetic particle imaging system matrix. AB - In magnetic particle imaging (MPI), the relation between the particle distribution and the measurement signal can be described by a linear system of equations. For 1D imaging, it can be shown that the system matrix can be expressed as a product of a convolution matrix and a Chebyshev transformation matrix. For multidimensional imaging, the structure of the MPI system matrix is not yet fully explored as the sampling trajectory complicates the physical model. It has been experimentally found that the MPI system matrix rows have symmetries and look similar to the tensor products of Chebyshev polynomials. In this work we will mathematically prove that the 2D MPI system matrix has symmetries that can be used for matrix compression. PMID- 25919401 TI - Selective intraoperative cholangiography and risk of bile duct injury during cholecystectomy. AB - BACKGROUND: Whether intraoperative cholangiography can prevent iatrogenic bile duct injury during cholecystectomy remains controversial. METHODS: Data from the national Swedish Registry for Gallstone Surgery, GallRiks (May 2005 to December 2010), were analysed for evidence of iatrogenic bile duct injury during cholecystectomy. Patient- and procedure-related risk factors for bile duct injury with a focus on the rate of intended intraoperative cholangiography were analysed using multivariable logistic regression. RESULTS: A total of 51 041 cholecystectomies and 747 bile duct injuries (1.5 per cent) were identified; 9008 patients (17.6 per cent) were diagnosed with acute cholecystitis. No preventive effect of intraoperative cholangiography was seen in uncomplicated gallstone disease (odds ratio (OR) 0.97, 95 per cent c.i. 0.74 to 1.25). Operating in the presence (OR 1.23, 1.03 to 1.47) or a history (OR 1.34, 1.10 to 1.64) of acute cholecystitis, and open surgery (OR 1.56, 1.26 to 1.94), were identified as significant risk factors for bile duct injury. The intention to perform intraoperative cholangiography was associated with a reduced risk of bile duct injury in patients with concurrent (OR 0.44, 0.30 to 0.63) or a history of (OR 0.59, 0.35 to 1.00) acute cholecystitis. CONCLUSION: Any proposed protective effect of intraoperative cholangiography was restricted to patients with (or a history of) acute cholecystitis. PMID- 25919402 TI - Outcome Measurement in Adult Auditory Rehabilitation: A Scoping Review of Measures Used in Randomized Controlled Trials. AB - OBJECTIVES: This review documented the range and nature of reported outcome measures in the context of adult auditory rehabilitative research. DESIGN: A scoping review conducted as a part of the development of a systematic review of the effect of interventions to improve hearing aid use. The authors searched the Cochrane Ear, Nose and Throat Disorders Group Trials Register; the Cochrane Central Register of Controlled Trials; PubMed; EMBASE; CINAHL; Web of Science; Cambridge Scientific Abstracts; ICTRP; and additional sources for published and unpublished randomized control trials. The date of the search was November 6, 2013. Outcomes were grouped using a framework suggested by the Cochrane Effective Practice and Organization of Care group. RESULTS: Patient outcomes included adherence to hearing aid use, daily hours of aid use, hearing handicap, hearing aid benefit, quality of life, and communication and psychological outcome. Satisfaction and speech perception were frequent secondary outcomes. There was diversity in measures used to report patient outcomes. Outcome categories other than patient health status and behavior were rarely reported. The timing of outcome measurement was often short term (<12 weeks), with a relative lack of evidence on long-term outcomes (>1 year). CONCLUSIONS: This review has highlighted considerable diversity in patient-reported outcome measurements in randomized control trials in the context of adult auditory rehabilitation. In addition, there are gaps in the literature with respect to measurement of other outcome types of potential interest to stakeholders, including policymakers and commissioners. Long-term outcome assessment is rare. PMID- 25919403 TI - Association between Maturation and Aging and Pulmonary Responses in Animal Models of Lung Injury: A Systematic Review. AB - BACKGROUND: Advanced age is associated with an increased susceptibility and mortality of the acute respiratory distress syndrome. This may be due to the progressive changes in innate immune responses and intrinsic properties of the lung that occur during the process of aging. Therefore, this study assesses the association between maturation and aging and pulmonary responses to injury in animal models of lung injury. METHODS: A systematic search was conducted in PubMed, EMBASE (up to June 2014) and in the references of relevant articles to identify the studies using in vivo models of lung injury caused by an acute pulmonary insult, in which at least two age groups were compared. Because methodological diversity precluded combining these studies in a quantitative meta analysis, data are presented based on the qualitative comparison with the adult group. RESULTS: Of the 2,840 identified studies, 51 were included in this review. Most studies showed that, in response to a pulmonary insult, increasing age is associated with more pulmonary inflammation, edema, alveolar damage, and higher mortality. In addition, results indicate the existence of age-dependent changes in key components of the intracellular signaling pathways involved in the inflammatory response. CONCLUSIONS: Increasing age seems to be correlated with exaggerated pulmonary responses to injury, ultimately leading to more severe lung injury. Pulmonary inflammation seems relatively suppressed in infants/juveniles, whereas in the middle aged/elderly, the inflammatory response seems delayed but aggravated. This implies that investigators and clinicians need to use caution about extrapolating results from adolescent or youngadult animals to pediatric or elderly patients in clinical practice. PMID- 25919404 TI - The Effect of Halogen-to-Hydrogen Bond Substitution on Human Aldose Reductase Inhibition. AB - The effect of halogen-to-hydrogen bond substitution on the binding energetics and biological activity of a human aldose reductase inhibitor has been studied using X-ray crystallography, IC50 measurements, advanced binding free energy calculations, and simulations. The replacement of Br or I atoms by an amine (NH2) group has not induced changes in the original geometry of the complex, which made it possible to study the isolated features of selected noncovalent interactions in a biomolecular complex. PMID- 25919405 TI - Similar magnitude of post-exercise hyperglycemia despite manipulating resistance exercise intensity in type 1 diabetes individuals. AB - The aim of this study was to compare the glycemic and glucoregulatory hormone responses to low- and moderate-intensity morning resistance exercise (RE) sessions in type 1 diabetes (T1DM). Following maximal strength assessments (1RM), eight T1DM (HbA1C :72 +/- 12 mmol/mol, age:34 +/- 7 years, body mass index:25.7 +/- 1.6 kg/m(2) ) participants attended the research facility on two separate occasions, having fasted and taken their usual basal insulin but omitting rapid acting insulin. Participants performed six exercises for two sets of 20 repetitions at 30%1RM during one session [low-intensity RE session (LOW)] and two sets of 10 repetitions at 60%1RM during another session [moderate-intensity RE session (MOD)], followed by 65-min recovery. Sessions were matched for total mass lifted (kg). Venous blood samples were taken before and after exercise. Data (mean +/- SEM) were analyzed using analysis of variance (P <= 0.05). There were no hypoglycemic occurrences throughout the study. Blood glucose rose similarly between sessions during exercise (P = 0.382), remaining comparable between sessions throughout recovery (P > 0.05). There was no effect of RE intensity on metabolic acidosis (P > 0.05) or peak growth hormone responses (P = 0.644), but a tendency for greater catecholamine responses under LOW (individualized peak concentrations: adrenaline MOD 0.55 +/- 0.13 vs LOW 1.04 +/- 0.37 nmol/L, P = 0.155; noradrenaline MOD 4.59 +/- 0.86 vs LOW 7.11 +/- 1.82 nmol/L, P = 0.082). The magnitude of post-exercise hyperglycemia does not differ between equal volume low and moderate intensity RE sessions performed in the morning. PMID- 25919406 TI - Mutualistic root endophytism is not associated with the reduction of saprotrophic traits and requires a noncompromised plant innate immunity. AB - During a compatible interaction, the sebacinoid root-associated fungi Piriformospora indica and Sebacina vermifera induce modification of root morphology and enhance shoot growth in Arabidopsis thaliana. The genomic traits common in these two fungi were investigated and compared with those of other root associated fungi and saprotrophs. The transcriptional responses of the two sebacinoid fungi and of Arabidopsis roots to colonization at three different symbiotic stages were analyzed by custom-designed microarrays. We identified key genomic features characteristic of sebacinoid fungi, such as expansions for gene families involved in hydrolytic activities, carbohydrate-binding and protein protein interaction. Additionally, we show that colonization of Arabidopsis correlates with the induction of salicylic acid catabolism and accumulation of jasmonate and glucosinolates (GSLs). Genes involved in root developmental processes were specifically induced by S. vermifera at later stages during interaction. Using different Arabidopsis indole-GSLs mutants and measurement of secondary metabolites, we demonstrate the importance of the indolic glucosinolate pathway in the growth restriction of P. indica and S. vermifera and we identify indole-phytoalexins and specifically indole-carboxylic acids derivatives as potential key players in the maintenance of a mutualistic interaction with root endophytes. PMID- 25919407 TI - Identification of solid state fermentation degree with FT-NIR spectroscopy: Comparison of wavelength variable selection methods of CARS and SCARS. AB - The use of wavelength variable selection before partial least squares discriminant analysis (PLS-DA) for qualitative identification of solid state fermentation degree by FT-NIR spectroscopy technique was investigated in this study. Two wavelength variable selection methods including competitive adaptive reweighted sampling (CARS) and stability competitive adaptive reweighted sampling (SCARS) were employed to select the important wavelengths. PLS-DA was applied to calibrate identified model using selected wavelength variables by CARS and SCARS for identification of solid state fermentation degree. Experimental results showed that the number of selected wavelength variables by CARS and SCARS were 58 and 47, respectively, from the 1557 original wavelength variables. Compared with the results of full-spectrum PLS-DA, the two wavelength variable selection methods both could enhance the performance of identified models. Meanwhile, compared with CARS-PLS-DA model, the SCARS-PLS-DA model achieved better results with the identification rate of 91.43% in the validation process. The overall results sufficiently demonstrate the PLS-DA model constructed using selected wavelength variables by a proper wavelength variable method can be more accurate identification of solid state fermentation degree. PMID- 25919408 TI - Vibrational spectra, powder X-ray diffractions and physical properties of cyanide complexes with 1-ethylimidazole. AB - The heteronuclear tetracyanonickelate(II) complexes of the type [M(etim)Ni(CN)4]n (hereafter, abbreviated as M-Ni-etim, M=Mn(II), Fe(II) or Co(II); etim=1 ethylimidazole, C5H8N2) were prepared in powder form and characterized by FT-IR and Raman spectroscopy, powder X-ray diffraction (PXRD), thermal (TG; DTG and DTA), and elemental analysis techniques. The structures of these complexes were elucidated using vibrational spectra and powder X-ray diffraction patterns with the peak assignment to provide a better understanding of the structures. It is shown that the spectra are consistent with a proposed crystal structure for these compounds derived from powder X-ray diffraction measurements. Vibrational spectra of the complexes were presented and discussed with respect to the internal modes of both the etim and the cyanide ligands. The C, H and N analyses were carried out for all the complexes. Thermal behaviors of these complexes were followed using TG, DTG and DTA curves in the temperature range 30-700 degrees C in the static air atmosphere. The FT-IR, Raman spectra, thermal and powder X-ray analyses revealed no significant differences between the single crystal and powder forms. Additionally, electrical and magnetic properties of the complexes were investigated. The FT-IR and Raman spectroscopy, PXRD, thermal and elemental analyses results propose that these complexes are similar in structure to the Hofmann-type complexes. PMID- 25919409 TI - Merkel cell carcinoma in Scotland 2000-10. PMID- 25919410 TI - Determination of vertebral range of motion using inertial measurement units in 27 Franches-Montagnes stallions and comparison between conditions and with a mixed population. AB - REASONS FOR PERFORMING STUDY: The diagnosis of equine back disorders is challenging. Objectively determining movement of the vertebral column may therefore be of value in a clinical setting. OBJECTIVES: To establish whether surface-mounted inertial measurement units (IMUs) can be used to establish normal values for range of motion (ROM) of the vertebral column in a uniform population of horses trotting under different conditions. STUDY DESIGN: Vertebral ROM was established in Franches-Montagnes stallions and a general population of horses and the variability in measurements compared between the two groups. Repeatability and the influence of specific exercise condition (on ROM) were assessed. Finally, attempts were made to explain the findings of the study through the evaluation of factors that might influence ROM. METHODS: Dorsoventral (DV) and mediolateral (ML) vertebral ROM was measured at a trot under different exercise conditions in 27 Franches-Montagnes stallions and six general population horses using IMUs distributed over the vertebral column. RESULTS: Variability in the ROM measurements was significantly higher for general population horses than for Franches-Montagnes stallions (both DV and ML ROM). Repeatability was strong to very strong for DV measurements and moderate for ML measurements. Trotting under saddle significantly reduced the ROM, with sitting trot resulting in a significantly lower ROM than rising trot. Age is unlikely to explain the low variability in vertebral ROM recorded in the Franches-Montagnes horses, while this may be associated with conformational factors. CONCLUSIONS: It was possible to establish a normal vertebral ROM for a group of Franches-Montagnes stallions. While within-breed variation was low in this population, further studies are necessary to determine variation in vertebral ROM for other breeds and to assess their utility for diagnosis of equine back disorders. PMID- 25919411 TI - Chemical synthesis of La1 isolated from the venom of the scorpion Liocheles australasiae and determination of its disulfide bonding pattern. AB - La1 is a 73-residue cysteine-rich peptide isolated from the scorpion Liocheles australasiae venom. Although La1 is the most abundant peptide in the venom, its biological function remains unknown. Here, we describe a method for efficient chemical synthesis of La1 using the native chemical ligation (NCL) strategy, in which three peptide components of less than 40 residues were sequentially ligated. The peptide thioester necessary for NCL was synthesized using an aromatic N-acylurea approach with Fmoc-SPPS. After completion of sequential NCL, disulfide bond formation was carried out using a dialysis method, in which the linear peptide dissolved in an acidic solution was dialyzed against a slightly alkaline buffer to obtain correctly folded La1. Next, we determined the disulfide bonding pattern of La1. Enzymatic and chemical digests of La1 without reduction of disulfide bonds were analyzed by liquid chromatography/mass spectrometry (LC/MS), which revealed two of four disulfide bond linkages. The remaining two linkages were assigned based on MS/MS analysis of a peptide fragment containing two disulfide bonds. Consequently, the disulfide bonding pattern of La1 was found to be similar to that of a von Willebrand factor type C (VWC) domain. To our knowledge, this is the first report of the experimental determination of the disulfide bonding pattern of peptides having a single VWC domain as well as their chemical synthesis. La1 synthesized in this study will be useful for investigation of its biological role in the venom. PMID- 25919412 TI - Noninvasive Imaging of Acute Renal Allograft Rejection by Ultrasound Detection of Microbubbles Targeted to T-lymphocytes in Rats. AB - PURPOSE: We propose CD3-antibody-mediated contrast-enhanced ultrasonography using human T-lymphocytes for image-based diagnosis of acute allograft rejection (AR) established in a rat renal transplantation model. MATERIALS AND METHODS: 15 minutes after tail vein injection of 30 * 10(6) human T-lymphocytes, contrast media/microbubbles conjugated with an anti-human CD3 antibody was applied to uni nephrectomized 10-week-old allogeneically transplanted male rats (Lewis-Brown Norway (LBN) to Lewis, aTX) and ultrasound was performed to investigate the transplanted kidney as well as the native kidney. In vivo results were confirmed via immunohistochemical stainings of CD3 after post mortem dissection. Syngeneically transplanted rats (LBN to LBN, sTX), rats with ischemia/reperfusion injury (IRI, 45 min. warm ischemia), and rats subjected to acute cyclosporin A toxicity (CSA) (cyclosporine 50 mg/kg BW for 2 days i. p.) served as controls. RESULTS: Accumulation of human T-lymphocytes was clearly detected by antibody mediated sonography und was significantly increased in allografts undergoing AR (5.41 +/- 1.32 A. U.) when compared to native control kidneys (0.70 +/- 0.08 A. U.). CD3 signal intensity was low in native kidneys, sTX (0.99 +/- 0.30 A. U.), CSA (0.10 +/- 0.02 A. U.) and kidneys with IRI (0.46 +/- 0.29 A. U.). Quantification of the ultrasound signal correlated significantly with the T-cell numbers obtained by immunohistochemical analysis (R2 = 0.57). CONCLUSION: Contrast-enhanced sonography using CD3-antibodies is an option for quick and highly specific assessment of AR in a rat model of renal transplantation. PMID- 25919413 TI - German Survey on EUS-Guided Diagnosis and Management of Gastrointestinal Stromal Tumors (GISTs) - Evidence or "Gut-Feeling"? AB - PURPOSE: To examine practice patterns of endosonographers in diagnosing and managing gastrointestinal stromal tumors (GISTs) in Germany. MATERIALS AND METHODS: A modified published survey (Ha et al., Gastrointest Endosc 2009) was sent to endosonographic ultrasound (EUS) customers in Germany. The survey was also publicized on the homepage of an EUS interest group. To avoid duplicate opinions, participants were asked to return one survey per institution. RESULTS: 142 centers of roughly 850 German EUS centers responded. 25 % were from University hospitals and 74 % from community hospitals. 61 % performed > 2 EUS scans for suspected subepithelial lesions/week. Although 97 % of respondents believed that tissue acquisition with CD117 immunohistochemistry best predicts a GIST, 11 % do not perform EUS-FNA when suspecting a GIST, 68 % perform it occasionally and 18 % perform it regularly. The main EUS criteria used for a suspected GIST are the typical layer (85 %), hypoechoic appearance (80 %) and gastric location (51 %). 69 % would diagnose a GIST with negative CD117 if the EUS criteria and spindle cells are present. FNA was rated helpful in < 50 % by 55 % of participants. Size was the primary criterion for suspecting malignancy. 95 % of respondents would perform surveillance >= 1x/year of GISTs that are not resected. CONCLUSION: There is significant variability in the diagnosis and management of GISTs in Germany. Diagnostic certainty of EUS-FNA is suboptimal in many centers and EUS is frequently used for guidance. The diagnosis of a GIST is often guided by a "gut feeling" rather than evidence. Efforts should be made to unify existing guidelines. PMID- 25919414 TI - Factors Affecting the Enhancement Patterns of Intrahepatic Cholangiocarcinoma (ICC) on Contrast-Enhanced Ultrasound (CEUS) and their Pathological Correlations in Patients with a Single Lesion. AB - Purpose: To investigate the factors that influence the enhancement patterns of intrahepatic cholangiocarcinomas (ICC) on contrast-enhanced ultrasound (CEUS) and analyze the correlations between the enhancement patterns on CEUS and pathological findings. Materials and Methods: Ninety-six patients with 96 pathologically confirmed ICCs underwent CEUS. CEUS images were retrospectively evaluated for tumor enhancement patterns in the arterial, portal and late phases. The arterial enhancement patterns were correlated with clinicopathological factors. The possible influencing factors were correlated with pathologic findings. Results: Thirty-six patients with ICC demonstrated rim-like enhancement, and 60 exhibited non-rim-like enhancement in the arterial phase on CEUS. The incidence of non-rim-like-enhancing ICCs was higher in patients with cirrhosis and chronic viral hepatitis than patients with no chronic liver disease (p = 0.001). The sizes of the ICCs with homogeneous hyper-enhancement were significantly smaller than those with inhomogeneous hyper-enhancement (p = 0.007). Arterial non-rim-like-enhancing ICCs showed higher microvessel density (MVD) and arterial density (AD) and less fibrous stroma and necrosis than rim like-enhancing ICCs. Arterial inhomogeneous-enhancing ICCs had lower MVD and AD and much more fibrous stroma and necrosis than homogeneous-enhancing ICCs. Conclusion: The enhancement pattern of ICCs in the arterial phase on CEUS was affected by a liver cirrhosis and chronic viral hepatitis and tumor size. The amount of MVD, AD, fibrous stroma and necrosis in ICC tumors may be responsible for the difference in the enhancement patterns. PMID- 25919415 TI - Increased medical cost metrics for patients 50 years of age and older in the collaborate care model of treatment for depression. AB - BACKGROUND: The collaborative care model (CCM) has been consistently shown to achieve effectiveness in depression management compared to usual care. In the present study, we aimed to determine the impact of age on cost metrics in patients who were treated with CCM for 6 months after a diagnosis of depression. METHODS: The upper quartile of age was 50 years and older (n = 56), and the comparison group was composed of patients in the three younger quartiles, aged 18 49 years (n = 163). RESULTS: Patients in the older age group had an elevated median Current Procedure Terminology cost rank of 255.5 compared to 168.0 for the younger patients (P < 0.001). Multiple logistic regression analysis revealed that being in the upper quartile of age (>= 50 years) (odds ratio = 2.272, 95% confidence interval: 1.064-4.851; P = 0.034) and having higher numbers of clinical visits 6 months prior to index (odds ratio = 1.209, 95% confidence interval: 1.118-1.307; P < 0.001) were significant predictor variables of being cost rank outliers (>80th percentile) in patients with CCM. CONCLUSION: Medical cost utilization in the 6 months after diagnosis of depression was significantly higher in patients in the upper age quartile (>= 50 years) enrolled in CCM than those in the lower quartiles (age < 50). PMID- 25919416 TI - Simultaneous chromate reduction and azo dye decolourization by Lactobacillus paracase CL1107 isolated from deep sea sediment. AB - Lactobacillus paracase CL1107 capable of removing toxic chromium (Cr(VI)) and Acid Black (ATT) azo dye simultaneously was isolated from deep sea sediment of the North Atlantic. CL1107 exhibited appreciable dye-Cr(VI) bioremoval ability in the pH range from 5 to 7, temperature 25-35 degrees C and NaCl 0-6% under aerobic conditions. The maximum removal values of Cr(VI) (95.8%) and dye (92.3%) were obtained in the media including only Cr(VI) or dye at initial concentration of 100 mg/L. In the experiments for the simultaneous treatment of both pollutants, the reduction of Cr(VI) and dye was 58.5% and 51.9%, respectively. The azo dye and Cr(VI) reductive activities in strain CL1107 were located in the cell free extract and cell debris, respectively. The mechanisms of azo dye and Cr(VI) reduction were found to be enzyme-mediated. In the treatment of saline tannery wastewater, decolourization of about 76% and 63% Cr(VI) reduction of were achieved. Furthermore, Azo dyes, Cr(VI) and wastewater showed reduced toxicity toward Artemia salina after treatment. These results demonstrate the potential of CL1107 in bioremediation of dye or/and Cr(VI) contamination in salt environments. PMID- 25919417 TI - Optimizing techniques to capture and extract environmental DNA for detection and quantification of fish. AB - Few studies have examined capture and extraction methods for environmental DNA (eDNA) to identify techniques optimal for detection and quantification. In this study, precipitation, centrifugation and filtration eDNA capture methods and six commercially available DNA extraction kits were evaluated for their ability to detect and quantify common carp (Cyprinus carpio) mitochondrial DNA using quantitative PCR in a series of laboratory experiments. Filtration methods yielded the most carp eDNA, and a glass fibre (GF) filter performed better than a similar pore size polycarbonate (PC) filter. Smaller pore sized filters had higher regression slopes of biomass to eDNA, indicating that they were potentially more sensitive to changes in biomass. Comparison of DNA extraction kits showed that the MP Biomedicals FastDNA SPIN Kit yielded the most carp eDNA and was the most sensitive for detection purposes, despite minor inhibition. The MoBio PowerSoil DNA Isolation Kit had the lowest coefficient of variation in extraction efficiency between lake and well water and had no detectable inhibition, making it most suitable for comparisons across aquatic environments. Of the methods tested, we recommend using a 1.5 MUm GF filter, followed by extraction with the MP Biomedicals FastDNA SPIN Kit for detection. For quantification of eDNA, filtration through a 0.2-0.6 MUm pore size PC filter, followed by extraction with MoBio PowerSoil DNA Isolation Kit was optimal. These results are broadly applicable for laboratory studies on carps and potentially other cyprinids. The recommendations can also be used to inform choice of methodology for field studies. PMID- 25919419 TI - How does the healthcare system affect medication self-management among older adults with multimorbidity? AB - Individuals with multimorbidity commonly have several concurrent prescriptions and experience healthcare obstacles related to managing different diagnoses and medications. This study aimed to provide a deeper understanding of how older adults with multimorbidity experience medication self-management and how this is affected by the healthcare system. The National Board of Research Ethics approved the study, and 20 older adults with multimorbidity participated in in-depth interviews that were analysed using a hermeneutic approach. Three levels of interpretation emerged. At the first level, lack of participation in healthcare communication hinders adherence and safety, and feeling abandoned to self-care leads to health risk-taking. At the second level, the healthcare organisation is seen as an obstacle to medication self-management. The overall interpretation was a system of repairing 'parts' but not enabling the experience of health. This study shows that the healthcare system is able to treat and relieve an individual's symptoms, but seems unable to help them achieve and promote good health, or to provide the support they need to function in everyday life. PMID- 25919418 TI - Multiformat T-cell-engaging bispecific antibodies targeting human breast cancers. AB - Four different formats of bispecific antibodies (bsAbs) were generated that consist of anti-Her2 IgG or Fab site-specifically conjugated to anti-CD3 Fab using the genetically encoded noncanonical amino acid. These bsAbs varied in valency or in the presence or absence of an Fc domain. Different valencies did not significantly affect antitumor efficacy, whereas the presence of an Fc domain enhanced cytotoxic activity, but triggered antigen-independent T-cell activation. We show that the bsAbs can efficiently redirect T cells to kill all Her2 expressing cancer cells, including Her2 1+ cancers, both in vitro and in rodent xenograft models. This work increases our understanding of the structural features that affect bsAb activity, and underscores the potential of bsAbs as a promising therapeutic option for breast cancer patients with low or heterogeneous Her2 expression. PMID- 25919420 TI - Broadband visible light-harvesting naphthalenediimide (NDI) triad: study of the intra-/intermolecular energy/electron transfer and the triplet excited state. AB - A triad based on naphthalenediimides (NDI) was prepared to study the intersystem crossing (ISC), the fluorescence-resonance-energy-transfer (FRET), as well as the photoinduced electron transfer (PET) processes. In the triad, the 2-bromo-6 alkylaminoNDI moiety was used as singlet energy donor and the spin converter, whereas 2,6-dialkylaminoNDI was used as the singlet/triplet energy acceptor. This unique structural protocol and thus alignment of the energy levels ensures the competing ISC and FRET in the triad. The photophysical properties of the triad and the reference compounds were studied with steady-state UV-vis absorption spectra, fluorescence spectra, nanosecond transient absorption spectra, cyclic voltammetry, and DFT/TDDFT calculations. FRET was confirmed with steady-state UV vis absorption and fluorescence spectroscopy. Intramolecular electron transfer was observed in polar solvents, demonstrated by the quenching of both the fluorescence and triplet state of the energy acceptor. Nanosecond transient absorption spectroscopy shows that the T1 state of the triad is exclusively localized on the 2,6-dialkylaminoNDI moiety in the triad upon selective photoexcitation into the energy donor, which indicates the intramolecular triplet state energy transfer. The intermolecular triplet state energy transfer between the two reference compounds was investigated with nanosecond transient absorption spectroscopy. The photophysical properties were rationalized by TDDFT calculations. PMID- 25919421 TI - Ecological effects of combined pollution associated with e-waste recycling on the composition and diversity of soil microbial communities. AB - The crude processing of electronic waste (e-waste) has led to serious contamination in soils. While microorganisms may play a key role in remediation of the contaminated soils, the ecological effects of combined pollution (heavy metals, polychlorinated biphenyls, and polybrominated diphenyl ethers) on the composition and diversity of microbial communities remain unknown. In this study, a suite of e-waste contaminated soils were collected from Guiyu, China, and the indigenous microbial assemblages were profiled by 16S rRNA high-throughput sequencing and clone library analysis. Our data revealed significant differences in microbial taxonomic composition between the contaminated and the reference soils, with Proteobacteria, Acidobacteria, Bacteroidetes, and Firmicutes dominating the e-waste-affected communities. Genera previously identified as organic pollutants-degrading bacteria, such as Acinetobacter, Pseudomonas, and Alcanivorax, were frequently detected. Canonical correspondence analysis revealed that approximately 70% of the observed variation in microbial assemblages in the contaminated soils was explained by eight environmental variables (including soil physiochemical parameters and organic pollutants) together, among which moisture content, decabromodiphenyl ether (BDE-209), and copper were the major factors. These results provide the first detailed phylogenetic look at the microbial communities in e-waste contaminated soils, demonstrating that the complex combined pollution resulting from improper e-waste recycling may significantly alter soil microbiota. PMID- 25919422 TI - Gut-brain axis dysfunction may be associated with psoriatic arthritis: comment on the article by Scher et al. PMID- 25919423 TI - Nanoengineered Polystyrene Surfaces with Nanopore Array Pattern Alters Cytoskeleton Organization and Enhances Induction of Neural Differentiation of Human Adipose-Derived Stem Cells. AB - Human adipose-derived stem cells (hADSCs) can differentiate into various cell types depending on chemical and topographical cues. One topographical cue recently noted to be successful in inducing differentiation is the nanoengineered polystyrene surface containing nanopore array-patterned substrate (NP substrate), which is designed to mimic the nanoscale topographical features of the extracellular matrix. In this study, efficacies of NP and flat substrates in inducing neural differentiation of hADSCs were examined by comparing their substrate-cell adhesion rates, filopodia growth, nuclei elongation, and expression of neural-specific markers. The polystyrene nano Petri dishes containing NP substrates were fabricated by a nano injection molding process using a nickel electroformed nano-mold insert (Diameter: 200 nm. Depth of pore: 500 nm. Center-to-center distance: 500 nm). Cytoskeleton and filopodia structures were observed by scanning electron microscopy and F-actin staining, while cell adhesion was tested by vinculin staining after 24 and 48 h of seeding. Expression of neural specific markers was examined by real-time quantitative polymerase chain reaction and immunocytochemistry. Results showed that NP substrates lead to greater substrate-cell adhesion, filopodia growth, nuclei elongation, and expression of neural specific markers compared to flat substrates. These results not only show the advantages of NP substrates, but they also suggest that further study into cell-substrate interactions may yield great benefits for biomaterial engineering. PMID- 25919424 TI - Quantum dot imaging in the second near-infrared optical window: studies on reflectance fluorescence imaging depths by effective fluence rate and multiple image acquisition. AB - Quantum dot (QD) imaging capability was investigated by the imaging depth at a near-infrared second optical window (SOW; 1000 to 1400 nm) using time-modulated pulsed laser excitations to control the effective fluence rate. Various media, such as liquid phantoms, tissues, and in vivo small animals, were used and the imaging depths were compared with our predicted values. The QD imaging depth under excitation of continuous 20 mW/cm(2) laser was determined to be 10.3 mm for 2 wt%hemoglobin phantom medium and 5.85 mm for 1 wt% intralipid phantom, which were extended by more than two times on increasing the effective fluence rate to 2000 mW/cm(2). Bovine liver and porcine skin tissues also showed similar enhancement in the contrast-to-noise ratio (CNR) values. A QD sample was inserted into the abdomen of a mouse.With a higher effective fluence rate, the CNR increased more than twofold and the QD sample became clearly visualized, which was completely undetectable under continuous excitation.Multiple acquisitions of QD images and averaging process pixel by pixel were performed to overcome the thermal noise issue of the detector in SOW, which yielded significant enhancement in the imaging capability, showing up to a 1.5 times increase in the CNR. PMID- 25919425 TI - Multimodal noncontact photoacoustic and optical coherence tomography imaging using wavelength-division multiplexing. AB - We present multimodal noncontact photoacoustic (PA) and optical coherence tomography (OCT) imaging. PA signals are acquired remotely on the surface of a specimen with a Mach-Zehnder interferometer. The interferometer is realized in a fiber-optic network using a fiber laser at 1550 nm as the source. In the same fiber-optic network, a spectral-domain OCT system is implemented. The OCT system utilizes a supercontinuum light source at 1310 nm and a spectrometer with an InGaAs line array detector. Light from the fiber laser and the OCT source is multiplexed into one fiber using a wavelength-division multiplexer; the same objective is used for both imaging modalities. Reflected light is spectrally demultiplexed and guided to the respective imaging systems. We demonstrate two dimensional and three-dimensional imaging on a tissue-mimicking sample and a chicken skin phantom. The same fiber network and same optical components are used for PA and OCT imaging, and the obtained images are intrinsically coregistered. PMID- 25919427 TI - Phosphine-free palladium-catalyzed direct bisarylation of pyrroles with aryl iodides on water. AB - The Pd-catalyzed bisarylation of pyrroles with aryl iodides on water is described. The reaction proceeds under mild reaction conditions, i.e., relatively low temperature (40 degrees C) and phosphine-free. PMID- 25919426 TI - Automated frame selection process for high-resolution microendoscopy. AB - We developed an automated frame selection algorithm for high-resolution microendoscopy video sequences. The algorithm rapidly selects a representative frame with minimal motion artifact from a short video sequence, enabling fully automated image analysis at the point-of-care. The algorithm was evaluated by quantitative comparison of diagnostically relevant image features and diagnostic classification results obtained using automated frame selection versus manual frame selection. A data set consisting of video sequences collected in vivo from 100 oral sites and 167 esophageal sites was used in the analysis. The area under the receiver operating characteristic curve was 0.78 (automated selection) versus 0.82 (manual selection) for oral sites, and 0.93 (automated selection) versus 0.92 (manual selection) for esophageal sites. The implementation of fully automated high-resolution microendoscopy at the point-of-care has the potential to reduce the number of biopsies needed for accurate diagnosis of precancer and cancer in low-resource settings where there may be limited infrastructure and personnel for standard histologic analysis. PMID- 25919428 TI - Infants with complex congenital heart diseases show poor short-term memory in the mobile paradigm at 3 months of age. AB - The purpose of this study was to examine learning, short-term memory and general development including cognitive, motor, and language domains in infants with Complex Congenital Heart Defects (CCDH). Ten infants with CCHD (4 males, 6 females) and 14 infants with typical development (TD) were examined at 3 months of age. The mobile paradigm, where an infant's leg is tethered to an overhead mobile, was used to evaluate learning and short-term memory. The Bayley Scales of Infant Development 3rd edition (Bayley-III) was used to evaluate general development in cognitive, motor, and language domains. Infants with CCHD and infants with TD both showed learning with significant increase in kicking rate (p<0.001) across periods of the mobile paradigm, but only infants with TD demonstrated short-term memory (p=0.017) in the mobile paradigm. There were no differences on cognitive, motor, and language development between infants with CCHD and infants with TD on the Bayley-III. Early assessment is necessary to guide targeted treatment in infants with CCHD. One-time assessment may fail to detect potential cognitive impairments during early infancy in infants with CCHD. Supportive intervention programs for infants with CCHD that focuses on enhancing short-term memory are recommended. PMID- 25919429 TI - Statin Use and Risk of Sepsis After Percutaneous Nephrolithotomy. AB - PURPOSE: To examine the association between statin medication use and sepsis risk after percutaneous nephrolithotomy (PCNL). MATERIALS AND METHODS: Using medical claims data, we identified working-age adults with urinary stone disease who were treated with PCNL. Among this cohort, we determined which patients had a prescription fill for a statin agent that encompassed their surgery date. We then fitted logistic regression models to examine for differences in rates of postoperative sepsis between statin users and nonusers. In addition, we evaluated the frequency of nonfebrile urinary tract infections (UTIs) and intensive care unit (ICU) services utilization and hospital length of stay (LOS) as a function of statin use. RESULTS: During the study period, at total of 2046 patients underwent PCNL, 382 (18.7%) of whom had a prescription fill for a statin agent preceding their surgery. The overall rate of sepsis in this population was 3.8%. After adjusting for patient health status and sociodemographic factors, the rate of postoperative sepsis was comparable between statin users and nonusers (5.3% vs 3.5%, respectively; P=0.105). In addition, UTI and ICU utilization rates did not relate to statin use (P>0.05 for all associations). Adjusted hospital LOS was shorter among statin users, but the difference was clinically trivial (3.6 vs 4.1 days; P=0.007). CONCLUSIONS: Statin use is not associated with reductions in postoperative sepsis, nonfebrile UTIs, ICU utilization, or hospital LOS after PCNL. To increase the safety of PCNL, urologists will have to consider other processes of care (e.g., clinical care pathways). PMID- 25919430 TI - The role of steric interactions in dispersion of carbon nanotubes by poly(3-alkyl thiophenes) in organic solvents. AB - The dispersion mechanism of carbon nanotubes (CNTs) in organic solutions of poly(3-alkyl thiophenes, P3ATs) was examined in a study that combines experimental investigation of the dispersion mechanism and molecular theory calculations of the effective intertube potential for polymer wrapped CNTs. The minimal polymer concentration required for dispersion of CNT served as a comparative measure of the efficiency of P3AT derivatives that differ in the length of the alkyl side chains or the regiochemistry of the monomers in three solvents: 1,2 and 1,3 dichlorobenzene and chloroform. While previous studies focused on the adsorption mechanism of P3ATs onto SWNT, we find that the dispersing efficiency depends not only on the stacking of the polymer backbone onto the CNT ("wrapping"), but also on the steric repulsion among the side chains of adsorbed P3ATs. In accordance with the experiments, our calculations indicate that high surface density of polymers with longer side chains and large tube diameter promote the formation of stable dispersions of relatively high loadings of CNTs, at low polymer:CNT ratios. PMID- 25919431 TI - Preparation of iron nanoparticles-loaded Spondias purpurea seed waste as an excellent adsorbent for removal of phosphate from synthetic and natural waters. AB - The synthesis and characterization of nanoscale zerovalent iron particles (NZVI) supported on Spondias purpurea seed waste (S-NaOH-NZVI) was performed for the adsorption of phosphate (P) ions from waste waters. The effects of various parameters, such as contact time, pH, concentration, reusability and temperature were studied. The adsorption of phosphate ions has been studied in terms of pseudo-first- and -second-order kinetics, and the Freundlich, and Langmuir isotherms models have also been used to the equilibrium adsorption data. The adsorption kinetics followed the mechanism of the pseudo-second-order equation. The thermodynamic parameters (DeltaG, DeltaH and DeltaS) indicated that the adsorption of phosphate ions were feasible, spontaneous and endothermic at 25-80 degrees C. No significant loss of activity was observed; confirming that the S NaOH-NZVI has high stability during the adsorption process even after 12th runs. The suggested adsorbent in this paper was also implemented to remove P from the Persian Gulf water. XRD, FTIR and EDX analysis indicated the presence of Fe3 (PO4)2?8H2O (vivianite) on the S-NaOH-NZVI@P surface. PMID- 25919432 TI - The development of confocal arthroscopy as optical histology for rotator cuff tendinopathy. AB - MRI, ultrasound and video arthroscopy are traditional imaging technologies for noninvasive or minimal invasive assessment of the rotator cuff tendon pathology. However, these imaging modalities do not have sufficient resolution to demonstrate the pathology of rotator cuff tendons at a microstructural level. Therefore, they are insensitive to low-level tendon diseases. Although traditional histology can be used to analyze the physiology of rotator cuff tendons, it requires biopsy that traumatizes the rotator cuff, thus, potentially comprising the mechanical properties of tendons. Besides, it cannot offer real time histological information. Confocal endoscopy offers a way to assess the microstructural disorder in tissues without biopsy. However, the application of this useful technique for detecting low-level tendon diseases has been restricted by using clinical grade fluorescent contrast agent to acquire high-resolution microstructural images of tendons. In this study, using a clinical grade sodium fluorescein contrast agent, we have reported the development of confocal arthroscopy for optical histological assessment without biopsy. The confocal arthroscopic technique was able to demonstrate rotator cuff tendinopathy in human cadavers, which appeared macroscopically normal under video arthroscopic examinations. The tendinopathy status of the rotator cuff tendons was confirmed by corresponding traditional histology. The development of confocal arthroscopy may provide a minimally invasive imaging technique for real-time histology of rotator cuff without the need for tissue biopsy. This technique has the potential for surgeons to gain in real time the histological information of rotator cuff tendons, which may assist planning repair strategies and potentially improve intervention outcomes. PMID- 25919433 TI - Exploring Metabolic Profile Differences between Colorectal Polyp Patients and Controls Using Seemingly Unrelated Regression. AB - Despite the fact that colorectal cancer (CRC) is one of the most prevalent and deadly cancers in the world, the development of improved and robust biomarkers to enable screening, surveillance, and therapy monitoring of CRC continues to be evasive. In particular, patients with colon polyps are at higher risk of developing colon cancer; however, noninvasive methods to identify these patients suffer from poor performance. In consideration of the challenges involved in identifying metabolite biomarkers in individuals with high risk for colon cancer, we have investigated NMR-based metabolite profiling in combination with numerous demographic parameters to investigate the ability of serum metabolites to differentiate polyp patients from healthy subjects. We also investigated the effect of disease risk on different groups of biologically related metabolites. A powerful statistical approach, seemingly unrelated regression (SUR), was used to model the correlated levels of metabolites in the same biological group. The metabolites were found to be significantly affected by demographic covariates such as gender, BMI, BMI(2), and smoking status. After accounting for the effects of the confounding factors, we then investigated potential of metabolites from serum to differentiate patients with polyps and age matched healthy controls. Our results showed that while only valine was slightly associated, individually, with polyp patients, a number of biologically related groups of metabolites were significantly associated with polyps. These results may explain some of the challenges and promise a novel avenue for future metabolite profiling methodologies. PMID- 25919434 TI - Graphene oxide flakes as a cellular adhesive: prevention of reactive oxygen species mediated death of implanted cells for cardiac repair. AB - Mesenchymal stem cell (MSC) implantation has emerged as a potential therapy for myocardial infarction (MI). However, the poor survival of MSCs implanted to treat MI has significantly limited the therapeutic efficacy of this approach. This poor survival is primarily due to reactive oxygen species (ROS) generated in the ischemic myocardium after the restoration of blood flow. ROS primarily causes the death of implanted MSCs by inhibiting the adhesion of the MSCs to extracellular matrices at the lesion site (i.e., anoikis). In this study, we proposed the use of graphene oxide (GO) flakes to protect the implanted MSCs from ROS-mediated death and thereby improve the therapeutic efficacy of the MSCs. GO can adsorb extracellular matrix (ECM) proteins. The survival of MSCs, which had adhered to ECM protein-adsorbed GO flakes and were subsequently exposed to ROS in vitro or implanted into the ischemia-damaged and reperfused myocardium, significantly exceeded that of unmodified MSCs. Furthermore, the MSC engraftment improved by the adhesion of MSCs to GO flakes prior to implantation enhanced the paracrine secretion from the MSCs following MSC implantation, which in turn promoted cardiac tissue repair and cardiac function restoration. This study demonstrates that GO can effectively improve the engraftment and therapeutic efficacy of MSCs used to repair the injury of ROS-abundant ischemia and reperfusion by protecting implanted cells from anoikis. PMID- 25919435 TI - Assessing iodine intakes in pregnancy: why does this matter? PMID- 25919437 TI - A potential gradient along the layer-by-layer architecture for electron transfer rectification. AB - Electrochemical and photochemical measurements demonstrated that dendritic phenylazomethines, which can make complexes with SnCl2 by a stepwise process, only permit an outbound electron transfer. The unique dendrimer effect allows efficient production of photo-generated radical ion pairs by suppressing their charge recombination. In sharp contrast, the phenylenevinylene or benzylether dendrimers, which lack a heteroatom or pi-conjugation, did not exhibit such non symmetric characters. PMID- 25919436 TI - Effect of vitamin C and vitamin E supplementation on endothelial function: a systematic review and meta-analysis of randomised controlled trials. AB - Randomised controlled trials (RCT) testing the effects of antioxidant supplements on endothelial function (EF) have reported conflicting results. We aimed to investigate the effects of supplementation with antioxidant vitamins C and E on EF and to explore factors that may provide explanations for the inconsistent results. We searched four databases (MEDLINE, Embase, Cochrane Library and Scopus) from inception until May 2014 for RCT involving adult participants aged >=18 years who were supplemented with vitamins C and E alone or in combination for more than 2 weeks and reporting changes in EF measured using flow mediated dilation or forearm blood flow. Data were pooled as standardised mean difference (SMD) and analysed using a random-effects model. Significant improvements in EF were observed in trials supplementing with vitamin C alone (500-2000 mg/d) (SMD: 0.25, 95% CI 0.02, 0.49, P=0.043) and vitamin E alone (300-1800 IU/d; 1 IU vitamin E=0.67 mg natural vitamin E) (SMD: 0.48, 95% CI 0.23, 0.72, P=0.0001), whereas co-administration of both vitamins was ineffective (vitamin C: 500-2000 mg/d; vitamin E: 400-1200 IU/d) (SMD: 0.12, 95% CI-0.18, 0.42, P=0.428). The effect of vitamin C supplementation on EF increased significantly with age (beta 0.023, 95% CI 0.001, 0.05, P=0.042). There was a significant negative correlation between baseline plasma vitamin E concentration and the effect of vitamin E supplementation on EF (beta-0.03, 95% CI-0.06, -0.001, P=0.029). Supplementation with either vitamin C or vitamin E alone improves EF. However, subgroup analysis emphasises the importance of careful characterisation and selection of a population group which may benefit from such supplementation. PMID- 25919438 TI - Does elevated serum uric acid level predict the hypertension incidence? A Chinese prospective cohort study. AB - BACKGROUND AND AIMS: Hyperuricemia is an independent risk factor for hypertension. This study aims to investigate whether SUA predicts 2-year incidence of hypertension in population with pre-hypertension and ideal blood pressure in Tianjin, China. METHODS AND RESULTS: In this population-based prospective study, we analyzed 608 subjects (455 women) aged 40-70 with non hypertension (SBP < 140 mmHg and DBP < 90 mmHg) who were recruited with stratified cluster sampling method across six districts of Tianjin in 2011-2012. Participants were divided into pre-hypertensive group (group P) and ideal blood pressure group (group I) according to their first physical examination. After 2 years follow-up, the second physical examination was taken on the same crowd. The 2-year hypertension incidence rate in group P (35.6%) was higher than that of group I (8.3%) (p < 0.05). In group P, the hypertension incidence rate increased with the increase of SUA quartiles. Multivariate logistic regression analysis showed that the odd ratio (OR) between the highest SUA quartile group and the lowest SUA quartile group in group P were 2.02 (1.04-3.92), 3.34 (1.10-10.04) in men and 2.43 (1.08-5.45) in women (p < 0.05). However, there is no significant correlation between SUA and the risk for hypertension incidence in group I. Multiple linear regression showed that the SBP increased 0.017 mmHg with the increasing of 1 MUmol/L deviation of SUA in group P. CONCLUSIONS: SUA levels predict SBP elevation and hypertension incidence in population with pre hypertension, however, do not predict the DBP elevation in pre-hypertensive population as well as change of BP in ideal blood pressure population. PMID- 25919439 TI - Photocarrier drift distance in organic solar cells and photodetectors. AB - Light harvesting systems based upon disordered materials are not only widespread in nature, but are also increasingly prevalent in solar cells and photodetectors. Examples include organic semiconductors, which typically possess low charge carrier mobilities and Langevin-type recombination dynamics--both of which negatively impact the device performance. It is accepted wisdom that the "drift distance" (i.e., the distance a photocarrier drifts before recombination) is defined by the mobility-lifetime product in solar cells. We demonstrate that this traditional figure of merit is inadequate for describing the charge transport physics of organic light harvesting systems. It is experimentally shown that the onset of the photocarrier recombination is determined by the electrode charge and we propose the mobility-recombination coefficient product as an alternative figure of merit. The implications of these findings are relevant to a wide range of light harvesting systems and will necessitate a rethink of the critical parameters of charge transport. PMID- 25919440 TI - Localized exanthem due to echovirus 9. PMID- 25919441 TI - Spectrophotometry, not visual inspection for the detection of xanthochromia in suspected subarachnoid haemorrhage: A debate. PMID- 25919442 TI - Modifiable midlife risk factors, independent aging, and survival in older men: report on long-term follow-up of the Uppsala Longitudinal Study of Adult Men cohort. AB - OBJECTIVES: To examine relationships between modifiable midlife factors, aging, and physical and cognitive function (independent aging) and survival in very old age. DESIGN: Prospective cohort. SETTING: Uppsala Longitudinal Study of Adult Men, Uppsala, Sweden. PARTICIPANTS: Swedish men investigated in 1970-74 (aged 48.6-51.1) and followed up for four decades (N=2,293). MEASUREMENTS: Conventional cardiovascular risk factors, body mass index (BMI), and dietary biomarkers were measured, and a questionnaire was used to gather information on lifestyle variables at age 50. Four hundred seventy-two men were reinvestigated in 2008-09 (aged 84.8-88.9). Independent aging was defined as survival to age 85, Mini Mental State Examination score of 25 or greater, not living in an institution, independent in personal care and hygiene, able to walk outdoors without personal help, and no diagnosis of dementia. The National Swedish Death Registry provided survival data. RESULTS: Thirty-eight percent of the cohort survived to age 85. Seventy-four percent of the participants in 2008-09 were aging independently. In univariable analyses, high leisure-time physical activity predicted survival but not independent aging. Low work-time physical activity was associated more strongly with independent aging (odds ratio (OR)=1.84, 95% confidence interval (CI)=1.18-2.88) than with survival (OR=1.27, 95% CI=1.05-1.52). In multivariable analyses, midlife BMI was negatively associated (OR=0.80/SD, 95% CI=0.65 0.99/SD), and never or former smoking was positively associated (OR=1.66, 95% CI=1.07-2.59), with independent aging. As expected, conventional cardiovascular and lifestyle risk factors were associated with mortality. CONCLUSION: A normal midlife BMI and not smoking were associated with independent aging close to four decades later, indicating that normal weight at midlife has the potential not only to increase survival, but also to preserve independence with aging. PMID- 25919443 TI - pH-Manipulated Underwater-Oil Adhesion Wettability Behavior on the Micro/Nanoscale Semicircular Structure and Related Thermodynamic Analysis. AB - Controlling oil of wettability behavior in response to the underwater out stimulation has shown promising applications in understanding and designing novel micro- or nanofluidic devices. In this article, the pH-manipulated underwater-oil adhesion wetting phenomenon and superoleophobicity on the micro- and nanotexture copper mesh films (CMF) were investigated. It should be noted that the surface exhibits underwater superoleophobicity under different pH values of the solution; however, the underwater-oil adhesion behavior on the surface is dramatically influenced by the pH value of the solution. On the basis of the thermodynamic analysis, a plausible mechanism to explain the pH-controllable underwater-oil adhesion and superoleophobic wetting behavior observed on a micro- and nanoscale semicircular structure has been revealed. Furthermore, variation of chemistry (intrinsic oil contact angle (OCA)) of the responsive surface that due to the carboxylic acid groups is protonated or deprotonated by the acidic or basic solution on free energy (FE) with its barrier (FEB) and equilibrium oil contact angle (EOCA) with it hysteresis (OCAH) are discussed. The result shows that a critical intrinsic OCA on the micro- and nano- semicircular texture is necessary for conversion from the oil Cassie impregnating to oil Cassie wetting state. In a water/oil/solid system, the mechanism reveals that the differences between the underwater OCA and oil adhesive force of the responsive copper mesh film under different pH values of solution are ascribed to the different oil wetting state that results from combining the changing intrinsic OCA and micro /nanosemicircular structures. These results are well in agreement with the experiment. PMID- 25919444 TI - Gbps terahertz external modulator based on a composite metamaterial with a double channel heterostructure. AB - The past few decades have witnessed a substantial increase in terahertz (THz) research. Utilizing THz waves to transmit communication and imaging data has created a high demand for phase and amplitude modulation. However, current active THz devices, including modulators and switches, still cannot meet THz system demands. Double-channel heterostructures, an alternative semiconductor system, can support nanoscale two-dimensional electron gases (2DEGs) with high carrier concentration and mobility and provide a new way to develop active THz devices. In this Letter, we present a composite metamaterial structure that combines an equivalent collective dipolar array with a double-channel heterostructure to obtain an effective, ultrafast, and all-electronic grid-controlled THz modulator. Electrical control allows for resonant mode conversion between two different dipolar resonances in the active device, which significantly improves the modulation speed and depth. This THz modulator is the first to achieve a 1 GHz modulation speed and 85% modulation depth during real-time dynamic tests. Moreover, a 1.19 rad phase shift was realized. A wireless free-space-modulation THz communication system based on this external THz modulator was tested using 0.2 Gbps eye patterns. Therefore, this active composite metamaterial modulator provides a basis for the development of effective and ultrafast dynamic devices for THz wireless communication and imaging systems. PMID- 25919445 TI - Aberrant Behaviors and Co-occurring Conditions as Predictors of Psychotropic Polypharmacy among Children with Autism Spectrum Disorders. AB - OBJECTIVES: The purpose of this study was to identify rates and predictors of psychotropic medication polypharmacy among Medicaid-eligible children in South Carolina with autism spectrum disorder (ASD) from 2000 to 2008. METHODS: Population-based surveillance data were linked with state Medicaid records to obtain a detailed demographic, behavioral, educational, clinical, and diagnostic data set for all Medicaid-eligible 8-year-old children (n=629) who were identified and diagnosed with ASD using standardized criteria. Polypharmacy was defined as having interclass psychotropic medication claims overlapping for >=30 consecutive days at any time during the 2-year study period. Multivariable logistic regression was used to model predictors of any polypharmacy, and for the three most common combinations. RESULTS: Overall, 60% (n=377) used any psychotropic medication, and 41% (n=153) of those had interclass polypharmacy. Common combinations were attention-deficit/hyperactivity disorder (ADHD) medications with an antidepressant (A/AD), antipsychotic (A/AP) or a mood stabilizer (A/MS). Black children had lower odds of any polypharmacy, as did those eligible for Medicaid because of income or being foster care versus those eligible because of disability. There were no significant associations between polypharmacy and social deficits in ASD for any combination, although children with communication deficits diagnostic of ASD had lower odds of any polypharmacy and A/AP polypharmacy. Children with argumentative, aggressive, hyperactive/impulsive, or self-injurious aberrant behaviors had higher odds of polypharmacy, as did children with diagnosed co-occurring ADHD, anxiety or mood disorders, or conduct/oppositional defiant disorder (ODD) in Medicaid records. CONCLUSIONS: Future research is warranted to investigate how child-level factors impact combination psychotropic medication prescribing practices and outcomes in ASD. PMID- 25919446 TI - Antifungal Activity of Ellagic Acid In Vitro and In Vivo. AB - Ellagic acid (EA) has been shown to have antioxidant, antibacterial, and anti inflammatory activities. In Uighur traditional medicine, Euphorbia humifusa Willd is used to treat fungal diseases, and recent studies suggest that it is the EA content which is responsible for its therapeutic effect. However, the effects of EA on antifungal activity have not yet been reported. This study aimed to investigate the inhibitory effect of EA on fungal strains both in vitro and in vivo. The minimal inhibitory concentration (MIC) was determined by the National Committee for Clinical Laboratory Standards (M38-A and M27-A2) standard method in vitro. EA had a broad spectrum of antifungal activity, with MICs for all the tested dermatophyte strains between 18.75 and 58.33 ug/ml. EA was also active against two Candida strains, with MICs between 25.0 and 75.0 ug/ml. It was inactive against Candida glabrata. The susceptibility of six species of dermatophytes to EA was comparable with that of the commercial antifungal, fluconazole. The most sensitive filamentous species was Trichophyton rubrum (MIC = 18.75 ug/ml). Studies on the mechanism of action using an HPLC-based assay and an enzyme linked immunosorbent assay showed that EA inhibited ergosterol biosynthesis and reduced the activity of sterol 14alpha-demethylase P450 (CYP51) in the Trichophyton rubrum membrane, respectively. An in vivo test demonstrated that topical administration of EA (4.0 and 8.0 mg/cm(2) ) significantly enhanced the cure rate in a guinea-pig infection model of Trichophyton rubrum. The results suggest that EA has the potential to be developed as a natural antifungal agent. PMID- 25919447 TI - Dominance of paternalism in family-centered care in the pediatric intensive care unit (PICU): an ethnographic study. AB - This article examines the culture of family-centered care (FCC) in the pediatric intensive care unit (PICU) using focused ethnography. Data collection strategy was participant observation, fieldwork, and interviews with main actors of the PICU, namely supervisors, nurses, and parents. This study took place in one PICU in a hospital in Tehran, Iran. The results were in the main named as paternalism and were presented as five themes: "non-possessed environment," "separation of the children from their parents," non-interactive communication," "limited participation," and "affection and sympathy combined with superiority." In conclusion, the prevailing atmosphere in care was paternalistic as there was a huge gap between conceptually or theoretically accepted application of FCC in PICU and what is practically administrated. Bridging such a gap between theory and practice can be helpful in improving social, environment, and organizational culture for the children, their parents, and health care providers as well as their performance in the context of PICU. PMID- 25919448 TI - Corrective Taxes and Cigarette Characteristics. AB - If cigarette design was exogenous, inefficiencies arising from smoking could be addressed either with a tax per packet or with an ad valorem tax. However, it is well known that the consequences of these two instruments differ when product characteristics are endogenous. We consider three such characteristics: nicotine, tar, and flavor. Implementation of the first-best social optimum typically requires the capacity to tax or regulate harmful ingredients. Without such a capacity, the next-best policy often combines a per-unit tax on cigarettes with an ad valorem subsidy. Copyright (c) 2015 John Wiley & Sons, Ltd. PMID- 25919450 TI - Is ciliary muscle affected in migraine patients with aura and without aura? AB - BACKGROUND: The aim of this study was to compare spherical equivalents (SE) and spherical equivalents with cycloplegic (CSE) values of migraine patients with and without visual aura, with those patients without migraine complaints. MATERIAL/METHODS: We included patients over the age of 18 years, who had 20/20 uncorrected vision, and who did not have ocular pathology in their examination. The patients were divided into 3 groups: Group 1: 86 eyes of 43 migraine patients without aura, Group 2: 38 eyes of 19 migraine patients with aura, and Group 3: 60 eyes of 30 patients without migraine. Spherical equivalents and spherical equivalents with cycloplegic from the auto-refractometrical values of the patients were compared. RESULTS: The mean age of the migraine and control patients was 34.2+/-8.3 and 33.6+/-10.8 years, respectively. Forty-three (69%) of 62 migraine patients had migraine without aura and 19 (31%) had migraine with aura. The right and left eyes of the patients were evaluated together and a significant correlation was found between the groups. To evaluate the impact of cycloplegia in patients, SE and CSE values were obtained and differences between these values were evaluated. It was found that the change in Group 2 patients was significantly lower than the change in Group 3 patients (p=0.024). CONCLUSIONS: We found that the cycloplegic spherical equivalents values of our patients with aura were lower than control patients. We need further studies to reveal whether migraine with aura is the trigger or the result of those attacks. PMID- 25919451 TI - Promoter polymorphism of the serotonin transporter gene influences the number of sexual partners and smoking habits in a Mexican Mestizo population. PMID- 25919449 TI - Hyperdominance in Amazonian forest carbon cycling. AB - While Amazonian forests are extraordinarily diverse, the abundance of trees is skewed strongly towards relatively few 'hyperdominant' species. In addition to their diversity, Amazonian trees are a key component of the global carbon cycle, assimilating and storing more carbon than any other ecosystem on Earth. Here we ask, using a unique data set of 530 forest plots, if the functions of storing and producing woody carbon are concentrated in a small number of tree species, whether the most abundant species also dominate carbon cycling, and whether dominant species are characterized by specific functional traits. We find that dominance of forest function is even more concentrated in a few species than is dominance of tree abundance, with only ~1% of Amazon tree species responsible for 50% of carbon storage and productivity. Although those species that contribute most to biomass and productivity are often abundant, species maximum size is also influential, while the identity and ranking of dominant species varies by function and by region. PMID- 25919453 TI - Technology Use and Interest in Computerized Psychotherapy: A Survey of Veterans in Treatment for Substance Use Disorders. AB - INTRODUCTION: This study examined interest in computerized psychotherapies (CPTs) and its relation to use of information technology among individuals receiving Veterans Health Administration (VHA) outpatient treatment. MATERIALS AND METHODS: Veterans receiving treatment in a VHA substance use disorder outpatient clinic completed a self-report questionnaire. The survey addressed recent experience using information technology and potential interest in using CPTs for symptoms/functional problems associated with substance use and mental health disorders. Demographic, diagnostic, and information technology use data were compared between those expressing interest in CPT and those not expressing an interest, as well as with nationally representative veteran data from the 2010 National Survey of Veterans (NSV). RESULTS: Of 151 respondents, 82% were interested in CPT for at least one problem, and 60% were interested for more than one. The most commonly selected CPTs were for substance use (46%), depression (45%), problem solving (43%), and insomnia (42%). None of the 23 measures of information technology use was associated with interest in CPTs. Compared with respondents not interested in any CPTs, those interested in CPT were older (t150=2.1, p=0.042) and more likely to be African American [chi(2)(1)=8.8, p=0.032], to have reported a drug use disorder [chi(2)(1)=4.2, p=0.041], and to have reported more than one substance use or psychiatric disorder [chi(2)(1)=8.5, p=0.014]. The majority of respondents reported use of Internet and e-mail (65% and 64%, respectively), proportions comparable to respondents to the NSV. CONCLUSIONS: Among veterans receiving outpatient substance use treatment, interest in CPT is high and unrelated to information technology use. Efforts to implement CPTs may interest this population. PMID- 25919452 TI - Proteomic Analysis of Copper-Binding Proteins in Excess Copper-Stressed Roots of Two Rice (Oryza sativa L.) Varieties with Different Cu Tolerances. AB - To better understand the mechanisms involved in the heavy metal stress response and tolerance in plants, a proteomic approach was used to investigate the differences in Cu-binding protein expression in Cu-tolerant and Cu-sensitive rice varieties. Cu-binding proteins from Cu-treated rice roots were separated using a new IMAC method in which an IDA-sepharose column was applied prior to the Cu-IMAC column to remove metal ions from protein samples. More than 300 protein spots were reproducibly detected in the 2D gel. Thirty-five protein spots exhibited changes greater than 1.5-fold in intensity compared to the control. Twenty-four proteins contained one or more of nine putative metal-binding motifs reported by Smith et al., and 19 proteins (spots) contained one to three of the top six motifs reported by Kung et al. The intensities of seven protein spots were increased in the Cu-tolerant variety B1139 compared to the Cu-sensitive variety B1195 (p<0.05) and six protein spots were markedly up-regulated in B1139, but not detectable in B1195. Four protein spots were significantly up-regulated in B1139, but unchanged in B1195 under Cu stress. In contrast, two protein spots were significantly down-regulated in B1195, but unchanged in B1139. These Cu responsive proteins included those involved in antioxidant defense and detoxification (spots 5, 16, 21, 22, 28, 29 and 33), pathogenesis (spots 5, 16, 21, 22, 28, 29 and 33), regulation of gene transcription (spots 8 and 34), amino acid synthesis (spots 8 and 34), protein synthesis, modification, transport and degradation (spots 1, 2, 4, 10, 15, 19, 30, 31, 32 and 35), cell wall synthesis (spot 14), molecular signaling (spot 3), and salt stress (spots 7, 9 and 27); together with other proteins, such as a putative glyoxylate induced protein, proteins containing dimeric alpha-beta barrel domains, and adenosine kinase-like proteins. Our results suggest that these proteins, together with related physiological processes, play an important role in the detoxification of excess Cu and in maintaining cellular homeostasis. PMID- 25919454 TI - Clinically Indicated Corticosteroids Do Not Affect Bone Turnover During Immune Restoration of Severely Lymphopenic HIV-Infected Patients. AB - Lymphopenia, corticosteroids, antiretroviral therapy (ART), and inflammation negatively impact bone turnover and decrease bone mineral density, but their combined effect has not been evaluated. We examined the association between corticosteroids on bone turnover markers in severely lymphopenic HIV-infected patients initiating ART. Levels of osteocalcin (bone formation marker) and C terminal telopeptide (CTX; bone resorption marker) were measured at baseline, weeks 4, 12, and 48 of ART in individuals with severe lymphopenia and opportunistic infection (OI) who received (n=28) or did not receive corticosteroids (n=30) during the first year of ART, and in a control group with CD4 >200 (n=15). Wilcoxon tests were used to compare median values of variables between groups. Correlations between plasma interleukin (IL)-6 and tumor necrosis factor (TNF) levels with bone turnover marker levels were performed using Spearman's coefficient. Individuals given corticosteroids received a median of 21 days at a 35 mg prednisone-equivalent daily dose. Individuals with severe lymphopenia had lower osteocalcin levels at baseline and week 4 and higher CTX levels at ART initiation vs. CONTROLS: Bone turnover markers did not differ in severely lymphopenic persons according to corticosteroid receipt. In those with severe lymphopenia, higher IL-6 was associated with higher CTX levels at ART initiation only. HIV-infected patients with severe lymphopenia and OI had lower levels of bone formation and higher levels of bone resorption than those initiating ART at higher CD4. Corticosteroid use, as prescribed during OI, was not associated with bone turnover. In contrast, higher markers of systemic inflammation prior to ART were associated with greater bone resorption. PMID- 25919456 TI - Estimation of the optimal standardized ileal digestible lysine requirement for primiparous lactating sows fed diets supplemented with crystalline amino acids. AB - This experiment was conducted to determine the optimal standardized ileal digestible lysine (SID Lys) level in diets fed to primiparous sows during lactation. A total of 150 (Landrace * Large White) crossbred gilts (weighing 211.1 +/- 3.5 kg with a litter size of 11.1 +/- 0.2) were fed lactation diets (3325 kcal metabolizable energy (ME)/kg) containing SID Lys levels of 0.76, 0.84, 0.94, 1.04 or 1.14%, through 28 days lactation. Gilts were allocated to treatments based on their body weight and backfat thickness 48 h after farrowing. Gilt body weight loss was significantly (P < 0.05) decreased by increasing dietary SID Lys levels. Fitted broken-line (P < 0.05) and quadratic plot (P < 0.05) analysis of body weight loss indicated that the optimal SID Lys for primiparous sows was 0.85 and 1.01%, respectively. Average daily feed intake (ADFI), weaning-to-estrus interval and subsequent conception rate were not affected by dietary SID Lys levels. Increasing dietary lysine had no effect on litter performances. Protein content in milk was increased by dietary SID Lys (P < 0.05). Dietary SID Lys tended to increase concentrations of serum insulin-like growth factor I (P = 0.066). These results of this experiment indicate that the optimal dietary SID Lys for lactating gilts was at least 0.85%, which approaches the recommendation of 0.84% that is estimated by the National Research Council (2012). PMID- 25919455 TI - Investigating the Role of Gene-Gene Interactions in TB Susceptibility. AB - Tuberculosis (TB) is the second leading cause of mortality from infectious disease worldwide. One of the factors involved in developing disease is the genetics of the host, yet the field of TB susceptibility genetics has not yielded the answers that were expected. A commonly posited explanation for the missing heritability of complex disease is gene-gene interactions, also referred to as epistasis. In this study we investigate the role of gene-gene interactions in genetic susceptibility to TB using a cohort recruited from a high TB incidence community from Cape Town, South Africa. Our discovery data set incorporates genotypes from a large a number of candidate gene studies as well as genome-wide data. After limiting our search space to pairs of putative TB susceptibility genes, as well as pairs of genes that have been curated in online databases as potential interactors, we use statistical modelling to identify pairs of interacting SNPs. We attempt to validate the top models identified in our discovery data set using an independent genome-wide TB case-control data set from The Gambia. A number of models were successfully validated, indicating that interplay between the NRG1 - NRG3, GRIK1 - GRIK3 and IL23R - ATG4C gene pairs may modify susceptibility to TB. Gene pairs involved in the NF-kappaB pathway were also identified in the discovery data set (SFTPD - NOD2, ISG15 - TLR8 and NLRC5 - IL12RB1), but could not be tested in the Gambian study group due to lack of overlapping data. PMID- 25919457 TI - Colostrum of healthy Slovenian mothers: microbiota composition and bacteriocin gene prevalence. AB - Microbial communities inhabiting the breast milk microenvironment are essential in supporting mammary gland health in lactating women and in providing gut colonizing bacterial 'inoculum' for their infants' gastro-intestinal development. Bacterial DNA was extracted from colostrum samples of 45 healthy Slovenian mothers. Characteristics of the communities in the samples were assessed by polymerase chain reaction (PCR) coupled with denaturing gradient gel electrophoresis (DGGE) and by quantitative real-time PCR (qPCR). PCR screening for the prevalence of bacteriocin genes was performed on DNA of culturable and total colostrum bacteria. DGGE profiling revealed the presence of Staphylococcus and Gemella in most of the samples and exposed 4 clusters based on the abundance of 3 bands: Staphylococcus epidermidis/Gemella, Streptococcus oralis/pneumonia and Streptococcus salivarius. Bacilli represented the largest proportion of the communities. High prevalence in samples at relatively low quantities was confirmed by qPCR for enterobacteria (100%), Clostridia (95.6%), Bacteroides Prevotella group (62.2%) and bifidobacteria (53.3%). Bacterial quantities (genome equivalents ml-1) varied greatly among the samples; Staphylococcus epidermidis and staphylococci varied in the range of 4 logs, streptococci and all bacteria varied in the range of 2 logs, and other researched groups varied in the range of 1 log. The quantity of most bacterial groups was correlated with the amount of all bacteria. The majority of the genus Staphylococcus was represented by the species Staphylococcus epidermidis (on average 61%), and their abundances were linearly correlated. Determinants of salivaricin A, salivaricin B, streptin and cytolysin were found in single samples. This work provides knowledge on the colostrum microbial community composition of healthy lactating Slovenian mothers and reports bacteriocin gene prevalence. PMID- 25919458 TI - Analysis of heterosis and quantitative trait loci for kernel shape related traits using triple testcross population in maize. AB - Kernel shape related traits (KSRTs) have been shown to have important influences on grain yield. The previous studies that emphasize kernel length (KL) and kernel width (KW) lack a comprehensive evaluation of characters affecting kernel shape. In this study, materials of the basic generations (B73, Mo17, and B73 * Mo17), 82 intermated B73 * Mo17 (IBM) individuals, and the corresponding triple testcross (TTC) populations were used to evaluate heterosis, investigate correlations, and characterize the quantitative trait loci (QTL) for six KSRTs: KL, KW, length to width ratio (LWR), perimeter length (PL), kernel area (KA), and circularity (CS). The results showed that the mid-parent heterosis (MPH) for most of the KSRTs was moderate. The performance of KL, KW, PL, and KA exhibited significant positive correlation with heterozygosity but their Pearson's R values were low. Among KSRTs, the strongest significant correlation was found between PL and KA with R values was up to 0.964. In addition, KW, PL, KA, and CS were shown to be significant positive correlation with 100-kernel weight (HKW). 28 QTLs were detected for KSRTs in which nine were augmented additive, 13 were augmented dominant, and six were dominance * additive epistatic. The contribution of a single QTL to total phenotypic variation ranged from 2.1% to 32.9%. Furthermore, 19 additive * additive digenic epistatic interactions were detected for all KSRTs with the highest total R2 for KW (78.8%), and nine dominance * dominance digenic epistatic interactions detected for KL, LWR, and CS with the highest total R2 (55.3%). Among significant digenic interactions, most occurred between genomic regions not mapped with main-effect QTLs. These findings display the complexity of the genetic basis for KSRTs and enhance our understanding on heterosis of KSRTs from the quantitative genetic perspective. PMID- 25919459 TI - Improvements in Bone Density and Structure during Anti-TNF-alpha Therapy in Pediatric Crohn's Disease. AB - CONTEXT: Pediatric Crohn's Disease (CD) is associated with deficits in trabecular bone mineral density (BMD) and cortical structure, potentially related to TNF alpha effects to decrease bone formation and promote bone resorption. OBJECTIVE: This study aimed to examine changes in bone density and structure in children and adolescents with CD following initiation of anti-TNF-alpha therapy. DESIGN AND PARTICIPANTS: Participants (n = 74; age 5-21 years) with CD completed a 12-month prospective cohort study. MAIN OUTCOME MEASURES: Tibia peripheral quantitative computed tomography scans were obtained at initiation of anti-TNF-alpha therapy and 12 months later. Musculoskeletal outcomes were expressed as sex-and race specific z scores relative to age, based on >650 reference participants. RESULTS: At baseline, CD participants had lower height, trabecular BMD, cortical area (due to smaller periosteal and larger endocortical circumferences), and muscle area z scores, compared with reference participants (all P < .01). Pediatric CD activity index decreased during the 10-week induction (P < .001), in association with subsequent gains in height, trabecular BMD, cortical area (due to recovery of endocortical bone), and muscle area z scores over 12 months (height P < .05; others P < .001). Bone-specific alkaline phosphatase levels, a biomarker of bone formation, increased a median of 75% (P < .001) during induction with associated 12-month improvements in trabecular BMD and cortical area z scores (both P < .001). Younger age was associated with greater increases in trabecular BMD z scores (P < .001) and greater linear growth with greater recovery of cortical area (P < .001). CONCLUSIONS: Anti-TNF-alpha therapy was associated with improvements in trabecular BMD and cortical structure. Improvements were greater in younger and growing participants, suggesting a window of opportunity for treatment of bone deficits. PMID- 25919460 TI - Rabphilin-3A as a Targeted Autoantigen in Lymphocytic Infundibulo neurohypophysitis. AB - CONTEXT: Central diabetes insipidus (CDI) can be caused by several diseases, but in about half of the patients the etiological diagnosis remains unknown. Lymphocytic infundibulo-neurohypophysitis (LINH) is an increasingly recognized entity among cases of idiopathic CDI; however, the differential diagnosis from other pituitary diseases including tumors can be difficult because of similar clinical and radiological manifestations. The definite diagnosis of LINH requires invasive pituitary biopsy. OBJECTIVE: The study was designed to identify the autoantigen(s) in LINH and thus develop a diagnostic test based on serum autoantibodies. DESIGN: Rat posterior pituitary lysate was immunoprecipitated with IgGs purified from the sera of patients with LINH or control subjects. The immunoprecipitates were subjected to liquid chromatography-tandem mass spectrometry to screen for pituitary autoantigens of LINH. Subsequently, we made recombinant proteins of candidate autoantigens and analyzed autoantibodies in serum by Western blotting. RESULTS: Rabphilin-3A proved to be the most diagnostically useful autoantigen. Anti-rabphilin-3A antibodies were detected in 22 of the 29 (76%) patients (including 4 of the 4 biopsy-proven samples) with LINH and 2 of 18 (11.1%) patients with biopsy-proven lymphocytic adeno hypophysitis. In contrast, these antibodies were absent in patients with biopsy proven sellar/suprasellar masses without lymphocytic hypophysitis (n = 34), including 18 patients with CDI. Rabphilin-3A was expressed in posterior pituitary and hypothalamic vasopressin neurons but not anterior pituitary. CONCLUSIONS: These results suggest that rabphilin-3A is a major autoantigen in LINH. Autoantibodies to rabphilin-3A may serve as a biomarker for the diagnosis of LINH and be useful for the differential diagnosis in patients with CDI. PMID- 25919461 TI - Prolonged Correction of Serum Phosphorus in Adults With X-Linked Hypophosphatemia Using Monthly Doses of KRN23. AB - CONTEXT: In X-linked hypophosphatemia (XLH), elevated fibroblast growth factor 23 (FGF23) decreases the renal tubular maximum reabsorption rate of phosphate/glomerular filtration rate (TmP/GFR) and serum inorganic phosphorus (Pi), resulting in rickets and/or osteomalacia. OBJECTIVE: The objective was to test the hypothesis that monthly KRN23 (anti-FGF23 antibody) would safely improve serum Pi in adults with XLH. DESIGN: Two sequential open-label phase 1/2 studies were done. SETTING: Six academic medical centers were used. PARTICIPANTS: Twenty eight adults with XLH participated in a 4-month dose-escalation study (0.05-0.6 mg/kg); 22 entered a 12-month extension study (0.1-1 mg/kg). INTERVENTION: KRN23 was injected sc every 28 days. MAIN OUTCOME MEASURE: The main outcome measure was the proportion of subjects attaining normal serum Pi and safety. RESULTS: At baseline, mean TmP/GFR, serum Pi, and 1,25-dihydroxyvitamin D [1,25(OH)2D] were 1.6 +/- 0.4 mg/dL, 1.9 +/- 0.3 mg/dL, and 36.6 +/- 14.3 pg/mL, respectively. During dose escalation, TmP/GFR, Pi, and 1,25(OH)2D increased, peaking at 7 days for TmP/GFR and Pi and at 3-7 days for 1,25(OH)2D, remaining above (TmP/GFR, Pi) or near [1,25(OH)2D] pre-dose levels at trough. After each of the four escalating doses, peak Pi was between 2.5 and 4.5 mg/dL in 14.8, 37.0, 74.1, and 88.5% of subjects, respectively. During the 12-month extension, peak Pi was in the normal range for 57.9-85.0% of subjects, and >=25% maintained trough Pi levels within the normal range. Serum Pi did not exceed 4.5 mg/dL in any subject. Although 1,25(OH)2D levels increased transiently, mean serum and urinary calcium remained normal. KRN23 treatment increased biomarkers of skeletal turnover and had a favorable safety profile. CONCLUSIONS: Monthly KRN23 significantly increased serum Pi, TmP/GFR, and 1,25(OH)2D in all subjects. KRN23 has potential for effectively treating XLH. PMID- 25919462 TI - Gross cystic disease fluid protein 15 in stratum corneum is a potential marker of decreased eccrine sweating for atopic dermatitis. AB - It is well known that eccrine sweating is attenuated in patients with atopic dermatitis (AD). We have reported by using proteome analysis that gross cystic disease fluid protein 15 (GCDFP15), a substance secreted from eccrine sweat glands, is decreased in tape-stripped stratum corneum (SC) samples from AD patients. The aim of this study was to evaluate GCDFP15 production by eccrine glands with SC samples and to assess sweating in AD. SC samples were obtained from 51 healthy control (HC) and 51 AD individuals. Sweat samples were from 18 HC and 12 AD subjects. GCDFP15 was quantified by ELISA. By immunohistochemistry, the expression of GCDFP15 in eccrine glands was examined in normal and AD skin specimens. To identify GCDFP15-producing cells, double immunofluorescence staining for GCDFP15 and S100 protein was performed in frozen sections. To address the mechanism underlying the decreased eccrine sweating in AD patients, we examined the expression of cholinergic receptor M3 (CHRM3), a receptor for acetylcholine-induced sweating, in eccrine sweat glands. The amounts of GCDFP15 in the SC extracts were significantly lower in AD than HC (P < 0.0001). The sweat samples from AD patients also had lower levels of GCDFP15 concentration (P < 0.05). Immunohistochemistry showed positive GCDFP15 staining in the eccrine gland secretory cells and the ductal and acrosyringial lumen in normal skin, but AD lacked clear staining. Immunofluorescence staining revealed that GCDFP15 was co expressed with S100 protein, suggesting that the clear cell of eccrine glands produces GCDFP15. Finally, we found that the expression of CHRM3 was depressed in AD, suggesting contribution to the low sweating. The SC of AD patients contains a low amount of GCDFP15 due to both low sweating and low GCDFP15 concentration in the sweat. GCDFP15 in SC is a potential marker for dysregulated sweating in AD. PMID- 25919463 TI - MOLECULAR DETECTION OF ANTIBIOTIC-RESISTANCE DETERMINANTS IN ESCHERICHIA COLI ISOLATED FROM THE ENDANGERED AUSTRALIAN SEA LION (NEOPHOCA CINEREA). AB - Greater interaction between humans and wildlife populations poses significant risks of anthropogenic impact to natural ecosystems, especially in the marine environment. Understanding the spread of microorganisms at the marine interface is therefore important if we are to mitigate adverse effects on marine wildlife. We investigated the establishment of Escherichia coli in the endangered Australian sea lion (Neophoca cinerea) by comparing fecal isolation from wild and captive sea lion populations. Fecal samples were collected from wild colonies March 2009-September 2010 and from captive individuals March 2011-May 2013. Using molecular screening, we assigned a phylotype to E. coli isolates and determined the presence of integrons, mobile genetic elements that capture gene cassettes conferring resistance to antimicrobial agents common in fecal coliforms. Group B2 was the most abundant phylotype in all E. coli isolates (n = 37), with groups A, B1, and D also identified. Integrons were not observed in E. coli (n = 21) isolated from wild sea lions, but were identified in E. coli from captive animals (n = 16), from which class I integrases were detected in eight isolates. Sequencing of gene cassette arrays identified genes conferring resistance to streptomycin-spectinomycin (aadA1) and trimethoprim (dfrA17, dfrB4). Class II integrases were not detected in the E. coli isolates. The frequent detection in captive sea lions of E. coli with resistance genes commonly identified in human clinical cases suggests that conditions experienced in captivity may contribute to establishment. Identification of antibiotic resistance in the microbiota of Australian sea lions provides crucial information for disease management. Our data will inform conservation management strategies and provide a mechanism to monitor microorganism dissemination to sensitive pinniped populations. PMID- 25919464 TI - A Recently Discovered Pathogenic Paramyxovirus, Sosuga Virus, is Present in Rousettus aegyptiacus Fruit Bats at Multiple Locations in Uganda. AB - In August 2012, a wildlife biologist became ill immediately following a 6-wk field trip to collect bats and rodents in South Sudan and Uganda. After returning to the US, the biologist was admitted to the hospital with multiple symptoms including fever, malaise, headache, generalized myalgia and arthralgia, stiffness in the neck, and sore throat. Soon after admission, the patient developed a maculopapular rash and oropharynx ulcerations. The patient remained hospitalized for 14 d. Several suspect pathogens, including viral hemorrhagic fever viruses such as Ebola viruses and Marburg viruses, were ruled out through standard diagnostic testing. However, deep sequencing and metagenomic analyses identified a novel paramyxovirus, later named Sosuga virus, in the patient's blood. To determine the potential source, bat tissues collected during the 3-wk period just prior to the onset of symptoms were tested for Sosuga virus, and several Egyptian rousette bats (Rousettus aegyptiacus) were found to be positive. Further analysis of archived Egyptian rousette tissues collected at other localities in Uganda found additional Sosuga virus-positive bats, suggesting this species could be a potential natural reservoir for this novel paramyxovirus. PMID- 25919466 TI - WEST NILE VIRUS-RELATED TRENDS IN AVIAN MORTALITY IN CALIFORNIA, USA, 2003-12. AB - West Nile virus (WNV) is an arbovirus transmitted enzootically by Culex mosquitoes among avian hosts. Since 2000, the California Dead Bird Surveillance Program (DBSP) has tracked avian mortality reported by the public on a telephone hotline and website and measured the prevalence of WNV infection in dead birds. We summarize herein WNV prevalence in dead birds tested and variation of WNV transmission over time and space with the use of DBSP data from 2003 to 2012. Prevalence among dead birds was highest in 2004, 2008, and 2012. This pattern was similar to peak WNV infection years for mosquitoes but not to human WNV incidence. Although American Crows (Corvus brachyrhynchos) were most frequently reported and tested, this species ranked third in infection prevalence (44%) after Yellow-billed Magpies (Pica nuttalli; 62%) and Western Scrub-Jays (Aphelocoma californica; 48%). Overall prevalence in American Robin (Turdus migratorius), House Finch (Haemorhous mexicanus), and House Sparrow (Passer domesticus) carcasses ranged from 18% to 22%. Corvid WNV prevalence was highest in South Coast, Bay/Delta, Sacramento, and San Joaquin valleys, and Klamath/North Coast bioregions, overlapping areas of elevated WNV activity in other surveillance measurements. Bioregional analysis revealed the avian species most likely to be reported and found positive in each bioregion. Our results may be useful to WNV surveillance and control efforts and provide insight into bird population trends in California. PMID- 25919465 TI - WEST NILE VIRUS ANTIBODY DECAY RATE IN FREE-RANGING BIRDS. AB - Antibody duration, following a humoral immune response to West Nile virus (WNV) infection, is poorly understood in free-ranging avian hosts. Quantifying antibody decay rate is important for interpreting serologic results and for understanding the potential for birds to serorevert and become susceptible again. We sampled free-ranging birds in Chicago, Illinois, US, from 2005 to 2011 and Atlanta, Georgia, US, from 2010 to 2012 to examine the dynamics of antibody decay following natural WNV infection. Using serial dilutions in a blocking enzyme linked immunosorbent assay, we quantified WNV antibody titer in repeated blood samples from individual birds over time. We quantified a rate of antibody decay for 23 Northern Cardinals (Cardinalis cardinalis) of 0.198 natural log units per month and 24 individuals of other bird species of 0.178 natural log units per month. Our results suggest that juveniles had a higher rate of antibody decay than adults, which is consistent with nonlinear antibody decay at different times postexposure. Overall, most birds had undetectable titers 2 yr postexposure. Nonuniform WNV antibody decay rates in free-ranging birds underscore the need for cautious interpretation of avian serology results in the context of arbovirus surveillance and epidemiology. PMID- 25919467 TI - Dilated Cardiomyopathy in a Rio Grande Wild Turkey (Meleagris gallopavo intermedia) in Southern Utah, USA, 2013. AB - A male Rio Grande Wild Turkey (Meleagris gallopavo intermedia) living in semidomestication was submitted for necropsy. Emaciation, a greatly enlarged heart, and chronic passive congestion of the liver were present. Dilated cardiomyopathy occurs in domestic turkey flocks but has not been reported in Wild Turkeys. PMID- 25919468 TI - Gastrointestinal Parasites in the Waved Albatross (Phoebastria irrorata) of Galapagos. AB - Using a fecal flotation technique, we detected three genera of endoparasites in the critically endangered Waved Albatross (Phoebastria irrorata) of Galapagos. These genera were Contracaecum, Tetrabothrius, and Cardiocephaloides. Juvenile albatrosses were more likely to be infected than adults, but we found no effect of sex or mass on infection probability. PMID- 25919469 TI - Trichomonas gallinae Persistence in Four Water Treatments. AB - Trichomonas gallinae is a protozoan parasite commonly found in columbids, passerines, and several raptor species. Although T. gallinae is thought to spread between individuals and across species through shared water sources, little research has been conducted regarding the persistence of T. gallinae in the environment. To determine the persistence of T. gallinae in various communal water sources, we inoculated 1 * 10(6) trichomonads into 500 mL samples of distilled water, quarry water, bird bath water, and rain barrel water in two replicates. Aliquots of 0.5 mL were collected from each source at -1, 0, 15, 30, and 60 min; aliquots were incubated at 37 C and examined for trichomonads by light microscopy for five consecutive days. Live trichomonads were observed in all samples and at all sampling times except prior to inoculation (-1 min). The pH of water sources ranged from an average of 5.9 to 7.4 postsampling. Our findings indicate that T. gallinae can persist for up to 60 min in various water treatments and thus be infectious for birds drinking T. gallinae-contaminated water. PMID- 25919470 TI - HISTOPATHOLOGY AND RISK FACTORS ASSOCIATED WITH NEOTROMBICULA MICROTI INFESTATION IN THE ENDANGERED AMARGOSA VOLE (MICROTUS CALIFORNICUS SCIRPENSIS). AB - The Amargosa vole (Microtus californicus scirpensis) is a profoundly endangered rodent found only in the Central Mojave Desert, Inyo County, California, US. In 2010, severe cases of trombiculiasis, caused by larval Neotrombicula microti mites, were discovered among voles and sympatric small mammals. We evaluated Amargosa voles and sympatric rodents for infestation with N. microti December 2011-November 2012 and evaluated histopathology of ear tissue from 13 actively N. microti-infested Amargosa voles and 10 Amargosa voles with no gross evidence of current or past infestation. Rodents with current infestation had mites visible on tissue, typically ear pinnae, whereas mites were not seen on rodents with presumptive past infestation, but some of these animals had gross tissue scarring and loss consistent with healing from infestation. Ears from infested voles had severe granulocytic and necrotizing dermatitis, most associated with stylostome fragments, whereas few lesions were present in grossly uninfested voles. There was no association between body condition and infestation or severity of lesions. Significantly more voles were infested (37%) with N. microti than sympatric rodents (3%), suggesting that sympatric rodents do not serve as an important source of N. microti exposure to voles. Although this chigger infestation was common and induced severe localized pathology, we did not detect a fitness cost to infestation and recommend further evaluation of the disease to discern its significance in this conservation context. PMID- 25919471 TI - Circulating total testosterone and PSA concentrations in a nationally representative sample of men without a diagnosis of prostate cancer. AB - BACKGROUND: The association between serum sex steroid hormones and PSA in a general population has not been described. METHODS: Included were 378 men aged 40 85 years who participated in the National Health and Nutrition Examination Survey in 2001-2004, who did not have a prostate cancer diagnosis, and had not had a recent biopsy, rectal examination, cystoscopy, or prostate infection or inflammation. Serum total PSA, total testosterone, androstanediol glucuronide (3alpha-diol-G), estradiol, and sex hormone binding globulin (SHBG) concentrations were previously measured. Free testosterone was estimated by mass action. We applied sampling weights and calculated geometric mean PSA concentration by hormone quintiles adjusting for age and race/ethnicity, and also for body mass index, waist circumference, smoking, diabetes, and mutually for hormones. We estimated the OR of PSA >=2.5 ng/ml per hormone quintile using logistic regression. RESULTS: Geometric mean PSA increased across testosterone quintiles after age and race/ethnicity (Q1: 0.80, Q5: 1.14 ng/ml; P-trend = 0.002) and multivariable (Q1: 0.79, Q5: 1.16 ng/ml; P-trend = 0.02) adjustment; patterns were similar for free testosterone and 3alpha-diol-G. SHBG was inversely associated with PSA only after multivariable adjustment (Q1: 1.32, Q5: 0.82 nmol/L; P-trend = 0.01). Estradiol and PSA were not associated. The OR of PSA >=2.5 ng/ml was 1.54 (95% CI 1.18-2.01) per testosterone quintile after age and race/ethnicity adjustment, and 1.78 (95% CI 1.16-2.73) after multivariable adjustment. CONCLUSIONS: In this nationally representative sample, men with higher testosterone had higher PSA even after taking into account other hormones and modifiable factors. Men with higher SHBG had lower PSA, but only after multivariable adjustment. PMID- 25919473 TI - Ultrasound-guided intra-articular and rotator interval corticosteroid injections in adhesive capsulitis of the shoulder: a double-blind, sham-controlled randomized study. AB - Adhesive capsulitis (frozen shoulder) is a common cause of shoulder pain and disability. Previous studies have reported that intra-articular corticosteroid injections are of benefit compared with placebo up to 6 weeks. It has been suggested that the structures primarily involved in adhesive capsulitis are the capsule and the rotator interval. Systematic reviews have concluded that there is limited evidence of the treatment effectiveness of intra-articular corticosteroid injections and that high-quality primary research is required. The aim of this study was to compare ultrasound-guided intra-articular corticosteroid injection and combined intra-articular and rotator interval injection in a double-blind, sham-controlled randomized clinical trial. The main outcome measure was the group difference in change in shoulder pain (0-10) at 6 weeks. One hundred twenty-two patients were randomized (42 to intra-articular injection, 40 to combined intra articular/interval injection, and 40 to sham injection). For both corticosteroid injection groups, there was a significant difference compared with sham injection at week 6. The mean group difference (adjusted for gender, age, dominant arm, and duration) in change in shoulder pain for the intra-articular vs sham injection was -1.7 (95% confidence interval, -2.7 to -0.6, P = 0.002) and -2.1 (95% confidence interval, -3.2 to -1.1, P = 0.0001) for the combined injection vs sham injection. The significant group differences were maintained at week 12 but not at week 26. Similar results were found for the secondary outcome measures (night pain, Shoulder Pain and Disability Index). Differences between the corticosteroid groups were not significant at any time. PMID- 25919474 TI - Efficacy and safety of tanezumab in the treatment of pain from bone metastases. AB - Patients with metastatic bone cancer report life-altering pain. Nerve growth factor is involved in pain signaling. Tanezumab, a nerve growth factor monoclonal antibody, has demonstrated efficacy in chronic pain. Placebo-controlled parent (NCT00545129; study 1003) and noncontrolled open-label extension (NCT00830180; study 1029) studies evaluated efficacy and safety of tanezumab in patients with painful bone metastases taking daily opioids. Patients in study 1003 received a single intravenous injection of 10 mg tanezumab or placebo and were followed up to 16 weeks. Efficacy analyses included change from baseline in daily average and worst pain at week 6 on an 11-point numeric rating scale. At week 8, patients could enroll in study 1029 and receive 4 infusions of 10 mg tanezumab at 8-week intervals with follow-up to 40 weeks. Safety assessments included adverse events and physical and neurologic examinations. Overall, 59 patients were randomized and treated (placebo, n = 30; tanezumab, n = 29). At the primary endpoint of study 1003, least squares mean (SE) difference in change from baseline in daily average pain vs placebo was -0.26 (0.45; P = 0.569). Post hoc analyses suggested that tanezumab had greater efficacy in patients with lower baseline opioid use and/or higher baseline pain. Mean (SE) pain scores in study 1029 were reduced through week 40 compared with study 1029 or 1003 baselines (-0.21 [0.76] and 1.27 [0.68], respectively). Adverse event incidence of study 1003 was similar between groups. Although the primary endpoint was not achieved, tanezumab may provide additional sustained analgesia in patients with metastatic bone pain taking daily opioids. Additional larger studies are warranted. PMID- 25919472 TI - Transcranial magnetic stimulation of the brain: guidelines for pain treatment research. AB - Recognizing that electrically stimulating the motor cortex could relieve chronic pain sparked development of noninvasive technologies. In transcranial magnetic stimulation (TMS), electromagnetic coils held against the scalp influence underlying cortical firing. Multiday repetitive transcranial magnetic stimulation (rTMS) can induce long-lasting, potentially therapeutic brain plasticity. Nearby ferromagnetic or electronic implants are contraindications. Adverse effects are minimal, primarily headaches. Single provoked seizures are very rare. Transcranial magnetic stimulation devices are marketed for depression and migraine in the United States and for various indications elsewhere. Although multiple studies report that high-frequency rTMS of the motor cortex reduces neuropathic pain, their quality has been insufficient to support Food and Drug Administration application. Harvard's Radcliffe Institute therefore sponsored a workshop to solicit advice from experts in TMS, pain research, and clinical trials. They recommended that researchers standardize and document all TMS parameters and improve strategies for sham and double blinding. Subjects should have common well-characterized pain conditions amenable to motor cortex rTMS and studies should be adequately powered. They recommended standardized assessment tools (eg, NIH's PROMIS) plus validated condition-specific instruments and consensus-recommended metrics (eg, IMMPACT). Outcomes should include pain intensity and qualities, patient and clinician impression of change, and proportions achieving 30% and 50% pain relief. Secondary outcomes could include function, mood, sleep, and/or quality of life. Minimum required elements include sample sources, sizes, and demographics, recruitment methods, inclusion and exclusion criteria, baseline and posttreatment means and SD, adverse effects, safety concerns, discontinuations, and medication-usage records. Outcomes should be monitored for at least 3 months after initiation with prespecified statistical analyses. Multigroup collaborations or registry studies may be needed for pivotal trials. PMID- 25919475 TI - Concurrent central nervous system and endobronchial tuberculosis mimicking a metastatic lung cancer. AB - BACKGROUND AND AIMS: Early diagnosis and treatment of central nervous system tuberculosis are important because of high mortality and morbidity. Airways must be carefully evaluated in differential diagnosis. METHODS: We present a rare case of intracranial-endobronchial tuberculosis mimicking lung cancer with brain metastasis. RESULTS: A vegetative mass lesion, confirmed as necrotic granulomatous inflammation, originating from the entrance of the right upper lobe entry, was coagulated and extracted by argon plasma coagulation and cryotherapy to prevent permanent upper lobe atelectasis. Mycobacterium tuberculosis complex was detected in bronchoscopic material. A four-drug initial anti-tuberculous treatment regimen was given in 2 months. The upper lobe atelectasis was resolved at the fourth month of therapy despite upper lobar bronchus patency. The patient was doing well and completed the two-drug maintenance therapy of 7 months with complete resolution. CONCLUSION: In such cases, tissue diagnosis should be achieved as early as possible and anti-tuberculous treatment was commenced along with advanced interventional techniques. PMID- 25919476 TI - Binary gene expression patterning of the molt cycle: the case of chitin metabolism. AB - In crustaceans, like all arthropods, growth is accompanied by a molting cycle. This cycle comprises major physiological events in which mineralized chitinous structures are built and degraded. These events are in turn governed by genes whose patterns of expression are presumably linked to the molting cycle. To study these genes we performed next generation sequencing and constructed a molt related transcriptomic library from two exoskeletal-forming tissues of the crayfish Cherax quadricarinatus, namely the gastrolith and the mandible cuticle forming epithelium. To simplify the study of such a complex process as molting, a novel approach, binary patterning of gene expression, was employed. This approach revealed that key genes involved in the synthesis and breakdown of chitin exhibit a molt-related pattern in the gastrolith-forming epithelium. On the other hand, the same genes in the mandible cuticle-forming epithelium showed a molt independent pattern of expression. Genes related to the metabolism of glucosamine 6-phosphate, a chitin precursor synthesized from simple sugars, showed a molt related pattern of expression in both tissues. The binary patterning approach unfolds typical patterns of gene expression during the molt cycle of a crustacean. The use of such a simplifying integrative tool for assessing gene patterning seems appropriate for the study of complex biological processes. PMID- 25919477 TI - A safer alternative: Cannabis substitution as harm reduction. AB - INTRODUCTION AND AIMS: Substitution is operationalised as a conscious choice made by users to use one drug instead of, or in conjunction with another based on: perceived safety, level of addiction potential, effectiveness in relieving symptoms, access and level of acceptance. Harm reduction is a set of strategies that aim to minimise problems associated with drug use while recognising that for some users, abstinence may be neither a realistic nor a desirable goal. In this paper, we aim for deeper understandings of older adult cannabis users' beliefs and substitution practices as part of the harm reduction framework. DESIGN AND METHODS: We present selected findings from our qualitative study of Baby Boomer (born 1946-1964) marijuana users in the San Francisco Bay Area. Although the sample consisted of primary cannabis users, many had personal experience with other drugs throughout their lifetimes. Data collection consisted of an audio recorded, semi-structured in-depth life history interview followed by a questionnaire and health survey. Qualitative interviews were analysed to discover users' harm reduction beliefs and cannabis substitution practices. RESULTS: Study participants described using cannabis as a safer alternative for alcohol, illicit drugs and pharmaceuticals based on their perceptions of less adverse side effects, low-risk for addiction and greater effectiveness at relieving symptoms, such as chronic pain. DISCUSSION AND CONCLUSIONS: Cannabis substitution can be an effective harm reduction method for those who are unable or unwilling to stop using drugs completely. More research is needed on cannabis as a safer alternative. PMID- 25919478 TI - Relative roles of ecological and energetic constraints, diversification rates and region history on global species richness gradients. AB - Regions worldwide differ markedly in species richness. Here, for birds and mammals worldwide, we directly compare four sets of hypotheses regarding geographical richness gradients: (1) evolutionary, emphasising heterogeneity in diversification rates, (2) historical, related to differences in region ages and sizes, (3) energetic, associated with variation in productive or ambient energy and (4) ecological, reflecting differences in ecological niche diversity. Among highly independent regions, or 'evolutionary arenas', we find that richness is weakly influenced by richness-standardised ecological niche diversity, questioning the significance of ecological constraints for producing large-scale diversity gradients. In contrast, we find strong evidence for the importance of region area and its changes over time, together with a role for temperature. These predictors affect richness predominately directly without concomitant positive effects on diversification rates. This suggests that regional richness is governed by historical and evolutionary processes, which promote region specific accumulation of diversity through time or following asymmetrical dispersal. PMID- 25919479 TI - Physics of microswimmers--single particle motion and collective behavior: a review. AB - Locomotion and transport of microorganisms in fluids is an essential aspect of life. Search for food, orientation toward light, spreading of off-spring, and the formation of colonies are only possible due to locomotion. Swimming at the microscale occurs at low Reynolds numbers, where fluid friction and viscosity dominates over inertia. Here, evolution achieved propulsion mechanisms, which overcome and even exploit drag. Prominent propulsion mechanisms are rotating helical flagella, exploited by many bacteria, and snake-like or whip-like motion of eukaryotic flagella, utilized by sperm and algae. For artificial microswimmers, alternative concepts to convert chemical energy or heat into directed motion can be employed, which are potentially more efficient. The dynamics of microswimmers comprises many facets, which are all required to achieve locomotion. In this article, we review the physics of locomotion of biological and synthetic microswimmers, and the collective behavior of their assemblies. Starting from individual microswimmers, we describe the various propulsion mechanism of biological and synthetic systems and address the hydrodynamic aspects of swimming. This comprises synchronization and the concerted beating of flagella and cilia. In addition, the swimming behavior next to surfaces is examined. Finally, collective and cooperate phenomena of various types of isotropic and anisotropic swimmers with and without hydrodynamic interactions are discussed. PMID- 25919481 TI - Cortisol, salivary alpha-amylase and children's perceptions of their social networks. AB - In recent years there has been a growing interest in the use of social network analysis in biobehavioral research. Despite the well-established importance of social relationships in influencing human behavior and health, little is known about how children's perception of their immediate social relationships correlates with biological parameters of stress. In this study we explore the association between two measures of children's personal social networks, perceived network size and perceived network density, with two biomarkers of stress, cortisol and salivary alpha-amylase. Forty children (mean age = 8.30, min age = 5, and max age = 12) were interviewed to collect information about their friendships and three samples of saliva were collected. Our results show that children characterized by a lower pre-interview cortisol concentration and a lower salivary alpha-amylase reactivity to the interview reported the highest density of friendships. We discuss this result in light of the multisystem approach to the study of children's behavioral outcomes, emphasizing that future work of this kind is needed in order to understand the cognitive and biological mechanisms underlying children's and adolescents' social perceptual biases. PMID- 25919482 TI - Dual dimensionality reduction reveals independent encoding of motor features in a muscle synergy for insect flight control. AB - What are the features of movement encoded by changing motor commands? Do motor commands encode movement independently or can they be represented in a reduced set of signals (i.e. synergies)? Motor encoding poses a computational and practical challenge because many muscles typically drive movement, and simultaneous electrophysiology recordings of all motor commands are typically not available. Moreover, during a single locomotor period (a stride or wingstroke) the variation in movement may have high dimensionality, even if only a few discrete signals activate the muscles. Here, we apply the method of partial least squares (PLS) to extract the encoded features of movement based on the cross covariance of motor signals and movement. PLS simultaneously decomposes both datasets and identifies only the variation in movement that relates to the specific muscles of interest. We use this approach to explore how the main downstroke flight muscles of an insect, the hawkmoth Manduca sexta, encode torque during yaw turns. We simultaneously record muscle activity and turning torque in tethered flying moths experiencing wide-field visual stimuli. We ask whether this pair of muscles acts as a muscle synergy (a single linear combination of activity) consistent with their hypothesized function of producing a left-right power differential. Alternatively, each muscle might individually encode variation in movement. We show that PLS feature analysis produces an efficient reduction of dimensionality in torque variation within a wingstroke. At first, the two muscles appear to behave as a synergy when we consider only their wingstroke-averaged torque. However, when we consider the PLS features, the muscles reveal independent encoding of torque. Using these features we can predictably reconstruct the variation in torque corresponding to changes in muscle activation. PLS-based feature analysis provides a general two-sided dimensionality reduction that reveals encoding in high dimensional sensory or motor transformations. PMID- 25919483 TI - Excess relative risk as an effect measure in case-control studies of rare diseases. AB - Epidemiologists often use ratio-type indices (rate ratio, risk ratio and odds ratio) to quantify the association between exposure and disease. By comparison, less attention has been paid to effect measures on a difference scale (excess rate or excess risk). The excess relative risk (ERR) used primarily by radiation epidemiologists is of peculiar interest here, in that it involves both difference and ratio operations. The ERR index (but not the difference-type indices) is estimable in case-control studies. Using the theory of sufficient component cause model, the author shows that when there is no mechanistic interaction (no synergism in the sufficient cause sense) between the exposure under study and the stratifying variable, the ERR index (but not the ratio-type indices) in a rare disease case-control setting should remain constant across strata and can therefore be regarded as a common effect parameter. By exploiting this homogeneity property, the related attributable fraction indices can also be estimated with greater precision. The author demonstrates the methodology (SAS codes provided) using a case-control dataset, and shows that ERR preserves the logical properties of the ratio-type indices. In light of the many desirable properties of the ERR index, the author advocates its use as an effect measure in case-control studies of rare diseases. PMID- 25919480 TI - Controlling translation via modulation of tRNA levels. AB - Transfer RNAs (tRNAs) are critical adaptor molecules that carry amino acids to a messenger RNA (mRNA) template during protein synthesis. Although tRNAs have commonly been viewed as abundant 'house-keeping' RNAs, it is becoming increasingly clear that tRNA expression is tightly regulated. Depending on a cell's proliferative status, the pool of active tRNAs is rapidly changed, enabling distinct translational programs to be expressed in differentiated versus proliferating cells. Here, I highlight several post-transcriptional regulatory mechanisms that allow the expression or functions of tRNAs to be altered. Modulating the modification status or structural stability of individual tRNAs can cause those specific tRNA transcripts to selectively accumulate or be degraded. Decay generally occurs via the rapid tRNA decay pathway or by the nuclear RNA surveillance machinery. In addition, the CCA-adding enzyme plays a critical role in determining the fate of a tRNA. The post-transcriptional addition of CCA to the 3' ends of stable tRNAs generates the amino acid attachment site, whereas addition of CCACCA to unstable tRNAs prevents aminoacylation and marks the tRNA for degradation. In response to various stresses, tRNAs can accumulate in the nucleus or be further cleaved into small RNAs, some of which inhibit translation. By implementing these various post transcriptional control mechanisms, cells are able to fine-tune tRNA levels to regulate subsets of mRNAs as well as overall translation rates. PMID- 25919484 TI - Intravenous dexamethasone in acute management of vestibular neuritis: a randomized, placebo-controlled, single-blind trial. AB - INTRODUCTION: The aim of the present study was to evaluate the role of intravenous dexamethasone in relieving the symptoms and signs of vestibular neuritis in the emergency department setting. PATIENTS AND METHODS: This was a randomized, placebo-controlled, superiority, single-blind study. Patients were randomized either to intravenous dexamethasone (group A) or to placebo (group B), with all patients receiving symptomatic therapy. The primary outcome was defined as necessity to hospitalize patients who present with vestibular neuritis in the emergency department. The secondary outcomes were (a) improvement in nystagmus, (b) improvement in postural instability, (c) lessening of nausea, (d) lessening of vomiting, and (e) recovery of subjective symptoms. RESULTS: Altogether, 100 patients were randomized, 51 into group A and 49 into group B. There was no difference in the hospitalization rate between groups (P=0.284). In both groups, there was a statistically significant difference in the values of all measured variables 2 h after therapy intervention compared with the baseline values. In group A, significantly fewer patients had third-degree nystagmus 2 h after therapy intervention whereas the difference in group B did not reach statistical significance. After therapy, more patients had first-degree nystagmus in group A as well as in group B than before the intervention. There was a significantly greater absolute difference in European Evaluation of Vertigo scale results in group A compared with group B. CONCLUSION: The value of dexamethasone cannot be established, given the small sample and limitations of the present study. Some observations consistent with clinical improvement cannot exclude a true treatment effect, and further study is still warranted. PMID- 25919485 TI - Modified Early Warning Score and VitalPac Early Warning Score in geriatric patients admitted to emergency department. AB - OBJECTIVE: The aim of this study was to evaluate the value of the Modified Early Warning Score (MEWS) and the VitalPac Early Warning Score (VIEWS) in predicting hospitalization and in-hospital mortality in geriatric emergency department (ED) patients. PATIENTS AND METHODS: This prospective, single-centered observational study was carried out over 1 month at the ED of a university hospital in patients 65 years of age and older presenting to the ED. The vital parameters of the patients measured on admission to ED were recorded. The MEWS and VIEWS were calculated using the recorded physiological parameters of the patients. Hospitalization and in-hospital mortality were used as the primary outcomes. RESULTS: A total of 671 patients included in the study. The median age of the patients was 75 (11) years, and 375 (55.9%) were men. The MEWS is effective for discriminating patient groups that have been discharged from ED, admitted to a ward and admitted to ICU [1 (2) vs. 1 (1) vs. 3 (3), respectively, P<0.001]. The VIEWS is also effective for discriminating patient groups that have been discharged from ED, admitted to a ward, and admitted to ICU [2 (3) vs. 5 (5) vs. 8 (8), respectively, P<0.001]. The AUCs of the MEWS and VIEWS were 0.727 [95% confidence interval (CI) 0.689-0.765] and 0.756 (95% CI 0.720-0.792) in predicting hospitalization, respectively. The AUCs of the MEWS and VIEWS were 0.891 (95% CI 0.844-0.937) and 0.900 (95% CI 0.860-0.941) in predicting in hospital mortality, respectively. CONCLUSION: The MEWS and VIEWS are powerful scoring systems that are easy-to-use for predicting the hospitalization and in hospital mortality of geriatric ED patients. PMID- 25919486 TI - Dose-dependent Association between Intermediate-acting Neuromuscular-blocking Agents and Postoperative Respiratory Complications. AB - BACKGROUND: Duration of action increases with repeated administration of neuromuscular-blocking agents, and intraoperative use of high doses of neuromuscular-blocking agent may affect respiratory safety. METHODS: In a hospital-based registry study on 48,499 patients who received intermediate-acting neuromuscular-blocking agents, the authors tested the primary hypothesis that neuromuscular-blocking agents are dose dependently associated with the risk of postoperative respiratory complications. In the secondary analysis, the authors evaluated the association between neostigmine dose given for reversal of neuromuscular-blocking agents and respiratory complications. Post hoc, the authors evaluated the effects of appropriate neostigmine reversal (neostigmine <= 60 MUg/kg after recovery of train-of-four count of 2) on respiratory complications. The authors controlled for patient-, anesthesia-, and surgical complexity-related risk factors. RESULTS: High doses of neuromuscular-blocking agents were associated with an increased risk of postoperative respiratory complications (n = 644) compared with low doses (n = 205) (odds ratio [OR], 1.28; 95% CI, 1.04 to 1.57). Neostigmine was associated with a dose-dependent increase in the risk of postoperative respiratory complications (OR, 1.51; 95% CI, 1.25 to 1.83). Post hoc analysis revealed that appropriate neostigmine reversal eliminated the dose-dependent association between neuromuscular-blocking agents and respiratory complications (for neuromuscular-blocking agent effects with appropriate reversal: OR, 0.98; 95% CI, 0.63 to 1.52). CONCLUSIONS: The use of neuromuscular-blocking agents was dose dependently associated with increased risk of postoperative respiratory complications. Neostigmine reversal was also associated with a dose-dependent increase in the risk of respiratory complications. However, the exploratory data analysis suggests that the proper use of neostigmine guided by neuromuscular transmission monitoring results can help eliminate postoperative respiratory complications associated with the use of neuromuscular-blocking agents. PMID- 25919488 TI - Orthogonalization of regressors in FMRI models. AB - The occurrence of collinearity in fMRI-based GLMs (general linear models) may reduce power or produce unreliable parameter estimates. It is commonly believed that orthogonalizing collinear regressors in the model will solve this problem, and some software packages apply automatic orthogonalization. However, the effects of orthogonalization on the interpretation of the resulting parameter estimates is widely unappreciated or misunderstood. Here we discuss the nature and causes of collinearity in fMRI models, with a focus on the appropriate uses of orthogonalization. Special attention is given to how the two popular fMRI data analysis software packages, SPM and FSL, handle orthogonalization, and pitfalls that may be encountered in their usage. Strategies are discussed for reducing collinearity in fMRI designs and addressing their effects when they occur. PMID- 25919487 TI - Evaluation of (68)Ga- and (177)Lu-DOTA-PEG4-LLP2A for VLA-4-Targeted PET Imaging and Treatment of Metastatic Melanoma. AB - Malignant melanoma is a highly aggressive cancer, and the incidence of this disease is increasing worldwide at an alarming rate. Despite advances in the treatment of melanoma, patients with metastatic disease still have a poor prognosis and low survival rate. New strategies, including targeted radiotherapy, would provide options for patients who become resistant to therapies such as BRAF inhibitors. Very late antigen-4 (VLA-4) is expressed on melanoma tumor cells in higher levels in more aggressive and metastatic disease and may provide an ideal target for drug delivery and targeted radiotherapy. In this study, we evaluated (177)Lu- and (68)Ga-labeled DOTA-PEG4-LLP2A as a VLA-4-targeted radiotherapeutic with a companion PET agent for diagnosis and monitoring metastatic melanoma treatment. DOTA-PEG4-LLP2A was synthesized by solid-phase synthesis. The affinity of (177)Lu- and (68)Ga-labeled DOTA-PEG4-LLP2A to VLA-4 was determined in B16F10 melanoma cells by saturation binding and competitive binding assays, respectively. Biodistribution of the LLP2A conjugates was determined in C57BL/6 mice bearing B16F10 subcutaneous tumors, while PET/CT imaging was performed in subcutaneous and metastatic models. (177)Lu-DOTA-PEG4-LLP2A showed high affinity to VLA-4 with a Kd of 4.1 +/- 1.5 nM and demonstrated significant accumulation in the B16F10 melanoma tumor after 4 h (31.5 +/- 7.8%ID/g). The tumor/blood ratio of (177)Lu-DOTA-PEG4-LLP2A was highest at 24 h (185 +/- 26). PET imaging of metastatic melanoma with (68)Ga-DOTA-PEG4-LLP2A showed high uptake in sites of metastases and correlated with bioluminescence imaging of the tumors. These data demonstrate that (177)Lu-DOTA-PEG4-LLP2A has potential as a targeted therapeutic for treating melanoma as well as other VLA-4-expressing tumors. In addition, (68)Ga-DOTA-PEG4-LLP2A is a readily translatable companion PET tracer for imaging of metastatic melanoma. PMID- 25919489 TI - Constant infusion transpulmonary thermodilution for the assessment of cardiac output in exercising humans. AB - To determine the accuracy and precision of constant infusion transpulmonary thermodilution cardiac output (CITT-Q) assessment during exercise in humans, using indocyanine green (ICG) dilution and bolus transpulmonary thermodilution (BTD) as reference methods, cardiac output (Q) was determined at rest and during incremental one- and two-legged pedaling on a cycle ergometer, and combined arm cranking with leg pedaling to exhaustion in 15 healthy men. Continuous infusions of iced saline in the femoral vein (n = 41) or simultaneously in the femoral and axillary (n = 66) veins with determination of temperature in the femoral artery were used for CITT-Q assessment. CITT-Q was linearly related to ICG-Q (r = 0.82, CITT-Q = 0.876 * ICG-Q + 3.638, P < 0.001; limits of agreement ranging from -1.43 to 3.07 L/min) and BTD-Q (r = 0.91, CITT-Q = 0.822 * BTD + 4.481 L/min, P < 0.001; limits of agreement ranging from -1.01 to 2.63 L/min). Compared with ICG-Q and BTD-Q, CITT-Q overestimated cardiac output by 1.6 L/min (~ 10% of the mean ICG and BTD-Q values, P < 0.05). For Q between 20 and 28 L/min, we estimated an overestimation < 5%. The coefficient of variation of 23 repeated CITT-Q measurements was 6.0% (CI: 6.1-11.1%). In conclusion, cardiac output can be precisely and accurately determined with constant infusion transpulmonary thermodilution in exercising humans. PMID- 25919490 TI - Fe(II)-Polypyridines as Chromophores in Dye-Sensitized Solar Cells: A Computational Perspective. AB - Over the past two decades, dye-sensitized solar cells (DSSCs) have become a viable and relatively cheap alternative to conventional crystalline silicon-based systems. At the heart of a DSSC is a wide band gap semiconductor, typically a TiO2 nanoparticle network, sensitized with a visible light absorbing chromophore. Ru(II)-polypyridines are often utilized as chromophores thanks to their chemical stability, long-lived metal-to-ligand charge transfer (MLCT) excited states, tunable redox potentials, and near perfect quantum efficiency of interfacial electron transfer (IET) into TiO2. More recently, coordination compounds based on first row transition metals, such as Fe(II)-polypyridines, gained some attention as potential sensitizers in DSSCs due to their low cost and abundance. While such complexes can in principle sensitize TiO2, they do so very inefficiently since their photoactive MLCT states undergo intersystem crossing (ISC) into low-lying metal-centered states on a subpicosecond time scale. Competition between the ultrafast ISC events and IET upon initial excitation of Fe(II)-polypyridines is the main obstacle to their utilization in DSSCs. Suitability of Fe(II) polypyridines to serve as sensitizers could therefore be improved by adjusting relative rates of the ISC and IET processes, with the goal of making the IET more competitive with ISC. Our research program in computational inorganic chemistry utilizes a variety of tools based on density functional theory (DFT), time dependent density functional theory (TD-DFT) and quantum dynamics to investigate structure-property relationships in Fe(II)-polypyridines, specifically focusing on their function as chromophores. One of the difficult problems is the accurate determination of energy differences between electronic states with various spin multiplicities (i.e., (1)A, (1,3)MLCT, (3)T, (5)T) in the ISC cascade. We have shown that DFT is capable of predicting the trends in the energy ordering of these electronic states in a set of structurally related complexes with the help of appropriate benchmarks, based either on experimental data or higher-level ab initio calculations. Models based on TD-DFT and quantum dynamics approaches have proven very useful in understanding IET processes in Fe(II)-polypyridine-TiO2 assemblies. For example, they helped us to elucidate the origin of "band selective" sensitization in the [Fe(bpy-dca)2(CN)2]-TiO2 assembly (bpy-dca = 2,2' bipyridine-4,4'-dicarboxylic acid), first observed by Ferrere and Gregg [ Ferrere , S. ; Gregg , B. A. J. Am. Chem. Soc. 1998 , 120 , 843 . ]. They also shed light on the relationship between the linker group that anchors Fe(II)-polypyridines onto the TiO2 surface and the speed of IET in Fe(II)-polypyridine-TiO2 assemblies. More interestingly, our results show that the IET efficiency is strongly correlated with the amount of electron density on the linker group and that one can obtain insights into the IET in dye-semiconductor assemblies based on ground state electronic structure calculations alone. This may be useful for quick screening of a large number of complexes for use as potential sensitizers in DSSCs, especially if followed up by TD-DFT and quantum dynamics simulations for selected target compounds to confirm efficient sensitization. While our focus over the past few years has been exclusively on Fe(II)-polypyridines, the computational strategies outlined in this Account are applicable to a wide variety of sensitizers. PMID- 25919491 TI - Combined genetic and transcriptomic analysis reveals three major signalling pathways activated by Myc-LCOs in Medicago truncatula. AB - Myc-LCOs are newly identified symbiotic signals produced by arbuscular mycorrhizal (AM) fungi. Like rhizobial Nod factors, they are lipo chitooligosaccharides that activate the common symbiotic signalling pathway (CSSP) in plants. To increase our limited understanding of the roles of Myc-LCOs we aimed to analyse Myc-LCO-induced transcriptional changes and their genetic control. Whole genome RNA sequencing (RNA-seq) was performed on roots of Medicago truncatula wild-type plants, and dmi3 and nsp1 symbiotic mutants affected in nodulation and mycorrhizal signalling. Plants were treated separately with the two major types of Myc-LCOs, sulphated and nonsulphated. Generalized linear model analysis identified 2201 differentially expressed genes and classified them according to genotype and/or treatment effects. Three genetic pathways for Myc LCO-regulation of transcriptomic reprogramming were highlighted: DMI3- and NSP1 dependent; DMI3-dependent and NSP1-independent; and DMI3- and NSP1-independent. Comprehensive analysis revealed overlaps with previous AM studies, and highlighted certain functions, especially signalling components and transcription factors. These data provide new insights into mycorrhizal signalling mechanisms, supporting a role for NSP1, and specialisation for NSP1-dependent and independent pathways downstream of DMI3. Our data also indicate significant Myc LCO-activated signalling upstream of DMI3 and/or parallel to the CSSP and some constitutive activity of the CSSP. PMID- 25919492 TI - Merkel cell carcinoma and Merkel cell polyomavirus: a systematic review and meta analysis. AB - Several observational studies have assessed the correlation between Merkel cell carcinoma and Merkel cell polyomavirus with variable results. The objective of this systematic review was to determine whether there is a correlation between Merkel cell carcinoma and Merkel cell polyomavirus. Studies assessing the relationship between Merkel cell carcinoma and Merkel cell polyomavirus from January 2008 to August 2014 were pooled from Medline, Embase, PubMed, Cochrane Database of Systemic Reviews and Google Scholar. From each study we collected the first author's last name, publication year, country of origin, type of study design, characteristics of participants, possible variables incorporated into the multivariable analyses and the risk ratio (RR) for Merkel cell carcinoma associated with Merkel cell polyomavirus combined with the corresponding 95% confidence interval (CI). Methodological assessment of the study was evaluated using the Newcastle-Ottawa scale. Crude RR was calculated from the data provided in each article. Meta-analyses for the global RR and for the proportion of positives in both case and control samples were performed. In addition, in order to explore the sources of heterogeneity among the studies, meta-regression and sensitivity analyses are also provided. A total of 22 studies were identified for the analysis. The pooled RR from random-effects analysis was determined to be 6.32 (95% CI, 4.02-9.93). Global proportions of positive samples were 0.79 (95% CI, 0.72-0.84) and 0.12 (95% CI, 0.08-0.19) in the case and control groups, respectively. The findings support the association between Merkel cell carcinoma and Merkel cell polyomavirus. However, a non-negligible percentage of positive results have been identified in controls. Some caution must be taken in the interpretation of these results because heterogeneity between studies was found. PMID- 25919493 TI - Vitamin D Deficiency After Oral Retinoid Therapy for Ichthyosis. AB - Oral retinoids are being increasingly used to treat ichthyotic disorders in children. We report on two children with ichthyotic disorders who developed unusual manifestations after they were started on oral retinoids. The first case is a 10-year-old girl with nonbullous ichthyosiform erythroderma and the second is a 2-year-old girl with lamellar ichthyosis. The child with ichthyosiform erythroderma developed features of rickets within months of initiation of systemic retinoids. Her baseline examination before initiation of oral retinoids was normal. The second patient with lamellar ichthyosis was found to have low vitamin D levels after 6 months of retinoid therapy, and prompt supplementation reversed the levels in 2 months. These cases are being reported to bring attention to the probable need for initiation of vitamin D supplementation with systemic retinoid therapy in ichthyotic disorders in children. PMID- 25919494 TI - Nkx2.2 and Nkx2.9 are the key regulators to determine cell fate of branchial and visceral motor neurons in caudal hindbrain. AB - Cranial motor nerves in vertebrates are comprised of the three principal subtypes of branchial, visceral, and somatic motor neurons, which develop in typical patterns along the anteroposterior and dorsoventral axes of hindbrain. Here we demonstrate that the formation of branchial and visceral motor neurons critically depends on the transcription factors Nkx2.2 and Nkx2.9, which together determine the cell fate of neuronal progenitor cells. Disruption of both genes in mouse embryos results in complete loss of the vagal and spinal accessory motor nerves, and partial loss of the facial and glossopharyngeal motor nerves, while the purely somatic hypoglossal and abducens motor nerves are not diminished. Cell lineage analysis in a genetically marked mouse line reveals that alterations of cranial nerves in Nkx2.2; Nkx2.9 double-deficient mouse embryos result from changes of cell fate in neuronal progenitor cells. As a consequence progenitors of branchiovisceral motor neurons in the ventral p3 domain of hindbrain are transformed to somatic motor neurons, which use ventral exit points to send axon trajectories to their targets. Cell fate transformation is limited to the caudal hindbrain, as the trigeminal nerve is not affected in double-mutant embryos suggesting that Nkx2.2 and Nkx2.9 proteins play no role in the development of branchiovisceral motor neurons in hindbrain rostral to rhombomere 4. PMID- 25919495 TI - COX-2 is required for the modulation of spinal nociceptive information related to ephrinB/EphB signalling. AB - BACKGROUND: EphB receptors and their ephrinB ligands are implicated in modulating spinal nociceptive information processing. Here, we investigated whether cyclooxygenase-2 (COX-2), acts as a downstream effector, participates in the modulation of spinal nociceptive information related to ephrinB/EphB signalling. METHODS: Thermal hyperalgesia and mechanical allodynia were measured by using radiant heat and von Frey filaments test, respectively. Real-time PCR (RT-PCR) was used to detect the expression of spinal COX-2 mRNA. Spinal COX-2 and extracellular signal-regulated kinase (ERK) protein were determined by Western blot analysis. RESULTS: Intrathecal injection of ephrinB2-Fc caused thermal hyperalgesia and mechanical allodynia, which were accompanied by increased expression of spinal COX-2 mRNA and protein. Inhibition of spinal COX-2 prevented and reversed pain behaviours induced by the intrathecal injection of ephrinB2-Fc. Blockade of EphB receptors by intrathecal injection of EphB2-Fc reduced complete Freund's adjuvant (CFA)-induced inflammatory pain behaviours, which were accompanied by decreased expression of spinal COX-2 mRNA and protein. Furthermore, treatment with U0126, a mitogen-activated protein/extracellular signal-regulated kinase kinase (MEK) inhibitor, suppressed spinal ERK activation and COX-2 mRNA and protein expression induced by intrathecal injection of ephrinB1-Fc. CONCLUSIONS: These results confirmed the important involvement of COX-2 in the modulation of spinal nociceptive information related to ephrinBs EphBs signalling. PMID- 25919496 TI - Patients as stakeholders in setting kidney disease research priorities. PMID- 25919497 TI - Diabetes-Induced Congenital Anomalies of the Kidney and Urinary Tract (CAKUT): Nurture and Nature at Work? PMID- 25919498 TI - Islands in the stream: the risk of kidney disease from cardiovascular disease. PMID- 25919499 TI - Measuring GFR Using the Plasma Clearance of (99m)Tc-DTPA. PMID- 25919500 TI - In Reply to 'Measuring GFR Using the Plasma Clearance of (99m)Tc-DTPA'. PMID- 25919501 TI - Quiz page May 2015: crystalline nephropathy in an identical twin. PMID- 25919503 TI - Recent advances in pediatric rheumatology. PMID- 25919502 TI - Entrapped elemental selenium nanoparticles affect physicochemical properties of selenium fed activated sludge. AB - Selenite containing wastewaters can be treated in activated sludge systems, where the total selenium is removed from the wastewater by the formation of elemental selenium nanoparticles, which are trapped in the biomass. No studies have been carried out so far on the characterization of selenium fed activated sludge flocs, which is important for the development of this novel selenium removal process. This study showed that more than 94% of the trapped selenium in activated sludge flocs is in the form of elemental selenium, both as amorphous/monoclinic selenium nanospheres and trigonal selenium nanorods. The entrapment of the elemental selenium nanoparticles in the selenium fed activated sludge flocs leads to faster settling rates, higher hydrophilicity and poorer dewaterability compared to the control activated sludge (i.e., not fed with selenite). The selenium fed activated sludge showed a less negative surface charge density as compared to the control activated sludge. The presence of trapped elemental selenium nanoparticles further affected the spatial distribution of Al and Mg in the activated sludge flocs. This study demonstrated that the formation and subsequent trapping of elemental selenium nanoparticles in the activated sludge flocs affects their physicochemical properties. PMID- 25919504 TI - The meaning of quality of care in home care settings: older lesbian and bisexual women's perspectives. AB - Research suggests that the experience of being a lesbian or bisexual woman influences women's interactions with health care providers, and their perception of the quality of care. Limited research to date, however, has examined how ageing and sexuality mediates women's experiences of quality, when accessing health care in the community. To fill a gap in the literature, this study investigated older lesbian and bisexual women's perspectives on the meaning of quality of care in the context of receiving home care services. This was a qualitative single case study. Sixteen participants, aged 55-72 from Ontario, Canada, participated in semi-structured interviews between 2011 and 2012. The interviews were recorded and transcribed. The interview data were analysed using iterative thematic analysis and guided by a feminist ethic of care perspective. Participants described quality of care in ways that were in line with a feminist ethic of care; that is, they wanted care providers to be responsive and attentive to their needs, to involve them in the caring process and to demonstrate respect and caring. Participants also indicated that providers' comfort with, and knowledge of, sexual diversity was important for enabling quality of care. These findings deepen our understanding of how to support quality of care for this population through changes to provider education and training, and health policy. PMID- 25919505 TI - Interpretation of semiclassical transition moments through wave function expansion of dipole moment functions with applications to the OH stretching spectra of simple acids and alcohols. AB - Semiclassical description of molecular vibrations has provided us with various computational approximations and enhanced our conceptual understanding of quantum mechanics. In this study, the transition moments of the OH stretching fundamental and overtone intensities (Deltav = 1-6) of some alcohols and acids are calculated by three kinds of semiclassical methods, correspondence-principle (CP) approximation, quasiclassical approximation, and uniform WKB approximation, and their respective transition moments are compared to those by the quantum theory. On the basis of the local mode picture, the one-dimensional potential energy curves and the dipole moment functions (DMFs) were obtained by density functional theory calculations and then fitted to Morse functions and sixth-order polynomials, respectively. It was shown that both the transition energies and the absorption intensities derived in the semiclassical methods reproduced their respective quantum values. In particular, the CP approximation reproduces the quantum transition moments if the formula given by Naccache is used for the action integral value. On the basis of these semiclassical results, we present a picture to understand the small variance in the overtone intensities of these acids and alcohols. Another important result is the ratios of semiclassical-to quantum transition moment are almost independent of the applied molecules even with a great molecular variance of the DMFs, and they depend only on the nature of the semiclassical approximations and the quantum number. The difference between the semiclassical and quantum transition moments was analyzed in terms of a hitherto unrecognized concept that the Fourier expansion of the time dependent DMF in the CP treatment is a kind of the wave function expansion method using trigonometric functions as the quotient functions. For a Morse oscillator, we derive the analytic and approximate expressions of the quotient functions in terms of the bond displace coordinate in both the CP and the quantum mechanical frameworks and discuss the methodological dependence of the calculated transition moments. As a byproduct, we have found a simple derivation of the DMF expression first derived by Timm and Mecke long time ago. PMID- 25919506 TI - Direct and complete phosphorus recovery from municipal wastewater using a hybrid microfiltration-forward osmosis membrane bioreactor process with seawater brine as draw solution. AB - We report a hybrid microfiltration-forward osmosis membrane bioreactor (MF-FOMBR) for direct phosphorus recovery from municipal wastewater in the course of its treatment. In the process, a forward osmosis (FO) membrane and a microfiltration (MF) membrane are operated in parallel in a bioreactor. FO membrane rejects the nutrients (e.g., PO4(3-), Ca(2+), Mg(2+), etc.) and results in their enrichment in the bioreactor. The nutrients are subsequently extracted via the MF membrane. Phosphorus is then recovered from the nutrients enriched MF permeate via precipitation without addition of an external source of calcium or magnesium. The use of seawater brine as a draw solution (DS) is another novel aspect of the system. The process achieved 90% removal of total organic carbon and 99% removal of NH4(+)-N. 97.9% of phosphate phosphorus (PO4(3-)-P) was rejected by the FO membrane and enriched within the bioreactor. >90% phosphorus recovery was achieved at pH 9.0. The precipitates were predominantly amorphous calcium phosphate with a phosphorus content of 11.1-13.3%. In principal, this process can recover almost all the phosphorus, apart from that assimilated by bacteria for growth. Global evaluation showed an overall phosphorus recovery of 71.7% over 98 days. PMID- 25919510 TI - Galleries of the Stelvio-Lake Como: Sanford Robinson Gifford. PMID- 25919507 TI - Sequential Treatment with SDF-1 and BMP-2 Potentiates Bone Formation in Calvarial Defects. AB - Stromal cell-derived factor-1 (SDF-1) protein and its receptor, CXCR-4, play an important role in tissue repair and regeneration in various organs, including the bone. SDF-1 is indispensable for bone morphogenetic protein-2 (BMP-2)-induced osteogenic differentiation. However, SDF-1 is not needed after the osteogenic induction has been activated. Since the precise condition for the additive effects of combined DF-1 and BMP-2 in bone healing had not been fully investigated, we aimed to determine the optimal conditions for SDF-1- and BMP-2 mediated bone regeneration. We examined the in vitro osteoblastic differentiation and cell migration after sequential treatments with SDF-1 and BMP-2. Based on the in vitro additive effects of SDF-1 and BMP-2, the critical size defects of mice calvaria were treated with these cytokines in various sequences. Phosphate buffered saline (PBS)-, SDF-1-, or BMP-2-soaked collagen scaffolds were implanted into the calvarial defects (n=36). Periodic percutaneous injections of PBS or the cytokine SDF-1 and BMP-2 into the implanted scaffolds were performed on days 3 and 6, postoperatively. Six experimental groups were used according to the types and sequences of the cytokine treatments. After 28 days, the mice were euthanized and bone formation was evaluated with microcomputed tomography and histology. The molecular mechanism of the additive effect of SDF-1 and BMP-2 was evaluated by analyzing intracellular signal transduction through Smad and Erk phosphorylation. The in vitro experiments revealed that, among all the treatments, the treatment with BMP-2 after SDF-1 showed the strongest osteoblastic differentiation and enhanced cell migration. Similarly, in the animal model, the treatment with SDF-1 followed by BMP-2 treatment showed the highest degree of new bone regeneration than any other groups, including the one with continuous BMP-2 treatment. This new bone formation can be partially explained by the activation of Smad and Erk pathways and enhanced cell migration. These results suggest that sequential treatment with the cytokines, SDF-1 and BMP-2, may be a promising strategy for accelerating bone regeneration in critical size defects. PMID- 25919511 TI - Filling the gaps in preventive care services for older adults. PMID- 25919512 TI - Payment reform is about to become a reality. PMID- 25919522 TI - Induced pluripotent stem cells. PMID- 25919523 TI - A piece of my mind. Gripers and whiners. PMID- 25919524 TI - The genetics of rheumatoid arthritis: new insights and implications. PMID- 25919525 TI - Researchers, readers, and reporting guidelines: writing between the lines. PMID- 25919526 TI - Effect of a retrievable inferior vena cava filter plus anticoagulation vs anticoagulation alone on risk of recurrent pulmonary embolism: a randomized clinical trial. AB - IMPORTANCE: Although retrievable inferior vena cava filters are frequently used in addition to anticoagulation in patients with acute venous thromboembolism, their benefit-risk ratio is unclear. OBJECTIVE: To evaluate the efficacy and safety of retrievable vena cava filters plus anticoagulation vs anticoagulation alone for preventing pulmonary embolism recurrence in patients presenting with acute pulmonary embolism and a high risk of recurrence. DESIGN, SETTING, AND PARTICIPANTS: Randomized, open-label, blinded end point trial (PREPIC2) with 6 month follow-up conducted from August 2006 to January 2013. Hospitalized patients with acute, symptomatic pulmonary embolism associated with lower-limb vein thrombosis and at least 1 criterion for severity were assigned to retrievable inferior vena cava filter implantation plus anticoagulation (filter group; n = 200) or anticoagulation alone with no filter implantation (control group; n = 199). Initial hospitalization with ambulatory follow-up occurred in 17 French centers. INTERVENTIONS: Full-dose anticoagulation for at least 6 months in all patients. Insertion of a retrievable inferior vena cava filter in patients randomized to the filter group. Filter retrieval was planned at 3 months from placement. MAIN OUTCOMES AND MEASURES: Primary efficacy outcome was symptomatic recurrent pulmonary embolism at 3 months. Secondary outcomes were recurrent pulmonary embolism at 6 months, symptomatic deep vein thrombosis, major bleeding, death at 3 and 6 months, and filter complications. RESULTS: In the filter group, the filter was successfully inserted in 193 patients and was retrieved as planned in 153 of the 164 patients in whom retrieval was attempted. By 3 months, recurrent pulmonary embolism had occurred in 6 patients (3.0%; all fatal) in the filter group and in 3 patients (1.5%; 2 fatal) in the control group (relative risk with filter, 2.00 [95% CI, 0.51-7.89]; P = .50). Results were similar at 6 months. No difference was observed between the 2 groups regarding the other outcomes. Filter thrombosis occurred in 3 patients. CONCLUSIONS AND RELEVANCE: Among hospitalized patients with severe acute pulmonary embolism, the use of a retrievable inferior vena cava filter plus anticoagulation compared with anticoagulation alone did not reduce the risk of symptomatic recurrent pulmonary embolism at 3 months. These findings do not support the use of this type of filter in patients who can be treated with anticoagulation. TRIAL REGISTRATION: clinicaltrials.gov Identifier: NCT00457158. PMID- 25919527 TI - Emergency department-initiated buprenorphine/naloxone treatment for opioid dependence: a randomized clinical trial. AB - IMPORTANCE: Opioid-dependent patients often use the emergency department (ED) for medical care. OBJECTIVE: To test the efficacy of 3 interventions for opioid dependence: (1) screening and referral to treatment (referral); (2) screening, brief intervention, and facilitated referral to community-based treatment services (brief intervention); and (3) screening, brief intervention, ED initiated treatment with buprenorphine/naloxone, and referral to primary care for 10-week follow-up (buprenorphine). DESIGN, SETTING, AND PARTICIPANTS: A randomized clinical trial involving 329 opioid-dependent patients who were treated at an urban teaching hospital ED from April 7, 2009, through June 25, 2013. INTERVENTIONS: After screening, 104 patients were randomized to the referral group, 111 to the brief intervention group, and 114 to the buprenorphine treatment group. MAIN OUTCOMES AND MEASURES: Enrollment in and receiving addiction treatment 30 days after randomization was the primary outcome. Self reported days of illicit opioid use, urine testing for illicit opioids, human immunodeficiency virus (HIV) risk, and use of addiction treatment services were the secondary outcomes. RESULTS: Seventy-eight percent of patients in the buprenorphine group (89 of 114 [95% CI, 70%-85%]) vs 37% in the referral group (38 of 102 [95% CI, 28%-47%]) and 45% in the brief intervention group (50 of 111 [95% CI, 36%-54%]) were engaged in addiction treatment on the 30th day after randomization (P < .001). The buprenorphine group reduced the number of days of illicit opioid use per week from 5.4 days (95% CI, 5.1-5.7) to 0.9 days (95% CI, 0.5-1.3) vs a reduction from 5.4 days (95% CI, 5.1-5.7) to 2.3 days (95% CI, 1.7 3.0) in the referral group and from 5.6 days (95% CI, 5.3-5.9) to 2.4 days (95% CI, 1.8-3.0) in the brief intervention group (P < .001 for both time and intervention effects; P = .02 for the interaction effect). The rates of urine samples that tested negative for opioids did not differ statistically across groups, with 53.8% (95% CI, 42%-65%) in the referral group, 42.9% (95% CI, 31% 55%) in the brief intervention group, and 57.6% (95% CI, 47%-68%) in the buprenorphine group (P = .17). There were no statistically significant differences in HIV risk across groups (P = .66). Eleven percent of patients in the buprenorphine group (95% CI, 6%-19%) used inpatient addiction treatment services, whereas 37% in the referral group (95% CI, 27%-48%) and 35% in the brief intervention group (95% CI, 25%-37%) used inpatient addiction treatment services (P < .001). CONCLUSIONS AND RELEVANCE: Among opioid-dependent patients, ED-initiated buprenorphine treatment vs brief intervention and referral significantly increased engagement in addiction treatment, reduced self-reported illicit opioid use, and decreased use of inpatient addiction treatment services but did not significantly decrease the rates of urine samples that tested positive for opioids or of HIV risk. These findings require replication in other centers before widespread adoption. TRIAL REGISTRATION: clinicaltrials.gov Identifier: NCT00913770. PMID- 25919528 TI - Association of HLA-DRB1 haplotypes with rheumatoid arthritis severity, mortality, and treatment response. AB - IMPORTANCE: Advances have been made in identifying genetic susceptibility loci for autoimmune diseases, but evidence is needed regarding their association with prognosis and treatment response. OBJECTIVE: To assess whether specific HLA-DRB1 haplotypes associated with rheumatoid arthritis (RA) susceptibility are also associated with radiological severity, mortality, and response to tumor necrosis factor (TNF) inhibitor drugs. DESIGN, SETTING, AND PARTICIPANTS: The Norfolk Arthritis Register (NOAR; 1691 patients and 2811 radiographs; recruitment: 1989 2008; 2008 as final follow-up) was used as a discovery cohort and the Early Rheumatoid Arthritis Study (421 patients and 3758 radiographs; recruitment: 1986 1999; 2005 as final follow-up) as an independent replication cohort for studies of radiographic outcome. Mortality studies were performed in the NOAR cohort (2432 patients; recruitment: 1990-2007; 2011 as final follow-up) and studies of treatment response in the Biologics in Rheumatoid Arthritis Genetics and Genomics Study Syndicate cohort (1846 patients enrolled at initiation of TNF inhibitor; recruitment: 2006-2010; 2011 as final follow-up). Longitudinal statistical modeling was performed to integrate multiple radiograph records per patient over time. All patients were from the United Kingdom and had self-reported white ancestry. EXPOSURES: Sixteen HLA-DRB1 haplotypes defined by amino acids at positions 11, 71, and 74. MAIN OUTCOMES AND MEASURES: Radiological outcome using the Larsen score (range: 0 [none] to 200 [severe joint damage]) and erosions of the hands and feet on radiographs, all-cause mortality, and treatment response measured by change in Disease Activity Score based on 28 joint counts and European League Against Rheumatism (EULAR) response. RESULTS: Patients with RA and valine at position 11 of HLA-DRB1 had the strongest association with radiological damage (OR, 1.75 [95% CI, 1.51-2.05], P = 4.6E-13). By year 5, the percentages of patients with erosions of the hands and feet were 48% of noncarriers (150/314) of valine at position 11, 61% of heterozygote carriers (130/213), and 74% of homozygote carriers (43/58). Valine at position 11 also was associated with higher all-cause mortality in patients with inflammatory polyarthritis (hazard ratio, 1.16 [95% CI, 1.03-1.31], P = .01) (noncarriers: 319 deaths in 1398 patients over 17,196 person-years, mortality rate of 1.9% per year; carriers: 324 deaths in 1116 patients in 13,208 person-years, mortality rate of 2.5% per year) and with better EULAR response to TNF inhibitor therapy (OR, 1.14 [95% CI, 1.01-1.30], P = .04) (noncarriers: 78% [439/561 patients] with moderate or good EULAR response; heterozygote carriers: 81% [698/866]; and homozygote carriers: 86% [277/322]). The risk hierarchy defined by HLA-DRB1 haplotypes was correlated between disease susceptibility, severity, and mortality, but inversely correlated with TNF inhibitor treatment response. CONCLUSIONS AND RELEVANCE: Among patients with RA, the HLA-DRB1 locus, which is associated with disease susceptibility, was also associated with radiological severity, mortality, and treatment response. Replication of these findings in other cohorts is needed as a next step in evaluating the role of HLA-DRB1 haplotype analysis for management of RA. PMID- 25919530 TI - Telemedicine screening for eye disease. PMID- 25919529 TI - Preferred Reporting Items for Systematic Review and Meta-Analyses of individual participant data: the PRISMA-IPD Statement. AB - IMPORTANCE: Systematic reviews and meta-analyses of individual participant data (IPD) aim to collect, check, and reanalyze individual-level data from all studies addressing a particular research question and are therefore considered a gold standard approach to evidence synthesis. They are likely to be used with increasing frequency as current initiatives to share clinical trial data gain momentum and may be particularly important in reviewing controversial therapeutic areas. OBJECTIVE: To develop PRISMA-IPD as a stand-alone extension to the PRISMA (Preferred Reporting Items for Systematic Reviews and Meta-Analyses) Statement, tailored to the specific requirements of reporting systematic reviews and meta analyses of IPD. Although developed primarily for reviews of randomized trials, many items will apply in other contexts, including reviews of diagnosis and prognosis. DESIGN: Development of PRISMA-IPD followed the EQUATOR Network framework guidance and used the existing standard PRISMA Statement as a starting point to draft additional relevant material. A web-based survey informed discussion at an international workshop that included researchers, clinicians, methodologists experienced in conducting systematic reviews and meta-analyses of IPD, and journal editors. The statement was drafted and iterative refinements were made by the project, advisory, and development groups. The PRISMA-IPD Development Group reached agreement on the PRISMA-IPD checklist and flow diagram by consensus. FINDINGS: Compared with standard PRISMA, the PRISMA-IPD checklist includes 3 new items that address (1) methods of checking the integrity of the IPD (such as pattern of randomization, data consistency, baseline imbalance, and missing data), (2) reporting any important issues that emerge, and (3) exploring variation (such as whether certain types of individual benefit more from the intervention than others). A further additional item was created by reorganization of standard PRISMA items relating to interpreting results. Wording was modified in 23 items to reflect the IPD approach. CONCLUSIONS AND RELEVANCE: PRISMA-IPD provides guidelines for reporting systematic reviews and meta-analyses of IPD. PMID- 25919531 TI - D-dimer for pulmonary embolism. PMID- 25919532 TI - Proportion of adults with sickle cell anemia and pain crises receiving hydroxyurea. PMID- 25919533 TI - Intracytoplasmic sperm injection and reproductive outcomes. PMID- 25919534 TI - Intracytoplasmic sperm injection and reproductive outcomes--reply. PMID- 25919535 TI - Cardiovascular screening for young athletes. PMID- 25919536 TI - Cardiovascular screening for young athletes. PMID- 25919537 TI - Cardiovascular screening for young athletes--reply. PMID- 25919539 TI - The immoderate publicity of science. PMID- 25919540 TI - JAMA patient page. The immune system. PMID- 25919541 TI - Integration of cell line and process development to overcome the challenge of a difficult to express protein. AB - This case study addresses the difficulty in achieving high level expression and production of a small, very positively charged recombinant protein. The novel challenges with this protein include the protein's adherence to the cell surface and its inhibitory effects on Chinese hamster ovary (CHO) cell growth. To overcome these challenges, we utilized a multi-prong approach. We identified dextran sulfate as a way to simultaneously extract the protein from the cell surface and boost cellular productivity. In addition, host cells were adapted to grow in the presence of this protein to improve growth and production characteristics. To achieve an increase in productivity, new cell lines from three different CHO host lines were created and evaluated in parallel with new process development workflows. Instead of a traditional screen of only four to six cell lines in bioreactors, over 130 cell lines were screened by utilization of 15 mL automated bioreactors (AMBR) in an optimal production process specifically developed for this protein. Using the automation, far less manual intervention is required than in traditional bench-top bioreactors, and much more control is achieved than typical plate or shake flask based screens. By utilizing an integrated cell line and process development incorporating medium optimized for this protein, we were able to increase titer more than 10-fold while obtaining desirable product quality. Finally, Monte Carlo simulations were performed to predict the optimal number of cell lines to screen in future cell line development work with the goal of systematically increasing titer through enhanced cell line screening. PMID- 25919542 TI - Divalent metals can reside on bonds in fullerenes. AB - DFT calculations consistently suggest that a lanthanide will sit on either the 6/6 bond inside C60 having a divalent state or the hexagonal center having a trivalent state. Some lanthanides can stay only above the 6/6 bond inside C60 to form stabilized structures, despite the greatly reduced metal-cage coordination numbers. The preference for C-C bonds by a divalent metal has been confirmed by revisiting the structures of Yb@C2v(3)-C80, Yb@Cs(6)-C82 and Yb@C2v(9)-C82, for which the calculations suggest that the Yb atoms are indeed situated above the C C bonds, close to the reported structures obtained by single crystal XRD experiments. The result will guide the characterization of structures and electronic structures of endohedral metallofullerenes (EMFs), especially C60 mono EMFs, in the future. PMID- 25919543 TI - [Epidemiological study on nasal carriage in hospitalized children infected with Staphylococcus aureus]. AB - OBJECTIVE: To study the relationship between nasal carriage and Staphylococcus aureus (S. aureus) infection in hospitalized children. METHODS: Fifty-six hospitalized children infected with S. aureus were recruited in this study. Nasal swabs were collected and cultured, and the nasal carriage rate of S. aureus was examined. PVL virulence gene and mecA resistance gene were both detected in clinical strains and nasal carriage strains by PCR. RESULTS: Twenty-two (39%) of the 56 children had nasal carriage of S. aureus, and most of them (18 cases) were younger than one year. Among these 22 children, 11 (50%) had previous hospitalization over the past year. In the infected strains, the rate of methicillin-resistant S. aureus (MRSA) was 29% (16/56), while it was 32% (7/22) in carriage strains. The mecA positive results in clinical strains were consistent with the results in nasal carriage strains. Among 5 PVL-positive nasal carriage strains, 4 (90%) could be matched with their clinical strains, all of which were MRSA. CONCLUSIONS: Nasal carriage is a potential risk factor for S. aureus infection. Nosocomial transmission may lead to nasal carriage, which can cause S. aureus infection. The isolation rate of MRSA is high in hospitalized children infected with S. aureus, which implies that more attention is needed for this situation. The isolates from noses may be clonally identical to the isolates from clinical secretions, and the homology between them needs to be confirmed by multi-locus sequence typing. PMID- 25919544 TI - [Control study on antimicrobial resistance of invasive and non-invasive Streptococcus pneumoniae in children]. AB - OBJECTIVE: To investigate the antimicrobial resistance of invasive and non invasive Streptococcus pneumoniae (SP) strains in children and to provide a basis for proper use of antimicrobial drugs in the treatment of SP infection. METHODS: Seventy children who were diagnosed with invasive pneumococcal diseases (IPD) between January 2009 and December 2013 were enrolled, and 164 children with lower respiratory tract infection caused by SP were randomly selected as the control group. The samples from sterile sites (blood, cerebrospinal fluid, etc) of children with IPD, as well as the sputum samples of children in the control group, were collected for bacterial culture, and the drug susceptibility tests for isolated SP strains were conducted. RESULTS: A total of 82 invasive strains of SP were isolated from sterile sites of 70 children with IPD; 49 strains (60%) were isolated from blood, and 19 strains (23%) from cerebrospinal fluid. The detection rate of invasive SP strains decreased from 2009 to 2013 (P<0.01). The total detection rates of penicillin-nonsusceptible SP from the invasive and non invasive strains were 27% and 17% respectively (P>0.05). Among invasive strains, the penicillin-nonsusceptible SP strains had significantly higher rates of insusceptibility to cefotaxime, ceftriaxone, and cefepime than the penicillin susceptible SP (P<0.01). There were significant differences in the rates of insusceptibility to cefotaxime, ceftriaxone, and meropenem between the sensitive and non-sensitive SP strains (P<0.05). The multidrug resistance rates of the invasive and non-invasive SP strains were 89% and 93% respectively (P>0.05). CONCLUSIONS: Invasive SP can easily invade the blood in children, but the total detection rate has decreased year by year. The results of drug sensitivity tests have guiding significance for proper use of antimicrobial drugs for different SP infections. PMID- 25919545 TI - [Determination of Th9 cells and IL-9 in children with Mycoplasma pneumoniae infection]. AB - OBJECTIVE: To investigate the clinical significance of T helper type 9 (Th9) cells and interleukin-9 (IL-9) in children suffering from Mycoplasma pneumoniae (MP) infection. METHODS: A total of 86 children who were diagnosed with MP infection between January 2013 and June 2014 were classified into upper respiratory infection (URI) group (n=29), mild MP pneumonia (MPP) group (n=32) and severe MPP group (n=25). Twenty-eight healthy children were used as the control group. Peripheral blood mononuclear cells were isolated by Ficoll density gradient centrifugation, and the percentage of Th9 cells in peripheral blood was measured by flow cytometry. Serum IL-9 level was determined using ELISA. RESULTS: The URI, mild MPP, and severe MPP groups had significantly higher percentages of Th9 cells and IL-9 levels than the control group (P<0.05); the mild MPP and severe MPP groups had significantly higher percentages of Th9 cells and IL-9 levels than the URI group (P<0.05), and the two indices were significantly higher in the severe MPP group than in the mild MPP group (P<0.01). CONCLUSIONS: Children with MP infection have an elevated percentage of Th9 cells and IL-9 expression, both of which are positively correlated with the severity of the disease. It can be predicted that Th9 cells and IL-9 can be used as evaluation indicators for the progression and outcome of children with MP infection. PMID- 25919546 TI - [Measurement of myeloid-derived suppressor cells and T-helper 17 cells in peripheral blood of young children with recurrent wheezing]. AB - OBJECTIVE: To determine the frequencies and significance of myeloid-derived suppressor cells (MDSCs) and T-helper 17 (Th17) cells in peripheral blood of young children with recurrent wheezing. METHODS: Thirty young children with an acute exacerbation of recurrent wheezing were randomly enrolled. Twenty age matched children with bronchopneumonia (pneumonia group) and 23 age-matched preoperative children with non-infectious or non-neoplastic diseases (hernia or renal calculus) (control group) were selected. The frequencies of MDSCs and Th17 cells in the peripheral blood were measured using flow cytometry and their correlation was determined by the Spearman's correlation coefficient. RESULTS: The percentage of MDSCs in nucleated cells was significantly higher in the wheezing group than in the pneumonia and control groups (P<0.05), and it was significantly higher in the pneumonia group than in the control group (P<0.05). The percentage of Th17 cells in mononuclear cells was significantly higher in the wheezing group than in the pneumonia and control groups (P<0.05), but it showed no significant difference between the pneumonia and control groups (P>0.05). The frequency of MDSCs was positively correlated with the frequency of Th17 cells in the wheezing group (r=0.645, P<0.01). CONCLUSIONS: MDSCs and Th17 cells may contribute to the pathogenesis of recurrent wheezing in young children. PMID- 25919547 TI - [Correlation of fractional exhaled nitric oxide with peripheral blood eosinophils and lung function in 1-3-year-old children with asthma]. AB - OBJECTIVE: To examine fractional exhaled nitric oxide (FeNO) values in 1-3-year old children with asthma and analyze the correlation of FeNO with peripheral blood eosinophils (EOS) and lung function in these children. METHODS: A total of 111 children aged 1-3 years with asthma were enrolled. The children were classified into acute exacerbation (n=62) and remission groups (n=49) according to their symptoms. FeNO values, lung function, and peripheral blood EOS count were measured in these children. Sixty age-matched healthy children were enrolled as the control group. RESULTS: FeNO values were significantly higher in the acute exacerbation group (24.4 ppb) than in the remission group (18.0 ppb) and the control group (13.7 ppb) (P<0.05). The FeNO values in the remission group were significantly higher than in the control group (P<0.05). FeNO values were not significantly correlated with peripheral blood EOS count and lung function parameters (PEF, TEF25, TEF50, and TEF75). CONCLUSIONS: Measurement of FeNO is useful to evaluate the disease activity in children with asthma aged 1 to 3 years, but the FeNO values are not correlated with peripheral blood EOS count and lung function. PMID- 25919548 TI - [Clinical features of children with relapsed acute lymphoblastic leukemia treated with the CCLG-ALL2008 protocol]. AB - OBJECTIVE: To study the clinical features of children with relapsed acute lymphoblastic leukemia (ALL) treated with the CCLG-ALL2008 protocol. METHODS: The data of 591 children who were newly diagnosed with ALL and were treated with the CCLG-ALL 2008 protocol between April 2008 and June 2013 were collected, and the clinical features of 80 children with relapsed ALL were retrospectively analyzed. RESULTS: After treatment with the CCLG-ALL2008 protocol, the recurrence rate in the standard-risk, intermediate-risk and the high-risk groups were 7.0%, 10.7% and 28.7% respectively (P<0.05). The recurrence rate in patients with TEL/AML1 positive ALL was 8.0%, and the 5-year overall survival (OS) of the relapsed patients was 37.04%. The recurrence rates in patients with MLL-positive and BCR/ABL-positive ALL were 35.0% and 24.2% respectively, and none of the relapsed patients had long-term survival. The recurrence mainly occurred at the very early stage (53%), and none of patients with recurrence at the very early stage had long-term survival. The recurrence occurred at early stage and late stage accounted for 34% and 14% respectively, and the 5-year OS rates of patients with recurrence at early stage and late stage were 11.44% and 60.00% respectively. The sites of recurrence were mainly bone marrow alone (83%), and the 5-year OS of patients with recurrence at bone marrow alone was 9.23%. The recurrence in bone marrow and outside bone marrow accounted for 11%, and the 5-year OS of patients with recurrence in both bone marrow and outside bone marrow was 25.00%. The recurrence only outside bone marrow accounted for 6%, and the 5-year OS of patients with recurrence only outside bone marrow was 100%. The recurrence rate in patients with T-cell ALL was 9.5%, and none of the relapsed patients had long term survival. The recurrence rate in patients with B-cell ALL was 14.3%, and the 5-year OS of the relapsed patients was 15.52%. CONCLUSIONS: After treatment with the CCLG-ALL2008 protocol, a relatively high recurrence rate is observed in children with high-risk ALL. Positive MLL and positive BCR/ABL are high-risk factors for recurrence. The recurrence rate is not significantly correlated with immunophenotype. A very low survival rate is seen in children whose recurrence have the following features: at early stage, only in bone marrow, T-cell ALL, and abnormal BCR/ABL and MLL. PMID- 25919549 TI - [Outcome of childhood high-risk acute lymphoblastic leukemia treated with the ALL BFM 95 protocol]. AB - OBJECTIVE: To evaluate the effectiveness and the practicability of the Acute Lymphoblastic Leukemia Berlin-Frankfurt-Munster 95 (ALL-BFM 95) protocol in treating childhood high-risk acute lymphoblastic leukemia (HR-ALL). METHODS: A retrospective analysis of 47 children with newly diagnosed HR-ALL between July 2003 and August 2013 was performed. These children were treated by the ALL-BFM 95 protocol. Survival was evaluated by Kaplan Meier analysis and Log-Rank test. RESULTS: Relapse-related death occurred in 12 of 47 patients (26%), and 5 of 47 patients (11%) were treatment-related mortality. Five-year probability of event free-survival (pEFS) was 62%. Children with hematopoietic stem cell transplantation (HSCT) after chemotherapy achieved significantly better pEFS than those with chemotherapy alone (77% vs 52%; P=0.035). The patients who were only poor responders to prednisone had a better outcome (5-year pEFS 80%) than the Days 15 and 33 bone marrow M3 subgroups (5-year pEFS 60% and 0 respectively). CONCLUSIONS: ALL-BFM 95 protocol can improve the outcome of children with high risk ALL. The major cause of death is attributed to relapse. Chemotherapy plus HSCT can produce a better outcome than chemotherapy alone. The Days 15 and 33 bone marrow M3 subgroups have a poor prognosis. PMID- 25919550 TI - [One-step multiplex RT-PCR for identifying common fusion transcripts in childhood acute lymphoblastic leukemia]. AB - OBJECTIVE: To evaluate the efficiency of one-step multiplex RT-PCR for identifying four common fusion transcripts (TEL/AML1, E2A/PBX1, MLL/AF4 and BCR/ABL) in children with acute lymphoblastic leukemia (ALL). METHODS: Total RNA was extracted from bone marrow samples of 76 children who were newly diagnosed with ALL between January 2003 and December 2010. These RNAs were analyzed for TEL/AML1, E2A/PBX1, MLL/AF4 and BCR/ABL by one-step multiplex RT-PCR or common nested-multiplex PCR. The PCR products were confirmed by DNA sequencing. RESULTS: TEL/AML1 was found in 12 cases (the length of products was 298 bp in 9 cases and 259 bp in 3 cases), E2A/PBX1 was found in 3 cases (the length of products was 373 bp), BCR/ABL was found in 1 case (the length of products was 2 124 bp), and MLL/AF4 was found in 7 cases (the length of products was 427 bp in 1 case and 673 bp in 6 cases) using one-step multiplex RT-PCR combined with DNA sequencing. The results were consistent with those using common nested-multiplex PCR. CONCLUSIONS: One-step multiplex RT-PCR may be another alternative for detection of common fusion transcripts in children with ALL. PMID- 25919551 TI - [Effects of blood transfusion on vital signs and heart function in preterm infants with anemia]. AB - OBJECTIVE: To explore the effects of blood transfusion on the vital signs and heart function in preterm infants with anemia. METHODS: A total of 40 anemic preterm infants with gestational age less than 34 weeks who accepted blood transfusion one week after birth were enrolled for a prospective cohort study. Left ventricular ejection fraction (LVEF), fractional shortening (FS), stroke volume (SV), and cardiac output (CO) were determined with portable ultrasonic equipment before blood transfusion and within 24 hours after blood transfusion. Apnea was detected and the times of apnea were recorded within 24 hours before and after blood transfusion. The resting body temperature and blood pressure were also determined before and after blood transfusion. Additionally the resting heart rate, respiratory rate, and transcutaneous oxygen saturation were recorded within 4 hours before and after blood transfusion. RESULTS: The heart rate and respiratory rate decreased significantly within 4 hours after blood transfusion (P<0.05). Four infants had apnea within 24 hours before blood transfusion, and nobody had apnea within 24 hours after blood transfusion. The systolic pressure, diastolic pressure, mean arterial pressure, and body temperature showed no significant changes after blood transfusion (P>0.05), and the LVEF, SV, CO, and FS showed no significant changes after blood transfusion as well (P>0.05). CONCLUSIONS: Blood transfusion can improve the clinical symptoms and shows no significant effect on the heart function in preterm infants with anemia. PMID- 25919552 TI - [Risk factors for early disseminated intravascular coagulation in neonates with sepsis]. AB - OBJECTIVE: To investigate the risk factors for early disseminated intravascular coagulation (DIC) in neonates with sepsis. METHODS: A retrospective clinical study was performed on 100 neonates with a confirmed diagnosis of sepsis between 2012 and 2013. The children were classified into normal coagulation group, non overt DIC group (early DIC group), and overt DIC group (late DIC group) based on the ISTH overt DIC scoring system. The clinical manifestations and risk factors were analyzed statistically. RESULTS: Early DIC occurred in 44 (44%) cases in the 100 neonates with sepsis. The incidence of sclerema showed significant differences between the three groups (P<0.05). Asphyxia, bleeding, and Gram negative bacterial infection were independent risk factors for early DIC. CONCLUSIONS: Coagulation function should be actively monitored and early intervention measures should be taken for neonates with asphyxia, bleeding, and Gram-negative bacterial infection to prevent early DIC from progressing to late DIC. PMID- 25919553 TI - [Clinical efficacy of high-frequency oscillatory ventilation combined with pulmonary surfactant in treatment of neonatal pulmonary hemorrhage]. AB - OBJECTIVE: To explore the clinical efficacy of high-frequency oscillatory ventilation (HFOV) combined with pulmonary surfactant (PS) in the treatment of neonatal pulmonary hemorrhage (NPH). METHODS: A total of 122 neonates diagnosed with NPH between January 2010 and June 2014 were enrolled. After being stratified by gestational age, the neonates were randomly divided into treatment (HFOV+PS) and control (HFOV alone) groups (n=61 each). Both groups were treated with HFOV after the onset of NPH. After 2-4 hours of HFOV treatment, the treatment group received PS via intratracheal injections, followed by continuous use of HFOV. Dynamic changes in the blood gas, oxygenation index (OI), and PaO2/FiO2 (P/F) values of the neonates were determined before HFOV treatment and after 6, 12, and 24 hours of HFOV treatment. The time to hemostasis, duration of ventilation, incidence of complications, and cure rate were compared between groups. RESULTS: After 6, 12, and 24 hours of HFOV treatment, the treatment group had significantly improved PaO2, PaCO2, O/I, and P/F values compared with the control group (P<0.05). The time to hemostasis and the duration of ventilation were significantly shorter in the treatment group than in the control group (P<0.01), and the incidence of complications was lower in the former than in the latter (P<0.05). There was no significant difference in the cure rate between the treatment (87%) and control (82%) groups (P>0.05). CONCLUSIONS: HFOV combined with PS is an effective treatment to improve oxygenation, shorten the time to hemostasis and the duration of ventilation, and reduce the incidence of complications in neonates with NPH. However, the dual therapy is unable to reduce the mortality of neonates compared with HFOV monotherapy. PMID- 25919554 TI - [Neonatal complications and birth defects in infants conceived by in vitro fertilization]. AB - OBJECTIVE: To investigate the survival quality of infants conceived by in vitro fertilization (IVF) and to identify the factors that cause birth defects and neonatal complications in IVF infants. METHODS: The study included 150 IVF infants (IVF group) and 200 naturally conceived infants (control group). Indicators such as birth situation, gestational disease, birth defects, and neonatal complications were compared between groups. The influencing factors for birth defects and neonatal complications were analyzed by non-conditional logistic regression analysis. RESULTS: Compared with the control group, the IVF group had increased incidences of twin pregnancy and low birth weight (P<0.01) but decreased average birth weight (P<0.05). In the IVF group, the mother's age was elder, with higher incidence of cesarean section, premature rupture of membranes, and pregnancy complications, as compared with the control group (P<0.05). There was no significant difference in the incidence of birth defects between the two groups (P>0.05). The IVF group had higher incidence rates of low birth weight and neonatal scleroderma (P<0.05), with a longer hospital stay (P<0.01), as compared with the control group. The non-conditional logistic regression analysis indicated that IVF, prematurity, twin pregnancy, and pregnancy complications were risk factors for low birth weight (P<0.05). CONCLUSIONS: There is no significant difference in the incidence of birth defects between IVF and naturally conceived infants. However, IVF infants have higher incidences of twin pregnancy and low birth weight, with a longer hospital stay, as compared with naturally conceived infants. Natural conceiving, avoiding prematurity, twin pregnancy, and pregnancy complications will reduce the incidence of low birth weight. PMID- 25919555 TI - [Mutation screening and function prediction of melanocortin-4 receptor gene in obese children]. AB - OBJECTIVE: To screen the coding region of melanocortin-4 receptor gene (MC4R) for mutations in children, analyze the association of the identified variants with obesity-related phenotypes, and predict the potential functions of the identified variants. METHODS: A case-control study was conducted in 160 severely obese children and 100 normal-weight controls, all aged 7-18 years. Their anthropometric data were collected and blood tests were performed. The coding region of MC4R gene was screened by polymerase chain reaction (PCR), single strand conformation polymorphism and sequencing, and the potential functions of the identified variants were predicted by related online databases. RESULTS: Three heterozygous missense mutations were identified in obese children (Val95Ile, Val166Ile and Val179Ala), and one heterozygous missense mutation was found in controls (Met218Thr). Val103Ile variant was found to be carried by seven subjects in the obese group and six in the control group (P>0.05). Val179Ala was a newly identified heterozygous mutation. No significant differences in BMI, weight, waist circumstance, hip circumstance, serum lipid parameters, fasting glucose, and body fat percentage were found between Val95Ile, Val166Ile or Val179Ala mutation carriers and non-carriers in obese children. The function prediction of the variants showed that all the five identified variants influenced the protein function. CONCLUSIONS: Five variants were identified in the coding region of MC4R gene, among which Val179Ala was newly identified. All the five variants might influence the protein function as evidenced by online prediction. PMID- 25919556 TI - [SLC2A2 gene analysis in three Chinese children with Fanconi-Bickel syndrome]. AB - Fanconi-Bickel syndrome (FBS, OMIM 227810), a rare autosomal recessive disorder of carbohydrate metabolism, is caused by SLC2A2 (GLUT2) mutations. The study reported 3 cases of FBS who were confirmly diagnosed by SLC2A2 gene analysis. The three patients showed typical features like glycogen storage disease and proximal renal tubular nephropathy. Homozygous splice-site mutation IVS8+5G>C (c.1068+5 G>C) was found in patient A and homozygous nonsense mutation c.1194T>A (p.Tyr398X) in patient B. Patient C harboured a missense mutation c.380C>A (p.Ala127Asp) and a de novo insertion c.970dupT (p.324TyrfsX392) which was not inherited from her parents. Four mutations were identified in the 3 Chinese FBS patients. Except IVS8+5G>C mutation, the other 3 mutations were novel in Chinese population. To the best of our knowledge, patient C may be the first FBS case worldwide with de novo mutation. PMID- 25919557 TI - [Analysis of MLC1 gene mutation in a Chinese family with megalencephalic leukoencephalopathy with subcortical cysts]. AB - The clinical data of a patient with megalencephalic leukoencephalopathy (MLC) with subcortical cysts and her parents were collected. MLC1 gene mutation was detected by polymerase chain reaction and direct DNA sequencing. The patient presented with motor developmental delay and giant skull, and brain magnetic resonance imaging showed diffuse white matter swelling accompanied by subcortical cysts in bilateral frontal and parietal lobes. Gene sequencing identified two heterozygous mutations of MLC1, including missense mutation in exon 3 (c.217G>A, p.Gly73Arg) and splice site mutation in intron 9 (c.772-1G>C in IVS9-1). The patient's parents both had heterozygous mutation c.772-1G>C in IVS9-1 with normal phenotype. It can be presumed that c.772-1G>C in IVS9-1 comes from the parents, and c.217G>A (p.Gly73Arg) is a de novo mutation. PMID- 25919558 TI - [Clinical and pathological differences between children with various genotypes of hepatitis B virus-associated glomerulonephritis]. AB - OBJECTIVE: To compare the clinical and pathological features between children with various genotypes of hepatitis B virus-associated glomerulonephritis (HBV GN). METHODS: Forty-one children with HBV-GN concurrently undergoing liver and renal biopsy were randomly selected. Serum specimens were collected for genotyping and hepatitis B virus (HBV) cccDNA assay. The clinical, pathological, and HBV cccDNA differences between HBV-GN children of various genotypes were analyzed. RESULTS: Among the 41 HBV-GN children, 29 (71%) were genotype C, 10 (24%) were genotype B, and 2 (5%) were genotype B/C. The incidence rates of hematuria, albuminuria, complement 3 decrease, alanine transaminase increase, and renal insufficiency in the genotype C group were significantly higher than those in the genotype B group (P<0.05). Similarly, the HBV cccDNA positive rate was significantly higher in the genotype C group than that in the genotype B group. No difference was observed in the distribution of pathological types of renal tissues betwee the two geonotype groups. There were no significant differences in the degrees of hepatic inflammation and fibrosis between the two groups. CONCLUSIONS: Mainly genotypes C and B occur in children with HBV-GN and the former genotype is dominant. The clinical symptoms of patients with genotype C are more serious than those with genotype B. However, there is no difference in the pathological features between them. PMID- 25919559 TI - [Association of vitamin D concentrations with juvenile idiopathic arthritis]. AB - OBJECTIVE: 25-Hydroxyvitamin D3 [25(OH)D3] is the main product of vitamin D and can reflect the absolute concentration of active vitamin D in the body. This study examined serum 25(OH)D3 levels in children with juvenile idiopathic arthritis (JIA) in order to explore the association of vitamin D concentrations with the pathogenesis and disease activity of JIA. METHODS: Serum samples were collected from 53 children confirmed as having JIA between January 2013 and March 2014, as well as 106 healthy children (control group) who underwent physical examination in the same period. Serum concentrations of 25(OH)D3 were measured using ELISA and compared between the cases and healthy controls. The association of serum 25(OH)D3 levels with JIA subtypes, ACR Pediatric 30 Score, peripheral blood C-reactive protein (CRP), and erythrocyte sedimentation rate (ESR) were analyzed in children with JIA. RESULTS: Compared with the control group, the JIA group had significantly reduced serum 25(OH)D3 levels (median: 42.6 nmol/L vs 49.9 nmol/L; P<0.01). The percentage of subjects with severe deficiency of vitamin D in the JIA group was significantly higher than that in the control group (17.0% vs 6.6%; P<0.05). Serum 25(OH)D3 showed no significant correlations with JIA subtypes, ACR Pediatric 30 Score, CRP, and ESR in children with JIA. CONCLUSIONS: Vitamin D concentrations are significantly decreased in children with JIA. Decreased vitamin D concentrations may be associated with the pathogenesis of JIA. However, vitamin D concentrations may have no correlations with JIA subtypes, disease severity, and disease activity. PMID- 25919560 TI - [Relationship between clinical features and cognitive function in patients with childhood and adolescence-onset schizophrenia]. AB - OBJECTIVE: To explore the factors influencing cognitive functions in patients with childhood and adolescence-onset schizophrenia. METHODS: The clinical data of 78 patients with childhood and adolescence-onset schizophrenia who met with the criteria of ICD-10 for schizophrenia were retrospectively reviewed. The cognitive functions were evaluated by the Chinese Wechsler Intelligence Scale for Children (C-WISC), the Wisconsin Card Sorting Test (WCST), digit span backward and P300. The clinical symptoms were evaluated by the Positive and Negative Syndrome Scale (PANSS). RESULTS: The patients with a lower education level or earlier onset of age had a longer P3 latency at the P300Fz area. The patients with a higher parental education level had higher scores of full intelligence quotient (FIQ), verbal intelligence quotient (VIQ), performance intelligence quotient (PIQ), conceptual level and completed categories of WCST and backward numeric order reciting. The patients with higher PANSS negative subscale scores had lower scores of FIQ, VIQ, PIQ, completed categories and conceptual level of WCST and backward numeric order reciting. The patients with a longer stabilization time had higher backward numeric order reciting scores. CONCLUSIONS: The severity of negative symptoms of the patients and the educational level of their parents are major factors influencing cognitive functions in patients with childhood and adolescence-onset schizophrenia. PMID- 25919561 TI - [Transcatheter closure in various types of congenital coronary artery fistula: a follow-up study]. AB - OBJECTIVE: To evaluate the short- and medium-term efficacy, complications, and anti-coagulation therapies related to transcatheter closure (TCC) of coronary artery fistula (CAF) in children. METHODS: We conducted a retrospective review of the medical records of 12 children with CAF who underwent TCC between January 2006 and January 2014, focusing on details such as preoperative, radiographic, and postoperative follow-up data, to record closure methods for CAF, anti coagulation therapies, postoperative complications, and results of auxiliary examinations. RESULTS: Among the 12 cases who underwent successful TCC and whose age was 1-158 months, four patients had proximal/medium-sized CAF, five had proximal/large CAF, and three had distal/medium-sized CAF. The mean period of postoperative follow-up was 3.5+/-2.4 years. Eleven patients took aspirin for 6 months post closure, and one took it for 18 months. Neither coronary thrombosis nor interventional complications were found. Left ventricular ejection fraction, cardiothoracic ratio, pulmonary artery pressure, and the diameters of coronary artery lesions decreased post TCC. CONCLUSIONS: TCC is feasible and safe in proximal and distal/medium-sized CAF patients. Postoperative anti-coagulation with aspirin may prevent short- and medium-term thrombosis, but treatment course and safety need to be investigated by further follow-ups. PMID- 25919562 TI - [Analysis of mortality among children under 5 years of age in Shenzhen from 2003 to 2013]. AB - OBJECTIVE: To study the trend of the mortality rate and the leading causes of death among children under 5 years of age in Shenzhen, China, from 2003 to 2013. METHODS: The surveillance data of mortality among children under 5 years of age in Shenzhen from 2003 to 2013 were collected, and the mortality rates among infants (IMR) and children under 5 years of age (U5MR) with different household types and the leading causes of death were determined. RESULTS: Between 2003 and 2013 the IMR and U5MR in Shenzhen dropped by 61.56% and 60.56%, respectively from 7.830/00 and 10.040/00 in 2003 to 3.010/00 and 3.960/00 in 2013. The IMR and U5MR of the non-household population were significantly higher than those of the household population. The leading causes of death among children under 5 years of age were preterm birth/low birth weight, congenital heart disease, accidental asphyxia, septicemia, and birth asphyxia. CONCLUSIONS: The U5MR has substantially reduced in Shenzhen. To further reduce the U5MR, it is important to improve prenatal diagnosis and neonatal resuscitation, enhance perinatal health care and accident prevention, and strengthen health care of floating population. PMID- 25919563 TI - [Site-directed mutagenesis and protein expression of ABCA3 gene in A549 cells]. AB - OBJECTIVE: To study the protocol of construction of the mutation E292V and M723I of hABCA3 gene associated with neonatal respiratory distress syndrome, as well as their eukaryotic green fluorescent protein expression rectors, and to examine the expression of mutation proteins in human lung carcinoma epithelial cells (A549). METHODS: Site-directed mutagenesis method based on overlap extension PCR was used to introduce mutations in the two sites which were E292V and M723I in the ABCA3. The PCR fragments were subcloned to PEGFP-C2 vectors to construct the eukaryotic green fluorescent protein expression rectors. A549 cells were transiently transfected with the recombinants using Lipofectamine 2000 and the transfection efficiency was confirmed through GFP signal. The expression and location of recombinants were detected by FV1000 laser scanning microscope. RESULTS: Direct sequence analysis confirmed an A to T transition at position 875 in E292V and a G to A transition at position 2169 in M723I. Recombinants were transfected to A549 cells and both wild type and mutant ABCA3 proteins were expressed in the cytoplasm. CONCLUSIONS: The eukaryotic green fluorescent protein expression rectors of wild type and mutant ABCA3 gene were constructed and they were successfully expressed in A549 cells. This experiment provides a basis for subsequent research. PMID- 25919564 TI - [Changes in expression of autophagy-related proteins, Beclin-1 and LC3, and effects of rapamycin on their expression in hypoxic-ischemic hippocampus]. AB - OBJECTIVE: To observe changes in the expression of autophagy-related proteins, Beclin-1 and LC3, in the hippocampal tissue of neonatal rats with hypoxic ischemic brain damage (HIBD) at different time points, and to investigate the effect of rapamycin (Ra) on the expression of the above two proteins. METHODS: A total of 108 7-day-old Sprague-Dawley rats were randomly divided into sham, HIBD, and Ra groups (n=36 each). The HIBD model was established using the modified Rice method. For sham rats, only the left common carotid artery was separated without ligation or hypoxic treatment. For Ra-treated rats, 0.5 mg/kg Ra was administered by an intraperitoneal injection 1 hour before model establishment. The rats were anesthetized and sacrificed to collect brain tissues at 0, 6, 12, 24, 48, and 72 hours after model establishment. Changes in the expression of Beclin-1 and LC3 proteins in rat hippocampus were examined by Western blot. RESULTS: The expression level of Beclin-1 in HIBD rats began to increase at 0 hour, peaked at 24 hours, and then declined thereafter, similar as those of Beclin-1 and LC3-II in Ra-treated rats. The expression level of LC3-II in HIBD rats began to increase at 0 hour, peaked at 12 hours, and then declined thereafter. At all time points, both Beclin-1 and LC3-II expression levels were significantly higher in HIBD and Ra-treated rats than in sham rats (P<0.05); except LC3-II at 12 hours, Beclin-1 and LC3-II expression levels were significantly higher in Ra-treated rats than in HIBD rats (P<0.05). CONCLUSIONS: Hypoxia-ischemia activates autophagy in rat hippocampal cells, while Ra enhances the expression process of autophagy. PMID- 25919565 TI - [Efficiency and safety of linezol in the treatment of neonatal sepsis]. PMID- 25919566 TI - [Neonatal food allergy]. AB - Food allergy is defined as abnormal immune response elicited by food intake, in which a variety of clinical symptoms will appear as a result of physiological dysfunction and/or tissue damage. Possible mechanisms for food allergy include gastrointestinal tract barrier damage, failure to induce oral immune tolerance, intrauterine sensitization, and allergen transmission during pregnancy and breastfeeding. Hereditary and environmental factors can also contribute to the disease. Gastrointestinal disorders are the main clinical manifestations of the disease. However, hypoalbuminemia, growth retardation, and even acute circulatory failure or shock may occur in severe cases. Oral food challenges are the "gold standard" for the diagnosis of food allergy. Avoidance and replacement of the responsible food are the only effective treatment options for neonatal food allergy. The use of probiotics can offer protection against the disease. PMID- 25919567 TI - [Adverse effects of oxcarbazepine]. AB - Oxcarbazepine is a new antiepileptic drug. The results of clinical trials suggest that oxcarbazepine is well tolerated and has less drug interactions. It is being used more and more widely in clinical practice, but its adverse effects should not be ignored. The most common adverse effects of oxcarbazepine are usually related to the central nervous system and digestive system, including fatigue, drowsiness, diplopia, dizziness, nausea and vomit. The common skin adverse reaction is rash. Long-term use of oxcarbazepine may also cause hyponatremia. This article reviews the literature from China and overseas about the adverse effets of oxcarbazepine over the last 10 years in order to find information about rational clinical use of oxcarbazepine. PMID- 25919568 TI - Highly active chromium-based selective ethylene tri-/tetramerization catalysts supported by PNPO phosphazane ligands. AB - Novel Cr(iii) catalysts supported by PNPO phosphazane ligands of the type Ph2PN(R)P(Ph)OAr have been prepared, all of which, upon activation with MMAO-3A, are highly active in ethylene tri-/tetramerization with considerable selectivity. The effect of ligand substitution on the catalytic performance has been examined. The Cr precatalyst supported by the PNPO phosphazane ligand with an N-cyclohexyl achieved high activity of 316.7 kg (g Cr h(-1))(-1) and a high total selectivity of 85.1% towards valuable 1-hexene (45.7%) and 1-octene (39.4%) using chlorobenzene as the solvent at 35 bar and 40 degrees C. In methylcyclohexane, the precatalyst supported by [Ph2PN((i)Pr)P(Ph)OPh] exhibited a higher 1-octene selectivity (54.0%) with a considerable activity of 73.3 kg (g Cr h(-1))(-1) at 35 bar and 40 degrees C. With the fine-tuned ligand backbone, such a PNPO phosphazane-based catalyst system provides a mode for precise understanding of the impact of ligand variations on catalytic performance. PMID- 25919569 TI - New inflammatory markers for prediction of non-dipper blood pressure pattern in patients with essential hypertension: Serum YKL-40/Chitinase 3-like protein 1 levels and echocardiographic epicardial adipose tissue thickness. AB - The aim of the present study was to investigate whether YKL-40 levels and epicardial adipose tissue (EAT) thickness were associated with non-dipping pattern in essential hypertension (HT). Age- and sex-matched 40 dipper hypertensive patients and 40 non-dipper hypertensive patients were included in the study. Non-dippers had significantly increased EAT thickness and higher YKL 40 and high-sensitivity C-reactive protein levels than dippers. Multivariate logistic regression analysis showed that the EAT thickness and serum levels of YKL-40 and high-sensitivity C-reactive protein were independent predictors of non dipping pattern in essential HT. In essential HT, presence of non-dipping pattern is associated with increased inflammatory response. PMID- 25919570 TI - MicroRNA-33b Inhibits Breast Cancer Metastasis by Targeting HMGA2, SALL4 and Twist1. AB - MicroRNAs are a class of small noncoding RNAs that regulate gene expression post transcriptionally either by inhibiting protein translation or by causing the degradation of target mRNAs. Current evidence indicates that miR-33b is involved in the regulation of lipid metabolism, cholesterol homeostasis, glucose metabolism and several human diseases; however, whether miR-33b contributes to the pathogenesis of human cancers and participates in the regulation of self renewal of human cancer stem cells remains unknown. Here, we report the identification of miR-33b as a negative regulator of cell stemness and metastasis in breast cancer. Compared with paired normal breast tissues, miR-33b expression is downregulated in breast tumor samples and is inversely correlated with lymph node metastatic status. Ectopic overexpression of miR-33b in highly metastatic breast cancer cells suppresses cell self-renewal, migration and invasion in vitro and inhibits lung metastasis in vivo. Conversely, miR-33b knockdown promotes the self-renewal, migration and invasion capabilities of noncancerous mammary epithelial cells. The mechanism through which miR-33b inhibits the stemness, migration and invasion of breast cancer cells is by targeting HMGA2, SALL4 and Twist1. These data indicate that miR-33b acts as an onco-suppressive microRNA in breast cancer progression by inhibiting the stemness and metastasis of breast cancer cells. PMID- 25919571 TI - Fluid resuscitation for paediatric sepsis: A survey of senior emergency physicians in Australia and New Zealand. AB - OBJECTIVE: It is unclear whether emerging evidence for harm from aggressive fluid resuscitation for paediatric sepsis has altered clinical practice. We surveyed senior emergency physicians to see if their fluid resuscitation practices conformed to published clinical guidelines. METHODS: This is a cross-sectional, Internet-based survey of senior emergency medical staff in any of 12 Paediatric Research in Emergency Departments International Collaborative (PREDICT) Network centres in Australia and New Zealand. RESULTS: There were 110 of 120 (92%) senior medical staff who responded. Ninety-eight per cent of respondents used 0.9% saline as their primary resuscitation fluid. Sixty-two per cent of respondents used 20 mL/kg fluid bolus for every bolus, 30% used 20 mL/kg for the first bolus and 10 mL/kg subsequently. Response to fluid bolus administration was based on clinical parameters in 92% of respondents (heart rate, BP, skin perfusion/mottling and central capillary refill), conscious state in 80% and venous lactate in 75%. Harm from fluid bolus administration was routinely monitored for by 81% of respondents. In those assessing for harm, clinical parameters were reported to be most commonly used (respiratory rate and effort in 60%, SpO2 in 55%, presence of crackles on lung auscultation in 50% and hepatomegaly in 42%). Invasive or ultrasound-based monitoring was used infrequently. CONCLUSIONS: Paediatric sepsis is reported to be managed by senior emergency physicians largely according to published guidelines. At this time, evidence for potential harm from fluid bolus resuscitation has not altered practice. PMID- 25919572 TI - Molecular epidemiology of HBV infection in chronic hepatitis B virus infected patients in northeast India. AB - The present study aimed to evaluate the molecular epidemiology of HBV in chronic HBV infected cases from northeast India (NEI), since scanty data are available from the region which has a predominant ethnically distinct tribal population. A total of 523 clinically diagnosed index chronic HBV infected cases and 172 asymptomatic patients (based on family screening) were enrolled with informed consent. Patients were stratified based on serology, imaging, pathology, and clinical data and grouped as chronic HBV and cirrhotic cohorts. Analysis for serum HBV DNA levels and HBV genotyping was performed, and was statistically co related with disease severity. Males were more prone to chronic HBV infection. Majority of the patients who had Chronic HBV infection based on family screening were females (59.88%), majorly wives of index patients. Mean viral load in Chronic HBV patients was almost 4.5-folds higher than cirrhosis patients, and was significantly associated with e-antigen positive status(P < 0.001) in both groups. HBV genotype D was the most prevalent genotype (62.30%) in NEI. Mixed genotype infection of A + D was found from Assam, along with C + D cases (1.29%) cumulatively. There is a high prevalence of HBV genotype C (13.96%) in our studied cohort which was found to be associated with higher viral load(P = 0.018), e-antigen positivity(P = 0.043), and increased cirrhosis risk compared to Chronic HBV cases [OR = 1.670]. Family contacts in NEI are prone to infection with HBV and development of Chronic HBV. Higher presence of e-positive cases and genotype C along with the mixed genotypes in NEI is unique and of significance with reference to predisposition to disease severity and even response to antiviral therapy. PMID- 25919573 TI - Neuromodulation for Overactive Bladder Symptoms in Women Utilizing Either Motor or Sensory/Motor Provocation With a Minimum Nine-Year Follow-Up. AB - INTRODUCTION: This study is an evaluation of whether motor provocation compared to mixed sensory/motor provocation for tined lead placement affects its efficacy with quality of life measurements and Likert patient satisfaction. MATERIALS AND METHODS: An observational, retrospective cohort study was conducted with the analysis of 128 charts of adult women who, between January 2002 and September 2005, underwent a two-staged approach for sacral neuromodulation by the lead author SPM. Both groups did not differ statistically in their mean preoperative American Anesthesiologist Status Classification Score's of two or less, or frequency, urgency, urgency incontinence daily episodes or Urinary Distress Inventory scores. A seven-point Likert Scale was utilized for post-operative patient satisfaction. Sixty-eight patients (Group 1) received pure motor provocation for tined lead placement under general anesthetic and 60 patients (Group 2) received mixed sensory/motor provocation tined lead placement under intravenous sedation and local anesthetic. RESULTS: Sixty-two of 68 (91%) patients in Group 1 proceeded to Stage Two while 53/60 (88%) in Group 2 proceeded to Stage Two implantation (p = 0.28). Median follow-ups were 124.7 +/- 21.5 months for Group 1 and 120.4 +/- 19.7 months for Group 2 (p = 0.45). Mean preoperative/postoperative Urinary Distress Inventory short form and number of voids per 24 hours were for Group 1, 15.5 +/- 6.6/8.9 +/- 4.3 and 16.3 +/- 5.3/9.2 +/- 3.9 and for Group 2, 16.3 +/- 6.4/8.4 +/- 3.9 and 17.82 +/- 7.17/8.34 +/- 4.26 voids/24 hours (p < 0.001). Mean preoperative and postoperative ultrasound post void residual urines were 62.2 +/- 29.3 milliliters/46.9 +/- 20.6 milliliters (Group 1) and 68.0 +/- 26.8 milliliters /42.0 +/- 27.8 milliliters (Group 2) (p < 0.01). Mean operative times were 29.5 +/- 16.8 minutes (Group 1) and 59.3 +/- 25.8 minutes (Group 2) (p < 0.001). Mean Likert patient satisfaction score (1, 2, 3) for Group 1 was 2.6 and 1.8 for Group 2 (p < 0.21). The mean numbers of office visits/year for reprogramming were 1.4 +/- 0.7 (Group 1) and 2.8 +/- 1.1 (Group 2) (p < 0.001). CONCLUSION: Women with mixed sensory/motor provocation tined lead placement incurred statistically significant longer operating room times and an increased number of annual reprogramming sessions. Singular motor provocation tined lead placement may, in fact, improve outcomes by significantly decreasing operating room time, improving patient satisfaction, and decreasing mean yearly reprogramming sessions, compared to mixed sensory/motor tined lead placement. PMID- 25919575 TI - The Functional Property Changes of Muscular Na(v)1.4 and Cardiac Na(v)1.5 Induced by Scorpion Toxin BmK AGP-SYPU1 Mutants Y42F and Y5F. AB - Scorpion toxins are invaluable therapeutic leads and pharmacological tools which influence the voltage-gated sodium channels. However, the details were still unclear about the structure-function relationship of scorpion toxins on VGSC subtypes. In the previous study, we reported one alpha-type scorpion toxin Bmk AGP-SYPU1 and its two mutants (Y5F and Y42F) which had been demonstrated to ease pain in mice acetic acid writhing test. However, the function of Bmk AGP-SYPU1 on VGSCs is still unknown. In this study, we examined the effects of BmK AGP-SYPU1 and its two mutants (Y5F and Y42F) on hNa(v)1.4 and hNa(v)1.5 heterologously expressed CHO cell lines by using Na+-specialized fluorescent dye and whole-cell patch clamp. The data showed that BmK AGP-SYPU1 displayed as an activator of hNa(v)1.4 and hNa(v)1.5, which might indeed contribute to its biotoxicity to muscular and cardiac system and exhibited the functional properties of both the alpha-type and beta-type scorpion toxin. Notably, Y5F mutant exhibited lower activatory effects on hNa(v)1.4 and hNa(v)1.5 compared with BmK AGP-SYPU1. Y42F was an enhanced activator and confirmed that the conserved Tyr42 was the key amino acid involved in bioactivity or biotoxicity. These data provided a deep insight into the structure-function relationship of BmK AGP-SYPU1, which may be the guidance for engineering alpha-toxin with high selectivity on VGSC subtypes. PMID- 25919576 TI - Magnetic Properties of Nonmagnetic Nanostructures: Dangling Bond Magnetic Polaron in CdSe Nanocrystals. AB - We predict theoretically that nonmagnetic CdSe nanocrystals may possess macroscopic magnetic moments due to the formation of dangling-bond magnetic polarons (DBMPs). A DBMP is created in optically pumped nanocrystals by dynamic polarization of dangling bond spins (DBSs) at the nanocrystal surface during radiative recombination of the ground state "dark" exciton assisted by a spin flip of the DBS. The formation of DBMPs suppresses the radiative recombination of the dark exciton and leads to a temperature-dependent contribution to the Stokes shift of the photoluminescence. This model consistently explains the experimentally observed low-temperature photoluminescence features of nonmagnetic CdSe nanocrystals as manifestations of their spin-related magnetic properties. PMID- 25919574 TI - Low Levels of a Urinary Biomarker of Dietary Polyphenol Are Associated with Substantial Cognitive Decline over a 3-Year Period in Older Adults: The Invecchiare in Chianti Study. AB - OBJECTIVES: To investigate the association between total urinary polyphenols (TUPs) and total dietary polyphenols (TDPs) and cognitive decline in an older population. DESIGN: The Invecchiare in Chianti (InCHIANTI) study, a cohort study with 3 years of follow-up. SETTING: Tuscany, Italy. PARTICIPANTS: Individuals without dementia aged 65 and older (N=652). MEASUREMENTS: TUP and TDP concentrations were analyzed at baseline using the Folin-Ciocalteu assay and a validated food frequency questionnaire, respectively. Cognition was assessed using the Mini-Mental State Examination (MMSE) and Trail-Making Test (TMT) at baseline and after 3 years of follow-up. Substantial cognitive decline was defined as a reduction in MMSE score of three or more points and an increase of at least 29 seconds on the TMT Part A (TMT-A) and 68 seconds on the TMT Part B (TMT-B) (the worst 10% of the distribution of decline) or as test discontinued because of multiple mistakes on the TMT A and B at follow-up. RESULTS: Higher TUP levels were associated with lower risk of substantial cognitive decline on the MMSE (odds ratio (OR) comparing extreme tertiles=0.53, 95% confidence interval (CI)=0.34-0.85, P-trend=.008) and on the TMT-A (OR=0.52, 95% CI=0.28-0.96, P trend=.03), but not on TMT-B in a logistic regression model that adjusted for baseline cognitive score and potential confounding factors. TDP did not affect the development of substantial cognitive decline in either test. CONCLUSION: High concentrations of polyphenols, a nutritional biomarker of polyphenol intake, were associated with lower risk of substantial cognitive decline in an older population studied over a 3-year period, suggesting a protective effect against cognitive impairment. PMID- 25919577 TI - MnO2-Nanosheet-Modified Upconversion Nanosystem for Sensitive Turn-On Fluorescence Detection of H2O2 and Glucose in Blood. AB - Blood glucose monitoring has attracted extensive attention because diabetes mellitus is a worldwide public health problem. Here, we reported an upconversion fluorescence detection method based on manganese dioxide (MnO2)-nanosheet modified upconversion nanoparticles (UCNPs) for rapid, sensitive detection of glucose levels in human serum and whole blood. In this strategy, MnO2 nanosheets on the UCNP surface serve as a quencher. UCNP fluorescence can make a recovery by the addition of H2O2, which can reduce MnO2 to Mn(2+), and the glucose can thus be monitored based on the enzymatic conversion of glucose by glucose oxidase to generate H2O2. Because of the nonautofluorescent assays offered by UCNPs, the developed method has been applied to monitor glucose levels in human serum and whole blood samples with satisfactory results. The proposed approach holds great potential for diabetes mellitus research and clinical diagnosis. Meanwhile, this nanosystem is also generalizable and can be easily expanded to the detection of various H2O2-involved analytes. PMID- 25919579 TI - A microcontroller platform for the rapid prototyping of functional electrical stimulation-based gait neuroprostheses. AB - Functional electrical stimulation (FES) has been used over the last decades as a method to rehabilitate lost motor functions of individuals with spinal cord injury, multiple sclerosis, and post-stroke hemiparesis. Within this field, researchers in need of developing FES-based control solutions for specific disabilities often have to choose between either the acquisition and integration of high-performance industry-level systems, which are rather expensive and hardly portable, or develop custom-made portable solutions, which despite their lower cost, usually require expert-level electronic skills. Here, a flexible low-cost microcontroller-based platform for rapid prototyping of FES neuroprostheses is presented, designed for reduced execution complexity, development time, and production cost. For this reason, the Arduino open-source microcontroller platform was used, together with off-the-shelf components whenever possible. The developed system enables the rapid deployment of portable FES-based gait neuroprostheses, being flexible enough to allow simple open-loop strategies but also more complex closed-loop solutions. The system is based on a modular architecture that allows the development of optimized solutions depending on the desired FES applications, even though the design and testing of the platform were focused toward drop foot correction. The flexibility of the system was demonstrated using two algorithms targeting drop foot condition within different experimental setups. Successful bench testing of the device in healthy subjects demonstrated these neuroprosthesis platform capabilities to correct drop foot. PMID- 25919581 TI - Abstracts of the British Psychosocial Oncology Society, 2015 Annual Conference, 19 - 20 March 2015, England, UK. PMID- 25919578 TI - Relationship among Glutamine, gamma-Aminobutyric Acid, and Social Cognition in Autism Spectrum Disorders. AB - OBJECTIVE: An imbalance of excitatory and inhibitory neurotransmission in autism spectrum disorder (ASD) has been proposed. We compared glutamate (Glu), glutamine (Gln), and gamma-aminobutyric acid (GABA) levels in the anterior cingulate cortex (ACC) of 13 males with ASD and 14 typically developing (TD) males (ages 13-17), and correlated these levels with intelligence quotient (IQ) and measures of social cognition. METHODS: Social cognition was evaluated by administration of the Social Responsiveness Scale (SRS) and the Reading the Mind in the Eyes Test (RMET). We acquired proton magnetic resonance spectroscopy ((1)H-MRS) data from the bilateral ACC using the single voxel point resolved spectroscopy sequence (PRESS) to quantify Glu and Gln, and Mescher-Garwood point-resolved spectroscopy sequence (MEGA-PRESS) to quantify GABA levels referenced to creatine (Cr). RESULTS: There were higher Gln levels (p=0.04), and lower GABA/Cre levels (p=0.09) in the ASD group than in the TD group. There was no difference in Glu levels between groups. Gln was negatively correlated with RMET score (rho=-0.62, p=0.001) and IQ (rho=-0.56, p=0.003), and positively correlated with SRS scores (rho=0.53, p=0.007). GABA/Cre levels were positively correlated with RMET score (rho=0.34, p=0.09) and IQ (rho=0.36, p=0.07), and negatively correlated with SRS score (rho=-0.34, p=0.09). CONCLUSIONS: These data suggest an imbalance between glutamatergic neurotransmission and GABA-ergic neurotransmission in ASD. Higher Gln levels and lower GABA/Cre levels were associated with lower IQ and greater impairments in social cognition across groups. PMID- 25919580 TI - Childhood stress in healthcare settings: awareness and suggested interventions. AB - Pivotal to healthy adulthood is a supportive and nurturing environment that enables successful progression through the developmental tasks of childhood and adolescence. For many children there are events that disrupt this development. Illness, injury, painful medical interventions, and hospitalization have been reported by children and families as causing medical trauma and psychological stress. Frequently pediatric health professionals focus primarily on achieving positive physical treatment outcomes. Creating an environment that will support the developmental tasks of childhood and limit the trauma and distress associated with illness and treatment is also required. Strategies and practices to deliver holistic and comprehensive pediatric care are well established in many Western settings. Opportunity exists to broaden the focus of pediatric care in developing healthcare systems such as the United Arab Emirates (UAE) to encompass psychological well-being. The study focused on two key objectives, firstly to assess healthcare professionals' awareness of the stressful and potentially traumatic nature of healthcare settings and treatment for children. Second the study explored the views of healthcare participants regarding possible strategies to minimize medically induced stress and trauma for children and adolescents in UAE healthcare settings. The study utilized a mixed methods design in which participants views were examined through administration of a survey comprised of close-ended questions that were analyzed quantitatively and open-ended questions analyzed qualitatively. One hundred and seventeen healthcare professionals from a range of disciplines in two government hospitals completed the survey. Data revealed that one third of the participating healthcare professionals were unaware of or did not think that their healthcare settings could provoke stress for pediatric patients. Respondents suggested three main strategies to minimize stress for children and parents while receiving treatments, specifically; providing focused information for both children and healthcare providers, adapting the environment and systems to fit children's needs, and, improving the interpersonal skills and attitudes of healthcare professionals. The findings from this study could inform the development of standards for pediatric services and policy directions in regard to post-graduate training for health professionals working in pediatric healthcare settings. PMID- 25919582 TI - In-operando high-speed tomography of lithium-ion batteries during thermal runaway. AB - Prevention and mitigation of thermal runaway presents one of the greatest challenges for the safe operation of lithium-ion batteries. Here, we demonstrate for the first time the application of high-speed synchrotron X-ray computed tomography and radiography, in conjunction with thermal imaging, to track the evolution of internal structural damage and thermal behaviour during initiation and propagation of thermal runaway in lithium-ion batteries. This diagnostic approach is applied to commercial lithium-ion batteries (LG 18650 NMC cells), yielding insights into key degradation modes including gas-induced delamination, electrode layer collapse and propagation of structural degradation. It is envisaged that the use of these techniques will lead to major improvements in the design of Li-ion batteries and their safety features. PMID- 25919583 TI - Separase Cleaves the N-Tail of the CENP-A Related Protein CPAR-1 at the Meiosis I Metaphase-Anaphase Transition in C. elegans. AB - Centromeres are defined epigenetically in the majority of eukaryotes by the presence of chromatin containing the centromeric histone H3 variant CENP-A. Most species have a single gene encoding a centromeric histone variant whereas C. elegans has two: HCP-3 (also known as CeCENP-A) and CPAR-1. Prior RNAi replacement experiments showed that HCP-3 is the functionally dominant isoform, consistent with CPAR-1 not being detectable in embryos. GFP::CPAR-1 is loaded onto meiotic chromosomes in diakinesis and is enriched on bivalents until meiosis I. Here we show that GFP::CPAR-1 signal loss from chromosomes precisely coincides with homolog segregation during anaphase I. This loss of GFP::CPAR-1 signal reflects proteolytic cleavage between GFP and the histone fold of CPAR-1, as CPAR 1::GFP, in which GFP is fused to the C-terminus of CPAR-1, does not exhibit any loss of GFP signal. A focused candidate screen implicated separase, the protease that initiates anaphase by cleaving the kleisin subunit of cohesin, in this cleavage reaction. Examination of the N-terminal tail sequence of CPAR-1 revealed a putative separase cleavage site and mutation of the signature residues in this site eliminated the cleavage reaction, as visualized by retention of GFP::CPAR-1 signal on separating homologous chromosomes at the metaphase-anaphase transition of meiosis I. Neither cleaved nor uncleavable CPAR-1 were centromere-localized in mitosis and instead localized throughout chromatin, indicating that centromere activity has not been retained in CPAR-1. Although the functions of CPAR-1 and of its separase-dependent cleavage remain to be elucidated, this effort reveals a new substrate of separase and provides an in vivo biosensor to monitor separase activity at the onset of meiosis I anaphase. PMID- 25919584 TI - [Evoked potentials N200/P300 disorders and clinical phenotype in Cuban families with paranoid schizophrenia: a family-based association study]. AB - INTRODUCTION: N200 and P300 event-related evoked potentials provide sensitive measurements of sensory and cognitive function and have been used to study information processing in patients with schizophrenia and their unaffected first degree relatives. Reduced amplitude and increased latency of N200 and P300 potentials have been consistently reported in schizophrenia. Thus, event-related evoked potentials abnormalities are promising possible biological markers for genetic vulnerability to schizophrenia. OBJECTIVE: To assess the association of changes in latency, amplitude and topographic distribution of potentials N200 and P300 of patients with paranoid schizophrenia and their healthy first-degree relatives, in families with schizophrenia multiplex. METHODOLOGY: We measured latency and amplitude of the N200 and P300 component of evoked potentials using an auditory odd-ball paradigm in 25 schizophrenic patients (probands) from 60 families multiply affected with paranoid schizophrenia, 23 of their non schizophrenic first-degree relatives and 25 unrelated healthy controls, through a study of family association. RESULTS: Schizophrenic patients and their relatives showed significant latency prolongation and amplitude reduction of the N200 and P300 waves compared to controls. Left-temporal as compared to right-temporal N200 and P300 were significantly smaller in schizophrenic patients and their non schizophrenic first-degree relatives than in controls. Our results suggest that event-related evoked potentials abnormalities may serve as markers of genetic vulnerability in schizophrenia. CONCLUSIONS: Confirming results of other researchers, this present study suggests that latency prolongation and amplitude reduction of the N200 and P300 waves and an altered topography at temporal sites may be a trait ?marker? of paranoid schizophrenia. PMID- 25919585 TI - Optimizing Telehealth Strategies for Subspecialty Care: Recommendations from Rural Pediatricians. AB - BACKGROUND: Telehealth offers strategies to improve access to subspecialty care for children in rural communities. Rural pediatrician experiences and preferences regarding the use of these telehealth strategies for children's subspecialty care needs are not known. We elicited rural pediatrician experiences and preferences regarding different pediatric subspecialty telehealth strategies. MATERIALS AND METHODS: Seventeen semistructured telephone interviews were conducted with rural pediatricians from 17 states within the United States. Interviewees were recruited by e-mails to a pediatric rural health listserv and to rural pediatricians identified through snowball sampling. Themes were identified through thematic analysis of interview transcripts. Institutional Review Board approval was obtained. RESULTS: Rural pediatricians identified several telehealth strategies to improve access to subspecialty care, including physician access hotlines, remote electronic medical record access, electronic messaging systems, live video telemedicine, and telehealth triage systems. Rural pediatricians provided recommendations for optimizing the utility of each of these strategies based on their experiences with different systems. Rural pediatricians preferred specific telehealth strategies for specific clinical contexts, resulting in a proposed framework describing the complementary role of different telehealth strategies for pediatric subspecialty care. Finally, rural pediatricians identified additional benefits associated with the use of telehealth strategies and described a desire for telehealth systems that enhanced (rather than replaced) personal relationships between rural pediatricians and subspecialists. CONCLUSIONS: Rural pediatricians described complementary roles for different subspecialty care telehealth strategies. Additionally, rural pediatricians provided recommendations for optimizing individual telehealth strategies. Input from rural pediatricians will be crucial for optimizing specific telehealth strategies and designing effective telehealth systems. PMID- 25919586 TI - Association between Fish Consumption and Prefrontal Function during a Cognitive Task in Male Japanese Workers: A Multi-Channel Near-Infrared Spectroscopy Study. AB - The purpose of this study was to examine the relationship between fish consumption and prefrontal function during a cognitive task in male Japanese workers. The study included 208 male workers who underwent medical health examinations 3 months after a change in their work assignment. We measured the hemoglobin concentration changes in the prefrontal region during working memory tasks using 52-channel near-infrared spectroscopy. The frequency of fish consumption was calculated on the basis of the subjects' self-reported customary intake frequency over the previous 3 months. A significant positive relationship was observed between fish consumption and left dorsolateral prefrontal function during a working memory task. To our knowledge, this is the first study to report an association between fish consumption and functional cortical activity with an ample sample size, suggesting that fish consumption modulates functional activity in the left dorsolateral prefrontal cortex. PMID- 25919587 TI - Vaccination against Bm86 Homologues in Rabbits Does Not Impair Ixodes ricinus Feeding or Oviposition. AB - Human tick-borne diseases that are transmitted by Ixodes ricinus, such as Lyme borreliosis and tick borne encephalitis, are on the rise in Europe. Diminishing I. ricinus populations in nature can reduce tick exposure to humans, and one way to do so is by developing an anti-vector vaccine against tick antigens. Currently, there is only one anti-vector vaccine available against ticks, which is a veterinary vaccine based on the tick antigen Bm86 in the gut of Rhipicephalus microplus. Bm86 vaccine formulations cause a reduction in the number of Rhipicephalus microplus ticks that successfully feed, i.e. lower engorgement weights and a decrease in the number of oviposited eggs. Furthermore, Bm86 vaccines reduce transmission of bovine Babesia spp. Previously two conserved Bm86 homologues in I. ricinus ticks, designated as Ir86-1 and Ir86-2, were described. Here we investigated the effect of a vaccine against recombinant Ir86 1, Ir86-2 or a combination of both on Ixodes ricinus feeding. Recombinant Ixodes ricinus Bm86 homologues were expressed in a Drosophila expression system and rabbits were immunized with rIr86-1, rIr86-2, a combination of both or ovalbumin as a control. Each animal was infested with 50 female adults and 50 male adults Ixodes ricinus and tick mortality, engorgement weights and egg mass were analyzed. Although serum IgG titers against rIr86 proteins were elicited, no effect was found on tick feeding between the rIr86 vaccinated animals and ovalbumin vaccinated animals. We conclude that vaccination against Bm86 homologues in Ixodes ricinus is not an effective approach to control Ixodes ricinus populations, despite the clear effects of Bm86 vaccination against Rhipicephalus microplus. PMID- 25919588 TI - Impact of acute malaria on pre-existing antibodies to viral and vaccine antigens in mice and humans. AB - Vaccine-induced immunity depends on long-lived plasma cells (LLPCs) that maintain antibody levels. A recent mouse study showed that Plasmodium chaubaudi infection reduced pre-existing influenza-specific antibodies--raising concerns that malaria may compromise pre-existing vaccine responses. We extended these findings to P. yoelii infection, observing decreases in antibodies to model antigens in inbred mice and to influenza in outbred mice, associated with LLPC depletion and increased susceptibility to influenza rechallenge. We investigated the implications of these findings in Malian children by measuring vaccine-specific IgG (tetanus, measles, hepatitis B) before and after the malaria-free 6-month dry season, 10 days after the first malaria episode of the malaria season, and after the subsequent dry season. On average, vaccine-specific IgG did not decrease following acute malaria. However, in some children malaria was associated with an accelerated decline in vaccine-specific IgG, underscoring the need to further investigate the impact of malaria on pre-existing vaccine-specific antibodies. PMID- 25919589 TI - Women's Health Fellowships: Examining the Potential Benefits and Harms of Accreditation. AB - This commentary responds to the assertions by Foreman et al. that credentialing of women's health (WH) fellows by the American Board of Medical Subspecialties and accreditation of current and future WH fellowships by the Accreditation Council for Graduate Medical Education would improve the health and healthcare of women by increasing the number of primary care providers competent to meet a growing clinical need. They speculate that such accreditation would raise the status of WH fellowships, increase the number of applicants, and result in more academic leaders in WH. They assert that curricular deficiencies in WH exist in physician training and that WH fellowships are the preferred means of training physicians to care for midlife women. We review the evidence to support or refute these claims and conclude that accrediting WH fellowships would not have the forecasted outcomes and would jeopardize the success of current WH fellowships. PMID- 25919590 TI - Consequences of a restrictive syringe exchange policy on utilisation patterns of a syringe exchange program in Baltimore, Maryland: Implications for HIV risk. AB - INTRODUCTION AND AIMS: Syringe distribution policies continue to be debated in many jurisdictions throughout the USA. The Baltimore Needle and Syringe Exchange Program (NSP) operated under a 1-for-1 syringe exchange policy from its inception in 1994 through 1999, when it implemented a restrictive policy (2000-2004) that dictated less than 1-for-1 exchange for non-program syringes. DESIGN AND METHODS: Data were derived from the Baltimore NSP, which prospectively collected data on all client visits. We examined the impact of this restrictive policy on program level output measures (i.e. distributed : returned syringe ratio, client volume) before, during and after the restrictive exchange policy. Through multiple logistic regression, we examined correlates of less than 1-for-1 exchange ratios at the client level before and during the restrictive exchange policy periods. RESULTS: During the restrictive policy period, the average annual program-level ratio of total syringes distributed : returned dropped from 0.99 to 0.88, with a low point of 0.85 in 2000. There were substantial decreases in the average number of syringes distributed, syringes returned, the total number of clients and new clients enrolling during the restrictive compared to the preceding period. During the restrictive period, 33 508 more syringes were returned to the needle exchange than were distributed. In the presence of other variables, correlates of less than 1-for-1 exchange ratio were being white, female and less than 30 years old. DISCUSSION AND CONCLUSIONS: With fewer clean syringes in circulation, restrictive policies could increase the risk of exposure to HIV among Injection Drug Users (IDUs) and the broader community. The study provides evidence to the potentially harmful effects of such policies. PMID- 25919591 TI - Dynamic Metabolic Profiles and Tissue-Specific Source Effects on the Metabolome of Developing Seeds of Brassica napus. AB - Canola (Brassica napus) is one of several important oil-producing crops, and the physiological processes, enzymes, and genes involved in oil synthesis in canola seeds have been well characterized. However, relatively little is known about the dynamic metabolic changes that occur during oil accumulation in seeds, as well as the mechanistic origins of metabolic changes. To explore the metabolic changes that occur during oil accumulation, we isolated metabolites from both seed and silique wall and identified and characterized them by using gas chromatography coupled with mass spectrometry (GC-MS). The results showed that a total of 443 metabolites were identified from four developmental stages. Dozens of these metabolites were differentially expressed during seed ripening, including 20 known to be involved in seed development. To investigate the contribution of tissue-specific carbon sources to the biosynthesis of these metabolites, we examined the metabolic changes of silique walls and seeds under three treatments: leaf-detachment (Ld), phloem-peeling (Pe), and selective silique darkening (Sd). Our study demonstrated that the oil content was independent of leaf photosynthesis and phloem transport during oil accumulation, but required the metabolic influx from the silique wall. Notably, Sd treatment resulted in seed senescence, which eventually led to a severe reduction of the oil content. Sd treatment also caused a significant accumulation of fatty acids (FA), organic acids and amino acids. Furthermore, an unexpected accumulation of sugar derivatives and organic acid was observed in the Pe- and Sd-treated seeds. Consistent with this, the expression of a subset of genes involved in FA metabolism, sugar and oil storage was significantly altered in Pe and Sd treated seeds. Taken together, our studies suggest the metabolite profiles of canola seeds dynamically varied during the course of oil accumulation, which may provide a new insight into the mechanisms of the oil accumulation at the metabolite level. PMID- 25919593 TI - Validity of the effort/reward imbalance questionnaire in health professionals from six Latin-American countries. AB - BACKGROUND: This study tests the validity and the invariance of ERI questionnaire (ERIQ) data from health professionals in six different Latin-American countries. METHODS: One thousand two hundred ninety-two (1292) participants who worked in hospitals in Argentina, Chile, Colombia, Mexico, Peru and Venezuela completed the ERI and GHQ questionnaires. Partial correlations were carried out as well as reliability statistics and confirmatory factor analyses to examine factor structure and invariance of ERIQ in each subsample. RESULTS: Overall confirmatory factor analyses confirmed the theoretical structure of the ERIQ. The effort and overcommitment scales were invariant (equivalent) across the six countries, but the reward scale was only partially invariant. Several associations between ERIQ and mental health remain significant after controlling for sociodemographic variables. CONCLUSIONS: Although the validity of the ERIQ' scales were generally satisfactory in most Latin-American samples, future research should examine in depth the equivalence of reward scale across Latin-American cultures. PMID- 25919592 TI - Applying personal genetic data to injury risk assessment in athletes. AB - Recent studies have identified genetic markers associated with risk for certain sports-related injuries and performance-related conditions, with the hope that these markers could be used by individual athletes to personalize their training and diet regimens. We found that we could greatly expand the knowledge base of sports genetic information by using published data originally found in health and disease studies. For example, the results from large genome-wide association studies for low bone mineral density in elderly women can be re-purposed for low bone mineral density in young endurance athletes. In total, we found 124 single nucleotide polymorphisms associated with: anterior cruciate ligament tear, Achilles tendon injury, low bone mineral density and stress fracture, osteoarthritis, vitamin/mineral deficiencies, and sickle cell trait. Of these single nucleotide polymorphisms, 91% have not previously been used in sports genetics. We conducted a pilot program on fourteen triathletes using this expanded knowledge base of genetic variants associated with sports injury. These athletes were genotyped and educated about how their individual genetic make-up affected their personal risk profile during an hour-long personal consultation. Overall, participants were favorable of the program, found it informative, and most acted upon their genetic results. This pilot program shows that recent genetic research provides valuable information to help reduce sports injuries and to optimize nutrition. There are many genetic studies for health and disease that can be mined to provide useful information to athletes about their individual risk for relevant injuries. PMID- 25919594 TI - Impedance Spectroscopy of Ionic Ligand-Modulated Charge Transport of Gold Nanoparticle Films. AB - Assembled monolayer-protected nanoparticles (NPs) possess unique electrical properties that are determined by the coupled effects of their nano-sized electroactive inorganic cores that are capable of donating and accepting electrons and the organic shells. Core and ligand engineering for NP conductance modulation has been extensively explored; however, most studies focus on electron transport and not the interplay between the ion and electron transport processes. It is demonstrated here that electronic- and ionic-conducting properties of nanoparticle assemblies can be controlled by engineering the charge and flexibility of the ligand shell. By using impedance spectroscopy, the electronic, mixed ionic and electronic, and responsive conductance of the nanoparticle film and structure-function correlation are systematically investigated, and this correlation is used to provide a prototype volatile gas sensor based on the combined ionic and electronic conductance behavior of ionic ligand-functionalized gold NPs. PMID- 25919595 TI - From the editors. PMID- 25919596 TI - Predatory publishing: what do perinatal and neonatal nurses need to know. PMID- 25919597 TI - Medication use during pregnancy and lactation: the new FDA drug labeling. PMID- 25919598 TI - Differentiating between research and quality improvement. PMID- 25919599 TI - Patient safety organizations. PMID- 25919600 TI - Internet resources. PMID- 25919601 TI - Crosswalk: the joint commission and centers for medicare and medicaid services pathway to patient safety and quality. AB - Perinatal nurses rely upon a myriad of resources in the course of providing care. Although not always appreciated by direct-care nurses, nurse managers, and administrators, regulatory and accrediting bodies exert a pervasive influence over the provision of care in almost every hospital in the United States. The Centers for Medicare and Medicaid Services (CMS), a federal agency, and The Joint Commission (TJC) offering voluntary accreditation programs for hospitals hold a primary goal in common. They both aim to protect the health and safety of patients and improve the quality of hospital care. To further that aim, TJC has published a matrix, the "TJC-CMS Crosswalk." The "Crosswalk" provides a visual illustration of the alignment between TJC hospital accreditation standards and the CMS "Conditions of Participation for Hospitals in Medicare." This article defines the Conditions of Participation and associated Joint Commission Standards. A secondary goal is to explain the collaborative role of TJC in hospital certification for reimbursement in Medicare and its impact on hospital based practice, perinatal education, and performance improvement activities. PMID- 25919602 TI - Navigating the perinatal quality landscape. AB - The National Quality Strategy, mandated by the Affordable Care Act, outlines the triple aim of better health, better care, and lower costs. Perinatal nurses are integral to the National Quality movement as care providers, leaders, and experts. The most notable accomplishments in perinatal care of the last decade relate to the endorsement of quality measures by the National Quality Forum that provide unified goals and the quality improvement frameworks provided by the Institute for Healthcare Improvement that help systems create action and change through education, team building, process improvement, and structure. Fourteen perinatal quality measures are currently endorsed by the National Quality Forum, 5 of which are mandated by The Joint Commission and required for accreditation. Understanding the current perinatal quality measures and the resources available for implementation is essential to nursing care delivery. Realizing the nurses' role within the quality improvement landscape and mobilizing nationally endorsed quality measures as levers for nurse-led improvement projects promise actualization of marked quality improvement in perinatal care. PMID- 25919603 TI - Patient safety during induction of labor. AB - Rates of induction of labor have risen rapidly since 1990, from 9.6% in that year to a peak of 23.8% of the 2010 singleton births in the United States. Even as the definition of term pregnancy has been refined to reflect the continuing maturation needs of the fetus, and mothers have been encouraged to "go the full forty," management strategies for pregnancy conditions that increase risk have included early induction. Labor induction should only be undertaken when there are specific indications for interrupting the normal processes of pregnancy. These indications may relate to maternal, fetal, or placental conditions or simply reflect the understanding that in all pregnancies, the placenta will eventually lose its ability to adequately provide oxygen, nutrition, and waste removal for the fetus. Patient safety-for both the mother and the child-can be improved when clinicians practice within clinical guidelines that follow the best available evidence and women are able to make informed decisions regarding plans for labor. PMID- 25919604 TI - REACT: An Interprofessional Education and Safety Program to Recognize and Manage the Compromised Obstetric Patient. AB - In recent years, there has been an increase in the number of pregnancies complicated by preexisting medical conditions as well as an increase in maternal morbidity and mortality in the United States. The goal of the REACT quality and safety initiative was to reduce maternal morbidity and mortality by providing an interprofessional education program for recognizing and managing the woman who becomes compromised during pregnancy, childbirth, or the puerperium. REACT is an acronym for Recognize, Educate, Activate, Communicate, and Treat early signs and symptoms of maternal compromise. Early signs and symptoms of maternal compromise outlined in the REACT program are similar to recently published recommendations by the American College of Obstetricians and Gynecologists, the Centers for Disease Control and Prevention, the Society for Maternal-Fetal Medicine, the Health Resources and Services Administration, the Association of Women's Health, Obstetric and Neonatal Nurses, and the American College of Nurse-Midwives. PMID- 25919605 TI - Following the evidence: enteral tube placement and verification in neonates and young children. AB - Enteral tube placement in hospitalized neonates and young children is a common occurrence. Accurate placement and verification are imperative for patient safety. However, despite many years of research that provides evidence for a select few methods and clearly discredits the safety of others, significant variation in clinical practice is still common. Universal adoption and implementation of evidence-based practices for enteral tube placement and verification are necessary to ensure consistency and safety of all patients. This integrative review synthesizes current and seminal literature regarding the most accurate enteral tube placement and verification methods and proposes clinical practice recommendations. PMID- 25919606 TI - Human Factors in the NICU: A Bedside Nurse Perspective. AB - Human factors have been identified as the most frequent cause of and contributory factor to sentinel events. Many human factor errors are preventable, and neonatal nurses are instrumental at the point of care in working with system leaders to identify various problems and potentially safe practices that can be hardwired into daily practice. This article defines human factors that often occur in daily processes of care in many neonatal intensive care units (NICU) and specific evidence-based strategies to implement to reduce preventable human errors. Human factor evidence from other high-risk industries is relevant to healthcare and can be applied to the complex adaptive environment of the NICU. Nurses need to be mindful of their complex environment and to have a basic understanding of the role of human factors principles. PMID- 25919607 TI - The Journey to High Reliability in the NICU. AB - Neonatal intensive care units (NICUs) are at high risk for medical errors due to the population, setting, and complexity of care. Furthermore, "near misses" often precede actual errors yet are mostly underreported and unrecognized as safety concerns. There is a growing recognition that a systems approach to quality and safety is foundational to improving care at the bedside and patient outcomes. The High Reliability Organization model is one such approach. It recognizes the challenges of a highly complex system and combines this recognition with a continual emphasis on reducing errors. Although the principles of the High Reliability Organization hold promise in accelerating quality and safety in the NICU, it is imperative that nurses at the bedside as well as nurse leaders actually learn how to operationalize high reliability principles and strategies that lead to better outcomes. This article outlines the necessary principles, culture, strategies, and behaviors that NICU nurses and nurse leaders must adopt to achieve high reliability in their units. PMID- 25919608 TI - Interdisciplinary teamwork and the power of a quality improvement collaborative in tertiary neonatal intensive care units. AB - Significant gaps in healthcare quality and outcomes can be reduced via quality improvement collaboratives (QICs), which improve care by leveraging data and experience from multiple organizations.The Children's Hospital Neonatal Consortium Collaborative Initiatives for Quality Improvement team developed an infrastructure for neonatal QICs. We describe the structure and components of an effective multi-institutional neonatal QIC that implemented the "SLUG Bug" project designed to reduce central line-associated bloodstream infections (CLABSIs).The operational infrastructure of SLUG Bug involved 17 tertiary care neonatal intensive care units with a goal to reduce CLABSI in high-risk neonates. Clinical Practice Recommendations were produced, and the Institute of Healthcare Improvement Breakthrough Series provided the framework for the collaborative. Process measures studied the effectiveness of the collaborative structure.CLABSI rates decreased by 20% during a 12-month study period. Compliance bundle reporting exceeded 80%. A QIC score of 2.5 or more ("improvement") was achieved by 94% of centers and a score 4 or more ("significant improvement") was achieved by 35%.Frequent interactive project meetings, well-defined project metrics, continual shared learning opportunities, and individual team coaching were key QIC success components. Through a coordinated approach and committed leadership, QICs can effectively implement change and improve the care of neonates with complex diagnoses and rare diseases. PMID- 25919609 TI - On mentoring. PMID- 25919612 TI - Economic evaluation of DNA ploidy analysis vs liquid-based cytology for cervical screening. AB - BACKGROUND: DNA ploidy analysis involves automated quantification of chromosomal aneuploidy, a potential marker of progression toward cervical carcinoma. We evaluated the cost-effectiveness of this method for cervical screening, comparing five ploidy strategies (using different numbers of aneuploid cells as cut points) with liquid-based Papanicolaou smear and no screening. METHODS: A state transition Markov model simulated the natural history of HPV infection and possible progression into cervical neoplasia in a cohort of 12-year-old females. The analysis evaluated cost in 2012 US$ and effectiveness in quality-adjusted life-years (QALYs) from a health-system perspective throughout a lifetime horizon in the US setting. We calculated incremental cost-effectiveness ratios (ICERs) to determine the best strategy. The robustness of optimal choices was examined in deterministic and probabilistic sensitivity analyses. RESULTS: In the base-case analysis, the ploidy 4 cell strategy was cost-effective, yielding an increase of 0.032 QALY and an ICER of $18 264/QALY compared to no screening. For most scenarios in the deterministic sensitivity analysis, the ploidy 4 cell strategy was the only cost-effective strategy. Cost-effectiveness acceptability curves showed that this strategy was more likely to be cost-effective than the Papanicolaou smear. CONCLUSION: Compared to the liquid-based Papanicolaou smear, screening with a DNA ploidy strategy appeared less costly and comparably effective. PMID- 25919613 TI - The functional interplay between the t(9;22)-associated fusion proteins BCR/ABL and ABL/BCR in Philadelphia chromosome-positive acute lymphatic leukemia. AB - The hallmark of Philadelphia chromosome positive (Ph(+)) leukemia is the BCR/ABL kinase, which is successfully targeted by selective ATP competitors. However, inhibition of BCR/ABL alone is unable to eradicate Ph(+) leukemia. The t(9;22) is a reciprocal translocation which encodes not only for the der22 (Philadelphia chromosome) related BCR/ABL, but also for der9 related ABL/BCR fusion proteins, which can be detected in 65% of patients with chronic myeloid leukemia (CML) and 100% of patients with Ph+ acute lymphatic leukemia (ALL). ABL/BCRs are oncogenes able to influence the lineage commitment of hematopoietic progenitors. Aim of this study was to further disclose the role of p96(ABL/BCR) for the pathogenesis of Ph(+) ALL. The co-expression of p96(ABL/BCR) enhanced the kinase activity and as a consequence, the transformation potential of p185(BCR/ABL). Targeting p96(ABL/BCR) by RNAi inhibited growth of Ph(+) ALL cell lines and Ph(+) ALL patient-derived long-term cultures (PD-LTCs). Our in vitro and in vivo stem cell studies further revealed a functional hierarchy of p96(ABL/BCR) and p185(BCR/AB)L in hematopoietic stem cells. Co-expression of p96(ABL/BCR) abolished the capacity of p185(BCR/ABL) to induce a CML-like disease and led to the induction of ALL. Taken together our here presented data reveal an important role of p96(ABL/BCR) for the pathogenesis of Ph(+) ALL. PMID- 25919614 TI - Hybrid De Novo Genome Assembly Using MiSeq and SOLiD Short Read Data. AB - A hybrid de novo assembly pipeline was constructed to utilize both MiSeq and SOLiD short read data in combination in the assembly. The short read data were converted to a standard format of the pipeline, and were supplied to the pipeline components such as ABySS and SOAPdenovo. The assembly pipeline proceeded through several stages, and either MiSeq paired-end data, SOLiD mate-paired data, or both of them could be specified as input data at each stage separately. The pipeline was examined on the filamentous fungus Aspergillus oryzae RIB40, by aligning the assembly results against the reference sequences. Using both the MiSeq and the SOLiD data in the hybrid assembly, the alignment length was improved by a factor of 3 to 8, compared with the assemblies using either one of the data types. The number of the reproduced gene cluster regions encoding secondary metabolite biosyntheses (SMB) was also improved by the hybrid assemblies. These results imply that the MiSeq data with long read length are essential to construct accurate nucleotide sequences, while the SOLiD mate-paired reads with long insertion length enhance long-range arrangements of the sequences. The pipeline was also tested on the actinomycete Streptomyces avermitilis MA-4680, whose gene is known to have high-GC content. Although the quality of the SOLiD reads was too low to perform any meaningful assemblies by themselves, the alignment length to the reference was improved by a factor of 2, compared with the assembly using only the MiSeq data. PMID- 25919615 TI - Extractive microbial fermentation in cloud point system. AB - Extractive microbial fermentation of organic compounds in liquid-liquid two-phase systems is a potential strategy to overcome the limitations of microbial fermentation in an aqueous solution, such as low substrate solubility, substrate/product inhibition and product further degradation. A conventional aqueous-organic solvent two-phase system is inaccessible to extractive fermentation of a relatively high polar bioproduct as the confliction between the biocompatibility and the extraction ability of the corresponding organic solvent. An exploitation of cloud point system as a novel medium engineering method for extractive microbial fermentation is reviewed in present work. The relationship between phase separation of nonionic surfactant aqueous solution forming cloud point system and its corresponding biocompatibility to microorganisms, and the relationship between solubilization and bioavailability of organic compounds in a cloud point system are discussed. Paradigms of extractive microbial fermentation in cloud point system are highlighted with some cases in our lab. The downstream processing for nonionic surfactant recovery and product separation with microemulsion extraction is also presented. PMID- 25919616 TI - Lipase-catalyzed acidolysis of tripalmitin with capric acid in organic solvent medium: Analysis of the effect of experimental conditions through factorial design and analysis of multiple responses. AB - The acidolysis of tripalmitin with capric acid catalyzed by an immobilized form of a 1,3-positionally selective lipase (Rhizomucor miehei) showed to be effective for the synthesis of structured lipids of the MLL and MLM type. The effects that reaction parameters such as substrate molar ratio (N), biocatalyst load (E), and reaction temperature (T) have on selected responses variables (i.e. total conversion of tripalmitin, selectivity and yield of the desired structured lipid, hydrolysis yield, and acyl migration importance), were evaluated by use of an experimental factorial design of three factors and three levels with two central points and with a confidence level of 95%. The range of each parameter was selected as follows: N=3-9, E=5-15wt%, T=50-70 degrees C. The statistical analysis of results was addressed by use of both simple linear models and more complicated quadratic models using specific commercial software. The results obtained showed that a proper selection of reaction conditions is needed in order to maximize not only the yield of the desired structured lipid, but also to minimize the generation of hydrolysis and acyl migration by-products. PMID- 25919617 TI - Chemical modification and immobilisation of laccase from Trametes hirsuta and from Myceliophthora thermophila. AB - Laccase from two different source organisms, Myceliophthora thermophila and Trametes hirsuta, were subjected to chemical modification in solution by (i) two bifunctional reagents, ethylene-glycol-N-hydroxy succinimide (EGNHS) and glutaraldehyde and (ii) by the monofunctional citraconic anhydride. The untreated and chemically modified forms of both enzymes were then immobilised onto three different types of mesoporous silicate (MPS) particle (MCM, CNS and SBA-15). Thermal stabilities of native, modified-soluble and immobilised laccases were then evaluated. Although the two laccases have similar lysine contents, those of M. thermophila are clearly more amenable to chemical modification. Treatment of the M. thermophila enzyme with EGNHS led to a 8.7-fold increase in thermal stability over the free soluble enzyme while glutaraldehyde gave a 5.7-fold increase. Increased activity of M. thermophila laccase occurred only with citraconic anhydride modification (a 3-fold increase), while the glutaraldehyde modification marginally increased the activity of the T. hirsuta enzyme (by 1.2 fold). Upon immobilisation onto MPS, the greatest increase in stability was for the glutaraldehyde-treated M. thermophila preparation on SBA-15 (24-fold over the soluble enzyme). Chemical modification of laccase from T. hirsuta with both glutaraldehyde and EGNHS gave only a 2-fold increase in stability, increasing >4 fold upon immobilisation onto SBA-15 and MCM-41/98. PMID- 25919618 TI - Hydrolysis of casein catalyzed by papain in n-propanol/NaCl two-phase system. AB - Enzymatic hydrolysis of casein to produce free amino acids by papain was performed in a kind of novel two-phase system, which was composed of n-propanol, NaCl and water. The phase diagram of the two-phase system was plotted. In this system, top phase contained more n-propanol and bottom phase contained more NaCl and water. Papain and casein were mainly distributed in bottom phase, and free aromatic amino acids (tyrosine, tryptophan and phenylalanine) produced by enzymatic hydrolysis were mainly in top phase. When the two-phase system consisted of 44% n-propanol, 60g/l NaCl, 0.15g/l papain and 13g/l casein at 55 degrees C and pH 5.6, the transformation yield was 99.5%, which was higher than those of n-propanol/water single phase, aqueous single phase, n-hexane/water two phase system and PEG/phosphate two-phase system. The novel two-phase system is practically applicable to some enzymatic reaction, if the substrates and products have different partition coefficients. PMID- 25919619 TI - Isolation and characterization of a beta-glucosidase from Penicillium decumbens and improving hydrolysis of corncob residue by using it as cellulase supplementation. AB - A beta-glucosidase from Penicillium decumbens was purified and characterized. The enzyme presented as a single band of 120kDa on SDS-PAGE, showed optimal temperature of 65-70 degrees C and optimal pH of 4.5-5.0. The beta-glucosidase showed relatively higher affinity to pNPG and the highest affinity to salicin with the Km value as 0.0064 and 0.0188mM, respectively. The gene coding for it was obtained with an ORF of 2586bp coding for 861 amino acids belonging to glycoside hydrolases family 3. The purified enzyme could improve the saccharifying ability of cellulose when it was added to the cellulase systems of Trichoderma reesei QM 9414. The several properties of it, including its pH and temperature optima, the high affinity to substrates and high specific activity, make it has great potential to be utilized as supplementation in conversion of corncob residue and other lignocellulosic biomass into simple sugars. PMID- 25919620 TI - Electricity generation from carbon monoxide in a single chamber microbial fuel cell. AB - Electricity production from carbon monoxide (CO) is demonstrated in a single chamber microbial fuel cell (MFC) with a CoTMPP-based air cathode. The MFC was inoculated with anaerobic sludge and continuously sparged with CO as a sole carbon source. Volumetric power output was maximized at a CO flow rate of 4.8LLR( 1)d(-1) reaching 6.4mWLR(-1). Several soluble and gaseous degradation products including hydrogen, methane, and acetate were detected, resulting in a relatively low apparent Coulombic efficiency of 8.7%. Tests also demonstrated electricity production from hydrogen and acetate with the highest and fastest increase in voltage exhibited after acetate injection. It is hypothesized that electricity generation in a CO-fed MFC is accomplished by a consortium of carboxydotrophic and carbon monoxide - tolerant anodophilic microorganisms. PMID- 25919621 TI - Hydroxynitrile lyase from Passiflora edulis: Purification, characteristics and application in asymmetric synthesis of (R)-mandelonitrile. AB - A hydroxynitrile lyase from leaves of Passiflora edulis (PeHNL) was purified and characterized for the first time. The enzyme is a monomer of 15kDa and 18kDa by SDS-PAGE, and gel filtration, respectively. Asymmetric synthesis of (R) mandelonitrile from benzaldehyde and acetone cyanohydrin in a biphasic system employing the PeHNL from rinds of P. edulis was carried out. Several parameters influenced the enantiomeric purity of the product and initial velocity of the reaction. Both pH and temperature were important parameters controlling the enantiomeric purity of the product. The optimum pH and temperature were pH 4 and 10 degrees C, respectively. At the optimum pH and temperature, the spontaneous non-enzymatic reaction yielding the racemic mandelonitrile was almost completely suppressed. The PeHNL was stable (more than 80% residual activity after incubation for 12h) in the system of methyl-t-butyl ether (MTBE), dibutyl ether (DBE), hexane (HEX), and diisopropyl ether (DIPE) while diethyl ether (DEE) and ethyl acetate (EA) were not suitable solvents. The initial velocity was markedly affected by the type of organic solvent in the biphasic system, while high enantiomeric purity was obtained when organic solvents having logP lower than 3.5 were used. The highest initial velocity of reaction and enantiomeric purity of (R)-mandelonitrile were obtained in the biphasic system of DBE with the aqueous phase content of 30% (v/v). The optimum substrate concentrations were 250mM for benzaldehyde and 900mM for acetone cyanohydrin, and the optimum enzyme concentration was 26.7units/ml. The highest enantiomeric purity of (R) mandelonitrile was successfully obtained with conversion and enantiomeric excess of 31.6% and 98.6%, respectively. The enzyme showed considerable reusability in batch reaction with high enantiomeric purity of product. Herein, we reported the characteristics of a unique (R)-PeHNL from leaves of P. edulis. The PeHNL from rinds had been isolated for the first time and the enzyme showed great ability in transcyanation of (R)-mandelonitrile with high e.e. in DBE as the co-organic solvent in a biphasic system. PMID- 25919622 TI - Effects of light intensity and light wavelength on the production of mycophenolic acid by Penicillium brevicompactum in batch cultures. AB - The influence of different light sources and light intensity on mycophenolic acid (MPA) by Penicillium brevicompactum in batch culture was significant and demonstrated in this study. MPA batch cultures under various light sources including fluorescent light, red LED light (630nm) and blue LED light (470nm), were investigated in a light controlled photo-bioreactor. Results of cultures under fluorescent light indicated that optimal maximum cell density and maximum MPA concentration (Pmax) achieved at 1400lux were 9.40 and 0.48gL(-1), respectively. Results of culture under LED lights indicated that the optimal culture condition for cell growth was red LED light at 600lux with cell yield, 0.88gg(-1), while that for MPA formation was blue LED light at 600lux with specific product yield, 0.056gg(-1). Red LED light stimulated both cell growth and MPA formation; however, blue LED light inhibited cell growth but stimulated MPA formation. A novel two-stage LED light process has been successfully demonstrated to optimize MPA fermentation of P. brevicompactum, and the highest Pmax of 0.56gL(-1) was achieved with 87% improvement as compared with that of the batch in the dark. PMID- 25919623 TI - Enzymatic properties and expression patterns of five extracellular lipases of Fusarium graminearum in vitro. AB - Fusarium graminearum is a filamentous fungus that causes devastating diseases on plants of economic importance including maize, wheat, and barley. F. graminearum is able to utilize triglycerides as a carbon source during growth. Extracellular lipases are the preferred enzymes to catalyze the hydrolysis of fats and oils. Lipases are ubiquitous enzymes of considerable physiological significance and industrial potential. Previously, FGL1 was the first described F. graminearum extracellular lipase associated with virulence. We report the biochemical characterization of FGL1 and four new secreted lipases of F. graminearum. The lipase genes of F. graminearum wild-type strain 8/1 were sequenced, cloned and over-expressed in Pichia pastoris. We show that the lipases have their temperature optimum between 30 and 40 degrees C and a pH optimum of ~7. A broad range of lipase substrates, from C4 to C18 p-nitrophenyl esters, were hydrolyzed efficiently by the lipases, indicating the true lipolytic activity of the enzymes. Expression patterns of these lipases were also analyzed by semiquantitative RT-PCR in F. graminearum cultured in water supplemented with 2% (v/v) wheat germ oil at 28 degrees C. Transcripts of all examined lipases are detectable and the genes are regulated differently under these culture conditions. Our data indicated that F. graminearum possesses a ubiquitous source of secreted lipases, which could be used for industrial intentions. We also provided the foundation of lipase expression in vitro, which is necessary for further characterization. PMID- 25919624 TI - Investigating antimicrobial activity in Rheinheimera sp. due to hydrogen peroxide generated by l-lysine oxidase activity. AB - A greenish yellow pigmented bacterial strain, designated GR5, was recently isolated from a freshwater culture pond for a soft-shell turtle. Phylogenetic analyses based on 16S rRNA gene sequences indicate that strain GR5 belongs to the genus Rheinheimera and its only closest neighbor is the type strain of Rheinheimera texasensis (98.2%). Based on the antibiogram assay, strain GR5 possesses a broad spectrum of antimicrobial activity including Gram-positive and Gram-negative bacteria, yeast, algae, and strain GR5 itself. Strain GR5 can synthesize a macromolecule with antimicrobial activity due to the generation of hydrogen peroxide and this antimicrobial effect can be inhibited by catalase. This antimicrobial activity is active only in complex culture media or chemically defined culture media containing l-lysine. This antimicrobial macromolecule in strain GR5 is shown to be a monomeric protein with a molecular mass of 71kDa and isoelectric point of approximately 3.68. Liquid chromatography-tandem mass spectrometry analyses reveal close similarity of a 19-amino acid fragment derived from this protein to the antibacterial protein, AlpP from the marine bacterium Pseudoalteromonas tunicata D2, and to the antibacterial protein, marinocine, from the marine bacterium Marinomonas mediterranea. This study explores the nature of antimicrobial macromolecule such as l-lysine oxidase. This is the first report on a freshwater bacterium producing antimicrobial activity by generating hydrogen peroxide through its enzymatic activity of l-lysine oxidase. PMID- 25919625 TI - Optimization of the heterologous production of a Rhizopus oryzae lipase in Pichia pastoris system using mixed substrates on controlled fed-batch bioprocess. AB - In this work a systematic study of the influence of methanol set-point and sorbitol feeding rate in fed-batch operation with a Pichia pastoris Mut(s) strain producing Rhizopus oryzae lipase is presented. Different experiments were made at a constant methanol set-point of 0.5, 2 and 4gl(-1), controlled by a predictive algorithm at two different sorbitol feeding rates to assure a constant specific growth rate of 0.01 and 0.02h(-1), by means of a pre-programmed exponential feeding rate strategy. Lipolytic activity, yields, productivity and specific productivity, but also specific growth, consumption and production rates were analyzed showing that the best values were reached when the methanol set-point was 2gl(-1) with a low influence of the constant specific growth rate tested. The sorbitol addition as a co-substrate during the induction phase avoids the severe decrease of the specific production rate obtained when methanol was used as a sole carbon source and it permits to achieve higher ROL production. PMID- 25919626 TI - Biological synthesis of platinum nanoparticles: Effect of initial metal concentration. AB - The unusual and novel properties of metal nanoparticles are highly sought after in a number of new and existing industries. Current chemical methods of nanoparticle synthesis have shown limited success and it is expected that the use of a biological approach may overcome many of these obstacles. The exploitation of microorganisms for the biosynthesis of metal nanoparticles is an area of research that has received increasing interest over the last decade. The use of living microbes as a tool for nanoparticle biosynthesis has been researched extensively, however the use of the cellular extract within the cells, excluding the living organism as a whole, has not received much attention. In this investigation, the cell-free, cell-soluble protein extract from a consortium of sulfate-reducing bacteria was used successfully in the biosynthesis of geometric Pt(0) nanoparticles, where previously, whole cells from the same culture had only resulted in amorphous Pt(0) deposits. It appears that by removing the spatial restrictions imposed by the cell itself, nanoparticles could form. It was also found that by altering the ratio of Pt(IV) to protein concentration in solution, a variety of particle morphologies resulted. PMID- 25919627 TI - A xylanase with broad pH and temperature adaptability from Streptomyces megasporus DSM 41476, and its potential application in brewing industry. AB - A xylanase gene, xynAM6, was isolated from the genomic DNA library of Streptomyces megasporus DSM 41476 using colony PCR screening method. The 1440-bp full-length gene encodes a 479-amino acid peptide consisting of a putative signal peptide of 36 residues, a family 10 glycoside hydrolase domain and a family 2 carbohydrate-binding module. The mature peptide of xynAM6 was successfully expressed in Pichia pastoris GS115. The optimal pH and temperature were pH 5.5 and 70 degrees C, respectively. The enzyme showed broad temperature adaptability (>60% of the maximum activity at 50-80 degrees C), had good thermostability at 60 degrees C and 70 degrees C, remained stable at pH 4.0-11.0, and was resistant to most proteases. The Km and Vmax values for oat spelt xylan were 1.68mgml(-1) and 436.76MUmolmin(-1)mg(-1), respectively, and 2.33mgml(-1) and 406.93MUmolmin( 1)mg(-1) for birchwood xylan, respectively. The hydrolysis products of XYNAM6 were mainly xylose and xylobiose. Addition of XYNAM6 (80U) to the brewery mash significantly reduced the filtration rate and viscosity by 36.33% and 35.51%, respectively. These favorable properties probably make XYNAM6 a good candidate for application in brewing industry. PMID- 25919628 TI - Enzyme-catalyzed production of 1-glyceryl benzoate in compressed n-butane. AB - The aim of this work is to report the enzymatic transesterification production of 1-glyceryl benzoate in compressed n-butane, using a commercial immobilized lipase, Novozym 435. For this purpose, reaction experiments were performed on the basis of phase equilibrium data of the system methyl benzoate/n-butane, measured using the static synthetic method with a variable-volume view cell in the temperature range of 313.15-343.15K and pressures up to 12MPa, in the entire compositional range of n-butane. Results indicate the existence of a relatively complex phase behavior for all temperatures investigated with the occurrence of vapor-liquid and liquid-liquid phase transitions. Reaction results showed that the strategy adopted for the experimental design proved to be useful in optimizing the reaction conversion in pressurized n-butane and Novozym 435. The optimum conditions were found to be 5.5wt% of enzyme, methyl benzoate to glycerol molar ratio of 3:1, 50 degrees C and 6h of reaction, affording about 6% of 1 glyceryl benzoate yield. PMID- 25919629 TI - Formation, physical characteristics and microbial community structure of aerobic granules in a pilot-scale sequencing batch reactor for real wastewater treatment. AB - In this study, aerobic granular sludge was successfully developed in a pilot scale sequencing batch reactor (SBR) installed on site to treat real wastewater using traditional activated sludge as inoculum. Compared with 1 or 2 months required by lab-scale reactor for aerobic granulation, it took about 400 days for activated sludge to transform into granule-dominant sludge in the pilot-scale SBR on site. Although the sludge in the reactor after 400-day operation was a mixture of flocs and granules with floc ratio ranged from 5 to 30%, sludge volume index with 5min settling (SVI5) always maintained at around 30mL/g. The similar microbial community structures represented by denaturing gradient gel electrophoresis (DGGE) between coexisted flocs and granules in the reactor indicated no strong microbial selection after the granules were dominant in the reactor. Chemical oxygen demand (COD) and NH4(+)-N removal efficiencies were above 80 and 98%, respectively, after 50-day operation, and the total inorganic N removal efficiency was about 50%. The results in this study demonstrate that it is feasible to form aerobic granules in pilot-scale SBR reactor and maintain the long-term stability of granular sludge with a high influent quality fluctuation. Meanwhile, stable COD and NH4(+)-N removal efficiencies can be obtained in the reactor. PMID- 25919630 TI - Optimization of sodium dedecyl sulfate (SDS) addition coupled with adenosine triphosphate (ATP) regeneration for glutathione overproduction in high density cultivation of Candida utilis. AB - In the previous study, glutathione production was elevated by adding precursor amino acids and adenosine triphosphate (ATP) in high cell density cultivation of Candida utilis. Furthermore, in the present research, glutathione production was further improved by optimizing sodium dedecyl sulfate (SDS) addition coupled with ATP regeneration. Results indicated that with 2g/l ATP added at 60h and 0.8g/l SDS added repeatedly at 60, 63, 66 and 69h, final glutathione yield reached 2286mg/l after 72h cultivation. Moreover, by applying the novel strategies of regenerating ATP by feeding glucose at 6g/(lh) from 60 to 72h coupled with impulse SDS treatments, a total glutathione yield of 2485mg/l was achieved at 72h, which was 8.7% higher than with addition of ATP and SDS, suggesting application of the proposed strategies as being feasible for glutathione overproduction on industrial scales. PMID- 25919631 TI - Copper inducing effect on laccase production of white rot fungi native from Misiones (Argentina). AB - Fungi may be selected as models for gene expression studies and further adaptation for biotechnological enzyme production. The aim of this work was to evaluate laccase production and to analyze the effect of Cu(2+) on selected fungi natives of Misiones, Ganoderma applanatum (strain F), Peniophora sp. (BAFC 633), Pycnoporus sanguineus (BAFC 2126) and Coriolus versicolor f. antarcticus (BAFC 266). Fungi secretion system of G. applanatum, Peniophora sp., P. sanguineus and C. versicolor f. antarcticus is sensitive to stimulation by copper. Biomass values of G. applanatum, Peniophora sp. and C. versicolor f. antarcticus did not show differences between treatments. P. sanguineus biomass underwent a dramatic growth inhibition with 1mM Cu(2+) and marked delay in growth with 0.5mM Cu(2+). Proteins were increased with copper in Peniophora sp., C. versicolor and G. applanatum. G. applanatum and Peniophora sp. reached the highest enzyme activity at 10th day equivalent to 49.2-fold and 19.7-fold higher than the control samples, respectively. Copper produced an increase of constitutive laccases in all fungi and an additional inducible isoenzyme in Peniophora sp., C. versicolor f. antarcticus and G. applanatum. PMID- 25919632 TI - Pathway for Biodegrading Microcystin-YR by Sphingopyxis sp. USTB-05. AB - Harmful cyanobacterial blooms in waters have become a global environmental problem, this mainly due to the production and release of various microalgal toxins, in which microcystins (MCs) are distributed widely. Here, we focused on the study of a typical form of microcystins called microcystin-YR (MC-YR). It was found that initial 14.8 mg/L of MC-YR could be completely eliminated within 10 hr by the crude enzymes (CEs) of Sphingopyxis sp. USTB-05, a promising bacterial strain we isolated and identified in our previous study. During the enzymatic biodegradation of MC-YR with time course, the peaks of two intermediate and two final products were observed on the profiles of HPLC at the wavelengths of 238 nm and 230 nm, respectively. Based on the analysis of m/z ratios of MC-YR and its four products by LC-MS/MS, we suggested that at least four enzymes were involved in the biodegradation of MC-YR by Sphingopyxis sp. USTB-05. The first enzyme microcystinase converted cyclic MC-YR to linear MC-YR as the first product. Then the second enzyme serine protease was found to cleave the target peptide bond between alanine (Ala) and tyrosine (Tyr) of linearized MC-YR, producing a tetrapeptide and a tripeptide as second products, which were Adda-Glu-Mdha-Ala and Tyr-Masp-Arg, respectively. Next, the third enzyme peptidase converted the tetrapeptide of Adda-Glu-Mdha-Ala to Adda. And the fourth enzyme cleaved the tripeptide of Tyr-Masp-Arg to produce Tyr and dipeptide (Masp-Arg), which has never been reported. These findings will help us better understand the biodegradation pathway of MC-YR by Sphingopyxis sp. USTB-05. PMID- 25919633 TI - Hardness Alternation in alpha,omega-Alkanedicarboxylic Acids. AB - The variation of hardness as a function of the number of carbon atoms in alpha,omega-alkanedicarboxylic acids, C(N)H(2N-2)O4 (4<=N<=9), was examined by recourse to nanoindentation on the major faces of single crystals. Hardness exhibits odd-even alternation, with the odd acids being softer and the even ones harder; the differences decrease with increasing chain length. These variations are similar to those seen for other mechanical, physical, and thermal properties of these diacids. The softness of odd acids is rationalized due to strained molecular conformations in them, which facilitate easier plastic deformation. Relationships between structural features, such as interplanar spacing, interlayer separation distance, molecular chain length, and signatures of the nanoindentation responses, namely, discrete displacement bursts, were also examined. Shear sliding of molecular layers past each other during indentation is key to the mechanism for plastic deformation in these organic crystals. PMID- 25919635 TI - Apolipoprotein E genotype modulates effects of vitamin B12 and homocysteine on grey matter volume in Alzheimer's disease. AB - AIMS: The aim of the present study was to investigate whether the effects of vitamin B12 and homocysteine on brain volume are influenced by apolipoprotein E (APOE) genotype. We examined the effects in each subgroup (APOE epsilon4 carriers and non-carriers) of Alzheimer's disease (AD) patients and healthy normal controls. METHODS: Forty participants with AD and 20 healthy normal controls were recruited from memory impairment clinics at Pusan National University Hospital in Korea. All participants were APOE genotyped and underwent magnetic resonance imaging, including 3-D volumetric images for grey matter (GM) volume. A multiple regression model integrated into statistical parametric mapping was used to see if there was any correlation between vitamin B12 or homocysteine and GM volume in each subgroup (APOE epsilon4 carriers and non-carriers) of AD patients and healthy normal controls. RESULTS: There was a significant positive correlation between serum concentrations of vitamin B12 and regional GM volume in APOE epsilon4 carriers with AD but not in non-carriers. We also found that there was a significant negative correlation between serum concentrations of homocysteine and regional GM volume in APOE epsilon4 non-carriers with AD but not in carriers (P < 0.001, uncorrected for multiple comparisons; extent threshold = 100 voxel). CONCLUSION: The present findings suggest that the effects of vitamin B12 and homocysteine on GM volume might be influenced by APOE genotype. PMID- 25919634 TI - A Complete Pathway Model for Lipid A Biosynthesis in Escherichia coli. AB - Lipid A is a highly conserved component of lipopolysaccharide (LPS), itself a major component of the outer membrane of Gram-negative bacteria. Lipid A is essential to cells and elicits a strong immune response from humans and other animals. We developed a quantitative model of the nine enzyme-catalyzed steps of Escherichia coli lipid A biosynthesis, drawing parameters from the experimental literature. This model accounts for biosynthesis regulation, which occurs through regulated degradation of the LpxC and WaaA (also called KdtA) enzymes. The LpxC degradation signal appears to arise from the lipid A disaccharide concentration, which we deduced from prior results, model results, and new LpxK overexpression results. The model agrees reasonably well with many experimental findings, including the lipid A production rate, the behaviors of mutants with defective LpxA enzymes, correlations between LpxC half-lives and cell generation times, and the effects of LpxK overexpression on LpxC concentrations. Its predictions also differ from some experimental results, which suggest modifications to the current understanding of the lipid A pathway, such as the possibility that LpxD can replace LpxA and that there may be metabolic channeling between LpxH and LpxB. The model shows that WaaA regulation may serve to regulate the lipid A production rate when the 3-deoxy-D-manno-oct-2-ulosonic acid (KDO) concentration is low and/or to control the number of KDO residues that get attached to lipid A. Computation of flux control coefficients showed that LpxC is the rate-limiting enzyme if pathway regulation is ignored, but that LpxK is the rate-limiting enzyme if pathway regulation is present, as it is in real cells. Control also shifts to other enzymes if the pathway substrate concentrations are not in excess. Based on these results, we suggest that LpxK may be a much better drug target than LpxC, which has been pursued most often. PMID- 25919636 TI - Plasma Sclerostin in HIV-Infected Adults on Effective Antiretroviral Therapy. AB - Sclerostin is linked to bone physiology and cardiovascular disease through the Wnt/beta-catenin signaling pathway. The goal of this study was to determine if sclerostin is related to bone physiology and cardiovascular disease during antiretroviral treatment in HIV-infected persons. This was a cross-sectional analysis from study entry into the Stopping Atherosclerosis and Treating Unhealthy bone with RosuvastatiN in HIV (SATURN) trial, an ongoing randomized trial comparing rosuvastatin to placebo in HIV-infected adults on antiretroviral therapy. Plasma sclerostin was measured at study entry by ELISA from participants with available samples. Spearman correlation and multivariable linear regression were used to test relationships between sclerostin and bone density or bone turnover and cardiovascular disease. Among 139 HIV-infected participants (median age 46 years, CD4 lymphocyte count 614 cells/MUl), the median plasma sclerostin level was 444.1 (IQR 330.3, 570.1) pg/ml. Correlations were detected between sclerostin and age (r=0.26), lumbar spine Z-score (r=0.31), RANKL (r=-0.21), carotid intima-media thickness (CIMT, r=0.19), and sVCAM-1 (r=0.27), p<0.05. No significant correlations were detected between sclerostin and current (r=0.006) or nadir CD4 count (r=0.11). While associations between sclerostin, lumbar spine Z-score, and sVCAM-1 were robust to covariate adjustment (p<0.01), association with CIMT was no longer significant (p=0.08). Our findings provide preliminary support for a relationship between sclerostin and bone mineral density in HIV infected persons. The Wnt/beta-catenin pathway should be investigated as a potential mechanism for loss of bone mineral density in treated HIV infection. PMID- 25919637 TI - An Organic Microlaser Array Based on a Lateral Microcavity of a Single J aggregation Microbelt. AB - A laser array on the nano- and microscale is a key component for integration in photonic devices, but remains a challenge when using semiconductor nanowire lasers. Here we report a low-threshold lateral-cavity microlaser, formed between two lateral-faces of a single-crystalline organic microbelt (OMB) of 1,4 dimethoxy-2,5-di[4'-(cyano)styryl]benzene (COPV). By cutting a single OMB into six pieces by a top-down two-photon processing technique, we successfully fabricated a compact and uniform 1*6 microlaser array along the length direction of the OMB. The microlasers had excellent reproducibility and addressable high precision, thus making them attractive candidates as miniaturized coherent light sources for future nanophotonics. PMID- 25919638 TI - Lack of strong evidence with regard to the depth of thick melanoma excision. PMID- 25919639 TI - Trastuzumab Labeled to High Specific Activity with (111)In by Site-Specific Conjugation to a Metal-Chelating Polymer Exhibits Amplified Auger Electron Mediated Cytotoxicity on HER2-Positive Breast Cancer Cells. AB - Our objective was to evaluate the cytotoxicity toward HER2-positive human breast cancer (BC) cells of trastuzumab modified site-specifically with a metal chelating polymer (MCP) that presents multiple DTPA chelators for complexing (111)In. (111)In emits subcellular range Auger electrons that induce multiple lethal DNA double-strand breaks (DSBs) in cells. MCPs were synthesized with a polyglutamide backbone with 24 or 29 pendant DTPA groups, with or without nuclear translocation sequence (NLS) peptide modification and a terminal hydrazide group for reaction with aldehydes generated by sodium periodate (NaIO4)-oxidation of glycans on the Fc-domain of trastuzumab. Trastuzumab was site-specifically modified with two DTPA and labeled with (111)In for comparison (trastuzumab-NH-Bn DTPA-(111)In). The maximum specific activity (SA) for labeling trastuzumab-Hy-MCP with (111)In was 90-fold greater than for trastuzumab-NH-Bn-DTPA-(111)In [8.9 MBq/MUg (1.5 * 10(6) MBq/MUmol) vs 0.1 MBq/MUg (1.2 * 10(4) MBq/MUmol)]. Trastuzumab-Hy-MCP-(111)In was bound, internalized, and imported into the nucleus of SK-BR-3 cells. NLS peptide modification of MCPs did not increase nuclear importation. A greater density of DNA DSBs was found for BC cells exposed to high SA (5.5 MBq/MUg) than low SA (0.37 MBq/MUg) radioimmunoconjugates. At 20 nmol/L, high SA trastuzumab-Hy-MCP-(111)In was 6-fold more effective at reducing the clonogenic survival (CS) of HER2 overexpressed and HER2 gene-amplified SK-BR-3 cells (1.3 * 10(6) receptors/cell) than low SA MCP-radioimmunoconjugates (CS = 1.8 +/- 1.3 vs 10.9 +/- 0.7%; P = 0.001). Low SA trastuzumab-NH-Bn-DTPA-(111)In (20 nmol/L) reduced the CS of SK-BR-3 cells to 15.8 +/- 2.1%. The CS of ZR-75-1 cells with intermediate HER2 density (4 * 10(5) receptors/cell) but without HER2 gene amplification was reduced to 20.5 +/- 4.3% by high SA trastuzumab-Hy-MCP (111)In (20 nmol/L). The CS of HER2-overexpressed (5 * 10(5) HER2/cell) but trastuzumab-resistant TrR1 cells was decreased to 17.1 +/- 1.6% by high SA trastuzumab-Hy-MCP-(111)In. Unlabeled trastuzumab (20 nmol/L) was 18-fold less potent than high SA trastuzumab-Hy-MCP-(111)In at reducing the CS of SK-BR-3 cells (CS = 37.0 +/- 5.3%) and 3-fold less effective against Zr-75-1 cells (CS = 53.1 +/- 9.8%). Unlabeled trastuzumab had no effect on the survival of TrR1 cells. We conclude that increasing the SA for labeling with (111)In by site specific conjugation of MCPs to trastuzumab greatly amplified the cytotoxic potency against HER2-overexpressed and gene-amplified BC cells and extended its cytotoxicity to cells with intermediate HER2 expression but without gene amplification and to cells that are HER2 overexpressed but trastuzumab-resistant. PMID- 25919640 TI - Characteristics in childhood and adolescence associated with future multiple sclerosis risk in men: cohort study. AB - BACKGROUND AND PURPOSE: Associations with multiple sclerosis (MS) of living conditions in childhood and characteristics in adolescence including physical fitness, cognitive function and psychological stress resilience were investigated. METHODS: A cohort of male Swedish residents born 1952-1956 who were included in the Swedish Military Conscription Register was used to create a nested case-control study comprising 628 MS cases and 6187 controls matched on birth year, county of residence and vital status at time of diagnosis. Conscription examination records were linked with other national register data. Conditional logistic regression was used to evaluate associations with MS subsequent to the conscription examination. RESULTS AND CONCLUSIONS: Men with MS were less likely to be from more crowded households in childhood (>two persons per room) with an adjusted odds ratio of 0.67 (95% confidence interval 0.51-0.86, P = 0.023). They had lower physical working capacity in adolescence with adjusted odds ratio of 0.94 (95% confidence interval 0.89-0.99, P = 0.026). Cognitive function and stress resilience scores displayed no significant differences between cases and controls. Parental occupation in childhood and body mass index in adolescence were not associated with future MS risk. The inverse association of MS risk with higher levels of household crowding may reflect environmental factors such as the pattern of exposure to microorganisms. Lower physical fitness in men at MS risk may indicate a protective effect of exercise or could be due to prodromal disease activity, although there was no association with cognitive function. Poor psychological stress resilience (and thus risk of chronic stress arousal) was not associated with MS. PMID- 25919642 TI - Long noncoding RNAs and their proposed functions in fibre development of cotton (Gossypium spp.). AB - Long noncoding RNAs (lncRNAs) are transcripts of at least 200 bp in length, possess no apparent coding capacity and are involved in various biological regulatory processes. Until now, no systematic identification of lncRNAs has been reported in cotton (Gossypium spp.). Here, we describe the identification of 30 550 long intergenic noncoding RNA (lincRNA) loci (50 566 transcripts) and 4718 long noncoding natural antisense transcript (lncNAT) loci (5826 transcripts). LncRNAs are rich in repetitive sequences and preferentially expressed in a tissue specific manner. The detection of abundant genome-specific and/or lineage specific lncRNAs indicated their weak evolutionary conservation. Approximately 76% of homoeologous lncRNAs exhibit biased expression patterns towards the At or Dt subgenomes. Compared with protein-coding genes, lncRNAs showed overall higher methylation levels and their expression was less affected by gene body methylation. Expression validation in different cotton accessions and coexpression network construction helped to identify several functional lncRNA candidates involved in cotton fibre initiation and elongation. Analysis of integrated expression from the subgenomes of lncRNAs generating miR397 and its targets as a result of genome polyploidization indicated their pivotal functions in regulating lignin metabolism in domesticated tetraploid cotton fibres. This study provides the first comprehensive identification of lncRNAs in Gossypium. PMID- 25919643 TI - Study of Antimicrobial Effects of Clarithromycin Loaded PLGA Nanoparticles against Clinical Strains of Helicobacter pylori. AB - Clarithromycin (CLR) formulation was prepared as PLGA nanoparticles in order to enhance the therapeutic effects using the distinctive features of a nanoparticulate delivery system. CLR loaded PLGA nanoparticles were prepared by Quasi Emulsion Solvent Diffusion (QESD) method using Poly lactic-co-Glycolic Acid (PLGA) as a biodegradable polymer. Antibacterial activity of the prepared formulations was evaluated against clinical strains of Helicobacter pylori, isolated from gastric biopsies of patients with gastritis, duodenal ulcer, peptic ulcer, and gastroesophageal reflux disease undergoing endoscopy, by using agar dilution method.Spherical nanoparticles with relatively narrow size distribution (between 200 and 800 nm) in the size range of 305 +/- 138, 344 +/- 148 and 362 +/ 110 nm were achieved for F22, F23 and F23 respectively. CLR encapsulation percentages were measured to be 57.4 +/- 4.3 to 80.2 +/- 4.0%. CLR loaded PLGA nanoparticles showed equal or enhanced eradication effect against H. pylori strains according to the declined MIC values in comparison with the untreated CLR.In conclusion, the prepared CLR nanoformulation showed appropriate physicochemical properties and improved activity against H. pylori that could be a suitable candidate for oral preparations. PMID- 25919641 TI - Interleukin-35: Expanding Its Job Profile. AB - Counter-regulation afforded by specialized regulatory cell populations and immunosuppressive cytokines is critical for balancing immune outcome. The inhibitory potential of the established suppressive cytokines, IL-10 and TGFbeta, has been well elucidated in diverse inflammatory scenarios in conjunction with their key roles in Treg development and function. Despite the early predictions for an immunomodulatory role for the Ebi3/p35 heterodimer in placental trophoblasts, IL-35 biology remained elusive until 2007 when it was established as a Treg-restricted inhibitory cytokine. Since then, Treg-derived IL-35 has been shown to exhibit its suppressive activities in a range of autoimmune diseases and cancer models. Recent studies are beginning to explore other cellular sources of IL-35, such as Bregs and CD8(+) Tregs. Despite these new cellular sources and targets, the mode of IL-35 suppression remains restricted to inhibition of proliferation and induction of an IL-35-producing induced regulatory T cell population referred to as iTr35. In this review, we explore the early beginnings, status quo, and future prospects of IL-35 biology. The unparalleled opportunity of targeting multiple immunosuppressive populations (Tregs, Bregs, CD8(+) Tregs) through IL-35 is highly exciting and offers tremendous promise from a translational standpoint, particularly for cancer immunotherapies. PMID- 25919644 TI - Finasteride Quantification in Human Plasma by High-Performance Liquid Chromatography Coupled to Electrospray Ionization Tandem Mass Spectrometry. Application to a Comparative Pharmacokinetics Study. AB - A specific, fast and sensitive LC-MS/MS assay was developed for the determination of finasteride in human plasma using betamethsone dipropionate as the internal standard (IS). The limit of quantification was 1.0 ng/ml and the method was linear in the range of 1.0-25.0 ng/ml. The retention times were 0.75 min for finasteride and 0.85 min for IS. Method intra-batch precision and accuracy ranged from 3.6 to 7.1%, and 96.6 to 103.9%, respectively. Inter-batch precision ranged from 2.5 to 3.4%, while Inter-batch accuracy ranged from 100.3 to 103.5%. The analytical method was applied to evaluate the pharmacokinetic and relative bioavailability of 2 different pharmaceutical formulations containing 1.0 mg of finasteride. This study evaluated 38 volunteers in a randomized, 2-period crossover study with 7 days washout period between doses. The geometric mean and respective 90% CI of finasteride test/reference percent ratios were 95.68% (91.2 104.6%) for Cmax, 97.5% (92.1-103.3%) for AUC0-t and 98.1 (92.67-103.8) for AUC0 inf. Based on the 90% confidence interval of the individual ratios (test formulation/reference formulation) for Cmax and AUC0-inf, it was concluded that the test formulation is bioequivalent to the reference one with respect to the rate and extent of absorption of finasteride. PMID- 25919646 TI - Identification of 4-Hydroxycumyl Alcohol As the Major MnO2-Mediated Bisphenol A Transformation Product and Evaluation of Its Environmental Fate. AB - Bisphenol A (BPA), an environmental contaminant with weak estrogenic activity, resists microbial degradation under anoxic conditions but is susceptible to abiotic transformation by manganese dioxide (MnO2). BPA degradation followed pseudo-first-order kinetics with a rate constant of 0.96 (+/-0.03) min(-1) in the presence of 2 mM MnO2 (0.017% w/w) at pH 7.2. 4-hydroxycumyl alcohol (HCA) was the major transformation product, and, on a molar basis, up to 64% of the initial amount of BPA was recovered as HCA. MnO2 was also reactive toward HCA, albeit at 5-fold lower rates, and CO2 evolution (i.e., mineralization) occurred. In microcosms established with freshwater sediment, HCA was rapidly biodegraded under oxic, but not anoxic conditions. With a measured octanol-water partition coefficient (Log K(ow)) of 0.76 and an aqueous solubility of 2.65 g L(-1), HCA is more mobile in saturated media than BPA (Log K(ow) = 2.76; aqueous solubility = 0.31 g L(-1)), and therefore more likely to encounter oxic zones and undergo aerobic biodegradation. These findings corroborate that BPA is not inert under anoxic conditions and suggest that MnO2-mediated coupled abiotic-biotic processes may be relevant for controlling the fate and longevity of BPA in sediments and aquifers. PMID- 25919647 TI - Post-ERCP pancreatitis. A single center experience and an update on prevention strategies. AB - OBJECTIVES: Pancreatitis is the most frequent complication of the ERCP; in unselected patients the incidence is 3.5%, reaching 25%, and is mild-moderate in 90%. A stratification of patients into low or high risk is important to provide adequate information to patients and to decide when refer them to tertiary centers; moreover, many prophylactic measures have been proposed over years. Our aim was to select risk factors for PEP and compare them with current literature in order to propose adequate preventive strategies. METHODS: It was analyzed the occurrence of Post-ERCP Pancreatitis in a series of 492 consecutives patients treated with ERCP by two expert interventional endoscopists. The possible risk factors were evidenced by a multivariate analysis, were states our proposals for Post-ERCP Pancreatitis prevention and compared them to the current literature. RESULTS: We observed 14 PEP (2.8%), 6 mild, 4 moderates and 4 severe. The multivariate analysis evidenced as risk factors the high number of attempts of cannulation and the pancreatic injection of contrast medium and found a protective role for pre-cut sphincterotomy. Our mortality rate was 0.4%. CONCLUSIONS: The guide-wire cannulation technique and, in selected cases, the pre cut permit to minimize the number of cannulation attempts and to increase the success rate of primary cannulation; we promote their use to reduce PEP occurrence. PMID- 25919645 TI - The control of reactive oxygen species production by SHP-1 in oligodendrocytes. AB - We have previously described reduced myelination and corresponding myelin basic protein (MBP) expression in the central nervous system of Src homology 2 domain containing protein tyrosine phosphatase 1 (SHP-1) deficient motheaten (me/me) mice compared with normal littermate controls. Deficiency in myelin and MBP expression in both brains and spinal cords of motheaten mice correlated with reduced MBP mRNA expression levels in vivo and in purified oligodendrocytes in vitro. Therefore, SHP-1 activity seems to be a critical regulator of oligodendrocyte gene expression and function. Consistent with this role, this study demonstrates that oligodendrocytes of motheaten mice and SHP-1-depleted N20.1 cells produce higher levels of reactive oxygen species (ROS) and exhibit corresponding markers of increased oxidative stress. In agreement with these findings, we demonstrate that increased production of ROS coincides with ROS induced signaling pathways known to affect myelin gene expression in oligodendrocytes. Antioxidant treatment of SHP-1-deficient oligodendrocytes reversed the pathological changes in these cells, with increased myelin protein gene expression and decreased expression of nuclear factor (erythroid-2)-related factor 2 (Nrf2) responsive gene, heme oxygenase-1 (HO-1). Furthermore, we demonstrate that SHP-1 is expressed in human white matter oligodendrocytes, and there is a subset of multiple sclerosis subjects that demonstrate a deficiency of SHP-1 in normal-appearing white matter. These studies reveal critical pathways controlled by SHP-1 in oligodendrocytes that relate to susceptibility of SHP-1 deficient mice to both developmental defects in myelination and to inflammatory demyelinating diseases. PMID- 25919648 TI - Biomonitoring heavy metal contaminations by moss visible parameters. AB - Traditional sampling for heavy metal monitoring is a time-consuming and inconvenient method, which also does not indicate contaminants non-invasively and instantaneously. Moss is sensitive to heavy metals and is therefore considered a pollution indicator. However, it is unknown what kind physiological parameters can indicate metal contaminations quickly and non-invasively. Here, we systematically examined the effects of six heavy metals on physiological parameters and photosynthetic activities of two moss species grown in aquatic media or moist soil surface. We suggest that a phenotype with anthocyanin accumulation pattern and chlorosis pattern and two chlorophyll fluorescence parameters with their images can roughly reflect metal species groups, concentrations and differences between the two moss species. In other words, metal contaminations could be roughly estimated visually using the naked eye. Enzymatic and non-enzymatic anti-oxidative abilities and photosynthetic protein contents of Eurhynchium eustegium were higher than those of Taxiphyllum taxirameum, indicating their differential metal tolerance. Neither anti-oxidative abilities nor photosynthetic proteins were found to be ideal indicators. This study provides new ideas to monitor heavy metals rapidly and non-invasively in water or on wetland and moist soil surface. PMID- 25919649 TI - Hepatitis E Virus and Related Viruses in Animals. AB - Hepatitis E is an acute human liver disease in healthy individuals which may eventually become chronic. It is caused by the hepatitis E virus (HEV) and can have a zoonotic origin. Nearly 57,000 people die yearly from hepatitis E-related conditions. The disease is endemic in both developing and developed countries with distinct epidemiologic profiles. In developing countries, the disease is associated with inadequate water treatment, while in developed countries, transmission is associated with animal contact and the ingestion of raw or uncooked meat, especially liver. All human HEV are grouped into at least four genotypes, while HEV or HEV-related viruses have been identified in an increasing number of domestic and wild animal species. Despite a high genetic diversity, only one single HEV serotype has been described to date for HEV genotypes 1-4. The discovery of new HEV or HEV-related viruses leads to a continuing increase in the number of genotypes. In addition, the genome organization of all these viruses is variable with overlapping open reading frames (ORF) and differences in the location of ORF3. In spite of the role of some domestic and wild animals as reservoir, the origin of HEV and HEV-related viruses in humans and animals is still unclear. This review discusses aspects of the detection, molecular virology, zoonotic transmission and origin of HEV and HEV-related viruses in the context of 'One Health' and establishes a link between the previous and the new taxonomy of this growing virus family. PMID- 25919650 TI - Clinical characteristics and survival of patients with pulmonary hypertension: a 40-month mean follow-up. AB - BACKGROUND AND AIMS: The aim of our study was to describe the characteristics and clinical outcomes of pulmonary hypertension (PH) patients who underwent their follow-up at a single centre. METHODS: We included patients who fulfilled the criteria for the diagnosis of PH by right heart catheterisation. A detailed clinical history and complete physical examination were recorded for each patient. Demographic data, laboratory testing, haemodynamic values and treatment records were also collected. A 6-min walk test was used to evaluate exercise capacity. Survival analysis was performed using the Kaplan-Meier method, and a log-rank test was used to compare survival curves among groups. A multivariate Cox's proportional hazards model was used in order to identify independent predictors of mortality in the overall PH population. RESULTS: A total of 93 patients (64 women and 29 men) were studied. The patients were distributed across the groups as follows: 50.5% in group 1, 20.4% in group 2, 9.7% in group 3, 14% in group 4 and 5.4% in group 5. The most common type of PH in our population was portopulmonary hypertension followed by PH associated with left heart disease, and idiopathic and chronic thromboembolic disease. Nineteen deaths, constituting 20.5% of the sample population, were reported. The Kaplan-Meier estimates of the 1-, 2- and 3-year survival rates were 91%, 89% and 85%, respectively. There were no statistically significant differences in survival among the groups (P = 0.18). A multivariate analysis revealed that the cardiac index (CI) was an independent predictor of death. CONCLUSIONS: The survival rates of PH patients are higher than previously reported. In our study, the largest number of deaths occurred in groups 1 and 2, and CI was found to be an independent predictor of mortality. PMID- 25919652 TI - Reduction of titanocene dichloride with dysprosium: access to a stable titanocene(ii) equivalent for phosphite-free Takeda carbonyl olefination. AB - The reduction of titanocene dichloride with dysprosium yields a new titanocene(ii) equivalent without the need for further stabilising ligands. This reagent can be employed in combination with dithioacetals for the olefination of different carbonyl groups and allows for a simplified all-in-one procedure. PMID- 25919651 TI - Psychometric properties of the German version of the Diabetes Eating Problem Survey-Revised: additional benefit of disease-specific screening in adolescents with Type 1 diabetes. AB - AIM: To examine the psychometric properties of the German version of the abbreviated 16-item Diabetes Eating Problem Survey-Revised in a sample of young people with Type 1 diabetes. METHODS: A total of 246 young people, aged 11-19 years, with Type 1 diabetes from six pediatric diabetes centres in Germany were assessed using the Diabetes Eating Problem Survey-Revised. In addition, they underwent screening with two generic tools as well as the WHO five-question well being index. A clinician's report was also obtained. RESULTS: The Diabetes Eating Problem Survey-Revised was found to have good internal consistency (Cronbach's alpha = 0.84). The Diabetes Eating Problem Survey-Revised scores significantly correlated with those provided by the non-specific screening tools (r = 0.37, P <= 0.000 and r = 0.50, P <= 0.000 for boys and r = 0.62, P <= 0.000 and r = 0.79, P <= 0.000 for girls), indicating convergent validity. The mean (sd) total of the scores was 12.0 (9.6). Criterion validity was confirmed against HbA1c value, BMI standard deviation score and expert (clinician) report. Of the boys included in the study, 11 scored higher than the threshold score on the Diabetes Eating Problem Survey-Revised, of whom only three (27%) were classified as 'suspected to have a disordered eating behaviour' by their clinicians. CONCLUSIONS: The Diabetes Eating Problem Survey-Revised delivered more specific information than generic screening instruments and identified more young people with eating disorders than did clinician report, especially regarding the detection of boys at risk. The results of this study support the utility of the German version of the Diabetes Eating Problem Survey-Revised to identify eating disorders in young people with Type 1 diabetes at an early stage. (German Clinical Trials Registry no.: DRKS00004699). PMID- 25919653 TI - Cardiovascular health in former elite male athletes. AB - To increase our knowledge on the effects of previous and current physical activity on cardiovascular health, we studied a group of Finnish male former elite athletes (endurance, n = 49; power, n = 50) and their 49 age and area matched controls, aged 64-89 years. Body mass index (BMI), fasting serum glucose, lipids, blood pressure, and ultrasonography of cardiac and carotid artery structure and function were measured. Former endurance athletes smoked less, had lower prevalence of hypertension, and had higher intensity and volume of leisure time physical activity (LTPA) than the controls. No difference was detected in cardiac or carotid artery structure and function between these groups. Former athletes performing high-intensity LTPA were slightly younger (possible selection bias), had lower BMI and waist circumference, lower use of antihypertensives, lower prevalence of diabetes, lower pulse wave velocity, and higher carotid artery elasticity than former athletes not performing high-intensity LTPA. In conclusion, former athletes had a higher intensity and volume of LTPA than the controls. Athletes performing vigorous LTPA had more elastic arteries than athletes performing moderately or no LTPA. Vigorous LTPA through the whole lifetime associates with good cardiovascular health, although the previous medical history may play an important role. PMID- 25919654 TI - Intestinal cytomegalovirus infection in patients hospitalized for exacerbation of inflammatory bowel disease: a 10-year tertiary referral center experience. AB - OBJECTIVES: This 10-year retrospective cohort study aims to determine the prevalence and risk factors of cytomegalovirus (CMV) infection in inpatients with exacerbated inflammatory bowel disease (IBD). METHODS: All patients admitted to the Department of Gastroenterology of the University Hospital Heidelberg for IBD exacerbation between January 2004 and June 2013 were enrolled. To identify the risk factors of CMV infection, infected individuals were compared with those with excluded infection. RESULTS: Among 297 patients with exacerbated IBD, 21 had confirmed CMV infection and 79 had excluded CMV infection, whereas the remaining patients had not been sufficiently tested for CMV. Taking into account only sufficiently tested individuals, the prevalence of CMV infection was 22.7% in ulcerative colitis and 16.0% in Crohn's disease. The occurrence of CMV infection was associated with the following variables at admission: age of 30 years or more [odds ratio (OR) 14.29; P=0.004], disease duration less than 60 months (OR 7.69; P=0.011), a blood leukocyte count less than 11/nl (OR 4.49; P=0.041), and immunosuppressive therapy (OR 6.73; P=0.0129). CMV-positive patients remained in the hospital longer than noninfected patients (P=0.0009). In the CMV-positive cohort, a 66-year-old woman died of CMV pneumonia and sepsis, whereas there was no death in the CMV-negative cohort. CONCLUSION: Immunuosuppressive therapy and age older than 30 years were identified as the main risk factors for the development of CMV infection in exacerbated IBD. Because of the risk of death, diagnostics of CMV infection should especially be initiated in older patients on immunosuppressive therapy. PMID- 25919655 TI - Is ultrasonography-diagnosed nonalcoholic fatty liver disease fibrosis score associated with the Framingham risk score? PMID- 25919657 TI - Stem Cell Transplantation for Pulpal Regeneration: A Systematic Review. AB - For treating pulpal pathological conditions, pulpal regeneration through transplanted stem/progenitor cells might be an alternative to conventional root canal treatment. A number of animal studies demonstrated beneficial effects of stem/progenitor cell transplantation for pulp-dentin complex regeneration, that is, pulpal tissue, neural, vascular, and dentinal regeneration. We systematically reviewed animal studies investigating stem/progenitor cell-mediated pulp-dentin complex regeneration. Studies quantitatively comparing pulp-dentin complex regeneration after transplantation of stem/progenitor cells versus no stem/progenitor cell transplantation controls in intraoral in vivo teeth animal models were analyzed. The following outcomes were investigated: regenerated pulp area per root canal total area, capillaries per total surface, regenerated dentinal area per total defect area, and nerves per total surface. PubMed and EMBASE were screened for studies published until July 2014. Cross-referencing and hand searching were used to identify further articles. Standardized mean differences (SMD) and 95% confidence intervals (95% CI) were calculated using random-effects meta-analysis. To assess possible bias, SYRCLE's risk of bias tool for animal studies was used. From 1364 screened articles, five studies (representing 64 animals) were included in the quantitative analysis. Risk of bias of all studies was high. Stem/progenitor cell-transplanted pulps showed significantly larger regenerated pulp area per root canal total area (SMD [95% CI]: 2.28 [0.35-4.21]) and regenerated dentin area per root canal total area (SMD: 6.91 [5.39-8.43]) compared with no stem/progenitor cell transplantation controls. Only one study reported on capillaries per or nerves per total surface and found both significantly increased in stem/progenitor cell-transplanted pulps compared with controls. Stem/progenitor cell transplantation seems to enhance pulp-dentin complex regeneration in animal models. Due to limited data quantity and quality, current evidence levels are insufficient for further conclusions. PMID- 25919658 TI - Echocardiographic evaluation of the effects of dexmedetomidine on cardiac function during total intravenous anaesthesia. AB - The purpose of this study was to investigate the effects of dexmedetomidine on biventricular systolic and diastolic function using transoesophageal echocardiography. Cardiac function was assessed in 30 healthy patients who received total intravenous anaesthesia with propofol and remifentanil. The echocardiographic examinations were performed just before and 20, 40 and 60 min after dexmedetomidine or saline administration. Patients who received dexmedetomidine, compared with saline after 20 min, had a lower mean (SD) heart rate (56.7 (5.2) vs. 67.1 (7.1) beats.min(-1) ), higher systolic blood pressure (125.7 (18.9) vs. 109 (7.9) mmHg), and lower cardiac output (2.9 (0.5) vs. 3.7 (1.0) l.min(-1) ), respectively (all p < 0.05). In contrast, no changes were observed in biventricular systolic and diastolic indices in either group, and there were no inter-group differences at any time point. Dexmedetomidine, as an adjuvant to total intravenous anaesthesia, does not impair biventricular systolic and diastolic function in healthy patients, but decreases cardiac output by reducing heart rate. PMID- 25919659 TI - Workplace social and organizational environments and healthy-weight behaviors. AB - BACKGROUND: The workplace is an important setting for health promotion including nutrition and physical activity behaviors to prevent obesity. This paper explores the relationship between workplace social environment and cultural factors and diet and physical activity (PA) behaviors and obesity among employees. METHODS: Between 2012 and 2013, telephone interviews were conducted with participants residing in four Missouri metropolitan areas. Questions included demographic characteristics, workplace socio/organizational factors related to activity and diet, and individual diet and PA behaviors, and obesity. Multivariate logistic regression was used to examine associations between the workplace socio/organizational environment and nutrition, PA, and obesity. RESULTS: There were differences in reported health behaviors and socio/organizational environment by gender, race, age, income, and worksite size. For example, agreement with the statement the 'company values my health' was highest among Whites, older employees, and higher income workers. As worksite size increased, the frequency of reporting seeing co-workers doing several types of healthy behaviors (eat fruits and vegetables, doing PA, and doing PA on breaks at work) increased. In adjusted analyses, employees agreeing the company values my health were more likely to engage in higher PA levels (aOR=1.54, 95% CI: 1.09-2.16) and less likely to be obese (aOR=0.73, 95% CI: 0.54-0.98). Seeing co-workers eating fruits and vegetables was associated with increased reporting of eating at least one vegetable per day (aOR=1.43, 95% CI: 1.06-1.91) and seeing co-workers being active was associated with higher PA levels (aOR 1.56, 95% CI: 1.19-2.05). CONCLUSIONS: This research suggests that social/organizational characteristics of the workplace environment, particularly feeling the company values the workers' health and to seeing co-workers engaging in healthy behaviors, may be related to nutrition and PA behaviors and obesity. These findings point to the potential for intervention targets including environment and policy changes. PMID- 25919660 TI - [Testosterone replacement therapy and prostate cancer: the downfall of a paradigm?]. AB - For six decades, it has been a part of the conventional medical wisdom that higher levels of testosterone increase the risk of prostate cancer. This belief is mostly derived from the well-documented regression of prostate cancer after surgical or pharmacological castration. However, there is an absence of scientific data supporting the concept that higher testosterone levels are associated with an increased risk of prostate cancer. Moreover, men with hypogonadism have substantial rates of prostate cancer in prostatic biopsies, suggesting that low testosterone has no protective effect against the development of prostate cancer. Moreover, prostate cancer rate is higher in elderly patients when hormonal levels are low. These results argue against an increased risk of prostate cancer with testosterone replacement therapy. PMID- 25919661 TI - Role of Caffeine Intake on Erectile Dysfunction in US Men: Results from NHANES 2001-2004. AB - OBJECTIVES: Caffeine is consumed by more than 85% of adults and little is known about its role on erectile dysfunction (ED) in population-based studies. We investigated the association of caffeine intake and caffeinated beverages with ED, and whether these associations vary among comorbidities for ED. MATERIAL AND METHOD: Data were analyzed for 3724 men (>=20 years old) who participated in the National Health and Nutrition Examination Survey (NHANES). ED was assessed by a single question during a self-paced, computer-assisted self-interview. We analyzed 24-h dietary recall data to estimate caffeine intake (mg/day). Multivariable logistic regression analyses using appropriate sampling weights were conducted. RESULTS: We found that men in the 3rd (85-170 mg/day) and 4th (171-303 mg/day) quintiles of caffeine intake were less likely to report ED compared to men in the lowest 1st quintile (0-7 mg/day) [OR: 0.58; 95% CI, 0.37 0.89; and OR: 0.61; 95% CI, 0.38-0.97, respectively], but no evidence for a trend. Similarly, among overweight/obese and hypertensive men, there was an inverse association between higher quintiles of caffeine intake and ED compared to men in the lowest 1st quintile, P<=0.05 for each quintile. However, only among men without diabetes we found a similar inverse association (Ptrend = 0.01). CONCLUSION: Caffeine intake reduced the odds of prevalent ED, especially an intake equivalent to approximately 2-3 daily cups of coffee (170-375 mg/day). This reduction was also observed among overweight/obese and hypertensive, but not among diabetic men. Yet, these associations are warranted to be investigated in prospective studies. PMID- 25919663 TI - Sex Differences in Working Memory after Mild Traumatic Brain Injury: A Functional MR Imaging Study. AB - PURPOSE: To evaluate sex differences in mild traumatic brain injury (MTBI) with working memory functional magnetic resonance (MR) imaging. MATERIALS AND METHODS: Research ethics committee approval and patient written informed consent were obtained. Working memory brain activation patterns were assessed with functional MR imaging in 30 patients (15 consecutive men and 15 consecutive women) with MTBI and 30 control subjects (15 consecutive men and 15 consecutive women). Two imaging studies were performed in patients: the initial study, which was performed within 1 month after the injury, and a follow-up study, which was performed 6 weeks after the first study. For each participant, digit span and continuous performance testing were performed before functional MR imaging. Clinical data were analyzed by using Kruskal-Wallis, Mann-Whitney U, Wilcoxon signed rank, and Fisher exact tests. Within- and between-group differences of functional MR imaging data were analyzed with one- and two-sample t tests, respectively. RESULTS: Among female participants, the total digit span score was lower in the MTBI group than in the control group (P = .044). In initial working memory functional MR imaging studies, hyperactivation was found in the male MTBI group and hypoactivation was found in the female MTBI group compared with control male and female groups, respectively. At the 6-week follow-up study, the female MTBI group showed persistent hypoactivation, whereas the male MTBI group showed a regression of hyperactivation at visual comparison of activation maps. The male MTBI group was also found to have a higher initial beta value than the male control group (P = .040), and there was no significant difference between the male MTBI group and the male control group (P = .221) at follow-up evaluation, which was comparable to findings on activation maps. In the female MTBI group, average beta values at both initial and follow-up studies were lower compared with those in the female control group but were not statistically significant (P = .663 and P = .191, respectively). CONCLUSION: Female patients with MTBI had lower digit span scores than did female control subjects, and functional MR imaging depicted sex differences in working memory functional activation; hypoactivation with nonrecovery of activation change at follow-up studies may suggest a worse working memory outcome in female patients with MTBI. PMID- 25919664 TI - Correction: Quantitative genetics of CTCF binding reveal local sequence effects and different modes of X-chromosome association. AB - [This corrects the article DOI: 10.1371/journal.pgen.1004798.]. PMID- 25919666 TI - Surface modified natural zeolite as a carrier for sustained diclofenac release: A preliminary feasibility study. AB - In view of zeolite potentiality as a carrier for sustained drug release, a clinoptilolite-rich rock from California (CLI_CA) was superficially modified with cetylpyridinium chloride and loaded with diclofenac sodium (DS). The obtained surface modified natural zeolites (SMNZ) were characterized by confocal scanning laser microscopy (CLSM), powder X-ray diffraction (XRPD) and laser light scattering (LS). Their flowability properties, drug adsorption and in vitro release kinetics in simulated intestinal fluid (SIF) were also investigated. CLI_CA is a Na- and K-rich clinoptilolite with a cationic exchange ability that fits well with its zeolite content (clinoptilolite=80 wt%); the external cationic exchange capacity is independent of the cationic surfactant used. LS and CLSM analyses have shown a wide distribution of volume diameters of SMNZ particles that, along with their irregular shape, make them cohesive with scarce flow properties. CLSM observation has revealed the localization of different molecules in/on SMNZ by virtue of their chemical nature. In particular, cationic and polar probes prevalently localize in SMNZ bulk, whereas anionic probes preferentially arrange themselves on SMNZ surface and the loading of a nonpolar molecule in/on SMNZ is discouraged. The adsorption rate of DS onto SMNZ was shown by different kinetic models highlighting the fact that DS adsorption is a pseudo-second order reaction and that the diffusion through the boundary layer is the rate controlling step of the process. DS release in an ionic medium, such as SIF, can be sustained for about 5h through a mechanism prevalently governed by anionic exchange with a rapid final phase. PMID- 25919667 TI - Approximate joint diagonalization and geometric mean of symmetric positive definite matrices. AB - We explore the connection between two problems that have arisen independently in the signal processing and related fields: the estimation of the geometric mean of a set of symmetric positive definite (SPD) matrices and their approximate joint diagonalization (AJD). Today there is a considerable interest in estimating the geometric mean of a SPD matrix set in the manifold of SPD matrices endowed with the Fisher information metric. The resulting mean has several important invariance properties and has proven very useful in diverse engineering applications such as biomedical and image data processing. While for two SPD matrices the mean has an algebraic closed form solution, for a set of more than two SPD matrices it can only be estimated by iterative algorithms. However, none of the existing iterative algorithms feature at the same time fast convergence, low computational complexity per iteration and guarantee of convergence. For this reason, recently other definitions of geometric mean based on symmetric divergence measures, such as the Bhattacharyya divergence, have been considered. The resulting means, although possibly useful in practice, do not satisfy all desirable invariance properties. In this paper we consider geometric means of covariance matrices estimated on high-dimensional time-series, assuming that the data is generated according to an instantaneous mixing model, which is very common in signal processing. We show that in these circumstances we can approximate the Fisher information geometric mean by employing an efficient AJD algorithm. Our approximation is in general much closer to the Fisher information geometric mean as compared to its competitors and verifies many invariance properties. Furthermore, convergence is guaranteed, the computational complexity is low and the convergence rate is quadratic. The accuracy of this new geometric mean approximation is demonstrated by means of simulations. PMID- 25919665 TI - Exosomes are unlikely involved in intercellular Nef transfer. AB - HIV-1 Nef is an important pathogenic factor for HIV/AIDS pathogenesis. Several recent studies including ours have demonstrated that Nef can be transferred to neighboring cells and alters the function of these cells. However, how the intercellular Nef transfer occurs is in dispute. In the current study, we attempted to address this important issue using several complementary strategies, a panel of exosomal markers, and human CD4+ T lymphocyte cell line Jurkat and a commonly used cell line 293T. First, we showed that Nef was transferred from Nef expressing or HIV-infected Jurkat to naive Jurkat and other non-Jurkat cells and that the transfer required the membrane targeting function of Nef and was cell density-dependent. Then, we showed that Nef transfer was cell-cell contact dependent, as exposure to culture supernatants or exosomes from HIV-infected Jurkat or Nef-expressing Jurkat and 293T led to little Nef detection in the target cells Jurkat. Thirdly, we demonstrated that Nef was only detected to be associated with HIV virions but not with acetylcholinesterase (AChE+) exosomes from HIV-infected Jurkat and not in the exosomes from Nef-expressing Jurkat. In comparison, when it was over-expressed in 293T, Nef was detected in detergent insoluble AChE+/CD81 low/TSG101 low exosomes, but not in detergent-soluble AChE /CD81 high/TSG101 high exosomes. Lastly, microscopic imaging showed no significant Nef detection in exosomal vesicle-like structures in and out 293T. Taken together, these results show that exosomes are unlikely involved in intercellular Nef transfer. In addition, this study reveals existence of two types of exosomes: AChE+/CD81 low/TSG101 low exosomes and AChE-/CD81 high/TSG101 high exosomes. PMID- 25919668 TI - A startling acoustic stimulus interferes with upcoming motor preparation: Evidence for a startle refractory period. AB - When a startling acoustic stimulus (SAS) is presented in a simple reaction time (RT) task, response latency is significantly shortened. The present study used a SAS in a psychological refractory period (PRP) paradigm to determine if a shortened RT1 latency would be propagated to RT2. Participants performed a simple RT task with an auditory stimulus (S1) requiring a vocal response (R1), followed by a visual stimulus (S2) requiring a key-lift response (R2). The two stimuli were separated by a variable stimulus onset asynchrony (SOA), and a typical PRP effect was found. When S1 was replaced with a 124dB SAS, R1 onset was decreased by 40-50ms; however, rather than the predicted propagation of a shortened RT, significantly longer responses were found for RT2 on startle trials at short SOAs. Furthermore, the 100ms SOA condition exhibited reduced peak EMG for R2 on startle trials, as compared to non-startle trials. These results are attributed to the startling stimulus temporarily interfering with cognitive processing, delaying and altering the execution of the second response. In addition to this "startle refractory period," results also indicated that RT1 latencies were significantly lengthened for trials that immediately followed a startle trial, providing evidence for longer-term effects of the startling stimulus. PMID- 25919669 TI - [Vascular lesions, Part 1: Classification and diagnosis]. PMID- 25919670 TI - [National respiration center support patients with tracheostomy tubes. Outpatient clinic for respiratory support in the home]. AB - It is now 60 years since the polio epidemic in Copenhagen and the first use of prolonged invasive positive pressure ventilation. After this pioneer work positive pressure ventilation rapidly became well established. Intubation/tracheostomy and mechanical ventilation are now standard in Intensive Care Units. In the late 1970 Gillis Andersson was the first in Sweden to discharge patients home with invasive mechanical ventilator support. His pioneer work included the development of a dedicated practical and technical support organization at National Respiration Centre at Danderyds Hospital. This unit developed skills in patient customized tracheostomy tube construction and home invasive ventilation supportive care. Tracheostomy tubes and home ventilators have since then developed rapidly. Some patients still need customized tracheostomy tubes, which the NRC supplies. The production is certified by the Swedish Medicinal Product Agency. Today invasive home ventilation is standard care. Invasive mechanical home ventilation when instituted as a life-saving therapy in, for example, progressive ALS patients is complex and resource intensive. New aspects such as training and education in order to secure quality of care in the home environment is one of many challenges. When commencing invasive ventilation in patients with progressive neurological disease ethical considerations must also be acknowledged, e.g. aspects such as patients' perhaps changing wishes during the course of illness regarding cessation of life support. PMID- 25919671 TI - [Charcots footnote--difficult for science to repress]. PMID- 25919672 TI - [Time for a renewed discussion about the role of the quality registries]. PMID- 25919662 TI - Gaussian Mixture Models and Model Selection for [18F] Fluorodeoxyglucose Positron Emission Tomography Classification in Alzheimer's Disease. AB - We present a method to discover discriminative brain metabolism patterns in [18F] fluorodeoxyglucose positron emission tomography (PET) scans, facilitating the clinical diagnosis of Alzheimer's disease. In the work, the term "pattern" stands for a certain brain region that characterizes a target group of patients and can be used for a classification as well as interpretation purposes. Thus, it can be understood as a so-called "region of interest (ROI)". In the literature, an ROI is often found by a given brain atlas that defines a number of brain regions, which corresponds to an anatomical approach. The present work introduces a semi data-driven approach that is based on learning the characteristics of the given data, given some prior anatomical knowledge. A Gaussian Mixture Model (GMM) and model selection are combined to return a clustering of voxels that may serve for the definition of ROIs. Experiments on both an in-house dataset and data of the Alzheimer's Disease Neuroimaging Initiative (ADNI) suggest that the proposed approach arrives at a better diagnosis than a merely anatomical approach or conventional statistical hypothesis testing. PMID- 25919673 TI - [A serious discussion about quality registries is welcome]. PMID- 25919674 TI - [Incorrect about how drugs are marketed]. PMID- 25919675 TI - [Not too late for reform]. PMID- 25919676 TI - [Medical consequences of whipping. Ethical dilemma for physicians]. PMID- 25919677 TI - [Is it dangerous to allow the patient to choose health care provider]. PMID- 25919678 TI - [The negative consequences of care choice have not been taken into account]. PMID- 25919679 TI - [Sweden does not prioritize important cancer drugs]. PMID- 25919680 TI - [Not Available]. PMID- 25919681 TI - [Not Available]. PMID- 25919682 TI - [Two questions before internship is abolished]. PMID- 25919683 TI - ["Reconsider the regulations for 'Note' in off-label prescribing"]. PMID- 25919684 TI - [Swedish pediatric research is still strong]. PMID- 25919686 TI - Nanofluids alter the surface wettability of solids. AB - We report the results of our studies on the changes in the contact angle and interfacial tension using a nanofluid composed of silica nanoparticles dispersed in water on three different solid substrates: gold (partially hydrophobic), glass (hydrophilic), and a silicon wafer (hydrophilic). We used both the goniometric method and drop-shape analysis to make the measurements. On the basis of the results of the drop-shape analysis using the Laplace equation, we evaluated the contributions of the interfacial tension change to the equilibrium contact angle and the presence of nanoparticles near the solid substrate, thereby elucidating the change in the wettability of the solid substrate. We found that the nanoparticles decrease the contact angle of the substrate with the increase in the nanoparticle concentration. To rationalize our experimental observations on the decrease in the contact angle of the solid substrate in the presence of nanoparticles, we calculated the surface volume fraction of the nanoparticles in the layer near the solid substrate using the particle layering model (based on the nanoparticles' excluded volume effect). We found that the volume fraction of the nanoparticles in the layer close to the substrate increased with an increase in the nanoparticle volume fraction in the bulk and correlated qualitatively with the change in the substrate wettability. The extent of the wettability alteration depends on the volume fraction of the nanoparticles, their size, and the type of substrate. We found a strong correlation between the change in the substrate wettability and the nanoparticle volume fraction in the layer closer to the substrate surface. PMID- 25919687 TI - 'Virtual lesion' in pain research; a study on magnetic stimulation of the primary motor cortex. AB - BACKGROUND: 'Virtual lesion' ('VL') is a transient disruption of cortical activity during task performance. It can be induced by single pulses or short trains of transcranial magnetic stimulation (TMS) directed to functionally relevant brain areas. We applied 'VL' methodology of a short train of TMS given on top of experimental tonic pain, expecting to see changes in pain scores. METHODS: Thirty young healthy subjects (15 women) were assessed with active ('VL') or 'sham' TMS in different sessions, randomly. In each session, 30 sec long contact heat (47.5 degrees C, right forearm) was applied stand-alone ('baseline') and with 5 sec-long 10 Hz-TMS over left primary motor cortex (M1) starting at 17 sec of the heat stimulation. RESULTS: Pain scores decreased after 'VL' or 'sham' (p < 0.001). Independently of the type of TMS, pain reduction was stronger in women (p = 0.012). A triple Sex x Stimulation type ('VL' or 'sham') x Condition ('baseline' heat pain vs. heat pain with TMS) interaction (p = 0.027) indicated stronger pain reduction by 'VL' in women (p = 0.008) and not in men (p = 0.78) as compared to 'baseline'. Pain catastrophizing and perceived stress ratings affected the model (p = 0.010 and p < 0.001, respectively), but without sex differences. CONCLUSIONS: This study indicates that interactions between cortical excitability of the motor cortex and nociceptive processing may be gender-related. PMID- 25919688 TI - LINE-1 Methylation Status Correlates Significantly to Post-Therapeutic Recurrence in Stage III Colon Cancer Patients Receiving FOLFOX-4 Adjuvant Chemotherapy. AB - BACKGROUND: Methylation levels of long interspersed nucleotide elements (LINE-1) are representative of genome-wide methylation status and crucial in maintaining genomic stability and expression. Their prognostic impact on colon cancer patients receiving adjuvant chemotherapy has not been well established. We evaluated the association between LINE-1 methylation status and clinicopathologic features and postoperative oncological outcomes in stage III colon cancer patients. MATERIALS AND METHODS: 129 UICC stage III colon cancer patients who had received radical resection and FOLFOX adjuvant chemotherapy were enrolled. Global methylation was estimated by analyzing tumor LINE-1 methylation status using bisulfite-polymerase chain reaction (PCR) and pyrosequencing assay. Demographics, clinicopathological data, and postoperative outcomes were recorded by trained abstractors. Outcome measurements included postoperative recurrence and disease free survival. Univariate, multivariate, and survival analyses were conducted to identify prognostic factors of oncological outcomes. RESULTS: The LINE-1 methylation of all 129 patients was measured on a 0-100 scale (mean 63.3; median 63.7, standard deviation 7.1), LINE-1 hypomethylation was more common in patients aged 65 years and above (61.7%+/-7.6% vs. 64.6+/-6.4, p=0.019) and those with post-therapeutic recurrence (61.7+/-7.4 vs 64.3+/-6.7, p=0.041). Considering risk adjustment, LINE-1 hypomethylation was found to be an independent risk factor of post-therapeutic recurrence (Adjusted OR=14.1, p=0.012). Kaplan-Meier analysis indicated that patients in the low methylation group had shorter period of disease free survival (p=0.01). In a stratified analysis that included 48 patients with post-therapeutic recurrence, it was found that those who experienced shorter period of disease free survival (?6 months) appeared to have lower LINE-1 methylation levels than patients who reported of recurrence after 6 months (56.68+/-15.75 vs. 63.55+/-7.57, p=0.041). CONCLUSION: There was a significantly greater risk of early postoperative recurrence and a shorter period of disease-free survival in Stage III colon cancer patients exhibiting LINE-1 hypomethylation status after being treated with radical resection and FOLFOX chemotherapy. PMID- 25919689 TI - Acute zonal occult outer retinopathy in Japanese patients: clinical features, visual function, and factors affecting visual function. AB - PURPOSE: To evaluate the clinical features and investigate their relationship with visual function in Japanese patients with acute zonal occult outer retinopathy (AZOOR). METHODS: Fifty-two eyes of 38 Japanese AZOOR patients (31 female and 7 male patients; mean age at first visit, 35.0 years; median follow-up duration, 31 months) were retrospectively collected: 31 untreated eyes with good visual acuity and 21 systemic corticosteroid-treated eyes with progressive visual acuity loss. Variables affecting the logMAR values of best-corrected visual acuity (BCVA) and the mean deviation (MD) on Humphrey perimetry at initial and final visits were examined using multiple stepwise linear regression analysis. RESULTS: In untreated eyes, the mean MD at the final visit was significantly higher than that at the initial visit (P = 0.00002). In corticosteroid-treated eyes, the logMAR BCVA and MD at the final visit were significantly better than the initial values (P = 0.007 and P = 0.02, respectively). The final logMAR BCVA was 0.0 or less in 85% of patients. Variables affecting initial visual function were moderate anterior vitreous cells, myopia severity, and a-wave amplitudes on electroretinography; factors affecting final visual function were the initial MD values, female sex, moderate anterior vitreous cells, and retinal atrophy. CONCLUSIONS: Our data indicated that visual functions in enrolled patients significantly improved spontaneously or after systemic corticosteroids therapy, suggesting that Japanese patients with AZOOR have good visual outcomes during the follow-up period of this study. Furthermore, initial visual field defects, gender, anterior vitreous cells, and retinal atrophy affected final visual functions in these patients. PMID- 25919690 TI - Surface Modification and Characterisation of Silk Fibroin Fabric Produced by the Layer-by-Layer Self-Assembly of Multilayer Alginate/Regenerated Silk Fibroin. AB - Silk-based medical products have a long history of use as a material for surgical sutures because of their desirable mechanical properties. However, silk fibroin fabric has been reported to be haemolytic when in direct contact with blood. The layer-by-layer self-assembly technique provides a method for surface modification to improve the biocompatibility of silk fibroin fabrics. Regenerated silk fibroin and alginate, which have excellent biocompatibility and low immunogenicity, are outstanding candidates for polyelectrolyte deposition. In this study, silk fabric was degummed and positively charged to create a silk fibroin fabric that could undergo self-assembly. The multilayer self-assembly of the silk fibroin fabric was achieved by alternating the polyelectrolyte deposition of a negatively charged alginate solution (pH = 8) and a positively charged regenerated silk fibroin solution (pH = 2). Finally, the negatively charged regenerated silk fibroin solution (pH = 8) was used to assemble the outermost layer of the fabric so that the surface would be negatively charged. A stable structural transition was induced using 75% ethanol. The thickness and morphology were characterised using atomic force microscopy. The properties of the self-assembled silk fibroin fabric, such as the bursting strength, thermal stability and flushing stability, indicated that the fabric was stable. In addition, the cytocompatibility and haemocompatibility of the self-assembled silk fibroin fabrics were evaluated. The results indicated that the biocompatibility of the self-assembled multilayers was acceptable and that it improved markedly. In particular, after the self-assembly, the fabric was able to prevent platelet adhesion. Furthermore, other non haemolytic biomaterials can be created through self-assembly of more than 1.5 bilayers, and we propose that self-assembled silk fibroin fabric may be an attractive candidate for anticoagulation applications and for promoting endothelial cell adhesion for vascular prostheses. PMID- 25919691 TI - Spectroscopy and Dynamics of Jet-Cooled Polyynes in a Slit Supersonic Discharge: Sub-Doppler Infrared Studies of Diacetylene HCCCCH. AB - Fundamental, bending (nu6, nu7, nu8, nu9), and CC-stretch (nu2, nu3) hot band spectra in the antisymmetric CH stretch (nu4) region near 3330 cm(-1) have been observed and analyzed for jet cooled diacetylene (HC=C-C=CH) under sub-Doppler conditions. Diacetylene is generated in situ in the throat of a pulsed supersonic slit expansion by discharge dissociation of acetylene to form ethynyl (C=CH) + H, followed by radical attack (HC=CH + C=C-H) to form HC=C-C=CH + H. The combination of (i) sub-Doppler line widths and (ii) absence of spectral congestion permits rotational structure and Coriolis interactions in the nu4 CH stretch fundamental to be observed and analyzed with improved precision. Of particular dynamical interest, the spectra reveal diacteylene formation in highly excited internal vibrational states. Specifically, multiple Pi <- Pi and Delta <- Delta hot bands built on the nu4 CH stretch fundamental are observed, due to doubly degenerate bending vibrations [cis C=C-H bend (nu6), trans C-C=C bend (nu7), trans C=C-H bend (nu8) and cis C-C=C bend (nu9)], as well as a heretofore unobserved Sigma <- Sigma band assigned to excitation of nu2 or 2nu3 CC stretch. Boltzmann analysis yields populations consistent with universally cold rotations (Trot ~ 15 +/- 5 K) and yet superthermal vibrations (Tvib ~ 85-430 K), the latter of which is quite anomalous for the high collision densities in a slit jet expansion. In order to elucidate the physical mechanism for this excess vibrational excitation, high level ab initio CCSD(T) calculations have been pursued with explicitly correlated basis sets (VnZ-f12; n = 2,3) and extrapolated to the complete basis set (CBS) limit using MOLPRO quantum chemistry software. The results suggest that the extensive hot band structure observed arises from (i) highly exothermic CCH + HCCH addition to yield a strongly bent HCCHCCH radical intermediate (DeltaH = 62.6 kcal/mol), followed by (ii) rapid fragmentation over a submerged transition state barrier (DeltaH = -18.9 kcal/mol) to form vibrationally hot diacetylene + H products (DeltaH = -25.6 kcal/mol), and consistent with crossed molecular beam studies by Kaiser et al. [Phys. Chem. Chem. Phys. 2002, 4, 2950.] Finally, RRKM fragmentation rates for this complex are calculated, which exceed collision frequencies in the slit jet expansion and suggest near unity quantum efficiency for diacetylene formation. PMID- 25919692 TI - Modulation of the leptin receptor mediates tumor growth and migration of pancreatic cancer cells. AB - Obesity has been implicated as a significant risk factor for development of pancreatic cancer. In the setting of obesity, a systemic chronic inflammatory response is characterized by alterations in the production and secretion of a wide variety of growth factors. Leptin is a hormone whose level increases drastically in the serum of obese patients. High fat diet induced obesity in mice leads to an overall increased body weight, pancreatic weight, serum leptin, and pancreatic tissue leptin levels. Here we report the contribution of obesity and leptin to pancreatic cancer growth utilizing an in vivo orthotopic murine pancreatic cancer model, which resulted in increased tumor proliferation with concomitant increased tumor burden in the diet induced obese mice compared to lean mice. Human and murine pancreatic cancer cell lines were found to express the short as well as the long form of the leptin receptor and functionally responded to leptin induced activation through an increased phosphorylation of AKT473. In vitro, leptin stimulation increased cellular migration which was blocked by addition of a PI3K inhibitor. In vivo, depletion of the leptin receptor through shRNA knockdown partially abrogated increased orthotopic tumor growth in obese mice. These findings suggest that leptin contributes to pancreatic tumor growth through activation of the PI3K/AKT pathway, which promotes pancreatic tumor cell migration. PMID- 25919694 TI - A Morphological and Molecular Study of Spectatus spectatus (Kathlaniidae), Including Redescription of the Species and Amendment of Genus Diagnosis. AB - Spectatus spectatus Travassos, 1923 (Nematoda: Kathlaniidae) found in the intestine of Piaractus mesopotamicus (Holmberg, 1887) (Characiformes: Serrasalmidae) from the River Miranda, Mato Grosso do Sul, Brazil is redescribed based on morphological evaluation of newly collected material and examination of type and voucher specimens from the Colecao Helmintologica do Instituto Oswaldo Cruz. The following characteristics previously unreported or insufficiently described were observed: morphology of lips, presence of lamellae-like supplementary lips, presence of pharynx and cuticular ring surrounding the oral opening associated with a complex cuticular apparatus anterior to the pharynx, the number and arrangement of caudal papillae (13 pairs plus 1 unpaired), and the position of nerve ring. Since S. spectatus is the type species of Spectatus, the diagnosis of this Neotropical genus is amended. Synonymy of Chabaudinema Diaz Ungria, 1968 with Spectatus, first proposed in 1980 by Baker, is supported by the present data. Molecular data that include the first sequence of the SSU rDNA for any species of Spectatus indicate a basal position of S. spectatus within Cosmocercoidea, forming a distant lineage from that comprising 2 species of Falcaustra Lane, 1915. This separate position of S. spectatus supports validity of the genus. PMID- 25919693 TI - Differences in Birth Weight Associated with the 2008 Beijing Olympics Air Pollution Reduction: Results from a Natural Experiment. AB - BACKGROUND: Previous studies have reported decreased birth weight associated with increased air pollutant concentrations during pregnancy. However, it is not clear when during pregnancy increases in air pollution are associated with the largest differences in birth weight. OBJECTIVES: Using the natural experiment of air pollution declines during the 2008 Beijing Olympics, we evaluated whether having specific months of pregnancy (i.e., 1st...8th) during the 2008 Olympics period was associated with larger birth weights, compared with pregnancies during the same dates in 2007 or 2009. METHODS: Using n = 83,672 term births to mothers residing in four urban districts of Beijing, we estimated the difference in birth weight associated with having individual months of pregnancy during the 2008 Olympics (8 August-24 September 2008) compared with the same dates in 2007 and 2009. We also estimated the difference in birth weight associated with interquartile range (IQR) increases in mean ambient particulate matter <= 2.5 MUm in aerodynamic diameter (PM2.5), sulfur dioxide (SO2), nitrogen dioxide (NO2), and carbon monoxide (CO) concentrations during each pregnancy month. RESULTS: Babies whose 8th month of gestation occurred during the 2008 Olympics were, on average, 23 g larger (95% CI: 5 g, 40 g) than babies whose 8th month occurred during the same calendar dates in 2007 or 2009. IQR increases in PM2.5 (19.8 MUg/m3), CO (0.3 ppm), SO2 (1.8 ppb), and NO2 (13.6 ppb) concentrations during the 8th month of pregnancy were associated with 18 g (95% CI: -32 g, -3 g), 17 g (95% CI: -28 g, -6 g), 23 g (95% CI: -36 g, -10 g), and 34 g (95% CI: -70 g, 3 g) decreases in birth weight, respectively. We did not see significant associations for months 1-7. CONCLUSIONS: Short-term decreases in air pollution late in pregnancy in Beijing during the 2008 Summer Olympics, a normally heavily polluted city, were associated with higher birth weight. CITATION: Rich DQ, Liu K, Zhang J, Thurston SW, Stevens TP, Pan Y, Kane C, Weinberger B, Ohman-Strickland P, Woodruff TJ, Duan X, Assibey-Mensah V, Zhang J. 2015. Differences in birth weight associated with the 2008 Beijing Olympics air pollution reduction: results from a natural experiment. Environ Health Perspect 123:880-887; http://dx.doi.org/10.1289/ehp.1408795. PMID- 25919695 TI - Rod-like beta-FeOOH@poly(dopamine)-Au-poly(dopamine) nanocatalysts with improved recyclable activities. AB - A novel rod-like beta-FeOOH@poly(dopamine)-Au-poly(dopamine) nanocomposite is developed for recyclable catalysis. Firstly, the rod-like beta-FeOOH template was coated in situ by a layer of poly(dopamine) (PDA) to form a core/shell nanostructure. Then the negatively charged Au nanocatalysts were well-immobilized onto the periphery of the beta-FeOOH@PDA nanorod. To protect the Au nanocrystals from leaching during the catalytic reactions, another PDA layer was coated onto the above particles to form a sandwich-like PDA-Au-PDA shell on the beta-FeOOH rod core. The reduction of Rhodamine B (RhB) was introduced as a model reaction to evaluate the catalytic activity of the as-prepared nanocomposites. It was found that the catalytic rate sharply increased with an increasing amount of the nanocatalyst. Benefitting from the thin outer layer of PDA, the recyclability of the nanocatalyst dramatically increased. After five times of catalytic reaction, the activity was maintained as high as 98.3%, while the beta-FeOOH@PDA-Au showed it to be retained at only 73.4%. PMID- 25919697 TI - Total Synthesis of 7-Hydroxymurrayazolinine, Murrayamine D, and Mahanine via m Nitro Group Activated Pyran Annulation. AB - The facile total synthesis of the natural product (+/-)-mahanine was obtained in eight steps with an overall 52% yield from readily accessible known nitrophenol derivative 6. After a one-step, acid-catalyzed annulation, two additional natural products were formed including 7-hydroxymurrayazolinine, representing its first reported total synthesis. In the whole process, the introduction of the m-nitro group significantly enhanced the key pyran annulation reaction through inductive effects. PMID- 25919696 TI - MicroRNA-224 is associated with colorectal cancer progression and response to 5 fluorouracil-based chemotherapy by KRAS-dependent and -independent mechanisms. AB - BACKGROUND: Colorectal cancers arise from benign adenomas, although not all adenomas progress to cancer and there are marked interpatient differences in disease progression. We have previously associated KRAS mutations with disease progression and reduced survival in colorectal cancer patients. METHODS: We used TaqMan low-density array (TLDA) qRT-PCR analysis to identify miRNAs differentially expressed in normal colorectal mucosa, adenomas and cancers and in isogeneic KRAS WT and mutant HCT116 cells, and used a variety of phenotypic assays to assess the influence of miRNA expression on KRAS activity, chemosensitivity, proliferation and invasion. RESULTS: MicroRNA-224 was differentially expressed in dysplastic colorectal disease and in isogeneic KRAS WT and mutant HCT116 cells. Antagomir-mediated miR-224 silencing in HCT116 KRAS WT cells phenocopied KRAS mutation, increased KRAS activity and ERK and AKT phosphorylation. 5-FU chemosensitivity was significantly increased in miR-224 knockdown cells, and in NIH3T3 cells expressing KRAS and BRAF mutant proteins. Bioinformatics analysis of predicted miR-224 target genes predicted altered cell proliferation, invasion and epithelial-mesenchymal transition (EMT) phenotypes that were experimentally confirmed in miR-224 knockdown cells. CONCLUSIONS: We describe a novel mechanism of KRAS regulation, and highlight the clinical utility of colorectal cancer-specific miRNAs as disease progression or clinical response biomarkers. PMID- 25919698 TI - Endoscopic clips for the closure of acute iatrogenic perforations: Where do we stand? AB - BACKGROUND AND AIM: Iatrogenic perforation of the gut during endoscopy remains an uncommon but critical complication with significant morbidity and probable mortality than usual surgical treatment. Some authors have adopted a non-surgical closure method in chosen cases and, since 1993, endoclips have been used to close perforation in the stomach. The endoscopic practice of endoclips has been commonly used in the gut for hemostasis. Currently, the use of endoscopic techniques is increasing for the closure of endoscopic submucosal dissection or endoscopic mucosal resection. Endoscopic perforations that improved with endoscopic closure in the literature prior to 2008 have been previously described. In the present article, we present a descriptive review of cases with iatrogenic perforation in the gut treated with endoclips between 2008 and 2014. METHODS: Comprehensive literature screening and a systematic review using PubMed and Medline was done for all reports published between January 2008 and December 2014 using the endoclip technique in the closure of iatrogenic perforations. RESULTS: A total of 47 studies published between 2008 and 2014 using endoclips for the closure of iatrogenic perforations of the gut (nine esophagus, 11 stomach, 15 duodenum, 12 colon and rectum) were found. All studies were explained briefly and summarized in a table. CONCLUSIONS: There is strong evidence to show the efficacy of endoclips in the management of iatrogenic perforations, especially when recognized early. Limitations of endoclipping such as inefficiency against large perforations may be overcome by improving novel techniques in the future. PMID- 25919699 TI - Views concerning patient dignity among relatives to patients experiencing psychosis. AB - BACKGROUND: Mental illness influences not only the suffering patient but often changes family life forever and results in experience of reduced dignity for both patients and relatives. AIM: The aim of this study was to reveal relatives' opinions regarding what is important for taking care of patients' dignity. PARTICIPANTS: Thirteen relatives of patients experiencing psychosis were recruited through a relatives' user organisation. RESEARCH DESIGN: The methodological approach is Q methodology. A Q sample of 51 statements was sorted in a quasinormal distribution curve. Postinterviews were conducted with all participants. RESULTS: Four viewpoints emerged described as 'value based', 'expectations', 'asymmetric' and 'nuanced'. CONCLUSION: Focus on overarching values such as honesty and respect, to involve patients and relatives in care, by reducing asymmetry between patients and staff, with staff taking total responsibility for a patient's situation when needed, all represent aspects of taking care of patient dignity. PMID- 25919701 TI - Efficient free fatty acid production in engineered Escherichia coli strains using soybean oligosaccharides as feedstock. AB - To be competitive with current petrochemicals, microbial synthesis of free fatty acids can be made to rely on a variety of renewable resources rather than on food carbon sources, which increase its attraction for governments and companies. Industrial waste soybean meal is an inexpensive feedstock, which contains soluble sugars such as stachyose, raffinose, sucrose, glucose, galactose, and fructose. Free fatty acids were produced in this report by introducing an acyl-ACP carrier protein thioesterase and (3R)-hydroxyacyl-ACP dehydratase into E. coli. Plasmid pRU600 bearing genes involved in raffinose and sucrose metabolism was also transformed into engineered E. coli strains, which allowed more efficient utilization of these two kinds of specific oligosaccharide present in the soybean meal extract. Strain ML103 (pRU600, pXZ18Z) produced ~1.60 and 2.66 g/L of free fatty acids on sucrose and raffinose, respectively. A higher level of 2.92 g/L fatty acids was obtained on sugar mixture. The fatty acid production using hydrolysate obtained from acid or enzyme based hydrolysis was evaluated. Engineered strains just produced ~0.21 g/L of free fatty acids with soybean meal acid hydrolysate. However, a fatty acid production of 2.61 g/L with a high yield of 0.19 g/g total sugar was observed on an enzymatic hydrolysate. The results suggest that complex mixtures of oligosaccharides derived from soybean meal can serve as viable feedstock to produce free fatty acids. Enzymatic hydrolysis acts as a much more efficient treatment than acid hydrolysis to facilitate the transformation of industrial waste from soybean processing to high value added chemicals. PMID- 25919700 TI - AMP-18 Targets p21 to Maintain Epithelial Homeostasis. AB - Dysregulated homeostasis of epithelial cells resulting in disruption of mucosal barrier function is an important pathogenic mechanism in inflammatory bowel diseases (IBD). We have characterized a novel gastric protein, Antrum Mucosal Protein (AMP)-18, that has pleiotropic properties; it is mitogenic, anti apoptotic and can stimulate formation of tight junctions. A 21-mer synthetic peptide derived from AMP-18 exhibits the same biological functions as the full length protein and is an effective therapeutic agent in mouse models of IBD. In this study we set out to characterize therapeutic mechanisms and identify molecular targets by which AMP-18 maintains and restores disrupted epithelial homeostasis in cultured intestinal epithelial cells and a mouse model of IBD. Tumor necrosis factor (TNF)-alpha, a pro-inflammatory cytokine known to mediate gastrointestinal (GI) mucosal injury in IBD, was used to induce intestinal epithelial cell injury, and study the effects of AMP-18 on apoptosis and the cell cycle. An apoptosis array used to search for targets of AMP-18 in cells exposed to TNF-alpha identified the cyclin-dependent kinase inhibitor p21 WAF1/CIP1. Treatment with AMP-18 blunted increases in p21 expression and apoptosis, while reversing disturbed cell cycle kinetics induced by TNF-alpha. AMP-18 appears to act through PI3K/AKT pathways to increase p21 phosphorylation, thereby reducing its nuclear accumulation to overcome the antiproliferative effects of TNF-alpha. In vitamin D receptor-deficient mice with TNBS-induced IBD, the observed increase in p21 expression in colonic epithelial cells was suppressed by treatment with AMP peptide. The results indicate that AMP-18 can maintain and/or restore the homeostatic balance between proliferation and apoptosis in intestinal epithelial cells to protect and repair mucosal barrier homeostasis and function, suggesting a therapeutic role in IBD. PMID- 25919702 TI - The impact of job status on quality of life: general population versus long-term cancer survivors. AB - OBJECTIVE: Cancer is one of the leading causes of morbidity and mortality worldwide. Recently, survival rates of cancer patients have been improving. Many patients are diagnosed with cancer at an age when their career is an important component of their lives, and job status can have a significant impact on health related quality of life (HRQOL). The purpose of this study was to determine the association of job status and HRQOL with respect to particular situations, such as long-term cancer survival and the presence of comorbid conditions, as compared with the general population. METHODS: Data on a total of 27,089 eligible participants from the 2007-2012 Korea National Health and Nutrition Examination Survey were used in the study. To identify factors associated with the HRQOL of long-term cancer survivors, multiple linear regression analysis was performed. HRQOL was measured by the EuroQol five-dimension instrument (EQ-5D). RESULTS: People who once had a job and lost it because of health issues have been shown to have a lower EQ-5D (beta =-8.997, p < 0.0001) than those who still have their jobs. Although long-term cancer survivors with comorbid conditions showed only a trend toward a lower EQ-5D, in a subgroup analysis, those in the 'Job loss due to health issue' group had a significantly lower EQ-5D (beta =-8.739, p < 0.0001). CONCLUSIONS: There was a significant association between job status and HRQOL in study participants. This study suggests that individuals who are long-term cancer survivors or have comorbid conditions need particular attention, and a specialized job rehabilitation program should be developed. PMID- 25919703 TI - Genome-wide gene expression dynamics of the fungal pathogen Dothistroma septosporum throughout its infection cycle of the gymnosperm host Pinus radiata. AB - We present genome-wide gene expression patterns as a time series through the infection cycle of the fungal pine needle blight pathogen, Dothistroma septosporum, as it invades its gymnosperm host, Pinus radiata. We determined the molecular changes at three stages of the disease cycle: epiphytic/biotrophic (early), initial necrosis (mid) and mature sporulating lesion (late). Over 1.7 billion combined plant and fungal reads were sequenced to obtain 3.2 million fungal-specific reads, which comprised as little as 0.1% of the sample reads early in infection. This enriched dataset shows that the initial biotrophic stage is characterized by the up-regulation of genes encoding fungal cell wall modifying enzymes and signalling proteins. Later necrotrophic stages show the up regulation of genes for secondary metabolism, putative effectors, oxidoreductases, transporters and starch degradation. This in-depth through-time transcriptomic study provides our first snapshot of the gene expression dynamics that characterize infection by this fungal pathogen in its gymnosperm host. PMID- 25919704 TI - Ethnic-specific relationships between haemostatic and oxidative stress markers in black and white South Africans: The SABPA study. AB - Haemostatic- and oxidative stress markers are associated with increased cardiovascular risk. In the black population, evidence exists that both an imbalance in the haemostatic system and oxidative stress link with the development of hypertension. However, it is unclear whether these two risk components function independently or are related, specifically in the black population, who is known to have a high prevalence of stroke. We aimed to investigate associations between the haemostatic system and oxidative stress in black and white South Africans. We performed a cross-sectional study including 181 black (mean age, 44; 51.4% women) and 209 white (mean age, 45; 51.7% women) teachers. Several markers of the haemostatic- (von Willebrand factor, fibrinogen, plasminogen activator inhibitor-1, d-dimer and clot lysis time) and oxidant antioxidant (serum peroxides, total glutathione, glutathione peroxidase- and glutathione reductase activities) systems were measured. Along with a worsened cardiovascular profile, the black group had higher haemostatic-, inflammation- and oxidative stress markers as well as decreased glutathione peroxidase activity. In multiple regression analyses, fibrinogen was positively associated with serum peroxides (p < 0.001) in both ethnic groups. In the black population, we found negative associations of von Willebrand factor and clot lysis time with glutathione peroxidase activity (p <= 0.008), while a positive association existed between clot lysis time and serum peroxides (p = 0.011) in the white population. We conclude that in the black population, decreased GPx activity accompanies an altered haemostatic profile, while in the white population associations may suggest that serum peroxides impair fibrin clot lysis. PMID- 25919705 TI - Neutrophil/lymphocyte ratio in granulomatous disease. PMID- 25919706 TI - Witnessing magnetic twist with high-resolution observation from the 1.6-m New Solar Telescope. AB - Magnetic flux ropes are highly twisted, current-carrying magnetic fields. They are crucial for the instability of plasma involved in solar eruptions, which may lead to adverse space weather effects. Here we present observations of a flaring using the highest resolution chromospheric images from the 1.6-m New Solar Telescope at Big Bear Solar Observatory, supplemented by a magnetic field extrapolation model. A set of loops initially appear to peel off from an overall inverse S-shaped flux bundle, and then develop into a multi-stranded twisted flux rope, producing a two-ribbon flare. We show evidence that the flux rope is embedded in sheared arcades and becomes unstable following the enhancement of its twists. The subsequent motion of the flux rope is confined due to the strong strapping effect of the overlying field. These results provide a first opportunity to witness the detailed structure and evolution of flux ropes in the low solar atmosphere. PMID- 25919707 TI - A High-Rate and Ultralong-Life Sodium-Ion Battery Based on NaTi2 (PO4 )3 Nanocubes with Synergistic Coating of Carbon and Rutile TiO2. AB - Highly regular NaTi2 (PO4 )3 nanocubes with synergistic nanocoatings of rutile TiO2 and carbon are prepared as an electrode material for sodium-ion batteries. It exhibits a high rate and ultralong life performance simultaneously, and a capacity retention of 89.3% after 10 000 cycles is achieved. PMID- 25919708 TI - Changing patterns of alpha agonist medication use in children and adolescents 2009-2011. AB - OBJECTIVES: The purpose of this study was to describe rates and patterns of long- and short-acting alpha agonist use for behavioral problems in a primary care population following Food and Drug Administration (FDA) approval of the long acting alpha agonists guanfacine and clonidine. METHODS: Children and adolescents 4-18 years of age, who received an alpha agonist prescription between 2009 and 2011, were identified from a sample of 45 United States primary care practices in two electronic health record-based research networks. Alpha agonist receipt was identified using National Drug Codes and medication names. The proportion of subjects receiving long- and short-acting prescriptions in each year was calculated and examined with respect to reported mental health diagnoses, and whether indications for use were on-label, had evidence from clinical trials, or had no trial evidence. RESULTS: In a cohort of 282,875 subjects, 27,671 (10%) received any psychotropic medication and only 4,227 subjects (1.5%) received at least one prescription for an alpha agonist, most commonly a short-acting formulation (83%). Only 20% of alpha agonist use was on-label (use of long-acting formulations for attention-deficit/hyperactivity disorder [ADHD]). Most subjects (68%) received alpha agonists for indications with evidence of efficacy from clinical trials but no FDA approval, primarily short-acting formulations for ADHD and autism; 12% received alpha agonists for diagnoses lacking randomized clinical trial evidence in children, including sleep disorders and anxiety, or for which there was no documented mental health diagnosis. Rates of long-acting alpha agonist use increased more than 20-fold from 0.2% to 4%, whereas rates of short acting alpha agonist use grew only slightly between 2009 and 2011 from 10.6% to 11.3%. CONCLUSIONS: Alpha agonist use was uncommon in this population, and most subjects received short-acting forms for conditions that were off-label, but with clinical trial evidence. The safety and efficacy of use for conditions, including sleep disorders and anxiety, lacking evidence from randomized trials, warrant further investigation. PMID- 25919709 TI - Involvement of Histidine Residue His382 in pH Regulation of MCT4 Activity. AB - Monocarboxylate transporter 4 (MCT4) is a pH-dependent bi-directional lactate transporter. Transport of lactate via MCT4 is increased by extracellular acidification. We investigated the critical histidine residue involved in pH regulation of MCT4 function. Transport of lactate via MCT4 was measured by using a Xenopus laevis oocyte expression system. MCT4-mediated lactate transport was inhibited by Zn2+ in a pH physiological condition but not in an acidic condition. The histidine modifier DEPC (diethyl pyrocarbonate) reduced MCT4 activity but did not completely inactivate MCT4. After treatment with DEPC, pH regulation of MCT4 function was completely knocked out. Inhibitory effects of DEPC were reversed by hydroxylamine and suppressed in the presence of excess lactate and Zn2+. Therefore, we performed an experiment in which the extracellular histidine residue was replaced with alanine. Consequently, the pH regulation of MCT4-H382A function was also knocked out. Our findings demonstrate that the histidine residue His382 in the extracellular loop of the transporter is essential for pH regulation of MCT4-mediated substrate transport activity. PMID- 25919710 TI - The protein quality control machinery regulates its misassembled proteasome subunits. AB - Cellular toxicity introduced by protein misfolding threatens cell fitness and viability. Failure to eliminate these polypeptides is associated with various aggregation diseases. In eukaryotes, the ubiquitin proteasome system (UPS) plays a vital role in protein quality control (PQC), by selectively targeting misfolded proteins for degradation. While the assembly of the proteasome can be naturally impaired by many factors, the regulatory pathways that mediate the sorting and elimination of misassembled proteasomal subunits are poorly understood. Here, we reveal how the dysfunctional proteasome is controlled by the PQC machinery. We found that among the multilayered quality control mechanisms, UPS mediated degradation of its own misassembled subunits is the favored pathway. We also demonstrated that the Hsp42 chaperone mediates an alternative pathway, the accumulation of these subunits in cytoprotective compartments. Thus, we show that proteasome homeostasis is controlled through probing the level of proteasome assembly, and the interplay between UPS mediated degradation or their sorting into distinct cellular compartments. PMID- 25919720 TI - Chairs and their faculty: reducing "top" stress; enhancing "middle" leadership. PMID- 25919711 TI - Cardiolipin remodeling by TAZ/tafazzin is selectively required for the initiation of mitophagy. AB - Tafazzin (TAZ) is a phospholipid transacylase that catalyzes the remodeling of cardiolipin, a mitochondrial phospholipid required for oxidative phosphorylation. Mutations of TAZ cause Barth syndrome, which is characterized by mitochondrial dysfunction and dilated cardiomyopathy, leading to premature death. However, the molecular mechanisms underlying the cause of mitochondrial dysfunction in Barth syndrome remain poorly understood. Here we investigated the role of TAZ in regulating mitochondrial function and mitophagy. Using primary mouse embryonic fibroblasts (MEFs) with doxycycline-inducible knockdown of Taz, we showed that TAZ deficiency in MEFs caused defective mitophagosome biogenesis, but not other autophagic processes. Consistent with a key role of mitophagy in mitochondria quality control, TAZ deficiency in MEFs also led to impaired oxidative phosphorylation and severe oxidative stress. Together, these findings provide key insights on mitochondrial dysfunction in Barth syndrome, suggesting that pharmacological restoration of mitophagy may provide a novel treatment for this lethal condition. PMID- 25919721 TI - When Medications Work, Let's Make Sure Patients Get Them! PMID- 25919722 TI - 50 Years Ago in The Journal of Pediatrics: Pulmonary Function in Children with Pectus Excavatum. PMID- 25919723 TI - 50 Years Ago in The Journal of Pediatrics: Teratogenic Effect of Azathioprine (Imuran). PMID- 25919724 TI - Economic Burden of Atopic Dermatitis in High-Risk Infants Receiving Cow's Milk or Partially Hydrolyzed 100% Whey-Based Formula. AB - OBJECTIVE: To estimate the health and economic impact of feeding partially hydrolyzed formula-whey (PHF-W) instead of standard cow's milk formula (CMF) for the first 4 months of life among US infants at high risk for developing atopic dermatitis (AD). STUDY DESIGN: A Markov model was developed integrating published data, a survey of US pediatricians, costing sources and market data, and expert opinion. Key modeled outcomes included reduction in AD risk, time spent post AD diagnosis, days without AD flare, and AD-related costs. Costs and clinical consequences were discounted at 3% annually. RESULTS: An estimated absolute 14 percentage point reduction in AD risk was calculated with the use of PHF-W compared with CMF (95% CI for difference, 3%-22%). Relative to CMF, PHF-W decreased the time spent post-AD diagnosis by 8.3 months (95% CI, 2.78-13.31) per child and increased days without AD flare by 39 days (95% CI, 13-63) per child. The AD-related, 6-year total cost estimate was $495 less (95% CI, -$813 to -$157) per child with PHF-W ($724 per child; 95% CI, $385-$1269) compared with CMF ($1219 per child; 95% CI, $741-$1824). CONCLUSION: Utilization of PHF-W in place of CMF as the initial infant formula administered to high-risk US infants not exclusively breastfed during the first 4 months of life may reduce the incidence and economic burden of AD. Broad implementation of this strategy could result in a minimum savings of $355 million per year to society. PMID- 25919725 TI - 50 Years Ago in The Journal of Pediatrics: An Approach to Well Baby Care during the First Months. PMID- 25919726 TI - The Association of Vitamin D Status with Acute Respiratory Morbidity in Preterm Infants. AB - OBJECTIVE: To assess the association between serum 25-hydroxyvitamin D (25OHD) levels and outcomes in preterm infants (<32 weeks gestation). STUDY DESIGN: Serum 25OHD was measured in mothers and their infants within 24 hours of birth, before the start of enteral vitamin D supplementation, and at discharge from the neonatal intensive care unit. We evaluated the associations between vitamin D status and various early preterm outcomes. RESULTS: Ninety-four preterm infants and their mothers were included; 92% of the infants had a 25OHD level<=50 nmol/L (20 ng/mL), and 64% had a 25OHD level<30 nmol/L (12 ng/mL). A low 25OHD level (<30 nmol/L) in preterm infants at birth was associated with increased oxygen requirement (P=.008), increased duration of intermittent positive-pressure ventilation during resuscitation at delivery (P=.032), and greater need for assisted ventilation (P=.013). CONCLUSION: We observed a high prevalence of low 25OHD (<30 nmol/L), and found an association between vitamin D status and acute respiratory morbidity in preterm infants after birth. PMID- 25919727 TI - Late-onset group B streptococcal meningitis has cerebrovascular complications. AB - OBJECTIVE: To describe cerebrovascular diseases related to late-onset group B Streptococcus (GBS) meningitis. STUDY DESIGN: Retrospective case series. Patients treated for cerebrovascular complication of late-onset GBS meningitis over 5 years were identified through neuroradiology and microbiology databases. Patient charts were reviewed with regard to clinical presentation, laboratory findings, including GBS subtype, treatment, clinical course, and outcome. Cerebral magnetic resonance imaging was reviewed with special emphasis on stroke pattern and cerebrovascular findings. RESULTS: Fourteen patients were identified. In 6 out of 9 patients serotype III was causative and positive for surface protein hvgA in 5. Ten had arterial ischemic stroke accompanied by a cerebral sinovenous thrombosis in 2 patients. Evidence of cerebral vasculopathy was found in 4 cases. The stroke pattern was variable with cortical, multifocal ischemia, basal ganglia involvement, or had a clear territorial arterial infarction. Ten patients were treated with anticoagulation. No significant bleeding complications, and no recurrent strokes occurred. Twelve patients had clinical and/or subclinical seizures. Developmental outcome was good in 8 cases. Six patients had moderate to severe developmental delay. Central nervous system complications included subdural empyema, hydrocephalus, epilepsy, microcephaly, and hemiplegia. CONCLUSIONS: Late-onset GBS meningitis can be complicated by severe cerebrovascular disease, including arterial ischemic stroke and cerebral sinovenous thrombosis. These complications may be underestimated. We recommend a low threshold for cerebral imaging in these cases. Future studies on the exact incidence, the role of GBS subtypes, and on safety and efficiency of preventive anticoagulation therapy are warranted. PMID- 25919728 TI - Neonatal sepsis 2004-2013: the rise and fall of coagulase-negative staphylococci. AB - OBJECTIVES: To evaluate data for the period 2004-2013 to identify changes in demographics, pathogens, and outcomes in a single, level IV neonatal intensive care unit. STUDY DESIGN: Sepsis episodes were identified prospectively and additional information obtained retrospectively from infants with sepsis while in the neonatal intensive care unit from 2004 to 2013. Demographics, hospital course, and outcome data were collected and analyzed. Sepsis was categorized as early (<=3 days of life) or late-onset (>3 days of life). RESULTS: Four hundred fifty-two organisms were identified from 410 episodes of sepsis in 340 infants. Ninety percent of cases were late-onset. Rates of early-onset sepsis remained relatively static throughout the study period (0.9 per 1000 live births). For the first time in decades, most (60%) infants with early-onset sepsis were very low birth weight and Escherichia coli (45%) replaced group B streptococcus (36%) as the most common organism associated with early-onset sepsis. Rates of late-onset sepsis, particularly due to coagulase-negative staphylococci, decreased significantly after implementation of several infection-prevention initiatives. Coagulase-negative staphylococci were responsible for 31% of all cases from 2004 to 2009 but accounted for no cases of late-onset sepsis after 2011. CONCLUSIONS: The epidemiology and microbiology of early- and late-onset sepsis continue to change, impacted by targeted infection prevention efforts. We believe the decrease in sepsis indicates that these interventions have been successful, but additional surveillance and strategies based on evolving trends are necessary. PMID- 25919730 TI - 50 Years Ago in The Journal of Pediatrics: Mycoplasma pneumoniae (Eaton Atypical Pneumonia Agent) in Children's Respiratory Infections. PMID- 25919729 TI - Neonatal morphine exposure in very preterm infants-cerebral development and outcomes. AB - OBJECTIVE: To investigate the association of morphine exposure in very preterm infants with cerebral volumes and neurodevelopmental outcome from birth through middle childhood. STUDY DESIGN: Observational study of very preterm infants in the Victorian Infant Brain Study cohort. A total of 230 infants born <30 weeks' gestational age or <1250 g were recruited from all admissions to the neonatal intensive care unit of the Royal Women's Hospital. Fifty-seven (25%) infants received morphine analgesia during their neonatal intensive care unit stay at the attending physician's discretion. Primary outcomes were regional brain volumes at term and 7 years; neurobehavioral performance at term; and cognitive, motor, emotional, behavioral, communication, and executive function scores at age 2 and 7 years. Linear regressions were used to compare outcomes between participants who did and did not receive morphine. RESULTS: At term, preterm infants who received morphine had similar rates of gray matter injury to no-morphine infants, but a trend toward smaller cortical volumes in the orbitofrontal (Pleft=.002, Pright=.01) and subgenual (Pleft=.01) regions. At 7 years, cortical volumes did not differ between groups. At 2 years, morphine-exposed children were more likely to show behavioral dysregulation (P=.007) than no-morphine children, but at 7 years no detrimental impacts of morphine on neurobehavioral outcome were observed. CONCLUSIONS: Low-dose morphine analgesia received during neonatal intensive care was associated with early alterations in cerebral structure and short-term neurobehavioral problems that did not persist into childhood. PMID- 25919731 TI - The diagnosis of concussion in a pediatric emergency department. AB - OBJECTIVES: To compare the proportion of children diagnosed with a concussion by pediatric emergency physicians vs the proportion who met criteria for this injury as recommended by Zurich Fourth International Conference on Concussion consensus statement and to determine clinical variables associated with a physician diagnosis of a concussion. STUDY DESIGN: This was a prospective, cross-sectional study conducted at a tertiary care pediatric emergency department. We enrolled children ages 5 through 17 who presented with a head injury and collected data on demographics, mechanism of injury, head injury-related symptoms/signs, physician diagnosis, and discharge advice. RESULTS: We identified 495 children whose mean age was 10.1 years (SD 3.4 years); 308 (62.2%) were male. Emergency physicians diagnosed concussion in 200 (40.4%; 95% CI 36.1, 44.7) children, and 443 (89.5%; 95% CI 86.8, 92.2) met criteria for concussion in accordance with the Zurich consensus statement (P<.0001). Age>=10 years (OR 1.8), presentation>=1 day after injury (OR 2.4), injury from collision sports (OR 5.6), and symptoms of headache (OR 2.2) or amnesia (OR 3.4) were the variables significantly associated with an emergency physician's diagnosis of concussion. CONCLUSIONS: Pediatric emergency physicians diagnosed concussion less often relative to international consensus based guidelines and used a limited number of variables to make this diagnosis compared with current recommendations. Thus, pediatric emergency physicians may be missing cases of concussion and the corresponding opportunity to provide critical advice for cognitive and physical management. PMID- 25919732 TI - Safety of deep sedation in young children with sickle cell disease: a retrospective cohort study. AB - OBJECTIVE: To assess the rates and types of complications associated with deep sedation in children with sickle cell disease (SCD) and to explore potential risk factors. STUDY DESIGN: This was a retrospective cohort study of children with SCD and a comparison group of children without SCD who underwent magnetic resonance imaging with deep sedation. The rates of general and SCD-associated sedation complications were calculated, and potential associated clinical and laboratory variables were assessed. RESULTS: A total of 162 sedation records in 94 subjects with SCD and 324 sedation records in 321 subjects without SCD were assessed (mean age, 4.3 years in both groups). Pentobarbital, fentanyl, and midazolam were used in the majority of sedation episodes without routine presedation transfusion. Sedation-related complication rates did not differ significantly between the SCD and comparison groups. Within 1 month after the sedation procedure, 17 children (10%) experienced a vaso-occlusive pain episode (VOE), and 2 children (1.2%) developed acute chest syndrome. Preprocedure and postprocedure rates of these complications did not differ significantly. Subjects who developed VOE after sedation had a significantly higher VOE rate before sedation, but no other significant clinical or laboratory risk factors were identified. CONCLUSION: Deep sedation in young children with SCD using a standard protocol is safe, with a sedation-related complication rate comparable to that of the general pediatric population. The observed rate of VOE, although not significantly higher than expected, warrants further investigation. PMID- 25919733 TI - Recognition of elevated blood pressure in an outpatient pediatric tertiary care setting. AB - OBJECTIVE: To assess the prevalence of elevated blood pressure (BP) and its identification among outpatients at a pediatric tertiary care hospital and to assess clinician attitudes towards BP management. STUDY DESIGN: A retrospective review was undertaken of electronic medical record data of visits over the course of 1 year to 10 subspecialty divisions and 3 primary care services at an urban tertiary care hospital. Interviews of division/service representatives and a clinician survey on perceived role on BP care, practices, and protocols related to BP management were conducted. Elevated BP was defined as >=90th percentile (using US references); identification of elevated BP was defined as the presence of appropriate codes in the problem list or visit diagnoses. RESULTS: Among 29,000 patients (ages 2-17 years), 70% (those with >=1 BP measurement) were analyzed. Patients were as follows: 50% male; 42% white, 31% Hispanic, 16% black, 5% Asian, and 5% other/missing; 52% had Medicaid insurance. A total of 64% had normal BPs, 33% had 1-2 elevated BP measurements, and 3% had >=3 elevated BP measurements. Among those with >=3 elevated BP measurements, the median frequency of identification by division/service was 17%; the greatest identification was for Kidney Diseases (67%), Wellness & Weight Management (60%), and Cardiology (33%). Among patients with >=3 elevated BP measurements, 21% were identified vs 7% identified among those with 1-2 increased measurements (P<.001). All clinician survey respondents perceived self-responsibility for identification of elevated BP, but opinions varied for their role in the management of elevated BP. CONCLUSIONS: The identification of patients with elevated BP measurements was low. Strategies to increase the identification of elevated BPs in outpatient tertiary care settings are needed. PMID- 25919734 TI - 50 Years Ago in The Journal of Pediatrics: Normal Response of Sickle Cell Anemia Patients to Immunization with Salmonella Vaccines. PMID- 25919736 TI - The Impact of Insurance, Race, and Ethnicity on Age at Surgical Intervention among Children with Nonsyndromic Craniosynostosis. AB - OBJECTIVE: To examine the impact of demographic factors, including insurance type, family income, and race/ethnicity, on patient age at the time of surgical intervention for craniosynostosis surgery in the US. STUDY DESIGN: The Kids' Inpatient Database was queried for admissions of children younger than 3 years of age undergoing craniosynostosis surgery in 2009. Descriptive data regarding age at surgery for various substrata are reported. Multivariate regression was used to evaluate the effect of patient and hospital characteristics on the age at surgery. RESULTS: Children with private insurance were, on average, 6.8 months of age (95% CI 6.2-7.5) at the time of surgery; children with Medicaid were 9.1 months old (95% CI 8.4-9.8). White children received surgery at mean age of 7.2 months (95% CI 6.5-8.0) and black and Hispanic children at a mean age of 9.1 months (95% CI 8.2-10.1). Multivariate regression analysis found Medicaid insurance (beta coefficient [B]=1.93, P<.001), black or Hispanic race/ethnicity (B=1.34, P=.022), and having 2 or more chronic conditions (B=2.86, P<.001) to be significant independent predictors of older age at surgery. CONCLUSION: Public insurance and nonwhite race/Hispanic ethnicity were statistically significant predictors for older age at surgery, adjusted for sex, zip code median family income, year, and hospital factors such as size, type, region, and teaching status. Further research into these disparities is warranted. PMID- 25919737 TI - Aplasia cutis congenita with "vanishing twin". PMID- 25919738 TI - Frenotomy may help resolve breastfeeding problems due to tongue-tie. PMID- 25919735 TI - Body mass index changes in youth in the first year after type 1 diabetes diagnosis. AB - OBJECTIVES: To describe changes in weight and body mass index (BMI) during the first year following diagnosis of type 1 diabetes (T1D) and associations with demographic and clinical characteristics. STUDY DESIGN: The Pediatric Diabetes Consortium includes 7 US centers with prospective longitudinal data from initial T1D diagnosis. This analysis includes 530 youth with diabetes duration of >=1 year and measures of BMI at 3 and 12 months after diagnosis. BMI trajectory of participants and relationships between the change in BMI z-score from baseline (3 months) to 12 months with demographic characteristics, hemoglobin A1c at baseline, and insulin delivery mode at baseline were evaluated. RESULTS: As a group, BMI z-scores increased sharply from diagnosis for 1-3 months but remained relatively stable from +0.51 at 3 months to +0.48 at 12 months. Children aged 2 <5 years experienced a significant positive change in BMI z-score between 3 and 12 months, and there was a similar trend among girls that did not reach statistical significance. No significant differences were found for race, socioeconomic status, or insulin delivery mode. CONCLUSIONS: These data suggest that increased BMI during the first year of treatment of most youth with T1D reflects regain of weight lost before diagnosis. There is, however, a propensity toward additional weight gain in younger children and girls. PMID- 25919739 TI - Independent predictors identified for developmental dysplasia of the hip. PMID- 25919740 TI - Limited efficacy of antigastroesophageal reflux medications in children. PMID- 25919741 TI - Demonstration of placebo effect for nonspecific cough medicine. PMID- 25919742 TI - Urokinase and VATS are equally effective for septated empyema. PMID- 25919743 TI - Reply: To PMID 25066063. PMID- 25919744 TI - Improving Care through Better Communication: Understanding the Benefits. PMID- 25919745 TI - Prevalence and Molecular Identification of Nematode and Dipteran Parasites in an Australian Alpine Grasshopper (Kosciuscola tristis). AB - In alpine Australia, Orthoptera are abundant, dominant herbivores, important prey species, and hosts for parasites and parasitoids. Despite the central role of orthopterans in alpine ecosystems, the impact of parasites on orthopteran populations is under-explored. In this study we describe the relationship between parasite prevalence and host sex, body size and year of collection. We accessed an existing, preserved collection of 640 Kosciuscola tristis collected from across its range between 2007 and 2011. Upon dissection we collected juvenile parasites and used molecular tools to identify them to three families (Nematoda; Mermithidae, and Arthropoda: Diptera: Tachinidae and Sarcophagidae). The prevalence of nematodes ranged from 3.5% to 25.0% and dipterans from 2.4% to 20.0%. Contrary to predictions, we found no associations between parasite prevalence and grasshopper sex or size. Although there was an association between prevalence of both nematodes and dipterans with year of collection, this is likely driven by a small sample size in the first year. Our results provide a foundation for future studies into parasite prevalence within the alpine environment and the abiotic factors that might influence these associations. PMID- 25919746 TI - Enhancement of Ion Activation and Collision-Induced Dissociation by Simultaneous Dipolar Excitation of Ions in x- and y-Directions in a Linear Ion Trap. AB - Collision-induced dissociation (CID) in linear ion traps is usually performed by applying a dipolar alternating current (AC) signal to one pair of electrodes, which results in ion excitation mainly in one direction. In this paper, we report simulation and experimental studies of the ion excitation in two coordinate directions by applying identical dipolar AC signals to two pairs of electrodes simultaneously. Theoretical analysis and simulation results demonstrate that the ion kinetic energy is higher than that using the conventional CID method. Experimental results show that more activation energy (as determined by the intensity ratio of the a4/b4 fragments from the CID of protonated leucine enkephalin) can be deposited into parent ions in this method. The dissociation rate constant in this method was about 3.8 times higher than that in the conventional method under the same experimental condition, at the Mathieu parameter qu (where u = x, y) value of 0.25. The ion fragmentation efficiency is also significantly improved. Compared with the conventional method, the smaller qu value can be used in this method to obtain the same internal energy deposited into ions. Consequently, the "low mass cut-off" is redeemed and more fragment ions can be detected. This excitation method can be implemented easily without changing any experimental parameters. PMID- 25919747 TI - Marketing dental sleep medicine. PMID- 25919748 TI - Dem bones. PMID- 25919749 TI - Upper cervical range of motion is impaired in patients with temporomandibular disorders. AB - AIMS: Clinicians increasingly suggest assessment and treatment of the cervical spine in patients with temporomandibular dysfunction (TMD); however, few studies have investigated upper cervical spine mobility in people who suffer from TMD. The purpose of this study was to investigate whether patients with TMD pain (with or without headache) present with upper cervical spine impairment when compared with asymptomatic subjects. METHODOLOGY: A single blind examiner evaluated cervical range of motion (ROM) measures including axial rotation during the flexion-rotation test (FRT) and sagittal plane ROM. Twenty asymptomatic subjects were compared with 37 subjects with pain attributed to TMD, confirmed by the Revised Research Diagnostic Criteria. Subjects with TMD were divided according to the presence of headache (26 without headache TMDNHA, 11 with headache TMDHA). One-way analysis of variance and planned orthogonal comparisons were used to determine differences in cervical mobility between groups. All subjects with TMD were positive on the FRT with restricted ROM, while none were in the control group. RESULTS: The analysis of variance revealed significant differences between groups for the FRT F(2,54) = 57.96, P<0.001) and for sagittal ROM [F(2,54) = 5.69, P = 0.006]. Findings show that the TMDHA group had less axial rotation than group TMDNHA, and both TMD groups had less ROM than controls. For sagittal ROM, the only difference was between group TMDHA and controls. CONCLUSIONS: Subjects with TMD had signs of upper cervical spine movement impairment, greater in those with headache. Only subjects with TMD and headache had impairment of cervical spine sagittal plane mobility. This study provides evidence for the importance of examination of upper cervical mobility determined by the FRT in patients who suffer from TMD. PMID- 25919750 TI - Effect of upper costal and costo-diaphragmatic breathing types on electromyographic activity of respiratory muscles. AB - AIM: To compare electromyographic (EMG) activity in young-adult subjects with different breathing types. METHODOLOGY: This study included 50 healthy male subjects with complete natural dentition, and no history of orofacial pain or craniomandibular-cervical-spinal disorders. Subjects were classified into two groups: upper costal breathing type, and costo-diaphragmatic breathing. Bipolar surface electrodes were located on sternocleidomastoid, diaphragm, external intercostal, and latissimus dorsi muscles. Electromyographic activity was recorded during the following tasks: (1) normal quiet breathing; (2) speaking the word 'Mississippi'; (3) swallowing saliva; and (4) forced deep breathing. RESULTS: Sternocleidomastoid and latissimus dorsi EMG activity was not significantly different between breathing types, whereas diaphragm and external intercostal EMG activity was significantly higher in the upper costal than costo diaphragmatic breathing type in all tasks (P<0.05; Wilcoxon signed rank-sum test). CONCLUSION: Diaphragm and external intercostal EMG activity suggests that there could be differences in motor unit recruitment strategies depending on the breathing type. PMID- 25919751 TI - Effect of the dental arches morphology on the masticatory muscles activities in normal occlusion young adults. AB - OBJECTIVES: The aim of this study was to assess the relationship between the morphology of dental arches and the activity of the masticatory muscles activities in healthy volunteers with full natural dentition. METHODS: Two hundred youthful Class I volunteers (113 females, 87 males) were clinically investigated. Alginate impressions of dental arches were taken, and plaster casts were prepared and measured. EMG data from eight masticatory muscles was recorded to assess their activities in central occlusion, lateral and protrusive movements. RESULTS: Clinical measurements and plaster casts analyses confirmed normal values of parameters investigated. Most of the arch measurements were significantly larger in the males than in the females. Weak positive correlations were found between overbite and masseter activity in centric occlusion (the right Mm R = 0.151, P <= 0.05; the left Mm R = 0.191, P <= 0.05). Also, the range of protrusive movement positively correlated with masseter activities in central occlusion (the right Mm R = 0.194, P <= 0.05; the left R = 0.201, P <= 0.05). CONCLUSIONS: The null hypothesis that morphology of dental arches does not affect the masticatory muscles' activities was rejected. The findings of this investigation indicate that systemic, longitudinal analyses of morphology of occlusion and muscular response, even in normal subjects, are needed. PMID- 25919752 TI - Conservative reduction by lever action of chronic bilateral mandibular condyle dislocation. AB - AIMS: The treatment of long-standing dislocation of the temporomandibular joint is broadly classified into open reduction and closed reduction. The current study presents a case of long-standing dislocation of the temporomandibular joint treated 3 years after dislocation. In this study, the authors evaluated the long term outcome of conservative reduction by lever action of chronic bilateral mandibular condyle dislocation. METHODOLOGY: Manual repositioning of temporomandibular joint dislocation lasting for 3 years in a 31-year-old woman was attempted without success; therefore, conservative reduction by lever action was carried out because the patient declined treatment under general anesthesia. RESULTS: The treatment was discontinued after 6 days because of the subluxation of the retaining tooth. The retainer was changed from tooth to screw for intermaxillary fixation, and treatment was reinstituted. Fifteen days later, reduction was achieved and retention was started and continued for 2 months. The outcome was good, with no recurrent dislocation within 24 months of the treatment. CONCLUSIONS: Conservative reduction by lever action, involving minimally invasive treatment and little dysfunction, should be considered an optional conservative treatment. PMID- 25919754 TI - Person-centred care after acute coronary syndrome, from hospital to primary care A randomised controlled trial. AB - AIM: To evaluate if person-centred care can improve self-efficacy and facilitate return to work or prior activity level in patients after an event of acute coronary syndrome. METHOD: 199 patients with acute coronary syndrome < 75 years were randomly assigned to person-centred care intervention or treatment as usual and followed for 6 months. In the intervention group a person-centred care process was added to treatment as usual, emphasising the patient as a partner in care. Care was co-created in collaboration between patients, physicians, registered nurses and other health care professionals and documented in a health plan. A team-based partnership across three health care levels included transparent knowledge about the disease and medical state to achieve agreed goals during recovery. Main outcome measure was a composite score of changes in general self-efficacy >= 5 units, return to work or prior activity level and re hospitalisation or death. RESULTS: The composite score showed that more patients (22.3%, n=21) improved in the intervention group at 6 months compared to the control group (9.5%, n=10) (odds ratio, 2.7; 95% confidence interval: 1.2-6.2; P=0.015). The effect was driven by improved self-efficacy >= 5 units in the intervention group. Overall general self-efficacy improved significantly more in the intervention group compared with the control group (P=0.026). There was no difference between groups on re-hospitalisation or death, return to work or prior activity level. CONCLUSION: A person-centred care approach emphasising the partnership between patients and health care professionals throughout the care chain improves general self-efficacy without causing worsening clinical events. PMID- 25919755 TI - Development of a risk score to predict sudden death in patients with Chaga's heart disease. AB - BACKGROUND: Sudden death is the most frequent mechanism of death in patients with chronic Chaga's cardiopathy, regardless of the degree of myocardial involvement. We developed a model to predict the risk of sudden death in patients with chronic Chaga's cardiopathy. METHODS: We retrospectively evaluated 373 patients. The association between the risk factors for chronic Chaga's cardiopathy and sudden death was assessed using Cox proportional-hazards analysis, and a risk score was determined. Receiver operating characteristic (ROC) curve analysis was performed to evaluate the predictive performance of the score and Kaplan Meier survival curves, which were stratified according to the score. RESULTS: During a mean follow-up period of 66+/-44months, 43 patients experienced sudden death. Four independent predictors were identified, each of which was assigned a number of points proportional to the following regression coefficients: QT-interval dispersion (3 points), syncope (2 points), ventricular extrasystoles (1 point), and severe dysfunction of the left ventricle (1 point). We calculated risk scores for each patient and defined three groups: low risk (0 to 2 points), intermediate (3 to 4 points), and high risk (>5 points). The mortality rates of the three groups were 1.5%, 25%, and 51%, respectively. The C statistic for the prediction score was 0.84, which demonstrated good clinical relevance of the model. CONCLUSION: This simple risk score predicted sudden death in patients with chronic Chaga's heart disease. PMID- 25919756 TI - Structural Variabilities in beta-Lactamase (blaA) of Different Biovars of Yersinia enterocolitica: Implications for beta-Lactam Antibiotic and beta Lactamase Inhibitor Susceptibilities. AB - Yersiniosis caused by Yersinia enterocolitica has been reported from all continents. The bacterial species is divided into more than fifty serovars and six biovars viz. 1A, 1B, 2, 3, 4 and 5 which differ in geographical distribution, ecological niches and pathogenicity. Most Y.enterocolitica strains harbor chromosomal genes for two beta-lactamases, blaA an Ambler class A penicillinase and blaB an Ambler class C inducible cephalosporinase. In the present study, susceptibility to b-lactam antibiotics and beta-lactamase inhibitor was studied for Y. enterocolitica strains of biovars 1A, 1B, 2 and 4. We observed that beta lactamases were expressed differentially among strains of different biovars. To understand the molecular mechanisms underlying such differential expression, the sequences of genes and promoters of blaA were compared. Also, the variants of blaA present in different biovars were modeled and docked with amoxicillin and clavulanic acid. The mRNA secondary structures of blaA variants were also predicted in-silico. Our findings indicated that neither variations in the promoter regions, nor the secondary structures of mRNA contributed to higher/lower expression of blaA in different biovars. Analysis of H-bonding residues of blaA variants with amoxicillin and clavulanic acid revealed that if amino acid residues of a beta-lactamase interacting with amoxicillin and the clavulanic acid were similar, clavulanic acid was effective in engaging the enzyme, accounting for a significant reduction in MIC of amoxicillin-clavulanate. This finding might aid in designing better beta-lactamase inhibitors with improved efficiencies in future. PMID- 25919757 TI - Intelligence after traumatic brain injury: meta-analysis of outcomes and prognosis. AB - Worldwide, 54-60 million individuals sustain traumatic brain injury (TBI) each year. This meta-analysis aimed to quantify intelligence impairments after TBI and to determine the value of age and injury severity in the prognosis of TBI. An electronic database search identified 81 relevant peer-reviewed articles encompassing 3890 patients. Full-scale IQ (FSIQ), performance IQ (PIQ) and verbal IQ (VIQ) impairments were quantified (Cohen's d) for patients with mild, moderate and severe TBI in the subacute phase of recovery and the chronic phase. Meta regressions explored prognostic values of age and injury severity measures for intelligence impairments. The results showed that, in the subacute phase, FSIQ impairments were absent for patients with mild TBI, medium-sized for patients with moderate TBI (d = -0.61, P < 0.001) and large for patients with severe TBI (d = -1.09, P < 0.001). In the chronic phase, FSIQ impairments were small for patients with mild or moderate TBI (d = -0.37 and -0.19, P <= 0.008) and large for patients with severe TBI (d = -0.80, P < 0.001). Adults with mild TBI had larger PIQ and VIQ impairments in the chronic phase than children (both Q >= 5.21, P <= 0.02), whilst children with severe TBI had larger FSIQ and VIQ impairments than adults (both Q >= 4.40, P <= 0.04). Glasgow Coma Scale score, duration of loss of consciousness and post-traumatic amnesia duration moderately to strongly predicted FSIQ, PIQ and VIQ impairments (0.41 <= r <= 0.82, P <= 0.02), but no differences in predictive value were observed. In conclusion, TBI causes persisting intelligence impairments, where children may have better recovery from mild TBI and poorer recovery from severe TBI than adults. Injury severity measures predict intelligence impairments and do not outperform one another. PMID- 25919758 TI - Finding a language of engagement. PMID- 25919759 TI - Latent Tuberculosis Infection and Associated Factors among Health Care Workers in Kigali, Rwanda. AB - INTRODUCTION: Data are limited regarding tuberculosis (TB) and latent TB infection prevalence in Rwandan health facilities. METHODS: We conducted a cross sectional survey among healthcare workers (HCWs) in Kigali during 2010. We purposively selected the public referral hospital, both district hospitals, and randomly selected 7 of 17 health centers. School workers (SWs) from the nearest willing public schools served as a local reference group. We tested for latent TB infection (LTBI) using tuberculin skin testing (TST) and asked about past TB disease. We assessed risk of LTBI and past history of TB disease associated with hospital employment. Among HCWs, we assessed risk associated with facility type (district hospital, referral hospital, health center), work setting (inpatient, outpatient), and occupation. RESULTS: Age, gender, and HIV status was similar between the enrolled 1,131 HCWs and 381 SWs. LTBI was more prevalent among HCWs (62%) than SWs (39%). Adjusted odds of a positive TST result were 2.71 (95% CI 2.01-3.67) times greater among HCWs than SWs. Among HCWs, there was no detectable difference between prevalence of LTBI according to facility type, work setting, or occupation. CONCLUSION: HCWs are at greater risk of LTBI, regardless of facility type, work setting, or occupation. The current status of TB infection control practices should be evaluated in the entire workforce in all Rwandan healthcare facilities. PMID- 25919760 TI - Genetic Changes in HIV-1 Gag-Protease Associated with Protease Inhibitor-Based Therapy Failure in Pediatric Patients. AB - Studies have shown a low frequency of HIV-1 protease drug resistance mutations in patients failing protease inhibitor (PI)-based therapy. Recent studies have identified mutations in Gag as an alternate pathway for PI drug resistance in subtype B viruses. We therefore genotyped the Gag and protease genes from 20 HIV 1 subtype C-infected pediatric patients failing a PI-based regimen. Major protease resistance mutations (M46I, I54V, and V82A) were identified in eight (40%) patients, as well as Gag cleavage site (CS) mutations (at codons 373, 374, 378, 428, 431, 449, 451, and 453) in nine (45%) patients. Four of these Gag CS mutations occurred in the absence of major protease mutations at PI failure. In addition, amino acid changes were noted at Gag non-CS with some predicted to be under HLA/KIR immune-mediated pressure and/or drug selection pressure. Changes in Gag during PI failure therefore warrant further investigation of the Gag gene and its role in PI failure in HIV-1 subtype C infection. PMID- 25919762 TI - Graft-copolymer-based approach to clear, durable, and anti-smudge polyurethane coatings. AB - Clear anti-smudge coatings with a thickness of up to tens of micrometers have been prepared through a graft-copolymer-based approach from commercial precursors. The coatings repel water, diiodomethane, hexadecane, ink, and an artificial fingerprint liquid. In addition, they can be readily applied onto different substrates using different coating methods. These coatings could find applications in protecting hand-held electronic devices from fingerprints, windows from stains, and buildings from graffiti. PMID- 25919763 TI - Characterization of Pathogenic Escherichia coli in River Water by Simultaneous Detection and Sequencing of 14 Virulence Genes. AB - The occurrence of pathogenic Escherichia coli in environmental waters increases the risk of waterborne disease. In this study, 14 virulence genes in 669 E. coli isolates (549 isolates from the Yamato River in Japan, and 30 isolates from each of the following hosts: humans, cows, pigs, and chickens) were simultaneously quantified by multiplex PCR and dual index sequencing to determine the prevalence of potentially pathogenic E. coli. Among the 549 environmental isolates, 64 (12%) were classified as extraintestinal pathogenic E. coli (ExPEC) while eight (1.5%) were classified as intestinal pathogenic E. coli (InPEC). Only ExPEC-associated genes were detected in human isolates and pig isolates, and 11 (37%) and five (17%) isolates were classified as ExPEC, respectively. A high proportion (63%) of cow isolates possessed Shiga-toxin genes (stx1 or stx2) and they were classified as Shiga toxin-producing E. coli (STEC) or enterohemorrhagic E. coli (EHEC). Among the chicken isolates, 14 (47%) possessed iutA, which is an ExPEC-associated gene. This method can determine the sequences as well as the presence/absence of virulence genes. By comparing the sequences of virulence genes, we determined that sequences of iutA were different among sources and may be useful for discriminating isolates, although further studies including larger numbers of isolates are needed. Results indicate that humans are a likely source of ExPEC strains in the river. PMID- 25919764 TI - Human in vivo regional intestinal permeability: quantitation using site-specific drug absorption data. AB - Application of information on regional intestinal permeability has been identified as a key aspect of successful pharmaceutical product development. This study presents the results and evaluation of an approach for the indirect estimation of site-specific in vivo intestinal effective permeability (Peff) in humans. Plasma concentration-time profiles from 15 clinical studies that administered drug solutions to specific intestinal regions were collected and analyzed. The intestinal absorption rate for each drug was acquired by deconvolution, using historical intravenous data as reference, and used with the intestinal surface area and the dose remaining in the lumen to estimate the Peff. Forty-three new Peff values were estimated (15 from the proximal small intestine, 11 from the distal small intestine, and 17 from the large intestine) for 14 active pharmaceutical ingredients representing a wide range of biopharmaceutical properties. A good correlation (r(2) = 0.96, slope = 1.24, intercept = 0.030) was established between these indirect jejunal Peff estimates and jejunal Peff measurements determined directly using the single-pass perfusion double balloon technique. On average, Peff estimates from the distal small intestine and large intestine were 90% and 40%, respectively, of those from the proximal small intestine. These results support the use of the evaluated deconvolution method for indirectly estimating regional intestinal Peff in humans. This study presents the first comprehensive data set of estimated human regional intestinal permeability values for a range of drugs. These biopharmaceutical data can be used to improve the accuracy of gastrointestinal absorption predictions used in drug development decision-making. PMID- 25919765 TI - Remifentanil Ameliorates Liver Ischemia-Reperfusion Injury Through Inhibition of Interleukin-18 Signaling. AB - BACKGROUND: Hepatic injury induced by ischemia-reperfusion (I/R) after transplantation or lobectomy is a major clinical problem. The potential benefit of remifentanil in these hepatic surgeries remains unknown. The current study investigated whether remifentanil protects the liver against I/R injury in a rat model and whether the underlying mechanism involves the modulation of interleukin (IL)-18 signaling. METHODS: Male Sprague-Dawley rats were subjected to 45 minutes of partial hepatic ischemia followed by 6 hours of reperfusion. Then, they received an intravenous saline or remifentanil (0.4, 2, or 10 MUg/kg per minute) infusion from 30 minutes before ischemia until the end of ischemia with or without previous administration of naloxone, a nonselective opioid receptor antagonist. Serum aminotransferase, hepatic morphology, and hepatic neutrophil infiltration were analyzed. The expression of hepatic IL-18; IL-18-binding protein (BP); and key cytokines downstream of IL-18 signaling were measured. RESULTS: Remifentanil significantly decreased serum aminotransferase levels and profoundly attenuated the liver histologic damages. Liver I/R injury increased the expression of both hepatic IL-18 and IL-18BP. Although remifentanil pretreatment significantly decreased I/R-induced IL-18 expression, it further upregulated IL-18BP levels in liver tissues. The I/R-induced increases of hepatic interferon-gamma, tumor necrosis factor-alpha and IL-1beta expression, and neutrophil infiltration were also significantly reduced by remifentanil. Naloxone inhibited the remifentanil-induced downregulation of IL-18, but not the elevation of IL-18BP, and significantly attenuated its protective effects on liver I/R injury. CONCLUSIONS: Remifentanil protects the liver against I/R injury. Modulating the hepatic IL-18/IL-18BP balance and inhibiting IL-18 signaling mediate, at least in part, the hepatoprotective effects of remifentanil. PMID- 25919766 TI - Estimating the Number of Organ Donors in Australian Hospitals--Implications for Monitoring Organ Donation Practices. AB - BACKGROUND: The Australian DonateLife Audit captures information on all deaths which occur in emergency departments, intensive care units and in those recently discharged from intensive care unit. This information provides the opportunity to estimate the number of donors expected, given present consent rates and contemporary donation practices. This may then allow benchmarking of performance between hospitals and jurisdictions. Our aim was to develop a method to estimate the number of donors using data from the DonateLife Audit on the basis of baseline patient characteristics alone. METHODS: All intubated patient deaths at contributing hospitals were analyzed. Univariate comparisons of donors to nondonors were performed. A logistic regression model was developed to estimate expected donor numbers from data collected between July 2012 and December 2013. This was validated using data from January to April 2014. RESULTS: Between July 2012 and April 2014, 6861 intubated patient deaths at 68 hospitals were listed on the DonateLife Audit of whom 553 (8.1%) were organ donors. Factors independently associated with organ donation included age, brain death, neurological diagnoses, chest x-ray findings, PaO2/FiO2, creatinine, alanine transaminase, cancer, cardiac arrest, chronic heart disease, and peripheral vascular disease. A highly discriminatory (area under the receiver operatory characteristic, 0.940 [95% confidence interval, 0.924-0.957]) and well-calibrated prediction model was developed which accurately estimated donor numbers. Three hospitals appeared to have higher numbers of actual donors than expected. CONCLUSIONS: It is possible to estimate the expected number of organ donors. This may assist benchmarking of donation outcomes and interpretation of changes in donation rates over time. PMID- 25919767 TI - Calcineurin Inhibitor Minimization With Ixazomib, an Investigational Proteasome Inhibitor, for the Prevention of Antibody Mediated Rejection in a Preclinical Model. AB - BACKGROUND: There is a need for new immunosuppression strategies to minimize calcineurin inhibitor (CNI) toxicity while effectively preventing antibody mediated rejection (AMR). METHODS: We tested the efficacy of an investigational proteasome inhibitor, ixazomib, alone and in a CNI minimization strategy in a rat kidney transplant model of transfusion-elicited acute AMR. Nonsensitized (naive) and sensitized allograft recipients were randomized into 4 treatment groups (8 groups total, n = 3 to 6 in each group) and treated for 1 week. Groups included: no treatment, full dose cyclosporine (CsA, 10 mg/kg per day), ixazomib (0.25 mg/kg on days -5, -2 and +2) alone, and half dose CsA (5 mg/kg per day) + ixazomib. RESULTS: Compared to untreated animals, ixazomib alone or in combination with 1/2 dose CsA reduced donor-specific antibody, intragraft transcripts for chemokines CCL-21 and CXCL-13, and CD19 expression in both sensitized and naive transplants. Compared to full dose CsA, the CNI minimization strategy with ixazomib inhibited AMR and allograft injury as evidenced by reduced C4d staining in peritubular capillaries, microcirculation inflammation, splenic plasma cells, circulating B cell activating factor, and intragraft transcripts for major histocompatibility complex class II, Toll-like receptors (TLR-1, TLR 10, and TLR-12) and CCL-21 and CXCL-13 in sensitized animals, indicating downregulation of B cell activation, antigen presentation and T-cell and B-cell signaling. CONCLUSIONS: These studies suggest that CNI minimization strategies including ixazomib are effective to prevent AMR including in sensitized kidney allograft recipients. Clinical studies are needed to determine the role of novel proteasome inhibitors for the prevention and treatment of AMR. PMID- 25919768 TI - Arsenic Trioxide Induces T Cell Apoptosis and Prolongs Islet Allograft Survival in Mice. AB - BACKGROUND: T cell-mediated immune rejection is a key barrier to islet transplantation. Preliminary studies have shown that arsenic trioxide (As2O3) can inhibit T cell responses and prolong heart allograft survival. Here, we sought to investigate the possibility of using As2O3 to prolong islet allograft survival in an acute rejection model of Balb/c to C57B/6 mice. METHODS: Recipient mice were treated with As2O3 and/or rapamycin after islet allograft transplantation. At day 10 after transplantation, the graft, spleen, lymph nodes, and blood of the recipient mice were recovered for analysis. In vitro, to further examine the mechanism underlying As2O3 protection of islet allografts against T cell-mediated rejection, mixed lymphocyte reaction and apoptosis analyses of T cells were performed. The phosphorylation levels of IkappaBalpha and p38 were also evaluated to confirm the proliferation and apoptosis of As2O3-treated T cells. RESULTS: We found that As2O3 prolonged islet allograft survival by reducing inflammatory reactions, influencing cytokine synthesis and secretion and T-cell subset proportions, and inhibiting T-cell responses. Furthermore, As2O3 and rapamycin showed a synergistic effect in suppressing islet allotransplant rejection. CONCLUSIONS: Arsenic trioxide may prevent allograft rejection by inhibiting T cell proliferation and inducing T-cell apoptosis. PMID- 25919769 TI - Determinants and Long-Term Effects of Attendance Levels in a Marital Enrichment Program for African American Couples. AB - Although most efficacious marital enrichment programs are multisession, few studies have explored whether outcomes differ according to session attendance, particularly among minority groups with lower than average participation in prevention programs. This study therefore investigates attendance levels and long term improvements in couple functioning among 164 couples participating in the Promoting Strong African American Families program. Structural equation models indicated session attendance predicted 2-year changes for men's reports of communication, commitment, and spousal support (marginally) but not for women's. Individual and couple characteristics that predicted attendance levels were also identified. Results highlight distinct gender differences in the effects of sustained attendance as well as characteristics that provide early identifiers for African American couples at increased risk of low program attendance. PMID- 25919770 TI - Effects of dietary education, followed by a tailored fructose-restricted diet in adults with fructose malabsorption. AB - OBJECTIVE: Fructose is absorbed by GLUT transporters in the small intestine. If this process is inadequate, abdominal symptoms because of fructose intolerance may arise. The effect of a tailored fructose-restricted diet on gastrointestinal complaints was assessed in patients with fructose intolerance. MATERIALS AND METHODS: Following an abnormal fructose breath test (50 g), 107 patients (64 also with lactose intolerance) entered three study periods: weeks 0-32 (free diet), weeks 32-36 (progressive increasing amount of fructose up to quantity inducing symptoms, 'trigger dose'), and weeks 36-48 (tailored fructose-restricted diet according to the 'trigger dose'). A subgroup of 15 patients underwent additional fructose breath tests (35, 25 g) to compare three different doses. RESULTS: At baseline, the most frequent symptoms were bloating and abdominal pain, and were more severe with combined fructose and lactose intolerance. During the free diet, patients reported eliminating (48%) or reducing (52%) fructose-containing foods, with a significant improvement in symptoms (abdominal pain from 79.7 +/- 1.3 to 19.3 +/- 1.8 mm; bloating from 83.1 +/- 1.3 to 19.4 +/- 1.8 mm; number of evacuations/day from 3.9 +/- 0.16 to 1.1 +/- 0.04; Bristol score from 5.1 +/- 0.14 to 3.8 +/- 0.1, P < 0.00001). During the tailored fructose-restricted diet, the consistent improvement in symptoms persisted and was similar to the improvement on free diet (abdominal pain 23.6 +/- 1.9 mm; bloating 19.4 +/- 1.8 mm; number of evacuations/day 1.7 +/- 0.07; Bristol score 3.5 +/- 0.06, P<0.00001 vs. baseline). A dose-dependent effect of fructose was observed on symptoms during the fructose breath test. CONCLUSION: In our setting, individuals with fructose intolerance show an inappropriate dietary self-management. By contrast, a tailored fructose-restricted diet improves gastrointestinal symptoms without senseless food deprivation. PMID- 25919771 TI - Tenofovir monotherapy after achieving complete viral suppression on entecavir plus tenofovir combination therapy. AB - OBJECTIVES: It is unclear whether patients with chronic hepatitis B with partial response to entecavir (ETV) who have achieved complete viral suppression (CVS) with ETV plus tenofovir (TDF) combination therapy maintain CVS if switched to TDF or ETV. Our goal was to examine virologic outcomes in such patients. METHODS: This is a retrospective cohort study of 57 ETV partial responders with chronic hepatitis B who showed CVS on ETV+TDF combination therapy, who were switched back to monotherapy with either ETV (n=16) or TDF (n=18), or continued on combination therapy (n=23). The majority of patients were Asian (91%) and male (65%), with a mean age of 41+/-12 years. RESULTS: The patients switched back to ETV had significantly higher rates of virologic breakthrough by 6 months after the switch compared with their TDF counterparts (88 vs. 39%, P=0.004). Patients who remained on ETV+TDF also had virologic breakthrough, due to either confirmed or suspected nonadherence. On multivariate analysis inclusive of age, sex, and hepatitis B virus DNA levels at initiation of combination therapy, ETV (compared with TDF) was found to be an independent predictor for virologic breakthrough (odds ratio 112.7, P=0.03), as well as duration of CVS of less than 12 months while on ETV+TDF (odds ratio 60.2, P=0.03). CONCLUSION: TDF monotherapy, especially in those who have had CVS for at least 12 months on combination therapy, may be considered for some ETV partial responders who have achieved CVS with combination therapy, given the financial advantage and convenience of monotherapy. PMID- 25919761 TI - Associations of common breast cancer susceptibility alleles with risk of breast cancer subtypes in BRCA1 and BRCA2 mutation carriers. AB - INTRODUCTION: More than 70 common alleles are known to be involved in breast cancer (BC) susceptibility, and several exhibit significant heterogeneity in their associations with different BC subtypes. Although there are differences in the association patterns between BRCA1 and BRCA2 mutation carriers and the general population for several loci, no study has comprehensively evaluated the associations of all known BC susceptibility alleles with risk of BC subtypes in BRCA1 and BRCA2 carriers. METHODS: We used data from 15,252 BRCA1 and 8,211 BRCA2 carriers to analyze the associations between approximately 200,000 genetic variants on the iCOGS array and risk of BC subtypes defined by estrogen receptor (ER), progesterone receptor (PR), human epidermal growth factor receptor 2 (HER2) and triple-negative- (TN) status; morphologic subtypes; histological grade; and nodal involvement. RESULTS: The estimated BC hazard ratios (HRs) for the 74 known BC alleles in BRCA1 carriers exhibited moderate correlations with the corresponding odds ratios from the general population. However, their associations with ER-positive BC in BRCA1 carriers were more consistent with the ER-positive associations in the general population (intraclass correlation (ICC) = 0.61, 95% confidence interval (CI): 0.45 to 0.74), and the same was true when considering ER-negative associations in both groups (ICC = 0.59, 95% CI: 0.42 to 0.72). Similarly, there was strong correlation between the ER-positive associations for BRCA1 and BRCA2 carriers (ICC = 0.67, 95% CI: 0.52 to 0.78), whereas ER-positive associations in any one of the groups were generally inconsistent with ER-negative associations in any of the others. After stratifying by ER status in mutation carriers, additional significant associations were observed. Several previously unreported variants exhibited associations at P <10(-6) in the analyses by PR status, HER2 status, TN phenotype, morphologic subtypes, histological grade and nodal involvement. CONCLUSIONS: Differences in associations of common BC susceptibility alleles between BRCA1 and BRCA2 carriers and the general population are explained to a large extent by differences in the prevalence of ER-positive and ER-negative tumors. Estimates of the risks associated with these variants based on population based studies are likely to be applicable to mutation carriers after taking ER status into account, which has implications for risk prediction. PMID- 25919772 TI - Comparative effectiveness of antiviral treatment for hepatitis B: a systematic review and Bayesian network meta-analysis. AB - OBJECTIVE: A wide variety of competing drugs are available to patients for the treatment of chronic hepatitis B. We update a recent meta-analysis to include additional trial evidence with the aim of determining which treatment is the most effective. METHODS: Twelve monotherapy or combination therapy were evaluated in treatment-naive individuals with hepatitis B e antigen (HBeAg) positive or negative patients. Databases were searched for randomized controlled trials in the first year of therapy. Bayesian random effects network meta-analysis was used to calculate the pairwise odds ratios, 95% credible intervals and ranking of six surrogate outcomes. RESULTS: In total, 22 studies were identified (7508 patients): 12 studies analysed HBeAg-positive patients, six analysed HBeAg negative patients, and four evaluated both. Tenofovir was most effective at increasing efficacy in HBeAg-positive patients, ranking first for three outcomes and increased odds of undetectable levels of hepatitis B virus (HBV) DNA compared with seven other therapies (such as lamivudine: odds ratio 33.0; 95% credible interval 7.0-292.7). For HBeAg-negative patients, the large network (seven therapies) ranked entecavir alone or in combination with tenofovir highly for reduction in HBV DNA and histologic improvement. In the smaller network (three therapies), tenofovir ranked first for undetectable HBV DNA and histologic improvement. No data existed to directly or indirectly compare these treatments. CONCLUSION: For HBeAg-positive patients tenofovir is the most effective at increasing efficacy, whereas for HBeAg-negative patients, either tenofovir or entecavir is most effective. Further research should focus on strengthening the network connections, in particular comparing tenofovir and entecavir in HBeAg negative patients. PMID- 25919773 TI - The impact of amalgam dental fillings on the frequency of Helicobacter pylori infection and H. pylori eradication rates in patients treated with concomitant, quadruple, and levofloxacin-based therapies. AB - BACKGROUND AND AIM: Mercury exposure is encountered most commonly in individuals with amalgam fillings. The toxic, bactericidal, and immunosuppressive effects of mercury are well known. Furthermore, multiple antibiotic resistance can be transferred, together with mercury resistance. The aim of this study was to investigate the frequency of Helicobacter pylori infection in dyspeptic patients with amalgam fillings and the effect of the amalgam fillings on H. pylori eradication rates in these patients. PATIENTS AND METHODS: Four hundred and seventy-five patients who presented with dyspeptic complaints and underwent upper gastrointestinal endoscopy and gastric biopsy were included in this study. One hundred and sixty-nine (35.6%) patients were negative and 306 (64.4%) patients were positive for H. pylori. All of the participants underwent dental examinations in a blinded manner. The participants were divided into two groups on the basis of the presence of amalgam fillings. The H. pylori-positive patients were divided randomly into three subgroups: patients who received concomitant therapy (CT) (rabeprazole-amoxicillin-clarithromycin-metronidazole for 14 days; n=122); patients who received quadruple therapy (QT) (rabeprazole-tetracycline metronidazole-colloidal bismuth subcitrate for 10 days; n=97); and patients who received levofloxacin-based therapy (LT) (rabeprazole-amoxicillin-levofloxacin for 10 days; n=87). Eradication success was detected by a urea breath test 6 weeks after the end of treatment. RESULTS: The frequency of H. pylori infection was significantly lower in the filling group compared with the nonfilling group (53.7 and 78.8%, respectively; P<0.001). The eradication rates in the CT, QT, and LT groups were 65.5, 67.0, and 58.6%, respectively, in the intention-to-treat (ITT) analysis and 69.6, 70.7, and 62.2%, respectively, in the per-protocol (PP) analysis. In all of the H. pylori-positive patients and separately in the CT and LT groups, the eradication rates were significantly lower in the filling group compared with the nonfilling group. However, in the QT group, there was no significant difference between the patients with and without fillings (P=0.001, 0.003, 0.012, 0.14, respectively). Logistic regression analysis showed that the absence of amalgam filling exerts independent effects on the increased frequency of H. pylori infection and increased rate of H. pylori eradication. CONCLUSION: This is the first study to show a lower frequency of H. pylori colonization in patients with amalgam fillings than without and that H. pylori eradication rates are lower in patients with amalgam fillings compared to those without. PMID- 25919774 TI - Bariatric surgery and nonalcoholic fatty liver disease. AB - The rising prevalence of nonalcoholic fatty liver disease (NAFLD) is associated with the increasing global pandemic of obesity. These conditions cluster with type II diabetes mellitus and the metabolic syndrome to result in obesity associated liver disease. The benefits of bariatric procedures on diabetes and the metabolic syndrome have been recognized for some time, and there is now mounting evidence to suggest that bariatric procedures improve liver histology and contribute to the beneficial resolution of NAFLD in obese patients. These beneficial effects derive from a number of weight-dependent and weight independent mechanisms including surgical BRAVE actions (bile flow changes, restriction of stomach size, anatomical gastrointestinal rearrangement, vagal manipulation, enteric hormonal modulation) and subsequent effects such as reduced lipid intake, adipocytokine secretion, modulation of gut flora, improvements in insulin resistance and reduced inflammation. Here, we review the clinical investigations on bariatric procedures for NAFLD, in addition to the mounting mechanistic data supporting these findings. Elucidating the mechanisms by which bariatric procedures may resolve NAFLD can help enhance surgical approaches for metabolic hepatic dysfunction and also contribute toward developing the next generation of therapies aimed at reducing the burden of obesity-associated liver disease. PMID- 25919775 TI - Cost-effectiveness of sorafenib as a first-line treatment for advanced hepatocellular carcinoma. AB - OBJECTIVE: Sorafenib has been shown to significantly improve the overall survival of patients with advanced hepatocellular carcinoma (HCC). This study aimed to assess the cost-effectiveness of sorafenib as a first-line treatment for patients with advanced HCC. MATERIALS AND METHODS: To carry out the analysis, we collected the data on the efficacy and safety of patients treated with sorafenib from medical records and follow-up of these patients. A Markov model comprising three health states (progression-free survival, progressive disease, and death) was created to simulate the process of advanced HCC. We calculated the data on cost from the perspective of Chinese patients. Sensitivity analyses were also carried out to explore the impact of several essential variables. RESULTS: Overall, 94 patients with advanced HCC were included in our study: 70 in the Child-Pugh A group and 24 in the Child-Pugh B group. The median overall survival was 8.0 months (95% confidence interval: 7.21-8.50). In general, treatment with sorafenib was estimated to increase costs by $18,251.84 compared with best supportive care, with a gain of 0.18 quality-adjusted life years (QALYs). Thus, the incremental cost-effective ratio was $101,399.11/QALY for sorafenib versus best supportive care. In addition, in patients with Child-Pugh A liver function, the total costs and effectiveness were $20,643.06 and 0.48 QALYs, respectively, whereas in the Child-Pugh class B group, the total costs and effectiveness were $15,844.33 and 0.28 QALYs. CONCLUSION: On the basis of the commonly accepted willingness-to-pay threshold ($20,301.00/QALY in China), sorafenib is not a cost-effective option as a first-line treatment for patients with advanced HCC. PMID- 25919776 TI - Beliefs and behaviour about smoking among inflammatory bowel disease patients. AB - BACKGROUND AND AIMS: We investigated the beliefs and behaviours about tobacco among inflammatory bowel disease (IBD) patients. MATERIALS AND METHODS: A questionnaire of 18 items was developed and administered to all consecutive patients followed for IBD at Nancy University Hospital from October 2012 to March 2013. RESULTS: Two hundred and thirty-one patients participated in the survey [Crohn's disease (CD)=171, ulcerative colitis (UC)=60]. Among IBD patients who were smokers at diagnosis, 10.5% of CD patients versus 14.3% of UC patients believed that tobacco could have triggered their IBD; about half the CD smokers at diagnosis were not aware that smoking might promote their disease. Three quarters of smokers after diagnosis knew that tobacco was not beneficial for their CD, whereas all UC were aware that smoking had a beneficial effect on their disease course. About half of the CD patients had stopped smoking during a flare up. Four former smokers with UC (21.1%) resumed smoking during a relapse. Nearly 90% of IBD current smokers wished to quit smoking. About half the IBD patients were aware of the relation between smoking and IBD, and the Internet was a source for 24.3% of these patients. CONCLUSION: The majority of IBD patients are unaware of the effects of tobacco on their disease. Better information through a therapeutic education programme should be systematically recommended in IBD. PMID- 25919777 TI - The importance of peripheral diabetic retinopathy. PMID- 25919778 TI - What is next in amblyopia treatment? PMID- 25919779 TI - Author reply: To PMID 24811963. PMID- 25919780 TI - Re: Cursiefen et al.: Aganirsen antisense oligonucleotide eye drops inhibit keratitis-induced corneal neovascularization and reduce need for transplantation: the I-CAN study (Ophthalmology 2014;121:1683-92). PMID- 25919781 TI - Author reply: To PMID 24835758. PMID- 25919782 TI - Re: Chang et al.: Cost evaluation of surgical and pharmaceutical options in treatment for vitreomacular adhesions and macular holes (Ophthalmology 2014;121:1720-6). PMID- 25919783 TI - Author reply: To PMID 24993081. PMID- 25919784 TI - Re: Thompson: Three kinds of lies (Ophthalmology 2014;121:1315-6). PMID- 25919785 TI - Author reply: To PMID 25017414. PMID- 25919786 TI - Re: Srikumaran et al.: Long-term outcomes of Boston type 1 keratoprosthesis implantation: a retrospective multicenter cohort (Ophthalmology 2014;121:2159 64). PMID- 25919787 TI - Prokaryotic genes in eukaryotic genome sequences: when to infer horizontal gene transfer and when to suspect an actual microbe. AB - Assessment of phylogenetic positions of predicted gene and protein sequences is a routine step in any genome project, useful for validating the species' taxonomic position and for evaluating hypotheses about genome evolution and function. Several recent eukaryotic genome projects have reported multiple gene sequences that were much more similar to homologues in bacteria than to any eukaryotic sequence. In the spirit of the times, horizontal gene transfer from bacteria to eukaryotes has been invoked in some of these cases. Here, we show, using comparative sequence analysis, that some of those bacteria-like genes indeed appear likely to have been horizontally transferred from bacteria to eukaryotes. In other cases, however, the evidence strongly indicates that the eukaryotic DNA sequenced in the genome project contains a sample of non-integrated DNA from the actual bacteria, possibly providing a window into the host microbiome. Recent literature suggests also that common reagents, kits and laboratory equipment may be systematically contaminated with bacterial DNA, which appears to be sampled by metagenome projects non-specifically. We review several bioinformatic criteria that help to distinguish putative horizontal gene transfers from the admixture of genes from autonomously replicating bacteria in their hosts' genome databases or from the reagent contamination. PMID- 25919788 TI - Strength and sensation after epidural ropivacaine in men and women. AB - We injected 15 ml epidural ropivacaine in 30 men and 30 women to determine the median dose required to impair a straight-leg raise. We started at a concentration of 0.425%, increasing the concentration by 0.025% after an ineffective injection and decreasing the concentration by 0.025% after an effective injection. The median (95% CI) concentration of ropivacaine that prevented straight-leg raise within 30 min of injection was 0.43% (0.41-0.45%) in men and 0.40% (0.39-0.41%) in women, p = 0.001. There were no differences in dermatome levels for loss of pinprick and cold sensation between men and women. PMID- 25919789 TI - Hidden diversity in the freshwater planktonic diatom Asterionella formosa. AB - Many freshwater and marine algal species are described as having cosmopolitan distributions. Whether these widely distributed morphologically similar algae also share a similar gene pool remains often unclear. In the context of island biogeography theory, stronger spatial isolation deemed typical of freshwater lakes should restrict gene flow and lead to higher genetic differentiation among lakes. Using nine microsatellite loci, we investigate the genetic diversity of a widely distributed freshwater planktonic diatom, Asterionella formosa, across different lakes in Switzerland and the Netherlands. We applied a hierarchical spatial sampling design to determine the geographical scale at which populations are structured. A subset of the isolates was additionally analysed using amplified fragment length polymorphism (AFLP) markers. Our results revealed complex and unexpected population structure in A. formosa with evidence for both restricted and moderate to high gene flow at the same time. Different genetic markers (microsatellites and AFLPs) analysed with a variety of multivariate methods consistently revealed that genetic differentiation within lakes was much stronger than among lakes, indicating the presence of cryptic species within A. formosa. We conclude that the hidden diversity found in this study is expected to have implications for the further use of A. formosa in biogeographical, conservation and ecological studies. Further research using species-level phylogenetic markers is necessary to place the observed differentiation in an evolutionary context of speciation. PMID- 25919790 TI - Serum copeptin levels in predicting nondippers in newly diagnosed hypertension. AB - OBJECTIVES: The nondipper pattern in hypertension is associated with worse cardiovascular outcomes. In this study, we hypothesized that high copeptin levels could predict nondippers among hypertensive patients and investigated the associations between copeptin levels and nondipper pattern in newly diagnosed hypertensive patients. METHODS: Ambulatory blood pressure measurements were obtained and the patients were divided into two groups according to ambulatory blood pressure measurement as nondippers and dippers. Serum copeptin levels were measured in addition to routine laboratory investigations. A total of 76 patients were included in the study. RESULTS: The clinical and laboratory characteristics of the two groups were similar. The mean copeptin values were found to be significantly higher in the nondipper hypertensive group [1.66 (1.19-4.01) and 1.35 (1.12-2.09) IU/ml, respectively, P=0.026]. In the correlation analysis, no correlation was found between copeptin levels and daytime diastolic blood pressure, but there were weak positive correlations with daytime systolic, 24 h systolic, and diastolic blood pressure values (r=0.335, P=0.034, r=0.350, P=0.027, r=0.372, P=0.018, respectively). However, there were significant positive correlations between serum copeptin levels and nocturnal systolic and diastolic blood pressure values (r=0.593, P<0.001, r=0.523, P=0.001, respectively). CONCLUSION: This study showed that high serum copeptin levels could predict the nondipper pattern in newly diagnosed hypertension. PMID- 25919791 TI - Methaemoglobinaemia in acute indoxacarb poisoning. PMID- 25919792 TI - Membrane-associated transcription factor peptidase, site-2 protease, antagonizes ABA signaling in Arabidopsis. AB - Abscisic acid plays important roles in maintaining seed dormancy while gibberellins (GA) and other phytohormones antagonize ABA to promote germination. However, how ABA signaling is desensitized during the transition from dormancy to germination is still poorly understood. We functionally characterized the role of membrane-associated transcription factor peptidase, site-2 protease (S2P), in ABA signaling during seed germination in Arabidopsis. Genetic analysis showed that loss-of-function of S2P conferred high ABA sensitivity during seed germination, and expression of the activated form of membrane-associated transcription factor bZIP17, in which the transmembrane domain and endoplasmic reticulum (ER) lumen facing C-terminus were deleted, in the S2P mutant rescued its ABA-sensitive phenotype. MYC and green fluorescent protein (GFP)-tagged bZIP17 were processed and translocated from the ER to the nucleus in response to ABA treatment. Furthermore, genes encoding negative regulators of ABA signaling, such as the transcription factor ATHB7 and its target genes HAB1, HAB2, HAI1 and AHG3, were up-regulated in seeds of the wild-type upon ABA treatment; this up-regulation was impaired in seeds of S2P mutants. Our results suggest that S2P desensitizes ABA signaling during seed germination through regulating the activation of the membrane-associated transcription factor bZIP17 and therefore controlling the expression level of genes encoding negative regulators of ABA signaling. PMID- 25919793 TI - Raman micro spectroscopy for in vitro drug screening: subcellular localisation and interactions of doxorubicin. AB - Vibrational spectroscopy, including Raman micro spectroscopy, has been widely used over the last few years to explore potential biomedical applications. Indeed, Raman micro spectroscopy has been demonstrated to be a powerful non invasive tool in cancer diagnosis and monitoring. In confocal microscopic mode, the technique is also a molecularly specific analytical tool with optical resolution which has potential applications in subcellular analysis of biochemical processes, and therefore as an in vitro screening tool of the efficacy and mode of action of, for example, chemotherapeutic agents. In order to demonstrate and explore the potential in this field, established, model chemotherapeutic agents can be valuable. In this study paper, Raman micro spectroscopy coupled with confocal microscopy were used for the localization and tracking of the commercially available drug, doxorubicin (DOX), in the intracellular environment of the lung cancer cell line, A549. Cytotoxicity assays were employed to establish clinically relevant drug doses for 24 h exposure, and Confocal Laser Scanning Fluorescence Microscopy was conducted in parallel with Raman micro spectroscopy profiling to confirm the drug internalisation and localisation. Multivariate statistical analysis, consisting of PCA (principal components analysis) was used to highlight doxorubicin interaction with cancer cells and spectral variations due to its effects before and after DOX spectral features subtraction from nuclear and nucleolar spectra, were compared to non exposed control spectra. Results show that Raman micro spectroscopy is not only able to detect doxorubicin inside cells and profile its specific subcellular localisation, but, it is also capable of elucidating the local biomolecular changes elicited by the drug, differentiating the responses in different sub cellular regions. Further analysis clearly demonstrates the early apoptotic effect in the nuclear regions and the initial responses of cells to this death process, demonstrating the potential of the technique to monitor the mechanisms of action and response on a molecular level, with subcellular resolution. PMID- 25919794 TI - Predictors of home discharge among patients hospitalized for behavioural and psychological symptoms of dementia. AB - BACKGROUND: The Japanese government recently announced the 'Five-Year Plan for Promotion of Measures Against Dementia (Orange Plan)' to promote people with dementia living in their communities. To achieve this, it is imperative that patients hospitalized with behavioural and psychological symptoms of dementia (BPSD) are helped to return to their own homes. The aim of the present study was to identify predictors of home discharge among patients hospitalized for BPSD. METHODS: A single-centre chart review study was conducted on consecutive patients hospitalized from home between April 2006 and March 2011 for the treatment of BPSD. The frequency of discharge back to home was examined in relation to a patient's active behavioural problems and demographics at the time of admission. Diagnoses of dementia were made on the basis of the Diagnostic and Statistical Manual of Mental Disorders, 4th edition, and consensus guidelines for the clinical and pathologic diagnosis of dementia with Lewy bodies. RESULTS: In all, 391 patients were enrolled in the study. Of these patients, 163 (42%) returned home. Multiple logistic regression analysis identified high Mini-Mental State Examination and Nishimura-style senile activities of daily living scores as significant independent predictors of home discharge. In contrast, living alone and manifestation of aggressiveness at the time of admission were negatively associated with home discharge. CONCLUSIONS: Few patients hospitalized for BPSD are discharged home, and this number is affected by a patient's clinical and demographic characteristics at the time of admission. These findings should be considered in designing and implementing optimal management and care strategies for patients with BPSD. PMID- 25919795 TI - A Potential Profibrogenic Role of Biliary Epithelium-Derived Cardiotrophin-1 in Pediatric Cholestatic Liver Disease. AB - As a cytokine of the interleukin-6 family, cardiotrophin-1 (CT-1) has been shown to be an important endogenous protector in liver injury. Our study aimed to investigate the role of CT-1 in liver fibrosis in pediatric cholestatic liver disease (PCLD). CT-1 mRNA and protein expression levels were upregulated in PCLD liver biopsy tissues compared with controls. Immunohistochemistry and confocal microscopy of liver sections showed that CT-1 was predominantly expressed by biliary epithelium cells. Serum CT-1 was elevated significantly in the children with PCLD compared with controls. Serum CT-1 levels exhibited a moderate positive correlation with the Scheuer stage of hepatic fibrosis and serum TB levels and a weak correlation with serum ALP levels. In vitro analysis indicated that LX-2 cells preconditioned with CT-1 exhibited significant increments in proliferation and accumulation of extracellular matrix components, while also positively regulating the STAT3 and p38MAPK pathways. In conclusion, biliary epithelium derived CT-1 may exert a profibrogenic potential in PCLD. PMID- 25919796 TI - Increased signaling entropy in cancer requires the scale-free property of protein interaction networks. AB - One of the key characteristics of cancer cells is an increased phenotypic plasticity, driven by underlying genetic and epigenetic perturbations. However, at a systems-level it is unclear how these perturbations give rise to the observed increased plasticity. Elucidating such systems-level principles is key for an improved understanding of cancer. Recently, it has been shown that signaling entropy, an overall measure of signaling pathway promiscuity, and computable from integrating a sample's gene expression profile with a protein interaction network, correlates with phenotypic plasticity and is increased in cancer compared to normal tissue. Here we develop a computational framework for studying the effects of network perturbations on signaling entropy. We demonstrate that the increased signaling entropy of cancer is driven by two factors: (i) the scale-free (or near scale-free) topology of the interaction network, and (ii) a subtle positive correlation between differential gene expression and node connectivity. Indeed, we show that if protein interaction networks were random graphs, described by Poisson degree distributions, that cancer would generally not exhibit an increased signaling entropy. In summary, this work exposes a deep connection between cancer, signaling entropy and interaction network topology. PMID- 25919797 TI - Independent organ donor facilities: The future of organ donation? AB - Since 2001 independent Organ Donor Facilities(OFOs) have been proposed within Organ Procurement Organizations (OPOs) with the aim of reducing organ procurement costs 1, cold ischemia time of donor organs and the flight-related risk 2 for donor surgeons, perfusionists and coordinators. An independent OFO has been established in 2001 in St. Louis 3, half away between the 2 Transplant Centers (TCs) (Washington University School of Medicine and St. Louis University) and now includes a two-bed intensive care facility, a complete laboratory, a cardiac catheterization facility, a Computed Tomography (CT) scanner and an operating room. All brain-dead (BD) patients within OPO (Mid-America Transplant Services), after family's informed consent, are transferred, if necessary by an OPO owned and operated airplane, to this facility, where undergo multiorgan harvesting. By doing so the organ acquisition charges (OACs) apparently decreased, as well as delay in recovery, which can affect organ viability and move families to withdraw consent; also risks and tiring of transplant surgeons were reduced. This independent OFO successfully procured in 2001 not only livers, but also pancreas, kidneys, hearts and lungs 4-6. Cold ischemia time was reduced and there was no Primary Non Function (PNF) of harvested organs, but only kidney delayed graft function (DGF). In the past, heart donors were moved to the recipient's hospital. With the development of multiorgan harvesting, usually donor surgeons are sent by the TCs in order to evaluate liver, pancreas, heart and lungs, while the only local surgeons is the "nephrectomist", that in local hospital is not a transplant surgeon. To move a donor, although hemodinamically stable, is always a risk. Finally, the decrease of OAC must balance the extra expenses to create and operate independent OFOs. In all the papers published by the members of this OFO, the control group of the retrospective analysis consisted of less selected BD donors, requiring more vasosuppressor support, which can be a study bias. It has been proposed that OPOs should organize "recovery teams" for multiple TCs but most transplant surgeons, in case of marginal donors, would like to inspect the organ prior to starting recipient surgery or would send their own team to harvest organs. According to literature, there are no other independent OFOs in US, probably because there is no need for them, and increasing their numbers would not increase organ donation rate. Considering Europe, we do not have information about the existence of independent OFOs: this may be a consequence of logistical organization and minor distances, as well as the higher concentration of TCs. However, the acceptance of such a procedure from donors' families may be less enthusiastic in Europe than in USA, particularly from minorities. In Italy would not be acceptable that the maintenance of BD donors and more generally the operation of independent OFO would rely on non-physicians, to save costs. Finally it is not clear from the reviewed papers who pay for transportation of the donor's body from the independent OFO back to home, but donor's family should not be charged for these expenses. At least 5 donors were lost during transportation, confirming that moving of BD donors remains a risky procedure. The potential economical and organizative benefits of independent OFOs could be counterweighted by the perceived (by relatives and public opinion) commodification/ reification of BD patients. Anyway, the authors of these papers should be congratulated for their innovative proposal. However, a prospective randomized trial would be needed to draw more definitive conclusions on the real benefits of independent OFOs. PMID- 25919798 TI - Anger Rumination as a Mediator of the Relationship Between Mindfulness and Aggression: The Utility of a Multidimensional Mindfulness Model. AB - OBJECTIVES: Mindfulness training reduces anger and aggression, but the mechanisms of these effects are unclear. Mindfulness may reduce anger expression and hostility via reductions in anger rumination, a process of thinking repetitively about angry episodes that increases anger. Previous research supports this theory but used measures of general rumination and assessed only the present-centered awareness component of mindfulness. The present study investigated associations between various aspects of mindfulness, anger rumination, and components of aggression. METHOD: The present study used self-report measures of these constructs in a cross-sectional sample of 823 students. RESULTS: Structural equation modeling revealed that anger rumination accounts for a significant component of the relationship between mindfulness and aggression, with the largest effect sizes demonstrated for the nonjudgment of inner experiences facet of mindfulness. CONCLUSION: Nonjudgment and present-centered awareness may influence aggression via reduced anger rumination. The importance of examining mindfulness as a multidimensional construct is discussed. PMID- 25919799 TI - Hydrothermal synthesis of self-assembled hierarchical tungsten oxides hollow spheres and their gas sensing properties. AB - Hierarchical self-assembled hollow spheres (HS) of tungsten oxide nanosheets have been synthesized via a template-free hydrothermal method. Morphology evolution of the products is determined by the amount of H2C2O4 (oxalic acid) which serves as chelating agent. Structural features of the products were characterized by X-ray diffraction (XRD), and morphology was investigated by scanning electron microscopy (SEM) and transmission electron microscopy (TEM). In addition, the porous structure was analyzed using the Brunauer-Emmett-Teller (BET) approach. The synthesis mechanism of the products with self-assembled hierarchical structures was proposed. The NO2 gas sensing properties of self-assembled hierarchical WO3 HS materials were investigated, the gas sensing properties of WO3 synthesized by a variety of formulations were compared, and the possible gas sensing mechanism was discussed. The obvious enhancement of the gas sensing properties was ascribed to the structure of the hierarchical HS. PMID- 25919800 TI - Investigating m-Health Acceptance from a Protection Motivation Theory Perspective: Gender and Age Differences. AB - BACKGROUND: Mobile health (m-health) services are becoming increasingly important and widely accepted. However, empirical studies on potential users' m-health acceptance behavior remain underexplored. Indeed, m-health adoption is not only a technology acceptance behavior, but also a health-related behavior. MATERIALS AND METHODS: Based on the Protection Motivation Theory, this article explores users' m-health adoption behavior from the perspectives of threat appraisal and coping appraisal, and also examines the moderating role of gender and age through a survey of potential users. The survey was conducted among 500 potential m-health service participants. RESULTS: Our results show that threat appraisal and coping appraisal factors influence adoption intention through attitude. It is also found that gender and age play different moderating roles with threat appraisal and coping appraisal factors. CONCLUSIONS: Gender and age play different roles between threat appraisal and coping appraisal factors in the acceptance of m health. Implications for research and practice are discussed. PMID- 25919801 TI - Effects of the murine skull in optoacoustic brain microscopy. AB - Despite the great promise behind the recent introduction of optoacoustic technology into the arsenal of small-animal neuroimaging methods, a variety of acoustic and light-related effects introduced by adult murine skull severely compromise the performance of optoacoustics in transcranial imaging. As a result, high-resolution noninvasive optoacoustic microscopy studies are still limited to a thin layer of pial microvasculature, which can be effectively resolved by tight focusing of the excitation light. We examined a range of distortions introduced by an adult murine skull in transcranial optoacoustic imaging under both acoustically- and optically-determined resolution scenarios. It is shown that strong low-pass filtering characteristics of the skull may significantly deteriorate the achievable spatial resolution in deep brain imaging where no light focusing is possible. While only brain vasculature with a diameter larger than 60 um was effectively resolved via transcranial measurements with acoustic resolution, significant improvements are seen through cranial windows and thinned skull experiments. PMID- 25919802 TI - A case of bullous pemphigoid associated with infiltration and activation of basophils. PMID- 25919803 TI - Accuracy of Contrast-enhanced US for Differentiating Benign from Malignant Solid Small Renal Masses. AB - PURPOSE: To test the hypothesis that qualitative and quantitative features of contrast material-enhanced ultrasonography (US) can be used to differentiate benign from malignant small renal masses. MATERIALS AND METHODS: This is an institutional review board approved, HIPAA-compliant prospective study with written informed consent. Patients with histologically characterized solid small renal masses, excluding lipid-rich angiomyolipomas, underwent qualitative contrast-enhanced US with a combination of three different US machines. A subgroup of patients underwent quantitative contrast-enhanced US. Patients received a bolus injection of 0.2 mL of contrast material for qualitative and quantitative evaluations and were followed for 3 minutes. Two radiologists independently reviewed videotaped qualitative contrast-enhanced US examinations and were blinded to the final diagnoses. Features that were evaluated included lesion vascularity relative to the adjacent cortex in the arterial phase, the presence of a capsule, homogeneity, the pattern of vascularity, and washout. One radiologist separately reviewed a subset of contrast-enhanced US examinations that were performed with all three machines. Parameters of a first-pass time intensity curve were calculated for quantitative analysis. The Mann-Whitney test was used for quantitative parameters, the chi(2) or Fisher exact test was used for qualitative parameters, and kappa statistics and Fleiss methodology were used to determine interobserver and intermachine agreement. RESULTS: The study population consisted of 91 patients (35 women and 56 men) with 94 lesions. The mean age was 62 years +/- 14 (range, 21-91). Three patients had two lesions each, which were evaluated at two different sessions. There were 26 benign small renal masses (including 18 oncocytomas, seven lipid-poor angiomyolipomas, and one hemangioblastoma) and 68 malignant masses (including 41 clear cell, 20 papillary, and seven chromophobe renal cell carcinomas [RCCs[) that were 1.1-4.0 cm in diameter (mean, 2.7 cm +/- 0.9). All patients underwent contrast-enhanced US on the same one machine, and 68 patients were imaged on all three machines. Vascularity was present in all lesions (n = 94) at contrast-enhanced US. Lesion hypovascularity relative to the adjacent cortex in the arterial phase was seen in only malignant lesions by both reviewers; reviewer 1 saw hypovascularity in 24 of 94 lesions (P = .0001), and reviewer 2 saw hypovascularity in 21 of 94 lesions (P = .0006), for a specificity of 100% (95% confidence interval [CI]: 84, 100). This feature had kappa values of 0.91 (95%CI: 0.82, 1.00) between the two reviewers and 0.85 (95% CI: 0.72, 0.99) between the three machines. Eighteen of 20 papillary RCCs were hypovascular. Quantitative parameters of area under the receiver operating characteristics curve, peak intensity, wash-in slope of 10% 90% and 5%-45%, and washout slope of 100%-10% and 50%-10% were significantly higher in malignant renal masses (P = .018, P = .002, P = .036, P = .016, P = .001, and P = .005, respectively) than in benign lesions. CONCLUSION: Excluding lipid-rich angiomyolipoma, hypovascularity-which has high interobserver and intermachine agreement-of solid small renal masses relative to the cortex in the arterial phase has 100% specificity (95% CI: 84, 100) for detecting malignancy, most often papillary RCC. PMID- 25919804 TI - Symmetric limb overgrowth following anterior cruciate ligament reconstruction in a skeletally immature patient. AB - This report describes a case of symmetric femoral and tibial overgrowth of 2.8 cm in a 13-year-old patient after undergoing reconstruction surgery for his torn right anterior cruciate ligament. A literature review of previous cases is also provided. Following a pediatric anterior cruciate ligament tear, delaying surgery until the patient approaches skeletal maturity may avoid long-term growth disturbances, however, delaying this procedure may increase the probability of further joint damage. This growth disturbance was managed with a percutaneous epiphysiodesis that corrected the limb length deformity. PMID- 25919805 TI - Unusual humeral medial condyle fracture in an adolescent because of a previous post-traumatic fishtail deformity: a case report. AB - A fishtail deformity is a well-known complication following pediatric lateral condyle fracture of the humerus. We report a rare case of a medial humeral condyle fracture in a 12-year-old boy who had had a fishtail deformity because of a lateral condyle fracture in childhood. Radiographs showed a longitudinal fracture plane of the medial condyle extending to the articular surface, which is different from the three types of medial condyle fracture classified by Kilfoyle. We present our case and reviewed the literature to clarify the difference in the mechanism of medial humeral condyle fracture after a fishtail deformity. PMID- 25919806 TI - Osteochondritis dissecans of the lateral femoral condyle in a patient affected by osteogenesis imperfecta: a case report. AB - Osteochondritis dissecans is a very uncommon phenomenon in osteogenesis imperfecta (OI). A 14-year-old boy, affected by OI and followed in our Center for Congenital Osteodystrophies, had a knee trauma and MRI indicated a hollowed area of 2.5*1.5 cm in the lateral femoral condyle, which was classified as grade III. The patient underwent surgery, performed as a one-step surgical treatment: the osteochondral fragment was removed, curettage of lesion's bottom was performed, and a biphasic scaffold was used to fill the defect, implanted with a press-fit technique. MRI at 12 and 24 months after surgery showed scaffold integration. At the final follow-up, the patient did not feel any pain or articular limitations. It is difficult to provide a guideline on osteochondritis dissecans in patients affected by OI because of the lack of literature reports on this rare disorder in a rare disease. According to our experience, in these patients, osteosynthesis of the bone fragment and the use of autograft are not recommended because of the patient's bone weakness and osteoporosis. Moreover, compared with two-step surgery, one-step surgery is preferred to reduce the risk related to anesthesia, often observed to be higher in these patients. PMID- 25919808 TI - Peer review: strengthening the weak link of academic radiology. PMID- 25919807 TI - Docking and migration of carbon monoxide in nitrogenase: the case for gated pockets from infrared spectroscopy and molecular dynamics. AB - Evidence of a CO docking site near the FeMo cofactor in nitrogenase has been obtained by Fourier transform infrared spectroscopy-monitored low-temperature photolysis. We investigated the possible migration paths for CO from this docking site using molecular dynamics calculations. The simulations support the notion of a gas channel with multiple internal pockets from the active site to the protein exterior. Travel between pockets is gated by the motion of protein residues. Implications for the mechanism of nitrogenase reactions with CO and N2 are discussed. PMID- 25919809 TI - Detection of Interferon gamma using graphene and aptamer based FET-like electrochemical biosensor. AB - One of the primary goals in the scientific community is the specific detection of proteins for the medical diagnostics and biomedical applications. Interferon gamma (IFN-gamma) is associated with the tuberculosis susceptibility, which is one of the major health problems globally. We have therefore developed a DNA aptamer-based electrochemical biosensor that is used for the detection of IFN gamma with high selectivity and sensitivity. A graphene monolayer-based FET-like structure is incorporated on a PDMS substrate with the IFN-gamma aptamer attached to graphene. Addition of target molecule induces a change in the charge distribution in the electrolyte, resulting in increase in electron transfer efficiency that was actively sensed by monitoring the change in current from the device. Change in current appears to be highly sensitive to the IFN-gamma concentrations ranging from nanomolar (nM) to micromolar (MUM) range. The detection limit of our IFN-gamma electrochemical biosensor is found to be 83 pM. Immobilization of aptamer on graphene surface is verified using unique structural approach by Atomic Force Microscopy. Such simple and sensitive electrochemical biosensor has potential applications in infectious disease monitoring, immunology and cancer research in the future. PMID- 25919810 TI - In situ monitoring of doxorubicin release from biohybrid nanoparticles modified with antibody and cell-penetrating peptides in breast cancer cells using surface enhanced Raman spectroscopy. AB - In situ monitoring of drug release in cancer cells is very important for real time assessment of drug release dynamics in chemotherapy. In this study, we report label-free in situ monitoring and control of intracellular anti-cancer drug delivery process using biohybrid nanoparticles based on surface-enhanced Raman spectroscopy (SERS) for the first time. Each biohybrid nanoparticle consisted of gold nanoparticle, cell-penetrating peptide (Tat peptide), and cancer-targeting antibody to increase the efficacy of the anti-cancer drug delivery with specific targeting and increased uptake rate. The doxorubicin (Dox) loaded biohybrid nanoparticles were showed specific SERS spectra of Dox, specifically immobilized on the target cell membrane and quickly penetrated into the cells when treated on the mixed cell culture condition. The intracellular release of Dox from the biohybrid nanoparticle was continuously monitored with time-dependent change of intracellular SERS signals of Dox. The releasing rate of Dox was successfully controlled with the addition of glutathione on the cells. The anti-cancer effect of intracellular released Dox was confirmed with cell viability assay. With the proposed monitoring system, specific cancer cell targeting and improved uptake of the anti-cancer drug were detected and time dependent intracellular release of the anti-cancer drug was monitored successfully. The proposed novel in situ monitoring system can be used as a spectroscopic analysis tool for label-free monitoring of the time-dependent release of various kinds of anti-cancer drugs inside cells. PMID- 25919811 TI - Highly sensitive bacterial susceptibility test against penicillin using parylene matrix chip. AB - This work presented a highly sensitive bacterial antibiotic susceptibility test through beta-lactamase assay using Parylene-matrix chip. beta-lactamases (EC 3.5.2.6) are an important family of enzymes that confer resistance to beta-lactam antibiotics by catalyzing the hydrolysis of these antibiotics. Here we present a highly sensitive assay to quantitate beta-lactamase-mediated hydrolysis of penicillin into penicilloic acid. Typically, MALDI-TOF mass spectrometry has been used to quantitate low molecular weight analytes and to discriminate them from noise peaks of matrix fragments that occur at low m/z ratios (m/z<500). The beta lactamase assay for the Escherichia coli antibiotic susceptibility test was carried out using Parylene-matrix chip and MALDI-TOF mass spectrometry. The Parylene-matrix chip was successfully used to quantitate penicillin (m/z: [PEN+H](+)=335.1 and [PEN+Na](+)=357.8) and penicilloic acid (m/z: [PA+H](+)=353.1) in a beta-lactamase assay with minimal interference of low molecular weight noise peaks. The beta-lactamase assay was carried out with an antibiotic-resistant E. coli strain and an antibiotic-susceptible E. coli strain, revealing that the minimum number of E. coli cells required to screen for antibiotic resistance was 1000 cells for the MALDI-TOF mass spectrometry/Parylene matrix chip assay. PMID- 25919812 TI - Chirality and gravitational parity violation. AB - In this review, parity-violating gravitational potentials are presented as possible sources of both true and false chirality. In particular, whereas phenomenological long-range spin-dependent gravitational potentials contain both truly and falsely chiral terms, it is shown that there are models that extend general relativity including also coupling of fermionic degrees of freedom to gravity in the presence of torsion, which give place to short-range truly chiral interactions similar to that usually considered in molecular physics. Physical mechanisms which give place to gravitational parity violation together with the expected size of the effects and their experimental constraints are discussed. Finally, the possible role of parity-violating gravity in the origin of homochirality and a road map for future research works in quantum chemistry is presented. PMID- 25919813 TI - Comparison of the Prevalence of Latent Tuberculosis Infection among Non-Dialysis Patients with Severe Chronic Kidney Disease, Patients Receiving Dialysis, and the Dialysis-Unit Staff: A Cross-Sectional Study. AB - BACKGROUND: Patients with renal failure are vulnerable to tuberculosis, a common worldwide infectious disease. In the growing dialysis population, the risk for tuberculosis among the associated sub-groups is important but unclear. This study investigated latent tuberculosis infection (LTBI) in patients with severe chronic kidney disease (CKD) and among dialysis-unit staff caring for patients on dialysis. METHODS: From January 2012 to June 2013, patients undergoing dialysis, those with severe CKD (estimated glomerular filtration rate <30 ml/min/1.73 m2), and the dialysis-unit staff (nursing staff and doctors in hemodialysis units) in several Taiwan hospitals were prospectively enrolled. Interferon-gamma release assay (IGRA) through QuantiFERON-TB Gold In-tube was used to determine LTBI. Predictors for LTBI were analyzed. RESULTS: Of the 599 participants enrolled, 106 (25%) in the dialysis group were IGRA positive. This was higher than the seven (11%) among severe CKD patients and 12 (11%) in the dialysis-unit staff. Independent predictors of LTBI in patient with renal dysfunction were old age (odds ratio [OR]: 1.03 [1.01-1.04] per year increment), prior TB lesion on chest radiograph (OR: 2.90 [1.45-5.83]), serum albumin (OR: 2.59 [1.63-4.11] per 1 g/dl increment), and need for dialysis (OR: 2.47, [1.02-5.95]). The QFT-GIT response was similar among the three groups. Malignancy (OR: 4.91 [1.84-13.10]) and low serum albumin level (OR: 0.22 [0.10-0.51], per 1 g/dl decrease) were associated with indeterminate IGRA results. CONCLUSIONS: More patients on dialysis have LTBI compared to those with severe CKD and the dialysis-unit staff. Old age, prior radiographic TB lesion, high serum albumin, and need for dialysis are predictors of LTBI in patients with renal failure. Patients with severe CKD are a lower priority for LTBI screening. The hemodialysis environment is not a risk for LTBI and dialysis-unit staff may be treated as general healthcare workers. PMID- 25919814 TI - Synthesis, characterization, DNA/BSA interactions and anticancer activity of achiral and chiral copper complexes. AB - Six novel copper(ii) complexes of [CuCl]ClO4 (), [Cu(acac)]PF6 (), [CuCl]2(PF6)2 (), [CuCl]2(PF6)2 (), [Cu(acac)]PF6 () and [Cu(acac)]PF6 (), ( = 1-naphthyl-N,N [bis(2-pyridyl)methyl]amine, = R/S-1-naphthyl-N,N-[bis(2 pyridyl)methyl]ethanamine, acac = diacetone) were synthesized to serve as artificial nucleases. All complexes were structurally characterized using X-ray crystallography. The crystal structures showed the presence of distorted square planar CuLCl (, and ) and distorted tetragonal-pyramidal CuL(acac) (, and ) geometry. The interaction of these complexes with calf thymus DNA (CT-DNA) was researched by means of several spectroscopy methods, which indicated that the complexes were bound to CT-DNA by an intercalation binding mode. DNA cleavage experiments revealed that the complexes exhibited remarkable DNA cleavage activities in the presence of H2O2, and single oxygen ((1)O2) or hydroxyl radicals may serve as the major cleavage active species. In particular, the in vitro cytotoxicity of the complexes on four human cancer cell lines (HeLa, MCF-7, Bel-7404 and HepG-2) demonstrated that the six compounds had broad-spectrum anti cancer activity with low IC50 values. The stronger cytotoxicity and DNA cleavage activity of the chiral enantiomers compared with chiral analogues verified the influence of chirality on the antitumor activity of complexes. Meanwhile, the protein binding ability was revealed by quenching of tryptophan emission with the addition of complexes using BSA as a model protein. The results indicated that the quenching mechanism of BSA by the complexes was a static process. PMID- 25919815 TI - Adsorption of Surface-Modified Silica Nanoparticles to the Interface of Melt Poly(lactic acid) and Supercritical Carbon Dioxide. AB - With the purpose of fabricating polymer nanocomposite foams and preventing coalescence in foaming processes, the interfacial tension of poly(lactic acid) (PLA)-silica composites is investigated in this work. Synthesized silica nanoparticles (SNs) with a CO2-philic surface modification are used as the dispersed nanoparticles. Interfacial tension is a key parameter in processing of polymer foams since it directly affects the final foam properties, such as cell size and cell density. Interfacial tension of silica-containing PLA and supercritical carbon dioxide (CO2) is measured using axisymmetric drop shape analysis profile (ADSA-P) pendant drop method at high pressures and high temperatures. The interfacial tension between PLA and supercritical CO2 is observed to decrease as a result of the nanoparticles' adsorption to the interface. These results indicate that the reduction in interfacial tension with increasing silica content significantly deviates from a linear trend; there is a minimum at 2 wt % loading of the SNs and then the interfacial tension curve reaches a plateau. Contact angle measurements show an affinity of the SNs for the polymer-supercritical CO2 interface, and these obtained results are used to calculate the binding energy of the nanoparticles to the PLA/CO2 interface. In addition to interfacial properties, the adsorption of silica nanoparticles at the interface is also studied in detail with scanning electron microscopy. PMID- 25919816 TI - Thermoregulation and pain perception: Evidence for a homoeostatic (interoceptive) dimension of pain. AB - BACKGROUND: Experimental and clinical observations of interactions between the nociceptive and thermoceptive systems have suggested that they could be part of the homoeostatic system relating to the condition of the body, described as 'interoception'. Homoeostatic physiological systems are extensively interconnected. Thus, consistent with this hypothesis, we would expect thermoregulatory challenges to be associated with changes in pain perception. METHODS: The effects of whole-body warming or cooling inducing significant changes in mean body temperature were tested in 15 healthy volunteers (29 +/- 6 years old) on: (i) the paradoxical burning pain induced by the application of simultaneous non-noxious thermal stimuli with a 'thermal grill' and (ii) the 'normal' pain evoked by noxious thermal stimuli. RESULTS: Whole-body warming and cooling induced changes in opposite direction of the threshold of the paradoxical pain induced by the thermal grill, consisting of an increase by 1.2 +/- 1.7 degrees C (p = 0.02) during the warming session and a nonsignificant decrease by 0.7 +/- 2.7 degrees C (p = 0.15) during the cooling session. In addition, there was a correlation (r = 0.54; p = 0.002) between the magnitude of the change in mean body temperature and the magnitude of the change in the threshold of the paradoxical pain induced by the thermal grill. By contrast, the thermal challenges induced no significant change in pain evoked by noxious hot or cold stimuli. CONCLUSIONS: Our results are consistent with the notion that pain has a homoeostatic (interoceptive) dimension and showed that the thermal grill-induced pain is a unique experimental model to investigate this differentiable pain dimension. PMID- 25919817 TI - [Happy birthday: 50 years of AINS]. PMID- 25919819 TI - [Anesthesiology in interventional pneumology- endoscopic interventions: part 1]. AB - Less invasive bronchoscopic techniques for lung-volume-reduction have almost replaced surgical resections. Tracheobronchial obstructions and - to a certain degree - even bronchial tumors can be treated bronchoscopically. However all these procedures show specific risks anesthesiologists have to consider. PMID- 25919820 TI - [Antiemetic therapy in preclinical emergency medicine - a literature review]. AB - Nausea and vomiting are frequent symptoms in emergency medicine and require a targeted drug intervention. Despite known disadvantages in terms of efficacy and side effects, metoclopramide is still often used in the emergency medical service to treat nausea and vomiting. Recent studies show that, especially in the therapy of opioid-triggered vomiting, metoclopramide is not significantly effective when compared to placebo. Dimenhydrinate seems to be an effective drug for various forms of nausea, but can often be relatively or absolutely contraindicated in emergency medicine due to its sedative effect. Based on a literature review, 5 HT3-antagonists appear to be a good alternative for the treatment of emesis in the emergency service. However, as for all antiemetics, the maximum dosage and potential side effects need to be paid attention to. In addition, neither of the 5-HT3-antagonists are approved for therapy of non-chemotherapy-induced vomiting or PONV. In conclusion, it may be considered to include 5-HT3-antagonists in addition to dimenhydrinate in the ambulance medical equipment. The routine use of a specific antiemetic is not recommended. PMID- 25919821 TI - [Intensive quiz--make the diagnosis!]. PMID- 25919822 TI - [Anesthesia in orthopedic/trauma surgery --the domain of regional anesthesia]. PMID- 25919823 TI - [Treatment of hip fractures in elderly patients]. AB - Hip fractures are among the most common fractures in elderly people. The annual number of femoral fractures is even expected to increase because of an aging society. Due to the high number of comorbidities, there are special challenges in treating geriatric hip fracture patients, which require a multidisciplinary management. This includes surgical treatment allowing full weight bearing in the immediate postoperative period, osteoporosis treatment and falls prevention as well as an early ortho-geriatric rehabilitation program. PMID- 25919824 TI - [Regional anaesthesia in patients with lower limb injury]. AB - Almost all surgical procedures following injury can be provided in peripheral regional anaesthesia or spinal anaesthesia - under consideration of specific contraindications. The majority of injuries at the lower limb are associated with severe pain and immobilization during the postoperative phase. Moreover, opioids are often required which are related to nausea, vomiting and impairment of vigilance. For avoidance of those side effects, regional anaesthesia techniques should be considered as a more effective approach with a better profile of side effects. Hip and proximal femur fractures are more frequent in elder patients with a corresponding high morbidity. Therefore anaesthesia is challenging in those patients. Even injuries of the long bones - like the femur and the tibia - are causing severe pain, therefore an appropriate concept for acute pain therapy is required. Moreover, for injuries with affection of bony joint-structures (i. e. knee, ankle, calcaneus) and marked soft-tissue injuries continuous regional anaesthesia techniques could provide advantages during acute pain therapy. PMID- 25919825 TI - [Regional anaesthesia in injuries of the upper extremity]. AB - Regional anaesthesia has significant advantages compared to general anaesthesia with an opiate-based postoperative analgesia in injuries of the upper extremity. Severe pain may be considered a risk factor for the development of chronic postoperative pain syndromes in adults and children. Depending on the anticipated postoperative pain level, a catheter procedure should be used. Fractures of the upper extremity are common and may also be associated with seemingly minor injuries with a high postoperative pain level. Nerve damage can be caused mainly by traumatic fractures, or iatrogenically during surgical procedures. Reduced possible neurological evaluability should not prevent the excellent pain control which regional anesthesia can provide. Since the brachial plexus is predominantly responsible for the sensory innervation of the entire upper extremity, therefore all known block techniques in regional anaesthesia apply. Since the introduction of ultrasound in regional anaesthesia (USGRA), older methods like the supraclavicular approach, which were previously banned due to high complication rates, are now being rediscovered. Both new and old blockade methods are much more effective and safe with ultrasound support because of the rapid visualization of the anatomy and needle. PMID- 25919826 TI - [Anesthesia and hemodynamic management in the sitting position]. AB - Every year thousands of patients are operated in the sitting position. The most common position is the beach chair position. Due to case reports with deleterious neurologic outcome, the safety of the beach chair position in combination with general anesthesia is discussed controversially. In this review article the possible complications according to the beach chair position are explained and practical advice is given for the daily anesthetic routine. PMID- 25919827 TI - [Additional training in the interdisciplinary emergency room--what is the current status?]. PMID- 25919832 TI - Understanding and managing Cognition in the Depressed Patient. AB - Cognition is a renewed area of clinical focus in major depressive disorder (MDD). Cognitive problems such as difficulty concentrating and making decisions are common symptoms of MDD, and while these symptoms improve as depressive symptoms improve in some patients, a substantial portion of patients experience cognitive impairment even while euthymic. In turn, impaired cognition hinders restoration of psychosocial functioning, allowing for continued difficulty at work, at home, and in social settings. Therefore, clinicians must routinely measure and manage cognitive functioning in patients with MDD. PMID- 25919833 TI - Introduction. PMID- 25919834 TI - Impaired insight into delusions predicts treatment outcome during a randomized controlled trial for Psychotic Depression (STOP-PD study). AB - BACKGROUND: Insight into delusional beliefs varies in patients with major depressive disorder (MDD) with psychotic features ("psychotic depression"). The relationship between impaired insight and illness severity and its impact on treatment outcomes has not been studied in psychotic depression. As such, the aim of this analysis was to explore the relationship among impaired insight, patient characteristics (ie, illness severity, cognition, suicidality, and social functioning), and treatment outcome (ie, remission) during acute treatment of psychotic depression. METHOD: This secondary analysis is based on the data from the Study of Pharmacotherapy for Psychotic Depression (STOP-PD) in which 259 participants meeting DSM-IV criteria for MDD with psychotic features enrolled between December 2002 and June 2007 (including 142 aged >= 60 years) in a 4 center, 12- week, double-blind, randomized controlled trial funded by the US National Institutes of Health. Insight into delusions was assessed using the Delusion Assessment Scale (DAS). The primary outcomes were the predictive utility of insight into illness (ie, Hamilton Depression Rating Scale [HDRS] insight item) and insight into delusions (conviction factor derived from the DAS) on final treatment outcome at 12 weeks of treatment (ie, full remission, partial remission, and nonremission). RESULTS: At baseline, impaired insight into delusions was positively associated with illness severity (HDRS-16 which excluded the insight item, r = 0.15, P = .016) and negatively correlated with measures of cognition (P < .05). Improvement in insight was not associated with changes in cognition, suicidality, or social functioning after adjusting for covariates. Independent of the severity of depression or psychosis, impaired insight into delusions at baseline (chi2 = 11.65, P = .020) and after 3 (chi2 = 9.62, P = .047), 6 (chi2 = 6.97, P = .031), and 8 (chi2 = 9.08, P = .011) weeks of treatment predicted remission at the end of the trial. CONCLUSIONS: Impaired insight into delusions appears to be an independent predictor of remission in MDD with psychotic features during acute treatment, suggesting that more attention should be paid to this symptom. Longitudinal studies are required to determine the impact of impaired insight into delusions on long-term outcomes, including relapse. TRIAL REGISTRATION: ClinicalTrials.gov identifier: NCT00056472. PMID- 25919835 TI - Whether to increase or maintain dosage of mirtazapine in early nonimprovers with depression. AB - OBJECTIVE: To compare outcomes between increasing versus maintaining the dose of mirtazapine in patients with depression without initial improvement. METHOD: Data from a 6-week double-blind randomized placebo-controlled trial of mirtazapine in major depressive disorder (DSM-IV) conducted from November 2004 to December 2005 were used. Percentages of remitters (ie, a score of <= 7 in the 17-item Hamilton Depression Rating Scale [HDRS-17]) and HDRS-17 score changes from baseline to week 6 were compared in the following 2 pairs, using Fisher exact test or mixed effects model for repeated measures: (1) subjects who failed to show a >= 20% decrease in the HDRS-17 total scores at week 1 but were assigned to continue 15 mg/d (stay(15) group) versus those who were assigned to increase the dose to 30 mg/d (increase(30) group) and (2) subjects who failed to show a >= 20% decrease in the HDRS-17 total scores with 30 mg/d at week 2 but were assigned to continue 30 mg/d (stay(30) group) versus those who were assigned to increase the dose to 45 mg/d (increase(45) group). RESULTS: The increase(30) group showed a numerically but not significantly higher remission rate and a significantly greater decrease in the HDRS-17 total score at week 6 than the stay(15) group (34.7% [8 of 23 patients] vs 14.3% [3 of 21 patients], P = .2; least squares mean, -15.8 vs -10.9, P = .003). No significant differences were found between the increase(45) and stay(30) groups. CONCLUSIONS: Dose increase of mirtazapine from 15 mg/d to 30 mg/d may be effective for patients with depression without initial improvement. However, effectiveness may not be the case beyond 30 mg/d. TRIAL REGISTRATION: JapicCTI identifier: 152830. PMID- 25919836 TI - Impact of the Body Worlds exhibition on mental health indices and death-related fears: a before-after study. PMID- 25919839 TI - Factors affecting exits from homelessness among persons with serious mental illness and substance use disorders. AB - OBJECTIVE: We sought to understand the housing trajectories of homeless consumers with serious mental illness (SMI) and co-occurring substance use disorders (SUD) and to identify factors that best predicted achievement of independent housing. METHOD: Using administrative data, we identified homeless persons with SMI and SUD admitted to a residential rehabilitation program from December 2008 to November 2011. Our primary outcome measure was independent housing status. On a random sample (N = 36), we assessed a range of potential predictors of housing outcomes, including symptoms, cognition, and social/community supports. We used the Residential Time-Line Follow-Back (TLFB) Inventory to gather housing histories since exiting rehabilitation and to identify housing outcomes. We used Recursive Partitioning (RP) to identify variables that best differentiated participants by these outcomes. RESULTS: We identified 3 housing trajectories: stable housing (n = 14), unstable housing (n = 15), and continuously engaged in housing services (n = 7). In RP analysis, 2 variables (Symbol Digit Modalities Test [SDMT], a neurocognitive speed of processing measure, and Behavior and Symptom Identification Scale [BASIS-24] Relationships subscale, which quantifies symptoms affecting relationships) were sufficient to capture information provided by 26 predictors to classify participants by housing outcome. Participants predicted to continuously engage in services had impaired processing speeds (SDMT score < 32.5). Among consumers with SDMT score >= 32.5, those predicted to achieve stable housing had fewer interpersonal symptoms (BASIS-24 Relationships subscale score < 0.81) than those predicted to have unstable housing. This model explains 57% of this sample's variability and 14% of this population's variability in housing outcomes. CONCLUSIONS: Because cognition and symptoms influencing relationships predicted housing outcomes for homeless adults with SMI and SUD, cognitive and social skills training may be useful for this population. PMID- 25919840 TI - A meta-review of lifestyle interventions for cardiovascular risk factors in the general medical population: lessons for individuals with serious mental illness. AB - OBJECTIVE: Individuals with serious mental illness die years younger than members of the general population, with cardiovascular disease and related risk factors accounting for the majority of deaths. Lifestyle interventions targeting these risk factors have begun to be developed for those with serious mental illness, but they have largely been created de novo rather than with information from work already done in the general population. This review aims to synthesize for a mental health audience the common factors for success in nonpharmacologic lifestyle interventions and identify specific considerations in adapting these models for those with serious mental illness. DATA SOURCES: We searched the PubMed and Cochrane databases for English-language reviews from 2003 to 2013. The search employed combinations of the following terms: diabetes, diabetes mellitus, hypertension, hyperlipidemia, dyslipidemia, obesity, mental illness, schizophrenia, psychosis, bipolar disorder, lifestyle intervention, non pharmacologic intervention, lifestyle modification, and weight gain. STUDY SELECTION: We identified 8,147 review articles from the PubMed and Cochrane databases. 123 articles were selected. The selected articles were reviews of dietary, behavioral, or exercise interventions that focused on obesity and related cardiometabolic risk factors. DATA EXTRACTION: We undertook a qualitative "review of reviews" focusing on nonpharmacologic interventions for obesity and related cardiometabolic risk factors. RESULTS: Effects of interventions in the general population were meaningful but generally modest. Specific elements of diet, exercise, and behavioral therapy produced larger effects. Additionally, successful programs employed multiple components, personalization, longer duration, more frequent contact, and trained treatment providers. Interventions addressing these risk factors in people with serious mental illness typically incorporated some, but not all, of the elements demonstrated to be effective in general medical populations. CONCLUSIONS: Studies from the general medical literature demonstrate considerable promise in addressing lifestyle risk factors. Existing programs will require tailoring to address the needs of those with serious mental illness and may be harder to implement given the challenges faced by this population. However, successful lifestyle interventions for those with serious mental illness can make a significant impact on the health and well-being of this vulnerable population and may inform future strategies for other underserved groups. PMID- 25919841 TI - Comparative efficacy, acceptability, and tolerability of augmentation agents in treatment-resistant depression: systematic review and network meta-analysis. AB - OBJECTIVE: To comparatively analyze the efficacy, acceptability, and tolerability of various augmentation agents in adult patients with treatment-resistant depression. DATA SOURCES: An electronic literature search of PubMed, EMBASE, the Cochrane Library, Web of Science, EBSCO, PsycINFO, EAGLE, and NTIS for trials published up to December 2013 was conducted. Several clinical trial registry agencies and US Food and Drug Administration reports were also reviewed. No language, publication date, or publication status restrictions were imposed. STUDY SELECTION: Randomized controlled trials comparing 11 augmentation agents (aripiprazole, bupropion, buspirone, lamotrigine, lithium, methylphenidate, olanzapine, pindolol, quetiapine, risperidone, and thyroid hormone) with each other and with placebo for adult treatment-resistant depression were included. DATA EXTRACTION: The proportion of patients who responded to treatment was defined as primary efficacy, and the proportion of all-cause discontinuation and side-effects discontinuation were respectively defined as acceptability and tolerability, which were assessed with odds ratios (ORs) and a Bayesian random effects model with 95% credible intervals (CrIs). RESULTS: A total of 48 trials consisting of 6,654 participants were eligible. In terms of the primary efficacy, quetiapine (OR = 1.92; 95% CrI, 1.39-3.13), aripiprazole (OR = 1.85; 95% CrI, 1.27-2.27), thyroid hormone (OR = 1.84; 95% CrI, 1.06-3.56), and lithium (OR = 1.56; 95% CrI, 1.05-2.55) were significantly more effective than placebo. Sensitivity analyses indicated that efficacy estimates for aripiprazole and quetiapine were more robust than those for thyroid hormone and lithium. In terms of acceptability, no significant difference was found between active agents and placebo. In terms of tolerability, compared to placebo, quetiapine (OR = 3.85; 95% CrI, 1.92-8.33), olanzapine (OR = 3.36; 95% CrI, 1.60-8.61), aripiprazole (OR = 2.51; 95% CrI, 1.11-7.69), and lithium (OR = 2.30; 95% CrI, 1.04-6.03) were significantly less well tolerated. CONCLUSIONS: Quetiapine and aripiprazole appear to be the most robust evidence-based options for augmentation therapy in patients with treatment-resistant depression, but clinicians should interpret these findings cautiously in light of the evidence of potential treatment-related side effects. PMID- 25919842 TI - Depression in the US population during the time periods surrounding the great recession. AB - OBJECTIVE: To determine whether the time periods surrounding the 2008 US economic downturn were accompanied by an increase in prevalence of depression in the US adult population. METHOD: We used data from the 24,182 adults aged >= 18 years who participated in the National Health and Nutrition Examination Survey during 2005-2012. A cross-sectional analysis was performed at each time period to determine prevalence of major and other depression as assessed by standardized questionnaires based on 9 criteria for major depressive episodes defined by DSM IV. RESULTS: The demographic characteristics of the US population were similar across time periods except for the percentage of adults living in poverty, which increased from 26.43% during 2005-2006 to 33.46% during 2011-2012. The prevalence of major depression increased from 2.33% (95% CI, 1.64%-3.01%) during 2005-2006 to 3.49% (95% CI, 2.84%-4.03%) in 2009-2010 to 3.79% (95% CI, 3.01%-4.57%) in 2011-2012. Prevalence of other depression increased from 4.10% (95% CI, 3.37% 4.88%) in 2005-2006 to 4.79% (95% CI, 4.10%-5.44%) in the 2009-2010 period but then declined to 3.68% (95% CI, 2.84%-4.48%) in the 2011-2012 time period (P = .4). After adjustment for the distribution of age, sex, race/ethnicity, education, insurance status, and poverty status in the US adult noninstitutionalized population, each 2-year period after the 2005-2006 time period was associated with a 0.4% increase in major depression prevalence (P < .001). No significant differences in other depression prevalence were noted by time period (P = .6). CONCLUSIONS: The time periods surrounding the recent economic recession were accompanied by a significant and sustained increase in major depression prevalence in the US population. It is plausible that the recession, given its strong, persistent, and negative effects on employment, job and housing security, and stock investments, contributed to the sustained increase in prevalence of major depression in the US population, but other factors associated with the recession time period could have played a role. The impact of the economic downturn on depression prevalence should be considered when formulating future policies and programs to promote and maintain the health of the US population. PMID- 25919843 TI - Association of pulmonary tuberculosis and ethambutol with incident depressive disorder: a nationwide, population-based cohort study. AB - BACKGROUND: Inflammatory responses from chronic infection might affect the brain and increase the risk of depressive disorder. However, the temporal association between chronic infection (eg, tuberculosis [TB]) and incident depressive disorder has not been prospectively evaluated. OBJECTIVE: To determine the association of pulmonary tuberculosis (PTB) and anti-TB drugs with incident depressive disorder (ICD-9-CM codes 296.2x-296.3x, 300.4, and 311.x). METHOD: From January 1, 2000, we identified adult patients with PTB from the Taiwan National Health Insurance Research Database. A control cohort without PTB, matched for age (+/- 5 years), sex, comorbidities, and income level, was selected for comparison. The 2 cohorts were followed until December 31, 2011, and observed for occurrence of depressive disorder. RESULTS: Of the 23,145 patients (4,629 study patients and 18,516 matched controls), 302 (1.3%) had depressive disorder during a mean follow-up period of 6.53 years, including 79 study patients (1.71%) and 223 controls (1.20%). After adjusting for age, sex, comorbidities, and income level in the Cox proportional hazards model, PTB was found to be an independent risk factor of incident depressive disorder (adjusted hazard ratio [HR], 1.74; 95% CI, 1.35-2.25). The risk of incident depressive disorder was significantly higher (adjusted HR, 2.54; 95% CI, 1.19-5.45) in patients with TB who received more than 60 defined daily doses (DDDs) of ethambutol, and the effect was dose dependent. CONCLUSIONS: PTB patients had a higher risk of incident depressive disorder, particular in those with an ethambutol dose of more than 60 DDDs. Depressive disorder should be sought in patients following tuberculosis. PMID- 25919844 TI - The use of psychotropic medication in patients with emotionally unstable personality disorder under the care of UK mental health services. AB - BACKGROUND: Guideline recommendations for the pharmacologic treatment of personality disorder lack consensus, particularly for emotionally unstable personality disorder (EUPD), and there is limited information on current prescribing practice in the United Kingdom. OBJECTIVE: To characterize the nature and quality of current prescribing practice for personality disorder across the United Kingdom, as part of a quality improvement program. METHOD: A cross sectional survey of self-selected psychiatric services providing care for adults with personality disorder (ICD-10 criteria) was conducted. Data were collected during May 2012. RESULTS: Of 2,600 patients with a diagnosis of personality disorder, more than two-thirds (68%) had a diagnosis of EUPD. Almost all (92%) patients in the EUPD subgroup were prescribed psychotropic medication, most commonly an antidepressant or antipsychotic, principally for symptoms and behaviors that characterize EUPD, particularly affective dysregulation. Prescribing patterns were similar between those who had a diagnosed comorbid mental illness and those who had EUPD alone, but the latter group was less likely to have had their medication reviewed over the previous year, particularly with respect to tolerability (53% vs 43%). CONCLUSIONS: The use of psychotropic medication in EUPD in the United Kingdom is largely outside the licensed indications. Whether the treatment target is identified as intrinsic symptoms of EUPD or comorbid mental illness may depend on the diagnostic threshold of individual clinicians. Compared with prescribing for EUPD where there is judged to be a comorbid mental illness, the use of off-label medication for EUPD alone is less systematically reviewed and monitored, so opportunities for learning may be lost. Treatment may be continued long term by default. PMID- 25919845 TI - Making evidence-based lifestyle modification programs available in community mental health centers: why so slow? AB - Lifestyle modification programs to promote healthy diet and physical fitness should be an integral component of the treatment provided in community mental health centers. Over 50% of adults with serious mental illness are obese. Persons with schizophrenia consume more calories and saturated fats, on average, than the general population, while fewer than 20% engage in regular physical activity. PMID- 25919846 TI - Why patients with severe personality disorders are overmedicated. AB - Emotionally unstable personality disorder (EUPD), more widely known as borderline personality disorder (BPD), has long been considered a clinical challenge. Patients meeting criteria for these diagnoses are emotionally dysregulated, impulsive, and involved in troubled relationships; in clinical settings, they may threaten suicide or attempt it and are frequently seen in emergency departments. Patients with BPD can be treatment resistant, even when clinically depressed, to both pharmacotherapy and standard types of psychotherapy. PMID- 25919847 TI - Pharmacotherapy for borderline patients: business as usual or by default? AB - In their analysis of a representative sample from the Prescribing Observatory for Mental Health in the UK health services, Paton et al found that 92% of patients with borderline personality disorder (BPD) received prescriptions for psychotropic medications. Although international guidelines recommend pharmacotherapy for comorbid psychiatric disorders whenever necessary, 82% of the UK BPD patients without such comorbid conditions nevertheless received pharmacotherapy "by default," mostly off-label polypharmacy without adequate psychiatric controls for effectiveness and tolerability. Business as usual? Bad care? International practice guidelines for the treatment of BPD all recommend evidence-based psychological treatment whenever possible (especially manualized psychotherapy like dialectical behavior therapy, schema-focused therapy, mentalization-based treatment, transference-focused psychotherapy) as the first choice treatment. PMID- 25919848 TI - Management and effectiveness of psychopharmacology in emotionally unstable and borderline personality disorder. AB - The article by Paton and colleagues on the use of psychotropic medication in patients with emotionally unstable personality disorder (EUPD) in the current issue of JCP is an important article. Making the assumption that EUPD as defined by ICD-10 (F60.3) is reasonably equivalent to borderline personality disorder (BPD) as defined in the United States by DSM, we are provided some insight into how practitioners think about prescribing medications to people with EUPD/BPD. The article not only offers information as to the class of medication these practitioners are using but also provides reasons why, ie, for what clinical signs and symptoms, the medications are being prescribed. PMID- 25919849 TI - Antidepressant augmentation: good news, limitations, and stumbling blocks. AB - Dr Zhou and colleagues have done an excellent job of reviewing and analyzing the world's literature on the efficacy and tolerability of pharmacologic agents used to augment antidepressants in treatment-resistant unipolar major depression. It seems we have some good news, but a lot remains to be accomplished. The good news is that several agents were found to have significant efficacy in terms of response (4 agents) and remission (6 agents) in comparison to placebo. PMID- 25919850 TI - Improving the care of patients who have treatment-resistant depression: the promise of the PCORnet Mood Network. AB - In this issue of JCP, Zhou and colleagues review and integrate placebo-controlled efficacy trials of medications for treatment-resistant depression (TRD) to compare efficacy in a meta-analysis. They conclude that, among 11 augmentation options for TRD, aripiprazole and quetiapine have the most robust evidence for efficacy, with the caveats that these treatments carry substantial risks of adverse events and no long-term data are available. In the absence of direct comparisons, this exercise highlights the formidable challenges that clinicians face when making decisions. PMID- 25919851 TI - What are the comparative benefits and harms of augmentation treatments in major depression? AB - The majority of depressed patients do not experience sufficient response to their initial antidepressant medication. Augmentation strategies, particularly the use of atypical antipsychotics to augment selective serotonin reuptake inhibitors (SSRIs), have proliferated over the last 15 years, and 2 atypical antipsychotics, aripiprazole and quetiapine, have received US Food and Drug Administration approval for adjunctive therapy in treatment-resistant depression. Alternatively, data in treatment-resistant depression exist for most of the atypicals and for other treatments, including lithium, bupropion, methylphenidate, pindolol, and buspirone. PMID- 25919852 TI - Cost of treatment as a placebo effect in psychopharmacology: importance in the context of generic drugs. AB - Nonspecific factors have long been known in both psychotherapy and psychopharmacology. In recent years, 2 studies showed that placebo benefits were lower when the treated subjects were told that the placebo, presented as an active treatment, cost less. One of these studies had assessed motor and other outcomes in Parkinson disease patients; the other had assessed analgesia in paid, healthy volunteers to whom electric shocks were administered. The implication of the finding that lower treatment cost may diminish treatment gains is that patients who receive generic medicines may have lower expectations and may consequently derive less placebo-related benefit. This could be of concern in psychiatric disorders that are characterized by a large placebo response. Although the 2 "placebo cost" studies cannot be easily generalized to clinical and especially psychiatric contexts, clinicans should consider offering reassurance to patients receiving generic drugs that cost, per se, has no bearing on treatment-related benefit. PMID- 25919853 TI - Association of the rs2242446 polymorphism in the norepinephrine transporter gene SLC6A2 and anxious arousal symptoms of posttraumatic stress disorder. PMID- 25919854 TI - On the threshold: older people's concerns about needs after discharge from hospital. AB - Discharge from hospital is often strenuous for older people and requires adjustments from living an independent life to being in need of care and support. This study aims to explore older people's concerns about their needs after discharge. Twenty-seven observations recorded at hospital discharge planning meetings were analysed with content analysis. An overarching theme emerged: being in a life transition, which reflected the older person's vulnerable and ambiguous situation in the discharge process. The theme was developed from three categories: obtaining a secure life situation, need of continuous care and support, and influencing and regaining independence. The findings highlight that older patients want to influence their care after discharge. They strive to regain independence and express their concerns about how to obtain a secure life situation through care organised to fit their individual needs. Knowledge about older people's concerns is important for healthcare providers and social workers involved in planning and individualised care and services. PMID- 25919855 TI - Kinetics and Products of Vinyl + 1,3-Butadiene, a Potential Route to Benzene. AB - The reaction between vinyl radical, C2H3, and 1,3-butadiene, 1,3-C4H6, has long been recognized as a potential route to benzene, particularly in 1,3-butadiene flames, but the lack of reliable rate coefficients has hindered assessments of its true contribution. Using laser flash photolysis and visible laser absorbance (lambda = 423.2 nm), we measured the overall rate coefficient for C2H3 + 1,3 C4H6, k1, at 297 K <= T <= 494 K and 4 <= P <= 100 Torr. k1 was in the high pressure limit in this range and could be fit by the simple Arrhenius expression k1 = (1.1 +/- 0.2) * 10(-12) cm(3) molecule(-1) s(-1) exp(-9.9 +/- 0.6 kJ mol( 1)/RT). Using photoionization time-of-flight mass spectrometry, we also investigated the products formed. At T <= 494 K and P = 25 Torr, we found only C6H9 adduct species, while at 494 K <= T <= 700 K and P = 4 Torr, we observed <=~10% branching to cyclohexadiene in addition to C6H9. Quantum chemistry master equation calculations using the modified strong collision model indicate that n C6H9 is the dominant product at low temperature, consistent with our experimental results, and predict the rate coefficient and branching ratios at higher T where chemically activated channels become important. Predictions of k1 are in close agreement with our experimental results, allowing us to recommend the following modified Arrhenius expression in the high-pressure limit from 300 to 2000 K: k1 = 6.5 * 10(-20) cm(3) molecule(-1) s(-1) T(2.40) exp(-1.76 kJ mol(-1)/RT). PMID- 25919856 TI - The Economic Impact of Helmet Use on Motorcycle Accidents: A Systematic Review and Meta-analysis of the Literature from the Past 20 Years. AB - OBJECTIVE: The incidence and cost of motorcycle accidents are projected to increase. Motorcycle helmets are accepted as an effective strategy for reducing the morbidity and therefore the cost of motorcycle accidents. Despite this, states have continued to repeal helmet laws in the past 20 years. In addition, variations in the methodologies and outcomes of published reports have contributed to uncertainty regarding the health care dollars saved due to motorcycle helmet use. The purpose of this systematic review and meta-analysis is to clarify the economic impact of motorcycle helmet use. METHODS: Our primary source was Medline. Search terms included "motorcycle," "motorbike," "motorcycle helmet," "head protective devices," and "cost and cost analysis." The review only included articles that were primary studies, written in English, evaluations of periods after 1994, and published in a peer-reviewed journal. Two independent authors extracted data using predefined data fields. Meta-analysis was done using the R-metafor package. RESULTS: Twelve papers met the criteria for inclusion. Meta-analysis demonstrated that nonhelmeted patients required $12,239 more in hospital costs per patient. Nonhelmeted patients also required more postdischarge care and were more likely to use publicly funded insurance. Studies also found lower injury severity and better hospital course in the helmeted population. Study limitations included selection bias, unclear statistical assumptions, lack of precision measures, confounding variables, and lack of standardization to a common year. Meta-analysis demonstrated an I2 of 67%, attributing a significant proportion of outcome variation to study differences. CONCLUSIONS: Motorcycle helmet use reduces morbidity and contributes to significant health care cost savings. Continuing antihelmet legislation will impose a substantial economic burden to the health care system, the government, and the public. PMID- 25919857 TI - Letharia vulpina, a vulpinic acid containing lichen, targets cell membrane and cell division processes in methicillin-resistant Staphylococcus aureus. AB - CONTEXT: Antibiotic resistance in humans is a major concern. Drugs that target traditional sites and pathways are becoming obsolete; thus, compounds affecting novel targets are needed. Screening lichen metabolites for antimicrobials has yielded promising antimicrobial compounds, yet their mode of action is poorly understood. Letharia vulpina (L.) Hue (Parmeliaceae) has traditionally been used to poison predators, and treat stomach disorders; more recently L. vulpina extracts have demonstrated promising antimicrobial properties. OBJECTIVE: This study investigates the mode of action of L. vulpina acetone extract against a methicillin-resistant Staphylococcus aureus (MRSA). MATERIAL AND METHODS: We treated MRSA with L. vulpina extracts at 1*, 5*, and 10 * MIC values (MIC = 31.25 ug/ml) for 24 h and optical density (OD660) was measured over time to determine bacteriolytic activity; counted colony forming units (CFUs) to determine time kill dynamics; the propidium iodide (PI) assay and transmission electron microscopy were used to assess membrane-damage potential, and thin-layer chromatography was used to identify secondary compounds. RESULTS: Bacteriolytic assays showed that L. vulpina extracts, containing only vulpinic acid, do not cause cell lysis, even at 10 * MIC values but there was 92% reduction in bacterial CFUs when treated with increased concentrations of lichen extracts over 24 h at 4 h intervals. Our data indicate that the L. vulpina extract compromises membrane integrity of the MRSA isolate and disrupts cell division processes. DISCUSSION AND CONCLUSION: Based on this study, detailed examination of acetone extracts of L. vulpina as well as pure extracts of vulpinic acid as potential antibacterial compounds merit further study. PMID- 25919858 TI - Synthetic Progress toward Azadirachtins. 1. Enantio- and Diastereoselective Synthesis of the Left-Wing Fragment of 11-epi-Azadirachtin I. AB - A highly enantio- and diastereoselective synthesis of the left-wing fragment of 11-epi-azadirachtin I characterized with the pairwise use of palladium- and gold catalyzed cascade reactions is presented. By enlisting a sequence of stereocontrolled transformations, our 21-step route established the stereocenters of the left-wing fragment from one chiral starting material, (-)-carvone, which would significantly facilitate the synthetic studies of the azadirachtin-type limonoids. PMID- 25919859 TI - Activation of PI3Kgamma/Akt pathway mediates bone cancer pain in rats. AB - Bone cancer pain (BCP) is one of the most common and severe complications in patients suffering from primary bone cancer or metastatic bone cancer such as breast, prostate, or lung, which profoundly compromises their quality of life. Emerging lines of evidence indicate that central sensitization is required for the development and maintenance of BCP. However, the underlying mechanisms are largely unknown. In this study, we investigated the role of PI3Kgamma/Akt in the central sensitization in rats with tumor cell implantation in the tibia, a widely used model of BCP. Our results showed that PI3Kgamma and its downstream target pAkt were up-regulated in a time-dependent manner and distributed predominately in the superficial layers of the spinal dorsal horn neurons, astrocytes and a minority of microglia, and were colocalized with non-peptidergic, calcitonin gene related peptide-peptidergic, and A-type neurons in dorsal root ganglion ipsilateral to tumor cell inoculation in rats. Inhibition of spinal PI3Kgamma suppressed BCP-associated behaviors and the up-regulation of pAkt in the spinal cord and dorsal root ganglion. This study suggests that PI3Kgamma/Akt signal pathway mediates BCP in rats. Central sensitization is required for the development and maintenance of bone cancer pain (BCP). In this study, we reported that PI3Kgamma/Akt mediated the function of ephrinBs/EphBs in the central sensitization under BCP condition, and inhibition of spinal PI3Kgamma suppressed BCP-associated behaviors. Our results suggest that inhibition of PI3Kgamma/Akt may be a new target for the treatment of BCP. PMID- 25919861 TI - Rapid diagnosis of tinea incognito using handheld reflectance confocal microscopy: a paradigm shift in dermatology? AB - Dermatophytoses are common skin infections. Traditional diagnostic tests such as skin scrapings for light microscopy examination, fungal cultures and biopsies remain imperfect due to false-negative test results, cost, time required to perform the procedure, time delays in test results and/or a requirement for an invasive procedure. Herein, we present a case of an 80-year-old female whose tinea incognito was non-invasively diagnosed within seconds using handheld reflectance confocal microscopy (RCM). As non-invasive skin imaging continues to improve, we expect light-based office microscopy to be replaced with technologies such as RCM, which has multiple and continually expanding diagnostic applications. PMID- 25919860 TI - Covalent immobilization of pullulanase on alginate and study of its hydrolysis of pullulan. AB - The immobilization of pullulanase from Klebsiella pneumoniae by grafting was investigated. Pullulanase was linked after activation of alginate via a covalent bond between the amine groups of the enzyme and the carboxylic acid groups of alginate. The immobilization yield was 60%. The activity of free pullulanase and immobilized pullulanase was followed by the quantification of reducing ends by colorimetric assay and the determination of the molar masses of the hydrolyzed pullulan by SEC/MALS/DRI. Compared to free pullulanase, the kinetics is largely slowed. The evolution of the weight average molar mass of pullulan leading to high production of shorter oligosaccharides during hydrolysis is not the same as that obtained with free enzyme. Immobilized pullulanase retained 75% and 30% of its initial activity after 24 h and 14 days of incubation at 60 degrees C, respectively while free pullulanase lost its activity after 5 h of hydrolysis at the same temperature. The kinetic parameters of immobilized pullulanase were also investigated by isothermal titration calorimetry (ITC). The affinity of immobilized enzyme to its substrate was reduced compared to the free pullulanase due to steric hindrance and chemical links. PMID- 25919862 TI - Associations between CLCNKA_B tag SNPs with essential hypertension and interactions between genetic and environmental factors in an island population in China. AB - OBJECTIVE: Essential hypertension (EH) is known as the result from the interaction of environmental and genetic factors. We selected tag SNPs of CLCNKA_B genes as gene markers, to elucidate the relationship between CLCNKA_B and EH, and to determine the possible interaction among tag SNPs and dietary factors in island of China. METHODS: A case-control study was conducted in Changshan islands of China, blood samples of 806 participants were genotyped, and the general characteristics and dietary habits of them were collected. Unconditional logistic regression (ULR) was used to assess the effects of CLCNKA_B tag SNPs and dietary factors on EH. Generalized multifactor dimensionality reduction (GMDR) was used to test gene-environment interaction for EH risk. RESULTS: Four SNPs were identified as the tag SNPs of CLCNKA_B. Recessive model for rs5253 and rs2275166 were marginal associated with the decrease risk of EH (OR = 0.36, 95% CI = 0.12-1.07 for rs5253; OR = 0.40, 95% CI = 0.16-1.05 for rs2275166). In GMDR, the five-factor interaction model of rs1010069, salt, marine products, meat and edible oil consumption was the best model, with a maximum CVC of 10/10 and a TBA of 0.638 (p = 0.001). In ULR, compared with subjects carried wild genotypes and null dietary risk factor, those with three or more dietary risk factors and mutation genotypes had 5.90-fold EH risk (95% CI:2.24-15.53). CONCLUSION: Though the single loci of tag SNPs of CLCNKA_B are not enough to significantly increase the EH susceptibility, the combination of CLCNKA tag SNP, salt, marine products, meat and edible oil consumption is associated with elevated risk. PMID- 25919863 TI - Changes in lung volumes and gas trapping in patients with large hiatal hernia. AB - BACKGROUND AND AIMS: Studies assessing hiatal hernia (HH)-related effects on lung volumes derived by body plethysmography are limited. We aimed to evaluate the effect of hernia size on lung volumes (including assessment by body plethysmography) and the relationship to functional capacity, as well as the impact of corrective surgery. METHODS: Seventy-three patients (70 +/- 10 years; 54 female) with large HH [mean +/- standard deviation, intra-thoracic stomach (ITS) (%): 63 +/- 20%; type III in 65/73] had respiratory function data (spirometry, 73/73; body plethysmography, 64/73; diffusing capacity, 71/73) and underwent HH surgery. Respiratory function was analysed in relation to hernia size (groups I, II and III: <=50, 50%-75% and >=75% ITS, respectively) and functional capacity. Post-operative changes were quantified in a subgroup. RESULTS: Total lung capacity (TLC) and vital capacity (VC) correlated inversely with hernia size (TLC: 97 +/- 11%, 96 +/- 13%, 88 +/- 10% predicted in groups I, II and III, respectively, P = 0.01; VC: 110 +/- 17%, 111 +/- 14%, 98 +/- 14% predicted, P = 0.02); however, mean values were normal and only 14% had abnormal lung volumes. Surgery increased TLC (93 +/- 11% vs 97 +/- 10% predicted) and VC (105 +/- 15% vs 116 +/- 18%), and decreased residual volume/total lung capacity (RV/TLC) ratio (39 +/- 7% vs 37 +/- 6%) (P < 0.01 for all). Respiratory changes were modest relative to the marked functional class improvement. Among parameters that improved following HH surgery, decreased TLC and forced expiratory volume in 1 s and increased RV/TLC ratio correlated with poorer functional class pre operatively. CONCLUSIONS: Increasing HH size correlates with reduced TLC and VC. Surgery improves lung volumes and gas trapping; however, the changes are mild and within the normal range. PMID- 25919864 TI - Cyborgs, biotechnologies, and informatics in health care - new paradigms in nursing sciences. AB - Nursing Sciences are at a moment of paradigmatic transition. The aim of this paper is to reflect on the new epistemological paradigms of nursing science from a critical approach. In this paper, we identified and analysed some new research lines and trends which anticipate the reorganization of nursing sciences and the paradigms emerging from nursing care: biotechnology-centred knowledge; the interface between nursing knowledge and new information technologies; body care centred knowledge; the human body as a cyborg body; and the rediscovery of an aesthetic knowledge in nursing care. PMID- 25919865 TI - Zn(2+)-Triggered Drug Release from Biocompatible Zirconium MOFs Equipped with Supramolecular Gates. AB - A new theranostic nanoplatform, comprising of monodisperse zirconium metal organic frameworks (MOFs) as drug carriers and carboxylatopillar[5]arene-based supramolecular switches as gating entities, is constructed, and controlled drug release triggered by bio-friendly Zn(2+) ions (abundant in synaptic vesicles) and auxiliary thermal stimulus is realized. This on-command drug delivery system exhibits large pore sizes for drug encapsulation, excellent biodegradability and biocompatibility, extremely low cytotoxicity and premature drug release, and superior dual-stimuli responsiveness, opening a new avenue in targeted drug delivery and controlled release of therapeutic agents, especially in the treatment of central nervous system diseases. PMID- 25919867 TI - [Kolb's learning styles in medical students]. AB - The objective of this work was to study the relationship of Kolb's learning styles in academic success or failure in medical students. A prospective cohort study in 116 medical students of a private Argentine university was performed between March 2005 and March 2011. The follow-up included two cut-offs; during 2005-2006 the students' learning styles were determined and five years later, when individuals had to end their career, they were grouped into graduated, delayed or dropped status. At the end of the period, 50% of the students ended successfully, 24.1% abandoned and 25.9% was delayed. Learning styles were assimilator in 60.3% of cases, divergent in 14.7%, accommodator in 6.9%, convergent in 6.0% and undefined in 12.1%. In conclusion, the follow-up during the career demonstrated that convergent or undefined styles had a tendency to abandon the career, while delayed students had a more theoretical and reflexive style than successful individuals. The results observed in convergent students differed from other reports. This difference would be explained by a particular characteristic of the sample or by the teaching and evaluation profile of the university. PMID- 25919868 TI - [Molecular bases of alpha-thalassemia in Argentina]. AB - The alpha-thalassemia is one of the most common hereditary disorders worldwide. Currently, molecular diagnostics is the only available tool to achieve an accurate diagnosis. The purpose of this study was to characterize the molecular bases of these syndromes in our environment and to establish genotype-phenotype associations. Through a combination of different molecular techniques and fluorescent in situ hybridization (FISH),we were able to find alpha-thalassemic mutations in 145 of the 184 patients (78.8%) studied with hematological parameters compatible with alpha-thalassemia. Deletions of the alpha-globin genes resulted the major molecular cause of the disease, and the most frequent mutation was -alpha(3.7), found in homozygous and heterozygous genotypes. In patients with alpha degrees phenotypes, other prevalent mutations were( _MED) and (_CAL/CAMP). The description of a sub-telomeric deletion in a patient with alpha-thalassemia and mental retardation was also achieved. beta-thalassemic mutations in heterozygous state were found in 7.6% of the patients, who presented alpha thalassemic clinical features (microcytosis and Hb A2levels below 3.5%). Hematologic profiles for the alpha+ and alpha degrees genotypes were established for adult and pediatric patients. Hopefully, this work will provide guidelines for the detection of possible alpha-thalassemic carriers. It also highlights the collaborative work of hematologists, the biochemical and molecular biology laboratory and genetists, in order to provide appropriate genetic counseling. PMID- 25919866 TI - Association between Plasma 25-Hydroxyvitamin D, Ancestry and Aggressive Prostate Cancer among African Americans and European Americans in PCaP. AB - BACKGROUND: African Americans (AAs) have lower circulating 25-hydroxyvitamin D3 [25(OH)D3] concentrations and higher prostate cancer (CaP) aggressiveness than other racial/ethnic groups. The purpose of the current study was to examine the relationship between plasma 25(OH)D3, African ancestry and CaP aggressiveness among AAs and European Americans (EAs). METHODS: Plasma 25(OH)D3 was measured using LC-MS/MS (Liquid Chromatography Tandem Mass Spectrometry) in 537 AA and 663 EA newly-diagnosed CaP patients from the North Carolina-Louisiana Prostate Cancer Project (PCaP) classified as having either 'high' or 'low' aggressive disease based on clinical stage, Gleason grade and prostate specific antigen at diagnosis. Mean plasma 25(OH)D3 concentrations were compared by proportion of African ancestry. Logistic regression was used to calculate multivariable adjusted odds ratios (OR) and 95% confidence intervals (95%CI) for high aggressive CaP by tertile of plasma 25(OH)D3. RESULTS: AAs with highest percent African ancestry (>95%) had the lowest mean plasma 25(OH)D3 concentrations. Overall, plasma 25(OH)D3 was associated positively with aggressiveness among AA men, an association that was modified by calcium intake (ORT 3vs.T1: 2.23, 95%CI: 1.26-3.95 among men with low calcium intake, and ORT 3vs.T1: 0.19, 95%CI: 0.05 0.70 among men with high calcium intake). Among EAs, the point estimates of the ORs were <1.0 for the upper tertiles with CIs that included the null. CONCLUSIONS: Among AAs, plasma 25(OH)D3 was associated positively with CaP aggressiveness among men with low calcium intake and inversely among men with high calcium intake. The clinical significance of circulating concentrations of 25(OH)D3 and interactions with calcium intake in the AA population warrants further study. PMID- 25919869 TI - [Osteosarcoma lung metastases. Survival after chemotherapy and surgery]. AB - Five years overall survival in osteosarcoma patients is around 70%, although in patients with metastatic disease it is only 10-30%. The objective of this study was to analyze overall survival and prognostic factors in a group of patients with metastatic osteosarcoma treated with surgical removal of the lung metastases. A retrospective review from our oncology data base revealed 38 patients treated between 1992 and 2006. The mean age at diagnosis was 18 +/- 9.4 years (3-45) and mean follow-up was 57 +/- 53.8 months (12-231). All patients were treated with chemotherapy and oncologic resection of the primary tumor and surgical removal of the lung metastases. We analyzed overall survival and prognostic factors: age, gender, site, time of metastasis, local recurrences, number of lung metastasis and chemotherapy response (necrosis). Overall survival of the entire series was 29% at 5 years (CI 95%: 14.5-43.5) and 26% at 10 years (CI 95%: 12-40). Significant difference in 5 year overall survival was found between good and bad responders to chemotherapy, 53% (IC 95%: 28-78) vs. 8% (IC 95%: 0-20) (p = 0.0008). No statistically significant relationship between other prognostic factors analyzed was observed. Five and ten years overall survival rates in osteosarcoma patients with lung metastasis treated with chemotherapy and surgically resection is poor. Patients with good response to chemotherapy have better prognosis. PMID- 25919870 TI - [Neurofibromatosis type 1. Splicing mutation detected by MLPA and DNA sequencing in Argentina]. AB - Neurofibromatosis type 1 (NF1) is a dominant autosomic genetic disorder, with a birth incidence of 1 in 2500-3000. Diagnosis is difficult because of the size of gene NF1 that has few hot-spots sites, the absence of a clear genotype-phenotype relation, and a heterogeneous clinical manifestation. A NF1 suspected case from Jujuy province was analyzed by multiplex ligation-dependent probe amplification (MLPA). Mestizo female teenage (Amerindian/European), with a maxilar osteoma, lumbar lordosis, cutaneous neurofibromas and cafe au lait spots. MLPA detected an alteration in exon 13 of the NF1 gene. By sequencing of exon 13, a missense mutation (NM_000267.3:c.1466A>G) was found which introduces an aberrant splicing site and is registered as pathogenic in the clinical variants database of NCBI. As far as we are aware, this is the first report of a NF1 mutation in mestizo population of Northwest Argentina. 1466A>G has been described before in patients of European origin, suggesting that the affected site could be a hot-spot site of the gene. For countries as Argentina, with limited availability of molecular diagnostic methods, we propose a diagnosis algorithm by starting the mutational analysis of NF1 with MLPA. This methodology is relatively simple and of low cost, avoiding to send samples abroad for genetic analyses. PMID- 25919871 TI - [Hughes-Stovin Syndrome, a case report]. AB - The Hughes-Stovin syndrome is a rare entity characterized by deep vein thrombosis and pulmonary artery aneurysms of unknown etiology and pathogenesis. Some authors considered a variant of Behcet's disease. Its natural course is usually fatal. The symptoms are cough, dyspnea, hemoptysis, chest pain and fever. The treatment goes from steroids and cytotoxic agents to surgery. We present the case of a 41 year old man who shows dyspnea, hemoptysis, and chest pain leading to the diagnosis of deep venous thrombosis of the right leg, lung thromboembolism and pulmonary artery aneurysms. He was treated with high-dose corticosteroids and 6 cyclophosphamide pulses of 1 gram each per 6 months with complete regression of aneurysms and symptomatology. PMID- 25919872 TI - [Letter of Einstein to Marie Curie in 1911, and apocryphal letter to Bernardo Houssay in 1947]. PMID- 25919873 TI - [Tumoral form of neurocysticercosis]. PMID- 25919874 TI - [Mario Bunge's memories and his philosophy of science]. PMID- 25919875 TI - [Brain positioning system]. PMID- 25919876 TI - [New paradigms in universitary education. David Kolb's learning styles]. PMID- 25919877 TI - [Residence in clinical research]. PMID- 25919878 TI - [Severe community-acquired pneumonia and ventilator associated pneumonia (VAP) in a patient with behavioral disinhibition]. PMID- 25919879 TI - [Tenosynovitis and Chikungunya virus]. PMID- 25919880 TI - [Tenosynovitis associated to Chikungunya virus (CHKV) infection: a response]. PMID- 25919881 TI - [Miltefosine or meglumine antimoniate in leishmaniasis]. PMID- 25919882 TI - [More about miltefosine in the treatment of mucosal leishmaniasis]. PMID- 25919883 TI - [Less cold ischemia time in renal transplantation. Proposal for a priority]. PMID- 25919884 TI - Correction: Esophageal Adenocarcinoma and Its Rare Association with Barrett's Esophagus in Henan, China. PMID- 25919885 TI - Histone deacetylase inhibitors induce autophagy through FOXO1-dependent pathways. AB - Autophagy is a catabolic process in response to starvation or other stress conditions to sustain cellular homeostasis. At present, histone deacetylase inhibitors (HDACIs) are known to induce autophagy in cells through inhibition of mechanistic target of rapamycin (MTOR) pathway. FOXO1, an important transcription factor regulated by AKT, is also known to play a role in autophagy induction. At present, the role of FOXO1 in the HDACIs-induced autophagy has not been reported. In this study, we first observed that HDACIs increased the expression of FOXO1 at the mRNA and protein level. Second, we found that FOXO1 transcriptional activity was enhanced by HDACIs, as evidenced by increased FOXO1 nuclear accumulation and transcriptional activity. Third, suppression of FOXO1 function by siRNA knockdown or by a chemical inhibitor markedly blocked HDACIs-induced autophagy. Moreover, we found that FOXO1-mediated autophagy is achieved via its transcriptional activation, leading to a dual effect on autophagy induction: (i) enhanced expression of autophagy-related (ATG) genes, and (ii) suppression of MTOR via transcription of the SESN3 (sestrin 3) gene. Finally, we found that inhibition of autophagy markedly enhanced HDACIs-mediated cell death, indicating that autophagy serves as an important cell survival mechanism. Taken together, our studies reveal a novel function of FOXO1 in HDACIs-mediated autophagy in human cancer cells and thus support the development of a novel therapeutic strategy by combining HDACIs and autophagy inhibitors in cancer therapy. PMID- 25919887 TI - Diffusion tensor imaging abnormalities in photosensitive juvenile myoclonic epilepsy. AB - BACKGROUND AND PURPOSE: Multiple structural white matter abnormalities have been described in patients with juvenile myoclonic epilepsy (JME). In the present study, the question of whether microstructural variations exist between the two subgroups of JME, with and without photoparoxysmal responses (PPR positive and negative), was addressed using diffusion tensor imaging. METHODS: A selection of 18 patients (eight PPR positive) from a tertiary epilepsy center diagnosed with JME and 27 healthy controls was studied. The following regions of interest were investigated: the ascending reticular activating system, lateral geniculate nucleus, genu of the internal capsule, ventromedial thalamus and inferior cerebellar peduncle. RESULTS: Widespread white matter microstructural abnormalities in JME and in particular in PPR positive cases were identified. PPR positive patients demonstrated increased fractional anisotropy in the ascending reticular activating system and ventromedial thalamus compared to PPR negative patients and healthy controls. Reduced fractional anisotropy of the lateral geniculate nucleus was observed in the entire JME group compared to healthy controls. CONCLUSIONS: Several microstructural variations between PPR positive and negative JME patients have been identified. Our findings highlight the pivotal role of the thalamus in the pathophysiology of primary generalized seizures and suggest that thalamo-premotor connections are both an essential part of epileptic networks and important in the pathogenesis of photosensitivity. PMID- 25919886 TI - Test and Evaluation of ff99IDPs Force Field for Intrinsically Disordered Proteins. AB - Over 40% of eukaryotic proteomic sequences have been predicted to be intrinsically disordered proteins (IDPs) or intrinsically disordered regions (IDRs) and confirmed to be associated with many diseases. However, widely used force fields cannot well reproduce the conformers of IDPs. Previously the ff99IDPs force field was released to simulate IDPs with CMAP energy corrections for the eight disorder-promoting residues. In order to further confirm the performance of ff99IDPs, three representative IDP systems (arginine-rich HIV-1 Rev, aspartic proteinase inhibitor IA3, and alpha-synuclein) were used to test and evaluate the simulation results. The results show that for free disordered proteins, the chemical shifts from the ff99IDPs simulations are in quantitative agreement with those from reported NMR measurements and better than those from ff99SBildn. Thus, ff99IDPs can sample more clusters of disordered conformers than ff99SBildn. For structural proteins, both ff99IDPs and ff99SBildn can well reproduce the conformations. In general, ff99IDPs can successfully be used to simulate the conformations of IDPs and IDRs in both bound and free states. However, relative errors could still be found at the boundaries of ordered residues scattered in long disorder-promoting sequences. Therefore, polarizable force fields might be one of the possible ways to further improve the performance on IDPs. PMID- 25919888 TI - Time-course mass spectrometry imaging for depicting drug incorporation into hair. AB - In order to investigate the incorporation of drugs into hair, matrix-assisted laser desorption/ionization-time-of-flight tandem mass spectrometry (MS/MS) imaging was performed on the longitudinal sections of single scalp hair shafts sampled from volunteers after a single oral administration of methoxyphenamine (MOP), a noncontrolled analogue of methamphetamine. Hair specimens were collected by plucking out with the roots intact, and these specimens were prepped by an optimized procedure based on freeze-sectioning to detect the drug inside the hair shaft and hair root. Time-course changes in the imaging results, with confirmatory quantitative liquid chromatography-tandem mass spectrometry (LC MS/MS) analysis for each 1-mm segment of single hair strands, revealed a substantial concentration of the drug first onto the hair bulbs after ingestion, while only a small portion appeared to be incorporated into the hair matrix, forming a 2-3 mm distinctive drug band with tailing. Comparable amount of the drug also appeared to be incorporated into the keratinized hair shaft in the upper dermis zone, forming another distinct drug band of about 2 mm, which both moved toward the distal side, following the strand's growth rate. These findings provide forensically crucial information: there are two major drug incorporation sites, at least for MOP, which cause overlap of the recordings and deteriorates its chronological resolution down to about 11 days or perhaps longer. PMID- 25919889 TI - Clar as Mud? Origins of the head mirror: A historical note. AB - In Europe, the name "Clar" immediately evokes to any otorhinolaryngologist the classic head mirror that remains a symbol of our profession. Yet, the origin of Clar has never been investigated. In this clinical and historical review, based on an Internet and PubMed database search together with perusal of Fischer's Biographical Lexikon, the authors seek to elucidate this medical enigma. The data presented suggest that Clar was not a physician but rather a term picked by the company that designed the mirror by the end of the 19th century to underscore the bright and sharp view provided by this then innovative medical device. (c) 2015 Wiley Periodicals, Inc. Head Neck 38: 930-932, 2016. PMID- 25919890 TI - Undifferentiated Neuroblastoma Cells Are More Sensitive to Photogenerated Oxidative Stress Than Differentiated Cells. AB - Neuroblastoma is one of the most aggressive cancers and has a complex form of differentiation. We hypothesized that advanced cellular differentiation may alter the susceptibility of neuroblastoma to photodynamic treatment (PDT) and confer selective survival advantage. We demonstrated that hematoporphyrin uptake by undifferentiated SH-SY5Y cells was lower than that of differentiated counterparts, yet the former were more susceptible to PDT-induced oxidative stress killing. Photogenerated reactive oxygen species (ROS) in undifferentiated cells efficiently stimulated cell cycle arrest at G2/M phase, mitochondrial apoptotic pathway activation, the sustained phosphorylation of Akt/GSK-3beta and ERK. Differentiated cells with more resistance to PDT exhibited a ROS-independent and a prolonged activation of ERK. Both SH-SY5Y cells exposed to PDT exhibited ROS-independent p38 and JNK activation. These results may have important implications for neuroblastoma patients undergoing photodynamic therapy. PMID- 25919891 TI - Structural and functional changes in HDL with low grade and chronic inflammation. AB - OBJECTIVE: HDL functionality has been shown to be impaired in inflammatory conditions, including coronary artery disease. The present study aims to determine the impact of low grade and acute inflammation on HDL function and structure. APPROACH AND RESULTS: i) The endothelial protective effects of HDL were compared between 26 periodontal patients and 26 age and sex matched controls by measuring paraoxonase activity in serum and nitric oxide bioavailability and superoxide production in endothelial cells. Paraoxonase activity and nitric oxide bioavailability were reduced, while superoxide production was increased (p<0.01) in periodontal patients compared to controls. ii) HDL function, including cholesterol efflux and vascular cell adhesion molecule-1 expression, was subsequently measured in the periodontal patients following an inflammatory stimulus. There was an acute deterioration in HDL's endothelial protective function, without change in cholesterol efflux, after 24h (p<0.01 for all). These functional changes tracked increases of inflammatory markers and altered HDL composition. Finally, HDL function returned to baseline levels after resolution of inflammation. CONCLUSION: This study demonstrates that even minor alterations in systemic inflammation can impair the endothelial protective effects of HDL. These functional changes were independent of cholesterol efflux and were associated with remodeling of the HDL proteome. All measures of HDL's endothelial protective functions recovered with resolution of inflammation. These findings suggest that HDL dysfunction may represent a novel mechanism linking inflammation with progression of atheroma. PMID- 25919892 TI - Right-sided hepatic hernia of normal left lobe resembling cardiac tumor. AB - A 3-year-old boy was referred for cardiac tumor diagnosed on transthoracic echocardiography (TTE) at another hospital. The tumor appeared to be in the right atrium and obstructed inferior vena cava flow. TTE, enhanced computed tomography (CT) and angiography were done to confirm diagnosis. Subsequently, cardiac tumor was ruled out and he was diagnosed with a very rare condition of hepatic hernia containing a normal left lobe. When cardiac tumor is suspected in the right atrium on the basis of TTE, enhanced CT or magnetic resonance imaging should be done for definitive diagnosis. PMID- 25919893 TI - Pressure vs controlled mode in laparoscopy cholecystectomy? Still more questions that answers. PMID- 25919895 TI - Investigating the Geochemical Model for Molybdenum Mineralization in the JEB Tailings Management Facility at McClean Lake, Saskatchewan: An X-ray Absorption Spectroscopy Study. AB - The geochemical model for Mo mineralization in the JEB Tailings Management Facility (JEB TMF), operated by AREVA Resources Canada at McClean Lake, Saskatchewan, was investigated using X-ray Absorption Near-Edge Spectroscopy (XANES), an elemental-specific technique that is sensitive to low elemental concentrations. Twenty five samples collected during the 2013 sampling campaign from various locations and depths in the TMF were analyzed by XANES. Mo K-edge XANES analysis indicated that the tailings consisted primarily of Mo(6+) species: powellite (CaMoO4), ferrimolybdite (Fe2(MoO4)3.8H2O), and molybdate adsorbed on ferrihydrite (Fe(OH)3 - MoO4). A minor concentration of a Mo(4+) species in the form of molybdenite (MoS2) was also present. Changes in the Mo mineralization over time were inferred by comparing the relative amounts of the Mo species in the tailings to the independently measured aqueous Mo pore water concentration. It was found that ferrimolybdite and molybdate adsorbed on ferrihydrite initially dissolves in the TMF and precipitates as powellite. PMID- 25919894 TI - Defining the Interaction of Human Soluble Lectin ZG16p and Mycobacterial Phosphatidylinositol Mannosides. AB - ZG16p is a soluble mammalian lectin that interacts with mannose and heparan sulfate. Here we describe detailed analysis of the interaction of human ZG16p with mycobacterial phosphatidylinositol mannosides (PIMs) by glycan microarray and NMR. Pathogen-related glycan microarray analysis identified phosphatidylinositol mono- and di-mannosides (PIM1 and PIM2) as novel ligand candidates of ZG16p. Saturation transfer difference (STD) NMR and transferred NOE experiments with chemically synthesized PIM glycans indicate that PIMs preferentially interact with ZG16p by using the mannose residues. The binding site of PIM was identified by chemical-shift perturbation experiments with uniformly (15)N-labeled ZG16p. NMR results with docking simulations suggest a binding mode of ZG16p and PIM glycan; this will help to elucidate the physiological role of ZG16p. PMID- 25919896 TI - Genetic Diversity and Drug Resistance Among Antiretroviral Treatment-Failed Individuals from 2010 to 2012 in Honghe, China. AB - The most common antiretroviral treatment (ART) received by individuals infected with HIV-1 in China is the combination therapy, comprised of nucleoside reverse transcriptase inhibitors (NRTIs) and nonnucleoside reverse transcriptase inhibitors (NNRTIs). To assess the prevalence of HIV-1 drug resistance and subtypes in Honghe of Yunnan, China, patient plasmas from ART-failed individuals were collected from January 2010 to December 2012. Genotyping was conducted using an in-house assay on patient plasmas. A total of 254 pol sequences were obtained. The prevalence of drug resistance was 47.2% in ART-failed individuals. Of these drug-resistant individuals, 51.7% harbored HIV strains dually resistant to NRTIs and NNRTIs or protease inhibitors (PIs) (34.2% for NNRTIs and 14.2% for NRTIs). Mutations such as M184V, A62V, T69Ins, K103N, Y181C, and G190A were common among the ART-failed individuals. The frequencies of M184V, A62V, and K103N were 20.5%, 11.0%, and 23.6%, respectively. The most common subtypes in Honghe were CRF08_BC (68.50%) and CRF07_BC (12.20%). The subtypes were almost consistent in different time points for one individual. When receiving ART for 6-12 months, the frequency of HIV-1 drug-resistant variants ranked first. This study shows that the high prevalence of HIV drug resistance observed among the ART-failed individuals should be of increasing concern (monitoring of resistance mutations) in ART regions and facilitate developing novel strategies for prevention and control of HIV infection in China. PMID- 25919897 TI - Six degrees of nursing science: message from the president. PMID- 25919898 TI - N-acetyl-L-histidine, a Prominent Biomolecule in Brain and Eye of Poikilothermic Vertebrates. AB - N-acetyl-L-histidine (NAH) is a prominent biomolecule in brain, retina and lens of poikilothermic vertebrates. In fish lens, NAH exhibits an unusual compartmentalized metabolism. It is synthesized from L-histidine (His) and acetyl Co-enzyme A. However, NAH cannot be catabolized by lens cells. For its hydrolysis, NAH is exported to ocular fluid where a specific acylase cleaves His which is then actively taken up by lens and re-synthesized into NAH. This energy dependent cycling suggested a pump mechanism operating at the lens/ocular fluid interface. Additional studies led to the hypothesis that NAH functioned as a molecular water pump (MWP) to maintain a highly dehydrated lens and avoid cataract formation. In this process, each NAH molecule released to ocular fluid down its gradient carries with it 33 molecules of bound water, effectively transporting the water against a water gradient. In ocular fluid the bound water is released for removal from the eye by the action of NAH acylase. In this paper, we demonstrate for the first time the identification of NAH in fish brain using proton magnetic resonance spectroscopy (MRS) and describe recent evidence supporting the NAH MWP hypothesis. Using MRS, we also document a phylogenetic transition in brain metabolism between poikilothermic and homeothermic vertebrates. PMID- 25919899 TI - Phenotypic changes contributing to Enterobacter gergoviae biocide resistance. AB - Enterobacter gergoviae is a recurrent contaminant of cosmetic and hygiene products. To understand how this bacterium adapts to biocides, we studied Ent. gergoviae CIP 76.01 and its triclosan and Methylisothiazolinone chloromethylisothiazolinone (MIT-CMIT) tolerant isogenic mutants. They were compared with others also isolated from contaminated cosmetics. Phenotypic differences were noted and these included changes in the bacterial envelope and flagella along with differences in motility, and biofilm growth rates. Triclosan and MIT-CMIT derivatives expressed flagella and other MIT-CMIT derivatives exhibited some external appendages. Those bacteria expressing a high-level minimal inhibitory concentration to MIT-CMIT, expressed a strong biofilm formation. No differential phenotypes were noted for carbon source utilisation. Enterobacter gergoviae demonstrated a diverse response to both of these preservatives contained in cosmetic preparations, depending on their concentrations. Interestingly, this adaptive response is associated with modifications of filament structure-related proteins contributing to increase the organism motility and the production of biofilm. SIGNIFICANCE AND IMPACT OF THE STUDY: Recurrent contaminations of cosmetics products by Ent. gergoviae, needed a better understanding concerning the bacterial adaptation to preservative agents, with particular concern to triclosan and MIT-CMIT. We demonstrated that bacteria response is associated to various mechanisms represented by expression of external appendages (pili or fimbriae) that control cell motility and biofilm formation and evolving as the concentration of biocides adaptation increased. Such mechanisms which are not chemical specific can also promote a cross resistance to other biocidal agents. The characterization of Ent. gergoviae adaptability to biocides allows industry to adjust the ranges of concentrations and composition of preservatives in formula. PMID- 25919900 TI - No evidence for predictors of response to atomoxetine treatment of attention deficit/hyperactivity disorder symptoms in children and adolescents with autism spectrum disorder. PMID- 25919901 TI - Air-assisted implantation of anterior chamber intraocular lens. AB - PURPOSE: We describe a technique of air-assisted anterior chamber intraocular lens (ACIOL) implantation. METHODS: Lens aspiration and ACIOL implantation was performed in patients with progressive subluxation of lenses associated with systemic disorders. RESULTS: Surgery was performed in nine eyes of six patients. No intraoperative adverse events were noted. There was air leak from the main port in three patients while inserting the intraocular lens; however the ACIOL was successfully implanted after re-injecting air from the side port. The mean best-corrected visual acuity improved from 0.67 to 0.25 log of minimal angle of resolution at 6-month follow-up. Mean intraocular pressure preoperatively was 14.54+1.38 mm Hg and 15.16+1.15 mm Hg at 6-month follow-up. Mean corneal endothelial count was 3,151+240.49 cells per square millimeter in the preoperative period and 2,947+194.9 cells per square millimeter at 6-month follow up. CONCLUSIONS: Air-assisted ACIOL implantation seems to be a safe and effective technique for implantation of ACIOL in cases with progressive lens subluxation. PMID- 25919902 TI - Morphological changes and clinical impact of unstable plaques within untreated segments of acute myocardial infarction patients during a 3-year follow-up: an analysis from the HORIZONS-AMI trial. AB - OBJECTIVES: Plaque ruptures and attenuated plaques are considered to be unstable and have been identified in both culprit and nonculprit lesions of patients with ST-segment elevation myocardial infarction (STEMI). However, there are limited data available on the natural evolution of these plaques and their long-term clinical outcome. We investigated the natural evolution and long-term impact of plaque ruptures and attenuated plaques in untreated segments of infarct-related arteries in patients with STEMI. METHODS: In the Harmonizing Outcomes with Revascularization and Stents in Acute Myocardial Infarction trial, 389 patients with 429 lesions underwent intravascular ultrasound (IVUS) at baseline. Follow-up IVUS at 13 months was conducted in 245 patients. Three-year follow-up data were available for all patients. RESULTS: Segments not treated between baseline and follow-up were compared. Baseline IVUS identified 29 plaque ruptures in 27 patients (7%). Of 11 plaque ruptures with follow-up IVUS, four healed and seven persisted. Conversely, through follow-up IVUS, nine new plaque ruptures in nine patients (4%) were identified. Attenuated plaques were identified in 31 of 38 plaque ruptures (81.5%), of which 24 were in the same circumferential segment as the ruptured cavity and seven were within 5 mm proximal or distal to the plaque rupture. Morphologic changes during follow-up, including new plaque ruptures and changes in the attenuated plaque frequency and distribution, were not accompanied by either serious lumen compromise or clinical events. CONCLUSION: Serial IVUS analysis demonstrated that the morphology of unstable plaques within untreated segments in STEMI patients treated with optimal systemic therapies markedly changed during the 13-month follow-up period, without lumen compromise or clinical events at the 3-year follow-up. PMID- 25919903 TI - The neutrophil-to-lymphocyte ratio is associated with bare-metal stent restenosis in STEMI patients treated with primary PCI. AB - BACKGROUND: The clinical importance of complete blood count (CBC) parameters such as the neutrophil-to-lymphocyte ratio (NLR) has been shown in cardiovascular diseases. Stent restenosis (SR) is a major adverse event after stent implantation. In this study, we aimed to investigate the correlation of CBC parameters with SR rates after primary percutaneous coronary intervention (PCI). METHODS: Patients who had undergone primary PCI for ST-segment elevation myocardial infarction (STEMI) and control angiography during follow-up were retrospectively recruited. Patients were categorized according to admission NLR tertiles, and clinical, hematological, and angiographic data were compared. RESULTS: A total of 404 patients (207 patients with SR and 197 patients without SR) were included in the study. Patients were categorized into three groups according to the tertiles of admission NLRs; the NLR was less than 3.38 in tertile 1 (n=134), between 3.38 and 6.26 in tertile 2 (n=135), and greater than 6.26 in tertile 3 (n=135). During a follow-up period of a median of 14 months (minimum 6 months, maximum 60 months) SR developed in 80 patients of tertile 3 (59%), 74 patients of tertile 2 (55%), and 53 patients of tertile 1 (40%), which were significantly different (P=0.01). According to multivariate Cox regression analysis, male sex, stent length (odds ratio 1.04, 95% confidence interval 1.01 1.06, P=0.01), admission NLRs (odds ratio 1.13, 95% confidence interval 1.08 1.19, P=0.01), and white blood cell and neutrophil counts remained the independent predictors of SR in the study population. Other CBC parameters and admission C-reactive protein, creatinine, and fasting glucose levels were not independently correlated with SR. On receiver operating curve analysis, admission NLRs higher than 3.84 were found to predict SR with a sensitivity of 73.4% and a specificity of 50.8% (area under the curve 0.604, P=0.01). CONCLUSION: High NLR levels, white blood cell counts, and neutrophil counts at admission are independently correlated with SR after primary PCI. PMID- 25919904 TI - Bioresorbable vascular scaffold for ST elevation myocardial infarction: optical coherence tomography observations at the 2-year follow-up. PMID- 25919906 TI - Applying ecological models to communities of genetic elements: the case of neutral theory. AB - A promising recent development in molecular biology involves viewing the genome as a mini-ecosystem, where genetic elements are compared to organisms and the surrounding cellular and genomic structures are regarded as the local environment. Here, we critically evaluate the prospects of ecological neutral theory (ENT), a popular model in ecology, as it applies at the genomic level. This assessment requires an overview of the controversy surrounding neutral models in community ecology. In particular, we discuss the limitations of using ENT both as an explanation of community dynamics and as a null hypothesis. We then analyse a case study in which ENT has been applied to genomic data. Our central finding is that genetic elements do not conform to the requirements of ENT once its assumptions and limitations are made explicit. We further compare this genome-level application of ENT to two other, more familiar approaches in genomics that rely on neutral mechanisms: Kimura's molecular neutral theory and Lynch's mutational-hazard model. Interestingly, this comparison reveals that there are two distinct concepts of neutrality associated with these models, which we dub 'fitness neutrality' and 'competitive neutrality'. This distinction helps to clarify the various roles for neutral models in genomics, for example in explaining the evolution of genome size. PMID- 25919907 TI - Toxic and essential metals determination in commercial seafood: Paracentrotus lividus by ICP-MS. AB - Toxic and essential metals content was determined by inductively coupled plasma mass spectrometry in commercial sea urchins samples from the Mediterranean Sea and Pacific Ocean. Results show that Chilean samples have the highest values of Cd, As, Ni, Cr and V; Spanish samples have the maximum Hg content while Sicilian samples have the lowest content of toxic metals. The toxic metal traces were compared with the limits of European Community (EC) No. 1881/2006 for bivalve molluscs. All samples exceed Pb and Cd limit levels; regarding Hg levels, only Sicilian and Sardinian samples have Hg content below the EC limits. The dietary intake of toxic and essential elements was evaluated for an adult. Furthermore, our study highlights a correlation between the toxic elements content and the marine environmental conditions of the places of origin even though only the generic FAO fishing area is specified. PMID- 25919905 TI - Development and Characterization of Acellular Extracellular Matrix Scaffolds from Porcine Menisci for Use in Cartilage Tissue Engineering. AB - Given the growing number of arthritis patients and the limitations of current treatments, there is great urgency to explore cartilage substitutes by tissue engineering. In this study, we developed a novel decellularization method for menisci to prepare acellular extracellular matrix (ECM) scaffolds with minimal adverse effects on the ECM. Among all the acid treatments, formic acid treatment removed most of the cellular contents and preserved the highest ECM contents in the decellularized porcine menisci. Compared with fresh porcine menisci, the content of DNA decreased to 4.10%+/-0.03%, and there was no significant damage to glycosaminoglycan (GAG) or collagen. Histological staining also confirmed the presence of ECM and the absence of cellularity. In addition, a highly hydrophilic scaffold with three-dimensional interconnected porous structure was fabricated from decellularized menisci tissue. Human chondrocytes showed enhanced cell proliferation and synthesis of chondrocyte ECM including type II collagen and GAG when cultured in this acellular scaffold. Moreover, the scaffold effectively supported chondrogenesis of human bone marrow-derived mesenchymal stem cells. Finally, in vivo implantation was conducted in rats to assess the biocompatibility of the scaffolds. No significant inflammatory response was observed. The acellular ECM scaffold provided a native environment for cells with diverse physiological functions to promote cell proliferation and new tissue formation. This study reported a novel way to prepare decellularized meniscus tissue and demonstrated the potential as scaffolds to support cartilage repair. PMID- 25919908 TI - The sociocultural aspects, professional characteristics, and motivational factors of the first fellows of the European committee of sexual medicine. AB - INTRODUCTION: After a century of development in the field of sexology and decades of attempts to establish the field of sexual medicine, the first examination that led to the qualification as Fellows of the European Committee of Sexual Medicine (FECSM) was held in December 2012. AIM: This study aims to describe the first European specialists in sexual medicine, their clinical practice, motivation, and professional self-identification. METHODS: A web-based survey of the first FECSM on demographic data, data on the practices of their work (gender of clients, setting, and time frame), and reasons for entering the sexual medicine (five point Likert rating of motives and open question on other reasons) was conducted. MAIN OUTCOME MEASURE: Gender, religion, specialty, region, and their association with professional practices of the first FECSM. RESULTS: The first FECSM have a wide range of experience in the field of sexual medicine (0-30 years) and were mainly men (79%) and urologists (56%). Only 15.5% had other qualifications related to sexual medicine and 60% self-identified as sexual medicine specialists. Only a small proportion of the professional time was dedicated to the practice of sexual medicine. The primary speciality influenced the gender of their patients seen, setting of work (couple vs. individuals), and time spent with patients. Only a minority managed sexual problems in women; hypoactive sexual desire is treated by 41% of FECSM and dyspareunia by 17%. The participants were motivated by the pleasure of knowing new things and desire to understand and to help patients, whereas prestige, finances, and own sex lives are less important. CONCLUSIONS: The first FECSM are very diverse in terms of age, culture, religion, and primary specialty. Their practice is strongly influenced by their primary specialty, and this needs to be taken into account in future development of the speciality. PMID- 25919909 TI - A turn-on near-infrared fluorescent chemosensor for selective detection of lead ions based on a fluorophore-gold nanoparticle assembly. AB - A turn-on fluorescent chemosensor of Pb(2+) in the near-infrared (NIR) region, which is based on the Pb(2+)-tuned restored fluorescence of a weakly fluorescent fluorophore-gold nanoparticle (AuNPs) assembly, has been reported. In this fluorophore-AuNP assembly, NIR fluorescent dye brilliant cresyl blue (BCB) molecules act as fluorophores and are used for signal transduction of fluorescence, while AuNPs act as quenchers to quench the nearby fluorescent BCB molecules via electron transfer. In the presence of Pb(2+), fluorescent BCB molecules detached from AuNPs and restored their fluorescence due to the formation of a chelating complex between Pb(2+) and glutathione confined on AuNPs. Under the optimal conditions, the present BCB-AuNP assembly is capable of detecting Pb(2+) with a concentration ranging from 7.5 * 10(-10) to 1 * 10(-8) mol L(-1) (0.16-2.1 ng mL(-1)) and a detection limit of 0.51 nM (0.11 ng mL(-1)). The present BCB-AuNP assembly can be used in aqueous media for the determination of Pb(2+) unlike common organic fluorescent reagents, and also shows advantages of NIR fluorescence spectrophotometry such as less interference, lower detection limit, and higher sensitivity. Moreover, the present method was successfully applied for the detection of Pb(2+) in water samples with satisfactory results. PMID- 25919910 TI - Visualization and translocation of ternary Calcineurin-A/Calcineurin-B/Calmodulin 2 protein complexes by dual-color trimolecular fluorescence complementation. AB - Fluorescence complementation (FC) techniques are expedient for analyzing bimolecular protein-protein interactions. Here we aimed to develop a method for visualization of ternary protein complexes using dual-color trimolecular fluorescence complementation (TriFC). Dual-color TriFC combines protein fragments of mCherry and mVenus, in which a scaffold protein is bilaterally fused to C terminal fragments of both fluorescent proteins and combined with potential interacting proteins fused to an N-terminal fluorescent protein fragment. For efficient visual verification of ternary complex formation, TriFC was combined with a cytoplasm to plasma membrane translocation assay. Modular vector sets were designed which are fully compatible with previously reported bimolecular fluorescence complementation (BiFC) vectors. As a proof-of-principle, the ternary complex formation of the PP2B protein phosphatase Calcineurin-A/Calcineurin-B with Calmodulin-2 was investigated in transiently transformed Nicotiana benthamiana leaf epidermal cells. The results indicate a Calcineurin-B-induced interaction of Calmodulin-2 with Calcineurin-A. TriFC and the translocation of TriFC complexes provide a novel tool to investigate ternary complex formations with the simplicity of a BiFC approach. The robustness of FC applications and the opportunity to quantify fluorescence complementation render this assay suitable for a broad range of interaction analyses. PMID- 25919911 TI - Elevated expression of CCAT2 is associated with poor prognosis in esophageal squamous cell carcinoma. AB - BACKGROUND AND OBJECTIVES: CCAT2, a novel long non-coding RNAs (lncRNAs), is found to promote the metastasis and invasion of colon, lung, and breast cancers. This study aimed to investigate the level of CCAT2 in esophageal squamous cell carcinoma (ESCC) and to elucidate its clinical significance. METHODS: The expression level of CCAT2 and the status of MYC amplification were examined in 229 ESCC samples using quantitative real- time PCR. RESULTS: CCAT2 was upregulated in ESCC tissues, especially in cases with lymph node metastasis (LNM), advanced TNM stages, and MYC amplification. Furthermore, the level of CCAT2 was positively correlated with TNM stages, LNM, and the number of positive lymph nodes. High CCAT2 expression and MYC amplification were significantly associated with TNM stages and LNM. Survival analyses revealed that high CCAT2 expression and MYC amplification were significantly associated with poorer overall survival in ESCC patients. Furthermore, patients with high CCAT2 expression and MYC amplification had a 2.199-fold increased risk of death compared with those with low CCAT2 expression and MYC non-amplification. CONCLUSIONS: Our study provides the first evidence associating CCAT2 expression and poor survival in ESCC. CCAT2 may be a prognostic biomarker and therapeutic target for ESCC. PMID- 25919912 TI - Surface modifications induced by high fluxes of low energy helium ions. AB - Several metal surfaces, such as titanium, aluminum and copper, were exposed to high fluxes (in the range of 10(23) m(-2) s(-1)) of low energy (<100 eV) Helium (He) ions. The surfaces were analyzed by scanning electron microscopy and to get a better understanding on morphology changes both top view and cross sectional images were taken. Different surface modifications, such as voids and nano pillars, are observed on these metals. The differences and similarities in the development of surface morphologies are discussed in terms of the material properties and compared with the results of similar experimental studies. The results show that He ions induced void growth and physical sputtering play a significant role in surface modification using high fluxes of low energy He ions. PMID- 25919913 TI - A comparative analysis of dementia inpatient characteristics: results from a nationwide survey of different care facilities in Japan. AB - BACKGROUND: In Japan, the number of dementia patients admitted to hospitals and other care facilities has been increasing and their hospital stays prolonged. Until now, there has been no study examining the differences between patients in psychiatric hospitals and other care facilities. Here we attempt a comparative analysis of characteristics of dementia patients in psychiatric hospitals and other types of facilities based on a nationwide survey. METHOD: A nationwide, cross-sectional survey was conducted in 2009-2011. Questionnaires were sent to randomly selected facilities and asked about each facility's status as of September 2009 and about individuals with dementia residing in each facility during the 2008 fiscal year. The portion about individuals consisted of items to assess eligibility for the Long-Term Care Insurance programme. Based on data from 6121 patients residing in seven different types of facilities, features of dementia patients in psychiatric hospitals and differences among facilities were analyzed. RESULTS: There was a significant difference in average age, activities of daily living level, and dementia severity level among the seven types of facilities. The average age in all types of facilities, except for psychiatric hospitals, was higher than the national average life expectancy of 82.59 years. The results of the study revealed that in psychiatric hospitals the proportion of men, those aged <75 years, demented patients with severe behavioural and psychological symptoms of dementia, and those with frontotemporal dementia was significantly greater than in other types of facilities. In other Long-Term Care Insurance care facilities, dementia patients >80 years and women accounted for 80% of all patients. CONCLUSION: Result showed that dementia patients in psychiatric hospitals had a higher proportion of men, younger age groups, and severe dementia than other types of facilities. These features contrast markedly with status of dementia patients in other Long-Term Care Insurance care facilities. In order to facilitate dementia patients' early discharge from psychiatric hospitals to other care facilities or to home, further fulfillment care services corresponding to severe dementia and early-onset dementia may be needed. PMID- 25919914 TI - Thymectomy and systemic lupus erythematosus (SLE). AB - Dear Sir The thymus plays a crucial role in the context of cellmediated immunity in the differentiation of T lymphocytes, not only during the embryogenesis and fetal period but also during the adulthood, even after its involution 1,2,3. It has been proved, indeed, that thymectomy in adult rat entails a decrease of the T lymphocite response to mitogens and eventually its abolition 4,5,6. The removal of the thymus can decrease the activity of T-helper cells but in the same time it might enhance the activity of T-suppressor whose function is depressed in autoimmune diseases 7. The therapeutic role of thymectomy is proved in Myasthenia Gravis even if the exact mechanism underlying its effect remains largely unknown. The role of thymectomy as a treatment of autoimmune diseases other than Myasthenia Gravis (i.e. sistemic lupus erythematosus, rheumatoid arthritis, autoimmune hemolytic anemia, multiple sclerosis) has been investigated but the results of these studies are questionable 7. Our aim is to evaluate the role of thymectomy in order to clarify whether it may be regarded not just as therapeuytic, but, on the contrary, as a factor paving the way to the onset of autoimmune diseases. Therefore, the relevant literature has been taken into account along our study. Thymus has an important role in regulating immune reaction through its control on T-cell differentiation of both T-helper and T suppressor/cytotoxic cells. That is the reason why thymectomy produces a shift in autoimmune diseases with disregulation of the immune networks2. After thymectomy, indeed, an induction and an acceleration of autoimmune processes has been observed. A relevant work focusing on those mechanisms was written by Gerli et al1 . In their work, the authors consider the long term immunologic effects of therapeutic thymectomy in patients with Myasthenia Gravis comparing 16 patients with Myasthenia Gravis and previous Thymectomy (at least 8 years before), 6 patients with Myasthenia Gravis and recent Thymectomy (<1year) and 13 with Myasthenia Gravis non Thymectomized and 32 healthy subjects used as control. The study shows that the long term thymectomized patients had mild T-cell lymphopenia and an expansion of CD4+ and CD8+ cells. These serologic abnormalities were not detectable in not and recently thymectomized patients. Myasthenia Gravis and SLE are autoimmune disorders. They have positivity for antinuclear antibodies (ANA) and thymus hyperplasia. SLE is characterized by an alteration of the immune system that involves B cells and T lymphocites, resulting in polyclonal B cell activation and autoantybody production. The thymus deletes self-reactive T-cells with high avidity T-cell receptors for self antigens expressed in the thymus 8,9. This, hence, means that thymus has a protective role against autoimmunity. The prevalence of SLE in pts with Myasthenia Gravis has been reported 0,2%-2,7% 10. Cases in which the SLE has developed after thymectomy for Myasthenia Gravis have been reported in the literature, but there are also cases in which SLE developed before thymectomy in pts with both SLE and MG. Iwadate at al reported from a review of the literature in a period of 40 years (1963- 2004) 21 patients in whom LES developed after thymectomy. Their ages ranged from 11 to 66 years (mean 40.4 years) with SLE developing from 2 months to 13 years (mean 4.9 years) after thymectomy. Polyarthritis was the most common manifestation of SLE 11. The proof that thymectomy can facilitate the development of SLE can be traced in the cases reported by the literature. The prevalence of SLE among patients with thymoma varies between 1,5 and 10% 12. Boonen et al identified in a period of 20 years (1975-1998) 18 new cases of thymoma and SLE. In 39% of the patients SLE was diagnosed before detection of thymoma. In 33% of the patients, thymoma and SLE was found simultaneously and in 28% SLE was discovered after thymoma. In five cases thymectomy had no clear effect on SLE. In two cases an exacerbation was reported and in one case SLE was attenuated 11,13. However, Vaiopoulos et al 14 described in a series of 28 patients with both LES and Myasthenia Gravis, 17 cases in which LES developed before thymectomy. CONCLUSIONS: Thymectomy may thus be a precipitating factor for the development of SLE due to the loss of central tolerance and the overproduction of antibodies. Therefore, after a thymectomy, it is important to perform a timely follow up of the patient. PMID- 25919915 TI - Anti-Inflammatory Effects of 3-(4'-Hydroxyl-3',5'-Dimethoxyphenyl)Propionic Acid, an Active Component of Korean Cabbage Kimchi, in Lipopolysaccharide-Stimulated BV2 Microglia. AB - We investigated the protective ability of 3-(4'-hydroxyl-3',5' dimethoxyphenyl)propionic acid (HDMPPA), an active principle in Korean cabbage kimchi, against the production of proinflammatory mediators and cytokines, and the mechanisms involved in lipopolysaccharide (LPS)-stimulated BV2 microglial cells. HDMPPA significantly suppressed the production of nitric oxide (NO) and prostaglandin E2, along with the expression of inducible NO synthase and cyclooxygenase-2 in LPS-stimulated BV2 cells, at concentrations with no cytotoxicity. HDMPPA also attenuated the LPS-induced expression and secretion of proinflammatory cytokines, such as tumor necrosis factor-alpha and interleukin 1beta. Furthermore, HDMPPA inhibited LPS-induced nuclear factor-kappaB (NF kappaB) activation, which was associated with the abrogation of IkappaB-alpha degradation and phosphorylation, and subsequent decreases in NF-kappaB p65 levels. Moreover, the phosphorylation of mitogen-activated protein kinases (MAPKs) and Akt, a downstream molecule of phosphatidylinositol-3-kinase (PI3K), in LPS-stimulated BV2 cells was suppressed markedly by HDMPPA. This effect was associated with a significant reduction in the formation of intracellular reactive oxygen species. The findings in this study suggest that HDMPPA may exert anti-inflammatory responses by suppressing LPS-induced expression of proinflammatory mediators and cytokines through blockage of NF-kappaB, MAPKs, and PI3K/Akt signaling pathways and oxidative stress in microglia. PMID- 25919917 TI - Strongly improved electrochemical cycling durability by adding iridium to electrochromic nickel oxide films. AB - Anodically colored nickel oxide (NiO) thin films are of much interest as counter electrodes in tungsten oxide based electrochromic devices such as "smart windows" for energy-efficient buildings. However, NiO films are prone to suffering severe charge density degradation upon prolonged electrochemical cycling, which can lead to insufficient device lifetime. Therefore, a means to improve the durability of NiO-based films is an important challenge at present. Here we report that the incorporation of a modest amount of iridium into NiO films [Ir/(Ir + Ni) = 7.6 atom %] leads to remarkable durability, exceeding 10000 cycles in a lithium conducting electrolyte, along with significantly improved optical modulation during extended cycling. Structure characterization showed that the face-centered cubic-type NiO structure remained after iridium addition. Moreover, the crystallinity of these films was enhanced upon electrochemical cycling. PMID- 25919918 TI - The Development and User Satisfaction Evaluation of Internet-Based N-Screen Healthcare Walking Content to Increase Continuous Usage Motivation. AB - OBJECTIVE: The purpose of the current study is (1) to apply Internet-based N Screen (this is used like the term "emultiscreen"; as the technology that provides services of shared content or application via N devices, it includes all screens such as personal computers [PCs], TV, and mobile devices) services to healthcare services by developing games for improving one's health and (2) to present ways to activate the use of health promotion contents in the future by investigating user satisfaction and whether there is any intention to accept the contents and/or use the services continuously. MATERIALS AND METHODS: In order to evaluate the customized health maintenance content provided by the healthcare walking system developed in the current study, 98 adult men and women residing in Seoul, Korea, were instructed to use 10 minutes' worth of the walking content. Perceived quality, level of trust in the results, effectiveness of the exercise, and overall satisfaction were measured in regard to the N-Screen-based walking content, including those for the cell phone, PC, and Internet protocol TV (IPTV). RESULTS: Walking contents using N-Screen services were perceived with high levels of trust in the results of the exercise, the effectiveness of the exercise, and overall satisfaction. In terms of the usability of N-Screen services, the younger the participants, the more usable they found the mobile or PC programs. The older the participants, the more usable they found the IPTV screens, although they still struggled with using the content given; operating IPTVs proved to be difficult for them. Furthermore, participants who were engaged in exercise on a regular basis were less satisfied with the program, in general. CONCLUSIONS: The present study has developed a walking system using N-Screen programs to make the most common and effective forms of exercise-walking and running-accessible indoors. This may increase motivation to exercise by offering services that boost one's interest in exercising, such as personal monitoring and real-time feedback regarding one's workout progress. PMID- 25919919 TI - The need for people-first language in our Obesity journal. PMID- 25919920 TI - Response to "The need for people-first language in our Obesity journal". PMID- 25919921 TI - Efficacy of SmartLoss, a smartphone-based weight loss intervention: results from a randomized controlled trial. AB - OBJECTIVE: Test the efficacy of SmartLoss, a smartphone-based weight loss intervention, in a pilot study. DESIGN AND METHODS: A 12-week randomized controlled trial. Adults (25 <= BMI <= 35 kg/m2) were randomized to SmartLoss (n = 20) or an attention-matched Health Education control group (n = 20). SmartLoss participants were prescribed a 1,200 to 1,400 kcal/d diet and were provided with a smartphone, body weight scale, and accelerometer that wirelessly transmitted body weight and step data to a website. In the SmartLoss Group, mathematical models were used to quantify dietary adherence based on body weight and counselors remotely delivered treatment recommendations based on these objective data. The Health Education group received health tips via smartphone. A mixed model determined if change in weight and other endpoints differed between the groups (baseline was a covariate). RESULTS: The sample was 82.5% female. Mean +/- SD baseline age, weight (kg), and BMI were 44.4 +/- 11.8 years, 80.3 +/- 11.5 kg, and 29.8 +/- 2.9 kg/m2, respectively. One participant was lost to follow-up in each group before week 4. Weight loss was significantly (P < 0.001) larger in the SmartLoss (least squares mean +/- SEM: -9.4 +/- 0.5%) compared with the Health Education group (-0.6 +/- 0.5%). CONCLUSIONS: SmartLoss efficaciously promote clinically meaningful weight loss compared with an attention-matched control group. Smartphone-based interventions might prove useful in intervention dissemination. PMID- 25919922 TI - Direct conversion of human myoblasts into brown-like adipocytes by engineered super-active PPARgamma. AB - OBJECTIVE: To determine whether super-activation of PPARgamma can reprogram human myoblasts into brown-like adipocytes and to establish a new cell model for browning research. METHODS: To enhance the PPARgamma signaling, M3, the transactivation domain of MyoD, was fused to PPARgamma. PPARgamma and M3 PPARgamma-lentiviral vectors were used to convert human myoblasts into adipocytes. Brown adipocyte markers of the reprogrammed adipocytes were assessed by qPCR and protein analyses. White adipocytes differentiated from subcutaneous stromal vascular cells and perithyroid brown fat tissues were used as references. RESULTS: In transient transfections, M3-PPARgamma had a stronger constitutive activity than PPARgamma by reporter assay. Although the transduction of either PPARgamma or M3-PPARgamma induced adipogenesis in myoblasts, M3-PPARgamma drastically induced the brown adipocyte markers of UCP1, CIDEA, and PRDM16 by 1,050, 2.4, and 5.0 fold, respectively and increased mitochondria contents by 4 fold, compared to PPARgamma. CONCLUSIONS: Super-activation of PPARgamma can effectively convert human myoblasts into brown-like adipocytes and a new approach to derive brown-like adipocytes. PMID- 25919923 TI - Trends in SSBs and snack consumption among children by age, body weight, and race/ethnicity. AB - OBJECTIVE: To describe national trends in discretionary calories from sugar sweetened beverage (SSB) and snacks by age-specific body weight categories and by age- and weight-specific race/ethnicity groups. Examining these subpopulations is important as population averages may mask important differences. DESIGN AND METHODS: 24-hour dietary recall data obtained from the National Health and Nutrition Examination Survey 2003-2010 among children aged 2 to 19 (N = 14,092) were used. Logistic and linear regression methods were used to adjust for multiple covariates and survey design. RESULTS: The number of calories from SSBs declined significantly for nearly all age-specific body weight groups. Among overweight or obese children, significant declines in the number of calories from SSBs were observed among Hispanic children aged 2 to 5 (117 vs. 174 kcal) and white adolescents aged 12 to 19 (299 vs. 365 kcal). Significant declines in the number of calories from salty snacks were observed among white children aged 2 to 5 (192 to 134 kcal) and 6 to 11 (273 vs. 200 kcal). CONCLUSIONS: The decrease in SSB consumption and increase in snack consumption observed in prior research are not uniform when children are examined within subgroups accounting for age, weight, and race/ethnicity. PMID- 25919925 TI - Changes in children's meal orders following healthy menu modifications at a regional U.S. restaurant chain. AB - OBJECTIVE: To examine changes in children's meal orders, price, and revenue following the implementation of a healthier children's menu in a full-service restaurant chain. METHODS: In April 2012, the healthier menu was implemented, featuring more meals meeting nutrition standards, healthy side dishes by default, and removal of French fries and soda (which could be substituted). Orders (n = 352,192) were analyzed before (September 2011 to March 2012; PRE) and after (September 2012 to March 2013; POST) implementation. RESULTS: Children's meal prices increased by $0.79 for breakfasts and $0.19 for non-breakfast meals from PRE to POST. Revenue continued to increase post-implementation. Orders of healthy meals, strawberry and vegetable sides, milk, and juice increased, and orders of French fries and soda decreased (P < 0.0001). Orders at POST were more likely to include healthy sides (P < 0.0001) and substitutions (P < 0.0001) and less likely to include a la carte sides (P < 0.0001) and desserts (P < 0.01), versus PRE. Total calories ordered by children accepting all defaults decreased (684.2 vs. 621.2; P < 0.0001) and did not change for those not accepting defaults (935.0 vs. 942.9; P = 0.57). CONCLUSIONS: Healthy children's menu modifications were accompanied by healthier ordering patterns, without removing choice or reducing revenue, suggesting that they can improve child nutrition while restaurants remain competitive. PMID- 25919924 TI - Maternal adiposity negatively influences infant brain white matter development. AB - OBJECTIVE: To study potential effects of maternal body composition on central nervous system (CNS) development of newborn infants. METHODS: Diffusion tensor imaging (DTI) was used to evaluate brain white matter development in 2-week-old, full-term, appropriate for gestational age (AGA) infants from uncomplicated pregnancies of normal-weight (BMI < 25 at conception) or obese ( BMI = 30 at conception) and otherwise healthy mothers. Tract-based spatial statistics (TBSS) analyses were used for voxel-wise group comparison of fractional anisotropy (FA), a sensitive measure of white matter integrity. DNA methylation analyses of umbilical cord tissue focused on genes known to be important in CNS development were also performed. RESULTS: Newborns from obese women had significantly lower FA values in multiple white matter regions than those born of normal-weight mothers. Global and regional FA values negatively correlated (P < 0.05) with maternal fat mass percentage. Linear regression analysis followed by gene ontology enrichment showed that methylation status of 68 CpG sites representing 57 genes with GO terms related to CNS development was significantly associated with maternal adiposity status. CONCLUSIONS: These results suggest a negative association between maternal adiposity and white matter development in offspring. PMID- 25919926 TI - Visceral adipose tissue is associated with microstructural brain tissue damage. AB - OBJECTIVE: Obesity has been associated with microstructural brain tissue damage. Different fat compartments demonstrate different metabolic and endocrine behaviors. The aim was to investigate the individual associations between abdominal visceral adipose tissue (VAT) and subcutaneous adipose tissue (SAT) and microstructural integrity in the brain. METHODS: This study comprised 243 subjects aged 65.4 +/- 6.7 years. The associations between abdominal VAT and SAT, assessed by CT, and magnetization transfer imaging markers of brain microstructure for gray and white matter were analyzed and adjusted for confounding factors. RESULTS: VAT was associated with normalized MTR peak height in gray (beta -0.216) and white matter (beta -0.240) (both P < 0.01) after adjustment for confounding factors. After adjustment for sex, age, and descent, SAT was associated with normalized MTR peak height in gray and white matter, but not after additional correction for BMI, hypertension, current smoking, statin use, and type 2 diabetes (respectively, beta -0.055 and beta 0.035, both P > 0.05). Stepwise linear regression analysis showed that only VAT was associated with normalized MTR peak height in gray and white matter (both P < 0.001). CONCLUSIONS: Our data indicate that increased abdominal VAT rather than SAT is associated with microstructural brain tissue damage in elderly individuals. PMID- 25919928 TI - Novel DNA methylation markers with potential prognostic relevance in advanced malignant melanoma identified using COBRA assays. AB - Aberrant methylation of promoter regions involved in silencing of tumor suppressor genes is a key feature of many human cancers including melanoma. These DNA methylation events occur early in cancer development, increase with progression, and may therefore serve as biomarkers for the detection and staging of cancer. In our study, we used an epigenomic reactivation screening approach including Combined Bisulfite Restriction Analyses (COBRA) assays to identify novel methylation markers in late-stage melanoma. Two human xenograft melanoma models have been used to identify genes methylated in cancer and reactivated upon treatment with a histone deacetylase inhibitor. Gene expression analysis and promoter scanning for DNA methylation by COBRA assays and bisulfite sequencing were used to identify candidate genes. The methylation status of the CpG island promoter region of genes related to melanoma pathophysiology in skin, lymph node, and visceral metastatic metastases in 28 patients (samples n=35) were assessed. These methylation markers have been evaluated in melanoma metastasis tissue and in control samples from normal skin. The screening in in-vitro and in-vivo systems for methylated genes in melanoma samples showed 10 candidate genes. Using COBRA assays, we detected a methylation pattern in the promoter region of 10 genes with two genes (BASP1, CDH11), together with the patient's age and the log S100B-level at biopsy, constructing a descriptor with a trend to correlate with shorter time to death. PMID- 25919927 TI - A common variant in the MTNR1b gene is associated with increased risk of impaired fasting glucose (IFG) in youth with obesity. AB - OBJECTIVE: To explore the role of MTNR1B rs10830963 and G6PC2 rs560887 variants in the pathogenesis of impaired fasting glucose (IFG) in obese adolescents. METHODS: A total of 346 Caucasians, 218 African-Americans, and 217 Hispanics obese children and adolescents underwent an oral glucose tolerance test (OGTT) and 518 underwent the evaluation of insulin secretion by the oral minimal model (OMM). Also, 274 subjects underwent a second OGTT after 3.0 +/- 2.1 years. RESULTS: The MTNR1B rs10830963 variant was associated with higher fasting glucose levels and lower dynamic beta-cell response in Caucasians and Hispanics (P < 0.05) and conferred an increased risk of showing IFG to Caucasians (P = 0.05), African-Americans (P = 0.0066), and Hispanics (P = 0.024). Despite the association between the G6PC2 rs560887 and higher fasting glucose levels (P < 0.05), there was no association between this variant and IFG at baseline or at follow-up (all P > 0.10). CONCLUSIONS: It has been shown for the first time in obese youth that the MTNR1B variant is associated with an increased risk of IFG. PMID- 25919929 TI - Defining the dermoscopic characteristics of fast-growing cutaneous melanomas. AB - A high growth rate in melanomas has been associated with a more aggressive phenotype and worse survival. The aim of this study was to define the dermoscopic characteristics associated with this type of cutaneous melanoma. We carried out a retrospective study of 132 cutaneous melanomas, analyzing certain clinical characteristics and the most important dermoscopic variables related to the melanomas. Fast-growing melanomas were considered to be those with a growth rate of more than 0.5 mm per month. Fast-growing melanomas more often lacked an atypical network, were symmetrical, presented ulceration, and were hypopigmented. The dermoscopic vascular pattern often showed atypical irregular vessels and milky-red areas. The association of these two is a specific characteristic. Fast growing melanomas have a characteristic phenotype and dermoscopy can be useful for their identification. PMID- 25919930 TI - Effects of Polymer Hydrophobicity on Protein Structure and Aggregation Kinetics in Crowded Milieu. AB - We examined the effects of water-soluble polymers of various degrees of hydrophobicity on the folding and aggregation of proteins. The polymers we chose were polyethylene glycol (PEG) and UCON (1:1 copolymer of ethylene glycol and propylene glycol). The presence of additional methyl groups in UCON makes it more hydrophobic than PEG. Our earlier analysis revealed that similarly sized PEG and UCON produced different changes in the solvent properties of water in their solutions and induced morphologically different alpha-synuclein aggregates [Ferreira, L. A., et al. (2015) Role of solvent properties of aqueous media in macromolecular crowding effects. J. Biomol. Struct. Dyn., in press]. To improve our understanding of molecular mechanisms defining behavior of proteins in a crowded environment, we tested the effects of these polymers on secondary and tertiary structure and aromatic residue solvent accessibility of 10 proteins [five folded proteins, two hybrid proteins; i.e., protein containing ordered and disordered domains, and three intrinsically disordered proteins (IDPs)] and on the aggregation kinetics of insulin and alpha-synuclein. We found that effects of both polymers on secondary and tertiary structures of folded and hybrid proteins were rather limited with slight unfolding observed in some cases. Solvent accessibility of aromatic residues was significantly increased for the majority of the studied proteins in the presence of UCON but not PEG. PEG also accelerated the aggregation of protein into amyloid fibrils, whereas UCON promoted aggregation to amyloid oligomers instead. These results indicate that even a relatively small change in polymer structure leads to a significant change in the effect of this polymer on protein folding and aggregation. This is an indication that protein folding and especially aggregation are highly sensitive to the presence of other macromolecules, and an excluded volume effect is insufficient to describe their effect. PMID- 25919931 TI - Effect of aging on volatile compounds in cooked beef. AB - Volatiles in the headspace of beef cooked at 180 degrees C were analyzed using solid-phase microextraction (SPME) and gas chromatography-mass spectrometry (GC MS), and the effects of aging were evaluated. Seventy volatile substances including non-aromatic, homocyclic, and heterocyclic compounds were identified. A significant positive regression model for storage could be adopted for toluene, benzeneacetaldehyde, 2-formylfuran, pyrazine, 2,6-dimethylpyrazine, 2,3 dimethylpyrazine, 2-acetylthiazole, and 2-formyl-3-methylthiophene. Increases in the quantity of these compounds, with the exception of toluene, suggest the importance of the Strecker and Maillard reactions in cooked meat previously aged under vacuum conditions. As such, the aging process may lead to an increase not only in the amount of compounds related to the taste of meat, but also in the quantity of odor-active compounds. The increased quantity of toluene during storage seemed to be influenced by lipid oxidation. PMID- 25919932 TI - Novel synthesis of a versatile magnetic adsorbent derived from corncob for dye removal. AB - Corncob, an agricultural waste, was successfully converted into a novel magnetic adsorbent by a low-temperature hydrothermal method (453K), including carbonization under saline conditions and magnetization using iron (III) salt. The resultant magnetic carbonaceous adsorbent (MCA) exhibited a porous structure with a higher specific surface area and more oxygen-containing functional groups than its carbonaceous precursor (CP), which can be attributed to the catalytic effect of Fe (III). The adsorption behaviors of both MCA and CP could be described well by Langmuir isotherm and pseudo-second-order model. The adsorption capacity for Methylene blue (MB) revealed by adsorption isotherms were 163.93mg/g on MCA and 103.09mg/g on CP, respectively. Moreover, MCA was demonstrated as a versatile adsorbent for removal of both anionic and cationic dyes, and it showed good reusability in regeneration studies. This work provides an alternative approach for effective conversion of biomass waste and application of them in pollutant removal. PMID- 25919933 TI - Microbial communities, extracellular proteomics and polysaccharides: A comparative investigation on biofilm and suspended sludge. AB - Biofilm and suspended sludge (S-sludge) floc exhibit distinct physicochemical properties and process performances in an integrated fixed-film and suspended growth sequencing batch reactor. However, the mechanisms of governing these differences between the two aggregates were unknown. Current work evaluated the diversity of morphologies, microbial communities, extracellular proteins and polysaccharides between the biofilm and S-sludge. Contrast to biofilm, the denitrification was much more extensive performed in S-sludge. Furthermore, many microbial cells in the biofilm acted as the backbone of aggregates and maintained the structure stability. An extracellular protein observed only in the biofilm can promote the cell adhesion. In contrast, more extracellular proteins related to catalytic activity in the S-sludge could decrease the compactness of floc. In addition, the monosaccharide compositions from the two aggregates were various. These results could elucidate how the diversities of architecture and biochemical process between the two aggregates occurred. PMID- 25919934 TI - Enhanced flashing light effect with up-down chute baffles to improve microalgal growth in a raceway pond. AB - Novel up-down chute baffles that sequentially generate clockwise and anticlockwise liquid vortexes were developed to increase vertical liquid velocity between the bottom dark area and the top light area in a raceway pond. The vertical liquid velocity, mixing time, and mass transfer coefficient were measured as functions of paddlewheel speed and air aeration rate by using a particle imaging velocimeter, pH probes, and dissolved oxygen probes. The up-down chute baffles decreased the liquid mixing time and increased the mass transfer coefficient by 41% and 25%, respectively. Besides, the vertical liquid velocity increased from ~0.5cm/s to ~6.1cm/s. As a result, the dark-light cycle period was reduced to 1/12. This enhanced flashing light effect with up-down chute baffles increased biomass yield by 32.6% in the same raceway pond. PMID- 25919935 TI - A kinetics modeling study on the inhibition of glucose on cellulosome of Clostridium thermocellum. AB - A simplified kinetics model was built to study the inhibition of glucose on cellulosome of Clostridium thermocellum. Suitable reaction conditions were adopted to evaluate the model. The model was evaluated at different temperatures and further with various activated carbon additions as adsorbent for glucose. Investigation results revealed that the model could describe the hydrolysis kinetics of cellulose by cellulosome quite well. Glucose was found to be an inhibitor for cellulosome based on the kinetics analysis. Inhibition increased with the increase in temperature. Activated carbon as adsorbent could lower the inhibition. Parameters in the model were further discussed based on the experiment. The model might also be used to describe the strong inhibition of cellobiose on cellulosome. Saccharification of cellulose by both cellulosome and C. thermocellum could be enhanced efficiently by activated carbon addition. PMID- 25919936 TI - Synthesis and characterization of carbon cryogel microspheres from lignin furfural mixtures for biodiesel production. AB - The aim of this work was to study the potential of biofuel and biomass processing industry side-products as acid catalyst. The synthesis of carbon cryogel from lignin-furfural mixture, prepared via sol-gel polycondensation at 90 degrees C for 0.5h, has been investigated for biodiesel production. The effect of lignin to furfural (L/F) ratios, lignin to water (L/W) ratios and acid concentration on carbon cryogel synthesis was studied. The carbon cryogels were characterized and tested for oleic acid conversion. The thermally stable amorphous spherical carbon cryogel has a large total surface area with high acidity. Experimental results revealed the optimum FAME yield and oleic acid conversion of 91.3wt.% and 98.1wt.%, respectively were attained at 65 degrees C for 5h with 5wt.% catalyst loading and 20:1 methanol to oleic acid molar ratio. Therefore, carbon cryogel is highly potential for heterogeneous esterification of free fatty acid to biodiesel. PMID- 25919937 TI - Prediction of the effect of fine grit on the MLVSS/MLSS ratio of activated sludge. AB - This paper investigated the suspension properties of fine grit with different particle sizes in a bioreactor and developed a model to predict its effect on the ratio of mixed liquor volatile suspended solids to the mixed liquor suspended solids (MLVSS/MLSS) of activated sludge. The experimental results revealed that a smaller particle size corresponds to a larger suspension ratio, defined as the proportion of fine grit brought in by influent that is suspended in the activated sludge, and a smaller MLVSS/MLSS ratio. The model demonstrated that the effect of fine grit on the MLVSS/MLSS ratio is related to the fine grit concentration and chemical oxygen demand in influent and the observed sludge yield. However, fine grit has no influence on the activity of microorganisms. Wastewater treatment plants (WWTPs) can adjust MLSS based on the MLVSS/MLSS ratio to ensure the stability of MLVSS, which can achieve the stable operation of WWTPs. PMID- 25919938 TI - Enantioseparation on Riboflavin Derivatives Chemically Bonded to Silica Gel as Chiral Stationary Phases for HPLC. AB - Acetylated and/or 3,5-dimethylphenylcarbamated riboflavins were prepared and the resulting riboflavin derivatives as well as natural riboflavin were regioselectively immobilized on silica gel through chemical bonding at the 5'-O- or 3-N-position of the riboflavin to develop novel chiral stationary phases (CSPs) for enantioseparation by high-performance liquid chromatography (HPLC). The chiral recognition abilities of the obtained CSPs were significantly dependent on the structures of the riboflavin derivatives, the position of the chemical bonding on the silica gel, and the structures of the racemic compounds. The CSPs bonded at the 5'-O-position on the silica gel tended to well separate helicene derivatives, while the CSPs bonded at the 3-N-position composed of acetylated and 3,5-dimethylphenylcarbamated riboflavins showed a better resolving ability toward helicene derivatives and bulky aromatic racemic alcohols, respectively, and some of them were completely separated into the enantiomers. The observed difference in the chiral recognition abilities of these riboflavin based CSPs is discussed based on the difference in their structures, including the substituents of riboflavin and the positions immobilized on the silica gel. PMID- 25919939 TI - Letter to the Editor: Concepts and methods when considering negative symptom course: a reply. PMID- 25919940 TI - Syntheses, structures and theoretical investigations of [Au10S2(PPh2)2(dppma2)4(dppma3)].[Au6S2(dppma2)2(dppma3)]. AB - The synthesis, crystal structure and theoretical studies of a high-nuclear gold(i) complex stabilized by bridging aromatic phosphane ligands are reported. The complex is composed of a neutral Au10 complex unit with a horseshoe-like structure around a neutral Au6 complex unit with a distorted cubane-like structure. PMID- 25919941 TI - Rutin antinociception involves opioidergic mechanism and descending modulation of ventrolateral periaqueductal grey matter in rats. AB - BACKGROUND: Rutin is a bioflavonoid found in fruits, vegetables and plants used in traditional medicine to alleviate pain. However, rutin's scientific evidence for the modulation of pain and its mechanism of action is lacking. It is well known that the periaqueductal grey matter (PAG) contains opioidergic neural circuits involved in the modulation of descending nociception. The aim of this study was to investigate if antinociceptive activity of rutin is modulated by the PAG circuitry involving participation of opioid receptors. METHODS: The experimental design included groups of rats receiving rutin systemically (30-1000 mg/kg) or microinjected into the vlPAG (8-32 nmol/4 MUL) alone or in the presence of an opioid antagonist, naltrexone (5 mg/kg, i.p. or 26 nmol/4 MUL, respectively). Nociception was assessed using the formalin test and compared versus the reference drugs, tramadol and morphine. RESULTS: Systemic or intra vlPAG administration of rutin significantly decreased both phases of the formalin test. Antinociceptive responses of the reference drugs were prevented by naltrexone, whereas the antinociceptive effect of rutin was inhibited by this antagonist mainly in the phase II of the formalin test. CONCLUSIONS: Our results provide evidence that rutin produces antinociceptive effects involving central modulation of the vlPAG descending circuit partly mediated by an opioidergic mechanism. PMID- 25919942 TI - Decoupling of mass transport mechanisms in the stagewise swelling of multiple emulsions. AB - This contribution reports on the mass transport kinetics of osmotically imbalanced water-in-oil-in-water (W1/O/W2) emulsions. Although frequently studied, the control of mass transport in W1/O/W2 emulsions is still challenging. We describe a microfluidics-based method to systematically investigate the impact of various parameters, such as osmotic pressure gradient, oil phase viscosity, and temperature, on the mass transport. Combined with optical microscopy analyses, we are able to identify and decouple the various mechanisms, which control the dynamic droplet size of osmotically imbalanced W1/O/W2 emulsions. So, swelling kinetics curves with a very high accuracy are generated, giving a basis for quantifying the kinetic aspects of transport. Two sequential swelling stages, i.e., a lag stage and an osmotically dominated stage, with different mass transport mechanisms are identified. The determination and interpretation of the different stages are the prerequisite to control and trigger the swelling process. We show evidence that both mass transport mechanisms can be decoupled from each other. Rapid osmotically driven mass transport only takes place in a second stage induced by structural changes of the oil phase in a lag stage, which allow an osmotic exchange between both water phases. Such structural changes are strongly facilitated by spontaneous water-in-oil emulsification. The duration of the lag stage is pressure-independent but significantly influenced by the oil phase viscosity and temperature. PMID- 25919943 TI - The perioperative dialogue--a model of caring for the patient undergoing a hip or a knee replacement surgery under spinal anaesthesia. AB - The aim of the study was to describe how patients undergoing either a hip or a knee replacement surgery under spinal anaesthesia experienced to be a part of the perioperative dialogue as an ideal model of caring. A qualitative approach was chosen as a method. Nineteen patients undergoing either a hip or a knee replacement surgery under spinal anaesthesia participated. These patients and their nurse anaesthetists had three perioperative dialogues in the pre-, intra- and postoperative phase of care. Data were collected by means of conversational interviews by four voluntary nurse anaesthetists who wrote the dialogues from each perioperative phase. The text from the collected data was analysed by qualitative, latent content analysis. The findings of the analysis show three identified themes: Suffering while waiting for surgery (preoperative dialogue), Continuity creates togetherness (intraoperative dialogue) and Uniqueness - the patient has been seen (postoperative dialogue). The findings show evidence that the perioperative dialogue is an ideal model of caring and serves the patients' desires of individual and dignified care. The patients have a deep appreciation when there is time to develop a caring encounter with his or her own nurse. When a caring encounter has been established, the patient is involved in his or her own care. This model of caring offers the perioperative nurses a new way of caring and arouses reflections about their main task caring for the suffering patient. The continuity created by the perioperative dialogue probably has an influence on both patient satisfaction and patient safety. PMID- 25919944 TI - Benign distal jejunal stricture treated by a partially covered esophageal stent with the use of spiral enteroscopy. PMID- 25919945 TI - Prediction of viral filtration performance of monoclonal antibodies based on biophysical properties of feed. AB - Controlling viral contamination is an important issue in the process development of monoclonal antibodies (MAbs) produced from mammalian cell lines. Virus filtration (VF) has been demonstrated to be a robust and effective clearance step which can provide >=4 logs of reduction via size exclusion. The minimization of VF area by increasing flux and filter loading is critical to achieving cost targets as VFs are single use and often represent up to 10% of total purification costs. The research presented in this publication describes a development strategy focused on biophysical attributes of product streams that are directly applicable to VF process performance. This article summarizes a case study where biophysical tools (high-pressure size exclusion chromatography, dynamic light scattering, and absolute size exclusion chromatography) were applied to a specific MAb program to illustrate how changes in feed composition (pH, sodium chloride concentration, and buffer salt type) can change biophysical properties which correlate with VF performance. The approach was subsequently refined and expanded over the course of development of three MAbs where performance metrics (i.e., loading and flux) were evaluated for two specific virus filters (Viresolve Pro and Planova 20N) during both unspiked control runs and virus clearance experiments. The analyses of feed attributes can be applied to a decision tree to guide the recommendation of a VF filter and operating conditions for use in future MAb program development. The understanding of the biophysical properties of the feed can be correlated to virus filter performance to significantly reduce the mass of product, time, and costs associated with virus filter step development. PMID- 25919947 TI - Synthetic Progress toward Azadirachtins. 2. Enantio- and Diastereoselective Synthesis of the Right-Wing Fragment of 11-epi-Azadirachtin I. AB - A stereoselective three-component coupling reaction of allylzinc bromide, silyl glyoxylate, and a beta-lactone has been developed. This has been successfully applied to the enantio- and diastereoselective synthesis of the fully functionalized furopyran moiety of azadirachtins. PMID- 25919946 TI - Identification of precursor microRNAs within distal axons of sensory neuron. AB - A set of specific precursor microRNAs (pre-miRNAs) are reported to localize into neuronal dendrites, where they could be processed locally to control synaptic protein synthesis and plasticity. However, it is not clear whether specific pre miRNAs are also transported into distal axons to autonomously regulate intra axonal protein synthesis. Here, we show that a subset of pre-miRNAs, whose mature miRNAs are enriched in axonal compartment of sympathetic neurons, are present in axons of neurons both in vivo and in vitro by quantitative PCR and by in situ hybridization. Some pre-miRNAs (let 7c-a and pre-miRs-16, 23a, 25, 125b-1, 433, and 541) showed elevated axonal levels, while others (pre-miRs-138-2, 185, and 221) were decreased in axonal levels following injury. Dicer and KSRP proteins are also present in distal axons, but Drosha is found restricted to the cell body. These findings suggest that specific pre-miRNAs are selected for localization into distal axons of sensory neurons and are presumably processed to mature miRNAs in response to extracellular stimuli. This study supports the notion that local miRNA biogenesis effectively provides another level of temporal control for local protein synthesis in axons. PMID- 25919948 TI - Analysis of the Gas Phase Kinetics Active during GaN Deposition from NH3 and Ga(CH3)3. AB - The results of a systematic investigation aimed at determining the dominant gas phase chemistry active during GaN MOVPE are reported and discussed in this work. This study was performed developing a thermodynamic database including the most stable GaN gas phase species and a gas phase mechanism that could efficiently describe their interconversion kinetics. The thermodynamic data and the kinetic mechanism were calculated combining density functional theory and ab initio simulations. Structures and vibrational frequencies of reactants and transition states were determined at the M062X/6-311+G(d,p) level, while energies were computed at the ROCBS-QB3 level. Rate constants were calculated using transition state theory using the rigid rotor - harmonic oscillator approximation and considering the possible degeneration of internal motions in torsional rotations. The thermodynamic analysis indicated that the Ga gas phase species formed in the highest concentration at the standard GaN deposition temperature (1300 K) is GaNH2, followed by GaH and Ga. The diatomic GaN gas phase species, often considered to be the main precursor to the film growth, is predicted to be unstable with respect to GaNH2. Among the gas phase species containing two Ga atoms, the most stable are GaNHGaH(NH2)3, GaNHGaH2(NH2)2, and GaNHGa(NH2)4, thus indicating that the substitution of the methyl groups of the precursor with H or amino groups is thermodynamically favored. Several kinetic routes leading to the formation of these species were examined. It was found that the condensation of Ga(R1)x(R2)3-x species, with R1 and R2 being either CH3, NH2, or H, is a fast process, characterized by the formation of a precursor state whose decomposition to products requires overcoming submerged energy barriers. It is suggested that these species play a key role in the formation of the first GaN nuclei, whose successive growth leads to the formation of GaN powders. A kinetic analysis performed using a fluid dynamic model allowed us to identify the main reactive routes of this complex system. PMID- 25919949 TI - Bronchial thermoplasty: a non-pharmacological approach. AB - INTRODUCTION: Asthma is a chronic inflammatory disorder of the airway characterized by the episodic symptoms of breathlessness, wheezes and cough. Even with the use of maximum anti-asthmatic pharmacological treatment sometimes it remains uncontrolled. For such patients, bronchial thermoplasty is the new mode of treatment. OBJECTIVE: To review published article on bronchial thermoplasty. METHODS: We identified 102 English articles on PubMed, and 56 were excluded by the abstract. The remaining articles were retrieved for full-text detailed evaluation by authors, and 28 relevant articles were selected for final review. RESULTS: Bronchial thermoplasty is the radiofrequency ablation of the airway smooth muscle with the help of flexible fiberoptic bronchoscope. It reduces the smooth muscle mass of the bronchial wall and decreases its contractility. CONCLUSION: Bronchial thermoplasty causes improvement in the quality of life, and causes reduction in the emergency room visit and exacerbation due to asthma. Long term safety has been established by various prospective studies. PMID- 25919950 TI - Troubling practices of control: re-visiting Hannah Arendt's ideas of human action as praxis of the unpredictable. AB - In this article, Hannah Arendt's concept of action will be used to problematize current transformations of the health care sector and examine some responses by ethicists in light of those transformations. The sphere of human interaction that should typify health care work is identified as an action of unpredictable praxis in contrast to controllable procedures and techniques which increasingly take place in the health care sector. PMID- 25919951 TI - The transcriptional cofactor TRIM33 prevents apoptosis in B lymphoblastic leukemia by deactivating a single enhancer. AB - Most mammalian transcription factors (TFs) and cofactors occupy thousands of genomic sites and modulate the expression of large gene networks to implement their biological functions. In this study, we describe an exception to this paradigm. TRIM33 is identified here as a lineage dependency in B cell neoplasms and is shown to perform this essential function by associating with a single cis element. ChIP-seq analysis of TRIM33 in murine B cell leukemia revealed a preferential association with two lineage-specific enhancers that harbor an exceptional density of motifs recognized by the PU.1 TF. TRIM33 is recruited to these elements by PU.1, yet acts to antagonize PU.1 function. One of the PU.1/TRIM33 co-occupied enhancers is upstream of the pro-apoptotic gene Bim, and deleting this enhancer renders TRIM33 dispensable for leukemia cell survival. These findings reveal an essential role for TRIM33 in preventing apoptosis in B lymphoblastic leukemia by interfering with enhancer-mediated Bim activation. PMID- 25919955 TI - Technology of Single-Incision Laparoscopic Surgery in Treatment of Inguinal Hernia in Small Babies. AB - PURPOSE: The aim of this study was the comparison of single-port and multiport laparoscopic methods for the treatment of inguinal hernia in children during the first 3 months of life. SUBJECTS AND METHODS: Between January 2002 and December 2012, we performed 260 laparoscopic operations in neonates and infants with the diagnosis of inguinal hernia. Surgical procedures were single-port endoscopic herniorraphy (Group I; 180 patients) and multiport laparoscopic herniorraphy (Group II; 80 patients). The two groups were compared for demographics of patients, operative report, and early and late postoperative outcomes. RESULTS: We applied the single-port laparoscopic method for correction of inguinal hernia in small babies. The mean operative time (duration of one-sided and bilateral repair) in Group I was 16 minutes, whereas the mean duration of the operation in Group II was 15.73 minutes. The number of doses of postoperative analgesia was 1.19 and 1.22, respectively. The length of hospital stay was 8.12 hours in Group I and 8.27 hours in Group II. No differences between the two groups were recorded in the follow-up period: no recurrence in either group and hydrocele formation in only 1 patient in Group II. CONCLUSIONS: There are similar functional results in treatment of inguinal hernia in babies during the first 3 months of the life using single- and multiport laparoscopy. Scarless cosmetic results are seen in the single-incision laparoscopic surgery group. PMID- 25919954 TI - Coadministration of Vascular Disrupting Agents and Nanomedicines to Eradicate Tumors from Peripheral and Central Regions. AB - A strategy for enhancing the treatment efficacy of nanomedicines within the central region of solid tumors is developed by combining nanomedicines and free small-molecule vascular disrupting agents (VDAs). The nanomedicines (cis diamminedichloroplatinum-loaded nanoparticles) primarily target cells at the tumor periphery whereas the free small-molecule VDA (combretastatin A4 disodium phosphate) efficiently kills the cancer cells within the central regions of the tumor. PMID- 25919953 TI - Related factors for worsening renal function following percutaneous transluminal renal angioplasty (PTRA) in patients with atherosclerotic renal artery stenosis. AB - PURPOSE: To identify candidates for PTRA in terms of the preservation of renal function, we herein evaluated factors that caused worsening renal function (WRF) after PTRA. METHODS: We evaluated 92 patients with atherosclerotic renal artery stenosis (mean age 70.7 +/- 8.4 years). WRF was defined as a >=0.3 mg/dL increase in creatinine levels after PTRA compared to before PTRA. RESULTS: A total of 92 patients exhibited non-WRF 83 (90.2%), WRF 9 (9.8%). Significant differences were observed in serum creatinine levels between two groups both before (non-WRF 1.34 +/- 0.49 versus WRF 1.70 +/- 0.68 mg/dL, p = 0.0462) and after PTRA (non-WRF 1.31 +/- 0.43 versus WRF 2.42 +/- 1.12 mg/dL, p < 0.0001). Patients with WRF had higher comorbidity rate of diabetes mellitus (DM) (non-WRF 31.3% versus WRF 66.7%, p = 0.0345) and proteinuria (non-WRF 27.7% versus WRF 66.7%, p = 0.0169), and had higher systolic blood pressure (non-WRF 143.6 +/- 18.7 versus WRF 157.1 +/- 19.9 mmHg, p = 0.0436), higher plasma B-type natriuretic peptide (BNP) levels, and larger left atrial and left ventricular end-diastolic dimensions before PTRA. Patients with WRF had a higher rate of taking diuretics (non-WRF 27.7% versus WRF 66.7%, p = 0.0169) after PTRA. Multiple logistic regression analysis revealed that comorbidity of DM was an independent related factor for WRF (comorbidity of DM, yes: OR 31.0, 95% CI 2.44-1024.62, p = 0.0055). CONCLUSIONS: Comorbidity of DM, coexisting of proteinuria, high creatinine level, high blood pressure, high BNP levels, and large left atrial and ventricular dimensions were related to WRF after PTRA in patients with atherosclerotic renal artery stenosis. PMID- 25919956 TI - Exome sequencing uncovers hidden pathways in familial and sporadic ALS. PMID- 25919957 TI - Stem cells: slow and steady wins the race. PMID- 25919958 TI - Strength in more than numbers. PMID- 25919959 TI - Divide and conquer: strategic decision areas. PMID- 25919960 TI - Good vibrations with deep brain stimulation. PMID- 25919961 TI - The cost of brain structure. PMID- 25919964 TI - Do you know your guidelines? An initiative of the American Head and Neck Society's Education Committee. AB - Clinical practice guidelines abound in medicine. Head and neck oncology is no exception. Well-crafted guidelines can promote evidence-based diagnosis, treatment, and followup for patients with head and neck cancers. Recognizing this, the Education Committee of the American Head and Neck Society has developed a series of articles to review clinical practice guidelines germane to our field, the evidence behind them, and opportunities for improvement and better adherence to them. This paper serves to introduce the concepts relevant to guideline development and clinical application. It serves as a framework for the topical guideline papers that will follow. PMID- 25919963 TI - Family Cohesion and Moderate-to-Vigorous Physical Activity Among Mexican Origin Adolescents: A Longitudinal Perspective. AB - BACKGROUND: Existing racial/ethnic disparities in physical activity during childhood increase Hispanics' risk of developing chronic diseases, which serves to increase health disparities. This study examined associations of family cohesion and conflict with self-reported moderate-to-vigorous physical activity (MVPA), controlling for psychosocial covariates such as subjective social status, anxiety, and sensation-seeking. METHODS: 1000 Mexican origin adolescents reported their MVPA levels approximately 2 years apart. Psychosocial covariates, family cohesion and conflict were measured at the first assessment. Generalized Linear Models were used to prospectively examine the relationship between family cohesion and conflict and subsequent MVPA based on 711 participants who had low levels of baseline MVPA. RESULTS: 35% of boys and 24% of girls reported adequate MVPA levels at follow-up; girls were less likely to report adequate MVPA (RR = 0.76; 95% CI: 0.61-0.93) than boys. Overall, family cohesion was associated with MVPA (P = .01), but family cohesion was not (P = .41). Gender-based analyses revealed that adequate MVPA was associated with family cohesion (RR = 1.40; 95% CI: 1.03-1.88), sensation seeking (RR = 1.05; 95% CI: 1.00-1.10), and age (RR = 0.85; 95% CI: 0.74-0.98) among girls and with subjective social status (RR = 1.20; 95% CI: 1.08-1.33) among boys. CONCLUSIONS: The family social environment and gender differences should be addressed in health promotion programs targeting MVPA. PMID- 25919962 TI - What the orbitofrontal cortex does not do. AB - The number of papers about the orbitofrontal cortex (OFC) has grown from 1 per month in 1987 to a current rate of over 50 per month. This publication stream has implicated the OFC in nearly every function known to cognitive neuroscience and in most neuropsychiatric diseases. However, new ideas about OFC function are typically based on limited data sets and often ignore or minimize competing ideas or contradictory findings. Yet true progress in our understanding of an area's function comes as much from invalidating existing ideas as proposing new ones. Here we consider the proposed roles for OFC, critically examining the level of support for these claims and highlighting the data that call them into question. PMID- 25919966 TI - Arterial stiffening and systemic endothelial activation induced by smoking: The role of COX-1 and COX-2. AB - BACKGROUND: Arterial stiffness is an established predictor of cardiovascular risk. We explored the effects of acute smoking on arterial stiffness, systemic inflammation and endothelial activation in chronic smokers and the contribution of cyclooxygenases-1 and 2 (COX-1 and COX-2). METHODS AND RESULTS: In a randomized, double-blind, cross-over study, we investigated in 28 young smokers the vascular and systemic effects of smoking one cigarette, 3h after receiving 1000 mg of aspirin (a non-selective COX-1 and COX-2 inhibitor) or placebo (aspirin substudy), or 200 mg of celecoxib (a selective COX-2 inhibitor) or placebo (celecoxib substudy). Smoking increased carotid-femoral pulse wave velocity (PWV, a marker of aortic stiffness), indicating an adverse effect on arterial elastic properties. Similarly, circulating levels of asymmetric dimethylarginine (ADMA) were increased after smoking. Aspirin fully prevented the smoking-induced increase of PWV after smoking. In contrast, celecoxib only partially prevented the smoking-induced increase of PWV. Both aspirin and celecoxib prevented to a similar extent the increase of ADMA levels after smoking. CONCLUSIONS: Smoking one cigarette is associated with a deterioration of arterial stiffness and with systemic endothelial activation in chronic smokers. Both COX-1 and COX-2, but primarily COX-1, mediate these unfavorable effects of smoking. PMID- 25919965 TI - Nitric oxide mediates bleomycin-induced angiogenesis and pulmonary fibrosis via regulation of VEGF. AB - Pulmonary fibrosis is a progressive lung disease hallmarked by increased fibroblast proliferation, amplified levels of extracellular matrix deposition and increased angiogenesis. Although dysregulation of angiogenic mediators has been implicated in pulmonary fibrosis, the specific rate-limiting angiogenic markers involved and their role in the progression of pulmonary fibrosis remains unclear. We demonstrate that bleomycin treatment induces angiogenesis, and inhibition of the central angiogenic mediator VEGF using anti-VEGF antibody CBO-P11 significantly attenuates bleomycin-induced pulmonary fibrosis in vivo. Bleomycin induced nitric oxide (NO) was observed to be the key upstream regulator of VEGF via the PI3k/Akt pathway. VEGF regulated other important angiogenic proteins including PAI-1 and IL-8 in response to bleomycin exposure. Inhibition of NO and VEGF activity significantly mitigated bleomycin-induced angiogenic and fibrogenic responses. NO and VEGF are key mediators of bleomycin-induced pulmonary fibrosis, and could serve as important targets against this debilitating disease. Overall, our data suggests an important role for angiogenic mediators in the pathogenesis of bleomycin-induced pulmonary fibrosis. PMID- 25919967 TI - Internet use and well-being in older adults. AB - The Internet has become an important social context in the lives of older adults. Extant research has focused on the use of the Internet and how it influences well being. However, conflicting findings exist. The purpose of the study was to develop an integrative research model in order to determine the nature of the relationships among Internet use, loneliness, social support, life satisfaction, and psychological well-being. Specifically, loneliness and social support were tested as potential mediators that may modify the relationship between Internet use and indicators of well-being. Data from the U.S. Health and Retirement Study (HRS) were used, and the association among Internet use, social support, loneliness, life satisfaction, and psychological well-being was explored. The sample consisted of 5,203 older adults (aged 65 years and older). The results indicated that higher levels of Internet use were significant predictors of higher levels of social support, reduced loneliness, and better life satisfaction and psychological well-being among older adults. PMID- 25919968 TI - Autofluorescence from NADH Conformations Associated with Different Metabolic Pathways Monitored Using Nanosecond-Gated Spectroscopy and Spectral Phasor Analysis. AB - Cellular NADH conformation is increasingly recognized as an endogenous optical biomarker and metabolic indicator. Recently, we reported a real-time approach for tracking metabolism on the basis of the quantification of UV-excited autofluorescence spectrum shape. Here, we use nanosecond-gated spectral acquisition, combined with spectrum-shape quantification, to monitor the long excited-state lifetime autofluorescence (usually associated with protein-bound NADH conformations) separately from the autofluorescence signal as a whole. We observe that the autofluorescence response induced by two NADH-oxidation inhibitors-cyanide and ethanol-are similar in Saccharomyces cerevisiae when monitored using time-integrated detection but easily distinguished using time gated detection. Results are consistent with the observation of multiple NADH conformations as assessed using spectral phasor analysis. Further, because well known oxidation inhibitors are used, changes in spectrum shape can be associated with NADH conformations involved in the different metabolic pathways, giving bioanalytic utility to the spectral responses. PMID- 25919969 TI - The role of EBUS-TBNA and standard bronchoscopic modalities in the diagnosis of sarcoidosis. AB - BACKGROUND AND AIMS: Endobronchial ultrasound-guided transbronchial needle aspiration (EBUS-TBNA) is an accurate and minimally invasive technique that has been shown to have excellent diagnostic yield in the diagnosis of mediastinal and hilar lymphadenopathy. However, endoscopic bronchial biopsy (EBB) and transbronchial lung biopsy (TBLB) are still the standard method for making a pathologic diagnosis of sarcoidosis. The aim of this study was to compare the diagnostic yield of EBUS-TBNA and TBLB through a flexible bronchoscope in patients with stage I and II sarcoidosis. METHODS: A total of 653 patients with suspected stage I and II sarcoidosis were included in this retrospective study. After radiological assessment, patients were qualified to bronchoscopy. Patients underwent sequential EBUS-TBNA followed by TBLB and/or EBB. In all patients, 1056 biopsies from mediastinal lymph nodes group were taken. RESULTS: In all of the biopsied lymph nodes, positive results were obtained in 549 patients (84%). In 180 patients with stage II TBLB, a biopsy was taken from affected part of the lung. Positive results were found in 79 patients (43.9%). EBB was performed in 340 patients, with a positive result in 101 (29.7%). Mediastinoscopy was performed in 60 patients (9.2%) with a negative result in EBUS-TBNA, TBLB and/or EBB. Non-caseating granulomas were found in 48 patients. The sensitivity of TBLB technique alone was significantly lower at 43.9% (79/180) (P < 0.001). The sensitivity of EBB was significantly lower than EBUS-TBNA and TBLB and reached 29.7% (101/340) (P < 0.0001, P < 0.003). The overall diagnostic accuracy for EBUS TBNA was 84%, and the combination of EBUS-TBNA with standard bronchoscopic techniques had a diagnostic accuracy of 89%. CONCLUSION: The diagnostic yield of the EBUS-TBNA for stage I and II sarcoidosis is clearly higher than for TBLB and EBB. The combination of EBUS-TBNA with standard bronchoscopic techniques is safe and feasible, and optimizes the diagnostic yield in patients with pulmonary sarcoidosis and enlarged intrathoracic lymph nodes. EBUS-TBNA in combination with standard bronchoscopy may be considered to be the first-line investigation in patients with suspected sarcoidosis and enlarged intrathoracic lymphadenopathy. PMID- 25919970 TI - Syntheses of Mononuclear and Dinuclear Aluminum Complexes Stabilized by Phenolato Ligands and Their Applications in the Polymerization of epsilon-Caprolactone: A Comparative Study. AB - A series of mono- and dinuclear aluminum alkyl complexes stabilized by phenolato ligands have been prepared through alkane elimination reactions. Treatment of piperazidine-bridged bis(phenol)s C4H8N2[1,4-(2-OH-3,5-Me2-C6H2CH2)2] (H2[ONNO](1)), C4H8N2[1,4-(2-OH-3-(t)Bu-5-Me-C6H2CH2)2] (H2[ONNO](2)), and C4H8N2[1,4-(2-OH-3,5-(t)Bu2-C6H2CH2)2] (H2[ONNO](3)) with 2.5-3 equiv of AlR3 (R = Me, Et) afforded dinuclear aluminum complexes (AlMe2)2[ONNO](1) (1), (AlMe2)2[ONNO](2) (2), (AlMe2)2[ONNO](3) (3), (AlEt2)2[ONNO](1) (4), (AlEt2)2[ONNO](2) (5), and (AlEt2)2[ONNO](3) (6), respectively. In order to compare the catalytic activities of these bimetallic complexes with their mononuclear counterparts, mono(phenolato) aluminum complexes AlMe2[ON](1) (7), AlMe2[ON](2) (8), AlMe2[ON](3) (9), AlEt2[ON](2) (10), and AlEt2[ON](3) (11) were synthesized from reactions of 1 equiv of AlMe3 or 2 equiv of AlEt3 with phenols that bear piperidine moieties, i.e., [2-(CH2NC5H10)-4,6-Me2-C6H2OH (H[NO](1)), 2 (CH2NC5H10)-4-Me-6-(t)Bu-C6H2OH (H[NO](2)), and 2-(CH2NC5H10)-4,6-(t)Bu2-C6H2OH (H[NO](3))], respectively. In comparison, reactions of H[NO](n) (n = 2, 3) with 0.5 equiv of AlEt3 led to the isolation of mononuclear monoalkyl complexes AlEt[NO](2)2 (12) and AlEt[NO](3)2 (13), respectively. All complexes have been characterized by elemental analysis and NMR spectroscopy, and the solid state structures of 5 complexes have been determined by X-ray diffraction analysis. The activities of both binuclear and mononuclear aluminum complexes in initiating the ring-opening polymerization (ROP) of epsilon-caprolactone have also been investigated and compared. In general, these phenolato-Al complexes showed high activities in initiating the ROP in the absence of alcohols. More importantly, dinuclear complexes have been found to be 2-8 times more active than their mononuclear counterparts, which provides evidence for the cooperation between two metal centers in the former. PMID- 25919971 TI - Meaning and Measurability of Single-Ion Activities, the Thermodynamic Foundations of pH, and the Gibbs Free Energy for the Transfer of Ions between Dissimilar Materials. AB - Considering the relationship between concentration and vapor pressure (or the relationship between concentration and fugacity) single-ion activity coefficients are definable in purely thermodynamic terms. The measurement process involves measuring a contact potential between a solution and an external electrode. Contact potentials are measurable by using thermodynamically reversible processes. Extrapolation of an equation to zero concentration and ionic strength enables determination of single-ion activity coefficients. Single-ion activities can be defined and measured without using any extra-thermodynamic assumptions, concepts, or measurements. This method could serve as a gold standard for the validation of extra-thermodynamic methods for determining single-ion activities. Furthermore, it places the concept of pH on a thermodynamically solid foundation. Contact potential measurements can also be used to determine the Gibbs free energy for the transfer of ions between dissimilar materials. PMID- 25919972 TI - Functional neuroimaging correlates of autobiographical memory deficits in subjects at risk for depression. AB - Overgeneral autobiographical memory (AM) manifests in individuals with major depressive disorder (MDD) tested during depressed (dMDD) or remitted phases (rMDD), and healthy individuals at high-risk (HR) for developing MDD. The current study aimed to elucidate differences in hemodynamic correlates of AM recall between rMDDs, HRs, and controls (HCs) to identify neural changes following previous depressive episodes without the confound of current depressed mood. HCs, HRs, and unmedicated rMDDs (n = 20/group) underwent fMRI while recalling AMs in response to emotionally valenced cue words. HRs and rMDDs recalled fewer specific and more categorical AMs relative to HCs. During specific AM recall, HRs had increased activity relative to rMDDs and HCs in left ventrolateral prefrontal cortex (VLPFC) and lateral orbitofrontal cortex. During positive specific AM recall, HRs and HCs had increased activity relative to rMDDs in bilateral dorsomedial prefrontal cortex (DMPFC) and left precuneus. During negative specific AM recall HRs and HCs had increased activity in left VLPFC and right DMPFC, while rMDDs had increased activity relative to HRs and HCs in right DLPFC and precuneus. Differential recruitment of medial prefrontal regions implicated in emotional control suggests experiencing a depressive episode may consequently reduce one's ability to regulate emotional responses during AM recall. PMID- 25919974 TI - From the editors. PMID- 25919975 TI - Response to Commentary by Fann et al. on "Enhancing the Characterization of Epistemic Uncertainties in PM2.5 Risk Analyses". PMID- 25919973 TI - Neurogenetic and epigenetic correlates of adolescent predisposition to and risk for addictive behaviors as a function of prefrontal cortex dysregulation. AB - As addiction professionals, we are becoming increasingly concerned about preteenagers and young adults' involvement with substance abuse as a way of relieving stress and anger. The turbulent underdeveloped central nervous system, especially in the prefrontal cortex (PFC), provides impetus to not only continue important neuroimaging studies in both human and animal models, but also to encourage preventive measures and cautions embraced by governmental and social media outlets. It is well known that before people reach their 20s, PFC development is undergoing significant changes and, as such, hijacks appropriate decision making in this population. We are further proposing that early genetic testing for addiction risk alleles will offer important information that could potentially be utilized by their parents and caregivers prior to use of psychoactive drugs by these youth. Understandably, family history, parenting styles, and attachment may be modified by various reward genes, including the known bonding substances oxytocin/vasopressin, which effect dopaminergic function. Well-characterized neuroimaging studies continue to reflect region specific differential responses to drugs and food (including other non-substance addictive behaviors) via either "surfeit" or "deficit." With this in mind, we hereby propose a "reward deficiency solution system" that combines early genetic risk diagnosis, medical monitoring, and nutrigenomic dopamine agonist modalities to combat this significant global dilemma that is preventing our youth from leading normal productive lives, which will in turn make them happier. PMID- 25919976 TI - Immunogenicity of 13-Valent Pneumococcal Conjugate Vaccine in Pediatric Patients with Inflammatory Bowel Disease. AB - BACKGROUND: There are only a few studies on immune response to pneumococcal vaccines in patients with inflammatory bowel disease (IBD); all of them assessed polysaccharide vaccines only. The aim of the study was to evaluate the immunogenicity and safety of 13-valent pneumococcal conjugate vaccine (PCV13) in IBD pediatric patients compared with healthy controls. METHODS: This was a multicenter, prospective, and controlled study on children and adolescents aged 5 to 18 years with IBD with no history of pneumococcal immunization. The subjects for the study belonged to one of the following groups: patients with IBD on no immunosuppressive therapy (group A), those on tumor necrosis factor agents or immunomodulators (group B), and healthy controls (group C). The study population received 1 intramuscular injection of PCV13. The primary outcome measure was adequate vaccine response defined as postvaccination titer >=0.35 MUg/mL to all 13 serotypes. Geometric mean titers and geometric mean titer rises were measured for all serotypes. The evidence of local and systemic adverse effects for 5 days after the vaccine was registered. RESULTS: A total of 178 subjects (122 patients and 56 controls) completed the study course. There was no significant difference in the rate of adequate vaccine response between patients with IBD and controls measured 4 to 8 weeks after vaccination (90.4% versus 96.5%, P = 0.5281). Children in group A had higher geometric mean titer rises than children in group B (P = 0.0369). There were no serious adverse events related to PCV13 during the study. CONCLUSIONS: PCV13 is both immunogenic and safe in pediatric patients with IBD. PMID- 25919977 TI - The Immunostimulatory Nature of NSAIDs in Inflammatory Bowel Disease. PMID- 25919979 TI - A similarity-based QSAR model for predicting acute toxicity towards the fathead minnow (Pimephales promelas). PMID- 25919978 TI - Pain as a predictor of heavy drinking and any drinking lapses in the COMBINE study and the UK Alcohol Treatment Trial. AB - AIMS: To test the association between pain and heavy drinking lapses during and following treatment for alcohol use disorders (AUD). DESIGN: Secondary data analysis of data from two clinical trials for AUD. SETTING AND PARTICIPANTS: Participants included 1383 individuals from the Combined Pharmacotherapies and Behavioral Interventions (COMBINE) Study in the United States [69.0% male, 76.8% non-Hispanic White average age=44.4, standard deviation (SD) = 10.2] and 742 individuals from the UK Alcohol Treatment Trial (UKATT) in the United Kingdom [74.1% male, 95.6% White, average age=41.6 (SD=10.1)]. MEASUREMENTS: Form-90 (a structured assessment interview) was used to assess the primary outcome: time to first heavy drinking day. The Short Form Health Survey and Quality of Life measures were used to assess pain interference and pain intensity. FINDINGS: Pain was a significant predictor of heavy drinking lapses during treatment in UKATT [odds ratio (OR)=1.19, 95% confidence interval (CI)=1.08, 1.32, P=0.0003] and COMBINE (OR=1.12, 95% CI=1.03, 1.21, P=0.009), and was a significant predictor of heavy drinking lapses following treatment in COMBINE (OR=1.163, 95% CI=1.15, 1.17, P<0.00001). After controlling for other relapse risk factors (e.g. dependence severity, self-efficacy, temptation, psychiatric distress), pain remained a significant predictor of heavy drinking lapses during treatment in UKATT (OR=1.19, 95% CI=1.06, 1.34, P=0.004) and following treatment in COMBINE (OR=1.44, 95% CI=1.07, 1.92, P=0.01). CONCLUSIONS: Among people treated for alcohol use disorder, being in physical pain appears to predict heavy drinking lapses during or after treatment. PMID- 25919980 TI - Longitudinal Strain by Speckle Tracking Echocardiography in Pediatric Heart Transplant Recipients. AB - INTRODUCTION: Heart transplant recipients are at risk for developing left ventricular (LV) dysfunction. While traditional echocardiographic parameters have limitations, speckle tracking echocardiography (STE) is a novel technique shown to be more sensitive and accurate in adult studies for evaluating ventricular systolic and diastolic function. DESIGN: Pediatric heart transplant recipients undergoing routine cardiac catheterization were included. Ratio of mitral early diastolic velocity-to-strain rate during early LV filling (E/SR(E)) and global longitudinal peak systolic strain (GLPSS) was measured by STE imaging. These were compared with wedge pressures by catheterization and traditional echocardiographic parameters. RESULTS: A total of 50 subjects (46% males) were included. Mean age of the subjects was 13.0 +/- 6.3 years and time since transplant was 4.1 years (range 0.2-17.1 years). While peak mitral inflow to late diastolic velocity (E/A ratio) was the only traditional diastolic function parameter having significant correlation with pulmonary capillary wedge pressure (PCWP) (r = 0.3; P = .3), STE-derived E/SR(E) had modest correlation with PCWP (r = 0.55; P < .01). Also, while most traditional systolic function parameters were normal, 12 subjects (24%) had GLPSS > -18%. Interestingly, subjects with coronary artery disease (n = 6) had significantly higher E/SR(E) (71.9 +/- 28.4) compared to subjects without (45.2 +/- 10.8; P < .001). CONCLUSION: Diastolic function parameters by STE imaging correlate better with gold standard PCWP measurement than traditional echocardiographic parameters. Also, utilizing STE, abnormalities of longitudinal LV systolic function may be more common than previously thought in pediatric heart transplant recipients without acute graft rejection, despite "normal" systolic function by traditional echocardiogram. PMID- 25919981 TI - Magnetic Zn (II) ion-imprinted polymer prepared by the surface imprinting technique and its adsorption properties. AB - A novel magnetic Zn (II) ion-imprinted polymer was prepared by the surface ion imprinted technique by using magnetic Fe3O4@SiO2 microspheres as supporter, methacrylic acid and salicylaldoxime as monomers, ethylene glycol dimethacrylate as the crosslinker. The products were characterized by Fourier transform infrared, X-ray photoelectron spectrometer, vibrating sample magnetometer and scanning electron microscope. The adsorption experiments showed that the imprinted polymer was employed successfully in comparison with non-imprinted polymer. When the temperature was in a range of 291-297 K, the maximum adsorption was about 52.69 mg g(-1) with an optimal pH 6.0 for an equilibrium time of 40 min. The imprinted polymer possessed high selectivity and specific recognition towards Zn (II). The Langmuir adsorption model was more favourable than the Freundlich or the Temkin adsorption model. Thermodynamic experiment showed that the adsorption was a spontaneous and endothermic process for Zn (II). The mechanism for Zn (II) adsorption on the imprinted polymer was investigated. PMID- 25919982 TI - An iridium oxide microelectrode for monitoring acute local pH changes of endothelial cells. AB - pH sensors were fabricated by anodically electrodepositing iridium oxide films (AEIROFs) onto microelectrodes on chips and coated with poly(ethyleneimine) (PEI) for mechanical stability. These demonstrate super-Nernstian response to pH from pH 4.0 to 7.7 in chloride-free phosphate buffer. The surface of the chip was coated with fibronectin for the attachment of porcine aortic endothelial cells (PAECs). The working capability of the pH sensor for monitoring acute local pH changes was investigated by stimulating the PAECs with thrombin. Our results show that thrombin induced acute extracellular acidification of PAECs and dissolution of fibronectin, causing the local pH to decrease. The use of PD98059, a mitogen activated protein kinase (MAPK) inhibitor, reduced extracellular acidification and an increase in local pH was observed. This study shows that our pH sensors can facilitate the investigation of acute cellular responses to stimulation by monitoring the real-time, local pH changes of cells attached to the sensors. PMID- 25919983 TI - Introduction. Kasha - memories. PMID- 25919984 TI - Trends and predictors of resection of the primary tumor for patients with stage IV colorectal cancer. AB - BACKGROUND AND OBJECTIVES: Over 130,000 patients are diagnosed with colorectal cancer annually, with approximately 20% presenting with unresectable metastatic disease. Recent consensus guidelines recommend against primary tumor resection for asymptomatic patients with unresectable metastases. Our goal was to examine the trends and predictors of surgical resection. METHODS: Cases of colorectal cancer with synchronous metastases diagnosed between 1988-2010 were identified using the Surveillance, Epidemiology and End Results (SEER) Database. Associations between resection and clinicopathologic variables were sought using univariate and multivariate logistic regression. RESULTS: Overall, 68% of patients with synchronous metastatic colorectal cancer underwent primary tumor resection. Resection rates were as high as 76% in the earliest time period (1988 1992) and steadily dropped to 60% in the most recent period (2008-2010). Socioeconomic factors associated with resection on univariate analysis included age, race, gender, marital status, insurance status, and geographic region. Clinicopathologic characteristics associated with resection included tumor location, grade, size, and CEA level. In the multivariate model, gender, geographic region, insurance status, tumor location, grade and CEA level were independent predictors of primary tumor resection. CONCLUSIONS: Surgical resection of the primary site remains common practice for patients with synchronous metastatic colorectal cancer. Treatment disparities are associated with socioeconomic as well as clinicopathologic factors. PMID- 25919985 TI - Simultaneous silence organizes structured higher-order interactions in neural populations. AB - Activity patterns of neural population are constrained by underlying biological mechanisms. These patterns are characterized not only by individual activity rates and pairwise correlations but also by statistical dependencies among groups of neurons larger than two, known as higher-order interactions (HOIs). While HOIs are ubiquitous in neural activity, primary characteristics of HOIs remain unknown. Here, we report that simultaneous silence (SS) of neurons concisely summarizes neural HOIs. Spontaneously active neurons in cultured hippocampal slices express SS that is more frequent than predicted by their individual activity rates and pairwise correlations. The SS explains structured HOIs seen in the data, namely, alternating signs at successive interaction orders. Inhibitory neurons are necessary to maintain significant SS. The structured HOIs predicted by SS were observed in a simple neural population model characterized by spiking nonlinearity and correlated input. These results suggest that SS is a ubiquitous feature of HOIs that constrain neural activity patterns and can influence information processing. PMID- 25919986 TI - Additional donepezil treatment for patients with geriatric depression who exhibit cognitive deficit during treatment for depression. AB - BACKGROUND: Depression is a frequent comorbid condition in patients with Alzheimer's disease (AD). In the present study, we reported the effect of additional donepezil treatment for patients with geriatric depression who exhibited cognitive deficit and were diagnosed with AD during treatment for depression. METHODS: The present retrospective study investigated 14 AD outpatients who were diagnosed with geriatric depression at first and received antidepressant treatment. When apparent cognitive decline was observed, all of them were diagnosed with AD and received donepezil (5 mg/day) for at least 1 year. All patients underwent periodic examination of cognitive function (Mini Mental State Examination, Rorschach Cognitive Index) and clinical evaluation (Clinical Dementia Rating). The 14 patients were classified into three groups according to their treatment course: (i) 'A' group, patients who showed cognitive impairment during a long course of treatment for depression; (ii) 'B' group, patients who showed cognitive impairment at an early stage of treatment for depression and started to take additional donepezil at least 20 months after the first examination; and (iii) 'C' group, patients who showed cognitive impairment at an early stage of treatment for depression and began taking additional donepezil within 10 months of the first examination. The clinical feature and treatment effects were examined for each group. RESULTS: At 1 and 2 years after the start of treatment, the proportion of patients who had improved or maintained their Clinical Dementia Rating score was higher in 'A' and 'C' groups than in 'B' group. In 'B' group, additional donepezil treatment commenced later than in the other groups. Therefore, donepezil had an insufficient curative effect. CONCLUSION: The results of this study suggested that early induction of donepezil treatment was necessary when apparent cognitive decline was identified during the treatment of geriatric depression. PMID- 25919989 TI - Electromechanical Response from LaAlO3/SrTiO3 Heterostructures. AB - LaAlO3 ultrathin films, 10 unit cells in thickness, have been deposited epitaxially on TiO2-terminated (001) SrTiO3 substrates with various O2 pressures. Electromechanical response from the LaAlO3/SrTiO3 heterostructures is studied using combined piezoresponse force microscopy, electrostatic force microscopy, and scanning Kelvin probe microscopy. Oxygen vacancies are found to be responsible for the observed piezoelectric response but only for samples deposited with an oxygen pressure lower than 10(-5) mbar. However, ambient humidity is demonstrated to have a significant effect on the electromechanical response. The observations are discussed in terms of modulations on the intrinsic electrostriction in LAO/STO by an electric field induced by nonuniform distribution of either oxygen vacancies in the bulk or ionic adsorbates on the surface of LAO. PMID- 25919990 TI - The premonitory phase of migraine--what can we learn from it? AB - This review aims to understand the prevalence of premonitory symptoms in migraine, postulate their mechanisms, and compare these with functional imaging studies. A thorough literature review was conducted using PubMed for prevalence studies of premonitory symptoms in migraine and functional imaging studies in the premonitory phase. The majority of studies have been retrospective reporting a prevalence of 7-88% for premonitory symptoms in migraine. Only one study has investigated premonitory symptoms prospectively and used preselected patients with recognized premonitory symptoms. The majority of patients were able to predict correctly the onset of migraine headache. Only one functional imaging study has been conducted in the premonitory phase that showed activation of posterolateral hypothalamus, midbrain tegmental area and substantia nigra, periaqueductal gray, dorsal pons, and various cortical areas including occipital, temporal, and prefrontal cortex. Subgroup analysis of patients with photophobia more than without photophobia in the premonitory phase showed activation of the occipital cortex. Comparison of patients with nausea more than without nausea in the premonitory phase showed activation in upper dorsal medulla and periaqueductal gray. Premonitory symptoms are common in migraine, although the true prevalence cannot be stated with certainty in the absence of prospective studies in unselected patients. Hypothalamic involvement can explain many of the premonitory symptoms. Activation of the the brainstem structures and hypothalamus before pain suggests a pivotal role of these structures in the pathogenesis of migraine. Hypersensitivity to light and occurrence of nausea in migraine is associated with activation of central brain structures involved in these pathways, and this can occur in the absence of pain. PMID- 25919991 TI - Anatomy and humanity: Examining the effects of a short documentary film and first anatomy laboratory experience on medical students. AB - Medical students begin their education inside a laboratory dissecting cadavers to learn human gross anatomy. Many schools use the course experience as a way to instill empathy and some have begun integrating video and recorded interviews with body donors to humanize the experience, but their impact has yet to be measured. This study examines the effects of a brief documentary film and the initial cadaver encounter on student perceptions and attitudes towards the laboratory experience. A pre-test, exposure, post-test design was used with 77 first-year medical students at the University of Central Florida. A previously validated questionnaire was adapted to measure attitudes, emotions, initial reaction to cadaver, perception of the donor as a person, and impressions of the film. An online questionnaire was completed before the first day of laboratory, in which students watched the film Anatomy and Humanity and handled their respective cadavers (no dissection was performed). The post-test was administered immediately following the activities of the first laboratory day. Results indicate an increase in negative attitudes towards dissection, but a more positive initial reaction to the cadaver than originally anticipated. Students also experienced a decrease in emotions like sadness and guilt regarding anatomy laboratory and were less likely to view the cadaver as a once-living person. Findings suggest a higher comfort level, but also greater detachment toward the cadavers from day one despite the video intervention. These results provide novel insight that may aid other interventions aimed at promoting humanism in the anatomy laboratory experience. PMID- 25919992 TI - Neuroprotection of medial septal cholinergic neurons by memantine after intralateral septal injection of Abeta1-40. AB - Alzheimer's disease (AD) is a progressive disorder of the brain that leads to memory loss, dementia, and death. Several lines of evidence suggest that the accumulation of amyloid-beta (Abeta) peptides may trigger the dysfunction and degeneration observed in the AD brain. The basal forebrain, including the septal region, which regulates the excitability of the hippocampus and neocortex, is affected early in AD because its neurons are vulnerable to Abeta peptides. In addition, connections between lateral and medial septal regions (medial septum and diagonal band of Broca) have been demonstrated in previous studies. To demonstrate the involvement of excitotoxicity in Abeta-induced septal damage, we compared rats injected with Abeta1-40 into the lateral septal region structure with rats treated with memantine (a noncompetitive NMDA receptor antagonist), before, during, and after Abeta1-40 injection. Medial septal cholinergic neurons were immunochemically identified and their numbers were estimated using Image J cell count. Our results show that Abeta1-40-treated animals have a significantly low number of medial septum and diagonal band of Broca cholinergic neurons compared with the Abeta/memantine-treated group. PMID- 25919993 TI - Lifelong parental voluntary wheel running increases offspring hippocampal Pgc 1alpha mRNA expression but not mitochondrial content or Bdnf expression. AB - When exercise is initiated during pregnancy, offspring of physically active mothers have higher hippocampal expression of brain-derived neurotrophic factor (Bdnf) and other plasticity-associated and mitochondria-associated genes, resulting in hippocampal structural and functional adaptations. In the present study, we examined the effects of lifelong parental voluntary wheel running (before, during, and after pregnancy) on offspring hippocampal mRNA expression of genes implicated in the exercise-induced improvement of cognitive function. C57BL/6 mice were individually housed at 8 weeks of age with (EX, n=20) or without (SED, n=20) access to a computer-monitored voluntary running wheel for 12 weeks before breeding. EX breeders maintained access to the voluntary running wheel throughout breeding, pregnancy, and lactation. Male offspring were housed in sedentary cages, regardless of the parental group, and were killed at 8 (n=18) or 28 weeks (n=19). PCR was used to assess mRNA expression of several genes and mitochondrial content (ratio of mitochondrial to nuclear DNA) in hippocampal homogenates. We found significantly higher peroxisome proliferator-activated receptor gamma coactivator 1 alpha (Pgc-1alpha) mRNA expression in EX offspring compared with SED offspring at 8 weeks (P=0.04), although the effect was no longer present at 28 weeks. There was no difference in mitochondrial content or expression of Bdnf or any other mRNA target between offspring at 8 and 28 weeks. In contrast to exercise initiated during pregnancy, parental voluntary physical activity initiated early in life and maintained throughout pregnancy has little effect on offspring mRNA expression of genes implicated in exercise-induced hippocampal plasticity. PMID- 25919994 TI - Autonomous assembly of epithelial structures by subrenal implantation of dissociated embryonic inner-ear cells. AB - Microenvironment and cell-cell interactions play an important role during embryogenesis and are required for the stemness and differentiation of stem cells. The inner-ear sensory epithelium, containing hair cells and supporting cells, is derived from the stem cells within the otic vesicle at early embryonic stages. However, whether or not such microenvironment or cell-cell interactions within the embryonic otic tissue have the capacity to regulate the proliferation and differentiation of stem cells and to autonomously reassemble the cells into epithelial structures is unknown. Here, we report that on enzymatic digestion and dissociation to harvest all the single cells from 13.5-day-old rat embryonic (E13.5) inner-ear tissue as well as on implantation of these cells under renal capsules; the dissociated cells are able to reassemble themselves to form epithelial structures as early as 7 days after implantation. By 25 days after implantation, more mature epithelial structures are formed. Immunostaining with cell-type-specific markers reveals that hair cells and supporting cells are not only formed, but are also well aligned with the hair cells located in the apical layer surrounded by the supporting cells. These findings suggest that microenvironment and cell-cell interactions within the embryonic inner-ear tissue have the autonomous signals to induce the formation of sensory epithelial structures. This method may also provide a useful system to study the potential of stem cells to differentiate into hair cells in vivo. PMID- 25919995 TI - The cochlear size of bats and rodents derived from MRI images and histology. AB - From the evolutionary perspective, the ear of each animal species is built for effective processing of the biologically relevant signals used for communication and acoustically guided orientation. Because the sound pulses used by echolocating bats for orientation and rodents for communication are quite different, the basic design of the mammalian auditory system commonly shared by echolocating bats must be specialized in some manner to effectively process their species-specific sounds. The present study examines the difference in the cochlea of these animal species using MRI images and histological techniques. We report here that, although all these animal species share a similar cochlear structure, they vary in their cochlear size and turns. Bats using constant frequency frequency-modulated pulses (CF-FM bats) and frequency-modulated pulses (FM bats) for echolocation have a larger cochlear size and more cochlear turns than rodents (mice and rats). However, CF-FM bats have the largest cochlear size and most cochlear turns. This difference in cochlear size and turns of these animal species is discussed in relation to their biologically relevant sounds and acoustic behavior. PMID- 25919996 TI - Right-ear advantage drives the link between olivocochlear efferent 'antimasking' and speech-in-noise listening benefits. AB - The mammalian cochlea receives feedback from the brainstem medial olivocochlear (MOC) efferents, whose putative 'antimasking' function is to adjust cochlear amplification and enhance peripheral signal detection in adverse listening environments. Human studies have been inconsistent in demonstrating a clear connection between this corticofugal system and behavioral speech-in-noise (SIN) listening skills. To elucidate the role of brainstem efferent activity in SIN perception, we measured ear-specific contralateral suppression of transient evoked otoacoustic emissions (OAEs), a proxy measure of MOC activation linked to auditory learning in noisy environments. We show that suppression of cochlear emissions is stronger with a more basal cochlear bias in the right ear compared with the left ear. Moreover, a strong negative correlation was observed between behavioral SIN performance and right-ear OAE suppression magnitudes, such that lower speech reception thresholds in noise were predicted by larger amounts of MOC-related activity. This brain-behavioral relation was not observed for left ear SIN perception. The rightward bias in contralateral MOC suppression of OAEs, coupled with the stronger association between physiological and perceptual measures, is consistent with left-hemisphere cerebral dominance for speech language processing. We posit that corticofugal feedback from the left cerebral cortex through descending MOC projections sensitizes the right cochlea to signal in-noise detection, facilitating figure-ground contrast and improving degraded speech analysis. Our findings demonstrate that SIN listening is at least partly driven by subcortical brain mechanisms; primitive stages of cochlear processing and brainstem MOC modulation of (right) inner ear mechanics play a critical role in dictating SIN understanding. PMID- 25919997 TI - Hyperbilirubinemia and phototherapy in newborns: Effects on cardiac autonomic control. AB - BACKGROUND: Neonatal jaundice and its phototherapeutic treatment can lead to several side effects involving activation of autonomic control mechanisms. AIM: The aims of this study are to investigate the autonomic nervous system changes in icteric neonates using heart rate variability (HRV) and to assess the effect of phototherapy on short-term heart rate dynamics as an indicator of autonomic nervous control of cardiovascular system. METHODS: HRV recordings from 20 icteric full-term neonates before, during and after phototherapy and from 20 healthy controls were analyzed. In addition to traditional time and frequency domain measures, heart rate complexity parameters including normalized complexity index (NCI), normalized unpredictability index (NUPI), pattern classification indices (0V%, 1V%, 2LV%, 2UV%) and irreversibility index (P%) on four time scales were evaluated. All measures were derived from data segments of 1000 RR intervals. RESULTS: The analysis revealed higher values of 1V%, 2LV%, and lower P% in neonates with hyperbilirubinemia compared to controls. While HRV magnitude did not change, mean heart rate increased during and after the phototherapy. Nonlinear analysis showed a decrease of complexity, unpredictability and pattern classification measures 2LV% and 2UV%. In contrast, 0V% and irreversibility index P% were increased during and at least 30min after phototherapy. CONCLUSION: The results suggest a shifted autonomic balance in icteric neonates compared to the controls and its further alterations during phototherapy. As the nonlinear HRV parameters are independent of the linear methods, they can provide new information about the cardiac regulatory mechanisms and their changes in neonates. PMID- 25919998 TI - Neonatal creatinemia trends as biomarker of subsequent cognitive outcome in extremely low birth weight neonates. AB - BACKGROUND AND AIMS: Serum creatinine is traditionally used as a marker of renal function in neonates and relates to gestational age and disease severity in extremely low birth weight (ELBW) infants. Creatinine is commonly used as a biomarker for early morbidity, but we aim to compare postnatal creatinemia trends as a biomarker for subsequent cognitive outcome. We hypothesize that impaired microcirculation not only in the kidney, but also in general (i.e. brain development) can explain this possible link. STUDY DESIGN AND OUTCOME MEASURES: A cohort of ELBW infants was analyzed by Bayley Scales of Infant Development (BSID II) at the corrected age of 2years old. Besides other perinatal indicators, neonatal creatinemia trends of survivors (n=140) and BSID scores (n=96) are compared and analyzed using optimal matching analysis. Hierarchical clustering analysis is applied to identify createnimia trends. RESULTS: Four different creatinemia trends were identified (persistently high, normal, low, high but normalizing). A low creatinemia trend is significantly associated with the lowest percentages of postnatal corticosteroids, NSAIDS and intraventricular hemorrhage (p=0.005, p=0.013 and p=0.041 respectively) compared to a normal or persistently high creatinemia trend and associated with the best cognitive outcome (+13 points compared to the mean creatinemia trend and +23 points compared to a persistently high creatinemia trend). CONCLUSIONS: Creatinemia trends after birth are not only useful to predict renal function, but are also associated with cognitive outcome in extremely low birth weight infants. Neonates who have low creatinemia trends after birth, have the highest BSID scores at the age of two years old. PMID- 25919999 TI - Imprinting, latchment and displacement: a mini review of early instinctual behaviour in newborn infants influencing breastfeeding success. AB - Instinctive behaviours have evolved favouring the mother-infant dyad based on fundamental processes of neurological development, including oral tactile imprinting and latchment. Latchment is the first stage of emotional development based on the successful achievement of biological imprinting. The mechanisms underpinning imprinting are identified and the evolutionary benefits discussed. CONCLUSION: It is proposed that the oral tactile imprint to the breast is a keystone for optimal latchment and breastfeeding, promoting evolutionary success. PMID- 25920000 TI - The effects of acute alcohol on psychomotor, set-shifting, and working memory performance in older men and women. AB - A limited number of publications have documented the effects of acute alcohol administration among older adults. Among these, only a few have investigated sex differences within this population. The current project examined the behavioral effects of acute low- and moderate-dose alcohol on 62 older (ages 55-70) male and female, healthy, light to moderate drinkers. Participants were randomly assigned to one of three dose conditions: placebo (peak breath alcohol concentration [BrAC] of 0 mg/dL), low (peak BrAC of 40 mg/dL), and moderate (peak BrAC of 65 mg/dL). Tasks assessed psychomotor, set-shifting, and working memory performance. Better set-shifting abilities were observed among women, whereas men demonstrated more efficient working memory, regardless of dose. The moderate-dose group did not significantly differ from the placebo group on any task. However, the low dose group performed better than the moderate-dose group across measures of set shifting and working memory. Relative to the placebo group, the low-dose group exhibited better working memory, specifically for faces. Interestingly, there were no sex by dose interactions. These data suggest that, at least for our study's task demands, low and moderate doses of alcohol do not significantly hinder psychomotor, set-shifting, or working memory performance among older adults. In fact, low-dose alcohol may facilitate certain cognitive abilities. Furthermore, although sex differences in cognitive abilities were observed, these alcohol doses did not differentially affect men and women. Further investigation is necessary to better characterize the effects of sex and alcohol dose on cognition in older adults. PMID- 25920001 TI - High-risk drinking is associated with a higher risk of diabetes mellitus in Korean men, based on the 2010-2012 KNHANES. AB - We examined the association between alcohol-drinking pattern and diabetes mellitus (DM) in Korean adults. This cross-sectional study included 12,486 participants (5551 men and 6935 women) who participated in the 2010-2012 Korean National Health and Nutrition Examination Survey. We categorized alcohol-drinking pattern into three groups based on the alcohol-use disorders identification test (AUDIT): low-risk (score: 0-7), intermediate-risk (score: 8-14), and high-risk (score: >=15). DM was defined as having fasting plasma glucose >=126 mg/dL or taking glucose-lowering medication, including insulin therapy. In the study population, 25.2% of men and 4.7% of women were high-risk drinkers. DM prevalence was 9.2% in men and 5.4% in women. DM prevalence was 9.0% and 5.7% in the low risk drinking group, 7.6% and 4.1% in the intermediate-risk drinking group, and 11.2% and 3.5% in the high-risk drinking group in men and women, respectively. Compared to the low-risk drinking group, odds ratios (95% confidence intervals) of men and women in the intermediate-risk drinking group for DM were 1.043 (0.779 1.396) and 1.139 (0.712-1.824), respectively, and 1.480 (1.133-1.933) and 0.827 (0.296-2.311) in the high-risk drinking group, after adjusting for age and other confounding factors. In conclusion, high-risk drinking appears to be associated with a higher risk of DM in men, but not in women. PMID- 25920002 TI - Multidrug-Resistant Gram-Negative Bacteria: Inter- and Intradissemination Among Nursing Homes of Residents With Advanced Dementia. AB - OBJECTIVE: To quantify the extent of inter- and intra-nursing home transmission of multidrug-resistant gram-negative bacteria (MDRGN) among residents with advanced dementia and characterize MDRGN colonization among these residents. DESIGN: Prospective cohort study. SETTING: Twenty-two nursing homes in the greater Boston, Massachusetts, area. PATIENTS: Residents with advanced dementia. METHODS: Serial rectal surveillance cultures for MDRGN and resident characteristics were obtained every 3 months for 12 months or until death. Molecular typing of MDRGN isolates was performed by pulsed-field gel electrophoresis. RESULTS: A total of 190 MDRGN isolates from 152 residents with advanced dementia were included in the analyses. Both intra- and inter-nursing home transmission were identified. Genetically related MDRGN strains, recovered from different residents, were detected in 18 (82%) of the 22 nursing homes. The percent of clonally related strains in these nursing homes ranged from 0% to 86% (average, 35%). More than 50% of strains were clonally related in 3 nursing homes. Co-colonization with more than 1 different MDRGN species occurred among 28 residents (18.4%). A total of 168 (88.4%), 20 (10.5%), and 2 (1.0%) of MDRGN isolates were resistant to 3, 4, and 5 different antimicrobials or antimicrobial classes, respectively. CONCLUSIONS: MDRGN are spread both within and between nursing homes among residents with advanced dementia. Infection control interventions should begin to target this high-risk group of nursing home residents. PMID- 25920003 TI - Effects of edible bird's nest on hippocampal and cortical neurodegeneration in ovariectomized rats. AB - The aim of this research is to investigate whether edible bird's nest (EBN) attenuates cortical and hippocampal neurodegeneration in ovariectomized rats. Ovariectomized rats were randomly divided into seven experimental groups (n = 6): the ovariectomy (OVX) group had their ovaries surgically removed; the sham group underwent surgical procedure similar to OVX group, but ovaries were left intact; estrogen group had OVX and received estrogen therapy (0.2 mg kg(-1) per day); EBN treatment groups received 6%, 3%, and 1.5% EBN, respectively. Control group was not ovariectomized. After 12 weeks of intervention, biochemical assays were performed for markers of neurodegeneration, and messenger ribonucleic acid (mRNA) levels of oxidative stress-related genes in the hippocampus and frontal cortex of the brain were analysed. Caspase 3 (cysteine-aspartic proteases 3) protein levels in the hippocampus and frontal cortex were also determined using western blotting. The results show that EBNs significantly decreased estrogen deficiency associated serum elevation of advanced glycation end-products (AGEs), and they changed redox status as evidenced by oxidative damage (malondialdehyde content) and enzymatic antioxidant defense (superoxide dismutase and catalase) markers. Furthermore, genes associated with neurodegeneration and apoptosis were downregulated in the hippocampus and frontal cortex by EBN supplementation. Taken together, the results suggest that EBN has potential for neuroprotection against estrogen deficiency-associated senescence, at least in part via modification of the redox system and attenuation of AGEs. PMID- 25920004 TI - Arctigenin, a Natural Lignan Compound, Induces Apoptotic Death of Hepatocellular Carcinoma Cells via Suppression of PI3-K/Akt Signaling. AB - In this study, we explored the cytotoxic effects of arctigenin, a natural lignan compound, on human hepatocellular carcinoma (HCC) cells and check the involvement of phosphatidylinositol 3-kinase (PI3-K)/Akt signaling. HCC cells were treated with different concentrations of arctigenin and cell viability and apoptosis were assessed. Manipulating Akt signaling was used to determine its role in the action of arctigenin. Arctigenin significantly inhibited the viability of HCC cells in a concentration-dependent manner. Arctigenin induced apoptosis and activation of caspase-9 and -3. Overexpression of a constitutively active Akt mutant blocked arctigenin-induced apoptosis. Combinational treatment with arctigenin and the PI3 K inhibitor LY294002 significantly enhanced apoptosis. Arctigenin reduced the expression of Bcl-xL, Mcl-1, and survivin and the phosphorylation of mTOR and S6K, which were significantly reversed by overexpression of constitutively active Akt. This is the first report about the anticancer activity of arctigenin in HCC cells, which is mediated by inactivation of PI3-K/Akt signaling. PMID- 25920005 TI - Synthesis, thymidine phosphorylase inhibition and molecular modeling studies of 1,3,4-oxadiazole-2-thione derivatives. AB - Thymidine phosphorylase (TP) inhibitors have attracted great attention due to their ability to suppress the tumors formation. In our ongoing research, a series of 1,3,4-oxadiazole-2-thione (1-12) has been synthesized under simple reaction conditions in good to excellent yields (86-98%) and their TP inhibition potential has also been evaluated. The majority of synthesized compounds showed moderate thymidine phosphorylase inhibitory activity with IC50 values ranging from 38.24+/ 1.28 to 258.43+/-0.43MUM, and 7-deazaxanthine (7DX) was used as a reference compound (IC50 38.68+/-4.42). The TP activity was very much dependent on the C-5 substituents; among this series the compound 6 bearing 4-hydroxyphenyl group was found to be the most active with IC50 38.24+/-1.28MUM. Molecular docking studies revealed their binding mode. PMID- 25920006 TI - BRAF-mutated carcinomas among thyroid nodules with prior indeterminate FNA report: a systematic review and meta-analysis. AB - BACKGROUND: Several molecular analyses have been investigated for risk stratification of thyroid nodules, with a particular focus on the V600E mutation of the BRAF gene [BRAF(V600E)]. To date, there is no high-level evidence supporting or refuting a role for BRAF analysis in thyroid nodules with prior indeterminate cytology. To obtain more robust evidence, we reviewed and meta analysed data from published articles. RESEARCH DESIGN AND METHODS: A comprehensive literature search of the PubMed/MEDLINE, Embase and Scopus databases was conducted using the terms 'BRAF', 'thyroid' and 'indeterminate'. The search was updated until March 2015, and references of the retrieved articles were also screened. Only original articles reporting BRAF mutation testing within nodules with indeterminate FNA were eligible for inclusion. RESULTS: The literature search revealed 82 articles, of which 8 were eligible for the study. Five studies were prospective and three retrospective. The majority of authors analysed BRAF mutations in FNA samples which were classified by the British or Bethesda system. Of the initial series of studies, a pooled number of 1361 cases were achieved of which 43 were BRAF mutated. Overall, the BRAF mutation rate was 4.6% (95% CI: 1-10.8%), ranging from 0 to 22.9%. When we included only histological series, 978 thyroid nodules were found. Of these, 245 were cancers. CONCLUSIONS: A very low rate of lesions with indeterminate cytology are BRAF mutated. Thus, the role of this biomarker to detect or exclude cancers in patients with such FNA reports is marginal and should be reconsidered in guidelines. PMID- 25920007 TI - Safety and efficacy of carbon dioxide cryotherapy for treatment of neoplastic Barrett's esophagus. PMID- 25920008 TI - Proteomics-level analysis of myelin formation and regeneration in a mouse model for Vanishing White Matter disease. AB - Vanishing white matter (VWM) is a recessive neurodegenerative disease caused by mutations in translation initiation factor eIF2B and leading to progressive brain myelin deterioration, secondary axonal damage, and death in early adolescence. Eif2b5(R132H/R132H) mice exhibit delayed developmental myelination, mild early neurodegeneration and a robust remyelination defect in response to cuprizone induced demyelination. In the current study we used Eif2b5(R132H/R132H) mice for mass-spectrometry analyses, to follow the changes in brain protein abundance in normal- versus cuprizone-diet fed mice during the remyelination recovery phase. Analysis of proteome profiles suggested that dysregulation of mitochondrial functions, altered proteasomal activity and impaired balance between protein synthesis and degradation play a role in VWM pathology. Consistent with these findings, we detected elevated levels of reactive oxygen species in mutant derived primary fibroblasts and reduced 20S proteasome activity in mutant brain homogenates. These observations highlight the importance of tight translational control to precise coordination of processes involved in myelin formation and regeneration and point at cellular functions that may contribute to VWM pathology. Eif2b5(R132H/R132H) mouse model for vanishing white matter (VWM) disease was used for mass spectrometry of brain proteins at two time points under normal conditions and along recovery from cuprizone-induced demyelination. Comparisons of proteome profiles revealed the importance of mitochondrial function and tight coordination between protein synthesis and degradation to myelination formation and regeneration, pointing at cellular functions that contribute to VWM pathology. PMID- 25920009 TI - Cell culture media supplementation of bioflavonoids for the targeted reduction of acidic species charge variants on recombinant therapeutic proteins. AB - Charge variants in recombinant proteins are an important series of protein modifications, whose potential role on protein stability, activity, immunogenicity, and pharmacokinetics continues to be studied. Monoclonal antibodies in particular have been shown to have a wide range of acidic species variants, including those associated with the addition of covalent modifications as well as the chemical degradation at specific peptide regions on the antibody. These variants play a significant role toward the overall heterogeneity of recombinant therapeutic proteins and are typically monitored during manufacturing to ensure they lie within proven acceptable ranges. In this work, it has been found that the supplementation of members of the bioflavonoid chemical family into mammalian cell culture media was effective toward the reduction of acidic species charge variants on recombinant monoclonal antibodies and dual variable domain immunoglobulins. The demonstrated reduction in acidic species through the use of bioflavonoids facilitates the manufacturing of a less heterogeneous product with potential improvements in antibody structure and function. PMID- 25920010 TI - Flexible Fabrication of Shape-Controlled Collagen Building Blocks for Self Assembly of 3D Microtissues. AB - Creating artificial tissue-like structures that possess the functionality, specificity, and architecture of native tissues remains a big challenge. A new and straightforward strategy for generating shape-controlled collagen building blocks with a well-defined architecture is presented, which can be used for self assembly of complex 3D microtissues. Collagen blocks with tunable geometries are controllably produced and released via a membrane-templated microdevice. The formation of functional microtissues by embedding tissue-specific cells into collagen blocks with expression of specific proteins is described. The spontaneous self-assembly of cell-laden collagen blocks into organized tissue constructs with predetermined configurations is demonstrated, which are largely driven by the synergistic effects of cell-cell and cell-matrix interactions. This new strategy would open up new avenues for the study of tissue/organ morphogenesis, and tissue engineering applications. PMID- 25920011 TI - Agreement between veterinary students and anesthesiologists regarding postoperative pain assessment in dogs. AB - OBJECTIVE: To determine the levels of agreement among first- and second-year veterinary students and experienced anesthesiologists in assessing postoperative pain in dogs from video-recordings. STUDY DESIGN: Cross-sectional study. SUBJECTS: Twenty-seven veterinary students, five anesthesiologists and 13 canine clinical patients. METHODS: Prior to their enrolment in a core anesthesia course, veterinary students volunteered to watch 13 90 second videos of dogs. Dogs were hospitalized in an intensive care unit after a variety of surgical procedures. Students were asked to score the level of the dogs' pain using the Dynamic Interactive Visual Analog Scale and the Short Form of the Glasgow Composite Measure Pain Scale. The same videotapes were scored by five board-certified anesthesiologists. The differences and agreement between the ratings of anesthesiologists and students, and first- and second-year students were determined with Mann-Whitney U-tests and Fleiss' or Cohen's kappa, respectively. RESULTS: Pain scores assigned by students and anesthesiologists differed significantly (p < 0.01). Students assigned higher pain scores to dogs that were given low pain scores by anesthesiologists, and lower pain scores to dogs deemed to be in more pain by anesthesiologists. On average, students assigned higher scores on both scales. CONCLUSIONS AND CLINICAL RELEVANCE: Veterinary students early in their training assigned pain scores to dogs that differed from scores assigned by experienced anesthesiologists. PMID- 25920012 TI - Transoral Video-Assisted Thyroidectomy and Its Clinical Implementation. PMID- 25920013 TI - Individualized Low-Amplitude Seizure Therapy: Minimizing Current for Electroconvulsive Therapy and Magnetic Seizure Therapy. AB - Electroconvulsive therapy (ECT) at conventional current amplitudes (800-900 mA) is highly effective but carries the risk of cognitive side effects. Lowering and individualizing the current amplitude may reduce side effects by virtue of a less intense and more focal electric field exposure in the brain, but this aspect of ECT dosing is largely unexplored. Magnetic seizure therapy (MST) induces a weaker and more focal electric field than ECT; however, the pulse amplitude is not individualized and the minimum amplitude required to induce a seizure is unknown. We titrated the amplitude of long stimulus trains (500 pulses) as a means of determining the minimum current amplitude required to induce a seizure with ECT (bilateral, right unilateral, bifrontal, and frontomedial electrode placements) and MST (round coil on vertex) in nonhuman primates. Furthermore, we investigated a novel method of predicting this amplitude-titrated seizure threshold (ST) by a non-convulsive measurement of motor threshold (MT) using single pulses delivered through the ECT electrodes or MST coil. Average STs were substantially lower than conventional pulse amplitudes (112-174 mA for ECT and 37.4% of maximum device amplitude for MST). ST was more variable in ECT than in MST. MT explained 63% of the ST variance and is hence the strongest known predictor of ST. These results indicate that seizures can be induced with less intense electric fields than conventional ECT that may be safer; efficacy and side effects should be evaluated in clinical studies. MT measurement could be a faster and safer alternative to empirical ST titration for ECT and MST. PMID- 25920014 TI - Barriers to Physical Activity in Children With Autism Spectrum Disorders: Relationship to Physical Activity and Screen Time. AB - BACKGROUND: Individual, social, and community barriers to physical activity (PA) experienced by children with autism spectrum disorder (ASD) make PA participation more difficult and may contribute to increased screen time. METHODS: We compared the prevalence of parent-reported barriers to PA among 58 typically developing (TD) children and 53 children with an ASD, 3 to 11 years, and assessed the association between barriers and PA participation and screen time among children with ASD. RESULTS: Parents of children with ASD reported significantly more barriers than parents of TD children. Based on parent-report, 60% of children with ASD required too much supervision compared with no TD children (P < .001). Parents of children with ASD were more likely to report that adults lack skills needed to include their child (58%), that their child has few friends (45%), and that other children exclude their child (23%). The number of parent-reported barriers to PA was inversely correlated with the hours spent in PA per year (r = 0.27, P = .05) and positively related to total screen time (r = .32, P < .03). CONCLUSIONS: These findings underscore the need for community-based PA programs designed to meet the special requirements of this population and policies that compel schools and other government-supported organizations for inclusion and/or targeted programming. PMID- 25920015 TI - Predictors of mucositis in oropharyngeal and oral cavity cancer in patients treated with volumetric modulated radiation treatment: A dose-volume analysis. AB - BACKGROUND: The purpose of this study was to assess predictors of mucositis in oropharyngeal and oral cavity cancer after definitive or adjuvant volumetric modulated arc radiotherapy (VMAT) +/- chemotherapy. METHODS: Fifty patients were evaluated. Statistical analysis was performed for the following parameters as potential predictors of mucositis >= G2: total oral mucosa and oral mucosa minus target high-low radiation dose regions (planning target volumes [PTVs]), mean dose (Dmean ), maximum dose (Dmax ), chemotherapy, weight loss, and dysphagia. RESULTS: Mucositis >= G2 was found to be statistically related to chemotherapy, weight loss, dysphagia >= G2, total oral mucosa Dmean >=50 Gy and Dmax >=65 Gy, V45 Gy >40%, V50 Gy >30%, and V55 Gy >20% of the oral mucosa minus target PTVs. A ratio between total oral mucosa and oral mucosa minus target PTVs >2.5 is related to G3 mucositis (p = .03). CONCLUSION: New parameters were found as predictors of moderate-severe mucositis. (c) 2015 Wiley Periodicals, Inc. Head Neck 38: E815 E819, 2016. PMID- 25920016 TI - Histone demethylase Utx regulates differentiation and mineralization in osteoblasts. AB - Alteration of methylation status of lysine 27 on histone H3 (H3K27) associates with dramatic changes in gene expression in response to various differentiation signals. Demethylation of H3K27 is controlled by specific histone demethylases including ubiquitously transcribed tetratricopeptide repeat X chromosome (Utx). However, the role of Utx in osteoblast differentiation remains unknown. In this study, we examined whether Utx should be involved in osteoblast differentiation. Expression of Utx increased during osteoblast differentiation in MC3T3-E1 cells and primary osteoblasts. GSK-J1, a potent inhibitor of H3K27 demethylase, increased the levels of trimethylated H3K27 (H3K27me3) and decreased the expressions of Runx2 and Osterix and ALP activity in MC3T3-E1 cells. Stable knockdown of Utx by shRNA attenuated osteoblast differentiation and decreased ALP activity, calcium content, and bone-related gene expressions. Silencing of Utx increased the level of H3K27me3 on the promoter regions of Runx2 and Osterix and decreased the promoter activities of Runx2 and Osterix. Taken together, our present results propose that Utx plays important roles in osteoblast differentiation by controlling the expressions of Runx2 and Osterix. PMID- 25920017 TI - Hyperkalemia induced sinoatrial block or atrial fibrillation? PMID- 25920018 TI - Diagnostic performance of myocardial perfusion imaging with SPECT, CT and MR compared to fractional flow reserve as reference standard. PMID- 25920019 TI - Left atrial myxoma presenting as acute coronary syndrome. PMID- 25920020 TI - Discordant changes in peak O2 consumption and peak cardiac power during weight loaded treadmill exercise. PMID- 25920021 TI - Fractional flow reserve derived from conventional coronary angiograms and computational fluid dynamics. PMID- 25920022 TI - Use of copeptin and high-sensitive cardiac troponin T for diagnosis and prognosis in patients with diabetes mellitus and suspected acute myocardial infarction. AB - BACKGROUND: Diabetes is a major risk factor for acute myocardial infarction (AMI). Assessment of diabetic patients is challenging due to an often atypical presentation of symptoms. We aimed to evaluate the two novel biomarkers copeptin and high-sensitive cardiac troponin (hs-TnT) for the improvement of early diagnosis and risk-stratification in patients with diabetes and suspected AMI. METHODS: In this prospective international multicenter study we evaluated 379 patients with diabetes in a cohort of 1991 patients presenting with symptoms suggestive of AMI. The measurement of biomarkers was performed at presentation. RESULTS: Among the 379 diabetic patients, 32.7% had AMI, and in the 1621 patients without diabetes, 18.8% had AMI. The additional use of copeptin improved the diagnostic accuracy provided by conventional troponin alone (AUC 0.86 vs. 0.79, p=0.004). During a median follow-up of 814 days, 49 (13.1%) diabetic patients died. Cumulative 2-year survival rate for patients with copeptin levels below 9 pmol/l was 96.6% compared to 82.8% in patients above that level (p<0.001). The same was observed for hs-TnT with a cutoff level of 14 ng/l (97.7% vs. 82.0%, p<0.001) respective of cTnT with a cutoff level of 10 ng/l (93.5% vs. 75.6%, p<0.001). In multivariate Cox analysis, copeptin, hs-TnT and cTnT were strong and independent predictors of 24-month-mortality. Using the dual marker strategy (copeptin and troponin) identified two groups of high-risk patients where 22.5% of the group with hs-cTnT and copeptin above the cutoff and 28.6% with cTnT and copeptin above the cutoff died. CONCLUSION: In diabetic patients, copeptin only slightly improves the early diagnosis of AMI provided by hs-cTnT. However, both markers (copeptin and troponin) predict long-term mortality accurately and independently of each other. PMID- 25920023 TI - Recurrent ventricular tachycardia in a patient with continuous flow left ventricle assist device: Successful management with radiofrequency ablation and medical treatment. PMID- 25920024 TI - Morbidity and mortality in systolic heart failure also associated with raised serum neprilysin levels. Reply. PMID- 25920025 TI - P wave dispersion in cryptogenic stroke: A risk factor for cardioembolism? PMID- 25920026 TI - Association of functional genetic variants in PPARgamma and PPARalpha encoding peroxisome proliferator-activated receptors with ischemic stroke in a unique Chinese population. PMID- 25920027 TI - A response to "The importance of vasodilator therapy before or during angiography, is ICD necessary or not?" by Tamer Kirat and Nuri Kose. PMID- 25920028 TI - Fried food consumption and ischemic heart disease: A systematic literature review. PMID- 25920029 TI - Withdrawal of heart failure medications in peripartum cardiomyopathy after myocardial recovery. PMID- 25920030 TI - Monocyte dysfunction as a previously unrecognized pathophysiological mechanism in ApoE-/- mice contributing to impaired arteriogenesis. PMID- 25920031 TI - Secreted Frizzled-Related Protein 3 (sFRP3) in acute coronary syndromes. PMID- 25920032 TI - Short-term effects of catheter-based renal denervation on cardiac sympathetic drive and cardiac baroreflex function in heart failure. AB - OBJECTIVES: Sympathetic drive, especially to the heart, is elevated in heart failure and is strongly associated with poor outcome. The mechanisms causing the increased sympathetic drive to the heart remain poorly understood. Catheter-based renal denervation (RDN), which reduces blood pressure (BP) and sympathetic drive in hypertensive patients, is a potential treatment in heart failure. The aim of this study was to investigate the short-term effects of catheter-based RDN on BP, heart rate (HR) and cardiac sympathetic nerve activity (CSNA) and on baroreflex function in a conscious, large animal model of heart failure. METHODS: Adult Merino ewes were paced into heart failure (ejection fraction<40%) and then instrumented to directly record CSNA. The resting levels and baroreflex control of CSNA and HR were measured before and 24h after bilateral renal (n=6) or sham (n=6) denervation. RDN was performed using the Symplicity Flex Catheter System(r) (Medtronic) using the same algorithm as in patients. RESULTS: Catheter-based RDN significantly reduced resting diastolic BP (P<0.01) and mean arterial blood pressure (P<0.05), but did not change resting HR or CSNA compared with sham denervation. Renal denervation reduced the BP at which CSNA was at 50% of maximum (BP50; P<0.005) compared with sham denervation. CONCLUSIONS: In an ovine model of heart failure, catheter-based RDN did not reduce resting CSNA in the short-term. There was, however, a lack of a reflex increase in CSNA in response to the fall in arterial pressure due to a leftward shift in the baroreflex control of CSNA, which may be due to denervation of renal efferent and/or afferent nerves. PMID- 25920033 TI - Long-term outcomes of catheter ablation of atrial fibrillation in dilated cardiomyopathy. AB - OBJECTIVE: The long-term outcomes, efficacy and safety of catheter ablation in atrial fibrillation (AF) patients with dilated cardiomyopathy (DCM) have not been reported previously. METHODS AND RESULTS: Forty nine patients with AF (59% longstanding persistent AF, LSP-AF) and DCM were enrolled. Circumferential pulmonary vein ablation (CPVA, paroxysmal AF), bidirectional block of lines and disappearance of complex fractionated atrial electrograms (CFAEs, persistent and LSP-AF) were the endpoints of the index and repeat procedures. Cumulative success rate reached 49% (mean, 1.4 procedures) during the first year, and dropped to 38% at median follow-up of 45 months (range, 36-64 months) for multiple procedures (mean, 1.9 +/- 0.8 [1-4]). Incidence of procedural complications was similar to that of conventional procedures. In multivariate analysis, LSP-AF (OR, 7.40 [95% CI, 1.42-38.34]; P = 0.017) and larger left ventricular end-diastolic diameter (OR, 1.24 [95% CI, 1.01-1.52]; P = 0.034) were significant independent predictors of recurrent atrial tachyarrhythmia (ATa). Compared with patients with ATa recurrence, those free from ATa had better New York Heart Association functional class, 6-minute walk distance and left ventricular ejection fraction during long term follow-up compared with pre-ablation, but this improvement was not sustained beyond 3 years. CONCLUSION: In patients with DCM, current commonly used ablation strategies including CPVA, linear ablation and CFAE ablation are not associated with long-term AF treatment success up to five years. Freedom from ATa is associated with improved heart failure during but not beyond 3 years post ablation. PMID- 25920034 TI - Is pentraxin 3 a cardiovascular marker in patients with chronic Chagas disease? PMID- 25920035 TI - Real Time Extraction Kinetics of Electro Membrane Extraction Verified by Comparing Drug Metabolism Profiles Obtained from a Flow-Flow Electro Membrane Extraction-Mass Spectrometry System with LC-MS. AB - A simple to construct and operate, "dip-in" electromembrane extraction (EME) probe directly coupled to electrospray ionization-mass spectrometry (ESI-MS) for rapid extraction and real time analysis of various analytes was developed. The setup demonstrated that EME-MS can be used as a viable alternative to conventional protein precipitation followed by liquid chromatography-mass spectrometry (LC-MS) for studying drug metabolism. Comparison of EME-MS with LC MS for drug metabolism analysis demonstrated for the first time that real time extraction of analytes by EME is possible. Metabolism kinetics were investigated for three different drugs: amitriptyline, promethazine, and methadone. By comparing the EME-MS extraction profiles of the drug substances and formed drug metabolites with the metabolism profiles obtained by conventional protein precipitation followed by LC-MS good correlation was obtained with only very limited time delay in the extraction. The results indicate that, by tuning the electromembrane properties, for example, by optimizing the extraction voltage, extremely fast extraction kinetics can be obtained. A metabolic profile could be generated while the drug was metabolized offering a significant time saving as compared to conventional LC-MS where laborious protein precipitation or other sample pretreatments are required before analysis. This makes the developed EME MS setup a highly promising sample preparation method for various kinds of applications where fast and real-time analysis of analytes is of interest. PMID- 25920036 TI - Three-dimensional quantitative T1 and T2 mapping of the carotid artery: Sequence design and in vivo feasibility. AB - PURPOSE: A novel three-dimensional (3D) T1 and T2 mapping protocol for the carotid artery is presented. METHODS: A 3D black-blood imaging sequence was adapted allowing carotid T1 and T2 mapping using multiple flip angles and echo time (TE) preparation times. B1 mapping was performed to correct for spatially varying deviations from the nominal flip angle. The protocol was optimized using simulations and phantom experiments. In vivo scans were performed on six healthy volunteers in two sessions, and in a patient with advanced atherosclerosis. Compensation for patient motion was achieved by 3D registration of the inter/intrasession scans. Subsequently, T1 and T2 maps were obtained by maximum likelihood estimation. RESULTS: Simulations and phantom experiments showed that the bias in T1 and T2 estimation was < 10% within the range of physiological values. In vivo T1 and T2 values for carotid vessel wall were 844 +/- 96 and 39 +/- 5 ms, with good repeatability across scans. Patient data revealed altered T1 and T2 values in regions of atherosclerotic plaque. CONCLUSION: The 3D T1 and T2 mapping of the carotid artery is feasible using variable flip angle and variable TE preparation acquisitions. We foresee application of this technique for plaque characterization and monitoring plaque progression in atherosclerotic patients. PMID- 25920038 TI - The Relationship between Acute Dyskinesia with a Single Dose of Methylphenidate and Recent Risperidone Discontinuation in a Child with Attention Deficit/Hyperactivity Disorder. PMID- 25920039 TI - Reducing the cost of proton radiation therapy: the feasibility of a streamlined treatment technique for prostate cancer. AB - Proton radiation therapy is an effective modality for cancer treatments, but the cost of proton therapy is much higher compared to conventional radiotherapy and this presents a formidable barrier to most clinical practices that wish to offer proton therapy. Little attention in literature has been paid to the costs associated with collimators, range compensators and hypofractionation. The objective of this study was to evaluate the feasibility of cost-saving modifications to the present standard of care for proton treatments for prostate cancer. In particular, we quantified the dosimetric impact of a treatment technique in which custom fabricated collimators were replaced with a multileaf collimator (MLC) and the custom range compensators (RC) were eliminated. The dosimetric impacts of these modifications were assessed for 10 patients with a commercial treatment planning system (TPS) and confirmed with corresponding Monte Carlo simulations. We assessed the impact on lifetime risks of radiogenic second cancers using detailed dose reconstructions and predictive dose-risk models based on epidemiologic data. We also performed illustrative calculations, using an isoeffect model, to examine the potential for hypofractionation. Specifically, we bracketed plausible intervals of proton fraction size and total treatment dose that were equivalent to a conventional photon treatment of 79.2 Gy in 44 fractions. Our results revealed that eliminating the RC and using an MLC had negligible effect on predicted dose distributions and second cancer risks. Even modest hypofractionation strategies can yield substantial cost savings. Together, our results suggest that it is feasible to modify the standard of care to increase treatment efficiency, reduce treatment costs to patients and insurers, while preserving high treatment quality. PMID- 25920040 TI - Family caregivers' views on coordination of care in Huntington's disease: a qualitative study. AB - BACKGROUND: Collaboration between family caregivers and health professionals in specialised hospitals or community-based primary healthcare systems can be challenging. During the course of severe chronic disease, several health professionals might be involved at a given time, and the patient's illness may be unpredictable or not well understood by some of those involved in the treatment and care. AIM: The aim of this study was to explore the experiences and expectations of family caregivers for persons with Huntington's disease concerning collaboration with healthcare professionals. METHODS: To shed light on collaboration from the perspectives of family caregivers, we conducted an explorative, qualitative interview study with 15 adult participants experienced from caring for family members in all stages of Huntington's disease. Data were analysed with systematic text condensation, a cross-case method for thematic analysis of qualitative data. RESULTS: We found that family caregivers approached health services hoping to understand the illness course and to share their concerns and stories with skilled and trustworthy professionals. Family caregivers felt their involvement in consultations and access to ongoing exchanges of knowledge were important factors in improved health services. They also felt that the clarity of roles and responsibilities was crucial to collaboration. CONCLUSIONS: Family caregivers should be acknowledged for their competences and should be involved as contributors in partnerships with healthcare professionals. Our study suggests that building respectful partnerships with family caregivers and facilitating the mutual sharing of knowledge may improve the coordination of care. It is important to establish clarity of roles adjusted to caregivers' individual resources for managing responsibilities in the care process. PMID- 25920041 TI - Factors associated with six-month outcome of pediatric stroke. AB - BACKGROUND: Pediatric stroke outcome studies are often cross sectional in design. Prospective information regarding the clinical course following diagnosis is lacking, but may inform clinical management beyond the acute period. AIMS: To describe the outcome of arterial ischemic stroke in infants, children and adolescents at one-month and six-months post-stroke across health domains, and explore the relationship between lesion characteristics and early outcome with six-month adaptive behavior. METHODS: A single center prospective longitudinal study at a tertiary level children's hospital. Recruitment was undertaken from December 2007 to January 2012. Participants were children aged birth to 18 years presenting acutely with first diagnosed arterial ischemic stroke. Lesion characteristics on brain imaging were classified. Children were grouped according to age at diagnosis for analysis (neonates vs. those aged >30 days). RESULTS: In 50 children with a median age of 47 months at diagnosis, sensorimotor impairments were most evident upon neurological examination acutely, especially in the older children. At both one-month and six-months motor functioning was significantly impaired in the older age group but no significant cognitive or language sequelae were identified. Lesion characteristics alone were not associated with six-month adaptive behavior outcomes. CONCLUSIONS: For patients surviving arterial ischemic stroke, the most significant clinical consequences both acutely and at six months, are sensorimotor impairments, particularly evident in the older children. In contrast cognitive or language sequelae were not identified. Long-term surveillance is required to describe clinical course and rehabilitation needs, particularly for neonates and infants. PMID- 25920042 TI - Fluorescent water-soluble organic aerosols in the High Arctic atmosphere. AB - Organic aerosols are ubiquitous in the earth's atmosphere. They have been extensively studied in urban, rural and marine environments. However, little is known about the fluorescence properties of water-soluble organic carbon (WSOC) or their transport to and distribution in the polar regions. Here, we present evidence that fluorescent WSOC is a substantial component of High Arctic aerosols. The ratios of fluorescence intensity of protein-like peak to humic-like peak generally increased from dark winter to early summer, indicating an enhanced contribution of protein-like organics from the ocean to Arctic aerosols after the polar sunrise. Such a seasonal pattern is in agreement with an increase of stable carbon isotope ratios of total carbon (deltaCTC) from -26.80/00 to -22.50/00. Our results suggest that Arctic aerosols are derived from a combination of the long range transport of terrestrial organics and local sea-to-air emission of marine organics, with an estimated contribution from the latter of 8.7-77% (mean 45%). PMID- 25920043 TI - Presenile onset of spinocerebellar ataxia type 1 presenting with conspicuous psychiatric symptoms and widespread anti-expanded polyglutamine antibody- and fused in sarcoma antibody-immunopositive pathology. AB - A 50-year-old Japanese man showed slowly progressive gait disturbance and dysarthria. Neurological examination 5 years after onset revealed slow eye movement with nystagmus as well as limb and truncal ataxia. Magnetic resonance imaging showed atrophy of the cerebellum and brainstem. Because genetic examination revealed CAG repeat expansion of the ataxin-1 gene, the patient was diagnosed with spinocerebellar ataxia type 1. Ten years after onset, he showed psychiatric symptoms with cognitive impairment, and antipsychotic drugs were administered. As psychiatric symptoms gradually worsened, particularly with regard to resisting nursing care and shouting, the doses of the drugs were increased. Although the clinicopathologic findings were generally identical to previously reported spinocerebellar ataxia type 1 cases with the exception of the conspicuous psychiatric symptoms, there are two notable immunohistochemical findings. Firstly, numerous anti-expanded polyglutamine antibody-immunopositive neuronal inclusions were extensively observed, including in the cerebral cortex and limbic system, but not in the Purkinje cells. Secondly, anti-fused in sarcoma antibody-immunopositive intranuclear inclusions were extensively observed. We posit that the anti-expanded polyglutamine antibody-immunopositive neuronal inclusions and possibly the anti-fused in sarcoma antibody-immunopositive inclusions, particularly those in the neocortex and limbic system, may correspond to the psychiatric symptoms and cognitive impairment that were observed in the patient. PMID- 25920044 TI - Anorexia nervosa and body dysmorphic disorder: A comparison of body image concerns and explicit and implicit attractiveness beliefs. AB - Although body image is central to the etiological models of anorexia nervosa and body dysmorphic disorder, studies comparing body image and beliefs about attractiveness between the disorders are rare. Sixty-nine individuals (anorexia nervosa: n=24, body dysmorphic disorder: n=23, healthy controls: n=22) completed self-report measures (body image and general psychopathology), diagnostic interviews, and Go/No-Go Association tasks measuring implicit associations. Compared to controls, both clinical groups exhibited greater negative body image, a more negative attitude toward their physical selves, and more dysfunctional coping strategies (ps<.001). Also, both clinical groups shared greater explicit beliefs about the importance of attractiveness (ps<.001). In addition to supporting previous research with regard to comparable body image disturbance, this study also showed that beliefs regarding the importance of appearance (e.g., "one must be attractive to be successful") might be a fruitful target for therapy across both disorders. PMID- 25920047 TI - PET imaging in neurology: Alzheimer's and Parkinson's diseases. AB - PET studies play an important role in the early detection of Alzheimer's and Parkinson's diseases (AD and PD). Fluorine-18 fluorodeoxyglucose (F-FDG) PET imaging of regional cerebral glucose metabolism and PET amyloid imaging are the two major PET studies for AD. F-FDG PET is highly sensitive for the early diagnosis of AD, in predicting conversion from mild cognitive impairment to AD, and in differentiating AD from other dementias. PET amyloid imaging is positive in the majority of patients with AD. Negative amyloid PET reduces the likelihood of AD. The main limitations of PET amyloid imaging is its high positivity in the normal elderly population and in other medical conditions with amyloid pathologies. Various PET tracers are available to assess motor and cognitive dysfunctions in PD. PET tracers targeting presynaptic dopaminergic function (F DOPA, radiolabeled PET tracers assessing the availability of dopamine transporters and vesicular monoamine transporters) and postsynaptic dopamine receptors are used to assess motor dysfunction in PD. PET tracers, particularly dopamine transporters, are highly sensitive in the early diagnosis of PD. Uptake of PET tracers in the striatum is inversely correlated with disease severity. PET is valuable in differentiating PD from other movement disorders. PET studies, particularly F-FDG PET, help to evaluate cortical metabolism in PD patients with cognitive dysfunction and dementia. PMID- 25920048 TI - Correlation and discordance of tumour proliferation index and molecular imaging characteristics and their implications for treatment decisions and outcome pertaining to peptide receptor radionuclide therapy in patients with advanced neuroendocrine tumour: developing a personalized model. AB - This communication critically illustrates the molecular imaging features and correlates them with the histopathological characteristics (focussing primarily on Ki-67 or MiB1 index) of neuroendocrine tumours (NETs), their implications for important treatment decision-making, and their response to peptide receptor radionuclide therapy. Such multiparametric analysis of functional imaging (along with conventional size, site-specific and stage-specific morphological assessment and histopathology) is crucial for developing a personalized model for the treatment of advanced and metastatic NET and to fine-tune the multimodal therapies, including the combination regimens. Illustrations with case examples have been made with respect to (a) concordant and (b) discordant tumour proliferation index and functional imaging features, (c) the variable molecular imaging parameters at the intermediate MiB1 indices, including (d) outliers with respect to their MiB1 index, and (e) interlesional heterogeneity between primary and metastatic sites in the same individual as demonstrated by molecular imaging features and its possible implications for therapeutic strategy. In each case, the treatment outcome has been described that would aid in better understanding of the potential usefulness of functional imaging in managing patients with NETs on an individual basis. PMID- 25920049 TI - Comparison of phenobarbitone and ursodeoxycholic acid in drug-augmented hepatobiliary scintigraphy for excluding the diagnosis of obstructive cholestasis in neonatal cholestasis syndrome. AB - OBJECTIVES: Neonatal cholestasis is a common cause of jaundice among newborns. Hepatobiliary scintigraphy plays an important role in the diagnosis of neonatal cholestasis by ruling out extrahepatic biliary atresia, which is one of the common causes. Phenobarbitone and ursodeoxycholic acid (UDCA) have been used to improve the specificity of hepatobiliary scintigraphy in ruling out obstructive causes of neonatal cholestasis syndrome (NCS). The present study was undertaken to compare the utility of phenobarbitone and UDCA in augmenting hepatobiliary scintigraphy in the evaluation of NCS. MATERIALS AND METHODS: Seventy-four consecutive patients with NCS referred for hepatobiliary scintigraphy were initially subjected to a baseline scan. Twenty patients showed tracer activity in the intestine within 24 h after injection, thus ruling out obstructive cholestasis. Fifty-four patients who did not show any tracer activity in the intestine were categorized as nonexcretors. Four nonexcretors were lost to follow up and were excluded from the study. Fifty nonexcretors showing scan features suggestive of obstructive cholestasis were further randomized into those receiving phenobarbitone (n=20), UDCA (n=20), or placebo (n=10). These groups were further evaluated with drug-augmented hepatobiliary scintigraphy, after premedication, for any excretory activity in the intestine. RESULTS AND CONCLUSION: Out of 50 patients who were evaluated with drug-augmented hepatobiliary scintigraphy two patients from the phenobarbitone group and one patient each from UDCA and placebo groups showed a change in excretory pattern from the baseline scan. However, these results were statistically nonsignificant (P=1.00). In the present study, drug-augmented (phenobarbitone or UDCA) hepatobiliary scintigraphy did not seem to improve the results (negative predictive value) for ruling out an obstructive cause of neonatal cholestasis. PMID- 25920050 TI - Validation of the CT iterative reconstruction technique for low-dose CT attenuation correction for improving the quality of PET images in an obesity simulating body phantom and clinical study. AB - OBJECTIVE: The aim of this study was to validate the efficacy of computed tomography (CT) iterative reconstruction (CT-IR) for low-dose CT attenuation correction in terms of the estimation of attenuation coefficient and quality of PET images. MATERIALS AND METHODS: We used normal and obesity-simulating body phantoms. PET images were reconstructed using two attenuation correction maps obtained using filtered back projection (CT-FBP) and CT-IR. The CT numbers, attenuation coefficients, contrast-to-noise ratio (CNR10 mm), and coefficient of variation were evaluated. Fifty-two consecutive patients who underwent F-FDG PET/CT with low-dose CT scans were selected for the clinical study. Clinical PET images were reconstructed using CT-FBP and CT-IR, and the effects of CT-IR were examined according to the maximum standardized uptake value (SUVmax), contrast-to noise ratio in the tumor (CNRtumor), and signal-to-noise ratio in the liver (SNRliver). RESULTS: The CT number on the CT-IR was significantly lower than that of CT-FBP in the obesity-simulating body phantom. The decrease in attenuation coefficients obtained using CT-IR was smaller than that obtained using CT-FBP. The CNR10 mm and coefficient of variation obtained using CT-IR were superior to those obtained using CT-FBP. The SUVmax was not significantly different between the CT-FBP and CT-IR. Although the difference in the SNRliver between the CT-FBP and CT-IR was not significant, the CNRtumor of the CT-IR was significantly higher than that obtained using CT-FBP in obese patients. CONCLUSION: We demonstrated that CT-IR improved the estimation of the attenuation coefficient and provided significant improvement in the CNR of the clinical PET images. PMID- 25920051 TI - Diagnostic value of single-photon emission computed tomography combined with computed tomography in relation to MRI on osteochondral lesions of the talus. AB - BACKGROUND: Osteochondral lesion of the talus (OLT) involves the separation of a fragment of articular cartilage, as defined by Kappis in 1922. MRI is the current standard for noninvasive diagnosis of OLT. Single-photon emission computed tomography combined with computed tomography (SPECT/CT) provides both morphologic and functional information. The purpose of the study was to compare SPECT/CT with MRI for image interpretation and treatment decision making in talar osteochondral lesions. MATERIALS AND METHODS: A total of 21 patients (four bilateral) were evaluated with MRI and SPECT/CT. Diagnostic arthroscopy was performed to validate the indication by identifying unstable cartilage areas. Activation was assessed in nine regions of interest, as described by Elias and colleagues. SPECT/CT findings were assessed by the modified scoring system of Hart and colleagues, and MRI findings with the modified classification system of Hepple and colleagues. Sensitivity, specificity, positive and negative predictive values, and accuracy were calculated for SPECT/CT and MRI. RESULTS: A total of 25 lesions were identified. Seventeen lesions were located on the medial third of the talar dome, eight on the lateral third, and seven on the central third. Four patients revealed diffuse uptake on more than one zone on SPECT/CT. SPECT/CT identified two subchondral lesions, which were not visualized on MRI. CONCLUSION: MRI is the current standard for OLT diagnosis. SPECT/CT allows a three-dimensional localization of scintigraphic osteoblastic activity in the area of interest, providing additional information about the involvement of the subchondral bone and the vitality of the osteochondral lesion and the location of multiple lesions. We recommend the use of SPECT/CT and MRI together for comprehensive diagnostic assessment of OLT. PMID- 25920052 TI - An investigation of client mood in the initial and final sessions of cognitive behavioral therapy and psychodynamic-interpersonal therapy. AB - OBJECTIVE: Our aim was to examine client mood in the initial and final sessions of cognitive-behavioral therapy (CBT) and psychodynamic-interpersonal therapy (PIT) and to determine how client mood is related to therapy outcomes. METHODS: Hierarchical linear modeling was applied to data from a clinical trial comparing CBT with PIT. In this trial, client mood was assessed before and after sessions with the Session Evaluation Questionnaire-Positivity Subscale (SEQ-P). RESULTS: In the initial sessions, CBT clients had higher pre-session and post-session SEQ P ratings and greater pre-to-post session mood change than did clients in PIT. In the final sessions, these pre, post, and change scores were generally equivalent across CBT and PIT. CBT outcome was predicted by pre- and post-session SEQ-P ratings from both the initial sessions and the final sessions of CBT. However, PIT outcome was predicted by pre- and post-session SEQ-P ratings from the final sessions only. Pre-to-post session mood change was unrelated to outcome in both treatments. CONCLUSIONS: These results suggest different change processes are at work in CBT and PIT. PMID- 25920054 TI - Complementary and integrative medicine for older adults in palliative care. AB - Complementary and Integrative Medicine (CIM) encompasses many diverse therapies, including natural products and mind and body practices. Use of CIM is common and can benefit patients in palliative care. However, because patients in palliative care are often frail and elderly, the clinician should consider a patient's comorbidities before recommending certain therapies, such as natural products. In this article, specific examples of CIM are provided for symptoms commonly seen in palliative care. PMID- 25920053 TI - Symptom management in the older adult: 2015 update. AB - This article updates the 2002 Jamie von Roenn article about "the palliation of commonly observed symptoms in older patients, including pain, neuropsychiatric, gastrointestinal, and respiratory symptoms." When palliative care was last covered in Clinics in Geriatric Medicine, President George W. Bush had just signed the No Child Left Behind Act, Homeland Security was being established, Michael Jackson won the Artist of the Century Award at the American Music Awards, and gas cost $1.61 a gallon. What has changed in the last decade and a half? PMID- 25920055 TI - Palliative care in the ambulatory geriatric practice. AB - Geriatrics and palliative care often overlap. This article focuses on 2 areas where the disciplines may differ in their approach. The first is planning for extreme illness and death, with explicit acknowledgment that limiting therapy might be a good idea. This situation is likely to have a different impact in the course of a routine geriatrics visit than in a palliative care context. The second is pain management, especially chronic pain. In patients with sharply limited life expectancy, the risk/benefit equation tilts easily toward narcotic use. In frail elders working to remain independent, the calculus may be quite different. PMID- 25920056 TI - Interaction of palliative care and primary care. AB - Primary care physicians are often the first medical providers patients seek out, and are in an excellent position to provide primary palliative care. Primary palliative care encompasses basic skills including basic evaluation and management of symptoms and discussions about goals of care and advance care planning. Specialty palliative care consultation complements primary care by assisting with complex psychosocial-spiritual patient and family situations. This article reviews primary palliative care skill sets and criteria for when to consider referring patients to specialty palliative care and hospice services. PMID- 25920057 TI - Communication with older, seriously ill patients. AB - This article describes effective communication strategies in caring for older, seriously ill patients and their surrogates/caregivers. Specific skills in three core functions are highlighted: (i) empathic communication (ii) information provision and (iii) enabling decision making. Empathy skills include using 'NURSE' statements and assuring a continuous relationship. Tailored information and empathic communication can be used to facilitate information processing and overcome age-related communication barriers. Eliciting patients' goals of care is critical in decision making. Surrogates need assistance when making decisions for patients and often themselves have support and information needs. Suggestions are made to ensure patients' and caregivers' needs are met. PMID- 25920058 TI - Communications by professionals in palliative care. AB - In this article, the author first examines the ageist bias that is prevalent in clinics today. The author then reviews the basic communication principles and strategies that can help clinicians make their conversations with patients more focused and meaningful, thereby preparing patients and their family caregivers to make decisions in a crisis and to engage in planning for end-of-life care as early and intensively as possible. PMID- 25920059 TI - Spirituality in geriatric palliative care. AB - This article presents an overview of spirituality as an essential domain of geriatrics palliative care, and provides guidelines for clinicians to diagnose spiritual distress and to integrate spirituality into their clinical practice. PMID- 25920060 TI - Public health and palliative care in 2015. AB - Palliative care is a public health concern, because the problems faced by patients and their families represent a substantial burden of illness and cost to the society that is likely to increase markedly in the future as the world's population continues to age. There are also inequities in access to palliative care and continued unmet need. There is evidence to support palliative care services, but not yet enough information on the cost-effectiveness of many specific treatments/interventions. PMID- 25920061 TI - Palliative care in the era of health care reform. AB - Research shows that early access to palliative care can significantly improve the quality of care for patients with chronic and advanced illnesses and reduce the overall costs of care. However, factors such as poor provider reimbursement mechanisms, inadequate formal education and training, workforce shortages, and low provider acceptance and patient engagement have created barriers to the widespread uptake of palliative care. Expanding access to these services requires their integration into new models of payment and delivery, such as Accountable Care Organizations, an overhaul of formal palliative care education and training, and improved messaging about these services to patients and providers. PMID- 25919952 TI - Whole genome comparison of a large collection of mycobacteriophages reveals a continuum of phage genetic diversity. AB - The bacteriophage population is large, dynamic, ancient, and genetically diverse. Limited genomic information shows that phage genomes are mosaic, and the genetic architecture of phage populations remains ill-defined. To understand the population structure of phages infecting a single host strain, we isolated, sequenced, and compared 627 phages of Mycobacterium smegmatis. Their genetic diversity is considerable, and there are 28 distinct genomic types (clusters) with related nucleotide sequences. However, amino acid sequence comparisons show pervasive genomic mosaicism, and quantification of inter-cluster and intra cluster relatedness reveals a continuum of genetic diversity, albeit with uneven representation of different phages. Furthermore, rarefaction analysis shows that the mycobacteriophage population is not closed, and there is a constant influx of genes from other sources. Phage isolation and analysis was performed by a large consortium of academic institutions, illustrating the substantial benefits of a disseminated, structured program involving large numbers of freshman undergraduates in scientific discovery. PMID- 25920062 TI - Culturally relevant palliative care. AB - The journey to excellence in palliative care practice is to recognize the three identities of patients, refine skills in assessment to understand these interrelated dimensions of personhood, and hone the practices of caring to deliver truly comprehensive and personalized care. These practices require clinicians to first connect to persons with illness on a human-human level. Being fully present and engaged with patients is critical to practicing high-quality palliative care. Clinicians must encourage and elicit the story of the illness and the life of the person experiencing the illness. PMID- 25920065 TI - Geriatrics and palliative care: all in the same family. PMID- 25920063 TI - International palliative care: Middle East experience as a model for global palliative care. AB - Care for elderly people with life-limiting illness cannot be delivered primarily by geriatricians or palliative care practitioners. The role of these clinicians is to help carers become adept in palliative care medicine. In a culture in which family ties run deep, the offer of palliative care from an outsider may be met with suspicion. The family bond in the Middle East is strong, but the emotional response to terminal illness may push families to request futile treatments, and physicians to comply. When palliative care is well developed and well understood, it provides a viable alternative to such extreme terminal measures. PMID- 25920064 TI - Emergency medicine and palliative care. AB - The emergency department cares for seriously ill patients across the trajectory of illness from diagnosis to death or cure. Emergency departments participate in critical illness trajectories that include initiation of life-sustaining therapies as well as caring for patients and families in their final moments of life. Emergency clinicians are uniquely poised to identify critical palliative care interventions to be used when patients and families are most in need with respect to symptom management, decisions regarding intervention and procedures to sustain life and participate in critically important decisions regarding withdrawing and withholding nonbeneficial life-sustaining therapies. PMID- 25920067 TI - Stretchable Thin-Film Electrodes for Flexible Electronics with High Deformability and Stretchability. AB - Flexible and stretchable electronics represent today's cutting-edge electronic technologies. As the most-fundamental component of electronics, the thin-film electrode remains the research frontier due to its key role in the successful development of flexible and stretchable electronic devices. Stretchability, however, is generally more challenging to achieve than flexibility. Stretchable electronic devices demand, above all else, that the thin-film electrodes have the capacity to absorb a large level of strain (>>1%) without obvious changes in their electrical performance. This article reviews the progress in strategies for obtaining highly stretchable thin-film electrodes. Applications of stretchable thin-film electrodes fabricated via these strategies are described. Some perspectives and challenges in this field are also put forward. PMID- 25920066 TI - Impact of climate change on cold hardiness of Douglas-fir (Pseudotsuga menziesii): environmental and genetic considerations. AB - The success of conifers over much of the world's terrestrial surface is largely attributable to their tolerance to cold stress (i.e., cold hardiness). Due to an increase in climate variability, climate change may reduce conifer cold hardiness, which in turn could impact ecosystem functioning and productivity in conifer-dominated forests. The expression of cold hardiness is a product of environmental cues (E), genetic differentiation (G), and their interaction (G * E), although few studies have considered all components together. To better understand and manage for the impacts of climate change on conifer cold hardiness, we conducted a common garden experiment replicated in three test environments (cool, moderate, and warm) using 35 populations of coast Douglas-fir (Pseudotsuga menziesii var. menziesii) to test the hypotheses: (i) cool temperature cues in fall are necessary to trigger cold hardening, (ii) there is large genetic variation among populations in cold hardiness that can be predicted from seed-source climate variables, (iii) observed differences among populations in cold hardiness in situ are dependent on effective environmental cues, and (iv) movement of seed sources from warmer to cooler climates will increase risk to cold injury. During fall 2012, we visually assessed cold damage of bud, needle, and stem tissues following artificial freeze tests. Cool-temperature cues (e.g., degree hours below 2 degrees C) at the test sites were associated with cold hardening, which were minimal at the moderate test site owing to mild fall temperatures. Populations differed 3-fold in cold hardiness, with winter minimum temperatures and fall frost dates as strong seed-source climate predictors of cold hardiness, and with summer temperatures and aridity as secondary predictors. Seed-source movement resulted in only modest increases in cold damage. Our findings indicate that increased fall temperatures delay cold hardening, warmer/drier summers confer a degree of cold hardiness, and seed-source movement from warmer to cooler climates may be a viable option for adapting coniferous forest to future climate. PMID- 25920068 TI - Yulangsan polysaccharide improves redox homeostasis and immune impairment in D galactose-induced mimetic aging. AB - Yulangsan polysaccharide (YLSP) is a traditional Chinese medicine used in long term treatment as a modulator of brain dysfunction and immunity. In this study, we evaluated the protective effect of YLSP against D-galactose-induced impairment of oxidative stress and the immune system and evaluated its possible mechanism of action. D-galactose was subcutaneously injected into the dorsal neck of mice daily for 8 weeks to establish the aging model. YLSP was simultaneously administered once daily. The results indicate that YLSP significantly improves the general appearance of the aging mice. YLSP significantly increased the levels of antioxidant enzymes, such as super oxide dismutase, glutathione peroxidase, catalase and total anti-oxidation capability, while decreasing the content of malondialdehyde in different tissues, including the liver, brain, and serum. YLSP also increased the interleukin-2 level while decreasing the interleukin-6 level. Moreover, YLSP significantly inhibited advanced glycation end product formation. Furthermore, YLSP decreased p21 and p53 gene expressions in the liver and brain of D-galactose-treated mice. These results suggest that YLSP may have a protective effect suppressing the aging process by enhancing antioxidant activity and immunity, as well as modulating aging-related gene expression. PMID- 25920069 TI - Functional photostability and cutaneous compatibility of bioactive UVA sun care products. AB - Sunscreens are the most-established approach for photoprotection. The strategy of providing antioxidant properties to sun care products by addition of natural and potent anti-free radical compounds has led to the development of bioactive sunscreens, able to neutralize the harmful effects of ultraviolet (UV) radiation. UVA filters, such as benzophenone-3 (BP) and butyl methoxydibenzoylmethane (BMDBM), can exhibit photodegradation which limits the development of broad spectrum sunscreens. Previous research verified that rutin interacts with filters incorporated in sunscreens. In this work, we focused on the development and evaluation of the efficacy of the sunscreens containing either BP or BMDBM with and without rutin. The addition of rutin to the UVA filters afforded antioxidant properties to the formulations and they were considered safe for human use. Additionally, rutin in combination with either BP or BMDBM increased the antioxidant activity about 40 times when compared with the UVA filters alone. Remarkably, the addition of rutin 0.1% (w/w) to BP 6.0% (w/w) raised the SPF from 24.3+/-1.53 to 33.3+/-2.89. In conclusion, these findings demonstrated that the addition of rutin into sunscreens can markedly improve the antioxidant properties of the formulation as well as photostabilize some of the UVA filters. PMID- 25920070 TI - Temperature modifies the association between particulate air pollution and mortality: A multi-city study in South Korea. AB - Substantial epidemiologic literature has demonstrated the effects of air pollution and temperature on mortality. However, there is inconsistent evidence regarding the temperature modification effect on acute mortality due to air pollution. Herein, we investigated the effects of temperature on the relationship between air pollution and mortality due to non-accidental, cardiovascular, and respiratory death in seven cities in South Korea. We applied stratified time series models to the data sets in order to examine whether the effects of particulate matter <10 MUm (PM10) on mortality were modified by temperature. The effect of PM10 on daily mortality was first quantified within different ranges of temperatures at each location using a time-series model, and then the estimates were pooled through a random-effects meta-analysis using the maximum likelihood method. From all the data sets, 828,787 non-accidental deaths were registered from 2000-2009. The highest overall risk between PM10 and non-accidental or cardiovascular mortality was observed on extremely hot days (daily mean temperature: >99th percentile) in individuals aged <65 years. In those aged >=65 years, the highest overall risk between PM10 and non-accidental or cardiovascular mortality was observed on very hot days and not on extremely hot days (daily mean temperature: 95-99th percentile). There were strong harmful effects from PM10 on non-accidental mortality with the highest temperature range (>99th percentile) in men, with a very high temperature range (95-99th percentile) in women. Our findings showed that temperature can affect the relationship between the PM10 levels and cause-specific mortality. Moreover, the differences were apparent after considering the age and sex groups. PMID- 25920071 TI - Occurrence of fungal metabolites--fumonisins at the ng/L level in aqueous environmental samples. AB - The B-series fumonisins (FBs) are some of the most prevalent mycotoxins produced as a secondary metabolite by Fusarium species growing on cereals. For decades they have been studied extensively in food and feed products, but there is no information about their occurrence in the aquatic environment or about how these mycotoxins are transported to the surface water and the groundwater. The aim of this study was to clarify the causes of fumonisin occurrence in aquatic ecosystems by examining the relation between mycotoxin contamination of crops and their levels in the aquatic environment. Water samples were collected from drainage ditches and wells or watercourses located in agricultural areas in the Wielkopolska region, Poland. Our research conducted on an annual basis showed the seasonal variability of fumonisin B1 concentration in the analyzed water samples, with the highest concentration in the post-harvest season (September to October) at 48.2 ng L(-1), and the lowest in winter and spring at 21.9 ng L(-1). Fumonisins B2 and B3 in water samples were not detected. Cereal samples were collected in the harvest season from each agricultural area close to tested water bodies. Mycotoxins were present in all cereal samples at concentrations from 43.3 to 1055.9 ng g(-1). Our results confirm that fumonisins are transported to aquatic systems by rainwater through soil. On the basis of available literature, this is the first report concerning the presence of fumonisin B1 in different aquatic environments. To date their ecotoxicological effects are largely unknown and require further investigation. PMID- 25920072 TI - Use of Tc-99 m thyroid scans in borderline congenital hypothyroidism. AB - BACKGROUND: Mild or borderline congenital hypothyroidism [often referred to as mild neonatal hyperthyrotropinemia (MNH)] is characterized by an abnormal newborn screen (NBS), followed by mildly elevated TSH and normal FT4 on confirmatory testing. This condition is increasingly observed, but data regarding optimal management are limited. OBJECTIVE: Examine the use of routine technetium thyroid scanning (TS) in the management of MNH. METHODS: Retrospective study of infants with MNH between 2000 and 2011. We assessed the clinical course of infants with MNH according to TS results; as a comparator, infants with classic congenital hypothyroidism (CH) were analysed in parallel. RESULTS: We identified 69 infants (52% boys) with MNH and 164 (34% boys) with classic CH. TS results were divided into four subgroups: no uptake in 7% of MNH vs 24% of classic CH (P < 0.01), decreased uptake/anatomical abnormalities in 39% vs 46% (p = NS), increased uptake in 35% vs 26% (p = NS) and normal uptake in 19% vs 4% (P < 0.01). In MNH, neither NBS-TSH, confirmatory TSH and FT4, mean LT-4 treatment doses and number of dose escalations, nor post-treatment FT4 and TSH differed among the four subgroups. In contrast, clinical features in infants with classic CH differed among the subgroups. Among MNH infants who reached 3 years of age, trial-off treatment was successful in 6 of 11 (55%) with no apparent difference in success rates among TS subgroups. CONCLUSIONS: The information provided by TS during evaluation of MNH does not predict clinical course; obtaining these scans in infants with MNH may not be an effective use of healthcare resources. PMID- 25920073 TI - Identification and characterization of a novel salt-tolerant esterase from a Tibetan glacier metagenomic library. AB - A salt-tolerant esterase, designated H9Est, was identified from a metagenomic library of the Karuola glacier. H9Est gene comprised 1071 bp and encoded a polypeptide of 357 amino acids with a molecular mass of 40 kDa. Sequence analysis revealed that H9Est belonged to the family IV of bacterial lypolitic enzyme. H9Est was overexpressed in Escherichia coli and the purified enzyme showed hydrolytic activity towards p-nitrophenyl esters with carbon chain from 2 to 8. The optimal esterase activity was at 40 degrees C and pH 8.0 and the enzyme retained its activity towards some miscible organic solvents such as polyethylene glycol. A three-dimensional model of H9Est revealed that S200, D294, and H324 formed the H9Est catalytic triad. Circular Dichroism spectra and molecular dynamic simulation indicated that the esterase had a wide denaturation temperature range and flexible loops that would be beneficial for H9Est performance at low temperatures while retaining heat-resistant features. PMID- 25920074 TI - Interexamination repeatability and spatial heterogeneity of liver iron and fat quantification using MRI-based multistep adaptive fitting algorithm. AB - PURPOSE: To assess the interexamination repeatability and spatial heterogeneity of liver iron and fat measurements using a magnetic resonance imaging (MRI)-based multistep adaptive fitting algorithm. MATERIALS AND METHODS: This prospective observational study was Institutional Review Board-approved and Health Insurance Portability and Accountability Act-compliant. Written informed consent was waived. In all, 150 subjects were imaged on 3T MRI systems. A whole-liver volume acquisition was performed twice using a six-echo 3D spoiled gradient echo sequence during two immediately adjacent examinations. Colocalized regions of interest (ROIs) in three different hepatic segments were placed for R2 * and proton density fat fraction (PDFF) measurements by two readers independently. Mean R2 * and PDFF values between readers and acquisitions were compared using the Wilcoxon signed-rank test, intraclass correlation coefficients (ICCs), linear regression, Bland-Altman analysis, and analysis of variance (ANOVA). RESULTS: The mean R2 * and PDFF values across all ROIs and measurements were 51.2 +/- 25.2 s( 1) and 6.9 +/- 6.4%, respectively. Mean R2 * and PDFF values showed no significant differences between the two acquisitions (P = 0.05-0.87). Between the two acquisitions, R2 * and PDFF values demonstrated almost perfect agreement (ICCs = 0.979-0.994) and excellent correlation (R(2) = 0.958-0.989). Bland Altman analysis also demonstrated excellent agreement. In the ANOVA, the individual patient and ROI location were significant effects for both R2 * and PDFF values (P < 0.05). CONCLUSION: MRI-based R2 * and PDFF measurements are repeatable between examinations. Between-measurement changes in R2 * of more than 10.1 s(-1) and in PDFF of more than 1.7% are likely due to actual tissue changes. Liver iron and fat content are variable between hepatic segments. PMID- 25920075 TI - Online Corrections are Faster Because Movement Initiation Must Disengage Postural Control. PMID- 25920076 TI - Motion robust GRAPPA for echo-planar imaging. AB - PURPOSE: A readout-segmented method for acquiring robust GRAPPA calibration data for echo-planar imaging (EPI) was proposed and compared with two previous methods, including the gold standard interleaved approach and a single shot method with halved phase encode resolution. THEORY AND METHODS: The readout segmented and single shot techniques acquire adjacent phase encode lines in the same shot to obtain the calibration data, rather than interleaving of lines between shots, to decrease sensitivity to motion. Additionally, it uses multiple segments with shortened frequency encode extent to match the phase encode bandwidth to the undersampled data, which decreases sensitivity to B0 inhomogeneity. The three methods were tested using simulations and EPI scans of the brain in healthy volunteers. RESULTS: The interleaved approach exhibited high sensitivity to motion, while residual undersampling artifacts remained in the single shot method due to mismatch of B0 inhomogeneity between the calibration and undersampled data. The readout segmented method exhibited no such errors, having 30% lower ghosting intensity than the single shot method and 90% lower ghosting intensity than the interleaved approach in moving subjects. CONCLUSION: Artifacts from B0 inhomogeneity and motion during calibration scans for EPI GRAPPA can be mitigated with a readout segmented calibration scan. PMID- 25920077 TI - Uncovering dental implants using a new thermo-optically powered (TOP) technology with tissue air-cooling. AB - BACKGROUND AND OBJECTIVES: Uncovering implants with lasers, while bloodless, has been associated with a risk of implant and bone overheating. The present study evaluated the effect of using a new generation of high-power diode lasers on the temperature of a dental implant and the surrounding tissues using an in vitro model. STUDY DESIGN/MATERIALS AND METHODS: The implant temperature was measured at three locations using micro thermocouples. Collateral thermal damage of uncovered soft tissues was evaluated using NTBC stain. Implant temperature rise during and collateral thermal soft-tissue damage following implant uncovering with and without tissue air-cooling was studied using both the classic operational mode and the new thermo-optically powered (TOP) technology. RESULTS: For the classic surgical mode using a cork-initiated tip and constant laser power set at 3.4 W, the maximum temperature rise in the coronal and apical parts of the implant was 23.2 +/- 4.1 degrees S and 9.5 +/- 1.8 degrees S, respectively, while 1.5 +/- 0.5 mm of collateral thermal damage of the soft tissue surrounding the implant model occurred. Using the TOP surgical tip with constant laser power reduced implant overheating by 30%; collateral thermal soft-tissue damage was 0.8 +/- 0.2 mm. Using the TOP surgical mode with a tip temperature setting of 800 degrees C and air-cooling reduced the implant temperature rise by more than 300%, and only 0.2 +/- 0.1 mm of collateral thermal soft-tissue damage occurred, typical for optimized CO2 laser surgery. Furthermore, use of the new generation diode technology (TOP surgical mode) appeared to reduce the time required for implant uncovering by a factor of two, compared to the standard surgical mode. CONCLUSIONS: Use of the new generation diode technology (TOP surgical mode) may significantly reduce overheating of dental implants during uncovering and seems to be safer for the adjacent soft and hard tissues. Use of such diode lasers with air-cooling can radically reduce the rise in implant temperatures (by more than three times), potentially making this technology safe and effective for implant uncovering. PMID- 25920078 TI - Emerging trends in hepatology: 30 years of the Journal of Hepatology and 50 years of EASL. PMID- 25920079 TI - Autoimmune hepatitis--Update 2015. PMID- 25920080 TI - Acute liver failure: A curable disease by 2024? AB - Over the last three decades acute liver failure (ALF) has been transformed from a rare and poorly understood condition with a near universally fatal outcome, to one with a well characterized phenotype and disease course. Complex critical care protocols are now applied and emergency liver transplantation (ELT) is an established treatment option. These improvements in care are such that the majority of patients may now be expected to survive (Fig. 1). Key features of the condition have changed dramatically over time, with a remarkable fall in the incidence of cerebral edema and intracranial hypertension, a much feared complication. In this review, we summarize the current understanding of key aspects of the classification, pathophysiology and management of ALF, and discuss the foreseeable challenges that will need to be addressed for further improvements to be achieved. PMID- 25920081 TI - Evolution in the understanding of the pathophysiological basis of portal hypertension: How changes in paradigm are leading to successful new treatments. AB - Among the common complication of cirrhosis portal hypertension witnessed a major improvement of prognosis during the past decades. Principally due to the introduction of rational treatments based on new pathophysiological paradigms (concepts of thought) developed in the 1980s. The best example being the use of non-selective beta-blockers and of vasopressin analogs, somatostatin, and its analogs. Further refinement in the knowledge of the molecular mechanisms involved in the regulation of both the splanchnic and hepatic circulation has led to the emergence of new treatments, which are based on evidence that show not only structural but also vasoactive components increase the hepatic vascular resistance, as well as of angiogenesis. This knowledge and future improvements will most likely result in more effective treatment of portal hypertension and effective prevention of its complications in early stages. PMID- 25920082 TI - Acute-on-chronic liver failure: A new syndrome that will re-classify cirrhosis. AB - Acute-on-chronic liver failure (ACLF) is a recently recognized syndrome characterized by acute decompensation (AD) of cirrhosis and organ/system failure(s) (organ failure: liver, kidney, brain, coagulation, circulation and/or respiration) and extremely poor survival (28-day mortality rate 30-40%). ACLF occurs in relatively young patients. It is especially frequent in alcoholic- and untreated hepatitis B associated-cirrhosis, in addition it is related to bacterial infections and active alcoholism, although in 40% of cases no precipitating event can be identified. It may develop at any time during the course of the disease in the patient (from compensated to long-standing cirrhosis). The development of ACLF occurs in the setting of a systemic inflammation, the severity of which correlates with the number of organ failures and mortality. Systemic inflammation may cause ACLF through complex mechanisms including an exaggerated inflammatory response and systemic oxidative stress to pathogen- or danger/damage-associated molecular patterns (immunopathology) and/or alteration of tissue homeostasis to inflammation caused either by the pathogen itself or through a dysfunction of tissue tolerance. A scoring system composed of three scores (CLIF-C OFs, CLIF-C AD, and CLIF-C ACLFs) specifically designed for patients with AD, with and without ACLF, allows a step-wise algorithm for a rational indication of therapy. The management of ACLF should be carried out in enhanced or intensive care units. Current therapeutic measures comprise the treatment for associated complications, organ failures support and liver transplantation. PMID- 25920084 TI - Hepatic fibrosis: Concept to treatment. AB - Understanding the molecular mechanisms underlying liver fibrogenesis is fundamentally relevant to developing new treatments that are independent of the underlying etiology. The increasing success of antiviral treatments in blocking or reversing the fibrogenic progression of chronic liver disease has unearthed vital information about the natural history of fibrosis regression, and has established important principles and targets for antifibrotic drugs. Although antifibrotic activity has been demonstrated for many compounds in vitro and in animal models, none has been thoroughly validated in the clinic or commercialized as a therapy for fibrosis. In addition, it is likely that combination therapies that affect two or more key pathogenic targets and/or pathways will be needed. To accelerate the preclinical development of these combination therapies, reliable single target validation is necessary, followed by the rational selection and systematic testing of combination approaches. Improved noninvasive tools for the assessment of fibrosis content, fibrogenesis and fibrolysis must accompany in vivo validation in experimental fibrosis models, and especially in clinical trials. The rapidly changing landscape of clinical trial design for liver disease is recognized by regulatory agencies in the United States (FDA) and Western Europe (EMA), who are working together with the broad range of stakeholders to standardize approaches to testing antifibrotic drugs in cohorts of patients with chronic liver diseases. PMID- 25920085 TI - Cell therapy for liver disease: From liver transplantation to cell factory. AB - Work over several decades has laid solid foundations for the advancement of liver cell therapy. To date liver cell therapy in people has taken the form of hepatocyte transplantation for metabolic disorders with a hepatic basis, and for acute or chronic liver failure. Although clinical trials using various types of autologous cells have been implemented to promote liver regeneration or reduce liver fibrosis, clear evidence of therapeutic benefits have so far been lacking. Cell types that have shown efficacy in preclinical models include hepatocytes, liver sinusoidal endothelial cells, mesenchymal stem cells, endothelial progenitor cells, and macrophages. However, positive results in animal models have not always translated through to successful clinical therapies and more realistic preclinical models need to be developed. Studies defining the optimal repopulation by transplanted cells, including routes of cell transplantation, superior engraftment and proliferation of transplanted cells, as well as optimal immunosuppression regimens are required. Tissue engineering approaches to transplant cells in extrahepatic locations have also been proposed. The derivation of hepatocytes from pluripotent or reprogrammed cells raises hope that donor organ and cell shortages could be overcome in the future. Critical hurdles to be overcome include the production of hepatocytes from pluripotent cells with equal functional capacity to primary hepatocytes and long-term phenotypic stability in vivo. PMID- 25920083 TI - Liver cancer: Approaching a personalized care. PMID- 25920086 TI - From immunosuppression to tolerance. AB - The past three decades have seen liver transplantation becoming a major therapeutic approach in the management of end-stage liver diseases. This is due to the dramatic improvement in survival after liver transplantation as a consequence of the improvement of surgical and anaesthetic techniques, of post transplant medico-surgical management and of prevention of disease recurrence and other post-transplant complications. Improved use of post-transplant immunosuppression to prevent acute and chronic rejection is a major factor in these improved results. The liver has been shown to be more tolerogenic than other organs, and matching of donor and recipients is mainly limited to ABO blood group compatibility. However, long-term immunosuppression is required to avoid severe acute and chronic rejection and graft loss. With the current immunosuppression protocols, the risk of acute rejection requiring additional therapy is 10-40% and the risk of chronic rejection is below 5%. However, the development of histological lesions in the graft in long-term survivors suggest atypical forms of graft rejection may develop as a consequence of under immunosuppression. The backbone of immunosuppression remains calcineurin inhibitors (CNI) mostly in association with steroids in the short-term and mycophenolate mofetil or mTOR inhibitors (everolimus). The occurrence of post transplant complications related to the immunosuppressive therapy has led to the development of new protocols aimed at protecting renal function and preventing the development of de novo cancer and of dysmetabolic syndrome. However, there is no new class of immunosuppressive drugs in the pipeline able to replace current protocols in the near future. The aim of a full immune tolerance of the graft is rarely achieved since only 20% of selected patients can be weaned successfully off immunosuppression. In the future, immunosuppression will probably be more case oriented aiming to protect the graft from rejection and at reducing the risk of disease recurrence and complications related to immunosuppressive therapy. Such approaches will include strategies aiming to promote stable long-term immunological tolerance of the liver graft. PMID- 25920087 TI - New paradigms in the treatment of hepatic cholestasis: from UDCA to FXR, PXR and beyond. AB - Cholestasis is an impairment of bile formation/flow at the level of the hepatocyte and/or cholangiocyte. The first, and for the moment, most established medical treatment is the natural bile acid (BA) ursodeoxycholic acid (UDCA). This secretagogue improves, e.g. in intrahepatic cholestasis of pregnancy or early stage primary biliary cirrhosis, impaired hepatocellular and cholangiocellular bile formation mainly by complex post-transcriptional mechanisms. The limited efficacy of UDCA in various cholestatic conditions urges for development of novel therapeutic approaches. These include nuclear and membrane receptor agonists and BA derivatives. The nuclear receptors farnesoid X receptor (FXR), retinoid X receptor (RXR), peroxisome proliferator-activated receptor alpha (PPARalpha), and pregnane X receptor (PXR) are transcriptional modifiers of bile formation and at present are under investigation as promising targets for therapeutic interventions in cholestatic disorders. The membrane receptors fibroblast growth factor receptor 4 (FGFR4) and apical sodium BA transporter (ASBT) deserve attention as additional therapeutic targets, as does the potential therapeutic agent norUDCA, a 23-C homologue of UDCA. Here, we provide an overview on established and future promising therapeutic agents and their potential molecular mechanisms and sites of action in cholestatic diseases. PMID- 25920089 TI - 30 years of the Journal of Hepatology--The flagship journal and the crown-jewel of EASL. PMID- 25920088 TI - Trends in the management and burden of alcoholic liver disease. AB - Alcoholic liver disease (ALD) is the most prevalent cause of advanced liver disease in Europe and is the leading cause of death among adults with excessive alcohol consumption. There is a dose-response relationship between the amount of alcohol consumed and the risk of ALD. The relative risk of cirrhosis increases in subjects who consume more than 25 g/day. The burden of alcohol-attributable liver cirrhosis and liver cancer is high and is entirely preventable. Health agencies should develop population-based policies to reduce the prevalence of harmful and/or hazardous alcohol consumption and foster research in this field to provide new diagnostic and therapeutic tools. Disease progression of patients with ALD is heavily influenced by both genetic and environmental factors. Non-invasive methods for the diagnosis of fibrosis have opened new perspectives in the early detection of advanced ALD in asymptomatic patients. Alcoholic hepatitis, the most severe form of ALD, carries a high short-term mortality (around 30-50% at 3 months). Corticosteroids improve short-term survival in patients with severe alcoholic hepatitis but duration of therapy should be adapted to early response. Liver transplantation is the best option for patients with severe liver dysfunction. However, alcohol relapse after transplantation remains a critical issue and drinking habits of transplanted patients need to be routinely screened. PMID- 25920090 TI - NAFLD: a multisystem disease. AB - Non-alcoholic fatty liver disease (NAFLD) is the most common cause of chronic liver disease in Western countries that is predicted to become also the most frequent indication for liver transplantation by 2030. Over the last decade, it has been shown that the clinical burden of NAFLD is not only confined to liver related morbidity and mortality, but there is now growing evidence that NAFLD is a multisystem disease, affecting extra-hepatic organs and regulatory pathways. For example, NAFLD increases risk of type 2 diabetes mellitus (T2DM), cardiovascular (CVD) and cardiac diseases, and chronic kidney disease (CKD). Although the primary liver pathology in NAFLD affects hepatic structure and function to cause morbidity and mortality from cirrhosis, liver failure and hepatocellular carcinoma, the majority of deaths among NAFLD patients are attributable to CVD. This narrative review focuses on the rapidly expanding body of clinical evidence that supports the concept of NAFLD as a multisystem disease. The review discusses the factors involved in the progression of liver disease in NAFLD and the factors linking NAFLD with other extra-hepatic chronic diseases, such as T2DM, CVD, cardiac diseases and CKD. The review will not discuss NAFLD treatments as these are discussed elsewhere in this issue of the Journal. For this review, PubMed was searched for articles using the keywords "non-alcoholic fatty liver disease" or "fatty liver" combined with "diabetes", "cardiovascular (or cardiac) disease", "cardiovascular mortality" or "chronic kidney disease" between 1990 and 2014. Articles published in languages other than English were excluded. PMID- 25920091 TI - Genetics of liver disease: From pathophysiology to clinical practice. AB - Paralleling the first 30 years of the Journal of Hepatology we have witnessed huge advances in our understanding of liver disease and physiology. Genetic advances have played no small part in that. Initial studies in the 1970s and 1980s identified the strong major histocompatibility complex associations in autoimmune liver diseases. During the 1990 s, developments in genomic technologies drove the identification of genes responsible for Mendelian liver diseases. Over the last decade, genome-wide association studies have allowed for the dissection of the genetic susceptibility to complex liver disorders, in which also environmental co-factors play important roles. Findings have allowed the identification and elaboration of pathophysiological processes, have indicated the need for reclassification of liver diseases and have already pointed to new disease treatments. In the immediate future genetics will allow further stratification of liver diseases and contribute to personalized medicine. Challenges exist with regard to clinical implementation of rapidly developing technologies and interpretation of the wealth of accumulating genetic data. The historical perspective of genetics in liver diseases illustrates the opportunities for future research and clinical care of our patients. PMID- 25920092 TI - Current efforts and trends in the treatment of NASH. AB - Of all the aspects of non-alcoholic fatty liver disease (NAFLD), the slowest advances have occurred in the therapeutic field. Thirty-five years after its formal description and after 15 years of intense scrutiny from researchers worldwide, there is still no approved drug for the treatment of non-alcoholic steatohepatits (NASH). In the meantime, progress in the understanding of pathophysiology, diagnosis - both invasive and non-invasive, epidemiology and even natural history have been substantial or, at times, spectacular. In contrast, hepatitis C virus (HCV) therapy underwent constant improvement and even before the great acceleration of the past few years, patients were already being offered approved therapies that were increasingly more efficient. What then explains such a slow pace of therapeutic advances in NASH, and will this change in the near future? Here we will review commonly-held myths that have diverted attention from therapy of NASH, obstacles that have slowed down industrial development of drugs for this indication, and recent achievements that will create better conditions for drug development programs. We will also briefly review current knowledge of non-pharmacological and pharmacological management in this early era of NASH therapies. PMID- 25920093 TI - Strategies to control hepatitis B: Public policy, epidemiology, vaccine and drugs. AB - The last 50 years of hepatitis B research has resulted in the development of effective screening assays for surveillance, vaccines for prevention and antiviral drugs that significantly improve patient clinical outcomes. Not surprisingly then, the global epidemiology of hepatitis B virus (HBV) is set to change dramatically over the next decade. For example, the success and the high coverage of universal HBV vaccination and the ageing cohorts of patients with chronic hepatitis B (CHB) will result in reductions of incidence and prevalence of chronic hepatitis, cirrhosis and probably hepatocellular carcinoma. This will be further accelerated by the impressive progress in the treatment outcomes for patients with CHB. In spite of this success, challenges remain, such as planning for the impact of migration from countries with high prevalence rates to those countries with low rates of HBV infection. The recent establishment of the World Health Organisation Global Hepatitis Program with the provision of a framework for global action has become the cornerstone for all countries to now frame their own particular national responses to control hepatitis B. An effective policy framework can prevent new infections, ensure people can access clinical care, and in doing so reduce the burden of infection at an individual, country and regional level. These developments present a real opportunity to reduce the significant, social and economic burden of global hepatitis B, ultimately the critical next steps to render the world hepatitis B free. PMID- 25920094 TI - From non-A, non-B hepatitis to hepatitis C virus cure. AB - The hepatitis C virus (HCV) was discovered in the late 1980s. Interferon (IFN) alpha was proposed as an antiviral treatment for chronic hepatitis C at about the same time. Successive improvements in IFN-alpha-based therapy (dose finding, pegylation, addition of ribavirin) increased the rates of sustained virologic response, i.e. the rates of curing HCV infection. These rates were further improved by adding the first available direct-acting antiviral (DAA) drugs to the combination of pegylated IFN-alpha and ribavirin. An IFN-free era finally started in 2014, yielding rates of sustained virologic response over 90% in patients treated for 8 to 24 weeks with all-oral regimens. Major challenges however remain in implementation of these new treatment strategies, not only in low- to middle income countries, but also in high-income countries where the price of these therapies is still prohibitive. Elimination of HCV infection through treatment in certain areas is possible but raises major public health issues. PMID- 25920095 TI - MR-derived cerebral spinal fluid hydrodynamics as a marker and a risk factor for intracranial hypertension in astronauts exposed to microgravity. AB - PURPOSE: To quantify the change in cerebral spinal fluid (CSF) production rate and maximum systolic velocity in astronauts before and after exposure to microgravity and identify any physiologic trend and/or risk factor related to intracranial hypertension. MATERIALS AND METHODS: Following Institutional Review Board (IRB) approval, with waiver of informed consent, a retrospective review of 27 astronauts imaged at 3T was done. Qualitative analysis was performed on T2 weighted axial images through the orbits for degree of flattening of the posterior globe according to the following grades: 0 = none, 1 = mild, 2 = moderate, and 3 = severe. One grade level change postflight was considered significant for exposure to intracranial hypertension. CSF production rate and maximum systolic velocity was calculated from cine phase-contrast magnetic resonance imaging and compared to seven healthy controls. RESULTS: Fourteen astronauts were studied. The preflight CSF production rate in astronauts was similar to controls (P = 0.83). Six astronauts with significant posterior globe flattening demonstrated a 70% increase in CSF production rate postflight compared to baseline (P = 0.01). There was a significant increase in CSF maximum systolic velocity in the subgroup without posterior globe flattening (P = 0.01). CONCLUSION: The increased postflight CSF production rate in astronauts with positive flattening is compatible with the hypothesis of microgravity-induced intracranial hypertension inferring downregulation in CSF production in microgravity that is upregulated upon return to normal gravity. Increased postflight CSF maximum systolic velocity in astronauts with negative flattening suggests increased craniospinal compliance and a potential negative risk factor to microgravity-induced intracranial hypertension. PMID- 25920096 TI - [Genitourinary tumor]. PMID- 25920097 TI - [I. Technological advances in computational imaging for urological surgery virtual surgical simulation for partial nephrectomy]. PMID- 25920098 TI - [II. Radiotherapy for prostate cancer-the role of multi-disciplinary team]. PMID- 25920099 TI - [III. Topics of chemotherapy]. PMID- 25920100 TI - [IV. Multidisciplinary team for testicular cancer]. PMID- 25920101 TI - Neuroanatomy and pathology of sporadic Alzheimer's disease. PMID- 25920102 TI - Reply: To PMID 25694204. PMID- 25920103 TI - Erratum. AB - The publisher found that the following CE tests were published with incorrect DOIs:In the CE Test for "The Baltimore Buprenorphine Initiative: Understanding the Role of Buprenorphine in Addressing Heroin Addiction in an Urban-Based Community." (2014). Journal of Addictions Nursing, 25(1), 26Y27, doi: 10.1097/JAN.0000000000000013 should have been doi: 10.1097/JAN.0000000000000024. In the CE Test for "Substance Abuse Treatment Processes and Outcomes in Day/Outpatient Health Maintenance Organization Setting." (2014). Journal of Addictions Nursing, 25(3), 137Y138, doi: 10.1097/JAN.0000000000000013 should have been doi: 10.1097/JAN.0000000000000044. In the CE Test for "NADA Protocol: Integrative Acupuncture in Addictions." (2014). Journal of Addictions Nursing, 25(4), 188Y189, doi: 10.1097/JAN.0000000000000013 should have been doi: 10.1097/JAN.0000000000000057. PMID- 25920104 TI - Reply: To PMID 25437479. PMID- 25920105 TI - Reply: To PMID 24576651. PMID- 25920106 TI - [Discovery of Burkholderia Thailandensis isolated from melioidosis endemic areas of Hainan China]. PMID- 25920107 TI - [Effect of central obesity on cardiac structure in middle aged men having health examination from the Kailuan group]. PMID- 25920108 TI - [Medical audit: the beginning of a new era]. PMID- 25920109 TI - [Renewal of work philosophy at the IMSS]. AB - The Instituto Mexicano del Seguro Social (IMSS) is the main institution of social security in Mexico and has been a pioneer in Latin America in the comprehensive organization of medical attention. This and many other achievements have been possible due to the preparation and performance of its staff, their professionalism, humanitarian sense, commitment to the institution and solidarity with the population. Today, the IMSS is ready to face not only the present but also the future and anticipate what is best for the institution and its insured population. PMID- 25920110 TI - [Why chikunguna instead of chikungunya?]. PMID- 25920111 TI - [Comment regarding the article "new coronavirus infections: new challenges, new legacies"]. PMID- 25920113 TI - The times they are a changin'. PMID- 25920112 TI - [Answer to comments regarding the article "new coronavirus infections: new challenges, new legacies"]. PMID- 25920114 TI - [A chronicle about Jorge Martinez Manautou, illustrious doctor of the IMSS]. PMID- 25920115 TI - Are compliance programs now required by law? PMID- 25920116 TI - Engaging patients in the age of meaningful use. PMID- 25920117 TI - Should physicians friend or unfriend social media? 'It's complicated'. PMID- 25920118 TI - As narrow networks make their way to Michigan, physician leaders consider their impact on health care spending. PMID- 25920119 TI - ICD-10 preparation starts now. PMID- 25920120 TI - Hospital collaboration boosts system quality, patient outcomes. It all began with a checklist. PMID- 25920121 TI - Nick Lyon, Director of the Michigan Department of Community Health. PMID- 25920122 TI - DTaP vaccination. It takes the full series to protect children. PMID- 25920123 TI - Mandatory flu shots for employees. Policy implementation & best practices. PMID- 25920124 TI - Alliance update on immunizations. PMID- 25920125 TI - Year-end planning can save you time and money. PMID- 25920126 TI - Our babies are growing up to be doctors. PMID- 25920127 TI - The difference between a Living Will and a Medical Treatment Power of Attorney. PMID- 25920128 TI - Medical clearance does not clear the patient or physician of risks. PMID- 25920129 TI - Michigan brain drain: how many physicians are we losing from underfunded GME? PMID- 25920130 TI - MSMS-backed EpiPen law will save children's lives, combat food allergies at schools. PMID- 25920131 TI - The art & science of end-of-life care: navigating the road less traveled. PMID- 25920132 TI - From babies to Michigan's newest medical school, it's all in the delivery for Doctor Burns. PMID- 25920133 TI - Electronic health record malpractice risks. PMID- 25920134 TI - Diversification matters: ignore the temptation to chase last year's winners. PMID- 25920135 TI - Travelers' health: what you need to know about immunizations. PMID- 25920136 TI - Michigan 7,325-Mississippi 23. PMID- 25920137 TI - The growing void of leadership training in medical education. PMID- 25920138 TI - Closing your practice: medical record retention, storage and destruction. PMID- 25920139 TI - Rising number of infectious disease cases creates patient safety issues. PMID- 25920140 TI - What now? The new proposed rule change for Stage 2 meaningful use. PMID- 25920141 TI - Hospital consolidations: the bottom line for physicians. PMID- 25920143 TI - Why physicians should run for political office ... and how to get started. PMID- 25920142 TI - Voice of medicine heard in state budget process. PMID- 25920144 TI - Active vs passive investing--which is better for you? PMID- 25920145 TI - Northern Physician Organization, MSMS group member, launches physician-led ACO. PMID- 25920146 TI - Influenza--looking back, looking forward, and looking for ways to improve. PMID- 25920147 TI - Reducing Michigan's high rate of unvaccinated children. PMID- 25920148 TI - Changing health care world needs our voice. PMID- 25920150 TI - CMS releases final rule for meaningful use Stage 2 flexibility. PMID- 25920149 TI - Some closely held corporations no longer required to provide contraception coverage. PMID- 25920151 TI - Be cybersecure: protect patient records, avoid fines, and safeguard your reputation. PMID- 25920152 TI - Home grown--community partnerships shape Michigan's newest medical school. PMID- 25920153 TI - New Huron Valley Physician Association President positions organization for the future. PMID- 25920154 TI - Michigan licensure renewal requirements. PMID- 25920155 TI - MSMS Physicians Insurance Agency. PMID- 25920156 TI - Justices for law. PMID- 25920157 TI - Employer mandate deadline is approaching for some. PMID- 25920158 TI - It's time to take a seat at the table. PMID- 25920159 TI - There's always hope. PMID- 25920160 TI - Inspiration on the island. PMID- 25920161 TI - Randomized controlled trial study design. PMID- 25920162 TI - When a baby dies. Families and care providers need help coping with unexpected loss. PMID- 25920163 TI - Blood conservation coordinators and the ONTraC program. Ensuring the appropriate and judicious use of blood in surgical patients. PMID- 25920164 TI - Inspiring confidence to overcome incontinence. Nurse continence advisors help their patients regain control. PMID- 25920165 TI - Reducing the treatment of asymptomatic bacteriuria in seniors in a long-term care facility. AB - Cases of asymptomatic bacteriuria (ASB) in elderly people are often treated with antibiotics, but current guidelines recommend that bacteriuria in seniors not be treated unless it is associated with a urinary tract infection (UTI). Stanford Place Care Campus is a 182-bed complex-care facility in Parksville, B.C., catering primarily to seniors. To increase the accuracy of the clinical diagnosis of UTIs and reduce the treatment of ASB in this facility, the author developed a self-learning package and a clinical pathway to help nurses and other care providers better assess, manage and monitor residents with suspected UTIs. She also provided education sessions for the nursing and support staff. In the year after the new clinical pathway was introduced, the number of treated UTIs decreased, as did the percentage of treated UTIs that had been inadequately assessed (i.e., diagnosed solely on the basis of a dipstick urinalysis). PMID- 25920166 TI - The pillars of CNS practice. PMID- 25920167 TI - An emerging leader in her field. Manal Kleib helps students and nurses embrace informatics. PMID- 25920168 TI - Tobacco lawsuits hold public health potential. PMID- 25920169 TI - [The internal quality control of medical care in military medical organizations]. AB - Quality control of medical care and safety of medical practice in the military medical organizations of the Ministry of Defence of Russia is one of the priorities. Guidelines set by The plan for improvement of effectiveness of health protection in servicemen and certain categories of citizens, which is approved by the relevant order of the Minister of Defence of the Russian Federation, can be regarded as a criteria for quality assessment of medical care. The internal quality control and safety of medical practice is a multilevel system of making and implementing. management decisions aimed at ensuring the rights of patients to receive quality medical care, as.well as provides a continuous internal audit of medical diagnostic work-military medical organization. The overriding objective is the use of technical means during all forms of internal control. . .. PMID- 25920170 TI - [Lines of research in the field of cellular technologies and its application in military medicine]. AB - The paper presents an overview of cellular therapy products and medical tissue engineering of the leading countries of the world (including the US) and identifies lines of research in the field of cellular technology application in the interests of national military medicine. The authors gave information concerning practical implementation of the achievements of biomedical research in the field of regenerative cellular products and technologies in Russia as different products, which may be used at the stages of medical evacuation. The authors presented results of research, which was, performed on the model of mine blast injury in accordance with principle possibility of the usage of cellular technologies products (multipotent mesenchymal stromal cells) in medical practice. PMID- 25920171 TI - [Problems of military medical examination of military servicemen suffering from chronic obstructive pulmonary disease]. AB - The authors showed that at the present time military much more servicemen, suffering from obstructive pulmonary disease, may receive medical examination in outpatient conditions. Series of researches allow us to perform a medical examination on an outpatient basis. The calculation of the cost-effectiveness of health services to such patients during a military medical examination in the hospital and clinics was made. Savings during the examination in the clinic for 1 patient was 2829 rubbles. PMID- 25920172 TI - [Combined burn trauma in the array of modern civilian and combat burns]. AB - The current article positions the combined burn and non-burn injuries in the general array of civilian and combat burns. For that purpose the official state statistics and scientific medical publications, domestic as well as foreign, have been analyzed. It has been shown that in peace time the combined burn/trauma injuries are infrequent. But the same type of injury becomes routine especially among the civilian population in the conditions of the modern so called "hybrid war". And the medical service should be prepared for it. PMID- 25920173 TI - [Pneumonia in wounded]. AB - Pneumonia is one of the common complications of wounds of any localization. Therapists are involved into the treatment of lung lesions in wounded in the ICU, in the surgical and if the patient arrives "on follow-up care,"--in the medical ward. The article analyzes the main statistical indicators reflecting the prevalence and clinical and pathogenetic characteristics of lung pathology in wounded during the Great Patriotic War, during the fighting Soviet troops in the Republic of Afghanistan, the 1st and 2nd Chechen campaign. Pneumonia as a manifestation of traumatic disease can occur in two ways. Primary pneumonia is in close connection with the pathogenetic traumatic injury. Secondary lung lesions complicate the injury at a later date and are due to the introduction of a nosocomial infection process flora. We describe the clinical picture of pneumonia in the affected, the basic pathogenesis, principles of therapy. Successful treatment of lung pathology in wounded depends on the performance of a complex of activities involving a wide range of doctors of various specialties. PMID- 25920174 TI - [Hypertension morbidity in contract military personnel serving in the Eastern Military District according to dynamic monitoring]. AB - The authors researched the changes in the prevalence of hypertension and major risk factors (overweight, obesity, smoking and high cholesterol) in men of young age--officers of the Eastern Military District during the five-year dynamic observation (2009-2014). 1043 servicemen were selected for the survey. 96.5% of selected servicemen or 1011 people agreed to take part in the survey, the average age was from 25 to 45 years. It was found that among young men the prevalence of hypertension decreased to 24.4%; this result is lower than in the group of civilian population of the same age. It was also found that commitment to healthy lifestyle has increased and the prevalence of the most common risk factors (overweight and obesity, hypercholesterolemia, smoking, alcohol consumption) has decreased but in comparison with the civil population prevalence of modifiable risk factors remains high. The study showed that during the reform of the Armed Forces of the Russian Federation and the inherent strength of military labour remains high, which can not but affect the health officers, 95.5% identified hypertensive patients in our study, young men 35 years with 1st stage of the disease. PMID- 25920175 TI - [The treatment of patients with circulatory system pathology in health resorts "Tarkhovskii" and "Priozerskii"]. AB - The authors showed the history of foundation and development of health resorts "Tarkhovsky" and "Priozersky", as well as an analysis of the treatment of patients with circulatory system diseases in these health resorts. It was found that the structure of patients fitted the profile of health resorts and in recent years has remained stable. Patients with circulatory system diseases accounted for 47.8%. The existing system of medical rehabilitation and restorative treatment of patients with diseases of the circulatory system in the health resorts "Tarkhovsky" and "Priozersky" ensures the implementation in full rehabilitation and recovery programs for all categories of contingent attached. PMID- 25920176 TI - [The experience of realization of health resort rehabilitation programs for children under conditions of "The Central military health resort for children"]. AB - Health resort treatment is one of the stages of rehabilitation for children. The Central Military health resort for children is a dynamic diversified health resort for the treatment of children and adults, using its arsenal all available, at the resort natural factors. In the conditions of sanatorium for the treatment of children apply advanced medical technologies, the development of modern medical equipment. PMID- 25920177 TI - [Medical support of the 65th Army during the East Prussian offensive operation performed by the 2nd Belorussian Front]. AB - Prussian offensive operation performed by the 2nd Belorussian Front. An activity of the medical An activity of the medical service of the 65th Army during the East Prussian offensive operation performed by the 2nd Belorussian Front is a typical example of the medical support of troops during the final stages of World War II. Forms and methods of medical support management, which were developed during the war, haven't lost their importance in modern conditions. These methods include the establishment of specialized surgical and therapeutic field hospital, establishment of medical institutions in the Army, which worked on the evacuation directions and reserve of mobile hospitals and transport, timely extension of the first echelons of the hospital base front to change institutions hospital deployed the army base. A research of experience in organizing medical support of the offensive operations performed during the last year of World War II provides the material for the development of the theory of modern medical support operations and ability to provide on this basis, the continuity of the hospitals, the continuity of qualified and specialized medical care, improve the performance of diagnostic and treatment work. PMID- 25920178 TI - [Viktor Borisovich von Gyubbenet--a military physician, a surgeon and a social activist]. AB - The current article is dedicated to a talented surgeon, an organizer of military health care, an extraordinary personality and a public figure--Doctor of Medicine, a privy councilor Victor Borisovich von Guebbenet. A talent of von Gyubbenea as a doctor-surgeon and an organizer of the surgical help on theater of war was especially brightly shown during two big military conflicts of the beginning of the XX century--the Russo-Japanese War (1904-1905) and the First World War I (1914-1918). In the first case doctor von Gyubbenet, being a surgeon of the 3rd Siberian corps successfully manage the activity of military-medical divisions and establishments of Port Arthur garrison. In the second military conflict Victor Borisovich as a doctor and an organizer headed sanitary part of armies of the Western front and successfully directed a medical support of armies of the front since 1915 and until the end of war. PMID- 25920179 TI - [A corps physician V.P. Kravkov and his notes about the First World War]. PMID- 25920180 TI - [Reflections in our 55th anniversary]. AB - Investigacion Clinica has been published uninterruptedly for 55 years and for this reason, the University of Zulia has recognized the work of its editorial team with the imposition of the Order "Jesus Enrique Lossada". Despite some financial and structural problems we are optimistic because our journal has been included in new international indices and it is connected to the scientific world through the contributions from all continents; by the selfless collaboration of hundreds of domestic and foreign referees who respond with great professionalism; and through the visits to our website, from virtually around the world. Reviewing the SCImago statistical analysis, we found that among the Venezuelan medical journals, Investigacion Clinica is first in cites per document (2 years) and second in the H index, and compares favorably with prestigious Latin-American journals. It is noteworthy that both in Venezuela and beyond our borders, the submission of topic reviews has increased in detriment of original papers or contributions. It seems that the lack of financial support to research institutes and universities, has led to a decline in experimental projects, at least in the medical field that occupies this journal, so researchers resort to reviews in their respective fields, as a compensation to maintain their productivity. This has caused that the Editorial Board has limited the reception of reviews to keep intact the percentage of published original contributions. Finally, we would like to think that there are no obstacles that can not be overcome to maintain our excellence in publishing Investigacion Clinica. PMID- 25920181 TI - [Case reports of drug-induced liver injury in a reference hospital of Zulia state, Venezuela]. AB - Drug-induced liver injury (DILI) is an important cause of morbidity and mortality worldwide, with varied geographical differences. The aim of this prospective, descriptive, cross-sectional study was to identify and characterize cases of DILI in a hospital of Zulia state, Venezuela. Thirteen patients with a presumptive diagnosis of DILI attended by the Department of Gastroenterology, Hospital Universitario, Zulia state, Venezuela, from December-2012 to December-2013 were studied. Ibuprofen (n = 3; 23.1%), acetaminophen (n = 3; 23.1), isoniazid (n = 2; 15.4%) and Herbalife products (n = 2; 15.4%) were the main drugs involved with DILI. Acetaminophen and ibuprofen showed a mixed pattern of liver injury (n = 3; 23.1%) and isoniazid presented a hepatocellular pattern (n = 2; 15.4%). The CIOMS/RUCAMS allowed the identification of possible (n = 7; 53.9%), probable (n = 4; 30.8%) and highly-probable cases (n = 2; 15.4%) of DILI. Amoxicillin/clavulanate, isoniazid, isotretinoin, methotrexate and Herbalife nutritional products were implicated as highly-probable and probable agents. The highest percentage of DILI corresponded to mild cases that recovered after the discontinuation of the agent involved (n = 9; 69.3%). The consumption of Herbalife botanical products is associated with probable causality and fatality (n = 1; 7.7%). In conclusion, the frequency of DILI cases controlled by the Department of Gastroenterology of the Hospital Universitario of Maracaibo was low, being ibuprofen, acetaminophen, isoniazid and products Herbalife the products most commonly involved. It is recommended to continue with the prospective registration of cases, with an extended follow up monitoring period and to facilitate the incorporation of other hospitals in the Zulia State and Venezuela. PMID- 25920182 TI - [Tests of liver function in obese school children]. AB - The non alcoholic fatty liver disease (NAFLD) manifests with liver damage and it is associated with obesity. The objective of this work was to detect the risk of obese school students of developing NAFLD, through an analytical, observational study, comparing their liver function with that of a control group, and its relationship with physical activity, dietary, biochemical and anthropometric variables. One hundred and sixty school students (ages 7-11) were evaluated according to their socio-economic status; nutritional status by the body mass index (BMI) and mid-upper arm fat area (MUAC) (Project Venezuela 1994); body fat percentage by anthropometry (% BF), waist circumference (WC); and metabolism by oral glucose tolerance, basal insulin and post-load glucose, total cholesterol (TC), cLDL, cVLDL, cHDL, triglycerides (TG), glutamic oxaloacetic transaminase (GOT), glutamic pyruvic transaminase (GPT), gamma glutamil transpeptidasa (GGTP) and albumin. Their diet was analyzed by the 24-hour recall and their physical activity by a clinical trial. Mean levels of GPT (p < 0.05), greater frequencies of elevated GOT and GPT (p < 0.05) and lower albumin levels (p < 0.05) were observed in 88 obese school students when compared to controls. The GPT correlated significantly with the BMI, MUAC, % BF, WC, basal insulin and post load glucose, HOMA, cVLDL, cHDL and TG, while the GOT correlated with MUAC and the GGTP with MUAC, basal insulin, HOMA and cLDL. Albumin was negatively correlated with BMI, MUAC, % BF and WC. TGP reflected better the hepatic compromise of obesity. To assess the risk of NAFLD, the TGO/TGP values should be standardized according to age, gender and race. PMID- 25920183 TI - [Prone position: effect on gas exchange and functional capacity for exercise in patients with pulmonary hypertension]. AB - The objective of this investigation was to evaluate gas exchange and cardiopulmonary functional behavior in patients with pulmonary hypertension (PH) before, during and after the change to a prone position. Thirty patients with PH and alterations in gas exchange were included in the study. Gas exchange measurements were performed in four stages: at the baseline supine position and after 30, 120 and 240 minutes in prone position. Also, the patients were evaluated by the six minutes walking test (6MWT) after 30 days in prone position during night's sleep. After four hours in prone position, all patients showed an increase of PaO2 and arterial saturation of oxygen (SaO2), with a decrease of intrapulmonary shunts, improving the gas exchange and therefore the physiological demand imposed by exercise in patients with PH. PMID- 25920184 TI - Myopathy in patients with Hashimoto's disease. AB - Hashimoto thyroiditis (HT) is an autoimmune disease of the thyroid gland. Patients may present or not a hypothyroid state, and frequently have manifestations of myopathy. The present work was aimed to assess the clinical symptoms and signs of skeletal muscle alterations in HT, describe the muscular pathological changes and relate them to the functional thyroid status and to the autoimmune condition of the patient. Clinical and laboratory studies were performed in ten HT patients and three control subjects (hormonal levels and electromyography). Biopsies from their vastus lateralis of quadriceps femoris muscle were analyzed under light (histochemistry and immunofluorescense) and electron microscopy. All patients showed muscle focal alterations, ranging from moderate to severe atrophy, necrosis, activation of satellite cells, presence of autophagosomes, capillary alterations and macrophage and mast cell infiltration, common to autoimmune diseases. The intensity of clinical signs and symptoms was not related to the morphological muscle findings, the electromyography results, or to the state of the thyroid function. Reactions for immunoglobulin in muscle fibers were positive in 80% of the patients. Fiber type II proportion was increased in all patients, with the exception of those treated with L-thyroxine. In conclusion, autoimmune processes in several of the patients may be associated to the skeletal muscle alterations, independently of the functional state of the thyroid gland; however, fiber II type proportion could have been normalized by L thyroxine treatment. PMID- 25920185 TI - P16(INK 4a) and Ki-67 expression in human papilloma virus-related head and neck mucosal lesions. AB - Human papilloma virus (HPV) is postulated as a risk factor in the etiology of some specific mucosal pathologies in the head and neck regions. Despite the frequent use of p16(INK4a) as a surrogate marker for HPV-infection, there is still controversy with respect to its reliability. This study has been undertaken to assess the potential role of p16(INK 4a) and Ki-67 expression in HPV-related lesions. The study was conducted on 71 specimens of oral, tonsillar and laryngeal lesions which comprised 25 dysplasia and 46 papilloma specimens. Specimens were immunohistochemically stained for p16(INK4A) and Ki-67 proteins. HPV DNA was determined by one step multiplex polymerase chain reaction. HPV DNA was detected in 33.8% of all lesions. Tonsil and larynx lesions showed significant differences with oral lesions for HPV positivity (p < 0.001). p16(INK 4a) over-expression was seen in 56.5% of papilloma and 60% of dysplasia specimens. HPV status showed a positive correlation with p16(INK 4a) expression in tonsillar dysplasias (p < 0.001). p16(INK 4a) expression may have a value as a marker in high risk HPV induced dysplasias, but not in low risk infected lesions. The proliferation index is not related to HPV-induced lesions and may be evaluated as an independent marker in head and neck premalignant lesions. PMID- 25920186 TI - Syringoma of vulva: an unusual presentation. Clinical, morphological and immunohistochemical aspects. AB - The case of a 34-year-old woman, who consulted because she observed the appearance of numerous yellow-white asymptomatic papules on the vulva, is presented. Clinical diagnosis of syringoma of vulva was established. The pathological and immunohistochemical studies confirmed the diagnosis. Vulvar syringoma usually occurs as a multiple flesh-colored or brownish papules on both sides of labia majora of women in their third decade. Its diagnosis should be considered when the patient complaints of vulvar pruritus and/or sweating. PMID- 25920187 TI - Cystic fibrosis and pregnancy: counseling, obstetrical management and perinatal outcome. AB - The progress in research of in vitro fertilization and fetal-maternal medicine allows more women and men, with fertility problems due to cystic fibrosis, to have a baby. In the majority of cases, pregnancy in women with cystic fibrosis results in favorable maternal and fetal outcomes. However, the incidence of preterm delivery, intrauterine growth restriction, caesarean section and deterioration of the maternal health are increased. Pre-pregnancy counseling is a crucial component of overall obstetric care, especially in women with poor pulmonary function. Additionally, closer monitoring during pregnancy with a multidisciplinary approach is required. The value of serial ultrasound scans and fetal Doppler assessment is important for the control of maternal and fetal wellbeing, as well as for the definition of the appropriate timing of delivery. In this article, clinical issues of pregnant women with cystic fibrosis are reviewed; counseling, obstetrical management and perinatal outcomes are being discussed. PMID- 25920188 TI - [Inflammasome: activation mechanisms]. AB - Inflammation is a rapid biologic response of the immune system in vascular tissues, directed to eliminate stimuli capable of causing damage and begin the process of repair. The macromolecular complexes known as "inflammasomes" are formed by a receptor, either NOD (NLR) or ALR, the receptor absent in melanoma 2 (AIM2). In addition, the inflammasome is formed by the speck-like protein associated to apoptosis (ASC) and procaspase-1, that may be activated by variations in the ionic and intracellular and extracellular ATP concentrations; and the loss of stabilization of the fagolisosomme by internalization of insoluble crystals and redox mechanisms. As a result, there is activation of the molecular platform and the processing of inflammatory prointerleukins to their active forms. There are two modalities of activation of the inflammasome: canonical and non-canonical, both capable of generating effector responses. Recent data associate NLRP 3, IL-1beta and IL-18 in the pathogenesis of a variety of diseases, including atherosclerosis, type II diabetes, hyperhomocysteinemia, gout, malaria and hypertension. The inflammasome cascade is emerging as a new chemotherapeutic target in these diseases. In this review we shall discuss the mechanisms of activation and regulation of the inflammasome that stimulate, modulate and resolve inflammation. PMID- 25920189 TI - [The role of SIRT1 in the treatment of diabetic nephropathy]. AB - Diabetic nephropathy presents an increasing trend worldwide. It has been an attractive area to find novel targets for the treatment of diabetic nephropathy. SIRT1 (Sirtuin 1), a member of deacetylation enzymes, regulates cell senescence, metabolism, and apoptosis. In last ten years, lots of studies showed that SIRT1 exerts a protective effect in the progression of the diabetic nephropathy by promoting reconstruction of energy homeostasis, modulating cell redox state, resisting cell apoptosis, inhibiting inflammation and ameliorating renal fibrosis. SIRT1 has become a potential new target for the treatment of diabetic nephropathy. PMID- 25920190 TI - [The recent advances in the host targets of anti-influenza drugs]. AB - The challenge of the emergence of drug-resistant influenza strains, which is caused by wide spread utilization of direct-acting antivirals (DAAs), accelerates the research and exploration towards host targeted agents. In contrast to DAAs targeting viral replication components, host targeted agents, which regulate host factors and pathways linked to viral replication, can interfere the replication of influenza. Additionally, the innate immune system is activated by influenza during the early stage of infection, so manipulating the innate immune response may prevent the viral infection. However, the excessive inflammatory response induced at the late phase of influenza infection would lead to severe tissue injures. Thus, it is very important to explore drugs with anti-inflammatory actions to suppress these immune imbalances and tissue injures. Here we overview the current progresses about host targets related to anti-influenza drugs. PMID- 25920191 TI - [Application of activatable cell-penetrating peptide in the field of tumor therapy]. AB - Cell-penetrating peptide (CPP) is a kind of small molecular peptide which can pass through a variety of cell membranes. It can carry bioactive macromolecules into cells. Due to lacking of tissue-selecting and targeting behavior, the application of CPP in the field of tumor treatment is limited. Activatable cell- penetrating peptide (ACPP) has brought the dawn to the application of CPP. This review mainly introduces the applications of ACPP in the targeting antitumor drug delivery which was designed based on the differences between tumor microenvironment and normal tissues as well as the exogenous physical stimulation. PMID- 25920192 TI - [Research advances of the influence factors of high level expression of recombinant protein in Pichia pastoris]. AB - Pichia pastoris is one of the most important systems used in the field of molecular biology for the expression of recombinant proteins. The system has advantages of high expression, high stability, high secretion, easy high-density fermentation and low cost. Many factors affect the expression of recombinant protein, such as gene copy number, codon usage preference, type of promoter, molecular chaperones, glycosylation, signal peptide and fermentation process. In this review, research advances of the above aspects are summarized, which lay a foundation for improving the expression of recombinant proteins in P. pastoris. PMID- 25920193 TI - [RNA-Seq and genuine traditional Chinese medicine]. AB - RNA-Sequencing (RNA-Seq) is a newly-developed method in transcriptome research, it can afford more accurate transcription information and be more quickly by using Next-generation Sequencing (NGS) technology. RNA-Seq has been widely used in various biological fields. Genuine traditional Chinese medicines (TCM), with good quality and therapeutic effect, were always praised highly and used by famous physicians. The geo-herbalism formation of TCM is based on the product of the gene expression at specific space and time. So it has been a research hotspot to analyze the mechanism of biosynthesis through RNA-Seq in the study on the secondary metabolism of medicinal plant. This article mainly illustrates the RNA Seq and its advantages, it also discusses the potential application in genuine TCM, and it can provide useful information for other researchers. PMID- 25920194 TI - [Establishment and application of screening methods for non-agonist PPARgamma ligand]. AB - In-vitro assay methods were established to evaluate transactivation and binding activity of compounds on peroxisome proliferator-activated receptor y (PPARgamma). Firstly, plasmids were constructed for transactivation assay of PPARgamma response element (PPRE) triggered reporter gene expression, and for cell-based binding activity assay of the chimeric receptor, which was fused with PPARgamma ligand binding domain (LBD) and yeast transcriptional activator Gal4. Secondly, by using PPARy competitive binding assay based on time resolved fluorescence resonance energy transfer (TR-FRET), affinities of compounds and drugs to PPARgamma were evaluated. In application of these above methods, the PPARgamma activating potency and characteristics of different compounds were evaluated, and a novel benzeneselfonamide derivative, ZLJ01, was found to have comparable binding activity and affinity with the well-known PPARy agonist, but lack of PPRE mediated transactivation activity. In preliminary study on in-vitro hypoglycemic activity, ZLJ1 was found to promote insulin-stimulated glucose uptake by liver cells. Therefore, we believe that combining transactivation and binding activity as well as affinity evaluation, the system could be used to screen non-agonist PPARgamma ligand as anovel PPARgamma modulator PMID- 25920195 TI - [Construction and functional analysis of a bispecific antibody that targets TNF alpha and ED-B]. AB - In order to enhance the specificity of TNF-alpha monoclonal antibody to inflamed site, a bispecific antibody BsDb that targets TNF-alpha and the extra-domain B (ED-B) of fibronectin (FN) was constructed by covalently linking the anti-TNF alpha single chain Fv antibody (TNF-scFv) and the anti-ED-B scFv L19 via a flexible peptide linker deriving from human serum albumin (HSA). ED-B is an antigen specifically expressed at the inflamed site. BsDb is expressed in E. coli, identified by immunoblot, and purified with affinity chromatography. This was followed by further examination of its bioactivities and pharmacokinetics. We demonstrated that BsDb retained the immunoreactivity of its original antibodies as it could simultaneously bind to TNF-alpha and ED-B and neutralize the biological action of TNF-alpha. In the collagen-induced arthritis mice model, BsDb selectively accumulate in the inflamed joint with a maximal uptake of (12.2 +/- 1.50)% ID/g in a single inflamed paw and retain in the inflamed paw for at least 72 h. In contrast, BsDb showed a short serum half-life of (0.50 +/- 0.05) h and a rapid clearance from normal tissues. The findings reported herein indicate that BsDb has good specificity to the inflamed site and low toxicity to normal tissues. BsDb is therefore likely to have greater clinical applications in the treatment of rheumatoid arthritis and other autoimmune diseases. This laid a stable basis for its preclinical study. PMID- 25920196 TI - [A model-based meta-analysis to compare urate-lowering response rate of febuxostat and allopurinol in gout patient]. AB - This study aims to compare the urate-lowering response rate of febuxostat and allopurinol in gout patient using a model-based meta-analysis. The literature search identified 22 clinical trials of gout with a total of 43 unique treatment arms that met our inclusion criteria, and a total of 6 365 gout patients were included in the study. The response rates of allopuriol and febuxostat were characterized by Tmax model and Emax model respectively, and the effect of baseline serum uric acid (sUA) and patient type on the drug effect was tested. The results showed that allopurinol can reach an average maximum response rate of 50.8% while febuxostat can reach a 100% response rate within a very short time, and the ED50 was 34.3 mg. Covariate analysis revealed that baseline sUA has a negative effect on response rate of allopurinol, and a positive effect on the predicted ED50 of febuxostat. For patients who had shown inadequate response to prior allopurinol treatment, the average response rate was about half that of the allopurinol responder patients. PMID- 25920197 TI - [Predicting pharmacokinetics of anti-cancer drug, famitinib in human using physiologically based pharmacokinetic model]. AB - This study is to establish physiologically based pharmacokinetic (PBPK) models of famitinib in rat and monkey, and then to predict the pharmacokinetics and tissue distribution of famitinib in human based on the PBPK models. According to published paper, previous studies and the chemical properties of famitinib predicted by ACD/ADME suite and SimCYP, the PBPK models of rat and monkey were established and optimized using GastroPlus. And then, the PBPK models were applied to predict the pharmacokinetic and tissue distribution of famitinib in human. The results showed that the PBPK models of rat and monkey can fit the observed data well, and the AUC0-infinity, ratios of observed and calculated data in rat and monkey were 1.00 and 0.97, respectively. The AUC0-infinity, ratios of observed and predicted data in human were 1.63 (rat to human) and 1.57 (monkey to human), respectively. The rat and monkey PBPK models of famitinib were well established, and the PBPK models were applied in predicting pharmacokinetic of famitinib in human successfully. Hence, the PBPK model of famitinib in human could be applied in future drug-drug interaction study. PMID- 25920198 TI - Twelve benzene derivatives from Clausena excavata. AB - A new phenethanol, (2'R)-4-(2', 3'-dihydroxy-3'-methyl-butanoxy)-phenethanol (1), along with other eleven known benzene derivatives (2-12) were isolated from the roots, stems and leaves of Clausena excavata (Rutaceae). Compounds 3 and 4 are new natural products, and compounds 5-8, 10-12 were isolated from C. excavata for the first time. Their structures were elucidated on the basis of MS, 1D and 2D NMR spectroscopic analyses including HSQC, COSY and HMBC experiments. 1 was tested for its cytotoxicities against A549, HeLa and BGC-823 cancer cell lines, and antimicrobial activities against Candida albicans and Staphylococcus aureus. The results showed that 1 did not exhibit cytotoxic and antimicrobial activities. PMID- 25920199 TI - [Synthesis, antitumor activity and SAR of C-3 oxadiazole sulfanylacetylhydrazone substituted fluoroquinolone analogues]. AB - To explore an efficient strategy for the conversion of antibacterial fluoroquinolones into antitumor fluoroquinolones, an azole heterocyclic ring of oxadiazole instead of the C-3 carboxylic acid group with a functionalized hydrazone group as a modified side-chain, fifteen novel 2-(fluoroquinolon-3-yl) oxadiazole-5- sulfanylacetylhydrazone derivatives 7a-7o were designed and synthesized on the basis of the pharmacophore hybridization principle from pefloxacin, separately. The structures for fifteen title compounds were characterized by elemental analysis, 1H NMR and MS, and their in vitro antitumor activity against Hep-3B cell line was evaluated by a MTT assay. The results showed that the title compounds exhibited more significantly inhibitory activity than that of the parent pefloxacin, in which compounds with electron-withdrawing group attached on aryl ring had more potency than that of compounds with electron donating group, especially compounds with a carboxylic substituent were comparable to comparison doxorubicin. It suggests that it is favorable for an improvement of antitumor activity to remain a carboxylic acid unit at the aromatic ring. PMID- 25920200 TI - [Identification of aminoalcohol-diterpenoid alkaloids in Aconiti Lateralis Radix Praeparata and study of their cardiac effects]. AB - In order to affirm the cardioactive components in Fuzi, we identified a group of aminoalcohol- diterpenoid alkaloids in Fuzi using ultra high-performance liquid chromatography coupled with electrospray ionization mass spectrometer (UPLC-ESI MS) method. Among a total of forty-one isolated ingredients, thirteen major aminoalcohol-diterpenoid alkaloids were identified by comparing their retention times and MS spectra with those of the reference substances. Moreover, Fuzi samples from different places of origin and with different processing methods were examined and their components displayed a pattern of high similarity, though the relative abundance varies probably due to their different processing methods. Furthermore, the cardiac effect of each identified alkaloid was individually evaluated using the isolated bullfrog heart perfusion experiment. Among the thirteen aminoalcohol diterpenoid alkaloids tested, six of them significantly enhanced the amplitude rates. Taken together, we affirm that the cardioactive components in Fuzi are aminoalcohol-diterpenoid alkaloids, shedding light on future studies of the mechanisms and development of these cardioactive compounds. PMID- 25920201 TI - [The metabolic fingerprint of the compatibility of Radix Aconite and Radix Paeoniae Alba and its effect on CYP450 enzymes]. AB - Using a UPLC-MS/MS (MRM) and cocktail probe substrates method, the metabolic fingerprint of the compatibility of Radix Aconite (RA) and Radix Paeoniae Alba (RPA) and its effect on CYP450 enzymes were investigated. These main CYP isoforms include CYP 1A2, CYP 2C, CYP 2E1, CYP 2D and CYP 3A. Compared with the inhibition effect of RA decoctions on CYP450 isoforms, their co-decoctions of RA and RPA with different proportions can decrease RA' inhibition on CYP3A, CYP2D, CYP2C and CYP1A2, but can not reduce RA' effect on CYP2E1. The metabolic fingerprints of RA decoction and co-decoctions with different proportions of RPA in CYP450 of rat liver were analyzed by UPLC-MS. Compared with the metabolic fingerprints of RA decoction, the intensity of diester-diterpenoid aconitum alkaloids decreased significantly, while the intensity of monoester-diterpenoid alkaloids significantly increased in the metabolic fingerprints of co-decoctions of RA and RPA. The results suggest that RA coadministration with RPA increased the degradation of toxic alkaloid and show the effect of toxicity reducing and efficacy enhancing. PMID- 25920202 TI - [Rapid simultaneous determination of ten major flavonoids in Tetrastigma hemsleyanum by UPLC-MS/MS]. AB - In this study, a rapid and sensitive analytical method was developed for the determination of 10 major compounds (procyanidin B1, catechin, procyanidin B2, rutin, isoquercitrin, kaempferol-3-O-rutinoside, astragalin, quercitrin, quercetin, and kaempferol) in Tetrastigma hemsleyanum by using ultra-performance liquid chromatography coupled with triple-quadrupole tandem mass spectrometry (UPLC-MS/MS) in multiple-reaction monitoring (MRM) mode. UPLC-MS/MS assay with negative ion mode was performed on a Waters CORTECS C18 (2.1 mm x 100 mm, 1.6 MUm) with the mobile phase consisting of acetonitrile (A) and 0.1% aqueous formic acid (B) in gradient elution at a flow rate of 0.25 mL . min(-1) and the column temperature was set at 45 degrees C. Under the optimized chromatographic conditions, good separation for 10 target compounds were obtained including chiral isomer procyanidins B1 and B2 were completely separated within 8.5 min. Satisfactory linearity was achieved with wide linear range and fine determination coefficient (r > 0.996 6), the overall recoveries were ranged from 95.44%-110.40% with the RSD ranging from 2.37%-8.69%. It is the first report about simultaneous analysis of 10 major flavonoids components in Tetrastigma hemsleyanum by using UPLC-MS/MS method, which affords highly sensitive, specific, speedy and efficient method for quality control of Tetrastigma hemsleyanum PMID- 25920203 TI - [Cell-penetrating chimeric apoptotic peptide AVPI-LMWP/DNA co-delivery system for cancer therapy]. AB - To develop a cell-penetrating chimeric apoptotic peptide AVPI-LMWP/DNA co delivery system for cancer therapy, we prepared the AVPI-LMWP/pTRAIL self assembled complexes containing a therapeutic combination of peptide drug AVPI and DNA drug TRAIL. The chimeric apoptotic peptide AVPI-LMWP was synthesized using the standard solid-phase synthesis. The cationic AVPI-LMWP could condense pTRAIL by electrostatic interaction. The physical-chemical properties of the AVPI LMWP/pTRAIL complexes were characterized. The cellular uptake efficiency and the inhibitory activity of the AVPI-LMWP/pTRAIL complexes on tumor cell were also performed. The results showed that the AVPI-LMWP/pTRAIL complexes were successfully prepared by co-incubation. With the increase of mass ratio (AVPI LMWP/DNA), the particle size was decreased and the zeta potential had few change. Agarose gel electrophoresis showed that AVPI-LMWP could fully bind and condense pTRAIL at a mass ratio above 15:1. Cellular uptake efficiency was improved along with the increased ratio of W(AVPI-LMWP)/WpTRAIL. The in vitro cytotoxicity experiments demonstrated that the AVPI-LMWP/pTRAIL (W:W = 20:1) complexes was significantly more effective than the pTRAIL, AVPI-LMWP alone or LMWP/pTRAIL complexes on inhibition of HeLa cell growth. Our studies indicated that the AVPI LMWP/pTRAIL co-delivery system could deliver plasmid into HeLa cell and induce tumor cell apoptosis efficiently, which showed its potential in cancer therapy using combination of apoptoic peptide and gene drugs. PMID- 25920204 TI - [Cloning, prokaryotic expression, and functional identification of a sesquiterpene synthase gene (AsSS4) from Aquilaria sinensis]. AB - A sesquiterpene synthase (AsSS4) full-length open reading frame (ORF) cDNA was cloned from wounded stems of Aquilaria sinensis by RT-PCR method. The result showed that the ORF of AsSS4 was 1,698 bp encoding 565 amino acids. Prokaryotic expression vector pET28a-AsSS4 was constructed and transformed into E. coli BL21 (DE3) pLysS. Recombinant AsSS4 protein was obtained after induction by IPTG and SDS-PAGE analysis with a MW of 64 kD. Enzymatic reactions using farnesyl pyrophosphate showed that recombinant AsSS4 protein purified by Ni-agarose gel yielded five sesquiterpene compounds, cyclohexane, 1-ethenyl-1-methyl-2, 4-bis(1 methylethenyl)-, beta-elemene, alpha-guaiene, alpha-caryophyllene and delta guaiene. This paper reported the first cloning and functional characterization of AsSS4 gene from A. sinensis, which will establish a foundation for future studies on the molecular mechanisms of wound-induce agarwood formation in A. sinensis PMID- 25920205 TI - [Molecular identification in genus of Lilium based on DNA barcoding]. AB - To establish a new method for identifying genus of Lilium by DNA barcoding technology, ITS, ITS2, psbA-trnH, matK and rbcL sequences were analyzed in term of variation of inter- and intra-species, barcoding gap, neighbor-joining tree to distinguish genus of Lilium based on 978 sequences from experimental and GenBank database, and identification efficiency was evaluated by Nearest distance and BLAST1 methods. The results showed that DNA barcoding could identify different species in genus of Lilium. ITS sequence performed higher identification efficiency, and had significant difference between intra- and inter-species. And NJ tree could also divide species into different clades. Results indicate that DNA barcoding can identify genus of Lilium accurately. ITS sequence can be the optimal barcode to identify species of Lilium. PMID- 25920206 TI - [Anti-hyperuricemia effect and mechanism of polydatin in mice]. AB - Hyperuricemia mice model was established with uricase inhibitor (potassium oxonate) and uric acids in serum were observed. Polydatin (5, 10, 20 mg . kg(-1)) and benzbromarone (16.7 mg . kg(-1)) were given ig for 7 d in mice. Kidney tissues were used to detect gene contents ofurate anion transporter 1 (URAT1), organic anion transporter 1 (OAT1) and organic anion transporter 3 (OAT3) by real time-PCR. The results showed that polydatin and benzbromarone can significantly reduce uric acid in blood of hyperuricemia mice (P < 0.05), compared with the model group. URAT1, OAT1 and OAT3 contents of the kidney in hyperuricemia mice changed significantly (P < 0.05), compared with the blank group. Polydatin can significantly inhibit the changing trends in these genes induced by potassium oxonate in a dose-dependent manner, the difference was significant (P < 0.05), compared with the model group. Those indicated that polysatin could reduce the level of the serum uric acid through promoting uric acid excretion. PMID- 25920207 TI - Expedient access to enantiopure cyclopentanic natural products: total synthesis of (-)-cyclonerodiol. AB - Following the principles of collective total synthesis, a number of natural products sharing an optically pure, multifunctional, cyclopentanic core were synthesized from a common precursor: plinol A (1). This intermediate was efficiently obtained in only four steps from (-)-linalool (2) using as the key step a Ti(III)-mediated diastereoselective radical cyclization. The feasibility of this approach was confirmed with the expedient enantiospecific synthesis of cyclonerodiol (3), and the formal synthesis of chocol G (4) and piperitone (5). PMID- 25920208 TI - Identification of sesquiterpene lactones in the Bryophyta (mosses) Takakia: Takakia species are closely related chemically to the Marchantiophyta (liverworts). AB - Takakia lepidozioides has been considered to be the most primitive liverwort morphologically and classified initially in the Marchantiophyta (liverworts). However, the Takakia have been reclassified from liverworts to mosses on the basis of the similarity of the male sporophyte of T. ceratophylla to that of some mosses. Reinvestigation of secondary metabolites of fresh T. lepidozioides resulted in identification of eudesmane-type sesquiterpene lactones and hydrocarbon that are significant chemical markers of several liverworts. T. lepidozioides also produces a small amount of hop-22(29)-ene, together with coumarin, which produce the characteristic odor of T. lepidozioides, and 1,4 hydroquinone; these are the predominant volatile components, whereas dihydrocoumarin, 1,4-benzoquinone, dihydrobenzofuran, alpha-asarone and alpha tocopherol are minor components. These chemical results indicated that T. lepidozioides is more closely related to the Marchantiophyta than the Bryophyta. T. lepidozioides is morphologically similar to the liverwort Haplomitrium species. However, both species are totally different chemically. PMID- 25920209 TI - Chemotypes of Ligularia vellerea, its hybrids, and L. melanothyrsa. AB - Ligularia vellerea and L. melanothyrsa have been found to share chemical characteristics based on geography. In one chemotype (Shangrila type), the major components were either 15-oxygenated furanoeremophilanes or eremophilanolides; and in another (Luguhu type), either 1-angeloyloxyfuranoeremophilanes or corresponding lactones. The two L. vellerea samples were found to have experienced hybridization with either L. cyathiceps or L. kanaitzensis; however, compounds typical of L. vellerea alone were isolated from them. PMID- 25920210 TI - Neo-Clerodane diterpenoids from Scutellaria altissima. AB - Nine neo-clerodane diterpenoids, scutaltisins B-G, scupolin I, scutecolumnin C and 11-epi-scutecolumnin C have been isolated from the acetone extract of the aerial parts of Scutellaria altissima. Scutaltisins B-G are new compounds, whereas scupolin I, scutecolumnin C and 11-epi-scutecolumnin C are reported in this species for the first time. PMID- 25920211 TI - Phytotoxicity of triterpenes and limonoids from the Rutaceae and Meliaceae. 5alpha,6beta,8alpha,12alpha-Tetrahydro-28-norisotoonafolin--a potent phytotoxin from Toona ciliata. AB - Limonoids and triterpenes are the largest groups of secondary metabolites and have notable biological activities. Meliaceae and Rutaceae are known for their high diversity of metabolites, including limonoids, and are distinguished from other families due to the frequent occurrence of such compounds. The increased interest in crop protection associated with the diverse bioactivity of these compounds has made these families attractive in the search for new allelopathic compounds. In the study reported here we evaluated the bioactivity profiles of four triterpenes (1-4) and six limonoids (5-10) from Meliaceae and Rutaceae. The compounds were assessed in a wheat coleoptile bioassay and those that had the highest activities were tested on the standard target species Lepidinum sativum (cress), Lactuca sativa (lettuce), Lycopersicon esculentum (tomato) and Allium cepa (onion). Limonoids showed phytotoxic activity and 5alpha,6beta,8alpha, 12alpha- tetrahydro-28-norisotoonafolin (10) and gedunin (5) were the most active, with bioactivity levels similar to, and in some cases better than, those of the commercial herbicide Logran. The results indicate that these products could also be allelochemicals involved in the ecological interactions of these plant species. PMID- 25920212 TI - Triterpene glycosides of sea cucumbers (Holothuroidea, Echinodermata) as taxonomic markers. AB - Triterpene glycosides are characteristic metabolites of sea cucumbers (Holothurioidea, Echinodermata). The majority of the glycosides belong to the holostane type {lanostane derivatives with an 18(20)-lactone}. Carbohydrate chains of these glycosides contain xylose, glucose, quinovose, 3-O-methylglucose, and, rarely, 3-O-methylxylose, 3-O-methylglucuronic acid, 3-O-methylquinovose, and 6-O-acetyl-glucose. The glycosides are specific for genera, groups of genera and even for species. The advantages and problems in the use of triterpene glycosides as taxonomic markers in the systematics of sea cucumbers are discussed. PMID- 25920213 TI - Amurensiosides L-P, five new cardenolide glycosides from the roots of Adonis amurensis. AB - Five new cardenolide glycosides, amurensiosides L-P (1-5), were isolated from the roots of Adonis amurensis. Their structures were determined based on extensive spectroscopic analysis, including two-dimensional (2D) NMR data, and on the results of hydrolytic cleavage. Compounds 1-5 were evaluated for their cytotoxic activities against HL-60 human promyelocytic leukemia and HSC-2 human oral squamous cell carcinoma cell lines. PMID- 25920214 TI - UV-protective effects of phytoecdysteroids from Microsorum grossum extracts on human dermal fibroblasts. AB - Microsorum grossum (Polypodiaceae), locally called metuapua'a, is one of the most frequently used fern species in Polynesian traditional medicine. Fronds or rhizomes of this species are common ingredients of popular medicine recipes to cure various ailments. M. grossum frond and rhizome extracts contain, as their main bioactive components, phytoecdysteroids such as 20-hydroxyecdysone, known to have many interesting biological activities and considered to be adaptogenic compounds [1]. The skin-active effect of M. grossum extract was investigated in two ways on human dermal fibroblasts: a transcriptomic study with c-DNA array for gene expression modulation and a Stress Induced Premature Senescence (SIPS) test. The total extract of M. grossum up-regulates Heme Oxygenase 1 (HO1), an enzyme which protects cells from oxidative stress and which is responsible for skin photoimmunoprotection. The present paper also reports that premature senescence of human skin induced by repeated UV irradiations can be prevented by an ecdysteroid fraction of M. grossum. Our data indicate that extracts of M. grossum could protect skin against oxidative stresses and suggest that they could be used as innovative active cosmetic ingredients. PMID- 25920215 TI - Spirostane-type saponins from Dracaena fragrans "Yellow Coast". AB - Three steroidal glycosides were isolated from the bark of Dracaena fragrans (L.) Ker Gawl. "Yellow Coast", and a fourth from the roots and the leaves. Their structures were characterized on the basis of extensive 1D and 2D NMR experiments and mass spectrometry, and by comparison with NMR data of the literature. These saponins have the spirostane-type skeleton and are reported in this species for the first time. PMID- 25920216 TI - Secondary metabolites from a strain of Alternaria tenuissima Isolated from Northern Manitoba soil. AB - Deoxyphomalone (1), dimethyl 4-methyl-2,6-pyridinedicarboxylate (2), stemphyperylenol (3), and N-methyl-2-pyrrolidone (4) were isolated from the fermentation broth of a strain of the fungus, Alternaria tenuissima. This fungus was isolated from the soil underlying the lichen, Peltigera didactyla, which had been collected from Wapusk National Park in Northern Manitoba. The structures of the compounds were determined by comprehensive analysis of their spectroscopic data including FT-IR, 1D and 2D NMR spectroscopy and mass spectrometry; and their bioactivities were tested against E.coli cells. The taxonomic identity of the fungus was confirmed by ITS sequencing of its ribosomal DNA. PMID- 25920217 TI - Chemical prospection of important ayurvedic plant Tinospora cordifolia by UPLC DAD-ESI-QTOF-MS/MS and NMR. AB - A rapid, sensitive, and accurate ultra-performance liquid chromatography coupled with mass spectrometric method (UPLC-MS) was developed and validated for simultaneous determination of four bioactive compounds, syringin (3), cordifolioside A (4), magnoflorine (6) and tinocordiside (10) in the stem of Tinospora cordifolia. The analysis was performed using an Acquity C18 column and gradient elution of 0.05% formic acid in water and acetonitrile at a detection wavelength of 267 nm in 5 min. A high correlation coefficient (r2 > 0.998) indicated good correlation between investigated compounds concentration and their peak area within the test ranges. The LODs for compounds 3, 4, 6 and 10 were 1.95, 0.97, 3.90 and 0.97 ng/mL, respectively, and LOQs were 6.64, 3.20, 12.87 and 3.20 ng/mL, respectively. The overall intra- and inter-day variations of the four compounds were less than 1%. The variation of these four bioactive compounds in T. cordifolia hosted on fifteen different trees was also determined. The compounds (3, 4, 6 and 10) were found in high amount in the T. cordifolia hosted on Azadirachta indica and Mangifera indica as compared with other plants. Twelve compounds were identified on the basis of their mass and UV-vis spectra. The NMR fingerprinting of the extract revealed the presence of alkaloids, fatty acid methyl esters, polysaccharides and marker components of T. cordifolia. PMID- 25920218 TI - Kopsiyunnanines J1 and J2, new strychnos-type homo-monoterpenoid indole alkaloids from Kopsia arborea. AB - Two new indole alkaloids, kopsiyunnanines J1 and J2, were isolated from Yunnan Kopsia arborea, and their structures were determined by spectroscopic analyses. Kopsiyunnanines J1 and J2 are unprecedented Strychnos-type indole alkaloids having an additional C1 unit in the secologanin moiety of the molecule. PMID- 25920219 TI - Diversity in the flavonoid composition of Stellera chamaejasme in the Hengduan Mountains. AB - The presence of diversity in the Stellera chamaejasme population was found via their chemical composition. The eight collected samples were grouped into two chemotypes on the basis of the amount of neochamaejasmin B and chamaejasmine. Diversity was also found in the amount of afzelechin. The stereochemistry of neochamaejasmin B was confirmed by NOE experiment. PMID- 25920220 TI - Constituents of Indonesian medicinal plant Averrhoa bilimbi and their cytochrome P450 3A4 and 2D6 inhibitory activities. AB - As constituents of Averrhoa bilimbi leaves we identified three new compounds (1 3) together with 12 known ones (4-15); their inhibitory activities on cytochrome P450 3A4 (CYP3A4) and 2D6 (CYP2D6) were examined. Among the isolated compounds, the mixture of 1 and 2, and compounds 4 and 9 showed strong inhibition on CYP3A4, but mild or no inhibition on CYP2D6. These compounds revealed the characteristics of 1) time- and concentration-dependent inhibition, 2) requirement of NADPH for the inhibition, 3) no protection by nucleophiles, and 4) suppression of the inhibition by competitive inhibitor. Thus, they are suggested to be mechanism based inactivators of CYP3A4 and CYP2D6. The kinetic parameters for the inactivation (k(inact) and K(I)) were 0.19 min(-1) and 36.7 MUM for the mixture of 1 and 2, 0.126 min(-1) and 10.5 MUM for 4, and 0.29 min(-1) and 23.4 MUM for 9. PMID- 25920221 TI - Flavonoids from Curcuma longa leaves and their NMR assignments. AB - Chemical investigation of the n-BuOH-soluble fraction of the EtOH extract of the aerial part of Curcuma longa led to the isolation of 11 flavonol glycosides and one dihydroflavonol glucoside (1) via chromatography over Sephadex LH-20 and Lobar RP-18 columns. Although they are known, the 1H and 13C NMR data recorded in CD3OD rather than the common DMSO-d6 are doubly checked via extensive 2D NMR spectroscopic analyses, leading to some revisions of the reported data, especially for the glycon part. PMID- 25920222 TI - Phytochemical analysis and biological evaluation of selected African propolis samples from Cameroon and Congo. AB - The objective of this study was the chemical analysis of four selected samples of African propolis (Congo and Cameroon) and their biological evaluation. Twenty-one secondary metabolites belonging to four different chemical groups were isolated from the 70% ethanolic extracts of propolis and their structures were elucidated on the basis of spectral evidence. Three triterpenes and two diprenyl-flavonoids were identified from Congo propolis, which has been investigated for the first time, while thirteen triterpenes, three diprenyl-flavonoids, two monoterpenic alcohols and one fatty acid ester have been identified from Cameroon propolis samples. To our knowledge, the identified diprenyl-flavonoids, as well as five of the isolated and determined triterpenes, are reported for the first time in propolis. Moreover, the total polyphenol content was estimated in all extracts and the antimicrobial activities of all four extracts were studied against six Gram-positive and -negative bacteria and three pathogenic fungi, showing an interesting antibacterial profile. PMID- 25920223 TI - Improved chromatographic fingerprinting combined with multi-components quantitative analysis for quality evaluation of Penthorum chinense by UHPLC-DAD. AB - A high performance liquid chromatographic (HPLC) fingerprint is commonly used for quality consistency evaluation of herbal medicines. Recently, an improved chromatographic technique resulted in ultra high performance liquid chromatography (UHPLC), which could provide higher resolution in less time under higher pressure using finer particles (less than 2MUm) of stationary phase. A simple and sensitive method was developed and validated for fingerprint analysis of Penthorum chinense Pursh (PC), with the simultaneous determination of seven components using UPLC coupled with a diode-array detector (DAD). It took less than 20 min for analysis of one sample. Both similarity analysis and principle components analysis (PCA) were employed to evaluate the quality consistency of 17 sample batches. The analysis was performed on a Waters ACQUITY UPLC HSS T3 (2.1 x 150 mm, 1.7 MUm) column, which was maintained at 45 degrees C and the eluents were monitored with DAD at 270 nm. A gradient elution with acetonitrile and water containing 0.075% phosphoric acid was used. The solvent flow rate was 0.4 mL/min. Standard calibration curves showed good linear behavior (R2 > 0.9994) in the range of 0.20-337.05 MUg/mL. Acceptable repeatability (RSD < 0.61%), reproducibility (RSD < 2.72%), stability (RSD < 1.59%) and recovery in the range of 94.7%-102.9% were obtained (precision and accuracy). The validated method was successfully applied to evaluate the quality of 21 samples of PC. PMID- 25920224 TI - Anthocyanins of Hibiscus sabdiffera calyces from Sudan. AB - Extracts of the calyces of Hibiscus sabdariffa are widely used in folk medicine to combat many illnesses. The active constituents of the extracts have been shown on several occasions to be anthocyanins. In our current studies the biological activities of an extract of H. sabdariffa calyces purchased in Oman, but grown in Sudan, are being compared with those of the anthocyanins isolated from them, and, for this, the anthocyanin profile of the extract needed to be ascertained. Although several anthocyanins were detected by UHPLC-ESI-MS/MS, delphinidin-3 sambubioside (major) and cyanidin-3-sambubioside were predominant. PMID- 25920225 TI - Maqui berry vs Sloe berry--liquor-based beverage for new development. AB - "Pacharin" is an aniseed liquor-based beverage made with sloe berry (Prunus spinosa L.) that has been produced in northern Spain. On the other hand, maqui berry (Aristotelia chilensis) is a common edible berry from Chile, and currently under study because of its multiple beneficial effects on health. The aim of this work was to design a new aniseed liquor-based beverage with maqui berry, as an industrial alternative to a traditional alcoholic product with bioactive berries. The characterization of its composition, compared with the traditional "Pacharin", and its evolution during maceration (6 and 12 months) showed that the new maqui liquor had significantly-higher anthocyanin retention over time. More studies on the organoleptic properties and bioactivity are underway. PMID- 25920226 TI - Phytochemical profile of the aerial parts of Sedum sediforme and anti inflammatory activity of myricitrin. AB - The aim of this study was to investigate the phytochemical profile of the methanol extract of the aerial parts of Sedum sediforme and to identify its secondary metabolites. By means of chromatographic separation and enrichment of compounds, HPLC-ESI-MS, HRMS, 1D-, 2D- NMR and/or comparison with reference compounds, three triterpenes, two sterols, ten flavonoids and twelve phenolic compounds were identified, together with two new compounds, i.e. (2R*, 3R*)-5,7 dihydroxy-2,3-dimethyl-4-chromanone-7-O-beta-D-glucoside (27) and butan-2-O rutinoside (28). Out of the 29 identified secondary metabolites, 18 are described as ingredients of S. sediforme herein for the first time. Furthermore, myricitrin, one of the major constituents, was tested for its ability to inhibit different enzymes within the arachidonic acid cascade in order to determine its anti-inflammatory properties. Whereas there was only either weak or no inhibition of the microsomal prostaglandin E2 synthase-1 (mPGES-1) and the soluble epoxide hydrolase (sEH), myricitrin showed strong inhibition of 5-lipoxygenase (5-LO), with an IC50 of 7.8 +/- 0.2 MUM. PMID- 25920227 TI - Diarylheptanoids of Curcuma comosa with inhibitory effects on nitric oxide production in macrophage RAW 264.7 cells. AB - Eight new diarylheptanoids, a 1.2:1 mixture of (3S)- and (3R)-1-(4-hydroxyphenyl) 7-phenyl-(4E,6E)-4,6-heptadien-3-ol (1a and 1b), a racemic mixture of (3S)- and (3R)-1-(4-hydroxyphenyl)-3-methoxy-7-phenyl-(4E,6E)-4,6-heptadiene (2a and 2b), a ca. 1:1 mixture of (3S)- and (3R)-1-(4-hydroxy-3- methoxyphenyl)-3-methoxy-7 phenyl)-(4E,6E)-4,6-heptadiene (3a and 3b), 3-acetoxy-1-(3,4-dihydroxyphenyl)-7 phenylheptan-5-ol (4), (3R)-1-(4,5- dihydroxyphenyl)-7-phenyl-(6E)-6-hepten-3,2' epoxide (5), and thirteen known diarylheptanoids, 6-12, a 3:1 mixture of 13a and 13b, and 14-17, were isolated from the rhizomes of Curcuma comosa from Sakon Nakhon, northeastern part of Thailand. The isolated compounds were evaluated for their anti- inflammatory activities on the inhibition of lipopolysaccharide induced nitric oxide production in macrophage RAW 264.7 cells and the diarylheptanoids 1a and 1b mixture and 14 exhibited potent inhibitory activity. PMID- 25920228 TI - Rapid dereplication and identification of the bioactive constituents from the fungus, Leucocoprinus birnbaumii. AB - A series of fatty acids were rapidly dereplicated and partially identified from the flowerpot fungus, Leucocoprinus birnbaumii using HPLC-NMR and HPLC-MS. Subsequent off-line isolation unequivocally established the structures, and anti microbial testing concluded that the fatty acids displayed moderate but selective anti-microbial activity. This represents the first report of these compounds occurring in this particular terrestrial fungus. PMID- 25920229 TI - Pterandric acid--its isolation, synthesis and stereochemistry. AB - Some plant families have a specialized type of pollination system, with floral lipid rewards for pollinators, which is common. In neotropical Malpighiaceae species like Pterandra pyroidea, this specialized type of pollination system is apparently shifting from floral oils/lipids to pollen reward. Mass spectrometric analysis (GC/MS-EI) indicated that P. pyroidea floral oil has a unique chemical composition, i.e., few fatty acid constituents possessing acetoxy groups at positions 5 and 7, which is distinct from the other floral oils of sympatric Malpighiaceae species. The structure of the major floral oil constituent, a novel fatty acid, anti-5,7-diacetoxydocosanoic acid, was confirmed based on synthesis, mass fragmentation, and 1H and 13C NMR analyses; the compound is herein named pterandric acid. PMID- 25920230 TI - Cardanols, long chain cyclohexenones and cyclohexenols from Lannea schimperi (Anacardiaceae). AB - Alkenyl cyclohexenones (1a-d), alkenyl cyclohexenols (2a-c and 3b-d) and cardanols (4a-d) were isolated from the stem bark and root of Lannea schimperi. The alkenyl cyclohexenones (1a and 1d) and cardanols (4a and 4d) have side chains which have not been reported previously, in combination with the core skeletal structures. In addition, compounds 2a-c and 3b-d are all new cyclohexenols. Also isolated were the triterpenes, taraxerone and taraxerol, and sitosterol. The suite of compounds isolated (cyclohexenones and cyclohexenols) make up a nice biosynthetic pathway to the cardanols. The 5-[alkenyl]-4,5- dihydroxycyclohex-2 enone mixture (1a-d) exhibited good in vitro cytotoxicity against the Chinese Hamster Ovarian mammalian cell-line. The compounds were identified mainly from GCMS and NMR spectroscopic techniques. PMID- 25920231 TI - Pulvinulin A, graminin C, and cis-gregatin B--new natural furanones from Pulvinula sp. 11120, a fungal endophyte of Cupressus arizonica. AB - Three new natural furanones, pulvinulin A (1), graminin C (2), and cis-gregatin B (3), together with the known fungal metabolites, graminin B (4) and 10 norparvulenone (5), were isolated from Pulvinula sp. 11120, an endophytic fungal strain occurring in healthy foliage of Cupressus arizonica (Arizona cypress). The structures of 1 and 2 were elucidated by the analysis of their spectroscopic data and chemical interconversions, and that of 3 was determined by comparison with data for synthetic cis-gregatin B. Comparison of spectroscopic data of 4 and 5 with those reported identified them as graminin B and 10-norparvulenone, respectively. Metabolites 1-4 exhibited antibacterial activity against E. coli. PMID- 25920232 TI - Potent anti-calmodulin activity of cyclotetradepsipeptides isolated from Isaria fumosorosea using a newly designed biosensor. AB - Seven cyclotetradepsipeptides, namely beauverolides C (1), F (2), I (3), Ja (4), L (5), M (6), and N (7), were isolated from the entomopathogenic fungus Isaria fumosorosea. The beauverolides were evaluated as potential calmodulin (CaM) inhibitors using the newly designed CaM biosensor hCaM M124C-AF350; these peptides displayed high affinity to the protein with dissociation constants (Kd) ranging from 0.078 MUM to 3.44 MUM. Beauverolide Ja, the only one containing a tryptophan residue in its structure, showed the highest affinity. The docking study predicted that beauverolides could bind to CaM in the same site of interaction as chlorpromazine, a well-known calmodulin ligand. PMID- 25920233 TI - Mutagenesis of lysines 156 and 159 in human immunodeficiency virus type 1 integrase (IN) reveals differential interactions between these residues and different IN inhibitors. AB - Human immunodeficiency virus (HIV) type I integrase (IN) active site, and viral DNA-binding residues K156 and K159 are predicted to interact both with strand transfer-selective IN inhibitors (STI), e.g. L-731,988, Elvitegravir (EVG), and the FDA-approved IN inhibitor, Raltegravir (RGV), and strand transfer non selective inhibitors, e.g. dicaffeoyltartaric acids (DCTAs), e.g. L-chicoric acid (L-CA). To test posited roles for these two lysine residues in inhibitor action we assayed the potency of L-CA and several STI against a panel of K156 and K159 mutants. Mutagenesis of K156 conferred resistance to L-CA and mutagenesis of either K156 or K159 conferred resistance to STI indicating that the cationic charge at these two viral DNA-binding residues is important for inhibitor potency. IN K156N, a reported polymorphism associated with resistance to RGV, conferred resistance to L-CA and STI as well. To investigate the apparent preference L-CA exhibits for interactions with K156, we assayed the potency of several hybrid inhibitors containing combinations of DCTA and STI pharmacophores against recombinant IN K156A or K159A. Although K156A conferred resistance to diketo acid-branched bis-catechol hybrid inhibitors, neither K156A nor K159A conferred resistance to their monocatechol counterparts, suggesting that bis catechol moieties direct DCTAs toward K156. In contrast, STI were more promiscuous in their interaction with K156 and K159. Taken together, the results of this study indicate that DCTAs interact with IN in a manner different than that of STI and suggest that DCTAs are an attractive candidate chemotype for development into drugs potent against STI-resistant IN. PMID- 25920234 TI - Herbal medicinal products versus botanical-food supplements in the European market: state of art and perspectives. AB - Botanical products marketed in Europe are diverse, classified as herbal medicinal products, dietary supplements, cosmetics, foods and beverages depending on the relevant applicable legislation. Many factors are taken into account in the classification of a botanical product (e.g. intended use, labeling, preparations and dosages) according to how it is placed on the market. Herbal medicinal products (HMPs) can only be sold in pharmacies, under the supervision of a pharmacist, and are marketed after full or simplified registration procedures according to their classification, i.e. as over-the-counter drugs (OTC) available without special restrictions and prescription only medicine (POM), which must be prescribed by a licensed medical practitioner. The dietary supplement segment is also sold in the market in dose form (such as capsules, tablets, ampoules of liquids, drops etc) and represents 15-20% of the botanical market at the European level with high variability among each country (i.e. in Italy it reaches up to 80%). In many cases the distinction between medicinal products and food supplements has generated borderline botanical-sourced products, which generally produce confusion and mislead the consumers. As a consequence, there is an urgent need of consumer education and in addition to collect comprehensive data and make this database systematically available to herbalists, nutritionists and medical specialists for a proper classification and harmonization of the use of botanical ingredients, and, as consequence, a correct use of these products. PMID- 25920235 TI - Chemical composition and biological activity of essential oils of Dracocephalum heterophyllum and Hyssopus officinalis from Western Himalaya. AB - The essential oils of two representatives of the Lamiaceae, Dracocephalum heterophyllum Benth. and Hyssopus officinalis L., are described for their antifungal, antibacterial, larvicidal and inect biting deterrent activities. Additionally, the chemical compositions of the essential oils, analyzed by simultaneous GC-MS and GC-FID, and odor descriptions are given. The main components of H. officinalis oil were pinocarvone, cis-pinocamphone, and beta pinene. Citronellol was found as the main compound of D. heterophyllum essential oil. Antibacterial testing by agar dilution assay revealed greater activity of D. heterophyllum against Staphylococcus aureus compared with H. officinalis. D. heterophyllum essential oil also showed promising antifungal activity against Colletotrichum species and was more toxic to Aedes aegypti larvae in a larvicial bioassay. Both essential oils showed high activity in the biting deterrent bioassay. PMID- 25920236 TI - Cytotoxic active constituents of essential oils of Curcuma longa and Curcuma zanthorrhiza. AB - The polar and apolar fractions of Curcuma longa and C. zanthorriza enriched by ar turmerone, ar-curcumene and xanthorrizol were screened for cytotoxic activity against the HeLa cell line. Actinomycin D and curcumin were used as reference samples, both known for their cytotoxic properties. Amongst all fractions tested, the xanthorrizol fraction (CC50: 26.1 +/- 1.9 MUM) showed the strongest cytotoxic properties similar to those of curcumin (CC50: 8.1 +/- 1.7 MUM). Further studies also revealed that the cytotoxic effects of the extracts and pure compounds are caused by apoptosis induction identified by the cleaved form of PARP protein. PMID- 25920237 TI - Antimicrobial activity of nerolidol and its derivatives against airborne microbes and further biological activities. AB - Nerolidol and its derivatives, namely cis-nerolidol, O-methyl-nerolidol, O-ethyl nerolidol, (-)-alpha-bisabolol, trans,trans-farnesol and its main natural source cabreuva essential oil, were tested for their antimicrobial activity against airborne microbes and antifungal properties against plant pathogens. Among the tested compounds, alpha-bisabolol was the most effective antimicrobial agent and trans,trans-farnesol showed the best antifungal activity. PMID- 25920238 TI - Chemical composition and antifungal activity of Aaronsohnia pubescens essential oil from Algeria. AB - In the present study, the chemical composition of the essential oil obtained from the aerial parts of Aaronsohnia pubescens (Desf.) K.Bremer & Humphries (Asteraceae), a chamomile-like medicinal plant, was studied. Using both GC-MS and GC-FID methods, 58 volatile compounds could be identified representing 96.6% of the total essential oil composition. The main compounds in the essential oil were monoterpene hydrocarbons such as (Z)-beta-ocimene (53.8%), myrcene (15.2%) and alpha-pinene (7.7%). Moreover, the essential oil of A. pubescens was tested for its antifungal activity against seven strains of phytopathogenic fungi , i.e. Aspergillus niger, A. flavus, Penicillium purpurogenum, P. jensenii, P. expansum, and Fusarium oxysporum f.sp. albedinis, using the disc diffusion method. With the exception of P. jensenii, A. pubescens essential oil demonstrated a considerable antifungal activity against all tested strains. The present results confirm the traditional use of A. pubescens as a food preservative. PMID- 25920239 TI - Radical scavenging and antioxidant activities of essential oil components--an experimental and computational investigation. AB - The antioxidant activities of eighteen different essential oil components have been determined using the 2,2-diphenyl-1-picrylhydrazyl (DPPH) radical-scavenging assay, the 2,2'-azino-bis(3-ethylbenzothiazoline-6-sulphonic acid (ABTS) radical cation assay, and the ferric reducing antioxidant power (FRAP) assay. The phenolic compounds, carvacrol, thymol, and eugenol, showed the best antioxidant activities, while camphor, menthol, and menthone were the least active. The structural and electronic properties of the essential oil components were assessed using density functional theory (DFT) at the B3LYP/6-311++G** level. Correlations between calculated electronic properties and antioxidant activities were generally poor, but bond-dissociation energies (BDEs) seem to correlate with DPPH radical-scavenging activities, and the ferric reducing antioxidant power (FRAP) assay correlated with vertical ionization potentials calculated at the Hartree-Fock/6-311++G** level. PMID- 25920240 TI - Enzyme-mediated synthesis of sesquiterpenes. AB - This review article focuses mainly on the scientific developments concerning the enzyme-mediated synthesis of sesquiterpenes which have been reported in the academic and patent literature during the last twenty years. Nevertheless, this is not a comprehensive description of every single biotransformation involving sesquiterpenes. Only synthetic approaches that have represented a new and innovative perspective from a scientific standpoint are reported. More specifically, the review describes in depth how the use of metabolic engineering of the microbial biotransformations and of the isolated enzymes were exploited in order to perform chemo- and stereoselective chemical transformations of interest for sesquiterpenes synthesis. PMID- 25920241 TI - Triterpenoids as neutrophil elastase inhibitors. AB - Neutrophile elastase has the capacity to degrade elastin, a protein found in the connective tissue of the lungs. Unchecked elastase leads to pulmonary pathologies. Therefore, the development of elastase inhibitors is currently actively pursued in the therapeutic field. Several triterpenoids have been reported as inhibitors against elastase or its release. Such compounds could be valuable for the design of new drugs. This review is aimed at giving a comprehensive insight into the recent work performed in the field of triterpenoid induced elastase inhibition. PMID- 25920242 TI - Mechanistic insights to the cytotoxicity of Amaryllidaceae alkaloids. AB - With over 500 individual compounds, the Amaryllidaceae alkaloids represent a large and structurally diverse group of phytochemicals. Coupled to this structural diversity is the significant array of biological properties manifested by many of its members, of which their relevance in motor neuron disease and cancer chemotherapy has attracted considerable attention. To this extent, galanthamine has evolved into a successful commercial drug for Alzheimer's disease since its approval by the FDA in 2001. Concurrently, there have been several positive indicators for the emergence of an anticancer drug from the Amaryllidaceae due to the potency of several of its representatives as cell line specific antiproliferative agents. In this regard, the phenanthridones such as pancratistatin and narciclasine have offered most promise since their advancement into clinical trials, following which there has been renewed interest in the cytotoxic properties of these alkaloids. Given this background, this review seeks to highlight the various mechanisms which have been invoked to corroborate the cytotoxic effects of Amaryllidaceae alkaloids. PMID- 25920243 TI - Review of beta-carboline alkaloids from the genus Aspidosperma. AB - Plants belonging to the genus Aspidosperma, a member of the family Apocynaceae, provide a rich source of beta-carboline alkaloids, which makes them potentially poisonous. However, some of these alkaloids possess antitumor and antimicrobial activity. The present review is a survey of the beta-carboline alkaloids and shows that they comprise of a diverse array of structural modifications. PMID- 25920244 TI - Natural flavonoids as potential herbal medication for the treatment of diabetes mellitus and its complications. AB - Diabetes mellitus, together with its various complications, is becoming a serious threat to human health. Natural products are secondary metabolites widely distributed in plants, having a broad range of biological activities. The development of antidiabetic medication from natural products, especially those originating from plants with a traceable folk-usage history in treating diabetes, is receiving more attention. Many studies highlighted not only the benefits of natural flavonoids with hypoglycemic effects, but also their importance in the management of diabetic complications. This review describes selected natural flavonoids that have been validated for their hypoglycemic properties, together with their mechanisms of action. Also discussed are their activities in the treatment of diabetic complications demonstrated via laboratory diabetic animal models, in vitro and clinical trials using human subjects. Published papers from 2000 to date on flavonoids and diabetes were covered through accessing Web of Science and multiple databases for biomedical sciences. The major potential benefits of natural flavonoids discussed in this review clearly suggest that these substances are lead compounds with sufficient structural diversity of great importance in the antidiabetic drug developing process. PMID- 25920245 TI - Lignins of bioenergy crops: a review? AB - Lignin provides structural support, a mechanical barrier against microbial infestation and facilitates movement of water inside plant systems. It is the second most abundant natural polymer in the terrestrial environments and possesses unique routes for the production of bulk and specialty chemicals with aromatic/phenolic skeletons. The commercial applications of lignin are limited and it is often recognized for its negative impact on the biochemical conversion of lignocellulosic biomass to fuels and chemicals. Understanding of the structure of lignin monomers and their interactions among themselves, as well as with carbohydrate polymers in biomass, is vital for the development of innovative biomass deconstruction processes and thereby valorization of all biopolymers of lignocellulosic residues, including lignin. In this paper, we review the major energy crops and their lignin structure, as well as the recent developments in biomass lignin characterization, with special focus on 1D and 2D Nuclear Magnetic Resonance (NMR) techniques. PMID- 25920246 TI - Plant chemical defenses: are all constitutive antimicrobial metabolites phytoanticipins? AB - A critical perspective on phytoanticipins, constitutive plant secondary metabolites with defensive roles against microbes is presented. This mini-review focuses on the chemical groups and structural types of defensive plant metabolites thus far not reviewed from the phytoanticipin perspective: i) fatty acid derivatives and polyketides, ii) terpenoids, iii) shikimates, phenylpropanoids and derivatives, and iv) benzylisoquinoline and pyrrolizidine alkaloids. The more traditional groups of phytoanticipins are briefly summarized, with particular focus on the latest results: i) benzoxazinoids, ii) cyanogenic glycosides, iii) glucosinolates and their metabolic products, and iv) saponins. Current evidence suggests that a better understanding of the functions of plant metabolites will drive their application to protect crops against microbial diseases. PMID- 25920247 TI - Sponge derived bromotyrosines: structural diversity through natural combinatorial chemistry. AB - Sponge derived bromotyrosines are a multifaceted class of marine bioactive compounds that are important for the chemical defense of sponges but also for drug discovery programs as well as for technical applications in the field of antifouling constituents. These compounds, which are mainly accumulated by Verongid sponges, exhibit a diverse range of bioactivities including antibiotic, cytotoxic and antifouling effects. In spite of the simple biogenetic building blocks, which consist only of brominated tyrosine and tyramine units, an impressive diversity of different compounds is obtained through different linkages between these precursors and through structural modifications of the side chains and/or aromatic rings resembling strategies that are known from combinatorial chemistry. As examples for bioactive, structurally divergent bromotyrosines psammaplin A, Aplysina alkaloids featuring aerothionin, aeroplysinin-1 and the dienone, and the bastadins, including the synthetically derived hemibastadin congeners, have been selected for this review. Whereas all of these natural products are believed to be involved in the chemical defense of sponges, some of them may also be of particular relevance to drug discovery due to their interaction with specific molecular targets in eukaryotic cells. These targets involve important enzymes and receptors, such as histone deacetylases (HDAC) and DNA methyltransferases (DNMT), which are inhibited by psammaplin A, as well as ryanodine receptors that are targeted by bastadine type compounds. The hemibastadins such as the synthetically derived dibromohemibastadin are of particular interest due to their antifouling activity. For the latter, a phenoloxidase which catalyzes the bioglue formation needed for firm attachment of fouling organisms to a given substrate was identified as a molecular target. The Aplysina alkaloids finally provide a vivid example for dynamic wound induced bioconversions of natural products that generate highly efficient chemical weapons precisely when and where needed. PMID- 25920248 TI - Antitumor constituents of the wetland plant Nymphoides peltata: a case study for the potential utilization of constructed wetland plant resources. AB - The efficient utilization of plant resources is a necessary and important measure for sustainable management of constructed wetlands. Screening bioactive metabolites from wetland plants could reveal potential solutions for the utilization of constructed wetland plant resources. In this study, the constructed wetland macrophyte Nymphoides peltata was screened for constituents with antitumor activity. The secondary metabolites of N. peltata were extracted and separated by MCI gel, silica gel, and Sephadex gel column chromatography. Antitumor tests were then carried out with MTT assay against the human prostate cancer cell PC3 and the human osteosarcoma cell U2OS. The secondary metabolite group with the most significant antitumor activity was further examined, and four constituents were obtained and identified. This study provides a scientific basis for the potential efficient utilization of N. peltata and other constructed wetland plant resources. PMID- 25920249 TI - Preparation and characterization of colon-targeted particles of Pulsatilla chinensis saponins. AB - Pulsatilla chinensis (Bunge) Regel is a traditional Chinese medicine used to treat ulcerative colitis. This study prepared and characterized colon-targeted particles of P. chinensis saponins by particle design. Most of the P. chinensis saponins in the composite particles were coated with Eudragit S100, as seen in SEM micrographs; meanwhile, the characteristic diffraction peaks in X-RD, surface wettability, and particle size distribution of the composite particles were basically the same as those of Eudragit S100. These results suggested that the mechanochemical process could be used to prepare colon-targeted particles with core-shell structures with the drug coated by the excipient; the results also showed similar surface characteristics in the coating. PMID- 25920250 TI - Ursolic acid and oleanolic acid from Eriobotrya fragrans inhibited the viability of A549 cells. AB - Loquat {Eriobotrya japonica (Lindl.)}, a kind of Chinese herb, has many efficacies such as anti-inflammatory, antimicrobial and curing chronic bronchitis. However, reports on the pharmacological action of wild loquat extract are limited. In this work, the A549 cell line was selected to study the inhibitory effect of ursolic acid and oleanolic acid (UA, OA) from the leaves of E. fragrans. Results showed that UA/OA inhibited A549 cell viability and induced apoptosis in a dose and time dependent manner. The cell fraction in the G0/G1 phase dramatically increased under treatment with UA/OA. Data showed that UA activated the expression of PARP. UA and OA down-regulated MMP-2 and Bcl-2; on the contrary, they up-regulated Bid. This work demonstrated that UA/OA extracted from wild loquat leaves can significantly inhibit the viability of A549 cells. PMID- 25920251 TI - Protective effect of compound K on diabetic rats. AB - Purpose: Compound K (CK), the metabolic product of protopanaxadiol saponin in vivo, has many pharmacological activities. In this study, we discuss the preparation of CK, and its protective effect on kidneys of diabetic rats. CK was prepared from ginsenoside Rbt after transformation by 3-glucosidase, separation and purification by silica gel column chromatography. In the present study, we established a rat model of diabetes mellitus using high-fat diet and streptozotocin (STZ). After seven weeks of treatment, the levels of fasting blood glucose (FBG), total cholesterol (TC), total glycerin (TG), high-density lipoprotein (HDL-C), low-density lipoprotein (LDL-C), blood urea nitrogen (BUN), uric acid (UA), serum creatinine (Scr), malondialdehyde (MDA), glutathione (GSH), and superoxide dismutase (SOD) activity and glutathione peroxidase (GSH-PX) were evaluated in normal and diabetic rats. Also, renal pathomorphism changes were observed by HE stain, and TGF-beta1 protein expression in the renal tissue was measured by Western blot. The yield of CK was 14.55 mg/mL, which was higher than that of other methods. After seven weeks, CK could decrease FBG, TC, TG, LDL-C, BUN, UA, Scr and MDA of diabetic rats, while CK also enhanced HDL-C and GSH, SOD and GSH-PX. Additionally, CK improved the pathological changes and decreased TGF beta1 protein expression in the renal tissue. CK improved the pathological changes in the renal tissue, enhanced the antioxidant capacity, reduced the damage of TGF-beta1 to renal tissue, and protected the diabetic rats. PMID- 25920252 TI - New cytotoxic triterpene glycoside from the East China Sea cucumber Holothuria nobilis. AB - A new cytotoxic triterpene glycoside named nobiliside E (1) has been obtained from the East China Sea cucumber Holothuria nobilis Selenka. Its structure was determined on the basis of NMR spectroscopic and MS analyses, together with chemical evidence. The new compound showed significant cytotoxicity to eight human tumor cell lines with IC50 values in the range of 0.53-4.06 MUg/mL. PMID- 25920253 TI - Ovarian cancer HO-8910 cell apoptosis induced by crocin in vitro. AB - The effect and mechanism of ovarian cancer HO-8910 cell apoptosis induced by crocin.MTT assay was performed to detect the inhibitory action of crocin on the proliferation of HO-8910 cells. Flow cytometry was used to test the cell cycle distribution and apoptosis rate of ovarian cancer HO-8910 cells. Western blot analysis was utilized to measure the levels of apoptotic proteins such as p53, Fas/APO-1, and Caspase-3. MTT analysis revealed that crocin significantly inhibited the growth of HO-8910 cells. Additionally, flow cytometry illustrated that crocin raised the proportion of HO-8910 cells in the G0/G1 phase and increased their apoptosis rate. Furthermore, Western blot analysis revealed that crocin up-regulated the expression of p53, Fas/APO-1, and Caspase-3. The results of this study showed that crocin can significantly inhibit the growth of HO-8910 cells and arrest them in the G0/G1 phase. Crocin can also promote ovarian cancer HO-8910 cell apoptosis, most likely by increasing p53 and Fas/APO-1 expression, and then activating the apoptotic pathway regulated by Caspase-3. PMID- 25920254 TI - Effect of puerarin on expression of Fas/FasL mRNA in pulmonary injury induced by ischemia-reperfusion in rabbits. AB - The effect of puerarin (Pur) on expressions of Fas/FasL mRNAs in pulmonary ischemia and reperfusion injury (PIRI) in rabbit was investigated. The sole side lung ischemia and reperfusion model was used. Rabbits were randomly divided into three groups, a sham operated group (sham, n = 10), PIR group (IR, n = 30) and PIR + Pur group (Pur, n = 30). Changes of several parameters including apoptotic index (AI), wet to dry ratio of lung tissue weight (W/D) and index of quantitative assessment of histologic lung injury (IQA) were measured after 60, 180 and 300 minutes of reperfusion. Meanwhile, the location and expression of Fas/FasL mRNA were investigated. Lung tissue was prepared for light microscopic and electron microscopic observation after 60, 180 and 300 minutes of reperfusion. Compared with group IR, Fas/FasL mRNAs were slightly expressed in intima and extima of small pulmonary artery, alveoli, and bronchiole epithelia in group Pur. The values of AI, W/D and IQA were significantly lower than those in group IR after 60, 180, and 300 minutes of reperfusion in lung tissue (P <0.01 or P <0.05). Meanwhile, the abnormal changes in lung tissue morphology were markedly less in group Pur. Puerarin notably protects lung from PIRI by inhibiting Fas/FasL mRNA expression and decreasing lung cell apoptosis in rabbits. PMID- 25920255 TI - Proanthocyanidin from grape seed extract inhibits airway inflammation and remodeling in a murine model of chronic asthma. AB - Asthma is characterized by airway inflammation and airway remodeling. Our previous study revealed that grape seed proanthocyanidin extract (GSPE) could inhibit asthmatic airway inflammation and airway hyper-responsiveness by down regulation of inducible nitric oxide synthase in a murine model of acute asthma. The present study aimed to evaluate GSPE's effects on airway inflammation and airway remodeling in a chronic asthmatic model. BALB/c mice were sensitized with ovalbumin (OVA) and then were challenged three times a week for 8 weeks. Airway responsiveness was measured at 24 h after the last OVA challenge. HE staining, PAS staining, and Masson staining were used to observe any airway inflammation in the lung tissue, airway mucus secretion, and subepithelial fibrosis, respectively. The cytokines levels in the lavage fluid (BALF) in addition to the total serum immunoglobulin E (IgE) levels were detected by ELISA. Furthermore, lung collagen contents, alpha-smooth muscle actin (alpha-SMA), and transforming growth factor-beta1 (TGF-beta1) expression in the airway were assessed by hydroxyproline assay, immunohistochemistry, and Western blot analysis, respectively. GSPE administration significantly suppressed airway resistance as well as reduced the amount of inflammatory cells, especially the eosinophil count, in BALF. Additionally, the GSPE treatment markedly decreased interleukin (IL)-4, IL-13, and vascular endothelial growth factor (VEGF) levels in BALF in addition to the total serum IgE levels. A histological examination demonstrated that GSPE significantly ameliorated allergen-induced lung eosinophilic inflammation and decreased PAS-positive epithelial cells in the airway. The elevated hydroxyproline contents, lung alpha-SMA contents, and TGF-beta1 protein expression that were observed in the OVA mice were also inhibited by GSPE. In conclusion, GSPE could inhibit airway inflammation and airway remodeling in a murine model of chronic asthma, thus providing a potential treatment for asthma. PMID- 25920256 TI - Protective effect of silymarin against rapamycin-induced apoptosis and proliferation inhibition in endothelial progenitor cells. AB - For this study, peripheral blood samples were collected from human volunteers. Mononuclear cells (MNC) were separated by density centrifugation and were induced to differentiate into endothelial progenitor cells (EPCs) in vitro. Different concentrations of rapamycin and silymarin were introduced to the EPCs over 24 hours and then EPCs were analyzed for proliferation, migration, apoptosis and angiogenesis. Compared with the control group, rapamycin (1, 10, 100 ng/mL) inhibited the proliferation and migration of EPCs in a concentration dependent manner (P<0.05). Silymarin (50, 100 MUg/mL) enhanced the proliferation and migration of EPCs and inhibited apoptosis in a concentration dependent manner (P<0.05). By adding rapamycin (1 ng/mL) and silymarin (25, 50, 100 MUg/mL) over 24 hours, silymarin inhibited the pro-apoptotic effect of rapamycin on EPCs, and reversed the inhibition of proliferation, migration and angiogenesis of EPCs by rapamycin (P<0.05). PMID- 25920257 TI - Cs2CO3-catalyzed synthesis of N-sulfonyl-substituted allenamides. AB - Several novel N-sulfonyl substituted allenamides were obtained in good yields via Cs2CO3-catalyzed isomerization of propargyl amides in THF at room temperature. The easily available starting materials and mild reaction conditions are features of this protocol. PMID- 25920258 TI - Theoretical studies on the mechanism of the azido-tetrazole of azido-s-triazine. AB - The B3LYP/aug-cc-pvDZ level of theory has been applied to the study of the molecular structures, electronic structures and the azido-tetrazole isomerization of 1-azido-s-triazine, 1,3-diazido-s-triazine and 1,3,5-triazido-s-triazine. NBO analysis was applied to investigate the atomic natural charge and stabilization interaction energies among molecules. The results showed that the reaction initially proceeds through the loss of the linearity of the azido group and the approaching of the terminal nitrogen atom of the azide group to the nitrogen atom of the ring. This is followed by an attack of the lone pairs on N atoms in the ring to the azido group, leading to the formation of the N-N bonds. Many factors, including bending of the bond angle, electrostatic attraction, orbital delocalization and the stabilization interaction give rise to a large free energy barrier for the cyclization process. The results also show that the second and third cyclization is relatively easier than the first one. PMID- 25920259 TI - Isolation and identification of a polygalacturonase inhibiting protein from Isatidis root. AB - Isatis indigotica Fort. (Chinese woad) has been widely used as a dye- and medicinal-plant in traditional Chinese medicine. Although I. indigotica has been cultivated in various regions across China in recent years, its innate immunity is little known. In this study, a protein with MW 37.5 kDa was purified from the extract of fresh Isatidis roots by SP-5PW cationic exchange and POROS HP2 hydrophobic interaction chromatography. The N-terminal amino acid sequence of the purified protein was subsequently determined as T-D-L-C-H-K-D-P-K-N-T-L-L by Edman degradation. The N-terminal sequence and PG inhibitory activity identified the purified substance as a polygalacturonase inhibiting protein. This purified Isatidis PGIP with a specific activity of 7.64x10(4) U/mg showed strong inhibitory activity against 160 U of Aspergillus niger polygalacturonase. Compared with PGIPs from guava and bean pods, Isatidis PGIP showed very poor pH and heat stabilities, which may represent the different need of plant innate immunity between plant underground and aboveground organs. PMID- 25920260 TI - Antibacterial triterpenoids from the bark of Sonneratia alba (Lythraceae). AB - The new lupane-type triterpenoid, 3beta-hydroxy-lup-9(11),12-diene, 28-oic acid (1), along with two known lupane-type triterpenoids, lupeol (2) and lupan-3beta ol (3), were isolated from the bark of Sonnetaria alba. The structure of the new compound was elucidated on the basis of spectroscopic and mass spectrometric data analysis. Using the broth microdilution method, all compounds exhibited antibacterial activity against the Gram-positive bacteria Staphylococcus aureus ATCC 6538 and Streptococcus mutans ATCC 25175, with minimum inhibitory concentrations ranging from 15-33 to 35-55 MUg/mL, respectively. PMID- 25920261 TI - Hypotensive and bradycardic effects of quinovic acid glycosides from Aspidosperma fendleri in spontaneously hypertensive rats. AB - The Aspidosperma genus (Apocynaceae) represents one of the largest sources of indole alkaloids widely associated with cardiovascular effects. Aspidosperma fendleri, a plant found mainly in Venezuela, has a single phytochemical report in which is revealed the presence of alkaloids in its seeds. This study explored the cardiovascular effects of an ethanolic extract of A. fendleri leaves (EEAF) in spontaneously hypertensive rats (SHR) and its potential bioactive compounds. Using bioguided fractionation, fractions and pure compounds were intravenously administered to SHR and their effects on mean arterial blood pressure (MABP) and heart rate (HR) monitored over time. EEAF induced hypotensive and bradycardic effects as shown by significant reductions in mean arterial blood pressure (MABP) and heart rate (HR), respectively. Bioactivity-guided fractionation led to the isolation of a mixture of two known isomeric triterpenoid glycosides identified by spectral evidence as quinovic acid 3-O-beta-rhamnopyranoside and quinovic acid 3-O-beta-fucopyranoside. This mixture of triterpenoid saponins induced reductions in MABP and HR similar to those induced by propranolol. Together, these findings indicate that the two quinovic acid glycosides are responsible for the hypotensive and bradycardic effects which suggest their potential use in cardiovascular therapy. PMID- 25920262 TI - Chemical composition and in vitro cytotoxic and antileishmanial activities of extract and essential oil from leaves of Piper cernuum. AB - Fractionation of the MeOH extract from leaves of Piper cernuum Vell. (Piperaceae) afforded six phenylpropanoid derivatives: 3',4'-dimethoxydihydrocinnamic acid (1), piplaroxide (2), methyl 4'-hydroxy-3',5'-dimethoxy cinnamate (3), 3',4',5' trimethoxydihydrocinnamic acid (3), dihydropiplartine (5), and piplartine (6). The structures of isolated metabolites were characterized by NMR and MS spectral data analysis. The chemical composition of essential oil from the leaves was determined using GC/LREIMS followed by the determination of Kovats indexes. This procedure allowed the identification of nineteen terpenoids, with beta-elemene (7), bicyclogermacrene (8), germacrene D (9), and (E)-caryophyllene (10) as the main compounds. Compounds 1 and 3-6 displayed no in vitro cytotoxicity against cancer cell lineages B16F10-Nex2, U87, HeLa, HL-60, HCT, and A2058 while 2 showed moderate activity against B16F10-Nex2 and HL-60 lines. Otherwise, compounds 7-10 displayed high cytotoxic activity. Evaluation against non-tumorigenic HFF cells indicated a reduced selectivity of compounds 7-10 to tumoral cells. No antileishmanial activity on macrophages infected with L. (L.) amnazonensis was found for the crude MeOH extract and compounds 1-6. The crude essential oil and compounds 7-10 reduced parasitism and eliminated the majority of infected and non infected cells at 50 MUg/mL. PMID- 25920263 TI - Synthesis and antihyperlipidemic activity of piperic acid derivatives. AB - A series of piperic acid derivatives were designed and synthesized from piperine/piperlonguminine, and their antihyperlipidemic activities evaluated in diet-induced hyperlipidemic rats with respect to simvastatin. Two promising analogues 3 and 10 were discovered and their antihyperlipidemic activities were comparable to or better than those of simvastatin. PMID- 25920264 TI - A new benzylisoquinoline alkaloid from Leontice altaica. AB - A new benzylisoquinoline alkaloid, lincangenine-4-beta-D-glucopyranoside (1), has been isolated from the roots of Leontice altaica, together with 5 known alkaloids. Its structure was elucidated on the basis of 1D and 2D NMR data, and chemical means. PMID- 25920265 TI - Quantitative analysis of bioactive carbazole alkaloids in Murraya koenigii. AB - Carbazole alkaloids induce apoptosis in HL-60 cells through activation of the caspase-9/caspase-3 pathway and they are targeted as potential anticancer agents. Thus, the naturally occurring carbazole alkaloids become important as precursors for lead optimization in drug development. A method based on ultra performance liquid chromatography coupled with photodiode-array detection was developed using reverse phase isocratic elution with 85:15 acetonitrile and ammonium acetate buffer (5 mM). Seven samples of Murrya koenigii (L.) Spreng. from north-central India (Uttar Pradesh) were analyzed. All three targeted analytes, koenimbidine (mk1), koenimbine (mk2) and mahanimbine (mk3), were well separated within 4.0 min with linearity of the calibration curves (r2 > 0.999). The limits of detection and quantification of mk1, mk2 and mk3 were 0.7, 0.4, 0.04 MUg/mL and 2.14, 1.21, 0.12 MUg/mL, respectively. The natural abundance of mk1, mk2 and mk3 was 0.06 0.20, 0.04-0.69 and 0.13-0.42%, w/w, respectively, in the dried powdered leaves, whereas, the tissue specific distribution of carbazole alkaloids was observed in the order of predominance, mk1 leaf>root>fruit>stem, mk2 fruit>leaf >stem>root, and mk3 fruit>leaf>root>stem. The developed method was validated for limits of detection and quantification, repeatability, accuracy, precision and stability. This is the first report on the natural abundance of the major carbazole alkaloids in M. koenigii and the method developed can be used in HPLC/UPLC systems. PMID- 25920266 TI - Anthocephaline, a new indole alkaloid and cadambine, a potent inhibitor of DNA topoisomerase IB of Leishmania donovani (LdTOP1LS), isolated from Anthocephalus cadamba. AB - Chemical investigation of the stem bark of Anthocephalus cadamba has resulted in the isolation of anthocephaline (1), a new indole alkaloid, along with strictosamide (2), vincosamide (3) and cadambine (4). The structures of the isolated alkaloids (1-4) were established by detailed 2D NMR spectral analysis. Cadambine (4) exhibited potent DNA topoisomerase IB inhibitory activity. PMID- 25920267 TI - Phosphodiesterase inhibitory activity of the flavonoids and xanthones from Anaxagorea luzonensis. AB - Five flavonoids, one isoflavone and five xanthones were isolated from Anaxagorea luzonensis. Of these eleven isolated compounds, 1,3,5-trihydroxy-4-prenylxanthone (3) was a relatively potent inhibitor of phosphodiesterase type 5 (PDE5), with an IC50 value of 3.0 MUM. This is the first report showing that natural xanthones can exhibit promising PDE5 inhibitory activity. Moreover, this study revealed that the presence of the C-4 prenyl residue attached to the xanthone core is correlated with the significant PDE5 inhibitory activity. PMID- 25920268 TI - Xanthone derivatives from the fermentation products of an endophytic fungus Phomopsis sp. AB - Three new xanthones, 1-hydroxy-3-hydroxyethyl-5-methoxy-6-methoxycarbonylxanthone (1), 1,4-dihydroxy-3-hydroxyethyl-5-methoxy-6-methoxycarbonylxanthone (2), and 1 hydroxy-3-hydroxyethyl-4-methoxy-8-methoxycarbonylxanthone (3), together with five known xanthones (4-8) were isolated from the fermentation products of an endophytic fungus Phomopsis sp.. Their structures were elucidated by spectroscopic methods including extensive 1D- and 2D-NMR spectroscopic techniques. Compounds 1-3 and 7 were also tested for their cytotoxicity against five human tumor cell lines (NB4, A549, SHSY5Y, PC3, and MCF7) by the MTT method, with paclitaxel used as the positive control. Compound 1 showed cytotoxicity against A549 and PC3 cells with IC50 values of 3.2 and 2.5 MUM, respectively, 2 showed potential cytotoxicity against NB4 cells, with an IC50 value of 3.6 MUM, and 3 showed cytotoxicity against A549 cells with an IC50 value of 3.5 MUM. PMID- 25920269 TI - Coumarins from Murraya paniculata var. zollingeri endemic to the Timor Islands. AB - Four new coumarins, murrangatin-1'-senecioate (1), 5-methoxypanial (2), mexoticin 2'-senecioate (3) and murralongic acid (4), were isolated from the leaves of Murraya paniculata var. zollingeri, together with 23 known coumarins. The structures of the new compounds were elucidated based on spectroscopic data. The taxonomic status of M. paniculata var. zollingeri is briefly discussed, along with its similarity to M. paniculata. PMID- 25920270 TI - A new geranylbenzofuranone from Zanthoxylum armatum. AB - A new geranylbenzofuranone, zantholide (1), and eight known compounds, dodeca 2E,4E-dienoic acid isobutylamide (2), dodeca-2E,4E,8Z,11-tetraenoic acid isobutyl amide (3), zanthoxylin (4), sesamin (5), kobusin (6), asarinin (7), fargesin (8) and armatamide (9), have been isolated from the bark of Zanthoxylum armatum. The structures of the isolated compounds were determined on the basis of spectroscopic (1D, 2D NMR) and HR-ESI-MS data. This is the first report on the isolation of 2 and 3 from the Rutaceae family and 4 from Z. armatum. PMID- 25920271 TI - A new antioxidant pyrano[4,3-c][2]benzopyran-1,6-dione derivative from the medicinal mushroom Fomitiporia ellipsoidea. AB - A new pyrano[4,3-c][2]benzopyran-1,6-dione derivative antioxidant, named phelligridin K (1), was isolated from the methanol extract of the fruiting bodies of Fomitiporia ellipsoidea, together with the known compounds, (E)-4-(3,4 dihydroxyphenyl)but-3-en-2-one (2), hispidin (3), inoscavin C (4), and inonoblin B (5). Their structures were elucidated by means of extensive NMR and MS data analysis. Compounds 1, 4 and 5 exhibited significant scavenging activity against the ABTS radical cation. PMID- 25920272 TI - Anti-inflammatory anthraquinones from the crinoid Himerometra magnipinna. AB - Chemical investigation of a crinoid Himerometra magnipinna has afforded three anthraquinones (1-3), including one new metabolite, (+)-rhodoptilometrin (1). The structures of these compounds were elucidated on the basis of their spectroscopic data and the absolute configuration of 1 was further confirmed by single-crystal X-ray diffraction analysis. In the in vitro anti-inflammatory effects test, compound 2 was found to significantly inhibit the accumulation of the pro inflammatory iNOS protein of the LPS-stimulated RAW264.7 macrophage cells. PMID- 25920273 TI - Phenolic compounds from Limonium pruinosum. AB - A new phenolic compound, 6'-O-sulfonyl-salidroside (1), together with fifteen known compounds, were isolated from the all parts of Limonium pruinosum. Their structures were elucidated by 1D and 2D NMR experiments including 1D TOCSY, DQF COSY, HSQC and HMBC spectroscopy, as well as ESIMS analysis. The antioxidant activity of the extracts and all isolated compounds was evaluated by DPPH test. PMID- 25920274 TI - Two new compounds from Paeonia lactiflora. AB - Two new compounds, namely 5-methyl-4,2',3',5'-tetrahydroxy-4'-methoxy-2-aldehyde biphenyl (1) and 1,8-dioxo-1,8-dihydropyrano[3,4-c]pyran-3,6- dicarboxyl acid, diethyl ester (2), were isolated from the 95% ethanol extract of the roots of Paeonia lactiflora Pall. The structures of 1 and 2 were elucidated by spectroscopic methods, including UV, IR, HR-ESI-MS and extensive 1D and 2D NMR techniques. PMID- 25920275 TI - Arylalkanones from Horsfieldia macrobotrys are effective antidiabetic agents achieved by alpha-glucosidase inhibition and radical scavenging. AB - Horsfieldia macrobotrys Merr has long been used by Dayak people in East Kalimantan of Indonesia, for diabetes therapy. Inspired by ethnopharmacological use and promising alpha-glucosidase and radical scavenging activities, an attempt to identify the active components was carried out. Bioassay-guided isolation yielded two related arylalkanones named 1-(2,4,6-trihydroxyphenyl)-9-phenylnonan 1-one (1) and malabaricone A (2). Arylalkanone 1 showed potent radical scavenging comparable with that of the standard antioxidant, ascorbic acid, and promising inhibition against alpha-glucosidases. Noticeably, arylalkanone 1 was 3-30 times more potent than malabaricone A (2) in all bioassays examined, thus suggesting the critical role in exerting bioactivities of the hydroxy group on the aryl moiety. This hypothesis was also supported by reduction in inhibitory effects of the methyl ether analogues la and 2a. Arylalkanone 1 inhibited yeast alpha glucosidase in a mixed-type manner in which the noncompetitive pathway was dominant over competitive inhibition. This study is the first report of alpha glucosidase inhibition of arylalkenone-type compounds and the first phytochemicals from H. macrobotrys. PMID- 25920276 TI - Metabolomic characterization of a low phytic acid and high anti-oxidative cultivar of turmeric. AB - Turmeric, the rhizome of Curcuma longa, has a long history of use as a spice and also as a traditional medicine in many Asian countries. To reveal unique morphological features of a newly registered Curcuma cultivar, C. longa cv. Okinawa Ougon (Ougon), non-targeted LC-MS and GC-MS analyses were conducted. The analysis revealed its distinctive chemical properties: lower amount of phytic acid and inorganic metals such as Fe, Mn, and Al, as well as higher concentrations of reduced derivatives of curcuminoids, such as dihydrobisdemethoxycurcumin, tetrahydrobisdemethoxycurcumin, dihydrodemethoxycurcumin, and tetrahydrodemethoxycurcumin. In addition, germacrane-type sesquiterpenes were almost absent although alpha-humulene and beta-caryophyllene, generated by the same biosynthetic route, were present. Presumably the alternation of the metal ion content, serving as a cofactor of sesquiterpene synthase, modulates the resulting variation of the sesquiterpenes. In summary, the cultivar Ougon is considered a promising candidate for functional food additives. PMID- 25920277 TI - The cardioprotective effects of resveratrol in rats with simultaneous type 2 diabetes and renal hypertension. AB - This study aimed at examining the cardioprotective effects of resveratrol in rats with simultaneous type 2 diabetes and renal hypertension. Eight groups (8-10 each) of male Sprague-Dawley rats, including a control, a diabetic, a renal hypertensive, a sham, a simultaneously hypertensive-diabetic receiving vehicle, and 3 simultaneously hypertensive-diabetic receiving resveratrol at 5, 10 or 20 mg/kg/day were used. After 4 weeks of treatment, blood pressure and glucose, and serum markers of oxidative stress were measured, and animals' hearts were used for isolated studies. Resveratrol prevented the increase of systolic blood pressure, serum malondialdehyde, fasting blood glucose, infarct size, coronary resistance, and coronary effluent creatine kinase-MB. Moreover, it prevented the decrease of serum superoxide dismutase and glutathione reductase, heart rate, left ventricular developed pressure, rate of increase of ventricular pressure, and rate of decrease of ventricular pressure. In conclusion, our findings show that resveratrol alleviates cardiac dysfunction in diabetic-hypertensive rats by virtue of antioxidant, antihypertensive, and coronary vasodilating activities. PMID- 25920278 TI - A specific process to purify 2-methyl-D-erythritol-4-phosphate enzymatically converted from D-glyceraldehyde-3-phosphate and pyruvate. AB - A one-pot enzymatic cascade was established to synthesize MEP, one of the key intermediates in the MEP terpenoid biosynthetic pathway. D-GAP and sodium pyruvate were converted to MEP in a reaction catalyzed by DXP synthase and DXP reductoisomerase (DXR) in the presence of the coenzymes ThPP, NADPH, and Mg2+. The product was then isolated by using a specific two-step purification process and MEP was obtained in a yield of nearly 60% and high purity. Importantly, MEP prepared by this way was totally free from contamination by minor amounts of DXP that was not completely convertible by DXR. PMID- 25920279 TI - Two new ramulosin derivatives from the entomogenous fungus Truncatella angustata. AB - Two new ramulosin derivatives, 7alpha-hydroxy-8-dihydroramulosin (1) and 7 ketoramulosin (2), along with three known metabolites, (+)-ramulosin (3), 6 hydroxyramulosin (4), and 8-dihydroramulosin (5), were isolated from the crude extract of Truncatella angustata, an entomogenous fungus isolated from the Septobasidium-infected insect Aspidiotus sp. The structures of 1 and 2 were elucidated by nuclear magnetic resonance experiments, and 1 was further confirmed by X-ray crystallography. The absolute configuration of 1 was assigned by single crystal X-ray diffraction analysis using Cu Kalpha radiation, whereas that of 2 was determined by electronic circular dichroism (ECD) calculations. Compounds 1-5 were tested for cytotoxicity against four human carcinoma cell lines, HeLa, A549, MCF-7, and T24. Compound 4 showed weak cytotoxic effects against A549 and T24. PMID- 25920280 TI - Anti-inflammatory and cytotoxic compounds from Solanum macaonense. AB - One new cerebroside, macaocerebroside A (1), and 15 known compounds (2-16) were isolated from Solanum macaonense for the first time. In an antineutrophilic inflammatory assay, four caffeic acid derivatives (2-5) were active against superoxide anion generation with IC50 values of 3.3-4.8 MUM; especially, 3 inhibited elastase release with an IC50 value of 4.0 MUM. Additionally, kaempferol (8) also showed inhibition against elastase release with an IC50 value of 4.0 MUM. In a cytotoxic assay, rutin (14) had selective moderate cytotoxicity toward human lung (A549), bladder (NTUB1), and prostate (DU145) cancer cell lines with IC50 values of 34.6, 41.3, and 31.8 MUM, respectively. PMID- 25920281 TI - Crassaostrea gigas oyster shell extract inhibits lipogenesis via suppression of serine palmitoyltransferase. AB - Oysters are widely consumed seafood, but their shells impose a serious environmental problem. To extend the utilization of oyster shell waste, we investigated the biological role of oyster shell extract. In this study, we verified that the ethanol extract of oyster shell (EOS) contains taurine and betaine, the major components of oyster body. EOS downregulated transcription of Sptlc1 and Sptlc2 mRNA, the subunits of serine palmitoyltransferase (SPT). Suppression of SPT subunits reduced sphinganine and sphingomyelin by inhibiting de novo sphingolipid biosynthesis. Inhibition of sphingomyelin biosynthesis resulted in downregulation of lipogenic gene expression such as ACC, FAS, SCD1, and DGAT2. Consistent with inhibition of lipogenesis, cellular triglyceride levels were diminished by EOS, but cholesterol levels were not altered. Taken together, these results suggest that EOS has a lipid-lowering effect and could be applied as either a therapeutic or preventive measure for metabolic dysfunction. PMID- 25920282 TI - Using the gene expression signature of scutebarbalactone VN isolated from Scutellaria barbata to elucidate its anticancer activities. AB - Bioassay-guided fractionation led to the discovery of a novel neo-clerodane diterpenoid, scutebarbalactone VN (BalA: 8,13-epoxy-3-en-7-hydroxy-6,11-O- dibenzoyl-15,16-clerodanolide), from the methanol extract of the whole-plant of Vietnamese Scutellaria barbata D. Don. A microarray technique combined with bioinformatic analyses showed that BalA could inhibit cell cycle pathways by downregulating genes such as CDC25A and AURKA. BalA also showed the potential to reactivate downregulated genes in hepatocellular carcinoma cells and genes in antioxidant pathways such as HMOX1 and HSPA1A. Querying Connectivity map 2.0 resulted in a match of the BalA-modulated gene signature with that of 10 known compounds, most of which are currently marketed chemotherapy drugs. The highest matching scores belonged to lomustine, semustine, and withaferin A. Lomustine and semustine were found to alkylate DNA and RNA, while withaferin A inhibits nuclear factor kappa B (NF-kappaB) activity. A luciferase reporter assay was also conducted on 293/NF-kappaB human embryonic kidney cells that had been transfected with the NF-kappaB-luciferase plasmid to verify the anticancer activity of BalA. The assay showed that BalA effectively blocked NF-kappaB with an IC50 of 38.6 +/- 0.05 MUM. PMID- 25920283 TI - Comparison of different methodologies for detailed screening of Taraxacum officinale honey volatiles. AB - Headspace solid-phase microextraction (HS-SPME), ultrasonic solvent extraction (USE) and solid phase extraction (SPE), followed by GC-FID/MS were used for screening of dandelion (Taraxacum officinale Weber) honey headspace, volatiles and semi-volatiles. The obtained results constitute a breakthrough towards screening of dandelion honey since dominant compounds identified in the extracts were not previously reported for this honey type. Nitriles dominated in the headspace, particularly 3-methylpentanenitrile (up to 29.9%) and phenylacetonitrile (up to 20.9%). Lower methyl branched aliphatic acids and norisoprenoids were relevant minor constituents of the headspace. The extracts contained phenylacetic acid (up to 24.0%) and dehydrovomifoliol (up to 19.3%) as predominant compounds, while 3-methylpentanenitrile and phenylacetonitrile were detected in the extracts in minor abundance. Dehydrovomifoliol can be considered more characteristic for dandelion honey in distinction from phenylacetic acid. Low molecular aliphatic acids, benzene derivatives and an array of higher aliphatic compounds were also found in the extracts. The results of SPE/GC-FID/MS were very similar to USE/GC-FID/MS with the solvent dichloromethane. The use of all applied methodologies was relevant for the comprehensive chemical fingerprinting of dandelion honey volatiles. PMID- 25920284 TI - Volatile constituents from the leaves, fruits (berries), stems and roots of Solanum xanthocarpum from Nepal. AB - The essential oils from the leaves, fruits, roots, and stems of Solanum xanthocarpum, growing wild in Nepal, have been obtained and analyzed by gas chromatography-mass spectrometry. The fruit volatiles were dominated by benzyl benzoate (21.7%) and (E,E)-geranyl linalool (12.6%); heptacosane (20.0%) was the major component of the leaf oil; the stem oil was dominated by palmitic acid (28.9%), heptacosane (12.8%) and linoleic acid (10.1%); while solavetivone (22.9%), palmitic acid (21.0%), and linoleic acid (8.2%) were the major components of the root essential oil. There do not seem to be any common phytochemical taxonomic markers in the essential oils of Solanum spp; the chemical diversity observed in this genus mirrors the taxonomic diversity. PMID- 25920285 TI - Essential oil constituents of Etlingera yunnanensis and Hornstedtia sanhan grown in Vietnam. AB - The chemical composition of the essential oils obtained from the hydrodistillation of different parts of Etlingera yunnanensis (T.L. Wu & S.J. Chen) R.M. Sm. and Hornstedtia sanhan M.F. Newman (Zingiberaceae) grown in Vietnam are reported. The analysis was performed by means of a gas chromatography flame ionization detector (GC-FID) and gas chromatography coupled with mass spectrometry (GC-MS). The essential oil of the leaves of E. yunnanensis comprised mainly germacrene D (19.2%), beta-pinene (11.6%), and alpha-amorphene (11.2%), while that of the stems was rich in beta-pinene (23.7%), 1,8-cineole (11.0%) and alpha-pinene (9.6%). The major components of the root oil of E. yunnanensis were beta-pinene (31.9%), alpha-pinene (13.7%) and 1,8-cineole (9.4%). However, alpha pinene (25.9%, 36.3% and 14.1% for leaves, stems and roots, respectively), beta pinene (9.7%, 11.8% and 7.2% for leaves, stems and roots, respectively) and limonene (22.1%, 24.6% and 16.2% for leaves, stems and roots, respectively) were the major compounds of H. sanhan. In addition, alpha-humulene (15.9%) was present in larger amounts in the leaf oil while the root oil contained the largest proportion of methyl chavicol (43.7%). PMID- 25920286 TI - Chemical constituents of essential oils from the leaves, stems, roots and fruits of Alpinia polyantha. AB - The essential oils obtained from the leaves, stems, roots and fruits of Alpinia polyantha D. Fang (Zingiberaceae) have been studied. The leaf oil was comprised mainly of camphor (16.1%), alpha-pinene (15.2%) and beta-agarofuran (12.9%), while the major constituents of the stem oil were alpha-pinene (12.4%), beta cubebene (10.6%), beta-agarofuran (10.3%) and globulol (8.8%). However, beta cubebene (12.6%), fenchyl acetate (10.8%), beta-maaliene (9.0%), aristolone (8.8%) and alpha-pinene (8.2%) were the compounds occurring in higher amounts in the root oil. The quantitatively significant compounds of the fruit oil were delta-cadinene (10.9%), beta-caryophyllene (9.1%), beta-pinene (8.7%) and alpha muurolene (7.7%). PMID- 25920287 TI - Volatile constituents of the fruit and roots of Cymbopogon olivieri. AB - The essential oil contents of the fruit and roots of Cymbopogon olivieri growing wild in south of Iran were found to be 0.7% and 0.4% (v/w), respectively based on the fresh weight. The oils were analyzed by GC and GC-MS. Forty and twenty six constituents, representing 93.1% and 93.4% of the oils were identified, respectively. The major components of the C. olivieri fruit oil were identified as piperitone (44.1%), alpha-terpinene (13.7%), neral (6.3%), elemol (5.6%) and beta-eudesmol (5.3%), while the main components of that of roots were characterized as piperitone (20.6%), alpha-muurolol (9.5%), beta-eudesmol (8.5%), selina-6-en-4-ol (7.9%), 5-epi-7-epi-alpha-eudesmol (6.8%) and elemol (5.8%). PMID- 25920288 TI - Composition of essential oils isolated from the needles of Pinus uncinata and P. uliginosa grown in Poland. AB - The compositions of mountain pine (Pinus uncinata) and peat-bog pine (P. uliginosa) needle essential oils were investigated. Enantiomeric compositions of selected monoterpene hydrocarbons were also examined. Respectively, fifty-three and seventy-six components of the essential oils were identified using GC-MS and retention indexes. The main group of essential oil components of mountain pine needles were monoterpenes, and bornyl acetate constituted approximately 30% (46.3 g/100 g) of the oil. In peat-bog pine essential oil, monoterpenes and sesquiterpenes exhibited a similar content (ca. 40%). Bornyl acetate and alpha pinene were the main constituents of both essential oils. In the essential oil of P. uncinata needles, limonene, camphene, myrcene and (E)-beta-caryophyllene were also noticeable, while in the essential oil of P. uliginosa needles, Delta-car-3 ene, (E)-beta-caryophyllene, germacrene D, delta-cadinene, germacrene D 4-ol and alpha-cadinol were present in notable quantities. In both essential oils, borneol propionate, isobutyrate, 2-methylbutyrate and isovalerate were detected. Their presence was confirmed by synthesis and analysis of the standards; retention indexes on a non-polar column are published herein. PMID- 25920289 TI - Essential oil composition and antimicrobial activity of Vismia macrophylla leaves and fruits collected in Tachira-Venezuela. AB - Hydrodistillation of Vismia macrophylla Kunth (Hypericaceae) leaves (L) and fruits (F) yielded 1.3%, v/w, and 5.6%, v/w, of essential oil, respectively. GC and GC-MS analyses showed the presence of twenty-four (96.4%, L) and thirty-one (96.6%, F) components, respectively. Major compounds identified in the leaf oil were gamma-bisabolene (44.4%) and beta-bisabolol (14.9%), while those in the fruit oil were germacrene-D (12.1%), 6-cadinene (10.7%) and gamma-bisabolene (22.3 %). Oil obtained from the fruits of V. macrophylla showed antibacterial activity against Gram-positive (S. aureus ATCC 25923 and E. faecalis ATCC 29212) as well as Gram-negative bacteria (E. coli ATCC 25922), with MIC values ranging from 150 MUL/mL to 740 MUL/mL. Oil obtained from leaves were active only on the Gram-positive bacteria S. aureus (100 MUL/mL) and E. faecalis (500 MUL/mL), but also showed antiyeast activity against Candida albicans CDC-B385 and C. krusei ATCC 6258 (600 MUL/mL, each). PMID- 25920290 TI - Development of a pelvic floor muscle strength evaluation device. AB - OBJECTIVE: To validate the device and investigate the effect of this device on symptoms, quality of life, and pelvic floor muscle strength. MATERIAL AND METHOD: The device was designed to measure vaginal pressure changes using air-pressure balloon and abdominal wall muscle activities using surface electromyography. To test the accuracy of the device, for vaginal pressure measurement, a Mercury sphygmomanometer was used as a gold standard, and for abdominal wall muscle activity, a standard biofeedback machine was used as a reference device. A randomized, controlled trial was conducted in sixty-one women with stress urinary incontinence. They were randomly divided into two groups undergoing PFMT with a single 15-minute biofeedback session (BF + PFMT group) or without biofeedback (PFMT group). The pelvic floor muscle strength, abdominal wall muscle activity and incontinence-specific quality of life questionnaire (I-QOL), measurements were evaluated at baseline and at 8- and 16-week after treatment. RESULTS: The accuracy of vaginal probe pressure perineometry was 98% compared to a standard sphygmomanometer. The device could detect abdominal wall muscles activities at 10 milliseconds (100 Hz), 20 milliseconds (50 Hz), and 50 milliseconds (20 Hz). After 8 and 16 weeks of treatment, there were statistically significant intra group differences in the maximum vaginal squeeze pressure in both groups. However, the inter-group differences were not demonstrated. The proportion of women who performed pelvic floor muscle exercise correctly was significantly higher in the BF + PFMT group (72.41%) compared to the PFMT group (21.88%) at week 16 (p < 0.05). CONCLUSION: The simple pelvic floor muscle strength evaluation device might be helpful in pelvic floor muscle training in a low resource setting. PMID- 25920291 TI - Clinical characteristics of hepatitis B and C virus infections in HIV-infected patients. AB - BACKGROUND: Hepatitis B virus (HBV) and hepatitis C virus (HCV) share a common route of transmission with human immunodeficiency virus (HIV). HIV co-infected with HBV or HCV was associated with a progression to severe liver disease, increased risk of hepatotoxicity from antiretroviral therapy and reduced survival. Data regarding HBV and HCV infection in HIV-positive individuals in Thailand is limited. OBJECTIVES: To investigate the prevalence and clinical characteristics of HBV and HCV infection in HIV-infected patients in Siriraj Hospital. MATERIAL AND METHOD: A retrospective study was conducted in adult HIV positive followed up at the Infectious Disease Clinic, Siriraj Hospital. Prevalence of HBV and HCV infections and clinical characteristics were analyzed. RESULTS: 250 HIV-positive patients were enrolled, mean age was 38.8 years and 57.2% were male. HBV infection was found in 6.5% (15/231), and HCV infection was 7.7% (17/222). One patient had both HBV and HCV infections. In multivariate analysis, factors associated with either HBV or HCV co-infection included male gender (77.4% vs. 55%; p 0.008), history of salmonellosis (9.7% vs. 2.5%; p 0.042) or elevated serum alanine aminotransferase (ALT) level (34 U/L vs. 25 U/L; p 0.018). Factors associated with HBV infection, compared with those without hepatitis virus infection, included male gender (86.7% vs. 56%; p 0.038), history of salmonellosis (20% vs. 2.3%; p 0.005), elevated serum ALT level (42 U/L vs. 25 U/L; p 0.012) and low CD4 percent (1.05% vs. 5.02%; p 0.04). In this study, we did not find any factor associated with HCV infection in HIV patients. CONCLUSION: The prevalence of HBV and HCV infection in HIV-infected Thai patients is significant. Male gender, history of salmonellosis, elevated serum ALT levels, and low CD4 percent are associated with HBV co-infection. PMID- 25920292 TI - Effect of proton pump inhibitor on plasma voriconazole concentration in Thai patients. AB - BACKGROUND: Voriconazole is an antifungal drug used for treatment of invasive aspergillosis. It is metabolized mainly via the cytochrome P450 isoenzymes CYP2C19, through which its enzymatic activity can be inhibited by proton pump inhibitors (PPI), especially omeprazole. Previous reports demonstrated that omeprazole might be used to boost plasma voriconazole levels in infected patients. However; there was no difference in plasma voriconazole concentration in healthy individuals, who received omeprazole versus placebo. Therefore, the interaction between PPI and voriconazole may be different between healthy and infected individuals. OBJECTIVE: To determine the effects of omeprazole on plasma voriconazole concentration in Thai patients who had invasive fungal diseases. MATERIAL AND METHOD: The present study is a prospective observational study and is a sub-study of the voriconazole therapeutic drug monitoring study. Patients treated with voriconazole admitted at Siriraj Hospital during July 2011 to September 2013 were enrolled. Blood samples were drawn for plasma voriconazole concentration assays at day 0, 3, 7, 14 and 28. Data regarding PPI use were collected and analyzed in correlation with plasma voriconazole concentration. RESULTS: Of 54 patients enrolled, 47 had sufficient clinical data but 46 patients had complete data of voriconazole levels. Patients mean age was 47 years and 60% were male. Thirty-nine patients (83%) had invasive pulmonary aspergillosis. Forty one patients (87.2%) received PPI, among which 37 (90.2%) were omeprazole. Patients with PPI use had no difference in plasma voriconazole concentration, when compared with those without PPI use, at day 3 (5.89 vs. 5.44 mg/L, p = 0.744), day 7 (5.4 vs. 5.29 mg/L, p = 0.471), day 14 (2.40 vs. 3.13 mg/L, p = 0.372) and day 28 (1.77 vs. 3.23 mg/L, p = 0.314). Although there was a trend toward higher plasma voriconazole concentration in patients receiving higher omeprazole dose (> 20 mg/day), the difference between those treated with high (> 20 mg/day) and low (20 mg/day) doses of omeprazole was not statistically significant at day 3 (6.27 vs. 4.87 mg/L, p = 0.429), day 7 (7.44 vs. 3.78 mg/L, p = 0.166), day 14 (2.52 vs. 1.68 mg/L, p = 0.534) and day 28 (2.51 vs. 1.44 mg/L, p = 0.154). Similarly, the duration of omeprazole use in concurrent with voriconazole treatment was not associated with plasma voriconazole concentration in infected patients. CONCLUSION: Omeprazole does not affect plasma voriconazole concentration in infected patients. However, patients who received higher doses ofomeprazole (> 20 mg/day) tend to have a higher concentrations of plasma voriconazole. PMID- 25920293 TI - Epidemiology and clinical characteristic of mycobacterial infections in human immunodeficiency virus-infected patients in Siriraj Hospital. AB - BACKGROUND: Mycobacterium tuberculosis (MTB) and non-tuberculous mycobacteria (NTM) infections are major health problems in Human Immunodeficiency Virus (HIV) infected patients. Most previous studies focused mainly on tuberculosis (TB) rather than NTM infections. OBJECTIVE: To determine clinical features of mycobacterial infections, from both MTB and NTM in HIV-infected patients in Siriraj Hospital. MATERIAL AND METHOD: A retrospective study of adult HIV infected patients in Infectious Disease Clinic, Siriraj Hospital, was conducted. Clinical characteristics and factors associated with mycobacterial infections were analyzed. RESULTS: Of 253 patients enrolled, 65 (25.7%) developed mycobacterial infections, in which 56 patients (86%) were tuberculosis (TB), whereas NTM was diagnosed in 9 (14%). Of these 65 patients, 45 (69.2%) were culture-proven, 14 (21.6%) were diagnosed TB by positive acid-fast bacilli smears and 6 (9.2%) were diagnosed TB by clinical response to anti-tuberculosis treatment only. Among culture-positive patients, MTB was found in 36 (80%) and NTM in 9 (20%), in which Mycobacterium avium complex (MAC) was the most common among NTMisolates (n = 5),followed by unidentifiable slowly-growing mycobacteria (n = 3) and M. fortuitum (n = 1). Among patients with MTB infection, 58.3% were disseminated. The most affected organ in patients with mycobacterial infections was lung (75%), followed by lymph node (66.7%). Factors associated with mycobacterial infections included male gender (64.6% vs. 54.3%; p = 0.026), higher HIV Viral load (1.04 x 10(6) VS. 0.3 x 10(6); p = 0.004), lower hematocrit (32.7% vs. 35.3%; p = 0.032) and higher alkaline phosphatase (ALP) (146 U/L vs. 107 U/L;p = 0.032). In contrast, Pneumocystis pneumonia (PCP) was negatively associated with mycobacterial infections in HIV-infected individuals (28.8% vs. 10.9%; p = 0.004). Favorable treatment response was 86.1% and 77.8% for MTB and NTM infection, respectively, and the 6-month mortality rates were 2.78% and 11.1% for MTB and NTM infection, respectively. In patients who received treatment for TB, 22.2% had hepatitis, 13.9% had drug allergy and 8.3% had immune reconstitution inflammatory syndrome. CONCLUSION: Disseminated infection is the most common form of mycobacterial infection in HIV-infected patients, resulting in anemia and high ALP levels. PCP was negatively associated with mycobacterial infection. MAC is the most common of the NTM isolates in HIV-infected patients. PMID- 25920294 TI - Implementation of antibiotic use guidelines for fresh traumatic wound at Siriraj Hospital. AB - OBJECTIVE: To determine the effectiveness of implementing a clinical practice guideline (CPG) on antibiotic use for adults with fresh traumatic wounds who attended the trauma center at Siriraj Hospital, Bangkok. MATERIAL AND METHOD: A prospective study of 600 adult patients who had fresh traumatic wounds (<= 6 hours) was conducted at Siriraj Trauma Center from March 2013 to March 2014. The CPG was introduced to physicians, nurses and medical students by posting the CPG at the patient care areas of the trauma center. The outcomes were an appropriate classification of wounds according to the CPG recommendations, prevalence of antibiotic prescribing, incidence of wound infection and compliance with the CPG. RESULTS: Clean-contaminated wounds that did not need antibiotic treatment and clean-contaminated and contaminated wounds that required antibiotics were observed in 63.2, 6.7, and 30.1% ofthe patients, respectively. Antibiotics were given to 512 patients (85.3%). Infections occurred in six patients (1.0%). Antibiotic prescription according to CPG recommendations was observed for 243 patients (40.5%). The prevalence of antibiotic use in the CPG-compliant group (65.8%) was significantly less than that in the CPG-noncompliant group (98.6%) (p < 0.001). The patients in the CPG-compliant group had more contaminated wounds than those in the CPG-noncompliant group (51.4 vs. 15.7%, p < 0.001). The incidences of wound infection were very low in both groups and not significantly different (1.2 vs. 0.8%, p = 0.690). CONCLUSION: Antibiotic prophylaxis was necessary in less than 36.8% of adults with fresh traumatic wounds who attended Siriraj Trauma Center Compliance to CPG implementation using simple intervention seemed to be low. Adhering to CPG recommendations for antibiotic prophylaxis in adults with fresh traumatic wounds can reduce the unnecessary prescribing of antibiotics without increasing the rate of wound infection. PMID- 25920295 TI - Randomized controlled study of probiotics containing Lactobacillus casei (Shirota strain) for prevention of ventilator-associated pneumonia. AB - OBJECTIVE: To evaluate the efficacy ofprobiotics, Lactobacillus casei (Shirvta strain), in reducing the incidence ofventilator- associated pneumonia (VAP) in medical patients who received mechanical ventilation at Siriraj Hospital. MATERIAL AND METHOD: A prospective, randomized, open-label controlled trial was conducted in 150 adult hospitalized patients in medical wards who were expected to receive mechanical ventilation for 72 hours or longer: The patients were randomized to the probiotics group or the control group. All patients received regular care for mechanical ventilation. The patients in the probiotics group received 80 ml of Lactobacillus casei (Shirota strain) for oral care after having standard oral care once daily and additional 80 ml of the aforementionedfermented dairy product was given via enteralfeeding once daily. The primary outcomes were incidence of VAP and incidence rate of VAP episodes per 1,000 ventilator-days. The secondary outcomes were length ofhospital stay, mortality at day 28 and 90, incidence ofdiarrhea, andpresence of resistant bacteria in oropharyngeal and rectal swab samples taken from the patients at baseline, day 7 and day 28 after enrollment. RESULTS: The baseline characteristics of the patients in the probiotics group (75) and the control group (75) were not significantly different. The patients in the probiotics group were less likely to develop VAP compared with the control group (24% vs. 29.3%, p = 0.46), respectively. The incidence rates of VAP in the probiotics and control groups were 22.64 and 30.22 episodes per 1,000 ventilator-days, respectively (p = 0.37). A trend of lower prevalence of some resistant bacteria cultured from oropharyngeal swabs in the probiotics group than that in the control group was observed. Overall 28- and 90 day mortality and length of hospital stay of the patients in both groups were not significantly different. CONCLUSION: Administration of probiotics containing Lactobacillus casei (Shirota strain) has a tendency to reduce the incidence of VAP and colonization with resistant bacteria in oropharyngeal cavity without significant effects on mortality and length of hospital stay. PMID- 25920296 TI - Stroke awareness and factors influencing hospital arrival time: a prospective observational study. AB - BACKGROUND: Data concerning stroke awareness and factors associated with time of hospital arrival for acute stroke patients in Thailand are still lacking. OBJECTIVE: To assess stroke awareness and to identify factors influencing hospital arrival time after an acute stroke. MATERIAL AND METHOD: This is aprospective study comprising consecutive acute stroke patients admitted in Siriraj Hospital, Bangkok, Thailand between August 2010 and December 2011. Demographic data, stroke severity using the NIHSS, diagnosis and stroke awareness questionnaire were collected. RESULTS: Of 217 acute stroke patients, mean age was 66 +/- 13.7 years. Mean stroke severity was 10 +/- 7.6. Patients arrived at the Emergency Department within 4.5 hours (early hospital arrival: EHA) in 38.2% of the cases, 16.6% by ambulance. Only 34.6% of patients recognized that they were having stroke. Factors associated with EHA were 1) stroke awareness (OR 1.96, 95% CI 1.07-3.60, p = 0.030), 2) arrival by ambulance (OR 2.23, 95% CI 1.03-4.81, p = 0.042), and 3) NIHSS >15 (OR 2.26, 95% CI 1.17-4.35, p = 0.015). CONCLUSION: Only one-third of patients were aware of stroke symptoms. Only one in six patients used emergency transportation. Public educational campaign is needed to increase the community awareness of stroke warning symptoms and the urgent emergency medical services. PMID- 25920297 TI - Metoclopramide, versus its combination with dexamethasone in the prevention of postoperative nausea and vomiting after laparoscopic cholecystectomy: a double blind randomized controlled trial. AB - BACKGROUND: Postoperative nausea and vomiting (PONV) are significant problems in laparoscopic surgery. OBJECTIVE: Compare the prophylactic use of metoclopramide and its combination with dexamethasone in the prevention of PONV in patients undergoing laparoscopic cholecystectomy (LC). MATERIAL AND METHOD: One hundred patients aged 18 to 75 with American Society of Anesthesiologists (ASA) class 1-2 who candidates for elective LC at Chiang Mai University Hospital, were included in this double-blind, randomized controlled trial (parallel design). Patients were randomly divided into two groups, by 'Block offour 'randomization. Treatment group received 8 mg dexamethasone and 10 mg metoclopramide, and control group received 10 mg metoclopramide and normal saline solution 1.6 ml. These medications were administered intravenously when the gallbladder was removedfrom gallbladder bed. All of investigators, anesthetists, patients, care providers, and outcome assessor were blinded. Patients were asked to assess their nausea and vomiting at 2, 6, 12, and 24 hours postoperatively, and at discharge. The overall score of PONV in each patient based on afour-point whole number of nausea and vomiting by verbal rating scale 0-3 (0 = no nausea and vomiting, 1 = nausea, 2 = nausea with vomiting, and 3 = repeated vomiting >2 times). RESULTS: Fifty eligible patients were randomized to each group, and all were analyzed. There were no significant differences between baseline characteristics of patients in the two groups. The combination of dexamethasone and metoclopramide indicated a greater antiemetic effect with significant statistical analysis, odds ratio = 0.25 (95% confidence interval O. 11-0.55, p = 0.001). Thepostoperative hospital stay in the combined group and metoclopramide group were, 1 day = 47 (94%) and 37 (74%), >1 day = 3 (6%) and 13 (26%), respectively (p = 0.012). There were no postoperative complications occurred in both groups. CONCLUSION: Intravenous administration of dexamethasone combined with metoclopramide had significant effects in prophylaxis of nausea and vomiting after LC and shorten the hospital stay. Clinical trials registration number: TCTR20140128001 PMID- 25920298 TI - Malignant tumors of temporal bone in Songklanagarind Hospital: management and results. AB - OBJECTIVE: To evaluate the clinical course and treatment in patients with carcinoma of temporal bone MATERIAL AND METHOD: The authors retrospectively reviewed the patients treated for primary carcinoma of temporal bone in Otolaryngology Head and Neck Surgery department, at Songklanagarind Hospital between 2002 and 2013. Thirty-two patients, including 10 cancer ofpinna and 22 carcinoma of the External Auditory Canal (EAC), were included in this study. The treatment modality was lateral temporal bone resection and postoperative radiotherapy and palliative radiotherapy for advanced stage tumors (T4). Twelve patients were excluded due to difference in modality. Twenty patients remained in the study. RESULTS: Twenty patients had carcinoma of EAC, early stage (T1, T2) 36.4% and late stage (T3, T4) 63.6%. The overall survival of this group was 46.9%. The median survival period was 22 months (0.286-0.769, 95% CI). CONCLUSION: The complete resection is the treatment of choice in primary cancer of temporal bone. Postoperative radiotherapy for a microscopic residual tumor is highly recommended. The most important thing is early diagnosis. PMID- 25920299 TI - Lifestyle Change Plus Dental Care (LCDC) program improves knowledge, attitude, and practice (KAP) toward oral health and diabetes mellitus among the elderly with type 2 diabetes. AB - BACKGROUND: Currently, there is an increased prevalence of diabetes mellitus among the elderly. Chronic inflammation from diabetes mellitus effects glycemic control and increases risk of diabetes complications. OBJECTIVE: To assess the effectiveness of a Lifestyle Change plus Dental Care (LCDC) program by improved knowledge, attitude, and practice (KAP) toward oral health and diabetes mellitus among the elderly with type 2 diabetes. MATERIAL AND METHOD: A quasi-experimental study was conducted in two Health Centers (HC 54 intervention and HC 59 control) between October 2013 and April 2014. Sixty-six diabetic patients per health center were recruited. At baseline, the intervention group attended a 20-minute lifestyle and oral health education program, individual lifestyle counseling using motivational interviewing, application of self-regulation manual, and individual oral hygiene instruction. At 3-month follow-up, the intervention group received individual lifestyle counseling and oral hygiene instruction. The intervention group received booster education every visit by viewing a 15-minute educational video. The control group received the routine program. Participants were assessed at baseline, 3-month, and 6-month follow-up for knowledge, attitude, and practice (KAP) toward oral health and diabetes mellitus. Data was analyzed by using descriptive statistic, Chi-square test, Fisher's exact test, and repeated measure ANOVA. RESULTS: After the 6-month follow-up, repeated measure ANOVA analysis showed that participants in the intervention group had significantly higher knowledge and attitude toward oral health and diabetes mellitus. The participants in the intervention group were more likely to exercise, modify diet, have foot examinations, always wear covered shoes, participate in self-feet screening, use dental floss, and use inter-proximal brush than the control group with statistically significant differences. CONCLUSION: The combination of lifestyle change and dental care in one program improved knowledge, attitude, andpractice (KAP) toward oral health and diabetes mellitus in the elderly with type 2 diabetes. Trial registration: ClinicalTrials.in.th: TCTR20140602001. PMID- 25920300 TI - Oral and maxillofacial lesions in a Thai pediatric population: a retrospective review from two dental schools. AB - OBJECTIVE: To determine the prevalence of oral and maxillofacial lesions in a Thai pediatric population. MATERIAL AND METHOD: Oral biopsy records from pediatric patients between the ages of 0 and 15 years in the files ofFaculty of Dentistry, Mahidol University, and the files of Faculty of Dentistry, Khon Kaen University were reviewed. The patients were divided into three age groups, including 0 to 5, 6 to 10, and 11 to 15 years. Excluding the diagnosis of normal tissues, the oral and maxillofacial lesions were classified into nine categories. RESULTS: Of 13,050 biopsied oral and maxillofacial lesions, 1,389 cases (10.6%) came from pediatric patients. The largest number of lesions was odontogenic cysts and tumors, followed by inflammatory and reactive lesions, and salivary gland pathology The top ten most prevalent lesions contributed 73% of all oral biopsies. The most common lesion was dentigerous cyst, followed by mucocele and pyogenic granuloma. CONCLUSION: The vast majority of oral diseases in children were benign and related to either developmental or tissue reaction, while malignant lesions were found in a very small proportion of all oral biopsies. PMID- 25920301 TI - Causes and course of falls resulting in hip fracture among elderly Thai patients. AB - OBJECTIVE: To investigate causes and course off all-related hip fractures in elderly individuals admitted to a hospital. MATERIAL AND METHOD: The authors collected data from older patients admitted with fall-related hip fractures. The cause and the clinical course of falls were evaluated by consultants in geriatric medicine. All patients were followed-up until discharge from the hospital. RESULTS: Falls usually occurred indoors (78.6%) during the daytime (67.5%). Only 27.5% of the falls were attributable to purely extrinsic causes. Neurological, musculoskeletal, and visual problems along with orthostatic hypotension were the leading causes of falls in the present study. Women demonstrated more intrinsic causes (41.9% vs. 28.9%), such as musculoskeletal (33.9% vs. 11.1%), and visual impairment (21.0% vs. 11.1%), whereas falls involving men were more likely to be caused by orthostatic hypotension (21.8% vs. 8.1%). Most patients received surgical treatment (92.5%). The most common complications during the hospital stay were delirium (45%). The modified Rankin Scale of 2-5 at discharge was noted in 46.3% ofpatients, and mortality was 3.8%. The median length of hospital stay was 15 days (7-75 days). The direct costs of in-hospital care were 2,427.2 (761.9 8,348.6) US dollars for general wards, and 3,739.1 (1,333.6-11,871.7) US dollars for special wards. CONCLUSION: Intrinsic causes (pure and combined with extrinsic) lead to falls with hip fractures more often than purely extrinsic causes. Women and men had different etiologies for falls. Hip fracture leads to a number of in-hospital complications and significantfunctional impairment. Preventive strategies following the present study would likely lead to more accurate and beneficial outcomes. PMID- 25920302 TI - Physical effects and cognitive function after exercising "Rue-si-dad-ton" (exercise using the posture of the hermit doing body contortion): a randomized controlled pilot trial. AB - BACKGROUND: This study aims to preliminarily evaluate effect on physical properties of shoulder joints and cognitive function after practicing Rue-si-dad ton, a Thai traditional exercise using the postures of the hermit doing body contortion which still lacks systematically conducted evidence-based regarding its benefits. MATERIAL AND METHOD: Thirty-seven participants who have routinely worked on computer at least 3 hours per day were recruited and randomized into intervention (n = 19) or control group (n = 18). Physical effect on shoulder joints was evaluated by measuring shoulder range of motion (ROM) and evaluating shoulder function with the American Shoulder & Elbow Surgeons Standardized Shoulder Assessment Form. Cognitive function was determined by Verbal Fluency Test, Trail Maker B Test, and Digit Span Test. Both study groups were assessed by all tests at the beginning and at the end of study by blinded assessors. The intervention group performed 3 postures of Rue-si-dad-ton exercise (an hour per day for 4 days by a well-trained instructor) before thefinal measurement. RESULTS: Only left and right shoulder flexion of the intervention group (p-value = 0.006 and 0.010 respectively) showed significant increment compared with the control group using ANCOVA test with baseline adjusted as covariate. Other variables, including joint and cognitive function, indicated no significant changes between groups. No complications from exercise were found during the study CONCLUSION: Rue-si-dad-ton may safely help improve range of joint motion with potential benefit for joint and cognitive function. Additional extensive studies with adequate number of participants and longer period of exercise are warranted. PMID- 25920303 TI - Pathological confirmed diagnosis of asbestosis: the first case report in Thailand. AB - Asbestosis is an occupational lung disease defined as pulmonary fibrosis caused by asbestos. Asbestosis was previously reported in Thailand based on radiologic findings, which demonstrated interstitial lung with calcified pleural plaques, and the patient worked in a fiber cement factory. However there was some doubt about the diagnosis because clinical and radiological findings are nonspecific; there was no data support of asbestos exposure in the patient and no histologic confirmed diagnosis. Histologic diagnosis is most useful when an equivocal of ahistory of asbestos exposure in patients with interstitial lung diseases take place. The authors report a patient presenting with progressive dyspnea for 2 years. She worked in an electric, wire, mesh fan cover factory to check quality of protective wire mesh for 10 years until the factory was closed 6 years ago. This type of factory had never officially reported asbestos use. Her clinical manifestations and radiologic findings are compatible with interstitial lung disease. She subsequently underwent thoracotomy with wedge lung resection. Pathology revealed interstitial fibrosis with honeycombing. Asbestos bodies were found more than 10 per cm2 in the fibrosis. She was diagnosed asbestosis. The patient is suffering from dyspnea, severe hypoxemia and cor pulmonale. The patient is put on waiting lists for heart lung transplantation. The authors thus confirmed that asbestosis exists in Thailand. A policy to protect workers and people who may have risk of asbestos exposure is necessary, since diseases related to asbestos are incurable, but preventable. PMID- 25920304 TI - Postoperative visual loss in orthopedic spine surgery in the prone position: a case report. AB - Postoperative visual loss is rare but a devastating postoperative complication. It is a multifactorial etiology. The practice advisory for perioperative visual loss associated with spine surgery reported by the American Society of Anesthesiologists task force on perioperative visual loss was developed from several case reports and case series. We reported a new case of postoperative visual loss diagnosed as ischemic optic neuropathy after undergoing a spine surgery in prone position. This case should be added to the overall incidence of postoperative visual loss. The possible risk factors were categorized in order to identify the POVL-susceptible patients. The pathophysiology of ischemic optic neuropathy was briefly reviewed. PMID- 25920305 TI - The role of episiotomy in prevention of genital lacerations during vaginal deliveries--results from two European centers. AB - OBJECTIVES: There is an ongoing debate regarding the routine versus restrictive use of episiotomy The study aim was to investigate if episiotomy during vaginal deliveries can reduce both, the number and severity of genital lacerations. MATERIAL AND METHODS: The study included all women who gave vaginal birth at AOU. "G. Martino" Messina (n=382) and the Clinic for Ob/Gyn Clinical Center of Serbia, Belgrade (n=4227) during 2011. Lacerations during birth were recorded and divided according to location and severity Women with lacerations were subdivided into two groups: with or without mediolateral episiotomy We assessed potential risk factors for laceration: maternal age, parity use of labor stimulants and epidural analgesia, participation in antenatal classes, fetal presentation, neonatal birth weight, and duration of the second stage of labor. RESULTS: Older women had higher grade perineum or combined lacerations. Children with higher birth weight in occipito-posterior presentation caused higher grade lacerations. Performance of episiotomy was connected with fewer perineum and labial lacerations. There were no differences in laceration grade between patients with and without episiotomy Assessed parameters proved to be good discriminating factors between lacerations sites. According to logistic regression, laceration site was the most important risk factor for laceration grade. Combined lacerations had the highest grade. CONCLUSIONS: Episiotomy can significantly reduce the number of genital lacerations, but it does not influence laceration grade. Advanced maternal age, higher parity occipitoposterior presentation and fetal macrosomia can cause lacerations during vaginal birth. Therefore, we suggest analysis of maternal and fetal factors to prevent widespread genital lacerations. PMID- 25920306 TI - Maternal and fetal parameters including umbilical artery PI and fibrinogen/CRP ratio as predictive factors of perinatal outcome in women with HELLP syndrome. AB - INTRODUCTION: HELLP syndrome appears in approximately 0.2-1% of all pregnancies and is associated with in- creased maternal and fetal mortality and morbidity. It is diagnosed in cases when all three of the following criteria are present: (1) microangiopathic hemolytic anemia with abnormal blood smear low serum haptoglobin and elevated LDH levels; (2) elevated ASPATand ALAT (levels of both enzymes more than twice the upper limit of normal values), or bilirubin more than 1.2 mg/dl; 3) platelet count below 150x1009 L(-1). The etiopathogenesis of HELLP syndrome is associated with abnormal placentation in the first trimester production of cellular active substances, and pathological response of the maternal organism. Objectives: The aim of the study was to establish maternal and fetal characteristics and perinatal outcome in HELLP syndrome. The examination protocol included comparison of maternal blood parameters, umbilical artery pulsatility index (UmbA PI) in relation to short-term neonatal outcomes. MATERIAL AND METHODS: Retrospective data analysis of patients hospitalized at the Perinatology and Gynecology Department, Polish Mother's Memorial Hospital Research Institute between 2009-2013, due to HELLP syndrome was conducted. RESULTS: None of the investigated maternal or fetal parameters correlated with the neonatal outcome. CONCLUSIONS: Our study demonstrated that maternal parameters do not influence the perinatal outcome in women with HELLP syndrome. Moreover UmbA PI and fibrinogen/CRP ratio do not correspond to neonatal parameters, either Thus, none of the examined features can be used as a prognostic factor of the neonatal outcome. Further studies with large sample size are necessary but the rarity of this complication limits the possibility of research. PMID- 25920307 TI - Increase of nuclear expression of metallothionein I/II in neoplastic transformation of the endomnetrium. AB - OBJECTIVES: The aim of our study was to investigate the expression of epidermal growth factor receptor (EGFR), metallothionein (MT) 1/11, and Ki-67 antigen in endometrial cancer We analyzed cytoplasmic (cMT) and nuclear (nMT) metallothionein fractions separately Moreover we evaluated the relationships between expressions of the above mentioned proteins and compared them with clinicopathologic data. MATERIAL AND METHODS: The study material included paraffin-embedded endometrial cancer samples from 84 patients. The control group consisted of 52 non-neoplastic endometrium samples. Immunohistochemical reactions were performed using monoclonal antibodies against EGFR, MT 1/11 and Ki-67. Expression intensity of the tested proteins was assessed by computer image analysis software. Chi-square, Spearman's correlation, Mann-Whitney and Kruskal Wallis tests were used for statistical analysis with Statistica 8.0 PL. RESULTS: Strong expression of nMT was revealed in endometrial cancer cells in relation to benign hyperplasia (p<0.0017) and normal cells (p<0.001) of the endometrium. Statistically significant but weaker expressions in analogous relationships were observed for cMT Moreover higher grade of histological malignancy G was positively associated with increased expression of nMT (p=0.009). CONCLUSIONS: Expression of nMT remains in distinct correlation with neoplastic transformation of the endometrium and histologic grades. Our results clearly indicate a need for further research on metallothionein expression in tumor cells. PMID- 25920308 TI - [Concentration of selected angiogenic factors in serum and peritoneal fluid of women with endometriosis]. AB - INTRODUCTION: Endometriosis is a sex hormone-dependent and successively progressing gynecological disease, characterized by the presence of endometrial tissue outside the uterus. The etiology of endometriosis is known to be multifactorial, and its growth depends on immunological, hormonal, genetic and environmental factors. Angiogenesis plays a key role in implantation and growth of endometriotic lesions, as well as in adhesion formation. Physiologically angiogenesis is responsible for neoangiogenesis and recruitment of new capillaries from the already existing capillaries. It is well-documented that altered angiogenesis provokes improper follicular maturation, infertility recurrent miscarriages, ovarian hyperstimulation syndrome, and carcinogenesis. Factors stimulating angionesis include angiogenin, vascular endothelial growth factor (VEGF) and fibroblast growth factor (FGF). OBJECTIVES: The aim of the study was to analyze angiogenic factor concentration (angiogenin, VEGF, FGF) in blood serum and peritoneal fluid in patients with diagnosed endometriosis and idiopathic infertility. MATERIAL AND METHODS: A total of 39 patients were recruited for the study including 19 patients (study group) diagnosed with endometriosis during the laparoscopic procedure and 20 patients (control group) with idiopathic infertility and no morphologic changes within the pelvis revealed during the laparoscopic procedure. All patients underwent laparoscopy during the follicular phase of the menstrual cycle. Vein blood sample was obtained before the procedure and during laparoscopy the entire peritoneal fluid was aspirated for further measurement of VEGF, FGF and angiogenin concentrations. RESULTS: Angiogenin concentration in peritoneal fluid was statistically higher in patient with idiopathic infertility in comparison to endometriosis (p<0.05). Higher angiogenin concentration was detected also in blood serum of patients with idiopathic infertility as compared to patients with endometriosis, but no statistical significance was found. VEGF and FGF concentration in blood serum and peritoneal fluid was similar in both groups (p>0.05). There were no significant differences between serum and peritoneal fluid in case of VEGF FGF and angiogenin in any of the groups. CONCLUSIONS: Angiogenic factors concentration (VEGF FGF agiogenin) in the peritoneal fluid and blood serum during the follicular phase of the menstrual cycle is not a diagnostic criterion for endometriosis. PMID- 25920309 TI - [Evaluation of applicability of HE4 and ROMA in the preoperative diagnosis of adnexal masses]. AB - OBJECTIVE: The aim of the study was to evaluate the effectiveness of HE4 alone and in combination with CA 125 (ROMA) in selecting patients at high risk of adnexal malignancy. MATERIAL AND METHODS: Serum CA 125 and HE4 levels were determined and the ROMA value was calculated in 259 women qualified for surgery due to adnexal mass. The results were compared with histopathological findings. RESULTS: Sensitivity and specificity in preoperative diagnosis of primary ovarian cancer were 93.2% and 71.5% for CA 125 and 95.4% and 81.3% for HE4, respectively ROMA algorithm achieved sensitivity of 95.4% and specificity of 79.8%. All methods reached sensitivity of 100% at specificity of 65.6% for CA125, 93.4% for HE4 and 82.0% for ROMA in premenopausal women, whereas in postmenopausal women sensitivity and specificity achieved levels of 92.1% and 81.7% for CA 125, 94.7% and 60.6% for HE4 and 94.7% and 76.1% for ROMA, respectively Serum levels of both CA 125 and HE4 were significantly higher in women with primary ovarian cancer as compared to benign disease. Concentrations of CA 125 in patients with endometriosis were significantly elevated as compared to women with other benign tumors. Such relation was not observed when HE4 levels were concerned. CONCLUSIONS: CA 125, HE4 and ROMA are useful in preoperative diagnosis of ovarian malignancy HE4 improves the diagnostic accuracy in cases of endometriosis, verifying false positive results of CA 125. PMID- 25920310 TI - [(Un)Forgotten Neugebauer-Le Fort operation. Paramedian closure of the vagina- safe and effective surgical procedure for treating of pelvic organ prolapse in older women]. AB - OBJECTIVES: The aim of the study is to present data concerning Neugebauer-Le Fort operations performed at the Gynecologic Oncology Clinic, Polish Mother's Health Center Research Institute in Lodz between 2000-2009, including the effects of the surgeries on improving quality of life. MATERIAL AND METHODS: Our research included all patients (90 women) operated due to total pelvic organ prolapse (stage IV of POP-Q) in Gynecologic Oncology Clinic. The data was collected retrospectively from medical records. Results of the treatment were evaluated based upon surveys and control checkups. The p-value of 0.05 was considered statistically significant. RESULTS: Mean patient age was 76.5 years. The analysis of medical records showed that 35% of the subjects had a BMI index >30. Out of 90 patients, 53%, 30% and 4% of the women had 2, 3, and 4 natural deliveries, respectively whereas 16% had forceps delivery Of the 65 operated patients, in more than 92% all the symptoms connected with pelvic organ prolapse disappeared. Problems with the urinary tract (urinary incontinence 'de novo', urinary tract infections) emerged in 13% and constipation in 5% of the women. As far as improved quality of life after the surgery is concerned, 93% of the subjects answered 4 and 5 (in a scale from 1 to 5). CONCLUSIONS: Neugebauer-Le Fort surgery is characterized by high effectiveness both, in objective research and subjective ratings of the operated patients. A high safety profile constitutes a great advantage of the surgery as was confirmed in our study In carefully selected group of patients with stage IV of POP-Q, Neugebauer-Le Fort surgery is a safe and effective procedure. PMID- 25920311 TI - [Polymorphism of bone morphogenetic protein (BMP2) and osteoporosis etiology]. AB - OBJECTIVES: Osteoporosis is a chronic, generalized bone disease conditioned by many factors among which the genetic background plays the significant role. Bone morphogenetic protein (BMP2), a growth factor belong to su- perfamily of TNF- proteins, is actively involved in bone tissue metabolism. BMP2 protein shows the osteoinduction potential and regulates growth of cartilage plate, and the same directly influences the process of osteogenesis. THE AIM: The aim of study was to examine the frequency of genotypes and alleles of 570A>T and 5375G>A of BMP2 gene polymorphisms in population of Polish postmenopausal women, as well as to analyze the relationship between investigated polymorphic variants and bone turnover parameters. MATERIAL AND METHODS: Into the study 117 postmenopausal women, Caucasian race (average age 55,1 years) living in Wielkopolska region were classified. The analysis of 570A>T and 5375G>A BMP2 polymorphisms was performed by polymerase chain reaction/restriction fragment length polymorphism (PCR/RFLP) while bone mineral density (BMD) was measured by DEXA method. In the research the chosen clinical and bone turnover parameters were analysed. RESULTS: In both 570A>T and 5375G>A BMP2 polymorphisms the similar frequency of genotypes and alleles in investigated groups of postmenopausal women with osteoporosis, osteopenia and in the group with correct T-score were noted. The analysis do not show the relationship of clinical and bone turnover parameters with particular genotypes of BMP2 polymorphisms in women with osteoporosis, osteopenia and in the group with correct T-score. CONCLUSIONS: The research did not confirm directly relationship of 570A>T and 5375G>A BMP2 polymorphisms with osteoporosis development in population of Polish postmenopausal women. The investigation also shows lack of correlation of 570A>T and 5375G>A BMP2 polymorphisms polymorphisms with analysed clinical and bone turnover parameters. PMID- 25920312 TI - [The diagnostic algorithm in twin pregnancy]. AB - This paper presents the diagnostic algorithm in twin pregnancy. The most important sonographic parameters in the assessment of twins have been discussed. Moreover, the most significant complications of twin pregnancy as well as diagnostic possibilities and management, have been also presented and defined. PMID- 25920313 TI - Insulin resistance in pregnancy complicated by type 1 diabetes mellitus. Do we know enough? AB - Insulin resistance (IR) is defined clinically as the inability of a known quantity of exogenous or endogenous insulin to increase glucose uptake and utilization. In recent years the increasing role of IR in the pathogenesis of type 1 diabetes mellitus (T1DM) related complications has been taken into account. The aim of this article is to discuss the possible role of IR in pregnancy complicated by T1DM. At the moment, there is no doubt that IR is not only frequently observed in T1DM patients, but also is a separate risk factor of several complications in nonpregnant patients. The role of IR in pregnancy complicated by T1DM has not been widely studied yet. However, data from the studies on different populations showed that IR may predispose to such conditions as miscarriage, preeclampsia and macrosomia. Interestingly all of these are more frequently diagnosed in women with T1DM in comparison to healthy subjects. The literature on the role of IR in human pregnancy is relatively rich. However despite its significance in pathophysiology of T1DM and its complications in general population, there is a lack of understanding of how it affects maternal and fetal health in pregnancy complicated by this disease. Nonetheless, based on the available literature, IR may be proposed as an additional factor modifying pregnancy outcome in woman with T1DM. Therefore, measures that might reduce IR such as good glycemic control and control of weight gain should be recommended for every woman with T1DM, optimally when planning but also throughout the pregnancy PMID- 25920314 TI - Application of osteopathic manipulative technique in the treatment of back pain during pregnancy. AB - Changes in body posture, musculoskeletal disorders and somatic dysfunctions are frequently observed during pregnancy especially ligament, joint and myofascial impairment. The aim of the paper is to present the use of osteopathic manipulative treatment (OMT) for back and pelvic pain in pregnancy on the basis of a review of the available literature. MEDLINE and Cochrane Library were searched in January 2014 for relevant reports, randomized controlled trials, clinical and case studies of OMT use in pregnant women. Each eligible source was verified and analyzed by two independent reviewers. OMT procedures appear to be effective and safe for pelvic and spinal pain management in the lumbosacral area in pregnant women. PMID- 25920315 TI - Spuriously high androstendione concentrations due to assay interference as a cause of diagnostic conundrum in women with oligomenorrhoea. AB - Polycystic ovary syndrome (PCOS) is a diagnosis of exclusion. We present two cases of women with oligomenorrhoea and high concentration of androstendione, suggestive of possible androgen-secreting tumour; caused by assay interference. The first patient, investigated for oligomenorrhoea, had no significant hirsutism or acne. Androstendione concentration was above 10.0 ng/ml (rr: 0.3-3.3 ng/ml). In order to rule out possible androgen-secreting tumour or hypercortisolaemia we performed 48-hour low dose dexamethasone suppression test (LDDST). This failed to demonstrate adequate suppression of androstendione (6.05 ng/ml and 9.32 ng/ml after the first and the second day respectively). Pelvic ultrasound examination showed polycystic ovaries, while abdominal CTscan failed to show any ovarian or adrenal lesion. Despite such high androstendione concentrations, urinary steroid profile (gas chromatography/mass spectrometry method) yielded normal results. Hence a possibility of androstendione assay interference was raised. The second patient was also admitted for investigations of oligomenorrhoea. Clinical examination was unremarkable. There was a high concentration of testosterone 0.78 ng/ml (rr. 0.084-0.481 ng/ml) and androstendione above 10.0 ng/ml (rr: 0.3-3.3 ng/ml). LDDST failed to demonstrate any suppression of androstendione, while recalculated concentrations of androstendione after serial dilutions were markedly lower in comparison to initial values. Therefore, such high androstendione concentrations (i.e. above the upper limit of the assay) must have resulted from assay interference. In both cases a final diagnosis of PCOS was established. CONCLUSIONS: In the absence of clinical features, contrasting with unusually high androgen levels, a possibility of androgen assay interference should be considered in differential diagnosis of hyperandrogenism or PCOS. PMID- 25920316 TI - [Recommendations of the Polish Gynecological Society concerning application of progesterone in obstetrics and gynecology]. PMID- 25920317 TI - Complications of a totally implantable venous access device. PMID- 25920318 TI - Association Between State Assistance on the Topic of Indoor Air Quality and School District-Level Policies That Promote Indoor Air Quality in Schools. AB - Nationally representative data from the 2012 School Health Policies and Practices Study examined whether state assistance on indoor air quality (IAQ) was associated with district-level policies and practices related to IAQ and integrated pest management (IPM). Districts in states that provided assistance on IAQ were more likely than districts not in such states to (1) have an IAQ management program (p < .001); (2) require schools to conduct periodic inspections of the heating, ventilation, and air conditioning system (p < .05); of the building for cracks, leaks, or past water damage (p < .01); for mold (p < .01); for clutter that prevents effective cleaning and maintenance (p < .05); of the plumbing system (p < .01); and for condensation in and around school facilities (p < .001); (3) have an engine idling reduction program ( < .001); (4) have a policy to purchase low-emitting products (p < .05); and (5) require IPM strategies (p < .05). Increasing the number of states that provide IAQ-related assistance to school districts and schools may improve school IAQ. PMID- 25920319 TI - Genetic Changes at the Glycoprotein Editing Site Associated With Serial Passage of Sudan Virus. AB - Sudan virus (SUDV), like the closely related Ebola virus (EBOV), is a filovirus that causes severe hemorrhagic disease. They both contain an RNA editing site in the glycoprotein gene that controls expression of soluble and full-length protein. We tested the consequences of cell culture passage on the genome sequence at the SUDV editing site locus and determined whether this affected virulence. Passage resulted in expansion of the SUDV editing site, similar to that observed with EBOV. We compared viruses possessing either the wild-type or expanded editing site, using a nonhuman primate model of disease. Despite differences in virus serum titer at one time point, there were no significant differences in time to death or any other measured parameter. These data imply that changes at this locus were not important for SUDV lethality. PMID- 25920321 TI - Danger of generalising findings on paracetamol for low back pain. PMID- 25920320 TI - Loss of Microbiota-Mediated Colonization Resistance to Clostridium difficile Infection With Oral Vancomycin Compared With Metronidazole. AB - Antibiotic administration disrupts the intestinal microbiota, increasing susceptibility to pathogens such as Clostridium difficile. Metronidazole or oral vancomycin can cure C. difficile infection, and administration of these agents to prevent C. difficile infection in high-risk patients, although not sanctioned by Infectious Disease Society of America guidelines, has been considered. The relative impacts of metronidazole and vancomycin on the intestinal microbiota and colonization resistance are unknown. We investigated the effect of brief treatment with metronidazole and/or oral vancomycin on susceptibility to C. difficile, vancomycin-resistant Enterococcus, carbapenem-resistant Klebsiella pneumoniae, and Escherichia coli infection in mice. Although metronidazole resulted in transient loss of colonization resistance, oral vancomycin markedly disrupted the microbiota, leading to prolonged loss of colonization resistance to C. difficile infection and dense colonization by vancomycin-resistant Enterococcus, K. pneumoniae, and E. coli. Our results demonstrate that vancomycin, and to a lesser extent metronidazole, are associated with marked intestinal microbiota destruction and greater risk of colonization by nosocomial pathogens. PMID- 25920322 TI - Forceps delivery is associated with increased risk of pelvic organ prolapse and muscle trauma: a cross-sectional study 16-24 years after first delivery. AB - OBJECTIVES: To study possible associations between mode of delivery and pelvic organ prolapse (POP) and pelvic floor muscle trauma 16-24 years after first delivery and, in particular, to identify differences between forceps and vacuum delivery. METHODS: This was a cross-sectional study including 608 women who delivered their first child in 1990-1997 and were examined with POP quantification (POP-Q) and pelvic floor ultrasound in 2013-2014. Outcome measures were POP >= Stage 2 or previous prolapse surgery, levator avulsion and levator hiatal area on Valsalva. Univariable and multivariable logistic regression analyses and ANCOVA were applied to identify outcome variables associated with mode of delivery. RESULTS: Comparing forceps to vacuum delivery, the adjusted odds ratios (aOR) were 1.72 (95% CI, 1.06-2.79; P = 0.03) for POP >= Stage 2 or previous prolapse surgery and 4.16 (95% CI, 2.28-7.59; P < 0.01) for levator avulsion. Hiatal area on Valsalva was larger, with adjusted mean difference (aMD) of 4.75 cm(2) (95% CI, 2.46-7.03; P < 0.01). Comparing forceps with normal vaginal delivery, the adjusted odds ratio (aOR) was 1.74 (95% CI, 1.12-2.68; P = 0.01) for POP >= Stage 2 or surgery and 4.35 (95% CI, 2.56-7.40; P < 0.01) for levator avulsion; hiatal area on Valsalva was larger, with an aMD of 3.84 cm(2) (95% CI, 1.78-5.90; P < 0.01). Comparing Cesarean delivery with normal vaginal delivery, aOR was 0.06 (95% CI, 0.02-0.14; P < 0.01) for POP >= Stage 2 or surgery and crude OR was 0.00 (95% CI, 0.00-0.30; P < 0.01) for levator avulsion; hiatal area on Valsalva was smaller, with an aMD of -8.35 cm(2) (95% CI, -10.87 to -5.84; P < 0.01). No differences were found between vacuum and normal vaginal delivery. CONCLUSIONS: We found that mode of delivery was associated with POP and pelvic floor muscle trauma in women from a general population, 16-24 years after their first delivery. Forceps was associated with significantly more POP, levator avulsion and larger hiatal areas than were vacuum and normal vaginal deliveries. There were no statistically significant differences between vacuum and normal vaginal deliveries. Cesarean delivery was associated with significantly less POP and pelvic floor muscle trauma than were normal or operative vaginal delivery. PMID- 25920323 TI - Spin-resolved NOCV analysis of the zeolite framework influence on the interaction of NO with Cu(I/II) sites in zeolites. AB - In the present work the function of a zeolite framework in modifying the properties of copper sites has been studied. The [Al(OH)4CuNO](0/+) systems were studied by applying the analysis of the electron density flows - contributions to deformation density between two interacting fragments. The systems were divided in the following partition scheme: the first fragment, [Al(OH)4](-) (tagged T1), and the second one, [CuNO](+/2+). The analysis allowed us to elucidate the function of the zeolite fragment in modification of the cation properties towards activating the NO molecule. For both [(T1)CuNO](0/+) systems several channels showing the role of the zeolite framework have been identified. The geometry of the adducts influences either the efficiency of the channels or spin polarization. The two most important channels, zeolites-cations, influence the flow of electrons between the copper site and the antibonding NO orbitals. One channel favors the pi-backdonation in the plane perpendicular to the Cu-N-O plane while the other contribution influences the pi-backdonation in the C-N-O plane. The first one is found only in the system with copper(I) and it is essential for facilitating the pi-backdonation and activating the NO molecule. The second channel is spin sensitive for both copper(I) and copper(II) sites. In the case of the system with copper(i) the second channel favors the pi-backdonation while in the system containing copper(ii) the direction of these flows is opposite for alpha and beta electrons. PMID- 25920325 TI - Group sparsity model for stain unmixing in brightfield multiplex immunohistochemistry images. AB - Multiplex immunohistochemistry (IHC) staining is a new, emerging technique for the detection of multiple biomarkers within a single tissue section. The initial key step in multiplex IHC image analysis in digital pathology is of tremendous clinical importance due to its ability to accurately unmix the IHC image and differentiate each of the stains. The technique has become popular due to its significant efficiency and the rich diagnostic information it contains. The intriguing task of unmixing a three-channel CCD color camera acquired RGB image into more than three colors is very challenging, and to the best of our knowledge, hardly studied in academic literature. This paper presents a novel stain unmixing algorithm for brightfield multiplex IHC images based on a group sparsity model. The proposed framework achieves robust unmixing for more than three chromogenic dyes while preserving the biological constraints of the biomarkers. Typically, a number of biomarkers co-localize in the same cell parts named priori. With this biological information in mind, the number of stains at one pixel therefore has a fixed up-bound, i.e. equivalent to the number of co localized biomarkers. By leveraging the group sparsity model, the fractions of stain contributions from the co-localized biomarkers are explicitly modeled into one group to yield the least square solution within the group. A sparse solution is obtained among the groups since ideally only one group of biomarkers is present at each pixel. The algorithm is evaluated on both synthetic and clinical data sets, and demonstrates better unmixing results than the existing strategies. PMID- 25920327 TI - Long-term lung function in postinfectious bronchiolitis obliterans. PMID- 25920326 TI - Vitamin D Deficiency and Pain: Clinical Evidence of Low Levels of Vitamin D and Supplementation in Chronic Pain States. AB - INTRODUCTION: A number of studies suggest a link between low levels of 25-hydroxy vitamin D and incidence of acute and chronic pain. Clinical studies of vitamin D supplementation in patients with known vitamin D deficiency have shown mixed results in improving pain scores. METHODS: In this article, vitamin D deficiency risk factors are observed and adequate levels of 25-hydroxy vitamin D defined. Clinical supplementation with vitamin D is explored, including the schedules used in published clinical trials. Evidence of the effectiveness of vitamin D supplementation for the treatment of chronic pain conditions from double-blind randomized controlled trials (RCTs) is examined. RESULTS: The scientific evidence for vitamin D as a treatment option for chronic pain is limited due to lack of RCTs. It cannot be stated conclusively that vitamin D deficiency is directly linked to the etiology or maintenance of chronic pain states. CONCLUSION: There remains a growing body of both clinical and laboratory evidence pointing to a potential relationship between low levels of 25-hydroxy vitamin D and a variety of chronic pain states. More focused research involving large RCTs is necessary. PMID- 25920328 TI - Identifying areas and risk groups with localised Mycobacterium tuberculosis transmission in northern England from 2010 to 2012: spatiotemporal analysis incorporating highly discriminatory genotyping data. AB - BACKGROUND: Information on geographical variation in localised transmission of TB can inform targeting of disease control activities. The aim of this study was to estimate the proportion of TB attributable to localised transmission for the period 2010-2012 in northern England and to identify case characteristics associated with spatiotemporal-genotypical clusters. METHODS: We combined genotyping data with spatiotemporal scan statistics to define an indicator of localised TB transmission and identified factors associated with localised TB transmission thus defined in a multivariable logistics regression model. RESULTS: The estimated proportion of TB cases in northern England attributable to localised transmission was 10% (95% CI 9% to 12%). Clustered cases (cases which were spatiotemporally clustered with others of identical genotype) were on average younger than non-clustered cases (mean age 34 years vs 43 years; p value <0.05). Being UK born (adjusted OR (aOR) 3.6, 95% CI 2.9 to 6.0), presenting with pulmonary disease (aOR 2.2, 95% CI 1.3 to 3.6) and history of homelessness (aOR 2.8, 95% CI 1.2 to 6.8) or incarceration (aOR 2.6, 95% CI 1.2 to 5.9) were independently associated with being part of a spatiotemporal-genotypical cluster in a multivariable model. Belonging to an ethnic group other than white or mixed/other was also significantly associated with localised transmission. We identified localised transmission in 103/1958 middle super output areas mostly in urban areas. CONCLUSIONS: Incorporating highly discriminatory genotyping data into spatiotemporal analysis of TB incidence is feasible as part of routine surveillance and can provide valuable information on groups at greater risk and areas with localised transmission of TB, which could be used to inform control measures, such as intensified contact tracing. PMID- 25920329 TI - Isolation and maintenance of Balantidium coli (Malmsteim, 1857) cultured from fecal samples of pigs and non-human primates. AB - Balantidium coli is a protozoa that can determine dysentery in humans, pigs and non-human primates having zoonotic potential. The lack of standardization in isolation and maintenance hinders the development of research on its biology and epidemiology. This study is aimed to standardize the isolation and maintenance of this parasite from animal feces, in culture medium, Pavlova modified. From 2012 to 2014, 1905 fecal samples were collected from captive animals of Rio de Janeiro. Were selected for isolation samples with a minimum of 10 trophozoites and/or 30 cysts of B. coli, totaling 88 pigs, 26 Cynomolgus and 90 rhesus macaques. In the presence of cysts, the sample was homogenized in saline solution, 500 MUL was removed and inoculated into culture medium. The material that contained trophozoites the inoculum was made from 240 MUL of fecal solution. All inoculate tubes with the subcultures were kept at 36 degrees C, and sterile rice starch was always added to the medium. The parasites isolate from pigs, 34%, and from Cynomolgus 38.4% were maintained in vitro for a period of more than 24 months. These procedures proved to be adequate for isolation and maintenance of B. coli from different animals, they were found to be inexpensive and easy to perform. PMID- 25920330 TI - Erratum to: Bioremediation of Cd by Microbially Induced Calcite Precipitation. PMID- 25920331 TI - Effects of Surfactants and Microwave-assisted Pretreatment of Orange Peel on Extracellular Enzymes Production by Aspergillus japonicus PJ01. AB - The effects of surfactants and microwave pretreatment of orange peel powder (OPP) on the production of pectinase, cellulase, and xylanase by Aspergillus japonicus PJ01 in submerged fermentation were investigated. The results showed that when OPP was pretreated only by microwave (630 W, 9 min, and liquid/solid ratio 5), the activities of exo-pectinase, carboxymethyl cellulase (CMCase), xylanase, and filter paper cellulase (FPase) were increased by 11.8, 20.6, 16.2, and 24.0 %, respectively, and when OPP was pretreated by microwave at the same conditions cited above plus PEG 4000 at the concentration of 3 g/L, the activities of the above four enzymes were enhanced by 40.2, 30.3, 40.4, and 40.0 % after 84-h cultivation, respectively. It is suggested a synergistic effect between microwave and surfactant treatment in enhancing the multiextracellular enzymes production by OPP fermentation of A. japonicus PJ01. Chemical composition and Fourier transform infrared spectroscopy (FTIR) analysis displayed that the microwave pretreatment of OPP led to the decrease of hemicellulose and essential oil contents. Scanning electron microscope (SEM) showed that OPP surface after microwave pretreatment became porous and more susceptible to be invaded by A. japonicus. The results demonstrated that pretreatment of OPP by surfactant PEG 4000 and microwave irradiation as environment-friendly way was cost-effective in enhancing the multienzyme production from agricultural waste orange peel. PMID- 25920332 TI - Gallic Acid Production with Mouldy Polyurethane Particles Obtained from Solid State Culture of Aspergillus niger GH1. AB - Gallic acid production in a batch bioreactor was evaluated using as catalytic material the mouldy polyurethane solids (MPS) obtained from a solid-state fermentation (SSF) bioprocess carried out for tannase production by Aspergillus niger GH1 on polyurethane foam powder (PUF) with 5 % (v/w) of tannic acid as inducer. Fungal biomass, tannic acid consumption and tannase production were kinetically monitored. SSF was stopped when tannase activity reached its maximum level. Effects of washing with distilled water and drying on the tannase activity of MPS were determined. Better results were obtained with dried and washed MPS retaining 84 % of the tannase activity. Maximum tannase activity produced through SSF after 24 h of incubation was equivalent to 130 U/gS with a specific activity of 36 U/mg. The methylgallate was hydrolysed (45 %) in an easy, cheap and fast bioprocess (30 min). Kinetic parameters of tannase self-immobilized on polyurethane particles were calculated to be 5 mM and 04.1 * 10(-2) mM/min for K M and V max, respectively. Results demonstrated that the MPS, with tannase activity, can be successfully used for the production of the antioxidant gallic acid from methyl-gallate substrate. Direct use of PMS to produce gallic acid can be advantageous as no previous extraction of enzyme is required, thus reducing production costs. PMID- 25920333 TI - In vivo targeted magnetic resonance imaging and visualized photodynamic therapy in deep-tissue cancers using folic acid-functionalized superparamagnetic upconversion nanocomposites. AB - Multifunctional nanoprobes used in magnetic resonance imaging (MRI) and photodynamic therapy (PDT) also have potential applications in diagnosis and visualized therapy of cancers, and hence it is important to investigate the active-targeting ability and in vivo reliability of these nanoprobes. In this work, folic acid (FA)-targeted, photosensitizer (PS)-loaded Fe3O4@NaYF4:Yb/Er (FA NPs-PS) nanocomposites were synthesized for in vivo T2-weighted MRI and visualized PDT of cancers by modeling MCF-7 tumor-bearing nude mice. By measuring the upconversion luminescence (UCL) and fluorescence emission spectra, the as prepared FA-NPs-PS nanocomposites showed near-infrared (NIR)-triggered PDT performance due to the production of a singlet oxygen species. Moreover, by tracing PS fluorescence in MCF-7, HeLa cells and in MCF-7 tumors, the FA-targeted nanocomposites demonstrated good targeting ability both in vitro and in vivo. Under the irradiation of a 980 nm laser, the viabilities of MCF-7 and HeLa cells incubated with FA-NPs-PS nanocomposites could decrease to about 18.4% and 30.7%, respectively, and the inhibition of MCF-7 tumors could reach about 94.9%. The transverse MR relaxivity of 63.79 mM(-1) s(-1) (r2 value) and in vivo MR imaging of MCF-7 tumors indicated an excellent T2-weighted MR performance. This work demonstrated that FA-targeted MRI/PDT nanoprobes are effective for in vivo diagnosis and visualized therapy of breast cancers. PMID- 25920335 TI - A Case for Wide-Angle Breast Tomosynthesis. AB - RATIONALES AND OBJECTIVES: Conventional mammography is largely limited by superimposed anatomy. Digital breast tomosynthesis (DBT) and computed tomography (CT) alleviate this limitation but with added out-of-plane artifacts or limited chest wall coverage. This article presents a wide-angle breast tomosynthesis (WBT), aimed to provide a practical solution to these limitations, and offers an initial study of its utility in comparison with DBT and CT using a singular evaluation platform. MATERIALS AND METHODS: Using an anthropomorphic virtual breast phantom, a Monte Carlo code modeled a breast imaging system for three modalities of DBT, WBT, and breast CT (44 degrees , 99 degrees , and 198 degrees total angle range, respectively) at four breast compression levels, all at a constant mean glandular dose level of 1.5 mGy. Reconstructed volumes were generated using iterative reconstruction methods. Lesion detectability was estimated using contrast-to-noise ratio and a channelized Hotelling observer model in terms of the area under the receiver operating characteristic (AUC). RESULTS: Results showed improved detection with increased angular span and compression. The estimated AUCs for WBT were similar to that of CT. Comparative performance averaged over all thicknesses between CT and WBT was 4.3 +/- 3.0%, whereas that between WBT and DBT was 5.6 +/- 1.0%. At compression levels reflective of the modality (7-, 5-, and 4-cm thickness for CT, WBT, and DBT, respectively), WBT yielded an AUC comparable to CT (performance difference of 1.2%) but superior to DBT (performance difference of 5.5%). CONCLUSIONS: The proposed imaging modality showed significant advantages over conventional DBT. WBT exhibited superior imaging performance over DBT at lower compression levels, highlighting further potential for reduced breast compression. PMID- 25920334 TI - Hypertension in a Brazilian urban slum population. AB - Low- and middle-income countries account for the majority of hypertension disease burden. However, little is known about the distribution of this illness within subpopulations of these countries, particularly among those who live in urban informal settlements. A cross-sectional hypertension survey was conducted in 2003 among 5649 adult residents of a slum settlement in the city of Salvador, Brazil. Hypertension was defined as either an elevated arterial systolic (>=140 mmHg) or diastolic (>=90 mmHg) blood pressure. Sex-specific multivariable models of systolic blood pressure were constructed to identify factors associated with elevated blood pressure. The prevalence of hypertension in the population 18 years and older was 21% (1162/5649). Men had 1.2 times the risk of hypertension compared with women (95% confidence intervals (CI), 1.05, 1.36). Increasing age and lack of any schooling, particularly for women, were also significantly associated with elevated blood pressure (p < 0.05). There was also a direct association between men who were black and an elevated blood pressure. Among those who were hypertensive, 65.5% were aware of their condition, and only 36.3% of those aware were actively using anti-hypertensive medications. Men were less likely to be aware of their diagnosis or to use medications (p < 0.01 for both) than women. The prevalence of hypertension in this slum community was lower than reported frequencies in the non-slum population of Brazil and Salvador, yet both disease awareness and treatment frequency were low. Further research on hypertension and other chronic non-communicable diseases in slum populations is urgently needed to guide prevention and treatment efforts in this growing population. PMID- 25920336 TI - Changing beliefs for changing movement and pain: Classification-based cognitive functional therapy (CB-CFT) for chronic non-specific low back pain. AB - This case report presents the effect of classification-based cognitive functional therapy in a patient with chronic disabling low back pain. The patient was assessed using a multidimensional biopsychosocial classification system and was classified as having flexion pattern of movement impairment disorder. Management of this patient was to change her belief that bending over and sitting would cause damage to her disc, combined with active exercises for graded exposure to lumbar flexion to restore normal movement. Three months after the first appointment, the treatment resulted in reduced pain, the mitigation of fear avoidance beliefs and the remediation of functional disability. The patient returned to work and was walking for one hour a day on a treadmill. The cognitive intervention to change the patient's negative beliefs related to the biomedical model was important to make the graded exercises and the lifestyle changes possible. PMID- 25920337 TI - Manual therapy in the management of a patient with a symptomatic Morton's Neuroma: A case report. AB - Patients with Morton's neuroma are rarely referred to physical therapy. This case reports the resolution of pain, increase in local pressure pain thresholds, and improvement of scores on the Lower Extremity Functional Scale and Foot and Ankle Ability Measure following a course of joint based manual therapy for a patient who had failed standard conservative medical treatment. PMID- 25920338 TI - A randomised, independent groups study investigating the sympathetic nervous system responses to two manual therapy treatments in patients with LBP. AB - Manual therapy (MT) and exercise therapy techniques are commonly utilised, guideline recommended treatment strategies in the management of non-specific low back pain (LBP). Preliminary evidence on asymptomatic participants indicates that two manual therapy techniques; repeated lumbar extension in lying exercise (EIL); and segmental rotational grade V manipulation (manipulation), have significant effects on the sympathetic nervous system (SNS) as detectable with skin conductance (SC) responses. However, it is not known if these responses occur in patients with LBP. A randomised, independent group's design was utilised to investigate the immediate SC responses in 50 patients with LBP of less than 12 weeks duration. Patients received either the manipulation technique (n = 25) or the EIL exercise (n = 25) and SC activity was recorded, in a single treatment session, pre-, peri- and post-treatment. Both treatments resulted in a sympatho excitatory response during the intervention period with the manipulation technique having a 255% increase (p < 0.005), and the EIL technique a 94% increase (p = 0.019) with both treatments having responses that were sustained into the final rest period (p < 0.005). Between-group comparisons indicate that the manipulation technique had a significantly greater magnitude of effect (p < 0.001). The results support the sympatho-excitatory responses seen in normative studies but challenge the assumption that normative and patient populations are analogous with respect to the magnitude of effect observed and suggest that SC responses may be a feasible, proxy method of detecting dorsal horn sensitisation and neuro-plastic adaptations occurring in the presence of LBP. PMID- 25920339 TI - A preliminary study into the effect of jumping-landing training and strength training on frontal plane projection angle. AB - The presence of increased knee valgus angles during functional tasks has been associated with a range of knee pathologies. A number of different exercise interventions have been undertaken to improve knee alignment during functional tasks. The most successful of these interventions are multi-modal incorporating both strength and jump-landing training. Little research has been undertaken to compare these elements individually to assess if success is due to an individual element or the training as a whole. The study assessed the between group effects of strength training or jump-landing training alone on knee valgus alignment during a number of functional tasks, using a cohort specific treatment superiority design. Thirty asymptomatic female participants undertook a 6 week (minimum 15 sessions) strength or jump-landing programme, the effects of which were examined by assessing for any change in frontal plane projection angle (FPPA) during single leg squat and landing and bilateral drop jump landing. Both training methods had positive effects of FPPA during some but not all of the tasks. Strength training brought about significant changes in FPPA during single leg squat and landing, whilst jump-landing training significantly influenced single leg landing and drop jump landing performance. The changes reported, therefore appear to be related to the nature of the training and the tasks undertaken during that training. The findings indicating that a combined training protocol incorporating both strengthening and jump-landing training may bring about the greatest improvement across a spectrum of tasks for the patient, supporting the previous work on multimodal training. PMID- 25920340 TI - Is exercise effective for the management of subacromial impingement syndrome and other soft tissue injuries of the shoulder? A systematic review by the Ontario Protocol for Traffic Injury Management (OPTIMa) Collaboration. AB - BACKGROUND: Exercise is a key component of rehabilitation for soft tissue injuries of the shoulder; however its effectiveness remains unclear. OBJECTIVE: Determine the effectiveness of exercise for shoulder pain. METHODS: We searched seven databases from 1990 to 2015 for randomized controlled trials (RCTs), cohort and case control studies comparing exercise to other interventions for shoulder pain. We critically appraised eligible studies using the Scottish Intercollegiate Guidelines Network (SIGN) criteria. We synthesized findings from scientifically admissible studies using best-evidence synthesis methodology. RESULTS: We retrieved 4853 articles. Eleven RCTs were appraised and five had a low risk of bias. Four studies addressed subacromial impingement syndrome. One study addressed nonspecific shoulder pain. For variable duration subacromial impingement syndrome: 1) supervised strengthening leads to greater short-term improvement in pain and disability over wait listing; and 2) supervised and home based strengthening and stretching leads to greater short-term improvement in pain and disability compared to no treatment. For persistent subacromial impingement syndrome: 1) supervised and home-based strengthening leads to similar outcomes as surgery; and 2) home-based heavy load eccentric training does not add benefits to home-based rotator cuff strengthening and physiotherapy. For variable duration low-grade nonspecific shoulder pain, supervised strengthening and stretching leads to similar short-term outcomes as corticosteroid injections or multimodal care. CONCLUSION: The evidence suggests that supervised and home-based progressive shoulder strengthening and stretching are effective for the management of subacromial impingement syndrome. For low-grade nonspecific shoulder pain, supervised strengthening and stretching are equally effective to corticosteroid injections or multimodal care. SYSTEMATIC REVIEW REGISTRATION NUMBER: CRD42013003928. PMID- 25920341 TI - Does changing the plane of abduction influence shoulder muscle recruitment patterns in healthy individuals? AB - STUDY DESIGN: Observational laboratory study. BACKGROUND: Abduction is a movement commonly used in the assessment of shoulder dysfunction and prescription of exercises to improve shoulder function. Abduction in the scapular and coronal planes are used interchangeably. It is not known if the activation of individual shoulder muscles differ between abduction performed in these planes and therefore, if they represent different tests/exercises. OBJECTIVE: To quantify and compare the muscle activation patterns and levels for each shoulder muscle during abduction performed in the scapular plane with that performed in the coronal (scapular -30 degrees ) and scapular +30 degrees planes. METHODS: Electromyographic recordings were taken from eight shoulder muscles of fourteen healthy volunteers during shoulder abduction in the scapular and coronal planes and in a plane 30 degrees anterior to the scapular plane (scapular +30 degrees ) at 50% of maximum load. RESULTS: Similar average muscle activation levels were demonstrated during abduction in the scapular plane and within a 30 degrees arc of this plane for all muscles except: middle deltoid (5% MVC higher activation in the coronal and 4% MVC lower activation in the scapular +30 degrees plane) and upper trapezius (6% MVC lower activation in the scapular +30 degrees plane). Activation patterns between planes for all muscles were similar (ICC(3,1) >= 0.87). CONCLUSIONS: Abduction can be performed within a 30 degrees arc of the scapular plane with no change in shoulder muscle activation patterns. Only middle deltoid activation levels change between the scapular and coronal planes and middle deltoid and upper trapezius between the scapular and scapular +30 degrees planes. PMID- 25920342 TI - Weight stigma in physiotherapy practice: Patient perceptions of interactions with physiotherapists. AB - BACKGROUND: Weight management is increasingly considered part of physiotherapists' scope of practice in order to improve patient outcomes by, for example, reducing load on joints, or improving chronic pain. However, interactions with patients involving weight may result in patient perceptions of negative judgement from health professionals, which can result in poorer health outcomes. How physiotherapist/patient interactions involving weight are perceived by patients has not yet been investigated. OBJECTIVES: To explore patients' perceptions of interactions with physiotherapists that involved weight, and investigate how these perceptions may inform physiotherapy practice. DESIGN: Face to-face interviews with physiotherapy patients, with follow up interviews conducted by telephone. Data were analysed thematically. METHOD: First interviews were held in a physiotherapy practice with follow up interviews conducted two weeks later. Interviews were audio recorded, transcribed and analysed using an inductive thematic method established by Braun and Clarke. FINDINGS: Thirty interviews with 15 patients were analysed. Four main themes relevant to weight were identified: 1) perceptions of being 'in physiotherapy' including pre conceptions, the physical environment, and exposing the body, 2) emphasis placed on weight in physiotherapy interactions, 3) communication styles, and 4) judgement perception. CONCLUSION: Some patients perceived negative weight judgements from elements of physiotherapy interactions and environments. Physiotherapists need to be aware of this perception because it may result in poorer patient outcomes and patients avoiding physiotherapy appointments. The results suggest strategies to counteract weight stigma include: adjusting the physical environment of the clinic, portraying an understanding of complex determinants of weight, and employing collaborative, non-judgemental communication styles. PMID- 25920343 TI - Common features of extraordinary rate theories. AB - We examine the capabilities and foundations of three landmark rate theories: harmonic transition state theory, classical nucleation theory, and the Marcus theory of electron transfer. Each of the three classic rate theories is widely used to predict rates and trends. They are also used "in reverse" to interpret experimental data with no computation at all. Their common foundations include a quasi-equilibrium assumption and dimensionality reduction to a physically meaningful, one-dimensional, and broadly applicable reaction coordinate. Many applications lie beyond the scope of the classic theories, so rare events research has pursued trajectory-based methods that efficiently predict accurate rate constants even when the reaction coordinate and mechanistic details are unknown. Trajectory based rare events methods achieved these ambitious goals, but (by construction) they provide rates rather than mechanistic understanding. We briefly discuss recent efforts to identify reaction coordinates, including methods which provide abstract statistically defined coordinates and those which identify physical collective variables. Finally, we note some natural synergies between existing simulation methods which might help discover simple and powerful quasi-equilibrium theories for the many applications that fall beyond the scope of the classic rate theories. PMID- 25920344 TI - Varying penicillin allergy testing practices in the United States: A time for consensus. PMID- 25920345 TI - Clarifying the Montgomery judgment. PMID- 25920346 TI - Plasmon-free SERS self-monitoring of catalysis reaction on Au nanoclusters/TiO2 photonic microarray. AB - Here, using the (Au/TiO2)-catalyzed reduction of 4-nitrothiophenol as a probe reaction, a catalysis/SERS bifunctional composite fabricated by uniformly dispersing catalysis-active Au nanoclusters (~2 nm) on a SERS-active TiO2 photonic microarray was successfully applied to the non-plasmonic SERS self monitoring of a catalytic reaction for the first time, which is superiorly sensitive and interference-free. PMID- 25920347 TI - Analysis of expression and function of the co-stimulatory receptor SLAMF1 in immune cells from patients with systemic lupus erythematosus (SLE). AB - The signaling lymphocytic activation molecule SLAMF1 (CD150) is a co-stimulatory molecule that is expressed by most immune cells, including T regulatory (Treg) lymphocytes. Since different abnormalities have been reported regarding the number and function of Foxp3+ Treg cells in patients with systemic lupus erythematosus (SLE), we decided to analyze the expression and function of CD150 in these regulatory lymphocytes in this condition. We isolated peripheral blood mononuclear cells from 20 patients with SLE, and 20 healthy controls. The expression of SLAMF1 was determined by multi-parametric flow cytometry and the suppressive function of CD4+CD25+ lymphocytes, upon engagement or not of CD150 with an agonistic monoclonal antibody, was analyzed by an assay of inhibition of cell proliferation. We observed a significantly increased expression of SLAMF1 by CD3+CD4+ helper T cells and CD19+ B cells in patients with SLE and active disease. However, similar levels of SLAMF1 expression were detected in Foxp3+ Treg cells from patients and controls. In contrast, a higher proportion of SLE patients increased their suppressive function of Treg cells upon CD150 engagement compared to healthy controls. Our data suggest that SLAMF1 is another significant piece in the intricate defective immune-regulatory function of patients with SLE. PMID- 25920348 TI - Multifactor analysis for risk factors involved in the fear of falling in patients with chronic stroke from mainland China. AB - OBJECTIVE: To analyze the risk factors involved in FOF in patients with chronic stroke from mainland China. METHODS: A cohort of 245 patients with chronic stroke were included in this study. Fear of falling severity was assessed using the Activities-specific Balance Confidence (ABC) Scale. Physical function was assessed using the Berg Balance Scale (BBS), the Timed Up and Go Test (TUGT), and the lower extremity of Fugl-Meyer Assessment. Psychosocial function was assessed with the Center for Epidemiologic Studies Depression (CES-D) Scale, the State Trait Anxiety Inventory, and the Social Support Rating Scale, respectively. All factors related to FOF severity were analyzed by regression analysis. RESULTS: Statistically significant factors affecting FOF severity included age, history of falling, balance, functional mobility, economic burden, and depression. Participants with a history of falls (N = 81) were divided into high (score >= 70, N = 19) and low ABC score (score < 70, N = 62) groups. Compared with the low ABC score group, the high ABC score group had higher BBS scores, and lower CES-D scores. CONCLUSIONS: Our findings suggest that - in addition to age, economic burden, and a history of falls - balance, functional mobility, and depression are risk factors associated with FOF in patients with chronic stroke in mainland China. PMID- 25920349 TI - Genome Medicine in Cancer: What's in a Name? AB - This is an exciting time to be in cancer medicine. New technologies, such as next generation sequencing (NGS), have increased our understanding of the molecular aberrations that define cancer. This, in turn, has led to the identification of cancer-specific molecular targets and potential drugs to confront these targets. As these new technologies move toward clinical application, a new vocabulary of "genome medicine" has been introduced to the field of oncology. Unfortunately, unclear or incorrect use of the new terminology has led to semantic misunderstandings that impair communication between the basic research and clinical practice arenas. These misunderstandings have led to assumptions regarding the clinical application of NGS and other technologies that may or may not be true. For example, some organizations that perform NGS testing on clinical samples have endorsed use of the results of such tests to direct specific therapies based on laboratory hypotheses, but without clinical testing of the hypotheses to show utility for these potential predictive claims. Here, we review some simple, and hopefully universally acceptable, definitions, concepts, and trial designs so that laboratory researchers and clinicians can move closer toward speaking the same language. PMID- 25920350 TI - Advanced glycation end-products: a biological consequence of lifestyle contributing to cancer disparity. AB - Low income, poor diet, obesity, and a lack of exercise are interrelated lifestyle factors that can profoundly alter our biologic make up to increase cancer risk, growth, and development. We recently reported a potential mechanistic link between carbohydrate-derived metabolites and cancer, which may provide a biologic consequence of lifestyle that can directly affect tumor biology. Advanced glycation end-products (AGE) are reactive metabolites produced as a by-product of sugar metabolism. Failure to remove these highly reactive metabolites can lead to protein damage, aberrant cell signaling, increased stress responses, and decreased genetic fidelity. Critically, AGE accumulation is also directly affected by our lifestyle choices and shows a race-specific, tumor-dependent pattern of accumulation in cancer patients. This review will discuss the contribution of AGEs to the cancer phenotype, with a particular emphasis on their biologic links with the socioeconomic and environmental risk factors that drive cancer disparity. Given the potential benefits of lifestyle changes and the potential biologic role of AGEs in promoting cancer, opportunities exist for collaborations affecting basic, translational, epidemiologic, and cancer prevention initiatives. PMID- 25920351 TI - A case-control study of stomach cancer in relation to Camellia sinensis in China. AB - OBJECTIVE: The purpose of our study was to investigate the association between green tea (Camellia sinensis) drinking habits and risk of stomach cancer in China. METHOD: A 1:2 matched hospital-based case-control study including 160 cases and 320 controls was conducted. A self-designed questionnaire was used to collect information on possible risk factors of stomach cancer, and to assess the green tea drinking habit. Conditional logistic regression was used to calculate odds ratios (ORs) and corresponding 95% confidence intervals (CIs). RESULT: Our study proposed that green tea was associated with risk of stomach cancer. Regular drinking (OR = 0.72), larger amount of consumption (>=35 g/week) (OR = 0.53) were protective factors. Among regular tea drinkers, lower temperature and longer interval between tea being poured and drunk also reduced the risk. Moreover, a strong agreement was found between temperature at which tea was drunk and tea interval (Correlation coefficient p value = 0.73). CONCLUSION: Habits of green tea drinking, including regular drinking, larger amount of consumption, lower temperature and longer interval were strongly associated with a lower risk of stomach cancer. PMID- 25920352 TI - Design, synthesis and characterization of novel binary V(V)-Schiff base materials linked with insulin-mimetic vanadium-induced differentiation of 3T3-L1 fibroblasts to adipocytes. Structure-function correlations at the molecular level. AB - Among the various roles of vanadium in the regulation of intracellular signaling, energy metabolism and insulin mimesis, its exogenous activity stands as a contemporary challenge currently under investigation and a goal to pursue as a metallodrug against Diabetes mellitus II. In this regard, the lipogenic activity of vanadium linked to the development of well-defined anti-diabetic vanadodrugs has been investigated through: a) specifically designing and synthesizing Schiff base organic ligands L, bearing a variable number of terminal alcohols, b) a series of well-defined soluble binary V(V)-L compounds synthesized and physicochemically characterized, c) a study of their cytotoxic effect and establishment of adipogenic activity in 3T3-L1 fibroblasts toward mature adipocytes, and d) biomarker examination of a closely-linked molecular target involving or influenced by the specific V(V) forms, cumulatively delineating factors involved in potential pathways linked to V(V)-induced insulin-like activity. Collectively, the results a) project the importance of specific structural features in Schiff ligands bound to V(V), thereby influencing the emergence of its (a)toxicity and for the first time its insulin-like activity in pre-adipocyte differentiation, b) contribute to the discovery of molecular targets influenced by the specific vanadoforms seeking to induce glucose uptake, and c) indicate an interplay of V(V) structural speciation and cell differentiation biological activity, thereby gaining insight into vanadium's potential as a future metallodrug in Diabetes mellitus. PMID- 25920353 TI - Hypoglycemic, lipid-lowering and metabolic regulation activities of metforminium decavanadate (H2Metf)3 [V10O28].8H2O using hypercaloric-induced carbohydrate and lipid deregulation in Wistar rats as biological model. AB - Because of the increasing global spread of type 2 diabetes mellitus, there is a need to develop new antidiabetic agents. Recently we have synthesized new decavanadates using metformin as counterion. In particular, the compound containing three metforminium dications has been obtained in high yield and has been completely characterized. Biological studies using Wistar rats that have been fed with a high caloric diet inducing insulin resistance and metabolic syndrome were carried out. Results of the impact on key biochemical parameters mediated by metformin alone and the new compound are here presented. The metforminium decavanadate (H2Metf)3[V10O28].8H2O, abbreviated as Metf-V10O28, was shown to have pharmacological potential as a hypoglycemic, lipid-lowering and metabolic regulator, since the resulting compound made of the two components with antidiabetic activities, reduces both dosage and time of administration (twice a week). Hence, due to the beneficial effects induced by the metforminium decavanadate we recommend to continue the exploration into the mechanism and toxicology of this new compound. PMID- 25920354 TI - Five critical elements to ensure the precision medicine. AB - The precision medicine as a new emerging area and therapeutic strategy has occurred and was practiced in the individual and brought unexpected successes, and gained high attentions from professional and social aspects as a new path to improve the treatment and prognosis of patients. There will be a number of new components to appear or be discovered, of which clinical bioinformatics integrates clinical phenotypes and informatics with bioinformatics, computational science, mathematics, and systems biology. In addition to those tools, precision medicine calls more accurate and repeatable methodologies for the identification and validation of gene discovery. Precision medicine will bring more new therapeutic strategies, drug discovery and development, and gene-oriented treatment. There is an urgent need to identify and validate disease-specific, mechanism-based, or epigenetics-dependent biomarkers to monitor precision medicine, and develop "precision" regulations to guard the application of precision medicine. PMID- 25920355 TI - Tracking implementation and (un)intended consequences: a process evaluation of an innovative peripheral health facility financing mechanism in Kenya. AB - In many African countries, user fees have failed to achieve intended access and quality of care improvements. Subsequent user fee reduction or elimination policies have often been poorly planned, without alternative sources of income for facilities. We describe early implementation of an innovative national health financing intervention in Kenya; the health sector services fund (HSSF). In HSSF, central funds are credited directly into a facility's bank account quarterly, and facility funds are managed by health facility management committees (HFMCs) including community representatives. HSSF is therefore a finance mechanism with potential to increase access to funds for peripheral facilities, support user fee reduction and improve equity in access. We conducted a process evaluation of HSSF implementation based on a theory of change underpinning the intervention. Methods included interviews at national, district and facility levels, facility record reviews, a structured exit survey and a document review. We found impressive achievements: HSSF funds were reaching facilities; funds were being overseen and used in a way that strengthened transparency and community involvement; and health workers' motivation and patient satisfaction improved. Challenges or unintended outcomes included: complex and centralized accounting requirements undermining efficiency; interactions between HSSF and user fees leading to difficulties in accessing crucial user fee funds; and some relationship problems between key players. Although user fees charged had not increased, national reduction policies were still not being adhered to. Finance mechanisms can have a strong positive impact on peripheral facilities, and HFMCs can play a valuable role in managing facilities. Although fiduciary oversight is essential, mechanisms should allow for local decision-making and ensure that unmanageable paperwork is avoided. There are also limits to what can be achieved with relatively small funds in contexts of enormous need. Process evaluations tracking (un)intended consequences of interventions can contribute to regional financing and decentralization debates. PMID- 25920356 TI - Cell-assisted autologous fat grafting. PMID- 25920357 TI - Cell-assisted lipotransfer. AB - BACKGROUND: Because of their easy accessibility and versatile biological properties, mesenchymal stem cells taken from fatty tissue (adipose-derived stem cells, ADSC) are attractive for various potential clinical uses. For example, ADSC can be added to fatty tissue before transplantation in the hope of improving the outcome of autologous lipotransfer: the modified procedure is called cell assisted lipotransfer. The clinical use and commercial promotion of this novel stem-cell treatment (and others) are spreading rapidly, even though there is not yet any clear clinical evidence for its safety and efficacy. METHODS: In cooperation with the German Cochrane Center, we systematically searched the literature according to the PRISMA criteria. Eight major medical databases were searched. The retrieved publications were examined by two independent reviewers and assessed using objective criteria. RESULTS: After screening of the 3161 retrieved publications by title, abstract, and (where appropriate) full text, 78 were still considered relevant. 13 of these were reports of clinical studies; only 3 of the 13 met criteria for grade II or III evidence. The studies that were analyzed involved a total of 286 cell-assisted lipotransfer procedures with a longest follow-up time of 42 months. Oncological safety was not demonstrated. CONCLUSION: The studies published to date have not shown that cell-assisted lipotransfer is generally superior to conventional autologous lipotransfer. They dealt with safety aspects inappropriately or not at all. The case of cell assisted lipotransfer illustrates the indispensability of high-quality clinical evidence before the introduction of novel stem-cell-based treatments. PMID- 25920358 TI - The indications for allogeneic stem cell transplantation in myeloid malignancies. AB - BACKGROUND: The overall incidence of myeloid malignancies is 8.6 per 100 000 persons. Allogeneic stem-cell transplantation (SCT) is a major therapeutic option despite its risks, which include graft-versus-host disease (GvHD) and infection. In Germany, about 1600 patients with myeloid malignancies undergo SCT each year. The indications for SCT have changed since the introduction of tyrosine kinase inhibitors (TKI) and improved methods of SCT. METHODS: This article is based on relevant guidelines from Germany and abroad and on a selective review of the literature from 2010 onward. RESULTS: The individual indication for SCT is based on the risk of disease progression, accompanying illnesses, the probability that SCT will result in cure, and the risk of complications. There is good evidence favoring allogeneic SCT in the following situations affecting 20% to 50% of patients with the respective disease: advanced chronic myeloid leukemia (CML) or CML that does not respond to TKI, Philadelphia chromosome-negative myeloproliferative neoplasm (Ph- MPN) or myelodysplastic syndrome (MDS) with a high risk of progression, and acute myeloid leukemia (AML) that has high-risk cytogenetic features or is recurrent. Good evidence is accumulating in favor of allogeneic SCT in older patients as well. CONCLUSION: The prognosis of patients with myeloid neoplasm can now be assessed more accurately than before. This facilitates well-founded clinical decision-making about SCT, which is the only potentially curative treatment for most patients with myeloid neoplasm. Patients up to about age 75 should be referred to a transplantation center for consultation at an early stage of their disease so that the treatment options can be evaluated. A major goal of current research is to reduce toxicity with innovative forms of treatment. PMID- 25920359 TI - Neoadjuvant chemotherapy in locally advanced colon cancer. A phase II trial. AB - BACKGROUND: Neoadjuvant chemotherapy has proven valuable in several tumors, but it has not been elucidated in colon cancer. The present phase II trial addressed the issue in high-risk patients selected by computed tomography (CT) scan. MATERIAL AND METHODS: Patients with resectable colon cancer fulfilling the following criteria were offered inclusion; Histopathological verification of adenocarcinoma, T3 tumor on CT scan with extramural tumor invasion > 5 mm or T4 tumor, age >= 18 years, PS <= 2, adequate hematology, and informed consent. Patients with KRAS, BRAF or PIK3CA mutation or unknown mutational status received three cycles of capecitabine 2000 mg/m(2) days 1-14 q3w and oxaliplatin 130 mg iv day 1 q3w. Wild-type patients received the same chemotherapy supplemented with panitumumab 9 mg/kg iv q3w. After the operation, patients fulfilling the international criteria for adjuvant chemotherapy, i.e. high-risk stage II and III patients, received five cycles of the same chemotherapy without panitumumab. Patients not fulfilling the criteria were offered follow-up only. The primary endpoint was the fraction of patients not fulfilling the criteria for adjuvant chemotherapy (converted patients). Secondary endpoints were recurrence rate, disease-free survival (DFS), and toxicity. RESULTS: The study included 77 patients. The conversion rate was 42% in the wild-type group compared to 51% in patients with a mutation. The cumulative recurrence rate in converted versus unconverted patients was 6% versus 32% (p = 0.005) translating into a three-year DFS of 94% versus 63% (p = 0.005). CONCLUSION: Neoadjuvant chemotherapy in colon cancer is feasible and the results suggest that a major part of the patients can be spared adjuvant chemotherapy. Validation in a randomized trial is warranted. PMID- 25920360 TI - A phase I study on the combination of neoadjuvant radiotherapy plus pazopanib in patients with locally advanced soft tissue sarcoma of the extremities. AB - Accumulating evidence suggests significant synergism combining radiotherapy (RT) with angiogenesis targeted therapies. This multicenter prospective phase I clinical trial established the safety profile and recommended dose for further studies of pazopanib concurrent with preoperative RT in patients with extremity soft tissue sarcomas (ESTS) in curative setting. METHODS: Patients with deep seated intermediate and high grade sarcomas, >= 5 cm, received once daily pazopanib (dose-escalation cohorts 400 mg, 600 mg and 800 mg) for 6 weeks and 50 Gy preoperative RT starting Day 8. Surgery was performed 5-7 weeks later. Toxicity was scored according to CTC criteria 4.0. Dose limiting toxicities (DLT) were divided into two separate sets; DLT-I being toxicities occurring during the 6-week chemoradiotherapy period within the radiation portals until day of surgery (designated as DLT-I) and those occurring perioperatively until Day 21 after surgery (DLT-II). RESULTS: A total of 12 patients were enrolled, 11 were evaluable (3 females and 8 males, median age 58 years, range 24-78 years, median tumor size 9 cm, range 5-15 cm). Ten underwent surgery. No increased toxicity inside the radiation fields was seen, but two of 10 patients (one each in the 400 mg and 600 mg cohorts) showed delayed wound healing after surgery. None of the patients showed significant volume reductions after RT. Evaluation of the resection specimen showed pathological (near) complete responses (>= 95% necrosis rate) in four of 10 cases. Unexpectedly, grade 3 + hepatotoxicity led to premature pazopanib interruption in three of 11 (27%) of cases. CONCLUSION: Apart from hepatotoxicity, neoadjuvant pazopanib 800 mg daily in combination with 50 Gy seems tolerable; the regimen appears to demonstrate promising activity in ESTS and is the recommended dose for further studies. PMID- 25920361 TI - Dose-volume factors correlating with trismus following chemoradiation for head and neck cancer. AB - BACKGROUND: To investigate the dose-volume factors in mastication muscles that are implicated as possible causes of trismus in patients following treatment with intensity-modulated radiotherapy (IMRT) and concurrent chemotherapy for head and neck cancers. MATERIAL AND METHODS: All evaluable patients treated at our institution between January 2004 and April 2009 with chemotherapy and IMRT for squamous cell cancers of the oropharynx, nasopharynx, hypopharynx or larynx were included in this analysis (N = 421). Trismus was assessed using CTCAE 4.0. Bi lateral masseter, temporalis, lateral pterygoid and medial pterygoid muscles were delineated on axial computed tomography (CT) treatment planning images, and dose volume parameters were extracted to investigate univariate and multimetric correlations. RESULTS: Forty-six patients (10.9%) were observed to have chronic trismus of grade 1 or greater. From analysis of baseline patient characteristics, toxicity correlated with primary site and patient age. From dose-volume analysis, the steepest dose thresholds and highest correlations were seen for mean dose to ipsilateral masseter (Spearman's rank correlation coefficient Rs = 0.25) and medial pterygoid (Rs = 0.23) muscles. Lyman-Kutcher-Burman modeling showed highest correlations for the same muscles. The best correlation for multimetric logistic regression modeling was with V68Gy to the ipsilateral medial pterygoid (Rs = 0.29). CONCLUSION: Chemoradiation-induced trismus remains a problem particularly for patients with oropharyngeal carcinoma. Strong dose-volume correlations support the hypothesis that limiting dose to the ipsilateral masseter muscle and, in particular, the medial pterygoid muscle may reduce the likelihood of trismus. PMID- 25920362 TI - Very low rate of circulating tumour cells (CTCs) in patients with PSA recurrence after radical prostatectomy referred to salvage radiotherapy. PMID- 25920364 TI - Is docosahexaenoic acid synthesis from alpha-linolenic acid sufficient to supply the adult brain? AB - Docosahexaenoic acid (DHA) is important for brain function, and can be obtained directly from the diet or synthesized in the body from alpha-linolenic acid (ALA). Debate exists as to whether DHA synthesized from ALA can provide sufficient DHA for the adult brain, as measures of DHA synthesis from ingested ALA are typically <1% of the oral ALA dose. However, the primary fate of orally administered ALA is beta-oxidation and long-term storage in adipose tissue, suggesting that DHA synthesis measures involving oral ALA tracer ingestion may underestimate total DHA synthesis. There is also evidence that DHA synthesized from ALA can meet brain DHA requirements, as animals fed ALA-only diets have brain DHA concentrations similar to DHA-fed animals, and the brain DHA requirement is estimated to be only 2.4-3.8 mg/day in humans. This review summarizes evidence that DHA synthesis from ALA can provide sufficient DHA for the adult brain by examining work in humans and animals involving estimates of DHA synthesis and brain DHA requirements. Also, an update on methods to measure DHA synthesis in humans is presented highlighting a novel approach involving steady-state infusion of stable isotope-labeled ALA that bypasses several limitations of oral tracer ingestion. It is shown that this method produces estimates of DHA synthesis that are at least 3-fold higher than brain uptake rates in rats. PMID- 25920365 TI - Clinical management levels. PMID- 25920363 TI - Sigma 1 receptor regulates the oxidative stress response in primary retinal Muller glial cells via NRF2 signaling and system xc(-), the Na(+)-independent glutamate-cystine exchanger. AB - Oxidative stress figures prominently in retinal diseases, including diabetic retinopathy, and glaucoma. Ligands for sigma1R, a unique transmembrane protein localized to the endoplasmic reticulum, mitochondria, and nuclear and plasma membranes, have profound retinal neuroprotective properties in vitro and in vivo. Studies to determine the mechanism of sigma1R-mediated retinal neuroprotection have focused mainly on neurons. Little is known about the effects of sigma1R on Muller cell function, yet these radial glial cells are essential for homeostatic support of the retina. Here we investigated whether sigma1R mediates the oxidative stress response of Muller cells using wild-type (WT) and sigma1R knockout (sigma1RKO) mice. We observed increased endogenous reactive oxygen species (ROS) levels in sigma1RKO Muller cells compared to WT, which was accompanied by decreased expression of Sod1, catalase, Nqo1, Hmox1, Gstm6, and Gpx1. The protein levels of SOD1, CAT, NQO1, and GPX1 were also significantly decreased. The genes encoding these antioxidants contain an antioxidant response element (ARE), which under stress is activated by NRF2, a transcription factor that typically resides in the cytoplasm bound by KEAP1. In the sigma1RKO Muller cells Nrf2 expression was decreased significantly at the gene (and protein) level, whereas Keap1 gene (and protein) levels were markedly increased. NRF2-ARE binding affinity was decreased markedly in sigma1RKO Muller cells. We investigated system xc(-), the cystine-glutamate exchanger important for synthesis of glutathione (GSH), and observed decreased function in sigma1RKO Muller cells compared to WT as well as decreased GSH and GSH/GSSG ratios. This was accompanied by decreased gene and protein levels of xCT, the unique component of system xc(-). We conclude that Muller glial cells lacking sigma1R manifest elevated ROS, perturbation of antioxidant balance, suppression of NRF2 signaling, and impaired function of system xc(-). The data suggest that the oxidative stress mediating function of retinal Muller glial cells may be compromised in the absence of sigma1R. The neuroprotective role of sigma1R may be linked directly to the oxidative stress-mediating properties of supportive glial cells. PMID- 25920366 TI - Modulatory effects of propolis samples from Latin America (Brazil, Cuba and Mexico) on cytokine production by human monocytes. AB - OBJECTIVES: Propolis has been used in folk medicine in different regions of the world including Latin America. Propolis is a resinous mixture of substances collected by honey bees from several botanical sources, and its composition contains a rich chemical variety, depending on the geographical area and plant sources. Our aim was to compare the modulatory effect of propolis samples from three different countries of Latin America (Brazil, Cuba and Mexico) on pro- and anti-inflammatory cytokine production (tumor necrosis factor (TNF)-alpha and interleukin (IL)-10, respectively) by human monocytes. METHODS: Cells were incubated with propolis for 18 h at 37 degrees C. Cell viability was assessed by 3-(4,5-dimethyl-thiazol-2-yl)-2,5-diphenyltetrazolium bromide method, and cytokine production was determined by ELISA. KEY FINDINGS: All samples did not affect monocyte viability. Brazilian propolis stimulated both TNF-alpha and IL-10 production by monocytes. Cuban propolis stimulated TNF-alpha and inhibited IL-10 production, while Mexican sample exerted the opposite effect, inhibiting TNF alpha and stimulating IL-10 production. The major compounds found in Brazilian, Cuban and Mexican propolis samples were artepillin C, isoflavonoids and pinocembrin, respectively. CONCLUSION: Brazilian, Cuban and Mexican propolis contained different components that may exert pro- and anti-inflammatory activity depending on concentration, what may provide a novel approach to the development of immunomodulatory drugs containing propolis. PMID- 25920367 TI - Dynamic Contrast-Enhanced MRI Parameters as Biomarkers in Assessing Head and Neck Lesions After Chemoradiotherapy Using a Wide-Bore 3 Tesla Scanner. AB - Pilot studies have shown promising results in characterizing head and neck tumors (HNT) using dynamic contrast-enhanced magnetic resonance imaging (DCE-MRI), differentiating between malignant and benign lesions and evaluating changes in response to chemoradiotherapy (CRT). Our aim was to find DCE-MRI parameters, biomarkers in evaluating the post-CRT status. Two hundred and five patients with head and neck lesions were examined with DCE-MRI sequences. The time intensity curves (TIC) were extracted and processed to acquire time-to-peak (TTP), relative maximum enhancement (RME), relative wash-out (RWO), and two new parameters attack and decay. These parameters were analyzed using univariate tests in SPSS (Statistical Package for the Social Sciences, version 17, SPSS Inc. Chicago, USA) to identify parameters that could be used to infer tumor malignancy and post-CRT changes. Multiple parameters of curve characteristics were significantly different between malignant tumors after CRT (MACRT) and changes caused by CRT. The best-performing biomarkers were the attack and the decay. We also found multiple significant (p < 0.05) parameters for both the benign and malignant status as well as pre- and post-CRT status. Our large cohort of data supports the increasing role of DCE-MRI in HNT differentiation, particularly for the assessment of post-CRT status along with accurate morphological imaging. PMID- 25920368 TI - Birth of plant proteomics in India: a new horizon. AB - In the post-genomic era, proteomics is acknowledged as the next frontier for biological research. Although India has a long and distinguished tradition in protein research, the initiation of proteomics studies was a new horizon. Protein research witnessed enormous progress in protein separation, high-resolution refinements, biochemical identification of the proteins, protein-protein interaction, and structure-function analysis. Plant proteomics research, in India, began its journey on investigation of the proteome profiling, complexity analysis, protein trafficking, and biochemical modeling. The research article by Bhushan et al. in 2006 marked the birth of the plant proteomics research in India. Since then plant proteomics studies expanded progressively and are now being carried out in various institutions spread across the country. The compilation presented here seeks to trace the history of development in the area during the past decade based on publications till date. In this review, we emphasize on outcomes of the field providing prospects on proteomic pathway analyses. Finally, we discuss the connotation of strategies and the potential that would provide the framework of plant proteome research. BIOLOGICAL SIGNIFICANCE: The past decades have seen rapidly growing number of sequenced plant genomes and associated genomic resources. To keep pace with this increasing body of data, India is in the provisional phase of proteomics research to develop a comparative hub for plant proteomes and protein families, but it requires a strong impetus from intellectuals, entrepreneurs, and government agencies. Here, we aim to provide an overview of past, present and future of Indian plant proteomics, which would serve as an evaluation platform for those seeking to incorporate proteomics into their research programs. This article is part of a Special Issue entitled: Proteomics in India. PMID- 25920369 TI - Complementing DIGE proteomics and DNA subarray analyses to shed light on Oenococcus oeni adaptation to ethanol in wine-simulated conditions. AB - Direct addition of Oenococcus oeni starters into wine can cause viability problems. In the present study, the influence of ethanol in wine-simulated conditions on O. oeni has been evaluated by complementing microarray techniques and DIGE proteomics. Two different ethanol concentrations were studied. In 12% ethanol, pyrimidine anabolism was stimulated, but in 8% ethanol some energy consuming biosynthetic pathways were limited. The most significant result was the stress response induced by alcohol that concerned both the cell-envelope and specific stress proteins. Interestingly, 8% and 12% ethanol triggered different stress responses: in mild ethanol stress (8%), chaperones with prevalent refolding activity (like HSP20) were over-expressed, whereas at higher alcohol concentration (12%), together with HSP20 and the refolding DNAJ/K, also chaperones having proteolytic activity (like ClpP) were induced. Furthermore the stress response repressor HrcA was downregulated only at 12% ethanol, suggesting that it controls stress pathways, which are different from those active at 8% alcohol. This result confirms that the HrcA system is operative in O. oeni where the CtrS system is prevalent. BIOLOGICAL SIGNIFICANCE: The use of malolactic starter cultures has become widespread to control the MLF process and to prevent off-flavors. There is significant interest in understanding the molecular mechanisms that O. oeni uses to adapt to harsh wine conditions. The overall results highlight that the alcohol-induced stress response involves not only biosynthesis of stress proteins but also envelope-linked mechanisms. From a practical point of view this research underlines the importance of starters acclimation to induce responses that would allow better adaptation to the wine. As a consequence, a well adapted starter can complete malolactic fermentation and improve the final wine quality. PMID- 25920370 TI - Hydrogen-rich water protects against ischemic brain injury in rats by regulating calcium buffering proteins. AB - Hydrogen-rich water (HRW) has anti-oxidant activities, and it exerts neuroprotective effects during ischemia-reperfusion brain injury. Parvalbumin and hippocalcin are two calcium buffering proteins, which are involved in neuronal differentiation, maturation and apoptosis. The aim of this study was to investigate whether HRW could moderate parvalbumin and hippocalcin expression during ischemic brain injury and glutamate toxicity-induced neuronal cell death. Focal brain ischemia was induced in male Sprague-Dawley rats by middle cerebral artery occlusion (MCAO). Rats were treated with H2O or HRW (6 ml/kg per rat) before and after MCAO, and cerebral cortical tissues were collected 1, 7 and 14 days after MCAO. Based on our results, HRW treatment was able to reduce brain infarct volume and improve neurological function following ischemic brain injury. In addition, HRW prevented the ischemia-induced reduction of parvalbumin and hippocalcin levels in vivo and also reduced the glutamate toxicity-induced death of neurons, including the dose-dependent reduction of glutamate toxicity associated proteins in vitro. Moreover, HRW attenuated the glutamate toxicity induced elevate in intracellular Ca(2+) levels. All these results suggest that HRW could protect against ischemic brain injury and that the maintenance of parvalbumin and hippocalcin levels by HRW during ischemic brain injury might contribute to the neuroprotective effects against neuron damage. PMID- 25920371 TI - Secondary metabolites for antiulcer activity. AB - Peptic ulcers are open sores or erosions in the lining of either the duodenum (duodenal ulcers) or the stomach (gastric ulcers). Peptic ulcer, which is mainly caused by bacterial attack or excess of acid secretion, can be cured effectively by these isolated plant compounds. In this present scenario, demand for herbal medicines are increasing due to easy availability in surrounding place at low cost. This review article is all about such isolated plant compounds such as alkaloids, flavonoids and terpenoids. Various plants have been used as folk medicine by the people of rural area, which shows significant effect against peptic ulcer. Further study should be conducted upon these herbal plants because there is possibility for minimising the adverse effect caused by the present antiulcer drugs. PMID- 25920372 TI - Functional status following injury: what recovery pathways do people follow? AB - OBJECTIVES: Functional status can be affected for considerable time after injury. Individual's functional status trajectories, or pathways, following injury may provide insights into achieving, or not achieving, optimal functional status. This study aims to (1) investigate functional status trajectories of injured individuals over two years by multiple dimensions and, (2) determine whether there are differences in functional status trajectories between those hospitalised and non-hospitalised. METHODS: Data from the Prospective Outcomes of Injury Study, a longitudinal cohort (n=2856) of injured New Zealanders, was used. Functional status was assessed using the EQ-5D (plus a cognitive dimension) at 3, 12 and 24 months post injury. For each dimension (mobility, self-care, usual activities, pain/discomfort anxiety/depression and cognition), individual-level trajectories were created based on whether participants had attained (or exceeded) their pre-injury functional status at each time-point. RESULTS: Participants had varied pathways to attaining their pre-injury functional status which was not revealed by cross-sectional group-level data. When all dimensions were considered together, 24% of participants attained their pre-injury functional status but did not maintain it at a subsequent phase. By EQ-5D dimension, this varied from 5% (self-care) to 22% (pain/discomfort). Twenty-six percent of non-hospitalised participants attained, but did not maintain, their pre-injury status compared to 18% of those hospitalised. CONCLUSIONS: Cross sectional group-level prevalence does not adequately depict the underlying pathways experienced by individual participants. Our analyses indicate the importance of following up all study participants in longitudinal studies, including those reporting to have attained 'recovery' and of not under-estimating the impact of non-hospitalised injuries. PMID- 25920373 TI - Feasibility study of collagen membranes derived from bovine pericardium and intestinal serosa for the repair of cranial defects in ovariectomised rats. AB - The indication of biomaterials has increased substantially in the regenerative therapy of bone defects. However, in addition to evaluating the physicochemical properties of biomaterials, the quality of the recipient tissue is also essential for the osseointegration of implants, as abnormalities in bone metabolism, such as gonadal hormone deficiency, can influence bone healing. This study evaluated the osteoregenerative capacity of collagen membranes derived from bovine pericardium and intestinal serosa in the repair of cranial defects in ovariectomised rats. Thirty female Wistar rats were submitted to surgical creation of a 5-mm cranial bone defect. The rats were divided into a control group (not ovariectomised) and an ovariectomised group. The non-ovariectomised group was divided into three subgroups: control (G1) in which the defect was not filled with the biomaterial, and two subgroups (G2 and G3) that received the bovine pericardium- and serosa-derived collagen membranes, respectively. The ovariectomised group was divided into the same subgroups (G4, G5, and G6). The animals were sacrificed 8 weeks after surgery. The calvaria were removed for macroscopic and radiographic photodocumentation and processed for histomorphometric analysis of bone healing at the surgical site. Macroscopic, radiological, and microscopic analyses demonstrated the biocompatibility of the implanted collagen membranes, as indicated by the absence of infiltration and signs of inflammation at the surgical site. Histologically, discrete immature bone neoformation projecting from the margins of the defect was observed at the surgical site in ovariectomised groups when compared to the non-ovariectomised groups. The volume of newly formed bone was significantly higher in the non ovariectomised groups (G1: 7.83%+/-1.32; G2: 21.33%+/-1.96; and G3: 22.83%+/ 0.98) compared to the respective ovariectomised subgroups (G4: 3.16%+/-0.75; G5: 16.83%+/-0.98; and G6: 16.16%+/-0.75), thus demonstrating the deleterious effects of ovariectomy on bone homeostasis. Higher volumes of newly formed bone were observed in the groups receiving the membrane grafts (G2, G3, G5, and G6) compared to the control groups (G1 and G4). In conclusion, the bilateral ovariectomy compromises the ability to repair bone lesions grafted with osteoconductive biomaterials as in the case of collagen membranes derived from both bovine pericardium and intestinal serosa. PMID- 25920374 TI - Towards a correct timing and dosage in PRP applications. PMID- 25920376 TI - Review of the Mid-Atlantic Tick Summit III: A model for regional information sharing. AB - Ticks are the most significant vectors of infectious diseases in the United States, inspiring many researchers to study aspects of their biology, ecology, and their effects on public health. However, regional differences in tick abundance and pathogen infection prevalence result in the inability to assume results from one area are relevant in another. Current local information on tick ranges, infection rates, and human cases is needed to assess tick-borne disease risk in any given region. The Mid-Atlantic Tick Summit III brought together over 100 area experts and researchers to share regional updates on ticks and their associated pathogens. We report some meeting highlights here. Regional meetings foster cross-disciplinary collaborations that benefit the community, and open novel lines of inquiry so that tick-bite risk can be reduced and tick-borne diseases can be treated effectively. PMID- 25920375 TI - Epstein-Barr virus-targeted therapy in nasopharyngeal carcinoma. AB - PURPOSE: Despite successful primary treatment of nasopharyngeal carcinoma (NPC), the incidence of distant metastasis remains 25-34 %. Treatment options are limited, and survival is poor. Intratumoural Epstein-Barr virus (EBV) was used as treatment target. In NPC, EBV is present in a latent state, expressing only few non-immunogenic viral products. Gemcitabine and valproic acid can trigger EBV to the lytic state, wherein viral kinases are expressed, making EBV-positive tumour cells susceptible for antiviral therapy with, i.e. valganciclovir, and inducing an EBV-specific immune response. METHODS: This drug combination was applied in eight patients with EBV-positive NPC, refractory to conventional treatment. The primary endpoints were safety, tolerability and clinical response. Secondary endpoint was to get proof of concept based on biomarkers, i.e. pharmacokinetics, EBV-DNA load in whole blood and nasopharyngeal brushes, EBV-RNA profiling for proof of lytic induction, EBV-IgG and EBV-IgA levels and diversity and EBV specific T cell response. RESULTS: The best observed clinical response was partial in two patients (25 %) and stable disease in three patients (37.5 %). The median survival was 9 months (95 % confidence interval 7-17 months). Effective dose levels were reached. Peaking of EBV-DNA loads in blood and brush proved the biological effect on EBV during most treatment cycles. In one patient, RNA profiling confirmed lytic EBV induction. EBV-IgG and EBV-IgA antibody levels were already high before treatment and did not change during treatment. No changes in EBV-specific T cell response were detected. CONCLUSION: The treatment was safe with manageable side effects, clinical response was observed, and viral activation corroborated. PMID- 25920378 TI - Current status and future prospects for platelet function testing in the diagnosis of inherited bleeding disorders. AB - Platelets play a crucial role in haemostasis by preventing bleeding at the site of vascular injury. Several defects in platelet morphology and function have been identified and described over the years. Although a range of methodologies is available to assess platelet function, a significant proportion of subjects with bleeding symptoms and normal coagulation parameters still appear to have normal results on platelet function testing. This might suggest that the reason for bleeding is multifactorial and is due to a combination of several minor defects in platelet function and/or other parts of the haemostatic system or might indicate that the currently available platelet function tests do not provide optimal diagnostic power. This review will summarize the established platelet function tests used for diagnosing inherited platelet abnormalities in adults and children, and discuss the newly developed methodologies as well as unmet challenges and potential areas for further improvement in this field. PMID- 25920377 TI - Dysregulated flow-mediated vasodilatation in the human placenta in fetal growth restriction. AB - Increased vascular resistance and reduced fetoplacental blood flow are putative aetiologies in the pathogenesis of fetal growth restriction (FGR); however, the regulating sites and mechanisms remain unclear. We hypothesised that placental vessels dictate fetoplacental resistance and in FGR exhibit endothelial dysfunction and reduced flow-mediated vasodilatation (FMVD). Resistance was measured in normal pregnancies (n = 10) and FGR (n = 10) both in vivo by umbilical artery Doppler velocimetry and ex vivo by dual placental perfusion. Ex vivo FMVD is the reduction in fetal-side inflow hydrostatic pressure (FIHP) following increased flow rate. Results demonstrated a significant correlation between vascular resistance measured in vivo and ex vivo in normal pregnancy, but not in FGR. In perfused FGR placentas, vascular resistance was significantly elevated compared to normal placentas (58 +/- 7.7 mmHg and 36.8 +/- 4.5 mmHg, respectively; 8 ml min(-1) ; means +/- SEM; P < 0.0001) and FMVD was severely reduced (3.9 +/- 1.3% and 9.1 +/- 1.2%, respectively). In normal pregnancies only, the highest level of ex vivo FMVD was associated with the lowest in vivo resistance. Inhibition of NO synthesis during perfusion (100 MUm l-NNA) moderately elevated FIHP in the normal group, but substantially in the FGR group. Human placenta artery endothelial cells from FGR groups exhibited increased shear stress-induced NO generation, iNOS expression and eNOS expression compared with normal groups. In conclusion, fetoplacental resistance is determined by placental vessels, and is increased in FGR. The latter also exhibit reduced FMVD, but with a partial compensatory increased NO generation capacity. The data support our hypothesis, which highlights the importance of FMVD regulation in normal and dysfunctional placentation. PMID- 25920379 TI - Role of chemotherapy in treatment of squamous cell carcinoma of the penis. PMID- 25920380 TI - Control of Histamine-Producing Bacteria and Histamine Formation in Fish Muscle by Trisodium Phosphate. AB - Scombrotoxin fish poisoning remains the primary cause of seafood poisoning outbreaks despite preventive guidelines. The purpose of this study was to investigate the use of pH for the control of growth and histamine formation by histamine-producing bacteria in fish muscle. We examined pH effects on growth and histamine formation in tuna fish infusion broth and in inoculated tuna and mahi mahi fish muscle. Histamine production was significantly less for all bacterial strains at pH 8.5 compared to pH 5.5 in tuna fish infusion broth with no significant difference in growth. Elevated pH due to phosphate treatment of fish muscle tissues significantly reduced histamine formation with no effect on the growth of histamine-producing bacteria. This study revealed that phosphate treatment of mahi-mahi and tuna fish muscle resulted in significantly lower histamine production over 4 d of storage at 10 degrees C. Phosphate treatment of fish muscle may serve as a secondary barrier in addition to FDA recommended time and temperature controls for reducing public health concerns of scombrotoxin fish poisoning. PMID- 25920381 TI - Effects of fluvastatin and coenzyme Q10 on skeletal muscle in normo- and hypercholesterolaemic rats. AB - Myalgia and muscle weakness may appreciably contribute to the poor adherence to statin therapy. Although the pathomechanism of statin-induced myopathy is not completely understood, changes in calcium homeostasis and reduced coenzyme Q10 levels are hypothesized to play important roles. In our experiments, fluvastatin and/or coenzyme Q10 was administered chronically to normocholesterolaemic or hypercholaestherolaemic rats, and the modifications of the calcium homeostasis and the strength of their muscles were investigated. While hypercholesterolaemia did not change the frequency of sparks, fluvastatin increased it on muscles both from normocholesterolaemic and from hypercholesterolaemic rats. This effect, however, was not mediated by a chronic modification of the ryanodine receptor as shown by the unchanged ryanodine binding in the latter group. While coenzyme Q10 supplementation significantly reduced the frequency of the spontaneous calcium release events, it did not affect their amplitude and spatial spread in muscles from fluvastatin-treated rats. This indicates that coenzyme Q10 supplementation prevented the spark frequency increasing effect of fluvastatin without having a major effect on the amount of calcium released during individual sparks. In conclusion, we have found that fluvastatin, independently of the cholesterol level in the blood, consistently and specifically increased the frequency of calcium sparks in skeletal muscle cells, an effect which could be prevented by the addition of coenzyme Q10 to the diet. These results support theories favouring the role of calcium handling in the pathophysiology of statin-induced myopathy and provide a possible pathway for the protective effect of coenzyme Q10 in statin treated patients symptomatic of this condition. PMID- 25920382 TI - Is mastectomy undertreatment for low-risk breast cancers eligible for breast conserving therapy? AB - BACKGROUND: Biomarkers are routinely used to predict responses to systemic therapies, but their utility for predicting responses to local therapy for breast cancer is not known. This study determined whether biomarkers could predict responses to breast-conserving therapy (BCT) and mastectomy. METHODS: A review of the Surveillance, Epidemiology, and End Results database identified women diagnosed with early-stage invasive ductal breast cancer and treated with BCT or mastectomy from 1998 to 2008. The estrogen receptor (ER) status and the histologic grade were used to construct 3 biomarker profiles: low risk (ER positive, low/intermediate grade), intermediate risk (ER-positive, high grade), and high risk (ER-negative, any grade). The primary measured outcome was disease specific survival (DSS). RESULTS: BCT and mastectomy were performed in 114,486 patients (59.2%) and 79,035 patients (40.8%), respectively. There were 122,420 low-risk patients (63.3%), 34,341 intermediate-risk patients (17.7%), and 36,760 high-risk patients (19.0%). Multivariate analyses were performed separately for patients with low-, intermediate-, and high-risk tumors. The adjusted hazard ratios for DSS for patients who underwent mastectomy versus BCT for low-, intermediate-, and high-risk tumors were 1.66 (95% confidence interval [CI], 1.54 1.79; P < .001), 1.40 (95% CI, 1.29-1.53; P < .001), and 1.27 (95% CI, 1.19-1.35; P < .001), respectively. CONCLUSIONS: Patients with ER-positive, low-grade breast cancers who underwent mastectomy had a 66% increase in disease-specific mortality versus those who underwent BCT. Biomarker profiles defined by the ER status and grade may improve the selection of local therapy for breast cancer. PMID- 25920383 TI - Has the Gold Lost Its Luster? PMID- 25920385 TI - Does Colchicine Improve Pain in an Acute Gout Flare? PMID- 25920384 TI - Successful Tobacco Dependence Treatment in Low-Income Emergency Department Patients: A Randomized Trial. AB - STUDY OBJECTIVE: Tobacco use is common among emergency department (ED) patients, many of whom have low income. Our objective is to study the efficacy of an intervention incorporating motivational interviewing, nicotine replacement, and quitline referral for adult smokers in an ED. METHODS: This was a 2-arm randomized clinical trial conducted from October 2010 to December 2012 in a northeastern urban US ED with 90,000 visits per year. Eligible subjects were aged 18 years or older, smoked, and were self-pay or had Medicaid insurance. Intervention subjects received a motivational interview by a trained research assistant, 6 weeks' worth of nicotine patches and gum initiated in the ED, a faxed referral to the state smokers' quitline, a booster call, and a brochure. Control subjects received the brochure, which provided quitline information. The primary outcome was biochemically confirmed tobacco abstinence at 3 months. Secondary endpoints included quitline use. RESULTS: Of 778 enrolled subjects, 774 (99.5%) were alive at 3 months. The prevalence of biochemically confirmed abstinence was 12.2% (47/386) in the intervention arm versus 4.9% (19/388) in the control arm, for a difference in quit rates of 7.3% (95% confidence interval 3.2% to 11.5%). In multivariable logistic modeling controlling for age, sex, and race or ethnicity, study subjects remained more likely to be abstinent than controls (odds ratio 2.72; 95% confidence interval 1.55 to 4.75). CONCLUSION: An intensive intervention improved tobacco abstinence rates in low-income ED smokers. Because approximately 20 million smokers, many of whom have low income, visit US EDs annually, these results suggest that ED-initiated treatment may be an effective technique to treat this group of smokers. PMID- 25920386 TI - Tumefactive appearance of peripheral nerve involvement in hematologic malignancies: a new imaging association. AB - OBJECTIVE: In neurolymphomatosis (NL), the affected nerves are typically described to be enlarged and hyperintense on T2W MR sequences and to avidly enhance on gadolinium-enhanced T1WI. This pattern is highly non-specific. We recently became aware of a "tumefactive pattern" of NL, neuroleukemiosis (NLK) and neuroplasmacytoma (NPLC), which we believe is exclusive to hematologic diseases affecting peripheral nerves. MATERIALS AND METHODS: We defined a "tumefactive" appearance as complex, fusiform, hyperintense on T2WI, circumferential tumor masses encasing the involved peripheral nerves. The nerves appear to be infiltrated by the tumor. Both structures show varying levels of homogenous enhancement. We reviewed our series of 52 cases of NL in search of this pattern; two extra outside cases of NL, three cases of NLK, and one case of NPLC were added to the series. RESULTS: We identified 20 tumefactive lesions in 18 patients (14 NL, three NLK, one NPLC). The brachial plexus (n = 7) was most commonly affected, followed by the sciatic nerve (n = 6) and lumbosacral plexus (n = 3). Four patients had involvement of other nerves. All were proven by biopsy: the diagnosis was high-grade lymphoma (n = 12), low-grade lymphoma (n = 3), acute leukemia (n = 2), and plasmacytoma (n = 1). CONCLUSIONS: We present a new imaging pattern of "tumefactive" neurolymphomatosis, neuroleukemiosis, or neuroplasmacytoma in a series of 18 cases. We believe this pattern is associated with hematologic diseases directly involving the peripheral nerves. Knowledge of this association can provide a clue to clinicians in establishing the correct diagnosis. Bearing in mind that tumefactive NL, NLK, and NPLC is a newly introduced imaging pattern, we still recommend to biopsy patients with suspicion of a malignancy. PMID- 25920388 TI - Erratum to: A comparison of magnetic resonance arthrography and arthroscopic findings in the assessment of anterior shoulder dislocations. PMID- 25920387 TI - Long head of the biceps brachii tendon: unenhanced MRI versus direct MR arthrography. AB - OBJECTIVE: We sought to determine the diagnostic accuracy of unenhanced MRI and direct MR arthrography (MRA) for evaluation of the intra-articular long head of the biceps brachii tendon (LHBT) using arthroscopy as the gold standard. MATERIALS AND METHODS: A retrospective review of patients who underwent shoulder MRI (n = 132) and MRA (n = 67) within 12 months prior to arthroscopy was performed. MR images were independently reviewed by two blinded musculoskeletal radiologists. Routinely recorded arthroscopic photos/videos were reviewed by an orthopedic surgeon. The LHBT was graded as normal, tendinosis, partial thickness tear less or greater than 50%, and complete tear. Sensitivity, specificity, positive predictive value (PPV), negative predictive value (NPV), and accuracy for tendinosis and tear detection were calculated. RESULTS: MRI correctly diagnosed fewer normal LHBTs compared to MRA (39-54% versus 74-84%, respectively; p < 0.005). MRI and MRA did not differ significantly in the diagnosis of tendinosis (18-36% and 15-38%, respectively; p > 0.05) and tears (75-83% and 64 73%, respectively; p > 0.05). For tendinosis, MRI versus MRA showed 18-36% and 15 38% sensitivity, 69-79% and 83-91% specificity, 22-28% and 18-50% PPV, 74-76% and 80-86% NPV, and 61-64% and 70-81% accuracy; respectively. For tears, MRI versus MRA showed 75-83% and 64-73% sensitivity, 73-75% and 82-91% specificity, 66-69% and 41-62% PPV, 82-87% and 92-94% NPV, and 74-78% and 79-88% accuracy; respectively. CONCLUSIONS: No significant difference was found between unenhanced MRI and direct MRA for the detection of tendinosis and tears of LHBTs. PMID- 25920390 TI - New insights into the mechanisms of diastolic dysfunction in patients with type 2 diabetes. AB - BACKGROUND: Little is known about the role of advanced glycation end products (AGEs) and their receptor (RAGE) in diabetic cardiovascular complications. Therefore, we aimed to evaluate the association of serum soluble RAGE (sRAGE) levels and left ventricular (LV) diastolic dysfunction in patients with type 2 diabetes. METHODS: Our study consisted of 40 patients with type 2 diabetes and 40 age- and sex-matched healthy control group. Subjects with age >= 50 years old and any cardiovascular risk factors or conditions were excluded from the study. Serum sRAGE levels determined by enzyme-linked immunosorbent assay and LV diastolic dysfunction were evaluated according to current American Society of Echocardiography guidelines. RESULTS: Baseline characteristics were similar between groups except body mass index, waist-hip ratio, and fasting glucose levels. Serum sRAGE level was significantly lower in diabetic group compared with control group (676 +/- 128 vs. 1044 +/- 344, p < 0.05). Diastolic dysfunction was observed in 50% of diabetic patients (40% grade I and 10% grade II). Correlation analysis showed that serum sRAGE was negatively correlated with duration of diabetes, septal E'/A', lateral E'/A', and average E/E'. In multivariate regression analysis, serum sRAGE level was strongly associated with diastolic dysfunction in patients with type 2 diabetes. CONCLUSION: Our study showed that serum sRAGE level was significantly lower in type 2 diabetic patients aged < 50 years old. Also, sRAGE has negative correlation with the duration of diabetes and it was significantly associated with the presence of diastolic dysfunction in type 2 diabetes. PMID- 25920391 TI - Fluorescence spectroscopy and docking study in two flavonoids, isolated tectoridin and its aglycone tectorigenin, interacting with human serum albumin: a comparison study. AB - Two flavonoids, tectoridin (TD) isolated from rhizomes of Iris tectorum and hydrolyzed aglycone tectorigenin (TG) were prepared and characterized to compare their different interaction ability with human serum albumin (HSA). Based on the results, the affinity of TG-HSA was stronger than that of TD-HAS, and TG combined more closely with HSA than did TD. HSA fluorescence was quenched by TD/TG. The interactions between TD/TG and HSA involved static quenching. The thermodynamic parameters indicated that both binding processes were spontaneous; hydrogen binding and van der Waals force were the main forces between TD and HSA, whereas a hydrophobic interaction was the main binding force between TG and HSA. Synchronous and 3D fluorescence spectra showed that the binding of TD/TG to HSA induced conformational changes. Moreover, a docking study confirmed the experimental results. PMID- 25920393 TI - Bacterial nitric oxide reductase: a mechanism revisited by an ONIOM (DFT:MM) study. AB - Bacterial nitric oxide reductase (cNOR) is an important binuclear iron enzyme responsible for the reduction of nitric oxide to nitrous oxide in the catalytic cycle of bacterial respiration. The reaction mechanism of cNOR as well as the key reactive intermediates of the reaction are still under debate. Here, we report a computational study based on ONIOM (DFT:MM) calculations aimed at investigating the reaction mechanism of cNOR. The results suggest that the reaction proceeds via the mono-nitrosyl mechanism which starts off by the binding of an NO molecule to the heme b3 center, N-N hyponitrite bond formation as a result of the reaction with a second NO molecule was found to proceed with an exothermic energy barrier to yield a hyponitrite adduct forming an open (incomplete) ring conformation with the non-heme FeB center (O-N-N-O-FeB). N-O bond cleavage to yield N2O was shown to be the rate-limiting step with an activation barrier of 22.6 kcal mol(-1). The dinitrosyl (trans) mechanism, previously proposed by several studies, was also examined and found unfavorable due to high activation barriers of the resulting intermediates. PMID- 25920394 TI - Prevalence of founder mutations in the BRCA1 and BRCA2 genes among unaffected women from the Bahamas. AB - Population-based testing for BRCA1/2 mutations detects a high proportion of carriers not identified by cancer family history-based testing. We sought to determine whether population-based testing is an effective approach to genetic testing in the Bahamas, where 23% of women with breast cancer carry one of seven founder mutations in the BRCA1 or BRCA2 gene. We determined the prevalence of founder BRCA mutations in 1847 Bahamian women without a personal history of breast or ovarian cancer, unselected for age or family history. We found that 2.8% (20/705) of unaffected women with a family history of breast/ovarian cancer and 0.09% (1/1089) of unaffected women without a family history carry a BRCA mutation. A total of 38% of unaffected women with a known mutation in the family were found to carry the familial mutation. We previously suggested that all Bahamian women with breast or ovarian cancer be offered genetic testing. These current data suggest that additionally all unaffected Bahamian women with a family history of breast/ovarian cancer should be offered genetic testing for the founder BRCA mutations. PMID- 25920395 TI - Correlation of C/EBPalpha expression with response and resistance to imatinib in chronic myeloid leukaemia. AB - OBJECTIVE: Altered differentiation is a common feature of haematopoietic malignancies with poor prognosis. CAAT/enhancer binding protein alpha (C/EBPalpha) is a key transcription factor that regulates myeloid differentiation. This study is aimed to know the prognostic value of CAAT/enhancer binding protein alpha expression and correlate its expression with response to imatinib therapy. METHODS: We quantified the expression of C/EBPalpha gene in 126 chronic myeloid leukaemia samples (82 from newly diagnosed and 44 from imatinib-resistant patients) and 20 control samples. C/EBPalpha mRNA level was measured by real-time quantitative polymerase chain reaction using the DeltaDeltaCT method. RESULTS: C/EBPalpha expression level was significantly lower in the imatinib-resistant group than in the pretreatment and control group (P = 0.0398). Low CAAT/enhancer binding protein alpha levels in the imatinib-resistant group were significantly associated with advanced phase (P = 0.04), with more peripheral blasts (P = 0.0001), high BCR-ABL levels (P = 0.018) and T315I and P loop mutations (P = 0.0002). In the pretreatment group, low expression showed association with high EUTOS risk score (P = 0.03) and possible partial cytogenetic response (P = 0.010). CONCLUSIONS: Our results suggest that low expression of CAAT/enhancer binding protein alpha might have a role in the response to imatinib and progression of disease in patients with chronic myeloid leukaemia. PMID- 25920396 TI - Reappraisal of short-term low-volume hydration in cisplatin-based chemotherapy; hoping for it as a public domain. PMID- 25920397 TI - Fresh Frozen Plasma Use in a Neonatal Unit in South Africa. AB - BACKGROUND: Despite limited evidence, fresh frozen plasma (FFP) transfusions are a relatively common neonatal procedure. OBJECTIVES: Quantify FFP usage in our unit; determine indications for transfusions and compliance with published guidelines. METHODS: Data were retrospectively collected on infants who received FFP from January 2009 to December 2013. RESULTS: Admissions totalled 10 912 infants during the study period. In total, 113 case notes were reviewed and 142 FFP transfusions were administered. Infants receiving FFP had a high mortality rate (54.87%) and an increased odds ratio for mortality 17.9 (95% confidence interval 12.0-26.6). In total, 75% FFP transfusions were compliant with guidelines. The difference between pre- and post-transfusion coagulation profile in 36.3% of infants was not statistically significant. CONCLUSIONS: FFP was often used in accordance with published guidelines in our neonatal unit. However, the appropriate use and effectiveness of FFP in improving neonatal outcomes undermines the rationale for FFP usage in current guidelines. PMID- 25920398 TI - Time to end the political rhetoric on health tourism. PMID- 25920400 TI - Separating the contributions of the volume change upon mixing, permittivity contrast and molecular interactions in the excess relative permittivity of liquid mixtures. AB - The excess relative permittivity of binary systems is separated into three parts. The excess molar volume is the basis for estimating the volume-change contribution. It is proposed to evaluate the electrical permittivity of liquid mixtures, which is solely due to the composition and the relative permittivities of pure components, named permittivity contrast contribution, using the classic local field approach in the case of point-dipoles contained in Lorentz's spherical cavities embedded in the corresponding ideal mixture. The effect of molecular interactions is simply estimated by the difference required to make up experimental excess relative permittivities. This analysis has been applied to 16 binary aqueous organic and organic-organic systems and the estimated values for the contribution of molecular interactions provide interesting insights into the molecular arrangement of these liquid mixtures and the suitability of solvents for determining solute dipole moments. PMID- 25920399 TI - A snapshot of the scope of obesity prevention practice in Australia. AB - Community-based initiatives (CBIs) that build capacity and promote healthy environments hold promise for preventing obesity and non-communicable disease, however their characteristics remain poorly understood and lessons are learned in isolation. This limits understanding of likely effectiveness of CBIs; the potential for actively supporting practice; and the translation of community based knowledge into policy. Building on an initial survey (2010), an online survey was launched (2013) with the aim to describe the reach and characteristics of Australian CBIs and identify and evaluate elements known to contribute to best practice, effectiveness and sustainability. Responses from 104 CBIs were received in 2013. Geographic location generally reflected population density in Australia. Duration of CBIs was short-term (median 3 years; range 0.2-21.0 years), delivered mostly by health departments and local governments. Median annual funding had more than doubled since the 2010 survey, but average staffing had not increased. CBIs used at least two strategy types, with a preference for individual behaviour change strategies. Targeting children was less common (31%) compared with the 2010 survey (57%). Logic models and theory were used in planning, but there was low use of research evidence and existing prevention frameworks. Nearly, all CBIs had an evaluation component (12% of budget), but dissemination was limited. This survey provides information on the scope and varied quality of the current obesity prevention investment in Australia. To boost the quality and effectiveness of CBIs, further support systems may be required to ensure that organizations adopt upstream, evidence-informed approaches; and integrate CBIs into systems, policies and environments. PMID- 25920402 TI - The role of heart rate may differ according to pathophysiological setting: from SHIFT to SIGNIFY. PMID- 25920401 TI - A minimal or maximal ablation strategy to achieve pulmonary vein isolation for paroxysmal atrial fibrillation: a prospective multi-centre randomized controlled trial (the Minimax study). AB - AIMS: Pulmonary vein isolation (PVI) is the cornerstone of catheter ablation of atrial fibrillation (AF). The intervenous ridge (IVR) may be incorporated into ablation strategies to achieve PVI; however, randomized trials are lacking. We performed a randomized multi-centre international study to compare the outcomes of (i) circumferential antral PVI (CPVI) alone (minimal) vs. (ii) CPVI with IVR ablation to achieve individual PVI (maximal). METHODS AND RESULTS: Two hundred and thirty-four patients with paroxysmal AF underwent CPVI and were randomized to a minimal or maximal ablation strategy. The primary outcome of recurrent atrial arrhythmia was assessed with 7-day Holter monitoring at 6 and 12 months. PVI was achieved in all patients. Radiofrequency ablation time was longer in the maximal group (46.6 +/- 14.6 vs. 41.5 +/- 13.1 min; P < 0.01), with no significant differences in procedural or fluoroscopy times. At mean follow-up of 17 +/- 8 months, there was no difference in freedom from AF after a single procedure between a minimal (70%) and maximal ablation strategy (62%; P = 0.25). In the minimal group, ablation was required on the IVR to achieve electrical isolation in 44%, and was associated with a significant reduction in freedom from AF (57%) compared with the minimal group without IVR ablation (80%; P < 0.01). CONCLUSION: There was no statistically significant difference in freedom from AF between a minimal and maximal ablation strategy. Despite attempts to achieve PVI with antral ablation, IVR ablation is commonly required. Patients in whom antral isolation can be achieved without IVR ablation have higher long-term freedom from AF (the Minimax study; ACTRN12610000863033). PMID- 25920403 TI - Tako-tsubo cardiomyopathy, acute coronary syndrome, or both? PMID- 25920404 TI - Chronic obstructive pulmonary disease and sudden cardiac death: the Rotterdam study. AB - AIMS: Both sudden cardiac death (SCD) and chronic obstructive pulmonary disease (COPD) are common conditions in the elderly. Previous studies have identified an association between COPD and cardiovascular disease, and with SCD in specific patient groups. Our aim was to investigate whether there is an association between COPD and SCD in the general population. METHODS AND RESULTS: The Rotterdam study is a population-based cohort study among 14 926 subjects aged 45 years and older with up to 24 years of follow-up. Analyses were performed with a (time dependent) Cox proportional hazard model adjusted for age, sex, and smoking. Of the 13 471 persons included in the analysis; 1615 had a diagnosis of COPD and there were 551 cases of SCD. Chronic obstructive pulmonary disease was associated with an increased risk of SCD (age- and sex-adjusted hazard ratio, HR, 1.34, 95% CI 1.06-1.70). The risk particularly increased in the period 2000 days (5.48 years) after the diagnosis of COPD (age- and sex-adjusted HR 2.12, 95% CI 1.60-2.82) and increased further to a more than three-fold higher risk in COPD subjects with frequent exacerbations during this period (age- and sex-adjusted HR 3.58, 95% CI 2.35-5.44). Analyses restricted to persons without prevalent myocardial infarction or heart failure yielded similar results. CONCLUSION: Chronic obstructive pulmonary disease is associated with an increased risk for SCD. The risk especially increases in persons with frequent exacerbations 5 years after the diagnosis of COPD. This risk indicator could provide new directions for better-targeted actions to prevent SCD. PMID- 25920405 TI - Ultrathin CuO nanorods: controllable synthesis and superior catalytic properties in styrene epoxidation. AB - Ultrathin copper oxide (CuO) nanorods with diameters of ~3.6 nm were obtained in one step using oleylamine (OAm) as both the solvent and the surface controller. The oriented attachment is responsible for the formation of the ultrathin CuO nanorods. Furthermore, this ultrathin nanostructure catalyst exhibited excellent activity and high styrene oxide yields in styrene epoxidation. PMID- 25920407 TI - Non-radiative deactivation in phenol-pyridine complex: theoretical study. AB - Minimum energy structures of the ground and lowest excited states of the phenol (PhOH)-pyridine (Py) hydrogen-bonded complex in the gas phase were determined by ab initio calculations. Photophysical and photochemical features of the complex under Cs symmetry (planar (Pl) and perpendicular (Pe) conformers) and without any symmetry constraints (unconstrained (Un) conformer) were studied with respect to nonradiative decay processes to the ground state. The mechanism involves internal conversion (IC) and intersystem crossing (ISC) along the O-H bond elongation coordinate, where a coupled electron/proton-transfer reaction plays a decisive role in the photophysics of this complex. For the Pl conformer, nonradiative decay proceeds from a locally excited (1)pipi*(LE) minimum over a conical intersection barrier (0.12 eV) to a charge-transfer (CT) minimum, which corresponds to a hydrogen-bonded PhOHPy biradical. Near this second minimum, a barrierless conical intersection (1)A'(pipi*(CT))-S0 funnels the electron population from the CT to the ground S0 state, completing the nonradiative deactivation. Calculations performed for the Pe and Un conformers confirmed that the same radiationless mechanism proceeds with no (1)pipi*(LE)/(1)pipi*(CT) conical intersection near the Franck-Condon region. Furthermore, the population of the lowest triplet states via ISC and their contribution to the photophysics of PhOH-Py complex have been discussed. These findings appear to suggest that there is no single dominant path, but rather many distinct paths involving different quenching mechanisms. PMID- 25920409 TI - Characterization of Zn(q+)-imidazole (q = 0, 1, 2) organometallic complexes: DFT methods vs. standard and explicitly correlated post-Hartree-Fock methods. AB - In the present work, we investigate the bonding, structures, stability and spectra of the Zn(q+)Im (where q = 0, 1, and 2) complexes, which are zeolitic imidazolate frameworks (ZIFs) and Zn-enzyme sub-units. Through a benchmark work, we used density functional theory (DFT) with dispersion correction and standard and explicitly correlated ab initio methods. For neutral Zn(0)Im, we found two stable weakly bound forms: (i) a stacked ferrocene-like complex and (ii) a planar sigma-type complex. This is the first report of the Zn(0) organic compound with a stacked ferrocene-like structure. The most stable isomers of the ionic species consist of sigma-type bonded complexes. The role of various types of covalent and noncovalent interactions within these complexes is discussed after performing vibrational, NBO, charge and orbital analyses. For neutral species, van der Waals (vdWs) and charge transfer through covalent as well as noncovalent interactions are in action; whereas the bonding is dominated by charge transfer from Zn to Im within the ionic species. These findings are important to understand, at the microscopic level, the structure and the bonding within the ZIFs and the Zn enzymes. Moreover, we establish the ability and reliability of M05-2X and PBE0 functionals for the simultaneous correct description of covalent and noncovalent interactions since this DFT leads to a close agreement with post-Hartree-Fock methods. The newly launched M11 functional is also suited for the description of noncovalent interactions. Therefore, M05-2X and PBE0 functionals are recommended for studying the larger complexes formed by Zn and Im, such as the ZIFs and Zn enzymes. PMID- 25920410 TI - The rate of lactate removal after maximal exercise: the effect of intensity during active recovery. AB - AIM: The aim of the present investigation was to determine the greater rate of lactate removal after a maximal rowing test using different intensities during active recovery. METHODS: Thirty elite male rowers performed a simulated incremental exercise protocol on rowing ergometer to determine their maximal oxygen uptake and they divided into three equal sized group according to the type of the recovery that followed the assessment. The first group (N.=10) subjected to 20 min of passive recovery, while the second (N.=10) and the third (N.=10) groups performed 20 min of active recovery using the 25% and the 50% of each individual's maximal power output, respectively. During the recovery period, every two min were performed measurements for the assessment of blood lactate, oxygen consumption and heart rate (HR). RESULTS: It was found that after 10 min of active recovery at 50% and 25% of maximal power output lactate concentration reduced by 43% and 15%, respectively, while during passive recovery lactate concentration found to be slightly elevated by 1%. It was also found that during recovery period, HR, oxygen consumption and pulmonary ventilation was significant elevated at higher exercise intensity compared to lower exercise intensity and passive recovery. CONCLUSION: It is concluded that in elite male rowers the active recovery provided higher rate of lactate removal compared to passive recovery. Moreover, active recovery at 50% of maximal power output had better results in lactate clearance compared to the active recovery of lower intensity (25% of maximal power output). PMID- 25920411 TI - Observed and modeled effects of pH on bioconcentration of diphenhydramine, a weakly basic pharmaceutical, in fathead minnows. AB - A need exists to better understand the influence of pH on the uptake and accumulation of ionizable pharmaceuticals in fish. In the present study, fathead minnows were exposed to diphenhydramine (DPH; disassociation constant = 9.1) in water for up to 96 h at 3 nominal pH levels: 6.7, 7.7, and 8.7. In each case, an apparent steady state was reached by 24 h, allowing for direct determination of the bioconcentration factor (BCF), blood-water partitioning (PBW,TOT), and apparent volume of distribution (approximated from the whole-body-plasma concentration ratio). The BCFs and measured PBW,TOT values increased in a nonlinear manner with pH, whereas the volume of distribution remained constant, averaging 3.0 L/kg. The data were then simulated using a model that accounts for acidification of the gill surface caused by elimination of metabolically produced acid. Good agreement between model simulations and measured data was obtained for all tests by assuming that plasma binding of ionized DPH is 16% that of the neutral form. A simpler model, which ignores elimination of metabolically produced acid, performed less well. These findings suggest that pH effects on accumulation of ionizable compounds in fish are best described using a model that accounts for acidification of the gill surface. Moreover, measured plasma binding and volume of distribution data for humans, determined during drug development, may have considerable value for predicting chemical binding behavior in fish. PMID- 25920412 TI - A fluorimetric study on the interaction between a Trp-containing beta-strand peptide and amphiphilic polymer-coated gold nanoparticles. AB - Owing to the inevitability of nanoparticles encountering proteins/peptides in current bio-nano-medicine development, it is important to know how they interact with each other in vitro before developing in vivo applications. To this end, a model de novo beta-sheet-forming peptide and typical biocompatible nanoparticles were selected to study thermodynamic aspects of their interactions via a fluorescence quenching method. The results showed that Pep11 and AuNPs spontaneously formed conjugates, mainly driven by a coulombic interaction with a binding affinity of ~ 0.1 uM(-1); the physical adsorption process was cooperative. These results deepen our quantitative understanding of nanoparticle peptide interactions. The results may also be helpful in further nanoparticle peptide hybrid nanofabrication and also useful for the application of nanoparticles in the treatment of amyloid diseases. PMID- 25920413 TI - The history of the oldest self-sustaining laboratory animal: 150 years of axolotl research. AB - Today the Mexican axolotl is critically endangered in its natural habitat in lakes around Mexico City, but thrives in research laboratories around the world, where it is used for research on development, regeneration, and evolution. Here, we concentrate on the early history of the axolotl as a laboratory animal to celebrate that the first living axolotls arrived in Paris in 1864, 150 years ago. Maybe surprisingly, at first the axolotl was distributed across Europe without being tied to specific research questions, and amateurs engaged in acclimatization and aquarium movements played an important role for the rapid proliferation of the axolotl across the continent. But the aquarium also became an important part of the newly established laboratory, where more and more biological and medical research now took place. Early scientific interest focused on the anatomical peculiarities of the axolotl, its rare metamorphosis, and whether it was a larva or an adult. Later, axolotl data was used to argue both for (by August Weismann and others) and against (by e.g., Albert von Kolliker) Darwinism, and the axolotl even had a brief history as a laboratory animal used in a failed attempt to prove Lysenkoism in Jena, Germany. Nowadays, technical developments such as transgenic lines, and the very strong interest in stem cell and regeneration research has again catapulted the axolotl into becoming an important laboratory animal. PMID- 25920416 TI - Elucidating the intercalation mechanism of zinc ions into alpha-MnO2 for rechargeable zinc batteries. AB - The intercalation mechanism of zinc ions into 2 * 2 tunnels of an alpha-MnO2 cathode for rechargeable zinc batteries was revealed. It involves a series of single and two-phase reaction steps and produces buserite, a layered compound with an interlayer spacing of 11 A as a discharge product. PMID- 25920414 TI - A neural circuitry that emphasizes spinal feedback generates diverse behaviours of human locomotion. AB - KEY POINTS: It is often assumed that central pattern generators, which generate rhythmic patterns without rhythmic inputs, play a key role in the spinal control of human locomotion. We propose a neural control model in which the spinal control generates muscle stimulations mainly through integrated reflex pathways with no central pattern generator. Using a physics-based neuromuscular human model, we show that this control network is sufficient to compose steady and transitional 3-D locomotion behaviours, including walking and running, acceleration and deceleration, slope and stair negotiation, turning, and deliberate obstacle avoidance. The results suggest feedback integration to be functionally more important than central pattern generation in human locomotion across behaviours. In addition, the proposed control architecture may serve as a guide in the search for the neurophysiological origin and circuitry of spinal control in humans. ABSTRACT: Neural networks along the spinal cord contribute substantially to generating locomotion behaviours in humans and other legged animals. However, the neural circuitry involved in this spinal control remains unclear. We here propose a specific circuitry that emphasizes feedback integration over central pattern generation. The circuitry is based on neurophysiologically plausible muscle-reflex pathways that are organized in 10 spinal modules realizing limb functions essential to legged systems in stance and swing. These modules are combined with a supraspinal control layer that adjusts the desired foot placements and selects the leg that is to transition into swing control during double support. Using physics-based simulation, we test the proposed circuitry in a neuromuscular human model that includes neural transmission delays, musculotendon dynamics and compliant foot-ground contacts. We find that the control network is sufficient to compose steady and transitional 3-D locomotion behaviours including walking and running, acceleration and deceleration, slope and stair negotiation, turning, and deliberate obstacle avoidance. The results suggest feedback integration to be functionally more important than central pattern generation in human locomotion across behaviours. In addition, the proposed control architecture may serve as a guide in the search for the neurophysiological origin and circuitry of spinal control in humans. PMID- 25920417 TI - Effect of urethral infusion of atracurium besylate on manual bladder expression in dogs and cats with spinal cord injuries: a randomised trial. AB - The aim of this randomised trial was to assess the effect of urethral infusion of atracurium besylate in dogs and cats with signs of urinary retention secondary to lesions affecting spinal cord segments T3-L3. Eighteen dogs and six cats with urinary retention were examined and scored before treatment on the degree of difficulty of inducing bladder emptying by manual bladder compression. Animals were subsequently treated in a blinded fashion by the same operator with urethral infusion of 2-4 ml of either a solution of 0.5 mg/ml of atracurium (treatment group) or placebo (control group) and, after five minutes, a second attempt was made to induce bladder emptying by manual compression and a post-treatment score assigned. Pretreatment scores did not differ between the treatment and control groups (5.6+/-0.8 v 6.2+/-0.7, respectively; P=0.22); however, post-treatment scores were significantly lower in the treatment group compared with the control group (2.9+/-0.4 v 5.9+/-0.3; P<0.05). Urethral infusion of atracurium facilitates manual bladder expression in dogs and cats with urinary retention secondary to spinal cord injuries. No side effects were recognised. PMID- 25920418 TI - Synthesis of multivalent silica nanoparticles combining both enthalpic and entropic patchiness. AB - Silica particles with a controlled number of entropic patches, i.e. dimples, are synthesized through the growth of the silica core of binary multipods that have been produced by a seeded-growth emulsion polymerization reaction. Transmission electron microscopy studies indicate that the silica surface conforms to the shape of the polystyrene (PS) nodules of the multipods while growing, allowing good control of the final shape of the dimpled silica particles. The PS nodules are also used as protecting masks to regioselectively graft amino groups, as revealed by the adsorption of gold markers. After dissolution of the PS nodules, some polymer chains remain grafted onto the silica surface, forming organic bumps. These residues are also selectively functionalized, leading to silica particles with both entropic and enthalpic patches. PMID- 25920419 TI - Generic drug firm settles claim that it was paid to stay out of market. PMID- 25920420 TI - Neuropeptide Y levels are associated with nutritional status and cardiovascular events in adults with chronic kidney disease. AB - BACKGROUND/OBJECTIVES: Neuropeptide Y (NpY) is an important factor in neuropeptide signalling, and significantly change in the blood and cerebrospinal fluid (CSF) during chronic kidney disease (CKD) progression. However, the role of NpY remains unclear. We aimed to investigate the associations between NpY levels, nutritional status and cardiovascular disease (CVD) in patients with CKD. SUBJECTS/METHODS: In this cohort study, we performed Pearson's correlation analysis and multiple linear regressions to assess the relationship between CSF and serum NpY levels, as well as nutritional indices. Receiver operating characteristic curves were used to evaluate the sensitivity and specificity of CSF NpY levels. As NpY affects the cardiovascular system, Kaplan-Meier analysis was used to investigate the relationship between serum NpY levels and CVD. RESULTS: CSF NpY levels and nutritional indices were related during CKD progression (energy intake: beta=0.236, P<0.001; mid-arm muscle circumference: beta=0.953, P=0.014; prealbumin: beta=0.067, P<0.001), and had high specificity (79.9%). High serum NpY levels may be a risk factor associated with CVD (relative risk=1.8015, 95% confidence interval: 1.0509-3.0881). CONCLUSIONS: Our results suggested a relationship between CSF NpY levels and nutritional indices in CKD patients. High serum NpY concentrations may be a risk factor associated with CVD. PMID- 25920421 TI - The effect of fruit and vegetable intake on the development of lung cancer: a meta-analysis of 32 publications and 20,414 cases. AB - BACKGROUND/OBJECTIVES: Quantification of the association between the intake of vegetables and fruits and the risk of lung cancer is controversial. Thus, we conducted a meta-analysis to assess the relationship between vegetables and fruits and lung cancer risk. SUBJECTS/METHODS: Pertinent studies were identified by a search in PubMed and Web of Knowledge. Random-effects models were used to calculate summary relative risks (RR) and the corresponding 95% confidence intervals (CI). Publication bias was estimated using Begg's test. RESULTS: Finally, 30 articles with 37 studies comprising of 20,075 lung cancer cases for vegetables intake with lung cancer risk and 31 articles with 38 studies comprising of 20,213 lung cancer cases for fruits intake with lung cancer risk were included in this meta-analysis. The combined results showed that there were significant associations between vegetables and fruits intake and lung cancer risk. The pooled RR were 0.74 (95% CI: 0.67, 0.82) for vegetables and 0.80 (95% CI: 0.74, 0.88) for fruits. Significant association was found in females on vegetables intake and lung cancer but not in males. The association was also stronger in females than males on fruits intake and lung cancer risk. No publication bias was detected. CONCLUSIONS: Our analysis indicated that intake of vegetables and fruits may have a protective effect on lung cancer, and the associations were stronger in females. As the potential biases and confounders could not be ruled out completely in this meta-analysis, further studies are needed. PMID- 25920422 TI - Longitudinal development of obesity in the post-Fontan population. AB - BACKGROUND/OBJECTIVES: An elevated body mass index (BMI) in childhood is a significant risk factor for cardiovascular disease, and it may pose an additional risk to children and adults with palliated univentricular congenital heart disease. However, little is known about longitudinal development of obesity in this population. The objective of this study is to determine the prevalence of overweight (OW) and obese (OB) habitus at the time of Fontan palliative surgery, to track changes in BMI after surgery, and ultimately to determine whether factors such as gender, ethnicity, preoperative heart defect and ventricular dominance are associated with later development of OW or OB. SUBJECTS/METHODS: A retrospective chart review of 84 patients undergoing Fontan palliation was performed. Demographic data including gender, ethnicity, preoperative heart defect and ventricular dominance were recorded. Height, weight and BMI were obtained at the time of Fontan and on a yearly basis post surgery. RESULTS: At the time of Fontan palliation, 10.7% of patients were OB or OW. During the five years following palliation, the percentage of OB or OW patients trended upward, from 20.3% the year following surgery to 30% at 5 years post Fontan. Repeated measures generalized estimating equation showed a significant association between Hispanic ethnicity and increased BMI Z-scores for the 5 years after Fontan palliation (P<0.001); there was no association between BMI Z-scores and patient sex, lesion or ventricular dominance. CONCLUSIONS: During the first 5 years after Fontan palliation, there is a trend toward increasing percentages of OB and OW patients. In addition, there is a significant association between Hispanic ethnicity and being OW or OB before and after surgery. Further study is needed to determine whether OW/OB status is associated with worse health outcomes in this patient population. PMID- 25920423 TI - Nutritional management in patients with chyle leakage: a systematic review. AB - BACKGROUND/OBJECTIVES: To investigate all the available evidence assessing the effect of nutrition intervention on patients with chyle leakage and its effectiveness at reducing the need for surgical intervention. SUBJECTS/METHODS: A systematic review was undertaken of all English language studies using MEDLINE, Cinahl and Web of Science from January 1980 to September 2013. Case series were included because of limited available evidence. Exclusion criteria included animal studies, pediatrics and studies without nutritional intervention. Assessment of study quality was included. Because of the heterogeneity of the data, no meta-analysis was performed. RESULTS: Thirty-one articles were identified for analysis, all of which were retrospective case series studies. The data within these studies were greatly limited. A total of 550 subjects were identified from these studies, 72% of whom had a chyle leak successfully resolved without surgical intervention. However, there was no significant difference between the type of dietary intervention and the rate of resolution (chi(2)=11.14, P=0.08). CONCLUSIONS: Although there is evidence to suggest that nutrition may have a role in the management of patients with chyle leakage, it is not possible to determine which dietary methods are most effective. More research is required before any guidelines for best practice can be established. PMID- 25920425 TI - Impact of weight loss in patients with head and neck carcinoma undergoing radiotherapy: is it an underestimated phenomenon? A radiation oncologist's perspective. PMID- 25920424 TI - Zinc intake, status and indices of cognitive function in adults and children: a systematic review and meta-analysis. AB - In developing countries, deficiencies of micronutrients are thought to have a major impact on child development; however, a consensus on the specific relationship between dietary zinc intake and cognitive function remains elusive. The aim of this systematic review was to examine the relationship between zinc intake, status and indices of cognitive function in children and adults. A systematic literature search was conducted using EMBASE, MEDLINE and Cochrane Library databases from inception to March 2014. Included studies were those that supplied zinc as supplements or measured dietary zinc intake. A meta-analysis of the extracted data was performed where sufficient data were available. Of all of the potentially relevant papers, 18 studies met the inclusion criteria, 12 of which were randomised controlled trials (RCTs; 11 in children and 1 in adults) and 6 were observational studies (2 in children and 4 in adults). Nine of the 18 studies reported a positive association between zinc intake or status with one or more measure of cognitive function. Meta-analysis of data from the adult's studies was not possible because of limited number of studies. A meta-analysis of data from the six RCTs conducted in children revealed that there was no significant overall effect of zinc intake on any indices of cognitive function: intelligence, standard mean difference of <0.001 (95% confidence interval (CI) 0.12, 0.13) P=0.95; executive function, standard mean difference of 0.08 (95% CI, -0.06, 022) P=0.26; and motor skills standard mean difference of 0.11 (95% CI 0.17, 0.39) P=0.43. Heterogeneity in the study designs was a major limitation, hence only a small number (n=6) of studies could be included in the meta analyses. Meta-analysis failed to show a significant effect of zinc supplementation on cognitive functioning in children though, taken as a whole, there were some small indicators of improvement on aspects of executive function and motor development following supplementation but high-quality RCTs are necessary to investigate this further. PMID- 25920426 TI - Eating practices and diet quality: a population study of four Nordic countries. AB - BACKGROUND/OBJECTIVES: Daily practices related to eating are embedded in the social and cultural contexts of everyday life. How are such factors associated with diet quality relative to motivational factors? And, are associations universal or context-specific? We analyze the relationship between diet quality and the following practices: social company while eating, the regularity and duration of eating and the activity of watching TV while eating. SUBJECTS/METHODS: A cross-sectional, questionnaire-based internet survey was conducted in April 2012 with stratified random samples of the populations (aged 15-80 years) in Denmark, Finland, Norway and Sweden (N=7531, completion rate 9 13%). The questionnaire elicited detailed accounts of one day of eating focusing on social and practical aspects of eating events. The validated Dietary Quality Score was the dependent variable. This measure is based on eight food frequency questions focusing on fats, vegetables, fruits and fish in the diet. RESULTS: Eating activities were associated with diet quality even when motivation to eat healthily and sociodemographic factors were controlled for. The number of daily eating events and eating main meals was positively correlated with diet quality in all countries. Beyond that, activities that were significantly associated with diet quality varied with country. When measured separately, the association between each activity and diet quality was weaker than motivation to eat healthily, but in combinations that are found in parts of the populations, the association was substantial. CONCLUSIONS: Daily practices related to eating are correlated with diet quality. Practices that are important are in part universal but also country-specific. Efforts to promote healthy eating should address not only cognitive factors but also everyday contexts of eating that facilitate or hamper healthy practices. PMID- 25920427 TI - Validity and reliability of the new Canadian Nutrition Screening Tool in the 'real-world' hospital setting. PMID- 25920428 TI - Validity and reliability of the new Canadian Nutrition Screening Tool in the 'real-world' hospital setting: Methodological issues. PMID- 25920429 TI - Il10 and poly-dl-lactide-E-caprolactone conduits in critical size nerve defect bridging-An experimental study. AB - INTRODUCTION: Aim of this study is to evaluate if regeneration in repair of nerve defects can be improved by combination of a poly-dl-lactide-E-caprolactone conduit (PLC) with long-term release of anti-inflammatory Interleukin 10 (IL10), which is known to reduce intraneural scarring in nerve regeneration through its anti-inflammatoric properties. METHOD: Experiments were performed at 30 female Lewis rats. Conduits filled with fibrin (PLC-group n = 10) and fibrin loaded with IL10 (IL10-group n = 10) were compared to autologs nerve grafts (NG-group n = 10) in a 15 mm sciatic nerve gap lesion. Sciatic function index (SFI) and electrophysiological analyses were performed 16 weeks after surgery prior to histological evaluation. In histological analyses total nerve count, total nerve area, myelination index, and N-ratio were measured. Additionally, gastrocnemius muscle was weighed. RESULTS: SFI (NG-group:-50.68 +/- 7.03%; PLC-group:-56.48 +/ 2.30%; IL10-group:-56.54 +/- 8.22%) and nerve conduction velocity (NG-group: 92.52 +/- 4.64 m/s; PLC-group: 92.77 +/- 5.07 m/s; IL10-group: 93.78 +/-3.63 m/s) showed no significant differences after 16 weeks (P > 0.05). Significant higher axon count (17.592 +/- 483) were observed in the NG-group compared to PLC (6.722 +/- 553) and IL10-group (6.842 +/- 681) (P < 0.001). NG-group had significant highest nerve cross sections (604.214 +/- +/-15.217 um2 ) as compared to PLC- (245.669 +/- +/-28.034 um2 ) and IL10-group (244.698 +/- 26.772 um2 ) (P < 0.001). Comparison of myelination index showed significant higher values for NG-group (0.46 +/- 0.02) than PLC- (0.64 +/- 0.01) and IL10-group (0.62 +/- 0.01) (P < 0.001). N-ratios in PLC-group (0.21 +/- 0.01) and IL10 group (0.24 +/- 0.01) were lower than in NG-group (0.51 +/- 0.03) (P < 0.001). Between PLC- and IL10-group no differences were observed (P > 0.05). Gastrocnemius muscle was heavier in NG-group (0.86 +/- 0.21g) as compared to PLC- (0.26 +/- 0.05g) and IL-10 group (0.29 +/- 0.06 g) (P < 0.05). CONCLUSION: Bridging critical nerve defects through fibrin-filled PLC conduits is possible. Although, autologs nerve graft showed superior histological results. Long-term release of IL10 in the conduit did not improve regeneration of critical nerve defects. (c) 2015 Wiley Periodicals, Inc. Microsurgery 36:410-416, 2016. PMID- 25920430 TI - Comparative studies on the interactions of baicalein and Al(III)-baicalein complex with human serum albumin. AB - A new potential drug aluminum(III)-baicalein complex (ALBC) was synthesized and characterized. The binding mechanisms of baicalein (BC) and ALBC to human serum albumin (HSA) under simulative physiological conditions were investigated, in order to understand the pharmacokinetics of BC and ALBC. Fluorescence spectroscopy results suggested that the binding level of BC is higher than that of ALBC. Results of UV-vis, synchronous fluorescence, 3D fluorescence, circular dichroism and Fourier transform infrared spectroscopic analyses consistently demonstrated that the conformation of HSA was altered when bound to BC or ALBC. The distance between HSA as a donor and BC (or ALBC) as an acceptor was determined via fluorescence resonance energy transfer. The results of competitive experiments and molecular docking studies indicated that BC was located in site I (subdomain IIA) on HSA and that ALBC was bound to HSA mainly within site II (subdomain IIIA). PMID- 25920431 TI - Nano-scale displacement sensing based on van der Waals interactions. AB - We propose that a nano-scale displacement sensor with high resolution in weak force systems can be realized based on vertically stacked two-dimensional (2D) atomic corrugated layer materials bound through van der Waals (vdW) interactions. Using first-principles calculations, we found that the electronic structures of bi-layer blue phosphorus (BLBP) vary appreciably with lateral and vertical interlayer displacements. The variation of the electronic structure is attributed to the change of the interlayer distance dz for both the lateral and vertical displacement. For lateral displacement, the change of dz is induced by atomic layer corrugation. Despite the different stacking configurations of BLBP, we find that the change of the indirect band gap is proportional to dz(-2). Furthermore, this dz(-2) dependence is found to be applicable to other graphene-like corrugated bi-layer materials such as MoS2. BLBP represents a large family of bi layer 2D atomic corrugated materials for which the electronic structure is sensitive to the interlayer vertical and lateral displacement, and thus could be used for a nano-scale displacement sensor. This can be done by monitoring the tunable electronic structure using absorption spectroscopy. Because this type of sensor is established on atomic layers coupled through vdW interactions, it provides unique applications in the measurements of nano-scale displacement induced by tiny external forces. PMID- 25920432 TI - Estimation of serum malondialdehyde and assessment of DNA damage using comet assay in patients with oral submucous fibrosis. AB - AIM: To quantify the level of serum malondialdehyde and extent of DNA damage using comet assay in patients with oral submucous fibrosis (SMF) in comparison to normal individuals and to correlate the extent of DNA damage with MDA levels. METHODS: Study included 30 cases of SMF (n = 30) and equal number of healthy volunteers. Serum malondialdehyde was measured using the thiobarbituric trichloroacetitic acid (TBA-TCA) method. Comet assay was used to assess the DNA damage. Association between the extent of DNA damage and serum MDA levels was analyzed in SMF statistically. RESULTS: Comet assay results showed that there was an increase in tail length, percentage of tail DNA and tail moment among SMF subjects (P < 0.05). Serum MDA levels were elevated in SMF patients compared with healthy subjects. A significant positive correlation was observed between serum MDA levels and comet tail length in SMF group (r = 0.56; P < 0.05). CONCLUSIONS: Patients with SMF have increased DNA damage and elevated levels of lipid peroxidation compared with healthy controls. Evaluation of MDA levels as an oxidative biomarker along with comet assay analysis will serve as a diagnostic tool to identify patients with high risk of malignant potential in SMF. PMID- 25920433 TI - Visible-light photocatalysis in Cu2Se nanowires with exposed {111} facets and charge separation between (111) and (1[combining macron]1[combining macron]1[combining macron]) polar surfaces. AB - The search for active narrow band gap semiconductor photocatalysts that directly split water or degrade organic pollutants under solar irradiation remains an open issue. We synthesized Cu2Se nanowires with exposed {111} facets using ethanol and glycerol as morphology controlling agents. The {111} facets were found to be the active facets for decomposing organic contaminants in the entire solar spectrum. Based on the polar structure of the Cu2Se {111} facets, a charge separation model between polar (111) and (1[combining macron]1[combining macron]1[combining macron]) surfaces is proposed. The internal electric field between polar (111) and (1[combining macron]1[combining macron]1[combining macron]) surfaces created by spontaneous polarization drives charge separation. The reduction and oxidation reactions occur on the positive (111) and negative (1[combining macron]1[combining macron]1[combining macron]) polar surfaces, respectively. This suggests the surface-engineering of narrow band gap semiconductors as a strategy to fabricate photocatalysts with high reactivity in the entire solar spectrum. The charge separation model can deepen the understanding of charge transfer in other semiconductor nanocrystals with high photocatalytic activities and offer guidance to design more effective photocatalysts as well as new types of solar cells, photoelectrodes and photoelectric devices. PMID- 25920434 TI - Leiomyosarcoma: One disease or distinct biologic entities based on site of origin? AB - BACKGROUND: Leiomyosarcoma (LMS) can originate from the retroperitoneum, uterus, extremity, and trunk. It is unclear whether tumors of different origin represent discrete entities. We compared clinicopathologic features and outcomes following surgical resection of LMS stratified by site of origin. METHODS: Patients with LMS undergoing resection at a single institution were retrospectively reviewed. Clinicopathologic variables were compared across sites. Survival was calculated using the Kaplan-Meier method and compared using log-rank and Cox regression analyses. RESULTS: From 1983 to 2011, 138 patients underwent surgical resection for LMS. Retroperitoneal and uterine LMS were larger, higher grade, and more commonly associated with synchronous metastases. However, disease-specific survival, recurrence-free survival, and recurrence patterns were not significantly different across the four sites. Synchronous metastases (HR 3.20, P < 0.001), but not site of origin, size, grade, or margin status, were independently associated with worse DSS. A significant number of recurrences and disease-related deaths were noted beyond 5 years. CONCLUSIONS: Although larger and higher grade, retroperitoneal and uterine LMS share similar survival and recurrence patterns with their trunk and extremity counterparts. LMS of various anatomic sites may not represent distinct disease processes based on clinical outcomes. The presence of metastatic disease remains the most important prognostic factor for LMS. PMID- 25920435 TI - Mutations in the RAS and PI3K pathways are associated with metastatic location in colorectal cancers. AB - BACKGROUND AND OBJECTIVES: Identification of mutations in the downstream epidermal growth factor receptor (EGFR) signaling pathway could provide important insights of EGFR-targeted therapies in colorectal cancers. We analyzed the mutation spectra of the PI3K/PTEN/AKT and RAS/RAF/MAPK pathways in colorectal cancers and the associations of these mutations with sites of metastases or recurrence. METHODS: The study population comprised 1,492 retrospectively collected stages I-IV colorectal cancer specimens. Tissue was obtained between 2000 and 2010 at a single hospital. We analyzed 61 hot spots using MALDI-TOF mass spectrometry for nucleic acid analysis. RESULTS: Mutations were found in the RAS pathway in 47.3% of patients and in the PI3K pathway in 14.3% of patients, with 9.2% of patients carrying mutations in both pathways. Both the RAS and PI3K pathway mutations were significantly associated with proximal tumors, mucinous tumors, and microsatellite instability. Tumors carrying a RAS pathway mutation exhibited a higher frequency of lung and peritoneal metastasis than did tumors with a wild-type gene (P = 0.025 and 0.009, respectively). NRAS gene mutation was significantly associated with lung metastasis (P = 0.001). CONCLUSIONS: Somatic mutations in the RAS pathway of the primary tumor in colorectal cancer can influence patterns of metastasis and recurrence. PMID- 25920436 TI - Hand dermatitis: a review of clinical features, prevention and treatment. AB - Hand dermatitis is a socially significant health problem. This review provides a discussion on the clinical features and patterns as well as the differential diagnosis of hand dermatitis, because these are essential for proper diagnosis in clinical practice. The morphology, however, is poorly related to the etiology in chronic cases. In all cases of chronic hand dermatitis, a full diagnostic examination should be undertaken and the etiology should be clarified and addressed in the treatment concept, instead of just moving directly from a morphological diagnosis to therapy. Preventive measures should be included in the treatment concept according to etiology. A stepwise approach for escalating therapy is advised, including basic topical therapy, topical corticosteroids, calcineurin inhibitors, as well as phototherapy and systemic therapy with corticosteroids, alitretinoin, cyclosporine, methotrexate, azathioprine, and others. PMID- 25920437 TI - Selenium and Polysaccharides of Atractylodes macrocephala Koidz Play Different Roles in Improving the Immune Response Induced by Heat Stress in Chickens. AB - The aim of the present study was to investigate the effect of acute heat stress (HS) on the chicken immune response and to examine the role of selenium (Se) and the polysaccharides of Atractylodes macrocephala Koidz (PAMK) in immune regulation in the chicken immune system. Two hundred chickens were randomly divided into two groups: the HS group and the control (Con) group. These chickens were treated with Se (0.3 mg/kg), PAMK (200 mg/kg) alone, and a combination of Se (0.3 mg/kg) and PAMK (200 mg/kg). The cytokines; antioxidative enzymes; and HSP60, HSP70, and HSP90 levels were examined in chicken immune organs. The results indicated that HS-induced immune dysfunction included increased levels of TNF-alpha, IFN-gamma, IL-2, IL-4, HSP60, HSP70, HSP90, and malondialdehyde (MDA) as well as decreased levels of glutathione peroxidase (GPx) and superoxide dismutase (SOD) in immune organs (P < 0.05). Among the affected organs, the bursa of Fabricius was one primary target of HS. The immune dysfunction induced by HS was alleviated (P < 0.05 or not) by treatment with Se and PAMK in different immune organs. However, Se only regulated the expression of TNF-alpha and IFN gamma, and PAMK influenced more cytokines in immune organs. The results showed that Se specifically regulated the TNF-alpha and IFN-gamma pathways. Therefore, Se and PAMK played different roles in improving the immune response in HS chicken. PMID- 25920438 TI - Evaluation based on Monte Carlo simulation of lifetime attributable risk of cancer after neck X-ray radiography. AB - At present, concern regarding radiation exposure is increasing with the prevalence of radiologic examination. As radiation damages the human body, we have evaluated medical radiation dose values and studied the importance of optimizing radiation exposure. We measured entrance surface dose (ESD) values using a RANDO((r)) phantom (neck) in 94 randomly selected locations in the central region of Korea. Thyroid and organ doses were calculated using Monte Carlo simulations (PCXMC 2.0.1) based on measured values. In addition, the lifetime attributable risk (LAR) of cancer was calculated for the thyroid, using the method proposed in the biological effects of ionizing radiation VII report. The average measured ESD values obtained using the RANDO((r)) phantom (neck) were antero-posterior 1.33 mGy and lateral 1.23 mGy, for a total of 2.56 mGy. Based on the ESD values measured using the phantom, the organ doses were obtained using a Monte Carlo simulation (PCXMC 2.0.1). The thyroid dose was 1.48 mSv on average. In evaluating the LAR of thyroid cancer incidence, a frequency of 0.02 per 100,000 from 2.94 per 100,000 males and a frequency of 0.10 per 100,000 from 16.23 per 100,000 females were found. The risk of cancer was found to be higher when the patient's age was lower, and was also higher in females than in males. It was concluded that beneficial exams in the medical field should not be prohibited because of a statistically small risk, although acknowledgement of the dangers of ionizing radiation is necessary. PMID- 25920439 TI - Determination of Rare Earth Elements in Hypersaline Solutions Using Low-Volume, Liquid-Liquid Extraction. AB - Complex, hypersaline brines-including those coproduced with oil and gas, rejected from desalination technologies, or used as working fluids for geothermal electricity generation-could contain critical materials such as the rare earth elements (REE) in valuable concentrations. Accurate quantitation of these analytes in complex, aqueous matrices is necessary for evaluation and implementation of systems aimed at recovering those critical materials. However, most analytical methods for measuring trace metals have not been validated for highly saline and/or chemically complex brines. Here we modified and optimized previously published liquid-liquid extraction (LLE) techniques using bis(2 ethylhexyl) phosphate as the extractant in a heptane diluent, and studied its efficacy for REE recovery as a function of three primary variables: background salinity (as NaCl), concentration of a competing species (here Fe), and concentration of dissolved organic carbon (DOC). Results showed that the modified LLE was robust to a range of salinity, Fe, and DOC concentrations studied as well as constant, elevated Ba concentrations. With proper characterization of the natural samples of interest, this method could be deployed for accurate analysis of REE in small volumes of hyper-saline and chemically complex brines. PMID- 25920440 TI - [Quality and compassion]. PMID- 25920441 TI - The effects on health of ambient particles: time for an agonizing reappraisal? PMID- 25920442 TI - Proteomic Analysis of the Endosperm Ontogeny of Jatropha curcas L. Seeds. AB - Seeds of Jatropha curcas L. represent a potential source of raw material for the production of biodiesel. However, this use is hampered by the lack of basic information on the biosynthetic pathways associated with synthesis of toxic diterpenes, fatty acids, and triacylglycerols, as well as the pattern of deposition of storage proteins during seed development. In this study, we performed an in-depth proteome analysis of the endosperm isolated from five developmental stages which resulted in the identification of 1517, 1256, 1033, 752, and 307 proteins, respectively, summing up 1760 different proteins. Proteins with similar label free quantitation expression pattern were grouped into five clusters. The biological significance of these identifications is discussed with special focus on the analysis of seed storage proteins, proteins involved in the metabolism of fatty acids, carbohydrates, toxic components and proteolytic processing. Although several enzymes belonging to the biosynthesis of diterpenoid precursors were identified, we were unable to find any terpene synthase/cyclase, indicating that the synthesis of phorbol esters, the main toxic diterpenes, does not occur in seeds. The strategy used enabled us to provide a first in depth proteome analysis of the developing endosperm of this biodiesel plant, providing an important glimpse into the enzymatic machinery devoted to the production of C and N sources to sustain seed development. PMID- 25920444 TI - Analysis of the effects of dietary fat on body and skin lipids of hamsters by Raman spectroscopy. AB - Raman spectroscopy has previously been applied for studying lipid metabolism. In this study, a ball lens-installed hollow optical fiber Raman probe (BHRP) was used for the noninvasive measurement of skin lipids in hamsters. Our analysis suggested that multi-unsaturated lipids, once converted into a structure containing conjugated double bonds, were oxidized to form peroxides. These results were applied for analyzing lipid metabolism in adipose and skin tissues in hamsters fed tricaprin, saturated medium-chain triglyceride and trilinolein, unsaturated long-chain triglyceride fat diets. Unsaturated lipids formed conjugated structures in skin tissue but not in adipose tissue. Principal component analysis (PCA) revealed that the dietary fat intake correlated strongly with lipid composition in body and skin tissues. Hence, the present results successfully demonstrate that Raman spectroscopy with a BHRP can be a powerful tool for analyzing lipid metabolism. PMID- 25920443 TI - 2015 Guidelines for Establishing Genetically Modified Rat Models for Cardiovascular Research. AB - The rat has long been a key physiological model for cardiovascular research, most of the inbred strains having been previously selected for susceptibility or resistance to various cardiovascular diseases (CVD). These CVD rat models offer a physiologically relevant background on which candidates of human CVD can be tested in a more clinically translatable experimental setting. However, a diverse toolbox for genetically modifying the rat genome to test molecular mechanisms has only recently become available. Here, we provide a high-level description of several strategies for developing genetically modified rat models of CVD. PMID- 25920445 TI - Fasciola hepatica: the redial generations in juvenile Pseudosuccinea columella. AB - Juvenile Pseudosuccinea columella, measuring 1 or 2 mm in height, were subjected to single-miracidium infections with Fasciola hepatica to determine the developmental pattern of redial generations and count free and live rediae according to their generation. Controls were constituted of juvenile Galba truncatula infected according to the same protocol. In the four groups, redial counts were performed in snails dissected every week from day 7 to day 49 post exposure at 20 degrees C. Most infected snails showed a normal development of redial generations, whatever the lymnaeid species. In P. columella, the total number of live rediae on day 49 was 24.6 and 34.6 per infected snail in the 1 and 2-mm groups, respectively (instead of 11.5 and 18.8 rediae in the corresponding groups of G. truncatula). A single mother redia (R1a) producing only daughter rediae of the second generation was noted in each snail of three groups, while the 2-mm P. columella showed the presence of a single (43 snails/71) or two (28/71) R1a redia(e) within their bodies. The mean number of other mother rediae and that of daughter rediae of the second generation were low in the 1 and 2-mm groups of both lymnaeids. Besides, there was a delay in redial development. The development of two live R1a rediae in several P. columella from the 2-mm group needs to verify if this process would be specific to P. columella or would occur in other lymnaeid species known for their good susceptibility to the digenean and their larger size to allow harbouring rediae. PMID- 25920446 TI - Inhibitory effects of peroxisome proliferator-activated receptor gamma agonists on collagen IV production in podocytes. AB - Peroxisome proliferator-activated receptor-gamma (PPAR-gamma) agonists have beneficial effects on the kidney diseases through preventing microalbuminuria and glomerulosclerosis. However, the mechanisms underlying these effects remain to be fully understood. In this study, we investigate the effects of PPAR-gamma agonist, rosiglitazone (Rosi) and pioglitazone (Pio), on collagen IV production in mouse podocytes. The endogenous expression of PPAR-gamma was found in the primary podocytes and can be upregulated by Rosi and Pio, respectively, detected by RT-PCR and Western blot. PPAR-gamma agonist markedly blunted the increasing of collagen IV expression and extraction in podocytes induced by TGF-beta. In contrast, adding PPAR-gamma antagonist, GW9662, to podocytes largely prevented the inhibition of collagen IV expression from Pio treatment. Our data also showed that phosphorylation of Smad2/3 enhanced by TGF-beta in a time-dependent manner was significantly attenuated by adding Pio. The promoter region of collagen IV gene contains one putative consensus sequence of Smad-binding element (SBE) by promoter analysis, Rosi and Pio significantly ameliorated TGF-beta-induced SBE4 luciferase activity. In conclusion, PPAR-gamma activation by its agonist, Rosi or Pio, in vitro directly inhibits collagen IV expression and synthesis in primary mouse podocytes. The suppression of collagen IV production was related to the inhibition of TGF-beta-driven phosphorylation of Smad2/3 and decreased response activity of SBEs of collagen IV in PPAR-gamma agonist-treated mouse podocytes. This represents a novel mechanistic support regarding PPAR-gamma agonists as podocyte protective agents. PMID- 25920448 TI - Roles of miRNA-24 in regulating endothelial nitric oxide synthase expression and vascular endothelial cell proliferation. AB - This study is to investigate the effect of miRNA-24 on endothelial nitric oxide synthase (eNOS) expression and vascular endothelial cell proliferation. Constructed high expression miRNA-24 plasmids were introduced into human umbilical vein endothelial cells (HUVECs) by liposome. Cell numbers were counted by a Hemocytometer, and cell proliferation was detected by MTT assay. The expression levels of eNOS and specificity protein 1 (Sp1) at mRNA and protein levels were, respectively, examined by real-time PCR, immunohistochemistry, and Western blotting. Compared with the control group, endothelial cell proliferation in miRNA-24 group significantly decreased by 64.24 % (6.53 +/- 0.11 vs 18.26 +/- 0.45, P < 0.01). The expression of eNOS at mRNA and protein levels in miRNA-24 group decreased by 64.21 % (0.34 +/- 0.01 vs 0.95 +/- 0.02, P < 0.05) and 82.86 % (0.072 +/- 0.06 vs 0.42 +/- 0.06, P < 0.05), respectively. Meanwhile, the expression of Sp1 at mRNA and protein levels in miRNA-24 group decreased by 64.64 % (0.35 +/- 0.01 vs 0.99 +/- 0.03, P < 0.05) and 60.34 % (0.23 +/- 0.05 vs 0.58 +/- 0.07, P < 0.05), respectively. In anti-miRNA-24 group, endothelial cell proliferation decreased by 33.46 % compared with the control group (12.15 +/- 0.21 vs 18.26 +/- 0.45, P < 0.01), while it increased by 46.25 % compared with the miRNA-24 group (12.15 +/- 0.21 vs 6.53 +/- 0.11, P < 0.01). The expression of eNOS at mRNA and protein levels in anti-miRNA-24 group decreased by 44.21 % (0.53 +/- 0.04 vs 0.95 +/- 0.02, P < 0.05) and by 30.95 %(0.29 +/- 0.05 vs 0.42 +/- 0.06, P < 0.05) compared with the control group, while it increased by 35.84 % (0.53 +/- 0.04 vs 0.34 +/- 0.01, P < 0.05) and by 75.17 % (0.29 +/- 0.05 vs 0.072 +/- 0.06, P < 0.05) compared with miRNA-24 group. The expression of Sp1 at mRNA and protein levels in ant-miRNA-24 group decreased by 36.36 % (0.63 +/- 0.04 vs 0.99 +/- 0.03, P < 0.05) and by 22.41 % (0.45 +/- 0.06 vs 0.58 +/- 0.07, P < 0.05) compared with the control group, while it increased by 44.44 % (0.63 +/- 0.04 vs 0.35 +/- 0.01, P < 0.05) and by 48.88 % (0.45 +/- 0.06 vs 0.23 +/- 0.05, P < 0.05) compared with miRNA-24 group. HUVECs proliferation and eNOS expression are significantly inhibited by miRNA-24. Sp1, which is regulated by miRNA-24, might act as one of the important factors involved in eNOS gene expression. PMID- 25920447 TI - Nano-Se attenuates cyclophosphamide-induced pulmonary injury through modulation of oxidative stress and DNA damage in Swiss albino mice. AB - Chemotherapy is an integral part of modern day treatment regimen but anticancer drugs fail to demarcate between cancerous and normal cells thereby causing severe form of systemic toxicity. Among which pulmonary toxicity is a dreadful complication developed in cancer patients upon cyclophosphamide (CP) therapy. Oxidative stress, fibrosis, and apoptosis are the major patho-mechanisms involved in CP-induced pulmonary toxicity. In the present study, we have synthesized Nano Se, nanotechnology-based new form of elemental selenium which has significantly lower toxicity and acceptable bioavailability. In order to meet the need of effective drugs against CP-induced adverse effects, nano selenium (Nano-Se) was tested for its possible protective efficacy on CP-induced pulmonary toxicity and bone marrow toxicity. CP intoxication resulted in structural and functional lung impairment which was revealed by massive histopathological changes. Lung injury was associated with oxidative stress/lipid peroxidation as evident by increased in reactive oxygen species, nitric oxide level, and malondialdehyde (MDA) formation with decreased in level of antioxidants such as reduced glutathione, glutathione-S-transferase, glutathione peroxidase, superoxide dismutase, and catalase. Furthermore, CP at a dose of 25 mg/kg b.w. increased pulmonary DNA damage ('comet tail') and triggered DNA fragmentation and apoptosis in mouse bone marrow cells. On the other hand, Nano-Se at a dose of 2 mg Se/kg b.w., significantly inhibited CP-induced DNA damage in bronchoalveolar lavage cells, and decreased the apoptosis and percentage of DNA fragmentation in bone marrow cells and also antagonized the reduction of the activities of antioxidant enzymes and the increase level of MDA. Thus, our results suggest that Nano-Se in pre- and co-administration may serve as a promising preventive strategy against CP-induced pulmonary toxicity. PMID- 25920449 TI - A CD63(+ve)/c-kit(+ve) stem cell population isolated from the mouse heart. AB - Cardiac cell regeneration from endogenous cardiac stem cells (CSCs) following MI is rather low. Therefore, identifying mechanisms to boost endogenous CSC activation and participation in cardiac repair appears to be the most promising strategy for MI patients. We previously engineered tissue inhibitor of metalloproteinases-1 (TIMP-1) overexpressing embryonic stem (ES-TIMP-1) cells and transplanted them into the infarcted murine heart. Collected data demonstrated that TIMP-1 enhanced transplanted ES cell engraftment, survival and differentiation into cardiac myocytes post-transplantation. Therefore, we postulated that there may be a new stem cell population present in the heart that is regulated by extracellular protein TIMP-1. Furthermore, we hypothesized that this cell population has a potential for cell proliferation and differentiation into cardiac cell types. Therefore, we isolated CSCs from 4 weeks old C57BL/6 mice and cultured them in vitro in presence of ESCM, ES-TIMP-1-CM or TIMP-1. Our immunostaining data demonstrated the existence of a novel CSC subpopulation, CD63(+ve)/c-kit(+ve). When treated with TIMP-1, these cells showed significantly (p < 0.05) increased proliferation rates compared to control cells, enhanced TIMP 1 receptor (CD63), along with improved expression of phospho and total beta catenin proteins as demonstrated by Western blot analysis. Next, we demonstrate significantly (p < 0.05) improved cardiac myocyte, vascular smooth muscle cell, and endothelial cell differentiation. Furthermore, our RT-PCR data shows increase in cardiac gene (GATA-4, Mef2C, and Nkx-2.5) expression when compared to ESCM and control cells. Collectively, these data, for the first time, establish the existence of a new CD63(+ve)/c-kit(+ve) CSC subpopulation that has a significant potential for proliferation and differentiation into cardiac cell types once stimulated with TIMP-1. PMID- 25920450 TI - Molecular-level understanding of the adsorption mechanism of a graphite-binding peptide at the water/graphite interface. AB - The association of proteins and peptides with inorganic material has vast technological potential. An understanding of the adsorption of peptides at liquid/solid interfaces on a molecular-level is fundamental to fully realising this potential. Combining our prior work along with the statistical analysis of 100+ molecular dynamics simulations of adsorption of an experimentally identified graphite binding peptide, GrBP5, at the water/graphite interface has been used here to propose a model for the adsorption of a peptide at a liquid/solid interface. This bottom-up model splits the adsorption process into three reversible phases: biased diffusion, anchoring and lockdown. Statistical analysis highlighted the distinct roles played by regions of the peptide studied here throughout the adsorption process: the hydrophobic domain plays a significant role in the biased diffusion and anchoring phases suggesting that the initial impetus for association between the peptide and the interface may be hydrophobic in origin; aromatic residues dominate the interaction between the peptide and the surface in the adsorbed state and the polar region in the middle of the peptide affords a high conformational flexibility allowing strongly interacting residues to maximise favourable interactions with the surface. Reversible adsorption was observed here, unlike in our prior work focused on a more strongly interacting surface. However, this reversibility is unlikely to be seen once the peptide surface interaction exceeds 10 kcal mol(-1). PMID- 25920451 TI - Mechanical properties of self-assembled nanoparticle membranes: stretching and bending. AB - Monolayers composed of colloidal nanoparticles, with a thickness of less than ten nanometers, have remarkable mechanical strength and can suspend over micron-sized holes to form free-standing membranes. We discuss experiments probing the tensile strength and bending stiffness of these self-assembled nanoparticle sheets. The fracture behavior of monolayers and multilayers is investigated by attaching them to elastomer substrates which are then stretched. For different applied strain, the fracture patterns are imaged down to the scale of single particles. The resulting detailed information about the crack width distribution allows us to relate the measured overall tensile strength to the distribution of local bond strengths within a layer. We then introduce two methods by which freestanding nanoparticle monolayers can be rolled up into hollow, tubular "nano-scrolls", either by electron beam irradiation during imaging with a scanning electron microscope or by spontaneous self-rolling. Indentation measurements on the nano scrolls yield values for the bending stiffness that are significantly larger than expected from the response to stretching. The ability to stretch, bend, and roll up nanoparticle sheets offers new possibilities for a variety of applications, including sensors and mechanical transducers. PMID- 25920452 TI - Fumarates modulate microglia activation through a novel HCAR2 signaling pathway and rescue synaptic dysregulation in inflamed CNS. AB - Dimethyl fumarate (DMF), recently approved as an oral immunomodulatory treatment for relapsing-remitting multiple sclerosis (MS), metabolizes to monomethyl fumarate (MMF) which crosses the blood-brain barrier and has demonstrated neuroprotective effects in experimental studies. We postulated that MMF exerts neuroprotective effects through modulation of microglia activation, a critical component of the neuroinflammatory cascade that occurs in neurodegenerative diseases such as MS. To ascertain our hypothesis and define the mechanistic pathways involved in the modulating effect of fumarates, we used real-time PCR and biochemical assays to assess changes in the molecular and functional phenotype of microglia, quantitative Western blotting to monitor activation of postulated pathway components, and ex vivo whole-cell patch clamp recording of excitatory post-synaptic currents in corticostriatal slices from mice with experimental autoimmune encephalomyelitis (EAE), a model for MS, to study synaptic transmission. We show that exposure to MMF switches the molecular and functional phenotype of activated microglia from classically activated, pro inflammatory type to alternatively activated, neuroprotective one, through activation of the hydroxycarboxylic acid receptor 2 (HCAR2). We validate a downstream pathway mediated through the AMPK-Sirt1 axis resulting in deacetylation, and thereby inhibition, of NF-kappaB and, consequently, of secretion of pro-inflammatory molecules. We demonstrate through ex vivo monitoring of spontaneous glutamate-mediated excitatory post-synaptic currents of single neurons in corticostriatal slices from EAE mice that the neuroprotective effect of DMF was exerted on neurons at pre-synaptic terminals by modulating glutamate release. By exposing control slices to untreated and MMF-treated activated microglia, we confirm the modulating effect of MMF on microglia function and, thereby, its indirect neuroprotective effect at post-synaptic level. These findings, whereby DMF-induced activation of a new HCAR2-dependent pathway on microglia leads to the modulation of neuroinflammation and restores synaptic alterations occurring in EAE, represent a possible novel mechanism of action for DMF in MS. PMID- 25920453 TI - Transitional care in clinical networks for young people with juvenile idiopathic arthritis: current situation and challenges. AB - Clinical networks for paediatric and adolescent rheumatology are evolving, and their effect and role in the transition process between paediatric and adult services are unknown. We therefore explored the experiences of those involved to try and understand this further. Health professionals, young people with juvenile idiopathic arthritis and their families were recruited via five national health service paediatric and adolescent rheumatology specialist centres and networks across the UK. Seventy participants took part in focus groups and one-to-one interviews. Data was analysed using coding, memoing and mapping techniques to identify features of transitional services across the sector. Variation and inequities in transitional care exist. Although transition services in networks are evolving, development has lagged behind other areas with network establishment focusing more on access to paediatric rheumatology multidisciplinary teams. Challenges include workforce shortfalls, differences in service priorities, standards and healthcare infrastructures, and managing the legacy of historic encounters. Providing equitable high-quality clinically effective services for transition across the UK has a long way to go. There is a call from within the sector for more protected time, staff and resources to develop transition roles and services, as well as streamlining of local referral pathways between paediatric and adult healthcare services. In addition, there is a need to support professionals in developing their understanding of transitional care in clinical networks, particularly around service design, organisational change and the interpersonal skills required for collaborative working. Key messages * Transitional care in clinical networks requires collaborative working and an effective interface with paediatric and adult rheumatology.* Professional centrism and historic encounters may affect collaborative relationships within clinical networks.* Education programmes need to support the development of interpersonal skills and change management, to facilitate professionals in networks delivering transitional care. PMID- 25920455 TI - Comparison of the repeatability of GABA-edited magnetic resonance spectroscopy with and without macromolecule suppression. AB - PURPOSE: The inhibitory neurotransmitter gamma-aminobutyric acid (GABA) can be measured in vivo using edited magnetic resonance spectroscopy (MRS), but quantification suffers from contamination by macromolecules (MM). It is possible to suppress this contamination using symmetric editing, but this procedure potentially compromises reliability of the GABA measurement. The aim of this study was to compare the repeatability of GABA-edited MRS with and without MM suppression. METHODS: GABA' (non-MM contaminated) and GABA'+MM (MM-contaminated) concentration was measured in the occipital lobe (OCC) and anterior cingulate (AC) using symmetric and standard editing (n = 15). Each method was performed twice in each region. RESULTS: Within-participant coefficients of variation for each technique were 4.0% (GABA'+MM) and 8.6% (GABA') in the OCC and 14.8% (GABA'+MM) and 12.6% (GABA') in the AC. Intraclass correlation coefficients were better for the suppression method than standard editing in both the OCC (0.72 versus 0.67) and AC (0.41 versus 0.16). These findings were replicated in the OCC of a second cohort (n = 15). CONCLUSION: Symmetric suppression is shown to be comparable in repeatability to standard GABA-editing. Measuring a purer quantification of GABA becomes increasingly important as more research is conducted on links between GABA concentration, pathology and healthy behavior. PMID- 25920454 TI - Single nucleotide polymorphism of toll-like receptor 4 (TLR4) is associated with juvenile spondyloarthritis in Croatian population. AB - Single nucleotide polymorphisms (SNP) of toll-like and NOD-like receptors have been associated with altered receptor activity and modified production of proinflammatory cytokines leading to a number of diseases. Our aim was to determine whether SNP of TLR2 (Arg753Gln), TLR4 (Asp299Gly, Thr399Ile), and NLRP3 (Q705K) influence susceptibility to juvenile spondyloarthrtis (jSpA) and juvenile idiopathic arthritis (JIA). After the DNA extraction, 26 patients with jSpA, 11 with oligoarticular, polyarticular, or systemic JIA, and 40 healthy controls were genotyped for Arg753Gln, Asp299Gly, Thr399Ile, and Q705K SNP using real-time PCR SNP analysis. Statistically significant difference in genotype frequency for Thr399Ile SNP of TLR4 was observed in the jSpA (chi2 = 6.705, p = 0.035) and not in the JIA group (chi2 = 3005, p = 0.223). Regarding Asp299Gly SNP, no significant difference in genotype frequency was found; however, allele frequency was significant in both jSpA and JIA patients. No significant difference in genotype or allele frequency was observed for Arg735Gln and Q705K SNP. The399Ile polymorphism of TLR4 may be responsible for altered immune response to microbial infection in variant carriers and represent a mechanism of triggering overproduction of proinflammatory cytokines and long-term inflammation in jSpA. SNP of TLR2, NLRP3, and TLR4 (Asp299Gly) were not associated with jSpA or JIA. PMID- 25920456 TI - Photoluminescence and thermoluminescence studies of CaAl2O4:Dy(3+) phosphor. AB - Calcium aluminate phosphors activated by Dy(3+) have been prepared by a combustion method at a temperature of 600 degrees C. Photoluminescence (PL) and thermoluminescence (TL) properties of gamma-irradiated Dy-doped calcium aluminate were investigated. The PL spectrum shows a broad peak around 488 nm and 573 nm, under 347 nm excitation. Thermoluminescence studies were performed for different concentrations of Dy. Optimum intensity of photoluminescence was found for 0.02 mol% concentration of Dy. It was found that initially the peak TL intensity increases with increasing concentration of Dy in the CaAl2O4 host, attains a maximum value for 0.05 mol% concentration and decreases with further increase in the doping concentration due to concentration quenching. PMID- 25920457 TI - Heterogeneous catalytic conversion of CO2: a comprehensive theoretical review. AB - The conversion of CO2 into fuels and useful chemicals has been intensively pursued for renewable, sustainable and green energy. However, due to the negative adiabatic electron affinity (EA) and large ionization potential (IP), the CO2 molecule is chemically inert, thus making the conversion difficult under normal conditions. Novel catalysts, which have high stability, superior efficiency and low cost, are urgently needed to facilitate the conversion. As the first step to design such catalysts, understanding the mechanisms involved in CO2 conversion is absolutely indispensable. In this review, we have summarized the recent theoretical progress in mechanistic studies based on density functional theory, kinetic Monte Carlo simulation, and microkinetics modeling. We focus on reaction channels, intermediate products, the key factors determining the conversion of CO2 in solid-gas interface thermocatalytic reduction and solid-liquid interface electrocatalytic reduction. Furthermore, we have proposed some possible strategies for improving CO2 electrocatalysis and also discussed the challenges in theory, model construction, and future research directions. PMID- 25920460 TI - Constructing the next 50 years of nurse practitioner history. PMID- 25920461 TI - Hydrogen bonding motifs in a hydroxy-bisphosphonate moiety: revisiting the problem of hydrogen bond identification. AB - Bisphosphonates are important therapeutic agents in bone-related diseases and exhibit complex H-bonding networks. To assess the role of H-bonds in biophosphonate stability, a full conformational search was performed for methylenebisphosphonate (MBP) and 1-hydroxyethylidene-1,1-diphosphonate (HEDP) using the MP2 method in conjunction with the continuum solvation model. The most stable structures and their equilibrium populations were analyzed at two protonation states via assignment of H-bonding motifs to each conformer. Geometrical and topological approaches for the identification and characterization of H-bonds were compared with each other, and some of the important correlations between H-bond features were described over the entire conformational space of a hydroxy-bisphosphonate moiety. The topologically derived H-bond energy obtained from the local density of potential energy at bond critical points shows consistent correlations with other measures such as H-bond frequency shift. An inverse power form without an intercept predicts topological H-bond energies from hydrogen-acceptor distances with an RMS error of less than 1 kcal mol(-1). The consistency of this measure was further checked by building a model that reasonably reproduces the relative stabilities of different conformers from their hydrogen-acceptor distances. In all systems, the predictions of this model are improved by the consideration of weak H-bonds that have no bond critical point. PMID- 25920462 TI - Re: Video-assisted thoracoscopic surgery versus open lobectomy for primary non small-cell lung cancer: a propensity-matched analysis of outcome from the European Society of Thoracic Surgeon database. PMID- 25920463 TI - How are you feeling today? Quality of life after aortic surgery. PMID- 25920464 TI - Functionality of kumquat (Fortunella margarita) in the production of fruity ice cream. AB - BACKGROUND: The aim of this study was to investigate the effect of kumquat (Fortunella margarita) on the quality characteristics of ice cream. Kumquat paste (KP) was added to an ice cream mix at four concentrations, 0 (control), 5, 10 and 15% (w/w), for ice cream production. RESULTS: The increment of KP level caused an increase in acidity, vitamin C content, b* value and overrun value compared with the control ice cream. The apparent viscosity of samples decreased with the addition of KP at concentrations of 5 and 10% compared with the control. Results indicated that lyophilized water extract of KP (LKE) contained remarkable phenolic compounds. It was observed that LKE exhibited moderate in vitro antioxidant capacity. KP enhanced the color, flavor, vitamin C content and Mg and K contents of the ice cream. The addition of KP positively affected the sensory properties. CONCLUSION: KP may be used as a suitable source of natural color and flavor agent in ice cream production. KP enhanced the vitamin C content and Mg and K contents of ice cream and improved its sensory properties. PMID- 25920465 TI - Alpha-Linolenic Acid-Induced Increase in Neurogenesis is a Key Factor in the Improvement in the Passive Avoidance Task After Soman Exposure. AB - Exposure to organophosphorous (OP) nerve agents such as soman inhibits the critical enzyme acetylcholinesterase (AChE) leading to excessive acetylcholine accumulation in synapses, resulting in cholinergic crisis, status epilepticus and brain damage in survivors. The hippocampus is profoundly damaged after soman exposure leading to long-term memory deficits. We have previously shown that treatment with three sequential doses of alpha-linolenic acid, an essential omega 3 polyunsaturated fatty acid, increases brain plasticity in naive animals. However, the effects of this dosing schedule administered after a brain insult and the underlying molecular mechanisms in the hippocampus are unknown. We now show that injection of three sequential doses of alpha-linolenic acid after soman exposure increases the endogenous expression of mature BDNF, activates Akt and the mammalian target of rapamycin complex 1 (mTORC1), increases neurogenesis in the subgranular zone of the dentate gyrus, increases retention latency in the passive avoidance task and increases animal survival. In sharp contrast, while soman exposure also increases mature BDNF, this increase did not activate downstream signaling pathways or neurogenesis. Administration of the inhibitor of mTORC1, rapamycin, blocked the alpha-linolenic acid-induced neurogenesis and the enhanced retention latency but did not affect animal survival. Our results suggest that alpha-linolenic acid induces a long-lasting neurorestorative effect that involves activation of mTORC1 possibly via a BDNF-TrkB-mediated mechanism. PMID- 25920467 TI - Safety and Tolerability of Lisdexamfetamine: A Retrospective Cohort Study. AB - BACKGROUND: Attention-deficit hyperactivity disorder (ADHD) is a common neurobehavioural disorder in children. Pharmacotherapy plays a main role in multimodal treatment, albeit adverse effects are a concern. Lisdexamfetamine is a newer pharmacological option and post-marketing studies on adverse events are limited. OBJECTIVE: The aim of this study was to investigate the treatment emergent adverse events (TEAEs) in patients receiving lisdexamfetamine in a clinical setting. METHODS: We performed a retrospective cohort study at the Department of Child and Adolescent Psychiatry of Glostrup Hospital in Copenhagen, Denmark. We included all consecutive patients >6 years old, with an ICD-10 diagnosis of ADHD who were initiated on lisdexamfetamine between May 2013 and July 2014. TEAEs were assessed by a clinician and chart audit. RESULTS: Forty three patients (91 % male) with a median age of 11 (range 8-15) years were included and received lisdexamfetamine for a median of 188 days (range 3-433). In total, 23.3 % of the patients discontinued treatment due to a TEAE. 88 % of the patients experienced at least one TEAE and the time to first TEAE <=4 weeks in 83.8 % of the patients. A new TEAE was experienced by 39.5 % of the patients compared with the TEAEs that patients had experienced when taking previous ADHD medication. The most common TEAEs (>= 5 %) were decreased appetite, difficulty falling asleep, tics, stomach ache and weight loss. A subjectively assessed good or good but time-limited (during the day only) effect was observed in 62.7 %. CONCLUSION: Lisdexamfetamine treatment in this small group of patients who had received previous stimulant medication for ADHD was well tolerated and the TEAEs were consistent with findings in previous trials, although more than one third of the patients experienced TEAEs not observed with previously taken ADHD medication. Both the number of patients experiencing TEAEs and the rates of discontinuation due to TEAEs were higher than previously reported. PMID- 25920466 TI - Neuronal Network Oscillations in Neurodegenerative Diseases. AB - Cognitive and behavioral acts go along with highly coordinated spatiotemporal activity patterns in neuronal networks. Most of these patterns are synchronized by coherent membrane potential oscillations within and between local networks. By entraining multiple neurons into a common time regime, such network oscillations form a critical interface between cellular activity and large-scale systemic functions. Synaptic integrity is altered in neurodegenerative diseases, and it is likely that this goes along with characteristic changes of coordinated network activity. This notion is supported by EEG recordings from human patients and from different animal models of such disorders. However, our knowledge about the pathophysiology of network oscillations in neurodegenerative diseases is surprisingly incomplete, and increased research efforts are urgently needed. One complicating factor is the pronounced diversity of network oscillations between different brain regions and functional states. Pathological changes must, therefore, be analyzed separately in each condition and affected area. However, cumulative evidence from different diseases may result, in the future, in more unifying "oscillopathy" concepts of neurodegenerative diseases. In this review, we report present evidence for pathological changes of network oscillations in Alzheimer's disease (AD), one of the most prominent and challenging neurodegenerative disorders. The heterogeneous findings from AD are contrasted to Parkinson's disease, where motor-related changes in specific frequency bands do already fulfill criteria of a valid biomarker. PMID- 25920469 TI - Chemical composition and larvicidal activity of Zanthoxylum armatum against diamondback moth, Plutella xylostella. AB - The diamondback moth, Plutella xylostella (L.) (Lepidoptera: Yponomeutidae) is the most serious pest of cruciferous crops grown in the world causing economic yield loss. Several synthetic insecticides have been used against P. xylostella but satisfactory control was not achieved due to development of resistance to insecticides. Therefore, the present study was carried out to screen different fractions of Zanthoxylum armatum for their insecticidal activities against second instar larvae of P. xylostella. Results indicate, all the fractions showed activity to P. xylostella. However, n-hexane fraction of Z. armatum showed maximum larvicidal activity with minimum LC50 value of 2988.6 ppm followed by ethanol (LC50 = 12779.7 ppm) and methanol fraction (LC50 = 12908.8 ppm) whereas chloroform fraction was least toxic (LC50 = 16750.6 ppm). The GC-MS analysis of n hexane fraction of leaf extract showed maximum larvicidal activity, which may be due to two major compounds i.e. 2-undecanone (19.75%) and 2-tridecanone (11.76%). PMID- 25920468 TI - Picture Good Health: A Church-Based Self-Management Intervention Among Latino Adults with Diabetes. AB - BACKGROUND: Churches may provide a familiar and accessible setting for chronic disease self-management education and social support for Latinos with diabetes. OBJECTIVE: We assessed the impact of a multi-faceted church-based diabetes self management intervention on diabetes outcomes among Latino adults. DESIGN: This was a community-based, randomized controlled, pilot study. SUBJECTS: One-hundred adults with self-reported diabetes from a Midwestern, urban, low-income Mexican American neighborhood were included in the study. INTERVENTIONS: Intervention participants were enrolled in a church-based diabetes self-management program that included eight weekly group classes led by trained lay leaders. Enhanced usual care participants attended one 90-minute lecture on diabetes self management at a local church. OUTCOME MEASURES: The primary outcome was change in glycosylated hemoglobin (A1C). Secondary outcomes included changes in low-density lipoproteins (LDL), blood pressure, weight, and diabetes self-care practices. KEY RESULTS: Participants' mean age was 54 +/- 12 years, 81 % were female, 98 % were Latino, and 51 % were uninsured. At 3 months, study participants in both arms decreased their A1C from baseline (-0.32 %, 95 % confidence interval [CI]: -0.62, -0.02 %). The difference in change in A1C, LDL, blood pressure and weight from baseline to 3-month and 6-month follow-up was not statistically significant between the intervention and enhanced usual care groups. Intervention participants reported fewer days of consuming high fat foods in the previous week (-1.34, 95 % CI: -2.22, -0.46) and more days of participating in exercise (1.58, 95 % CI: 0.24, 2.92) compared to enhanced usual care from baseline to 6 months. CONCLUSIONS: A pilot church-based diabetes self-management intervention did not reduce A1C, but resulted in decreased high fat food consumption and increased participation in exercise among low-income Latino adults with diabetes. Future church-based interventions may need to strengthen linkages to the healthcare system and provide continued support to participants to impact clinical outcomes. PMID- 25920470 TI - Effect of motor training involving the less-affected side (MTLA) in post-stroke subjects: a pilot randomized controlled trial. AB - INTRODUCTION: Poststroke, less-severe motor impairment occurs on the ipsilesional side of body. The objective of the present study was to evaluate the effectiveness of the motor training involving the less-affected side (MTLA) in stroke. METHODS: This was a randomized, controlled, double-blinded pilot study conducted in the occupational therapy unit of a rehabilitation Institute. A convenience sample of 35 stroke subjects (mean poststroke duration, 28.76 weeks) was randomized into two groups (the experimental group: 17 and control group: 18). Thirty-two participants completed the entire study protocol. The experimental group and control group were provided MTLA and neurophysiological based conventional therapy respectively. Both the groups received 24 treatment sessions (60 minutes each) over the period of two months. The Affected side was assessed using Brunnstrom recovery stage (BRS) and Fugl-Meyer assessment (FMA) whereas the less-affected side was evaluated by Minnesota manual dexterity test (MMDT), Purdue peg board test (PPBT) and Manual Muscle Testing (MMT). RESULTS: Postintervention, the less-affected side of experimental group demonstrated significant improvement for MMDT (P = 0.003), PPBT (P = 0.01) and MMT (P < 0.001 to 0.043) in comparison to the control group. Further, as compared to the control group, the experimental group exhibited positive significant change for the measure of affected side [BRS (P < 0.001) and FMA (P < 0.001 to 0.03)] at post assessment. CONCLUSION: MTLA enhanced the muscle strength, dexterity and coordination of the less-affected side as well as the motor recovery of the affected side in poststroke hemiparetic subjects. PMID- 25920471 TI - [Complications in thoracic surgery : reports from experienced thoracic surgeons]. PMID- 25920473 TI - [Increased mortality due to lack of experience with minimally invasive pancreatoduodenectomy]. PMID- 25920472 TI - [Persistent pleural effusion following thoracic surgery]. AB - BACKGROUND: Persistent postoperative pleural effusion can occur after thoracic surgery and might lead to progressive dyspnea with a subsequent complicated and prolonged hospital stay. OBJECTIVES: The etiology, prevention and therapy of persistent pleural effusion after thoracic surgical interventions are presented. MATERIAL AND METHODS: A selective literature search was carried out in Medline (pleural effusion, pleural empyema and chylothorax). RESULTS: Persistent pleural effusions were observed especially after lung resection due to disorders in the pleural fluid balance and reduced postoperative lung expansion. An adequate chest tube management and postoperative physical therapy can reduce the incidence of postoperative pleural effusion. Relevant postoperative bleeding causes a hemothorax. An infection of the pleural effusion is defined as pleural empyema. These patients suffer from a significantly higher postoperative morbidity and require an adjusted multimodal treatment. Intraoperative injury of the thoracic duct can result in a postoperative chylothorax, which should be diagnosed early with specific laboratory investigations of the milky fluid. Interventional radiological procedures have now taken their place alongside conservative measures and surgical procedures in the therapy of chylothorax. CONCLUSION: Persistent postoperative pleural effusion after thoracic surgical interventions warrant early diagnosis and an adjusted treatment in order to avoid further complications and to shorten the postoperative hospital stay. PMID- 25920474 TI - [Intra-arterial and systemic administration of chemotherapy for unresectable liver metastases from colorectal carcinoma]. PMID- 25920475 TI - [Risk factors for colorectal anastomotic leaks]. PMID- 25920476 TI - An Electrochemical Cell for Selective Lithium Capture from Seawater. AB - Lithium (Li) is a core element of Li-ion batteries (LIBs). Recent developments in mobile electronics such as smartphones and tablet PCs as well as advent of large scale LIB applications including electrical vehicles and grid-level energy storage systems have led to an increase in demand for LIBs, giving rise to a concern on the availability and market price of Li resources. However, the current Lime-Soda process that is responsible for greater than 80% of worldwide Li resource supply is applicable only in certain regions on earth where the Li concentrations are sufficiently high (salt lakes or salt pans). Moreover, not only is the process time-consuming (12-18 months), but post-treatments are also required for the purification of Li. Here, we have devised a location-independent electrochemical system for Li capture, which can operate within a short time period (a few hours to days). By engaging olivine LiFePO4 active electrode that improves interfacial properties via polydopamine coating, the electrochemical cell achieves 4330 times amplification in Li/Na ion selectivity (Li/Na molar ratio of initial solution = 0.01 and Li/Na molar ratio of final electrode = 43.3). In addition, the electrochemical system engages an I(-)/I3(-) redox couple in the other electrode for balancing of the redox states on both electrode sides and sustainable operations of the entire cell. Based on the electrochemical results, key material and interfacial properties that affect the selectivity in Li capture are identified. PMID- 25920477 TI - Usefulness of notched duration to predict response to cardiac resynchronization therapy. AB - OBJECTIVES: The presence of notches in the biventricular paced QRS complex (BiP QRS) from the posterolateral cardiac vein displays delays in the activation of the left ventricle and may consequently be linked with longer times of stimulus conduction. Our objective was to determine the relationship between the notch duration >= 0.1 mV in the BiP-QRS and the effectiveness of cardiac resynchronization therapy (CRT). DESIGN: A total of 210 patients, who underwent de novo CRT implantation previously and had >= 1 follow-up between August 2009 and February 2014, were enrolled in the study. Echocardiographic response to CRT was defined as "an increase of >= 5% in ejection fraction" and clinical response to CRT was defined as "an improvement >= 1 in New York Heart Association class without heart failure hospitalization after 6 months of CRT implantation." RESULTS: At a mean follow-up of 9.2 +/- 2.1 months, 142 patients (67%) were classified as responders to CRT. BiP-QRS duration was significantly longer among non-responders compared with responders (p = 0.036). More of the non-responders have notched in their BiP-QRS than responders (63% vs. 40%, p = 0.002). Median duration of notch was significantly higher among non-responders (80 ms vs. 67.5 ms, p = 0.041). Notch duration > 67.5 ms was associated with 2.8 times higher non response to therapy (odds ratio: 2.8; 95% confidence interval: 1.075-7.588, p = 0.035). CONCLUSIONS: Patients with notch duration greater than 67.5 ms are associated with poor response to CRT. Notch duration > 67.5 ms predicts non response to therapy with 50.0% specificity and 72.1% sensitivity. PMID- 25920478 TI - Can (and should) Africa make its own medicines? PMID- 25920480 TI - Hierarchical structured alpha-Al2O3 supported S-promoted Fe catalysts for direct conversion of syngas to lower olefins. AB - Hierarchical structured alpha-Al2O3 is shown to be able to effectively disperse and immobilize iron species, in comparison with commercial alpha-Al2O3. After promotion using an appropriate amount of sulfur, iron catalysts exhibit not only enhanced Fischer-Tropsch synthesis activity and selectivity toward lower olefins, but also increased resistance against carbon deposits. PMID- 25920479 TI - AZD3514, an oral selective androgen receptor down-regulator in patients with castration-resistant prostate cancer - results of two parallel first-in-human phase I studies. AB - BACKGROUND: AZD3514 is a first-in-class, orally bio-available, androgen-dependent and -independent androgen receptor inhibitor and selective androgen-receptor down regulator (SARD). METHODS: In study 1 and 2, castration-resistant prostate cancer (CRPC) patients (pts) were initially recruited into a once daily (QD) oral schedule (A). In study 1, pharmacokinetic assessments led to twice daily (BID) dosing (schedule B) to increase exposure. Study 2 explored a once daily schedule. RESULTS: In study 1, 49 pts were treated with escalating doses of AZD3514 (A 35 pts, B 14 pts). Starting doses were 100 mg (A) and 1000 mg (B). The AZD3514 formulation was switched from capsules to tablets at 1000 mg QD. 2000 mg BID was considered non-tolerable due to grade (G) 2 toxicities (nausea [N], vomiting [V]). No adverse events (AEs) met the dose-limiting toxicity (DLT) definition. Thirteen pts received AZD3514 in study 2, with starting doses of 250 mg QD. The most frequent drug-related AEs were N: G1/2 in 55/70 pts (79 %); G3 in 1 pt (1.4 %); & V: G1/2 in 34/70 pts (49 %) & G3 in 1 pt (1.4 %). PSA declines (>=50 %) were documented in 9/70 patients (13 %). Objective soft tissue responses per RECIST1.1 were observed in 4/24 (17 %) pts in study 1. CONCLUSION: AZD3514 has moderate anti-tumour activity in pts with advanced CRPC but with significant levels of nausea and vomiting. However, anti-tumour activity as judged by significant PSA declines, objective responses and durable disease stabilisations, provides the rationale for future development of SARD compounds. PMID- 25920481 TI - Hopelessly mortal: The role of mortality salience, immortality and trait self esteem in personal hope. AB - Do people lose hope when thinking about death? Based on Terror Management Theory, we predicted that thoughts of death (i.e., mortality salience) would reduce personal hope for people low, but not high, in self-esteem, and that this reduction in hope would be ameliorated by promises of immortality. In Studies 1 and 2, mortality salience reduced personal hope for people low in self-esteem, but not for people high in self-esteem. In Study 3, mortality salience reduced hope for people low in self-esteem when they read an argument that there is no afterlife, but not when they read "evidence" supporting life after death. In Study 4, this effect was replicated with an essay affirming scientific medical advances that promise immortality. Together, these findings uniquely demonstrate that thoughts of mortality interact with trait self-esteem to cause changes in personal hope, and that literal immortality beliefs can aid psychological adjustment when thinking about death. Implications for understanding personal hope, trait self-esteem, afterlife beliefs and terror management are discussed. PMID- 25920482 TI - Review of cardiovascular imaging in The Journal of Nuclear Cardiology in 2014: Part 2 of 2: Myocardial perfusion imaging. AB - In this new feature of The Journal of Nuclear Cardiology we will summarize key articles that were published in the Journal in the previous year. In the first article of this 2-part series we concentrated on publications dealing with cardiac positron emission tomography, computed tomography, and neuronal imaging. This review will focus on myocardial perfusion imaging summarizing advances in the field including in diagnosis, prognosis, appropriateness, and safety of testing. PMID- 25920483 TI - Maternal deprivation disrupts mitochondrial energy homeostasis in the brain of rats subjected to ketamine-induced schizophrenia. AB - Maternal deprivation (MD) appears to be one of the environmental factors involved in the pathophysiology of schizophrenia. A widely used animal model of the schizophrenia involves the administration of ketamine, a dissociative anesthetic, NMDA receptors noncompetitive antagonist, that induce symptoms such as schizophrenia. To clarify the molecular mechanism of schizophrenia induced by MD, we investigated alterations in energetic metabolism, oxidative stress and neurotrophic factor levels in the brain of rats following MD and/or a single administration of ketamine during adulthood. Male Wistar rats were subjected to MD for 10 days. Additionally, these animals received acute ketamine (5, 15 or 25 mg/kg by intraperitoneal route, i.p.) during adulthood, and 30 min later, they were killed and the prefrontal cortex (PFC), the hippocampus and the striatum were removed for molecular analyses. Ketamine 25 mg/kg and/or MD and Ketamine 15 and 5 mg/kg with MD decreased the creatine kinase (CK) activity in the hippocampus. The enzyme activity of succinate dehydrogenase (SDH) in the Krebs cycle had increased in the striatum following the administration of ketamine 25 mg/kg, MD per se or MD plus ketamine 5 and 15 mg/kg. MD per se or MD combined with ketamine in different doses increased the activity of mitochondrial complexes. The PFC of animals subjected to MD and administered with ketamine 5 mg/kg exhibited increased protein carbonyl content. In the hippocampus, ketamine 15 mg/kg, ketamine 25 mg/kg and MD each increased the carbonyl content. In the striatum, the TBARS levels were increased by the administration of ketamine 25 mg/kg. Finally, in the hippocampus, MD alone or in combination with ketamine reduced the Nerve Growth Factor (NGF) levels; however, the Brain-derived Neurotrophic Factor (BDNF) levels were unaltered. In the present study, we suggest that MD increased the risk of psychotic symptoms in adulthood, altering different parameters of energy and oxidative stress. Our results suggest that adverse experiences occurring early in life may sensitize specific neurocircuits to subsequent stressors, inducing vulnerability, and may help us understand the pathophysiological mechanisms involved in this disorder. PMID- 25920484 TI - Progression rate of myelopathy in X-linked adrenoleukodystrophy heterozygotes. AB - X-linked adrenoleukodystrophy heterozygote women can present adult onset myeloneuropathy and little is known about its natural history. We aimed to describe the progression rate of the neurological impairment in the prospective follow-up of our cohort and to look for prognostic factors. The neurological scales Japanese Orthopaedic Association (JOA) and Severity Score System for Progressive Myelopathy (SSPROM) were applied at baseline in 29 symptomatic carriers and in follow-up visits. Age at onset, disease duration, X inactivation pattern, determination of the allele expressed, plasma levels of the very long chain fatty acids and of the neuron-specific enolase, and somato-sensory evoked potentials, were taken at baseline. The slope of the linear regression of both JOA and SSPROM versus disease duration since the first symptom was estimated using mixed modeling. JOA and SSPROM decreased 0.42 and 1.87 points per year, respectively (p < 0.001). None of the parameters under study influenced these rates. We estimated that the number of carriers per arm needed in a future 12 month trial with 80% power and a 50% reduction in disease progression would be 225 women for JOA and 750 for SSPROM. The progression rates of the studied neurological scales were small, did not depend on any modifier factor known, and reflected the characteristically slow worsening of symptoms in X-ALD heterozygotes. Better biomarkers are still necessary for future studies. PMID- 25920485 TI - Sequences enhancing cassava mosaic disease symptoms occur in the cassava genome and are associated with South African cassava mosaic virus infection. AB - Cassava is an important food security crop in Sub-Saharan Africa. Two episomal begomovirus-associated sequences, named Sequences Enhancing Geminivirus Symptoms (SEGS1 and SEGS2), were identified in field cassava affected by the devastating cassava mosaic disease (CMD). The sequences reportedly exacerbated CMD symptoms in the tolerant cassava landrace TME3, and the model plants Arabidopsis thaliana and Nicotiana benthamiana, when biolistically co-inoculated with African cassava mosaic virus-Cameroon (ACMV-CM) or East African cassava mosaic virus-UG2 (EACMV UG2). Following the identification of small SEGS fragments in the cassava EST database, the intention of this study was to confirm their presence in the genome, and investigate a possible role for these sequences in CMD. We report that multiple copies of varying lengths of both SEGS1 and SEGS2 are widely distributed in the sequenced cassava genome and are present in several other cassava accessions screened by PCR. The endogenous SEGS1 and SEGS2 are in close proximity or overlapping with cassava genes, suggesting a possible role in regulation of specific biological processes. We confirm the expression of SEGS in planta using EST data and RT-PCR. The sequence features of endogenous SEGS (iSEGS) are unique but resemble non-autonomous transposable elements (TEs) such as MITEs and helitrons. Furthermore, many SEGS-associated genes, some involved in virus-host interactions, are differentially expressed in susceptible (T200) and tolerant TME3) cassava landraces infected by South African cassava mosaic virus (SACMV) of susceptible (T200) and tolerant (TME3) cassava landraces. Abundant SEGS-derived small RNAs were also present in mock-inoculated and SACMV-infected T200 and TME3 leaves. Given the known role of TEs and associated genes in gene regulation and plant immune responses, our observations are consistent with a role of these DNA elements in the host's regulatory response to geminiviruses. PMID- 25920487 TI - Pediatric inflammatory bowel disease: imaging issues with targeted solutions. AB - To date, there have been many advances in inflammatory bowel disease (IBD) imaging in every cross-sectional imaging modality, particularly in children. The main emphasis in pediatric IBD imaging is on robust and reproducible measures of small bowel Crohn's disease inflammation, accurate diagnosis of IBD-related complications, and minimizing radiation burden to the patient, as repeat imaging is necessary over the course of their disease. In this article, we discuss the current state-of-the-art imaging techniques, in addition to routine fluoroscopy, including MR and CT enterography and bowel ultrasound. We also present the emerging use of new methods to characterize disease severity and distinguish active inflammation from fibrosis such as diffusion-weighted imaging, bowel elastography, and contrast-enhanced ultrasound. The diagnostic performance of particular examinations, their strengths and weaknesses, and role in IBD management will be discussed. Although these advanced imaging techniques applied to children are similar to those performed in adults, special considerations related to their application in pediatric patients will also be reviewed. PMID- 25920486 TI - Promoter analysis and RNA interference of CYP6ab4 in the silkworm Bombyx mori. AB - In insects, cytochrome P450 monooxygenases (P450s) are involved in the metabolism of endogenous compounds such as steroid hormones and lipids. In this study, we measured the 20-hydroxyecdysone (20E)-induced transcriptional level of the CYP6ab4 gene using reverse transcription-quantitative real-time polymerase chain reaction (RT-qPCR) with a dual spike-in strategy. We then probed possible physiological functions using RNAi experiments in the silkworm Bombyx mori. The activity of the CYP6ab4 promoter in various silkworm tissues was measured by firefly luciferase activity and normalized by Renilla luciferase activity. Our results showed that the activity of the CYP6ab4 promoter was highest in the malpighian tubule, followed by the fat body, the silk gland, the midgut, the epidermis, and the hemocyte. The essential region for basal and 20E-induced transcriptional activity was between -908 and -456 bp from the transcription start site. Through promoter truncation analysis using a dual-luciferase reporter assay in B. mori ovary cells (BmN), we showed that the region between -827 and 722 bp was essential for basal and 20E-induced transcriptional activity. Sequence analysis of this region revealed several potential transcriptional regulatory elements such as Hunchback (Hb) and BR-C Z. Mutation of the core bases of the BR C Z binding site demonstrated that BR-C Z induces 20E-mediated CYP6ab4 transcription. Further identification of cis- and trans-elements and their roles in the upregulation of CYP6ab4 may be useful for elucidating the contribution of P450 to the response mechanism to 20E. PMID- 25920488 TI - Localized dealloying corrosion mediated by self-assembled monolayers used as an inhibitor system. AB - The structure and chemistry of thiol or selenol self-assembled organic monolayers have been frequently addressed due to the unique opportunities in functionalization of materials. Such organic films can also act as effective inhibition layers to mitigate oxidation or corrosion. Cu-Au alloy substrates covered by self-assembled monolayers show a different dealloying mechanism compared to bare surfaces. The organic surface layer inhibits dealloying of noble metal alloys by a suppression of surface diffusion at lower potentials but at higher applied potentials dealloying proceeds in localized regions due to passivity breakdown. We present an in situ atomic force microscopy study of a patterned thiol layer applied on Cu-Au alloy surfaces and further explore approaches to change the local composition of the surface layers by exchange of molecules. The pattern for the in situ experiment has been applied by micro contact printing. This allows the study of corrosion protection with its dependence on different molecule densities at different sites. Low-density thiol areas surrounding the high-density patterns are completely protected and initiation of dealloying proceeds only along the areas with the lowest inhibitor concentration. Dealloying patterns are highly influenced and controlled by molecular thiol to selenol exchange and are also affected by introducing structural defects such as scratches or polishing defects. PMID- 25920489 TI - Proteolytic processing of anti-Mullerian hormone differs between human fetal testes and adult ovaries. AB - From early embryonic life, anti-Mullerian hormone (AMH) is produced by Sertoli cells and is essential for male sex differentiation. In females, AMH is produced by immature granulosa cells (GCs) but a definitive function in females is uncertain. We have assessed the cellular localization and specificity of a panel of five novel high-affinity AMH monoclonal antibodies. Two recognize the mature C terminal form of AMH, whereas three recognize the active pro-mature form of AMH in human tissue. The antibodies were tested on fetal male testicular and mesonephric tissue aged 8-19 weeks post conception (pc), fetal male serum aged 16 26 weeks pc and human immature GCs by immunofluorescence, immunohistochemistry, ELISA and western blotting. The active pro-mature forms of AMH were expressed in both Sertoli cells from human fetal testis and human immature GCs. In contrast, the mature C-terminal form of AMH was hardly detected in Sertoli cells, but was readily detected in GCs. This particular form was also located to the nucleus in GCs, whereas the other investigated AMH forms remained in the cytoplasm. Interestingly, the distribution of the AMH forms in the fetal serum of boys showed that the fraction of inactive precursor AMH only accounted for 4.5% +/- 0.6 (mean +/- SD) of the total AMH measured, and the remaining AMH was the active pro-mature form. Furthermore, western blot analysis demonstrated a number of previously unrecognized molecular forms of AMH. The present findings suggest that processing of AMH is a tightly regulated process, which is likely to be important for the function of AMH and which differs between the two sexes. PMID- 25920490 TI - Laser engravings as reason for mechanical failure of titanium-alloyed total hip stems. AB - INTRODUCTION: Two revisions of broken beta-titanium total hip stems had to be performed in our hospital after 2 and 4 years in situ. Since both fractures were located at the level of a laser engraving, a failure analysis was conducted. MATERIALS AND METHODS: Both retrieved hip stems were disinfected and collected in our retrieval database after patient's signed agreement. Each fragment was macroscopically photographed. Fracture surfaces were analyzed using scanning electron microscopy (SEM). Quantification of element content was conducted using energy dispersive X-ray (EDX) analysis. RESULTS: Both stems show fatigue fracture, as displayed by the lines of rest on the fracture surface. The origin of fracture was identified directly at the laser engraving of the company logo at both stems by means of SEM. The EDX analysis showed an oxygen level beneath the laser engraving about twice as high as in the substrate, causing material embrittlement. CONCLUSIONS: Laser engravings need to be reduced to a minimum of necessary information, and should be placed at locations with minimum mechanical load. Biomechanical analyses are recommended to identify less loaded areas in implant components to avoid such implant failures. PMID- 25920492 TI - A comparison of paediatric and adult infectious diseases consultations in Australia and New Zealand. AB - The objective of this paper is to describe paediatric infectious diseases consultations across Australia and New Zealand. We surveyed infectious diseases physicians at 51 hospitals over a period of 2 weeks in 2012. Compared with adult consults, paediatric consults were more frequently received from general paediatricians/physicians and intensive care, yet less frequently from surgeons and emergency. Respiratory, skin/soft tissue and bone/joint infections were the most frequent consultations in children. These data demonstrate the breadth of formal infectious diseases consults in children. Differences between paediatric and infectious diseases consultations need to be considered when planning both paediatric and adult physician training and future curriculum development. PMID- 25920491 TI - The microstructural correlates of T1 in white matter. AB - PURPOSE: Several studies have shown strong correlations between myelin content and T1 within the brain, and have even suggested that T1 can be used to estimate myelin content. However, other micro-anatomical features such as compartment size are known to affect longitudinal relaxation rates, similar to compartment size effects in porous media. METHODS: T1 measurements were compared with measured or otherwise published axon size measurements in white matter tracts of the rat spinal cord, rat brain, and human brain. RESULTS: In both ex vivo and in vivo studies, correlations were present between the relaxation rate 1/T1 and axon size across regions of rat spinal cord with nearly equal myelin content. CONCLUSION: While myelination is likely the dominant determinant of T1 in white matter, variations in white matter microstructure, independent of myelin volume fraction, may also be reflected in T1 differences between regions or subjects. PMID- 25920493 TI - A rural worker infected with a bovine-prevalent genotype of Campylobacter fetus subsp. fetus supports zoonotic transmission and inconsistency of MLST and whole genome typing. AB - Whole-genome characterisation in clinical microbiology enables to detect trends in infection dynamics and disease transmission. Here, we report a case of bacteraemia due to Campylobacter fetus subsp. fetus in a rural worker under cancer treatment that was diagnosed with cellulitis; the patient was treated with antibiotics and recovered. The routine typing methods were not able to identify the microorganism causing the infection, so it was further analysed by molecular methods and whole-genome sequencing. The multi-locus sequence typing (MLST) revealed the presence of the bovine-associated ST-4 genotype. Whole-genome comparisons with other C. fetus strains revealed an inconsistent phylogenetic position based on the core genome, discordant with previous ST-4 strains. To the best of our knowledge, this is the first C. fetus subsp. fetus carrying the ST-4 isolated from humans and represents a probable case of zoonotic transmission from cattle. PMID- 25920495 TI - The intrinsic luminescence of individual plasmonic nanostructures in aqueous suspension by photon time-of-flight spectroscopy. AB - We have studied the intrinsic one-photon excited luminescence of freely diffusing gold nanoparticles of different shapes in aqueous suspension. Gold nanospheres were used as a reference, since their luminescence has been investigated previously and their light absorption and scattering properties are described analytically by Mie theory. We then studied gold nanobipyramids and nanostars that have recently gained interest as building blocks for new plasmonic nanosensors. The aim of our study is to determine whether the luminescence of gold nanoparticles of complex shape (bipyramids and nanostars) is a plasmon assisted process, in line with the conclusions of recent spectroscopic studies on spheres and nanorods. Our study has been performed on particles in suspension in order to avoid any artefact from the heterogeneous environment created when particles are deposited on a substrate. We employ a recently developed photon time-of-flight method in combination with correlation spectroscopy of the light scattered by the particles to probe the luminescent properties of individual particles based on a particle-by-particle spectral analysis. Furthermore, we have performed resonant light scattering spectroscopic measurements on the same samples. Our work demonstrates the power of our time-of flight method for uncovering the plasmonic signatures of individual bipyramids and nanostars during their brief passage in the focal volume of a confocal set-up. These spectral features of individual particles remain hidden in macroscopic measurements. We find that the intrinsic photoluminescence emission of gold bipyramids and gold nanostars is mediated by their localized surface plasmons. PMID- 25920494 TI - OKN-007 decreases tumor necrosis and tumor cell proliferation and increases apoptosis in a preclinical F98 rat glioma model. AB - BACKGROUND: Glioblastoma is a malignant World Health Organization (WHO) grade IV glioma with a poor prognosis in humans. New therapeutics are desperately required. The nitrone OKN-007 (2,4-disulfophenyl-PBN) has demonstrated effective anti-glioma properties in several rodent models and is currently being used as a clinical investigational drug for recurrent gliomas. We assessed the regional effects of OKN-007 in the tumor necrotic core and non-necrotic tumor parenchyma. METHODS: An F98 rat glioma model was evaluated using proton magnetic resonance spectroscopy ((1) H-MRS), diffusion-weighted imaging (DWI), morphological T2 weighted imaging (T2W) at 7 Tesla (30 cm-bore MRI), as well as immunohistochemistry and microarray assessments, at maximum tumor volumes (15-23 days following cell implantation in untreated (UT) tumors, and 18-35 days in OKN 007-treated tumors). RESULTS: (1) H-MRS data indicates that Lip0.9/Cho, Lip0.9/Cr, Lip1.3/Cho, and Lip1.3/Cr ratios are significantly decreased (all P < 0.05) in the OKN-007-treated group compared with UT F98 gliomas. The Cho/Cr ratio is also significantly decreased in the OKN-007-treated group compared with UT gliomas. In addition, the OKN-007-treated group demonstrates significantly lower ADC values in the necrotic tumor core and the nonnecrotic tumor parenchyma (both P < 0.05) compared with the UT group. There was also an increase in apoptosis following OKN-007 treatment (P < 0.01) compared with UT. CONCLUSION: OKN-007 reduces both necrosis and tumor cell proliferation, as well as seems to mediate multiple effects in different tumor regions (tumor necrotic core and nonnecrotic tumor parenchyma) in F98 gliomas, indicating the efficacy of OKN-007 as an anti cancer agent and its potential clinical use. PMID- 25920496 TI - Biomonitoring of the Genotoxic and Hepatotoxic Effects and Oxidative Stress Potentials of Itraconazole in Pregnant Rats. AB - BACKGROUND: Pregnant women are more susceptible to both vaginal colonization and infection by yeast. One hundred million fungal infected patients have been treated worldwide with itraconazole (Caputo, 2003. METHOD: Itraconazole was administrated orally to pregnant rats at doses of 75, 100, or 150 mg/kg during gestational days (GD) 1 to 7 or GD 8 to 14 or GD 14 to 20. The genotoxicity and hepatotoxicity of the antifungal drug itraconazole were assessed during different periods of pregnancy using different methods. RESULTS: It was found that itraconazole was a genotoxic drug for both mothers and fetuses. This finding was observed via significant elevation in the estimated comet assay parameters (percentage of fragmented DNA, tail moment, and olive moment), percentage of fragmented DNA measured by diphenylamine assay and mixed smearing and laddering of DNA fragments of liver samples. In addition, itraconazole caused significant elevation in the level of hepatic malondialdehyde and depletion in the catalase activity and glutathione level. Furthermore, itraconazole induced histopathological alterations in the hepatic tissues of both mothers and fetuses. CONCLUSION: These findings indicate that itraconazole administration at doses of 75, 100, or 150 mg/kg during pregnancy induced maternal and fetal toxicity that could be induced by the genotoxicity and the oxidative damage. PMID- 25920497 TI - Excited state lifetimes and energies of okenone and chlorobactene, exemplary keto and non-keto aryl carotenoids. AB - Photophysical properties of two typical aryl carotenoids, okenone and chlorobactene, were studied with application of femtosecond and microsecond time resolved absorption spectroscopies. These carotenoids are structurally similar and differ only by keto-group and character of the aryl ring. The studies have concentrated on aspects of the photochemistry of these carotenoids as possibility of solvent polarity induced formation of intramolecular charge transfer state in okenone, which contains a keto-group directly attached to the carbon-carbon double bond conjugation, estimating the energy of the forbidden first excited singlet electronic state, S1 (2(1)Ag(-)) and testing the photoprotective capabilities of okenone and chlorobactene in real biological systems. The energies of the S1 (2(1)Ag(-)) state obtained for these carotenoids are 12 750 cm(-1) for okenone and 13 450 cm(-1) for chlorobactene and are not affected either by temperature or solvent polarity. The effect of cryogenic temperature on the excited states lifetimes and energies was also studied at 77 K in 2 methyltetrahydrofuran, which forms a transparent glass upon freezing. The ability to quench bacteriochlorophylls triplets was studied on model bacteriochlorophyll a-carotenoid mixtures with application of flash photolysis. The triplet state lifetime obtained from the anticipated kinetic modelling of the rise and decay of the pool of carotenoid triplets are 2.1 MUs for okenone and 2.8 MUs for chlorobactene. PMID- 25920498 TI - Effects of growth hormone therapeutic supplementation on hematopoietic stem/progenitor cells in children with growth hormone deficiency: focus on proliferation and differentiation capabilities. AB - We investigated the direct effects of growth hormone (GH) replacement therapy (GH RT) on hematopoiesis in children with GH deficiency (GHD) with the special emphasis on proliferation and cell cycle regulation. Peripheral blood (PB) was collected from sixty control individuals and forty GHD children before GH-RT and in 3rd and 6th month of GH-RT to measure hematological parameters and isolate CD34(+)-enriched hematopoietic progenitor cells (HPCs). Selected parameters of PB were analyzed by hematological analyzer. Moreover, collected HPCs were used to analyze GH receptor (GHR) and IGF1 expression, clonogenicity, and cell cycle activity. Finally, global gene expression profile of collected HPCs was analyzed using genome-wide RNA microarrays. GHD resulted in a decrease in several hematological parameters related to RBCs and significantly diminished clonogenicity of erythroid progenies. In contrast, GH-RT stimulated increases in clonogenic growth of erythroid lineage and RBC counts as well as significant up regulation of cell cycle-propagating genes, including MAP2K1, cyclins D1/E1, PCNA, and IGF1. Likewise, GH-RT significantly modified GHR expression in isolated HPCs and augmented systemic IGF1 levels. Global gene expression analysis revealed significantly higher expression of genes associated with cell cycle, proliferation, and differentiation in HPCs from GH-treated subjects. (i) GH-RT significantly augments cell cycle progression in HPCs and increases clonogenicity of erythroid progenitors; (ii) GHR expression in HPCs is modulated by GH status; (iii) molecular mechanisms by which GH influences hematopoiesis might provide a basis for designing therapeutic interventions for hematological complications related to GHD. PMID- 25920499 TI - Circulating irisin levels and muscle FNDC5 mRNA expression are independent of IL 15 levels in mice. AB - Interleukin-15 (IL-15) and irisin are exercise-induced myokines that exert favorable effects on energy expenditure and metabolism. IL-15 can induce PGC 1alpha expression, which in turn induces expression of irisin and its precursor, FNDC5. Therefore, the present study tested the hypothesis that increases in circulating irisin levels and muscle FNDC5 mRNA expression are dependent on IL 15. Circulating irisin levels and gastrocnemius muscle FNDC5 mRNA expression were examined following acute exercise in control and IL-15-deleted (IL-15 KO) mice, following injection of IL-15 into IL-15 KO mice, and in transgenic mice with elevated circulating IL-15 levels (IL-15 Tg mice). Circulating IL-15 levels and muscle PGC-1alpha and PPARdelta mRNA expressions were determined as positive controls. No effect of IL-15 deletion on post-exercise serum irisin levels or muscle FNDC5 mRNA expression was detected. While serum IL-15 levels and muscle PGC-1alpha expression were elevated post-exercise in control mice, both serum irisin levels and muscle FNDC5 expression decreased shortly after exercise in both control and IL-15 KO mice. A single injection of recombinant IL-15 into IL 15 KO mice that significantly increased muscle PPARdelta and PGC-1alpha mRNA expressions had no effect on circulating irisin release, but modestly induced muscle FNDC5 expression. Additionally, serum irisin and gastrocnemius muscle FNDC5 expression in IL-15 Tg mice were similar to those of control mice. Muscle FNDC5 mRNA expression and irisin release are not IL-15-dependent in mice. PMID- 25920500 TI - Budesonide MMX((r)): a review of its use in patients with mild to moderate ulcerative colitis. AB - Budesonide MMX((r)) (Cortiment((r)); Uceris((r))) is a novel once-daily oral formulation of budesonide using Multi Matrix (MMX((r))) colonic delivery technology to permit the release of budesonide at a controlled rate throughout the colon. It is available in the USA for the induction of remission in patients with active, mild to moderate ulcerative colitis, and in various European countries for the induction of remission in patients with active, mild to moderate ulcerative colitis where 5-aminosalicylic acid (5-ASA) therapy is not sufficient. In three 8-week multinational, phase III studies in patients with active, mild to moderate ulcerative colitis, once-daily budesonide MMX((r)) 9 mg, as monotherapy (CORE I and II studies) or add-on therapy to 5-ASAs (CONTRIBUTE), was significantly more effective than placebo in inducing combined clinical and endoscopic remission. In an 8-week extension of the CORE I study, the efficacy of budesonide MMX((r)) 9 mg monotherapy was demonstrated among patients who completed the CORE I study, but did not achieve clinical remission. In phase III studies, the tolerability profile of budesonide MMX((r)) 9 mg as monotherapy or add-on therapy to 5-ASAs was generally similar to that of placebo. Adverse events were generally mild or moderate in intensity, with exacerbation, relapse or worsening of ulcerative colitis, headache, nausea, abdominal pain and nasopharyngitis the most frequently reported following budesonide MMX((r)) 9 mg monotherapy. Although final data from the CONTRIBUTE study are awaited, current evidence suggests budesonide MMX((r)) 9 mg extends the treatment options currently available for patients with active, mild to moderate ulcerative colitis. PMID- 25920501 TI - Homeolog-specific targeted mutagenesis in Xenopus laevis using TALENs. AB - Transcription activator-like effector nucleases (TALENs) have previously been used for targeted genome editing in various organisms including Xenopus laevis. However, because of genomic polyploidization, X. laevis usually possess homeologous genes (homeologs) with quite similar sequences that make the analysis of gene function difficult. In the present study, we show methodological examples of targeted gene modification of X. laevis homeologs. The X. laevis cytoglobin gene (cygb) consists of two homeologs (xlcygba and xlcygbb), and molecular phylogenetic analysis suggested that they have potentially different functions. Thus, there is a need to establish a method of homeolog-specific gene disruption to clarify gene functions in detail. Here, we show successful examples of homeolog-specific and simultaneous gene disruption for xlcygba and xlcygbb. We found that selective digestion can be performed with at least three mismatches in TALEN target sites in both homeologs. This report paves the way for the functional analyses of X. laevis homeologs, even those containing nearly identical sequences. PMID- 25920502 TI - Toward an understanding of autophagosome-lysosome fusion: The unsuspected role of ATG14. AB - Although largely overlooked relative to the process of phagophore formation, the mechanism through which autophagosomes fuse with lysosomes is a critical aspect of macroautophagy that is not fully understood. In particular, this step must be carefully regulated to prevent premature fusion of an incomplete autophagosome (that is, a phagophore) with a lysosome, because such an event would not allow access of the partially sequestered cargo to the lysosome lumen. The identification of the autophagosome-associated SNARE protein STX17 (syntaxin 17) provided some clue in the understanding of this process. STX17 is recruited specifically to mature autophagosomes, and functions in mediating autophagosome lysosome fusion by forming a complex with the Qbc SNARE SNAP29 and the lysosomal R-SNARE VAMP8. Additionally, STX17 plays a role in the early events of autophagy by interacting with the phosphatidylinositol 3-kinase complex component ATG14. Upon autophagy induction STX17 is strictly required for ATG14 recruitment to the ER-mitochondria contact sites, a critical step for the assembly of the phagophore and therefore for autophagosome formation. In their recent paper, Diao and collaborators now show that the ATG14-STX17-SNAP29 interaction mediates autophagosome-lysosome tethering and fusion events, thus revealing a novel function of ATG14 in the later steps of the autophagy pathway. PMID- 25920503 TI - Effects of task-oriented treadmill-walking training on walking ability of stoke patients. AB - BACKGROUND: Generally, treadmill-walking training focuses on weight bearing and the speed of walking. However, changes in direction, speed, and slope while walking require adaptation. OBJECTIVE: The effects of task-oriented treadmill walking training (TOTWT) on the walking ability of stroke patients were evaluated. METHODS: Subjects were randomly divided into two groups: the task oriented treadmill-walking training (TOTWT) group and the conventional treadmill walking training (CTWT) group. Evaluation was performed before the commencement of the training and again 4 and 8 wk after training was initiated. The OptoGait system measured gait parameters. The Timed Up and Go test and 6-min walk test were also performed. RESULTS: Within each group, both the TOTWT and the CTWT groups significantly differed before and after the intervention in all tests (P < 0.05); the CTWT group showed greater improvement in all tests following TOTWT (P < 0.05). CONCLUSION: TOTWT improves gait and rehabilitation in the stroke affected limb, and also improves general gait characteristics. PMID- 25920504 TI - [Enthesitis in connection with spondyloarthritides]. AB - Enthesitis is a frequent manifestation in spondyloarthritis (SpA) and psoriatic arthritis (PsA) and can be found in up to 40% of patients with SpA. Because of the pathognomonic relevance the classification criteria for SpA and PsA use enthesitis as an entrance or secondary criterion. Enthesitis is most frequently localized at the heel but it can occur at any insertion of an enthesis into the bone. When diagnosing enthesitis differential diagnoses should be considered, mechanical-degenerative causes and fibromyalgia in particular should be excluded. The imaging techniques power Doppler ultrasound (PDUS) and magnetic resonance imaging (MRI) are most helpful in making the diagnosis. The therapeutic options for enthesitis are limited. Nonsteroidal antirheumatic drugs (NSARD) and local injections of corticosteroids are recommended. In small clinical trials no efficacy of disease modifying antirheumatic drugs (DMARD) could be demonstrated. In contrast, tumor necrosis factor alpha (TNF-alpha) blockers were shown to be highly effective in randomized controlled trials for SpA and PsA but they are not currently approved for enthesitis only. PMID- 25920505 TI - A novel application of radiomimetic compounds as antibiotic drugs. AB - OBJECTIVE: This study aims to examine the potential of radiomimetic compounds as antimicrobial therapeutics, as the recent advances in radiomimetic targeting as well as rapid increase of multidrug resistant bacteria make these compounds attractive for future development. METHODS: Representative radiomimetics from each of the three major categories was examined; C-1027 and neocarzinostatin from the protein-chromophore enediyne family; Calicheamicin from the non-protein chromophore enediyne family and Bleomycin and Tallysomycin S10b from the glycopeptide family. The activity of these compounds was examined against 12 distinct bacteria species. Inhibition was determined using disc diffusion assays and a subsequent examination of minimum inhibitory concentration of a representative organism. The onset of action of the compounds was also determined by incubating the organisms with drug in liquid media, before plating, and then determining if growth occurred. RESULTS: We found that the radiomimetic glycopeptides were more active against Gram-negative species, while the enediynes were more effective against Gram-positive species. The radiomimetics also maintained their rapid onset of action, working as quickly as 5 min. CONCLUSIONS: Radiomimetic compounds have activity against a wide variety of microorganisms and would support the development of radiomimetic-antibody conjugates as potential antibiotics as an option against severe bacterial infections. PMID- 25920506 TI - Correction to: Safety considerations when prescribing immunosuppression medication to pregnant women. PMID- 25920507 TI - Hydrodynamics of C-Start Escape Responses of Fish as Studied with Simple Physical Models. AB - One of the most-studied unsteady locomotor behaviors exhibited by fishes is the c start escape response. Although the kinematics of these responses have been studied extensively and two well-defined kinematic stages have been documented, only a few studies have focused on hydrodynamic patterns generated by fishes executing escape behaviors. Previous work has shown that escape responses by bluegill sunfish generate three distinct vortex rings, each with central orthogonal jet flows, and here we extend this conclusion to two other species: stickleback and mosquitofish. Jet #1 is formed by the tail during Stage 1, and moves in the same direction as Stage-2 movement of the fish, thereby reducing final escape-velocity but also rotating the fish. Jet #2, in contrast, moves approximately opposite to the final direction of the fish's motion and contains the bulk of the total fluid-momentum powering the escape response. Jet #3 forms during Stage 2 in the mid-body region and moves in a direction approximately perpendicular to jets 1 and 2, across the direction of movement of the body. In this study, we used a mechanical controller to impulsively move passively flexible plastic panels of three different stiffnesses in heave, pitch, and heave + pitch motions to study the effects of stiffness on unsteady hydrodynamics of escape. We were able to produce kinematics very similar to those of fish c-starts and also to reproduce the 3-jet hydrodynamic pattern of the c-start using a panel of medium flexural stiffness and the combined heave + pitch motion. This medium stiffness panel matched the measured stiffness of the near-tail region of fish bodies. This motion also produced positive power when the panel straightened during stage 2 of the escape response. More flexible and stiffer panels resulted in non-biological kinematics and patterns of flow for all motions. The use of simple flexible models with a mechanical controller and program of fish-like motion is a promising approach for studying unsteady behaviors of fish which can be difficult to manipulate experimentally in live animals. PMID- 25920508 TI - Origins, Innovations, and Diversification of Suction Feeding in Vertebrates. AB - We review the origins, prominent innovations, and major patterns of diversification in suction feeding by vertebrates. Non-vertebrate chordates and larval lamprey suspension-feed by capturing small particles in pharyngeal mucous. In most of these lineages the gentle flows that transport particles are generated by buccal cilia, although larval lamprey and thaliacean urochordates have independently evolved a weak buccal pump to generate an oscillating flow of water that is powered by elastic recovery of the pharynx following compression by buccal muscles. The evolution of jaws and the hyoid facilitated powerful buccal expansion and high-performance suction feeding as found today throughout aquatic vertebrates. We highlight three major innovations in suction feeding. Most vertebrate suction feeders have mechanisms that occlude the corners of the open mouth during feeding. This produces a planar opening that is often nearly circular in shape. Both features contribute to efficient flow of water into the mouth and help direct the flow to the area directly in front of the mouth's aperture. Among several functions that have been identified for protrusion of the upper jaw, is an increase in the hydrodynamic forces that suction feeders exert on their prey. Protrusion of the upper jaw has evolved five times in ray-finned fishes, including in two of the most successful teleost radiations, cypriniforms and acanthomorphs, and is found in about 60% of living teleost species. Diversification of the mechanisms of suction feeding and of feeding behavior reveals that suction feeders with high capacity for suction rarely approach their prey rapidly, while slender-bodied predators with low capacity for suction show the full range of attack speeds. We hypothesize that a dominant axis of diversification among suction feeders involves a trade-off between the forces that are exerted on prey and the volume of water that is ingested. PMID- 25920510 TI - The clinical impact of staging bone marrow examination on treatment decisions and prognostic assessment of lymphoma patients. AB - This study investigates the value of performing a staging bone marrow in patients with diffuse large B-cell lymphoma (DLBCL), follicular lymphoma (FL) and classical hodgkin lymphoma (CHL). The results of 3112 staging bone marrow examinations were assessed for impact on prognostic assessment and critical treatment decisions. The detection of marrow involvement altered the disease specific prognostic index for 4.3% of DLBCL, 6.2% of FL and 0.6% of CHL but marrow involvement in DLBCL was an independent prognostic factor. Knowing the marrow status potentially changed treatment in 92 patients, detection of these patients would have required 854 examinations to be performed. PMID- 25920509 TI - Population growth rate and genetic variability of small and large populations of Red flour beetle (Tribolium castaneum) following multigenerational exposure to copper. AB - We reared large (1000 individuals) and small (20 individuals) populations of Tribolium castaneum on diet contaminated with copper in order to determine if the size of a population affects its ability to adapt to adverse environmental conditions. After 10 generations, we used microsatellite markers to estimate and subsequently compare the genetic variability of the copper-treated populations with that of the control populations, which were reared on uncontaminated medium. Additionally, we conducted a full cross-factorial experiment which evaluated the effects of 10 generations of "pre-exposure" to copper on a population's fitness in control and copper-contaminated environments. In order to distinguish results potentially arising from genetic adaptation from those due to non-genetic effects associated to parental exposure to copper, we subjected also F11 generation, originating from parents not exposed to copper, to the same cross-factorial experiment. The effects of long-term exposure to copper depended on population size: the growth rates of small populations that were pre-exposed to copper were inhibited compared to those of small populations reared in uncontaminated environments. Large Cu-exposed populations had a higher growth rate in the F10 generation compared to the control groups, while the growth rate of the F11 generation was unaffected by copper exposure history. The only factor that had a significant effect on genetic variability was population size, but this was to be expected given the large difference in the number of individuals between large and small populations. Neither copper contamination nor its interaction with population size affected the number of microsatellite alleles retained in the F10 generation. PMID- 25920511 TI - Conducting silver networks based on electrospun poly(methyl methacrylate) and silver trifluoroacetate. AB - Silver networks with high transmittance and low resistance were prepared on transparent substrates via a polymer-assisted electrospinning technique and post treatments. Nonaqueous media containing poly(methyl methacrylate) (PMMA) and silver trifluoroacetate (STA) were formulated and electrospun as polymer/metal precursor nanofibers with as-spun fiber diameters ranging from 640 to 3000 nm. Nanofibers randomly deposited on transparent substrates formed a plane scaffold, which served as the raw material for the conducting silver network. Post-thermal treatment at a moderate temperature of 100 degrees C reduced the STA precursors to silver nanoparticles (Ag NPs). Further heat treatment at elevated temperatures thermally decomposed the organic polymer and triggered sintering of the Ag NPs into a connected one-dimensional (1D) domain. Silver fibers with diameters ranging between 800 and 4500 nm formed continuous conducting networks on the substrate surface. The sheet resistances of these conducting silver networks revealed strong correlations with the original STA/PMMA ratios and with the silver network morphologies after the polymers were removed. The material fabrication was carefully investigated, and the surface plasmon resonances (SPRs), fiber morphologies, and electrical and optical properties of the products were examined. The optimized conducting silver networks exhibited sheet resistances as low as 15 Omega/sq and diffusive optical transparencies of approximately 54%. PMID- 25920513 TI - Perfluoro-alcohol-induced complex coacervates of polyelectrolyte-surfactant mixtures: phase behavior and analysis. AB - Perfluorinated alcohols and acids such as hexafluoroisopropanol (HFIP), trifluoroethanol, trifluoroacetic acid, pentafluoropropionic acid, and heptafluorobutyric acid induce coacervation and phase separation in aqueous solutions of a wide variety of individual and mixed amphiphiles [ Khaledi Langmuir 2013 , 29 , 2458 ]. This paper focuses on HFIP-induced complex coacervate formation in the mixtures of anionic polyelectrolytes, such as sodium salt of poly(methacrylic acid) (PMA) or poly(acrylic acid) (PAA) and cationic surfactants of alkyltrimethylammonium bromides. In purely aqueous media and over a wide concentration range, mixtures of PMA and CTAB form the catanionic complex (CTA(+)PM(-)) that is insoluble in water (white precipitate). Upon addition of a small percentage of HFIP, the mixture goes through phase transition and formation of two distinctly clear liquid phases. The phase diagram for the HFIP-PMA-CTAB coacervate system was studied. The coacervate volume was determined as a function of system variables such as charge ratio as well as total and individual concentrations of the system components. These results, combined with the chemical composition analysis of the separated aqueous top-phase and coacervate bottom-phase, shed light on the coacervation mechanism. The results suggest that exchange of counterions and ion-pair formation play critical roles in the coacervation process. This process facilitated by HFIP through solvation of the head groups and dehydration of the hydrophobic moieties of the catanionic complex. Because of the presence of HFIP, coacervation occurs over a wide range of concentrations and charge ratios of the oppositely charged polyelectrolyte and surfactant. PMID- 25920512 TI - H(+) -pyrophosphatase from Salicornia europaea confers tolerance to simultaneously occurring salt stress and nitrogen deficiency in Arabidopsis and wheat. AB - High salinity and nitrogen (N) deficiency in soil are two key factors limiting crop productivity, and they usually occur simultaneously. Here we firstly found that H(+) -PPase is involved in salt-stimulated NO3 (-) uptake in the euhalophyte Salicornia europaea. Then, two genes (named SeVP1 and SeVP2) encoding H(+) -PPase from S. europaea were characterized. The expression of SeVP1 and SeVP2 was induced by salt stress and N starvation. Both SeVP1 or SeVP2 transgenic Arabidopsis and wheat plants outperformed the wild types (WTs) when high salt and low N occur simultaneously. The transgenic Arabidopsis plants maintained higher K(+) /Na(+) ratio in leaves and exhibited increased NO3 (-) uptake, inorganic pyrophosphate-dependent vacuolar nitrate efflux and assimilation capacity under this double stresses. Furthermore, they had more soluble sugars in shoots and roots and less starch accumulation in shoots than WT. These performances can be explained by the up-regulated expression of ion, nitrate and sugar transporter genes in transgenic plants. Taken together, our results suggest that up regulation of H(+) -PPase favours the transport of photosynthates to root, which could promote root growth and integrate N and carbon metabolism in plant. This work provides potential strategies for improving crop yields challenged by increasing soil salinization and shrinking farmland. PMID- 25920514 TI - Form and function, both matter. PMID- 25920515 TI - Achieving room temperature DNA amplification by dialling in destabilization. AB - The ability to amplify nucleic acid biomarkers at room temperature has remained elusive despite the great need of diagnostics suitable for the point of care. To exponentially amplify DNA within a wide range of ambient temperatures (18-26 degrees C), we explore combining two destabilizing elements in our isothermal lesion-induced DNA amplification system. We demonstrate rapid DNA amplification at the bench without a heat source. PMID- 25920516 TI - Diagnosis and treatment of inherited thrombocytopenias. AB - Knowledge in the field of inherited thrombocytopenias (ITs) has greatly improved over the last 15 years. Several new genes responsible for thrombocytopenia have been identified leading to the definition of novel nosographic entities and to a much better characterization of the phenotypes of these diseases. To date, ITs encompass 22 disorders caused by mutations in 24 genes and characterized by different degrees of complexity and great variability in prognosis. Making a definite diagnosis is important for setting an appropriate follow-up, choosing the best treatments and providing proper counseling. Despite the abovementioned progress, diagnosis of ITs remains difficult and these disorders are still underdiagnosed. The purpose of this review is to provide an updated guide to the diagnosis of ITs based on simple procedures. Moreover, the currently available therapeutic options for these conditions are recapitulated and discussed. PMID- 25920517 TI - Cross-modal and intra-modal binding between identity and location in spatial working memory: The identity of objects does not help recalling their locations. AB - In this study we tested incidental feature-to-location binding in a spatial task, both in unimodal and cross-modal conditions. In Experiment 1 we administered a computerised version of the Corsi Block-Tapping Task (CBTT) in three different conditions: the first one analogous to the original CBTT test; the second one in which locations were associated with unfamiliar images; the third one in which locations were associated with non-verbal sounds. Results showed no effect on performance by the addition of identity information. In Experiment 2, locations on the screen were associated with pitched sounds in two different conditions: one in which different pitches were randomly associated with locations and the other in which pitches were assigned to match the vertical position of the CBTT squares congruently with their frequencies. In Experiment 2 we found marginal evidence of a pitch facilitation effect in the spatial memory task. We ran a third experiment to test the same conditions of Experiment 2 with a within subject design. Results of Experiment 3 did not confirm the pitch-location facilitation effect. We concluded that the identity of objects does not affect recalling their locations. We discuss our results within the framework of the debate about the mechanisms of "what" and "where" feature binding in working memory. PMID- 25920519 TI - Computational Design of Biomimetic Phosphate Scavengers. AB - Phosphorus has long been the target of much research, but in recent years the focus has shifted from being limited only to reducing its detrimental environmental impact, to also looking at how it is linked to the global food security. Therefore, the interest in finding novel techniques for phosphorus recovery, as well as improving existing techniques, has increased. In this study we apply a hybrid simulation approach of molecular dynamics and quantum mechanics to investigate the binding modes of phosphate anions by a small intrinsically disordered peptide. Our results confirm that the conformational ensemble of the peptide is significantly changed, or stabilized, by the binding of phosphate anions and that binding does not take place purely as a result of a stable P-loop binding nest, but rather that multiple binding modes may be involved. Such small synthetic peptides capable of binding phosphate could be the starting point of new novel technological approaches toward phosphorus recovery, and they represent an excellent model system for investigating the nature and dynamics of functional de novo designed intrinsically disordered proteins. PMID- 25920518 TI - The heritability of gestational age in a two-million member cohort: implications for spontaneous preterm birth. AB - Preterm birth (PTB), defined as birth prior to a gestational age (GA) of 37 completed weeks, affects more than 10% of births worldwide. PTB is the leading cause of neonatal mortality and is associated with a broad spectrum of lifelong morbidity in survivors. The etiology of spontaneous PTB (SPTB) is complex and has an important genetic component. Previous studies have compared monozygotic and dizygotic twin mothers and their families to estimate the heritability of SPTB, but these approaches cannot separate the relative contributions of the maternal and the fetal genomes to GA or SPTB. Using the Utah Population Database, we assessed the heritability of GA in more than 2 million post-1945 Utah births, the largest familial GA dataset ever assembled. We estimated a narrow-sense heritability of 13.3% for GA and a broad-sense heritability of 24.5%. A maternal effect (which includes the effect of the maternal genome) accounts for 15.2% of the variance of GA, and the remaining 60.3% is contributed by individual environmental effects. Given the relatively low heritability of GA and SPTB in the general population, multiplex SPTB pedigrees are likely to provide more power for gene detection than will samples of unrelated individuals. Furthermore, nongenetic factors provide important targets for therapeutic intervention. PMID- 25920520 TI - Rapid Detection of Melamine in Milk Using Immunological Separation and Surface Enhanced Raman Spectroscopy. AB - We integrated immunological separation and surface-enhanced Raman spectroscopy (SERS) to detect melamine in milk. Antimelamine was produced by New Zealand white rabbits following the injection with melamine hapten-ovalbumin immunogen. Melamine was separated from milk by binding to the converted protein G antimelamine complex. After releasing antimelamine and melamine from the complex, the eluents were deposited directly onto the silver dendrite SERS-active substrate for spectral collection. Multivariate statistical analysis including unsupervised principal component analysis and supervised soft independent modeling of class analogy validated the feasibility of applying this method to detect trace levels of melamine in milk. The limit of detection can be as low as 0.79*10(-3) mmol/L. The overall analysis can be completed in 20 min, thus, it is a high-throughput technique to screen for melamine in milk samples. PMID- 25920522 TI - Magnetic field-induced self-assembly of iron oxide nanocubes. AB - Self-assembly of inorganic nanoparticles has been studied extensively for particles having different sizes and compositions. However, relatively little attention has been devoted to how the shape and surface chemistry of magnetic nanoparticles affects their self-assembly properties. Here, we undertook a combined experiment-theory study aimed at better understanding of the self assembly of cubic magnetite (Fe3O4) particles. We demonstrated that, depending on the experimental parameters, such as the direction of the magnetic field and nanoparticle density, a variety of superstructures can be obtained, including one dimensional filaments and helices, as well as C-shaped assemblies described here for the first time. Furthermore, we functionalized the surfaces of the magnetic nanocubes with light-sensitive ligands. Using these modified nanoparticles, we were able to achieve orthogonal control of self-assembly using a magnetic field and light. PMID- 25920523 TI - Entangled F-actin displays a unique crossover to microscale nonlinearity dominated by entanglement segment dynamics. AB - We drive optically trapped microspheres through entangled F-actin at constant speeds and distances well beyond the linear regime, and measure the microscale force response of the entangled filaments during and following strain. Our results reveal a unique crossover to appreciable nonlinearity at a strain rate of [small gamma, Greek, dot above]c ~ 3 s(-1) which corresponds remarkably well with the theoretical rate of relaxation of entanglement length deformations 1/tauent. Above [small gamma, Greek, dot above]c, we observe stress stiffening which occurs over very short time scales comparable to the predicted timescale over which mesh size deformations relax. Stress softening then takes over, yielding to an effectively viscous regime over a timescale comparable to the entanglement length relaxation time, tauent. The viscous regime displays shear thinning but with a less pronounced viscosity scaling with strain rate compared to flexible polymers. The relaxation of induced force on filaments following strain shows that the relative relaxation proceeds more quickly for increasing strain rates; and for rates greater than [small gamma, Greek, dot above]c, the relaxation displays a complex power-law dependence on time. Our collective results reveal that molecular-level nonlinear viscoelasticity is driven by non-classical dynamics of individual entanglement segments that are unique to semiflexible polymers. PMID- 25920521 TI - Optimal selection of natural killer cells to kill myeloma: the role of HLA-E and NKG2A. AB - Immunotherapy with allogeneic natural killer (NK) cells offers therapeutic perspectives for multiple myeloma patients. Here, we aimed to refine NK cell therapy by evaluation of the relevance of HLA-class I and HLA-E for NK anti myeloma reactivity. We show that HLA-class I was strongly expressed on the surface of patient-derived myeloma cells and on myeloma cell lines. HLA-E was highly expressed by primary myeloma cells but only marginally by cell lines. HLA E(low) expression on U266 cells observed in vitro was strongly upregulated after in vivo (bone marrow) growth in RAG-2(-/-) gammac(-/-) mice, suggesting that in vitro HLA-E levels poorly predict the in vivo situation. Concurrent analysis of inhibitory receptors (KIR2DL1, KIR2DL2/3, KIR3DL1 and NKG2A) and NK cell degranulation upon co-culture with myeloma cells revealed that KIR-ligand mismatched NK cells degranulate more than matched subsets and that HLA-E abrogates degranulation of NKG2A+ subsets. Inhibition by HLA-class I and HLA-E was also observed with IL-2-activated NK cells and at low oxygen levels (0.6 %) mimicking hypoxic bone marrow niches where myeloma cells preferentially reside. Our study demonstrates that NKG2A-negative, KIR-ligand-mismatched NK cells are the most potent subset for clinical application. We envision that infusion of high numbers of this subclass will enhance clinical efficacy. PMID- 25920524 TI - Predictive factors of early moderate/severe ovarian hyperstimulation syndrome in non-polycystic ovarian syndrome patients: a statistical model. AB - PURPOSE: To evaluate demographic, medical history and clinical cycle characteristics of infertile non-polycystic ovary syndrome (NPCOS) women with the purpose of investigating their associations with the prevalence of moderate-to severe OHSS. METHODS: In this retrospective study, among 7073 in vitro fertilization and/or intracytoplasmic sperm injection (IVF/ICSI) cycles, 86 cases of NPCO patients who developed moderate-to-severe OHSS while being treated with IVF/ICSI cycles were analyzed during the period of January 2008 to December 2010 at Royan Institute. To review the OHSS risk factors, 172 NPCOS patients without developing OHSS, treated at the same period of time, were selected randomly by computer as control group. We used multiple logistic regression in a backward manner to build a prediction model. RESULTS: The regression analysis revealed that the variables, including age [odds ratio (OR) 0.9, confidence interval (CI) 0.81-0.99], antral follicles count (OR 4.3, CI 2.7-6.9), infertility cause (tubal factor, OR 11.5, CI 1.1-51.3), hypothyroidism (OR 3.8, CI 1.5-9.4) and positive history of ovarian surgery (OR 0.2, CI 0.05-0.9) were the most important predictors of OHSS. The regression model had an area under curve of 0.94, presenting an allowable discriminative performance that was equal with two strong predictive variables, including the number of follicles and serum estradiol level on human chorionic gonadotropin day. CONCLUSION(S): The predictive regression model based on primary characteristics of NPCOS patients had equal specificity in comparison with two mentioned strong predictive variables. Therefore, it may be beneficial to apply this model before the beginning of ovarian stimulation protocol. PMID- 25920525 TI - Correlation between dioxin and endometriosis: an epigenetic route to unravel the pathogenesis of the disease. AB - INTRODUCTION: Environmental toxicants can act as endocrine disrupters on the female reproductive system. 2,3,7,8-Tetrachlorodibenzo-p-dioxin (TCDD) is resistant to degradation and due to its lipophilic nature, accumulates in the fat tissue and in the food chain. Human and animal exposure to TCDD affects levels of the steroid receptors and steroid-responsive gene expression and has an impact on metabolism and serum transport of steroids. Gene expression is commonly altered in endometriosis and in the eutopic endometrium of women with the disease. Aberrantly expressed genes include those associated with the regulation of transcription, proliferation, sex steroid metabolism, apoptosis, cell cycle, the immune response and cell adhesion. METHODS: In this paper, we review the evidence about TCDD's effect on eutopic and ectopic endometrium, in order to unravel the machinery behind the dysregulation of immune and hormonal homeostasis caused by this environmental toxicant. CONCLUSION: The evidence collected in this review suggests that TCDD could modulate transcription at multiple levels, including the epigenetic level, and via microRNAs, thus disturbing the physiologic processes mediated through the aryl hydrocarbon receptor pathways. Exposure to TCDD also modulates the immune response by influencing the production and action of endometrial cytokines and chemokines, destroying mucosal immunity of the reproductive tract and re-directing the tissue distribution and behavior of leukocytes. Despite this large body of evidence, current human-based epidemiological studies on the association between TCDD and endometriosis remain controversial. PMID- 25920526 TI - Comparison of the diagnostic efficacy of white light endoscopy and magnifying endoscopy with narrow band imaging for early gastric cancer: a meta-analysis. AB - OBJECTIVE: Magnifying endoscopy with narrow band imaging (ME-NBI) is widely used in gastroscopy, especially in the diagnosis of early gastric cancer. The purpose of this meta-analysis is to compare the diagnostic efficacy of white light imaging (WLI) and that of ME-NBI for early gastric cancer. METHODS: PubMed/MEDLINE, EMBASE, and the Cochrane Library were searched to identify studies which met the inclusion criteria. A random-effects model was used to calculate overall sensitivity, specificity, and the area under the receiver operating characteristic curve (AUC) to assess the diagnostic efficacy of WLI and ME-NBI in early gastric cancer. Sensitivity analysis was performed to assess the stability of the results. RESULTS: Ten studies met the inclusion criteria, and included 1724 patients and 2153 lesions. The pooled sensitivity, specificity, and AUC for the diagnosis of early gastric cancer using WLI were 0.48 [95 % confidence interval (CI) 0.39-0.57; I (2) = 78.6 %], 0.67 (95 % CI 0.62-0.71; I (2) = 81.9 %), and 0.62, respectively. The pooled sensitivity, specificity, and AUC using ME-NBI were 0.83 (95 % CI 0.79-0.87; I (2) = 79.8 %), 0.96 (95 % CI 0.95-0.97; I (2) = 89.3 %), and 0.96, respectively. The studies showed a high degree of heterogeneity. Further sensitivity analysis was mainly performed for the studies of small lesions (mean size 10 mm or less) and the studies with a the score of 12 points or greater in the literature quality assessment, and the AUCs for ME-NBI for diagnosis of early gastric cancer were between 0.93 and 0.98, which suggested that the diagnostic value was still high and stable. CONCLUSION: Compared with WLI, ME-NBI can effectively diagnose early gastric cancer. PMID- 25920527 TI - Is the NHS really safe from international trade agreements? PMID- 25920528 TI - Correlates of quality of life in overweight or obese breast cancer survivors at enrollment into a weight loss trial. AB - OBJECTIVE: The purpose of this analysis was to examine the correlates of the physical and psychosocial domains of quality of life (QOL) in a cohort of breast cancer survivors participating in a weight loss intervention trial. METHODS: Correlates of QOL and psychosocial functioning were examined in 692 overweight or obese breast cancer survivors at entry into a weight loss trial. QOL was explored with three measures: Short-form 36 (SF-36), Impact of Cancer scale (IOC), and the Breast Cancer Prevention Trial (BCPT) symptom scales. Available data included information on weight and physical activity, as well as demographic and medical characteristics. Multivariate analyses were used to identify associations adjusted for other characteristics. RESULTS: In multivariate analysis, younger age was associated with higher negative impact scores (p < 0.0001). Hispanic, African-American, and Asian women had higher positive IOC impact scores compared with White non-Hispanic women (p < 0.01). Increased number of comorbidities was associated with lower physical and mental QOL scores (p < 0.01). Body mass index was not independently associated with QOL measures. Physical activity was directly associated with physical and mental QOL and IOC positive impact, and inversely related to IOC negative impact and Breast Cancer Prevention Trial symptom scales. CONCLUSIONS: Quality-of-life measures in breast cancer survivors are differentially associated with demographic and other characteristics. When adjusted for these characteristics, degree of adiposity among overweight or obese women does not appear to be independently associated with QOL. Among overweight or obese breast cancer survivors, higher level of physical activity is associated with higher QOL across various scales and dimensions. PMID- 25920529 TI - Seroreactivity against Merkel cell polyomavirus and other polyomaviruses in chronic lymphocytic leukaemia, the MCC-Spain study. AB - Merkel cell polyomavirus (MCPyV) has been suspected to cause chronic lymphocytic leukaemia (CLL) but previous data are inconsistent. We measured seroreactivities of nine polyomaviruses (MCPyV, BKPyV, JCPyV, LPyV, KIPyV, WUPyV, HPyV-6, HPyV-7 and TSPyV) in 359 CLL cases and 370 controls using bead-based multiplex serology technology. We additionally tested two herpesviruses (HSV-1 and CMV). Associations between disease and viral seroreactivities were assessed using logistic regression. All human viruses showed high seroprevalences (69-99%) against structural proteins in controls but significantly lower viral seroprevalences in cases (58-94%; OR range = 0.21-0.70, P value < 0.05), except for MCPyV (OR = 0.79, 95% CI = 0.54-1.16). Lower seroreactivity levels were observed among CLL subjects, with significant differences already observed at early stages of disease, unrelated to treatment status. Seroreactivities against polyomavirus related oncoproteins were almost null. Our data suggest no association for MCPyV polyomavirus with CLL development and an unlikely association for other polyomaviruses tested. PMID- 25920530 TI - Delayed IFN response differentiates replication of West Nile virus and Japanese encephalitis virus in human neuroblastoma and glioblastoma cells. AB - West Nile virus (WNV) and Japanese encephalitis virus (JEV) are important causes of human encephalitis cases, which result in a high mortality ratio and neurological sequelae after recovery. Understanding the mechanism of neuropathogenicity in these viral infections is important for the development of specific antiviral therapy. Here, we focused on human-derived neuronal and glial cells to understand the cellular responses against WNV and JEV infection. It was demonstrated that early IFN-beta induction regulated virus replication in glioblastoma tbl98G cells, whereas delayed IFN-beta induction resulted in efficient virus replication in neuroblastoma SK-N-SH cells. Moreover, the concealing of viral dsRNA in the intracellular membrane resulted in the delayed IFN response in SK-N-SH cells. These results, which showed different IFN responses between human neuronal and glial cells after WNV or JEV infection, are expected to contribute to our understanding of the molecular mechanisms for neuropathology in these viral infections. PMID- 25920532 TI - Meaningful patient education: How can pulmonary rehabilitation help to bridge the gap for those with interstitial lung disease? PMID- 25920531 TI - HIV Vpr protein upregulates microRNA-122 expression and stimulates hepatitis C virus replication. AB - Human immunodeficiency virus (HIV)/hepatitis C virus (HCV) co-infection is characterized by higher serum HCV RNA loads compared with HCV mono-infection. However, the relationship between HIV and HCV replication remains to be clarified. HIV Vpr has been shown to play an essential role in HIV replication. In this study, we aimed to explore the role of Vpr in HCV replication and pathogenesis. We therefore used the genotype 2a full-length HCV strain JFH1 infection system and the genotype 1b full-length HCV replicon OR6 cell line to analyse the effects of Vpr on HCV replication. We found that Vpr promoted HCV 5' UTR activity, HCV RNA replication and HCV protein expression in two HCV infection cell models. Additionally, lymphocyte-produced Vpr significantly induced HCV 5' UTR activity and HCV replication in hepatocytes. We also found that Vpr upregulated the expression of miR-122 by stimulating its promoter activity. Furthermore, an miR-122 inhibitor suppressed the Vpr-mediated enhancement of both HCV 5' UTR activity and HCV replication. In summary, our results revealed that the Vpr-upregulated expression of miR-122 is closely related to the stimulation of HCV 5' UTR activity and HCV replication by Vpr, providing new evidence for how HIV interacts with HCV during HIV/HCV co-infection. PMID- 25920533 TI - Ultrasound findings of incidental adnexal and ovarian lesions on emergency CT scans. AB - A search through 6076 nontraumatic emergency computed tomography (CT) scans of female patients yielded 266 (4.4%) CT scans with an incidentally detected adnexal lesion and ultrasound follow-up within 7days. The population was 87% premenopausal and 13% postmenopausal. Follow-up ultrasound yielded an ultrasound diagnosis 32% of the time. Potentially serious diagnoses included pelvic infection (3%) and suspected malignancy (2%). Benign diagnoses included normal ovaries (16%), hemorrhagic cyst (6%), and benign cyst (5%). The remaining 68% of cases were equivocal, requiring further evaluation. PMID- 25920534 TI - From DIADEM to BigNeuron. PMID- 25920535 TI - Parental strategies to help children with phenylketonuria (PKU) cope with feeling different. AB - This study assessed feelings of differentness in children with phenylketonuria (PKU) and elicited parental coping strategies. A total of 22 parents of 7- to 12 year-old patients with PKU completed qualitative interviews, which assessed whether they think their children feel different from their peers and identified potential solution strategies. The results showed that most parents indicated their child feels different due to PKU, which is frequently triggered by situations surrounding food. PKU community involvement and educating others about PKU were perceived by parents as useful coping strategies. Talking to children about differences was frequently used but one of the least effective strategies. Extended family, clinicians, and teachers also attempted to help children cope with feeling different with varying degrees of success. We concluded that most parents perceive that their child with PKU feels different and have developed strategies to manage these feelings. However, a subset struggle with helping their child cope and may benefit from assistance from healthcare providers. PMID- 25920536 TI - Role of heteroplasmic mutations in the mitochondrial genome and the ID4 gene promoter methylation region in the pathogenesis of chronic aplastic anemia in patients suffering from Kidney yin deficiency. AB - OBJECTIVE: To analyze changes in gene amplification in the mitochondrial genome and in the ID4 gene promoter methylation region in patients with chronic aplastic anemia (CAA) suffering from Kidney (Shen) yin deficiency or Kidney yang deficiency. METHODS: Bone marrow and oral epithelium samples were collected from CAA patients with Kidney yin deficiency or Kidney yang deficiency (20 cases). Bone marrow samples were collected from 20 healthy volunteers. The mitochondrial genome was amplified by polymerase chain reaction (PCR), and PCR products were used for sequencing and analysis. RESULTS: Higher mutational rates were observed in the ND1-2, ND4-6, and CYTB genes in CAA patients suffering from Kidney yin deficiency. Moreover, the ID4 gene was unmethylated in bone marrow samples from healthy individuals, but was methylated in some CAA patients suffering from Kidney yin deficiency (positive rate, 60%) and Kidney yang deficiency (positive rate, 55%). CONCLUSIONS: These data supported that gene mutations can alter the expression of respiratory chain enzyme complexes in CAA patients, resulting in energy metabolism impairment and promoting the physiological and pathological processes of hematopoietic failure. Functional impairment of the mitochondrial respiration chain induced by gene mutation may be an important reason for hematopoietic failure in patients with CAA. This change is closely related to maternal inheritance and Kidney yin deficiency. Finally, these data supported the assertion that it is easy to treat disease in patients suffering from yang deficiency and difficult to treat disease in patients suffering from yin deficiency. PMID- 25920537 TI - Effects of Dachengqi Decoction () on morphological changes in enteric nerve system of rats with multiple organ dysfunction syndrome. AB - OBJECTIVE: To observe the morphological changes in enteric nerve system (ENS) of rats with multiple organ dysfunction syndrome (MODS) treated by Dachengqi Decoction (, DCQD). METHODS: Fifty Wistar rats were randomly assigned to the control group, MODS model group and DCQD treated group. The rats in MODS model group and DCQD treated group were injected Escherichia coli (E. coli) suspension into abdominal cavity under sterile condition. The DCQD treated group was gavaged with DCQD 2 days before the E. coli suspension was injected. Twenty-four hours after injection, the proximal segment of intestine was resected and studied by immunohistofluorescence using vesicular acetylcholine transporter, vasoactive intestinal polypeptide (VIP), substance P (SP) and neuronal nitric oxide synthase (nNOS) antibodies. The whole-mount preparations were observed by laser scanning confocal microscope to detect the changes of quantity and fluorescence integral optical density (IOD) value of intestine enteric nerves. RESULTS: Compared with the control group, the quantity and IOD value of acetylcholine (ACh), VIP, SP and nitric oxide (NO) nerves of intestine in the MODS group were significantly decreased (P<0.01), and the network of enteric nerves was remarkably disrupted. Compared with the MODS group, the quantity and fluorescence IOD value of ACh, VIP, SP and NO nerves in the DCQD group were significantly increased (P<0.01), and the network of enteric nerves was remarkably recovered. CONCLUSION: DCQD can protect and repair damage in the network of ACh, SP, NO and VIP nerves in rats with MODS, which may be one of mechanisms involved in promoting gastrointestinal motility by DCQD. PMID- 25920538 TI - Survey of survivors' perspective on return to work after stroke. AB - PURPOSE: To describe the development and results of a detailed survey on return to work (RTW) after stroke completed by survivors at various stages of recovery. METHOD: This study used a multi-method qualitative and quantitative research strategy to design and implement a 39-item survey for stroke survivors. Individual interviews, focus groups, and working committees were used to conceptualize the issues and translate them into a survey format. Surveys were distributed in regular and electronic mail. Groups of rehabilitation professionals, employers, and stroke survivors were assembled to review findings and obtain feedback to aide in interpretation. RESULTS: Overall 715 surveys were completed. The respondents were on average 54 years of age, mostly white, well educated, urban dwelling, and in skilled occupations. Results are described in seven areas: financial, stroke impairments, organizational, work and psychological issues, interpersonal support, and therapy. Several salient findings are described including the role of fatigue, under utilization of vocational rehabilitation (VR) services, and motivational factors related to finances, self-esteem, work, and workplace relationships. CONCLUSION: Although earning an income is a strong motivation to RTW, salary decreases in importance when compared with other psychological benefits. Fatigue was rated as the second highest impairment barrier to RTW and persisted as a relevant impediment over time. Attitudes of co-workers and flexibility in work schedule were viewed as most helpful to the RTW process, whereas work stress was viewed as the greatest impediment to return. Only 24% of the sample received VR counseling with more respondents receiving counseling if they returned 6 months or longer after their stroke. Other trends and clinical and research implications are discussed. PMID- 25920539 TI - Antimicrobial activity and synergy of antibiotics with two biphenyl compounds, protosappanins A and B from Sappan Lignum against methicillin-resistant Staphylococcus aureus strains. AB - OBJECTIVES: This study aims to investigate antimicrobial ingredients from Sappan Lignum and to evaluate their synergy on methicillin-resistant Staphylococcus aureus strains with antibiotics. METHODS: Bioactivity-guided phytochemical procedures were used to screen the active compounds. Minimum inhibitory concentrations (MICs) and minimum bactericidal concentrations (MBCs) were assayed by broth microdilution. The synergy was evaluated through checkerboard microdilution and loss of viability assays. KEY FINDINGS: Protosappanins A (PsA) and B (PsB) were identified from Sappan Lignum extracts. They showed active against both S. aureus and MRSA with MIC or MIC50 at 64 (PsA) and 128 (PsB) mg/L alone. When they were used in combination with antibiotics, they showed best synergy with amikacin and gentamicin with MIC50 (mg/L) of amikacin reduced more significantly from 32 to four (with PsA) and eight (with PsB), and the fractional inhibitory concentration index (FICI) ranged between 0.078 and 0.500 (FICI50 = 0.375). Moreover, the resistance of MRSA towards amikacin and gentamicin could be reversed by the Clinical and Laboratory Standards Institute criteria. The combined bactericidal mode could as well be synergy. PsA and PsB showed very low cytotoxicity in comparison with their promising activity against MRSA. CONCLUSIONS: Protosappanins A and B showed both alone activities and resistance reversal effects of amikacin and gentamicin against MRSA, which warrant further investigations for potential combinatory therapy of MRSA infection. PMID- 25920541 TI - Structural and functional neuroimaging in patients with Parkinson's disease and visual hallucinations: A critical review. AB - Patients with Parkinson's disease (PD) may develop various non-motor symptoms (NMS) during the course of the illness and psychosis is one of the common NMS of PD. Visual hallucinations (VH) are the most common manifestation of psychosis in PD. The exact pathogenesis of VH in patients with PD is not clearly understood. Presence of VH has been described to be associated with rapid cognitive decline and increased nursing home placements in PD patients. A large number of structural and functional neuroimaging studies have been conducted to understand the cerebral basis of VH in PD. Structural imaging studies (Voxel Based Morphometry) have reported grey matter atrophy in multiple regions of the brain such as primary visual cortex, visual association cortex, limbic regions, cholinergic structures such as pedunculopontine nucleus and substantia innominata, which conclude possible alterations of brain regions associated with functions such as visuospatial-perception, attention control and memory. Most functional neuroimaging studies (functional MRI, positron emission tomography and single photon emission computerized tomography) have reported altered activation, blood flow, or reduced metabolism in both dorsal and ventral visual pathways, which probably indicates an alteration in the normal bottom-top visual processing and the presence of an aberrant top-down visual processing. This review critically analyzes the published studies on the structural and functional neuroimaging in PD patients with VH. PMID- 25920542 TI - Eumelanin-driven production of molecular hydrogen: A novel element of skin defense? AB - Molecular hydrogen (H2, dihydrogen) has been recognized as a unique cell protectant. Dihydrogen protects tissues against oxidative injuries by selectively reducing reactive oxygen species (ROS). It seems that melanin, natural pigment of skin and hair, might produce endogenous hydrogen. The protective role of skin melanin (eumelanin) could be due to its capacity for molecular hydrogen production. An effective pooling of dihydrogen by eumelanin should be considered as a novel element of skin defense system against oxidative stress-related disorders. PMID- 25920540 TI - An overview of investigational toxin-directed therapies for the adjunctive management of Bacillus anthracis infection and sepsis. AB - INTRODUCTION: Sepsis with Bacillus anthracis infection has a very high mortality rate despite appropriate antibiotic and supportive therapies. Over the past 15 years, recent outbreaks in the US and in Europe, coupled with anthrax's bioterrorism weapon potential, have stimulated efforts to develop adjunctive therapies to improve clinical outcomes. Since lethal toxin and edema toxin (LT and ET) make central contributions to the pathogenesis of B. anthracis, these have been major targets in this effort. AREAS COVERED: Here, the authors review different investigative biopharmaceuticals that have been recently identified for their therapeutic potential as inhibitors of LT or ET. Among these inhibitors are two antibody preparations that have been included in the Strategic National Stockpile (SNS) and several more that have reached Phase I testing. Presently, however, many of these candidate agents have only been studied in vitro and very few tested in bacteria-challenged models. EXPERT OPINION: Although a large number of drugs have been identified as potential therapeutic inhibitors of LT and ET, in most cases their testing has been limited. The use of the two SNS antibody therapies during a large-scale exposure to B. anthracis will be difficult. Further testing and development of agents with oral bioavailability and relatively long shelf lives should be a focus for future research. PMID- 25920543 TI - Oxidative phosphorylation gene expression falls at onset and throughout the development of meningococcal sepsis-induced multi-organ failure in children. PMID- 25920544 TI - Considerations regarding safe transport and transfer for Ebola patients in western countries. PMID- 25920545 TI - Common genomic variation in the FER gene: useful to stratify patients with sepsis due to pneumonia? PMID- 25920546 TI - Personalized disease-specific protein corona influences the therapeutic impact of graphene oxide. AB - The hard corona, the protein shell that is strongly attached to the surface of nano-objects in biological fluids, is recognized as the first layer that interacts with biological objects (e.g., cells and tissues). The decoration of the hard corona (i.e., the type, amount, and conformation of the attached proteins) can define the biological fate of the nanomaterial. Recent developments have revealed that corona decoration strongly depends on the type of disease in human patients from which the plasma is obtained as a protein source for corona formation (referred to as the 'personalized protein corona'). In this study, we demonstrate that graphene oxide (GO) sheets can trigger different biological responses in the presence of coronas obtained from various types of diseases. GO sheets were incubated with plasma from human subjects with different diseases/conditions, including hypofibrinogenemia, blood cancer, thalassemia major, thalassemia minor, rheumatism, fauvism, hypercholesterolemia, diabetes, and pregnancy. Identical sheets coated with varying protein corona decorations exhibited significantly different cellular toxicity, apoptosis, and uptake, reactive oxygen species production, lipid peroxidation and nitrogen oxide levels. The results of this report will help researchers design efficient and safe, patient-specific nano biomaterials in a disease type-specific manner for clinical and biological applications. PMID- 25920547 TI - Litchi freshness rapid non-destructive evaluating method using electronic nose and non-linear dynamics stochastic resonance model. AB - In this paper, litchi freshness rapid non-destructive evaluating method using electronic nose (e-nose) and non-linear stochastic resonance (SR) was proposed. EN responses to litchi samples were continuously detected for 6 d Principal component analysis (PCA) and non-linear stochastic resonance (SR) methods were utilized to analyze EN detection data. PCA method could not totally discriminate litchi samples, while SR signal-to-noise ratio (SNR) eigen spectrum successfully discriminated all litchi samples. Litchi freshness predictive model developed using SNR eigen values shows high predictive accuracy with regression coefficients R(2) = 0 .99396. PMID- 25920548 TI - The role of microRNAs 371 and 34a in androgen receptor control influencing prostate cancer behavior. AB - BACKGROUND: The molecular mechanisms involved in androgen receptor (AR) signaling pathways are not completely understood, and deregulation of microRNAs (miRNAs) expression may play a role in prostate cancer (PC) development and progression. METHODS: The expression levels of miRNA and AR were evaluated with quantitative real-time polymerase chain reaction using frozen tissue from the surgical specimens of 83 patients submitted to radical prostatectomy. The expression level of miRNAs was correlated with prognostic factors and biochemical recurrence during a follow-up period of 45 months. In vitro and in vivo experiments were performed to understand the effect of miRNAs over AR in the context of that seen in a PC model. RESULTS: MiR-371 underexpression correlated with non-organ confined (pT3) disease (P = 0.009). In vitro transfection of miR-371 reduced the levels of AR by 22% and 28% in LNCaP and PC3 cell lines, respectively, and in kallikrein 3, it was reduced by 51%. PC was induced in Balb/c mice using PC-3M luc-C6 cells, and animals were treated with 3 local doses of miR-371. Tumor growth evaluated by in vivo imaging after luciferase injection was slower in animals treated with miR-371. To explore further the possible role of miRNAs in the AR pathway, LNCaP cell line was treated with 5alpha-dihydrotestosterone and flutamide showing alteration in miRNAs expression, especially miR-34a, which was significantly underexpressed after treatment with high doses of 5alpha dihydrotestosterone. CONCLUSION: Our data support a role for miRNAs, especially miR-371 and miR-34a, in the complex disarrangement of AR signaling pathway and in the behavior of PC. PMID- 25920549 TI - Highly active electrolytes for rechargeable Mg batteries based on a [Mg2(MU Cl)2](2+) cation complex in dimethoxyethane. AB - A novel [Mg2(MU-Cl)2](2+) cation complex, which is highly active for reversible Mg electrodeposition, was identified for the first time in this work. This complex was found to be present in electrolytes formulated in dimethoxyethane (DME) through dehalodimerization of non-nucleophilic MgCl2 by reacting with either Mg salts (such as Mg(TFSI)2, TFSI = bis(trifluoromethane)sulfonylimide) or Lewis acid salts (such as AlEtCl2 or AlCl3). The molecular structure of the cation complex was characterized by single crystal X-ray diffraction, Raman spectroscopy and NMR. The electrolyte synthesis process was studied and rational approaches for formulating highly active electrolytes were proposed. Through control of the anions, electrolytes with an efficiency close to 100%, a wide electrochemical window (up to 3.5 V) and a high ionic conductivity (>6 mS cm(-1)) were obtained. The understanding of electrolyte synthesis in DME developed in this work could bring significant opportunities for the rational formulation of electrolytes of the general formula [Mg2(MU-Cl)2][anion]x for practical Mg batteries. PMID- 25920550 TI - DUPLICATE: Cinnarizine: A Promising Agent for Migraine Prevention You May Never Get the Chance to Use. AB - The Publisher regrets that this article is an accidental duplication of an article that has already been published, http://dx.doi.org/10.1016/j.pediatrneurol.2014.07.002. The duplicate article has therefore been removed. The full Elsevier Policy on Article Removal can be found at http://www.elsevier.com/locate/withdrawalpolicy. PMID- 25920551 TI - Milestones on a Shoestring: A Cost-Effective, Semi-automated Implementation of the New ACGME Requirements for Radiology. AB - RATIONALE AND OBJECTIVES: The advent of the ACGME's Next Accreditation System represents a significant new challenge for residencies and fellowships, owing to its requirements for more complex and detailed information. MATERIAL AND METHODS: We developed a system of online assessment tools to provide comprehensive coverage of the twelve ACGME Milestones and digitized them using freely available cloud-based productivity tools. These tools include a combination of point-of care procedural assessments, electronic quizzes, online modules, and other data entry forms. Using free statistical analytic tools, we also developed an automated system for management, processing, and data reporting. RESULTS: After one year of use, our Milestones project has resulted in the submission of over 20,000 individual data points. The use of automated statistical methods to generate resident-specific profiles has allowed for dynamic reports of individual residents' progress. These profiles both summarize data and also allow program directors access to more granular information as needed. CONCLUSION: Informatics driven strategies for data assessment and processing represent feasible solutions to Milestones assessment and analysis, reducing the potential administrative burden for program directors, residents, and staff. PMID- 25920552 TI - Lipids, obesity and gallbladder disease in women: insights from genetic studies using the cardiovascular gene-centric 50K SNP array. AB - Gallbladder disease (GBD) has an overall prevalence of 10-40% depending on factors such as age, gender, population, obesity and diabetes, and represents a major economic burden. Although gallstones are composed of cholesterol by products and are associated with obesity, presumed causal pathways remain unproven, although BMI reduction is typically recommended. We performed genetic studies to discover candidate genes and define pathways involved in GBD. We genotyped 15,241 women of European ancestry from three cohorts, including 3216 with GBD, using the Human cardiovascular disease (HumanCVD) BeadChip containing up to ~ 53,000 single-nucleotide polymorphisms (SNPs). Effect sizes with P-values for development of GBD were generated. We identify two new loci associated with GBD, GCKR rs1260326:T>C (P = 5.88 * 10(-7), beta = -0.146) and TTC39B rs686030:C>A (P = 6.95 x 10(-7), beta = 0.271) and detect four independent SNP effects in ABCG8 rs4953023:G>A (P=7.41 * 10(-47), beta = 0.734), ABCG8 rs4299376:G(>)T (P = 2.40 * 10(-18), beta = 0.278), ABCG5 rs6544718:T>C (P = 2.08 * 10(-14), beta = 0.044) and ABCG5 rs6720173:G>C (P = 3.81 * 10(-12), beta(=)0.262) in conditional analyses taking genotypes of rs4953023:G>A as a covariate. We also delineate the risk effects among many genotypes known to influence lipids. These data, from the largest GBD genetic study to date, show that specific, mainly hepatocyte-centred, components of lipid metabolism are important to GBD risk in women. We discuss the potential pharmaceutical implications of our findings. PMID- 25920553 TI - Common polygenic variation in coeliac disease and confirmation of ZNF335 and NIFA as disease susceptibility loci. AB - Coeliac disease (CD) is a chronic immune-mediated disease triggered by the ingestion of gluten. It has an estimated prevalence of approximately 1% in European populations. Specific HLA-DQA1 and HLA-DQB1 alleles are established coeliac susceptibility genes and are required for the presentation of gliadin to the immune system resulting in damage to the intestinal mucosa. In the largest association analysis of CD to date, 39 non-HLA risk loci were identified, 13 of which were new, in a sample of 12,014 individuals with CD and 12 228 controls using the Immunochip genotyping platform. Including the HLA, this brings the total number of known CD loci to 40. We have replicated this study in an independent Irish CD case-control population of 425 CD and 453 controls using the Immunochip platform. Using a binomial sign test, we show that the direction of the effects of previously described risk alleles were highly correlated with those reported in the Irish population, (P=2.2 * 10(-16)). Using the Polygene Risk Score (PRS) approach, we estimated that up to 35% of the genetic variance could be explained by loci present on the Immunochip (P=9 * 10(-75)). When this is limited to non-HLA loci, we explain a maximum of 4.5% of the genetic variance (P=3.6 * 10(-18)). Finally, we performed a meta-analysis of our data with the previous reports, identifying two further loci harbouring the ZNF335 and NIFA genes which now exceed genome-wide significance, taking the total number of CD susceptibility loci to 42. PMID- 25920554 TI - LRP5 variants may contribute to ADPKD. AB - Mutations in Polycystic Kidney Disease proteins (PKD1 or PKD2) are causative for autosomal dominant polycystic kidney disease (ADPKD). However, a small subset of ADPKD probands do not harbor a mutation in any of the known genes. Low density lipoprotein Receptor-related Protein 5 (LRP5) was recently associated with hepatic cystogenesis in isolated polycystic liver disease (PCLD). Here, we demonstrate that this gene may also have a role in unlinked and sporadic ADPKD patients. In a cohort of 79 unrelated patients with adult-onset ADPKD, we identified a total of four different LRP5 variants that were predicted to be pathogenic by in silico tools. One ADPKD patient has a positive family history for ADPKD and variant LRP5 c.1680G>T; p.(Trp560Cys) segregated with the disease. Although also two PKD1 variants probably affecting protein function were identified, luciferase activity assays presented for three LRP5 variants significant decreased signal activation of canonical Wnt signaling. This study contributes to the genetic spectrum of ADPKD. Introduction of the canonical Wnt signaling pathway provides new avenues for the study of the pathophysiology. PMID- 25920555 TI - Joubert syndrome: genotyping a Northern European patient cohort. AB - Joubert syndrome (JBS) is a rare neurodevelopmental disorder belonging to the group of ciliary diseases. JBS is genetically heterogeneous, with >20 causative genes identified to date. A molecular diagnosis of JBS is essential for prediction of disease progression and genetic counseling. We developed a targeted next-generation sequencing (NGS) approach for parallel sequencing of 22 known JBS genes plus 599 additional ciliary genes. This method was used to genotype a cohort of 51 well-phenotyped Northern European JBS cases (in some of the cases, Sanger sequencing of individual JBS genes had been performed previously). Altogether, 21 of the 51 cases (41%) harbored biallelic pathogenic mutations in known JBS genes, including 14 mutations not previously described. Mutations in C5orf42 (12%), TMEM67 (10%), and AHI1 (8%) were the most prevalent. C5orf42 mutations result in a purely neurological Joubert phenotype, in one case associated with postaxial polydactyly. Our study represents a population-based cohort of JBS patients not enriched for consanguinity, providing insight into the relative importance of the different JBS genes in a Northern European population. Mutations in C5orf42 are relatively frequent (possibly due to a Dutch founder mutation) and mutations in CEP290 are underrepresented compared with international cohorts. Furthermore, we report a case with heterozygous mutations in CC2D2A and B9D1, a gene associated with the more severe Meckel-Gruber syndrome that was recently published as a potential new JBS gene, and discuss the significance of this finding. PMID- 25920556 TI - Attitudes of nearly 7000 health professionals, genomic researchers and publics toward the return of incidental results from sequencing research. AB - Genome-wide sequencing in a research setting has the potential to reveal health related information of personal or clinical utility for the study participant. There is increasing pressure to return research findings to participants that may not be related to the project aims, particularly when these could be used to prevent disease. Such secondary, unsolicited or 'incidental findings' (IFs) may be discovered unintentionally when interpreting sequence data, or as the result of a deliberate opportunistic screen. This cross-sectional, web-based survey investigated attitudes of 6944 individuals from 75 countries towards returning IFs from genome research. Participants included four relevant stakeholder groups: 4961 members of the public, 533 genetic health professionals, 843 non-genetic health professionals and 607 genomic researchers who were invited via traditional media, social media and professional e-mail list-serve. Treatability and perceived utility of incidental results were deemed important with 98% of stakeholders personally interested in learning about preventable life-threatening conditions. Although there was a generic interest in receiving genomic information, stakeholders did not expect researchers to opportunistically screen for IFs in a research setting. On many items, genetic health professionals had significantly more conservative views compared with other stakeholders. This finding demonstrates a disconnect between the views of those handling the findings of research and those participating in research. Exploring, evaluating and ultimately addressing this disconnect should form a priority for researchers and clinicians alike. This social sciences study offers the largest dataset, published to date, of attitudes towards issues surrounding the return of IFs from sequencing research. PMID- 25920559 TI - Matrix biologists in action. PMID- 25920557 TI - Ten new cases further delineate the syndromic intellectual disability phenotype caused by mutations in DYRK1A. AB - The dual-specificity tyrosine-phosphorylation-regulated kinase 1A (DYRK1A) gene, located on chromosome 21q22.13 within the Down syndrome critical region, has been implicated in syndromic intellectual disability associated with Down syndrome and autism. DYRK1A has a critical role in brain growth and development primarily by regulating cell proliferation, neurogenesis, neuronal plasticity and survival. Several patients have been reported with chromosome 21 aberrations such as partial monosomy, involving multiple genes including DYRK1A. In addition, seven other individuals have been described with chromosomal rearrangements, intragenic deletions or truncating mutations that disrupt specifically DYRK1A. Most of these patients have microcephaly and all have significant intellectual disability. In the present study, we report 10 unrelated individuals with DYRK1A-associated intellectual disability (ID) who display a recurrent pattern of clinical manifestations including primary or acquired microcephaly, ID ranging from mild to severe, speech delay or absence, seizures, autism, motor delay, deep-set eyes, poor feeding and poor weight gain. We identified unique truncating and non synonymous mutations (three nonsense, four frameshift and two missense) in DYRK1A in nine patients and a large chromosomal deletion that encompassed DYRK1A in one patient. On the basis of increasing identification of mutations in DYRK1A, we suggest that this gene be considered potentially causative in patients presenting with ID, primary or acquired microcephaly, feeding problems and absent or delayed speech with or without seizures. PMID- 25920558 TI - Epidemiological, clinical and biochemical characterization of the p.(Ala359Asp) SMPD1 variant causing Niemann-Pick disease type B. AB - Niemann-Pick disease type B (NPDB) is a rare, inherited lysosomal storage disorder that occurs due to variants in the sphingomyelin phosphodiesterase 1 (SMPD1) gene and the resultant deficiency of acid sphingomyelinase (ASM) activity. While numerous variants causing NPDB have been described, only a small number have been studied in any detail. Herein, we describe the frequency of the p.(Ala359Asp) variant in the healthy Chilean population, and determine the haplotype background of homozygous patients to establish if this variant originated from a common founder. Genomic DNA samples from 1691 healthy individuals were analyzed for the p.(Ala359Asp) variant. The frequency of p.(Ala359Asp) was found to be 1/105.7, predicting a disease incidence of 1/44 960 in Chile, higher than the incidence estimated by the number of confirmed NPDB cases. We also describe the clinical characteristics of 13 patients homozygous for p.(Ala359Asp) and all of them had moderate to severe NPDB disease. In addition, a conserved haplotype and shared 280 Kb region around the SMPD1 gene was observed in the patients analyzed, indicating that the variant originated from a common ancestor. The haplotype frequency and mitochondrial DNA analysis suggest an Amerindian origin for the variant. To assess the effect of the p.(Ala359Asp) variant, we transfected cells with the ASM-p.(Ala359Asp) cDNA and the activity was only 4.2% compared with the wild-type cDNA, definitively demonstrating the causative effect of the variant on ASM function. Information on common variants such as p.(Ala359Asp) is essential to guide the successful implementation for future therapies and benefit to patients. PMID- 25920560 TI - Determination of biomarkers for polycyclic aromatic hydrocarbons (PAHs) toxicity to earthworm (Eisenia fetida). AB - Polycyclic aromatic hydrocarbon (PAH) compounds are persistent, carcinogenic, and mutagenic. When PAHs enter agricultural soils through sewage sludge, they pose an environmental risk to soil organisms, including earthworms. Therefore, we aimed to determine the toxic effects of PAHs on earthworms. Five PAHs were used: fluorene, anthracene, phenanthrene, fluoranthene, and pyrene. Only fluorene and phenanthrene exhibited toxicity (LC50 values 394.09 and 114.02 g L(-1), respectively) against the earthworm Eisenia fetida. None of the other PAHs tested in this study enhanced the mortality of adult earthworm until the concentrations reached to 1000 g L(-1). After exposure to PAHs, acetylcholinesterase (AChE) activity in E. fetida decreased in a concentration-dependent manner, and phenanthrene exhibited the strongest inhibitory effect on AChE, followed by fluorene. Activity of a representative detoxifying enzyme, carboxylesterase, was dramatically reduced in E. fetida exposed to all tested PAHs in comparison with that observed in the control test. The remaining glutathione S-transferase activity significantly decreased in E. fetida after exposure to PAHs. To profile small proteins <20 kDa, SELDI-TOF MS with Q10 ProteinChips was used, and 54 proteins were identified as being significantly different from the control (p = 0.05). Among them, the expressions of three proteins at 4501.8, 4712.4, and 4747.9 m/z were only enhanced in E. fetida exposed to anthracene and pyrene. One protein with 16,174 m/z was selectively expressed in E. fetida exposed to fluorene, phenanthrene, and fluoranthene. These proteins may be potential biomarkers for the five PAHs tested in E. fetida. PMID- 25920561 TI - Spectrum of adult Parvovirus B19 infection according to the underlying predisposing condition and proposals for clinical practice. AB - The virological diagnosis of Parvovirus B19 (PvB19) infection is currently based on sero-diagnosis, molecular methods or both, yet without clear recommendations. We retrospectively identified patients with polymerase chain reaction-positive PvB19 and/or positive serological assay between 2007 and 2013. Eighty-two adults with at least one diagnostic criterion of recent PvB19 infection (IgM antibodies, viral DNA in blood and/or in marrow) were included and classified into three homogeneous groups: 30 patients had no underlying predisposing condition, 25 a hereditary haemolytic anaemia, 27 an underlying immunodeficiency. The classical PvB19-related manifestations were less frequent in immunocompromised than in immunocompetent patients (arthromyalgia: 5 vs. 14; erythema: 4 vs. 17, respectively). Only 41.4% of patients with no underlying disease were anaemic. Bicytopenia and pancytopenia were observed mainly in immunocompromised patients. Classical pure red cell aplasia was observed in only 9 of the 27 marrow smears performed. Specific IgM were found in 93% of immunocompetent patients, whereas only 58% had detectable viral DNA in blood. IgM and DNA were present alone or together in all patients with hereditary haemolytic anaemia. In immunocompromised patients, the diagnosis was confirmed by marrow analysis in 91% of cases. We make some proposals based on this large series of PvB19-infected patients. PMID- 25920562 TI - Prestin as a biochemical marker for early detection of acquired sensorineural hearing loss. AB - Acquired sensorineural hearing loss and tinnitus can come about through various etiologies such as exposure to excessively loud noise or drugs with ototoxic properties. As such, acquired hearing loss is a common source of morbidity which deleteriously affects the ability to communicate. At present our ability to detect acquired hearing loss and tinnitus at its earliest stages is limited and there are no adjuncts to audiometric evaluation. The earliest cellular targets of noise and ototoxins in the cochlea are the outer hair cells (OHC). I hypothesize that serum assays of OHC specific protein, prestin, will allow detection and quantification of OHC damage before audiometric testing can identify presence of hearing loss. At present, there are no data available to evaluate this hypothesis, but initial evaluation can readily be carried out using existing experimental animal models of ototoxicity and noise-induced hearing loss. Early detection of OHC damage is critical to adoption of measures aimed at ameliorating hearing loss and tinnitus, thus reducing permanent deficits and disability. PMID- 25920563 TI - Novel synthetic bisbenzimidazole that targets angiogenesis in Ehrlich ascites carcinoma bearing mice. AB - Cancer is a leading cause of death in developed countries and second cause in developing countries. Herein we are reporting the synthesis of novel bisbenzimidazole derivatives and their anticancer properties. Among the newly synthesized bisbenzimidazoles, 3-(4-flurophenylsulfonyl)-1,7-dimethyl-2-propyl 1H,3H-2,5-bibenzo[d]imidazole (FDPB) presented as a potent antiproliferative agent against HeLa, HCT116 and A549 cells with selectivity over normal Vero cells (IC50 >50 MUM). Additionally, we evaluated the efficacy of lead compound against Ehrlich ascites tumor (EAT) bearing mice for its antitumor and antiangiogenic properties. Our lead compound significantly reduced the cell viability, body weight, ascites volume and downregulated the formation of neovasculature and production of Vascular Endothelial Growth Factor (VEGF). PMID- 25920564 TI - New quinoline derivatives demonstrate a promising antimalarial activity against Plasmodium falciparum in vitro and Plasmodium berghei in vivo. AB - Malaria continues to be an important public health problem in the world. Nowadays, the widespread parasite resistance to many drugs used in antimalarial therapy has made the effective treatment of cases and control of the disease a constant challenge. Therefore, the discovery of new molecules with good antimalarial activity and tolerance to human use can be really important in the further treatment of the disease. In this study we have investigated the antiplasmodial activity of 10 synthetic compounds derived from quinoline, five of them combined to sulfonamide and five to the hydrazine or hydrazide group. The compounds were evaluated according to their cytotoxicity against HepG2 and HeLa cell lines, their antimalarial activity against CQ-sensitive and CQ-resistant Plasmodium falciparum strains and, finally, their schizonticide blood action in mice infected with Plasmodium berghei NK65. The compounds exhibited no cytotoxic action in HepG2 and HeLa cell lines when tested up to a concentration of 100 MUg/mL. In addition, the hydrazine or hydrazide derivative compounds were less cytotoxic against cell lines and more active against CQ-sensitive and CQ resistant P. falciparum strains, showing high SI (>1000 when SI was calculated using the CC50 from the 3D7 strain as reference). When tested in vivo, the hydrazine derivative 1f compound showed activity against the development of blood parasites similar to that observed with CQ, the reference drug. Interestingly, the 1f compound demonstrated the best LipE value (4.84) among all those tested in vivo. Considering the in vitro and in vivo activities of the compounds studied here and the LipE values, we believe the 1f compound to be the most promising molecule for further studies in antimalarial chemotherapy. PMID- 25920565 TI - Development of reverse transcription loop-mediated isothermal amplification assays to detect Hantaan virus and Seoul virus. AB - We developed two assays based on one-step reverse transcription loop-mediated isothermal amplification (RT-LAMP) to identify Hantaan virus (HTNV) and Seoul virus (SEOV), members of the Hantavirus genus that cause hemorrhagic fever with renal syndrome (HFRS). Our results showed that these assays can be conducted within 30min under isothermal conditions. The detection limit for HTNV was around 10 copies per reaction, similar to detection levels for quantitative reverse transcription polymerase chain reaction (qRT-PCR) assays. The detection limit for SEOV was 100 copies per reaction, a sensitivity that was 10-fold lower than that for qRT-PCR assays but 10-fold higher than that for RT-PCR assays. The method we developed was specific for both HTNV and SEOV without any cross-reaction with other pathogens. We conclude that RT-LAMP assays could be useful for the rapid and direct detection of HTNV and SEOV clinically, and for the epidemiological investigation of HFRS. PMID- 25920566 TI - Detection of specific UL49 sequences of Marek's disease virus CVI988/Rispens strain using loop-mediated isothermal amplification. AB - Marek's disease (MD) is a tumoral disease of chickens that can be controlled by vaccines based on non-pathogenic strains of turkey herpesvirus (HVT), SB-1 strain belonging to serotype 2, or the attenuated CVI988/Rispens strain belonging to serotype 1 of Marek's disease virus (MDV). Currently, the 'gold standard' in MD prophylaxis is the Rispens strain-based vaccine which protects against very virulent MDV and disease onset. Previous studies have shown that loop-mediated isothermal amplification (LAMP) is a rapid alternative to polymerase chain reaction (PCR) for detection and differentiation of HVT, SB-1 and virulent MDV strains. The aim of this study was to develop and evaluate a novel LAMP assay for the detection of the UL49 Rispens-specific region. This assay was validated using material from infected chicken embryo fibroblasts (CEFs) and tissue samples from vaccinated chickens. The analytical sensitivity of the assay was 10-times higher than PCR and reliably amplified 0.1 log10 TCID50/ml. The MDV Rispens was also detected at 18h after infection of CEFs. The results showed LAMP to be selective and a sensitive method to detect Rispens as early as 3 d.p.v. in all internal organs of chickens. Furthermore, the method was also capable to detect Rispens in 5 out of 26 chickens originating from different flocks. A mismatch amplification mutation assay (MAMA-PCR) confirmed the presence of Rispens strain in all LAMP positive chickens. This is the first report of the specific visual detection of Rispens in vitro and in vivo using LAMP. The method may be useful for monitoring of successful chicken vaccination as well as in vitro studies in infected cell cultures. PMID- 25920567 TI - The application of single strand conformation polymorphism (SSCP) analysis in determining Hepatitis E virus intra-host diversity. AB - Genetic heterogeneity of RNA populations influences virus pathogenesis, epidemiology and evolution. Therefore, accurate information regarding virus genetic structure is highly important for both diagnostic and scientific purposes. For the Hepatitis E virus (HEV), the causal agent of hepatitis in humans, the intra-host population structure has been poorly investigated, mainly using the less sensitive RFLP-based approach. The objective of this study was to assess the suitability and the accuracy of single strand conformation polymorphism (SSCP) analysis, a well-established tool in genetic variation research, for the characterization of HEV quasispecies. The analysis was conducted on 50 clones of five swine isolates and 30 clones of three human HEV isolates. To identify and quantify the sequence variants present in each HEV isolate, 348bp long fragments of the amplified conserved ORF2 region were separated by cloning. Ten clones per isolate were subjected to SSCP and sequenced in a parallel experiment. The results show a high correlation of SSCP haplotype profiling with the sequencing results, confirming the sensitivity and reliability of this simple, rapid and low cost approach in the characterization of HEV quasispecies. PMID- 25920568 TI - Detection of viable murine norovirus using the plaque assay and propidium monoazide-combined real-time reverse transcription-polymerase chain reaction. AB - Human norovirus (HuNoV) is the most common cause of gastroenteritis worldwide. The lack of a virus culture system makes it difficult to determine the viability of norovirus by only reverse transcription-polymerase chain reaction (RT-PCR) or real-time quantitative RT-PCR (qRT-PCR). The aim of this study was to investigate the detection of viable murine norovirus (MNV) by combining propidium monoazide (PMA) or ethidium monoazide (EMA) with qRT-PCR. MNV (5.21log10PFU/mL) was subjected to heat treatment at room temperature, 65, 70, 75, 80, 85, or 90 degrees C in a water bath for 1min. The plaque assay, qRT-PCR, PMA-combined qRT PCR, and EMA-combined qRT-PCR were then performed with heat exposed MNV samples. The MNV titer was reduced by 0.38, 1.34, and 3.71log10PFU/mL at temperatures of 65, 70, and 75 degrees C, respectively. MNV was reduced >4.21log10PFU/mL at 80, 85, and 90 degrees C heat inactivation. PMA (EMA) value equation for the interpretation of the viability of MNV was derived as follows: PMA (EMA) value= logRN-logRP (RN: the relative quantity value of the not-treated sample, and RP: the relative quantity value of the PMA- or EMA-treated sample as determined by qRT-PCR). By PMA-combined qRT-PCR, the viable PMA value was 0.32, 0.83, and 2.62 for the 65, 70, and 75 degrees C preheated MNVs, respectively. The viable PMA values for the viruses heated at 80, 85, and 90 degrees C were all greater than 3.0, which was the cutoff value for discriminating between live and dead MNVs. The results of EMA-combined qRT-PCR were similar to those of qRT-PCR. Thus, PMA combined qRT-PCR correlated well with the plaque assay in detecting viable MNVs. PMID- 25920569 TI - APJ Regulates Parallel Alignment of Arteries and Veins in the Skin. AB - Molecular pathways regulating the development of arterial and venous endothelial cells (ECs) are now well established, but control of parallel arterial-venous alignment is unclear. Here we report that arterial-venous alignment in the skin is determined by apelin receptor (APJ) expression in venous ECs. One of the activators of APJ is apelin. We found that apelin is produced by arterial ECs during embryogenesis, induces chemotaxis of venous ECs, and promotes the production of secreted Frizzled-related protein 1 (sFRP1) by APJ(+) ECs. sFRP1 stimulates matrix metalloproteinase production by Ly6B.2(+) neutrophil-like cells located between the arteries and veins, resulting in remodeling of extracellular matrices to support venous displacement. Moreover, using apelin- or APJ-deficient mice, which exhibit arterial-venous disorganization, we found that arterial venous alignment is involved in thermoregulation, possibly by regulating countercurrent heat exchange. We hypothesize that the evolution of parallel juxtapositional arterial-venous alignment was an adaptation to reduce body heat loss. PMID- 25920570 TI - REPTOR and REPTOR-BP Regulate Organismal Metabolism and Transcription Downstream of TORC1. AB - TORC1 regulates growth and metabolism, in part, by influencing transcriptional programs. Here, we identify REPTOR and REPTOR-BP as transcription factors downstream of TORC1 that are required for ~ 90% of the transcriptional induction that occurs upon TORC1 inhibition in Drosophila. Thus, REPTOR and REPTOR-BP are major effectors of the transcriptional stress response induced upon TORC1 inhibition, analogous to the role of FOXO downstream of Akt. We find that, when TORC1 is active, it phosphorylates REPTOR on Ser527 and Ser530, leading to REPTOR cytoplasmic retention. Upon TORC1 inhibition, REPTOR becomes dephosphorylated in a PP2A-dependent manner, shuttles into the nucleus, joins its partner REPTOR-BP to bind target genes, and activates their transcription. In vivo functional analysis using knockout flies reveals that REPTOR and REPTOR-BP play critical roles in maintaining energy homeostasis and promoting animal survival upon nutrient restriction. PMID- 25920572 TI - Global surgery opportunities for U.S. surgical residents: an interim report. AB - INTRODUCTION: In 2011, the Accreditation Council for Graduate Medical Education (ACGME) and the American Board of Surgery developed guidelines that allowed time spent and cases performed outside of the United States by surgical residents from ACGME-accredited training programs to be applied toward program completion. We hypothesized that the number of programs with global surgical rotations would have increased after that important development. We also sought to determine the characteristics that led to sustainment of such programs. METHODS: An Institutional Review Board-approved electronic survey was sent to all 253 program directors of ACGME-approved general surgery residencies requesting information on international rotations available to residents. Responses were requested from program directors with extant rotations. Survey questions focused on locations, funding, nature of the rotations, faculty involvement, keys to success, and the barriers to overcome during program development and sustainment. RESULTS: The survey reported 34 surgery residency programs offering global surgery rotations, up from 23 just 5 years previously. Of these reporting programs, 25 have been approved by the ACGME. Most rotations occur in the postgraduate year 3 or 4 and are primarily clinical rotations. Africa is the main destination. Resident supervision is provided by a mixture of host and home surgeons. A dedicated faculty is considered to be the most important element for success while funding remains a major impediment. CONCLUSIONS: The interest in global surgery continues to increase, and general surgical programs will strive to meet the expectations of residents looking for international exposure. Collaboration could facilitate resident opportunities and potentially be more cost-effective. PMID- 25920571 TI - Asthma Treatments and Mental Health Visits After a Food and Drug Administration Label Change for Leukotriene Inhibitors. AB - PURPOSE: In 2009, the US Food and Drug Administration (FDA) mandated a label change for leukotriene inhibitors (LTIs) to include neuropsychiatric adverse events (eg, depression and suicidality) as a precaution. This study investigated how this label change affected the use of LTIs and other asthma controller medications, mental health visits, and suicide attempts. METHODS: We analyzed data (2005-2010) from 5 large health plans in the US Population-Based Effectiveness in Asthma and Lung Diseases (PEAL) Network. The study cohort included children and adolescents (n = 30,000), young adults (n = 20,000), and adults (n = 90,000) with asthma. We used interrupted time series to examine changes in rates of LTI dispensings, non-LTI dispensings, mental health visits, and suicide attempts (using a validated algorithm based on a combination of diagnoses of injury or poisoning and psychiatric conditions). FINDINGS: The label change was associated with abrupt reductions in LTI use among all age groups (relative reductions of 8.3%, 15.1%, and 6.0% among adolescents, young adults, and adults, respectively, compared with expected rates at 1 year after the warnings). Although we detected immediate offset increases in non-LTI asthma medication use, these increases were not sustained among adolescents and young adults. There were small increases in mental health visits among LTI users. IMPLICATIONS: The FDA label change for LTIs communicated possible risk of neuropsychiatric events. Communication and enhanced awareness may have increased reporting of mental health symptoms among young adults and adults. It is important to assess intended and unintended consequences of FDA warnings and label changes. PMID- 25920573 TI - Improving Learning Efficiency of Factual Knowledge in Medical Education. AB - OBJECTIVE: The purpose of this review is to synthesize recent literature relating to factual knowledge acquisition and retention and to explore its applications to medical education. RESULTS: Distributing, or spacing, practice is superior to massed practice (i.e. cramming). Testing, compared to re-study, produces better learning and knowledge retention, especially if tested as retrieval format (short answer) rather than recognition format (multiple choice). Feedback is important to solidify the testing effect. CONCLUSIONS: Learning basic factual knowledge is often overlooked and under-appreciated in medical education. Implications for applying these concepts to smartphones are discussed; smartphones are owned by the majority of medical trainees and can be used to deploy evidence-based educational methods to greatly enhance learning of factual knowledge. PMID- 25920574 TI - Schwannoma of the Fourth Ventricle: The Eighth Case Report. AB - OBJECTIVE: We report an uncommon case of a surgical resection of a fourth ventricle tumor in an adult that proved to be a schwannoma. METHODS: A 53-year old man presented with a 1.5-year history of gait unsteadiness and vertigo and a few-week history of headache, emesis, and neurogenic dysphagia. A brain magnetic resonance imaging revealed a large, heterogeneously contrast enhancing mass located within the fourth ventricle, compressing the brainstem and causing supratentorial ventricle enlargement. A suboccipital craniotomy and a telovelar approach were performed to resect the tumor. The ventricular system was repermeabilized at the end of the operation. RESULTS: A postoperative magnetic resonance imaging confirmed complete tumor removal. There was an initial worsening of the preoperative deficits, which progressively improved. The tumor was classified as a fourth ventricle schwannoma. There has been no evidence of tumor recurrence during the 6 years of follow-up. At present, the patient is ambulatory and reports an intermittent diplopia on conjugated gaze. CONCLUSION: This case report intends to reveal the eighth case of a fourth ventricle schwannoma since 1957. Schwannomas of the fourth ventricle are infrequent but should be accounted in the differential diagnosis of space-occupying lesions in this location. Gross total resection might be the definite treatment of these tumors if deemed possible. PMID- 25920575 TI - The peroxidase activity of ADM-Fe(3+) cooperates with lipid peroxidation: The participation of hydroperoxide and hydroxyl radicals in the damage to proteins and DNA. AB - To investigate the mechanisms of cardiotoxicity induced by adriamycin (ADM), the enzymatic activities of ADM-Fe(3+), including the peroxidase and lipoxygenase (LOX) activity, and participation of active oxygen species in the damage to biological components were examined. ADM-Fe(3+), but not ADM, steadily oxidized tetramethyl-p-phenylenediamine in the presence of peroxides, indicating that ADM Fe(3+) acts as a peroxidase. However, the activity of ADM-Fe(3+) as peroxidase was very low compared with that of heme peroxidase, but was similar to that of LOX, which has a known peroxidase activity. Conversely, the activity of ADM Fe(3+) as a LOX was also very low compared with that of LOX itself. However, the lipid hydroperoxides (LOOH) produced by ADM-Fe(3+) were the substrate for ADM Fe(3+) as a peroxidase. These findings indicate that lipid peroxidation cooperates with the peroxidase activity of ADM-Fe(3+). Hydroxyl radicals (HO) were generated when ADM-Fe(3+) was incubated with H2O2, but not with LOOH. Alcohol dehydrogenase was inactivated by LOOH. Conversely, DNA was mainly damaged by ADM-Fe(3+) with H2O2. A small amount of DNA remained at the starting point on agarose gels during incubation with ADM-Fe(3+) with LOOH and ADM-Fe(3+) with H2O2. It seems that HO and compound I-like species participate in the strand breaks and the aggregation of DNA, respectively. PMID- 25920576 TI - The impact of cationic solid lipid nanoparticles on human neutrophil activation and formation of neutrophil extracellular traps (NETs). AB - Cationic solid lipid nanoparticles (cSLNs) are extensively employed as the nanocarriers for drug/gene targeting to tumors and the brain. Investigation into the possible immune response of cSLNs is still lacking. The aim of this study was to evaluate the impact of cSLNs upon the activation of human polymorphonuclear neutrophil cells (PMNs). The cytotoxicity, pro-inflammatory mediators, Ca(2+) mobilization, mitogen-activated protein kinases (MAPKs), and neutrophil extracellular traps (NETs) as the indicators of PMN stimulation were examined in this work. The cSLNs presented a diameter of 195 nm with a zeta potential of 44 mV. The cSLNs could interact with the cell membrane to produce a direct membrane lysis and the subsequent cytotoxicity according to lactate dehydrogenase (LDH) elevation. The interaction of cSLNs with the membrane also triggered a Ca(2+) influx, followed by the induction of oxidative stress and degranulation. The cationic nanoparticles elevated the levels of superoxide anion and elastase by 24 and 9-fold, respectively. The PMN activation by cSLNs promoted the phosphorylation of p38 and Jun-N-terminal kinases (JNK) but not extracellular signal-regulated kinases (ERK). The imaging of scanning electron microscopy (SEM) and immunofluorescence demonstrated the production of NETs by cSLNs. This phenomenon was not significant for the neutral SLNs (nSLNs), although histones in NETs also increased after treatment of nSLNs. Our results suggest an important role of cSLNs in governing the activation of human neutrophils. PMID- 25920577 TI - Synthesis of thiiranes by rhodium-catalyzed sulfur addition reaction to reactive alkenes. AB - A rhodium complex derived from RhH(PPh3)4, dppe, and 4-ethynyltoluene catalyzes the addition reaction of sulfur to norbornenes giving the corresponding thiiranes under acetone reflux conditions. The rhodium complex effectively transfers a sulfur atom to the double bond from sulfur, and exo-adducts are obtained. The reaction is also applicable to (E)-cyclooctene and cyclic allenes. The ring opening reaction of the thiiranes with lithium aluminium hydride gives the corresponding thiols. PMID- 25920579 TI - Heterotopic pregnancy identified in the postpartum period. PMID- 25920578 TI - The effects of age, education, and treatment on physical, sexual and body concern symptoms among multimorbid, colorectal cancer survivors. AB - OBJECTIVE: Less is known about longitudinal changes in quality of life between treatment completion and early survivorship among multimorbid cancer survivors. The current study describes longitudinal changes in quality of life among a multimorbid cohort of US Veterans diagnosed and treated for colorectal cancer. MATERIALS AND METHODS: A sample of 68 multimorbid adults with colon and/or rectal cancer who received one or more treatment options (surgery, chemo or radiation therapy) was recruited. Participants were not excluded by cancer stage unless they reported being in hospice or similar status. Comprehensive assessments of quality of life and treatment side-effects were conducted 6, 12, and 18months after diagnosis. Descriptive statistics characterized treatment side-effects and changes in quality-of-life domains longitudinally. Multivariate Analysis of Variance identified sociodemographic and clinical variables associated with quality of life changes. RESULTS: Many physical symptoms improved from 6 to 18months following diagnosis, while some remained stable. Sexual symptoms worsened, attributable to increasing rates of dysfunction in older patients. Low education attainment was predictive of worse physical symptoms (F=5.59, p=.023) and associated with body concerns (F=5.7; p=.005) over time. Advanced cancer stage (F=4.94; p<.04) and receipt of chemotherapy (F=4.21; p<.05) independently predicted body concerns in multivariate analyses. CONCLUSION: Endorsement of physical and sexual symptoms and body concerns occurs in different patterns over time among multimorbid colorectal cancer survivors. Low education attainment is consistently associated with physical symptoms and body concerns. Cancer stage and chemotherapy are predictive of body concerns, but not physical or sexual symptoms. PMID- 25920580 TI - Announcing the winner of the John J. Sciarra IJGO Prize Paper Award for 2014. AB - The editors of the International Journal of Gynecology and Obstetrics (IJGO) are pleased to announce the winner of the prize paper award for the best clinical research paper from a low- or middle-income country published in the IJGO during 2014. The winning paper is: Dan K. Kaye, Othman Kakaire, Annettee Nakimuli, Scovia N. Mbalinda,Michael O. Osinde, Nelson Kakande. Survivors' understanding of vulnerability and resilience to maternal near-miss obstetric events in Uganda. Int J Gynecol Obstet 2014;127(3):265-8. It was published in the December 2014 issue of the IJGO. PMID- 25920581 TI - Professionalism: The Patient's Perspective. PMID- 25920582 TI - The disruptive radiologist. AB - Radiologists interact with many individuals during daily practice, including patients, technologists, and other physicians. Some interactions may potentially negatively affect patient care and are termed "disruptive" behaviors. These actions are not uncommon and may begin during training, long before a radiologist enters clinical practice. The causes of disruptive behavior are multifactorial, and it is important that educators and radiologists in practice alike be able to identify them and respond accordingly. An escalated approach for both trainees and practicing radiologists is recommended, with substantial penalties after each incident that can include termination of employment. Training programs and practices must have clearly defined methods for confronting this potentially time consuming and difficult issue. PMID- 25920583 TI - Emotions experienced at event recall and the self: Implications for the regulation of self-esteem, self-continuity and meaningfulness. AB - The intensity of positive affect elicited by recall of positive events exceeds the intensity of negative affect elicited by recall of negative events (fading affect bias, or FAB). The research described in the present article examined the relation between the FAB and three regulatory goals of the self: esteem, continuity and meaningfulness. The extent to which an event contributed to esteem (Study 1), continuity (Study 2) or meaningfulness (Study 3) was related to positive affect at event recall provoked by positive memories and to negative affect at event recall provoked by negative memories. The relation between affect experienced at recall and the three regulatory goals was bidirectional. The results showcase how individuals use recall for self-regulatory purposes and how they implement self-regulatory goals for positive affect. PMID- 25920584 TI - Diminished swelling of cross-linked aromatic oligoamide surfaces revealing a new fouling mechanism of reverse-osmosis membranes. AB - Swelling of the active layer of reverse osmosis (RO) membranes has an important effect on permeate water flux. The effects of organic- and biofouling on the swelling of the RO membrane active layer and the consequent changes of permeate flux are examined here. A cross-linked aromatic oligoamide film that mimics the surface chemistry of an RO polyamide membrane was synthesized stepwise on gold coated surfaces. Foulant adsorption to the oligoamide film and its swelling were measured with a quartz crystal microbalance, and the effects of fouling on the membrane's performance were evaluated. The foulants were extracellular polymeric substances (EPS) extracted from fouled RO membranes and organic compounds of ultrafiltration permeate (UFP) from a membrane bioreactor used to treat municipal wastewater. The adsorbed foulants affected the swelling of the cross-linked oligoamide film differently. EPS had little effect on the swelling of the oligoamide film, whereas UFP significantly impaired swelling. Permeate flux declined more rapidly under UFP fouling than it did under EPS. Foulant adsorption was shown to diminish swelling of the aromatic oligoamide surfaces. Among the already known RO membrane fouling mechanisms, a novel RO fouling mechanism is proposed, in which foulant-membrane interactions hinder membrane swelling and thus increase hydraulic resistance. PMID- 25920585 TI - Stripping surgery in facial nerve schwannomas with favorable facial nerve function. AB - OBJECTIVE: We report 18 cases of facial nerve schwannomas in which stripping surgery was attempted to preserve facial nerve integrity and favorable facial nerve function. METHODS: We attempted stripping surgery on 18 cases of facial nerve schwannomas. Postoperative facial nerve function was evaluated. RESULTS: Stripping surgery was successfully achieved in 11 cases, and facial nerve decompression was performed on the remaining 7 cases in which stripping surgery was impossible. Favorable facial nerve function was successfully maintained in all cases who underwent stripping surgery and 5 of 7 cases who underwent facial nerve decompression. CONCLUSIONS: It was possible to accomplish stripping surgery in most cases with favorable facial nerve function, which maintained good facial nerve function after total tumor removal. PMID- 25920586 TI - Cervical and ocular vestibular evoked myogenic potentials in Behcet's disease. AB - OBJECTIVE: To investigate vestibular evoked myogenic potentials combined with audiologic status in Behcet's disease (BD) and to compare the results with normal healthy subjects. METHODS: Cervical vestibular evoked myogenic potential (cVEMP) test, ocular vestibular evoked myogenic potential (oVEMP) test, Dix-Hallpike test, conventional pure tone audiometry (cPTA) and high frequency audiometry (HFA), and 226 and 1000Hz tympanometry were performed to each subject of the study. Cranial magnetic resonance imaging (MRI) with contrast enhancement was also performed to evaluate the central nervous system (CNS) in patients with BD. RESULTS: VEMP parameters including the mean peak latencies of p13-n23 and n10 p15, AR values and thresholds were not statistically different both in cVEMP and oVEMP between the BD and control groups. Except for 250Hz, mean audiological thresholds were significantly higher in the BD group. Five of the 20 patients had pathological cranial MRI findings that may be compatible with central nervous system involvement. CONCLUSION: To our knowledge, the present study is the first report investigating oVEMP and cVEMP responses combined with MRI findings in patients with BD. The presence of high frequency hearing loss is a common finding in BD and HFA may help early detection of hearing loss in patients with BD when combined with cPTA. PMID- 25920587 TI - Basic response properties of auditory nerve fibers: a review. AB - All acoustic information from the periphery is encoded in the timing and rates of spikes in the population of spiral ganglion neurons projecting to the central auditory system. Considerable progress has been made in characterizing the physiological properties of type-I and type-II primary auditory afferents and understanding the basic properties of type-I afferents in response to sounds. Here, we review some of these properties, with emphasis placed on issues such as the stochastic nature of spike timing during spontaneous and driven activity, frequency tuning curves, spike-rate-versus-level functions, dynamic-range and spike-rate adaptation, and phase locking to stimulus fine structure and temporal envelope. We also review effects of acoustic trauma on some of these response properties. PMID- 25920588 TI - Alteration in the podoplanin-ezrin-cytoskeleton linkage is an important initiation event of the podocyte injury in puromycin aminonucleoside nephropathy, a mimic of minimal change nephrotic syndrome. AB - Podoplanin was identified as a protein associated with the transformation of arborized foot processes of glomerular epithelial cells (podocytes) to flat feet. However, the function of podoplanin in the podocyte is not yet fully clarified. In this study, we analyzed the molecular nature of podoplanin, and its expression in rat nephrotic models and patients with minimal change nephrotic syndrome (MCNS). We demonstrated here that podoplanin has two forms: one contains abundant sialic acid and the other a lesser amount of sialic acid. Podoplanin bound ezrin to interact with the cytoskeleton. The silencing of podoplanin in cultured podocytes caused a change in the cell shape and the distribution of ezrin and actin. The expression of podoplanin was clearly reduced before the onset of proteinuria in puromycin aminonucleoside (PAN) nephropathy, a mimic of MCNS, and the decrease in the expression of podoplanin became more evident at the proteinuric stage. Podoplanin was detected in normal urine samples, and the amount of urinary podoplanin markedly increased on day 1 of PAN nephropathy. Urinary ezrin was also detected. The amount of the phosphorylated ezrin was reduced, while the amount of the podoplanin-interacting ezrin increased. The podoplanin expression was reduced in a patient with active-phase MCNS. It is conceivable that the alteration of the podoplanin-ezrin-cytoskeleton linkage is an important event of the podocyte injury in MCNS. PMID- 25920589 TI - miR-124 disinhibits neurite outgrowth in an inflammatory environment. AB - Lesions of the central nervous system elicit inflammatory responses that counteract the regeneration of neurites. Microglia and infiltrating macrophages that were activated by trauma have been identified as cellular sources of inhibitory factors. We examine cultured macrophage (RAW264.7) and neuronal (PC12) cell lines to ascertain the potential modulators of the inflammatory impact on neurons. By exposing quiescent macrophages to lipopolysaccharide (LPS) and interferon gamma (IFN-gamma), cells can be transformed into an activated M1 phenotype. Neurite extension was induced in PC12 cells by culturing them in the presence of nerve growth factor. Neurite outgrowth was quantified by analyzing immunofluorescence and phase contrast microscopy images. Activated macrophages significantly reduced neurite extension. Macrophage activation by LPS/IFN-gamma induced a 1000-fold increase in tumor necrosis factor alpha (TNF-alpha) secretion, as quantified by enzyme-linked immunosorbent assays (ELISA). Recombinant TNF-alpha inhibited neurite formation at concentrations as low as 0.016 ng/ml. In contrast, the masking of TNF-alpha with specific functional antibodies abrogated neurite growth inhibition by activated macrophages. Taken together, these results indicated that TNF-alpha is a key component of inhibitory macrophage action. The transfection of PC12 neurons with microRNA-124 (miR-124) counteracted the inhibition of neurites mediated by both recombinant TNF-alpha and macrophages. miR-124 did not stimulate neurite formation per se, nor was cell viability affected. These data suggest that miR-124 might be a valuable tool for desensitizing neurons to a repulsive inflammatory environment. PMID- 25920591 TI - Prognostic significance of cytokine receptor-like factor 2 alterations in acute lymphoblastic leukemia: a meta-analysis. AB - BACKGROUND: Cytokine receptor-like factor 2 (CRLF2) has been shown to play a role in the pathogenesis of acute lymphoblastic leukemia (ALL). Studies have examined the relationship between CRLF2 alterations such as over-expression or deregulation and clinical outcome in childhood ALL, but the results are conflicting. This meta-analysis aimed to explore the association between CRLF2 alterations and survival of pediatric patients with ALL. METHODS: Electronic databases updated to March 2014 were searched for relevant studies. A meta analysis was made of twelve studies including 5945 patients to evaluate the prognostic significance of CRLF2 alterations on survival in childhood ALL. Hazards ratios (HRs) with 95% confidence intervals (CIs) were pooled across the studies using a fixed-effects model. RESULTS: CRLF2 over-expression in childhood ALL was associated with poor prognosis in terms of relapse-free survival (RFS; HR=1.70, 95% CI=1.28-2.24, P=0.000), event-free survival (EFS; HR=1.78, 95% CI=1.05-3.01, P=0.032), and overall survival (OS; HR=2.28, 95% CI=1.42-3.65, P=0.001). The combined data also suggested that CRLF2 deregulation in childhood ALL was correlated with poor EFS (HR=1.95, 95% CI=1.46-2.61, P=0.000), RFS (HR=2.20, 95% CI=1.53-3.18, P=0.000), and OS (HR=1.89, 95% CI=1.24-2.87, P=0.003). Subgroup analysis on multivariate HRs showed that CRLF2 deregulation independently predicted a poor prognosis for childhood ALL. CONCLUSIONS: The present meta-analysis reveals that both CRLF2 over-expression and deregulation are associated with poor prognosis in pediatric patients with ALL. PMID- 25920590 TI - Childhood obesity and food intake. AB - BACKGROUND: The prevalence of obesity among children is growing in China at present. Childhood obesity reflects complex interactions of genetic, environmental, social and behavioral factors. Foods, nutritional components, and food intake patterns may be associated with the increasing obesity rate in children. DATA SOURCES: Articles about the relationship between childhood obesity and food intake were collected from the databases including Web of Knowledge, PubMed, Elsevier and Google Scholar. RESULTS: Foods and nutritional components such as calcium, dietary fiber are inversely related to obesity, whereas others such as vitamin B and sugar-sweeten beverages play a positive role in obesity development. The differences in food intake pattern also influence the risk of obesity. CONCLUSIONS: Food intake is an important factor influencing childhood obesity. One strategy to prevent childhood obesity is to take foods of moderate amount in a proper pattern. PMID- 25920592 TI - A novel large deletion (exons 12, 13) and a missense mutation (p.G46R) in the PAH in a Japanese patient with phenylketonuria. AB - BACKGROUND: Phenylketonuria (PKU) is caused by a defect in phenylalanine hydroxylase (PAH). More than 500 mutations have been reported for the gene encoding PAH. However, approximately 1%-5% of these include large deletions and large duplications that cannot be detected by conventional methods. METHODS: In this report we tried to fully characterize a PAH-deficient patient. The patient was a 2-year-old Japanese boy who was diagnosed with classical PKU at the time of neonatal screening, which was confirmed by the tetrahydrobiopterin-loading test. PCR-related direct sequencing and multiplex ligation-dependent probe amplification (MLPA) were used to analyze of the PAH of the patient. RESULTS: Using PCR-related direct sequencing method, we could detect only a heterozygous novel missense mutation: p.136G>C (p.G46R). A second mutation was detected by MLPA. The patient was heterozygous for a novel large deletion of exons 12 and 13: c.1200-?_1359+?del (EX12_13del). For genetic counseling, an accurate genetic diagnosis is often necessary. CONCLUSIONS: Through a combination of MLPA and conventional methods, the success rate of PAH mutation identification can be close to 100%. PMID- 25920593 TI - Betaine alleviates hepatic lipid accumulation via enhancing hepatic lipid export and fatty acid oxidation in rats fed with a high-fat diet. AB - To assess the effects of betaine on hepatic lipid accumulation and investigate the underlying mechanism, thirty-two male Sprague-Dawley rats weighing 100 (sd 2.50) g were divided into four groups, and started on one of four treatments: basal diet, basal diet with betaine administration, high-fat diet and high-fat diet with betaine administration. The results showed that no significant difference of body weight was found among experimental groups. Compared with high fat diet-fed rats, a betaine supplementation decreased (P< 0.05) hepatic TAG accumulation induced by high-fat diet, which was also supported by hepatic histology results. Additionally, hepatic betaine-homocysteine methyltransferase concentration [corrected] as well as its mRNA abundance and lecithin level were found increased (P< 0.05) by betaine supplementation in both basal diet-fed rats and high-fat diet-fed rats. Betaine administration in high-fat diet-fed rats exhibited a higher (P< 0.05) concentration [corrected] of hepatic carnitine palmitoyltransferase 1 (CPT1) compared with high-fat diet-fed rats. High-fat diet inhibited (P< 0.05) the gene expression of hepatic PPARalpha and CPT1. However, betaine administration in high-fat diet-fed rats elevated (P< 0.05) the gene expression of PPARalpha and CPT1. Moreover, concentration, gene and protein expressions of hepatic fibroblast growth factor 21 (FGF21) were increased (P< 0.05) in response to betaine administration in high-fat diet group; meanwhile the gene expression of hepatic AMP-activated protein kinase was increased (P< 0.05) as well. The results suggest that betaine administration enhanced hepatic lipid export and fatty acid oxidation in high-fat diet-fed rats, thus effectively alleviating fat accumulation in the liver. PMID- 25920595 TI - Magnetophoretic assembly of flexible nanoparticles/lipid microfilaments. AB - The directed assembly of colloidal particles into linear chains and clusters is of fundamental and practical importance. In this study we characterize and analyse the mechanism of the magnetic field driven assembly of lipid-coated iron oxide nanoparticles into flexible microfilaments. Recently we showed that nanocapillary lipid binding can form a new class of magnetic nanoparticle-lipid microfilaments with unprecedented flexibility and self-healing properties. In the presence of a uniform magnetic field, the magnetophoretic attraction of the particles combined with interparticle dipole-dipole attraction drives the microfilament assembly. The fluid like lipid layer on the particles leads to stickiness on the surface of the filaments and the magnetic field concentration overcomes the potential electrostatic repulsion in the water phase. The lipid capillary bridges formed between the particles facilitate their permanent binding and sustain the flexible microfilament structure. We demonstrate that this surface stickiness combined with the magnetic response of the filaments can be used further to twist, bend and bundle the microfilaments into unusual structures. PMID- 25920594 TI - Synthesis of 2-(2,4-dihydroxyphenyl)thieno-1,3-thiazin-4-ones, their lipophilicity and anticancer activity in vitro. AB - A new one-step synthesis of novel biologically active 2-substituted 2,4 dihydroxyphenyl-4[Formula: see text]-thieno[3,2-[Formula: see text]][1,3]thiazin 4-ones and 4[Formula: see text]-thieno[2,3-[Formula: see text]][1,3]thiazin-4 ones has been elaborated and described. The compounds were prepared by the reaction of aryl-modified sulfinylbis [(2,4-dihydroxyphenyl)methanethione]s and the corresponding aminothiophenecarboxamides. The derivatives showed anticancer activity in vitro. These compounds inhibited the proliferation and viability of lung cancer A549, colon cancer HT-29 and glioma C6 cells in a concentration dependent manner. Some of the derivatives had no influence on normal skin fibroblasts culture viability. Moreover, one compound (1b) showed the ability to inhibit DNA synthesis in cancer cells, especially in C6 cells, and was not toxic for normal oligodendrocytes and hepatocytes. Using reversed phase RP 18 HPLC and immobilised artificial membrane (IAM) chromatography the phase affinity of the compounds was determined. The influence of lipophilicity on the activity of compounds has been discussed. PMID- 25920596 TI - Methodological issues identified during cognitive interviews in the development of a pediatric cancer symptom screening tool. PMID- 25920597 TI - Botulinum toxin therapy for temporomandibular joint disorders: a systematic review of randomized controlled trials. AB - The objective of this study was to undertake a systematic review to assess the efficacy of botulinum toxin therapy (BTX) for temporomandibular joint disorders (TMDs). A comprehensive search of major databases through PubMed, EMBASE, and Cochrane CENTRAL was conducted to locate all relevant articles published from inception to October 2014. Eligible studies were selected based on inclusion criteria and included English language, peer-reviewed publications of randomized controlled trials comparing BTX versus any alternative intervention or placebo. Quality assessment and data extraction were done according to the Cochrane risk of bias tool and recommendations. The entire systematic search and selection process was done independently by two reviewers. Five relevant study trials were identified, involving 117 participants. Two trials revealed a significant between group difference in myofascial pain reduction, another trial that compared BTX with fascial manipulation showed equal efficacy of pain relief on TMDs, while the remaining two trials showed no significant difference between the BTX and placebo groups. Because of considerable variations in study methods and evaluation of results, a meta-analysis could not be performed. Based on this review, no consensus could be reached on the therapeutic benefits of BTX on TMDs. A more rigorous design of trials should be carried out in future studies. PMID- 25920598 TI - Pre-operative embolisation of spinal metastasis: technique, complication rate and outcome-clinical experience. AB - PURPOSE: Pre-operative embolisation of metastatic spinal tumours has the potential to decrease intra-operative blood loss. Intra-operative blood loss is multifactorial and one factor may be the embolisation technique used. The purpose of this study was to retrospectively analyse the effect of three different pre operative embolisation techniques on intra-operative blood loss, complication rate and tumour aetiology in patients treated with a corpectomy and dorsoventral stabilisation at our institution. METHODS: We conducted a retrospective analysis of embolisation procedures for vertebral metastases performed from January 2002 to December 2011. Only pre-operatively embolised patients treated by a single level hemicorpectomy or corpectomy procedure from T4-L5, including posterior spinal stabilisation using pedicle screws, were included. All patient charts and examinations were analysed regarding the embolisation technique, gender, age, primary tumour, time between the embolisation and surgery, intra-operative blood loss, intra-operative transfusions and complications related to embolisation. RESULTS: We identified a total of 46 patients, 25 male and 21 female patients. The mean age at the time of surgery was 66 years (range 39-84 years). The tumours treated were: 15 (33%) renal cell carcinomas, six (13%) breast carcinomas, five (11%) lung carcinomas, five (11%) urothelial carcinomas, four (9%) myelomas and 11 (24%) miscellaneous types including rectal carcinoma, thymoma and melanoma. Embolisation with coils was performed in 23 patients, particles were used in six and a combination of coils and particles in 18. The mean time between the embolisation and surgery was 23 hours (range 80-4,430 minutes). The median overall intra-operative estimated blood loss (EBL) was 2,300 ml (range 500-15,000 ml). In patients embolised with coils and particles, EBL was 2,200 ml compared to 1,450 ml in patients embolised with particles and 2,500 ml in the coil group. No statistically significant differences between the three groups could be detected. There were no complications related to the embolisation techniques. CONCLUSIONS: Pre-operative embolisation of spinal metastases using coils, particles or a combination of both is a safe and reproducible procedure. In our cohort we reported no complications during the three different embolisation techniques. No statistically significant difference regarding blood loss between the three embolisation techniques could be detected. Our data confirm existing studies concerning the control of intra-operative blood loss using different embolisation techniques. The benefit of embolisation with a combination of coils and particles compared to embolisation with particles only is questionable. PMID- 25920599 TI - Effectiveness of polydeoxyribonucleotide injection versus normal saline injection for treatment of chronic plantar fasciitis: a prospective randomised clinical trial. AB - PURPOSE: Polydeoxyribonucleotide (PDRN) has been used for the treatment of chronic tendinosis. This prospective randomised study was conducted to evaluate the efficacy and complications of PDRN injection for treatment of plantar fasciitis. METHODS: Forty patients with a clinical diagnosis of plantar fasciitis were randomly allocated to PDRN injection (PDRN group, n = 20) or normal saline injection (placebo group, n = 20). Injections were performed weekly for three weeks. Clinical evaluations were done at baseline and four and 12 weeks after treatment began using the visual analogue scale (VAS) for foot pain and Manchester-Oxford Foot Questionnaire (MOXFQ). We also monitored the complications in both groups at one, two, four and 12 weeks after initial treatment. RESULTS: The PDRN group achieved a significant improvement in VAS and MOXFQ scores at four weeks after treatment, and this improvement continued until 12 weeks after treatment. On the other hand, the placebo group did not achieve a significant improvement in the VAS or MOXFQ scores at four or 12 weeks. The initial VAS and MOXFQ scores of the PDRN group were not significantly different from those of the placebo group. At four weeks after treatment, the VAS and MOXFQ scores of the PDRN group were better than those of the placebo group, but the difference was not statistically significant. At 12 weeks after treatment, the VAS and MOXFQ scores of the PDRN group were significantly better than those of the placebo group. We noticed no injection-related complications, such as itching, urticaria, redness or infection signs around the injection site in either group. CONCLUSIONS: PDRN injection is an effective and safe treatment option and may be considered for plantar fasciitis. PMID- 25920600 TI - The impact of standard combined anteversion definitions on gait and clinical outcome within one year after total hip arthroplasty. AB - PURPOSE: Different target areas within the concept of combined cup and stem anteversion have been published for total hip arthroplasty (THA). We asked whether component positioning according to eight standard combined anteversion rules is associated with (1) more physiological gait patterns, (2) higher improvement of gait variables and (3) better clinical outcome after THA. METHODS: In a prospective clinical study, 60 patients received cementless THA through an anterolateral MIS approach in a lateral decubitus position. Six weeks postoperatively, implant position was analysed using 3D-CT by an independent external institute. Preoperatively, six and 12 months postoperatively range of motion, normalized walking speed and hip flexion symmetry index were measured using 3D motion-capture gait analysis. Patient-related outcome measures (HHS, HOOS, EQ-5D) were obtained by an observer blinded to 3D-CT results. Eight combined anteversion definitions and Lewinnek's "safe zone" were evaluated regarding their impact on gait patterns and clinical outcome. RESULTS: Combined cup and stem anteversion according to standard combined anteversion definitions as well as cup placement within Lewinnek's "safe zone" did not influence range of motion, normalized walking speed and/or hip flexion symmetry index six and 12 months after THA. Similarly, increase of gait parameters within the first year after THA was comparable between all eight combined anteversion rules. Clinical outcome measures like HHS, HOOS and EQ-5D did not show any benefit for either of the combined anteversion definitions. CONCLUSIONS: Standard combined cup and stem anteversion rules do not improve postoperative outcome as measured by gait analysis and clinical scores within one year after THA. PMID- 25920602 TI - The risk of contralateral breast cancer in daughters of women with and without breast cancer. AB - We aimed to estimate the 15-year and lifetime risks of contralateral breast cancer in breast cancer patients according to the age of diagnosis of the first cancer and the history of breast cancer in the mother. The risks of contralateral breast cancer were estimated for all 78,775 breast cancer patients in the Swedish Family-Cancer Database (age at diagnosis of first breast cancer <70 years). The risk of experiencing a contralateral breast cancer within 15 years of diagnosis was 8.4% [95% confidence interval (CI): 8.1-8.7%] for women with an unaffected mother, was 12% (95%CI: 11-13%) for a woman with a mother with unilateral breast cancer and was 13% (95%CI: 9.5-17%) for women with a mother with bilateral breast cancer. In early-onset diagnosed women (<50 years) with an unaffected mother, the risk of contralateral breast cancer until age 80 was 23% (95%CI: 20-26%) and for late-onset (50-69 years) diagnosed women it was 17% (95%CI: 14-21%). In a woman with a mother with an early-onset unilateral breast cancer, risk of contralateral breast cancer by age 80 was 35% (95%CI: 25-46%). Women with a mother with early onset bilateral breast cancer had 31% (95%CI: 12-67%) lifetime risk of contralateral breast cancer. The risk of contralateral breast cancer is higher for daughters of breast cancer patients than for daughters of women without breast cancer. Maternal cancer history and age at onset of first breast cancer in women should be taken into account when counseling breast cancer patients about their risk of contralateral breast cancer. PMID- 25920601 TI - Comparison of the histopathological findings of patients with diabetic and idiopathic carpal tunnel syndrome. AB - PURPOSE: This study is aimed to investigate whether there are any histopathological differences between diabetic and idiopathic carpal tunnel syndromes. METHODS: The biopsy specimens were taken from transverse carpal ligament (TCL), tenosynovium adjacent to median nerve and epineurium of median nerve and evaluated in 47 patients (21 diabetic and 26 idiopathic) who were diagnosed with carpal tunnel syndrome (CTS) and treated surgically with open carpal tunnel release. Fibroblast proliferation, fibrosis, perivascular inflammation, oedema, vascular proliferation and vascular wall thickness were determined and scored in all specimens. RESULTS: There weren't any histopathological abnormalities in TCL specimens of both groups. Synovial hyperplasia, fibrosis and perivascular inflammation were not observed in tenosynovial analysis of both groups. Diabetic CTS patients, when compared with idiopathic CTS patients, had higher rates of synovial edema (idiopathic CTS 57 %, diabetic CTS 87 %), vascular proliferation (idiopathic CTS 30.8 %, diabetic CTS 90.5 %) and increased vascular wall thickness (idiopathic CTS 11.5 %, diabetic CTS 90.5 %). There was no oedema, fibrosis and perivascular inflammation of the epineurium in specimens of either group. But increases in vascular proliferation (idiopathic CTS 7.7 %, diabetic CTS 71.4 %) and vascular wall thickness (idiopathic CTS 3.8 %, diabetic CTS 71.4 %) was seen in the epineurium of diabetic patients and these differences were statistically significant (p < 0.05). CONCLUSION: Because of the severe synovial and epineurial histopathological abnormalities and inadequate neural regeneration capacity, surgical open carpal tunnel decompression should be planned earlier in diabetic CTS patients. Further studies should be considered to evaluate the histopathological features of diabetic CTS patients early in the course of the disease. PMID- 25920603 TI - Saving for delivery through technology: an inquiry into an electronic commitment savings product for maternal healthcare in Kenya. AB - Many women in low-income countries cannot afford maternal healthcare services. Changamka, a Kenyan company, developed an electronic, stored-value card to help pregnant women save for maternal healthcare at a Nairobi hospital. This paper reports results from a mixed-methods process evaluation of the card's implementation. The study found high levels of uptake and identified several benefits of the program, such as facilitating payment for services. The evaluation also identified several challenges. Most users completed only one transaction before discontinuing card use; only 6% of women who acquired the card used it to pay for delivery, and slightly less than 1% used it as it was originally intended-to pay for several antenatal care visits and for delivery. According to respondents, the main reason for this discontinuation was a lack of understanding about how to use the card. Users were, on average, of a higher socioeconomic and educational status than non-card users. Most users obtained the card in their third trimester, and among those who used the card to save for delivery, most started to do so too late in pregnancy to accumulate sufficient savings to pay for that service. Copyright (c) 2015 John Wiley & Sons, Ltd. PMID- 25920604 TI - Less may be more: nodal treatment in neck positive head neck cancer patients. AB - Ongoing debates about the need and extent of planned neck dissection (PND), and required nodal radiation doses volumes lead to this evaluation. Aim was to assess nodal control after definitive intensity modulated radiation therapy (IMRT +/- systemic therapy) followed by PND in our head neck cancer cohort with advanced nodal disease. Between 01/2005 and 12/2013, 99 squamous cell cancer HNC patients with pre-therapeutic nodal metastasis >=3 cm were treated with definitive IMRT followed by PND. In addition, outcome in 103 patients with nodal relapse after IMRT and observation only (no-PND cohort) were analyzed. Prior to PND, PET-CT, fine needle aspirations, ultrasound and palpation were assessed regarding its predictive value. Patterns of nodal relapse were assessed in patients with isolated neck failure after definitive IMRT alone. 70/99 (70 %) PND specimens showed histopathological complete response (hCR), which translated into statistically significantly superior survival compared with partial response (hPR) with 4-year overall survival, disease specific survival and nodal control rates of 90/83/96 vs 67/60/78 % (p = 0.002/0.001/0.003). 1/99 patient developed isolated subsequent nodal disease. 64/2147 removed nodes contained viable tumor (3 %). Predictive information of the performed diagnostic investigations was not reliable. 17/70 hCR patients showed true negative findings in available three to four investigations (0/29 hPR). 27/103 no-PND patients developed isolated neck disease (26 %) with successful salvage in 21/24 [88 %, or 21/27 (78 %)]. Nearly all failures occurred in the prior nodal gross tumor volume area. A more restrictive approach regarding PND and/or nodal IMRT dose-volumes may be justified. PMID- 25920605 TI - Meta-analysis of microRNA expression profiling studies in human cervical cancer. AB - Cervical cancer is one of the most common malignant tumors in women, and numerous studies have associated the disease with changes in microRNA (miRNA) expression. This meta-analysis aimed to consolidate and assess the results of these studies in order to identify potential miRNA biomarkers of cervical cancer. We systematically searched the literature for studies comparing miRNA expression between cervical cancer tissues and normal cervical tissues, and we meta-analyzed the result of 27 studies comprising 1,132 cancer samples and 943 normal samples. We used a vote-counting strategy that took into account total sample and mean fold-change, in order to comprehensively assess associations between certain miRNAs and cervical cancer occurrence and progression. The studies described 195 miRNAs that were significantly up-regulated and 96 microRNAs that were down regulated in cervical cancer tissues (stage I-IV) relative to normal cervical tissues. Vote-counting analysis showed that up-regulation was most consistently reported for miR-20a and miR-21 (four studies), followed by miR-10a, miR-15b, miR 20b, miR-141, miR-200a, and miR-224 (three studies). Down-regulation was reported most consistently for miR-143 (seven studies), followed by miR-203 and miR-145 (six studies). Fourteen miRNA, respectively, showed a significantly correlated lymphatic node metastasis in eight studies. This meta-analysis has identified several miRNAs whose expression correlates reliably with cervical cancer. These should be probed in further studies to explore their potential as diagnostic biomarkers. PMID- 25920606 TI - Interference of Notch1 inhibits the growth of glioma cancer cells by inducing cell autophagy and down-regulation of Notch1-Hes-1 signaling pathway. AB - Glioma is the most common malignant tumors in adult brains, and Notch signaling pathway plays an important role in cell differentiation. The aim of the present study is to investigate the role of Notch1 in the progression of glioma cancers and clarify the mechanism of Notch1 silencing on inhibiting the proliferation of glioma cancer cells. First, endogenous Notch1 expression was interfered with a lentiviral vector of Notch1 shRNA. RT-PCR and western blotting were used for detecting the expression of Notch1 mRNA and protein, respectively. MTT assay results demonstrated that transfection with Notch1 shRNA and treatment with MRK003, a Notch1 inhibitor, both inhibited the proliferation of glioma cancer cells (p < 0.01). The lentiviral vector of Notch1 shRNA transfected into U251 cells induced cell cycle arrest at G0/G1 phase by FACS with PI staining analysis. Meanwhile, the expression levels of LC3-II and Beclin1 significantly increase in Notch1 shRNA-transfected U251 cells, suggesting that cell autophagy was induced when interfering with Notch1 in glioma cells. The downstream transcription factors were also detected by RT-PCR and western blotting analysis, and the data showed that interference with Notch1 increased the expression level of Hes-1, but not Hes-5. Taken together, all the data obviously revealed that Notch1 played an important role in the progression of glioma cancers. The clarification of the mechanism will be helpful for the diagnosis of glioma cancer and would provide new clues to molecular targets for cancer therapy. PMID- 25920607 TI - Review of microRNA in osteosarcoma and chondrosarcoma. AB - MicroRNAs (miRNAs) are small noncoding RNAs, which play a complex role in posttranscriptional gene expression and can theoretically be used as a diagnostic or prognostic tool, or therapeutic target for neoplasia. Despite advances in the diagnosis and treatment of skeletal sarcomas, including osteosarcoma and chondrosarcoma, much remains unknown regarding their underpinning molecular mechanisms. Given the recent increasing knowledge base of miRNA roles in neoplasia, both as oncogenes and tumor suppressor genes, this review will focus on the available literature regarding the expression profiles and potential roles of miRNA in skeletal sarcomas. Although this is an emerging field, miRNA profiling may be of use in clarifying competing diagnoses of skeletal sarcomas and possibly indicate patient risk of resistance to traditional chemotherapeutic agents. While detecting and targeting miRNAs is currently limited to experimental investigations, miRNA may be utilized for future clinical management of skeletal sarcomas. PMID- 25920608 TI - Chloride intracellular channel 1 (CLIC1) is activated and functions as an oncogene in pancreatic cancer. AB - Chloride intracellular channel 1 (CLIC1), a newly discovered member of the chloride channel protein family, has been implicated in multiple human cancers. However, little is known with regard to its expression and biological functions in pancreatic cancer. In this study, we focused on the clinical significance and biological functions of CLIC1 in pancreatic cancer and found that this protein was overexpressed in pancreatic cancer tissues. Patients with CLIC1-positive tumours had worse overall survival than those with CLIC1-negative tumours. Furthermore, the treatment of pancreatic cancer cell lines with CLIC1-targeting siRNA oligonucleotides significantly reduced cell proliferation and diminished anchorage-independent growth on both soft agar and cell migration. These data indicate that CLIC1 acts as a putative oncogene in pancreatic cancer and may represent a novel diagnostic and therapeutic target for pancreatic cancer. PMID- 25920609 TI - Cancer-associated fibroblast-derived CXCL12 causes tumor progression in adenocarcinoma of the esophagogastric junction. AB - Although cancer-associated fibroblasts (CAFs) mainly produce CXCL12 and stimulate CXCL12/CXCR4 signaling in cancer cells, the significance of this interaction in adenocarcinoma of the esophagogastric junction (AEG) was unclear. This study investigated the functional characteristics of CAF-derived CXCL12 in AEG. Immunohistochemical staining for CXCL12 was performed on sections from 123 AEG patients and analyzed against clinicopathological data. Newly isolated CAFs and normal fibroblasts were examined for phenotype. An invasion assay was performed with AEG cells co-cultured with CAFs isolated from AEG. CXCL12 expression was significantly associated with age, depth of invasion, lymphatic invasion, and lymph node metastases. High CXCL12 expression significantly correlated with poor prognosis. Isolated CAFs had abundant alpha-smooth muscle actin expression and showed various CXCL12 expression patterns. Notably, AEG cells co-cultured with CXCL(high)-expressing CAFs invaded more than when co-cultured with CXCL(low) expressing CAFs; these invasive properties were impeded by CXCR4 antagonist AMD3100. We demonstrated that AEG cells co-cultured with CXCL12(high) CAFs were significantly more invasive than those co-cultured with CXCL12(low) CAFs and that high CXCL12 expression correlates with poor prognosis in AEG patients. CXCL12 derived from CAFs in tumor microenvironment stimulates CXCL12/CXCR4 signaling in AEG cells and promotes their invasive ability, resulting in tumor progression. PMID- 25920611 TI - Integrative analysis of gene expression in response to low-dose ionizing radiation in a human skin model. AB - The advance in medical imaging and utilization has raised the concern about exposure to low-dose ionizing radiation (LDIR). Cellular and molecular responses to high-dose ionizing radiation have been characterized, but in the range of low dose, these responses are poorly understood. Here, we investigate the gene expression in response to LDIR (10 cGy) in the EpiDermFT human skin model. We identified 3299 differentially expressed genes (DEGs) in response to LDIR. Among these DEGs, we noted several well-characterized long noncoding RNAs. Gene Ontology and KEGG pathway analysis were performed to detect altered molecular response. GO and KEGG pathway results showed that genes corresponding to "regulation of cell proliferation" were enriched. Gene set enrichment analysis showed that KRAS signaling pathway was enriched in response to LDIR and transcription targets of NF-kappaB were also enriched when exposed to LDIR. PMID- 25920610 TI - Therapeutic potential of cancer stem cells. AB - Cancer stem cells (CSCs) play an important role in cancer growth, self-renewal, metastasis, recurrence and radio/chemotherapy. However, the underlying mechanisms remain elusive. In this review, we explore the roles of CSCs in cancer's relapse and progression and discuss the biomarkers of CSCs to predict clinical outcome and their diagnostic potential. The different approaches of CSC therapies are also reviewed, including cytotoxic, radiation, differentiation and targeting signaling pathways. We also discuss the challenge of targeting CSCs in cancer therapy. In addition, non-coding RNAs in CSC therapies are also discussed. PMID- 25920612 TI - Retrievable inferior vena cava filters in patients with cancer are safe but are they beneficial? AB - The availability and insertion of permanent and retrievable inferior vena cava filter devices have increased substantially over the past decade. Our retrospective study provides the first detailed assessment of the safety and efficacy of retrievable inferior vena cava filters in a large cohort of cancer patients with predominantly advanced malignancies. We retrospectively reviewed the medical records of consecutive patients with the diagnosis of cancer who underwent inferior vena cava filter placement at a single academic medical center from 2007 to 2012 with special attention to safety, recurrent venous thromboembolism, and survival data. Three hundred thirty-seven cancer patients were included in the analysis. Gastrointestinal, lung, and genitourinary malignancies were the most commonly represented malignancies [94 (27.8 %), 70 (20.8 %), and 37 (10.9 %) patients, respectively]. Immediate complications were diagnosed in one of 258 (1 %) evaluable patients following placement of a retrievable filter. Delayed complications occurred in 23 of 258 (8 %) patients. The 7, 14, 30, 90, and 365 day post-filter survival rates for patients with stage IV cancer were 0.91, 0.86, 0.71, 0.52, and 0.29, respectively. Patients with lung and gastrointestinal tumors demonstrated a significantly reduced post-filter survival rate compared with those with genitourinary, brain, and breast cancers. Retrievable and non-retrievable inferior vena cava filters are associated with an overall low rate of complications in patients with cancer. However, survival rates following filter placement are poor in this patient population. PMID- 25920613 TI - Apple Aminoacid Profile and Yeast Strains in the Formation of Fusel Alcohols and Esters in Cider Production. AB - The amino acid profile in dessert apple must and its effect on the synthesis of fusel alcohols and esters in cider were established by instrumental analysis. The amino acid profile was performed in nine apple musts. Two apple musts with high (>150 mg/L) and low (<75 mg/L) nitrogen content, and four enological yeast strains, were used in cider fermentation. The aspartic acid, asparagine and glutamic acid amino acids were the majority in all the apple juices, representing 57.10% to 81.95%. These three amino acids provided a high consumption (>90%) during fermentation in all the ciders. Principal component analysis (PCA) explained 81.42% of data variability and the separation of three groups for the analyzed samples was verified. The ciders manufactured with low nitrogen content showed sluggish fermentation and around 50% less content of volatile compounds (independent of the yeast strain used), which were mainly 3-methyl-1-butanol (isoamyl alcohol) and esters. However, in the presence of amino acids (asparagine, aspartic acid, glutamic acid and alanine) there was a greater differentiation between the yeasts in the production of fusel alcohols and ethyl esters. High contents of these aminoacids in dessert apple musts are essential for the production of fusel alcohols and most of esters by aromatic yeasts during cider fermentation. PMID- 25920615 TI - Comment on 'Bariatric Surgery Can Lead to Net Cost Savings to Health Care Systems: Results from a Comprehensive European Decision Analytic Model'. PMID- 25920614 TI - Proceedings from the Turner Resource Network symposium: the crossroads of health care research and health care delivery. AB - Turner syndrome, a congenital condition that affects ~1/2,500 births, results from absence or structural alteration of the second sex chromosome. There has been substantial effort by numerous clinical and genetic research groups to delineate the clinical, pathophysiological, cytogenetic, and molecular features of this multisystem condition. Questions about the molecular-genetic and biological basis of many of the clinical features remain unanswered, and health care providers and families seek improved care for affected individuals. The inaugural "Turner Resource Network (TRN) Symposium" brought together individuals with Turner syndrome and their families, advocacy group leaders, clinicians, basic scientists, physician-scientists, trainees and other stakeholders with interest in the well-being of individuals and families living with the condition. The goal of this symposium was to establish a structure for a TRN that will be a patient-powered organization involving those living with Turner syndrome, their families, clinicians, and scientists. The TRN will identify basic and clinical questions that might be answered with registries, clinical trials, or through bench research to promote and advocate for best practices and improved care for individuals with Turner syndrome. The symposium concluded with the consensus that two rationales justify the creation of a TRN: inadequate attention has been paid to the health and psychosocial issues facing girls and women who live with Turner syndrome; investigations into the susceptibility to common disorders such as cardiovascular or autoimmune diseases caused by sex chromosome deficiencies will increase understanding of disease susceptibilities in the general population. PMID- 25920616 TI - Prevalence of Non-alcoholic Fatty Liver Disease and Steatohepatitis Risk Factors in Patients Undergoing Bariatric Surgery. AB - BACKGROUND: Non-alcoholic fatty liver disease (NAFLD) associated with obesity comprises pathological changes ranging from steatosis to steatohepatitis; these can evolve to cirrhosis and hepatocellular carcinoma. OBJECTIVES: The objectives of this study are to assess the prevalence of and predictive markers for steatohepatitis in obese patients undergoing bariatric surgery. METHODS: A prospective study of 184 morbidly obese patients undergoing bariatric surgery formed the study cohort. Patients taking potentially hepatotoxic medications and those with viral diseases and a history of excessive alcohol consumption were excluded. Liver biopsies were performed during surgery with a "Trucut" needle. Patients were classified into the following groups according to the histopathological findings: normal, steatosis, mild steatohepatitis, and moderate severe steatohepatitis. Factors associated with steatohepatitis were evaluated using logistic regression. p values <0.05 were considered significant. RESULTS: The prevalence of NAFLD was 84 % (steatosis, 22.0 %; mild steatohepatitis, 30.8 %; moderate-severe steatohepatitis, 32.0 %). Independent predictive factors for steatohepatitis were age (odds ratio (OR), 1.05; 95 % confidence interval (CI), 1.01-1.09; p = 0.011), waist circumference (OR, 1.03; 95 % CI, 1.00-1.06; p = 0.021), serum alanine aminotransferase (ALT) levels (OR, 1.04; 95 % CI, 1.01 1.08; p = 0.005), and serum triglyceride levels (OR, 1.01; 95 % CI, 1.00-1.01; p = 0.042). Score values for each predictor were derived from regression coefficients and odds ratio, and a total (risk) score was obtained from the sum of the points to evaluate the probability of having steatohepatitis. CONCLUSION: Age, waist circumference, serum ALT levels, and serum triglyceride levels are efficient and non-invasive predictive markers for the diagnosis and management of steatohepatitis in morbidly obese patients. PMID- 25920617 TI - Moving towards treatments for spinal muscular atrophy: hopes and limits. AB - Spinal muscular atrophy (SMA), one of the most frequent and devastating genetic disorders causing neuromuscular degeneration, has reached the forefront of clinical translation. The quite unique genetic situation of SMA patients, who lack functional SMN1 but carry the misspliced SMN2 copy gene, creates the possibility of correcting SMN2 splicing by antisense oligonucleotides or drugs. Both strategies showed impressive results in pre-clinical trials and are now in Phase II-III clinical trials. SMN gene therapy approaches using AAV9-SMN vectors are also highly promising and have entered a Phase I clinical trial. However, careful analysis of SMA animal models and patients has revealed some limitations that need to be taken very seriously, including: i) a limited time-window for successful therapy delivery, making neonatal screening of SMA mandatory; ii) multi-organ impairment, requiring systemic delivery of therapies; and iii) a potential need for combined therapies that both increase SMN levels and target pathways that preserve/rescue motor neuron function over the lifespan. Meeting these challenges will likely be crucial to cure SMA, instead of only ameliorating symptoms, particularly in its most severe form. This review discusses therapies currently in clinical trials, the hopes for SMA therapy, and the potential limitations of these new approaches. PMID- 25920618 TI - Markers of bone remodeling are associated with arterial stiffness in renal transplanted subjects. AB - BACKGROUND: Bone-vessel interaction in chronic renal failure remains poorly understood and could be driven by bone remodeling factors including osteoprotegerin (OPG), fibroblast growth factor 23 (FGF23), parathormone and vitamin D. Only few data are available in renal transplantation. The aim of this study was to investigate the relationship between bone remodeling factors and large artery function in renal transplant patients. METHODS: 89 renal transplant patients were enrolled in this cross-sectional study. Carotid to femoral pulse wave velocity (PWV) and central augmentation index (AIx) were determined as an estimation of large artery function. Blood samples were collected for measurement of vascular risk markers. Independent predictors were identified by multivariate linear regression through backward feature selection using Akaike's information criteria. RESULTS: At multivariate analysis, age (p < 0.001) and systolic arterial pressure (p = 0.003) were significantly associated with PWV but not AIx. In addition, both elevated blood concentrations of 1.25(OH)2 vitamin D (p = 0.013) and OPG (p = 0.047) were still significantly related to high PWV. CONCLUSIONS: These results underline that age and mean arterial pressure are the main determinants of PWV following renal transplantation. Among bone remodeling biomarkers, plasma OPG and active vitamin D were the strongest determinants of arterial stiffness. PMID- 25920619 TI - The pooled incidence of post-stroke seizure in 102 008 patients. AB - BACKGROUND: Post-stroke seizures and epilepsy may worsen the recovery and increase the disability of stroke patients during their daily lives. However, few meta-analysis studies have been conducted on post-stroke seizures incidence. We carried on a meta-analysis on the incidence rate of post-stroke seizures and associated factors. METHODS: We searched the Medline, Embase, Web of Science, Science Citation Index, and Cochrane Library electronic databases (1990-2013) to identify observational studies of post-stroke seizures. Two authors independently extracted the related information from all included studies. We calculated the pooled incidence by meta-analysis using the software R version 12.3. RESULTS: A total of 34 longitudinal cohort studies involving 102 008 patients were included in our meta-analysis. The pooled incidence rate of post-stroke seizures was found to be 0.07 [95% confidence interval (CI), 0.05-0.09] while the rate of post stroke epilepsy (PSE) was 0.05 (95% CI, 0.04-0.06). The incidence of post-stroke seizures in hemorrhagic stroke (0.10, 0.08-0.13) was much higher than in ischemic stroke (0.06, 0.04-0.08) and when the cortical region was involved (0.15, 0.10 0.21). CONCLUSIONS: Our meta-analysis showed that seizures occurred in about 6.93% of people with stroke. Seizures occurred more commonly after hemorrhagic stroke and when stroke occurred in the cortical region. PMID- 25920620 TI - The Effect of the Epitendinous Suture on Gliding in a Cadaveric Model of Zone II Flexor Tendon Repair. AB - PURPOSE: We hypothesized that increasing core sutures (4-6) may be preferable in terms of gliding coefficient (GC) measurements when compared with adding an epitendinous suture to zone II flexor tendon repairs. We hypothesized that the inclusion of epitendinous suture in 2 standard repairs would contribute negatively to the GC of the repaired tendon. METHODS: Nineteen fresh-frozen cadaveric fingers were used for testing. We compared a control group (dissected digits without repair) and 4-strand or 6-strand core tendon repairs with and without epitendinous suture. Arc of motion was driven by direct loading, and digital images were acquired and analyzed. Outcomes were defined as the difference in GC between the native uninjured and the repaired state at each load. A linear mixed-model analysis was performed with comparisons between repairs to evaluate the statistically relevant differences between groups. RESULTS: The test of fixed effects in the linear model revealed that repair type and the use of epitendinous suture significantly affected the change in GC. The addition of an epitendinous suture produced a significant decrement in gliding regardless of repair type. CONCLUSIONS: There was significant improvement in GC with the omission of the epitendinous suture in both repair types (4- or 6 strand). CLINICAL RELEVANCE: The epitendinous suture used in this model resulted in poorer gliding of the repair, which may correspond with an expected increase in catching or triggering. PMID- 25920622 TI - Ab initio ground-state potential energy function and vibration-rotation energy levels of imidogen, NH. AB - The accurate ground-state potential energy function of imidogen, NH, has been determined from ab initio calculations using the multireference averaged coupled pair functional (MR-ACPF) method in conjunction with the correlation-consistent core-valence basis sets up to octuple-zeta quality. The importance of several effects, including electron correlation beyond the MR-ACPF level of approximation, the scalar relativistic, adiabatic, and nonadiabatic corrections were discussed. Along with the large one-particle basis set, all of these effects were found to be crucial to attain "spectroscopic" accuracy of the theoretical predictions of vibration-rotation energy levels of NH. PMID- 25920621 TI - Short-term and long-term effects of small incision lenticule extraction (SMILE) on corneal endothelial cells. AB - PURPOSE: Small incision lenticule extraction (SMILE) is being used increasingly as a novel approach to correct refractive errors with femtosecond laser. The study was aimed to investigate the corneal endothelial changes 1 day (short term) and 1 year (long term) after SMILE procedure. METHODS: In this prospective study, a total of 56 eyes of 30 patients with myopia ranging from -3.25 to -8.25 diopters (D) and cylinder up to -3.50D were treated by SMILE. Postoperative uncorrected distance visual acuity (UDVA) and complications were assessed. Endothelial cell density (ECD), the coefficient of variation (CV), and the percentage of hexagonal cells were measured using a noncontact specular microscope preoperatively and at 1 day and 1 year postoperatively. The estimated residual stromal thickness (RST) of each patient was recorded. RESULTS: The median UDVA improved significantly from 1.00logMAR preoperatively to -0.10logMAR both at 1 day and 1 year (p<0.001). No eyes developed corneal edema or other complications during the follow-up period. There were no significant changes in the ECD, CV or the percentage of hexagonal cells at any visit point (all p>0.05). The mean estimated RST was 355.1+/-32.2MUm (range 290-429MUm). Endothelial cell changes in terms of ECD, CV or the percentage of hexagonal cells were not correlated with the estimated RST (p>0.05). CONCLUSIONS: SMILE yielded improvement in visual acuity and no adverse effects to corneal endothelial cells were found. However, further studies with a lower preoperative ECD and deeper lenticule extraction are needed to conduct. PMID- 25920623 TI - Characterization of lung-delivered in-situ forming controlled release formulations. AB - OBJECTIVES: This study investigated the controlled drug release potential of formulations revealing temperature-induced sol-gel transition following administration to the respiratory tract. METHODS: Diverse sildenafil-containing aqueous poloxamer 407 preparations were evaluated for critical gelation temperature and rheological properties. The in-vitro drug release profiles of the in-situ forming formulations were studied in a Franz type cell, while the drug absorption characteristics were determined in an isolated lung model. Furthermore, the weight gain of isolated lungs was monitored and the bronchoalveolar lavage fluid was analysed for the total protein content. KEY FINDINGS: Poloxamer 407 solutions with concentrations of >12 wt.% revealed gelation upon temperature increase (>20 degrees C). Compared with free sildenafil solution, sildenafil-containing polymer formulations showed a prolonged in-vitro drug release profile. Likewise, 17 and 21 wt.% of poloxamer 407 were characterized by a sustained sildenafil transfer from the lung into the perfusate. However, a 10 wt.% polymer solution displayed an immediate sildenafil absorption. Interestingly, increasing the poloxamer 407 concentration (21 and 17 vs. 10 wt.%) led to decreased organ weight gain kinetics and a lower total protein content found in the bronchoalveolar lavage fluid. CONCLUSIONS: In-situ forming controlled release hydrogels represent a viable approach for inhalative therapy. PMID- 25920624 TI - In situ growth of capping-free magnetic iron oxide nanoparticles on liquid-phase exfoliated graphene. AB - We report a facile approach for the in situ synthesis of very small iron oxide nanoparticles on the surface of high-quality graphene sheets. Our synthetic strategy involved the direct, liquid-phase exfoliation of highly crystalline graphite (avoiding any oxidation treatment) and the subsequent chemical functionalization of the graphene sheets via the well-established 1,3-dipolar cycloaddition reaction. The resulting graphene derivatives were employed for the immobilization of the nanoparticle precursor (Fe cations) at the introduced organic groups by a modified wet-impregnation method, followed by interaction with acetic acid vapours. The final graphene-iron oxide hybrid material was achieved by heating (calcination) in an inert atmosphere. Characterization by X ray diffraction, transmission electron and atomic force microscopy, Raman and X ray photoelectron spectroscopy gave evidence for the formation of rather small (<12 nm), spherical, magnetite-rich nanoparticles which were evenly distributed on the surface of few-layer (<1.2 nm thick) graphene. Due to the presence of the iron oxide nanoparticles, the hybrid material showed a superparamagnetic behaviour at room temperature. PMID- 25920625 TI - The many facets of RNA-binding protein HuR. PMID- 25920626 TI - Cardiac memory: A learning experience. PMID- 25920627 TI - Sudden cardiac death syndromes: Changing the paradigm of diagnosis from ECG to molecular genetics. PMID- 25920628 TI - Stent graft surface movement after infrarenal abdominal aortic aneurysm repair: comparison of patients with and without a type 2 endoleak. AB - OBJECTIVES: The aim was to compare multidirectional stent graft movement in patients with and without a type 2 endoleak. METHODS: This was a retrospective case control study of patients being followed up after elective endovascular aneurysm repair of abdominal aortic aneurysms. The post-procedural and final follow up multislice computed tomography (MSCT) of 69 patients with and 74 without a type 2 endoleak were analyzed. Three dimensional (3D) surface models of the stent graft, delimited by landmarks using custom built software, were derived from these MSCT data. The stent graft was segmented in different zones, and the proportion of the total stent graft surface moving >9 mm between the post procedural and the final follow up MSCT was calculated, given in percentages, and compared between groups. Changes of infrarenal neck, renal artery to stent graft distance, and freedom from stent graft related endoleaks were evaluated. RESULTS: Overall surface movement was higher in the no endoleak (18.8%, IQR 0.1-45.1%) than in the type 2 endoleak group (5.3%, IQR 0-29.7%; p = .06). Furthermore, significantly higher surface movement in the no endoleak group was found in the proximal anchoring zone (p = .04) and the distal left limb (p = .01), which was the modular limb in 81.1% (p < .01). Neck diameter increase (1.0 mm, IQR 0-3.0 mm; p < .01) and renal artery to stent graft distance difference (0 mm, IQR 0-3.3 mm; p < .01) were significantly higher in the no endoleak group. Five patients in the no endoleak and one patient in the type 2 endoleak group suffered from a stent graft related endoleak (p = .27). CONCLUSIONS: The presence of a type 2 endoleak is associated with decreased surface movement of the proximal anchoring zone and the distal modular limb of bifurcated stent grafts. PMID- 25920630 TI - Clinical Assessment of Endovascular Stenting Compared with Compression Therapy Alone in Post-thrombotic Patients with Iliofemoral Obstruction. AB - OBJECTIVE: The study aimed to evaluate the clinical results of stent placement in post-thrombotic patients with iliofemoral obstruction compared with results in those treated with elastic compression stockings (ECS). METHODS: A retrospective analysis of post-thrombotic patients with iliofemoral obstruction was conducted in a single institution from January 2007 to December 2012. Duplex ultrasound and selective phlebography were performed in patients with chronic venous disease and previous deep venous thrombosis (DVT). Post-thrombotic syndrome (PTS) with iliofemoral vein obstruction (Villalta score >=10) was diagnosed in 216 patients. Among these, 122 patients were treated by stent placement, and the remaining 94 patients were treated conservatively with 30-40 mmHg ECS therapy. Technical success, stent patency rates, and complications were recorded after the interventions. Results including Villalta score, pain, edema, ulcer, and popliteal vein reflux were assessed in both groups. RESULTS: Percutaneous iliofemoral venous stenting was successful in 116 of 122 patients (95.1%) without major complications. Follow up periods ranged from 3 to 58 months (median 21 months). Cumulative primary, assisted primary, and secondary stent patency rates at 3 years were 68.9%, 79.0%, and 91.6%, respectively. Among patients with severe PTS, the Villalta score decreased significantly with endotreatment, compared to the score of those treated by ECS therapy (16.12 +/- 4.91 vs. 10.98 +/- 5.89, p < .01). However, there was no significant score improvement between the two therapies in patients with moderate PTS (6.59 +/- 2.37 vs. 5.75 +/- 3.03, p = .22). There was a significantly higher 24 month recurrence free ulcer healing rate in the endotreatment groups (86.6% vs. 70.6%, p < .01). Both edema and pain improved significantly in the two groups. The popliteal vein reflux rate showed no significant change after endotreatment. CONCLUSIONS: Endovascular treatment is a safe, effective, and feasible method to correct the iliofemoral obstruction of PTS. Only post-thrombotic patients with severe PTS as assessed by the Villalta score appear to benefit from the endovascular treatment. PMID- 25920631 TI - Editor's Choice - Management of Chronic Venous Disease: Clinical Practice Guidelines of the European Society for Vascular Surgery (ESVS). PMID- 25920632 TI - Surgical infrarenal "neo-neck" technique during elective conversion after EVAR with suprarenal fixation. AB - OBJECTIVES: Conversion of a previous endovascular aneurysm repair (EVAR) with suprarenal fixation is a challenging situation even in the elective setting. The outcomes of a technique based on preservation of the first proximal covered stent of the endograft, used as a "neo-neck" for proximal anastomosis, are presented. METHODS: From 2001 to 2014, nine patients underwent elective conversion of a previous suprarenally fixed EVAR. After supraceliac clamping, the aneurysm sac was opened and the endograft identified; the fabric was cut beyond the first covered stent together with its native aortic wall in order to create a "neo neck." An aortic balloon was inflated into the visceral aorta to avoid back bleeding. A Dacron bifurcated tube graft (Intergard, Maquet) was then sutured to the neo-neck mimicking endobanding, passing the stitches into the aortic wall and the first covered stent. RESULTS: The mean age was 68 years (range, 52-84 years). The stent grafts removed were four Zenith (Cook Medical), three Endurant (Medtronic), and two E-vita (Jotec). The indication for conversion was type 1A (n = 2), type 2 (n = 2), and type 3 (n = 1) endoleak, complete endograft thrombosis (n = 2), and abdominal pain with sac enlargement with no radiological sign of endoleak (n = 2). Blood loss was 1,428 mL (range 500-3,000 mL); the visceral ischemic time to perform the proximal anastomosis was 23.5 min +/- 2.3 min). The post-operative complication rate was 11% (n = 1/9) related to a case of sac wall bleeding requiring re-intervention; mortality at 30 days was 0%. At 22 months (range, 8-41) the computed tomography angiogram demonstrated no signs of leaks or anastomotic pseudoaneurysm. CONCLUSION: Preservation of the proximal covered stent of an endograft with suprarenal fixation used as an infrarenal "neo-neck" with incorporation of the aorta to the suture line during elective surgical explantation simplifies the procedure, and can be achieved with very low early morbidity and mortality; furthermore, it seems to be durable over mid-term follow up. PMID- 25920634 TI - Leukocyte-poor platelet-rich plasma versus bupivacaine for recalcitrant lateral epicondylar tendinopathy. AB - PURPOSE: To compare a single leukocyte-poor (type-4B) platelet-rich plasma (PRP) injection versus bupivacaine injection for recalcitrant lateral epicondylar tendinopathy (LET). METHODS: 25 patients aged 27 to 50 years with painful and recalcitrant LET of the humerus were randomised to receive leukocyte-poor (type 4B) PRP (n=15) or bupivacaine (n=10) injection. Outcome measures included visual analogue scale (VAS) for pain, modified Mayo clinic performance index for elbow (MMCPIE) for elbow function, and Nirschl score for activity-related pain at 1, 3, 6, and 12 months by a single assessor. RESULTS: At baseline, the PRP and bupivacaine groups were comparable in terms of age, sex, duration of symptoms, VAS for pain, MMCPIE score, and Nirschl score. After one month, the percentage of improvement was less in the PRP than bupivacaine group in terms of the VAS for pain (17.7% vs. 26.5%), MMCPIE score (24.0% vs. 27.6%), and Nirschl score (20.7% vs. 31.1%). Nonetheless, improvement in the respective scores was greater in the PRP than bupivacaine group after 3 months (42.5% vs. 30.9%, 34.1% vs. 27.2%, and 50.7% vs. 39.6%), 6 months (67.3% vs. 20.1%, 40.6% vs. 16.3%, and 71.4% vs. 31.1%), and one year (83.2% vs. 45.6%, 47.0% vs. 21.7%, and 76.6% vs. 56.3%). The differences in scores between groups were significant at 6 months and one year only (p<0.001). CONCLUSION: Leukocyte-poor (type-4) PRP injection for recalcitrant LET enabled good improvement in pain and function. PMID- 25920633 TI - Platelet-rich plasma versus corticosteroid injection for recalcitrant lateral epicondylitis: clinical and ultrasonographic evaluation. AB - PURPOSE: To evaluate the clinical and ultrasonographic changes in the morphology and vascularity of the common extensor tendon after injecting platelet-rich plasma (PRP) or corticosteroid (CS) for recalcitrant lateral epicondylitis (LE). METHODS: 30 patients aged 18 to 60 years with recalcitrant (>6 months) LE not responsive to oral medication or non-invasive treatment were randomised to receive PRP (n=15) or CS (n=15) injection. Patients were assessed using the visual analogue scale (VAS) for pain, Disabilities of the Arm, Shoulder and Hand Scale (DASH) score, Oxford Elbow Score, modified Mayo Clinic performance index for the elbow (modified Mayo score), and hand grip strength. Ultrasonography was performed by a musculoskeletal ultrasonologist to evaluate for tear at the common extensor origin, oedema at the common extensor origin, cortical erosion, probe induced tenderness, and thickness of the tendon. RESULTS: The VAS for pain, DASH score, Oxford Elbow Score, modified Mayo score, and hand grip strength all improved significantly from pre-injection to the 6-month follow-up in the PRP and CS groups. However, in the CS group, the scores generally peaked at 3 months and then deteriorated slightly at 6 months indicating recurrence of symptoms, which involved 46.7% of the CS patients. At 6 months, the number of patients positive for various ulrasonographic findings generally decreased. However, in the CS group, the number of patients with reduced thickness of the common extensor tendon increased from 2 to 12, and the number of patients with cortical erosion at the lateral epicondyle increased from 9 to 11. CONCLUSION: PRP appeared to enable biological healing of the lesion, whereas CS appeared to provide short term, symptomatic relief but resulted in tendon degeneration. PMID- 25920635 TI - Arthroscopic resection of humeroradial synovial plica for persistent lateral elbow pain. AB - PURPOSE: To review the outcome of 121 patients who underwent arthroscopic resection of a humeroradial synovial plica for persistent lateral elbow pain. METHODS: 92 men and 29 women aged 24 to 56 (mean, 38) years with chronic lateral elbow pain underwent arthroscopic resection of a humeroradial synovial plica using a motorised soft tissue shaver, followed by intensive physiotherapy. The modified elbow score and range of motion were assessed, as were wound healing, infection, soft tissue swelling or effusion, tenderness, ligamentous instability, and motor strength. RESULTS: No patient had any ligamentous instability. 80 patients were pain-free at 3 months; only 3 patients were taking pain medication at 6 months. All patients had full pronation and supination; the mean range of motion was 3o to 135o of flexion. The mean modified elbow score at 12 months was 93.2 (range, 72-100). The percentages of patients with excellent, good, fair, and poor score were 70%, 17%, 8%, and 5% at 3 months, 74%, 20%, 3%, and 3% at 6 months, and 76%, 18%, 3%, and 3% at 12 months, respectively. CONCLUSION: A humeroradial synovial plica is one of the causes of chronic lateral elbow pain. Arthroscopic resection of the synovial plica followed by intensive physiotherapy achieved good outcome. PMID- 25920636 TI - Zancolli lasso procedure for correction of paralytic claw hands. AB - PURPOSE: To evaluate the outcome of 20 claw hands corrected with the Zancolli lasso procedure. METHODS: 20 patients aged 7 to 48 (mean, 28) years with claw hand deformity for a mean of 33.3 months secondary to leprosy (n=17), traumatic ulnar nerve injury (n=2), or tardy ulnar nerve palsy (n=1) underwent the Zancolli lasso procedure, in which the flexor digitorum superficialis (FDS) of the middle finger was divided in to 4 slips (one for each finger) and reattached to itself after passing through the proximal pulley. Deformity, power, movement, and function of the hands were evaluated before and after surgery. RESULTS: The mean duration of surgery was 58.4 (range, 50-107) minutes. The mean duration of follow up was 18 (range, 12-24) months. Deformity correction was good in 15 patients, fair in 3, and poor in 2. The mean angle improvement was maximum in the little finger, followed by the ring, index, and middle fingers. The transverse metacarpal arch (compared with the normal hand) was increased/reversed in 7 patients and decreased in 13 patients. The grip and pinch strength increased in 13 patients, remained unchanged in 6, and decreased in one. Motion and function of the hand was good in 12 patients, fair in 6, and poor in 2. One patient developed swan neck deformity in the little finger owing to suture tension of the transferred slip, and another had paraesthesia over the index finger. They underwent reoperation using the FDS of the ring finger; no sensory or motor recovery was achieved. CONCLUSION: The Zancolli lasso procedure is easy to perform and does not require extensive postoperative training. It restores synchronous finger flexion and spares other superficialis tendons, thus avoiding swan neck deformity of the fingers. PMID- 25920637 TI - Combined volar and dorsal plating for complex comminuted distal radial fractures. AB - PURPOSE: To review outcomes of combined volar and dorsal locked plating for AO type-C3 complex comminuted distal radial fractures. METHODS: Records of 24 patients aged 17 to 77 (mean, 53.3) years who underwent combined volar and dorsal locked plating for AO type-C3 distal radial fractures with volar and dorsal metaphyseal and intra-articular comminution were reviewed. 21 were closed fractures, and 3 were Gustilo-Anderson type-1 open fractures. Bone union, volar tilt, radial inclination, radial height, range of motion, grip strength, and any complications were assessed by a single hand surgeon. RESULTS: After a mean follow-up of 17 (range, 14-25) months, the mean palmar flexion was 49o (range, 30o-80o), dorsiflexion was 52o (range, 30o-80o), supination was 86o (range, 60o 90o), pronation was 77o (range, 30o-90o), radial deviation was 16o (range, 5o 30o), and ulnar deviation was 27o (range, 10o-50o). The mean grip strength of the injured hand was 69.2% of the uninjured side. The mean time to radiological union was 3.9 (range, 2.5-6.0) months; no patient had non-union. At the time of union, the mean volar tilt was 5o (-22o-14o), radial inclination was 18.6o (8o-28o), and radial height was 8.5 mm (5.0 mm-13.6 mm). One patient had collapse of the dorsal fragment resulting in a dorsal tilt of 22o and limited (30o) forearm pronation. The severity of dorsal metaphyseal comminution had not been recognised and bone grafting was not performed. The patient also had minor complications of little finger flexor tendon irritation and carpal tunnel syndrome. She underwent implant removal and carpal tunnel release at 8 months. One patient had implant-related extensor digitorum communis irritation. Another patient had non-specific chronic wrist pain, which was resolved at one year. No patient had infection, tendon rupture, or complex regional pain syndrome. Four patients underwent implant removal, including 2 who had no implant-related problems. CONCLUSION: Combined volar and dorsal plating enables early mobilisation and good outcome for certain complex comminuted distal radial fractures. PMID- 25920638 TI - Factors associated with one-year outcome after distal radial fracture treatment. AB - PURPOSE: To identify factors that affect functional outcome one year after distal radial fracture treatment. METHODS: 521 women and 121 men aged 16 to 92 (mean, 59) years with distal radial fractures underwent external fixation (n=123), open reduction and internal fixation (n=63), a combination of both (n=10), distal radial osteotomy for symptomatic malunion (n=90), or casting with (n=194) or without (n=162) prior closed manipulation under regional anaesthesia. The indication for surgery (rather than casting) was metaphyseal instability. Radiographic evaluation (dorsal angulation, radial shortening, carpal malalignment, and malunion) was made before and after treatment and after fracture healing. Functional evaluation (range of movement, grip strength, and activities of daily living) was made at a mean of 16 (range, 6-54) months after injury. RESULTS: After multiple regression analysis, poorer functional score was associated with increasing age (p<0.001), dorsal angulation after healing (p<0.016), presence of volar comminution (p=0.005), and pain (p<0.001). Poorer grip strength was associated with non-dominant side injury, increasing age, dorsal angulation after healing, positive ulnar variance, comminution, and pain (all p<0.001). Predicted malunion showed colinearity with age (r=0.657), dorsal comminution (r=0.694), and dorsal angulation (r=0.626). CONCLUSION: Understanding factors associated with outcome helps surgeons to make the treatment decision for distal radial fracture to achieve optimum outcome. PMID- 25920639 TI - Effects of anticoagulants on outcome of femoral neck fracture surgery. AB - PURPOSE: To review records of 330 patients who underwent surgery for femoral neck fractures with or without preoperative anticoagulation therapy. METHODS: Medical records of 235 women and 95 men aged 48 to 103 years (mean, 81.6; standard deviation [SD], 13.1) who underwent surgery for femoral neck fractures with or without preoperative anticoagulation therapy were reviewed. 30 patients were on warfarin, 105 on aspirin, 28 on clopidogrel, and 167 were controls. The latter 3 groups were combined as the non-warfarin group and compared with the warfarin group. Hospital mortality, time from admission to surgery, length of hospital stay, return to theatre, and postoperative complications (wound infection, deep vein thrombosis, and pulmonary embolism) were assessed. RESULTS: The warfarin and control groups were significantly younger than the clopidogrel and aspirin groups (80.8 vs. 80.0 vs. 84.2 vs. 83.7 years, respectively, p<0.05). 81% of the patients underwent surgery within 48 hours of admission. The overall mean time from admission to surgery was 1.8 days; it was longer in the warfarin than the aspirin, clopidogrel, and control groups (3.3 vs. 1.8 vs. 1.6 vs. 1.6 days, respectively, p<0.001). The mean length of hospital stay was 17.5 (SD, 9.6; range, 3-54) days. The overall hospital mortality was 3.9%; it was 6.7% in the warfarin group, 3.8% in the aspirin group, 3.6% in the clopidogrel group, and 3.6% in the control group (p=0.80). Four patients returned to theatre for surgery: one in the warfarin group for washout of a haematoma, 2 in the aspirin group for repositioning of a mal-fixation and for debridement of wound infection, and one in the control group for debridement of wound infection. The warfarin group did not differ significantly from non-warfarin group in terms of postoperative complication rate (6.7% vs. 2.7%, p=0.228) and the rate of return to theatre (3.3% vs. 1%, p=0.318). CONCLUSION: It is safe to continue aspirin and clopidogrel prior to surgical treatment for femoral neck fracture. The risk of delaying surgery outweighs the peri-operative bleeding risk. PMID- 25920640 TI - Preoperative warfarin reversal for early hip fracture surgery. AB - PURPOSE: To evaluate our hospital protocol of low-dose vitamin K titration for preoperative warfarin reversal for early hip fracture surgery. METHODS: Records of 16 men and 33 women aged 63 to 93 (mean, 81) years who were taking warfarin for atrial fibrillation (n=40), venous thromboembolism (n=9), cerebrovascular accident (n=3), and prosthetic heart valve (n=3) and underwent surgery for hip fractures were reviewed. The 3 patients with a prosthetic heart valve were deemed high risk for thromboembolism and the remainder low-risk. The international normalised ratio (INR) of patients was checked on admission and 6 hours after administration of vitamin K; an INR of <1.7 was considered safe for surgery. RESULTS: No patient developed venous thromboembolism within one year. The 30-day and one-year mortality was 8.2% and 32.6%, respectively. For the 46 low-risk patients, the mean INR on admission was 2.6 (range, 1.1-4.6) and decreased to <1.7 after a mean of 2.2 (range, 0-4) administrations of 2 mg of vitamin K. Their INR was <1.7 within 18 hours (mean, 14 hours). 78% of patients underwent surgery within 36 hours. In the 22% of patients who did not undergo surgery within 36 hours, the delay was due to insufficient operative time or the patient being medically unfit for surgery. The 3 high-risk patients underwent bridging therapy of low-molecular-weight heparin and received no vitamin K; their mean INR on admission was 3.2 (range, 3.1-3.3) and the mean time to surgery was 5.3 (range, 3 8) days. Two low-risk patients and one high-risk patient died within 5 days of surgery. CONCLUSION: The low-dose intravenous vitamin K protocol is safe and effective in reversing warfarin within 18 hours. Hip fracture surgery within 36 to 48 hours of admission improves morbidity and mortality. PMID- 25920641 TI - Rate of venous thromboembolism after complex lower-limb fracture surgery without pharmacological prophylaxis. AB - PURPOSE: To evaluate the rate of venous thromboembolism (VTE) after complex lower limb fracture surgery without pharmacological prophylaxis. METHODS: Between July 2005 and April 2009, 11 men and 6 women (mean age, 45 years) underwent temporary external fixation followed by internal fixation for a total of 3 femoral and 20 tibial fractures. Patients were screened for VTE using contrast-enhanced computed tomography (CT) when the D-dimer value was beyond normal range. Between May 2009 and December 2012, 18 men and 4 women (mean age, 45 years) underwent temporary external fixation followed by internal fixation for a total of 8 femoral and 20 tibial fractures. Patients were routinely screened for deep vein thrombosis (DVT) using ultrasonography and for pulmonary embolism (PE) using contrast-enhanced CT (in high-risk patients with multiple injuries or pelvic and acetabular fractures). In both groups, pharmacological prophylaxis was not used; only mechanical prophylaxis was used. RESULTS: The 2 groups were comparable in terms of age, sex, and proportion of bilateral external fixation, open fracture, and associated injury, except that the duration of external fixation was longer in the early group (29.8+/-28.0 vs. 11.6+/-4.0 days, p=0.001). Of the 17 patients in the early group, 5 developed VTEs (3 DVTs and 2 PEs) at a mean of 13.6 (range, 6 20) days after injury; 2 of whom developed VTE during the external fixation period. Of the 22 patients in the later period, 10 developed VTEs (10 DVTs and 4 PEs) at a mean of 13 (range, 5-33) days after injury; 7 of whom developed VTE during the external fixation period. CONCLUSION: The rate of VTE was high in patients undergoing complex lower-limb fracture surgery without pharmacological prophylaxis. PMID- 25920642 TI - Cannulated versus non-cannulated cancellous screw fixation for femoral neck fractures: a synthetic bone biomechanical study. AB - PURPOSE: To compare the compressive strength of cannulated versus non-cannulated cancellous screws for undisplaced femoral neck fractures in synthetic bones. METHODS: 18 synthetic proximal femurs simulating an AO B1 valgus impacted femoral neck fracture in osteoporotic bone were used. The fracture angles were between 55o and 63o (Pauwels grade 2). Fixation was made using 6.5-mm non-cannulated screws (n=6), 6.5-mm cannulated screws (n=6), or 7.3-mm cannulated screws (n=6). A custom-built jig was designed to guide the insertion of the screws in an identical triangular configuration. Screws were tightened by a single operator using a torque-measuring screwdriver. The femoral head was subjected to progressive axial loading at 5 mm/min. The load to failure and displacement were recorded. RESULTS: The 3 groups did not differ significantly except that the load to failure was higher in the construct with 6.5-mm non-cannulated screws than that with 6.5-mm cannulated screws (1222 N vs 1008 N, p=0.003). CONCLUSION: The compressive strength of a synthetic bone hip fracture model fixed with non cannulated screws was higher than that of cannulated screws of the same diameter. PMID- 25920644 TI - Salvage of infected non-union of the tibia with an Ilizarov ring fixator. AB - PURPOSE: To review outcomes of 24 patients who underwent Ilizarov ring fixation for infected nonunion of the tibia. METHODS: Medical records of 21 men and 3 women aged 13 to 74 (mean, 38) years who underwent Ilizarov ring fixation for infected non-union of the tibia were reviewed. The mean bone defect was 3.3 (range, 2-5) cm. The mean time from injury to presentation was 11.9 (range, 1-36) months. The mean number of previous surgeries was 2 (range, 0-14). A local flap was used in 2 patients and a free flap was used in one patient. Nine of the patients underwent Ilizarov ring fixation without soft tissue and bony resection, as inadequate stability was the reason for non-union. Patients were assessed using the Association for the Study and Application of the Method of Ilizarov criteria. RESULTS: Patients were followed up for a mean of 11 (range, 8-46) months. Functional outcome was excellent in 8 patients, good in 12, fair in 2, and failure in one, whereas bone union outcome was excellent in 6 patients, good in 14, fair in one, and poor in 2. The mean time to union was 8 (range, 3-31) months. The mean external fixation index was 4.2 (range, 1.5-15.7) cm/month. Complications encountered were pin tract infection (n=5), re-fracture (n=2), soft tissue impingement by Ilizarov rings (n=2), recurrence of wound infection (n=1), mal-union (n=1), and mortality (n=1). CONCLUSION: Ilizarov ring fixation is a viable option for infected non-union of the tibia. Adequate assessment of bone union is crucial before removal of fixator to prevent re-fracture. PMID- 25920643 TI - Effect of soft-tissue attachment on tibial fracture healing in rats. AB - PURPOSE: To compare tibial fracture healing in rats with or without soft-tissue attachment. METHODS: The left tibias of 30 Wistar rats were osteotomised and equally randomised into 3 groups. In the avascular segmental fracture group, an 8 mm bone segment were first removed and then immediately put back. In the vascular segmental fracture group, the 8-mm bone segment was not displaced, with periosteal and muscular attachments. In the simple fracture group, a simple fracture in the middle tibia was made. All tibias were then stabilised with an intramedullary nail through the patellar tendon, and the wound was closed with sutures. After 8 weeks, all left tibias and 9 of the intact right tibias were harvested. Bone mineral content and density of the calluses were assessed using dual energy X-ray absorptiometry scanning. The maximum torsional strength, rigidity, and energy to failure of the tibias were measured. RESULTS: All tibias healed (callus formation), without mal-union or pin migration. The 3 groups did not differ significantly in terms of torsional strength, rigidity, energy to failure, bone mineral content, and bone mineral density. The mean torsional strength of the 9 intact tibias was significantly higher than the healed tibias (14.9 vs. 10.6 Nmm, p=0.021). CONCLUSION: Soft-tissue detachment from bone segments did not impair bone healing in rats. PMID- 25920645 TI - Bicycle and motorcycle wheel spoke injury in children. AB - PURPOSE: To review bicycle and motorcycle wheel spoke injuries around the foot and ankle in 24 children. METHODS: Medical records of 12 boys and 12 girls aged 2 to 11 (mean, 5.3) years who presented with an isolated posterior heel injury caused by wheel spokes of a motorcycle (n=9) or bicycle (n=15) were reviewed. RESULTS: All 9 motorcycle injury patients and 8 of 15 bicycle injury patients had lacerations. The remaining 7 bicycle injury patients had abrasions and developed skin necrosis and ulcerations, with 5 requiring debridement. The most common site of laceration was the posterolateral heel; 7 of these patients had deep soft tissue injury, and in 5 the Achilles tendon was partially cut or completely severed. The mean number of operations was 2.2 in the motorcycle group and 1.3 in the bicycle group. Seven patients with severe skin loss required skin grafting or flap surgery for wound coverage. The mean time from injury to definitive treatment was 8.2 days. The mean length of hospital stay was 18.4 days in the motorcycle group and 8.1 days in the bicycle group. Delayed definitive treatment was associated with more operations (r=0.499, p=0.013) and longer hospital stay (r=0.567, p=0.004). CONCLUSION: Wheel spoke injuries may result in severe soft tissue damage and bony trauma. Poor prognostic factors included high-energy injury, contamination and infection, and delayed treatment. PMID- 25920646 TI - Infection rates in Singaporeans with and without complicated diabetes after ankle fracture surgery. AB - PURPOSE: To compare infection rates in Singaporeans with and without complicated diabetes after ankle fracture surgery. METHODS: Medical records of 18 men and 27 women aged 38 to 84 (mean, 62) years with complicated (n=12) or uncomplicated (n=33) diabetes who underwent internal fixation for closed ankle fractures were reviewed. Complicated diabetes was defined as having end organ dysfunction. The control of diabetes was categorised as good (n=19), fair (n=10), and poor (n=16), based on HbA1c level within 4 months before or after surgery. Patients were followed up at weeks 2, 6, 12, and 24, with bone union as the end point. RESULTS: The mean follow-up period was 9 (range, 4-12) months. 2 (6%) of 33 patients with uncomplicated diabetes and 6 (50%) of 12 patients with complicated diabetes developed superficial or deep infection. No patient died or underwent amputation secondary to infection. In multivariable logistic regression analysis after adjusting for co-morbidities, only complicated diabetes was a risk factor for postoperative infection (odds ratio=11.85, p=0.01). The odds of postoperative infection was 11.85 times higher in patients with complicated diabetes than with uncomplicated diabetes. CONCLUSION: In patients with complicated diabetes, careful patient selection, peri-operative precaution, and closer monitoring are recommended if surgery is necessary. PMID- 25920647 TI - Ankle lateral ligament reconstruction for chronic instability. AB - PURPOSE: To report the outcome of a technique combining direct anatomic reconstruction of the anterior talofibular ligament (ATFL) with augmented reconstruction using the peroneus brevis tendon fixed by a bio-absorbable interference screw. METHODS: 13 men and 2 women aged 17 to 36 (mean, 24) years with recurrent inversion injuries of the right (n=5) and left (n=10) ankles underwent lateral ankle reconstruction by a single surgeon. All patients had a positive anterior drawer test and heel eversion stress test, and some degree of tenderness to palpation over the anterolateral joint capsule. All patients had complete or partial tear of the ATFL and the calcaneofibular ligament, except for one. The torn ligaments were repaired anatomically and reinforced with a split peroneus brevis tendon rerouted through the fibula and fixed with a bioabsorbable interference screw. The outcome was assessed using the American Orthopaedic Foot and Ankle Society (AOFAS) ankle and hindfoot score and the Foot and Ankle Outcome Score (FAOS) at 6 months. RESULTS: The mean time from injury to surgery was 40.5 months. The mean follow-up duration was 13.6 (range, 6-26) months. No patient had surgical or wound complications. The mean AOFAS ankle and hindfoot score was 91.5 (median, 93; range, 79-100). The mean FAOS was 78.8 (median, 77; range, 61-100). 10 patients had no limitation in both daily and recreational activities; 3 had limitation in recreational activities, and 2 had limitation in both. 12 patients had normal and 3 had moderate limitation in hindfoot motion. One patient had hindfoot instability. CONCLUSION: The combination of augmented and direct anatomic reconstructions enables early mobilisation despite limitation in hindfoot motion and is a viable option for chronic hindfoot instability. PMID- 25920648 TI - Blood management protocol for total knee arthroplasty to reduce blood wastage and unnecessary transfusion. AB - PURPOSE: To compare outcomes of 2 cohorts of patients who underwent total knee arthroplasty (TKA) before and after the introduction of a blood management protocol. METHODS: Records of 97 and 96 consecutive patients who underwent unilateral TKA before and after introduction of the blood management protocol, respectively, were reviewed. Before introduction of the protocol, patients were cross-matched for blood before surgery. Transfusion after surgery was at the discretion of the surgeons or the on-call doctors. After introduction of the protocol, only patients with a preoperative haemoglobin level of <110 g/l underwent 'type and screening' of blood group. 2 units of blood were cross matched preoperatively when multiple red-cell antibodies were identified or postoperatively when blood transfusion was required. Only patients with a postoperative haemoglobin level of <80 g/l or being symptomatic received blood transfusion until the haemoglobin level reached >100 g/l. Those with a postoperative haemoglobin level of 80 to 100 g/l were given iron sulphate 300 mg twice daily for a month. RESULTS: The 2 groups did not differ significantly in age, sex ratio, pre- and post-operative haemoglobin levels, and drain output. Comparing outcome before and after introduction of the protocol, the transfusion rate (10.3% vs. 3.1%, p=0.046), crossmatch rate (100% vs. 3.1%, p<0.001), and crossmatch to transfusion ratio (9.7:1 vs. 1:1, p<0.001) decreased. Among transfused patients, the decreased postoperative haemoglobin level indicated a lower transfusion trigger point (100 g/l vs. 75 g/l, p<0.006) No patient developed infection, cardiovascular or cerebrovascular complications within 30 days. CONCLUSION: The blood management protocol for TKA is effective in reducing unnecessary allogeneic blood transfusions and wastage of unused blood, without an increase in postoperative complications. PMID- 25920649 TI - Short-term outcome after computer-assisted versus conventional total knee arthroplasty: a randomised controlled trial. AB - PURPOSE: To compare the short-term functional outcome after computer-assisted total knee arthroplasty (TKA) versus conventional TKA. METHODS: 23 men and 67 women aged 48 to 80 years were randomised to undergo (1) conventional TKA using an intramedullary guide, (2) conventional TKA using an extramedullary guide, or (3) computer-assisted TKA. Two senior surgeons performed all the TKAs using the same TKA system and the standard anteromedial arthrotomy with eversion of the patella. Patients were assessed by physiotherapists before and 6 months and 2 years after TKA using the Short Form-36 Health Survey, Oxford Knee Score, and Knee Society Score. RESULTS: Of the 90 patients, 67 and 70 were assessed at 6 months and 2 years after TKA, respectively. No patient developed deep infection or required revision surgery. Functional outcomes of the 3 groups did not differ significantly at the corresponding follow-ups. CONCLUSION: Significant improvement in the functional outcome was not shown in patients treated with computer-assisted TKA, compared with conventional TKA. Thus, computer-assisted TKA has limited additional short-term benefits. Further studies with longer follow-up are required to examine the benefits of computer-assisted TKA. PMID- 25920650 TI - Gait parameters in women with bilateral osteoarthritis after unilateral versus sequential bilateral total knee arthroplasty. AB - PURPOSE: To compare gait parameters in women after unilateral total knee arthroplasty (TKA) versus sequential bilateral TKA to determine the need for sequential TKA. METHODS: 35 women aged 60 to 74 (mean, 70) years with bilateral varus knee osteoarthritis (OA) underwent unilateral (n=23) or sequential bilateral (n=12) TKA by a single surgeon. All patients underwent unilateral TKA; 12 patients then underwent sequential TKA after 3 to 6 months of the first TKA. Gait parameters (step length, step width, gait velocity, single support phase value, and the maximum centre of gravity ratio) were compared before and after TKA, and between patients with unilateral versus bilateral TKA. RESULTS: Patients with sequential bilateral TKA had more severe OA in their contralateral knee than patients with unilateral TKA. In patients with unilateral and sequential bilateral TKA respectively, the mean step width differed at postoperative one month (12.9 vs. 19.1, p<0.01) and 3 months (11.9 vs. 16, p=0.03), and the mean maximum centre of gravity ratio differed at postoperative 3 months (2.43 vs. 1.75, p=0.02), whereas the mean step length, mean gait velocity, and mean single support phase values did not differ significantly between groups. CONCLUSION: After unilateral TKA, contralateral TKA may not be necessary in some patients whose gait has improved. PMID- 25920651 TI - Preoperative antibiotics for septic arthritis in children: delay in diagnosis. AB - PURPOSE: To review the records of 50 children who underwent open joint washout for septic arthritis with (n=25) or without (n=25) preoperative antibiotics. METHODS: Records of 50 children who underwent open joint washout for presumed septic arthritis with (n=25) or without (n=25) preoperative antibiotics were reviewed. 17 boys and 8 girls aged 3 weeks to 16 years (median, 1.5 years) who were prescribed preoperative antibiotics before joint washout were compared with 12 boys and 13 girls aged one month to 14 years (median, 2 years) who were not. Following arthrotomy and washout, all patients were commenced on high-dose intravenous antibiotics. Patients were followed up for 6 to 18 months until asymptomatic. RESULTS: Patients who were referred from places other than our emergency department were twice as likely to have been prescribed preoperative antibiotics (p=0.0032). Patients prescribed preoperative antibiotics had a longer median (range) time from symptom onset to joint washout (8 [2-23] vs. 4 [1-29] days, p=0.05) and a higher mean erythrocyte sedimentation rate (93.1 vs. 54.3 mm/h, p=0.023) at presentation. Nonetheless, the 2 groups were comparable for weight bearing status, fever, and positive culture, as well as the mean (range) duration of antibiotic treatment (4.9 [4-7] vs. 4.7 [1-8] weeks, p=0.586). CONCLUSION: Preoperative antibiotics should be avoided in the management of septic arthritis in children. Their prescription delays diagnosis and definitive surgery, and leads to additional washouts and complications. A high index of suspicion and expedite referral to a specialist paediatric orthopaedic unit is needed if septic arthritis is suspected. PMID- 25920652 TI - Tuberculosis of the calcaneus in children. AB - PURPOSE: To review 10 children with calcaneal tuberculosis in terms of presentation, healing, and functional outcome. METHODS: Medical records of 7 boys and 3 girls aged 7 to 12 (mean, 9.8) years who presented with calcaneal tuberculosis were reviewed. The erythrocyte sedimentation rate of all patients was elevated. All patients presented with pain and swelling around the lateral malleolus and a 'heal-up' sign; 7 of them presented with an additional discharging sinus. Three patients had palpable lymph nodes in the right inguinal or left popliteal region. Symptoms had lasted for one month to 1.5 years. Two patients had healed tuberculosis in the lungs; 8 patients had no pulmonary involvement. Seven patients had a single lytic lesion in the calcaneal body (n=1), tuberosity (n=3), and extension to anterior process (n=3). Three patients had multiple lytic lesions in the calcaneum; one of them had bilateral involvement who had lesions in the phalanges, lumbar spine, and ulna. Two patients had subtalar joint involvement. RESULTS: The mean follow-up period was 17 (range, 8-60) months. The erythrocyte sedimentation rate returned to normal after 3 months in 7 patients and after >6 months in 3 patients. The subtalar range of movement was normal in all except for 2 patients. One patient developed subtalar ankylosis. Sinuses healed in a mean of 10 (range, 2-16) weeks. No patient had pain on level walking after treatment. At 3 months, remineralisation of bone was evident in all patients. Sclerosis of cavity margins and sequestra resorption was noted from 6 to 9 months. No patient experienced recurrence. CONCLUSION: The 'heel up' sign was common in children with calcaneal tuberculosis in this endemic region. The central granuloma-type presentation was the most common. Pathological fractures and involvement of the subtalar joint were not common. Subtalar joint involvement was a poor prognostic factor. PMID- 25920653 TI - Total hip arthroplasty using a short-stem prosthesis: restoration of hip anatomy. AB - PURPOSE: To evaluate hip parameters such as vertical centre of rotation (VCR), horizontal centre of rotation (HCR), femoral offset, and leg length after total hip arthroplasty (THA) using the Nanos short-stem prosthesis. METHODS: Medical records of 73 men and 74 women aged 25 to 92 (mean, 63) years who underwent THA using the Nanos short-stem prosthesis by a single surgeon were reviewed. Prior to the surgery, the optimal cup and stem size, head length, and level of the neck osteotomy were determined using radiographs. Intra-operatively, the leg length and femoral offset were checked, and the level of neck resection and head length were adjusted. VCR, HCR, femoral offset, and leg length of the operated and contralateral sides were compared. Functional outcomes were assessed using the Harris Hip Score (HHS). RESULTS: Compared with the normal contralateral hips, the operated hips had a mean increase of 0.4 mm in VCR (p=0.032), a mean decrease of 1.4 mm in HCR (p=0.027), a mean increase of 0.6 mm in femoral offset (p=0.043), and a mean increase of 0.36 mm in leg length (p=0.035). For these respective parameters, the difference between the normal contralateral side and the operated side was within 5 mm in 89%, 80%, 71%, and 96% of patients. The HHS improved from a mean of 53 to 91 at one year (p<0.001). CONCLUSION: THA using the Nanos short stem prosthesis enabled restoration of hip anatomy (VCR, HCR, femoral offset, and leg length). PMID- 25920654 TI - Effects of thermoablation with or without caffeine on giant cell tumour of bone. AB - PURPOSE: To evaluate the effect of caffeine on the apoptosis rate of giant cell tumour of bone cells during thermoablation. METHODS: Giant cell tumour of bone tissue (2 cm3) was collected from 10 patients. Cells were incubated at 37oC, 40oC, 45oC, 50oC, 52.5oC, and 55oC for 20 minutes (3 tubes for each temperature). Caffeine was added to the tubes in amounts of 0 MUg/ml (control), 50 MUg/ml, and 100 MUg/ml. The apoptotic effect of thermoablation with or without caffeine was evaluated. RESULTS: In all test conditions, the apoptotic rate of tumour cells increased when the temperature increased. Compared with controls (no caffeine), adding 50 or 100 MUg/ml of caffeine did not increase the apoptotic rate significantly at 40oC to 52.5oC. Caffeine had no enhancing effect at any temperature. Conversely, at 55oC, the apoptotic rate was lower when 100 MUg/ml of caffeine was added than when no or 50 MUg/ml of caffeine added (p=0.045). CONCLUSION: Thermoablation at 40oC to 52.5oC for 20 minutes increased the apoptosis rate of giant cell tumour of bone cells. Caffeine had no enhancing effect at any temperature. Conversely, at 55oC, caffeine had cytoprotective effects on the tumour cells against thermoablation. PMID- 25920655 TI - Review article: Patient-specific versus standard instrumentation for total knee arthroplasty. AB - This meta-analysis reviewed 12 studies comparing patient-specific instrumentation (PSI) with standard instrumentation (SI) for total knee arthroplasty in terms of postoperative coronal alignment and operation time. There is no significant difference between PSI and SI in terms of hip-knee-ankle angle (overall coronal alignment or mechanical axis), tibial coronal alignment, and operation time. PMID- 25920656 TI - Review article: Outcome of total knee arthroplasty in obese patients. AB - The MEDLINE database was searched using the key words: 'obesity' and 'knee arthroplasty'. 41 articles focused on the topic were reviewed; most studies were prospective case series (providing low-level evidence) and 3 were systematic reviews. 16 studies reported no adverse association between obesity and total knee arthroplasty (TKA) outcome, whereas 24 studies reported a poorer TKA outcome in obese patients. In the 3 systematic reviews, obesity was reported to adversely affect the outcome, the rate of complications, implant survival, and the cost of TKA. PMID- 25920657 TI - Pedicled vascularised fibular grafting in a flow-through manner for reconstruction of infected non-union of the tibia with preservation of the peroneal artery: a case report. AB - We report on an 82-year-old man with an infected non-union of the right tibia in which the peroneal artery was the sole artery supplying the lower leg, owing to peripheral arterial disease. He underwent tibial reconstruction using the pedicled vascularised fibular graft in a flow-through manner (without ligation of either the proximal or distal ends of the peroneal artery) and achieved successful bony union. PMID- 25920658 TI - Arthroscopic debridement for bilateral calcific tendinitis of the subscapularis tendons: a case report. AB - We report on a 36-year-old man who underwent arthroscopic debridement for bilateral calcific tendinitis of the subscapularis tendons. The patient had a positive coracoid impingement test for both shoulders. Radiology showed calcific deposits at the insertion of both subscapularis tendons, close to the lesser tuberosities and just posterior to the coracoid tips. The patient underwent sequential arthroscopic coracoplasty and removal of calcific deposits in the subscapularis tendons. The patient returned to work 6 weeks after each surgery. At 2 years, the patient had no shoulder pain, with full range of motion and full power of the subscapularis muscles. The coracoid impingement test was negative for both shoulders. There was no evidence of recurrence. PMID- 25920659 TI - Extensor tendon rupture of the index finger secondary to avascular necrosis of the scaphoid: a case report. AB - We report on a 74-year-old man with extensor indicis proprius (EIP) tendon rupture secondary to avascular necrosis and collapse of the scaphoid. The collapsed scaphoid was removed, followed by 4-corner fusion and tendon transfer of the extensor digiti minimi to the EIP. At the 3-year follow-up, the patient was painfree and had full extension of his left index finger, with proper alignment of the carpal bones and union of the 4 bones. PMID- 25920660 TI - Inferior dislocation of the hip: a case report and literature review. AB - We report on a 17-year-old man who underwent open reduction and internal fixation for an inferior dislocation of the right hip and displaced fractures of the right femoral head and neck, and antegrade intramedullary nailing for a displaced fracture of the left femoral shaft. In addition, 13 men and 4 women aged 5 to 56 (mean, 23) years with 16 unilateral and one bilateral inferior dislocation of the hip were reviewed from the literature. PMID- 25920661 TI - Bipartite patella causing knee pain in young adults: a report of 5 cases. AB - We report on 5 patients who underwent arthroscopic excision or open reduction and internal fixation for bipartite patella. All patients presented with refractory anterior knee pain. The diagnosis of bipartite patella was made using radiography, and confirmed with magnetic resonance imaging or computed tomographic arthrography. All 5 patients achieved complete resolution of symptoms after surgery, and remained pain-free after a mean followup period of 13 months. PMID- 25920662 TI - Letter to the editor: Clavicular hook plate for grade-III acromioclavicular dislocation. PMID- 25920663 TI - Letter to the editor: Use of sutures as Kirschner wire and tension-band wire for olecranon fractures: a technical note. PMID- 25920664 TI - Letter to the editor: Proximal femoral locking compression plate for proximal femoral fractures. PMID- 25920665 TI - Letter to the editor: Hospital mortality after arthroplasty using a cemented stem for displaced femoral neck fractures. PMID- 25920666 TI - Rhizobial root hair infection requires auxin signaling. AB - Legumes can enter into a mutualistic relationship with nitrogen-fixing rhizobacteria. A recent study by A. Breakspear et al. sheds new light on the mechanisms involved in rhizobial infection of their host root hair during symbiosis establishment and reveals a new role for auxin signaling in this process. PMID- 25920667 TI - Gas-phase chemistry of technetium carbonyl complexes. AB - Gas-phase chemical behaviors of short-lived technetium carbonyl complexes were studied using a low temperature isothermal chromatograph (IC) coupled with a (252)Cf spontaneous fission (SF) source. Fission products recoiled from the (252)Cf SF source were thermalized in a mixed gas containing CO, and then technetium carbonyl complexes were formed from reactions between CO gas and various technetium isotopes. A gas-jet system was employed to transport the volatile carbonyl complexes from a recoil chamber to the IC. Short IC columns made of Fluorinated Ethylene Propylene (FEP) Teflon and quartz were used to obtain chemical information about the technetium carbonyl complexes. The results for the (104)Tc-(106)Tc carbonyl complexes were found to be strongly influenced by the precursors, and showed the chemical behaviors of (104)Mo-(106)Mo carbonyl complexes, respectively. However, (107)Tc and (108)Tc could represent the chemical information of the element technetium due to their high independent yields and the very short half-lives of their precursors (107)Mo and (108)Mo. An adsorption enthalpy of about DeltaHads = -43 kJ mol(-1) was determined for the Tc carbonyl complexes on both the Teflon and quartz surfaces by fitting the breakthrough curves of the (107)Tc and (108)Tc carbonyl complexes with a Monte Carlo simulation program. Chemical yields of around 25% were measured for the Tc carbonyl complexes relative to the transport yields obtained with the gas-jet transport of KCl aerosol particles with Ar carrier gas. Furthermore, the influence of a small amount of O2 gas on the yields of the Mo and Tc carbonyl complexes was studied. PMID- 25920668 TI - Genome-wide QTL mapping of saltwater tolerance in sibling species of Anopheles (malaria vector) mosquitoes. AB - Although freshwater (FW) is the ancestral habitat for larval mosquitoes, multiple species independently evolved the ability to survive in saltwater (SW). Here, we use quantitative trait locus (QTL) mapping to investigate the genetic architecture of osmoregulation in Anopheles mosquitoes, vectors of human malaria. We analyzed 1134 backcross progeny from a cross between the obligate FW species An. coluzzii, and its closely related euryhaline sibling species An. merus. Tests of 2387 markers with Bayesian interval mapping and machine learning (random forests) yielded six genomic regions associated with SW tolerance. Overlap in QTL regions from both approaches enhances confidence in QTL identification. Evidence exists for synergistic as well as disruptive epistasis among loci. Intriguingly, one QTL region containing ion transporters spans the 2Rop chromosomal inversion that distinguishes these species. Rather than a simple trait controlled by one or a few loci, our data are most consistent with a complex, polygenic mode of inheritance. PMID- 25920669 TI - Short-term genetic consequences of habitat loss and fragmentation for the neotropical palm Oenocarpus bataua. AB - Habitat loss and fragmentation may impact animal-mediated dispersal of seed and pollen, and a key question is how the genetic attributes of plant populations respond to these changes. Theory predicts that genetic diversity may be less sensitive to such disruptions in the short term, whereas inbreeding and genetic structure may respond more strongly. However, results from studies to date vary in relation to species, context and the parameter being assessed, triggering calls for more empirical studies, especially from the tropics, where plant-animal dispersal mutualisms are both disproportionately common and at risk. We compared the genetic characteristics of adults and recruits in a long-lived palm Oenocarpus bataua in a recently fragmented landscape (<2 generations) in northwest Ecuador using a suite of 10 polymorphic microsatellite markers. We sampled individuals from six forest fragments and one nearby continuous forest. Our goal was to assess short-term consequences of fragmentation, with a focus on how well empirical data from this system follow theoretical expectations. Mostly congruent with predictions, we found stronger genetic differentiation and fine scale spatial genetic structure among recruits in fragments compared with recruits in continuous forest, but we did not record differences in genetic diversity or inbreeding, nor did we record any differences between adults in fragments and adults in continuous forest. Our findings suggest that genetic characteristics of populations vary in their sensitivity to change in response to habitat loss and fragmentation, and that fine-scale spatial genetic structure may be a particularly useful indicator of genetic change in recently fragmented landscapes. PMID- 25920670 TI - Quantifying heritable variation in fitness-related traits of wild, farmed and hybrid Atlantic salmon families in a wild river environment. AB - Farmed fish are typically genetically different from wild conspecifics. Escapees from fish farms may contribute one-way gene flow from farm to wild gene pools, which can depress population productivity, dilute local adaptations and disrupt coadapted gene complexes. Here, we reanalyse data from two experiments (McGinnity et al., 1997, 2003) where performance of Atlantic salmon (Salmo salar) progeny originating from experimental crosses between farm and wild parents (in three different cohorts) were measured in a natural stream under common garden conditions. Previous published analyses focussed on group-level differences but did not account for pedigree structure, as we do here using modern mixed-effect models. Offspring with one or two farm parents exhibited poorer survival in their first and second year of life compared with those with two wild parents and these group-level inferences were robust to excluding outlier families. Variation in performance among farm, hybrid and wild families was generally similar in magnitude. Farm offspring were generally larger at all life stages examined than wild offspring, but the differences were moderate (5-20%) and similar in magnitude in the wild versus hatchery environments. Quantitative genetic analyses conducted using a Bayesian framework revealed moderate heritability in juvenile fork length and mass and positive genetic correlations (>0.85) between these morphological traits. Our study confirms (using more rigorous statistical techniques) previous studies showing that offspring of wild fish invariably have higher fitness and contributes fresh insights into family-level variation in performance of farm, wild and hybrid Atlantic salmon families in the wild. It also adds to a small, but growing, number of studies that estimate key evolutionary parameters in wild salmonid populations. Such information is vital in modelling the impacts of introgression by escaped farm salmon. PMID- 25920671 TI - Using ABC and microsatellite data to detect multiple introductions of invasive species from a single source. AB - The introduction of invasive species to new locations (that is, biological invasions) can have major impact on biodiversity, agriculture and public health. As such, determining the routes and modality of introductions with genetic data has become a fundamental goal in molecular ecology. To assist with this goal, new statistical methods and frameworks have been developed, such as approximate Bayesian computation (ABC) for inferring invasion history. Here, we present a model of invasion accounting for multiple introductions from a single source (MISS), a heretofore largely unexplored model. We simulate microsatellite data to evaluate the power of ABC to distinguish between single and multiple introductions from the same source, under a range of demographic parameters. We also apply ABC to microsatellite data from three invasions of bumblebee in New Zealand. In addition, we assess the performance of several methods of summary statistics selection. Our simulated results suggested good ability to distinguish between one- and two-wave models over much but not all of the parameter space tested, independent of summary statistics used. Globally, parameter estimation was good except for bottleneck timing. For one of the bumblebee species, we clearly rejected the MISS model, while for the other two we found inconclusive results. Since a second wave may provide genetic reinforcement to initial colonists, help relieve inbreeding among founders, or increase the hazard of the invasion, its detection may be crucial for managing invasions; we suggest that the MISS model could be considered as a potential model in future theoretical and empirical studies of invasions. PMID- 25920672 TI - Vicariance and marine migration in continental island populations of a frog endemic to the Atlantic Coastal forest. AB - The theory of island biogeography is most often studied in the context of oceanic islands where all island inhabitants are descendants from founding events involving migration from mainland source populations. Far fewer studies have considered predictions of island biogeography in the case of continental islands, where island formation typically splits continuous populations and thus vicariance also contributes to the diversity of island populations. We examined one such case on continental islands in southeastern Brazil, to determine how classic island biogeography predictions and past vicariance explain the population genetic diversity of Thoropa taophora, a frog endemic to the Atlantic Coastal Forest. We used nuclear microsatellite markers to examine the genetic diversity of coastal and island populations of this species. We found that island isolation has a role in shaping the genetic diversity of continental island species, with island populations being significantly less diverse than coastal populations. However, area of the island and distance from coast had no significant effect on genetic diversity. We also found no significant differences between migration among coastal populations and migration to and from islands. We discuss how vicariance and the effects of continued migration between coastal and island populations interact to shape evolutionary patterns on continental islands. PMID- 25920673 TI - WHO calls for $5m for earthquake relief. PMID- 25920674 TI - Ventricular arrhythmia incidence in the rat is reduced by naloxone. AB - This study characterized the antiarrhythmic effects of the opioid receptor antagonist naloxone in rats subject to electrically induced and ischemic arrhythmias. Naloxone (2, 8 and 32 MUmol/kg/min) was examined on heart rate, blood pressure, and the electrocardiogram (EKG) as well as for effectiveness against arrhythmias produced by occlusion of the left anterior descending coronary artery or electrical stimulation of the left ventricle. Naloxone reduced blood pressure at the highest dose tested while heart rate was dose-dependently reduced. Naloxone dose-dependently prolonged the P-R and QRS intervals and increased the RSh amplitude indicative of effects on cardiac sodium (Na) channels. Naloxone prolonged the Q-T interval suggesting a delay in repolarization. Naloxone effects were comparable to the comparator quinidine. Naloxone (32 MUmol/kg/min) reduced ventricular fibrillation (VF) incidence to 38% (from 100% in controls). This same dose significantly increased the threshold for induction of ventricular fibrillation (VFt), prolonged the effective refractory period (ERP) and reduced the maximal following frequency (MFF). The patterns of ECG changes, reduction in ischemic arrhythmia (VF) incidence and changes in electrically induced arrhythmia parameters at high doses of naloxone suggest that it directly blocks cardiac Na and potassium (K) ion channels. PMID- 25920675 TI - A validation study of the Facial-Oral Tract Therapy Swallowing Assessment of Saliva. AB - OBJECTIVE: To investigate the validity and reliability of the Swallowing Assessment of Saliva in detection of aspiration risk. DESIGN: Validation study. SETTING: Inpatient neurorehabilitation centre. SUBJECTS: Adult patients with acquired brain injury. A total of 43 patients for concurrent validity and 33 other patients for inter-rater reliability. INTERVENTIONS: Concurrent validity was established with blinded Swallowing Assessment of Saliva and endoscopic evaluation within a 24-hour time interval. Inter-rater reliability was established with two blinded Swallowing Assessments of Saliva within a one-hour time interval. MAIN MEASURES: The Swallowing Assessment of Saliva is a seven-item scale with a combination of swallowing and non-swallowing items. It is based on the Facial-Oral Tract Therapy approach. RESULTS: The Swallowing Assessment of Saliva had a sensitivity of 91%, 95% confidence interval (CI) (59; 100), a specificity of 88% %, 95% CI (71; 97) and a kappa coefficient of 0.87 +/-0.17 in detection of aspiration risk. Furthermore, analyses showed that experienced and inexperienced occupational therapists performed equally in detection of aspiration risk. CONCLUSION: The Swallowing Assessment of Saliva is a simple, sensitive and reliable assessment for detecting aspiration risk in patients with acquired brain injury. PMID- 25920677 TI - The effect of river damming on vegetation: is it always unfavourable? A case study from the River Tiber (Italy). AB - River damming leads to strong hydromorphological alterations of the watercourse, consequently affecting river vegetation pattern. A multitemporal and spatial analysis of the dam effect on composition, structure and dynamic of the upstream vegetation was performed on Tiber River at Nazzano-dam (Rome). The main research questions were as follows: How does plant landscape vary over time and along the river? Where does the dam effect on vegetation end? How does naturalistic importance of the vegetation affected by damming change over time? Data collection was performed mapping the vegetation in aerial photos related to the period before (1944), during (1954) and after dam construction (1984, 2000). The plant landscape has significantly changed over time and along the river, particularly as a result of the dam construction (1953). The major vegetation changes have involved riparian forests and macrophytes. Dam effect on vegetation is evident up to 3 km, and gradually decreases along an attenuation zone for about another 3 km. Despite the fact that the damming has caused strong local hydromorphological modification of the river ecosystem transforming it into a sub lacustrine habitat, it has also led to the formation of wetlands of considerable naturalistic importance. Indeed, in these man-made wetlands, optimal hydrological conditions have been created by favouring both the expansion of pre-existing riparian communities and the rooting of new aquatic communities, albeit typical of lacustrine ecosystems. Some of these plant communities have become an important food resource, refuge or nesting habitats for aquatic fauna, while others fall into category of Natura 2000 habitats. Therefore, river damming seems to have indirectly had a "favourable" effect for habitat conservation and local biodiversity. PMID- 25920676 TI - A rapid, fully automated and highly sensitive ADAMTS13 gold particle immunoassay using a routine biochemistry analyser. PMID- 25920678 TI - Essential Role of Calmodulin in RyR Inhibition by Dantrolene. AB - Dantrolene is the first line therapy of malignant hyperthermia. Animal studies suggest that dantrolene also protects against heart failure and arrhythmias caused by spontaneous Ca(2+) release. Although dantrolene inhibits Ca(2+) release from the sarcoplasmic reticulum of skeletal and cardiac muscle preparations, its mechanism of action has remained controversial, because dantrolene does not inhibit single ryanodine receptor (RyR) Ca(2+) release channels in lipid bilayers. Here we test the hypothesis that calmodulin (CaM), a physiologic RyR binding partner that is lost during incorporation into lipid bilayers, is required for dantrolene inhibition of RyR channels. In single channel recordings (100 nM cytoplasmic [Ca(2+)] + 2 mM ATP), dantrolene caused inhibition of RyR1 (rabbit skeletal muscle) and RyR2 (sheep) with a maximal inhibition of Po (Emax) to 52 +/- 4% of control only after adding physiologic [CaM] = 100 nM. Dantrolene inhibited RyR2 with an IC50 of 0.16 +/- 0.03 uM. Mutant N98S-CaM facilitated dantrolene inhibition with an IC50 = 5.9 +/- 0.3 nM. In mouse cardiomyocytes, dantrolene had no effect on cardiac Ca(2+) release in the absence of CaM, but reduced Ca(2+) wave frequency (IC50 = 0.42 +/- 0.18 uM, Emax = 47 +/- 4%) and amplitude (IC50 = 0.19 +/- 0.04 uM, Emax = 66 +/- 4%) in the presence of 100 nM CaM. We conclude that CaM is essential for dantrolene inhibition of RyR1 and RyR2. Its absence explains why dantrolene inhibition of single RyR channels has not been previously observed. PMID- 25920679 TI - Targeted disruption of organic cation transporter 3 attenuates the pharmacologic response to metformin. AB - Metformin, the most widely prescribed antidiabetic drug, requires transporters to enter tissues involved in its pharmacologic action, including liver, kidney, and peripheral tissues. Organic cation transporter 3 (OCT3, SLC22A3), expressed ubiquitously, transports metformin, but its in vivo role in metformin response is not known. Using Oct3 knockout mice, the role of the transporter in metformin pharmacokinetics and pharmacodynamics was determined. After an intravenous dose of metformin, a 2-fold decrease in the apparent volume of distribution and clearance was observed in knockout compared with wild-type mice (P < 0.001), indicating an important role of OCT3 in tissue distribution and elimination of the drug. After oral doses, a significantly lower bioavailability was observed in knockout compared with wild-type mice (0.27 versus 0.58, P < 0.001). Importantly, metformin's effect on the plasma glucose concentration-time curve was reduced in knockout compared with wild-type mice (12 versus 30% reduction, respectively, P < 0.05) along with its accumulation in skeletal muscle and adipose tissue (P < 0.05). Furthermore, the effect of metformin on phosphorylation of AMP activated protein kinase, and expression of glucose transporter type 4 was absent in the adipose tissue of Oct3(-/-) mice. Additional analysis revealed that an OCT3 3' untranslated region variant was associated with reduced activity in luciferase assays and reduced response to metformin in 57 healthy volunteers. These findings suggest that OCT3 plays an important role in the absorption and elimination of metformin and that the transporter is a critical determinant of metformin bioavailability, clearance, and pharmacologic action. PMID- 25920680 TI - Aneuploidy identifies subsets of patients with poor clinical outcome in grade 1 and grade 2 breast cancer. AB - OBJECTIVE: Histological grade is a well-established prognostic/predictive factor in breast cancer. However, mainly within intermediate categories, patients may have unpredictable outcome. We hypothesised whether ploidy status can distinguish different prognostic groups among breast cancer patients with similar tumour grade. MATERIAL AND METHODS: The study involved 684 patients with invasive breast carcinoma, and median follow-up of 134.5 months. Pathological staging was evaluated according to WHO classification. Tumour differentiation was assessed using the Nottingham grading system. Ploidy was determined prospectively by DNA flow cytometry. Disease-free survival (DFS) and overall survival (OS) were estimated by the Kaplan-Meier method. RESULTS: There were 179 (26.2%) deaths and 239 (33.3%) disease recurrences. For grading, tumours were classified as follows: 163 (23.8%) G1, 356 (52.1%) G2 and 165 (24.1%) G3, while 389 (56.9%) tumours presented aneuploidy. Ploidy and grading are strongly associated (P < 0.001). Patients with aneuploid G2 tumours showed worse DFS (P = 0.001) and OS (P < 0.001), as well as those with aneuploid G1 tumours in relation to OS (P = 0.013). When a subset analysis was performed in early breast cancer patients (n = 451) with Stage I/IIA of disease, it remained the same significant associations of aneuploid G1 (to OS) and G2 tumours (to DFS and OS) with unfavourable prognosis. CONCLUSIONS: Aneuploidy identifies subsets of breast cancer patients with G1 and G2 tumours who showed poor clinical outcome. The finding has therapeutic implications, as these patients are potential candidates to risk-adapted adjuvant therapy. PMID- 25920681 TI - Risk of antenatal psychosocial distress in indigenous women and its management at primary health care centres in Australia. AB - OBJECTIVE: This study explored the risk of antenatal psychosocial distress (APD) and associated potential factors and examined management aspects of risk of APD in women attending Aboriginal primary health care services in Australia. METHOD: Audits of medical records of 797 pregnant women from 36 primary health centres in five jurisdictions (NSW, QLD, SA, WA and NT) were undertaken as part of a quality improvement programme. Information collected included mental health assessed by a standard screening tools, enquiry regarding social and emotional well-being (SEWB), depression management (including antidepressant medications) and referral. RESULTS: Around 18% (n=141) of women were at risk of APD based on assessment using a standard screening tool or by SEWB enquiry. There was a significant association between risk of distress and women's life style behaviours (e.g., alcohol, illicit drug use) and health centre characteristics. Of the 141 women, 16% (n= 22) were prescribed antidepressant drugs during pregnancy. A range of nonpharmaceutical mental health interventions were also recorded, including brief intervention of 61% (n=86), counselling of 57% (n=80) and cognitive behaviour therapy of 5% (n=7). About 39% (n=55) of women with APD were referred to external services for consultations with a psychiatrist, psychologist or social worker or to a women's refuge centre. CONCLUSIONS: The higher risk of APD associated with women's life style behaviour indicates that the better understanding of mental health in its cultural context is essential. PMID- 25920682 TI - Hippocampal volume reduction in female but not male recent abstinent methamphetamine users. AB - Growing evidence suggests abnormalities in brain morphology including hippocampal structure in patients with methamphetamine (MA) dependence. This study was performed to examine hippocampal volume in abstinent MA users, and to further explore its relationship with cognitive function. 30 abstinent MA users (20 males and 10 females) with average 5.52 months of duration of abstinence and 29 healthy controls (19 males and 10 females) age 18-45 years old were recruited for clinical assessment and imaging scan. FreeSurfer was used to segment the hippocampus bilaterally, and hippocampal volumes were extracted for group and gender comparisons. Cognitive function was measured using the CogState Battery Chinese language version (CSB-C). Analysis of covariance (ANCOVA) controlling for education showed a significant group by gender interaction for the right hippocampal relative volume adjusted for total brain size (p = 0.020); there was a significant difference between male controls and female controls (p < 0.001), but such a difference did not exist between male patients and female patients (p = 0.203). No significant correlations were found between hippocampal volume and cognitive measures. There seems to be a gender difference in how MA affects hippocampal volume in abstinent MA users. Hippocampus might be an important treatment target for cognitive improvement and functional recovery in this patient population, especially in females. PMID- 25920684 TI - Sensorless Viscosity Measurement in a Magnetically-Levitated Rotary Blood Pump. AB - Controlling the flow rate in an implantable rotary blood pump based on the physiological demand made by the body is important. Even though various methods to estimate the flow rate without using a flow meter have been proposed, no adequate method for measuring the blood viscosity, which is necessary for an accurate estimate of the flow rate, without using additional sensors or mechanisms in a noninvasive way, has yet been realized. We have developed a sensorless method for measuring viscosity in magnetically levitated rotary blood pumps, which requires no additional sensors or mechanisms. By applying vibrational excitation to the impeller using a magnetic bearing, we measured the viscosity of the working fluid by measuring the phase difference between the current in the magnetic bearing and the displacement of the impeller. The measured viscosity showed a high correlation (R(2) > 0.992) with respect to a reference viscosity. The mean absolute deviation of the measured viscosity was 0.12 mPa.s for several working fluids with viscosities ranging from 1.18 to 5.12 mPa.s. The proposed sensorless measurement method has the possibility of being utilized for estimating flow rate. PMID- 25920683 TI - Inherited and Somatic Defects in DDX41 in Myeloid Neoplasms. AB - Most cases of adult myeloid neoplasms are routinely assumed to be sporadic. Here, we describe an adult familial acute myeloid leukemia (AML) syndrome caused by germline mutations in the DEAD/H-box helicase gene DDX41. DDX41 was also found to be affected by somatic mutations in sporadic cases of myeloid neoplasms as well as in a biallelic fashion in 50% of patients with germline DDX41 mutations. Moreover, corresponding deletions on 5q35.3 present in 6% of cases led to haploinsufficient DDX41 expression. DDX41 lesions caused altered pre-mRNA splicing and RNA processing. DDX41 is exemplary of other RNA helicase genes also affected by somatic mutations, suggesting that they constitute a family of tumor suppressor genes. PMID- 25920685 TI - A molecular level mechanism for uranium (VI) toxicity through Ca(2+) displacement in pyrroloquinoline quinone-dependent bacterial dehydrogenase. AB - Dipicolinic acid (DPA), a small molecule analogue for the pyrroloquinoline quinone (PQQ) bacterial dehydrogenase cofactor, was used to model displacement of the complexing ion, Ca(2+), by a uranium (VI) dioxo-cation, UO2(2+). Complexation of UO2(2+) with DPA through the displacement of Ca(2+) was examined with UV/visible spectroscopy, ESI (electrospray ionization)-Mass spectrometry, and density functional theory based-modeling. The UO2(2+) displacement of other biologically important metal cations (Zn(2+), Cu(2+), Ni(2+), and Fe(3+)) from DPA was also examined. Results show that UO2(2+) has a distinctly higher binding affinity (logbeta = 10.2 +/- 0.1) for DPA compared to that of Ca(2+) (logbeta = 4.6 +/- 0.1), and provide molecular level insight into the mechanism of uranium toxicity associated with the {ONO} site. These results support those of VanEngelen et al. (2011) where a key interaction between PQQ and UO2(2+) produced significant uranium toxicity in bacteria. The observed toxicity mechanism was determined to be the displacement of a Ca(2+) cation bound to the {ONO} site on PQQ and was observed even at submicromolar UO2(2+) concentrations. Here we couple experimental findings with density functional theory (DFT) calculations to investigate the electronic and structural properties that make the {ONO} site so distinctively favorable for UO2(2+) binding. This novel approach using integrated experimental and fundamental atomic based models opens the path to identify a library of potential uranium interactions with critical biological molecules. PMID- 25920686 TI - Complexes of N-hydroxyethyl-N-benzimidazolylmethylethylenediaminediacetic acid with group 12 metals and vanadium-Synthesis, structure and bioactivity of the vanadium complex. AB - Four new complexes of group 12 metals [Zn(II), Cd(II) and Hg(II)], along with vanadyl bound to the ligand N-hydroxyethyl-N benzimidazolylmethylethylenediaminediacetic acid, have been synthesized and characterized. The structure of the complexes with Zn(II), Hg(II) and V(IV) was determined by X-ray structural analysis. In all observed cases, the symmetry of these complexes was found to be distorted octahedral. The inhibition of protein tyrosine phosphatase 1B by the vanadium(IV) complex was demonstrated. The cytotoxicity of the vanadium(IV) complex was tested in vitro against three cancer cell lines, with a comparison of the activity of the free ligand and of vanadyl acetylacetonate and sodium orthovanadate. The IC50 values of the complex were in the range of 9 to 21MUM. Remarkably, cytotoxic potency in the multidrug-resistant non-small cell lung cancer cell line A549 was at least as high as in the broadly chemosensitive ovarian teratocarcinoma cell line CH1(PA-1). PMID- 25920687 TI - Imaging features of lower limb malformations above the foot. AB - Lower limb malformations are generally isolated or sporadic events. However, they are sometimes associated with other anomalies of the bones and/or viscera in patients with constitutional syndromes or disorders of the skeleton. This paper reviews the main imaging features of these abnormalities, which generally exhibit a broad spectrum. This paper focuses on several different bone malformations: proximal focal femoral deficiency, congenital short femur and femoral duplication for the femur, tibial hemimelia (aplasia/hypoplasia of the tibia) and congenital bowing for the tibia, fibular hemimelia (aplasia/hypoplasia) for the fibula, and aplasia, hypoplasia and congenital dislocation for the patella. PMID- 25920688 TI - CMR detection of membraneous ventricular septal aneurysm causing ventricular tachycardia. PMID- 25920690 TI - Variation of bone layer thicknesses and trabecular volume fraction in the adult male human calvarium. AB - The human calvarium is a sandwich structure with two dense layers of cortical bone separated by porous cancellous bone. The variation of the three dimensional geometry, including the layer thicknesses and the volume fraction of the cancellous layer across the population, is unavailable in the current literature. This information is of particular importance to mathematical models of the human head used to simulate mechanical response. Although the target geometry for these models is the median geometry of the population, the best attempt so far has been the scaling of a unique geometry based on a few median anthropometric measurements of the head. However, this method does not represent the median geometry. This paper reports the average three dimensional geometry of the calvarium from X-ray computed tomography (CT) imaging and layer thickness and trabecular volume fraction from micro CT (MUCT) imaging of ten adult male post mortem human surrogates (PMHS). Skull bone samples have been obtained and MUCT imaging was done at a resolution of 30 MUm. Monte Carlo simulation was done to estimate the variance in these measurements due to the uncertainty in image segmentation. The layer thickness data has been averaged over areas of 5mm(2). The outer cortical layer was found to be significantly (p < 0.01; Student's t test) thicker than the inner layer (median of thickness ratio 1.68). Although there was significant location to location difference in all the layer thicknesses and volume fraction measurements, there was no trend. Average distribution and the variance of these metrics on the calvarium have been shown. The findings have been reported as colormaps on a 2D projection of the cranial vault. PMID- 25920689 TI - The associations of 25-hydroxyvitamin D levels, vitamin D binding protein gene polymorphisms, and race with risk of incident fracture-related hospitalization: Twenty-year follow-up in a bi-ethnic cohort (the ARIC Study). AB - BACKGROUND: Deficient levels of 25-hydroxyvitamin D [25(OH)D] have been associated with increased fracture risk. Racial differences in fracture risk may be related to differences in bioavailable vitamin D due to single nucleotide polymorphism (SNP) variations in the vitamin D binding protein (DBP). METHODS: We measured 25(OH)D levels in 12,781 middle-aged White and Black participants [mean age 57 years (SD 5.7), 25% Black] in the ARIC Study who attended the second examination from 1990-1992. Participants were genotyped for two DBP SNPs (rs4588 and rs7041). Incident hospitalized fractures were measured by abstracting hospital records for ICD-9 codes. We used Cox proportional hazards models to evaluate the association between 25(OH)D levels and risk of fracture with adjustment for possible confounders. Interactions were tested by race and DBP genotype. RESULTS: There were 1122 incident fracture-related hospitalizations including 267 hip fractures over a median of 19.6 years of follow-up. Participants with deficient 25(OH)D (<20 ng/mL) had a higher risk of any fracture hospitalization [HR=1.21 (95% CI 1.05-1.39)] and hospitalization for hip fracture [HR=1.35 (1.02-1.79)]. No significant racial interaction was noted (p interaction=0.20 for any fracture; 0.74 for hip fracture). There was no independent association of rs4588 and rs7041 with fracture. However, there was a marginal interaction for 25(OH)D deficiency with rs7041 among Whites (p interaction=0.065). Whites with both 25(OH)D deficiency and the GG genotype [i.e., with predicted higher levels of DBP and lower bioavailable vitamin D] were at the greatest risk for any fracture [HR=1.48 (1.10-2.00)] compared to Whites with the TT genotype and replete 25(OH)D (reference group). CONCLUSIONS: Deficient 25(OH)D levels are associated with higher incidence of hospitalized fractures. Marginal effects were seen in Whites for the DBP genotype associated with lower bioavailable vitamin D, but result inconclusive. Further investigation is needed to more directly evaluate the association between bioavailable vitamin D and fracture risk. PMID- 25920691 TI - Genetic and functional studies reveal a novel noncoding variant in GALT associated with a false positive newborn screening result for galactosemia. AB - BACKGROUND: Classic galactosemia (CG) is a potentially lethal genetic disorder that results from profound loss of galactose-1-phosphate uridylyltransferase (GALT). CG is detected by newborn screening (NBS) in many countries; however, conclusive diagnosis can be complex due to broad and overlapping ranges of GALT activity. Molecular studies can also be complex due to allelic heterogeneity at the GALT locus. METHODS: We conducted both biochemical and molecular follow-up studies for an infant flagged by NBS for possible galactosemia. To clarify the diagnosis we also conducted biochemical and RNA studies of lymphoblasts prepared from the child and one parent. RESULTS: We identified a novel noncoding GALT variant, c.377+17C>T, that was homozygous in the child and heterozygous in both parents. The child and both parents also showed diminished GALT activity in red blood cells, and transformed lymphoblasts from the child and one parent further showed diminished GALT activity. However, qRT-PCR studies demonstrated apparently normal GALT mRNA levels in lymphoblasts, and Gal-1P values measured in the child following galactose exposure in infancy and at 1 year were normal. CONCLUSIONS: These results highlight the existence of rare but apparently benign variants in GALT and underscore the need for functional studies to distinguish pathogenic from benign variants. PMID- 25920692 TI - Median of patient results as a tool for assessment of analytical stability. AB - BACKGROUND: In spite of the well-established external quality assessment and proficiency testing surveys of analytical quality performance in laboratory medicine, a simple tool to monitor the long-term analytical stability as a supplement to the internal control procedures is often needed. METHOD: Patient data from daily internal control schemes was used for monthly appraisal of the analytical stability. This was accomplished by using the monthly medians of patient results to disclose deviations from analytical stability, and by comparing divergences with the quality specifications for allowable analytical bias based on biological variation. RESULTS: Seventy five percent of the twenty analytes achieved on two COBASs INTEGRA 800 instruments performed in accordance with the optimum and with the desirable specifications for bias. DISCUSSION: Patient results applied in analytical quality performance control procedures are the most reliable sources of material as they represent the genuine substance of the measurements and therefore circumvent the problems associated with non commutable materials in external assessment. CONCLUSION: Patient medians in the monthly monitoring of analytical stability in laboratory medicine are an inexpensive, simple and reliable tool to monitor the steadiness of the analytical practice. PMID- 25920693 TI - Is enhanced platelet activation the missing link leading to increased cardiovascular risk in psoriasis? AB - BACKGROUND: Psoriasis is an immune mediated inflammatory skin disease associated with systemic inflammation resulting in increased risk for associated cardiovascular co-morbidities. The role of platelet activation in the pathophysiology of this condition has not been clearly studied. We undertook to study the platelet activation markers in psoriasis, as compared to controls and to identify its association with disease severity in psoriasis. METHODS: Sixty two patients with psoriasis and 62 age and gender matched healthy controls were enrolled in this cross-sectional study. The severity of the disease was assessed using the psoriasis area severity index (PASI) scoring. The platelet indices [mean platelet volume (MPV) and platelet distribution width (PDW)] were estimated by an automated haematological laser optical analyzer. Plasma soluble P-selectin and platelet derived microparticle (PDMP) concentrations, serum high sensitivity C-reactive protein (hs-CRP) and interleukin (IL)-6 concentrations were estimated in all study participants. Platelet aggregation was assessed using adenosine diphosphate (ADP) as aggregating agent. RESULTS: We observed that there was significantly higher platelet indices (MPV and PDW) in patients with psoriasis, when compared to controls. Plasma soluble P-selectin concentrations, PDMP and platelet aggregation were significantly elevated in patients with psoriasis, as compared to controls. We also found significantly higher concentrations of hs-CRP and IL-6 in patients with psoriasis, as compared to controls. Platelet activation and systemic inflammation markers correlated positively with PASI, except PDW. We also observed significant positive correlation between platelet activation and systemic inflammation in psoriasis. CONCLUSION: Significant platelet activation and systemic inflammation were observed in patients with psoriasis, especially when associated with severe disease. The increased platelet activation might be the missing link between the persistent inflammation and the development of atherosclerotic plaque leading onto cardiovascular co-morbidities seen associated with psoriasis. PMID- 25920694 TI - Association between cardiometabolic index and atherosclerotic progression in patients with peripheral arterial disease. AB - BACKGROUND: Cardiometabolic index (CMI), calculated as a product of waist-to height ratio and triglycerides-to-HDL cholesterol ratio, is a new index for discriminating diabetes mellitus. Patients with peripheral arterial disease (PAD) are prone to have other atherosclerotic diseases such as coronary artery disease and stroke. The purpose of this study was to clarify the relationships between CMI and indicators of atherosclerotic progression in patients with PAD. METHODS: The subjects were 63 outpatients with PAD. Relationships of CMI with variables related to atherosclerotic progression were investigated using multivariate linear regression analysis and analysis of covariance with adjustment for age, sex and histories of smoking and alcohol drinking. RESULTS: Log-transformed CMI was significantly correlated with mean intima-media thickness of the common carotid artery (IMT) (standardized regression coefficient: 0.350, p < 0.01) and % decrease in ankle-brachial systolic pressure index (ABI) after treadmill exercise (standardized regression coefficient: 0.365, p < 0.01). Mean IMT and % decrease in ABI by treadmill exercise were significantly higher (p < 0.01) in the group of the 3rd tertile for CMI than in the group of its 1st tertile (mean +/- SE: mean IMT (mm), 0.94 +/- 0.06 (1st tertile) vs. 0.94 +/- 0.06 (2nd tertile) vs. 1.19 +/ 0.06 (3rd tertile); % decrease in ABI, 14.1 +/- 3.4 [1st tertile] vs. 26.0 +/- 3.5 [2nd tertile] vs. 30.0 +/- 3.5 [3rd tertile]). CONCLUSION: CMI was shown to be associated with the degrees of atherosclerosis in the common carotid artery and ischemia in leg arteries and is therefore a useful discriminator of atherosclerotic progression in patients with PAD. PMID- 25920695 TI - Comparison of traditional, trimmed traditional and robust Youden charts. AB - BACKGROUND: Traditional Youden chart can be distorted by non-normally distributed data. Here, an optimized Youden chart was developed and compared with the traditional and trimmed traditional Youden charts. METHODS: The urea concentrations were determined by 28 laboratories to provide data for the construction of Youden charts. Normality of these data was tested. Outliers were excluded prior to construction of the trimmed traditional Youden chart. Non robust and robust estimators were computed to construct the traditional and robust Youden charts, respectively. Robust between-laboratory z-score (ZBi) and within-laboratory z-score (ZWi) were obtained to assess whether or not these charts can reasonably present the urea results. Expected outcomes were the points related to acceptable (|ZBi| and |ZWi| <= 2), questionable (2 < |ZBi| < 3 and/or 2 < |ZWi| < 3), and unacceptable (|ZBi| and/or |ZWi| >= 3) results fall inside, on/near, and outside the ellipse, respectively. RESULTS: Only the data from lot 201111 are non-normally distributed. Five- and 2-pair outliers are excluded from the data of lots 201111 and 201112, respectively. The concordance rates of the traditional, trimmed traditional and robust Youden charts are 87.1%, 92.9%, and 94.3%, respectively. CONCLUSIONS: Among the three charts, the robust Youden chart presents the urea results best. PMID- 25920696 TI - Body mass index does not influence human epididymis protein 4 concentrations in serum. PMID- 25920697 TI - Stereo-controlled synthesis of polyheterocycles via the diene-transmissive hetero Diels-Alder reaction of beta,gamma-unsaturated alpha-keto esters. AB - We describe the stereoselective synthesis of polyring-fused heterocyclic compounds based on diene-transmissive hetero-Diels-Alder reactions utilizing beta,gamma-unsaturated alpha-keto esters. This protocol involves the initial endo or exo-selective Diels-Alder (DA) reactions with electron-rich dienophiles, methylenation of the ester carbonyl groups with the Tebbe reagent, and a stereoselective second DA reaction with electron-deficient dienophiles. The use of enantioselective DA reactions in the initial reaction enables access to chiral polyring-fused heterocyclic compounds with multiple chiral centres. PMID- 25920698 TI - A highly selective phenothiazine-based fluorescence 'turn-on' indicator based on cyanide-promoted novel protection/deprotection mechanism. AB - A cyanide anion (CN(-))-triggered deprotection of NH-protected phenothiazine, (E) 10-(10H-phenothiazin-3'-yl)propenal, has been discovered as a novel mechanism for the highly selective fluorescence detection of CN(-) under ambient conditions. The present protocol may pave the way for its broad application in organic synthesis in the near future. PMID- 25920699 TI - Summary of major radiation fractionation and chemotherapy trials for organ preservation therapy in locally advanced head and neck squamous cell carcinoma. AB - PURPOSE: To review radiation fractionation and chemotherapy trials for patients undergoing organ preservation therapy for locally advanced head and neck squamous cell carcinoma. METHODS AND MATERIALS: Radiation therapy fractionation and chemotherapy trial results as well as historical evidence are systematically reviewed. RESULTS: Trial results, which involve nearly 30,000 patients, have been interpreted, compared, and presented in a structured manner to demonstrate the changing approaches in treatment over the years from the 1960s to the present. The review includes data from the split-course radiation therapy era, meta analyses of chemotherapy and radiation therapy fractionation trials, cetuximab trials, "triple-drug trials," and modern trials of induction chemotherapy followed by concomitant chemotherapy and radiation therapy. CONCLUSIONS: This summary will be useful to clinicians making treatment decisions today and to investigators designing trials in the future. PMID- 25920700 TI - Ward-based interventions for patients with hemispatial neglect in stroke rehabilitation: a systematic literature review. AB - OBJECTIVES: To identify rehabilitation interventions that can be integrated into ward-based nursing for patients with hemispatial neglect following stroke in the right brain hemisphere. DESIGN: A systematic review of interdisciplinary literature. DATA SOURCES: A preliminary literature search without time limits was conducted in the Cochrane Controlled Trials Register. We then searched the PubMed, CINAHL and PsychINFO databases for relevant articles published between January 2006 and June 2014. Selected journals were searched manually. Additional resources were explored by scrutinizing reference lists and tracking citations of the selected articles. REVIEW METHODS: Titles and abstracts were matched with the inclusion criteria. Articles were read in their entirety if the abstracts adhered to inclusion criteria or if there was any uncertainty. Two reviewers evaluated the risk of methodological bias independently by using quantitative appraisal forms from the Johanna Briggs Institute (JBI). Any disagreements were resolved by consensus. Authors of nine studies were contacted to acquire additional information. The JBI Reviewers' Manual was used to guide the overall procedure of the review. We used the PRISMA statement to ensure precise reporting of the results. The selected studies were graded according to the strength of their evidence (Levels 1-5); the proposed interventions were given recommendation grades (Grades A-D). RESULTS: Using 41 original studies, 11 interventions were identified. These comprise: (1) contralesional neck vibration (Grade C); (2) emotionally salient stimuli and reward (Grade D); (3) family participation and intensity of training (Grade C); (4) limb activation training (Grade C); (5) mental imagery training, (Grade D); (6) mirror therapy (Grade C); (7) music therapy (Grade D); (8) right half-field eye patching (Grade D); (9) smooth pursuit eye-movement training (Grade B); (10) virtual reality and computer-based training (Grade C); and (11) visual scanning training (Grade D). CONCLUSION: A total of 11 promising rehabilitation interventions were found. Encouraging results were, in particular, seen with smooth pursuit eye-movement training. It should be noted that the general low level of evidence and the diversity of interventions makes it difficult to endorse specific priorities and combinations for implementation. Instead, interventions should be applied after careful evaluation of each patient's unique capacities and problems. We include suggestions for operationalization into ward-based care in "Discussion" section. We also emphasize the need to integrate evidence-based interventions into nursing care to further stimulate rehabilitation outcomes and future research. PMID- 25920701 TI - Radiologist: Clinical Imager or Ancillary Medical Staff? PMID- 25920702 TI - High-boron-content porphyrin-cored aryl ether dendrimers: controlled synthesis, characterization, and photophysical properties. AB - The synthesis and characterization of a set of poly(aryl ether) dendrimers with tetraphenylporphyrin as the core and 4, 8, 16, or 32 closo-carborane clusters are described. A regioselective hydrosilylation reaction on the allyl-terminated functions with carboranylsilanes in the presence of Karstedt's catalyst leads to different generations of boron-enriched dendrimers. This versatile approach allows the incorporation of a large number of boron atoms in the dendrimers' periphery. Translational diffusion coefficients (D) determined by DOSY NMR experiments permit estimation of the hydrodynamic radius (RH) and molecular size for each dendrimer. Furthermore, a notable correlation between D and the molecular weight (MW) is found and can be used to predict their overall size and folding properties. The UV-vis and emission behavior are not largely affected by the functionalization, therefore implying that the presence of carboranes does not alter their photoluminescence properties. PMID- 25920703 TI - What does the public know about Ebola? The public's risk perceptions regarding the current Ebola outbreak in an as-yet unaffected country. AB - BACKGROUND: The unexpected developments surrounding the Ebola virus in the United States provide yet another warning that we need to establish communication preparedness. This study examines what the Israeli public knew about Ebola after the initial stages of the outbreak in a country to which Ebola has not spread and assesses the association between knowledge versus worries and concerns about contracting Ebola. METHODS: Online survey using Google Docs (Google, Mountain View, CA) of Israeli health care professionals and the general public (N = 327). RESULTS: The Israeli public has knowledge about Ebola (mean +/- SD, 4.18 +/- 0.83), despite the fact that the disease has not spread to Israel. No statistically significant difference was found between health care workers versus non-health care workers in the knowledge score. Additionally, no statistically significant association was found between knowledge and worry levels. The survey indicated that Israelis expect information about Ebola from the health ministry, including topics of uncertainty. More than half of the participants thought the information provided by the health ministry on Ebola and Ebola prevention was insufficient (50.5% and 56.4%, respectively), and almost half (45.2% and 41.1%, respectively) were unsure if the information was sufficient. CONCLUSION: The greatest challenges that the organizations face is not only to convey knowledge, but also to find ways to convey comprehensive information that reflects uncertainty and empowers the public to make fact-based decisions about health. PMID- 25920704 TI - Increase in hospital purchase of hand hygiene products: The importance of focusing on the right product. AB - Alcohol-based handrub (AHR) consumption is positively correlated with increases in hand hygiene (HH) compliance. In our 2,000-bed hospital in India, multiple awareness drives have been conducted to promote HH. This study aimed to determine the quantitative effect of these campaigns on use of HH products (soap and AHR) in the hospital. Over the last 6 years, bar soap consumption has increased by 389.15%, whereas that of AHR increased by 146.7%. We also evaluated microbial contamination of 99 bar soap and 60 liquid soap samples in our hospital for a year. Of the samples, 61 (61.6%) of the bar soaps and 2 (3.3%) of the liquid soaps were found to be contaminated with various organisms (P < .0002). To conclude, the focus should be to increase the right kind of HH product so that hospitals in developing countries procure liquid soaps instead of bar soaps for handwashing purposes. PMID- 25920705 TI - Catheter-associated candiduria: Risk factors, medical interventions, and antifungal susceptibility. AB - BACKGROUND: Catheter-associated candiduria is a common clinical finding in hospitalized patients, especially in the intensive care unit. The objective of this study was to obtain demographic and clinical data regarding the prevalence of Candida spp in catheterized in-patients and the medical interventions provided to these patients in a northern Israeli hospital between 2011 and 2013. METHODS: Isolation and identification of microorganisms were performed on 1,408 urine culture samples 48 hours after catheter insertion. Antifungal Etest susceptibility tests were carried out on every Candida-positive urine sample. Demographic and clinical data were gathered to determine risk factors and medical interventions. RESULTS: Candiduria was detected in 146 catheterized in-patients out of the 1,408 patients included in this study. C albicans was detected in most cases (69.1%). Fever was observed in 52 (35.61%) patients, and leukocyturia was observed in 48 cases (32.87%). Diabetes mellitus was associated with C albicans candiduria. There were 93 patients (63.69%) who did not receive any medical intervention for their candiduria. CONCLUSION: Candida is the second leading pathogen causing catheter-associated urinary tract infection or asymptomatic colonization, whereas previous studies showed Candida as the third leading pathogen. Clinical signs and symptoms, such as fever and laboratory tests, cannot distinguish between asymptomatic colonization and infection. Because the management of catheter-associated candiduria is still controversial, additional studies should be carried out. PMID- 25920706 TI - Delirium and other clinical factors with Clostridium difficile infection that predict mortality in hospitalized patients. AB - BACKGROUND: Clostridium difficile infection (CDI) severity has increased, especially among hospitalized older adults. We evaluated clinical factors to predict mortality after CDI. METHODS: We collected data from inpatients diagnosed with CDI at a U.S. academic medical center (HSR-IRB#13630). We evaluated age, Charlson comorbidity index (CCI), whether patients were admitted from a long-term care facility, whether patients were in an intensive care unit (ICU) at the time of diagnosis, white blood cell count (WBC), blood urea nitrogen (BUN), low body mass index, and delirium as possible predictors. A parsimonious predictive model was chosen using the Akaike information criterion (AIC) and a best subsets model selection algorithm. The area under the receiver operating characteristic curve was used to assess the model's comparative, with the AIC as the selection criterion for all subsets to measure fit and control for overfitting. RESULTS: From the 362 subjects, the selected model included CCI, WBC, BUN, ICU, and delirium. The logistic regression coefficients were converted to a points scale and calibrated so that each unit on the CCI contributed 2 points, ICU admission contributed 5 points, each unit of WBC (natural log scale) contributed 3 points, each unit of BUN contributed 5 points, and delirium contributed 11 points.Our model shows substantial ability to predict short-term mortality in patients hospitalized with CDI. CONCLUSION: Patients who were diagnosed in the ICU and developed delirium are at the highest risk for dying within 30 days of CDI diagnosis. PMID- 25920707 TI - Multidisciplinary Intervention in Patients with Musculoskeletal Pain: a Randomized Clinical Trial. AB - BACKGROUND: Musculoskeletal pain is associated with comorbidity, extensive use of health services, long-term disability and reduced quality of life. The scientific literature on effects of treatment for musculoskeletal pain is inconclusive. PURPOSE: The purpose of this study is to compare a multidisciplinary intervention (MI), including use of the novel Interdisciplinary Structured Interview with a Visual Educational Tool (ISIVET), with a brief intervention (BI), on effects on mental and physical symptoms, functioning ability, use of health services and coping in patients sick-listed due to musculoskeletal pain. METHOD: Two hundred eighty-four adults aged 18-60, referred to a specialist clinic in physical rehabilitation, were randomized to MI or BI. Patients received a medical examination at baseline and completed a comprehensive questionnaire at baseline, 3 months and 12 months. RESULTS: Both groups reported improvements in mental and physical symptoms, including pain, and improved functioning ability at 3 and 12 months, but the MI group improved faster than the BI group except from reports of pain, which had a similar course. Significant interactions between group and time were found on mental symptoms (anxiety (p < 0.05), depression (p < 0.01), somatization (p < 0.01)) and functioning ability (p < 0.01) due to stronger effects in the MI group at 3 months. At 3 and 12 months, the MI group reported significantly less use of health services (general practitioner (p < 0.05)). At 12 months, the MI group reported better self-evaluated capability of coping with complaints (p < 0.001) and they took better care of their own health (p < 0.001), compared to the BI group. CONCLUSION: The results indicate that the MI may represent an important supplement in the treatment of musculoskeletal pain. PMID- 25920708 TI - Larger and More Prominent Graphic Health Warnings on Plain-Packaged Tobacco Products and Avoidant Responses in Current Smokers: a Qualitative Study. AB - BACKGROUND: The introduction of tobacco plain packaging legislation in Australia meant that all tobacco products were to be sold in plain dark-brown packaging with 75% front-of-pack graphic health warnings and standardised font type and size for brand name and product variant. The change in the size and prominence of the warnings has been proposed as a reason for behaviour change in smokers in terms of increased intentions to quit and quit attempts. PURPOSE: The current research examined attitudes and beliefs of cigarette smokers toward the increased size and prominence of the warnings and effects on their behaviour. METHOD: Participants (N = 160) completed open-ended responses to questions on beliefs, attitudes and responses to plain packaging. Responses were subjected to inductive thematic content analysis for key themes. RESULTS: Four themes emerged from the analysis: emotional response to packaging, scepticism of health warnings, warnings and cessation behaviour, and avoidant coping behaviours. Participants reported increased negative emotional responses to the packaging and made specific reference to the graphic health warnings. Some participants attempted to discredit the messages. Others reported increased intentions to quit or quitting attempts. There were pervasive reports of avoidant responses including covering or hiding the warnings. CONCLUSION: Consistent with theories of illness perceptions and coping, current findings indicate that the larger, prominent graphic health warnings on plain-packaged tobacco products had pervasive effects on threat perceptions and subsequent behavioural responses. While some of the reported responses were adaptive (e.g. attempts to quit), others were maladaptive (e.g. avoiding the warnings). PMID- 25920709 TI - Radiotherapy and temozolomide for anaplastic astrocytic gliomas. AB - We previously reported results of a phase II non-comparative trial that randomized patients with glioblastoma following radiotherapy to one of two different temozolomide schedules, followed by 13-cis-retinoic acid (RA) maintenance. Here we report the results of an exploratory cohort of patients accrued with anaplastic astrocytic tumors. Patients with newly diagnosed anaplastic astrocytoma (AA) or anaplastic oligo-astrocytoma (AOA) were treated with concurrent radiotherapy (60 Gy over 6 weeks) and temozolomide (75 mg/m(2)), and six adjuvant 28-day cycles of either dose-dense (150 mg/m(2), days 1-7, 15 21) or metronomic (50 mg/m(2), days 1-28) temozolomide. Subsequently, maintenance RA (100 mg/m(2), days 1-21/28) was administered until disease progression. All outcome measures were descriptive without intention to compare between treatment arms. Survival was measured by the Kaplan-Meier method. There were 31 patients (21 men, 10 women) with median age 48 years (range 28-74), median KPS 90 (range 60-100). Extent of resection was gross-total in 35%, subtotal 23%, and biopsy 42%. Histology was AA in 90%, and AOA in 10%. MGMT promoter methylation was methylated in 20%, unmethylated in 50%, and uninformative in 30% of 30 tested. Median progression-free survival was 2.1 years (95% CI 0.95-Not Reached), and overall survival 2.9 years (95 % CI 2.0-Not Reached). We report outcomes among a homogeneously treated population with anaplastic astrocytic tumors. Survival was unexpectedly short compared to other reports. These data may be useful as a contemporary historic control for other ongoing or future randomized trials. PMID- 25920710 TI - Hypofractionated-intensity modulated radiotherapy (hypo-IMRT) and temozolomide (TMZ) with or without bevacizumab (BEV) for newly diagnosed glioblastoma multiforme (GBM): a comparison of two prospective phase II trials. AB - To compare progression-free (PFS) and overall survival (OS) in patients treated in two consecutive phase II trials of hypofractionated-intensity modulated radiotherapy (hypo-IMRT) and temozolomide (TMZ) with or without bevacizumab (BEV). Patients with newly diagnosed glioblastoma multiforme (GBM) after biopsy or resection were enrolled on a clinical trial with hypo-IMRT and TMZ (hypo IMRT/TMZ alone) from 2008 to 2010, or in the second protocol with the same hypo IMRT and TMZ plus BEV (hypo-IMRT/TMZ/BEV) from 2010 to 2013. All patients received postoperative hypo-IMRT to the surgical cavity and residual tumor plus margin to a total dose of 60 Gy and to the T2 abnormality with margin to 30 Gy, both in ten fractions. Concurrent TMZ (75 mg/m(2)/day) was given to all patients for 28 consecutive days followed by adjuvant TMZ (150-200 mg/m(2)/day). Patients enrolled on the hypo-IMRT/TMZ/BEV trial received concurrent and adjuvant BEV (10 mg/kg) on days 1 and 15 of each 28-day cycle. Hazard ratios of PFS and OS were compared between trials in a Cox proportional hazards model. Twenty-six patients were enrolled on the hypo-IMRT/TMZ alone trial and 30 patients on the hypo IMRT/TMZ/BEV trial. Median follow-up was 13.9 and 14.7 months, respectively. Median PFS was 3.4 months longer with hypo-IMRT/TMZ/BEV but the difference was not statistically significant (12.8 vs. 9.4 months, p = 0.58). Median (OS) was 16.3 months for both trials. The addition of BEV to TMZ and hypo-IMRT did not improve OS for patients with GBM in two phase II trials with small patient numbers; PFS was longer with BEV, but the difference was not statistically significant. PMID- 25920711 TI - Radioiodine therapy increases the risk of cerebrovascular events in hyperthyroid and euthyroid patients. AB - BACKGROUND AND OBJECTIVE: Hyperthyroid patients treated with radioiodine have increased morbidity and mortality from cerebrovascular events. This risk has until now has been attributed to the hyperthyroidism. However, radioiodine therapy of benign thyroid diseases exposes the carotid arteries to radiation and is capable of inducing atherosclerosis. The objective of the study was to elucidate whether ionizing radiation from radioiodine might contribute to cerebrovascular morbidity. METHODS: In a retrospective register cohort study, 4000 hyperthyroid and 1022 euthyroid goitre patients treated with radioiodine between 1975 and 2008 were matched 1:4 on age and sex with random controls. The cohort was followed from the date of treatment until hospitalization due to cerebrovascular event, death, 20 years of follow-up or March 2013. Data were analyzed in competing risk models adjusting for age, sex, Charlson's comorbidity score, atrial fibrillation and previous cerebrovascular events. RESULTS: Mean follow-up time was 11.5 years, mean age 61 years, with a total number of 3228 events. Comparing all radioiodine-treated patients with controls, the fully adjusted model showed increased risk of cerebrovascular events among all treated patients, hazard ratio (HR) 1.18 (95% CI 1.09-1.29). The risk was increased among hyperthyroid (HR 1.17; 95% CI 1.07-1.28) as well as euthyroid patients (HR 1.21; 95% CI 1.02-1.44). CONCLUSIONS: We report an increased risk of cerebrovascular events in hyperthyroid as well as euthyroid patients treated with radioiodine for benign thyroid disorders. That these patient groups have similar risks suggests the possibility that radiation from radioiodine contributes to cerebrovascular morbidity via acceleration or initiation of atherosclerosis. PMID- 25920712 TI - A new case of poecilogony from South America and the implications of nurse eggs, capsule structure, and maternal brooding behavior on the development of different larval types. AB - Poecilogony is the production of different larval types within the same species. Although rare, poecilogonous species are ideal systems for testing the evolutionary and ecological implication of different developmental modes in marine invertebrates. Here, we described a new case of poecilogony, the Southern Hemisphere spionid Boccardia wellingtonensis. We used a combination of common garden experiments, video recordings, and in vitro manipulations of individuals from three sites to (1) document the type of poecilogony, the brooding behavior of the mother, and the hatching process; (2) experimentally measure the effect of nurse eggs on the growth and type of larvae produced; and (3) document variation in the length of the brooding period, number of capsules, larvae, and nurse eggs of mothers from three sites to explore the potential for plasticity in reproductive traits. These results were compared to the previously reported poecilogonous species B. proboscidea, which resembles B. wellingtonensis in size, morphology, ecology, and reproductive strategy but differs in capsule structure. We found that in contrast to B. proboscidea, B. wellingtonensis produced larvae that, in isolation and in the presence of nurse eggs, developed into a wide range of offspring sizes. Mothers brood and hatch the larvae with frequent partial hatching of the brood during the brooding period. Although larvae could not liberate themselves, larvae crossed to other capsules as interconnections between capsules broke during the developmental period, potentially affecting food availability, sibling competition for nurse eggs, and cannibalism. Variation in brooding time and number of capsules deposited among sites suggest local adaptations. PMID- 25920713 TI - Induction of Larval Settlement in the Reef Coral Porites astreoides by a Cultivated Marine Roseobacter Strain. AB - Successful larval settlement and recruitment by corals is critical for the survival of coral reef ecosystems. Several closely related strains of gamma proteobacteria have been identified as cues for coral larval settlement, but the inductive properties of other bacterial taxa naturally occurring in reef ecosystems have not yet been explored. In this study, we assayed bacterial strains representing taxonomic groups consistently detected in corals for their ability to influence larval settlement in the coral Porites astreoides. We identified one alpha-proteobacterial strain, Roseivivax sp. 46E8, which significantly increased larval settlement in P. astreoides. Logarithmic growth phase (log phase) cell cultures of Roseivivax sp. 46E8 and filtrates (0.22MUm) from log phase Roseivivax sp. 46E8 cultures significantly increased settlement, suggesting that an extracellular settlement factor is produced during active growth phase. Filtrates from log phase cultures of two other bacterial isolates, Marinobacter sp. 46E3, and Cytophaga sp. 46B6, also significantly increased settlement, but the cell cultures themselves did not. Monospecific biofilms of the three strains did not result in significant increases in larval settlement. Organic and aqueous/methanol extracts of Roseivivax sp. 46E8 cultures did not affect larval settlement. Examination of filtrates from cell cultures showed that Roseivivax sp. 46E8 spontaneously generated virus-like particles in log and stationary phase growth. Though the mechanism of settlement enhancement by Roseivivax sp. 46E8 is not yet elucidated, our findings point to a new aspect of coral-Roseobacter interactions that should be further investigated, especially in naturally occurring, complex microbial biofilms on reef surfaces. PMID- 25920714 TI - Effects of 17alpha-Methyltestosterone and Aromatase Inhibitor Letrozole on Sex Reversal, Gonadal Structure, and Growth in Yellow Catfish Pelteobagrus fulvidraco. AB - Monosex populations are in demand in many fish species with sexual dimorphism, e.g., better growth performance, higher gonad value, superior ornamental value. From the point of view of research, a monosex population is one of the best materials for investigating sex-determining mechanisms, sex differentiation, and sex-linked markers. Sex reversal of females (phenotypic reversal from XX female to XX male) is the first step in all-female production in species with an XX/XY system for sex determination. In the present study, masculinization of yellow catfish, a species with XX/XY sex determination, was investigated by oral administration of various doses of 17alpha-methyltestosterone (MT) or an aromatase inhibitor (AI) letrozole (LZ); effects on survival, growth performance, sex ratio, and changes in gonadal structure were evaluated. Three doses (20, 50, and 100 mg kg(-1) diet) of oral MT or LZ were administered to fry from 10 days post-hatching (DPH) to 59 DPH. Oral administration of MT at all doses did not significantly change the ratio of males (45.8%, 33.3%, and 50.0% respectively) compared to the control group (37.5%), while yielding intersex fish at all doses (4.2% to 8.3%). Oral administration of LZ produced a significantly higher proportion of males in all doses (75.5%, 83.3%, and 75.0%, respectively). Additionally, the lowest dose of LZ improved the growth of treated fish compared to the control, and all doses of LZ enhanced spermatogenesis in treated males. PMID- 25920715 TI - Hemolymph Levels of Methyl Farnesoate During Ovarian Development of the Swimming Crab Portunus trituberculatus, and Its Relation to Transcript Levels of HMG-CoA Reductase and Farnesoic Acid O-Methyltransferase. AB - Methyl farnesoate (MF) is a sesquiterpene compound and the crustacean homolog of insect juvenile hormones. MF has multiple physiological functions involving the regulation of molting, reproduction, metamorphogenesis, behavior, and osmoregulation. In this study, the hemolymph levels of MF during ovarian development of Portunus trituberculatus were measured by gas chromatography-mass spectrometry (GC-MS). The results showed that the hemolymph level of MF in P. trituberculatus was low during stages I and II, increased considerably in stage III, and remained high in stage IV. Correlation of MF level with ovarian maturation indicates the putative stimulatory role of MF in this physiological process. As 3-hydroxy-3-methylglutaryl-coenzyme A reductase (HMGR) and farnesoic acid O-methyltransferase (FAMeT) are two essential enzymes in MF biosynthesis, their transcript levels during ovarian development were detected by quantitative real-time PCR (qPCR). Transcript levels of HMGR and FAMeT exhibited variation trends similar to that of the level of MF in hemolymph. This might indicate that high expression of HMGR and FAMeT could result in an increase in the production of MF, which ultimately affects ovarian development. PMID- 25920716 TI - Analysis of life-history traits in a sex-changing marine shrimp (decapoda: caridea: rhynchocinetidae). AB - The hypothesis of protandrous (male to female) sex change was tested for the first time in a rhynchocinetid shrimp, Rhynchocinetes uritai, with an analysis of life-history traits. Samples were taken monthly for 2 years in Oura Bay, Japan, using a combination of bait and refuge traps. Breeding was seasonal but extended from spring through autumn, with female-phase individuals (FPs) producing broods successively, with their ovaries maturing for a new spawn during incubation of a previous brood. Females incubated numerous (~500-4000) embryos that suffered insignificant mortality before hatching. Recruitment of juveniles after planktonic larval development began in summer and peaked during the autumn, with negligible recruitment during winter and spring. Cohort analysis confirmed the hypothesis of protandric sex change in this species, with juveniles maturing into the male phase (MP) during their first reproductive season at an age of 6-10 mon, depending on the time of recruitment. Sex change occurred during the following winter when transitional individuals matured into FPs during their second reproductive season at an age of >=18 mon. Two cohorts were followed from recruitment until the end of the study, indicating a life span of 21-25 mon. Aside from its sexual system, this sex-changing species showed no obvious differences in reproductive and other life-history traits from those of gonochoric species from similar latitudes and habitats. PMID- 25920717 TI - Monitoring bioeroding sponges: using rubble, Quadrat, or intercept surveys? AB - Relating to recent environmental changes, bioerosion rates of calcium carbonate materials appear to be increasing worldwide, often driven by sponges that cause bioerosion and are recognized bioindicators for coral reef health. Various field methods were compared to encourage more vigorous research on bioeroding sponges and their inclusion in major monitoring projects. The rubble technique developed by Holmes et al. (2000) had drawbacks often due to small specimen sizes: it was time-costly, generated large variation, and created a biased impression about dominant species. Quadrat surveys were most rapid but overestimated cover of small specimens. Line intercepts are recommended as easiest, least spatially biased, and most accurate, especially when comparing results from different observers. Intercepts required fewer samples and provided the best statistical efficiency, evidenced by better significances and test power. Bioeroding sponge abundances and biodiversities are influenced by water depth, sediment quality, and most importantly by availability of suitable attached substrate. Any related data should thus be standardized to amount of suitable substrate to allow comparison between different environments, concentrating on dominant, easily recognized species to avoid bias due to experience of observers. PMID- 25920718 TI - Coelomic Transport and Clearance of Durable Foreign Bodies by Starfish (Asterias rubens). AB - Echinoderms have excellent healing and regeneration abilities, but little is known about how they deal with the related challenge of durable foreign bodies that become lodged within their bodies. Here we report a novel mechanism for foreign body elimination in starfish. When injected into the arm of a starfish, passive integrated transponder tags and magnets of similar dimensions are eliminated at a rate approximating 10% per day. These objects are forcefully ejected through the body wall at the distal tip of an arm. Ultrasound images reveal that foreign bodies are moved within the body cavity, and tracking of magnets injected into starfish suggests that the movements are haphazard rather than directed. Constrictions of the body wall near the foreign object are the likely mechanism for this transport process. Open questions include the ecological relevance of this behavior, why clearance occurs through the distal tips of the arms, the neurological and muscular control of this behavior, what other animals use this mechanism, and the range of objects starfish can eliminate in this way. PMID- 25920719 TI - Salinity and Temperature Tolerance of the Nemertean Worm Carcinonemertes errans, an Egg Predator of the Dungeness Crab. AB - Estuaries can be harsh habitats for the marine animals that enter them, but they may also provide these species with sub-saline refuges from their parasites. The nemertean egg predator Carcinonemertes errans is known to occur less frequently and in smaller numbers on its host, the Dungeness crab Metacarcinus magister, when the hosts are found within estuaries. We examined the temperature and salinity tolerances of C. errans to determine if this observed distribution represents a true salinity refuge. We monitored the survival of juvenile and larval worms exposed to ecologically relevant salinities (5-30) and temperatures (8-20 degrees C) over the course of several days under laboratory conditions. Juvenile worms were unaffected by the experimental temperature levels and exhibited robustness to salinity treatments 25 and 30. However, significant mortality was seen at salinity treatments 20 and below. Larvae were less tolerant than juveniles to lowered salinity and were also somewhat more susceptible to the higher temperatures tested. Given that the Dungeness crab can tolerate forays into mesohaline (salinity 5-18) waters for several days at a time, our findings suggest that salinity gradients play an important role in creating a parasite refuge for this species within the estuaries of the Pacific Northwest. PMID- 25920720 TI - Caregiver burden, patients' self-perceived burden, and preference for palliative care among cancer patients and caregivers. AB - OBJECTIVE: Recently, caregiver burden (CB) has emerged as an important issue in the area of palliative medicine. However, patients' feelings related to being a burden to their families (i.e., self-perceived burden [SPB]) is also a significant issue. We evaluated the relation of CB and SPB as preference for palliative care. METHODS: A national, multicenter, cross-sectional survey of 326 patient-caregiver dyads was performed. A set of paired questionnaires evaluating CB and SPB (five domain items assessed on a four-point Likert scale) were independently administered to patients and their caregivers. Among the respondents, only the patients with distant stage cancer and their caregivers were included. Multivariate analyses were conducted to identify the associations between CB and SPB and preference for palliative care. RESULTS: Caregivers and patients who preferred palliative care to life sustaining treatment reported higher CB and SPB scores, respectively. Caregivers who felt more of a burden were more likely to prefer palliative care over life sustaining treatment for their patients (adjusted odds ratio [aOR] = 1.67, 95% CI: 1.21-2.31). In addition, patients who perceived their caregivers' burden as large tended to prefer palliative care (aOR = 1.61, 95% CI: 1.16-2.22). CONCLUSIONS: Both CB and SPB increased preference for palliative care. This could be interpreted that high CB can lead to preference for palliative care in both patients and their caregivers, potentially threatening patient autonomy. Efforts to relieve CB and SPB are needed. PMID- 25920721 TI - Towards an understanding of the nucleation of alpha-para amino benzoic acid from ethanolic solutions: a multi-scale approach. AB - The molecular assembly and subsequent nucleation of para-amino benzoic acid (PABA) from ethanolic solutions is probed using a multi-scale and multi-technique approach. This is applied by examining and interrelating information regarding the molecular, solution-state, cluster, solid-state and surface structures to understand why the alpha form of PABA is crystallised in preference to its low temperature beta form. Calculations suggest that conformational changes within the solute molecule play little or no role in directing the nucleation of either the alpha or beta crystal forms. Combined ab initio and molecular dynamics calculations of the stability of small clusters in solution suggests that the hydrogen-bonded carboxylic acid dimers, present in the alpha structure, are the most stable in solution and play a major role in the self-assembly and polymorphic expression of the alpha form in ethanol in preference to the beta form. These calculations are in good agreement with X-ray small-angle scattering analysis which reveals the presence of PABA clusters in ethanol which are consistent with the size and shape of a carboxylic acid dimer. SAXS studies also reveal the presence of larger cluster structures in a size range 10-40 nm which appear to grow, perhaps reflecting a change in the balance between monomers and dimers within the solution during the nucleation process. The results of crystallisation-kinetics experiments indicate an instantaneous nucleation mechanism where the number of instantaneously nucleated crystallites is calculated to be 1360-660 nuclei per ml and the subsequent growth is found to be only rate limited by diffusion of the growth unit to the crystallite surface. A linear dependence of growth rate with respect to supersaturation is observed for the (0 1 -1) capping face, which is associated with strong pi-pi stacking interactions. This is consistent with a solid-on-solid mechanism associated with surface roughened growth and concomitant poor lattice-perfection. Conversely, the side (1 0 -1) surface has a growth mechanism consistent with a 2D nucleation birth and spread mechanism. Hence, these mechanisms result in very fast growth along the b-axis and the needle-like morphology that is observed for alpha-PABA. PMID- 25920722 TI - Halolamina sediminis sp. nov., an extremely halophilic archaeon isolated from solar salt. AB - An extremely halophilic archaeal strain, halo-7T, was isolated from brine sediment of the Gomso solar saltern, Republic of Korea. Cells of strain halo-7T were pleomorphic, stained Gram-negative, lysed in distilled water and formed red pigmented colonies. Strain halo-7T grew in the range of 25-45 degrees C (optimum 37-40 degrees C), pH 6.5-9.5 (optimum pH 7.0-8.0), 15-30% (w/v) NaCl (optimum, 20 25%), and 0.05-0.5 M MgCl2 (optimum 0.1-0.3 M). The minimal NaCl concentration to prevent cell lysis of strain halo-7T was 10% (w/v). The major polar lipids of the isolate were phosphatidylglycerol, phosphatidylglycerolphosphate methyl ester, an unidentified phospholipid, an unidentified lipid, and two unidentified glycolipids. Phylogenetic analysis based on 16S rRNA gene sequences showed that strain halo-7T is closely related to the members of the genus Halolamina, Halolamina salina WSY15-H3T (98.7% 16S rRNA gene sequence similarity), Halolamina pelagica TBN21T (98.2%) and Halolamina rubra CBA1107T (97.4%). The genomic DNA G+C content determined for strain halo-7T (68.0 mol%) was slightly higher than those of H. salina JCM 18549T and H. rubra CBA1107T. DNA-DNA hybridization values between strain halo-7T and reference strains were < 25%. Based on phenotypic, chemotaxonomic and phylogenetic properties, we describe a novel species of the genus Halolamina, represented by strain halo-7T, for which we propose the name Halolamina sediminis sp. nov. The type strain is halo-7T ( = JCM 30187T = CECT 8739T). PMID- 25920723 TI - Proposal to modify Rule 27 of the International Code of Nomenclature of Prokaryotes. AB - We propose emendation of Rule 27(2)(b) of the International Code of Nomenclature of Prokaryotes so that for new combinations the basonym and its reference must be given. We also propose minor changes to Note 1 and Note 2 of Rule 27. PMID- 25920724 TI - Thermus amyloliquefaciens sp. nov., isolated from a hot spring sediment sample. AB - A Gram-stain-negative, aerobic bacterium, designated strain YIM 77409T, was isolated from the Niujie hot spring in the Eryuan county of Dali, Yunnan province, south-west China. Cells of the strain were rod-shaped and colonies were yellow and circular. The strain grew at pH 6.0-8.0 (optimum, pH 7.0) and 50-70 degrees C (optimum, 60-65 degrees C). The predominant menaquinone was MK-8 and the DNA G+C content was 66.4 mol%. Major fatty acids (>10 %) were iso-C15 : 0 and iso-C17 : 0.The polar lipids consisted of one aminophospholipid, one phospholipid and two glycolipids. 16S rRNA gene sequence analysis showed that strain YIM 77409T formed a cluster with Thermus scotoductus DSM 8553T, Thermus antranikianii DSM 12462T, Thermus caliditerrae YIM 77925T and Thermus tengchongensis YIM 77924T, with highest 16S rRNA gene sequence similarity to T. scotoductus DSM 8553T (97.57%). However, DNA-DNA hybridization indicated that strain YIM 77409T should be viewed as a representative of a novel species, as there was only 30.6 +/- 1.6% reassociation with T. scotoductus DSM 8553T. On the basis of the morphological and chemotaxonomic characteristics, as well as the genotypic data, it is proposed that strain YIM 77409T represents a novel species of the genus Thermus, with the name Thermus amyloliquefaciens sp. nov. The type strain is YIM 77409T ( = DSM 25898T = KCTC 32024T). PMID- 25920725 TI - Lactobacillus plajomi sp. nov. and Lactobacillus modestisalitolerans sp. nov., isolated from traditional fermented foods. AB - Three Lactobacillus-like strains, NB53T, NB446T and NB702, were isolated from traditional fermented food in Thailand. Comparative 16S rRNA gene sequence analysis indicated that these strains belong to the Lactobacillus plantarum group. Phylogenetic analysis based on the dnaK, rpoA, pheS and recA gene sequences indicated that these three strains were distantly related to known species present in the L. plantarum group. DNA-DNA hybridization with closely related strains demonstrated that these strains represented two novel species; the novel strains could be differentiated based on chemotaxonomic and phenotypic characteristics. Therefore, two novel species of the genus Lactobacillus, Lactobacillus plajomi sp. nov. (NB53T) and Lactobacillus modestisalitolerans sp. nov. (NB446T and NB702), are proposed with the type strains NB53T ( = NBRC 107333T = BCC 38054T) and NB446T ( = NBRC 107235T = BCC 38191T), respectively. PMID- 25920727 TI - Long-term outcome after the original and simple modified technique of valve sparing aortic root reimplantation in Marfan-based population, David V University of Tokyo modification. AB - BACKGROUND: In valve-sparing aortic root replacement (VSARR), how to reproduce Valsalva sinus has been an issue. In the original David V procedure, they put plication stitches at sinotubular junction level, although the reefing effect is limited and distal graft remains larger than native. Other modified techniques are two-grafts technique and ready-made Valsalva graft. However, the former needs graft-graft anastomosis and may not be cost-effective, while in the latter, the shape of sinus is fixed and minor adjustment is difficult. David V University of Tokyo modification (David V-UT) is our original solution to that, creating pseudosinus with one straight graft by longitudinal size-reduction running sutures above each pseudosinus. The purpose of the present study is to investigate long-term outcome of David V-UT. METHODS: We analyzed 59 David V-UT patients from February 2004 to February 2013 and long-term outcomes were investigated by Kaplan-Meier methods. Risk factors for adverse events "death or recurrent aortic insufficiency (AI) with or without aortic valve reoperation" were analyzed by using Cox proportional hazard models. RESULTS: Mean age was 33.1+/-14.5 years, and 38 patients (64%) were male. Marfan syndrome (MFS) accounts for 47 patients (80%). Only one patient was with bicuspid aortic valve. No in-hospital mortality was observed. Mean follow-up was 4.9+/-2.4 years. Estimated survival was 94.0+/-3.4% at 5 years. Freedoms from aortic valve reoperation and recurrent AI greater than mild were 95.7+/-3.0% and 88.9+/-4.7% at 5 years, respectively. In Cox proportional hazard analysis, preoperative AI greater than mild and Z score of annular diameter were significant risks for adverse events (p=0.027 and 0.045, hazard ratio 6.084 and 1.432, 95% C.I. 1.225 30.21 and 1.008-2.035, respectively). CONCLUSIONS: Even in Marfan-characterized population, David V-UT provided satisfactory long-term outcome, comparable to other VSARR modifications. It is simple but can freely reproduce trilobed sinus with one straight graft. PMID- 25920726 TI - Parental history of psychiatric diagnoses and unipolar depression: a Danish National Register-based cohort study. AB - BACKGROUND: Depression is known to run in families, but the effects of parental history of other psychiatric diagnoses on depression rates are less well studied. Few studies have examined the impact of parental psychopathology on depression rates in older age groups. METHOD: We established a population-based cohort including all individuals born in Denmark after 1954 and alive on their 10th birthday (N = 29 76 264). Exposure variables were maternal and paternal history of schizophrenia, bipolar disorder, depression, anxiety or 'other' psychiatric diagnoses. Incidence rate ratios (IRRs) were estimated using Poisson regressions. RESULTS: Parental history of any psychiatric diagnosis increased incidence rates of outpatient (maternal: IRR 1.88, p < 0.0001; paternal: IRR 1.68, p < 0.0001) and inpatient (maternal: IRR 1.99, p < 0.0001; paternal: IRR 1.83, p < 0.0001) depression relative to no parental history. IRRs for parental history of non affective disorders remained relatively stable across age groups, while IRRs for parental affective disorders (unipolar or bipolar) decreased with age from 2.29 3.96 in the youngest age group to 1.53-1.90 in the oldest group. IRR estimates for all parental diagnoses were similar among individuals aged ?41 years (IRR range 1.51-1.90). CONCLUSIONS: Parental history of any psychiatric diagnosis is associated with increased incidence rates of unipolar depression. In younger age groups, parental history of affective diagnoses is more strongly associated with rates of unipolar depression than non-affective diagnoses; however, this distinction disappears after age 40, suggesting that parental psychopathology in general, rather than any one disorder, confers risk for depression in middle life. PMID- 25920728 TI - Bradykinin and cysteinyl leukotriene concentrations in cell-salvaged blood before and after passage through negatively charged filters during clinical use in cancer patients: a pilot study. AB - It has been suggested that giving cell-salvaged blood through a leucocyte depletion filter can cause hypotension due to bradykinin released when factor XII and platelets are activated by the negatively charged surface of the filter. We measured the concentration of bradykinin and cysteinyl leukotrienes in cell salvaged blood sampled before and after passage through a negatively charged leucodepletion filter in 24 consecutive patients with gynaecological or bowel cancer undergoing elective surgery with cell salvage. In no case was an increase in bradykinin concentration observed after passage through the filter; in 23 patients the post-filtration bradykinin concentration was zero (p = 0.007). The change in the concentration of cysteinyl leukotrienes detected during passage across the filter was not statistically significant (p = 0.1). Our findings do not support the suggestion that either bradykinin or cysteinyl leukotrienes are generated in cell-salvaged blood during passage through leucodepletion filters. PMID- 25920729 TI - Merged Near-Infrared Fluorescence and White Light Imaging in Minimally Invasive Surgery. PMID- 25920730 TI - Factors affecting the progression of renal dysfunction and the importance of salt restriction in patients with type 2 diabetic kidney disease. AB - BACKGROUND: Type 2 diabetic kidney disease (DKD) is the most common cause of end stage renal failure, and the prevention of its progression has been a topic of discussion. METHODS: Sixty type 2 DKD patients were retrospectively evaluated for 1 year. Factors independently affecting the annual Ccr decline were examined by multivariable linear regression analysis. Patients were further divided into 2 groups based on their degree of renal function, and between-group differences at study initiation were evaluated. RESULTS: Ccr values were 21.0 +/- 11.8 mL/min/1.73 m(2) at study initiation, and 15.7 +/- 10.9 mL/min/1.73 m(2) after 1 year of observation. The multivariable linear regression analysis indicated salt intake (standardized coefficient: -0.34, P = 0.010) and urinary protein excretion (standardized coefficient: -0.33, P = 0.011) to be factors independently affecting the annual Ccr decline. Although decliners (-9.8 +/- 4.7 mL/min/1.73 m(2)/year) had a significantly higher salt intake than non-decliners (-1.1 +/- 3.8 mL/min/1.73 m(2)/year) at study initiation, this difference disappeared at the end of the study as a result of intensive dietary education. In 21 decliners with an additional year of follow-up, the annual Ccr decline significantly improved from -10.1 +/- 5.3 to -5.3 +/- 7.4 mL/min/1.73 m(2)/year (P = 0.02). CONCLUSION: Salt intake and urinary protein excretion were associated with annual Ccr decline in type 2 DKD patients. Furthermore, dietary education covering salt intake may have positively affected the change in Ccr. PMID- 25920731 TI - Frequency of squamous cell carcinoma (SCC) invasion in transected SCC in situ referred for Mohs surgery: the Dartmouth-Hitchcock experience. AB - BACKGROUND: Squamous cell carcinoma (SCC) in situ may be transected in a superficial biopsy, which makes it difficult to distinguish between in situ and invasive carcinoma. This study investigated the frequency of invasive SCC in transected SCC in situ referred for Mohs surgery. METHODS: A retrospective chart review was performed to identify subjects with biopsy-proven, transected SCC in situ referred for Mohs surgery. The incidence of invasion, histologic variables, preoperative and intraoperative correlations, and clinical factors were determined and recorded. RESULTS: Of 51 cases identified, five (9.8%) were found to harbor invasive SCC, 15 (29.4%) showed SCC in situ, and 28 (54.9%) showed evidence of scarring, inflammation, or actinic keratosis at the prior biopsy site. Invasive lesions required significantly more stages of Mohs surgery to obtain tumor clearance but were similar with regard to patient age, symptoms, and family and personal histories of skin cancer. Preoperative lesion size and duration were greater in invasive cases, but these differences did not reach statistical significance. CONCLUSIONS: A small number of transected SCCs in situ, to which the caveat "invasion cannot be ruled out" can be applied, have an invasive component that is identified during Mohs surgery. Definitive treatment choices should depend on the physician's impression, the clinical characteristics of the lesion, tumor location, patient comorbidities, and patient desires. PMID- 25920732 TI - Diffusion tensor imaging of the nigrostriatal fibers in Parkinson's disease. AB - BACKGROUND: Parkinson's disease (PD) is histopathologically characterized by the loss of dopamine neurons in the substantia nigra pars compacta. The depletion of these neurons is thought to reduce the dopaminergic function of the nigrostriatal pathway, as well as the neural fibers that link the substantia nigra to the striatum (putamen and caudate), causing a dysregulation in striatal activity that ultimately leads to lack of movement control. Based on diffusion tensor imaging, visualizing this pathway and measuring alterations of the fiber integrity remain challenging. The objectives were to 1) develop a diffusion tensor tractography protocol for reliably tracking the nigrostriatal fibers on multicenter data; 2) test whether the integrities measured by diffusion tensor imaging of the nigrostriatal fibers are abnormal in PD; and 3) test whether abnormal integrities of the nigrostriatal fibers in PD patients are associated with the severity of motor disability and putaminal dopamine binding ratios. METHODS: Diffusion tensor tractography was performed on 50 drug-naive PD patients and 27 healthy control subjects from the international multicenter Parkinson's Progression Marker Initiative. RESULTS: Tractography consistently detected the nigrostriatal fibers, yielding reliable diffusion measures. Fractional anisotropy, along with radial and axial diffusivity of the nigrostriatal tract, showed systematic abnormalities in patients. In addition, variations in fractional anisotropy and radial diffusivity of the nigrostriatal tract were associated with the degree of motor deficits in PD patients. CONCLUSION: Taken together, the findings imply that the diffusion tensor imaging characteristic of the nigrostriatal tract is potentially an index for detecting and staging of early PD. PMID- 25920733 TI - Chest wall abscesses due to continuous application of silicone gel sheets for keloid management. AB - A patient with three episodes of chest wall abscesses as a result of 6 years of round-the-clock, uninterrupted (except during bathing) application of silicone gel sheets to a chest wall keloid is described. Two of the episodes occurred during hot weather. It is suggested that, in the space beneath the silicone sheet, the higher humidity and temperature, both generated as a result of prolonged sheeting, especially during hot weather, might have caused the keloid and its neighbouring skin to become soggy. This sogginess might have facilitated bacterial invasion. It is suggested that some sheeting-free time during a 24 h period might be indicated so that a keloid and its adjacent skin have the time to recover from their sheeting-induced sogginess. A sheeting-free period might especially be needed in the face of sweat accumulation beneath the silicone sheet. PMID- 25920734 TI - Lower motor neuron facial palsy after ventriculoperitoneal shunt surgery. AB - A 40-year-old woman underwent marsupialisation of a symptomatic retrocerebellar cyst. She developed pseudomeningocoele after the procedure. CT of the brain showed hydrocephalus. Therefore, a right-sided ventriculoperitoneal shunt procedure was performed. Unfortunately, the patient developed lower motor neuron type facial paralysis immediately after the surgery. We localised the site of injury in the distal fallopian canal probably during tunnelling of the subcutaneous tract for passage of the shunt. We discuss the steps to be followed to avoid such mishaps with a brief review of the literature. PMID- 25920735 TI - Diagnosis of double splenic artery pseudoaneurysm: CT scan versus angiography. AB - The formation of splenic artery pseudoaneurysms is a commonly reported complication of chronic pancreatitis. Angiography has an established role in the diagnosis of splenic artery pseudoaneurysms while CT scan is thought to be less accurate for making this diagnosis. In this report, we present a rare case of two separate concomitant splenic artery pseudoaneurysms, illustrating the value of combining CT and angiography for optimal visualisation and treatment. PMID- 25920736 TI - Placental mesenchymal dysplasia associated with spontaneous ovarian hyperstimulation syndrome. AB - Placental mesenchymal dysplasia (PMD) is a rare disorder of unknown aetiology characterised by placentomegaly, serpiginous surface blood vessels and large cystic villi. Although a mimic of molar pregnancies and other entities, it can be distinguished from them by its association with intrauterine growth restriction or death of a relatively normal fetus and its characteristic histopathology. We report the case of a 20-year-old primigravida who presented at 16 weeks with heavy clotty vaginal bleeding and subsequent miscarriage. The placenta was grossly abnormal and resembled a partial molar pregnancy. PMD was confirmed by microscopic examination. Postmiscarriage, ultrasound revealed enlarged and multicystic ovaries similar to those seen in ovarian hyperstimulation syndrome (OHSS), which returned to normal a few weeks after miscarriage. This is the first report of PMD associated with OHSS, and we hypothesise that the most likely pathogenesis is ovarian stimulation from PMD-derived vascular endothelial growth factor. PMID- 25920737 TI - Shigella sonnei bacteraemia occurring in a young man with shigellosis. AB - A 34-year-old man presented with a 6-day history of diarrhoea, abdominal cramps and fever. Blood cultures were initially reported as positive for Escherichia coli using matrix-assisted laser desorption/ionisation time of flight (MALDI-TOF) mass spectrometry. Contrast CT of the abdomen and pelvis revealed pancolitis and terminal ileal thickening. The patient was treated empirically with ampicillin, ciprofloxacin and metronidazole. Stool cultures were positive for Shigella sonnei. Subsequent testing on the initial blood culture correctly identified the organism as S. sonnei. On further questioning, the patient reported unprotected men who have sex with men (MSM) 3 months previously. His symptoms resolved during his 3-day admission, and he was discharged on 14 days of ciprofloxacin. He remains well. This case highlights that shigellosis is increasingly seen in MSM, with no history of travel, and may result in bacteraemia. This case also highlights the benefits (rapid identification of organisms) and limitations (inability to distinguish between E. coli and Shigella spp) of new technologies such as MALDI-TOF. PMID- 25920738 TI - Metastatic renal cell carcinoma presenting with mediastinal eggshell calcification. AB - An 81-year-old South Asian man normally resident in the UK presented with night sweats for over 2 months on a background of weight loss of 4 kg in 6 months. His medical history was significant for metastatic renal cell carcinoma treated 5 years previously with cytoreductive nephrectomy and adjuvant chemotherapy. Following an abnormal chest radiograph showing an ill-defined right paratracheal mass, a CT scan showed eggshell calcification (circumferential calcification) of enlarged low right paratracheal lymph nodes. An endobronchial ultrasound-guided transbronchial needle aspiration of an involved large paratracheal lymph node showed cytology consistent with metastatic renal cell carcinoma. PMID- 25920739 TI - Visceral leishmaniasis in an infant following a holiday trip to Spain. AB - Imported leishmaniasis is rare in non-endemic countries such as the UK. Visceral leishmaniasis (VL) can be life-threatening and its recognition is imperative for successful clinical management. We present a case of VL in an 11-month-old infant several months after returning from a 1-week holiday trip to the South of Spain. The infant suffered from intermittent fever for 5 weeks, and hepatosplenomegaly and pancytopenia, and was successfully treated with a short course of liposomal amphotericin B. This case of VL is to highlight the possibility of transmission of unusual pathogens when travelling to the Mediterranean and therefore the importance of taking a detailed travel history. VL should be considered in the differential diagnosis in returning travellers presenting with prolonged fever, hepatosplenomegaly and/or pancytopenia. PMID- 25920740 TI - Erectile dysfunction: a window to the heart. AB - Erectile dysfunction (ED) is an early marker of coronary artery disease (CAD) and often manifests before the development of symptomatic CAD. In this case report, we present a 60-year-old man with ED, who demonstrated limited response to the standard management strategies and was subsequently treated with percutaneous pelvic intervention (PPI) of the internal pudendal artery. While on the table for PPI, the patient described a classical history of angina, on which basis he underwent coronary angiography and was found to have narrow proximal left anterior descending stenosis. Coronary artery stent placement was then performed using standard techniques. PPI of pudendal artery stenoses with stents is feasible and can improve cavernosal blood flow and venous leakage as well as erectile function. PMID- 25920741 TI - Intestinal malrotation and acute left side appendicitis: an indication for laparoscopic exploration. PMID- 25920742 TI - Increased iPLA2 activity and levels of phosphorylated GSK3B in platelets are associated with donepezil treatment in Alzheimer's disease patients. AB - Reduced phospholipase A2 (PLA2) activity and increased phosphorylation of glycogen synthase kinase 3B (GSK3B) participate in the production of beta-amyloid plaques and of neurofibrillary tangles, which are two neuropathological hallmarks of Alzheimer's disease (AD). Experimental evidences suggest a neuroprotective effect of the cholinesterase inhibitor donepezil in the treatment the disease. The aims of the present study were to evaluate in AD patients the effects of treatment with donepezil on PLA2 activity and GSK3B level. Thirty patients with AD were treated during 6 months with 10 mg daily of donepezil. Radio-enzymatic assays were used to measure PLA2 activity and Elisa assays for GSK3B level, both in platelets. Before treatment and after 3 and 6 months on donepezil, AD patients underwent a cognitive assessment and platelet samples were collected. Values were compared to a healthy control group of 42 sex- and age-matched elderly individuals. Before treatment, iPLA2 activity was lower in patients with AD as compared to controls (p < 0.001). At baseline, no differences were found in GSK3B level between both groups. After 3 and 6 months of treatment, we found a significant increase in iPLA2 activity (p = 0.015 and p < 0.001, respectively). iPLA2 increment was related to the cognitive improvement during treatment (p = 0.037). After 6 months, we found an increase in phosphorylated GSK3B (p = 0.02). The present findings suggest two possible mechanisms by which donepezil delays the progression of AD. The increment of iPLA2 activity may reduce the production of beta-amyloid plaques, whereas the phosphorylation of GSK3B inactivates the enzyme, reducing thus the phosphorylation of tau protein. PMID- 25920743 TI - Epigenetic regulation of insulin-like growth factor binding protein-3 (IGFBP-3) in cancer. AB - Epigenetics refers to heritable changes in gene expression that are independent of alterations in DNA sequence. It is now accepted that disruption of epigenetic mechanisms plays a key role in the pathogenesis of cancer: culminating in altered gene function and malignant cellular transformation. DNA methylation and histone modifications are the most widely studied changes but non-coding RNAs such as miRNAs are also considered part of the epigenetic machinery. The insulin-like growth factor (IGF) axis is composed of two ligands, IGF-I and -II, their receptors and six high affinity IGF binding proteins (IGFBPs). The IGF axis plays a key role in cancer development and progression. As IGFBP genes have consistently been identified among the most common to be aberrantly altered in tumours, this review will focus on epigenetic regulation of IGFBP-3 in cancer for which the majority of evidence has been obtained. PMID- 25920744 TI - Controlling Listeria monocytogenes in Cold Smoked Salmon with the Antimicrobial Peptide Salmine. AB - Listeria monocytogenes (LM) is a major safety concern for smoked salmon producers, as it can survive both the brining and smoking process in cold smoked salmon production. Salmine is a cationic antimicrobial peptide derived from the milt of salmon that has been shown to inhibit the growth of LM in vitro. Commercialization of this peptide would add value to a waste product produced when raising salmon. The purpose of this study was to determine the anti-listeria activity of salmine in smoked salmon by measuring the viable counts of LM over time. Cold smoked salmon was treated with a salmine solution or coated with agar or k-carrageenan films incorporating salmine to maintain a high surface concentration of the antimicrobial. Samples were then inoculated with approximately 1.0 * 10(3) cells of LM. The viable counts were then enumerated throughout 4 wk at 4 degrees C storage. It was found that 5 mg/g salmine delayed the growth of LM on smoked salmon. These samples had significantly (P < 0.05) lower LM counts than on the untreated samples on days 13 and 22. Edible films did not significantly (P > 0.05) improve the antimicrobial efficacy of salmine. The peptide combined with biopolymers also had lower antimicrobial activity in vitro when compared to salmine alone. These results suggest there is potential for salmine to be used as a natural hurdle to inhibit growth of LM due to post process contamination; however, future investigations for extending this effect throughout the shelf life of smoked salmon products are warranted. PMID- 25920745 TI - High functioning male with fragile X syndrome and fragile X-associated tremor/ataxia syndrome. AB - Fragile X syndrome (FXS) affects individuals with more than 200 CGG repeats (full mutation) in the fragile X mental retardation 1 (FMR1) gene. Those born with FXS experience cognitive and social impairments, developmental delays, and some features of autism spectrum disorders. Carriers of a premutation (55-200 CGG repeats) are generally not severely affected early in life; however, are at high risk of developing the late onset neurodegenerative disorder, Fragile X associated Tremor/Ataxia Syndrome (FXTAS), or Fragile X-associated Primary Ovarian Insufficiency (FXPOI), and may have other medical conditions such as developmental delay, autism spectrum disorders, hypertension, anxiety, and immune mediated disorders. Here we present a case of a 58-year-old man with a borderline IQ, average memory skills, and executive function deficits. He met criteria for multiple psychiatric diagnoses and presented with tremor and ataxia, meeting criteria for FXTAS. Molecular testing unveiled a completely unmethylated FMR1 full mutation in peripheral blood mononucleated cells with elevated FMR1 mRNA and premutation alleles of different sizes in two other tissues (primary fibroblasts and sperm), indicating the presence of allele instability based on both inter- and intra-tissue mosaicism. The observation of FXTAS in this case of a full mutation mosaic man suggests that the pathogenic mechanism underlying this disorder is not observed exclusively in premutation carriers as it was originally thought. The concomitant presence of features of FXS and late onset neurological deterioration with probable FXTAS likely result from a combined molecular pathology of elevated FMR1 mRNA levels, a molecular hallmark of FXTAS and low FMRP expression that leads to FXS. PMID- 25920746 TI - High saturated fat diet alters the lipid composition of triacylglycerol and polar lipids in the femur of dam and offspring rats. AB - Previous work has shown that dietary lipids alter femur lipid composition. Specifically, we have shown that exposure to high saturated fatty acid (SFA) diets in utero, during suckling, or post-weaning alters femur total lipid composition, resulting in higher percent bone mass in males and females and bone mineral density (BMD) in female offspring with no effect on bone mineral outcomes in dams. Comparatively, high n-3 polyunsaturated fatty acid (PUFA) diets increase femur polar (PL) lipid n-3 content, which has been associated with increased bone mineral content and strength. However, the extent that PL or triacylglycerol (TAG) lipids change with high SFA diets is unknown. The current investigation examined the influence of a high SFA diet (20 % lard by weight) on femur PL and TAG lipid composition in 5-month old female Wistar rats (fed high SFA diet from age 28 days onwards; dams) and their 19-day old offspring (exposed to high SFA in utero and during suckling; pups). High SFA exposure resulted in increased monounsaturates and decreased n-3 and n-6 PUFA in the TAG fraction in both dams and pups, and higher SFA and n-6:n-3 ratio in dams only. The PL fraction showed decreased n-6 PUFA in both dams and pups. The magnitude of the diet-mediated responses, specifically TAG 18:1 and PL n-6 PUFA, may have contributed to the previously reported altered BMD, which was supported with correlation analysis. Future research should investigate the relationship of diet-induced changes in bone lipids on bone structure, as quantified through micro-computed tomography. PMID- 25920747 TI - Quality of life aspects in the management of thyroid cancer. AB - While there is agreement that quality of life (QoL) is a central aim of medical treatment, the methods of its evaluation as well as its role in the patient's overall treatment experience are under continuous scrutiny. Different perspectives on patients' QoL have emerged; from the treating physician, from the psychologist, and naturally from the patient him/herself. This article provides insights into each of these views within the context of thyroid cancer where, as a consequence of increasing incidence and decreasing mortality rates, QoL aspects deserve close attention. Physicians often find themselves in situations where they perform a balancing act between what they know is best from a somatic point of view and learning about what is best for the individual patient. For psychologists in the field of oncology, a main area of interest is the incorporation of the patient's perspective into research by using patient reported outcomes (PROs) which include QoL assessment. PROs can also be used in clinical practice as a way to start a conversation about symptoms and QoL aspects that perhaps patients might not volunteer, and this allows physicians to address QoL issues more directly. Patients usually appreciate being asked about all aspects of QoL, and need sound information about how their QoL might be affected by the disease and its treatment. By examining and understanding the different perspectives on QoL, and how QoL differs in patients with thyroid cancer compared with other cancers, it is hoped that the QoL can be enhanced in this particular patient group. PMID- 25920748 TI - The HSP90 inhibitor alvespimycin enhances the potency of telomerase inhibition by imetelstat in human osteosarcoma. AB - The unsatisfactory outcomes for osteosarcoma necessitate novel therapeutic strategies. This study evaluated the effect of the telomerase inhibitor imetelstat in pre-clinical models of human osteosarcoma. Because the chaperone molecule HSP90 facilitates the assembly of telomerase protein, the ability of the HSP90 inhibitor alvespimycin to potentiate the effect of the telomerase inhibitor was assessed. The effect of single or combined treatment with imetelstat and alvespimycin on long-term growth was assessed in osteosarcoma cell lines (143B, HOS and MG-63) and xenografts derived from 143B cells. Results indicated that imetelstat as a single agent inhibited telomerase activity, induced telomere shortening, and inhibited growth in all 3 osteosarcoma cell lines, though the bulk cell cultures did not undergo growth arrest. Combined treatment with imetelstat and alvespimycin resulted in diminished telomerase activity and shorter telomeres compared to either agent alone as well as higher levels of gammaH2AX and cleaved caspase-3, indicative of increased DNA damage and apoptosis. With dual telomerase and HSP90 inhibition, complete growth arrest of bulk cell cultures was achieved. In xenograft models, all 3 treatment groups significantly inhibited tumor growth compared with the placebo-treated control group, with the greatest effect seen in the combined treatment group (imetelstat, p = 0.045, alvespimycin, p = 0.034; combined treatment, p = 0.004). In conclusion, HSP90 inhibition enhanced the effect of telomerase inhibition in pre clinical models of osteosarcoma. Dual targeting of telomerase and HSP90 warrants further investigation as a therapeutic strategy. PMID- 25920749 TI - Disuse rescues the age-impaired adaptive response to external loading in mice. AB - We aimed to determine whether aged bone's diminished response to mechanical loading could be rescued by modulating habitual activity. By reducing background loading, aged bone's response to loading increased to a level no different to young mice. This suggests, given the right stimulus, that ageing bone can respond to mechanical loading. INTRODUCTION: Age-related decline in bone mass has been suggested to represent an impaired ability of bone to adapt to its mechanical environment. In young mice, the tibia's response to external mechanical loading has been shown to increase when habitual activity is reduced by sciatic neurectomy. Here we investigate if neurectomy can rescue bone's response to loading in old mice. METHODS: The effect of tibial disuse, induced by unilateral sciatic neurectomy (SN), on the adaptive response to a single peak magnitude of dynamic load-engendered mechanical strain was assessed in 19-month-old (aged) mice. In a second experiment, a range of peak loads was used to assess the load magnitude-related effects of loading on a background of disuse in young adult and aged mice. Bone architecture was analysed using micro-computed tomography (MUCT) and dynamic histomorphometry. RESULTS: In the first experiment, SN in aged mice was associated with a significant periosteal osteogenic response to loading not observed in sham-operated mice (7.98 +/- 1.7 vs 1.02 +/- 2.2 % increase in periosteally enclosed area, p < 0.05). In the second experiment, SN abrogated the expected age-related difference in the bones' osteogenic response to peak strain magnitude (p > 0.05). CONCLUSIONS: These data suggest that bones' age-related decline in osteogenic responsiveness to loading does not originate in bone cells to either assess, or appropriately respond to strain, but rather is likely to be due to inhibitory "averaging" effects derived from the habitual strains to which the bone is already adapted. If such "strain averaging" is applicable to humans, it suggests that gentle exercise may degrade the beneficially osteogenic effects of short periods of more vigorous activity. PMID- 25920750 TI - Ezetimibe plus simvastatin for the treatment of hypercholesterolemia. AB - INTRODUCTION: Cardiovascular disease is a major cause of death, and hypercholesterolemia is a major risk factor. Statins, with simvastatin among the most widely used, have ample evidence demonstrating prevention of cardiovascular events and mortality. Ezetimibe is effective at improving serum lipids in combination with statins or alone, but its role has been controversial. AREAS COVERED: Here, we provide an overview of the pharmacokinetics and pharmacodynamics of each component of the combination, as well as pharmacogenetic contributors. Regarding clinical efficacy, our focus will be on the post marketing clinical trials of ezetimibe-simvastatin combination therapy. We broach the controversy around the role of ezetimibe, particularly in light of the results of the IMProved Reduction of Outcomes: Vytorin Efficacy International Trial (IMPROVE-IT). EXPERT OPINION: Ezetimibe in combination with simvastatin or other statins provides an excellent means of incremental lipid-lowering effect, although the clinical benefit has been uncertain. IMPROVE-IT is the first to demonstrate incremental cardiovascular risk reduction with the addition of ezetimibe to simvastatin. What the literature lacks is evidence around the common use of ezetimibe as monotherapy or add-on therapy to lower doses of statins in patients who fail to achieve adequate lipid lowering or do not tolerate high-dose statins. PMID- 25920751 TI - The dopant type and amount governs the electrochemical performance of graphene platforms for the antioxidant activity quantification. AB - Graphene doped with heteroatoms can show new or improved properties as compared to the original undoped material. It has been reported that the type of heteroatoms and the doping conditions can have a strong influence on the electronic and electrochemical properties of the resulting material. Here, we wish to compare the electrochemical behavior of two n-type and two p-type doped graphenes, namely boron-doped graphenes and nitrogen-doped graphenes containing different amounts of heteroatoms. We show that the boron-doped graphene containing a higher amount of dopants provides the best electroanalytical performance in terms of calibration sensitivity, selectivity and linearity of response for the detection of gallic acid normally used as the standard probe for the quantification of antioxidant activity of food and beverages. Our findings demonstrate that the type and amount of heteroatoms used for the doping have a profound influence on the electrochemical detection of gallic acid rather than the structural properties of the materials such as amounts of defects, oxygen functionalities and surface area. This finding has a profound influence on the application of doped graphenes in the field of analytical chemistry. PMID- 25920752 TI - The 10-second stroke: a case report. AB - BACKGROUND: Acute infarction is detected in a third of patients undergoing diffusion-weighted magnetic resonance imaging (DW-MRI) with clinically suspected transient ischemic attack. The longer symptoms are present, the more likely an infarct will be identified on DW-MRI. Events as short as 10 minutes have been reported in association with a DW-MRI lesion. METHODS: We present a case of an otherwise healthy man with a 10-second episode of neurologic dysfunction associated with DW-MRI lesions from a cardioembolic source. RESULTS: The atypical symptoms and lack of risk factors for cerebrovascular disease made his diagnosis easy to miss. CONCLUSIONS: Early DW-MRI may be of benefit beyond clinical judgment in patients with fleeting symptoms of neurologic dysfunction. PMID- 25920753 TI - Multidisciplinary protocol for rapid head computed tomography turnaround time in acute stroke patients. AB - BACKGROUND: The door-to-computed tomography (CT) head reporting time is an essential step to determining eligibility for thrombolysis in acute stroke patients, but the specific components of the process have not been reported in detail. METHODS: We performed a retrospective cross-sectional analysis of the prospectively collected Get-With-The-Guidelines database in our comprehensive stroke center to evaluate the effect of a structured multidisciplinary protocol on head CT times in acute stroke patients under consideration for thrombolysis. RESULTS: The median CT turnaround time in the first 6-month period was 27 (interquartile range [IQR], 27) and decreased in all subsequent periods after implementation of a formal protocol to 18 (IQR, 12; range, 17-20 minutes; P < .0001 for all pairwise comparisons). The median CT turnaround time was 18 (IQR, 12) versus 20 (IQR, 14) minutes for patients with admission diagnosis of stroke (n = 1123) versus nonstroke (n = 685; P < .0001), respectively. CONCLUSIONS: A structured multidisciplinary protocol for obtaining acute stroke protocol head CT scan was associated with reduced CT turnaround time over the study period. Prospective studies should be done to determine if implementation in other stroke centers confirms the effectiveness of our protocol. PMID- 25920754 TI - PPARgamma-Dependent and -Independent Inhibition of the HMGB1/TLR9 Pathway by Eicosapentaenoic Acid Attenuates Ischemic Brain Damage in Ovariectomized Rats. AB - High mobility group box 1 (HMGB1) elevation after cerebral ischemia activates inflammatory pathways via receptors such as the receptor for advanced glycation end products (RAGE) and toll-like receptors (TLRs) and leads to brain damage. Eicosapentaenoic acid (EPA), a peroxisome proliferator-activated receptor gamma (PPARgamma) agonist, attenuates postischemic inflammation and brain damage in male animals. However, postischemic HMGB1 signaling and the effects of EPA on ovariectomized (OVX(+)) rats remain unclear. We hypothesized that EPA attenuates brain damage in OVX(+) rats via the inhibition of HMGB1 signaling in a PPARgamma dependent manner. Seven-week-old female Sprague-Dawley rats were divided into 3 groups; nonovariectomized (OVX(-)) rats and EPA-treated and EPA-untreated OVX(+) rats before cerebral ischemia induction. Another set of EPA-treated OVX(+) rats was injected with the PPARgamma inhibitor GW9662. OVX(+) decreased the messenger RNA level of PPARgamma and increased that of HMGB1, RAGE, TLR9, and tumor necrosis factor alpha (TNFalpha) in parallel with ischemic brain damage. EPA restored the PPARgamma expression, downregulated the HMGB1 signal-related molecules, and attenuated the ischemic brain damage. Neither OVX(+) nor EPA affected the expression of TLR2 or TLR4. Interestingly, GW9662 partially abrogated the EPA-induced neuroprotection and the downregulation of RAGE and TLR9. In contrast, GW9662 did not affect HMGB1 or TNFalpha. These results suggest that EPA exerts PPARgamma-dependent and PPARgamma-independent effects on postischemic HMGB1/TLR9 pathway. The cortical infarct volume exacerbated by OVX(+) is associated with the upregulation of the HMGB1/TLR9 pathway. Suppression of this pathway may help to limit ischemic brain damage in postmenopausal women. PMID- 25920755 TI - Care provision for poststroke visual impairment. AB - BACKGROUND: We sought to explore the care provision for poststroke visual impairment and variations in this in the United Kingdom. METHODS: Survey questions were developed and piloted with clinicians, academics, and users. Questions addressed types of visual problems; how these were identified, treated, and followed up; care pathways in use; links with other professions; and referral options. The survey was accessed via a Weblink, which was circulated through UK professional organizations to multiprofessional members of ophthalmic and stroke teams. RESULTS: A total of 548 completed electronic surveys were obtained. In all, 49.5% of respondents represented stroke teams, 42.5% eye teams, and 8% from other teams, for example, emergency care. Many respondents (41%) saw patients within 1 week of stroke. Nineteen percent did not personally test vision: 11% had a visiting clinician to test vision, and 22% used screening tools. Validated tests were used for the assessment of visual acuity (39.5%), visual field (57.5%), eye movement (48.5%), and visual function (58.5%). Visual problems suspected by family or professionals were high (88.5%). Typical overall follow-up period of vision care was less than 3 months. In all, 46% of respondents used designated care pathways for stroke survivors with visual problems; 33.5% of respondents did not provide visual information leaflets. CONCLUSIONS: Significant inequality exists in care for stroke survivors who experience visual problems. There is great variability in how vision screening is undertaken, which vision tests are used, methods of referral to eye care services, how visual problems are managed, and what vision information is provided to stroke survivors/carers. Further work is required to ensure equality and effective care. PMID- 25920756 TI - Computed Tomography--Verified Leukoaraiosis Is a Risk Factor for Post thrombolytic Hemorrhage. AB - BACKGROUND: Is computed tomography (CT)-verified leukoaraiosis (LA) a risk factor for post-thrombolytic hemorrhagic transformation and symptomatic hemorrhage? METHODS: (1) Retrospective analysis based on a prospectively planned single center registry of consecutive tissue plasminogen activator (tPA)-treated patients within 4.5 hours from symptom onset. Standard work-up included baseline noncontrast CT and CT angiography and next day follow-up noncontrast CT. Baseline noncontrast CT LA was graded using Fazekas' score and dichotomized as the absence (Fazekas, 0) or the presence (Fazekas, 1-3). Hemorrhagic transformation was rated using European Cooperative Acute Stroke Study (ECASS) criteria. Symptomatic intracerebral hemorrhage was defined as hemorrhage and deterioration of National Institutes of Health Stroke Scale (NIHSS) of 4 or greater within 36 hours from symptom onset. Endovascularly treated patients were excluded. (2) Pooled analysis with 1312 tPA-treated patients from literature. RESULTS: In all, 311 tPA-treated patients were included between April 2009 and July 2012. LA was present in 113 (36%). Twenty-three (7%) showed hemorrhagic transformation. LA positive patients had significantly higher hemorrhagic transformation frequency (11.5%, P = .04). LA doubled hemorrhagic transformation risk (odds ratio [OR], 2.4; 95% confidence interval [CI], 1.4-5.8). Only 4 patients developed symptomatic intracerebral hemorrhage, 3 with LA. LA was not an independent risk factor for hemorrhagic transformation (P = .2). Pooled analysis of 1623 patients in total, hereof 479 LA positive patients, showed significantly higher symptomatic intracerebral hemorrhage frequency in 35 (7.3%) LA positive than that in 44 (3.8%) LA negative patients, (P = .005) and doubled symptomatic intracerebral hemorrhage risk in LA positives (OR, 1.97; 95% CI 1.22-3.19). CONCLUSIONS: LA doubles the risk of post thrombolytic hemorrhagic transformation and symptomatic hemorrhage; this finding does not support withholding thrombolysis from patients with LA. PMID- 25920757 TI - A simple surgical treatment for bovine digital dermatitis-associated white line lesions and sole ulcers. AB - Non-healing white line disease (nhWLD) and sole ulcers (nhSU) are seen increasingly in herds endemically affected with bovine digital dermatitis (BDD). In 35 cows with 42 nhWLD or nhSU lesions, the healing process was monitored for up to 28 or 38 days following extensive debridement of loose horn and infected corium under regional anaesthesia, and topical application of tetracycline spray with bandaging. By 28 days, 27/42 (64%) nhWLD and nhSU were completely covered by a new horn layer and this increased to 30/42 (71%) that had healed by 38 days. Lesion sizes on day 0 correlated with clinical healing within the study period. In view of this satisfying therapeutic result, the terms nhWLD and nhSU are proposed for BDD-associated white line disease (BDD-WLD) and BDD-associated sole ulcers (BDD-SU), respectively. PMID- 25920758 TI - Management of transitional cell carcinoma of the urinary bladder in dogs: important challenges to consider. PMID- 25920759 TI - Efficacy of a combined inactivated porcine reproductive and respiratory syndrome virus vaccine using North American and European strains in specific pathogen free pigs. AB - In Korea, porcine reproductive and respiratory syndrome (PRRS) is caused by European (type 1) and North American (type 2) strains of PRRS virus (PRRSV). In the present study, the efficacy of a multi-strain PRRSV vaccine inactivated with binary ethylenimine (BEI) was evaluated in pigs. The vaccine contained one type 1 strain (GCEU0907) and two type 2 strains (GC4019 and GC6262). Three vaccinated groups (four pigs per group) and three mock vaccinated groups (four pigs per group) were challenged with infectious PRRSV (strains GC4019, GC6262 or GCEU0907), then euthanased at 28 days post-infection. Mean anti-PRRSV neutralising antibody titres were significantly higher in the vaccinated groups than in the mock vaccinated groups. Mean blood virus titres in the mock vaccinated groups were significantly higher than those in the vaccinated groups from 5 to 28 days post-infection. On pathological examination, there were less severe macroscopic and microscopic lesions in vaccinated pigs compared with mock vaccinated pigs. PMID- 25920760 TI - Big endothelin-1 as a tumour marker for canine haemangiosarcoma. AB - Haemangiosarcoma (HSA) is an important malignant neoplasm of dogs that originates from vascular endothelial cells. This study explored the suitability of using serum big endothelin-1 (ET-1) as a tumour marker for canine spontaneous HSA. Serum big ET-1 was measured in dogs with splenic HSA (n = 14), splenic malignant tumours other than HSA (n = 10), benign splenic lesions (n = 11) and normal healthy dogs (n = 17) by ELISA. Serum big ET-1 levels in dogs with HSA were significantly (P < 0.01) higher than in other dogs. High sensitivity (100%, 95% confidence interval 86-100%) and specificity (95%, 95% confidence interval 86 95%) for HSA diagnosis were obtained using a cut-off of 17 pg/mL according to receiver operating characteristic (ROC) curves (area under ROC curve 0.93). PPET1, ETA, VEGF and Hif1-alpha mRNA expression, measured by real-time PCR, were elevated in HSA compared with normal tissues. These findings suggest that elevated serum big ET-1 could be used as a diagnostic marker for canine HSA. PMID- 25920761 TI - Evaluation of rapid methods for diagnosis of tuberculosis in slaughtered free range pigs. AB - Free-range pigs can be infected by Mycobacterium tuberculosis complex (MTC) and may contribute to the spread of bovine tuberculosis (bTB). In the present study, the diagnostic values of bacteriological culture, a duplex real-time quantitative PCR and an antibody ELISA were evaluated in an abattoir study of submandibular lymph nodes and serum samples from 73 pigs with and without lesions consistent with bTB. The duplex qPCR was an accurate method for diagnosis of TB in pigs (specificity 100%; sensitivity 80%). Combining qPCR with histopathology improved sensitivity and had very good concordance (kappa = 0.94) with the reference method. Serological results suggest that the antibody ELISA can be used for monitoring herds but not individuals. PMID- 25920762 TI - Energy-related parameters and their association with age, gender, and morphometric measurements in healthy donkeys. AB - Donkeys are commonly afflicted by endocrine and metabolic disturbances but few studies have investigated endocrine variables involved in energy regulation and their association with morphometric indices, age or gender in this species. Hemostatic and clinical differences have been demonstrated between horses and donkeys, so to consider both species as metabolically and endocrinologically similar could lead to misdiagnosis. In this study, plasma concentrations of glucose, triglycerides and endocrine factors involved in energy homeostasis (insulin, glucagon, leptin, adiponectin, ghrelin and insulin-like growth factor [IGF]-1) were measured and their association with morphometric variables (body condition score, neck scoring and body mass index), gender and age was determined in 62 healthy donkeys. In addition, a neck scoring system specific for donkeys was developed. Insulin, glucagon, leptin and IGF-1 concentrations were found to be similar between donkeys and other species, but adiponectin and active ghrelin were lower in donkeys than horses. Donkeys with larger neck scores and body mass indices had higher triglyceride, leptin and IGF-1 concentrations. A sexual dimorphism was observed on all morphometric measurements and plasma glucose concentrations independent of adiposity. Younger animals had lower morphometric measurements and triglyceride and leptin concentrations. PMID- 25920763 TI - Illicit drug use, early age at first use and risk of premenstrual syndrome: A longitudinal study. AB - BACKGROUND: Premenstrual syndrome (PMS) is common among women of reproductive age. Limited studies have investigated the long-term association between illicit drug use and PMS. METHODS: The 1973-1978 cohort from the Australian Longitudinal Study on Women's Health, a prospective cohort study, was followed up for 13-year from 2000 to 2012. Data were collected through self-reported questionnaires on all variables, including PMS, illicit drug use and a range of sociodemographic, lifestyle, reproductive and psychological factors. RESULTS: When the women were 22-27 years of age, over 40% use illicit drug in the last 12 months, 9% first used drug before age 15 years and approximately 35% reported PMS. Over the study period, the prevalence of drug use in the last 12 months declined whereas that of PMS remained fairly stable except an increase when they were 34-39 years old. Generalised estimating equations analysis showed that, compared to never drug users, significantly higher odds of reporting PMS were detected for illicit drug use in the last 12 months: multiple drugs (odds ratio (OR) 1.31, 95% confidence interval (CI) 1.21, 1.43), exclusive marijuana (OR 1.23, 95% CI 1.08, 1.40). A higher odds of PMS was identified for age at first drug use before 15 years (OR 1.20, 95% CI 1.03, 1.40). CONCLUSIONS: Illicit drug use in the last 12 months, especially early age at first use and multiple drug use, is associated with increased risk of PMS. However current study is unable to prove causality. PMID- 25920764 TI - Baseline prevalence and emergence of protease inhibitor resistance mutations following treatment in chronic HCV genotype-1-infected individuals. AB - BACKGROUND: The HCV NS3/4A serine protease inhibitors (PIs) boceprevir (BOC), telaprevir (TVR) and simeprevir (SMV) are approved for treatment of chronic hepatitis C infection in combination with pegylated interferon and ribavirin. The present study investigated the prevalence of HCV NS3 drug resistance mutations (DRMs) associated with HCV genotype-1-infected individuals at baseline and in viral breakthrough following BOC and TVR treatment. METHODS: HCV genotype-1 infected individuals were enrolled in a multicentre, prospective outcomes study. The HCV NS3 viral protease was analysed for DRMs at baseline (n=164) and at viral breakthrough (n=18) following BOC/TVR treatment. RESULTS: Viral NS3 protease subtype analysis showed 65.2% (107/164) were HCV subtype-1a and 34.8% (57/164) were HCV subtype-1b infections. Naturally occurring PI DRMs in NS3 (V36L, T54S, V55A, Q80K/R and I132V) were identified in 57.3% (94/164) cases at baseline. The NS3 Q80K polymorphism was found in 43/107 (40.2%) of HCV subtype-1a and exclusively in clade 1 (43/82; 52.4%) versus clade 2 viruses (0/25; 0%, P<10( 6)). The pretreatment I132V variant was found in 78.9% (45/57) of subtype-1b. Of 18 patients who had viral breakthrough, the majority was subtype-1a (77.8%, 14/18). BOC/TVR-associated DRMs were detected in 94.4% (17/18), of which 64.7% (11/17) emerged on-treatment. CONCLUSIONS: To ensure the most appropriate direct acting antiviral-based treatment regimen is employed, baseline reporting of clade and resistance mutations for HCV subtype-1a using nucleotide sequence-based analysis is warranted prior to commencement of therapy. PMID- 25920765 TI - Cancer stem cells and field cancerization of oral squamous cell carcinoma. AB - Oral squamous cell carcinoma (OSCC) has a high propensity for local failure, which is attributed to recurrence at the primary site or the development of second primary tumors (SPT). Field cancerization that refers to the existence of transformed cells in areas adjacent to the primary tumor, has been attributed to be one of the probable reasons underlying disease relapse. The carcinogenic process necessitates multiple molecular events for the transformation of a normal cell into a cancer cell. This implies that only the long-time residents of the epithelium, such as the stem cells, might be the candidates capable of accumulating these genetic hits. These transformed stem cells- the 'Cancer stem cells' (CSCs), are further known to be equipped with the properties of tumor initiation and migration, both of which are essential for orchestrating field cancerization. The concept that the CSCs might be responsible for field cancerization in OSCC has not been explored extensively. If the role of CSCs as the primary units of field cancerization process is established, their presence in the mucosa adjacent to the tumor may be an indicator for local recurrence and/or development of second primary tumors. In this review, we examine the available evidence in literature exploring the possibilities of CSCs driving the process of field cancerization and thereby being the underlying mechanism for disease recurrence and development of SPT. PMID- 25920766 TI - Custom implants for medialization laryngoplasty: a model that considers tissue compression. AB - OBJECTIVE: Unilateral vocal fold paralysis can be treated with surgical medialization with a carved silastic implant. One challenge to this approach is anticipating the dimensions of the implant for adequate medialization. The purpose of this study was to develop a predictive model for implant design based on a patient's unique laryngeal anatomy and considering compression of the vocal fold. STUDY DESIGN: Retrospective chart review, prospective cadaver study, and prospective patient study. METHODS: A retrospective chart review was performed on patients who received silastic medialization laryngoplasty with favorable outcome and who had preoperative computed tomography. Data including Voice Handicap Index, maximum phonation time, and implant dimensions were collected from medical records, and laryngeal measurements were taken from preoperative imaging. Measurements were taken from computed tomography scans of three cadavers who underwent laryngoplasty for this study. Tissue compression (TC) was calculated and analyzed. A model to predict successful implant dimensions was developed and applied prospectively in 16 patients. RESULTS: Eleven patients from the chart review and three cadavers were included. Of all laryngeal metrics, width of the vocal fold at maximal medialization was most strongly correlated to TC (r = 0.728). Linear regression was performed (y = 0.50x - 1.2, R(2) = 0.53, P = 0.005, F = 12.39). Of the prospective patients, 15 of 16 demonstrated complete glottis closure with the premeasured silastic implant. CONCLUSIONS: Vocal fold compression by silastic implants is linearly correlated with vocal fold-width at maximal medialization. A predictive formula was generated to anticipate TC and was successful in designing custom implants for patients. PMID- 25920767 TI - The biocompatibility and anti-biofouling properties of magnetic core-multishell Fe@C NWs-AAO nanocomposites. AB - Soft-magnetic core-multishell Fe@C NWs-AAO nanocomposites were synthesized using anodization, electrodeposition and low-pressure chemical vapour deposition (CVD) at 900 degrees C. High chemical and mechanical stability is achieved by the conversion from amorphous to theta- and delta-Al2O3 phases above 600 degrees C. Moreover, the surface properties of the material evolve from bioactive, for porous AAO, to bioinert, for Fe@C NW filled AAO nanocomposite. Although the latter is not cytotoxic, cells do not adhere onto the surface of the magnetic nanocomposite, thus proving its anti-biofouling character. PMID- 25920768 TI - Myofiber damage precedes macrophage infiltration after in vivo injury in dysferlin-deficient A/J mouse skeletal muscle. AB - Mutations in the dysferlin gene (DYSF) lead to human muscular dystrophies known as dysferlinopathies. The dysferlin-deficient A/J mouse develops a mild myopathy after 6 months of age, and when younger models the subclinical phase of the human disease. We subjected the tibialis anterior muscle of 3- to 4-month-old A/J mice to in vivo large-strain injury (LSI) from lengthening contractions and studied the progression of torque loss, myofiber damage, and inflammation afterward. We report that myofiber damage in A/J mice occurs before inflammatory cell infiltration. Peak edema and inflammation, monitored by magnetic resonance imaging and by immunofluorescence labeling of neutrophils and macrophages, respectively, develop 24 to 72 hours after LSI, well after the appearance of damaged myofibers. Cytokine profiles 72 hours after injury are consistent with extensive macrophage infiltration. Dysferlin-sufficient A/WySnJ mice show much less myofiber damage and inflammation and lesser cytokine levels after LSI than do A/J mice. Partial suppression of macrophage infiltration by systemic administration of clodronate-incorporated liposomes fails to suppress LSI-induced damage or to accelerate torque recovery in A/J mice. The findings from our studies suggest that, although macrophage infiltration is prominent in dysferlin deficient A/J muscle after LSI, it is the consequence and not the cause of progressive myofiber damage. PMID- 25920769 TI - Secreted phospholipase A2 inhibitor modulates fatty acid composition and reduces obesity-induced inflammation in Beagle dogs. AB - Secreted phospholipase A2 inhibitor (sPLA2i) has been reported to have an anti inflammatory function by blocking the production of inflammatory mediators. Obesity is characterized by low-grade inflammation and oxidative stress. The aim of this study was to investigate the effects of dietary supplementation of sPLA2i on inflammation, oxidative stress and serum fatty acid profile in dogs. Seven obese and seven lean Beagle dogs were used in a 28-day double blind cross-over design. Dogs were fed a control diet without supplemental sPLA2i or an sPLA2i supplemented diet. The sPLA2i diet decreased plasma fibrinogen levels and increased the protein:fibrinogen ratio in obese dogs to levels similar to those of lean dogs fed the same diet. Obese dogs had a higher plasma concentration of the lipophilic vitamin A with potential antioxidative capacity and a lower ratio of retinol binding protein 4:vitamin A compared to lean dogs, independent of the diets. A higher proportion of myristic acid (C14:0) and a lower proportion of linoleic acid (C18:2n-6) were observed in the dogs fed with the sPLA2i diet compared to dogs fed with the control diet. Furthermore, a higher ratio of n-6 to n-3, a lower proportion of n-3 polyunsaturated fatty acids and lower omega-3 index were observed in obese compared to lean dogs. The results indicate that obese dogs are characterized by a more 'proinflammatory' serum fatty acid profile and that diet inclusion of sPLA2i may reduce inflammation and alter fatty acid profile. PMID- 25920770 TI - Influence of clinical and laboratory variables on faecal antigen ELISA results in dogs with canine parvovirus infection. AB - False negative faecal canine parvovirus (CPV) antigen ELISA results in dogs with CPV infection are common, but the factors that lead to these false negative results are still unknown. The aim of this study was to investigate whether dogs with a false negative faecal CPV antigen ELISA result have milder clinical signs and laboratory changes, a lower faecal virus load, higher faecal and serum CPV antibody titres and a faster recovery than dogs with a positive result. Eighty dogs with CPV infection, confirmed by the presence of clinical signs and a positive faecal CPV polymerase chain reaction (PCR), were assigned to two groups according to their faecal antigen ELISA result. Time until presentation, severity of symptoms, laboratory parameters, faecal virus load, faecal and serum antibody titres, and CPV sequencing data were compared between both groups. In 38/80 dogs that were hospitalised until recovery, the time to recovery, mortality, and the course of the disease were compared between dogs with positive and negative faecal antigen ELISA results. Of the 80 dogs included, 41 (51.3%) had a false negative faecal antigen ELISA result. ELISA-negative dogs had a significantly shorter time until presentation, lower frequency of defaecation, lower faecal virus load, and higher serum antibody concentrations than ELISA-positive dogs. Laboratory changes, CPV shedding, and outcomes were not associated with faecal antigen ELISA results. In conclusion, low faecal CPV load and antibodies binding to CPV antigen in faeces are likely to be important reasons for false negative faecal antigen ELISA results. Dogs with clinical signs of CPV infection should be retested by faecal PCR. PMID- 25920771 TI - Accuracy of different oxygenation indices in estimating intrapulmonary shunting at increasing infusion rates of dobutamine in horses under general anaesthesia. AB - The aim of this study was to evaluate the correlation of commonly used oxygenation indices with venous admixture (Qs/Qt) in anaesthetised horses under different infusion rates of dobutamine. Six female horses were anaesthetised with acepromazine, xylazine, diazepam, ketamine, and isoflurane, and then intubated and mechanically ventilated with 100% O2. A Swan-Ganz catheter was introduced into the left jugular vein and its tip advanced into the pulmonary artery. Horses received different standardised rates of dobutamine. For each horse, eight samples of arterial and mixed venous blood were simultaneously obtained at fixed times. Arterial and venous haemoglobin (Hb) concentration and O2 saturation, arterial oxygen partial pressure (PaO2), venous oxygen partial pressure (PvO2), and barometric pressure were measured. Arterial (CaO2), mixed venous (CvO2), and capillary (Cc'O2) oxygen contents were calculated using standard formulae. The correlations between F-shunt, arterial oxygen tension to fraction of inspired oxygen ratio (PaO2/FiO2), arterial to alveolar oxygen tension ratio (PaO2/PAO2), alveolar to arterial oxygen tension difference (P[A - a]O2), and respiratory index (P[A - a]O2/PaO2) were tested with linear regression analysis. The goodness of-fit for each calculated formula was evaluated by means of the coefficient of determination (r(2)). The agreement between Qs/Qt and F-shunt was analysed with the Bland-Altman test. All tested oxygen tension-based indices were weakly correlated (r(2) < 0.2) with the Qs/Qt, whereas F-shunt showed a stronger correlation (r(2) = 0.73). F-shunt also showed substantial agreement with Qs/Qt independent of the dobutamine infusion rate. F-shunt better correlated with Qs/Qt than other oxygen indices in isoflurane-anaesthetised horses under different infusion rates of dobutamine. PMID- 25920772 TI - Increased bone morphogenetic protein 7 signalling in the kidneys of dogs affected with a congenital portosystemic shunt. AB - Dogs with a congenital portosystemic shunt (CPSS) often have enlarged and hyper filtrating kidneys. Although expression of different growth factors has been well described in the livers of dogs affected with a CPSS, their expression in the kidneys has yet to be determined. Bone morphogenetic protein 7 (BMP-7), hepatocyte growth factor (HGF) and transforming growth factor (TGF)-beta have been implicated in renal development (BMP-7, HGF) or the onset of renal fibrosis (TGF-beta). Moreover, BMP-7 and HGF have protective properties in renal fibrosis. In this study, the expression and activity of BMP-7 were investigated in renal biopsies obtained from 13 dogs affected with a CPSS and compared to similar samples from age-matched healthy control dogs. Both quantitative reverse transcriptase PCR and Western blotting showed up-regulated BMP-7 signalling in kidneys of CPPS-affected dogs. These research findings may help to explain the renal pathology/dysfunction in dogs affected with a CPSS. PMID- 25920773 TI - Visceral abdominal fat accumulation predicts the conversion of metabolically healthy obese subjects to an unhealthy phenotype. AB - BACKGROUND: A proportion of obese subjects appear metabolically healthy (MHO) but little is known about the natural history of MHO and factors predicting its future conversion to metabolically unhealthy obese (MUO). OBJECTIVES: The aim was to determine prospectively the frequency of conversion of MHO to MUO and the clinical variables that independently predicted this conversion, with a particular focus on the role of body composition. METHODS: We identified 85 Japanese Americans with MHO (56 men, 29 women), aged 34-73 years (mean age 49.8 years) who were followed at 2.5, 5 and 10 years after enrollment with measurements of metabolic characteristics, lifestyle and abdominal and thigh fat areas measured by computed tomography. Obesity was defined using the Asian body mass index criterion of ?25 kg m(-2). Metabolically healthy was defined as the presence of ?2 of 5 metabolic syndrome components proposed by the National Cholesterol Education Program Adult Treatment Panel III, while metabolically unhealthy was defined as ?3 components. RESULTS: Over 10 years of follow-up, 55 MHO individuals (64.7%) converted to MUO. Statistically significant univariate predictors of conversion included dyslipidemia, greater insulin resistance and greater visceral abdominal (VAT) and subcutaneous abdominal fat area (SAT). In multivariate analysis, VAT (odds ratio per 1-s.d. increment (95% confidence interval) 2.04 (1.11-3.72), P=0.021), high-density lipoprotein (HDL) cholesterol (0.24 (0.11-0.53), P<0.001), fasting plasma insulin (2.45 (1.07-5.62), P=0.034) and female sex (5.37 (1.14-25.27), P=0.033) were significantly associated with future conversion to MUO. However, SAT was not an independent predictor for future conversion to MUO. CONCLUSIONS: In this population, MHO was a transient state, with nearly two-thirds developing MUO over 10 years, with higher conversion to MUO independently associated with VAT, female sex, higher fasting insulin level and lower baseline HDL cholesterol level. PMID- 25920774 TI - Effect of lifestyle weight loss intervention on disease severity in patients with psoriasis: a systematic review and meta-analysis. AB - BACKGROUND: Psoriasis is a chronic inflammatory disease of the skin with joint manifestations. Greater psoriasis severity and lower response to treatment have been linked to obesity. However, the effect of weight reduction by non pharmacologic intervention on disease severity is still questionable. This is a systematic review and meta-analysis of randomized controlled trials (RCTs) on the effect of dietary and lifestyle weight loss interventions on psoriasis severity. METHODS: We comprehensively searched PubMed/MEDLINE, EMBASE and CENTRAL from their inception to August 2014. Inclusion criteria were RCTs that examined lifestyle intervention by diet or exercise in overweight or obese patients with psoriasis and measured the severity of psoriasis as an outcome compared with controls. Two authors independently assessed article quality and extracted the data. RESULTS: Out of 12 full-text articles, 7 RCTs involving 878 participants met our inclusion criteria. Five of these RCTs were included in the meta analysis, which was based on the random-effects model. There was a greater reduction in the Psoriasis Area Severity Index (PASI) score in patients receiving weight loss intervention than in controls, with a pooled mean difference of -2.49 (95% confidence interval (CI), -3.90 to -1.08; P=0.004). More participants in the intervention group than in the control group achieved a 75% reduction in the PASI score, with a pooled odds ratio of 2.92 (95% CI, 1.39-6.13; P=0.005). CONCLUSION: Nonpharmacologic, nonsurgical weight loss intervention is associated with reduction in the severity of psoriasis in overweight or obese patients. However, more RCTs with more participants are needed to provide better quality of evidence. PMID- 25920775 TI - Cross-sectional population associations between detailed adiposity measures and C reactive protein levels at age 6 years: the Generation R Study. AB - OBJECTIVES: High body mass index is associated with increased C-reactive protein levels in childhood and adulthood. Little is known about the associations of detailed adiposity measures with C-reactive protein levels in childhood. We examined the associations of general and abdominal adiposity measures with C reactive protein levels at school age. To gain insight into the direction of causality, we used genetic risk scores based on known genetic variants in adults as proxies for child adiposity measures and C-reactive protein levels. METHODS: Within a population-based cohort study among 4338 children at the median age of 6.2 years, we measured body mass index, fat mass percentage, android/gynoid fat mass ratio and preperitoneal abdominal fat mass. We also measured C-reactive protein blood levels and defined increased levels as ?3.0 mg l(-1). Single nucleotide polymorphisms (SNPs) for the weighted genetic risk scores were extracted from large genome-wide association studies on adult body mass index, waist-hip ratio and C-reactive protein levels. RESULTS: All fat mass measures were associated with increased C-reactive protein levels, even after adjusting for multiple confounders. Fat mass percentage was most strongly associated with increased C-reactive protein levels (odds ratio 1.46 (95% confidence interval 1.30-1.65) per increase standard deviation scores in fat mass percentage). The association was independent of body mass index. The genetic risk score based on adult body mass index SNPs, but not adult waist-hip ratio SNPs, tended to be associated with increased C-reactive protein levels at school age. The genetic risk score based on adult C-reactive protein level SNPs was not associated with adiposity measures at school age. CONCLUSION: Our results suggest that higher general and abdominal fat mass may lead to increased C-reactive protein levels at school age. Further studies are needed to replicate these results and explore the causality and long-term consequences. PMID- 25920776 TI - Targeted inhibition of galectin 1 by thiodigalactoside dramatically reduces body weight gain in diet-induced obese rats. AB - BACKGROUND: Galectin 1 (GAL1), an animal lectin is well characterized in the context of cancer, tumor environment, but its physiological roles in obesity remain to be demonstrated. In this study, we investigated whether targeted inhibition of GAL1 prevents obesity based on the previous observations that GAL1 is highly expressed in adipose tissues of high-fat diet (HFD)-induced obese rats. METHODS: Lipogenic capacity of Lgals1 knocked down adipocytes was evaluated by determining the expression levels of major lipogenic markers using real-time PCR and immunoblot analysis. GAL1 partner proteins were identified using co immunoprecipitation followed by protein mass fingerprinting. Finally, inhibitory effect of GAL1 by thiodigalactoside (TDG) was assessed in adipocytes and HFD induced obese rats. RESULTS: Knockdown of GAL1-encoding gene (Lgals1) attenuated adipogenesis and lipogenesis in both 3T3-L1 and HIB1B adipocytes. Further, direct treatment with TDG, a potent inhibitor of GAL1, to cultured adipocytes in vitro significantly reduced fat accumulation. Our animal experiment revealed that intraperitoneal injection of TDG (5 mg kg(-1)) once per week for 5 weeks in Sprague-Dawley (SD) rats resulted in dramatic inhibition of HFD-induced body weight gain (27.3% reduction compared with HFD-fed controls) by inhibiting adipogenesis and lipogensis as well as by increasing expression of the proteins associated with thermogenesis and energy expenditure. CONCLUSION: GAL1 has an essential role in HFD-induced obesity development. From a clinical viewpoint, pharmaceutical targeting of GAL1 using TDG and other inhibitor compounds would be a novel therapeutic approach for the treatment of obesity. PMID- 25920777 TI - A percutaneous needle biopsy technique for sampling the supraclavicular brown adipose tissue depot of humans. AB - Brown adipose tissue (BAT) has been proposed as a potential target tissue against obesity and its related metabolic complications. Although the molecular and functional characteristics of BAT have been intensively studied in rodents, only a few studies have used human BAT specimens due to the difficulty of sampling human BAT deposits. We established a novel positron emission tomography and computed tomography-guided Bergstrom needle biopsy technique to acquire human BAT specimens from the supraclavicular area in human subjects. Forty-three biopsies were performed on 23 participants. The procedure was tolerated well by the majority of participants. No major complications were noted. Numbness (9.6%) and hematoma (2.3%) were the two minor complications noted, which fully resolved. Thus, the proposed biopsy technique can be considered safe with only minimal risk of adverse events. Adoption of the proposed method is expected to increase the sampling of the supraclavicular BAT depot for research purposes so as to augment the scientific knowledge of the biology of human BAT. PMID- 25920778 TI - The optimisation of electrokinetic remediation for heavy metals and radioactivity contamination on Holyrood-Lunas soil (acrisol species) in Sri Gading Industrial Area, Batu Pahat, Johor, Malaysia. AB - The optimisation of electrokinetic remediation of an alluvial soil, locally named as Holyrood-Lunas from Sri Gading Industrial Area, Batu Pahat, Johor, Malaysia, had been conducted in this research. This particular soil was chosen due to its relatively high level of background radiation in a range between 139.2 and 539.4 nGy h(-1). As the background radiation is correlated to the amount of parent nuclides, (238)U and (232)Th, hence, a remediation technique, such as electrokinetic, is very useful in reducing these particular concentrations of heavy metal and radionuclides in soils. Several series of electrokinetics experiments were performed in laboratory scale in order to study the influence of certain electrokinetic parameters in soil. The concentration before (pre electrokinetic) and after the experiment (post-electrokinetic) was determined via X-ray fluorescence (XRF) analysis technique. The best electrokinetic parameter that contributed to the highest achievable concentration removal of heavy metals and radionuclides on each experimental series was incorporated into a final electrokinetic experiment. Here, High Pure Germanium (HPGe) was used for radioactivity elemental analysis. The XRF results suggested that the most optimised electrokinetic parameters for Cr, Ni, Zn, As, Pb, Th and U were 3.0 h, 90 volts, 22.0 cm, plate-shaped electrode by 8 * 8 cm and in 1-D configuration order whereas the selected optimised electrokinetic parameters gave very low reduction of (238)U and (232)Th at 0.23 +/- 2.64 and 2.74 +/- 23.78 ppm, respectively. PMID- 25920779 TI - Preparation and characterisation of ceramic-based thoron sources for thoron calibration chamber. AB - The aim of this study is to explore the correlations between the properties of the source's material and the thoron flux produced. This means a complex procedure that involves morphological characterisation (the determination of specific surface area and pore size distribution) and thoron emanation and exhalation measurements as well. In this work, the preparation of 27 thoron sources has been carried out. Three types of ceramics with different morphological properties were used as a matrix material with three different thorium contents. Spheres were formed from the dollop, and they were fired at different temperatures (200, 600 and 900 degrees C). The phase analysis of the samples was performed by powder X-ray diffraction. The pore size distribution was determined by mercury penetration. The thoron emanation was measured using an accumulation chamber; the measured thoron emanation coefficients were from 0.34 +/- 0.03 to 7.69 +/- 0.13 %. Based on the results, the preparation parameters of the thoron source optimised for the calibration procedure have been given. PMID- 25920780 TI - Radon in underground waters as a natural analogue to study the escape of CO2 in geological repositories. AB - Activity concentrations of dissolved (222)Rn and (226)Ra were measured in several underground aquifers, which are candidates for repositories or for the study of analogue natural escapes of CO2. The concentration of both radionuclides in water was determined using liquid scintillation counting. The values obtained for the (222)Rn concentrations varied from 0 to 150 Bq l(-1), while the levels of (226)Ra were in general very low. This indicates that (222)Rn is coming from the decay of the undissolved (226)Ra existing in the rocks and deep layers of the aquifers, being later transported by diffusion in water. PMID- 25920781 TI - Systematic approach to characterisation of NORM in Thailand. AB - The aim of this article is to provide information on the systematic approach that has been developed for the measurement of natural radiation exposure and the characterisation of naturally occurring radioactive materials (NORM) in terms of occurrence and distribution in various industrial processes, including the produced waste from the mineral industries in Thailand. The approach can be adapted for various types of study areas. The importance of collaboration among research institutions is discussed. Some developments include 25 documents; the redesign of the field equipment, such as the gamma survey meter, for convenient access to conduct measurement in various study areas; the method to collect and analyse radon gas from a natural gas pipeline and the manganese dioxide fibre to adsorb radium on-site for laboratory analysis. The NORM project in Thailand has been carried out for more than 10 y to support the development of NORM regulation in Thailand. In the previous studies as well as current, international standards for action levels have been adopted for safety purpose. PMID- 25920782 TI - Quantitative evaluation of 218Po behaviour in air in an artificial environment. AB - Experiments were carried out in a small enclosed booth for the purpose of understanding and modelling (218)Po behaviour. The experiment was conducted under two kinds of conditions without and with injection of incense smoke. A working model of (218)Po behaviour was applied to analyse the measured data. Under the condition without incense smoke, temporal changes in aerosol-attached and unattached (218)Po concentrations were successfully reproduced by the model. The deposition rate of unattached fraction and the rate of attachment were determined by the working model. Under the condition with incense smoke, temporal changes in (218)Po concentration were poorly simulated by the model. This can be attributed to the significantly increased aerosol concentration in small size ranges which is not properly considered in the attachment rate calculation in the model. PMID- 25920783 TI - Natural radioactivity and radon exhalation rates in man-made tiles used as building materials in Japan. AB - Man-made tiles frequently used in Japan were collected, and activity concentrations and radon ((222)Rn) exhalation rates in these tiles were measured. Dose estimations for inhabitants living in houses built using these tiles were also carried out. The activity concentrations of (226)Ra, (228)Ra and (40)K in the man-made tiles were 31-170, 35-110 and 260-980 Bq kg(-1), respectively. The (222)Rn exhalation rates in the tiles were 8.8-21 MUBq m(-2) s(-1). The ranges of experimental activity concentrations and (222)Rn exhalation rates were almost identical to those of natural rocks used as typical building materials in Japan. The maximum value of effective dose to inhabitants living in houses built with the man-made tiles was 0.14 mSv y(-1), which is lower than the reference level range (1-20 mSv y(-1)) for abnormally high levels of natural background radiation published in the ICRP Publication 103. PMID- 25920784 TI - An improved electrostatic integrating radon monitor with the CR-39 as alpha particle detector. AB - In this study, based on the electrostatic integrating radon monitor (EIRM) developed by Iida et al., a new type of EIRM with the allyl glycol carbonate (CR 39) as alpha-particle detector was developed for outdoor radon measurements. Besides using the CR-39 to replace the cellulose nitrate film as alpha-particle detector, the electrode and the setting place of the CR-39 were also optimally designed based on the simulation results of the electric field and the detection efficiency. The calibration factor of the new EIRM was estimated to be 0.136+/ 0.002 tracks cm(-2) (Bq m(-3) h)(-1), with the lower detection limit of 0.6 Bq m( 3) for a 2-month exposure. Furthermore, both the battery and the dry agent were also replaced to protect the environment. The results of intercomparison and field experiments showed that the performances of the new EIRM were much better than the original one. It suggests that the new type of ERIM is more suitable for large-scale and long-term outdoor radon surveys. PMID- 25920785 TI - Comparative study of various techniques for environmental radon, thoron and progeny measurements. AB - Long-term average concentrations of radon, thoron and progeny were measured in normal and high background radiation areas in India using different techniques. Radon, thoron and progeny concentrations were measured using Raduet, Pin-Hole dosimeter, deposition-based CR-39 and deposition-based direct radon/thoron progeny sensor (DRPS/DTPS) detector system. All these techniques were used at a same time inside an individual dwelling. Radon concentration was recorded higher than thoron concentration in Garhwal Homes (NBRA) while thoron concentration was found relatively higher in the houses of Chhatarpur area (HBRA) in Odisha, India. The values measured with the CR-39 detector-based technique were found comparable with the values measured with the LR-115 detector-based technique. The comparisons of results using various techniques and their usefulness in radiation measurements are discussed in detail. PMID- 25920786 TI - Soil features and indoor radon concentration prediction: radon in soil gas, pedology, permeability and 226Ra content. AB - This work aims at relating some physicochemical features of soils and their use as a tool for prediction of indoor radon concentrations of the Metropolitan Region of Belo Horizonte (RMBH), Minas Gerais, Brazil. The measurements of soil gas radon concentrations were performed by using an AlphaGUARD monitor. The (226)Ra content analysis was performed by gamma spectrometry (high pure germanium) and permeabilities were performed by using the RADON-JOK permeameter. The GEORP indicator and soil radon index (RI) were also calculated. Approximately 53 % of the Perferric Red Latosols measurement site could be classified as 'high risk' (Swedish criteria). The Litholic Neosols presented the lowest radon concentration mean in soil gas. The Perferric Red Latosols presented significantly high radon concentration mean in soil gas (60.6 +/- 8.7 kBq m(-3)), high indoor radon concentration, high RI, (226)Ra content and GEORP. The preliminary results may indicate an influence of iron formations present very close to the Perferric Red Latosols in the retention of uranium minerals. PMID- 25920787 TI - Estimation of the front-to-total activity ratio for wire screens using CFD simulation. AB - Wire screens are widely used for sampling radioactive aerosols. The front-to total activity ratio is a critical factor in describing the self-shielding effect of the wire screens. In this study, computational fluid dynamic method was applied to simulate the deposition of aerosols on the surface of the wire screens. Four different types of screens were investigated for particle size varying from 1 nm to 10 um. Experimental verification was carried out in a radon chamber. The results showed good agreement between experimental data interception and the simulation. Significant differences on the front-to-total activity ratio for the different types of screens were observed when the size of particle was <20 nm. PMID- 25920788 TI - Estimation of radon emanation coefficient for representative soils in Okinawa, Japan. AB - Radon ((222)Rn) emanation coefficients for the representative soils distributed in Okinawa Island, Japan, have been estimated empirically. Arithmetic means of the emanation coefficients for dry and moist conditions were calculated to be 0.19 and 0.29, respectively. In Okinawa, the soils are traditionally classified into three types, namely the dark red soils, the residual regosols and the red and yellow soils. The dark red soils have relatively high coefficients. The residual regosols and the red and yellow soils have relatively low coefficients. To investigate the variable factor of the emanation coefficients, analyses of radioactive elements and physical properties have also been performed on the soils. For the dark red soils, the contents of the fine particle and the (226)Ra are relatively higher than those for the other soils. Based on these results, it is suggested that the variation in the radon emanation coefficient is mainly regulated by the (226)Ra concentration, the particle sizes and the water contents of the soils. PMID- 25920789 TI - From cellular doses to average lung dose. AB - Sensitive basal and secretory cells receive a wide range of doses in human bronchial and bronchiolar airways. Variations of cellular doses arise from the location of target cells in the bronchial epithelium of a given airway and the asymmetry and variability of airway dimensions of the lung among airways in a given airway generation and among bronchial and bronchiolar airway generations. To derive a single value for the average lung dose which can be related to epidemiologically observed lung cancer risk, appropriate weighting scenarios have to be applied. Potential biological weighting parameters are the relative frequency of target cells, the number of progenitor cells, the contribution of dose enhancement at airway bifurcations, the promotional effect of cigarette smoking and, finally, the application of appropriate regional apportionment factors. Depending on the choice of weighting parameters, detriment-weighted average lung doses can vary by a factor of up to 4 for given radon progeny exposure conditions. PMID- 25920790 TI - Measurements of radon and thoron progeny concentrations in dwellings of Tehri Garhwal, India, using LR-115 deposition-based DTPS/DRPS technique. AB - This paper presents the values of radon and thoron progeny concentrations for different seasons in the dwellings of Tehri Garhwal, India. The measurements have been carried out using LR-115 solid-state nuclear track detector-based passive time-integrated direct thoron progeny sensor/direct radon progeny sensor technique. In summer, the radon and thoron progeny have been found to vary from 5.7+/-0.8 to 153.2+/-4.3 Bq m(-3) with an average of 37.6 Bq m(-3) and 0.3+/-0.06 to 3.2+/-0.19 Bq m(-3) with an average of 1.3 Bq m(-3), respectively. In the rainy season, the radon and thoron progeny have been found to vary from 3.2+/-0.6 to 120+/-3.7 Bq m(-3) with an average of 58.2 Bq m(-3) and 0.2+/-0.05 to 11.3+/ 0.37 Bq m(-3) with an average of 3.4 Bq m(-3), respectively. In autumn, the radon and thoron progeny have been found to vary from 4.1+/-0.7 to 374.4+/-6.7 Bq m(-3) with an average of 95.6 Bq m(-3) and from 0.3+/-0.06 to 30.5+/-0.60 Bq m(-3) with an average of 6.6 Bq m(-3), respectively. In winter, the radon and thoron progeny have been found to vary from 9.8+/-1.1 to 188.9+/-4.8 Bq m(-3) with an average of 70.7 Bq m(-3) and 0.1+/-0.03 to 7.5+/-0.30 Bq m(-3) with an average of 2.3 Bq m( 3), respectively. It has been observed that the average value of radon and thoron progeny concentrations is maximum for autumn and minimum for summer seasons. The seasonal variations in radon and thoron progeny concentrations in different houses are discussed in detail. PMID- 25920791 TI - Status of the European Atlas of Natural Radiation. AB - According to the EURATOM (European Atomic Energy Community) Treaty, one of the missions of the Joint Research Centre (JRC) of the European Commission (EC) is to collect, process, evaluate and present data on environmental radioactivity. In 2006, the JRC started the 'European Atlas of Natural Radiation' project, in order to give an overview of the geographic distribution of sources of, and exposures to, natural radiation. As a first task, a map of indoor radon concentration was created, because in most cases this is the most important contribution to exposure, and since it could be expected that data collection would take quite some time, because radon (Rn) surveys are very differently advanced between European countries. The authors show the latest status of this map. A technically more ambitious map proved the one of the geogenic Rn potential (RP), due to heterogeneity of data sources across Europe and the need to develop models to estimate a harmonised quantity which adequately measures or classifies the RP. Further maps currently in the making include those of secondary cosmic radiation, of terrestrial gamma radiation and of the concentrations of the elements U, Th and K that are its source. In this article, the authors show the progress of some of these maps. PMID- 25920792 TI - Estimation of annual effective dose due to radon and thoron concentrations in mud dwellings of Mrima Hill, Kenya. AB - This study presents radon and thoron concentration measurements and the corresponding effective dose rates in mud dwellings located in the high background radiation area of Mrima Hill, Kenya. Discriminative technique was used for simultaneous measurement of radon and thoron. The effective dose was evaluated based on the concentration of the isotopes and the time spent indoors. Radon concentration ranged from 16 to 56 Bq m(-3) with an average of 35+/-14 Bq m(-3) and a corresponding annual effective dose of 0.67 mSv y(-1), while that of thoron ranged from 132 to 1295 Bq m(-3) with an average of 652+/-397 Bq m(-3) and an effective dose of 13.7 mSv y(-1). PMID- 25920793 TI - An investigation of the potential causes for the seasonal and annual variations in indoor radon concentrations. AB - Indoor radon concentrations exhibit strong variations on short and long timescales. Besides human influences, meteorological factors significantly affect the radon concentrations indoors as well as outdoors. In this article, long-term measurements showing strong annual variations are presented, which take a very similar course in different buildings located in largely separated regions in Switzerland. Also, seasonal variations can be very significant. In general, variations in indoor radon levels can primarily be attributed to human influences. On the other hand, specific weather conditions can have a significant impact on indoor radon levels. In order to further investigate the connection between indoor radon levels and meteorological factors, a measuring campaign has been started in two buildings located in two different regions in Switzerland exhibiting different climatic characteristics. Preliminary results of these investigations are presented, which provide evidence for correlations between indoor radon levels and in particular outdoor temperatures, contributing to seasonal and annual as well as short-term variations in indoor radon concentrations. PMID- 25920794 TI - Characteristics of indoor radon and its progeny in a Japanese dwelling while using air appliances. AB - Characteristics of radon and its progeny were investigated in different air conditions by turning four types of indoor air appliances on and off in a two story concrete Japanese dwelling. The four appliances were air conditioner, air cleaner, gas heater and cooker hood. The measurements were done using two devices: (1) a Si-based semiconductor detector for continuous measurement of indoor radon concentration and (2) a ZnS(Ag) scintillation counting system for equilibrium-equivalent radon concentration. Throughout the entire experiment, the cooker hood was the most effective in decreasing indoor radon concentration over a long period of time and the less effective was the air conditioner, while the air cleaner and gas heater did not affect the concentration of radon. However, the results measured in each air condition will differ according to the lifestyles and activities of the inhabitants. In this study, indoor radon and its progeny in a Japanese dwelling will be characterised by the different air conditions. PMID- 25920795 TI - Study on peak shape fitting method in radon progeny measurement. AB - Alpha spectrum measurement is one of the most important methods to measure radon progeny concentration in environment. However, the accuracy of this method is affected by the peak tailing due to the energy losses of alpha particles. This article presents a peak shape fitting method that can overcome the peak tailing problem in most situations. On a typical measured alpha spectrum curve, consecutive peaks overlap even their energies are not close to each other, and it is difficult to calculate the exact count of each peak. The peak shape fitting method uses combination of Gaussian and exponential functions, which can depict features of those peaks, to fit the measured curve. It can provide net counts of each peak explicitly, which was used in the Kerr method of calculation procedure for radon progeny concentration measurement. The results show that the fitting curve fits well with the measured curve, and the influence of the peak tailing is reduced. The method was further validated by the agreement between radon equilibrium equivalent concentration based on this method and the measured values of some commercial radon monitors, such as EQF3220 and WLx. In addition, this method improves the accuracy of individual radon progeny concentration measurement. Especially for the (218)Po peak, after eliminating the peak tailing influence, the calculated result of (218)Po concentration has been reduced by 21 %. PMID- 25920796 TI - Developmental roles of protein N-terminal acetylation. AB - Discovered more than 50 years ago, N-terminal acetylation (N-Ac) is one of the most common protein modifications. Catalyzed by different N-terminal acetyltransferases (NATs), N-Ac was originally believed to mostly promote protein stability. However, several functional consequences at substrate level were recently described that yielded important new insights about the distinct molecular functions for this modification. The ubiquitous and apparent irreversible nature of this protein modification leads to the assumption that N Ac mostly executes constitutive functions. In spite of the large number of substrates for each NAT, recent studies in multicellular organisms have nevertheless indicated very specific phenotypes after NAT loss. This raises the hypothesis that in vivo N-Ac is only functionally rate limiting for a small subset of substrates. In this review, we will discuss the function of N-Ac in the context of a developing organism. We will propose that some rate limiting NAT substrates may be tissue-specific leading to differential functions of N-Ac during development of multicellular organisms. Moreover, we will also propose the existence of tissue and developmental-specific mechanisms that differentially regulate N-Ac. PMID- 25920798 TI - Numerous Howell-Jolly bodies in a patient with idiopathic splenic calcification. PMID- 25920799 TI - Utilizing mHealth methods to identify patterns of high risk illicit drug use. AB - INTRODUCTION: We assessed patterns of illicit drug use using mobile health (mHealth) methods and subsequent health care indicators among drug users in Baltimore, MD. METHODS: Participants of the EXposure Assessment in Current Time (EXACT) study were provided a mobile device for assessment of their daily drug use (heroin, cocaine or both), mood and social context for 30 days from November 2008 through May 2013. Real-time, self-reported drug use events were summed for individuals by day. Drug use risk was assessed through growth mixture modeling. Latent class regression examined the association of mHealth-defined risk groups with indicators of healthcare access and utilization. RESULTS: 109 participants were a median of 48.5 years old, 90% African American, 52% male and 59% HIV infected. Growth mixture modeling identified three distinct classes: low intensity drug use (25%), moderate intensity drug use (65%) and high intensity drug use (10%). Compared to low intensity drug users, high intensity users were younger, injected greater than once per day, and shared needles. At the subsequent study visit, high intensity drug users were nine times less likely to be medically insured (adjusted OR: 0.10, 95%CI: 0.01-0.88) and at greater risk for failing to attend any outpatient appointments (aOR: 0.13, 95%CI: 0.02-0.85) relative to low intensity drug users. CONCLUSIONS: Real-time assessment of drug use and novel methods of describing sub-classes of drug users uncovered individuals with higher-risk behavior who were poorly utilizing healthcare services. mHealth holds promise for identifying individuals engaging in high-risk behaviors and delivering real-time interventions to improve care outcomes. PMID- 25920800 TI - Prevalence of depressive symptoms and associated factors among people who inject drugs in China. AB - BACKGROUND: People who inject drugs (PWID) have a high prevalence of mental health problems (e.g., depression) which compromise the effects of HIV prevention. We investigated the prevalence of depression and associated factors among PWID in Dazhou, China. METHODS: Anonymous face-to-face interviews were administered to eligible participants by well-trained doctors. The Center of Epidemiological Studies Depression Scale (CES-D) was used to measure depression, using hierarchical linear regression models. RESULTS: Among the 257 participants, 7.0%, 11.3%, and 75.1% were probable cases of mild (16 <= CES-D < 21), moderate (21 <= CES-D < 25), and severe (CES-D >= 25) depression, respectively. Hopefulness (standardized beta = -0.34, p < 0.001) and emotional family support (beta = -0.21, p < 0.001) were negatively associated, whereas severity of drug dependence (beta = 0.12, p = 0.034) and unmet service needs (beta = 0.20, p < 0.001) were positively associated, respectively, with CES-D scores. The adjusted analysis showed that resilience was negatively associated with CES-D, but it was not selected by the stepwise model containing hopefulness and emotional family support. Protective factors (i.e., hopefulness and emotional family support) and risk factors (i.e., severity of drug dependence and unmet service needs) remained significant in the same regression model. CONCLUSION: Protective and risk factors were independently associated with depressive symptoms. Integrated interventions covering basic and psychosocial needs for PWID are warranted. Such interventions should strengthen emotional family support and cultivate positive factors such as hopefulness. PMID- 25920797 TI - Cell intrinsic and extrinsic activators of the unfolded protein response in cancer: Mechanisms and targets for therapy. AB - A variety of cell intrinsic or extrinsic stresses evoke perturbations in the folding environment of the endoplasmic reticulum (ER), collectively known as ER stress. Adaptation to stress and re-establishment of ER homeostasis is achieved by activation of an integrated signal transduction pathway called the unfolded protein response (UPR). Both ER stress and UPR activation have been implicated in a variety of human cancers. Although at early stages or physiological conditions of ER stress, the UPR generally promotes survival, when the stress becomes more stringent or prolonged, its role can switch to a pro-cell death one. Here, we discuss historical and recent evidence supporting an involvement of the UPR in malignancy, describe the main mechanisms by which tumor cells overcome ER stress to promote their survival, tumor progression and metastasis and discuss the current state of efforts to develop therapeutic approaches of targeting the UPR. PMID- 25920801 TI - Post-treatment drinking among HIV patients: Relationship to pre-treatment marijuana and cocaine use. AB - BACKGROUND: For individuals with HIV, heavy drinking can pose serious threats to health. Some interventions are effective at reducing drinking in this population, but many HIV-infected heavy drinkers also use marijuana or cocaine. Although these drugs have predicted poor alcohol outcomes in other treatment studies, whether this occurs among HIV patients who drink heavily is unknown. METHODS: Participants were binge-drinking HIV primary care patients (N=254) enrolled in a randomized trial of three brief drinking interventions over 60 days that varied in intensity. We investigated the relationship of baseline past-year drug use (marijuana-only, cocaine-only, both, neither) to end-of-treatment drinking quantity and frequency. We also evaluated whether the relationship between intervention type and end-of-treatment drinking varied by baseline drug use. Final models incorporated control for patients' demographic and HIV characteristics. RESULTS: In final models, drinking frequency at the end of treatment did not vary by baseline drug use, but drinking quantity did (X(2)[3] = 13.87, p < 0.01), with individuals using cocaine-only drinking significantly more per occasion (B = 0.32, p < 0.01). Baseline drug use also interacted with intervention condition in predicting end-of-treatment drinking quantity (X(2)[6] = 13.98, p < 0.05), but not frequency, with the largest discrepancies in end-of treatment drinks per drinking day by intervention intensity among cocaine-only patients. CONCLUSIONS: In general, HIV patients using cocaine evidenced the highest levels of drinking after alcohol intervention. However, these individuals also evidenced the most pronounced differences in end-of-treatment drinking by intervention intensity. These results suggest the importance of more intensive intervention for individuals using alcohol and cocaine. PMID- 25920802 TI - Continuous in-the-field measurement of heart rate: Correlates of drug use, craving, stress, and mood in polydrug users. AB - BACKGROUND: Ambulatory physiological monitoring could clarify antecedents and consequences of drug use and could contribute to a sensor-triggered mobile intervention that automatically detects behaviorally risky situations. Our goal was to show that such monitoring is feasible and can produce meaningful data. METHODS: We assessed heart rate (HR) with AutoSense, a suite of biosensors that wirelessly transmits data to a smartphone, for up to 4 weeks in 40 polydrug users in opioid-agonist maintenance as they went about their daily lives. Participants also self-reported drug use, mood, and activities on electronic diaries. We compared HR with self-report using multilevel modeling (SAS Proc Mixed). RESULTS: Compliance with AutoSense was good; the data yield from the wireless electrocardiographs was 85.7%. HR was higher when participants reported cocaine use than when they reported heroin use (F(2,9)=250.3, p<.0001) and was also higher as a function of the dose of cocaine reported (F(1,8)=207.7, p<.0001). HR was higher when participants reported craving heroin (F(1,16)=230.9, p<.0001) or cocaine (F(1,14)=157.2, p<.0001) than when they reported of not craving. HR was lower (p<.05) in randomly prompted entries in which participants reported feeling relaxed, feeling happy, or watching TV, and was higher when they reported feeling stressed, being hassled, or walking. CONCLUSIONS: High-yield, high-quality heart rate data can be obtained from drug users in their natural environment as they go about their daily lives, and the resultant data robustly reflect episodes of cocaine and heroin use and other mental and behavioral events of interest. PMID- 25920804 TI - Clinical presentation and pharmacotherapy response in social anxiety disorder: The effect of etiological beliefs. AB - Therapies for social anxiety disorder (SAD) leave many patients symptomatic at the end of treatment and little is known about predictors of treatment response. This study investigated the predictive relationship of patients' etiological attributions to initial clinical features and response to pharmacotherapy. One hundred thirty-seven individuals seeking treatment for SAD received 12 weeks of open treatment with paroxetine. Participants completed the Attributions for the Etiology of Social Anxiety Scale at baseline in addition to measures of social anxiety and depression at baseline and over the course of treatment. A latent class analysis suggested four profiles of etiological beliefs about one's SAD that may be characterized as: Familial Factors, Need to be Liked, Bad Social Experiences, and Diffuse Beliefs. Patients in the more psychosocially-driven classes, Need to be Liked and Bad Social Experiences, had the most severe social anxiety and depression at baseline. Patients in the Familial Factors class, who attributed their SAD to genetic, biological, and early life experiences, had the most rapid response to paroxetine.These results highlight the effect of biological and genetically-oriented etiological beliefs on pharmacological intervention, have implications for person-specific treatment selection, and identify potential points of intervention to augment treatment response. PMID- 25920805 TI - Subjective pleasure experience in patients with recent-onset schizophrenia: A preliminary report. AB - Little is known about subjective pleasure experience in recent-onset schizophrenia, and its relationship with neurocognitive functions. Twenty-seven recent-onset schizophrenia people and 26 controls completed the TEPS and neuropsychological tests. The results showed that schizophrenia people self reported less anticipatory pleasure than controls. Semantic verbal fluency was apparently correlated with anticipatory pleasure. PMID- 25920806 TI - Relationships over time of subjective and objective elements of recovery in persons with schizophreni. AB - Recovery from schizophrenia involves both subjective elements such as self appraised wellness and objective elements such as symptom remission. Less is known about how they interact. To explore this issue, this study examined the relationship over the course of 1 year of four assessments of symptoms with four assessments of self-reports of subjective aspects of recovery. Participants were 101 outpatients with schizophrenia. Symptoms were assessed with the Positive and Negative Syndrome Scale (PANSS) while subjective recovery was assessed with the Recovery Assessment Scale (RAS). Separate Pearson's or Spearman's rank's correlation coefficients, calculated at all four measurement points, revealed the total symptom score was linked with lower levels of overall self-recovery at all four measurement points. The PANSS emotional discomfort subscale was linked with self-reported recovery at all four measurement points. RAS subscales linked to PANSS total symptoms at every time point were Personal confidence and hope, Goal and success orientation, and No domination by symptoms. Results are consistent with conceptualizations of recovery as a complex process and suggest that while there may be identifiably different domains, changes in subjective and objective domains may influence one another. PMID- 25920803 TI - Surviving apoptosis: life-death signaling in single cells. AB - Tissue development and homeostasis are regulated by opposing pro-survival and pro death signals. An interesting feature of the Tumor Necrosis Factor (TNF) family of ligands is that they simultaneously activate opposing signals within a single cell via the same ligand-receptor complex. The magnitude of pro-death events such as caspase activation and pro-survival events such as Nuclear Factor (NF)-kappaB activation vary not only from one cell type to the next but also among individual cells of the same type due to intrinsic and extrinsic noise. The molecules involved in these pro-survival and/or pro-death pathways, and the different phenotypes that result from their activities, have been recently reviewed. Here we focus on the impact of cell-to-cell variability in the strength of these opposing signals on shaping cell fate decisions. PMID- 25920808 TI - Effects of Ergosterol, Isolated from Scleroderma Polyrhizum Pers., on Lipopolysaccharide-Induced Inflammatory Responses in Acute Lung Injury. AB - The present study aimed to investigate the protective role of ergosterol, isolated from Scleroderma polyrhizum Pers., in lipopolysaccharide (LPS)-induced acute lung injury (ALI). ALI was induced in mice by LPS (0.5 mg/kg), and ergosterol (25 and 50 mg/kg) was administrated orally 1 h prior to LPS administration. Ergosterol pretreatment at doses of 25 and 50 mg/kg decreased LPS induced lung histopathological changes, lung wet-to-dry weight ratio. In addition, pretreatment with ergosterol inhibited inflammatory cells and proinflammatory cytokines including tumor necrosis factor-alpha (TNF-alpha) and interleukin-6 (IL-6). Furthermore, we demonstrated that ergosterol blocked the activation of nuclear factor-kappaB (NF-kappaB), cyclooxygenase (COX)-2, and nitric oxide synthase (iNOS) pathways. The results presented here suggest that the protective mechanism of ergosterol may be attributed partly to the inhibition of NF-kappaB, COX-2, and iNOS pathways. PMID- 25920807 TI - Genetic variants within the serotonin transporter associated with familial risk for major depression. AB - The role of the serotonin transporter promoter linked polymorphism (5HTTLPR) in depression, despite much research, remains unclear. Most studies compare persons with and without depression to each other. We show offspring at high (N = 192) as compared to low (N = 101) familial risk for major depressive disorder were almost four times as likely to have two copies of the short allele at 5HTTLPR, suggesting that incorporation of family history could be helpful in identifying genetic differences. PMID- 25920809 TI - GSKIP- and GSK3-mediated anchoring strengthens cAMP/PKA/Drp1 axis signaling in the regulation of mitochondrial elongation. AB - GSK3beta binding of GSKIP affects neurite outgrowth, but the physiological significance of PKA binding to GSKIP remains to be determined. We hypothesized that GSKIP and GSK3beta mediate cAMP/PKA/Drp1 axis signaling and modulate mitochondrial morphology by forming a working complex comprising PKA/GSKIP/GSK3beta/Drp1. We demonstrated that GSKIP wild-type overexpression increased phosphorylation of Drp1 S637 by 7-8-fold compared to PKA kinase inactive mutants (V41/L45) and a GSK3beta binding-defective mutant (L130) under H2O2 and forskolin challenge in HEK293 cells, indicating that not only V41/L45, but also L130 may be involved in Drp1-associated protection of GSKIP. Interestingly, silencing either GSKIP or GSK3beta but not GSK3alpha resulted in a dramatic decrease in Drp1 S637 phosphorylation, revealing that both GSKIP and GSK3beta are required in this novel PKA/GSKIP/GSK3beta/Drp1 complex. Moreover, overexpressed kinase-dead GSK3beta-K85R, which retains the capacity to bind GSKIP, but not K85M which shows total loss of GSKIP-binding, has a higher Drp1 S637 phosphorylation similar to the GSKIP wt overexpression group, indicating that GSK3beta recruits Drp1 by anchoring rather than in a kinase role. With further overexpression of either V41/L45P or the L130P GSKIP mutant, the elongated mitochondrial phenotype was lost; however, ectopically expressed Drp1 S637D, a phosphomimetic mutant, but not S637A, a non-phosphorylated mutant, restored the elongated mitochondrial morphology, indicating that Drp1 is a downstream effector of direct PKA signaling and possibly has an indirect GSKIP function involved in the cAMP/PKA/Drp1 signaling axis. Collectively, our data revealed that both GSKIP and GSK3beta function as anchoring proteins in the cAMP/PKA/Drp1 signaling axis modulating Drp1 phosphorylation. PMID- 25920810 TI - MOZ and MORF acetyltransferases: Molecular interaction, animal development and human disease. AB - Lysine residues are subject to many forms of covalent modification and one such modification is acetylation of the epsilon-amino group. Initially identified on histone proteins in the 1960s, lysine acetylation is now considered as an important form of post-translational modification that rivals phosphorylation. However, only about a dozen of human lysine acetyltransferases have been identified. Among them are MOZ (monocytic leukemia zinc finger protein; a.k.a. MYST3 and KAT6A) and its paralog MORF (a.k.a. MYST4 and KAT6B). Although there is a distantly related protein in Drosophila and sea urchin, these two enzymes are vertebrate-specific. They form tetrameric complexes with BRPF1 (bromodomain- and PHD finger-containing protein 1) and two small non-catalytic subunits. These two acetyltransferases and BRPF1 play key roles in various developmental processes; for example, they are important for development of hematopoietic and neural stem cells. The human KAT6A and KAT6B genes are recurrently mutated in leukemia, non hematologic malignancies, and multiple developmental disorders displaying intellectual disability and various other abnormalities. In addition, the BRPF1 gene is mutated in childhood leukemia and adult medulloblastoma. Therefore, these two acetyltransferases and their partner BRPF1 are important in animal development and human disease. PMID- 25920811 TI - Time to loading and locoregional control in perioperative high-dose-rate brachytherapy: The tumor bed effect revisited. AB - PURPOSE: To determine whether the time to loading (TTL) affects locoregional control. METHODS AND MATERIALS: Locoregional control status was determined in 301 patients enrolled in several perioperative high-dose-rate brachytherapy (PHDRB) prospective studies conducted at the University of Navarre. The impact of the time elapsed from catheter implantation to the first PHDRB treatment (TTL) was analyzed. Patients treated with PHDRB alone (n = 113), mainly because of prior irradiation, received 32 Gy in eight twice-a-day treatments or 40 Gy in 10 twice a-day treatments for negative or close/positive margins, respectively. Patients treated with PHDRB + external beam radiation therapy (EBRT) (n = 188) received 16 Gy in four twice-a-day treatments or 24 Gy in six twice-a-day treatments for negative or close/positive margins followed by 45 Gy of EBRT in 25 treatments. RESULTS: After a median followup of 6.5 years (range, 2-13.6+), 113 patients have failed (37.5%), 65 in the PHDRB-alone group (57.5%) and 48 in the combined PHDRB + EBRT group (25.5%). Patients who started PHDRB before Postoperative Day 5 had a 10-year locoregional control rate of 66.7% and patients who started PHDRB on Postoperative Day 5 or longer had a 10-year locoregional control rate of 51.8% (p = 0.009). Subgroup analysis detected that this difference was only observed in the recurrent cases treated with PHDRB alone (Subset 2; n = 99; p = 0.004). No correlation could be detected between locoregional control rate and TTL in the other patient subsets although a trend toward a decreased locoregional control rate after a longer TTL was observed when they were grouped together (p = 0.089). CONCLUSIONS: Patients should start PHDRB as soon as possible to maximize locoregional control especially in those recurrent cases treated with PHDRB alone. The time effect in other disease scenarios is less clear. PMID- 25920812 TI - In Vitro Investigation of the Hemodynamics of Transcatheter Heterotopic Valves Implantation in the Cavo-Atrial Junction. AB - Severe tricuspid regurgitation (TR) is life-threatening but is often undertreated. Many patients with severe TR are denied heart valve replacement surgery because their old age or comorbidities predispose them to a higher risk of surgical complications associated with open-heart surgery. With the advent of transcatheter technology, it is now possible to deliver the valve to the desired location without the need for open-heart surgery. However, presently, there is no commercially available transcatheter tricuspid valve. This may be due to the complex tricuspid valve anatomy, which lacks an anchorage zone for the percutaneous valves. In view of this drawback, we have recently developed and tested two percutaneous caval heart valves that are designed to deploy at the vena cava and atrium junction. The hemodynamic characteristics of these valves are tested in a mock circulatory system with patient-specific silicone atrium and vena cava, which emulates the physiological pressure and flow conditions at the right side of the human heart. Particle imaging velocimetry results showed that flow velocity and the associated Reynolds shear stress (RSS) and the turbulent kinetic energy (TKE) downstream of the valves increased after the implantation of the valves. A maximum flow velocity of 0.94 m/s was observed at the region downstream of the percutaneous valve at the superior vena cava (SVC). Maximum RSS value of 2076.1 dynes/cm(2) was observed downstream of the valve at the inferior vena cava during the deceleration phase while maximum TKE measured was 572.6 J/m(3) at the upstream of the valve in the SVC during the peak flow phase. While these values appear high, they are significantly lower than those reported in prosthetic mitral and aortic valves. Hence, caval stented valves can be potentially considered as a minimally invasive option to treat TR. PMID- 25920813 TI - Boston addiction doctor is jailed for defrauding Medicaid. PMID- 25920814 TI - Keeping ahead of the resistance curve: product bundling to conserve artemisinin based combination therapy. PMID- 25920815 TI - Effects of exposure to intermittent and continuous 6-7 kHz sonar sweeps on harbor porpoise (Phocoena phocoena) hearing. AB - Safety criteria for mid-frequency naval sonar sounds are needed to protect harbor porpoise hearing. A porpoise was exposed to sequences of one-second 6-7 kHz sonar down-sweeps, with 10-200 sweeps in a sequence, at an average received sound pressure level (SPLav.re.) of 166 dB re 1 MUPa, with duty cycles of 10% (intermittent sounds) and 100% (continuous). Behavioral hearing thresholds at 9.2 kHz were determined before and after exposure to the fatiguing noise, to quantify temporary hearing threshold shifts (TTS1-4 min) and recovery. Significant TTS1-4 min occurred after 10-25 sweeps when the duty cycle was 10% (cumulative sound exposure level, SELcum: ~178 dB re 1 MUPa(2)s). For the same SELcum, the TTS1-4 min was greater for exposures with 100% duty cycle. The difference in TTS between the two duty cycle exposures increased as the number of sweeps in the exposure sequences increased. Therefore, to predict TTS and permanent threshold shift, not only SELcum needs to be known, but also the duty cycle or equivalent sound pressure level (Leq). It appears that the injury criterion for non-pulses proposed by Southall, Bowles, Ellison, Finneran, Gentry, Greene, Kastak, Ketten, Miller, Nachtigall, Richardson, Thomas, and Tyack [(2007). Aquat. Mamm. 33, 411 521] for cetaceans echolocating at high frequency (SEL 215 dB re 1 MUPa(2)s) is too high for the harbor porpoise. PMID- 25920816 TI - Effects of multiple impulses from a seismic air gun on bottlenose dolphin hearing and behavior. AB - To investigate the auditory effects of multiple underwater impulses, hearing thresholds were measured in three bottlenose dolphins before and after exposure to 10 impulses produced by a seismic air gun. Thresholds were measured at multiple frequencies using both psychophysical and electrophysiological (auditory evoked potential) methods. Exposures began at relatively low levels and gradually increased over a period of several months. The highest exposures featured peak sound pressure levels from 196 to 210 dB re 1 MUPa, peak-peak sound pressure levels of 200-212 dB re 1 MUPa, and cumulative (unweighted) sound exposure levels from 193 to 195 dB re 1 MUPa(2)s. At the cessation of the study, no significant increases were observed in psychophysical thresholds; however, a small (9 dB) shift in mean auditory evoked potential thresholds, accompanied by a suppression of the evoked potential amplitude function, was seen in one subject at 8 kHz. At the highest exposure condition, two of the dolphins also exhibited behavioral reactions indicating that they were capable of anticipating and potentially mitigating the effects of impulsive sounds presented at fixed time intervals. PMID- 25920817 TI - The equivalent translational compliance of steel or wood studs and resilient channel bars. AB - A number of recent papers have determined the compliance of steel studs for use in models for predicting the sound insulation of cavity stud walls. However, in these papers, the compliance of resilient channel bars on one or both sides of wood studs or on one side of steel studs has not been determined across the whole of the frequency range. The present paper determines the compliance of the combination of resilient channel bars, mounted on wooden or steel studs and modeled as point or as line connections. Steel studs have usually been modeled as line connections. In this paper, they are also modeled as point connections where the points are the screws attaching the wall leaves to the steel studs and individual results rather than average results are analyzed. The compliance that makes Davy's sound insulation predictions agree with experimental sound insulation data was calculated by inverting Davy's equations for sound insulation. Linear regressions of the logarithm of the compliance, against the logarithms of frequency, reduced surface density, cavity depth and number of point connections or stud spacing, were conducted in a low frequency range and in a high frequency range. PMID- 25920818 TI - Bayesian-based estimation of acoustic surface impedance: Finite difference frequency domain approach. AB - Acoustic performance for an interior requires an accurate description of the boundary materials' surface acoustic impedance. Analytical methods may be applied to a small class of test geometries, but inverse numerical methods provide greater flexibility. The parameter estimation problem requires minimizing prediction vice observed acoustic field pressure. The Bayesian-network sampling approach presented here mitigates other methods' susceptibility to noise inherent to the experiment, model, and numerics. A geometry agnostic method is developed here and its parameter estimation performance is demonstrated for an air-backed micro-perforated panel in an impedance tube. Good agreement is found with predictions from the ISO standard two-microphone, impedance-tube method, and a theoretical model for the material. Data by-products exclusive to a Bayesian approach are analyzed to assess sensitivity of the method to nuisance parameters. PMID- 25920819 TI - Passive estimation of internal temperatures making use of broadband ultrasound radiated by the body. AB - The internal temperatures of plasticine models and the human forearm in vivo were determined, based on remote measurements of their intrinsic ultrasonic radiation. For passive detection of the thermal ultrasonic radiation an acoustic radiometer was developed, based on a broadband 0.8-3.3 MHz disk-shaped ultrasonic detector with an 8 mm aperture. To reconstruct temperature profiles using the experimentally measured spectra of thermal acoustic radiation a priori information was used regarding the temperature distribution within the objects being investigated. The temperature distribution for heated plasticine was considered to be a monotonic function. The distribution for the human forearm was considered to fit a heat equation incorporating blood flow parameters. Using sampling durations of 45 s the accuracy of temperature measurement inside a plasticine model was 0.5 K. The measured internal temperature of the forearm in vivo, at 36.3 degrees C, corresponded to existing physiological data. The results obtained verify the applicability of this passive method of wideband ultrasonic thermometry to medical applications that involve local internal heating of biological tissue. PMID- 25920820 TI - Exact solution for a photoacoustic wave from a finite-length cylindrical source. AB - In wide-field pulsed photoacoustics, a nearly instantaneous source of electromagnetic energy is applied uniformly to an absorbing medium to create an acoustic wave. In this work, an exact solution is derived for the photoacoustic wave originating from a finite-length solid cylindrical source in terms of known analytic functions involving elliptic integrals of canonical form. The solution is compared with the output of a finite-element simulation. PMID- 25920821 TI - Fast characterization of two ultrasound longitudinal waves in cancellous bone using an adaptive beamforming technique. AB - The received signal in through-transmission ultrasound measurements of cancellous bone consists of two longitudinal waves, called the fast and slow waves. Analysis of these fast and slow waves may reveal characteristics of the cancellous bone that would be good indicators of osteoporosis. Because the two waves often overlap, decomposition of the received signal is an important problem in the characterization of bone quality. This study proposes a fast and accurate decomposition method based on the frequency domain interferometry imaging method with a modified wave transfer function that uses a phase rotation parameter. The proposed method accurately characterized the fast and slow waves in the experimental study, and the residual intensity, which was normalized with respect to the received signal intensity, was less than -20 dB over the bone specimen thickness range from 6 to 15 mm. In the simulation study, the residual intensity was less than -20 dB over the specimen thickness range from 3 to 8 mm. Decomposition of a single received signal takes only 5 s using a laptop personal computer with a single central processing unit. The proposed method has great potential to provide accurate and rapid measurements of indicators of osteoporosis in cancellous bone. PMID- 25920823 TI - Comparison between experimental and computational methods for the acoustic and thermal characterization of therapeutic ultrasound fields. AB - For high intensity therapeutic ultrasound (HITU) devices, pre-clinical testing can include measurement of power, pressure/intensity and temperature distribution, acoustic and thermal simulations, and assessment of targeting accuracy and treatment monitoring. Relevant International Electrotechnical Commission documents recently have been published. However, technical challenges remain because of the often focused, large amplitude pressure fields encountered. Measurement and modeling issues include using hydrophones and radiation force balances at HITU power levels, validation of simulation models, and tissue mimicking material (TMM) development for temperature measurements. To better understand these issues, a comparison study was undertaken between simulations and measurements of the HITU acoustic field distribution in water and TMM and temperature rise in TMM. For the specific conditions of this study, the following results were obtained. In water, the simulated values for p+ and p- were 3% lower and 10% higher, respectively, than those measured by hydrophone. In TMM, the simulated values for p+ and p- were 2% and 10% higher than those measured by hydrophone, respectively. The simulated spatial-peak temporal-average intensity values in water and TMM were greater than those obtained by hydrophone by 3%. Simulated and measured end-of-sonication temperatures agreed to within their respective uncertainties (coefficients of variation of approximately 20% and 10%, respectively). PMID- 25920822 TI - Impulse response method for characterization of echogenic liposomes. AB - An optical characterization method is presented based on the use of the impulse response to characterize the damping imparted by the shell of an air-filled ultrasound contrast agent (UCA). The interfacial shell viscosity was estimated based on the unforced decaying response of individual echogenic liposomes (ELIP) exposed to a broadband acoustic impulse excitation. Radius versus time response was measured optically based on recordings acquired using an ultra-high-speed camera. The method provided an efficient approach that enabled statistical measurements on 106 individual ELIP. A decrease in shell viscosity, from 2.1 * 10(-8) to 2.5 * 10(-9) kg/s, was observed with increasing dilatation rate, from 0.5 * 10(6) to 1 * 10(7) s(-1). This nonlinear behavior has been reported in other studies of lipid-shelled UCAs and is consistent with rheological shear thinning. The measured shell viscosity for the ELIP formulation used in this study [kappas = (2.1 +/- 1.0) * 10(-8) kg/s] was in quantitative agreement with previously reported values on a population of ELIP and is consistent with other lipid-shelled UCAs. The acoustic response of ELIP therefore is similar to other lipid-shelled UCAs despite loading with air instead of perfluorocarbon gas. The methods described here can provide an accurate estimate of the shell viscosity and damping for individual UCA microbubbles. PMID- 25920824 TI - Vibration and sound radiation of an electrostatic speaker based on circular diaphragm. AB - This study investigated the lumped parameter method (LPM) and distributed parameter method (DPM) in the measurement of vibration and prediction of sound pressure levels (SPLs) produced by an electrostatic speaker with circular diaphragm. An electrostatic speaker with push-pull configuration was achieved by suspending the circular diaphragm (60 mm diameter) between two transparent conductive plates. The transparent plates included a two-dimensional array of holes to enable the visualization of vibrations and avoid acoustic distortion. LPM was used to measure the displacement amplitude at the center of the diaphragm using a scanning vibrometer with the aim of predicting symmetric modes using Helmholtz equations and SPLs using Rayleigh integral equations. DPM was used to measure the amplitude of displacement across the entire surface of the speaker and predict SPL curves. LPM results show that the prediction of SPL associated with the first three symmetric resonant modes is in good agreement with the results of DPM and acoustic measurement. Below the breakup frequency of 375 Hz, the SPL predicted by LPM and DPM are identical with the results of acoustic measurement. This study provides a rapid, accurate method with which to measure the SPL associated with the first three symmetric modes using semi-analytic LPM. PMID- 25920825 TI - A numerical investigation on the vortex formation and flow separation of the oscillatory flow in jet pumps. AB - A two-dimensional computational fluid dynamics model is used to predict the oscillatory flow through a tapered cylindrical tube section (jet pump) placed in a larger outer tube. Due to the shape of the jet pump, an asymmetry in the hydrodynamic end effects will exist which will cause a time-averaged pressure drop to occur that can be used to cancel Gedeon streaming in a closed-loop thermoacoustic device. The performance of two jet pump geometries with different taper angles is investigated. A specific time-domain impedance boundary condition is implemented in order to simulate traveling acoustic wave conditions. It is shown that by scaling the acoustic displacement amplitude to the jet pump dimensions, similar minor losses are observed independent of the jet pump geometry. Four different flow regimes are distinguished and the observed flow phenomena are related to the jet pump performance. The simulated jet pump performance is compared to an existing quasi-steady approximation which is shown to only be valid for small displacement amplitudes compared to the jet pump length. PMID- 25920826 TI - A micromachined efficient parametric array loudspeaker with a wide radiation frequency band. AB - Parametric array (PA) loudspeakers generate directional audible sound via the PA effect, which can make private listening possible. The practical applications of PA loudspeakers include information technology devices that require large power efficiency transducers with a wide frequency bandwidth. Piezoelectric micromachined ultrasonic transducers (PMUTs) are compact and efficient units for PA sources [Je, Lee, and Moon, Ultrasonics 53, 1124-1134 (2013)]. This study investigated the use of an array of PMUTs to make a PA loudspeaker with high power efficiency and wide bandwidth. The achievable maximum radiation bandwidth of the driver was calculated, and an array of PMUTs with two distinct resonance frequencies (f1 = 100 kHz, f2 = 110 kHz) was designed. Out-of-phase driving was used with the dual-resonance transducer array to increase the bandwidth. The fabricated PMUT array exhibited an efficiency of up to 71%, together with a +/-3 dB bandwidth of 17 kHz for directly radiated primary waves, and 19.5 kHz (500 Hz to 20 kHz) for the difference frequency waves (with equalization). PMID- 25920827 TI - Gap seal dissipation in linear alternators. AB - Earlier models of the coupling between a thermoacoustic system and an electrodynamic motor/alternator considered mechanical damping but ignored the viscous friction and blow-by losses produced by the motor/alternator's piston oscillating within a tight-fitting gap. The model presented here extends previous models to demonstrate that the inclusion of these effects leads to a better estimate of the electroacoustic conversion efficiency and can be used to determine the optimal load resistance for such an alternator's electrical power output. Model predictions were shown to be in excellent agreement with the performance measurements made using two different thermoacoustic engines and using a sealed volume (dummy load) connected to multiple, horizontally opposed motor/alternators, using an empirical determination of the piston-cylinder gap. PMID- 25920828 TI - Oscillation regimes produced by an alto saxophone: Influence of the control parameters and the bore inharmonicity. AB - The aim of this work is to highlight experimentally how inharmonicity of the bore resonance frequencies of an alto saxophone influences the nature of the oscillation regimes. A variable volume branching from the neck of an alto sax at an appropriate position allows one to change the frequency of the first resonance independently from the second. A blowing machine with artificial lips is used to make the saxophone play while controlling independently the control parameters: the blowing pressure and an embouchure parameter. Values of these parameters are estimated experimentally through the measurement of the nonlinear characteristics linking the mean air flow blown into the instrument to the static pressure difference across the reed. Experiments with different values of the control parameters as well as of the inharmonicity produce different kinds of oscillation regimes. These regimes are categorized through the analysis of the pressure signal inside the mouthpiece. The resulting maps demonstrate that the emergence of quasi-periodic regimes, and their extent, depend on the level of inharmonicity, but also on the values of the control parameters. Periodic regimes playable by choosing appropriate values of the control parameters also differ according to the level of inharmonicity, a higher inharmonicity facilitating the emergence of the third register. PMID- 25920829 TI - Coupling of transverse and longitudinal waves in piano strings. AB - The existence of longitudinal waves in vibrating piano strings has been previously established, as has their importance in producing the characteristic sound of the piano. Modeling of the coupling between the transverse and longitudinal motion of strings indicates that the amplitude of the longitudinal waves are quadratically related to the transverse displacement of the string, however, experimental verification of this relationship is lacking. In the work reported here this relationship is tested by driving the transverse motion of a piano string at only two frequencies, which simplifies the task of unambiguously identifying the constituent signals. The results indicate that the generally accepted relationship between the transverse motion and the longitudinal motion is valid. It is further shown that this dependence on transverse displacement is a good approximation when a string is excited by the impact of the hammer during normal play. PMID- 25920830 TI - Acoustical properties of air-saturated porous material with periodically distributed dead-end pores. AB - A theoretical and numerical study of the sound propagation in air-saturated porous media with straight main pores bearing lateral cavities (dead-ends) is presented. The lateral cavities are located at "nodes" periodically spaced along each main pore. The effect of periodicity in the distribution of the lateral cavities is studied, and the low frequency limit valid for the closely spaced dead-ends is considered separately. It is shown that the absorption coefficient and transmission loss are influenced by the viscous and thermal losses in the main pores as well as their perforation rate. The presence of long or short dead ends significantly alters the acoustical properties of the material and can increase significantly the absorption at low frequencies (a few hundred hertz). These depend strongly on the geometry (diameter and length) of the dead-ends, on their number per node, and on the periodicity along the propagation axis. These effects are primarily due to low sound speed in the main pores and to thermal losses in the dead-end pores. The model predictions are compared with experimental results. Possible designs of materials of a few cm thicknesses displaying enhanced low frequency absorption at a few hundred hertz are proposed. PMID- 25920831 TI - Directional cloaking of flexural waves in a plate with a locally resonant metamaterial. AB - This paper deals with the numerical design of a directional invisibility cloak for backward scattered elastic waves propagating in a thin plate (A0 Lamb waves). The directional cloak is based on a set of resonating beams that are attached perpendicular to the plate and are arranged at a sub-wavelength scale in ten concentric rings. The exotic effective properties of this locally resonant metamaterial ensure coexistence of bandgaps and directional cloaking for certain beam configurations over a large frequency band. The best directional cloaking was obtained when the resonators' length decreases from the central to the outermost ring. In this case, flexural waves experience a vanishing index of refraction when they cross the outer layers, leading to a frequency bandgap that protects the central part of the cloak. Numerical simulation shows that there is no back-scattering in these configurations. These results might have applications in the design of seismic-wave protection devices. PMID- 25920832 TI - Generation of random microstructures and prediction of sound velocity and absorption for open foams with spherical pores. AB - This paper proposes and discusses an approach for the design and quality inspection of the morphology dedicated for sound absorbing foams, using a relatively simple technique for a random generation of periodic microstructures representative for open-cell foams with spherical pores. The design is controlled by a few parameters, namely, the total open porosity and the average pore size, as well as the standard deviation of pore size. These design parameters are set up exactly and independently, however, the setting of the standard deviation of pore sizes requires some number of pores in the representative volume element (RVE); this number is a procedure parameter. Another pore structure parameter which may be indirectly affected is the average size of windows linking the pores, however, it is in fact weakly controlled by the maximal pore-penetration factor, and moreover, it depends on the porosity and pore size. The proposed methodology for testing microstructure-designs of sound absorbing porous media applies the multi-scale modeling where some important transport parameters responsible for sound propagation in a porous medium-are calculated from microstructure using the generated RVE, in order to estimate the sound velocity and absorption of such a designed material. PMID- 25920833 TI - Wave energy transfer in elastic half-spaces with soft interlayers. AB - The paper deals with guided waves generated by a surface load in a coated elastic half-space. The analysis is based on the explicit integral and asymptotic expressions derived in terms of Green's matrix and given loads for both laminate and functionally graded substrates. To perform the energy analysis, explicit expressions for the time-averaged amount of energy transferred in the time harmonic wave field by every excited guided or body wave through horizontal planes and lateral cylindrical surfaces have been also derived. The study is focused on the peculiarities of wave energy transmission in substrates with soft interlayers that serve as internal channels for the excited guided waves. The notable features of the source energy partitioning in such media are the domination of a single emerging mode in each consecutive frequency subrange and the appearance of reverse energy fluxes at certain frequencies. These effects as well as modal and spatial distribution of the wave energy coming from the source into the substructure are numerically analyzed and discussed. PMID- 25920834 TI - Ultrasound tomography for simultaneous reconstruction of acoustic density, attenuation, and compressibility profiles. AB - A fast and efficient forward scattering solver is developed for use in ultrasound tomography. The solver is formulated so as to enable the calculation of scattering from large and relatively high-contrast objects with inhomogeneous physical properties that vary simultaneously in acoustic attenuation, compressibility, and density. It is based on the method of moments in conjunction with a novel implementation of the conjugate gradient algorithm which requires the use of the adjoints of the scattering operators. The solver takes advantage of the symmetric block Toeplitz matrix with symmetric Toeplitz blocks property of the Green's function matrix to increase efficiency and only stores the first row of this matrix to reduce memory requirements. This row is then used for the matrix-vector multiplication using the fast Fourier transform technique, thus, resulting in the computational complexity of O(n log n). The marching-on-source technique is also used to provide a good initial guess which allows the conjugate gradient technique to converge faster than initializing with an arbitrary guess. This feature is important in tomographic inversion algorithms which require that the object to be imaged be interrogated via several incident fields. Forward scattering and inversion examples, based on the Conjugate Gradient Least Squares regularized Born Iterative Method, are shown, in two-dimensions, for objects varying in all three physical properties. PMID- 25920835 TI - Finite series expansion of a Gaussian beam for the acoustic radiation force calculation of cylindrical particles in water. AB - This paper focuses on studying the interaction between an acoustical Gaussian beam and cylindrical particles. Based on the finite series method, the Gaussian beam is expanded as cylindrical functions and the beam coefficient of a Gaussian beam is obtained. An expression for the acoustic radiation force function that is the radiation force per unit energy density and unit cross-sectional surface area for a cylinder in a Gaussian beam is presented. Numerical results for the radiation force function of a Gaussian beam are presented for rigid cylinders, liquid cylinders, elastic cylinders, and viscoelastic cylinders to illustrate the theory. The radiation force function versus the dimensionless frequency ka (where k is the wave number and a is the radius of the cylinder) are discussed for different beam waists. The simulation results show the differences from those of a plane wave when the beam waist w0<=5lambda (where lambda is the wave length). The beam waist has no effects on the radiation force function when ka<1, while the beam waist has greater effects when ka>1. The radiation force function reaches the plane wave limit when w0>5lambda. The acoustic radiation force function is also determined by the parameters of the particles. PMID- 25920836 TI - Automatic identification of multiply diffracted waves and their ordered scattering paths. AB - An automated algorithm uses recordings of acoustic energy across a spatially distributed array to derive information about multiply scattered acoustic waves in heterogeneous media. The arrival time and scattering-order of each recorded diffracted acoustic wave, and the exact sequence of diffractors encountered by that wave, are estimated without requiring an explicit model of the medium through which the wave propagated. Individual diffractors are identified on the basis of their unique single-scattering relative travel-time curves (move-outs) across the array, and secondary (twice-scattered) waves are detected using semblance analysis along temporally offset primary move-outs. This information is sufficient to estimate travel times and scattering paths of all multiply diffracted waves of any order, and for these events to be identified in recorded data. The algorithm is applied to synthetic acoustic data sets from a variety of media, including different numbers of point-diffractors and a medium with strong heterogeneity and non-hyperbolic move-outs. PMID- 25920837 TI - The stratospheric arrival pair in infrasound propagation. AB - The ideal case of a deep and well-formed stratospheric duct for long range infrasound propagation in the absence of tropospheric ducting is considered. A canonical form, that of a pair of arrivals, for ground returns of impulsive signals in a stratospheric duct is determined. The canonical form is derived from the geometrical acoustics approximation, and is validated and extended through full wave modeling. The full caustic structure of the field of ray paths is found and used to determine phase relations between the contributions to the wavetrain from different propagation paths. Finally, comparison with data collected from the 2005 fuel gas depot explosion in Buncefield, England is made. The correspondence between the theoretical results and the observations is shown to be quite good. PMID- 25920838 TI - A unified approach to an augmented Burgers equation for the propagation of sonic booms. AB - Nonlinear propagation through a relaxing atmosphere of pressure disturbances extracted from a computational fluid dynamics (CFD) solution of the flow around a supersonic aircraft is simulated using an augmented Burgers equation. The effects of nonlinearity, geometrical spreading, atmospheric inhomogeneity, thermoviscous attenuation, and molecular vibration relaxation are taken into account. The augmented Burgers equation used for sonic boom propagation calculations is often solved by the operator splitting method, but numerical difficulties arise with this approach when dissipation is not effective. By re-examining the solution algorithms for the augmented Burgers equation, a stable method for handling the relaxation effect has been developed. This approach can handle the Burgers equation in a unified manner without operator splitting and, therefore, the resulting scheme is twice as fast as the original one. The approach is validated by comparing it with an analytical solution and a detailed CFD of dispersed plane wave propagation. In addition, a rise time prediction of low-boom supersonic aircraft is demonstrated. PMID- 25920839 TI - Effects of wide dynamic-range compression on the perceived clarity of individual musical instruments. AB - The effects of wide-dynamic-range compression (WDRC) on the ability of hearing impaired subjects to hear out individual instruments or voices (called "sources") in a mixture were explored. On each trial, the subjects were asked to judge the relative clarity of the target in two repetitions of the same music excerpt (mixture of sources) that were processed in different ways. The stimuli were processed via a five-channel simulated WDRC hearing aid, using individual insertion gains and compression ratios recommended by the CAM2 fitting procedure. Both fast- and slow-acting WDRC and a condition with linear amplification and frequency-response shaping were used. To investigate the role of cross-modulation (the partial correlation of the envelopes of different sources caused by the time varying gain applied by the compressor), conditions were included where the sounds from different sources were compressed before being added together and where the sounds were added together before being compressed. The results showed no effect of cross-modulation, lower clarity with WDRC than with linear amplification, and no significant overall effect of compression speed, although some subjects consistently rated clarity as greater with slow compression. The deleterious effect of WDRC may be related to changes in temporal-envelope shape or reduced spectral contrast produced by WDRC. PMID- 25920840 TI - Acoustical transmission-line model of the middle-ear cavities and mastoid air cells. AB - An acoustical transmission line model of the middle-ear cavities and mastoid air cell system (MACS) was constructed for the adult human middle ear with normal function. The air-filled cavities comprised the tympanic cavity, aditus, antrum, and MACS. A binary symmetrical airway branching model of the MACS was constructed using an optimization procedure to match the average total volume and surface area of human temporal bones. The acoustical input impedance of the MACS was calculated using a recursive procedure, and used to predict the input impedance of the middle-ear cavities at the location of the tympanic membrane. The model also calculated the ratio of the acoustical pressure in the antrum to the pressure in the middle-ear cavities at the location of the tympanic membrane. The predicted responses were sensitive to the magnitude of the viscothermal losses within the MACS. These predicted input impedance and pressure ratio functions explained the presence of multiple resonances reported in published data, which were not explained by existing MACS models. PMID- 25920841 TI - Spatial release of cognitive load measured in a dual-task paradigm in normal hearing and hearing-impaired listeners. AB - This study investigated whether spatial separation between talkers helps reduce cognitive processing load, and how hearing impairment interacts with the cognitive load of individuals listening in multi-talker environments. A dual-task paradigm was used in which performance on a secondary task (visual tracking) served as a measure of the cognitive load imposed by a speech recognition task. Visual tracking performance was measured under four conditions in which the target and the interferers were distinguished by (1) gender and spatial location, (2) gender only, (3) spatial location only, and (4) neither gender nor spatial location. Results showed that when gender cues were available, a 15 degrees spatial separation between talkers reduced the cognitive load of listening even though it did not provide further improvement in speech recognition (Experiment I). Compared to normal-hearing listeners, large individual variability in spatial release of cognitive load was observed among hearing-impaired listeners. Cognitive load was lower when talkers were spatially separated by 60 degrees than when talkers were of different genders, even though speech recognition was comparable in these two conditions (Experiment II). These results suggest that a measure of cognitive load might provide valuable insight into the benefit of spatial cues in multi-talker environments. PMID- 25920843 TI - Estimation of aircraft angular coordinates using a directional-microphone array- An experimental study. AB - Ground reflections cause problems when estimating the direction of arrival of aircraft noise. In traditional methods, based on the time differences between the microphones of a compact array, they may cause a significant loss of accuracy in the vertical direction. This study evaluates the use of first-order directional microphones, instead of omnidirectional, with the aim of reducing the amplitude of the reflected sound. Such a modification allows the problem to be treated as in free field conditions. Although further tests are needed for a complete evaluation of the method, the experimental results presented here show that under the particular conditions tested the vertical angle error is reduced ~10 degrees for both jet and propeller aircraft by selecting an appropriate directivity pattern. It is also shown that the final level of error depends on the vertical angle of arrival of the sound, and that the estimates of the horizontal angle of arrival are not influenced by the directivity pattern of the microphones nor by the reflective properties of the ground. PMID- 25920842 TI - Categorical loudness scaling and equal-loudness contours in listeners with normal hearing and hearing loss. AB - This study describes procedures for constructing equal-loudness contours (ELCs) in units of phons from categorical loudness scaling (CLS) data and characterizes the impact of hearing loss on these estimates of loudness. Additionally, this study developed a metric, level-dependent loudness loss, which uses CLS data to specify the deviation from normal loudness perception at various loudness levels and as function of frequency for an individual listener with hearing loss. CLS measurements were made in 87 participants with hearing loss and 61 participants with normal hearing. An assessment of the reliability of CLS measurements was conducted on a subset of the data. CLS measurements were reliable. There was a systematic increase in the slope of the low-level segment of the CLS functions with increase in the degree of hearing loss. ELCs derived from CLS measurements were similar to standardized ELCs (International Organization for Standardization, ISO 226:2003). The presence of hearing loss decreased the vertical spacing of the ELCs, reflecting loudness recruitment and reduced cochlear compression. Representing CLS data in phons may lead to wider acceptance of CLS measurements. Like the audiogram that specifies hearing loss at threshold, level-dependent loudness loss describes deficit for suprathreshold sounds. Such information may have implications for the fitting of hearing aids. PMID- 25920844 TI - Grid-free compressive beamforming. AB - The direction-of-arrival (DOA) estimation problem involves the localization of a few sources from a limited number of observations on an array of sensors, thus it can be formulated as a sparse signal reconstruction problem and solved efficiently with compressive sensing (CS) to achieve high-resolution imaging. On a discrete angular grid, the CS reconstruction degrades due to basis mismatch when the DOAs do not coincide with the angular directions on the grid. To overcome this limitation, a continuous formulation of the DOA problem is employed and an optimization procedure is introduced, which promotes sparsity on a continuous optimization variable. The DOA estimation problem with infinitely many unknowns, i.e., source locations and amplitudes, is solved over a few optimization variables with semidefinite programming. The grid-free CS reconstruction provides high-resolution imaging even with non-uniform arrays, single-snapshot data and under noisy conditions as demonstrated on experimental towed array data. PMID- 25920845 TI - Modeling local active sound control with remote sensors in spatially random pressure fields. AB - A general formulation is presented for the optimum controller in an active system for local sound control in a spatially random primary field. The sound field in a control region is selectively attenuated using secondary sources, driven by reference sensors, all of which are potentially remote from this control region. It is shown that the optimal controller is formed of the combination of a least squares estimation of the primary source signals from the reference signals, and a least-squares controller driven by the primary source signals themselves. The optimum controller is also calculated using the remote microphone technique, in both the frequency and the time domains. The sound field under control is assumed to be stationary and generated by an array of primary sources, whose source strengths are specified using a spectral density matrix. This can easily be used to synthesize a diffuse primary field, if the primary sources are uncorrelated and far from the control region, but can also generate primary fields dominated by contributions from a particular direction, for example, which is shown to significantly affect the shape of the resulting zone of quiet. PMID- 25920846 TI - Acoustic centering of sources with high-order radiation patterns. AB - Surrounding spherical microphone arrays have recently been used in order to model the radiation pattern of acoustic sources that are assumed to be at the center of the array. Source centering algorithms are applied to the measurements in order to reduce the negative effect of acoustic source misalignment with regard to the physical center of the microphone array. Recent works aim to minimize the energy that is contained in the high-order coefficients of the radiation pattern in the spherical harmonics domain, in order to directly address the problem of increased order and spatial aliasing resulted by this misalignment. However, objective functions which directly minimize the norm of these coefficients were shown to be convex only when employed on sources with low-order radiation patterns. This work presents a source centering algorithm that operates on plane sections and aims to achieve a convex objective function on every plane section. The results of the proposed algorithm are shown to be more convex than the previous algorithms for sources with higher-order radiation pattern, usually at higher frequencies. PMID- 25920847 TI - Change-point detection for recursive Bayesian geoacoustic inversions. AB - In order to carry out geoacoustic inversion in low signal-to-noise ratio (SNR) conditions, extended duration observations coupled with source and/or receiver motion may be necessary. As a result, change in the underlying model parameters due to time or space is anticipated. In this paper, an inversion method is proposed for cases when the model parameters change abruptly or slowly. A model parameter change-point detection method is developed to detect the change in the model parameters using the importance samples and corresponding weights that are already available from the recursive Bayesian inversion. If the model parameters change abruptly, a change-point will be detected and the inversion will restart with the pulse measurement after the change-point. If the model parameters change gradually, the inversion (based on constant model parameters) may proceed until the accumulated model parameter mismatch is significant and triggers the detection of a change-point. These change-point detections form the heuristics for controlling the coherent integration time in recursive Bayesian inversion. The method is demonstrated in simulation with parameters corresponding to the low SNR, 100-900 Hz linear frequency modulation pulses observed in the Shallow Water 2006 experiment [Tan, Gerstoft, Yardim, and Hodgkiss, J. Acoust. Soc. Am. 136, 1187-1198 (2014)]. PMID- 25920848 TI - Identification of high-pass filtered male, female, and child vowels: The use of high-frequency cues. AB - Vowels are characteristically described according to low-frequency resonance characteristics, which are presumed to provide the requisite information for identification. Classically, the study of vowel perception has focused on the lowest formant frequencies, typically F1, F2, and F3. Lehiste and Peterson [Phonetica 4, 161-177 (1959)] investigated identification accuracy of naturally produced male vowels composed of various amounts of low- and high-frequency content. Results showed near-chance identification performance for vowel segments containing only spectral information above 3.5 kHz. The authors concluded that high-frequency information was of minor importance for vowel identification. The current experiments report identification accuracy for high-pass filtered vowels produced by two male, two female, and two child talkers using both between- and within-subject designs. Identification performance was found to be significantly above chance for the majority of vowels even after high-pass filtering to remove spectral content below 3.0-3.5 kHz. Additionally, the filtered vowels having the highest fundamental frequency (child talkers) often had the highest identification accuracy scores. Linear discriminant function analysis mirrored perceptual performance when using spectral peak information between 3 and 12 kHz. PMID- 25920849 TI - Fuzzy information transmission analysis for continuous speech features. AB - Feature information transmission analysis (FITA) estimates information transmitted by an acoustic feature by assigning tokens to categories according to the feature under investigation and comparing within-category to between-category confusions. FITA was initially developed for categorical features (e.g., voicing) for which the category assignments arise from the feature definition. When used with continuous features (e.g., formants), it may happen that pairs of tokens in different categories are more similar than pairs of tokens in the same category. The estimated transmitted information may be sensitive to category boundary location and the selected number of categories. This paper proposes a fuzzy approach to FITA that provides a smoother transition between categories and compares its sensitivity to grouping parameters with that of the traditional approach. The fuzzy FITA was found to be sufficiently robust to boundary location to allow automation of category boundary selection. Traditional and fuzzy FITA were found to be sensitive to the number of categories. This is inherent to the mechanism of isolating a feature by dividing tokens into categories, so that transmitted information values calculated using different numbers of categories should not be compared. Four categories are recommended for continuous features when twelve tokens are used. PMID- 25920850 TI - Gender typicality in children's speech: A comparison of boys with and without gender identity disorder. AB - This study examined whether boys with gender identity disorder (GID) produced less prototypically male speech than control boys without GID, a possibility that has been suggested by clinical observations. Two groups of listeners participated in tasks where they rated the gender typicality of single words (group 1) or sentences (group 2) produced by 15 5-13 year old boys with GID and 15 age-matched boys without GID. Detailed acoustic analyses of the stimuli were also conducted. Boys with GID were rated as less boy-like than boys without GID. In the experiment using sentence stimuli, these group differences were larger than in the experiment using single-word stimuli. Listeners' ratings were predicted by a variety of acoustic parameters, including ones that differ between the two groups and ones that are stereotypically associated with adult men's and women's speech. Future research should examine how these variants are acquired. PMID- 25920852 TI - Cognitive predictors of perceptual adaptation to accented speech. AB - The present study investigated the effects of inhibition, vocabulary knowledge, and working memory on perceptual adaptation to accented speech. One hundred young, normal-hearing adults listened to sentences spoken in a constructed, unfamiliar accent presented in speech-shaped background noise. Speech Reception Thresholds (SRTs) corresponding to 50% speech recognition accuracy provided a measurement of adaptation to the accented speech. Stroop, vocabulary knowledge, and working memory tests were performed to measure cognitive ability. Participants adapted to the unfamiliar accent as revealed by a decrease in SRTs over time. Better inhibition (lower Stroop scores) predicted greater and faster adaptation to the unfamiliar accent. Vocabulary knowledge predicted better recognition of the unfamiliar accent, while working memory had a smaller, indirect effect on speech recognition mediated by vocabulary score. Results support a top-down model for successful adaptation to, and recognition of, accented speech; they add to recent theories that allocate a prominent role for executive function to effective speech comprehension in adverse listening conditions. PMID- 25920851 TI - Measuring the effects of spectral smearing and enhancement on speech recognition in noise for adults and children. AB - Broadened auditory filters associated with sensorineural hearing loss have clearly been shown to diminish speech recognition in noise for adults, but far less is known about potential effects for children. This study examined speech recognition in noise for adults and children using simulated auditory filters of different widths. Specifically, 5 groups (20 listeners each) of adults or children (5 and 7 yrs), were asked to recognize sentences in speech-shaped noise. Seven-year-olds listened at 0 dB signal-to-noise ratio (SNR) only; 5-yr-olds listened at +3 or 0 dB SNR; and adults listened at 0 or -3 dB SNR. Sentence materials were processed both to smear the speech spectrum (i.e., simulate broadened filters), and to enhance the spectrum (i.e., simulate narrowed filters). Results showed: (1) Spectral smearing diminished recognition for listeners of all ages; (2) spectral enhancement did not improve recognition, and in fact diminished it somewhat; and (3) interactions were observed between smearing and SNR, but only for adults. That interaction made age effects difficult to gauge. Nonetheless, it was concluded that efforts to diagnose the extent of broadening of auditory filters and to develop techniques to correct this condition could benefit patients with hearing loss, especially children. PMID- 25920853 TI - Structure in time-frequency binary masking errors and its impact on speech intelligibility. AB - Although requiring prior knowledge makes the ideal binary mask an impractical algorithm, substantial increases in measured intelligibility make it a desirable benchmark. While this benchmark has been studied extensively, many questions remain about the factors that influence the intelligibility of binary-masked speech with non-ideal masks. To date, researchers have used primarily uniformly random, uncorrelated mask errors and independently presented error types (i.e., false positives and negatives) to characterize the influence of estimation errors on intelligibility. However, practical estimation algorithms produce masks that contain errors of both types and with non-trivial amounts of structure. This paper introduces an investigation framework for binary masks and presents listener studies that use this framework to illustrate how interactions between error types and structure affect intelligibility. First, this study demonstrates that clustering (i.e., a form of structure) of mask errors reduces intelligibility. Furthermore, while previous research has suggested that false positives are more detrimental to intelligibility than false negatives, this study indicates that false negatives can be equally detrimental to intelligibility when they contain structure or when both error types are present. Finally, this study shows that listeners tolerate fewer mask errors when both types of errors are present, especially when the errors contain structure. PMID- 25920854 TI - Self-entrainment of the right and left vocal fold oscillators. AB - This article presents an analysis of entrained oscillations of the right and left vocal folds in the presence of asymmetries. A simple one-mass model is proposed for each vocal fold. A stiffness asymmetry and open glottis oscillations are considered first, and regions of oscillation are determined by a stability analysis and an averaging technique. The results show that the subglottal threshold pressure for 1:1 entrainment increases with the asymmetry. Within that region, both folds oscillate with the same amplitude and with the lax fold delayed in time with regard to the tense fold. At large asymmetries, a region involving several different phase entrainments or toroidal regimes at constant threshold pressure appears. The effect of vocal fold collisions and asymmetry in the damping coefficients of the oscillators are explored next by means of numerical analyses. It is shown that the damping asymmetry expands the 1:1 entrainment region at low subglottal pressures across the whole asymmetry range. In the expanded region, the oscillator with the lowest natural frequency is dominant and the other oscillator has a large phase advance and small amplitude. The theoretical results are finally compared with data collected from a mechanical replica of the vocal folds. PMID- 25920855 TI - Separable spectro-temporal Gabor filter bank features: Reducing the complexity of robust features for automatic speech recognition. AB - To test if simultaneous spectral and temporal processing is required to extract robust features for automatic speech recognition (ASR), the robust spectro temporal two-dimensional-Gabor filter bank (GBFB) front-end from Schadler, Meyer, and Kollmeier [J. Acoust. Soc. Am. 131, 4134-4151 (2012)] was de-composed into a spectral one-dimensional-Gabor filter bank and a temporal one-dimensional-Gabor filter bank. A feature set that is extracted with these separate spectral and temporal modulation filter banks was introduced, the separate Gabor filter bank (SGBFB) features, and evaluated on the CHiME (Computational Hearing in Multisource Environments) keywords-in-noise recognition task. From the perspective of robust ASR, the results showed that spectral and temporal processing can be performed independently and are not required to interact with each other. Using SGBFB features permitted the signal-to-noise ratio (SNR) to be lowered by 1.2 dB while still performing as well as the GBFB-based reference system, which corresponds to a relative improvement of the word error rate by 12.8%. Additionally, the real time factor of the spectro-temporal processing could be reduced by more than an order of magnitude. Compared to human listeners, the SNR needed to be 13 dB higher when using Mel-frequency cepstral coefficient features, 11 dB higher when using GBFB features, and 9 dB higher when using SGBFB features to achieve the same recognition performance. PMID- 25920856 TI - The effect of vocal and demographic traits on speech intelligibility over bone conduction. AB - Bone conduction (BC) communication systems provide benefits over air conduction systems but are not in widespread use, partly due to problems with speech intelligibility. Contributing factors like device location and background noise have been explored, but little attention has been paid to the role of individual user differences. Because BC signals travel through an individual's skull and facial tissues, demographic factors such as user age, sex, race, or regional origin may influence sound transmission. Vocal traits such as pitch, spectral tilt, jitter, and shimmer may also play a role. Along with microphone placement and background noise, these factors can affect BC speech intelligibility. Eight diverse talkers were recorded with bone microphones on two different skull locations and in different background noise conditions. Twenty-four diverse listeners listened to these samples over BC and completed Modified Rhyme Tests for speech intelligibility. Forehead bone recordings were more intelligible than condyle recordings. In condyle recordings, female talkers, talkers with high fundamental frequency, and talkers in background noise were understood better, as were communications between talkers and listeners of the same regional origin. Listeners' individual traits had no significant effects. Thoughtful application of this knowledge can help improve BC communication for diverse users. PMID- 25920858 TI - Flat acoustic sources with frequency response correction based on feedback and feed-forward distributed control. AB - This paper presents an acoustic source with a small thickness and high bending stiffness. The high bending stiffness is obtained with a sandwich structure in which the face of the sandwich structure internal to the source is perforated to increase the acoustic compliance, thereby leading to increased electroacoustic conversion efficiency. Multiple actuators are used to drive the moving component of the acoustic source. Control of the acoustic resonances and structural resonances is required to obtain an even frequency response. The use of collocated decentralized feedback control based on velocity sensing was found to be ineffective for controlling these resonances due to the destabilizing asymmetric modes caused by the coupling of the internal acoustic cavity and the rigid body vibration of the moving component. Resonances can be controlled by a set of independent combinations of symmetric driving patterns with corresponding velocity feedback controllers such that the fundamental mass-air resonance is effectively controlled, as is the lowest bending mode of the moving component. Finally, a compensation scheme for low frequencies is used which enables a flat frequency response in the range of 30 Hz to 1 kHz with deviations smaller than 3 dB. PMID- 25920857 TI - Amplitude fluctuations in a masker influence lexical segmentation in cochlear implant users. AB - Normal-hearing listeners show masking release, or better speech understanding in a fluctuating-amplitude masker than in a steady-amplitude masker, but most cochlear implant (CI) users consistently show little or no masking release even in artificial conditions where masking release is highly anticipated. The current study examined the hypothesis that the reduced or absent masking release in CI users is due to disruption of linguistic segmentation cues. Eleven CI subjects completed a sentence keyword identification task in a steady masker and a fluctuating masker with dips timed to increase speech availability. Lexical boundary errors in their responses were categorized as consistent or inconsistent with the use of the metrical segmentation strategy (MSS). Subjects who demonstrated masking release showed greater adherence to the MSS in the fluctuating masker compared to subjects who showed little or no masking release, while both groups used metrical segmentation cues similarly in the steady masker. Based on the characteristics of the segmentation cues, the results are interpreted as evidence that CI listeners showing little or no masking release are not reliably segregating speech from competing sounds, further suggesting that one challenge faced by CI users listening in noisy environments is a reduction of reliable segmentation cues. PMID- 25920859 TI - Isogeometric analysis of free vibration of simple shaped elastic samples. AB - The paper is devoted to numerical solution of free vibration problems for elastic bodies of canonical shapes by means of a spline based finite element method (FEM), called Isogeometric Analysis (IGA). It has an advantage that the geometry is described exactly and the approximation of unknown quantities is smooth due to higher-order continuous shape functions. IGA exhibits very convenient convergence rates and small frequency errors for higher frequency spectrum. In this paper, the IGA strategy is used in computation of eigen-frequencies of a block and cylinder as benchmark tests. Results are compared with the standard FEM, the Rayleigh-Ritz method, and available experimental data. The main attention is paid to the comparison of convergence rate, accuracy, and time-consumption of IGA against FEM and also to show a spline order and parameterization effects. In addition, the potential of IGA in Resonant Ultrasound Spectroscopy measurements of elastic properties of general anisotropy solids is discussed. PMID- 25920860 TI - Analyzing panel acoustic contributions toward the sound field inside the passenger compartment of a full-size automobile. AB - The Helmholtz equation least squares (HELS)-based nearfield acoustical holography (NAH) is utilized to analyze panel acoustic contributions toward the acoustic field inside the interior region of an automobile. Specifically, the acoustic power flows from individual panels are reconstructed, and relative contributions to sound pressure level and spectrum at any point of interest are calculated. Results demonstrate that by correlating the acoustic power flows from individual panels to the field acoustic pressure, one can correctly locate the panel allowing the most acoustic energy transmission into the vehicle interior. The panel on which the surface acoustic pressure amplitude is the highest should not be used as indicative of the panel responsible for the sound field in the vehicle passenger compartment. Another significant advantage of this HELS-based NAH is that measurements of the input data only need to be taken once by using a conformal array of microphones in the near field, and ranking of panel acoustic contributions to any field point can be readily performed. The transfer functions between individual panels of any vibrating structure to the acoustic pressure anywhere in space are calculated not measured, thus significantly reducing the time and effort involved in panel acoustic contributions analyses. PMID- 25920861 TI - Exploring the resonant vibration of thin plates: Reconstruction of Chladni patterns and determination of resonant wave numbers. AB - The Chladni nodal line patterns and resonant frequencies for a thin plate excited by an electronically controlled mechanical oscillator are experimentally measured. Experimental results reveal that the resonant frequencies can be fairly obtained by means of probing the variation of the effective impedance of the exciter with and without the thin plate. The influence of the extra mass from the central exciter is confirmed to be insignificant in measuring the resonant frequencies of the present system. In the theoretical aspect, the inhomogeneous Helmholtz equation is exploited to derive the response function as a function of the driving wave number for reconstructing experimental Chladni patterns. The resonant wave numbers are theoretically identified with the maximum coupling efficiency as well as the maximum entropy principle. Substituting the theoretical resonant wave numbers into the derived response function, all experimental Chladni patterns can be excellently reconstructed. More importantly, the dispersion relationship for the flexural wave of the vibrating plate can be determined with the experimental resonant frequencies and the theoretical resonant wave numbers. The determined dispersion relationship is confirmed to agree very well with the formula of the Kirchhoff-Love plate theory. PMID- 25920862 TI - Passive probing of the sound fixing and ranging channel with hydro-acoustic observations from ridge earthquakes. AB - The International Monitoring System includes a hydro-acoustic part to verify the Comprehensive Nuclear-Test-Ban Treaty. Besides explosive signals, monitoring stations also detect acoustic waves from earthquakes that travel through the SOund Fixing And Ranging (SOFAR) channel. The travel times of such detections are listed in the Reviewed Event Bulletin, which is statistically evaluated for the stations located in the Pacific, Indian, and Atlantic Oceans. The celerities of ridge earthquakes are calculated to build up a homogeneous data-set, based on similar source mechanisms. The celerity is defined as the epicentral distance divided by the travel time. The global characteristics of these celerities can be well understood in terms of temperature variations in the SOFAR channel. A detailed velocity profile has been retrieved for the Atlantic Ocean where large differences (14 m/s) are found between the southern and northern parts of the basin. Propagation modeling with normal modes supports these findings, which shows that the celerity gives an estimate of the sound speed in the SOFAR channel. These results compare remarkably well with those from active experiments, showing the ability of passively probing the SOFAR channel with hydro-acoustic waves from earthquake sources. PMID- 25920863 TI - Ray-based description of mode coupling by sound speed fluctuations in the ocean. AB - A traditional approach to the analysis of mode coupling in a fluctuating underwater waveguide is based on solving the system of coupled equations for the second statistical moments of mode amplitudes derived in the Markov approximation [D. B. Creamer, J. Acoust. Soc. Am. 99, 2825-2838 (1996)]. In the present work, an alternative approach is considered. It is based on an analytic solution of the mode coupling equation derived in the high frequency approximation [A. L. Virovlyanskii and A. G. Kosterin, Sov. Phys. Acoust. 35, 138-142 (1987)]. This solution, representing the mode amplitude as a sum of contributions from two geometrical rays, is convenient for statistical averaging. It allows one to easily derive analytical expressions for any statistical moments of mode amplitudes. The applicability of this approach is demonstrated by comparing its predictions for a deep water acoustic waveguide with results of a full wave numerical simulation carried out using the method of wide angle parabolic equation. PMID- 25920865 TI - Acoustic coupled fluid-structure interactions using a unified fast multipole boundary element method. AB - This paper presents a numerical model for the acoustic coupled fluid-structure interaction (FSI) of a submerged finite elastic body using the fast multipole boundary element method (FMBEM). The Helmholtz and elastodynamic boundary integral equations (BIEs) are, respectively, employed to model the exterior fluid and interior solid domains, and the pressure and displacement unknowns are coupled between conforming meshes at the shared boundary interface to achieve the acoustic FSI. The low frequency FMBEM is applied to both BIEs to reduce the algorithmic complexity of the iterative solution from O(N(2)) to O(N(1.5)) operations per matrix-vector product for N boundary unknowns. Numerical examples are presented to demonstrate the algorithmic and memory complexity of the method, which are shown to be in good agreement with the theoretical estimates, while the solution accuracy is comparable to that achieved by a conventional finite element boundary element FSI model. PMID- 25920864 TI - Calibration of a broadband acoustic transducer with a standard spherical target in the near field. AB - This paper investigates the applicability of calibrating a broadband acoustic system in the near field. The calibration was performed on a single transducer with a mono-static configuration using a single standard target, a 25-mm tungsten carbide sphere in the nearfield of both the transducer and the sphere. A theoretical model was developed to quantify the nearfield effect. Numerical simulations revealed that the frequency responses at different distances varied significantly, the null positions were essentially invariant-a unique characteristic for determination of the compressional and shear wave speeds in the calibration sphere. The calibration curves obtained in the near field could be applied to farfield once the nearfield effects were accounted for. Since the transducer was located in the near field, the signal-to-noise ratio was high, resulting in a much wider useable bandwidth than the nominal bandwidth. The resultant calibration uncertainty, i.e., root-mean-square uncertainty over the entire usable frequency band was 1.05 dB and reduces to 0.33 dB when the regions corresponding to nulls were excluded. The methods reported here could potentially be applied to the calibration of multibeam and broadband echosounder/sonar systems since it is difficult to meet the farfield condition for outermost beams when shipboard calibrations are needed. PMID- 25920866 TI - Time reversal technique for gas leakage detection. AB - The acoustic remote sensing of subsea gas leakage traditionally uses sonars as active acoustic sensors and hydrophones picking up the sound generated by a leak as passive sensors. When gas leaks occur underwater, bubbles are produced and emit sound at frequencies intimately related to their sizes. The experimental implementation of an acoustic time-reversal mirror (TRM) is now well established in underwater acoustics. In the basic TRM experiment, a probe source emits a pulse that is received on an array of sensors, time reversed, and re-emitted. After time reversal, the resulting field focuses back at the probe position. In this study, a method for enhancing operation of the passive receiving system has been proposed by using it in the regime of TRM. Two factors, the local character of the acoustic emission signal caused by the leakage and a resonant nature of the bubble radiation at their birth, make particularly effective scattering with the conjugate wave (CW). Analytical calculations are performed for the scattering of CW wave on a single bubble when CW is formed by bubble birthing wail received on an array, time reversed, and re-emitted. The quality of leakage detection depends on the spatio-temporal distribution of ambient noise. PMID- 25920867 TI - Erratum: Frequency-domain model of tonal blade thickness and loading noise [J. Acoust. Soc. Am. 135, 93-103 (2014)]. PMID- 25920868 TI - Erratum: An integral equation formulation for the diffraction from convex plates and polyhedra [J. Acoust. Soc. Am. 133(6), 3681-3691 (2013)]. PMID- 25920871 TI - A comparison of finite element and analytic models of acoustic scattering from rough poroelastic interfaces. AB - The finite element method is used to model acoustic scattering from rough poroelastic surfaces. Both monostatic and bistatic scattering strengths are calculated and compared with three analytic models: Perturbation theory, the Kirchhoff approximation, and the small-slope approximation. It is found that the small-slope approximation is in very close agreement with the finite element results for all cases studied and that perturbation theory and the Kirchhoff approximation can be considered valid in those instances where their predictions match those given by the small-slope approximation. PMID- 25920872 TI - Equalization of loudspeaker response using balanced model truncation. AB - Traditional loudspeaker equalization algorithms cannot decide the order of an equalizer before the whole equalization procedure has been completed. Designers have to try many times before they determine a proper order of the equalization filter. A method which solves this drawback is presented for loudspeaker equalization using balanced model truncation. The order of the equalizer can be easily decided using this algorithm and the error between the model and the loudspeaker can also be readily controlled. Examples are presented and the performance of the proposed method is discussed with comparative experiments. PMID- 25920873 TI - A comparison of spectral estimation methods for the analysis of sibilant fricatives. AB - It has been argued that, to ensure accurate spectral feature estimates for sibilants, the spectral estimation method should include a low-variance spectral estimator; however, no empirical evaluation of estimation methods in terms of feature estimates has been given. The spectra of /s/ and /?/ were estimated with different methods that varied the pre-emphasis filter and estimator. These methods were evaluated in terms of effects on two features (centroid and degree of sibilance) and on the detection of four linguistic contrasts within these features. Estimation method affected the spectral features but none of the tested linguistic contrasts. PMID- 25920874 TI - Localization of low-frequency coherent sound sources with compressive beamforming based passive synthetic aperture. AB - The localization of low-frequency coherent sources requires a proper aperture to ensure a high spatial resolution. Attaining a large aperture is difficult in practice when the conditions involved are limited. This letter investigated a compressive beamforming-based passive synthetic aperture approach with a reference sensor in a fixed position. Localization findings on acoustic sources in a semi-anechoic chamber were compared with conventional beamforming, compressive beamforming, passive synthetic aperture, and compressive beamforming based passive synthetic aperture. Results suggest that the proposed method can produce a higher spatial resolution and higher detection ability than the others. PMID- 25920875 TI - Experimental validation of a coprime linear microphone array for high-resolution direction-of-arrival measurements. AB - Coprime linear microphone arrays allow for narrower beams with fewer sensors. A coprime microphone array consists of two staggered uniform linear subarrays with M and N microphones, where M and N are coprime with each other. By applying spatial filtering to both subarrays and combining their outputs, M+N-1 microphones yield M?N directional bands. In this work, the coprime sampling theory is implemented in the form of a linear microphone array of 16 elements with coprime numbers of 9 and 8. This coprime microphone array is experimentally tested to validate the coprime array theory. Both predicted and measured results are discussed. Experimental results confirm that narrow beampatterns as predicted by the coprime sampling theory can be obtained by the coprime microphone array. PMID- 25920876 TI - Extension of a spectral time-stepping domain decomposition method for dispersive and dissipative wave propagation. AB - For time-domain modeling based on the acoustic wave equation, spectral methods have recently demonstrated promise. This letter presents an extension of a spectral domain decomposition approach, previously used to solve the lossless linear wave equation, which accommodates frequency-dependent atmospheric attenuation and assignment of arbitrary dispersion relations. Frequency dependence is straightforward to assign when time-stepping is done in the spectral domain, so combined losses from molecular relaxation, thermal conductivity, and viscosity can be approximated with little extra computation or storage. A mode update free from numerical dispersion is derived, and the model is confirmed with a numerical experiment. PMID- 25920877 TI - Optimization of absorption placement using geometrical acoustic models and least squares. AB - Given a geometrical model of a space, the problem of optimally placing absorption in a space to match a desired impulse response is in general nonlinear. This has led some to use costly optimization procedures. This letter reformulates absorption assignment as a constrained linear least-squares problem. Regularized solutions result in direct distribution of absorption in the room and can accommodate multiple frequency bands, multiple sources and receivers, and constraints on geometrical placement of absorption. The method is demonstrated using a beam tracing model, resulting in the optimal absorption placement on the walls and ceiling of a classroom. PMID- 25920878 TI - Contextual plasticity, top-down, and non-auditory factors in sound localization with a distractor. AB - Localization of a 2-ms-click target was previously shown to be influenced by interleaved localization trials in which the target was preceded by an identical distractor [Kopco, Best, and Shinn-Cunningham (2007). J. Acoust. Soc. Am. 121, 420-432]. Here, two experiments were conducted to explore this contextual effect. Results show that context-related bias is not eliminated (1) when the response method is changed so that vision is available or that no hand-pointing is required; or (2) when the distractor-target order is reversed. Additionally, a keyboard-based localization response method is introduced and shown to be more accurate than traditional pointer-based methods. PMID- 25920879 TI - Underwater acoustic signals induced by intense ultrashort laser pulse. AB - Acoustic signals generated in water by terawatt (TW) laser pulses undergoing filamentation are studied. The acoustic signal has a very broad spectrum, spanning from 0.1 to 10 MHz and is confined in the plane perpendicular to the laser direction. Such a source appears to be promising for the development of remote laser based acoustic applications. PMID- 25920880 TI - Model-based auralizations of violin sound trends accompanying plate-bridge tuning or holding. AB - To expose systematic trends in violin sound accompanying "tuning" only the plates or only the bridge, the first structural acoustics-based model auralizations of violin sound were created by passing a bowed-string driving force measured at the bridge of a solid body violin through the dynamic filter (DF) model radiativity profile "filter" RDF(f) (frequency-dependent pressure per unit driving force, free-free suspension, anechoic chamber). DF model auralizations for the more realistic case of a violin held/played in a reverberant auditorium reveal that holding the violin greatly diminishes its low frequency response, an effect only weakly compensated for by auditorium reverberation. PMID- 25920881 TI - Path specific Doppler compensation in time-reversal communications. AB - Passive time reversal (pTR) is a low complexity receiver scheme that uses multichannel probing for time signal refocusing, thus reducing time spreading and improving inter-symbol interference. Recognizing that signals traveling through different paths are subject to arrival-angle-related Doppler displacements, this letter proposes a further improvement to pTR that applies correcting frequency shifts optimized for beams formed along each specific path arrival angle. The proposed channel equalizer is tested with real data, and the results show that the proposed approach outperforms both pTR and the modified pTR channel combiners providing an MSE gain of 4.9 and 4.2 dB, respectively. PMID- 25920882 TI - Asymmetries in the exploitation of phonetic features for word recognition. AB - French listeners' reliance on voicing, manner, and place was tested in a mispronunciation detection task. Mispronounced words were more likely to be recognized when the mispronunciation concerned voicing rather than manner or place. This indicates that listeners rely less on the former than on the latter for the purposes of word recognition. Further, the role of visual cues to phonetic features was explored by the task being conducted in both an audio-only and an audiovisual version, but no effect of modality was found. Discussion focuses on crosslinguistic comparisons and lexical factors that might influence the weight of individual features. PMID- 25920883 TI - A Monte Carlo experiment for measuring acoustic properties of macroalgae living tissue. AB - A methodology is developed to measure ex situ ultrasonic velocity of submerged aquatic vegetation tissue, in particular, macroalgae, in a nondestructive and efficient manner. An entire thallus is submerged in artificial seawater-filled tank through which many ultrasonic pulse-echo measurements are recorded while thallus parts are randomly displaced. Average sound speed of tissue is estimated from normal fit to extracted travel times given measured total volume fraction of tissue and travel time in water alone. For species Ecklonia radiata the resulting values for sound speed 1573.4 +/- 4.8 m s(-1) and adiabatic compressibility 3.134 *10(-10) +/- 1.34 *10(-11) Pa(-1) at 18 degrees C agree with more laborious and destructive methods. PMID- 25920884 TI - Analysis of moving source characteristics using polynomial chirplet transform. AB - The received Doppler signal of a stationary sensor, as emitted by a transiting acoustic source, is used to estimate source motion parameters, including speed, closest distance, rest frequency, and closest point of approach (CPA) time. First, the instantaneous frequency, amplitude, and CPA time are accurately estimated by the polynomial chirplet transform of the Doppler signal. Thereafter, the three other source motion parameters are obtained with a simplified amplitude weighted nonlinear least squares method. The proposed scheme is successfully applied to the analysis of the characteristics of a moving truck. PMID- 25920885 TI - Active control of excessive sound emission on a mobile device. AB - During a phone conversation, loud vocal emission from the far-end to the near-end space can disturb nearby people. In this paper, the possibility of actively controlling such unwanted sound emission using a control source placed on the mobile device is investigated. Two different approaches are tested: Global control, minimizing the potential energy measured along a volumetric space surface, and local control, minimizing the squared sound pressure at a discrete point on the phone. From the test results, both approaches can reduce the unwanted sound emission by more than 6 dB in the frequency range up to 2 kHz. PMID- 25920886 TI - Optimization on microlattice materials for sound absorption by an integrated transfer matrix method. AB - Materials with well-defined microlattice structures are superlight, stable, and thus bear great potential in sound absorption. An integrated transfer matrix method (TMM) is proposed to evaluate the sound absorbing efficiency of these lattice materials, in which a massive number of micropores are densely placed. A comparison between integrated TMM and conventional TMM reveals that the proposed approach offers better predictions on sound absorption of microlattice. This approach is then employed to optimize the microlattice material to determine the best pore and porosity that lead to maximum absorbing efficiency capability and minimum required thickness to attain a target sound absorption. PMID- 25920887 TI - How broadband speech may avoid neural firing rate saturation at high intensities and maintain intelligibility. AB - Three experiments examined the intelligibility enhancement produced when noise bands flank high intensity rectangular band speech. When white noise flankers were added to the speech individually at a low spectrum level (-30 dB relative to the speech) only the higher frequency flanker produced a significant intelligibility increase (i.e., recovery from intelligibility rollover). However, the lower-frequency flanking noise did produce an equivalent intelligibility increase when its spectrum level was increased by 10 dB. This asymmetrical intensity requirement, and other results, support previous suggestions that intelligibility loss at high intensities is reduced by lateral inhibition in the cochlear nuclei. PMID- 25920888 TI - Infrasonic and low-frequency insert earphone hearing threshold. AB - Low-frequency and infrasonic pure-tone monaural hearing threshold data down to 2.5 Hz are presented. These measurements were made by means of a newly developed insert-earphone source. The source is able to generate pure-tone sound pressure levels up to 130 dB between 2 and 250 Hz with very low harmonic distortions. Behavioral hearing thresholds were determined in the frequency range from 2.5 to 125 Hz for 18 otologically normal test persons. The median hearing thresholds are comparable to values given in the literature. They are intended for stimulus calibration in subsequent brain imaging investigations. PMID- 25920889 TI - Human preferences for colorful birds: Vivid colors or pattern? AB - In a previous study, we found that the shape of a bird, rather than its color, plays a major role in the determination of human preferences. Thus, in the present study, we asked whether the preferences of human respondents towards uniformly shaped, colorful birds are determined by pattern rather than color. The experimental stimuli were pictures of small passerine birds of the family Pittidae possessing uniform shape but vivid coloration. We asked 200 participants to rank 43 colored and 43 identical, but grayscaled, pictures of birds. To find the traits determining human preferences, we performed GLM analysis in which we tried to explain the mean preference ranks and PC axes by the following explanatory variables: the overall lightness and saturation, edges (pattern), and the portion of each of the basic color hues. The results showed that the mean preference ranks of the grayscale set is explained mostly by the birds' pattern, whereas the colored set ranking is mostly determined by the overall lightness. The effect of colors was weaker, but still significant, and revealed that people liked blue and green birds. We found no significant role of the color red, the perception of which was acquired relatively recently in evolution. PMID- 25920891 TI - A review on the possible molecular mechanism of action of N-acetylcysteine against insulin resistance and type-2 diabetes development. AB - OBJECTIVE: N-acetylcysteine (NAC), a cysteine pro-drug and glutathione precursor has been used in therapeutic practices for several decades, as a mucolytic agent and for the treatment of numerous disorders including paracetamol intoxication. There is a growing interest concerning the beneficial effects of NAC against the early stages of type-2 diabetes development. Nevertheless, the mechanisms underlying the therapeutic and clinical applications of NAC are not fully understood. In this review we aimed to focus on the protective effects of NAC against insulin resistance. DESIGN AND METHODS: The possible mechanisms of action were reviewed using the major findings of more than 100 papers relating to the antioxidant, anti-inflammatory and anti-apoptotic properties of NAC. RESULTS: The anti-oxidative activity of NAC has been attributed to its fast reactions with free radicals as well as the restitution of reduced glutathione. Further, NAC has anti-inflammatory and anti-apoptotic properties which can have positive effects during the inflammatory process in insulin resistance. Moreover, NAC can modulate certain signaling pathways in both insulin target cells and beta cells. CONCLUSIONS: The diverse biological effects of NAC may make it a potential adjuvant or therapeutic target in the treatment of type-2 diabetes. So, further studies are required for determining its ability to alleviate insulin resistance and to improve insulin sensitivity. PMID- 25920890 TI - Vitamins D and A can be successfully measured by LC-MS/MS in cord blood diluted plasma. AB - OBJECTIVES: In widely used protocols for the collection and isolation of cord blood mononuclear cells, investigators are left with substantial volumes of diluted plasma which could be used for other measurements. The aim of this study was to ascertain the validity of umbilical cord blood (UCB) diluted plasma samples for vitamin D, A and E analysis compared to UCB serum samples. DESIGN & METHODS: Twenty UCB matched samples of diluted plasma and serum were collected. The samples were analysed by two liquid chromatography-tandem mass spectrometry (LC-MS/MS) methods on two separate occasions. RESULTS: The results of 25(OH)D3 obtained by the two laboratories demonstrated close agreement with a mean difference of 0.14nmol/L [95% confidence interval (95% CI), -6.8 to 7.1]. Both methods demonstrate close agreement for 25(OH)D3 in UCB serum versus diluted UCB plasma; mean difference 2.2nmol/L [95% CI, -9.5 to 13.9] and 4.1nmol/L [95% CI, 14.5 to 6.1] for the results from Lab A and Lab B, respectively. Vitamin A was quantified by Lab A in UCB serum and diluted UCB plasma; mean difference 0.07MUmol/L [95% CI, -0.41 to 0.28]. Results of 25(OH)D3 epimer and vitamin E in the diluted UCB plasma were below the limit of quantification, and could not be compared with UCB serum. CONCLUSIONS: Diluted UCB plasma can be used for the quantification of retinol and 25(OH)D3 by LC-MS/MS. By contrast, quantification of 25(OH)D3 epimer and vitamin E in diluted UCB plasma is not supported by this study due to limitations in analytical sensitivity. PMID- 25920892 TI - Prediction of the severity of acute pancreatitis on admission by carboxypeptidase B activation peptide: A systematic review and meta-analysis. AB - OBJECTIVES: The assessment of acute pancreatitis severity on admission currently remains a challenge to clinicians. A single, rapid biochemical marker would be preferable to clinical and radiological scoring systems. The aim of this study was to undertake a meta-analysis on the value of carboxypeptidase-B activation peptide (CAPAP) in predicting severity of acute pancreatitis on admission. METHODS: Major databases and trial registries were searched to identify all relevant studies from January 1998 to March 2015. Pooled sensitivity, specificity and the diagnostic odds ratios (DOR) with 95% confidence interval (CI) were calculated for each study and were compared to other biomarkers, if included, within the same study. Summary receiver-operating curves (ROC) were conducted and the area under the curve (AUC) was evaluated. RESULTS: In total, six studies were included. At the time of admission, the AUC of serum CAPAP for predicting severity of acute pancreatitis was 0.86 with pooled sensitivity, specificity and DOR of 0.90, 0.70 and 19.08, respectively. When serum CAPAP was compared with urinary CAPAP, the AUC, pooled sensitivity, specificity and DOR were 0.69 vs 0.88, 0.90 vs 0.81, 0.68 vs. 0.77 and 17.96 vs. 18.58, respectively. Similarly, the AUC, pooled sensitivity, specificity and DOR of serum CAPAP vs maximal serum C-reactive protein within the first 3 days of admission were found to be 0.97 vs. 0.82, 0.92 vs. 0.88, 0.81 vs 0.68 and 37.90 vs. 18.80, respectively. CONCLUSIONS: Both serum and urinary CAPAP have the potential to act as a stratification marker on admission in predicting severity of acute pancreatitis. PMID- 25920893 TI - Kinamycin biosynthesis employs a conserved pair of oxidases for B-ring contraction. AB - The biosynthesis of diazobenzofluorene kinamycins requires a hitherto uncharacterized B-ring contraction. Via detailed genetic and enzymatic analyses we unambiguously characterized the conserved pairs of oxidases, AlpJ and AlpK homologs, as nature's machinery for benzofluorenone formation, which paves the way for the investigation of the following diazo assembly. PMID- 25920894 TI - [Initial experiences of an orthogeriatric unit]. AB - OBJECTIVE: To report the design and outcomes obtained during the first operational years of the Orthogeriatric Unit (OGU) established in the Zaragoza-1 (Spain) Health-Sector. MATERIAL AND METHODS: A total of 494 patients >70 years old treated in the OGU from February 2009 to December 2012. An analysis was performed using the following variables: demography, previous functional level, comorbidities, surgical delay, fracture type and surgical technique, complications, hospital stay, functional outcomes, destination after hospital discharge, and short and long term mortality. RESULTS: Mean age 85.22 years. High incidence of comorbidities (Charlson Index): 24.3%. Dementia: 38.5%. Surgical delay: 2.57 days. Mean hospital stay between admission and discharge/transfer to convalescence unit, 20.9 days (Traumatology 6.45+OGU 14.49). More than a third (34.6%) of patients suffered from delirium. Mean functional improvement (Barthel index at hospital discharge-Barthel index at hospital admission): 27.25 points. Montebello index: 0.49. In-hospital mortality: 6.9%. CONCLUSION: Hip fracture is such a frequent and disabling pathology among the geriatric population that its treatment requires an interdisciplinary approach. This must be managed by the geriatrician, who has to assure the continuity and integration of the diverse treatment and care schedules, with the participation of the entire professional team in the decision-making process. We are very satisfied with the creation of our interdisciplinary Unit that enables us to report competitive outcomes. We believe that the progression of this Unit from providing subacute to acute care will improve the general outcomes in the future. PMID- 25920895 TI - Quantification of the role of tibial posterior slope in knee joint mechanics and ACL force in simulated gait. AB - The anterior cruciate ligament (ACL) rupture is a common knee joint injury with higher prevalence in female athletes. In search of contributing mechanisms, clinical imaging studies of ACL-injured individuals versus controls have found greater medial-lateral posterior tibial slope (PTS) in injured population irrespective of the sex and in females compared to males, with stronger evidence on the lateral plateau slope. To quantify these effects, we use a lower extremity musculoskeletal model including a detailed finite element (FE) model of the knee joint to compute the role of changes in medial and/or lateral PTS by +/-5 degrees and +/-10 degrees on knee joint biomechanics, in general, and ACL force, in particular, throughout the stance phase of gait. The model is driven by reported kinematics/kinetics of gait in asymptomatic subjects. Our predictions showed, at all stance periods, a substantial increase in the anterior tibial translation (ATT) and ACL force as PTS increased with reverse trends as PTS decreased. At mid stance, for example, ACL force increased from 181 N to 317 N and 460 N as PTS increased by 5 degrees and 10 degrees , respectively, while dropped to 102 N and 0 N as PTS changed by -5 degrees and -10 degrees , respectively. These effects are caused primarily by change in PTS at the tibial plateau that carries a larger portion of joint contact force. Steeper PTS is a major risk factor, especially under activities with large compression, in markedly increasing ACL force and its vulnerability to injury. Rehabilitation and ACL injury prevention programs could benefit from these findings. PMID- 25920896 TI - Mechanical characterization of matrix-induced autologous chondrocyte implantation (MACI(r)) grafts in an equine model at 53 weeks. AB - There has been much interest in using autologous chondrocytes in combination with scaffold materials to aid in cartilage repair. In the present study, a total of 27 animals were used to compare the performance of matrix-assisted chondrocyte implantation (MACI(r)) using a collagen sponge as a chondrocyte delivery vehicle, the sponge membrane alone, and empty controls. A total of three distinct types of mechanical analyses were performed on repaired cartilage harvested from horses after 53 weeks of implantation: (1) compressive behavior of samples to measure aggregate modulus (HA) and hydraulic permeability (k) in confined compression; (2) local and global shear modulus using confocal strain mapping; and (3) boundary friction coefficient using a custom-built tribometer. Cartilage defects receiving MACI(r) implants had equilibrium modulus values that were 70% of normal cartilage, and were not statistically different than normal tissue. Defects filled with MaixTM membrane alone or left empty were only 46% and 51-63% of control, respectively. The shear modulus of tissue from all groups of cartilage defects were between 4 and 10 times lower than control tissue, and range from 0.2 to 0.4 MPa. The average values of boundary mode friction coefficients of control tissue from all groups ranged from 0.42 to 0.52. This study represents an extensive characterization of the mechanical performance of the MACI(r) grafts implant in a large animal model at 53 weeks. Collectively, these data demonstrate a range of implant performance, revealing similar compressive and frictional properties to native tissue, with inferior shear properties. PMID- 25920897 TI - Soft tissue artifact distribution on lower limbs during treadmill gait: Influence of skin markers' location on cluster design. AB - Segment poses and joint kinematics estimated from skin markers are highly affected by soft tissue artifact (STA) and its rigid motion component (STARM). While four marker-clusters could decrease the STA non-rigid motion during gait activity, other data, such as marker location or STARM patterns, would be crucial to compensate for STA in clinical gait analysis. The present study proposed 1) to devise a comprehensive average map illustrating the spatial distribution of STA for the lower limb during treadmill gait and 2) to analyze STARM from four marker clusters assigned to areas extracted from spatial distribution. All experiments were realized using a stereophotogrammetric system to track the skin markers and a bi-plane fluoroscopic system to track the knee prosthesis. Computation of the spatial distribution of STA was realized on 19 subjects using 80 markers apposed on the lower limb. Three different areas were extracted from the distribution map of the thigh. The marker displacement reached a maximum of 24.9 mm and 15.3 mm in the proximal areas of thigh and shank, respectively. STARM was larger on thigh than the shank with RMS error in cluster orientations between 1.2 degrees and 8.1 degrees . The translation RMS errors were also large (3.0 mm to 16.2 mm). No marker-cluster correctly compensated for STARM. However, the coefficient of multiple correlations exhibited excellent scores between skin and bone kinematics, as well as for STARM between subjects. These correlations highlight dependencies between STARM and the kinematic components. This study provides new insights for modeling STARM for gait activity. PMID- 25920898 TI - Disturbed flow in a patient-specific arteriovenous fistula for hemodialysis: Multidirectional and reciprocating near-wall flow patterns. AB - Actual surgical creation of vascular access has unacceptable failure rates of which stenosis formation is a major cause. We have shown previously in idealized models of side-to-end arteriovenous fistula that disturbed flow, a near-wall hemodynamic condition characterized by low and oscillating fluid shear stress, develops in focal points that corresponds closely to the sites of future stenosis. Our present study was aimed at investigating whether disturbed flow occurs in patient-specific fistulae, too. We performed an image-based computational fluid dynamics study within a realistic model of wrist side-to-end anastomosis fistula at six weeks post-surgery, with subject-specific blood rheology and boundary conditions. We then categorized disturbed flow by means of established hemodynamic wall parameters. The numerical analysis revealed laminar flow within the arterial limbs and a complex flow field in the swing segment, featuring turbulent eddies leading to high frequency oscillation of the wall shear stress vectors. Multidirectional disturbed flow developed on the anastomosis floor and on the whole swing segment. Reciprocating disturbed flow zones were found on the distal artery near the floor and on the inner wall of the swing segment. We have found that both multidirectional and reciprocating disturbed flow develop on the inner side of the swing segment in a patient specific side-to-end fistula used for vascular access after six weeks post operatively. This has obvious implications for elucidating the hemodynamic forces involved in the initiation of venous wall thickening in vascular access. PMID- 25920899 TI - Deleterious impact of hyperglycemia on cystic fibrosis airway ion transport and epithelial repair. AB - BACKGROUND: Cystic fibrosis (CF)-related diabetes (CFRD) is associated with faster pulmonary function decline. Thus, we evaluated the impact of hyperglycemia on airway epithelial repair and transepithelial ion transport, which are critical in maintaining lung integrity and function. METHODS: Non-CF and CF airway epithelial cells were exposed to low (LG) or high (HG) glucose before ion current and wound repair rate measurements. RESULTS: CFTR and K+ currents decreased after HG treatments. HG also reduced the wound healing rates of non-CF and CF cell monolayers. Although CFTR correction with VRT-325 accelerated the healing rates of CF cells monolayers under LG conditions, this improvement was significantly abrogated under HG conditions. CONCLUSIONS: Our data highlights a deleterious impact of hyperglycemia on ion transport and epithelial repair functions, which could contribute to the deterioration in lung function in CFRD patients. HG may also interfere with the beneficial effects of CFTR rescue on airway epithelial repair. PMID- 25920900 TI - Solid-State NMR Study of Paramagnetic Bis(alaninato-kappa(2)N,O)copper(II) and Bis(1-amino(cyclo)alkane-1-carboxylato-kappa(2)N,O)copper(II) Complexes: Reflection of Stereoisomerism and Molecular Mobility in (13)C and (2)H Fast Magic Angle Spinning Spectra. AB - Solid-state stereochemistry and mobility of paramagnetic copper(II) complexes formed by aliphatic amino acids (l-alanine, d,l-alanine, 1-amino-2-methyl alanine) and 1-amino(cyclo)alkane-1-carboxylic acids (alkane = propane, butane, pentane, hexane) as bidentate ligands has been studied by (13)C and (2)H solid state fast magic angle spinning (MAS) NMR spectroscopy. We examined the prospective method to characterize solid-state paramagnetic compounds in a routine way. Both (13)C and (2)H MAS spectra can distinguish d,l and l,l diastereomers of natural and polydeuterated bis([Dn]alaninato)copper(II) (n = 0, 2, 8) complexes with axial and/or equatorial methyl positions (conformations) primarily due to different Fermi-contact (FC) contributions. The three-bond hyperfine couplings clearly show Karplus-like dependence on the torsional angles which turned out to be a useful assignment aid. Density functional theory calculations of the FC term and crystal structures were also used to aid the final assignments. The correlations obtained for bis(alaninato kappa(2)N,O)copper(II) complexes were successfully used to characterize other complexes. The usefulness of the (2)H MAS spectra of the deuterated complexes was underlined. Even the spectra of the easily exchangeable amine protons contained essential stereochemical information. In the case of a dimer structure of bis(1 aminohexane-1-carboxylato-kappa(2)N,O)copper(II) both the (13)C and (2)H resolutions were good enough to confirm the presence of the cis and trans forms in the asymmetric unit. With regard to the internal solid-state motions in the crystal lattice, the obtained quadrupolar tensor parameters were similar for the d,l- and l,l-alaninato isomers and also for the cis-trans forms suggesting similar crystal packing effects, static amine deuterons involved in hydrogen bonding, and fast rotating methyl groups. PMID- 25920901 TI - What is it that lingers? Garden-path (mis)interpretations in younger and older adults. AB - Previous research has shown that comprehenders do not always conduct a full (re)analysis of temporarily ambiguous "garden-path" sentences. The present study used a sentence-picture matching task to investigate what kind of representations are formed when full reanalysis is not performed: Do comprehenders "blend" two incompatible representations as a result of shallow syntactic processing or do they erroneously maintain the initial incorrect parsing without incorporating new information, and does this vary with age? Twenty-five younger and 15 older adults performed a multiple-choice sentence-picture matching task with stimuli including early-closure garden-path sentences. The results suggest that the type of erroneous representation is affected by linguistic variables, such as sentence structure, verb type, and semantic plausibility, as well as by age. Older adults' response patterns indicate an increased reliance on inferencing based on lexical and semantic cues, with a lower bar for accepting an initial parse and with a weaker drive to reanalyse a syntactic representation. Among younger adults, there was a tendency to blend two representations into a single interpretation, even if this was not licensed by the syntax. PMID- 25920902 TI - Salvaging catastrophe in transcatheter aortic valve implantation: rehearsal, preassigned roles, and emergency preparedness. AB - PURPOSE: Emergency rescue plans for acute complications during transcatheter aortic valve implantation (TAVI) commonly include cardiopulmonary resuscitation, femoro-femoral cardiopulmonary bypass (CPB), and hemodynamic stabilization before definitive intervention is achieved. Nevertheless, most cases of emergency resuscitation remain chaotic and disorganized and often take longer than necessary, even in experienced centres. We sought to determine which factors and procedures may be associated with improved patient outcomes when emergencies arise during TAVI. SOURCES: MEDLINE((r)) and EMBASETM were searched with the following key words: "TAVI" or "TAVR" or "transcatheter valve implantation" or "transcatheter valve replacement" and "emergency cardiac surgery" or "conversion". Two hundred seventeen articles met the criteria and were reviewed. PRINCIPAL FINDINGS: Utilization of a formal emergency checklist by a multidisciplinary TAVI team may reduce procedural errors, smooth the transition to CPB, and ultimately speed the delivery of corrective measures including emergency cardiac surgery. CONCLUSION: A well-organized regularly-rehearsed emergency rescue plan that preassigns resuscitative roles may shorten the duration of patient instability and resuscitation and improve patient outcomes when catastrophe occurs in TAVI. The anesthesia team plays a central role in preventing, detecting, and treating intraprocedural complications during TAVI. PMID- 25920903 TI - Estimated glomerular filtration rate better predicts 30-day mortality after non cardiac surgery than serum creatinine: a retrospective analysis of 92,888 patients. AB - BACKGROUND: Serum creatinine is the most commonly used indicator of renal function, but its derivative, estimated glomerular filtration rate (eGFR), has been shown to be superior in non-surgical settings. It remains unknown if eGFR better predicts postoperative mortality in non-cardiac surgical patients. We thus tested the hypothesis that eGFR predicts 30-day mortality after non-cardiac surgery better than serum creatinine. METHODS: We evaluated patients who had inpatient non-cardiac surgery of at least one hour duration during January 2006 to December 2011 at the Cleveland Clinic Main Campus and whose preoperative serum creatinine was measured within 30 days before surgery. The eGFR was calculated using the Chronic Kidney Disease-Epidemiology Collaboration equation. Preoperative eGFR was compared in a multivariable analysis with preoperative serum creatinine (both assessed as continuous variables) on the ability to predict 30-day mortality in all patients. Secondarily, the comparison was made within subgroups based on amount of blood loss, blood transfusion, and sex. RESULTS: There were 92,888 patients included in the final analysis. The eGFR was a modestly better discriminator of 30-day mortality than serum creatinine, with an estimated c-statistic (95% confidence interval) of 0.67 (0.65 to 0.68) for eGFR vs 0.61 (0.59 to 0.63) for serum creatinine (P < 0.001). Furthermore, the eGFR was consistently a better discriminator of 30-day mortality across blood loss, transfusion, and sex groups. Reclassification analyses suggested improved individual predictions of 30-day mortality using eGFR compared with serum creatinine. Nevertheless, a multivariable combination of baseline characteristics of American Society of Anesthesiologists physical status, age, and body mass index (all P < 0.001) discriminated 30-day mortality with a c-statistic of 0.850. Adding eGFR to the model improved the c-statistic to only 0.851, while separately adding serum creatinine did not change the c-statistic. CONCLUSION: The eGFR is a modestly better predictor of 30-day mortality than serum creatinine in patients having inpatient non-cardiac surgery. Given that eGFR is often reported by clinical laboratories and is otherwise easy to calculate, it should generally be used in preference to creatinine alone. PMID- 25920905 TI - Fast and safe microwave-assisted glass channel-shaped microstructure fabrication. AB - Glass micromachining is a basic technology to achieve microfluidic networks for lab-on-a-chip applications. Among several methods to microstructure glass, the simplest and most widely applied is wet chemical etching (WE). However, accurate control of the reaction conditions to perform reproducible, fast and safe glass etching is not straightforward. Herein, microwave-assisted WE is demonstrated to intensify the glass etching action under safe working and finely monitored operative conditions and to produce smooth deep channels in short processing times with reduced underetching effects. PMID- 25920904 TI - Nest-dwelling ectoparasites reduce antioxidant defences in females and nestlings of a passerine: a field experiment. AB - Ectoparasites may imply a cost in terms of oxidative stress provoked by inflammatory responses in hosts. Ectoparasites may also result in costs for nestlings and brooding females because of the direct loss of nutrients and reduced metabolic capacity resulting from parasite feeding activities. These responses may involve the production of reactive oxygen and nitrogen species that may induce oxidative damage in host tissues. Our goal was to examine the effect of ectoparasites in terms of oxidative stress for nestlings and adult females in a population of pied flycatchers Ficedula hypoleuca. We manipulated the entire nest ectoparasite community by reducing ectoparasite loads in some nests through a heating treatment and compared them with a control group of nests with natural loads. A marker of total antioxidant capacity (TAS) in plasma and total levels of glutathione (tGSH) in red blood cells as well as a marker of oxidative damage in plasma lipids (malondialdehyde; MDA) were assessed simultaneously. Levels of tGSH were higher in heat-treated nests than in controls for both females and nestlings. Higher TAS values were observed in females from heat-treated nests. In nestlings there was a negative correlation between TAS and MDA. Our study supports the hypothesis that ectoparasites expose cavity-nesting birds to an oxidative challenge. This could be paid for in the long term, ultimately compromising individual fitness. PMID- 25920906 TI - Psychological distress and quality of life in lung cancer: the role of health related stigma, illness appraisals and social constraints. AB - OBJECTIVE: Health-related stigma is associated with negative psychological and quality of life outcomes in lung cancer patients. This study describes the impact of stigma on lung cancer patients' psychological distress and quality of life and explores the role of social constraints and illness appraisal as mediators of effect. METHODS: A self-administered cross-sectional survey examined psychological distress and quality of life in 151 people (59% response rate) diagnosed with lung cancer from Queensland and New South Wales. Health-related stigma, social constraints and illness appraisals were assessed as predictors of adjustment outcomes. RESULTS: Forty-nine percent of patients reported elevated anxiety; 41% were depressed; and 51% had high global distress. Health-related stigma was significantly related to global psychological distress and quality of life with greater stigma and shame related to poorer outcomes. These effects were mediated by illness appraisals and social constraints. CONCLUSIONS: Health related stigma appears to contribute to poorer adjustment by constraining interpersonal discussions about cancer and heightening feelings of threat. There is a need for the development and evaluation of interventions to ameliorate the negative effects of health-related stigma among lung cancer patients. PMID- 25920907 TI - Medicines taken by older Australians after transient ischaemic attack or ischaemic stroke: a retrospective database study. AB - BACKGROUND: Guidelines recommend patients diagnosed with transient ischaemic attack (TIA) or ischaemic stroke receive antihypertensive, antithrombotic and lipid lowering medicines. Reassessment of the need for medicines associated with an increased risk of stroke is also recommended. OBJECTIVE: To determine changes in the use of medicines recommended for secondary stroke prevention, medicines commonly used for treating stroke-related complications and medicines not recommended for use after ischaemic stroke, and to determine patient characteristics associated with use of all three stroke prevention medicines after TIA or ischaemic stroke. Setting Administrative health claims data from the Australian Government Department of Veterans' Affairs. METHOD: This retrospective study included patients with a first-ever hospitalisation for TIA or ischaemic stroke in 2009 and alive at 4 months after discharge. Changes to medicines dispensed in the 4 months before and after hospitalisation were compared using McNemar's test. Log binomial regression analysis was used to determine patient characteristics associated with use of all three secondary stroke prevention medicines after hospitalisation for TIA or ischaemic stroke. MAIN OUTCOME MEASURE: Prevalence of medicine use after hospitalisation. RESULTS: 1541 patients (853 TIA, 688 ischaemic stroke) were included, with a median age of 85 years. High use of antihypertensive (82% TIA, 86 % ischaemic stroke) and antithrombotic (84% TIA, 90% ischaemic stroke) medicines was observed postdischarge, with 58% of TIA and 73% of ischaemic stroke patients receiving lipid lowering therapy. Half of the population (47% TIA, 61% ischaemic stroke) were dispensed all three classes of medicines recommended for secondary stroke prevention after discharge. Ischaemic stroke patients, younger patients, patients with more comorbid conditions and those discharged home were more likely to receive all three recommended medicine classes. Antibiotics (45% TIA, 46% ischaemic stroke), paracetamol (44% TIA, 47% ischaemic stroke), antidepressants (26% TIA, 31% ischaemic stroke) and laxatives (24% TIA, 32% ischaemic stroke) were commonly used after discharge. Increased use of sedatives and reduced use of non-steroidal anti-inflammatories was also observed after discharge. CONCLUSION: Changes to pharmacotherapy after TIA or ischaemic stroke were consistent with treatment for stroke risk factors and common stroke-related complications. Use of secondary stroke prevention medicines may be further improved among TIA patients. PMID- 25920908 TI - Developing and testing evidence-based weight management in Australian pharmacies: A Healthier Life Program. AB - BACKGROUND: Pharmacies represent a valuable opportunity to deliver weight management services, rather than just the routine supply of weight-loss products. In order to provide optimal services and translation of evidence-based weight management in community pharmacy, a best practice model program was designed and pilot tested to facilitate implementation of such services in pharmacies in Australia. OBJECTIVE: To develop and pilot a pharmacist-delivered, evidence based, non-product-centred weight management service for community pharmacy in Australia. Setting Sydney, New South Wales, Australia. METHOD: A pharmacy-based weight management service called the A Healthier Life Program (AHLP), for overweight and obese individuals, was developed based on current Australian weight management guidelines and recommendations made by key stakeholders. The pharmacist undertook training to acquire specific competencies to deliver the program. The AHLP involved six individual face-to-face sessions with the pharmacist over 3 months. The intervention targeted three areas: diet, physical activity and behavioural change. MAIN OUTCOME MEASURES: Weight, BMI, waist circumference, blood pressure, dietary intake, and physical activity levels at 3 months were compared with values at baseline. Qualitative feedback on participants' satisfaction and willingness to pay were also analysed. RESULTS: Eight pharmacies provided the AHLP between February and December 2013. Thirty four participants were enrolled in the AHLP; mean age 50.7 years (SD 15.7) and mean BMI 34.3 kg/m(2) (SD 5.3). Of the 22 (65%) participants who completed the program, six had achieved the target weight loss of >=5%. The mean change in weight was -3.5 kg (95% CI -4.8, -2.2) and waist circumference -2.0 cm (95% CI 2.8, -1.3) for program completers at 3 months. Furthermore, participants reported overall positive experiences of the program, and identified accessibility of the pharmacy and high comfort level with the pharmacist, as the major advantages. CONCLUSION: The AHLP was well received and participants achieved targeted weight loss. This study demonstrated that an evidence-based patient-centred weight management program can be implemented in Australian pharmacies. PMID- 25920909 TI - Extended pancreatoduodenectomy as defined by the International Study Group for Pancreatic Surgery is associated with worse survival but not with increased morbidity. AB - BACKGROUND: Recently, the International Study Group for Pancreatic Surgery presented a consensus statement on the definition of an extended pancreatoduodenectomy (PD) for pancreatic ductal adenocarcinoma (PDAC). Because extended resections are associated with increased morbidity and mortality, prognostic factors for outcome are mandatory to optimize patient selection. The aim of this study was to apply the new definition of an extended PD and to assess prognostic factors for short-term complications and survival in patients with PDAC. METHODS: A retrospective analysis was performed on a prospectively collected database running from 2004 to 2014. Inclusion criteria were all PD resections with histopathology-proven PDAC. Clinical data, operative results, and short- and long-term outcomes were analyzed. RESULTS: We included 177 patients who underwent PD for PDAC in this study. Sixty-six patients (37%) underwent a standard PD and 111 (63%) underwent an extended PD. No differences were found in duration of postoperative stay (median, 13 days) or overall complication rate of 35% (n = 61). Severe complications occurred in 24 patients (13%). Male sex (odds ratio, 2.4; 95% CI, 0.9-6.6) was a prognostic factor for severe complications. There was no in-hospital or 90-day mortality in either group. Multivariate survival analysis showed that poor tumor differentiation (hazard ratio [HR], 2.0; 95% CI, 1.3-3.1), lymph node metastasis (HR, 2.3; 95% CI, 1.4-3.9), neural invasion (HR, 1.9; 95% CI, 1.2-3.1), were independent prognostic factors for worse survival. An extended resection was associated with worse survival, but was not an independent prognostic factor (HR, 1.5; 95% CI, 1.0-2.3). CONCLUSION: Extended PD is associated with worse survival but not with increased morbidity. PMID- 25920910 TI - "V-Plasty" technique using dual synthetic vascular grafts to reconstruct outflow channel in living donor liver transplantation. AB - BACKGROUND: The reconstruction of outflow is a crucial step in living donor liver transplantation. This study describes a suitable technique that uses synthetic vascular conduits in presence of multiple draining veins of right lobe of liver and the outcome of the recipients to evaluate safety of using multiple synthetic grafts. METHODS: From March 2011 to September 2014, 325 patients underwent right lobe living donor liver transplantation. Expanded polytetra-fluoroethylene (ePTFE) grafts were used in total 155 of the liver allografts. Among these, 16 liver grafts required dual ePTFE grafts to reconstruct the outflow due to presence of multiple hepatic veins. RESULTS: The mean diameters for venous branches of segment 5 (V5) and 8 (V8) were 5 mm (range, 4-8 mm) and 7 mm (range, 5-9 mm). The mean diameter of inferior right hepatic veins was 8 mm (7-10 mm). All the recipients who received the right liver with dual ePTFE grafts showed satisfactory inflow and outflow immediately after reconstruction as measured by Doppler flowmetry. Postoperative ultrasonographic studies showed no disturbances in outflow. Protocol dynamic computed tomography performed in the second postoperative month showed 100% patency rates of the artificial grafts. At median follow-up of 24 months graft survival was achieved in 88%, whereas the patency rates of the ePTFE grafts were 100%. CONCLUSION: The use of "V-Plasty" technique using dual artificial vascular grafts is a safe and feasible technique in the presence of various allograft venous anomalies & ensures a single venous channel for outflow reconstruction. Our study also suggests that ePTFE graft may be a useful interposition material without serious complications. PMID- 25920911 TI - Do surgical care bundles reduce the risk of surgical site infections in patients undergoing colorectal surgery? A systematic review and cohort meta-analysis of 8,515 patients. AB - BACKGROUND: Care bundles are a strategy that can be used to reduce the risk of surgical site infection (SSI), but individual studies of care bundles report conflicting outcomes. This study assesses the effectiveness of care bundles to reduce SSI among patients undergoing colorectal surgery. METHODS: We performed a systematic review and meta-analysis of randomized controlled trials, quasi experimental studies, and cohort studies of care bundles to reduce SSI. The search strategy included database and clinical trials register searches from 2012 until June 2014, searching reference lists of retrieved studies and contacting study authors to obtain missing data. The Downs and Black checklist was used to assess the quality of all studies. Raw data were used to calculate pooled relative risk (RR) estimates using Cochrane Review Manager. The I(2) statistic and funnel plots were performed to identify publication bias. Sensitivity analysis was carried out to examine the influence of individual data sets on pooled RRs. RESULTS: Sixteen studies were included in the analysis, with 13 providing sufficient data for a meta-analysis. Most study bundles included core interventions such as antibiotic administration, appropriate hair removal, glycemic control, and normothermia. The SSI rate in the bundle group was 7.0% (328/4,649) compared with 15.1% (585/3,866) in a standard care group. The pooled effect of 13 studies with a total sample of 8,515 patients shows that surgical care bundles have a clinically important impact on reducing the risk of SSI compared to standard care with a CI of 0.55 (0.39-0.77; P = .0005). CONCLUSION: The systematic review and meta-analysis documents that use of an evidence-based, surgical care bundle in patients undergoing colorectal surgery significantly reduced the risk of SSI. PMID- 25920912 TI - The epidemiology, microbiology and clinical impact of Shiga toxin-producing Escherichia coli in England, 2009-2012. AB - Between 1 January 2009 and 31 December 2012 in England, a total of 3717 cases were reported with evidence of Shiga toxin-producing E. coli (STEC) infection, and the crude incidence of STEC infection was 1.80/100 000 person-years. Incidence was highest in children aged 1-4 years (7.63/100 000 person-years). Females had a higher incidence of STEC than males [rate ratio (RR) 1.24, P < 0.001], and white ethnic groups had a higher incidence than non-white ethnic groups (RR 1.43, P < 0.001). Progression to haemolytic uraemic syndrome (HUS) was more frequent in females and children. Non-O157 STEC strains were associated with higher hospitalization and HUS rates than O157 STEC strains. In STEC O157 cases, phage type (PT) 21/28, predominantly indigenously acquired, was also associated with more severe disease than other PTs, as were strains encoding stx2 genes. Incidence of STEC was over four times higher in people residing in rural areas than urban areas (RR 4.39, P < 0.001). Exposure to livestock and/or their faeces was reported twice as often in cases living in rural areas than urban areas (P < 0.001). Environmental/animal contact remains an important risk factor for STEC transmission and is a significant driver in the burden of sporadic STEC infection. The most commonly detected STEC serogroup in England was O157. However, a bias in testing methods results in an unquantifiable under ascertainment of non-O157 STEC infections. Implementation of PCR-based diagnostic methods designed to detect all STEC, to address this diagnostic deficit, is therefore important. PMID- 25920913 TI - RNAi-mediated downregulation of CDKL1 inhibits growth and colony-formation ability, promotes apoptosis of human melanoma cells. AB - BACKGROUND: Cyclin-dependent kinase-like 1 (CDKL1) is a member of cell division control protein 2 (CDC-2)-related serine threonine protein kinase family, and is reported to be overexpressed in malignant tumors such as breast cancer and gastric cancer. OBJECTIVE: This study aimed to evaluate the whether CDKL1 can serve as a potential molecular target for melanoma gene therapy. METHODS: CDKL1 expression in two melanoma cell lines, A375 and MV3 was measured by real-time PCR. To investigate the role of CDKL1 in cell growth of melanoma, we constructed CDKL1-siRNA expressing lentivirus and infected A375 and MV3 cells. The effects of RNAi-mediated CDKL1 downregulation on A375 and MV3 cell proliferation and colony formation ability were detected by methylthiazoletetrazolium (MTT) assay and colony-formation assay. The effects of CDKL1 downregulation on A375 and MV3 cell cycle and apoptosis were analyzed by FACS analysis. RESULTS: Human melanoma cell lines A375 and MV3 expressed CDKL1 mRNA. Knockdown of CDKL1 in A375 and MV3 by CDKL1-siRNA lentivirus infection significantly inhibited cell growth and colony formation ability, promoted cell apoptosis, and arrested cells in G1 phase. CONCLUSION: CDKL1 is associated with melanoma cell growth, colony formation, apoptosis, and cell cycle regulation. It may be considered as a valuable target for anti-melanoma therapeutic strategies. PMID- 25920914 TI - Survival of diabetes patients with major amputation is comparable to malignant disease. AB - INTRODUCTION: Almost all studies on diabetic foot syndrome focused on prevention of amputation and did not investigate long-term prognosis and survival of patients as a primary outcome parameter. METHODS: We did a retrospective cohort study including 314 patients who had diabetic foot syndrome and underwent amputation between December 1995 and January 2001. RESULTS: A total of 48% of patients received minor amputation (group I), 15% only major amputation (group II) and 36% initially underwent a minor amputation that was followed by a major amputation (group III). Statistically significant differences were observed in comparison of the median survival of group I to group II (51 vs. 40 months; p = 0.016) and of group II to group III (40 vs. 55 months; p = 0.003). DISCUSSION: The prognosis of patients with major amputation due to diabetic foot syndrome is comparable to patients with malignant diseases. Vascular interventions did not improve the individual prognosis of patients. PMID- 25920915 TI - Hyperhomocysteinaemia is associated with low plasma apolipoprotein AI levels in patients with impaired glucose tolerance. AB - Homocysteine suppresses hepatic apolipoprotein AI synthesis in mice. We assessed the relationship between homocysteine and apolipoprotein AI levels in patients with impaired glucose tolerance. A total of 217 participants, including 95 impaired glucose tolerance patients and 122 healthy subjects, were classified as normal control subjects without hyperhomocysteinaemia, control subjects with hyperhomocysteinaemia, impaired glucose tolerance patients without hyperhomocysteinaemia (n-IGT) and impaired glucose tolerance patients with hyperhomocysteinaemia (H-IGT). The impaired glucose tolerance patients had higher plasma levels of homocysteine and homeostasis model assessment index of insulin resistance values, and lower plasma apolipoprotein AI levels than the normal control and control subjects with hyperhomocysteinaemia (all p < 0.01). Decreased plasma apolipoprotein AI levels and increased homeostasis model assessment index of insulin resistance values were observed in the H-IGT group compared with the n IGT group (p < 0.05). Plasma homocysteine levels were negatively correlated with apolipoprotein AI levels after adjusting for age, gender, body mass index and homeostasis model assessment index of insulin resistance. Plasma homocysteine level independently influenced the apolipoprotein AI levels (beta = -0.02, p < 0.05). In conclusion, increased plasma homocysteine levels were associated with decreased apolipoprotein AI levels in impaired glucose tolerance subjects. PMID- 25920916 TI - Association of mitochondrial DNA haplogroups and vascular complications of diabetes mellitus: A population-based study. AB - We investigated whether mitochondrial (mtDNA) haplogroups and maternal family history of diabetes mellitus were associated with vascular diabetes mellitus complications in a population-based cohort of 299 Finnish diabetes mellitus patients with disease onset in young adult age. We found that haplogroup U was more prevalent among patients with no vascular diabetes mellitus complications than among those with at least one complication (p = 0.038). Haplogroup U was also more prevalent among the patients who reported maternal family history of diabetes mellitus than among those who did not (p = 0.0013). Furthermore, haplogroup U was more prevalent among patients with maternal family history of diabetes mellitus but no vascular diabetes mellitus complications than among those with at least one vascular diabetes mellitus complication but no maternal family history of diabetes mellitus (p = 0.0003 for difference). These findings suggest that different mtDNA-related factors may influence the risk of diabetes mellitus per se and the risk of vascular diabetes mellitus complications. Further studies are, however, warranted to replicate and elaborate on these results. PMID- 25920917 TI - The Effect of Needle Gauge on the Risk of Pneumothorax and Chest Tube Placement After Percutaneous Computed Tomographic (CT)-Guided Lung Biopsy. AB - BACKGROUND: The aim of this study was to evaluate the effect of coaxial guide needle gauge (18 vs. 19 gauge) on the risk of pneumothorax and chest tube placement after CT-guided lung biopsy. METHODS: Imaging records of all patients who had undergone CT-guided lung biopsies at our institution from March 1, 2006 to December 9, 2010 were retrospectively reviewed. Univariate and multivariate logistic regression analyses were performed to assess the effect of various patient-, lesion-, and procedure-related variables on subsequent pneumothorax and chest tube placement rates. RESULTS: The study included 4262 biopsies (2304 with 18-gauge and 1958 with 19-gauge coaxial guide needles) in 3917 patients. The rates of pneumothorax and chest tube placement were 30.2 and 15%, respectively. Pneumothorax occurred in 35% of procedures performed with 18-gauge needles and in 24.5% of procedures performed with 19-gauge needles (p < 0.0001). Chest tube insertion occurred in 16.7% of procedures performed with 18-gauge needles and in 13.1% of procedures performed with 19-gauge needles (p = 0.0011). Multivariate logistic regression models demonstrated that the use of an 18-gauge needle was associated with a higher rate of pneumothorax (p < 0.0001) and chest tube placement (p = 0.0003). The following factors were also associated with higher rates of pneumothorax and chest tube placement: older age, emphysema, greater number of pleural surfaces crossed, and a longer biopsy needle path length. CONCLUSIONS: The use of a 19-gauge coaxial guide needle significantly decreases the risk of pneumothorax and chest tube placement compared with an 18-guage needle. PMID- 25920918 TI - Contralateral Prophylactic Mastectomy: Anxiety, Knowledge and Shared Decision Making. PMID- 25920919 TI - Ambulatory aortic blood pressure, wave reflections and pulse wave velocity are elevated during the third in comparison to the second interdialytic day of the long interval in chronic haemodialysis patients. AB - BACKGROUND: Increased arterial stiffness and aortic blood pressure (BP) are independent predictors of cardiovascular outcomes in end-stage renal disease. The 3-day interdialytic interval is associated with elevated risk of cardiovascular morbidity and mortality in haemodialysis. This study investigated differences in ambulatory aortic BP and arterial stiffness between the second and third day of the long interdialytic interval. METHODS: Ambulatory BP monitoring with Mobil-O Graph monitor (IEM, Stolberg, Germany) was performed in 55 haemodialysis patients during a 3-day interval. Mobil-O-Graph records oscillometric brachial BP and pulse waves and calculates aortic BP and augmentation index (AIx) as measure of wave reflections, and pulse wave velocity (PWV) as measure of arterial stiffness. RESULTS: Ambulatory aortic systolic blood pressure (SBP) and diastolic blood pressure (DBP) were higher during the third versus second interdialytic day (123.6 +/- 17.0 versus 118.5 +/- 17.1 mmHg, P < 0.001; 81.5 +/- 11.8 versus 78 +/ 11.9 mmHg, P < 0.001, respectively). Similar differences were noted for brachial BP. Ambulatory AIx and PWV were also significantly increased during the third versus second day (30.5 +/- 9.9 versus 28.8 +/- 9.9%, P < 0.05; 9.6 +/- 2.3 versus 9.4 +/- 2.3 m/s, P < 0.001, respectively). Differences between Days 2 and 3 remained significant when day-time and night-time periods were compared separately. Aortic SBP and DBP, AIx and PWV showed gradual increases from the end of dialysis session onwards. Interdialytic weight gain was a strong determinant of the increase in the above parameters. CONCLUSIONS: This study showed significantly higher ambulatory aortic BP, AIx and PWV levels during the third compared with the second interdialytic day. These findings support a novel pathway for increased cardiovascular risk during the third interdialytic day in haemodialysis. PMID- 25920920 TI - Lupus nephritis management guidelines compared. AB - In the past years, many (randomized) trials have been performed comparing the treatment strategies for lupus nephritis. In 2012, these data were incorporated in six different guidelines for treating lupus nephritis. These guidelines are European, American and internationally based, with one separate guideline for children. They offer information on different aspects of the management of lupus nephritis including induction and maintenance treatment of the different histological classes, adjunctive treatment, monitoring of the patient, definitions of response and relapse, indications for (repeat) renal biopsy, and additional challenges such as the presence of vascular complications, the pregnant SLE patient, treatment in children and adolescents and considerations about end-stage renal disease and transplantation. In this review, we summarize the guidelines, determine the common ground between them, highlight the differences and discuss recent literature. PMID- 25920921 TI - Improvement of mineral and bone metabolism markers is associated with better survival in haemodialysis patients: the COSMOS study. AB - BACKGROUND: Abnormalities in serum phosphorus, calcium and parathyroid hormone (PTH) have been associated with poor survival in haemodialysis patients. This COSMOS (Current management Of Secondary hyperparathyroidism: a Multicentre Observational Study) analysis assesses the association of high and low serum phosphorus, calcium and PTH with a relative risk of mortality. Furthermore, the impact of changes in these parameters on the relative risk of mortality throughout the 3-year follow-up has been investigated. METHODS: COSMOS is a 3 year, multicentre, open-cohort, prospective study carried out in 6797 adult chronic haemodialysis patients randomly selected from 20 European countries. RESULTS: Using Cox proportional hazard regression models and penalized splines analysis, it was found that both high and low serum phosphorus, calcium and PTH were associated with a higher risk of mortality. The serum values associated with the minimum relative risk of mortality were 4.4 mg/dL for serum phosphorus, 8.8 mg/dL for serum calcium and 398 pg/mL for serum PTH. The lowest mortality risk ranges obtained using as base the previous values were 3.6-5.2 mg/dL for serum phosphorus, 7.9-9.5 mg/dL for serum calcium and 168-674 pg/mL for serum PTH. Decreases in serum phosphorus and calcium and increases in serum PTH in patients with baseline values of >5.2 mg/dL (phosphorus), >9.5 mg/dL (calcium) and <168 pg/mL (PTH), respectively, were associated with improved survival. CONCLUSIONS: COSMOS provides evidence of the association of serum phosphorus, calcium and PTH and mortality, and suggests survival benefits of controlling chronic kidney disease-mineral and bone disorder biochemical parameters in CKD5D patients. PMID- 25920922 TI - Concurrent pyoderma gangrenosum and infection with Scedosporium apiospermum. AB - We present a patient with pyoderma gangrenosum (PG) following hip surgery, who developed an exacerbation of her ulceration in conjunction with new areas on her lower limbs. Clinically, features of PG and deep fungal infection were apparent. Scedosporium apiospermum was isolated from the ulcers. PMID- 25920923 TI - Searching for molecular-targeted interventions for NF1 cognitive deficits in the classroom. PMID- 25920924 TI - Severe regional myocardial dysfunction by stress echocardiography does not predict the presence of transmural scarring in chronic coronary artery disease. AB - AIMS: Detection and correct localization of transmural lesions can be important for optimal treatment of patients with chronic coronary artery disease (CAD). The aim of the study was to investigate the ability of peak longitudinal ejection strain (PLS) to detect the presence and extent of scar-tissue in CAD patients with normal or near normal ejection fraction, in comparison to cardiac magnetic resonance (CMR). METHODS AND RESULTS: Before coronary artery bypass grafting, 57 patients underwent late gadolinium enhancement (LGE) CMR and echocardiography at rest and dobutamine stress (DS). According to the degree of LGE, segments were allocated to groups of none, subendocardial (1-50%), subtotal (51-75%), and total transmural scars (>75%). Dysfunctional segments were identified by PLS or wall motion scores (WMS). The finding of normal/near normal resting WMS and PLS, excellently identified segments without transmural LGE (AUC 94.0 CI 90.6-97.3 and AUC 85.7 CI 79.0-92.3, respectively). However, the finding of akinesia did not necessarily indicate transmural scarring. The negative predictive value was high (99%, CI 98-100%) while the positive predictive value was low. Detection-rates for subendocardial LGE were low. CONCLUSION: Normo- and slightly hypokinetic myocardium by resting WMS or strain detects the absence of transmural scars. However, the finding of severe hypo- and akinesia does not reliably predict transmural scarring, with no improvement by the addition of DS. Detection of predominant akinesia with less than two normo- or hypokinetic segments in the territory of a high-grade coronary stenosis or occlusion, warrants further examination by LGE-CMR. PMID- 25920925 TI - EuroEcho-Imaging 2014: highlights. AB - The annual meeting of the European Association of Echocardiography (EuroEcho Imaging) was held in Vienna, Austria. In the present paper, we present a summary of the 'Highlights' session. PMID- 25920926 TI - Combined Application of Antibrowning, Heat Treatment and Modified-Atmosphere Packaging to Extend the Shelf Life of Fresh-Cut Lotus Root. AB - This work aimed to determine the effects of different concentrations of antibrowning treatments (that is, distilled water [DW], 1% ascorbic acid [AA], 0.5% chamomile [CM], and 1% AA + 0.5% CM) and heat-treatment (55 degrees C for 45 s) combined with packaging under 4 different modified-atmosphere gas compositions (that is, air, vacuum, 100% CO2 , 50% CO2 /50% N2 ) on the quality and microbiological characteristics of fresh-cut lotus root. The quality characteristics (that is, color, weight loss, texture, pH, polyphenoloxidase activity, and total phenolic content) of the AA + CM-dipped sample in 100% CO2 packaging were maintained significantly better than those of the other samples (P < 0.05). The microbiological counts observed in the DW-dipped sample during storage were higher than those of the AA, CM, and AA + CM samples, and heat treatment retarded the microbiological deterioration of fresh-cut lotus root. Therefore, the results revealed that dipping in an antibrowning treatment (AA + CM), and 100% CO2 MAP with heat treatment effectively extend the shelf life of fresh-cut lotus root to 21 d at 5 degrees C. PMID- 25920927 TI - The prognostic value of the head-shaft angle on hip displacement in children with cerebral palsy. AB - BACKGROUND: Hip displacement is the second most common deformity in cerebral palsy (CP). The risk for hip displacement is related to the Gross Motor Function Classification System (GMFCS). Recently, the head-shaft angle (HSA) has been identified as a predictor for hip displacement and the aim of this study is to assess the predictive value of the HSA for hip displacement in CP. METHODS: In this retrospective cohort, we performed radiological measurements in 50 children on both hips. In children with GMFCS level II (30 hips), III (30 hips), IV (20 hips) and V (20 hips), we measured the HSA and migration percentage (MP) in three age intervals: age two years (T1), age four years (T2) and age seven years (T3). RESULTS: At T1, the HSA was larger (more valgus) in hips that will displace than in hips that will not displace (174 degrees vs. 166 degrees ; p = 0.001) and was also larger in higher GMFCS levels (IV-V vs. II-III) (172 degrees vs. 165 degrees ; p < 0.001). At T1, GMFCS [odds ratio (OR) 14.7; p = 0.001] and HSA (OR 1.102; p = 0.043) were predictors for hip displacement at T3, but at T2, MP (OR 1.071; p = 0.010) was the only predictor for hip displacement at T3. CONCLUSIONS: The HSA at two years is larger in hips that will displace and larger in children with higher GMFCS levels (IV-V). At age two years, GMFCS and HSA are valuable predictors for hip displacement, but at the age of four years, only MP should be used in the prediction of hip displacement. LEVEL OF EVIDENCE: Prognostic study, level II. PMID- 25920928 TI - Adoption of clinical decision support systems in a developing country: Antecedents and outcomes of physician's threat to perceived professional autonomy. AB - OBJECTIVE: The basic objective of this research is to study the antecedents and outcomes of professional autonomy which is a central construct that affects physicians' intention to adopt clinical decision support systems (CDSS). The antecedents are physicians' attitude toward knowledge sharing and interactivity perception (about CDSS) and the outcomes are performance expectancy and intention to adopt CDSS. Besides, we include (1) the antecedents of attitude toward knowledge sharing-subjective norms, social factors and OCB (helping behavior) and (2) roles of physicians' involvement in decision making, computer self-efficacy and effort expectancy in our framework. METHODS: Data from a stratified sample of 335 Malaysian physicians working in 12 public and private hospitals in Malaysia were collected to test the hypotheses using Structural Equation Modeling (SEM). RESULTS: The important findings of our research are: (1) factors such as perceived threat to professional autonomy, performance expectancy, and physicians' involvement in making decision about CDSS have significant impact on physicians' intention to adopt CDSS; (2) physicians' attitude toward knowledge sharing, interactivity perception and computer self-efficacy of physicians play a crucial role in influencing their perceived threat to professional autonomy; and (3) social network, shared goals and OCB (helping behavior) impact physicians' attitude toward knowledge sharing. CONCLUSIONS: The findings provide a comprehensive understanding of the factors that influence physicians' intention to adopt CDSS in a developing country. The results can help hospital managers manage CDSS implementation in an effective manner. PMID- 25920929 TI - Novel biologic agents for non-Hodgkin lymphoma and chronic lymphocytic leukemia part 2: adoptive cellular immunotherapy, small-molecule inhibitors, and immunomodulation. AB - Globally, the incidence of non-Hodgkin lymphoma is increasing. Aggressive non Hodgkin lymphomas like diffuse large B-cell lymphoma are treated with curative intent in the frontline setting, but indolent diseases like chronic lymphocytic leukemia/small lymphocytic lymphoma are not considered to be curable in general. Additionally, relapsed/refractory non-Hodgkin lymphomas have a poor overall outcome, with treatment response durations often decreasing with each relapse. Novel therapies are sought to improve outcomes in this patient population. In a two-part review, we describe the promising new biologic therapies that have emerged over the last 5 years, some approved by the US Food and Drug Administration and others undergoing active investigation. In Part 1, we discussed monoclonal antibodies. Here, in Part 2, we discuss adoptive cellular immunotherapies, small-molecule inhibitors, and immunomodulatory agents. We also mention other novel therapies on the horizon. PMID- 25920930 TI - Small molecules, big challenges. PMID- 25920931 TI - Multidrug resistance in hepatic cancer stem cells: the emerging role of miRNAs. AB - There is a fast growing body of evidence that shows several miRNAs are essential to the key features of cancer stem cells (CSC) in hepatocellular carcinoma. However, the function of the miRNAs in different hepatic CSCs and their role in multidrug resistance mechanisms, in particular in those related to the CSC marker ABCG2, is still poorly understood. This limitation is mainly due to the heterogeneity of hepatocellular carcinoma tissues, different CSC markers and high number of deregulated miRNAs, both in primary tumor sites as well as in the circulation. The identification of CSC-related miRNAs and the modulation of hepatocellular carcinoma multidrug resistance would provide a systemic approach in the management of the disease. PMID- 25920932 TI - First implantation in man of a new magnetically levitated left ventricular assist device (HeartMate III). PMID- 25920933 TI - The expression of beta3-adrenoceptor and muscarinic type 3 receptor immuno reactivity in the major pelvic ganglion of the rat. AB - Bladder afferent outflow, linked to sensation, plays a critical role in bladder pathology: abnormal outflow results in altered sensation, leading to increased voiding frequency, urge and often incontinence. beta3-adrenoceptor agonists have been suggested to be beneficial in treating these symptoms. However, the absence of a significant sympathetic innervation of the detrusor and only a modest relaxation of bladder muscle by beta3 agonists has questioned the therapeutic site of action of beta3 agonists in the bladder. The present study was done to explore the possibility that beta3-adrenoceptors might be located in the pelvic plexus. Using the rat, where the pelvic plexus is located primarily within a single ganglion, the major pelvic ganglion (MPG), immuno-histochemical approaches were used to identify structures expressing beta3-adrenoceptor immuno-reactivity (beta3AR-IR). The only structures found to express beta3AR-IR were small-diameter tyrosine hydroxylase and vesicular mono-amine transporter immuno-reactive (TH-IR and vmat-IR) neurones. These neurones, found in clusters or singly on the periphery of the ganglion, or dispersed in smaller clumps throughout the MPG, are similar to the small intensely fluorescent (SIF) cells described previously. Not all small cells expressed beta3AR-IR. A population of the small cells were also immuno-reactive to the type 3 muscarinic receptor (M3R-IR) and the P2X3 purinergic receptor (P2X3-IR). Clumps of small cells were associated with calcitonin gene-related peptide immuno-reactive (CGRP-IR) nerve fibres (putative sensory fibres) and a small number were contacted by putative cholinergic nerves expressing immuno-reactivity to vesicular acetylcholine transporter (vacht-IR). These observations are consistent with the idea that small cells are interneurons and one of the components making up complex neural circuits within the MPG. The precise physiological role of these neural elements in the MPG is unknown. However, as one therapeutic action of beta3-adrenoceptor agonists is to modulate sensation, it is possible that these neural circuits may be involved in the regulation of afferent outflow and sensation. PMID- 25920934 TI - Inhibition of myosin light chain kinase reduces NADPH oxidase-mediated oxidative injury in rat brain following cerebral ischemia/reperfusion. AB - Previous studies have demonstrated that nicotinamide adenine dinucleotide phosphate (NADPH) oxidase (NOX)-mediated oxidative stress plays a key role in brain injury following cerebral ischemia/reperfusion (I/R) and myosin regulatory light chain kinase (MLCK) has been reported to be involved in NOX activation in lung endothelium. This study was performed to explore the correlation between MLCK and NOX following cerebral I/R and the underlying mechanisms. Sprague-Dawley (SD) rats were subjected to 2 h middle cerebral artery occlusion and 24 h reperfusion to establish a model of focal cerebral I/R injury. At the end of experiments, neurological function, infarct volume, cellular apoptosis, activities of MLCK and NOX, messenger RNA (mRNA) and protein expression of NOX (NOX1-NOX4), phosphorylation level of myosin regulatory light chain (MLC20) and hydrogen peroxide (H2O2) level were determined. The results showed that I/R treatment led to increase in neurological deficit score, infarct volume and cellular apoptosis, accompanied by the elevated activities of MLCK and NOX, expressions of NOX2 and NOX4, levels of phosphorylation MLC20 and H2O2, these effects were attenuated by MLCK specific inhibitor (ML-7). NOX inhibitors (diphenylene iodonium (DPI) or apocynin) were able to achieve similar results to that of ML-7 except no effect on MLCK activity and MLC20 phosphorylation. These results suggest that activation of MLCK contributes to cerebral I/R oxidative injury through upregulation of NOX2 and NOX4 expression, which is involved in phosphorylation of MLC20. PMID- 25920935 TI - Investigation of the binding modes between AIE-active molecules and dsDNA by single molecule force spectroscopy. AB - AIE (aggregation-induced emission)-active molecules hold promise for the labeling of biomolecules as well as living cells. The study of the binding modes of such molecules to biomolecules, such as nucleic acids and proteins, will shed light on a deeper understanding of the mechanisms of molecular interactions and eventually facilitate the design/preparation of new AIE-active bioprobes. Herein, we studied the binding modes of double-stranded DNA (dsDNA) with two types of synthetic AIE active molecules, namely, tetraphenylethene-derived dicationic compounds (cis TPEDPy and trans-TPEDPy) and anthracene-derived dicationic compounds (DSAI and DSABr-C6) using single molecule force spectroscopy (SMFS) and circular dichroism (CD) spectroscopy. The experimental data indicate that DSAI can strongly intercalate into DNA base pairs, while DSABr-C6 is unable to intercalate into DNA due to the steric hindrance of the alkyl side chains. Cis-TPEDPy and trans-TPEDPy can also intercalate into DNA base pairs, but the binding shows strong ionic strength dependence. Multiple binding modes of TPEDPy with dsDNA have been discussed. In addition, the electrostatic interaction enhanced intercalation of cis-TPEDPy with dsDNA has also been revealed. PMID- 25920936 TI - Down-regulating HIF-1alpha by lentivirus-mediated shRNA for therapy of triple negative breast cancer. AB - Hypoxia is associated with poor response to treatment in various cancers. Hypoxia inducible factor 1 (HIF-1) is a major transcription factor that mediates adaptation of cancer cells to a hypoxic environment and regulates many genes that are involved in key cellular functions, including cell immortalization, stem cell maintenance, autocrine growth/survival, angiogenesis, invasion/metastasis, and resistance to chemotherapy. HIF-1alpha has been considered as an attractive therapeutic target for cancer treatment, but there is limited success in this research field. In the present study, we designed a recombinant lentivirus containing HIF-1alpha siRNA, developed stably transfected cell lines, and tested the anticancer effects of the siRNA on cancer cells in vitro and in vivo. Our results indicated that the stable downregulation of HIF-1alpha reversed chemoresistance, inhibited proliferation, migration and invasion of cancer cells, and slowed down the tumor growth in breast cancer xenograft models. In conclusion, the recombinant lentivirus containing HIF-1alpha siRNA provides a new avenue for developing novel therapy for triple negative breast cancer. PMID- 25920937 TI - The phenotype of multiple congenital anomalies-hypotonia-seizures syndrome 1: report and review. AB - The Multiple Congenital Anomalies-Hypotonia-Seizures Syndrome 1 (MCAHS1) has been described in two families to date. We describe a 2-year-old Mexican American boy with the syndrome and additional manifestations not yet reported as part of the phenotype. The patient presented with severe hypotonia, microphallus and left cryptorchidism, and was later diagnosed with epilepsy and severe cortical visual impairment. He also had supernumerary nipples, pectus excavatum, a short upturned nose, fleshy ear lobes, and a right auricular pit. Massively parallel exome sequencing and analysis revealed two novel compound heterozygous missense (Trp136Gly and Ser859Thr) variants in the PIGN gene. This report extends and further defines the phenotype of this syndrome. PMID- 25920938 TI - Metal-insulator transition in the quasi-one-dimensional transport of fractional quantum Hall states. AB - We investigate edge state transmission in quantum point contacts (QPCs) in the fractional quantum-Hall regime, finding behavior reminiscent of a metal-insulator transition. The transition is suggested by an unusual behavior of the differential conductance in the fractional-quantum-Hall regime, and by the presence of a fixed point and universal scaling in the temperature dependence of the linear conductance. Noting that the 0.7 feature evolves continuously into a last fractional plateau at high magnetic fields, we suggest that this still unresolved feature may itself be viewed as a manifestation of a local, microscopic, metal-insulator transition. PMID- 25920939 TI - Pattern of SMARCB1 (INI1) and SMARCA4 (BRG1) in poorly differentiated endometrioid adenocarcinoma of the uterus: analysis of a series with emphasis on a novel SMARCA4-deficient dedifferentiated rhabdoid variant. AB - The role of the switch/sucrose nonfermenting chromatin remodeling complex in the initiation and progression of cancer is emerging. In the female genital tract, only ovarian small cell carcinoma, hypercalcemic type harbors recurrent inactivating SMARCA4 mutations. Otherwise, only rare case reports documented SMARCB1 involvement in endometrial cancer. We analyzed 24 grade 3 uterine endometrioid adenocarcinomas and 2 undifferentiated carcinomas for immunohistochemical expression of SMARCB1 and SMARCA4. All tumors showed high grade nuclear features with a predominance of solid growth pattern. All cases showed intact nuclear SMARCB1 expression in all tumor cells. However, 1 case of a 78-year-old woman showed complete loss of SMARCA4 in 90% of the tumor with retained expression in 10% of the tumor. The SMARCA4-intact component was a moderate-to-poorly differentiated endometrioid adenocarcinoma. The SMARCA4 deficient dominating component showed solid growth of highly anaplastic undifferentiated large cells with prominent rhabdoid features. None of the 25 SMARCA4-intact cases showed rhabdoid cell morphology. To our knowledge, this is the first systematic study of SMARCB1 and SMARCA4 expression in endometrioid adenocarcinoma of uterus and the first description of a novel SMARCA4-deficient variant of dedifferentiated/undifferentiated endometrial carcinoma. The presence of a differentiated SMARCA4-intact endometrioid component points to a novel pathway of dedifferentiation in endometrioid adenocarcinoma as a consequence of a "second hit." This case further underlines the close link between the "rhabdoid phenotype" and the SWI/SNF pathway. PMID- 25920940 TI - Ictal infraslow activity in stereoelectroencephalography: Beyond the "DC shift". AB - OBJECTIVES: The significance of infraslow activity (ISA) in focal epilepsies is largely unknown. Recent work has demonstrated ictal ISA to be more widespread in expression than originally understood. Analysis of ISA by stereoelectroencephalography (SEEG) may help to clarify its localizing value, namely the focal versus widespread expression of ISA. METHODS: The ictal SEEG records for fifteen consecutive adult patients were retrospectively analyzed, using both conventional (1.6-70 Hz) and infraslow (0.01-0.1 Hz) bandpass filters. When justified, seizures were averaged in the infraslow band to clarify their stereotypy. Wavelets were used to quantify the time-frequency characteristics of ISA. RESULTS: All clinical seizures were found to possess ISA, and this was markedly invariant across seizures in a given patient. ISA showed biphasic peaks in power, both at ictal onset and offset, with this most prominent in the anatomical structures implicated by conventional analysis. In addition, ISA demonstrated an association with low voltage fast activity, and possessed a more restricted field than conventional activity. CONCLUSIONS: ISA is both widespread (anatomically distributed) and focal (closed electric field). Seizures possess an infraslow spatiotemporal signature. SIGNIFICANCE: Beyond representing a "focus" of paroxysmal activity, ISA must arise from a network process as a component of wideband ictal dynamics. How this relates to clinical definition of the epileptogenic zone requires further study. PMID- 25920941 TI - Response variability to non-invasive brain stimulation protocols. PMID- 25920942 TI - Effect of a stroke support service in Germany: a randomized trial. AB - PURPOSE: This trial investigated the effect of a stroke support service on physical functioning in post-stroke outpatients. METHODS: The randomized trial took place in two urban hospitals in Germany. The intervention covered a post discharge stroke support service including following components: outreach work (via telephone contact and home-visit), informational events, training sessions, online portal, and written patient information. The control group received optimized standard care by written patient information. The primary outcome measure was physical function assessed by the physical scale of the stroke impact scale (SIS) 2.0 at baseline and after 12 months follow-up. Secondary outcomes covered health-related quality of life, depression, somatization, reinfarcts, and mortality. Use of health services was recorded. RESULTS: A total of 265 patients were randomized either to the intervention (n = 130) or to the control group (n = 135); n = 230 patients were analyzed after 12 months. The mean group difference on the physical SIS scale was - 2.7 points (95% CI, - 5.5-0.2) in favor of the control group. The overall risk of mortality in the control versus the intervention group was 11.6and 3.9%, respectively (hazard ratio 0.32, 95% CI, 0.12-0.88). All other outcomes were neither statistically nor clinically relevant, different between the two study groups. CONCLUSION: An additional stroke support service did not improve physical function, health-related quality of life, depression, somatization, or reinfarcts in stroke patients. Data suggest a lower overall risk of mortality in the intervention group. PMID- 25920943 TI - Analytical results in longitudinal studies depended on target of inference and assumed mechanism of attrition. AB - OBJECTIVES: To compare methods for analysis of longitudinal studies with missing data due to participant dropout and follow-up truncated by death. STUDY DESIGN AND SETTING: We analyzed physical functioning in an Australian longitudinal study of elderly women where the missing data mechanism could either be missing at random (MAR) or missing not at random (MNAR). We assumed either an immortal cohort where deceased participants are implicitly included after death or a mortal cohort where the target of inference is surviving participants at each survey wave. To illustrate the methods a covariate was included. Simulation was used to assess the effect of the assumptions. RESULTS: Ignoring attrition or restricting analysis to participants with complete follow up led to biased estimates. Linear mixed model was appropriate for an immortal cohort under MAR but not MNAR. Linear increment model and joint modeling of longitudinal outcome and time to death were the most robust to MNAR. For a mortal cohort, inverse probability weighting and multiple imputation could be used, but care is needed in specifying dropout and imputation models, respectively. CONCLUSION: Appropriate analysis methodology to deal with attrition in longitudinal studies depends on the target of inference and the missing data mechanism. PMID- 25920944 TI - Professionally designed information materials and telephone reminders improved consent response rates: evidence from an RCT nested within a cohort study. AB - OBJECTIVES: To investigate whether different study-to-participant communication methods increase response, increase response from hard-to-engage individuals, and influence participants' consent decisions. STUDY DESIGN AND SETTING: A randomized controlled trial within the Avon Longitudinal Study of Parents and Children. Cohort members were invited to re-enroll at age 18 and consent to linkage to their health and administrative records. Participants were randomized to receive one of eight combinations of three interventions: a prior-notification postcard or no contact, a standard or professionally designed consent pack, and a phone or postal reminder. The primary outcome was return of the consent form ("response"), with consent decision being the secondary outcome. RESULTS: Of 1,950 participants, 806 (41%) responded. Response rates were 2.7% higher (95% confidence interval: -0.06, 5.5%; P = 0.06) among those receiving designed packs than among those receiving standard packs and 6.4% higher (2.3, 10.6%; P = 0.002) among those receiving phone reminders (compared with postal reminders). The prior notification postcard did not influence response rates [difference = 0% (-2.8, 2.8%; P = 1.0)], and we found no evidence that the communication method influenced consent decision. CONCLUSION: This trial provides evidence that communication material design can influence response rates and that phone reminders have superior cost/benefit returns over designed materials. Experimental evaluation of communications strategies and dissemination of findings may benefit cohort studies. PMID- 25920946 TI - Doped golden fullerene cages. AB - A first-principles investigation of the effect of the doping of golden cages of 32 atoms is proposed. It is shown that Ag and Cu doping affects the geometrical stability of the icosahedral fullerene Au32 cage, where Ag-doping leads to a new, low symmetric, and prolate motif while Cu-doping leads to a lump, incomplete decahedral shape. Most significantly, the HOMO-LUMO gap depends strongly on the cluster geometry while its dependence on the cluster chemical composition seems to be weaker. PMID- 25920945 TI - Relating gas phase to solution conformations: Lessons from disordered proteins. AB - In recent years both mass spectrometry (MS) and ion mobility mass spectrometry (IM-MS) have been developed as techniques with which to study proteins that lack a fixed tertiary structure but may contain regions that form secondary structure elements transiently, namely intrinsically disordered proteins (IDPs). IM-MS is a suitable method for the study of IDPs which provides an insight to conformations that are present in solution, potentially enabling the analysis of lowly populated structural forms. Here, we describe the IM-MS data of two IDPs; alpha Synuclein (alpha-Syn) which is implicated in Parkinson's disease, and Apolipoprotein C-II (ApoC-II) which is involved in cardiovascular diseases. We report an apparent discrepancy in the way that ApoC-II behaves in the gas phase. While most IDPs, including alpha-Syn, present in many charge states and a wide range of rotationally averaged collision cross sections (CCSs), ApoC-II presents in just four charge states and a very narrow range of CCSs, independent of solution conditions. Here, we compare MS and IM-MS data of both proteins, and rationalise the differences between the proteins in terms of different ionisation processes which they may adhere to. PMID- 25920947 TI - Controlled Fabrication of Microparticles with Complex 3D Geometries by Tunable Interfacial Deformation of Confined Polymeric Fluids in 2D Micromolds. AB - Polymeric microparticles with complex shapes have attracted substantial attention in many application areas because particle shape is a critical parameter to impart programmable functionalities. The formation of specific three-dimensional (3D) microstructures in a simple, scalable, and controllable manner is difficult. Here, we report the controlled fabrication of microparticles with complex 3D shapes based on the simple tuning of mold swelling and capillarity. Specifically, a photocurable solution loaded in micromolds is spatially deformed into complex shapes depending on the degree of molding swelling and capillarity, thereby producing polymeric microparticles with controlled 3D shapes upon photopolymerization. The results show that highly uniform microparticles with controlled two-dimensional (2D) and 3D shapes were fabricated from identical 2D micromolds via the simple tuning of the wetting fluids. This technique can be extended to produce highly complex microarchitectures with controlled 3D geometric domains via 2D mold designs. Finally, multicompartment microparticles with independently controlled 3D shapes for each compartment are produced by a simple combination of fabrication sequences. We envision that this strategy of producing 3D microarchitectures from easily designed simple micromolds could provide a path to new materials and new properties. PMID- 25920948 TI - Chromosomal microarray in unexplained severe early onset epilepsy - A single centre cohort. AB - BACKGROUND: Severe early onset epilepsy may lead to impaired cognitive and motor development, and consists of a group of specific and overlapping electro-clinical phenotypes which may be the result of an inborn error of metabolism, congenital or acquired structural brain lesion, known chromosomal or mono-genetic disorder. A significant proportion of cases however remain unexplained, representing a major diagnostic and management challenge. METHODS: In this study we describe a cohort of children with severe early onset epilepsy and examine the clinical utility of chromosomal microarray (array-comparative genomic hybridisation, CGH) in this group of epilepsies. RESULTS: In 51 children with unexplained severe early onset epilepsy, all of whom had chromosomal array tested, copy number variants were detected in 17.6% and pathogenic variants in 5.9% of infants. CONCLUSIONS: Chromosomal microarray is a useful investigation in early onset refractory epilepsy and epileptic encephalopathy. Detailed review of the precise array abnormality and phenotypes associated are important for determining significance. PMID- 25920949 TI - Virtual screening, ADMET profiling, molecular docking and dynamics approaches to search for potent selective natural molecules based inhibitors against metallothionein-III to study Alzheimer's disease. AB - MOTIVATION: Metallothionein-III (MT-III) displays neuro-inhibitory activity and is involved in the repair of neuronal damage. An altered expression level of MT III suggests that it could be a mitigating factor in Alzheimer's disease (AD) neuronal dysfunction. Currently there are limited marketed drugs available against MT-III. The inhibitors are mostly pseudo-peptide based with limited ADMET. In our present study, available database InterBioScreen (natural compounds) was screened out for MT-III. Pharmacodynamics and pharmacokinetic studies were performed. Molecular docking and simulations of top hit molecules were performed to study complex stability. RESULTS: Study reveals potent selective molecules that interact and form hydrogen bonds with amino acids Ser-6 and Lys-22 are common to established melatonin inhibitors for MT-III. These include DMHMIO, MCA B and s27533 derivatives. The ADMET profiling was better with comparable interaction energy values. It includes properties like blood brain barrier, hepatotoxicity, druggability, mutagenicity and carcinogenicity. Molecular dynamics studies were performed to validate our findings. PMID- 25920950 TI - mRNA detection in living cells: A next generation cancer stem cell identification technique. AB - Cancer stem cells (CSC) are a distinct subpopulation within a tumor shown to drive tumor progression, metastasis, and recurrence. A review of the literature reveals poor consensus, with the use of a wide variety of surface markers and functional assays to identify and isolate cancer stem cells. Utilizing a novel technology that enables live-cell mRNA quantitation, we have demonstrated the ability to identify and sort viable CSC based on markers associated with stemness in pluripotent cells. Fresh tumor samples from a variety of cancer types were examined by flow cytometry for Nanog expression. Levels of CSC detected ranged from 6% to 19%. This method of CSC detection was cross-validated with other commonly used surface markers with good correlation. Matrigel invasion assays confirmed that CSC isolated using this method are both highly motile and invasive. This approach simplifies the process of identifying viable CSC from fresh tumor tissue, providing a level of accuracy not previously available. This method may also provide a valuable tool for screening and validating new CSC biomarkers. PMID- 25920951 TI - Trazodone induced galactorrhea: a case report. AB - Trazodone is a heterocyclic antidepressant that exerts its effect via the inhibition of selective serotonin reuptake and the antagonism of 5-HT2A and 5 HT2C receptors. Antidepressant-induced galactorrhea and increases in prolactin levels have rarely been reported. Trazodone can potentiate the serotonergic activity of citalopram. To our knowledge, no cases of galactorrhea associated with use of trazodone have been reported to date. This report describes a unique case of the development of galactorrhea following the addition of trazodone (100 mg/day, 2 weeks) to the treatment of a patient who was receiving citalopram (40 mg/day, 6 weeks) therapy for a diagnosis of depressive disorder, which improved upon the discontinuation of trazodone. PMID- 25920952 TI - Eggplant-derived microporous carbon sheets: towards mass production of efficient bifunctional oxygen electrocatalysts at low cost for rechargeable Zn-air batteries. AB - We report 2D microporous carbon sheets with high surface area, derived from eggplant via simple carbonization and KOH activation, as low cost yet efficient bifunctional catalysts for high performance rechargeable zinc-air batteries. PMID- 25920953 TI - Is L-lactate a novel signaling molecule in the brain? AB - In the brain, L-lactate is produced by both neurons and astrocytes. There is no doubt that neurons use L-lactate as a supplementary fuel although the importance of this energy source is disputed. Irrespective of its caloric value, L-lactate might also have a signaling role in the brain. Here, we review several current hypotheses of L-lactate mediated signaling. Some proposed mechanisms require L lactate entry into the neurons leading to a shift in ATP/ADP ratio or redox state. Others postulate interaction with either known receptor HCA1 (GPR81) or a novel, yet unidentified receptor. We argue that the sensitivity of any such mechanism has to match the concentration range of extracellular L-lactate, which is less than ~1.5 mmol/L under physiologic conditions. From that point of view, some of the proposed mechanisms require supraphysiologic levels of L-lactate and could be engaged during ischemia or seizures when L-lactate concentration rises dramatically. Currently, we do not know whether L-lactate production in the brain occurs in microdomains, which might create higher than average local concentrations. Nevertheless, it is clear that in the brain, as in the peripheral tissues, L-lactate is not only used as a source of energy but also acts as a signaling molecule. PMID- 25920954 TI - Early identification of individuals at high risk for cerebral infarction after aneurysmal subarachnoid hemorrhage: the BEHAVIOR score. AB - Cerebral infarction (CI) is a crucial complication of aneurysmal subarachnoid hemorrhage (SAH) associated with poor clinical outcome. We aimed at developing an early risk score for CI based on clinical characteristics available at the onset of SAH. Out of a database containing 632 consecutive patients with SAH admitted to our institution from January 2005 to December 2012, computed tomography (CT) scans up to day 42 after ictus were evaluated for CIs. Different parameters from admission up to aneurysm treatment were collected with subsequent construction of a risk score. Seven clinical characteristics were independently associated with CI and included in the Risk score (BEHAVIOR Score, 0 to 11 points): Blood on CT scan according to Fisher grade ?3 (1 point), Elderly patients (age ?55 years, 1 point), Hunt&Hess grade ?4 (1 point), Acute hydrocephalus requiring external liquor drainage (1 point), Vasospasm on initial angiogram (3 points), Intracranial pressure elevation >20 mm Hg (3 points), and treatment of multiple aneurysms ('Overtreatment', 1 point). The BEHAVIOR score showed high diagnostic accuracy with respect to the absolute risk for CI (area under curve=0.806, P<0.0001) and prediction of poor clinical outcome at discharge (P<0.0001) and after 6 months (P=0.0002). Further validation in other SAH cohorts is recommended. PMID- 25920955 TI - APOE E2 is associated with white matter hyperintensity volume in CADASIL. AB - Apolipoprotein E (APOE) increases the risk for Alzheimer's disease (E4 allele) and cerebral amyloid angiopathy (E2 and E4), but its role in small vessel disease (SVD) is debated. Here we studied the effects of APOE on white matter hyperintensity volume (WMHV) in CADASIL (cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy), a nonamyloidogenic angiopathy and inherited early-onset form of pure SVD. Four hundred and eighty-eight subjects were recruited through a multicenter consortium. Compared with APOE E3/E3, WMHV was increased in APOE E2 (P = 0.02) but not APOE E4. The results remained significant when controlled for genome-wide genetic background variation. Our findings suggest a modifying influence of APOE E2 on WMHV caused by pure SVD. PMID- 25920956 TI - 20-HETE is associated with unfavorable outcomes in subarachnoid hemorrhage patients. AB - Emerging evidence has suggested that patients experiencing aneurysmal subarachnoid hemorrhage (aSAH) develop vascular dysregulation as a potential contributor to poor outcomes. Preclinical studies have implicated the novel microvascular constrictor, 20-hydroxyeicosatetraenoic acid (20-HETE) in aSAH pathogenesis, yet the translational relevance of 20-HETE in patients with aSAH is largely unknown. The goal of this research was to determine the relationship between 20-HETE cerebrospinal fluid (CSF) levels, gene variants in 20-HETE synthesis, and acute/long-term aSAH outcomes. In all, 363 adult patients (age 18 to 75) with aSAH were prospectively recruited from the University of Pittsburgh Medical Center neurovascular Intensive Care Unit. Patients were genotyped for polymorphic variants and cytochrome P450 (CYP)-eicosanoid CSF levels were measured over 14 days. Outcomes included delayed cerebral ischemia (DCI), clinical neurologic deterioration (CND), and modified Rankin Scores (MRS) at 3 and 12 months. Patients with CND and unfavorable 3-month MRS had 2.2- and 2.7 fold higher mean 20-HETE CSF levels, respectively. Patients in high/moderate 20 HETE trajectory groups (35.7%) were 2.5-, 2.1-, 3.1-, 3.3-, and 2.1-fold more likely to have unfavorable MRS at 3 months, unfavorable MRS at 12 months, mortality at 3 months, mortality at 12 months, and CND, respectively. These results showed that 20-HETE is associated with acute and long-term outcomes and suggest that 20-HETE may be a novel target in aSAH. PMID- 25920957 TI - Structural plasticity of remote cortical brain regions is determined by connectivity to the primary lesion in subcortical stroke. AB - Cortical atrophy as demonstrated by measurement of cortical thickness (CT) is a hallmark of various neurodegenerative diseases. In the wake of an acute ischemic stroke, brain architecture undergoes dynamic changes that can be tracked by structural and functional magnetic resonance imaging studies as soon as 3 months after stroke. In this study, we measured changes of CT in cortical areas connected to subcortical stroke lesions in 12 patients with upper extremity paresis combining white-matter tractography and semi-automatic measurement of CT using the Freesurfer software. Three months after stroke, a significant decrease in CT of -2.6% (median, upper/lower boundary of 95% confidence interval -4.1%/ 1.1%) was detected in areas connected to ischemic lesions, whereas CT in unconnected cortical areas remained largely unchanged. A cluster of significant cortical thinning was detected in the superior frontal gyrus of the stroke hemisphere using a surface-based general linear model correcting for multiple comparisons. There was no significant correlation of changes in CT with clinical outcome parameters. Our results show a specific impact of subcortical lesions on distant, yet connected cortical areas explainable by secondary neuro-axonal degeneration of distant areas. PMID- 25920958 TI - Successful serial imaging of the mouse cerebral arteries using conventional 3-T magnetic resonance imaging. AB - Serial imaging studies can be useful in characterizing the pathologic and physiologic remodeling of cerebral arteries in various mouse models. We tested the feasibility of using a readily available, conventional 3-T magnetic resonance imaging (MRI) to serially image cerebrovascular remodeling in mice. We utilized a mouse model of intracranial aneurysm as a mouse model of the dynamic, pathologic remodeling of cerebral arteries. Aneurysms were induced by hypertension and a single elastase injection into the cerebrospinal fluid. For the mouse cerebrovascular imaging, we used a conventional 3-T MRI system and a 40-mm saddle coil. We used non-enhanced magnetic resonance angiography (MRA) to detect intracranial aneurysm formation and T2-weighted imaging to detect aneurysmal subarachnoid hemorrhage. A serial MRI was conducted every 2 to 3 days. MRI detection of aneurysm formation and subarachnoid hemorrhage was compared against the postmortem inspection of the brain that was perfused with dye. The imaging times for the MRA and T2-weighted imaging were 3.7+/-0.5 minutes and 4.8+/-0.0 minutes, respectively. All aneurysms and subarachnoid hemorrhages were correctly identified by two masked observers on MRI. This MRI-based serial imaging technique was useful in detecting intracranial aneurysm formation and subarachnoid hemorrhage in mice. PMID- 25920959 TI - Hypertension enhances Abeta-induced neurovascular dysfunction, promotes beta secretase activity, and leads to amyloidogenic processing of APP. AB - Hypertension (HTN) doubles the risk of Alzheimer's disease (AD), but the mechanisms remain unclear. Amyloid-beta (Abeta), a key pathogenic factor in AD, induces cerebrovascular dysfunction. We hypothesized that HTN acts in concert with Abeta to amplify its deleterious cerebrovascular effects and to increase Abeta production. Infusion of angiotensin II (ANGII; intravenously) elevated blood pressure and attenuated the cerebral blood flow (CBF) response to whisker stimulation or the endothelium-dependent vasodilator acetylcholine (ACh) (P < 0.05). Neocortical application of Abeta in mice receiving ANGII worsened the responses to ACh (P < 0.05). The cerebrovascular dysfunction observed in Tg2576 mice, in which Abeta is elevated both in blood and in brain due to expression of mutated amyloid precursor protein (APP), was not aggravated by neocortical application of ANGII or by a 2-week administration of 'slow pressor' of ANGII (600 ng/kg per minute; subcutaneously). In contrast, ANGII aggravated the dysfunction in TgSwDI mice, in which Abeta is increased only in brain. Slow pressor ANGII induced microvascular amyloid deposition in Tg2576 mice and enhanced beta-secretase APP cleavage. In Chinese hamster ovary (CHO) cells producing Abeta, ANGII increased beta-secretase activity, Abeta1-42, and the Abeta42/40 ratio. We conclude that HTN enhances amyloidogenic APP processing, effects that may contribute to the pathogenic interaction between HTN and AD. PMID- 25920961 TI - Comparison of two devices for the treatment of keloid scars with the use of intralesional cryotherapy: An experimental study. AB - BACKGROUND: Intralesional (IL) cryotherapy is a new technique for the treatment of keloid scars, in which the scar is frozen from inside. Two cryodevices are available, which were recently evaluated. Both devices showed promising results, but differed in clinical outcome. To explain these differences, more understanding of the working mechanism of both devices is required. OBJECTIVE: This experimental study was designed to investigate and compare the thermal behavior of an argon gas- and a liquid nitrogen-based device. Thermal behavior constitutes: (1) minimum tissue temperature ( degrees C), (2) the freezing rate ( degrees C/min). The thermal behavior was measured inside and on the outer surface of the scar. Both devices were tested ex vivo and in vivo. RESULTS: Ex vivo, when determining the maximum freezing capacity, the argon gas device showed a higher end temperature compared to the liquid nitrogen device (argon gas: -120 degrees C, liquid nitrogen: -140 degrees C) and a faster freezing rate (argon gas: -1300 degrees C/min, liquid nitrogen: -145 degrees C/min). In vivo, measured inside the keloid, the argon gas device showed a lower end temperature than the liquid nitrogen device (argon gas: -36.4 degrees C, liquid nitrogen: -8.1 degrees C) and a faster freezing rate (argon gas: -14.7 degrees C/min, liquid nitrogen: -5 degrees C/min). The outer surface of the scar reached temperatures below -20 degrees C with both devices as measured with the thermal camera. CONCLUSION: In conclusion, the argon gas device displayed a lower end temperature and a faster freezing rate in vivo compared to the liquid nitrogen device. Although this resulted in lower recurrence rates for the argon gas device, more hypopigmentation was seen compared to the liquid nitrogen device following treatment. Finally, the low outer surface temperatures measured with both devices, suggest that some hypopigmentation following treatment is inevitable. PMID- 25920960 TI - Subcortical ischemic vascular disease: Roles of oligodendrocyte function in experimental models of subcortical white-matter injury. AB - Oligodendrocytes are one of the major cell types in cerebral white matter. Under normal conditions, they form myelin sheaths that encircle axons to support fast nerve conduction. Under conditions of cerebral ischemia, oligodendrocytes tend to die, resulting in white-matter dysfunction. Repair of white matter involves the ability of oligodendrocyte precursors to proliferate and mature. However, replacement of lost oligodendrocytes may not be the only mechanism for white matter recovery. Emerging data now suggest that coordinated signaling between neural, glial, and vascular cells in the entire neurovascular unit may be required. In this mini-review, we discuss how oligodendrocyte lineage cells participate in signaling and crosstalk with other cell types to underlie function and recovery in various experimental models of subcortical white-matter injury. PMID- 25920963 TI - Absolute quantification of podocalyxin, a potential biomarker of glomerular injury in human urine, by liquid chromatography-mass spectrometry. AB - Podocalyxin is a protein present in specialized glomerulus cells called podocytes and may be released in the urine in case of kidney injury. In this context, its quantification could be of great interest in order to monitor glomerular injury. Liquid chromatography tandem mass spectrometry (LC-MS/MS), in selected reaction monitoring (SRM) mode, has been demonstrated as a powerful technique that can be applied to protein quantification. This paper describes the development of a quantification method of human podocalyxin in urine by LC-MS/MS in SRM mode by monitoring one proteotypic peptide with an isotope-dilution standardization strategy employing (13)C/(15)N labelled peptides. Inter/intra assay precisions and accuracies of the assay were below 10% and between 90% and 106.1%, respectively. In addition, the method was linear between 0.78 and 100 ng/mL and could therefore be used to quantify endogenous level of podocalyxin that was estimated between 15.2 and 44.2 ng/mL in urine samples from healthy donor. PMID- 25920962 TI - Issues and considerations for using the scalp surface Laplacian in EEG/ERP research: A tutorial review. AB - Despite the recognition that the surface Laplacian may counteract adverse effects of volume conduction and recording reference for surface potential data, electrophysiology as a discipline has been reluctant to embrace this approach for data analysis. The reasons for such hesitation are manifold but often involve unfamiliarity with the nature of the underlying transformation, as well as intimidation by a perceived mathematical complexity, and concerns of signal loss, dense electrode array requirements, or susceptibility to noise. We revisit the pitfalls arising from volume conduction and the mandated arbitrary choice of EEG reference, describe the basic principle of the surface Laplacian transform in an intuitive fashion, and exemplify the differences between common reference schemes (nose, linked mastoids, average) and the surface Laplacian for frequently measured EEG spectra (theta, alpha) and standard event-related potential (ERP) components, such as N1 or P3. We specifically review common reservations against the universal use of the surface Laplacian, which can be effectively addressed by employing spherical spline interpolations with an appropriate selection of the spline flexibility parameter and regularization constant. We argue from a pragmatic perspective that not only are these reservations unfounded but that the continued predominant use of surface potentials poses a considerable impediment on the progress of EEG and ERP research. PMID- 25920964 TI - Reliability of video-based identification of footstrike pattern and video time frame at initial contact in recreational runners. AB - INTRODUCTION: Two-dimensional video recordings are used in clinical practice to identify footstrike pattern. However, knowledge about the reliability of this method of identification is limited. OBJECTIVE: To evaluate intra- and inter rater reliability of visual identification of footstrike pattern and video time frame at initial contact during treadmill running using two-dimensional (2D) video recordings. METHODS: Thirty-one recreational runners were recorded twice, 1 week apart, with a high-speed video camera. Two blinded raters evaluated each video twice with an interval of at least 14 days. RESULTS: Kappa values for within-day identification of footstrike pattern revealed intra-rater agreement of 0.83-0.88 and inter-rater agreement of 0.50-0.63. Corresponding figures for between-day identification of footstrike pattern were 0.63-0.69 and 0.41-0.53, respectively. Identification of video time frame at initial contact ranged from five frames to 12 frames (95% limits of agreement). CONCLUSION: For clinical use, the intra-rater within-day identification of footstrike pattern is highly reliable (kappa>0.80). For the inter-rater between-day identification inconsistencies may, in worst case, occur in 36% of the identifications (kappa=0.41). The 95% limits of agreement for identification of video time frame at initial contact may, at times, allow for different identification of footstrike pattern. Clinicians should, therefore, be encouraged to continue using clinical 2D video setups for intra-rater identification of footstrike pattern, but bear in mind the restrictions related to the between day identifications. PMID- 25920965 TI - Morphometric aspects of the facial and skeletal muscles in fetuses. AB - OBJECTIVES: There are few research reports providing a comparison of the muscle fiber morphometry between human fetuses and adults. Data on fetal and adult muscle fibers would be valuable in understanding muscle development and a variety of muscle diseases. This study investigated human muscle fiber growth to clarify the difference between the facial muscles and other skeletal muscles. METHODS: The materials were obtained from three male fetuses (6-month-old) and 11 Japanese male cadavers aged 43-86 years (average: 71.8). Human buccinator muscles (facial muscles), masseter and biceps brachii muscles (skeletal muscles) were resected. We counted the muscle fibers and measured their transverse area. We also calculated the number of muscle fibers per mm(2) (NMF) and the average transverse area of the muscle fibers (TAMFs). RESULTS: The average of the NMF of the buccinator, masseter and biceps brachii muscles in fetuses had, respectively, 19, 37, and 22 times as many fibers as those in adults. The average fetus/adult ratios of the TAMF of the buccinator, masseter and biceps brachii muscles were 4.0%, 2.4%, 4.1%, respectively. CONCLUSIONS: The average NMF for all kinds of muscles decreased after birth; however, the peak in life-span or decreases with the aging process tended to vary with the kind of muscles examined. The average TAMF for all kinds of muscles enlarged after birth. We considered that the enlargement of the TAMF was connected with the emergence of fetal movements and functional demands after birth. PMID- 25920966 TI - Enhanced expression of hepatocyte growth factor in the healing of experimental acute tympanic membrane perforation. AB - OBJECTIVES: The present study was performed to investigate the expression of hepatocyte (HGF), epidermal (EGF) and vascular endothelial (VEGF) growth factors in the course of healing of experimental tympanic membrane (TM) perforations in rats. The goal was to explain the role of these growth factors in the healing process of TM and to assess the possibility of their future application as healing promoters. METHODS: Seventy rats were used, of which 10 served as controls and the others had their TM perforated. The experimental animals were divided into six subgroups on the basis of time points (01, 03, 05, 07, 09, 15 day after injury). Videootoscopy and histology were employed to assess the morphology of the healing process. The expressions of HGF, EGF and VEGF were evaluated using Western blot analysis. Tissue localization of HGF was determined by the immunofluorescence method. RESULTS: HGF was hardly detectable in normal TM; however, a significant increase was noted in its expression starting from the third day after injury throughout the follow-up period, with the highest level on day 05. The analysis of HGF tissue localization with immunofluorescence revealed diffuse staining in the cytoplasm of proliferating epithelial cells. The expression of EGF was elevated on the first day after injury, not reaching statistical significance, and then returned to the level observed in the control TM. No significant differences were noted in the expression of VEGF. CONCLUSION: High expression of HGF during the healing process of acute TM perforations makes it a promising candidate for further studies oriented towards its possible use in augmentation of TM healing. PMID- 25920967 TI - Poor functional antibody responses are present in nearly all patients with chronic lymphocytic leukaemia, irrespective of total IgG concentration, and are associated with increased risk of infection. PMID- 25920969 TI - Draft National Health Policy 2015: getting behind the rhetoric. PMID- 25920968 TI - The process of justifying assisted reproductive technologies in Iran. AB - Infertility is medically defined as one year of unprotected intercourse that does not result in pregnancy. Infertility is a noticeable medical problem in Iran, and about a quarter of Iranian couples experience primary infertility at some point in their lives. Since having children is a basic social value in Iran, infertility has an adverse effect on the health of the couple and affects their well-being. The various methods of assisting infertile couples raise several ethical questions and touch upon certain sensitive points. Although the present Iranian legislative system, which is based on the Shi'a school of Islam, has legalised some aspects of assisted reproductive technologies (ARTs), given the absence of a general officially ratified act (official pathway), such medical interventions are usually justified through a fatwa system (non-official pathway). Officially registered married couples can access almost all ART methods, including third-party gamete donation, if they use such pathways. The process of justifying ART interventions generally began when in vitro fertilisation was given the nod and later, Ayatollah Khamenei (the political religious leader of the country) issued a fatwa which permitted gamete donation by third parties. This open juristic approach paved the way for the ratification of the Embryo Donation to Infertile Spouses Act in 2003. PMID- 25920970 TI - Listening to the voices of the general public in India on biomedical research--an exploratory study. AB - Medical research, from clinical trials to novel research on stored samples, is growing rapidly in India. Ethical regulations largely reflect standard international guidelines and the norms of "good clinical practice". Through in depth interviews, this study aimed to explore the perceptions, motivations and concerns of the public with respect to participation in clinical trials and biobanking-related research. It was found that the expectation of therapeutic benefit reflects "therapeutic misconception" and this, along with a poor understanding of research, leads to favourable participation in clinical trials. A relatively low level of awareness and knowledge of health matters and research (health literacy), along with the differences in the power of the doctor and the participant, lead to an unquestioning trust in the physician or the institution conducting the research. "Informed consent" is thought to protect the interests of the researcher and the institution rather than the participants' rights. Biobanking research was very new to the participants and relatively unknown. Thus, it has not yet filtered into the public consciousness. As a result, the perceptions of the general public do not appear to be sufficiently evolved. PMID- 25920971 TI - Making medical care and research rational and affordable. AB - Expenditure on insurance, consultations, the multitude of tests ordered by the doctor, and very expensive drugs make the treatment of illness a great burden. Should the patient need admission to a hospital and, worse, an intensive care unit, the load becomes almost unbearable. Medical research has moved from the domain of the single keen observer to that of highly qualified experts working in laboratories containing costly equipment. The budget for these projects now runs into lakhs or crores of rupees. PMID- 25920972 TI - IJME Fifth National Bioethics Conference: a summary report. AB - The Fifth National Bioethics Conference (NBC) was co-hosted by St John's National Academy of Health Sciences (SJNAHS), Bangalore; Society for Community Health Research Awareness and Action (SOCHARA), Bangalore; and Forum for Medical Ethics Society (FMES), Mumbai, which publishes the Indian Journal of Medical Ethics (IJME). The conference was held at the St John's campus, Bangalore from December 11 to 13, 2014. The theme of the Fifth NBC was "Integrity in medical care, public health, and health research". PMID- 25920973 TI - Arab doctors, evolving society and corruption: a medical student's perspective. AB - Doctors, especially junior doctors, face immense pressure in their day-to-day work. As a result, the rates of depression and anxiety are particularly high in this demanding profession. The pressure, which is compounded by constantly being under societal scrutiny, can unfortunately drive the doctor to breaking point. However, we can help doctors deal with these pressures in a more meaningful way if we make them aware of their wider environment (within a social paradigm) and the implications of their actions. PMID- 25920974 TI - Ethics approval: a challenge for public health researchers in India. AB - There is increasing impetus, interest and opportunity for people working in public health programmes in India to carry out operational research (OR) around relevant programme issues and then publish that in peer-reviewed publications. These published researches are valuable in analysing, documenting and advocating for locally generated evidence to inform policy and practice. Ethics review and approval is an essential step in the process of OR but is often viewed as a barrier rather than a prerequisite of good practice in OR. Journals and peer reviewers are also increasingly requiring approvals from local institutional ethics committees (IECs). PMID- 25920975 TI - Phlebotomy consent: ethical concerns. AB - Phlebotomy is one of the common invasive procedures carried out all round the globe. The practice of phlebotomy varies widely. In terms of the technique, the procedure may involve the use of a syringe or a vacutainer, and as for the technicians, some are not specifically trained to perform the procedure and others are qualified phlebotomists. Finally, some may receive training on the job, while others undergo formal, focused training. However, the underlying ethical principles of respect for autonomy and informed consent do not change. This commentary, which is supported by data collected during training in phlebotomy, reflects on the ethical issue of obtaining consent for the procedure. PMID- 25920976 TI - Dr Ajay Khare: a personal tribute to a dear comrade. PMID- 25920977 TI - Margaret McCartney: Rigging the NHS for votes. PMID- 25920979 TI - Changeover-time in psychosocial wellbeing of people living with HIV and people living close to them after an HIV stigma reduction and wellness enhancement community intervention. AB - HIV stigma continues to affect the psychosocial wellbeing of people living with HIV (PLWH) and people living close to them (PLC). Literature unequivocally holds the view that HIV stigma and psychosocial wellbeing interact with and have an impact on each other. This study, which is part of a larger research project funded by the South Africa Netherlands research Programme on Alternatives in Development (SANPAD), responds to the lack of interventions mitigating the impactful interaction of HIV stigma and psychosocial wellbeing and tests one such intervention. The research objectives were to test the changeover-time in the psychosocial wellbeing of PLWH and PLC in an urban and a rural setting, following a comprehensive community-based HIV stigma reduction and wellness enhancement intervention. An experimental quantitative single system research design with a pre- and four repetitive post-tests was used, conducting purposive voluntary sampling for PLWH (n = 18) and snowball sampling for PLC (n = 60). The average age of participants was 34 years old. The five measuring instruments used for both groups were the mental health continuum short-form scale, the patient health questionnaire, the satisfaction with life scale, the coping self-efficacy scale and the spirituality wellbeing scale. No significant differences were found between the urban-rural settings and data were pooled for analysis. The findings show that initial psychosocial wellbeing changes after the intervention were better sustained (over time) by the PLC than by the PLWH and seemed to be strengthened by interpersonal interaction. Recommendations included that the intervention should be re-utilised and that its tenets, content and activities be retained. A second intervention three to six months after the first should be included to achieve more sustainability and to add focused activities for the enhancement of psychosocial wellbeing. PLWH and PLC are to be encouraged to engage with innovative community mechanisms to make psychosocial wellbeing a way of life in the community at large. PMID- 25920980 TI - Reducing the overall HIV-burden in South Africa: is 'reviving ABC' an appropriate fit for a complex, adaptive epidemiological HIV landscape? AB - This article questions the recommendations to 'revive ABC (abstain, be faithful, condomise)' as a mechanism to 'educate' people in South Africa about HIV prevention as the South African National HIV Prevalence, Incidence and Behaviour Survey, 2012, suggests. We argue that ABC was designed as a response to a particular context which has now radically changed. In South Africa the contemporary context reflects the mass roll-out of antiretroviral treatment; significant bio-medical knowledge gains; a generalised population affected by HIV that has made sense of and embodied those diverse experiences; and a government committed to confronting the epidemic. We suggest that the situation can now be plausibly conceptualised as a complex, adaptive epidemiological landscape that could benefit from an expansion of the existing, 'descriptive' prevention paradigm towards strategies that focus on the dynamics of transmission. We argue for this shift by proposing a theoretical framework based on complexity theory and pattern management. We interrogate one educational prevention heuristic that emphasises the importance of risk-reduction through the lens of transmission, called A-3B-4C-T. We argue that this type of approach provides expansive opportunities for people to engage with the epidemic in contextualised, innovative ways that supersede the opportunities afforded by ABC. We then suggest that framing the prevention imperative through the lens of 'dynamic prevention' at scale opens more immediate opportunities, as well as developing a future oriented mind-set, than the 'descriptive prevention' parameters can facilitate. The parameters of the 'descriptive prevention' paradigm, that maintain - and partially reinforce - the presence of ABC, do not have the flexibility required to develop the armamentarium of tools required to contribute to the management of a complex epidemiological landscape. Uncritically adhering to both the 'descriptive paradigm', and ABC, represents an historically dislocated form of prevention - with restrictive options for reducing the overall burden of HIV related challenges in South Africa. PMID- 25920981 TI - Attitudes of women and men living with HIV and their healthcare providers towards pregnancy and abortion by HIV-positive women in Nigeria and Zambia. AB - Fertility decisions among people living with HIV/AIDS (PLWHA) are complicated by disease progression, the health of their existing children and possible antiretroviral therapy (ART) use, among other factors. Using a sample of HIV positive women (n = 353) and men (n = 299) from Nigeria and Zambia and their healthcare providers (n = 179), we examined attitudes towards childbearing and abortion by HIV-positive women. To measure childbearing and abortion attitudes, we used individual indicators and a composite measure (an index). Support for an HIV-positive woman to have a child was greatest if she was nulliparous or if her desire to have a child was not conditioned on parity and lowest if she already had an HIV-positive child. Such support was found to be lower among HIV-positive women than among HIV-positive men, both of which were lower than reported support from their healthcare providers. There was wider variation in support for abortion depending on the measure than there was for support for childbearing. Half of all respondents indicated no or low support for abortion on the index measure while between 2 and 4 in 10 respondents were supportive of HIV-positive women being able to terminate a pregnancy. The overall low levels of support for abortion indicate that most respondents did not see HIV as a medical condition which justifies abortion. Respondents in Nigeria and those who live in urban areas were more likely to support HIV-positive women's childbearing. About a fifth of HIV-positive respondents reported being counselled to end childbearing after their diagnosis. In summary, respondents from both Nigeria and Zambia demonstrate tempered support of (continued) childbearing among HIV-positive women while anti-abortion attitudes remain strong. Access to ART did not impart a strong effect on these attitudes. Therefore, pronatalist attitudes remain in place in the face of HIV infection. PMID- 25920978 TI - Integrating chemical mutagenesis and whole-genome sequencing as a platform for forward and reverse genetic analysis of Chlamydia. AB - Gene inactivation by transposon insertion or allelic exchange is a powerful approach to probe gene function. Unfortunately, many microbes, including Chlamydia, are not amenable to routine molecular genetic manipulations. Here we describe an arrayed library of chemically induced mutants of the genetically intransigent pathogen Chlamydia trachomatis, in which all mutations have been identified by whole-genome sequencing, providing a platform for reverse genetic applications. An analysis of possible loss-of-function mutations in the collection uncovered plasticity in the central metabolic properties of this obligate intracellular pathogen. We also describe the use of the library in a forward genetic screen that identified InaC as a bacterial factor that binds host ARF and 14-3-3 proteins and modulates F-actin assembly and Golgi redistribution around the pathogenic vacuole. This work provides a robust platform for reverse and forward genetic approaches in Chlamydia and should serve as a valuable resource to the community. PMID- 25920982 TI - Silence, blame and AIDS conspiracy theories among the Xhosa people in two townships in Cape Town. AB - Conspiratorial expressions about the origins of HIV/AIDS have been recognised as an outcome of the AIDS epidemic in South Africa. This article examines the reasons behind AIDS conspiracy theories, which include a reoccurring repertory of themes, motifs and characters. In these expressions, the malevolent antagonist is the replaced apartheid regime, along with other more archetypal adversaries. So far, AIDS conspiracy theories have been interpreted in terms of currently perceived injustices and frustrations related to the complex past of South Africa. Based on ethnographic fieldwork conducted among Xhosa people in two townships in Cape Town, this article goes further to examine how AIDS conspiracy theories in South Africa can be ascribed to gender-based communication. Sporadic but pronounced expressions of conspiratorial thinking should be understood as connected to local traditions of avoidance and respect. Moreover, the fact that conspiratorial expressions are more common among men can be seen in terms of a counter-narrative mechanism, which is to some extent due to the blame that is cast on men for being the main culprits behind the spread of HIV/AIDS. PMID- 25920983 TI - Experiences of work among people with disabilities who are HIV-positive in Zambia. AB - This paper focuses on accounts of how having a disability and being HIV-positive influences experiences of work among 21 people (12 women, 9 men) in Lusaka, Zambia. In-depth semi-structured interviews were conducted in English, Bemba, Nyanja, or Zambian sign language. Descriptive and thematic analyses were conducted. Three major themes were generated. The first, a triple burden, describes the burden of having a disability, being HIV-positive, and being unemployed. The second theme, disability and HIV is not inability, describes participants' desire for work and their resistance to being regarded as objects of charity. Finally, how work influences HIV management, describes the practicalities of working and living with HIV. Together these themes highlight the limited options available to persons with disabilities with HIV in Lusaka, not only secondary to the effects of HIV influencing their physical capacity to work, but also because of the attendant social stigma of being a person with a disability and HIV-positive. PMID- 25920984 TI - Gender and HIV infection in the context of alcoholism in Kenya. AB - Women in sub-Saharan Africa account for more than half (58%) of people living with the HIV and it is the only continent where HIV prevalence is higher for women than for men. Studies have attributed alcoholism with the high rates of HIV infection due to its impact on sexual behaviour and arousal. African countries with high rates of alcoholism also reportedly have higher rates of HIV infection. This study explores rural communities' perspectives on the risk factors for HIV infection among women who are in alcohol discordant relationships where the man drinks alcohol excessively. Data were gathered through focus group discussions in rural central Kenya where alcoholism has reached epidemic levels. Key findings indicate the perceived severity of alcoholism, the perceived impact of alcoholism on men's reproductive health and the unmet sexual and reproductive needs of women in alcohol discordant relationships. Women engage in risky sexual behaviours in an attempt to meet these needs. Such risky behaviour in addition to alcohol related sexual violence and low response-efficacy for safer sexual practices make them vulnerable to HIV infection and enhances the spread of HIV within communities. The study concludes that in preventing HIV infection among women in alcohol communities affected by alcohol, it is important to focus on their response efficacy. Intervention programmes that focus on HIV prevention among older married women and that integrate alcohol and HIV prevention are long overdue. PMID- 25920985 TI - HIV-related stigma: implications for symptoms of anxiety and depression among Malawian women. AB - An estimated 11% of the adult population in Malawi, Africa, is living with HIV/AIDS. The disease has taken a toll on communities, resulting in high morbidity and mortality. Malawian women carry the burden of being caretakers for individuals infected with HIV while also worrying about their own health. However, little is known about how HIV/ AIDS affects psychological functioning among Malawian women in areas hit hardest by the epidemic. To that end, this paper examined the influence of HIV-related stigma on symptoms of anxiety and depression among 59 women 17-46 years old who were recruited from the Namitete area of Malawi. Women who reported greater worry about being infected with HIV and greater HIV-related stigma were significantly more likely to report greater symptoms of anxiety and depression. These findings suggest that interventions that reduce HIV-related stigma are likely to enhance psychological functioning among Malawian women, which in turn will improve the women's quality of life and well-being. PMID- 25920986 TI - Re-imagining decision making: addressing a discrete social driver of HIV/AIDS through the lens of complexity science. AB - This article argues that decision making is a discrete social driver that can be associated with the HIV/AIDS epidemic in the Limpopo province in South Africa. The authors argue that complexity science can inform future research and interventions by presenting two decision making frameworks arising out of complexity science that have the potential to enable young people to better negotiate decision-making contexts whilst simultaneously opening spaces of dialogue that can mitigate the impact of HIV-risk in specific, punctuated contexts. The methodological design was prompted by findings from youth-oriented community engagement projects that include Communication Conversations and Sex & Relationships Education. The proposed methods have the potential to exploit the phenomenon of leadership emergence as a product of decision making at critical moments. This has the potential to promote the growth of home-grown leadership skill sets that make sense to young people and to enable them better manage their own health, thus reducing risk and vulnerability to HIV infection and sexual violence. PMID- 25920987 TI - 'Deadly gonorrhoea': history, collective memory and early HIV epidemiology in East Central Africa. AB - This article combines local oral reminiscences with recent epidemiological literature to sketch a historical context around the onset and expansion of the HIV-1 epidemic in southern Uganda and north-western Tanzania. The local historical imagination has associated the appearance of AIDS in two ways. First, with specific socio-economic structures and circumstances common in the region since the 1960s and their enhancement during the 1970s due to economic changes at national and global levels. Second, the epidemic is associated with changes in the epidemiological situation. Local perspectives are supported by recent phylogenetic research and circumstantial historical evidence, on the basis of which a hypothesis on the expansion of HIV-1 in East Central Africa (southern Uganda, north-western Tanzania, Rwanda) is presented. PMID- 25920988 TI - Extending HIV/AIDS policy abroad through international collaboration aimed at promoting positive sexual behaviours of African students schooling in foreign countries. PMID- 25920989 TI - Conformational order in aggregates of conjugated polymers. AB - With the abundant variety and increasing chemical complexity of conjugated polymers proliferating the field of organic semiconductors, it has become increasingly important to correlate the polymer molecular structure with its mesoscale conformational and morphological attributes. For instance, it is unknown which combinations of chemical moieties and periodicities predictably produce mesoscale ordering. Interestingly, not all ordered morphologies result in efficient devices. In this work we have parametrized accurate classical force fields and used these to compute the conformational and aggregation characteristics of single strands of common conjugated polymers. Molecular dynamics trajectories are shown to reproduce experimentally observed polymeric ordering, concluding that efficient organic photovoltaic devices span a range of polymer conformational classes, and suggesting that the solution-phase morphologies have far-reaching effects. Encouragingly, these simulations indicate that despite the wide-range of conformational classes present in successful devices, local molecular ordering, and not long-range crystallinity, appears to be the necessary requirement for efficient devices. Finally, we examine what makes a "good" solvent for conjugated polymers, concluding that dispersive pi electron solvent-polymer interactions, and not the electrostatic potential of the backbone interacting with the solvent, are what primarily determine a polymer's solubility in a particular solvent, and consequently its morphological characteristics. PMID- 25920990 TI - Intensive Home Hemodialysis: An Eye at the Past Looking for the Hemodialysis of the Future. AB - Multiple observational studies along with a limited number of randomized clinical trials suggest that intensive hemodialysis (IHD) not only improves outcomes for uremic patients undergoing chronic dialysis but does so with a more favorable cost/benefit ratio compared with conventional hemodialysis. As a result of this, there has been a rapid increase in the interest in home hemodialysis (HHD) as HHD represents the easiest means of implementing IHD. While HHD has generated increased interest given its association with better outcomes/reduced hospitalizations, there are very few randomized controlled trials comparing HHD with other hemodialysis methods. Reported HHD-associated increased survival benefits compared with in-center hemodialysis are from uncontrolled studies, which raise patient selection bias as underlying the differences found. Thus, while HHD draws increasing attention, studies that pay careful attention to the psychosocial, demographic, and clinical factors associated with patients selected to undergo HHD will be needed to ultimately demonstrate its benefits, clarify the clinical applications, and determine the limits of IHD use in dialysis patients. PMID- 25920991 TI - Is gastroesophageal reflux disease in south Indian population influenced by waist hip ratio and body mass index? PMID- 25920992 TI - External validation of FXYD3 and KRT20 as predictive biomarkers for the presence of micrometastasis in muscle invasive bladder cancer lymph nodes. AB - INTRODUCTION: Recent studies have proposed that FXYD3 and KRT20 mRNA quantified by quantitative reverse transcription polymerase chain reaction (qRT-PCR) in paraffin could be biomarkers to detect lymph nodes with micrometastases that avoid detection by conventional analysis with hematoxylin-eosin (HE). A validation study was conducted on the lymph nodes of patients who underwent radical cystectomy. OBJECTIVE: To classify the adenopathic state of a sample of patients who underwent cystectomy, based on the lymph node expression of FXYD3 and KRT20. The secondary objective was to assess whether there is a differential oncologic evolution for the patients, depending on the lymph node expression of these proteins. MATERIAL AND METHOD: The study included lymph nodes from 64 patients who underwent cystectomy for infiltrating bladder tumor: The model was developed using metastatic lymph nodes from 15 patients and lymph nodes from 4 patients with no known tumor. Genetic expression was measured using real-time qRT PCR. We calculated (using qRT-PCR) the median expression of FXYD3 and KRT20 mRNA in the lymph node tissue. We then analyzed the receiver operating characteristic (ROC) curves, according to the function y=0.1400+0.250FXYD3-2.532. The cutoff was established using an ROC curve. The formula was applied to the remaining lymph node tissue, based on the previously established cutoff. The sample was classified into 4 subgroups: HE- qRT-PCR-, HE- qRT-PCR+, HE+ qRT-PCR+ y HE+, qRT PCR-. A descriptive, comparative analysis was performed, as well as a metastatic progression-free survival analysis, calculating the Kaplan and Meyer curves for the 3 established subgroups. The test results were considered statistically significant at P<.05. RESULTS: Using qRT-PCR, we verified that there were differences in the median expression of FXYD3 (P=.05) and KRT20 (P=.009) between the lymph node tissues of patients with benign prostate hyperplasia and those of patients with lymph node metastasis. A cutoff was assigned to 0.377. The sample was classified as follows: 37.5% of the patients were pN0 by HE and pN0 by qRT PCR (-HE -qRT-PCR), 39.1% were pN0 by HE but metastatic by qRT-PCR (-HE +qRT PCR), and 15 patients (23.4%) were metastatic by both techniques (+HE +qRT-PCR). The Kaplan and Meyer curves showed poorer metastatic progression-free survival for the patients who were +HE and +qRT-PCR than for the other subgroups, with no significant differences between -HE +qRT-PCR and -HE -qRT-PCR. CONCLUSIONS: According to our results, 39.1% of the patients with infiltrating vesical tumors overexpressed the FXYD3 and KRT20 biomarkers and were N0 by HE. We observed no differential clinical behavior among the patients who underwent cystectomy according to their expression of FXYD3 and KRT20 when they were N0 by HE. PMID- 25920993 TI - The Relationship Between Pharyngeal Constriction and Post-swallow Residue. AB - Pharyngeal constriction has been proposed as a parameter that may distinguish functional from impaired swallows. We employed anatomically normalized pixel based measures of pharyngeal area at maximum constriction, and the ratio of this measure to area at rest, and explored the association between these measures and post-swallow residue using the normalized residue ratio scale (NRRS). Videofluoroscopy data for 5 ml boluses of 22 % (w/v) liquid barium were analyzed from 20 healthy young adults and 40 patients with suspected neurogenic dysphagia. The frames of maximum pharyngeal constriction and post-swallow hyoid rest were extracted. Pixel-based measures of pharyngeal area were made using ImageJ and size-normalized using the squared C2-C4 vertebral distance as a reference scalar. Post-swallow residue and the areas of the vallecular and pyriform sinus spaces were measured on the hyoid rest frame to calculate the NRRSv and NRRSp. The dataset was divided into swallows with residue within or exceeding the upper confidence interval boundary seen in the healthy participants. Mixed model repeated measures ANOVAs were used to compare pharyngeal area (rest, constriction) and the pharyngeal constriction ratio, between individuals with and without residue. Measures of pharyngeal area at maximum constriction were significantly larger (i.e., less constricted, p = 0.000) in individuals with post swallow residue in either the valleculae or the pyriform sinus. These results support the idea that interventions targeted toward improving pharyngeal constriction have the potential to be effective in reducing post-swallow residue. PMID- 25920994 TI - Low-Dose Estramustine Phosphate and Concomitant Low-Dose Acetylsalicylic Acid in Heavily Pretreated Patients With Advanced Castration-Resistant Prostate Cancer. AB - BACKGROUND: The aim of this phase 2 study was to evaluate the activity and tolerability of low-dose estramustine phosphate (EMP) with concomitant low-dose acetylsalicylic acid (ASA) as a thromboprophylactic agent in heavily pretreated patients with advanced castration-resistant prostate cancer. METHODS: Patients received 420 mg of oral EMP twice daily and oral ASA 100 mg once daily. The primary endpoint was prostate-specific antigen response. All of the patients had been previously treated with docetaxel and abiraterone acetate, and 12 had also received cabazitaxel. RESULTS: Thirty-one patients were enrolled. Prostate specific antigen response was observed in 9 patients (29.0%; 95% confidence interval [CI], 14-48). Median progression-free survival was 3.6 months (95% CI, 2.2-5.6), and median overall survival was 7.6 months (95% CI, 6.9-9.7). Treatment was generally well tolerated, and no grade 3/4 toxicity was observed. Ten patients (32.2%) had grade 2 nausea and vomiting. No cardiovascular event and no major bleeding occurred. No venous thromboembolism event was observed. CONCLUSION: Low-dose EMP with concomitant low-dose ASA seems to be a safe treatment option with some activity for patients with advanced castration resistant prostate cancer who have been heavily pretreated. PMID- 25920995 TI - Prognostic Impact of Preoperative Anemia on Urothelial and Extraurothelial Recurrence in Patients With Upper Tract Urothelial Carcinoma. AB - BACKGROUND: To investigate the prognostic impact of preoperative anemia on urothelial and extraurothelial recurrence after radical nephroureterectomy. METHODS: A single-center series of 238 consecutive patients who were treated with radical nephroureterectomy for upper tract urothelial carcinoma was evaluated. We categorized patients on the basis of hemoglobin level into 2 groups, including normal or anemia. Survival was estimated using the Kaplan-Meier method. Cox proportional hazard regression models were used to evaluate the association of preoperative anemia with outcome, controlling for clinicopathologic variables. RESULTS: Ninety-seven patients (40.8%) had anemia (median hemoglobin level, 143 vs. 107 g/L). Preoperative anemia was associated with history of bladder cancer (P = .01), tumor multifocality (P = .03), lymphovascular invasion (P = .05), and adjuvant chemotherapy (P = .01). Higher tumor stage and grade, and lymph node metastasis were significantly associated with preoperative anemia. Preoperative anemia was independently associated with extraurothelial recurrence (hazard ratio, 1.95; 95% confidence interval, 1.14-3.34; P = .01) in multivariate Cox regression analyses. Only a history of bladder tumor (hazard ratio, 2.07; P = .009) and tumor multifocality (hazard ratio, 3.97; 95% confidence interval, 2.37 6.67; P < .001) were independently associated with urothelial recurrence. The 5 year cancer-specific survival for patients with normal hemoglobin level was 82.1% and for patients with preoperative anemia was 54.2%. CONCLUSION: Patients with preoperative anemia had a greater probability of having upper tract urothelial carcinoma with higher tumor stages, higher tumor grades, and lymph node metastasis (pN+). Preoperative anemia was statistically significantly associated with worse cancer-specific survival and extraurothelial recurrence in patients who underwent radical nephroureterectomy. PMID- 25920997 TI - The willingness and actual situation of Chinese cancer patients and their family members participating in medical decision-making. AB - OBJECTIVE: In China, not only patients and physicians are involved in medical decision-making (MDM) but also the patients' family members. The objective is to investigate the willingness and actual situation of cancer patients and their family members participating in the MDM process. METHODS: In this cross-sectional study, questionnaires were administered to 247 pairs of cancer inpatients and their relatives. Information regarding participants' willingness and actual experience during the decision-making process was documented. Eligible participants were cancer inpatients or their relatives, 18 years of age or older, and informed of the cancer diagnosis. All the patients should have received chemotherapy. RESULTS: The effective response rate was 72.9% (180/247). Over half of the patients (53.3%) and family members (57.8%) were willing to be part of the MDM process. In contrast, only 35.0% of patients and 46.1% of family members actually experienced this process (p = 0.001 and p = 0.011, respectively). Fewer family members (42.2%) than patients (53.3%) believed that patients should be involved in the MDM process (p < 0.001). Patients who were the head of their family (odds ratio 2.577, 95% CI 1.198-5.556, p = 0.015) experienced more involvement in MDM. CONCLUSIONS: Although more than half of Chinese cancer patients and family members wanted to be part of MDM, the actual participation was below their expectation. Majority of family members do not want the patients to be involved in the process of MDM. PMID- 25920996 TI - A single-repeat MYB transcription repressor, MYBH, participates in regulation of leaf senescence in Arabidopsis. AB - Leaf senescence, the final stage of leaf development, is regulated tightly by endogenous and environmental signals. MYBS3, a MYB transcription factor with a single DNA-binding domain, mediates sugar signaling in rice. Here we report that an Arabidopsis MYBS3 homolog, MYBH, plays a critical role in developmentally regulated and dark-induced leaf senescence by repressing transcription. Expression of MYBH was enhanced in older and dark-treated leaves. Gain- and loss of-function analysis indicated that MYBH was involved in the onset of leaf senescence. Plants constitutively overexpressing MYBH underwent premature leaf senescence and showed enhanced expression of leaf senescence marker genes. In contrast, the MYBH mutant line, mybh-1, exhibited a delayed-senescence phenotype. The EAR repression domain was required for MYBH-regulated leaf senescence. Overexpression and knockout of MYBH repressed and enhanced auxin-responsive gene expression, respectively. MYBH repressed the auxin-amido synthase genes DFL1/GH3.6 and DFL2/GH3.10, which regulate auxin homoeostasis, by binding directly to the TA box in each of their regulatory regions. An auxin-responsive phenotype was enhanced in MYBH overexpression lines and reduced in mybh knockout lines. Overexpression of MYBH enhanced gene expression of SAUR36, an auxin promoted leaf senescence key regulator, and accelerated ABA- and ethylene-induced leaf senescence in transgenic Arabidopsis plants. Our results suggest that the role of MYBH in controlling auxin homeostasis accounts for its capacity to participate in regulation of age- and darkness-induced leaf senescence in Arabidopsis. PMID- 25920998 TI - Fine-tuning of T-cell development by the CD3gamma di-leucine-based TCR-sorting motif. AB - The CD3gamma di-leucine-based (diL) receptor-sorting motif plays a central role in TCR down-regulation and in clonal expansion of virus-specific T cells. However, the role of the CD3gamma diL motif in T-cell development is not known. In this study, we show that protein kinase C-induced TCR down-regulation is abolished in thymocytes from CD3gammaLLAA mice with a mutated CD3gamma diL motif, and that CD3gammaLLAA mice have reduced numbers of thymocytes compared with aged matched wild-type mice. We found that early thymocyte development at the beta selection checkpoint is impaired resulting in reduced numbers of double negative (DN) 4 cells in CD3gammaLLAA mice. This was not caused by reduced proliferation but most probably by increased down-regulation of the antiapoptotic molecule Bcl 2 causing enhanced apoptosis during the transition from the DN3 to the DN4 stage. In contrast, proliferation of immature CD8 single positive (ISP) thymocytes was increased resulting in normal numbers of ISP in CD3gammaLLAA mice. Despite the normal numbers of ISP, CD3gammaLLAA mice had reduced numbers of double positive and SP thymocytes indicating that the CD3gamma diL motif also affected later stages of T-cell development. In accordance, we found that positive and negative selection, differentiation toward CD4 and CD8 SP T cells and the development of nonconventional T cells were affected in CD3gammaLLAA mice. In conclusion, our study identifies an important role of the CD3gamma diL motif in T-cell development most probably mediated by its fine-tuning of pre-TCR and TCR expression, down-regulation and signaling. PMID- 25920999 TI - Expression and functional activity of neurotransmitter system components in sea urchins' early development. AB - Reverse-transcription polymerase chain reaction (RT-PCR) investigation of the expression of the components supposedly taking part in serotonin regulation of the early development of Paracentrotus lividus has shown the presence of transcripts of five receptors, one of which has conservative amino acid residues characteristic of monoaminergic receptors. At the early stages of embryogenesis the expressions of serotonin transporter (SERT) and noradrenaline transporter (NET) were also recognized. The activities of the enzymes of serotonin synthesis and serotonin transporter were shown using immunohistochemistry and incubation with para-chlorophenylalanine (PSRA) and 5-hydroxytryptophan (HTP). Pharmacological experiments have shown a preferential cytostatic activity of ligands characterized as mammalian 5-hydroxytryptamine (5-HT)1-antagonists. On the basis of the sum of the data from molecular biology and embryo physiological experiments, it is suggested that metabotropic serotonin receptors and membrane transporters take part in the regulatory processes of early sea urchin embryogenesis. PMID- 25921000 TI - Erratum to: Clinical Applications of Naturally Derived Biopolymer-Based Scaffolds for Regenerative Medicine. PMID- 25921001 TI - Effect of Intensified Decellularization of Equine Carotid Arteries on Scaffold Biomechanics and Cytotoxicity. AB - Decellularized equine carotid arteries (dEAC) are suggested to represent an alternative for alloplastic vascular grafts in haemodialysis patients to achieve vascular access. Recently it was shown that intensified detergent treatment completely removed cellular components from dEAC and thereby significantly reduced matrix immunogenicity. However, detergents may also affect matrix composition and stability and render scaffolds cytotoxic. Therefore, intensively decellularized carotids (int-dEAC) were now evaluated for their biomechanical characteristics (suture retention strength, burst pressure and circumferential compliance at arterial and venous systolic and diastolic pressure), matrix components (collagen and glycosaminoglycan content) and indirect and direct cytotoxicity (WST-8 assay and endothelial cell seeding) and compared with native (n-EAC) and conventionally decellularized carotids (con-dEAC). Both decellularization protocols comparably reduced matrix compliance (venous pressure compliance: 32.2 and 27.4% of n-EAC; p < 0.01 and arterial pressure compliance: 26.8 and 23.7% of n-EAC, p < 0.01) but had no effect on suture retention strength and burst pressure. Matrix characterization revealed unchanged collagen contents but a 39.0% (con-dEAC) and 26.4% (int-dEAC, p < 0.01) reduction of glycosaminoglycans, respectively. Cytotoxicity was not observed in either dEAC matrix which was also displayed by an intact endothelial lining after seeding. Thus, even intensified decellularization generates matrix scaffolds highly suitable for vascular tissue engineering purposes, e.g., the generation of haemodialysis shunts. PMID- 25921002 TI - High-dose erlotinib for refractory leptomeningeal metastases after failure of standard-dose EGFR-TKIs. AB - BACKGROUND: After initial response to epidermal growth factor receptor-tyrosine kinase inhibitors (EGFR-TKIs), approximately one-third of patients develop central nervous system (CNS) metastases, including leptomeningeal metastases (LM). To achieve longer survival, control of CNS metastases is important, but therapeutic options are limited for LM after failure of standard-dose EGFR-TKIs. METHODS: We retrospectively evaluated the efficacy and safety of high-dose erlotinib in EGFR-mutant non-small cell lung cancer (NSCLC) patients with refractory LM after failure of standard-dose EGFR-TKIs. Survivals from diagnosis of LM to death were compared in patients with or without high-dose erlotinib. RESULTS: Between January 2007 and April 2013, we identified 35 patients with EGFR mutant NSCLC, complicated with LM, and 12 underwent high-dose erlotinib, while the other 23 received only standard-dose EGFR-TKIs. In patients receiving high dose erlotinib, magnetic resonance imaging response was confirmed in 3 (30 %) of 10 evaluable patients. Median time to CNS progression was 2.3 months (95 % confidence interval [CI] 1.8-5.5 months). Performance status and neurological symptoms improved in 4 (33 %) of 12 and 6 (50 %) of 12 patients, respectively. No severe adverse events (>=grade 3) associated with high-dose erlotinib were observed. Median survival time from diagnosis of LM in patients with high-dose erlotinib was 6.2 months (95 % CI 2.5-8.5 months), and in those without 5.9 months (95 % CI 1.3-7.8 months) (p = 0.94). CONCLUSION: High-dose erlotinib suggested its efficacy and safety in some patients with refractory LM. It represents a potential therapeutic option against LM after failure of standard dose EGFR-TKIs, especially to palliate LM-related neurological symptoms. PMID- 25921003 TI - Descriptive epidemiology of epilepsy in the U.S. population: A different approach. AB - OBJECTIVE: Determine prevalence and incidence of epilepsy within two health insurance claims databases representing large sectors of the U.S. METHODS: A retrospective observational analysis using Commercial Claims and Medicare (CC&M) Supplemental and Medicaid insurance claims data between January 1, 2007 and December 31, 2011. Over 20 million continuously enrolled lives of all ages were included. Our definition of a prevalent case of epilepsy was based on International Classification of Diseases, Ninth Revision, Clinical Modification coded diagnoses of epilepsy or seizures and evidence of prescribed antiepileptic drugs. Incident cases were identified among prevalent cases continuously enrolled for >= 2 years before the year of incidence determination with no epilepsy, seizure diagnoses, or antiepileptic drug prescriptions recorded. RESULTS: During 2010 and 2011, overall age-adjusted prevalence estimate, combining weighted estimates from all datasets, was 8.5 cases of epilepsy/1,000 population. With evaluation of CC&M and Medicaid data separately, age-adjusted prevalence estimates were 5.0 and 34.3/1,000 population, respectively, for the same period. The overall age-adjusted incidence estimate for 2011, combining weighted estimates from all datasets, was 79.1/100,000 population. Age-adjusted incidence estimates from CC&M and Medicaid data were 64.5 and 182.7/100,000 enrollees, respectively. Incidence data should be interpreted with caution due to possible misclassification of some prevalent cases. SIGNIFICANCE: The large number of patients identified as having epilepsy is statistically robust and provides a credible estimate of the prevalence of epilepsy. Our study draws from multiple U.S. population sectors, making it reasonably representative of the U.S.-insured population. PMID- 25921004 TI - Early clinical experience of cell-free DNA-based aneuploidy screening: A survey of obstetric sonologists in Australia and New Zealand. AB - BACKGROUND: Cell-free DNA-based non-invasive prenatal testing for aneuploidy (NIPT) is now established as the most accurate screening test for trisomy 21. This test became clinically available on a patient-funded basis in Australia and New Zealand in 2013. AIM: To investigate the clinical implementation of NIPT use by members of the Australian Association of Obstetrical and Gynaecological Ultrasonologists (AAOGU) during its first year of local availability. METHOD: Email invitations with an embedded link to an anonymous online survey were sent to all 140 members of the AAOGU in December 2013. RESULTS: We received 54 responses to the survey (39% response rate). Two thirds of respondents were subspecialists in obstetric and gynaecological ultrasound or maternal fetal medicine. The majority of respondents had already used NIPT in their practice (94%). There was no significant difference in the proportion of respondents offering NIPT to high-risk women in private versus public practice (95 versus 82%, P = 0.14). However, inequity of access due to cost was the most common ethical issue encountered. The vast majority continued to offer an 11-13 week ultrasound in addition to NIPT. Almost all respondents (96%) were also willing to offer NIPT to low-risk women in December 2013 after appropriate genetic counselling. CONCLUSIONS: Non-invasive prenatal testing was introduced into clinical care by obstetric sonologists with confidence and in accordance with the current recommended guidelines. These results may help inform future prenatal screening policy and cost-effectiveness analyses. PMID- 25921005 TI - Why birthplace still matters for infants born before 32 weeks: Infant mortality associated with birth at 22-31 weeks' gestation in non-tertiary hospitals in Victoria over two decades. AB - BACKGROUND: Very preterm infants born in non-tertiary hospitals ('outborn') are known to have higher mortality rates compared with infants 'inborn' in tertiary centres. AIM: The aim of this study was to report changes over time in the incidence of outborn livebirths, 22-31 weeks and infant mortality rates for outborn compared with inborn births. METHODS: We conducted a population-based cohort study of consecutive livebirths, 22-31 weeks' gestation in Victoria from 1990 to 2009. The relationship between birthplace, gestational age, birthweight, sex and infant mortality were analysed by logistic regression. RESULTS: There were 13,760 livebirths, 22-31 weeks: 14% were outborn. The proportion of outborn livebirths fell from 19% in 1991 to a nadir of 9% in 1997, but climbed to 17% by 2009. At all times, outborns had higher mortality rates compared with inborns. The overall infant mortality rate was 250.6 per 1000 outborn compared with 113.3 per 1000 inborn livebirths (adjusted odds ratio (aOR) 2.76 (95% CI 2.32, 3.27, P < 0.001). There were no differences between outborn and inborn mortality risks for 22-week livebirths (OR 7.04, 95% CI 0.87, 56.8, P = 0.067), but there were at 23-27 weeks (aOR 3.16, 95% CI 2.52, 3.96, P < 0.001) and at 28-31 weeks (aOR 1.66, 95% CI 1.19, 2.31, P = 0.003). Over time, mortality rates fell for inborn 23-27 week infants. Mortality rates fell for outborn 23-27 week infants in 1990 2005, but rose in 2006-2009. CONCLUSIONS: Outborn livebirths at 22-31 weeks' gestation occur too frequently and are associated with a significantly increased risk of mortality. Strategies to reduce outborn livebirths are required. PMID- 25921006 TI - Re: Kapoor S, Thomas JT, Petersen SG, Gardener GJ. Is the third trimester repeat ultrasound scan for placental localisation needed if the placenta is low lying but clear of the os at the mid-trimester morphology scan? Aust N Z J Obstet Gynaecol 2014; 54(5): 428-32. PMID- 25921007 TI - Re: Is the third trimester repeat ultrasound scan for placental localisation needed if the placenta is low lying but clear of the os at the mid-trimester morphology scan? PMID- 25921008 TI - Regarding "Improving VBAC rates: The combined impact of two management strategies". PMID- 25921009 TI - Re: Paxton JL, Presneill J, Aitken L. Characteristics of obstetric patients referred to intensive care in an Australian tertiary hospital. Aust N Z J Obstet Gynaecol 2014; 54: 445-449. PMID- 25921010 TI - Re: Improving VBAC rates: The combined impact of two management strategies. PMID- 25921011 TI - Re: Characteristics of obstetric patients referred to intensive care in an Australian tertiary hospital. PMID- 25921012 TI - Chemical shift assignments of zinc finger domain of methionine aminopeptidase 1 (MetAP1) from Homo sapiens. AB - Methionine aminopeptidase Type I (MetAP1) cleaves the initiator methionine from about 70 % of all newly synthesized proteins in almost every living cell. Human MetAP1 is a two domain protein with a zinc finger on the N-terminus and a catalytic domain on the C-terminus. Here, we report the chemical shift assignments of the amino terminal zinc binding domain (ZBD) (1-83 residues) of the human MetAP1 derived by using advanced NMR spectroscopic methods. We were able to assign the chemical shifts of ZBD of MetAP1 nearly complete, which reveal two helical fragments involving residues P44-L49 (alpha1) and Q59-K82 (alpha2). The protein structure unfolds upon complex formation with the addition of 2 M excess EDTA, indicated by the appearance of amide resonances in the random coil chemical shift region of (15)NHSQC spectrum. PMID- 25921013 TI - Agreement Between the World Health Organization Algorithm and Lung Consolidation Identified Using Point-of-Care Ultrasound for the Diagnosis of Childhood Pneumonia by General Practitioners. AB - PURPOSE: The World Health Organization (WHO) case management algorithm for acute lower respiratory infections has moderate sensitivity and poor specificity for the diagnosis of pneumonia. We sought to determine the feasibility of using point of-care ultrasound in resource-limited settings to identify pneumonia by general health practitioners and to determine agreement between the WHO algorithm and lung consolidations identified by point-of-care ultrasound. METHODS: An expert radiologist taught two general practitioners how to perform point-of-care ultrasound over a seven-day period. We then conducted a prospective study of children aged 2 months to 3 years in Peru and Nepal with and without respiratory symptoms, which were evaluated by point-of-care ultrasound to identify lung consolidation. RESULTS: We enrolled 378 children: 127 were controls without respiratory symptoms, 82 had respiratory symptoms without clinical pneumonia, and 169 had clinical pneumonia by WHO criteria. Point-of-care ultrasound was performed in the community (n = 180), in outpatient offices (n = 95), in hospital wards (n = 19), and in Emergency Departments (n = 84). Average time to perform point-of-care ultrasound was 6.4 +/- 2.2 min. Inter-observer agreement for point of-care ultrasound interpretation between general practitioners was high (kappa = 0.79, 95 % CI 0.73-0.81). The diagnosis of pneumonia using the WHO algorithm yielded a sensitivity of 69.6 % (95 % CI 55.7-80.8 %), specificity of 59.6 % (95 % CI 54.0-65.0 %), and positive and negative likelihood ratios of 1.73 (95 % CI 1.39-2.15) and 0.51 (95 % CI 0.30-0.76) when lung consolidation on point-of-care ultrasound was used as the reference. CONCLUSIONS: The WHO algorithm disagreed with point-of-care ultrasound findings in more than one-third of children and had an overall low performance when compared with point-of-care ultrasound to identify lung consolidation. A paired approach with point-of-care ultrasound may improve case management in resource-limited settings. PMID- 25921014 TI - Anesthesia for Advanced Bronchoscopic Procedures: State-of-the-Art Review. AB - The bronchoscopic procedures have seen a remarkable increase in both numbers and complexity. Although many anesthesia providers have kept pace with the challenge, the practice is varied and frequently suboptimal. Shared airway during bronchoscopy poses unique challenges. The available reviews have tried to address this lacuna; however, these have frequently dealt with the technical aspects of bronchoscopy than anesthetic challenges. The present review provides evidence based management insights into anesthesia for bronchoscopy-both flexible and rigid. A systematic approach toward pre-procedural evaluation and risk stratification is presented. The possible anatomical and physiological factors that can influence the outcomes are discussed. Pharmacological principles guiding sedation levels and appropriate selection of sedatives form the crux of safe anesthetic management. The newer and safer drugs that can have potential role in anesthesia for bronchoscopy in the near future are discussed. Ventilatory strategies during bronchoscopy for prevention of hypoxia and hypercarbia are emphasized. PMID- 25921015 TI - Misdiagnosis Among Frequent Exacerbators of Clinically Diagnosed Asthma and COPD in Absence of Confirmation of Airflow Obstruction. AB - PURPOSE: Clinical diagnosis of severe asthma and chronic obstructive lung disease (COPD) remains a challenge and often flawed with lack of objective confirmation of airflow obstruction (AO). Misdiagnosis of asthma and COPD has been reported in stable disease, data are non-existent in frequent exacerbators. We investigated misdiagnosis and its predictors in frequent exacerbators. METHODS: The cohort comprised of frequent severe exacerbators (requiring >=2 emergency room (ER) visits or hospitalizations) of physician diagnosed (PD)-asthma and PD-COPD. All patients underwent a rigorous diagnostic algorithm over a follow-up period of 10 +/- 6 months. Two board-certified pulmonologists ascertained final diagnosis. Patients with persistent absence of AO were identified to have misdiagnosis. Multivariate logistic regression analyses were used to identify predictors of misdiagnoses. RESULTS: Among 333 frequent exacerbators analyzed (171 patients with PD-asthma, 162 with PD-COPD, mean annual exacerbations 3.4 +/- 2.8), 24 % of patients had a baseline post-bronchodilator spirometry. Misdiagnosis was found in 26 % (87 of 333) of patients. Another 12 % (41 of 333) of patients had obstructive lung diseases other than asthma and COPD. Independent risk factors for misdiagnosis were spirometry underutilization (PD-asthma: OR = 2.8, 95 % CI 1.16-6.78, p = 0.02 and PD-COPD: OR = 10.7, 95 % CI 2.05-56.27, p = 0.005) and pack years of smoking (PD-COPD: OR = 1.05, 95 % CI 1.01-1.11, p = 0.03). CONCLUSIONS: Objective confirmation of AO is essential in preventing misdiagnosis in frequent severe exacerbators of clinically diagnosed asthma and COPD, a third of whom have neither. Spirometry utilization is strongly associated with a reduced risk of misdiagnosis. Smoking is associated with increased risk of misdiagnosis in severe COPD, but not asthma. PMID- 25921016 TI - Gastrointestinal hemorrhage in aluminum phosphide poisoning. PMID- 25921017 TI - Private speech use in arithmetical calculation: relationship with phonological memory skills in children with and without mathematical difficulties. AB - The majority of recent studies conclude that children's private speech development (private speech internalisation) is important for mathematical development and subject to disabling. The main concern of the present study was whether or not the two phonological memory factors evaluated in the study (i.e. the results of children's digit span assessments, both forward and backward) relates to private speech internalisation and whether this relationship changes with children's age, or mathematical achievement levels, or both. We made comparisons between children with acknowledged mathematical difficulties (MD) and children without mathematical difficulties (MN), basing on private speech differences, phonological memory differences and differences in the relationship between private speech internalisation and phonological memory skills. The results not only confirm the impact of private speech internalisation but also emphasise a possible parallel role of phonological memory for subsequent mathematical achievement. In contrast to the MD children, children without MD showed an age-determined shift from a lesser to greater relationship between a high level of private speech internalisation and a high level phonological memory skills. As a whole, the results are consistent with a developmental difference and not with a developmental delay model and suggest that relationships between private speech internalisation and phonological memory may reflect individual differences in children's mathematical achievement. The results are discussed in terms of directions for future research. PMID- 25921018 TI - Mycoplasma genitalium serum antibodies in infertile couples and fertile women. AB - OBJECTIVES: The association between Mycoplasma genitalium (M. genitalium) serum antibodies and infertility in women and men, as well as infertility subtypes, was investigated. METHODS: Stored serum was obtained from two patient cohorts: infertile couples (239 women and 243 men) attending a gynaecological outpatient clinic between October 1997 and February 2001 and 244 age-matched spontaneously pregnant women. An enzyme immunoassay was used to detect serum immunoglobulin G (IgG) antibodies to M. genitalium in these samples. Patient's Chlamydia trachomatis seropositivity had been previously determined. Risks were calculated using multivariate logistic regression. RESULTS: M. genitalium serum IgG was more common among women of infertile couples (5.4%) than among fertile controls (1.6%) (OR (95%CI) 3.45 (1.10 to 10.75)), adjusting for C. trachomatis IgG (adjusted OR=3.00 (0.95 to 9.47)). Of the women with tubal factor infertility (TFI) 9.1% had M. genitalium IgG compared with 4.6% of women without TFI (OR=2.07 (0.60 to 7.05)); (AOR=1.20 (0.32 to 74.40)). In patients IgG positive to both microorganisms the OR for having TFI was increased (OR=4.86 (1.22 to 19.36)) compared with those positive to C. trachomatis IgG only (AOR=3.14 (1.58 to 6.20)). No associations were found with other infertility diagnoses. Only two men of the infertile couples were M. genitalium IgG positive (0.8%). CONCLUSIONS: M. genitalium serum IgG was associated with infertility in women, however insignificant after adjustment for C. trachomatis IgG, but not with infertility subtypes within this study. M. genitalium IgG seroprevalence among men was very low and not associated with male factor infertility. PMID- 25921019 TI - Evaluating the effect of HIV prevention strategies on uptake of HIV counselling and testing among male most-at-risk-populations in Nigeria; a cross-sectional analysis. AB - OBJECTIVE: The aim of this study was to evaluate the effects of three strategies in increasing uptake of HIV counselling and testing (HCT) among male most-at-risk population (M-MARPs) using programmatic data. DESIGN: HIV prevention strategies were evaluated in a cross-sectional analysis. METHODS: Three HCT strategies were implemented between July 2009 and July 2012 among men who have sex with men (MSM) and people who inject drugs (PWIDs) in four states in Nigeria. The first strategy (S1), involved key opinion leaders (KOLs) who referred M-MARPs to health facilities for HCT. The second strategy (S2) involved KOLs referring M-MARPs to nearby mobile HCT teams while the third (S3) involved mobile M-MARPs peers conducting the HCT. chi(2) statistics were used to test for differences in the distribution of categorical variables across groups while logistic regression was used to measure the effect of the different strategies while controlling for confounding factors. RESULTS: A total of 1988, 14 726 and 14 895 M-MARPs were offered HCT through S1, S2 and S3 strategies, respectively. Overall, S3 (13%) identified the highest proportion of HIV-positive M-MARPs compared with S1 (9%) and S2 (3%), p<=0.001. Also S3 (13%) identified the highest proportion of new HIV diagnosis compared with S1 (8%) and S2 (3%), respectively, p<=0.001. When controlled for age, marital status and occupation, MSM reached via S3 were 9 times (AOR: 9.21; 95% CI 5.57 to 15.23) more likely to uptake HCT when compared with S1 while PWIDs were 21 times (AOR: 20.90; 95% CI 17.33 to 25.21) more likely to uptake to HCT compared with those reached via S1. CONCLUSIONS: Peer-led HCT delivered by S3 had the highest impact on the total number of M-MARPs reached and in identifying HIV-positive M-MARPs and new testers. Training M-MARPs peers to provide HCT is a high impact approach in delivering HCT to M-MARPs. PMID- 25921020 TI - Sex, drugs and smart phone applications: findings from semistructured interviews with men who have sex with men diagnosed with Shigella flexneri 3a in England and Wales. AB - OBJECTIVES: To inform control strategies undertaken as part of an outbreak of Shigella flexneri 3a among men who have sex with men (MSM). METHODS: All men aged >=18 years diagnosed with S flexneri 3a between October 2012 and May 2013 were invited to participate. Semistructured in-depth quantitative interviews were conducted to explore lifestyle and sexual behaviour factors. RESULTS: Of 53 men diagnosed, 42 were interviewed of whom 34 were sexually active MSM. High numbers of sexual partners were reported (median=22) within the previous year; most were casual encounters met through social media networking sites (21/34). 63% (20/32) were HIV-positive and actively sought positive partners for condomless sex. 62% (21/34) of men had used chemsex drugs (mephedrone, crystal methamphetamine and gamma-butyrolactone/gamma-hydroxybutrate), which facilitate sexually disinhibiting behaviour during sexual encounters. 38% (8/21) reported injecting chemsex drugs. Where reported almost half (12/23) had attended or hosted sex parties. All reported oral-anal contact and fisting was common (16/34). Many had had gonorrhoea (23/34) and chlamydia (17/34). HIV-positive serostatus was associated with both insertive anal intercourse with a casual partner and receptive fisting (adjusted OR=15.0, p=0.01; adjusted OR=18.3, p=0.03) as was the use of web applications that promote and facilitate unprotected sex (adjusted OR=19.8, p=0.02). CONCLUSIONS: HIV-positive MSM infected with S flexneri 3a used social media to meet sexual partners for unprotected sex mainly at sex parties. The potential for the transmission of S flexneri, HIV and other infections is clear. MSM need to be aware of the effect that chemsex drugs have on their health. PMID- 25921021 TI - Per capita incidence of sexually transmitted infections increases systematically with urban population size: a cross-sectional study. AB - OBJECTIVES: Rampant urbanisation rates across the globe demand that we improve our understanding of how infectious diseases spread in modern urban landscapes, where larger and more connected host populations enhance the thriving capacity of certain pathogens. METHODS: A data-driven approach is employed to study the ability of sexually transmitted diseases (STDs) to thrive in urban areas. The conduciveness of population size of urban areas and their socioeconomic characteristics are used as predictors of disease incidence, using confirmed-case data on STDs in the USA as a case study. RESULTS: A superlinear relation between STD incidence and urban population size is found, even after controlling for various socioeconomic aspects, suggesting that doubling the population size of a city results in an expected increase in STD incidence larger than twofold, provided that all other socioeconomic aspects remain fixed. Additionally, the percentage of African-Americans, income inequalities, education and per capita income are found to have a significant impact on the incidence of each of the three STDs studied. CONCLUSIONS: STDs disproportionately concentrate in larger cities. Hence, larger urban areas merit extra prevention and treatment efforts, especially in low-income and middle-income countries where urbanisation rates are higher. PMID- 25921022 TI - Acute effects of surgery on emotion and personality of brain tumor patients: surgery impact, histological aspects, and recovery. AB - BACKGROUND: Cognitive effects of brain surgery for the removal of intracranial tumors are still under investigation. For many basic sensory/motor or language based functions, focal, albeit transient, cognitive deficits have been reported low-grade gliomas (LGGs); however, the effects of surgery on higher-level cognitive functions are still largely unknown. It has recently been shown that, following brain tumors, damage to different brain regions causes a variety of deficits at different levels in the perception and interpretation of emotions and intentions. However, the effects of different tumor histologies and, more importantly, the effects of surgery on these functions have not been examined. METHODS: The performance of 66 patients affected by high-grade glioma (HGG), LGG, and meningioma on 4 tasks tapping different levels of perception and interpretations of emotion and intentions was assessed before, immediately after, and (for LGG patients) 4 months following surgery. RESULTS: Results showed that HGG patients were generally already impaired in the more perceptual tasks before surgery and did not show surgery effects. Conversely, LGG patients, who were unimpaired before surgery, showed a significant deficit in perceptual tasks immediately after surgery that was recovered within few months. Meningioma patients were substantially unimpaired in all tasks. CONCLUSIONS: These results show that surgery can be relatively safe for LGG patients with regard to the higher-level, more complex cognitive functions and can provide further useful information to the neurosurgeon and improve communication with both the patient and the relatives about possible changes that can occur immediately after surgery. PMID- 25921024 TI - Quantitative assessment of nerve echogenicity as an additional tool for evaluation of common fibular neuropathy. AB - OBJECTIVE: Quantitative assessment of nerve echogenicity using the MaxEntropy, RenyiEntropy and Yen methods has shown promise in the assessment of ulnar neuropathy at the elbow. The purpose of this study was to determine the clinical usefulness of quantitative echogenicity measurement when using these three automatic thresholding methods in the evaluation of patients with common fibular (CF) neuropathy. METHODS: High-resolution ultrasonography (HRUS) images of the CF nerve from 45 patients with CF neuropathy were compared to 42 healthy controls. RESULTS: With all three methods patients with CF neuropathy had significantly higher mean hypoechoic fraction than healthy controls at the level of the fibular head (FH): MaxEntropy 87.4% versus 71.9% (p<0.001), RenyiEntropy 84.7% versus 68% (p<0.001) and Yen 87.6% versus 68.2% (p<0.001). Patients with CF neuropathy could be differentiated from healthy controls at a hypoechoic fraction cut-off point of 82% (MaxEntropy), 80% (RenyiEntropy) and 80% (Yen) with a sensitivity of 82%, 82% and 84% respectively, and a specificity of 93%, 95% and 83% respectively. Similar results were found for sonographic measurements above the FH. CONCLUSION: Quantitative assessment of nerve echogenicity using the MaxEntropy, RenyiEntropy and Yen methods can be used to distinguish between patients with CF neuropathy and healthy controls with high sensitivity and specificity. SIGNIFICANCE: These three proven automatic thresholding methods can be used to assess nerve echogenicity in future studies. Quantitative echogenicity assessment with HRUS shows promise for the future as a potential diagnostic tool in daily clinical practice. PMID- 25921023 TI - Impaired expression of ATP-binding cassette transporter G2 and liver damage in erythropoietic protoporphyria. PMID- 25921025 TI - Electrophysiological and behavioural processing of complex acoustic cues. AB - OBJECTIVES: To examine behavioural and neural processing of pitch cues in adults with normal hearing (NH) and adults with sensorineural hearing loss (SNHL). METHODS: All participants completed a test of behavioural sensitivity to pitch cues using the TFS1 test (Moore and Sek, 2009a). Cortical potentials (N1, P2 and acoustic change complex) were recorded in response to frequency shifted (deltaF) tone complexes in an 'ABA' pattern. RESULTS: The SNHL group performed more poorly than the NH group for the TFS1 test. P2 was more reflective of pitch differences between the complexes than N1. The presence of acoustic change complex in response to the TFS transitions in the ABA stimulus varied with deltaF. Acoustic change complex amplitudes were reduced for the group with SNHL compared to controls. CONCLUSION: Behavioural performance and cortical responses reflect pitch processing depending on the salience of pitch cues. SIGNIFICANCE: These data support the use of cortical potentials and behavioural sensitivity tests to measure processing of complex acoustic cues in people with hearing loss. This approach has potential for evaluation of benefit from auditory training and hearing instrument digital signal processing strategies. PMID- 25921027 TI - Efficacy and safety of pulse immunosuppressive therapy with glucocorticoid and cyclophosphamide in patients with paraquat poisoning: A meta-analysis. AB - PURPOSE: Paraquat (PQ) is widely used in developing countries. Accidental or suicidal PQ poisoning is a public health concern due to lack of effective treatment. Because the role of pulse immunosuppressive therapy with glucocorticoid and cyclophosphamide for PQ poisoning is uncertain, we performed a meta-analysis to investigate the efficacy and safety of the therapy. METHOD: A systematic literature search for randomized controlled trials (RCTs) and other clinical studies was performed in Pub Med, Embase, Chinese National Knowledge Infrastructure, Chinese Biomedical Literature and Retrieval System, and Chinese Medical Current Contents. We estimated pooled relative risk ratios (RRs) and 95% confidence intervals (CIs) using a fixed effect model or random effect model. Outcomes included mortality, incidence of acute renal failure (ARF) and hypoxia, and leucopenia. RESULTS: Five studies (three RCTs) involving 332 PQ poisoning patients met the criteria. The mortality of moderate to fulminant poisoning patients receiving the pulse therapy was lower than that of the controls (60.4% vs. 85.3%; RR 0.71, 95% CI: 0.59, 0.86, P=0.0004). The therapy also reduced the mortality of patients with moderate to severe PQ poisoning (45.1% vs. 79.1%, RR 0.45; 95% CI: 0.28, 0.75, P=0.002). However, the therapy did not decrease the incidence of ARF and hypoxia. In addition, the pulse therapy caused more leucopenia than the controls (36.9% vs. 2.6%; RR: 9.12; 95% CI: 3.65, 22.81, P<0.00001). CONCLUSION: Pulse immunosuppressive therapy with glucocorticoid and cyclophosphamide may reduce the mortality of PQ poisoning patients, although the therapy may cause leucopenia. PMID- 25921026 TI - Choline metabolism-based molecular diagnosis of cancer: an update. AB - Abnormal choline metabolism continues to be identified in multiple cancers. Molecular causes of abnormal choline metabolism are changes in choline kinase alpha, ethanolamine kinase-alpha, phosphatidylcholine-specific phospholipase C and -D and glycerophosphocholine phosphodiesterases, as well as several choline transporters. The net outcome of these enzymatic changes is an increase in phosphocholine and total choline (tCho) and, in some cancers, a relative decrease of glycerophosphocholine. The increased tCho signal detected by (1)H magnetic resonance spectroscopy is being evaluated as a diagnostic marker in multiple cancers. Increased expression and activity of choline transporters and choline kinase-alpha have spurred the development of radiolabeled choline analogs as PET imaging tracers. Both tCho (1)H magnetic resonance spectroscopy and choline PET are being investigated to detect response to treatment. Enzymes mediating the abnormal choline metabolism are being explored as targets for cancer therapy. This review highlights recent molecular, therapeutic and clinical advances in choline metabolism in cancer. PMID- 25921028 TI - Genipin attenuates sepsis-induced immunosuppression through inhibition of T lymphocyte apoptosis. AB - Sepsis, a systemic inflammatory response to infection, initiates a complex immune response consisting of an early hyperinflammatory response and a subsequent hypoinflammatory response that impairs the removal of infectious organisms. The importance of sepsis-induced immunosuppression and its contribution to mortality has recently emerged. Apoptotic depletion of T lymphocytes is a critical cause of immunosuppression in the late phase of sepsis. Genipin is a major active compound of gardenia fruit that has anti-apoptotic and anti-microbial properties. This study investigated the mechanisms of action of genipin on immunosuppression in the late phase of sepsis. Mice received genipin (1, 2.5 and 5mg/kg, i.v.) at 0 (immediately) and 24h after cecal ligation and puncture (CLP). Twenty-six hours after CLP, the spleen and blood were collected. Genipin improved the survival rate compared to controls. CLP increased the levels of FADD, caspase-8 and caspase-3 protein expression, which were attenuated by genipin. Genipin increased the level of anti-apoptotic B-cell lymphoma-2 protein expression, while it decreased the level of pro-apoptotic phosphorylated-Bim protein expression in CLP. CLP decreased the CD4(+) and CD8(+) T cell population, while it increased the regulatory T cell (Treg) population and the level of cytotoxic T lymphocyte associated antigen 4 protein expression on Treg. These changes were attenuated by genipin. The splenic levels of interferon-gamma and interleukin (IL)-2 were reduced, while the levels of IL-4 and IL-10 increased after CLP. Genipin attenuated these alterations. These findings suggest that genipin reduces immunosuppression by inhibiting T lymphocyte apoptosis in the late phase of sepsis. PMID- 25921029 TI - Resveratrol rescued the TNF-alpha-induced impairments of osteogenesis of bone marrow derived mesenchymal stem cells and inhibited the TNF-alpha-activated NF-kB signaling pathway. AB - Resveratrol, trans-3,4'-trihydroxystilbene, is a natural phytoalexin. Its anti inflammatory activity has attracted more and more attention in clinic over the years for the treatment of inflammatory diseases. However, its effect on bone repair and new bone formation in an inflammatory microenvironment is quite little understood, especially when bone-marrow derived mesenchymal stem cells (MSCs) are used in stem cell therapy for the treatment of inflammatory bone diseases. In the present study, we investigated the effect of resveratrol on osteogenic differentiation of primary mouse bone marrow derived MSCs and potential mechanism involved when cells were exposed to TNF-alpha treatment. We found that resveratrol reversed the apoptotic effect of TNF-alpha and abrogated its inhibitory effect on osteogenic differentiation of bone marrow derived MSCs. Mechanistic studies demonstrated that resveratrol rescued the TNF-alpha-induced impairments of osteogenesis, and inhibited TNF-alpha-activated NF-kappaB signaling. Our study may help understand the mechanism involved in the inhibitory effect of inflammatory cytokines on osteogenic differentiation, and highlights the role of resveratrol as a potential therapeutic agent for bone repair and especially in MSC-based cell therapy for the treatment of inflammation-associated bone diseases. PMID- 25921031 TI - Efficient and durable oxygen reduction and evolution of a hydrothermally synthesized La(Co0.55Mn0.45)0.99O3-delta nanorod/graphene hybrid in alkaline media. AB - The increasing global energy demand and the depletion of fossil fuels have stimulated intense research on fuel cells and batteries. Oxygen electrocatalysis plays essential roles as the electrocatalytic reduction and evolution of di oxygen are always the performance-limiting factors of these devices relying on oxygen electrochemistry. A novel perovskite with the formula La(Co0.55Mn0.45)0.99O3-delta (LCMO) is designed from molecular orbital principles. The hydrothermally synthesized LCMO nanorods have unique structural and chemical properties and possess high intrinsic activities for oxygen reduction reaction (ORR) and oxygen evolution reaction (OER). The synergic covalent coupling between LCMO and NrGO enhances the bifunctional ORR and OER activities of the novel LCMO/NrGO hybrid catalyst. The ORR activity of LCMO/NrGO is comparable to the state-of-the-art Pt/C catalyst and its OER activity is competitive to the state-of-the-art Ir/C catalyst. LCMO/NrGO generally outperforms Pt/C and Ir/C with better bifunctional ORR and OER performance and operating durability. LCMO/NrGO represents a new class of low-cost, efficient and durable electrocatalysts for fuel cells, water electrolysers and batteries. PMID- 25921030 TI - Effect of elevated carbon dioxide on bronchial epithelial innate immune receptor response to organic dust from swine confinement barns. AB - Hypercapnia is known to have immunoregulatory effects within the lung. Cell culture systems demonstrate this in both macrophages and alveolar cell lines, suggesting that the alveoli are affected by changes in CO2 levels. We hypothesized that hypercapnia would also modulate human bronchial epithelial cell immune responses. Innate immune responses to Pam3CSK4 (TLR2 ligand), LPS (TLR4 ligand) and a complex innate immune stimulus, an extract from the organic dust of swine confinement barns (barn dust extract or BDE), were tested in a human bronchial epithelial cell line, BEAS-2B. Both TLR ligands showed a decrease in IL 6 and IL-8 production, and an increase in MCP-1 in response to elevated CO2 indicating an enhancement in cytokine production to hypercapnia. This change was not reflected in expression levels of TLR receptor RNA which remained unchanged in response to elevated CO2. Interestingly, barn dust showed an increase in IL-6, IL-8 and MCP-1 response at 9% CO2, suggesting that elevated CO2 exerts different effects on different stimuli. Our results show that airway epithelial cell immune responses to barn dust respond differently to hypercapnic conditions than individual TLR ligands. PMID- 25921032 TI - Effects of marijuana use on prefrontal and parietal volumes and cognition in emerging adults. AB - RATIONALE: Chronic marijuana (MJ) use among adolescents has been associated with structural and functional abnormalities, particularly in developing regions responsible for higher order cognition. OBJECTIVES: This study investigated prefrontal (PFC) and parietal volumes and executive function in emerging adult MJ users and explored potential gender differences. METHODS: Participants (ages 18 25) were 27 MJ users and 32 controls without neurologic or psychiatric disorders or heavy other drug use. A series of multiple regressions examined whether group status, past year MJ use, and their interactions with gender predicted ROI volumes. Post hoc analyses consisted of brain-behavior correlations between volumes and cognitive variables and Fisher's z tests to assess group differences. RESULTS: MJ users demonstrated significantly smaller medial orbitofrontal (mOFC; p = 0.004, FDR p = 0.024) and inferior parietal volumes (p = 0.04, FDR p = 0.12); follow-up regressions found that increased past year MJ use did not significantly dose-dependently predict smaller mOFC volume in a sub-sample of individuals with at least one past year MJ use. There were no significant gender interactions. There was a significant brain-behavior difference by group, such that smaller mOFC volumes were associated with poorer complex attention for MJ users (p < 0.05). CONCLUSIONS: Smaller mOFC volumes among MJ users suggest disruption of typical neurodevelopmental processes associated with regular MJ use for both genders. These results highlight the need for longitudinal, multi-modal imaging studies providing clearer information on timing of neurodevelopmental processes and neurocognitive impacts of youth MJ initiation. PMID- 25921034 TI - Role of CB2 receptors in social and aggressive behavior in male mice. AB - RATIONALE: Male CB1KO mice exhibit stronger aggressive responses than wild-type mice. OBJECTIVE: This study was designed to examine the role of cannabinoid CB2r in social and aggressive behavior. METHODS: The social interaction test and resident-intruder paradigm were performed in mice lacking CB2r (CB2KO) and in wild-type (WT) littermates. The effects of the CB2r selective agonist JWH133 (1 and 2 mg/kg) on aggression were also evaluated in Oncins France 1 (OF1) mice. Gene expression analyses of monoamine oxidase-A (MAO-A), catechol-o methyltransferase (COMT), 5-hydroxytryptamine transporter (5-HTT), and 5-HT1B receptor (5HT1Br) in the dorsal raphe nuclei (DR) and the amygdala (AMY) were carried out using real-time PCR. RESULTS: Group-housed CB2KO mice exhibited higher levels of aggression in the social interaction test and displayed more aggression than resident WT mice. Isolation increased aggressive behavior in WT mice but did not affect CB2KO animals; however, the latter mice exhibited higher levels of social interaction with their WT counterparts. MAO-A and 5-HTT gene expression was significantly higher in grouped CB2KO mice. The expression of 5HT1Br, COMT, and MAO-A in the AMY was more pronounced in CB2KO mice than in WT counterparts. Acute administration of the CB2 agonist JWH133 significantly reduced the level of aggression in aggressive isolated OF1 mice, an effect that decreased after pretreatment with the CB2 receptor antagonist AM630. CONCLUSION: Our results suggest that CB2r is implicated in social interaction and aggressive behavior and deserves further consideration as a potential new target for the management of aggression. PMID- 25921035 TI - Effects of a home-based step training programme on balance, stepping, cognition and functional performance in people with multiple sclerosis--a randomized controlled trial. AB - BACKGROUND: Stepping impairments increase fall risk in people with MS. No studies have evaluated step training for reducing fall risk in this population. OBJECTIVES: To determine if step training can improve physical and neuropsychological measures associated with falls in MS. METHODS: 50 PwMS with moderate disability participated in a randomized controlled trial in which intervention group participants (n = 28) performed step training for 12 weeks while controls (n = 22) continued usual physical activity. The primary outcomes were choice stepping reaction time (CSRT) and Stroop stepping test (SST) time. Secondary outcomes included balance test (postural sway, CSRT components), gait speed and cognitive tests, nine-hole peg test (9-HPT) and MS functional composite (MSFC) score. RESULTS: 44 participants completed the study and no adverse events were reported. Compared with the control group, the intervention group performed significantly better at retest in CSRT and SST times, and tests of sway with eyes open, 9-HPT, single and dual task gait speed and MSFC score. There was a non significant trend for fewer falls in the intervention group. CONCLUSIONS: The findings indicate that the step training programme is feasible, safe and effective in improving stepping, standing balance, coordination and functional performance in people with MS. PMID- 25921036 TI - Comparative analysis of first-year fingolimod and natalizumab drug discontinuation among Swedish patients with multiple sclerosis. AB - BACKGROUND: Natalizumab (NTZ) and fingolimod (FGL) are mainly used second line in relapsing-remitting multiple sclerosis (MS), although pivotal trials included mainly treatment-naive patients. OBJECTIVE: This study aims to provide real-world data on safety and discontinuation rates. METHODS: Using IMSE, a drug monitoring registry for all newer MS drugs in Sweden, we analysed differences in baseline characteristics and 1-year drug survival for patients registered 2011-2013, initiating treatment with NTZ (n=640) or FGL (n=876). Among FGL initiators, n=383 (44%) had previously used NTZ (FGL(afterNTZ)). RESULTS: Compared with NTZ, the FGL cohort was older and more often male (36/38 years, 24%/33% males). Baseline Expanded Disability Status Scale was similar across groups, but MS Severity Score was higher in NTZ patients, and Symbol Digit Modalities Test and MS Impact Scale (MSIS-29) was higher in FGL(afterNTZ) versus FGL(NTZ-naive) patients. Proportion on drug after 1 year was high, NTZ=87%, FGL(NTZ-naive)=83% and FGL(afterNTZ)=76%. Adverse events was the most frequent reason for discontinuing FGL (FGL(NTZ naive)=9%, FGL(afterNTZ)=12%), and was significantly higher than on NTZ (3%). In contrast, the proportion of patients stopping treatment due to lack of effect was more similar: NTZ=4%, FGL(NTZ-naive)=3%, FGL(afterNTZ)=8%. CONCLUSION: FGL and NTZ were both well tolerated, but FGL less so than NTZ, especially in patients switching to FGL from NTZ. Group differences were not explained by differences in recorded baseline characteristics. PMID- 25921038 TI - Cognitive reserve moderates the impact of subcortical gray matter atrophy on neuropsychological status in multiple sclerosis. AB - BACKGROUND: Cognitive decline is characterized in multiple sclerosis (MS), but the rate and severity vary. The reserve hypothesis proposes that baseline neurological differences impact cognitive outcome in neurodegenerative disease. OBJECTIVE: To elucidate how brain reserve and cognitive reserve influence subcortical gray matter (SCGM) atrophy and cognitive decline in MS over 3 years. METHODS: Seventy-one MS patients and 23 normal controls underwent magnetic resonance imaging and cognitive assessment at baseline and 3-year follow-up. The influence of reserve on cognitive processing speed (CPS) and memory was examined. RESULTS: SCGM volume and cognitive scores were lower in MS than normal controls (P?0.001). Accounting for baseline, comparison of follow-up means yielded a difference between groups in SCGM volume (P<0.001) but not cognition (NS). Cognitive reserve (P=0.005), but not brain reserve, contributed to CPS, with only low cognitive reserve MS subjects showing decline in CPS (P=0.029). SCGM change predicted CPS outcome in MS with low cognitive reserve (P=0.002) but not high cognitive reserve. There were no effects in the domain of memory. CONCLUSIONS: SCGM atrophy occurs in normal controls, but significantly more so in MS. While CPS did not change in normal controls, low cognitive reserve was associated with CPS decline in MS. High cognitive reserve protect MS patients from cognitive decline related to SCGM atrophy. PMID- 25921037 TI - Demographic and clinical features of neuromyelitis optica: A review. AB - The comparative clinical and demographic features of neuromyelitis optica (NMO) are not well known. In this review we analyzed peer-reviewed publications for incidence and prevalence, clinical phenotypes, and demographic features of NMO. Population-based studies from Europe, South East and Southern Asia, the Caribbean, and Cuba suggest that the incidence and prevalence of NMO ranges from 0.05-0.4 and 0.52-4.4 per 100,000, respectively. Mean age at onset (32.6-45.7) and median time to first relapse (8-12 months) was similar. Most studies reported an excess of disease in women and a relapsing course, particularly in anti aquaporin 4 antibody (anti AQP4-IgG)-positive patients. Ethnicity may have a bearing on disease phenotype and clinical outcome. Despite limitations inherent to the review process, themes noted in clinical and demographic features of NMO among different populations promote a more global understanding of NMO and strategies to address it. PMID- 25921039 TI - Mindfulness-based interventions for people with multiple sclerosis. PMID- 25921033 TI - Application of cross-species PET imaging to assess neurotransmitter release in brain. AB - RATIONALE: This review attempts to summarize the current status in relation to the use of positron emission tomography (PET) imaging in the assessment of synaptic concentrations of endogenous mediators in the living brain. OBJECTIVES: Although PET radioligands are now available for more than 40 CNS targets, at the initiation of the Innovative Medicines Initiative (IMI) "Novel Methods leading to New Medications in Depression and Schizophrenia" (NEWMEDS) in 2009, PET radioligands sensitive to an endogenous neurotransmitter were only validated for dopamine. NEWMEDS work-package 5, "Cross-species and neurochemical imaging (PET) methods for drug discovery", commenced with a focus on developing methods enabling assessment of changes in extracellular concentrations of serotonin and noradrenaline in the brain. RESULTS: Sharing the workload across institutions, we utilized in vitro techniques with cells and tissues, in vivo receptor binding and microdialysis techniques in rodents, and in vivo PET imaging in non-human primates and humans. Here, we discuss these efforts and review other recently published reports on the use of radioligands to assess changes in endogenous levels of dopamine, serotonin, noradrenaline, gamma-aminobutyric acid, glutamate, acetylcholine, and opioid peptides. The emphasis is on assessment of the availability of appropriate translational tools (PET radioligands, pharmacological challenge agents) and on studies in non-human primates and human subjects, as well as current challenges and future directions. CONCLUSIONS: PET imaging directed at investigating changes in endogenous neurochemicals, including the work done in NEWMEDS, have highlighted an opportunity to further extend the capability and application of this technology in drug development. PMID- 25921040 TI - Temporal lobe cortical pathology and inhibitory GABA interneuron cell loss are associated with seizures in multiple sclerosis. AB - BACKGROUND: Seizures are recognised in multiple sclerosis (MS), but their true incidence and the mechanism by which they are associated with MS is unclear. OBJECTIVE: The objective of this paper is to determine the lifetime frequency of seizures in the United Kingdom MS Tissue Bank (UKMSTB) population and any pathological features associated with seizures. METHODS: We evaluated 255 individuals from the UKMSTB. A subset underwent analysis of cortical thickness, grey matter lesion (GML) (type and number) and cortical neuronal numbers (total and GABAergic). RESULTS: A total of 37/255 patients had seizures (14.5% lifetime incidence); in 47% they were associated with concurrent infection. In those with seizures, death and wheelchair use occurred earlier and in 59% seizures developed after 15 years of disease. Seizures were associated with Type 1 GMLs and reduced cortical thickness in the middle temporal gyrus. Localised selective GABAergic interneuron loss in layers IV and VI was related to GMLs but was not explained by the presence of inflammation or by mitochondrial dysfunction within Type I GMLs. CONCLUSION: We confirm that seizure frequency rises in MS. Type I GMLs in the temporal lobe underlie a loss of inhibitory interneurons in cortical layers IV and VI and these changes could together with concurrent infection enhance susceptibility to seizures. PMID- 25921041 TI - Evidence for early, non-lesional cerebellar damage in patients with multiple sclerosis: DTI measures correlate with disability, atrophy, and disease duration. AB - BACKGROUND: Common symptoms of multiple sclerosis (MS) such as gait ataxia, poor coordination of the hands, and intention tremor are usually the result of dysfunctionality in the cerebellum. Magnetic resonance imaging (MRI) has frequently failed to detect cerebellar damage in the form of inflammatory lesions in patients presenting with symptoms of cerebellar dysfunction. OBJECTIVE: To detect microstructural cerebellar tissue alterations in early MS patients with a "normal appearing" cerebellum using diffusion tensor imaging (DTI). METHODS: A total of 68 patients with relapsing-remitting MS (RRMS) and without cerebellar lesions and 26 age-matched healthy controls were admitted to high-resolution MRI and DTI to assess microstructure and volume of the cerebellar white matter (CBWM). RESULTS: We found cerebellar fractional anisotropy (FA) and CBWM volume reductions in the group of 68 patients. Interestingly, a subgroup of these patients that was derived by including only patients with early and mild MS (N=23, median age 30 years, median Expanded Disability Status Scale =1.5, median duration 28 months) showed already cerebellar FA but no CBWM volume reductions. FA reductions were correlated with disability, atrophy, and disease duration. CONCLUSION: "Normal appearing" cerebellar white matter can be damaged in a very early stage of RRMS. DTI seems to be a sensitive tool for detecting this hidden cerebellar damage. PMID- 25921042 TI - Placebo studies should not be undertaken in NMO--Yes. PMID- 25921043 TI - Placebo Studies should not be Undertaken in Neuromyelitis Optica: Commentary. PMID- 25921044 TI - Placebo studies should not be undertaken in NMO--No. PMID- 25921045 TI - The re-emergence of antigen-specific tolerance as a potential therapy for MS. AB - Ideal therapy for inflammatory disease in the nervous system would preserve normal immune function, while suppressing only the pathologic immune responses that damage tissue and allowing for repair. In principle, antigen-specific therapy would eradicate unwanted adaptive immune responses-antibody and T-cell mediated--while preserving the integrity of other adaptive responses to infectious agents and retaining the ability to fight malignancy. However, at this time, for multiple sclerosis (MS) we do not have compelling evidence that would support any particular dominant immune response to any specific antigen or even a limited group of antigens. In fact, there are adaptive immune responses to a wide swathe of proteins and lipids found on neurons and myelin in MS. Unless controlling a few of the known immune responses is sufficient, antigen-specific therapy in MS may not have enough of an impact to modulate clinical outcome. However, in other neuroinflammatory conditions, such as neuromyelitis optica, the adaptive immune response is highly focused. Trials of antigen-specific therapy for neuroinflammatory disease might first be tested in diseases with a more limited adaptive immune response like neuromyelitis optica. The likelihood of a significant success for this therapeutic strategy might then ensue. PMID- 25921046 TI - Reply to article: High inbreeding in the Faroe Islands does not appear to constitute a risk factor for multiple sclerosis. PMID- 25921047 TI - Treatment of acute relapses in neuromyelitis optica: Steroids alone versus steroids plus plasma exchange. AB - BACKGROUND: Although adding plasma exchange (PLEX) to steroids in severe neuromyelitis optica (NMO) attacks is common practice in steroid-resistant cases, the benefit of this strategy has not been previously quantified. OBJECTIVE: The objective of this paper is to compare the efficacy of high-dose intravenous methylprednisolone (IVMP) versus IVMP+PLEX in treatment of acute NMO relapses. METHODS: We conducted a retrospective review of the last 83 NMO admissions to the Johns Hopkins Hospital treated with IVMP alone versus IVMP+PLEX (for steroid resistant cases). Extended Disability Status Scale (EDSS) score was calculated at baseline, at presentation, at discharge, and on follow-up. RESULTS: Eighteen NMO relapses (16 patients, 87% female, mean age at relapse: 33.9+/-23.8, median baseline EDSS 2.5) were treated with IVMP alone and 65 relapses (43 patients, 95% female, mean age at relapse: 43.8+/-15.7, median baseline EDSS 5.75) were treated with IVMP + PLEX. Sixty-five percent of IVMP + PLEX patients achieved an EDSS equal or below their baseline at follow-up while only 35% of the IVMP-only patients achieved their baseline EDSS on follow-up (odds ratio=3.36, 95% CI 1.0657 to 10.6004, p = 0.0386). PLEX was more effective in improving EDSS in patients on preventive immunosuppressive medications at time of relapse. CONCLUSIONS: PLEX+IVMP are more likely to improve EDSS after NMO relapses compared to IVMP alone, especially in patients taking preventive medications. PMID- 25921048 TI - Linking synaptopathy and gray matter damage in multiple sclerosis. PMID- 25921049 TI - HLA associations in South Asian multiple sclerosis. AB - BACKGROUND: Previous efforts to identify Human Leukocyte Antigen (HLA) gene associations with multiple sclerosis (MS) in the South Asian population have been underpowered. AIM: To identify the primary HLA class II alleles associated with MS in Indians. METHODS: We typed HLA-DRB1, -DQA1 and -DQB1 in 419 patients and 451 unrelated controls by polymerase chain reaction using sequence specific oligonucleotide probes (PCR-SSOP). RESULTS: At the gene level DRB1 showed significant evidence of association (p=0.0000012), DQA1 showed only marginal evidence of association (p=0.04) and there was no evidence for association at DQB1 (p=0.26). At the DRB1 locus association is confirmed with the *15:01 (p=0.00002) and the *03 (p=0.00005) alleles. CONCLUSION: Our study confirms that the risk effects attributable to the HLA- DRB1*15:01and DRB1*03 alleles seen in Europeans are also seen in Indians. The absence of any evidence of association with DQB1 alleles reflects the lower linkage disequilibrium between DQB1 alleles and DRB1 risk alleles present in this population, and illustrates the potential value of fine mapping signals of association in different ethnic groups. PMID- 25921051 TI - miRNA in multiple sclerosis: search for novel biomarkers. AB - A major challenge in multiple sclerosis (MS) is to develop biomarkers that could help in understanding individual MS patients, i.e. whether they are a responder or non-responder to therapy, which medicine is more effective, and the degree to which they may be entering the progressive phase of disease. In the last few years, a lot of attention has been drawn toward identification of diagnostic, prognostic, process-specific, and treatment-related biomarkers for MS. In this review, we will focus on the micro RNAs (miRNAs) as potential candidates for MS biomarkers. PMID- 25921050 TI - Prolonged-release fampridine and walking and balance in MS: randomised controlled MOBILE trial. AB - BACKGROUND: Mobility impairment is a common disability in MS and negatively impacts patients' lives. OBJECTIVE: Evaluate the effect of prolonged-release (PR) fampridine (extended-release dalfampridine in the United States) on self-assessed walking disability, dynamic/static balance and safety in patients with MS. METHODS: MOBILE was a randomised, double-blind, exploratory, placebo-controlled trial. Patients with progressive/relapsing-remitting MS and Expanded Disability Status Scale score of 4.0-7.0 were treated with PR-fampridine or placebo twice daily for 24 weeks. Efficacy endpoints included change from baseline in the 12 item MS Walking Scale (MSWS-12), Timed Up and Go (TUG) test and Berg Balance Scale (BBS). RESULTS: 132 patients were randomised at 24 sites in six countries. PR-fampridine therapy resulted in greater median improvements from baseline in MSWS-12 score, TUG speed and BBS total score versus placebo over 24 weeks. A higher proportion of patients receiving PR-fampridine versus placebo experienced significant improvements at MSWS-12 improvement thresholds ?7 (p = 0.0275), ?8 (p = 0.0153) and ?9 points (p = 0.0088) and TUG speed thresholds ?10% (p = 0.0021) and ?15% (p = 0.0262). PR-fampridine was well tolerated. CONCLUSIONS: PR fampridine therapy resulted in early and sustained improvements in broad measures of walking and balance over six months. PMID- 25921052 TI - Diffusivity signatures characterize trigeminal neuralgia associated with multiple sclerosis. AB - BACKGROUND: Trigeminal neuralgia secondary to multiple sclerosis (MS-TN) is a facial neuropathic pain syndrome similar to classic trigeminal neuralgia (TN). While TN is caused by neurovascular compression of the fifth cranial nerve (CN V), how MS-related demyelination correlates with pain in MS-TN is not understood. OBJECTIVES: We aim to examine diffusivities along CN V in MS-TN, TN, and controls in order to reveal differential neuroimaging correlates across groups. METHODS: 3T MR diffusion weighted, T1, T2 and FLAIR sequences were acquired for MS-TN, TN, and controls. Multi-tensor tractography was used to delineate CN V across cisternal, root entry zone (REZ), pontine and peri-lesional segments. Diffusion metrics including fractional anisotropy (FA), and radial (RD), axial (AD), and mean diffusivities (MD) were measured from each segment. RESULTS: CN V segments showed distinctive diffusivity patterns. The TN group showed higher FA in the cisternal segment ipsilateral to the side of pain, and lower FA in the ipsilateral REZ segment. The MS-TN group showed lower FA in the ipsilateral peri lesional segments, suggesting differential microstructural changes along CN V in these conditions. CONCLUSIONS: The study demonstrates objective differences in CN V microstrucuture in TN and MS-TN using non-invasive neuroimaging. This represents a significant improvement in the methods currently available to study pain in MS. PMID- 25921053 TI - Pregnancy-related relapse risk factors in women with anti-AQP4 antibody positivity and neuromyelitis optica spectrum disorder. AB - BACKGROUND: Few reports describe the influence pregnancy has on the annualized relapse rate (ARR) in neuromyelitis optica spectrum disorder (NMOSD). OBJECTIVE: To examine pregnancy-related attacks (attacks during pregnancy or within 1 year postpartum) and identify the risk factors for an attack in Japanese NMOSD patients. METHODS: We retrospectively reviewed 139 Japanese women whom had aquaporin-4 (AQP4) antibody-positive NMOSD. Among the 114 patients with information, 47 women had 56 pregnancies. We compared the ARR before, during and after pregnancy. RESULTS: Of the 47 NMOSD patients with pregnancy, 22 women (46.8%) had a pregnancy-related attack of the disease (either an onset event or a relapse). The ARR was significantly higher in the first 3 months postpartum (1.80 +/- 2.04), than before the pregnancy (0.57 +/- 1.16; p = 0.0043) and did not significantly decrease during pregnancy. The ARR before hospitalization and treatment was analyzable in 55 patients without pregnancy and was 1.09 +/- 1.17. Among the 11 patients with onset before pregnancy, nine patients had a pregnancy related attack with a relapse in the previous year, and their immunosuppression was discontinued or made to be at low doses; while the two patients on higher dose therapies were relapse-free. CONCLUSION: In the present study, pregnancy related attack was common in NMOSD, and unlike in multiple sclerosis, the ARR was not reduced during pregnancy. Discontinued or insufficient immunosuppression appeared to increase the risk of pregnancy-related attack. PMID- 25921054 TI - Enrichment for Northern European-derived multiple sclerosis risk alleles in Sardinia. AB - BACKGROUND: The list of genomic loci associated with multiple sclerosis (MS) susceptibility outside the major histocompatibility complex (MHC) in patients of Northern European (NE) ancestry has increased to 103. Despite the extraordinarily high MS prevalence in the isolated Sardinian population, the contribution of genetic risk factors to MS in Sardinia is largely not understood. OBJECTIVE: The objective of this paper is to examine the relevance of non-MHC MS susceptibility variants in Sardinia. METHODS: We examined a log-additive MS-specific genetic burden score (MSGB) using 110 NE-derived risk alleles in a dataset of 75 Sardinian cases, 346 Sardinian controls and 177 cases and 1967 controls from the United States (US). RESULTS: Sardinian cases demonstrate a heavier non-MHC MSGB load than Sardinian controls and US cases (p = 2E-06, p = 1E-06, respectively). Furthermore, Sardinian controls carry a heavier burden than US controls (p = 2E 14). Our results confirm the limited ability of the 110-SNP MSGB to predict disease status in Sardinia (AUROC = 0.629). CONCLUSIONS: Risk alleles discovered in samples of NE ancestry are relevant to MS in Sardinia. Our results suggest a general enrichment of MS susceptibility alleles in Sardinians, encouraging the pursuit of further studies of MS in this population. PMID- 25921055 TI - Detection of pediatric obstructive sleep apnea syndrome: history or anatomical findings? AB - OBJECTIVE: To assess how history and/or anatomical findings differ in diagnosing pediatric obstructive sleep apnea (OSA). METHODS: Children aged 2-18 years were recruited and assessed for anatomical (ie, tonsil size, adenoid size, and obesity) and historical findings (ie, symptoms) using a standard sheet. History and anatomical findings, as well as those measures significantly correlated with OSA, were identified to establish the historical, anatomical, and the combined model. OSA was diagnosed by polysomnography. The effectiveness of those models in detecting OSA was analyzed by model fit, discrimination (C-index), calibration (Hosmer-Lemeshow test), and reclassification properties. RESULTS: A total of 222 children were enrolled. The anatomical model included tonsil hypertrophy, adenoid hypertrophy, and obesity, whereas the historical model included snoring frequency, snoring duration, awakening, and breathing pause. The C-index was 0.84 for the combined model, which significantly differed from that in the anatomical (0.78, p = 0.003) and historical models (0.72, p < 0.001). The Hosmer-Lemeshow test revealed an adequate fit for all of the models. Additionally, the combined model more accurately reclassified 10.3% (p = 0.044) and 21.9% (p = 0.003) of all of the subjects than either the anatomical or historical model. Internal validation of the combined model by the bootstrapping method showed a fair model performance. CONCLUSION: Overall performance of combined anatomical and historical findings offers incremental utility in detecting OSA. Results of this study suggest integrating both history and anatomical findings for a screening scheme of pediatric OSA. PMID- 25921056 TI - Quantitative association between nocturnal voiding frequency and objective sleep quality in the general elderly population: the HEIJO-KYO cohort. AB - OBJECTIVE: A significant association between nocturia and subjective sleep quality has previously been reported; however, the association between nocturia and objective sleep quality remains unclear. The purpose of this study was to evaluate the quantitative association between nocturnal voiding (NV) frequency and objective sleep quality in a large, general, elderly population. METHODS: Nocturnal voiding frequency, objective sleep quality, and subjective sleep quality were measured among 1086 community-based elderly individuals using actigraphy and the Pittsburgh Sleep Quality Index (PSQI) questionnaire. RESULTS: In multivariate analyses adjusted for potential confounding factors (such as age, gender, body mass index, medication use, renal function, bedtime, rising time, daytime physical activity, endogenous melatonin levels, and bedroom light levels), increased NV frequency, ranging from zero, one, two, three or more voids, was significantly associated with poorer objective sleep quality, including lower sleep efficiency (SE) and longer wake after sleep onset (WASO) (mean SE, 86.3, 84.8, 83.6, and 81.2%, respectively; p for trend <0.001; mean WASO: 42.6, 49.0, 53.6, and 66.1 min, respectively; p for trend <0.001), but shorter sleep onset latency (SOL) (mean SOL, 3.0, 3.0, 2.8, and 2.8 log min, respectively; p for trend = 0.018). In addition, an increased NV frequency was significantly associated with poorer subjective sleep quality in a multivariate model (mean PSQI global score, 4.60, 4.86, 5.22, and 5.48, respectively; p for trend 0.012). CONCLUSION: The present study revealed a quantitative association between NV frequency and objective sleep quality in the general elderly population. PMID- 25921058 TI - Probing single magnon excitations in Sr2IrO4 using O K-edge resonant inelastic x ray scattering. AB - Resonant inelastic x-ray scattering (RIXS) at the L-edge of transition metal elements is now commonly used to probe single magnon excitations. Here we show that single magnon excitations can also be measured with RIXS at the K-edge of the surrounding ligand atoms when the center heavy metal elements have strong spin-orbit coupling. This is demonstrated with oxygen K-edge RIXS experiments on the perovskite Sr2IrO4, where low energy peaks from single magnon excitations were observed. This new application of RIXS has excellent potential to be applied to a wide range of magnetic systems based on heavy elements, for which the L-edge RIXS energy resolution in the hard x-ray region is usually poor. PMID- 25921057 TI - Clinical management of patients with ASXL1 mutations and Bohring-Opitz syndrome, emphasizing the need for Wilms tumor surveillance. AB - Bohring-Opitz syndrome is a rare genetic condition characterized by distinctive facial features, variable microcephaly, hypertrichosis, nevus flammeus, severe myopia, unusual posture (flexion at the elbows with ulnar deviation, and flexion of the wrists and metacarpophalangeal joints), severe intellectual disability, and feeding issues. Nine patients with Bohring-Opitz syndrome have been identified as having a mutation in ASXL1. We report on eight previously unpublished patients with Bohring-Opitz syndrome caused by an apparent or confirmed de novo mutation in ASXL1. Of note, two patients developed bilateral Wilms tumors. Somatic mutations in ASXL1 are associated with myeloid malignancies, and these reports emphasize the need for Wilms tumor screening in patients with ASXL1 mutations. We discuss clinical management with a focus on their feeding issues, cyclic vomiting, respiratory infections, insomnia, and tumor predisposition. Many patients are noted to have distinctive personalities (interactive, happy, and curious) and rapid hair growth; features not previously reported. PMID- 25921059 TI - The mTORC1 inhibitor everolimus has antitumor activity in vitro and produces tumor responses in patients with relapsed T-cell lymphoma. AB - Everolimus is an oral agent that targets the mammalian target of rapamycin (mTOR) pathway. This study investigated mTOR pathway activation in T-cell lymphoma (TCL) cell lines and assessed antitumor activity in patients with relapsed/refractory TCL in a phase 2 trial. The mTOR pathway was activated in all 6 TCL cell lines tested and everolimus strongly inhibited malignant T-cell proliferation with minimal cytotoxic effects. Everolimus completely inhibited phosphorylation of ribosomal S6, a raptor/mTOR complex 1 (mTORC1) target, without a compensatory activation of the rictor/mTORC2 target Akt (S475). In the clinical trial, 16 patients with relapsed TCL were enrolled and received everolimus 10 mg by mouth daily. Seven patients (44%) had cutaneous (all mycosis fungoides); 4 (25%) had peripheral T cell not otherwise specified; 2 (13%) had anaplastic large cell; and 1 each had extranodal natural killer/T cell, angioimmunoblastic, and precursor T lymphoblastic leukemia/lymphoma types. The overall response rate was 44% (7/16; 95% confidence interval [CI]: 20% to 70%). The median progression-free survival was 4.1 months (95% CI, 1.5-6.5) and the median overall survival was 10.2 months (95% CI, 2.6-44.3). The median duration of response for the 7 responders was 8.5 months (95% CI, 1.0 to not reached). These studies indicate that everolimus has antitumor activity and provide proof-of-concept that targeting the mTORC1 pathway in TCL is clinically relevant. This trial was registered at www.clinicaltrials.gov as #NCT00436618. PMID- 25921060 TI - STAT1 is phosphorylated and downregulated by the oncogenic tyrosine kinase NPM ALK in ALK-positive anaplastic large-cell lymphoma. AB - The tumorigenicity of most cases of ALK-positive anaplastic large-cell lymphoma (ALK+ ALCL) is driven by the oncogenic fusion protein NPM-ALK in a STAT3 dependent manner. Because it has been shown that STAT3 can be inhibited by STAT1 in some experimental models, we hypothesized that the STAT1 signaling pathway is defective in ALK+ ALCL, thereby leaving the STAT3 signaling unchecked. Compared with normal T cells, ALK+ ALCL tumors consistently expressed a low level of STAT1. Inhibition of the ubiquitin-proteasome pathway appreciably increased STAT1 expression in ALK+ ALCL cells. Furthermore, we found evidence that NPM-ALK binds to and phosphorylates STAT1, thereby promoting its proteasomal degradation in a STAT3-dependent manner. If restored, STAT1 is functionally intact in ALK+ ALCL cells, because it effectively upregulated interferon-gamma, induced apoptosis/cell-cycle arrest, potentiated the inhibitory effects of doxorubicin, and suppressed tumor growth in vivo. STAT1 interfered with the STAT3 signaling by decreasing STAT3 transcriptional activity/DNA binding and its homodimerization. The importance of the STAT1/STAT3 functional interaction was further highlighted by the observation that short interfering RNA knockdown of STAT1 significantly decreased apoptosis induced by STAT3 inhibition. Thus, STAT1 is a tumor suppressor in ALK+ ALCL. Phosphorylation and downregulation of STAT1 by NPM-ALK represent other mechanisms by which this oncogenic tyrosine kinase promotes tumorigenesis. PMID- 25921061 TI - Effects of weight-shift training on walking ability, ambulation, and weight distribution in individuals with chronic stroke: a pilot study. AB - BACKGROUND: People with gait difficulties after a stroke usually have an asymmetrical gait and slower gait speed than age-matched controls. These difficulties restrict people with stroke in their daily life activities. OBJECTIVE: This pilot study sought to evaluate the effects of weight-shift training on gait, weight distribution in standing, and ambulation in people with gait difficulties after a stroke. METHODS: Ten subjects with chronic stroke (3-11 years since insult) and remaining gait difficulties participated in a 3-week weight-shift training program. Spatial and temporal gait parameters were assessed pre-, post-, and 3-month post-training with a motion analysis system. Weight distribution was assessed with force plates and ambulation with the Swedish version of the Clinical Outcome Variables Scale (S-COVS). Wilcoxon signed-rank tests were used to explore differences between test occasions. RESULTS: Significant changes were seen between pre-and post-tests in decreased stance time on the non-paretic leg (P = 0.005) and increased score on the S-COVS (P = 0.043). At the 3-month follow-up test, the subjects had also increased their gait speed significantly (P = 0.037). Standing weight distribution did not change between pre- and post-tests (P = 0.575), but between the pre-and follow-up tests it shifted from the paretic leg to the non-paretic (P = 0.007). CONCLUSION: Weight shift training seems to improve gait and ambulation in subjects with chronic stroke, but not with standing weight distribution. However, this pilot study has several limitations and a larger sample size with a control group is necessary. PMID- 25921063 TI - The distribution and time-dependent expression of MAGL during skeletal muscle wound healing in rats. AB - Monoacylglycerol lipase (MAGL) is widely distributed in mammals and largely responsible for metabolizing 2-arachidonoylglycerol (2-AG). Little is known about its expression in skeletal muscles after trauma. A preliminary study on time dependent expression and distribution of MAGL was performed by immunohistochemical staining, Western blotting and quantitative real-time PCR (qPCR) during skeletal muscle wound healing in rats. An animal model of skeletal muscle contusion was established in 40 Sprague-Dawley male rats. Samples were taken at 1, 3, 5, 7, 9, 13, 17 and 21 days after contusion, respectively (5 rats in each posttraumatic interval). 5 rats were employed as control. Weak immunoreactivity of MAGL was observed in the sarcoplasm of myofibers in control rats. Intensive immunoreactivities of MAGL were observed in polymorphonuclear cells (PMNs), round-shaped mononuclear cells (MNCs), spindle-shaped fibroblastic cells (FBCs) and regenerated multinucleated myotubes in the injured tissue. Subsequently, neutrophils, macrophages and myofibroblasts were identified as MAGL positive cells by double immunofluorescent procedure. MAGL expression was remarkably up-regulated after contusion by qPCR and Western blot analysis. The results demonstrate that the expression of MAGL is distributed in certain cell types and time-dependently expressed in skeletal muscles after trauma, suggesting that MAGL may be involved in inflammatory response, fibrogenesis and muscle regeneration during skeletal muscle wound healing. PMID- 25921062 TI - Okazaki fragment maturation involves alpha-segment error editing by the mammalian FEN1/MutSalpha functional complex. AB - During nuclear DNA replication, proofreading-deficient DNA polymerase alpha (Pol alpha) initiates Okazaki fragment synthesis with lower fidelity than bulk replication by proofreading-proficient Pol delta or Pol epsilon. Here, we provide evidence that the exonuclease activity of mammalian flap endonuclease (FEN1) excises Pol alpha replication errors in a MutSalpha-dependent, MutLalpha independent mismatch repair process we call Pol alpha-segment error editing (AEE). We show that MSH2 interacts with FEN1 and facilitates its nuclease activity to remove mismatches near the 5' ends of DNA substrates. Mouse cells and mice encoding FEN1 mutations display AEE deficiency, a strong mutator phenotype, enhanced cellular transformation, and increased cancer susceptibility. The results identify a novel role for FEN1 in a specialized mismatch repair pathway and a new cancer etiological mechanism. PMID- 25921064 TI - Widely divergent transcriptional patterns between SLE patients of different ancestral backgrounds in sorted immune cell populations. AB - Systemic lupus erythematosus (SLE) is a complex autoimmune disease of uncertain etiology. Patients from different ancestral backgrounds demonstrate differences in clinical manifestations and autoantibody profiles. We examined genome-wide transcriptional patterns in major immune cell subsets across different ancestral backgrounds. Peripheral blood was collected from African-American (AA) and European-American (EA) SLE patients and controls. CD4 T-cells, CD8 T-cells, monocytes, and B cells were purified by flow sorting, and each cell subset from each subject was run on a genome-wide expression array. Cases were compared to controls of the same ancestral background. The overlap in differentially expressed gene (DEG) lists between different cell types from the same ancestral background was modest (<10%), and only 5-8% overlap in DEG lists was observed when comparing the same cell type between different ancestral backgrounds. IFN stimulated gene (ISG) expression was not up-regulated synchronously in all cell types from a given patient, for example a given subject could have high ISG expression in T and B cells, but not in monocytes. AA subjects demonstrated more concordance in ISG expression between cell types from the same individual, and AA patients demonstrated significant down-regulation of metabolic gene expression which was not observed in EA patients. ISG expression was significantly decreased in B cells in patients taking immunosuppressants, while ISGs in other cell types did not differ with medication use. In conclusion, gene expression was strikingly different between immune cell subsets and between ancestral backgrounds in SLE patients. These findings emphasize the critical importance of studying multiple ancestral backgrounds and multiple cell types in gene expression studies. Ancestral backgrounds which are not studied will not benefit from personalized medicine strategies in SLE. PMID- 25921065 TI - Surface-Eroding Poly(ortho ester amides) for Highly Efficient Oral Chemotherapy. AB - Two new poly(ortho ester amide) copolymers (POEA-4 and POEA-5) were synthesized via polycondensation of a new ortho ester diamine monomer with active esters of different aliphatic diacids. The kinetics of POEA mass loss and release of 5-FU were both nearly zero-order, suggesting predominantly surface-restricted polymer erosion and drug release. In vitro cytotoxicity tests demonstrated that both copolymers have excellent biocompatibility. In vivo acute toxicity tests suggested that oral administration of POEA-4 and POEA-5 did not cause any adverse effects on mice even at a very high dose (2000 mg/kg). In vivo antitumor efficacy against H22 transplanted tumors of 5-FU-loaded POEA tablets were fully examined. We envision that, with further optimization, POEA-based materials could have great potential as drug carriers for oral chemotherapy. PMID- 25921066 TI - Characterization of soluble RNA-dependent RNA polymerase from dengue virus serotype 2: The polyhistidine tag compromises the polymerase activity. AB - The viral RNA polymerase is an attractive target for inhibition in the treatment of viral infections. In the case of dengue virus (DENV), a member of the genus Flavivirus, the RNA-dependent RNA polymerase (RdRp) activity resides in the C terminal two-thirds of non-structural protein (NS) 5 responsible for the de novo synthesis of the viral RNA genome. Among four distinct, but closely related dengue serotypes, serotype 2 (DENV-2) produces more severe diseases than other serotypes. It has been reported that bacterial production of the recombinant DENV 2 RdRp was difficult due to its low expression and solubility levels. To facilitate functional and structural analyses, we here demonstrate complete protocols for overexpression and purification of soluble DENV-2 RdRp, increasing protein yields by a remarkable 10 times compared to earlier reports. Three different forms of DENV-2 RdRp as either N- or C-terminally His-tagged fusions, or without tag, were purified to homogeneity. We show here that the presence of both the N- and C-terminal His-tag had a deleterious effect on polymerase activity and, in contrast to earlier studies, our non-tagged RdRp did not require manganese ions to activate RNA polymerization. We also determined an apparent Kd value of 53nM for binding to the 5'-UTR RNA by surface plasmon resonance (SPR). Our work provide a more suitable material for basic research of viral RdRp and for drug development. PMID- 25921067 TI - Human chromosome segregation involves multi-layered regulation of separase by the peptidyl-prolyl-isomerase Pin1. AB - Ring-shaped cohesin keeps sister chromatids paired until cleavage of its Scc1/Rad21 subunit by separase triggers chromosome segregation in anaphase. Vertebrate separase is held inactive by mutually exclusive binding to securin or Cdk1-cyclin B1 and becomes unleashed only upon ubiquitin-dependent degradation of these regulators. Although most separase is usually found in association with securin, this anaphase inhibitor is dispensable for murine life while Cdk1-cyclin B1-dependent control of separase is essential. Here, we show that securin independent inhibition of separase by Cdk1-cyclin B1 in early mitosis requires the phosphorylation-specific peptidyl-prolyl cis/trans isomerase Pin1. Furthermore, isomerization of previously securin-bound separase at the metaphase to-anaphase transition renders it resistant to re-inhibition by residual securin. At the same time, isomerization also limits the half-life of separase's proteolytic activity, explaining how cohesin can be reloaded onto telophase chromatin in the absence of securin and cyclin B1 without being cleaved. PMID- 25921068 TI - Circular RNAs in the Mammalian Brain Are Highly Abundant, Conserved, and Dynamically Expressed. AB - Circular RNAs (circRNAs) are an endogenous class of animal RNAs. Despite their abundance, their function and expression in the nervous system are unknown. Therefore, we sequenced RNA from different brain regions, primary neurons, isolated synapses, as well as during neuronal differentiation. Using these and other available data, we discovered and analyzed thousands of neuronal human and mouse circRNAs. circRNAs were extraordinarily enriched in the mammalian brain, well conserved in sequence, often expressed as circRNAs in both human and mouse, and sometimes even detected in Drosophila brains. circRNAs were overall upregulated during neuronal differentiation, highly enriched in synapses, and often differentially expressed compared to their mRNA isoforms. circRNA expression correlated negatively with expression of the RNA-editing enzyme ADAR1. Knockdown of ADAR1 induced elevated circRNA expression. Together, we provide a circRNA brain expression atlas and evidence for important circRNA functions and values as biomarkers. PMID- 25921069 TI - Global Promotion of Alternative Internal Exon Usage by mRNA 3' End Formation Factors. AB - The mechanisms that regulate alternative precursor mRNA (pre-mRNA) splicing are largely unknown. Here, we perform an RNAi screen to identify factors required for alternative splicing regulation by RBFOX2, an RNA-binding protein that promotes either exon inclusion or exclusion. Unexpectedly, we find that two mRNA 3' end formation factors, cleavage and polyadenylation specificity factor (CPSF) and SYMPK, are RBFOX2 cofactors for both inclusion and exclusion of internal exons. RBFOX2 interacts with CPSF/SYMPK and recruits it to the pre-mRNA. RBFOX2 and CPSF/SYMPK then function together to regulate binding of the early intron recognition factors U2AF and U1 small nuclear ribonucleoprotein particle (snRNP). Genome-wide analysis reveals that CPSF also mediates alternative splicing of many internal exons in the absence of RBFOX2. Accordingly, we show that CPSF/SYMPK is also a cofactor of NOVA2 and heterologous nuclear ribonucleoprotein A1 (HNRNPA1), RNA-binding proteins that also regulate alternative splicing. Collectively, our results reveal an unanticipated role for mRNA 3' end formation factors in global promotion of alternative splicing. PMID- 25921070 TI - Transcriptional elongation factor ENL phosphorylated by ATM recruits polycomb and switches off transcription for DSB repair. AB - Transcription is repressed if a DNA double-strand break (DSB) is introduced in close proximity to a transcriptional activation site at least in part by H2A ubiquitination. While ATM signaling is involved, how it controls H2A ubiquitination remains unclear. Here, we identify that, in response to DSBs, a transcriptional elongation factor, ENL (MLLT1), is phosphorylated by ATM at conserved SQ sites. This phosphorylation increases the interaction between ENL and the E3-ubiquitin-ligase complex of Polycomb Repressive Complex 1 (PRC1) via BMI1. This interaction promotes enrichment of PRC1 at transcription elongation sites near DSBs to ubiquitinate H2A leading to transcriptional repression. ENL SQ sites and BMI1 are necessary for KU70 accumulation at DSBs near active transcription sites and cellular resistance to DSBs. Our data suggest that ATM dependent phosphorylation of ENL functions as switch from elongation to Polycomb mediated repression to preserve genome integrity. PMID- 25921071 TI - Crystal structure of the CRISPR-Cas RNA silencing Cmr complex bound to a target analog. AB - In prokaryotes, Clustered regularly interspaced short palindromic repeat (CRISPR) derived RNAs (crRNAs), together with CRISPR-associated (Cas) proteins, capture and degrade invading genetic materials. In the type III-B CRISPR-Cas system, six Cas proteins (Cmr1-Cmr6) and a crRNA form an RNA silencing Cmr complex. Here we report the 2.1 A crystal structure of the Cmr1-deficient, functional Cmr complex bound to single-stranded DNA, a substrate analog complementary to the crRNA guide. Cmr3 recognizes the crRNA 5' tag and defines the start position of the guide-target duplex, using its idiosyncratic loops. The beta-hairpins of three Cmr4 subunits intercalate within the duplex, causing nucleotide displacements with 6 nt intervals, and thus periodically placing the scissile bonds near the crucial aspartate of Cmr4. The structure reveals the mechanism for specifying the periodic target cleavage sites from the crRNA 5' tag and provides insights into the assembly of the type III interference machineries and the evolution of the Cmr and Cascade complexes. PMID- 25921073 TI - FunRich: An open access standalone functional enrichment and interaction network analysis tool. AB - As high-throughput techniques including proteomics become more accessible to individual laboratories, there is an urgent need for a user-friendly bioinformatics analysis system. Here, we describe FunRich, an open access, standalone functional enrichment and network analysis tool. FunRich is designed to be used by biologists with minimal or no support from computational and database experts. Using FunRich, users can perform functional enrichment analysis on background databases that are integrated from heterogeneous genomic and proteomic resources (>1.5 million annotations). Besides default human specific FunRich database, users can download data from the UniProt database, which currently supports 20 different taxonomies against which enrichment analysis can be performed. Moreover, the users can build their own custom databases and perform the enrichment analysis irrespective of organism. In addition to proteomics datasets, the custom database allows for the tool to be used for genomics, lipidomics and metabolomics datasets. Thus, FunRich allows for complete database customization and thereby permits for the tool to be exploited as a skeleton for enrichment analysis irrespective of the data type or organism used. FunRich (http://www.funrich.org) is user-friendly and provides graphical representation (Venn, pie charts, bar graphs, column, heatmap and doughnuts) of the data with customizable font, scale and color (publication quality). PMID- 25921074 TI - A facile approach to synthesize 3,5-disubstituted-1,2,4-oxadiazoles via copper catalyzed-cascade annulation of amidines and methylarenes. AB - Various 3,5-disubstituted-1,2,4-oxadiazoles are smoothly formed via copper catalyzed cascade annulation of amidines and methylarenes. This tandem oxidation amination-cyclization transformation represents a straightforward protocol to prepare 1,2,4-oxadiazoles from easily available starting materials, with inexpensive copper catalysts and green oxidants. It has the advantages of atom- and step-economy, good functional group tolerance, as well as operational simplicity. PMID- 25921072 TI - The dynamics of eukaryotic replication initiation: origin specificity, licensing, and firing at the single-molecule level. AB - Eukaryotic replication initiation is highly regulated and dynamic. It begins with the origin recognition complex (ORC) binding DNA sites called origins of replication. ORC, together with Cdc6 and Cdt1, mediate pre-replicative complex (pre-RC) assembly by loading a double hexamer of Mcm2-7: the core of the replicative helicase. Here, we use single-molecule imaging to directly visualize Saccharomyces cerevisiae pre-RC assembly and replisome firing in real time. We show that ORC can locate and stably bind origins within large tracts of non origin DNA and that Cdc6 drives ordered pre-RC assembly. We further show that the dynamics of the ORC-Cdc6 interaction dictate Mcm2-7 loading specificity and that Mcm2-7 double hexamers form preferentially at a native origin sequence. Finally, we demonstrate that single Mcm2-7 hexamers propagate bidirectionally, monotonically, and processively as constituents of active replisomes. PMID- 25921075 TI - Primary cervical ganglioneuroblastoma. AB - OBJECTIVES: Ganglioneuroblastomas represent a histological subgroup of the rare neuroblastic tumours with intermediate malignant potential arising from neural crest progenitor cells of sympathetic nerves. Diagnosis can often be difficult based on imaging alone. We describe 4 cases of children presenting with a solitary neck mass with histology ultimately revealing ganglioneuroblastoma. METHODS: A retrospective case note review was carried out of all patients with cervical ganglioneuroblastoma seen at Great Ormond Street Hospital, UK. RESULTS: Mean age at presentation was 5 years. Based on imaging, the initial diagnoses for three of the cases were: lymphatic malformation, carotid body tumour, paraganglioma, respectively, whilst the remaining case had an immediate incisional biopsy revealing the correct diagnosis. All cases were managed by surgical excision with no evidence of recurrence after a median follow up of 6 years. CONCLUSION: Otolaryngologists should be aware of ganglioneuroblastoma when establishing the differential diagnosis of a child presenting with a neck mass. Biopsy is recommended as the gold standard investigation to avoid an incorrect diagnosis. PMID- 25921076 TI - Sildenafil for microcystic lymphatic malformations of the head and neck: A prospective study. AB - BACKGROUND: Microcystic lymphatic malformations (LM) are congenital birth defects that can cause severe functional or esthetic deformity. At this time, several treatment interventions are possible, but there is no ideal therapy. A recently published article noted a coincidental improvement in microcystic LMs with the use of sildenafil for pulmonary hypertension, but conclusive and reproducible data is lacking regarding its efficacy. METHODS AND RESULTS: A prospective study was conducted to examine the subjective and objective results associated with sildenafil use in the treatment of microcystic LMs. Patients under the age of 18 were enrolled, and after evaluation with pre-intervention magnetic resonance imaging (MRI) studies, each was given a 6-week course of sildenafil. Subjective outcomes were obtained, and postoperative MRIs were used to objectively quantify changes. Five patients between the ages of 4 and 11 were enrolled in the study. All patients had microcystic LMs of the head and neck. All patients had undergone previous treatment interventions utilizing various modalities, and each was now seeking treatment for functional and cosmetic purposes. All patients had minimal to no response from a subjective standpoint. Comparison of pre- and post treatment MRIs also demonstrated minimal to no response. CONCLUSIONS: The use of sildenafil for the treatment of microcystic lymphatic malformations did not have any appreciable effect on our selected population of pediatric patients who had been resistant to previous therapies. Further studies would be necessary to determine if other cohorts may benefit. PMID- 25921077 TI - Clinical features of bilateral temporal bone xanthoma with LDLR gene mutation. AB - Here we presented a rare case of bilateral temporal bone xanthoma associated with type II hyperlipidemia. The lesion caused osteolytic destruction in mastoid air cells, auditory ossicles and bony labyrinth. The patient was operated on the symptomatic side and the lesion was totally removed. The type of LDLR gene mutation had been clarified for the members of the patient's family. This case was the first one regarding bilateral temporal bone leading to retroauricular swelling. The patient need life-long follow-up by either CT or MR imaging. PMID- 25921078 TI - Outcomes with OAE and AABR screening in the first 48 h--Implications for newborn hearing screening in developing countries. AB - OBJECTIVE: Early discharge of newborns (<24h after birth) from birthing centres is an important barrier to successful newborn hearing screening (NHS) in developing countries. This study evaluated the outcome of NHS within the first 48 h using an automated auditory brainstem response (AABR) device without the need for costly disposables typically required, and transient evoked otoacoustic emissions (TEOAE). METHODS: NHS was performed on 150 healthy newborns (300 ears) with TEOAE and AABR techniques before discharge at a hospital. A three-stage screening protocol was implemented consisting of an initial screen with TEOAE (GSI AUDIOscreener+) and AABR (BERAphone((r)) MB 11). Infants were screened at several time points as early as possible after birth. Infants were only re screened if either screening technique (TEOAE or AABR) initially yielded a refer outcome. The same audiologist performed all TEOAE and AABR screenings. RESULTS: Over the three-stage screen AABR had a significantly lower refer rate of 16.7% (24/144 subjects) compared to TEOAE (37.9%; 55/145 subjects). Screening refer rate showed a progressive decrease with increasing age. For both TEOAE and AABR, refer rate per ear screened 24h post birth was significantly lower than for those screened before 24h. For infants screened before 12h post birth, the AABR refer rate per ear (51.1%) was significantly lower than the TEOAE refer rate (68.9%). Overall AABR refer rate per ear was similar for infants screened between 24 to 36 h (20.2%) and 36 to 48 h (18.9%) but significantly lower than for TEOAE (40.7% and 41.9%, respectively). Lowest initial refer rates per ear (TEOAE 25.8%, AABR 3.2%) were obtained after 48 h post birth. CONCLUSION: In light of the early post birth discharge typical in developing countries like South Africa, in-hospital screening with AABR technology is significantly more effective than TEOAEs. AABR screening with a device like the MB 11 is particularly appropriate because disposable costs are negligible. PMID- 25921079 TI - Spatial variation in inversion-focused vs 24-h integrated samples of PM2.5 and black carbon across Pittsburgh, PA. AB - A growing literature explores intra-urban variation in pollution concentrations. Few studies, however, have examined spatial variation during "peak" hours of the day (e.g., rush hours, inversion conditions), which may have strong bearing for source identification and epidemiological analyses. We aimed to capture "peak" spatial variation across a region of complex terrain, legacy industry, and frequent atmospheric inversions. We hypothesized stronger spatial contrast in concentrations during hours prone to atmospheric inversions and heavy traffic, and designed a 2-year monitoring campaign to capture spatial variation in fine particles (PM2.5) and black carbon (BC). Inversion-focused integrated monitoring (0600-1100 hours) was performed during year 1 (2011-2012) and compared with 1 week 24-h integrated results from year 2 (2012-2013). To allocate sampling sites, we explored spatial distributions in key sources (i.e., traffic, industry) and potential modifiers (i.e., elevation) in geographic information systems (GIS), and allocated 37 sites for spatial and source variability across the metropolitan domain (~388 km(2)). Land use regression (LUR) models were developed and compared by pollutant, season, and sampling method. As expected, we found stronger spatial contrasts in PM2.5 and BC using inversion-focused sampling, suggesting greater differences in peak exposures across urban areas than is captured by most integrated saturation campaigns. Temporal variability, commercial and industrial land use, PM2.5 emissions, and elevation were significant predictors, but did not more strongly predict concentrations during peak hours. PMID- 25921080 TI - Potential health impacts of changes in air pollution exposure associated with moving traffic into a road tunnel. AB - A planned 21 km bypass (18 km within a tunnel) in Stockholm is expected to reduce ambient air exposure to traffic emissions, but same time tunnel users could be exposed to high concentrations of pollutants. For the health impacts calculations in 2030, the change in annual ambient NOX and PM10 exposure of the general population was modelled in 100 * 100 m(2) grids for Greater Stockholm area. The tunnel exposure was estimated based on calculated annual average NOX concentrations, time spent in tunnel and number of tunnel users. For the general population, we estimate annually 23.7 (95% CI: 17.7-32.3) fewer premature deaths as ambient concentrations are reduced. At the same time, tunnel users will be exposed to NOX levels up to 2000 MUg/m(-3). Passing through the whole tunnel two times on working days would correspond to an additional annual NOX exposure of 9.6 MUg/m(3). Assuming that there will be ~55,000 vehicles daily each way and 1.3 persons of 30-74 years of age in each vehicle, we estimate the tunnel exposure to result in 20.6 (95% CI: 14.1-25.6) premature deaths annually. If there were more persons per vehicle, or older and vulnerable people travelling, or tunnel dispersion conditions worsen, the adverse effect would become larger. PMID- 25921081 TI - Factors influencing time-location patterns and their impact on estimates of exposure: the Multi-Ethnic Study of Atherosclerosis and Air Pollution (MESA Air). AB - We assessed time-location patterns and the role of individual- and residential level characteristics on these patterns within the Multi-Ethnic Study of Atherosclerosis and Air Pollution (MESA Air) cohort and also investigated the impact of individual-level time-location patterns on individual-level estimates of exposure to outdoor air pollution. Reported time-location patterns varied significantly by demographic factors such as age, gender, race/ethnicity, income, education, and employment status. On average, Chinese participants reported spending significantly more time indoors and less time outdoors and in transit than White, Black, or Hispanic participants. Using a tiered linear regression approach, we predicted time indoors at home and total time indoors. Our model, developed using forward-selection procedures, explained 43% of the variability in time spent indoors at home, and incorporated demographic, health, lifestyle, and built environment factors. Time-weighted air pollution predictions calculated using recommended time indoors from USEPA overestimated exposures as compared with predictions made with MESA Air participant-specific information. These data fill an important gap in the literature by describing the impact of individual and residential characteristics on time-location patterns and by demonstrating the impact of population-specific data on exposure estimates. PMID- 25921082 TI - Airborne asbestos take-home exposures during handling of chrysotile-contaminated clothing following simulated full shift workplace exposures. AB - The potential for para-occupational, domestic, or take-home exposures from asbestos-contaminated work clothing has been acknowledged for decades, but historically has not been quantitatively well characterized. A simulation study was performed to measure airborne chrysotile concentrations associated with laundering of contaminated clothing worn during a full shift work day. Work clothing fitted onto mannequins was exposed for 6.5 h to an airborne concentration of 11.4 f/cc (PCME) of chrysotile asbestos, and was subsequently handled and shaken. Mean 5-min and 15-min concentrations during active clothes handling and shake-out were 3.2 f/cc and 2.9 f/cc, respectively (PCME). Mean airborne PCME concentrations decreased by 55% 15 min after clothes handling ceased, and by 85% after 30 min. PCM concentrations during clothes handling were 11-47% greater than PCME concentrations. Consistent with previously published data, daily mean 8-h TWA airborne concentrations for clothes-handling activity were approximately 1.0% of workplace concentrations. Similarly, weekly 40-h TWAs for clothes handling were approximately 0.20% of workplace concentrations. Estimated take-home cumulative exposure estimates for weekly clothes handling over 25-year working durations were below 1 f/cc-year for handling work clothes contaminated in an occupational environment with full shift airborne chrysotile concentrations of up to 9 f/cc (8-h TWA). PMID- 25921084 TI - Aneuploidy rates and blastocyst formation after biopsy of morulae and early blastocysts on day 5. AB - PURPOSE: Studies have demonstrated high implantation rates after trophectoderm biopsy of day 5 expanded blastocysts. However, biopsy of cleavage stage embryos may adversely affect embryo development and implantation. No studies have assessed the utility of day 5 morulae and early blastocyst biopsy. This study sought to better understand these slower embryos' aneuploidy rates and implantation potential. METHODS: This was a retrospective review of all autologous IVF cycles utilizing PGS at a single academic infertility center. RESULTS: The biopsy of day 5 morulae and early blastocysts provided 22 % additional euploid blastocysts available for fresh day 6 transfer compared to day 5 biopsy of only expanded blastocysts. Aneuploidy did correlate with embryo stage on day 5, even after controlling for maternal age, with 16 % of morulae and 35 % of blastocysts being euploid. The majority (83 %) of euploid morulae progressed to the blastocyst stage by day 6. Experience transferring slower developing embryos is limited, but preliminary pregnancy and implantation rates appear similar to euploid embryos biopsied as expanded blastocysts. CONCLUSIONS: The biopsy of all non-arrested embryos on day 5 provides genetic information for all blastocysts on day 6, increasing the pool of euploid blastocysts available for fresh transfer and avoiding the need to cryopreserve developmentally competent embryos without genetic information. PMID- 25921083 TI - Time-location patterns of a diverse population of older adults: the Multi-Ethnic Study of Atherosclerosis and Air Pollution (MESA Air). AB - The primary aim of this analysis was to present and describe questionnaire data characterizing time-location patterns of an older, multiethnic population from six American cities. We evaluated the consistency of results from repeated administration of this questionnaire and between this questionnaire and other questionnaires collected from participants of the Multi-Ethnic Study of Atherosclerosis and Air Pollution (MESA Air). Participants reported spending most of their time inside their homes (average: 121 h/week or 72%). More than 50% of the participants reported spending no time in several of the location options, including at home outdoors, at work/volunteer/school locations indoors or outdoors, or in "other" locations outdoors. We observed consistency between self reported time-location patterns from repeated administration of the time-location questionnaire and compared with other survey instruments. Comparisons with national cohorts demonstrated the differences in time-location patterns in the MESA Air cohort due to differences in demographics, but the data showed similar trends in patterns by age, gender, season, and employment status. This study was the first to explicitly examine the time-location patterns in an older, multiethnic population and the first to add data on Chinese participants. These data can be used to inform future epidemiological research of MESA Air and other studies that include diverse populations. PMID- 25921085 TI - Au-Ag nanoalloy molecule-like clusters for enhanced quantum efficiency emission of Er3+ ions in silica. AB - The occurrence of a very efficient non-resonant energy transfer process forming ultrasmall Au-Ag nanoalloy clusters and Er(3+) ions is investigated in silica. The enhancement of the room temperature Er(3+) emission efficiency by an order of magnitude is achieved by coupling rare-earth ions to molecule-like (Au(x)Ag(1 x))N alloy nanoclusters with N = 10-15 atoms and x = 0.6 obtained by optimized sequential ion implantation on Er-implanted silica. For comparison, AuN nanoclusters obtained by the same approach and with the same size and numerical density showed an enhancement by only a factor of 2 with respect to pure Er emission, demonstrating the beneficial effect of using nanoalloyed clusters. The temperature evolution of the energy transfer process is investigated by photoluminescence and exhibits a maximum efficiency at about 600 degrees C, where the clusters reach the optimal size and the silica matrix completely recovers the implantation damage. The nanoalloy cluster composition and size have been studied by EXAFS analysis, which indicated a stronger Ag-O interaction with respect to the Au-O one and a preferential location of the Ag atoms at the nanoalloy cluster surface. PMID- 25921086 TI - The histone demethylase PHF8 represses cardiac hypertrophy upon pressure overload. AB - BACKGROUND: Mammalian hearts undergo hypertrophy upon pressure overload to support increased workload. Sustained hypertrophy results in cardiac decompensation and subsequently heart failure. The mechanism that prevents the development of cardiac hypertrophy is still not fully understood. Here we elucidate the anti-hypertrophic role of the histone demethylase PHF8. METHODS AND RESULTS: PHF8 protein and mRNA levels were down-regulated in human failing hearts, mouse hypertrophic hearts and neonatal rat ventricle myocytes that underwent hypertrophy. Then we generated a cardiac-specific PHF8 transgenic mice, and found that PHF8 overexpression reversed cardiac dysfunction, hypertrophy and fibrosis upon pressure overload. In vivo evidence showed that PHF8 blocked protein synthesis and hypertrophic fetal genes expression. Furthermore, we found that PHF8 inhibited Akt-mTOR pathway in hypertrophic hearts and neonatal rat ventricle myocytes, and rapamycin treatment rescues the effects of PHF8 loss. CONCLUSION: These results indicate that PHF8 serves as an endogenous factor that the host uses to attenuate cardiac hypertrophy upon cardiac overload. Strategies based on its enhancement might be of benefit in the treatment of hypertrophic cardiomyopathy. PMID- 25921088 TI - Recent progress in biomedical applications of Pluronic (PF127): Pharmaceutical perspectives. AB - Most of the administered anti-cancer drugs are hydrophobic in nature and are known to have poor water solubility, short residence time, rapid clearance from the body and systemic side effects. Polymeric-based targeted particulate carrier system has shown to directly deliver the encapsulated anti-cancer drug to the desired site of action and prevent the interaction of encapsulated drug with the normal cells. Pluronic F127 (PF127) has been widely investigated for its broad range of therodiagnostic applications in biomedical and pharmaceutical sciences, but rapid dissolution in the physiological fluids, short residence time, rapid clearance, and weak mechanical strength are the main shortcomings that are associated with PF127 and have recently been overcome by making various modifications in the structure of PF127 notably through preparation of PF127 based mixed polymeric micelles, PF127-conjugated nanoparticles and PF127-based hydrophobically modified thermogels. In this article, we have briefly discussed the recent studies that have been conducted on various anti-cancer drugs using PF127 as nano-carrier modified with other copolymers and/or conjugated with magnetic nanoparticles. The key findings of these studies demonstrated that the modified form of PF127 can significantly increase the stability of incorporated hydrophobic drugs with enhanced in vitro cytotoxicity and cellular uptake of anti cancer drugs. Moreover, the modified form of PF127 has also shown its therapeutic potentials as therodiagnostics in various types of tumors and cancers. Hence, it can be concluded that the modified form of PF127 exhibits significant therodiagnostic effects with increased tumor-specific delivery of anti-cancer drugs having minimal toxic effects as compared to PF127 alone and/or other copolymers. PMID- 25921087 TI - Synergistic antitumor activity of camptothecin-doxorubicin combinations and their conjugates with hyaluronic acid. AB - Combinations of topoisomerase inhibitors I and II have been found to synergistically inhibit cancer cell growth in vitro, yet clinical studies of these types of combinations have not progressed beyond phase II trials. The results of clinical combinations of topoisomerase (top) I and II inhibitors typically fall within one of two categories: little to no improvement in therapeutic efficacy, or augmented toxicity compared to the single drug counterparts. Hence, despite the promising activity of top I and II inhibitor combinations in vitro, their clinical applicability has not been realized. Here, we report the use of polymer-drug conjugates as a means to co-deliver synergistic doses of top I and II inhibitors camptothecin (CPT) and doxorubicin (DOX) to tumors in vivo in a 4T1 breast cancer model. At specific molar ratios, DOX and CPT were found to be among the most synergistic combinations reported to date, with combination indices between 0.01 and 0.1. The identified optimal ratios were controllably conjugated to hyaluronic acid, and elicited significant tumor reduction of murine 4T1 breast cancer model when administered intravenously. This study elucidates a method to identify synergistic drug combinations and translate them to in vivo by preserving the synergistic ratio via conjugation to a carrier polymer, thus opening a promising approach to translate drug combinations to clinically viable treatment regimens. PMID- 25921089 TI - Answer to the comment by Per Eystein Lonning on "The serum estradiol concentration is the main determinant of the estradiol concentration in normal breast tissue". PMID- 25921090 TI - SIRT1-Mediated eNAMPT Secretion from Adipose Tissue Regulates Hypothalamic NAD+ and Function in Mice. AB - Nicotinamide phosphoribosyltransferase (NAMPT), the key NAD(+) biosynthetic enzyme, has two different forms, intra- and extracellular (iNAMPT and eNAMPT), in mammals. However, the significance of eNAMPT secretion remains unclear. Here we demonstrate that deacetylation of iNAMPT by the mammalian NAD(+)-dependent deacetylase SIRT1 predisposes the protein to secretion in adipocytes. NAMPT mutants reveal that SIRT1 deacetylates lysine 53 (K53) and enhances eNAMPT activity and secretion. Adipose tissue-specific Nampt knockout and knockin (ANKO and ANKI) mice show reciprocal changes in circulating eNAMPT, affecting hypothalamic NAD(+)/SIRT1 signaling and physical activity accordingly. The defect in physical activity observed in ANKO mice is ameliorated by nicotinamide mononucleotide (NMN). Furthermore, administration of a NAMPT-neutralizing antibody decreases hypothalamic NAD(+) production, and treating ex vivo hypothalamic explants with purified eNAMPT enhances NAD(+), SIRT1 activity, and neural activation. Thus, our findings indicate a critical role of adipose tissue as a modulator for the regulation of NAD(+) biosynthesis at a systemic level. PMID- 25921092 TI - Geographic association of liquor licenses and gunshot wounds in Chicago. AB - BACKGROUND: The association between alcohol and interpersonal violence is well established. Up to 80% of homicide perpetrators and victims are known to have used alcohol before the incident. However, the association between proximity to a liquor-selling establishment and gun violence is more controversial. METHODS: Scene address data from the Illinois State Trauma Registry from 1999 to 2009 were used to geocode all gunshot wounds (GSWs) presenting to trauma centers in Chicago during the study period. These data were linked to publicly available US Census Demographic Data and City of Chicago Liquor Board data. A combination of ordinary least squares and geographically weighted regression was performed to identify "risk regions" throughout the study area. Logistic regression analysis was then performed to assess the independent effect of proximity to an establishment with a liquor license (LL) on trauma center admissions for GSWs. RESULTS: A total of 11,744 GSWs were geocoded. No association between LLs and GSWs was identified for the city overall (odds ratio [OR] .97, 95% confidence interval [CI] .96 to .99). However, 5 distinct regions of influence between LLs and GSWs were found. In regions with the highest association, likelihood of a GSW near a packaged LL was extraordinarily high (OR 518.08, 95% CI 10.23 to 1,000), and tavern LLs were also very significant (OR 21.51, 95% CI 1.81 to 255.53). CONCLUSIONS: We found that proximity to an establishment with an LL was a strong independent predictor of GSW incidence for many areas of the city, even after controlling for neighborhood characteristics. However, this association was not demonstrable for the entire city, and, in fact, marked regional variation was apparent. These data may contribute to our understanding of the interplay between alcohol and violent injury disparities. PMID- 25921091 TI - De Novo Reconstruction of Adipose Tissue Transcriptomes Reveals Long Non-coding RNA Regulators of Brown Adipocyte Development. AB - Brown adipose tissue (BAT) protects against obesity by promoting energy expenditure via uncoupled respiration. To uncover BAT-specific long non-coding RNAs (lncRNAs), we used RNA-seq to reconstruct de novo transcriptomes of mouse brown, inguinal white, and epididymal white fat and identified ~1,500 lncRNAs, including 127 BAT-restricted loci induced during differentiation and often targeted by key regulators PPARgamma, C/EBPalpha, and C/EBPbeta. One of them, lnc BATE1, is required for establishment and maintenance of BAT identity and thermogenic capacity. lnc-BATE1 inhibition impairs concurrent activation of brown fat and repression of white fat genes and is partially rescued by exogenous lnc BATE1 with mutated siRNA-targeting sites, demonstrating a function in trans. We show that lnc-BATE1 binds heterogeneous nuclear ribonucleoprotein U and that both are required for brown adipogenesis. Our work provides an annotated catalog for the study of fat depot-selective lncRNAs and establishes lnc-BATE1 as a regulator of BAT development and physiology. PMID- 25921093 TI - Alcohol intoxication may be associated with reduced truncal injuries after blunt trauma. AB - BACKGROUND: Prior studies suggest that positive blood alcohol concentration (BAC) is associated with lower mortality after motor vehicle collisions (MVCs). We investigated the relationship between increasing BAC and mortality after MVC. METHODS: A retrospective review of the Los Angeles County trauma database from January 2003 to December 2008 was performed. MVC patients greater than or equal to 16 years of age with admission BAC were considered. Patients were stratified by BAC as follows: BAC0 (<.01), BAC1 (.01 to .08), BAC2 (.09 to .16), BAC3 (.17 to .24), BAC4 (.25 to .32), and BAC5 (>.32). Logistic regression was used to determine predictors of mortality. RESULTS: A total of 12,540 patients were included. Overall mortality rate was 2.2%. Mortality was lowest in BAC3 (1.6%) and BAC4 (1.3%), although the difference among all groups was not statistically significant (P = .07). Decreased rates of Injury Severity Score greater than or equal to 16 were noted with increasing BAC, which was largely because of reduced chest and abdomen/pelvis Abbreviated Injury Scale. Adjusted mortality was lower in BAC3 and BAC4 (both adjusted odds ratio .4, P < .001). CONCLUSION: A protective effect of alcohol after MVC may be related to decreased truncal injury burden rather than protection after head injury. PMID- 25921094 TI - Continuity of care in general surgery resident education. AB - BACKGROUND: Lack of continuity of care for patients managed by general surgery residents is a commonly recognized problem but objective data evaluating its incidence are limited. The goal of this pilot study was to determine the extent to which senior residents at a large American urban academic center participate in the full course of care for patients on whom they operate. METHODS: Two hundred twenty-eight total cases performed between January 1, 2012 and December 31, 2012 were reviewed and the operative senior resident was noted: laparoscopic cholecystectomy (n = 50), breast lumpectomy (n = 33), thyroidectomy (n = 50), laparoscopic appendectomy (n = 50), and open partial colectomy (n = 45). Frequency of operative resident involvement in the initial preoperative clinic visit, initial postoperative visit, or both (the entire course of care) was recorded. RESULTS: Overall rate of operative resident involvement was 9.2% for the initial preoperative consultation, 9.0% for the initial follow-up visit, and 0% for the entire course of a patient's care. Residents were on service for greater than 40 days, whereas the average total duration of care for an individual patient was 26 days. CONCLUSIONS: The results of this pilot study suggest that continuity of care among general surgery residents is lacking and cannot be entirely accounted for by rotation-specific time constraints. Further research is needed to identify and validate effective curricular strategies for improving opportunities to participate in this essential experience. PMID- 25921095 TI - Rehabilitation following first-time patellar dislocation: a randomised controlled trial of purported vastus medialis obliquus muscle versus general quadriceps strengthening exercises. AB - BACKGROUND: We aimed to define whether distal vastus medialis (VM) muscle strengthening improves functional outcomes compared to general quadriceps muscle strengthening following first-time patellar dislocation (FTPD). METHODS: Fifty patients post-FTPD were randomised to either a general quadriceps exercise or rehabilitation programme (n=25) or a specific-VM exercise and rehabilitation regime (n=25). The primary outcome was the Lysholm knee score, and secondary outcomes included the Tegner Level of Activity score, the Norwich Patellar Instability (NPI) score, and isometric knee extension strength at various knee flexion ranges of motion. Outcomes were assessed at baseline, six weeks, six months and 12months. RESULTS: There were statistically significant differences in functional outcome and activity levels with the Lysholm knee score and Tegner Level of Activity score at 12months in the general quadriceps exercise group compared to the VM group (p=0.05; 95% confidence interval (CI): -14.0 to 0.0/p=0.04; 95% CI: -3.0 to 0.0). This did not reach a clinically important difference. There was no statistically significant difference between the groups for the NPI score and isometric strength at any follow-up interval. The trial experienced substantial participant attrition (52% at 12months). CONCLUSIONS: Whilst there was a statistical difference in the Lysholm knee score and Tegner Level of Activity score between general quadriceps and VM exercise groups at 12months, this may not have necessarily been clinically important. This trial highlights that participant recruitment and retention are challenges which should be considered when designing future trials in this population. LEVEL OF EVIDENCE: Therapeutic study, Level I. PMID- 25921096 TI - The efficacy and safety of epidural filter catheters when used for post-operative intra-articular anaesthesia. AB - There are concerns about the risk of iatrogenic infection when employing local anaesthetic techniques with post-operative intra-articular infusions in total knee arthroplasty. This study aimed to determine the efficacy of intact epidural filters in preventing transit of bacteria and to develop a technique of administration which would prevent membrane rupture. Filter efficacy was assessed using a standardised test suspension of Pseudomonas aeruginosa. Twenty millilitres of suspension was injected through isolated epidural filters (n=10) or filters with 40cm of catheter tubing attached (n=30). For each filter, injections were carried out at 0, 8 and 24h. Filtrates were collected, incubated, sub-cultured onto Columbia horse blood agar and examined for bacterial growth. Three delivery techniques were tested: manually controlled syringe with 5ml of water at 20ml/min, forced administration syringe with 5ml of water at >240ml/min and an automated syringe driver delivering 40ml of water at 6.7ml/min. For the two techniques using syringes, three syringe sizes, 5ml, 10ml and 20ml, were tested. Each test condition was carried out on 10 filters (total n=70). Filters were examined for rupture. Intact epidural filters prevented bacterial transit in all cases. Manual controlled and automated syringe driver administration generated no filter ruptures. Manual forced administration generated 93% filter rupture. Ruptures occurred at peak pressures of approximately 620kPa. Epidural filters can be used to prevent bacterial transit. These results suggest automated devices remove the risk of filter rupture. This study is relevant to all specialties that utilise these filters during infiltration such as epidurals or other regional anaesthetic techniques. CLINICAL RELEVANCE: This study identified that filters are prone to rupture with high infusion rates and that manual techniques are particularly vulnerable. From these results, it is recommended that pumps are used to minimise risk of filter rupture. PMID- 25921097 TI - Frailty predictors and outcomes among older patients with cardiovascular disease: Data from Fragicor. AB - The aim of this study was to evaluate predictive factors for frailty among older outpatient adults with cardiovascular disease (CVD) and to assess the predictive value of frailty in regard to mortality, disability and hospitalization at 1-year follow-up. A prospective cohort study was carried out with subjects over 65 years of age from an outpatient Cardiology clinic, with at least one CVD. At baseline, we classified frailty as proposed by Fried, i.e.; unintentional weight loss (10lbs in the past year), self-reported exhaustion, weakness (measured by grip strength), slow walking speed, and low physical activity. A frail person was defined by the presence of three or more criteria, prefrail by one or two and robust by the absence of them. Disability, previous hospitalizations, falls, morphometric and socio-demographic variables were collected; as well as the presence of CVD and hemodynamic parameters (HP): systolic (SPB) and diastolic blood pressure (DBP), heart rate (HR) and ejection fraction (EF). At 1-year follow-up, the outcomes assessed were: disability, number of hospitalizations and death. 172 subjects were included in this study with a mean age of 77 years old. The prevalence of frail was 39.8%, prefrail 51.5% and robust was 8.7%. Among the CVD and HP evaluated, myocardial infarction (MI), presence of three or more CVDs, lower SPB and DBP were significant and independent factors associated with the frailty phenotype. At 1-year follow up, frailty was an independent predictor for disability (Odds Ratio (OR): 3.94 (1.59-9.75); p=0.003) and it increased death probability by three times if compared to the robust group. In conclusion, older outpatients with CVD have a higher probability to be frail than older adults who do not have a CVD. Low SPB and DBP must always be taken into consideration due to their high association with frailty. It is also important to diagnose frailty in this population due to the high association with mortality and disability. PMID- 25921098 TI - Longer-term follow-up and outcome by tumour cell proliferation rate (Ki-67) in patients with relapsed/refractory mantle cell lymphoma treated with lenalidomide on MCL-001(EMERGE) pivotal trial. AB - Patients with mantle cell lymphoma (MCL) generally respond to first-line immunochemotherapy, but often show chemoresistance upon subsequent relapses, with poor outcome. Several studies of the immunomodulator, lenalidomide, have demonstrated its activity in MCL including the MCL-001 study in relapsed/refractory patients who had failed defined prior therapies of anthracyclines or mitoxantrone, cyclophosphamide, rituximab and also bortezomib. We present here the long-term efficacy follow-up of the prospective phase II MCL 001 study (N = 134), including new exploratory analyses with baseline Ki-67 (MIB1), a biological marker of tumour proliferation. With longer follow-up, lenalidomide showed a 28% overall response rate [ORR; 8% complete response (CR)/CR unconfirmed (CRu)]. Median duration of response (DOR), progression-free survival and overall survival were 16.6, 4.0 and 20.9 months, respectively. Myelosuppression continued to be the most common grade 3/4 toxicity. Several studies of MCL patients treated with chemotherapy, rituximab and bortezomib have shown an inverse association between survival and Ki-67. Ki-67 data in 81/134 MCL 001 patients showed similar ORRs in both low (<30% or <50%) versus high (>=30% or >=50%) Ki-67-expressing groups, yet lower Ki-67 levels demonstrated superior CR/CRu, DOR and survival outcomes. Overall, lenalidomide showed durable efficacy with a consistent safety profile in heavily pretreated, relapsed/refractory MCL post-bortezomib. PMID- 25921100 TI - Morphological distribution of esophageal cancer from Cancer Incidence in Five Continents Vol. X. PMID- 25921099 TI - miR-128 modulates chemosensitivity and invasion of prostate cancer cells through targeting ZEB1. AB - OBJECTIVE: Recent reports strongly suggest the profound role of miRNAs in cancer therapeutic response and progression, including invasion and metastasis. The sensitivity to therapy and invasion is the major obstacle for successful treatment in prostate cancer. We aimed to investigate the regulative effect of miR-128/zinc-finger E-box-binding homeobox 1 axis on prostate cancer cell chemosensitivity and invasion. METHODS: The miR-128 expression pattern of prostate cancer cell lines and tissues was detected by real-time reverse transcriptase-polymerase chain reaction, while the mRNA and protein expression levels of zinc-finger E-box-binding homeobox 1 were measured by real-time reverse transcriptase-polymerase chain reaction and western blot assay, respectively. Dual-luciferase reporter gene assay was used to find the direct target of miR 128. Furthermore, prostate cancer cells were treated with miR-128 mimic or zinc finger E-box-binding homeobox 1-siRNA, and then the cells' chemosensitivity and invasion were detected by 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide assay and transwell assay, respectively. RESULTS: We found miR-128 expression obviously decreased in prostate cancer tissues compared with paired normal tissues. Restored miR-128 expression sensitized prostate cancer cells to cisplatin and inhibited the invasion. Furthermore, there was an inverse expression pattern between miR-128 and zinc-finger E-box-binding homeobox 1 in prostate cancer cells and tissues, and zinc-finger E-box-binding homeobox 1 was identified as a direct target of miR-128 in prostate cancer. Knockdown of zinc finger E-box-binding homeobox 1 expression efficiently sensitized prostate cancer cells to cisplatin and inhibited the invasion. However, ectopic zinc-finger E-box binding homeobox 1 expression impaired the effects of miR-128 on chemosensitivity and invasion in prostate cancer cells. CONCLUSIONS: miR-128 functions as a potential cancer suppressor in prostate cancer progression and rational therapeutic strategies for prostate cancer would be developed based on miR 128/zinc-finger E-box-binding homeobox 1 axis. PMID- 25921101 TI - Shelterin proteins and cancer. AB - The telomeric end structures of the DNA are known to contain tandem repeats of TTAGGG sequence bound with specialised protein complex called the "shelterin complex". It comprises six proteins, namely TRF1, TRF2, TIN2, POT1, TPP1 and RAP1. All of these assemble together to form a complex with double strand and single strand DNA repeats at the telomere. Such an association contributes to telomere stability and its protection from undesirable DNA damage control specific responses. However, any alteration in the structure and function of any of these proteins may lead to undesirable DNA damage responses and thus cellular senescence and death. In our review, we throw light on how mutations in the proteins belonging to the shelterin complex may lead to various malfunctions and ultimately have a role in tumorigenesis and cancer progression. PMID- 25921102 TI - Benefits and harms of phytoestrogen consumption in breast cancer survivors. AB - Worldwide, breast cancer is the most common malignant neoplasm and the second most common cause of cancer death in women. This malignancy is recognized to be estrogen-dependent and due to this feature, hormone replacement therapy is regarded as potentially dangerous in breast cancer survivors who seek relief of their menopausal symptoms. Whereas hot flashes are detected in nearly half of postmenopausal women with a relatively high frequency and severity, botanic sources of estrogens have been proposed as an alternative treatment. Nevertheless, estrogenic properties of these compounds suggest possibility of stimulating cancer recurrence or worsening prognosis in survivors. As well, effects in improving vasomotor climacteric changes is controversial. Many studies have considered the subject, some focusing on efficacy of phytoestrogens for control of menopausal symptoms, and others discussing effects of these compounds on breast cancer outcome in terms of survival or recurrence. The present article is a concise review of the effects of consumption of phytoestrogens on menopausal symptoms, namely hot flashes, and breast cancer recurrence and mortality in survivors of the disease. Overall, the major part of the current existing literature is in favor of positive effects of phytoestrogens on breast cancer prognosis, but the efficacy on menopausal symptoms is probably minimal at the best. PMID- 25921103 TI - What is the Most Suitable Time Period to Assess the Time Trends in Cancer Incidence Rates to Make Valid Predictions--an Empirical Approach. AB - Projections of cancer cases are particularly useful in developing countries to plan and prioritize both diagnostic and treatment facilities. In the prediction of cancer cases for the future period say after 5 years or after 10 years, it is imperative to use the knowledge of past time trends in incidence rates as well as in population at risk. In most of the recently published studies the duration for which the time trend was assessed was more than 10 years while in few studies the duration was between 5-7 years. This raises the question as to what is the optimum time period which should be used for assessment of time trends and projections. Thus, the present paper explores the suitability of different time periods to predict the future rates so that the valid projections of cancer burden can be done for India. The cancer incidence data of selected cancer sites of Bangalore, Bhopal, Chennai, Delhi and Mumbai PBCR for the period of 1991-2009 was utilized. The three time periods were selected namely 1991-2005; 1996-2005, 1999-2005 to assess the time trends and projections. For the five selected sites, each for males and females and for each registry, the time trend was assessed and the linear regression equation was obtained to give prediction for the years 2006, 2007, 2008 and 2009. These predictions were compared with actual incidence data. The time period giving the least error in prediction was adjudged as the best. The result of the current analysis suggested that for projections of cancer cases, the 10 years duration data are most appropriate as compared to 7 year or 15 year incidence data. PMID- 25921104 TI - Allele and Genotype Frequencies of the Polymorphic Methylenetetrahydrofolate Reductase and Lung Cancer in ther Jordanian Population: a Case Control Study. AB - BACKGROUND: Methylenetetrahydrofolate reductase (MTHFR) is involved in amino acid synthesis and DNA function. Two common polymorphisms are reported, C677T and A1298C, that are implicated in a number of human diseases, including cancer. OBJECTIVE: The association between MTHFR C677T and A1298C genotype and haplotype frequencies in risk for lung cancer (LC) was investigated in the Jordanian population. MATERIALS AND METHODS: A total of 98 LC cases were studied for MTHFR C677T and A1298C polymorphisms, compared to 89 controls taken from the general population, employing the PCR-RFLP technique. RESULTS: The frequency of the genotypes of MTHFR C677T among Jordanians was: CC, 59.6%, CT, 33%; and TT, 7.4% among LC cases and 49.4%, 40.2% and 10.3% among controls. No significant association was detected between genetic polymorphism at this site and LC. At MTHFR A12987C, the genotype distribution was AA, 29.5%; AC, 45.3%, and CC 25.3% among LC cases and 36.8%, 50.6% and 12.6% among controls. Carriers of the CC genotype were more likely to have LC (OR=2.5; 95%CI: 1.04-6; p=0.039) as compared to AA carriers. Smokers and males with the CC genotype were 9.9 and 6.7 times more likely to have LC, respectively (ORsmokers=9.9; 95%CI: 1.2-84.5, p=0.018; ORmen=6.6; 95%CI: 1.7-26.2, p=0.005). Haplotype analysis of MTHFR polymorphism at the two loci showed differential distribution of the CC haplotype (677C-1298C) between cases and controls. The CC haplotype was associated with an increased risk for lung cancer (OR=1.6; 95% CI: 1.03-2.4, p=0.037). CONCLUSIONS: The genetic polymorphism of MTHFR at 1298 and the CC haplotype (risk is apparently lower with the C allele at position 677) may modulate the risk for LC development among the Jordanian population. Risk associated with the 1298C allele is increased in smokers and in males. The results indicate that a critical gene involved in folate metabolism plays a modifying role in lung cancer risk, at least in the Jordanian population. PMID- 25921105 TI - Changing patterns of Serum CEA and CA199 for Evaluating the Response to First line Chemotherapy in Patients with Advanced Gastric Adenocarcinoma. AB - BACKGROUND: This study was designed to investigate the value of CEA and CA199 in predicting the treatment response to palliative chemotherapy for advanced gastric cancer. MATERIALS AND METHODS: We studied 189 patients with advanced gastric cancer who received first-line chemotherapy, measured the serum CEA and CA199 levels, used RECIST1.1 as the gold standard and analyzed the value of CEA and CA199 levels changes in predicting the treatment efficacy of chemotherapy. RESULTS: Among the 189 patients, 80 and 94 cases had increases of baseline CEA (>=5 ng/ml) and CA199 levels (>= 27U/ml), respectively. After two cycles of chemotherapy, 42.9% patients showed partial remission, 33.3% stable disease, and 23.8% progressive disease. The area under the ROC curve (AUC) for CEA and CA199 reduction in predicting effective chemotherapy were 0.828 (95%CI 0.740-0.916) and 0.897 (95%CI 0.832-0.961). The AUCs for CEA and CA199 increase in predicting progression after chemotherapy were 0.923 (95%CI 0.865-0.980) and 0.896 (95%CI 0.834-0.959), respectively. Patients who exhibited a CEA decline >=24% and a CA199 decline >=29% had significantly longer PFS (log rank p=0.001, p<0.001). With the exception of patients who presented with abnormal levels after chemotherapy, changes of CEA and CA199 levels had limited value for evaluating the chemotherapy efficacy in patients with normal baseline tumor markers. CONCLUSIONS: Changes in serum CEA and CA199 levels can accurately predict the efficacy of first-line chemotherapy in advanced gastric cancer. Patients with levels decreasing beyond the optimal critical values after chemotherapy have longer PFS. PMID- 25921106 TI - Association Study of Single-Nucleotide Polymorphisms of STAT2/STAT3/IFN-gamma Genes in Cervical Cancer in Southern Chinese Han Women. AB - OBJECTIVE: Interferon-gamma (IFN-gamma) and signal transducers and activators of transcription (STATs) each play an important role in carcinogenesis associated with viral infection. Cervical cancer is almost invariably associated with infection by human papillomavirus (HPV), and previous studies suggested that dysregulation of the signal pathway involved in IFN-gamma and STATs is associated. Our objective was to evaluate the association of SNPs in STAT2, STAT3, and IFN-gamma with cervical cancer susceptibility in Chinese Han women in Hunan province. MATERIALS AND METHODS: Genomic DNA was extracted from peripheral blood samples of 234 cervical cancer patients and 216 healthy female controls. STAT2 and STAT3 genotyping was performed using polymerase chain reaction restriction enzyme (PCR-RE) analysis. IFN-gamma genotyping was detected by PCR amplification of specific allele (PASA). RESULTS: For STAT2 rs2066807 polymorphisms, there was no significant difference of genotype distribution (P=0.827) and allele frequencies (P=0.830, OR=1.09, 95% CI: 0.51-2.31) between cases and controls. For STAT3 rs957970 polymorphisms, there was no significant difference of genotype distribution (P=0.455) and allele frequencies (P=0.560, OR=0.92, 95% CI: 0.71-1.20) between cases and controls. For IFN-gamma +874A/T polymorphisms, there was no significant difference of genotype distribution (P=0.652) and allele frequencies (P=0.527, OR=1.12, 95% CI: 0.79-1.59) between cases and controls. CONCLUSION: These results suggest that polymorphisms in STAT2, STAT3 and IFN-gamma genes are not likely to be strong predictors of cervical cancer in Han women in southern China. PMID- 25921107 TI - Association of educational levels with survival in Indian patients with cancer of the uterine cervix. AB - The main objective of this paper was to assess the influence of educational level on the survival of uterine cervix cancer patients in our population. A total of 224 patients were registered in our registry, of which 178 had information on stage and different educational levels. The overall median survival (MS) was 23 months, with values of 18.5, 20.7 and 41.3 months for the illiterate, literate and qualified groups, respectively. In the illiterate patients, stage I was seen in 2.6% and stage IV in 11.8%, while in other 2 groups stage I was seen in 10% to 17% of patients at the time of diagnosis. The survival probability at around 50 months was around 42%, 30% and 26% (approximately) for qualified, literates and illiterates respectively [Log Rank (Mantel-Cox) showed p=0.023]. Emphasis on imparting education to females can be a part of comprehensive cancer control programme for improving the overall survival in patients with carcinoma of the uterine cervix in our population. PMID- 25921108 TI - Complementary alternative medicine use amongst breast cancer patients in the Northern region of peninsular Malaysia. AB - BACKGROUND: Breast cancer is a common cancer affecting women in Malaysia and the use of complementary/ alternative medicine (CAM) has been associated with delays in getting treatment. The aim of the study was to explore the use of CAM and the influencing factors in the Northern region of Peninsular Malaysia. MATERIALS AND METHODS: This was a cross-sectional descriptive study on a convenience sample of 100 Malaysian breast cancer survivors. FINDINGS: The reported use of CAM among the breast cancer survivors was lower than in other studies but the types of CAM used had a similar pattern with nutrition supplements/vitamins being the most common. The factors that positively influenced the use of complimentary/traditional therapy were income and getting information from television or radio. Survivors with access to internet/blogs appear to have lower odds of using complimentary/traditional therapy compared to the respondents who reported no such access. CONCLUSIONS: Information transmitted via television and radio appears to have a positive influence on CAM use by breast cancer patients compared to other information sources and it is important to ensure that such information is accurate and impartial. PMID- 25921109 TI - The high expressed serum soluble neural cell adhesion molecule, a high risk factor indicating hepatic encephalopathy in hepatocelular carcinoma patients. AB - OBJECTIVE: To investigate whether the expression of serum soluble neural cell adhesion molecule (sNCAM) is associated with hepatic encephalopathy (HE) in hepatocelular carcinoma (HCC) patients. MATERIALS AND METHODS: The Oncomine Cancer Microarray database was used to determine the clinical relevance of NCAM expression in different kinds of human cancers. Sera from 75 HCC cases enrolled in this study were assessed for expression of sNCAM by enzyme linked immunosorbent assay (ELISA). RESULTS: Dependent on the Oncomine Cancer Microarray database analysis, NCAM was down regulated in 10 different kinds of cancer, like bladder cancer, brain and central nervous system cancer, while up-regulated in lung cancer, uterine corpus leiomyoma and sarcoma, compared to normal groups. Puzzlingly, NCAM expression demonstrated no significant difference between normal and HCC groups. However, we found by quantitative ELISA that the level of sNCAM in sera from HCC patients with HE (347.4+/-151.9 ng/ml) was significantly more up regulated than that in HCC patients without HE (260.3+/-104.2 ng/ml), the p-value being 0.008. sNCAM may be an important risk factor of HE in HCC patients, the correlation coefficients was 0.278 (P< 0.05) on rank correlation analysis. CONCLUSIONS: This study highlights that up-regulated level of serum sNCAM is associated with HE in HCC patients and suggests that the high expression can be used as an indicator. PMID- 25921110 TI - Immune Reconstitution of CD4+T Cells after Allogeneic Hematopoietic Stem Cell Transplantation and its Correlation with Invasive Fungal Infection in Patients with Hematological Malignancies. AB - OBJECTIVE: To explore the immune reconstitution of CD4+T cells after allogeneic hematopoietic stem cell transplantation (Allo-HSCT) and its relationship with invasive fungal infection (IFI) in patients with hematological malignancies. MATERIALS AND METHODS: Forty-seven patients with hematological malignancies undergoing Allo- HSCT in Binzhou Medical University Hospital from February, 2010 to October, 2014 were selected. At 1, 2 and 3 months after transplantation, the immune subpopulations and concentration of cytokines were assessed respectively using flow cytometry (FCM) and enzyme linked immunosorbent assay (ELISA). The incidence of IFI after transplantation and its correlation with immune reconstitution of CD4+T cells were investigated. RESULTS: The number of CD4+T cells and immune subpopulations increased progressively after transplantation as time went on, but the subpopulation cell count 3 months after transplantation was still significantly lower than in the control group (p<0.01). In comparison to the control group, the levels of interleukin-6 (IL-6) and IL-10 after transplantation rose evidently (p<0.01), while that of transforming growth factor beta (TGF-beta) was decreased (p<0.01). There was no statistically significant difference level of interferon-gamma (IFN-gamma) (p>0.05). The incidence of IFI was 19.2% (9/47), and multivariate logistic regression revealed that IFI might be related to Th17 cell count (p<0.05), instead of Th1, Th2 and Treg cell counts as well as IL-6, IL-10, TGF-beta and IFN-gamma levels (p>0.05). CONCLUSIONS: After Allo-HSCT, the immune reconstitution of CD4+T cells is delayed and Th17 cell count decreases obviously, which may be related to occurrence of IFI. PMID- 25921111 TI - Accuracy of endoscopic ultrasonography for determination of tumor invasion depth in gastric cancer. AB - BACKGROUND: Gastric cancer (GC) is one the common lethal cancers in Iran. Detection of GC in the early stages would assesses to improve the survival of patients. In this study, we attempt to evaluate the accuracy of EUS in detection depth of invasion of GC among Iranian Patients. MATERIALS AND METHODS: This study is a retrospective study of patients with pathologically confirmed GC. They underwent EUS before initiating the treatment. The accuracy of EUS and agreement between the two methods was evaluated by comparing pre treatment EUS finding with post operative histopathological results. RESULTS: The overall accuracy of EUS for T and N staging was 67.9% and 75.47, respectively. Underestimation and overestimation was seen in 22 (14.2%) and 40 (25.6%) respectively. The EUS was more accurate in large tumors and the tumors located in the middle and lower parts of the stomach. The EUS was more sensitive in T3 staging. The values of weighted Kappa from the T and N staging were 0.53 and 0.66, respectively. CONCLUSIONS: EUS is a useful modality for evaluating the depth of invasion of GC. The accuracy of EUS was higher if the tumor was located in the lower parts of the stomach and the size of the tumor was more than 3 cm. Therefore, judgments made upon other criteria evaluated in this study need to be reconsidered. PMID- 25921112 TI - Role of CD10 Immunohistochemical Expression in Predicting Aggressive Behavior of Phylloides Tumors. AB - BACKGROUND: Phylloides tumors are rare breast neoplasms with a variable clinical course depending on the tumor category. Along with histologic features, the role of immunohistochemical staining has been studied in predicting their behavior. OBJECTIVES: Our aim was to evaluate the role of CD 10 immunohistochemical staining in predicting survival, recurrence and metastasis in phylloides tumor. We also evaluated correlations of other clinicopathological features with overall and disease-free survival. MATERIALS AND METHODS: CD10 expression was studied in 82 phylloides tumors divided into recurrent/metastatic and non-recurrent/non metastatic cohorts. The Chi-square test was applied to determine the significance of differences in CD10 expression between outcome cohorts. Uni and multivariate survival analyses were also performed using log-rank test and Cox regression hazard models. RESULTS: All 3 metastatic cases, 5 out of 6 (83.3%) recurrent cases and 37out of 73 (50.7%) non-recurrent and non-metastatic cases expressed significant (2+ or 3+) staining for CD10. This expression significantly varied between outcome cohorts (p<0.03). Tumor category and histological features including mitotic count and necrosis correlated significantly with recurrence and metastasis. A significant decrease in overall and disease free survival was seen with CD10 positivity, malignant category, increased mitoses and necrosis. Neither CD10 expression nor any other clinicopathologic feature proved to be an independent prognostic indicator in multivariate analysis. CONCLUSIONS: CD10 immunohistochemical staining can be used as a predictive tool for phylloides tumor but this expression should be interpreted in conjunction with tumor category. PMID- 25921113 TI - Factors related to treatment refusal in Taiwanese cancer patients. AB - BACKGROUND: Incidence and mortality rates for cancer have increased dramatically in the recent 30 years in Taiwan. However, not all patients receive treatment. Treatment refusal might impair patient survival and life quality. In order to improve this situation, we proposed this study to evaluate factors that are related to refusal of treatment in cancer patients via a cancer case manager system. MATERIALS AND METHODS: This study analysed data from a case management system during the period from 2010 to 2012 at a medical center in Northern Taiwan. We enrolled a total of 14,974 patients who were diagnosed with cancer. Using the PRECEDE Model as a framework, we conducted logistic regression analysis to identify independent variables that are significantly associated with refusal of therapy in cancer patients. A multivariate logistic regression model was also applied to estimate adjusted the odds ratios (ORs) with 95% confidence intervals (95%CI). RESULTS: A total of 253 patients (1.69%) refused treatment. The multivariate logistic regression result showed that the high risk factors for refusal of treatment in cancer patient included: concerns about adverse effects (p<0.001), poor performance(p<0.001), changes in medical condition (p<0.001), timing of case manager contact (p=.026), the methods by which case manager contact patients (p<0.001) and the frequency that case managers contact patients (>=10times) (p=0.016). CONCLUSIONS: Cancer patients who refuse treatment have poor survival. The present study provides evidence of factors that are related to refusal of therapy and might be helpful for further application and improvement of cancer care. PMID- 25921114 TI - Nedaplatin salvage chemotherapy for cervical cancer. AB - PURPOSE: This systematic analysis was conducted to evaluate the efficacy and safety of nedaplatin based salvage chemotherapy for treatment of patients with advanced cervical cancer. METHODS: Clinical studies evaluating the efficacy and safety of nedaplatin based regimens on response and safety for patients with cervical cancer were identified using a predefined search strategy. Pooled response rates (RRs) were calculated. RESULTS: For nedaplatin based regimens, 5 clinical studies including 264 patients with advanced cervical cancer were considered eligible for inclusion. The analysis showed that, in all patients, pooled RR was 74.6% (197/264). Major adverse effects were leukopenia, thrombocytopenia and nausea/vomiting. No treatment related death occurred with nedaplatin based treatment. CONCLUSION: This systematic analysis suggests that nedaplatin based regimens are associated with good activity with acceptable tolerability in treating patients with advanced cervical cancer. PMID- 25921115 TI - Pooled analysis of pomalidomide for treating patients with multiple myeloma. AB - BACKGROUND: Patients with refractory or relapsed multiple myeloma are considered to have a very poor prognosis, and new regimens are needed to improve this setting. Pomalidomide is a new immunomodulatory drug with high in vitro potency. Immunomodulatory drugs are hypothesized to act through multiple mechanisms. Here we performed a systemic analysis to evaluate pomalidomide-based chemotherapy (pomalidomide in combination with low-dose dexamethasone) as salvage treatment for patients with refractory and relapsed multiple myeloma. METHODS: Clinical studies evaluating the efffectiveness of pomalidomide based regimens on response and safety for patients with refractory and relapsed multiple myeloma were identified using a predefined search strategy. Pooled response rate (RR) of treatment were calculated. RESULTS: For pomalidomide based regimens, 4 clinical studies which including 291 patients with refractory and relapsed multiple myeloma were considered eligible for inclusion. Systemic analysis suggested that, in all patients, pooled RR was 41.2% (120/291). Major adverse effects were hematologic toxicity, including grade 1 or 2 anemia, leucopenia and thrombocytopenia with pomalidomide based treatment. No treatment related death occurred. CONCLUSION: This pooled analysis suggests that pomalidomide in combination with low-dose dexamethasone is active with good tolerability in treating patients with refractory or relapsed multiple myeloma. PMID- 25921116 TI - Investigation of Transition Types of HPV DNA Test Results over Time in Korean Women. AB - BACKGROUND: Understanding the history of human papilloma virus (HPV) infection is important for interpretation of a positive HPV DNA screening test, future work-up and treatment. We investigated the transition of HPV DNA test results in Korean women, and analyzed the association of cytology result with transition type. MATERIALS AND METHODS: We retrospectively reviewed annual HPV DNA test results for 5,274 subjects between January 2005 and December 2012. Each subject had a minimum of five annual tests over the eight-year period. Based on the pattern of results, the transition type for each subject was assigned to one of the following: negative, persistent, latent, transient, and unclassifiable. Associations of cytology results with the HPV DNA transition types, number of positive results, and the durations of positive results were also analyzed. RESULTS: The proportion of abnormal cytology findings decreased in the following order of transition patterns: persistent, latent, transient, and negative. Among transient patterns, a duration of three years or more significantly correlated with cytology results of non-high grade squamous intraepithelial lesion (HSIL; p<0.001). In the persistent group, duration of five years or more correlated with both non-HSIL and HSIL (p<0.001). Latent group showed no correlation with duration. Irrespective of patterns, having five or more positive results was significantly associated with HSIL (p<0.001). CONCLUSIONS: Our findings may contribute to better understanding of HPV infection, interpretation of HPV DNA screening results, and prediction of prognosis according to transition type. PMID- 25921117 TI - Pro-(IL-18) and Anti-(IL-10) Inflammatory Promoter Genetic Variants (Intrinsic Factors) with Tobacco Exposure (Extrinsic Factors) May Influence Susceptibility and Severity of Prostate Carcinoma: A Prospective Study. AB - BACKGROUND: It has been hypothesized that IL-18 (pro-) and IL-10 (anti-) inflammatory genetic variants at -607 C/A-137G/C and -819C/T,-592C/A, respectively, may generate susceptibility and severity risk with various modes of tobacco exposure in prostate carcinoma (PCa) patients. IL-18 is a pro inflammatory cytokine expressed on various cells including prostate gland elements, and is a key mediator of immune responses with anti-cancerous properties. IL-10 is an anti-inflammatory cytokine that is associated with tumour malignancy which causes immune escape. MATERIALS AND METHODS: The present study was conducted with 540 subjects, comprising 269 prostate carcinoma patients and 271 controls. Genotyping was performed by PCR-RFLP and confirmed by real time PCR probe-based methods. RESULTS: The findings indicated that the mutant heterozygous and homozygous genotype CC and GC+CC showed significant negative associations (p=0.01, OR=0.21; 95% CI: 0.08-0.51 and p=0.011, OR=0.43; 95% CI: 0.22-0.81, respectively) thus, less chance to be diagnosed as cancer against GG genotype of tobacco smoking patients. In addition, a heterozygous GC genotype at the same locus of IL-18 pro-inflammatory cytokine may aggravate the severity (OR=2.82; 95%CI 1.09-7.29 :p=001) so that patients are more likely to be diagnosed in advanced stage than with the GG wild homozygous genotype. Our results also illustrated that anti-inflammatory cytokine (IL-10) genetic variants, although showing no significant association with susceptibility to cancer of the prostate, may gave profound effects on severity of the disease, as -819 TC (OR=4.60; 95%CI 1.35-15.73), and -592 AC (OR=5.04; 95%CI 1.08-25.43) of IL-10 in tobacco chewers and combined users (both chewers and smokers) respectively, are associated with diagnosis in more advanced stage than with other variants. CONCLUSIONS: We conclude that promoter genetic variants of IL-18 and IL-10 with various modes of tobacco exposure may affect not only susceptibility risk but also severity in prostate cancer. PMID- 25921118 TI - Assessment of arsenic levels in body samples and chronic exposure in people using water with a high concentration of arsenic: a field study in Kutahya. AB - OBJECTIVE: This study aimed to evaluate the prevalence of skin lesions, which is a health effect of chronic arsenic (As) exposure, and determine the hair/blood arsenic concentrations of people living in Kutahya villages who are using and drinking tap water with a high concentration of arsenic. MATERIALS AND METHODS: A total of 303 people were included in the present cross-sectional study. A prepared questionnaire form was used to collect the participants' information and environmental history. Skin examination was performed on all participants. Hair, blood and water samples were analyzed using atomic absorption spectroscopy. The cumulative arsenic index (CAI) was calculated for all participants. RESULTS: Villages were divided into two groups according to the arsenic level (<20 MUg/L, Group I; >20 MUg/L, Group II) in their water. The prevalence of skin lesions, hair and blood arsenic level, and CAI were found to be higher in the Group II participants. There was a positive association between body arsenic levels and CAI in the participants of each group. CONCLUSIONS: The number of skin lesions and arsenic concentrations in body samples were found to increase with the water arsenic level and exposure time. We hope that sharing this study's results with local administrators will help accelerate the rehabilitation of water sources in Kutahya. PMID- 25921119 TI - Expression of TS, RRM1, ERCC1, TUBB3 and STMN1 Genes in Tissues of Non-small Cell Lung Cancer and its Significance in Guiding Postoperative Adjuvant Chemotherapy. AB - BACKGROUND: To explore the expression of TS, RRM, ERCC1, TUBB3 and STMN1 genes in the tissues of patients with non-small cell lung cancer (NSCLC) and its significance in guiding the postoperative adjuvant chemotherapy. MATERIALS AND METHODS: Real time polymerase chain reaction (PCR) was applied to detect the expression of TS, RRM, ERCC1, TUBB3 and STMN1 genes in the tissues of NSCLC patients so as to analyze the relationship between the expression of each gene and the clinical characteristics and to guide the postoperative individualized chemotherapy according to the detection results of NSCLC patients. RESULTS: Expression of TS gene was evidently higher in patients with adenocarcinoma than those with non-adenocarcinoma (P=0.013) and so was the expression of ERCC1 (P=0.003). The expression of TUBB3 gene was obviously higher in NSCLC patients in phases I/II and IV than those in phase III (P1=0.021; P2=0.004), and it was also markedly higher in patients without lymph node metastasis than those with (P=0.008). The expression of STMN1 gene was apparently higher in patients in phase I/II than those in phase IV (P=0.002). There was no significant difference between the rest gene expression and the clinical characteristics of NSCLC patients (P>0.05). Additionally, the disease- free survival (DFS) was significantly longer in patients receiving gene detections than those without (P=0.021). CONCLUSIONS: The selection of chemotherapeutic protocols based singly on patients' clinical characteristics has certain blindness. However, the detection of tumor-susceptible genes can guide the postoperative adjuvant chemotherapy and prolong the DFS of NSCLC patients. PMID- 25921120 TI - Betaine Effects on Morphology, Proliferation, and p53-induced Apoptosis of HeLa Cervical Carcinoma Cells in Vitro. AB - OBJECTIVES: To investigate the effects of betaine on HeLa cell growth and apoptosis and molecular mechanisms. MATERIALS AND METHODS: Concentrations of 0.1, 1.0, 5.0, 20.0, 100.0 mg/ml of betaine were used to evaluate the anticancer efficacy for HeLa cells respectively, and MCF-10A was also detected as a normal diploid cell control. RESULTS: We found that proliferation of HeLa cells was inhibited significantly upon exposure to increasing betaine levels with the MTT test (p<0.05). The percentage of S phase cells in the low dose groups (< 5mg/ml) were distinctly higher than in high dose groups, and the rates of Sub-G1 phase were the opposite (p<0.01); A high concentration of betaine (>5.0mg/ml) significantly promoted the apoptosis of HeLa cells (p<0.01). SOD activities of the low dose groups were slightly higher than the control group (p<0.05) and there were obvious synchronicity and correlation among the expression of promoting apoptosis genes Bax, P53, Caspase 3 and apoptosis suppression gene Bcl 2. In response to an apoptosis-inducing stimulus, p53 and cyclin D1 could be activated with blockage of the cell cycle at G1/S or S/G2 checkpoints. CONCLUSIONS: Our data showed that betaine could promote HeLa cells proliferation in vitro at low concentrations.In contrast, high concentrations could significantly inhibit cell growth and migration, and induce apoptosis of HeLa cells through caspase 3 signaling and further promoted necrosis. This might imply that betaine exhibits tumoricidal effects and acts as a biological response modifier in cancer treatment by inducing apoptosis and cell cycle arrest in a dose and time-dependent manner. PMID- 25921121 TI - Safety Management Status among Nurses Handling Anticancer Drugs: Nurse Awareness and Performance Following Safety Regulations. AB - This study identified the actual conditions for safe anticancer drug management among nurses and the relationship between level of awareness and performance of anticancer drug safety regulations in terms of preparation, administration, and disposal. The respondents were 236 nurses working with chemotherapy in wards and outpatient clinics in five hospitals in and near Seoul. Safety regulations provided for the anticancer drug the Occupational Safety Health Administration (OSHA, 1999), as modified for an earlier study, were used. The results showed that the level of awareness and performance on the anticancer drug safety regulations indicate their preparation (3.38+/-0.55, 2.38+/-0.98), administration (3.52+/-0.46, 3.17+/-0.70), general handling and disposal (3.33+/-0.54, 2.42+/ 0.90) on a scale 0 to 5. Also, there were significant differences in job positions, work experience, type of preparation, and continuing education and a positive relationship between the level of awareness and nursing performance. Thus, nurses should receive continuing education on the handling of anticancer drugs to improve the level of performance following safety regulations. PMID- 25921122 TI - 2-deoxy-D-Glucose Synergizes with Doxorubicin or L-Buthionine Sulfoximine to Reduce Adhesion and Migration of Breast Cancer Cells. AB - BACKGROUND: Cancer metastasis depends on cell motility which is driven by cycles of actin polymerization and depolymerization. Reactive oxygen species (ROS) and metabolic oxidative stress have long been associated with cancer. ROS play a vital role in regulating actin dynamics that are sensitive to oxidative modification. The current work aimed at studying the effects of sub-lethal metabolic oxidative stress on actin cytoskeleton, focal adhesion and cell migration. MATERIALS AND METHODS: T47D human breast cancer cells were treated with 2-deoxy- D-glucose (2DG), L-buthionine sulfoximine (BSO), or doxorubicin (DOX), individually or in combination, and changes in intracellular total glutathione and malondialdehyde (MDA) levels were measured. The expression of three major antioxidant enzymes was studied by immunoblotting, and cells were stained with fluorescent- phalloidin to evaluate changes in F-actin organization. In addition, cell adhesion and degradation ability were measured. Cell migration was studied using wound healing and transwell migration assays. RESULTS: Our results show that treating T47D human breast cancer cells with drug combinations (2DG/BSO, 2DG/DOX, or BSO/DOX) decreased intracellular total glutathione and increased oxidized glutathione, lipid peroxidation, and cytotoxicity. In addition, the drug combinations caused a reduction in cell area and mitotic index, prophase arrest and a decreased ability to form invadopodia. The formation of F-actin aggregates was increased in treated T47D cells. Moreover, combination therapy reduced cell adhesion and the rate of cell migration. CONCLUSIONS: Our results suggest that exposure of T47D breast cancer cells to combination therapy reduces cell migration via effects on metabolic oxidative stress. PMID- 25921123 TI - Laparoscopic Retroperitoneal Nephroureterectomy is a Safe and Adherent Modality for Obese Patients with Upper Urinary Tract Urothelial Carcinoma. AB - OBJECTIVE: We evaluated the association of body mass index (BMI) with perioperative outcomes in patients who underwent laparoscopic or open radical nephroureterectomy. MATERIALS AND METHODS: This retrospective single-center study included 113 patients who had been diagnosed with upper urinary tract cancer from January 1998 to June 2013 and were treated with laparoscopic nephroureterectomy (Lap group, n=60) or open nephroureterectomy (Open group, n=53). Laparoscopic nephroureterectomy was performed via a retroperitoneal approach following an open partial cystectomy. The two surgical groups were stratified into a normal-BMI group (<25) and a high-BMI group (BMI>=25). The high-BMI group included 27 patients: 13 in the Lap group and 14 in the Open group. RESULTS: Estimated blood loss (EBL) in the Lap group was much lower than that in the Open group irrespective of BMI (p<0.01). Operative time was significantly prolonged in normal-BMI patients in the Lap group compared to those in the Open group (p=0.03), but there was no difference in operative time between the Open and Lap groups among the high-BMI patients. Multivariate logistic regression analysis of the data for all the cohorts revealed that the open procedure was a significant risk factor for high EBL (p<0.0001, hazard ratio 8.02). Normal BMI was an independent predictor for low EBL (p=0.01, hazard ratio 0.25). There was no significant risk factor for operative time in multivariate analysis. There were no differences in blood transfusion rates or adverse event rates between the two surgical groups. CONCLUSIONS: Laparoscopic radical nephroureterectomy via a retroperitoneal approach can be safely performed with significantly reduced EBL even in obese patients with upper urinary tract cancer. PMID- 25921124 TI - Ultrasonographic features of triple-negative breast cancer: a comparison with other breast cancer subtypes. AB - BACKGROUND: Triple-negative breast cancer (TNBC) is known to be associated with aggressive biologic features and a poor clinical outcome. Therefore, early detection of TNBC without missed diagnosis is a requirement to improve prognosis. Preoperative ultrasound features of TNBC may potentially assist in early diagnosis as characteristics of disease. PURPOSE: To retrospectively evaluate the sonographic features of TNBC compared to ER (+) cancers which include HER(-) and HER2 (+), and HER2 (+) cancers which are ER (-). MATERIALS AND METHODS: From June 2012 through June 2014, sonographic features of 321 surgically confirmed ER (+) cancers (n=214), HER2 (+) cancers (n=66), and TNBC (n=41) were retrospectively reviewed by two ultrasound specialists in consensus. The preoperative ultrasound and clinicopathological features were compared between the three subtypes. In addition, all cases were analyzed using morphologic criteria of the ACR BI-RADS lexicon. RESULTS: Ultrasonographically, TNBC presented as microlobulated nodules without microcalcification (p=0.034). A lower incidence of ductal carcinoma in situ (p<0.001), invasive tumor size that is>2 cm (p=0.011) and BI-RADS category 4 (p<0.001) were significantly associated with TNBC. With regard to morphologic features of 41 TNBC cases, ultrasonographically were most likely to be masses with irregular (70.7%) microlobulated shape (48.8%), be circumscribed (17.1%) or have indistinct margins (17.1%) and parallel orientation (68.9%). Especially TNBC microlobulated mass margins were more more frequent than with ER (+) (2.0%) and HER2 (+) (4.8%) cancers. CONCLUSIONS: TNBC have specific characteristic in sonograms. Ultrasonography may be useful to avoid missed diagnosis and false negative cases of TNBC. PMID- 25921125 TI - Depression and the risk of breast cancer: a meta-analysis of cohort studies. AB - BACKGROUND: Whether depression causes increased risk of the development of breast cancer has long been debated. We conducted an updated meta-analysis of cohort studies to assess the association between depression and risk of breast cancer. MATERIALS AND METHODS: Relevant literature was searched from Medline, Embase, Web of Science (up to April 2014) as well as manual searches of reference lists of selected publications. Cohort studies on the association between depression and breast cancer were included. Data abstraction and quality assessment were conducted independently by two authors. Random-effect model was used to compute the pooled risk estimate. Visual inspection of a funnel plot, Begg rank correlation test and Egger linear regression test were used to evaluate the publication bias. RESULTS: We identified eleven cohort studies (182,241 participants, 2,353 cases) with a follow-up duration ranging from 5 to 38 years. The pooled adjusted RR was 1.13(95% CI: 0.94 to 1.36; I2=67.2%, p=0.001). The association between the risk of breast cancer and depression was consistent across subgroups. Visual inspection of funnel plot and Begg's and Egger's tests indicated no evidence of publication bias. Regarding limitations, a one-time assessment of depression with no measure of duration weakens the test of hypothesis. In addition, 8 different scales were used for the measurement of depression, potentially adding to the multiple conceptual problems concerned with the definition of depression. CONCLUSIONS: Available epidemiological evidence is insufficient to support a positive association between depression and breast cancer. PMID- 25921126 TI - Results of Intravesical Chemo-Hyperthermia in High-risk Non-muscle Invasive Bladder Cancer. AB - PURPOSE: To examine the effectiveness of mitomycin-C and chemo-hyperthermia in combination for patients with high-risk non-muscle-invasive bladder cancer. MATERIALS AND METHODS: Between November 2011-September 2013, 43 patients with high-risk non-muscle-invasive bladder cancer undergoing adjuvant chemo hyperthermia in two centers were evaluated retrospectively. Treatment consisted of 6 weekly sessions, followed by 6 sessions. Recurrence and progression rate, recurrence-free interval and side effects were examined. Analyzed factors included age, gender, smoking status, AB0 blood group, body mass index, T stage and grade, concominant CIS assets. The associations between predictors and recurrence were assessed using multivariate Cox proportional hazard analyses. RESULTS: A total of 40 patients completed induction therapy. Thirteen (32.5%) were diagnosed with tumor recurrence. Median follow-up was 30 months (range 9 39). Median recurrence-free survival was 23 months (range 6-36). The Kaplan-Meier estimated recurrence-free rates for the entire group at 12 and 24 months were 82% and 61%. There was no statistically significant difference between patient subgroups. Cox hazard analyses showed that an A blood type (OR=6.23, p=0.031) was an independent predictor of recurrence- free. Adverse effects were seen in 53% of patients and these were frequently grades 1 and 2. CONCLUSIONS: Intravesical therapy with combination of mitomycin-C and chemohyperthermia seems to be appropriate in high-risk patients with non-muscle-invasive bladder cancer who cannot tolerate or have contraindications for standard BCG therapy. PMID- 25921127 TI - Lay beliefs, knowledge, and attitudes towards cancer: a pilot study in Japan. AB - BACKGROUND: The attendance rates for cancer screening are low in Japan. Little is actually known about how the Japanese perceive cancer. Since beliefs about illness affect individuals' health care practice, the aim of this study was to explore beliefs about cancer and factors associated with those beliefs, focusing on representative cancer sites. MATERIALS AND METHODS: Japanese adults (>=20 years old) who had not been diagnosed with any cancers and were not health care professionals were recruited, using a convenience sampling approach. A total of 91 participants completed questionnaires including open-ended questions. Thematic analysis was used to analyze the responses. RESULTS: Five themes were suggested: (i) a threatening illness that might greatly change one's future life; (ii) basic cancer knowledge; (iii) a curable illness with early detection and adequate treatment; (iv) causes of cancer; and (v) anyone can develop cancer. Families or friends' negative consequences of cancer were associated with negative beliefs about the disease. Gestational cancer was the most representative site of most themes. CONCLUSIONS: A threatening illness (e.g., death or incurable illness) was the most common belief among the Japanese laypeople. Importance of early detection and treatments should be more emphasized, and future screening programs should include strategies modifying negative cancer beliefs among Japanese laypeople. PMID- 25921128 TI - CYP2C19 Genotype Could be a Predictive Factor for Aggressive Manifestations of Hepatocellular Carcinoma Related with Chronic Hepatitis B Infection in Thailand. AB - BACKGROUND: Chronic hepatitis B virus (HBV) infection related hepatocellular carcinoma (HCC) is a major health problem in the Asia-Pacific region including Thailand. Several factors have been proposed as contributing to hepatocarcinogenesis. This study was aimed to investigate the impact of CYP2C19 genotypic polymorphism in HCC related to chronic HBV infection in Thailand. MATERIALS AND METHODS: A cross-sectional study was performed between April 2014 and January 2015. Chronic HBV patients with HCC (n=50) and without HCC (n=50) were included. Clinical information and blood samples of all patients were collected. The CYP2C19 genotype was determined by polymerase chain reaction restriction fragment length polymorphism method, and was classified as rapid metabolizer (RM), intermediate metabolizer (IM) or poor metabolizer (PM). RESULTS: The CYP2C19 genotype frequencies of RM, IM and PM in HBV patients were found to be 19/50 (38%), 25/50 (50%) and 6/50 (12%), respectively. The CYP2C19 genotype frequencies of RM, IM and PM in HBV with HCC patients were 21/50 (42%), 25/50 (50%) and 4/50 (8%), respectively. The distribution of CYP2C19 genotype was not different between patients with and without HCC. Interestingly, among HBV with HCC patients, the RM genotype of CYP2C19 tended to increase risk of aggressive manifestation (OR=2.89, 95%CI=0.76-11.25, P-value = 0.07), compared with non RM genotype carriers. CONCLUSIONS: CYP2C19 genotype IM was the most common genotype in Thai patients with chronic HBV infection. In addition, genotype RM could be an associated factor for aggressive presentation in HCC related to chronic HBV infection. PMID- 25921129 TI - Adjuvant Radiotherapy after Breast Conserving Treatment for Breast Cancer: A Dosimetric Comparison between Volumetric Modulated Arc Therapy and Intensity Modulated Radiotherapy. AB - BACKGROUND: Radiotherapy is an important treatment of choice for breast cancer patients after breast- conserving surgery, and we compare the feasibility of using dual arc volumetric modulated arc therapy (VMAT2), single arc volumetric modulated arc therapy (VMAT1) and Multi-beam Intensity Modulated Radiotherapy (M IMRT) on patients after breast-conserving surgery. MATERIALS AND METHODS: Thirty patients with breast cancer (half right-sided and half left-sided) treated by conservative lumpectomy and requiring whole breast radiotherapy with tumor bed boost were planned with three different radiotherapy techniques: 1) VMAT1; 2) VMAT2; 3) M-IMRT. The distributions for the planning target volume (PTV) and organs at risk (OARs) were compared. Dosimetries for all the techniques were compared. RESULTS: All three techniques satisfied the dose constraint well. VMAT2 showed no obvious difference in the homogeneity index (HI) and conformity index (CI) of the PTV with respect to M-IMRT and VMAT1. VMAT2 clearly improved the treatment efficiency and can also decrease the mean dose and V5Gy of the contralateral lung. The mean dose and maximum dose of the spinal cord and contralateral breast were lower for VMAT2 than the other two techniques. The very low dose distribution (V1Gy) of the contralateral breast also showed great reduction in VMAT2 compared with the other two techniques. For the ipsilateral lung of right-sided breast cancer, the mean dose was decreased significantly in VMAT2 compared with VMAT1 and M-IMRT. The V20Gy and V30Gy of the ipsilateral lung of the left- sided breast cancer for VMAT2 showed obvious reduction compared with the other two techniques. The heart statistics of VMAT2 also decreased considerably compared to VMAT1 and M-IMRT. CONCLUSIONS: Compared to the other two techniques, the dual arc volumetric modulated arc therapy technique reduced radiation dose exposure to the organs at risk and maintained a reasonable target dose distribution. PMID- 25921130 TI - Comparative Effectiveness of Risk-adapted Surveillance vs Retroperitoneal Lymph Node Dissection in Clinical Stage I Nonseminomatous Germ Cell Testicular Cancer: A Retrospective Follow-up Study of 81 Patients. AB - PURPOSE: To retrospective assess the potential predictors for relapse and create an effective clinical mode for surveillance after orchidectomy in clinical stage I non-seminomatous germ cell testicular tumors (CSI-NSGCTs). MATERIALS AND METHODS: We analyzed data for CSI-NSGCTs patients with non-lymphatic vascular invasion, %ECa < 50% (percentage of embryonal carcinoma < 50%), and negative or declining tumor markers to their half-life following orchidectomy (defined as low risk patients); these patients were recruited from four Chinese centers between January 1999 and October 2013. Patients were divided into active surveillance group and retroperitoneal lymph node dissection (RPLND) group according to different therapeutic methods after radical orchidectomy was performed. The disease-free survival rates (DFSR) and overall survival rates (OSR) of the two groups were compared by Kaplan-Meier analysis. RESULTS: A total of 121 patients with CSI-NSGCT were collected from four centers, and 81 low-risk patients, including 54 with active surveillance and 27 with RPLND, were enrolled at last. The median follow-up duration was 66.2 (range 6-164) months in the RPLND group and 65.9 (range 8-179) months in the surveillance group. OSR was 100% in active surveillance and RPLND groups, and DFSR was 89.8% and 87.0%, respectively. No significant difference was observed between these two groups (X2=0.108, P=0.743). No significant difference was observed between the patients with a low percentage of embryonal carcinoma (<50%) and those without embryonal carcinoma (87.0% and 91.9%, X2=0.154, P=0.645). No treatment-related complications were observed in the active surveillance group whereas minor and major complications were observed in 13.0% and 26.1% of the RPLND group, respectively. CONCLUSIONS: Active surveillance resulted in similar DFSR and OSR compared with RPLND in our trial. Patients with low-risk CSI-NSGCTs could benefit from risk-adapted surveillance after these patients were subjected to radical orchidectomy. PMID- 25921131 TI - Application of a Network Scale-up Method to Estimate the Size of Population of Breast, Ovarian/Cervical, Prostate and Bladder Cancers. AB - Network scale up (NSU) is a novel approach to estimate parameters in hard to reach populations through asking people the number of individuals they know in their active social network. Although the method have been used in hidden populations, advantages of NSU indicate that exploration of applicability to disease like cancer might be feasible. The aim of this study was to assess the application of NSU to estimate the size of the population of breast, ovarian/cervical, prostate, and bladder cancers in the South-east of Iran. A total of 3,052 (99% response rate) Kermanian people were interviewed in 2012 2013. Based on NSU, participants were asked about if they know any people on their social network who suffered from breast, ovarian/cervical, prostate, and bladder cancers, if yes, they should enumerate them. A total of 1,650 persons living with four types of cancers (breast, ovary/cervix, prostate, and bladder) were identified by the respondents. Totally, the prevalence of people living with the four types of cancers was 228.4 per 100,000 Kermanian inhabitants. The most prevalent cancer was breast cancer, at 168.9 per 100,000, followed by prostate cancer with 116.9, ovarian/cervical cancer with 99.8, and bladder cancer with 36.3 per 100000 Kerman city population. NSU values provide a usable but not very precise way of estimating the size of subpopulations in the context of the four major cancers (breast, ovary/ cervix, prostate, and bladder). PMID- 25921133 TI - Association of XRCC1 Arg399Gln Polymorphism with Colorectal Cancer Risk: A HuGE Meta Analysis of 35 Studies. AB - BACKGROUND: Non-synonymous polymorphisms in XRCC1 hase been shown to reduce effectiveness of DNA repair and be associated with risk of certain cancers. In this study we aimed to clarify any association between XRCC1 Arg399Gln and colorectal cancer (CRC) risk by performing a meta-analysis of published case control studies. MATERIALS AND METHODS: PubMed and Google Scholar were searched to explore the association between XRCC1 and CRC. Odds ratios (ORs) and 95% confidence intervals (CIs) were calculated to estimate the association strength. Publication bias was assessed by Egger's and Begg's tests. RESULTS: Up to January 2015, 35 case control studies involving 9,114 CRC cases and 13,948 controls were included in the present meta-analysis. The results showed that the Arg399Gln polymorphism only under an allele genetic model was associated with CRC risk (A vs. G: OR 0.128, 95% CI 0.119-0.138, p<0.001). Also, this meta-analysis suggested that the XRCC1 Arg399Gln polymorphism might associated with susceptibility to CRC in Asians (A vs G: OR 0.124, 95% CI 0.112-0.138, p<0.001) and Caucasian (A vs G: OR 0.132, 95% CI 0.119-0.146, p<0.001) only under an allele genetic model. CONCLUSIONS: This meta-analysis confirms the association between XRCC1 Arg399Gln polymorphism and CRC risk and suggests that the heterogeneity is not strongly modified by ethnicity and deviation from the Hardy-Weinberg equilibrium. PMID- 25921132 TI - Characteristics of young colorectal cancer in Brunei Darussalam: an epidemiologic study of 29 years (1986-2014). AB - BACKGROUND: Colorectal cancer (CRC) is the most common gastrointestinal cancer and the incidence is increasing. CRC is more common with increasing age, but a proportion occurs in young adults, termed young CRC. This study assessed the incidence and the demographic of young CRC in Brunei Darussalam. MATERIALS AND METHODS: All histologically proven CRC between 1986 and 2014 registered with the Department of Pathology cancer registry were reviewed and data extracted for analyses. Young CRC was defined as cancer in patients aged less than 45 years. The various population groups were categorized into locals (Malays, Chinese and Indigenous) and expatriates. RESULTS: Over the study period, there were 1,126 histologically proven CRC (mean age 59.1 +/- 14.7 years, Male 58.0%, Locals 91.8% and 8.2% expatriates). Young CRC accounted for 15.1% with the proportion declining over the years, from 29% (1986-1990) to 13.2% (2011-2014). The proportion of young CRC was highest among the indigenous (30.8%), followed by the expatriates (29.3%), Malays (14.3%) and lowest among the Chinese (10.8%). The mean age of young CRC was 35.9 +/- 6.2; lowest among the indigenous (33.5 +/- 6.7), expatriate (34.9 +/- 6.0) groupd and the Malays (35.6 +/- 6.5) compared to the Chinese (38.6 +/- 4.6), a similar trend being observed in the non-young CRC groups. There were no difference between the genders and tumor locations (rectum or colon) between the young and the non-young CRC cases. Female young CRC was significantly younger than male (p<0.05) without any significant variation between the various population groups (p>0.05). CONCLUSIONS: Our study showed that the young CRC accounted for 15.1% of all CRC with declining trend observed over recent years. Young CRC was more common among indigenous, expatriates and Malays and least common among the Chinese. There were no differences in the gender and tumor locations. PMID- 25921134 TI - ALEX1 Regulates Proliferation and Apoptosis in Breast Cancer Cells. AB - BACKGROUND: Arm protein lost in epithelial cancers, on chromosome X (ALEX) is a novel subgroup within the armadillo (ARM) family, which has one or two ARM repeat domains as opposed to more than six-thirteen repeats in the classical Armadillo family members. MATERIALS AND METHODS: In the study, we explore the biological functions of ALEX1 in breast cancer cells. Overexpression of ALEX1 and silencing of ALEX1 were performed with SK-BR3 and MCF-7 cell lines. Cell proliferation and colony formation assays, along with flow cytometry, were carried out to evaluate the roles of ALEX1. RESULTS: ALEX1 overexpression in SK-BR3 breast cancer cells inhibited proliferation and induced apoptosis. Furthermore, depletion of ALEX1 in MCF-7 breast cancer cells increased proliferation and inhibited apoptosis. Additional analyses demonstrated that the overexpression of ALEX1 activated the intrinsic apoptosis cascades through up-regulating the expression of Bax, cytosol cytochrome c, active caspase-9 and active caspase-3 and down-regulating the levels of Bcl-2 and mitochondria cytochrome c. Simultaneouly, silencing of ALEX1 inhibited intrinsic apoptosis cascades through down-regulating the expression of Bax, cytosol cytochrome c, active caspase-9, and active caspase-3 and up regulating the level of Bcl-2 and mitochondria cytochrome c. CONCLUSIONS: Our data suggest that ALEX1 as a crucial tumor suppressor gene has been involved in cell proliferation and apoptosis in breast cancer, which may serve as a novel candidate therapeutic target. PMID- 25921135 TI - Knocking Down Nucleolin Expression Enhances the Radiosensitivity of Non-Small Cell Lung Cancer by Influencing DNA-PKcs Activity. AB - Nucleolin (C23) is an important anti-apoptotic protein that is ubiquitously expressed in exponentially growing eukaryotic cells. In order to understand the impact of C23 in radiation therapy, we attempted to investigate the relationship of C23 expression with the radiosensitivity of human non-small cell lung cancer (NSCLC) cells. We investigated the role of C23 in activating the catalytic subunit of DNA-dependent protein kinase (DNA- PKcs), which is a critical protein for DNA double-strand breaks (DSBs) repair. As a result, we found that the expression of C23 was negatively correlated with the radiosensitivity of NSCLC cell lines. In vitro clonogenic survival assays revealed that C23 knockdown increased the radiosensitivity of a human lung adenocarcinoma cell line, potentially through the promotion of radiation-induced apoptosis and adjusting the cell cycle to a more radiosensitive stage. Immunofluorescence data revealed an increasing quantity of gamma-H2AX foci and decreasing radiation-induced DNA damage repair following knockdown of C23. To further clarify the mechanism of C23 in DNA DSBs repair, we detected the expression of DNA-PKcs and C23 proteins in NSCLC cell lines. C23 might participate in DNA DSBs repair for the reason that the expression of DNA-PKcs decreased at 30, 60, 120 and 360 minutes after irradiation in C23 knockdown cells. Especially, the activity of DNA-PKcs phosphorylation sites at the S2056 and T2609 was significantly suppressed. Therefore we concluded that C23 knockdown can inhibit DNA-PKcs phosphorylation activity at the S2056 and T2609 sites, thus reducing the radiation damage repair and increasing the radiosensitivity of NSCLC cells. Taken together, the inhibition of C23 expression was shown to increase the radiosensitivity of NSCLC cells, as implied by the relevance to the notably decreased DNA-PKcs phosphorylation activity at the S2056 and T2609 clusters. Further research on targeted C23 treatment may promote effectiveness of radiotherapy and provide new targets for NSCLC patients. PMID- 25921136 TI - Stromal modulation and its role in the diagnosis of papillary patterned thyroid lesions. AB - The papillary patterned lesion of thyroid may be challenging with many diagnostic pitfalls. Tumor stroma plays an important part in the determination of the tumor phenotype. CD34 is thought to be involved in the modulation of cell adhesion and signal transduction as CD34(+) fibrocytes are potent antigen-presenting cells. Smooth muscle actin (SMA) positivity could be diagnostic for fibroblast activation during tumorigenesis. We aimed to examine the expression of CD34 and alphaSMA in the stroma of papillary thyroid hyperplasia, papillary thyroid carcinoma and papillary tumors of uncertain malignant potential in order to elucidate their possible differential distribution and roles. A total number of 54 cases with papillary thyroid lesions were studied by routine HandE staining, CD34 and ASMA immunostaining. ASMA was not expressed in benign papillary hyperplastic lesions while it was expressed in papillary carcinoma, indicating that tumors have modulated stroma. Although the stroma was not well developed in papillary lesions with equivocal features of uncertain potentiality, CD34 was notable in such cases with higher incidence in malignant cases. So ASMA as well as CD34 could predict neoplastic behavior, pointing to the importance of the stromal role. Differences between groups suggest that the presence of CD34 + stromal cells is an early event in carcinogensis and is associated with neoplasia, however ASMA+ cells are more likely to be associated with malignant behavior and metastatic potential adding additional tools to the light microscopic picture helping in diagnosis of problematic cases with HandE. PMID- 25921137 TI - Caregiver Burden and Perceived Social Support among Caregivers of Patients with Cancer. AB - The purpose of this study is to describe the relationship between caregiver burden and perceived social support among caregivers of patients with cancer. The research was conducted in a university hospital in Izmir, Turkey. Eighty patient relatives who provided care service to patients with cancer who were admitted at hematology and oncology clinics participated in the study. The findings indicated that the care burden score was mild level. The mean of the perceived social support score was 58.4+/-21.0 supporting the conclusion that there is a weak and negative-direct relation between caregiver and perceived social support and that as the perceived social support increased, conversely, care burden decreased. PMID- 25921138 TI - Impact of smoking cessation training for community pharmacists in Indonesia. AB - BACKGROUND: Community pharmacists play an important role in tobacco control and adequate training on smoking cessation is essential. MATERIALS AND METHODS: A quasi-experimental pre-test/post-test design was used. A one-day workshop on smoking cessation organized by Indonesian Pharmacists Association as part of PCE program was offered to 133 community pharmacists. The workshop consisted of a 3 hour lecture and a 3-hour role-play session. Pre-training and post-training surveys assessed the impact of training on parameters including knowledge, perceived role and self-efficacy with respect to smoking cessation counseling practices. Intention and ability to perform counseling using the 5A framework was assessed after training only. RESULTS: After PCE, knowledge score significantly increased from 24.9+/-2.58 to 35.7+/-3.54 (p<0.001). Perceived role and self efficacy in smoking cessation counseling also significantly increased from 25.8+/ 2.73 to 28.7+/-2.24, and 27.6+/-4.44 to 32.6+/-3.63, respectively (p<0.001). After the workshop, most participants were willing to ask, advise, and assess patients who ready to quit, but were still less likely to assist in quitting plans and arranging follow up counseling. More than 75% pharmacists were able to perform cessation counseling and 65% of them can completely perform a 5A brief intervention. CONCLUSIONS: PCE can enhance pharmacists' knowledge, perceived role, self-efficacy in cessation counseling practices, and create willingness and ability to perform cessation counseling. Future training is recommended to improve skills in assisting quitting plans and arranging follow up. PMID- 25921139 TI - Aberrant expression of pim-3 promotes proliferation and migration of ovarian cancer cells. AB - Pim kinase-3(Pim-3), a member of serine/threonine protein kinases, has been implicated in multiple human cancers and involved in Myc-induced tumorigenesis. However, little is known regarding its expression and biological function in human ovarian cancer. In this study we showed that the clinical significance and biological functions of Pim-3 in ovarian cancer and found that higher Pim-3 mRNA level are detected in ovarian cancer tissues than those in normal ovarian tissues. There are significant correlations between higher Pim-3 expression levels with the FIGO stage, histopathological subtypes, and distant metastasis in ovarian cancer patients. Lentivirus-mediated gene overexpression of Pim-3 significantly promotes the proliferation and migration of SKOV3 cell lines. Furthermore, MACC1 and Pim-3 expression were significantly correlated in human ovarian cancer cells, and overexpression of Pim-3 in ovary cancer cells increased MACC1 mRNA and protein expression. The data indicate that Pim-3 acts as a putative oncogene in ovary cancer and could be a viable diagnostic and therapeutic target for ovarian cancer. PMID- 25921140 TI - Imaging Anatomy of Waldeyer's Ring and PET/CT and MRI Findings of Oropharyngeal Non-Hodgkin's Lymphoma. AB - BACKGROUND: This study was conducted to analyze positron emission tomography (PET) / computed tomography (CT) and magnetic resonance imaging (MRI) performance with oropharyngeal non-Hodgkin's lymphoma (ONHL). MATERIALS AND METHODS: The complete image data of 30 ONHL cases were analyzed, all patients were performed PET / CT and MRI examination before the treatment, with the time interval of these two inspections not exceeding 14 days. The distribution, morphology, MRI signal characteristics, enhancement feature, standardized uptake value (SUV) max value and lymph node metastasis way of the lesions were analyzed. RESULTS: Among the 30 cases, 23 cases were derived from the B-cell (76.7%), 5 cases were derived from the peripheral T cells (16.7%) and 2 cases were derived from the NK/T cells (6.7%). 19 cases exhibited the palatine tonsil involvement (63.3%). As for the lesion appearance, 10 cases appeared as mass, 8 cases were the diffused type and 12 cases were the mixed type. 25 cases exhibited the SUVmax value of PET / CT primary lesions as 11 or more (83.3%). MRI showed that all patients exhibited various degrees of parapharyngeal side-compressed narrowing, but MRI still exhibited the high-signal fat, and the oropharyngeal mucosa was intact. 25 cases were associated with the neck lymph node metastasis, among who 22 cases had no necrosis in the metastatic lymph nodes, while the rest 3 cases exhibited the central necrosis in the metastatic lymph nodes. CONCLUSIONS: PET / CT and MRI have important value in diagnosing and determining the lesion extent of ONHL. PMID- 25921141 TI - Single nucleotide polymorphisms in the Gc gene for vitamin D binding protein in common cancers in Thailand. AB - BACKGROUND: This case-control study aimed to determine if there were any associations between the two single nucleotide polymorphisms (SNPs) in Gc, rs7041 (Asp416Glu) and rs4588 (Thr420Lys) and 3 common cancers (breast, lung and colorectal) in Thai patients. MATERIALS AND METHODS: Two hundred and eighty two colorectal, 101 breast and 113 lung cancer patients were recruited from one institute during 2011-2013. The controls were age-matched volunteers who had a negative history of index cancers. In addition, vitamin D levels were compared among different genotypes in the 2 SNPs. RESULTS: The minor allele frequencies of rs7041 (G) and rs4588 (A) were 0.32 and 0.24, respectively. Under the dominant model, the study found significant associations between minor-allele genotypes of the SNP rs7041 (TG/GG) and lung cancer (odds ratio [OR] 1.78, 95% CI 1.05-3.03). When subgroup analysis was performed according to sex and age at diagnosis, the study found that the minor- allele genotypes of rs7041 (TG/GG) were significantly associated with colorectal cancer in patients whose age at diagnosis was more than 60 years (OR 1.67, 95%CI 1.06-2.61) and the minor-allele genotypes of rs4588 (CA/AA) were significantly associated with colorectal cancer in males aged 60 years or less (OR 2.34, 95%CI 1.25-4.37). When SNP combinations (rs7041-rs4588) were examined, the TT-CA combination had a significant protective association with lung cancer (OR 0.44, 95% CI 0.22-0.85). On evaluation of serum 25(OH)D levels in 205 individuals without cancer (males 144, females 61), the proportion of subjects with low serum vitamin D (< 20 ng/ml) in those harboring CA or AA genotypes of rs4588 (41.7%) was significantly higher than the CC genotype (15.5%, p-value < 0.01). CONCLUSIONS: Genetic polymorphisms in Gc were associated with lung and colorectal cancers in Thai patients. Lower serum 25(OH)D in minor variants of rs4588 may explain this association. PMID- 25921142 TI - Evaluation of Health-Related Quality of Life among Patients with Cervical Cancer in Indonesia. AB - BACKGROUND: Evaluation of health-related quality of life (HRQOL) in cervical cancer patients is important in order to design the interventions for improving patient outcomes. Reports of HRQOL among cervical cancer patients in Indonesia are limited. Moreover, measurement using EQ-5D-3L is to our best knowledge has hitherto not been performed. This study aimed to examine the HRQOL of cervical cancer patients in Indonesia using EQ- 5D-3L. MATERIALS AND METHODS: A cross sectional study was conducted by interviewing cervical cancer patients using the EQ-5D-3L questionnaire. Percentages of patients who reported having problems in each dimension of EQ-5D as well as EQ-5D index score (utility) were calculated. RESULTS: Our findings indicated that the most frequent reported problems were pain/discomfort (67.8%) followed by anxiety/depression (57.5%). The mean of EQ-5D VAS was 75.8 (SD=17.0). The mean (SD) utility scores were 0.85 (0.19), 0.76 (0.20), 0.71 (0.21), and 0.77 (0.13) for cervical cancer patients in stage I, II, III, and IV, respectively. CONCLUSIONS: Cervical cancer significantly affects patient HRQOL. Efforts should be made to improve the quality of life of cervical cancer patients especially in terms of pain /discomfort and anxiety/depression reduction. PMID- 25921143 TI - Replacing actinomycin-D with Carboplatin for newly diagnosed rhabdomyosarcoma. AB - BACKGROUND: Rhabdomyosarcoma (RMS) is the most common soft tissue sarcoma in the pediatric age group. All patients with RMS regardless of their initial stage or group receive combination chemotherapy as 'standard therapy' consisting of vincristine, actinomycin-D and cyclophosphamide. Actinomycin-D was not readily available in Turkey at one time. Carboplatin was used instead in order to prevent delays in treatment. The aim of this report is to present the results of patients with rhabdomyosarcoma receiving carboplatin or actinomycin-D therapy. MATERIALS AND METHODS: Twenty four patients with rhabdomyosarcoma treated between December 2000 and June 2011 were included in this retrospective study. The patients were treated according to International Rhabdomyosarcoma Study Group guidelines. Eleven patients were treated with actinomycin-D and 13 with carboplatin (250 mg/m2/dose for 2 days). The two groups were then compared in terms of 2- and 5 year overall survival (OS) and hematological and non-hematological toxicities. RESULTS: Age, sex, stage and the mean duration of follow-up were similar in both groups (p>0.05 ). Two- and five-year OS levels were 68.2% in the carboplatin group and 78.0% and 40.0%, respectively, in the actinomycin-D group. There was no statistical difference in the number of febrile episodes (p=0.86 ) and no other hematological and non-hematological adverse effects were recorded in both groups. CONCLUSIONS: The findings show that carboplatin can be used as an alternative drug in the primary treatment of rhabdomyosarcoma in the event that actinomycin-D is unavailable or not tolerated. PMID- 25921144 TI - Expression Profile Analysis of Zinc Transporters (ZIP4, ZIP9, ZIP11, ZnT9) in Gliomas and their Correlation with IDH1 Mutation Status. AB - BACKGROUND: Zinc transporters have been considered as essential regulators in many cancers; however, their mechanisms remain unknown, especially in gliomas. Isocitrate dehydrogenase 1(IDH1) mutation is crucial to glioma. This study aimed to investigate whether zinc transporters are correlated with glioma grade and IDH1 mutation status. MATERIALS AND METHODS: IDH1 mutation status and mRNA expression of four zinc transporters (ZIP4, ZIP9, ZIP11, and ZnT9) were determined by subjecting a panel of 74 glioma tissue samples to quantitative real time PCR and pyrosequencing. The correlations between the expression levels of these zinc transporter genes and the grade of glioma, as well as IDH1 mutation status, were investigated. RESULTS: Among the four zinc transporter genes, high ZIP4 expression and low ZIP11 expression were significantly associated with higher grade (grades III and IV) tumors compared with lower grade (grades I and II) counterparts (p<0.0001). However, only ZIP11 exhibited weak correlation with IDH1 mutation status (p=0.045). Samples with mutations in IDH1 displayed higher ZIP11 expression than those without IDH1 mutations. CONCLUSIONS: This finding indicated that zinc transporters may interact with IDH1 mutation by direct modulation or action in some shared pathways or genes to promote the development of glioma. Zinc transporters may play an important role in glioma. ZIP4 and ZIP11 are promising molecular diagnostic markers and novel therapeutic targets. Nevertheless, the detailed biological function of zinc transporters and the mechanism of the potential interaction between ZIP11 and IDH1 mutation in gliomagenesis should be further investigated. PMID- 25921145 TI - Risk Factors for Nodal Metastasis in cN0 Papillary Thyroid Microcarcinoma. AB - BACKGROUND: Despite the majority of papillary thyroid microcarcinoma (PTMC) patients having an excellent prognosis, cervical lymph node metastases are common. The purpose of this study was to investigate the incidence and the predictive risk factors for occult central compartment lymph node metastasis (CLNM) in PTMC patients. MATERIALS AND METHODS: 178 patients with clinically node negative (cN0) PTMC undergoing prophylactic central compartment neck dissection in our hospital from January 2008 to Jun 2010 were enrolled. The relationship between CLNM and the clinical and pathological factors such as gender, age, tumor size, tumor number, tumor location, extracapsular spread (ECS), and coexistance of chronic lymphocytic thyroiditis was analyzed. RESULTS: Occult CLNM was observed in 41% (73/178) of PTMC patients. Multivariate analysis showed that male gender, tumor size (>=6mm) and ECS were independent variables predictive of CLNM in PTMC patients. CONCLUSIONS: Male gender, tumor size (>=6mm) and ECS were risk factors of CLNM. We recommend a prophylactic central lymph node dissection (CLND) should be considered in PTMC patients with such risk factors. PMID- 25921146 TI - Comparison of three dimensional conformal radiation therapy, intensity modulated radiation therapy and volumetric modulated arc therapy for low radiation exposure of normal tissue in patients with prostate cancer. AB - Radiotherapy has an important role in the treatment of prostate cancer. Three dimensional conformal radiation therapy (3D-CRT), intensity modulated radiation therapy (IMRT) and volumetric modulated arc therapy (VMAT) techniques are all applied for this purpose. However, the risk of secondary radiation-induced bladder cancer is significantly elevated in irradiated patients compared surgery only or watchful waiting groups. There are also reports of risk of secondary cancer with low doses to normal tissues. This study was designed to compare received volumes of low doses among 3D-CRT, IMRT and VMAT techniques for prostate patients. Ten prostate cancer patients were selected retrospectively for this planning study. Treatment plans were generated using 3D-CRT, IMRT and VMAT techniques. Conformity index (CI), homogenity index (HI), receiving 5 Gy of the volume (V5%), receiving 2 Gy of the volume (V2%), receiving 1 Gy of the volume (V1%) and monitor units (MUs) were compared. This study confirms that VMAT has slightly better CI while thev olume of low doses was higher. VMAT had lower MUs than IMRT. 3D-CRT had the lowest MU, CI and HI. If target coverage and normal tissue sparing are comparable between different treatment techniques, the risk of second malignancy should be a important factor in the selection of treatment. PMID- 25921147 TI - Purple rice bran extract attenuates the aflatoxin B1-induced initiation stage of hepatocarcinogenesis by alteration of xenobiotic metabolizing enzymes. AB - Pigmented rice bran has been suggested to be a valuable source of beneficial phytochemicals. We investigated genotoxic and anti-genotoxic effects of purple rice bran extract (PRBE) in rats using a liver micronucleus assay. Purple rice bran was extracted with methanol, obtaining large amounts of phenolic compounds, including anthocyanins and small amounts of gamma-oryzanol. The experimental protocols were divided into two sets. Male rats were divided into three groups. Group 1 was a negative control, while Groups 2 and 3 were fed with 100 and 500 mg/kg bw of PRBE, respectively, for 28 days. PRBE had no effect on micronucleus formation or xenobiotic metabolizing enzymes in rat liver. Experiments concerning the effect of PRBE on AFB1 showed that PRBE significantly lessened the amount of micronucleated hepatocytes in AFB1 treated rats. Furthermore, it modulated metabolic activation of AFB1 metabolism in the liver by suppressing activity and protein expression of CYP1A2, CYP3A and CYP 450 reductase, and enhancing phase II enzymes including GST and UGT. Overall, purple rice bran extract was not genotoxic in rats. It exhibited anti-genotoxicity by modulation some xenobiotic enzymes active in AFB1 metabolism. PMID- 25921148 TI - Oral cancer awareness of the general public in Saudi Arabia. AB - BACKGROUND: The aim of this study was to assess the level of awareness and knowledge about signs and risk factors of oral cancer in the general population in Saudi Arabia. MATERIALS AND METHODS: A self-administered questionnaire was used to collect information from Saudi adults aged 15 years and older. A total of 679 persons participated in the survey. Descriptive statistics were calculated and chi-square tests, t-tests, and one-way analysis of variance (ANOVA) were used to examine differences between groups. The significance level was set at p<0.05. RESULTS: Only 53.6% of the participants had heard of oral cancer. Smoking and alcohol consumption were identified as the major risk factors by 81.7% and 56.3% of the participants, respectively. Only 22.2% and 18.2%, respectively, were able to correctly identify red and white lesions as early signs of oral cancer. Participants with less than high school education were significantly less aware, and had much less knowledge, of the signs and risk factors of oral cancer (p<0.05). CONCLUSIONS: This survey demonstrates a general lack of awareness among the public about oral cancer and a lack of knowledge about its signs and risk factors. There is a clear need to inform and educate the public in matters relating to the known risk factors associated with oral cancer. A media campaign informing the public about oral cancer is clearly required. PMID- 25921149 TI - Portulaca oleracea Seed Oil Exerts Cytotoxic Effects on Human Liver Cancer (HepG2) and Human Lung Cancer (A-549) Cell Lines. AB - Portulaca oleracea (Family: Portulacaceae), is well known for its anti inflammatory, antioxidative, anti- bacterial, and anti-tumor activities. However, cytotoxic effects of seed oil of Portulaca oleracea against human liver cancer (HepG2) and human lung cancer (A-549) cell lines have not been studied previously. Therefore, the present study was designed to investigate the cytotoxic effects of Portulaca oleracea seed oil on HepG2 and A-549 cell lines. Both cell lines were exposed to various concentrations of Portulaca oleracea seed oil for 24h. After the exposure, percentage cell viability was studied by (3-(4,5 dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide) (MTT), neutral red uptake (NRU) assays, and cellular morphology by phase contrast inverted microscopy. The results showed a concentration-dependent significant reduction in the percentage cell viability and an alteration in the cellular morphology of HepG2 and A-549 cells. The percentage cell viability was recorded as 73%, 63%, and 54% by MTT assay and 76%, 61%, and 50% by NRU assay at 250, 500, and 1000 MUg/ml, respectively in HepG2 cells. Percentage cell viability was recorded as 82%, 72%, and 64% by MTT assay and 83%, 68%, and 56% by NRU assay at 250, 500, and 1000 MUg/ml, respectively in A-549 cells. The 100 MUg/ml and lower concentrations were found to be non cytotoxic to A-549 cells, whereas decrease of 14% and 12% were recorded by MTT and NRU assay, respectively in HepG2 cells. Both HepG2 and A-549 cell lines exposed to 250, 500, and 1000 MUg/ ml of Portulaca oleracea seed oil lost their normal morphology, cell adhesion capacity, become rounded, and appeared smaller in size. The data from this study showed that exposure to seed oil of Portulaca oleracea resulted in significant cytotoxicity and inhibition of growth of the human liver cancer (HepG2) and human lung cancer (A-549) cell lines. PMID- 25921150 TI - Changes of Plasma Tumor Necrosis Factor alpha and C-Reactive Protein Levels in Patients with Hypertension Accompanied by Impaired Glucose Tolerance and their Clinical Significance. AB - BACKGROUND: Chronic inflammation could affect the occurrence and development of malignant tumors. To explore the levels of tumor necrosis factor alpha (TNF alpha) and C-reactive protein (CRP) in patients accompanied by impaired glucose tolerance (IGT) and their clinical significance. MATERIALS AND METHODS: A total of 210 patients hospitalized in Affiliated Hospital of Taishan Medical University from Jun., 2013 to Dec., 2014 were selected, in which 92 cases were accompanied by IGT. Meanwhile, 80 randomly-selected healthy people by physical examination were as the control. The levels of routine biochemical indexes, plasma TNF-alpha and CRP in all subjects were measured. RESULTS: Both systolic and diastolic pressures in hypertension group and hypertension plus IGT group were significantly higher than in control group (p<0.01), but there was no statistical significance between these two groups (p>0.05). The levels of fasting plasma glucose (FPG) and blood glucose 2 h after taking glucose in hypertension plus IGT group were markedly higher than other groups (p<0.01). Homeostasis model assessment-insulin resistance (HOMA-IR), TNF-alpha and CRP contents were on the progressive increase in control, hypertension and hypertension plus IGT groups, but significant differences were presented among each group (P<0.01). Hypertension accompanied by IGT had a significantly-positive association with CRP, TNF-alpha, FPG and blood glucose 2h after taking glucose. CONCLUSIONS: The levels of plasma TNF-alpha and CPR in patients with hypertension accompanied by IGT increase significantly, indicating that inflammatory reaction in these patient increases, thus suggesting that these patients should be focused regarding cancer prevention. PMID- 25921151 TI - Microarray Analysis of Long Non-coding RNA Expression Profile Associated with 5 Fluorouracil-Based Chemoradiation Resistance in Colorectal Cancer Cells. AB - BACKGROUND: Preoperative 5-fluorouracil (5-FU)-based chemoradiotherapy is a standard treatment for locally advanced colorectal cancer (CRC). However, CRC cells often develop chemoradiation resistance (CRR). Recent studies have shown that long non-coding RNA (lncRNA) plays critical roles in a myriad of biological processes and human diseases, as well as chemotherapy resistance. Since the roles of lncRNAs in 5-FU-based CRR in human CRC cells remain unknown, they were investigated in this study. MATERIALS AND METHODS: A 5-FU-based concurrent CRR cell model was established using human CRC cell line HCT116. Microarray expression profiling of lncRNAs and mRNAs was undertaken in parental HCT116 and 5 FU-based CRR cell lines. RESULTS: In total, 2,662 differentially expressed lncRNAs and 2,398 mRNAs were identified in 5-FU-based CRR HCT116 cells when compared with those in parental HCT116. Moreover, 6 lncRNAs and 6 mRNAs found to be differentially expressed were validated by quantitative real time PCR (qRT PCR). Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway analysis for the differentially expressed mRNAs indicated involvement of many, such as Jak- STAT, PI3K-Akt and NF-kappa B signaling pathways. To better understand the molecular basis of 5-FU-based CRR in CRC cells, correlated expression networks were constructed based on 8 intergenic lncRNAs and their nearby coding genes. CONCLUSIONS: Changes in lncRNA expression are involved in 5-FU-based CRR in CRC cells. These findings may provide novel insight for the prognosis and prediction of response to therapy in CRC patients. PMID- 25921152 TI - Profile of skin biopsies and patterns of skin cancer in a tertiary care center of Western Nepal. AB - BACKGROUND: Skin biopsy is the method to assist clinicians to make definite dermatological diagnosis which further helps in holistic management. Skin cancers are relatively rare clinical diagnosis in developing countries like Nepal, but the prevalence is on rise. OBJECTIVES: To investigate the profile of skin biopsies and frequencies and pattern of skin cancers in a tertiary care centre of Western Nepal. MATERIALS AND METHODS: The materials consisted of 434 biopsies (1.37%) out of 31,450 OPD visits performed in the Department of Dermatology, Manipal Teaching Hospital, Pokhara, Nepal, during the period of Dec 2011-Nov 2014. Data were collected and analyzed using SPSS-16 with reference to incidence, age, sex, race and clinical and histopathological features. RESULTS: The commonest disorders observed in biopsies were papulosquamous lesions, skin tuberculosis of different types, benign skin tumors, leprosy, collagen and fungal diseases. Viral diseases were rarely seen, probably due to straight forward clinical diagnosis. Dermatological malignancies accounted for 55/434 (12.67%) of biopsies. Skin disorders in general were commoner in females 280/434 (64%), including malignancies 32/55(58.2%). Mean age of patients with skin cancer was 54.5 years. Facilities for proper laboratory investigation of dermatological disorders will improve the quality of life. CONCLUSIONS: The most prevalent lesion in skin biopsies was papulosquamous disorders followed by skin tuberculosis of different types. Dermatological malignancy constituted 55/434 (12.67%) cases. The prevalence of skin malignancy is on rise in Nepalese society probably due to increase in life expectancy and better diagnostic services. PMID- 25921153 TI - Differentiation of benign from malignant adnexal masses by functional 3 tesla MRI techniques: diffusion-weighted imaging and time-intensity curves of dynamic contrast-enhanced MRI. AB - BACKGROUND: The aim of this study was to evaluate and compare the accuracy of diffusion-weighted imaging (DWI), apparent diffusion coefficient (ADC) value, and time-intensity curve (TIC) type analysis derived from dynamic contrast-enhanced MR imaging (DCE-MRI) in differentiating benign from malignant adnexal masses. MATERIALS AND METHODS: 47 patients with 56 adnexal masses (27 malignant and 29 benign) underwent DWI and DCE-MRI examinations, prior to surgery. DWI signal intensity, mean ADC value, and TIC type were determined for all the masses. RESULTS: High signal intensity on DWI and type 3 TIC were helpful in differentiating benign from malignant adnexal masses (p<0.001). The mean ADC value was significantly lower in malignant adnexal masses (p<0.001). An ADC value<1.20?10-3 mm2/s may be the optimal cutoff for differentiating between benign and malignant tumors. The negative predictive value for low signal intensity on DWI, and type 1 TIC were 100%. The pairwise comparison among the receiver operating characteristic (ROC) curves showed that the area under the curve (AUC) of TIC was significantly larger than the AUCs of DWI and ADC (p<0.001 for comparison of TIC and DWI, p<0.02 for comparison of TIC and ADC value). CONCLUSIONS: DWI, ADC value and TIC type derived from DCE-MRI are all sensitive and relatively specific methods for differentiating benign from malignant adnexal masses. By comparing these functional MR techniques, TIC was found to be more accurate than DWI and ADC. PMID- 25921154 TI - Re-examination of Opisthorchis viverrini Infection in Northeast Thailand. AB - BACKGROUND: Liver fluke infection caused by the parasite Opisthorchis viverrini (O. viverrini), a human carcinogen, is endemic in north-eastern Thailand and remains a major health problem. OBJECTIVES: The objectives of the study were to (1) resurvey the prevalence of O. viverrini infection in a field site from the Khon Kaen Cohort Study (in newly recruited subjects as well as previous cohort subjects surveyed in 1992); (2) investigate how subjects' lifestyle habits and their exposure to health promotion initiatives influence changes in prevalence of O. viverrini infection. MATERIALS AND METHODS: The prevalence of O. viverrini infection in the cohort subjects (as well as new subjects) was investigated using faecal egg counts. Information on demographic factors, lifestyle and awareness of health promotion initiatives were obtained through questionnaires. RESULTS: O. viverrini infection rates in the same individuals of the cohort were lower in 2006 than in 1992. Also, by studying the period effect, the current 35-44 year olds had a 12.4% (95% CI 3.9% to 20.9%) lower prevalence of O. viverrini infection than the 35-44 year olds in 1992 (24.2% versus 11.8%). Lifestyle choices showed that smoking and alcohol consumption were associated with an increased chance of acquiring O. viverrini infection with adjusted odds ratios of 10.1 (95%CI 2.4-41.6) and 5.3 (95%CI 1.2-23.0), respectively. CONCLUSIONS: Our study has demonstrated that although the prevalence of O. viverrini infection over a 14-year period has decreased, unhealthy lifestyle was common with smoking and alcohol consumption being associated with increased chances of infection, emphasising the double burden of disease which developing countries are facing. PMID- 25921155 TI - Organ-sparing Surgery in Treating Patients with Liposarcoma of the Spermatic Cord: Institutional Experience and Pooled Analysis. AB - BACKGROUND: Liposarcoma of the spermatic cord is rare and frequently misdiagnosed. The standard therapeutic approach has been radical inguinal orchiectomy with wide local resection of surrounding soft tissues. The current trend of organ preservation in the treatment of several cancers has started to evolve. Herein we present our testis-sparing surgery experience in the treatment of spermatic cord liposarcoma and a pooled analysis on this topic. MATERIALS AND METHODS: Clinical information from patient receiving organ-sparing surgery was described. Clinical studies evaluating this issue were identified by using a predefined search strategy, e.g., Pubmed database with no restriction on date of published papers. The literature search used the following terms: epidemiology , surgery , chemotherapy , radiotherapy , testis sparing surgery, spermatic cord sarcomas/ liposarcomas. RESULTS: Patient received a complete excision of the lesion, preserving the spermatic cord and the testis. The final pathological report showed a well differentiated liposarcoma with negative surgical margins and no signs of local invasion. After 2-year of follow-up, there was no evidence of local recurrence. Since the first case reported in 1952, a total of about 200 well-documented spermatic cord liposarcoma cases have been published in English literature. Among these patients, only three instances were reported to have received an organ-sparing surgery in the treatment of spermatic cord liposarcoma. CONCLUSIONS: Radical inguinal orchiectomy and resection of the tumor with a negative microscopic margin is the recommended treatment for liposarcoma of the spermatic cord. But for small, especially well-differentiated, lesions, testis sparing surgery might be a good option if an adequate negative surgical margin is assured. PMID- 25921156 TI - Clinical Application of Serum Tumor Abnormal Protein (TAP) in Colorectal Cancer Patients. AB - OBJECTIVE: To explore the association of serum tumor abnormal protein (TAP) with other serological biomarkers e.g. carcinoembryonic antigen (CEA), carbohydrate antigen 125 (CA125), carbohydrate antigen 19-9 (CA19-9) and its clinical application in colorectal cancer (CRC) patients. METHODS: Patients (N=98) were enrolled into this study with histologically or cytologically confirmed CRC. Using a test kit, the level of TAP was determined, while chemiluminescence was used to measure the levels of some other common serological biomarkers e.g. CEA, CA125 and CA19-9. RESULTS: The area of TAP condensed particulate matter decreased after chemotherapy compared with before chemotherapy when CT or MRI scans showed disease control. In contrast, it increased with disease progression (P<0.05). Furthermore, a statistically significant difference was confirmed in monitoring of TAP and common serological biomarkers e.g. CEA and CA19-9 (p<0.05). CONCLUSIONS: Detecting TAP in CRC patients has high sensitivity and specificity and can be used as a new independent indicator for clinically monitoring CRC patients in the course of chemotherapy. PMID- 25921157 TI - Effects of attitude, social influence, and self-efficacy model factors on regular mammography performance in life-transition aged women in Korea. AB - BACKGROUND: This study analyzed predictors of regular mammography performance in Korea. In addition, we determined factors affecting regular mammography performance in life-transition aged women by applying an attitude, social influence, and self-efficacy (ASE) model. MATERIALS AND METHODS: Data were collected from women aged over 40 years residing in province J in Korea. The 178 enrolled subjects provided informed voluntary consent prior to completing a structural questionnaire. RESULTS: The overall regular mammography performance rate of the subjects was 41.6%. Older age, city residency, high income and part time job were associated with a high regular mammography performance. Among women who had undergone more breast self-examinations (BSE) or more doctors' physical examinations (PE), there were higher regular mammography performance rates. All three ASE model factors were significantly associated with regular mammography performance. Women with a high level of positive ASE values had a significantly high regular mammography performance rate. Within the ASE model, self-efficacy and social influence were particularly important. Logistic regression analysis explained 34.7% of regular mammography performance and PE experience (beta=4.645, p=.003), part- time job (beta=4.010, p=.050), self-efficacy (beta=1.820, p=.026) and social influence (beta=1.509, p=.038) were significant factors. CONCLUSIONS: Promotional strategies that could improve self-efficacy, reinforce social influence and reduce geographical, time and financial barriers are needed to increase the regular mammography performance rate in life-transition aged. PMID- 25921158 TI - Mapping HPV Vaccination and Cervical Cancer Screening Practice in the Pacific Region-Strengthening National and Regional Cervical Cancer Prevention. AB - OBJECTIVE: To provide background information for strengthening cervical cancer prevention in the Pacific by mapping current human papillomavirus (HPV) vaccination and cervical cancer screening practices, as well as intent and barriers to the introduction and maintenance of national HPV vaccination programmes in the region. MATERIALS AND METHODS: A cross-sectional questionnaire based survey among ministry of health officials from 21 Pacific Island countries and territories (n=21). RESULTS: Cervical cancer prevention was rated as highly important, but implementation of prevention programs were insufficient, with only two of 21 countries and territories having achieved coverage of cervical cancer screening above 40%. Ten of 21 countries and territories had included HPV vaccination in their immunization schedule, but only two countries reported coverage of HPV vaccination above 60% among the targeted population. Key barriers to the introduction and continuation of HPV vaccination were reported to be: (i) Lack of sustainable financing for HPV vaccine programs; (ii) Lack of visible government endorsement; (iii) Critical public perception of the value and safety of the HPV vaccine; and (iv) Lack of clear guidelines and policies for HPV vaccination. CONCLUSION: Current practices to prevent cervical cancer in the Pacific Region do not match the high burden of disease from cervical cancer. A regional approach, including reducing vaccine prices by bulk purchase of vaccine, technical support for implementation of prevention programs, operational research and advocacy could strengthen political momentum for cervical cancer prevention and avoid risking the lives of many women in the Pacific. PMID- 25921159 TI - Distribution of testicular tumors in Lebanon: a single institution overview. AB - BACKGROUND: Testicular tumors constitute a rare type of cancer affecting adolescents and young adults with recent reports confirming an increase in incidence worldwide. The purpose of this study was to estimate the epidemiological characteristics and histological subtypes of testicular tumors in the Lebanese population according to the WHO classification of testicular and paratesticular tumors. MATERIALS AND METHODS: In this single institutional retrospective study, all patients diagnosed with a testicular tumor in Hotel-Dieu de France Hospital University in Beirut between 1992 and 2014 were enrolled. The age, subtype based on the 2004 WHO classification and body side of tumor were analyzed. RESULTS: A total of two hundred and forty-four (244) patients diagnosed with a testicular tumor in our institution were included in the study. Two hundred and one patients (82.4% of all testicular tumors) had germ cell tumors (TGCT). Among TGCT, 50% were seminomatous tumors, 48% non-seminomatous tumors (NST) and 2% were spermatocytic seminomas. The NST were further divided into mixed germ cell tumors (63.9%), embryonic carcinomas (18.6%), teratomas (15.4%) and yolk sac tumors (2.1%). The mean age for testicular tumors was 32 years. The mean age for germ cell tumors was 31 years and further subtypes such as seminomatous tumors had a mean age of 34 years, 28 years in non-seminomatous tumors and 56 years in spermatocytic seminoma. Patients with right testicular tumor were the predominant group with 55% of patients. Three patients (1.2%) presented with bilateral tumors. CONCLUSIONS: The distribution of different subgroups and the mean age for testicular tumors proved comparable to most countries of the world except for some Asian countries. Germ cell tumors are the most common subtype of testicular tumors with seminomatous tumors being slightly more prevalent than non-seminomatous tumors in Lebanese patients. PMID- 25921160 TI - Sensitivity of gastric cancer cells to chemotherapy drugs in elderly patients and its correlation with cyclooxygenase-2 expression. AB - OBJECTIVE: To explore the sensitivity of gastric cancer cells to chemotherapy drugs in elderly patients and its correlation with cyclooxygenase-2 (COX-2) expression in cancer tissue. MATERIALS AND METHODS: Forty-three elderly patients with gastric cancer (observation group) and 31 young patients with gastrointestinal tumors (control group) who were all diagnosed by pathology and underwent surgery in the 89th Hospital of Chinese People's Liberation Army were selected. Drug sensitivity testing of tumor cells in primary culture was carried out in both groups using a methyl thiazolyl tetrazolium (MTT) method, and the expression of COX-2 and the factors related to multi-drug resistance (MDR) in cancer tissue were assessed by immunohistochemistry. RESULTS: The inhibition rates (IR) of vincristine (VCR), 5-fluorouracil (5-FU), oxaliplatin (L-OHP), mitomycin (MMC) and epirubicin (eADM) on tumor cells in the observation group were dramatically lower than in the control group, with statistical significance (P<0.05 or P<0.01). The positive rates of COX-2, glutathione s-transferase-pi (GST-pi) and P glycoprotein (P-gp) expression in cancer tissue in the observation group were all higher than in control group (P<0.05), while that of DNA topoisomerase IIalpha (TopoIIalpha) expression lower than in the control group (P<0.01). In the observation group, COX-2 expression in cancer tissue had a significantly-positive correlation with GST-pi and P-gp (r=0.855, P=0.000; r=0.240, P=0.026), but a negative correlation with TopoIIalpha (r=-0.328, P=0.002). In the control group, COX-2 expression in cancer tissue was only correlated with P-gp positively (r=0.320, P=0.011). Bivariate correlation analysis displayed that COX-2 expression in cancer tissue in the observation group had a significantly-negative correlation with the IRs of 5-FU, L-OHP, paclitaxel (PTX) and eADM in tumor cells (r=-0.723, P=0.000; r=-0.570, P=0.000; r=-0.919, P=0.000; r=-0.781, P=0.000), but with hydroxycamptothecine (HCPT), VCR and 5-FU in the control group (r=-0.915, P=0.000; r=-0.890, P=0.000; r=-0.949, P=0.000). CONCLUSIONS: Gastric cancer cells in elderly patients feature stronger MDR, which may be related to high COX-2 expression. PMID- 25921161 TI - Application of Joint Detection of AFP, CA19-9, CA125 and CEA in Identification and Diagnosis of Cholangiocarcinoma. AB - OBJECTIVE: To explore the application of joint detection of serum AFP, CA19-9, CA125 and CEA in identification and diagnosis of cholangiocarcinoma (CC). MATERIALS AND METHODS: The levels of serum AFP, CA19-9, CA125 and CEA of both 30 patients with CC and 30 patients with hepatocellular carcinoma (HCC) were assessed. Receiver operating characteristic (ROC) curves were used to evaluate the diagnostic effects of single and joint detection of those 4 kinds of tumor markers for CC. RESULTS: The levels of serum CA19-9, CA125 and CEA in CC patients were higher than that in HCC patients,whereas that of serum AFP was significantly lower s. The area under ROC curve of single detection of serum AFP, CA19-9, CA125 and CEA were 0.05, 0.86, 0.84 and 0.83, with the optimal cutoff values of 15.4 ng/ml, 125.1 U/ml, 95.7 U/ml and 25.9 ng/ml, correspondingly, and the percentage correct single diagnosis was <79%. With joint detection, the diagnostic effect of combined AFP, CA19-9, CA125 and CEA was the highest, with an area under the ROC curve of 0.94 (95%CI 0.88~0.99). CONCLUSIONS: Single detection of serum CA19-9, CA125 and EA is not meaningful. The sensitivity, specificity, the rate of correct diagnosis and the area under ROC curve of joint detection of AFP, CA19-9, CA125 and CEA are highest, indicating that the joint detection of these 4 tumor markers is of great importance in the diagnosis of CC. PMID- 25921162 TI - Influence of Morinda citrifolia (Noni) on Expression of DNA Repair Genes in Cervical Cancer Cells. AB - BACKGROUND: Previous studies have suggested that Morinda citrifolia (Noni) has potential to reduce cancer risk. OBJECTIVE: The purpose of this study was to investigate the effect of Noni, cisplatin, and their combination on DNA repair genes in the SiHa cervical cancer cell line. MATERIALS AND METHODS: SiHa cells were cultured and treated with 10% Noni, 10 MUg/dl cisplatin or their combination for 24 hours. Post culturing, the cells were pelleted, RNA extracted, and processed for investigating DNA repair genes by real time PCR. RESULTS: The expression of nucleotide excision repair genes ERCC1, ERCC2, and ERCC4 and base excision repair gene XRCC1 was increased 4 fold, 8.9 fold, 4 fold, and 5.5 fold, respectively, on treatment with Noni as compared to untreated controls (p<0.05). In contrast, expression was found to be decreased 22 fold, 13 fold, 16 fold, and 23 fold on treatment with cisplatin (p<0.05). However, the combination of Noni and cisplatin led to an increase of 2 fold, 1.6 fold, 3 fold, 1.2 fold, respectively (p<0.05). CONCLUSIONS: Noni enhanced the expression of DNA repair genes by itself and in combination with cisplatin. However, high expression of DNA repair genes at mRNA level only signifies efficient DNA transcription of the above mentioned genes; further investigations are needed to evaluate the DNA repair protein expression. PMID- 25921163 TI - Breast Cancer Screening Barriers from the Womans Perspective: a Meta-synthesis. AB - BACKGROUND: The principal aim of health service providers in the field of breast cancer is to detect and treat lesions at an appropriate time. Therefore, identification of barriers to screening can be very helpful. The present study aimed to systematically review the qualitative studies for extracting and reporting the barriers of screening for breast cancer from the womans perspective. MATERIALS AND METHODS: In this systematic review; Pubmed, Google Scholar, Ovid Scopus, Cochrane Library, Iranmedex, and SID were searched using the keywords: screening barriers, cancer, qualitative studies, breast and their Persian equivalents, and the needed data were extracted and analyzed using an extraction table. To assess the quality of the studies, the Critical Appraisal Skills Programme (CASP) tool was used. RESULTS: From 2,134 related articles that were found, 21 articles were eventually included in the study. The most important barriers from the point of view of 1,084 women were lack of knowledge, access barriers (financial, geographical, cultural), fear (of results and pain), performance of service providers, women's beliefs, procrastination of screening, embarrassment, long wait for getting an appointment, language problems, and previous negative experiences. Articles' assessment score was 68.9. CONCLUSIONS: Increasing women's knowledge, reducing the costs of screening services, cultural promotion for screening, presenting less painful methods, changing beliefs of health service providers, provision of privacy for giving service, decreasing the waiting time, and providing high quality services in a respectful manner can be effective ways to increase breast cancer screening. PMID- 25921164 TI - Phytonutrient Effects of Date Pit Extract against Azoxymethane--Induced Oxidative Stress in the Rat Colon. AB - Plants and their by-products offer a diverse mixture of chemical constituents like natural antioxidants. Date- pits are rich in phenolic compounds that have antioxidant potential. The main objective of this study was to investigate the protective effect of a date-pit extract (DPE) against AOM-induced colonic carcinogenicity and oxidative stress. Thirty-two weanling male Sprauge-Dawley rats were randomly divided into four groups (eight rats in each group). All rats were fed basic diet and water ad libitum, and randomly distributed per treatment groups as follows: negative controls injected with normal saline once a week for two weeks, a cancer group injected intra-peritoneally with azoxymethane (15mg/kg body weight) for two consecutive weeks, and DPE treated groups receiving the extract via the oral route (1.5ml/day) for the entire experiment in the presence or absence of AOM injection. Results showed that DPE contained phytonutrients that were capable of inhibiting chemically-induced oxidative stress in the rat colonic cells. In those animals that consumed DPE, a protective effect was observed against AOM-induced oxidative stress in rat colonic cells as evident by a significant decrease in MDA and oxidized DCF formation in AOM injected and DPE fed groups. It is concluded that DPE has potential antioxidant and anticarcinogenic properties. PMID- 25921165 TI - Analysis on Postoperative Efficacy of Radical Hepatectomy for Patients with Non HBV/HCV Hepatocellular Carcinoma. AB - OBJECTIVE: Patients with hepatocellular carcinoma (HCC) in stage Barcelona Clinic Liver Cancer (BCLC)-A were grouped based on whether they were accompanied with hepatitis B virus (HBV) infection or not so as to explore the clinical characteristics and prognostic conditions of HCC patients with non-HBV/hepatitis C virus (HCV). MATERIALS AND METHODS: Clinical data of 64 stage BCLC-A HCC patients with non-HBV/HCV infection (observation group) who received radical hepatectomy in the Affiliated Cancer Hospital of Guangxi Medical University from January, 2006 to November, 2014 were retrospectively analyzed and compared with those of 409 stage BCLC-A HCC patients with HBV infection (control group) in corresponding period. RESULTS: The postoperative 1-, 3- and 5-year recurrent rates of the observation group were 25%, 38.6% and 48.8%, with postoperative mean and median disease-free survival time being 49.1 months and 62.0 months, respectively. Additionally, the postoperative 1-, 3- and 5-year survival rates of observation group were 90.1%, 72.7% and 62.0%, with the mean and median survival times being 54.4 months and 70.0 months, respectively. CONCLUSIONS: The 1-year recurrent rate is the highest in HCC patients with non-HBV/HCV, and almost half of the patients have recurrence within 1 year, after which the recurrent rate decreases along with the time. PMID- 25921166 TI - Diagnostic Value of Endorectal Ultrasound in Preoperative Assessment of Lymph Node Involvement in Colorectal Cancer: a Meta-analysis. AB - BACKGROUND: Nodal invasion by colorectal cancer is a critical determinant in estimating patient survival and in choosing appropriate preoperative treatment. The present meta-analysis was designed to evaluate the diagnostic value of endorectal ultrasound (EUS) in preoperative assessment of lymph node involvement in colorectal cancer. MATERIALS AND METHODS: We systematically searched PubMed, Web of Science, Embase, and China National Knowledge Infrastructure (CNKI) databases for relevant studies published on or before December 10th, 2014. The sensitivity, specificity, likelihood ratios, diagnostic odds ratio (DOR) and area under the summary receiver operating characteristics curve (AUC) were assessed to estimate the diagnostic value of EUS. Subgroup analysis and meta-regression were performed to explore heterogeneity across studies. RESULTS: Thirty-three studies covering 3,016 subjects were included. The pooled sensitivity and specificity were 0.69 (95%CI: 0.63-0.75) and 0.77 (95%CI: 0.73-0.82), respectively. The positive and negative likelihood ratios were 3.09 (95%CI: 2.52-3.78) and 0.39 (95%CI: 0.32-0.48), respectively. The DOR was 7.84 (95%CI: 5.56-11.08), and AUC was 0.80 (95%CI: 0.77-0.84). CONCLUSIONS: This meta-analysis indicated that EUS has moderate diagnostic value in preoperative assessment of lymph node involvement in colorectal cancer. Further refinements in technology and diagnostic criteria are necessary to improve the diagnostic accuracy of EUS. PMID- 25921167 TI - TP53 Codon 72 Polymorphisms and Lung Cancer Risk in the Bangladeshi Population. AB - OBJECTIVE: To assess associations between codon 72 polymorphisms (Pro or B and Arg or b alleles) of the TP53 gene and lung cancer risk among Bangladeshis. MATERIALS AND METHODS: The distribution of the BB, Bb, and bb genotypes and the frequencies of the B and b alleles were determined by PCR-RFLP method using DNA extracted from leucocytes of 50 confirmed lung cancer patients and 50 age-matched controls and the data were analysed. RESULTS: The ratio of BB, Bb, and bb genotypes were in Hardy-Weinberg equilibrium except for the male patients (chi2=4.6). The B allele is overrepresented among all patients (OR=2.0, p=0.02) and the female patients (OR=4.1, p<=0.01) compared to the controls. The BB/bb ratio was also higher among the patients (OR=3.0, p=0.03). The relative risk of cancer for having BB over bb genotype was 1.8 (p=0.04) but no effect was observed for the Bb genotype. The B allele was overrepresented among patients with adenocarcinomas (OR=2.4, p<=0.01) and squamous cell carcinomas (OR=2.7, p<=0.01) over the controls but the difference was not significant for those with small cell lung carcinomas (OR=1.1, p=0.66). The B allele was overrepresented among patients age 50 or younger (OR=2.7, p<=0.01), but not for older patients (OR=1.7, p=0.07), and among smokers compared to the controls (OR=1.8-10.0, p<=0.01-0.03). However, no correlation between increasing pack-years and lung cancer was observed. CONCLUSIONS: The Pro/Pro (BB) genotype and the B allele are risk factors for lung cancer among Bangladeshis, particularly for people under age 50, women and smokers. PMID- 25921168 TI - Epidemiological Trends of GI Cancers in Patients Visiting a Tertiary Care Hospital in Chandigarh, North India. AB - BACKGROUND: Cancer has become an epidemic disease. Nearly ten million new cancer cases are diagnosed annually in the world and out of these about half are from the developing world. To appropriately plan for treatment, management and prevention of the disease, it becomes necessary to study the trends about morbidity caused by cancers. MATERIALS AND METHODS: Data for patients diagnosed with any form of gastrointestinal (GI) cancers was extracted from records maintained in the outpatient department registers of the Oncology Department of Government Medical College and Hospital in Chandigarh from 1999 to 2012. Trends were analysed for different categories of GI cancers for the period of 12 years. RESULTS: In present study GI cancers accounted for 23 % of all registered cases (n-9603) of carcinomas. Males predominated for all GI cancers except in the gall bladder. Gastrointestinal cancers as a proportion of total cancers increased from 21% in 1999 to 25.9% in 2012 with a significant increasing trend in our series (chi2 for linear trend=9.36, p<0.003). Cancers of the tonsil, oral cavity and pharynx taken together showed an increasing trend over the years (chi2 for trend=55.2, p<0.001) whereas cancers of the lower GI (chi2=19.6, p<0.0001) and gall bladder (chi2=19.5, p<0.0001) showed a declining trend in our series. CONCLUSIONS: GI cancers form a significant proportion of all cancers reporting to our data. In depth studies to ascertain the reasons for the changing trends are required to design intervention programs. Further information is necessary from cancer registries and from the hospital records of oncology departments. PMID- 25921169 TI - High Frequency of Codon 12 but not Codon 13 and 61 K-ras Gene Mutations in Invasive Ductal Carcinoma of Breast in a South Indian Population. AB - BACKGROUND: Ras genes are thought to play an important role in human cancer since they have been found to be activated frequently in several types of tumors including breast cancer, where the overall incidence of K-RAS oncogene activation is 0-10%. Evaluation of K-RAS gene not only for mutational frequency but also for mutation types in this downstream signaling gene pathway is necessary to determine the mechanisms of action. The present study was conducted to test the hypothesis that K-RAS activation is involved in breast cancer risk of south Indian population. MATERIALS AND METHODS: A total of 70 paired pathologically confirmed tumor and non-tumor tissues from the same breast cancer patients were analysed for most common K-RAS mutations of codon 12,13 and 61 by polymerase chain reaction followed by restriction digestion and direct nucleotide sequencing method. RESULTS: We found that a high rate of homozygous and heterozygous mutations of codon 12, but not codon 13 and 61, may influence the invasive ductal carcinoma of breast risk in this study. CONCLUSIONS: Our study indicated that only codon 12 may be involved in initiating breast carcinogenesis in India. PMID- 25921170 TI - Induction of Apoptosis in Human Leukemic Cell Lines by Diallyl Disulfide via Modulation of EGFR/ERK/PKM2 Signaling Pathways. AB - BACKGROUND: Diallyl disulfide (DADS) may exert potent anticancer action both in vitro and in vivo. Although its effects on cancer are significant, the underlying mechanisms remain unknown. In this study, we sought to elucidate possible links between DADS and pyruvate kinase (PKM2). MATERIALS AND METHODS: KG1alpha, a leukemia cell line highly expressing PKM2 was used with a cell counting kit (CCK) 8 and flow cytometry (FCM) to investigate the effects of DADS. Relationships between PKM2 and DADS associated with phosphorylation of EGFR, ERK1/2 and MEK, were assessed by western blot analysis. RESULTS: In KG1alpha cells highly expressing PKM2, we found that DADS could affect proliferation, apoptosis and EGFR/ERK/PKM2 signaling pathways, abrogating EGF-induced nuclear accumulation of PKM2. CONCLUSIONS: These results suggested that DADS suppressed the proliferation of KG1alpha cells, providing evidence that its proapoptotic effects are mediated through the inhibition of EGFR/ERK/PKM2 signaling pathways. PMID- 25921171 TI - Involvement of GRP78 in the Resistance of Ovarian Carcinoma Cells to Paclitaxel. AB - BACKGROUND: Glucose regulated protein 78 (GRP78) is a type of molecular chaperone. It is a possible candidate protein that contributes to development of drug resistance. We first examined the involvement of GRP78 in chemotherapy resistance in human ovarian cancer cell. MATERIALS AND METHODS: The expression of GRP78 mRNA and protein were examined by RT-PCR and western blotting, respectively, in human ovarian cancer cells line (HO-8910). Sensitivity of HO 8910 to paclitaxel was determined with methyl thiazolyl tetrazolium (MTT). Suppression of GRP78 expression was performed using specific small-interfering RNA (siRNA) in HO-8910 cells, and cell apoptosis was assessed by flow cytometry. Statistical analysis was performed using the SPSS 15.0 statistical package. RESULTS: HO-8910 cells, with high basal levels of GRP78, exhibited low sensitivity to paclitaxel. The mRNA and protein levels of GRP78 were dramatically decreased at 24h, 48h and 72h after transfection and the sensitivity to paclitaxel was increased when the GRP78 gene was disturbed by specific siRNA transfection. CONCLUSIONS: The results suggested that high GRP78 expression might be one of the molecular mechanisms causing resistance to paclitaxel, and therefore siRNA of GRP78 may be useful in tumor-specific gene therapy for ovarian cancer. PMID- 25921172 TI - Promyelocytic Leukemia (PML) Gene Mutations may not Contribute to Gastric Adenocarcinoma Development. AB - Gastric cancer is the second most common cause of cancer death worldwide. Environmental as well as genetic factors have been shown to be involved in its genesis. Among genetic factors, loss of function of a tumor suppressive gene named promyelocytic leukemia (PML) has been demonstrated in gastric cancer. In order to cast light in the mechanism by which PML protein is under-expressed in gastric cancer cells, we analyzed all exons and intron-exon boundaries of PML gene in 50 formalin-fixed paraffin-embedded tissue blocks from gastric carcinoma tumors by means of PCR-SSCP and CSGE, with direct sequencing of abnormally shifted bands. We found a novel sequence variant of unknown significance localized in intron 5 in 3 samples (c.1398+84delA). We did not detect any deleterious mutations of the PML gene. This study shows that PML mutations may not contribute to gastric adenocarcinoma development. Post-translational modifications or protein degradation might be mechanisms by which PML is not expressed in gastric tumors. PMID- 25921173 TI - Development of a risk index for prediction of abnormal pap test results in Serbia. AB - BACKGROUND: Serbia is one of the countries with highest incidence and mortality rates for cervical cancer in Central and South Eastern Europe. Introducing a risk index could provide a powerful means for targeting groups at high likelihood of having an abnormal cervical smear and increase efficiency of screening. The aim of the present study was to create and assess validity ofa index for prediction of an abnormal Pap test result. MATERIALS AND METHODS: The study population was drawn from patients attending Departments for Women's Health in two primary health care centers in Serbia. Out of 525 respondents 350 were randomly selected and data obtained from them were used as the index creation dataset. Data obtained from the remaining 175 were used as an index validation data set. RESULTS: Age at first intercourse under 18, more than 4 sexual partners, history of STD and multiparity were attributed statistical weights 16, 15, 14 and 13, respectively. The distribution of index scores in index-creation data set showed that most respondents had a score 0 (54.9%). In the index-creation dataset mean index score was 10.3 (SD-13.8), and in the validation dataset the mean was 9.1 (SD=13.2). CONCLUSIONS: The advantage of such scoring system is that it is simple, consisting of only four elements, so it could be applied to identify women with high risk for cervical cancer that would be referred for further examination. PMID- 25921174 TI - Influence of residential environment and lifestyle on multiple primary malignancies in Taiwan. AB - BACKGROUND: Multiple primary malignancies (MPM) have become increasingly prevalent worldwide. This investigation was aimed at establishing the clinicopathological characteristics of MPM patients and evaluating the impact of the living environment on MPM in the Taiwanese population. MATERIALS AND METHODS: From January 2009 to December 2013, a total of 8,268 cancer patients were identified in our institutional center. Of these, 125 were diagnosed as MPM and thus enrolled. Data for clinicopathological features and treatment approaches for these MPM patients living in urban or suburb zone were obtained. Findings for the air pollution status in Taiwan were also collected. RESULTS: The most common cancer match of MPM was esophageal cancer with hypopharyngeal cancer (12.8%), followed by colorectal cancer with gastric cancer (6.4%) and colorectal cancer with breast cancer (5.6%). The air quality was significantly worse in the urban than in the suburban zone and there was a remarkably higher portion of MPM patients in the urban zone suffering from grade III and IV post-chemotherapeutic neutropenia (30.8% vs 15.1%, P=0.036). CONCLUSIONS: The tumor frequency and site distribution should be taken into the clinical evaluation because there is a relatively high risk of developing MPM. This study also highlighted the potential influence of environmental factors on post-chemotherapeutic neutropenia for patients with MPM. PMID- 25921175 TI - Parotid gland tumours in Turkish population: analysis of 165 patients. AB - BACKGROUND: Retrospective data on 165 patients who presented with a parotid mass and underwent surgery in our clinics during 2000-2009 were examined. The obtained data (demographic data, surgical procedures, histopathological diagnoses) were compared to similar studies to make contributions to the literature. MATERIALS AND METHODS: Patients were classified according to their histopathological diagnosis. Surgical procedures and patient follow-up were clarified. The results are presented as means and standard deviations. RESULTS: Of the 165 masses, 134 (81.3%) were benign and 31 (18.7%) were malignant. Pleomorphic adenoma was the most common benign tumour (79 patients, 59%). Lymphoma and adenoid cystic carcinoma were equally common and were the most common malignant parotid gland tumours (both 6 patients, 19.3%). The most frequent surgical procedure was superficial parotidectomy (92 patients, 55.7%), and the most commonly encountered surgical complication was facial paralysis (12 patients, 7.2%). CONCLUSIONS: Our data are generally in line with the literature but lymphoma was more common than in most previous reports. Although the number of cases was low, the high incidence of parotid gland lymphoma was remarkable. PMID- 25921176 TI - Differentially expressed genes in metastatic advanced Egyptian bladder cancer. AB - BACKGROUND: Bladder cancer is one of the most common cancers worldwide. Gene expression profiling using microarray technologies improves the understanding of cancer biology. The aim of this study was to determine the gene expression profile in Egyptian bladder cancer patients. MATERIALS AND METHODS: Samples from 29 human bladder cancers and adjacent non-neoplastic tissues were analyzed by cDNA microarray, with hierarchical clustering and multidimensional analysis. RESULTS: Five hundred and sixteen genes were differentially expressed of which SOS1, HDAC2, PLXNC1, GTSE1, ULK2, IRS2, ABCA12, TOP3A, HES1, and SRP68 genes were involved in 33 different pathways. The most frequently detected genes were: SOS1 in 20 different pathways; HDAC2 in 5 different pathways; IRS2 in 3 different pathways. There were 388 down-regulated genes. PLCB2 was involved in 11 different pathways, MDM2 in 9 pathways, FZD4 in 5 pathways, p15 and FGF12 in 4 pathways, POLE2 in 3 pathways, and MCM4 and POLR2E in 2 pathways. Thirty genes showed significant differences between transitional cell cancer (TCC) and squamous cell cancer (SCC) samples. Unsupervised cluster analysis of DNA microarray data revealed a clear distinction between low and high grade tumors. In addition 26 genes showed significant differences between low and high tumor stages, including fragile histidine triad, Ras and sialyltransferase 8 (alpha) and 16 showed significant differences between low and high tumor grades, like methionine adenosyl transferase II, beta. CONCLUSIONS: The present study identified some genes, that can be used as molecular biomarkers or target genes in Egyptian bladder cancer patients. PMID- 25921177 TI - Signs, Symptoms and Complications of Non-Hodgkin's Lymphoma According to Grade and Stage in South Iran. AB - BACKGROUND: Non-Hodgkin's lymphoma (NHL) is a heterogeneous type of neoplasm of the lymphatic system. To have a more accurate and early diagnosis we need to know signs, symptoms and complications of lymphoma in early stages besides pathology and immunohistochemistry. MATERIALS AND METHODS: This prospective study included 110 cases of NHL that were followed since February 2012 till November 2013. Biopsies were taken from all the patients besides bone marrow study. Signs and symptoms were categorized into "B" symptoms, general, lymphadenopathy and extranodal involvement and we compared the frequencies by stage and grade. RESULTS: Of 110 cases, 88.9% had B-cell and 11.1% T-cell type with mean age 48.5+/-18.6 years. "B" symptoms and lymphadenopathy were more common in men. Cervical lymphadenopathy was the most common sign (44.8%). and hematologic, bone marrow, bone and neurologic lesions were the most common complications. All complications were more common in males. "B" symptoms were seen mostly in stage III, general signs and symptoms in stage IV, and lymphadenopathy in stage II. Intermediate grade was also the most common in all signs and symptoms. In this study 12 (10.9%) patients had relapse, with neurologic and bone marrow as the most common sites of tumor recurrence. CONCLUSIONS: There is a meaningful relationship between male gender for NHL and anemia that can be due in part to higher incidence of bone marrow involvement and stage IV disease in male cases. We also found a strong relationship between low grade NHL and age. On the other hand extranodal involvement is more common in female groups. PMID- 25921178 TI - Breast Cancer Association with CYP1A2 Activity and Gene Polymorphisms--a Preliminary Case-control Study in Tunisia. AB - The aim of the present study was to evaluate the relative contribution of CYP1A2 isoforms (-3860 G/A, -2467T/delT and -163C/A) in control subjects and breast cancer patients to the metabolism of caffeine in human liver. Restriction fragment length polymorphism analysis of PCR-amplified Fragments (PCR-RFLP) was used for the genotyping of CYP1A2 SNPs and HPLC allowed the phenotyping through the measurement of CYP1A2 activity using the 17X + 13X + 37X/137X urinary metabolite ratio (CMR) and plasma caffeine half life (T1/2). The CYP1A2 -3860A genotype was associated with a decreased risk of breast cancer. In contrast, distributions of the CYP1A2 -2467T/delT or -2467delT/delT and -163A/C or A/A genotypes among breast cancer patients and controls were similar. When the genotype and phenotype relationship was measured by comparing the mean CMR ratios and caffeine half life within the genotype groups between subjects and breast cancer patients, there were no significant differences except for -3860 A, most of them being homozygous for the -3860 G/G SNP and had a significant higher mean CMR ratio and half life than those with -3860 G/A (P=0.02). The results of this preliminary study show a significant association between CP1A2 -3860 G variant and CYP1A2 phenotype which must be confirmed by further large-size case-control studies. PMID- 25921179 TI - Effects of Breast Cancer Fatalism on Breast Cancer Awareness among Nursing Students in Turkey. AB - BACKGROUND: Breast cancer is the most common cancer among women and leading cause of death worldwide, including in Turkey. High perceptions of cancer fatalism are associated with lower rates of participation in screening for breast cancer. This study was conducted to evaluate the effect of breast cancer fatalism and other factors on breast cancer awareness among nursing students in Turkey. MATERIALS AND METHODS: This cross-sectional descriptive study was conducted at three universities in the Western Black Sea region. The sample was composed of 838 nursing students. Data were collected by Personal Information Form, Powe Fatalism Inventory (PFI) and Champion's Health Belief Model Scale (CHBMS). RESULTS: Breast cancer fatalism perception of the students was at a low level. It was determined that students' seriousness perception was moderate, health motivation, BSE benefits and BSE self-efficacy perceptions were high, and BSE barriers and sensitivity perceptions were low. In addition, it was determined that students awareness of breast cancer was affected by breast cancer fatalism, class level, family history of breast cancer, knowledge on BSE, source of information on BSE, frequency of BSE performing, having breast examination by a healthcare professional within the last year and their health beliefs. CONCLUSIONS: In promoting breast cancer early diagnosis behaviour, it is recommended to evaluate fatalism perceptions and health beliefs of the students and to arrange training programs for this purpose. PMID- 25921180 TI - SIRT7 Exhibits Oncogenic Potential in Human Ovarian Cancer Cells. AB - BACKGROUND: Sirtuin7 (SIRT7) is a type of nicotinamide adenine dinucleotide oxidized form (NAD+)-dependent deacetylase and the least understood member of the sirtuins family; it is implicated in various processes, such as aging, DNA damage repair and cell signaling transduction. There is some evidence that SIRT7 may function as a tumor trigger for human malignancy. Here, we aimed to explore the biological function of SIRT7 in ovarian carcinoma cells and its potential mechanism. MATERIALS AND METHODS: Expression of SIRT7 in ovarian cancer cell lines was detected by western blotting. Transduced cell lines with SIRT7 knockdown or overexpression were constructed. Cell viability, cologenic, apoptosis-associated and motility assays were performed to elucidate the biological function of SIRT7 in ovarian cancer cells. RESULTS: SIRT7 demonstrated a higher level in ovarian cancer cell lines compared with normal cells. On the one hand, down-regulation of SIRT7 significantly reduced ovarian cancer cell growth, repressed colony formation and increased cancer cell apoptosis; on the other hand, up-regulation promoted the migration of cancer cells. Additionally, repression of SIRT7 also induced change in apoptosis-related molecules and subunits of the NF-kappaB family. CONCLUSIONS: In the present study, our data indicated that SIRT7 might play a role of oncogene in ovarian malignancy and be a potential therapeutic target. PMID- 25921181 TI - Anisotropic patterns of liver cancer prevalence in Guangxi in Southwest China: is local climate a contributing factor? AB - Geographic information system (GIS) technology has useful applications for epidemiology, enabling the detection of spatial patterns of disease dispersion and locating geographic areas at increased risk. In this study, we applied GIS technology to characterize the spatial pattern of mortality due to liver cancer in the autonomous region of Guangxi Zhuang in southwest China. A database with liver cancer mortality data for 1971-1973, 1990-1992, and 2004-2005, including geographic locations and climate conditions, was constructed, and the appropriate associations were investigated. It was found that the regions with the highest mortality rates were central Guangxi with Guigang City at the center, and southwest Guangxi centered in Fusui County. Regions with the lowest mortality rates were eastern Guangxi with Pingnan County at the center, and northern Guangxi centered in Sanjiang and Rongshui counties. Regarding climate conditions, in the 1990s the mortality rate of liver cancer positively correlated with average temperature and average minimum temperature, and negatively correlated with average precipitation. In 2004 through 2005, mortality due to liver cancer positively correlated with the average minimum temperature. Regions of high mortality had lower average humidity and higher average barometric pressure than did regions of low mortality. Our results provide information to benefit development of a regional liver cancer prevention program in Guangxi, and provide important information and a reference for exploring causes of liver cancer. PMID- 25921182 TI - Cigarette Alternatives: Are they Safe? AB - In spite of limited data regarding the safety or effectiveness of electronic cigarette introduced into the market as a healthier alternative to tobacco smoking, its popularity has increased enormously. E-cigarettes have penetrated the market rapidly owing to the elaborate marketing network and attractive marketing strategies. Stated advantages include the claim that they help quit smoking and produce less exposure than conventional smoking. The list of disadvantages is even more elaborate. While the majority of the studies supporting health claims and efficacy for quitting smoking are not scientifically sound, they are also challenged by studies providing contradictory results. Owing to the limited evidence on the potential advantages and disadvantages of e cigarettes, the debate on their safety continues. PMID- 25921183 TI - Have we Comprehensively Evaluated the Effectiveness of Endoscopic Screening for Gastric Cancer? AB - Endoscopy has been increasingly used in clinical practice and as a standardized examination procedure for gastrointestinal diseases. However, only a few studies on endoscopic screening for evaluating mortality reduction from gastric cancer have been carried out. Even if a high detection rate is obtained in clinical practice, such a rate cannot be directly accepted as evidence providing the effectiveness of cancer screening. Endoscopic screening for gastric cancer is not an exception of possibility to detect overdiagnosis. If detection rate is used for the evaluation of the effectiveness of cancer screening, the possibility of overestimating the effectiveness of cancer screening cannot be ruled out. To avoid the effect of overdiagnosis and confirm the effectiveness of endoscopic screening, mortality reduction from gastric cancer must be carefully evaluated by conducting reliable studies. The burden of gastric cancer remains real and this cannot be ignored in Eastern Asian countries. To determine the best available method for gastric cancer screening, evaluation of its effectiveness is a must. Endoscopic screening for gastric cancer has shown promising results, and thus deserves further comprehensive evaluation to reliably confirm its effectiveness and how its optimal use can be strategically promoted. PMID- 25921184 TI - Universal health coverage for cancer in Asia. PMID- 25921185 TI - Using a 3D virtual supermarket to measure food purchase behavior: a validation study. AB - BACKGROUND: There is increasing recognition that supermarkets are an important environment for health-promoting interventions such as fiscal food policies or front-of-pack nutrition labeling. However, due to the complexities of undertaking such research in the real world, well-designed randomized controlled trials on these kinds of interventions are lacking. The Virtual Supermarket is a 3 dimensional computerized research environment designed to enable experimental studies in a supermarket setting without the complexity or costs normally associated with undertaking such research. OBJECTIVE: The primary objective was to validate the Virtual Supermarket by comparing virtual and real-life food purchasing behavior. A secondary objective was to obtain participant feedback on perceived sense of "presence" (the subjective experience of being in one place or environment even if physically located in another) in the Virtual Supermarket. METHODS: Eligible main household shoppers (New Zealand adults aged >=18 years) were asked to conduct 3 shopping occasions in the Virtual Supermarket over 3 consecutive weeks, complete the validated Presence Questionnaire Items Stems, and collect their real supermarket grocery till receipts for that same period. Proportional expenditure (NZ$) and the proportion of products purchased over 18 major food groups were compared between the virtual and real supermarkets. Data were analyzed using repeated measures mixed models. RESULTS: A total of 123 participants consented to take part in the study. In total, 69.9% (86/123) completed 1 shop in the Virtual Supermarket, 64.2% (79/123) completed 2 shops, 60.2% (74/123) completed 3 shops, and 48.8% (60/123) returned their real supermarket till receipts. The 4 food groups with the highest relative expenditures were the same for the virtual and real supermarkets: fresh fruit and vegetables (virtual estimate: 14.3%; real: 17.4%), bread and bakery (virtual: 10.0%; real: 8.2%), dairy (virtual: 19.1%; real: 12.6%), and meat and fish (virtual: 16.5%; real: 16.8%). Significant differences in proportional expenditures were observed for 6 food groups, with largest differences (virtual - real) for dairy (in expenditure 6.5%, P<.001; in items 2.2%, P=.04) and fresh fruit and vegetables (in expenditure: -3.1%, P=.04; in items: 5.9%, P=.002). There was no trend of overspending in the Virtual Supermarket and participants experienced a medium-to-high presence (88%, 73/83 scored medium; 8%, 7/83 scored high). CONCLUSIONS: Shopping patterns in the Virtual Supermarket were comparable to those in real life. Overall, the Virtual Supermarket is a valid tool to measure food purchasing behavior. Nevertheless, it is important to improve the functionality of some food categories, in particular fruit and vegetables and dairy. The results of this validation will assist in making further improvements to the software and with optimization of the internal and external validity of this innovative methodology. PMID- 25921186 TI - A Simulation Curriculum for Management of Trauma and Surgical Critical Care Patients. AB - BACKGROUND: Expectations continue to rise for residency programs to provide integrated simulation training to address clinical competence. How to implement such training sustainably remains a challenge. We developed a compact module for first-year surgery residents integrating theory with practice in high-fidelity simulations, to reinforce the preparedness and confidence of junior residents in their ability to manage common emergent patient care scenarios in trauma and critical care surgery. METHODS: The 3-day module features a combination of simulated patient encounters using standardized patients and electronic manikins, didactic sessions, and hands-on training. Manikin-based scenarios developed in house were used to teach trauma and critical care management concepts and skills. Separate scenarios in collaboration with the regional organ donation program addressed communication in difficult situations such as brain death. Didactic material based on contemporary evidence, as well as skills stations, was developed to complement the scenarios. Residents were surveyed before and after training on their confidence in meeting the 14 learning objectives of the curriculum on a 5-point Likert scale. RESULTS: Data from 15 residents who underwent this training show an overall improvement in confidence across all learning objectives defined for the module, with confidence scores before to after training improving significantly from 2.8 (sigma = 0.85, median = 3) to 3.9 (sigma = 0.87, median = 4) of 5, p < 0.001. Although female residents reported higher posttraining confidence scores compared with male residents (average 4.2 female vs 3.8 male, p = 0.002), there were no other significant differences in confidence scores or changes to scores owing to resident sex or program status (categorical or preliminary). CONCLUSION: We successfully implemented a multimodal simulation-based curriculum that provides skills training integrated with the clinical context of managing trauma and critical care patients, simultaneously addressing a range of clinical competencies. Results to date show consistent improvement in residents' confidence in meeting learning objectives. Development of the curriculum continues for sustainability, as well as measures to embed objective evaluations of resident competence. PMID- 25921187 TI - Proficiency for Advanced Laparoscopic Procedures in Gynecologic Residency Program: Do all Residents Need to be Trained? AB - OBJECTIVES: To assess the current state of laparoscopic gynecologic surgery in the Dutch residency program, the level of competence among graduated residents, and whether they still perform these procedures. Furthermore, their current attitudes toward the implementation of minimally invasive surgery into residency training were assessed. DESIGN: An online survey (Canadian Task Force Classification III) regarding the level of competence, performance, training, and interest for gynecologic laparoscopic procedures. PARTICIPANTS/SETTING: Gynecologists who finished residency training between 2008 and 2013 in the Netherlands. RESULTS: Response rate was 73% (171/235). The scores for all basic and intermediate laparoscopic procedures performed immediately after residency showed the highest competence level (median 5, of scale 1-5). The competence level for advanced laparoscopic procedures was less at 3, indicating that the graduated residents are not able to perform these procedures without supervision. Overall, 56% of the gynecologists no longer perform any level 3 advanced procedures, and 86% do not perform level 4 advanced procedures. Gynecologists who still perform the inquired laparoscopic procedures scored a significantly higher competence level immediately after residency training for most of procedures compared with the gynecologists who do not perform these procedures. CONCLUSION: Residents are sufficiently trained for basic and intermediate laparoscopic procedures during residency training. However, they are not sufficiently equipped to perform advanced laparoscopic procedures without supervision. We should consider training advanced procedures especially to a selected group of residents because most gynecologists do not perform these procedures after residency. The learning curve for advanced procedures continues to rise after finishing residency for those who keep on performing these procedures, therefore an additional fellowship is recommended for this group. PMID- 25921188 TI - Burnout Among Otolaryngology Residents in Saudi Arabia: A Multicenter Study. AB - OBJECTIVE: Determine the prevalence of, and associated risk factors for, burnout among otolaryngologist residents in Saudi Arabia. DESIGN AND SETTING: A cross section study of multicenter hospitals in Saudi Arabia conducted in March 2013. PARTICIPANTS: Registered residents in Saudi Otolaryngology Board Program. MAIN OUTCOMES MEASURES: The Maslach Burnout Inventory was used to measure burnout status. Questions supplementary to the Maslach Burnout Inventory were also included to identify associated potential risk factors such as demographic data, resident satisfaction, and work conditions. RESULTS: Of the initial 123 questionnaires that were distributed, 85 yielded responses, a rate of 69%. The mean age (standard deviation [SD]) of respondents was 29 (2.3) years. Of those, 67% (57/85) were men and 66% (55/85) were married. Resident levels were delineated: level 2, 19%; level 3, 33%; level 4, 29%; and level 5, 19%. The mean number of on-call days/month (SD) was 7 (2), clinics/week (SD) was 3 (1), sleep hours/day (SD) was 6 (1), and operations/week (SD) was 2 (1). The mean emotional exhaustion (EE) and depersonalization scores were high at 29.5 (SD = 9.6) and 10.7 (SD = 6), respectively. The mean personal accomplishment was low at 32.33 (SD = 6). The mean of all subscales did not differ by sex (EE p = 0.5; depersonalization p = 0.09; personal accomplishment p = 0.4). Mean EE differed by marital status, which was 31.2, 31.3, and 25.6 for married, divorced, and single, respectively, analysis of variance test p = 0.045. CONCLUSION: Burnout prevalence was found to be high among otolaryngologist residents in Saudi Arabia. The associated variables examined in this study should be addressed to decrease this level of burnout and provide residents with a less stressful work environment. PMID- 25921189 TI - Attitudes Toward Research During Residency: A Survey of Canadian Residents in Obstetrics and Gynecology. AB - OBJECTIVES: Obstetrics and Gynecology (Ob/Gyn) residency programs in Canada mandate participation in scholarly research activity, yet there remains a lack of literature on trainees' opinions regarding its value, feasibility, and perceived effect on future practice. An understanding of resident attitudes toward research during residency is essential in effectively engaging trainees and fostering a robust research community in the field. We sought to identify factors reported to influence involvement in resident research, including perceived barriers. DESIGN: Anonymous data were collected via an online survey distributed to all residents enrolled in accredited Ob/Gyn residency programs throughout Canada. The 10 minute, previously piloted questionnaire covered questions related to demographic information, research experience, career goals, current research activities, opinions on research environment, and opinions regarding the effect of research on future practice. Descriptive statistics were used to describe demographics, research background, and current research activities. Categorical variables were compared using the chi-square analysis and continuous variables were compared using the Mann-Whitney rank sum tests. RESULTS: A total of 175 residents completed the survey; 61% agreed/strongly agreed that they participate in research solely because it is mandated by their program, 22% felt that their training environment did not promote research, 19% disagreed/strongly disagreed that research is a positive experience, while 70% agreed/strongly agreed that they would prefer to complete another educational activity other than a research project. Time constraints owing to residency duties, time constraints owing to personal reasons, and lack of statistical knowledge were reported as barriers to research involvement by 97%, 90%, and 74% of trainees, respectively. Residents with graduate degrees were less likely to report lack of training on research design as a moderate/extreme barrier (7% vs 32%, p = 0.007). CONCLUSIONS: There exists considerable disparity in enthusiasm for scholarly research activity among Ob/Gyn residents. Curricular development should focus on addressing resident reported barriers, including the provision of protected time for research and access to statistical support and education, particularly for residents without graduate degrees. PMID- 25921190 TI - Evaluation of a "Subintern" Role: Action Over Observation For Final-Year Medical Students in Surgery. AB - BACKGROUND: This study sought to investigate the potential of a subinternship apprentice role as a structured experiential learning opportunity by enabling final-year medical students to learn through action rather than observation. METHODS: A convenience sample of 65 final-year medical students was allocated to "intern shadow" (control group) or "subintern" (research group) for 2 weeks during the first clinical attachment of their final year. "Intern shadow" involved direct observation of the intern role, whereas "subintern" involved a fully immersive performance of the intern role under direct supervision by the surgical team. All students completed an evaluation form that was devised in house and based on course learning objectives. This consisted of Likert scales and free text. RESULTS: Wilcoxon rank sum test results showed that students participating in the "subintern" group had a statistically significantly better clinical experience than the "intern-shadow" group regarding role modeling (p = 0.0002), learning and teaching (p = 0.0021), organization and support (p = 0.0219), and patient interaction (p = 0.0063). CONCLUSION: The "subintern" apprentice role shows strong potential for enabling final-year students to learn on the job by actually performing the intern role rather than merely observing an intern at work. Subinterns reported feeling valued within the team structure and expressed a desire to emulate expert practice directly experienced through close collaboration with consultant surgeons. PMID- 25921191 TI - Improving the Teaching Skills of Residents in a Surgical Training Program: Results of the Pilot Year of a Curricular Initiative in an Ophthalmology Residency Program. AB - OBJECTIVE: To design and implement a teaching skills curriculum that addressed the needs of an ophthalmology residency training program, to assess the effect of the curriculum, and to present important lessons learned. DESIGN: A teaching skills curriculum was designed for the Harvard Medical School (HMS) Residency Training Program in Ophthalmology. Results of a needs assessment survey were used to guide curriculum objectives. Overall, 3 teaching workshops were conducted between October 2012 and March 2013 that addressed areas of need, including procedural teaching. A postcurriculum survey was used to assess the effect of the curriculum. SETTING: Massachusetts Eye and Ear Infirmary, a tertiary care institution in Boston, MA. PARTICIPANTS: Overall, 24 residents in the HMS Residency Training Program in Ophthalmology were included. RESULTS: The needs assessment survey demonstrated that although most residents anticipated that teaching would be important in their future career, only one-third had prior formal training in teaching. All residents reported they found the teaching workshops to be either very or extremely useful. All residents reported they would like further training in teaching, with most residents requesting additional training in best procedural teaching practices for future sessions. CONCLUSIONS: The pilot year of the resident-as-teacher curriculum for the HMS Residency Training Program in Ophthalmology demonstrated a need for this curriculum and was perceived as beneficial by the residents, who reported increased comfort in their teaching skills after attending the workshops. PMID- 25921192 TI - Poor association between the progression criteria in active surveillance and subsequent histopathological findings following radical prostatectomy. AB - OBJECTIVE: The objective of this study was to investigate the association between active surveillance (AS) progression criteria and histopathology features in subsequent radical prostatectomy (RP) specimens. MATERIALS AND METHODS: Of 229 patients managed on AS, 80 patients underwent RP, of whom 68 met at least one of the following three progression criteria: progression on rebiopsy, short prostate specific antigen (PSA) doubling time (PSAdt) and increase clinical tumour category (cT). Patients revealing histopathological features in the RP specimens involving GS >= 7 (3 + 4) were considered to have achieved a potential survival gain from the procedure (timely RP). The association between the progression criteria and timely RP was analysed using univariate logistic regression analyses. RESULTS: Of the 68 patients who met at least one of the progression criteria, 66% had timely RP features. Progression on rebiopsy was significantly associated with timely RP [odds ratio (OR) = 5.00, 95% confidence interval (CI) 1.51-16.51]. Although not statistically significant, progression defined by PSAdt was negatively associated with timely RP (OR = 0.36, 95% CI 0.13-1.00). Increase in cT showed no association with timely RP (OR = 1.17, 95% CI 0.35-3.87). CONCLUSIONS: A poor association was found between the progression criteria employed in the AS programme and histopathology features after subsequent RP. Only progression on rebiopsy was significantly associated with final histopathology. PMID- 25921193 TI - Language limits the experience of emotions: Comment on "The quartet theory of human emotions: An integrative and neurofunctional model" by S. Koelsch et al. PMID- 25921194 TI - Catalytic enantioselective intermolecular desymmetrization of azetidines. AB - The first catalytic asymmetric desymmetrization of azetidines is disclosed. Despite the low propensity of azetidine ring opening and challenging stereocontrol, smooth intermolecular reactions were realized with excellent efficiency and enantioselectivity. These were enabled by the suitable combination of catalyst, nucleophile, protective group, and reaction conditions. The highly enantioenriched densely functionalized products are versatile precursors to other useful chiral molecules. Mechanistic studies, including DFT calculations, revealed that only one catalyst molecule is involved in the key transition state, though both reactants can be activated. Also, the Curtin-Hammett principle dictates the reaction proceeds via amide nitrogen activation. PMID- 25921195 TI - Comparison of Coagulation Parameters, Anticoagulation, and Need for Transfusion in Patients on Interventional Lung Assist or Veno-Venous Extracorporeal Membrane Oxygenation. AB - Clinical data on anticoagulation needs of modern extracorporeal membrane oxygenation (ECMO) and its impact on coagulation are scarce. Therefore, we analyzed coagulation-related parameters, need for transfusion, and management of anticoagulation in adult patients with severe acute respiratory failure during treatment with either pumpless interventional lung assist (iLA) or veno-venous ECMO (vv-ECMO). Sixty-three patients treated with iLA and 192 patients treated with vv-ECMO at Regensburg University Hospital between January 2005 and May 2011 were analyzed. Data related to anticoagulation, transfusion, and coagulation parameters were collected prospectively by the Regensburg ECMO registry. Except for a higher, sequential organ failure assessment (SOFA) score in the ECMO group (12 [9-15] vs. 11 [7-14], P = 0.007), a better oxygenation, and a lower dosage of vasopressors in the iLA patients, both groups had similar baseline characteristics. No difference was noted in terms of outcome and overall transfusion requirements. Factors of the plasmatic coagulation system were only marginally altered over time and did not differ between groups. Platelet counts in ECMO-treated patients, but not in those treated with iLA, dropped significantly during extracorporeal support. A more intense systemic anticoagulation with a mean activated partial thromboplastin time (aPTT) > 53 s led to a higher need for transfusions compared with the group with a mean aPTT < 53 s, whereas the average durability of membrane oxygenators was not affected. Need for red blood cell (RBC) transfusion was highest in patients with extrapulmonary sepsis (257 mL/day), and was significantly lower in primary pulmonary adult respiratory distress syndrome (ARDS) (102 mL/day). Overall, 110 (0-274) mL RBC was transfused in the ECMO group versus 146 (41-227) mL in the iLA group per day on support. The impact of modern iLA and ECMO systems on coagulation allows comparatively safe long-term treatment of adult patients with acute respiratory failure. A moderate systemic anticoagulation seems to be sufficient. Importantly, platelets are more affected by vv-ECMO compared with pumpless iLA. PMID- 25921196 TI - Isolated Subtalar Distraction Arthrodesis Using Porous Tantalum: A Pilot Study. AB - BACKGROUND: During reconstructive procedures of the hindfoot, a structural graft is often needed to fill gaps. To eliminate donor site morbidity and limited availability of autografts, porous tantalum was used. METHODS: Eighteen patients who underwent subtalar joint distraction arthrodesis by means of trabecular metal augment were reviewed retrospectively. The results were evaluated clinically, with the American Orthopaedic Foot & Ankle Society (AOFAS) score and the visual analog scale (VAS) for pain, and were assessed radiologically. The mean follow-up period was 18 months. RESULTS: Computed tomography showed sound fusion. There was a marked increase in AOFAS scores and a decrease in VAS scores. Arthrodesis was achieved in all cases with no major postoperative complications. Radiographically, there was a marked increase in all measured parameters (talocalcaneal angle, talocalcaneal height, talar declination angle), and the intraoperatively achieved correction was maintained at the last follow-up visit. CONCLUSION: Our data suggest that porous tantalum may be used as a structural graft option for subtalar arthrodesis. LEVEL OF EVIDENCE: Level IV, retrospective case series. PMID- 25921197 TI - Fibular Lengthening Using the Elongated Combi-hole of a Locking Compression Plate: Technical Tip. PMID- 25921198 TI - CPGs and AUCs. PMID- 25921199 TI - Anatomical Reconstruction of Lateral Ankle Ligaments Using Free Tendon Allografts and Biotenodesis Screws. AB - BACKGROUND: Lateral ankle instability is one of the most common musculoskeletal disorders and can result in ankle damage. This study reports on the results of the anatomical reconstruction of ligaments using semitendinosus tendon allograft and bioabsorbable tenodesis screws for chronic lateral ankle instability, as well as the functional and radiological results of this procedure. METHODS: From February 2007 to January 2013, 70 patients (72 ankles) underwent this procedure. Six patients were lost to follow-up, and ultimately 64 patients (66 ankles) were evaluated. Visual Analog Scale (VAS) pain scores, American Orthopaedic Foot & Ankle Society (AOFAS) scores, Karlsson-Peterson ankle scores, and patient satisfaction were evaluated at a mean of 22.1 months (range, 12-68 months) postoperatively. The talar tilt angle and anterior translation were assessed radiographically in pre- and postoperative ankle stress views. The mean patient age at surgery was 30.1 years (range, 16-59 years). RESULTS: The mean VAS pain score decreased from 5.5 to 1.3 (P < .05), and the mean AOFAS improved from 71.0 to 90.9 (P < .05). The mean Karlsson-Peterson score improved from 55.1 to 90.3, whereas talar tilt decreased from 14.8 degrees to 3.9 degrees. There was no significant difference in clinical outcomes between the pretensioned and nonpretensioned groups. CONCLUSION: This procedure yielded successful results, including satisfactory ankle stability and clinical outcomes, in ankles with poor lateral ligament tissues. LEVEL OF EVIDENCE: Level IV, case series. PMID- 25921201 TI - Erratum to: Surgical completeness of robotic thyroidectomy: a prospective comparison with conventional open thyroidectomy in papillary thyroid carcinoma patients. PMID- 25921200 TI - VGF, Which Is Induced Transcriptionally in Stroke Brain, Enhances Neurite Extension and Confers Protection Against Ischemia In Vitro. AB - Ischemic stroke is a devastating neural event as currently no therapies other than physical rehabilitation are available to enhance recovery after stroke. To identify endogenous mediators to repair stroke brain, we performed the expression profiling analysis of transcripts in the mouse photothrombotic stroke brain. Based on real-time PCR analysis, we found VGF, identified as a nerve growth factor (NGF)-regulated transcript, was induced transcriptionally in stroke brain at 1-7 days after insult. The immunoreactivites of VGF were observed in the neurons around the ischemic core of stroke brain. Experiments with various inhibitors and plasmid transfections indicated that cAMP response element binding protein-mediated complex signaling pathways are possibly implicated in the NGF mediated VGF expressions in vitro. Furthermore, the over-expression of VGF promoted neurite extensions and conferred protections from ischemic stress in vitro. These findings raise the possibility the application of VGF could be one of the promising therapeutic strategies to enhance recovery after stroke. PMID- 25921202 TI - Transanal total mesorectal excision for rectal carcinoma: short-term outcomes and experience after 80 cases. AB - BACKGROUND: Low anterior resection for distal and mid-rectal cancer is associated with high positive resection margins. Transanal total mesorectal excision (TaTME) is a new treatment in which the rectum is dissected transanally according to TME principles. The short-term results and oncological follow-up of the first 80 patients were described. METHODS: Between June 2012 and September 2014, all patients in the Gelderse Vallei Hospital and the VU University Medical Center with histologically proven distal or mid-rectal carcinomas without evidence of distant metastases underwent TaTME. Patients with T4 tumors were excluded. Transanal mobilization was performed with the aid of a single port and endoscopic instruments according to TME criteria. RESULTS: Eighty patients were operated in a period of 2 years. Laparotomy was recommended and performed in four patients. Postoperative morbidity was 39%. Ten (12%) complications were graded as severe (Clavien-Dindo grade 3, 4 and 5) and needed re-intervention. Median operative time was 204 min (range 91-447). Median hospital stay was 8 days (range 3-41). Specimens were graded as complete in 88% of the patients, nearly complete in 9% and incomplete in 3%. A positive circumferential resection margin (<2 mm) was observed in two patients. During the two and half years study period, a local recurrence was observed in two patients. CONCLUSION: TaTME is a safe alternative to standard laparoscopic TME in selected low-risk patients with rectal carcinoma when treated by an experienced colorectal team. In the future, randomized trials are necessary to prove its oncological safety. PMID- 25921203 TI - Association between intake of dairy products and short-term memory with and without adjustment for genetic and family environmental factors: A twin study. AB - BACKGROUND & AIMS: Previous studies have indicated associations between intake of dairy products and better cognitive function and reduced risk of dementia. However, these studies did not adjust for genetic and family environmental factors that may influence food intake, cognitive function, and metabolism of dairy product nutrients. In the present study, we investigated the association between intake of dairy products and short-term memory with and without adjustment for almost all genetic and family environmental factors using a genetically informative sample of twin pairs. METHODS: A cross-sectional study was conducted among twin pairs aged between 20 and 74. Short-term memory was assessed as primary outcome variable, intake of dairy products was analyzed as the predictive variable, and sex, age, education level, marital status, current smoking status, body mass index, dietary alcohol intake, and medical history of hypertension or diabetes were included as possible covariates. Generalized estimating equations (GEE) were performed by treating twins as individuals and regression analyses were used to identify within-pair differences of a twin pair to adjust for genetic and family environmental factors. Data are reported as standardized coefficients and 95% confidence intervals (CI). RESULTS: Analyses were performed on data from 78 men and 278 women. Among men, high intake of dairy products was significantly associated with better short-term memory after adjustment for the possible covariates (standardized coefficients = 0.22; 95% CI, 0.06-0.38) and almost all genetic and family environmental factors (standardized coefficients = 0.38; 95% CI, 0.07-0.69). Among women, no significant associations were found between intake of dairy products and short-term memory. Subsequent sensitivity analyses were adjusted for small samples and showed similar results. CONCLUSIONS: Intake of dairy product may prevent cognitive declines regardless of genetic and family environmental factors in men. PMID- 25921204 TI - Changes in body composition in heart failure patients after a resistance exercise program and branched chain amino acid supplementation - Letter to Editor. PMID- 25921205 TI - A comprehensive impedance journey to continuous microbial fuel cells. AB - The aim of the present work was to characterize the impedance response of an air cathode MFC operating in a continuous mode and to determine intrinsic properties that define its performance which are crucial to be controlled for scalability purposes. The limiting step on electricity generation is the anodic electrochemically-active biofilm, independently of the external resistance, Rext, utilized. However, for Rext below 3 kOmega the internal impedance of the bioanode remained invariable, in good correspondence to the power density profile. The hydraulic retention time (HRT) had an effect on the impedance of both the bioanode and the air-cathode and especially on the overall MFC. The lowest HRT at which the MFC was operable was 3h. Yet, the variation on the HRT did not have a significant impact on power generation. A two constant phase element-model was associated with the EIS response of both bioanode and air-cathode, respectively. Consistency was found between the CPE behaviour and the normal power-law distribution of local resistivity with a uniform dielectric constant, which represented consistent values with the electrical double layer, the Nernst diffusion layer and presumably the biofilm thickness. These results have future implications on MFC monitoring and control, as well as in providing critical parameters for scale-up. PMID- 25921206 TI - Is "boarding" appropriate to help reduce crowding in emergency departments? PMID- 25921208 TI - Site-directed mutagenesis of amino acid residues of D1 protein interacting with phosphatidylglycerol affects the function of plastoquinone QB in photosystem II. AB - Recent X-ray crystallographic analysis of photosystem (PS) II at 1.9-A resolution identified 20 lipid molecules in the complex, five of which are phosphatidylglycerol (PG). In this study, we mutagenized amino acid residues S232 and N234 of D1, which interact with two of the PG molecules (PG664 and PG694), by site-directed mutagenesis in Synechocystis sp. PCC 6803 to investigate the role of the interaction in PSII. The serine and asparagine residues at positions 232 and 234 from the N-terminus were mutagenized to alanine and aspartic acid, respectively, and a mutant carrying both amino acid substitutions was also produced. Although the obtained mutants, S232A, N234D, and S232AN234D, exhibited normal growth, they showed decreased photosynthetic activities and slower electron transport from QA to QB than the control strain. Thermoluminescence analysis suggested that this slower electron transfer in the mutants was caused by more negative redox potential of QB, but not in those of QA and S2. In addition, the levels of extrinsic proteins, PsbV and PsbU, were decreased in PSII monomer purified from the S232AN234D mutant, while that of Psb28 was increased. In the S232AN234D mutant, the content of PG in PSII was slightly decreased, whereas that of monogalactosyldiacylglycerol was increased compared with the control strain. These results suggest that the interactions of S232 and N234 with PG664 and PG694 are important to maintain the function of QB and to stabilize the binding of extrinsic proteins to PSII. PMID- 25921209 TI - Mismatch repair status and synchronous metastases in colorectal cancer: A nationwide cohort study. AB - The causality between the metastatic potential, mismatch repair status (MMR) and survival in colorectal cancer (CRC) is complex. This study aimed to investigate the impact of MMR in CRC on the occurrence of synchronous metastases (SCCM) and survival in patients with SCCM on a national basis. A nationwide cohort study of 6,692 patients diagnosed with CRC between 2010 and 2012 was conducted. Data were prospectively entered into the Danish Colorectal Cancer Group's database and merged with data from the Danish Pathology Registry and the National Patient Registry. Multivariable and multinomial logistic- and Cox-regression and proportional excess hazards analyses were used for confounder adjustment and to adjust for the general population mortality. In total, 983 of 6,692 patients (14.7%) had dMMR and 935 (14.0%) had SCCM. dMMR was associated with a decreased risk of SCCM, adjusted Odds Ratio (aOR) = 0.54 (95% confidence interval (CI):0.40 0.70, p < 0.001). The association only applied to confined hepatic metastases (aOR = 0.30, 95%CI: 0.18-0.49, p < 0.001), whereas the presence of confined pulmonary metastases (aOR = 0.71, 95% CI: 0.39-1.29, p = 0.258) or synchronous hepatic and pulmonary metastases (aOR = 0.69, 95% CI:0.26-1.29, p = 0.436) were unaffected by MMR. MMR in patients with SCCM had no impact on survival (Cox: adjusted Hazard Ratio (aHR) = 0.76, 95% CI: 0.54-1.06, p = 0.101; Proportional excess hazards: aHR = 0.73, 95% CI: 0.50-1.07, p = 0.111) when adjusting for other prognostic factors. The metastatic pattern varied according to MMR status. MMR had no impact on survival in patients with UICC Stage IV CRC. These findings may be important for the understanding of the metastatic processes and thus for optimizing staging and treatment in CRC patients. PMID- 25921207 TI - Production of carotenoids by microalgae: achievements and challenges. AB - Carotenoids are a wide group of lipophylic isoprenoids synthesized by all photosynthetic organisms and also by some non-photosynthetic bacteria and fungi. Animals, which cannot synthesize carotenoids de novo, must include them in their diet to fulfil essential provitamin, antioxidant, or colouring requirements. Carotenoids are indispensable in light harvesting and energy transfer during photosynthesis and in the protection of the photosynthetic apparatus against photooxidative damage. In this review, we outline the factors inducing carotenoid accumulation in microalgae, the knowledge acquired on the metabolic pathways responsible for their biosynthesis, and the recent achievements in the genetic engineering of this pathway. Despite the considerable progress achieved in understanding and engineering algal carotenogenesis, many aspects remain to be elucidated. The increasing number of sequenced microalgal genomes and the data generated by high-throughput technologies will enable a better understanding of carotenoid biosynthesis in microalgae. Moreover, the growing number of industrial microalgal species genetically modified will allow the production of novel strains with enhanced carotenoid contents. PMID- 25921210 TI - A Novel KCNJ13 Nonsense Mutation and Loss of Kir7.1 Channel Function Causes Leber Congenital Amaurosis (LCA16). AB - Mutations in the KCNJ13 gene that encodes the inwardly rectifying potassium channel Kir7.1 cause snowflake vitreoretinal degeneration (SVD) and leber congenital amaurosis (LCA). Kir7.1 controls the microenvironment between the photoreceptors and the retinal pigment epithelium (RPE) and also contributes to the function of other organs such as uterus and brain. Heterologous expressions of the mutant channel have suggested a dominant-negative loss of Kir7.1 function in SVD, but parallel studies in LCA16 have been lacking. Herein, we report the identification of a novel nonsense mutation in the second exon of the KCNJ13 gene that leads to a premature stop codon in association with LCA16. We have determined that the mutation results in a severe truncation of the Kir7.1 C terminus, alters protein localization, and disrupts potassium currents. Coexpression of the mutant and wild-type channel has no negative influence on the wild-type channel function, consistent with the normal clinical phenotype of carrier individuals. By suppressing Kir7.1 function in mice, we were able to reproduce the severe LCA electroretinogram phenotype. Thus, we have extended the observation that Kir7.1 mutations are associated with vision disorders to include novel insights into the molecular mechanism of disease pathobiology in LCA16. PMID- 25921211 TI - Response to: "Antimicrobial drug-resistant microbes have a higher risk of health care-associated pneumonia in eastern Taiwan". PMID- 25921212 TI - The age-related emergence of cranial morphological variation. AB - Evaluation of ancestry from skeletal remains is problematic for subadults because of a lack of systematic research on the topic. This paper addresses the need for systematic research into geographical variation through childhood and puberty through the examination of the emergence of cranial morphological traits through an analysis of 756 subadults from 4 months in utero to <20 years of age. The first appearance of a trait, changes in the morphology of a trait through time, age stability as related to the age of maturation of the structure, and the developmental mechanisms and processes that cause traits to appear together are addressed. Most traits are influenced by patterns of growth and development and become age stable in conjunction with the larger growth complexes of which they are a part. Geographic cranial variation is present from an early age. Population specific differences in the expression of most traits are apparent from their first appearance. PMID- 25921213 TI - Safety of brilliant cresyl blue staining protocols on human granulosa and cumulus cells. AB - The selection of human immature oocytes destined for in vitro maturation (IVM) is performed according to their cumulus-oocyte complex (COC) morphology. In animal models, oocyte pre-selection with brilliant cresyl blue (BCB) staining improves fertilization and blastocyst rates and even increases the number of calves born. As the granulosa cells and cumulus cells (GCs and CCs) have a close relationship with the oocyte and are available in in vitro fertilization (IVF) programs, applying BCB staining to these cells may help to elucidate whether BCB shows toxicity to human oocytes and to determine the safest protocol for this dye. GCs and CCs were isolated from 24 patients who underwent controlled ovarian stimulation. After 48 h, cells were exposed to: Dulbecco's Modified Eagle Medium (DMEM) with or without phenol red, DPBS and mDPBS for 60 min; 13, 20 and 26 MUM BCB for 60 min; and 60, 90 or 120 min to 13 MUM BCB. Cellular viability was tested using 3-(4,5-dimethylthiazolyl-2)-2,5-diphenyltetrazolium bromide (MTT) and trypan blue assays. The 20 and 26 MUM BCB exposures resulted in lower cell viability, similar to when cells were exposed to BCB for 90 or 120 min. GCs and CCs viabilities were equal among control group and 13 MUM BCB group after 60 min. BCB staining was not toxic to GCs and CCs when the regime of 13 MUM BCB for 60 min was used. Due to the close molecular/biochemical relationship between these cells and the gamete, we propose that it is unlikely that the use of BCB could interfere with the viability/health of human oocytes. PMID- 25921214 TI - CD8+ T cells in Trypanosoma cruzi infection. AB - Trypanosoma cruzi infection and Chagas disease remains among the most neglected of the neglected tropical diseases. Despite this, studies of the immune response to T. cruzi have provided new insights in immunology and guidance for approaches for prevention and treatment of the disease. T. cruzi represents one of the very best systems in which to study CD8(+) T cell biology; mice, dogs, and primates (and many other mammals) are all natural hosts for this parasite, the robust T cell responses generated in these hosts can be readily monitored using the full range of cutting edge techniques, and the parasite can be easily modified to express (or not) a variety of tags, reporters, immune enhances, and endogenous or model antigens. The infection in most hosts is characterized by vigorous and largely effective immune responses, including CD8(+) T cells capable of controlling T. cruzi at the level of the infected host cells. However, this immune control is only partially effective and most hosts maintain a low level infection for life. This review addresses the interplay of highly effective CD8(+) T cell responses with elaborate pathogen immune evasion mechanisms, including the generation and simultaneous expression of highly variant CD8(+) T cell targets and a host cell invasion mechanisms that largely eludes innate immune detection. PMID- 25921216 TI - Assessment of 99mTc-MIBI SPECT(/CT) to monitor multidrug resistance-related proteins and apoptosis-related proteins in patients with ovarian cancer: a preliminary study. AB - OBJECTIVE: Multidrug resistance (MDR) has been suggested to be a major cause of failure of chemotherapy treatment for cancer. It is associated with the expression of MDR-related and apoptosis-related proteins. Recently, technetium 99m hexakis 2-methoxyisobutylisonitrile ((99m)Tc-MIBI) has been suggested as a tumor-seeking agent for the detection of MDR. The aim of this study was to evaluate (99m)Tc-MIBI single-photon emission computed tomography (SPECT)(/CT) for functional imaging of MDR-related and apoptosis-related proteins in patients with ovarian cancer. METHODS: Eleven women (mean age 63 years, range 53-76) with a clinical suspicion of ovarian cancer were prospectively studied. All patients were examined with (99m)Tc-MIBI imaging before surgery. After intravenous injection of 740 MBq (99m)Tc-MIBI, SPECT(/CT) imaging at 10 min and 2 h was performed. Based on the semiquantitative analysis of (99m)Tc-MIBI SPECT(/CT), both early and delayed tumor uptake ratios and washout rate % were calculated. The expression of MDR-related and apoptosis-related proteins was assessed in surgically excised tumors. Immunohistochemical staining was performed to quantify the expression levels of multidrug resistance protein 1 (MDR1), multidrug resistance-associated protein1 (MRP1), MRP3, lung resistance protein (LRP), breast cancer resistance protein (BCRP), Y-box-binding protein-1 (YB-1), Bcl-2, Bax and glutathione-S-transferase. (99m)Tc-MIBI imaging results and immunohistochemical results were compared. RESULTS: Laparotomy was performed in all patients. Six ovarian cancers were proven by histopathological examination. Five of the six ovarian cancers were positive for (99m)Tc-MIBI uptake on both early and delayed images with (99m)Tc-MIBI SPECT(/CT). MDR-related and apoptosis related proteins were found to be expressed in all tumors. For the five positive (99m)Tc-MIBI uptake cases, the washout rate % of (99m)Tc-MIBI uptake showed a significant positive correlation with the expression of YB-1 (r = 0.988, P = 0.0015), and the early tumor uptake ratio showed a significant positive correlation with the expression of Bax (r = 0.882, P = 0.047). CONCLUSIONS: Our results suggested that (99m)Tc-MIBI SPECT(/CT) might be a valuable diagnostic imaging technique to evaluate MDR-associated YB-1 and Bax-mediated apoptosis in patients with ovarian cancer. PMID- 25921215 TI - Epileptogenic zone localization using magnetoencephalography predicts seizure freedom in epilepsy surgery. AB - OBJECTIVE: The efficacy of epilepsy surgery depends critically upon successful localization of the epileptogenic zone. Magnetoencephalography (MEG) enables noninvasive detection of interictal spike activity in epilepsy, which can then be localized in three dimensions using magnetic source imaging (MSI) techniques. However, the clinical value of MEG in the presurgical epilepsy evaluation is not fully understood, as studies to date are limited by either a lack of long-term seizure outcomes or small sample size. METHODS: We performed a retrospective cohort study of patients with focal epilepsy who received MEG for interictal spike mapping followed by surgical resection at our institution. RESULTS: We studied 132 surgical patients, with mean postoperative follow-up of 3.6 years (minimum 1 year). Dipole source modeling was successful in 103 patients (78%), whereas no interictal spikes were seen in others. Among patients with successful dipole modeling, MEG findings were concordant with and specific to the following: (1) the region of resection in 66% of patients, (2) invasive electrocorticography (ECoG) findings in 67% of individuals, and (3) the magnetic resonance imaging (MRI) abnormality in 74% of cases. MEG showed discordant lateralization in ~5% of cases. After surgery, 70% of all patients achieved seizure freedom (Engel class I outcome). Whereas 85% of patients with concordant and specific MEG findings became seizure-free, this outcome was achieved by only 37% of individuals with MEG findings that were nonspecific to or discordant with the region of resection (chi(2) = 26.4, p < 0.001). MEG reliability was comparable in patients with or without localized scalp electroencephalography (EEG), and overall, localizing MEG findings predicted seizure freedom with an odds ratio of 5.11 (95% confidence interval [CI] 2.23-11.8). SIGNIFICANCE: MEG is a valuable tool for noninvasive interictal spike mapping in epilepsy surgery, including patients with nonlocalized findings receiving long-term EEG monitoring, and localization of the epileptogenic zone using MEG is associated with improved seizure outcomes. PMID- 25921217 TI - Exploring the molecular basis of action of ring D aromatic steroidal antiestrogens. AB - Salpichrolides are natural plant steroids that contain an unusual six-membered aromatic ring D. We recently reported that some of these compounds, and certain analogs with a simplified side chain, exhibited antagonist effects toward the human estrogen receptor (ER), a nuclear receptor whose endogenous ligand has an aromatic A ring (estradiol). Drugs acting through the inhibition or modulation of ERs are frequently used as a hormonal therapy for ER(+) breast cancer. Previous results suggested that the aromatic D ring was a key structural motif for the observed activity; thus, this modified steroid nucleus may provide a new scaffold for the design of novel antiestrogens. Using molecular dynamics (MD) simulation we have modeled the binding mode of the natural salpichrolide A and a synthetic analog with an aromatic D ring within the ERalpha. These results taken together with the calculated energetic contributions associated to the different ligand binding modes are consistent with a preferred inverted orientation of the steroids in the ligand-binding pocket with the aromatic ring D occupying a position similar to that observed for the A ring of estradiol. Major changes in both dynamical behavior and global positioning of H11 caused by the loss of the ligand-His524 interaction might explain, at least in part, the molecular basis of the antagonism exhibited by these compounds. Using steered MD we also found a putative unbinding pathway for the steroidal ligands through a cavity formed by residues in H3, H7, and H11, which requires only minor changes in the overall receptor conformation. PMID- 25921219 TI - Customary Homicides in Diyarbakir Province. AB - This study presents an analysis of the causes of so-called honor killings in the context of "customary homicide" and a discussion of preventive measures. Finalized case files of customary homicide between January 1, 2007 and December 31, 2012 were retrospectively examined in Diyarbakir Province, Turkey. Of a total of 28 case victims, 17 (60.7%) were females and 11 (39.3%) were males. All perpetrators were male. There was a significant difference between male and female victims in terms of economic independence (p=0.000). A direct blood relationship or relationship by marriage (such as brother-in-law) was found to have a significant association with the gender of the victim (p<0.001). Multilevel educational activities targeting a transformation of the perception of women by society, replacement of patriarchal models with more modern attitudes, and encouragement of individuality may represent effective strategies that may help reduce the number of customary homicide, which represents a multifaceted problem. PMID- 25921220 TI - Image-based focused counting of dividing cells for non-invasive monitoring of regenerative medicine products. AB - Despite the growing numbers of successful applications in regenerative medicine, biotechnologies for evaluating the quality of cells remain limited. To evaluate the cultured cells non-invasively, image-based cellular assessment method holds great promise. However, although there are various image-processing algorithms, very few studies have focused to prove the effectiveness of phase contrast images with risk assessment example that reflects actual difficulties in regenerative medicine products. In this study, we developed a simple image-processing method to recognize the number of dividing cells in time-course phase-contrast microscopic images, and applied this method to assess the irregular proliferation behavior in normal cells. Practically, as a model, rapid proliferating human fibrosarcoma cells were mixed in normal human fibroblasts in the same culture dish, and their sarcoma existence was evaluated. As a result, the existence of sarcoma population in normal cell sample could be feasibly detected within earliest period of cell culture by their irregular rise of accumulated counts of dividing cells. Our image-processing technique also illustrates the technical effectiveness of combining intra-frame and inter-frame image processing to accurately count only the dividing cells. Our concept of focused counting of dividing cells shows a successful example of image-based analysis to quickly and non-invasively monitor the regular state of regenerative medicine products. PMID- 25921218 TI - Germline-specific H1 variants: the "sexy" linker histones. AB - The eukaryotic genome is packed into chromatin, a nucleoprotein complex mainly formed by the interaction of DNA with the abundant basic histone proteins. The fundamental structural and functional subunit of chromatin is the nucleosome core particle, which is composed by 146 bp of DNA wrapped around an octameric protein complex formed by two copies of each core histone H2A, H2B, H3, and H4. In addition, although not an intrinsic component of the nucleosome core particle, linker histone H1 directly interacts with it in a monomeric form. Histone H1 binds nucleosomes near the exit/entry sites of linker DNA, determines nucleosome repeat length and stabilizes higher-order organization of nucleosomes into the ~30 nm chromatin fiber. In comparison to core histones, histone H1 is less well conserved through evolution. Furthermore, histone H1 composition in metazoans is generally complex with most species containing multiple variants that play redundant as well as specific functions. In this regard, a characteristic feature is the presence of specific H1 variants that replace somatic H1s in the germline and during early embryogenesis. In this review, we summarize our current knowledge about their structural and functional properties. PMID- 25921221 TI - Hepatocellular carcinoma associated with tight-junction protein 2 deficiency. PMID- 25921223 TI - All your data are always missing: incorporating bias due to measurement error into the potential outcomes framework. AB - Epidemiologists often use the potential outcomes framework to cast causal inference as a missing data problem. Here, we demonstrate how bias due to measurement error can be described in terms of potential outcomes and considered in concert with bias from other sources. In addition, we illustrate how acknowledging the uncertainty that arises due to measurement error increases the amount of missing information in causal inference. We use a simple example to show that estimating the average treatment effect requires the investigator to perform a series of hidden imputations based on strong assumptions. PMID- 25921224 TI - Advances in sperm proteomics: best-practise methodology and clinical potential. AB - The recent application of mass spectrometry to the study of the sperm cell has led to an unprecedented capacity for identification of sperm proteins in a variety of species. Knowledge of the proteins that make up the sperm cell represents the first step towards understanding its normal function and the molecular anomalies associated with male infertility. The present review starts with an introduction of the sperm cell biology and is followed by the consideration of the methodological key aspects to be aware of during sample sourcing and preparation, including data interpretation. It then overviews the initiatives developed so far towards the completion of the sperm proteome, with a particular focus in human but with the inclusion of some comments on different model species. Finally, all studies performing differential proteomics in infertile patients are reviewed, pointing to future potential applications. PMID- 25921222 TI - Common genetic variants in epigenetic machinery genes and risk of upper gastrointestinal cancers. AB - BACKGROUND: Populations in north central China are at high risk for oesophageal squamous cell carcinoma (ESCC) and gastric cancer (GC), and genetic variation in epigenetic machinery genes and pathways may contribute to this risk. METHODS: We used the adaptive multilocus joint test to analyse 192 epigenetic genes involved in chromatin remodelling, DNA methylation and microRNA biosynthesis in 1942 ESCC and 1758 GC cases [1126 cardia (GCA) and 632 non-cardia adenocarcinoma (GNCA)] and 2111 controls with Chinese ancestry. We examined potential function of risk alleles using in silico and expression quantitative trait loci (eQTLs) analyses. RESULTS: Suggestive pathway-based associations were observed for the overall epigenetic (P-value(PATH) = 0.034) and chromatin remodelling (P-value(PATH) = 0.039) pathways with risk of GCA, but not GC, GNCA or ESCC. Overall, 37 different epigenetic machinery genes were associated with risk of one or more upper gastrointestinal (UGI) cancer sites (P-value(GENE )< 0.05), including 14 chromatin remodelling genes whose products are involved in the regulation of HOX genes. We identified a gastric eQTL (rs12724079; rho = 0.37; P = 0.0006) which regulates mRNA expression of ASH1L. Several suggestive eQTLs were also found in oesophageal (rs10898459 in EED), gastric cardia (rs7157322 in DICER1; rs8179271 in ASH1L), and gastric non-cardia (rs1790733 in PPP1CA) tissues. CONCLUSIONS: Results of our analyses provide limited but suggestive evidence for a role of epigenetic gene variation in the aetiology of UGI cancer. PMID- 25921225 TI - The synthesis of new amphiphilic p-tert-butylthiacalix[4]arenes containing peptide fragments and their interaction with DNA. AB - New water-soluble p-tert-butylthiacalix[4]arenes containing peptide and quaternary ammonium fragments in cone and 1,3-alternate conformations were synthesized and characterized. The interaction of the macrocycles with DNA was studied by UV-spectroscopy, DLS and TEM. It was shown that the interaction of the self-associates based on p-tert-butylthiacalix[4]arenes tetrasubstituted at the lower rim with glycine and quaternary ammonium fragments in cone and 1,3 alternate conformations with DNA led to the formation of particles of about 99 192 nm in size. PMID- 25921226 TI - Identifying bvFTD Within the Wide Spectrum of Late Onset Frontal Lobe Syndrome: A Clinical Approach. AB - OBJECTIVE: The behavioral variant of frontotemporal dementia (bvFTD) can be difficult to diagnose because of the extensive differential diagnosis, including many other diseases presenting with a frontal lobe syndrome. We aimed to identify the diagnostic spectrum causing a late onset frontal lobe syndrome and examine the quality of commonly used instruments to distinguish between bvFTD and non bvFTD patients, within this syndrome. METHODS: A total of 137 patients fulfilling the criteria of late onset frontal lobe syndrome, aged 45 to 75 years, were included in a prospective observational study. Diagnoses were made after clinical and neuropsychological examination, and neuroimaging and cerebral spinal fluid results were taken into account. Baseline characteristics and the scores on the Mini-Mental State Exam (MMSE), frontal assessment battery (FAB), Frontal Behavioral Inventory (FBI), and Stereotypy Rating Inventory (SRI) were compared between the bvFTD and the non-bvFTD group. RESULTS: Fifty-five (40%) of the patients received a bvFTD diagnosis (33% probable and 7% possible bvFTD). Fifty one patients (37%) had a psychiatric disorder, including 20 with major depressive disorder. Thirty-one patients received an alternative neurological, including neurodegenerative, diagnosis. MMSE and FAB scores were unspecific for a particular diagnosis. A score above 12 on the positive FBI subscale or a score above 5 on the SRI were indicative of a bvFTD diagnosis. CONCLUSION: A broad spectrum of both neurological and psychiatric disorders underlies late onset frontal lobe syndrome, of which bvFTD was the most prevalent diagnosis in our cohort. The commonly used MMSE and the FAB could not successfully distinguish between bvFTD and non-bvFTD, but this could be achieved with the more specific FBI and SRI. PMID- 25921227 TI - MicroRNA-triggered, cascaded and catalytic self-assembly of functional "DNAzyme ferris wheel" nanostructures for highly sensitive colorimetric detection of cancer cells. AB - The construction of DNA nanostructures with various sizes and shapes has significantly advanced during the past three decades, yet the application of these DNA nanostructures for solving real problems is still in the early stage. On the basis of microRNA-triggered, catalytic self-assembly formation of the functional "DNAzyme ferris wheel" nanostructures, we show here a new signal amplification platform for highly sensitive, label-free and non-enzyme colorimetric detection of a small number of human prostate cancer cells. The microRNA (miR-141), which is catalytically recycled and reused, triggers isothermal self-assembly of a pre-designed, G-quadruplex sequence containing hairpin DNAs into "DNAzyme ferris wheel"-like nanostructures (in association with hemin) with horseradish peroxidase mimicking activity. These DNAzyme nanostructures catalyze an intensified color transition of the probe solution for highly sensitive detection of miR-141 down to 0.5 pM with the naked eye, and the monitoring of as low as 283 human prostate cancer cells can also, theoretically, be achieved in a colorimetric approach. The work demonstrated here thus offers new opportunities for the construction of functional DNA nanostructures and for the application of these DNA nanostructures as an effective signal amplification means in the sensitive detection of nucleic acid biomarkers. PMID- 25921228 TI - Tilted frames of reference have similar effects on the perception of gravitational vertical and the planning of vertical saccadic eye movements. AB - We investigated the effects of a tilted reference frame (i.e., allocentric visual context) on the perception of the gravitational vertical and saccadic eye movements along a planned egocentric vertical path. Participants (n = 5) in a darkened room fixated a point in the center of a circle on an LCD display and decided which of two sequentially presented dots was closer to the unmarked '6 o'clock' position on that circle (i.e., straight down toward their feet). The slope of their perceptual psychometric functions showed that participants were able to locate which dot was nearer the vertical with a precision of 1 degrees -2 degrees . For three of the participants, a square frame centered at fixation and tilted (in the roll direction) 5.6 degrees from the vertical caused a strong perceptual bias, manifest as a shift in the psychometric function, in the direction of the traditional 'rod-and-frame' effect, without affecting precision. The other two participants showed negligible or no equivalent biases. The same subjects participated in the saccade version of the task, in which they were instructed to shift their gaze to the 6 o'clock position as soon as the central fixation point disappeared. The participants who showed perceptual biases showed biases of similar magnitude in their saccadic endpoints, with a strong correlation between perceptual and saccadic biases across all subjects. Tilting of the head 5.6 degrees reduced both perceptual and saccadic biases in all but one observer, who developed a strong saccadic bias. Otherwise, the overall pattern and significant correlations between results remained the same. We conclude that our observers' saccades-to-vertical were dominated by perceptual input, which outweighed any gravitational or head-centered input. PMID- 25921229 TI - The effects of self-control on cognitive resource allocation during sustained attention: a transcranial Doppler investigation. AB - Vigilance, or sustained attention, is a required ability in many operational professions. While past research has consistently indicated that vigilance performance declines over time, referred to as the vigilance decrement, the theoretical mechanisms underlying the decrement continue to be explored. In the current study, trait self-control was examined to determine how this individual differences measure may contribute to the theoretical explanation of vigilance decrement. Transcranial Doppler sonography (TCD) was used as a measure of cerebral blood flow velocity (CBFV), as previous research has indicated that CBFV may index attentional resource allocation during vigilance (e.g., Shaw et al. in Hum Factors Ergon Soc 50:1619-1623, 2009). Participants performed a demanding 12 min computer-based vigilance task. Prior to the task, a validated self-report measure was used to determine trait-level self-control, and subjective workload was measured after the task was completed. Participants were divided, based upon survey responses, as either low- or high-trait self-control. Performance results showed a significant decrement across participants, but no significant main effect or interaction relating to the self-control measure was observed. Results relating to the TCD measure showed a significant decline in CBFV in the low self control group, but no CBFV decrement was observed in the high self-control group. The subjective workload results revealed a nonsignificant trend of the low self control group becoming more frustrated after the task. These results suggest that there are differences in the resource allocation strategies between low and high self-control participants. How trait self-control can add to an understanding of the theoretical underpinnings of sustained attention performance is discussed. PMID- 25921230 TI - Recurrence, retreatment, and rebleed rates of coiled aneurysms with respect to the Raymond-Roy scale: a meta-analysis. AB - BACKGROUND AND PURPOSE: The Raymond-Roy grading scale is used for aneurysm coiling with only limited data on its validity. The scale was developed based on the extent of initial aneurysm occlusion from 1 to 3. However, the model usefulness in evaluating recurrence, retreatment, and rebleeding is unknown. Our goal was to perform a meta-analysis to evaluate the predictiveness of the Raymond scale. METHODS: We performed a systematic review of the English literature for aneurysm coiling which reported the initial embolization results, based on the Raymond-Roy grading scale, and the respective recurrence rates, retreatment rates, and rebleed rates. This yielded data for 4587 aneurysms. We conducted a Bayesian random effects meta-analysis to evaluate the outcomes with respect to the reported initial embolization results. RESULTS: We found the Raymond scale to be predictive of retreatment, with statistically higher rates of retreatment with higher initial Raymond grade. Furthermore, we found a higher probability of rebleeding for initial grades 2 or 3 versus grade 1, which approached significance. The rebleed rates were probably affected by monitoring and treatment of recurrence. However, although there was a trend towards higher recurrence rates with initial grade, this was not statistically significant. CONCLUSIONS: The modified Raymond-Roy scale appears to provide reasonable predictive value for treated aneurysm, especially for the clinically more important aspects of retreatment and rebleed rates. PMID- 25921231 TI - The role of pancreatic ducts in the pathogenesis of acute pancreatitis. AB - Pancreatic ducts secrete 2.5 l of alkaline, HCO3(-)-rich fluid daily which greatly contributes to the homeostasis of the pancreas. Ducts are also important in the pathophysiology of the pancreas; alteration of ductal function can lead to severe diseases such as cystic fibrosis and chronic pancreatitis. The role of pancreatic ducts in the development of acute pancreatitis has only been uncovered recently. Pancreatitis inducing agents like bile acids and ethanol dose dependently affect pancreatic ductal secretion; low concentrations stimulate, whereas high concentrations inhibit secretion. The majority of the review will focus on the central role of cystic fibrosis transmembrane conductance regulator (CFTR), a critical protein in the regulation of ductal secretion, in the pathogenesis of acute pancreatitis which is highlighted by numerous investigations. Downregulation of CFTR expression results in increased severity of acute pancreatitis in mice. Furthermore, human genetic studies have demonstrated statistically significant association of CFTR mutations with acute recurrent pancreatitis. Overall, the data support the involvement of pancreatic ducts in the pathogenesis of acute pancreatitis. PMID- 25921233 TI - Electronic properties of epitaxial silicene on diboride thin films. AB - The Si counterpart of graphene-silicene-has partially similar but also unique electronic properties that relate to the presence of an extended pi electronic system, the flexible crystal structure and the large spin-orbit coupling. Driven by predictions for exceptional electronic properties like the presence of massless charge carriers, the occurrence of the quantum Hall effect and perfect spin-filtering in free-standing, unreconstructed silicene, the recent experimental realization of largely sp(2)-hybridized, Si honeycomb lattices grown on a number of metallic substrates provided the opportunity for the systematic study of the electronic properties of epitaxial silicene phases. Following a discussion of theoretical predictions for free-standing silicene, we review properties of (?3 * ?3)-reconstructed, epitaxial silicene phases but with the emphasis on the extensively studied case of silicene on ZrB2(0 0 0 1) thin films. As the experimental results show, the structural and electronic properties are highly interlinked and leave their fingerprint on the chemical states of individual Si atoms as revealed in core-level photoelectron spectra as well as in the valence electronic structure and low-energy interband transitions. With the critical role of substrates and of the chemical stability of epitaxial silicene highlighted, finally, benefits and challenges for any future silicene-based nanoelectronics are being put into perspective. PMID- 25921232 TI - Lymph node status predicts the benefit of adjuvant chemoradiotherapy for patients with resected pancreatic cancer. AB - BACKGROUND: The role of adjuvant chemoradiotherapy in pancreatic cancer remains limited. The primary aim of this study was to determine the prediction of lymph node (LN) status to the benefit of adjuvant chemoradiotherapy for patients with resected pancreatic adenocarcinoma. METHODS: Between December 2010 and December 2012, a total of 152 patients undergoing curative R0 resection for pancreatic adenocarcinoma from multi-institutions were retrospectively analyzed. RESULTS: Overall median survival was 16.3 months. Sixty-four patients (42.1%) received adjuvant chemoradiotherapy, whereas 88 (57.9%) did not receive adjuvant therapy after surgery. Patients who received chemoradiotherapy could achieve an improved median OS compared with surgery alone (20.3 versus 13.9 months, p=0.027). Stratified by different lymph node status, multivariate analysis demonstrated the benefit of adjuvant chemoradiotherapy was only seen among patients with lymphatic positive disease (HR = 0.54, 95% CI, 0.33-0.88; p=0.014), not lymphatic negative disease (HR = 0.80, 95% CI, 0.44-1.46; p=0. 468). CONCLUSIONS: This study suggests adjuvant chemoradiotherapy is associated with a significant improvement of survival only in patients with LN-positive disease, while the effects of chemoradiotherapy on patients with LN-negative disease may be limited. This study may add incremental knowledge of the role of lymph node status in offering treatment with adjuvant chemoradiotherapy. PMID- 25921234 TI - Child abuse and child protection: The role of the expert. PMID- 25921235 TI - Safety and feasibility of laparoscopic colo-rectal surgery for cancer at a tertiary center in a developing country: Egypt as an example. AB - BACKGROUND: Laparoscopic colectomy has been shown to have significant short- and long-term benefits compared to open approach. The incorporation of laparoscopy in developing countries is challenging, due to the high costs of equipment and lack of expertise. The aim of this study was to evaluate the safety and feasibility of laparoscopic colorectal surgery for cancer that could be performed in developing countries under different circumstances in developed countries. METHODS: Thirty seven patients (23 males and 14 females) with colorectal cancer with a median age of 46 years (39-72) have been enrolled for laparoscopic colo-rectal surgery in a tertiary center in Egypt (South Egypt Cancer Institute) with the trend of reuse of some disposable laparoscopic instruments. RESULTS: The median operative time was 130 min (95-195 min). The median estimated blood loss was 70 ml (30-90 ml). No major intra-operative complications have been encountered. Two cases (5.5%) have been converted because of local advancement (one case) and bleeding with unavailability of vessel sealing device at that time (one case). The median time for passing flatus after surgery was 36 h (12-72 h). The median hospital stay was 4.8 days (4-7 days). The peri-operative period passed without events. Pathologic outcome revealed that the median number of retrieved lymph nodes was 14 (range 9 23 lymph node) and all cases had free surgical margin. CONCLUSION: Laparoscopic colorectal surgery for cancer in developing countries could be safe and feasible. Safe reuse of disposable expensive parts of some laparoscopic instruments could help in propagation of this technique in developing countries. PMID- 25921237 TI - Engineering Control of Noise From 4-Roll Calender Operations in Tire Manufacturing. PMID- 25921236 TI - Exome sequencing of patients with histiocytoid cardiomyopathy reveals a de novo NDUFB11 mutation that plays a role in the pathogenesis of histiocytoid cardiomyopathy. AB - Histiocytoid cardiomyopathy (Histiocytoid CM) is a rare form of cardiomyopathy observed predominantly in newborn females that is fatal unless treated early in life. We have performed whole exome sequencing on five parent-proband trios and identified nuclear-encoded mitochondrial protein mutations in three cases. The molecular genetic basis of Histiocytoid CM remains unknown despite several hypotheses in medical literature. The findings presented in this manuscript may represent components of genetic etiologies for this heterogeneous disease. Two probands had de novo non-sense mutations in the second exon of the X-linked nuclear gene NDUFB11. A third proband was doubly heterozygous for inherited rare variants in additional components of complex I, NDUFAF2 and NDUFB9, confirming that Histiocytoid CM is genetically heterogeneous. In a fourth case, the proband with Histiocytoid CM inherited a mitochondrial mutation from her heteroplasmic mother, as did her brother who presented with cardiac arrhythmia. Strong candidate recessive or compound heterozygous variants were not found for this individual or for the fifth case. Although NDUFB11 has not been implicated before in cardiac pathology, morpholino-mediated knockdown of ndufb11 in zebrafish embryos generated defective cardiac tissue with cardiomegaly, looping defects, and arrhythmia which suggests the role of NDUFB11 in the pathogenesis of this abnormal cardiac pathology. Taken together, the unbiased whole exome sequencing approach confirms the suspected genetic heterogeneity of Histiocytoid CM. Therefore, the novel NDUFB11 mutation may cause a complex 1 deficiency in synergy with additional unknown mtDNA variants. PMID- 25921238 TI - The effects of feeding immunostimulant beta-glucan on the immune response of Pangasianodon hypophthalmus. AB - Immunostimulants are food additives used by the aquaculture industry to enhance the immune response of fish, and although beta-glucans are now commonly used for this purpose in aquaculture, little is known about their effects on the immune response of Pangasianodon hypophthalmus. Thus, a variety of immune parameters (e.g. phagocytosis, respiratory burst, lysozyme, complement, peroxidase, total protein, total anti-protease, total IgM, natural antibody titres, and specific IgM titres) was examined in this species after feeding fish with a basal control diet or diets supplemented with 0.05, 0.1, or 0.2 g/kg fungal-derived beta-glucan or 0.1% commercial yeast-derived beta-glucan, as a positive control diet, for a period of four weeks. The effect of the glucans on disease resistance was then evaluated by experimentally infecting the fish with Edwardsiella ictaluri by immersion and mortalities monitored for 14 days. Samples were collected from fish for analysis at 0, 1, 3, 7, 14, 21 and 28 days post-feeding (dpf), and also at 14 days post infection (dpi). The lowest dose of fungal-derived beta-glucan (0.05%) appeared insufficient to effectively stimulate the immune response of the fish, while those fed with the two highest levels of fungal-derived beta-glucan had enhanced immune responses compared to the control group. Significantly elevated levels of respiratory burst activity on all days examined (P < 0.05) and lysozyme activity on 7 dpf were found in the group fed 0.2% fungal-derived beta-glucan, while plasma anti-protease activity was significantly enhanced (P < 0.05) by 21 dpf, natural antibody titres by 3 dpf and complement activity by 7 dpf and also at 14 dpi in the group fed 0.1% fungal-derived beta-glucan. No statistical differences was seen in the level of mortalities between the dietary groups, although the group fed with the control diet had the highest level of mortalities and the groups fed with commercial yeast-derived beta-glucan and 0.2% fungal derived beta-glucan the lowest. PMID- 25921239 TI - Reinventing clinical trials: a review of innovative biomarker trial designs in cancer therapies. AB - INTRODUCTION: Recently, new clinical trial designs involving biomarkers have been studied and proposed in cancer clinical research, in the hope of incorporating the rapid growing basic research into clinical practices. SOURCES OF DATA: Journal articles related to various biomarkers and their role in cancer clinical trial, articles and books about statistical issues in trial design, and regulatory website, documents, and guidance for submission of targeted cancer therapies. AREAS OF AGREEMENT: The drug development process involves four phases. The confirmatory Phase III is essential in regulatory approval of a special treatment. AREAS OF CONTROVERSY: Regulatory agency has restrictions on confirmatory trials 'using adaptive designs'. No rule of thumb to pick the most appropriate design for biomarker-related trials. GROWING POINTS: Statistical issues to solve in new designs. Regulatory acceptance of the 'newly proposed trial designs'. AREAS TIMELY FOR DEVELOPING RESEARCH: Biomarker-related trial designs that can resolve the statistical issues and satisfy the regulatory requirement. PMID- 25921240 TI - How intravenous nitroglycerine transit time from bag-to-bloodstream can be affected by infusion technique: a simulation study. AB - OBJECTIVE: To measure the possible delays in intravenous nitroglycerine administration. METHODS: This was a simulation study of sham intravenous nitroglycerine using a standard nitroglycerine titration protocol. Variables studied were (i) common cannulae/needles, (ii) infusion accessories and (iii) presence of a parallel intravenous saline carrier line (or drive line) infusing at 30 mL/h. Outcomes were (i) delay from bag-to-bloodstream arrival and (ii) the dosage showing on the infusion pump when the sham drug first exits the cannula (aka the 'presumed initial dosage'). RESULTS: There was a statistically significant difference in both (i) time-to-bloodstream arrival and (ii) the dosage showing on the infusion pump as the sham first exits the cannula with (i) different cannulae, (ii) different accessories and (iii) presence of a carrier line. The bag-to-bloodstream time varied 10-fold: 197-2062 s. The 'presumed initial dosage' varied sixfold: 5-30 ug/min. Adding the medication to an already flowing carrier line reduced the time for the sham to exit the cannula fourfold: from 2062 to 469 s. CONCLUSIONS: Despite limitations, this study outlines the importance of cannula type, infusion accessories and carrier lines. Larger cannulae and greater priming volumes substantially delay drug delivery, whereas carrier lines/drive lines substantially accelerate drug delivery. Our study also shows how patients could be exposed to clinical delays, as well as incorrect presumptions about drug dosage. Guidelines, and education efforts, should highlight the clinical importance of factors that affect bag-to-bloodstream time. PMID- 25921241 TI - Clinical significance of anaplasia in childhood rhabdomyosarcoma. AB - BACKGROUND: The presence of anaplastic features has been known to correlate with poor clinical outcome in various pediatric malignancies, including Wilms tumor and medulloblastoma but not in rhabdomyosarcoma. AIM: Aim was to study the frequency of anaplasia at presentation in childhood rhabdomyosarcoma and its relationship to clinical and pathological characteristics as well as to outcome. PATIENTS AND METHODS: Anaplasia was retrospectively assessed in 105 consecutive pediatric rhabdomyosarcoma patients who were registered at the Children's Cancer Hospital in Egypt (CCHE) during the period from July 2007 till the end of May 2010. RESULTS: Anaplasia was diagnosed in 18 patients (17.1%), focal in 10 (9.5%) and diffuse in 8 (7.6%). The distribution of anaplasia was found to be more common in older patients having age?10 years. Also it was more likely to occur in the high risk group and in tumors with unfavorable histology (alveolar subtype), and stage IV. The 3-year failure free survival rates for patients with and without anaplasia were 27.8+/-10.6% and 53.4+/-5.8%, respectively (p=0.014) and the 3-year overall survival rates were 35.3+/-11.6% and 61+/-6%, respectively (p=0.019). CONCLUSIONS: The frequency of anaplasia in pediatric patients with rhabdomyosarcoma in our study was 17.1%. The presence of anaplasia had statistically significant worse clinical outcome. PMID- 25921242 TI - Large-scale identification of secretome glycoproteins recognized by Wisteria floribunda agglutinin: A glycoproteomic approach to biomarker discovery. AB - One of the promising approaches to the development of cancer diagnostic systems is quantification of a specific protein carrying cancerous glycans. Potential utility of Wisteria floribunda agglutinin (WFA) for such assays has been suggested for several cancer types. To develop such diagnostic systems, identification of WFA-recognized glycoproteins is essential. Here, we successfully identified 504 WFA-recognized glycoproteins from the secretome of HEK293T cells. Most of the identified proteins were likely soluble or single-pass transmembrane proteins, which may serve as specific proteins for the diagnosis using biological fluids. Our method may help to discover marker glycoproteins for various cancers generating WFA-recognized glycans. PMID- 25921243 TI - Studies with radiation-based imaging techniques: Where to stop? PMID- 25921244 TI - Reprint of PopGen: A virtual human population generator. AB - The risk assessment of environmental chemicals and drugs is moving towards a paradigm shift in approach which seeks the full replacement animal testing with high throughput, mechanistic, in vitro systems. This new vision will be reliant on the measurement in vitro, of concentration-dependent responses where prolonged excessive perturbations of specific biochemical pathways are likely to lead to adverse health effects in an intact organism. Such an approach requires a framework, into which disparate data generated using in vitro, in silico and in chemico systems, can be integrated and utilised for quantitative in vitro-to-in vivo extrapolation (QIVIVE), ultimately to the human population level. Physiologically based pharmacokinetic (PBPK) models are ideally suited for this and are obligatory in order to translate in vitro concentration-response relationships to an exposure or dose, route and duration regime in people. In this report we describe PopGen a virtual human population generator which is a user friendly, open access web-based application for the prediction of realistic anatomical, physiological and phase 1 metabolic variation in a wide range of healthy human populations. We demonstrate how PopGen can be used for QIVIVE by providing input to a PBPK model, at an appropriate level of detail, to reconstruct exposure from human biomonitoring data. We discuss how the process of exposure reconstruction from blood biomarkers, in general, is analogous to exposure or dose reconstruction from concentration-response measurements made in proposed in vitro cell based systems which are assumed to be surrogates for target organs. PMID- 25921245 TI - Redistribution of subcellular calcium and its effect on apoptosis in primary cultures of rat proximal tubular cells exposed to lead. AB - Previous studies have shown that cytosolic Ca(2+) ([Ca(2+)]c) overload was involved in Pb-induced apoptosis in primary cultures of rat proximal tubular (rPT) cells, but the source of elevated Ca(2+) and the effect of potential subcellular Ca(2+) redistribution on apoptosis are still unknown. In this study, variations of [Ca(2+)]c in two culture media (Ca(2+)-containing and Ca(2+)- free) were analyzed, indicating that Pb-induced elevation of [Ca(2+)]c was primarily generated intracellularly. Fluo-4-AM, dihydro-Rhod-2-AM and Mag-Fluo-4-AM was loaded to Pb-exposed rPT cells to monitor the imaging of Ca(2+) concentrations in the cytoplasm ([Ca(2+)]c), mitochondria ([Ca(2+)]mit) and endoplasmic reticulum (ER) ([Ca(2+)]ER), respectively, under the confocal microscope. Data indicate that elevations of [Ca(2+)]c and [Ca(2+)]mit with depletion of [Ca(2+)]ER were revealed in Pb-treated rPT cells, but this subcellular Ca(2+) redistribution could be significantly suppressed by 2-APB, a specific inhibitor of inositol 1,4,5-trisphosphate receptor (IP3R) that functions to release Ca(2+) from ER stores. Simultaneously, Pb-mediated mitochondrial Ca(2+) overload can be partially suppressed by the cytosolic Ca(2+) chelator BAPTA-AM, suggesting that Ca(2+) uptake into mitochondria occurs via diverse pathways and ER Ca(2+) storage was the chief source. Furthermore, Pb-induced apoptosis was markedly inhibited by 2-APB and BAPTA-AM, respectively. Additionally, elevated IP3 levels with up regulated IP3R-1 and IP3R-2 (mRNA and protein) levels were revealed in Pb-exposed rPT cells. In summary, IP3R-mediated ER Ca(2+) release promoted the elevations of [Ca(2+)]c and [Ca(2+)]mit in Pb-exposed rPT cells, which played a chief role in apoptosis induced by impaired calcium homeostasis. PMID- 25921246 TI - Gene expression analysis of plasmablastic lymphoma identifies downregulation of B cell receptor signaling and additional unique transcriptional programs. PMID- 25921248 TI - Deoxycytidine-kinase knockdown as a novel myeloprotective strategy in the context of fludarabine, cytarabine or cladribine therapy. PMID- 25921247 TI - Hypoxia inducible factor (HIF)-2alpha accelerates disease progression in mouse models of leukemia and lymphoma but is not a poor prognosis factor in human AML. AB - Hypoxia-inducible factor (HIF)-1alpha accumulation promotes hematopoietic stem cells' quiescence and is necessary to maintain their self-renewal. However, the role of HIF-2alpha in hematopoietic cells is less clear. We investigated the role of HIF-2alpha in leukemia and lymphoma cells. HIF-2alpha expression was high in subsets of human and mouse leukemia and lymphoma cells, whereas it was low in normal bone marrow leukocytes. To investigate the role of HIF-2alpha, we transduced human HIF-2alpha cDNA in mouse syngeneic models of myeloid preleukemia and a transgenic model of B lymphoma. Ectopic expression of HIF-2alpha accelerated leukemia cell proliferation in vitro. Mice transplanted with cells transduced with HIF-2alpha died significantly faster of leukemia or B lymphoma than control mice transplanted with empty vector-transduced cells. Conversely, HIF-2alpha knockdown in human myeloid leukemia HL60 cells decreased proliferation in vitro and significantly prolonged animal survival following transplantation. In human acute myeloid leukemia (AML), HIF-2alpha mRNA was significantly elevated in several subsets such as the t(15;17), inv(16), complex karyotype and favorable cytogenetic groups. However, patients with high HIF-2alpha expression had a trend to higher disease-free survival in univariate analysis. The different effects of HIF-2alpha overexpression in mouse models of leukemia and human AML illustrates the complexity of this mutliclonal disease. PMID- 25921249 TI - A new ligand skeleton for imaging applications with d-f complexes: combined lifetime imaging and high relaxivity in an Ir/Gd dyad. AB - A new rigid and conjugated ligand structure connecting phenanthroline and poly(amino-carboxylate) binding sites provides d-f complexes which show high potential for use in dual (luminescence + magnetic resonance) imaging and for optimisation of d -> f photoinduced energy-transfer. PMID- 25921250 TI - In response to: "Increased dog population and potential for bat-borne rabies spillover in Chile in response to "Dog management, abundance and potential for bat-borne rabies spillover in Chile" by Astorga et al. [Prev. Vet. Med. 118:397 405]" by Acosta-Jammet, G. PMID- 25921251 TI - High-resolution probing heparan sulfate-antithrombin interaction on a single endothelial cell surface: single-molecule AFM studies. AB - Heparan sulfate (HS) plays diverse functions in multiple biological processes by interacting with a wide range of important protein ligands, such as the key anticoagulant factor, antithrombin (AT). The specific interaction of HS with a protein ligand is determined mainly by the sulfation patterns on the HS chain. Here, we reported the probing single-molecule interaction of AT and HS (both wild type and mutated) expressed on the endothelial cell surface under near physiological conditions by atomic force microscopy (AFM). Functional AFM imaging revealed the uneven distribution of HS on the endothelial cell surface though they are highly expressed. Force spectroscopy measurements using an AT functionalized AFM tip revealed that AT interacts with endothelial HS on the cell surface through multiple binding sites. The interaction essentially requires HS to be N-, 2-O- and/or 6-O-sulfated. This work provides a new tool to probe the HS protein ligand interaction at a single-molecular level on the cell surface to elucidate the functional roles of HS. PMID- 25921252 TI - An integrated suite of modeling tools that empower scientists in structure- and property-based drug design. AB - Structure- and property-based drug design is an integral part of modern drug discovery, enabling the design of compounds aimed at improving potency and selectivity. However, building molecules using desktop modeling tools can easily lead to poor designs that appear to form many favorable interactions with the protein's active site. Although a proposed molecule looks good on screen and appears to fit into the protein site X-ray crystal structure or pharmacophore model, doing so might require a high-energy small molecule conformation, which would likely be inactive. To help scientists make better design decisions, we have built integrated, easy-to-use, interactive software tools to perform docking experiments, de novo design, shape and pharmacophore based database searches, small molecule conformational analysis and molecular property calculations. Using a combination of these tools helps scientists in assessing the likelihood that a designed molecule will be active and have desirable drug metabolism and pharmacokinetic properties. Small molecule discovery success requires project teams to rapidly design and synthesize potent molecules with good ADME properties. Empowering scientists to evaluate ideas quickly and make better design decisions with easy-to-access and easy-to-understand software on their desktop is now a key part of our discovery process. PMID- 25921253 TI - The Association Between Aortic Valve Leaflet Morphology and Patterns of Aortic Dilation in Patients With Bicuspid Aortic Valves. AB - BACKGROUND: Dilation of the aorta is a frequent complication in patients with bicuspid aortic valves. The aim of this study was to determine the relationship between the subtype of leaflet fusion, right and noncoronary leaflet (R/N) fusion versus right and left leaflet (R/L) fusion, and the patterns of aortic dilation and valve dysfunction in young patients with bicuspid aortic valves. METHODS: We performed a retrospective review of 642 patients who presented with bicuspid aortic valves between 1994 and 2014. Of these patients, 210 (33%) had aortic dilation (z score >3) by echocardiogram. For each patient, the most recent study or the last study before intervention was reviewed. RESULTS: Median patient age was 15 years (range, 0 to 40 years) with patients with R/N fusion being younger. The most prevalent subtype was R/N fusion (R/N, n = 114, 54% versus R/L, n = 96, 46%). Dilation of the ascending aorta was seen more often in patients with R/N fusion (R/N, 88% versus R/L, 68%; p = 0.004), whereas the prevalence of dilation of the sinuses of Valsalva was significantly higher in patients with R/L fusion (R/L, 46% versus R/N, 20%; p = 0.01). The magnitude of dilation differed as well. The z value of the sinuses of Valsalva was significantly higher in patients with R/L fusion (R/L, 2.03 versus R/N, 1.2; p = 0.003), whereas the z values of the ascending aorta and sinotubular junction were similar between the groups. Patients with R/N fusion were more likely to have aortic stenosis, and within the R/N group, patients with aortic insufficiency had a greater degree of ascending aorta dilation (p = 0.04). CONCLUSIONS: Our study suggests that in young patients with bicuspid aortic valves and aortic dilation, aortic valve morphology may be associated with the patterns of aortic dilation and valve dysfunction. Patients with R/N fusion were more likely to have ascending aorta dilation, whereas patients with R/L fusion were more likely to have dilation of the aortic root. In addition, patients with R/N fusion presented at a younger age and were more likely to have aortic stenosis. Recognition of these differences may eventually be helpful for patient counseling and the planning of follow-up. PMID- 25921254 TI - Feasibility Study of Pulsatile Left Ventricular Assist Device for Prolonged Ex Vivo Lung Perfusion. AB - BACKGROUND: Ex vivo lung perfusion (EVLP) has the potential to increase the donor pool for lung transplantation by facilitating resuscitation and extended evaluation of marginal organs. Current EVLP methodology employs continuous flow (CF) pumps that produce non-pulsatile EVLP hemodynamics. In this feasibility study, we tested the hypothesis that a pulsatile flow (PF) pump will provide better EVLP support than a CF pump through delivery of physiologic hemodynamics. METHODS: Porcine lungs were supported in an EVLP model by centrifugal CF (n = 3) or PF (n = 4) left ventricular assist devices. Lungs were ventilated at 4 to 5 mL/kg, 0.21 fraction of inspired oxygen (FiO2), and perfused with an acellular, albumin-based solution corrected for osmolarity, acid-base balance, and carbon dioxide pressure (<=20 hours at 30 degrees C) for a minimum of 12 hours support. Prostaglandin E1 and 30% albumin were infused continuously. Hemodynamic, respiratory, and blood gas parameters were continuously monitored and digitally recorded hourly. Parenchymal biopsies were used for quantification of wet to dry weight ratio. RESULTS: All lungs maintained function in the EVLP circuit for a minimum of 12 hours (mean 14.7 +/- 1 hours) and demonstrated minimal edema formation. The PF EVLP produced higher pulsatility as demonstrated by greater energy equivalent pressure and surplus hemodynamic energy compared with CF EVLP (p < 0.05). There were no statistically significant differences in pulmonary impedance, arterial partial pressure of oxygen/fraction of inspired oxygen, wet to dry weight ratio, and peak airway pressure between CF and PF EVLP. CONCLUSIONS: The CF and PF EVLP systems successfully maintained lungs 12+ hours using a modified Steen perfusate (XVIVO Perfusion, Inc, Goteborg, Sweden); however, there were no statistically significant differences between CF and PF groups despite higher pulsatility, suggesting that PF may not offer immediate benefits over CF for prolonged ex vivo lung preservation. PMID- 25921255 TI - Heart Transplantation in Adults With Congenital Heart Disease: 100% Survival With Operations Performed by a Surgeon Specializing in Congenital Heart Disease in an Adult Hospital. AB - BACKGROUND: Cardiac transplantation in adult patients with congenital heart disease poses numerous challenges. The optimal operative and postoperative management strategies remain unclear. The purpose of our study was to (1) characterize the adult patient with a congenital heart condition undergoing transplantation, the operation, and the postoperative course; (2) report the survival after heart transplantation at our center; and (3) discuss issues surrounding the unique setting we provide for the operative and postoperative care of this complex patient cohort. METHODS: We performed a retrospective cohort study of 12 consecutive adult patients with a prior history of congenital heart disease who underwent heart transplantation at a single, large, academic center between September 1, 2005, and September 1, 2013. The operations were performed by a surgeon specializing in congenital heart disease in an adult hospital. Postoperative care was provided jointly by that surgeon and the adult cardiac transplantation team. RESULTS: At operation, the median age and weight were 41 years (range, 16 to 72 years) and 65 kg (range, 45 to 104 kg), and 100% of patients had undergone previous operations. The median donor ischemic time was 197 minutes (range, 137 to 282 minutes). The median cardiopulmonary bypass time was 210 minutes (range, 175 to 457 minutes), and the median total operating time was 582 minutes (range, 389 to 968 minutes). Three patients required mechanical support to be weaned from cardiopulmonary bypass. Postoperatively, 3 patients required the addition of mechanical support in the intensive care unit, and 3 patients required tracheostomy for prolonged ventilation. The majority of patients had a complicated postoperative course (66%). The median number of noncardiac consultants required to help care for these patients was four (range, two to 12). The mortality was 0%. CONCLUSIONS: Cardiac transplantation in adults with congenital cardiac disease is challenging, is fraught with adverse events, and requires meticulous care and teamwork for success. A surgeon specializing in congenital heart conditions may be best to handle the operative challenges, and an adult hospital with access to certain technology and consultant services may be best to handle the postoperative challenges in this difficult patient population. PMID- 25921256 TI - Hybrid Technique for Repair of Recurrent Pectus Excavatum After Failed Open Repair. AB - BACKGROUND: Successful repair of recurrent pectus excavatum (PE) after failed open procedure has been reported using minimally invasive repair (MIRPE) and open approaches. Neither approach alone may be adequate for some patients. A hybrid technique for repair is presented for revision of recurrent PE. METHODS: A retrospective review of adults undergoing repair for recurrent PE after prior open repair from January 2010 to June 2014 was performed. RESULTS: Seventy-three adult patients underwent repair for recurrent PE, with 48 patients (65.8%) undergoing repair for recurrence after at least one prior open PE repair. Mean patient age was 34.5 years (range, 19 to 54 years); mean Haller index was 4.7 (range, 2.8 to 14.7). Fourteen (29%) recurrences with adequate chest wall pliability and no malunion were repaired with MIRPE alone; 34 patients (71%) underwent a hybrid procedure for repair (20 for PE recurrence alone; 14 for PE with acquired thoracic dystrophy). All had at least two support bars placed, and 11 patients (23%) had three bars placed. Mean hospitalization for MIRPE was 5 days, for hybrid was 7 days, and for hybrid because of acquired thoracic dystrophy was 10 days. One patient died of unexpected out-of-hospital arrest; there was one emergent conversion to open sternotomy for bleeding. CONCLUSIONS: Most recurrent PE may be repaired with excellent results and minimal complications. Those with adequate chest pliability and no malunion are candidates for MIPRE alone. A hybrid procedure with thoracoscopic support bars combined with sternal elevation, multiple open osteotomies, and chest wall fixation is appropriate for recurrences associated with malunion or fixation of the anterior chest and failure to lift with MIRPE. PMID- 25921257 TI - Age-Related Outcomes of the Ross Procedure Over 20 Years. AB - BACKGROUND: The Ross procedure is an alternative for patients with aortic valve disease not amenable to repair. Long-term follow-up after a Ross has demonstrated the need for autograft (left ventricular outflow tract [LVOT]) and homograft (right ventricular outflow tract [RVOT]) reinterventions. We assessed the age stratified outcomes of the LVOT and RVOT after the Ross procedure performed by a single surgeon during a 20-year period. METHODS: We retrospectively reviewed 305 consecutive patients aged 4 days to 70 years, stratified by age younger than than 1 (n = 41), 1 to 10 (n = 85), 10 to 20 (n = 84), 20 to 40 (n = 59), and older than 40 years (n = 36). Median follow-up was 8.2 years (interquartile range, 1 month to 19.2 years). Primary end points were survival and freedom from reintervention on the LVOT and RVOT. Outcomes were compared by Kaplan-Meier analysis. RESULTS: A total of 173 patients (57%) had prior intervention on their aortic valve, 95 (31%) had isolated regurgitation, 91 (30%) had stenosis, and 119 (39%) had mixed pathology. There were 92 concomitant procedures (43 congenital lesions, 18 aorta, 9 mitral valve). In-hospital morbidity was 11.5% (35 of 305); mortality was 3.6% (11 of 305) and highest in infants. Need for an emergency operation (p < 0.05) predicted mortality in infants. The LVOT reintervention rate was lowest in infants compared with older patients (p < 0.05); conversely, age was directly related to RVOT reintervention (p < 0.01). Autograft encasement in a Hemashield (Atrium, Hudson, NH) tube in patients aged older than 10 years improved 5-year freedom from reintervention on the LVOT from 81% to 91% (p < 0.001). At last follow-up, aortic insufficiency was mild or less in 290 (95%) patients, and heart function was normal in 285 (93%). CONCLUSIONS: The Ross procedure is a safe, effective, and anti-coagulation-free alternative for aortic valve replacement across all age groups. Long-term survival and preservation of heart function are highly favorable. Surgical mortality is related to salvage procedures in infants. When feasible, autograft durability can be improved by using a Hemashield graft for support. PMID- 25921258 TI - Cardiac Hemangioma: A Comprehensive Analysis of 200 Cases. AB - Cardiac hemangioma is a rare clinical entity. An increasing number of cases have been reported in recent years. Most of them were found incidentally at autopsy or during clinical practice, and reported as isolated cases. Our study is the most comprehensive review of cardiac hemangioma to date. The clinical demographics, clinical features, histopathologic features, treatment, and prognosis of 200 cases are reported. Logistic regression analysis was performed to identify the independent predictors of hemangioma-related death and long-term adverse events. We provide a few recommendations for diagnosis and treatment of this uncommon and sometimes lethal disorder. PMID- 25921259 TI - Arterioplasty for Right Ventricular Outflow Tract Obstruction After Arterial Switch Is a Durable Procedure. AB - BACKGROUND: Right ventricular outflow tract obstruction (RVOT) is the most common late complication requiring intervention after arterial switch operation (ASO). The durability of surgical management of this complication has not been well established. METHODS: We retrospectively reviewed the charts of 38 consecutive patients who underwent RVOT reconstruction after ASO at our institution between 2004 and 2013. During the same time period, 223 consecutive patients underwent ASO for transposition of the great arteries at our institution. Thirty-five (16%) of the 223 patients developed RVOT obstruction, and 3 additional patients who had ASO done elsewhere presented to us with RVOT obstruction. Patient characteristics, site of stenosis, type of intervention, and outcomes were analyzed. Data are presented as median with interquartile ranges. RESULTS: The time interval between ASO and echocardiographic diagnosis of significant RVOT obstruction was 12.5 (3 to 23.7) months. After echocardiographic diagnosis, 33 (87%) children underwent cardiac catheterization. Obstruction involved the supravalvar main pulmonary artery (PA) in 21 (64%), branch PA in 14 (42%), pulmonary valve in 4 (12%), and sub-valvar area in 1 (3%). Ten of 33 patients who underwent catheterization had attempted percutaneous intervention, with 4 (40%) demonstrating significant response. Surgical intervention was performed at a median of 4 months in responders compared with 2.3 months in non-responders. Surgical repair included main PA plasty (36), extended to 1 or both branch PAs (26), or crossed the RVOT annulus (7). Surgical morbidity was 13% and there was no hospital or late mortality. At last follow-up, 41.2 months (21.4 to 81) after RVOT reconstruction, all patients had New York Heart Association grade 0 or 1 symptoms, and RV pressure was a median 36% of systemic pressure. Five (13%) patients underwent catheterization 26 months after surgery, with 2 requiring dilation at site of arterioplasty and 3 requiring distal branch PA intervention. One patient required reoperation for main PA stenosis. Freedom from re intervention after surgery is 89%, 86%, and 86% at 2, 3, and 5 years, respectively. CONCLUSIONS: Surgical management of RVOT obstruction after ASO is an effective and durable intervention in the intermediate term. Our results serve as a benchmark for expected outcomes in this disease process. PMID- 25921260 TI - Long-Term Survival and Reintervention After the Ross Procedure Across the Pediatric Age Spectrum. AB - BACKGROUND: There are limited data regarding long-term outcomes after the Ross procedure in children. We evaluated mortality and reintervention in a large pediatric cohort. METHODS: A retrospective analysis of all patients aged younger than 18 years who underwent the Ross procedure at our institution (1991 to 2013) was conducted. Kaplan-Meier curves and Cox proportion hazard models were used to evaluate long-term outcomes and associated risk factors. RESULTS: Included were 240 consecutive patients undergoing a Ross/Ross-Konno procedure: 18% infants, 48% children, and 33% adolescents. Infants were more likely to have complex left heart disease (p = 0.005). Overall survival to hospital discharge was 96%; infants had the highest mortality (18%). Long-term survival status was known for 99.6% (median follow-up, 10.7 years). Overall 15-year survival was 87% (lowest in infants, 72%; p = 0.003). Reintervention status was known in 87%. Overall 15-year freedom from any left ventricular outflow tract reintervention was 59%; 85% still had their autograft valve at the latest follow-up. Left ventricular outflow tract reintervention was uncommon in infants (n = 2). Overall 15-year freedom from right ventricular outflow tract reintervention was 53%, and was lower in infants (19%) than in children (51%) and adolescents (76%; p < 0.0001). CONCLUSIONS: Outcomes after the Ross procedure in children vary by age. Infants more commonly have complex left heart disease and experience higher mortality but have excellent long-term autograft durability. Children and adolescents have higher rates of left ventricular outflow tract reintervention, whereas infants are at highest risk of right ventricular outflow tract reintervention. PMID- 25921261 TI - Aspirin Resistance in Single-Ventricle Physiology: Aspirin Prophylaxis Is Not Adequate to Inhibit Platelets in the Immediate Postoperative Period. AB - BACKGROUND: Incidence of thrombosis after initial stage 1 single-ventricle palliation is high. Most centers use aspirin as an antiplatelet agent to prevent thrombosis in surgically placed shunts. We hypothesize there is a significant incidence of aspirin resistance in infants after stage 1 palliation and this resistance can be overcome by an increased aspirin dose. METHODS: This is a prospective observational study of 20 patients with single-ventricle physiology who required single-ventricle palliation with a controlled source of pulmonary blood flow (Norwood/Sano, Norwood/Blalock-Taussig [BT] shunt or BT shunt alone). Aspirin resistance was determined using thromboelastography with platelet mapping (TEG) and urine thromboxane (UTX). The UTX level of less than 1,500 pg/mL and TEG value of more than 50% were used to define as adequate platelet inhibition. The UTX was measured prior to starting aspirin (20 mg/day) and TEG and UTX were obtained after 5 days of aspirin therapy A repeat UTX was measured for patients who were determined to be aspirin resistant by TEG (<50% arachidonic acid inhibition) after doubling the dose (40 mg/day). Clinical variables including patient diagnosis, age of surgery, and cardiopulmonary bypass requirement, weight, hemoglobin, and platelet count were assessed to determine their association with aspirin resistance. RESULTS: Eighty percent of patients were aspirin resistant using TEG (95% CI, 56% to 94%) and none of the patients achieved a UTX level of less than 1,500 pg/mL. Aspirin resistant patients did not respond to an increased dose of aspirin between the fifth and tenth days of therapy (p = 0.820). Patients did, however, respond to aspirin treatment when comparing the baseline UTX measurement with those recorded on the fifth day (p = 0.008) and the tenth day (p = 0.0361) of aspirin therapy. The UTX levels did not differ between those who were and those who were not aspirin resistant by TEG at any of the measurement times. The clinical variables were not associated with aspirin resistance status. CONCLUSIONS: There is a high incidence of aspirin resistance in the immediate postoperative period after single-ventricle shunt palliation. Aspirin might not be an adequate agent for shunt prophylaxis in this patient population. Further studies are needed to identify at-risk patients who might benefit from additional testing and specific anticoagulation. PMID- 25921262 TI - Topical cyclodextrin reduces amyloid beta and inflammation improving retinal function in ageing mice. AB - Retinal ageing results in chronic inflammation, extracellular deposition, including that of amyloid beta (Abeta) and declining visual function. In humans this can progress into age-related macular degeneration (AMD), which is without cure. Therapeutic approaches have focused on systemic immunotherapies without clinical resolution. Here, we show using aged mice that 2-Hydroxypropyl-beta cyclodextrin, a sugar molecule given as eye drops over 3 months results in significant reductions in Abeta by 65% and inflammation by 75% in the aged mouse retina. It also elevates retinal pigment epithelium specific protein 65 (RPE65), a key molecule in the visual cycle, in aged retina. These changes are accompanied by a significant improvement in retinal function measured physiologically. 2 Hydroxypropyl-beta-cyclodextrin is as effective in reducing Abeta and inflammation in the complement factor H knockout (Cfh(-/-)) mouse that shows advanced ageing and has been proposed as an AMD model. beta-cyclodextrin is economic, safe and may provide an efficient route to reducing the impact of retinal ageing. PMID- 25921263 TI - Increased dog population and potential for bat-borne rabies spillover in Chile in response to "Dog management, abundance and potential for bat-borne rabies spillover in Chile" by Astorga et al. [Prev. Vet. Med. 118: 397-405]. PMID- 25921265 TI - Novel type of plasmin inhibitors: providing insight into P4 moiety and alternative scaffold to pyrrolopyrimidine. AB - Here we report a series of plasmin inhibitors which were originally derived from the parent structure of 1 and 2. Our efforts focused on the optimization of the P4 moiety of 2 and on the quest of alternative scaffold to pyrrolopyrimidine in the parent compounds. The results of the former gave us pivotal information on the further optimization of the P4 moiety in plasmin inhibitors and those of the latter revealed that appropriate moieties extending from the benzimidazole scaffold engaged with S4 pocket in the active site of plasmin. PMID- 25921266 TI - New pyrazolo[4,3-e][1,2,4]triazine sulfonamides as carbonic anhydrase inhibitors. AB - New sulfonamide derivatives of pyrazolo[4,3-e][1,2,4]triazine were synthesized and investigated as antitumor agents through carbonic anhydrase (CA, EC 4.2.1.1) inhibition. The newly prepared compounds were tested for their anticancer activity against human breast cancer cell lines (MCF-7, MDA-MB-231) using a MTT assay and inhibition of [(3)H]thymidine incorporation into DNA. Preliminary biological studies with several CA isoforms, revealed that the new derivatives were ineffective as CA I and II inhibitors, but they showed activity against tumor-associated enzymes, such as CA IX. The most effective inhibitor against CA IX was compound 8e that exhibited an inhibition constant KI of 13.8nM, and derivatives 8c-8d with moderate activity (8c: KI=25.4nM; 8d: KI=24.5nM). Compounds 8g-8h exhibited acceptable activity (8g: KI=27.7nM; 8d: KI=26.6nM). The detailed synthesis, spectroscopic and biological data are also reported. PMID- 25921264 TI - Perspective: Tyrosine phosphatases as novel targets for antiplatelet therapy. AB - Arterial thrombosis is the primary cause of most cases of myocardial infarction and stroke, the leading causes of death in the developed world. Platelets, highly specialized cells of the circulatory system, are key contributors to thrombotic events. Antiplatelet drugs, which prevent platelets from aggregating, have been very effective in reducing the mortality and morbidity of these conditions. However, approved antiplatelet therapies have adverse side effects, most notably the increased risk of bleeding. Moreover, there remains a considerable incidence of arterial thrombosis in a subset of patients receiving currently available drugs. Thus, there is a pressing medical need for novel antiplatelet agents with a more favorable safety profile and less patient resistance. The discovery of novel antiplatelet targets is the matter of intense ongoing research. Recent findings demonstrate the potential of targeting key signaling molecules, including kinases and phosphatases, to prevent platelet activation and aggregation. Here, we offer perspectives to targeting members of the protein tyrosine phosphatase (PTP) superfamily, a major class of enzymes in signal transduction. We give an overview of previously identified PTPs in platelet signaling, and discuss their potential as antiplatelet drug targets. We also introduce VHR (DUSP3), a PTP that we recently identified as a major player in platelet biology and thrombosis. We review our data on genetic deletion as well as pharmacological inhibition of VHR, providing proof-of-principle for a novel and potentially safer VHR-based antiplatelet therapy. PMID- 25921267 TI - Synthesis, anti-mycobacterial activity and DNA sequence-selectivity of a library of biaryl-motifs containing polyamides. AB - The alarming rise of extensively drug-resistant tuberculosis (XDR-TB) strains, compel the development of new molecules with novel modes of action to control this world health emergency. Distamycin analogues containing N-terminal biaryl motifs 2(1-5)(1-7) were synthesised using a solution-phase approach and evaluated for their anti-mycobacterial activity and DNA-sequence selectivity. Thiophene dimer motif-containing polyamide 2(2,6) exhibited 10-fold higher inhibitory activity against Mycobacterium tuberculosis compared to distamycin and library member 2(5,7) showed high binding affinity for the 5'-ACATAT-3' sequence. PMID- 25921268 TI - New matrix metalloproteinase inhibitors based on gamma-fluorinated alpha aminocarboxylic and alpha-aminohydroxamic acids. AB - Matrix metalloproteinases (MMPs) are involved in a number of physiological as well as pathological processes such as atherosclerosis and tumorigenesis, where an up-regulation of MMPs is predominant. Fluorinated analogues of the hydroxamate based non-peptidic broad-spectrum MMP inhibitor (MMPI) CGS 27023A were synthesized and inhibition potencies for MMP-2 and MMP-9 in the nanomolar range were measured using fluorimetric in vitro assays. The inhibition potencies of the herein reported fluorinated MMPIs were comparable or even superior in some cases to their non-fluorinated analogues. In contrast to the lead structure, both enantiomers of fluorinated MMPs were almost equally potent. Modelling studies suggest that the core alpha-amino hydroxamic acid residues appear to influence the relative potencies via specific inhibitor-peptidase interactions, including short fluorine-hydrogen contacts, within the enzyme's pockets. The binding of the essential hydroxamate group to the zinc ion is rather unaffected by the rest of the molecule. In contrast, the corresponding alpha-aminocarboxylic acid derivatives are 10(3) times less potent or were even inactive. PMID- 25921269 TI - Discovery of potent carbonic anhydrase and acetylcholine esterase inhibitors: novel sulfamoylcarbamates and sulfamides derived from acetophenones. AB - In this study, several novel sulfamides were synthesized and evaluated for their acetylcholine esterase (AChE) and human carbonic anhydrase I, and II isoenzymes (hCA I and II) inhibition profiles. Reductive amination of methoxyacetophenones was used for the synthesis of amines. Amines were converted to sulfamoylcarbamates with chlorosulfonyl isocyanate (CSI) in the presence of BnOH. Pd-C catalyzed hydrogenolysis of sulfamoylcarbamates afforded sulfamides. These novel compounds were good inhibitors of the cytosolic hCA I, and hCA II with Ki values in the range of 45.9+/-8.9-687.5+/-84.3 pM for hCA I, and 48.80+/-8.2 672.2+/-71.9pM for hCA II. The inhibitory effects of the synthesized novel compounds on AChE were also investigated. The Ki values of these compounds were in the range of 4.52+/-0.61-38.28+/-6.84pM for AChE. These results show that hCA I, II, and AChE were effectively inhibited by the novel sulfamoylcarbamates 17-21 and sulfamide derivatives 22-26. All investigated compounds were docked within the active sites of the corresponding enzymes revealing the reasons of the effective inhibitory activity. PMID- 25921270 TI - Subglottic laryngitis--Changes in therapy approach over the past 20 years. AB - OBJECTIVE: To show changes in the management of subglottic laryngitis over the last twenty years in Croatia. METHODS: We sent questionnaires to paediatricians and otolaryngologists (ENT) in 9 Croatian hospitals in 1993, 2003 and 2013. In the questionnaire we presented a case of a child with moderately difficult subglottic laryngitis, after which they had to answer questions about the management of this kind of a patient and common therapy practice in their hospitals. All data were categorical, described in absolute frequencies and with relative percentages. The Cochran-Armitage test for trend was used in the analysis of different treatments over the years among ENT and paediatricians. Associations were statistically significant if p<0.05. RESULTS: During a twenty year period main novelties included the introduction of racemic epinephrine use (ENT from 3.3% in 1993 to 92.3% in 2013; paediatricians from 17.2% in 1993 to 100.0% in 2013) and downfall of humidification (ENT from 60.0% to 23.3%; paediatricians from 60.0% to 12.0%), antibiotic (ENT from 53.0% to 2.3%; paediatricians from 21.0% to 0.0%) and antihistaminic use (ENT from 67.7% to 0%; paediatricians from 43.2% to 2%), while corticosteroids (both parenteral and nebulized form) remained the cornerstone in treatment of moderately severe subglottic laryngitis. CONCLUSION: Main novelties included the use of racemic epinephrine and downfall of antibiotic, antihistaminic and humidification therapy use, while corticosteroids remained the cornerstone in the treatment of moderately severe subglottic laryngitis. Differences between approaches among specialities are minimized during 20-year period. PMID- 25921271 TI - Antibody-mediated transfusion-related acute lung injury; from discovery to prevention. AB - Transfusion-related acute lung injury (TRALI), a syndrome of respiratory distress caused by blood transfusion, is the leading cause of transfusion-related mortality. The majority of TRALI cases have been related to passive infusion of human leucocyte antigen (HLA) and human neutrophil antigen (HNA) antibodies in donor blood. In vitro, ex vivo and in vivo animal models have provided insight in TRALI pathogenesis. The various classes of antibodies implicated in TRALI appear to have different pathophysiological mechanisms for the induction of TRALI involving endothelial cells, neutrophils, monocytes and, as very recently has been discovered, lymphocytes. The HLA and HNA-antibodies are found mainly in blood from multiparous women as they have become sensitized during pregnancy. The incidence of TRALI has decreased rapidly following the introduction of a male only strategy for plasma donation. This review focuses on pre-clinical and clinical studies investigating the pathophysiology of antibody-mediated TRALI. PMID- 25921272 TI - Erosion of X Chromosome Inactivation in Human Pluripotent Cells Initiates with XACT Coating and Depends on a Specific Heterochromatin Landscape. AB - Human pluripotent stem cells (hPSCs) display extensive epigenetic instability, particularly on the X chromosome. In this study, we show that, in hPSCs, the inactive X chromosome has a specific heterochromatin landscape that predisposes it to erosion of X chromosome inactivation (XCI), a process that occurs spontaneously in hPSCs. Heterochromatin remodeling and gene reactivation occur in a non-random fashion and are confined to specific H3K27me3-enriched domains, leaving H3K9me3-marked regions unaffected. Using single-cell monitoring of XCI erosion, we show that this instability only occurs in pluripotent cells. We also provide evidence that loss of XIST expression is not the primary cause of XCI instability and that gene reactivation from the inactive X (Xi) precedes loss of XIST coating. Notably, expression and coating by the long non-coding RNA XACT are early events in XCI erosion and, therefore, may play a role in mediating this process. PMID- 25921273 TI - beta-Catenin Regulates Primitive Streak Induction through Collaborative Interactions with SMAD2/SMAD3 and OCT4. AB - Canonical Wnt and Nodal signaling are both required for induction of the primitive streak (PS), which guides organization of the early embryo. The Wnt effector beta-catenin is thought to function in these early lineage specification decisions via transcriptional activation of Nodal signaling. Here, we demonstrate a broader role for beta-catenin in PS formation by analyzing its genome-wide binding in a human embryonic stem cell model of PS induction. beta-catenin occupies regulatory regions in numerous PS and neural crest genes, and direct interactions between beta-catenin and the Nodal effectors SMAD2/SMAD3 are required at these regions for PS gene activation. Furthermore, OCT4 binding in proximity to these sites is likewise required for PS induction, suggesting a collaborative interaction between beta-catenin and OCT4. Induction of neural crest genes by beta-catenin is repressed by SMAD2/SMAD3, ensuring proper lineage specification. This study provides mechanistic insight into how Wnt signaling controls early cell lineage decisions. PMID- 25921275 TI - A Tutorial on Reliability Testing in AAC Language Sample Transcription and Analysis. AB - Establishing reliability is an essential step in language sample transcription and analysis. This tutorial provides an illustration of replicable procedures for reliability testing during transcription and analysis of language samples generated by people who use augmentative and alternative communication (AAC) systems. Statistical measures used for testing agreement between raters coding categorical data are summarized. Detailed procedures for reliability testing in AAC language sample transcription and analysis are provided, beginning with the collection of raw language sample data. Procedures include guidelines for (a) establishing inter-judge agreement during the transcription process, and (b) using Cohen's kappa to establish inter-rater reliability during deeper analysis of transcribed utterances. All procedures are demonstrated in a case example using language samples from children who use AAC. PMID- 25921274 TI - The effectiveness of technology-based strategies to promote engagement with digital interventions: a systematic review protocol. AB - BACKGROUND: Digital interventions provide effective and potentially cost effective models for improving health outcomes as they deliver health information and services that are widely disseminated, confidential, and can be tailored to needs of the individual user. Digital interventions have been used successfully for health promotion, mental health, and for enabling self-management of long term conditions. However, their effectiveness is limited by low usage rates, with non-engagement a major challenge. Hence, it is crucial to find effective strategies to increase user engagement with digital interventions. OBJECTIVE: This systematic review will aim to evaluate the effectiveness of technology-based strategies to promote engagement with digital interventions. METHODS: We will follow Cochrane Collaboration guidelines on systematic review methodology. The search strategy will be executed across seven e-databases (including MEDLINE, EMBASE, PsycINFO, CINAHL) using the concepts "digital intervention" and "engagement", limited by study type (randomized controlled trial). Grey literature and reference lists of included studies will be searched. Titles and abstracts will be independently screened by 2 authors. Then the full text of potentially eligible papers will be obtained and double screened. Data from eligible papers will be extracted by 1 author and checked for accuracy by another author. Bias will be assessed using the Cochrane bias assessment tool. Narrative synthesis will report on all included studies, and where appropriate, data will be pooled using meta-analysis. All findings will be reported according to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines. Sources of heterogeneity will be further investigated if required. RESULTS: Our research is in progress. The final draft of the systematic review is being written and will be submitted before the end of 2015. CONCLUSIONS: The review findings will inform researchers and digital intervention providers about optimal use of technology-based strategies to promote engagement with digital interventions. TRIAL REGISTRATION: PROSPERO International Prospective Register of Systematic Reviews: CRD42014010164; http://www.crd.york.ac.uk/PROSPERO/display_record.asp?ID=CRD42014010164#.VTZmmiFV ko (Archived by WebCite at http://www.webcitation.org/6XxQC8fT8). PMID- 25921276 TI - Detection rate of proximal serrated lesions: A new quality indicator for colonoscopy? PMID- 25921277 TI - Consensus guidelines on severe acute pancreatitis. AB - This Position Paper contains clinically oriented guidelines by the Italian Association for the Study of the Pancreas (AISP) for the diagnosis and treatment of severe acute pancreatitis. The statements were formulated by three working groups of experts who searched and analysed the most recent literature; a consensus process was then performed using a modified Delphi procedure. The statements provide recommendations on the most appropriate definition of the complications of severe acute pancreatitis, the diagnostic approach and the timing of conservative as well as interventional endoscopic, radiological and surgical treatments. PMID- 25921278 TI - Immunohistochemical assessment of lymphatic and blood vessel invasion in T1 urothelial carcinoma of the bladder. AB - OBJECTIVE: The aim of this study was evaluate the incidence and significance of immunohistochemically assessed lymphatic (LVI) and blood vessel invasion (BVI) in primary T1 urothelial carcinoma of the bladder (UCB) treated with radical cystectomy (RC). MATERIALS AND METHODS: Thirty-two patients with T1 UCB at primary diagnosis were identified who underwent radical cystectomy (RC) subsequently. Of these, 16 (50%) had pT1N0M0 (group I) and 16 (50%) >= pT2aN0-3M0 UCB (group II) at RC. The presence of LVI and BVI in transurethral resection of bladder tumor (TURBT) and corresponding RC specimens was assessed using hematoxylin & eosin (H&E) and immunohistochemical (IHC) staining against the lymphatic (D2-40) and vascular endothelium (CD31). RESULTS: At TURBT and RC, none of the patients in group I showed LVI or BVI on H&E and IHC sections. In group II, at TURBT, LVI and BVI were negative on H&E staining in all patients, but detectable by IHC in two patients (13%) and one patient (6%), respectively (p = 0.48 and p = 0.99 compared to group I). At RC, LVI and BVI were detected by IHC in eight (50%) and five (31%) of the 16 patients, respectively (p = 0.002 and p = 0.021 compared to group I). Of these eight and five patients, detection of LVI and BVI was only possible with IHC in six (75%) and three (60%), respectively. CONCLUSIONS: Although this hypothesis-generating study did not show a high degree of concordance between TURBT and RC specimens, IHC assessment on a regular basis may increase the detection rates of LVI and BVI at initial diagnosis and improve the selection of those T1 patients who should be offered early radical treatment. PMID- 25921279 TI - Clinicopathological features of gastric adenocarcinoma patients with metachronous distant metastasis. AB - Metachronous distant metastasis influences the postoperative survival of gastric adenocarcinoma patients with radical gastrectomy. We retrospectively reviewed 108 gastric adenocarcinoma patients with metachronous distant metastasis admitted to our hospital between January 2006 and December 2011. First, these patients were divided into two groups according to the time of metastasis: the early metastasis group (EMG) and late metastasis group (LMG). Second, according to the survival time after metastasis, these patients were divided into the longer survival group (LSG) and shorter survival group (SSG). Chi-square and Fisher exact tests were used to analyze associations between categorical variables. Survival data were estimated using the Kaplan-Meier method. Multivariate analyses of the prognostic factors related to overall survival were conducted using the Cox stepwise proportional hazards test. Results shows that the EMG was significantly associated with depth of invasion (p = 0.005), Union for International Cancer Control (UICC) stage (p = 0.003), degree of differentiation (p = 0.002), and vascular invasion (p = 0.001). The SSG was significantly associated with depth of invasion (p = 0.026) and normal carcinoembryonic antigen (CEA) level of after metastasis (p = 0.003). Survival analysis showed that depth of invasion (p < 0.001), degree of differentiation (p = 0.001), and vascular invasion (p = 0.011) were independent prognostic factors for gastric adenocarcinoma patients with metachronous distant metastasis. Gastric adenocarcinoma patients with metachronous distant metastasis exhibit characteristics that can be used to effectively estimate the possibility of early distant metastasis and the prognosis of these patients. PMID- 25921280 TI - ABCB1 polymorphisms correlate with susceptibility to adult acute leukemia and response to high-dose methotrexate. AB - The aim of this study is to investigate the association of ABCB1 polymorphisms with susceptibility to adult acute leukemia, and the influence of ABCB1 polymorphisms on the efficacy of high-dose methotrexate (HDMTX). ABCB1 polymorphisms in 178 acute leukemia patients (case group) and 150 healthy subjects (control group) were analyzed by polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) method. All patients received HDMTX therapy. Correlation analysis was performed to explore the associations of ABCB1 polymorphisms with MTX concentration and efficacy of MTX therapy. All statistical analyses were conducted with SPSS 19.0 software. The frequency of TT genotype and T allele on ABCB1 3435C > T in case group were significantly higher than the control group (P < 0.05), while no statistical difference between the two groups was observed in genotypic distribution and allele frequencies of ABCB1 2677G > T/A (P > 0.05). Furthermore, 24-h MTX concentration of patients carrying TT and TA genotypes on 2677G > T/A was higher than carriers with other genotypes (P < 0.05), and 24-h MTX concentration of patients with TT and CT genotypes on 3435C > T was also apparently higher than carriers with CC genotype (P < 0.05). In addition, ABCB1 polymorphisms were connected with increased risk of liver dysfunction and infection (P < 0.05). Complete remission (CR) rate in patients carrying GG on 2677G > T/A was markedly lower than carriers with non-GG genotype (P < 0.05). ABCB1 3435C > T polymorphisms may be associated with susceptibility to acute leukemia, and ABCB1 polymorphisms might be a sensitive indicator for predicting efficacy of MTX therapy in the treatment of acute leukemia. PMID- 25921281 TI - Assessment of promoter methylation and expression of SIX2 as a diagnostic and prognostic biomarker in Wilms' tumor. AB - This study was designed to evaluate the utility of expression and DNA methylation patterns of the sine oculis homeobox homolog 2 (SIX2) gene in early diagnosis and prognosis of Wilms' tumor (WT). Methylation-specific polymerase chain reaction (MSP), real-time quantitative polymerase chain reaction (qRT-PCR), receiver operating characteristic (ROC), and survival curve analyses were utilized to measure the expression and DNA methylation patterns of SIX2 in a cohort of WT tissues, with a view to assessing their diagnostic and prognostic value. Relative expression of SIX2 mRNA was higher, while the promoter methylation level was lower in the WT than control group (P < 0.05) and closely associated with poor survival prognosis of WT children (P < 0.05). Increased expression and decreased methylation of SIX2 were correlated with increasing tumor size, clinical stage, vascular invasion, and unfavorable histological differentiation (P < 0.05). ROC curve analysis showed areas under the curve (AUCs) of 0.579 for methylation and 0.917 for expression in WT venous blood, indicating higher diagnostic yield of preoperative SIX2 expression. The preoperative venous blood SIX2 expression level serves as an underlying biomarker for early diagnosis of WT. SIX2 overexpression and concomitantly decreased promoter methylation are significantly associated with poor survival of WT children. PMID- 25921282 TI - Usefulness of the neutrophil-to-lymphocyte ratio in predicting lymph node metastasis in patients with non-small cell lung cancer. AB - Preoperative neutrophil-to-lymphocyte ratio (NLR) is a new hotspot for its prognostic significance in many types of cancers. In this study, a novel diagnosing model-the combination of enhanced contrast computed tomography (ECCT) and NLR (COCT-NLR) was constructed to detect the lymph nodal involvement in patients with non-small cell lung cancer (NSCLC). The clinicopathological parameters and thoracic ECCT images of 353 NSCLC patients were retrospectively reviewed. The COCT-NLR model was constructed and evaluated in detecting regional lymph nodal metastasis in patients with NSCLC. Univariate and multivariate analyses of clinicopathological parameters revealed that NLR value was independently associated with regional nodal involvement rate in patients with NSCLC (odds ratio (OR) = 4.770; 95 % confidence interval (CI), 2.487-9.146; P < 0.001). Compared with ECCT and NLR, the COCT-NLR model showed the highest efficacy in predicting nodal involvement. The sensitivity and specificity of COCT NLR were 70.59 and 74.89 %, respectively. The COCT-NLR model is a valuable tool in detecting regional lymph node metastasis in patients with NSCLC. PMID- 25921283 TI - Long noncoding RNA CCHE1 promotes cervical cancer cell proliferation via upregulating PCNA. AB - Long noncoding RNAs (lncRNAs) have been shown to play important roles in carcinogenesis and progression. However, the roles and functional mechanisms of lncRNAs in cervical cancer remain largely unknown. In this study, we found that cervical carcinoma high-expressed lncRNA 1 (lncRNA-CCHE1) was significantly upregulated in cervical cancer tissues. The higher expression of CCHE1 was significantly correlated with large tumor size, advanced Federation of Gynecology and Obstetrics stage, uterine corpus invasion, and poor survival. Gain-of function and loss-of-function experiments demonstrated that CCHE1 overexpression promotes the proliferation of cervical cancer cell. By contrast, the depletion of CCHE1 inhibits the proliferation of cervical cancer cells. RNA pull-down assays confirmed that CCHE1 physically associates with proliferating cell nuclear antigen (PCNA) messenger RNA, consequently enhances the expression of PCNA. The expression of CCHE1 and PCNA is significantly correlated in cervical cancer tissues. The depletion of PCNA abolishes the effects of CCHE1 on the proliferation of cervical cancer cells. Taken together, these findings indicate that CCHE1 plays a pivotal role in cervical cancer cell proliferation via increasing PCNA expression and serves as a potential prognostic biomarker and therapeutic target in human cervical cancer. PMID- 25921284 TI - Prognostic significance of the absolute monocyte counts in lung cancer patients with venous thromboembolism. AB - We investigated the clinical significance of the absolute monocyte count (AMC) as a predictor of the response to anticoagulation and survival in lung cancer patients with venous thromboembolism (VTE). We retrospectively reviewed 1707 patients with pathologically proven lung cancer who visited the hospital between July 2008 and May 2014. Among them, the clinical data of patients newly diagnosed with VTE and treated with anticoagulation were compared between the low and high AMC groups according to the median value of AMC (640/MUL) at the time of VTE diagnosis. The incidence of VTE was 7.9 % during the study period. Most of the patients had non-small-cell lung cancer (82.1 %), stage IV (64.2 %), and pulmonary thromboembolism (76.1 %) and were incidentally diagnosed with VTE (76.9 %). The patients' characteristics and laboratory values were not significantly different between the low and high AMC groups. Among patients available for evaluation of the response to anticoagulation, the high AMC group was significantly more refractory to anticoagulation than the low AMC group (no response to anticoagulation, 21.7 vs. 6.8 %, respectively; p = 0.044). Additionally, the high AMC group showed worse overall survival (OS) than the low AMC group (median, 9.6 vs. 5.9 months; p = 0.038). On multivariate analysis, high AMC, low albumin, and advanced stage were independent poor prognostic factors for OS. High AMC is associated with refractoriness to anticoagulation and poor prognosis in lung cancer patients with VTE. PMID- 25921285 TI - CDKN2A (p16) mRNA decreased expression is a marker of poor prognosis in malignant high-grade glioma. AB - Human high-grade glioma is heterogeneous in nature based on pathological and genetic profiling. Various tumour suppressor gene alterations are considered as prognostic markers in high-grade glioma. Gene expression of CDKN2A (p16) is used in various cancers as a prognostic biomarker along with methylation and deletion status of this gene. Expression levels of p16 mRNA were not studied as a biomarker in gliomas before. In this study, we have performed mRNA quantification analysis on 48 high-grade glioma tissues and checked for a possible prognostic role. The decreased expression of p16 mRNA in majority of the tumour tissues (57.1 %) was observed when compared to control tissues (P = 0.02). mRNA expression level was correlated with clinical variables also. p16 deletion status and BMI1 mRNA expression were also considered for comparison. p16 mRNA was negatively correlated with the BMI1 mRNA (P = <0.0001) but not with p16 deletion. p16 mRNA expression, midline shift in MRI and tumour type were able to predict patient survival in overall survival (OS) and progression-free survival (PFS). p16 mRNA could independently predict prognosis of OS (P = 0.0146) and PFS (P = 0.0305) in multivariate analysis. We have shown that p16 mRNA expression can act as an independent prognostic biomarker in high-grade glioma. PMID- 25921287 TI - Pulsatility Produced by the Hemodialysis Roller Pump as Measured by Doppler Ultrasound. AB - Microbubbles have previously been detected in the hemodialysis extracorporeal circuit and can enter the blood vessel leading to potential complications. A potential source of these microbubbles is highly pulsatile flow resulting in cavitation. This study quantified the pulsatility produced by the roller pump throughout the extracorporeal circuit. A Sonosite S-series ultrasound probe (FUJIFILM Sonosite Inc., Tokyo, Japan) was used on a single patient during normal hemodialysis treatment. The Doppler waveform showed highly pulsatile flow throughout the circuit with the greatest pulse occurring after the pump itself. The velocity pulse after the pump ranged from 57.6 +/- 1.74 cm/s to -72 +/- 4.13 cm/s. Flow reversal occurred when contact between the forward roller and tubing ended. The amplitude of the pulse was reduced from 129.6 cm/s to 16.25 cm/s and 6.87 cm/s following the dialyzer and venous air trap. This resulted in almost nonpulsatile, continuous flow returning to the patient through the venous needle. These results indicate that the roller pump may be a source of microbubble formation from cavitation due to the highly pulsatile blood flow. The venous air trap was identified as the most effective mechanism in reducing the pulsatility. The inclusion of multiple rollers is also recommended to offer an effective solution in dampening the pulse produced by the pump. PMID- 25921286 TI - Clinicopathological significance and prognostic value of the expression of the cancer stem cell marker CD133 in hepatocellular carcinoma: a meta-analysis. AB - To conduct a meta-analysis to assess the association between CD133 expression and clinicopathological significance and prognostic value in hepatocellular carcinoma patients. Studies were identified via an electronic comprehensive literature search through the Pubmed, Chinese CNKI, and Wanfang databases. This meta analysis was performed using Stata statistical software version 12.0. The outcomes included various clinicopathological and survival parameters (P < 0.05 was consider to indicate a statistical significance). A total of 21 studies comprising 2592 patients were included in this meta-analysis. CD133 overexpression was significantly associated with a series of clinicopathological parameters, such as low tumor differentiation (pooled odds ratio (OR) = 2.26, 95% CI: 1.59-3.21, P < 0.00001), advanced tumor stage (pooled OR = 2.17, 95% CI: 1.70 2.77, P < 0.00001), vascular invasion (pooled OR = 2.06, 95% CI: 1.25-3.39, P = 0.005), and vascular thrombosis (pooled OR = 1.47, 95% CI: 1.08-1.99, P = 0.015). However, CD133 expression was not correlated with hepatitis, cirrhosis, alpha fetoprotein level, tumor number, tumor size, encapsulation, or metastasis. Regarding survival outcome, CD133 overexpression was significantly correlated with poor overall survival (pooled hazard ratio (HR) = 2.01, 95% CI: 1.45-2.80, P = 0.00002) and poor disease-free survival (pooled HR = 1.82, 95% CI: 1.45-2.29, P < 0.00001). This meta-analysis indicated that CD133 overexpression is significantly associated with clinicopathological factors and poorer survival outcome. PMID- 25921289 TI - Temporal proteomics of NGF-TrkA signaling identifies an inhibitory role for the E3 ligase Cbl-b in neuroblastoma cell differentiation. AB - SH-SY5Y neuroblastoma cells respond to nerve growth factor (NGF)-mediated activation of the tropomyosin-related kinase A (TrkA) with neurite outgrowth, thereby providing a model to study neuronal differentiation. We performed a time resolved analysis of NGF-TrkA signaling in neuroblastoma cells using mass spectrometry-based quantitative proteomics. The combination of interactome, phosphoproteome, and proteome data provided temporal insights into the molecular events downstream of NGF binding to TrkA. We showed that upon NGF stimulation, TrkA recruits the E3 ubiquitin ligase Cbl-b, which then becomes phosphorylated and ubiquitylated and decreases in abundance. We also found that recruitment of Cbl-b promotes TrkA ubiquitylation and degradation. Furthermore, the amount of phosphorylation of the kinase ERK and neurite outgrowth increased upon Cbl-b depletion in several neuroblastoma cell lines. Our findings suggest that Cbl-b limits NGF-TrkA signaling to control the length of neurites. PMID- 25921288 TI - A review of typhoid fever transmission dynamic models and economic evaluations of vaccination. AB - Despite a recommendation by the World Health Organization (WHO) that typhoid vaccines be considered for the control of endemic disease and outbreaks, programmatic use remains limited. Transmission models and economic evaluation may be informative in decision making about vaccine programme introductions and their role alongside other control measures. A literature search found few typhoid transmission models or economic evaluations relative to analyses of other infectious diseases of similar or lower health burden. Modelling suggests vaccines alone are unlikely to eliminate endemic disease in the short to medium term without measures to reduce transmission from asymptomatic carriage. The single identified data-fitted transmission model of typhoid vaccination suggests vaccines can reduce disease burden substantially when introduced programmatically but that indirect protection depends on the relative contribution of carriage to transmission in a given setting. This is an important source of epidemiological uncertainty, alongside the extent and nature of natural immunity. Economic evaluations suggest that typhoid vaccination can be cost-saving to health services if incidence is extremely high and cost-effective in other high incidence situations, when compared to WHO norms. Targeting vaccination to the highest incidence age-groups is likely to improve cost-effectiveness substantially. Economic perspective and vaccine costs substantially affect estimates, with disease incidence, case-fatality rates, and vaccine efficacy over time also important determinants of cost-effectiveness and sources of uncertainty. Static economic models may under-estimate benefits of typhoid vaccination by omitting indirect protection. Typhoid fever transmission models currently require per-setting epidemiological parameterisation to inform their use in economic evaluation, which may limit their generalisability. We found no economic evaluation based on transmission dynamic modelling, and no economic evaluation of typhoid vaccination against interventions such as improvements in sanitation or hygiene. PMID- 25921290 TI - Redundant and specialized roles for diacylglycerol kinases alpha and zeta in the control of T cell functions. AB - The diacylglycerol kinases (DGKs) attenuate diacylglycerol (DAG)-mediated signals by catalyzing the conversion of DAG to phosphatidic acid. In T lymphocytes, the antigen-stimulated generation of DAG links signal strength to the intensity and duration of signaling by the Ras-extracellular signal-regulated kinase (ERK) and protein kinase C (PKC)-dependent pathways. The generation of DAG at the plasma membrane of T cells lies at the core of the mechanisms that delimit T cell functions. DGKalpha and DGKzeta are the two main isoforms that are found in T cells, and several approaches define their precise contribution to T cell responses. Each of these isoforms has specialized and redundant functions that limit the intensity of DAG-regulated signals downstream of antigenic stimulation. This ability, which in normal T cells contributes to maintaining homeostasis and function, is exploited by tumors to evade immune surveillance. Modification of DGK activity offers new perspectives for the therapeutic manipulation of T cell functions for treatment of autoimmune pathologies, or for overcoming tumor induced T cell tolerance. Precise knowledge of the mechanisms that sustain DGK isoform-specific regulation in T lymphocytes is indispensable for the development of new tools for pharmacological intervention. PMID- 25921291 TI - Dynamic phosphoproteomics reveals TORC1-dependent regulation of yeast nucleotide and amino acid biosynthesis. AB - Phosphoproteomics studies have unraveled the extent of protein phosphorylation as a key cellular regulation mechanism, but assigning functionality to specific phosphorylation events remains a major challenge. TORC1 (target of rapamycin complex 1) is a kinase-containing protein complex that transduces changes in nutrient availability into phosphorylation signaling events that alter cell growth and proliferation. To resolve the temporal sequence of phosphorylation responses to nutritionally and chemically induced changes in TORC1 signaling and to identify previously unknown kinase-substrate relationships in Saccharomyces cerevisiae, we performed quantitative mass spectrometry-based phosphoproteomic analyses after shifts in nitrogen sources and rapamycin treatment. From early phosphorylation events that were consistent over at least two experimental perturbations, we identified 51 candidate and 10 known proximal targets of TORC1 that were direct substrates of TORC1 or of one of its kinase or phosphatase substrates. By correlating these phosphoproteomics data with dynamic metabolomics data, we inferred the functional role of phosphorylation on the metabolic activity of 12 enzymes, including three candidate TORC1-proximal targets: Amd1, which is involved in nucleotide metabolism; Hom3, which is involved in amino acid metabolism; and Tsl1, which mediates carbohydrate storage. Finally, we identified the TORC1 substrates Sch9 and Atg1 as candidate kinases that phosphorylate Amd1 and Hom3, respectively. PMID- 25921292 TI - In vivo imaging of the spatiotemporal activity of the eIF2alpha-ATF4 signaling pathway: Insights into stress and related disorders. AB - The eIF2alpha-ATF4 pathway is involved in cellular adaptation to stress and is dysregulated in numerous diseases. Activation of this pathway leads to phosphorylation of the alpha subunit of eukaryotic initiation factor 2 (eIF2alpha) and the recruitment of the transcription factor ATF4 (activating transcription factor 4) to specific CCAAT/enhancer binding protein (C/EBP)-ATF response elements (CAREs) located in the promoters of target genes. To monitor the spatiotemporal modulation of this pathway in living animals, we generated a novel CARE-driven luciferase mouse model (CARE-LUC). These transgenic mice enable the investigation of the eIF2alpha-ATF4 pathway activity in the whole organism and at the tissue and cellular levels by combining imaging, luciferase assays, and immunochemistry. Using this mouse line, we showed the tissue-specific activation pattern of this pathway in response to amino acid deficiency or endoplasmic reticulum stress and the hepatic induction of this pathway in a stress-related pathology model of liver fibrosis. The CARE-LUC mouse model represents an innovative tool to investigate the eIF2alpha-ATF4 axis and to develop drugs targeting this important pathway in the remediation of related pathologies. PMID- 25921293 TI - Nutritional values of available ruminant feed resources in smallholder dairy farms in Rwanda. AB - Smallholder dairy farmers in Rwanda use diversity of resources to cope with endemic feed shortages. However, there is inadequate real farm data to support farmer decisions on choices of options. The main objective of this study was to evaluate nutritional quality of feed types that farmers use in different agro ecological zones of Rwanda. Samples of feed types were collected from 90 randomly selected households in the low- and mid-high-altitude zones of Rwanda and analysed for proximate composition, contents of metabolisable energy (ME), organic matter digestibility (OMD) and neutral detergent fibre digestibility (NDFd). Rumen fermentation characteristics and efficiency of energy utilisation were examined by determining partitioning factor (PF). Results showed that only five out of 24 feed types were common in both districts. Chemical composition, OMD, ME, NDFd and PF of these feed types differed significantly (P < 0.05) in their nutritional attributes. This suggests that a common feed composition table can be used as a component of the decision support tool for rational feed resource development and utilisation in the smallholder farms in the selected agro-ecologies of Rwanda. PMID- 25921294 TI - Functional research and cognitive-process research in behavioural science: An unequal but firmly connected pair. AB - Drawing on illustrative examples of the functional and cognitive psychology in contemporary research, the present article emphasizes the primacy of functional relationships, which provide the fundament for all attempts to uncover invisible cognitive processes. Cognitive research is not only inherently more difficult and much more ambitious than functional research. It also suffers from several home made problems, such as unwarranted inferences from model fitting, the mediation analysis cult and the failure to take environmental influences into account. However, despite the primacy of functional psychology and the problems associated with the ambitious goals of cognitive research, the two partners in this unequal pair are firmly connected and jointly responsible for the most impressive examples of progress in behavioural science. PMID- 25921295 TI - Posterior regeneration following fission in the holothurian Cladolabes schmeltzii (Dendrochirotida: Holothuroidea). AB - The regeneration of the posterior portion of the body after fission was studied in the holothurian Cladolabes schmeltzii using electron microscopy methods. Following fission, the aquapharyngeal complex, gonad and anterior portion of the first descending part of the intestine remain in the anterior fragment of the body. The entire regeneration process is divided into five stages. In the first three stages, the digestive system and damaged ends of the longitudinal muscle bands regenerate. The intestine is formed through the rearrangement and growth of the remaining portion of the first descending part of the intestine. The gut anlage grows down the mesentery and joins the regenerating cloaca. The cloaca is formed from two sources: its posterior portion appears as a result of immersion of the epidermis, while the anterior portion develops from the terminal segment of the growing intestine. Regeneration of muscles progresses in the typical manner for echinoderms: through immersion and myogenic transformation of the coelomic epithelium. Respiratory trees appear in animals when the growth of the external part of the body has begun (fourth stage). They are formed as an outgrowth of the dorsal wall of the anterior portion of the cloaca. It was concluded that regeneration of the posterior portion of the body in the holothurian C. schmeltzii following fission is realized through morphallactic rearrangements of the remaining parts of organs. The main mechanism through which the digestive, respiratory, and contractile systems are formed is epithelial morphogenesis. PMID- 25921296 TI - Cu-catalyzed debrominative cyanation of gem-dibromoolefins: a facile access to alpha,beta-unsaturated nitriles. AB - An efficient catalytic route for the synthesis of alpha,beta-unsaturated nitriles from easily accessible gem-dibromoolefins has been developed. The method utilized inexpensive reagents such as Cu2O as a catalyst, L-proline as a ligand and NaCN as a cyanide source to afford alpha,beta-unsaturated nitriles in high yields (62 86%). A deuterium exchange study has shown that one of the bromide atoms of gem dibromoolefins exchanges with cyanide while the other with a deuterium atom. PMID- 25921298 TI - Leucobacter humi sp. nov., Isolated from Forest Soil. AB - A novel bacterial strain, designated Re6(T), was isolated from forest soil collected in Campbell University, North Carolina. The cells are aerobic, Gram positive, non-motile, and rod shaped. Growth occurred at 4-42 degrees C (optimum, 25 degrees C), pH 6-9 (optimum, pH 6), and in 0-3 % NaCl (w/v). Phylogenetic analysis based on 16S rRNA gene sequences indicated that strain Re6(T) belonged to the genus Leucobacter and showed the highest 16S rRNA gene sequence similarities with Leucobacter iarius JCM 14736(T) (98.3 %), Leucobacter luti JCM 14920(T) (97.9 %), Leucobacter komagatae JCM 9414(T) (97.8 %), and Leucobacter denitrificans KACC 14055(T) (97.7 %). Strain Re6(T) contained anteiso C15:0 (45.2 %), iso-C16:0 (17.1 %), and anteiso-C17:0 (32.6 %) as the major cellular fatty acids; MK-11 as the major respiratory quinone; L-diaminobutyric acid as the diagnostic diamine acid in cell wall peptidoglycan; and diphosphatidylglycerol and phosphatidylglycerol as the main polar lipids. The DNA G+C content of the strain Re6(T) was 66.6 mol%. DNA-DNA hybridization results showed similarity values less than 50 % for DNA samples from the most closely related type strains of L. iarius, L. luti, and L. komagatae. On the basis of the data from the polyphasic analysis, strain Re6(T) is considered to be a representative novel species in the genus Leucobacter, for which the name Leucobacter humi sp. nov. is proposed. The type strain is Re6(T) (KEMC 7301 006(T) = JCM 18638(T)). PMID- 25921297 TI - Docosahexaenoic acid differentially affects TNFalpha and IL-6 expression in LPS stimulated RAW 264.7 murine macrophages. AB - Docosahexaenoic acid (DHA) is generally reported to have anti-inflammatory properties, however, prior work has documented differential effects on individual pro-inflammatory cytokines: reduced IL-6, but not TNFalpha, mRNA expression in macrophages. To elucidate the mechanism, the roles of prostaglandin E2 (PGE2), cyclic AMP response element-binding protein (CREB), and NFkappaB were examined in RAW 264.7 macrophages. DHA did not influence CREB activity, but significantly reduced PGE2 production by 41% and NFkappaB activity by 32%. Exogenous PGE2 inhibited TNFalpha mRNA expression dose dependently. Unexpectedly, inhibiting PGE2 production with NS-398 also decreased TNFalpha mRNA expression, suggesting a concentration-dependent dual role of PGE2 in regulating TNFalpha expression. IL-6 expression was unaffected by endogenous or exogenous PGE2. Partial block of NFkappaB activation (SN50; 46%, or, BAY-11-7082; 41%) lowered IL-6 to a greater extent than TNFalpha mRNA expression. The differential effect of DHA on TNFalpha and IL-6 mRNA expression may be mediated via reduction in NFkappaB activity. PMID- 25921299 TI - Review of the effect of music interventions on symptoms of anxiety and depression in older adults with mild dementia. AB - BACKGROUND: Treatment of anxiety and depression, the most common psychiatric symptoms in older adults with mild dementia, requires innovative approaches due to the high cost and significant side effects associated with traditional pharmacological interventions. Alternative non-pharmacological therapies, such as music, when used in conjunction with pharmacological treatment, have the potential to alleviate symptoms of anxiety and depression in older adults diagnosed with mild dementia. The purpose of this review was to examine the evidence of music's efficacy in improving symptoms of anxiety and depression in older adults with mild dementia. METHODS: Four databases (Medline, CINAHL, PsychInfo, PubMed) were searched using the terms "music," "music therapy," "music intervention," "singing," "dementia," "anxiety," and/or "depression," identifying ten studies that met the inclusion and exclusion criteria. RESULTS: The poor methodological rigor of the studies precluded reaching consensus on the efficacy of a music intervention in alleviating symptoms of anxiety and depression in older adults with mild dementia. CONCLUSIONS: There was inconclusive evidence as to whether music interventions are effective in alleviating symptoms of anxiety and depression in older adults with mild dementia due to the poor methodological rigor. However, with improved designs guided by a deeper understanding of how music engages the aging brain, music may emerge as an important adjunct therapy to improving the lives of older adults with mild dementia. PMID- 25921300 TI - Diagnostic value of platelet indices for pulmonary embolism: the authors respond. PMID- 25921301 TI - Peritoneal dialysis and potassium: pains and gains in the ED. PMID- 25921302 TI - Trusting a Virtual Driver That Looks, Acts, and Thinks Like You. AB - OBJECTIVE: We examined whether participants would trust an agent that was similar to them more than an agent that was dissimilar to them. BACKGROUND: Trust is an important psychological factor determining the acceptance of smart systems. Because smart systems tend to be treated like humans, and similarity has been shown to increase trust in humans, we expected that similarity would increase trust in a virtual agent. METHODS: In a driving simulator experiment, participants (N = 111) were presented with a virtual agent that was either similar to them or not. This agent functioned as their virtual driver in a driving simulator, and trust in this agent was measured. Furthermore, we measured how trust changed with experience. RESULTS: Prior to experiencing the agent, the similar agent was trusted more than the dissimilar agent. This effect was mediated by perceived similarity. After experiencing the agent, the similar agent was still trusted more than the dissimilar agent. CONCLUSION: Just as similarity between humans increases trust in another human, similarity also increases trust in a virtual agent. When such an agent is presented as a virtual driver in a self driving car, it could possibly enhance the trust people have in such a car. APPLICATION: Displaying a virtual driver that is similar to the human driver might increase trust in a self-driving car. PMID- 25921303 TI - "Such Behaviors Are Not in My Home Village, I Got Them Here": A Qualitative Study of the Influence of Contextual Factors on Alcohol and HIV Risk Behaviors in a Fishing Community on Lake Victoria, Uganda. AB - In Uganda, elevated HIV prevalence in fishing communities along Lake Victoria have been attributed in part to heavy alcohol use, but qualitative research is needed to understand the contextual factors influencing alcohol and sexual risk. Eight focus group discussions were conducted (n = 50; 23 male, 27 female) in Gerenge, Uganda with five occupational groups: fishermen, fishmongers, alcohol sellers, commercial sex workers, and restaurant owners. Data was analyzed using content analysis. Alcohol use was prevalent and said to influence risky sex. Sex related alcohol expectancies and occupational factors influenced individuals to drink during sex and structural factors related to the built environment, economy, and policy were identified as key contributors to both alcohol use and sexual risk in general. The findings highlight alcohol reduction as an important component of HIV/AIDS prevention and suggest structural interventions should be prioritized in this context. PMID- 25921304 TI - Sin3A-associated protein, 18 kDa, a novel binding partner of TRIB1, regulates MTTP expression. AB - Mammalian tribbles homolog 1 (TRIB1) is a human locus that has been shown to significantly impact plasma lipid levels across several ethnic groups. In addition, the gene has been associated with the occurrence of nonalcoholic fatty liver disease. In the present study, a yeast-two-hybrid system was used to screen for novel molecular targets of TRIB1 binding. Loci corresponding to clones that were positive for TRIB1 binding subsequently were assessed for roles in lipid metabolism in mice using adenoviral constructs to induce knockdown or overexpression. Sin3A-associated protein, 18 kDa (SAP18) was identified as a novel binding partner of TRIB1. Knockdown of the Sap18 in mouse liver decreased plasma lipid levels and increased hepatic lipid levels; SAP18 overexpression showed the opposite effects. Transcriptome analysis of the mouse liver revealed that Sap18 knockdown decreased and SAP18 overexpression increased microsomal TG transfer protein (MTTP) expression levels. Chromatin immunoprecipitation analysis showed that halo-tagged SAP18, halo-tagged TRIB1, and anti-mSin3A antibody enriched precipitates for regulatory sequences of the MTTP gene. Enforced expression of SAP18 enhanced and SAP18 knockdown conversely attenuated the enrichment of MTTP regulatory sequences seen with anti-mSin3A antibody. These studies indicated that SAP18 expression enhanced the recruitment of mSin3A in coordination with TRIB1 to MTTP regulatory elements and increased MTTP expression. PMID- 25921305 TI - Botanical oils enriched in n-6 and n-3 FADS2 products are equally effective in preventing atherosclerosis and fatty liver. AB - Echium oil (EO), which is enriched in 18:4 n-3, the immediate product of fatty acid desaturase 2 (FADS2) desaturation of 18:3 n-3, is as atheroprotective as fish oil (FO). The objective of this study was to determine whether botanical oils enriched in the FADS2 products 18:3 n-6 versus 18:4 n-3 are equally atheroprotective. LDL receptor KO mice were fed one of four atherogenic diets containing 0.2% cholesterol and 10% calories as palm oil (PO) plus 10% calories as: 1) PO; 2) borage oil (BO; 18:3 n-6 enriched); 3) EO (18:4 n-3 enriched); or 4) FO for 16 weeks. Mice fed BO, EO, and FO versus PO had significantly lower plasma total and VLDL cholesterol concentrations; hepatic neutral lipid content and inflammation, aortic CE content, aortic root intimal area and macrophage content; and peritoneal macrophage inflammation, CE content, and ex vivo chemotaxis. Atheromas lacked oxidized CEs despite abundant generation of macrophage 12/15 lipooxygenase-derived metabolites. We conclude that botanical oils enriched in 18:3 n-6 and 18:4 n-3 PUFAs beyond the rate-limiting FADS2 enzyme are equally effective in preventing atherosclerosis and hepatosteatosis compared with saturated/monounsaturated fat due to cellular enrichment of >=20 PUFAs, reduced plasma VLDL, and attenuated macrophage inflammation. PMID- 25921306 TI - Crystal structure of the protein At3g01520, a eukaryotic universal stress protein like protein from Arabidopsis thaliana in complex with AMP. AB - Members of the universal stress protein (USP) family are conserved in a phylogenetically diverse range of prokaryotes, fungi, protists, and plants and confer abilities to respond to a wide range of environmental stresses. Arabidopsis thaliana contains 44 USP domain-containing proteins, and USP domain is found either in a small protein with unknown physiological function or in an N terminal portion of a multi-domain protein, usually a protein kinase. Here, we report the first crystal structure of a eukaryotic USP-like protein encoded from the gene At3g01520. The crystal structure of the protein At3g01520 was determined by the single-wavelength anomalous dispersion method and refined to an R factor of 21.8% (Rfree = 26.1%) at 2.5 A resolution. The crystal structure includes three At3g01520 protein dimers with one AMP molecule bound to each protomer, comprising a Rossmann-like alpha/beta overall fold. The bound AMP and conservation of residues in the ATP-binding loop suggest that the protein At3g01520 also belongs to the ATP-binding USP subfamily members. PMID- 25921307 TI - Can the Affective Response to Exercise Predict Future Motives and Physical Activity Behavior? A Systematic Review of Published Evidence. AB - BACKGROUND: Consistent with hedonic theories of behavior, the affective response to physical activity has been posited as an important determinant of future physical activity; yet, we are unaware of an overview of evidence regarding this relationship. PURPOSE: The purpose of this study was to review the published literature regarding whether the affective response to physical activity relates to future physical activity behavior and key motivational constructs. METHODS: A systematic review following PRISMA guidelines was undertaken. RESULTS: Twenty four studies met the inclusion criteria. A positive change in the basic affective response during moderate intensity exercise was linked to future physical activity, but postexercise affect had a null relationship. Affective responses during and after exercise had a relatively negligible relationship with intention, mixed results for self-efficacy, and a reliable correlation with affective judgments about future physical activity. DISCUSSION: The findings support the basic premise of hedonic theory. Practical application studies with a focus on sustained behavioral interventions are warranted. PMID- 25921308 TI - UK government postpones publishing report on sexual health services. PMID- 25921309 TI - Heart rate and use of beta-blockers in Mexican stable outpatients with coronary artery disease. AB - OBJECTIVE: To evaluate the use of beta-blockers and to monitor heart rate in Mexican patients with coronary artery disease. METHODS: CLARIFY is an outpatients registry with stable CAD. A total of 33,283 patients from 45 countries were enrolled between November 2009 and July 2010 from which 1342 were Mexican patients. RESULTS: The mean HR pulse was 70 bpm (beats per minute). Patients in Mexico were compared with the remaining global CLARIFY population. Patients in Mexico had a higher incidence of acute myocardial infarction and percutaneous coronary intervention, and lower incidence of revascularization surgery compared with the remaining CLARIFY population. More often, Mexican patients presented with diabetes, but less often hypertension and stroke. These patients were split into three mutually exclusive groups of HR <= 60 (N=263), HR 61-69 (N=356) and HR >= 70 (N=722). Patients with elevated HR had a higher incidence of diabetes and higher diastolic blood pressure on average than those with controlled HR. Regarding the use of beta-blockers, they were used in 63.3% of patients, 2.7% showed intolerance or contraindication to treatment to monitor heart rate, and ivabradine was used in 2.3%. Out of approximately 849 patients receiving treatment of beta-blockers, 52.1% had >= 70 bpm HR. CONCLUSIONS: In a large proportion of Mexican patients with stable coronary disease the HR remain elevated, > 70 bpm, even with the use of beta-blockers; this requires further attention. PMID- 25921311 TI - Peripheral T-cell lymphoma with unusual clinical presentation of rhabdomyolysis. AB - Primary extranodal lymphoma is known to occur in nose, gastrointestinal tract, skin, bone, and central nervous system. However, it is extremely rare for primary lymphoma to arise in skeletal muscle. We report a case of a 32-year-old man who presented initially with fever and fatigue. He had a history of alcohol abuse. Laboratory studies and computerized tomography scan showed results consistent with rhabdomyolysis, but the cause of the rhabdomyolysis was undetermined. After biopsy of abdominal skeletal muscle with histologic examination and T-cell receptor gamma chain gene rearrangement analysis, the diagnosis of peripheral T cell lymphoma was established. After two cycles of the cyclophosphamide, doxorubicin, vincristine, prednisone, and etoposide regimen, the patient's symptoms greatly improved. This is the third reported case of peripheral T-cell lymphoma arising in skeletal muscle reported in the literature and which presented clinically with rhabdomyolysis. The alcohol abuse during the clinical course likely worsens the pathologic process of the rhabdomyolysis. Copyright (c) 2015 John Wiley & Sons, Ltd. PMID- 25921310 TI - ICD and CRT use in ischemic heart disease in women. AB - Although the role of implantable cardioverter defibrillator (ICD) and cardiac resynchronization therapy (CRT) in improving outcomes in ischemic cardiomyopathy (ICM) has been described, the data regarding gender-based survival outcomes are limited. There is a higher preponderance of non-ischemic cardiomyopathy (NICM) in women, and most of the ICM literature is derived from sub-study analysis. This review summarizes the current body of literature on prognosis, pathophysiology, and the present clinical practice for device implantation in women with ICM. PMID- 25921312 TI - Novel inhaled combined antibiotic formulations in the treatment of Pseudomonas aeruginosa airways infections in cystic fibrosis. AB - In cystic fibrosis, chronic airways infection caused by Pseudomonas aeruginosa can be treated with inhaled antibiotics such as inhaled tobramycin, aztreonam or colistin. However, biofilm formation induced by this bacterium can reduce the effectiveness of such therapies and can contribute to antibiotic resistance. Inhaled antibiotic combination might represent an optimal antibiofilm strategy in this setting. This review discusses the rationale for combining the antibiotics as well as some emerging or existing combinations. Most of the combinations except for fosfomycin/tobramycin are at an early stage of development. The latter combination was found to be effective in Phase II clinical studies and is planned to be tested in Phase III trials. The clinical data on long-term efficacy are currently missing, but the existing evidence as well as the unmet therapeutic need can prompt the further evaluation of such compounds. PMID- 25921313 TI - Gene protein detection platform--a comparison of a new human epidermal growth factor receptor 2 assay with conventional immunohistochemistry and fluorescence in situ hybridization platforms. AB - Human epidermal growth factor receptor 2 (HER2) immunohistochemistry (IHC) and fluorescence in situ hybridization (FISH) are widely used semiquantitative assays for selecting breast cancer patients for HER2 antibody therapy. However, both techniques have been shown to have disadvantages. Our aim was to test a recent automated technique of combined IHC and brightfield dual in situ hybridization gene protein detection platform (GPDP)-in breast cancer HER2 protein, gene, and chromosome 17 centromere status evaluations, comparing the results in accordance to the American Society of Clinical Oncology/College of American Pathologists recommendations for HER2 testing in breast cancer from both 2007 and 2013. The GPDP technique performance was evaluated on 52 consecutive whole slide invasive breast cancer cases with HER2 IHC 2/3+ scoring results. Applying in turns the American Society of Clinical Oncology/College of American Pathologists recommendations for HER2 testing in breast cancer from 2007 and 2013 to both FISH and GPDP DISH assays, the HER2 gene amplification results showed 100% concordance among amplified/nonamplified cases, but there was a shift in 4 cases toward positive from equivocal results and toward equivocal from negative results. This might be related to the emphasis on the average HER2 copy number in the 2013 criteria. HER2 expression by IVD market IHC kit (Pathway(r)) has a strong correlation with GPDP HER2 protein, including a full concordance for all cases scored as 3+ and a reduction from 2+ to 1+ in 7 cases corresponding to nonamplified cases. Gene protein detection platform HER2 protein "solo" could have spared the need for 7 FISH studies. In addition, the platform offered advantages on interpretation reassurance including selecting areas for counting gene signals paralleled with protein IHC expression, on heterogeneity detection, interpretation time, technical time, and tissue expense. PMID- 25921314 TI - Failing hospitals: mission statements to drive service improvement? AB - PURPOSE: This paper aims to consider whether the hospital mission statement can be used as a management tool to improve service provision in failing hospitals. DESIGN/METHODOLOGY/APPROACH: A literature search into the potential value and harm of hospital mission statements was done, followed by a survey of initial attitudes within a failing hospital. Do they indicate likely success of the tool? FINDINGS: Mission statement is a potentially valuable leadership tool in the hospital environment. The success of its implementation is broadly dependent on its being developed with the support of stakeholders and its real application to all management decisions and questions of asset allocation. The potential danger lies in the fact that it can be seen as an expensive expression of politically correct platitudes which leads to cynical alienation of stakeholders. RESEARCH LIMITATIONS/IMPLICATIONS: This was a small study within a single UK failing hospital, and extending its range will help to clarify whether its findings are typical of attitudes within such institutions. PRACTICAL IMPLICATIONS: The likely success of the hospital mission statement as a management tool within a failing hospital is significantly limited by initial attitudes and preconceptions. Our research suggests that implementation is likely to be detrimental without preparatory involvement of the local community and hospital staff at all levels. SOCIAL IMPLICATIONS: Hospital management cannot be divorced from the local community where patient confidence must be maintained. ORIGINALITY/VALUE: This paper complements previous research, which has looked at mission statement acceptance among the upper echelons of hospital management. PMID- 25921315 TI - The medical leadership challenge in healthcare is an identity challenge. AB - PURPOSE: The purpose of this article is to describe and analyse the identity challenges that physicians with medical leadership positions face. DESIGN/METHODOLOGY/APPROACH: Four qualitative case studies were performed to address the fact that identity is processual, relational and situational. Physicians with managerial roles were interviewed, as well as their peers, supervisors and subordinates. Furthermore, observations were made to understand how different identities are displayed in action. FINDINGS: This study illustrates that medical leadership implies identity struggles when physicians have manager positions, because of the different characteristics of the social identities of managers and physicians. Major differences are related between physicians as autonomous individuals in a system and managers as subordinates to the organizational system. There are psychological mechanisms that evoke the physician identity more often than the managerial identity among physicians who are managers, which explains why physicians who are managers tend to remain foremost physicians. RESEARCH LIMITATIONS/IMPLICATIONS: The implications of the findings, that there are major identity challenges by being both a physician and manager, suggest that managerial physicians might not be the best prerequisite for medical leadership, but instead, cooperative relationships between physicians and non-physician managers might be a less difficult way to support medical leadership. PRACTICAL IMPLICATIONS: Acknowledging and addressing identity challenges can be important both in creating structures in organizations and designing the training for managers in healthcare (both physicians and non physicians) to support medical leadership. ORIGINALITY/VALUE: Medical leadership is most often related to organizational structure and/or leadership skills, but this paper discusses identity requirements and challenges related to medical leadership. PMID- 25921316 TI - Workplace-based clinical leadership training increases willingness to lead. AB - PURPOSE: The purpose of this paper is to reflect upon a workplace-based, interdisciplinary clinical leadership training programme (CLP) to increase willingness to take on leadership roles in a large regional health-care centre in Victoria, Australia. Strengthening the leadership capacity of clinical staff is an advocated strategy for improving patient safety and quality of care. An interdisciplinary approach to leadership is increasingly emphasised in the literature; however, externally sourced training programmes are expensive and tend to target a single discipline. DESIGN/METHODOLOGY/APPROACH: Appraisal of the first two years of CLP using multiple sourced feedback. A structured survey questionnaire with closed-ended questions graded using a five-point Likert scale was completed by participants of the 2012 programme. Participants from the 2011 programme were followed up for 18 months after completion of the programme to identify the uptake of new leadership roles. A reflective session was also completed by a senior executive staff that supported the implementation of the programme. FINDINGS: Workplace-based CLP is a low-cost and multidisciplinary alternative to externally sourced leadership courses. The CLP significantly increased willingness to take on leadership roles. Most participants (93 per cent) reported that they were more willing to take on a leadership role within their team. Fewer were willing to lead at the level of department (79 per cent) or organisation (64 per cent). Five of the 11 participants from the 2011 programme had taken on a new leadership role 18 months later. Senior executive feedback was positive especially around the engagement and building of staff confidence. They considered that the CLP had sufficient merit to support continuation for at least another two years. ORIGINALITY/VALUE: Integrating health-care professionals into formal and informal leadership roles is essential to implement organisational change as part of the drive to improve the safety and quality of care for patients and service users. This is the first interdisciplinary, workplace-based leadership programme to be described in the literature, and demonstrates that it is possible to deliver low-cost, sustainable and productive training that increases the willingness to take on leadership roles. PMID- 25921317 TI - Lean leadership: an ethnographic study. AB - PURPOSE: The purpose of this study is to provide a critical analysis of contemporary Lean leadership in the context of a healthcare practice. The Lean leadership model supports professionals with a leading role in implementing Lean. This article presents a case study focusing specifically on leadership behaviours and issues that were experienced, observed and reported in a Dutch university medical centre. DESIGN/METHODOLOGY/APPROACH: This ethnographic case study provides auto-ethnographic accounts based on experiences, participant observation, interviews and document analysis. FINDINGS: Characteristics of Lean leadership were identified to establish an understanding of how to achieve successful Lean transformation. This study emphasizes the importance for Lean leaders to go to the gemba, to see the situation for one's own self, empower health-care employees and be modest. All of these are critical attributes in defining the Lean leadership mindset. ORIGINALITY/VALUE: In this case study, Lean leadership is specifically related to healthcare, but certain common leadership characteristics are relevant across all fields. This article shows the value of an auto-ethnographic view on management learning for the analysis of Lean leadership. The knowledge acquired through this research is based on the first author's experiences in fulfilling his role as a health-care leader. This may help the reader examining his/her own role and reflecting on what matters most in the field of Lean leadership. PMID- 25921318 TI - Leading processes of patient care and treatment in hierarchical healthcare organizations in Sweden--process managers' experiences. AB - PURPOSE: The purpose of this study is to gain better understanding of the roles and functions of process managers by describing Swedish process managers' experiences of leading processes involving patient care and treatment when working in a hierarchical health-care organization. DESIGN/METHODOLOGY/APPROACH: This study is based on an explorative design. The data were gathered from interviews with 12 process managers at three Swedish hospitals. These data underwent qualitative and interpretative analysis with a modified editing style. FINDINGS: The process managers' experiences of leading processes in a hierarchical health-care organization are described under three themes: having or not having a mandate, exposure to conflict situations and leading process development. The results indicate a need for clarity regarding process manager's responsibility and work content, which need to be communicated to all managers and staff involved in the patient care and treatment process, irrespective of department. There also needs to be an emphasis on realistic expectations and orientation of the goals that are an intrinsic part of the task of being a process manager. RESEARCH LIMITATIONS/IMPLICATIONS: Generalizations from the results of the qualitative interview studies are limited, but a deeper understanding of the phenomenon was reached, which, in turn, can be transferred to similar settings. ORIGINALITY/VALUE: This study contributes qualitative descriptions of leading care and treatment processes in a functional, hierarchical health-care organization from process managers' experiences, a subject that has not been investigated earlier. PMID- 25921319 TI - Impact of service attributes on customer satisfaction and loyalty in a healthcare context. AB - PURPOSE: The purpose of this paper is to examine the role of perceived service attributes in the development of overall customer satisfaction (OCS) and customer loyalty (CL) in a health-care setting. This paper also sheds light on the role of hospitalist physicians (HPs) and offers suggestions to improve patient satisfaction and loyalty. DESIGN/METHODOLOGY/APPROACH: A telephone survey was used to collect data from recently hospitalized patients with respect to their HP. Structural equations modeling (SEM) was used to confirm the overall relationships between perceived service quality (PSQ), OCS and CL. The sample was then divided into customer relationship groups (CRGs) based on satisfaction and loyalty measures. Discriminant analysis was used to determine which attributes differentiated most between high and low satisfaction and loyalty groups. FINDINGS: Overall relationships among PSQ, OCS and CL were in conformity with the conceptual model. Findings also revealed that service attributes played an important role in distinguishing between high and low satisfaction and loyalty groups, although some attributes were more important than others and different attributes emerged as being key influencers for satisfaction and loyalty. RESEARCH LIMITATIONS/IMPLICATIONS: The conceptual model used is a fairly straight forward model, and we have not considered the impact of individual factors such as expectations and value perceptions or involvement levels and demographic characteristics on service quality and overall satisfaction. The data for this study were provided by a major health maintenance organization (HMO), and there is room for improvement in the manner in which certain constructs were measured. For example, OCS, recommendation and retention all used single item measures, and it might have been preferable to use multiple item measures for these constructs. PRACTICAL IMPLICATIONS: The study shows that organizations can benefit by identifying and focusing on critical attributes as part of their customer relationship management program. SOCIAL IMPLICATIONS: The SEM results provide strong support for the overall model linking service quality, OCS and CL in a health-care setting. As one would expect, PSQ has a strong impact on OCS, which, in turn, has a fairly strong impact on CL. However, there is also a significant direct linkage between PSQ and CL. This linkage shows that at least a certain portion of CL could evolve independent of the satisfaction level with the HP. This shows that, in addition to trying to improve satisfaction, organizations should also explore influencing loyalty directly, perhaps by the strategic use of service attribute perceptions. ORIGINALITY/VALUE: The study shows that customer perceptions at the service attribute level can often be the key to the generation and management of customer satisfaction and loyalty. It also has significance for how satisfaction and loyalty with HPs can be improved in a hospital setting. PMID- 25921320 TI - Large-area few-layered graphene film determination by multispectral imaging microscopy. AB - A multispectral imaging method for the rapid and accurate identification of few layered graphene using optical images is proposed. Commonly rapid identification relies on optical interference effects which limits the choice of substrates and light sources. Our method is based on the comparison of spectral characteristics with principle components from a database which is populated by correlation of micro-Raman registration, spectral characteristics, and optical microscopy. Using this approach the thickness and extent of different graphene layers can be distinguished without the contribution of the optical interference effects and allows characterization of graphene on glass substrates. The high achievable resolution, easy implementation and large scale make this approach suitable for the in-line metrology of industrial graphene production. PMID- 25921322 TI - Existence, uniqueness, and construction of the density-potential mapping in time dependent density-functional theory. AB - In this work we review the mapping from densities to potentials in quantum mechanics, which is the basic building block of time-dependent density-functional theory and the Kohn-Sham construction. We first present detailed conditions such that a mapping from potentials to densities is defined by solving the time dependent Schrodinger equation. We specifically discuss intricacies connected with the unboundedness of the Hamiltonian and derive the local-force equation. This equation is then used to set up an iterative sequence that determines a potential that generates a specified density via time propagation of an initial state. This fixed-point procedure needs the invertibility of a certain Sturm Liouville problem, which we discuss for different situations. Based on these considerations we then present a discussion of the famous Runge-Gross theorem which provides a density-potential mapping for time-analytic potentials. Further we give conditions such that the general fixed-point approach is well-defined and converges under certain assumptions. Then the application of such a fixed-point procedure to lattice Hamiltonians is discussed and the numerical realization of the density-potential mapping is shown. We conclude by presenting an extension of the density-potential mapping to include vector-potentials and photons. PMID- 25921321 TI - The association of brain structure with gait velocity in older adults: a quantitative volumetric analysis of brain MRI. AB - INTRODUCTION: While cortical processes play an important role in controlling locomotion, the underlying structural brain changes associated with slowing of gait in aging are not yet fully established. Our study aimed to examine the relationship between cortical gray matter volume (GM), white matter volume (WM), ventricular volume (VV), hippocampal and hippocampal subfield volumes, and gait velocity in older adults free of dementia. METHODS: Gait and cognitive performance was tested in 112 community-residing adults, age 70 years and over, participating in the Einstein Aging Study. Gait velocity (cm/s) was obtained using an instrumented walkway. Volumetric MRI measures were estimated using a FreeSurfer software. We examined the cross-sectional relationship of GM, WM, VV, and hippocampal total and subfield volumes and gait velocity using linear regression models. In complementary models, the effect of memory performance on the relationship between gait velocity and regional volumes was evaluated. RESULTS: Slower gait velocity was associated with smaller cortical GM and total hippocampal volumes. There was no association between gait velocity and WM or VV. Among hippocampal subfields, only smaller presubiculum volume was significantly associated with decrease in gait velocity. Addition of the memory performance to the models attenuated the association between gait velocity and all volumetric measures. CONCLUSIONS: Our findings indicate that total GM and hippocampal volumes as well as specific hippocampal subfield volumes are inversely associated with locomotor function. These associations are probably affected by cognitive status of study population. PMID- 25921323 TI - [Spanish version of the Satisfaction With Decision scale: cross-cultural adaptation, validity and reliability]. AB - OBJECTIVE: The aim of this study is to develop a Spanish version of the Satisfaction With Decision scale (SWDs) and analyse the psychometric properties of validity and reliability. DESIGN: An observational, descriptive study and validation of a tool to measure satisfaction with the decision. SETTING: Urology, Radiation oncology, and Medical oncology Departments of the Hospital Universitari Germans Trias i Pujol, Institut Catala d'Oncologia and the Institut Oncologic del Valles - Hospital General de Catalunya. PARTICIPANTS: A total of 170 participants diagnosed with prostate cancer, and who could read and write in Spanish and gave their informed consent. MAIN MEASUREMENTS: A translation, back-translation and cross-cultural adaptation to Spanish was performed on the SWDs. The content validity, criterion validity, construct validity and reliability (internal consistency and stability) of the Spanish version were evaluated. RESULTS: The SWDs contains 6 items with 5-item Likert scales. A Spanish version (ESD) was obtained that was linguistically and conceptually equivalent to the original version. Criterion validity, the ESD correlated with "satisfaction with the decision" using a linear analogue scale, was significant (r=0.63, P<.01) for all items. The factorial analysis showed a unique dimension to explain 82.08% of the variance. The ESD showed excellent results in terms of internal consistency (Cronbach alpha=0.95) and good test-retest reliability with intraclass correlation coefficient of 0.711. CONCLUSIONS: The ESD is a validated Spanish scale to measure the satisfaction with the decisions taken in health, and demonstrates a correct validity and reliability. PMID- 25921324 TI - [Nurses as a support to improve the quality of life during assisted reproduction]. AB - OBJECTIVE: The aim of this study was to measure how infertility and assisted reproduction treatments (including artificial insemination) could affect the quality of life, and to evaluate how nurses could be helpful in this process, by alleviating anxiety and increasing the quality of life. METHOD: A cross-sectional observational study was conducted on 48 patients (26 cycles) in an Assisted Reproduction Unit from 2nd December 2013 to 30th April 2014. Socio-demographic data were obtained, with the quality of life being assessed using the FertiQoL questionnaire before and after the treatment, and the consultations with a nurse by telephone or e-mail of these patients were also analyzed. RESULTS: The study results show a decreased quality of life in these patients, which was worse in men and in couples who had no previous children. Patient-centered care improved quality of life and tolerability to the assisted reproduction treatment. Patients frequently telephoned the nurse to solve their doubts and problems. CONCLUSION: The present study suggests that nurses can play an important role in improving the quality of life of patients undergoing assisted reproduction treatment. PMID- 25921325 TI - Association between genetic variants in SLC25A12 and risk of autism spectrum disorders: An integrated meta-analysis. AB - The solute carrier family 25 (aspartate/glutamate carrier), member 12 gene (SLC25A12) has been strongly posed as a candidate gene for autism spectrum disorder (ASD) given its important role in mitochondrial function and adenosine triphosphate (ATP) synthesis. Evidence is mounting for the association between SLC25A12 variants (rs2056202 and rs2292813) and ASD risk, but the results are inconsistent. To clarify the effect of these two variants on ASD, a meta-analysis integrating case-control and transmission disequilibrium test (TDT) studies was performed. The PubMed, Embase, Cochrane Library, Web of Science, Chinese BioMedical Literature (CBM), Wanfang, and Chinese National Knowledge Infrastructure (CNKI) databases were systematically searched to identify relevant studies published up to May 2014. Odds ratios (ORs) and 95% confidence intervals (95%CIs) were calculated to assess the strength of association. A total of 775 cases, 922 controls, and 1289 families available from 8 studies concerning rs2056202, and 465 cases, 450 controls, and 1516 families available from 7 studies concerning rs2292813 were finally included. In the overall meta-analysis, the rs2056202 T allele and rs2292813 T allele were both significantly associated with a decreased risk of ASD (rs2056202: OR = 0.809, P = 0.001, 95%CI: 0.713 0.917, I(2) = 0.0%, and P(heterogeneity) = 0.526; rs2292813: OR = 0.752, P < 0.001, 95%CI: 0.649-0.871, I(2) = 0.0%, P(heterogeneity) = 0.486). Besides, subjects with T-T haplotype of rs2056202-rs2292813 had a significantly reduced risk of ASD (OR = 0.672, P < 0.001, 95%CI: 0.564-0.801, I(2) = 0.0%, P(heterogeneity) = 0.631). Sensitivity analysis, cumulative meta-analysis, and publication bias diagnostics confirmed the reliability and stability of our results. Our meta-analysis suggests that rs2056202 and rs2292813 in SLC25A12 may contribute significantly to ASD risk. PMID- 25921326 TI - Gunnar Blix and his discovery of sialic acids. Fascinating molecules in glycobiology. PMID- 25921327 TI - Sharpened cortical tuning and enhanced cortico-cortical communication contribute to the long-term neural mechanisms of visual motion perceptual learning. AB - Much has been debated about whether the neural plasticity mediating perceptual learning takes place at the sensory or decision-making stage in the brain. To investigate this, we trained human subjects in a visual motion direction discrimination task. Behavioral performance and BOLD signals were measured before, immediately after, and two weeks after training. Parallel to subjects' long-lasting behavioral improvement, the neural selectivity in V3A and the effective connectivity from V3A to IPS (intraparietal sulcus, a motion decision making area) exhibited a persistent increase for the trained direction. Moreover, the improvement was well explained by a linear combination of the selectivity and connectivity increases. These findings suggest that the long-term neural mechanisms of motion perceptual learning are implemented by sharpening cortical tuning to trained stimuli at the sensory processing stage, as well as by optimizing the connections between sensory and decision-making areas in the brain. PMID- 25921328 TI - Prevalence of Bimolecular Routes in the Activation of Diatomic Molecules with Strong Chemical Bonds (O2, NO, CO, N2) on Catalytic Surfaces. AB - Dissociation of the strong bonds in O2, NO, CO, and N2 often involves large activation barriers on low-index planes of metal particles used as catalysts. These kinetic hurdles reflect the noble nature of some metals (O2 activation on Au), the high coverages of co-reactants (O2 activation during CO oxidation on Pt), or the strength of the chemical bonds (NO on Pt, CO and N2 on Ru). High barriers for direct dissociations from density functional theory (DFT) have led to a consensus that "defects", consisting of low-coordination exposed atoms, are required to cleave such bonds, as calculated by theory and experiments for model surfaces at low coverages. Such sites, however, bind intermediates strongly, rendering them unreactive at the high coverages prevalent during catalysis. Such site requirements are also at odds with turnover rates that often depend weakly on cluster size or are actually higher on larger clusters, even though defects, such as corners and edges, are most abundant on small clusters. This Account illustrates how these apparent inconsistencies are resolved through activations of strong bonds assisted by co-adsorbates on crowded low-index surfaces. Catalytic oxidations occur on Au clusters at low temperatures in spite of large activation barriers for O2 dissociation on Au(111) surfaces, leading to proposals that O2 activation requires low-coordination Au atoms or Au-support interfaces. When H2O is present, however, O2 dissociation proceeds with low barriers on Au(111) because chemisorbed peroxides (*OOH* and *HOOH*) form and weaken O-O bonds before cleavage, thus allowing activation on low-index planes. DFT-derived O2 dissociation barriers are much lower on bare Pt surfaces, but such surfaces are nearly saturated with CO* during CO oxidation. A dearth of vacant sites causes O2* to react with CO* to form *OOCO* intermediates that undergo O-O cleavage. NO-H2 reactions occur on Pt clusters saturated with NO* and H*; direct NO* dissociation requires vacant sites that are scarce on such surfaces. N-O bonds cleave instead via H*-assistance to form *HNOH* intermediates, with barriers much lower than for direct NO* dissociation. CO hydrogenation on Co and Ru occurs on crowded surfaces saturated with CO*; rates increase with increasing Co and Ru cluster size, indicating that low-index surfaces on large clusters can activate CO*. Direct CO*dissociation, however, occurs with high activation barriers on low-index Co and Ru surfaces, and even on defect sites (step-edge, corner sites) at high CO* coverages. CO* dissociation proceeds instead with H* assistance to form *HCOH* species that cleave C-O bonds with lower barriers than direct CO* dissociation, irrespective of surface coordination. H2O increases CO activation rates by assisting H-additions to form *HCOH*, as in the case of peroxide formation in Au-catalyzed oxidations. N2 dissociation steps in NH3 synthesis on Ru and Fe are thought to also require defect sites; yet, barriers on Ru(0001) indicate that H*-assisted N2 activation - unlike O2, CO, and NO - is not significantly more facile than direct N2 dissociation, suggesting that defects and low-index planes may both contribute to NH3 synthesis rates. The activation of strong chemical bonds often occurs via bimolecular reactions. These steps weaken such bonds before cleavage on crowded low-index surfaces, thus avoiding the ubiquitous kinetic hurdles of direct dissociations without requiring defect sites. PMID- 25921329 TI - National dosimetric audit network finds discrepancies in AAA lung inhomogeneity corrections. AB - This work presents the Australian Clinical Dosimetry Service's (ACDS) findings of an investigation of systematic discrepancies between treatment planning system (TPS) calculated and measured audit doses. Specifically, a comparison between the Anisotropic Analytic Algorithm (AAA) and other common dose-calculation algorithms in regions downstream (>=2cm) from low-density material in anthropomorphic and slab phantom geometries is presented. Two measurement setups involving rectilinear slab-phantoms (ACDS Level II audit) and anthropomorphic geometries (ACDS Level III audit) were used in conjunction with ion chamber (planar 2D array and Farmer-type) measurements. Measured doses were compared to calculated doses for a variety of cases, with and without the presence of inhomogeneities and beam modifiers in 71 audits. Results demonstrate a systematic AAA underdose with an average discrepancy of 2.9 +/- 1.2% when the AAA algorithm is implemented in regions distal from lung-tissue interfaces, when lateral beams are used with anthropomorphic phantoms. This systemic discrepancy was found for all Level III audits of facilities using the AAA algorithm. This discrepancy is not seen when identical measurements are compared for other common dose-calculation algorithms (average discrepancy -0.4 +/- 1.7%), including the Acuros XB algorithm also available with the Eclipse TPS. For slab phantom geometries (Level II audits), with similar measurement points downstream from inhomogeneities this discrepancy is also not seen. PMID- 25921330 TI - Posterior kV-CBCT scanning of the head and neck region minimizes doses to critical organs with sustained image quality. AB - We evaluated the absorbed dose to critical organs, as well as the image quality, at different partial angles in kV-CBCT (Cone Beam Computed Tomography) scanning of the head and neck region. CBCT images of phantom from a 200 degrees rotation were performed by using three different scanning paths, anterior, posterior, and right lateral with Catphan504 and RANDO phantoms. Critical organ dose was measured using TLD 100H in the RANDO phantom. The image quality of those phantoms was evaluated, using HU uniformity, HU linearity, contrast-to-noise ratio, low contrast visibility and spatial resolution with the Catphan504 dataset; and 5 point grading scales for the RANDO phantom dataset by five radiation oncologists. The image qualities from Catphan504 and RANDO phantom of every scanning path were comparable, with no statistically significant difference (p >= 0.05). However, there was a significant difference in the critical organ dose in all paths (p < 0.05), depending on the critical organ location and the scanning direction. Scanning directions show no effects on the image quality. Differences in absorbed dose to critical organs should were evaluated. The posterior scanning path for the CBCT was deemed preferable due because of considerably lower doses to several critical organs of the head and neck region. PMID- 25921331 TI - Ultrafiltration modeling of non-ionic microgels. AB - Membrane ultrafiltration (UF) is a pressure driven process allowing for the separation and enrichment of protein solutions and dispersions of nanosized microgel particles. The permeate flux and the near-membrane concentration polarization (CP) layer in this process is determined by advective-diffusive dispersion transport and the interplay of applied and osmotic transmembrane pressure contributions. The UF performance is thus strongly dependent on the membrane properties, the hydrodynamic structure of the Brownian particles, their direct and hydrodynamic interactions, and the boundary conditions. We present a macroscopic description of cross-flow UF of non-ionic microgels modeled as solvent-permeable spheres. Our filtration model involves recently derived semi analytic expressions for the concentration-dependent collective diffusion coefficient and viscosity of permeable particle dispersions [Riest et al., Soft Matter, 2015, 11, 2821]. These expressions have been well tested against computer simulation and experimental results. We analyze the CP layer properties and the permeate flux at different operating conditions and discuss various filtration process efficiency and cost indicators. Our results show that the proper specification of the concentration-dependent transport coefficients is important for reliable filtration process predictions. We also show that the solvent permeability of microgels is an essential ingredient to the UF modeling. The particle permeability lowers the particle concentration at the membrane surface, thus increasing the permeate flux. PMID- 25921332 TI - Patients' experiences of dental implant treatment: A literature review of key qualitative studies. AB - OBJECTIVES: To identify and summarise the findings of previous qualitative studies relating to patients' experience of dental implant treatment (DIT) at various stages of their implant treatment, by means of textual narrative synthesis. DATA/SOURCES: Original articles reporting patients' experience with dental implant were included. A two-stage search of the literature, electronic and hand search identified relevant qualitative studies up to July 2014. An extensive electronic search was conducted of databases including PubMed, Embase, Scopus, Web of Knowledge, Cochrane Database and Google Scholar. STUDY SELECTION: Included primary studies (n=10) used qualitative research methods and qualitative analysis to investigate patients' experiences with dental implants treatment. CONCLUSIONS: While the growing interest in implant treatment for the replacement of missing dentition is evident, it is essential to investigate patients' perceptions of different aspects of implant treatment. This textual narrative synthesis conducted to review qualitative studies which provided insight into patients' experience of two types of implant prostheses namely ISOD (implant supported overdenture) and FISP (fixed implant supported prostheses). Primary reviewed studies tended to include samples of older patients with more extensive tooth loss, and to focus on experiences prior to and post-treatment rather than on the treatment period itself. Findings across reviewed studies (n=10) suggested that patients with FISP thought of implant treatment as a process of 'normalisation'(1) and believed that such implant restorations could be similar to natural teeth, whereas patients with ISOD focused more on the functional and social advantages of their implant treatment. CLINICAL SIGNIFICANCE: The growing interest in qualitative research is evident in several branches of clinical dentistry and dental implantology is not an exception. Qualitative studies concerning the patients account of their experience of dental implants is however limited. The aim of this review is to firstly identify recent work within this field and to subsequently categorise it more consistently by means of textural narrative synthesis, thus highlighting similarities and differences and enabling identification of gaps in research knowledge thereby setting the direction of further research. PMID- 25921333 TI - No clinically significant lymphocyte count change in pediatric patients treated with levetiracetam. PMID- 25921334 TI - The protein interactome of collapsin response mediator protein-2 (CRMP2/DPYSL2) reveals novel partner proteins in brain tissue. AB - PURPOSE: Collapsin response mediator protein-2 (CRMP2) is a CNS protein involved in neuronal development, axonal and neuronal growth, cell migration, and protein trafficking. Recent studies have linked perturbations in CRMP2 function to neurodegenerative disorders such as Alzheimer's disease, neuropathic pain, and Batten disease, and to psychiatric disorders such as schizophrenia. Like most proteins, CRMP2 functions though interactions with a molecular network of proteins and other molecules. EXPERIMENTAL DESIGN: Here, we have attempted to identify additional proteins of the CRMP2 interactome to provide further leads about its roles in neurological functions. We used a combined co immunoprecipitation and shotgun proteomic approach in order to identify CRMP2 protein partners. RESULTS: We identified 78 CRMP2 protein partners not previously reported in public protein interaction databases. These were involved in seven biological processes, which included cell signaling, growth, metabolism, trafficking, and immune function, according to Gene Ontology classifications. Furthermore, 32 different molecular functions were found to be associated with these proteins, such as RNA binding, ribosomal functions, transporter activity, receptor activity, serine/threonine phosphatase activity, cell adhesion, cytoskeletal protein binding and catalytic activity. In silico pathway interactome construction revealed a highly connected network with the most overrepresented functions corresponding to semaphorin interactions, along with axon guidance and WNT5A signaling. CONCLUSIONS AND CLINICAL RELEVANCE: Taken together, these findings suggest that the CRMP2 pathway is critical for regulating neuronal and synaptic architecture. Further studies along these lines might uncover novel biomarkers and drug targets for use in drug discovery. PMID- 25921335 TI - Emergency cooling doesn't improve outcomes in children with cardiac arrest, study shows. PMID- 25921336 TI - The relationship between accessibility of healthcare facilities and medical care utilization among the middle-aged and elderly population in Taiwan. AB - OBJECTIVE: The purpose of this study was to explore the relationship between accessibility of healthcare facilities and medical care utilization among the middle-aged and elderly population in Taiwan. DESIGN: Cross-sectional study from 2007 Taiwan Longitudinal Study on Ageing (TLSA) survey. SETTING: Community-based study. PARTICIPANTS: A total of 4249 middle-aged and elderly subjects were recruited. INTERVENTIONS: None. MAIN OUTCOME MEASURES: Outpatient visits within 1 month, and hospitalization, emergency visits as well as to shop in pharmacy stores within 1 year, respectively. RESULTS: Adjusting for important confounding variables, the middle-aged and elderly with National Health Insurance (NHI) and commercial insurance compared with those with NHI alone tended to have outpatient visits. The middle-aged and elderly with longer time to access healthcare facilities were less likely to shop in pharmacy stores compared with those with <30 min. The middle-aged and elderly who perceived inconvenient to access health care tended to shop in pharmacy stores compared with those with perceived convenience. CONCLUSIONS: Our study of Taiwan's experience could provide a valuable lesson for countries that are planning to launch universal health insurance system, locate budgets in health care and transportation. The middle aged and elderly who were facing more challenges in accessing health care, no matter in perceived accessibility or real time to access health care, had less outpatient visits and more drug stores shopping. Strategic policies are needed to improve accessibility in increasing patients' perception on access and escalating convenience of transportation system for improving accessibility. PMID- 25921337 TI - Compliance with hospital accreditation and patient mortality: a Danish nationwide population-based study. AB - OBJECTIVE: To examine the association between compliance with hospital accreditation and 30-day mortality. DESIGN: A nationwide population-based, follow up study with data from national, public registries. SETTING: Public, non psychiatric Danish hospitals. PARTICIPANTS: In-patients diagnosed with one of the 80 primary diagnoses. INTERVENTION: Accreditation by the first version of The Danish Healthcare Quality Programme for hospitals from 2010 to 2012. Compliance were assessed by surveyors on an on-site survey and awarded the hospital as a whole; fully (n = 11) or partially accredited (n = 20). A follow-up activity was requested for partially accredited hospitals; submitting additional documentation (n = 11) or by having a return-visit (n = 9). MAIN OUTCOME MEASURES: All-cause mortality within 30-days after admission. Multivariable logistic regression was used to compute odds ratios (ORs) for 30-day mortality adjusted for six confounding factors and for cluster effect at hospital level. RESULTS: A total of 276 980 in-patients were identified. Thirty-day mortality risk for in-patients at fully (n = 76 518) and partially accredited hospitals (n = 200 462) was 4.14% (95% confidence interval (CI):4.00-4.28) and 4.28% (95% CI: 4.20-4.37), respectively. In-patients at fully accredited hospitals had a lower risk of dying within 30-days after admission than in-patients at partially accredited hospitals (adjusted OR of 0.83; 95% CI: 0.72-0.96). A lower risk of 30-day mortality was observed among in-patients at partially accredited hospitals required to submit additional documentation compared with in-patients at partially accredited hospitals requiring a return-visit (adjusted OR 0.83; 95% CI: 0.67-1.02). CONCLUSION: Admissions at fully accredited hospitals were associated with a lower 30-day mortality risk than admissions at partially accredited hospitals. PMID- 25921338 TI - Colonic MUC2 mucin regulates the expression and antimicrobial activity of beta defensin 2. AB - In this study we identified mechanisms at the colonic mucosa by which MUC2 mucin regulated the production of beta-defensin in a proinflammatory milieu but functionally protected susceptible bacteria from its antimicrobial effects. The regulator role of MUC2 on production of beta-defensin 2 in combination with the proinflammatory cytokine interleukin-1beta (IL-1beta) was confirmed using purified human colonic MUC2 mucin and colonic goblet cells short hairpin RNA (shRNA) silenced for MUC2. In vivo, Muc2(-/-) mice showed impaired beta-defensin mRNA expression and peptide localization in the colon as compared with Muc2(+/-) and Muc2(+/+) littermates. Importantly, purified MUC2 mucin abrogated the antimicrobial activity of beta-defensin 2 against nonpathogenic and enteropathogenic Escherichia coli. Sodium metaperiodate oxidation of MUC2 removed the capacity of MUC2 to stimulate beta-defensin production and MUC2's inhibition of defensin antimicrobial activity. This study highlights that a defective MUC2 mucin barrier, typical in inflammatory bowel diseases, may lead to deficient stimulation of beta-defensin 2 and an unbalanced microbiota that favor the growth of beta-defensin-resistant microbes such as Clostridium difficile. PMID- 25921339 TI - Gut dendritic cell activation links an altered colonic microbiome to mucosal and systemic T-cell activation in untreated HIV-1 infection. AB - HIV-1-associated disruption of intestinal homeostasis is a major factor contributing to chronic immune activation and inflammation. Dendritic cells (DCs) are crucial in maintaining intestinal homeostasis, but the impact of HIV-1 infection on intestinal DC number and function has not been extensively studied. We compared the frequency and activation/maturation status of colonic myeloid DC (mDC) subsets (CD1c(+) and CD1c(neg)) and plasmacytoid DCs in untreated HIV-1 infected subjects with uninfected controls. Colonic mDCs in HIV-1-infected subjects had increased CD40 but decreased CD83 expression, and CD40 expression on CD1c(+) mDCs positively correlated with mucosal HIV-1 viral load, with mucosal and systemic cytokine production, and with frequencies of activated colon and blood T cells. Percentage of CD83(+)CD1c(+) mDCs negatively correlated with frequencies of interferon-gamma-producing colon CD4(+) and CD8(+) T cells. CD40 expression on CD1c(+) mDCs positively associated with abundance of high prevalence mucosal Prevotella copri and Prevotella stercorea but negatively associated with a number of low prevalence mucosal species, including Rumminococcus bromii. CD1c(+) mDC cytokine production was greater in response to in vitro stimulation with Prevotella species relative to R. bromii. These findings suggest that, during HIV infection, colonic mDCs become activated upon exposure to mucosal pathobiont bacteria leading to mucosal and systemic immune activation. PMID- 25921342 TI - Effect of ionic interaction on the mechanochromic properties of pyridinium modified tetraphenylethene. AB - A pyridinium modified tetraphenylethene-based salt shows aggregation-induced emission enhancement properties and irreversible mechanochromic behaviours. PMID- 25921341 TI - Modulation of nasopharyngeal innate defenses by viral coinfection predisposes individuals to experimental pneumococcal carriage. AB - Increased nasopharyngeal colonization density has been associated with pneumonia. We used experimental human pneumococcal carriage to investigate whether upper respiratory tract viral infection predisposes individuals to carriage. A total of 101 healthy subjects were screened for respiratory virus before pneumococcal intranasal challenge. Virus was associated with increased odds of colonization (75% virus positive became colonized vs. 46% virus-negative subjects; P=0.02). Nasal Factor H (FH) levels were increased in virus-positive subjects and were associated with increased colonization density. Using an in vitro epithelial model we explored the impact of increased mucosal FH in the context of coinfection. Epithelial inflammation and FH binding resulted in increased pneumococcal adherence to the epithelium. Binding was partially blocked by antibodies targeting the FH-binding protein Pneumococcal surface protein C (PspC). PspC epitope mapping revealed individuals lacked antibodies against the FH binding region. We propose that FH binding to PspC in vivo masks this binding site, enabling FH to facilitate pneumococcal/epithelial attachment during viral infection despite the presence of anti-PspC antibodies. We propose that a PspC based vaccine lacking binding to FH could reduce pneumococcal colonization, and may have enhanced protection in those with underlying viral infection. PMID- 25921340 TI - Macrophages are critical to the maintenance of IL-13-dependent lung inflammation and fibrosis. AB - The roles of macrophages in type 2-driven inflammation and fibrosis remain unclear. Here, using CD11b-diphtheria toxin receptor (DTR) transgenic mice and three models of interleukin 13 (IL-13)-dependent inflammation, fibrosis, and immunity, we show that CD11b(+) F4/80(+) Ly6C(+) macrophages are required for the maintenance of type 2 immunity within affected tissues but not secondary lymphoid organs. Direct depletion of macrophages during the maintenance or resolution phases of secondary Schistosoma mansoni egg-induced granuloma formation caused a profound decrease in inflammation, fibrosis, and type 2 gene expression. Additional studies with CD11c-DTR and CD11b/CD11c-DTR double-transgenic mice suggested that macrophages but not dendritic cells were critical. Mechanistically, macrophage depletion impaired effector CD4(+) T helper type 2 (Th2) cell homing and activation within the inflamed lung. Depletion of CD11b(+) F4/80(+) Ly6C(+) macrophages similarly reduced house dust mite-induced allergic lung inflammation and suppressed IL-13-dependent immunity to the nematode parasite Nippostrongylus brasiliensis. Consequently, therapeutic strategies targeting macrophages offer a novel approach to ameliorate established type 2 inflammatory diseases. PMID- 25921343 TI - The injectable neurostimulator: an emerging therapeutic device. AB - Injectable neurostimulators are currently applied in clinical trials to minimize the side effects such as discomfort, risk of infection, and post-surgery trauma, which can be pronounced with conventional, bulky implantable neurostimulators. Owing to its smaller size, wireless-updatable software, and wireless power supply, the injectable neurostimulator is presumably less invasive, 'smarter', and has a longer lifetime. We discuss the concept and development of the injectable neurostimulator, persistent implementation challenges, and obstacles to be overcome in its evolution. We survey the use of new materials, technologies, and design methods for injectable electrodes, batteries, antennas, and packaging to enhance reliability and other features. These advances in the field are accompanied by progress in electrophysiology, neuroscience, neurology, clinical trials, and treatments. PMID- 25921344 TI - The correlation of the binding mechanism of the polypyrrole-carbon capacitive interphase with electrochemical stability of the composite electrode. AB - Carbon-polymer composites have great application potential in the field of organic batteries, capacitors, capacitive water desalination reactors and as the conductive platforms for electrochemical sensors. Although numerous studies have been carried out with respect to the synthesis, the optimization of composition, the carbon type and the morphology control, there is still a lack of understanding about which kind of intermolecular connection between carbon and polymer phases is preferential, and how the system should be designed to achieve the application demand of long-term electrochemical stability. Herein, we propose two model systems that employ the most well-known commercial carbons (SWCNTs and carbon black Vulcan XC72-R) to generate polypyrrole-C composites and validate the type of chemical bonding that is preferential to maintain electrochemical stability. In this work we used a simple oxidative polymerization of pyrrole and generated various formulations (with variable polymer content). Based on the surface XPS combined with bulk TGA-MS analysis we were able to evaluate the concentration and type of oxygen-containing functionalities, revealing a high oxygen content for the carbon black. It was further correlated with XPS analysis of the respective composites showed evidence of the electronic interaction called pi-pi* stacking between SWCNTs and PPy, and the binding energy shifts associated with the formation of hydrogen bridge bonds in the case of Vulcan XC-72R-PPy. Furthermore, the electrochemical stability of these model samples was investigated by AC impedance spectroscopy. The charge transfer resistance (Rct) was analyzed upon the oxidative potential, revealing SWCNT-PPy as an ultra-stable composite, even for the high polymer content (1 : 4 weight ratio of C-PPy). In contrast, the carbon black-PPy underwent rapid degradation in the whole composition range. The durability is associated with the type and strength of the polymer-carbon bonding as revealed by EIS impedance correlated with spectroscopic studies. The electronic interactions between SWCNTs and PPy result in superior stability while the carbon black-PPy, where the hydrogen bridge bonds are generated, is not stable under the same experimental conditions. PMID- 25921345 TI - Effect of vitamin D supplementation on insulin kinetics and cardiovascular risk factors in polycystic ovarian syndrome: a pilot study. AB - To assess the effect of vitamin D supplementation on parameters of insulin sensitivity/resistance (IS/IR) and insulin secretion in subjects with polycystic ovarian syndrome (PCOS). A prospective double-blind randomized control trial was conducted to assess the effect of vitamin D on insulin kinetics in women with PCOS. The trial was conducted in a tertiary care research hospital. A total of 36 subjects with PCOS, aged 18-35 years, were included in this study. Vitamin D3 4000 IU/day versus placebo was given once a month for 6 months and both groups received metformin. IS (by whole-body IS index or Matsuda index), IR (by homeostasis model assessment IR (HOMA-IR)), and insulin secretion (by insulinogenic index; II30) were the main outcome measures. Secondary outcome included blood pressure (BP), lipid profile, disposition index (DI), and vascular stiffness. Out of 36 subjects who consented, 32 completed the study. Subjects were randomized into two groups: group A (n=15; metformin and vitamin D 4000 IU/day) or group B (n=17; metformin and placebo). Oral glucose tolerance tests with 75 g glucose were carried out at baseline and 6 months after supplementation. Hypovitaminosis D was observed in 93.8% of all subjects with mean serum 25 hydroxy vitamin D level of 7.30+/-4.45 ng/ml. After 6 months of vitamin D supplementation, there was no significant difference in any of the parameters of IS/IR (area under curve (AUC)-glucose, AUC-insulin, insulin:glucose ratio, HOMA-IR, Matsuda index, insulinogenic index, and DI), II30, and cardiovascular risk factors between the two groups. Supplementation of vitamin D, at a dose of 4000 IU/day for 6 months, did not have any significant effect on parameters of IS/IR and insulin secretion in subjects with PCOS. PMID- 25921346 TI - Silent cerebral events as a result of left atrial catheter ablation do not cause neuropsychological sequelae--a MRI-controlled multicenter study. AB - PURPOSE: Recently, diffusion-weighted magnetic resonance imaging (DW-MRI) revealed silent cerebral events (SCEs) as an acute complication of pulmonary vein isolation (PVI). We investigated whether SCEs following PVI are associated with neuropsychological deficits observed during patients' follow-up examinations. METHODS: After PVI, 52 patients were eligible for follow-up. PVI was performed using a variety of ablation technologies (duty-cycled phased radiofrequency (RF) multipolar ablation with the Pulmonary Vein Ablation Catheter(r) (PVAC) in 24 patients, cooled-tip RF ablation in 23 patients, and cryoballoon ablation in five patients). Fluid-attenuated inversion recovery (FLAIR)- and DW-MRI studies were performed 1 day before PVI and 1 day and 1 month afterward to detect pre-existing cerebral lesions or post-ablation SCEs. At the same times, eight neuropsychological tests were administered. We evaluated changes in patients' neuropsychological capabilities and compared changes in patients with SCEs to those without SCEs. RESULTS: FLAIR-MRI revealed pre-existing cerebral lesions in 42 patients (81 %), and DW-MRI demonstrated new SCEs in 25 patients (48 %) (17 treated with phased RF (PVAC) (71 %), six treated with irrigated RF (26 %), and two treated with cryoablation (40 %)). Neuropsychological test results showed no significant impairment (in median z scores) 1 day and 1 month after the ablation procedure. There was no difference in neuropsychological capabilities between patients with SCEs and those without SCEs except in one subtest (part of the verbal working memory test). CONCLUSIONS: The incidence of pre-existing cerebral lesions and post-ablation SCEs was high. The frequency of SCEs depends on the ablation technology used. Neither PVI nor post-ablation SCEs have any effect on neuropsychological capabilities. PMID- 25921347 TI - Use of vascular closure device is safe and effective in electrophysiological procedures. AB - PURPOSE: Little is known about the usefulness and safety of vascular closure devices (VCDs) in electrophysiological procedures. We present a retrospective analysis of our experience assessing the utility and outcomes of collagen vascular closure device (Angioseal) in patients that required periprocedural anticoagulation and multiple vascular access sites. METHODS: An retrospective chart review of patients who have undergone the deployment of VCD following electrophysiological procedures. RESULTS: In 26 patients (16 males, age 57 +/- 15 years, weight 96 +/- 21 kg), a total of 76 VCD were deployed. Seventy-three VCDs in femoral veins (right or left) and three in femoral artery. The mean number of VCD per patient was 3 (range, 2-4). VCD was successfully deployed in 75 out of 76 access sites. One patient was noted to have ecchymosis in both groins during follow-up visit. No other complications were noted. CONCLUSIONS: We provide evidence that a collagen plug-based VCD designed for arterial closure can be safely and effectively used to close multiple venous accesses even in the same vein. This can be accomplished with a venotomy size up to 2 Fr larger than the size of the closure device. PMID- 25921348 TI - Impact of baseline PR interval on cardiac resynchronization therapy outcomes in patients with narrow QRS complexes: an analysis of the ReThinQ Trial. AB - PURPOSE: Heart failure (HF) is a major cause of morbidity and mortality, and ventricular dyssynchrony is an important contributor. The ReThinQ trial reported no improvement with cardiac resynchronization therapy (CRT) in HF patients with left ventricular ejection fraction (LVEF) <35%, narrow QRS (<130 ms), New York Heart Association (NYHA) class III, and echocardiographically detected dyssynchrony, in spite of echocardiographic optimization. We investigated whether a subset of narrow QRS patients might derive benefit from CRT, based on baseline PR interval. METHODS: We retrospectivelyanalyzed the 87 patients from ReThinQ who were randomized to CRT. Patients were divided into two groups: baseline PR interval <180 ms and baseline PR interval >=180 ms. The primary outcome was change in VO2 max at 6 months; secondary outcomes were change in LVEF, 6-min walk distance, and change in NYHA class. RESULTS: Forty-six patients had PR < 180 ms and 41 had PR >= 180 ms. The baseline characteristics were similar in the two groups. As compared to patients with a short PR interval, at 6 months, only patients with PR >= 180 ms showed a statistically significant increase in VO2 max from 12.2 to 13.6 mL/kg min (P = 0.045). Similarly, LVEF was significantly improved only in the long PR group (0.26 to 0.28, P = 0.038). A greater percentage of patients in the long PR group showed improvement by at least one NYHA class (59 vs. 35%, P = 0.033). CONCLUSIONS: A longer baseline PR interval may allow more efficacious delivery of CRT by allowing programming of physiologic AV delays. A short baseline PR interval may contribute to LV under-filling and CRT non-response. PMID- 25921350 TI - Reliability and Responsiveness of Upper Limb Motor Assessments for Children With Central Neuromotor Disorders: A Systematic Review. AB - BACKGROUND: To investigate the effectiveness of upper limb rehabilitation, sound measures of upper limb function, capacity, and performance are paramount. OBJECTIVES: This systematic review investigates reliability and responsiveness of upper limb measurement tools used in pediatric neurorehabilitation. METHODS: A 2 tiered search was conducted up to July 2014. The first search identified upper limb motor assessments for 1- to 18-year-old children with neuromotor disorders. The second search examined the psychometric properties of the tools. Methodological quality was rated according to COSMIN guidelines, and results for each tool were assembled in a "best evidence synthesis." Furthermore, we delineated whether tools were unimanual or bimanual tests and if they measured recovery or did not distinguish between physiological and compensatory movements. RESULTS: The first search delivered 2546 hits. Of these, 110 articles on 51 upper limb assessment tools were included. The second search resulted in 58 studies on reliability, 11 on measurement error, and 10 on responsiveness. Best evidence synthesis revealed only 2 assessments with moderate positive evidence for reliability, whereas no evidence on measurement error and responsiveness was found. The Melbourne Assessment showed moderate positive evidence for interrater and a fair positive level of evidence for intrarater reliability. The Pediatric Motor Activity Log Revised revealed moderate positive evidence for test-retest reliability. CONCLUSIONS: There is a lack of high-quality studies about psychometric properties of upper limb measurement tools in children with neuromotor disorders. To date, upper limb rehabilitation trials in children and adolescents risk being biased by insensitive measurement tools lacking reliability. PMID- 25921349 TI - Dynamic Changes in White Matter Abnormalities Correlate With Late Improvement and Deterioration Following TBI: A Diffusion Tensor Imaging Study. AB - OBJECTIVE: Traumatic brain injury (TBI) is not a single insult with monophasic resolution, but a chronic disease, with dynamic processes that remain active for years. We aimed to assess patient trajectories over the entire disease narrative, from ictus to late outcome. METHODS: Twelve patients with moderate-to-severe TBI underwent magnetic resonance imaging in the acute phase (within 1 week of injury) and twice in the chronic phase of injury (median 7 and 21 months), with some undergoing imaging at up to 2 additional time points. Longitudinal imaging changes were assessed using structural volumetry, deterministic tractography, voxel-based diffusion tensor analysis, and region of interest analyses (including corpus callosum, parasagittal white matter, and thalamus). Imaging changes were related to behavior. RESULTS: Changes in structural volumes, fractional anisotropy, and mean diffusivity continued for months to years postictus. Changes in diffusion tensor imaging were driven by increases in both axial and radial diffusivity except for the earliest time point, and were associated with changes in reaction time and performance in a visual memory and learning task (paired associates learning). Dynamic structural changes after TBI can be detected using diffusion tensor imaging and could explain changes in behavior. CONCLUSIONS: These data can provide further insight into early and late pathophysiology, and begin to provide a framework that allows magnetic resonance imaging to be used as an imaging biomarker of therapy response. Knowledge of the temporal pattern of changes in TBI patient populations also provides a contextual framework for assessing imaging changes in individuals at any given time point. PMID- 25921351 TI - Kif7 expression is decreased in the diaphragmatic and pulmonary mesenchyme of nitrofen-induced congenital diaphragmatic hernia. AB - PURPOSE: Developmental mutations that inhibit diaphragmatic and pulmonary mesenchyme formation have been shown to cause congenital diaphragmatic hernia (CDH) and pulmonary hypoplasia (PH). Kinesin family member 7 (Kif7) plays a crucial role in diaphragmatic and pulmonary morphogenesis by controlling proliferation of mesenchymal cells. Loss of Kif7 has been reported to result in diaphragmatic defects and PH. We hypothesized that diaphragmatic and pulmonary Kif7 expression is decreased in the nitrofen-induced CDH model. METHODS: Timed pregnant rats were exposed to either nitrofen or vehicle on gestational day 9 (D9). Fetal diaphragms and lungs were microdissected on D13, D15, and D18, and divided into control and nitrofen-exposed specimens. Gene expression levels of Kif7 were analyzed by qPCR. Immunohistochemical staining was performed to evaluate Kif7 protein expression. RESULTS: Relative mRNA expression of Kif7 was significantly reduced in pleuroperitoneal folds (D13), developing diaphragms and lungs (D15), and fully muscularized diaphragms and differentiated lungs (D18) of nitrofen-exposed fetuses compared to controls. Immunoreactivity/immunofluorescence of Kif7 was markedly decreased in diaphragmatic and pulmonary mesenchyme of nitrofen-exposed fetuses on D13, D15, and D18 compared to controls. CONCLUSION: Decreased Kif7 expression during diaphragmatic development may interfere with mesenchymal cell proliferation, leading to defective pleuroperitoneal folds, and resulting in diaphragmatic defects and associated PH in the nitrofen-induced CDH model. PMID- 25921352 TI - A framework for modeling electroactive microbial biofilms performing direct electron transfer. AB - A modeling platform for microbial electrodes based on electroactive microbial biofilms performing direct electron transfer (DET) is presented. Microbial catabolism and anabolism were coupled with intracellular and extracellular electron transfer, leading to biofilm growth and current generation. The model includes homogeneous electron transfer from cells to a conductive biofilm component, biofilm matrix conduction, and heterogeneous electron transfer to the electrode. Model results for Geobacter based anodes, both at constant electrode potential and in voltammetric (dynamic electrode potential) conditions, were compared to experimental data from different sources. The model can satisfactorily describe microscale (concentration, pH and redox gradients) and macroscale (electric currents, biofilm thickness) properties of Geobacter biofilms. The concentration of electrochemically accessible redox centers, here denominated as cytochromes, involved in the extracellular electron transfer, plays the key role and may differ between constant potential (300 mM) and dynamic potential (3mM) conditions. Model results also indicate that the homogeneous and heterogeneous electron transfer rates have to be within the same order of magnitude (1.2 s(-1)) for reversible extracellular electron transfer. PMID- 25921353 TI - Childhood CIDP: Study of 31 patients and comparison between slow and rapid-onset groups. AB - OBJECTIVES: To describe 31 children presenting a CIDP; to compare patients with rapid-onset disease vs. patients with slow-onset disease, a rapid-onset disease being defined by a time to peak impairment of less than 8 weeks. STUDY DESIGN: A retrospective chart review identified 31 patients completing criteria for childhood CIDP, with 24 "confirmed CIDP" and 7 "possible CIDP". Data collected were time to peak impairment, clinical presentation, cerebrospinal fluid analysis, nerve conduction study, nerve biopsy, treatments. Evaluation at the end of follow-up was reported according to modified Rankin scale. RESULTS: Thirteen patients (42%) exhibited symptoms in less than 2 months with more often cranial nerve abnormalities (38% vs. 6%, p = 0.059), and sensitive symptoms (62% vs. 11%, p = 0.0057). They evolved predominantly in a relapsing way (69% vs. 22%, p = 0.0047). Length of the disease was also longer in the rapid-onset group (5.5 years vs. 3.83 years) but without statistical difference. The slow-onset group exhibited more frequently ataxia at onset (28% vs. 8%, p > 0.05), and evolved predominantly in a progressive manner (61% vs. 15%, p > 0.05). Outcome was similar and good in the two groups. At least 3 out of the 4 major electrophysiological criteria were positive for 27/31 children (87%). Axonal involvement could be present very early. Immunoglobulins were given in 29 cases and corticosteroids in 22. A partial or complete recovery 1 month after first treatment was reported in 30 cases. Among second-line treatments, only azathioprine seemed effective in two out of three intractable children. CONCLUSIONS: The differences noted between the two groups should be tested in wider populations. Electrophysiological criteria are restrictive and axonal involvement should be studied. Prospective trials are required to find out the best first and second line treatments. PMID- 25921354 TI - Effect of anticoagulant therapy on cell-derived microparticles and pregnancy outcome in women with pregnancy loss. PMID- 25921355 TI - A Re-evaluation of the Cognitive Effects From Single-session Transcranial Direct Current Stimulation. PMID- 25921356 TI - Assessing Trends in Tobacco Cessation in Diverse Patient Populations. AB - INTRODUCTION: This study examined change in tobacco use over 4 years among the general population of patients in six diverse health care organizations using electronic medical record data. METHODS: The study cohort (N = 34 393) included all patients age 18 years or older who were identified as smokers in 2007, and who then had at least one primary care visit in each of the following 4 years. RESULTS: In the 4 years following 2007, this patient cohort had a median of 13 primary care visits, and 38.6% of the patients quit smoking at least once. At the end of the fourth follow-up year, 15.4% had stopped smoking for 1 year or more. Smokers were more likely to become long-term quitters if they were 65 or older (OR = 1.32, 95% CI = [1.16, 1.49]), or had a diagnoses of cancer (1.26 [1.12, 1.41]), cardiovascular disease (1.22 [1.09, 1.37]), asthma (1.15 [1.06, 1.25]), or diabetes (1.17 [1.09, 1.27]). Characteristics associated with lower likelihood of becoming a long-term quitter were female gender (0.90 [0.84, 0.95]), black race (0.84 [0.75, 0.94]) and those identified as non-Hispanic (0.50 [0.43, 0.59]). CONCLUSIONS: Among smokers who regularly used these care systems, one in seven had achieved long-term cessation after 4 years. This study shows the practicality of using electronic medical records for monitoring patient smoking status over time. Similar methods could be used to assess tobacco use in any health care organization to evaluate the impact of environmental and organizational programs. PMID- 25921357 TI - Ultrasonography as a diagnostic tool for skin metastasis of a prostate adenocarcinoma. PMID- 25921358 TI - Participation and Enjoyment in Play with a Robot between Children with Cerebral Palsy who use AAC and their Peers. AB - This study explores children with complex communication needs, their peers and adult support persons in play with the talking and moving robot LekBot. Two triads were filmed playing with LekBot at pre-school. LekBot was developed to facilitate independent and enjoyable play on equal terms for children with significant communication disabilities and their peers. Using Conversation Analysis, participatory symmetry and enjoyment were investigated in relation to spoken and gestural communication, embodied stance, gaze, and affective display. Data originated from three video-recorded sessions that were approximately 2 hours long. Four different interaction situations were identified and explored: Participatory Asymmetry, Adult Facilitation, Greater Participatory Symmetry and Creativity, and Turn-taking and Enjoyable Play with LekBot. Neither participatory symmetry nor enjoyment were easily achieved in the play sessions and may require considerable effort, including adult involvement, but creative, spontaneous and highly enjoyable play, correlating with participatory symmetry to various degrees, was observed in a few instances. The findings are discussed with regard to play, AAC and the future development of robots to facilitate play. PMID- 25921359 TI - The "I-Pouch": Results of a new ileal neobladder technique. AB - OBJECTIVE: The aim of this study was to investigate perioperative, oncological and functional outcomes of the "I-Pouch" neobladder. MATERIALS AND METHODS: From 2002 to 2011, 97 patients (72 men, 25 women, median age 65, range 42-84 years) underwent radical cystectomy with I-Pouch neobladder reconstruction. Complications were graded according to the Clavien-Dindo classification. Oncological and functional outcomes were assessed. The median oncological and functional follow-up was 41 months (range 3-107 months) and 18 months (3-111 months), respectively. RESULTS: In the total cohort, the 5 year cancer-specific survival was 67.9%. The major 30 and 90 day complication rates were 14.4% and 17.5%, respectively. Open reimplantation for ureterointestinal stricture was necessary in two (2.1%). Of the 95 functionally evaluable patients postoperatively, 93 urinated spontaneously (97.9%) and two patients (2.1%) required clean intermittent catheterization to empty their neobladder. The median postvoid residual urine volume (PVR) was 0 ml (range 0-200 ml). One patient had postoperative reflux (1%), as evidenced by voiding cystography. The median number of urinary tract infections per year was 0 (range 0-2) and showed no association with increased PVR (p = 0.18). CONCLUSIONS: The perioperative, oncological and functional outcomes of the I-Pouch are comparable to those of other types of ileal neobladder. An advantage of the I-Pouch is that the implantation of the ureters lies on the neobladder floor, which facilitates later instrumentation of the upper tract. PMID- 25921360 TI - Prophylactic negative pressure wound therapy in colorectal surgery. Effects on surgical site events: current status and call to action. AB - Surgical site events, including surgical site infections (SSI), represent a major problem in general surgery. SSI are responsible of nuisance for patients, and can lead to important complications and disability, often needing prolonged postoperative stay with specific treatment and recovery in Intensive Care Units. These justify the higher costs due to SSI. Despite the growing body of evidence concerning SSI in general surgery, literature dealing with SSI after colorectal surgery is scarce, reflecting in suboptimal perception of such a relevant issue by colorectal surgeons and health authorities in Italy, though colorectal surgery is associated with higher rates of SSI. The best strategy for reducing the impact of SSI on costs of care and patients quality of life would be the development of a preventive bundle, similar to that adopted in the US through the colorectal section of the National Surgery Quality Improvement Project of the American College of Surgeons (ACS-NSQIP). This policy has been showed to significantly reduce the rates of SSI. In this scenario, incisional negative pressure wound therapy (NPWT) is likely to play a pivotal role. We herein reviewed the literature to report on the current status of preventive NPWT on surgical wounds of patients undergoing colorectal procedures with primary wound closure, suggesting evidence-based measures to reduce the impact of SSI, and to contain the costs associated with conventional NPWT devices by means of newer available technologies. Some explicative real life cases are presented. PMID- 25921361 TI - Effects of Cardiopulmonary Support With a Novel Pediatric Pump-Lung in a 30-Day Ovine Animal Model. AB - The scarcity of donor organs has led to the development of devices that provide optimal long-term respiratory or cardiopulmonary support to bridge recipients as they wait for lung and/or heart transplantation. This study was designed to evaluate the 30-day in vivo performance of the newly developed pediatric pump lung (PediPL) for cardiopulmonary support using a juvenile sheep model. The PediPL device was placed surgically between the right atrium and descending aorta in eight sheep (25.4-31.2 kg) and evaluated for 30 days. Anticoagulation was maintained with continuous heparin infusion (activated clotting time 150-200 s). The flow rate was measured continually, and gas transfer was measured daily. Plasma free hemoglobin, platelet activation, hematologic data, and blood biochemistry were assessed twice a week. Sheep were euthanized after 30 days. The explanted devices were examined for gross thrombosis. Six sheep survived for 30 32 days. During the study, the oxygen transfer rate of the devices was 54.9 +/- 13.2 mL/min at a mean flow rate of 1.14 +/- 0.46 L/min with blood oxygen saturation of 95.4% +/- 1.7%. Plasma free hemoglobin was 8.2 +/- 3.7 mg/dL. Platelet activation was 5.35 +/- 2.65%. The animals had normal organ chemistries except for surgery-related transient alterations in kidney and liver function. Although we found some scattered thrombi on the membrane surfaces of some explanted devices during the necropsy, the device function and performance did not degrade. The PediPL device was capable of providing cardiopulmonary support with long-term reliability and good biocompatibility over the 30-day duration and offers the potential option for bridging pediatric patients with end-stage heart or lung disease to heart and/or lung transplantation. PMID- 25921362 TI - Modeling sugarcane ripening as a function of accumulated rainfall in Southern Brazil. AB - The effect of weather variables on sugarcane ripening is a process still not completely understood, despite its huge impact on the quality of raw material for the sugar energy industry. The aim of the present study was to evaluate the influence of weather variables on sugarcane ripening in southern Brazil, propose empirical models for estimating total recoverable sugar (TRS) content, and evaluate the performance of these models with experimental and commercial independent data from different regions. A field experiment was carried out in Piracicaba, in the state of Sao Paulo, Brazil, considering eight sugarcane cultivars planted monthly, from March to October 2002. In 2003, at the harvest, 12 months later, samples were collected to evaluate TRS (kg t(-1)). TRS and weather variables (air temperature, solar radiation, relative humidity, and rainfall) were analyzed using descriptive and multivariate statistical analysis to understand their interactions. From these correlations, variables were selected to generate empirical models for estimating TRS, according to the cultivar groups and their ripening characteristics (early, mid, and late). These models were evaluated by residual analysis and regression analysis with independent experimental data from two other locations in the same years and with independent commercial data from six different locations from 2005 to 2010. The best performances were found with exponential models which considered cumulative rainfall during the 120 days before harvest as an independent variable (R (2) adj ranging from 0.92 to 0.95). Independent evaluations revealed that our models were capable of estimating TRS with reasonable to high precision (R (2) adj ranging from 0.66 to 0.99) and accuracy (D index ranging from 0.90 to 0.99), and with low mean absolute percentage errors (MAPE <= 5 %), even in regions with different climatic conditions. PMID- 25921363 TI - Effect of low speed drilling on osseointegration using simplified drilling procedures. AB - Our aim was to find out whether simplified drilling protocols would provide biological responses comparable to those of conventional drilling protocols at the low rotational speed of 400rpm. Seventy-eight root form endosseous implants with diameters of 3.75, 4.2, and 5mm were placed into canine tibias and allowed to heal for 3 and 5 weeks. After the dogs had been killed, the samples of implanted bone were retrieved and processed for non-decalcified histological sectioning. Bone-to-implant contact (BIC) and bone area fraction occupancy (BAFO) analyses were made on the histological sections. Implants treated by the simplified protocol resulted in BIC and BAFO values comparable to those obtained with the conventional drilling protocol, and there were no significant differences in the technique or diameter of the drilling. The results suggest that the simplified procedure gives biological outcomes comparable to those of the conventional procedure. PMID- 25921364 TI - Assessment of compression and strength of divergent screws mounted on miniplates for fixation of mandibular fractures: an in vitro experimental study. AB - An efficient band of tension is critical for the adequate fixation of mandibular fractures, so fixation devices that compress are helpful. We aimed to evaluate the possibility of creating compression using screws inserted divergently into miniplates placed in the tension zone of mandibular fractures and record the effects on the strength of fixation. For this in vitro experimental study we prepared 20 sheep hemimandibles. After angle fractures had been created, the specimens were divided into standard and study groups (n=10 in each). In the standard group the tension zones were fixed in the standard manner with 4-hole miniplates and 4 parallel screws. Those in the study group were fixed as for the standard group but with 4*45 degrees divergent screws. The differences in the gap in the fracture line before and after fixation were measured as indicators of compression. The strength of fixation was also assessed with a universal testing machine in vitro. The amount of compression was significant only in the study group (p<0.001), and there was no difference in the strength of fixation between the two groups (p=0.7). We conclude that divergent drilling and insertion of screws creates more horizontal force when miniplates are used, and results in reduction in the size of the probable gap in the fracture line. Insertion of divergent screws in miniplates may create compression between fractured segments without jeopardising the strength of fixation. PMID- 25921365 TI - The role of simultaneous and successive processing in EFL reading. AB - This study examines the relationship between simultaneous and successive processing (the Planning, Attention, Simultaneous and Successive processing [PASS] theory processes) and reading skills in English as a foreign language (EFL). A group of 81 children were administered two batteries of tests. One was used to measure EFL reading skills, while the other one assessed simultaneous and successive processing. We hypothesised (a) cognitive processes to predict reading ability, as well as (b) the presence of a significant relationship between (c) simultaneous processing and reading comprehension and (d) successive processing and letter and word decoding. The findings confirmed that the anticipated relationships between these domains exist and are of moderate effect size. The research has helped to contribute to the understanding of how simultaneous and successive processing can affect EFL reading skills both on the level of basic word and letter decoding and reading comprehension. PMID- 25921366 TI - Light and electron microscopy study of the spermatheca of Eupholidoptera chabrieri bimucronata (Ramme, 1927) and Uromenus brevicollis trinacriae La Greca 1964 (Orthoptera: Tettigoniidae). AB - A study by both optical and electron microscopy has been carried out on the spermatheca of Eupholidoptera chabrieri bimucronata and Uromenus brevicollis trinacriae (Orthoptera: Tettigoniidae). In both the examined species, the spermatheca consists of a sac/kidney-shaped seminal receptacle and a more or less tortuous spermathecal duct that opens into the common oviduct. The wall of both the organs consists of a pseudostratified epithelium surmounted by a cuticular intima; the latter is made up of a thicker endocuticle and an epicuticle. The epithelium shows two different cell types, irregularly arranged and with well differentiated functions: cuticle-forming and gland cells. In both the species, the cuticle-forming cells perform other functions, in addition to producing the cuticular intima. The gland cells never come in contact with the cuticular intima, have inside the reservoir a secretion whose appearance can diversify also in contiguous zones of the seminal receptacle. Based on our findings in both the species, the functions of the seminal receptacle would differ from those of the spermathecal duct. In the latter, some areas of the wall of the connecting tract show an activity of lysis, by contiguous epithelial cells, that could play a role in control and selection of spermatozoa. As for the feather-shaped spermatodesms, similar in both the species, freeze-fracture observations have shown that the acrosome of each spermatozoon regularly covers three-quarters of the extension of the acrosome of the following spermatozoon. Finally, the significance of our findings, compared with what is known in literature, is discussed. PMID- 25921367 TI - Combination of a double-lumen tracheal tube and bronchial blocker for a patient with continuous bleeding due to invasive lung infection. PMID- 25921368 TI - Proteus syndrome: what the anesthetist should know. AB - Proteus syndrome (PS), a rare hamartomatous disorder, manifests itself in asymmetric and disproportionate overgrowth of multiple body tissues. Because of complexity of the disorder, the anesthetic problems encountered during patients' perioperative management are very varied. We discuss the case of a 14-year-old adolescent boy diagnosed with PS who underwent corrective osteotomy of right knee joint under subarachnoid block. The salient points the anesthetists need to be aware of while caring for patients with PS are highlighted. PMID- 25921369 TI - Website Review: Review of patient-oriented websites on hemorrhoids. PMID- 25921370 TI - How to position for the gastroenterology fellowship of your choice: the program director perspective. PMID- 25921372 TI - Drug Level-based Anti-Tumor Necrosis Factor Therapy: Ready for Prime Time? PMID- 25921371 TI - LRIG1 Regulates Ontogeny of Smooth Muscle-Derived Subsets of Interstitial Cells of Cajal in Mice. AB - BACKGROUND & AIMS: Interstitial cells of Cajal (ICC) control intestinal smooth muscle contraction to regulate gut motility. ICC within the plane of the myenteric plexus (ICC-MY) arise from KIT-positive progenitor cells during mouse embryogenesis. However, little is known about the ontogeny of ICC associated with the deep muscular plexus (ICC-DMP) in the small intestine and ICC associated with the submucosal plexus (ICC-SMP) in the colon. Leucine-rich repeats and immunoglobulin-like domains protein 1 (LRIG1) marks intestinal epithelial stem cells, but the role of LRIG1 in nonepithelial intestinal cells has not been identified. We sought to determine the ontogeny of ICC-DMP and ICC-SMP, and whether LRIG1 has a role in their development. METHODS: Lrig1-null mice (homozygous Lrig1-CreERT2) and wild-type mice were analyzed by immunofluorescence and transit assays. Transit was evaluated by passage of orally administered rhodamine B-conjugated dextran. Lrig1-CreERT2 mice or mice with CreERT2 under control of an inducible smooth muscle promoter (Myh11-CreERT2) were crossed with Rosa26-LSL-YFP mice for lineage tracing analysis. RESULTS: In immunofluorescence assays, ICC-DMP and ICC-SMP were found to express LRIG1. Based on lineage tracing, ICC-DMP and ICC-SMP each arose from LRIG1-positive smooth muscle progenitors. In Lrig1-null mice, there was loss of staining for KIT in DMP and SMP regions, as well as for 2 additional ICC markers (anoctamin-1 and neurokinin 1 receptor). Lrig1-null mice had significant delays in small intestinal transit compared with control mice. CONCLUSIONS: LRIG1 regulates the postnatal development of ICC-DMP and ICC-SMP from smooth muscle progenitors in mice. Slowed small intestinal transit observed in Lrig1-null mice may be due, at least in part, to loss of the ICC-DMP population. PMID- 25921373 TI - Hepatocellular carcinoma: optimal staging impacts survival. PMID- 25921374 TI - Somatostatin receptor subtype 2 as pancreatic tumorigenesis suppressor: identification of a new targetable signaling node. PMID- 25921375 TI - Combining biomarkers in irritable bowel syndrome: a forward step toward making a positive diagnosis and directing therapy? PMID- 25921376 TI - Polymerase Slippage Restoration of Frameshifted TGFBR2 in Colorectal Cancer: A Novel Paradigm. PMID- 25921378 TI - Drug-induced liver injury: expanding our knowledge by enlarging population analysis with prospective and scoring causality assessment. PMID- 25921379 TI - On some mortality rate processes and mortality deceleration with age. AB - A specific mortality rate process governed by the non-homogeneous Poisson process of point events is considered and its properties are studied. This process can describe the damage accumulation in organisms experiencing external shocks and define its survival characteristics. It is shown that, although the sample paths of the unconditional mortality rate process are monotonically increasing, the population mortality rate can decrease with age and, under certain assumptions, even tend to zero. The corresponding analysis is the main objective of this paper and it is performed using the derived conditional distributions of relevant random parameters. Several meaningful examples are presented and discussed. PMID- 25921377 TI - Effect of Amitriptyline and Escitalopram on Functional Dyspepsia: A Multicenter, Randomized Controlled Study. AB - BACKGROUND & AIMS: Antidepressants are frequently prescribed to treat functional dyspepsia (FD), a common disorder characterized by upper abdominal symptoms, including discomfort or postprandial fullness. However, there is little evidence of the efficacy of these drugs in patients with FD. We performed a randomized, double-blind, placebo-controlled trial to evaluate the effects of antidepressant therapy on symptoms, gastric emptying (GE), and meal-induced satiety in patients with FD. METHODS: We performed a study at 8 North American sites of patients who met the Rome II criteria for FD and did not have depression or use antidepressants. Patients (n = 292; 44 +/- 15 years old, 75% were female, 70% with dysmotility-like FD, and 30% with ulcer-like FD) were randomly assigned to groups given placebo, 50 mg amitriptyline, or 10 mg escitalopram for 10 weeks. The primary end point was adequate relief of FD symptoms for >=5 weeks of the last 10 weeks (of 12). Secondary end points included GE time, maximum tolerated volume in Nutrient Drink Test, and FD-related quality of life. RESULTS: An adequate relief response was reported by 39 subjects given placebo (40%), 51 given amitriptyline (53%), and 37 given escitalopram (38%) (P = .05, after treatment, adjusted for baseline balancing factors including all subjects). Subjects with ulcer-like FD given amitriptyline were >3-fold more likely to report adequate relief than those given placebo (odds ratio = 3.1; 95% confidence interval: 1.1-9.0). Neither amitriptyline nor escitalopram appeared to affect GE or meal-induced satiety after the 10-week period in any group. Subjects with delayed GE were less likely to report adequate relief than subjects with normal GE (odds ratio = 0.4; 95% confidence interval: 0.2-0.8). Both antidepressants improved overall quality of life. CONCLUSIONS: Amitriptyline, but not escitalopram, appears to benefit some patients with FD, particularly those with ulcer-like (painful) FD. Patients with delayed GE do not respond to these drugs. ClinicalTrials.gov ID: NCT00248651. PMID- 25921380 TI - Can compassionate healthcare be measured? The Schwartz Center Compassionate Care ScaleTM. AB - OBJECTIVE: Assess psychometric characteristics of an instrument to measure patient ratings of treating physicians' compassionate care in a recent hospitalization. METHODS: We used Cronbach's alpha to examine scale reliability, exploratory and confirmatory factor analysis to examine scale structure of two sets of items on compassionate care. We used Mokken analysis to determine if items in each set belonged to a unidimensional scale. RESULTS: Results indicated that both sets of items had strong reliability when used to rate individual physicians (Cronbach's alpha=.97 and .95). A one factor model was a good fit to both sets of items. Mokken analysis supported unidimensional scales. Both sets of items correlated with an overall measure of patient satisfaction with physicians and even more strongly with an item measuring emotional support. CONCLUSIONS: A patient-rated scale reliably measured hospital physicians' compassion and correlated significantly with an item measuring overall patient satisfaction and a specific measure of satisfaction with emotional support. Measurement of compassionate healthcare should be included in research, educational assessment, and quality improvement programs. PRACTICE IMPLICATIONS: Clinicians should participate in efforts to enhance their ability to demonstrate compassionate care including eliciting and sharing information and acting collaboratively to ameliorate patients' socioemotional concerns and needs. PMID- 25921381 TI - The applicability of the cognitive abilities screening instrument-short (CASI-S) in primary care in Brazil. AB - BACKGROUND: The Cognitive Abilities Screening Instrument - Short (CASI-S) is a brief cognitive screening test. However, there is limited information regarding its applicability in primary care. OBJECTIVES: To ascertain whether the CASI-S differentiates between dementia patients and normal controls in primary care; to examine its correlation with other cognitive instruments, to analyze its internal consistency, test-retest stability, and diagnostic accuracy. METHODS: In a case control study, carried out at two Primary Care Units (PCUs) in the eastern region of the city of Sao Paulo, 47 older adults were diagnosed with dementia according to DSM-IV criteria (mean age = 76.81 +/- 7.03 years), and 55 were classified as normal controls (mean age = 72.78 +/- 7.37 years), by a multidisciplinary panel which had access to results from a comprehensive cognitive battery and the patients' health data. The present analyses included results from the Mini-Mental State Examination (MMSE). The CASI-S was not used to determine diagnostic status. RESULTS: The CASI-S was easily applied in the primary care setting. There was a significant performance difference (p < 0.001) between dementia patients (15.57 +/- 7.40) and normal controls (26.67 +/- 3.52) on the CASI-S. CASI-S scores correlated with age (rho = -0.410, p < 0.001), educational level (rho = 0.373, p < 0.001), and MMSE score (rho = 0.793, p < 0.001). The internal consistency of the CASI-S was high (alpha = 0.848) and the correlation between test and retest was 0.688, suggesting adequate temporal stability. In the ROC curve analyses, scores of 22/23 generated an area under the curve of 0.907, with sensitivity of 93% and specificity of 81%. CONCLUSIONS: The CASI-S can be useful for dementia screening in primary care in Brazil. PMID- 25921382 TI - Clinical complete response (cCR) after neoadjuvant chemoradiotherapy and conservative treatment in rectal cancer. Findings from the ACCORD 12/PRODIGE 2 randomized trial. AB - BACKGROUND: During the ACCORD 12 randomized trial, an evaluation of the clinical tumor response was prospectively performed after neoadjuvant chemoradiotherapy. The correlations between clinical complete response and patient characteristics and treatment outcomes are reported. MATERIAL AND METHODS: Between 2005 and 2008 the Accord 12 trial accrued 598 patients with locally advanced rectal cancer and compared two different neoadjuvant chemoradiotherapies (Capox 50: capecitabine+oxaliplatin+50Gy vs Cap 45: capecitabine+45Gy). An evaluation of the clinical tumor response with rectoscopy and digital rectal examination was planned before surgery. A score to classify tumor response was used adapted from the RECIST definition: complete response: no visible or palpable tumor; partial response, stable and progressive disease. RESULTS: The clinical tumor response was evaluable in 201 patients. Score was: complete response: 8% (16 patients); partial response: 68% (137 patients); stable: 21%; progression: 3%. There was a trend toward more complete response in the Capox 50 group (9.3% vs 6.7% with Cap 45). In the whole cohort of 201 pts complete response was significantly more frequent in T2 tumors (28%; p=0.025); tumors <4cm in diameter (14%; p=0.017), less than half rectal circumference and with a normal CEA level. Clinical complete response observed in 16 patients was associated with more conservative treatment (p=0.008): 2 patients required an abdomino-perineal resection, 11 an anterior resection and 3 patients benefited from organ preservation (2 local excision, 1 "watch and wait". A complete response was associated with more ypT0 (73%; p<0.001); ypNO (92%); R0 circumferential margin (100%). CONCLUSION: These data support the hypothesis that a clinical complete response assessed using rectoscopy and digital rectal examination after neoadjuvant therapy may increase the chance of a sphincter or organ preservation in selected rectal cancers. PMID- 25921384 TI - Maternal obesity increases type 1 diabetes risk in offspring, study shows. PMID- 25921383 TI - Progressive influence of body mass index-associated genetic markers in rural Gambians. AB - BACKGROUND: In populations of European ancestry, the genetic contribution to body mass index (BMI) increases with age during childhood but then declines during adulthood, possibly due to the cumulative effects of environmental factors. How the effects of genetic factors on BMI change with age in other populations is unknown. SUBJECTS AND METHODS: In a rural Gambian population (N=2535), we used a combined allele risk score, comprising genotypes at 28 'Caucasian adult BMI associated' single nucleotide polymorphisms (SNPs), as a marker of the genetic influence on body composition, and related this to internally-standardised z scores for birthweight (zBW), weight-for-height (zWT-HT), weight-for-age (zWT), height-for-age (zHT), and zBMI cross-sectionally and longitudinally. RESULTS: Cross-sectionally, the genetic score was positively associated with adult zWT (0.018+/-0.009 per allele, p=0.034, N=1426) and zWT-HT (0.025+/-0.009, p=0.006), but not with size at birth or childhood zWT-HT (0.008+/-0.005, p=0.11, N=2211). The effect of the genetic score on zWT-HT strengthened linearly with age from birth through to late adulthood (age interaction term: 0.0083 z scores/allele/year; 95% CI 0.0048 to 0.0118, p=0.0000032). CONCLUSIONS: Genetic variants for obesity in populations of European ancestry have direct relevance to bodyweight in nutritionally deprived African settings. In such settings, genetic obesity susceptibility appears to regulate change in weight status throughout the life course, which provides insight into its potential physiological role. PMID- 25921385 TI - A novel, intuitive instrument positioner for endoscopy, involving surgeons in design and feasibility. AB - BACKGROUND: Existing laparoscopic instrument holders do not seem to sufficiently fulfil the needs of surgeons performing minimally invasive surgery (MIS) in several respects. Therefore, we developed and tested a novel laparoscopic instrument positioner in close cooperation between surgeons and engineers. MATERIAL AND METHODS: Design requirements were established by attending laparoscopic interventions, interviews and involving surgeons during the design cycle by evaluation of early mock-ups and prototypes. RESULTS: Two concepts, based on a scissor- and a deflectable ball principle, were elaborated and evaluated yielding a simple, affordable system, fixating all degrees of freedom in the centre of motion. A sterile functional prototype was fabricated and successfully tested during three clinical interventions. Users reported a stable image, easy and intuitive handling and no interference with other surgical instrumentation. The posture was conceived to be more ergonomic and surgeons liked the ability to control the positioning of the endoscope directly themselves. CONCLUSIONS: Three successful interventions show that involving surgeons in the design and testing phase of product development leads to a novel instrument positioner that can be used safely in a clinical setting. It can be concluded that the system is simple and intuitive to use, as there was no learning curve. PMID- 25921386 TI - Role of Microenvironment in Resistance to Therapy in AML. AB - As part of the dynamic interactions between leukemic cells and cells of the bone marrow microenvironment, specific niches provide a sanctuary where subpopulations of leukemic cells evade chemotherapy-induced death and acquire a drug-resistant phenotype. This review focuses on the cellular and molecular biology of the leukemia stem cell (LSC) niche and of microenvironment/leukemia interactions. Key emerging therapeutic targets include chemokine receptors, adhesion molecules, the sympathetic nervous system, and hypoxia-related proteins, as well as the genetic and epigenetic abnormalities of the leukemia-associated stroma. The complex interplay between LSCs and microenvironment components provides a rationale for appropriately tailored molecular therapies designed to improve outcomes in leukemia. Further understanding of the contribution of the bone marrow niche to the process of leukemogenesis may provide new targets that allow destruction of LSCs without adversely affecting normal stem cell self-renewal. PMID- 25921387 TI - Selecting the best frontline treatment in chronic myeloid leukemia. AB - With the discovery of Philadelphia chromosome, understanding of chronic myeloid leukemia (CML) pathobiology has tremendously increased. Development of tyrosine kinase inhibitors (TKI) targeting the BCR/ABL1 oncoprotein has changed the landscape of the disease. Today, the expected survival of CML patients, if properly managed, is likely to be similar to the general population. Imatinib is the first-approved TKI in CML treatment, and for several years, it was the only option in the frontline setting. Four years ago, second-generation TKIs (nilotinib and dasatinib) were approved as alternative frontline options. Now, clinicians are faced the challenge of making decision for which TKI to chose upfront. Second-generation TKIs have been demonstrated to induce deeper and faster responses compared to imatinib; however, none of three TKIs have been shown to have a clear survival advantage, they all are reasonable options. In contrast, when considering therapy in individual patients, the case may be stronger for a specific TKI. Co-morbidities of the patient and side effect profile of the TKI of interest should be an important consideration in decision making. At present, the cost nilotinib or dasatinib is not remarkably different from imatinib. However, patent for imatinib is expected to expire soon, and it will be available as a generic. Clinicians, then, need to weigh the advantages some patients gain with nilotinib or dasatinib in the frontline setting against the difference in cost. Whatever TKI is chosen as frontline, intolerance, non compliance, or treatment failure should be recognized early as a prompt intervention increases the chance of achieving best possible response. PMID- 25921388 TI - Targeting the microenvironment in acute myeloid leukemia. AB - The bone marrow microenvironment plays a critical role in the development, progression, and relapse of acute myeloid leukemia (AML). Similar to normal hematopoietic stem cells, AML blasts express receptors on their surface, allowing them to interact with specific components of the marrow microenvironment. These interactions contribute to both chemotherapy resistance and disease relapse. Preclinical studies and early phase clinical trials have demonstrated the potential for targeting the tumor-microenvironment interactions in AML. Agents currently under investigation include hypoxia-inducible agents and inhibitors of CXCR4 and adhesion molecules such as VLA-4 and E-selectin. PMID- 25921389 TI - Milestones and monitoring. AB - In chronic myeloid leukemia (CML), the presence of a specific chromosome marker (Ph-chromosome) as well as of the corresponding molecular marker (BCR-ABL fusion transcripts) provides suitable and precise tools to monitor the burden of the disease present at diagnosis and that of the residual disease present at specific time points during treatment. A huge number of studies have clearly demonstrated that in CML cytogenetic and molecular responses are strictly correlated to the final outcome of the patients and the correct use of standardized methods to assess the achievement of specific degrees of disease reduction at specific time points during treatment has become an essential part of proper clinical management of CML. The target to be achieved and the corresponding "optimal response" definition are however evolving, and at least for some patients, they may be represented not only by best possible overall survival (OS) but also by the possibility to discontinue the tyrosine-kinase inhibitor (TKI) treatment and therefore to live in a treatment-free remission (TFR) status. Therefore, at least for some patients, deep degrees of molecular response, as MR(4) and MR(4.5), whose precise definition has been recently introduced and that are prerequisites to try to discontinuation, are becoming the target to be achieved even in common clinical practice. As a fast initial decline of the disease burden after therapy start may be highly predictive for the final outcome of patients not only in terms of progression-free survival (PFS) and of PS but also in terms of possibility of achieving deep molecular responses, a more intense and punctual monitoring of the response of CML patients during the first 6 months of TKI therapy is now recommended by the more recent versions of the European Leukemia Net (ELN) and National Comprehensive Cancer Network (NCCN) guidelines, as this represents the major driver to decide therapy. PMID- 25921390 TI - Marked dissociation of photopic and mesopic contrast sensitivity even in normal observers. AB - AIM: Although contrast vision is not routinely tested, it is important: for instance, it predicts traffic incidents better than visual acuity. Mesopic contrast sensitivity (CS) testing approximates low-lighting conditions but entails dark adaptation, which can disrupt clinical routine. In receptor-specific diseases, a dissociation of photopic and mesopic sensitivity would be expected, but can photopic CS act as a surrogate measure for mesopic CS, at least for screening purposes? METHODS: Photopic and mesopic contrast sensitivities were studied in three groups: 47 normal subjects, 23 subjects with glaucoma, and three subjects with cataract. Twenty-eight of the normal subjects were additionally tested with artificial blur. Photopic contrast sensitivity was assessed with both the Freiburg Acuity and Contrast Test (FrACT) and the Mars Letter Contrast Sensitivity Charts. Mesopic contrast sensitivity, without and with glare, was measured with the Mesoptometer IIb. Coefficients of repeatability and limits of agreement were calculated for all tests. RESULTS: Test-retest limits of agreement were +/- 0.17 logCS for Mars, +/- 0.21 logCS for FrACT, and +/-0.20 logCS / +/- 0.14 logCS for Mesoptometer IIb without and with glare, respectively. In terms of inter-test comparison, Mars and FrACT largely agreed, except for ceiling effects in the Mars test. While mesopic and photopic contrast sensitivities correlate significantly (r = 0.51, p < 0.01), only 27 % of the variance is in common. In particular, subjects with high photopic results may be nearly as likely to have low as well as high mesopic results. CONCLUSIONS: The photopic contrast sensitivity tests assessed here cannot serve as surrogate measures for current mesopic contrast sensitivity tests. Low photopic CS predicts low mesopic CS, but with normal photopic CS, mesopic CS can be normal or pathologic. PMID- 25921392 TI - Step-wise and lineage-specific diversification of plant RNA polymerase genes and origin of the largest plant-specific subunits. AB - Proteins often function as complexes, yet little is known about the evolution of dissimilar subunits of complexes. DNA-directed RNA polymerases (RNAPs) are multisubunit complexes, with distinct eukaryotic types for different classes of transcripts. In addition to Pol I-III, common in eukaryotes, plants have Pol IV and V for epigenetic regulation. Some RNAP subunits are specific to one type, whereas other subunits are shared by multiple types. We have conducted extensive phylogenetic and sequence analyses, and have placed RNAP gene duplication events in land plant history, thereby reconstructing the subunit compositions of the novel RNAPs during land plant evolution. We found that Pol IV/V have experienced step-wise duplication and diversification of various subunits, with increasingly distinctive subunit compositions. Also, lineage-specific duplications have further increased RNAP complexity with distinct copies in different plant families and varying divergence for subunits of different RNAPs. Further, the largest subunits of Pol IV/V probably originated from a gene fusion in the ancestral land plants. We propose a framework of plant RNAP evolution, providing an excellent model for protein complex evolution. PMID- 25921391 TI - Deficiency of aldose reductase attenuates inner retinal neuronal changes in a mouse model of retinopathy of prematurity. AB - Retinopathy of prematurity (ROP) is a leading cause of childhood blindness where vascular abnormality and retinal dysfunction are reported. We showed earlier that genetic deletion of aldose reductase (AR), the rate-limiting enzyme in the polyol pathway, reduced the neovascularization through attenuating oxidative stress induction in the mouse oxygen-induced retinopathy (OIR) modeling ROP. In this study, we further investigated the effects of AR deficiency on retinal neurons in the mouse OIR. Seven-day-old wild-type and AR-deficient mice were exposed to 75 % oxygen for 5 days and then returned to room air. Electroretinography was used to assess the neuronal function at postnatal day (P) 30. On P17 and P30, retinal cytoarchitecture was examined by morphometric analysis and immunohistochemistry for calbindin, protein kinase C alpha, calretinin, Tuj1, and glial fibrillary acidic protein. In OIR, attenuated amplitudes and delayed implicit time of a wave, b-wave, and oscillatory potentials were observed in wild-type mice, but they were not significantly changed in AR-deficient mice. The morphological changes of horizontal, rod bipolar, and amacrine cells were shown in wild-type mice and these changes were partly preserved with AR deficiency. AR deficiency attenuated the Muller cell gliosis induced in OIR. Our observations demonstrated AR deficiency preserved retinal functions in OIR and AR deficiency could partly reduce the extent of retinal neuronal histopathology. These findings suggested a therapeutic potential of AR inhibition in ROP treatment with beneficial effects on the retinal neurons. PMID- 25921393 TI - Oncostatin M protects against demyelination by inducing a protective microglial phenotype. AB - Multiple sclerosis (MS) is a chronic disabling disease of the central nervous system (CNS), in which destruction of myelin sheaths leads to disturbed axonal conduction. Available MS therapies modulate the immune response, but are unable to prevent neurological decline. Therefore, great efforts are made to develop therapies that limit demyelination and axonal degeneration. Oncostatin M (OSM), a member of the interleukin (IL)-6 cytokine family, is produced in demyelinating lesions of MS patients and stimulates neuronal survival. In this study, we reveal that the OSM receptor (OSMR) was robustly upregulated on microglia/macrophages and astrocytes in the cuprizone-induced demyelination model. While OSMR deficiency led to aggravated demyelination, CNS-targeted OSM treatment largely prevented demyelination. OSM treatment increased IL-4 expression and induced polarization of myeloid cells towards an anti-inflammatory M2 phenotype in vivo. This study reveals a previously uncharacterized and protective role for OSM during demyelination, and indicates that OSM is a promising therapeutic candidate to limit CNS damage in demyelinating diseases including MS. PMID- 25921394 TI - Joint model of multiple longitudinal measures and a binary outcome: An application to predict orthostatic hypertension for subacute stroke patients. AB - Stroke patients with orthostatic hypertensive responses that are one of the blood pressure regulation problems can easily fall down while doing rehabilitation, which may result in prolonged hospitalization and delayed treatment and recovery. This may result in increasing the medical cost and burden. In turn, developing a diagnostic test for the orthostatic hypertension (OH) is clinically important for patients who are suffering from stroke. Clinically, a patient needs to have a tilt testing that requires measuring the change of blood pressures and heart rate at all angles to determine whether a stroke patient has OH. It takes lots of time and effort to perform the test. Assuming there exist measurement errors when obtaining the blood pressures and heart rate at all angles, this paper proposes using multiple mixed-effect models to obtain the true trajectories of these measurements, which take into account the measurement error and the possible correlation among multiple measurements, and a logistic regression uses these true trajectories at a given time and other fixed-effect covariates as predictors to predict the status of OH. The joint likelihood function is derived to estimate parameters and the area under the receiver operating characteristics curve is used to estimate the predictive power of the model. Monte Carlo simulations are performed to evaluate the feasibility of the proposed methods. Also, the proposed model is implemented in the real data and provides an acceptable predictive power. PMID- 25921395 TI - Academic medicinal chemistry: no country for young men (or women)? PMID- 25921396 TI - Making a case for albumin - a highly promising drug-delivery system. PMID- 25921397 TI - Is it time to integrate sex and gender into drug design and development? PMID- 25921398 TI - Lycorine-derived phenanthridine downregulators of host Hsc70 as potential hepatitis C virus inhibitors. AB - BACKGROUND: A new series of potential phenanthridine hepatitis C virus (HCV) inhibitors which work by suppressing Hsc70 expression in the host cell was designed and synthesized from lycorine. RESULTS: Thirty-one new potential phenanthridine HCV inhibitors were synthesized and five of these compounds exhibited good anti-HCV activity and these inhibitors probably inhibit HCV by downregulating the host Hsc70 expression. Structure-activity analysis of these compounds revealed that the double bond between C-11 and C-12 and the substituents at C-8 and C-9 are important for their activity against HCV. CONCLUSION: Suppression of Hsc70 expression in the host cell to limit HCV replication is a potential anti-HCV strategy. Phenanthridines are probably the HCV inhibitors with this mode of action. PMID- 25921399 TI - In silico prediction of hERG inhibition. AB - The voltage-gated potassium channel encoded by hERG carries a delayed rectifying potassium current (IKr) underlying repolarization of the cardiac action potential. Pharmacological blockade of the hERG channel results in slowed repolarization and therefore prolongation of action potential duration and an increase in the QT interval as measured on an electrocardiogram. Those are possible to cause sudden death, leading to the withdrawals of many drugs, which is the reason for hERG screening. Computational in silico prediction models provide a rapid, economic way to screen compounds during early drug discovery. In this review, hERG prediction models are classified as 2D and 3D quantitative structure-activity relationship models, pharmacophore models, classification models, and structure based models (using homology models of hERG). PMID- 25921400 TI - Recent advance of the hepatitis B virus inhibitors: a medicinal chemistry overview. AB - Hepatitis B Virus (HBV) is one of the most prevalent viral infections of human worldwide. The therapies are limited in the clinical context because of negative side effects of interferons and the development of viral resistance to the nucleoside/nucleotide inhibitors. In this review, we summarize the recent advances in design and development of potent anti-HBV inhibitors from natural sources and synthetic compounds, targeting different steps in the life cycle of HBV. We attempt to emphasize the major structural modifications, mechanisms of action and computer-aided docking analysis of novel potent inhibitors that need to be addressed in the future to design potent anti-HBV molecules. PMID- 25921401 TI - Propargylamine as functional moiety in the design of multifunctional drugs for neurodegenerative disorders: MAO inhibition and beyond. AB - Much progress has been made in designing analogues that can potentially confer neuroprotection against debilitating neurodegenerative disorders, yet the multifactorial pathogenesis of this cluster of diseases remains a stumbling block for the successful design of an 'ultimate' drug. However, with the growing popularity of the "one drug, multiple targets" paradigm, many researchers have successfully synthesized and evaluated drug-like molecules incorporating a propargylamine function that shows potential to serve as multifunctional drugs or multitarget-directed ligands. It is the aim of this review to highlight the reported activities of these propargylamine derivatives and their prospect to serve as drug candidates for the treatment of neurodegenerative disorders. PMID- 25921402 TI - Small-molecule MDM2-p53 inhibitors: recent advances. AB - Potent and selective small-molecule inhibitors of the p53-MDM2 interaction intended for the treatment of p53 wild-type tumors have been designed and optimized in a number of chemical series. This review details recent disclosures of compounds in advanced optimization and features key series that have given rise to clinical trial candidates. The structure-activity relationships for inhibitor classes are discussed with reference to x-ray structures, and common structural features are identified. PMID- 25921403 TI - Agents that inhibit bacterial biofilm formation. AB - In the biofilm form, bacteria are more resistant to various antimicrobial treatments. Bacteria in a biofilm can also survive harsh conditions and withstand the host's immune system. Therefore, there is a need for new treatment options to treat biofilm-associated infections. Currently, research is focused on the development of antibiofilm agents that are nontoxic, as it is believed that such molecules will not lead to future drug resistance. In this review, we discuss recent discoveries of antibiofilm agents and different approaches to inhibit/disperse biofilms. These new antibiofilm agents, which contain moieties such as imidazole, phenols, indole, triazole, sulfide, furanone, bromopyrrole, peptides, etc. have the potential to disperse bacterial biofilms in vivo and could positively impact human medicine in the future. PMID- 25921404 TI - Hemophagocytic lymphohistiocytosis in a patient with dengue infection. PMID- 25921406 TI - Materials discovery via CALYPSO methodology. AB - The structure prediction at the atomic level is emerging as a state-of-the-art approach to accelerate the functionality-driven discovery of materials. By combining the global swarm optimization algorithm with first-principles thermodynamic calculations, it exploits the power of current supercomputer architectures to robustly predict the ground state and metastable structures of materials with only the given knowledge of chemical composition. In this Review, we provide an overview of the basic theory and main features of our as-developed CALYPSO structure prediction method, as well as its versatile applications to design of a broad range of materials including those of three-dimensional bulks, two-dimensional reconstructed surfaces and layers, and isolated clusters/nanoparticles or molecules with a variety of functional properties. The current challenges faced by structure prediction for materials discovery and future developments of CALYPSO to overcome them are also discussed. PMID- 25921405 TI - Curative haploidentical BMT in a murine model of X-linked chronic granulomatous disease. AB - Chronic granulomatous disease (CGD) is a primary immunodeficiency disorder characterized by defective microbial killing in phagocytes. Long-term prognosis for CGD patients is generally poor, highlighting the need to develop minimally toxic, curative therapeutic approaches. We here describe the establishment of a mouse model in which X-linked CGD can be cured by allogeneic bone marrow transplantation. Using a combination of non-myeloablative-dose total body irradiation and a single injection of anti-CD40 ligand monoclonal antibody, transplantation of whole bone marrow cells achieved long-lasting mixed chimerism in X-linked CGD mice in a haploidentical transplantation setting. Stable mixed chimerism was maintained for up to 1 year even at a low range (<20 % donor cells), indicating induction of donor-specific tolerance. The regimen induced mild myelosuppression without severe acute complications. Stable chimerism was therapeutic, as it suppressed cutaneous granuloma formation in an in vivo test suited for evaluation of treatment efficacy in murine CGD models. These results warrant future development of a simplified allogeneic hematopoietic cell transplantation regimen that would benefit CGD patients by allowing the use of haploidentical donor grafts without serious concerns of severe treatment-related toxicity. PMID- 25921407 TI - Effects of bioisosteric fluorine in synthetic cannabinoid designer drugs JWH-018, AM-2201, UR-144, XLR-11, PB-22, 5F-PB-22, APICA, and STS-135. AB - Synthetic cannabinoid (SC) designer drugs featuring bioisosteric fluorine substitution are identified by forensic chemists and toxicologists with increasing frequency. Although terminal fluorination of N-pentyl indole SCs is sometimes known to improve cannabinoid type 1 (CB1) receptor binding affinity, little is known of the effects of fluorination on functional activity of SCs. This study explores the in vitro functional activities of SC designer drugs JWH 018, UR-144, PB-22, and APICA, and their respective terminally fluorinated analogues AM-2201, XLR-11, 5F-PB-22, and STS-135 at human CB1 and CB2 receptors using a FLIPR membrane potential assay. All compounds demonstrated agonist activity at CB1 (EC50 = 2.8-1959 nM) and CB2 (EC50 = 6.5-206 nM) receptors, with the fluorinated analogues generally showing increased CB1 receptor potency (~2-5 times). Additionally, the cannabimimetic activities and relative potencies of JWH 018, AM-2201, UR-144, XLR-11, PB-22, 5F-PB-22, APICA, and STS-135 in vivo were evaluated in rats using biotelemetry. All SCs dose-dependently induced hypothermia and reduced heart rate at doses of 0.3-10 mg/kg. There was no consistent trend for increased potency of fluorinated SCs over the corresponding des-fluoro SCs in vivo. Based on magnitude and duration of hypothermia, the SCs were ranked for potency (PB-22 > 5F-PB-22 = JWH-018 > AM-2201 > APICA = STS-135 = XLR-11 > UR-144). PMID- 25921408 TI - [Visual hallucinations without cognitive impairment. Charles Bonnet Syndrome. A little known syndrome]. PMID- 25921409 TI - Soft nanofluidics governing minority ion exclusion in charged hydrogels. AB - We investigate ionic partition of negatively charged molecular probes into also negatively charged, covalently crosslinked alginate hydrogels. The aim is to delimit the domain of validity of the major nanoelectrostatic models, and in particular to assess the influence of hydrogel chain mobility on ionic partition. We find that the widely used Gibbs-Donnan model greatly overestimates exclusion of the co-ion probes used. For low molecular weight probes, a much better fit is obtained by taking into account the electrostatics in the nanometric gel pores by means of the Poisson-Boltzmann framework; the fit is improved slightly when taking into account alginate chain mobility. For high molecular weight probes, we find it essential to take into account local gel deformation due to electrostatic repulsion between the flexible gel strands and the probe. This is achieved by combining Poisson-Boltzmann simulations with heterogeneous pore size distribution given by the Ogston model, or more simply and precisely, by applying a semi empirical scaling law involving the ratio between Debye length and pore size. PMID- 25921410 TI - Dose Related Patterns of Ventricular Arrhythmia due to Carvedilol Withdrawal in Patients with Systolic Heart Failure. AB - OBJECTIVES: This study evaluates the impact of carvedilol dose changes on the ventricular arrhythmia event rates for patients > 18 years of age with systolic heart failure and examines dose dependent effects of carvedilol withdrawal in dose reduction and discontinuation subgroups. METHODS: This retrospective cohort study included patients with systolic heart failure (EF < 40%) receiving carvedilol. The primary outcome was incidence of ventricular arrhythmia. Ventricular arrhythmia event rates were compared among carvedilol dose continuation, reduction and discontinuation groups. To assess dose dependent effects of beta-blocker withdrawal, dose reduction and discontinuation groups were divided into subgroups. RESULTS: Dose discontinuation (n=64) or reduction group (n=83) had significantly higher ventricular arrhythmia rates compared with dose continuation group (n=262) (65.6 vs. 33.7 vs. 15.3%, p < 0.001 for both comparisons). Dose discontinuation group also had a significantly higher ventricular arrhythmia event rate compared with dose reduction group (p<0.001). There were no significant differences in ventricular arrhythmia event rates among dose discontinuation or reduction subgroups. CONCLUSION: Continuation of carvedilol therapy was associated with a substantially lower ventricular arrhythmia event rate compared with reduction or discontinuation of carvedilol therapy. Dose dependent effects of beta-blocker withdrawal in subgroup analyses were not found. PMID- 25921411 TI - Cucurbitacin E suppresses cytokine expression in human Jurkat T cells through down-regulating the NF-kappaB signaling. AB - Cucurbitacin E (CucE), a triterpenoid isolated from Cucurbitaceae plants, has been shown to possess an anti-inflammatory or immunosuppressive activity in vitro and in vivo, yet the underlying mechanism has been incompletely understood. The aim of the present study was to explore its effect on cytokine expression and the underlying mechanism in human Jurkat T cells as a cellular model. The results showed that CucE significantly inhibited the production of interleukin-2, tumor necrosis factor-alpha, and interferon-gamma in culture medium of cells treated with phorbol 12,13-dibutyrate (PDB) plus ionomycin (Ion). Furthermore, the mRNA levels of these cytokines in activated Jurkat T cells were also decreased upon CucE treatment, suggesting a potential modulatory effect on the critical signaling pathways for cytokine expression, including nuclear factor-kappaB (NF kappaB) or mitogen-activated protein kinases (MAPKs). In support of its effect on the NF-kappaB signaling pathway, CucE decreased the phosphorylation levels of inhibitor of kappaB (IkappaB) and NF-kappaB/p65 in PDB + Ion-stimulated cells. Further supporting this, the nuclear translocation of NF-kappaB/p65 was significantly suppressed in response to PDB plus Ion stimulation in the presence of CucE. The phosphorylation of p38MAPK, c-Jun N-terminal kinase (JNK), and Erk1/2, however, was not decreased or slightly increased at some time points by CucE treatment. Collectively, these data suggest that CucE may exhibit immunosuppressive effect by attenuating critical cytokine expression through down regulating the NF-kappaB signaling pathway. PMID- 25921412 TI - Establishment, characterization, and application of pAcr-SP-NTP-EGFP transgenic mice in visualizing the oviduct-migrating ability of sperm from Prss37-null mice. AB - Transgenic mouse model with fluorescently labeled sperm has extensive application value. It is an auxiliary tool for investigating the mechanism of fertilization, especially for visualizing the oviduct-migrating ability of sperm in vivo. Here, we produced transgenic mouse lines whose sperm were tagged with enhanced green fluorescent protein (EGFP) according to the previously described method. Polymerase chain reaction analysis of tail-tip genomic DNA identified 13 founders, of which 5 male founders produced offspring to form transgenic lines. We showed that EGFP was testis-specifically expressed, sharing similar expression pattern with endogenous acrosin. It has luminal side restricted distribution in seminiferous tubules and acrosomal aggregation in mature sperm. In addition, interstrain hybridization obtained Prss37(-/-)EGFP(tg/+) males produced sperm with impaired oviduct-migrating ability as visualized under fluorescence microscope, compared with Prss37(+/+)EGFP(tg/+) counterparts. These results indicate that a transgenic mouse model with fluorescently labeled sperm has been successfully established and it is a useful tool for evaluating the oviduct migrating ability of sperm. PMID- 25921413 TI - Oxidative damage and cell signaling transduction in patients of chronic myeloid leukemia. PMID- 25921414 TI - Pannexin-1 channels and their emerging functions in cardiovascular diseases. AB - Pannexin-1, Pannexin-2, and Pannexin-3 are three members of the Pannexin family of channel-forming glycoprotein. Their primary function is defined by their ability to form single-membrane channels. Pannexin-1 ubiquitously exists in many cells and organs throughout the body and is specially distributed in the circulatory system, while the expressions of Pannexin-2 and Pannexin-3 are mostly restricted to organs and tissues. Pannexin-1 oligomers have been shown to be functional single membrane channels that connect intracellular and extracellular compartments and are not intercellular channels in appositional membranes. The physiological functions of Pannexin-1 are to link to the adenosine triphosphate efflux that acts as a paracrine signal, and regulate cellular inflammasomes in a variety of cell types under physiological and pathophysiological conditions. However, there are still many functions to be explored. This review summarizes recent reports and discusses the role of Pannexin-1 in cardiovascular diseases, including ischemia, arrhythmia, cardiac fibrosis, and hypertension. Pannexin-1 has been suggested as an exciting, clinically relevant target in cardiovascular diseases. PMID- 25921415 TI - Core-shell-like Au sub-nanometer clusters in Er-implanted silica. AB - The very early steps of Au metal cluster formation in Er-doped silica have been investigated by high-energy resolution fluorescence-detected X-ray absorption spectroscopy (HERFD-XAS). A combined analysis of the near-edge and extended part of the experimental spectra shows that Au cluster nucleation starts from a few Au and O atoms covalently interconnected, likely in the presence of embryonic Au-Au correlation. The first Au clusters, characterized by a well defined Au-Au coordination distance, form upon 400 degrees C inert annealing. The estimated upper limit of the Gibbs free energy for the associated heterogeneous nucleation is 0.06 eV per atom, suggesting that the Au nucleation is assisted by matrix defects, most likely non-bridging oxygen atoms. The experimental results indicate that the formed subnanometer Au clusters can be applied as effective core-shell systems in which the Au atoms of the 'core' develop a metallic character, whereas the Au atoms in the 'shell' can retain a partially covalent bond with O atoms of the silica matrix. High structural disorder at the Au site is found upon neutral annealing at a moderate temperature (600 degrees C), likely driven by the configurational disorder of the defective silica matrix. A suitable choice of the Au concentration and annealing temperature allows tailoring of the Au cluster size in the sub-nanometer range. The interaction of the Au cluster surface with the surrounding silica matrix is likely responsible for the infrared luminescence previously reported on the same systems. PMID- 25921416 TI - Tafenoquine for preventing relapse in people with Plasmodium vivax malaria. AB - BACKGROUND: Plasmodium vivax malaria is widespread, and the persistent liver stage causes relapse of the disease which contributes to continued P. vivax transmission. Primaquine is currently the only drug that cures the parasite liver stage, but requires 14 days to be effective and can cause haemolysis in people with glucose-6-phosphate dehydrogenase (G6PD) deficiency. In addition, there is some evidence of parasite resistance to the drug. Tafenoquine is a new alternative with a longer half-life. OBJECTIVES: To assess the effects of tafenoquine in people with P. vivax infection. SEARCH METHODS: We searched the following databases up to 13 April 2015: the Cochrane Infectious Diseases Group Specialized Register; the Cochrane Central Register of Controlled Trials (CENTRAL), published in The Cochrane Library; MEDLINE; EMBASE; CINAHL; SCOPUS; and LILACS. We also searched the World Health Organization (WHO) International Clinical Trial Registry Platform and the metaRegister of Controlled Trials (mRCT) for ongoing trials using "tafenoquine" and "malaria" as search terms up to 13 April 2015. SELECTION CRITERIA: Randomized controlled trials (RCTs) in people with P. vivax malaria. Adverse effects of tafenoquine are assessed in populations where people with G6PD deficiency have been excluded, and in populations without screening for G6PD deficiency. DATA COLLECTION AND ANALYSIS: All review authors independently extracted data and assessed trial quality. Meta-analysis was carried out where appropriate, and estimates given as relative risk with 95% confidence intervals. We assessed the quality of the evidence using the GRADE approach. MAIN RESULTS: Three RCTs met our inclusion criteria, with the asexual infection in both the tafenoquine and comparator arm treated with chloroquine, and in all trials G6PD deficiency patients were excluded. Tafenoquine dose comparisonsThree of the included trials compared eight different dosing regimens. Tafenoquine doses of 300 mg and above resulted in fewer relapses than no hypnozoite treatment over six months follow-up in adults (300 mg single dose: RR 0.19, 95% CI 0.08 to 0.41, one trial, 110 participants, moderate quality evidence; 500 to 600 mg single dose: RR 0.14, 95%CI 0.06 to 0.34, two trials, 122 participants, moderate quality evidence; 1800 mg to 3000 mg in divided doses: RR 0.05, 95% CI 0.01 to 0.23, two trials, 63 participants, low quality evidence).In people with normal G6PD status, there may be little or no difference in serious adverse events (three trials, 358 participants, low quality evidence); or any adverse event (one trial, 272 participants, low quality evidence). Tafenoquine versus primaquine Two of the included trials compared four different dosing regimens of tafenoquine against the standard primaquine regimen of 15 mg/day for 14 days. A single tafenoquine dose of 600 mg may be more effective than primaquine in relation to relapses at six months follow-up (RR 0.29, 95% CI 0.10 to 0.84, two trials, 98 participants, low quality evidence)In people with normal G6PD status, there may be little or no difference for serious adverse events (two trials, 323 participants, low quality evidence) or any adverse event (two trials, 323 participants, low quality evidence) between tafenoquine and primaquine. AUTHORS' CONCLUSIONS: Tafenoquine prevents relapses after clinically and parasitologically confirmed P. vivax malaria. The drug is untested in pregnancy, children and in G6PD-deficient people. The shorter treatment course is an important practical advantage in people who do not have G6PD deficiency, but the longer half-life may have more substantive consequences if given inadvertently to people with G6PD deficiency. PMID- 25921417 TI - Monoclonal antibodies are shown to be safe and effective in patients with dyslipidaemia. PMID- 25921418 TI - Management of metastatic pancreatic cancer: Current treatment options and potential new therapeutic targets. AB - Pancreatic ductal adenocarcinoma is a malignancy with a poor prognosis, with the majority of patients diagnosed with advanced disease on presentation. Treatment options remain limited with little progress over the last 40 years. This review will focus on the current management of metastatic pancreatic ductal adenocarcinoma, with a discussion of new and future treatment strategies based on an improved understanding of tumour biology and mechanisms of pathogenesis. PMID- 25921419 TI - Selection of chemotherapy for hyperthermic intraperitoneal use in gastric cancer. AB - PURPOSE: Several studies have shown the potential benefit of cytoreductive surgery combined with hyperthermic intraperitoneal chemotherapy (HIPEC) in gastric cancer patients. At present the most effective chemotherapeutic regime in HIPEC for gastric cancer is unknown. The aim of this review was to provide a comprehensive overview of chemotherapeutic agents used for HIPEC in gastric cancer. METHODS: A literature search was conducted using the PubMed database to identify studies on chemotherapy used for HIPEC in gastric cancer patients. RESULTS AND CONCLUSION: The chemotherapeutic regime of choice in HIPEC for gastric cancer has yet to be determined. The wide variety in studies and study parameters, such as chemotherapeutic agents, dosage, patient characteristics, temperature of perfusate, duration of perfusion, carrier solutions, intraperitoneal pressure and open or closed perfusion techniques, warrant more experimental and clinical studies to determine the optimal treatment schedule. A combination of drugs probably results in a more effective treatment. PMID- 25921420 TI - Different associations of body mass index and visceral fat area with metabolic parameters and adipokines in Japanese patients with type 2 diabetes. PMID- 25921421 TI - A novel heterozygous mutation in the glucokinase gene is responsible for an early onset mild form of maturity-onset diabetes of the young, type 2. PMID- 25921422 TI - Use of chemotherapy in patients with metastatic lung cancer. PMID- 25921423 TI - Repeal of SGR: US payment reform for Medicare reimbursement. PMID- 25921424 TI - UK Research Councils' new funding criteria for animal studies. PMID- 25921425 TI - Pembrolizumab for patients with advanced melanoma. PMID- 25921426 TI - The salmochelin receptor IroN itself, but not salmochelin-mediated iron uptake promotes biofilm formation in extraintestinal pathogenic Escherichia coli (ExPEC). AB - The key to success of extraintestinal pathogenic Escherichia coli (ExPEC) to colonize niches outside the intestinal tract and to establish infection is the coordinated action of numerous virulence and fitness factors. Intense research revealed not only an arsenal of unique virulence determinants with specific action, but also the multi-functionality of single elements. Especially iron uptake systems of ExPEC proved to be of prime importance. Apart from iron acquisition they optimize certain virulence properties. Here we analyzed the contribution of the salmochelin siderophore system to the ability of ExPEC to form biofilms. In the same iron limited environment, ExPEC displayed a distinct transcriptional profile of siderophore systems. During biofilm formation the iroN gene coding for the specific receptors of the siderophore salmochelin was highly upregulated. Almost no induction was observed during planctonic growth. Disruption of iroN resulted in a reduction of almost 50% in biofilm production. Efficient biofilm formation was not affected in a salmochelin synthesis mutant. Thus, the contribution of IroN is independent from the ability to produce salmochelin. Enhanced expression of IroN did not increase significantly the capacity to form biofilms in ExPEC. Interestingly, the additional expression of IroN or even the acquisition of the entire salmochelin system was not able to improve biofilm formation in a poor biofilm producer like a laboratory E. coli K12 strain. However, complementation with only IroN in an ExPEC iroA deletion mutant was able to restore biofilm formation. The contribution of IroN to biofilm formation appears to require a certain background found in ExPEC, but not in E. coli K12. This study identified the contribution of IroN to biofilm formation and highlights the multi-functional role of iron uptake systems in ExPEC. PMID- 25921427 TI - Two-dimensional bricklayer arrangements of tolans using halogen bonding interactions. AB - Diphenylacetylene (tolan) derivatives with self-complementary aryl halides and halogen bond-accepting nitriles form 2D bricklayer packing motifs when halogen bonding occurs. When halogen bonding is absent, as occurred with fluorinated aryl bromides, the molecules adopt other packing motifs. These results suggest halogen bonding is potentially useful for producing rarely observed 2D bricklayer motifs in organic semiconductors. PMID- 25921428 TI - Ascending Aorta Elastography After Kawasaki Disease Compared to Systemic Hypertension. AB - Kawasaki disease (KD) is a systemic vasculitis, classically affecting large- and medium-size arteries. The coronary arteries draw most of the clinical attention, whereas few studies have taken interest in the ascending aorta. Using a proprietary imaging-based mechanical biomarker (ImBioMark), we sought to determine aortic stiffness in KD compared to systemic hypertension (HTN) and healthy children. We evaluated parasternal long-axis views focused on the ascending aorta in 20 controls, 12 KD, and 8 HTN as a comparative clinical model of vascular stiffness. We calculated systolic and diastolic aortic wall strain with ImBioMark. Strain was tested for normality against height, systolic, and diastolic blood pressure in normal subjects. Strain from KD and HTN was normalized (Z score) accordingly. Z score comparisons were performed using nonparametric statistics. Age was similar between KD and HTN (9.1 +/- 5.3 and 9.9 +/- 5.3 years old; p = NS). Systolic and diastolic strain values were normally distributed against height, systolic blood pressure, and diastolic blood pressure in healthy subjects. HTN subjects had abnormal systolic and diastolic strain values (p < 0.0001). Whereas KD subjects had normal diastolic strain, systolic strain was significantly lower (p < 0.001), and systolic strain was intermediate between controls and HTN. There were no significant differences in aortic strain among KD, however, according to the presence of coronary artery aneurysms. Despite normal blood pressure, the ascending aorta in KD exhibits reduced strain during systole. This may reflect in situ rigidity of the aorta. The normal diastolic strain in KD may, in contrast, reflect normal peripheral vascular resistance. PMID- 25921429 TI - Rare de novo deletion of metabotropic glutamate receptor 7 (GRM7) gene in a patient with autism spectrum disorder. AB - GRM7, the gene encoding metabotropic glutamate receptor 7 (mGluR7), have been implicated in multiple neuropsychiatric disorders and shown to mediate excitatory synaptic neurotransmitter signaling and plasticity in the mammalian brain. Here we report a 303 kb de novo deletion at band 3p26.1, disrupting five coding exons of GRM7 in a proband with autism spectrum disorder, and hyperactivity. Our exon transcriptome-mutation contingency index method shows that three of the exons within the breakpoint boundaries are under purifying selection and highly expressed in prenatal brain regions. Based on our results and a thorough review of the literature, we propose that haploinsufficiency of the GRM7 product (mGluR7) contributes to autism spectrum disorders and hyperactivity phenotype as seen in the patient described here. PMID- 25921431 TI - Are lifestyle shifts fuelling the obesity epidemic in urbanised Africans? AB - Humans evolved for active lifestyles involving hunting-gathering and agriculture. To sustain these energy-intensive lifestyles, diets consisting of energy-dense foods were selected. It can therefore be argued that humans are physiologically adapted for active lifestyles. However, with rapid industrialisation, there has been an upsurge in the usage of labour-saving devices as well as a glut in the supply of energy-dense foods. This mismatch between energy supply and expenditure in modern man may be fuelling the contemporary trends in obesity in urbanised man. On the other hand, recent emerging evidence indicates that air pollution related to motorised transportation in urban areas may be obesogenic by causing alterations in the lipid metabolic pathways, resulting in fat deposition. These lifestyle shifts are drastically different from traditional rural African lifestyles and mirror the different prevalence rates of obesity and related co morbidities between rural versus urban areas. PMID- 25921430 TI - Pituitary tumors contain a side population with tumor stem cell-associated characteristics. AB - Pituitary adenomas cause significant endocrine and mass-related morbidity. Little is known about the mechanisms that underlie pituitary tumor pathogenesis. In the present study, we searched for a side population (SP) in pituitary tumors representing cells with high efflux capacity and potentially enriched for tumor stem cells (TSCs). Human pituitary adenomas contain a SP irrespective of hormonal phenotype. This adenoma SP, as well as the purified SP (pSP) that is depleted from endothelial and immune cells, is enriched for cells that express 'tumor stemness' markers and signaling pathways, including epithelial-mesenchymal transition (EMT)-linked factors. Pituitary adenomas were found to contain self renewing sphere-forming cells, considered to be a property of TSCs. These sphere initiating cells were recovered in the pSP. Because benign pituitary adenomas do not grow in vitro and have failed to expand in immunodeficient mice, the pituitary tumor cell line AtT20 was further used. We identified a SP in this cell line and found it to be more tumorigenic than the non-SP 'main population'. Of the two EMT regulatory pathways tested, the inhibition of chemokine (C-X-C motif) receptor 4 (CXCR4) signaling reduced EMT-associated cell motility in vitro as well as xenograft tumor growth, whereas the activation of TGFbeta had no effect. The human adenoma pSP also showed upregulated expression of the pituitary stem cell marker SOX2. Pituitaries from dopamine receptor D2 knockout (Drd2(-/-)) mice that bear prolactinomas contain more pSP, Sox2(+), and colony-forming cells than WT glands. In conclusion, we detected a SP in pituitary tumors and identified TSC associated characteristics. The present study adds new elements to the unraveling of pituitary tumor pathogenesis and may lead to the identification of new therapeutic targets. PMID- 25921433 TI - Multiphotochromic molecular systems. AB - Molecular systems encompassing more than one photochromic entity can be used to build highly functional materials, thanks to their potential multi-addressability and/or multi-response properties. Over the last decade, the synthesis and spectroscopic and kinetic characterisation as well as the modeling of a wide range of multiphotochromes have been achieved in a field that is emerging as a distinct branch of photochemistry. In this review, we provide an overview of the available multiphotochromic compounds which use a variety of photoactive building blocks, e.g., diarylethene, azobenzene, spiropyran, naphthopyran or fulgimide derivatives. Their efficiency in terms of multi-responsiveness is discussed and several strategies to circumvent the most common limitation (i.e., the loss of photochromism of one part) are described. PMID- 25921432 TI - An integrated platform for simultaneous multi-well field potential recording and Fura-2-based calcium transient ratiometry in human induced pluripotent stem cell (hiPSC)-derived cardiomyocytes. AB - INTRODUCTION: Human induced pluripotent stem cell-derived cardiomyocytes are available from various sources and they are being evaluated for safety testing. Several platforms are available offering different assay principles and read-out parameters: patch-clamp and field potential recording, imaging or photometry, impedance measurement, and recording of contractile force. Routine use will establish which assay principle and which parameters best serve the intended purpose. METHODS: We introduce a combination of field potential recording and calcium ratiometry from spontaneously beating cardiomyocytes as a novel assay providing a complementary read-out parameter set. Field potential recording is performed using a commercial multi-well multi-electrode array platform. Calcium ratiometry is performed using a fiber optic illumination and silicon avalanche photodetectors. Data condensation and statistical analysis are designed to enable statistical inference of differences and equivalence with regard to a solvent control. RESULTS: Simultaneous recording of field potentials and calcium transients from spontaneously beating monolayers was done in a nine-well format. Calcium channel blockers (e.g. nifedipine) and a blocker of calcium store release (ryanodine) can be recognized and discriminated based on the calcium transient signal. An agonist of L-type calcium channels, FPL 64176, increased and prolonged the calcium transient, whereas BAY K 8644, another L-type calcium channel agonist, had no effect. Both FPL 64176 and various calcium channel antagonists have chronotropic effects, which can be discriminated from typical "chronotropic" compounds, like (+/-)isoprenaline (positive) and arecaidine propargyl ester (negative), based on their effects on the calcium transient. DISCUSSION: Despite technical limitations in temporal resolution and exact matching of composite calcium transient with the field potential of a subset of cells, the combined recording platform enables a refined interpretation of the field potential recording and a more reliable identification of drug effects on calcium handling. PMID- 25921434 TI - Urinary proteomics in renal pathophysiology: Impact of proteinuria. AB - Urinary differential proteomics is used to study renal pathophysiological mechanisms, find novel markers of biological processes and renal diseases, and stratify patients according to proteomic profiles. The proteomic procedure determines the pathophysiological meaning and clinical relevance of results. Urine samples for differential proteomic studies are usually normalized by protein content, regardless of its pathophysiological characteristics. In the field of nephrology, this approach translates into the comparison of a different fraction of the total daily urine output between proteinuric and nonproteinuric samples. Accordingly, alterations in the level of specific proteins found by this method reflect the relative presence of individual proteins in the urine; but they do not necessarily show alterations in their daily excretion, which is a key parameter for the understanding of the pathophysiological meaning of urinary components. For renal pathophysiology studies and clinical biomarker identification or determination, an alternative proteomic concept providing complementary information is based on sample normalization by daily urine output, which directly informs on changes in the daily excretion of individual proteins. This is clinically important because daily excretion (rather than absolute or relative concentration) is the only self-normalized way to evaluate the real meaning of urinary parameters, which is also independent of urine concentration. PMID- 25921435 TI - Metal promiscuity and metal-dependent substrate preferences of Trypanosoma brucei methionine aminopeptidase 1. AB - Methionine aminopeptidases play a major role in posttranslational protein processing and are therefore promising targets for the discovery of novel therapeutical agents. We here describe the heterologous expression, purification, and characterization of recombinant Trypanosoma brucei methionine aminopeptidase, type 1 (TbMetAP1). We investigated the dependency of TbMetAP1 activity on pH and metal cofactor (type and concentration) using in particular the substrates Met Gly-Met-Met and Met-AMC along with related compounds, and determined kinetic values (Km, vmax, kcat). The optimal pH for TbMetAP1 activity is between 7.0 and 8.0. Surprisingly, the two substrates have different cofactor requirements: Both substrates are processed by the cobalt-activated TbMetAP1, but only the Met-Gly Met-Met substrate is processed with nearly identical catalytical properties by the zinc-activated enzyme. Depending on the substrate, various other metal ions (iron(II), manganese, nickel) were also accepted as cofactors. Two aspects of this work are relevant for the biochemistry of MetAPs and further drug discovery efforts: 1. Zinc, and not cobalt ions are probably the physiological cofactor of TbMetAP1 and possibly other MetAPs. 2. In MetAP assays for compound screening, the combination of the Met-AMC substrate with cobalt, manganese or iron ions may not represent the physiological reality, thereby leading to results that can not be extrapolated towards a phenotypic effect. PMID- 25921436 TI - The importance of codon-anticodon interactions in translation elongation. AB - Translation is the process by which genetic information is turned into amino acid sequence, following the instructions of the genetic code. The formation of a correct codon-anticodon pair is essential to ensure efficiency and fidelity during translation. Here we review the influence that codon-anticodon interactions play over the elongation phase of translation; including the role of this interaction in cognate tRNA selection by ribosomes, the importance of relative codon frequencies in the cell, and the roles of tRNA modifications in the process of codon-anticodon recognition. PMID- 25921437 TI - Noncoding RNAs connect genetic risk factors to the neurodevelopmental basis of bipolar disorder. PMID- 25921438 TI - The changing landscape of microbial biodiversity exploration and its implications for systematics. AB - A vast diversity of Bacteria and Archaea exists in nature that has evaded axenic culture. Advancements in single-cell genomics, metagenomics, and molecular microbial ecology approaches provide ever-improving insight into the biology of this so-called "microbial dark matter"; however, due to the International Code of Nomenclature of Prokaryotes, yet-uncultivated microorganisms are not accommodated in formal taxonomy regardless of the quantity or quality of data. Meanwhile, efforts to calibrate the existing taxonomy with phylogenetic anchors and genomic data are increasingly robust. The current climate provides an exciting opportunity to leverage rapidly expanding single-cell genomics and metagenomics datasets to improve the taxonomy of Bacteria and Archaea. However, this opportunity must be weighted carefully in light of the strengths and limitations of these approaches. We propose to expand the definition of the Candidatus taxonomy to include taxa, from the phylum level to the species level, that are described genomically, particularly when genomic work is coupled with advanced molecular ecology approaches to probe metabolic functions in situ. This system would preserve the rigor and value of traditional microbial systematics while enabling growth of a provisional taxonomic structure to facilitate communication about "dark" lineages on the tree of life. PMID- 25921440 TI - Children with Thoracic Aortic Aneurysm: Challenges in Diagnosis and Therapy. PMID- 25921439 TI - Serial Free Bisphenol A and Bisphenol A Glucuronide Concentrations in Neonates. AB - OBJECTIVE: To determine the balance of metabolism of free bisphenol A (BPA) to the inactive conjugate, BPA glucuronide (BPAG), in neonates. STUDY DESIGN: Free BPA and BPAG concentrations were measured in 78 urine samples collected between December 2012 and August 2013 from a cohort of 44 healthy full term (>= 37 weeks' gestation) neonates at 2 intervals (3-6 days and 7-27 days of age). A questionnaire was administered at the time of sample collection. Neonates recruited into the study were born in an urban, tertiary care hospital. RESULTS: Only BPAG was detected in the urine samples; concentrations ranged from <0.1 MUg/L to 11.21 MUg/L (median: 0.27 MUg/L). Free BPA concentrations were below the limit of quantification of 0.1 MUg/L. Age, but not sex or type of diet, was significantly associated with urinary BPAG concentration (P = .002). CONCLUSIONS: Our results illustrate widespread BPA exposure in healthy full-term neonates and efficient conjugation of BPA to its readily excretable and biologically inactive form (BPAG) as early as 3 days of age. Factors other than type of diet may be important contributors to BPA exposure in neonates. PMID- 25921441 TI - Clinical and functional implications of a history of childhood ADHD in first episode psychosis. AB - There is mounting evidence indicating that a childhood history of attention deficit/hyperactivity disorder (ADHD) is associated with an increased risk for psychotic disorders, including schizophrenia. However, the implications of such a history on the symptomatic and functional outcomes of patients with psychotic disorders are still not well documented. This study examined the prevalence of childhood ADHD in patients with first episode psychosis (FEP) consecutively admitted to a specialized early intervention clinic covering a well-defined catchment area, and compared patients with and without a history of childhood ADHD on socio-demographic, clinical, and functional outcomes over a six to twelve months period. Out of 179 patients with FEP, 27 (15%) were treated for ADHD during childhood, consistent with previous literature indicating an association between childhood ADHD and psychosis. FEP patients with childhood history of ADHD had lower academic achievement, earlier onset of psychosis, and higher rates of childhood conduct and learning disorder. While the two groups had similar scores on psychopathology and functioning at baseline, patients with childhood ADHD showed significantly less improvement in positive and negative symptoms, as well as social and occupational functioning. These results strongly indicate that a history of childhood ADHD in FEP is more frequent than that reported in the general population and predictive of poorer clinical response to treatment. This emphasizes the need for actively screening for a history of ADHD in FEP patients and for treatments that are tailored for these patients. PMID- 25921442 TI - Causes of women's postpartum depression symptoms: Men's and women's perceptions. AB - OBJECTIVES: To describe men's and women's perceptions of the causes of women's PPD symptoms and to explore similarities and differences between men's and women's perceptions. DESIGN: Qualitative-descriptive study involving in-depth semi-structured individual interviews and content analysis. SETTING: In-home interviews of participants recruited in two tertiary care hospitals, both in urban centres of the province of Quebec, Canada. PARTICIPANTS: Both members of 30 heterosexual couples from which women scored at least 12 on the Edinburgh Postnatal Depression Scale. FINDINGS: Participants described nine causes underlying women's depressive symptoms: societal expectations and pressure on women, physical health problems, transition to parenthood, social connectedness, personality and past psychological history, child health and temperament challenges, unmet care needs, unmet expectations for childbirth, and other life stressors. With one exception, all causes were endorsed by both men and women. Only men mentioned societal pressure on women. KEY CONCLUSIONS AND IMPLICATIONS FOR PRACTICE: Men and women mainly perceived similar causes, which could be explained by socio-cultural factors and extended paternal leaves. Understanding men's and women's perceptions could help tailoring health- care professionals' interventions to couples' needs. PMID- 25921443 TI - Laboratory parameters identify familial haemophagocytic lymphohistiocytosis from other forms of paediatric haemophagocytosis. AB - Haemophagocytic lymphohistiocytosis (HLH) is a life-threatening syndrome of immune dysregulation and is classified as primary or secondary according to the underlying aetiology. The treatment strategies recommended for these two groups differ substantially; however, it is thought to be impossible to predict the underlying causes of HLH using conventional laboratory tests. Recent studies show that serum levels of soluble interleukin-2 receptor (sIL2R) and ferritin are useful for differentiating some forms of HLH. The present study reports that combinations of common laboratory parameters, such as the percentage of total lymphocytes within the peripheral blood leucocyte population, serum levels of lactate dehydrogenase and the sIL2R/ferritin ratio, are useful for identifying patients with familial haemophagocytic lymphohistiocytosis and for differentiating the underlying aetiology of paediatric HLH during the early course of the disease. These findings suggest that the pathogenesis of HLH differs greatly in terms of innate and adaptive immunity depending on the aetiology and may provide a new approach to unravelling the complex pathophysiology underlying this syndrome. PMID- 25921444 TI - Left Ventricular Assist Device Implantation in a Patient With Congenitally Corrected Transposition of the Great Arteries. PMID- 25921445 TI - Physiology of the fetal and transitional circulation. AB - The fetal circulation is an entirely transient event, not replicated at any point in later life, and functionally distinct from the pediatric and adult circulations. Understanding of the physiology of the fetal circulation is vital for accurate interpretation of hemodynamic assessments in utero, but also for management of circulatory compromise in premature infants, who begin extrauterine life before the fetal circulation has finished its maturation. This review summarizes the key classical components of circulatory physiology, as well as some of the newer concepts of physiology that have been appreciated in recent years. The immature circulation has significantly altered function in all aspects of circulatory physiology. The mechanisms and significance of these differences are also discussed, as is the impact of these alterations on the circulatory transition of infants born prematurely. PMID- 25921446 TI - CHIMALI 2014: Bioactive Metabolites and Contaminants in Fruits and Vegetables. AB - The X Italian Congress of Food Chemistry (CHIMALI 2014) was organized in Florence, Italy, in July 2014 with 9 plenary lectures including 2 held by international guests, 51 oral communications, and 116 posters. These contributions were presented in five sessions: food authentication and traceability; botanicals and nutraceutical products; bioactive metabolites in foods: effects of extraction and processing; health foods: chemical composition, technological aspects, and biological properties; and treatment and valorization of food byproducts. The day dedicated to botanicals continued with a round table discussion titled "Botanicals, nutraceuticals and health claims: future perspectives and contribution of the scientific community", during which the role of European Food Safety and Authority (EFSA) was discussed and some experiences of well-known producers of botanical extracts were illustrated, together with the contributions of some experts on this theme. PMID- 25921447 TI - Multi-element concentrations in plant parts and fluids of Malaysian nickel hyperaccumulator plants and some economic and ecological considerations. AB - Information about multi-elemental concentrations in different plant parts of tropical Ni hyperaccumulator species has the potential to provide insight into their unusual metabolism relative to a range of essential and non-essential elements, but this information is scant in the literature. As Ni hyperaccumulation, and possibly co-accumulation of other toxic elements, has been hypothesized to provide herbivore (insect) protection, there is a need to quantify a range of these elements in plant tissues and transport fluids to at least verify the possibility of this explanation. In this study, multiple elements were analyzed in a range of different plant parts and transport fluids from Ni hyperaccumulator species collected from Sabah (Malaysia). The results show preferential accumulation of Ni in leaves over woody parts, but the highest concentrations were found in the phloem tissue (up to 7.9 % in Rinorea bengalensis) and phloem sap (up to 16.9 % in Phyllanthus balgooyi), visible by a bright green coloration in the field fresh material. The amount of Ni contained in one mature R. bengalensis tree was calculated at 4.77 kg. The high Ni concentration in the flowers of Phyllanthus securinegoides could affect insect floral visitors and pollination. High concentrations of Ni in the seeds of this species also could supply the seedling with Ni and aid in herbivory protection during the first stages of development. Foliar Ca and Ni in P. cf. securinegoides and R. bengalensis are positively correlated. Low accumulation of Ca is desirable for phytomining but concentrations of Ca are high in most Ni hyperaccumulators examined, and this could have consequences for the economic viability of Ni extraction from bio ore if these species were to be used as 'metal crops'. PMID- 25921448 TI - Proteomic analysis of reproduction proteins involved in litter size from porcine placenta. AB - A gel-free and label-free quantitative proteomic approach based on a spectral counting strategy was performed to discover prolificacy-related proteins. Soluble proteins of porcine placenta from small litter size group (SLSG) and large litter size group (LLSG) were extracted and subsequently applied to in-solution tryptic digestion followed by liquid chromatography-tandem mass spectrometry analysis. Six and thirteen proteins were highly expressed in SLSG and LLSG, respectively. Of the dominantly expressed proteins, we chose prolificacy-related proteins such as puromycin-sensitive aminopeptidase (PSA) and retinol-binding protein 4 (RBP4). Western blot analysis confirmed that the processed form (70 kDa) of PSA was more expressed and RBP4 (23 kDa) was dominantly expressed in LLSG. These results indicate that PSA and RBP4 are representative proteins involved in porcine fertility traits, and this finding may help to increase litter size of pigs. PMID- 25921450 TI - Gender differences in lung function recovery after cessation of occupational endotoxin exposure: a complex story. PMID- 25921449 TI - Clinical use of ferric carboxymaltose in patients with solid tumours or haematological malignancies in France. AB - PURPOSE: This study collected data on the use of ferric carboxymaltose (FCM) in a cancer patient population in France to evaluate the feasibility and the conditions of use of FCM in routine clinical practice beyond the limiting criteria of clinical trials. METHODS: This observational, prospective study of patients with a solid tumour or a haematological malignancy who have received treatment with FCM after 01 July 2011 evaluated data about the circumstances of iron administration, concomitant medication and laboratory tests in the period from 3 months prior to the first FCM administration (baseline) until 3 months post-baseline. RESULTS: Data from 367 FCM-treated patients were analysed. FCM was mainly given as a single dose at baseline (69.2%) and without additional erythropoiesis-stimulating agent (ESA, 64.3%). The median total iron dose was 1000 mg per patient. Median haemoglobin (Hb) levels of FCM-treated patients improved from 10.3 g/dL (interquartile range 9.5, 11.1 g/dL) at baseline to 11.8 g/dL (11.1, 13.0 g/dL) until the end of the 3-month observational period. Patients treated with FCM alone or additional ESA achieved similar median Hb increase (1.3 [0.4, 2.1] g/dL and 1.4 [0.4, 2.5] g/dL, respectively). Patients with baseline Hb up to 11.0 g/dL and serum ferritin up to 500 ng/mL and beyond achieved stable median Hb levels >=11.0 g/dL without signs of iron overload. No severe or serious adverse reaction and no hypersensitivity reactions were reported. CONCLUSIONS: The results of this observational study confirm the effectiveness and tolerability of FCM when given in clinical routine practice alone or in combination with an ESA. PMID- 25921451 TI - Randomized trial of efficacy and safety of dornase alfa delivered by eRapid nebulizer in cystic fibrosis patients. AB - BACKGROUND: Dornase alfa administered via jet nebulizer is indicated as a chronic respiratory medication for cystic fibrosis (CF) patients. Efficacy and safety of dornase alfa via an electronic nebulizer with vibrating membrane technology have not been formally assessed in randomized clinical trials. METHODS: 87 CF patients (>=6 years) were randomized in a crossover study to receive dornase alfa 2.5 mg/d in 2-week periods with the Pari eRapid and Pari LC Plus jet nebulizers. The primary end point was comparison of forced expiratory volume in the first second. Safety, quality of life, and treatment satisfaction/preference were also compared between devices. RESULTS: Lung function was equivalent between nebulizers. Most domain scores from the Cystic Fibrosis Questionnaire-Revised and Treatment Satisfaction Questionnaire for Medication instruments were similar but patients strongly preferred the eRapid. Mean patient-reported administration times were shorter with the eRapid vs the LC Plus (2.7 vs 10.2 min). Adverse events were similar between devices. CONCLUSIONS: Administration of dornase alfa via the eRapid nebulizer resulted in comparable efficacy and safety, shorter nebulization times, and higher patient preference. PMID- 25921452 TI - Outcomes of Hypertensive Patients with Renal Fibromuscular Dysplasia Compared with Patients with Concomitant Atherosclerotic Renal Artery Stenosis following Endovascular Therapy. AB - PURPOSE: To examine if the outcomes after endovascular treatment in hypertensive patients with renal artery fibromuscular dysplasia (FMD) and incidental atherosclerotic renal artery stenosis (ARAS) differ from the outcomes in patients with FMD alone. MATERIALS AND METHODS: All cases of patients with renal artery FMD undergoing percutaneous transluminal angioplasty during the period 2002-2012 were reviewed. The patients with complete data before and after the procedure were identified (N = 84). Based on the procedural reports, these patients were separated into two cohorts: patients with isolated FMD (n = 59) and patients with concomitant atherosclerotic renal artery stenosis and FMD (ARAS-FMD) (n = 25). The medical record of each patient was reviewed for baseline blood pressure, antihypertensive medication use, and renal function data and the same data after the procedure. Procedural details including the angiographic findings, the number of stents placed, the average number of revascularization procedures, and the number of patients requiring more than one revascularization procedure were noted. RESULTS: The study population included 68 patients (FMD, n = 46; ARAS-FMD, n = 22). Patients in the FMD and ARAS-FMD cohorts experienced comparable significant decreases in systolic and mean arterial pressures after endovascular intervention. There was no change in the number of antihypertensive medications after the procedure within or between groups. Patients in the ARAS-FMD cohort had lower baseline estimated glomerular filtration rates (P = .007); however, renal function stabilized in both groups after endovascular therapy. CONCLUSIONS: Patients with ARAS-FMD respond to endovascular therapy with outcomes similar to patients with isolated renal artery FMD. PMID- 25921453 TI - Percutaneous cryoablation for the treatment of recurrent thymoma: preliminary safety and efficacy. AB - Thymoma is the most common primary tumor of the anterior mediastinum and often recurs after initial surgical resection. In this case series, percutaneous cryoablation, a locally ablative technique, was used to treat 25 mediastinal and pleural recurrent thymoma lesions in five patients. Safety and short-term efficacy data were collected. In 23 percutaneous cryoablations (92%), there were no or minimal complications. One serious complication, myasthenia gravis flare, occurred. Over the duration of follow-up (median, 331 d), 18 of 20 ablated lesions (90%) showed no evidence of local recurrence. Percutaneous cryoablation shows promise as a safe and effective treatment modality for recurrent thymoma. PMID- 25921454 TI - Transradial intervention: basics. AB - For many interventions, transradial access can be used as an alternative to transfemoral access. However, many operators who are proficient at transfemoral access may find transradial access unfamiliar and cumbersome. This Video (see Fig; available online at www.jvir.org) aims to demonstrate the basics of patient evaluation, preparation, and vascular access for transradial interventions. PMID- 25921455 TI - A step closer to individualization of hepatocellular carcinoma therapy. PMID- 25921456 TI - Catheter-based intramural delivery of red blood cells in an animal model of atherosclerosis. AB - This report demonstrates intramural red blood cell (RBC) delivery in an atherosclerotic rabbit aorta model and validates the ability of fluoroscopy and computed tomography to verify RBC deposition. A microinfusion catheter with a 35 gauge needle delivered RBCs mixed with iodinated contrast agent to the aorta wall. Six rabbits were sacrificed after injection to confirm RBC delivery. Iron deposition was examined in four additional rabbits 3-7 weeks after injection. Imaging demonstrated 86% sensitivity and 100% specificity for the detection of RBC deposition (n = 25 injection attempts). Iron deposits were found in all intraplaque injection sites 3-7 weeks after injection. PMID- 25921457 TI - Percutaneous coil embolization of traumatic juxtacardiac right inferior pulmonary vein pseudoaneurysm. PMID- 25921458 TI - Isolated Common Iliac Aneurysm and Spontaneous Ilioiliac Arteriovenous Fistula in a Patient with Subsequent Type II Endoleak and Successful Endovascular Management. PMID- 25921459 TI - Endovascular diagnosis of radiographically and intraoperatively occult insulinoma. PMID- 25921460 TI - Treatment of neovaginal variceal bleeding after transgender surgery with transjugular intrahepatic portosystemic shunt. PMID- 25921461 TI - Prone positioning for transjugular intrahepatic portosystemic shunt revision to prevent exacerbation of existing radiation dermatitis. PMID- 25921462 TI - Closure of carcinoid mucinous tumor-vaginal fistula using an occluder device. PMID- 25921463 TI - Coil Embolization to Redirect Embolic Flow during Prostatic Artery Embolization. PMID- 25921464 TI - c-Src-dependent transactivation of EGFR mediates CORM-2-induced HO-1 expression in human tracheal smooth muscle cells. AB - Carbon monoxide (CO), a reaction product of the cytoprotective heme oxygenase (HO)-1, displays an anti-inflammatory effect in various cellular injuries, but the precise mechanisms of HO-1 expression remain unknown. We used the transition metal carbonyl compound carbon monoxide-releasing molecule-2 (CORM-2) that acts as carbon monoxide donor. The effects of CORM-2 on expression of HO-1 in human tracheal smooth muscle cells (HTSMCs) were determined by Western blot, real-time PCR, and promoter activity assay. In HTSMCs, CORM-2 activated Nrf2 through the activation of a c-Src/EGFR/PI3K/Akt-dependent pathway, resulting in HO-1 expression. We showed that CORM-2-induced HO-1 protein and mRNA levels were inhibited by the inhibitor of c-Src (PP1 or SU6656), EGFR (AG1478), PI3K (LY294002), Akt (SH-5), JNK1/2 (SP600125), or p38 MAPK (SB202190) and transfection with siRNA of c-Src, EGFR, Akt, p38, JNK2, or Nrf2 in HTSMCs. We also showed that CORM-2 stimulated c-Src, EGFR, Akt, p38 MAPK, and JNK1/2 phosphorylation. CORM-2 also enhanced Nrf2 translocation from the cytosol to the nucleus and antioxidant response element (ARE) promoter activity. Moreover, CORM 2 mediated p38 MAPK and JNK1/2 activation via a c-Src/EGFR/PI3K/Akt pathway, which further enhanced Nrf2 activation and translocation. Finally, we observed that CORM-2 induced in vivo binding of Nrf2 to the HO-1 promoter. CORM-2 activates the c-Src/EGFR/PI3K/Akt/JNK1/2 and p38 MAPK pathways, which in turn trigger Nrf2 activation and ultimately induces HO-1 expression in HTSMCs. Thus, the HO-1/CO system might be potential therapeutics in airway diseases. PMID- 25921465 TI - An assemblage of divergent variants of a novel putative closterovirus from American persimmon. AB - Deep-sequencing analysis of nucleic acids extracted from leaf tissue of an American persimmon (Diospyros virginiana L.) and subsequent-sequencing analyses uncovered at least four distinct closterovirus-like molecules. Two complete genomes of 18,569 and 18,030 nucleotides (nt) and partial genomes of 4,899 and 9,019 nt were determined. The two complete genomes encoded 11 potential open reading frames and the characteristic organization of closteroviruses. Among the four genomes, the putative heat shock protein 70 homolog (HSP70h), RNA-dependent RNA polymerase, and coat protein showed 82-85, 72-91, and 84-87 % amino acid sequence identities, respectively. These results suggested that the four identified viruses could be divergent variants in a single host plant. The phylogenetic tree based on HSP70h showed that their closest relative, although distant, is Olive leaf yellowing-associated virus, a putative unassigned member of the family Closteroviridae. The name Persimmon virus B was proposed for this new virus, representing another unassigned member of the family. PMID- 25921466 TI - Use of the LC16m8 Smallpox Vaccine in Immunocompromised Individuals Is Still Too Risky. PMID- 25921467 TI - Reply to "Use of the LC16m8 Smallpox Vaccine in Immunocompromised Individuals Is Still Too Risky". PMID- 25921468 TI - Better method for evaluating a new laboratory test for syphilis. PMID- 25921469 TI - Reply to "Better method for evaluating a new laboratory test for syphilis". PMID- 25921470 TI - Erratum for Pirson et al., Highly purified mycobacterial phosphatidylinositol mannosides drive cell-mediated responses and activate NKT cells in cattle. AB - Volume 22, no. 2, p. 178-184, 2015. Page 180, column 1, final line: "IgG2a" should read "IgG1." PMID- 25921472 TI - The added value of preparedness for aeromedical evacuation of a patient with Ebola. PMID- 25921473 TI - Muscular strength as a strong predictor of mortality: A narrative review. AB - Muscular strength, an important component of physical fitness, has an independent role in the prevention of chronic diseases whereas muscular weakness is strongly related to functional limitations and physical disability. Our purpose was to investigate the role of muscular strength as a predictor of mortality in health and disease. We conducted a systematic search in EMBASE and MEDLINE (1980-2014) looking for the association between muscular strength and mortality risk (all cause and cause-specific mortality). Selected publications included 23 papers (15 epidemiological and 8 clinical studies). Muscular strength was inversely and independently associated with all-cause mortality even after adjusting for several confounders including the levels of physical activity or even cardiorespiratory fitness. The same pattern was observed for cardiovascular mortality; however more research is needed due to the few available data. The existed studies failed to show that low muscular strength is predictive of cancer mortality. Furthermore, a strong and inverse association of muscular strength with all-cause mortality has also been confirmed in several clinical populations such as cardiovascular disease, peripheral artery disease, cancer, renal failure, chronic obstructive pulmonary disease, rheumatoid arthritis and patients with critical illness. However, future studies are needed to further establish the current evidence and to explore the exact independent mechanisms of muscular strength in relation to mortality. Muscular strength as a modifiable risk factor would be of great interest from a public health perspective. PMID- 25921474 TI - Implication for the regulation of catabolism drawn from the single insulin-like growth factor binding domain protein (SIBD) gene in the mud crab, Scylla paramamosain. AB - Insulin-like growth factor (IGF) signaling system holds a central position in regulating growth and metabolism in vertebrates. As critical components of this system, the IGF-binding proteins (IGFBPs) play important roles in regulating the biological activities of IGFs. Recently, the single IGF-binding domain protein (SIBD) was identified in invertebrates and its sequence was highly homologous with the N-terminal domain of IGFBP. In view of the possible role as counterparts of vertebrate IGFBPs, SIBDs have attracted the ever-increasing attention. This study reports the identification of a 1284bp SIBD gene (Sp-SIBD) from a member of commercially important family of Portunidae. The tissue distribution analysis showed that Sp-SIBD was mainly expressed in the nervous tissues and hepatopancreas. RNA in situ hybridization analysis showed that the positive signals were predominantly distributed in the secretory cells of the hepatopancreas. Subsequently, we examined the effects of various stresses, including hyperosmotic stress, hyperthermia, activated stress and fasting, on glucose levels in the hemolymph and Sp-SIBD expressions in the hepatopancreas. Interestingly, we found that Sp-SIBD expression was strongly up-regulated in response to these catabolic circumstances. Given the previous findings of insulin like peptides (ILPs) in invertebrates, we speculate that invertebrate ILPs and SIBDs promise to serve as a pair of counterparts of IGFs and IGFBPs from vertebrate species respectively. In this context, the combined results suggested, by analogy with IGFBP 1 from vertebrates, for the first time that SIBD might play a key physiological role by sequestering ILPs to inhibit energy-expensive growth until conditions are more favorable. PMID- 25921475 TI - Medicaid coverage of medications to treat alcohol and opioid dependence. AB - Substance use disorders affect 12% of Medicaid beneficiaries. The prescription drug epidemic and growing need for treatment of alcohol and opioid dependence have refocused states' attention on their provision of substance use disorder treatment services, including medications. This study characterized how Medicaid programs cover these treatment medications. Data were from 2013 Medicaid pharmacy documents, 2011 and 2012 Medicaid state drug utilization records, and a 2013 American Society of Addiction Medicine survey. Results showed that only 13 state Medicaid programs included all medications approved for alcohol and opioid dependence on their preferred drug lists. The most commonly excluded were extended-release naltrexone (19 programs), acamprosate (19 programs), and methadone (20 programs). For combined buprenorphine-naloxone, 48 Medicaid programs required prior authorization, and 11 programs used 1- to 3-year lifetime treatment limits. Given the chronic nature of substance use disorders and the overwhelming evidence supporting ongoing coverage for many of these medications, states may want to reexamine substance use disorder benefits. PMID- 25921476 TI - The emotions and action tendencies associated with viewing online cancer information among patients' loved ones. AB - Loved ones of cancer patients are vulnerable, often reporting psychological distress and inadequate information provision. This research examined the use and emotional and behavioral effects of online cancer information. Compassion and fear were the strongest emotions elicited by online content, and respondents reported several cognitive, communicative, and helping behaviors. Multiple relationships between emotions and behaviors were found, including between hope and helping behaviors, anger and problem-solving, fear and seeking comfort, and sadness and a decreased likelihood of engaging in cancer prevention and detection. This study extends research on emotions and action tendencies and provides guidance for developing future online resources. PMID- 25921477 TI - Understanding how adolescents and young adults with cancer talk about needs in online and face-to-face support groups. AB - We compared adolescent and young adult cancer patient and survivor language between mediated and face-to-face support communities in order to understand how the use of certain words frame conversations about family, friends, health, work, achievement, and leisure. We analyzed transcripts from an online discussion board ( N = 360) and face-to-face support group ( N = 569) for adolescent and young adults using Linguistic Inquiry and Word Count, a word-based computerized text analysis software that counts the frequency of words and word stems. There were significant differences between the online and face-to-face support groups in terms of content (e.g. friends, health) and style words (e.g. verb tense, negative emotion, and cognitive process). PMID- 25921478 TI - Extent and orientation of coping in chemical intolerance. AB - Chemical intolerance is a long-standing illness with minimal guidelines regarding treatment. Hence, individual attempts to cope with the illness gain importance in dealing with its consequences. This study used data from 164 persons with self reported chemical intolerance to understand the nature of coping with the illness. Coping was studied along two dimensions, the extent and predominant orientation of coping. The association of these coping dimensions with mental health variables of stress, depression, anxiety, burnout, and non-restorative sleep was examined as well. Results revealed that the persons with chemical intolerance used a moderate amount of coping strategies which were slightly more emotion-focused than problem-focused in orientation. Users of both problem focused and emotion-focused orientations report scores in the normal range on all mental health indices. However, significantly higher level of anxiety was found to be associated with predominantly emotion-focused coping, whereas coping orientation did not differ with respect to the four other mental health indices. The above findings are discussed in relation to existing literature on coping with long-term illness. PMID- 25921479 TI - Interventions to increase condom use among middle-aged and older adults: A systematic review of theoretical bases, behaviour change techniques, modes of delivery and treatment fidelity. AB - This systematic review collates, examines and syntheses condom use interventions for middle-aged and older adults. Associations between effectiveness and theoretical basis, behaviour change techniques, mode of delivery and treatment fidelity were explored. Five interventions were included; one was effective. Compared to interventions with non-significant findings, the effective telephone administered intervention used theory to a greater extent, had a higher number of behaviour change techniques and employed more treatment fidelity strategies. There is a need to develop theory-based interventions targeting condom use among this population and evaluate these in randomised controlled trials that are rigorously designed and reported. Health psychologists have a key role in this endeavour. PMID- 25921480 TI - An exploratory study comparing psychological profiles and its congruence with clinical performance among patients with functional or motility digestive disorders. AB - Functional gastrointestinal disorders have been related with different psychological conditions. On the contrary, the role of psychological factors within gastrointestinal motor disorders remains unclear. The objective of this study was to explore the differences and congruence with clinical performance of the psychological profile and subjective functionality among patients diagnosed with functional gastrointestinal disorders and gastrointestinal motor disorders. Using a double-blind design, 56 inpatients from a Gastroenterology Department were included in the study. No major differences were detected between the two groups. However, clinical performance was coherent with subjective physical functioning only among patients diagnosed with gastrointestinal motor disorders. These results may provide useful information for gastroenterologists dealing with patients' complaints not consistent with their clinical profile. PMID- 25921481 TI - Optimal timing of initiation of oral P2Y12-receptor antagonist therapy in patients with non-ST elevation acute coronary syndromes. Lessons learnt from the ACCOAST-trial. AB - The optimal time-point of the initiation of P2Y12 antagonist therapy in patients with non-ST elevation acute coronary syndromes (NTSE-ACS) is still a matter of debate. European guidelines recommend P2Y12 as soon as possible after first medical contact. However, the only trial which compared the two strategies did not demonstrate any benefit of pre-treatment with prasugrel before angiography compared to starting therapy after angiography and just prior to percutaneous coronary intervention (PCI). This paper summarizes the results of pharmacodynamic and previous studies, and gives recommendations for the initiation of P2Y12 antagonist therapy in NSTE-ACS in different clinical situations. PMID- 25921482 TI - Gastro-Enteropancreatic Neuroendocrine Tumor Cell Dynamics in Liver Microvasculature. AB - For many cancers, liver metastasis is common and usually indicates poor prognosis. Gastro-enteropancreatic neuroendocrine tumors (GEPNETs) of the midgut are a heterogeneous group of cancers that typically remain asymptomatic until they metastasize to the liver. However, the mechanisms by which these usually indolent cancers establish distal metastasis remain unclear. To begin to elucidate this process, we performed standard in vitro assays to assess cell motility, transendothelial migration, and invasion using BON cells, a widely used model GEPNET cell line. In addition, transmission electron microscopy was used in combination with a novel ex vivo organ slice xenograft model to reveal ultrastructural details of the initial events of BON cell extravasation and re distribution within the liver. The ultrastructural resolution of the extravasation process revealed the route, sequence, and time course by which tumor cells migrated from the sinusoidal lumen into the hepatic parenchyma in this organ slice model. Both standard in vitro assays and our organ slice model indicated that tumor cells migrated through the discontinuous sinusoidal endothelium to invade the liver parenchyma. PMID- 25921483 TI - Chemically assisted peroral endoscopic myotomy with submucosal mesna injection in a porcine model. AB - BACKGROUND: Peroral endoscopic myotomy (POEM) is a less invasive alternative to standard surgery for the treatment of achalasia. Previous studies have demonstrated that submucosal injections of mesna soften tissues and facilitate endoscopic submucosal dissection. MATERIAL AND METHODS: We studied the technical feasibility of a chemically assisted POEM procedure with mesna injection (CA POEM) in ten pigs compared with POEM with saline injection in five pigs. We also compared two dissection techniques in CA-POEM, diathermy needle knife dissection (n = 5) and balloon mechanical dissection (n = 5). A 10 cm esophageal submucosal tunnel was created with a needle knife or with balloon mechanical dissection following mesna or saline submucosal injection. Approximately 5 cm of inner circular muscle was then dissected within the tunnel. The tunnel was closed with endoclip application at the mucosal endoscopic entry point. Pigs were sacrificed one week post procedure. RESULTS: All procedures were successful and all pigs survived for one week. Submucosal tunneling time was significantly shorter in the mesna group (363.8 sec for needle knife dissection and 294.2 sec for balloon dissection) than in the saline group (640 sec), regardless of the dissection method (p < 0.05). CONCLUSIONS: Our study demonstrated the technical feasibility of CA-POEM. PMID- 25921484 TI - Social position modifies the association between severe shoulder/arm and knee/leg pain, and quality of life after retirement. AB - PURPOSE: Musculoskeletal disorders are extremely frequent and account for an important part of the global burden of disease. Risk factors for musculoskeletal disorders include sustained occupational exposure to physically demanding jobs. The effects of sustained occupational physical exposures on knee and shoulder pain are known to persist after retirement; also, several studies have shown a socio-economic gradient in health and quality-of-life outcomes, including for musculoskeletal pain. It is thus possible that prolonged occupational exposures affect workers differently in the long-term along a socio-economic gradient. This study was conducted to investigate whether the impacts of severe shoulder/arm and knee/leg pain on the quality of life of retired workers follow a socio-economic gradient. METHODS: Data from the French GAZEL cohort study (n = 14,249) were used to compare the impacts of severe shoulder/arm and knee/leg pain separately on the SF-36, Nottingham Health Profile and limitations in activities of daily living measured in 2006 and 2007, between four groups of social position (measured in 1989). Analyses were made in 2014 with multiple linear and logistic regressions and stratified by sex. RESULTS: For both pain sites, in men and women, there was a strong general tendency for the impacts of severe pain to be smaller among participants in higher social positions. Most important differences were related to pain and physical limitations. CONCLUSIONS: These results suggest inequalities in the impacts of severe joint pain by socio-economic status. The source of these inequalities is still speculative and merits the scientific attention. PMID- 25921486 TI - Chemical constituents of Euonymus fortunei. AB - A new flavonol glycoside, kaempferol-3-O-beta-D-(2-O-E-p-coumaroyl) glucopyranosyl-7-O-alpha-l-rhamnopyranoside (1), along with eleven known compounds including five flavonol glycosides (2-6), one phenolic glycoside (7), two megastigmane glycosides (8 and 9), two triterpenoids (10 and 11) and one alditol (12), was isolated from the aerial parts of Euonymus fortunei. Their structures were determined on the basis of spectroscopic analysis and chemical evidence. Compounds 2-4, 7, 8, and 10-12 were evaluated their antimicrobial activities against Ureaplasma urealyticumin vitro, but all tested compounds have no useful activities against Ureaplasma urealyticum. PMID- 25921485 TI - Detection of TDP-43 oligomers in frontotemporal lobar degeneration-TDP. AB - OBJECTIVE: The proteinaceous inclusions in TDP-43 proteinopathies such as frontotemporal lobar degeneration (FTLD)-TDP are made of high-molecular-weight aggregates of TDP-43. These aggregates have not been classified as amyloids, as prior amyloid staining results were not conclusive. Here we used a specific TDP 43 amyloid oligomer antibody called TDP-O to determine the presence and abundance of TDP-43 oligomers among different subtypes of FTLD-TDP as well as in hippocampal sclerosis (HS), which represents a non-FTLD pathology with TDP-43 inclusions. METHODS: Postmortem tissue from the hippocampus and anterior orbital gyrus from 54 prospectively assessed and diagnosed subjects was used for immunostaining with TDP-O. Electron microscopy was used to assess the subcellular locations of TDP-O-decorated structures. RESULTS: TDP-43 inclusions staining with TDP-O were present in FTLD-TDP and were most conspicuous for FTLD-TDP type C, the subtype seen in most patients with semantic variant primary progressive aphasia. TDP-O immunoreactivity was absent in the hippocampus of HS patients despite abundant TDP-43 inclusions. Ultrastructurally, TDP-43 oligomers resided in granular or tubular structures, frequently in close proximity to, but not within, neuronal lysosomes. INTERPRETATION: TDP-43 forms amyloid oligomers in the human brain, which may cause neurotoxicity in a manner similar to other amyloid oligomers. Oligomer formation may contribute to the conformational heterogeneity of TDP-43 aggregates and mark the different properties of TDP-43 inclusions between FTLD-TDP and HS. PMID- 25921487 TI - Utility of respiratory-gated small-animal PET/CT in the chronologic evaluation of an orthotopic lung cancer transplantation mouse model. AB - Our aim in this study was to clarify the effects of respiratory-gated PET in the evaluation of lung cancer according to the (18)F-FDG uptake in an orthotopic transplantation mouse model. We created such a model, and we performed PET/CT. The mice were divided into two groups according to tumor volume: a small-tumor group (<20 mm(3)) and a large-tumor group (>20 mm(3)). We reconstructed the following conditions based on list-mode data: non-gated (3D) images and gated (4D) images, divided based on the respiratory cycle (expiration phase, stable phase, and inspiration phase). We calculated the maximum standardized uptake values (SUVmax) in each phase. We used the % difference [= (4D SUVmax - 3D SUVmax)/3D PET SUVmax * 100 (%)] to evaluate the differences in the 4D SUVmax and 3D SUVmax. The 4D SUVmax values were significantly higher than the 3D SUVmax, regardless of the tumor size. The % difference for the small tumors was greater than that for the large tumors, and it was highest in the stable phase. We conclude that the SUVmax in the stable phase under respiratory-gated PET are the most reliable. The SUVmax observed under non-gated PET are considered to be more frequently underestimated in cases involving small tumors than in those involving large tumors. In the chronologic study evaluating the time course of tumor development, the size of the tumor is small in early stage, and respiratory-gated PET is effective in reducing the underestimation of such tumors caused by respiratory motion. PMID- 25921488 TI - Review and resolution of some nomenclatural issues regarding the genus Psoroptes (Acari: Psoroptidae), scab-mites of domestic and wild mammals. AB - Some classifications recognize a number of species in the scab-mite genus, Psoroptes, mites that are of considerable importance in livestock production and veterinary medicine. However, modern studies suggest that populations from some host species are not morphologically or genetically distinct, creating taxonomic confusion with older names, which treated mites from different hosts as separate species. We review the taxonomy and nomenclature of the genus and the two oldest binomens, most recently known as Psoroptes ovis and Psoroptes equi. Prior authors have attributed these names to various authorities, with most attributing both names to Hering (Nova Acta Phys-Med Acad Caesar Leopold-Carol Nat Curios 18(2):573-624, 1838). In particular, the priority between these names was recently a point of contention, with P. ovis being treated as junior synonym of P. equi. A review of all relevant nineteenth and twentieth century publications indicates, however, that these binomens should be cited as P. ovis (Viborg in Veterinair-Selskabets Skrifter 2:139-152, 1813) and P. equi (Raspail in Bull gener Theraput Med Chir 7:169-184, 1834), with the former having priority over the latter assuming their conspecificity. We also clarify attribution of the authorship and the type species of the genus Psoroptes. PMID- 25921490 TI - Drug firms must cut price of pneumonia vaccine, says MSF. PMID- 25921489 TI - Evidence for horizontal transfer of Wolbachia by a Drosophila mite. AB - Mites are common ectoparasites of Drosophila and have been implicated in bacterial and mobile element invasion of Drosophila stocks. The obligate endobacterium, Wolbachia, has widespread effects on gene expression in their arthropod hosts and alters host reproduction to enhance its survival and propagation, often with deleterious effects in Drosophila hosts. To determine whether Wolbachia could be transferred between Drosophila melanogaster laboratory stocks by the mite Tyrophagus putrescentiae, mites were introduced to Wolbachia infected Drosophila vials. These vials were kept adjacent to mite-free and Wolbachia-uninfected Drosophila stock vials. The Wolbachia infection statuses of the infected and uninfected flies were checked from generation 1 to 5. Results indicate that Wolbachia DNA could be amplified from mites infesting Wolbachia infected fly stocks and infection in the previously uninfected stocks arose within generation 1 or 2, concomitant with invasion of mites from the Wolbachia infected stock. A possible mechanism for the transfer of Wolbachia from flies to mites and vice versa, can be inferred from time-lapse photography of fly and mite interactions. We demonstrated that mites ingest Drosophila corpses, including Wolbachia-infected corpses, and Drosophila larva ingest mites, providing possible sources of Wolbachia infection and transfer. This research demonstrated that T. putrescentiae white mites can facilitate Wolbachia transfer between Drosophila stocks and that this may occur by ingestion of infected corpses. Mite-vectored Wolbachia transfer allows for rapid establishment of Wolbachia infection within a new population. This mode of Wolbachia introduction may be relevant in nature as well as in the laboratory, and could have a variety of biological consequences. PMID- 25921491 TI - Endogenous neural stem cell responses to stroke and spinal cord injury. AB - Stroke and spinal cord injury (SCI) are among the most frequent causes of central nervous system (CNS) dysfunction, affecting millions of people worldwide each year. The personal and financial costs for affected individuals, their families, and the broader communities are enormous. Although the mammalian CNS exhibits little spontaneous regeneration and self-repair, recent discoveries have revealed that subpopulations of glial cells in the adult forebrain subventricular zone and the spinal cord ependymal zone possess neural stem cell properties. These endogenous neural stem cells react to stroke and SCI by contributing a significant number of new neural cells to formation of the glial scar. These findings have raised hopes that new therapeutic strategies can be designed based on appropriate modulation of endogenous neural stem cell responses to CNS injury. Here, we review the responses of forebrain and spinal cord neural stem cells to stroke and SCI, the role of these responses in restricting injury-induced tissue loss, and the possibility of directing these responses to promote anatomical and functional repair of the CNS. PMID- 25921492 TI - [Epidemiological profile of Tinea capitis in Dakar (Senegal). A 6-year retrospective study (2008-2013)]. AB - INTRODUCTION: Tinea capitis is considered as a public health problem in Senegal. The aim of this study was to investigate trends in the incidence, the mycological and epidemiological aspects of tinea capitis diagnosed at Le Dantec Hospital in Dakar. METHOD: Our work is a retrospective study concerning all scalp samples taken by the parasitology laboratory, over a 6-year period (2008-2013). RESULTS: A total of 1640 specimens were examined. Of these, 566 were positive with direct examination and after culture. We noted the reduction of patients and of the incidence of tineas during 6 years with variations of 147 (46.82%) to 37 (22.02%). The average incidence of the tineas during six years was 34.51%. Patients' age varied between 1 to 83 years with a mean of 27.33 years. Prevalence varied between age groups, with 10.61 % in adults between 20 to 29 years, 7.19% in children between 0 to 9 years, 6.04% between 10 to 19 years, and 5.91% in adults between 30 to 39 years. Women were more infected 469 (82.9%) than men 97 (17.1%). The main dermatophytes isolated were: T. soudanense in 318 cases (56.18%), T. rubrum in 104 cases (18.37%), M. langeronii in 72 cases (12.72%), M. canis in 36 cases (6.36%), and T. mentagrophytes in 26 cases (4.60%). CONCLUSION: Our study showed a decrease in the annual incidence of tinea capitis over the study period with an evident increase in trichophytic tinea. This study showed that tinea is endemic in Senegal mainly among women between 20 and 29 years. PMID- 25921493 TI - Controlled preparation of Au/Ag/SnO2 core-shell nanoparticles using a photochemical method and applications in LSPR based sensing. AB - A photochemical method for the controlled preparation of core-shell Au/Ag/SnO2 nanorods (NRs) and nanospheres (NSs) has been developed based on photo-induced electron transfer processes in the plasmonic metal-semiconductor system. Au/AgNR/SnO2 and Au/AgNS/SnO2 were prepared by the UV irradiation of a mixture of mesoporous SnO2 coated AuNRs, or AuNSs, and AgNO3, in which AgNO3 was reduced by electrons transferred from the photo-excited mesoporous SnO2 (semiconductor) to the gold (metal). This method allows precise control over the composition and optical properties of the obtained nanoparticles. The LSPR refractive index sensitivity of the obtained Au/AgNR/SnO2 nanoparticles has been optimized to obtain a refractive index sensitivity of ~442 nm RIU(-1). The optimized nanoparticles were subsequently chosen for the LSPR based sensing of glutathione (GSH) with the limit of detection of ~7.5 * 10(-7) M. This photochemical method allows the controlled preparation of various Au/Ag/SnO2 nanoparticles to adjust their LSPR to suit various applications. PMID- 25921494 TI - X-ray investigation of lateral hetero-structures of inversion domains in LiNbO3, KTiOPO4 and KTiOAsO4. AB - In this paper periodically domain-inverted (PDI) ferroelectric crystals are studied using high-resolution X-ray diffraction. Rocking curves and reciprocal space maps of the principal symmetric Bragg reflections in LiNbO3 (LN) (Lambda = 5 um), KTiOPO4 (KTP) (Lambda = 9 um) and KTiOAsO4 (KTA) (Lambda = 39 um) are presented. For all the samples strong satellite reflections were observed as a consequence of the PDI structure. Analysis of the satellites showed that they were caused by a combination of coherent and incoherent scattering between the adjacent domains. Whilst the satellites contained phase information regarding the structure of the domain wall, this information could not be rigorously extracted without a priori knowledge of the twinning mechanism. Analysis of the profiles reveals strain distributions of Deltad/d = 1.6 * 10(-4) and 2.0 * 10(-4) perpendicular to domain walls in KTP and LN samples, respectively, and lateral correlation lengths of 63 um (KTP), 194 um (KTA) and 10 um (LN). The decay of crystal truncation rods in LN and KTP was found to support the occurrence of surface corrugations. PMID- 25921495 TI - Symmetry of semi-reduced lattices. AB - The main result of this work is extension of the famous characterization of Bravais lattices according to their metrical, algebraic and geometric properties onto a wide class of primitive lattices (including Buerger-reduced, nearly Buerger-reduced and a substantial part of Delaunay-reduced) related to low restricted semi-reduced descriptions (s.r.d.'s). While the 'geometric' operations in Bravais lattices map the basis vectors into themselves, the 'arithmetic' operators in s.r.d. transform the basis vectors into cell vectors (basis vectors, face or space diagonals) and are represented by matrices from the set {?bb V} of all 960 matrices with the determinant +/-1 and elements {0, +/-1} of the matrix powers. A lattice is in s.r.d. if the moduli of off-diagonal elements in both the metric tensors M and M(-1) are smaller than corresponding diagonal elements sharing the same column or row. Such lattices are split into 379 s.r.d. types relative to the arithmetic holohedries. Metrical criteria for each type do not need to be explicitly given but may be modelled as linear derivatives {?bb M}(p,q,r), where {?bb M} denotes the set of 39 highest-symmetry metric tensors, and p,q,r describe changes of appropriate interplanar distances. A sole filtering of {?bb V} according to an experimental s.r.d. metric and subsequent geometric interpretation of the filtered matrices lead to mathematically stable and rich information on the Bravais-lattice symmetry and deviations from the exact symmetry. The emphasis on the crystallographic features of lattices was obtained by shifting the focus (i) from analysis of a lattice metric to analysis of symmetry matrices [Himes & Mighell (1987). Acta Cryst. A43, 375-384], (ii) from the isometric approach and invariant subspaces to the orthogonality concept {some ideas in Le Page [J. Appl. Cryst. (1982), 15, 255-259]} and splitting indices [Stroz (2011). Acta Cryst. A67, 421-429] and (iii) from fixed cell transformations to transformations derivable via geometric information (Himes & Mighell, 1987; Le Page, 1982). It is illustrated that corresponding arithmetic and geometric holohedries share space distribution of symmetry elements. Moreover, completeness of the s.r.d. types reveals their combinatorial structure and simplifies the crystallographic description of structural phase transitions, especially those observed with the use of powder diffraction. The research proves that there are excellent theoretical and practical reasons for looking at crystal lattice symmetry from an entirely new and surprising point of view - the combinatorial set {?bb V} of matrices, their semi-reduced lattice context and their geometric properties. PMID- 25921496 TI - Structure factor for an icosahedral quasicrystal within a statistical approach. AB - This paper describes a detailed derivation of a structural model for an icosahedral quasicrystal based on a primitive icosahedral tiling (three dimensional Penrose tiling) within a statistical approach. The average unit cell concept, where all calculations are performed in three-dimensional physical space, is used as an alternative to higher-dimensional analysis. Comprehensive analytical derivation of the structure factor for a primitive icosahedral lattice with monoatomic decoration (atoms placed in the nodes of the lattice only) presents in detail the idea of the statistical approach to icosahedral quasicrystal structure modelling and confirms its full agreement with the higher dimensional description. The arbitrary decoration scheme is also discussed. The complete structure-factor formula for arbitrarily decorated icosahedral tiling is derived and its correctness is proved. This paper shows in detail the concept of a statistical approach applied to the problem of icosahedral quasicrystal modelling. PMID- 25921497 TI - Absolute refinement of crystal structures by X-ray phase measurements. AB - A pair of enantiomer crystals is used to demonstrate how X-ray phase measurements provide reliable information for absolute identification and improvement of atomic model structures. Reliable phase measurements are possible thanks to the existence of intervals of phase values that are clearly distinguishable beyond instrumental effects. Because of the high susceptibility of phase values to structural details, accurate model structures were necessary for succeeding with this demonstration. It shows a route for exploiting physical phase measurements in the crystallography of more complex crystals. PMID- 25921498 TI - Icosahedral symmetry breaking: C(60) to C(84), C(108) and to related nanotubes. AB - This paper completes the series of three independent articles [Bodner et al. (2013). Acta Cryst. A69, 583-591, (2014), PLOS ONE, 10.1371/journal.pone.0084079] describing the breaking of icosahedral symmetry to subgroups generated by reflections in three-dimensional Euclidean space {?bb R}^3 as a mechanism of generating higher fullerenes from C60. The icosahedral symmetry of C60 can be seen as the junction of 17 orbits of a symmetric subgroup of order 4 of the icosahedral group of order 120. This subgroup is noted by A1 * A1, because it is isomorphic to the Weyl group of the semi-simple Lie algebra A1 * A1. Thirteen of the A1 * A1 orbits are rectangles and four are line segments. The orbits form a stack of parallel layers centered on the axis of C60 passing through the centers of two opposite edges between two hexagons on the surface of C60. These two edges are the only two line segment layers to appear on the surface shell. Among the 24 convex polytopes with shell formed by hexagons and 12 pentagons, having 84 vertices [Fowler & Manolopoulos (1992). Nature (London), 355, 428-430; Fowler & Manolopoulos (2007). An Atlas of Fullerenes. Dover Publications Inc.; Zhang et al. (1993). J. Chem. Phys. 98, 3095-3102], there are only two that can be identified with breaking of the H3 symmetry to A1 * A1. The remaining ones are just convex shells formed by regular hexagons and 12 pentagons without the involvement of the icosahedral symmetry. PMID- 25921499 TI - Unique atom hyper-kagome order in Na4Ir3O8 and in low-symmetry spinel modifications. AB - Group-theoretical and thermodynamic methods of the Landau theory of phase transitions are used to investigate the hyper-kagome atomic order in structures of ordered spinels and a spinel-like Na4Ir3O8 crystal. The formation of an atom hyper-kagome sublattice in Na4Ir3O8 is described theoretically on the basis of the archetype (hypothetical parent structure/phase) concept. The archetype structure of Na4Ir3O8 has a spinel-like structure (space group Fd?bar 3m) and composition [Na1/2Ir3/2](16d)[Na3/2](16c)O(32e)4. The critical order parameter which induces hypothetical phase transition has been stated. It is shown that the derived structure of Na4Ir3O8 is formed as a result of the displacements of Na, Ir and O atoms, and ordering of Na, Ir and O atoms, ordering dxy, dxz, dyz orbitals as well. Ordering of all atoms takes place according to the type 1:3. Ir and Na atoms form an intriguing atom order: a network of corner-shared Ir triangles called a hyper-kagome lattice. The Ir atoms form nanoclusters which are named decagons. The existence of hyper-kagome lattices in six types of ordered spinel structures is predicted theoretically. The structure mechanisms of the formation of the predicted hyper-kagome atom order in some ordered spinel phases are established. For a number of cases typical diagrams of possible crystal phase states are built in the framework of the Landau theory of phase transitions. Thermodynamical conditions of hyper-kagome order formation are discussed by means of these diagrams. The proposed theory is in accordance with experimental data. PMID- 25921500 TI - Determination of small crystal structures from a minimum set of diffraction intensities by homotopy continuation. AB - No deterministic approach to obtaining a crystal structure from a set of diffraction intensities exists, despite significant progress in traditional probabilistic direct methods. One of the biggest hurdles in determining a crystal structure algebraically is solving a system of many polynomial equations of high power on intensities in terms of atomic coordinates. In this study, homotopy continuation is used for exhaustive investigation of such systems and an optimized homotopy continuation method is developed with random restarts to determine small (N < 5) crystal structures from a minimum set of error-free intensities. PMID- 25921501 TI - Magnetic structure determination from the magnetic pair distribution function (mPDF): ground state of MnO. AB - An experimental determination of the magnetic pair distribution function (mPDF) defined in an earlier paper [Frandsen et al. (2014). Acta Cryst. A70, 3-11] is presented for the first time. The mPDF was determined from neutron powder diffraction data from a reactor and a neutron time-of-flight total scattering source on a powder sample of the antiferromagnetic oxide MnO. A description of the data treatment that allowed the measured mPDF to be extracted and then modelled is provided and utilized to investigate the low-temperature structure of MnO. Atomic and magnetic co-refinements support the scenario of a locally monoclinic ground-state atomic structure, despite the average structure being rhombohedral, with the mPDF analysis successfully recovering the known antiferromagnetic spin configuration. The total scattering data suggest a preference for the spin axis to lie along the pseudocubic [10{?overline 1}] direction. Finally, r-dependent PDF refinements indicate that the local monoclinic structure tends toward the average rhombohedral R{?overline 3}m symmetry over a length scale of approximately 100 A. PMID- 25921502 TI - More statistics on intermetallic compounds - ternary phases. AB - How many different intermetallic compounds are known so far, and in how many different structure types do they crystallize? What are their chemical compositions, the most abundant ones and the rarest ones? These are some of the questions we are trying to find answers for in our statistical analysis of the structures of the 20,829 intermetallic phases included in the database Pearson's Crystal Data, with the goal of gaining insight into some of their ordering principles. In the present paper, we focus on the subset of 13,026 ternary intermetallics, which crystallize in 1391 different structure types; remarkably, 667 of them have just one representative. What makes these 667 structures so unique that they are not adopted by any other of the known intermetallic compounds? Notably, ternary compounds are known in only 5109 of the 85,320 theoretically possible ternary intermetallic systems so far. In order to get an overview of their chemical compositions we use structure maps with Mendeleev numbers as ordering parameters. PMID- 25921503 TI - Axial point groups: rank 1, 2, 3 and 4 property tensor tables. AB - The form of a physical property tensor of a quasi-one-dimensional material such as a nanotube or a polymer is determined from the material's axial point group. Tables of the form of rank 1, 2, 3 and 4 property tensors are presented for a wide variety of magnetic and non-magnetic tensor types invariant under each point group in all 31 infinite series of axial point groups. An application of these tables is given in the prediction of the net polarization and magnetic-field induced polarization in a one-dimensional longitudinal conical magnetic structure in multiferroic hexaferrites. PMID- 25921504 TI - Molecular identification of rare FY*Null and FY*X alleles in Caucasian thalassemic family from Sardinia. AB - Molecular genetic studies on Duffy blood group antigens have identified mutations underlying rare FY*Null and FY*X alleles. FY*Null has a high frequency in Blacks, especially from sub-Saharan Africa, while its frequency is not defined in Caucasians. FY*X allele, associated with Fy(a-b+w) phenotype, has a frequency of 2-3.5% in Caucasian people while it is absent in Blacks. During the project of extensive blood group genotyping in patients affected by hemoglobinopathies, we identified FY*X/FY*Null and FY*A/FY*Null genotypes in a Caucasian thalassemic family from Sardinia. We speculate on the frequency of FY*X and FY*Null alleles in Caucasian and Black people; further, we focused on the association of FY*X allele with weak Fyb antigen expression on red blood cells and its identification performing high sensitivity serological typing methods or genotyping. PMID- 25921505 TI - Continual advancements in the innovative field of extracorporeal photochemotherapy: Time to wake up, to shake up, to shape up the future direction. PMID- 25921506 TI - The aging human recipient of transfusion products. AB - In this review the different mechanisms of aging and frailty such as DNA defects due to impaired DNA repair, inflammatory processes, disturbances of oxidative phosphorylation are discussed together with mechanisms of cell repair. Components of blood plasma, such as the growth-differentiation protein GDF11, were shown to enhance neurogenesis and to improve the vasculature in the animal cortex and to rejuvenate muscle tissue. Advances in laboratory assays allow to identify plasma proteins that may affect tissue regeneration. This new knowledge from animal research might affect transfusion practice in geriatric patients in the future. Provided it can be translated and confirmed in human research, blood products might no longer be considered only as oxygen carriers or drugs to improve hemostasis. In the present time blood transfusion (RBCs, plasma or platelets) should be directed by differentiated guidelines considering not only cut-off values of hemoglobin, platelet count or coagulation but also old age-specific biologic variation, comorbidities and the clinical context e.g. of bleeding. PMID- 25921507 TI - [Relevance of the sentinel lymph node biopsy in breast multifocal and multicentric cancer]. AB - OBJECTIVES: The sentinel lymph node biopsy is a gold standard in the management of breast cancer. Its role in multifocal or multicentric tumors is still evolving. The aim of this study is to assess the feasibility and pertinence of sentinel lymph node biopsy in multifocal and multicentric tumors based on a systematic review of literature. METHODS: A systematic review was conducted searching in the following electronic databases PubMed using "sentinel lymph node biopsy", "breast cancer", "multifocal tumor", "multicentric tumor" and "multiple tumor" as keywords. We included original articles published between 2000 and 2014, both French and English, studying feasibility of sentinel lymph node biopsy in invasive breast cancer, multicentric and/or multifocal tumors. The first end point was success rate and false negative rate. RESULTS: Twenty-six articles were included in this literature review, with 2212 cases (782 multifocal, 737 multicentric and 693 multiple tumors). Percentage of tumors whose stage was higher than stage T2 ranged from 0 to 86.3%. Success rate average was 83.1%. False negative average was 8.2%. False negative rate was less than 10% in 15 articles. Mean of sentinel lymph node biopsy was 2 (1-9). The average rate of sentinel lymph node positive was 50.6%. Axillary recurrence rate was 0.5%. CONCLUSION: Despite the methodological biases of the studies included in this review of literature, the false negative rate of sentinel node biopsy in multifocal and multicentric breast cancers are less than 10% with a low rate of axillary recurrence. Despite the lack of randomized study, this procedure can be routinely performed in accordance with rigorous technical process. PMID- 25921508 TI - [Outbreak of caesarean sections and fear of birth injury]. PMID- 25921509 TI - [Pelvic floor muscle training and pelvic floor disorders in women]. AB - Our goal is to provide an update on the results of pelvic floor rehabilitation in the treatment of urinary incontinence and genital prolapse symptoms. Pelvic floor muscle training allows a reduction of urinary incontinence symptoms. Pelvic floor muscle contractions supervised by a healthcare professional allow cure in half cases of stress urinary incontinence. Viewing this contraction through biofeedback improves outcomes, but this effect could also be due by a more intensive and prolonged program with the physiotherapist. The place of electrostimulation remains unclear. The results obtained with vaginal cones are similar to pelvic floor muscle training with or without biofeedback or electrostimulation. It is not known whether pelvic floor muscle training has an effect after one year. In case of stress urinary incontinence, supervised pelvic floor muscle training avoids surgery in half of the cases at 1-year follow-up. Pelvic floor muscle training is the first-line treatment of post-partum urinary incontinence. Its preventive effect is uncertain. Pelvic floor muscle training may reduce the symptoms associated with genital prolapse. In conclusion, pelvic floor rehabilitation supervised by a physiotherapist is an effective short-term treatment to reduce the symptoms of urinary incontinence or pelvic organ prolapse. PMID- 25921510 TI - Mutations of the human interferon alpha-2b (hIFN-alpha2b) gene in occupationally protracted low dose radiation exposed personnel. PMID- 25921511 TI - Sulphate-selective optical microsensors: overcoming the hydration energy penalty. AB - Novel membrane-free chemically modified polystyrene microspheres for the optical detection of sulphate in aqueous media are introduced. The working principle of this sensor is based on the surface mass-extraction equilibrium of the target species. This allows overcoming the strong hydration energy penalty, a typical problem for the detection of divalent anions. This optical sensor exhibits both enhanced sensitivity and selectivity, which allows the accurate detection of sulphate in biological samples. To illustrate these features the determination of sulphate in urine is presented. PMID- 25921512 TI - Characterization of MDR and XDR Streptococcus pneumoniae in Canada, 2007-13. AB - OBJECTIVES: The goal of this study was to characterize Streptococcus pneumoniae demonstrating MDR (resistant to three or more antimicrobial classes) or XDR (resistant to five or more classes) phenotypes, collected from Canada during the CANWARD 2007-13 study. METHODS: From 2007 to 2013 inclusive, S. pneumoniae isolates were collected as a part of the CANWARD surveillance study. MDR and XDR isolates were subjected to PFGE, MLST, molecular detection of pneumococcal pili and macrolide resistance determinants mef(A/E) and erm(B), sequencing of PBPs 1A, 2B and 2X and comparison with Pneumococcal Molecular Epidemiology Network (PMEN) clones. RESULTS: Of 2129 S. pneumoniae isolates collected during the CANWARD 2007 13 study, 61 (2.9%) were found to be MDR. Of these MDR isolates, 43 (70.5%) were XDR. The most common serotypes for both MDR and XDR S. pneumoniae were 19A and 19F. Twenty-nine of 61 isolates (48%) demonstrated resistance to clarithromycin, clindamycin, doxycycline, penicillin and trimethoprim/sulfamethoxazole. All isolates possessed at least one macrolide resistance determinant and mutations in PBPs 1A, 2B and 2X. The most common clone was piliated, XDR ST320, an internationally circulating double-locus variant of Taiwan(19F)-14 (ST236). CONCLUSIONS: Though the rate of MDR S. pneumoniae has remained relatively stable since 2007, XDR strains have emerged in Canada. These strains are virulent, possess resistance determinants and are related to international clones. PMID- 25921513 TI - Enhanced efficacy of putative efflux pump inhibitor/antibiotic combination treatments versus MDR strains of Pseudomonas aeruginosa in a Galleria mellonella in vivo infection model. AB - OBJECTIVES: The objectives of this study were to compare the antibiotic susceptibility of Pseudomonas aeruginosa strains with increased efflux pump expression in vitro and in vivo and to use these same strains to evaluate the efficacy of combinations of antibiotics with putative efflux pump inhibitors in vivo. METHODS: A collection of P. aeruginosa strains that overexpress three efflux pumps (MexAB-OprM, MexCD-OprJ and MexEF-OprN), in addition to a strain with all three Mex pumps deleted, were used. The virulence of these strains and their antibiotic susceptibility was measured in vivo using a Galleria mellonella larval infection model. The inhibitory effect of combinations of putative efflux pump inhibitors (trimethoprim and sertraline) with antibiotics on the strain overexpressing MexAB-OprM was also measured in vitro and compared with their efficacy in vivo in terms of larval survival and bacterial burden. RESULTS: Increased expression of the individual efflux pumps, or deletion of all three, had no significant effect on the virulence of P. aeruginosa in vivo. Expression levels of the efflux pumps clearly influenced antibiotic efficacy in vivo. The efficacy of levofloxacin, piperacillin and meropenem against larvae infected with the efflux pump mutants reflected susceptibility to the same drugs in vitro. Treatment of G. mellonella larvae infected with a strain that overexpressed MexAB OprM with a combination of putative efflux pump inhibitors and levofloxacin resulted in enhanced therapeutic benefit compared with the constituent monotherapies. CONCLUSIONS: This study has demonstrated the utility of using G. mellonella to screen for novel therapeutic options for MDR P. aeruginosa and has shown that antibiotic/efflux pump inhibitor combinations should be further investigated for clinical application. PMID- 25921515 TI - A novel alanine to serine substitution mutation in SoxS induces overexpression of efflux pumps and contributes to multidrug resistance in clinical Escherichia coli isolates. AB - OBJECTIVES: The purpose of this study was to describe a putative role for a novel soxS mutation in contributing to multiple-antibiotic resistance in canine fluoroquinolone-associated MDR (FQ-MDR) Escherichia coli. This soxS mutation was discovered in canine faecal E. coli isolates during a study investigating the effect of oral fluoroquinolone administration on faecal E. coli in healthy dogs. METHODS: We determined via quantitative real-time RT-PCR that both soxS and acrB were overexpressed in the clinical soxS Ala-12->Ser (soxS(A12S)) mutants and this may account for their FQ-MDR phenotype. We validated the FQ-MDR phenotype of the clinical isolates by reconstructing the WT and the soxS(A12S) mutation in the E. coli soxS null mutant JW4023 (soxS::kn) via allelic exchange. RESULTS: The JW4023 soxS(A12S) derivative showed an increase in MICs of ciprofloxacin, enrofloxacin and chloramphenicol compared with the JW4023 derivative in which the WT soxS had been restored. The soxS and acrB genes were overexpressed in the JW4023 soxS(A12S) mutant compared with JW4023 with WT soxS. A similar overexpression of efflux pump genes and an increase in antibiotic resistance were observed upon stimulation with paraquat to resemble the phenotype of the clinical soxS(A12S) isolates. CONCLUSIONS: Our data suggest that the soxS(A12S) substitution mutation is selected in clinical isolates when dogs are exposed to a fluoroquinolone and that this mutation contributes to the FQ-MDR phenotype of E. coli isolates. PMID- 25921514 TI - Mitochondrial and apoptotic in vitro modelling of differential HIV-1 progression and antiretroviral toxicity. AB - OBJECTIVES: Ex vivo analysis of mitochondrial function may reveal HIV progression and the impact of ART. We propose a mitochondrial and apoptotic in vitro model using Jurkat T cells incubated with plasma. The objectives of this study were to evaluate mitochondrial and apoptotic lesions in this model in relation to HIV progression, and to assess the effect of >1 year of standard non-thymidine containing therapy. METHODS: This was a cross-sectional comparison among three age- and gender-matched groups (n = 19 * 3): healthy non-HIV-infected participants, HIV-infected long-term non-progressors (LTNPs) and standard antiretroviral-naive chronically infected patients [standard progressors (Sps)], longitudinally evaluated before (Sp1) and after (Sp2) >1 year of efavirenz + tenofovir + emtricitabine therapy. We analysed mitochondrial DNA content by RT PCR, mitochondrial function by spectrophotometry, mitochondrial protein synthesis by western blot analysis, mitochondrial dynamics by western blot analysis (MFN2), apoptotic transition pore formation by western blot analysis (VDAC-1) and mitochondrial membrane potential and annexin V/propidium iodide fluorescence by flow cytometry. RESULTS: There was a decreasing non-significant trend towards lower mitochondrial parameters for HIV-infected values with respect to uninfected control reference values. HIV progression (LTNP versus Sp1) was associated with decreased mitochondrial genetic, functional and translational parameters, which partially recovered after treatment intervention (Sp2). Mitochondrial fusion showed a trend to decrease non-significantly in Sp patients compared with LTNP patients, especially after therapy. All apoptotic parameters showed a trend to increase in Sp1 with respect to LTNP, followed by recovery in Sp2. CONCLUSIONS: We proposed an in vitro model for mitochondrial and apoptotic assessment to test the effects of HIV infection and its therapy, resembling in vivo conditions. This model could be useful for clinical research purposes. PMID- 25921516 TI - Low-level HIV-1 viraemia in patients on HAART: risk factors and management in clinical practice. AB - OBJECTIVES: Characterization of the conditions favouring HIV-1 low-level viraemia (LLV) during treatment is required to guide strategies for prevention and cure. METHODS: The characteristics and treatments of 171 patients experiencing a confirmed LLV of 50-1000 copies/mL (PLLVs) were compared with those of 146 patients with persistently controlled viraemia. We analysed the risk factors for LLV, the parameters affecting the level of viraemia and the presence of resistance-associated mutations (RAMs). We compared outcomes for PLLVs on fully effective HAART as a function of treatment modifications. RESULTS: LLV was <500 copies/mL in at least 90% of cases. A higher zenith viral load (VL) (5.27 versus 4.91 log10 copies/mL, OR 2.23; P = 0.0003), a shorter time on continuous HAART (4.3 versus 6.8 years, OR 0.88; P = 0.0003) and previously detected RAMs (43% versus 23%, OR 2.42; P = 0.0033) were independent predictors of LLV. NNRTIs were less frequently used in PLLVs and were associated with more stable treatment. The presence of any RAM during LLV was associated with a lower zenith VL and a higher LLV. In the absence of resistance, virological success was achieved in similar proportions of patients with and without treatment modification. CONCLUSIONS: Viraemia >500 copies/mL should no longer be considered to be LLV. In patients with a high zenith VL, several years on continuous HAART may be required to decrease the HIV reservoir and prevent LLV. Resistance testing is useful to detect RAMs, leading if necessary to treatment modifications. In the absence of resistance, treatment changes seemed dispensable. PMID- 25921517 TI - ZNF804A rs1344706 is associated with cortical thickness, surface area, and cortical volume of the unmedicated first episode schizophrenia and healthy controls. AB - The effects of ZNF804A rs1344706, a prominent susceptibility gene for schizophrenia, on gray matter (GM) structure in unmedicated schizophrenia (SZ) patients are still unknown, although several previous studies investigated the effects in medicated SZ patients and healthy controls (HC). Analyzing cortical thickness, surface area, and GM volume simultaneously may provide a more precise and complete picture of the effects. We genotyped 59 unmedicated first episode SZ patients and 60 healthy controls for the ZNF804A single nucleotide polymorphism (SNP) rs1344706, and examined between-group differences in cortical thickness, surface area, and cortical volume using a full-factorial 2 * 2 analysis of variance (ANOVA). We found the risk allele (T) in ZNF804A rs1344706, compared to the non-risk allele (G), was associated with thinner cortex in the bilateral precuneus, left precentral gyrus, and several other regions, associated with a smaller cortical surface area in the left superior parietal, precuneus cortex and left superior frontal, and associated with a lower cortical volume in the left superior frontal, left precentral, and right precuneus in SZ patients. In contrast, in the controls, the T allele was associated with the increased cortical measurements compared to the G allele in the same regions as those mentioned above. ZNF804A rs1344706 has significant, but different, effects on cortical thickness, surface area, and cortical volume in multiple regions of the brain cortex. Our findings suggest that ZNF804A rs1344706 may aggravate the risk for schizophrenia by exerting its effects on cortical thickness, surface area, and cortical volume in these brain regions. PMID- 25921518 TI - Comparison of Rock Varnish Bacterial Communities with Surrounding Non-Varnished Rock Surfaces: Taxon-Specific Analysis and Morphological Description. AB - Rock varnish is a thin layer of Fe and Mn oxyhydroxides with embedded clay minerals that contain an increased Mn/Fe ratio compared to that of the Earth's crust. Even if the study of rock varnish has important implications in several fields, the composition of epilithic bacterial communities and the distribution of taxa on varnish surfaces are still not wholly described. The aim of this study was (i) to identify the bacterial taxa which show the greatest variation between varnish and non-varnish environments, collected from the same rock, and (ii) to describe the morphology of epilithic communities through scanning electron microscopy (SEM). Triplicate samples of rock surfaces with varnish and triplicate samples without varnish were collected from five sites in Matsch Valley (South Tyrol, Italy). The V4 region of 16S rRNA gene was analyzed by Illumina sequencing. Fifty-five ubiquitous taxa have been examined to assess variation between varnish and non-varnish. Cyanobacteria, Chloroflexi, Proteobacteria along with minor taxa such as Solirubrobacterales, Conexibaxter, and Rhodopila showed significant variations of abundance, diversity, or both responding to the ecology (presence/absence of varnish). Other taxa, such as the genus Edaphobacter, showed a more marked spatial variation responding to the sampling site. SEM images showed a multitude of bacterial morphologies and structures involved in the process of attachment and creation of a suitable environment for growth. The features emerging from this analysis suggest that the highly oxidative Fe and Mn rich varnish environment favors anoxigenic autotrophy and establishment of highly specialized bacteria. PMID- 25921519 TI - Reptiles as Reservoirs of Bacterial Infections: Real Threat or Methodological Bias? AB - Bacterial infections secondary to snakebites and human pathogens (e.g., Salmonella) have been linked to the oral microbiota of snakes and pet reptiles. Based on culture-dependent studies, it is speculated that snakes' oral microbiota reflects the fecal flora of their ingested preys. However, cultured-based techniques have been shown to be limited as they fail to identify unculturable microorganisms which represent the vast majority of the microbial diversity. Here, we used culture-independent high-throughput sequencing to identify reptile associated pathogens and to characterize the oral microbial community of five snakes, one gecko, and two terrapins. Few potential human pathogens were detected at extremely low frequencies. Moreover, bacterial taxa represented in the snake's oral cavity bore little resemblance to their preys' fecal microbiota. Overall, we found distinct, highly diverse microbial communities with consistent, species specific patterns contrary to previous culture-based studies. Our study does not support the widely held assumption that reptiles' oral cavity acts as pathogen reservoir and provides important insights for future research. PMID- 25921520 TI - Association between perfluoroalkyl substances and reproductive hormones in adolescents and young adults. AB - BACKGROUND: Few studies have explored the association between perfluoroalkyl substances (PFAS) and reproductive hormones in adolescents and young adults. OBJECTIVES: This study aimed to investigate the association of PFAS with reproductive hormones in adolescents and young adults. METHODS: We recruited 540 subjects aged 12-30 years from a 1992 to 2000 mass urine screening population and established a cohort from 2006 to 2008 via invitations by mail or/and telephone. Serum PFAS levels were analyzed with a Waters ACQUITY UPLC system coupled with a Waters Quattro Premier XE triple quadrupole mass spectrometer. Serum reproductive hormone levels were measured by immunoluminometric assay with an Architect random access assay system. PFAS levels were divided into different percentiles according to their detection limits in the multiple regression models to analyze associations between reproductive hormone levels and exposure with PFAS. RESULTS: The adjusted mean serum level of sex hormone-binding globulin (SHBG) decreased significantly in association with the <50th, 50-75, 75-90 and >90th percentile categories of perfluorooctanoic acid (PFOA) compared with a reference category for the females in the 12-17-year-old group. The follicle-stimulating hormone (FSH) levels were significantly decreased in association with the different percentile categories of perfluorooctane sulfonate (PFOS) in the male 12-17-year old group and the different percentile categories of perfluoroundecanoic acid (PFUA) in the female 12-17-year-old group. The serum FSH levels in the females aged 12-17 were also decreased in association with the different percentile categories of PFUA. On the other hand, there was a significantly negative association between the different percentile categories of PFOS and the serum testosterone level among the female 12-17-year-old group. CONCLUSIONS: We found that the serum concentrations of PFOA, PFOS, and PFUA were negatively associated with the serum levels of SHBG, FSH, and testosterone in the young Taiwanese population and that these effects were the strongest in the females aged 12-17. Further studies are needed to determine whether these associations are causal. PMID- 25921521 TI - Systemic Inflammatory Response Syndrome After Contentious-Flow Left Ventricular Assist Device Implantation and Change in Platelet Mitochondrial Membrane Potential. AB - BACKGROUND: The objective of this study was to investigate the change of platelet function and platelet mitochondrial membrane potential in contentious-flow left ventricular assist device (CF-LVAD)-implanted heart failure (HF) patients with or without systemic inflammatory response syndrome (SIRS). METHODS AND RESULTS: We recruited 31 CF-LVAD patients (16 SIRS and 15 non-SIRS) and 11 healthy volunteers as control. Pre- and post-implantation blood samples were collected. We used PFA 100 to test platelet functionality. Mitochondrial potential-sensitive dye was used to detect platelet dysfunction (mitochondrial membrane potential; DeltaPsim) via flow cytometry. The percentage of depolarized-DeltaPsim platelets was found to be a preexisting condition in all HF patients before CF-LVAD implantation compared with control subjects (10.3 +/- 6.3% vs 2.8 +/- 2.2%; P < .001). As evident from the PFA-100 test, the HF patients who developed SIRS after CF-LVAD implantation had significantly more qualitative platelet defects and thrombocytopathies compared with baseline. After implantation, the depolarized platelets in the SIRS patients increased by 2-fold compared with baseline (18.2 +/- 8.4% vs 9.0 +/- 6.6%; P < .01); whereas no change was noticed in the non-SIRS patients (10.9 +/- 6.2% vs 11.7 +/- 5.8%; P = .75). CONCLUSIONS: We identified that platelet function and mitochondrial damage were enhanced in CF-LVAD patients with SIRS. Our findings suggest that depolarization of mitochondrial membrane potential is associated with SIRS after CF-LVAD implantation surgery. PMID- 25921522 TI - Rationale and Design of the Left Atrial Pressure Monitoring to Optimize Heart Failure Therapy Study (LAPTOP-HF). AB - BACKGROUND: Daily measurements of left atrial pressure (LAP) may be useful for guiding adjustments in medical therapy that prevent clinical decompensation in patients with severe heart failure (HF). STUDY DESIGN: LAPTOP-HF is a prospective, multicenter, randomized, controlled clinical trial in ambulatory patients with advanced heart failure in which the safety and clinical effectiveness of a physician-directed patient self-management therapeutic strategy based on LAP measured twice daily by means of an implantable sensor will be compared with a control group receiving optimal medical therapy. The trial will enroll up to 730 patients with New York Heart Association functional class III symptoms and either a hospitalization for HF during the previous 12 months or an elevated B-type natriuretic peptide level, regardless of ejection fraction, at up to 75 investigational centers. Randomization to the treatment group or control group will be at a 1:1 ratio in 3 strata based on the ejection fraction (EF > or <=35%) and the presence of a de novo CRT device indication. SUMMARY: LAPTOP-HF will provide essential information about the role of implantable LAP monitoring in conjunction with a new HF treatment paradigm across the spectrum of HF patients. PMID- 25921523 TI - Enrollment in Heart Failure Clinical Trials: Insights Into Which Entry Criteria Exclude Patients. PMID- 25921524 TI - Molecular dynamics at the endocytic portal and regulations of endocytic and recycling traffics. AB - Endocytic and recycling pathways involve the transportation of soluble and transmembrane cargos to destinations within the cell or back to the plasma membrane for reuse. Common mechanistic themes for the traffic pathways in eukaryotic cells from yeast to mammalian cells are well-conserved, manifested by the molecular choreography of cargo segregation, membrane budding and coating, pinching off of the invaginated vesicle, cytoskeleton-mediated vesicle motility and fusion with target compartments. Here, we discuss recent insights into the spatiotemporal dynamics of endocytic machinery at the plasma membrane and the molecular details of bifurcating traffics at the endosome either to the lysosome or to the trans-Golgi network (TGN). PMID- 25921525 TI - Multifunctional luminescence properties of co-doped lanthanide metal organic frameworks. AB - Two novel lanthanide metal organic frameworks [Eu4(bpt)4(DMF)2(H2O)6].(DMF)5.(H2O)4 () and [Tb4(bpt)4(DMF)2(H2O)8].(DMF)5.(H2O)3 () were synthesized under hydrothermal conditions, forming a three-dimensional structure (H3bpt = biphenyl-3,4',5 tricarboxylate). Single crystal X-ray diffraction reveals that compounds and are heteromorphic and have different topologies due to the change of metal ions with different radii and coordination steric hindrance. The unique luminescence properties of Eu(3+) and Tb(3+) ions motivated us to dope different amounts of Tb(3+) into a single host to obtain light tunable materials. The tunable multicolor emissions, including red, red-orange, orange, yellow and green, can be readily achieved from the doped Ln-MOFs by increasing the concentration of Tb(3+). In addition, compounds and also exhibit different temperature-dependent luminescence behaviors when the concentration of Eu(3+) is low, generating new Ln MOF thermometers. PMID- 25921526 TI - An oncogenic role for alternative NF-kappaB signaling in DLBCL revealed upon deregulated BCL6 expression. AB - Diffuse large B cell lymphoma (DLBCL) is a complex disease comprising diverse subtypes and genetic profiles. Possibly because of the prevalence of genetic alterations activating canonical NF-kappaB activity, a role for oncogenic lesions that activate the alternative NF-kappaB pathway in DLBCL has remained elusive. Here, we show that deletion/mutation of TRAF3, a negative regulator of the alternative NF-kappaB pathway, occurs in ~15% of DLBCLs and that it often coexists with BCL6 translocation, which prevents terminal B cell differentiation. Accordingly, in a mouse model constitutive activation of the alternative NF kappaB pathway cooperates with BCL6 deregulation in DLBCL development. This work demonstrates a key oncogenic role for the alternative NF-kappaB pathway in DLBCL development. PMID- 25921527 TI - Selective role of the catalytic PI3K subunit p110beta in impaired higher order cognition in fragile X syndrome. AB - Distinct isoforms of the PI3K catalytic subunit have specialized functions in the brain, but their role in cognition is unknown. Here, we show that the catalytic subunit p110beta plays an important role in prefrontal cortex (PFC)-dependent cognitive defects in mouse models of Fragile X syndrome (FXS), an inherited intellectual disability. FXS is caused by loss of function of the fragile X mental retardation protein (FMRP), which binds and translationally represses mRNAs. PFC-selective knockdown of p110beta, an FMRP target that is translationally upregulated in FXS, reverses deficits in higher cognition in Fmr1 knockout mice. Genetic full-body reduction of p110beta in Fmr1 knockout mice normalizes excessive PI3K activity, restores stimulus-induced protein synthesis, and corrects increased dendritic spine density and behavior. Notably, adult-onset PFC-selective Fmr1 knockdown mice show impaired cognition, which is rescued by simultaneous p110beta knockdown. Our results suggest that FMRP-mediated control of p110beta is crucial for neuronal protein synthesis and cognition. PMID- 25921528 TI - Neddylation promotes ubiquitylation and release of Ku from DNA-damage sites. AB - The activities of many DNA-repair proteins are controlled through reversible covalent modification by ubiquitin and ubiquitin-like molecules. Nonhomologous end-joining (NHEJ) is the predominant DNA double-strand break (DSB) repair pathway in mammalian cells and is initiated by DSB ends being recognized by the Ku70/Ku80 (Ku) heterodimer. By using MLN4924, an anti-cancer drug in clinical trials that specifically inhibits conjugation of the ubiquitin-like protein, NEDD8, to target proteins, we demonstrate that NEDD8 accumulation at DNA-damage sites is a highly dynamic process. In addition, we show that depleting cells of the NEDD8 E2-conjugating enzyme, UBE2M, yields ionizing radiation hypersensitivity and reduced cell survival following NHEJ. Finally, we demonstrate that neddylation promotes Ku ubiquitylation after DNA damage and release of Ku and Ku-associated proteins from damage sites following repair. These studies provide insights into how the NHEJ core complex dissociates from repair sites and highlight its importance for cell survival following DSB induction. PMID- 25921529 TI - Discovery and characterization of an endogenous CXCR4 antagonist. AB - CXCL12-CXCR4 signaling controls multiple physiological processes and its dysregulation is associated with cancers and inflammatory diseases. To discover as-yet-unknown endogenous ligands of CXCR4, we screened a blood-derived peptide library for inhibitors of CXCR4-tropic HIV-1 strains. This approach identified a 16 amino acid fragment of serum albumin as an effective and highly specific CXCR4 antagonist. The endogenous peptide, termed EPI-X4, is evolutionarily conserved and generated from the highly abundant albumin precursor by pH-regulated proteases. EPI-X4 forms an unusual lasso-like structure and antagonizes CXCL12 induced tumor cell migration, mobilizes stem cells, and suppresses inflammatory responses in mice. Furthermore, the peptide is abundant in the urine of patients with inflammatory kidney diseases and may serve as a biomarker. Our results identify EPI-X4 as a key regulator of CXCR4 signaling and introduce proteolysis of an abundant precursor protein as an alternative concept for chemokine receptor regulation. PMID- 25921530 TI - Continuously growing rodent molars result from a predictable quantitative evolutionary change over 50 million years. AB - The fossil record is widely informative about evolution, but fossils are not systematically used to study the evolution of stem-cell-driven renewal. Here, we examined evolution of the continuous growth (hypselodonty) of rodent molar teeth, which is fuelled by the presence of dental stem cells. We studied occurrences of 3,500 North American rodent fossils, ranging from 50 million years ago (mya) to 2 mya. We examined changes in molar height to determine whether evolution of hypselodonty shows distinct patterns in the fossil record, and we found that hypselodont taxa emerged through intermediate forms of increasing crown height. Next, we designed a Markov simulation model, which replicated molar height increases throughout the Cenozoic and, moreover, evolution of hypselodonty. Thus, by extension, the retention of the adult stem cell niche appears to be a predictable quantitative rather than a stochastic qualitative process. Our analyses predict that hypselodonty will eventually become the dominant phenotype. PMID- 25921531 TI - The selective autophagy receptor p62 forms a flexible filamentous helical scaffold. AB - The scaffold protein p62/SQSTM1 is involved in protein turnover and signaling and is commonly found in dense protein bodies in eukaryotic cells. In autophagy, p62 acts as a selective autophagy receptor that recognizes and shuttles ubiquitinated proteins to the autophagosome for degradation. The structural organization of p62 in cellular bodies and the interplay of these assemblies with ubiquitin and the autophagic marker LC3 remain to be elucidated. Here, we present a cryo-EM structural analysis of p62. Together with structures of assemblies from the PB1 domain, we show that p62 is organized in flexible polymers with the PB1 domain constituting a helical scaffold. Filamentous p62 is capable of binding LC3 and addition of long ubiquitin chains induces disassembly and shortening of filaments. These studies explain how p62 assemblies provide a large molecular scaffold for the nascent autophagosome and reveal how they can bind ubiquitinated cargo. PMID- 25921532 TI - Hsp70 forms antiparallel dimers stabilized by post-translational modifications to position clients for transfer to Hsp90. AB - Protein folding in cells is regulated by networks of chaperones, including the heat shock protein 70 (Hsp70) system, which consists of the Hsp40 cochaperone and a nucleotide exchange factor. Hsp40 mediates complex formation between Hsp70 and client proteins prior to interaction with Hsp90. We used mass spectrometry (MS) to monitor assemblies formed between eukaryotic Hsp90/Hsp70/Hsp40, Hop, p23, and a client protein, a fragment of the glucocorticoid receptor (GR). We found that Hsp40 promotes interactions between the client and Hsp70, and facilitates dimerization of monomeric Hsp70. This dimerization is antiparallel, stabilized by post-translational modifications (PTMs), and maintained in the stable heterohexameric client-loading complex Hsp902Hsp702HopGR identified here. Addition of p23 to this client-loading complex induces transfer of GR onto Hsp90 and leads to expulsion of Hop and Hsp70. Based on these results, we propose that Hsp70 antiparallel dimerization, stabilized by PTMs, positions the client for transfer from Hsp70 to Hsp90. PMID- 25921533 TI - Cis regulatory effects on A-to-I RNA editing in related Drosophila species. AB - Adenosine-to-inosine RNA editing modifies maturing mRNAs through the binding of adenosine deaminase acting on RNA (Adar) proteins to double-stranded RNA structures in a process critical for neuronal function. Editing levels at individual editing sites span a broad range and are mediated by both cis-acting elements (surrounding RNA sequence and secondary structure) and trans-acting factors. Here, we aim to determine the roles that cis-acting elements and trans acting factors play in regulating editing levels. Using two closely related Drosophila species, D. melanogaster and D. sechellia, and their F1 hybrids, we dissect the effects of cis sequences from trans regulators on editing levels by comparing species-specific editing in parents and their hybrids. We report that cis sequence differences are largely responsible for editing level differences between these two Drosophila species. This study presents evidence for cis sequence and structure changes as the dominant evolutionary force that modulates RNA editing levels between these Drosophila species. PMID- 25921534 TI - High-resolution profiling of Drosophila replication start sites reveals a DNA shape and chromatin signature of metazoan origins. AB - At every cell cycle, faithful inheritance of metazoan genomes requires the concerted activation of thousands of DNA replication origins. However, the genetic and chromatin features defining metazoan replication start sites remain largely unknown. Here, we delineate the origin repertoire of the Drosophila genome at high resolution. We address the role of origin-proximal G-quadruplexes and suggest that they transiently stall replication forks in vivo. We dissect the chromatin configuration of replication origins and identify a rich spatial organization of chromatin features at initiation sites. DNA shape and chromatin configurations, not strict sequence motifs, mark and predict origins in higher eukaryotes. We further examine the link between transcription and origin firing and reveal that modulation of origin activity across cell types is intimately linked to cell-type-specific transcriptional programs. Our study unravels conserved origin features and provides unique insights into the relationship among DNA topology, chromatin, transcription, and replication initiation across metazoa. PMID- 25921535 TI - Astrocytes control food intake by inhibiting AGRP neuron activity via adenosine A1 receptors. AB - It is well recognized that feeding behavior in mammals is orchestrated by neurons within the medial basal hypothalamus. However, it remains unclear whether food intake is also under the control of glial cells. Here, we combine chemical genetics, cell-type-specific electrophysiology, pharmacology, and feeding assays to show that stimulation of astrocytes within the medial basal hypothalamus reduces both basal- and ghrelin-evoked food intake. This occurs by a mechanism of adenosine-mediated inactivation of the orexigenic agouti-related peptide (AGRP) neurons in the hypothalamic arcuate nucleus (ARC) via adenosine A1 receptors. Our data suggest that glial cells participate in regulating food intake by modulating extracellular levels of adenosine. These findings reveal the existence of a glial relay circuit that controls feeding behavior, one that might serve as a target for therapeutic intervention in the treatment of appetite disorders. PMID- 25921536 TI - A systems approach identifies networks and genes linking sleep and stress: implications for neuropsychiatric disorders. AB - Sleep dysfunction and stress susceptibility are comorbid complex traits that often precede and predispose patients to a variety of neuropsychiatric diseases. Here, we demonstrate multilevel organizations of genetic landscape, candidate genes, and molecular networks associated with 328 stress and sleep traits in a chronically stressed population of 338 (C57BL/6J * A/J) F2 mice. We constructed striatal gene co-expression networks, revealing functionally and cell-type specific gene co-regulations important for stress and sleep. Using a composite ranking system, we identified network modules most relevant for 15 independent phenotypic categories, highlighting a mitochondria/synaptic module that links sleep and stress. The key network regulators of this module are overrepresented with genes implicated in neuropsychiatric diseases. Our work suggests that the interplay among sleep, stress, and neuropathology emerges from genetic influences on gene expression and their collective organization through complex molecular networks, providing a framework for interrogating the mechanisms underlying sleep, stress susceptibility, and related neuropsychiatric disorders. PMID- 25921537 TI - DNA-damage-induced type I interferon promotes senescence and inhibits stem cell function. AB - Expression of type I interferons (IFNs) can be induced by DNA-damaging agents, but the mechanisms and significance of this regulation are not completely understood. We found that the transcription factor IRF3, activated in an ATM IKKalpha/beta-dependent manner, stimulates cell-autonomous IFN-beta expression in response to double-stranded DNA breaks. Cells and tissues with accumulating DNA damage produce endogenous IFN-beta and stimulate IFN signaling in vitro and in vivo. In turn, IFN acts to amplify DNA-damage responses, activate the p53 pathway, promote senescence, and inhibit stem cell function in response to telomere shortening. Inactivation of the IFN pathway abrogates the development of diverse progeric phenotypes and extends the lifespan of Terc knockout mice. These data identify DNA-damage-response-induced IFN signaling as a critical mechanism that links accumulating DNA damage with senescence and premature aging. PMID- 25921538 TI - APP metabolism regulates tau proteostasis in human cerebral cortex neurons. AB - Accumulation of Abeta peptide fragments of the APP protein and neurofibrillary tangles of the microtubule-associated protein tau are the cellular hallmarks of Alzheimer's disease (AD). To investigate the relationship between APP metabolism and tau protein levels and phosphorylation, we studied human-stem-cell-derived forebrain neurons with genetic forms of AD, all of which increase the release of pathogenic Abeta peptides. We identified marked increases in intracellular tau in genetic forms of AD that either mutated APP or increased its dosage, suggesting that APP metabolism is coupled to changes in tau proteostasis. Manipulating APP metabolism by beta-secretase and gamma-secretase inhibition, as well as gamma secretase modulation, results in specific increases and decreases in tau protein levels. These data demonstrate that APP metabolism regulates tau proteostasis and suggest that the relationship between APP processing and tau is not mediated solely through extracellular Abeta signaling to neurons. PMID- 25921539 TI - Innate and adaptive immune functions of peyer's patch monocyte-derived cells. AB - Peyer's patches (PPs) are primary inductive sites of mucosal immunity. Defining PP mononuclear phagocyte system (MPS) is thus crucial to understand the initiation of mucosal immune response. We provide a comprehensive analysis of the phenotype, distribution, ontogeny, lifespan, function, and transcriptional profile of PP MPS. We show that monocytes give rise to macrophages and to lysozyme-expressing dendritic cells (LysoDCs), which are both involved in particulate antigen uptake, display strong innate antiviral and antibacterial gene signatures, and, upon TLR7 stimulation, secrete IL-6 and TNF, but neither IL 10 nor IFNgamma. However, unlike macrophages, LysoDCs display a rapid renewal rate, strongly express genes of the MHCII presentation pathway, and prime naive helper T cells for IFNgamma production. Our results show that monocytes differentiate locally into LysoDCs and macrophages, which display distinct features from their adjacent villus counterparts. PMID- 25921540 TI - Degree of recruitment of DOT1L to MLL-AF9 defines level of H3K79 Di- and tri methylation on target genes and transformation potential. AB - The MLL gene is a common target of chromosomal translocations found in human leukemia. MLL-fusion leukemia has a consistently poor outcome. One of the most common translocation partners is AF9 (MLLT3). MLL-AF9 recruits DOT1L, a histone 3 lysine 79 methyltransferase (H3K79me1/me2/me3), leading to aberrant gene transcription. We show that DOT1L has three AF9 binding sites and present the nuclear magnetic resonance (NMR) solution structure of a DOT1L-AF9 complex. We generate structure-guided point mutations and find that they have graded effects on recruitment of DOT1L to MLL-AF9. Chromatin immunoprecipitation sequencing (ChIP-seq) analyses of H3K79me2 and H3K79me3 show that graded reduction of the DOT1L interaction with MLL-AF9 results in differential loss of H3K79me2 and me3 at MLL-AF9 target genes. Furthermore, the degree of DOT1L recruitment is linked to the level of MLL-AF9 hematopoietic transformation. PMID- 25921542 TI - Cholangiocyte senescence caused by lysophosphatidylcholine as a potential implication in carcinogenesis. AB - BACKGROUND: The incidence of biliary tract cancer in patients with pancreaticobiliary maljunction or intrahepatic cholelithiasis is markedly high with undefined mechanism. In these diseases, biliary lysophosphatidylcholine (LPC) level is reportedly increased. This study investigated the influence of LPC on cholangiocytes focusing on cellular senescence and its potential contribution to carcinogenesis. METHODS: Cultured MMNK-1, an immortalized human cholangiocyte was treated with LPC in vitro and its effect was evaluated. RESULTS: Lysophosphatidylcholine demonstrated cytotoxicity with generation of intracellular reactive oxygen species. Accordingly, LPC provoked oxidative DNA injury, whereas the gene expressions of DNA repair enzyme (OGG1, MUTYH, MTH1) remained unchanged. Interestingly, LPC caused global DNA hypomethylation, which is frequently observed in cancer tissues. Microarray analysis identified differentially regulated genes in response to LPC, which included the components of senescence-associated secretory phenotype (SASP) including interleukin-8 (IL 8), IL-6, transforming growth factor-beta and plasminogen activator inhibitor-1. Significant induction of these genes was further confirmed by quantitative real time polymerase chain reaction. In addition to upregulation of p21 gene expression, senescence-associated beta-galactosidase activity, a widely used marker of cellular senescence was significantly induced by the treatment of LPC. CONCLUSIONS: Based on these data, cholangiocyte senescence and SASP caused by LPC are potential pathogenic mechanisms in the development of biliary tract cancer. PMID- 25921541 TI - Increased expression of the PI3K enhancer PIKE mediates deficits in synaptic plasticity and behavior in fragile X syndrome. AB - The PI3K enhancer PIKE links PI3K catalytic subunits to group 1 metabotropic glutamate receptors (mGlu1/5) and activates PI3K signaling. The roles of PIKE in synaptic plasticity and the etiology of mental disorders are unknown. Here, we show that increased PIKE expression is a key mediator of impaired mGlu1/5 dependent neuronal plasticity in mouse and fly models of the inherited intellectual disability fragile X syndrome (FXS). Normalizing elevated PIKE protein levels in FXS mice reversed deficits in molecular and cellular plasticity and improved behavior. Notably, PIKE reduction rescued PI3K-dependent and independent neuronal defects in FXS. We further show that PI3K signaling is increased in a fly model of FXS and that genetic reduction of the Drosophila ortholog of PIKE, CenG1A rescued excessive PI3K signaling, mushroom body defects, and impaired short-term memory in these flies. Our results demonstrate a crucial role of increased PIKE expression in exaggerated mGlu1/5 signaling causing neuronal defects in FXS. PMID- 25921543 TI - Education for cardiac arrest--Treatment or prevention? AB - In-hospital cardiac arrests (IHCA) occur infrequently and individual staff members working on general wards may only rarely encounter one. Mortality following IHCA is high and the evidence for the benefits of many advanced life support (ALS) interventions is scarce. Nevertheless, regular, often frequent, ALS training is mandatory for many hospital medical staff and nurses. The incidence of pre-cardiac arrest deterioration is much higher than that of cardiac arrests, and there is evidence that intervention prior to cardiac arrest can reduce the incidence of IHCA. This article discusses a proposal to reduce the emphasis on widespread ALS training and to increase education in the recognition and response to pre-arrest clinical deterioration. PMID- 25921544 TI - Neurological prognostication after cardiac arrest and targeted temperature management 33 degrees C versus 36 degrees C: Results from a randomised controlled clinical trial. AB - BACKGROUND: The reliability of some methods of neurological prognostication after out-of-hospital cardiac arrest has been questioned since the introduction of induced hypothermia. The aim of this study was to determine whether different treatment temperatures after resuscitation affected the prognostic accuracy of clinical neurological findings and somatosensory evoked potentials (SSEP) in comatose patients. METHODS: We calculated sensitivity and false positive rate for Glasgow Coma Scale motor score (GCS M), pupillary and corneal reflexes and SSEP to predict poor neurological outcome using prospective data from the Target Temperature Management after Out-of-Hospital Cardiac Arrest Trial which randomised 939 comatose survivors to treatment at either 33 degrees C or 36 degrees C. Poor outcome was defined as severe disability, vegetative state or death (Cerebral Performance Category scale 3-5) at six months. RESULTS: 313 patients (33%) were prognostically assessed; 168 in the 33 degrees C, and 145 in the 36 degrees C group. A GCS M <= 2 had a false positive rate of 19.1% to predict poor outcome due to nine false predictions. Bilaterally absent pupillary reflexes had a false positive rate of 2.1% and absent corneal reflexes had a false positive rate of 2.2% due to one false prediction in each group. The false positive rate for bilaterally absent SSEP N20-peaks was 2.6%. CONCLUSIONS: Bilaterally absent pupillary and corneal reflexes and absent SSEP N20-peaks were reliable markers of a poor prognosis after resuscitation from out-of-hospital cardiac arrest but low GCS M score was not. The reliability of the tests was not altered by the treatment temperature. PMID- 25921545 TI - Nutrition and physical activity on hypertension: implication of current evidence and guidelines. AB - Hypertension (HTN) is the leading cause of worldwide mortality and is responsible for approximately 40% of deaths from cardiovascular disease, chronicle kidney disease (CKD) and type 2 diabetes mellitus (T2DM) according to the World Health Organization (WHO). It is known that about 80% of all mortality from cardiovascular disorders could be prevented if a healthy diet and higher levels of physical activity were included among general population's lifestyle. Besides, guidelines for the treatment and control of HTN were recently modified for adequate nutritional and physical activity recommendations highlighted in meta analysis and strong evidences such as randomized clinical trials. Therefore, to discuss nutrition and physical activity in the context of HTN seems to be crucial. PMID- 25921547 TI - Tobacco industry sought to prevent Islamic fatwas against smoking. PMID- 25921546 TI - Role of polysaccharides in food, digestion, and health. AB - Polysaccharides derived from plant foods are major components of the human diet, with limited contributions of related components from fungal and algal sources. In particular, starch and other storage carbohydrates are the major sources of energy in all diets, while cell wall polysaccharides are the major components of dietary fiber. We review the role of these components in the human diet, including their structure and distribution, their modification during food processing and effects on functional properties, their behavior in the gastrointestinal tract, and their contribution to healthy diets. PMID- 25921548 TI - Silencing of miR-101 Prevents Cartilage Degradation by Regulating Extracellular Matrix-related Genes in a Rat Model of Osteoarthritis. AB - Osteoarthritis (OA) is a common, degenerative joint disease characterized by articular cartilage degradation. Currently, clinical trials based on microRNA therapy have been performed to treat various diseases. However, no treatment has been found for arthritis. This study investigated the functions of miR-101 in cartilage degradation in vivo and evaluated the feasibility of using miR-101 as a therapeutic agent for OA. Mono-iodoacetate-induced arthritis (MIA) rats were used as an animal model of OA. miR-101 mimic or miR-101 inhibitor was injected into the rats' knees to evaluate its effects on cartilage degradation. Cartilage degradation aggravated at 14 days after the injection of miR-101 mimic. By contrast, miR-101 silencing reduced cartilage degradation. Moreover, the administration of miR-101 mimic is sufficient to cause cartilage degradation in the normal cartilage of rats. By contrast, miR-101 inhibitor could prevent this change. Microarray and qPCR were used to investigate the different expressed genes after injecting miR-101 mimic and miR-101 inhibitor in the rats' articular cartilage. Several cartilage degradation-related genes were selected and validated to function in cartilage degradation with miR-101. Our results demonstrated the therapeutic effect of miR-101 inhibition on cartilage degradation in MIA rats by regulating several cartilage degradation-related genes. PMID- 25921549 TI - Extreme delta brush guides to the diagnosis of anti-NMDAR encephalitis. AB - Anti-N-methyl-D-aspartate receptor (anti-NMDAR) encephalitis is a treatable but often misdiagnosed autoimmune encephalitis. Diagnosis depends on NMDAR antibody testing, which may not be readily available. Alternatively, the electroencephalogram (EEG) extreme delta brush pattern may provide a valuable immediate indicator for the diagnosis of anti-NMDAR encephalitis. A 32-year-old female (case 1) presented with fever, headache, behavioral changes, confusion, intractable seizures, central hypoventilation, dysautonomia, facial and limb dyskinesias, and comorbid ovarian teratoma. Cerebral spinal fluid (CSF) testing revealed mild lymphocytic pleocytosis while brain MRI results were normal. A 45 year-old male (case 2) presented with major behavioral changes and rare seizures. Results of routine CSF testing and brain MRI scanning were unremarkable. In both cases, EEG initially revealed the extreme delta brush (EDB) pattern of beta bursting on the peaks and/or the troughs of delta waves, which led to subsequent NMDAR antibody testing and the confirmative diagnosis. Thus, EDB may be a readily accessible sign for suspected anti-NMDAR encephalitis. PMID- 25921550 TI - Associations between polymorphisms in the SYK promoter and susceptibility to sporadic colorectal cancer in a Southern Han Chinese population - a short report. AB - PURPOSE: Down-regulated expression of the putative tumor suppressor gene spleen tyrosine kinase (SYK) is strongly associated with the development of various cancers, including colorectal cancer (CRC). SYK gene promoter polymorphisms have been shown to be involved in the pathogenesis of multiple malignant tumors. In this study, we investigated associations of SYK gene promoter polymorphisms with the susceptibility to colorectal cancer development in a Southern Han Chinese population. METHODS: SNPs in the promoter region of the human SYK gene were identified using in silico analysis tools, linkage disequilibrium analysis, and a search for likely transcription factor binding sites via TFSEARCH in the NCBI SNP database (gene ID: 6850). Based on this information, -803A>T and -534T>C were selected as candidates for further analysis. TaqMan-MGB probe analyses were performed in 567 CRC patients and 569 age- and gender-matched healthy controls for SYK gene promoter genotyping. Associations between CRC risk and SNPs were estimated using an unconditional logistic regression model, and environmental risk factors were included in a multivariate logistic regression model for correction. RESULTS: The frequencies of the TA and TT genotypes and the T allele of the -803A>T SNP were found to be significantly higher in the CRC patients compared to the healthy individuals of the control group (P=0.020, 0.023, and 0.013, respectively). Synergistic effects between -803A>T genotypes (i.e., TA+TT) and age (<=60 years; P=0.039), male gender (P=0.011), smoking (P=0.005), drinking alcohol (P=0.002), and high BMI (>=24.0 kg/m2; P=0.009) were found to increase the risk to develop CRC by stratified analyses. CONCLUSIONS: The SYK -803 A>T genotypes TA and TT are independent risk factors for CRC development in Han Chinese in Southern China, and an association with TA+TT genotypes appears predominant among younger patients, male patients, patients with a high BMI, and patients who smoke or drink alcohol. PMID- 25921551 TI - Modafinil combined with cognitive training: pharmacological augmentation of cognitive training in schizophrenia. AB - Several efforts to develop pharmacological treatments with a beneficial effect on cognition in schizophrenia are underway, while cognitive remediation has shown modest effects on cognitive performance. Our goal was to test if pharmacological augmentation of cognitive training would result in enhancement of training induced learning. We chose modafinil as the pharmacological augmenting agent, as it is known to have beneficial effects on learning and cognition. 49 participants with chronic schizophrenia were enroled in a double-blind, placebo-controlled study across two sites and were randomised to either modafinil (200mg/day) or placebo. All participants engaged in a cognitive training program for 10 consecutive weekdays. The primary outcome measure was the performance on the trained tasks and secondary outcome measures included MATRICS cognitive battery, proxy measures of everyday functioning and symptom measures. 84% of the participants completed all study visits. Both groups showed significant improvement in the performance of the trained tasks suggesting potential for further learning. Modafinil did not induce differential enhancement on the performance of the trained tasks or any differential enhancement of the neuropsychological and functional measures compared to placebo. Modafinil showed no significant effects on symptom severity. Our study demonstrated that combining pharmacological compounds with cognitive training is acceptable to patients and can be implemented in large double-blind randomised controlled trials. The lack of differential enhancement of training-induced learning raises questions, such as choice and optimal dose of drug, cognitive domains to be trained, type of cognitive training, intervention duration and chronicity of illness that require systematic investigation in future studies. PMID- 25921553 TI - Rifampicin-dependent antibodies target glycoprotein IIb/IIIa and cause clearance of human platelets in NOD/SCID mice. PMID- 25921552 TI - Gait behaviors as an objective surgical outcome in low back disorders: A systematic review. AB - BACKGROUND: Objective motor performance measures, especially gait assessment, could improve evaluation of low back disorder surgeries. However, no study has compared the relative effectiveness of gait parameters for assessing motor performance in low back disorders after surgery. The purpose of the current review was to determine the sensitive gait parameters that address physical improvements in each specific spinal disorder after surgical intervention. METHODS: Articles were searched with the following inclusion criteria: 1) population studied consisted of individuals with low back disorders requiring surgery; 2) low back disorder was measured objectively using gait assessment tests pre- and post-surgery. The quality of the selected studies was assessed using Delphi consensus, and meta-analysis was performed to compare pre- and post surgical changes. FINDINGS: Thirteen articles met inclusion criteria, which, almost exclusively, addressed two types of spinal disorders/interventions: 1) scoliosis/spinal fusion; and 2) stenosis/decompression. For patients with scoliosis, improvements in hip and shoulder motion (effect size=0.32-1.58), energy expenditure (effect size=0.59-1.18), and activity symmetry of upper-body muscles during gait were present after spinal fusion. For patients with spinal stenosis, increases in gait speed, stride length, cadence, symmetry, walking smoothness, and walking endurance (effect size=0.60-2.50), and decrease in gait variability (effect size=1.45) were observed after decompression surgery. INTERPRETATION: For patients with scoliosis, gait improvements can be better assessed by measuring upper-body motion and EMG rather than the lower extremities. For patients with spinal stenosis, motor performance improvements can be captured by measuring walking spatio-temporal parameters, gait patterns, and walking endurance. PMID- 25921554 TI - Auricular therapy for chronic pain management in adults: A synthesis of evidence. AB - OBJECTIVE: To evaluate the efficacy and safety of auricular therapy (AT) on chronic pain. METHODS: A systematic review. Randomized controlled trials investigating AT for chronic pain were retrieved and RevMan 5.3 was used for meta analysis. RESULTS: Fifteen trials were included. The overall assessment indicated that AT could be a promising intervention for chronic pain relief. Meta-analyses showed that AT decreased pain intensity, especially for chronic low back pain and chronic tension headache. The lasting effect of AT was not obvious, and it began to diminish 3 months after the completion of treatment. CONCLUSIONS: AT may positively control pain intensity for patients with chronic pain. However, due to the significant heterogeneity and methodological flaws identified in the analyzed trials, the current evidence on AT for chronic pain management is still uncertain. More rigorously designed large-scale randomized controlled trials are required to evaluate the efficacy of AT for patients with chronic pain. PMID- 25921555 TI - Characterization of the key aroma compounds in a commercial Amontillado sherry wine by means of the sensomics approach. AB - An aroma extract dilution analysis (AEDA) carried out on the volatile fraction isolated by extraction/solvent-assisted flavor evaporation (SAFE) distillation from a commercial Amontillado sherry wine revealed 37 odor-active compounds with flavor dilution (FD) factors in the range of 16-4096. Among them, 2-phenylethanol (flowery, honey-like) and ethyl methylpropanoate (fruity) showed the highest FD factors, followed by ethyl (2S,3S)-2-hydroxy-3-methylpentanoate (fruity) reported for the first time in sherry wine. A total of 36 aroma-active compounds located by AEDA were then quantitated by a stable isotope dilution assay, and their odor activity values (OAVs; ratio of concentration to odor threshold) were calculated. The highest OAV was displayed by 1,1-diethoxyethane (2475; fruity), followed by 2 and 3-methylbutanals (574; malty) and methylpropanal (369; malty). Aroma reconstitution experiments and a comparative aroma profile analysis revealed that the entire orthonasal aroma profile of the Amontillado sherry wine could be closely mimicked. PMID- 25921556 TI - Analysis of the Reasons for Non-Uptake of Predictive Testing for Huntington's Disease in Spain: A Qualitative Study. AB - Children of persons affected by Huntington's disease (HD) have a 50% chance of inheriting the disease. Genetic testing in Spain is offered to individuals (presymptomatic test) or mothers of fetuses (prenatal) who run the risk of suffering from HD. The objective of this study is to analyze the factors that influence the decisions of adult children of persons affected with HD regarding predictive testing. A qualitative research methodology was used involving 4 focus groups (FGs) made up of adult children of persons with HD in different cities in Spain. The results of the study showed that over half of the focus group participants were inclined to decline genetic testing. The main explanatory determinants for taking or not taking the predictive test are: Maturity of the individual at risk, which was directly related to age; Ability to cope with a positive test result; Experience of living with HD sufferers; Information about testing and psychological support; Attitude of the family; Social visibility of genetic testing; Personality and temperament of each subject at risk of HD. These results imply that these factors should be analyzed in more detail in quantitative studies in order to help the Spanish Department of Health understand why some children of parents with HD decline genetic testing, so that they may and apply these data when creating specific policy regarding this issue. PMID- 25921557 TI - Plasma galectin-3 predicts clinical outcomes after catheter ablation in persistent atrial fibrillation patients without structural heart disease. AB - AIMS: This study sought to explore the relationship between plasma galectin-3 (Gal-3) and persistent atrial fibrillation (PsAF), and investigate whether Gal-3 predicts clinical outcomes in patients with PsAF undergoing catheter ablation. METHODS: Fifty consecutive PsAF patients without coexisting structural heart disease undergoing first-time catheter ablation and 46 healthy controls were included. Blood samples were collected on admission for analysis of plasma Gal-3. Pre-ablation clinical and laboratory data were also recorded. Persistent atrial fibrillations patients were followed after ablation and AF recurrence was defined as episodes of AF or atrial tachycardia lasting >30 s after the blanking period. RESULTS: Plasma Gal-3 concentrations were higher in PsAF patients than in healthy controls (P < 0.001). In PsAF group, those with AF recurrence had higher plasma Gal-3 than did those without recurrence (P = 0.007). Both Gal-3 (hazard ratio 1.28, P = 0.006) and left atrial diameter (LAD) (hazard ratio 1.1, P = 0.025) were independent predictors of AF recurrence after ablation. Moreover, adding Gal 3 to LAD had an incremental predictive value for ablation outcomes (global chi(2) of LAD alone: 8.2; LAD and Gal-3 concentrations: 15.7; P = 0.006). CONCLUSION: Plasma Gal-3 concentrations are elevated in PsAF patients without structural heart disease and independently predict AF recurrence after ablation. Plasma Gal 3 concentration may be helpful in identifying appropriate candidates for AF ablation. PMID- 25921558 TI - Traditional vs. genetic pathogenesis of arrhythmogenic right ventricular cardiomyopathy. AB - Arrhythmogenic right ventricular cardiomyopathy (ARVC), a predominantly familial and autosomal dominant inherited heart muscle disorder, is pathologically characterized by progressive right ventricular myocardial atrophy and fibrofatty replacement and clinically by ventricular arrhythmias with left bundle branch block morphology. Symptoms poorly reflect disease severity, with disease commonly first manifesting as sudden death among the young. The inflammatory and apoptotic theories first put forth to explain ARVC pathogenesis do not explain all cases, and advances in genetic technology have allowed to elucidate genetic mechanisms, with desmosomal mutations attracting much attention. As reviewed here, various non-mutually exclusive pathogenetic mechanisms therefore appear to underlie ARVC. PMID- 25921559 TI - A hot water extract of Curcuma longa inhibits adhesion molecule protein expression and monocyte adhesion to TNF-alpha-stimulated human endothelial cells. AB - The recruitment of arterial leukocytes to endothelial cells is an important step in the progression of various inflammatory diseases. Therefore, its modulation is thought to be a prospective target for the prevention or treatment of such diseases. Adhesion molecules on endothelial cells are induced by proinflammatory cytokines, including tumor necrosis factor-alpha (TNF-alpha), and contribute to the recruitment of leukocytes. In the present study, we investigated the effect of hot water extract of Curcuma longa (WEC) on the protein expression of adhesion molecules, monocyte adhesion induced by TNF-alpha in human umbilical vascular endothelial cells (HUVECs). Treatment of HUVECs with WEC significantly suppressed both TNF-alpha-induced protein expression of adhesion molecules and monocyte adhesion. WEC also suppressed phosphorylation and degradation of nuclear factor of kappa light polypeptide gene enhancer in B-cells inhibitor, alpha (IkappaBalpha) induced by TNF-alpha in HUVECs, suggesting that WEC inhibits the NF-kappaB signaling pathway. PMID- 25921560 TI - Oleanolic Acid Improves Gut Atrophy Induced by Parenteral Nutrition. AB - BACKGROUND: Nutrition support with parenteral nutrition (PN) is associated with gut atrophy. Prior studies have shown improvement with enteral chenodeoxycholic acid, a dual agonist for the farnesoid X receptor (FXR) and bile acid receptor TGR5. We hypothesized that gut growth is induced by TGR5 activation, and gut atrophy during PN administration could be prevented with the TGR5-specific agonist oleanolic acid (OA). METHODS: Neonatal pigs were implanted with duodenal and jugular vein catheters. Animals were provided equi-nutritious PN or enteral swine milk. A PN subgroup received enteral OA at 50 mg/kg/d. RESULTS: PN caused marked gut atrophy compared with enterally fed (EN) control animals. OA treatment led to preservation of gut mass demonstrated grossly and histologically. The mean +/- SD gut weight as a percentage of body weight was 4.30 +/- 0.26 for EN, 1.92 +/- 0.06 for PN (P < .05, EN vs PN), and 3.39 +/- 0.79 for PN+OA (P < .05, PN+OA vs PN). Mean +/- SD gut density (g/cm) was 0.31 +/- 0.03 for EN, 0.18 +/- 0.03 for PN (P < .05 EN vs PN), and 0.27 +/- 0.01 for PN+OA (P < .05 PN+OA vs PN). Histologically, a markedly decreased villous to crypt ratio was noted with PN, and OA significantly prevented this decrease. The mean +/- SD v/c ratio was 3.51 +/- 0.59 for EN, 1.69 +/- 0.10 for PN (P < .05, EN vs PN), and 2.90 +/- 0.23 for PN+OA (P < .05, PN+OA vs PN). Gut TGR5 messenger RNA expression was significantly elevated with OA treatment compared with both PN and EN. CONCLUSION: The bile acid-activated G protein-coupled receptor TGR5 agonist OA prevented gut atrophy associated with PN. PMID- 25921561 TI - Parenteral Nutrition Utilization After Implementation of Multidisciplinary Nutrition Support Team Oversight: A Prospective Cohort Study. AB - BACKGROUND: Multidisciplinary nutrition teams can help guide the use of parenteral nutrition (PN), thereby reducing infectious risk, morbidity, and associated costs. Starting in 2007 at Harborview Medical Center, weekly multidisciplinary meetings were established to review all patients receiving PN. This study reports on observed changes in utilization from 2005-2010. MATERIALS AND METHODS: All patients who received PN from 2005-2010 were followed prospectively. Clinical data and PN utilization data were recorded. Patients were grouped into cohorts based on exposure to weekly multidisciplinary nutrition team meetings (from 2005-2007 and from 2008-2010). Patients were also stratified by location, primary service, and ultimate disposition. RESULTS: In total, 794 patients were included. After initiation of multidisciplinary nutrition meetings, the rate of patients who started PN decreased by 27% (relative risk [RR], 0.73; 95% confidence interval [CI], 0.63-0.84). A reduction in the number of patients receiving PN was observed in both the intensive care unit (ICU) and on the acute care floor (RR, 0.64; 95% CI, 0.53-0.77 and RR, 0.80; 95% CI, 0.64-0.99, respectively). The rate of patients with short-duration PN use (PN duration of <5 days) declined by 30% in the ICU (RR, 0.70; 95% CI, 0.51-0.97) and by 27% on acute care floors (RR, 0.73; 95% CI, 0.51-1.03). CONCLUSIONS: Weekly multidisciplinary review of patients receiving PN was associated with reductions in the number of patients started on PN, total days that patients received PN, and number of patients who had short-duration (<5 days) PN use. PMID- 25921562 TI - Antifertility activity of medicinal plants. AB - The aim of this review was to provide a comprehensive summary of medicinal plants used as antifertility agents in females throughout the world by various tribes and ethnic groups. We undertook an extensive bibliographic review by analyzing classical text books and peer reviewed papers, and further consulting well accepted worldwide scientific databases. We performed CENTRAL, Embase, and PubMed searches using terms such as "antifertility", "anti-implantation", "antiovulation", and "antispermatogenic" activity of plants. Plants, including their parts and extracts, that have traditionally been used to facilitate antifertility have been considered as antifertility agents. In this paper, various medicinal plants have been reviewed for thorough studies such as Polygonum hydropiper Linn, Citrus limonum, Piper nigrum Linn, Juniperis communis, Achyanthes aspera, Azadirachta indica, Tinospora cordifolia, and Barleria prionitis. Many of these medicinal plants appear to act through an antizygotic mechanism. This review clearly demonstrates that it is time to expand upon experimental studies to source new potential chemical constituents from medicinal plants; plant extracts and their active constituents should be further investigated for their mechanisms. This review creates a solid foundation upon which to further study the efficacy of plants that are both currently used by women as traditional antifertility medicines, but also could be efficacious as an antifertility agent with additional research and study. PMID- 25921563 TI - Brow/Upper lid anatomy, aging and aesthetic analysis. AB - The upper eyelid serves the important anatomic function of protecting the eye and rewetting the cornea to maintain vision. The complex dynamic action of the upper eyelid explains its relatively complex anatomy. The brow has an important supportive role. Studies have revealed facial characteristics perceived as youthful and aged, and the anatomic basis of these changes is defined at many levels. Characteristic aging changes in the upper eyelid and brow create an appearance of aging and opportunities for functional and aesthetic improvement. PMID- 25921564 TI - Midface anatomy, aging, and aesthetic analysis. AB - This article reviews the key anatomic structures in the region of the midface, including important surface and bony landmarks, innervation, blood supply, muscle layers, and fat compartments. It also discusses changes in these structures related to the aging process and aesthetic analysis of the midface to aid with operative planning. PMID- 25921565 TI - Minimally invasive surgical adjuncts to upper blepharoplasty. AB - A variety of surgical adjuncts can be added to upper eyelid blepharoplasty with the goal of enhancing surgical results and patient satisfaction. All of these procedures are minimally invasive and most are performed through a standard eyelid crease incision. These procedures can be added to stabilize or conservatively lift the outer brow, prevent the stigmata of postoperative volume loss, improve the brow-eyelid transition and contour, and reposition a prolapsed lacrimal gland. The procedures are generally straightforward, easily learned, and complication free. Familiarity with these techniques provides the aesthetic eyelid surgeon with added options to improve surgical results. PMID- 25921566 TI - Minimally invasive options for the brow and upper lid. AB - Eyebrow and upper eyelid aging occurs in all tissue planes, and manifests most commonly in skin quality, tissue volume loss (soft tissue and bone), and tissue descent. All these involutional changes are amenable to less-invasive (nonsurgical) interventions with natural and aesthetically pleasing results. It is critical for aesthetic facial surgeons to familiarize themselves with these procedures because they are in high demand by patients. This article outlines current concepts of nonsurgical management options for brow and upper eyelid aging. The anatomy and age-related changes in these structures are reviewed, and minimally invasive techniques to address these changes are detailed. PMID- 25921567 TI - Surgical treatment of the brow and upper eyelid. AB - Surgical management of the aging upper face has taken on a critical role in total facial rejuvenation, with a variety of techniques available. The hallmarks of the aging upper third of the face and periorbital region most commonly manifest as rhytids, brow descent, prolapse of periorbital fat, dermatochalasis, and volume loss and hollowing. The surrounding structures should be assessed individually and their relationships carefully analyzed to guide selection of the appropriate treatment. In this article, the authors explore the various approaches and techniques available for rejuvenation of the upper face, including the upper periorbital region. PMID- 25921568 TI - Midface skeletal enhancement. AB - Alloplastic malar augmentation offers a reliable means of achieving a permanent, yet reversible, form of midfacial volume enhancement that serves to correct the changes associated with facial aging, hypoplasia, and congenital malar asymmetry. The degree of augmentation depends on the severity of existing malar bony hypoplasia, soft tissue volume loss/ptosis, or both. Facial aesthetic surgeons have a multitude of implant designs and shapes and implant materials available. The transoral surgical approach with transcutaneous implant suture stabilization is the most commonly used surgical protocol in alloplastic midface augmentation and is, therefore, the technique specifically chosen for review in this article. PMID- 25921569 TI - Management of the midface during rhytidectomy. AB - No nonsurgical technique can come close to rejuvenating the face like a cervicofacial rhytidectomy. However, one of the most difficult areas to improve during a facelift is the midface. The multi-vector high superficial musculoaponeurotic system (SMAS) facelift and extended lower-lid midface lift are important techniques that can adequately address the midface during rhytidectomy. The multi-vector high SMAS facelift is a natural extension of a traditional SMAS plication or imbrication facelift. The extended lower-lid midface lift can be an important adjunct during a facelift or as an independent procedure to address the midface. PMID- 25921570 TI - Endoscopic midfacial rejuvenation. AB - Early facial rejuvenation focused largely on the upper and lower thirds of the face. More recently, improvements in understanding of midfacial aging and anatomy have paralleled the development of endoscopic and minimally invasive surgical techniques. The midface is now understood to include both the lower lid subunit and the cheek down to the nasolabial fold. Many surgical techniques for midface rejuvenation have been used, including skin tightening with direct excision, skin muscle flaps, isolated fat pad transposition, and subperiosteal lifting. The methods of endoscopic subperiosteal midface lifting and endoscopic malar fat pad lifting are discussed. PMID- 25921571 TI - Transpalpebral midface lift. AB - Aging of the midface is a complex aesthetic problem requiring an individualized and multifaceted surgical approach. The objective of harmonious rejuvenation of the entire face as well as increasing patient interest in midface rejuvenation mandates surgical familiarity with these techniques. Midface rejuvenation procedures have evolved from traditional laterally based rhytidectomy techniques with superolateral elevation to modern centrofacial approaches designed to achieve more vertical vectors of elevation. These approaches are informed by an evolving understanding of the multiple processes that contribute to the aged appearance of the midface and are based on lower blepharoplasty surgical techniques. PMID- 25921572 TI - Midface sculpting with autologous fat. AB - There is currently a major paradigm shift from excision-based surgery to strictly volume enhancement. Because there is still no perfect facial filler, development of synthetic facial injectables continue to advance at a remarkable pace. Each type of filler carries a specific characteristic that makes it more suitable for a certain clinical application. The continuing change in facial fillers offers the possibility for volume augmentation procedures with less downtime and without the need for harvesting fat. We predict that volume enhancement will continue to play an increasing role as both a complementary and as a stand-alone procedure in facial rejuvenation. PMID- 25921573 TI - Midface volumization with injectable fillers. AB - The aging midface has long been overlooked in cosmetic surgery. Our understanding of facial aging in terms of 3 dimensions has placed increased importance on volume restoration. Although an "off-label" indication for most fillers in this facial region, volumization of the midface with injectable fillers is usually a safe and straightforward procedure technically. Injectors, nevertheless, need to have an excellent understanding of facial anatomy and the characteristics of the injected products should problems arise. PMID- 25921574 TI - The role of neurotoxins in the periorbital and midfacial areas. AB - Initially popularized for the treatment of strabismus and blepharospasm, injection of botulinum neurotoxin has become the most commonly performed cosmetic treatment in the United States. Injection techniques have been particularly well studied in the midface and periocular region, and patient satisfaction tends to be very high. We review the salient differences among available neurotoxins, how to optimally reconstitute them, how to inject the forehead, glabella, lateral canthal lines ("crow's feet"), infralid region, and transverse nasal lines ("bunny lines"), how to sculpt the brow, and how to manage potential complications. PMID- 25921575 TI - Avoiding and managing complications in the periorbital area and midface. AB - The eyes play a central role in the perception of facial beauty. The goal of periorbital rejuvenation surgery is to restore youthful proportions and focus attention on the eyes. Blepharoplasty is the third most common cosmetic procedure performed today. Because of the attention placed on the periorbital region, preventing and managing complications is important. Obtaining a thorough preoperative history and physical examination can significantly reduce the incidence of many of the complications. This article focuses on the preoperative evaluation as it relates to preventable complications, followed by common intraoperative and postoperative complications and their management. PMID- 25921577 TI - Possible Involvement of Palmitate in Pathogenesis of Periodontitis. AB - Type 2 diabetes (T2D) is characterized by decreased insulin sensitivity and higher concentrations of free fatty acids (FFAs) in plasma. Among FFAs, saturated fatty acids (SFAs), such as palmitate, have been suggested to promote inflammatory responses. Although many epidemiological studies have shown a link between periodontitis and T2D, little is known about the clinical significance of SFAs in periodontitis. In this study, we showed that gingival fibroblasts have cell-surface expression of CD36, which is also known as FAT/fatty acid translocase. Moreover, CD36 expression was increased in gingival fibroblasts of high-fat diet-induced T2D model mice, compared with gingival fibroblasts of mice fed a normal diet. DNA microarray analysis revealed that palmitate increased mRNA expression of pro-inflammatory cytokines and chemokines in human gingival fibroblasts (HGF). Consistent with these results, we confirmed that palmitate induced interleukin (IL)-6, IL-8, and CXCL1 secretion in HGF, using a cytokine array and ELISA. SFAs, but not an unsaturated fatty acid, oleate, induced IL-8 production. Docosahexaenoic acid (DHA), which is one of the omega-3 polyunsaturated fatty acids, significantly suppressed palmitate-induced IL-6 and IL-8 production. Treatment of HGF with a CD36 inhibitor also inhibited palmitate induced pro-inflammatory responses. Finally, we demonstrated that Porphyromonas gingivalis (P.g.) lipopolysaccharide and heat-killed P.g. augmented palmitate induced chemokine secretion in HGF. These results suggest a potential link between SFAs in plasma and the pathogenesis of periodontitis. PMID- 25921578 TI - IL-15 concentrations in skeletal muscle and subcutaneous adipose tissue in lean and obese humans: local effects of IL-15 on adipose tissue lipolysis. AB - Animal/cell investigations indicate that there is a decreased adipose tissue mass resulting from skeletal muscle (SkM) IL-15 secretion (e.g., SkM-blood-adipose tissue axis). IL-15 could regulate fat mass accumulation in obesity via lipolysis, although this has not been investigated in humans. Therefore, the purpose was to examine whether SkM and/or subcutaneous adipose tissue (SCAT) IL 15 concentrations were correlated with SCAT lipolysis in lean and obese humans and determine whether IL-15 perfusion could induce lipolysis in human SCAT. Local SkM and abdominal SCAT IL-15 (microdialysis) and circulating IL-15 (blood) were sampled in lean (BMI: 23.1 +/- 1.9 kg/m(2); n = 10) and obese (BMI: 34.7 +/- 3.5 kg/m(2); n = 10) subjects at rest/during 1-h cycling exercise. Lipolysis (SCAT interstitial glycerol concentration) was compared against local/systemic IL-15. An additional probe in SCAT was perfused with IL-15 to assess direct lipolytic responses. SkM IL-15 was not different between lean and obese subjects (P = 0.45), whereas SCAT IL-15 was higher in obese vs. lean subjects (P = 0.02) and was correlated with SCAT lipolysis (r = 0.45, P = 0.05). Exercise increased SCAT lipolysis in lean and obese (P < 0.01), but exercise-induced SCAT lipolysis changes were not correlated with exercise-induced SCAT IL-15 changes. Microdialysis perfusion resulting in physiological IL-15 concentrations in the adipose tissue interstitium increased lipolysis in lean (P = 0.04) but suppressed lipolysis in obese (P < 0.01). Although we found no support for a human IL-15 SkM blood-adipose tissue axis, IL-15 may be produced in/act on the abdominal SCAT depot. The extent to which this autocrine/paracrine IL-15 action regulates human body composition remains unknown. PMID- 25921579 TI - Inactivation of PPARbeta/delta adversely affects satellite cells and reduces postnatal myogenesis. AB - Peroxisome proliferator-activated receptor beta/delta (PPARbeta/delta) is a ubiquitously expressed gene with higher levels observed in skeletal muscle. Recently, our laboratory showed (Bonala S, Lokireddy S, Arigela H, Teng S, Wahli W, Sharma M, McFarlane C, Kambadur R. J Biol Chem 287: 12935-12951, 2012) that PPARbeta/delta modulates myostatin activity to induce myogenesis in skeletal muscle. In the present study, we show that PPARbeta/delta-null mice display reduced body weight, skeletal muscle weight, and myofiber atrophy during postnatal development. In addition, a significant reduction in satellite cell number was observed in PPARbeta/delta-null mice, suggesting a role for PPARbeta/delta in muscle regeneration. To investigate this, tibialis anterior muscles were injured with notexin, and muscle regeneration was monitored on days 3, 5, 7, and 28 postinjury. Immunohistochemical analysis revealed an increased inflammatory response and reduced myoblast proliferation in regenerating muscle from PPARbeta/delta-null mice. Histological analysis confirmed that the regenerated muscle fibers of PPARbeta/delta-null mice maintained an atrophy phenotype with reduced numbers of centrally placed nuclei. Even though satellite cell numbers were reduced before injury, satellite cell self-renewal was found to be unaffected in PPARbeta/delta-null mice after regeneration. Previously, our laboratory had showed (Bonala S, Lokireddy S, Arigela H, Teng S, Wahli W, Sharma M, McFarlane C, Kambadur R. J Biol Chem 287: 12935-12951, 2012) that inactivation of PPARbeta/delta increases myostatin signaling and inhibits myogenesis. Our results here indeed confirm that inactivation of myostatin signaling rescues the atrophy phenotype and improves muscle fiber cross-sectional area in both uninjured and regenerated tibialis anterior muscle from PPARbeta/delta-null mice. Taken together, these data suggest that absence of PPARbeta/delta leads to loss of satellite cells, impaired skeletal muscle regeneration, and postnatal myogenesis. Furthermore, our results also demonstrate that functional antagonism of myostatin has utility in rescuing these effects. PMID- 25921580 TI - Dysregulation of low-density lipoprotein receptor contributes to podocyte injuries in diabetic nephropathy. AB - Dyslipidemia plays crucial roles in the progression of diabetic nephropathy (DN). This study investigated the effects of high glucose on lipid accumulation in podocytes and explored its underlying mechanisms. Male db/m and db/db mice were fed a normal chow diet for 8 wk. Immortalised mouse podocytes were treated with or without high glucose for 24 h. The changes to the morphology and ultramicrostructures of the kidneys in mice were examined using pathological staining and electron microscopy. Intracellular lipid accumulation was evaluated by Oil Red O staining and a free cholesterol quantitative assay. The expressions of the molecules involved in low-density lipoprotein receptor (LDLr) pathway and podocyte injury were examined using immunofluorescent staining, real-time PCR, and Western blot. There were increased levels of plasma lipid, serum creatinine, and proteinuria in db/db mice compared with db/m mice. Moreover, there was significant mesangial matrix expansion, basement membrane thickening, podocyte foot process effacement, and phenotypic alteration in the db/db group. Additionally, lipid accumulation in the kidneys of db/db mice was increased due to increased protein expressions of LDLr, sterol regulatory element-binding protein (SREBP) cleavage-activating protein, and SREBP-2. These effects were further confirmed by in vitro studies. Interestingly, the treatment with LDLr siRNA inhibited lipid accumulation in podocytes and decreased the protein expression of molecules associated with phenotypic alteration in podocytes. High glucose disrupted LDLr feedback regulation in podocytes, which may cause intracellular lipid accumulation and alteration of podocyte phenotype, thereby accelerating DN progression. PMID- 25921581 TI - A new alkaline lipase obtained from the metagenome of marine sponge Ircinia sp. AB - Microorganisms associated with marine sponges are potential resources for marine enzymes. In this study, culture-independent metagenomic approach was used to isolate lipases from the complex microbiome of the sponge Ircinia sp. obtained from the South China Sea. A metagenomic library was constructed, containing 6568 clones, and functional screening on 1 % tributyrin agar resulted in the identification of a positive lipase clone (35F4). Following sequence analysis 35F4 clone was found to contain a putative lipase gene lipA. Sequence analysis of the predicted amino acid sequence of LipA revealed that it is a member of subfamily I.1 of lipases, with 63 % amino acid similarity to the lactonizing lipase from Aeromonas veronii (WP_021231793). Based on the predicted secondary structure, LipA was predicted to be an alkaline enzyme by sequence/structure analysis. Heterologous expression of lipA in E. coli BL21 (DE3) was performed and the characterization of the recombinant enzyme LipA showed that it is an alkaline enzyme with high tolerance to organic solvents. The isolated lipase LipA was active in the broad alkaline range, with the highest activity at pH 9.0, and had a high level of stability over a pH range of 7.0-12.0. The activity of LipA was increased in the presence of 5 mM Ca(2+) and some organic solvents, e.g. methanol, acetone and isopropanol. The optimum temperature for the activity of LipA is 40 degrees C and the molecular weight of LipA was determined to be ~30 kDa by SDS-PAGE. LipA is an alkaline lipase and shows good tolerance to some organic solvents, which make it of potential utility in the detergent industry and enzyme mediated organic synthesis. The result of this study has broadened the diversity of known lipolytic genes and demonstrated that marine sponges are an important source for new enzymes. PMID- 25921582 TI - Responses of methanotrophic activity, community and EPS production to CH4 and O2 concentrations in waste biocover soils. AB - Biocover soils are known to be a good alternative material to mitigate CH4 emissions from landfills to the atmosphere. In this study, 16 treatments with four O2 concentrations (~0%, 5%, 10% and 21%) and four CH4 concentrations (i.e. 1%, 10%, 20% and 50%) were conducted to estimate extracellular polymeric substances (EPS) production, methanotrophic activity and community in response to CH4 and O2 concentrations in waste biocover soil (WBS). When the CH4 concentration was saturated for CH4 oxidation in the WBS, the continuous exposure of CH4 above the saturated concentrations could not obviously enhance CH4 oxidation activity. In the WBS, extracellular protein (ECP) production was negatively related with the tested CH4 concentrations, while both ECP and extracellular polysaccharides (ECPS) productions were positively related with the tested O2 concentrations. Cloning and terminal restriction fragment length polymorphism analyses showed that type I methanotrophs (Methylocaldum, Methylococcaceae, Methylomicrobium and Methylobacter) and type II methanotrophs (Methylosinus) dominated in the WBS. Among them, Methylocaldum and/or Methylococcaceae were sensitive to low O2 concentrations of ~0%. Methylobacter had propensity to grow at low O2 concentrations of ~0% and 5%, while Methylosinus preferred environments with high concentrations of CH4 (?10%) and O2 (21%). In the tested five environmental variables of ECPS, O2, EPS, CH4 and ECP, only ECPS and O2 concentrations had significant effect on the methanotrophic communities. These results suggested that O2 concentration in landfill covers should be paid more attention to optimize and sustain CH4 oxidation for mitigating CH4 emission from landfills. PMID- 25921583 TI - Conjunctive Coding of Complex Object Features. AB - Critical to perceiving an object is the ability to bind its constituent features into a cohesive representation, yet the manner by which the visual system integrates object features to yield a unified percept remains unknown. Here, we present a novel application of multivoxel pattern analysis of neuroimaging data that allows a direct investigation of whether neural representations integrate object features into a whole that is different from the sum of its parts. We found that patterns of activity throughout the ventral visual stream (VVS), extending anteriorly into the perirhinal cortex (PRC), discriminated between the same features combined into different objects. Despite this sensitivity to the unique conjunctions of features comprising objects, activity in regions of the VVS, again extending into the PRC, was invariant to the viewpoints from which the conjunctions were presented. These results suggest that the manner in which our visual system processes complex objects depends on the explicit coding of the conjunctions of features comprising them. PMID- 25921585 TI - Effect of feed restriction and subsequent re-alimentation on hormones and genes of the somatotropic axis in cattle. AB - The objective of this study was to characterize the effect of feed restriction and compensatory growth during re-alimentation on the functionality of the somatotropic axis. We blocked 60 bulls into one of two groups: 1) restricted feed allowance for 125 days (period 1) (RES, n = 30) followed by ad libitum feeding for 55 days (period 2) or 2) ad libitum access to feed throughout (ADLIB, n = 30). A growth hormone releasing hormone (GHRH) challenge was performed during each period. At the end of each period, 15 animals from each treatment were slaughtered and hepatic tissue collected. Hepatic expression of 13 genes of the somatotropic axis was measured by qRT-PCR. RES displayed a lower growth rate during period 1 (0.6 vs. 1.9 kg/day; P < 0.001), subsequently gaining more than ADLIB animals during period 2 (2.5 vs. 1.4 kg/day; P < 0.001). Growth hormone response to GHRH was not different between treatments at either time-point (P > 0.05); however, resultant plasma IGF-1 was lower in period 1 and greater in period 2 in RES animals (P < 0.05). Expression of IGFBP2 was higher (P < 0.01) and IGF1 (P < 0.001) and GHRIA (P < 0.05) lower in RES compared with ADLIB during period 1, with no difference evident in period 2 (P > 0.05). Collectively, the results of this study are consistent with uncoupling of the somatotropic axis following feed restriction. However, there is no evidence from this study that the somatotropic axis per se is a significant contributor to compensatory growth. PMID- 25921584 TI - FOXA2 regulates a network of genes involved in critical functions of human intestinal epithelial cells. AB - The forkhead box A (FOXA) family of pioneer transcription factors is critical for the development of many endoderm-derived tissues. Their importance in regulating biological processes in the lung and liver is extensively characterized, though much less is known about their role in intestine. Here we investigate the contribution of FOXA2 to coordinating intestinal epithelial cell function using postconfluent Caco2 cells, differentiated into an enterocyte-like model. FOXA2 binding sites genome-wide were determined by ChIP-seq and direct targets of the factor were validated by ChIP-qPCR and siRNA-mediated depletion of FOXA1/2 followed by RT-qPCR. Peaks of FOXA2 occupancy were frequent at loci contributing to gene ontology pathways of regulation of cell migration, cell motion, and plasma membrane function. Depletion of both FOXA1 and FOXA2 led to a significant reduction in the expression of multiple transmembrane proteins including ion channels and transporters, which form a network that is essential for maintaining normal ion and solute transport. One of the targets was the adenosine A2B receptor, and reduced receptor mRNA levels were associated with a functional decrease in intracellular cyclic AMP. We also observed that 30% of FOXA2 binding sites contained a GATA motif and that FOXA1/A2 depletion reduced GATA-4, but not GATA-6 protein levels. These data show that FOXA2 plays a pivotal role in regulating intestinal epithelial cell function. Moreover, that the FOXA and GATA families of transcription factors may work cooperatively to regulate gene expression genome-wide in the intestinal epithelium. PMID- 25921586 TI - Signaling mechanisms mediating the regulation of synaptic plasticity and memory by estradiol. AB - This article is part of a Special Issue "Estradiol and Cognition". Estradiol participates in the regulation of the function and plasticity of synaptic circuits in key cognitive brain regions, such as the prefrontal cortex and the hippocampus. The mechanisms elicited by estradiol are mediated by the regulation of transcriptional activity by nuclear estrogen receptors and by intracellular signaling cascades activated by estrogen receptors associated with the plasma membrane. In addition, the mechanisms include the interaction of estradiol with the signaling of other factors involved in the regulation of cognition, such as brain derived neurotrophic factor, insulin-like growth factor-1 and Wnt. Modifications in these signaling pathways by aging or by a long-lasting ovarian hormone deprivation after menopause may impair the enhancing effects of estradiol on synaptic plasticity and cognition. PMID- 25921587 TI - Relationship between estradiol and progesterone concentrations and cognitive performance in normally cycling female cynomolgus monkeys. AB - Preclinical research has demonstrated that cognitive function may be influenced by estradiol (E2) and progesterone (P4) concentrations, although few cognition studies involve normally cycling females. The present study examined cognitive performance in normally cycling female cynomolgus macaques (n = 14), a species with similarities to humans in brain organization and a nearly identical menstrual cycle to women. Initial assessments compared cognitive measures to circulating concentrations of E2 and P4 (n = 12). Once a relationship was characterized between hormones and cognitive performance, the menstrual cycle was divided into four distinct phases: early follicular (EF), late follicular (LF), early luteal (EL) and late luteal (LL), verified by the onset of menses and serum concentrations of E2 and P4. Concentrations of E2 were highest during the LF phase and P4 concentrations peaked during the EL phase. All monkeys were trained on two cognitive tasks: reversal learning, involving simple discrimination (SD) and reversal (SDR), which measured associative learning and behavioral flexibility, respectively (n = 3-4 per phase) and a delayed match-to-sample (DMS) task which assessed working memory (n = 11). P4 concentrations were positively correlated with number of trials and errors during acquisition of SD performance, but not during acquisition of the SDR task or maintenance of the reversal learning task. Across the menstrual cycle, significantly fewer errors were made in the SDR task during the LF phase, when E2 concentrations were high and P4 concentrations low. Working memory, assessed with the DMS task, was not consistently altered based on previously characterized menstrual cycle phases. These findings demonstrate a relationship between P4, E2 and cognitive performance in normally cycling cynomolgus monkeys that is task dependent. Knowledge of these interactions may lead to a better understanding of sex specific cognitive performance. PMID- 25921588 TI - The association between affective psychopathic traits, time incarcerated, and cortisol response to psychosocial stress. AB - Previous research has demonstrated that psychopathic personality traits are significantly predictive of blunted cortisol reactivity to a performance-based stressor task (Trier Social Stress Test; TSST) in college students. However, the relationship between cortisol reactivity and psychopathy has not been explored in high risk samples such as incarcerated populations. Further, the role of imprisonment in relation to cortisol stress reactivity has not been previously explored, but could have practical and conceptual consequences in regard to rehabilitation and biological sensitivity to context, respectively. The current study tested the hypotheses that both psychopathic personality traits and amount of time incarcerated are related to cortisol blunting in response to stress among incarcerated young adults. A sample of 49 young adult male offenders was recruited to complete the TSST. Salivary hormone samples were taken just prior to and 20 min post-stressor, and participants were interviewed with the Psychopathy Checklist-Youth Version. Variables quantifying the amount of time at the present facility prior to the date of testing and number of commitments in juvenile facilities were also collected. Correlational analyses indicated that only number of incarcerations was related to blunted cortisol. Hierarchical Linear Modeling revealed that time incarcerated and number of commitments were related to a blunted cortisol response among responders and declining cortisol reactivity among nonresponders, respectively. Controlling for time incarcerated, psychopathic traits were significantly related to cortisol decline in response to the stressor among nonresponders, but were not related to blunted cortisol among responders. Results of this project highlight the potential biological effects of prolonged and repeated incarcerations, and extend our understanding about the relationship between psychopathic traits and cortisol reactivity in an incarcerated sample. PMID- 25921589 TI - Evaluating Primary Care Physician Performance in Diabetes Glucose Control. AB - This study demonstrates that it is possible to identify primary care physicians (PCPs) who perform better or worse than expected in managing diabetes. Study subjects were 14 033 adult diabetics and their 133 PCPs. Logistic regression was used to predict the odds that a patient would have uncontrolled diabetes (defined as HbA1c >=8%) based on patient-level characteristics alone. A second model predicted diabetes control from physician-level identity and characteristics alone. A third model combined the patient- and physician-level models using hierarchical logistic regression. Physician performance is calculated from the difference between the expected and observed proportions of patients with uncontrolled diabetes. After adjusting for important patient characteristics, PCPs were identified who performed better or worse than expected in managing diabetes. This strategy can be used to characterize physician performance in other chronic conditions. This approach may lead to new insights regarding effective and ineffective treatment strategies. PMID- 25921590 TI - Hepatic ADC map as an adjunct to conventional abdominal MRI to evaluate hepatic fibrotic and clinical cirrhotic severity in biliary atresia patients. AB - OBJECTIVES: Hepatic apparent diffusion coefficient (ADC) values and ADC-related indices were correlated with the Mayo risk score for primary biliary cirrhosis (MRSPBC) and METAVIR scores of liver specimens to determine the clinical and pathological significance of diffusion-weighted magnetic resonance imaging (DWMRI). METHODS: Thirty-two patients with biliary atresia (BA; mean age 461 days, range 11-4616 days) received magnetic resonance examinations from March 2009 to August 2013. A free-breathing DWMRI sequence was performed with the single-shot echo-planar imaging technique with b = 0 and 500 s/mm(2) in all 32 BA patients and 24 controls. We used the ordinal logistic regression test and Spearman rank correlation test to analyse the relationships between the MRSPBC and METAVIR fibrosis scores and right liver-to-psoas ADC ratios (LTPARs). RESULTS: BA patients had significantly lower LTPARs in both hepatic lobes than controls (p < 0.01). Right LTPARs, showing moderate intraobserver agreement (intraclass correlation coefficient = 0.736) and interobserver reliability (intraclass correlation coefficient = 0.659), were negatively correlated with MRSPBC and METAVIR fibrosis scores (R(2) = 0.398, p = 0.024 and R(2) = 0.628, p < 0.001, respectively). CONCLUSION: Right LTPARs may be used for long-term follow up of cirrhosis severity in BA patients. KEY POINTS: * Hepatic ADC values by DWI correlates well with clinical/pathologic fibrosis scores * Periodic, non invasive, quantitative imaging follow-up of patients with biliary cirrhosis is feasible * Information on cirrhosis severity could help decide on management options in children with BA * ADC values may be useful in this regard. PMID- 25921591 TI - Perfusion imaging of parotid gland tumours: usefulness of arterial spin labeling for differentiating Warthin's tumours. AB - OBJECTIVE: To assess prospectively the efficacy of arterial spin labelling (ASL) against conventional and diffusion-weighted (DW) MR imaging for differentiating parotid gland tumours. METHODS: We included 10 pleomorphic adenomas, 12 Warthin's tumours, and nine malignant tumours of the parotid glands. Only tumours larger than 10 mm were included in this study. All parotid gland tumours underwent T1 weighted, T2-weighted, DW, and ASL imaging. Tumour-to-parotid gland signal intensity ratios (SIRs) and apparent diffusion coefficients (ADCs) of solid components were correlated with these pathologies. RESULTS: SIRs on T2-weighted images and ADCs were higher in pleomorphic adenomas than in Warthin's tumours (p < .01) and malignant tumours (p < .01). SIRs on ASL were higher in Warthin's tumours than in pleomorphic adenomas (p < .01) and malignant tumours (p < .05). Az value of SIRs on ASL for differentiating Warthin's tumours from the other pathologies was 0.982. The sensitivity, specificity, and accuracy of SIRs on ASL for the diagnosis of Warthin's tumours at an optimal SIR threshold of over 8.70 were 91.7%, 94.7%, and 93.5%, respectively. CONCLUSIONS: ASL with SIR measurements could non-invasively evaluate tumour blood flow of parotid gland tumours and differentiate Warthin's tumours from pleomorphic adenomas and malignant tumours. KEY POINTS: * ASL non-invasively evaluates tumour blood flow of parotid gland tumours * ASL differentiates Warthin's tumours from pleomorphic adenomas and malignant tumours * ASL cannot differentiate between pleomorphic adenomas and malignant tumours. PMID- 25921592 TI - Electron Microprobe and Raman Spectroscopy Investigation of an Oxygen-Bearing Pt Fe-Pd-Ni-Cu Compound from Nurali Chromitite (Southern Urals, Russia). AB - One grain, about 100*80 MUm in size, occurring in chromitite associated with the layered sequence of the Nurali mafic-ultramafic complex (Southern Urals, Russia) was investigated by electron-microprobe analyses and Raman spectroscopy. The grain is characterized by a spotty, rugged appearance and chemical zoning from which two compositions were calculated: (Pt(0.35)Pd(0.26)Fe(0.22)Cu(0.01)Ni(0.05))(0.98)O(1.02) and (Fe(0.90)Pt(0.58)Ni(0.28)Pd(0.13)Cu(0.08)Rh(0.01))(1.98)O(1.02). In the lack of X ray data, Raman spectroscopy established the presence of a diffuse 500-700 band and a sharp peak at 657 cm-1 of relative wavenumber that strongly resemble the Raman spectra of synthetic PtO and PdO (palladinite). It is concluded that the Nurali grain probably represents a platinum group element (PGE) oxide, and does not consist of a mixture of PGE alloys with Fe oxide or hydroxide as reported for other natural PGE-O compounds. PMID- 25921594 TI - Regional variation in expression of pro-inflammatory mediators in the intestine following a combined insult of alcohol and burn injury. AB - The intestine is segmented into functionally discrete compartments (duodenum, jejunum, ileum, and colon). The present study examined whether alcohol combined with burn injury differently influences cytokine levels in different parts of the intestine. Male mice were gavaged with alcohol (~2.9 g/kg) 4 h prior to receiving a ~12.5% total body surface area full thickness burn. Mice were sacrificed 1, 3, and 7 days after injury. The intestine segments (duodenum, jejunum, ileum, and colon) were harvested, homogenized, and analyzed for inflammatory mediators (IL 6, IL-18, and KC) using their respective ELISAs. KC levels were significantly increased in the jejunum, ileum, and colon following alcohol and burn injury as compared to shams. The increase in KC was ~28-fold higher in the colon as compared to the levels observed in duodenum following alcohol and burn injury. Both IL-6 and IL-18 levels were significantly elevated in both the ileum and colon following the combined insult. There was a ~7-fold increase in IL-6 levels in the colon as compared with the duodenum after the combined insult. Levels of IL-18 were increased by ~1.5-fold in the colon as compared to the ileum following alcohol and burn injury. The data suggest that pro-inflammatory mediators are differentially expressed in the intestine following alcohol and burn injury. PMID- 25921595 TI - Using Glubran 2 acrylic glue to maximize results of transcatheter arterial embolization for refractory upper gastrointestinal bleeding. PMID- 25921593 TI - New insights on Schwann cell development. AB - In the peripheral nervous system, Schwann cells are glial cells that are in intimate contact with axons throughout development. Schwann cells generate the insulating myelin sheath and provide vital trophic support to the neurons that they ensheathe. Schwann cell precursors arise from neural crest progenitor cells, and a highly ordered developmental sequence controls the progression of these cells to become mature myelinating or nonmyelinating Schwann cells. Here, we discuss both seminal discoveries and recent advances in our understanding of the molecular mechanisms that drive Schwann cell development and myelination with a focus on cell-cell and cell-matrix signaling events. PMID- 25921596 TI - Suprachiasmatic neuron numbers and rest-activity circadian rhythms in older humans. AB - The suprachiasmatic nucleus (SCN) of the hypothalamus, the master mammalian circadian pacemaker, synchronizes endogenous rhythms with the external day-night cycle. Older humans, particularly those with Alzheimer disease (AD), often have difficulty maintaining normal circadian rhythms compared to younger adults, but the basis of this change is unknown. We report that the circadian rhythm amplitude of motor activity in both AD subjects and age-matched controls is correlated with the number of vasoactive intestinal peptide-expressing SCN neurons. AD was additionally associated with delayed circadian phase compared to cognitively healthy subjects, suggesting distinct pathologies and strategies for treating aging- and AD-related circadian disturbances. PMID- 25921597 TI - Malaria morbidity and mortality in Ebola-affected countries caused by decreased health-care capacity, and the potential effect of mitigation strategies: a modelling analysis. AB - BACKGROUND: The ongoing Ebola epidemic in parts of west Africa largely overwhelmed health-care systems in 2014, making adequate care for malaria impossible and threatening the gains in malaria control achieved over the past decade. We quantified this additional indirect burden of Ebola virus disease. METHODS: We estimated the number of cases and deaths from malaria in Guinea, Liberia, and Sierra Leone from Demographic and Health Surveys data for malaria prevalence and coverage of malaria interventions before the Ebola outbreak. We then removed the effect of treatment and hospital care to estimate additional cases and deaths from malaria caused by reduced health-care capacity and potential disruption of delivery of insecticide-treated bednets. We modelled the potential effect of emergency mass drug administration in affected areas on malaria cases and health-care demand. FINDINGS: If malaria care ceased as a result of the Ebola epidemic, untreated cases of malaria would have increased by 45% (95% credible interval 43-49) in Guinea, 88% (83-93) in Sierra Leone, and 140% (135-147) in Liberia in 2014. This increase is equivalent to 3.5 million (95% credible interval 2.6 million to 4.9 million) additional untreated cases, with 10,900 (5700-21,400) additional malaria-attributable deaths. Mass drug administration and distribution of insecticide-treated bednets timed to coincide with the 2015 malaria transmission season could largely mitigate the effect of Ebola virus disease on malaria. INTERPRETATION: These findings suggest that untreated malaria cases as a result of reduced health-care capacity probably contributed substantially to the morbidity caused by the Ebola crisis. Mass drug administration can be an effective means to mitigate this burden and reduce the number of non-Ebola fever cases within health systems. FUNDING: UK Medical Research Council, UK Department for International Development, Bill & Melinda Gates Foundation. PMID- 25921598 TI - Ebola: the hidden toll. PMID- 25921599 TI - Experimental study on restricting the robotic end-effector inside a lesion for safe telesurgery. AB - INTRODUCTION: Using an endoscopic telesurgical robot system (ETSRS), the authors propose a strategy for improving the safety of telesurgery by restricting the movement of an end-effector within a lesion. The strategy is validated by phantom model experiments. MATERIAL AND METHODS: The method focused on generation of force feedback and restriction of robotic end-effector movement of ETSRS based on a virtual wall. Collision detection and case classification procedures were used to determine whether the generation of force feedback or restricting the end effector's movement was continued. The method was implemented in ETSRS and tested using a brain and tofu phantom. RESULTS: Force feedback was well generated proportional to a linear combination of the insertion depth and the velocity of the end-effector of the ETSRS from the surface of the predefined virtual wall. The movement of the end-effector was well limited inside the virtual wall by the method. The virtual wall update was sufficiently fast to check the current surgical situation. The control rate of the entire system was >30 fps so that the method showed acceptable performance in phantom experiments. CONCLUSION: The results show that the strategy allows for well controlled robotic end-effectors inside a predefined virtual wall by the robot itself and an operator through the signal and force feedback. PMID- 25921600 TI - Attenuation of indirect markers of eccentric exercise-induced muscle damage by curcumin. AB - PURPOSE: Polyphenolic curcumin is known to have potent anti-inflammatory effects; thus the present study investigated the hypothesis that curcumin ingestion would attenuate muscle damage after eccentric exercise. METHODS: Fourteen untrained young men (24 +/- 1 years) performed 50 maximal isokinetic (120 degrees /s) eccentric contractions of the elbow flexors of one arm on an isokinetic dynamometer and the same exercise with the other arm 4 weeks later. They took 150 mg of curcumin (theracurmin) or placebo (starch) orally before and 12 h after each eccentric exercise bout in a randomised, crossover design. Maximal voluntary contraction (MVC) torque of the elbow flexors, range of motion of the elbow joint, upper-arm circumference, muscle soreness, serum creatine kinase (CK) activity, and plasma interleukin-6 (IL-6) and tumor necrosis factor-alpha (TNF alpha) concentration were measured before, immediately after, and 24, 48, 72 and 96 h after each eccentric exercise. Changes in these variables over time were compared between curcumin and placebo conditions by two-way repeated measures ANOVA. RESULTS: MVC torque decreased smaller and recovered faster (e.g., 4 days post-exercise: -31 +/- 13 % vs. -15 +/- 15 %), and peak serum CK activity was smaller (peak: 7684 +/- 8959 IU/L vs. 3398 +/- 3562 IU/L) for curcumin than placebo condition (P < 0.05). However, no significant differences between conditions were evident for other variables, and no significant changes in IL-6 and TNF-alpha were evident after exercise. CONCLUSION: It is concluded that theracurmin ingestion attenuates some aspects of muscle damage such as MVC loss and CK activity increase. PMID- 25921601 TI - Insight into the mechanism revealing the peroxidase mimetic catalytic activity of quaternary CuZnFeS nanocrystals: colorimetric biosensing of hydrogen peroxide and glucose. AB - Artificial enzyme mimetics have attracted immense interest recently because natural enzymes undergo easy denaturation under environmental conditions restricting practical usefulness. We report for the first time chalcopyrite CuZnFeS (CZIS) alloyed nanocrystals (NCs) as novel biomimetic catalysts with efficient intrinsic peroxidase-like activity. Novel peroxidase activities of CZIS NCs have been evaluated by catalytic oxidation of the peroxidase substrate 3,3',5,5'-tetramethylbenzidine (TMB) in the presence of hydrogen peroxide (H2O2). CZIS NCs demonstrate the synergistic effect of elemental composition and photoactivity towards peroxidase-like activity. The quaternary CZIS NCs show enhanced intrinsic peroxidase-like activity compared to the binary NCs with the same constituent elements. Intrinsic peroxidase-like activity has been correlated with the energy band position of CZIS NCs extracted using scanning tunneling spectroscopy and ultraviolet photoelectron spectroscopy. Kinetic analyses indicate Michaelis-Menten enzyme kinetic model catalytic behavior describing the rate of the enzymatic reaction by correlating the reaction rate with substrate concentration. Typical color reactions arising from the catalytic oxidation of TMB over CZIS NCs with H2O2 have been utilized to establish a simple and sensitive colorimetric assay for detection of H2O2 and glucose. CZIS NCs are recyclable catalysts showing high efficiency in multiple uses. Our study may open up the possibility of designing new photoactive multi-component alloyed NCs as enzyme mimetics in biotechnology applications. PMID- 25921603 TI - Understanding the contribution of environmental factors in the spread of antimicrobial resistance. AB - The overuse and abuse of antibiotics have contributed to the global epidemic of antibiotic resistance. Current evidence suggests that widespread dependency on antibiotics and complex interactions between human health, animal husbandry and veterinary medicine, have contributed to the propagation and spread of resistant organisms. The lack of information on pathogens of major public health importance, limited surveillance, and paucity of standards for a harmonised and coordinated approach, further complicates the issue. Despite the widespread nature of antimicrobial resistance, limited focus has been placed on the role of environmental factors in propagating resistance. There are limited studies that examine the role of the environment, specifically water, sanitation and hygiene factors that contribute to the development of resistant pathogens. Understanding these elements is necessary to identify any modifiable interactions to reduce or interrupt the spread of resistance from the environment into clinical settings. This paper discusses some environmental issues that contribute to antimicrobial resistance, including soil related factors, animal husbandry and waste management, potable and wastewater, and food safety, with examples drawn mainly from the Asian region. The discussion concludes that some of the common issues are often overlooked and whilst there are numerous opportunities for environmental factors to contribute to the growing burden of antimicrobial resistance, a renewed focus on innovative and traditional environmental approaches is needed to tackle the problem. PMID- 25921604 TI - Sudden infant death syndrome and advice for safe sleeping. PMID- 25921602 TI - New genes for focal epilepsies with speech and language disorders. AB - The last 2 years have seen exciting advances in the genetics of Landau-Kleffner syndrome and related disorders, encompassed within the epilepsy-aphasia spectrum (EAS). The striking finding of mutations in the N-methyl-D-aspartate (NMDA) receptor subunit gene GRIN2A as the first monogenic cause in up to 20% of patients with EAS suggests that excitatory glutamate receptors play a key role in these disorders. Patients with GRIN2A mutations have a recognizable speech and language phenotype that may assist with diagnosis. Other molecules involved in RNA binding and cell adhesion have been implicated in EAS; copy number variations are also found. The emerging picture highlights the overlap between the genetic determinants of EAS with speech and language disorders, intellectual disability, autism spectrum disorders and more complex developmental phenotypes. PMID- 25921605 TI - Increased methylation of interleukin 6 gene is associated with obesity in Korean women. AB - Obesity is the fifth leading risk for death globally, and a significant challenge to global health. It is a common, complex, non-malignant disease and develops due to interactions between the genes and the environment. DNA methylation can act as a downstream effector of environmental signals; analysis of this process therefore holds substantial promise for identifying mechanisms through which genetic and environmental factors jointly contribute to disease risk. To assess the effects of excessive weight and obesity on gene-specific methylation levels of promoter regions, we determined the methylation status of four genes involved in inflammation and oxidative stress [interleukin 6 (IL6), tumor necrosis factor alpha (TNFalpha), mitochondrial transcription factor A (TFAM), and glucose transport 4 (GLUT4)] in blood cell-derived DNA from healthy women volunteers with a range of body mass indices (BMIs) by methylation-specific PCR. Interestingly, the samples from obese individuals (BMI >= 30 kg/m(2)) showed significantly increased hypermethylation for IL6 gene compared to normal weight (BMI < 23 kg/m(2)) and overweight samples (23 kg/m(2) <= BMI < 30 kg/m(2)) (P = 0.034 and P = 0.026). However, there was no statistically significant difference in promoter methylation of the other 3 genes between each group. These findings suggest that aberrant DNA methylation of IL6 gene promoter may play an important role in the etiology and pathogenesis of obesity and IL6 methylation could be used as molecular biomarker for obesity risk assessment. Further studies are required to elucidate the potential mechanisms underlying this relationship. PMID- 25921606 TI - N-acetyl-D-glucosamine kinase is a component of nuclear speckles and paraspeckles. AB - Protein O-GlcNAcylation, dictated by cellular UDP-N-acetylglucosamine (UDP GlcNAc) levels, plays a crucial role in posttranslational modifications. The enzyme GlcNAc kinase (NAGK, E.C. 2.7.1.59) catalyzes the formation of GlcNAc-6 phosphate, which is a major substrate for the biosynthesis of UDP-GlcNAc. Recent studies have revealed the expression of NAGK in different types of cells especially in neuronal dendrites. Here, by immunocytochemistry (ICC) and immunonucleochemistry (INC) of cultured rat hippocampal neurons, HEK293T and GT1 7 cells, we have showed that NAGK immuno-reactive punctae being present in the nucleoplasm colocalized with small nuclear ribonucleoprotein-associated protein N (snRNPN) and p54NRB, which are speckle and paraspeckle markers, respectively. Furthermore, NAGK IR cluster was also found to be colocalized with GTF2H5 (general transcription factor IIH, polypeptide 5) immuno reactive punctae. In addition, relative localization to the ring of nuclear lamin matrix and to GlcNAc, which is highly enriched in nuclear pore complexes, showed that NAGK surrounds the nucleus at the cytoplasmic face of the nuclear outer membrane. By in situ proximity ligation assay (PLA) we confirmed the colocalization of NAGK with snRNPN in the nucleus and in dendrites, while we also verified the interactions of NAGK with p54NRB, and with GTF2H5 in the nucleus. These associations between NAGK with speckle, paraspeckle and general transcription factor suggest its regulatory roles in gene expression. PMID- 25921607 TI - Morus alba Accumulates Reactive Oxygen Species to Initiate Apoptosis via FOXO Caspase 3-Dependent Pathway in Neuroblastoma Cells. AB - Morus alba root extract (MARE) has been used to treat hyperglycaemic conditions in oriental medicine. Here, we studied whether MARE possesses a cytotoxic effect on neuroblastoma. To check the cytotoxicity generated by MARE was whether relatively higher against the cancer cells rather than normal cells, we chose a neuroblastoma cell line (B103) and a normal cell line (Rat-2). A CCK assay revealed that MARE (10 MUg/ml) reduced cell viability to approximately 60% compared to an untreated control in B103 cells. But in Rat-2 cells, MARE induced relatively lower cytotoxicity. To investigate the mechanisms underlying the cytotoxic effect of MARE, we used flow cytometry combined with immunoblot analyses. We found that MARE-treatment could accumulate ROS and depolarize mitochondria membrane potential of B103 cells. Further treatment with MARE in B103 cells also could damage DNA and induce apoptosis. An expression study of p Akt also suggested that there was a reduction in cellular proliferation and transcription along with the process of apoptosis, which was further evidenced by an increase in Bax and cleaved-caspase 3 activity. Together, our findings suggest that MARE produces more cytotoxicity in cancer cells while having a relatively attenuated effect on normal cells. As such, MARE may be a safer option in cancer therapeutics, and it also shows potential for the patients with symptoms of hyperglycemia and cancer. PMID- 25921608 TI - Effect of high power low frequency ultrasound processing on the stability of lycopene. AB - The stability of lycopene was evaluated after application of high power low frequency ultrasound. The study was carried out on a solution containing pure lycopene to evaluate the direct effect of ultrasound on lycopene and on tomato puree to evaluate the direct and indirect effects of ultrasound application within a food matrix. Power densities ranging from 55 to 5000 W/L and temperatures ranging from 23 degrees C (ambient) to 60 degrees C were evaluated. The experiments on pure lycopene showed that the application of ultrasound did not have any direct effect over lycopene. However, the retention of lycopene in tomato puree has decreased indicating an indirect effect on lycopene stability caused by high concentration of hydrogen peroxide and the activation of peroxidase enzymes leading to the reduction of ascorbic acid and its regenerative action towards lycopene. PMID- 25921610 TI - [Use of social media by French urologists: Results from a study of the National French Urological Association]. AB - PURPOSE: Social Media (SoMe) have changed the face of modern medicine. Our purpose was to make an inventory on the use of SoMe within urologists members of the French Urological Association (AFU). MATERIAL AND METHODS: A 15 questions survey was sent by email 2 months to urologists AFU members before the 108th French Congress of Urology (#CFU2014). At the same time, the activity of urologists using Twitter was analyzed over the period of the national conference with the symplur software (www.symplur.com). RESULTS: Overall, 270 (17.3%) surveys were completed. Only 50% of responders had an online SoMe account. The most commonly used social media platforms were: Facebook (36.1%) followed by LinkedIn (28.2%), Google+ (19.6%), YouTube (18.7%) and Twitter (17.4%). The use of SoMe was higher in the age groups 30-40 and 40-50 years than in older age groups (83% versus 36%). Only 38.7% of respondents reported using SoMe in a professional field. At the congress #CFU2014, there were over 1000 tweets generated by 173 different contributors. CONCLUSION: Only a minority of French urologists have reported to be connected to SoMe and a predominantly personal use. The emergence of Twitter in French urological conferences is very new but seems promising. Further studies are needed, especially within the members of the residents French urological association to better characterize the true impact of SoMe in urology. LEVEL OF EVIDENCE: 4. PMID- 25921611 TI - Determination of freeze damage on HPV vaccines by use of flow cytometry. AB - The human papillomavirus (HPV) vaccines Gardasil, Silgard and Cervarix were labeled with antibodies against HPV strain 6 or 16/FITC conjugated secondary antibodies and analyzed by flow cytometry. The vaccines showed distinct peaks of fluorescent particles, and a shift towards decreased fluorescent particles was observed after incubation of the vaccines over night at -20 degrees C. Since parallel distributed vaccines could have longer route of transportation there is an increased risk of freeze damage for these types of vaccine. Shift in fluorescence of labeled vaccine particles was used to indicate whether parallel distributed Silgard, which is a vaccine type identical to Gardasil, was exposed to freeze damage during transportation, but no shift was observed. Additional experiments showed that the HPV vaccines could be degraded to smaller particles by citric acid/phosphate buffer treatment. The majority of particles detected in degraded Gardasil were very small indicating that the particles are HPV virus like particle (VLPs) labeled with antibodies, but Cervarix could only be degraded partially due to the presence of another type adjuvant in this vaccine. The described method may be useful in characterization of adjuvanted vaccines with respect to freeze damage, and to characterize vaccines containing particles corresponding to VLPs in size. PMID- 25921609 TI - Inflammaging decreases adaptive and innate immune responses in mice and humans. AB - Both the innate and adaptive immune systems decline with age, causing greater susceptibility to infectious diseases and reduced responses to vaccination. Diseases are more severe in elderly than in young individuals and have a greater impact on health outcomes such as morbidity, disability and mortality. Aging is characterized by increased low-grade chronic inflammation, called "inflammaging", measured by circulating levels of TNF-alpha, IL-6 and CRP, as well as by latent infections with viruses such as cytomegalovirus. Inflammaging has received considerable attention because it proposes a link between changes in immune cells and a number of diseases and syndromes typical of old age. In this review we aim at summarizing the current knowledge on pathways contributing to inflammaging, on immune responses down-regulated by inflammation and mechanisms proposed. The defects in the immune response of elderly individuals presented in this review should help to discover avenues for effective intervention to promote healthy aging. PMID- 25921612 TI - Oxidant controlled regio- and stereodivergent azidohydroxylation of alkenes via I2 catalysis. AB - A novel, I2 catalyzed regio- and stereodivergent vicinal azidohydroxylation of alkenes leading to 1,2-azidoalcohols in high yields (up to 92%) and excellent dr (up to 98%) has been developed. This unprecedented transformation employs NaN3 and DMF as N- and O-nucleophiles respectively. The role of DMF as the O-source in the reaction has been unequivocally proven by (18)O labelling studies. PMID- 25921614 TI - Patterns of cell thickness oscillations during directional migration of Physarum polycephalum. AB - The functional relationship between the velocity of cell locomotion and intracellular spatial patterns of thickness oscillations in the acellular slime mould Physarum polycephalum was studied. The freely migrating plasmodial cells of 300-800 um length were tadpole-shaped and displayed thickness oscillations along their longitudinal (body) axis. Two distinct patterns of intracellular thickness oscillations were observed in dependence on the locomotive velocity. The first mode consisted of a single travelling wave that propagated from the rear to the front of the cell. This pattern occurred when the plasmodium migrated slowly. The second mode was a multinodal standing wave that was found during events of fast propagation. Transitions between these two types of cell thickness oscillation patterns took place in narrow propagation velocity intervals. We discuss the possible mechanism leading to these patterns, which are conjectured to modulate both the intracellular pressure and the velocity of free locomotion of the cell. PMID- 25921613 TI - Quantitative analysis of annexin V-membrane interaction by flow cytometry. AB - We constructed a green fluorescent phosphatidylserine (PS)-binding probe, which was generated by fusing enhanced green fluorescent protein (EGFP) to the C terminus of human annexin V (anxV). With this probe, we investigated anxV membrane interaction under different calcium and anxV-EGFP concentrations through flow cytometry (FCM). A mathematical description of the binding characteristics is proposed and validated to quantify the relationship concerning the relative concentration of membrane-bound anxV (B), calcium concentration ([C]), and protein concentration ([P]). Further analyses reveal that [Formula: see text] is linear with [Formula: see text] or [Formula: see text] when [P] and [C] are fixed, respectively, which indicates that the anxV-membrane binding reaction may involve sequential multiple steps. Our study provides a reference for application of anxV in apoptosis detection. The mathematical expression facilitates exploration of the possible interactions between calcium, anxV, and membrane. The corresponding mathematical analysis strengthens the interpretation of the interaction data. PMID- 25921615 TI - An angiotensin-converting enzyme (ACE) polymorphism may mitigate the effects of angiotensin-pathway medications on posttraumatic stress symptoms. AB - Angiotensin, which regulates blood pressure may also act within the brain to mediate stress and fear responses. Common antihypertensive medication classes of angiotensin-converting enzyme inhibitors (ACE-Is) and angiotensin receptor blockers (ARBs) have been associated with lower PTSD symptoms. Here we examine the rs4311 SNP in the ACE gene, previously implicated in panic attacks, in the relationship between ACE-I/ARB medications and PTSD symptoms. Participants were recruited from outpatient wait rooms between 2006 and March 2014 (n= 803). We examined the interaction between rs4311 genotype and the presence of blood pressure medication on PTSD symptoms and diagnosis. PTSD symptoms were lower in individuals taking ACE-Is or ARBs (N = 776). The rs4311 was associated with PTSD symptoms and diagnosis (N = 3803), as the T-carriers at the rs4311 SNP had significantly greater likelihood of a PTSD diagnosis. Lastly, the rs4311 genotype modified the effect of ACE-Is or ARBs on PTSD symptoms (N = 443; F1,443 = 4.41, P < 0.05). Individuals with the CC rs4311 genotype showed lower PTSD symptoms in the presence of ACE-Is or ARBs. In contrast, T- carriers showed the opposite, such that the presence of ACE-Is or ARBs was associated with higher PTSD symptoms. These data suggest that the renin-angiotensin system may be important in PTSD, as ACE-I/ARB usage associates with lower symptoms. Furthermore, we provide genetic evidence that some individuals are comparatively more benefitted by ACE-Is/ARBs in PTSD treatment. Future research should examine the mechanisms by which ACE-Is/ARBs affect PTSD symptoms such that pharmaco-genetically informed interventions may be used to treat PTSD. PMID- 25921616 TI - Outcomes of emergent embolisation of ruptured hepatocellular carcinoma in a western population. AB - AIM: To evaluate the authors' experience with interventional radiological management of tumour rupture in hepatocellular carcinoma (HCC) in a Western population. MATERIALS AND METHODS: A retrospective review was performed of all consecutive patients treated at a single institution with transcatheter embolisation for ruptured HCC between 2000 and 2013. Patient age, sex, aetiology of liver disease, degree of underlying liver dysfunction, and clinical presentation were assessed. Embolisation was performed in a selective fashion when possible. Success, complications, and survival were assessed. RESULTS: Twenty-three patients were treated with embolisation for ruptured HCC. Of these patients, nine, nine, and five patients were Child-Pugh Class A, B, and C respectively. Embolisation was successful in 22 patients; one patient remained haemodynamically unstable and transfusion dependent despite embolisation. No major complications occurred. Median survival time was 260 days and the 30 day and 1 year survival rates were 83% and 45%, respectively. Child-Pugh class B or C (p = 0.04), Model for End-Stage Liver Disease score greater than 10 (p = 0.04), lobar embolisation (p = 0.04), and presence of portal vein thrombosis (p = 0.01) were significantly associated with worse prognosis. CONCLUSION: Transcatheter embolisation is effective at controlling haemorrhage in patients with ruptured HCC. Although major procedural complications are low, embolisation should proceed with an understanding of poor prognosis in patients with decompensated liver disease. Superselective embolisation is associated with improved prognosis and should be performed when feasible. PMID- 25921617 TI - Improved parenchymal liver enhancement with extended delay on Gd-EOB-DTPA enhanced MRI in patients with parenchymal liver disease: associated clinical and imaging factors. AB - AIM: To establish the effect of prolonged hepatobiliary phase (HBP) delay time on hepatic enhancement in patients with parenchymal liver disease (PLD). MATERIALS AND METHODS: Gadoxetate disodium (Gd-EOB-DTPA)-enhanced magnetic resonance imaging (MRI) examinations with HBP were obtained after 20- (HBP-20) and 30 minute (HBP-30) delays in patients with PLD. For each patient, the Model for End Stage Liver Disease (MELD) score, total and direct bilirubin, aspartate transaminase (AST), alanine transaminase (ALT), alkaline phosphatase (ALP), prothrombin time (PT), and partial thromboplastin time (PTT) were recorded. Signal intensities of the liver, main portal vein, and spleen on pre-contrast, HBP-20, and HBP-30 were documented. Signal intensities were used to calculate liver relative enhancement (LRE), liver-spleen index (LSI), and liver-portal vein index (LPI) for HBP-20 and HBP-30. Improved hepatic enhancement was considered if two or more indices were higher on HBP-30 than HBP-20. A logistic regression model was constructed with improved hepatic enhancement as the outcome. RESULTS: One hundred and twenty-nine patients underwent 142 MRIs. Mean LRE, LSI, and LPI each increased from HBP-20 to HBP-30 (p = 0.004, p < 0.001, and p < 0.001, respectively). Seventy-two point five percent of cases demonstrated improved hepatic enhancement. The odds ratios for improved hepatic enhancement were 0.85 for MELD score (p = 0.02) and 3.2 for the 3 T scanner (p = 0.02), adjusted for age and sex. CONCLUSION: Increasing HBP delay to 30 minutes improves hepatic enhancement in patients with PLD, particularly if using a 3 T scanner. This effect is attenuated with higher MELD scores. PMID- 25921618 TI - Dosimetric comparison of moderate deep inspiration breath-hold and free-breathing intensity-modulated radiotherapy for left-sided breast cancer. AB - PURPOSE: This study determined the dosimetric comparison of moderate deep inspiration breath-hold using active breathing control and free-breathing intensity-modulated radiotherapy (IMRT) after breast-conserving surgery for left sided breast cancer. PATIENTS AND METHODS: Thirty-one patients were enrolled. One free breathe and two moderate deep inspiration breath-hold images were obtained. A field-in-field-IMRT free-breathing plan and two field-in-field-IMRT moderate deep inspiration breath-holding plans were compared in the dosimetry to target volume coverage of the glandular breast tissue and organs at risks for each patient. RESULTS: The breath-holding time under moderate deep inspiration extended significantly after breathing training (P<0.05). There was no significant difference between the free-breathing and moderate deep inspiration breath-holding in the target volume coverage. The volume of the ipsilateral lung in the free-breathing technique were significantly smaller than the moderate deep inspiration breath-holding techniques (P<0.05); however, there was no significant difference between the two moderate deep inspiration breath-holding plans. There were no significant differences in target volume coverage between the three plans for the field-in-field-IMRT (all P>0.05). The dose to ipsilateral lung, coronary artery and heart in the field-in-field-IMRT were significantly lower for the free breathing plan than for the two moderate deep inspiration breath-holding plans (all P<0.05); however, there was no significant difference between the two moderate deep inspiration breath-holding plans. CONCLUSION: The whole-breast field-in-field-IMRT under moderate deep inspiration breath-hold with active breathing control after breast-conserving surgery in left-sided breast cancer can reduce the irradiation volume and dose to organs at risks. There are no significant differences between various moderate deep inspiration breath-holding states in the dosimetry of irradiation to the field-in-field-IMRT target volume coverage and organs at risks. PMID- 25921619 TI - [Ductal carcinoma in situ treated with radiation therapy and additional boost]. AB - PURPOSE: Women with ductal carcinoma in situ are treated with breast-conserving surgery and radiation therapy. The impact of an additive boost radiation is under evaluation. PATIENTS AND METHODS: All women treated for ductal carcinoma in situ with breast-conserving surgery and whole breast radiation therapy at a total dose of 45Gy with a boost radiation from 1990 to 2008 have been included in this retrospective monocentric retrospective study. RESULTS: We included 171 patients. Boost radiation to the surgical bed was delivered by brachytherapy in 66 patients (39%), by direct en-face electron beam in 86 patients (50%), and by tangential fields using photon beams in 19 patients (11%). Median follow-up was 95.1months. Eight local relapses (4.6%) have occurred. The 10-year local recurrence-free survival rate was 97%. The 10-year overall survival rate was 98%. On multivariable analysis, brachytherapy (P=0.05; HR=5.15; IC=1-26.3) was associated with a reduction risk of local recurrence-free survival. CONCLUSION: In our experience, women treated for a ductal carcinoma in situ with breast-conserving surgery and whole breast radiation therapy with a boost radiation have a high 10 year local recurrence-free survival rate. PMID- 25921620 TI - Not only ... but also: REM sleep creates and NREM Stage 2 instantiates landmark junctions in cortical memory networks. AB - This article argues both rapid eye movement (REM) and non-rapid eye movement (NREM) sleep contribute to overnight episodic memory processes but their roles differ. Episodic memory may have evolved from memory for spatial navigation in animals and humans. Equally, mnemonic navigation in world and mental space may rely on fundamentally equivalent processes. Consequently, the basic spatial network characteristics of pathways which meet at omnidirectional nodes or junctions may be conserved in episodic brain networks. A pathway is formally identified with the unidirectional, sequential phases of an episodic memory. In contrast, the function of omnidirectional junctions is not well understood. In evolutionary terms, both animals and early humans undertook tours to a series of landmark junctions, to take advantage of resources (food, water and shelter), whilst trying to avoid predators. Such tours required memory for emotionally significant landmark resource-place-danger associations and the spatial relationships amongst these landmarks. In consequence, these tours may have driven the evolution of both spatial and episodic memory. The environment is dynamic. Resource-place associations are liable to shift and new resource-rich landmarks may be discovered, these changes may require re-wiring in neural networks. To realise these changes, REM may perform an associative, emotional encoding function between memory networks, engendering an omnidirectional landmark junction which is instantiated in the cortex during NREM Stage 2. In sum, REM may preplay associated elements of past episodes (rather than replay individual episodes), to engender an unconscious representation which can be used by the animal on approach to a landmark junction in wake. PMID- 25921621 TI - Flexible superior electrode architectures based on three-dimensional porous spinous alpha-Fe2O3 with a high performance as a supercapacitor. AB - Flexible supercapacitors have recently attracted increasing attention as they show unique promising advantages, such as flexibility and shape diversity, and they are light-weight and so on. Herein, we designed a series of 3D porous spinous iron oxide materials synthesized on a thin iron plate through a facile method under mild conditions. The unique nanostructural features endow them with excellent electrochemical performance. The electrochemical properties of the integrated electrodes as active electrode materials for supercapacitors have been investigated using different electrochemical techniques including cyclic voltammetry, and galvanostatic charge-discharge in Na2SO4 and LiPF6/EC : DEC electrolyte solutions. These integrated electrodes showed high specific capacitance (as high as 524.6 F g(-1) at the current density of 1 A g(-1)) in 1.0 M Na2SO4 (see Table S1). Moreover, the integrated electrodes also show high power densities and high energy densities in a LiPF6/EC : DEC electrolyte solution; for example, the energy densities were 319.3, 252.5, 152.1, 74.13 and 38.6 W h kg(-1) at different power densities of 8.81, 21.59, 56.65, 92.09 and 152.64 kW kg(-1), respectively. Additionally, the flexible superior electrode exhibited excellent stability with capacitance retention of 92.9% after 5000 cycles. Therefore, such flexible integrated devices might be used in smart and portable electronics. PMID- 25921622 TI - Acute hamstring injury in football players: Association between anatomical location and extent of injury-A large single-center MRI report. AB - OBJECTIVES: To describe in detail the anatomic distribution of acute hamstring injuries in football players, and to assess the relationship between location and extent of edema and tears, all based on findings from MRI. DESIGN: Retrospective observational study. METHODS: We included 275 consecutive male football players who had sustained acute hamstring injuries and had positive findings on MRI. For each subject, lesions were recorded at specific locations of the hamstring muscles, which were divided into proximal or distal: free tendon, myotendinous junction, muscle belly, and myofascial junction locations. For each lesion, we assessed the largest cross-sectional area of edema and/or tears. We calculated the prevalence of injuries by location. The relationships between locations and extent of edema and tears were assessed using a one-sample t-test, with significance set at p<0.05. RESULTS: The long head of biceps femoris (LHBF) was most commonly affected (56.5%). Overall, injuries were most common in the myotendinous junction and in proximal locations. The proximal myotendinous junction was associated with a greater extent of edema in the LHBF and semitendinosus (ST) muscles (p<0.05). Proximal locations in the LHBF had larger edema than distal locations (p<0.05). Distal locations in the ST muscle had larger tears than proximal locations (p<0.05). CONCLUSIONS: The proximal myotendinous junction (LHBF and ST muscles) and proximal locations (LHBF muscle) are more commonly affected and are associated with a greater extent of edema in acute hamstring muscle injury. Distal locations (ST muscle), however, seem to be more commonly associated with larger tears. PMID- 25921623 TI - Importance of resectability status in neoadjuvant treatment for pancreatic cancer. AB - BACKGROUND: Much attention has been paid to neoadjuvant treatment (NAT) as a new strategy especially for borderline resectable pancreatic cancer (BRPC). However, the optimal indication of NAT remains undetermined. METHODS: We analyzed 248 patients with pancreatic cancer (PC). One hundred resectable tumors were classified as R group. Sixty-nine tumors with venous involvement were classified as BR-P group, while 31 tumors with arterial involvement were classified as BR-A group. Ninety-nine patients received NAT. Furthermore, 48 unresectable locally advanced PC served as controls (LAPC group). Among them, 11 patients received adjuvant surgery afterwards (Ad-surg group). RESULTS: The overall median survival time in the R, BR-P and BR-A groups was 45.3, 24.8 and 16.8 months. In the R and BR-P groups, patients treated with NAT had a better prognosis than those without. In contrast, NAT had no impact on prognosis in the BR-A group. Patients treated with NAT in the BR-P, but not BR-A group, had a better prognosis than patients in the LAPC group. Furthermore, patients in the Ad-surg group had a significantly better prognosis than patients in the BR-A group. CONCLUSIONS: Borderline resectable pancreatic cancer with venous involvement, but without arterial involvement, may be a good indication for NAT. Our data highlight the importance of preoperative resectability assessment to evaluate the indication and efficacy of NAT. PMID- 25921625 TI - Rare use of Atrieve Vascular SnareTM for percutaneous transcatheter retrieval of central venous port catheter fragments. PMID- 25921624 TI - The perimenopausal aging transition in the female rat brain: decline in bioenergetic systems and synaptic plasticity. AB - The perimenopause is an aging transition unique to the female that leads to reproductive senescence which can be characterized by multiple neurological symptoms. To better understand potential underlying mechanisms of neurological symptoms of perimenopause, the present study determined genomic, biochemical, brain metabolic, and electrophysiological transformations that occur during this transition using a rat model recapitulating fundamental characteristics of the human perimenopause. Gene expression analyses indicated two distinct aging programs: chronological and endocrine. A critical period emerged during the endocrine transition from regular to irregular cycling characterized by decline in bioenergetic gene expression, confirmed by deficits in fluorodeoxyglucose positron emission tomography (FDG-PET) brain metabolism, mitochondrial function, and long-term potentiation. Bioinformatic analysis predicted insulin/insulin-like growth factor 1 and adenosine monophosphate-activated protein kinase/peroxisome proliferator-activated receptor gamma coactivator 1 alpha (AMPK/PGC1alpha) signaling pathways as upstream regulators. Onset of acyclicity was accompanied by a rise in genes required for fatty acid metabolism, inflammation, and mitochondrial function. Subsequent chronological aging resulted in decline of genes required for mitochondrial function and beta-amyloid degradation. Emergence of glucose hypometabolism and impaired synaptic function in brain provide plausible mechanisms of neurological symptoms of perimenopause and may be predictive of later-life vulnerability to hypometabolic conditions such as Alzheimer's. PMID- 25921626 TI - Ultrasonographic assessment of liver fibrosis with computer-assisted analysis of liver surface irregularities. AB - PURPOSE: The goal of this study was to evaluate the diagnostic accuracy of a software program that automatically analyzes the liver surface to diagnose significant fibrosis, by comparing it to the subjective analysis of a radiologist and to transient elastography (Fibroscan((r))). PATIENTS AND METHODS: One hundred fourteen patients with chronic liver disease were included in the study. They underwent liver biopsy, FibroScan((r)) and ultrasonographic examination of the liver surface. The liver surface was analyzed by a software program that gave a score of surface irregularities. This evaluation was compared to subjective analysis by a radiologist expert in liver imaging and by two general radiologists. RESULTS: Fifty percent of the patients had significant fibrosis according to the METAVIR score. The AUROC for the diagnosis of significant fibrosis by the software program was 0.80 (95%CI: 0.71-0.87), which was equivalent (P=0.86) to that of FibroScan((r)) (0.81; 95%CI: 0.71-0.89). Results of the subjective analysis by the expert radiologist were poorer than those of the software analysis (P=0.02) (AUROC=0.66; 95%CI: 0.56-0.75). Interobserver agreement among radiologists was poor (0.25 ziram > maneb > carbaryl. In addition, it was also found that the degree of the reductions differed among the five proteins, with perforin more sensitive to pesticides than GRN, GrA, GrB, and Gr3/K, and the order was perforin > GRN > Gr3/K ? GrA ? GrB. PMID- 25921629 TI - The relative values of CD8+CD25+Foxp3brigh Treg cells correlate with selected lung function parameters in asthma. AB - The study aimed to detect CD8(+)CD25(+)FoxP3(brigh) Tregs and investigate their possible association with selected lung function values. CD8(+)CD25(+)FoxP3(brigh) Tregs were detected by flow cytometry in the peripheral blood of 25 patients with severe asthma (SA), 25 patients with mild-to-moderate asthma (MA), and 25 age-matched healthy donors (NC). The percentages of CD8(+)CD25(+)FoxP3(brigh) Tregs of the patients with severe (3.4 +/- 4.55), and mild-to-moderate asthma (7.5 +/- 8.15), were markedly lower than those of controls (12.1 +/- 13.2). The mean forced expiratory volume in 1 s (FEV1) % predicted value in severe asthma subpopulation was significantly lower (67.05 +/- 15.98%) when compared with that of mild-to-moderate asthma subgroup (87.71 +/- 16.12%). Interestingly, the percentages of CD8(+)CD25(+)FoxP3(brigh) Tregs correlate with mean peak expiratory flow (PEF)% predicted values in severe (r = 0.7, P <0.01) and mild-to-moderate (r = 0.73, P <0.01) asthma. In contrast, this parameter was positively correlated with FEV1% predicted values in the severe asthmatics only (r = 0.71, P <0.01). In summary, this study establishes a link between the percentage of CD8(+)CD25(+)FoxP3(brigh) Tregs and selected lung function parameters, suggesting that this parameter has potential as a marker for inflammation and airflow obstruction. PMID- 25921630 TI - Blockade of CXCR6 reduces invasive potential of gastric cancer cells through inhibition of AKT signaling. AB - Chemokines and their receptors have been implicated in cell migration and metastasis of multiple malignant tumors. But the function of CXCR6 signaling in gastric cancer is not comprehensively understood. In the present study, we hypothesized that CXCR6 signaling might play an essential role in the progression of gastric cancer. The expression of CXCR6 was examined by immunohistochemical assay in human gastric cancer, and lentivirus-mediated CXCR6 knockdown by shRNA (Lv-shCXCR6) was used for investigating cell migration and invasion indicated by Wound-healing and Transwell assays. Consequently, the expression level of CXCR6 was increased in gastric cancer compared with the adjacent non-tumor tissues (54.2% vs. 27.1%, P = 0.006), and was closely associated with the metastatic lymph node in gastric cancer (P = 0.021). Furthermore, blockade of the CXCR6 signaling reduced the migration and invasion of gastric cancer cells followed by decreased expression of AKT, MMP-2, and MMP-9. In conclusion, these findings demonstrate that CXCR6 may promote the development of gastric cancer cells through regulation of AKT signaling. PMID- 25921631 TI - Simultaneous Separation of Eight Benzodiazepines in Human Urine Using Field Amplified Sample Stacking Micellar Electrokinetic Chromatography. AB - A novel approach for the simultaneous quantification of eight benzodiazepines (BZDs) using dispersive liquid-liquid microextraction (DLLME) and field-amplified sample stacking (FASS) combined with micellar electrokinetic chromatography (MEKC) was investigated and evaluated in the context of precision, accuracy, sensitivity, linearity, detection and limits of quantification (LOQ). The absolute recovery rates of BZDs were above 90.65%. The limits of detection (LOD) were 20 ng/mL for chlordiazepoxide, estazolam, temazepam and midazolam, and 30 ng/mL for clonazepam, lorazepam, lormetazepam and medazepam, while the LOQ was set at 50 ng/mL for chlordiazepoxide, estazolam, temazepam and midazolam, and 100 ng/mL for clonazepam, lorazepam, lormetazepam and medazepam. Linearity was confirmed in the range of 50-2,000 ng/mL for chlordiazepoxide, estazolam, temazepam and midazolam, and 100-2,000 ng/mL for clonazepam, lorazepam, lormetazepam and medazepam, with a correlation coefficient greater than 0.9987 for all analytes. The elaborated procedure meets all the requirements of analytical methods. During the extraction procedure, a mixture of 1 mL of ethanol and 500 uL of dichloromethane, used as the disperser and extraction solvent, respectively, was rapidly injected into 3 mL of a urine sample. A significant improvement in sensitivity was achieved when DLLME was used to extract BZDs from the urine sample and FASS as an on-line preconcentration technique was developed. For the best separation of analytes, the running buffer was composed of 30 mM SDS, 10 mM sodium tetraborate and 15% methanol (pH 8.8), whereas a sample buffer was composed of 10 mM SDS and 2 mM sodium tetraborate. Moreover, a fused-silica capillary [inner diameter (i.d.) of 75 um and length of 50 cm], photodiode array detection, pneumatic injection for 15 s and a voltage of 23 kV were applied. The applicability of the method has been confirmed for the analysis of BZD in urine samples collected from patients who were treated with or abused these drugs. PMID- 25921632 TI - Relationship between NF-kappaB, MMP-9, and MICA expression in pituitary adenomas reveals a new mechanism of pituitary adenomas immune escape. AB - The aim of this study was to examine the expression levels of NF-kappaB, MMP-9, and MICA and their relationship between each other in pituitary adenomas as a histological basis for the study of the expression and shedding mechanism of MICA and mechanism of immune escape of pituitary adenomas. Our study indicated that MICA, MMP-9 and NF-kappaB mRNA and protein levels were more highly expressed in pituitary adenomas than healthy tissues. The expression levels of NF-kappaB, MMP 9, and MICA were positively related in patients with pituitary adenomas. In conclusion, the activation of NF-kappaB can up-regulate the expression of MICA and induce the expression of MMP-9, which hydrolyzes MICA into sMICA to promote tumor immune escape. The interactions of NF-kappaB, MMP-9, and MICA play an important role in the development of pituitary adenomas, and MMP-9 could be used as a new target for inhibiting tumor cell immune escape. PMID- 25921633 TI - Silent suppressive surrounds and optimal spatial frequencies of single neurons in cat V1. AB - The receptive fields of the clear majority of neurons in the primary visual cortex (V1) of cats contain silent surround regions beyond the classical receptive field (CRF). When stimulated on their own, the silent surround regions do not generate action potentials (spikes); instead, they modulate (and usually partially suppress) spike responses to stimuli presented in the CRF. In the present study, we subdivided our sample of single V1 neurons recorded from anesthetized cats into two distinct categories: surround-suppressive (SS) cells and surround-non-suppressive (SN) cells. Consistent with previous reports, we found a negative correlation between the size of the CRF and the optimal spatial frequency (SF) of circular patches of achromatic gratings presented in the cells' receptive fields. Furthermore, we found a positive correlation between the strength of the surround suppression and the optimal spatial frequency of the achromatic gratings presented in the cells' receptive fields. The correlation between the strength of surround suppression and the optimal spatial frequency was stronger in neurons with suppressive regions located in the so-called 'end' zones. The functional implications of these relationships are discussed. PMID- 25921634 TI - The multi-instrumentalist hippocampus: Comment on "The quartet theory of human emotions: An integrative and neurofunctional model" by S. Koelsch et al. PMID- 25921635 TI - What is reconfigured?: Comment on "The quartet theory of human emotions: An integrative and neurofunctional model" by S. Koelsch et al. PMID- 25921636 TI - Experimental and numerical investigations on reliability of air barrier on oil containment in flowing water. AB - Air barriers have been recently developed and employed as a new type of oil containment boom. This paper presents systematic investigations on the reliability of air barriers on oil containments with the involvement of flowing water, which represents the commonly-seen shearing current in reality, by using both laboratory experiments and numerical simulations. Both the numerical and experimental investigations are carried out in a model scale. In the investigations, a submerged pipe with apertures is installed near the bottom of a tank to generate the air bubbles forming the air curtain; and, the shearing water flow is introduced by a narrow inlet near the mean free surface. The effects of the aperture configurations (including the size and the spacing of the aperture) and the location of the pipe on the effectiveness of the air barrier on preventing oil spreading are discussed in details with consideration of different air discharges and velocities of the flowing water. The research outcome provides a foundation for evaluating and/or improve the reliability of a air barrier on preventing spilled oil from further spreading. PMID- 25921637 TI - Changes in abundance and composition of anthropogenic marine debris on the continental slope off the Pacific coast of northern Japan, after the March 2011 Tohoku earthquake. AB - Abundance and composition of anthropogenic marine debris were assessed on the basis of six bottom trawl surveys conducted on the continental slope off Iwate Prefecture, Pacific coast of northern Japan, in 2003, 2004 and 2011, and the temporal changes due to the Tohoku earthquake and tsunami in March 2011 evaluated. In 2003 and 2004, 54-94 items km(-2) of marine debris, dominated by sea-base sourced items mainly comprising fishing gear and related items from adjacent fishing grounds on the continental shelf, were quantified. In the post earthquake period, the density increased drastically to 233-332 items km(-2), due to an increase in land-base sourced items generated by the tsunami. However, a major increase in abundance after the disaster, compared to the total amount of tsunami debris swept into the sea, was not found. Additional sources of land based debris from the adjacent continental shelf are suggested in the present waters. PMID- 25921638 TI - Low levels of plasma omega 3-polyunsaturated fatty acids are associated with cerebral small vessel diseases in acute ischemic stroke patients. AB - Cerebral small vessel diseases (SVDs) are related to stroke or cognitive dysfunction. n-3-polyunsaturated fatty acids (PUFAs) such as eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) represent possible disease-modifying factors for cardiovascular disease or dementia. Our hypothesis was that a low proportion of plasma FAs would be associated with cerebral SVDs. We prospectively enrolled 220 patients with a first-episode cerebral infarction within 7 days after symptom onset. The composition of plasma FAs was analyzed by gas chromatography methods. The presence and burden of cerebral microbleeds (CMBs), high-grade white matter changes (HWCs), high-grade perivascular spaces (HPVSs), and asymptomatic lacunar infarctions (ALIs) were investigated. The mean proportion (+/- SD) was 2.0 +/- 0.7 for EPA, 8.9 +/- 1.5 for DHA, and 12.0 +/- 2.1 for ? n-3-PUFAs. In total, 46 (20.9%) patients had CMBs, 64 (29.1 %) had HWCs, 57 (25.9%) had HPVSs, and 65 (29.5%) had ALIs. In univariate analyses, CMBs, HWCs, and HPVSs were each negatively correlated with the proportion of EPA, DHA, and ? n-3-PUFAs. In the multivariate analysis, a lower proportion of EPA, DHA and ? n-3-PUFAs was associated with the presence of CMBs, HWCs and HPVS, but not ALIs. Total SVDs score was inversely correlated with the proportion of EPA, DHA and ? n-3-PUFAs. Overall, we found an association between low proportions of plasma n-3-PUFAs and cerebral SVDs pathologies. Further studies are needed to explore the association and potential therapeutic role of FAs in cerebral SVDs. PMID- 25921639 TI - Development of an LC-MS method for ultra trace-level determination of 2,2,6,6 tetramethylpiperidine-1-oxl (TEMPO), a potential genotoxic impurity within active pharmaceutical ingredients. AB - TEMPO (2,2,6,6-tetramethylpiperidine-1-oxyl) is a stable free radical which has been widely used for various research and industrial applications, including the manufacture of many active pharmaceutical ingredients. TEMPO has been identified as a potential genotoxic impurity resulting in the need for analytical methodology to accurately determine its level at several orders of magnitude less than typical impurity quantitation limits. TEMPO can undergo disproportionation to form both oxidized and reduced TEMPO, making individual determination unreliable. To overcome this challenge, all TEMPO related species were converted to the reduced form through reduction with sodium ascorbate. Given the ultra trace (0.5 ppm) level requirements and the lack of UV response in the reduced form, a single quadrupole mass spectrometer (MS) was utilized. In order to implement a highly sensitive MS method in a GMP environment, several approaches were employed to optimize accuracy and robustness including: internal standard correction for drift elimination, six-level standard addition to reduce matrix effects, and weighted linear regression to cover a broad analytical range. The method was fully validated according to ICH guidelines. The method is specific, linear, accurate, precise, and robust within a range of 0.5-100 ppm. PMID- 25921640 TI - Electrophoretic deposition of antibiotic loaded PHBV microsphere-alginate composite coating with controlled delivery potential. AB - Electrophoretic deposition (EPD) technique has been developed for the fabrication of antibiotic-loaded PHBV microsphere (MS)-alginate antibacterial coatings. The composite coatings deposited from suspensions with different MS concentrations were produced in order to demonstrate the versatility of the proposed method for achieving functional coatings with tailored drug loading and release profiles. Linearly increased deposit mass with increasing MS concentrations was obtained, and MS were found to be homogeneously stabilized in the alginate matrix. Chemical composition, surface roughness and wettability of the deposited coatings were measured by Fourier transform infrared (FTIR) spectroscopy, laser profilometer and water contact angle instruments, respectively. The co-deposition mechanism was described by two separate processes according to the results of relevant measurements: (i) the deposition of alginate-adsorbed MS and (ii) the non adsorbed alginate. Qualitative antibacterial tests indicated that MS containing coatings exhibit excellent inhibition effects against E. coli (gram-negative bacteria) after 1h of incubation. The proposed coating system combined with the simplicity of the EPD technique can be considered a promising surface modification approach for the controlled in situ delivery of drug or other biomolecules. PMID- 25921641 TI - N-Acetyl-D-glucosamine decorated polymeric nanoparticles for targeted delivery of doxorubicin: Synthesis, characterization and in vitro evaluation. AB - A novel targeting drug delivery system containing poly(styrene-alt-maleic anhydride)58-b-polystyrene130 (P(St-alt-MA)58-b-PSt130) as a copolymer backbone, N-acetyl glucosamine (NAG) as a targeting moiety was designed and synthesized. The NAG grafted copolymer (NAG-P(St-alt-MA)58-b-PSt130) was characterized by FTIR and (1)H NMR. The NAG-P(St-alt-MA)58-b-PSt130 nanoparticles exhibited spherical shapes with an average diameter about 56.27+/-0.43 nm, low critical micelle concentration of 0.028 mg/mL, negative zeta potential -41.46+/-0.99 mV, high drug loading 25.83+/-1.09% and encapsulation efficiency 69.69+/-3.98%. In vitro cell cytotoxicity was conducted to confirm the safety of the NAG-P(St-alt-MA)58-b PSt130 nanoparticles. Confocal laser scanning microscopy (CLSM) and flow cytometry (FCM) results showed that the NAG targeting moiety enhanced the internalization and targeting ability of NAG-P(St-alt-MA)58-b-PSt130 nanoparticles. Anticancer activity toward MCF-7 cells and HT29 cells showed that DOX-loaded NAG-P(St-alt-MA)58-b-PSt130 nanoparticles exhibited a higher antitumor activity compared to DOX-loaded P(St-alt-MA)58-b-PSt130 nanoparticles, which could attribute to NAG receptor-mediated endocytosis. These results suggest that the biocompatible and non-toxic NAG-P(St-alt-MA)58-b-PSt130 nanoparticles may be used as an effective targeting drug delivery system for cancer therapy. PMID- 25921642 TI - Chemical Synthesis and Medicinal Applications of Glycoporphyrins. AB - This review presents an in-depth overview of the modification of porphyrins with bioconjugates and their applications in medicine today. Porphyrin bioconjugates ranging from nucleotides to steroids are under active scrutiny. However, carbohydrates have been at the forefront of such research in recent years and offer significant potential. This is attributed to their own selectivity to lectins on the surface of cancer cells and their influence on the amphiphilicity of the porphyrin macrocycle. These characteristics and the tendency of porphyrin photosensitizers to accumulate in tumor tissues make glycoporphyrins promising candidates for use as photosensitizers. Thus, a detailed overview of the synthesis and biological evaluation of glycoporphyrins is given with a particular focus on their applications in photodynamic therapy and their future prospects as drug candidates have been reported. PMID- 25921643 TI - Computational development of selective nNOS inhibitors: binding modes and pharmacokinetic considerations. AB - Neuronal nitric oxide synthase (nNOS) produces the key signalling mediator nitric oxide, (NO). This gaseous, free radical molecule modulates a vast array of biological processes, from vascular pressure to immune responses and neurological signalling cascades. Overproduction of NO has been implicated in conditions including Alzheimer's disease, Parkinson's disease and schizophrenia. Inhibition of nNOS therefore offers a potential therapeutic approach for treatment of these conditions. This endeavour is made more complex by the fact that there are two other isoforms of nitric oxide synthase (NOS), endothelial NOS (eNOS) and inducible NOS (iNOS). The selectivity of nNOS inhibitors is therefore a key concern for therapeutic development. This review explores recent advances in the field of selective nNOS inhibition. A particular focus is placed on computational approaches towards the rational design of selective nNOS ligands with improved pharmacokinetic properties. These ligands have been targeted at four key binding sites of the nNOS enzyme - the tetrahydrobiopterin, calmodulin, nicotinamide adenine dinucleotide phosphate (NADPH) and arginine binding sites. The binding sites, and the compounds used to inhibit them, will be discussed in turn, along with the computational methods which have been employed in the field of nNOS inhibition. PMID- 25921644 TI - Mechanisms of thrombosis, available treatments and management challenges presented by thromboangiitis obliterans. AB - Thromboangiitis obliterans (TAO) is a thrombotic-occlusive and an inflammatory peripheral arterial disease with unidentified aetiology. Thrombotic events can lead to limb loss in TAO patients, who are typically young male smokers of low socioeconomic status. It is still unknown whether the initial process is thrombosis or inflammation, so it is difficult to ascertain whether managing inflammation or thrombosis improves the outcome of the disease. In this review, the possible mechanisms of thrombosis in TAO are evaluated; the treatments, based on the discussed mechanisms of thrombosis in TAO, are then reviewed and the challenges and limitations associated with the management of TAO are discussed. PMID- 25921645 TI - An evidence-based review of the mechanism of action, efficacy, and safety of biologic therapies in the treatment of psoriasis and psoriatic arthritis. AB - Biologic agents have expanded the repertoire of efficacious and safe systemic therapies for the treatment of moderate-to-severe psoriasis and active psoriatic arthritis. The biologics act to inhibit key inflammatory molecules that are thought to be involved in the pathogenesis of these chronic inflammatory disorders as well as physiologic immune responses. In this paper, we discuss the proposed molecular mechanisms of action, efficacy, and safety of the two FDA approved classes of biologics, the tumor necrosis factor inhibitors and the interleukin-12/23 inhibitor. The tumor necrosis factor inhibitors that are reviewed include etanercept, infliximab, adalimumab, golimumab, and certolizumab pegol. The interleukin- 12/23 inhibitor that is discussed is ustekinumab. Specifically, we review the mechanism of action for each biologic agent and the FDA-approved indications and dosing for these therapeutics. We provide up-to-date evidence for the efficacy of these systemic medications using key phase 3 clinical trial data, we highlight important safety information for each biologic based on long-term open-label extension trials and safety registries, and we discuss studies that investigate off-label dosing with the biologics. Each biologic is reviewed in these specific areas of focus for their indicated treatment of psoriasis and/or psoriatic arthritis. PMID- 25921646 TI - Novel Inflammatory Biomarkers in Cardiovascular Therapeutics. AB - Inflammation has been established as an important determinant of cardiovascular disease progression. Currently, clinical examination, laboratory and imaging tests are invaluable for the diagnosis, prognosis and disease monitoring. Novel inflammatory biomarkers are also used to better restratify patients in risk groups but their potential to guide treatment decisions and management of patients has not been extensively evaluated. Therefore, in this review article we present the most recent data concerning the use of inflammatory biomarkers in cardiovascular therapeutics. PMID- 25921647 TI - What the politicians aren't saying about health. PMID- 25921648 TI - Homeopathy in France in 2011-2012 according to reimbursements in the French national health insurance database (SNIIRAM). AB - BACKGROUND: The use of homeopathic medicine is poorly described and the frequency of combined allopathic and homeopathic prescriptions is unknown. OBJECTIVE: To analyse data on medicines, prescribers and patients for homeopathic prescriptions that are reimbursed by French national health insurance. METHODS: The French national health insurance databases (SNIIRAM) were used to analyse prescriptions of reimbursed homeopathic drugs or preparations in the overall French population, during the period July 2011-June 2012. RESULTS: A total of 6,705,420 patients received at least one reimbursement for a homeopathic preparation during the 12 month period, i.e. 10.2% of the overall population, with a predominance in females (68%) and a peak frequency observed in children aged 0-4 years (18%). About one third of patients had only one reimbursement, and one half of patients had three or more reimbursements. A total of 120,110 healthcare professionals (HCPs) prescribed at least one homeopathic drug or preparation. They represented 43.5% of the overall population of HCPs, nearly 95% of general practitioners, dermatologists and pediatricians, and 75% of midwives. Homeopathy accounted for 5% of the total number of drug units prescribed by HCPs. Allopathic medicines were coprescribed with 55% of homeopathic prescriptions. CONCLUSION: Many HCPs occasionally prescribe reimbursed homeopathic preparations, representing however a small percentage of reimbursements compared to allopathic medicines. About 10% of the French population, particularly young children and women, received at least one homeopathic preparation during the year. In more than one half of cases, reimbursed homeopathic preparations are prescribed in combination with allopathic medicines. PMID- 25921649 TI - Poor, Unsafe, and Overweight: The Role of Feeling Unsafe at School in Mediating the Association Among Poverty Exposure, Youth Screen Time, Physical Activity, and Weight Status. AB - This study applied socioecological and cumulative risk exposure frameworks to test the hypotheses that 1) the experience of poverty is associated with feeling less safe at school, and 2) feeling less safe is associated with engaging in poorer weight-related behaviors, as well as an increased probability of being overweight or obese. Data were from the ongoing Quebec Longitudinal Study of Child Development, initiated in 1998 with a population-based cohort of 2,120 Quebec (Canada) infants 5 months of age and their parent or primary caregiver. Measures of youths' (age, 13 years) self-reported feelings of safety, screen time, physical activity, and objectively assessed not overweight/obese (70%), overweight (22%), and obese (8%) weight status were collected in 2011. Family poverty trajectory from birth was assessed by using latent growth modeling. As hypothesized, exposure to poverty was associated with feeling less safe at school and, in turn, with an increased probability of being overweight or obese. The association was most pronounced for youths who experienced chronic poverty. Compared with youths who experienced no poverty and felt unsafe, those who experienced chronic poverty and felt unsafe were nearly 18% more likely to be obese (9.2% vs. 11.2%). Although feeling unsafe was associated with screen time, screen time did not predict weight status. PMID- 25921650 TI - Betting on Illusory Patterns: Probability Matching in Habitual Gamblers. AB - Why do people gamble? A large body of research suggests that cognitive distortions play an important role in pathological gambling. Many of these distortions are specific cases of a more general misperception of randomness, specifically of an illusory perception of patterns in random sequences. In this article, we provide further evidence for the assumption that gamblers are particularly prone to perceiving illusory patterns. In particular, we compared habitual gamblers to a matched sample of community members with regard to how much they exhibit the choice anomaly 'probability matching'. Probability matching describes the tendency to match response proportions to outcome probabilities when predicting binary outcomes. It leads to a lower expected accuracy than the maximizing strategy of predicting the most likely event on each trial. Previous research has shown that an illusory perception of patterns in random sequences fuels probability matching. So does impulsivity, which is also reported to be higher in gamblers. We therefore hypothesized that gamblers will exhibit more probability matching than non-gamblers, which was confirmed in a controlled laboratory experiment. Additionally, gamblers scored much lower than community members on the cognitive reflection task, which indicates higher impulsivity. This difference could account for the difference in probability matching between the samples. These results suggest that gamblers are more willing to bet impulsively on perceived illusory patterns. PMID- 25921651 TI - Chlorogenic Acid Biosynthesis Appears Linked with Suberin Production in Potato Tuber (Solanum tuberosum). AB - Potato (Solanum tuberosum L.) is a good source of dietary antioxidants. Chlorogenic acid (CGA) and caffeic acid (CA) are the most abundant phenolic acid antioxidants in potato and are formed by the phenylpropanoid pathway. A number of CGA biosynthetic routes that involve hydroxycinnamoyl-CoA quinate hydroxycinnamoyl transferase (HQT) and/or hydroxycinnamoyl-CoA shikimate/quinate hydroxycinnamoyl transferase (HCT) have been proposed, but little is known about their path in potato. CA production requires a caffeoyl shikimate esterase (CSE), and CA serves as a substrate of lignin precursor ferulic acid via the action of caffeic/5-hydroxyferulic acid O-methyltransferase (COMT I). CGA is precursor of caffeoyl-CoA and, via caffeoyl-CoA O-methyltransferase (CCoAOMT), of feruloyl CoA. Feruloyl-CoA is required for lignin and suberin biosynthesis, crucial for tuber development. Here, metabolite and transcript levels of the mentioned and related enzymes, such as cinnamate 4-hydroxylase (C4H), were determined in the flesh and skin of fresh and stored tubers. Metabolite and transcript levels were higher in skin than in flesh, irrespective of storage. CGA and CA production appear to occur via p-coumaroyl-CoA, using HQT and CSE, respectively. HCT is likely involved in CGA remobilization toward suberin. The strong correlation between CGA and CA, the correspondence with C4H, HQT, CCoAOMT2, and CSE, and the negative correlation of HCT and COMT I in potato tubers suggest a major flux toward suberin. PMID- 25921652 TI - The attractive lip: A photomorphometric analysis. AB - BACKGROUND: Throughout literature, there are different parameters defining the ideal shape of the lip and lower third of the face. This study was conducted to clarify what it is that makes lips attractive - and whether there are gender related differences of an attractive lip and lower third of the face. PATIENTS AND METHODS: Pictures of the lip and chin region of 176 patients were photographed in a standardised way and evaluated by 250 voluntary judges through an internet presentation by means of an analogue Likert scaling system. RESULTS: We found a significant higher ratio of upper vermillion height/mouth-nose distance in frontal-view images of attractive compared to unattractive female (p < 0.001) and male (p < 0.05) perioral regions. Furthermore, the ratio of upper vermillion height/chin-nose distance was significantly higher in attractive than in unattractive female (p < 0.005) and male (p < 0.05) lip and chin regions. The nasolabial angle was significantly sharper in attractive compared to unattractive female perioral regions (p < 0.001). Moreover, attractive female lip and chin regions showed a wider mentolabial angle compared to unattractive female lip and chin regions (p < 0.05). Comparing men and women, we found that attractive female perioral regions showed a higher ratio of lower vermillion height/chin-mouth distance (p < 0.05) and lower vermillion height/chin-nose distance than attractive male perioral regions (p < 0.05). CONCLUSION: We were able to define certain parameters of the lip and lower third of the face that seem to add to the attractivity of female and male individuals and prove that there are gender related differences in form and shape of an attractive lower third of the face. PMID- 25921653 TI - Combining pedicle screw stimulation with spinal navigation, a protocol to maximize the safety of neural elements and minimize radiation exposure in thoracolumbar spine instrumentation. AB - PURPOSE: The O-arm-based navigation increases the accuracy of pedicle screw positioning and offers the possibility of performing a 3D scan before wound closure. However, repeating the 3D scan exposes the patient to additional radiation. We combined O-arm navigation with pedicle screw (PS) stimulation followed by a 3D scan to evaluate their accuracy and aimed for the creation of a protocol that maximizes the safety and minimizes radiation. METHODS: Patients had pedicle screws insertion using O-arm spinal navigation, then had PS triggered electromyography (EMG), and finally a 3D scan to evaluate the accuracy of screw position. RESULTS: 447 screws were inserted in 71 patients. In 10 patients, 11 screws needed repositioning. Comparing results of PS triggered EMG responses to the 3D scan, we found: (a) negative stimulation response with negative 3D scan findings, corresponding to 432 acceptable screw position (96.6 %) in 58 patients (81.7 %). In these cases, the redo 3D scan could be avoided. (b) Positive stimulation response with positive 3D scan findings, corresponding to 7 unacceptable screw position (1.5 %) in 6 patients (8.4 %). In these cases, PS stimulation detected malpositioned screws that would be missed without a redo 3D scan. CONCLUSION: We propose a protocol of routinely performing PS stimulation after screw insertion using spinal navigation. In case of positive stimulation, a 3D scan must be performed to rule out a probable screw mal position (6 patients 8.4 %). However, in case of negative stimulation, redo 3D scan can be avoided in 81.7 % of patients. PMID- 25921654 TI - Kinetic magnetic resonance imaging analysis of lumbar segmental motion at levels adjacent to disc herniation. AB - PURPOSE: A retrospective radiographic study was carried out to analyze the effect of lumbar disc herniation on the kinetic motion of adjacent segments. METHODS: A total of 162 patients with low back pain or radicular pain in the lower limbs without a prior history of surgery were evaluated using kinetic magnetic resonance imaging. Translational motion, angular variation, and disc height were measured at each segment from L1-L2 to L5-S1. Other factors including the degree of disc degeneration, age, gender, and vertebral segment location were analyzed to determine any predisposing risk factors for segmental instability adjacent to disc herniations. RESULTS: Spinal levels above the disc herniation exhibited, on average, a 6.4 % increase in translational motion per mm of disc herniation (P = 0.496) and a 21.4 % increase in angular motion per mm herniation (P = 0.447). Levels below the herniation demonstrated a 5.2 % increase in translational motion per mm of disc herniation (P = 0.428) and a decrease of 10.7 % in angular motion per mm (P = 0.726). The degree of disc degeneration had no significant correlation with adjacent level motion. Similarly, disc herniation was not significantly correlated with disc height at adjacent levels, although there was a significant relationship between gender and adjacent segment disc height. CONCLUSIONS: Although disc height, translational motion, and angular variation are significantly affected at the level of a disc herniation, no significant changes are apparent in adjacent segments. Our results indicate that herniated discs have no effect on range of motion at adjacent levels regardless of the degree of disc degeneration or the size of disc herniation, suggesting that the natural progression of disc degeneration and adjacent segment disease may be separate, unrelated processes within the lumbar spine. PMID- 25921655 TI - Salidroside protects retinal endothelial cells against hydrogen peroxide-induced injury via modulating oxidative status and apoptosis. AB - Oxidative stress can cause injury in retinal endothelial cells. Salidroside is a strong antioxidative and cytoprotective supplement in Chinese traditional medicine. In this study, we investigated the effects of salidroside on H2O2 induced primary retinal endothelial cells injury. Salidroside decreased H2O2 induced cell death, and efficiently suppressed cellular ROS production, malondialdehyde generation, and cell apoptosis induced by H2O2 treatment. Salidroside induced the intracellular mRNA expression, protein expression, and enzymatic activities of catalase and Mn-SOD and increased the ratio of Bcl2/Bax. Our results demonstrated that salidroside protected retinal endothelial cells against oxidative injury through increasing the Bcl2/Bax signaling pathway and activation of endogenous antioxidant enzymes. This finding presents salidroside as an attractive agent with potential to attenuate retinopathic diseases. PMID- 25921656 TI - Lewis acid catalysed methylation of N-(9H-fluoren-9-yl)methanesulfonyl (Fms) protected lipophilic alpha-amino acid methyl esters. AB - This work reports an efficient Lewis acid catalysed N-methylation procedure of lipophilic alpha-amino acid methyl esters in solution phase. The developed methodology involves the use of the reagent system AlCl3/diazomethane as methylating agent and alpha-amino acid methyl esters protected on the amino function with the (9H-fluoren-9-yl)methanesulfonyl (Fms) group. The removal of Fms protecting group is achieved under the same conditions to those used for Fmoc removal. Thus the Fms group can be interchangeable with the Fmoc group in the synthesis of N-methylated peptides using standard Fmoc-based strategies. Finally, the absence of racemization during the methylation reaction and the removal of Fms group were demonstrated by synthesising a pair of diastereomeric dipeptides. PMID- 25921657 TI - What is and what is not positive body image? Conceptual foundations and construct definition. AB - A decade ago, research on positive body image as a unique construct was relatively nonexistent, and now this area is flourishing. How and why did positive body image scholarship emerge? What is known about this contemporary construct? This article situates and contextualizes positive body image within Cash's scholarship, eating disorder prevention efforts, feminist influences, strength-based disciplines within psychology, and Buddhism. Extracting insights from quantitative and qualitative research, this article demonstrates that positive body image is (a) distinct from negative body image; (b) multifaceted (including body appreciation, body acceptance/love, conceptualizing beauty broadly, adaptive investment in appearance, inner positivity, interpreting information in a body-protective manner); (c) holistic; (d) stable and malleable; (e) protective; (f) linked to self-perceived body acceptance by others; and (g) shaped by social identities. Complementing what positive body image is, this article further details what positive body image is not to provide a more nuanced understanding of this construct. PMID- 25921658 TI - Long-term neuroplasticity of the face primary motor cortex and adjacent somatosensory cortex induced by tooth loss can be reversed following dental implant replacement in rats. AB - Tooth loss is common, and exploring the neuroplastic capacity of the face primary motor cortex (face-M1) and adjacent primary somatosensory cortex (face-S1) is crucial for understanding how subjects adapt to tooth loss and their prosthetic replacement. The aim was to test if functional reorganization of jaw and tongue motor representations in the rat face-M1 and face-S1 occurs following tooth extraction, and if subsequent dental implant placement can reverse this neuroplasticity. Rats (n = 22) had the right maxillary molar teeth extracted under local and general anesthesia. One month later, seven rats had dental implant placement into healed extraction sites. Naive rats (n = 8) received no surgical treatment. Intracortical microstimulation (ICMS) and recording of evoked jaw and tongue electromyographic responses were used to define jaw and tongue motor representations at 1 month (n = 8) or 2 months (n = 7) postextraction, 1 month postimplant placement, and at 1-2 months in naive rats. There were no significant differences across study groups in the onset latencies of the ICMS evoked responses (P > 0.05), but in comparison with naive rats, tooth extraction caused a significant (P < 0.05) and sustained (1-2 months) decreased number of ICMS-defined jaw and tongue sites within face-M1 and -S1, and increased thresholds of ICMS-evoked responses in these sites. Furthermore, dental implant placement reversed the extraction-induced changes in face-S1, and in face-M1 the number of jaw sites even increased as compared to naive rats. These novel findings suggest that face-M1 and adjacent face-S1 may play a role in adaptive mechanisms related to tooth loss and their replacement with dental implants. PMID- 25921659 TI - In Vivo Tracking of Streptococcal Infections of Subcutaneous Origin in a Murine Model. AB - PURPOSE: Generation of plasmin in vivo by Streptococcus pyogenes is thought to localize the active protease complexes to the pathogen surface to aid in tissue dissemination. Here, we chose to follow cutaneous streptococcal infections by the use of non-invasive bioluminescence imaging to determine if this pathogen can be followed by this approach and the extent of bacterial spread in the absence of canonical plasminogen activation by streptokinase. PROCEDURES: Mice were injected subcutaneously with either bioluminescent strains of streptococci, namely Xen20 and Xen10 or S. pyogenes ALAB49. Bioluminescence imaging was performed daily and results were correlated with microbiological and histological analyses. RESULTS: Comparative analysis of chronologic non-invasive datasets indicated that Xen20 did not disseminate from the initial infection site. Contrary to this, microbiological and histological analyses of Xen20 mice for total bacterial burden indicated sepsis and widespread pathogen involvement. CONCLUSIONS: The use of bioluminescence in microbe-based studies requires genomic and pathologic characterization to correlate imaging results with underlying pathology. PMID- 25921661 TI - Anatomic pathology of hepatocellular carcinoma: histopathology using classic and new diagnostic tools. AB - Hepatocellular carcinoma can be diagnosed on a needle biopsy of the liver; however, uncertainty may arise because of the inherent complexity of liver histology. This article aims to provide practicing pathologists with tools for the approach to mass-directed liver biopsies clinically concerning for hepatocellular carcinoma. The examination of routine hematoxylin-eosin stains and the use of ancillary histochemical and immunohistochemical stains are discussed. Sections reviewing liver carcinoma with biphenotypic differentiation and the challenge of dysplastic nodules are included. PMID- 25921660 TI - Global epidemiology of hepatocellular carcinoma: an emphasis on demographic and regional variability. AB - Liver cancer is the second leading cause of global cancer mortality. The major risk factors for hepatocellular carcinoma (HCC) are being addressed with success by prevention efforts. Vaccination against hepatitis B virus has reduced incidence of HCC in Taiwan and is partly responsible for lower rates in China. New infections with hepatitis C virus are low in developed countries because of prevention of posttransfusion infections and reduced exposure to HCV by drug users. Aflatoxin exposure has been reduced by better grain storage and dietary changes. Obesity, metabolic syndrome, and diabetes are increasing in developed and developing countries and will lead to more cases of HCC. PMID- 25921662 TI - Pathogenesis and prognosis of hepatocellular carcinoma at the cellular and molecular levels. AB - Different approaches predict the outcome for patients with hepatocellular carcinoma (HCC). The expression of biliary-hepatic progenitor cell markers generally correlates with poor prognosis. This article focuses on the pathogenesis of HCC, how differentiation or dedifferentiation leads to a phenotype switch, and heterogeneity in the same tumor. A tumor cell decides its fate based on a complex interplay of signaling pathways. Interaction with the microenvironment decides whether it will invade, proliferate, or enter survival mode. Several signaling pathways contribute to stemness features, reflecting a small chemoresistant subpopulation of the tumor that expresses biliary-hepatic progenitor cell markers. PMID- 25921663 TI - Classification and staging of hepatocellular carcinoma: an aid to clinical decision-making. AB - Classification and staging of hepatocellular carcinoma in a way that allows optimal treatment selection is challenging. This article summarizes some of the classification and staging schemes and discusses the conceptual framework that guides optimal treatment selection for each patient. The article does not exhaustively discuss each staging system proposed in the last three decades, but rather reviews the most commonly used staging systems, evaluates the rationale behind some of the newer staging systems, and compares them focusing on their use in clinical decision-making, notably choice of therapy. PMID- 25921664 TI - Screening and detection of hepatocellular carcinoma. AB - The increasing incidence of hepatocellular carcinoma (HCC) has led to the need to identify patients at risk for HCC so that a program of screening can be undertaken. Screening for HCC has led to earlier diagnosis of tumors and thus has aided in initiating optimal medical treatment earlier in the disease course. Advances in radiological techniques and the identification of more accurate serum tests to diagnose HCC continue to be important areas of study and exploration. In particular, there have been efforts to develop new tumor markers to aid in the diagnosis of HCC and guide therapy of tumors. PMID- 25921665 TI - Elevated alpha-fetoprotein: differential diagnosis - hepatocellular carcinoma and other disorders. AB - The incidence of cirrhosis-related hepatocellular carcinoma (HCC) is rising. Curative surgical options are available; outcomes are acceptable with early diagnosis. Lens culinaris agglutinin-reactive fraction of alpha-fetoprotein (AFP L3) and des-gamma-carboxy prothrombin (DCP) are HCC risk markers. A high or increasing serum biomarker level can be predictive of the eventual development of HCC, large tumor size, advanced stage, extrahepatic metastases, portal vein thrombosis, and postoperative HCC recurrence. Based on FDA guidelines for HCC risk assessment, clinicians can consider using either the combination of AFP-L3 with DCP, or the combination of AFP-L3 with AFP and DCP. PMID- 25921666 TI - Imaging of hepatocellular carcinoma: new approaches to diagnosis. AB - The currently accepted major diagnostic criteria for identifying hepatocellular carcinoma (HCC) on dynamic cross-sectional imaging consist of diffuse arterial phase hyperenhancement within the lesion, portal venous or delayed phase washout, and the presence and appearance of a capsule; also included in this criteria is interval threshold growth. Ancillary features such as intralesional fat, blood products, and mosaic architecture also favor a diagnosis of HCC. Tumor in a portal or hepatic vein is a definitive finding for an HCC even if a parenchymal mass is not clearly seen. PMID- 25921667 TI - Oncogenic viruses and hepatocellular carcinoma. AB - About 80% of hepatocellular carcinoma (HCC) is caused by hepatitis B virus (HBV) and/or hepatitis C virus (HCV) infections especially in the setting of established cirrhosis or advanced fibrosis, making HCC prevention a major goal of antiviral therapy. HCC tumors are highly complex and heterogeneous resulting from the aberrant function of multiple molecular pathways. The roles of HCV or HBV in promoting HCC development are still either directly or indirectly are still speculative, but the evidence for both effects is compelling. In patients with chronic hepatitis viral infection, cirrhosis is not a prerequisite for tumorigenesis. PMID- 25921668 TI - Nonalcoholic Fatty liver disease, diabetes, obesity, and hepatocellular carcinoma. AB - Diabetes and obesity are associated with nonalcoholic fatty liver disease (NAFLD) and an increased incidence of hepatocellular carcinoma (HCC). NAFLD is the commonest cause of chronic liver disease. HCC can develop in NAFLD patients even without cirrhosis, suggesting an association between the metabolic process and HCC and raising a concern that many cancers could be missed given high NAFLD prevalence and screening limitations. The increasing prevalence of these conditions and lack of effective treatments necessitate a better understanding of their connection. This article defines the known interrelationships and common pathways between NAFLD, diabetes, obesity and HCC and possible chemoprevention strategies. PMID- 25921669 TI - Surgical resection and liver transplantation for hepatocellular carcinoma. AB - With a better understanding of the natural history of hepatocellular carcinoma (HCC) and the improvement in imaging, locoregional therapies, surgical techniques, and postoperative care, patients with HCC are now managed by a multidisciplinary team. Partial hepatic resection can be curative in patients developing HCC in the setting of normal liver parenchyma and in patients with early cirrhosis but well-preserved hepatic synthetic function. Liver transplantation offers the best long-term survival and lowest incidence of tumor recurrence in select patients with HCC and underlying cirrhosis. This article discusses the role of surgical resection and liver transplantation in the management of HCC. PMID- 25921670 TI - Locoregional therapy of hepatocellular carcinoma. AB - Hepatocellular carcinoma can be treated using minimally invasive, image-guided, catheter-based or percutaneous techniques. Such procedures offer compelling clinical outcomes with a favorable side-effect profile in a population of patients who are poor candidates for surgical or systemic treatment. This article discusses key data regarding the effectiveness of locoregional therapies in treating these patients. Disease-specific treatment is discussed in the context of hepatocellular carcinoma, with additional data discussed in the context of transplantation. As rapid innovation occurs in the realm of oncology, interventional oncology represents a safe, effective alternative that continues to generate impressive data that could potentially change treatment paradigms. PMID- 25921671 TI - Systemic therapy of hepatocellular carcinoma: current and promising. AB - Treatment of advanced hepatocellular carcinoma (HCC) remains challenging, particularly with the limited systemic therapy options. Sorafenib remains the only approved, targeted molecule for the treatment of advanced HCC. Although a survival benefit was demonstrated with sorafenib, it remains only true in the population of patients with Child-Turcotte-Pugh class A disease. Sorafenib also has distinct side effects that require close monitoring. Newer tyrosine kinase inhibitors and angiogenic inhibitors have been evaluated with disappointing results, particularly in phase III trials. Herein we review the pertinent trials for targeted therapy in HCC to date. PMID- 25921672 TI - Hepatocellular carcinoma in children. AB - Liver tumors are relatively rare in childhood, but may be associated with a range of diagnostic, genetic, therapeutic, and surgical challenges sufficient to tax even the most experienced clinician. This article outlines the epidemiology, etiology, pathologic condition, initial workup, and management of hepatocellular carcinoma in children and adolescents. PMID- 25921673 TI - Hepatocellular carcinoma in adults and children. PMID- 25921674 TI - Second-look surgery plus HIPEC for patients with colorectal cancer at high risk of peritoneal carcinomatosis: Should we resect the initial anastomosis? An observational study. AB - BACKGROUND: Cytoreductive surgery (CCRS) and hyperthermic intraperitoneal chemotherapy (HIPEC) improves the overall survival in selected cases of peritoneal carcinomatosis (PC) of colorectal origin. Second-look surgery in asymptomatic patients at high risk of developing PC has shown encouraging results. This study aims at identifying cases in which initial anastomosis should be resected. METHODS: Patients treated by second-look surgery and HIPEC were identified from a prospective database. High-risk was defined as synchronous resected and minimal PC, ovarian metastasis or perforated primary tumor. Patients were divided in two groups based on intra-operative evaluation of the anastomosis: possibly-invaded (PI) and unlikely-invaded (UI). PI was defined as 1) PC away from the anastomosis, 2) nodules resting on the anastomosis 3) anastomotic stenosis or anastomotic thickening. Anastomosis in the PI group were resected. RESULTS: Forty patients were included: 12 in the PI group and 28 in the UI group. Incidence of pathological anastomotic invasion was 42% (5 on 12 patients) in the PI group. In the UI group, 2 patients had anastomotic recurrence, both associated with peritoneal recurrence. Morbidity and mortality was not influenced by anastomosis resection. The presence of suspicious nodules on the anastomosis had a sensitivity of 100% and a specificity of 89% in predicting anastomotic invasion. CONCLUSION: In second-look surgery and HIPEC for colorectal cancer at high-risk of PC, anastomosis should be resected when overlying PC nodules are found. This attitude is supported by high sensitivity of this finding for anastomotic invasion and low morbidity related to anastomotic resection. PMID- 25921675 TI - Expressional and functional analysis of CYP15A1, a juvenile hormone epoxidase, in the red flour beetle Tribolium castaneum. AB - Juvenile hormone (JH) is synthesized and secreted by the corpora allata. In the final two steps of JH biosynthesis, farnesoic acid (FA) is converted to JH through methylation by JH acid O-methyltransferase (JHAMT) and epoxidation by the cytochrome P450 enzyme CYP15. In the present study, we identified a homolog of CYP15 from the red flour beetle Tribolium castaneum (TcCYP15A1), and analyzed its expression as well as its role in JH biosynthesis. Quantitative RT-PCR analysis showed that the level of TcCYP15A1 mRNA was high in the embryonic stage as well as in the middle of the final larval instar. In the embryonic stage, the transcript level of TcCYP15A1 started to increase 30h after egg laying (AEL), peaked 54-60h AEL, and was followed by an increase of TcJHAMT mRNA, suggesting that JH biosynthesis started at this time point. TcCYP15A1 mRNA was present, but not exclusively so in the larval corpora allata. The recombinant TcCYP15A1 protein epoxidized both FA and methyl farnesoate (MF) in highly stereo-specific manners. These results confirmed that TcCYP15A1 is involved in JH biosynthesis. The RNAi-mediated knockdown of TcCYP15A1 in the pre-final larval instar did not result in precocious metamorphosis to pupa, indicating that MF may exhibit JH like activity in order to maintain the larval status. The double knockdown of TcJHAMT and TcCYP15A1 resulted in pupae and adults with shorter wings, suggesting that the precursors of JH, JH acid and MF, may be essential for wing expansion. PMID- 25921676 TI - Water balance profiles, humidity preference and survival of two sympatric cockroach egg parasitoids Evania appendigaster and Aprostocetus hagenowii (Hymenoptera: Evaniidae; Eulophidae). AB - The impact of desiccation on habitat selection, foraging and survival has been characterized for many insects. However, limited information is available for parasitic wasps. In this study, water balance, relative humidity (RH) preference, and effect of humidity on survival of solitary Evania appendigaster (L.) (Hymenoptera: Evaniidae) and gregarious Aprostocetus hagenowii (Ratzeburg) (Hymenoptera: Eulophidae) were examined. These species are both oothecal parasitoids of the American cockroach Periplaneta americana (L.) (Dictyoptera: Blattidae). E. appendigaster had significantly higher cuticular permeability (CP) and a lower surface area to volume ratio but a similar percentage of total body water content compared to A. hagenowii. No differences in these attributes were found between sexes of each parasitoid species. The percentage of total body water loss rates among E. appendigaster males and females and A. hagenowii females were similar but significantly lower than that of A. hagenowii males. All parasitoids except E. appendigaster males exhibited reduced survival times as the RH of their enclosure decreased from 87% to 38%, but this phenomenon did not occur when parasitoids were given a sugar solution. In environmental chambers with a 44-87% RH gradient, both sexes of E. appendigaster resided significantly more often in the 87% RH chamber than in the 44% RH chamber. For A. hagenowii, females preferred both the driest and the wettest chambers and males preferred the driest ones. These results demonstrate the water balance profile and its relationship to life history traits and differential responses to RH in these competing parasitoid wasps, suggesting the role of physiological and behavioral adaptations in shaping their ecological niche. PMID- 25921677 TI - Characteristics of non-responders to self-reported questionnaires in a large inflammatory bowel disease cohort study. AB - BACKGROUND: A major threat to the validity of longitudinal cohort studies is non response to follow-up, which can lead to erroneous conclusions. The objective of this study was to evaluate the profile of non-responders to self-reported questionnaires in the Swiss inflammatory bowel disease (IBD) Cohort. METHODS: We used data from adult patients enrolled between November 2006 and June 2011. Responders versus non-responders were compared according to socio-demographic, clinical and psychosocial characteristics. Odds ratio for non-response to initial patient questionnaire (IPQ) compared to 1-year follow-up questionnaire (FPQ) were calculated. RESULTS: A total of 1943 patients received IPQ, in which 331 (17%) did not respond. Factors inversely associated with non-response to IPQ were age >50 and female gender (OR = 0.37; p < 0.001 respectively OR = 0.63; p = 0.003) among Crohn's disease (CD) patients, and disease duration >16 years (OR = 0.48; p = 0.025) among patients with ulcerative colitis (UC). FPQ was sent to 1586 patients who had completed the IPQ; 263 (17%) did not respond. Risk factors of non-response to FPQ were mild depression (OR = 2.17; p = 0.003) for CD, and mild anxiety (OR = 1.83; p = 0.024) for UC. Factors inversely associated with non response to FPQ were: age >30 years, colonic only disease location, higher education and higher IBD-related quality of life for CD, and age >50 years or having a positive social support for UC. CONCLUSIONS: Characteristics of non responders differed between UC and CD. The risk of non-response to repetitive solicitations (longitudinal versus transversal study) seemed to decrease with age. Assessing non-respondents' characteristics is important to document potential bias in longitudinal studies. PMID- 25921678 TI - Revolution: A Report on the UHC Annual Conference 2014. PMID- 25921679 TI - Mechanical experiments as moral exercise in the education of George III. AB - In 1761, George III commissioned a large group of philosophical instruments from the London instrument-maker George Adams. The purchase sprang from a complex plan of moral education devised for Prince George in the late 1750s by the third Earl of Bute. Bute's plan applied the philosophy of Frances Hutcheson, who placed 'the culture of the heart' at the foundation of moral education. To complement this affective development, Bute also acted on seventeenth-century arguments for the value of experimental philosophy and geometry as exercises that habituated the student to recognizing truth, and to pursuing it through long and difficult chains of reasoning. The instruments required for such exercise thus became tools for manipulating moral subjectivity. By the 1730s there was a variety of established modes in which the Newtonian philosophy might be used to argue for the legitimacy of Hanoverian rule. The education of George III represents a less recognized iteration of this relationship, concerned not with public apologetics, but rather with the transformation of an 'indolent' youth into a virtuous monarch. PMID- 25921680 TI - Sounding in silence: men, machines and the changing environment of naval discipline, 1796-1815. AB - Logbooks and sea charts may appear rather straightforward evidence to present at a naval court martial. However, their introduction into proceedings in the early nineteenth century reveals an important shift. Measuring the depth of water soon became a problem both of navigation and of discipline. Indeed, Captain Newcomb's knowledge of the soundings taken at the Battle of the Basque Roads proved crucial at Lord Gambier's court martial in June 1809. Through a case study of Edward Massey's sounding machine, this paper reveals the close connection between disciplinary practices on land and at sea. The Board of Longitude acted as a key intermediary in this respect. By studying land and sea together, this paper better explains the changing make-up of the British scientific instrument trade in this period. Massey is just one example of a range of new entrants, many of whom had little previous experience of the maritime world. More broadly, this paper emphasizes the role of both environmental history and material culture in the study of scientific instruments. PMID- 25921681 TI - George Combe and common sense. AB - This article examines the history of two fields of enquiry in late eighteenth- and early nineteenth-century Scotland: the rise and fall of the common sense school of philosophy and phrenology as presented in the works of George Combe. Although many previous historians have construed these histories as separate, indeed sometimes incommensurate, I propose that their paths were intertwined to a greater extent than has previously been given credit. The philosophy of common sense was a response to problems raised by Enlightenment thinkers, particularly David Hume, and spurred a theory of the mind and its mode of study. In order to succeed, or even to be considered a rival of these established understandings, phrenologists adapted their arguments for the sake of engaging in philosophical dispute. I argue that this debate contributed to the relative success of these groups: phrenology as a well-known historical subject, common sense now largely forgotten. Moreover, this history seeks to question the place of phrenology within the sciences of mind in nineteenth-century Britain. PMID- 25921682 TI - Catholics, science and civic culture in Victorian Belfast. AB - The connections between science and civic culture in the Victorian period have been extensively, and intensively, investigated over the past several decades. Limited attention, however, has been paid to Irish urban contexts. Roman Catholic attitudes towards science in the nineteenth century have also been neglected beyond a rather restricted set of thinkers and topics. This paper is offered as a contribution to addressing these lacunae, and examines in detail the complexities involved in Catholic engagement with science in Victorian Belfast. The political and civic geographies of Catholic involvement in scientific discussions in a divided town are uncovered through an examination of five episodes in the unfolding history of Belfast's intellectual culture. The paper stresses the importance of attending to the particularities of local politics and scientific debate for understanding the complex realities of Catholic appropriations of science in a period and urban context profoundly shaped by competing political and religious factions. It also reflects more generally on how the Belfast story supplements and challenges scholarship on the historical relations between Catholicism and science. PMID- 25921683 TI - Sinanthropus in Britain: human origins and international science, 1920-1939. AB - The Peking Man fossils discovered at Zhoukoudian in north-east China in the 1920s and 1930s were some of the most extensive palaeoanthropological finds of the twentieth century. This article examines their publicization and discussion in Britain, where they were engaged with by some of the world's leading authorities in human evolution, and a media and public highly interested in human-origins research. This international link - simultaneously promoted by scientists in China and in Britain itself - reflected wider debates on international networks; the role of science in the modern world; and changing definitions of race, progress and human nature. This article illustrates how human-origins research was an important means of binding these areas together and presenting scientific work as simultaneously authoritative and credible, but also evoking mystery and adventurousness. Examining this illustrates important features of contemporary views of both science and human development, showing not only the complexities of contemporary regard for the international and public dynamics of scientific research, but wider concerns over human nature, which oscillated between optimistic notions of unity and progress and pessimistic ones of essential differences and misdirected development. PMID- 25921684 TI - The Arabic original of (ps.) Masha'allah's Liber de orbe: its date and authorship. AB - Liber de orbe, attributed to Masha'allah (d. c.815), a court astrologer of the Abbasid dynasty, was one of the earliest Latin sources of Aristotelian physics. Until recently, its Arabic original could not be identified among Arabic works. Through extensive examination of Arabic manuscripts on exact sciences, I found two manuscripts containing the Arabic text of this Latin work, although neither of them is ascribed to Masha'allah: Berlin, Staatsbibliothek zu Berlin, Ms. or. oct. 273, and Philadelphia, Pennsylvania University Library, MS LJS 439. In this paper, I describe these two manuscripts in great detail, so that I confirm their originality of the Liber de orbe, and then by analysing the contents of the Arabic text, I deny the attribution to Masha'allah, and identify the title and author as Book on the Configuration of the Orb by Dunash ibn Tamim, a disciple of Isaac Israeli (c.855-c.955). PMID- 25921685 TI - The shock of the odd. PMID- 25921686 TI - Overlay Technique for Transcatheter Left Atrial Appendage Closure. AB - The Overlay technique is popular in peripheral artery interventions, but not in coronary or cardiac structural procedures. We present an initial experience using three-episode overlays during a transcatheter left atrial appendage closure. The first overlay was applied to facilitate advancement of the delivery sheath into left atrium. The second overlay was used to navigate the advancement of prepped delivery system containing the compressed occluder into its optimal position in the left atrium. The third overlay facilitated the real-time deployment of the closure device. This case report demonstrates the effectiveness of the overlay technique in facilitating each step of the transcatheter left atrial appendage closure. PMID- 25921687 TI - ALDH1 Expression and the Prognosis of Lung Cancer: A Systematic Review and Meta Analysis. AB - PURPOSE: Aldehyde dehydrogenase 1 (ALDH1) has been identified as a putative cancer stem cell (CSC) marker in lung cancer. However, the clinicopathological and prognostic value of this protein in lung cancer patients remains controversial. Thus, we performed a systematic review and meta-analysis of studies assessing the clinical and prognostic significance of ALDH1 expression in lung cancer. METHODS: An identification and review of publications assessing clinical or prognostic significance of ALDH1 expression in lung cancer until September 1, 2014 was undertaken. A meta-analysis was performed to clarify the association between ALDH1 expression and clinical outcomes. RESULTS: A total of 14 publications met the criteria and comprised 1926 cases. Analysis of these data showed that ALDH1 expression was not significantly associated with the patient age (OR = 0.82, 95% confidence interval [CI]: 0.45-1.50, P=0.52), tumour size (OR=0.68, 95% CI: 0.22-2.06, P=0.49), smoking status (OR=1.37, 95% CI: 0.85-2.22, P=0.19), or tumour grade (OR=1.65, 95% CI: 0.83-3.26, P=0.15). However, in the identified studies, ALDH1 expression was highly correlated with lymph node metastasis (OR=1.97, 95% CI: 1.16-3.34, P=0.01), tumour TNM staging (OR=1.68, 95% CI 1.28-2.22, P=0.0002), decreased overall survival (relative risk [RR]: 1.97,95% CI: 1.16-3.34, P =0.01) and decreased disease free survival (RR: 1.63, 95% CI: 1.01-2.64, P=0.05). CONCLUSIONS: This meta-analysis shows ALDH1 expression in lung cancer is connected with decreased overall and disease free survival and thus marks a worse prognosis. PMID- 25921688 TI - Association between Carotid Intima-media Thickness and Early-onset Coronary Artery Disease: Does the site of Sonographic Evaluation Matter? AB - BACKGROUND: Intima-media thickness (IMT) is frequently used for risk stratification (RS) due to the association with coronary artery disease (CAD). Nonetheless, the best carotid site to scan is uncertain, especially in the young. The aim of this study was to evaluate the diagnostic performance of IMT measurements performed at different carotid sites. METHODS: Eighty-nine subjects <=45 years were studied (55 with known CAD and 34 controls). IMT measurements were performed at the common carotid (CC), bulb and internal branch (IB) of both carotid arteries, (2112 measures). The diagnostic performance of IMT measurements performed at different sites, regarding the presence of CAD, was evaluated with ROC curves. RESULTS: Carotid plaques were found in 20.0% of the patients and 6.0% of the controls. The diagnostic performance of carotid IMT measures obtained at the CC, bulb or IB was not significantly different, with the CC and IB being slightly better (AUC ROC =0.82 and 0.80 respectively). CONCLUSIONS: IMT measures obtained at different carotid sites are associated with CAD in young (<=45 years) individuals. The diagnostic performance of IMT measured at the CC and IB is the more accurate measure, and this may be the most adequate for the measurement of IMT in this population. PMID- 25921689 TI - Plasma and Intracellular Pharmacokinetics of Tenofovir Disoproxil Fumarate 300 mg Every 48 Hours vs 150 mg Once Daily in HIV-Infected Adults With Moderate Renal Function Impairment. AB - BACKGROUND: The approved tenofovir disoproxil fumarate (TDF) dose of 300 mg every 48 hours for adults with moderate renal impairment is often confusing and inconvenient. Using a new TDF formulation, we compared the pharmacokinetics of the standard dose with a dose of 150 mg once daily in HIV-infected adults. METHODS: This was an open-label pharmacokinetic study. Virologically suppressed HIV-infected adults with a creatinine clearance 30 to <50 mL/minute receiving TDF 300 mg every 48 hours as part of a nonnucleoside reverse transcriptase inhibitor (NNRTI)- or lopinavir/ritonavir (LPV/r)-based regimen were enrolled. Intensive 48 hour blood sampling for pharmacokinetic assessment was performed at enrollment, after which the TDF dose was changed to 150 mg once daily. Two weeks later, 24 hour blood sampling was performed; subjects then returned to the standard dose. Tenofovir (TFV) pharmacokinetic parameters were calculated using a noncompartmental analysis. RESULTS: Forty adults (55% female) were enrolled: 20 receiving NNRTI-based and 20 receiving LPV/r-based treatment. Median age was 56 years (range, 44-65 years), weight 51 kg (range, 38-80 kg), and creatinine clearance 43.9 mL/minute (range, 30.9-49.7 mL/minute). The TFV geometric mean ratio of the area under the curve (AUC0-48 h) for every 24 hours vs every 48 hours was 1.09 (90% confidence interval [CI], .98-1.22) and 1.00 (90% CI, .92 1.09) for patients receiving NNRTI- and LPV/r-based treatment, respectively. Concomitant LPV/r use markedly increased TFV plasma concentrations, and AUC0-48 h was 67% higher with the standard dose, whereas no differences in intracellular TFV diphosphate concentrations were observed. All subjects remained virologically suppressed, and no drug-related adverse events were reported. CONCLUSIONS: TDF 150 mg every 24 hours provides comparable systemic exposure to the standard dose of 300 mg every 48 hours in patients with moderate renal impairment. CLINICAL TRIALS REGISTRATION: NCT01671982. PMID- 25921690 TI - Bifidobacterium species bacteremia: risk factors in adults and infants. PMID- 25921691 TI - Alcoholic drinks contribute to obesity and should come with mandatory calorie counts. PMID- 25921692 TI - A cross-national comparative study on the influence of individual life course factors on mammography screening. AB - OBJECTIVES: Drawing on insights from the life course perspective, the aim of this paper is to gain a better understanding of persistent socioeconomic inequalities related to the uptake of mammography screening in 13 European countries. We examine whether these inequalities originate in childhood and relate them to the history and progression of each country's screening programs. METHODS: Retrospective data from the third wave of the Survey of Health, Ageing and Retirement (SHARELIFE) is analyzed by means of event-history analyses to examine the role of childhood preventive health behavior on mammography screening initiation. The results are framed within the context of policy developments concerning mammography screening in each of the separate European countries. RESULTS: Childhood preventive health care behavior predicts mammography screening in 9 of the 13 countries after conventional measurements of socioeconomic position in childhood and adulthood are accounted for. Net effects of education and income are still found for respectively 6 and 7 countries, but in about half of these countries national screening programs are able to reduce the social gradient. Very strong cohort and period effects are found for every country. CONCLUSIONS: In a substantial number of the European countries, socioeconomic inequalities in preventive health behavior originate in childhood, which point to the deeply rooted nature of these inequalities. A long-term perspective is essential to further unravel how health policies can reduce or eliminate these persistent inequalities. PMID- 25921694 TI - A novel obstetric table tilt indicator. PMID- 25921693 TI - Identification of a gene controlling variation in the salt tolerance of rapeseed (Brassica napus L.). AB - MAIN CONCLUSION: By genome-wide association study, QTLs for salt tolerance in rapeseed were detected, and a TSN1 ortholog was identified as a candidate gene responsible for genetic variation in cultivars. Dissecting the genomic regions governing abiotic stress tolerance is necessary for marker-assisted breeding to produce elite breeding lines. In this study, a world-wide collection of rapeseed was evaluated for salt tolerance. These rapeseed accessions showed a large variation for salt tolerance index ranging from 0.311 to 0.999. Although no significant correlation between salt tolerance and Na(+) content was observed, there was a significant negative correlation between shoot biomass production under a control condition and salt tolerance. These rapeseed accessions were genotyped by DArTseq for a total of 51,109 genetic markers, which were aligned with 'pseudomolecules' representative of the genome of rapeseed to locate their hypothetical order for association mapping. A total of 62 QTLs for salt tolerance, shoot biomass, and ion-homeostasis-related traits were identified by association mapping using both the P and Q+K models. Candidate genes located within the QTL regions were also shortlisted. Sequence analysis showed many polymorphisms for BnaaTSN1. Three of them in the coding region resulting in a premature stop codon or frameshift were found in most of the sensitive lines. Loss-of-function mutations showed a significant association with salt tolerance in B. napus. PMID- 25921695 TI - Assessing eye orbits as predictors of Neandertal group size. AB - OBJECTIVES: The objective is to investigate the hypothesis that Neandertal eye orbits can predict group size and social cognition as presented by Pearce et al. (Proc R Soc B Biol Sci 280 (2013) 20130168). MATERIALS AND METHODS: We performed a linear regression of known orbital aperture diameter (OAD), neocortex ratio, and group size among 18 extant diurnal primate species. Our data were derived from Kirk (J Hum Evol 51 (2006) 159-170) and Dunbar (J Hum Evol 22 (1992), 469 493; J Hum Evol 28 (1995) 287-296). RESULTS: There is a positive correlation between OAD and group size; a positive correlation between neocortex and group size; and a positive correlation between OAD and neocortex size. The strength of the collinearity between OAD and neocortex ratio accounts for any significance of OAD in a model. The model that best accounts for variation in group size is one that includes only neocortex ratio; including OAD does not strengthen the model. OAD accounts for 29 percent of the variation in group size. DISCUSSION: Larger orbits are correlated with larger group sizes in primates, although not significantly when controlling for neocortex ratio. Moreover, the amount of variation in group size that can be explained by OAD is negligible. The larger orbits of Neandertals compared to the average modern human population do not permit any interpretation of cognitive ability related to group size. PMID- 25921696 TI - Cognition in school-aged children with "active" epilepsy: A population-based study. AB - INTRODUCTION: There is a lack of population-based data on specific cognitive profiles in childhood epilepsy. This study sought to determine the frequency of impairments in global cognition and aspects of working memory and processing speed in a population-based sample of children with "active" epilepsy (on antiepileptic Drugs (AEDs), and/or had a seizure in the last year). Factors significantly associated with global and specific difficulties in cognition were also identified. METHOD: A total of 85 (74% of eligible population) school-aged children (5-15 years) with "active" epilepsy underwent comprehensive psychological assessment including assessment of global cognition, working memory, and processing speed. Scores on cognitive subtests were compared via paired-samples t tests. The factors associated with cognitive difficulties were analyzed via linear regression. RESULTS: A total of 24% of children were functioning below IQ 50, and 40% had IQ scores below 70. Scores on the Processing Speed Index were significantly lower than scores on the Verbal or Performance indexes on Wechsler instruments. The Coding subtest was a significant weakness compared with the other Wechsler subtests. A total of 58% of children displayed "memory underachievement" (memory score 1 SD below assessed IQ) on at least one of the four administered working memory subtests. Factors significantly associated with globally impaired cognition included being on polytherapy (beta = -13.0; 95% CI [-19.3, -6.6], p = .000) and having attention-deficit/hyperactivity disorder (ADHD; beta = -11.1, 95% CI [-3.0, -19.3], p = .008). Being on polytherapy was also associated with lower scores on the working memory and processing speed composite scores. Having developmental coordination disorder (DCD) was associated with a lower score on the processing speed composite. CONCLUSIONS: There is a high rate of global and specific cognitive difficulties in childhood epilepsy. Difficulties are most pronounced in aspects of working memory and processing speed. Predictors of cognitive impairment in childhood epilepsy include epilepsy-related and behavioral factors, which may differ depending on the domain of cognition assessed. PMID- 25921697 TI - Personalized clinical data screening: Special issue on health informatics. PMID- 25921698 TI - B-doped 3C-SiC nanowires with a finned microstructure for efficient visible light driven photocatalytic hydrogen production. AB - B-doped 3C-SiC nanowires have been synthesized via a facile and simple carbothermal reduction method at 1500 degrees C for 2 h in a flowing purified argon atmosphere. The obtained nanowires possess a single crystalline and finned microstructure with fins about 100-200 nm in diameter and 10-20 nm in thickness. The diameter of the inner core stem is about 80 nm on average. Due to the smaller band gap, the finned microstructure and the single crystalline nature, the B doped 3C-SiC nanowires demonstrate efficient activity as high as 108.4 MUmol h( 1) g(-1) for H2 production, which is about 20 times higher than that of 3C-SiC nanowhiskers and 2.6 times higher than the highest value reported in the literature for SiC materials. PMID- 25921700 TI - High-Throughput Dose-Response Measurement Using a Label-Free Microarray-in Microplate Assay Platform. AB - Microarray-based binding assays facilitate the discovery of protein ligands from large collections of small molecules. Hundreds of ligands can be identified, yet only a small portion of them have interfering effects (competitive or noncompetitive) on a specific protein-receptor binding reaction. Further efficient screening of ligands for those with specific modifying effect is needed in order to take the full advantage of throughputs of microarray-based assays for drug discovery. We report a label-free "microarray-in-microplate" assay platform for simultaneous acquisition of at least 32 dose-response curves in a single experiment, each curve having 12 concentration points. When combined with ligand discovery, this makes the microarray-based platform a true high-throughout means of finding inhibitors to specific protein-receptor reactions starting from a large collection of small-molecule libraries. PMID- 25921701 TI - Perioperative effects of caudal and transversus abdominis plane (TAP) blocks for children undergoing urologic robot-assisted laparoscopic surgery. AB - INTRODUCTION: Regional anesthesia is often used in combination with general anesthesia for pediatric surgery, however, it is unknown if adjunctive regional blocks are beneficial to children undergoing urologic laparoscopic or robot assisted laparoscopic (RAL) procedures. OBJECTIVE: To compare perioperative outcomes in children with adjunctive caudal blocks, transversus abdominis plane (TAP) blocks, or no regional anesthesia for common RAL surgical procedures in pediatric urology. STUDY DESIGN: Inclusion in this retrospective study was limited to children who underwent RAL renal or ureteral/bladder procedures and received a standardized regimen of scheduled intravenous ketorolac and oral acetaminophen for acute postoperative pain control, with opioids as needed (PRN). Perioperative outcomes were compared between patients with an adjunctive caudal block (n = 25), bilateral TAP blocks (n = 44), or no regional anesthesia (n = 51). RESULTS: Children with a preoperative caudal block received less intraoperative opioids than children with TAP blocks or no regional anesthesia (p < 0.001). This difference was observed both for renal procedures (p < 0.01) and ureteral/bladder procedures (p = 0.01). Patients with caudal blocks were also the least likely to require postoperative antiemetics (p = 0.03). There were no significant differences between groups in postoperative opioid use, maximum pain scores within 6 and 24 hours postoperatively, or length of hospital stay (LOS). No complications attributable to regional blocks were identified by chart review. DISCUSSION: Use of adjunctive caudal blocks for pediatric RAL renal or ureteral/bladder surgical procedures may reduce need for alternate analgesic and/or anesthetic agents intraoperatively, as well as decrease postoperative nausea and vomiting. These findings may be related, since nausea and vomiting are common side effects of opioids and inhalational anesthetics. Consideration of the potential impact of caudal blocks on general anesthetic requirements is timely in light of concerns regarding the risk of anesthetic neurotoxicity in young patients. There was no evidence of improved postoperative pain control or shorter LOS for children who received regional anesthesia. It is unknown if regional blocks would have a greater impact in the absence of scheduled pain medications, which all patients in our study received. Limitations of this study include its retrospective nature and moderate sample size. Future randomized controlled trials are necessary to provide a more definitive understanding of regional anesthesia's role in minimizing pediatric surgical and anesthetic morbidity. CONCLUSION: Administration of caudal blocks should be considered for children of suitable age undergoing RAL surgery involving either the upper or lower urinary tract. PMID- 25921702 TI - Design, synthesis, and molecular docking studies of 2-(furan-2-yl)quinazolin-4 one derivatives as potential antiproliferative agents. AB - Fifteen new derivatives of quinazolin-4-one bearing the 2-furyl moiety at position 2 and a substituted phenyl moiety at position 3 were designed and synthesized to be evaluated as cytotoxic agents. Their chemical structures were confirmed by spectral and elemental analysis; cytotoxic activity evaluation was performed against HEPG2, HCT116, and MCF7 cancer cell lines using the sulforhodamine-B assay. All the tested compounds except 6a showed high potency against the HEPG2 cancer cell line (IC50 8-101 nM/mL); 11 compounds out of 15 proved to be potent against HCT116 cells (IC50 3-49 nM/mL), also 11 of the tested compounds showed high potency against MCF7 cells with IC50 values ranging from 7 to 63 nM/mL. The rest of the tested compounds showed IC50 values of more than 100 nM/mL. Compounds 3e and 4d are the most active compounds against HEPG2 cells; in addition, 3e is the most active compound against MCF7 cells. Also, compounds 4a, 3a, and 3b are the most active compounds against HCT116 cells. Compounds 3a, 3b, 3e, 4a, and 4d were also evaluated for their inhibitory activity against the EGFR tyrosine kinase (EGFR-TK) and showed a percentage inhibitory activity ranging from 53 to 84%. The most potent EGFR-TK inhibitors, 3a (84%), 3b (75%), and 3e (60%), were docked into the ATP binding site of the EGFR to explore their binding mode and possible interactions. PMID- 25921703 TI - The impact of genome wide supported microRNA-137 (MIR137) risk variants on frontal and striatal white matter integrity, neurocognitive functioning, and negative symptoms in schizophrenia. AB - Although genome wide association studies have highlighted MicroRNA 137 (MIR137) as a novel susceptibility gene for schizophrenia, the mechanisms by which MIR137 risk variants mediate the neurobiology of schizophrenia are not clear. Based on extant data linking MIR 137 gene with structural brain anomalies and functional brain activations in schizophrenia, we hypothesized that MIR137 risk variants rs1625579 and rs1198588 would be associated with reduced fractional anisotropy in frontostriatal brain regions, impaired neurocognitive functioning and worse psychotic symptoms in schizophrenia patients compared with healthy controls. A total of 147 Chinese participants (84 patients with DSM-IV diagnosis of schizophrenia (SCZ) and 63 healthy controls (HC)) were genotyped using blood samples and underwent diffusion tensor imaging. Neurocognitive domains and psychotic symptoms were assessed using The Brief Assessment of Cognition Battery for Schizophrenia and Positive and Negative Syndrome Scale respectively. We found significant diagnosis-genotype interactions in the right orbitofrontal regions (rs1625579: F = 5.44, P = 0.021; rs1198599: F = 7.55, P = 0.005), left striatum (rs1625579: F = 8.09, P=0.007; rs1198599: F=9.56, P = 0.002), and negative symptoms (rs1625579: t = 2.45, P = 0.016; rs1198588: t = 2.29, P = 0.024). Specifically, SCZ carrying the risk TT genotype had worse negative symptoms and decreased FA in the fronto-striatal regions compared to G and A allele carriers for rs1625579 and rs1198588 respectively, and worse attention and processing speed compared with G-allele for rs1625579. Our findings suggested that the MI137 risk variants were associated with decreased fronto-striatal brain white matter integrity which may underlie poorer attention, processing speed, and greater negative symptoms in schizophrenia. PMID- 25921704 TI - The androgen receptor for the radiation oncologist. AB - Androgen deprivation therapy is widely used in combination with radiotherapy for the treatment of prostate cancer. The knowledge of the biology of the androgen axis could help the radiation oncologist to combine both modalities in an efficient way. Moreover, new drugs have recently been approved and their role in combination with radiation needs pre-clinical and clinical studies. This review summarized the main data on the biology of androgen receptor and the potential implications for the physician. Mechanisms of interactions between androgen deprivation therapy and radiotherapy are also presented and discussed. PMID- 25921705 TI - Analysis of the reptile CD1 genes: evolutionary implications. AB - CD1, as the third family of antigen-presenting molecules, is previously only found in mammals and chickens, which suggests that the chicken and mammalian CD1 shared a common ancestral gene emerging at least 310 million years ago. Here, we describe CD1 genes in the green anole lizard and Crocodylia, demonstrating that CD1 is ubiquitous in mammals, birds, and reptiles. Although the reptilian CD1 protein structures are predicted to be similar to human CD1d and chicken CD1.1, CD1 isotypes are not found to be orthologous between mammals, birds, and reptiles according to phylogenetic analyses, suggesting an independent diversification of CD1 isotypes during the speciation of mammals, birds, and reptiles. In the green anole lizard, although the single CD1 locus and MHC I gene are located on the same chromosome, there is an approximately 10-Mb-long sequence in between, and interestingly, several genes flanking the CD1 locus belong to the MHC paralogous region on human chromosome 19. The CD1 genes in Crocodylia are located in two loci, respectively linked to the MHC region and MHC paralogous region (corresponding to the MHC paralogous region on chromosome 19). These results provide new insights for studying the origin and evolution of CD1. PMID- 25921706 TI - Rapid recovery after hip and knee arthroplasty: a process and a destination. PMID- 25921707 TI - Dying in the hospital setting: A systematic review of quantitative studies identifying the elements of end-of-life care that patients and their families rank as being most important. AB - BACKGROUND: The majority of expected deaths occur in hospitals where optimal end of-life care is not yet fully realised, as evidenced by recent reviews outlining experience of care. Better understanding what patients and their families consider to be the most important elements of inpatient end-of-life care is crucial to addressing this gap. AIM AND DESIGN: This systematic review aimed to ascertain the five most important elements of inpatient end-of-life care as identified by patients with palliative care needs and their families. DATA SOURCES: Nine electronic databases from 1990 to 2014 were searched along with key internet search engines and handsearching of included article reference lists. Quality of included studies was appraised by two researchers. RESULTS: Of 1859 articles, 8 met the inclusion criteria generating data from 1141 patients and 3117 families. Synthesis of the top five elements identified four common end-of life care domains considered important to both patients and their families, namely, (1) effective communication and shared decision making, (2) expert care, (3) respectful and compassionate care and (4) trust and confidence in clinicians. The final domains differed with financial affairs being important to families, while an adequate environment for care and minimising burden both being important to patients. CONCLUSION: This review adds to what has been known for over two decades in relation to patient and family priorities for end-of-life care within the hospital setting. The challenge for health care services is to act on this evidence, reconfigure care systems accordingly and ensure universal access to optimal end-of-life care within hospitals. PMID- 25921708 TI - Difficult decisions: An interpretative phenomenological analysis study of healthcare professionals' perceptions of oxygen therapy in palliative care. AB - BACKGROUND: The role of oxygen therapy to palliate dyspnoea is controversial. Without a clear evidence base oxygen is commonly prescribed, sometimes to the detriment of patients. This use of oxygen appears to be an entrenched culture, the roots of which remain obscure. AIM: To explore healthcare professionals' perceptions of oxygen therapy in palliative care. DESIGN: Interpretative phenomenological analysis study utilising semi-structured interviews to explore beliefs and behaviours of healthcare professionals regarding palliative oxygen therapy. Data were recorded, transcribed and analysed using interpretative phenomenological analysis. SETTING/PARTICIPANTS: A total of 34 healthcare professionals, including doctors, nurses, pharmacists and paramedics in the United Kingdom, who were involved in prescribing, or administering, oxygen therapy to palliate dyspnoea. RESULTS: Most healthcare professionals in this study were well informed about oxygen therapy; all recognised the role of oxygen in palliative care setting as important. The overarching theme of compassion identified sub-themes of 'comfort', 'do anything and everything' and 'family benefit'. However, the use of oxygen in the palliative care setting was not without its dilemmas, as additional sub-themes of 'controversy', 'doubt' and 'dependency' illustrated. CONCLUSION: Findings suggest that oxygen therapy in palliative care poses an on-going dilemma for healthcare professionals striving to provide optimum care. It seems patients and families often expect and welcome oxygen, but the perception of oxygen as a solution to dyspnoea can conflict with healthcare professionals' own doubt and experiences. There appears to be an emotional cost associated with this dilemma and the choices that need to be made. PMID- 25921710 TI - Oral carriage of Candida species in HIV-infected patients during highly active antiretroviral therapy (HAART) in Belem, Brazil. AB - OBJECTIVE: To identify the oral carriage of Candida spp in patients infected by human immunodeficiency virus (HIV) and the possible correlation with clinical characteristics. STUDY DESIGN: Mucosal swab samples collected from 246 patients who were infected by HIV, did not have oral candidiasis, and were being treated with highly active antiretroviral therapy were analyzed. Yeast colonies that developed were identified by using the VITEK 2 automated system. RESULTS: Candida yeasts were present in 41.87% of the samples, and Candida albicans was the most prevalent (32.52%). Other identified Candida species were C tropicalis (4.88%), C parapsilosis (2.85%), C dubliniensis (0.81%), and C famata (0.81%). CONCLUSIONS: There was low rate of oral Candida carriage in patients infected by HIV who were on highly active antiretroviral therapy. A greater prevalence of C albicans than non-albicans Candida species was found at the species level. Prior candidiasis predicted the oral carriage of C albicans; however, it did not influence the carriage of non-albicans species. This is the first report of oral carriage of C famata in patients with HIV infection. PMID- 25921711 TI - Multiple complex odontoma of the maxilla and the mandible. AB - OBJECTIVE: The aim of this study was to present a literature review and case report of multiple odontoma. METHODS: A case of multiple odontoma is presented with a review of the English-language literature. The clinical and radiologic features are summarized. RESULTS: In total, 12 cases of multiple odontoma were retrieved from the literature for analysis. The multiple odontomas were localized or extensive and involved two to four quadrants of the jaws. The histologic types were compound or complex. CONCLUSION: Odontomas can be multiple and involve multiple quadrants of the jaws. PMID- 25921709 TI - Establishing psychosocial palliative care standards for children and adolescents with cancer and their families: An integrative review. AB - BACKGROUND: Despite standardization in disease assessments and curative interventions for childhood cancer, palliative assessments and psychosocial interventions remain diverse and disparate. AIM: Identify current approaches to palliative care in the pediatric oncology setting to inform development of comprehensive psychosocial palliative care standards for pediatric and adolescent patients with cancer and their families. Analyze barriers to implementation and enabling factors. DESIGN: Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines framed the search strategy and reporting. Data analysis followed integrative review methodology. DATA SOURCES: Four databases were searched in May 2014 with date restrictions from 2000 to 2014: PubMed, Cochrane, PsycINFO, and Scopus. A total of 182 studies were included for synthesis. Types of studies included randomized and non-randomized trials with or without comparison groups, qualitative research, prior reviews, expert opinion, and consensus report. RESULTS: Integration of patient, parent, and clinician perspectives on end-of-life needs as gathered from primary manuscripts (using NVivo coding for first-order constructs) revealed mutual themes across stakeholders: holding to hope, communicating honestly, striving for relief from symptom burden, and caring for one another. Integration of themes from primary author palliative care outcome reports (second-order constructs) revealed the following shared priorities in cancer settings: care access; cost analysis; social support to include primary caregiver support, sibling care, bereavement outreach; symptom assessment and interventions to include both physical and psychological symptoms; communication approaches to include decision-making; and overall care quality. CONCLUSION: The study team coordinated landmark psychosocial palliative care papers into an informed conceptual model (third order construct) for approaching pediatric palliative care and psychosocial support in oncology settings. PMID- 25921712 TI - Induction of protective immunity against Eimeria tenella, Eimeria necatrix, Eimeria maxima and Eimeria acervulina infections using multivalent epitope DNA vaccines. AB - Avian coccidiosis is mostly caused by mixed infection of several Eimeria species under natural conditions and immunity to avian coccidiosis is largely dependent on T-cell immune response. In this study, 14 T-cell epitope fragments from eight antigens of Eimeria tenella (E. tenella), Eimeria necatrix (E. necatrix), Eimeria maxima (E. maxima) and Eimeria acervulina (E. acervulina) were ligated with pVAX1 producing 14 monovalent DNA vaccines, respectively. Protective immunity of the monovalent DNA vaccines was assessed by in vivo challenge experiments and then four most protective fragments of each species were chosen to construct multivalent epitope DNA vaccines with or without chicken IL-2 as genetic adjuvant. Protective efficacies of the epitope DNA vaccines on chickens against E. tenella, E. necatrix, E. maxima and E. acervulina were evaluated. The results showed that the constructed multivalent epitope DNA vaccines significantly increased body weight gain, alleviated enteric lesions and reduced oocyst output of the infected birds. Especially, the multivalent epitope DNA vaccines of pVAX1 NA4-1-TA4-1-LDH-2-EMCDPK-1 and pVAX1-NA4-1-TA4-1-LDH-2-EMCDPK-1-IL-2 not only significantly increased body weight gain, alleviated enteric lesions and reduced oocyst output of the infected birds, but also resulted in anti-coccidial index (ACI) more than 170 against E. tenella, E. necatrix, E. maxima and E. acervulina, which indicated they could induce protective immunity against E. tenella, E. necatrix, E. maxima and E. acervulina. Our findings suggest the constructed multivalent epitope DNA vaccines are the potential candidate multivalent vaccines against mixed infection of Eimeria. PMID- 25921713 TI - Concurrent and cross-season protection of inactivated influenza vaccine against A(H1N1)pdm09 illness among young children: 2012-2013 case-control evaluation of influenza vaccine effectiveness. AB - In 2012-2013, we examined 1729 laboratory-confirmed A(H1N1)pdm09 influenza cases matched 1:1 with healthy controls and estimated influenza vaccine effectiveness (VE) for trivalent inactivated influenza vaccine (IIV3) to be 67% (95% confidence interval=58-74%) for ages 8 months to 6 years old. Among children aged 8-35 months old, VE for fully vaccinated children (73%, 60-81%) was significantly higher than VE for partially vaccinated children (55%, 33-70%). Significant cross season protection from prior IIV3 was noted, including VE of 31% (8-48%) from IIV3 received in 2010-2011 against influenza illness in 2012--2013 without subsequent boosting doses. PMID- 25921714 TI - Understanding metastasis. PMID- 25921715 TI - Unmanipulated Haploidentical Reduced-Intensity Stem Cell Transplantation Using Fludarabine, Busulfan, Low-Dose Antithymocyte Globulin, and Steroids for Patients in Non-Complete Remission or at High Risk of Relapse: A Prospective Multicenter Phase I/II Study in Japan. AB - This prospective, multicenter phase I/II study of unmanipulated HLA haploidentical reduced-intensity stem cell transplantation using a low dose of anti-T lymphocyte globulin (ATG) and steroid was conducted in 5 institutions in Japan. Thirty-four patients with hematologic malignancies who were in an advanced stage or at a high risk of relapse at the time of transplantation were enrolled. Among them, 7 patients underwent transplantation as a second transplantation because of relapse after the previous allogeneic stem cell transplantation. The conditioning regimen consisted of fludarabine, busulfan, and ATG (Fresenius, 8 mg/kg), and graft-versus-host disease (GVHD) prophylaxis consisted of tacrolimus and methylprednisolone (1 mg/kg). All patients except 1 (97.1%) achieved donor type engraftment. Rapid hematopoietic engraftment was achieved, with neutrophils > .5 * 10(9)/L on day 11 and platelets > 20 * 10(9)/L on day 17.5. Treatment was started for >=grade I GVHD, and the cumulative incidences of acute grade I and grade II to IV GVHD were 27.5% and 30.7%, respectively. The incidence of chronic GVHD (extensive type) was 20%. Fourteen patients (41.2%) had a relapse. The cumulative incidence of transplantation-related mortality at 1 year after transplantation was 26.5%. The survival rate at day 100 was 88.2%. The survival rates at 1 year for patients with complete remission (CR)/chronic phase (n = 8) and non-CR (n = 26) status before transplantation were 62.5% and 42.3%, respectively. In the multivariate analysis, non-CR status before transplantation was the only factor significant prognostic factor of increased relapse (P = .0424), which tended to be associated with a lower survival rate (P = .0524). This transplantation protocol is safe and feasible, if a suitable donor is not available in a timely manner. As the main cause of death was relapse and not GVHD, more intensified conditioning or attenuation of GVHD prophylaxis and/or donor lymphocyte infusion may be desirable for patients with non-CR status. PMID- 25921716 TI - Diagnostic value of a pancreatic mass on computed tomography in patients undergoing pancreatoduodenectomy for presumed pancreatic cancer. AB - INTRODUCTION: Previous studies have shown that 5-14% of patients undergoing pancreatoduodenectomy for suspected malignancy ultimately are diagnosed with benign disease. A "pancreatic mass" on computed tomography (CT) is considered to be the strongest predictor of malignancy, but studies describing its diagnostic value are lacking. The aim of this study was to determine the diagnostic value of a pancreatic mass on CT in patients with presumed pancreatic cancer, as well as the interobserver agreement among radiologists and the additional value of reassessment by expert-radiologists. METHODS: Reassessment of preoperative CT scans was performed within a previously described multicenter retrospective cohort study in 344 patients undergoing pancreatoduodenectomy for suspected malignancy (2003-2010). Preoperative CT scans were reassessed by 2 experienced abdominal radiologists separately and subsequently in a consensus meeting, after defining a pancreatic mass as "a measurable space occupying soft tissue density, except for an enlarged papilla or focal steatosis". RESULTS: CT scans of 86 patients with benign and 258 patients with (pre)malignant disease were reassessed. In 66% of patients a pancreatic mass was reported in the original CT report, versus 48% and 50% on reassessment by the 2 expert radiologists separately and 44% in consensus (P < .001 vs original report). Interobserver agreement between the original CT report and expert consensus was fair (kappa = 0.32, 95% confidence interval 0.23-0.42). Among both expert-radiologists agreement was moderate (kappa = 0.47, 95% confidence interval 0.38-0.56), with disagreement on the presence of a pancreatic mass in 29% of cases. The specificity for malignancy of pancreatic masses identified in expert consensus was twice as high compared with the original CT report (87% vs 42%, respectively). Positive predictive value increased to 98% after expert consensus, but negative predictive value was low (12%). CONCLUSION: Clinicians need to be aware of potential considerable disagreement among radiologists about the presence of a pancreatic mass. The specificity for malignancy doubled by expert radiologist reassessment when a uniform definition of "pancreatic mass" was used. PMID- 25921717 TI - Comment on: Is central lymph node dissection necessary for parathyroid carcinoma? PMID- 25921718 TI - Intravenous solutions in the care of patients with volume depletion and electrolyte abnormalities. AB - Infusion fluids are often given to restore blood pressure (volume resuscitation), but may also be administered to replace ongoing losses, match insensible losses, correct electrolyte or acid-base disorders, or provide glucose. The development of new infusion fluids has provided clinicians with a wide range of products. Although the choice for a certain infusion fluid is often driven more by habit than by careful consideration, we believe it is useful to approach infusion fluids as drugs and consider their pharmacokinetic and pharmacodynamic characteristics. This approach not only explains why infusion fluids may cause electrolyte and acid-base disturbances, but also why they may compromise kidney function or coagulation. In this teaching case, we present a 19-year-old patient in whom severe hypernatremia developed as a result of normal saline solution infusion and explore the pharmacokinetic and pharmacodynamic effects of frequently used infusion fluids. We review clinical evidence to guide the selection of the optimal infusion fluid. PMID- 25921720 TI - Bacterial community structure in treated sewage sludge with mesophilic and thermophilic anaerobic digestion. AB - Stabilized sewage sludge is applied to agricultural fields and farmland due to its high organic matter content. The aim of this study was to investigate the effects of two types of sludge stabilization, mesophilic anaerobic digestion (MAD) and thermophilic anaerobic digestion (TAD), on bacterial communities in sludge, including the presence of pathogenic microorganisms. Bacterial community structure and phylogenetic diversity were analyzed in four sewage sludge samples from the Czech Republic. Analysis of 16S ribosomal RNA (rRNA) genes showed that investigated sludge samples harbor diverse bacterial populations with only a few taxa present across all samples. Bacterial diversity was higher in sludge samples after MAD versus TAD treatment, and communities in MAD-treated sludge shared the highest genetic similarities. In all samples, the bacterial community was dominated by reads affiliated with Proteobacteria. The sludge after TAD treatment had considerably higher number of reads of thermotolerant/thermophilic taxa, such as the phyla Deinococcus-Thermus and Thermotogae or the genus Coprothermobacter. Only one operational taxonomic unit (OTU), which clustered with Rhodanobacter, was detected in all communities at a relative abundance >1 %. All of the communities were screened for the presence of 16S rRNA gene sequences of pathogenic bacteria using a database of 122 pathogenic species and >=98 % identity threshold. The abundance of such sequences ranged between 0.23 and 1.57 % of the total community, with lower numbers present after the TAD treatment, indicating its higher hygienization efficiency. Sequences clustering with nontuberculous mycobacteria were present in all samples. Other detected sequences of pathogenic bacteria included Streptomyces somaliensis, Acinetobacter calcoaceticus, Alcaligenes faecalis, Gordonia spp., Legionella anisa, Bordetella bronchiseptica, Enterobacter aerogenes, Brucella melitensis, and Staphylococcus aureus. PMID- 25921719 TI - APOL1 Genotype and Glomerular and Tubular Kidney Injury in Women With HIV. AB - BACKGROUND: APOL1 genotype is associated with advanced kidney disease in African Americans, but the pathogenic mechanisms are unclear. Here, associations of APOL1 genotype with urine biomarkers of glomerular and tubular injury and kidney function decline were evaluated. STUDY DESIGN: Observational study. SETTING & PARTICIPANTS: 431 human immunodeficiency virus (HIV)-infected African American women enrolled in Women's Interagency HIV Study (WIHS). PREDICTOR: APOL1 genotype. OUTCOMES: Albumin-creatinine ratio (ACR), 4 tubular injury biomarkers (interleukin 18 [IL-18], kidney injury molecule 1 [KIM-1], neutrophil gelatinase associated lipocalin [NGAL], and alpha1-microglobulin [A1M]), and kidney function estimated using the CKD-EPI cystatin C equation. MEASUREMENTS: Participants were genotyped for APOL1 single-nucleotide polymorphisms rs73885319 (G1 allele) and rs71785313 (G2 allele). Urine biomarkers were measured using stored samples from 1999-2000. Cystatin C was measured using serum collected at baseline and 4- and 8 year follow-ups. RESULTS: At baseline, ACRs were higher among 47 women with 2 APOL1 risk alleles versus 384 women with 0/1 risk allele (median, 24 vs 11mg/g; P<0.001). Compared with women with 0/1 risk allele, women with 2 risk alleles had 104% higher ACRs (95% CI, 29-223mg/g) and 2-fold greater risk of ACR>30 (95% CI, 1.17-3.44) mg/g after multivariable adjustment. APOL1 genotype showed little association with urine IL-18:Cr ratio, KIM-1:Cr ratio, and NGAL:Cr ratio (estimates of -5% [95% CI, -24% to 18%], -20% [95% CI, -36% to -1%], and 10% [95% CI, -26% to 64%], respectively) or detectable urine A1M (prevalence ratio, 1.13; 95% CI, 0.65-1.97) in adjusted analyses. Compared with women with 0/1 allele, women with 2 risk alleles had faster eGFR decline, by 1.2 (95% CI, 0.2 to 2.2) mL/min/1.73m(2) per year, and 1.7- and 3.4-fold greater rates of incident chronic kidney disease (95% CI, 1.1 to 2.5) and 10% annual eGFR decline (95% CI, 1.7 to 6.7), respectively, with minimal attenuation after adjustment for glomerular and tubular injury biomarker levels. LIMITATIONS: Results may not be generalizable to men. CONCLUSIONS: Among HIV-infected African American women, APOL1-associated kidney injury appears to localize to the glomerulus, rather than the tubules. PMID- 25921721 TI - A comprehensive protocol to test instrumented treadmills. AB - Instrumented treadmills are becoming more common in gait analysis. Due to their large and compliant structure, errors in force measurements are expected to be higher compared with conventional force plates. There is, however, no consistency in the literature on testing the performance of these treadmills. Therefore, we propose a standard protocol to assess and report error sources in instrumented treadmills. The first part of this protocol consists of assessment of the accuracy of forces and center of pressure (COP), including non-linearity, hysteresis and crosstalk. The second part consists of (novel) instrumented resonance testing and belt speed variability tests. The third part focuses on measurement variability over time, including drift, warming of the system and noise. The performance of two in-house instrumented treadmills with different dynamics was measured. Differences were found between the treadmills in COP accuracy (4.0 mm versus 6.5 mm), lowest eigen frequency (35 Hz versus 23 Hz) and noise level at 5 km/h (10 N versus 29 N). The loaded treadmills both showed a 3.3% belt speed variability at 5 km/h. Thus, the protocol was able to characterize strong and weak characteristics of the treadmills and allowed for a proper judgement on the validity of the instruments and their application in the domain of gait analysis. We propose to use this protocol when testing and reporting the performance of instrumented treadmills. PMID- 25921722 TI - Processing of laser Doppler flowmetry signals from healthy subjects and patients with varicose veins: Information categorisation approach based on intrinsic mode functions and entropy computation. AB - The diagnosis of pathologies from signal processing approaches has shown to be of importance. This can provide noninvasive information at the earliest stage. In this work, the problem of categorising - in a quantifiable manner - information content of microvascular blood flow signals recorded in healthy participants and patients with varicose veins is addressed. For this purpose, laser Doppler flowmetry (LDF) signals - that reflect microvascular blood flow - recorded both at rest and after acetylcholine (ACh) stimulation (an endothelial-dependent vasodilator) are analyzed. Each signal is processed with the empirical mode decomposition (EMD) to obtain its intrinsic mode functions (IMFs). An entropy measure of each IMFs is then computed. The results show that IMFs of LDF signals have different complexity for different physiologic/pathological states. This is true both at rest and after ACh stimulation. Thus, the proposed framework (EMD + entropy computation) may be used to gain a noninvasive understanding of LDF signals in patients with microvascular dysfunctions. PMID- 25921723 TI - Individuals with low working memory spans show greater interference from irrelevant information because of poor source monitoring, not greater activation. AB - Although individuals with high and low working memory (WM) span appear to differ in the extent to which irrelevant information interferes with their performance on WM tasks, the locus of this interference is not clear. The present study investigated whether, when performing a WM task, high- and low-span individuals differ in the activation of formerly relevant, but now irrelevant items, and/or in their ability to correctly identify such irrelevant items. This was done in two experiments, both of which used modified complex WM span tasks. In Experiment 1, the span task included an embedded lexical decision task designed to obtain an implicit measure of the activation of both currently and formerly relevant items. In Experiment 2, the span task included an embedded recognition judgment task designed to obtain an explicit measure of both item and source recognition ability. The results of these experiments indicate that low-span individuals do not hold irrelevant information in a more active state in memory than high-span individuals, but rather that low-span individuals are significantly poorer at identifying such information as irrelevant at the time of retrieval. These results suggest that differences in the ability to monitor the source of information, rather than differences in the activation of irrelevant information, are the more important determinant of performance on WM tasks. PMID- 25921724 TI - Hydrothermal synthesis of Group 13 metal trifluoride complexes with neutral N donor ligands. AB - The reactions of the hydrated Group 13 fluorides, MF3.3H2O (M = Al, Ga or In) with 2,2':6',2''-terpyridyl, 2,2'-bipyridyl or 1,10-phenanthroline under hydrothermal conditions (180 degrees C/15 h) produced high yields of the complexes [MF3(terpy)].3H2O, [MF3(bipy)(OH2)].2H2O and [MF3(phen)(OH2)]. X-Ray crystal structures of [M'F3(terpy)].3H2O (M' = Al or Ga), [M'F3(bipy)(OH2)].2H2O and [GaF3(phen)(OH2)] show that all of them contain distorted octahedral geometries at the metal with mer-trifluoride coordination. Extensive H-bonding (FH-OH) links the molecules. The complexes have been further characterised by microanalysis, IR, (1)H, (19)F{(1)H} and (27)Al NMR spectroscopy. In contrast, reactions of the trifluorides with the acyclic triamine, N,N,N',N',N'' pentamethyldiethylenetriamine, under similar hydrothermal conditions results in cleavage of the triamine and ring-closure to form the 1,1,4-trimethylpiperazinium cation, [?Me2N(CH2)2NMe(CH2)2](+), with fluorometallate anions, and confirmed by X-ray analysis of [?Me2N(CH2)2NMe(CH2)2]2[Al2F8(OH2)2].2H2O. The strongly H bonded [GaF3(terpy)].3H2O was also obtained by Cl/F exchange from [GaCl3(terpy)] and [NBu4]F or [K(2,2,2-crypt)]F. Crystallisation of a mixture of [NH4][PF6] and [GaF3(terpy)].3H2O from aqueous solution produced the edge-bridged cationic complex, [{Ga(terpy)F}2(MU-F)2][PF6]2. The synthesis of the more sterically bulky [GaCl3((t)Bu3-terpy)] ((t)Bu3-terpy = 4,4'4''-tris-(t)Bu-2,2':6',2''-terpyridyl) and the crystal structure of [GaCl2((t)Bu3-terpy)][GaCl4], which contains a trigonal bipyramidal cation, are also reported. PMID- 25921725 TI - Factors related to Chinese older adults' suicidal thoughts and attempts. AB - OBJECTIVES: Guided by the biopsychosocial framework and empirical evidence, this study examined protective and risk factors of older adults' suicidal thoughts and attempts during the previous month, 12 months, and 5 years. METHOD: The data used in this study were extracted from the Sample Survey on Aged Population in Urban/Rural China conducted in 2006, which included 15,957 older adults from mainland China. Multiple penalized logistic regressions were used to conduct the analyses. RESULTS: During the previous month, 12 months, and 5 years, 5.10/00, 10.00/00, and 17.70/00 of older adults indicated that they thought about suicide, whereas 2.20/00, 3.50/00, and 6.30/00 reported suicidal attempts, respectively. Older adults' age, financial strain, functional limitations, depression, children's filial piety, social network, loneliness, and urban residence were significantly related to suicidal thoughts during the different time periods. In addition, older adults' religious affiliation, depression, loneliness, and urban residence were significantly related to suicidal attempts during the different time periods. CONCLUSION: Older adults' suicidal thoughts and attempts need to be assessed by mental health care professionals and primary care doctors. Programs addressing these important protective and risk factors may help reduce older adults' suicidal thoughts and attempts. PMID- 25921726 TI - A lipid-managing program maintains a stout Spitzenkorper. AB - The Spitzenkorper (SPK) is an accumulation of vesicles interleaved with actin microfilaments present at the cytosolic side of the apical plasma membrane (PM) of hyphal tips of many species of filamentous fungi. The physiological role of the SPK has captivated fungal biologists over the years, but only very recently this 'organelle' is starting to be understood in the molecular terminology used for cell biological models. One aspect that has received little attention is the role of cellular membrane asymmetry in the organization of membrane traffic, in particular in the genetic and cell biological model Aspergillus nidulans. The paper by Schultzhaus et al. (2015) in this issue breaks the ice, providing original insight that may foster research in phospholipid composition in the context of intracellular traffic and the organization of the SPK. Notably, it shows that like the stout Neurospora crassa SPK, the much slimmer one of A. nidulans, appears to be formed by different strata, altogether suggesting that the SPK might be a mosaic of exocytic carriers with different functional specializations, and a major sorting hub for intracellular membranes. PMID- 25921727 TI - Challenges in measuring complications and death due to invasive Salmonella infections. AB - Despite the highest burden of Typhoid fever in children globally, exact estimates of morbidity and mortality are lacking due to scarcity of published data. Despite a high prevalence and a socioeconomic burden in developing countries, published data with morbidity and mortality figures are limited especially Africa and South American regions. Data from the community is insufficient and most case fatality estimates are extrapolations from hospital based studies that do not cover all geographical regions, and include cases which may or not be culture confirmed, MDR resistant or sensitive cases, or from mixed populations of age (adults and children). Complications of typhoid such as intestinal perforation, bone marrow suppression, and encephalopathy are dependent on MDR/Fluoroquinolone resistant Salmonella infection, comorbidities such as malnutrition, and health-care access. Data is again insufficient to estimate the true burden of Typhoid Fever in different regions and groups of populations. Although there has been a rapid decline in cases in developed countries with the advent of improved sanitization, timely and easy access to health care and laboratories, this is still not the case in the developing countries where Typhoid deaths are still occurring. The way forward is to develop rapid and cost effective point of care diagnostic tests, put in place validated clinical algorithms for suspected clinical cases, and design prospective, and community based studies in different groups, implement maintenance of electronic health records in large public sector hospitals and regions to identify populations that will benefit most from the implementation of vaccine. Policies on public health education and typhoid vaccine may help to reduce morbidity and mortality due to the disease. PMID- 25921728 TI - Discerning mechanistically rewired biological pathways by cumulative interaction heterogeneity statistics. AB - Changes in response of a biological pathway could be a consequence of either pathway rewiring, changed input, or a combination of both. Most pathway analysis methods are not designed for mechanistic rewiring such as regulatory element variations. This limits our understanding of biological pathway evolution. Here we present a Q-method to discern whether changed pathway response is caused by mechanistic rewiring of pathways due to evolution. The main innovation is a cumulative pathway interaction heterogeneity statistic accounting for rewiring specific effects on the rate of change of each molecular variable across conditions. The Q-method remarkably outperformed differential-correlation based approaches on data from diverse biological processes. Strikingly, it also worked well in differentiating rewired chaotic systems, whose dynamics are notoriously difficult to predict. Applying the Q-method on transcriptome data of four yeasts, we show that pathway interaction heterogeneity for known metabolic and signaling pathways is indeed a predictor of interspecies genetic rewiring due to unbalanced TATA box-containing genes among the yeasts. The demonstrated effectiveness of the Q-method paves the way to understanding network evolution at the resolution of functional biological pathways. PMID- 25921730 TI - [Impact of guidelines on ambulatory pediatric antibiotic prescriptions]. AB - INTRODUCTION: The emergence of antibiotics resistance as a major public health threat has led, in France as in other countries, to the establishment of "antibiotics plans" based in part on practice guidelines. The objectives of this study were to determine the structure (number, causes, distribution of compounds) of antibiotic prescriptions by infectious diseases pediatricians (belonging to a pediatric infectious diseases research group), to check their compliance with guidelines and compare their prescriptions to other French pediatricians and general practitioners (GPs). PATIENTS AND METHODS: In a survey on acute otitis media (AOM), outpatient pediatricians reported prospectively from October 2013 to February 2014 all antibiotics prescribed and the reasons for these prescriptions. These results were compared with prescription data from a panel of other pediatricians and GPs in France (IMS Health panels). RESULTS: Between October 2013 and February 2014, 27 pediatricians from the Infectious Disease Pediatricians Group conducted 54,212 visits, 10.7 % of which resulted in antibiotic prescriptions, all diseases combined, compared to 12 % for other pediatricians and 21 % for GPs in the same period. AOM was the leading cause of prescriptions for infectious disease pediatricians and panel pediatricians, and GPs (respectively, 72.6 %, 33 %, and 25 %). Amoxicillin was the most frequently prescribed antibiotic (respectively, 71.7 %, 49.9 %, and 28.2 %). Cephalosporins were prescribed in 6.4 % of cases by infectious disease pediatricians versus 19 % for panel pediatricians and 19.9 % for GPs. CONCLUSION: The prescriptions of infectious disease pediatricians are in accordance with the French guidelines. The differences with the IMS data justify the need for continuous medical training and recommendations to promote these guidelines. PMID- 25921729 TI - Role of CD64 expression on neutrophils in the diagnosis of sepsis and the prediction of mortality in adult critically ill patients. AB - Intensive care unit patients who developed systemic inflammatory response syndrome (SIRS) with proven microbial etiology were assigned to the infectious causes (n = 29), while patients with negative cultures and more probable other etiology were assigned to the noninfectious causes (n = 37). Flow cytometry was used to detect the presence of CD64 on neutrophils. The multivariate analysis revealed that KPC-producing Klebsiella pneumoniae rectal colonization and >1.39 mean fluorescence intensity (MFI) of CD64 expression on neutrophils upon day 1 of SIRS were significantly associated with an infectious SIRS. The overall mortality was 29% (19 patients) and was independently associated with Simplified Acute Physiology Score II >44 points and multiple-organ dysfunction syndrome, while appropriate antibiotic treatment was identified as predictor of good prognosis. MFI of CD64 expression on neutrophils showed high sensitivity, specificity, and accuracy in the diagnosis of sepsis but not for the prediction of survival. PMID- 25921731 TI - Prevalence of Complementary and Alternative Medicine in Immigrants. AB - Immigrants face barriers to accessing conventional health care systems. Hence, they are expected to have comparatively greater use of complementary and alternative medicine (CAM). This study examines the prevalence of and reason for CAM use in the U.S. population by citizenship status. Data on 34,483 U.S.-born, naturalized, and non-U.S. citizens from the 2012 National Health Interview Survey was used. CAM was categorized into four domains. Analyses controlling for socioeconomic variables were identified patterns of utilization and reasons for use. The prevalence of all CAM domains was lowest among non-U.S. citizens followed by naturalized citizens. The odds of using CAM were also higher for the immigrants who attained citizenship than for non-citizens. Individuals in all groups reported using more CAM for prevention. Factors related to cost, accessibility, or knowledge of CAM use may contribute to lower use of CAM by naturalized and non-U.S. citizens. PMID- 25921733 TI - A NCS mediated oxidative C-H bond functionalization: direct esterification between a C(sp(3))-H bond and carboxylic acids. AB - A transition metal free oxidative C-H bond functionalization/esterification of alpha-alkoxy alkanes with acids is described in this report. This method is effectively mediated by NCS instead of traditional oxidants, like TBHP or its derivatives, and directly generates the esterification products in moderate to high yield under mild conditions. This tranformation constitutes a practical and general approach toward various alpha-acyloxy ethers with broad substrate generality; alkyl-, aryl-, alkenyl- and alkynyl-carboxylic acids are all well tolerated. PMID- 25921732 TI - The effect of mild traumatic brain injury on peripheral nervous system pathology in wild-type mice and the G93A mutant mouse model of motor neuron disease. AB - Traumatic brain injury (TBI) is associated with a risk of neurodegenerative disease. Some suggest a link between TBI and motor neuron disease (MND), including amyotrophic lateral sclerosis (ALS). To investigate the potential mechanisms linking TBI to MND, we measured motor function and neuropathology following mild-TBI in wild-type and a transgenic model of ALS, G93A mutant mice. Mild-TBI did not alter the lifespan of G93A mice or age of onset; however, rotarod performance was impaired in G93A verses wild-type mice. Grip strength was reduced only in G93A mice after mild-TBI. Increased electromyography (EMG) abnormalities and markers of denervation (AchR, Runx1) indicate that mild-TBI may result in peripheral effects that are exaggerated in G93A mice. Markers of inflammation (cell edema, astrogliosis and microgliosis) were detected at 24 and 72h in the brain and spinal cord in wild-type and G93A mice. Levels of F2 isoprostanes, a marker of oxidative stress, were increased in the spinal cord 24h post mild-TBI in wild-type mice but were not affected by TBI in G93A mice. In summary, our data demonstrate that mild-TBI induces inflammation and oxidative stress and negatively impacts muscle denervation and motor performance, suggesting mild-TBI can potentiate motor neuron pathology and influence the development of MND in mice. PMID- 25921734 TI - [Peritoneal dialysis catheter insertion under TAP block procedure: A pilot study]. AB - INTRODUCTION: The main objective of this study was to evaluate the feasibility of a laparotomy peritoneal dialysis insertion, under locoregional anesthesia, by transversus abdominis plane block anesthesia. METHODS: This was a retrospective study of the peritoneal dialysis catheter insertion under transversus abdominis plane block anesthesia in our center between the September 1, 2011 and July 31, 2013. The transversus abdominis plane block procedure was used as an alternative to general anesthesia. Patients who underwent a peritoneal dialysis catheter insertion under transversus abdominis plane block anesthesia were included in the study. The main criterion of the study was the pain expressed by the patient during the procedure. Postoperative complications were also evaluated. The catheter function was assessed by an infusion and drainage test just after surgical procedure, 10 days after the insertion and at dialysis initiation. RESULTS: Thirty-seven patients who had one catheter insertion were included in the study. Among those 37 patients, 28 (75.7%), 26 (70.3%) and 31 (83.8%) respectively did not express any pain during the procedure, two and four hours after the catheter insertion. Of the 37 patients, 5 had an early postoperative complication (hematoma: 11%, hemoperitoneum: 3%). The peritoneal dialysis catheter function was estimated to be good just after the insertion and 10 days after the surgery for 35/37 (95%) patients. Among these 36 patients, 29 (81%) had a catheter function peritoneal dialysis initiation. CONCLUSION: The transversus abdominis plane block anesthesia should be considered as an alternative to general anesthesia for the peritoneal dialysis insertion in comorbid end stage renal disease patient. PMID- 25921735 TI - [Diagnostic value of IgG subtypes in membranous nephropathy: A case report]. AB - The study of immunoglobulin G subtypes constituting immune deposits present in membranous nephropathy is useful to guide diagnosis. IgG4 deposits are more often seen in primitive forms of membranous nephropathy due to autoantibody (anti phospholipase A2 receptor in a majority of cases). These deposits are polytypic. In secondary forms, deposits are constituted of IgG1, IgG2 and IgG3. We report the case of a 52-year-old woman whose renal biopsy, done for glomerular proteinuria, shows membranous nephropathy with monotypic IgG4 deposits with no overt hematologic malignancy and no anti-PLA2R antibodies. PMID- 25921736 TI - Molecular mechanical properties of short-sequence peptide enzyme mimics. AB - While considerable attempts have been made to recreate the high turnover rates of enzymes using synthetic enzyme mimics, most have failed and only a few have produced minimal reaction rates that can barely be considered catalytic. One particular approach we have focused on is the use of short-sequence peptides that contain key catalytic groups in close proximity. In this study, we designed six different peptides and tested their ability to mimic the catalytic mechanism of the cysteine proteases. Acetylation and deacylation by Ellman's Reagent trapping experiments showed the importance of having phenylalanine groups surrounding the catalytic sites in order to provide greater proximity between the cysteine, histidine, and aspartate amino acid R-groups. We have also carried out all-atom molecular dynamics simulations to determine the distance between these catalytic groups and the overall mechanical flexibility of the peptides. We found strong correlations between the magnitude of fluctuations in the Cys-His distance, which determines the flexibility and interactions between the cysteine thiol and histidine imidazole groups, and the deacylation rate. We found that, in general, shorter Cys-His distance fluctuations led to a higher deacylation rate constant, implying that greater confinement of the two residues will allow a higher frequency of the acetyl exchange between the cysteine thiol and histidine imidazole R-groups. This may be the key to future design of peptide structures with molecular mechanical properties that lead to viable enzyme mimics. PMID- 25921737 TI - Inquiries into the Biological Significance of Transmembrane AMPA Receptor Regulatory Protein (TARP) gamma-8 Through Investigations of TARP gamma-8 Null MiceS. AB - Transmembrane AMPA (alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid) receptor regulatory protein (TARP) gamma-8 is an auxiliary protein associated with some AMPA receptors. Most strikingly, AMPA receptors associated with this TARP have a relatively high localization in the hippocampus. TARP gamma-8 also modifies the pharmacology and trafficking of AMPA receptors. However, to date there is little understanding of the biological significance of this auxiliary protein. In the present set of studies we provide a characterization of the differential pharmacology and behavioral consequences of deletion of TARP gamma-8 by comparing the wild type (WT) and gamma-8 -/- (knock-out, KO) mouse. KO mice were mildly hyperactive in a locomotor arena but not in other environments compared to WT mice. Additionally, the KO mice demonstrated enhanced locomotor stimulatory effects of both d-amphetamine and phencyclidine. Marble-burying and digging behaviors were dramatically reduced in KO mice. In another assay that can detect anxiety-like phenotypes, the elevated plus maze, no differences were observed in overall movement or open arm entries. In the forced-swim assay, KO mice displayed decreases in immobility time like the antidepressant imipramine and the AMPA receptor potentiator, LY392098. In KO mice, the antidepressant-like effects of LY392098 were prevented whereas the effects of imipramine were unaffected. Convulsions were induced by pentylenetetrazole, N-methyl-D-aspartate, and by kainic acid. However, in KO mice, kainic acid produced less tonic convulsions and lethality. KO mice had reduced levels of norepinephrine in hippocampus and cerebellum but not in hypothalamus or prefrontal cortex, decreased levels of cAMP in hippocampus, and increased levels of acetylcholine in the hypothalamus and prefrontal cortex. KO mice displayed decreased turnover of dopamine and increased histamine turnover in multiple brain areas In contrast, serotonin and its metabolites were not significantly affected by deletion of the gamma-8 protein. Of a large panel of plasma lipids, only two monoacylglycerols (1OG and 2OG) were marginally but nonsignificantly altered in WT vs KO mice. Overall, the data suggest genetic inactivation of this specific population of AMPA receptors results in modest changes in behavior characterized by a mild hyperactivity which is condition dependent and a marked reduction in digging and burying behaviors. Despite deletion of TARP gamma-8, chemoconvulsants were still active. Consistent with their predicted pharmacological actions, the convulsant effects of kainate and the antidepressant-like effects of an AMPA receptor potentiator (both acting upon AMPA receptors) were reduced or absent in KO mice. PMID- 25921738 TI - Role of pituitary adenylate cyclase-activating polypeptide in nociception and migraine. AB - Pituitary adenylate cyclase-activating polypeptide (PACAP) and its receptors are widely distributed at different levels of the pain-processing pathway. Its action at the peripheral sensory nerve terminals has been found to be divergent; it can exert both pro- and anti-nociceptive effects, depending on the mode of administration (local or systemic) and the mechanism of the pain process (acute or chronic, inflammatory or neuropathic). In the central nervous system it exerts mainly neuronal excitation, leading to increased nociceptive signalling. Since the clinical data strongly suggest the involvement of PACAP in the pathophysiology of migraine, special emphasis is placed on examinations of its role and the mechanisms of activation of the trigeminovascular system. The intravenous administration of PACAP to migraineurs induces migraine-like headache and extracranial arterial dilatation. Furthermore, an increased PACAP concentration has been detected in the peripheral blood of patients during a migraine attack. Animal experiments have also revealed that PACAP elicits peripheral and central sensitization of the neuronal elements of the trigeminovascular system and evokes meningeal vasodilatation. This review summarizes data relating to the expression of PACAP and its receptors, and the main effects and mechanisms in the nociceptive pathways, with special emphasis on migraine. It is clear that PACAP plays an excitatory role in migraine, but its target and signalling pathways have not yet been elucidated due to the lack of non-peptide, selective agonists and antagonists. Identification of its up- and downstream regulations and receptorial molecular mechanisms might open up future perspectives for the development of novel analgesic drugs. PMID- 25921739 TI - Drug targets of migraine and neuropathy: treatment of hyperexcitability. AB - Migraine and neuropathic pain are common causes of chronic pain. The exact pathomechanism has not been fully clarified for either disorder, but their pathophysiological backgrounds involve several similar mechanisms. Peripheral sensitization occurs in the neuronal elements of the dorsal root ganglion or the trigeminal ganglion, while central sensitization appears in the second-order neurons in the dorsal horn of the spinal cord or the trigeminal nucleus caudalis. Central neuronal hyperexcitability has been implicated in both disorders, and the emerging evidence suggests alterations in the glutamatergic neurotransmission and N-methyl-D-aspartate-receptor activation. Migraine and neuropathic pain additionally share certain clinical features, such as enhanced sensitivity to sensory stimuli and cutaneous allodynia. The pharmacotherapy of both diseases is often challenging, but several antiepileptic drugs that target hyperexcitability are beneficial for both migraine and neuropathic pain. Kynurenine pathway metabolites are capable of influencing the glutamate receptors, and might therefore be novel candidates for future drug development. PMID- 25921740 TI - Characterization of cancer stem cells and primary cilia in medulloblastoma. AB - Medulloblastoma, a tumor of the cerebellum, is the most common pediatric central nervous system malignancy. These tumors are etiologically linked to mutations in the Sonic hedgehog (Shh) pathway, which signals through the primary, non-motile cilium. The growth of these aggressive tumors relies on self-renewal of tumor propagating cells known as cancer stem cells (CSCs). Previous reports have implicated CD133-expressing cells as CSCs in brain tumors, while those expressing CD15 have been shown to propagate medulloblastoma. Here, we demonstrate that CD133+ and CD15+ cells are distinct medulloblastoma populations. CD15+ cells comprise approximately 0.5-1% of total human medulloblastoma cells, display CSC properties in culture and are detected in the Smoothened A1 transgenic mouse model of medulloblastoma. Additionally, we report on a medulloblastoma patient with enriched CD15+ cells in recurrent vs primary medulloblastoma. We also demonstrate that human medulloblastoma cells critically rely on establishment of primary cilia to drive Shh-mediated cell division. Primary cilia are found in external granule cells of human fetal cerebellum and in 12/14 medulloblastoma samples. Yet, CD15+ medulloblastoma cells lack primary cilia, suggesting that this CSC population signals independently of Shh. These results are important when considering the effects of current and prospective treatment modalities on medulloblastoma CSC populations. PMID- 25921741 TI - Intrahypothalamic Administration of Modafinil Increases Expression of MAP-Kinase in Hypothalamus and Pons in Rats. AB - Modafinil (MOD) it has to be considered as a wake-inducing drug to treat sleep disorders such as excessive sleepiness in narcolepsy, shift-work disorder, and obstructive/sleep apnea syndrome. Current evidence suggests that MOD induces waking involving the dopamine D1 receptor. However, little is known regarding the molecular elements linked in the wake-promoting actions of MOD. Since the D1 receptor activates the mitogen-activated protein kinase (MAP-K) cascade, it raises the interesting possibility that effects of MOD would depend upon the activation of MAP-K. Here we tested the expression of MAP-K in hypothalamus as well as pons after the microinjection of MOD (10 or 20 MUg/1 MUL) in rats into anterior hypothalamus, a wake-inducing brain area. Intrahypothalamic injections of MOD promoted MAP-K phosphorylation in hypothalamus and pons. Taken together, these results suggest that the wake-inducing compound MOD promotes the MAP-K phosphorylation. PMID- 25921742 TI - CypD: The Key to the Death Door. AB - Numerous studies have deciphered the importance of Cyclophilin D (CypD/ peptidyl prolyl cis-trans isomerase F) in the formation and regulation of mitochondrial permeability transition pore (MPTP), implicated in the cell death mechanisms in various neurological diseases. Decrease in the ATP and increase in the calcium levels are the most common aftermath consequences that are observed in these diseases. Increased calcium level leads to the persistent opening of MPTP and cell death, which is mediated by CypD. However, the underlying mechanisms that contribute to the abnormal calcium homeostasis in different diseases remain elusive. In this review, we attempted to connect the disruption of mitochondrial bioenergetics with abnormal calcium levels and MPTP. Further, various proteins that interact with the CypD and the subsequent consequences have been described. All the cell death pathways in various neurological disorders merge at CypD, which acts as a key regulatory protein in cellular demise. Agents inhibiting CypD may have a therapeutic potential for treating neurological disorders such as Alzheimer's disease, Parkinson's disease and cerebral ischemia. Further, the knowledge regarding the pathophysiological processes involved in CypD-regulated MPTP and cell death would assist in battling with these diseases. PMID- 25921743 TI - Targeting brain nicotinic acetylcholine receptors to treat major depression and co-morbid alcohol or nicotine addiction. AB - Major depressive disorder (MDD) is a serious mental illness that affects millions of people worldwide. There is now compelling evidence that the neuronal nicotinic acetylcholine receptors (nAChRs) play an important role in MDD and co-morbid alcohol or nicotine addiction. As a result, there has been growing interest for the treatment of MDD and co-morbid alcohol or nicotine use disorder by targeting nAChRs. Emerging evidence suggests that specific ligands that act at nAChRs significantly reduce depression-like behaviors in preclinical models that mimic MDD and co-morbid alcohol or nicotine use disorder. In this review, the pharmacological efficacy of nAChR ligands, such as mecamylamine, lobeline, cytisine, sazetidine-A, and others will be discussed. Overall, findings from preclinical and clinical studies included here suggest that the nAChR ligands may be of potential benefit in reducing MDD symptoms and that may aid in the prevention and treatment of MDD and co-morbid alcohol or nicotine use disorder. PMID- 25921746 TI - Modulation of endoplasmic reticulum stress: an opportunity to prevent neurodegeneration? AB - Neurodegenerative diseases (e.g. Alzheimer's disease, Parkinson's disease, Huntington's disease, amyotrophic lateral sclerosis and prion-related diseases) have in common the presence of protein aggregates in specific brain areas where significant neuronal loss is detected. In these pathologies, accumulating evidence supports a close correlation between neurodegeneration and endoplasmic reticulum (ER) stress, a condition that arises from ER lumen overload with misfolded proteins. Under these conditions, ER stress sensors initiate the unfolded protein response to restore normal ER function. If stress is too prolonged, or adaptive responses fail, apoptotic cell death ensues. Therefore, it was recently suggested that the manipulation of the ER unfolded protein response could be an effective strategy to avoid neuronal loss in neurodegenerative disorders. We will review the mechanisms underlying ER stress-associated neurodegeneration and discuss the possibility of ER as a therapeutic target. PMID- 25921745 TI - Is mental practice an effective adjunct therapeutic strategy for upper limb motor restoration after stroke? A systematic review and meta- analysis. AB - Stroke is one of the most common conditions requiring rehabilitation, and its motor impairments are a major cause of permanent disability. Hemiparesis is observed by 80% of the patients after acute stroke. Neuroimaging studies showed that real and imagined movements have similarities regarding brain activation, supplying evidence that those similarities are based on the same process. Within this context, the combination of mental practice (MP) with physical and occupational therapy appears to be a natural complement based on neurorehabilitation concepts. Our study seeks to investigate if MP for stroke rehabilitation of upper limbs is an effective adjunct therapy. PubMed (Medline), ISI knowledge (Institute for Scientific Information) and SciELO (Scientific Electronic Library) were terminated on 20 February 2015. Data were collected on variables as follows: sample size, type of supervision, configuration of mental practice, setting the physical practice (intensity, number of sets and repetitions, duration of contractions, rest interval between sets, weekly and total duration), measures of sensorimotor deficits used in the main studies and significant results. Random effects models were used that take into account the variance within and between studies. Seven articles were selected. As there was no statistically significant difference between the two groups (MP vs control), showed a - 0.6 (95% CI: -1.27 to 0.04), for upper limb motor restoration after stroke. The present meta-analysis concluded that MP is not effective as adjunct therapeutic strategy for upper limb motor restoration after stroke. PMID- 25921744 TI - mGluR5 Positive and Negative Allosteric Modulators Differentially Affect Dendritic Spine Density and Morphology in the Prefrontal Cortex. AB - Positive and negative allosteric modulators (PAMs and NAMs, respectively) of type 5 metabotropic glutamate receptors (mGluR5) are currently being investigated as novel treatments for neuropsychiatric diseases including drug addiction, schizophrenia, and Fragile X syndrome. However, only a handful of studies have examined the effects of mGluR5 PAMs or NAMs on the structural plasticity of dendritic spines in otherwise naive animals, particularly in brain regions mediating executive function. In the present study, we assessed dendritic spine density and morphology in pyramidal cells of the medial prefrontal cortex (mPFC) after repeated administration of either the prototypical mGluR5 PAM 3-cyano-N (1,3-diphenyl-1H-pyrazol-5- yl)benzamide (CDPPB, 20 mg/kg), the clinically utilized mGluR5 NAM 1-(3-chlorophenyl)-3-(3-methyl-5-oxo-4Himidazol- 2-yl)urea (fenobam, 20 mg/kg), or vehicle in male Sprague-Dawley rats. Following once daily treatment for 10 consecutive days, coronal brain sections containing the mPFC underwent diolistic labeling and 3D image analysis of dendritic spines. Compared to vehicle treated animals, rats administered fenobam exhibited significant increases in dendritic spine density and the overall frequency of spines with small (<0.2 MUm) head diameters, decreases in frequency of spines with medium (0.2-0.4 MUm) head diameters, and had no changes in frequency of spines with large head diameters (>0.4 MUm). Administration of CDPPB had no discernable effects on dendritic spine density or morphology, and neither CDPPB nor fenobam had any effect on spine length or volume. We conclude that mGluR5 PAMs and NAMs differentially affect mPFC dendritic spine structural plasticity in otherwise naive animals, and additional studies assessing their effects in combination with cognitive or behavioral tasks are needed. PMID- 25921747 TI - Testosterone replacement therapy in older male subjective memory complainers: double-blind randomized crossover placebo-controlled clinical trial of physiological assessment and safety. AB - Testosterone replacement therapy (TRT) has been investigated in older men as a preventative treatment against Alzheimer's disease and dementia. However, previous studies have been contradictory. We assessed TRT physiological effects in 44 older men (aged 61 +/- 7.7 years) with subjective memory complaints using a double blind, randomized, crossover, placebo-controlled study. Participants were randomized into 2 groups, one group received transdermal testosterone (50 mg) daily for 24 weeks, followed by a 4 week wash-out period, then 24 weeks of placebo; the other group received the reverse treatment. Blood evaluation revealed significant increases in total testosterone, free (calculated) testosterone, dihydrotestosterone, and a decrease in luteinizing hormone levels (p<0.001) following TRT. Although there were significant increases in red blood cell counts, hemoglobin and prostate specific antigen levels following TRT, they remained within normal ranges. No significant differences in plasma amyloid beta, estradiol, sex hormone binding globulin, insulin levels, body fat percentage, or body mass index were detected. This is the first carefully controlled study that has investigated the influence of TRT in Indonesian men on blood biomarkers linked to dementia risk. Our study suggests TRT is safe and well-tolerated in this Indonesian cohort, yet longitudinal studies with larger cohorts are needed to assess TRT further, and to establish whether TRT reduces dementia risk. PMID- 25921748 TI - Array-comparative genomic hybridization analysis of a cohort of Saudi patients with epilepsy. AB - Specific genetic anomalies or non-genetic factors could lead to epilepsy, but in various cases the underlying cause is unknown. Novel technologies, such as array comparative genomic hybridization, may reveal the copy number variants (CNVs), established as significant risk factor for epilepsy. This study carried out a high-density whole genome array- comparative genomic hybridization analysis with blood DNA samples from a cohort of twenty epilepsy patients to search for CNVs associated with epilepsy. Microdeletion of 14q31.1 was observed in four patients including two from the same family with loss of the NRXN3 gene; microdeletion of 15q12 in one patient with loss of the GABRG3 gene, and microduplication of 20q13.33 in three patients with loss of the gene group CHRNA4, KCNQ2, EEF1A2 and PPDPF were also found. These CNV findings were confirmed by real-time quantitative polymerase chain reaction. We have described, for the first time, numerous potential CNVs/genes implicated in epilepsy in the Saudi population. The study presents a better description of the genetic variations in epilepsy, and would eventually enable us to provide a foundation for understanding the critical genome regions which might be involved in the development of epilepsy. PMID- 25921749 TI - Palmitoylethanolamide relieves pain and preserves pancreatic islet cells in a murine model of diabetes. AB - We previously demonstrated that the intraperitoneal administration of palmitoylethanolamide (PEA) in mice with chronic constriction injury of the sciatic nerve evoked a relief of both thermal hyperalgesia and mechanical allodynia in neuropathic mice. Since diabetic neuropathy is one of the most common long-term complications of diabetes, we explored the ability of PEA to also relief this kind of chronic pain, employing the well established streptozotocin-induced animal model of type 1 diabetes. Our findings demonstrated that PEA relieves mechanical allodynia, counteracts nerve growth factor deficit, improves insulin level, preserves Langerhans islet morphology reducing the development of insulitis in diabetic mice. These results suggest that PEA could be effective in type 1-diabetic patients not only as pain reliever but also in controlling the development of pathology. PMID- 25921750 TI - Chronic stress impacts on olfactory system. AB - Chronic stress has detrimental effects on brain structures and functions. Previous studies mainly focused on prefrontal cortex and hippocampus, given their well-described roles in cognition and emotive processing. Chronic stress also leads to changes in other neural circuits, such as the olfactory system. Olfactory deficits were reported in both animal models and patients with depression. The present review summarizes the evidence linking chronic stress to neuropathology in the olfactory system, and analyzes the potential mechanistic insights underlying these changes. We propose also that olfactory system targeting therapies could be beneficial to certain symptoms of patients suffering from stress-related neurological diseases. PMID- 25921751 TI - Convenient synthesis of functionalized spiro[indoline-3,2'-pyrrolizines] or spiro[indoline-3,3'-pyrrolidines] via multicomponent reactions. AB - A general and practical route for the in situ generation of a new type of azomethine ylide and its sequential 1,3-dipolar cycloaddition reaction was successfully established. The three-component reaction of secondary alpha-amino acids including proline, sarcosine, thiazolidine-4-carboxylic acid with dialkyl acetylenedicarboxylate and 3-methyleneoxindoles in refluxing ethanol afforded the functionalized spiro[indoline-3,2'-pyrrolizines], spiro[indoline-3,3' pyrrolidines] and spiro[indoline-3,6'-pyrrolo[1,2-c]thiazoles] in good yields and with high diastereoselectivity. Furthermore, similar multicomponent reactions using primary alpha-amino acids such as glycine, alanine and phenylalanine resulted in the corresponding (spiro[indoline-3,3'-pyrrolidine]-1'-yl)maleates. PMID- 25921752 TI - Development of stapled helical peptides to perturb the Cdt1-Mcm6 interaction. AB - Six all-hydrocarbon-stapled Cdt1 MBD-derived peptides have been designed and synthesized to perturb the Cdt1-Mcm6 interaction, which is involved in DNA replication. Inconsistency between the helicity of the obtained peptidomimetics and their binding affinity has been observed. The helicity of 13-amino acid stapled peptides increased, while their binding to Mcm6 was decreased. On the other hand, the 30-amino acid stapled peptides exhibited decreased helicity but increased binding affinity. PMID- 25921753 TI - Limitations of current tuberculosis screening tests in immunosuppressed patients. PMID- 25921754 TI - Fetal and neonatal hemodynamics. PMID- 25921755 TI - Direct projections from the dorsal premotor cortex to the superior colliculus in the macaque (macaca mulatta). AB - The dorsal premotor cortex (PMd) is part of the cortical network for arm movements during reach-related behavior. Here we investigate the neuronal projections from the PMd to the midbrain superior colliculus (SC), which also contains reach-related neurons, to investigate how the SC integrates into a cortico-subcortical network responsible for initiation and modulation of goal directed arm movements. By using anterograde transport of neuronal tracers, we found that the PMd projects most strongly to the deep layers of the lateral part of the SC and the underlying reticular formation corresponding to locations where reach-related neurons have been recorded, and from where descending tectofugal projections arise. A somewhat weaker projection targets the intermediate layers of the SC. By contrast, terminals originating from prearcuate area 8 mainly project to the intermediate layers of the SC. Thus, this projection pattern strengthens the view that different compartments in the SC are involved in the control of gaze and in the control or modulation of reaching movements. The PMD SC projection assists in the participation of the SC in the skeletomotor system and provides the PMd with a parallel path to elicit forelimb movements. PMID- 25921756 TI - Competitive adsorption-desorption reactions of two hazardous heavy metals in contaminated soils. AB - Investigating the interactions of heavy metals is imperative for sustaining environment and human health. Among those, Cd is toxic for organisms at any concentration. While Ni acts as a micronutrient at very low concentration but is hazardous toxic above certain threshold value. In this study, the chemical adsorption and desorption reactions of Ni and Cd in contaminated soils were investigated in both single and binary ion systems. Both Ni and Cd experimental data demonstrated Langmuir type adsorption. In the competitive systems, an antagonistic effect was observed, implying that both ions compete for same type of adsorption sites. Adverse effect of Cd on Ni adsorption was slightly stronger than that of opposite system, consistent with adsorption isotherms in single ion systems. Variation in ionic strength indicated that Ca, a much weaker adsorbate, could also compete with Cd and Ni for adsorption on soil particles. Desorption data indicated that Cd and Ni are adsorbed very tightly such that after four successive desorption steps, less than 0.5 % of initially adsorbed ions released into the soil solution. This implies that Ca, at concentration in equilibrium with calcite mineral, cannot adequately compete with and replace adsorbed Ni and Cd ions. This adsorption behavior was led to considerable hysteresis between adsorption and desorption in both single and binary ion systems. In the binary ion systems, desorption of Cd and Ni was increased by increase in both equilibrium concentration of adsorbed ion and concentration of competitor ion. The overall results obtained in this research indicate that Cd and Ni are strongly adsorbed in calcareous soil and Ca, the major dissolved ion, insignificantly influences metal ions adsorption. Consequently, the contaminated soils by Ni and Cd can simultaneously be remediated by environmentally oriented technologies such as phytoremediation. PMID- 25921757 TI - Superoxide dismutase--mentor of abiotic stress tolerance in crop plants. AB - Abiotic stresses impact growth, development, and productivity, and significantly limit the global agricultural productivity mainly by impairing cellular physiology/biochemistry via elevating reactive oxygen species (ROS) generation. If not metabolized, ROS (such as O2 (*-), OH(*), H2O2, or (1)O2) exceeds the status of antioxidants and cause damage to DNA, proteins, lipids, and other macromolecules, and finally cellular metabolism arrest. Plants are endowed with a family of enzymes called superoxide dismutases (SODs) that protects cells against potential consequences caused by cytotoxic O2 (*-) by catalyzing its conversion to O2 and H2O2. Hence, SODs constitute the first line of defense against abiotic stress-accrued enhanced ROS and its reaction products. In the light of recent reports, the present effort: (a) overviews abiotic stresses, ROS, and their metabolism; (b) introduces and discusses SODs and their types, significance, and appraises abiotic stress-mediated modulation in plants; (c) analyzes major reports available on genetic engineering of SODs in plants; and finally, (d) highlights major aspects so far least studied in the current context. Literature appraised herein reflects clear information paucity in context with the molecular/genetic insights into the major functions (and underlying mechanisms) performed by SODs, and also with the regulation of SODs by post-translational modifications. If the previous aspects are considered in the future works, the outcome can be significant in sustainably improving plant abiotic stress tolerance and efficiently managing agricultural challenges under changing climatic conditions. PMID- 25921759 TI - Modeling and optimization of the flocculation processes for removal of cationic and anionic dyes from water by an amphoteric grafting chitosan-based flocculant using response surface methodology. AB - In this study, an amphoteric grafting chitosan-based flocculant (carboxymethyl chitosan-graft-poly(2-methacryloyloxyethyl) trimethyl ammonium chloride, denoted as CMC-g-PDMC) was applied to removal of the anionic and cationic dyes, acid Green 25 (AG25) and Basic Bright Yellow (7GL), from water. Flocculation conditions have been optimized by response surface methodology (RSM) on the basis of central composite design (CCD) using flocculant dosage, initial solution pH and temperature as input variables. The second-order and cubic regression models, which have been both tested by the analysis of variance (ANOVA), were constructed to link the output response (the dye removal factor) with the aforementioned input variables, respectively. The second-order regression model well described the process of AG25 removal, whereas the cubic one is more suitable for that of 7GL. The effects of those variables on the flocculation performance of CMC-g-PDMC for removal of the two dyes containing opposite charges from aqueous solutions have been studied, and the flocculation mechanisms including the interactive effects between various influencing factors have been discussed in detail also. PMID- 25921758 TI - Biodegradation and extracellular enzymatic activities of Pseudomonas aeruginosa strain GF31 on beta-cypermethrin. AB - Pseudomonas aeruginosa strain GF31, isolated from a contaminated soil, can effectively degrade beta-cypermethrin (beta-CP), as well as fenpropathrin, fenvalerate, and cyhalothrin. The highest level of degradation (81.2 %) was achieved with the addition of peptone. Surprisingly, the enzyme responsible for degradation was mainly localized to the extracellular areas of the bacteria, in contrast to the other known pyrethroid-degrading enzymes, which are intracellular. Although intact bacterial cells function at about 30 degrees C for biodegradation, similar to other degrading strains, the crude extracellular extract of strain GF31 remained biologically active at 60 degrees C. Moreover, the extract fraction showed good storage stability, maintaining >50 % of its initial activity following storage at 25 degrees C for at least 20 days. Significant differences in the characteristics of the crude GF31 extracellular extract compared with the known pyrethroid-degrading enzymes indicate the presence of a novel pyrethroid-degrading enzyme. Furthermore, the identification of 3-phenoxybenzoic acid and 2,2-dimethylcyclopropanecarboxylate from the degradation products suggests the possibility that beta-CP degradation by both the strain and the crude extracellular fraction is achieved through a hydrolysis pathway. Further degradation of these two metabolites may lead to the development of an efficient method for the mineralization of these types of pollutants. PMID- 25921760 TI - Spread of extended-spectrum beta-lactamase-producing Escherichia coli from a swine farm to the receiving river. AB - The dissemination of drug-resistant bacteria into different environments has posed a grave threat to public health, but data on the spread of extended spectrum beta-lactamase (ESBL)-producing Escherichia coli (E. coli) from animal farms to the receiving river are limited. Here, 57 ESBL-producing E. coli isolated from a pig farm and the receiving river were analyzed in terms of drug resistance, ESBL genes, and enterobacterial repetitive intergenic consensus (ERIC). The results showed that ESBL-producing E. coli from swine feces and downstream water of the pig farm outfall overlapped substantially in drug resistance and ESBL genes. Additionally, six ESBL-producing E. coli from the downstream water exhibited 100 % genetic similarity with strains from the swine feces. In conclusion, effluents of animal farms are a likely contributor to the presence of ESBL-producing E. coli in aquatic environments. PMID- 25921761 TI - Combined Arthroscopic Bankart Repair and Coracoid Process Transfer to Anterior Glenoid for Shoulder Dislocation in Rugby Players: Evaluation Based on Ability to Perform Sport-Specific Movements Effectively. AB - PURPOSE: To evaluate the outcomes of a combination of an arthroscopic Bankart repair and an open Bristow procedure in relation to the subjective quality of performance in movements that are typical in rugby. METHODS: Forty shoulders in 38 players who underwent surgery for traumatic anterior instability of the shoulder were reviewed. In all cases, arthroscopic Bankart repair was followed by a Bristow procedure, with preservation of the repaired capsular ligaments, during the same operation. The mean age at the time of surgery was 21 years. Patients were asked to describe common rugby maneuvers (tackle, hand-off, jackal, and saving) preoperatively and postoperatively as "no problem," "insufficient," or "impossible." RESULTS: There were no recurrent dislocations at a mean follow-up of 30.5 months. The mean Rowe score improved significantly from 65.0 (range, 55 to 75) to 97.5 (range, 95 to 100) (P < .001) after surgery. Preoperatively, regarding the tackling motion, none of the patients reported having no problem, whereas the ability was described as insufficient for 23 shoulders and impossible for 17 shoulders. Postoperatively, no problem with tackling was reported for 36 shoulders, whereas insufficiency was reported for 4. The results for the hand off, jackal, and saving maneuvers were similar (P < .001). No patient rated any of the motions as impossible postoperatively. CONCLUSIONS: This combined surgical procedure clearly is effective in preventing recurrent dislocation in rugby players; however, some players complained of insufficiency in the quality of their play when they were tackling or performing other rugby-specific movements. LEVEL OF EVIDENCE: Level IV, case series. PMID- 25921762 TI - The novel compound Z060228 inhibits assembly of the HBV capsid. AB - AIMS: The effective anti-HBV drugs on the market are mainly immunomodulators or nucleoside analogs. The uses of INF-alpha and lamivudine (3TC) are considerably limited by their low response rate, side effects, drug resistance and HBV recurrence. Thus, new mechanism-based drugs remain in urgent need. This study aimed to investigate the anti-HBV effects of the novel compound Z060228 and to confirm its anti-HBV mechanisms. MAIN METHODS: HepG2.2.15 cells and HBV transgenic mice were used to evaluate the anti-HBV activity of Z060228. Conformational changes of the capsid structure induced by Z060228 were detected with high-resolution electron microscopy (EM), size-exclusion chromatography (SEC), and atomic force microscopy (AFM). KEY FINDINGS: The HBV DNA replication in the supernatants of the HepG2.2.15 cells was effectively inhibited by Z060228 and Bay41-4109. In the liver of HBV-transgenic mice, the HBcAg content was significantly decreased and HBV DNA replication was also inhibited after high dose (30 mg/kg) Z060228 treatment. Z060228 and Bay41-4109 exhibited similar effects on the self-assembly of Cp149. SEC data revealed that Z060228 altered the equilibrium (a state of stability) of Cp149 assembly. EM data further demonstrated that Z060228 could prevent Cp149 from self-assembling to the correct core particles. Additionally, AFM results showed that a low concentration of Z060228 caused Cp149 syncretizing, whereas a high concentration caused Cp149 to polymerize. SIGNIFICANCE: Z060228 was demonstrated to be a potential capsid targeting anti-HBV drug candidate. The methods employed here could be used as a general strategy to study mechanisms of self-assembling protein-targeted drugs. PMID- 25921763 TI - Adhesion of platelets through thromboxane A2 receptor signaling facilitates liver repair during acute chemical-induced hepatotoxicity. AB - AIMS: Platelets have been suggested to play an important role in liver regeneration and repair after hepatic resection and acute liver injury. However, the underlying mechanisms of liver repair remain elusive. Signaling through thromboxane prostanoid (TP) receptor participates in inflammation and tissue injury through platelet aggregation. On the other hand, TP receptor signaling also is involved in tissue repair and tumor growth through angiogenesis. The present study was examined whether or not TP receptor signaling contributes to liver repair and sinusoidal restoration from acute liver injury through platelet adhesion to the hepatic sinusoids. MAIN METHODS: Carbon tetrachrolide (CCl4) was used to induce acute liver injury in TP receptor knockout mice (TP(-/-) mice) and their wild-type littermates (WT mice). KEY FINDINGS: Compared with WT mice, TP(-/ ) mice exhibited delayed in liver repair and sinusoidal restoration after CCl4 treatment, which were associated with attenuated hepatic expression of pro angiogenic factors. Intravital microscopic observation revealed that adhering platelets to the sinusoids was increased in WT livers during the repair phase as compared with TP(-/-) livers, and platelet adhesion was dependent on TP receptor signaling. The levels of hepatocyte growth factor (HGF) in platelets from WT mice treated with CCl4 for 48h were greater than those form TP(-/-) mice, and HGF enhanced the expression of angiogenic factors in cultured human umbilical vein endothelial cells (HUVECs). SIGNIFICANCE: These results suggested that TP receptor signaling facilitates liver repair and sinusoidal restoration from acute liver injury through HGF release from platelets adhering to the sinusoids. PMID- 25921764 TI - The investigation of the possible protective influence of selenium on antioxidant barrier in heart of rats exposed to lithium. AB - AIMS: Selenium is an essential element possessing antioxidant properties and the treatment with it has displayed protective effects against toxicity of different substances occurring in the environment and food as well as against the side effects of some drugs. Lithium is used in medicine although numerous side effects can occur during therapy, including disturbances of the heart. For these reasons studies to find protective adjuvants have been performed. In the current study the possibility of selenium (as sodium selenite) application as a protective adjuvant in lithium treatment was studied. MAIN METHODS: Male Wistar rats were treated: control - with saline; Li-group - with Li2CO3 (2.7 mg Li/kg b.w.); Se group - with Na2SeO3 (0.5 mg Se/kg b.w.); Li+Se-group simultaneously with Li2CO3 and Na2SeO3 (2.7 mg Li/kg b.w. and 0.5 mg Se/kg b.w., respectively) by a stomach tube for a period of three weeks, once a day. In heart homogenate activities of antioxidant enzymes - catalase (CAT), superoxide dismutase (SOD) and glutathione peroxidase (GPx), concentrations of low-molecular-weight antioxidants - ascorbic acid (AA) and reduced glutathione (GSH) as well as total antioxidant status (TAS) values were determined. GPx/SOD and CAT/SOD ratios were evaluated. KEY FINDINGS: In comparison with control selenium caused no significant changes of the studied parameters except for GPx, whereas lithium slightly disturbed TAS and markedly GPx, CAT and CAT/SOD ratio. In Li-treated rats co-administration of selenium displayed tendency towards restoring the impaired parameters. SIGNIFICANCE: The results suggest that research on selenium application as an adjuvant in lithium therapy is worthy to be continued. PMID- 25921765 TI - Prenatal dexamethasone-induced programmed hypertension and renal programming. AB - AIMS: Antenatal glucocorticoids can induce long-term effects on offspring health, including hypertension. Programmed hypertension has been observed in a prenatal dexamethasone (DEX) exposure model. However, how renal programming responds to prenatal DEX at different stages of development and the impact of DEX on programmed hypertension remain unclear. Therefore, we utilized RNA next generation sequencing (NGS) to analyze the renal transcriptome in the offspring to examine whether key genes and pathways are responsible for DEX-induced renal programming and hypertension. MAIN METHODS: Pregnant rats received intraperitoneal dexamethasone from gestational day 16 to 22. Prenatal DEX-induced programmed hypertension was examined in male offspring at 16 weeks of age. KEY FINDINGS: Prenatal DEX modified 431 renal transcripts from the nephrogenesis stage to adulthood in a constant manner. At the pre-hypertensive and established hypertension stages, we identified 11 and 13 differentially expressed genes related to blood pressure regulation, respectively. Among these genes, Npr3, Ptgs2, Agt, Edn3, Ephx2, Agtr1b, and Gucy1a3 are associated with endothelium derived hyperpolarizing and contractile factors (EDHF and EDCF). Genes in the arachidonic acid metabolism pathway may potentially be key genes contributing to programmed hypertension. In addition, DEX induced soluble epoxide hydrolase expression (Ephx2 gene encoding protein). SIGNIFICANCE: Prenatal DEX elicits an imbalance between EDHFs and EDCFs that might lead to renal programming and hypertension. The arachidonic acid metabolism pathway is a common pathway contributing to programmed hypertension. Our results highlight candidate genes and pathways involved in renal programming as targets for therapeutic approaches to prevent programmed hypertension in children exposed to antenatal corticosteroids. PMID- 25921766 TI - Protective effect of geranylgeranylacetone against hydrogen peroxide-induced oxidative stress in human neuroblastoma cells. AB - AIMS: Heat shock protein 70 (HSP70), one of the major HSPs, has been reported to suppress apoptosis and formation of pathogenic proteins in neurodegenerative disorders. Geranylgeranylacetone (GGA), an anti-ulcer drug, induces HSP70 and thereby protects against cellular damage in various diseases. We investigated the effect of GGA on hydrogen peroxide (H2O2)-induced neurotoxicity in human neuroblastoma SH-SY5Y cells. MAIN METHODS: H2O2-induced neuronal toxicity was measured by a CCK-8 assay and Hoechst 33342 staining. We also assessed oxidative stress and apoptosis by measuring reactive oxygen species (ROS) generation with 2',7'-dichlorofluorescein diacetate (DCFH-DA), caspase-3 activity, and mitogen activated protein kinase (MAPK) pathway. KEY FINDINGS: GGA showed a concentration dependent inhibition on H2O2-induced apoptotic cell death. H2O2-induced induction of HSP70 was enhanced by GGA pretreatment. GGA effectively suppressed the up regulation of Bax and down-regulation of Bcl-2. GGA also blocked the H2O2-induced phosphorylation of extracellular signal-regulated kinase 1/2 (ERK1/2). In addition, GGA attenuated H2O2-induced ROS generation and caspase-3 activity. SIGNIFICANCE: These results demonstrate that GGA protects SH-SY5Y cells from H2O2 induced apoptosis, at least in part by enhancing HSP70 production. Neuroprotective properties of GGA indicate that this compound may be a potential therapeutic agent for the treatment and prevention of neurodegenerative diseases. PMID- 25921767 TI - Methyl jasmonate enhances memory performance through inhibition of oxidative stress and acetylcholinesterase activity in mice. AB - AIMS: Current research effort focuses on the development of safer natural compounds with multipronged mechanisms of action that could be used to ameliorate memory deficits in patients with Alzheimer's disease, as cure for the disease still remains elusive. In this study, we evaluated the effect of methyl jasmonate (MJ), a naturally occurring bioactive compound on memory, acetylcholinesterase activity and biomarkers of oxidative stress in mice. MAIN METHODS: Male Swiss mice were treated with intraperitoneal injection of MJ (10-40 mg/kg) alone or in combination with scopolamine (3mg/kg) once daily for 7 days. Thirty minutes after the last treatment, memory functions were assessed using Y-maze and object recognition tests. Thereafter, acetylcholinesterase activity and levels of biomarkers of oxidative stress were assessed in mice brains using standard biochemical procedures. KEY FINDINGS: MJ significantly enhanced memory performance and reversed scopolamine-induced cognitive impairment in mice. MJ demonstrated significant inhibition of acetylcholinesterase activity suggesting increased cholinergic neurotransmission. It further decreased malondialdehyde concentrations in mouse brain indicating antioxidant activity. Moreover, MJ significantly increased glutathione levels and activity of antioxidant enzymes (catalase and superoxide dismutase) in mice brains. The increased oxidative stress; evidenced by elevated levels of malondialdehyde and decreased antioxidant defense systems in scopolamine-treated mice was attenuated by MJ. SIGNIFICANCE: The results of this study suggest that MJ may be useful in conditions associated with memory dysfunctions or age-related cognitive decline. The positive effect of MJ on memory may be related to inhibition of oxidative stress and enhancement of cholinergic neurotransmission through inhibition of acetylcholinesterase activity. PMID- 25921768 TI - Contribution of Musa paradisiaca in the inhibition of alpha-amylase, alpha glucosidase and Angiotensin-I converting enzyme in streptozotocin induced rats. AB - AIMS: Unripe plantain based-diets are part of folklore remedy for the management of diabetes in tropical Africa; however, with the dearth of information on the rationale behind this practice; this study therefore, sought to investigate the antihyperglycemic effect of traditional unripe plantain products (Amala and Booli) in high fat fed/low dose streptozotocin-induced diabetic rats and to provide a possible rationale for their antidiabetic properties. MAIN METHODS: Diabetes was induced experimentally by high fat fed/low dose streptozotocin diabetic rats (25mg/kg body wt.) and the diabetic rats were fed diets supplemented with 20-40% Amala and Booli for 14 days. The effect of the diets on the blood glucose level, pancreatic alpha-amylase, intestinal alpha-glucosidase and Angiotensin-I converting enzyme (ACE) activities and plasma antioxidant status as well as amylose/amylopectin content of the unripe plantain products were determined. KEY FINDINGS: A marked increase in the blood glucose, alpha amylase, alpha-glucosidase and ACE activities with a corresponding decrease in plasma antioxidant status was recorded in diabetic rats. However, these indices were significantly (P < 0.05) reversed after unripe plantain product supplemented diet treatments for 14 days. Also, the amylose/amylopectin ratio of the products is 1:3. SIGNIFICANCE: This study revealed that unripe plantain products exert antihyperglycemic effects which could be attributed to the inhibition of alpha amylase and alpha-glucosidase activities by their constituent phytochemicals as well as their amylose/amylopectin contents in the diabetic rats, hence, providing the possible rationale behind their antidiabetic properties. PMID- 25921769 TI - Role of licochalcone C in cardioprotection against ischemia/reperfusion injury of isolated rat heart via antioxidant, anti-inflammatory, and anti-apoptotic activities. AB - AIMS: This study aimed to evaluate the protective effect of licochalcone C against myocardial ischemia/reperfusion injury in rats. MAIN METHODS: Left ventricular developed pressure (LVDP) and its maximum up/down rate (+/-dp/dtmax) were recorded as myocardial function. Levels of creatine kinase (CK), lactate dehydrogenase (LDH), malondialdehyde (MDA), superoxide dismutase (SOD), glutathione/glutathione disulfide (GSH/GSSG) ratio, and tumor necrosis factor alpha (TNF-alpha) were determined by using enzyme-linked immunosorbent assay. Cell morphology was observed and mitochondrial damage was assessed by HE coloration and transmission electron microscopy, respectively. Cardiomyocyte apoptosis was determined by using terminal deoxynucleotidyl transferased UTP nick end labeling (TUNEL). KEY FINDINGS: Pretreatment with licochalcone C significantly improved the recovery of LVDP and +/-dp/dtmax, and increased the levels of SOD and GSH/GSSG ratio. However, pretreatment with licochalcone C not only decreased the TUNEL-positive cell ratio and morphological changes, but also weaken the mitochondrial injury and the levels of CK, LDH, MDA, and TNF-alpha. SIGNIFICANCE: These results suggested an important function of licochalcone C extracted from traditional Chinese medicine in the cardioprotection via antioxidant, anti-inflammatory, and anti-apoptotic activities. PMID- 25921770 TI - Enhanced function of inhibitory presynaptic cannabinoid CB1 receptors on sympathetic nerves of DOCA-salt hypertensive rats. AB - AIMS: This study was performed to examine whether hypertension affects the sympathetic transmission to resistance vessels of pithed rats via inhibitory presynaptic cannabinoid CB1 receptors and whether endocannabinoids are involved in this response. MATERIALS AND METHODS: We compared uninephrectomised rats rendered hypertensive by high salt diet and deoxycorticosterone acetate (DOCA) injections with normotensive animals (uninephrectomy only). Experiments were performed on vagotomised and pithed animals. Increases in diastolic blood pressure (DBP) were induced four times (S1-S4) by electrical stimulation or phenylephrine injection. KEY FINDINGS: Electrical stimulation (0.75Hz, 1ms, 50V, 5 impulses) of the preganglionic sympathetic nerve fibres innervating the blood vessels more strongly increased DBP in normotensive than in DOCA-salt rats. Phenylephrine (0.01MUmol/kg) induced similar increases in DBP in both groups. The cannabinoid receptor agonist CP55940 (0.01-1MUmol/kg) did not modify the rises in DBP induced by phenylephrine. However, it inhibited the electrically stimulated increases in DBP, more strongly in DOCA-salt than in normotensive animals (maximally by 50 and 30%, respectively). The effect of CP55940 was attenuated by the CB1 antagonist AM251 (3MUmol/kg). AM251 enhanced the neurogenic vasopressor response during S4 by itself in hypertensive rats only. URB597 (3MUmol/kg), which inhibits degradation of the endocannabinoid anandamide, did not modify the electrically stimulated increases in DBP. SIGNIFICANCE: The function of inhibitory presynaptic CB1 receptors on sympathetic nerves is enhanced in DOCA salt hypertensive rats. Thus, the CB1 receptor-mediated inhibition of noradrenaline release from the sympathetic nerve fibres innervating the resistance vessels might play a protective role in hypertension. PMID- 25921771 TI - Differential role of cannabinoids in the pathogenesis of skin cancer. AB - AIM: Cannabinoids (CB) like ?(9)-tetrahydrocannabinol (THC) can induce cancer cell apoptosis and inhibit angiogenesis. However, the use of cannabinoids for the treatment of malignant diseases is discussed controversially because of their immunomodulatory effects which can suppress anti-tumor immunity. Here we investigated the role of exogenous and endogenous cannabinoids in mouse skin cancer. MAIN METHODS: First we examined the effect of THC, which binds to CB receptors (CB1, CB2), on the growth of the mouse melanoma cell lines B16 and HCmel12 in vitro and in vivo in wild type (WT) and CB1/CB2-receptor deficient mice (Cnr1/2(-/-)). Next we evaluated the role of the endogenous cannabinoid system by studying the growth of chemically induced melanomas, fibrosarcoma and papillomas in WT and Cnr1/2(-/-) mice. KEY FINDINGS: THC significantly inhibited tumor growth of transplanted HCmel12 melanomas in a CB receptor-dependent manner in vivo through antagonistic effects on its characteristic pro-inflammatory microenvironment. Chemically induced skin tumors developed in a similar manner in Cnr1/2(-/-) mice when compared to WT mice. SIGNIFICANCE: Our results confirm the value of exogenous cannabinoids for the treatment of melanoma but do not support a role for the endogenous cannabinoid system in the pathogenesis of skin cancer. PMID- 25921772 TI - Celiac disease, collagenous sprue and microscopic colitis in IBD. Observations from a population-based cohort of IBD (ICURE). AB - OBJECTIVE: Inflammatory bowel disease (IBD), microscopic colitis and celiac disease are all diseases with worldwide distribution and increased incidence has been reported from many areas. There is a shortage of studies investigating the occurrence of these diseases in the same individual and whether those affected demonstrate any particular phenotype. The aim of the study was to describe the concomitant incidence of microscopic colitis and celiac disease in a population based IBD cohort. METHODS: All 790 individuals in a prospective population-based cohort included 2005-09 from Uppsala region, Sweden, were reviewed regarding the appearance of microscopic or celiac disease before or after IBD diagnosis. RESULTS: Fifty percent (396/790) of the patients had been examined for the possibility of celiac disease. Seventeen patients with celiac disease were found, representing 2.2% of the cohort. Patients with celiac disease were younger compared to the non-celiac patients and those with colitis had more often an extensive inflammation of the colon. Seventy-one percent (12/17) were women. The majority of the patients were diagnosed with celiac disease before IBD. Five patients with IBD had an earlier diagnosis of microscopic colitis or developed it after the IBD diagnosis. One teenager developed collagenous sprue, misinterpreted as a severe relapse of ulcerative colitis (UC) resulting in colectomy. CONCLUSIONS: The risk for celiac disease seems not to be increased in IBD, but those affected by both diseases seem to be predominantly women with extensive UC. There is a potential association between microscopic colitis and IBD. PMID- 25921773 TI - Synthesis of stable heterogeneous catalysts by supporting carbon-stabilized palladium nanoparticles on MOFs. AB - Cycling instability of catalysts is a persisting challenge in heterogeneous catalysis. In this work, we reported an effective in situ strategy for preparing ZIF-8 supported carbon-stabilized Pd nanoparticles (C@Pd/ZIF-8). The original ZIF 8 structure was well-preserved after the formation of Pd nanoparticles and amorphous carbon. Here, the Pd nanoparticles were encapsulated in the carbon matrix with a good dispersion. The as-prepared catalysts showed a better activity and cycling stability for the hydrogenation of C[double bond, length as m-dash]C containing substrates. C@Pd/ZIF-8 catalysts are reusable without significant loss of activity after 5 cycles, exhibiting higher cycling stability than those prepared from directly supported Pd nanoparticles on ZIF-8 (Pd/ZIF-8). PMID- 25921774 TI - Associations between family religious practices, internalizing/externalizing behaviors, and body mass index in obese youth. AB - The objective of the present study was to assess the associations among family religious practices, internalizing/externalizing behaviors, and body mass index in a sample of severely obese youth referred to an outpatient pediatric endocrinology clinic. The sample consisted of 43 obese youth (body mass index > 95th percentile) aged 6-16 years (mean age = 12.67 years). Approximately 93% of families endorsed their religious faith as Christian or Catholic. Parents of youth were administered a demographic questionnaire, religiosity questionnaire, and the Child Behavior Checklist. Three multiple linear regression models were examined with body mass index percentile, Child Behavior Checklist Internalizing Scale, and Child Behavior Checklist Externalizing Scale as outcome variables. A parent endorsing greater importance of religious faith in shaping family life was associated with lower child body mass index percentile (p < 0.05) in the present sample. Greater family attendance at religious services was associated with higher child body mass index percentile (p < 0.05). Our data suggest that church based interventions may be one viable option for the delivery of lifestyle interventions in families of youth with severe obesity. PMID- 25921775 TI - rs2043211 polymorphism in CARD8 is not associated with Tourette syndrome in a family-based association study in the Chinese Han population. AB - BACKGROUND: Previous studies showed that postinfectious autoimmunity and immune deficiency played an important role in the pathogenesis of Tourette syndrome. CARD8 can suppress activity of NF-KappaB activated by inflammatory mediators. OBJECTIVE: To study the association between the rs2043211 polymorphism in CARD8 and susceptibility to Tourette syndrome in Chinese Han population. METHODS: We recruited 279 patients diagnosed with Tourette syndrome and their parents for the study. Genotyping for CARD8 rs2043211 single-nucleotide polymorphism was performed using predesigned TaqMan single-nucleotide polymorphism genotyping assay. The genetic contribution of this single-nucleotide polymorphism was evaluated using transmission disequilibrium test and haplotype relative risk and the haplotype-based haplotype relative risk. RESULTS: The results of the allelic and genotypic distribution of rs2043211 polymorphism in CARD8 showed that both the Tourette syndrome patients group and the parents group are in Hardy-Weinberg equilibrium. No significant differences were observed in the mutant allele transmission (transmission disequilibrium test = 1.107, df = 1, p = 0.322). Results of haplotype relative risk analysis showed that no statistical significant difference was found in the genotypic frequency (AA/AT/TT) of Tourette syndrome patients passed from parents (haplotype relative risk = 1.152, chi(2 )= 0.494, p = 0.482, 95% CI = 0.777-1.708). Similarly, the analysis of haplotype-based haplotype relative risk was also not to support a statistically significant association in allelic frequency (A/T) of Tourette syndrome patients passed from parents (haplotype-based haplotype relative risk = 1.130, chi(2 )= 1.037, p = 0.308, 95% CI = 0.893-1.429). CONCLUSION: Our results suggest CARD8 might not play a role in the pathogenesis of Tourette syndrome in Chinese Han population. However, the results still need to be tested in a larger sample and different populations. PMID- 25921777 TI - Genome-wide epigenetic and proteomic analysis reveals altered Notch signaling in EPC dysfunction. AB - Endothelial progenitor cells (EPCs) are bone-marrow-derived mononuclear cells that participate in tube formation in vitro and vessel formation in vivo. EPC transplantation, as a therapeutic approach in cardiovascular diseases, has produced mixed results likely due to underlying disease states and environmental factors affecting EPC function. In this study, we investigated the mechanisms by which a high-salt diet impairs EPC function. The number of endothelial progenitor cells (CD34(+), VEGFR2(+), CD133(+), and c-Kit(+)) was decreased in the bone marrow of Sprague-Dawley (SD) rats fed a high-salt diet (HSD; 4% NaCl) as compared to SD rats on a normal-salt diet (NSD; 0.4% NaCl). NSD EPCs augmented endothelial cell tube formation in vitro, whereas HSD EPCs did not. NSD EPCs were a potent therapeutic restoring electrical stimulation-induced angiogenesis in vivo. HSD EPCs were not able to restore angiogenesis in vivo. EPC DNA methylation was analyzed by reduced representative bisulfite sequencing and membrane proteins were analyzed using high accuracy liquid chromatography mass spectrometry. Differentially methylated genes and differentially abundant membrane proteins measured between the NSD and HSD EPCs, revealed a total of 886 gene-protein sets where reciprocal methylation and expression occurred. Based on stringent criteria, Notch4 was found to be hypermethylated in HSD EPCs and had corresponding decrease in protein expression. Suppression of Notch4 protein expression in EPCs using siRNA confirmed a role for Notch4 in EPC-mediated angiogenesis, suggesting Notch4 suppression as a mechanism by which high-salt diet inhibits EPC-mediated angiogenesis. PMID- 25921776 TI - Diagnostic stability in young children at risk for autism spectrum disorder: a baby siblings research consortium study. AB - BACKGROUND: The diagnosis of autism spectrum disorder (ASD) made before age 3 has been found to be remarkably stable in clinic- and community-ascertained samples. The stability of an ASD diagnosis in prospectively ascertained samples of infants at risk for ASD due to familial factors has not yet been studied, however. The American Academy of Pediatrics recommends intensive surveillance and screening for this high-risk group, which may afford earlier identification. Therefore, it is critical to understand the stability of an ASD diagnosis made before age 3 in young children at familial risk. METHODS: Data were pooled across seven sites of the Baby Siblings Research Consortium. Evaluations of 418 later-born siblings of children with ASD were conducted at 18, 24, and 36 months of age and a clinical diagnosis of ASD or Not ASD was made at each age. RESULTS: The stability of an ASD diagnosis at 18 months was 93% and at 24 months was 82%. There were relatively few children diagnosed with ASD at 18 or 24 months whose diagnosis was not confirmed at 36 months. There were, however, many children with ASD outcomes at 36 months who had not yet been diagnosed at 18 months (63%) or 24 months (41%). CONCLUSIONS: The stability of an ASD diagnosis in this familial-risk sample was high at both 18 and 24 months of age and comparable with previous data from clinic- and community-ascertained samples. However, almost half of the children with ASD outcomes were not identified as being on the spectrum at 24 months and did not receive an ASD diagnosis until 36 months. Thus, longitudinal follow-up is critical for children with early signs of social-communication difficulties, even if they do not meet diagnostic criteria at initial assessment. A public health implication of these data is that screening for ASD may need to be repeated multiple times in the first years of life. These data also suggest that there is a period of early development in which ASD features unfold and emerge but have not yet reached levels supportive of a diagnosis. PMID- 25921778 TI - Acute mammary and liver transcriptome responses after an intramammary Escherichia coli lipopolysaccharide challenge in postpartal dairy cows. AB - The study investigated the effect of an intramammary lipopolysaccharide (LPS) challenge on the bovine mammary and liver transcriptome and its consequences on metabolic biomarkers and liver tissue composition. At 7 days of lactation, 7 cows served as controls (CTR) and 7 cows (LPS) received an intramammary Escherichia coli LPS challenge. The mammary and liver tissues for transcriptomic profiling were biopsied at 2.5 h from challenge. Liver composition was evaluated at 2.5 h and 7 days after challenge, and blood biomarkers were analyzed at 2, 3, 7 and 14 days from challenge. In mammary tissue, the LPS challenge resulted in 189 differentially expressed genes (DEG), with 20 down-regulated and 169 up regulated. In liver tissue, there were 107 DEG in LPS compared with CTR with 42 down-regulated and 65 up-regulated. In mammary, bioinformatics analysis highlighted that LPS led to activation of NOD-like receptor signaling, Toll-like receptor signaling, RIG-I-like receptor signaling and apoptosis pathways. In liver, LPS resulted in an overall inhibition of fatty acid elongation in mitochondria and activation of the p53 signaling pathway. The LPS challenge induced changes in liver lipid composition, a systemic inflammation (rise of blood ceruloplasmin and bilirubin), and an increase in body fat mobilization. The data suggest that cells within the inflamed mammary gland respond by activating mechanisms of pathogen recognition. However, in the liver the response likely depends on mediators originating from the udder that affect liver functionality and specifically fatty acid metabolism (beta-oxidation, ketogenesis, and lipoprotein synthesis). PMID- 25921780 TI - Copper(II)-catalyzed highly regio- and stereo-selective hydrosilylation of unactivated internal alkynes with silylborate in water. AB - The highly regio- and stereoselective hydrosilylation of internal alkynes with silylborate catalyzed by Cu(OTf)2 with 1,10-phenanthroline as the ligand in the presence of Cs2CO3 in water is developed. This protocol was applied efficiently in the aqueous synthesis of multi-substituted vinylsilanes. PMID- 25921779 TI - Disease course in mdx:utrophin+/- mice: comparison of three mouse models of Duchenne muscular dystrophy. AB - The mdx mouse model of Duchenne muscular dystrophy (DMD) is used to study disease mechanisms and potential treatments, but its pathology is less severe than DMD patients. Other mouse models were developed to more closely mimic the human disease based on knowledge that upregulation of utrophin has a protective effect in mdx muscle. An mdx:utrophin(-/-) (dko) mouse was created, which had a severe disease phenotype and a shortened life span. An mdx:utrophin(+/-) mouse was also created, which had an intermediate disease phenotype compared to the mdx and dko mice. To determine the usefulness of mdx:utrophin(+/-) mice for long-term DMD studies, limb muscle pathology and function were assessed across the life span of wild-type, mdx, mdx:utrophin(+/-), and dko mice. Muscle function assessment, specifically grip duration and rotarod performance, demonstrated that mdx:utrophin(+/-) mice were weaker for a longer time than mdx mice. Mean myofiber area was smaller in mdx:utrophin(+/-) mice compared to mdx mice at 12 months. Mdx:utrophin(+/-) mice had a higher percentage of centrally nucleated myofibers compared to mdx mice at 6 and 12 months. Collagen I and IV density was significantly higher in mdx:utrophin(+/-) muscle compared to mdx at most ages examined. Generally, mdx:utrophin(+/-) mice showed an intermediate disease phenotype over a longer time course compared to the mdx and dko mice. While they do not genetically mirror human DMD, mdx:utrophin(+/-) mice may be a more useful animal model than mdx or dko mice for investigating long-term efficacy of potential treatments when fibrosis or muscle function is the focus. PMID- 25921781 TI - Defining pathogenic verocytotoxin-producing Escherichia coli (VTEC) from cases of human infection in the European Union, 2007-2010. AB - During 2007-2010, 13 545 confirmed human verocytotoxin (VT)-producing Escherichia coli (VTEC) infections were reported in the European Union, including 777 haemolytic uraemic syndrome (HUS) cases. Clinical manifestations were reported for 53% of cases, 64% of which presented with diarrhoea alone and 10% with HUS. Isolates from 85% of cases were not fully serotyped and could not be classified on the basis of the Karmali seropathotype concept. There is no single or combination of phenotypic or genetic marker(s) that fully define 'pathogenic' VTEC. Isolates which contain the vtx2 (verocytotoxin 2) gene in combination with the eae (intimin-encoding) gene or aaiC (secreted protein of enteroaggregative E. coli) and aggR (plasmid-encoded regulator) genes have been associated with a higher risk of more severe illness. A molecular approach targeting genes encoding VT and other virulence determinants is thus proposed to allow an assessment of the potential severity of disease that may be associated with a given VTEC isolate. PMID- 25921782 TI - What drives you? PMID- 25921785 TI - Significantly improving enzymatic saccharification of high crystallinity index's corn stover by combining ionic liquid [Bmim]Cl-HCl-water media with dilute NaOH pretreatment. AB - In this study, a pretreatment by combining acidified aqueous ionic liquid 1-butyl 3-methylimidazolium chloride (IL [Bmim]Cl) solution with dilute NaOH extraction was employed to pretreat high crystallinity index (CrI) of corn stover before its enzymatic saccharification. After NaOH extraction, [Bmim]Cl-HCl-water (78.8:1.2:20, w/w/w) media was used for further pretreatment at 130 degrees C for 30 min. After being enzymatically hydrolyzed for 48 h, corn stover pretreated could be biotransformed into reducing sugars in the yield of 95.1%. Furthermore, SEM, XRD and FTIR analyses of untreated and pretreated corn stovers were examined. It was found that the intact structure was disrupted by combination pretreatment and resulted in a porous and amorphous regenerated cellulosic material that greatly improved enzymatic hydrolysis. Finally, the recovered hydrolyzates obtained from the enzymatic hydrolysis of pretreated corn stovers could be fermented into ethanol efficiently. In conclusion, the combination pretreatment shows high potential application in future. PMID- 25921783 TI - When bigger is better: the role of polyploidy in organogenesis. AB - Defining how organ size is regulated, a process controlled not only by the number of cells but also by the size of the cells, is a frontier in developmental biology. Large cells are produced by increasing DNA content or ploidy, a developmental strategy employed throughout the plant and animal kingdoms. The widespread use of polyploidy during cell differentiation makes it important to define how this hypertrophy contributes to organogenesis. I discuss here examples from a variety of animals and plants in which polyploidy controls organ size, the size and function of specific tissues within an organ, or the differentiated properties of cells. In addition, I highlight how polyploidy functions in wound healing and tissue regeneration. PMID- 25921786 TI - Performance evaluation of a green process for microalgal CO2 sequestration in closed photobioreactor using flue gas generated in-situ. AB - In the present study, carbon-dioxide capture from in situ generated flue gas was carried out using Chlorella sp. in bubble column photobioreactors to develop a cost effective process for concomitant carbon sequestration and biomass production. Firstly, a comparative analysis of CO2 sequestration with varying concentrations of CO2 in air-CO2 and air-flue gas mixtures was performed. Chlorella sp. was found to be tolerant to 5% CO2 concentration. Subsequently, inhibitory effect of pure flue gas was minimized using various strategies like use of high initial cell density and photobioreactors in series. The final biofixation efficiency was improved by 54% using the adopted strategies. Further, sequestered microalgal biomass was analyzed for various biochemical constituents for their use in food, feed or biofuel applications. PMID- 25921787 TI - Artificial asymmetric warming reduces nectar yield in a Tibetan alpine species of Asteraceae. AB - BACKGROUND AND AIMS: Asymmetric warming is one of the distinguishing features of global climate change, in which winter and night-time temperatures are predicted to increase more than summer and diurnal temperatures. Winter warming weakens vernalization and hence decreases the potential to flower for some perennial herbs, and night warming can reduce carbohydrate concentrations in storage organs. This study therefore hypothesized that asymmetric warming should act to reduce flower number and nectar production per flower in a perennial herb, Saussurea nigrescens, a key nectar plant for pollinators in Tibetan alpine meadows. METHODS: A long-term (6 years) warming experiment was conducted using open-top chambers placed in a natural meadow and manipulated to achieve asymmetric increases in temperature, as follows: a mean annual increase of 0.7 and 2.7 degrees C during the growing and non-growing seasons, respectively, combined with an increase of 1.6 and 2.8 degrees C in the daytime and night time, respectively, from June to August. Measurements were taken of nectar volume and concentration (sucrose content), and also of leaf non-structural carbohydrate content and plant morphology. KEY RESULTS: Six years of experimental warming resulted in reductions in nectar volume per floret (64.7 % of control), floret number per capitulum (8.7 %) and capitulum number per plant (32.5 %), whereas nectar concentration remained unchanged. Depletion of leaf non-structural carbohydrates was significantly higher in the warmed than in the ambient condition. Overall plant density was also reduced by warming, which, when combined with reductions in flower development and nectar volumes, led to a reduction of ~90 % in nectar production per unit area. CONCLUSIONS: The negative effect of asymmetric warming on nectar yields in S. nigrescens may be explained by a concomitant depletion of leaf non-structural carbohydrates. The results thus highlight a novel aspect of how climate change might affect plant-pollinator interactions and plant reproduction via induction of allocation shifts for plants growing in communities subject to asymmetric warming. PMID- 25921788 TI - Endogenous hormone concentrations correlate with fructan metabolism throughout the phenological cycle in Chrysolaena obovata. AB - BACKGROUND AND AIMS: Chrysolaena obovata, an Asteraceae of the Brazilian Cerrado, presents seasonal growth, marked by senescence of aerial organs in winter and subsequent regrowth at the end of this season. The underground reserve organs, the rhizophores, accumulate inulin-type fructans, which are known to confer tolerance to drought and low temperature. Fructans and fructan-metabolizing enzymes show a characteristic spatial and temporal distribution in the rhizophores during the developmental cycle. Previous studies have shown correlations between abscisic acid (ABA) or indole acetic acid (IAA), fructans, dormancy and tolerance to drought and cold, but the signalling mechanism for the beginning of dormancy and sprouting in this species is still unknown. METHODS: Adult plants were sampled from the field across phenological phases including dormancy, sprouting and vegetative growth. Endogenous concentrations of ABA and IAA were determined by GC-MS-SIM (gas chromatography-mass spectrometry-selected ion monitoring), and measurements were made of fructan content and composition, and enzyme activities. The relative expression of corresponding genes during dormancy and sprouting were also determined. KEY RESULTS: Plants showed a high fructan 1-exohydrolase (EC 3.2.1.153) activity and expression during sprouting in proximal segments of the rhizophores, indicating mobilization of fructan reserves, when ABA concentrations were relatively low and precipitation and temperature were at their minimum values. Concomitantly, higher IAA concentrations were consistent with the role of this regulator in promoting cell elongation and plant growth. With high rates of precipitation and high temperatures in summer, the fructan-synthesizing enzyme sucrose:sucrose 1 fructosyltransferase (EC 2.4.1.99) showed higher activity and expression in distal segments of the rhizophores, which decreased over the course of the vegetative stage when ABA concentrations were higher, possibly signalling the entry into dormancy. CONCLUSIONS: The results show that fructan metabolism correlates well with endogenous hormone concentrations and environmental changes, suggesting that the co-ordinated action of carbohydrate metabolism and hormone synthesis enables C. obovata to survive unfavourable field conditions. Endogenous hormone concentrations seem to be related to regulation of fructan metabolism and to the transition between phenophases, signalling for energy storage, reserve mobilization and accumulation of oligosaccharides as osmolytes. PMID- 25921789 TI - Looking into the new ASAS classification criteria for axial spondyloarthritis through the other side of the glass. AB - The new concept of axial spondylitis (axSpA) and the Assessment of Spondyloarthritis International Society (ASAS) classification criteria for axSpA have induced new clinical research that has broadened our understanding of spondyloarthritis (SpA) and has had indeed a positive impact on earlier diagnosis and treatment of patients with axSpA who have not yet developed radiographic sacroiliitis. The primary goal of any valid classification criteria for any disease is to provide a homogeneous study population with a common etiopathogenesis, similar prognosis, and similar response to identical treatment. Without such a homogeneous study population, robust clinical and basic science research in any subtype of SpA is not possible. All criteria are dynamic concepts that need updating as our knowledge advances and our review of the ASAS classification criteria of axSpA indicates that complex multi-selection design and unclear (not mutually exclusive) definitions of the imaging and clinical arms of the criteria results in patient heterogeneity across study populations. Therefore, there is a need to improve the validity of the ASAS criteria for axSpA. It is our opinion that in the meantime, the clinically well-established entity of AS, as defined by the modified New York (mNY) criteria, should be preserved for the most accurate comparison of the new research studies with those conducted over the last three decades, and that the use of the ASAS criteria should be restricted to patients with nr-axSpA, who are not recognized by the mNY criteria. PMID- 25921790 TI - The role of movement representation in episodic memory for actions: A study of patients with apraxia. AB - In attempting to memorize a sentence about an action, such as "Pick up the glass," performing the action (motor encoding) results in better memory performance than simply memorizing the words (verbal encoding). Such enhancement of memory is known as the enactment effect. Several theories have been proposed to explain this phenomenon using concepts such as physical motor information associated with speed, form, amplitude of movement and/or movement representations involved in movement imaging, knowledge on manipulating tools, and spatial relationships in the enactment effect. However, there have been no cognitive neuropsychological studies investigating whether the enactment effect is crucially influenced by physical motor information or movement representations. To clarify this issue, we compared healthy adult control participants with two different types of apraxia patients. One patient with left hemisphere lesions caused by cerebral infarction had a disability involving multiple movement representations. The other patient showed symptoms of corticobasal syndrome and was not able to benefit from feedback on the accuracy of her motor movements during enactment. Participants memorized action sentences via either verbal or motor encoding and responded to recall and recognition tests. Results indicated that the patient with the movement representation deficits exhibited worse memory performance than the other patient or control participants following both verbal and motor encoding. Although the enactment effect was present during recall in both patients, the effect was not observed for recognition in the patient with severe movement representation deficits. These results suggest that movement representations are involved in encoding episodic memories of action. Moreover, the role of movement representations appears to depend on the form of retrieval that is being used. PMID- 25921791 TI - Performance analysis of deciduous morphology for detecting biological siblings. AB - OBJECTIVES: Family-centered burial practices influence cemetery structure and can represent social group composition in both modern and ancient contexts. In ancient sites dental phenotypic data are often used as proxies for underlying genotypes to identify potential biological relatives. Here, we test the performance of deciduous dental morphological traits for differentiating sibling pairs from unrelated individuals from the same population. MATERIALS AND METHODS: We collected 46 deciduous morphological traits for 69 sibling pairs from the Burlington Growth Centre's long term Family Study. Deciduous crown features were recorded following published standards. After variable winnowing, inter individual Euclidean distances were generated using 20 morphological traits. To determine whether sibling pairs are more phenotypically similar than expected by chance we used bootstrap resampling of distances to generate P values. Multidimensional scaling (MDS) plots were used to evaluate the degree of clustering among sibling pairs. RESULTS: Results indicate an average distance between siblings of 0.252, which is significantly less than 9,999 replicated averages of 69 resampled pseudo-distances generated from: 1) a sample of non relative pairs (P < 0.001), and 2) a sample of relative and non-relative pairs (P < 0.001). MDS plots indicate moderate to strong clustering among siblings; families occupied 3.83% of the multidimensional space on average (versus 63.10% for the total sample). CONCLUSIONS: Deciduous crown morphology performed well in identifying related sibling pairs. However, there was considerable variation in the extent to which different families exhibited similarly low levels of phenotypic divergence. PMID- 25921792 TI - Probiotics. PMID- 25921793 TI - Phase-change material filled hollow magnetic nanoparticles for cancer therapy and dual modal bioimaging. AB - To develop carriers for anti-cancer drug delivery, this study reports a biocompatible and thermal responsive controlled drug delivery system based on hollow magnetic nanoparticles (HMNPs). The system is constructed simply by filling the hollow interiors of HMNPs with a phase-change material (PCM), namely, 1-tetradecanol, which has a melting point of 38 degrees C. The system achieves near "zero release" of both hydrophobic paclitaxel (PTX) and hydrophilic doxorubicin hydrochloride (DOX) and precise "on" or "off" drug delivery in vitro to efficiently induce cell apoptosis. Furthermore, the system displays both infrared thermal imaging and magnetic resonance imaging properties. More importantly, the system demonstrates great potential for thermo-chemo combination cancer therapy in vivo when an alternating magnetic field is applied. PMID- 25921794 TI - Kinetic analysis of IgG antibodies to beta-amyloid oligomers with surface plasmon resonance. AB - Surface plasmon resonance was used to investigate the kinetics, affinity, and specificity of binding between anti-Abeta (beta-amyloid) IgG antibodies and oligomeric Abeta. Two factors were needed to accurately characterize the IgG binding kinetics. First, a bivalent model was necessary to properly fit the kinetic association and dissociation sensograms. Second, a high concentration of IgG was necessary to overcome a significant mass transport limitation that existed regardless of oligomer density on the sensor surface. Using high IgG concentrations and bivalent fits, consistent kinetic parameters were found at varying sensor surface ligand densities. A comparison of binding specificity, affinity, and kinetic flux between monoclonal and natural human anti-Abeta IgG antibodies revealed the following findings. First, monoclonal antibodies 6E10 and 4G8 single-site binding affinity is similar between Abeta oligomers and monomers. Second, natural human anti-Abeta IgG binding readily binds Abeta oligomers but does not bind monomers. Third, natural human anti-Abeta IgG binds Abeta oligomers with a higher affinity and kinetic flux than 6E10 and 4G8. Both the current analytical methodology and antibody binding profiles are important for advances in antibody drug development and kinetic biomarker applications for Alzheimer's disease. PMID- 25921795 TI - Rainbow smelt: the unusual case of cryoprotection by sustained glycerol production in an aquatic animal. AB - Rainbow smelt flourish at -1.8 degrees C, the freezing point of sea water. An antifreeze protein contributes to freeze point depression but, more importantly, cryoprotection is due to an elevation in osmotic pressure, by the accumulation of glycerol. The lower the water temperature, the higher the plasma glycerol with levels recorded as high as 400 mmol l(-1). Glycerol freely diffuses out in direct relation to the glycerol concentration and fish may lose as much as 15% of their glycerol reserve per day. Glycerol levels decrease from a maximum in February/March while water temperature is still sub-zero. The decrease in glycerol may respond to a photoperiod signal as opposed to initiation which is triggered by low temperature. The initial increase in glycerol level is supported by liver glycogen but high sustained glycerol level is dependent upon dietary carbohydrate and protein. The metabolic pathways leading to glycerol involve flux from glycogen/glucose to the level of dihydroxyacetone phosphate (DHAP) via the initial part of glycolysis and from amino acids via a truncated gluconeogenesis again to the level of DHAP. DHAP in turn is converted to glycerol 3-phosphate (G3P) and then directly to glycerol. The key to directing DHAP to G3P is a highly active glycerol 3-P dehydrogenase. G3P is converted directly to glycerol via G3P phosphatase, the rate-limiting step in the process. The transition to glycerol production is associated with increased activities of enzymes at key loci in the top part of glycogenolysis/glycolysis. Curtailment of the final section of glycolysis may reside at the level of pyruvate oxidation with an inactivation of pyruvate dehydrogenase (PDH) driven by increased levels of PDH kinase. Enzymes associated with amino acid trafficking are elevated as is the pivotal enzyme phosphoenolpyruvate carboxykinase. PMID- 25921796 TI - Digesta retention patterns of solute and different-sized particles in camelids compared with ruminants and other foregut fermenters. AB - The mean retention times (MRT) of solute or particles in the gastrointestinal tract and the forestomach (FS) are crucial determinants of digestive physiology in herbivores. Besides ruminants, camelids are the only herbivores that have evolved rumination as an obligatory physiological process consisting of repeated mastication of large food particles, which requires a particle sorting mechanism in the FS. Differences between camelids and ruminants have hardly been investigated so far. In this study we measured MRTs of solute and differently sized particles (2, 10, and 20 mm) and the ratio of large-to-small particle MRT, i.e. the selectivity factors (SF(10/2mm), SF(20/2mm), SF(20/10mm)), in three camelid species: alpacas (Vicugna pacos), llamas (Llama glama), and Bactrian camels (Camelus bactrianus). The camelid data were compared with literature data from ruminants and non-ruminant foregut fermenters (NRFF). Camelids and ruminants both had higher SF(10/2mm)FS than NRFF, suggesting convergence in the function of the FS sorting mechanism in contrast to NRFF, in which such a sorting mechanism is absent. The SF(20/10mm)FS did not differ between ruminants and camelids, indicating that there is a particle size threshold of about 1 cm in both suborders above which particle retention is not increased. Camelids did not differ from ruminants in MRT(2mm)FS, MRTsoluteFS, and the ratio MRT(2mm)FS/MRTsoluteFS, but they were more similar to 'cattle-' than to 'moose type' ruminants. Camelids had higher SF(10/2mm)FS and higher SF(20/2mm)FS than ruminants, indicating a potentially slower particle sorting in camelids than in ruminants, with larger particles being retained longer in relation to small particles. PMID- 25921798 TI - Conversion of inhibition biosensing to substrate-like biosensing for quinalphos selective detection. AB - Since all of the organophosphorus pesticides (OPP) inhibit the cholinesterases with a common mechanism, it is still challenging to detect OPP selectively with inhibition-based biosensors. This study focuses on the conversion of a typical inhibition biosensing to a selective substrate-like biosensing. The interaction of quinalphos with plant-esterase involves not only a decrease in enzyme activity but also a heterolytic bond cleavage of quinalphos. The leaving group eliminated from quinalphos is an ideal biomarker due to its specificity in most OPP. Thus, using 2-hydroxyquinoxaline (HQO), the leaving group of quinalphos, as the biomarker and meso-tetra (4-sulfonatophenyl) porphine (TPPS4) as an optical probe, quinalphos can be selectively detected. The molecular recognition between TPPS4 and HQO leads to a considerable sensitivity of the detection. The spectral responses of TPPS4 show a linear dependence on quinalphos concentration in the presence of plant-esterase within the 0.01-1 mg kg(-1) range. The detection limit is 0.01 mg kg(-1), well below the maximum residue limits (MRLs) defined by European Union (0.05 mg kg(-1)) and China (0.2 mg kg(-1)). PMID- 25921799 TI - Using population-based critical care data to evaluate trauma outcomes. AB - BACKGROUND: The analysis of mortality is an integral part of the evaluation of trauma care. When specific data are not available, general prediction models can be used to adjust for case mix. The aim of this study was to evaluate the feasibility of conducting a population-based analysis of trends in trauma mortality, using critical care audit data, and to investigate whether such data could provide a benchmark for the assessment of service reconfiguration. METHODS: Retrospective cohort study of adult trauma patients, requiring admission to a critical care unit in Scotland, 2002-2011, using nationally collected data. Results are presented as standardised mortality ratios of observed mortality divided by APACHE II predicted mortality. Tests for trends in numbers and ratios over time were performed using linear regression. FINDINGS: 4503 patients were identified. There was a significant increase in the number of trauma patients admitted per year (p = 0.011). The median predicted probability of in-hospital death was 7% (interquartile range 1-13%), against an actual mortality was 11.6%. There was no significant change in the standardised mortality ratios of trauma patients (p = 0.1224). CONCLUSIONS: This study demonstrated the feasibility of utilising critical care unit audit data for analysing outcomes from trauma care. It also showed the potential of such an approach to establish a baseline against which to compare the impact of future service reconfiguration. In contrast to healthcare systems with regionalised trauma care, there appears to have been little change in the mortality of trauma patients requiring critical care unit admission in Scotland. PMID- 25921800 TI - Axillary hyperhidrosis: A review of the extent of the problem and treatment modalities. AB - BACKGROUND: The purpose of this review is to summarize the extent of the problem of axillary hyperhidrosis and treatment modalities available. The benefits and disadvantages of various treatments are reflected on with the hope of providing a starting point to investigate new ways of treating hyperhidrosis. MATERIAL & METHODS: A literature search was conducted using various databases and search criteria. RESULTS: Current treatments include aluminium chloride antiperspirants, iontophoresis, botox injections and endoscopic thoracic sympathectomy. Botox therapy is usually the most effective treatment, without surgery or unpleasant side effects. However it has to be administered by a skilled clinician and involves around 20 injections to treat axillary hyperhidrosis. Other ways of giving Botox are being developed, the most promising one being the use of microneedles which are able to penetrate the skin and deliver drugs to the target area of the dermis without causing pain. In comparison to the temporary effects of microneedles, laser and microwave therapies are also assessed as they offer the hope of permanent relief from hyperhidrosis. CONCLUSION: There is a considerable dearth in the literature on the management of axillary hyperhidrosis. Further study in larger populations with longer follow up times is critical to access the long term effects of treatment. Microneedles could be the future treatment of choice with the potential to deliver drugs in a safe and pain free way. PMID- 25921801 TI - Eye color: A potential indicator of alcohol dependence risk in European Americans. AB - In archival samples of European-ancestry subjects, light-eyed individuals have been found to consume more alcohol than dark-eyed individuals. No published population-based studies have directly tested the association between alcohol dependence (AD) and eye color. We hypothesized that light-eyed individuals have a higher prevalence of AD than dark-eyed individuals. A mixture model was used to select a homogeneous sample of 1,263 European-Americans and control for population stratification. After quality control, we conducted an association study using logistic regression, adjusting for confounders (age, sex, and genetic ancestry). We found evidence of association between AD and blue eye color (P = 0.0005 and odds ratio = 1.83 (1.31-2.57)), supporting light eye color as a risk factor relative to brown eye color. Network-based analyses revealed a statistically significant (P = 0.02) number of genetic interactions between eye color genes and AD-associated genes. We found evidence of linkage disequilibrium between an AD-associated GABA receptor gene cluster, GABRB3/GABRG3, and eye color genes, OCA2/HERC2, as well as between AD-associated GRM5 and pigmentation associated TYR. Our population-phenotype, network, and linkage disequilibrium analyses support association between blue eye color and AD. Although we controlled for stratification we cannot exclude underlying occult stratification as a contributor to this observation. Although replication is needed, our findings suggest that eye pigmentation information may be useful in research on AD. Further characterization of this association may unravel new AD etiological factors. (c) 2015 Wiley Periodicals, Inc. PMID- 25921802 TI - The detection of monosodium urate crystals in synovial fluid after long-term and varying storage conditions. PMID- 25921804 TI - Removal mechanism of low-concentration Cr (VI) in a submerged membrane bioreactor activated sludge system. AB - Removal mechanism of low-concentration Cr (VI) (0.4 mg/L) was studied in a submerged membrane bioreactor (SMBR) activated sludge system. SMBR was operated with the synthetic wastewater containing 0.4 mg/L Cr (VI). Bio-removal and inactivation batch experiments were also carried out for studying the low concentration Cr (VI) removal mechanism. SMBR activated sludge system recovered rapidly from the 0.4 mg/L Cr (VI) shock to achieve the excellent removal of chemical oxygen demand (COD) and NH4 (+)-N. Sulfuricurvum kujiense grew quickly in the bacterial community of activated sludge after Cr (VI) addition. Cr (VI) was mainly removed by the adsorption of extracellular polymeric substances, probably in the form as R2(SOH(+))2 (.)CrO4 (2-). Only few of Cr (VI) was transferred into Cr (III) under aerobic condition. All the results indicated that the sulfur was probably involved in 0.4 mg/L Cr (VI) removal process in SMBR. PMID- 25921803 TI - Trabecular Bone Score: Where are we now? AB - The Trabecular Bone Score is a rather new index obtained at the lumbar spine at the same time as a real bone mineral density. It was developed to reflect bone microarchitecture. It was proposed to be easily used in everyday practice as a surrogate of bone strength. Our aim was to review 1. technical points such as correlations between Trabecular Bone Score and bone microarchitectural parameters, Trabecular Bone Score and bone strength, the effects of dual-energy X ray absorptiometry image spatial resolution, age, macroarchitecture, body mass index, and osteoarthritis, on Trabecular Bone Score, and 2. evidences to use Trabecular Bone Score for separating individuals with fragility fractures from controls, predicting fragility fractures, and for longitudinally monitoring changes related to treatments. Correlations between Trabecular Bone Score and bone microarchitectural parameters vary widely across bone sites, microarchitectural parameters, and study designs. In vivo, the Trabecular Bone Score explains little of the variance in trabecular microarchitectural parameters. We emphasize that it is a texture parameter. The Trabecular Bone Score is reduced in patients with fragility fracture. Several retrospective and prospective studies have shown its discriminative ability regarding the fracture risk. When combining the areal Bone mineral Density and Trabecular Bone Score, the Trabecular Bone Score remains a predictor of fracture but not the areal Bone Mineral Density. However in prospective studies, the best predictor of fracture remains hip areal bone mineral density. Due to the lack of evidence, we recommend not to use Trabecular Bone Score for following patients treated by anti osteoporotic drugs. PMID- 25921805 TI - Membrane-anchored MucR mediates nitrate-dependent regulation of alginate production in Pseudomonas aeruginosa. AB - Alginates exhibit unique material properties suitable for medical and industrial applications. However, if produced by Pseudomonas aeruginosa, it is an important virulence factor in infection of cystic fibrosis patients. The alginate biosynthesis machinery is activated by c-di-GMP imparted by the inner membrane protein, MucR. Here, it was shown that MucR impairs alginate production in response to nitrate in P. aeruginosa. Subsequent site-specific mutagenesis of MucR revealed that the second MHYT sensor motif (MHYT II, amino acids 121-124) of MucR sensor domain was involved in nitrate sensing. We also showed that both c-di GMP synthesizing and degrading active sites of MucR were important for alginate production. Although nitrate and deletion of MucR impaired alginate promoter activity and global c-di-GMP levels, alginate yields were not directly correlated with alginate promoter activity or c-di-GMP levels, suggesting that nitrate and MucR modulate alginate production at a post-translational level through a localized pool of c-di-GMP. Nitrate increased pel promoter activity in the mucR mutant while in the same mutant the psl promoter activity was independent of nitrate. Nitrate and deletion of mucR did not impact on swarming motility but impaired attachment to solid surfaces. Nitrate and deletion of mucR promoted the formation of biofilms with increased thickness, cell density, and survival. Overall, this study provided insight into the functional role of MucR with respect to nitrate-mediated regulation of alginate biosynthesis. PMID- 25921806 TI - Molecular characterization of a Penicillium chrysogenum exo-rhamnogalacturonan lyase that is structurally distinct from other polysaccharide lyase family proteins. AB - We previously described an endo-acting rhamnogalacturonan (RG) lyase, termed PcRGL4A, of Penicillium chrysogenum 31B. Here, we describe a second RG lyase, called PcRGLX. We determined the cDNA sequence of the Pcrglx gene, which encodes PcRGLX. Based on analyses using a BLAST search and a conserved domain search, PcRGLX was found to be structurally distinct from known RG lyases and might belong to a new polysaccharide lyase family together with uncharacterized fungal proteins of Nectria haematococca, Aspergillus oryzae, and Fusarium oxysporum. The Pcrglx cDNA gene product (rPcRGLX) expressed in Escherichia coli demonstrated specific activity against RG but not against homogalacturonan. Divalent cations were not essential for the enzymatic activity of rPcRGLX. rPcRGLX mainly released unsaturated galacturonosyl rhamnose (DeltaGR) from RG backbones used as the substrate from the initial stage of the reaction, indicating that the enzyme can be classified as an exo-acting RG lyase (EC 4.2.2.24). This is the first report of an RG lyase with this mode of action in Eukaryota. rPcRGLX acted synergistically with PcRGL4A to degrade soybean RG and released DeltaGR. This DeltaGR was partially decorated with galactose (Gal) residues, indicating that rPcRGLX preferred oligomeric RGs to polymeric RGs, that the enzyme did not require Gal decoration of RG backbones for degradation, and that the enzyme bypassed the Gal side chains of RG backbones. These characteristics of rPcRGLX might be useful in the determination of complex structures of pectins. PMID- 25921807 TI - A plasmid-born Rap-Phr system regulates surfactin production, sporulation and genetic competence in the heterologous host, Bacillus subtilis OKB105. AB - According to the change of environment, soil-dwelling Bacillus species differentiate into distinct subpopulations, such as spores and competent cells. Rap-Phr systems have been found to be involved in this differentiation circuit by interacting with major regulatory proteins, such as Spo0A, ComA, and DegU. In this study, we report that the plasmid-born RapQ-PhrQ system found in Bacillus amyloliquefaciens B3 affects three regulatory pathways in the heterologous host Bacillus subtilis. Expression of rapQ in B. subtilis OKB105 strongly suppressed its sporulation efficiency, transformation efficiency, and surfactin production. Co-expression of phrQ or addition of synthesized PhrQ pentapeptide in vitro could compensate for the suppressive effects caused by rapQ. We also found that expression of rapQ decreased the transcriptional level of the sporulation-related gene spoIIE and surfactin synthesis-related gene srfA; meanwhile, the transcriptional levels of these genes could be rescued by co-expression of phrQ and in vitro addition of PhrQ pentapeptide. Electrophoretic mobility shift (EMSA) result also showed that RapQ could bind to ComA without interacting with ComA binding to DNA, and PhrQ pentapeptide antagonized RapQ activity in vitro. These results indicate that this new plasmid-born RapQ-PhrQ system controls sporulation, competent cell formation, and surfactin production in B. subtilis OKB105. PMID- 25921808 TI - Orotracheal administration of contrast agents: a new protocol for brain tumor targeting. AB - The development of new non-invasive diagnostic and therapeutic approaches is of paramount importance in order to improve the outcome of patients with glioblastoma (GBM). In this work we investigated a completely non-invasive pre clinical protocol to effectively target and detect brain tumors through the orotracheal route, using ultra-small nanoparticles (USRPs) and MRI. A mouse model of GBM was developed. In vivo MRI acquisitions were performed before and after intravenous or orotracheal administration of the nanoparticles to identify and segment the tumor. The accumulation of the nanoparticles in neoplastic lesions was assessed ex vivo through fluorescence microscopy. Before the administration of contrast agents, MR images allowed the identification of the presence of abnormal brain tissue in 73% of animals. After orotracheal or intravenous administration of USRPs, in all the mice an excellent co-localization of the position of the tumor with MRI and histology was observed. The elimination time of the USRPs from the tumor after the orotracheal administration was approximately 70% longer compared with intravenous injection. MRI and USRPs were shown to be powerful imaging tools able to detect, quantify and longitudinally monitor the development of GBMs. The absence of ionizing radiation and high resolution of MRI, along with the complete non-invasiveness and good reproducibility of the proposed protocol, make this technique potentially translatable to humans. To our knowledge, this is the first time that the advantages of a needle-free orotracheal administration route have been demonstrated for the investigation of the pathomorphological changes due to GBMs. PMID- 25921809 TI - Evaluation of immunochromatographic test for the detection of antibodies against Echinococcosis granulosus. AB - BACKGROUND: Echinococcosis in humans is a disease caused by the larvae of Echinococcus granulosus (E. granulosus) and Echinococcus multilocularis (E. multilocularis). Serological tests are valuable, especially in the clarification of unexplained clinical findings and imaging methods. For this reason, indirect hemagglutination (IHA), latex agglutination, immunoelectrophoresis, immunoblotting, immuno-enzymatic tests, indirect fluorescence antibody test (IFAT), and enzyme-linked immunosorbent assay (ELISA) are used. The purpose of this study was to investigate the value of an immunochromatographic test (ICT) specific for E. granulosus antibodies in the diagnosis of echinococcosis. MATERIAL/METHODS: ICT evaluated 102 cases of cystic echinococcosis, 38 cases of other parasitic diseases, and 50 healthy individuals. ELISA (DRG, Germany) that detects IgG antibodies specific for E. granulosus was used as the reference method. RESULTS: The sensitivity, specificity, and positive and negative predictive values of ICT were 96.8%, 87.5%, 98.9%, and 70%, respectively. Diagnostic value was 96.1%. No significant differences and high degrees of agreement were found between ELISA and immunochromatographic test for cystic echinococcosis. Serum samples included 4 taeniasis, 2 leishmaniasis, and 2 healthy individuals were diagnosed to be positive with immunochromatographic test. CONCLUSIONS: The ability of test to give fast results without need for equipment, devices, and specific storage conditions is an advantage. This test may be used due to its advantages in endemic regions for screening and diagnostic purposes. PMID- 25921810 TI - Thymosin beta4 has a major role in dermal burn wound healing that involves actin cytoskeletal remodelling via heat-shock protein 70. AB - Rapid vascular remodelling of damaged dermal tissue is required to heal burn wounds. Thymosin beta4 (Tbeta4) is a growth factor that has been shown to promote angiogenesis and dermal wound repair. However, the underlying mechanisms based on Tbeta4 function have not yet been fully investigated. In the present study, we investigated how Tbeta4 improves dermal burn wound healing via actin cytoskeletal remodelling and the action of heat-shock proteins (HSPs), which are a vital set of chaperone proteins that respond to heat shock. Our in vitro results achieved with the use of human umbilical vein endothelial cells (HUVECs) revealed a possible signal between Tbeta4 and HSP70. Moreover, we confirmed that remodelling of filamentous actin (F-actin) was regulated by Tbeta4-induced HSP70 in HUVECs. Based on these in vitro results, we confirmed the healing effects of Tbeta4 in an adapted dermal burn wound in vivo model. Tbeta4 improved wound-healing markers, such as wound closure and vascularization. Moreover, Tbeta4 maintained the long term expression of HSP70, which is associated with F-actin regulation during the wound-healing period. These results suggest that an association between Tbeta4 and HSP70 is responsible for the healing of burn wounds, and that this association may regulate F-actin remodelling. Copyright (c) 2015 John Wiley & Sons, Ltd. PMID- 25921811 TI - GRM7 regulates embryonic neurogenesis via CREB and YAP. AB - Metabotropic glutamate receptor 7 (GRM7) has recently been identified to be associated with brain developmental defects, such as attention deficit hyperactivity disorder (ADHD) and autism. However, the function of GRM7 during brain development remains largely unknown. Here, we used gain- and loss-of function strategies to investigate the role of GRM7 in early cortical development. We demonstrate that Grm7 knockdown increases neural progenitor cell (NPC) proliferation, decreases terminal mitosis and neuronal differentiation, and leads to abnormal neuronal morphology. GRM7 regulates the phosphorylation of cyclic AMP response element-binding protein (CREB) and the expression of Yes associated protein (YAP) by directly interacting with CaM, which subsequently regulates the expression of CyclinD1 and ultimately affects early cortical development. These defects in neurogenesis are ameliorated by Grm7 overexpression, Creb knockdown, or Yap knockdown. Thus, our findings indicate that GRM7 signaling via CREB and YAP is necessary for neurogenesis in the brain. PMID- 25921812 TI - Kinome-wide shRNA screen identifies the receptor tyrosine kinase AXL as a key regulator for mesenchymal glioblastoma stem-like cells. AB - Glioblastoma is a highly lethal cancer for which novel therapeutics are urgently needed. Two distinct subtypes of glioblastoma stem-like cells (GSCs) were recently identified: mesenchymal (MES) and proneural (PN). To identify mechanisms to target the more aggressive MES GSCs, we combined transcriptomic expression analysis and kinome-wide short hairpin RNA screening of MES and PN GSCs. In comparison to PN GSCs, we found significant upregulation and phosphorylation of the receptor tyrosine kinase AXL in MES GSCs. Knockdown of AXL significantly decreased MES GSC self-renewal capacity in vitro and inhibited the growth of glioblastoma patient-derived xenografts. Moreover, inhibition of AXL with shRNA or pharmacologic inhibitors also increased cell death significantly more in MES GSCs. Clinically, AXL expression was elevated in the MES GBM subtype and significantly correlated with poor prognosis in multiple cancers. In conclusion, we identified AXL as a potential molecular target for novel approaches to treat glioblastoma and other solid cancers. PMID- 25921814 TI - Myelination: An active process. PMID- 25921813 TI - SOX2 reprograms resident astrocytes into neural progenitors in the adult brain. AB - Glial cells can be in vivo reprogrammed into functional neurons in the adult CNS; however, the process by which this reprogramming occurs is unclear. Here, we show that a distinct cellular sequence is involved in SOX2-driven in situ conversion of adult astrocytes to neurons. This includes ASCL1(+) neural progenitors and DCX(+) adult neuroblasts (iANBs) as intermediates. Importantly, ASCL1 is required, but not sufficient, for the robust generation of iANBs in the adult striatum. These progenitor-derived iANBs predominantly give rise to calretinin(+) interneurons when supplied with neurotrophic factors or the small-molecule valproic acid. Patch-clamp recordings from the induced neurons reveal subtype heterogeneity, though all are functionally mature, fire repetitive action potentials, and receive synaptic inputs. Together, these results show that SOX2 mediated in vivo reprogramming of astrocytes to neurons passes through proliferative intermediate progenitors, which may be exploited for regenerative medicine. PMID- 25921816 TI - Computational neuroscience: Population coupling. PMID- 25921815 TI - Epigenetic and transgenerational reprogramming of brain development. AB - Neurodevelopmental programming - the implementation of the genetic and epigenetic blueprints that guide and coordinate normal brain development - requires tight regulation of transcriptional processes. During prenatal and postnatal time periods, epigenetic processes fine-tune neurodevelopment towards an end product that determines how an organism interacts with and responds to exposures and experiences throughout life. Epigenetic processes also have the ability to reprogramme the epigenome in response to environmental challenges, such as maternal stress, making the organism more or less adaptive depending on the future challenges presented. Epigenetic marks generated within germ cells as a result of environmental influences throughout life can also shape future generations long before conception occurs. PMID- 25921817 TI - Strict actions of the human wrist flexors: A study with an electrical neuromuscular stimulation method. AB - In order to elucidate strict actions of the human wrist flexors, motion and force produced by electrical neuromuscular stimulation (ENS) to each of musculus (m.) flexsor carpi radialis (FCR) and m. flexsor carpi ulnaris (FCU) with the prone, semiprone, and supine forearm were studied in ten healthy human subjects. Abduction, extension, adduction, and flexion directions were represented by, respectively, 0 degrees , 90 degrees , 180 degrees , and 270 degrees . ENS to FCR and FCU produced motion in direction of, respectively, 273 degrees (mean) and 265 degrees with the prone, 249 degrees and 232 degrees with the semiprone, and 242 degrees and 229 degrees with the supine forearm to the maximal range. Direction/strength (Nm) of force by ENS to FCR and FCU were, respectively, 298 degrees /1.16 and 239 degrees /1.70 with the prone, 279 degrees /1.30 and 241 degrees /1.62 with the semiprone, and 267 degrees /1.24 and 227 degrees /2.04 with the supine forearm. ENS to FCR exhibited force of 20-29% of maximal flexion and 7-15% of maximal abduction or 1-4% of maximal adduction and that to FCU force of 24-28% of maximal flexion and 15-25% of maximal adduction. The force study results suggest that FCU is a flexor rather than an adductor with every forearm position. FCR should be a flexor rather than an abductor with the prone and semiprone and a flexor with the supine forearm. The action of FCR as the abductor should diminish with supinating the forearm. PMID- 25921818 TI - Tutorial dialogues and gist explanations of genetic breast cancer risk. AB - The intelligent tutoring system (ITS) BRCA Gist is a Web-based tutor developed using the Shareable Knowledge Objects (SKO) platform that uses latent semantic analysis to engage women in natural-language dialogues to teach about breast cancer risk. BRCA Gist appears to be the first ITS designed to assist patients' health decision making. Two studies provide fine-grained analyses of the verbal interactions between BRCA Gist and women responding to five questions pertaining to breast cancer and genetic risk. We examined how "gist explanations" generated by participants during natural-language dialogues related to outcomes. Using reliable rubrics, scripts of the participants' verbal interactions with BRCA Gist were rated for content and for the appropriateness of the tutor's responses. Human researchers' scores for the content covered by the participants were strongly correlated with the coverage scores generated by BRCA Gist, indicating that BRCA Gist accurately assesses the extent to which people respond appropriately. In Study 1, participants' performance during the dialogues was consistently associated with learning outcomes about breast cancer risk. Study 2 was a field study with a more diverse population. Participants with an undergraduate degree or less education who were randomly assigned to BRCA Gist scored higher on tests of knowledge than those assigned to the National Cancer Institute website or than a control group. We replicated findings that the more expected content that participants included in their gist explanations, the better they performed on outcome measures. As fuzzy-trace theory suggests, encouraging people to develop and elaborate upon gist explanations appears to improve learning, comprehension, and decision making. PMID- 25921819 TI - Erratum to: The Oriented Difference of Gaussians (ODOG) model of brightness perception: Overview and executable Mathematica notebooks. PMID- 25921820 TI - Determination of amylose/amylopectin ratio of starches. PMID- 25921821 TI - Substance P stimulates proliferation of spinal neural stem cells in spinal cord injury via the mitogen-activated protein kinase signaling pathway. AB - BACKGROUND CONTEXT: Substance P (SP) is a neuropeptide that can influence neural stem/progenitor cell (NSPC) proliferation and neurogenesis in the brain. However, we could not find any experimental study that investigates SP action in the spinal cord. PURPOSE: The aims of our study were to investigate the potential of the neuropeptide SP in promoting the proliferation of spinal cord-derived NSPCs (SC-NSPCs) after spinal cord injury (SCI) and to clarify the roles of the mitogen activated protein (MAP) kinase signaling pathway in the process. STUDY DESIGN: This is a randomized animal study. METHODS: The SC-NSPCs were suspended in 100 MUL of a neurobasal medium containing SP (binds neurokinin-1 receptor [NK1R]) or L-703,606 (NK1R antagonist) and cultured in a 96-well plate for 5 days. A cell proliferation assay was performed using a 3-(4,5-dimethylthiazol-2-yl)-5-(3 carboxymethoxyphenyl)-2-(4-sulfophenyl)-2H-tetrazolium assay. A cord clipping method was used for the SCI model. Substance P and the NK1R antagonist (L 703,606) were infused intrathecally in SCI and sham models. Neural stem/progenitor cell proliferation was evaluated with immunostaining for bromodeoxyuridine (BrdU) and the immature neural marker nestin. An immunoblotting method was used for evaluating the MAP kinase signaling protein that contains extracellular signal-regulated kinases (ERKs and p38) and beta-actin as the control group. RESULTS: In vitro, SP (0.01-10 MUmol/L) increased the proliferation of cultured SC-NSPCs, with a peak increase of 35+/-2% at the 0.1 MUmol/L concentration. Substance P of 0.1 MUmol/L continuously increased SC-NSPC proliferation from 6 hours to 5 days, whereas the proliferation decreased from 18% to 98% with L-703,606 (1-10 MUM). Intrathecal infusion of SP (1 MUmol/L) for 7 days significantly increased the number of proliferating NPSCs (cells positive for both BrdU and nestin) in the spinal cord (by 120+/-17%, p<.05) in adult rats, but infusion of L-703,606 (10 MUmol/L) significantly decreased the post-SCI induction of NPSC proliferation in the spinal cord (by 87+/-4%). Also, SP stimulates proliferation of SC-NSPCs via the MAP kinase signaling pathway, especially the phosphorylated ERK and phosphorylated p38 proteins. The phosphorylated ERK and phosphorylated p38 protein levels increased with SP (0.1 MUmol/L, p<.05). CONCLUSIONS: These data indicate that SP can promote proliferation of SC-NSPCs in SCI and normal conditions and have important roles in neuronal regeneration after SCI. Also, ERKs and p38 MAP kinases are important signaling proteins in this process. PMID- 25921822 TI - Posterior lumbar subcutaneous edema. PMID- 25921823 TI - Ameloblastic Fibrosarcoma of the Mandible: A Case Report and a Review of the Literature. AB - Odontogenic sarcomas and their subtypes are very rare tumors. The authors' objectives were to report an additional case of ameloblastic fibrosarcoma, review the clinicopathologic features, discuss their treatment approach, and complete a thorough review of the literature. PMID- 25921824 TI - Risk Factors of Membrane Perforation and Postoperative Complications in Sinus Floor Elevation Surgery: Review of 407 Augmentation Procedures. AB - PURPOSE: To test patient- and sinus-related risk factors for an association with intraoperative membrane perforation and postoperative complications after sinus floor augmentation surgery. MATERIALS AND METHODS: Sinus floor elevation procedures using a lateral approach were retrospectively analyzed for patients' medical history and sinus anatomy on computed tomographic scans. Complications per sinus after membrane elevation and augmentation using a mixture of autologous bone and deproteinized bovine bone substitute (Bio-Oss) were recorded. Logic regression (adjusted using the generalized estimation equation approach) was performed to analyze the influence of patient age, gender, smoking habits, sinus septa, residual bone height, and mesiodistal elevation width. RESULTS: Of 407 sinus grafts in 300 patients (mean age, 56 yr), perforation of the Schneiderian membrane occurred in 35 sinuses (8.6%) and was significantly associated to the presence of sinus septa (odds ratio [OR] = 4.8; P = .002) and decreased residual bone height (OR = 0.01; P < .001). Smoking increased the risk of membrane perforation (OR = 4.8; P = .002), sinusitis (OR = 12.3; P < .001), and wound dehiscence (OR = 16.1; P = .005). Cases of sinus membrane perforation had higher odds for postoperative sinusitis (OR = 10.5; P < .001). The probability of wound dehiscence increased with the size of the elevated area (OR = 3; P < .001). CONCLUSION: The results of the study suggest that the presence of sinus septa and residual bone height less than 3.5 mm are the main risk factors increasing sinus membrane perforation rates. There was a higher prevalence for sinusitis in cases of membrane perforation (31.4%) despite intraoperative closure with resorbable membranes (Bio-Guide). Smokers generally exhibited greater chances for complications. PMID- 25921825 TI - Hyposmia correlates with SNCA variant and non-motor symptoms in Chinese patients with Parkinson's disease. AB - BACKGROUND: Hyposmia plays an important role in the early and differential diagnosis of Parkinson's disease (PD); however its underlying mechanism is poorly understood. The aim of the present study is to explore the clinical phenotypic and genotypic correlation of hyposmia in Chinese PD patients. METHODS: Olfactory function evaluated by 16-item odor identification test from Sniffin' Sticks (SS 16) of 218 Chinese Han PD patients and 110 healthy controls was compared. 186 patients also had the genetic information of two positive GWAS-linked SNCA loci (rs11931074, rs894278) previously validated in our center. The associations of hyposmia with SNCA variants and disease phenotypic characteristics including motor symptoms (UPDRS motor score) and other common NMSs (clinical possible RBD cpRBD, depression and chronic constipation) were analyzed. RESULTS: Nearly 39.9% (n = 87) of PD reported subjective complaints of hyposmia, while 60.1% (n = 131) patients had objective hyposmia (SS-16 < 8.3). Patients with hyposmia had older age (p = 0.001), later onset age (p = 0.020), higher SCOPA-AUT scores (p = 0.011), higher percentage of chronic constipation (p = 0.001) and cpRBD (p = 0.003). Binary logistic regression analysis revealed that ageing (OR = 1.058; 95%CI: 1.012-1.106; p = 0.013), chronic constipation (OR = 2.072; 95% CI: 1.157 3.710; p = 0.014) and cpRBD (OR = 2.234; 95% CI: 1.040-4.797; p = 0.039) were independent influential factors of hyposmia in Chinese PD patients. Subgroup analysis of patients with both clinical and genetic results demonstrated that after adjusting for age, sex, chronic constipation and cpRBD, rs11931074 TT genotype may increase the risk of hyposmia in PD (OR = 3.24 95% CI = 1.23-8.51, p = 0.017) compared to GG genotype via an additive model. CONCLUSIONS: Age, cpRBD, chronic constipation and SNCA rs11931074 may correlate with hyposmia in Chinese PD patients. PMID- 25921826 TI - Evidence for anti-inflammatory and antioxidative properties of dried plum polyphenols in macrophage RAW 264.7 cells. AB - This study presents the anti-inflammatory and antioxidative properties of dried plum (Prunus domestica L.) polyphenols in macrophage RAW 264.7 cells. We hypothesized that dried plum polyphenols have strong anti-inflammatory and antioxidant properties against lipopolysaccharide (LPS)-induced production of the pro-inflammatory markers, nitric oxide (NO) and cyclooxygenase-2 (COX-2), and the lipid peroxidation product, malondialdehyde, in activated macrophage RAW 264.7 cells. To test this hypothesis, macrophage RAW 264.7 cells were stimulated with either 1 MUg ml(-1) (for measurement of NO production) or 1 ng ml(-1) (for measurement of COX-2 expression) of LPS to induce inflammation and were treated with different doses of dried plum polyphenols (0.0, 0.1, 1, 10, 100 and 1000 MUg ml(-1)). Dried plum polyphenols at a dose of 1000 MUg ml(-1) was able to significantly (P < 0.05) reduce NO production by 43%. Additionally, LPS-induced expression of COX-2 was significantly (P < 0.05) reduced by 100 and 1000 MUg ml( 1) dried plum polyphenols. To investigate the antioxidant activity of dried plum polyphenols, macrophage RAW 264.7 cells were stimulated with 100 MUg ml(-1) of FeSO4 + 1 mM ml(-1) of H2O2 to induce lipid peroxidation. Dried plum polyphenols at a dose of 1000 MUg ml(-1) showed a 32% reduction in malondialdehyde production. These findings indicate that dried plum polyphenols are potent anti inflammatory and antioxidative agents in vitro. PMID- 25921827 TI - Outbreak of encephalitic listeriosis in red-legged partridges (Alectoris rufa). AB - An outbreak of neurological disease was investigated in red-legged partridges between 8 and 28 days of age. Clinical signs included torticollis, head tilt and incoordination and over an initial eight day period approximately 30-40 fatalities occurred per day. No significant gross post mortem findings were detected. Histopathological examination of the brain and bacterial cultures followed by partial sequencing confirmed a diagnosis of encephalitis due to Listeria monocytogenes. Further isolates were obtained from follow-up carcasses, environmental samples and pooled tissue samples of newly imported day-old chicks prior to placement on farm. These isolates had the same antibiotic resistance pattern as the isolate of the initial post mortem submission and belonged to the same fluorescent amplified fragment length polymorphism (fAFLP) subtype. This suggested that the isolates were very closely related or identical and that the pathogen had entered the farm with the imported day-old chicks, resulting in disease manifestation in partridges between 8 and 28 days of age. Reports of outbreaks of encephalitic listeriosis in avian species are rare and this is to the best of our knowledge the first reported outbreak in red-legged partridges. PMID- 25921829 TI - A novel regulatory pathway in granulosa cells, the LH/human chorionic gonadotropin-microRNA-125a-3p-Fyn pathway, is required for ovulation. AB - Granulosa cells support the developing oocytes and serve as transducers of the ovulatory stimulus induced by LH surge. Fyn kinase is expressed in granulosa cells, though its role in these cells has not been studied. In human embryonic kidney 293T cells, microRNA (miR)-125a-3p down-regulates Fyn expression, causing a decrease in cells' migratory ability. Our aim was to explore the role of miR 125a-3p and Fyn in granulosa cells toward ovulation, focusing on migration as a possible mechanism. We demonstrate expression of miR-125a-3p and Fyn in mouse mural granulosa cells of preovulatory follicles and miR-125a-3p-induced down regulation of Fyn expression in a granulosa cell line (rat). Administration of human chorionic gonadotropin (hCG; LH analog) caused a 75% decrease in the in vivo miR-125a-3p:Fyn mRNA ratio, followed by a 2-fold increased migratory ability of mural granulosa cells. In the hCG-treated granulosa cell line, miR-125a-3p expression was decreased, followed by Fyn up-regulation and phosphorylation of focal adhesion kinase and paxillin, enabling cell migration. An in vivo interference with miR-125a-3p:Fyn mRNA ratio in granulosa cells by intrabursal injections of Fyn small interfering RNA or miR-125a-3p mimic caused a 33 or 55% decrease in the number of ovulated oocytes, respectively. These observations reveal a new regulatory pathway in mural granulosa cells under the regulation of LH/hCG. Modulation of cell migration may account for the significance of the LH/hCG-miR-125a-3p-Fyn pathway to ovulation. PMID- 25921828 TI - Cm-p5: an antifungal hydrophilic peptide derived from the coastal mollusk Cenchritis muricatus (Gastropoda: Littorinidae). AB - Antimicrobial peptides form part of the first line of defense against pathogens for many organisms. Current treatments for fungal infections are limited by drug toxicity and pathogen resistance. Cm-p5 (SRSELIVHQRLF), a peptide derived from the marine mollusk Cenchritis muricatus peptide Cm-p1, has a significantly increased fungistatic activity against pathogenic Candida albicans (minimal inhibitory concentration, 10 ug/ml; EC50, 1.146 ug/ml) while exhibiting low toxic effects against a cultured mammalian cell line. Cm-p5 as characterized by circular dichroism and nuclear magnetic resonance revealed an alpha-helical structure in membrane-mimetic conditions and a tendency to random coil folding in aqueous solutions. Additional studies modeling Cm-p5 binding to a phosphatidylserine bilayer in silico and isothermal titration calorimetry using lipid monophases demonstrated that Cm-p5 has a high affinity for the phospholipids of fungal membranes (phosphatidylserine and phosphatidylethanolamine), only moderate interactions with a mammalian membrane phospholipid, low interaction with ergosterol, and no interaction with chitin. Adhesion of Cm-p5 to living C. albicans cells was confirmed by fluorescence microscopy with FITC-labeled peptide. In a systemic candidiasis model in mice, intraperitoneal administration of Cm-p5 was unable to control the fungal kidney burden, although its low amphiphaticity could be modified to generate new derivatives with improved fungicidal activity and stability. PMID- 25921830 TI - Slow binding kinetics of secreted protein, acidic, rich in cysteine-VEGF interaction limit VEGF activation of VEGF receptor 2 and attenuate angiogenesis. AB - VEGF-A (VEGF) drives angiogenesis through activation of downstream effectors to promote endothelial cell proliferation and migration. Although VEGF binds both VEGF receptor 1 (R1) and receptor 2 (R2), its proangiogenic effects are attributed to R2. Secreted protein, acidic, rich in cysteine (SPARC) is a matricellular glycoprotein thought to inhibit angiogenesis by preventing VEGF from activating R1, but not R2. Because R2 rather than R1 mediates proangiogenic activities of VEGF, the role of human SPARC in angiogenesis was reevaluated. We confirm that association of SPARC with VEGF inhibits VEGF-induced HUVEC adherence, motility, and proliferation in vitro and blocks VEGF-induced blood vessel formation ex vivo. SPARC decreases VEGF-induced phosphorylation of R2 and downstream effectors ERK, Akt, and p38 MAPK as shown by Western blot and/or phosphoflow analysis. Surface plasmon resonance indicates that SPARC binds slowly to VEGF (0.865 +/- 0.02 * 10(4) M(-1) s(-1)) with a Kd of 150 nM, forming a stable complex that dissociates slowly (1.26 +/- 0.003 * 10(-3) s(-1)). Only domain III of SPARC binds VEGF, exhibiting a 15-fold higher affinity than full length SPARC. These findings support a model whereby SPARC regulates angiogenesis by sequestering VEGF, thus restricting the activation of R2 and the subsequent activation of downstream targets critical for endothelial cell functions. PMID- 25921831 TI - The role of the gut microbiota in metabolic health. AB - The global prevalence of obesity and related comorbidities has increased considerably over the past decades. In addition to an increase in food consumption and a reduction in physical activity, growing evidence implicates the microorganisms in our gastrointestinal tract, referred to as the gut microbiota, in obesity and related metabolic disturbances. The composition of the gut microbiota can fluctuate markedly within an individual and between individuals. Changes in gut microbial composition may be unfavorable and predispose an individual to disease. Studies in mice that are germ free, mice that are cohoused, and mice that are treated with antibiotics have provided some evidence that changes in gut microbiota may causally contribute to metabolic disorders. Several mechanisms have been proposed and explored that may mediate the effects of the gut microbiota on metabolic disorders. In this review, we carefully analyze the literature on the connection between the gut microbiota and metabolic health, with a focus on studies demonstrating a causal relation and clarifying potential underlying mechanisms. Despite a growing appreciation for a role of the gut microbiota in metabolic health, more experimental evidence is needed to substantiate a cause-and-effect relationship. If a clear causal relationship between the gut microbiota and metabolic health can be established, dietary interventions can be targeted toward improving gut microbial composition in the prevention and perhaps even the treatment of metabolic diseases. PMID- 25921832 TI - Evidence for negative selection of gene variants that increase dependence on dietary choline in a Gambian cohort. AB - Choline is an essential nutrient, and the amount needed in the diet is modulated by several factors. Given geographical differences in dietary choline intake and disparate frequencies of single-nucleotide polymorphisms (SNPs) in choline metabolism genes between ethnic groups, we tested the hypothesis that 3 SNPs that increase dependence on dietary choline would be under negative selection pressure in settings where choline intake is low: choline dehydrogenase (CHDH) rs12676, methylenetetrahydrofolate reductase 1 (MTHFD1) rs2236225, and phosphatidylethanolamine-N-methyltransferase (PEMT) rs12325817. Evidence of negative selection was assessed in 2 populations: one in The Gambia, West Africa, where there is historic evidence of a choline-poor diet, and the other in the United States, with a comparatively choline-rich diet. We used 2 independent methods, and confirmation of our hypothesis was sought via a comparison with SNP data from the Maasai, an East African population with a genetic background similar to that of Gambians but with a traditional diet that is higher in choline. Our results show that frequencies of SNPs known to increase dependence on dietary choline are significantly reduced in the low-choline setting of The Gambia. Our findings suggest that adequate intake levels of choline may have to be reevaluated in different ethnic groups and highlight a possible approach for identifying novel functional SNPs under the influence of dietary selective pressure. PMID- 25921833 TI - Guided cutting of bone for intraoral vertical ramus osteotomy with a freer marking technique. PMID- 25921834 TI - Specific gamma-aminobutyrate chemotaxis in pseudomonads with different lifestyle. AB - The PctC chemoreceptor of Pseudomonas aeruginosa mediates chemotaxis with high specificity to gamma-aminobutyric acid (GABA). This compound is present everywhere in nature and has multiple functions, including being a human neurotransmitter or plant signaling compound. Because P. aeruginosa is ubiquitously distributed in nature and able to infect and colonize different hosts, the physiological relevance of GABA taxis is unclear, but it has been suggested that bacterial attraction to neurotransmitters may enhance virulence. We report the identification of McpG as a specific GABA chemoreceptor in non pathogenic Pseudomonas putida KT2440. As with PctC, GABA was found to bind McpG tightly. The analysis of chimeras comprising the PctC and McpG ligand-binding domains fused to the Tar signaling domain showed very high GABA sensitivities. We also show that PctC inactivation does not alter virulence in Caenorhabditis elegans. Significant amounts of GABA were detected in tomato root exudates, and deletion of mcpG reduced root colonization that requires chemotaxis through agar. The C. elegans data and the detection of a GABA receptor in non-pathogenic species indicate that GABA taxis may not be related to virulence in animal systems but may be of importance in the context of colonization and infection of plant roots by soil-dwelling pseudomonads. PMID- 25921835 TI - Home Visiting Start-Up: Lessons Learned From Program Replication in New Mexico. AB - Growth in federal, state, and private funding is fueling the initiation of home visiting programs around the country. As communities expand home visiting programs, they need information to help them successfully start up new sites. This paper documents lessons learned about home visiting installation and initial implementation from the replication of the First Born((r)) Program in six counties in New Mexico. Specifically, we examine how well sites met staffing, family referral and enrollment, program model fidelity, and financing goals in the first year of providing services. Data come from semi-structured interviews with program staff and document review. The findings are likely to be valuable to a wide spectrum of communities starting or expanding home visiting services, as well as to public and private funders of programs. PMID- 25921836 TI - Learning efficiency: The influence of cue salience during spatial navigation. AB - In three experiments, male Wistar rats were trained to find a hidden platform in the Morris water maze using two cues for five or ten days. Experiments 1 and 2 investigated two factors of cue salience; proximity to the goal and brightness. Results from Experiment 1 showed that rats tested with a bright distal cue were significantly better at locating the platform than rats tested with the proximal cue after five- and ten-day training with both cues. In Experiment 2, the position of the cues was reversed. Rats tested with a brighter proximal cue outperformed those tested with a distal cue. Findings from Experiments 1 and 2 suggest that brightness acquired more control over rats' behaviour than proximity to the goal. Animals in Experiment 3 were trained with equally bright proximal and distal cues. Unexpectedly, probe tests revealed that rats tested with the farther cue were more accurate than those tested with the proximal cue, but only after extended training. Possible explanations for this result are discussed with reference to errors in directional information estimation and cue assignment, cue elevation and the use of the pool wall as a navigational aid. Taken together, findings point towards the use of an elemental learning strategy involving the more salient of the two cues which emerged earlier when the relative saliences of the cues differed considerably. PMID- 25921837 TI - Effect of sucrose availability on wheel-running as an operant and as a reinforcing consequence on a multiple schedule: Additive effects of extrinsic and automatic reinforcement. AB - As a follow up to Belke and Pierce's (2014) study, we assessed the effects of repeated presentation and removal of sucrose solution on the behavior of rats responding on a two-component multiple schedule. Rats completed 15 wheel turns (FR 15) for either 15% or 0% sucrose solution in the manipulated component and lever pressed 10 times on average (VR 10) for an opportunity to complete 15 wheel turns (FR 15) in the other component. In contrast to our earlier study, the components advanced based on time (every 8min) rather than completed responses. Results showed that in the manipulated component wheel-running rates were higher and the latency to initiate running longer when sucrose was present (15%) compared to absent (0% or water); the number of obtained outcomes (sucrose/water), however, did not differ with the presentation and withdrawal of sucrose. For the wheel-running as reinforcement component, rates of wheel turns, overall lever-pressing rates, and obtained wheel-running reinforcements were higher, and postreinforcement pauses shorter, when sucrose was present (15%) than absent (0%) in manipulated component. Overall, our findings suggest that wheel running rate regardless of its function (operant or reinforcement) is maintained by automatically generated consequences (automatic reinforcement) and is increased as an operant by adding experimentally arranged sucrose reinforcement (extrinsic reinforcement). This additive effect on operant wheel-running generalizes through induction or arousal to the wheel-running as reinforcement component, increasing the rate of responding for opportunities to run and the rate of wheel-running per opportunity. PMID- 25921838 TI - Silver-catalyzed Meerwein arylation: intermolecular and intramolecular fluoroarylation of styrenes. AB - The first example of silver-catalyzed intermolecular and intramolecular Meerwein fluoroarylation of styrenes with aryl diazonium salts has been developed. This reaction is operationally simple, scalable and proceeds under mild conditions. Furthermore, fluorinated dihydrobenzofurans and indolines were easily accessed using this method. PMID- 25921839 TI - Cross analysis of knowledge and learning methods followed by French residents in cardiology. AB - BACKGROUND: No scientific assessment of the theoretical teaching of cardiology in France is available. AIM: To analyse the impact of the available teaching modalities on the theoretical knowledge of French residents in cardiology. METHODS: Electronic questionnaires were returned by 283 residents. In the first part, an inventory of the teaching/learning methods was taken, using 21 questions (Yes/No format). The second part was a knowledge test, comprising 15 multiple choice questions, exploring the core curriculum. RESULTS: Of the 21 variables tested, four emerged as independent predictors of the score obtained in the knowledge test: access to self-assessment (P=0.0093); access to teaching methods other than lectures (P=0.036); systematic discussion about clinical decisions (P=0.013); and the opportunity to prepare and give lectures (P=0.039). The fifth variable was seniority in residency (P=0.0003). Each item of the knowledge test was analysed independently: the score was higher when teaching the item was driven by reading guidelines and was lower if the item had not been covered by the programme (P<0.001). Finally, 91% of students would find it useful to have a national source for each topic of the curriculum; 76% of them would often connect to an e-learning platform if available. CONCLUSIONS: It is necessary to rethink teaching in cardiology by involving students in the training, by using teaching methods other than lectures and by facilitating access to self-assessment. The use of digital tools may be a particularly effective approach. PMID- 25921840 TI - Sildenafil in heart transplant candidates with pulmonary hypertension. AB - BACKGROUND: Severe pulmonary hypertension is a usual contraindication to heart transplantation. A few studies have found that sildenafil has a favourable effect on haemodynamic variables in patients with severe left ventricular systolic dysfunction. AIM: To report our clinical experience of sildenafil in patients with left ventricular systolic dysfunction and severe pulmonary hypertension. METHODS: All patients underwent echocardiography, radionuclide angiography, a cardiopulmonary exercise test and right heart catheterization before and after treatment with sildenafil. All patients were clinically stable and were receiving maximal tolerated doses of recommended drugs. RESULTS: We included 18 patients, with a mean+/-standard deviation age of 47+/-13 years. After a median of 8.7 months (interquartile range, 4.4-13.5 months) on sildenafil, there was a significant improvement in New York Heart Association classification (P=0.02) and mean right ventricular ejection fraction (from 26+/-7% to 30+/-9%; P=0.008), with a decrease in the VE/VCO2 slope (from 52+/-11 to 44+/-11; P=0.009) and in pulmonary vascular resistance (from 5.3+/-1.9 Wood units to 3.3+/-1.8 Wood units; P=0.01). During follow-up, three patients had urgent heart transplantation, two had non-urgent transplantation and six had left ventricular assist device implantation. All patients with pulmonary vascular resistance<3 Wood units after sildenafil were alive, compared with four in the other subgroup (44% survival). CONCLUSION: In patients with pulmonary hypertension related to left ventricular systolic dysfunction, sildenafil seems to improve cardiac haemodynamics. PMID- 25921841 TI - High circulating adiponectin levels predict decreased muscle strength among older adults aged 70 years and over: A prospective cohort study. AB - BACKGROUND AND AIMS: Population-based researches indicate that circulating adiponectin is inversely associated with muscle strength. However, interpretation of the findings has been limited by the use of a cross-sectional design. This study aimed to examine the prospective relationship between baseline circulating adiponectin concentration and change in muscular function-related physical performance in older adults. METHODS AND RESULTS: A 1-year prospective cohort study of Japanese community-dwelling elderly was conducted between 2002 and 2003. Four hundred thirty-four older persons participated in the measurements of physical function, including leg extension power, functional reach, timed up-and go test, and 10-m maximum walking speed, at baseline and follow-up. After adjustment for potential covariates, higher serum adiponectin concentration was found to be significantly associated with poorer physical performance at baseline (leg extension power [watt], P < 0.001; functional reach [cm], P < 0.001; log timed up-and-go test, P = 0.007; log 10-m maximum walking speed, P < 0.001). The results of the prospective analysis by analysis of covariance indicated that the elderly with higher serum adiponectin concentrations (tertiles) at baseline tended to have a decreased performance in leg extension power (means [95% confidence interval]: lowest, -105 [-125, -85.7]; middle, -117 [-135, -97.8]; highest, -140 [-160, -120], watt, P for trend = 0.021) and timed up-and-go test (lowest, -0.08 [-0.28, -0.12]; middle, -0.10 [-0.29, 0.10]; highest, 0.28 [0.07, 0.48], s, P for trend = 0.019), but not two other functioning. CONCLUSION: High circulating adiponectin concentration may be an indicator of decreased physical performance, especially muscle strength, in older adults. PMID- 25921842 TI - Non-HDL-cholesterol to HDL-cholesterol ratio as an independent risk factor for the development of chronic kidney disease. AB - BACKGROUND AND AIMS: Dyslipidemia contributes to the development and progression of renal disease. The objective of this study was to investigate whether an elevated non-HDL-cholesterol to HDL-cholesterol ratio (NonHDLc/HDLc) predicts new onset chronic kidney disease (CKD). METHODS AND RESULTS: We followed 1891 Chinese adults with normal or near-normal kidney function at baseline who participated in an annual health checkup program for the occurrence of new-onset CKD [defined as an estimated glomerular filtration rate (eGFR) of <60 mL/min/1.73 m(2) (low eGFR) and/or proteinuria (defined as urinary protein >=1 + on dipstick testing)] or low eGFR. Cox proportional hazards models were used to examine the independent relationship between the plasma NonHDLc/HDLc ratio and new-onset CKD. During a median follow-up period of 2.8 years, 3% (n = 57) of participants developed new onset CKD. Compared with patients in the lowest tertile, patients with NonHDLc/HDLc ratios in the highest tertile had a 1.45-fold higher risk of new onset CKD (hazard ratio [HR], 2.45; 95% confidence interval [95% CI], 1.07 to 5.61; P = 0.035) after adjustment for potential confounders. There was a marginally significant association with low eGFR (tertile 3 versus tertile 1: HR, 2.94; 95% CI, 0.98 to 8.82; P = 0.054). CONCLUSIONS: NonHDLc/HDLc ratio is an independent risk factor for the development of CKD. Assessment of NonHDLc/HDLc ratio may help identify high risk groups with chronic kidney disease. PMID- 25921843 TI - Metformin improves putative longevity effectors in peripheral mononuclear cells from subjects with prediabetes. A randomized controlled trial. AB - BACKGROUND AND AIMS: Prediabetes increases cardiovascular risk and is associated with excess mortality. In preclinical models, metformin has been shown to exert anti-ageing effects. In this study, we sought to assess whether metformin modulates putative effector longevity programs in prediabetic subjects. METHODS AND RESULTS: In a randomized, single-blind, placebo-controlled trial, 38 prediabetic subjects received metformin (1500 mg/day) or placebo for 2 months. At baseline and after treatment, we collected anthropometric and metabolic parameters. Gene and protein levels of SIRT1, mTOR, p53, p66Shc, SIRT1 activity, AMPK activation, telomere length, and SIRT1 promoter chromatin accessibility were determined in peripheral blood mononuclear cells (PBMCs). Plasma N-glycans, non invasive surrogate markers of ageing, were also analysed. Compared to baseline, metformin significantly improved metabolic parameters and insulin sensitivity, increased SIRT1 gene/protein expression and SIRT1 promoter chromatin accessibility, elevated mTOR gene expression with concomitant reduction in p70S6K phosphorylation in subjects' PBMCs, and modified the plasma N-glycan profile. Compared to placebo, metformin increased SIRT1 protein expression and reduced p70S6K phosphorylation (a proxy of mTOR activity). Plasma N-glycans were also favourably modified by metformin compared to placebo. CONCLUSION: In individuals with prediabetes, metformin ameliorated effector pathways that have been shown to regulate longevity in animal models. ClinicalTrials. gov identifier: NCT01765946 January 2013. PMID- 25921844 TI - Influence of urbanization on childhood obesity. PMID- 25921845 TI - Dietary style and acid load in an Italian population of calcium kidney stone formers. AB - BACKGROUND AND AIMS: Animal protein intake may cause an acid load that predisposes individuals to stones by influencing calcium and citrate excretion. These associations were not confirmed in recent studies. Therefore the present study was aimed to compare acid load of diet in stone formers and controls. METHODS AND RESULTS: Participants to the study were 157 consecutive calcium stone formers and 144 controls. Diet was analyzed in these subjects using a software that evaluated nutrient intake from a three-day food intake diary. This software also estimated the potential renal acid load (PRAL, mEq/day). Twenty-four-hour urine excretion of ions and citrate was measured in stone formers. Stone former diet had lower intake of glucose, fructose, potassium and fiber and higher PRAL in comparison with controls. The multinomial logistic regression analysis showed that stone risk decreased in association with the middle and the highest tertiles of fiber intake and increased in association with the highest tertile of PRAL. The linear multiple regression analysis showed that calcium excretion was associated with the sodium excretion and that citrate excretion was associated with the PRAL and animal protein intake in stone formers. CONCLUSION: Our findings suggest that stone formers may undergo a greater dietary acid load sustained by a low vegetable intake and base provision. Dietary acid load does not appear as the main determinant of calcium excretion, but may promote stone risk by decreasing citrate excretion. Sodium intake may predispose to stones by stimulating calcium excretion. PMID- 25921846 TI - Markers of cholesterol metabolism as biomarkers in predicting diabetes in the Finnish Diabetes Prevention Study. AB - BACKGROUND AND AIMS: We examined the effect of serum markers of cholesterol synthesis and absorption on the incidence of type 2 diabetes (T2D) in the randomized Finnish Diabetes Prevention Study (DPS). We also explored a possible interaction of ABCG8 rs4299376 on sterol levels and lifestyle intervention. METHODS AND RESULTS: We conducted a prospective cohort study including overweight, middle-aged people with impaired glucose tolerance at baseline who participated in the randomized DPS. The primary outcome of the DPS was the diagnosis of T2D based on repeated oral glucose tolerance tests (OGTTs). After active intervention (median of four years, 1994-2001), non-T2D participants were further followed until T2D diagnosis, dropout or the end of 2009. Of these, 340 participants who had beta-sitosterol, campesterol, lathosterol and desmosterol measured by gas chromatography-mass spectrometry during the active four-year follow-up and who were not using cholesterol lowering medications were analysed. Surrogate indexes of insulin sensitivity (IS) and secretion were calculated from an OGTT. In adjusted models, plant sterols during the four-year follow-up were associated with lower T2D incidence during the extended eight-year follow-up (HR for 1-SD change in beta-sitosterol and campesterol: 0.76 [0.63-0.92], and 0.81 [0.67-0.99], respectively). Lathosterol levels were associated with higher T2D incidence (HR: 1.35 [1.13-1.62]). These associations, though, were not independent of IS. There was an interaction between rs4299376 and study group on beta-sitosterol (p = 0.001) and campesterol (p = 0.004) levels during the follow up. CONCLUSIONS: Markers of low absorption and high synthesis of cholesterol were associated with the risk of developing T2D, mostly ascribed to IS. PMID- 25921847 TI - High normal albuminuria is associated with arterial stiffness and carotid atherosclerosis in Korean patients with type 2 diabetes. AB - BACKGROUND AND AIMS: Current evidence suggests that high normal albuminuria is significantly associated with increased cardiovascular risk. This study investigated the association between urine albumin-to-creatinine ratio (ACR) within the normal range and subclinical atherosclerosis in Korean patients with type 2 diabetes. METHODS AND RESULTS: This cross-sectional study involved 521 type 2 diabetic patients with normoalbuminuria. Brachial-ankle pulse wave velocity (baPWV) measurement and ultrasound assessment of carotid atherosclerosis was done. Subclinical atherosclerosis was assessed by the presence of high baPWV (>1682 cm/s), carotid atherosclerosis (intima-media thickness >0.8 mm or the presence of plaques), and carotid stenosis (>=50% of luminal narrowing). Across the tertiles of ACR, there was a trend for an increasing prevalence of high baPWV (16.8%, 20.0%, and 38.2%, P < 0.001), carotid atherosclerosis (46.9%, 55.4%, and 64.7%, P < 0.001), and carotid stenosis (12.7%, 16.0%, and 30.1%, P < 0.001). In multivariate analysis, patients in the highest ACR tertile had an odds ratio of 2.05 (95% confidence interval [CI], 1.13-3.72, P = 0.019) for high baPWV, 1.78 (95% CI, 1.08-2.93, P = 0.024) for carotid atherosclerosis, and 2.72 (95% CI, 1.44-5.11, P = 0.002) for carotid stenosis compared to those in the lowest tertile. The relation of ACR with carotid atherosclerosis and stenosis remained significant even in patients without diabetic retinopathy. CONCLUSION: High normal albuminuria was significantly associated with atherosclerotic vascular changes, independent of retinopathy and other cardiovascular risk factors. High normal albuminuria may be an early marker for subclinical atherosclerosis in type 2 diabetes. PMID- 25921848 TI - Diet heart controversies--Quality of fat matters. AB - There has been a lot a debate recently regarding the effect of the quality of dietary fat on the risk of atherosclerotic vascular diseases, especially coronary heart disease (CHD). Long term randomized controlled interventions are almost lacking and the body of evidence is based on epidemiological data which allows conclusions only regarding associations, instead of effects. However, a recent systematic review, which included prospective cohort studies with high or moderate quality, showed convincing evidence on the favorable effect of partially replacing saturated fatty acids by polyunsaturated fatty acids on the risk of CHD. For some reason it seems tempting even in the scientific discussion to question the evidence of the quality of dietary fat on the risk of CHD every time when a controversial scientific article is published. PMID- 25921849 TI - Endothelial function and insulin sensitivity during acute non-esterified fatty acid elevation: Effects of fat composition and gender. AB - BACKGROUND AND AIMS: We have reported that adverse effects on flow-mediated dilation of an acute elevation of non-esterified fatty acids rich in saturated fat (SFA) are reversed following addition of long-chain (LC) n-3 polyunsaturated fatty acids (PUFA), and hypothesised that these effects may be mediated through alterations in insulin signalling pathways. In a subgroup, we explored the effects of raised NEFA enriched with SFA, with or without LC n-3 PUFA, on whole body insulin sensitivity (SI) and responsiveness of the endothelium to insulin infusion. METHODS AND RESULTS: Thirty adults (mean age 27.8 y, BMI 23.2 kg/m(2)) consumed oral fat loads on separate occasions with continuous heparin infusion to elevate NEFA between 60 and 390 min. For the final 150 min, a hyperinsulinaemic euglycaemic clamp was performed, whilst FMD and circulating markers of endothelial function were measured at baseline, pre-clamp (240 min) and post clamp (390 min). NEFA elevation during the SFA-rich drinks was associated with impaired FMD (P = 0.027) whilst SFA + LC n-3 PUFA improved FMD at 240 min (P = 0.003). In males, insulin infusion attenuated the increase in FMD with SFA + LC n 3 PUFA (P = 0.049), with SI 10% greater with SFA + LC n-3 PUFA than SFA (P = 0.041). CONCLUSION: This study provides evidence that NEFA composition during acute elevation influences both FMD and SI, with some indication of a difference by gender. However our findings are not consistent with the hypothesis that the effects of fatty acids on endothelial function and SI operate through a common pathway. This trial was registered at clinical trials.gov as NCT01351324 on 6th May 2011. PMID- 25921851 TI - In silico deletion of PtsG gene in Escherichia coli genome-scale model predicts increased succinate production from glycerol. AB - Systems metabolic engineering and in silico analyses are necessary to study gene knockout candidate for enhanced succinic acid production by Escherichia coli. Metabolically engineered E. coli has been reported to produce succinate from glucose and glycerol. However, investigation on in silico deletion of ptsG/b1101 gene in E. coli from glycerol using minimization of metabolic adjustment algorithm with the OptFlux software platform has not yet been elucidated. Herein we report what is to our knowledge the first direct predicted increase in succinate production following in silico deletion of the ptsG gene in E. coli GEM from glycerol with the OptFlux software platform. The result indicates that the deletion of this gene in E. coli GEM predicts increased succinate production that is 20% higher than the wild-type control model. Hence, the mutant model maintained a growth rate that is 77% of the wild-type parent model. It was established that knocking out of the ptsG/b1101 gene in E. coli using glucose as substrate enhanced succinate production, but the exact mechanism of this effect is still obscure. This study informs other studies that the deletion of ptsG/b1101 gene in E. coli GEM predicted increased succinate production, enabling a model-driven experimental inquiry and/or novel biological discovery on the underground metabolic role of this gene in E. coli central metabolism in relation to increasing succinate production when glycerol is the substrate. PMID- 25921852 TI - Modifications in activation of lower limb muscles as a function of initial foot position in cycling. AB - Cyclic movements, such as walking/cycling, require the activity of spinal circuits, the central-pattern-generators (CPG). To our knowledge little work has been done to investigate the activation of these circuits, e.g., the muscular and kinematic activity during cycling initiation. This study aims to detail the muscle output properties as a function of the initial lower limb-position using a simple cycling paradigm. Therefore, subjects were required to pedal on a cycle ergometer in seated position starting at different-crank-angles (0-150 degrees ). Surface-electromyography was recorded from the gluteus major (GL), vastus lateralis (VL), and gastrocnemius medialis (GM), while crank position was recorded using a linear-encoder. Gluteus major peak-activity (PA) occurred at 65.0+/-12.4 degrees when starting with 0 degrees initial crank position (ICP), while occurred maximally at 110.5+/-2.9 when starting with 70 degrees ICP. Vastus lateralis PA occurred at 40.7+/-8.8 degrees with 0 degrees ICP, whereas with 70 degrees ICP PA occurred at 103.4+/-4.0 degrees . Similarly, GM PA occurred at 112.0+/-10.7 degrees with 0 degrees ICP, whereas with 70 degrees ICP PA occurred at 142.5+/-4.2 degrees PA. Gluteus major and gastrocnemius medialis showed similar PA phase shifts, which may suggest they are controlled by same local circuitry, in agreement with their common spinal origin, i.e., motoneurons pool in S1-S2. PMID- 25921853 TI - Changes in N-terminal pro-B-type natriuretic peptide levels and outcomes in heart failure with preserved ejection fraction: an analysis of the I-Preserve study. AB - AIMS: In patients with heart failure (HF) and reduced ejection fraction, decreases or increases in NT-proBNP levels are associated with better and worse outcomes, respectively. The association in HF and preserved ejection fraction (HF PEF) is unknown. We examined the association between change in level of NT-proBNP and prognosis in patients with HF-PEF. METHODS AND RESULTS: We examined the association between change in NT-proBNP from baseline to 6 months and cardiovascular (CV) death or HF hospitalization in 2612 participants in the Irbesartan in Patients with Heart Failure and Preserved Systolic Function Study (I-Preserve). Change in NT-proBNP was modelled as a restricted cubic spline in a Cox model after adjusting for baseline NT-proBNP and known prognostic variables. Median change in NT-proBNP from baseline was -7 pg/mL (interquartile range -143 to +108). After adjustment, a 1000 pg/mL decrease in NT-proBNP from baseline was associated with a reduction in the risk of CV death or HF hospitalization [hazard ratio (HR) 0.73, 95% confidence interval (CI) 0.53-1.02]; a 1000 pg/mL increase was associated with an increase in risk (HR 2.01, 95% CI 1.50-2.69). Beyond a 1000 pg/mL rise or fall, there was little additional change in risk. Addition of change in NT-proBNP at 6 months to a model with only baseline NT-proBNP improved the C-statistic from 0.752 to 0.769 (P = 0.013). CONCLUSION: In HF-PEF, a rise in NT-proBNP was associated with an increase in risk of CV death or HF hospitalization and a fall was associated with a trend towards a decrease in risk. NT-proBNP may be a useful marker to monitor prognosis in this condition. PMID- 25921854 TI - Response to: Is it worth performing suture of the cauda equina roots after traumatic penetrating lumbar injury in a combat support hospital? PMID- 25921855 TI - Intraoperative functional mapping of calculation in parietal surgery. New insights and clinical implications. AB - BACKGROUND: Parietal areas play a crucial role in calculation processing. The purpose of this study is to report our experience in the assessment of calculation processing during awake surgery in parietal areas, focusing on clinical implications and new insights provided by this approach. METHODS: We retrospectively reviewed clinical and surgical data of 13 patients who underwent parietal surgery with calculation mapping. Cortical and sub-cortical areas (in 13 and five patients, respectively) involved in single-digit multiplications and additions were identified using bipolar electro-stimulation. RESULTS: Cortical stimulation data showed that the inferior parietal lobule and the intraparietal sulcus were specifically related to calculation in all cases, regardless of the side (100% of cases, in both sides). Conversely, the superior parietal lobule was inconstantly involved in calculation processing (40% of cases in the left and 75% in the right side), whereas the somatosensory area was never involved. Sub cortical stimulation was able to detect functional areas for calculation in all patients: in 90% of cases the sub-cortical sites positive for calculation were in close anatomical connection with the cortical sites mapping for the same function. The intraoperative preservation (-or damaging-) of functional sites correlated with the absence (- or occurrence-) of post-operative calculation processing impairment. CONCLUSIONS: Our findings support the specificity of the reported technique in the intraoperative identification of sites functional for calculation. Our data show the bilateral involvement of parietal cortex, especially of the inferior lobule, in calculation processing. Furthermore, our study suggests the existence of a sub-cortical pathway specific for calculation, whose better understanding might be crucial for the clinical outcome of patients. PMID- 25921850 TI - Does the Mediterranean diet counteract the adverse effects of abdominal adiposity? AB - BACKGROUND AND AIM: We tested the hypothesis that an intervention with a Mediterranean diet (MeDiet) could mitigate the well-known harmful effects of abdominal obesity on cardiovascular health. METHODS AND RESULTS: We assessed the relationship between baseline waist-to-height ratio (WHtR) and major cardiovascular events during a median follow-up of 4.8 years in the Prevention with Mediterranean Diet (PREDIMED) randomized primary prevention trial, which tested a MeDiet against a control diet (advice on a low-fat diet). We also examined whether the MeDiet intervention was able to counteract the detrimental cardiovascular effects of an increased WHtR. The trial included 7447 participants (55-80 years old, 57% women) at high cardiovascular risk but free of cardiovascular disease (CVD) at enrollment. An increased risk of CVD events (myocardial infarction, stroke, or cardiovascular death) was apparent for the highest versus the lowest quartile of WHtR (multivariable-adjusted hazard ratio: 1.98) (95% confidence interval: 1.10-3.57; linear trend: p = 0.019) only in the control-diet group, but not in the two groups allocated to intervention with MeDiet (p for interaction = 0.034). This apparent interaction suggesting that the intervention counterbalanced the detrimental cardiovascular effects of adiposity was also significant for body mass index (BMI) (p = 0.01) and waist circumference (p = 0.043). CONCLUSIONS: The MeDiet may counteract the harmful effects of increased adiposity on the risk of CVD. PMID- 25921856 TI - An external use of a tissue expander. PMID- 25921857 TI - Morphology, innervation, and peripheral sensory cells of the siphon of aplysia californica. AB - The siphon of Aplysia californica has several functions, including involvement in respiration, excretion, and defensive inking. It also provides sensory input for defensive withdrawals that have been studied extensively to examine mechanisms that underlie learning. To better understand the neuronal bases of these functions, we used immunohistochemistry to catalogue peripheral cell types and innervation of the siphon in stage 12 juveniles (chosen to allow observation of tissues in whole-mounts). We found that the siphon nerve splits into three major branches, leading ultimately to a two-part FMRFamide-immunoreactive plexus and an apparently separate tyrosine hydroxylase-immunoreactive plexus. Putative sensory neurons included four distinct types of tubulin-immunoreactive bipolar cells (one likely also tyrosine hydroxylase immunoreactive) that bore ciliated dendrites penetrating the epithelium. A fifth bipolar neuron type (tubulin- and FMRFamide immunoreactive) occurred deeper in the tissue, associated with part of the FMRFamide-immunoreactive plexus. Our observations emphasize the structural complexity of the peripheral nervous system of the siphon, and the importance of direct tests of the various components to better understand the functioning of the entire organ, including its role in defensive withdrawal responses. PMID- 25921858 TI - Chikungunya virus (CHIKV) inhibitors from natural sources: a medicinal chemistry perspective. AB - Chikungunya virus (CHIKV) is one of the re-emerging "neglected" tropical diseases whose recent outbreak affected not only Africa and South-East Asia but also several parts of America and Europe. To date, despite its serious nature, no antivirals or vaccines were developed in order to counter this resurgent infectious disease. The recent advancement in crystallography and availability of crystal structures of certain domains of CHIKV initiates the development of anti CHIKV agents using structure-based drug design or synthetic medicinal chemistry approach. Despite the fact that almost 50% of the new chemical entities against several biological targets were either obtained from natural products or natural product analogues, a very humble effort was directed towards identification of novel CHIKV inhibitors from natural products. In this review, besides a brief overview on CHIKV as well as the nature as a source of medicines, we highlight the current progress and future steps towards the discovery of CHIKV inhibitors from natural products. This report could pave the road towards the design of novel semi-synthetic derivatives with enhanced anti-viral activities. PMID- 25921860 TI - Commentary. Low-grade non-resolving neuroinflammation: age does matter. PMID- 25921859 TI - Dipeptidyl peptidase-IV inhibitory activity of dimeric dihydrochalcone glycosides from flowers of Helichrysum arenarium. AB - A methanol extract of everlasting flowers of Helichrysum arenarium L. Moench (Asteraceae) was found to inhibit the increase in blood glucose elevation in sucrose-loaded mice at 500 mg/kg p.o. The methanol extract also inhibited the enzymatic activity against dipeptidyl peptidase-IV (DPP-IV, IC50 = 41.2 MUg/ml), but did not show intestinal alpha-glucosidase inhibitory activities. From the extract, three new dimeric dihydrochalcone glycosides, arenariumosides V-VII (2 4), were isolated, and the stereostructures were elucidated based on their spectroscopic properties and chemical evidence. Of the constituents, several flavonoid constituents, including 2-4, were isolated, and these isolated constituents were investigated for their DPP-IV inhibitory effects. Among them, chalconaringenin 2'-O-beta-D-glucopyranoside (16, IC50 = 23.1 MUM) and aureusidin 6-O-beta-D-glucopyranoside (35, 24.3 MUM) showed relatively strong inhibitory activities. PMID- 25921861 TI - Conference Report: 181st Annual Meeting of the American Association for the Advancement of Science (AAAS), San Jose Convention Center, San Jose, CA, USA February 12-16, 2015. PMID- 25921862 TI - Commentary: untangling Alzheimer disease pathology. PMID- 25921863 TI - The novel use of heart transplantation for the management of a case with multiple complications after acute myocardial infarction. AB - Rupture of the interventricular septum after myocardial infarction (MI) is an uncommon but serious complication, usually leading to congestive heart failure and cardiogenic shock. Surgical repair is usually the only definitive treatment for these patients because medical management is associated with a 30-day mortality approaching 100%. However with conventional surgical repair, operative mortality rates range from 33% to 53%. Furthermore, outcomes in patients with posterior ventricular septal defect (VSD) have been reported to have mortality rates up to 86%. Therefore, alternative treatment should be considered to improve management of this mechanical complication. We report the case of a 63-year-old man in whom VSD developed after an inferior MI. The patient presented with shortness of breath and a recent ST-elevation inferior MI. Transthoracic echocardiography revealed a 50% left ventricular ejection fraction with mild moderate right ventricular dysfunction. A posterior VSD (diameter >= 12 mm), moderate ischemic mitral regurgitation (MR), and a posterior pseudoaneurysm were also seen. The operative risk was considered to be too high for VSD repair because the surgery would have to include bypass grafting, mitral valve replacement, and pseudoaneurysm correction. Consequently, an urgent heart transplantation was considered the best option. The patient underwent heart transplantation 9 days after initial symptoms, and the recovery was unremarkable. To achieve a definitive optimal treatment, we propose that patients with posterior VSD with significant MR or pseudoaneurysm, or both, should be considered as heart transplant candidates. PMID- 25921864 TI - Body Mass Index and Repeat Revascularization After Percutaneous Coronary Intervention: A Meta-analysis. AB - BACKGROUND: The effect of obesity on restenosis in patients who undergo percutaneous coronary intervention (PCI) has not been fully understood. We undertook a meta-analysis for the effects of body mass index (BMI) on repeat revascularization in these patients. METHODS: A systematic search was conducted for published studies in OVID/MEDLINE, EMBASE, and the Cochrane library databases from 1980 to October, 2014. We identified studies that provided estimates for repeat revascularization on the basis of BMI in patients who underwent PCI. Summary estimates of risk ratios (RRs) were obtained for 5 prespecified BMI groups: underweight, normal weight, overweight, obese, and severely obese. RESULTS: A total of 13 studies with 49,002 patients were included in the final analyses. In contrast to a J-shaped association for mortality, a linear association was observed across BMI categories for repeat revascularization. Using normal weight as the reference, underweight was associated with a similar risk of repeat revascularization (RR, 0.93; 95% confidence interval [CI], 0.67 1.31), overweight, obesity, and severe obesity were all associated with incrementally greater risk of repeat revascularization (overweight: RR, 1.08; 95% CI, 1.02-1.14; obesity: RR, 1.10; 95% CI, 1.03-1.18; severe obesity: RR, 1.24; 95% CI, 1.04-1.48). The effect of overweight and obesity vs normal weight was consistent across stent types (drug-eluting stent and bare-metal stent) and definitions of repeat revascularization (target lesion revascularization, target vessel revascularization, and all revascularization). CONCLUSIONS: Our data revealed a linear relationship between BMI categories and repeat revascularization for patients who underwent PCI. The risk was lowest among underweight or normal weight patients, and highest among severely obese patients. PMID- 25921865 TI - New and existing risk factors in patients with hypertrophic cardiomyopathy. PMID- 25921866 TI - Pathogenic Vibrio parahaemolyticus isolated from biofouling on commercial vessels and harbor structures. AB - Ballast water is a significant vector of microbial dissemination; however, biofouling on commercial vessel hulls has been poorly studied with regard to pathogenic bacteria transport. Biofouling on three commercial vessels and seven port structures in Ensenada, Baja California, Mexico, was examined by qPCR to identify and quantify Vibrio parahaemolyticus, a worldwide recognized food-borne human pathogen. Pathogenic variants (trh+, tdh+) of V. parahaemolyticus were detected in biofouling homogenates samples from several docks in Ensenada and on the hulls of ships with Japanese and South Korean homeports, but not in reference sampling stations. A total of 26 tdh+ V. parahaemolyticus colonies and 1 ORF8+/O3:K6 strain were also isolated from enriched biofouling homogenate samples confirming the qPCR analysis. Our results suggest that biofouling is an important reservoir of pathogenic vibrios. Thus, ship biofouling might be an overlooked vector with regard to the dissemination of pathogens, primarily pathogenic V. parahaemolyticus. PMID- 25921867 TI - The social weight of spoken words. AB - Speech serves a linguistic function, cueing sounds and words, and a social function, cueing talkers and their social attributes. Listeners readily map sound patterns in speech to social representations. This mapping introduces social biases on the recognition and encoding of sound patterns produced by different groups and individuals. PMID- 25921870 TI - Being realistic about travelling when old or sick. PMID- 25921868 TI - Eyetracking of social preference choices reveals normal but faster processing in autism. AB - People with Autism Spectrum Disorder (ASD) have been reported to show atypical attention and evaluative processing, in particular for social stimuli such as faces. The usual measure in these studies is an explicit, subjective judgment, which is the culmination of complex-temporally extended processes that are not typically dissected in detail. Here we addressed a neglected aspect of social decision-making in order to gain further insight into the underlying mechanisms: the temporal evolution of the choice. We investigated this issue by quantifying the alternating patterns of gaze onto faces, as well as nonsocial stimuli, while subjects had to decide which of the two stimuli they preferred. Surprisingly, the temporal profile of fixations relating to choice (the so-called "gaze cascade") was entirely normal in ASD, as were the eventual preference choices. Despite these similarities, we found two key abnormalities: people with ASD made choices more rapidly than did control subjects across the board, and their reaction times for social preference judgments were insensitive to choice difficulty. We suggest that ASD features an altered decision-making process when basing choice on social preferences. One hypothesis motivated by these data is that a choice criterion is reached in ASD regardless of the discriminability of the options. PMID- 25921869 TI - Congenital anosmia and emotion recognition: A case-control study. AB - Patients with anosmia are not able to detect volatile chemicals signaling the presence of infectious and non-infectious environmental hazards, which typically elicit disgust and fear, respectively. Social animals may compensate a loss of olfaction by taking advantage of signals of threat that are produced by their conspecifics. Among humans and other primates, body postures and facial expressions are powerful cues conveying emotional information, including fear and disgust. The aim of the present study was to examine whether humans with agenesis of the olfactory bulb, a rare disorder characterized by congenital anosmia, would be more accurate in recognizing facial expressions of fear and disgust. A total of 90 participants with no history of mental disorder or traumatic brain injury were recruited, including 17 patients with congenital anosmia (10 men, mean age +/- standard deviation: 36.5 +/- 14.8 years), 34 patients with acquired anosmia (18 men, mean age +/- standard deviation: 57.2 +/- 11.8 years) and 39 healthy subjects (22 men, mean age +/- standard deviation: 36.7 +/- 13.2 years). For each patient with congenital anosmia, the agenesis of the olfactory bulb was ascertained through magnetic resonance imaging. Emotion recognition abilities were examined with a dynamic paradigm in which a morphing technique allowed displaying emotional facial expressions increasing in intensity over time. Adjusting for age, education, depression and anxiety, patients with congenital anosmia required similar levels of intensity to correctly recognize fear and disgust than healthy subjects while they displayed decreased error rates for both fear (mean difference [95% confidence interval] = -28.3% [-46.3%, -10.2%], P = 0.003) and disgust (mean difference [95% confidence interval] = -15.8% [-31.5%, 0.2%], P = 0.048). Furthermore, among patients with acquired anosmia, there was a negative correlation between duration of anosmia and the rate of errors for fearful (Spearman's rho = -0.531, P= 0.001) or disgust (Spearman's rho = -0.719, P < 0.001) faces recognition. No significant difference was observed for the other primary emotions. Overall, these results suggest that patients with congenital anosmia and long-lasting acquired anosmia may compensate their inability to detect environmental hazards through olfaction by an increased ability to detect fear or disgust as facially expressed by others. PMID- 25921871 TI - Efficacy and safety of morniflumate for the treatment of symptoms associated with soft tissue inflammation. AB - The effectiveness of nonsteroidal antiinflammatory drugs (NSAIDs) for the management of pain in osteoarthritis and other musculoskeletal diseases is well documented. The role of NSAIDs is less clear in the treatment of conditions involving soft tissue inflammation, including the airways, ear-nose-throat (ENT) system and urogenital tract. These conditions are often treated inappropriately with antibiotics. Morniflumate, the beta-morpholinoethyl ester of niflumic acid, is a member of the fenamate family of NSAIDs indicated for the treatment of inflammatory conditions (with or without pain) affecting airways, the ENT system, urogenital tract and the osteoarticular system. Morniflumate has a 30-year history of clinical use, particularly for the treatment of pain associated with paediatric ENT infection. This article reviews evidence supporting the efficacy and safety of morniflumate. Based on available evidence and the favourable tolerability profile emerging from extensive clinical use, morniflumate appears to be a valid and well-tolerated alternative to other NSAIDs, or to antibiotics, for the treatment of pain and other symptoms of soft tissue inflammation. PMID- 25921874 TI - A modified device to facilitate flow measurements during voiding cystometry studies in infants. AB - INTRODUCTION: Urodynamic studies (UDS) in infants are traditionally hampered by technique and flow collection; both are difficult and have not yet been standardized. METHODS: A very simple device has been developed to collect urine during the voiding phase in UDS. It is based on a urine-collection adhesive bag, which is connected to a tube that conducts the urine to a flowmeter. RESULTS: Eleven infants (4-23 months) were selected and a complete UDS was performed on all of them. A diagnosis was obtained for all of the infants. DISCUSSION: This device is easily available in every pediatric clinic; it is also disposable and inexpensive. It enables UDS in infants to be complete and achievable. PMID- 25921872 TI - Structures, Functions, and Interactions of ClpT1 and ClpT2 in the Clp Protease System of Arabidopsis Chloroplasts. AB - Plastid ClpT1 and ClpT2 are plant-specific proteins that associate with the ClpPR protease. However, their physiological significance and structures are not understood. Arabidopsis thaliana loss-of-function single clpt1 and clpt2 mutants showed no visible phenotypes, whereas clpt1 clpt2 double mutants showed delayed development, reduced plant growth, and virescent, serrated leaves but were viable and produced seed. The clpt1 and clpt1 clpt2 mutants showed partial destabilization of the ClpPR complex, whereas clpt2 null mutants showed only marginal destabilization. Comparative proteomics of clpt1 clpt2 plants showed a proteostasis phenotype similar to viable mutants in ClpPR core subunits, indicating reduced Clp protease capacity. In vivo and in vitro assays showed that ClpT1 and ClpT2 can independently interact with the single ClpP ring and ClpPR core, but not with the single ClpR ring. We determined ClpT1 and ClpT2 structures (2.4- and 2.0-A resolution) and detailed the similarities to the N-domains of bacterial ClpA/C chaperones. The ClpT structures suggested a conserved MYFF motif for interaction with the ClpPR core near the interface between the P- and R rings. In vivo complementation showed that ClpT function and ClpPR core stabilization require the MYFF motif. Several models are presented that may explain how ClpT1,2 contribute to ClpPR protease activity. PMID- 25921875 TI - Developments in cryo-electron tomography for in situ structural analysis. AB - Structural analysis of macromolecular assemblies and their remodeling during physiological processes is instrumental to defining the fundament of cellular and molecular biology. Recent advances in computational and analytical tools for cryo electron tomography have enabled the study of macromolecular structures in their native environment, providing unprecedented insights into cell function. Moreover, the recent implementation of direct electron detectors has progressed cryo-electron tomography to a stage where it can now be applied to the reconstruction of macromolecular structures at high resolutions. Here, we discuss some of the recent technical developments in cryo-electron tomography to reveal structures of macromolecular complexes in their physiological medium, focusing mainly on eukaryotic cells. PMID- 25921876 TI - Using GO-WAR for mining cross-ontology weighted association rules. AB - The Gene Ontology (GO) is a structured repository of concepts (GO terms) that are associated to one or more gene products. The process of association is referred to as annotation. The relevance and the specificity of both GO terms and annotations are evaluated by a measure defined as information content (IC). The analysis of annotated data is thus an important challenge for bioinformatics. There exist different approaches of analysis. From those, the use of association rules (AR) may provide useful knowledge, and it has been used in some applications, e.g. improving the quality of annotations. Nevertheless classical association rules algorithms do not take into account the source of annotation nor the importance yielding to the generation of candidate rules with low IC. This paper presents GO-WAR (Gene Ontology-based Weighted Association Rules) a methodology for extracting weighted association rules. GO-WAR can extract association rules with a high level of IC without loss of support and confidence from a dataset of annotated data. A case study on using of GO-WAR on publicly available GO annotation datasets is used to demonstrate that our method outperforms current state of the art approaches. PMID- 25921878 TI - Delirium classification by the Diagnostic and Statistical Manual - a moving target. PMID- 25921877 TI - Carers continuing to care after residential care placement. PMID- 25921879 TI - A systematic review of the validity and reliability of apathy scales in neurodegenerative conditions - CORRIGENDUM. PMID- 25921880 TI - Skill ontogeny among Tsimane forager-horticulturalists. AB - OBJECTIVES: We investigate whether age profiles of Tsimane forager horticulturalists' reported skill development are consistent with predictions derived from life history theory about the timing of productivity and reproduction. Previous studies of forager skill development have often focused on a few abilities (e.g. hunting), and neglected the broad range of skills and services typical of forager economies (e.g. childcare, craft production, music performance, story-telling). MATERIALS AND METHODS: By systematically examining age patterns in reported acquisition, proficiency, and expertise across a broad range of activities including food production, childcare, and other services, we provide the most complete skill development study of a traditional subsistence society to date. RESULTS: Our results show that: (1) most essential skills are acquired prior to first reproduction, then developed further so that their productive returns meet the increasing demands of dependent offspring during adulthood; (2) as postreproductive adults age beyond earlier years of peak performance, they report developing additional conceptual and procedural proficiency, and despite greater physical frailty than younger adults, are consensually regarded as the most expert (especially in music and storytelling), consistent with their roles as providers and educators. We find that adults have accurate understandings of their skillsets and skill levels -an important awareness for social exchange, comparison, learning, and pedagogy. DISCUSSION: These findings extend our understanding of the evolved human life history by illustrating how changes in embodied capital and the needs of dependent offspring predict the development of complementary skills and services in a forager horticulturalist economy. PMID- 25921881 TI - Use your vote on May 7. PMID- 25921882 TI - Not enough places for students yet number of nurses still short. PMID- 25921883 TI - Leadership to be judged on how BME staff are treated. PMID- 25921885 TI - Survey: 'dangerously' low levels of staff. PMID- 25921886 TI - NMC offers more time to prepare for revalidation. PMID- 25921887 TI - Clarity needed on who is responsible for cleaning up. PMID- 25921889 TI - UK Supreme Court ruling emphasises need to explain risks. PMID- 25921890 TI - Leadership is as important as money to the future of the NHS. PMID- 25921891 TI - Creating systems that work. PMID- 25921892 TI - A measure of good practice. PMID- 25921893 TI - Spread the news about the Code. PMID- 25921894 TI - Protecting maternity services. PMID- 25921897 TI - Vantage point--Ideally placed to pass on health advice. PMID- 25921907 TI - How nurses contribute to medicines reconciliation. AB - The process of obtaining an up-to-date and accurate patient medication list, medicines reconciliation (MedRec), is vital to ensuring patient safety. Despite its high status as a patient safety issue, and the efforts made to drive and implement robust MedRec processes, further efforts are required to identify and disseminate best practice (Greenwald et al 2010). This article outlines some of the principles involved in conducting effective MedRec and invites interested nurses to join a working group that aims to develop a best-practice toolkit. PMID- 25921908 TI - Staff perceptions of patient visibility systems in acute care settings. AB - Patient care visibility technology systems provide real-time information about patient admissions, discharges, transport, clinical activities and housekeeping services, in order to enhance patient care and flow. This article reports the results of a descriptive study that explored healthcare professionals' perceptions of and attitudes to a patient care visibility technology system in an acute care setting. The results indicate that staff find the system user friendly, and are positive about its staff- and patient-focused characteristics. Overall, positive staff perceptions and acceptance imply positive use of the system. This study forms the basis for further research on the effects on the patient-care outcomes of healthcare professionals' use of these systems. PMID- 25921909 TI - Factors that influence nurses' job satisfaction: a literature review. AB - Job satisfaction has become a critical issue for healthcare organisations in recent years, particularly in nursing, because of potential labour shortages, their effect on patient care, and the associated costs. Work satisfaction is a major factor in nurse retention and the delivery of high quality care, but rapid changes in healthcare services have placed more demands on nurses and this has increased the need for organisations to consider ways to sustain and improve nurses' job satisfaction. To achieve this, they need to understand the factors that affect job satisfaction and dissatisfaction. This article reports the results of a literature review that was aimed at examining and reaching a deeper understanding of the factors related to nurses' job satisfaction. PMID- 25921911 TI - A comparative study on autologous bone grafting combined with or without posterior interosseous nerve neurectomy for scaphoid nonunion treatment. AB - BACKGROUND AND AIM: Scaphoid nonunion (SN) is a challenging state after scaphoid fracture. The posterior interosseous nerve neurectomy (PINN) is often performed adjunctively with scaphoid reconstruction using autologous bone grafts. However, it remains unclear whether PINN has a prophylactic or therapeutic value, and thus it results superior to patients with SN without PINN. METHODS: A retrospective study was performed to evaluate patients with SN who were treated with autologous bone grafts with (cohort 1) or without PINN (cohort 2) between 1996 and 2010. Clinical outcomes, Mayo-wrist score, quality of life by Short Form (SF)-36 questionnaire, and analysis of risk factors were included. RESULTS: A total of 151 patients with SN met the inclusion criteria, and 48 were lost in follow-up. The mean follow-up was 71.3 +/- 39.0 months. Out of the remaining 103 patients, the union rate was without a statistical difference (P = 0.847) between cohorts 1 and 2. Functional results and the Mayo score were comparable in patients with bone union between both cohorts (P > 0.05). The results of wrist-pain measurements, including visual pain scales and wrist tenderness, were found to be similar (P > 0.05). Additionally, there was no significant difference in the quality of life. CONCLUSION: The comparative study on autologous bone grafts for scaphoid reconstruction revealed comparable results for both patients with and without PINN independent from the choice of bone graft. We anticipate a prophylactic value of PINN due to a potential injury or an irritation during dissection of the wrist capsule. Further research on PIN, its sensory characteristics, and its impact on wrist function is required. PMID- 25921910 TI - Breastfeeding, PAM50 tumor subtype, and breast cancer prognosis and survival. AB - BACKGROUND: Breastfeeding is associated with decreased breast cancer risk, yet associations with prognosis and survival by tumor subtype are largely unknown. METHODS: We conducted a cohort study of 1636 women from two prospective breast cancer cohorts. Intrinsic tumor subtype (luminal A, luminal B, human epidermal growth factor receptor 2 [HER2]-enriched, basal-like) was determined by the PAM50 gene expression assay. Breastfeeding history was obtained from participant questionnaires. Questionnaires and medical record reviews documented 383 recurrences and 290 breast cancer deaths during a median follow-up of nine years. Multinomial logistic regression was used to estimate odds ratios (ORs) and 95% confidence intervals (CIs) between breastfeeding and tumor subtype. Cox regression was used to estimate hazard ratios (HRs) for breast cancer recurrence or death. Statistical significance tests were two-sided. RESULTS: Breast cancer patients with basal-like tumors were less likely to have previously breastfed than those with luminal A tumors (OR = 0.56, 95% CI = 0.39 to 0.80). Among all patients, ever breastfeeding was associated with decreased risk of recurrence (HR = 0.70, 95% CI = 0.53 to 0.93), especially breastfeeding for six months or more (HR = 0.63, 95% CI = 0.46 to 0.87, P trend = .01). Similar associations were observed for breast cancer death. Among women with luminal A subtype, ever breastfeeding was associated with decreased risks of recurrence (HR = 0.52, 95% CI = 0.31 to 0.89) and breast cancer death (HR = 0.52, 95% CI = 0.29 to 0.93), yet no statistically significant associations were observed among the other subtypes. Effects appeared to be limited to tumors with lower expression of proliferation genes. CONCLUSIONS: History of breastfeeding might affect prognosis and survival by establishing a luminal tumor environment with lower proliferative activity. PMID- 25921912 TI - Surgical correction of constricted ear combined with Stahl's ear. AB - Constricted ear combined with Stahl's ear is a rare ear deformity, which is a kind of complex congenital auricular deformity. From 1 January 2007 to 1 January 2014, 19 patients with constricted ear combined with Stahl's ear (Spock ear) were enrolled in this study, most of which were unilaterally deformed. To correct the deformity, a double Z-shaped skin incision was made on the posterior side of the auricle, with the entire layer of cartilage cut parallel to the helix traversing the third crus to form a fan-shaped cartilage flap. The superior crura of the antihelix were shaped by the folding cartilage rim. The cartilage of the abnormal third crus was made part of the new superior crura of antihelix, and the third crus was eliminated. The postoperative aesthetic assessment of the reshaped auricle was graded by both doctors and patients (or their parents). Out of the 19 patients, the number of satisfying cases of the symmetry, helix stretch, elimination of the third crus, the cranioauricular angle, and the substructure of the reshaped ears was 14 (nine excellent and five good), 16 (six excellent and 10 good), 17 (eight excellent and nine good), 15 (five excellent and 10 good), and 13 (two excellent and 11 good), respectively. With a maximum of a 90-month follow up, no complication was observed. The results of the study suggested that this rare deformity could be corrected by appropriate surgical treatment, with a satisfied postoperative appearance. PMID- 25921914 TI - The weaker sex: Characterization of gender disparities in a nationwide lupus register (Reuma.pt/SLE). PMID- 25921915 TI - Modelling the rheology of anisotropic particles adsorbed on a two-dimensional fluid interface. AB - We present a general approach based on nonequilibrium thermodynamics for bridging the gap between a well-defined microscopic model and the macroscopic rheology of particle-stabilised interfaces. Our approach is illustrated by starting with a microscopic model of hard ellipsoids confined to a planar surface, which is intended to simply represent a particle-stabilised fluid-fluid interface. More complex microscopic models can be readily handled using the methods outlined in this paper. From the aforementioned microscopic starting point, we obtain the macroscopic, constitutive equations using a combination of systematic coarse graining, computer experiments and Hamiltonian dynamics. Exemplary numerical solutions of the constitutive equations are given for a variety of experimentally relevant flow situations to explore the rheological behaviour of our model. In particular, we calculate the shear and dilatational moduli of the interface over a wide range of surface coverages, ranging from the dilute isotropic regime, to the concentrated nematic regime. PMID- 25921916 TI - Lower 1,5-anhydroglucitol is associated with adverse clinical events after percutaneous coronary intervention. AB - Diabetes mellitus and impaired glucose tolerance are well-known risk factors for coronary artery disease (CAD) and adverse clinical events after percutaneous coronary intervention (PCI). Postprandial hyperglycemia is an important risk factor for CAD and serum 1,5-anhydroglucitol (1,5-AG) reflects postprandial hyperglycemia more robustly than hemoglobin (Hb)A1c. We aimed to clarify the relationship between serum 1,5-AG level and adverse clinical events after PCI. We enrolled 141 patients after PCI with follow-up coronary angiography. We evaluated associations between glycemic biomarkers including HbA1c and 1,5-AG and cardiovascular events during follow-up. Median serum 1,5-AG level was significantly lower in patients with any coronary revascularization and target lesion revascularization (TLR) [13.4 ug/ml (first quartile, third quartile 9.80, 18.3) vs. 18.7 (12.8, 24.2), p = 0.005; 13.4 ug/ml (10.2, 16.4) vs. 18.7 (12.9, 24.2), p = 0.001, respectively]. Multivariate logistic analysis showed lower 1,5 AG was independently associated with any coronary revascularization and TLR (odds ratio 0.93, 95 % confidence interval 0.86-0.99, p = 0.04; 0.90, 0.81-0.99, p = 0.044, respectively), whereas higher HbA1c was not. Postprandial hyperglycemia and lower 1,5-AG are important risk factors for adverse clinical events after PCI. PMID- 25921917 TI - A relative difference in systolic blood pressure between arms by synchronal measurement and conventional cardiovascular risk factors are associated with the severity of coronary atherosclerosis. AB - It is not known the relationships between a difference in systolic blood pressure (SBP) or diastolic BP (DBP) between arms by synchronal measurement and the presence of coronary artery disease (CAD), and between a difference in BP between arms and the severity of coronary atherosclerosis. We enrolled 425 consecutive patients (M/F = 286/139, 67 +/- 13 year) who were admitted to our University Hospital and in whom we could measure the absolute (|rt. BP - lt. BP|) and relative (rt. BP - lt. BP) differences in SBP and DBP using a nico PS-501((r)) (Parama-Tech). We divided all patients into those who did and did not have CAD. The relative differences in SBP between arms in patients with CAD were significantly lower than those in patients without CAD. However, the relative difference in SBP between arms was not a predictor of the presence of CAD. We also divided 267 patients who underwent coronary angiography into tertiles according to the Gensini score (low, middle, and high score groups). Interestingly, the middle + high score groups showed significantly lower relative differences in SBP between arms than the low score group. The mean Korotkoff sound graph in the middle + high Gensini score group was significantly higher than that in the low Gensini score group. Among conventional cardiovascular risk factors and nico parameters, the relative difference in SBP between arms in addition to the risk factors (age, gender, body mass index, hypertension, dyslipidemia, and diabetes mellitus) was associated with the score by a logistic regression analysis. In conclusion, the relative difference in SBP between arms as well as conventional risk factors may be associated with the severity of coronary arteriosclerosis. PMID- 25921918 TI - Experiencing life in a new way. PMID- 25921919 TI - Diabetes social media: a tool to engage patients. PMID- 25921920 TI - US initiative for prediabetes. AB - Health officials in the USA want physicians to help to reduce diabetes by asking at-risk patients to join diabetes prevention programmes. Susan Jaffe reports from Washington, DC. PMID- 25921921 TI - The 'prime-ome': towards a holistic approach to priming. AB - Plants can be primed to respond faster and more strongly to stress and multiple pathways, specific for the encountered challenge, are involved in priming. This adaptability of priming makes it difficult to pinpoint an exact mechanism: the same phenotypic observation might be the consequence of unrelated underlying events. Recently, details of the molecular aspects of establishing a primed state and its transfer to offspring have come to light. Advances in techniques for detection and quantification of elements spanning the fields of transcriptomics, proteomics, and metabolomics, together with adequate bioinformatics tools, will soon allow us to take a holistic approach to plant defence. This review highlights the state of the art of new strategies to study defence priming in plants and provides perspectives towards 'prime-omics'. PMID- 25921922 TI - Treatment with KLEPTOSE(r) CRYSMEB reduces mouse atherogenesis by impacting on lipid profile and Th1 lymphocyte response. AB - The ability of pharmacological agents to target both "classical" risk factors and inflammation may be key for successful outcomes in the prevention and treatment of atherogenesis. Among the promising drugs interfering with cholesterol metabolism, we investigated whether methyl beta-cyclodextrin (KLEPTOSE(r) CRYSMEB) could positively impact on atherogenesis, lipid profile and atherosclerotic plaque inflammation in ApoE-/- mice. Eleven-week old ApoE-/- mice were fed either a normal diet (N.D.) or a high-cholesterol diet (H.D.), resulting in different levels of hypercholesterolemia. KLEPTOSE(r) CRYSMEB (40mg/kg) or vehicle was intraperitoneally administrated 3 times per week in the last 16weeks before euthanasia in mice under N.D. and in the last 11weeks under H.D. Treatment with KLEPTOSE(r) CRYSMEB reduced triglyceride serum levels in both atherogenesis mouse models. In H.D. mice, treatment with KLEPTOSE(r) CRYSMEB increased HDL cholesterol levels and reduced free fatty acids and spleen weight. In both mouse models, treatment with KLEPTOSE(r) CRYSMEB reduced atherosclerotic plaque size in thoraco-abdominal aortas and intraplaque T lymphocyte content, but did not induce relevant improvements in other histological parameters of vulnerability (macrophage, neutrophil, MMP-9 and collagen content). Conversely and more markedly in H.D. mice, treatment with KLEPTOSE(r) CRYSMEB was associated with a reduction in genetic markers of Th1-mediated immune response. In vitro, KLEPTOSE(r) CRYSMEB dose-dependently abrogated Th1 proliferation and IFNgamma release. In conclusion, treatment with KLEPTOSE(r) CRYSMEB reduced atherosclerotic plaque size by improving triglyceride serum levels and Th1 mediated response. These results indicate this drug as a potential tool for blocking atheroprogression associated with different severity degrees of hypercholesterolemia. PMID- 25921923 TI - Mechanisms underlying uridine adenosine tetraphosphate-induced vascular contraction in mouse aorta: Role of thromboxane and purinergic receptors. AB - Uridine adenosine tetraphosphate (Up4A), a novel endothelium-derived vasoactive agent, is proposed to play a role in cardiovascular disorders and induces aortic contraction through activation of cyclooxygenases (COXs). We and others demonstrated that activation of A1 or A3 adenosine receptors (ARs) results in vascular contraction via thromboxane (TX) A2 production. However, the mechanisms of Up4A-induced vascular contraction in mouse aorta are not understood. We hypothesize that Up4A-induced aortic contraction is through COX-derived TXA2 production, which requires activation of A1 and/or A3AR. Concentration responses to Up4A were conducted in isolated aorta. The TXB2 production, a metabolite of TXA2, was also measured. Up4A (10(-9)-10(-5)M) produced a concentration-dependent contraction >70%, which was markedly attenuated by COX and COX1 but not by COX2 inhibition. Notably, Up4A-induced aortic contraction was blunted by both TX synthase inhibitor ozagrel and TXA2 receptor (TP) antagonist SQ29548. Surprisingly, A3AR deletion had no effect on Up4A-induced contraction. Moreover, A1AR deletion or antagonism as well as A1/A3AR deletion potentiated Up4A-induced aortic contraction, suggesting a vasodilator influence of A1AR. In contrast, non selective purinergic P2 receptor antagonist PPADS significantly blunted Up4A induced aortic contraction to a similar extent as selective P2X1R antagonist MRS2159, the latter of which was further reduced by addition of ozagrel. Endothelial denudation almost fully attenuated Up4A-induced contraction. Furthermore, Up4A (3MUM) increased TXB2 formation, which was inhibited by either MRS2159 or ozagrel. In conclusion, Up4A-induced aortic contraction depends on activation of TX synthase and TP, which partially requires the activation of P2X1R but not A1 or A3AR through an endothelium-dependent mechanism. PMID- 25921924 TI - Tubastatin A suppresses renal fibrosis via regulation of epigenetic histone modification and Smad3-dependent fibrotic genes. AB - Inflammation and fibrosis are implicated in the pathogenesis of hypertensive kidney damage. We previously demonstrated that a nonspecific histone deacetylase (HDAC) inhibitor attenuates cardiac fibrosis in deoxycorticosterone acetate-salt hypertensive rats, which induces HDAC6 protein and enzymatic activity. However, the HDAC inhibitor's effect and mechanism have not yet been demonstrated. We sought to determine whether an HDAC6-selective inhibitor could treat hypertension and kidney damage in angiotensin II-infused mice. Hypertension was induced by infusion of ANG in mice. Tubastatin A, an HDAC6 selective inhibitor, did not regulate blood pressure. Hypertensive stimuli enhanced the expression of HDAC6 in vivo and in vitro. We showed that the inhibition of HDAC6 prevents fibrosis and inflammation as determined by quantitative real-time PCR, western blot, and immunohistochemistry. Small interfering RNA (siRNA) against HDAC6 or Smad3 attenuated hypertensive stimuli-induced fibrosis and inflammation, whereas Smad2 siRNA failed to inhibit fibrosis. Interestingly, the combination of the HDAC6 inhibitor and Smad3 knockdown synergistically blocked transforming growth factor beta (TGF-beta) or ANG-induced fibrosis. We also demonstrated for the first time, to our knowledge, that acetylation of collagen type I can be regulated by HDAC6/p300 acetyltransferase. The chromatin immunoprecipitation assay revealed that the HDAC6 inhibitor suppressed TGF-beta-induced acetylated histone H4 or phospho-Smad2/3 to Smad3 binding elements in the fibrosis-associated gene promoters including collagen type I. These results suggest that HDAC6 may be a valuable therapeutic target for the treatment of hypertension-induced kidney fibrosis and inflammation. PMID- 25921925 TI - IGF-1 signaling in neonatal hypoxia-induced pulmonary hypertension: Role of epigenetic regulation. AB - Pulmonary hypertension is a fatal disease characterized by a progressive increase in pulmonary artery pressure accompanied by pulmonary vascular remodeling and increased vasomotor tone. Although some biological pathways have been identified in neonatal hypoxia-induced pulmonary hypertension (PH), little is known regarding the role of growth factors in the pathogenesis of PH in neonates. In this study, using a model of hypoxia-induced PH in neonatal mice, we demonstrate that the growth factor insulin-like growth factor-1 (IGF-1), a potent activator of the AKT signaling pathway, is involved in neonatal PH. After exposure to hypoxia, IGF-1 signaling is activated in pulmonary endothelial and smooth muscle cells in vitro, and the IGF-1 downstream signal pAKT(S473) is upregulated in lungs of neonatal mice. We found that IGF-1 regulates ET-1 expression in pulmonary endothelial cells and that IGF-1 expression is regulated by histone deacetylases (HDACs). In addition, there is a differential cytosine methylation site in the IGF-1 promoter region in response to neonatal hypoxia. Moreover, inhibition of HDACs with apicidin decreases neonatal hypoxia-induced global DNA methylation levels in lungs and specific cytosine methylation levels around the pulmonary IGF-1 promoter region. Finally, HDAC inhibition with apicidin reduces chronic hypoxia-induced activation of IGF-1/pAKT signaling in lungs and attenuates right ventricular hypertrophy and pulmonary vascular remodeling. Taken together, we conclude that IGF-1, which is epigenetically regulated, is involved in the pathogenesis of pulmonary hypertension in neonatal mice. This study implicates a novel HDAC/IGF-1 epigenetic pathway in the regulation of hypoxia induced PH and warrants further study of the role of IGF-1 in neonatal pulmonary hypertensive disease. PMID- 25921927 TI - Determination of metabolic profile of novel triethylamine containing thiophene S006-830 in rat, rabbit, dog and human liver microsomes. AB - CDRI S006-830 is a potent triethylamine containing thiophene antitubercular compound of the Central Drug Research Institute, India. The present study aimed to conduct comprehensive metabolic investigations of CDRI S006-830 to corroborate its preclinical investigations. Preliminary metabolic investigations were performed to assess the metabolic stability, enzyme kinetics, reaction phenotyping, and metabolite identification of CDRI S006-830 in rat, rabbit, dog, and human liver microsomes using liquid chromatography with mass spectrometry. The observed in vitro t1/2 and Clint values were 9.9 +/- 1.29, 4.5 +/- 0.52, 4.5 +/- 0.86, 17 +/- 5.21 min and 69.60 +/- 8.37, 152.0 +/- 17.26, 152.34 +/- 27.63, 33.62 +/- 21.04 MUL/min/mg in rat, rabbit, dog and human liver microsomes respectively. These observations suggested that CDRI S006-830 rapidly metabolized in the presence of NADPH in liver microsomes of rat, rabbit and dog while moderately metabolized in human liver microsomes. It was observed that CDRI S006 830 exhibited monophasic Michaelis-Menten kinetics. The metabolism of CDRI S006 830 was primarily mediated by CYP3A4 and was deduced by CYP reaction phenotyping with known potent inhibitors. CYP3A4 involvement was also confirmed by cDNA expressed recombinant human isozyme activity with different CYPs. Four major phase-I metabolites of S006-830, (M-1 to M-4) were detected in rat, rabbit, dog (except M4) and human liver microsomes. PMID- 25921926 TI - Increased beta2-adrenergic vasorelaxation at the early phase of endotoxemic shock in rats. AB - BACKGROUND AND PURPOSE: The early management of the cardiovascular dysfunction of septic shock is critical as it is associated with a poor outcome. Although the use of catecholamines is a common therapy in this syndrome, no data are available on the involvement of beta-adrenoceptor (beta-AR) subtypes and only few studies report an alteration of beta-adrenergic-induced vasodilation in septic shock. The purpose of the study was to evaluate vascular beta1, beta2 and beta3-AR expression and function in an endotoxemic rat model. EXPERIMENTAL APPROACH: Endotoxemia was induced in rats by intravenous injection of lipopolysaccharide (LPS). beta1, beta2 and beta3-AR mRNA expression was evaluated by RT-PCR in aorta and vascular beta1, beta2 and beta3-AR responses were determined on conducting (aorta) and/or resistance (mesenteric and renal) arteries by constructing relaxation curves in response to different beta-AR agonists. RESULTS: The maximal effect of isoproterenol decreased by 31 to 61% in the three vascular beds of LPS treated rats compared to controls. In aortas from LPS-treated rats, beta1 and beta3-AR mRNA expression was decreased and associated to a reduced beta1 and beta3-induced vasodilation. Conversely, albeit beta2-AR mRNA was unchanged, the maximal beta2-AR-induced vasodilation increased by 49% in aortas from LPS-treated rats compared to controls. This increase was not affected by endothelium removal but was abolished in the presence of a beta2-AR antagonist or an adenylate cyclase inhibitor. CONCLUSIONS: In endotoxemia, beta2-AR vasodilation was increased by a potential recruitment of beta2-AR located on smooth muscle cells. This study suggests that vascular beta2-AR should be a putative new therapeutic target in septic shock. PMID- 25921928 TI - Sociality and the telencephalic distribution of corticotrophin-releasing factor, urocortin 3, and binding sites for CRF type 1 and type 2 receptors: A comparative study of eusocial naked mole-rats and solitary Cape mole-rats. AB - Various aspects of social behavior are influenced by the highly conserved corticotrophin-releasing factor (CRF) family of peptides and receptors in the mammalian telencephalon. This study has mapped and compared the telencephalic distribution of the CRF receptors, CRF1 and CRF2 , and two of their ligands, CRF and urocortin 3, respectively, in African mole-rat species with diametrically opposed social behavior. Naked mole-rats live in large eusocial colonies that are characterized by exceptional levels of social cohesion, tolerance, and cooperation in burrowing, foraging, defense, and alloparental care for the offspring of the single reproductive female. Cape mole-rats are solitary; they tolerate conspecifics only fleetingly during the breeding season. The telencephalic sites at which the level of CRF1 binding in naked mole-rats exceeds that in Cape mole-rats include the basolateral amygdaloid nucleus, hippocampal CA3 subfield, and dentate gyrus; in contrast, the level is greater in Cape mole rats in the shell of the nucleus accumbens and medial habenular nucleus. For CRF2 binding, the sites with a greater level in naked mole-rats include the basolateral amygdaloid nucleus and dentate gyrus, but the septohippocampal nucleus, lateral septal nuclei, amygdalostriatal transition area, bed nucleus of the stria terminalis, and medial habenular nucleus display a greater level in Cape mole-rats. The results are discussed with reference to neuroanatomical and behavioral studies of various species, including monogamous and promiscuous voles. By analogy with findings in those species, we speculate that the abundance of CRF1 binding in the nucleus accumbens of Cape mole-rats reflects their lack of affiliative behavior. PMID- 25921930 TI - The role of structural flexibility and stability in the interaction of serine proteases with their inhibitors. AB - Serine proteases and their natural inhibitors have long been served as excellent models for studying (primary, secondary and tertiary) structure - activity relationships of biologically interacting proteins. As protein flexibility has been accepted as a "fourth dimension" of the protein structure, its contribution to the binding process has gained much interest. In this article we review extreme cases of serine protease interactions with canonical serine protease inhibitors that provide unique insights into the dynamics of protein- protein interactions. The major conclusions of our review article are: a) taxon-specific inhibitory effects of two highly homologous protease inhibitors from Schistocerca gregaria (SGCI and SGTI), as investigated by H/D exchange experiments and NMR spectroscopy, are due to their differential flexibilities, b) stabilities of some protease and inhibitor complexes, the wide-spread and increased flexibility of some segments in the protein-protein complexes, as studied by X-ray crystallography and NMR-spectroscopy, appear to be proportional to the physical stability of the complex. PMID- 25921929 TI - Angiotensin-dependent autonomic dysregulation precedes dilated cardiomyopathy in a mouse model of muscular dystrophy. AB - NEW FINDINGS: What is the central question of this study? Is autonomic dysregulation in a mouse model of muscular dystrophy dependent on left ventricular systolic dysfunction and/or activation of the renin-angiotensin system (RAS) and does it predict development of dilated cardiomyopathy (DCM)? What is the main finding and its importance? The results demonstrate that autonomic dysregulation precedes and predicts left ventricular dysfunction and DCM in sarcoglycan-delta-deficient (Sgcd-/-) mice. The autonomic dysregulation is prevented by treatment of young Sgcd-/- mice with the angiotensin II type 1 receptor blocker losartan. Measurements of RAS activation and autonomic dysregulation may predict risk of DCM, and therapies targeting the RAS and autonomic dysregulation at a young age may slow disease progression in patients. Sarcoglycan mutations cause muscular dystrophy. Patients with muscular dystrophy develop autonomic dysregulation and dilated cardiomyopathy (DCM), but the temporal relationship and mechanism of autonomic dysregulation are not well understood. We hypothesized that activation of the renin-angiotensin system (RAS) causes autonomic dysregulation prior to development of DCM in sarcoglycan-delta deficient (Sgcd-/-) mice and that the severity of autonomic dysfunction at a young age predicts the severity of DCM at older ages. At 10-12 weeks of age, when left ventricular function assessed by echocardiography remained normal, Sgcd-/- mice exhibited decreases in arterial pressure, locomotor activity, baroreflex sensitivity and cardiovagal tone and increased sympathetic tone compared with age matched C57BL/6 control mice (P < 0.05). Systemic and skeletal muscle RAS were activated, and angiotensin II type 1 receptor (AT1 R) expression, superoxide and fibrosis were increased in dystrophic skeletal muscle (P < 0.05). Treatment with the AT1 R blocker losartan for 7-9 weeks beginning at 3 weeks of age prevented or strongly attenuated the abnormalities in Sgcd-/- mice (P < 0.05). Repeated assessment of phenotypes between 10 and 75 weeks of age demonstrated worsening of autonomic function, progressive cardiac dysfunction and DCM and increased mortality in Sgcd-/- mice. High sympathetic tone predicted subsequent left ventricular dysfunction. We conclude that activation of the RAS causes severe autonomic dysregulation in young Sgcd-/- mice, which portends a worse long-term prognosis. Therapeutic targeting of the RAS at a young age may improve autonomic function and slow disease progression in muscular dystrophy. PMID- 25921931 TI - Illness perception of dropout patients followed up at bipolar outpatient clinic, Turkey. AB - Dropout is a common problem in the treatment of psychiatric illnesses including bipolar disorders (BD). The aim of the present study is to investigate illness perceptions of dropout patients with BD. A cross sectional study was done on the participants who attended the Mood Disorder Outpatient Clinic at least 3 times from January 2003 through June 2008, and then failed to attend clinic till to the last one year, 2009, determined as dropout. Thirty-nine dropout patients and 39 attendent patients with BD were recruited for this study. A sociodemographic form and brief illness perception questionnaire were used to capture data. The main reasons of patients with BD for dropout were difficulties of transport (31%), to visit another doctor (26%), giving up drugs (13%) and low education level (59%) is significant for dropout patients. The dropout patients reported that their illness did not critically influence their lives, their treatment had failed to control their illnesses, they had no symptoms, and that their illness did not emotionally affect them. In conclusion, the nonattendance of patients with serious mental illness can result in non-compliance of therapeutic drug regimens, and a recurrence of the appearance symptoms. The perception of illness in dropout patients with BD may be important for understanding and preventing nonattendance. PMID- 25921932 TI - Novel bioresorbable scaffolds technologies: current status and future directions. AB - Over the past century, coronary artery disease (CAD) has remained a leading cause of death worldwide, managed with enormous progress by medicine, from the development of advanced drugs to highly sophisticated revascularization modalities. Among them, as confirmed by recent studies, bioresorbable scaffolds (BRSs) have shown to have the potential to overtake conventional stents. This review presents their material composition and properties, those currently used in clinical evaluation, and their current limitations and potential improvements. PMID- 25921933 TI - Innovative DES technologies from Meril. AB - Technological advances and rise in global urbanity have paradoxically led to an increase in the incidence of metabolic syndrome and thankfully also in diagnosis and treatment of coronary artery disease. "Necessity is the mother of invention" remarked Plato and this statement could not have had a better place than in the field of angioplasty and stenting. Interventional cardiology still continues to remain a busy place for smart, iterative changes leading to better treatment options. This article sketches contemporary trends in coronary stent engineering borne out of unmet clinical needs ranging from novel ultra-thin strut designs marrying biodegradable polymeric drug eluting platforms to anatomically tapered stents and finally the intuitive bioresorbable vascular scaffolds which promise freedom from full metal jacket. PMID- 25921934 TI - Swallowing and pharyngo-esophageal manometry in obstructive sleep apnea. AB - INTRODUCTION: Upper airway nerve and muscle damage associated with obstructive sleep apnea may impair the strength and dynamics of pharyngeal and esophageal contractions during swallowing. OBJECTIVE: To evaluate the presence of alterations in pharyngoesophageal manometry in patients with obstructive sleep apnea with and without oropharyngeal dysphagia. METHODS: This study prospectively evaluated 22 patients with obstructive sleep apnea without spontaneous complaints of dysphagia, using a questionnaire, fiberoptic endoscopic evaluation of swallowing, and pharyngoesophageal manometry, including measurement of the upper and lower esophageal sphincter pressures and mean pharyngeal pressures at three levels during swallowing. RESULTS: The dysphagia group consisted of 17 patients (77.3%) in whom swallowing abnormalities were detected on fiberoptic endoscopic evaluation of swallowing (n=15; 68.2%) and/or in the questionnaire (n=7; 31.8%). The five remaining cases comprised a control group without oropharyngeal dysphagia. In all cases of abnormalities on fiberoptic endoscopic evaluation of swallowing, there was premature bolus leakage into the pharynx. There was no statistically significant difference between the groups regarding any of the pharyngoesophageal manometry measurements, age, or severity of obstructive sleep apnea. CONCLUSION: Pharyngoesophageal manometry detected no statistically significant difference between the groups with and without oropharyngeal dysphagia. PMID- 25921935 TI - Incidence and risk factors of early deep venous thrombosis after varicose vein surgery with routine use of a tourniquet. AB - INTRODUCTION: The incidence of early deep venous thrombosis (DVT) following varicose vein surgery (traditional open stripping) with routine use of a tourniquet remains unknown. MATERIALS AND METHODS: A retrospective analysis of all patients who underwent varicose vein surgery with a tourniquet in the authors' unit between 1 January 2012 and 30 November 2013 was undertaken. Cases of postoperative DVT were identified from the unit database, and re-assessments conducted 1, 3 and 6 months after the initial diagnosis were recorded from the outpatient department. RESULTS: Out of 1461 patients, 113 (7.7%) developed postoperative DVT. Nineteen (1.3%) patients had proximal DVT, and 94 (6.4%) patients had isolated distal DVT. The risk factors for postoperative DVT included old age (>=65 years), female sex and gastrocnemius vein dilation (GVD). GVD was found to be a significant independent risk factor for the occurrence of DVT, with an odds ratio of 2.437 (95% confidence interval 1.644-3.611). Five patients with distal DVT (5.7%) and eight patients with proximal DVT (44.4%) still exhibited a thrombus at 6-month follow-up, but with decreased size and at various stages of resolution. CONCLUSIONS: This study found a higher incidence of postoperative DVT (7.7%) with routine use of a tourniquet during varicose vein surgery than has been reported previously. Among the factors examined, GVD had the highest predictive power for postoperative DVT. Both distal and proximal DVT were associated with acceptable outcomes. PMID- 25921937 TI - Surgicel for microvascular decompression of the trigeminal nerve. PMID- 25921936 TI - Declining Long-term Risk of Adverse Events after First-time Community-presenting Venous Thromboembolism: The Population-based Worcester VTE Study (1999 to 2009). AB - INTRODUCTION: Contemporary trends in health-care delivery are shifting the management of venous thromboembolism (VTE) events (deep vein thrombosis [DVT] and/or pulmonary embolism [PE]) from the hospital to the community, which may have implications for its prevention, treatment, and outcomes. MATERIALS AND METHODS: Population-based surveillance study monitoring trends in clinical epidemiology among residents of the Worcester, Massachusetts, metropolitan statistical area (WMSA) diagnosed with an acute VTE in all 12 WMSA hospitals. Patients were followed for up to 3 years after their index event. Total of 2334 WMSA residents diagnosed with first-time community-presenting VTE (occurring in an ambulatory setting or diagnosed within 24 hours of hospitalization) from 1999 through 2009. RESULTS: While PE patients were consistently admitted to the hospital for treatment over time, the proportion diagnosed with DVT-alone admitted to the hospital decreased from 67% in 1999 to 37% in 2009 (p value for trend <0.001). Among hospitalized patients, the mean length of stay decreased from 5.6 to 4.8 days (p value for trend <0.001). Between 1999 and 2009, treatment of VTE shifted from warfarin and unfractionated heparin towards use of low molecular-weight heparins and newer anticoagulants; also, 3-year cumulative event rates decreased for all-cause mortality (41-26%), major bleeding (12-6%), and recurrent VTE (17-9%). CONCLUSIONS: A decade of change in VTE management was accompanied by improved long-term outcomes. However, rates of adverse events remained fairly high in our population-based surveillance study, implying that new risk-assessment tools to identify individuals at increased risk for developing major adverse outcomes over the long term are needed. PMID- 25921938 TI - Workshop Report: AAPS Workshop on Method Development, Validation, and Troubleshooting of Ligand-Binding Assays in the Regulated Environment. AB - A novel format was introduced at the recent AAPS NBC Workshop on Method Development, Validation and Troubleshooting in San Diego on 18th May 2014. The workshop format was initiated by Binodh De Silva; Marie Rock and Sherri Dudal joined the initiative to develop and chair the workshop. Questions were solicited by a variety of avenues, including a Linked-In Discussion Group. Once collated and clarified, the topics covered assay development, validation, and analysis of PK, Immunogenicity, and Biomarkers with an additional topic on alternative bioanalytical technologies. A panel of experts (workshop report co-authors) was assigned to each topic to bring forward thought-provoking aspects of each topic. The format of the workshop was developed to target the needs of bioanalytical scientists with intermediate to advanced experience in the field ranging to enable robust discussion and to delve deeper into the current bioanalytical hot topics. While the new format allowed for an interactive session with the topical discussion driven by the audience members, it did not foster equal discussion time for all of the proposed topics, especially Biomarkers and alternative LBA technologies. PMID- 25921940 TI - ADAMTS-7 promotes vascular smooth muscle cells proliferation in vitro and in vivo. AB - Vascular smooth muscle cell (VSMC) proliferation and migration are pivotal for the pathogenesis of atherosclerosis and post-angioplasty restenosis. We have recently reported that a disintegrin and metalloproteinase with thrombospondin motifs-7 (ADAMTS-7), a novel metalloproteinase, contributes directly to neointima formation by mediating VSMC migration. However, whether ADAMTS-7 affects VSMC proliferation remains unclear. In this study, we found that luminal adenoviral delivery of ADAMTS-7 aggravated intimal hyperplasia 7 d after injury, paralleled by an increased percentage of PCNA-positive cells in both intima and media. In contrast, perivascular administration of ADAMTS-7 siRNA, but not scrambled siRNA to injured arteries attenuated intimal thickening at day 7, paralleled with reduced intimal VSMC replication, without alteration of VSMC proliferation in the media. In accordance, [(3)H]-thymidine incorporation assay in primary cultured rat VSMCs revealed an enhanced replication rate (by 61%) upon ADAMTS-7 overexpression and retarded proliferation (by 23%) upon ADAMTS-7 siRNA administration. Our data demonstrates that ADAMTS-7 promotes VSMC proliferation both in vitro and in vivo. ADAMTS-7 may therefore serve as a novel therapeutic target for atherosclerosis and post-angioplasty restenosis. PMID- 25921939 TI - Translational Nano-Medicines: Targeted Therapeutic Delivery for Cancer and Inflammatory Diseases. AB - With the advent of novel and personalized therapeutic approaches for cancer and inflammatory diseases, there is a growing demand for designing delivery systems that circumvent some of the limitation with the current therapeutic strategies. Nanoparticle-based delivery of drugs has provided means of overcoming some of these limitations by ensuring the drug payload is directed to the disease site and insuring reduced off-target activity. This review highlights the challenges posed by the solid tumor microenvironment and the systemic limitations for effective chemotherapy. It then assesses the basis of nanoparticle-based targeting to the tumor tissues, which helps to overcome some of the microenvironmental and systemic limitations to therapy. We have extensively focused on some of the tumor multidrug resistance mechanisms (e.g., hypoxia and aerobic glycolysis) that contribute to the development of multidrug resistance and how targeted nano-approaches can be adopted to overcome drug resistance. Finally, we assess the combinatorial approach and how this platform has been used to develop multifunctional delivery systems for cancer therapy. The review article also focuses on inflammatory diseases, the biological therapies available for its treatment, and the concept of macrophage repolarization for the treatment of inflammatory diseases. PMID- 25921941 TI - An update: the role of Nephrin inside and outside the kidney. AB - Nephrin is a key molecule in podocytes to maintain normal slit diaphragm structure. Nephin interacts with many other podocyte and slit diaphragm protein and also mediates important cell signaling pathways in podocytes. Loss of nephrin during the development leads to the congenital nephrotic syndrome in children. Reduction of nephrin expression is often observed in adult kidney diseases including diabetic nephropathy and HIV-associated nephropathy. The critical role of nephrin has been confirmed by different animal models with nephrin knockout and knockdown. Recent studies demonstrate that knockdown of nephrin expression in adult mice aggravates the progression of unilateral nephrectomy and Adriamycin induced kidney disease. In addition to its critical role in maintaining normal glomerular filtration unit in the kidney, nephrin is also expressed in other organs. However, the exact role of nephrin in kidney and extra-renal organs has not been well characterized. Future studies are required to determine whether nephrin could be developed as a drug target to treat patients with kidney disease. PMID- 25921942 TI - Antifungal activity and phytochemical investigation of the asexual endophyte of Epichloe sp. from Festuca sinensis. PMID- 25921943 TI - Patterns and determinants of wood physical and mechanical properties across major tree species in China. AB - The physical and mechanical properties of wood affect the growth and development of trees, and also act as the main criteria when determining wood usage. Our understanding on patterns and controls of wood physical and mechanical properties could provide benefits for forestry management and bases for wood application and forest tree breeding. However, current studies on wood properties mainly focus on wood density and ignore other wood physical properties. In this study, we established a comprehensive database of wood physical properties across major tree species in China. Based on this database, we explored spatial patterns and driving factors of wood properties across major tree species in China. Our results showed that (i) compared with wood density, air-dried density, tangential shrinkage coefficient and resilience provide more accuracy and higher explanation power when used as the evaluation index of wood physical properties. (ii) Among life form, climatic and edaphic variables, life form is the dominant factor shaping spatial patterns of wood physical properties, climatic factors the next, and edaphic factors have the least effects, suggesting that the effects of climatic factors on spatial variations of wood properties are indirectly induced by their effects on species distribution. PMID- 25921944 TI - Three-dimensional bio-printing. AB - Three-dimensional (3D) printing technology has been widely used in various manufacturing operations including automotive, defence and space industries. 3D printing has the advantages of personalization, flexibility and high resolution, and is therefore becoming increasingly visible in the high-tech fields. Three dimensional bio-printing technology also holds promise for future use in medical applications. At present 3D bio-printing is mainly used for simulating and reconstructing some hard tissues or for preparing drug-delivery systems in the medical area. The fabrication of 3D structures with living cells and bioactive moieties spatially distributed throughout will be realisable. Fabrication of complex tissues and organs is still at the exploratory stage. This review summarize the development of 3D bio-printing and its potential in medical applications, as well as discussing the current challenges faced by 3D bio printing. PMID- 25921945 TI - Recent advance in the structural analysis of HIV-1 envelope protein. AB - Human immunodeficiency virus type I (HIV-1), a causative agent of AIDS, is affecting today more than 35 millions of people worldwide. The advance of anti HIV chemotherapy has made AIDS a chronic non-fatal disease in resourceful countries. Long-awaited anti-HIV-1 vaccine is still not with us yet; however, great progress in structural analyses of the envelope protein of HIV-1 in recent years starts to shed light on rational intervention targeted at the envelope protein, as will be reviewed in this article. PMID- 25921946 TI - A feeding model of oyster larvae (Crassostrea angulata). AB - There is a need to develop more efficient rearing systems for the aquaculture of economically important bivalves, such as oysters. Here, we constructed a model that describes the feeding behavior of larval Crassostrea angulata oysters and tested it in an experimental setting. Larval ingestion rate is closely correlated with larval length. Based on our model, we showed that larval swimming speed, velum diameter and the filtration coefficient, which also determine the ingestion rate, are also correlated with larval length. Our model integrates morphological, locomotory and feeding behavior parameters to establish a relation between them and so provides a mathematical way to describe variation in the feeding behavior of bivalve larvae. The results of this study could facilitate the precise management of the aquaculture of bivalve larvae, in particular the optimum prey density and feeding rate of these important organisms. PMID- 25921947 TI - Effects of spatial memory on morphine CPP and locomotor sensitization in mice. AB - Drug addiction is associated with memory processes. We simultaneously measured conditioned place preference (CPP) and locomotor sensitization to investigate the influence of spatial memory retrieval on morphine reward and psychomotor excitement. According to their performance in space probe trial involving the Morris water maze mice were assigned to high (including morphine and saline subgroups, H-Mor and H-Sal) and low spatial memory retrieval ability groups (L Mor and L-Sal). Morphine (10mg/kg) produced significant CPP in L-Mor and H-Mor mice, although, L-Mor mice showed a significantly greater response to morphine. During the development period of behavior sensitization, no significant group-by day interaction was found. However, locomotor activities of L-Mor mice were also significantly higher than H-Mor mice during the expression period of behavior sensitization. Our findings suggested that the spatial memory retrieval ability of mice influences morphine CPP, as well as behavioral sensitization. Thus, spatial memory might be implicated in drug addiction. PMID- 25921948 TI - The effect of histidine on mental fatigue and cognitive performance in subjects with high fatigue and sleep disruption scores. AB - Our previous study reported that a dried bonito broth known in Japan as 'dashi' improved or ameliorated mood states, including fatigue, during the daily lives of human subjects. Histidine is an amino acid that is present in dried bonito broth, and we sought to evaluate whether histidine would affect feelings of fatigue in humans. We investigated the effects of histidine intake on the feeling of fatigue, mood states and mental task performance by performing a placebo controlled, double-blind crossover trial. Twenty subjects with high fatigue and sleep disruption scores were asked to ingest histidine or a placebo every day for two weeks. The subjects' mood states were evaluated using the Profile of Mood States (POMS) scale and a visual analog scale (VAS) for eight feelings (fatigue, depression, carelessness, drowsiness, clear thinking, motivation, attentiveness and concentration). We also measured subjects' cognitive performance using the CogHealth test battery. The fatigue T-scores on the POMS test decreased significantly following histidine ingestion compared to placebo ingestion (p<0.05). After two weeks of histidine ingestion, the reaction time for the working memory task in the CogHealth test battery was significantly shorten compared to placebo ingestion. The VAS scores for clear thinking and for attentiveness were increased significantly following histidine ingestion compared to placebo ingestion (p<0.05). These results suggest that daily ingestion of histidine may ameliorate feelings of fatigue, increase performance during working memory tasks, and improve the clear thinking and attentiveness. PMID- 25921949 TI - Neurobehavioural effects of exposure to fluoride in the earliest stages of rat development. AB - It is known that exposure to high concentrations of Fluoride (F) produces deleterious health effects in human population. However, in the last years it has been concluded that low concentrations of F may have adverse health effects as well. Transplacental passage of F and its incorporation into foetal tissues has been demonstrated. Therefore, the purpose of the present work was to study the effects of the exposure to low levels of F during pregnancy and lactation on the central nervous system functionality. Wistar rats were exposed to low F concentrations (5 and 10 mg/l) during pregnancy and lactation. Sensorimotor reflexes in the each pup were analysed and the postnatal day on which both eyes and auditory canals were opened was recorded. Locomotor activity and anxiety were subsequently analysed in 45- and 90-day-old offspring by an open field test and plus maze test, respectively. A significant delay in the development of eye opening was observed in all offspring whose mothers had been exposed to the two F concentrations tested. Exposure to 5 and 10 mg/l F was also found to significantly decrease locomotor activity only in 90-day-old male and female offspring. A low index of anxiety in the young females and in all adult offspring exposed to the two F concentrations tested was also detected. Taken together, findings from the present study show that exposure to low F concentrations during pregnancy and lactation produces dysfunction in the central nervous system mechanisms which regulate motor and sensitive development, locomotor activity and anxiety PMID- 25921950 TI - Chemical composition and medicinal significance of Fagonia cretica: a review. AB - Members of the family Zygophyllaceae are distributed in arid areas of the world and are traditionally used against various health insults ranging from skin lesions to lethal cancer. Fagonia cretica Linn. is a plant having novel compounds responsive in diseases that are still considered as incurable or are curable with serious side effects. Researchers, particularly of the Asian region elaborately studied the chemical composition and pharmacological activities of this plant. But further studies are still required to evaluate this plant in clinical trials in order to save humanity from synthetic chemical drugs yet disputed as 'friends or foe'. PMID- 25921951 TI - Interaction between phosphorus removal and hybrid granular sludge formation under low hydraulic selection pressure at alternating anaerobic/aerobic conditions. AB - The hybrid granular sludge (HGS) formation and its performances on phosphorus removal were investigated in a sequencing batch airlift reactor. Under conditions of low superficial air velocity (SAV = 0.68 cm s(-1)) and relatively long settling time (15-30 min), aerobic granules appeared and coexisted with bio-flocs after 120 days operation. At the stable phase, 54% of total suspended solid (m/m) was granular sludge with the two typical sizes (D(mean) = 1.77 +/- 0.33 and 0.89 +/- 0.11 mm) in the reactor, where the settling velocity was 98.7 +/- 12.4 and 37.8 +/- 0.9 m h(-1) for the big and small granules. With progressive extension of anaerobic time from 15 to 60 min before aerobic condition per cycle during the whole experiment, the HGS system can be maintained at a high total phosphorus removal efficiency (ca. 99%) since Day-270. The phosphorus content (wt %) in biomass was respectively 9.54 +/- 0.29, 7.60 +/- 0.48 and 6.15 +/- 0.59 for the big granules, small granules and flocs. PMID- 25921952 TI - Asymmetric dimethylarginine (ADMA) in human blood: effects of extended haemodialysis in the critically ill patient with acute kidney injury, protein binding to human serum albumin and proteolysis by thermolysin. AB - Free, non-protein bound asymmetrically guanidine-dimethylated arginine (ADMA) is an endogenous inhibitor of nitric oxide (NO) synthesis. Human erythrocytic membrane comprises considerable amounts of large (>50 kDa) ADMA-containing proteins. Location in the erythrocyte membrane and identity and physiological functions of ADMA-containing proteins are unrevealed. In healthy subjects, the concentration of free ADMA in heparinised plasma is almost identical to that of serum. We hypothesised that the robustness of free ADMA concentration in human blood is due to a remarkable resistance of erythrocytic ADMA-containing proteins against proteases. In vivo, we investigated the course of the concentration of ADMA in serum and EDTA plasma of a critically ill patient with acute kidney injury during extended haemodialysis. In vitro, we studied the effects of thermolysin, a useful experimental proteolytic enzyme of erythrocyte membrane proteins, on erythrocytic ADMA. The protein binding (PB) of ADMA to human serum albumin (HSA) was also determined. In these studies, ADMA was measured by a previously reported, fully validated GC-MS/MS method. We measured almost identical ADMA concentrations in plasma and serum samples of the patient. During dialysis, the circulating ADMA concentration decreased slowly and moderately indicating removal of this substance, which was however much less than expected from its low molecular weight (202 Da) and high water solubility. After dialysis, circulating ADMA concentration increased again, a phenomenon called rebound, and ADMA reached higher levels compared to the baseline. The PB value of ADMA to HSA was about 30 %. This surprisingly high PB value of ADMA to HSA may be an explanation for the rather poor dialysance of ADMA. Washed human erythrocytes suspended in phosphate-buffered physiological saline were found not to release appreciable amounts of free and ADMA-containing proteins. The lack of effect of coagulation or anticoagulation on the concentration of circulating free ADMA in humans is likely to be due to a remarkable resistance of ADMA-containing proteins in the erythrocyte membrane against proteases in vivo in humans. Our study suggests that free ADMA is released in the circulating blood at relatively high rates. The considerable PB of ADMA to HSA is likely to add to the apparently poor dialysability of ADMA. Other contributing factors could be redistribution of free ADMA between plasma and erythrocytes in favour of plasma ADMA and parallel formation of free ADMA from erythrocytic ADMA-containing proteins during haemodialysis. PMID- 25921953 TI - Midwifery students' experiences of an innovative clinical placement model embedded within midwifery continuity of care in Australia. AB - BACKGROUND: midwifery continuity of care experiences can provide high quality clinical learning for students but can be challenging to implement. The Rural and Private Midwifery Education Project (RPMEP) is a strategic government funded initiative to (1) grow the midwifery workforce within private midwifery practice and rural midwifery, by (2) better preparing new graduates to work in private midwifery and rural continuity of care models. AIM: this study evaluated midwifery students' experience of an innovative continuity of care clinical placement model in partnership with private midwifery practice and rural midwifery group practices. METHOD: a descriptive cohort design was used. All students in the RPMEP were invited to complete an online survey about their experiences of clinical placement within midwifery continuity models of care. Responses were analysed using descriptive statistics. Correlations between total scale scores were examined. Open-ended responses were analysed using content analysis. Internal reliability of the scales was assessed using Cronbach's alpha. FINDINGS: sixteen out of 17 completed surveys were received (94% response rate). Scales included in the survey demonstrated good internal reliability. The majority of students felt inspired by caseload approaches to care, expressed overall satisfaction with the mentoring received and reported a positive learning environment at their placement site. Some students reported stress related to course expectations and demands in the clinical environment (e.g. skill acquisition and hours required for continuity of care). There were significant correlations between scales on perceptions of caseload care and learning culture (r=.87 p<.001) and assessment (r=.87 p<.001). Scores on the clinical learning environment scale were significantly correlated with perceptions of the caseload model (rho=.86 p<.001), learning culture (rho=.94 p<.001) and assessment (rho=.65 p<.01) scales. CONCLUSIONS: embedding students within midwifery continuity of care models was perceived to be highly beneficial to learning, developed partnerships with women, and provided appropriate clinical skills development required for registration, while promoting students' confidence and competence. The flexible academic programme enabled students to access learning at any time and prioritise continuity of care experiences. Strategies are needed to better support students achieve a satisfactory work-life balance. PMID- 25921954 TI - Back to normal: A retrospective, cross-sectional study of the multi-factorial determinants of normal birth in Queensland, Australia. AB - BACKGROUND: currently, care providers and policy-makers internationally are working to promote normal birth. In Australia, such initiatives are being implemented without any evidence of the prevalence or determinants of normal birth as a multidimensional construct. This study aimed to better understand the determinants of normal birth (defined as without induction of labour, epidural/spinal/general anaesthesia, forceps/vacuum, caesarean birth, or episiotomy) using secondary analyses of data from a population survey of women in Queensland, Australia. METHODS: women who birthed in Queensland during a two-week period in 2009 were mailed a survey approximately three months after birth. Women (n=772) provided retrospective data on their pregnancy, labour and birth preferences and experiences, socio-demographic characteristics, and reproductive history. A series of logistic regressions were conducted to determine factors associated with having labour, having a vaginal birth, and having a normal birth. FINDINGS: overall, 81.9% of women had labour, 66.4% had a vaginal birth, and 29.6% had a normal birth. After adjusting for other significant factors, women had significantly higher odds of having labour if they birthed in a public hospital and had a pre-existing preference for a vaginal birth. Of women who had labour, 80.8% had a vaginal birth. Women who had labour had significantly higher odds of having a vaginal birth if they attended antenatal classes, did not have continuous fetal monitoring, felt able to 'take their time' in labour, and had a pre-existing preference for a vaginal birth. Of women who had a vaginal birth, 44.7% had a normal birth. Women who had a vaginal birth had significantly higher odds of having a normal birth if they birthed in a public hospital, birthed outside regular business hours, had mobility in labour, did not have continuous fetal monitoring, and were non-supine during birth. CONCLUSIONS: these findings provide a strong foundation on which to base resources aimed at increasing informed decision-making for maternity care consumers, providers, and policy makers alike. Research to evaluate the impact of modifying key clinical practices (e.g., supporting women's mobility during labour, facilitating non-supine positioning during birth) on the likelihood of a normal birth is an important next step. PMID- 25921955 TI - Complement system and immunological mediators: Their involvements in the induced inflammatory process by Androctonus australis hector venom and its toxic components. AB - Androctonus australis hector scorpion venom is well known by its high toxicity, it induces massive release of neurotransmitters that lead to pathophysiological disorders in cardiovascular, neuro-hormonal and immune systems. Previous studies have shown the relationship between the severity of scorpion envenoming and immune system activation. This study was assessed to investigate the involvement of complement system and inflammatory mediators after sublethal injection of Aah venom, its toxic fraction (FtoxG50) and its main toxins (AahI and AahII) into NMRI mice. The Activation complement system by the venom is also compared to that induced of lipopolysaccharides (LPS). Obtained results showed that seric complement system (CS) is activated by the venom and by its toxic components; this activation is more pronounced into liver tissue when toxic components (FtoxG50, AahI or AahII) are used. Increase of cytokine levels (IL1beta, TNFalpha and ICAM) into hepatic tissue induced by AahI or AahII neurotoxins is correlated with tissue alterations. Aprotinin, a non specific inhibitor of complement system seems to be able to reduce CS consumption and to restore partially the induced tissue damage by venom. The mechanisms by which toxic fraction or LPS induced the activation of complement system seem to be different. Sensitivity of hepatic tissue is more pronounced after FtoxG50 injection; however lung tissue is more sensible to LPS than FoxG50. PMID- 25921956 TI - Obituary for professor Frank T. W. Jordan (1917-2015). PMID- 25921957 TI - Obituary for professor Dr Ahmed Ali Sami Ahmed (1933-2015). PMID- 25921960 TI - "America's Doctor" Dr Oz fights back against critics. PMID- 25921961 TI - Nursing and Respiratory Collaboration Prevents BiPAP-Related Pressure Ulcers. AB - In early 2012, an increase in the incidence of BiPAP-related pressure ulcers was noted in the progressive care unit of a large pediatric facility. An interdisciplinary team of nursing and respiratory staff and leadership formed a collaborative to address the gaps in practice, recommend, and implement evidence based interventions using a quality improvement model. Interventions included piloting new masks, changing the skin barrier from a hydrocolloid dressing to a foam dressing and using a template for better fit, including skin assessments every 4 hours as part of nursing and respiratory therapists' workflow, and implementing a notification process that included Wound Ostomy Continence Nurses, respiratory, and nursing leadership for any redness of skin noted. Weekly rounding and communication by nursing and respiratory leadership ensured consistency and sustainability of practice. Aside from implementation of interventions, the primary focus was to develop a collaborative relationship between nursing and respiratory teams for shared ownership and accountability of patients on BiPAP support. Three months after the implementation of interventions, the occurrence of BiPAP-related pressure ulcers decreased from eleven in the first three quarters to one occurrence in the fourth quarter of fiscal year (FY) 2012. In 2013, the occurrence decreased to five for the entire fiscal year. Since the end of FY 2013, there has only been one occurrence of a BiPAP-related pressure ulcer in the progressive care unit. Close collaboration between respiratory and nursing has been the primary factor in decreasing BiPAP related pressure ulcers. An important lesson learned is that interdisciplinary collaboration leads to improved patient outcomes. PMID- 25921962 TI - Wnt signaling in testis development: Unnecessary or essential? AB - Testis development is a fundamental process in sexual development and reproduction. It is under the regulation of multiple factors. Wnt signaling pathway is a classical pathway, which plays an essential role during early development. From a traditional view, Wnt signaling serves as a key regulator of female reproductive system. However, its role in testis development is relatively controversial. This paper reviews Wnt signaling's part in the major events during testis development, including primordial germ cell specification, proliferation and migration, testis determination, spermatogenesis and somatic cell regulation, and summarizes Wnt signaling's impact on testis-related disorders. We evaluate the outcomes of current studies in the field and suggest future research directions. PMID- 25921963 TI - Identification of tissue-specific regulatory region in the zebrafish lamin A promoter. AB - Lamins are major structural proteins present in the nuclei of metazoan cells and contribute significantly to nuclear organization and function. The expression of different types of lamins is developmentally regulated and lamin A is detectable in most differentiated tissues. Although the proximal promoter of the mammalian lamin A gene has been characterized, the tissue-specific regulatory elements of the gene have not been identified. In this study, we have cloned and functionally characterized a 2.99 kb segment upstream of exon 1 in the zebrafish lamin A gene. This fragment was able to drive GFP expression in several tissues of the developing embryo at 14-72 h post fertilization in stable transgenic lines. Deletion fragments of the 2.99 kb promoter were analyzed by microinjection into zebrafish embryos in transient assays as well as by luciferase reporter assays in cultured cells. A minimal promoter segment of 1.24 kb conferred tissue-specific expression of GFP in the zebrafish embryo as well as in a myoblast cell line. An 86 bp fragment of this 1.24 kb segment was able to activate a heterologous promoter in myoblasts. Mutational analysis revealed the importance of muscle specific regulatory motifs in the promoter. Our results have important implications for understanding the tissue-specific regulation and functions of the lamin A gene. PMID- 25921964 TI - Associations of the G1961E and D2177N variants in ABCA4 and the risk of age related macular degeneration. AB - OBJECTIVE: The aim of this study was to identify the relationship between G1961E and D2177N variants in the ABCA4 gene with AMD susceptibility. DESIGN AND METHODS: All eligible studies published up to October 2014 were obtained from MEDLINE, EMBASE, and ISI Web of Science. The pooled odds ratio (OR) with 95% confidence intervals (CIs) was calculated to evaluate the strength of this association. RESULTS: Twenty-four studies enrolling 4580 AMD cases and 5180 controls were identified. Both G1961E (OR = 3.22, 95% CI: 1.74-5.95) and D2177N (OR = 2.36, 95% CI: 1.41-3.93) variations showed significant associations with increased risk of AMD. In addition, a more significant relationship in the D2177N mutation with increased risk for AMD was found in Americans (OR = 4.31, 95% CI: 1.90-9.73), while no association was demonstrated in Europeans. For Asians, no carriers of the risk factor A allele in either variant were detected in any of AMD patients and control subjects. CONCLUSIONS: Significant evidence was found for a relationship between the G1961E and D2177N variants in ABCA4 with increased susceptibility to AMD, specifically for Americans. However, large-scale studies are still required to further validate these findings in different ethnicities. PMID- 25921965 TI - Early intervention and long-term outcome with cardiac resynchronization therapy in patients without a history of advanced heart failure symptoms. AB - AIMS: MADIT-CRT showed that cardiac resynchronization therapy with a defibrillator (CRT-D) improves long-term outcomes in currently mildly symptomatic heart failure (HF) patients with LBBB regardless of the presence of prior advanced HF symptoms. We aimed to evaluate the long-term benefit of CRT-D in patients who never experienced advanced HF symptoms prior to device implantation. METHODS AND RESULTS: Interaction term analysis was used to compare the clinical and echocardiographic benefit of CRT-D vs. implantable cardioverter defibrillator (ICD)-only therapy during long-term follow-up (median 5.6 years) between LBBB patients with or without a history of advanced HF [defined as NYHA class >= III or past hospitalization for worsening HF >3 months prior to enrolment in MADIT CRT (n = 529 and 752, respectively)]. Multivariable analysis showed that treatment with CRT-D was associated with a significant reduction in the risk of HF or death during long-term follow-up regardless of the presence of prior advanced HF symptoms [hazard ratio 0.53 (P < 0.001) and 0.47 (P < 0.001) in the respective groups of patients with and without prior advanced HF; interaction P for the difference = 0.58]. Echocardiographic response to CRT at 1 year was also similar between the two groups (P > 0.10 for all comparisons). CONCLUSION: Our findings suggest that treatment with CRT-D is associated with pronounced echocardiographic and long-term clinical benefit in patients with LV dysfunction and LBBB who never experienced advanced HF symptoms. These data further emphasize the benefit of early intervention with CRT in this population. PMID- 25921966 TI - Does accelerometer feedback on high-quality chest compression improve survival rate? An in-hospital cardiac arrest simulation. AB - OBJECTIVE: We investigated whether visual feedback from an accelerometer device facilitated high-quality chest compressions during an in-hospital cardiac arrest simulation using a manikin. METHODS: Thirty health care providers participated in an in-hospital cardiac arrest simulation with 1 minute of continuous chest compressions. Chest compressions were performed on a manikin lying on a bed according to visual feedback from an accelerometer feedback device. The manikin and accelerometer recorded chest compression data simultaneously. The simulated patient was deemed to have survived when the chest compression data satisfied all of the preset high-quality chest compression criteria (depth >=51 mm, rate >100 per minute, and >=95% full recoil). Survival rates were calculated from the feedback device and manikin data. RESULTS: The survival rate according to the feedback device data was 80%; however, the manikin data indicated a significantly lower survival rate (46.7%; P = .015). The difference between the accelerometer and manikin survival rates was not significant for participants with a body mass index greater than or equal to 20 kg/m(2) (93.3 vs 73.3%, respectively; P = .330); however, the difference in survival rate was significant in participants with body mass index less than 20 kg/m(2) (66.7 vs 20.0%, respectively; P = .025). CONCLUSIONS: The use of accelerometer feedback devices to facilitate high quality chest compression may not be appropriate for lightweight rescuers because of the potential for compression depth overestimation. TRIAL REGISTRATION: Clinical Research Information Service (KCT0001449). PMID- 25921967 TI - An alternate technique for assessing optic nerve in papilledema by ultrasound B scan. PMID- 25921968 TI - Comparison of antiemetics for nausea and vomiting of pregnancy in an emergency department setting. AB - OBJECTIVE: To compare time from medication administration to disposition from the Emergency Department (ED) between women treated for nausea and vomiting of pregnancy with different antiemetic agents. DESIGN: We performed a retrospective cohort study of women 13 weeks gestation or less treated in our Women and Infants Hospital ED for nausea and vomiting of pregnancy between 2009 and 2011. Data was collected on patient demographics, antiemetics used, and time to disposition. We analyzed time of administration of the antiemetic used first line (ondansetron versus metoclopramide versus promethazine or prochlorperazine) to time the discharge order was placed. RESULTS: We analyzed data from 439 women treated in the ED for nausea and vomiting of pregnancy. Forty-four percent received ondansetron alone, 47% received any other antiemetic alone, and 9% received more than one agent first line. Antiemetic agent selected did not differ by patient age, parity, current treatment for nausea and vomiting in pregnancy, orthostatics, ketonuria or disposition. We found no difference in time from medication administration to disposition between women who received ondansetron and women who received any other antiemetic (metoclopramide, prochlorperazine or promethazine). Adjusting for potential confounders, compared to patients who received any other first line therapy, patients who received ondansetron had 2.09 times the odds of having a time to disposition at or above the 75th percentile (95% CI 1.31-3.34). CONCLUSIONS: The use of ondansetron in the ED for nausea and vomiting of pregnancy was associated with similar mean time from administration to disposition as other antiemetics. PMID- 25921969 TI - Life-threatening flecainide overdose treated with intralipid and extracorporeal membrane oxygenation. AB - Flecainide is a Class Ic antiarrythmic agent associated with adverse events due to its pro-arrythmic effects. We report the case of a 33-year-old female presenting in cardiac arrest after a flecainide overdose treated with intravenous fat emulsion (IFE), sodium bicarbonate (NaHCO3), and extracorporeal membrane oxygenation (ECMO). This case reviews the pathophysiology and management of flecainide toxicity including novel strategies of IFE and ECMO. PMID- 25921970 TI - Early prophylactic anticoagulation via transjugular intrahepatic route for portal vein thrombosis after splenectomy in cirrhotic portal hypertension. AB - PURPOSE: To evaluate early transcatheter anticoagulation via the transjugular intrahepatic route to prevent portal vein thrombosis (PVT) after splenectomy in cirrhotic patients with portal hypertension. MATERIALS AND METHODS: This retrospective study included 98 cirrhotic patients with portal hypertension who underwent open splenectomy (48 men and 50 women; age, 45.4 y +/- 13.6). Systemic anticoagulation was given to 52 patients in group I, and transcatheter anticoagulation was performed in 46 patients in group II. RESULTS: The technical success rate of catheterization by the transjugular intrahepatic route was 93.5% in group II. The 30-day (6.52% vs 23.1%, P < .05) and 6-month (8.70% vs 26.9%, P < .05) incidences of PVT were significantly lower in group II than in group I. The postoperative bleeding rate was 6.52% in group II and 25% in group I (P < .05). There was no significant difference between groups in 30-day (5.77% vs 2.17%) and 6-month (1.92% vs 6.52%) mortality. After splenectomy, the portal trunk vessel diameter was 16.0 mm +/- 3.5 in group I and 14.5 mm +/- 2.5 in group II (P < .05). The portal flow velocity was 25.9 cm/s +/- 7.1 in group I and 28.2 cm/s +/- 5.3 in group II (P > .05). During the first week after splenectomy, notable hypercoagulability was detected within the portal vein compared with peripheral blood. Decreased portal flow velocity was considered an independent risk factor for PVT by univariate and multivariate analysis. CONCLUSIONS: Transcatheter anticoagulation via the transjugular intrahepatic route can decrease the incidence of PVT and postoperative bleeding after open splenectomy in cirrhotic patients with portal hypertension. PMID- 25921971 TI - Endovascular therapy for acute stroke is a safe and efficient evolving method: a single-center retrospective analysis. AB - PURPOSE: To determine the clinical outcome in patients undergoing endovascular therapy for acute stroke. MATERIALS AND METHODS: During the period 2009-2012, 134 patients with acute stroke and normal computed tomography (CT) findings were treated with endovascular therapy at a single center. Based on CT perfusion and CT angiography findings, all patients had large vessel occlusions. Intravenous thrombolysis was used in eligible patients. The recanalization rate, time to recanalization, periprocedural complications, and clinical outcome at discharge from the hospital (National Institutes of Health score, modified Rankin Scale [mRS]) were analyzed. RESULTS: The recanalization rate during the study interval increased from 70% (2008-2009) to 94% (2011-2012) (P <= .01). The procedure time was reduced from 124 minutes (2009) to 43 minutes (2012) (P <= .01), and the periprocedural complication rate decreased from 21% (2009) to 2% (2012) (P <= .01). Patients in 2009-2010 had a 2.21 times greater probability for an mRS score >= 2 after the procedure compared with patients in 2011-2012 (95% confidence interval, 1.0-5.0). If the procedure lasted 15 minutes longer, the prospect for an mRS score >=2 after the procedure was 1.30 times greater (P = .02). CONCLUSIONS: High recanalization rates, low procedural complications, and improved clinical outcomes were achieved using endovascular therapy in selected patients with acute stroke during a 4-year period. Endovascular therapy is an evolving safe and effective treatment for intracranial large vessel occlusion. PMID- 25921972 TI - The International Journal of Medical Microbiology 15 and 128 years on - Evolving for the future. PMID- 25921973 TI - What is needed for taking emergency obstetric and neonatal programmes to scale? AB - Scaling up an emergency obstetric and neonatal care (EmONC) programme entails reaching a larger number of people in a potentially broader geographical area. Multiple strategies requiring simultaneous attention should be deployed. This paper provides a framework for understanding the implementation, scale-up and sustainability of such programmes. We reviewed the existing literature and drew on our experience in scaling up the Essential Steps in the Management of Obstetric Emergencies (ESMOE) programme in South Africa. We explore the non linear change process and conditions to be met for taking an existing EmONC programme to scale. Important concepts cutting across all components of a programme are equity, quality and leadership. Conditions to be met include appropriate awareness across the board and a policy environment that leads to the following: commitment, health systems-strengthening actions, allocation of resources (human, financial and capital/material), dissemination and training, supportive supervision and monitoring and evaluation. PMID- 25921974 TI - Forward masking in the medial nucleus of the trapezoid body of the rat. AB - Perception of acoustic stimuli is modulated by the temporal and spectral relationship between sound components. Forward masking experiments show that the perception threshold for a probe tone is significantly impaired by a preceding masker stimulus. Forward masking has been systematically studied at the level of the auditory nerve, cochlear nucleus, inferior colliculus and auditory cortex, but not yet in the superior olivary complex. The medial nucleus of the trapezoid body (MNTB), a principal cell group of the superior olive, plays an essential role in sound localization. The MNTB receives excitatory input from the contralateral cochlear nucleus via the calyces of Held and innervates the ipsilateral lateral and medial superior olives, as well as the superior paraolivary nucleus. Here, we performed single-unit extracellular recordings in the MNTB of rats. Using a forward masking paradigm previously employed in studies of the inferior colliculus and auditory nerve, we determined response thresholds for a 20-ms characteristic frequency pure tone (the probe), and then presented it in conjunction with another tone (the masker) that was varied in intensity, duration, and frequency; we also systematically varied the masker-to-probe delay. Probe response thresholds increased and response magnitudes decreased when a masker was presented. The forward suppression effects were greater when masker level and masker duration were increased, when the masker frequency approached the MNTB unit's characteristic frequency, and as the masker-to-probe delay was shortened. Probe threshold shifts showed an exponential decay as the masker-to probe delay increased. PMID- 25921975 TI - Topographic organization of the human and non-human primate subthalamic nucleus. AB - Deep brain stimulation (DBS) of the subthalamic nucleus (STN) is used to relieve motor symptoms of Parkinson's disease. A tripartite system of STN subdivisions serving motoric, associative, and limbic functions was proposed, mainly based on tracing studies, which are limited by low numbers of observations. The evidence is compelling and raises the question as to what extent these functional zones are anatomically segregated. The majority of studies indicate that there is anatomical overlap between STN functional zones. Using ultrahigh-resolution magnetic resonance imaging techniques it is now possible to visualize the STN with high spatial resolution, and it is feasible that in the near future stereotactic guided placement of electrical stimulators aided by high-resolution imaging will allow for more specific stimulation of the STN. The neuroanatomical and functional makeup of these subdivisions and their level of overlap would benefit from clarification before serving as surgical targets. We discuss histological and imaging studies, as well as clinical observations and electrophysiological recordings in DBS patients. These studies provide evidence for a topographical organization within the STN, although it remains unclear to what extent functionally and anatomically distinct subdivisions overlap. PMID- 25921977 TI - Interventions designed to improve therapeutic communications between black and minority ethnic people and professionals working in psychiatric services: a systematic review of the evidence for their effectiveness. AB - BACKGROUND: Black and minority ethnic (BME) people using psychiatric services are at greater risk of non-engagement, dropout from care and not receiving evidence based interventions than white British people. OBJECTIVES: To identify effective interventions designed to improve therapeutic communications (TCs) for BME patients using psychiatric services in the UK, to identify gaps in the research literature and to recommend future research. PARTICIPANTS: Black African, black Caribbean, black British, white British, Pakistani and Bangladeshi patients in psychiatric services in the UK, or recruited from the community to enter psychiatric care. Some studies from the USA included Hispanic, Latino, Chinese, Vietnamese, Cambodian and African American people. INTERVENTIONS: Any that improve TCs between BME patients and staff in psychiatric services. DATA SOURCES: The published literature, 'grey' literature, an expert survey, and patients' and carers' perspectives on the evidence base. Databases were searched from their inception to 4 February 2013. Databases included MEDLINE, Applied Social Sciences Index and Abstracts, The Cochrane Library, Social Science Citation Index, Allied and Complementary Medicine Database, PsycINFO, Cumulative Index to Nursing and Allied Health Literature, EMBASE, The Campbell Collaboration and ProQuest for dissertations. REVIEW METHODS: Studies were included if they reported evaluation data about interventions designed to improve therapeutic outcomes by improving communication between BME patients and psychiatric professionals. Qualitative studies and reports in the grey literature were included only if they gave a critical evaluative statement. Two members of the team selected studies against pre-established criteria and any differences were resolved by consensus or by a third reviewer, if necessary. Data were extracted independently by two people and summarised in tables by specific study designs. Studies were subjected to a narrative synthesis that included a thematic analysis contrasting populations, countries and the strength of evidence for any intervention. The components of the interventions were compared. Patient perspectives on acceptability were considered alongside quality scores and methodological strengths and weaknesses. RESULTS: Twenty-one studies (19 from the published literature and two from the grey literature) met the inclusion criteria. There were 12 trials, two observational quantitative studies, three case series, a qualitative study and three descriptive case studies. Only two studies, one a pilot trial and one a case series, included economic data; in both, a favourable but weak economic case could be made for the intervention. The trials tested interventions to prepare patients for therapeutic interventions, variable levels of ethnic matching (of professional to patient), cultural adaptation of therapies, and interventions that included social community systems in order to facilitate access to services. Empowering interventions favoured by patients and carers included adapted cognitive-behavioural therapy, assessments of explanatory models, cultural consultation, ethnographic and motivational interviews, and a telepsychiatry intervention. LIMITATIONS: Studies tended to have small sample sizes or to be pilot studies, and to use proxy rather than direct measures for TCs. CONCLUSIONS: Empowering interventions should be further researched and brought to the attention of commissioners. Several promising interventions need further evaluative research and economic evaluations are needed. STUDY REGISTRATION: The study is registered as PROSPERO CRD42011001661. FUNDING: The National Institute for Health Research Health Technology Assessment programme. PMID- 25921978 TI - Associations of proactive coping and self-efficacy with psychosocial outcomes in individuals after stroke. AB - OBJECTIVE: To examine the associations of proactive coping and self-efficacy with psychosocial outcomes in individuals after stroke. DESIGN: Cross-sectional study. Regression analyses were performed. SETTING: Outpatient settings of hospitals and rehabilitation centers. PARTICIPANTS: Individuals after stroke (N=112; mean age +/- SD, 57.1+/-8.9y; mean time +/- SD since stroke, 18.9+/-28.5mo). INTERVENTIONS: Not applicable. MAIN OUTCOME MEASURES: Proactive coping was measured using the Utrecht Proactive Coping Competence scale (UPCC), and self efficacy was measured using the General Self-Efficacy Scale (GSES). Psychosocial outcomes were measured as (1) participation with the use of the restriction and satisfaction subscales of the Utrecht Scale for Evaluation of Rehabilitation Participation (USER-Participation); (2) emotional problems with the use of the Hospital Anxiety and Depression Scale (HADS); (3) life satisfaction with the use of 2 questions (2LS); and (4) health-related quality of life (HRQOL) with the use of the Short Stroke-Specific Quality of Life scale (SS-QOL-12). RESULTS: Higher UPCC scores were associated with lower HADS scores (beta=-.55, P<.001) and with higher USER-Participation satisfaction (beta=.31, P=.001), 2LS (beta=.34, P<.001), and SS-QOL-12 scores (beta=.44, P<.001). The influence of UPCC scores on HRQOL was indirect through self-efficacy. Higher GSES scores were associated with higher UPCC scores (beta=.65, P<.001), which in turn were associated with lower HADS scores (beta=-.51, P<.001). GSES scores were directly associated with higher SS-QOL-12 scores (beta=.32, P=.002). GSES scores did not influence the association between UPCC scores and any of the psychosocial outcomes (all P>.0025). CONCLUSIONS: Proactive coping and self-efficacy have different associations with each of the psychosocial outcomes. Therefore, outcome-specific models appear to be necessary to describe these associations. PMID- 25921976 TI - Complex motor task associated with non-linear BOLD responses in cerebro-cortical areas and cerebellum. AB - Previous studies have used fMRI to address the relationship between grip force (GF) applied to an object and BOLD response. However, whilst the majority of these studies showed a linear relationship between GF and neural activity in the contralateral M1 and ipsilateral cerebellum, animal studies have suggested the presence of non-linear components in the GF-neural activity relationship. Here, we present a methodology for assessing non-linearities in the BOLD response to different GF levels, within primary motor as well as sensory and cognitive areas and the cerebellum. To be sensitive to complex forms, we designed a feasible grip task with five GF targets using an event-related visually guided paradigm and studied a cohort of 13 healthy volunteers. Polynomial functions of increasing order were fitted to the data. MAJOR FINDINGS: (1) activated motor areas irrespective of GF; (2) positive higher-order responses in and outside M1, involving premotor, sensory and visual areas and cerebellum; (3) negative correlations with GF, predominantly involving the visual domain. Overall, our results suggest that there are physiologically consistent behaviour patterns in cerebral and cerebellar cortices; for example, we observed the presence of a second-order effect in sensorimotor areas, consistent with an optimum metabolic response at intermediate GF levels, while higher-order behaviour was found in associative and cognitive areas. At higher GF levels, sensory-related cortical areas showed reduced activation, interpretable as a redistribution of the neural activity for more demanding tasks. These results have the potential of opening new avenues for investigating pathological mechanisms of neurological diseases. PMID- 25921979 TI - Gender Influences on Return to Work After Mild Traumatic Brain Injury. AB - OBJECTIVE: To examine the influence of gender on the return to work experience of workers who sustained a work-related mild traumatic brain injury (TBI). DESIGN: Qualitative study using in-depth telephone interviews. SETTING: Community. PARTICIPANTS: Purposive sampling was used to recruit participants. Participants were adults (N=12; males, n=6, females, n=6) with a diagnosis of mild TBI sustained through a workplace injury. INTERVENTIONS: Not applicable. MAIN OUTCOME MEASURES: Not applicable. RESULTS: Our findings suggest that gender impacts return to work experiences in multiple ways. Occupational and breadwinner roles were significant for both men and women after work-related mild TBI. Women in this study were more proactive than men in seeking and requesting medical and rehabilitation services; however, the workplace culture may contribute to whether and how health issues are discussed. Among our participants, those who worked in supportive, nurturing (eg, feminine) workplaces reported more positive return to work (RTW) experiences than participants employed in traditionally masculine work environments. For all participants, employer and coworker relations were critical elements in RTW outcomes. CONCLUSIONS: The application of a gender analysis in this preliminary exploratory study revealed that gender is implicated in the RTW process on many levels for men and women alike. Further examination of the work reintegration processes that takes gender into account is necessary for the development of successful policy and practice for RTW after work-related MTBI. PMID- 25921980 TI - Coping, problem solving, depression, and health-related quality of life in patients receiving outpatient stroke rehabilitation. AB - OBJECTIVES: To investigate whether patients with high and low depression scores after stroke use different coping strategies and problem-solving skills and whether these variables are related to psychosocial health-related quality of life (HRQOL) independent of depression. DESIGN: Cross-sectional study. SETTING: Two rehabilitation centers. PARTICIPANTS: Patients participating in outpatient stroke rehabilitation (N=166; mean age, 53.06+/-10.19y; 53% men; median time poststroke, 7.29mo). INTERVENTIONS: Not applicable. MAIN OUTCOME MEASURES: Coping strategy was measured using the Coping Inventory for Stressful Situations; problem-solving skills were measured using the Social Problem Solving Inventory Revised: Short Form; depression was assessed using the Center for Epidemiologic Studies Depression Scale; and HRQOL was measured using the five-level EuroQol five-dimensional questionnaire and the Stroke-Specific Quality of Life Scale. Independent samples t tests and multivariable regression analyses, adjusted for patient characteristics, were performed. RESULTS: Compared with patients with low depression scores, patients with high depression scores used less positive problem orientation (P=.002) and emotion-oriented coping (P<.001) and more negative problem orientation (P<.001) and avoidance style (P<.001). Depression score was related to all domains of both general HRQOL (visual analog scale: beta=-.679; P<.001; utility: beta=-.009; P<.001) and stroke-specific HRQOL (physical HRQOL: beta=-.020; P=.001; psychosocial HRQOL: beta=-.054, P<.001; total HRQOL: beta=-.037; P<.001). Positive problem orientation was independently related to psychosocial HRQOL (beta=.086; P=.018) and total HRQOL (beta=.058; P=.031). CONCLUSIONS: Patients with high depression scores use different coping strategies and problem-solving skills than do patients with low depression scores. Independent of depression, positive problem-solving skills appear to be most significantly related to better HRQOL. PMID- 25921982 TI - The defeat-entrapment theory versus Beck's hopelessness theory of depression and suicidality: A cross-national analysis in Iran and the United States. AB - BACKGROUND: The defeat-entrapment theory has been proposed to explain both depression and suicidal behavior. METHODS: Measures of defeat, entrapment, hopelessness and depression were administered to Iranian and American students. RESULTS: Scores on measures of hopelessness, defeat, entrapment and depression were strongly associated. In both nations, scores for defeat and entrapment were stronger predictors of past suicidal ideation and attempted suicide. Overall, the Iranian respondents had higher scores on the measures of defeat, entrapment, hopelessness and depression, but less often reported prior suicidal ideation. CONCLUSION: The defeat-entrapment theory of depression and suicidal behavior appears to have validity in both Iran and America. PMID- 25921981 TI - Participants' barriers to diagnostic resolution and factors associated with needing patient navigation. AB - BACKGROUND: Patient navigation (PN) may improve cancer care by identifying and removing patient-reported barriers to care. In 2012, the American College of Surgeons Commission on Cancer (CoC) announced that health care facilities seeking CoC accreditation must have PN processes in place by January 1, 2015. Given these unfunded mandates, hospitals are looking for cost-effective ways to implement PN. This study examined demographic and psychosocial predictors of barriers to diagnostic resolution among individuals with a cancer screening abnormality enrolled in the Ohio Patient Navigation Research Project. METHODS: Data were obtained from patients who received care at 1 of 9 Ohio Patient Navigation Research Project intervention clinics. Descriptive statistics and logistic regression models were used. RESULTS: There were 424 participants, and 151 (35.6%) reported a barrier to diagnostic resolution within 90 days of study consent. The most commonly reported barriers were misconceptions about a test or treatment (16.4%), difficulty in communicating with the provider (15.0%), and scheduling problems (11.5%). Univariate analyses indicated that race, education, employment, income, insurance, clinic type, friend support, and physical and psychological functioning were significantly associated with reporting a barrier to diagnostic resolution. Multivariate analyses found that comorbidities (odds ratio, 1.65; 95% confidence interval, 1.04-2.61) and higher intrusive thoughts and feelings (odds ratio, 1.25; 95% confidence interval, 1.10-1.41) were significantly associated with reporting a barrier to diagnostic resolution. CONCLUSIONS: The results suggest that demographic and psychosocial factors are associated with barriers to diagnostic resolution. To ensure compliance with the CoC mandate and provide timely care to all patients, CoC-accredited facilities can systematically identify the patients most likely to have barriers to care and assign them to PN. PMID- 25921983 TI - Unsocial hours pay is a question of fairness. AB - Should you be paid extra for working weekends? What about nights, or public holidays? Unsocial hours go with the job for most nurses, but the issue of whether and how staff should be rewarded is currently being scrutinised by the NHS Pay Review Body. In the past week there has also been a heated political discussion, as the parties vie for nurses' votes. PMID- 25921984 TI - Scrap unsocial hours payments and nurses will retaliate, warns RCN. PMID- 25921985 TI - Nurse Helen is back in the driving seat after successful campaign. PMID- 25921986 TI - Lib Dem candidate calls on rival parties to remove politics from running of NHS. PMID- 25921987 TI - Key figures meet to discuss shape of caring review. PMID- 25921988 TI - Labour pledges to boost nursing numbers immediately. PMID- 25921989 TI - Rethink care home career pathways to boost recruitment, says professor. PMID- 25921990 TI - Shedding new light on nurses' role. PMID- 25921991 TI - Call for 'gay specific' end of life care. PMID- 25921992 TI - Age UK's integrated care pilot to be rolled out across England. PMID- 25921994 TI - Supporting youngest organ donor was 'a privilege'. PMID- 25921995 TI - New guidance on post-death care. PMID- 25921996 TI - Calls for 'living bursary' as students visit food banks or drop out. PMID- 25922002 TI - Encouraging physical activity. PMID- 25922003 TI - Helping new leaders take their first steps. PMID- 25922004 TI - Nutritional therapy when it is needed. PMID- 25922013 TI - Bladder and Bowel Foundation. PMID- 25922015 TI - Fallcheck. PMID- 25922017 TI - By bringing the van to the man, we can offer essential cancer support. PMID- 25922018 TI - EU agreement would limit scope for reversing NHS privatisation. PMID- 25922019 TI - UK nurse educators would do well to follow Canada's lead. PMID- 25922020 TI - The assumption that researchers are substandard seems unlikely. PMID- 25922021 TI - Now is a good time to find out what you need to do to revalidate. PMID- 25922022 TI - Would you like to contribute to my study of bullying in the NHS? PMID- 25922023 TI - I don't know how maternity leave affects my revalidation. PMID- 25922026 TI - Grounded theory. AB - Grounded theory is a popular research approach in health care and the social sciences. This article provides a description of grounded theory methodology and its key components, using examples from published studies to demonstrate practical application. It aims to demystify grounded theory for novice nurse researchers, by explaining what it is, when to use it, why they would want to use it and how to use it. It should enable nurse researchers to decide if grounded theory is an appropriate approach for their research, and to determine the quality of any grounded theory research they read. PMID- 25922027 TI - Understanding non-compliance with hand hygiene practices. AB - Healthcare-associated infections (HCAIs) continue to be a challenge in developed and developing countries. Hand hygiene practice is considered to be the most effective strategy to prevent HCAIs, but healthcare workers' compliance is poor. Using a human factors perspective, this article explores elements that affect healthcare workers' hand hygiene compliance. Slips, lapses and mistakes can occur depending on the worker's skills and knowledge levels. Violations of protocols may also occur, and these may be associated with the intention to provide care efficiently. Strong leadership and an understanding of why non-compliance with hand hygiene occurs assists with developing strategies to improve compliance. PMID- 25922028 TI - Writing an article. PMID- 25922029 TI - Your chance to shine. PMID- 25922031 TI - Finding logical interventions. PMID- 25922032 TI - Future-proofing services. PMID- 25922033 TI - Aiming even higher. PMID- 25922051 TI - Establishing a community of practice for Occupational Therapy curriculum development: the value of a two-way process. AB - INTRODUCTION: A novel application of the concept of a community of practice was adopted in the development of a revised curriculum for undergraduate occupational therapy education in July 2012. University Academic staff and invited practice scholars met together, half yearly for day long meetings to develop and review a new curriculum. The formation of this community of practice allowed for open discourse and feedback to integrate theory and practice. METHOD: A qualitative study utilised two focus groups, one for academic staff and one for practice scholars, at the end of the third meeting. The focus groups were facilitated by an external researcher, recorded and transcribed verbatim. Thematic analysis elicited five major themes. FINDINGS: Participants reported a sense of community and commitment to the curriculum process. Five themes emerged from the focus groups: (i) a sense of community; (ii) a two-way process with mutual benefits; (iii) benefits to the curriculum and to student learning; (iv) future opportunities including resilience of graduates, and potential research collaborations; and (v) the structure and process of engaging in the community of practice. CONCLUSION: The commitment of time, planning and resources required to establish and participate in collaborative curriculum development with practice scholars is shown to be a valuable investment for occupational therapy academics, expert practice scholars and ultimately for student learning. Further studies of student and graduate outcomes from the curriculum are warranted. Potential future outcomes of this process include resilience in graduates and collaborative research with practice scholars. PMID- 25922052 TI - Autistic spectrum disorder, epilepsy, and vagus nerve stimulation. AB - PURPOSE: In individuals with a comorbid autistic spectrum disorder and medically refractory epilepsy, vagus nerve stimulation may offer the potential of seizure control and a positive behavioral side effect profile. We aimed to examine the behavioral side effect profile using longitudinal and quantitative data and review the potential mechanisms behind behavioral changes. METHODS: We present a case report of a 10-year-old boy with autistic spectrum disorder and epilepsy, who underwent vagus nerve stimulation subsequent to unsuccessful treatment with antiepileptic medication. RESULTS: Following vagus nerve stimulation implantation, initial, if temporary, improvement was observed in seizure control. Modest improvements were also observed in behavior and development, improvements which were observed independent of seizure control. CONCLUSIONS: Vagus nerve stimulation in autistic spectrum disorder is associated with modest behavioral improvement, with unidentified etiology, although several candidates for this improvement are evident. PMID- 25922053 TI - Desmoplastic infantile ganglioglioma with associated giant aneurysm-case report. AB - Desmoplastic infantile ganglioglioma (DIG) and supratentorial giant cerebral aneurysm are each extremely rare entities in infants. Here, we present the case of an 8-day old boy who had both of these conditions concurrently. To our knowledge, there is no previous case reported of a patient with coexisting DIG and giant aneurysm. PMID- 25922054 TI - Surgical outcome of pancreaticoduodenectomy: high volume center or multidisciplinary management? AB - BACKGROUND: More recently mortality and morbidity related to PD has dramatically dropped, due to the new mini-invasive technology as well as to a trend leading towards centralization. Our hospital can be considered a high-volume center for pancreatic surgery; nevertheless, each of its 5 surgical units taken alone has a low/medium-volume activity. The aim of this study was to evaluate the results of PD in a low-medium volume unit with multidisciplinary support in a major high volume hospital. METHODS: A retrospective review was conducted: from January 2002 up to December 2013, 62 Whipple procedures were performed in our surgical unit. RESULTS: As to the operative outcome, the average number of days spent in ICU was of 4.28, the average days ventilated were 1.5 and the mean hospital stay was of 16 days. The in-hospital mortality was 3.2%, the late mortality was 1.6% and the perioperative morbidity was 27.4%. CONCLUSIONS: The effect of the surgeon volume on post-operative mortality is still controversial. As suggested by Gooiker, the centralization initiatives for pancreatic surgery should be based not only on volume quality criteria, but also on services and processes offered by a major hospital. The results of our study are similar to the ones of Italian and international studies performed in high-volume centers. According to our experience, we feel we can confirm that positive results in pancreatic surgery may be obtained also in low-medium volume units if there is a multidisciplinary support and services common to a major high volume hospital. PMID- 25922056 TI - Development and validation of a DESI-HRMS/MS method for the fast profiling of esomeprazole and its metabolites in rat plasma: a pharmacokinetic study. AB - The advances in pharmaceutical development and drug discovery impose the availability of reliable high-throughput screening methods for the rapid evaluation of drug metabolism and pharmacokinetic (PK) in biological samples. Here, a desorption electrospray mass spectrometry (DESI-MS) method has been developed and validated for the PK profiling of esomeprazole and its metabolites (5-hydroxyomeprazole and omeprazole sulfone) in rat plasma. Rats were treated with an esomeprazole solution (2.5 mg/mL) for endovenous administration and the analyte levels were profiled over 2 h after liquid-liquid extraction from plasma. MS and tandem mass spectrometry (MS/MS) experiments were performed by using a DESI-LTQ-Orbitrap XL instrument and an on-spot fixed time analysis on PMMA surfaces. Validation was performed for the esomeprazole. The DESI-MS/MS method exhibited for the esomepazole excellent sensitivity (limit of detection (LOD)=60 ng/mL), linearity (0.2-20 ug/mL concentration range; y=23848(+/-361)X, n=15; r(2) =0.987) and precision (RSD<9%) by using an internal standard method. The PK results were discussed in terms of Area Under the Curve, Cmax and Tmax . Data reliability was demonstrated by comparison with a liquid chromatography-tandem mass spectrometry method (p>0.05). The data achieved demonstrated that the DESI MS method is suitable for sensitive and fast profiling of a drug and its metabolites at the therapeutic concentration levels. PMID- 25922055 TI - Maternal obesity characterized by gestational diabetes increases the susceptibility of rat offspring to hepatic steatosis via a disrupted liver metabolome. AB - Maternal obesity is associated with a high risk for gestational diabetes mellitus (GDM), which is a common complication of pregnancy. The influence of maternal obesity and GDM on the metabolic health of the offspring is poorly understood. We hypothesize that GDM associated with maternal obesity will cause obesity, insulin resistance and hepatic steatosis in the offspring. Female Sprague-Dawley rats were fed a high-fat (45%) and sucrose (HFS) diet to cause maternal obesity and GDM. Lean control pregnant rats received low-fat (LF; 10%) diets. To investigate the interaction between the prenatal environment and postnatal diets, rat offspring were assigned to LF or HFS diets for 12 weeks, and insulin sensitivity and hepatic steatosis were evaluated. Pregnant GDM dams exhibited excessive gestational weight gain, hyperinsulinaemia and hyperglycaemia. Offspring of GDM dams gained more weight than the offspring of lean dams due to excess adiposity. The offspring of GDM dams also developed hepatic steatosis and insulin resistance. The postnatal consumption of a LF diet did not protect offspring of GDM dams against these metabolic disorders. Analysis of the hepatic metabolome revealed increased diacylglycerol and reduced phosphatidylethanolamine in the offspring of GDM dams compared to offspring of lean dams. Consistent with altered lipid metabolism, the expression of CTP:phosphoethanolamine cytidylyltransferase, and peroxisomal proliferator activated receptor-alpha mRNA was reduced in the livers of GDM offspring. GDM exposure programs gene expression and hepatic metabolite levels and drives the development of hepatic steatosis and insulin resistance in young adult rat offspring. PMID- 25922057 TI - Guidelines for management of intra-abdominal infections. AB - Intra-abdominal infections are one of the most common gastrointestinal emergencies and a leading cause of septic shock. A consensus conference on the management of community-acquired peritonitis was published in 2000. A new consensus as well as new guidelines for less common situations such as peritonitis in paediatrics and healthcare-associated infections had become necessary. The objectives of these Clinical Practice Guidelines (CPGs) were therefore to define the medical and surgical management of community-acquired intra-abdominal infections, define the specificities of intra-abdominal infections in children and describe the management of healthcare-associated infections. The literature review was divided into six main themes: diagnostic approach, infection source control, microbiological data, paediatric specificities, medical treatment of peritonitis, and management of complications. The GRADE((r)) methodology was applied to determine the level of evidence and the strength of recommendations. After summarising the work of the experts and application of the GRADE((r)) method, 62 recommendations were formally defined by the organisation committee. Recommendations were then submitted to and amended by a review committee. After 2 rounds of Delphi scoring and various amendments, a strong agreement was obtained for 44 (100%) recommendations. The CPGs for peritonitis are therefore based on a consensus between the various disciplines involved in the management of these patients concerning a number of themes such as: diagnostic strategy and the place of imaging; time to management; the place of microbiological specimens; targets of empirical anti-infective therapy; duration of anti-infective therapy. The CPGs also specified the value and the place of certain practices such as: the place of laparoscopy; the indications for image-guided percutaneous drainage; indications for the treatment of enterococci and fungi. The CPGs also confirmed the futility of certain practices such as: the use of diagnostic biomarkers; systematic relaparotomies; prolonged anti-infective therapy, especially in children. PMID- 25922058 TI - Algal dual-specificity tyrosine phosphorylation-regulated kinase, triacylglycerol accumulation regulator1, regulates accumulation of triacylglycerol in nitrogen or sulfur deficiency. AB - Although microalgae accumulate triacylglycerol (TAG) and starch in response to nutrient-deficient conditions, the regulatory mechanisms are poorly understood. We report here the identification and characterization of a kinase, triacylglycerol accumulation regulator1 (TAR1), that is a member of the yeast (Saccharomyces cerevisiae) Yet another kinase1 (Yak1) subfamily in the dual specificity tyrosine phosphorylation-regulated kinase family in a green alga (Chlamydomonas reinhardtii). The kinase domain of TAR1 showed auto- and transphosphorylation activities. A TAR1-defective mutant, tar1-1, accumulated TAG to levels 0.5- and 0.1-fold of those of a wild-type strain in sulfur (S)- and nitrogen (N)-deficient conditions, respectively. In N-deficient conditions, tar1 1 showed more pronounced arrest of cell division than the wild type, had increased cell size and cell dry weight, and maintained chlorophyll and photosynthetic activity, which were not observed in S-deficient conditions. In N deficient conditions, global changes in expression levels of N deficiency responsive genes in N assimilation and tetrapyrrole metabolism were noted between tar1-1 and wild-type cells. These results indicated that TAR1 is a regulator of TAG accumulation in S- and N-deficient conditions, and it functions in cell growth and repression of photosynthesis in conditions of N deficiency. PMID- 25922059 TI - Volatile Glycosylation in Tea Plants: Sequential Glycosylations for the Biosynthesis of Aroma beta-Primeverosides Are Catalyzed by Two Camellia sinensis Glycosyltransferases. AB - Tea plants (Camellia sinensis) store volatile organic compounds (VOCs; monoterpene, aromatic, and aliphatic alcohols) in the leaves in the form of water soluble diglycosides, primarily as beta-primeverosides (6-O-beta-D-xylopyranosyl beta-D-glucopyranosides). These VOCs play a critical role in plant defenses and tea aroma quality, yet little is known about their biosynthesis and physiological roles in planta. Here, we identified two UDP-glycosyltransferases (UGTs) from C. sinensis, UGT85K11 (CsGT1) and UGT94P1 (CsGT2), converting VOCs into beta primeverosides by sequential glucosylation and xylosylation, respectively. CsGT1 exhibits a broad substrate specificity toward monoterpene, aromatic, and aliphatic alcohols to produce the respective glucosides. On the other hand, CsGT2 specifically catalyzes the xylosylation of the 6'-hydroxy group of the sugar moiety of geranyl beta-D-glucopyranoside, producing geranyl beta-primeveroside. Homology modeling, followed by site-directed mutagenesis of CsGT2, identified a unique isoleucine-141 residue playing a crucial role in sugar donor specificity toward UDP-xylose. The transcripts of both CsGTs were mainly expressed in young leaves, along with beta-primeverosidase encoding a diglycoside-specific glycosidase. In conclusion, our findings reveal the mechanism of aroma beta primeveroside biosynthesis in C. sinensis. This information can be used to preserve tea aroma better during the manufacturing process and to investigate the mechanism of plant chemical defenses. PMID- 25922061 TI - ALK FISH rearranged and amplified tumor with negative immunohistochemistry: a rare and challenging case concerning ALK status screening in lung cancer. PMID- 25922060 TI - Association of proinflammatory cytokines and chemotherapy-associated cognitive impairment in breast cancer patients: a multi-centered, prospective, cohort study. AB - BACKGROUND: Existing evidence suggests that proinflammatory cytokines play an intermediary role in postchemotherapy cognitive impairment. This is one of the largest multicentered, cohort studies conducted in Singapore to evaluate the prevalence and proinflammatory biomarkers associated with cognitive impairment in breast cancer patients. PATIENTS AND METHODS: Chemotherapy-receiving breast cancer patients (stages I-III) were recruited. Proinflammatory plasma cytokines concentrations [interleukin (IL)-1beta, IL-2, IL-4, IL-6, IL-8, IL-10, granulocyte-macrophage colony-stimulating factor, interferon-gamma and tumor necrosis factor-alpha] were evaluated at 3 time points (before chemotherapy, 6 and 12 weeks after chemotherapy initiation). The FACT-Cog (version 3) was utilized to evaluate patients' self-perceived cognitive disturbances and a computerized neuropsychological assessment (Headminder) was administered to evaluate patients' memory, attention, response speed and processing speed. Changes of cognition throughout chemotherapy treatment were compared against the baseline. Linear mixed-effects models were applied to test the relationships of clinical variables and cytokine concentrations on self-perceived cognitive disturbances and each objective cognitive domain. RESULTS: Ninety-nine patients were included (age 50.5 +/- 8.4 years; 81.8% Chinese; mean duration of education = 10.8 +/- 3.3 years). Higher plasma IL-1beta was associated with poorer response speed performance (estimate: -0.78; 95% confidence interval (CI) -1.34 to -0.03; P = 0.023), and a higher concentration of IL-4 was associated with better response speed performance (P = 0.022). Higher concentrations of IL-1beta and IL 6 were associated with more severe self-perceived cognitive disturbances (P = 0.018 and 0.001, respectively). Patients with higher concentrations of IL-4 also reported less severe cognitive disturbances (P = 0.022). CONCLUSIONS: While elevated concentrations of IL-6 and IL-1beta were observed in patients with poorer response speed performance and perceived cognitive disturbances, IL-4 may be protective against chemotherapy-associated cognitive impairment. This study is important because cytokines would potentially be mechanistic mediators of chemotherapy-associated cognitive changes. PMID- 25922062 TI - Mito-FLAG with Ara-C as bolus versus continuous infusion in recurrent or refractory AML--long-term results of a prospective randomized intergroup study of the East German Study Group Hematology/Oncology (OSHO) and the Study Alliance Leukemia (SAL). AB - BACKGROUND: For patients with primary refractory or relapsed acute myeloid leukemia (AML), no treatment of choice has until now been defined to date. Cytarabine (Ara-C) is a key drug in the treatment of AML patients, there is still uncertainly regarding its optimal dose and infusion schedule. The aim of this study is to examine the impact of the Ara-C infusion schedule used as part of an intensive salvage regimen, in patients with relapsed or refractory AML. PATIENTS AND METHODS: A total of 252 adult patients (median age 59 years) with relapsed or refractory AML were randomly allocated to receive either Mito-FLAG with Ara-C as bolus (B) (1000 mg/m(2) over 1 h, every 12 h, days 1-5), or continuous infusion (CI) (150 mg/m(2) over 24 h, days 1-5) in combination with mitoxantrone, fludarabine, and granulocyte colony-stimulating factor (G-CSF). Autologous or allogeneic hematopoietic stem-cell transplantation was offered as consolidation therapy. Primary end point was the rate of complete remissions (CRs) after the first cycle of Mito-FLAG. RESULTS: The CR rates after Mito-FLAG (B) and Mito-FLAG (CI) were 54% and 43%, respectively (P = 0.1). There was no statistical difference between rates of grade 3/4 neutropenia, thrombocytopenia, mucositis, renal, and liver toxicity. More infections occurred, however, after Mito-FLAG (B) compared with Mito-FLAG (CI) (80% versus 69%, P = 0.01). The early death rate by day 42 was 13% in both arms. Median disease-free survival was comparable in the two arms (7.8 versus 7.1 months, P = 0.53) as was overall survival (7.1 versus 6.6 months, P = 0.53). CONCLUSION: A 5-day course of Ara-C 2 * 1000 mg/m(2) administered as bolus versus Ara-C 150 mg/m(2) administered by CI (in combination with mitoxantrone, fludarabine, and G-CSF), resulted in a nonsignificant trend in response rates in favor of Mito-FLAG (B) at the selected dose levels, but no differences in the survival outcome in relapsed or refractory AML. CLINICAL TRIAL NUMBER: LN_NN_2004_39/EudraCT number 2014-000083-18. PMID- 25922063 TI - Biomarker testing and time to treatment decision in patients with advanced nonsmall-cell lung cancer. AB - BACKGROUND: Testing for EGFR mutations and ALK rearrangement has become standard in managing advanced nonsmall-cell lung cancer (NSCLC). However, many institutions in Europe, North America and other world regions continue to face a common challenge of facilitating timely molecular testing with rapid result turnaround time. We assessed the prevalence of biomarker testing for advanced NSCLC patients and whether testing affected the timeliness of treatment decisions. METHODS: We conducted a retrospective chart review of a random sample of one-quarter of all patients with advanced NSCLC referred to the Princess Margaret Cancer Centre from 1 April 2010 to 31 March 2013. RESULTS: Of 300 patients reviewed, 175 seen by medical oncology had nonsquamous NSCLC, 72% of whom had biomarker testing carried out. Patients tested for biomarkers were more likely to be female (47% versus 21%, P = 0.002), Asian (27% versus 6%, P = 0.005) and never smokers (42% versus 8%, P < 0.0001). Only 21% of patients with biomarker testing had results available at their initial oncology consultation. This group had a shorter median time from consultation to treatment decision (0 versus 22 days, P = 0.0008) and time to treatment start (16 versus 29, P = 0.004). Thirteen percent underwent repeat biopsy for molecular testing after the initial consultation. Of those with positive EGFR or ALK results, 19% started chemotherapy before biomarker results became available. CONCLUSIONS: Awaiting biomarker testing results can delay treatment decisions and treatment initiation for patients with advanced NSCLC. This may be avoided by incorporating reflex biomarker testing into diagnostic algorithms for NSCLC at the level of the pathologist, and further education of specialists involved in obtaining diagnostic cancer specimens to ensure they are sufficient for molecular testing. PMID- 25922064 TI - Implementation of supportive care and best supportive care interventions in clinical trials enrolling patients with cancer?. AB - BACKGROUND: With the growing and evolving role of palliative care in oncology, we examined how supportive care (SC) and best supportive care (BSC) are implemented in clinical trials when used as a comparison treatment arm. METHODS: We conducted a systematic review of the literature for clinical trials published between 1980 and 2012 in which systemic anticancer therapy was compared with an SC-only arm and compared SC implementation with World Health Organization (WHO) published guidelines. RESULTS: Our search identified 189 articles, 73 of which met our inclusion criteria with the following cancer types: 29 lung, 7 colorectal, 6 pancreatic, 5 gastric and 26 others. Fifty-five studies (75%) provided some definition of SC, and 48 studies (66%) used the term BSC. Twenty-one of the 55 studies that provided a definition described the use of palliative therapies as being 'at the discretion of the treating physician' without standardization. Only two studies provided SC that incorporated routine physical, psychological and social assessments including rapid referral to SC specialists. SC interventions most commonly included analgesics (47%) and radiotherapy (44%). Trials using the term BSC versus SC were more likely to include blood transfusions (P = 0.002) and antibiotics (P = 0.033), but less likely to include steroids (P = 0.05) and palliative specialists (P = 0.047). CONCLUSIONS: The implementation of SC in clinical trials in this systematic review is highly variable. The vast majority of the studies did not meet the WHO guidelines on SC because palliative care therapies were not recommended or integrated into care. Future clinical trials utilizing a SC intervention arm should define these interventions in a standardized approach that meets current guidelines such as the WHO recommendations. PMID- 25922066 TI - Combining immunotherapy and anticancer agents: the right path to achieve cancer cure? AB - Recent clinical trials revealed the impressive efficacy of immunological checkpoint blockade in different types of metastatic cancers. Such data underscore that immunotherapy is one of the most promising strategies for cancer treatment. In addition, preclinical studies provide evidence that some cytotoxic drugs have the ability to stimulate the immune system, resulting in anti-tumor immune responses that contribute to clinical efficacy of these agents. These observations raise the hypothesis that the next step for cancer treatment is the combination of cytotoxic agents and immunotherapies. The present review aims to summarize the immune-mediated effects of chemotherapeutic agents and their clinical relevance, the biological and clinical features of immune checkpoint blockers and finally, the preclinical and clinical rationale for novel therapeutic strategies combining anticancer agents and immune checkpoint blockers. PMID- 25922065 TI - Different effects of the BIM deletion polymorphism on treatment of solid tumors by the tyrosine kinase inhibitors (TKI) pazopanib, sunitinib, and lapatinib. PMID- 25922067 TI - Mapping the Interaction of B Cell Leukemia 3 (BCL-3) and Nuclear Factor kappaB (NF-kappaB) p50 Identifies a BCL-3-mimetic Anti-inflammatory Peptide. AB - The NF-kappaB transcriptional response is tightly regulated by a number of processes including the phosphorylation, ubiquitination, and subsequent proteasomal degradation of NF-kappaB subunits. The IkappaB family protein BCL-3 stabilizes a NF-kappaB p50 homodimer.DNA complex through inhibition of p50 ubiquitination. This complex inhibits the binding of the transcriptionally active NF-kappaB subunits p65 and c-Rel on the promoters of NF-kappaB target genes and functions to suppress inflammatory gene expression. We have previously shown that the direct interaction between p50 and BCL-3 is required for BCL-3-mediated inhibition of pro-inflammatory gene expression. In this study we have used immobilized peptide array technology to define regions of BCl-3 that mediate interaction with p50 homodimers. Our data show that BCL-3 makes extensive contacts with p50 homodimers and in particular with ankyrin repeats (ANK) 1, 6, and 7, and the N-terminal region of Bcl-3. Using these data we have designed a BCL-3 mimetic peptide based on a region of the ANK1 of BCL-3 that interacts with p50 and shares low sequence similarity with other IkappaB proteins. When fused to a cargo carrying peptide sequence this BCL-3-derived peptide, but not a mutated peptide, inhibited Toll-like receptor-induced cytokine expression in vitro. The BCL-3 mimetic peptide was also effective in preventing inflammation in vivo in the carrageenan-induced paw edema mouse model. This study demonstrates that therapeutic strategies aimed at mimicking the functional activity of BCL-3 may be effective in the treatment of inflammatory disease. PMID- 25922068 TI - p47phox-Nox2-dependent ROS Signaling Inhibits Early Bone Development in Mice but Protects against Skeletal Aging. AB - Bone remodeling is age-dependently regulated and changes dramatically during the course of development. Progressive accumulation of reactive oxygen species (ROS) has been suspected to be the leading cause of many inflammatory and degenerative diseases, as well as an important factor underlying many effects of aging. In contrast, how reduced ROS signaling regulates inflammation and remodeling in bone remains unknown. Here, we utilized a p47(phox) knock-out mouse model, in which an essential cytosolic co-activator of Nox2 is lost, to characterize bone metabolism at 6 weeks and 2 years of age. Compared with their age-matched wild type controls, loss of Nox2 function in p47(phox-/-) mice resulted in age-related switch of bone mass and strength. Differences in bone mass were associated with increased bone formation in 6-week-old p47(phox-/-) mice but decreased in 2-year old p47(phox-/-) mice. Despite decreases in ROS generation in bone marrow cells and p47(phox)-Nox2 signaling in osteoblastic cells, 2-year-old p47(phox-/-) mice showed increased senescence-associated secretory phenotype in bone compared with their wild type controls. These in vivo findings were mechanistically recapitulated in ex vivo cell culture of primary fetal calvarial cells from p47(phox-/-) mice. These cells showed accelerated cell senescence pathway accompanied by increased inflammation. These data indicate that the observed age related switch of bone mass in p47(phox)-deficient mice occurs through an increased inflammatory milieu in bone and that p47(phox)-Nox2-dependent physiological ROS signaling suppresses inflammation in aging. PMID- 25922069 TI - Low Affinity and Slow Na+ Binding Precedes High Affinity Aspartate Binding in the Secondary-active Transporter GltPh. AB - GltPh from Pyrococcus horikoshii is a homotrimeric Na(+)-coupled aspartate transporter. It belongs to the widespread family of glutamate transporters, which also includes the mammalian excitatory amino acid transporters that take up the neurotransmitter glutamate. Each protomer in GltPh consists of a trimerization domain involved in subunit interactions and a transport domain containing the substrate binding site. Here, we have studied the dynamics of Na(+) and aspartate binding to GltPh. Tryptophan fluorescence measurements on the fully active single tryptophan mutant F273W revealed that Na(+) binds with low affinity to the apoprotein (Kd 120 mm), with a particularly low kon value (5.1 m(-1)s(-1)). At least two sodium ions bind before aspartate. The binding of Na(+) requires a very high activation energy (Ea 106.8 kJ mol(-1)) and consequently has a large Q10 value of 4.5, indicative of substantial conformational changes before or after the initial binding event. The apparent affinity for aspartate binding depended on the Na(+) concentration present. Binding of aspartate was not observed in the absence of Na(+), whereas in the presence of high Na(+) concentrations (above the Kd for Na(+)) the dissociation constants for aspartate were in the nanomolar range, and the aspartate binding was fast (kon of 1.4 * 10(5) m(-1)s(-1)), with low Ea and Q10 values (42.6 kJ mol(-1) and 1.8, respectively). We conclude that Na(+) binding is most likely the rate-limiting step for substrate binding. PMID- 25922070 TI - Critical Roles of Two Hydrophobic Residues within Human Glucose Transporter 9 (hSLC2A9) in Substrate Selectivity and Urate Transport. AB - High blood urate levels (hyperuricemia) have been found to be a significant risk factor for cardiovascular diseases and inflammatory arthritis, such as hypertension and gout. Human glucose transporter 9 (hSLC2A9) is an essential protein that mainly regulates urate/hexose homeostasis in human kidney and liver. hSLC2A9 is a high affinity-low capacity hexose transporter and a high capacity urate transporter. Our previous studies identified a single hydrophobic residue in trans-membrane domain 7 of class II glucose transporters as a determinant of fructose transport. A mutation of isoleucine 335 to valine (I355V) in hSLC2A9 can reduce fructose transport while not affecting glucose fluxes. This current study demonstrates that the I335V mutant transports urate similarly to the wild type hSLC2A9; however, Ile-335 is necessary for urate/fructose trans-acceleration exchange to occur. Furthermore, Trp-110 is a critical site for urate transport. Two structural models of the class II glucose transporters, hSLC2A9 and hSLC2A5, based on the crystal structure of hSLC2A1 (GLUT1), reveal that Ile-335 (or the homologous Ile-296 in hSLC2A5) is a key component for protein conformational changes when the protein translocates substrates. The hSLC2A9 model also predicted that Trp-110 is a crucial site that could directly interact with urate during transport. Together, these studies confirm that hSLC2A9 transports both urate and fructose, but it interacts with them in different ways. Therefore, this study advances our understanding of how hSLC2A9 mediates urate and fructose transport, providing further information for developing pharmacological agents to treat hyperuricemia and related diseases, such as gout, hypertension, and diabetes. PMID- 25922071 TI - Flap Endonuclease 1 Limits Telomere Fragility on the Leading Strand. AB - The existence of redundant replication and repair systems that ensure genome stability underscores the importance of faithful DNA replication. Nowhere is this complexity more evident than in challenging DNA templates, including highly repetitive or transcribed sequences. Here, we demonstrate that flap endonuclease 1 (FEN1), a canonical lagging strand DNA replication protein, is required for normal, complete leading strand replication at telomeres. We find that the loss of FEN1 nuclease activity, but not DNA repair activities, results in leading strand-specific telomere fragility. Furthermore, we show that FEN1 depletion induced telomere fragility is increased by RNA polymerase II inhibition and is rescued by ectopic RNase H1 expression. These data suggest that FEN1 limits leading strand-specific telomere fragility by processing RNA:DNA hybrid/flap intermediates that arise from co-directional collisions occurring between the replisome and RNA polymerase. Our data reveal the first molecular mechanism for leading strand-specific telomere fragility and the first known role for FEN1 in leading strand DNA replication. Because FEN1 mutations have been identified in human cancers, our findings raise the possibility that unresolved RNA:DNA hybrid structures contribute to the genomic instability associated with cancer. PMID- 25922073 TI - Exploitation of the Polymeric Immunoglobulin Receptor for Antibody Targeting to Renal Cyst Lumens in Polycystic Kidney Disease. AB - Autosomal-dominant polycystic kidney disease (ADPKD) is a common life-threatening genetic disease that leads to renal failure. No treatment is available yet to effectively slow disease progression. Renal cyst growth is, at least in part, driven by the presence of growth factors in the lumens of renal cysts, which are enclosed spaces lacking connections to the tubular system. We have shown previously shown that IL13 in cyst fluid leads to aberrant activation of STAT6 via the IL4/13 receptor. Although antagonistic antibodies against many of the growth factors implicated in ADPKD are already available, they are IgG isotype antibodies that are not expected to gain access to renal cyst lumens. Here we demonstrate that targeting antibodies to renal cyst lumens is possible with the use of dimeric IgA (dIgA) antibodies. Using human ADPKD tissues and polycystic kidney disease mouse models, we show that the polymeric immunoglobulin receptor (pIgR) is highly expressed by renal cyst-lining cells. pIgR expression is, in part, driven by aberrant STAT6 pathway activation. pIgR actively transports dIgA from the circulation across the cyst epithelium and releases it into the cyst lumen as secretory IgA. dIgA administered by intraperitoneal injection is preferentially targeted to polycystic kidneys whereas injected IgG is not. Our results suggest that pIgR-mediated transcytosis of antagonistic antibodies in dIgA format can be exploited for targeted therapy in ADPKD. PMID- 25922072 TI - Gastrin-stimulated Galpha13 Activation of Rgnef Protein (ArhGEF28) in DLD-1 Colon Carcinoma Cells. AB - The guanine nucleotide exchange factor Rgnef (also known as ArhGEF28 or p190RhoGEF) promotes colon carcinoma cell motility and tumor progression via interaction with focal adhesion kinase (FAK). Mechanisms of Rgnef activation downstream of integrin or G protein-coupled receptors remain undefined. In the absence of a recognized G protein signaling homology domain in Rgnef, no proximal linkage to G proteins was known. Utilizing multiple methods, we have identified Rgnef as a new effector for Galpha13 downstream of gastrin and the type 2 cholecystokinin receptor. In DLD-1 colon carcinoma cells depleted of Galpha13, gastrin-induced FAK Tyr(P)-397 and paxillin Tyr(P)-31 phosphorylation were reduced. RhoA GTP binding and promoter activity were increased by Rgnef in combination with active Galpha13. Rgnef co-immunoprecipitated with activated Galpha13Q226L but not Galpha12Q229L. The Rgnef C-terminal (CT, 1279-1582) region was sufficient for co-immunoprecipitation, and Rgnef-CT exogenous expression prevented Galpha13-stimulated SRE activity. A domain at the C terminus of the protein close to the FAK binding domain is necessary to bind to Galpha13. Point mutations of Rgnef-CT residues disrupt association with active Galpha13 but not Galphaq. These results show that Rgnef functions as an effector of Galpha13 signaling and that this linkage may mediate FAK activation in DLD-1 colon carcinoma cells. PMID- 25922074 TI - Estrogen Sulfotransferase Is an Oxidative Stress-responsive Gene That Gender specifically Affects Liver Ischemia/Reperfusion Injury. AB - Estrogen sulfotransferase (EST) regulates estrogen homeostasis by sulfonating and deactivating estrogens. Liver ischemia and reperfusion (I/R) involves both hypoxia during the ischemic phase and oxidative damage during the reperfusion phase. In this report, we showed that the expression of EST was markedly induced by I/R. Mechanistically, oxidative stress-induced activation of Nrf2 was responsible for the EST induction, which was abolished in Nrf2(-/-) mice. EST is a direct transcriptional target of Nrf2. In female mice, the I/R-responsive induction of EST compromised estrogen activity. EST ablation attenuated I/R injury as a result of decreased estrogen deprivation, whereas this benefit was abolished upon ovariectomy. The effect of EST ablation was sex-specific because the EST(-/-) males showed heightened I/R injury. Reciprocally, both estrogens and EST regulate the expression and activity of Nrf2. Estrogen deprivation by ovariectomy abolished the I/R-responsive Nrf2 accumulation, whereas the compromised estrogen deprivation in EST(-/-) mice was associated with increased Nrf2 accumulation. Our results suggested a novel I/R-responsive feedback mechanism to limit the activity of Nrf2 in which Nrf2 induces the expression of EST, which subsequently increases estrogen deactivation and limits the estrogen responsive activation of Nrf2. Inhibition of EST, at least in females, may represent an effective approach to manage hepatic I/R injury. PMID- 25922075 TI - Extended Synaptotagmin Interaction with the Fibroblast Growth Factor Receptor Depends on Receptor Conformation, Not Catalytic Activity. AB - We previously demonstrated that ESyt2 interacts specifically with the activated FGF receptor and is required for a rapid phase of receptor internalization and for functional signaling via the ERK pathway in early Xenopus embryos. ESyt2 is one of the three-member family of Extended Synaptotagmins that were recently shown to be implicated in the formation of endoplasmic reticulum (ER)-plasma membrane (PM) junctions and in the Ca(2+) dependent regulation of these junctions. Here we show that ESyt2 is directed to the ER by its putative transmembrane domain, that the ESyts hetero- and homodimerize, and that ESyt2 homodimerization in vivo requires a TM adjacent sequence but not the SMP domain. ESyt2 and ESyt3, but not ESyt1, selectively interact in vivo with activated FGFR1. In the case of ESyt2, this interaction requires a short TM adjacent sequence and is independent of receptor autophosphorylation, but dependent on receptor conformation. The data show that ESyt2 recognizes a site in the upper kinase lobe of FGFR1 that is revealed by displacement of the kinase domain activation loop during receptor activation. PMID- 25922076 TI - Expression of a Catalytically Inactive Mutant Form of Glutathione Peroxidase 4 (Gpx4) Confers a Dominant-negative Effect in Male Fertility. AB - The selenoenzyme Gpx4 is essential for early embryogenesis and cell viability for its unique function to prevent phospholipid oxidation. Recently, the cytosolic form of Gpx4 was identified as an upstream regulator of a novel form of non apoptotic cell death, called ferroptosis, whereas the mitochondrial isoform of Gpx4 was previously shown to be crucial for male fertility. Here, we generated and analyzed mice with a targeted mutation of the active site selenocysteine of Gpx4 (Gpx4_U46S). Mice homozygous for Gpx4_U46S died at the same embryonic stage (E7.5) as Gpx4(-/-) embryos as expected. Surprisingly, male mice heterozygous for Gpx4_U46S presented subfertility. Subfertility was manifested in a reduced number of litters from heterozygous breeding and an impairment of spermatozoa to fertilize oocytes in vitro. Morphologically, sperm isolated from heterozygous Gpx4_U46S mice revealed many structural abnormalities particularly in the spermatozoa midpiece due to improper oxidation and polymerization of sperm capsular proteins and malformation of the mitochondrial capsule surrounding and stabilizing sperm mitochondria. These findings are reminiscent of sperm isolated from selenium-deprived rodents or from mice specifically lacking mitochondrial Gpx4. Due to a strongly facilitated incorporation of Ser in the polypeptide chain as compared with selenocysteine at the UGA codon, expression of the catalytically inactive Gpx4_U46S was found to be strongly increased. Because the stability of the mitochondrial capsule of mature spermatozoa depends on the moonlighting function of Gpx4 both as an enzyme oxidizing capsular protein thiols and as a structural protein, tightly controlled expression of functional Gpx4 emerges as a key for full male fertility. PMID- 25922077 TI - Heparan Sulfate Proteoglycans Are Important for Islet Amyloid Formation and Islet Amyloid Polypeptide-induced Apoptosis. AB - Deposition of beta cell toxic islet amyloid is a cardinal finding in type 2 diabetes. In addition to the main amyloid component islet amyloid polypeptide (IAPP), heparan sulfate proteoglycan is constantly present in the amyloid deposit. Heparan sulfate (HS) side chains bind to IAPP, inducing conformational changes of the IAPP structure and an acceleration of fibril formation. We generated a double-transgenic mouse strain (hpa-hIAPP) that overexpresses human heparanase and human IAPP but is deficient of endogenous mouse IAPP. Culture of hpa-hIAPP islets in 20 mm glucose resulted in less amyloid formation compared with the amyloid load developed in cultured islets isolated from littermates expressing human IAPP only. A similar reduction of amyloid was achieved when human islets were cultured in the presence of heparin fragments. Furthermore, we used CHO cells and the mutant CHO pgsD-677 cell line (deficient in HS synthesis) to explore the effect of cellular HS on IAPP-induced cytotoxicity. Seeding of IAPP aggregation on CHO cells resulted in caspase-3 activation and apoptosis that could be prevented by inhibition of caspase-8. No IAPP-induced apoptosis was seen in HS-deficient CHO pgsD-677 cells. These results suggest that beta cell death caused by extracellular IAPP requires membrane-bound HS. The interaction between HS and IAPP or the subsequent effects represent a possible therapeutic target whose blockage can lead to a prolonged survival of beta cells. PMID- 25922078 TI - The Lipid Droplet Protein Hypoxia-inducible Gene 2 Promotes Hepatic Triglyceride Deposition by Inhibiting Lipolysis. AB - The liver is a major site of glucose, fatty acid, and triglyceride (TG) synthesis and serves as a major regulator of whole body nutrient homeostasis. Chronic exposure of humans or rodents to high-calorie diets promotes non-alcoholic fatty liver disease, characterized by neutral lipid accumulation in lipid droplets (LD) of hepatocytes. Here we show that the LD protein hypoxia-inducible gene 2 (Hig2/Hilpda) functions to enhance lipid accumulation in hepatocytes by attenuating TG hydrolysis. Hig2 expression increased in livers of mice on a high fat diet and during fasting, two states associated with enhanced hepatic TG content. Hig2 expressed in primary mouse hepatocytes localized to LDs and promoted LD TG deposition in the presence of oleate. Conversely, tamoxifen inducible Hig2 deletion reduced both TG content and LD size in primary hepatocytes from mice harboring floxed alleles of Hig2 and a cre/ERT2 transgene controlled by the ubiquitin C promoter. Hepatic TG was also decreased by liver specific deletion of Hig2 in mice with floxed Hig2 expressing cre controlled by the albumin promoter. Importantly, we demonstrate that Hig2-deficient hepatocytes exhibit increased TG lipolysis, TG turnover, and fatty acid oxidation as compared with controls. Interestingly, mice with liver-specific Hig2 deletion also display improved glucose tolerance. Taken together, these data indicate that Hig2 plays a major role in promoting lipid sequestration within LDs in mouse hepatocytes through a mechanism that impairs TG degradation. PMID- 25922080 TI - Advances in the neurological and neurosurgical management of peripheral nerve trauma. AB - Peripheral nerve trauma frequently affects younger people and may result in significant and long-lasting functional disability. Currently, diagnosis and monitoring of peripheral nerve injury relies on clinical and electrodiagnostic information, supplemented by intraoperative electrophysiological studies. However, in a significant proportion of nerve injuries, the likelihood of spontaneous regeneration resulting in good functional outcome remains uncertain and unnecessary delays to treatment may be faced while monitoring for recovery. Advances in non-invasive imaging techniques to diagnose and monitor nerve injury and regeneration are being developed, and have the potential to streamline the decision-making process. In addition, advances in operative and non-operative treatment strategies may provide more effective ways to maximise functional outcomes following severe peripheral nerve trauma. This review discusses these advances in light of the current state of the art of management of peripheral nerve trauma. PMID- 25922079 TI - Regulation of Adipose Tissue Inflammation and Insulin Resistance by MAPK Phosphatase 5. AB - Obesity and metabolic disorders such as insulin resistance and type 2 diabetes have become a major threat to public health globally. The mechanisms that lead to insulin resistance in type 2 diabetes have not been well understood. In this study, we show that mice deficient in MAPK phosphatase 5 (MKP5) develop insulin resistance spontaneously at an early stage of life and glucose intolerance at a later age. Increased macrophage infiltration in white adipose tissue of young MKP5-deficient mice correlates with the development of insulin resistance. Glucose intolerance in MKP5-deficient mice is accompanied by significantly increased visceral adipose weight, reduced AKT activation, enhanced p38 activity, and increased inflammation in visceral adipose tissue when compared with wild type (WT) mice. Deficiency of MKP5 resulted in increased inflammatory activation in macrophages. These findings thus demonstrate that MKP5 critically controls inflammation in white adipose tissue and the development of metabolic disorders. PMID- 25922081 TI - Neurological picture. FDG-PET findings in three cases of Mills' syndrome. PMID- 25922082 TI - Actions of Adjunctive Nutritional Antioxidants in Periodontitis and Prevalent Systemic Inflammatory Diseases. AB - Common risk markers for periodontitis and prevalent systemic comorbidities indicate similarities in their progression and molecular mechanisms involved. Resultant pro-oxidant disease profiles provide scope for attenuating their pathogeneses with appropriate adjunctive antioxidants. Levels of oxidative stress markers 8-hydroxy-deoxguanosine (8-HOdG) and malondialdehyde (MDA) are significantly higher in periodontitis and other chronic inflammatory conditions. There is a clear link between periodontitis and diseases associated with significant systemic inflammatory loading, such as metabolic syndrome. Micro- and macro-nutrients have proven to be effective in curbing molecular mechanisms that generate reactive oxygen and nitrogen species. A Mediterranean diet rich in fruits, vegetables, legumes, whole grain, nuts, fish, olive oil and red wine in moderation, could be attributed to the lower occurrence of cardiovascular disease, insulin resistance and other inflammatory diseases in this region. A significant number of naturally occurring flavonoids have been identified in these products. Flavonoids comprising flavonols, flavones and isoflavones are potent free radical scavengers, effective in inhibiting lipid peroxidation, with anti-atherosclerotic and antihypertensive effects.The phenolic compound oleocanthal isolated in virgin olive oil has similar anti-inflammatory actions to that of ibuprofen. The anti-atherogenic effects of MUFA and PUFA in nuts, enhance endothelial function by reducing total cholesterol, oxidized LDL, hs-CRP, sVCAM-1 levels, lipids, lipoproteins and inflammatory markers. Epigenetics influenced by environmental factors and interactions between genes and nutrients, are important considerations in influencing these effects. Using antioxidants as therapeutic adjuncts could enhance the antioxidant capacity of an inherent glutathione system and overcome oxidative effects, thereby mitigating therapeutic side-effects. PMID- 25922083 TI - Validation of self-reported post-treatment mammography surveillance among breast cancer survivors by electronic medical record extraction method. AB - Little is known about validity of self-reported mammography surveillance among breast cancer survivors. Most studies have focused on accuracy among healthy, average-risk populations and none have assessed validity by electronic medical record (EMR) extraction method. To assess validity of survivor-reported mammography post-active treatment care, we surveyed all survivors diagnosed 2004 2009 in an academic hospital cancer registry (n = 1441). We used electronic query and manual review to extract EMR data. Concordance, sensitivity, specificity, positive predictive value, and report-to-records ratio were calculated by comparing survivors' self-reports to data from each extraction method. We also assessed average difference in months between mammography dates by source and correlates of concordance. Agreement between the two EMR extraction methods was high (concordance 0.90; kappa 0.70), with electronic query identifying more mammograms. Sensitivity was excellent (0.99) regardless of extraction method; concordance and positive predictive value were good; however, specificity was poor (manual review 0.20, electronic query 0.31). Report-to-records ratios were both over 1 suggesting over-reporting. We observed slight forward telescoping for survivors reporting mammograms 7-12 months prior to survey date. Higher educational attainment and less time since mammogram receipt were associated with greater concordance. Accuracy of survivors' self-reported mammograms was generally high with slight forward telescoping among those recalling their mammograms between 7 and 12 months prior to the survey date. Results are encouraging for clinicians and practitioners relying on survivor reports for surveillance care delivery and as a screening tool for inclusion in interventions promoting adherence to surveillance guidelines. PMID- 25922084 TI - Exome sequencing of contralateral breast cancer identifies metastatic disease. AB - Women with contralateral breast cancer (CBC) have significantly worse prognosis compared to women with unilateral cancer. A possible explanation of the poor prognosis of patients with CBC is that in a subset of patients, the second cancer is not a new primary tumor but a metastasis of the first cancer that has potentially obtained aggressive characteristics through selection of treatment. Exome and whole-genome sequencing of solid tumors has previously been used to investigate the clonal relationship between primary tumors and metastases in several diseases. In order to assess the relationship between the first and the second cancer, we performed exome sequencing to identify somatic mutations in both first and second cancers, and compared paired normal tissue of 25 patients with metachronous CBC. For three patients, we identified shared somatic mutations indicating a common clonal origin thereby demonstrating that the second tumor is a metastasis of the first cancer, rather than a new primary cancer. Accordingly, these patients all developed distant metastasis within 3 years of the second diagnosis, compared with 7 out of 22 patients with non-shared somatic profiles. Genomic profiling of both tumors help the clinicians distinguish between true CBCs and subsequent metastases. PMID- 25922085 TI - Lyme neuroborreliosis in a patient treated with TNF-alpha inhibitor. AB - A 57-year-old woman, receiving TNF-alpha inhibitor adalimumab for psoriasis, presented with early Lyme neuroborreliosis (Bannwarth's syndrome). Discontinuation of adalimumab and 14-day therapy with ceftriaxone resulted in a smooth course and favorable outcome of Lyme borreliosis. This is the first report on Lyme neuroborreliosis in a patient treated with TNF-alpha inhibitor. PMID- 25922086 TI - A fatal infection caused by sequence type 398 methicillin-resistant Staphylococcus aureus carrying the Panton-Valentine leukocidin gene: A case report in Japan. AB - Methicillin-resistant Staphylococcus aureus (MRSA) has now been recognized as a common pathogen in the community. Sequence type (ST) 398 MRSA is generally considered as an emerging zoonotic agent spreading among livestock and personnel who have direct contact with animals, mainly in Europe. A 37-year-old Chinese woman receiving steroid therapy for systemic lupus erythematosus with general fatigue and myalgia was brought to the emergency department in critical condition. Her condition deteriorated despite aggressive management and she died on day 7. Her blood culture revealed ST398 MRSA-SCCmec V with Panton-Valentine Leukocidin (PVL) gene. This is the first case report of a fatal infection caused by this lineage. According to the results of molecular analyses, the isolate from this particular patient's blood was genetically close to a lineage detected in China, and is less likely to be related to an animal-associated lineage. PMID- 25922087 TI - Unexpected neonatal death caused by interrupted aortic arch, an uncommon congenital great vessel malformation: An autopsy case report. AB - A 21-day-old Japanese male infant became inactive and then collapsed unexpectedly. On autopsy, there was no connection between the ascending and descending thoracic aorta. The site of interruption was the aortic isthmus. The heart showed hypertrophy and exhibited intracardiac malformations, including subaortic valve stenosis resulting from posterior deviation of the ventricular outlet septum and ventricular septal defect. The cause of death was diagnosed as prolonged physiological closure of the ductus arteriosus complicated by interrupted aortic arch and followed by assumed ductal shock. PMID- 25922088 TI - Effects of AT1 receptor antagonism on kainate-induced seizures and concomitant changes in hippocampal extracellular noradrenaline, serotonin, and dopamine levels in Wistar-Kyoto and spontaneously hypertensive rats. AB - In the management of epilepsy, AT1 receptor antagonists have been suggested as an additional treatment strategy. A hyperactive brain angiotensin (Ang) II system and upregulated AT1 receptors are implicated in the cerebrovascular alterations in a genetic form of hypertension. Uncontrolled hypertension could also, in turn, be a risk factor for a seizure threshold decrease and development of epileptogenesis. The present study aimed to assess the effects of the selective AT1 receptor antagonist ZD7155 on kainic acid (KA)-induced status epilepticus (SE) development and accompanying changes in the hippocampal extracellular (EC) neurotransmitter levels of noradrenaline (NAD), serotonin (5-HT), and dopamine (DA) in spontaneously hypertensive rats (SHRs) and their parent strain Wistar Kyoto (WKY) rats, since monoamines are well-known neurotransmitters involved in mechanisms of both epilepsy and hypertension. Status epilepticus was evoked in freely moving rats by a repetitive intraperitoneal (i.p.) administration of KA in subconvulsant doses. In the treatment group, ZD7155 (5mg/kg i.p.) was coadministered with the first KA injection. Spontaneously hypertensive rats exhibited higher susceptibility to SE than WKY rats, but the AT1 receptor antagonist did not alter the development of SE in SHRs or in WKY rats. In vivo microdialysis demonstrated significant KA-induced increases of the hippocampal NAD and DA levels in SHRs and of NAD, 5-HT, and DA in WKY rats. Although SHRs developed more severe seizures while receiving a lower dose of KA compared to WKY rats, AT1 receptor antagonism completely prevented all KA-induced increases of hippocampal monoamine levels in both rat strains without affecting seizure development per se. These results suggest a lack of direct relationship between KA-induced seizure susceptibility and adaptive changes of hippocampal NAD, 5-HT, and DA levels in the effects of ZD7155 in WKY rats and SHRs. PMID- 25922089 TI - Influence of the Component Excipients on the Quality and Functionality of a Transdermal Film Formulation. AB - The influence of formulation variables, i.e., a hydrophilic polymer (Methocel((r)) E15) and a film-forming polymer (Eudragit((r)) RL 100 and Eudragit((r)) RS 100), on the physicochemical and functional properties of a transdermal film formulation was assessed. Several terpenes were initially evaluated for their drug permeation enhancement effects on the transdermal film formulations. D-Limonene was found to be the most efficient permeation enhancer among the tested terpenes. Transdermal film formulations containing granisetron (GRN) as a model drug, D-limonene as a permeation enhancer, and different ratios of a hydrophilic polymer (Methocel((r)) E15) and a film-forming polymer (Eudragit((r)) RL 100 or Eudragit((r)) RS 100) were prepared. The prepared films were evaluated for their physicochemical properties such as weight variation, thickness, tensile strength, folding endurance, elongation (%), flatness, moisture content, moisture uptake, and the drug content uniformity. The films were also evaluated for the in vitro drug release and ex vivo drug permeation. The increasing ratios of Methocel((r)):Eudragit((r)) polymers in the formulation linearly and significantly increased the moisture content, moisture uptake, water vapor transmission rate (WVTR), and the transdermal flux of GRN from the film formulations. Increasing levels of Methocel((r)) in the formulations also increased the rate and extent of the GRN release and the GRN permeation from the prepared films. PMID- 25922090 TI - Renal Toxicities of Targeted Therapies. AB - With the incorporation of targeted therapies in routine cancer therapy, it is imperative that the array of toxicities associated with these agents be well recognized and managed, especially since these toxicities are distinct from those seen with conventional cytotoxic agents. This review will focus on these renal toxicities from commonly used targeted agents. This review discusses the mechanisms of these side effects and management strategies. Anti-vascular endothelial growth factor (VEGF) agents including the monoclonal antibody bevacizumab, aflibercept (VEGF trap), and anti-VEGF receptor (VEGFR) tyrosine kinase inhibitors (TKIs) all cause hypertension, whereas some of them result in proteinuria. Monoclonal antibodies against the human epidermal growth factor receptor (HER) family of receptors, such as cetuximab and panitumumab, cause electrolyte imbalances including hypomagnesemia and hypokalemia due to the direct nephrotoxic effect of the drug on renal tubules. Cetuximab may also result in renal tubular acidosis. The TKIs, imatinib and dasatinib, can result in acute or chronic renal failure. Rituximab, an anti-CD20 monoclonal antibody, can cause acute renal failure following initiation of therapy because of the onset of acute tumor lysis syndrome. Everolimus, a mammalian target of rapamycin (mTOR) inhibitor, can result in proteinuria. Discerning the renal adverse effects resulting from these agents is essential for safe treatment strategies, particularly in those with pre-existing renal disease. PMID- 25922091 TI - Altering the concentration of silica tunes the functional properties of collagen silica composite scaffolds to suit various clinical requirements. AB - The success of a tissue engineering scaffold depends on a fine balance being achieved between the physicochemical and biological properties. This study attempts to understand the influence of silica concentration on the functional properties of collagen-silica (CS) composite scaffolds for soft tissue engineering applications. Increasing the ratio of silica to collagen (0.25, 0.5, 0.75, 1.0, 1.25, 1.5 and 2.0 w/w) gave a marked advantage in terms of improving the water uptake and compressive modulus of the CS scaffolds, while also enhancing the biological stability and the turnover time. With increase in silica concentration the water uptake and compressive modulus increased concurrently, whereas it was not so for surface porous architecture and biocompatibility which are crucial for cell adhesion and infiltration. Silica:collagen ratio of <=1 exhibits favourable surface biocompatibility, and any further increase in silica concentration has a detrimental effect. PMID- 25922092 TI - Structure-mechanics relationships in mineralized tendons. AB - In this paper, we review the hierarchical structure and the resulting elastic properties of mineralized tendons as obtained by various multiscale experimental and computational methods spanning from nano- to macroscale. The mechanical properties of mineralized collagen fibres are important to understand the mechanics of hard tissues constituted by complex arrangements of these fibres, like in human lamellar bone. The uniaxial mineralized collagen fibre array naturally occurring in avian tendons is a well studied model tissue for investigating various stages of tissue mineralization and the corresponding elastic properties. Some avian tendons mineralize with maturation, which results in a graded structure containing two zones of distinct morphology, circumferential and interstitial. These zones exhibit different amounts of mineral, collagen, pores and a different mineral distribution between collagen fibrillar and extrafibrillar space that lead to distinct elastic properties. Mineralized tendon cells have two phenotypes: elongated tenocytes placed between fibres in the circumferential zone and cuboidal cells with lower aspect ratios in the interstitial zone. Interestingly some regions of avian tendons seem to be predestined to mineralization, which is exhibited as specific collagen cross linking patterns as well as distribution of minor tendon constituents (like proteoglycans) and loss of collagen crimp. Results of investigations in naturally mineralizing avian tendons may be useful in understanding the pathological mineralization occurring in some human tendons. PMID- 25922094 TI - Implementation of the partograph in India's JSY cash transfer programme for facility births: a mixed methods study in Madhya Pradesh province. AB - OBJECTIVES: To study implementation of partograph use to monitor labour in facilities providing the JSY (Janani Suraksha Yojana) cash transfer programme for facility births in India by determining (1) adherence to partograph use, (2) staff abilities at partograph use and (3) staff responsiveness to the policy on partograph use. DESIGN: A mixed methods study using Carroll's framework for implementation fidelity. Methods include (1) obstetric case record review, (2) a vignette-based survey among nurse midwives and (3) interviews with staff. SETTING: Routine use of the partograph is recommended to monitor progress of labour in most low-and middle-income countries (LMICs), including India, although currently available evidence in this regard is insufficient. This study was conducted in the context of the highly successful JSY programme in three districts of Madhya Pradesh province. PARTICIPANTS: 73 different level JSY programme facilities participated in the record review, 233 nurse midwives at these facilities participated in the vignette survey and a total of 11 doctors and midwives participated in the interviews. RESULTS: The partograph was used in 6% of the 1466 records reviewed. The staff obtained a median score of 1.08 (maximum of 10) at competence in plotting a partograph. Three themes emerged from the qualitative data: (1) partographs are used rarely and retrospectively; (2) training does not support correct use of the partograph; and (3) partographs can be useful but are not feasible. CONCLUSIONS: Implementation fidelity of partograph use in the JSY programme is low. Successful implementation of the partograph can result in improved quality of care in the JSY programme only if potential moderators to its adherence, such as training, supervision, staff 'buy in' and practice environment are addressed so that staff find a conducive practice environment in which to use the partograph and women find it beneficial to present early in labour. PMID- 25922095 TI - Quality improvement and person-centredness: a participatory mixed methods study to develop the 'always event' concept for primary care. AB - OBJECTIVES: (1) To ascertain from patients what really matters to them on a personal level of such high importance that it should 'always happen' when they interact with healthcare professionals and staff groups. (2) To critically review existing criteria for selecting 'always events' (AEs) and generate a candidate list of AE examples based on the patient feedback data. DESIGN: Mixed methods study informed by participatory design principles. SUBJECTS AND SETTING: Convenience samples of patients with a long-term clinical condition in Scottish general practices. RESULTS: 195 patients from 13 general practices were interviewed (n=65) or completed questionnaires (n=130). 4 themes of high importance to patients were identified from which examples of potential 'AEs' (n=8) were generated: (1) emotional support, respect and kindness (eg, "I want all practice team members to show genuine concern for me at all times"); (2) clinical care management (eg, "I want the correct treatment for my problem"); (3) communication and information (eg, "I want the clinician who sees me to know my medical history") and (4) access to, and continuity of, healthcare (eg, "I want to arrange appointments around my family and work commitments"). Each 'AE' was linked to a system process or professional behaviour that could be measured to facilitate improvements in the quality of patient care. CONCLUSIONS: This study is the first known attempt to develop the AE concept as a person-centred approach to quality improvement in primary care. Practice managers were able to collect data from patients on what they 'always want' in terms of expectations related to care quality from which a list of AE examples was generated that could potentially be used as patient-driven quality improvement (QI) measures. There is strong implementation potential in the Scottish health service. However, further evaluation of the utility of the method is also necessary. PMID- 25922096 TI - Risk factors for HIV and syphilis infection among male sex workers who have sex with men: a cross-sectional study in Hangzhou, China, 2011. AB - OBJECTIVE: To investigate the prevalence and risk factors of HIV and syphilis infection among men who have sex with men (MSM) in male sex workers (MSW). DESIGN: Cross-sectional survey. SETTING: Hangzhou, China. PARTICIPANTS: 259 MSW in MSM were recruited by respondent-driven sampling from May 2011 to December 2011.The inclusion criteria were: (1) age >=18 years; (2) engaging in sex with men in the previous year and (3) willing to cooperate in the implementation of the study. OUTCOME MEASURES: HIV-related knowledge, high-risk behaviour and condom use. RESULTS: Among these MSW in MSM, 23.2% were infected with HIV and/or syphilis, 8.9% were infected only with HIV, 12.7% only with syphilis and 1.5% with HIV/syphilis co-infection; 96.6% sold sex to males, 8.9% bought sex from males and 15.4% sold sex to females; 49.0% had non-commercial sex behaviours with males and 24.3% with females. The rate of condom use while having commercial sex with clients was 86.9% and 53.3% (selling anal and oral sex to males, respectively), 95.5% (buying sex from males) and 77.5% (selling sex to females), respectively. Regarding their non-commercial sex behaviour, the rate of condom use was 77.2% (with males) and 49.2% (with females), respectively. Multivariate analysis showed that age >30 years (OR 1.055; 95% CIs 1.015 to 1.095) and having >=10 non-commercial male sex partners (OR, 1.573; 95% CI 1.018 to 2.452) were significantly associated with HIV/syphilis infection, while heterosexuality (OR, 0.238; 95% CI 0.066 to 0.855) was significantly associated with a low HIV/syphilis infection rate. CONCLUSIONS: The MSW in MSM population in Hangzhou has a high prevalence of HIV/syphilis infection, poor perceived risks of HIV and more engagement in unsafe sex with its clients and partners, in addition to a low rate of condom use. These risk factors may account for their relatively high infection rate of HIV/syphilis. PMID- 25922097 TI - Short-term outcomes and mortality after interhospital intensive care transportation: an observational prospective cohort study of 368 consecutive transports with a mobile intensive care unit. AB - OBJECTIVES: To evaluate short-term outcomes and mortality after interhospital transportation of intensive care patients performed by a mobile intensive care unit (MICU). SETTING: This study was performed in the tertiary care process of interhospital transportation using the local MICU system in the South East of the Netherlands. PARTICIPANTS: Between March 2009 and December 2011, all transports of adult patients being performed by the local MICU centre have been documented; data on 42 variables, including a 24 h follow-up Sequential Organ Failure Assessment (SOFA) score of 368 consecutive interhospital transports of intensive care patients, were recorded. In 24 cases, the follow-up SOFA score was missing, so 344 data sets were included. INTERVENTIONS: No interventions have been done. PRIMARY/SECONDARY OUTCOME MEASURES: Primary outcome measures were the mean SOFA score before and 24 h after transport, and the 24 h post-transport mortality. Moreover, the differences between the groups of 24 h post-transport survivors and non-survivors have been analysed. RESULTS: The mean SOFA score before transport was 8.8 for the whole population and 8.6 for those patients who were alive 24 h after transport, with a mean SOFA score of 8.4 after transport. The adverse events rate was 6.4%. Fourteen patients (4.1%) died within 24 h after transport. Patients in this group had a higher SOFA score, lower pH, higher age and more additional medical support devices than those patients in the survivor group. CONCLUSIONS: The non-significant decrease in the post-transport SOFA score and the lack of an association between transport and 24 h post-transport mortality indicates that in the study setting, interhospital transportation of intensive care patients performed by a MICU system was not associated with a clinically relevant deterioration of the patient. PMID- 25922098 TI - Recall of physical activity advice was associated with higher levels of physical activity in colorectal cancer patients. AB - OBJECTIVES: The present study tested the hypothesis that recall of receiving physical activity (PA) advice would be associated with higher levels of PA in patients with a diagnosis of colorectal cancer (CRC). SETTING: Colorectal cancer patients who were diagnosed in 2010 or 2011, and had been treated in the English National Health Service (NHS). PARTICIPANTS: 17,753 respondents completed at least one section of the survey relevant to the current study and after exclusion of 171 with dementia (since results relied on recall), 15,254 had complete data for the current study. 60% were male, 67% were >65 years and 96% were from a white ethnic group. PRIMARY AND SECONDARY OUTCOME MEASURES: Patients completed the 'Living with and Beyond Colorectal Cancer' Patient-Reported Outcome Measures (PROMS) survey in 2013. The survey included questions on receiving exercise advice/information ('PA advice'), and the frequency of currently doing at least 30 min of brisk PA per day ('PA level': 0, 1-4 or 5-7 days, within the past week; with the top category meeting UK guidelines). RESULTS: A third of respondents (31%) recalled receiving PA advice. Independent of demographics and treatment, patients who recalled having PA advice were more likely to be currently doing some brisk PA (51% in the advice group vs 42% in the no advice group; OR 1.74, 95% CI 1.60 to 1.90; p<0.001), and more likely to be meeting PA guidelines (25% vs 20%; OR 1.70, CI 1.54 to 1.88; p<0.001). CONCLUSIONS: Recalling being given PA advice after a diagnosis of CRC was associated with higher levels of PA. However, less than a third of patients recalled receiving advice. Future research should examine the context in which advice is given and randomised trials are required. However, encouraging clinicians working with patients with CRC to give brief PA advice is warranted and may help improve outcomes for CRC survivors. PMID- 25922099 TI - Does quality of life improve in octogenarians following cardiac surgery? A systematic review. AB - OBJECTIVES: Current outcome measures in cardiac surgery are largely described in terms of mortality. Given the changing demographic profiles and increasingly aged populations referred for cardiac surgery this may not be the most appropriate measure. Postoperative quality of life is an outcome of importance to all ages, but perhaps particularly so for those whose absolute life expectancy is limited by virtue of age. We undertook a systematic review of the literature to clarify and summarise the existing evidence regarding postoperative quality of life of older people following cardiac surgery. For the purpose of this review we defined our population as people aged 80 years of age or over. METHODS: A systematic review of MEDLINE, EMBASE, Cochrane Library, trial registers and conference abstracts was undertaken to identify studies addressing quality of life following cardiac surgery in patients 80 or over. RESULTS: Forty-four studies were identified that addressed this topic, of these nine were prospective therefore overall conclusions are drawn from largely retrospective observational studies. No randomised controlled data were identified. CONCLUSIONS: Overall there appears to be an improvement in quality of life in the majority of elderly patients following cardiac surgery, however there was a minority in whom quality of life declined (8-19%). There is an urgent need to validate these data and if correct to develop a robust prediction tool to identify these patients before surgery. Such a tool could guide informed consent, policy development and resource allocation. PMID- 25922100 TI - Public health implications of molecular point-of-care testing for chlamydia and gonorrhoea in remote primary care services in Australia: a qualitative study. AB - OBJECTIVES: With accurate molecular tests now available for diagnosis of chlamydia and gonorrhoea (Chlamydia trachomatis (CT)/Neisseria gonorrhoeae (NG)) at the point-of-care (POC), we aimed to explore the public health implications (benefits and barriers) of their integration into remote primary care in Australia. METHODS: Qualitative interviews were conducted with a purposively selected group of 18 key informants reflecting sexual health, primary care, remote Aboriginal health and laboratory expertise. RESULTS: Participants believed that POC testing may decrease community prevalence of sexually transmitted infections (STIs), and associated morbidity by reducing the time to treatment and infectious period and expediting partner notification. Also, POC testing could improve acceptability of STI testing, increase testing coverage and result in more targeted prescribing, thereby minimising the risk of antibiotic resistance. Conversely, some felt the immediacy of diagnosis could deter certain young people from being tested. Participants also noted that POC testing may reduce the completeness of communicable disease surveillance data given the current dependence on reporting from pathology laboratories. Others expressed concern about the need to maintain and improve the flow of NG antibiotic sensitivity data, already compromised by the shift to nucleic acid-based testing. This is particularly relevant to remote areas where culture viability is problematic. CONCLUSIONS: Results indicate a high level of support from clinicians and public health practitioners for wider access to CT/NG POC tests citing potential benefits, including earlier, more accurate treatment decisions and reductions in ongoing transmission. However, the data also highlight the need for new systems to avoid adverse impact on disease surveillance. TRIAL REGISTRATION NUMBER: Australian and New Zealand Clinical Trials Registry: ACTRN12613000808741. PMID- 25922101 TI - The stability of weight status through the early to middle childhood years in Australia: a longitudinal study. AB - OBJECTIVES: To investigate the sociodemographic and behavioural factors associated with incidence, persistence or remission of obesity in a longitudinal sample of Australian children aged 4-10 years. SETTING: Nationally representative Longitudinal Study of Australian Children (LSAC). PARTICIPANTS: The sample for this analysis included all children in the Kinder cohort (aged 4-5 years at wave 1) who participated in all four waves of LSAC (wave 1, 2004, aged 4-5 years; wave 2, 2006, aged 6-7 years; wave 3, 2008, aged 8-9 years and wave 4, 2010, aged 10 11 years). Of the 4983 children who participated in the baseline (wave 1) survey, 4169 (83.7%) children completed all four waves of data collection. PRIMARY AND SECONDARY OUTCOME MEASURES: Movement of children between weight status categories over time and individual-level predictors of weight status change (sociodemographic characteristics, selected dietary and activity behaviours). RESULTS: The study found tracking of weight status across this period of childhood. There was an inverse association observed between socioeconomic position and persistence of overweight/obesity. Sugar-sweetened beverages and fruit and vegetable intake and screen time appeared to be important predictors of stronger tracking. CONCLUSIONS: Overweight and obesity established early in childhood tracks strongly to the middle childhood years in Australia, particularly among children of lower socioeconomic position and children participating in some unhealthy behaviour patterns. PMID- 25922102 TI - Prognostic utility of serum CRP levels in combination with CURB-65 in patients with clinically suspected sepsis: a decision curve analysis. AB - OBJECTIVES: The prognostic utility of serum C reactive protein (CRP) alone in sepsis is controversial. We used decision curve analysis (DCA) to evaluate the clinical usefulness of combining serum CRP levels with the CUBR-65 score in patients with suspected sepsis. DESIGN: Retrospective cohort study. SETTING: Emergency department (ED) of an urban teaching hospital in Japan. PARTICIPANTS: Consecutive ED patients over 15 years of age who were admitted to the hospital after having a blood culture taken in the ED between 1 January 2010 and 31 December 2012. MAIN OUTCOME MEASURES: 30-day in-hospital mortality. RESULTS: Data from 1262 patients were analysed for score evaluation. The 30-day in-hospital mortality was 8.4%. Multivariable analysis showed that serum CRP >=150 mg/L was an independent predictor of death (adjusted OR 2.0; 95% CI 1.3 to 3.1). We compared the predictive performance of CURB-65 with the performance of a modified CURB-65 with that included CRP (>=150 mg/L) to quantify the clinical usefulness of combining serum CRP with CURB-65. The areas under the receiver operating characteristics curves of CURB-65 and a modified CURB-65 were 0.76 (95% CI 0.72 to 0.80) and 0.77 (95% CI 0.72 to 0.81), respectively. Both models had good calibration for mortality and were useful among threshold probabilities from 0% to 30%. However, while incorporating CRP into CURB-65 yielded a significant category-free net reclassification improvement of 0.387 (95% CI 0.193 to 0.582) and integrated discrimination improvement of 0.015 (95% CI 0.004 to 0.027), DCA showed that CURB-65 and the modified CURB-65 score had comparable net benefits for prediction of mortality. CONCLUSIONS: Measurement of serum CRP added limited clinical usefulness to CURB-65 in predicting mortality in patients with clinically suspected sepsis, regardless of the source. PMID- 25922103 TI - Prevalence of sexually transmitted infections in female clinic attendees in Honiara, Solomon Islands. AB - OBJECTIVES: This study sought to determine the prevalence of common bacterial sexually transmitted infections, including Chlamydia trachomatis and Neisseria gonorrhoeae, in women attending clinics in the Solomon Islands. METHODS: We conducted a sexual health survey among women attending three nurse-led community outpatient clinics in August 2014, to establish the prevalence of bacterial sexually transmitted infections in female clinic attenders in Honiara, Solomon Islands. Vaginal swab samples were tested for infection with C. trachomatis and N. gonorrhoeae using a commercial strand displacement amplification assay. Serum samples were tested for syphilis. RESULTS: We enrolled 296 women, aged 16-49, attending three clinics. Knowledge of safe sexual practices was high but reported condom usage was low. The prevalence of infection with C. trachomatis was 20%. The prevalence of infection with N. gonorrhoeae and syphilis were 5.1% and 4.1%, respectively. CONCLUSIONS: Bacterial sexually transmitted infections are a major health problem in the Solomon Islands. Interventions are urgently needed. PMID- 25922104 TI - Multicentre observational study of adults with asthma exacerbations: who are the frequent users of the emergency department in Japan? AB - OBJECTIVES: Emergency department (ED) visits for asthma exacerbation reflect a failure of longitudinal asthma management. However, little is known about the characteristics of patients with frequent ED visits (>=2 visits in a 1-year period). We aimed to characterise the adult patients who frequently presented to the ED for asthma exacerbation in Japan. DESIGN: A multicentre chart review study of 23 EDs across Japan. PARTICIPANTS: Adults aged 18-54 years who presented to the ED with asthma exacerbation from 2009 to 2011. OUTCOME MEASURES: Frequency of ED visits for asthma exacerbation in a 1-year period, including the index ED visit. RESULTS: Of the 1002 eligible patients, 218 (22%) had frequent ED visits, accounting for 48% of total ED visits for asthma exacerbation in the 1-year period. Specifically, 12% had 2 ED visits and 10% had >=3 visits. In these patients, guideline-recommended chronic management was suboptimal. For example, among patients with >=3 ED visits, only 63% were treated with inhaled corticosteroids and 49% were current smokers. In a multinomial logistic regression model, markers of chronic asthma severity (history of hospitalisation for asthma and use of inhaled corticosteroids) were significantly associated with a higher frequency of ED visits (both p<0.05). CONCLUSIONS: This multicentre study in Japan demonstrated that many patients are frequent ED users for asthma exacerbation. We also found that their asthma control management is suboptimal, most likely contributing to worse chronic severity and more frequent ED visits. Further dissemination and adoption of evidence-based guidelines are required to reduce asthma morbidity in this high-risk population. PMID- 25922105 TI - Acupuncture for treating sciatica: a systematic review protocol. AB - INTRODUCTION: This systematic review aims to assess the effectiveness and safety of acupuncture for treating sciatica. METHODS: The following nine databases will be searched from their inception to 30 October 2014: MEDLINE, EMBASE, the Cochrane Central Register of Controlled Trials (CENTRAL), the Chinese Biomedical Literature Database (CBM), the Chinese Medical Current Content (CMCC), the Chinese Scientific Journal Database (VIP database), the Wan-Fang Database, the China National Knowledge Infrastructure (CNKI) and Citation Information by National Institute of Informatics (CiNii). Randomised controlled trials (RCTs) of acupuncture for sciatica in English, Chinese or Japanese without restriction of publication status will be included. Two researchers will independently undertake study selection, extraction of data and assessment of study quality. Meta analysis will be conducted after screening of studies. Data will be analysed using risk ratio for dichotomous data, and standardised mean difference or weighted mean difference for continuous data. DISSEMINATION: This systematic review will be disseminated electronically through a peer-reviewed publication or conference presentations. TRIAL REGISTRATION NUMBER: PROSPERO CRD42014015001. PMID- 25922106 TI - Identification of stroke during the emergency call: a descriptive study of callers' presentation of stroke. AB - OBJECTIVES: To evaluate symptoms presented by the caller during emergency calls regarding stroke, and to assess if symptoms in the Face-Arm-Speech-Time Test (FAST) are related to identification of stroke. SETTING: Emergency calls to the Emergency Medical Communication Center (EMCC) concerning patients discharged with stroke diagnosis in a large teaching hospital in Stockholm, Sweden, in January June 2011. PARTICIPANTS: The emergency calls of 179 patients who arrived at hospital by ambulance, and who were discharged with a stroke diagnosis and consented to participate were included in the study. OUTCOME MEASURES: Frequencies of stroke symptoms presented and a comparison of symptoms presented in calls with dispatch code stroke or other dispatch code. RESULTS: Of the 179 emergency calls analysed, 64% were dispatched as 'Stroke'. FAST symptoms, that is, facial or arm weakness or speech disturbances, were presented in 64% of the calls and were spontaneously revealed in 90%. Speech disturbance was the most common problem (54%) in all calls, followed by fall/lying position (38%) and altered mental status (27%). For patients with dispatch codes other than stroke, the dominating problem presented was a fall or being in a lying position (66%), followed by speech disturbance (31%) and altered mental status (25%). Stroke specific symptoms were more common in patients dispatched as stroke. FAST symptoms were reported in 80% of patients dispatched as stroke compared with 35% in those dispatched as something else. CONCLUSIONS: This study implicates that fall/lying position and altered mental status could be considered as possible symptoms of stroke during an emergency call. Checking for FAST symptoms in these patients might uncover stroke symptoms. Future studies are needed to evaluate if actively asking for FAST symptoms in emergency calls presenting falls or a lying position can improve the identification of stroke. TRIAL REGISTRATION NUMBER: Stroke2010/703-31/2. PMID- 25922107 TI - Influence of lifestyle on the FAIM2 promoter methylation between obese and lean children: a cohort study. AB - OBJECTIVE: An obesity-related gene, Fas apoptotic inhibitory molecule 2 (FAIM2), is regulated by nutritional state and the methylation levels of the FAIM2 promoter are significantly associated with obesity. Lifestyle factors, such as sedentary behaviour and physical activity, might modify epigenetic patterns that have been related to obesity. Whether the molecular mechanisms by which FAIM2 affects obesity are involved in lifestyle is unclear. This study investigates the potential differences of the FAIM2 promoter methylation with sedentary behaviour and physical activity in obese and lean children. DESIGN: Cohort study. SETTING: Institute of Pediatrics in China. PARTICIPANTS: 59 obese cases and 39 lean controls aged 8-18 years recruited from a cross-sectional survey of children from Beijing in 2013. PRIMARY AND SECONDARY OUTCOME MEASURES: The FAIM2 promoter methylation was quantified using the Sequenom MassARRAY platform. Sedentary behaviour and physical activity were investigated using a questionnaire. The influences of different lifestyles on methylation variations in obese and lean children were examined by multiple linear regression. RESULTS: The methylation levels at seven CpG sites of the FAIM2 promoter were significantly associated with sedentary behaviour, especially the methylation levels at site -975, site 413, sites -362 and -360, and sites -353 and -349 (p=0.00004, 0.00009, 0.0006 and 0.00005, respectively). There were significant differences between the methylation levels at four CpG sites in obese and lean participants with high or moderate physical activity level <150 min/week. CONCLUSIONS: This study provides the first evidence that there are significant differences in the associations of the FAIM2 promoter methylation with sedentary behaviour and physical activity between obese and lean children. Our results suggest that lifestyle may possibly be mediating the process of the FAIM2 involved in obesity. PMID- 25922108 TI - A Comparison of Survival and Recurrence Outcomes in Patients With Endometrial Cancer Undergoing Robotic Versus Open Surgery. AB - OBJECTIVE: To compare recurrence and survival outcomes in women who underwent either robotic or open surgical procedures to treat endometrial cancer. DESIGN: A retrospective chart review (Canadian Tack Force classification II-2). SETTING: A single academic institution. PATIENTS: A total of 936 patients who underwent surgical staging for endometrial cancer between 2001 and 2013. INTERVENTION: Through retrospective chart review, data were collected on patient characteristics, surgical procedures, intraoperative and postoperative complications, histopathology, adjuvant therapies, and recurrence and survival outcomes. Estimated 3-year progression-free survival and 5-year overall survival were calculated using Kaplan-Meier curves. MAIN RESULTS: Of the 936 patients who underwent endometrial cancer surgery, 350 had robotic-assisted surgery and 586 had laparotomy. Both groups were comparable in terms of age, race, body mass index, and comorbid conditions. The laparotomy group had significantly more patients with grade 2-3 tumors, nonendometrioid histology, and stage III-IV disease. In a multivariate analysis, operative type was not an independent prognostic factor for intraoperative complications, but robotic surgery was associated with decreased postoperative complications and readmission rate. Median duration of follow-up was 30 months in the robotic cohort and 42 months in the laparotomy cohort. Estimated 3-year progression-free survival was 90.87% for the robotic group and 78.30% for the laparotomy group, and estimated 5-year overall survival was 89.14%for the robotic group and 79.47% for the laparotomy group. In a multivariate analysis, including stage, grade, histology, operative type, and adjuvant therapy, operative type was not an independent prognostic factor for recurrence or overall survival. CONCLUSION: Compared with laparotomy, robotic staging for endometrial cancer is associated with less postoperative morbidity without compromising short-term recurrence rates or survival outcomes. PMID- 25922109 TI - Spermicidal activity of the hexane extract of Piper longum: an in vitro study. AB - This study was carried out to assess the spermicidal action of hexane extract from the fruits of Piper longum Linn. The sperm immobilisation studies showed that 20 mg/mL of hexane extract was able to immobilise sperms completely within 20 s. The sperm revival test revealed that the effects were spermicidal as sperm immobilisation effect was irreversible. There was also a significant reduction in sperm viability in the treated group in comparison to the control. The hypo osmotic swelling of these sperms was significantly reduced, indicating that the hexane extract may probably cause injury to the sperm plasma membrane. Hence, this study showed that the hexane extract of P. longum possesses potential contraceptive spermicidal activity in vitro. PMID- 25922110 TI - Effectiveness of CT for the detection of glenoid bone graft resorption following reverse shoulder arthroplasty. AB - INTRODUCTION: Glenoid bone grafting is often used in cases of reverse shoulder arthroplasty (RSA) with glenoid deficiency. Additionally, bony increased-offset RSA (BIO-RSA) uses a cylindrical bonegraft harvested from the humeral head and is positioned beneath the glenoid baseplate to increase lateralization. Postoperative computed tomography (CT) has been used to detect glenoid bonegraft resorption, which is typically identified by a gap between the bonegraft and baseplate; however, CT images are often degraded by implant metal artifact. The purpose of this CT imaging study was to determine if a simulated bonegraft resorption gap is detectable following RSA with glenoid bone grafting. HYPOTHESIS: CT is unable to detect bone graft resorption following reverse shoulder arthroplasty conducted with bone grafting beneath the glenoid baseplate. MATERIALS AND METHODS: RSA with glenoid bone grafting was performed on four cadaver shoulders. Glenoid bonegraft resorption gaps were simulated by fixing the implant at six different gap widths (0, 1, 2, 4, 6 and 8mm). Clinical CT scans were acquired for each gap resulting in 6 scans per specimen. Two experienced observers (blinded) analyzed DICOM images in the axial and coronal directions, and measured gap widths using Mimics((r)) software. Each observer had access to approximately 200 images per condition per specimen. RESULTS: The sensitivity of CT imaging to positively identify bonegraft resorption was 38%, with an accuracy of 46%. Inter-observer agreement was 92%. Observers tended to visualize no-gap for most conditions. Resorption gap width measurements were consistently underestimated. DISCUSSION: Metal artifact prevented identification of simulated bonegraft resorption gaps and observers most often determined that there was bonegraft-to-implant "healing" on CT, when in fact a gap was clinically present. This study illustrates the need for more effective imaging techniques to determine if bonegraft resorption has occurred following RSA. PMID- 25922111 TI - A comprehensive assessment of the cross-training effect in ankle dorsiflexors of healthy subjects: A randomized controlled study. AB - PURPOSE: To investigate the cross-training effect, induced on ankle dorsiflexors (AD) by unilateral strength-training of the contralateral muscles, as transfer of peak torque (PT) and muscle work (MW) and their relative contributions to muscle performance. METHODS: Thirty healthy volunteers were randomly assigned to a training or control group. The trained group sustained a 4-week maximal isokinetic training of the stronger AD at 90 and 45 degrees /s. At both angular velocities, PT, MW and MW/PT ratio were measured from both legs at baseline and after intervention (trained group) or no-intervention (controls). The familiarization/learning-effect was calculated and subtracted by PT and MW measures to obtain their net changes. RESULTS: Net PT increased in both legs (untrained: +27.5% at 90 degrees /s and +17.9% at 45 degrees /s; trained: +15% at 90 degrees /s and +16.3% at 45 degrees /s). Similarly, net MW increased in both the untrained (90 degrees /s: +29.6%; 45 degrees /s: +37%) and trained (90 degrees /s: +23.4%; 45 degrees /s: +18.3%) legs. PT and MW gains were larger in the untrained than trained AD (p<0.0005), with MW improving more than PT at 45 degrees /s (p=0.04). The MW/PT ratio increased bilaterally only in the trained group (p<0.05), depending on the angular velocity. CONCLUSIONS: The cross training effect occurred in AD muscles in terms of both PT and MW, with MW adding valuable information to PT-analysis in describing muscle performance. Moreover, the MW/PT ratio allowed estimating the contributions of these parameters to muscle capability and may represent a novel index in isokinetic testing. The greater improvements in the untrained than trained limb raises interesting clinical implications in asymmetric conditions. PMID- 25922112 TI - Is 25(OH)D Associated with Cognitive Impairment and Functional Improvement in Stroke? A Retrospective Clinical Study. AB - BACKGROUND: In recent years, vitamin D deficiency has been suggested as a risk factor for ischemic stroke and stroke severity in both animal models and clinical studies. In this retrospective study, we investigated the relationship between 25 hydroxyvitamin D [25(OH)D] levels and functional outcomes in stroke patients during neurological rehabilitation program. We also investigated whether there is an association between 25(OH)D levels and cognitive impairment. METHODS: The study included the medical records of 120 stroke patients who participated in a neurological rehabilitation program. The motor and cognitive components of the Functional Independence Measurements of all patients at admission and discharge were recorded. The Functional Ambulatory Scale was used to assess motor functional status, and the Turkish-validated version of the minimental state examination test was used to assess cognitive status. RESULTS: A significant correlation was found between 25(OH)D level and cognitive impairment among patients who had ischemic strokes. High levels of 25(OH)D were associated with greater functional gain during the rehabilitation program in both ischemic stroke patients and hemorrhagic stroke patients. CONCLUSIONS: High 25(OH)D levels might be associated with greater functional improvement and with less cognitive impairment in stroke patients. PMID- 25922113 TI - Is prehydration necessary for cesarean delivery in women with Fontan repair under epidural anesthesia? PMID- 25922114 TI - Primary care is not urgent care, and we need more urgent care. PMID- 25922115 TI - Gut colonization by aerobic microorganisms is associated with route and type of nutrition in premature neonates. AB - We hypothesized that the beneficial effects of early enteral compared with parenteral feeding are related to the increased variety of aerobic microorganisms that colonize the gut. Our aim was to describe the relationship, first, between the type of feeding and mucosal colonization and, second, between the type of feeding and the development of late-onset sepsis (LOS) and necrotizing enterocolitis (NEC) in preterm neonates. In total, 159 neonates aged 72 hours or less with risk factors for early-onset sepsis were recruited to a prospective 2 center study. Rectal swabs were collected on admission and twice per week thereafter. The feeding regimen was recorded for the first 7 days and categorized into total parenteral nutrition (TPN) and 2 regimens of enteral nutrition, that is, breast milk containing regimen (BMCR), for which breast milk constituted at least 11% of the enteral diet, or formula. Herein, 70 neonates received formula, 48 received BMCR, and 41 received TPN; 69 cases of LOS and 15 cases of NEC were observed in 50 neonates. A multiple logistic regression analysis indicated that formula and BMCR were associated with 4- to 5-fold increases in colonization by Gram-negative bacteria (odds ratio [OR], 4.52; 1.87-10.95, and OR, 4.95; 1.90 12.87, respectively) and 5 to 9 times higher odds of colonization by Gram positive microorganisms (OR, 5.75; 1.89-16.72, and OR, 8.61; 2.52-29.36, respectively) compared with TPN. The only difference between BMCR and the other feeding groups was the higher colonization with Staphylococcus haemolyticus in the latter (formula-OR, 6.24; 1.73-22.50; TPN-OR, 2.75; 1.08-6.97). Compared with BMCR, TPN was associated with an increased odds of LOS (OR, 3.04; 1.02-9.07) and an increased odds of death (19.75; 3.64-107.12) compared with formula. Although early enteral feeding is associated with a higher odds of colonization with opportunistic microorganisms, it should be preferred over TPN whenever feasible, due to the favorable effect on the prevention of LOS. PMID- 25922116 TI - The Role of Self-Control and Early Adolescents' Friendships in the Development of Externalizing Behavior: The SNARE Study. AB - This social network study investigated the moderating role of self-control in the association between friendship and the development of externalizing behavior: Antisocial behavior, alcohol use, tobacco use. Previous studies have shown inconsistent findings, and did not control for possible friendship network or selection effects. We tested two complementary hypotheses: (1) That early adolescents with low self-control develop externalizing behavior regardless of their friends' behavior, or (2) as a result of being influenced by their friends' externalizing behavior to a greater extent. Hypotheses were investigated using data from the SNARE (Social Network Analysis of Risk behavior in Early adolescence) study (N = 1144, 50 % boys, M age 12.7, SD = 0.47). We controlled for selection effects and the network structure, using a data-analysis package called SIENA. The main findings indicate that personal low self-control and friends' externalizing behaviors both predict early adolescents' increasing externalizing behaviors, but they do so independently. Therefore, interventions should focus on all early adolescents' with a lower self-control, rather than focus on those adolescents with a lower self-control who also have friends who engage in externalizing behavior. PMID- 25922117 TI - Preventable Iatrogenic Disability in Elderly Patients During Hospitalization. AB - BACKGROUND: In older patients, hospitalization is often associated with new or worsening disability. This hospitalization-associated disability may be explained in part by the cumulative effect of aging, frailty, comorbidities, and illnesses that led to hospitalization but may also result from health care management issues and the hospital environment. Our objective was to determine the frequency, causes, and the preventability of disability induced by the processes of care or "iatrogenic disability." METHODS: A total of 503 patients, aged 75 years and older, hospitalized in the 105 medical and surgical units of Toulouse University Hospital between October 2011 and March 2012, with a minimal length of stay of 2 days, were included. Hospitalization-associated disability was defined as a loss of 0.5 points or more in the Katz Activity of Daily Living Score between the time of hospital admission and discharge. To determine the iatrogenic component of hospitalization-associated disability, an expert panel in geriatric medicine reviewed each medical chart using a standardized record review and identified precipitating iatrogenic adverse events resulting in functional decline. RESULTS: Incidence of iatrogenic disability was 11.9% (95% confidence interval, 9.2%-15.1%). Of the 60 cases of iatrogenic disability, 49 (81.7%, 95% confidence interval, 69.6%-90.5%) were judged to be potentially preventable. The most common health management issues identified in patients with preventable iatrogenic disability were low mobilization [by excessive bed rest (26.5%) and lack of physical therapist intervention (55.1%)], overuse of diapers (49.0%), and transurethral urinary catheterization (30.6%). CONCLUSIONS: The present study suggests that a significant proportion of hospitalization-associated disability may be induced by iatrogenic events, and that most of them are potentially preventable. Health care professionals need to be educated on the specific needs of elderly hospitalized patients and should consider hospitalization-associated disability as an outcome of care. PMID- 25922118 TI - Sarcopenia Should Reflect the Contribution of Age-Associated Changes in Skeletal Muscle to Risk of Morbidity and Mortality in Elderly People. PMID- 25922119 TI - Derivation and validation of a clinical diagnostic tool for the identification of older community-dwellers with hypovitaminosis D. AB - OBJECTIVES: Hypovitaminosis D is highly prevalent among seniors. Although evidence is insufficient to recommend routine vitamin D screening in seniors, universal vitamin D supplementation is not desirable either. To rationalize vitamin D determination, our objective was to elaborate and test a clinical diagnostic tool for the identification of seniors with hypovitaminosis D without using a blood test. DESIGN: Derivation of a clinical diagnostic tool using artificial neural networks (multilayer perceptron; MLP) in randomized training subgroup of Prevention des Chutes, Reseau 4' cohort, and validation in randomized testing subgroup. SETTING: Health Examination Centers of health insurance, Lyon, France. PARTICIPANTS: A total of 1924 community-dwellers aged >= 65 years without vitamin D supplements, consecutively recruited between 2009 and 2012. MEASUREMENTS: Hypovitaminosis D defined as serum 25-hydroxyvitamin (25OHD) concentration <= 75 nmol/L, <= 50 nmol/L, or <= 25 nmol/L. A set of clinical variables (age, gender, living alone, individual deprivation, body mass index, undernutrition, polymorbidity, number of drugs used daily, psychoactive drugs, biphosphonates, strontium, calcium supplements, falls, fear of falling, vertebral fractures, Timed Up and Go, walking aids, lower-limb proprioception, handgrip strength, visual acuity, wearing glasses, cognitive disorders, sad mood) were recorded. Several MLPs, based on varying amounts of variables according to their relative importance, were tested consecutively. RESULTS: A total of 1729 participants (89.9%) had 25OHD <= 75 nmol/L, 1288 (66.9%) had 25OHD <= 50 nmol/L, and 525 (27.2%) had 25OHD <= 25 nmol/L. MLP using 16 clinical variables was able to diagnose hypovitaminosis D <= 75 nmol/L with accuracy = 96.3%, area under curve (AUC) = 0.938, and kappa = 79.3 indicating almost perfect agreement. It was also able to diagnose hypovitaminosis D <= 50 nmol/L with accuracy = 81.5, AUC = 0.867, and kappa = 57.8 (moderate agreement); and hypovitaminosis D <= 25 nmol/L with accuracy = 82.5, AUC = 0.385, and kappa = 55.0 (moderate agreement). CONCLUSIONS: We elaborated an algorithm able to identify, from 16 clinical variables, seniors with hypovitaminosis D. PMID- 25922120 TI - Incidence of Disability in Frail Older Persons With or Without Slow Walking Speed. AB - OBJECTIVE: To identify the differences of incidence of disability between frail older persons with and without slow walking speed. DESIGN: Prospective cohort study. SETTING: Japanese community. PARTICIPANTS: A total of l4,081 older adults aged >=65 years living in the community, participated in a baseline assessment and were followed for incidence of disability for 29.5 months. MEASUREMENTS: Care needs certification in the national long-term care insurance system of Japan, physical frailty (slow walking speed, muscle weakness, exhaustion, low activity, weight loss), adjusted for several potential confounders such as demographic characteristics; Kaplan-Meier survival curves for incident disability by physical frailty with and without slow walking speed. RESULTS: During the follow-up period, 198 participants (4.9%) were certified as requiring long-term care insurance in accordance with incident disability. Participants who had prefrailty without slow walking speed (hazard ratio 1.86, 95% confidence interval 1.19 2.92), prefrailty with slow walking speed (3.62, 2.19-5.96), frailty without slow walking speed (4.33, 2.00-9.39), and frailty with slow walking speed (4.68, 2.72 8.05) at the baseline assessment had an increased risk of incident disability compared with nonfrail participants. In stratified analyses, frail older men and frail participants with low cognitive performance had the highest risk of incidence of disability. CONCLUSION: The presence of frailty or even prefrailty when older adults showed slow walking speed increased the risk of future disability in community-dwelling older adults. PMID- 25922121 TI - Subsyndromal delirium after cardiac surgery. AB - OBJECTIVES: To evaluate the incidence of subsyndromal delirium (SSD) after cardiac surgery and its impact on clinical outcome. DESIGN: In this prospective study, 506 patients were screened for SSD and clinical delirium (CD) using the Intensive Care Delirium Screening Checklist. RESULTS: 150 (34%) patients were classified as having SSD and 54 (12%) patients as having CD. 2% of SSD patients developed CD. Patients' age, EuroSCORE, postoperative the Acute Physiology and Chronic Health Evaluation II, the incidences of emergency operations, and the number of aortic surgery increased from non-delirious (ND) to SSD. Intensive care unit (ICU) and hospital stays were longer in CD compared with SSD patients. ND patients did not differ from SSD patients regarding duration of ventilation, ICU stay, or hospital stay. The rate of home discharge decreased from ND over SSD to CD patients. Mortality in SSD patients did not differ from ND or CD patients. CONCLUSION: SSD showed a prevalence of 34% in patients after cardiac surgery. SSD occurred independent of CD for the majority of patients. Except for a lower rate of home discharge, the clinical outcome did not differ from that of ND patients. According to our data, SSD does not represent a preliminary or resolving stage of delirium. PMID- 25922122 TI - Efficacy and Safety of a Novel Three-Step Medial Release Technique in Varus Total Knee Arthroplasty. AB - We investigated the efficacy and safety of our novel three-step medial release technique in varus total knee arthroplasty (TKA) over time. Two hundred sixty seven consecutive varus TKAs were performed by applying the algorithmic release technique which consisted of sequential release of the deep medial collateral ligament (step 1), the semimembranosus (step 2), and multiple needle puncturing of the superficial medial collateral ligament (step 3). One hundred seventeen, 114, and 36 knees were balanced after step 1, 2, and 3 releases, respectively. There were no significant differences in changes of medial and lateral laxities between groups in over a year. Our novel stepwise medial release technique was efficacious and safe in balancing varus knees during TKA. PMID- 25922123 TI - Arthroscopic Approach to Femoroacetabular Impingement. PMID- 25922124 TI - Midterm Outcome after Mega-Prosthesis Implanted in Patients with Bony Defects in Cases of Revision Compared to Patients with Malignant Tumors. AB - Use of mega-prostheses is a common option for the treatment of patients with malignant tumors as well as in patients with large osseous defects at the time of revision surgery. No studies have compared the two groups to determine whether there is a relative difference in clinical outcomes. We performed a midterm outcome-study to evaluate our results in these two patient populations. Deep infection was found more often in our revision group (29.5% vs. 9.1%), however no significant differences in WOMAC-results could be found between the two groups. Surgeons should recognize the high complication rate as well as the differences in results using mega-prostheses in these two distinct groups of patients. PMID- 25922125 TI - Surgical Treatment of Prosthetic Joint Infections of the Hip and Knee: Changing Paradigms? AB - Prosthetic joint infection (PJI) of the hip and knee remains one of the most common and feared arthroplasty complications. The impact and cost of PJI is significant, both to the patient and to the health care system. Recent reports of results of different treatment strategies have led many surgeons to modify their approach to management of PJI. This paper will explore apparent paradigm shifts, both to indications and technique, including the importance of waiting for bacterial identification, the decreasing role for irrigation and debridement (I&D) with retention of components, the increased utilization of single stage revision, and conversely a decreasing role for two-stage exchange. Strategies for treating drug-resistant organisms and management of failed treatment will also be examined. PMID- 25922126 TI - Differential DNA methylation profile of key genes in malignant prostate epithelial cells transformed by inorganic arsenic or cadmium. AB - Previous work shows altered methylation patterns in inorganic arsenic (iAs)- or cadmium (Cd)-transformed epithelial cells. Here, the methylation status near the transcriptional start site was assessed in the normal human prostate epithelial cell line (RWPE-1) that was malignantly transformed by 10MUM Cd for 11weeks (CTPE) or 5MUM iAs for 29weeks (CAsE-PE), at which time cells showed multiple markers of acquired cancer phenotype. Next generation sequencing of the transcriptome of CAsE-PE cells identified multiple dysregulated genes. Of the most highly dysregulated genes, five genes that can be relevant to the carcinogenic process (S100P, HYAL1, NTM, NES, ALDH1A1) were chosen for an in depth analysis of the DNA methylation profile. DNA was isolated, bisulfite converted, and combined bisulfite restriction analysis was used to identify differentially methylated CpG sites, which was confirmed with bisulfite sequencing. Four of the five genes showed differential methylation in transformants relative to control cells that was inversely related to altered gene expression. Increased expression of HYAL1 (>25-fold) and S100P (>40-fold) in transformants was correlated with hypomethylation near the transcriptional start site. Decreased expression of NES (>15-fold) and NTM (>1000-fold) in transformants was correlated with hypermethylation near the transcriptional start site. ALDH1A1 expression was differentially expressed in transformed cells but was not differentially methylated relative to control. In conclusion, altered gene expression observed in Cd and iAs transformed cells may result from altered DNA methylation status. PMID- 25922127 TI - Intra-individual variability in the response to anodal transcranial direct current stimulation. AB - OBJECTIVE: To test the intra-individual reliability in response to anodal transcranial direct current stimulation (AtDCS). METHODS: 45 healthy subjects received AtDCS (1 mA, 13 min) in two separate sessions, 6-12 months apart. Motor evoked potentials were collected at baseline and then at 5-min intervals after AtDCS for 1h. Short intracortical inhibition (SICI) was assessed at minutes 6 and 46 after AtDCS. RESULTS: AtDCS increased cortical excitability over minutes 0-30 post-stimulation in both sessions, with fair intra-individual reliability. 60% and 64% of subjects responded with the expected increase in cortical excitability in each session, respectively. 69% of the subjects maintained their response pattern between sessions during this timeframe. However, there were no significant effects on cortical excitability over the full hour post AtDCS in either session. SICI showed fair intra-individual reliability 6 min after AtDCS. CONCLUSION: A change in cortical excitability in the first half-hour post-AtDCS may be a good predictor of the response in a subsequent session. Furthermore, minute 15 post-stimulation showed the maximum increase in cortical excitability in both sessions. SIGNIFICANCE: We show for the first time that intra-individual variability is lower than inter-individual variability, and with fair intra individual inter-sessional reliability for 30 min after AtDCS-subjects are likely to maintain their response patterns to tDCS between sessions, with implications for experimental and therapeutic applications of tDCS. PMID- 25922128 TI - What do you feel if I apply transcranial electric stimulation? Safety, sensations and secondary induced effects. AB - OBJECTIVE: The goals of this work are to report data regarding a large number of stimulation sessions and to use model analyses to explain the similarities or differences in the sensations induced by different parameters of tES application. METHODS: We analysed sensation data relative to 693 different tES sessions. In particular, we studied the effects on sensations induced by different types of current, categories of polarity and frequency, different timing, levels of current density and intensity, different electrode sizes and different electrode locations (areas). RESULTS: The application of random or fixed alternating current stimulation (i.e., tRNS and tACS) over the scalp induced less sensation compared with transcranial direct current stimulation (tDCS), regardless of the application parameters. Moreover, anodal tDCS induced more annoyance in comparison to other tES. Additionally, larger electrodes induced stronger sensations compared with smaller electrodes, and higher intensities were more strongly perceived. Timing of stimulation, montage and current density did not influence sensations perception. The analyses demonstrated that the induced sensations could be clustered on the basis of the type of somatosensory system activated. Finally and most important no adverse events were reported. CONCLUSION: Induced sensations are modulated by electrode size and intensity and mainly pertain to the cutaneous receptor activity of the somatosensory system. Moreover, the procedure currently used to perform placebo stimulation may not be totally effective when compared with anodal tDCS. SIGNIFICANCE: The reported observations enrich the literature regarding the safety aspects of tES, confirming that it is a painless and safe technique. PMID- 25922129 TI - Increased antagonist muscle activity in cervical SCI patients suggests altered reciprocal inhibition during elbow contractions. AB - OBJECTIVE: After spinal cord injury (SCI), the antagonist muscles activation is increased during voluntary contractions and reflex conditioning protocols. This increase can be the result of both muscle atrophy and reciprocal facilitation mechanism. It remains however unclear to what extent increased antagonist muscles activation could be rather attributable to central vs. peripheral changes during voluntary contractions achieved by SCI participants. METHODS: We investigated the activations of elbow extensors and flexors during isometric elbow flexion and extension contractions performed at 3 force levels by 10 healthy participants and 8 participants with cervical SCI (cSCI). RESULTS: At similar force level and absolute net torque in flexion, the antagonist muscles activation was increased for the participants with cSCI. At similar absolute net torque in extension, the activations of agonist and antagonist muscles were increased for the participants with cSCI. CONCLUSION: During flexion contractions, increased antagonist muscles activation may be explained by extensors atrophy or reciprocal facilitation. During extension contractions, increased antagonist muscles activation may reflect the importance of reciprocal facilitation as antagonist muscles were evaluated as intact by clinical testing and maximal net joint torque recording. SIGNIFICANCE: These results in cSCI participants revealed an increased activation of antagonist muscles, which may reflect a reorganization of the spinal reflexes and their supraspinal control involved during isometric elbow contractions. PMID- 25922130 TI - Dental discoloration caused by bismuth oxide in MTA in the presence of sodium hypochlorite. AB - OBJECTIVES: The aim of this research was to analyse the dental discolouration caused by mineral trioxide aggregate (MTA) induced by bismuth oxide and also assess the colour stability of other dental cements. MATERIALS AND METHODS: Bismuth oxide, calcium tungstate and zirconium oxide were placed in contact with sodium hypochlorite for 24 h after which they were dried and photographed. Phase analyses were performed by X-ray diffraction (XRD) of radiopacifiers before and after immersion in sodium hypochlorite. Furthermore, teeth previously immersed in water or sodium hypochlorite were filled with MTA Angelus, Portland cement (PC), PC with 20 % zirconium oxide, PC with 20 % calcium tungstate and Biodentine. Teeth were immersed for 28 days in Hank's balanced salt solution after which they were sectioned and characterized using scanning electron microscopy (SEM) with energy-dispersive mapping and stereomicroscopy. RESULTS: Bismuth oxide in contact with sodium hypochlorite exhibited a change in colour from light yellow to dark brown. XRD analysis demonstrated peaks for radiopacifier and sodium chloride in samples immersed in sodium hypochlorite. The SEM images of the dentine to material interface showed alteration in material microstructure for MTA Angelus and Biodentine with depletion in calcium content in the material. The energy dispersive maps showed migration of radiopacifier and silicon in dentine. CONCLUSIONS: MTA Angelus in contact with a tooth previously immersed in sodium hypochlorite resulted in colour alteration at the cement/dentine interface. CLINICAL RELEVANCE: MTA Angelus should not be used after irrigation with sodium hypochlorite as this will result in tooth discoloration. PMID- 25922131 TI - The Equivalence and Difference between the English and Chinese Language Versions of the Repeatable Battery for the Assessment of Neuropsychological Status. AB - OBJECTIVE: Chinese is the most commonly spoken language in the world. The availability of Chinese translations of assessment scales is useful for research in multi-ethnic and multinational studies. This study aimed to establish whether each of the Chinese translations (Mandarin, Hokkien, Teochew, and Cantonese) of the Repeatable Battery for the Assessment of Neuropsychological Status (RBANS) achieved measurement equivalence to the English version. METHOD: Participants included 1856 ethnic Chinese, older adults. The RBANS was administered in the language/dialect according to the participants' preference by interviewers who were fluent in that language/dialect. Multiple regression analysis was used to adjust for demographic and clinical differences between participants who spoke different languages/dialects. Equivalence (practical equivalence) was declared if the 90% confidence interval for the adjusted mean difference fell entirely within the pre-specified equivalence margin, +/-.2 (+/-.4) standard deviations. RESULTS: The delayed memory index was at least practically equivalent across languages. The Mandarin, Hokkien, and Teochew versions of the immediate memory, language, and total scale score were practically equivalent to the English version; the Cantonese version showed small differences from the English version. Equivalence was not established for the Hokkien and Teochew versions of the visuospatial/constructional index. The attention index was different across languages. CONCLUSIONS: Data from the English and Chinese versions for the total scale score, language, delayed, and immediate memory indexes may be pooled for analysis. However, analysis of the attention and visuospatial/constructional indexes from the English and Chinese versions should include a covariate that represents the version in the statistical adjustment. PMID- 25922132 TI - Osteoblastogenesis of Mesenchymal Stem Cells in 3-D Culture Enhanced by Low Intensity Pulsed Ultrasound through Soluble Receptor Activator of Nuclear Factor Kappa B Ligand. AB - This study was performed to investigate osteoblastogenesis of human mesenchymal stem cells (hMSCs) cultured in 3-D scaffolds stimulated with low-intensity pulsed ultrasound and to identify the underlying mechanism mediated by soluble receptor activator of nuclear factor kappa B ligand (sRANKL) secreted by hMSCs. The results indicate that the mRNA levels of core-binding factor subunit alpha subunit 1 (CBFA1), osterix (OSX), alkaline phosphatase (ALP), osteocalcin and osteoprotegerin (OPG) and sRANKL production of hMSCs stimulated by ultrasound were significantly increased compared with the levels without ultrasound stimulation. Attenuating the sRANKL activity of ultrasound-treated hMSCs significantly reduced the mRNA expression of CBFA1, OSX, ALP and OPG. Adding sRANKL in hMSC culture significantly increased the mRNA expression of CBFA1, OSX and OPG. Together, the results suggest that osteoblastogenesis of hMSCs enhanced by ultrasound stimulation is mediated by endogenous sRANKL. PMID- 25922133 TI - Biologically and Acoustically Compatible Chamber for Studying Ultrasound-Mediated Delivery of Therapeutic Compounds. AB - Ultrasound (US), in combination with microbubbles, has been found to be a potential alternative to viral therapies for transfecting biological cells. The translation of this technique to the clinical environment, however, requires robust and systematic optimization of the acoustic parameters needed to achieve a desired therapeutic effect. Currently, a variety of different devices have been developed to transfect cells in vitro, resulting in a lack of standardized experimental conditions and difficulty in comparing results from different laboratories. To overcome this limitation, we propose an easy-to-fabricate and cost-effective device for application in US-mediated delivery of therapeutic compounds. It comprises a commercially available cell culture dish coupled with a silicon-based "lid" developed in-house that enables the device to be immersed in a water bath for US exposure. Described here are the design of the device, characterization of the sound field and fluid dynamics inside the chamber and an example protocol for a therapeutic delivery experiment. PMID- 25922134 TI - Automated Framework for Detecting Lumen and Media-Adventitia Borders in Intravascular Ultrasound Images. AB - An automated framework for detecting lumen and media-adventitia borders in intravascular ultrasound images was developed on the basis of an adaptive region growing method and an unsupervised clustering method. To demonstrate the capability of the framework, linear regression, Bland-Altman analysis and distance analysis were used to quantitatively investigate the correlation, agreement and spatial distance, respectively, between our detected borders and manually traced borders in 337 intravascular ultrasound images in vivo acquired from six patients. The results of these investigations revealed good correlation (r = 0.99), good agreement (>96.82% of results within the 95% confidence interval) and small average distance errors (lumen border: 0.08 mm, media adventitia border: 0.10 mm) between the borders generated by the automated framework and the manual tracing method. The proposed framework was found to be effective in detecting lumen and media-adventitia borders in intravascular ultrasound images, indicating its potential for use in routine studies of vascular disease. PMID- 25922135 TI - Delivering Agents Locally into Articular Cartilage by Intense MHz Ultrasound. AB - There is no cure for osteoarthritis. Current drug delivery relies on systemic delivery or injections into the joint. Because articular cartilage (AC) degeneration can be local and drug exposure outside the lesion can cause adverse effects, localized drug delivery could permit new drug treatment strategies. We investigated whether intense megahertz ultrasound (frequency: 1.138 MHz, peak positive pressure: 2.7 MPa, Ispta: 5 W/cm(2), beam width: 5.7 mm at -6 dB, duty cycle: 5%, pulse repetition frequency: 285 Hz, mechanical index: 1.1) can deliver agents into AC without damaging it. Using ultrasound, we delivered a drug surrogate down to a depth corresponding to 53% depth of the AC thickness without causing histologically detectable damage to the AC. This may be important because early osteoarthritis typically exhibits histopathologic changes in the superficial AC. In conclusion, we identify intense megahertz ultrasound as a technique that potentially enables localized non-destructive delivery of osteoarthritis drugs or drug carriers into articular cartilage. PMID- 25922136 TI - Maintenance Check-ups Following Treatment for Cannabis Dependence. AB - Substance use disorders, including cannabis use disorders and associated negative consequences, are best considered chronic and in need of continuing care. In contrast, most treatment efficacy studies evaluate a fixed number of intervention sessions at a single point in time. The present study evaluated the efficacy of posttreatment maintenance check-ups (MCUs) in maintaining and improving outcomes following nine sessions of motivational enhancement treatment/cognitive behavioral treatment (MET/CBT). Adults dependent on cannabis (n=74) were randomly assigned to the MCU or a no check-up (NCU) condition and followed up at 3- and 9 months. MCU sessions occurred 1 and 4months following the completion of the base treatment. Additional MET/CBT sessions were available to participants throughout the follow-up period. The MCUs specifically encouraged treatment re-entry for those showing ongoing signs of disorder. Participants in the MCU condition reported significantly greater abstinent rates at both follow-ups and were using on fewer days at the 3-month but not the 9-month follow-up. Contrary to hypotheses, MCU participants did not attend more additional treatment and differences in rates of cannabis use emerged prior to the first MCU session. Future research with longer follow-up periods and longer monitoring of outcomes is needed to fully evaluate the utility of MCUs or other forms of continuing care. PMID- 25922137 TI - The role of PP2A-associated proteins and signal pathways in microcystin-LR toxicity. AB - Microcystins are a family of monocyclic heptapeptides produced by cyanobacteria during water blooms. Microcystin-LR (MC-LR) is the most common member of this family. Microcystins induce a variety of toxic cellular effects, including oxidative damage, apoptosis, cytoskeletal destabilization, and cancer cell invasion. Recent studies have examined the molecular mechanism of their toxicity. Protein phosphatase 2A (PP2A) is emerging as a critical regulator of the microcystin-induced molecular network. Furthermore, it has been shown that several molecules or signal pathways associated with PP2A play important roles in microcystin-induced toxic effects. This review summarizes the recent research progress of the molecular mechanism and focuses on the role of PP2A in MC-LR toxicity, which will contribute to a better understanding of the mechanism of microcystin toxicity, and will provide biomarkers for toxicity assessment and control. PMID- 25922138 TI - The utility of bioimpedance analysis for monitoring the children with nutcracker syndrome. AB - We aimed to evaluate anthropometric and bioimpedance analysis (BIA) indices of children with nutcracker syndrome (NCS). Eighteen patients and 20 age-gender matched controls were enrolled. Weight, height, body mass index (BMI), mid-arm circumference (MAC), waist circumference (WC), waist/hip ratio measurements, and BIA results were assessed. Laboratory parameters and Doppler sonographic findings were recorded. The weight, BMI, MAC, WC, body fat z scores, and waist/hip ratio were significantly lower in patients than in controls (p < 0.05). Serum creatinine (Scr), albumin, HDL cholesterol, and urine protein (Up) were significantly increased in NCS patients compared to controls (p < 0.05). On multivariate analysis, body fat z score was independently related to Up and the degree of superior mesenteric artery (SMA) angle (beta = -0.965, p = 0.018 and beta = 0.841, p = 0.04, respectively). CONCLUSION: NCS might be considered in slim proteinuric patients with unproven etiology. Serial anthropometric measurements and BIA analysis would estimate the severity of entrapment in LRV. Long-term follow-up of Scr might be required in NCS. WHAT IS KNOWN: * Nutcracker syndrome (NCS) is very rare and characterized by the compression of LRV between aorta and SMA. What is new: * Patients with NCS have a slimmer body feature with lower anthropometric and BIA indices. * Fat percentage indicates the degree of LRV entrapment and amount of proteinuria in NCS. PMID- 25922139 TI - Limited effects of intravenous paracetamol on patent ductus arteriosus in very low birth weight infants with contraindications for ibuprofen or after ibuprofen failure. AB - Finding the optimal pharmacological treatment of a patent ductus arteriosus (PDA) in preterm neonates remains challenging. There is a growing interest in paracetamol as a new drug for PDA closure. In this prospective observational cohort study, we evaluated the effectiveness of intravenous paracetamol in closing a PDA in very low birth weight infants with a hemodynamically significant PDA who either did not respond to ibuprofen or had a contraindication for ibuprofen. They received high-dose paracetamol therapy (15 mg/kg/6 h intravenous) for 3-7 days. Cardiac ultrasounds were performed before and 3 and 7 days after treatment. Thirty-three patients were included with a median gestational age of 25(1/7) weeks (IQR 1.66), a median birth weight of 750 g (IQR 327), and a median postnatal age of 14 days (IQR 12). Paracetamol was ineffective in 27/33 patients (82 %). Even more, after previous exposure to ibuprofen, this was even 100 %. CONCLUSION: In this study, paracetamol after ibuprofen treatment failure was not effective for PDA closure in VLBW infants. From the findings of this study, paracetamol treatment for PDA closure cannot be recommended for infants with a postnatal age >2 weeks. Earlier treatment with paracetamol for PDA might be more effective. PMID- 25922140 TI - Comparison of pre- and intrapartum screening of group B streptococci and adherence to screening guidelines: a cohort study. AB - Implementation of guidelines for group B streptococcal (GBS) prepartum screening (PS) rarely has been prospectively evaluated. To assess PS at 35-37 weeks of gestation and compare its predictive value to that of an intrapartum screening (IS) within 7 days of delivery, a surveillance cohort study was conducted at a tertiary care center in Freiburg, Germany, during 2011-2012. Study participants included 937 pregnant women who had intrapartum cultures taken for vaginal and rectal GBS colonization. Colonization status was compared to PS, and intrapartum antibiotic prophylaxis (IAP) rates calculated. The neonates were tested for GBS transmission via cultures from their throats and external ear canals. While 67.5% (633/937) of study participants had a PS, only 22.7% (144/633) underwent a fully guideline-compatible PS. However, maternal GBS colonization rates were similar when comparing PS (18.5% [117/633]) versus IS (17.0% [133/784]). The positive predictive value of a positive PS result for GBS positivity at delivery was 77.2 %. Women with a positive PS received IAP in 89.3% of cases (75/84). The capsular serotype distribution pattern of colonizing GBS strains has not changed in comparison to our 2003-2004 study--one with a similar study design. CONCLUSIONS: Improved strategies for adoption of prepartum GBS screening are needed. WHAT IS KNOWN: * The prediction of prepartum GBS screening for intrapartum colonization status has not been well studied. * Longitudinal studies of GBS screening are needed for screening program evaluations and vaccine development. What is New: * The rate of GBS screening has improved over 10 years, and intrapartum GBS colonization prediction was accurate. * Serotype distribution was stable and suggests the potential long-term efficacy of GBS vaccines. PMID- 25922142 TI - Microscopic colitis that is not so microscopic. PMID- 25922141 TI - Childhood obesity and its physical and psychological co-morbidities: a systematic review of Australian children and adolescents. AB - Australia is predicted to have the highest overweight/obesity rate in the world by 2022 outranking the USA and UK. The purpose of this systematic review was to evaluate the associations between childhood obesity and physical and psychological health co-morbidities. Therefore, a systematic literature search was conducted from six databases (2004-2014). Studies were included if they investigated obesity-related co-morbidities with participants residing in Australia aged 0-18 years. Forty-seven studies fulfilled selection criteria. Evidence suggests that overweight/obese Australian children and adolescents, compared to normal-weight peers, had more cardio-metabolic risk factors and higher risk factors of non-alcohol fatty liver disease and were experiencing more negative psychological outcomes (depression, low self-esteem and lower scores of health-related quality of life). Many other health consequences have either not been investigated in Australia, or as frequently as in other countries. CONCLUSIONS: Given Australia's current overweight/obesity prevalence and trajectory, Australia-based studies are needed to identify the suspected co morbidities, understand the range of individual, social and environmental mechanisms driving obesity, and help identify policies, interventions and strategies that will change the future trajectory and 'disease burden' both in Australia and internationally. WHAT IS KNOWN: * Trend analyses have shown that obesity prevalence in Australia is increasing and will outrank UK and the USA by 2022. * Every third Australian child/adolescent between 5 and 19 years old is predicted to be classified as overweight or obese by 2025. * Childhood obesity is associated with multiple immediate physical and psychological health co morbidities as well as co-morbidities in adulthood. These have often been identified and examined individually. What is New: * This paper presents a holistic picture of childhood obesity and the associated multiple co-morbidities in Australia. * The extensive health-related outcomes from childhood obesity and those requiring further research are identified. * The findings of this paper will influence the development of local/regional, state and national strategies to change Australia's future trajectory. PMID- 25922143 TI - Outcome for stage II and III rectal and colon cancer equally good after treatment improvement over three decades. AB - PURPOSE: This study aimed to investigate the outcome for stage II and III rectal cancer patients compared to stage II and III colonic cancer patients with regard to 5-year cause-specific survival (CSS), overall survival, and local and combined recurrence rates over time. METHODS: This prospective cohort study identified 3,355 consecutive patients with adenocarcinoma of the colon or rectum and treated in our colorectal unit between 1981 and 2011, for investigation. The study was restricted to International Union Against Cancer (UICC) stages II and III. Postoperative mortality and histological incomplete resection were excluded, which left 995 patients with colonic cancer and 726 patients with rectal cancer for further analysis. RESULTS: Five-year CSS rates improved for colonic cancer from 65.0% for patients treated between 1981 and 1986 to 88.1% for patients treated between 2007 and 2011. For rectal cancer patients, the respective 5-year CSS rates improved from 53.4% in the first observation period to 89.8% in the second one. The local recurrence rate for rectal cancer dropped from 34.2% in the years 1981-1986 to 2.1% in the years 2007-2011. In the last decade of observation, prognosis for rectal cancer was equal to that for colon cancer (CSS 88.6 vs. 86.7%, p = 0.409). CONCLUSION: Survival of patients with colon and rectal cancer has continued to improve over the last three decades. After major changes in treatment strategy including introduction of total mesorectal excision and neoadjuvant (radio)chemotherapy, prognosis for stage II and III rectal cancer is at least as good as for stage II and III colonic cancer. PMID- 25922144 TI - Histological and mechanical differences in the skin of patients with rectal prolapse. AB - INTRODUCTION: It is still an enigma that some patients develop rectal prolapse whilst others with similar risk factors do not. Biomechanical assessment of the skin may provide further insight into the aetiology of this complex condition. Elastin fibres are an abundant and integral part of many extracellular matrices and are especially critical for providing the property of elastic recoil to tissues. The significance of elastin fibres is clearly reflected by the numerous human conditions in which a skin phenotype occurs as a result of elastin fibre abnormalities. METHOD: Between January and June 2013, skin specimens were obtained prospectively during surgery on 20 patients with rectal prolapse and 21 patients without prolapse undergoing surgery for other indications. Expression levels of elastin in the skin were measured by Orcein staining, and Image J. Tensile tests were performed using the Zwick Roell device, with custom ceramic clamps. For statistical analysis, Student's t test was used. RESULTS: Histological analysis of prolapse vs control showed percentage dermal elastin fibres of 9 vs 5.8 % (p = 0.001) in males and 6.5 vs 5.3 % (p = 0.05) in females. Patients with more severe prolapse (external) had a significantly (p = 0.05) higher percentage dermal elastin fibres 6.9 vs 6.1 % than internal prolapse. Young's modulus of patients with prolapse was lower in males (3.3 vs 2.8, p = 0.05) and females (3.1 vs 2.7, p = 0.05). CONCLUSION: Patients with prolapse have a higher concentration of elastin fibres in the skin, and these differences are quantitatively demonstrated through mechanical testing. This suggests that the aetiology may be a result of a dysfunction of elastin fibre assembly. PMID- 25922145 TI - Utility of contrast enema to assess anastomotic integrity and the natural history of radiological leaks after low rectal surgery: systematic review and meta analysis. AB - PURPOSE: There is no clear consensus on how to assess low rectal anastomotic integrity and patency prior to reversal of de-functioning stoma. The aim of this systematic review was to assess the utility of contrast enema (CE) in this context and to clarify the natural history of radiological leaks. METHODS: Keyword search of electronic databases (Embase, MEDLINE, Cochrane Library, Google Scholar) and bibliographic cross-referencing were performed to identify appropriate studies. Data extraction and synthesis was performed with the primary outcomes being the sensitivity and specificity of CE for detecting clinically significant abnormalities. Statistical analysis was performed using Open Meta Analyst software. Narrative review of outcomes including those of clinical and radiological leaks was also undertaken. RESULTS: A total of 1,142 CE from 11 articles were included in the final meta-analysis. CE had high specificity (95.4; 95 % confidence interval = 92.0-97.4) and negative predictive value (98.4; 97.4 99.1) and moderate sensitivity (79.9; 63.9-89.9) and positive predictive value (64.6; 55.5-72.9) for the detection of clinically significant anastomotic problems. There was a high degree of correlation between CE and clinical examination findings (96.7 %). Occult radiological leaks were seen in 5.7 % of CE, and all but one (97 %) eventually underwent successful reversal. Only three quarters of patients with clinical leak underwent successful reversal. CONCLUSION: CE is effective at excluding clinically significant anastomotic problems, especially after clinical anastomotic leaks. However, false positive results can be observed in asymptomatic patients, and it is unclear how much additional information CE provides over clinical assessment in the low uncomplicated anastomosis. PMID- 25922146 TI - Benefit of primary tumor resection in stage IV colorectal cancer with unresectable metastasis: a multicenter retrospective study using a propensity score analysis. AB - PURPOSE: Retrospective studies have shown that primary tumor resection improves the prognosis of patients with colorectal cancer (CRC) with unresectable metastasis (mCRC). The aim of this study was to investigate the prognostic impact of primary tumor resection in various subgroups of mCRC patients. METHODS: A total of 1982 patients with mCRC from January 1997 to December 2007 were retrospectively evaluated. The impact of primary tumor resection on cancer specific survival (CSS) was analyzed using propensity score analysis to mitigate selection bias. Covariates in the models for propensity scores included treatment period, age, gender, tumor location, depth, lymph node metastasis, number of metastatic organs, and carcinoembryonic antigen (CEA) levels. RESULTS: Among the whole patient population, primary tumor resection significantly improved CSS [hazard ratio (HR) 0.46, 95% confidence interval (CI) 0.32-0.66, p < 0.01]. However, primary tumor resection did not significantly improve CSS in the following subgroups: patients treated in the first 5 years of the study (HR 0.56, 95% CI 0.28-1.13, p = 0.08), patients aged >65 years (HR 0.72, 95% CI 0.36-1.42, p = 0.31), female patients (HR 0.60, 95% CI 0.31-1.17, p = 0.13), patients with right-sided colon cancer (HR 0.68, 95% CI 0.39-1.20, p = 0.17), and patients without nodal involvement (HR 0.54, 95% CI 0.25-1.17, p = 0.09). CONCLUSIONS: Our study suggests that primary tumor resection improves the survival of patients with mCRC. However, the prognostic benefit is different among patient subpopulations. PMID- 25922147 TI - Postoperative C-reactive protein measurement predicts the severity of complications following surgery for colorectal cancer. AB - PURPOSE: Studies have shown that postoperative serum C-reactive protein (CRP) measurement may be useful in predicting the type of complication, infective or otherwise, following surgery for colorectal cancer. It may be that the magnitude of the postoperative CRP is also associated with the severity of the complication. The aim of the present study was to examine the relationship between daily postoperative CRP concentrations and Clavien-Dindo complication grade. PATIENTS AND METHODS: Data was recorded prospectively for patients undergoing elective, potentially curative, surgery for colorectal cancer in two hospitals between January 2011 and January 2013, n = 241. All patients had daily CRP measurement following surgery for the first four postoperative days. Complications were retrospectively classified by Clavien-Dindo grade. RESULTS: Of the 241 patients, the majority were male (59%) and were over 65 years old (69%). The majority had colonic (86%) and node negative (65%) disease. One hundred nineteen patients (49%) developed a complication, and 28 (12%) of these were Clavien-Dindo grade 3, 4 or 5. Median and established threshold CRP concentrations on postoperative days 2 (>190 mg/L), 3 (>170 mg/L) and 4 (>125 mg/L) were directly associated with an increase in the Clavien-Dindo grade (all p < 0.001). CONCLUSION: There was a direct association between exceeding established postoperative day 2, 3 and 4 CRP thresholds and the severity of complications defined by the Clavien-Dindo grade. PMID- 25922148 TI - Inferring biotic interactions from proxies. AB - Inferring biotic interactions from functional, phylogenetic and geographical proxies remains one great challenge in ecology. We propose a conceptual framework to infer the backbone of biotic interaction networks within regional species pools. First, interacting groups are identified to order links and remove forbidden interactions between species. Second, additional links are removed by examination of the geographical context in which species co-occur. Third, hypotheses are proposed to establish interaction probabilities between species. We illustrate the framework using published food-webs in terrestrial and marine systems. We conclude that preliminary descriptions of the web of life can be made by careful integration of data with theory. PMID- 25922149 TI - Optimizing flushing parameters in intracoronary optical coherence tomography: an in vivo swine study. AB - Intracoronary optical frequency domain imaging (OFDI), requires the displacement of blood for clear visualization of the artery wall. Radiographic contrast agents are highly effective at displacing blood however, may increase the risk of contrast-induced nephropathy. Flushing media viscosity, flow rate, and flush duration influence the efficiency of blood displacement necessary for obtaining diagnostic quality OFDI images. The aim of this work was to determine the optimal flushing parameters necessary to reliably perform intracoronary OFDI while reducing the volume of administered radiographic contrast, and assess the influence of flushing media choice on vessel wall measurements. 144 OFDI pullbacks were acquired together with synchronized EKG and intracoronary pressure wire recordings in three swine. OFDI images were graded on diagnostic quality and quantitative comparisons of flushing efficiency and intracoronary cross-sectional area with and without precise refractive index calibration were performed. Flushing media with higher viscosities resulted in rapid and efficient blood displacement. Media with lower viscosities resulted in increased blood-media transition zones, reducing the pullback length of diagnostic quality images obtained. Flushing efficiency was found to increase with increases in flow rate and duration. Calculations of lumen area using different flushing media were significantly different, varying up to 23% (p < 0.0001). This error was eliminated with careful refractive index calibration. Flushing media viscosity, flow rate, and flush duration influence the efficiency of blood displacement necessary for obtaining diagnostic quality OFDI images. For patients with sensitivity to contrast, to reduce the risk of contrast induced nephrotoxicity we recommend that intracoronary OFDI be conducted with flushing solutions containing little or no radiographic contrast. In addition, our findings show that careful refractive index compensation should be performed, taking into account the specific contrast agent used, in order to obtain accurate intravascular OFDI measurements. PMID- 25922150 TI - Effect of Infrared Blanching on Enzyme Activity and Retention of beta-Carotene and Vitamin C in Dried Mango. AB - The objectives of this work were to evaluate infrared (IR) dry blanching in comparison with conventional water blanching prior to hot air drying of mango to inactivate polyphenol oxidase (PPO) and ascorbic acid oxidase (AAO) enzymes, and to study its effect on color change and retention of vitamin C and beta-carotene. Mango cylinders were blanched under similar temperature-time conditions either by IR heating or by immersion in a water bath during 2 min at 90 degrees C (high temperature-short-time-HTST) or for 10 min at 65 degrees C (low-temperature-long time-LTLT). After blanching mango was hot air dried at 70 degrees C. PPO was completely inactivated during the blanching treatments, but AAO had a moderate remaining activity after LTLT treatment (~30%) and a low remaining activity after HTST treatment (9% to 15%). A higher retention of vitamin C was observed in mango subjected to IR dry blanching, 88.3 +/- 1.0% (HTST) and 69.2 +/- 2.9% (LTLT), compared with water blanching, 61.4 +/- 5.3% (HTST) and 50.7 +/- 9.6% (LTLT). All trans-beta-carotene retention was significantly higher in water blanched dried mango, 93.2 +/- 5.2% (LTLT) and 91.4 +/- 5.1% (HTST), compared with IR dry blanched, 73.6 +/- 3.6% (LTLT) and 76.9 +/- 2.9% (HTST). Increased levels of 13 cis-beta-carotene isomer were detected only in IR dry blanched mango, and the corresponding dried mango also had a slightly darker color. IR blanching of mango prior to drying can improve the retention of vitamin C, but not the retention of carotenoids, which showed to be more dependent on the temperature than the blanching process. A reduction of drying time was observed in LTLT IR-blanching mango. PMID- 25922152 TI - The Epilepsy Foundation's 4th Biennial Epilepsy Pipeline Update Conference. AB - On June 5 and 6, 2014, the Epilepsy Foundation held its 4th Biennial Epilepsy Pipeline Update Conference, an initiative of the Epilepsy Therapy Project, which showcased the most promising epilepsy innovations from health-care companies and academic laboratories dedicated to pioneering and advancing drugs, biologics, technologies, devices, and diagnostics for epilepsy. Speakers and attendees included emerging biotech and medical technology companies, major pharmaceutical and device companies, as well as investigators and innovators at the cutting-edge of epilepsy. The program included panel discussions on collaboration between small and large companies, how to get products in need of funding to the marketplace, who is currently funding epilepsy and CNS innovation, and how the NIH facilitates early-stage drug development. Finally, the conference featured the third annual "Shark Tank" competition. The presentations are summarized in this paper, which is followed by a compilation of the meeting poster abstracts. PMID- 25922151 TI - Implicit and explicit self-esteem discrepancies in people with psychogenic nonepileptic seizures. AB - PURPOSE: Self-esteem (SE), or one's sense of competence and worth, is reduced in many mental and physical disorders. Low SE is associated with perceived stigma and disability and poor treatment outcomes. The present study examined implicit and explicit SE (automatic and deliberate views about the self) in people with epilepsy and people with psychogenic nonepileptic seizures (PNESs). Discrepancies between implicit SE and explicit SE have been found to correlate with psychological distress in disorders often associated with PNESs but are relatively unexplored in PNESs. We hypothesized that, compared with epilepsy, PNESs would be associated with lower self-reported SE and greater discrepancies between implicit SE and explicit SE. METHODS: Thirty adults with PNESs, 25 adults with epilepsy, and 31 controls without a history of seizures were asked to complete the Rosenberg Self-esteem Scale as a measure of explicit SE and an Implicit Relational Assessment Procedure as a measure of implicit SE. The State Trait Anxiety Inventory and Patient Health Questionnaire-15 (a somatic symptom inventory) were also administered. RESULTS: We found significant group differences in explicit (p<0.001) but not implicit SE. Patients with PNESs reported lower SE than the other groups. No group differences were found in implicit SE. Implicit-explicit SE discrepancies were larger in the group with PNESs than in the other groups (p<0.001). Higher frequency of PNESs (but not epileptic seizures) was associated with lower explicit SE (rs=-.83, p<0.01) and greater SE discrepancies (i.e., lower explicit relative to implicit SE; rs=.65, p<0.01). These relationships remained significant when controlling for anxiety and somatization. CONCLUSION: Patients with PNESs had lower explicit SE than those with epilepsy or healthy controls. In keeping with our expectations, there were greater discrepancies between implicit SE and explicit SE among patients with PNESs than in the other groups. Our results, including the strong relationship between PNES frequency, anxiety, and explicit-implicit SE discrepancies, support the interpretation that PNESs serve to reduce cognitive dissonance, perhaps protecting patients' implicit SE. PMID- 25922153 TI - Effect of lipid bilayer properties on the photocycle of green proteorhodopsin. AB - The significance of specific lipids for proton pumping by the bacterial rhodopsin proteorhodopsin (pR) was studied. To this end, it was examined whether pR preferentially binds certain lipids and whether molecular properties of the lipid environment affect the photocycle. pR's photocycle was followed by microsecond flash-photolysis in the visible spectral range. It was fastest in phosphatidylcholine liposomes (soy bean lipid), intermediate in 3-[(3 cholamidopropyl) dimethylammonio] propanesulfonate (CHAPS): 1,2-dioleoyl-sn glycero-3-phosphocholine (DOPC) bicelles and in Triton X-100, and slowest when pR was solubilized in CHAPS. In bicelles with different lipid compositions, the nature of the head groups, the unsaturation level and the fatty acid chain length had small effects on the photocycle. The specific affinity of pR for lipids of the expression host Escherichia coli was investigated by an optimized method of lipid isolation from purified membrane protein using two different concentrations of the detergent N-dodecyl-beta-d-maltoside (DDM). We found that 11 lipids were copurified per pR molecule at 0.1% DDM, whereas essentially all lipids were stripped off from pR by 1% DDM. The relative amounts of copurified phosphatidylethanolamine, phosphatidylglycerol, and cardiolipin did not correlate with the molar percentages normally present in E. coli cells. The results indicate a predominance of phosphatidylethanolamine species in the lipid annulus around recombinant pR that are less polar than the dominant species in the cell membrane of the expression host E. coli. PMID- 25922154 TI - Imaging of cerebrovascular disorders: precision medicine and the collaterome. AB - Imaging of stroke and neurovascular disorders has profoundly enhanced clinical practice and related research during the last 40 years since the introduction of computed tomography (CT) and magnetic resonance imaging (MRI) enabled mapping of the brain. We highlight recent advances in neurovascular imaging. We describe how the convergence of readily available data and new clinical trial paradigms will recast our methods for studying the neurovascular patient. The application of a precision medicine approach to the collaterome, a comprehensive synthesis of neurovascular pathophysiology, will entail novel methods for clinical trial randomization, collection of routine and clinical trial imaging results, data archiving, and analysis. PMID- 25922155 TI - Early Stroke Risk after Transient Ischemic Attack in Patients without Large Artery Disease or Atrial Fibrillation. AB - BACKGROUND: Patients with transient ischemic attack (TIA) without large-artery disease (LAD) or atrial fibrillation (AF) on admission may be at higher risk of stroke than previously thought. The aim of this study was to investigate early stroke risk and its predictors in such patients. METHODS: We studied 410 TIA patients admitted to our institute within 48 hours of onset. Urgent etiological workup revealed that 210 patients had neither symptomatic LAD nor AF. The outcome measure was the stroke occurrence within 7 days after admission. RESULTS: Stroke occurred within 7 days in 15 patients, 7.1% of patients without LAD or AF and 6.5% of those with LAD or AF, showing no statistical difference between the 2 groups. Twelve of the 15 patients were diagnosed with small-vessel disease as the stroke etiology. In multivariable regression analysis, motor lacunar symptoms (odds ratio [OR], 5.7; 95% confidence interval [CI], 1.4-41.1), high systolic blood pressure on admission of 183 mm Hg or greater (OR, 15.3; 95% CI, 3.8-80.2), and positive diffusion-weighted imaging findings (OR, 6.1; 95% CI, 1.6-28.1) were independent predictors for the stroke occurrence within 7 days in patients without LAD or AF. CONCLUSIONS: TIA patients should be cautiously managed, even when neither LAD nor AF are identified by urgent workup. Clinical findings as motor lacunar symptom or high admission blood pressure, besides diffusion weighted imaging findings, may be helpful to predict early stroke in such patients. PMID- 25922156 TI - Large-Vessel Occlusion Stroke: Effect of Recanalization on Outcome Depends on the National Institutes of Health Stroke Scale Score. AB - BACKGROUND: Arterial recanalization is currently considered the main standard of successful early management of acute ischemic stroke. Intravenous (IV) thrombolysis with tissue plasminogen activator (tPa) is the only Food and Drug Administration-approved medical treatment. Large-vessel occlusion, estimated to account for up to 40% of all acute ischemic strokes, is often refractory to IV thrombolysis and is associated with a poor patient outcome. Mechanical recanalization procedures are therefore increasingly used in the treatment of large-vessel occlusion refractory to, or presenting outside the accepted time window for, IV thrombolysis. The aim of this study was to investigate the effect of early vessel recanalization on clinical outcome in patients with large-vessel occlusion stroke. METHODS: This is a single-center cohort study, analyzing prospectively collected data on 152 patients with large-vessel occlusion and acute ischemic stroke. Seventy-one patients received endovascular treatment (of whom 57.7% also received IV tPA), and 81 (55.6% of whom also received IV tPa) were not treated with endovascular therapy. Clinical outcome was compared for 2 cohorts: patients who recanalized (n = 46) and patients with persisting large vessel occlusion (n = 106). RESULTS: Early recanalization was an independent predictor of a good clinical outcome in only those patients who presented with a severe ischemic stroke (National Institutes of Health Stroke Scale [NIHSS] score >15; P = .017). This was not the case for less severe strokes (NIHSS score <= 15) where recanalization did not lead to more patients with functional independence at 90-day follow-up (P = .21). CONCLUSIONS: In this study of acute large-vessel occlusion stroke, we found that clinical outcome following early recanalization was dependent on the patient's pretreatment NIHSS score. A non-negligible proportion of patients with milder strokes did well despite persistent large vessel occlusion. These results may suggest that in patients who are able to maintain adequate collateral flow despite proximal arterial occlusion, effective adaptive mechanisms are present, which for some patients are long-lasting. This may influence the process of appropriate patient selection for endovascular therapy. PMID- 25922157 TI - Manipulation of sarcoplasmic reticulum Ca(2+) release in heart failure through mechanical intervention. AB - Left ventricular assist devices (LVADs) were developed as a means of temporary circulatory support, but the mechanical unloading they offer also results in significant reverse remodelling. In selected patients, these improvements are sufficient to allow ultimate device explantation without requiring transplantation; this represents a fundamental shift in our understanding of heart failure. Like heart failure itself, LVADs influence multiple biological systems. The transverse tubules are a system of membrane invaginations in ventricular cardiomyocytes which allow rapid propagation of the action potential throughout the cell. Through their dense concentration of L-type Ca(2+) channels in close proximity to intracellular ryanodine receptors, the t-tubules enable synchronous Ca(2+) release throughout the cell. The t-tubules' structure appears to be specifically regulated by mechanical load, such that either the overload of heart failure (or the spontaneously hypertensive rat model) or the profound unloading in a chronically unloaded heart result in impaired t-tubule structure, with ineffective Ca(2+) release. While there are multiple molecular pathways which underpin t-tubule regulation, Telethonin (Tcap) appears to be important in regulating the effect of altered loading on the t-tubule system. PMID- 25922158 TI - A biopsychosocial primary care intervention (Back on Track) versus primary care as usual in a subgroup of people with chronic low back pain: protocol for a randomised, controlled trial. AB - INTRODUCTION: Multidisciplinary biopsychosocial interventions are effective at improving functional disability in people with chronic low back pain. However, these interventions are often expensive and have long waiting times before treatment starts. Therefore, implementing biopsychosocial interventions in primary care settings may be of interest. Because people with chronic low back pain show different biopsychosocial profiles, they might respond differently to specific interventions. RESEARCH QUESTIONS: This study will investigate the difference in (cost) effectiveness between a biopsychosocial primary care intervention, Back on Track, and primary care physiotherapy as usual in a subgroup of adults with chronic low back pain. DESIGN: Double-blind, multicentre (n = 8), randomised, controlled trial. PARTICIPANTS: Eighty-six adults with chronic low back pain, aged 18 to 65 years, experiencing low to moderate levels of disability and in whom the contributing role of psychosocial factors to this disability is restricted. INTERVENTION: The Back on Track intervention: four individual and eight group sessions, based on biopsychosocial approaches from multidisciplinary pain rehabilitation programs and provided by trained physiotherapists. CONTROL: Primary care physiotherapy as usual. MEASUREMENTS: The primary outcome is functional disability (Quebec Back Pain Disability Scale) at post treatment, and 3-month and 12-month follow-up. Secondary measures are: credibility and expectancy, anxiety and depression, catastrophising, pain intensity, kinesiophobia, self-efficacy, participant's global perceived effect, cost-effectiveness, and cost-utility estimated with cost diaries and quality adjusted life years. ANALYSIS: Linear mixed models using an intention-to-treat principle. Incremental cost-effectiveness and cost-utility ratios will be calculated and plotted on a cost-effectiveness plane. DISCUSSION: This study will provide useful information on a biopsychosocial intervention for chronic low back pain in primary care settings. PMID- 25922159 TI - Chondroid syringomas: an immunohistopatological analysis. AB - BACKGROUND: Chondroid syringoma is a rare benign skin adnexal tumor composed of both epithelial and mesenchymal components, and is known as a cutaneous mixed tumor. Its clinical diagnosis is generally incorrect, and an exact diagnosis can only be made with histopathological investigations. The aim of this study was to determine the clinicopathological findings of the cases diagnosed with chondroid syringoma. METHODS: In this study, over the period from January 2008 to March 2014, a total of 2661 excised skin lesions were evaluated for the clinicopathological findings, and fifteen cases were diagnosed with chondroid syringoma. Various parameters such as gender, mean age, tumor localization and immunohistochemical markers (pan-cytokeratin, vimentin, S-100 protein, CEA-(M) and p53 were examined. RESULTS: Of the15 cases diagnosed with chondroid syringoma, 10 (67%) were male and 5 (33%) were female. The mean age of the patients was 46 (range 11-80 years). The chondroid syringomas were positive for pan-cytokeratin (87%), vimentin (100%), S-100 protein (100%), CEA-M (53%) and p53 (80%). CONCLUSIONS: Chondroid syringomas should be included in the differential diagnosis of a slowly growing, nodular mass in the dermis. Definitive diagnosis of the tumor is made by histopathological examination. Difficult cases may benefit from immunohistochemical examination. PMID- 25922160 TI - Influence of postharvest ultrasounds treatments on tomato (Solanum lycopersicum, cv. Zinac) quality and microbial load during storage. AB - Whole tomato fruits were treated at ultrasonic power levels from 10% to 100%, and at a constant frequency of 45 kHz, for different times (1-19 min). A central composite rotatable design (CCRD) was applied to optimise ultrasonic treatments for tomato quality (colour, texture and total phenolic content (TPC)) maintenance. According to response surface analysis, the optimal treatment parameters were 55%_10 min, 80%_15 min and 100%_19 min. At these conditions, and especially at higher power levels, a maximum retention of colour and texture, as well as an increase of TPC and microbial reduction were obtained in comparison with untreated fruits during 15 storage days at 10 degrees C. The ultrasounds treatment was found to be effective in delaying colour development and texture losses, preserving sensorial quality of whole tomato, with increase of TPC and microbial load reduction. Moreover, this postharvest treatment can be used as an alternative for extending fresh fruits shelf-life. PMID- 25922161 TI - [Diagnostic challenges during cranial osteonecrosis elucidation]. AB - This is a case report of an 81-year-old male with severe headaches caused by osteonecrotic lesions in the frontotemporal part of the skull. Initially, metastatic lesions were suspected but other causes had to be identified because of chronic inflammation evidence in all biopsies. In the diagnostic process a discussion of missed malignancy, morbus Paget and steroid induced avascular necrosis are presented. PMID- 25922162 TI - [HIV may be cured]. AB - The symposium IAS Towards an HIV Cure was held in Melbourne, Australia, in July 2014. There are several challenges regarding an HIV cure, among these the reservoir of latently infected CD4+ T cells which are hidden from the immune system. A new promising approach towards an HIV cure is the "shock and kill" strategy. Here, the latently infected cells are shocked to express HIV on the surface, and afterwards the shocked cells can be eradicated by apoptosis or destruction by the immune system. In this paper the most important results from the symposium are presented. PMID- 25922163 TI - [Lower extremity arterial entrapment syndromes]. AB - Iliac endofibrosis or iliac kinking and popliteal artery entrapment syndrome are uncommon causes of arterial insufficiency and intermittent claudication in young physically active adults. Diagnostics can be difficult, as the symptoms often are confused with sport injuries and musculoskeletal disorders. Investigation of these patients relies on accurate clinical history and examination as well as both static and dynamic imaging. Early diagnosis and vascular intervention is essential for continued exercise and to prevent thromboembolic complications and, in worst case, limb loss. PMID- 25922164 TI - [First case of extensively drug-resistant tuberculosis in Denmark]. AB - In 2013 the first case of extensively drug-resistant tuberculosis was observed in Denmark. A 40-year-old male immigrant had previously been treated with several different antibiotics in his native country Russia. Because of earlier imprisonment in Russia and the fear of reincarceration he did not fully inform the Danish authorities about his disease and treatment. Therefore, he was initially treated with first-line drugs. Once the whole truth emerged and the result of the resistance test was available he was admitted to a highly specialized unit for further treatment. PMID- 25922165 TI - [Fatal reaction to wasp sting in a patient allergic to wasp venom]. AB - A 68-year-old man suffered from anaphylaxis and cardiac arrest following wasp sting. He was resuscitated and taken to hospital where he later died from anoxic brain injury. Previously he had had an anaphylactic reaction to wasp venom but did not carry his auto-adrenaline-injector. Patients with anaphylaxis due to insect venom must be referred to allergological investigations. Furthermore, they should be educated in recognition and handling of anaphylaxis and they should be provided with a management plan and an auto-adrenaline-injector along with a thorough instruction on the appropriate use. PMID- 25922166 TI - [Medicine-caused itch, wounds and bullous skin in three patients with pseudoporphyria]. AB - Pseudoporphyria cutanea tarda is a well described bullous skin disorder which resembles porphyria cutanea tarda. However, the levels of porphyrins in plasma, urine and faeces are normal. We present three cases of patients with classical symptoms of pseudoporphyria. Two of the patients developed pseudoporphyria after the combination of intensive sunbathing and medications well known to cause pseudoporphyria. The third case received haemodialysis and furosemide. PMID- 25922167 TI - Comparison of biotransformation and efficacy of aminoacetonitrile anthelmintics in vitro. AB - The present in vitro study was designed to test and compare anthelmintic activity, hepatotoxicity, and biotransformation of four selected aminoacetonitrile derivatives (AADs): monepantel (MOP, anthelmintic approved for the treatment), AAD-970, AAD-1154, and AAD-1336. Micro-agar larval development test, MTT test of cytotoxicity, and biotransformation study coupled with Ultra high performance liquid chromatography-tandem mass spectrometry (UHPLC-MS/MS) technique were used for this purpose. Larvae of two Haemonchus contortus strains (drug susceptible and multi-drug resistant) and primary cultures of rat and ovine hepatocytes served as model systems. All AADs (including MOP) exhibited significant larvicidal effect in H. contortus susceptible as well as multi resistant strains, much higher than those of reference anthelmintics thiabendazole and flubendazole. AAD-1154 provides the best results for most tested parameters among all AADs in this study. The cytotoxicity test showed that all AADs can be considered as nontoxic for hepatocytes. In the biotransformation study, Phase I and Phase II metabolites of AADs were identified and schemes of possible metabolic pathways in ovine hepatocytes were proposed. Biotransformation of MOP was much more extensive than biotransformation of other AADs. Based on obtained results, AAD-1154 and AAD-1336 can be considered as promising candidates for further in vivo testing. PMID- 25922168 TI - Recovery of indium from LCD screens of discarded cell phones. AB - Advances in technological development have resulted in high consumption of electrical and electronic equipment (EEE), amongst which are cell phones, which have LCD (liquid crystal display) screens as one of their main components. These multilayer screens are composed of different materials, some with high added value, as in the case of the indium present in the form of indium tin oxide (ITO, or tin-doped indium oxide). Indium is a precious metal with relatively limited natural reserves (Dodbida et al., 2012), so it can be profitable to recover it from discarded LCD screens. The objective of this study was to develop a complete process for recovering indium from LCD screens. Firstly, the screens were manually removed from cell phones. In the next step, a pretreatment was developed for removal of the polarizing film from the glass of the LCD panels, because the adherence of this film to the glass complicated the comminution process. The choice of mill was based on tests using different equipment (knife mill, hammer mill, and ball mill) to disintegrate the LCD screens, either before or after removal of the polarizing film. In the leaching process, it was possible to extract 96.4 wt.% of the indium under the following conditions: 1.0M H2SO4, 1:50 solid/liquid ratio, 90 degrees C, 1h, and stirring at 500 rpm. The results showed that the best experimental conditions enabled extraction of 613 mg of indium/kg of LCD powder. Finally, precipitation of the indium with NH4OH was tested at different pH values, and 99.8 wt.% precipitation was achieved at pH 7.4. PMID- 25922169 TI - Mitochondrial Lon protease controls ROS-dependent apoptosis in cardiomyocyte under hypoxia. AB - Apoptosis of cardiomyocytes, under ischemic conditions, has been identified as an essential process in the progression of heart failure. Under hypoxic conditions, mitochondria can become a threat to the cell because of their capacity to generate reactive oxygen species (ROS). As ROS appear to have a critical role in heart failure, there has been considerable interest in identifying the candidate proteins involved and in developing strategies to reduce oxidative stress. Lon protease (Lon) is a multifunctional protein that mediates protein quality control and stress response in mitochondria. However, comprehensive and detailed studies, on the role of Lon in hypoxia-induced cardiomyocyte apoptosis, have yet to be carried out. In the present study, we demonstrated that hypoxia induced ROS dependent cardiomyocyte apoptosis. Lon was upregulated in hypoxia-induced cardiomyocytes. Lon downregulation attenuated hypoxia-induced cardiomyocyte apoptosis through a reduction of ROS level. Moreover, overexpression of Lon stimulated ROS production and induced apoptosis under normoxic conditions in cardiomyocytes. Our results identify Lon as a novel regulator of cardiomyocyte fate and offers exciting new insights into the therapeutic potential of hypoxia induced cardiomyocyte apoptosis. PMID- 25922170 TI - Use of immobilized cryopreserved bovine semen in a blind artificial insemination trial. AB - To make timing of artificial insemination (AI) relative to ovulation less critical, methods for prolonging shelf life of spermatozoa in vivo after AI have been attempted to be developed. Encapsulation of sperm cells is a documented technology, and recently, a technology in which sperm cells are embedded in alginate gel has been introduced and commercialized. In this study, standard processed semen with the Biladyl extender (control) was compared with semen processed by sperm immobilization technology developed by SpermVital AS in a blind field trial. Moreover, in vitro acrosome and plasma membrane integrity was assessed and compared with AI fertility data for possible correlation. Semen from 16 Norwegian Red young bulls with unknown fertility was collected and processed after splitting the semen in two aliquots. These aliquots were processed with the standard Biladyl extender or the SpermVital extender to a final number of 12 * 10(6) and 25 * 10(6) spermatozoa/dose, respectively. In total, 2000 semen doses were produced from each bull, divided equally by treatment. Artificial insemination doses were set up to design a blinded AI regime; 5 + 5 straws from each extender within ejaculates in ten-straw goblets were distributed to AI technicians and veterinarians all over Norway. Outcomes of the inseminations were measured as 56-day nonreturn rate (NRR). Postthaw sperm quality was assessed by flow cytometry using propidium iodide and Alexa 488-conjugated peanut agglutinin to assess the proportion of plasma membrane and acrosome-intact sperm cells, respectively. In total, data from 14,125 first inseminations performed over a 12 month period, 7081 with Biladyl and 7044 with SpermVital semen, were used in the statistical analyses. There was no significant difference in 56-day NRR for the two semen categories, overall NRR being 72.5% and 72.7% for Biladyl and SpermVital, respectively. The flow cytometric results revealed a significant higher level of acrosome-intact live spermatozoa in Biladyl-processed semen compared to SpermVital semen. The results indicate that the level of acrosome intact live spermatozoa in the AI dose did not affect the 56-day NRR for the two semen processing methods. In conclusion, this study has showed that immobilized spermatozoa provide equal fertility results as standard processed semen when AI is performed in a blinded field trial, although the immobilization procedure caused increased sperm damage evaluated in vitro compared to standard semen processing procedure. PMID- 25922171 TI - Long-term characteristics of idiopathic persistent corpus luteum in the mare. AB - Persistent CL (PCL; n = 10) in mares was studied daily from Day 20 (Day 0 = ovulation) to the ending ovulation. In addition, the 10 days before ovulation at the end of a PCL were compared with the end of an interovulatory interval (IOI; n = 28) during the same months. Concentration of P4, cross-sectional area of CL, and percentage of CL with Doppler signals of blood flow during PCLs remained constant from 64 to about 33 days before the end of luteolysis and then decreased linearly. Concentration of LH between Day 20 and beginning of the ovulatory LH surge increased linearly. A dominant follicle developed on average every 15 days throughout each PCL. Novel transient P4 depressions were detected with the P4 nadir at a day of maximal diameter of a dominant follicle. At the apparent beginning of luteolysis before the ending ovulation, P4 concentration in PCLs (5.0 +/- 0.5 ng/mL) was less (P < 0.0001) than that in IOIs (9.3 +/- 0.6 ng/mL). Concentration of LH began to increase 2 days before the end of luteolysis in each group, but concentration on the day of the ending ovulation in PCLs (3.7 +/- 0.3 ng/mL) was less (P < 0.005) than that in IOIs (8.9 +/- 1.8 ng/mL). In a separate survey of PCLs (n = 23) and IOIs (n = 352), frequency of PCL (6.1%) differed significantly among mares indicating repeatability. These original and critical comparisons between PCLs and IOIs should provide hypotheses for further study. PMID- 25922172 TI - Serum antibody immunoreactivity to equine zona protein after SpayVac vaccination. AB - Immunocontraception with porcine ZP (pZP) can be an effective means of fertility control in feral horses. Previous studies suggest that antibodies produced after pZP vaccination may both inhibit fertilization and cause follicular dysgenesis. Zonastat-H, PZP-22, and SpayVac are three pZP vaccines proposed for use in horses. Although all these vaccines contain the pZP antigen, variations in antigen preparation and vaccine formulation lead to differences in antigenic properties among them. Likewise, despite numerous efficacy and safety studies of Zonastat-H and PZP-22, the contraceptive mechanisms of SpayVac remain unclear. The preparation of pZP for SpayVac is thought to include more nonzona proteins, making it less pure than the other two vaccines. This may result in increased antigenicity of the vaccine. We therefore investigated the immunoreactivity of serum antibodies from SpayVac-vaccinated mares to equine zona protein. Western blot analyses revealed an immunoreactivity of these antibodies to protein isolated from mature equine oocytes, ZP, follicular tissues, and ovarian tissues. Immunohistochemical analyses were used to locate the binding of serum antibodies to the ZP of immature oocytes in ovarian stromal tissue. We also found serum antibodies from SpayVac-treated mares to be predominantly specific for zona protein 3. Collectively, our results suggest a model where serum antibodies produced in response to SpayVac vaccination are immunoreactive to equine zona protein in vitro. Our study lends insight into the contraceptive mechanisms underlying the infertility observed after SpayVac vaccination. PMID- 25922173 TI - Can therapeutic hypothermia trigger propofol-related infusion syndrome? PMID- 25922174 TI - Exogenous attention to unseen objects? AB - Attention and awareness are closely related phenomena, but recent evidence has shown that not all attended stimuli give rise to awareness. Controversy still remains over whether, and the extent to which, a dissociation between attention and awareness encompasses all forms of attention. For example, it has been suggested that attention without awareness is more readily demonstrated for voluntary, endogenous attention than its reflexive, exogenous counterpart. Here we examine whether exogenous attentional cueing can have selective behavioural effects on stimuli that nevertheless remain unseen. Using a task in which object based attention has been shown in the absence of awareness, we remove all possible contingencies between cues and target stimuli to ensure that any cueing effects must be under purely exogenous control, and find evidence of exogenous object-based attention without awareness. In a second experiment we address whether this dissociation crucially depends on the method used to establish that the objects indeed remain unseen. Specifically, to confirm that objects are unseen we adopt appropriate signal detection task procedures, including those that retain parity with the primary attentional task (by requiring participants to discriminate the two types of trial that are used to measure an effect of attention). We show a significant object-based attention effect is apparent under conditions where the selected object indeed remains undetectable. PMID- 25922175 TI - Synthesis and Anti-tumor Activities of Novel Phenyl Substituted Suberoylanilide Hydroxamic Acid Derivatives Against Human Cancer Cells. AB - A facile and atom-economical boric acid catalyzed direct amidation without any coupling agents for the preparation of Suberoylanilide Hydroxamic Acid (SAHA) and SAHA-based inhibitors targeting anti-proliferation of cancer cells is described. It is applicable to the preparation of SAHA-based inhibitors having an unprotected hydroxyl group in the phenyl ring without the need of the protection. The in-vitro assays data indicate that the nature and the position of the substituents (activating and/or deactivating) in the capping group (phenyl ring) of SAHA-based inhibitors synthesized in this study have a vital impact on the potency of anti-proliferative activity against cancer cells. With low toxicity toward the normal cells, a number of synthesized SAHA-based inhibitors with two substituents in the phenyl ring possess higher antiproliferative activity than SAHA and Cisplatin toward six studied cancer cell lines: A375 human skin cancer cells, A549 human lung cancer cells, MGC80-3 human gastric cancer cells, H460 human lung cancer cells, H1299 human lung cancer cells, and HepG2 human liver cancer cells. Cisplatin is a common chemotherapeutic drug with high cytotoxicity for a variety of cancer treatments. The inhibitors provided in this study might signify future therapeutic drugs for cancer treatment. PMID- 25922176 TI - Gestational Influenza Increases the Risk of Psychosis in Adults. AB - Psychotic disorders are complex and caused by interplay of genetic and environmental factors. Influenza is a common infectious disease in humans, and it has been suggested that maternal influenza is an estimated risk factor for psychotic disorders, especially for schizophrenia. In view of conflicting results of this association in literature, we performed the strict meta-analysis to examine whether maternal influenza is a risk factor for psychosis in the children. Four ecological studies and three birth cohort studies were included in our meta-analysis. It has been observed that the Risk Ratio (RR) of maternal influenza on psychosis is 1.062 (95% Confidence Interval (CI) = 1.004-1.123) for the analysis of ecological studies and the RR is 1.564(95%CI=1.051-2.324) for the analysis of birth cohort studies. Furthermore, a survey of pregnant women and fetus' health in Nanjing of China indicated that only 1.5% of women received the influenza vaccine before pregnancy, 0.4% received it during pregnancy, and 5.1% were willing to receive the influenza vaccine if necessary. These results showed that gestational influenza could increase mental disorders risks in adult offspring besides its established harms for gravidas. Results suggest it might be effective to increase attention to gravidas to protect them from influenza infection through encouragement of vaccinations. PMID- 25922177 TI - Effects of UGT1A4 genetic polymorphisms on serum lamotrigine concentrations in Chinese children with epilepsy. AB - Lamotrigine (LTG) is widely used in the treatment of children with epilepsy. Genetic polymorphisms in genes encoding drug-metabolizing enzymes may be an important source of interindividual variability in LTG metabolism. The aim of this study was to evaluate the effects of genetic polymorphisms of uridine diphosphate glucuronosyltransferase (UGT) 1A4 (UGT1A4) gene on LTG serum concentrations in children with epilepsy. The UGT1A4 142T > G in the coding regions and -219C > T/-163G > A in the 5'-upstream regions were genotyped using polymerase chain reaction amplification followed by direct automated DNA sequencing in 148 patients treated with polytherapy with LTG and valproic acid (VPA). Our data showed that patients carrying the variant UGT1A4 -219C > T/-163G > A genotypes or alleles had significantly higher adjusted LTG concentrations than those carrying the wild-type genotypes or alleles. However, the significant association was abrogated after adjusted by age, body weight, and adjusted VPA concentration. No associations were detected between the UGT1A4 142T > G genotypes or alleles and adjusted LTG concentrations. Taken together, these results suggest that the -219C > T/-163G > A mutations in the 5'-upstream regions of the UGT1A4 gene affect LTG pharmacokinetics, with which is potentially interfered by age, body weight, and concomitant VPA administration. PMID- 25922178 TI - Global and country underestimation of hepatocellular carcinoma (HCC) in 2012 and its implications. AB - PURPOSE: The problems of screening costs, as well as poor data, potentially lead to the underestimation of the incidence of hepatocellular carcinoma (HCC). In particular, this is problematic in developing countries with limited resources and poor data. The study develops a model to inform policy makers of the true incidence and potential extra cost of HCC in a developing country context. METHODS: Using Globocan 2012 data, we employed an ecological correlation design at country level to associate HCC incidence data with relevant determinant data like HBV-HCV and other exposure factors. A Poisson regression model was used to estimate potentially missed incident cases of HCC by country and region based on the country risk factor covariate values. RESULTS: The results indicated that HBV and HCV prevalence were significantly associated with HCC incidence (p<0.001) and potentially accounted for 94%% of incident HCC in 2012. We estimated a total of 120,772 potentially missed incident HCC cases in 2012. These cases are largely predicted for South Asia (>21,000), North Asia (>15,000), Western Africa (14,500) and Eastern Africa (12,500). CONCLUSIONS: Developing countries, with poorer quality data and a high historical burden of hepatitis, were predicted to have the majority of missed HCC cases in 2012 based on our model. These countries are, therefore, less able to detect, budget for or manage HCC. The high cost of HCC treatment, as well as its economic implications, poses a challenge in resource poor settings. PMID- 25922179 TI - Design, synthesis and evaluation of novel 2-butyl-4-chloroimidazole derived peptidomimetics as Angiotensin Converting Enzyme (ACE) inhibitors. AB - A series of novel 2-butyl-4-chloro-1-methylimidazole derived peptidomimetics were designed, synthesized and evaluated for their Angiotensin Converting Enzyme (ACE) inhibitor activity. 2-Butyl-4-chloro-1-methylimidazole-5-carboxylic acid 2 obtained after oxidation of respective carboxaldehyde 1, was condensed with various amino acid methyl esters 3a-k to give imidazole-amino acid conjugates 4a k in very good yields. Ester hydrolysis of 4a-k with aqueous LiOH gave the desired peptidomimetics 5a-k. Screening all the new compounds 4a-k and 5a-k using ACE inhibition assay, resulted five compounds 4i, 4k, 5e, 5h and 5i as potent ACE inhibitors with IC50 of 0.647, 0.531, 1.12, 0.657 and 0.100MUM with minimal toxicity. Among them, 5i emerged as most active ACE inhibitor with greater potency than marketed drugs Lisinopril, Ramipril and relatively equipotent to Benazepril, Quinapril and Enalapril. PMID- 25922180 TI - Development and validation of a novel assay to identify radiosensitizers that target nucleophosmin 1. AB - A series of indole analogs that are synthesized using the scaffold of a potent radiosensitizer, YTR107, were tested for their ability to alter the solubility of phosphorylated nucleophosmin 1 (pNPM1). NPM1 is critical for DNA double strand break (DSB) repair. In response to formation of DNA DSBs, phosphorylated T199 NPM1 binds to ubiquitinated chromatin, in a RNF8/RNF168-dependent manner, forming irradiation-induced foci (IRIF) that promote repair of DNA DSBs. A Western blot assay was developed using lead molecule, YTR107, for the purpose of screening newly synthesized molecules that target pNPM1 in irradiated cells. A colony formation assay was used to demonstrate the radiosensitization properties of the compounds. Compounds that enhanced the extractability of pNPM1 upon radiation treatment possessed radiosensitization properties. PMID- 25922181 TI - Structure-based design, synthesis and biological testing of piperazine-linked bis epipodophyllotoxin etoposide analogs. AB - Drugs that target DNA topoisomerase II, such as the epipodophyllotoxin etoposide, are a clinically important class of anticancer agents. A recently published X-ray structure of a ternary complex of etoposide, cleaved DNA and topoisomerase IIbeta showed that the two intercalated etoposide molecules in the complex were separated by four DNA base pairs. Thus, using a structure-based design approach, a series of bis-epipodophyllotoxin etoposide analogs with piperazine-containing linkers was designed to simultaneously bind to these two sites. It was hypothesized that two-site binding would produce a more stable cleavage complex, and a more potent anticancer drug. The most potent bis-epipodophyllotoxin, which was 10-fold more growth inhibitory toward human erythroleukemic K562 cells than etoposide, contained a linker with eight methylene groups. All of the mono- and bis-epipodophyllotoxins, in a variety of assays, showed strong evidence that they targeted topoisomerase II. COMPARE analysis of NCI 60-cell GI50 endpoint data was also consistent with these compounds targeting topoisomerase II. PMID- 25922182 TI - Synthesis and evaluation of quinazoline amino acid derivatives as mono amine oxidase (MAO) inhibitors. AB - A series of quinazolinone amino acid ester and quinazolinone amino acid hydrazides were prepared under microwave irradiation as well as conventional condition. The microwave irradiation afforded the product in less reaction time, higher yield and purity. The structures of the synthesized compounds were confirmed by IR, NMR, and elemental analysis. The new synthesized compounds were studied for their monoamine oxidase inhibitory activity. They showed more selective inhibitory activity toward MAO-A than MAO-B. Compounds 7, 10, and 15 showed MAO-A inhibition activity (IC50=3.6*10(-9), 2.8*10(-9), 2.1*10(-9) M, respectively) comparable to that of the standard clorgyline (IC50=2.9*10(-9)M). 2 (2-(Benzo[d][1,3]dioxol-5-yl)-4-oxo-1,2-dihydroquinazolin-3(4H)-yl)acetohydrazide 15 showed selective MAO-A inhibition activity (SI=39524) superior to that of the standard clorgyline (SI=33793). The acute toxicity of the synthesized compounds was determined. In addition, computer-assisted simulated docking experiments were performed to rationalize the biological activity. PMID- 25922184 TI - The Relations Between Temperament, Character, and Executive Functions in Children With ADHD and Clinical Controls. AB - OBJECTIVE: The purpose of this study was to investigate the overlap between executive functions and temperament as measured by two questionnaires and to examine characteristic profiles in children with ADHD and clinical controls. METHOD: Parents of 111 clinically referred children, half of whom were diagnosed with ADHD and half with other or no diagnoses, completed the Behavior Rating Inventory of Executive Function (BRIEF) and the Cloninger Junior Temperament and Character Inventory (JTCI). RESULTS: Factor analysis of both instruments resulted in three common factors representing aspects of (1) cognitive regulation, (2) behavioral regulation, and (3) anxious/rigid tendencies. Factor (4) represented strengths and positive resources and loaded on JTCI scales only. Both instruments discriminated significantly between ADHD and non-ADHD children. Conduct disorder/oppositional defiant disorder (CD/ODD) but not ADHD accounted for problems in BRIEF Emotional Control and Self-Monitor and JTCI low Cooperativeness. CONCLUSION: The two instruments only partially overlap and may complement each other. PMID- 25922183 TI - Chimeric derivatives of functionalized amino acids and alpha-aminoamides: compounds with anticonvulsant activity in seizure models and inhibitory actions on central, peripheral, and cardiac isoforms of voltage-gated sodium channels. AB - Six novel 3"-substituted (R)-N-(phenoxybenzyl) 2-N-acetamido-3 methoxypropionamides were prepared and then assessed using whole-cell, patch clamp electrophysiology for their anticonvulsant activities in animal seizure models and for their sodium channel activities. We found compounds with various substituents at the terminal aromatic ring that had excellent anticonvulsant activity. Of these compounds, (R)-N-4'-((3"-chloro)phenoxy)benzyl 2-N-acetamido-3 methoxypropionamide ((R)-5) and (R)-N-4'-((3"-trifluoromethoxy)phenoxy)benzyl 2-N acetamido-3-methoxypropionamide ((R)-9) exhibited high protective indices (PI=TD50/ED50) comparable with many antiseizure drugs when tested in the maximal electroshock seizure test to mice (intraperitoneally) and rats (intraperitoneally, orally). Most compounds potently transitioned sodium channels to the slow-inactivated state when evaluated in rat embryonic cortical neurons. Treating HEK293 recombinant cells that expressed hNaV1.1, rNaV1.3, hNaV1.5, or hNaV1.7 with (R)-9 recapitulated the high levels of sodium channel slow inactivation. PMID- 25922185 TI - Association Between Continuous Performance and Response Inhibition Tests in Adults With ADHD. AB - OBJECTIVE: The study of ADHD uses various computerized tests to assess cognitive functions. Uncertainty exists regarding the association between deficits found by different tools testing similar or different cognitive functions (e.g., continuous performance tests [CPT] and response inhibition [RI] tests).We hypothesized that different tools that measure continuous performance will be better correlated between themselves than with a tool that examines RI. METHOD: Thirty-six adults with ADHD performed two different CPTs and a RI task. We analyzed correlations between different measures examined by the tasks. RESULTS: There were strong correlations between corresponding measures in the CPTs. Correlations between the results in CPT and the RI task were only minimal. CONCLUSION: These findings support the specificity of impairments in different cognitive domains (continuous attention vs. RI) beyond the specific test used in the study of ADHD. Also, these findings strengthen the importance of specific discriminative cognitive domains in ADHD. PMID- 25922186 TI - Development and validation of an LC-MS/MS method for the simultaneous analysis of 28 specific narcotic adulterants used in dietary supplements. AB - The purpose of this study was to develop a method to analyse the concentration of multiple illegal narcotics present in dietary supplements. To this end, we established and optimised a procedure using LC-MS/MS simultaneously to analyse 28 narcotic compounds in various forms of dietary supplements, including powders, tablets, liquids and capsules. In addition, candy and cookies that have also had detected cases of adulteration were also analysed. The specificity, linearity, accuracy, precision, limit of detection (LOD), limit of quantitation (LOQ), stability and recovery for these methods were validated accordingly. The LOD and LOQ of the LC-MS/MS ranged from 0.01-50.0 to 0.03-100 ng g(-1), respectively. The linearity of these results was good (r(2) > 0.99), with intra- and inter-day precision values of 0.2-5.2% and 0.2-4.8%, respectively. Further, the intra- and inter-day accuracies of this method were 97.0-103.4% and 94.6-103.1%, respectively. The stability RSD was less than 7.8%. The mean recovery for this LC MS/MS procedure was 81.1-117.4%, with an RSD less than 9.8%. Following the validation of our method, we analysed 47 commercially available dietary supplements obtained in Korea. Whilst none of these samples had detectable amounts of the 28 specified narcotic adulterants, our novel LC-MS/MS procedure can be utilised comprehensively and continually to monitor illegal drug adulteration in various forms of dietary supplements. PMID- 25922188 TI - Paracetamol should remain the first line option for persistent pain. PMID- 25922189 TI - The effect of oxygen content during an initial sustained inflation on heart rate in asphyxiated near-term lambs. AB - OBJECTIVE: At birth, an initial sustained inflation (SI) uniformly aerates the lungs, increases arterial oxygenation and rapidly improves circulatory recovery in asphyxiated newborns. We hypothesised that lung aeration, in the absence of an increase in arterial oxygenation, can increase heart rate (HR) in asphyxiated near-term lambs. INTERVENTIONS: Lambs were delivered and instrumented at 139+/-2 days of gestation. Asphyxia was induced by umbilical cord clamping and then delaying the onset of ventilation until mean carotid arterial pressures (CAPs) had decreased <20 mm Hg. Lambs then received a single 30-s SI using nitrogen (N2; n=6), 5% oxygen (O2; n=6), 21% O2 (n=6) or 100% O2 (n=6) followed by ventilation in air for 30 min. MAIN OUTCOME MEASURES: HR, CAP and pulmonary blood flow (PBF) were continuously recorded. RESULTS: HR and PBF increased more quickly in lambs resuscitated with 100% and 21% O2 than with 5% O2 or N2. HR and PBF recovery in the 5% O2 group was delayed relative to all other oxygen SI groups. HR in 5%, 21% and 100% O2 groups reached 100 bpm before the SI was complete. HR and PBF in the N2 group did not increase until 10 s after the SI was completed and ventilation was initiated with air. CAP tended to increase quicker in all O2 groups than in N2 group. CONCLUSIONS: Oxygen content during an SI is important for circulatory recovery in asphyxiated lambs. This increase in HR is likely driven by the increase in PBF and venous return to the heart. PMID- 25922191 TI - Geographic access to gynecologic cancer care in the United States. AB - BACKGROUND: Women who live distant from the closest subspecialty treatment center are at risk of failing to utilize high-quality care for gynecologic cancers. There has not yet been a comprehensive, national investigation of populations affected by geographic barriers to gynecologic cancer care. METHODS: Geographic Information Systems (GIS) were used to identify United States counties farther than 50miles from the closest gynecologic oncologist, and hospital referral regions (HRRs) that do not contain the primary professional address of at least one gynecologic oncologist. US Census data were used to analyze counties' demographic characteristics. County-level cancer incidence was estimated using the Centers for Disease Control and Prevention's State Cancer Profiles. RESULTS: Thirty-six percent (1125/3143) of counties are further than 50miles from the nearest gynecologic oncologist. A total of 14.8 million women live in low-access counties (LACs). Annually, approximately 7663 women with gynecologic cancers may experience geography-related disparities in access. Residents of LACs have lower median household income, are more likely to be White and/or Hispanic, and less likely to be Black. Forty percent (123/306) of HRRs do not contain the primary address of a gynecologic oncologist. CONCLUSIONS: Approximately 9% of the female population of the United States may experience geographic barriers to access high quality care for gynecologic malignancies. Future investigations should assess whether residents of low-access counties utilize high-quality care less often, and whether there is a disparity in clinical outcomes. Disparities might be addressed by ensuring subspecialty care in low-access regions, and/or adjusting system structures to minimize the burdens of traveling long distances for cancer care. PMID- 25922190 TI - A randomised trial of granulocyte-macrophage colony-stimulating factor for neonatal sepsis: childhood outcomes at 5 years. AB - OBJECTIVE: We performed a randomised trial in very preterm, small for gestational age (SGA) babies to determine if prophylaxis with granulocyte macrophage colony stimulating factor (GM-CSF) improves outcomes (the PROGRAMS trial). GM-CSF was associated with improved neonatal neutrophil counts, but no change in other neonatal or 2-year outcomes. As subtle benefits in outcome may not be ascertainable until school age we performed an outcome study at 5 years. PATIENTS AND METHODS: 280 babies born at 31 weeks of gestation or less and SGA were entered into the trial. Outcomes were assessed at 5 years to determine neurodevelopmental and general health status and educational attainment. RESULTS: We found no significant differences in cognitive, general health or educational outcomes between 83 of 106 (78%) surviving children in the GM-CSF arm compared with 81 of 110 (74%) in the control arm. Mean mental processing composite (equivalent to IQ) at 5 years were 94 (SD 16) compared with 95 (SD 15), respectively (difference in means -1 (95%CI -6 to 4), and similar proportions were in receipt of special educational needs support (41% vs 35%; risk ratio 1.2 (95% CI 0.8 to 1.9)). Performance on Kaufmann-ABC subscales and components of NEPSY were similar. The suggestion of worse respiratory outcomes in the GM-CSF group at 2 years was replicated at 5 years. CONCLUSIONS: The administration of GM CSF to very preterm SGA babies is not associated with improved or more adverse neurodevelopmental, general health or educational outcomes at 5 years. TRIAL REGISTRATION NUMBER: ISRCTN42553489. PMID- 25922192 TI - Long-term Efficacy and Safety Results: Can Enzalutamide Challenge the Dogma of Androgen Deprivation Therapy in Hormone-naive Prostate Cancer? PMID- 25922193 TI - Yin Yang. PMID- 25922196 TI - Management and Outcomes Among Chinese Hospitalized Patients With Established Cardiovascular Disease or Multiple Risk Factors. AB - We assessed the management and outcomes among hospitalized patients with coronary artery disease (CAD), stroke, peripheral artery disease (PAD), or with multiple (>= 2) cardiovascular (CV) risk factors (multiple risk factors [MRFs]). We retrospectively studied 3732 hospitalized patients of either CV disease or >= 2 risk factors for atherothrombosis from October 2004 to January 2005. Outcomes included CV death, myocardial infarction (MI), stroke, and hospitalization for atherothrombotic events. About one-third had disease involving >= 1 vascular bed. Medication was more intense in patients with CAD than in others. The lowest use of statins and antiplatelet treatment was in the PAD-only group. Patients with PAD experienced a higher CV mortality (5.1%) than the patients with CAD (3.73%) or stroke (4.1%), P < .001. Cardiovascular death ranged from 1.2% for patients with MRFs, 2.8% for patients with 1-bed disease, 4.7% for patients with 2-bed disease to 6.4% for patients with 3-bed disease (P for trend <.001). For hospitalized patients with established atherosclerotic arterial disease, a substantial increase in CV event rates occurs with increasing numbers of affected arterial beds. Patients with PAD were at an especially high risk. PMID- 25922197 TI - Association of Platelet to Lymphocyte Ratio With Inflammation and Severity of Coronary Atherosclerosis in Patients With Stable Coronary Artery Disease. AB - The platelet to lymphocyte ratio (PLR) has recently emerged as a potential inflammatory biomarker. Hence, we assessed the relationship between PLR and the extent/severity of coronary artery disease (CAD) using the Gensini score in association with the inflammatory marker C-reactive protein (CRP) in patients with stable CAD. Angiographic data of 1646 patients were analyzed in this cross sectional study. Patients were categorized according to Gensini scores as no CAD (control), mild, and severe CAD groups. The PLR in the control group was significantly lower than those of mild and severe CAD groups. In multivariate logistic regression analysis, PLR was found to be an independent predictor of the presence of severe CAD (odds ratio: 1.043 [1.036-1.049], P < .001). Furthermore, there was a significant correlation between PLR and the severity of CAD (r = .370, P < .001) and CRP levels (r = .312, P < .001). In conclusion, PLR was independently and positively associated with the severity of coronary atherosclerosis. These results suggest that PLR is an easily available and cheap inflammatory indicator that can be used in predicting the severity of CAD. PMID- 25922198 TI - EBV-associated lymphoepithelioma-like carcinoma of the pancreas: Case report with targeted sequencing analysis. AB - Lymphoepithelioma-like carcinomas are distinctive epithelial derived malignant neoplasms that have a syncytial growth pattern and lymphoid stroma. The majority of tumors with this appearance are Epstein Barr virus (EBV)-associated. We report a patient with a clinical presentation concerning for lymphoma who was diagnosed with an EBV-associated pancreatic carcinoma with a lymphoepithelioma-like pattern. Targeted sequencing analysis showed a molecular profile distinct from conventional ductal adenocarcinoma of the pancreas. PMID- 25922199 TI - Human FAN1 promotes strand incision in 5'-flapped DNA complexed with RPA. AB - Fanconi anaemia (FA) is a human infantile recessive disorder. Seventeen FA causal proteins cooperatively function in the DNA interstrand crosslink (ICL) repair pathway. Dual DNA strand incisions around the crosslink are critical steps in ICL repair. FA-associated nuclease 1 (FAN1) is a DNA structure-specific endonuclease that is considered to be involved in DNA incision at the stalled replication fork. Replication protein A (RPA) rapidly assembles on the single-stranded DNA region of the stalled fork. However, the effect of RPA on the FAN1-mediated DNA incision has not been determined. In this study, we purified human FAN1, as a bacterially expressed recombinant protein. FAN1 exhibited robust endonuclease activity with 5'-flapped DNA, which is formed at the stalled replication fork. We found that FAN1 efficiently promoted DNA incision at the proper site of RPA coated 5'-flapped DNA. Therefore, FAN1 possesses the ability to promote the ICL repair of 5'-flapped DNA covered by RPA. PMID- 25922200 TI - Eph/ephrin reverse signalling induces axonal retraction through RhoA/ROCK pathway. AB - Eph/ephrin signalling plays essential roles in various tissue developments, such as axon guidance, angiogenesis and tissue separation. Interaction between Ephs and ephrins upon cell-cell contact results in forward (towards Eph-expressing cells) and reverse (towards ephrin-expressing cells) signalling. Although the molecular mechanisms downstream of Eph/ephrin forward signalling have been extensively studied, the functions and intracellular molecular mechanisms of Eph/ephrin reverse signalling are not fully understood. Rho GTPases are key regulators of the actin cytoskeleton to regulate cell morphology. In this study, we revealed that stimulation with the extracellular domain of EphB2 to activate Eph/ephrin reverse signalling induced axonal retraction in hippocampal neurons. The reduction of axonal length and branching by Eph/ephrin reverse signalling was blocked by inhibition of RhoA or Rho-associated coiled-coil-containing protein kinase (ROCK). These results suggest that Eph/ephrin reverse signalling negatively regulates axonal outgrowth and branching through RhoA/ROCK pathway in hippocampal neurons. PMID- 25922201 TI - SIRT1-related inhibition of pro-inflammatory responses and oxidative stress are involved in the mechanism of nonspecific low back pain relief after exercise through modulation of Toll-like receptor 4. AB - Low back pain is a common clinical problem that causes disability and impaired quality of life. While the reason behind low back pain was largely considered to be of musculoskeletal origin, the contribution of inflammatory cytokines and oxidative stress could never be overlooked. Exercise has been proven to be an effective approach to treat low back pain. However, the mechanism of the exercise effect on the inflammatory cytokines and oxidative stress is still largely unknown. In this study, we revealed that exercise intervention reduces Toll-like receptor 4 (TLR-4) pathway and enhances Sirtuin 1 (SIRT1) expression in low back pain patients. We also confirmed that exercise up-regulates the expression of peroxisome proliferator-activated receptor-gamma, PPAR-gamma coactivator-1 and FoxOs family proteins and also increases the activity of catalase and superoxide dismutase in patients with low back pain. Furthermore, we found that exercise intervention attenuates the oxidative stress, pro-inflammatory cytokine concentrations and p53 expression in patients with low back pain. This study demonstrates that exercise intervention improves low back pain symptoms through regulation of the SIRT1 axis with repression of oxidative stress and TLR-4 inhibition. PMID- 25922202 TI - Author's reply to Clifford and colleagues. PMID- 25922203 TI - Ipilimumab-induced encephalopathy with a reversible splenial lesion. AB - Ipilimumab, an anticytotoxic T-lymphocyte antigen (CTLA)-4 monoclonal antibody, is a first-line therapy for stage IV melanoma. Although high-grade immune-related adverse events occur in 25% of patients receiving ipilimumab, serious neurologic toxicity, primarily consisting of transient sensory and motor neuropathies, affects less than 1% of patients. We present a case report of a patient with melanoma who received high-dose ipilimumab at 10 mg/kg as first-line therapy for metastatic disease. After the third dose, the patient developed "mild" encephalopathy with a reversible splenial lesion (MERS) of the corpus callosum by MRI and neurogenic bladder, two novel immune-related adverse events during checkpoint inhibition. In addition to headache, delirium, and altered consciousness commonly seen with MERS, the patient also developed tremor, gait instability, paresthesias, and neurogenic bladder. The latter two symptoms were thought to represent sensory and autonomic neuropathies, respectively. The syndrome gradually resolved following intravenous methylprednisolone at 2 mg/kg divided twice daily for 5 days and a slow taper of oral prednisone over 8 weeks. PMID- 25922204 TI - Non-surgical porto-mesenteric vein thrombosis is associated with worse long-term outcomes in inflammatory bowel diseases. AB - OBJECTIVE: Our aim was to assess the risk factors for non-surgery-related portal and mesenteric vein thrombosis (PMVT) and its impact on the outcomes of inflammatory bowel diseases (IBD). METHODS: All patients with a concurrent diagnosis of IBD and PMVT between January 2004 and October 2013 were identified from the electronic medical record (study group; n = 20). Patients were matched for age, sex, and IBD phenotype with control IBD patients who had no PMVT, with a ratio of 1:3 (control group; n = 60). Risk factors for PMVT and IBD-related outcomes at one year after diagnosis of PMVT were compared between the two groups. RESULTS: Of the 20 patients in the Study group, 6 (30%) had UC, 14 (70%) had CD and 11 (55%) were male. On multivariable analysis, inpatient status (odds ratio [OR] 6.88; 95% confidence interval [CI] 1.88-25.12) and baseline corticosteroid use (OR 4.39; 95% CI 1.27-15.19) were found to be independent risk factors for the development of PMVT. At one-year follow-up, PMVT patients were more likely to have an adverse outcome of IBD, including subsequent emergency room visit (26.3% vs. 1.7%; P = 0.003), hospitalization for medical management (60.0% vs. 20.0%; P = 0.001) or IBD-related surgery (65.0% vs. 26.7%; P = 0.003) than the non-PMVT controls. In multivariable analysis, PMVT (OR 5.19; 95% CI 1.07 25.28) and inpatient status (OR 8.92; 95% CI 1.33-59.84) were found to be independent risk factors for poor outcome, whereas baseline immunomodulator use (OR 0.07; 95% CI 0.01-0.51) was found to be a protective factor. CONCLUSIONS: IBD patients who were inpatients or receiving corticosteroid therapy had an increased risk of the development of PMVT. The presence of PMVT was associated with poor clinical outcomes in IBD. PMID- 25922205 TI - Extravascular Lung Water and Tissue Perfusion Biomarkers After Lung Resection Surgery Under a Normovolemic Fluid Protocol. AB - OBJECTIVE: The optimal fluid management for lung resection surgery remains undefined. Concern related to postoperative pulmonary edema has led to the practice of fluid restriction. This practice risks hypovolemia and tissue hypoperfusion. The authors examined the extravascular lung water accumulation and tissue perfusion biomarkers under protective lung ventilation and normovolemia. DESIGN: A prospective observational study. SETTING: A single-center study. PARTICIPANTS: Forty patients aged 18 years or older undergoing lung resection surgery. INTERVENTION: Patients were maintained on protective lung ventilation and a normovolemic fluid protocol. Hemodynamic variables, including global end diastolic volume index, cardiac index, and extravascular lung water index, together with tissue perfusion biomarkers, including serum creatinine, lactic acid, central venous oxygen saturation, and brain natriuretic peptide, were measured perioperatively. Parametric or nonparametric techniques were used to assess changes of these parameters over 72 hours postoperatively. MEASUREMENTS AND MAIN RESULTS: The global end-diastolic volume index was maintained; cardiac index was increased, without a significant change in extravascular lung water index. Acute kidney injury based on AKIN criteria occurred in 3 patients (7.5%), and in 1 patient (2.5 %) based on RIFLE criteria. Lactic acid and central venous oxygen saturation remained within normal limits, and brain natriuretic peptide showed an insignificant increase. CONCLUSION: In patients undergoing lesser lung resections, a fluid protocol targeting normovolemia together with protective lung ventilation did not increase extravascular lung water. These results suggest further study to identify the optimal fluid regimen to mitigate pulmonic and extrapulmonic complications after lung resection. PMID- 25922206 TI - X-ray microtomographic confirmation of the reliability of CBCT in identifying the scalar location of cochlear implant electrode after round window insertion. AB - Cone-beam computed tomography (CBCT) plays a key role in cochlear implantation in both planning implantation before surgery and quality control during surgery due to the high spatial resolution and convenience of application in the operation theater. We recently designed a novel, highresolution cone-beam acquisition system that has been tested in temporal bones with cochlear implantation to identify the scalar localization of the electrode arrays. The current study aimed to verify the reliability of the experimental CBCT set-up using high-resolution in vitro X-ray microtomography (MUCT) imaging as a reference. Nine human temporal bones were studied by inserting a straight electrode of a cochlear implant using the round window approach followed by sequential imaging using experimental CBCT and MUCT with and without 1% iodine as the contrast agent. In the CBCT images, the electrodes were located in the scala tympani and near the lateral wall in all temporal bones. In the MUCT images, the cochlear fine structures, including Reissner's membrane, stria vascularis, spiral ligament, basilar membrane, spiral limbus, osseous spiral lamina, and Rosenthal's canal that hosts the spiral ganglion cells, were clearly delineated; the electrode array avoided the lateral wall of the scala tympani in the hook region and then ran along the lateral wall of the scala tympani without any exception, a feature that was also detected in a temporal bone with ruptures in the basilar and Reissner's membranes. In conclusion, the current in vitro MUCT imaging system produced high-quality images that could demonstrate the fine cochlear structures faithfully and verify the reliability of a novel experimental CBCT set-up aimed for clinical application in identifying the scalar localization of the electrode array. The straight electrode is safe for cochlear structures with low risk of translocation and is suitable for atraumatic implantation, although a large gap between the contacts and the modiolus exists. PMID- 25922208 TI - "Man, I really like Vegas" - Elvis Presley. PMID- 25922207 TI - Correlative mRNA and protein expression of middle and inner ear inflammatory cytokines during mouse acute otitis media. AB - Although the inner ear has long been reported to be susceptible to middle ear disease, little is known of the inflammatory mechanisms that might cause permanent sensorineural hearing loss. Recent studies have shown inner ear tissues are capable of expressing inflammatory cytokines during otitis media. However, little quantitative information is available concerning cytokine gene expression in the inner ear and the protein products that result. Therefore, this study was conducted of mouse middle and inner ear during acute otitis media to measure the relationship between inflammatory cytokine genes and their protein products with quantitative RT-PCR and ELISA, respectively. Balb/c mice were inoculated transtympanically with heat-killed Haemophilus influenzae and middle and inner ear tissues collected for either quantitative RT-PCR microarrays or ELISA multiplex arrays. mRNA for several cytokine genes was significantly increased in both the middle and inner ear at 6 h. In the inner ear, these included MIP-2 (448 fold), IL-6 (126 fold), IL-1beta (7.8 fold), IL-10 (10.7 fold), TNFalpha (1.8 fold), and IL-1alpha (1.5 fold). The 24 h samples showed a similar pattern of gene expression, although generally at lower levels. In parallel, the ELISA showed the related cytokines were present in the inner ear at concentrations higher by 2-122 fold higher at 18 h, declining slightly from there at 24 h. Immunohistochemistry with antibodies to a number of these cytokines demonstrated they occurred in greater amounts in the inner ear tissues. These findings demonstrate considerable inflammatory gene expression and gene products in the inner ear following acute otitis media. These higher cytokine levels suggest one potential mechanism for the permanent hearing loss seen in some cases of acute and chronic otitis media. PMID- 25922209 TI - Curative pelvic exenteration for recurrent cervical carcinoma in the era of concurrent chemotherapy and radiation therapy. A systematic review. AB - OBJECTIVE: Pelvic exenteration requires complete resection of the tumor with negative margins to be considered a curative surgery. The purpose of this review is to assess the optimal preoperative evaluation and surgical approach in patients with recurrent cervical cancer to increase the chances of achieving a curative surgery with decreased morbidity and mortality in the era of concurrent chemoradiotherapy. METHODS: Review of English publications pertaining to cervical cancer within the last 25 years were included using PubMed and Cochrane Library searches. RESULTS: Modern imaging (MRI and PET-CT) does not accurately identify local extension of microscopic disease and is inadequate for preoperative planning of extent of resection. Today, only half of pelvic exenteration procedures obtain uninvolved surgical margins. CONCLUSION: Clear margins are required for curative pelvic exenterations, but are poorly predictable by pre operative assessment. More extensive surgery, i.e. the infra-elevator exenteration with vulvectomy, is a logical surgical choice to increase the rate of clear margins and to improve patient survival following surgery for recurrent cervical carcinoma. PMID- 25922210 TI - Envelopment filter and K-means for the detection of QRS waveforms in electrocardiogram. AB - The electrocardiogram (ECG) is a well-established technique for determining the electrical activity of the heart and studying its diseases. One of the most common pieces of information that can be read from the ECG is the heart rate (HR) through the detection of its most prominent feature: the QRS complex. This paper describes an offline version and a real-time implementation of a new algorithm to determine QRS localization in the ECG signal based on its envelopment and K-means clustering algorithm. The envelopment is used to obtain a signal with only QRS complexes, deleting P, T, and U waves and baseline wander. Two moving average filters are applied to smooth data. The K-means algorithm classifies data into QRS and non-QRS. The technique is validated using 22 h of ECG data from five Physionet databases. These databases were arbitrarily selected to analyze different morphologies of QRS complexes: three stored data with cardiac pathologies, and two had data with normal heartbeats. The algorithm has a low computational load, with no decision thresholds. Furthermore, it does not require any additional parameter. Sensitivity, positive prediction and accuracy from results are over 99.7%. PMID- 25922211 TI - Finite element analysis predicts experimental failure patterns in vertebral bodies loaded via intervertebral discs up to large deformation. AB - Vertebral compression fractures are becoming increasingly common. Patient specific nonlinear finite element (FE) models have shown promise in predicting yield strength and damage pattern but have not been experimentally validated for clinically relevant vertebral fractures, which involve loading through intervertebral discs with varying degrees of degeneration up to large compressive strains. Therefore, stepwise axial compression was applied in vitro on segments and performed in silico on their FE equivalents using a nonlocal damage-plastic model including densification at large compression for bone and a time independent hyperelastic model for the disc. The ability of the nonlinear FE models to predict the failure pattern in large compression was evaluated for three boundary conditions: healthy and degenerated intervertebral discs and embedded endplates. Bone compaction and fracture patterns were predicted using the local volume change as an indicator and the best correspondence was obtained for the healthy intervertebral discs. These preliminary results show that nonlinear finite element models enable prediction of bone localisation and compaction. To the best of our knowledge, this is the first study to predict the collapse of osteoporotic vertebral bodies up to large compression using realistic loading via the intervertebral discs. PMID- 25922212 TI - Drill wear monitoring in cortical bone drilling. AB - Medical drills are subject to intensive wear due to mechanical factors which occur during the bone drilling process, and potential thermal and chemical factors related to the sterilisation process. Intensive wear increases friction between the drill and the surrounding bone tissue, resulting in higher drilling temperatures and cutting forces. Therefore, the goal of this experimental research was to develop a drill wear classification model based on multi-sensor approach and artificial neural network algorithm. A required set of tool wear features were extracted from the following three types of signals: cutting forces, servomotor drive currents and acoustic emission. Their capacity to classify precisely one of three predefined drill wear levels has been established using a pattern recognition type of the Radial Basis Function Neural Network algorithm. Experiments were performed on a custom-made test bed system using fresh bovine bones and standard medical drills. Results have shown high classification success rate, together with the model robustness and insensitivity to variations of bone mechanical properties. Features extracted from acoustic emission and servomotor drive signals achieved the highest precision in drill wear level classification (92.8%), thus indicating their potential in the design of a new type of medical drilling machine with process monitoring capabilities. PMID- 25922213 TI - Design of an actively controlled steerable needle with tendon actuation and FBG based shape sensing. AB - This work presents a new steerable needle to facilitate active steering toward predefined target locations. It focuses on mechanical aspects and design choices in relation to the observed response in a tissue phantom. Tip steering with two rotational degrees of freedom was achieved by a tendon actuated ball joint mechanism. During insertion, the flexible cannula bends as a result of asymmetric tip-tissue interaction forces. The stylet was equipped with fiber Bragg gratings to measure the needle shape and tip position during use. A PI-controller was implemented to facilitate steering to predefined targets. During the validation study, nine targets were defined at a depth of 100 mm below the gelatin surface. One was located below the insertion point, the others at a radial offset of 30 mm in each of the eight principle steering directions. Per location, six repetitions were performed. The targeting accuracy was 6.2 +/- 1.4 mm (mean +/- std). The steering precision was 2.6 +/- 1.1 mm. The ability to steer with this new needle steering approach is presented and the mechanical characteristics are discussed for this representative subset of steering directions. PMID- 25922214 TI - Navy Bean Flour Particle Size and Protein Content Affect Cake Baking and Batter Quality(1). AB - Whole navy bean flour and its fine and coarse particle size fractions were used to completely replace wheat flour in cakes. Replacement of wheat flour with whole bean flour significantly increased the protein content. The protein content was adjusted to 3 levels with navy bean starch. The effect of navy bean flour and its fractions at 3 levels of protein on cake batter rheology and cake quality was studied and compared with wheat flour samples. Batters prepared from navy bean flour and its fractions had higher viscosity than the cake flour. Reducing the protein content by addition of starch significantly lowered the viscosity of cake batters. The whole navy bean flour and coarse bean fraction cakes were softer than cakes made with wheat flour but had reduced springiness. Principal component analysis showed a clear discrimination of cakes according to protein. It also showed that low protein navy bean flour cakes were similar to wheat flour cakes. Navy bean flour with protein content adjusted to the level of cake (wheat) flour has potential as a healthy alternative in gluten-free cakes. PMID- 25922215 TI - [The role of balneology in plastic surgery]. AB - Balneology can be part of the plastic surgery care sector. The objectives of this study were firstly to the state of knowledge about the hydrotherapy and specify the place reserved for hydrotherapy by surgeons as an adjunct in plastic and reconstructive surgery (adult and child). MATERIALS AND METHODS: Multicentric national study by poll (Google Drive(r)) focused at plastic and/or pediatric surgeons. The following information was analyzed: frequency, timing of prescription, indications, the surgeon's feelings towards hydrotherapy and the differences between adult's and children's prescriptions. RESULTS: Fifty-four teams were contacted: 22 responses were received (15 "adult" plastic surgeons, 9 "pediatric" plastic surgeons, 6 pediatric surgeons, with 12 out of 22 working with burnt patients). Eighteen out of 22 prescribed hydrotherapy. Twenty out of 22 thought that hydrotherapy had a role as adjuvant therapy in plastic surgery. The indications were: burns (11/20), skin-graft hypertrophy (10/20), inflammatory and pruritic scar and cutaneous trophic disorders (9/20), psychological (3/20), retractions (2/20), weight loss and smoking (1/20). The timing of the prescription was: < 3 months (2/20), < 6 months (7/20), > 6 months and < 1 year (15/20), > 1 year (8/20) after surgery/trauma. Twenty out of 22 found a beneficial effect: physical (19/20): reduction of inflammatory signs, pruritus and pain, scar maturation, skin thinning improvement; psychological (14/20): positive for patient/family. Five out of 17 made the difference between child/adult, 10/17 made no difference but only treated adults or children. CONCLUSION: The respondents in the study are probably more sensitive to the effects of hydrotherapy that non-respondents. It is difficult to assess the real impact of hydrotherapy in plastic surgery because distinguishing spontaneous favorable evolution of a scar from one only due to the hydrotherapy or multidisciplinary management is difficult. However, hydrotherapy seems to have its role among multidisciplinary management. PMID- 25922216 TI - What can platinum offer yet in the treatment of PS2 NSCLC patients? A systematic review and meta-analysis. AB - BACKGROUND: Randomized phase III trials showed interesting, but conflicting results, regarding the treatment of NSCLC, PS2 population. This meta-analysis aims to review all randomized trials comparing platinum-based doublets and single agents in NSCLC PS2 patients. MATERIALS AND METHODS: Data from all published randomized trials, comparing efficacy and safety of platinum-based doublets to single agents in untreated NSCLC, PS2 patients, were collected. Pooled ORs were calculated for the 1-year Survival-Rate (1y-SR), Overall Response Rate (ORR), and grade 3-4 (G3-4) hematologic toxicities. RESULTS: Six eligible trials (741 patients) were selected. Pooled analysis showed a significant improvement in ORR (OR: 3.243; 95% CI: 1.883-5.583) and 1y-SR (OR: 1.743; 95% CI: 1.203-2.525) in favor of platinum-based doublets. G3-4 hematological toxicities were also more frequent in this group. CONCLUSION: This meta-analysis suggests that platinum combination regimens are superior to singleagent both in terms of ORR and survival-rate with increase of severe hematological toxicities. PMID- 25922217 TI - Psychosocial interventions for adolescents and young adult cancer patients: A systematic review and meta-analysis. AB - Adolescent and young adult (AYA) cancer patients experience unique psychosocial needs and developmental challenges. A cancer diagnosis can stress this development and disrupt AYAs in their normal life. The aim of this systematic review and meta-analysis was to assess the impact of psychosocial interventions on mental health in AYAs. A literature research was conducted, which resulted in twelve eligible studies. The standardized mean difference between intervention and control conditions was 0.13 (95% CI: -0.16 to 0.42) for quality of life, 0.27 (95% CI: -0.22 to 0.76) for cancer-related knowledge and -0.16 (95% CI: -0.73 to 0.42) on psychological distress indicating, small and non-significant effects for interventions improving mental health. This work strengthens the need for age appropriated interventions in psycho-oncology. Future research should develop interventions more graduated by age. Randomized intervention studies with larger samples and focusing psychosocial outcomes are needed to establish evidence-based psycho-oncological interventions for AYAs. PMID- 25922218 TI - Knowledge, attitudes and preventive behaviors related to dengue vector breeding control measures among adults in communities of Vientiane, capital of the Lao PDR. AB - This research aimed to determine the knowledge, attitudes and preventive behaviors (KAP) of adults in relation to dengue vector control measures in the communities of Vientiane, the capital of the Lao PDR. A total of 207 respondents were actively participating in this cross-sectional descriptive study in 2011. Representatives of households were interviewed face-to-face by six trained interviewers using a structured questionnaire. KAP reliabilities of 0.89, 0.91 and 0.95 were reported in the pilot sample of 30 cases. The associations between each independent variable and prevention behavior were tested with chi-square tests. Multiple logistic regression was used to determine the factors that were significantly associated with preventive behavior while controlling for the other variables. The results revealed that 51.69% of the respondents had a high level of knowledge. More than 94% of the respondents knew that dengue fever is a dangerous communicable disease and that dengue fever is transmitted from person to person via mosquitoes. More than half (56.52%) of the participants had positive attitudes toward vector control measures, and 52.17% exhibited a high level of preventive behavior in terms of dengue vector control measures. Preventive behaviors were significantly associated with information provided from sources that included health personnel (p = 0.038) and heads of villages (p=0.031) and with knowledge levels (p < 0.001). This study suggests that proactive health education through appropriated mass media and community clean-up campaigns should strengthen and encourage community participation, particularly in terms of addressing mosquito larvae in overlooked places, such as the participants' own homes, for example, in flower vases and ant traps. PMID- 25922219 TI - Quality Indicators of End-of-Life Care in Patients With Cancer: What Rate Is Right? AB - PURPOSE: To develop data-driven and achievable benchmark rates for end-of-life quality indicators using administrative data from four provinces in Canada. METHODS: Indicators of end-of-life care were defined and measured using linked administrative data for 33 health regions across British Columbia, Alberta, Ontario, and Nova Scotia. These were emergency department use, intensive care unit admission, physician house calls and home care visits before death, and death in hospital. An empiric benchmark was defined using indicator rates from the top-ranked regions to include the top decile of patients overall. Funnel plots were used to graph each region's age- and sex-adjusted indicator rates along with the overall rate and 95% confidence limits. RESULTS: Rates varied approximately two- to four-fold across the regions, with physician house calls showing the greatest variation. Benchmark rates based on the top decile performers were emergency department use, 34%; intensive care unit admission, 2%; physician house calls, 34%; home care visits, 63%; and death in hospital, 38%. With the exception of intensive care unit admission, funnel plots demonstrated that overall indicator rates and their confidence limits were uniformly worse than benchmarks even after adjusting for age and sex. Few regions met the benchmark rates. CONCLUSION: There is significant variation in end-of-life quality indicators across regions in four provinces in Canada. Using this study's methods-deriving empiric benchmarks and funnel plots-regions can determine their relative performance with greater context that facilitates priority setting and resource deployment. Applying this study's methods can support quality improvement by decreasing variation and striving for a target. PMID- 25922220 TI - Intentional approach to team-based oncology care: evidence-based teamwork to improve collaboration and patient engagement. PMID- 25922221 TI - Tumor board participation among physicians caring for patients with lung or colorectal cancer. AB - PURPOSE: Multidisciplinary tumor board meetings are common in cancer care, but limited evidence is available about their benefits. We assessed the associations of tumor board participation and structure with care delivery and patient outcomes. METHODS: As part of the CanCORS study, we surveyed 1,601 oncologists and surgeons about participation in tumor boards and specific tumor board features. Among 4,620 patients with lung or colorectal cancer diagnosed from 2003 to 2005 and seen by 1,198 of these physicians, we assessed associations of tumor board participation with patient survival, clinical trial enrollment, guideline recommended care, and patient-reported quality, adjusting for patient and physician characteristics. RESULTS: Weekly physician tumor board participation (v participation less often or never) was not associated with patient survival, although in exploratory subgroup analyses, weekly participation was associated with lower mortality for extensive-stage small-cell lung cancer and stage IV colorectal cancer. Patients treated by the 54% of physicians participating in tumor boards weekly (v less often or never) were more likely to enroll onto clinical trials (odds ratio [OR], 1.6; 95% CI, 1.1 to 2.2). Patients with stage I to II non-small-cell lung cancer (NSCLC) whose physicians participated in tumor boards weekly were more likely to undergo curative-intent surgery (OR, 2.9; 95% CI, 1.3 to 6.8), although those with stage I to II NSCLC whose physicians' meetings reviewed > one cancer site were less likely to undergo curative-intent surgery (OR, 0.1; 95% CI, 0.03 to 0.4). CONCLUSION: Among patients with lung or colorectal cancer, frequent physician tumor board engagement was associated with patient clinical trial participation and higher rates of curative-intent surgery for stage I to II NSCLC but not with overall survival. PMID- 25922222 TI - Introduction to quality issues in vulnerable populations. PMID- 25922223 TI - Pharmacologic Treatment of Behavioral and Psychological Symptoms of Dementia in Nursing Homes: Update of the 2008 JAMDA Recommendations. PMID- 25922224 TI - How do voltage-gated sodium channels enhance migration and invasiveness in cancer cells? AB - Voltage-gated sodium channels are abnormally expressed in tumors, often as neonatal isoforms, while they are not expressed, or only at a low level, in the matching normal tissue. The level of their expression and their activity is related to the aggressiveness of the disease and to the formation of metastases. A vast knowledge on the regulation of their expression and functioning has been accumulated in normal excitable cells. This helped understand their regulation in cancer cells. However, how voltage-gated sodium channels impose a pro-metastatic behavior to cancer cells is much less documented. This aspect will be addressed in the review. This article is part of a Special Issue entitled: Membrane channels and transporters in cancers. PMID- 25922225 TI - Lipid-protein interactions: Lessons learned from stress. AB - Biological membranes are essential for normal function and regulation of cells, forming a physical barrier between extracellular and intracellular space and cellular compartments. These physical barriers are subject to mechanical stresses. As a consequence, nature has developed proteins that are able to transpose mechanical stimuli into meaningful intracellular signals. These proteins, termed Mechanosensitive (MS) proteins provide a variety of roles in response to these stimuli. In prokaryotes these proteins form transmembrane spanning channels that function as osmotically activated nanovalves to prevent cell lysis by hypoosmotic shock. In eukaryotes, the function of MS proteins is more diverse and includes physiological processes such as touch, pain and hearing. The transmembrane portion of these channels is influenced by the physical properties such as charge, shape, thickness and stiffness of the lipid bilayer surrounding it, as well as the bilayer pressure profile. In this review we provide an overview of the progress to date on advances in our understanding of the intimate biophysical and chemical interactions between the lipid bilayer and mechanosensitive membrane channels, focusing on current progress in both eukaryotic and prokaryotic systems. These advances are of importance due to the increasing evidence of the role the MS channels play in disease, such as xerocytosis, muscular dystrophy and cardiac hypertrophy. Moreover, insights gained from lipid-protein interactions of MS channels are likely relevant not only to this class of membrane proteins, but other bilayer embedded proteins as well. This article is part of a Special Issue entitled: Lipid-protein interactions. PMID- 25922226 TI - [Imaging of corneal dystrophies: Correlations between en face anterior segment OCT and in vivo confocal microscopy]. AB - PURPOSE: To evaluate the usefulness of en face Optical Coherence Tomography (OCT) for evaluation of corneal dystrophies and to describe correlations with in vivo confocal microscopy (IVCM). PATIENTS AND METHODS: Thirty-two eyes of 16 patients with 4 types of corneal dystrophies (epithelial basement membrane dystrophy, Fuchs dystrophy, Reis-Bucklers corneal dystrophy and Crocodile Shagreen dystrophy) were enrolled in this study. Axial and reconstructed en face scans were acquired using OCT. Images were then correlated to IVCM findings. RESULTS: En face OCT provided new insights into the structure, size and depth of corneal tissue alterations in various corneal dystrophies. OCT en face images were well correlated with IVCM features. Despite lower resolution than IVCM, en face OCT offers the advantages of being non-invasive and allowing the analysis of larger corneal areas. CONCLUSION: En face OCT provides useful new information in corneal dystrophies. This imaging technique will probably increase in popularity in the near future for the assessment of various anterior segment diseases. PMID- 25922227 TI - [Corneal collagen crosslinking in keratoconus]. AB - Corneal collagen crosslinking (CXL) is, at present, the only treatment that can slow or even stop the progression of keratoconus. It uses riboflavin and ultraviolet A (UVA) to create covalent bonds ("crosslinks") between collagen fibrils thus increasing corneal rigidity. Although to date there has been no direct evidence of intrastromal corneal crosslinking, several studies have reported the safety and efficacy of the conventional CXL protocol. This protocol is indicated for progressive keratoconus with a minimal corneal thickness (without the epithelium) of at least 400 MUm. It should be performed as early as possible in patients under 18 years with keratoconus or with post-LASIK ectasia. Because of the epithelial debridement, it may rarely induce complications such as infectious keratitis or stromal scars. A variety of new protocols is under investigation and may reduce the rate of these complications. In addition, combination of CXL with other surgical treatments (intracorneal ring segments or photorefractive keratectomy) may improve visual outcomes in patients with keratoconus. Finally, the antimicrobial and anti-edematous properties of CXL have been shown, suggesting new therapeutic indications of this procedure such as infectious keratitis or stromal edema in the future. PMID- 25922228 TI - Pretreatment with 5-hydroxymethyl-2-furaldehyde blocks scopolamine-induced learning deficit in contextual and spatial memory in male mice. AB - 5-Hydroxymethyl-2-furaldehyde (5-HMF) is a compound derived from the dehydration of certain sugars. The aim of the present study was to evaluate the effect of 5 HMF on the cognitive impairment induced by scopolamine, a muscarinic receptor antagonist. To measure various cognitive functions, we conducted the step-through passive avoidance task, the Y-maze task and the Morris water maze task. A single administration of 5-HMF (5 or 10mg/kg, p.o.) significantly attenuates scopolamine induced cognitive impairment in these behavioral tasks without changes in locomotor activity, and the effect of 5-HMF on scopolamine-induced cognitive impairment was significantly reversed by a sub-effective dose of MK-801, an NMDA receptor antagonist. In addition, a single administration of 5-HMF (10mg/kg, p.o.) enhanced the cognitive performance of normal naive mice in the passive avoidance task. Furthermore, Western blot analysis revealed that the levels of phosphorylated Ca(2+)/calmodulin-dependent protein kinase II-alpha (CaMKII) and extracellular signal-regulated kinases (ERK) were significantly enhanced by the single administration of 5-HMF in the hippocampal tissues. Taken together, the present study suggests that 5-HMF may block scopolamine-induced learning deficit and enhance cognitive function via the activation of NMDA receptor signaling, including CaMKII and ERK, and would be an effective candidate against cognitive disorders, such as Alzheimer's disease. PMID- 25922229 TI - Knowing More Than We Can Tell: People Are Aware of Their Biased Self-Perceptions. AB - There is no question that biases exist in self-perceptions of personality. To what extent do people have insight into their positive and negative self-biases? In two samples (total N = 130), people with positive biases (i.e., self perceptions that are more positive than a reputation-based criterion measure) accurately described themselves as positively biased, and people with negative biases accurately described themselves as negatively biased. Furthermore, people were able to distinguish which traits they were more or less biased about. These findings suggest that people may know more about themselves than they initially admit. Implications for the use of self-reports and the study of self-knowledge are discussed. PMID- 25922230 TI - The effect of presenting symptoms and patient characteristics on prehospital delay in MI patients presenting to emergency department by ambulance: a cohort study. AB - INTRODUCTION: There is little recent information about prehospital delay time for Australian patients with myocardial infarction (MI). OBJECTIVES: This study: (1) describes prehospital delay time for patients with MI; (2) identifies variables and presenting symptoms which contribute to the delay. METHODS: This retrospective cohort study identified patients with an Emergency Department (ED) discharge diagnosis of MI, transported by ambulance to one of the seven Perth metropolitan EDs, between January 2008 and October 2009. Prehospital delay times were analysed using linear regression models. Non-numeric (word descriptions) of delay time were categorised. RESULTS: Of 1,633 patients, symptom onset-time was available for 1,003. For 829 patients with a numeric onset-time, median delay was 2.2hours; decreased delay was associated with age <70 years, presenting with chest pain, and diaphoresis. Increased delay was associated with being with a primary health care provider, and if the patient was at home and if the person who called the ambulance was anyone other than the spouse. For 174 patients with non-numeric onset-times, 37% patients delayed one to three days and 110 (64.0%) patients described their symptoms as intermittent and/or of gradual onset. CONCLUSION: Given that prehospital delay times remain longer than is optimal, public awareness of MI symptoms should be enhanced in order to decrease prehospital delay. PMID- 25922231 TI - Acetylcholine protects mesenteric arteries against hypoxia/reoxygenation injury via inhibiting calcium-sensing receptor. AB - The Ca(2+)-sensing receptor (CaSR) plays an important role in regulating vascular tone. In the present study, we investigated the positive effects of the vagal neurotransmitter acetylcholine by suppressing CaSR activation in mesenteric arteries exposed to hypoxia/reoxygenation (H/R). The artery rings were exposed to a modified 'ischemia mimetic' solution and an anaerobic environment to simulate an H/R model. Our results showed that acetylcholine (10(-6) mol/L) significantly reduced the contractions induced by KCl and phenylephrine and enhanced the endothelium-dependent relaxation induced by acetylcholine. Additionally, acetylcholine reduced CaSR mRNA expression and activity when the rings were subjected to 4 h of hypoxia and 12 h of reoxygenation. Notably, the CaSR antagonist NPS2143 significantly reduced the contractions but did not improve the endothelium-dependent relaxation. When a contractile response was achieved with extracellular Ca(2+), both acetylcholine and NPS2143 reversed the H/R-induced abnormal vascular vasoconstriction, and acetylcholine reversed the calcimimetic R568-induced abnormal vascular vasoconstriction in the artery rings. In conclusion, this study suggests that acetylcholine ameliorates the dysfunctional vasoconstriction of the arteries after H/R, most likely by decreasing CaSR expression and activity, thereby inhibiting the increase in intracellular calcium concentration. Our findings may be indicative of a novel mechanism underlying ACh induced vascular protection. PMID- 25922232 TI - Molecular examinations of Babesia microti in rodents and rodent-attached ticks from urban and sylvatic habitats in Germany. AB - Small mammals serve as reservoir hosts for tick-borne pathogens, especially for those which are not transmitted transovarially in ticks - such as Babesia microti. Molecular investigations on the prevalence of B. microti in wild small mammals and on attached ticks from differently structured areas may provide information on the circulation of B. microti in different ecological niches. In 2012 and 2013, 622 rodents (396 Myodes glareolus, 178 Apodemus flavicollis, 36 Apodemus sylvaticus, 4 Apodemus agrarius, 7 Microtus arvalis, 1 Microtus agrestis) were captured from three differently structured habitats (urban, sylvatic, recultivated) in Germany. Attached ticks were collected from 449 small mammals (3250 Ixodes ricinus, 7 Ixodes trianguliceps, 133 Dermacentor reticulatus). A representative selection of a maximum of 5 ticks per developmental stage and species per 30 rodents of each species, location and year resulting in 965 ticks was further investigated. DNA was extracted from tick, blood and spleen samples, and tested by PCR for the partial 18S rRNA gene of B. microti with subsequent sequencing. The prevalence was significantly higher in rodents from the sylvatic site (4.6%) than in rodents captured at both other sites (-0.6%) (chi(2)=11.95; p=0.00125). Body and spleen weight of infected M. glareolus from the sylvatic site were significantly higher compared to those from non-infected individuals from that site (p=0.00288 and p=0.00017, respectively). Babesia microti DNA was detected in 3 out of 965 attached ticks (0.3%; 95%CI: 0 1) from all sites, but they derived exclusively from rodents captured at the sylvatic site. At the same site, I. ricinus nymphs (7.7%; 95%CI: 1-25.3) were significantly more often infected than I. ricinus larvae (0%; 95%CI: 0 1.3)(chi(2)=26.72; p<0.0001). The majority of positive rodents was also found at that site. I. trianguliceps occurred exclusively and the majority of M. glareolus at that site. Thus, it may be assumed that the circulation of B. microti is more efficient where this tick species and voles exist sympatrically than in areas with a predominant occurrence of Apodemus species. PMID- 25922233 TI - Combination antiemetic therapy with aprepitant/fosaprepitant in patients with colorectal cancer receiving oxaliplatin-based chemotherapy (SENRI trial): a multicentre, randomised, controlled phase 3 trial. AB - INTRODUCTION: The oral neurokinin-1 antagonist aprepitant is recommended in several guidelines for preventing chemotherapy-induced nausea & vomiting (CINV) due to highly emetogenic cancer chemotherapy. Little is known about the feasibility and safety of aprepitant in patients treated with oxaliplatin. METHODS: In this multicentre, open label, randomised, phase 3 trial, we recruited patients with colorectal cancer who underwent an oxaliplatin-based chemotherapy. Patients were centrally randomised in a 1:1 ratio to the control group (5-HT3 receptor antagonist+dexamethasone) or aprepitant group (5-HT3-receptor antagonist+dexamethasone+aprepitant or fosaprepitant) in the first course. All patients were treated with aprepitant/fosaprepitant therapy in the second course. The primary end-point was the proportion of patients with no emesis. RESULTS: A total of 413 patients entered this clinical trial from 25 centres in Japan. Significantly more patients in the aprepitant group achieved no vomiting overall and delayed phase than those in the control group (95.7% versus 83.6%, and 95.7% versus 84.7%, respectively). The aprepitant group also had statistically significantly higher percentages of no significant nausea, complete response and complete protection than the control group overall. In the control group, the percentages of no vomiting were higher in the second cycle than in the first cycle. The incidence of vomiting occurred day 7 or later was significantly higher in the control group compared with the aprepitant group. Other adverse events were not significant between the groups. CONCLUSION: The aprepitant therapy was more effective than the control therapy for prevention of CINV in colorectal cancer patients receiving an oxaliplatin-based regimen. PMID- 25922234 TI - Zinc significantly changes the aggregation pathway and the conformation of aggregates of human prion protein. AB - Prion diseases are caused by the conformational change of cellular prion protein PrP(C) into pathological prion protein PrP(Sc). Here we study the effect of zinc on the aggregation and conformational change of human prion protein (PrP). As revealed by thioflavin T binding assays, Sarkosyl-soluble SDS-PAGE, and transmission electron microscopy, aggregation of wild-type PrP in the absence of Zn(2+) undergoes four steps: amorphous aggregates, profibrils, mature fibrils, and fragmented fibrils. When the molar ratio of Zn(2+) to PrP was 9:1, however, aggregation of wild-type PrP undergoes another pathway in which wild-type PrP forms oligomers quickly and then forms short-rod aggregates. Unlike wild-type PrP, the octarepeats deletion mutant PrPDeltaocta forms typical mature fibrils either with or without zinc. As evidenced by isothermal titration calorimetry, Fourier transform infrared spectroscopy, and proteinase K digestion assays, Zn(2+) strongly binds to wild-type PrP monomers with the first binding constant exceeding 10(7)M(-1) under denaturing conditions, and changes the conformation of wild-type PrP aggregates remarkably, but weakly binds to PrPDeltaocta with binding affinity around 10(4)M(-1) and has no obvious effects on the conformation of PrPDeltaocta aggregates. Our data demonstrate that zinc significantly changes the aggregation pathway and the conformation of wild-type PrP aggregates mainly via interaction with its octarepeat region. Our findings could explain how zinc modifies pathological PrP conformation associated with prion diseases. PMID- 25922235 TI - [Not Available]. PMID- 25922236 TI - [Not Available]. PMID- 25922237 TI - [In Process Citation]. PMID- 25922238 TI - [In Process Citation]. PMID- 25922239 TI - [Laparoscopic surgery of endometriomas reduces pain and subfertility]. AB - The Cochrane collaboration has published two reviews on endometriosis in 2014. The review by Duffy et al analyses ten RCTs focussing on pain or subfertility, and laparoscopic surgery results in lower pain scores and increased clinical pregnancy rate compared to diagnostic laparoscopy. The other review by Brown & Farguhar describes 17 systematic reviews also reporting on pain and subfertility, and it highlights the finding of gestagen-releasing intrauterine system being more effective than expectant management regarding pain relief. Surgical treatment of endometriomas should be performed by excision rather than ablation. PMID- 25922240 TI - [Cannabinoid hyperemesis syndrome causing prolonged nausea and vomiting in patients with cannabis abuse]. AB - Cannabis is one of the most used drugs worldwide. The link between repeated episodes of nausea, vomiting, and cannabis abuse is often missed in patients with prolonged cannabis abuse and is named cannabinoid hyperemesis syndrome. Characteristically, the symptoms appear in a cyclical pattern and are relieved by long, hot baths. Physical examination, radiology and endoscopy are often normal. The symptoms resolve with cessation of cannabis abuse. Health professionals must be aware of this syndrome in order to detect the patients early and to avoid extensive medical workup. PMID- 25922241 TI - [Involvement of patients has not been fully implemented in Danish health care]. AB - In Denmark, there is a focus on patient involvement. Health professionals want to involve patients, but have diverse interpretations of what this entails, which complicates knowledge dissemination. Interventions are scattered and diverse, and often do not systematically involve patients' knowledge. Studies have shown that patients want to be involved and contribute with knowledge, but this only happens to a limited degree. Involvement of patients is often limited to involving their resources in the form of self care rather than integrating their knowledge into their treatment and care. PMID- 25922242 TI - [Insufficient evidence of the effect of the low FODMAP diet on irritable bowel syndrome]. AB - The low FODMAP (Fermentable Oligo-, Di- and Monosaccharides and Polyoles) diet (LFD) allegedly reduces symptoms of irritable bowel syndrome (IBS). Eleven studies have examined the effects of LFD on IBS. Most studies reported a symptomatic effect, but methodological weaknesses such as lack of relevant control group and of proper blinding means that a placebo response cannot be excluded. No studies have examined the effect of the important reintroduction phase nor the effects of LFD on IBS patients in primary care. Evidence suggests that intake of high dose FODMAP can induce gastrointestinal symptoms, but the clinical relevance of this is doubtful. PMID- 25922243 TI - [Endoscopic ultrasound guided rendezvous for biliary drainage]. AB - Endoscopic retrograde cholangiography (ERCP) is currently standard treatment for biliary drainage. Endoscopic ultrasound guided rendezvous (EUS-RV) is a novel method to overcome an unsuccessful biliary drainage procedure. Under endoscopic ultrasound guidance a guidewire is passed via a needle from the stomach or duodenum to the common bile duct and from there on to the duodenum enabling ERCP. With a relatively high rate of success EUS-RV should be considered as an alternative to biliary drainage and surgical intervention. PMID- 25922244 TI - Axillary Lymph Node Burden in Invasive Breast Cancer: A Comparison of the Predictive Value of Ultrasound-Guided Needle Biopsy and Sentinel Lymph Node Biopsy. AB - BACKGROUND: Recent studies suggest that axillary lymph node dissection (ALND) may be omitted in select breast cancer patients with a positive sentinel lymph node biopsy (SLNB). As we trend away from ALND, we must understand the burden of axillary disease among various patient subgroups. For patients with positive nodes determined using ultrasound-guided needle biopsy (USNB), there are no data regarding the extent of axillary disease. PATIENTS AND METHODS: An institutional breast cancer registry was retrospectively reviewed to identify women with invasive cancer and a positive USNB/SLNB who had completion ALND. For statistical analysis, we used chi(2) and 1-way analysis of variance. RESULTS: One hundred ninety-nine USNB-positive (USNB(+)) patients and 434 SLNB(+) patients were eligible for the study. Positive USNB patients were significantly older, had larger tumors, and were more likely to be estrogen receptor-negative/progesterone receptor-negative and HER2/neu(+) than SLNB(+) patients. USNB(+) patients had much higher rates of N2 (33.2% vs. 12.4%; P < .05) and N3 (17.1% vs. 3.9%; P < .05) disease compared with SLNB(+) patients. Higher axillary disease burden was demonstrated in USNB patients who were clinically node negative and those who met Z11 criteria. CONCLUSION: Patients with invasive breast cancer with a positive node on USNB have a significantly greater burden of axillary disease compared with patients with a positive SLNB. USNB(+) patients represent a distinct patient population and further research is required to determine if these patients can be safely exempted from axillary dissection. PMID- 25922245 TI - GI bleeding as the initial presentation of HIV/AIDS. PMID- 25922246 TI - Successful endoscopic dislodgement and removal of ingested glass from the esophagus: a medical emergency. PMID- 25922247 TI - Single-session EUS-guided FNA and biliary drainage with use of a biflanged lumen apposing stent on an electrocautery enhanced delivery system: one-stop shop for unresectable pancreatic mass with duodenal obstruction. PMID- 25922248 TI - Systematic review and meta-analysis of single-balloon enteroscopy-assisted ERCP in patients with surgically altered GI anatomy. AB - BACKGROUND: Surgically altered pancreaticobiliary anatomy increases the difficulty of performing ERCP. Single-balloon enteroscopy (SBE) is a relatively new technique that can be used for ERCP in patients with surgically altered anatomy. OBJECTIVE: To evaluate the therapeutic and diagnostic success of SBE ERCP among patients with surgically altered anatomy. DESIGN/SETTING: Systematic review and meta-analysis of studies involving SBE-ERCP in patients with Roux-en-Y gastric bypass, hepaticojejunostomy, or Whipple procedure. Enteroscopy success was defined as success in reaching the papilla and/or biliary anastomosis by using SBE. Diagnostic success was defined as obtaining a cholangiogram. Procedural success was defined as the ability to provide successful intervention, if appropriate. A random-effects model was used. RESULTS: A total of 461 patients underwent SBE-ERCP from 15 trials. The pooled enteroscopy, diagnostic, and procedural success rates were 80.9% (95% confidence interval [CI], 75.3%-86.4%), 69.4% (95% CI, 61.0%-77.9%), and 61.7% (95% CI, 52.9%-70.5%), respectively. There was statistical large heterogeneity for enteroscopy, diagnostic, and therapeutic success (P < .001 for all). Adverse events occurred in 6.5% (95% CI, 4.7%-9.1%) of patients. There was no evidence of publication bias in this meta-analysis. LIMITATIONS: Our findings and interpretations are limited by the quantity and heterogeneity of the studies included in the analysis. CONCLUSION: SBE-ERCP has high diagnostic and procedural success rates in this challenging patient population. It should be considered a first-line intervention when biliary access is required after Roux-en-Y gastric bypass, hepaticojejunostomy, or Whipple procedure. PMID- 25922249 TI - A case of tangled nasojejunal feeding tube and percutaneous transhepatic drain. PMID- 25922250 TI - A colon pseudotumor in Behcet's disease. PMID- 25922251 TI - Prospective, randomized comparison of 2 methods of cold snare polypectomy for small colorectal polyps. AB - BACKGROUND: Both cold-only snare and hot polypectomy snare are used for the removal of small colorectal polyps. OBJECTIVE: To compare the outcome of cold snare polypectomy of small colorectal polyps with a snare exclusively designed as a cold snare versus cold snare polypectomy by using a traditional polypectomy snare. DESIGN: Prospective, randomized, controlled study. SETTING: Municipal hospital in Japan. INTERVENTIONS: Patients with colorectal polyps 10 mm or smaller in diameter were randomized to dedicated cold snare (dedicated cold snare group) or traditional cold snare (traditional cold snare group). The primary outcome measure was complete resection rates by cold snaring based on pathological examination. Secondary outcomes included bleeding within 2 weeks after polypectomy and identification of submucosal arteries and injured arteries in the resected specimens. RESULTS: Seventy-six patients having 210 eligible polyps were randomized: dedicated cold snare group, N = 37 (98 polyps) and traditional cold snare group, N = 39 (112 polyps). Patient demographic characteristics including the number, size, and shape of the polyps removed were similar in the 2 groups. The complete resection rate was significantly greater with the dedicated cold than with the traditional cold snare (91% [89/98] vs 79% [88/112], P = .015), with a marked difference with 8- to 10-mm polyps, both flat and pedunculated. Immediate bleeding and hematochezia rates were similar (19% vs 21%, P = .86; 5.4% vs 7.7%, P = .69). No delayed bleeding occurred. Histology demonstrated a similar prevalence of arteries and injured arteries in the submucosa (33% [32/96] vs 30% [31/104], P = .59; 3.1% [3/96] vs 6.7% [7/104], P = .24). LIMITATIONS: Small sample size, single-center study. CONCLUSION: Polypectomy by using a dedicated cold snare resulted in complete polyp removal more often than did cold snaring with a traditional snare, especially polyps 8 to 10 mm in diameter, whether flat or pedunculated. ( CLINICAL TRIAL REGISTRATION NUMBER: NCT02036047.) PMID- 25922252 TI - Use of the stag-beetle knife for peroral endoscopic myotomy for achalasia: a novel method for myotomy. PMID- 25922253 TI - Successful reintervention of biliary stent occlusion after biliary and duodenal stenting by using argon plasma coagulation. PMID- 25922254 TI - Endoscopic vacuum therapy of esophageal anastomotic leakage. PMID- 25922255 TI - En bloc submucosal tunneling endoscopic resection for a giant esophageal leiomyoma. PMID- 25922256 TI - Esophageal EUS by filling water-soluble lubricating jelly for diagnosis of depth of invasion in superficial esophageal cancer. PMID- 25922257 TI - Novel use of an optical fiber in triple-lumen catheter for percutaneous choledochoscopy and holmium: yttrium aluminum garnet laser lithotripsy of intrahepatic bile duct stones. PMID- 25922258 TI - Endoscopic closure of a gastric sleeve leak by using an over-the-scope clip and fully covered esophageal stent. PMID- 25922259 TI - Vicryl patch and fibrin glue as treatment of an esophageal leak. PMID- 25922260 TI - Molecular determinants of TRPC1 regulation within ER-PM junctions. AB - Store-operated calcium entry (SOCE) is activated within the endoplasmic reticulum (ER)-plasma membrane (PM) junctions in the plasma membrane and involves assembly of the channels, Orai1 and TRPC1, with the regulatory protein, STIM1, in response to depletion of Ca(2+) in the ER. The dynamic assembly of the channel complexes as well as regulation of channel activity and cell function is dependent on critical components that are either already localized in and/or recruited to the junctions following cell stimulation. These include proteins and lipids in the plasma membrane, ER, and cytosol. Together, these coordinated interactions lead to assembly and activation of Orai1/STIM1 and TRPC1/STIM1 channels. Recent studies demonstrate that Ca(2+) signals generated by Orai1 are detected locally within the ER-PM junctions by various signaling proteins that trigger and regulate other Ca(2+)-dependent functions. One such function is the plasma membrane recruitment of TRPC1 channels where it is activated by STIM1. Activation of TRPC1 within the ER-PM junctions leads to generation of distinct [Ca(2+)]i signals and regulation of cellular functions different from those regulated by Orai1. Thus, it has been suggested that Orai1 and TRPC1 channels are compartmentalized in distinct microdomains. Such compartmentalization involves organization of plasma membrane lipids as well as structural and scaffolding proteins, the nature of which is still poorly understood. Importantly, there appears to be dynamic reorganization of the microdomains within existing ER-PM junctions that allow segregated proteins to interact. Together, these highly specific and coordinated remodeling of protein complexes and membrane domains results in generation of spatially- and temporally-controlled Ca(2+) signals that are critical for numerous downstream cellular functions. PMID- 25922261 TI - GPR56-Related Polymicrogyria: Clinicoradiologic Profile of 4 Patients. AB - Bilateral frontoparietal polymicrogyria is an autosomal recessive cortical malformation associated with abnormalities of neuronal migration, white matter changes, and mild brainstem and cerebellar abnormalities. Affected patients present with delayed milestones, intellectual disability, epilepsy, ataxia, and eye movement abnormalities. The clinicoradiologic profile resembles congenital muscular dystrophy. However, no muscle disease or characteristic eye abnormalities of congenial muscular dystrophy are detected in these children. GPR56 is the only confirmed gene associated with bilateral frontoparietal polymicrogyria. Antenatal diagnosis is possible if the index case is genetically confirmed. Four patients from different Indian families with a distinct clinicoradiologic profile resembling congenital muscular dystrophy with mutations in the GPR56 gene are described. PMID- 25922262 TI - Prognostic Predictors for Ambulation in Thai Children With Cerebral Palsy Aged 2 to 18 Years. AB - The objectives of this study were to determine prognostic predictors for ambulation among Thai children with cerebral palsy and identify their ambulatory status. A retrospective cohort study was performed at 6 special schools or hospitals for children with physical disabilities. The prognostic predictors for ambulation were analyzed by multivariable ordinal continuation ratio logistic regression. The 533 participants aged 2 to 18 years were divided into 3 groups: 186 with independent ambulation (Gross Motor Function Classification System [GMFCS I-II]), 71 with assisted ambulation (Gross Motor Function Classification System III), and 276 with nonambulation (Gross Motor Function Classification System IV-V). The significant positive predictors for ambulation were type of cerebral palsy (spastic diplegia, spastic hemiplegia, dyskinesia, ataxia, hypotonia, and mixed type), sitting independently at age 2 years, and eating independently. These predictors were used to develop clinical scoring for predicting the future ability to walk among Thai children with cerebral palsy. PMID- 25922263 TI - Cytotoxicity of arctigenin and matairesinol against the T-cell lymphoma cell line CCRF-CEM. AB - OBJECTIVES: Arctigenin and matairesinol possess a diversity of bioactivities. Here we investigated the cytotoxicity of arctigenin and matairesinol against a T cell lymphoma cell line CCRF-CEM and the underlying mechanisms that have not been explored before. METHODS: The cytotoxic activity was investigated using MTT assay. The cell cycle arrest and reactive oxygen species (ROS) accumulation were determined by flow cytometric analysis. The apoptosis induction was assessed using Annexin V/Propidium Iodide assay. The gene quantification analysis was measured through real-time polymerase chain reaction. KEY FINDINGS: Arctigenin and matairesinol exhibited significant antiproliferative activity against CCRF CEM cells after 72 h treatment with IC50 values of 1.21 +/- 0.15 MUm and 4.27 +/- 0.41 MUm, respectively. In addition, both lignans arrest CCRF-CEM cells in the S phase. Furthermore, they could induce apoptosis in CCRF-CEM cells in a concentration- and time-dependent manner. Interestingly, the lignans differentially regulated the expression of several key genes involved in apoptosis pathways, including Bax, Bad and caspase-9. Moreover, both lignans could increase ROS levels in CCRF-CEM cells. CONCLUSIONS: Our study provides an insight into the potential of arctigenin and matairesinol as good candidates for the development of novel agents against T-cell lymphoma. PMID- 25922264 TI - You-gui Pill ameliorates renal tubulointerstitial fibrosis via inhibition of TGF beta/Smad signaling pathway. AB - ETHNOPHARMACOLOGICAL RELEVANCE: You-gui Pill (YGP), a traditional Chinese medicinal prescription, was widely used to warm and recuperate "kidney-yang" clinically for hundreds of years in China. Recent studies found that YGP had a potential benefit for renoprotection. AIM OF THE STUDY: The present study aimed to elucidate the in vivo and in vitro efficacy of YGP on renal tubulointerstitial fibrosis, and the molecular mechanism is also investigated. MATERIALS AND METHODS: Rat renal tubulointerstitial fibrosis model was elicited by unilateral ureteral obstruction (UUO). Sprague-Dawley rats underwent UUO and were studied after 14 days. Animals were randomly subjected to six groups: sham, UUO, UUO/YGP (0.14, 0.42, 1.26g/kg/d), and UUO/enalapril (10mg/kg/d). HE, Masson and ELISA were used for evaluate renal injury and function. Immunohistochemical analysis and western blot were used to detect the expressions of alpha-SMA, fibronectin, collagen matrix and Smads. In vitro studies were investigated in TGF-beta1 stiumlated NRK-49F cell line. RESULTS: Oral administration of YGP significantly decreased UUO-induced inflammatory cell infiltration, tubular atrophy and interstitial fibrosis, and there was no significant difference between YGP at 1.26g/kg and enalapril at 10mg/kg treatment (P>0.05). Meanwhile, serum creatinine and blood urea nitrogen levels were reduced dramatically (P<0.01). In coincide with the decreased of TGF-beta1, alpha-SMA, fibronectin and collagen matrix expressions were also declined with YGP treatment in both UUO kidneys and TGF beta1-stimulated NRK-49F cell line. Additionally, nuclear translocation of p Smad2/3 was markedly down-regulated by YGP (P<0.001), with a relative mild up regulated expression of Smad7 (P<0.05). CONCLUSIONS: Our findings demonstrate that YGP had a renoprotective effect in ameliorating renal tubulointerstitial fibrosis, and this activity possibly via suppression of the TGF-beta and its downstream regulatory signaling pathway, including Smad2/3. PMID- 25922265 TI - Anti-diabetic effects of shubat in type 2 diabetic rats induced by combination of high-glucose-fat diet and low-dose streptozotocin. AB - ETHNOPHARMACOLOGICAL RELEVANCE: Shubat, probiotic fermented camel milk, has been used both as a drink with ethnic flavor and a medicine among Kazakh population for diabetic patients. Kazakh people have lower diabetic prevalence and impaired fasting glucose (IFG) than do other ethnic groups living in Xinjiang China, which might be related to the beneficial properties of shubat. We therefore prepared shubat in laboratory and tested anti-diabetic activity and evaluated its possible hypolipidemic and renoprotective effects in type 2 diabetic rats. MATERIALS AND METHODS: Type 2 diabetic rats were induced by an administration of high-glucose fat diet for 6 weeks and an intraperitoneal injection of streptozotocin (STZ, 30mg/kg). Diabetic rats were divided randomly into four groups and treated for 28 days with sitagliptin (30mg/kg) or shubat (6.97*10(6) lactic acid bacteria+2.20*10(4) yeasts) CFU/mL, (6.97*10(7) lactic acid bacteria+2.20*10(5) yeasts) CFU/mL and (6.97*10(8) lactic acid bacteria+2.20*10(6) yeasts) CFU/mL. In addition, a normal control group and a diabetic control group were used for comparison. All drugs were given orally once daily 10mL/kg for 4 weeks. Fasting blood glucose (FBG) and body weight (BW) were measured before treatment and every week thereafter. Total cholesterol (TC), triglycerides (TG), low-density lipoprotein cholesterol (LDL-c), high density lipoprotein cholesterol (HDL-c), serum creatinine (SCr), blood urea nitrogen (BUN), C-peptide, glycated hemoglobin (HbAlc), glucagon-like peptide-1 (GLP-1) levels and pancreas tissue sections were tested after 4 weeks. RESULTS: Shubat demonstrated positive hypoglycemic activity on FBG, HbAlc, C-peptide and GLP-1 levels, high dose shubat decreased FBG (P<0.01) and HbAlc (P<0.05), increased C-peptide (P<0.05) and GLP-1 (P<0.01), decreased serum TC, TG, LDL-c (P<0.05), increased HDL-c (P<0.01), and improved the reduction of body weight as well as decreased SCr and BUN levels (P<0.01) compared to diabetic controls. Histological analysis showed shubat protected the function of islets of type 2 diabetic rats. CONCLUSION: The results of this study indicate that shubat has significant hypoglycemic potential in T2D rats and may modulate lipid metabolism and protect renal function in the type 2 diabetic condition, which might be related to various probiotics acting through promoting the release of GLP-1 and improving the function of beta-cells. PMID- 25922266 TI - An LC-MS/MS method for simultaneous determination of three Polygala saponin hydrolysates in rat plasma and its application to a pharmacokinetic study. AB - ETHNOPHARMACOLOGICAL RELEVANCE: Radix Polygala has a long history of use as a sedative in traditional Chinese medicine and its major ingredients are saponins, which are recognized effective in memory improvement but highly toxic to gastricintestinal mucosa. Polygala saponin hydrolysates (PSH), an alkaline hydrolysis product and also the intestinal metabolites of the saponins, exhibited stronger effects in improving memory of mice and had less toxicity than its original saponins. The present study aims to develop a sensitive LC-MS/MS method for simultaneously determining PSH three major active components, 3,4,5 trimethoxycinnamylic acid (TMCA), p-methoxycinnamylic acid (PMCA) and tenuifolin (TF), in rat plasma and apply the method to a pharmacokinetic study. MATERIALS AND METHODS: The acidic plasma (100MUl) was treated by liquid-liquid extraction with ethyl acetate and reconstituted sample was analyzed on a C18 column eluted with acetonitrile-water (50:50) containing 0.2% formic acid at 0.4ml/min. The mass detection in negative electrospray ionization was used. The ion pairs for multiple reaction monitoring were set at m/z 237.0/103.0, 177.0/116.6 and 679.5/425.3 for TMCA, PMCA and TF, respectively. Their pharmacokinetic profiles were studied in rats after intravenous and oral dose of PSH at 20 and 100mg/kg, respectively. RESULTS: The calibration curves had good linearity (r(2)>0.99) for TMCA, PMCA and TF within the tested concentration ranges. The limits of detection and quantification were 1, 10, 0.5ng/ml and 10.0, 20.0, 1.0ng/ml, respectively. The intra-day and inter-day precisions were less than 18.9% and accuracies between 93.2% and 113.3%, and the extraction recovery ranged from 91.2% to 112.1% for all analytes. The pharmacokinetic study showed that TMCA, PMCA and TF could be rapidly absorbed into the circulation and reached their peak concentrations at about 9.1, 9.0 and 24.0min, respectively. TF had a lower oral bioavailability (2.0%) than TMCA (90.1%) and PMCA (96.5%), but it remained in the body much longer (t1/2, lambdaz, 4.8h, oral dose) than TMCA (0.6h) and PMCA (0.9h). CONCLUSIONS: A sensitive LC-MS/MS method was developed and applied to a pharmacokinetic study of TMCA, PMCA and TF of PSH in rats. The three components are proved to be bio-available active components of PSH and might display their in vivo pharmacological activities at different levels and different time periods after oral administration. PMID- 25922267 TI - Medicinal plants used for neurological and mental disorders in Navarra and their validation from official sources. AB - ETHNOPHARMACOLOGICAL RELEVANCE: This paper provides important ethnopharmacological information on plants used in neurological and mental disorders in Navarra. MATERIAL AND METHODS: Information was collected using semi structured ethnobotanical interviews with 667 informants in 265 locations. In order to confirm the pharmacological validation of the uses claimed by the informants, monographs from Official International Agencies (ESCOP, Commission E, WHO and EMA) were reviewed. A literature review was conducted focusing on the plants that were widely used but had no published monograph. RESULTS: A total of 172 pharmaceutical uses were reported, for 46 plants and 26 families, mainly represented by Lamiaceae (15%), Asteraceae (13%), Rosaceae and Rutaceae (7%, each one), and Clusiaceae, Malvaceae, Papaveraceae and Urticaceae (4%, each one). The most frequently used parts were inflorescence (39%), flowered aerial parts (16%), and aerial parts (13%), followed by inflorescence bract (8%) and leaves (7%). Nine out of 46 plants (20%) and 81 of 172 uses (47%), have already been pharmacologically validated. The remaining 37 plants (of total 46, 80%) have been reported for neurological and mental disorders and need to be screened through standard pharmacological and clinical procedures for their activities. The most used species are Chamaemelum nobile (L.) All., Jasonia glutinosa (L.) DC., and Santolina chamaecyparissus L. ssp. squarrosa (DC.) Nyman, in all cases the administration as infusion. CONCLUSIONS: Data indicate a high degree of plants knowledge in Navarra regarding neurological and mental disorders. The present study constitutes a good basis for further phytochemical and pharmacological research of C. nobile, J. glutinosa and S. chamaecyparissus, which could be of interest in the design of new inexpensive, effective and safe drugs. PMID- 25922268 TI - Astragaloside IV and cycloastragenol are equally effective in inhibition of endoplasmic reticulum stress-associated TXNIP/NLRP3 inflammasome activation in the endothelium. AB - ETHNOPHARMACOLOGICAL RELEVANCE: Astragaloside IV and cycloastragenol are present together in Astragalus membranaceus Moench (Fabaceae) and this study aims to simultaneously investigate their regulation of endothelial homeostasis in the setting of endoplasmic reticulum stress (ER stress). MATERIAL AND METHODS: We stimulated endothelial cells with palmitate (PA 100MUM) to evoked ROS-associated ER stress and observed the effects of astragaloside IV and cycloastragenol on thioredoxin-interacting protein (TXNIP) expression, NLRP3 inflammasome activation and mitochondrion-dependent apoptosis. RESULTS: Astragaloside IV and cycloastragenol inhibited ROS generation and attenuated ER stress inducer IRE1alpha phosphorylation, indicating the inhibition of ROS-associated ER stress. In response to ER stress, TXNIP expression increased, accompanied with NLRP3 induction and increased IL-1beta and IL-6 production, but these alternations were reversed by treatment with astragaloside IV and cycloastragenol, demonstrating the inhibitory effects of astragaloside IV and cycloastragenol on TXNIP/NLRP3 inflammasome activation. Inflammasome activation led to mitochondrial cell death in endothelial cells, whereas astragaloside IV and cycloastragenol restored the loss of the mitochondrial membrane potential with inhibition of caspase-3 activity, and thereby protected cells from ER stress-induced apoptosis. Astragaloside IV and cycloastragenol enhanced AMPK phosphorylation and AMPK inhibitor compound C diminished their beneficial effects, indicative of the potential role of AMPK in their regulation. CONCLUSIONS: Astragaloside IV and cycloastragenol suppressed ROS-associated ER stress and then inhibited TXNIP/NLRP3 inflammasome activation with regulation of AMPK activity, and thereby ameliorated endothelial dysfunction by inhibiting inflammation and reducing cell apoptosis. Simultaneous investigations further showed that astragaloside IV and cycloastragenol were equally effective in regulation of endothelial homeostasis. PMID- 25922269 TI - Cardiac resynchronization therapy in a patient with a failing systemic right ventricle. AB - Systemic right ventricular dysfunction is 1 of the late complications of the atrial switch operation for transposition of the great arteries. It has been reported that cardiac resynchronization therapy (CRT) for the failing systemic right ventricle (RV) improves symptoms and systolic function. However, patient selection for CRT in congenital heart disease is still challenging because the clinical standard for CRT in these patients is not established. We describe a case of successful implantation of a CRT device for a failing systemic RV aided by multimodality imaging and cardiac hemodynamic studies. PMID- 25922270 TI - Does the cerebellum intervene in the abnormal somatosensory temporal discrimination in Parkinson's disease? AB - INTRODUCTION: somatosensory temporal discrimination threshold (STDT) measures the ability to perceive two stimuli as being sequential. Altered STDT has been reported in Parkinson's disease (PD). The cerebellum seems to play a role in the pathophysiology of PD, and may consequently be involved in the pathophysiology of STDT abnormalities. METHODS: STDT was investigated in fifteen PD patients who underwent real and sham cerebellar continuous theta burst stimulation (cTBS) in the OFF condition. Eight patients underwent a further real cTBS session in ON condition. STDT was measured on both hands before, 5 and 25 min after real and sham cTBS delivered over the cerebellar hemisphere ipsilateral to the more affected side. We controlled the efficacy of our protocol by monitoring primary motor cortex (M1) excitability. Ten healthy subjects acted as control group. RESULTS: STDT values were increased in PD patients in the OFF condition compared with healthy subjects and PD patients in the ON condition. In PD patients OFF condition, real but not sham cerebellar cTBS, significantly reduced STDT values only in the hand ipsilateral to the stimulated cerebellar hemisphere. Cerebellar cTBS also decreased motor evoked potentials (MEP) size in the contralateral M1. When PD patients were tested in the ON condition, cerebellar cTBS failed to modify STDT values. CONCLUSION: cerebellar cTBS improved STDT values in PD patients exclusively in OFF condition. We hypothesize that cerebellar stimulation partially compensates for increased STDT values only when patients are OFF dopaminergic therapy. This suggests that the cerebellum may act as compensatory system in PD. PMID- 25922271 TI - Short walking distances compromise the stride length in Parkinson's disease patients. PMID- 25922272 TI - Physical Stability of Octenyl Succinate-Modified Polysaccharides and Whey Proteins for Potential Use as Bioactive Carriers in Food Systems. AB - The high cost and potential toxicity of biodegradable polymers like poly(lactic co-glycolic)acid (PLGA) has increased the interest in natural and modified biopolymers as bioactive carriers. This study characterized the physical stability (water sorption and state transition behavior) of selected starch and proteins: octenyl succinate-modified depolymerized waxy corn starch (DWxCn), waxy rice starch (DWxRc), phytoglycogen, whey protein concentrate (80%, WPC), whey protein isolate (WPI), and alpha-lactalbumin (alpha-L) to determine their potential as carriers of bioactive compounds under different environmental conditions. After enzyme modification and particle size characterization, glass transition temperature and moisture isotherms were used to characterize the systems. DWxCn and DWxRc had increased water sorption compared to native starch. The level of octenyl succinate anhydrate (OSA) modification (3% and 7%) did not reduce the water sorption of the DWxCn and phytoglycogen samples. The Guggenheim Andersen-de Boer model indicated that native waxy corn had significantly (P < 0.05) higher water monolayer capacity followed by 3%-OSA-modified DWxCn, WPI, 3% OSA-modified DWxRc, alpha-L, and native phytoglycogen. WPC had significantly lower water monolayer capacity. All Tg values matched with the solid-like appearance of the biopolymers. Native polysaccharides and whey proteins had higher glass transition temperature (Tg) values. On the other hand, depolymerized waxy starches at 7%-OSA modification had a "melted" appearance when exposed to environments with high relative humidity (above 70%) after 10 days at 23 degrees C. The use of depolymerized and OSA-modified polysaccharides blended with proteins created more stable blends of biopolymers. Hence, this biopolymer would be suitable for materials exposed to high humidity environments in food applications. PMID- 25922273 TI - Indications, techniques, outcomes, and limitations for minimally ischemic and off clamp partial nephrectomy: a systematic review of the literature. AB - CONTEXT: On-clamp partial nephrectomy (PN) has been considered the standard approach to minimize intraoperative bleeding and thus achieve adequate control of tumor margins. The potential negative impact of ischemia on renal function (RF) led to the development of techniques to minimize or avoid renal ischemia, such as off-clamp PN and minimally ischemic PN techniques. OBJECTIVE: To review current evidence on the indications and techniques for and outcomes of minimally ischemic and off-clamp PN. EVIDENCE ACQUISITION: A systematic review of English-language publications on PN without a main renal artery clamp from January 2005 to July 2014 was performed using the Medline, Embase, and Web of Science databases. EVIDENCE SYNTHESIS: The searches retrieved 52 papers. Off-clamp PN has been more commonly applied to small and peripheral renal tumors, while minimally ischemic PN is best suited for hilar and medially located renal tumors. These approaches are associated with increased intraoperative blood loss and perioperative transfusion rates compared to on-clamp PN. Minimally ischemic and off-clamp PN have potential functional benefits when longer ischemia time is anticipated, particularly for patients with lower baseline RF. Limitations include the lack of prospective randomized trials comparing minimally ischemic and off-clamp to on clamp techniques, and the small sample size and short follow-up of most published series. The impact of different resection and renorrhaphy techniques on postoperative RF and its assessment via renal scintigraphy requires further investigations. CONCLUSIONS: Minimally ischemic and off-clamp PN are established procedures that may be particularly applicable for patients with decreased baseline RF. However, these techniques are technically demanding, with potential for increased blood loss, and require considerable experience with PN surgery. The role of ischemia in patients with a contralateral healthy kidney and consequently an indication for elective minimally ischemic or off-clamp PN remains a debatable issue. PATIENT SUMMARY: In this review we analyzed available evidence on minimally ischemic and off-clamp partial nephrectomy. These techniques, although technically demanding, may be particularly applicable for patients with decreased baseline renal function. PMID- 25922274 TI - Utility of Risk Models in Decision Making After Radical Prostatectomy: Lessons from a Natural History Cohort of Intermediate- and High-Risk Men. AB - BACKGROUND: Current guidelines suggest adjuvant radiation therapy for men with adverse pathologic features (APFs) at radical prostatectomy (RP). We examine at risk men treated only with RP until the time of metastasis. OBJECTIVE: To evaluate whether clinicopathologic risk models can help guide postoperative therapeutic decision making. DESIGN, SETTING, AND PARTICIPANTS: Men with National Comprehensive Cancer Network intermediate- or high-risk localized prostate cancer undergoing RP in the prostate-specific antigen (PSA) era were identified (n=3089). Only men with initial undetectable PSA after surgery and who received no therapy prior to metastasis were included. APFs were defined as pT3 disease or positive surgical margins. OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS: Area under the receiver operating characteristic curve (AUC) for time to event data was used to measure the discrimination performance of the risk factors. Cumulative incidence curves were constructed using Fine and Gray competing risks analysis to estimate the risk of biochemical recurrence (BCR) or metastasis, taking censoring and death due to other causes into consideration. RESULTS AND LIMITATIONS: Overall, 43% of the cohort (n=1327) had APFs at RP. Median follow-up for censored patients was 5 yr. Cumulative incidence of metastasis was 6% at 10 yr after RP for all patients. Cumulative incidence of metastasis among men with APFs was 7.5% at 10 yr after RP. Among men with BCR, the incidence of metastasis was 38% 5 yr after BCR. At 10 yr after RP, time-dependent AUC for predicting metastasis by Cancer of the Prostate Risk Assessment Postsurgical or Eggener risk models was 0.81 (95% confidence interval [CI], 0.72-0.97) and 0.78 (95% CI, 0.67 0.97) in the APF population, respectively. At 5 yr after BCR, these values were lower (0.58 [95% CI, 0.50-0.66] and 0.70 [95% CI, 0.63-0.76]) among those who developed BCR. Use of risk model cut points could substantially reduce overtreatment while minimally increasing undertreatment (ie, use of an Eggener cut point of 2.5% for treatment of men with APFs would spare 46% from treatment while only allowing for metastatic events in 1% at 10 yr after RP). CONCLUSIONS: Use of risk models reduces overtreatment and should be a routine part of patient counseling when considering adjuvant therapy. Risk model performance is significantly reduced among men with BCR. PATIENT SUMMARY: Use of current risk models can help guide decision making regarding therapy after surgery and reduce overtreatment. PMID- 25922275 TI - Implication of Interleukin (IL)-18 in the pathogenesis of chronic obstructive pulmonary disease (COPD). AB - Interleukin (IL)-18 is a pro-inflammatory cytokine that was firstly described as an interferon (IFN)-gamma-inducing factor. Similar to IL-1beta, IL-18 is synthesized as an inactive precursor requiring processing by caspase-1 into an active cytokine. The platform for activating caspase-1 is known as the inflammasome, a multiple protein complex. Macrophages and dendritic cells are the primary sources for the release of active IL-18, whereas the inactive precursor remains in the intracellular compartment of mesenchymal cells. Finally, the IL-18 precursor is released from dying cells and processed extracellularly. IL-18 has crucial host defense and antitumor activities, and gene therapy to increase IL-18 levels in tissues protects experimental animals from infection and tumor growth and metastasis. Moreover, multiple studies in experimental animal models have shown that IL-18 over-expression results to emphysematous lesions in mice. The published data prompt to the hypothesis that IL-18 induces a broad spectrum of COPD-like inflammatory and remodeling responses in the murine lung and also induces a mixed type 1, type 2, and type 17 cytokine responses. The majority of studies identify IL-18 as a potential target for future COPD therapeutics to limit both the destructive and remodeling processes occurring in COPD lungs. PMID- 25922276 TI - Mechanisms of unconventional secretion of IL-1 family cytokines. AB - One of the most poorly understood processes in cell biology is the peculiar ability of specific leaderless proteins to be secreted via ER/Golgi-independent mechanisms ('unconventional protein secretion'). One such leaderless protein is the major immune-activating cytokine, interleukin-1beta (IL-1beta). Unusual amongst cytokines, IL-1beta is expressed in the cytosol as an inactive precursor protein. It requires maturation by the caspase-1 protease, which itself requires activation upon immune cell sensing of infection or cell stress. Despite 25 years of intensive research into IL-1beta secretory mechanisms, how it exits the cell is still not well understood. Here we will review the various mechanisms by which macrophages have been proposed to secrete IL-1 family cytokines, and the potential involvement of caspase-1 therein. Since aberrant IL-1beta production drives inherited and acquired human diseases (e.g. autoinflammatory diseases, arthritic diseases, gout, Alzheimer's disease), elucidation of the IL-1beta secretory pathway may offer new therapeutic opportunities for treatment across this wide range of human conditions. PMID- 25922277 TI - Humoral immune responses against the malaria vaccine candidate antigen Plasmodium vivax AMA-1 and IL-4 gene polymorphisms in individuals living in an endemic area of the Brazilian Amazon. AB - BACKGROUND: Several studies have recently demonstrated that the immune responses against malaria is governed by different factors, including the genetic components of the host. The IL-4 gene appears to be a strong candidate factor because of its role in the regulation of the Th2 response. The present study investigated the role of IL-4 polymorphisms in the development of IgG antibodies against PvAMA-1 and the IL-4 levels in individuals infected with Plasmodium vivax in a malaria endemic area in the Brazilian Amazon. METHODS: The study sample included 83 patients who were diagnosed with P. vivax infection using thick smear and confirmed by nested-PCR. The IL-4 -590C>T and IL-4 -33C>T polymorphisms were genotyped by PCR-RFLP, and the intron 3 VNTR was genotyped by PCR. A standardised ELISA protocol was used to measure the total IgG against PvAMA-1. The cytokine/chemokine levels were measured using a Milliplex multiplex assay (Millipore). All of the subjects were genotyped with 48 ancestry informative markers to determine the proportions of African, European and Amerindian ancestry using STRUCTURE software. RESULTS: Of the 83 patients, 60 (73%) produced IgG antibodies against PvAMA-1. A significant decrease in the percentage of respondents was observed among the primo-infected individuals. No significant differences were observed in the frequencies of genotypes and haplotypes among individuals who were positive or negative for IgG antibodies against PvAMA-1. Furthermore, no significant correlation was observed between the IL-4 polymorphisms, antibody levels, IL-4 levels, and parasitemia. CONCLUSIONS: This study indicated that the polymorphisms identified in the IL-4 gene are not likely to play a role in the regulation of the antibody response against PvAMA-1 and IL 4 production in vivax malaria. PMID- 25922278 TI - Psychometric development of the Gastrointestinal Symptom Rating Questionnaire (GSRQ) demonstrated good validity. AB - OBJECTIVES: To develop and validate a gastrointestinal (GI) symptom rating questionnaire for patients with luminal GI symptoms including where no diagnosis has been made. STUDY DESIGN AND SETTING: We developed and validated the Gastrointestinal Symptom Rating Questionnaire (GSRQ) in three stages: (1) item generation to identify the relevant items for scale inclusion; (2) development and piloting on patients with a known GI disorder; and (3) testing in a sample of trial patients. We examined the underlying dimensions of the scale, internal consistency, validity, reproducibility, and responsiveness. RESULTS: We identified four interpretable factors on the GSRQ. The GSRQ had good internal consistency (corrected item-subscale correlations between 0.4 and 0.8) and Cronbach's alpha greater than 0.7 for each subscale. Construct validity was demonstrated by modest but significant correlations with the Short Form 36 and the EQ5D index value. We demonstrated good reproducibility with intraclass correlations for test-retest scores between 0.71 and 0.77, and significant responsiveness ratios for all subscales in patients who had improved, and in two of the subscales in patients who had deteriorated. CONCLUSION: The GSRQ could be a useful tool to monitor quality of life in various luminal GI conditions and where a formal diagnosis has not been made. PMID- 25922279 TI - Stress and burnout among healthcare professionals working in a mental health setting in Singapore. AB - International literature suggests that the experience of high levels of stress by healthcare professionals has been associated with decreased work efficiency and high rates of staff turnover. The aims of this study are to identify the extent of stress and burnout experienced by healthcare professionals working in a mental health setting in Singapore and to identify demographic characteristics and work situations associated with this stress and burnout. A total of 220 Singaporean mental health professionals completed a cross-sectional survey, which included measures of stress, burnout (exhaustion and disengagement), participants' demographic details, and working situation. Independent t-tests and one-way ANOVAs were used to examine between-group differences in the dependent variables (stress and burnout). Analyses revealed that healthcare professionals below the age of 25, those with less than five years experience, and those with the lowest annual income, reported the highest levels of stress and burnout. No significant differences were found with other demographic or work situation variables. Findings suggest that healthcare professionals working in a mental health setting in Singapore are experiencing relatively high levels of stress and burnout. It is important that clinicians, administrators and policy makers take proactive steps to develop programs aimed at reducing stress and burnout for healthcare professionals. These programs are likely to also increase the well-being and resilience of healthcare professionals and improve the quality of mental health services in Singapore. PMID- 25922280 TI - Authors' reply to Adam and to Veal and Thompson. PMID- 25922281 TI - Coordinated tissue-specific regulation of adjacent alternative 3' splice sites in C. elegans. AB - Adjacent alternative 3' splice sites, those separated by <=18 nucleotides, provide a unique problem in the study of alternative splicing regulation; there is overlap of the cis-elements that define the adjacent sites. Identification of the intron's 3' end depends upon sequence elements that define the branchpoint, polypyrimidine tract, and terminal AG dinucleotide. Starting with RNA-seq data from germline-enriched and somatic cell-enriched Caenorhabditis elegans samples, we identify hundreds of introns with adjacent alternative 3' splice sites. We identify 203 events that undergo tissue-specific alternative splicing. For these, the regulation is monodirectional, with somatic cells preferring to splice at the distal 3' splice site (furthest from the 5' end of the intron) and germline cells showing a distinct shift toward usage of the adjacent proximal 3' splice site (closer to the 5' end of the intron). Splicing patterns in somatic cells follow C. elegans consensus rules of 3' splice site definition; a short stretch of pyrimidines preceding an AG dinucleotide. Splicing in germline cells occurs at proximal 3' splice sites that lack a preceding polypyrimidine tract, and in three instances the germline-specific site lacks the AG dinucleotide. We provide evidence that use of germline-specific proximal 3' splice sites is conserved across Caenorhabditis species. We propose that there are differences between germline and somatic cells in the way that the basal splicing machinery functions to determine the intron terminus. PMID- 25922282 TI - Mammographic and Ultrasonographic Findings of Oxidized Regenerated Cellulose in Breast Cancer Surgery: A 5-Year Experience. AB - BACKGROUND: The purpose of this study was to describe the ultrasonographic (US) and mammographic (MX) findings in patients who underwent breast-conserving surgery followed by oxidized regenerated cellulose (ORC) implantation in the surgical cavity and their size variations in follow-up. MATERIALS AND METHODS: We retrospectively reviewed 417 MX and 743 US images performed between January 2009 and January 2014 for 262 women who underwent breast-conserving surgery. All patients underwent US, only 203 women underwent MX examination. RESULTS: In 170 of 262 patients, US examinations showed abnormal findings. Three main US patterns were identified: (1) complex masses: well-encapsulated ipoisoechoic lesions with circumscribed margins with internal hyperechoic nodules (56%); (2) hypoanechoic lesions without internal hyperechoic nodules (24%); and (3) completely anechoic collections (20%). Moreover, Doppler ultrasound examination was performed on all of the patients. In 95 of 203 patients, MX examinations showed abnormalities. Four main MX patterns were identified: (1) round or oval opacity with circumscribed margins (58%); (2) round or oval opacity with indistinct or ill defined margins (17%); (3) irregular opacity with indistinct or spiculated margins (9%); and (4) architectural distortion or focal asymmetry (15%). Most of the lesions showed a decrease in size at US and MX follow-up examination and the decrease was statistically significant (P < .01). CONCLUSION: When applied to the surgical residual cavity, ORC aids to control local hemorrhage and reduce the risk of postoperative infections, but can lead to alterations in surgical scar. Thus, knowledge of the radiological findings might allow avoidance of misdiagnosis of tumor recurrence or unnecessary diagnostic examinations. PMID- 25922283 TI - Tamoxifen Treatment and the Reduced Risk of Hyperlipidemia in Asian Patients With Breast Cancer: A Population-Based Cohort Study. AB - PURPOSE: The association between tamoxifen (TMX) treatment and the risk of developing hyperlipidemia remains unclear. METHODS: The records of 41,726 patients with breast cancer (28,266 received TMX and 13,460 did not) were obtained from the Taiwan National Health Insurance Research Database for the period from January 2000 to December 2008. Three-fold women without breast cancer were the control group (N = 125, 178). The main end point was developing hyperlipidemia during the follow-up. RESULTS: During a mean follow-up of 9 years, the patients with breast cancer demonstrated a rate of developing hyperlipidemia that was 6% less (adjusted hazard ratio [HR], 0.94; 95% confidence interval [CI], 0.90-0.97) than that of the control participants without breast cancer. Stratification by age group indicated that only women aged >= 55 years who were diagnosed with breast cancer exhibited a significantly reduced risk of hyperlipidemia compared with the control group. With the use of 2 types of adjusted models, we observed that the TMX users (aged >= 55 years) consistently exhibited a significantly lower risk of hyperlipidemia than the non-TMX users and control participants (adjusted HRs, 0.79 and 0.82 from models 1 and 2, respectively). Within the 8-year follow-up period, patients with breast cancer and 366 to 1500 days of TMX therapy and > 1500 days of TMX therapy had significantly lower risks of hyperlipidemia compared with patients with <= 365 days of TMX therapy (adjusted HR, 0.54; 95% CI, 0.50-0.59; adjusted HR, 0.21; 95% CI, 0.18-0.24, respectively). CONCLUSIONS: In Asian patients with breast cancer, TMX use was associated with reduced risks of hyperlipidemia. PMID- 25922285 TI - Is there any advantage in placing an additional calcar screw in locked nailing of proximal humeral fractures? AB - BACKGROUND: The objective of this study was to evaluate the biomechanical effect of an additional unlocked calcar screw compared to a standard setting with three proximal humeral head screws alone for fixation of an unstable 2-part fracture of the surgical neck. HYPOTHESIS: The additional calcar screw improves stiffness and failure load. METHODS: Fourteen fresh frozen humeri were randomized into two equal sized groups. An unstable 2-part fracture of the surgical neck was simulated and all specimens were fixed with the MultiLoc((r))-nail. Group I represented a basic screw setup, with three locked head screws and two unlocked shaft screws. Group II was identical with a supplemental unlocked calcar screw (CS). Stiffness tests were performed in torsional loading, as well as in axial and in 20 degrees abduction/20 degrees adduction modes. Subsequently cyclic loading and load-to-failure tests were performed. Resulting stiffness, displacement under cyclic load and ultimate load were compared between groups using the t-test for independent variables (alpha=0.05). RESULTS: No significant differences were observed between the groups in any of the biomechanical parameters. Backing out of the CS was observed in three cases. DISCUSSION: The use of an additional unlocked calcar screw does not provide mechanical benefit in locked nailing of an unstable 2-part fracture of the surgical neck. PMID- 25922284 TI - Hormone Receptor Status and HER2 Expression in Primary Breast Cancer Compared With Synchronous Axillary Metastases or Recurrent Metastatic Disease. AB - Estrogen receptor (ER), progesterone receptor (PR), and HER2/neu are the most important tissue markers in the management of breast cancer, in the adjuvant setting and in the setting of metastatic disease. Many studies have demonstrated a discordance of expression between primary breast cancer, synchronous axillary metastases, and metastatic sites. The aim of this article is to review studies on discordance of expression of these predictive parameters to better understand the importance of a reassessment of biomolecular status to modify treatment strategies. We performed a literature review to identify studies that assessed ER, PR, and HER2 discordance between primary breast cancer, synchronous axillary lymph node metastasis, and other metastatic sites. We reviewed these data related to (1) relevance of discordance rates in clinical practice and (2) therapeutic consequences of discordance rate. Results were analyzed qualitatively. Changes in ER and particularly in PR are observed in locoregional and in distant metastases reaching a rate of 10% to 30% for ER and 20% to 50% for PR. The loss of PR is more frequent than ER loss. High HER2 concordance between primary tumors and axillary lymph node or distant metastases has been demonstrated in many studies; in the discordant cases, it is more frequent to have HER2-positive metastases with negative primary tumors than the opposite. A reassessment of biomolecular status in residual tumors after neoadjuvant treatment or in metastatic sites is advisable, whenever it is possible, to correct/modify the treatment schedule and to estimate the actual prognosis. PMID- 25922286 TI - Epidermis-dermis junction as a novel location for bone marrow-derived cells to reside in response to ionizing radiation. AB - Bone marrow-derived cells (BMDCs) can migrate into the various organs in the mice irradiated by ionizing radiation (IR). However, it may not be the case in the skin. While IR is used for bone marrow (BM) transplantation, studying with the epidermal sheets demonstrated that the BMDC recruitment is extraordinarily rare in epidermis in the mouse. Herein, using the chimera mice with BM from green fluorescent protein (GFP) transgenic mice, we simply examined if BMDCs migrate into any layers in the total skin, as opposed to the epidermal sheets, in response to IR. Interestingly, we identified the presence of GFP-positive (GFP(+)) cells in the epidermis-dermis junction in the total skin sections although the epidermal cell sheets failed to have any GFP cells. To examine a possibility that the cells in the junction could be mechanically dissociated during separating epidermal sheets, we then salvaged such dissociated cells and examined its characteristics. Surprisingly, some GFP(+) cells were found in the salvaged cells, indicating that these cells could be derived from BM. In addition, such BMDCs were also associated with inflammation in the junction. In conclusion, BMDCs can migrate to and reside in the epidermis-dermis junction after IR. PMID- 25922287 TI - Angiogenesis and lymphangiogenesis in inflammatory skin disorders. AB - Angiogenesis, the growth of new blood vessels from pre-existing vessels, occurs physiologically in wound healing, during inflammatory diseases, and in tumor growth. Lymphangiogenesis can be activated in inflammation and tumor metastasis. The family of vascular endothelial growth factors (VEGFs) and angiopoietins are essential for angiogenesis and lymphangiogenesis. The angiogenic process is tightly regulated by VEGFs, angiopoietins, and endogenous inhibitors. VEGFs and angiopoietins exert their effects by activating specific receptors present on blood and lymphatic endothelial cells. There is now compelling evidence that cells of innate and adaptive immunity (macrophages, mast cells, neutrophils, eosinophils, lymphocytes) are a major source of angiogenic and lymphangiogenic factors. Chronic inflammatory skin diseases such as psoriasis and atopic dermatitis are characterized by altered angiogenesis, lymphangiogenesis, or both. Also such acute inflammatory skin disorders as urticaria, ultraviolet B-induced damage, and angioedema are associated with changes in angiogenic factors. In systemic sclerosis there is a switch from proangiogenic to antiangiogenic factors that play a role in the defective vascular process of this disorder. As yet, there are no clinical trials showing that canonical VEGF/VEGF receptor-targeted strategies can modulate inflammatory skin diseases. Novel strategies targeting other angiogenic/lymphangiogenic pathways should also be investigated. PMID- 25922288 TI - Immunomodulation in sepsis-why blunting the response doesn't work? PMID- 25922289 TI - New options in the treatment of respiratory syncytial virus disease. AB - Respiratory syncytial virus (RSV) remains a significant cause of morbidity and mortality in infants, immunocompromised patients and the elderly. Despite the high disease burden, an effective vaccine or specific therapy are lacking which is largely due to our limited understanding of the immune response to RSV and how it relates to clinical disease severity. Current treatment for RSV remains largely supportive and RSV-specific options for prophylaxis and/or treatment are limited to palivizumab and ribavirin. There are a number of promising compounds currently under development, including new monoclonal antibodies and small molecules. These newer antivirals have the potential to impact both the prevention and treatment of RSV disease in the main target populations. PMID- 25922290 TI - Parainfluenza virus as a cause of acute respiratory infection in hospitalized children. AB - BACKGROUND: Human parainfluenza viruses account for a significant proportion of lower respiratory tract infections in children. OBJECTIVE: To assess the prevalence of Human parainfluenza viruses as a cause of acute respiratory infection and to compare clinical data for this infection against those of the human respiratory syncytial virus. METHODS: A prospective study in children younger than five years with acute respiratory infection was conducted. Detection of respiratory viruses in nasopharyngeal aspirate samples was performed using the indirect immunofluorescence reaction. Length of hospital stay, age, clinical history and physical exam, clinical diagnoses, and evolution (admission to Intensive Care Unit or general ward, discharge or death) were assessed. Past personal (premature birth and cardiopathy) as well as family (smoking and atopy) medical factors were also assessed. RESULTS: A total of 585 patients were included with a median age of 7.9 months and median hospital stay of six days. No difference between the HRSV+ and HPIV+ groups was found in terms of age, gender or length of hospital stay. The HRSV+ group had more fever and cough. Need for admission to the Intensive Care Unit was similar for both groups but more deaths were recorded in the HPIV+ group. The occurrence of parainfluenza peaked during the autumn in the first two years of the study. CONCLUSION: Parainfluenza was responsible for significant morbidity, proving to be the second-most prevalent viral agent in this population after respiratory syncytial virus. No difference in clinical presentation was found between the two groups, but mortality was higher in the HPIV+ group. PMID- 25922291 TI - Detection of Crizotinib-Sensitive Lung Adenocarcinomas With MET, ALK, and ROS1 Genomic Alterations via Comprehensive Genomic Profiling. PMID- 25922292 TI - Advanced Lung Cancer Inflammation Index, a New Prognostic Score, Predicts Outcome in Patients With Small-Cell Lung Cancer. AB - This report is the first to use the value of the Advanced Lung Cancer Inflammation Index (ALI) to predict the overall survival in patients with small cell lung cancer. We enrolled 365 patients who were eligible for analysis and found that lower ALI was significantly associated with worse overall survival in small-cell lung cancer patients. The results showed that evaluation using ALI could authenticate the patients with poor prognosis and be a useful prognostic marker in clinical practice. BACKGROUND: A recent study indicated that the Advanced Lung Cancer Inflammation Index (ALI) could predict overall survival (OS) in patients with non-small-cell lung cancer. However, the prognostic value in small-cell lung cancer (SCLC) has not been studied. Therefore, the aim of this study was to explore the relationship between ALI and the prognosis of SCLC. PATIENTS AND METHODS: We screened 460 patients who were diagnosed with SCLC from June 2006 to December 2011 in Sun Yat-Sen University Cancer Center. Data acquisition was through patients' medical information, and blood results recorded at the time of diagnosis. ALI was calculated as the formula: body mass index * serum albumin/neutrophil-lymphocyte ratio. RESULTS: In total, 365 patients were enrolled in this study. Patients were allocated to 2 groups: ALI < 19.5 (n = 60) and ALI >= 19.5 (n = 305). For patients with ALI < 19.5 and >= 19.5, the median OS was 10.97 and 20.14 months, respectively (P < .001). On multivariate analysis, clinical stage (P < .001), performance status (P = .001), lactate dehydrogenase (P < .001), and ALI (P = .005) were all independent prognostic factors for OS. CONCLUSION: The results of this study demonstrated that lower ALI was significantly associated with worse OS in SCLC patients. The evaluation of ALI could authenticate the patients with poor prognosis and be a useful prognostic marker in clinical practice. PMID- 25922293 TI - Individual variability analysis of fluorescence parameters measured in skin with different levels of nutritive blood flow. AB - Fluorescence spectroscopy has recently become more common in clinical medicine. However, there are still many unresolved issues related to the methodology and implementation of instruments with this technology. In this study, we aimed to assess individual variability of fluorescence parameters of endogenous markers (NADH, FAD, etc.) measured by fluorescent spectroscopy (FS) in situ and to analyse the factors that lead to a significant scatter of results. Most studied fluorophores have an acceptable scatter of values (mostly up to 30%) for diagnostic purposes. Here we provide evidence that the level of blood volume in tissue impacts FS data with a significant inverse correlation. The distribution function of the fluorescence intensity and the fluorescent contrast coefficient values are a function of the normal distribution for most of the studied fluorophores and the redox ratio. The effects of various physiological (different content of skin melanin) and technical (characteristics of optical filters) factors on the measurement results were additionally studied. The data on the variability of the measurement results in FS should be considered when interpreting the diagnostic parameters, as well as when developing new algorithms for data processing and FS devices. PMID- 25922294 TI - A dual mode breath sampler for the collection of the end-tidal and dead space fractions. AB - This work presents a breath sampler prototype automatically collecting end-tidal (single and multiple breaths) or dead space air fractions (multiple breaths). This result is achieved by real time measurements of the CO2 partial pressure and airflow during the expiratory and inspiratory phases. Suitable algorithms, used to control a solenoid valve, guarantee that a Nalophan((r)) bag is filled with the selected breath fraction even if the subject under test hyperventilates. The breath sampler has low pressure drop (<0.5 kPa) and uses inert or disposable components to avoid bacteriological risk for the patients and contamination of the breath samples. A fully customisable software interface allows a real time control of the hardware and software status. The performances of the breath sampler were evaluated by comparing (a) the CO2 partial pressure calculated during the sampling with the CO2 pressure measured off-line within the Nalophan((r)) bag; (b) the concentrations of four selected volatile organic compounds in dead space, end-tidal and mixed breath fractions. Results showed negligible deviations between calculated and off-line CO2 pressure values and the distributions of the selected compounds into dead space, end-tidal and mixed breath fractions were in agreement with their chemical-physical properties. PMID- 25922295 TI - Fathers and Asthma Care: Paternal Involvement, Beliefs, and Management Skills. AB - OBJECTIVE: To compare asthma care roles of maternal and paternal caregivers, and examine associations between caregiver involvement and the outcomes of adherence, morbidity, and parental quality of life (QoL). METHODS: Mothers and fathers in 63 families of children, ages 5-9 years, with persistent asthma completed semistructured interviews and questionnaires. Adherence was measured via electronic monitoring. Paired t tests compared parental asthma care roles, and analysis of covariance, controlling for socioeconomic status, evaluated associations of asthma outcomes with caregiver involvement scores. RESULTS: Mothers had higher scores on measures of involvement, beliefs in medication necessity, and on four subscales of the Family Asthma Management System Scale interview (Asthma Knowledge, Relationship with Provider, Symptom Assessment, and Response to Symptoms). Maternal QoL was lowest when both maternal and paternal involvement was high. Paternal involvement was associated with increased morbidity. CONCLUSIONS: There is room for enhancement of fathers' asthma care roles. Higher levels of paternal involvement may be driven by family need. PMID- 25922296 TI - Motivational and control mechanisms underlying adolescent cannabis use disorders: A prospective study. AB - Cannabis use disorders (CUDs) are the most prevalent substance use disorders among adolescents in treatment. Yet, little is known about the neuropsychological mechanisms underlying adolescent CUDs. Studies in adult cannabis users suggest a significant role for cognitive control and cannabis-oriented motivational processes, such as attentional bias, approach bias, and craving in CUDs. The current 6-month prospective study investigated the relationships between attentional bias, approach bias, craving, cognitive control, and cannabis use in adolescent patients in treatment for a primary or secondary CUD. Moreover, we investigated if these motivational processes and cognitive control could predict treatment progression after 6 months. Adolescents with a CUD had an attentional but no approach bias towards cannabis. In contrast to adult findings on the role of attentional bias, approach bias and cognitive control, only cannabis craving significantly correlated with current cannabis use and predicted cannabis use related problems and abstinence from cannabis 6 months later. These findings identify craving as a predictor of treatment outcome, thereby supporting an important role for craving in the course of adolescent cannabis use and dependence. This prospective study is among the first to investigate neuropsychological mechanisms underlying adolescent CUDs, warranting future longitudinal studies. PMID- 25922297 TI - Seed germination and seedling development in response to submergence in tree species of the Central Amazonian floodplains. AB - Successful germination and seedling establishment are crucial steps for maintenance and expansion of plant populations and recovery from perturbations. Every year the Amazon River and its tributaries overflow and flood the adjacent forest, exerting a strong selective pressure on traits related to seedling recruitment. We examined seed characteristics, stored reserves, germination, seedling development and survival under water of eight representative tree species from the lower portions of the flood-level gradient to identify adaptive strategies that contribute to their regeneration in this extreme ecosystem. Submerged seedlings were assessed for longevity and survival until they showed symptoms of injury. At this point, the remaining healthy seedlings were planted in unsaturated soil to monitor recovery after re-exposure to air over 30 days. All small (seed mass <=0.17 g) seeds had epigeal phanerocotylar-type germination, a trait that would allow plants to acquire light and CO2 in the shortest time. Cell wall storage polysaccharide was a major component of all seeds, suggesting plant investment in structural reserves. Seven of the eight species germinated and formed healthy seedlings under water that endured submersion without any apparent injury for periods of 20-115 days, depending on the species. Seedlings of some species changed the direction of root growth and grew towards the surface of the water, which might have increased the uptake of oxygen to the tissues. Only one of the seven species did not survive re-exposure to air. Species able to germinate and produce seedlings under submersion, which subsequently are able to establish in aerated soils, would have more time available for terrestrial growth. This is critical for colonization of lower portions of the flood-level gradient where establishment is constrained by the short terrestrial phase that precedes the next flood. PMID- 25922298 TI - Ecophysiological roles of abaxial anthocyanins in a perennial understorey herb from temperate deciduous forests. AB - Accumulation of abaxial anthocyanins is an intriguing leaf trait particularly common among deeply shaded understorey plants of tropical and temperate forests whose ecological significance is still not properly understood. To shed light on it, possible ecophysiological roles of abaxial anthocyanins were tested in the perennial understorey herb of temperate deciduous forests Saxifraga hirsuta, chosen as a model species due to the coexistence of green and anthocyanic leaves and the presence of an easily removable lower anthocyanic epidermis. Anthocyanins accumulated during autumn, which temporally matched the overstorey leaf fall. Patterns of development of abaxial anthocyanins and direct measurements of photochemical efficiency under monochromatic light were not consistent with a photoprotective hypothesis. Enhancement of light capture also seemed unlikely since the back-scattering of red light towards the lower mesophyll was negligible. Seed germination was similar under acyanic and anthocyanic leaves. A relevant consequence of abaxial anthocyanins was the dramatic reduction of light transmission through the leaf. The dark environment generated underneath the Saxifraga canopy was enhanced by the horizontal repositioning of leaves, which occurs in parallel with reddening. This might play a role in biotic interactions by inhibiting vital processes of competitors, which may be of especial importance in spring before the overstorey leaves sprout. PMID- 25922299 TI - Do standard burn mortality formulae work on a population of severely burned children and adults? AB - Accurate prediction of mortality following burns is useful as an audit tool, and for providing treatment plan and resource allocation criteria. Common burn formulae (Ryan Score, Abbreviated Burn Severity Index (ABSI), classic and revised Baux) have not been compared with the standard Acute Physiology and Chronic Health Evaluation II (APACHEII) or re-validated in a severely (>=20% total burn surface area) burned population. Furthermore, the revised Baux (R-Baux) has been externally validated thoroughly only once and the pediatric Baux (P-Baux) has yet to be. Using 522 severely burned patients, we show that burn formulae (ABSI, Baux, revised Baux) outperform APACHEII among adults (AUROC increase p<0.001 adults; p>0.5 children). The Ryan Score performs well especially among the most at-risk populations (estimated mortality [90% CI] original versus current study: 33% [26-41%] versus 30.18% [24.25-36.86%] for Ryan Score 2; 87% [78-93%] versus 66.48% [51.31-78.87%] for Ryan Score 3). The R-Baux shows accurate discrimination (AUROC 0.908 [0.869-0.947]) and is well-calibrated. However, the ABSI and P-Baux, although showing high measures of discrimination (AUROC 0.826 [0.737-0.916] and 0.848 [0.758-0.938]) in children), exceedingly overestimates mortality, indicating poor calibration. We highlight challenges in designing and employing scores that are applicable to a wide range of populations. PMID- 25922300 TI - Fire disaster caused by LPG tanker explosion at Lice in Diyarbakir (Turkey): July 21, 2014. AB - A disaster can be defined as a situation where the affected society cannot overcome its own resources. Our aim was to present the case of a fire disaster caused by a liquefied petroleum gas (LPG) tanker-based explosion on the Diyarbakir-Bingol road in Lice to determine the various kinds of challenges and patient groups that an emergency department faces and to discuss more effective interventions for similar disasters. This is a retrospective cross-sectional study. To find out the factors that affected mortality, we investigated the patient conditions presented at the time of admission. Among 69 patients included in the study, 62 were male (89.9%) and seven were female (10.1%). The average age of patients was 32.10+/-14.01 years, and the burn percentage was 51.1+/-32.2. One patient died during the first response, and a total of 34 patients (49.3%) died during the patient follow-up. Factors statistically related to mortality were determined to be inclusion in the severe burn group, presence of inhalation injuries, use of central venous catheter on patients, application of fasciotomy, presence of a tracheostomy opening, use of endotracheal intubation and sedoanalgesia, and transfer to centers outside the city (p-values <0.001, <0.001, <0.001, <0.001, <0.001, <0.001, 0.001, and 0.003, respectively). In conclusion, although fire disasters caused by LPG tanker explosions are rare, the frequency of such disasters will increase with the increase in LPG use. The factors affecting mortality should be determined to decrease mortality. We recommend that all personnel members who engage in work related to LPG from production to use, in addition to rescue and first-response personnel, be trained comprehensively and that advanced technological fire equipment be used to prevent such disasters. PMID- 25922301 TI - Involvement of impaired desmosome-related proteins in hypertrophic scar intraepidermal blister formation. AB - Hypertrophic scar is one of the unique fibrotic diseases in human. Intraepidermal blister is a common clinical symptom following the hypertrophic scar formation. However, little is known about the reason of blister creation. In this study, we selected three patients with hypertrophic scar as manifested by raised, erythematous, pruritic, blister and thickened appearance undergoing scar resection. The first scar sample was 6 months after burn from the neck of a 3 years old male patient with 10 score by Vancouver Scar Scale (VSS). The second scar sample was 12 months after burn from the dorsal foot of a 16 years old female patient with 13 score by VSS. The third one was 9 months after burn from the elbow of a 34 years old male patients with 13 score by VSS. In order to understand the molecular mechanism of blister formation, we screened the different protein expression between hypertrophic scar and normal skin tissue by means of isobaric tags for relative and absolute quantitation (iTRAQ) labeling technology and high throughput 2D LC-MS/MS. There were 48 proteins found to be downregulated in hypertrophic scar. Among the downregulated ones, plakophilin1 (PKP1), plakophilin3 (PKP3) and desmoplakin (DSP) were the desmosome-related proteins which were validated by immunohistochemistry and western blotting assay. Transmission electron microscopy further showed the considerably reduced size and intensity of hemidesmosome and desmosome in hypertrophic scar tissue, compared to control normal skin. Our data indicted for the first time that downregulation of DSP, PKP1 and PKP3 in hypertrophic scar might be responsible for intraepidermal blister formation. PMID- 25922302 TI - The effect of burn on serum concentrations of sclerostin and FGF23. AB - Severe burn results in acute bone resorption followed by an adynamic state, most likely due to changes brought about by the inflammatory and glucocorticoid responses to the injury. There is a consequent increase in annual extrapolated fracture incidence in children. While osteoblasts have been reported to disappear from the bone surface and stem cell differentiation into osteoblasts is impaired, the effect of burns on osteocyte function is unknown. We measured serum concentrations of two osteocyte proteins, sclerostin and fibroblast growth factor (FGF)-23 between 6 and 60 days post-burn in pediatric patients, ages 5-18 years who had participated in a randomized controlled double-blind study of acute administration of pamidronate to prevent the resorptive bone loss. While FGF-23 was undetectable in all samples, the plot of sclerostin concentration versus time post-burn yielded a statistically significant difference between slopes, -2.5 in the placebo control group and +3.5 in the group receiving pamidronate, p=0.016 by ANCOVA. The FGF23 data suggest that osteocytes may be apoptotic, although the sclerostin data may indicate partial preservation of osteocyte function in subjects receiving pamidronate or an ectopic source of sclerostin. PMID- 25922303 TI - Hybrid wound dressings with controlled release of antibiotics: Structure-release profile effects and in vivo study in a guinea pig burn model. AB - Over the last decades, wound dressings have evolved from a crude traditional gauze dressing to tissue-engineered scaffolds. Many types of wound dressing formats are commercially available or have been investigated. We developed and studied hybrid bilayer wound dressings which combine a drug-loaded porous poly(dl lactic-co-glycolic acid) top layer with a spongy collagen sublayer. Such a structure is very promising because it combines the advantageous properties of both layers. The antibiotic drug gentamicin was incorporated into the top layer for preventing and/or defeating infections. In this study, we examined the effect of the top layer's structure on the gentamicin release profile and on the resulting in vivo wound healing. The latter was tested on a guinea pig burn model, compared to the neutral non-adherent dressing material Melolin(r) (Smith & Nephew) and Aquacel(r) Ag (ConvaTec). The release kinetics of gentamicin from the various studied formulations exhibited burst release values between 8% and 38%, followed by a drug elution rate that decreased with time and lasted for at least 7 weeks. The hybrid dressing, with relatively slow gentamicin release, enabled the highest degree of wound healing (28%), which is at least double that obtained by the other dressing formats (8-12%). It resulted in the lowest degree of wound contraction and a relatively low amount of inflammatory cells compared to the controls. This dressing was found to be superior to hybrid wound dressings with fast gentamicin release and to the neat hybrid dressing without drug release. Since this dressing exhibited promising results and does not require frequent bandage changes, it offers a potentially valuable concept for treating large infected burns. PMID- 25922304 TI - Supermacroporous chemically cross-linked poly(aspartic acid) hydrogels. AB - Chemically cross-linked poly(aspartic acid) (PASP) gels were prepared by a solid liquid phase separation technique, cryogelation, to achieve a supermacroporous interconnected pore structure. The precursor polymer of PASP, polysuccinimide (PSI) was cross-linked below the freezing point of the solvent and the forming crystals acted as templates for the pores. Dimethyl sulfoxide was chosen as solvent instead of the more commonly used water. Thus larger temperatures could be utilized for the preparation and the drawback of increase in specific volume of water upon freezing could be eliminated. The morphology of the hydrogels was characterized by scanning electron microscopy and interconnectivity of the pores was proven by the small flow resistance of the gels. Compression tests also confirmed the interconnected porous structure and the complete re-swelling and shape recovery of the supermacroporous PASP hydrogels. The prepared hydrogels are of interest for several biomedical applications as scaffolding materials because of their cytocompatibility, controllable morphology and pH-responsive character. PMID- 25922305 TI - Age-related decline in the matrix contents and functional properties of human periodontal ligament stem cell sheets. AB - In this study, periodontal ligament (PDL) stem cells (PDLSCs) derived from different-aged donors were used to evaluate the effect of aging on cell sheet formation. The activity of PDLSCs was first determined based on their colony forming ability, surface markers, proliferative/differentiative potentials, senescence-associated beta-galactosidase (SA-betaG) staining, and expression of pluripotency-associated transcription factors. The ability of these cells to form sheets, based on their extracellular matrix (ECM) contents and their functional properties necessary for osteogenic differentiation, was evaluated to predict the age-related changes in the regenerative capacity of the cell sheets in their further application. It was found that human PDLSCs could be isolated from the PDL tissue of different-aged subjects. However, the ability of the PDLSCs to proliferate and to undergo osteogenic differentiation and their expression of pluripotency-associated transcription factors displayed age-related decreases. In addition, these cells exhibited an age-related increase in SA-betaG expression. Aged cells showed an impaired ability to form functional cell sheets, as determined by morphological observations and Ki-67 immunohistochemistry staining. Based on the production of ECM proteins, such as fibronectin, integrin beta1, and collagen type I; alkaline phosphatase (ALP) activity; and the expression of osteogenic genes, such as ALP, Runt-related transcription factor 2, and osteocalcin, cell sheets formed by PDLSCs derived from older donors demonstrated a less potent osteogenic capacity compared to those formed by PDLSCs from younger donors. Our data suggest that the age-associated decline in the matrix contents and osteogenic properties of PDLSC sheets should be taken into account in cell sheet engineering research and clinical periodontal regenerative therapy. PMID- 25922307 TI - Limitations of fibrosis grade as diagnostic criteria for post polycythemia vera and essential thrombocytosis myelofibrosis. AB - BACKGROUND: The clinical phenotype of patients with myeloproliferative neoplasms (MPNs) including primary myelofibrosis (PMF), polycythemia vera (PV), and essential thrombocytosis (ET) whom manifest WHO grade 1 marrow fibrosis is poorly defined. Current IWG-MRT criteria require 2+ marrow fibrosis for diagnosis of post PV/ET myelofibrosis (MF). In contrast, the 2008 WHO definition of PMF does not require a minimum fibrosis threshold. METHODS: We retrospectively analyzed the clinical characteristics of 91 MPN patients with 1+ marrow fibrosis. We compared the clinical phenotype of sub threshold fibrosis PV/ET with that manifested by PMF. We applied the IWG-MRT criteria for post-PV/ET MF with the fibrosis component omitted and evaluated for percentage of criteria fulfillment. RESULTS: When IWG-MRT criteria were applied to the PV/ET group, 38/58 (66%) of patients fulfilled criteria for diagnosis of post-PV/ET myelofibrosis except for the 2+ fibrosis requirement. Comparison of sub threshold fibrotic PV/ET clinical phenotype to PMF revealed similar characteristics including heavy symptomatic burden (57% and 52%), presence of splenomegaly (43% and 55%), leukoerythroblastic blood smear (38% and 45%), and median hemoglobin (12.8g/dL and 11.1g/dL). CONCLUSION: MPN progression represents a biological spectrum and definitions of progression in ET/PV may benefit from criteria not restricted by degree of fibrosis. PMID- 25922308 TI - Molecular basis of arsenite (As+3)-induced acute cytotoxicity in human cervical epithelial carcinoma cells. AB - BACKGROUND: Rapid industrialization is discharging toxic heavy metals into the environment, disturbing human health in many ways and causing various neurologic, cardiovascular, and dermatologic abnormalities and certain types of cancer. The presence of arsenic in drinking water from different urban and rural areas of the major cities of Pakistan, for example, Lahore, Faisalabad, and Kasur, was found to be beyond the permissible limit of 10 parts per billion set by the World Health Organization. Therefore the present study was initiated to examine the effects of arsenite (As(+3)) on DNA biosynthesis and cell death. METHODS: After performing cytotoxic assays on a human epithelial carcinoma cell line, expression analysis was done by quantitative polymerase chain reaction, western blotting, and flow cytometry. RESULTS: We show that As(+3) ions have a dose- and time dependent cytotoxic effect through the activation of the caspase-dependent apoptotic pathway. In contrast to previous research, the present study was designed to explore the early cytotoxic effects produced in human cells during exposure to heavy dosage of As(+3) (7.5 ug/ml). Even treatment for 1 h significantly increased the mRNA levels of p21 and p27 and caspases 3, 7, and 9. It was interesting that there was no change in the expression levels of p53, which plays an important role in G2/M phase cell cycle arrest. CONCLUSION: Our results indicate that sudden exposure of cells to arsenite (As(+3)) resulted in cytotoxicity and mitochondrial-mediated apoptosis resulting from up-regulation of caspases. PMID- 25922306 TI - The Mechanism and Function of Epigenetics in Uterine Leiomyoma Development. AB - Uterine leiomyomas, also known as uterine fibroids, are the most common pelvic tumors, occurring in nearly 70% of all reproductive-aged women and are the leading indication for hysterectomy worldwide. The development of uterine leiomyomas involve a complex and heterogeneous constellation of hormones, growth factors, stem cells, genetic, and epigenetic abnormalities. An increasing body of evidence emphasizes the important contribution of epigenetics in the pathogenesis of leiomyomas. Genome-wide methylation analysis demonstrates that a subset of estrogen receptor (ER) response genes exhibit abnormal hypermethylation levels that are inversely correlated with their RNA expression. Several tumor suppressor genes, including Kruppel-like factor 11 (KLF11), deleted in lung and esophageal cancer 1 (DLEC1), keratin 19 (KRT19), and death-associated protein kinase 1 (DAPK1) also display higher hypermethylation levels in leiomyomas when compared to adjacent normal tissues. The important role of active DNA demethylation was recently identified with regard to the ten-eleven translocation protein 1 and ten eleven translocation protein 3-mediated elevated levels of 5 hydroxymethylcytosine in leiomyoma. In addition, both histone deacetylase and histone methyltransferase are reported to be involved in the biology of leiomyomas. A number of deregulated microRNAs have been identified in leiomyomas, leading to an altered expression of their targets. More recently, the existence of side population (SP) cells with characteristics of tumor-initiating cells have been characterized in leiomyomas. These SP cells exhibit a tumorigenic capacity in immunodeficient mice when exposed to 17beta-estradiol and progesterone, giving rise to fibroid-like tissue in vivo. These new findings will likely enhance our understanding of the crucial role epigenetics plays in the pathogenesis of uterine leiomyomas as well as point the way to novel therapeutic options. PMID- 25922309 TI - Detection of undisclosed neuropathy and assessment of its impact on quality of life: a survey in 25,000 Romanian patients with diabetes. AB - AIMS: The objective of this cross-sectional survey was to capture undiagnosed neuropathy in Romanian patients with self-reported diabetes using Norfolk QoL-DN as a screening tool and to assess its impact on quality of life (QoL). METHODS: 25,000 Romanian-translated, validated Norfolk QoL-DN questionnaires were distributed between June and December 2012. 21,261 patients who self-reported diabetes and answered questions related to neuropathy, ulceration, gangrene and amputation were included in the analysis. RESULTS: 52% of diabetic patients (n = 6615) who answered "no" to the question "Do you have neuropathy?" had total QoL scores above the cut-off, suggesting the presence of diabetic neuropathy. 13,854 (65.2%) patients answered "yes" to the question "Do you have neuropathy?" and 3,150 (14.8%) reported at least one episode of ulceration, gangrene or amputation. Total QoL score was 3-fold higher (worse) for patients who answered "yes" to the question "Do you have neuropathy?" than for those who answered "no" (38.39 vs. 13.71; p < 0.001) and 1.4-fold worse for patients who reported ulceration, gangrene or amputation than for those who did not report any of these (50.38 vs. 34.87; p < 0.001). CONCLUSIONS: We found a high prevalence of undisclosed diabetic neuropathy in this population and showed that neuropathy severity has an increasing impact on total QoL and its domains. PMID- 25922310 TI - MTNR1B gene polymorphisms and susceptibility to Type 2 Diabetes: A pilot study in South Indians. AB - Type 2 Diabetes (T2D) is the major health concern in the Indian subcontinent. A genome-wide association study carried out with non-diabetic Indians showed association of MTNR1B variants with fasting glucose. MTNR1B mediates the effect of melatonin on insulin secretion. In light of the growing importance of MTNR1B in the etiology of T2D, we sought to test its association with the disease in the south Indian type 2 diabetics. Five single nucleotide polymorphisms of MTNR1B (rs10830962, rs10830963, rs3847554, rs1387153 and rs2166706) were genotyped in 346 T2D patients and 341 non-diabetic controls. None of the SNPs differed significantly between patients and controls with respect to allele and genotype frequencies. Linear regression analysis after adjustment for age, sex and BMI showed a significant positive association of rs3847554 with fasting glucose under recessive model (beta=14.98, p=0.012). Haplotypes constituted by minor alleles of rs3847554, rs1387153, rs2166706, rs10830963 and major allele of rs10830962 showed significant positive correlation with fasting glucose (p<0.05). Though the results obtained are suggestive of MTNR1B role in T2D etiology, they need to be confirmed with much larger sample sizes. PMID- 25922311 TI - The Comparison of Local Infiltration Analgesia with Peripheral Nerve Block following Total Knee Arthroplasty (TKA): A Systematic Review with Meta-Analysis. AB - Total knee arthroplasty (TKA) is usually associated with severe post-operative pain, which can prevent rehabilitation of patients' knee function and influence the satisfaction of surgery. Local infiltration analgesia (LIA) is a method that has been applied in clinical practice recently. However, the clinical use of this method is still under discussion. In this paper, we systematically reviewed randomized clinical trails (RCTs) comparing LIA with peripheral nerve block (PNB) to verify the efficacy and safety of LIA. During the analysis, we strictly filtered papers and chose ones that had fewer disturbance variables. We also analyzed the heterogeneity. We conclude that when compared with PNB, pain control with LIA is at least comparable. PMID- 25922312 TI - The Influence of Leg Length Discrepancy after Total Hip Arthroplasty on Function and Quality of Life: A Prospective Cohort Study. AB - We investigated whether patients with lengthening (> 9 mm), restoration (between 9 mm lengthening and 5 mm shortening) or shortening (> 5 mm) of the operated leg after total hip arthroplasty (THA) had different function (WOMAC score), quality of life (EQ-5D), residual hip pain, use of shoe lift and walking aid and leg length discrepancy (LLD) awareness, 12-15 months postoperatively. All patients had a significant postoperative improvement in WOMAC and EQ-5D regardless the LLD. However, the lengthening group showed less improvement in WOMAC, more use of shoe lift, residual hip pain and LLD awareness compared with the other two groups. No differences in EQ-5D were found. In spite of the improvement in function and quality of life, lengthening had adverse effects and should therefore be avoided. PMID- 25922313 TI - Inconsistent Patient Responses May Limit the Value of Using Multiple Total Knee Arthroplasty Assessment Tools to Define Implant Performance. AB - Prior studies have suggested that using single validated instruments may not adequately characterize total knee arthroplasty (TKA) performance. However, the consistency of patient responses when answering multiple inventories has not been defined. We retrospectively evaluated 269 patient responses to four postoperative TKA inventories, including 24 parallel questions related to 6 low demand activities. The influence of patient age, sex, and race on response consistency was assessed. Thirty percent of patients gave discordant responses for at least 2 of 11 question categories, unaffected by chronological or categorical age. Discordant answers were more commonly obtained from minority and female patients (P<0.01). Combining multiple instruments to assess TKA outcomes may introduce confounding effects that limit their benefit. PMID- 25922314 TI - Medicare's 3-Day Rule: Time for a Rethink. AB - A pilot study was undertaken to examine the impact of Medicare's 3-day rule on length of stay (LOS). One hundred consecutive patients who underwent primary total joint arthroplasty and were discharged to extended care facilities were retrospectively reviewed. Based on readiness for discharge criteria, delaying discharge until the third postoperative day increased LOS by 1.1 days (P<0.001). 60.6% of patients were ready for discharge by the second postoperative day, none of whom required re-admission within 30 days of discharge. There were no rehabilitation gains by staying an additional hospital day beyond readiness for discharge (P=0.092). This pilot study calls into question the value of Medicare's 3-day rule and demonstrates the feasibility and need for further research to address this seemingly antiquated policy. PMID- 25922315 TI - Evaluation of Quality of Lower Limb Arthroplasty Observational Studies Using the Assessment of Quality in Lower Limb Arthroplasty (AQUILA) Checklist. AB - This study used the assessment of quality in lower limb arthroplasty (AQUILA) checklist to assess the quality of lower limb arthroplasty observational studies. Among 132 studies the mean reporting quality score was 5.4 (SD=1.2) out of 8 possible points. Most studies adequately reported reasons for revisions (98%) and prosthesis brand and fixation (95%) in sufficient detail. Only 3% of studies adequately reported the number of patients unwilling to participate, 15% stated a clear primary research question or hypothesis, 11% reported a worst-case analysis or competing risk analysis for endpoints, and 42% reported more than 5% of patients were lost to follow-up. There is significant room for improvement in the reporting and methodology of lower limb arthroplasty observational studies. LEVEL OF EVIDENCE: Level III. PMID- 25922316 TI - Prevalence of Deep Vein Thrombosis and Pulmonary Embolism Treated with Mechanical Compression Device After Total Knee Arthroplasty in Asian Patients. AB - The purpose of this study was: (1) to determine the prevalence of deep vein thrombosis (DVT) after the use of a mechanical compression device only, without pharmacological thromboprophylaxis; (2) to investigate the factors associated with DVT; and (3) to investigate the natural course of DVT and PE. We reviewed consecutive series of 874 patients (1434 knees) who received treatment with a mechanical compression device only for prevention of DVT after primary TKA. The prevalence of DVT was 6.6% (94 of 1434 knees). Proximal thrombi were found in 6 of 1434 knees (0.4%). No patient had PE on perfusion lung scans. Further sonograms and venograms for the patients with thrombi at 6 months after the operation revealed that all thrombi were resolved. PMID- 25922317 TI - Drug resistance in Giardia duodenalis. AB - Giardia duodenalis is a microaerophilic parasite of the human gastrointestinal tract and a major contributor to diarrheal and post-infectious chronic gastrointestinal disease world-wide. Treatment of G. duodenalis infection currently relies on a small number of drug classes. Nitroheterocyclics, in particular metronidazole, have represented the front line treatment for the last 40 years. Nitroheterocyclic-resistant G. duodenalis have been isolated from patients and created in vitro, prompting considerable research into the biomolecular mechanisms of resistance. These compounds are redox-active and are believed to damage proteins and DNA after being activated by oxidoreductase enzymes in metabolically active cells. In this review, we explore the molecular phenotypes of nitroheterocyclic-resistant G. duodenalis described to date in the context of the protist's unusual glycolytic and antioxidant systems. We propose that resistance mechanisms are likely to extend well beyond currently described resistance-associated enzymes (i.e., pyruvate ferredoxin oxidoreductases and nitroreductases), to include NAD(P)H- and flavin-generating pathways, and possibly redox-sensitive epigenetic regulation. Mechanisms that allow G. duodenalis to tolerate oxidative stress may lead to resistance against both oxygen and nitroheterocyclics, with implications for clinical control. The present review highlights the potential for systems biology tools and advanced bioinformatics to further investigate the multifaceted mechanisms of nitroheterocyclic resistance in this important pathogen. PMID- 25922318 TI - Extraction and downstream processing of plant-derived recombinant proteins. AB - Plants offer the tantalizing prospect of low-cost automated manufacturing processes for biopharmaceutical proteins, but several challenges must be addressed before such goals are realized and the most significant hurdles are found during downstream processing (DSP). In contrast to the standardized microbial and mammalian cell platforms embraced by the biopharmaceutical industry, there are many different plant-based expression systems vying for attention, and those with the greatest potential to provide inexpensive biopharmaceuticals are also the ones with the most significant drawbacks in terms of DSP. This is because the most scalable plant systems are based on the expression of intracellular proteins in whole plants. The plant tissue must therefore be disrupted to extract the product, challenging the initial DSP steps with an unusually high load of both particulate and soluble contaminants. DSP platform technologies can accelerate and simplify process development, including centrifugation, filtration, flocculation, and integrated methods that combine solid-liquid separation, purification and concentration, such as aqueous two phase separation systems. Protein tags can also facilitate these DSP steps, but they are difficult to transfer to a commercial environment and more generic, flexible and scalable strategies to separate target and host cell proteins are preferable, such as membrane technologies and heat/pH precipitation. In this context, clarified plant extracts behave similarly to the feed stream from microbes or mammalian cells and the corresponding purification methods can be applied, as long as they are adapted for plant-specific soluble contaminants such as the superabundant protein RuBisCO. Plant-derived pharmaceutical proteins cannot yet compete directly with established platforms but they are beginning to penetrate niche markets that allow the beneficial properties of plants to be exploited, such as the ability to produce 'biobetters' with tailored glycans, the ability to scale up production rapidly for emergency responses and the ability to produce commodity recombinant proteins on an agricultural scale. PMID- 25922319 TI - Energy drink usage among university students in a Caribbean country: Patterns of use and adverse effects. AB - OBJECTIVE: There has been little inquiry addressing whether or not concerns about adverse effects of energy drink usage are relevant in the Caribbean. This survey investigated energy drink usage and adverse consequences among tertiary level students in Trinidad and Tobago. METHODS: A cross-sectional survey of 1994 students from eight institutions was conducted using a de novo questionnaire based on findings from a focus group of students. Chi-squared analyses and logistic regression were used to assess relationships between energy drink usage, adverse effects and other factors affecting energy drink use, and to verify predictors of energy drink use. RESULTS: Prevalence of use was 86%; 38% were current users. Males were more likely to use, used more frequently and at an earlier age. Energy drinks were used most commonly to increase energy (50%), combat sleepiness (45%) and enhance academic performance (40%), and occurred during sports (23%) and mixed with alcohol (22.2%). The majority (79.6%) consumed one energy drink per sitting; 62.2% experienced adverse effects, most commonly restlessness (22%), jolt and crash (17.1%) and tachycardia (16.6%). Awareness of adverse effects was associated with no use (p=0.004), but adverse effects were not a deterrent to continued use. CONCLUSION: Energy drink usage is prevalent among students. The use is not excessive, but associated with high rates of adverse effects and occurs in potentially dangerous situations like during exercise and with alcohol. There is a need to educate students about the potential adverse effects of energy drinks. PMID- 25922320 TI - Lebanese medical students' intention to deliver smoking cessation advice. AB - OBJECTIVES: Objectives of this study were to examine the constructs of the Theory of Planned Behavior and determine how they predict Lebanese medical students' behavioral intention to advise patients to quit smoking. STUDY DESIGN: This was a cross-sectional study conducted among 191 medical students from six medical schools in Lebanon. METHODS: The instrument contained scales that measured attitudes toward the behavior, behavioral beliefs, subjective norms, and perceived behavioral control. Psychometric properties of the scale were examined. Item to total scale score correlations were determined and linear regression was conducted to predict the intention to advise smokers to quit. RESULTS: Respondents had a positive, but not very high, intention to deliver smoking cessation advice. Students reported a positive attitude toward advising patients to quit cigarette smoking and a strong belief in the physician's obligations in smoking cessation advising. The majority reported lack of time to provide smoking cessation advice, insufficient knowledge of pharmacological aids, and the lack of openness of the patient to receive the advice. The attitude scale was the only variable that yielded a significant prediction of the intended behavior. CONCLUSIONS: The construct of attitude toward the behavior appeared to be the most predictive of the intention to deliver advice to quit smoking among Lebanese medical students. Focusing training efforts on this construct could improve the rate of delivery of brief cessation counseling. PMID- 25922321 TI - Adherence to medications and associated factors: A cross-sectional study among Palestinian hypertensive patients. AB - OBJECTIVE: To assess adherence of Palestinian hypertensive patients to therapy and to investigate the effect of a range of demographic and psychosocial variables on medication adherence. METHODS: A questionnaire-based, cross sectional descriptive study was undertaken at a group of outpatient clinics of the Ministry of Health, in addition to a group of private clinics and pharmacies in the West Bank. Social and demographic variables and self-reported drug adherence (Morisky scale) were determined for each patient. RESULTS: Low adherence with medications was present in 244 (54.2%) of the patients. The multivariate logistic regression showed that younger age (<45 years), living in a village compared with a city, evaluating health status as very good, good or poor compared with excellent, forgetfulness, fear of getting used to medication, adverse effect, and dissatisfaction with treatment had a statistically significant association with lower levels of medication adherence (P<0.05). CONCLUSIONS: Poor adherence to medications was very common. The findings of this study may be used to identify the subset of population at risk of poor adherence who should be targeted for interventions to achieve better blood pressure control and hence prevent complications. This study should encourage the health policy makers in Palestine to implement strategies to reduce non-compliance, and thus contribute toward reducing national health care expenditures. Better patient education and communication with healthcare professionals could improve some factors that decrease adherence such as forgetfulness and dissatisfaction with treatment. PMID- 25922322 TI - A cross-sectional study of pediatric eye care perceptions in Ghana, Honduras, and India. AB - Of the more than 1.4 million blind children worldwide, 75% live in developing countries. To reduce the prevalence of childhood blindness and associated diseases, attention is given to understanding the perceptions and level of awareness held by caregivers. This understanding can enable tailored health programs to reduce the global prevalence of blindness with increased efficiency. This study, which took place in Ghana, Honduras, and India, found that 95% of caregivers believed in the importance of eye exams for children, yet 66% of caregivers said that none of their children had ever received an eye exam. Participants' major reasons for not bringing their children included the belief that their child had no eye problems along with similar and unique socio-economic barriers. Further information was gained through the use of a five-question test on basic child eye care symptoms, which showed that out of the three country locations, the studied population in India had the least understanding about pediatric eye symptoms. Further analysis revealed significant gaps in understanding of general eye health while detected knowledge barriers provide evidence that fundamental misconceptions appear to be inhibiting caregivers' competence in facilitating their children's eye health. PMID- 25922323 TI - Point prevalence survey of antimicrobial utilization in a Canadian tertiary-care teaching hospital. AB - OBJECTIVES: Inappropriate antimicrobial use can promote antimicrobial resistance, which is associated with increased patient morbidity and mortality. Identifying the pattern of antimicrobial use can provide data from which targeted antimicrobial stewardship interventions can be made. The primary objective was to identify the prevalence of antimicrobial use at a tertiary care teaching hospital with both acute and long-term care patients. METHODS: A point prevalence study was conducted on July 19th, 2012. Data on antimicrobial utilization, indication for prescribing, duration of therapy, and frequency of infectious disease or antimicrobial stewardship consultations were collected using a customized integrated stewardship database (SPIRIT) and prospective chart review. RESULTS: One or more antimicrobial agents were ordered in 31% and 4% of acute care and long-term care patients, respectively. Respiratory and urinary tract infections were the most common indication for antimicrobial therapy in both acute and long term care. About 25% of surgical prophylaxis orders were prescribed for greater than 24h. CONCLUSION: This prospective point prevalence survey provided important baseline information on antimicrobial use within a large tertiary care teaching hospital and identified potential targets for future antimicrobial stewardship initiatives. A multi-center point prevalence survey should be considered to identify patterns of antimicrobial use in Canada and to establish the first steps toward international antimicrobial surveillance. PMID- 25922324 TI - Occlusal characteristics and prevalence of associated dental anomalies in the primary dentition. AB - INTRODUCTION: Morphological variations in primary dentition are of great concern to a pediatric dentist as it may pose clinical problems like dental caries, delayed exfoliation and also anomalies in the permanent dentition, such as impaction of successors, supernumerary teeth, permanent double teeth or aplasia of teeth. The present study was conducted to investigate the presence of dental anomalies in the primary dentition of 1000 schoolchildren in the 3-5 year-old age group in Faridabad. MATERIALS AND METHODS: One-thousand schoolchildren were examined using Type III examination (WHO, 1997) for primary molar relationship, occlusal characteristics, primate spaces, physiological spaces and other anomalies of teeth, including number and morphology. RESULTS AND CONCLUSIONS: The prevalence of physiological spaces in maxillary and mandibular arches was 50.9% and 46.7%, respectively, whereas primate spaces were found in 61.7% of the children in the maxillary arch and 27.9% in the mandibular arch. The prevalence of unilateral anterior and posterior cross-bite was 0.1% and 0.8%, respectively, in the present study. The prevalence of hypodontia in the primary dentition was found to be 0.4% and the prevalence of fusion and gemination in the present study was 0.5%. Double teeth (fusion and gemination) and hypodontia were the most common dental anomalies found in the primary dentition in the present study. PMID- 25922325 TI - Epidemiology, clinical manifestations, and molecular typing of salmonella typhi isolated from patients with typhoid fever in Lebanon. AB - The objective of this study was to examine the epidemiology and the clinical manifestations of typhoid fever as well as the susceptibility and strain relatedness of Salmonella typhi isolates in Lebanon from 2006 to 2007. A total of 120 patients with typhoid fever were initially identified from various areas of the country based on positive culture results for S. typhi from blood, urine, stools, bone marrow and/or positive serology. Clinical, microbiological and molecular analysis was performed on cases with complete data available. These results indicated that drinking water was an unlikely mode of transmission of the infection. Despite increasing reports of antimicrobial resistance among S. typhi isolates, the vast majority of these isolates were susceptible to various antibiotic agents, including ampicillin, cephalosporins, quinolones, and trimethoprim/sulfamethoxazole. Molecular analysis of the isolates revealed a predominance of one single genotype with no variation in distribution across the geographical regions. PMID- 25922326 TI - Cardiovascular risk factors in semi-urban communities in southwest Nigeria: Patterns and prevalence. AB - INTRODUCTION: Over 80% of cardiovascular deaths take place in low- and middle income countries; most of these deaths are due to modifiable risk factors. The study aimed at estimating the prevalence and pattern of major cardiovascular risk factors in both men and women older than 18 years. METHODS: This is a cross sectional study of cardiovascular risk factors among semi-urban dwellers in Ekiti State, south-western, Nigeria. 750 participants were drawn from 10 communities. The instrument used was the standard WHO STEPS (II) questionnaire, while blood samples were obtained for analysis. RESULTS: There were 750 participants with 529 (70.53%) females. The mean age of participants was 61.7+/-18.50 years and participants' ?65 years comprised 38.3%. There were 0.8%, 24.9% and 12.4%, who at the time of this study smoked cigarettes, consumed alcohol, and ate a high salt diet, respectively. The prevalence of hypertension, diabetes, generalized and abdominal obesity was 47.2%, 6.8%, 8.5% and 32.0%, respectively, with only 48.9% receiving hypertension treatment. Elevated total cholesterol, LDL-cholesterol, and low HDL was seen in 4.4%, 16.7% and 56.3% respectively. CONCLUSION: High prevalence of cardiovascular risk factors call for an urgent need for more public health attention and reinforcement of primary preventive strategies to curb its menace. PMID- 25922327 TI - Efficacy of prophylactic dexamethasone in prevention of postoperative nausea and vomiting. AB - OBJECTIVE: Many trials have been conducted with regard to the relative benefits of prophylactic anti-emetic interventions given alone or in combination, yet the results remain unknown. This study reviewed the efficacy of a single prophylactic dose of dexamethasone on postoperative nausea or vomiting (PONV) after abdominal hysterectomy. METHODS: In a prospective study of 100 women undergoing total abdominal hysterectomy (TAH) under general anesthesia, the dexamethasone group (n=50) received a single dose (8 mg) immediately after the operation, and the saline group (n=50) received a dose of saline as a placebo, in addition to conventional management. The incidence of nausea, vomiting, the need for an anti emetic and patient satisfaction with the management of PONV were evaluated during the first 24 postoperative hours. RESULTS: The overall frequency of nausea during the initial postoperative 24 in the dexamethasone and saline groups were 12% and 18%, respectively, and vomiting was 10% and 16%, respectively (P=0.001). However, there was a lower need for a rescue anti-emetic drugs in the dexamethasone group (18% vs 24%), but it was not statistically significant (P=0.06). CONCLUSION: The results of this study indicate that a single prophylactic dose of dexamethasone after an operation can reduce postoperative nausea and vomiting. PMID- 25922328 TI - A cluster-randomised controlled trial to test the efficacy of facemasks in preventing respiratory viral infection among Hajj pilgrims. AB - BACKGROUND: Cost-effective interventions are needed to control the transmission of viral respiratory tract infections (RTIs) in mass gatherings. Facemasks are a promising preventive measure, however, previous studies on the efficacy of facemasks have been inconclusive. This study proposes a large-scale facemask trial during the Hajj pilgrimage in Saudi Arabia and presents this protocol to illustrate its feasibility and to promote both collaboration with other research groups and additional relevant studies. METHODS/DESIGN: A cluster-randomised controlled trial is being conducted to test the efficacy of standard facemasks in preventing symptomatic and proven viral RTIs among pilgrims during the Hajj season in Mina, Mecca, Saudi Arabia. The trial will compare the 'supervised use of facemasks' versus 'standard measures' among pilgrims over several Hajj seasons. Cluster-randomisation will be done by accommodation tents with a 1:1 ratio. For the intervention tents, free facemasks will be provided to be worn consistently for 7days. Data on flu-like symptoms and mask use will be recorded in diaries. Nasal samples will be collected from symptomatic recruits and tested for nucleic acid of respiratory viruses. Data obtained from questionnaires, diaries and laboratory tests will be analysed to examine whether mask use significantly reduces the frequency of laboratory-confirmed respiratory viral infection and syndromic RTI as primary outcomes. CONCLUSIONS: This trial will provide valuable evidence on the efficacy of standard facemask use in preventing viral respiratory tract infections at mass gatherings. This study is registered at the Australian New Zealand Clinical Trials Registry (ANZCTR), ACTRN: ACTRN12613001018707 (http://www.anzctr.org.au). PMID- 25922329 TI - Work productivity among adults with varied Body Mass Index: Results from a Canadian population-based survey. AB - BACKGROUND: The relationship between Body Mass Index (BMI) and work productivity, including absenteeism and presenteeism remains unclear. The objective of this study was to examine work productivity among adults with varied BMI using population-based data. METHODS: Data source was the 2009-2010 Canadian Community Health Survey. The outcomes reflected work absence (absenteeism) and reduced activities at work (presenteeism). The key explanatory variable was BMI in six categories. Logistic regressions were used to measure the association between outcome and explanatory variables adjusting for potential confounders. RESULTS: The sample consisted of 56,971 respondents ranging in age from 20 to 69 years. Relative to normal BMI, the odds of absenteeism were higher for those in the obesity class III (OR=1.60, 95% CI: 1.39; 1.83). Presenteeism was weakly associated with all obesity categories (OR=1.49, 95% CI: 1.38; 1.61, for obesity class I). Overweight was marginally associated with absenteeism and presenteeism. Underweight was inversely associated with absenteeism. CONCLUSIONS: This study found that obesity is an independent risk factor for reduced work productivity. Both absenteeism and presenteeism were associated with obesity. However, being overweight was weakly associated with work productivity. PMID- 25922330 TI - Terrorism-related trauma in Africa, an increasing problem. AB - Global terrorist activities have increased significantly over the past decade. The impact of terrorism-related trauma on the health of individuals in low- and middle-income countries is under-reported. Trauma management in African countries in particular is uncoordinated, with little or no infrastructure to cater for emergency surgical needs. This article highlights the need for education, training and research to mitigate the problems related to terrorism and surgical public health. PMID- 25922331 TI - Tuberculosis screening among Bolivian sex workers and their children. AB - Bolivian sex workers were more likely than other employed women to report tuberculosis screening only if they reported HIV screening. Of all women with household tuberculosis exposure, <40% reported screening for themselves or their children. Coupling tuberculosis screening with sex workers' mandatory HIV screenings may be a cost-efficient disease-control strategy. PMID- 25922332 TI - Gpr177-mediated Wnt Signaling Is Required for Secondary Palate Development. AB - Cleft palate represents one of the major congenital birth defects in humans. Despite the essential roles of ectodermal canonical Wnt and mesenchymal Wnt signaling in the secondary palate development, the function of mesenchymal canonical Wnt activity in secondary palate development remains elusive. Here we show that Gpr177, a highly conserved transmembrane protein essential for Wnt trafficking, is required for secondary palate development. Gpr177 is expressed in both epithelium and mesenchyme of palatal shelves during mouse development. Wnt1(Cre)-mediated deletion of Gpr177 in craniofacial neural crest cells leads to a complete cleft secondary palate, which is formed mainly due to aberrant cell proliferation and increased cell death in palatal shelves. By BATGAL staining, we reveal an intense canonical Wnt activity in the anterior palate mesenchyme of E12.5 wild-type embryos but not in Gpr177(Wnt1-Cre) embryos, suggesting that mesenchymal canonical Wnt signaling activated by Gpr177-mediated mesenchymal Wnts is critical for secondary palate development. Moreover, phosphorylation of JNK and c-Jun is impaired in the Gpr177(Wnt1-Cre) palate and is restored by implantation of Wnt5a-soaked beads in the in vitro palate explants, suggesting that Gpr177 probably regulates palate development via the Wnt5a-mediated noncanonical Wnt pathway in which c-Jun and JNK are involved. Importantly, certain cellular processes and the altered gene expression in palates lacking Gpr177 are distinct from that of the Wnt5a mutant, further demonstrating involvement of other mesenchymal Wnts in the process of palate development. Together, these results suggest that mesenchymal Gpr177 is required for secondary palate development by regulating and integrating mesenchymal canonical and noncanonical Wnt signals. PMID- 25922333 TI - Parent Reports of Mental Health Concerns and Functional Impairment on Routine Screening With the Strengths and Difficulties Questionnaire. AB - OBJECTIVE: This study used the Strengths and Difficulties Questionnaire (SDQ) to describe the prevalence of parent-reported mental health (MH) concerns in youth presenting for primary care appointments and to examine relationships between children's MH issues and functional impairment. We hypothesized that increased MH symptomology would be associated with increased impairment and family burden. METHODS: Parents of 4- to 17-year-old children were approached at routine visits in 13 primary care sites. Chi-square tests, independent sample t tests, and a 1 way analysis of variance (ANOVA) were used to make comparisons between demographic groups. Age-, sex-, and race-adjusted ordered logistic regression models and ANOVAs examined relationships between impact and SDQ scales. RESULTS: Boys had higher total Hyperactivity and Peer Problems. Adolescents showed higher Emotional Symptoms, while younger children showed more Hyperactivity. Latinos reported more Conduct Problems, Hyperactivity, and Peer Problems. Latinos also indicated less distress on the child, impairment at home and school, and family burden. Regression analyses indicated increased odds of impairment with higher scale scores. MH symptoms identified with the SDQ in pediatric primary care settings were associated with parent-reported impairment affecting youth and their families. CONCLUSIONS: The presence of significant impairment suggests that parents' concerns identified by screening are likely to be clinically important and worthy of practice strategies designed to promote assessment, treatment, and referral for these common problems. Identifying and exploring parents' concerns with strategic use of screening tools may allow primary care providers to directly engage families around the MH issues that affect them most. PMID- 25922334 TI - Advising Medical Students for the Match: A National Survey of Pediatrics Clerkship Directors. AB - OBJECTIVE: To describe the role and perspectives of pediatrics clerkship directors (CDs) who provide advice to students who apply to Pediatrics residency training programs. METHODS: We developed a survey based on previous studies and data from the 2012 National Residency Matching Program- Program Director (NRMP PD) survey. Topics included CDs roles and confidence in advising, perspectives on applicants' competitiveness, and resources used to inform advising practice. This survey was disseminated as part of the 2013 Council on Medical Student Education in Pediatrics annual survey. RESULTS: CDs from 63 (45%) Liaison Committee for Medical Education-accredited medical schools in the United States responded. All CDs had some advising role, and most (68%) served in a formal advising capacity. Most (58%) also participated in the intern selection process at their institution. Those with formal advising roles were not significantly more confident in their advising than those without formal roles. CDs relied heavily on subjective resources and most did not use the NRMP-PD survey data. Despite this, the perspectives of CDs were similar to those of program directors based on the most recent NRMP-PD survey. CONCLUSIONS: Pediatrics CDs uniformly serve in advising capacities and have perspectives that compare favorably with those of program directors. Despite this concordance, the high reliance on subjective resources and the frequency in which CDs participate in intern selection raises concern. The results of this study have several implications for key stakeholders in the residency selection process. PMID- 25922336 TI - Clostridium difficile infection following outpatient parenteral antimicrobial therapy. PMID- 25922335 TI - Talocalcaneal Joint Middle Facet Coalition Resection With Interposition of a Juvenile Hyaline Cartilage Graft. AB - Talocalcaneal joint middle facet coalition is the most common tarsal coalition, occurring in <=2% of the population. Fewer than 50% of involved feet obtain lasting relief of symptoms after nonoperative treatment, and surgical intervention is commonly used to relieve symptoms, increase the range of motion, improve function, reconstruct concomitant pes planovalgus, and prevent future arthrosis from occurring at the surrounding joints. Several approaches to surgical intervention are available for patients with middle facet coalitions, ranging from resection to hindfoot arthrodesis. We present a series of 4 cases, in 3 adolescent patients, of talocalcaneal joint middle facet coalition resection with interposition of a particulate juvenile hyaline cartilaginous allograft (DeNovo((r)) NT Natural Tissue Graft, Zimmer, Inc., Warsaw, IN). With a mean follow-up period of 42.8 +/- 2.9 (range 41 to 47) months, the 3 adolescent patients in the present series were doing well with improved subtalar joint motion and decreased pain, and 1 foot showed no bony regrowth on a follow-up computed tomography scan. The use of a particulate juvenile hyaline cartilaginous allograft as interposition material after talocalcaneal middle facet coalition resection combined with adjunct procedures to address concomitant pes planovalgus resulted in good short-term outcomes in 4 feet in 3 adolescent patients. PMID- 25922337 TI - Biofouling of surgical power tools during routine use. AB - Surgical power tools (SPTs) are frequently used in many surgical specialties such as dentistry, orthopaedics, ophthalmology, neurology, and podiatry. They have complex designs that may restrict access to cleaning and sterilization agents and frequently become contaminated with microbial and tissue residues following use. Due to these challenges, surgical power tools can be considered the weak link in the decontamination cycle and present a potential for iatrogenic transmission of infection. We aimed to review the existing literature on the decontamination of surgical power tools and associated iatrogenic transmission of infection. A search of the medical literature was performed using Ovid online using the following databases: Ovid Medline 1950-2014, Embase 1980-2014, and EBM Reviews Full Text--Cochrane DSR, ACP Journal Club, and Dare. Despite challenges to decontamination processes, reported episodes of iatrogenic infection directly linked to SPTs appear rare. This may reflect a true picture but more likely represents incomplete reporting, failure to investigate power tools, or lack of surveillance linking surgical site infections (SSIs) to power tools. Healthcare professionals should be aware of the complexities associated with the decontamination of different SPTs, and should review manufacturers' reprocessing instructions prior to purchase. More clarity is required in the manufacturers' validation of these reprocessing instructions. This particularly applies to the emerging surgical robot systems that present extreme challenges to decontamination between uses. Investigation of cross-infection incidents or SSI surveillance should include an element of assessment of SPT decontamination to further elucidate the contribution of SPTs to skin and soft tissue infections. PMID- 25922338 TI - Development of a novel matrix-assisted laser desorption/ionization time-of-flight mass spectrum (MALDI-TOF-MS)-based typing method to identify meticillin-resistant Staphylococcus aureus clones. AB - BACKGROUND: Mass spectrum analysis enables species- and subspecies-level identification, and can be used as an epidemiological tool in outbreak management. However, its reliability at clonal level has yet to be established. AIM: To establish a matrix-assisted laser desorption/ionization time-of-flight mass-spectrum-based method that enables bacterial clone identification with accuracy equivalent to pulsed-field gel electrophoresis/phage open-reading frame typing (PFGE/POT). METHODS: Meticillin-resistant Staphylococcus aureus (MRSA) was used in this study. Mass spectra were obtained from a standard strain of S. aureus (ATCC29213) and 57 clinically isolated strains, categorized according to POT. Peaks associated with MRSA clone identification (N = 67) were extracted. Based on this peak information, the feasibility of MRSA clone identification was examined by cluster analysis. FINDINGS: In addition to the 58 strains used for peak extraction, mass spectrum analysis of 24 clinically isolated outbreak strains revealed that peak data could be used for successful identification of clones. These typing results were fully consistent with the PFGE and POT results. CONCLUSION: This novel method enables simple and rapid typing with accuracy equivalent to PFGE/POT. This method would be suited to rapid outbreak analysis, offering accurate information to combat infectious diseases. PMID- 25922339 TI - Food and the responsibility deal: how the salt reduction strategy was derailed. PMID- 25922340 TI - Role of Intestinal Microbiome in Lipid and Glucose Metabolism in Diabetes Mellitus. AB - PURPOSE: The contribution of intestinal bacterial strains (gut microbiota) in human metabolism and obesity is being increasingly recognized. The goal of this article was to provide a commentary on the clinical usefulness of these data. METHODS: We performed a review of the currently available articles on PubMed. FINDINGS: Because most of the data are based on germ-free animal research, translation to human disease may be difficult. However, changes in the intestinal bacterial composition and subsequent altered diversity have been associated with the presence of chronic low-grade inflammation, a known feature of insulin resistance and type 2 diabetes mellitus. IMPLICATIONS: It is still not proven whether intestinal bacteria play a causal role in glucose and lipid metabolism. Intervention studies including fecal transplantation and supplementation of single bacterial strains in humans might provide more insight. Moreover, prospective cohorts of healthy subjects using fecal samples collected at baseline can help to identify causally involved specific intestinal bacterial strains that drive aberrant human metabolism. Ultimately, it would be a great asset if potential diagnostic and therapeutic targets could be derived from this novel player in human cardiometabolism. PMID- 25922341 TI - DSR-71167, a novel mineralocorticoid receptor antagonist with carbonic anhydrase inhibitory activity, separates urinary sodium excretion and serum potassium elevation in rats. AB - Mineralocorticoid receptor (MR) antagonists, such as spironolactone (SPI) and eplerenone (EPL), are useful for treating hypertension and heart failure. However, these two agents have the serious side effect of hyperkalemia. We hypothesized that adding the ability to inhibit carbonic anhydrase (CA) would reduce the risk of hyperkalemia associated with MR antagonists. We investigated the profiles of DSR-71167 [2-([(2,2-difluoroethyl)amino]methyl)-2'-fluoro-N-(3 methoxy-4-sulfamoylphenyl)biphenyl-4-carboxamide hydrochloride; an MR antagonist with weak CA inhibitory activity] with regard to antimineralocorticoid actions by examining relationships between the urinary excretion of sodium (index of antimineralocorticoid action) in deoxycorticosterone acetate-treated rats and elevation of serum levels of potassium in potassium-loaded rats compared with a DSR-71167 derivative without CA inhibition (2-(hydroxymethyl)-N-[4 (methylsulfonyl)phenyl]-2'-(trifluoromethyl)biphenyl-4-carboxamide), SPI, and EPL. DSR-71167 dose-dependently increased urinary excretion of sodium in deoxycorticosterone acetate-treated rats without elevating serum levels of potassium in potassium-loaded rats. 2-(Hydroxymethyl)-N-[4 (methylsulfonyl)phenyl]-2'-(trifluoromethyl)biphenyl-4-carboxamide, SPI, and EPL elevated serum levels of potassium significantly in potassium-loaded rats at doses that increased MR inhibitory activity. We confirmed that DSR-71167 significantly increases urinary bicarbonate and decreases blood bicarbonate, as pharmacodynamic markers of CA inhibition, in intact rats. Chronic DSR-71167 administration showed antihypertensive effects in high salt-loaded Dahl hypertensive rats. These results demonstrate that DSR-71167 is a novel type of MR antagonist, with CA inhibitory activity, which is expected to become a safer MR antagonist with a low potential risk for hyperkalemia. PMID- 25922342 TI - Viral and other cell-penetrating peptides as vectors of therapeutic agents in medicine. AB - Efficient delivery of heterologous molecules for treatment of cells is a great challenge in modern medicine and pharmacology. Cell-penetrating peptides (CPPs) may improve efficient delivery of a wide range of macromolecular cargos, including plasmid DNA, small interfering RNA, drugs, nanoparticulate pharmaceutical carriers, and anticancer drugs. In this paper, we present the history of CPPs' discovery with special attention drawn to sequences of viral origin. We also describe different CPP families with regard to their physicochemical properties and numerous mechanisms of CPP cell uptake by direct penetration and endocytotic pathways. A detailed description is focused on formation of carrier-cargo complexes, which are needed for practical use of CPPs in medicine and biotechnology. Examples of successful application of CPPs in treatment of human diseases are also presented, including decreased tumor growth and induction of cancer cell death. Finally, we review modern design approaches to novel CPPs and prediction of their activity. To sum up, the current review presents a thorough and up-to-date knowledge of CPPs and may be a valuable source of information for researchers in pharmacology designing new therapeutic agents. PMID- 25922343 TI - Breastfeeding: sensitive mothers and intelligent offspring. PMID- 25922344 TI - Enterovirus D68: a new cause of acute paralysis? PMID- 25922345 TI - Autism phenotype versus registered diagnosis in Swedish children: prevalence trends over 10 years in general population samples. AB - OBJECTIVE: To compare the annual prevalence of the autism symptom phenotype and of registered diagnoses for autism spectrum disorder during a 10 year period in children. DESIGN: Population based study. SETTING: Child and Adolescent Twin Study and national patient register, Sweden. PARTICIPANTS: 19, 993 twins (190 with autism spectrum disorder) and all children (n=1,078,975; 4620 with autism spectrum disorder) born in Sweden over a 10 year period from 1993 to 2002. MAIN OUTCOME MEASURES: Annual prevalence of the autism symptom phenotype (that is, symptoms on which the diagnostic criteria are based) assessed by a validated parental telephone interview (the Autism-Tics, ADHD and other Comorbidities inventory), and annual prevalence of reported diagnoses of autism spectrum disorder in the national patient register. RESULTS: The annual prevalence of the autism symptom phenotype was stable during the 10 year period (P=0.87 for linear time trend). In contrast, there was a monotonic significant increase in prevalence of registered diagnoses of autism spectrum disorder in the national patient register (P<0.001 for linear trend). CONCLUSIONS: The prevalence of the autism symptom phenotype has remained stable in children in Sweden while the official prevalence for registered, clinically diagnosed, autism spectrum disorder has increased substantially. This suggests that administrative changes, affecting the registered prevalence, rather than secular factors affecting the pathogenesis, are important for the increase in reported prevalence of autism spectrum disorder. PMID- 25922347 TI - The Evolution of the WHI 80+ Cohort. AB - BACKGROUND: The Women's Health Initiative has collected data on the aging process of postmenopausal women for over two decades, including data on many women who have achieved age 80 years and older. However, there has not been any previous effort to characterize the 80+ cohort and to identify associated retention factors. METHODS: We include all women at baseline of the Women's Health Initiative who would be at least 80 years of age as of September 17, 2012. We summarize retention rates during the study and across two re-enrollment campaigns as well as the demographic and health-related characteristics that predicted retention. Further, we describe the longitudinal change from baseline in the women identified as members of the 80+ cohort. RESULTS: Retention rates were lower during each of two re-enrollment periods (74% and 83% retained during re enrollment periods 1 and 2, respectively) than during the first and second data collection periods (90% each). Women who were retained were more likely to be white, educated, and healthier at baseline. Women age 80 and older saw modest changes in body mass index and depression burden, despite lower physical activity and increased cardiovascular disease. CONCLUSIONS: The characteristics of women who were retained in the 80+ cohort differ in significant ways compared with their peers at baseline. Identifying the characteristics associated with attrition in older cohorts is important because aging and worsening health has a negative impact on study attrition. Strategies should be implemented to improve retention rates among less healthy older adults. PMID- 25922346 TI - Longevity GWAS Using the Drosophila Genetic Reference Panel. AB - We used 197 Drosophila melanogaster Genetic Reference Panel (DGRP) lines to perform a genome-wide association analysis for virgin female lifespan, using ~2M common single nucleotide polymorphisms (SNPs). We found considerable genetic variation in lifespan in the DGRP, with a broad-sense heritability of 0.413. There was little power to detect signals at a genome-wide level in single-SNP and gene-based analyses. Polygenic score analysis revealed that a small proportion of the variation in lifespan (~4.7%) was explicable in terms of additive effects of common SNPs (>=2% minor allele frequency). However, several of the top associated genes are involved in the processes previously shown to impact ageing (eg, carbohydrate-related metabolism, regulation of cell death, proteolysis). Other top-ranked genes are of unknown function and provide promising candidates for experimental examination. Genes in the target of rapamycin pathway (TOR; Chrb, slif, mipp2, dredd, RpS9, dm) contributed to the significant enrichment of this pathway among the top-ranked 100 genes (p = 4.79*10(-06)). Gene Ontology analysis suggested that genes involved in carbohydrate metabolism are important for lifespan; including the InterPro term DUF227, which has been previously associated with lifespan determination. This analysis suggests that our understanding of the genetic basis of natural variation in lifespan from induced mutations is incomplete. PMID- 25922349 TI - Don't throw out the baby with the bath water. PMID- 25922348 TI - Challenging the Inevitability of Prostate Enlargement: Low Levels of Benign Prostatic Hyperplasia Among Tsimane Forager-Horticulturalists. AB - BACKGROUND: Often considered an inevitable part of male aging, benign prostatic hyperplasia (BPH) is the most common non-life threatening disease to affect men in Western populations. We examine age-related change in prostate size and BPH risk and related serum biomarkers among the Tsimane Amerindians of the Bolivian Amazon who live a traditional lifestyle of hunting and small-scale horticulture. The Tsimane are a critical case study for understanding the etiology of BPH as they have low levels of obesity and metabolic syndrome, as well as lower levels of testosterone than age matched U.S. males, factors associated with BPH in previous research. METHODS: Ultrasounds were conducted on 348 men aged 28-89 years (median age 56 years). Testosterone, prostate specific antigen, sex hormone binding globulin, and glycosylated hemoglobin were examined in relationship to prostate size and BPH. RESULTS: Tsimane have less than half of the BPH prevalence experienced by U.S. men, and prostate volumes 62.6% smaller. While Tsimane have low levels of testosterone and subclinical levels of metabolic syndrome compared to U.S. men, Tsimane with high testosterone were more likely to experience BPH, as were those with higher glycosylated hemoglobin, suggesting targets for clinical interventions to reduce BPH. CONCLUSIONS: These results have clinical significance for the growing number of men taking testosterone supplementation; even at low levels the additional testosterone exposure could be placing these men at higher risk of BPH. Overall, these data suggest that BPH may not have been an inevitable part of male aging throughout human evolutionary history. PMID- 25922350 TI - Commentary on 'ADHD diagnosis continues to fail the reliability and validity tests' by Martin Whitely. PMID- 25922351 TI - Attention deficit hyperactive disorder diagnosis continues to fail the reliability and validity tests. PMID- 25922352 TI - Attention deficit hyperactivity disorder: 40 years consistent work. PMID- 25922353 TI - Attention deficit hyperactivity disorder is an example of bad medicine. PMID- 25922354 TI - Seeing is believing: Biological information may reduce mental health stigma amongst physicians. PMID- 25922355 TI - Post-partum obsessive-compulsive disorder associated with 9q33.1 deletion. PMID- 25922356 TI - Bethanechol and Aripiprazole for the management of refractory urinary incontinence in a patient on Clozapine. PMID- 25922357 TI - High-frequency ultrasound of Peyer's patches in the small intestine of young cats. AB - OBJECTIVES: A previously unreported, asymmetrically positioned hypoechoic extra layer (APHEL) in the submucosa of the feline distal jejunum and ileum has been recognised using high-frequency ultrasound. The objectives of this study were to characterise the APHEL histologically, and to describe the prevalence and ultrasonographic features of the APHEL in a population of clinically healthy young cats. METHODS: In an anatomical study, two cats were autopsied and histopathology of the small intestine was performed. An APHEL was detected with ultrasound in the distal jejunum and ileum ante-mortem in the first cat and post mortem in the second cat. Samples for histopathology were obtained from these areas. In the second, prospective part of the study, to document the presence or absence of an APHEL, high-frequency (18 MHz) ultrasound was performed of the intestinal tract in 20 other cats. These cats were client-owned cats aged 6-18 months presented for neutering. The cats were included in the study based on a normal clinical examination, lack of previous or concurrent signs of disease, and having no abnormalities detected at abdominal ultrasound. RESULTS: Histopathology from the distal jejunum and ileum in the two cats in the anatomical part of the study showed that the APHEL represented asymmetrically positioned normal lymphatic tissue (Peyer's patches) in the lamina propria and submucosa. In the second part of the study, an APHEL was identified in the submucosa of the distal part of the jejunum and ileum in all 20 cats. Additionally, a similar layer could also be seen further proximally in the jejunum in 10 (50%) of the cats. The thickness of the APHEL was 1.0 mm in both jejunum and ileum. CONCLUSIONS AND RELEVANCE: Presumed normal lymphatic tissue in the small intestinal submucosa can be seen with high-frequency ultrasound and is a common finding in young cats. PMID- 25922358 TI - Lack of effects of intramuscular medetomidine on intraocular pressure in clinically normal cats. AB - OBJECTIVES: This study aimed to determine the effects of intramuscular medetomidine on the results of tonometry in healthy cats. METHODS: Sixteen healthy cats were randomly divided into two groups of eight cats. The first group was sedated with intramuscular medetomidine alone (100 ug/kg) and the second group received only saline (0.5 ml/5 kg). Intraocular pressure (IOP) values were measured immediately before (T0) and after the injections at 15 mins (T15) and 25 mins (T25) in both groups. RESULTS: Sedation with medetomidine did not cause a statistically significant change in the mean IOP values. The pretreatment mean +/ SD IOPs in the treatment and control groups were 16.2 +/- 3.1 and 15.9 +/- 4.0 mmHg, respectively. In the medetomidine group the mean +/- SD IOPs at T15 and T25 were 16.1 +/- 4.1 (P = 0.9) and 14.6 +/- 2.2 (P = 0.1). CONCLUSIONS AND RELEVANCE: Based on this study in healthy cats, medetomidine may be a good choice as a sedative agent in uncooperative cats when IOP measurements are needed. Further investigations in cats with abnormal IOPs are warranted. PMID- 25922360 TI - A 55-year-old peruvian woman with unresponsive pulmonary tuberculosis. PMID- 25922361 TI - Paucimannosidic glycoepitopes are functionally involved in proliferation of neural progenitor cells in the subventricular zone. AB - Protein glycosylation has received much attention due to its multiple functional roles in physiological and pathophysiological conditions. Paucimannose is a common mannosidic N-glycoepitope in invertebrates and plants but has only recently been detected in vertebrates. Herein, we demonstrate the presence of paucimannosidic epitopes specifically in early postnatal neural progenitor cells (NPCs) between postnatal day 0 and 7 in mouse brain suggesting a possible role in the development of NPCs. Paucimannosidic epitopes were also detected in human glioblastoma cells and human macrophages by immunofluorescence and mass spectrometric analysis. Its expression was significantly increased after proliferation arrest indicating its importance in the regulation of cell proliferation. This hypothesis was further strengthened by reduced cell proliferation after the application of paucimannose-reactive Mannitou antibody into culture medium of growing cells. Most interestingly, this reduction in cell proliferation upon the administration of Mannitou antibody could also be observed in vivo in the subventricular zone of early postnatal mouse brain. Taken together, these observations demonstrate that paucimannosylation directly influences cell proliferation in various vertebrate cell types including early postnatal neural stem cells. PMID- 25922362 TI - NEU3 activity enhances EGFR activation without affecting EGFR expression and acts on its sialylation levels. AB - Several studies performed over the last decade have focused on the role of sialylation in the progression of cancer and, in particular, on the association between deregulation of sialidases and tumorigenic transformation. The plasma membrane-associated sialidase NEU3 is often deregulated in colorectal cancer (CRC), and it was shown that this enzyme co-immunoprecipitates in HeLa cells with epidermal growth factor receptor (EGFR), the molecular target of most recent monoclonal antibody-based therapies against CRC. To investigate the role of NEU3 sialidase on EGFR deregulation in CRC, we first collected data on NEU3 gene expression levels from a library of commercial colon cell lines, demonstrating that NEU3 transcription is upregulated in these cell lines. We also found EGFR to be hyperphosphorylated in all cell lines, with the exception of SW620 cells and the CCD841 normal intestinal cell line. By comparing the effects induced by overexpression of either the wild-type or the inactive mutant form of NEU3 on EGFR, we demonstrated that the active form of NEU3 enhanced receptor activation without affecting EGFR mRNA or protein expression. Moreover, through western blots and mass spectrometry analysis, we found that EGFR immunoprecipitated from cells overexpressing active NEU3, unlike the receptor from mock cells and cells overexpressing inactive NEU3, is desialylated. On the whole, our data demonstrate that, besides the already reported indirect EGFR activation through GM3, sialidase NEU3 could also play a role on EGFR activation through its desialylation. PMID- 25922363 TI - Does Diastasis Width Influence the Variation of the Intra-Abdominal Pressure After Correction of Rectus Diastasis? AB - BACKGROUND: It has been demonstrated that there is an increase of intra-abdominal pressure (IAP) after correction of rectus diastasis. OBJECTIVE: To evaluate the correlation between the diastasis width and IAP variation after the plication of the anterior rectus sheath. METHODS: Seventeen patients met the inclusion criteria and were selected. The diastasis width was measured at three levels: 3 cm above the umbilicus, 2 cm above the umbilicus, and 2 cm below the umbilicus. Rectus sheath plication was performed in two layers: the first layer with separate stitches, and the second with continuous suture. The IAP was measured at two stages: before and after the correction of rectus diastasis. The distance between the iliac spines (IS) and that between the xiphoid process and pubic symphysis (XP) were measured. The abdominal surface index (ASI) was calculated using the formula: ASI = (IS * XP)/2. This index was used to determine the individual abdominal surface. The relative diastasis coefficient (RDC) was calculated using the formula: RDC = diastasis/ASI. These measurements were correlated to the IAP variation. The results of the IAP measurements obtained in each stage and the RDC values were compared, using the Pearson's linear correlation coefficient. RESULTS: There was no statistically significant correlation between the IAP variation and the RDC values at the three levels studied. CONCLUSIONS: The diastasis width does not interfere with the increase of the IAP when a plication of the anterior aponeurosis is performed. LEVEL OF EVIDENCE: 3 Diagnostic. PMID- 25922364 TI - Influence of repeated aspiration on viability of fat grafts: a comparative study. AB - BACKGROUND: Fat grafting has been increasingly widely used in cosmetic and reconstructive surgery. However, the long-term retention of fat grafts is still unpredictable. Many critical variables have been found to significantly affect the viability of fat grafts; still, some of the ordinary impact factors are overlooked. OBJECTIVES: We performed this study to find out whether repeated aspiration had an impact on fat grafts through an in vitro analysis and a nude mouse model. METHODS: A 15 cm by 10 cm rectangle was marked at the lower abdomen. The cannula was gently advanced and retracted through the same incision in a fan fashion within the superficial layer to collect fat samples. Based on the sequence of harvesting, the collected adipose tissue was divided into five groups and labeled as syringes 1, 2, 3, 4, and 5. Part of the sample was dissociated and analyzed using cell staining, Cell Counting Kit-8 assay, and flow cytometry. The other part was injected in vivo and analyzed for weight and histology at varying time intervals. RESULTS: Fat grafts from the former syringes were presented with a greater number of viable adipocytes and a higher level of cellular function compared to the latter syringes. Additionally, fat grafts from former syringes had higher graft retention, better vascularity, and less cystic necrosis. Neither the viability of stromal vascular fractions (SVFs) nor the ratio of CD34 + CD45- cells within the SVFs were different among the five groups. CONCLUSIONS: Repeated aspiration had a negative impact on the adipocytes, but not on the SVFs. With an increasing time of aspiration, the viability of the adipocytes and long-term retention of fat grafts decreased gradually. Harvested fat grafts from the first few syringes may be more suitable for fat grafting. PMID- 25922365 TI - The Fountain of Stem Cell-Based Youth? Online Portrayals of Anti-Aging Stem Cell Technologies. AB - BACKGROUND: The hype surrounding stem cell science has created a market opportunity for the cosmetic industry. Cosmetic and anti-aging products and treatments that make claims regarding stem cell technology are increasingly popular, despite a lack of evidence for safety and efficacy of such products. OBJECTIVES: This study explores how stem cell-based products and services are portrayed to the public through online sources, in order to gain insight into the key messages available to consumers. METHODS: A content analysis of 100 web pages was conducted to examine the portrayals of stem cell-based cosmetic and anti aging products and treatments. A qualitative discourse analysis of one web page further examined how language contributes to the portrayals of these products and treatments to public audiences. RESULTS: The majority of web pages portrayed stem cell-based products as ready for public use. Very few web pages substantiated claims with scientific evidence, and even fewer mentioned any risks or limitations associated with stem cell science. The discourse analysis revealed that the framing and use of metaphor obscures the certainty of the efficacy of and length of time for stem cell-based anti-aging technology to be publicly available. CONCLUSIONS: This study highlights the need to educate patients and the public on the current limits of stem cell applications in this context. In addition, generating scientific evidence for stem cell-based anti-aging and aesthetic applications is needed for optimizing benefits and minimizing adverse effects for the public. Having more evidence on efficacy and risks will help to protect patients who are eagerly seeking out these treatments. PMID- 25922367 TI - Health profile and disease determinants among asylum seekers: a cross-sectional retrospective study from an Italian reception centre. AB - BACKGROUND: Data on diseases' determinants and health status of asylum seekers (ASs) are limited. METHODS: We performed a cross-sectional retrospective study in a large ASs centre in Italy. Data were collected during a 1-year period. Descriptive statistics were calculated. A chi(2) test was used to assess the association between socio-demographics characteristics of ASs and screening test results. A multiple logistic regression analysis was performed to identify diseases' predictors by using ICD-10 diagnoses classification as outcome variable, socio-demographic characteristics as independent variable and visits' number as confounding variable. RESULTS: Overall, data on 792 ASs (mean age 27 years, 80% males, 58% from Africa) were assessed, 43% underwent voluntary infectious diseases screening and 2843 diagnoses were recorded. The most frequent diagnoses were: respiratory diseases, symptoms/signs not elsewhere classified, digestive diseases and infectious diseases. Gender was the most frequent predictor of ICD-10 diagnoses, while African origin, civil status and education were, respectively, predictive of cardiovascular and infectious diseases, genitourinary diseases and pregnancy-related disorders. Higher mean age was associated with syphilis, HIV and HCV infection and African origin with HIV infection. CONCLUSIONS: Communicable diseases were not prevalent in the ASs population we analysed. A stronger cultural mediation support is needed to facilitate prevention, access and continuity of care for ASs. PMID- 25922368 TI - Social support and non-participation in breast cancer screening: a Danish cohort study. AB - BACKGROUND: Social support may have an impact on screening participation. We studied the association between social support in 2006, defined as frequencies of contacts, instrumental support and emotional support and participation in breast cancer screening in 2008-09. METHODS: This population-based cohort study included 4512 women who had participated in a Health Survey in 2006 and who also were in the target group for the first round of organized breast cancer screening in the Central Denmark region in 2008-09. RESULTS: Women with infrequent contacts with friends and family in 2006 were more likely not to participate in screening in 2008-09 [prevalence ratio (PR) 1.69, 95% confidence interval (CI) 1.26-2.26, P value < 0.001 and PR 1.56, 95% CI 1.21-2.20, P-value < 0.001, respectively] as were women who reported not to have someone to look after her home if she was away for some time and women who reported usually not or never having someone to turn to with personal concerns (PR 1.97, 95% CI 1.53-2.54, P-value < 0.001 and PR 1.42, 95% CI 1.14-1.77, P-value = 0.002, respectively). CONCLUSIONS: Low social support, indicated by items in each social support attribute, was associated with non-participation in breast cancer screening in 2008-09. Targeted social interventions may, therefore, have an impact on future screening behaviour, which calls for further research. PMID- 25922366 TI - The impact of human copy number variation on gene expression. AB - Recent years have witnessed a flurry of important technological and methodological developments in the discovery and analysis of copy number variations (CNVs), which are increasingly enabling the systematic evaluation of their impact on a broad range of phenotypes from molecular-level (intermediate) traits to higher-order clinical phenotypes. Like single nucleotide variants in the human genome, CNVs have been linked to complex traits in humans, including disease and drug response. These recent developments underscore the importance of incorporating complex forms of genetic variation into disease mapping studies and promise to transform our understanding of genome function and the genetic basis of disease. Here we review some of the findings that have emerged from transcriptome studies of CNVs facilitated by the rapid advances in -omics technologies and corresponding methodologies. PMID- 25922369 TI - Relocation at older age: results from the Cognitive Function and Ageing Study. AB - BACKGROUND: Community environment might play an important role in supporting ageing in place. This paper aims to explore relocation at older age and its associations with individual and community level factors. METHODS: The postcodes of the 2424 people in the year-10 interview of the Cognitive Function and Ageing Study (CFAS) in England were mapped onto Enumeration Districts and linked to their corresponding Townsend deprivation score and the 2011 rural/urban categories. Multilevel logistic regression was conducted to examine the influence of the baseline individual (age, gender, education and social class) and community (rural/urban categories and area deprivation) level factors on relocation over 10 years. RESULTS: One-third of people moved residence after the age of 65 years and over. Older age, low education, low social class and living in rural areas at baseline were associated with higher probability of moving later in life. The likelihood of relocation in later life increased from least to most deprived areas (odds ratio: 2.0, 95% confidence interval: 1.4, 2.8). CONCLUSIONS: Urban/rural contexts and area deprivation are associated with relocation at older age and indicate that community environment may be relevant to ageing in place. PMID- 25922370 TI - A process evaluation of the NHS Health Check care pathway in a primary care setting. AB - BACKGROUND: More evidence is needed concerning the implementation of the NHS Health Check programme in order to identify areas for improvement. The aim of the study was to investigate the way in which the Gloucestershire NHS Health Check programme care pathway was followed and interpreted compared with national programme indicators. METHODS: A cross sectional review of Gloucestershire's Health Checks was undertaken to assess programme performance via a primary care audit of key indicators within a cohort of 83 GP practices and an eligible population of 210 513. Data were assessed to compare differences between practices and to compare county data with national indicators. RESULTS: The annual programme uptake was 49.8% and a total of 1031 patients were diagnosed with cardiovascular disease (CVD). Variations in the detection of modifiable risk factors in relation to the NHS Ready Reckoner were identified: diabetes (-0.04%), CKD (-0.9%), hypertension (-19.9%); obesity (-7.1%); low physical activity ( 57.7%) and smoking (-14.3%). CONCLUSIONS: Disparities in uptake and implementation of the care pathway demonstrate inconsistencies in the application of processes and knowledge. There appears to be an overestimation of CVD risk by the Ready Reckoner tool likely to be attributable to a failure to adjust for existing local early identification efforts in primary care and prevention. PMID- 25922371 TI - Hypertension prevalence, awareness, treatment and control in the over 50s in Ireland: evidence from The Irish Longitudinal Study on Ageing. AB - BACKGROUND: To assess the prevalence, awareness, treatment and control of hypertension among adults in Ireland and to describe the determinants of awareness, treatment and control in order to inform public health policy. METHODS: A cross-sectional study of a nationally representative sample of community living adults aged 50 years and older using data collected from 2009 to 2011 for the first wave of the Irish Longitudinal Study on Ageing (TILDA) (n = 5857). Hypertension was defined as systolic blood pressure (BP) >=140 mmHg or diastolic BP >=90 mmHg and/or currently taking antihypertensive medications. RESULTS: The prevalence of hypertension was 63.7% [95% confidence interval (CI) 62.3-65.1%]. Among those with hypertension, 54.5% (95% CI 52.6-56.2%) were aware of their hypertensive status and 58.9% (95% CI 57.1-60.4%) were on antihypertensive medication. Among those on treatment, 51.6% (95% CI 49.3-53.9%) had their BP controlled to below 140/90 mmHg. Respondents facing financial barriers to primary care and medication were less likely to be on antihypertensive treatment compared with those without financial barriers. CONCLUSIONS: A high prevalence of hypertension was identified in this cohort, with low levels of awareness, treatment and control. Population and primary care interventions are required to reduce prevalence and to improve awareness, detection and management of hypertension. PMID- 25922372 TI - Toward a next-generation atlas of RNA secondary structure. AB - RNA structure plays a crucial role in gene maturation, regulation and function. Determining the form and frequency of RNA folds is essential for a better understanding of how RNA exerts its functions. Low-throughput studies have focused on RNA primary sequences and expression levels, but with an emphasis on relatively small numbers of transcripts. However, with the recent advent of high throughput technologies, it is realistic to begin analyzing RNA secondary structures on a genome-wide scale. Here, we review genome-wide RNA secondary structure profiles as well as advances in computational structure predictions. We further discuss the novel characteristics of RNA secondary structure across messenger RNAs. Probing RNA secondary structure by high-throughput sequencing will enable us to build atlases of RNA secondary structures, an important step in helping us to understand the versatility of RNA functions in diverse cellular processes. PMID- 25922374 TI - When the Analytic Patient has Attention Deficit Hyperactivity Disorder. AB - Most analysts are now treating or can expect to treat adult patients with cognitive deficits such as attention deficit hyperactivity disorder (ADHD), based on the prevalence of this syndrome in children and its continuation into adulthood. ADHD is a cognitive disorder considered by nonanalytic and analytic writers to be a dysfunction of affect regulation and behavioral inhibition. Analysis deals with these issues, and most analytic theories address affect regulation. Manifestations of ADHD can mimic the clinical expression of intrapsychic conflict, in which the cognitive deficits are embedded. If these symptoms are interpreted primarily as transference resistances without acknowledging the cognitive contribution, the patient may experience a resurgence of feeling misunderstood and shamed, helpless and defective. Confusion in the countertransference is a hallmark of analyses in which cognitive deficits are intertwined with psychic conflict, sometimes leading the analyst to compartmentalize the cognitive and the conflictual and to miss aspects of the patient and the process. Appropriate action within the analytic frame may be needed to help the patient seek information, specialists, or coaches to deal with limitations in executive functioning. A variety of technical considerations and confusions in the countertransference are illustrated. PMID- 25922373 TI - Retrospective biodosimetry using translocation frequency in a stable cell of occupationally exposed to ionizing radiation. AB - Two cases of hematological malignancies were reported in an industrial radiography company over a year, which were reasonably suspected of being consequences of prolonged exposure to ionizing radiation because of the higher incidence than expected in the general population. We analyzed chromosomal aberrations in the peripheral blood lymphocytes from the other workers who had been working under similar circumstances as the patients in the company. Among the subjects tested, 10 workers who belonged to the highest band were followed up periodically for 1.5 years since the first analysis. The aim of this study was to clarify pertinence of translocation analysis to an industrial set-up where chronic exposure was commonly expected. To be a useful tool for a retrospective biodosimetry, the aberrations need to be persistent for a decade or longer. Therefore we calculated the decline rates and half-lives of frequency for both a reciprocal translocation and a dicentric chromosome and compared them. In this study, while the frequency of reciprocal translocations was maintained at the initial level, dicentric chromosomes were decreased to 46.9% (31.0-76.5) of the initial frequency over the follow-up period. Our results support the long-term stability of reciprocal translocation through the cell cycle and validate the usefulness of translocation analysis as a retrospective biodosimetry for cases of occupational exposure. PMID- 25922375 TI - Castration Depression: Affect, Signal Affect, and/or Depressive Illness? AB - The value of Charles Brenner's ideas regarding depression is assessed, focusing on the significance of castration depressive affect. His discussion of whether depression is an affect, a signal affect, or an illness is examined, with special emphasis on his failure to sufficiently address depression as an illness or disorder as defined by psychiatry. Clinical material from the analysis of a man who suffers from severe depression suggests that incorporating psychiatric concepts (biological and pharmacological) with modern conflict theory can be a useful way to understand and treat some patients with depression. Theoretical and clinical controversies associated with combining psychiatric/biological and psychoanalytic views of depression are examined. PMID- 25922376 TI - Introduction: letter from Berlin. PMID- 25922377 TI - Letter from Berlin: the international psychoanalytic university. PMID- 25922378 TI - Brief communication: problems applying neuroscientific research to the clinical setting. PMID- 25922379 TI - Commentary on Tuch. PMID- 25922380 TI - Response to Alberini. PMID- 25922383 TI - Samberg and Auchincloss respond to Cavell. PMID- 25922384 TI - Incidence, Risk Factors, and Prognosis of Intra-Abdominal Hypertension in Critically Ill Children: A Prospective Epidemiological Study. AB - PURPOSE: To assess the incidence, risk factors, and outcomes of intra-abdominal hypertension (IAH) in a pediatric intensive care unit (PICU). METHODS: Prospective cohort study from January 2011 to January 2013. All children consecutively admitted to the PICU, staying more than 24 hours and requiring bladder catheterization, were included in the study. On admission, demographic data and risk factors for IAH were studied. The intra-abdominal pressure was measured every 6 hours through a bladder catheter until discharge, death, or removal of the catheter. RESULTS: Of the 175 patients, 22 (12.6%) had IAH and 7 (4%) had abdominal compartment syndrome during the intensive care unit (ICU) stay. The independent risk factors associated with IAH were the presence of abdominal distension (odds ratio [OR] 7.1; 95% confidence interval [CI], 2.6 19.9; P < .0001) and a plateau pressure of more than 30 cm H2O (OR 6.42; 95% CI, 2.13-19.36; P = .01). The presence of IAH was associated with higher mortality (40.9% vs 15.6%; P = .01) and prolonged ICU stay (19.5 [3-97] vs 8 [1-104] days, OR 1.02; 95% CI, 1.00-1.04; P = .02). Thirty-three (18.8%) patients died in the ICU, and IAH was an independent risk factor for mortality (OR 6.98; 95% CI, 1.75 27.86; P = .006). CONCLUSION: Intra-abdominal hypertension does occur in about 13% of the critically ill children, albeit less frequently than adult patients, probably related to a better compliance of the abdominal wall. The presence of abdominal distension and a plateau pressure of more than 30 cm H2O was found to be independent predictors of IAH. Children with IAH had higher mortality rate and more prolonged ICU stay. PMID- 25922385 TI - Venoarterial Extracorporeal Membrane Oxygenation in Adults With Cardiac Arrest. AB - Cardiac arrest (CA) is a major cause of morbidity and mortality worldwide. Despite the use of conventional cardiopulmonary resuscitation (CPR), rates of return of spontaneous circulation and survival with minimal neurologic impairment remain low. Utilization of venoarterial extracorporeal membrane oxygenation (ECMO) for CA in adults is steadily increasing. Propensity-matched cohort studies have reported outcomes associated with ECMO use to be superior to that of conventional CPR alone in in-hospital patients with CA. In this review, we discuss the mechanism, indications, complications, and evidence for ECMO in CA in adults. PMID- 25922386 TI - The Impact of Implementation of an ICU Consult Service on Hospital-Wide Outcomes and ICU-Specific Outcomes. AB - BACKGROUND: Rapid response teams (RRTs) were developed to promote assessment of and early intervention for clinically deteriorating hospitalized patients. Although the ideal composition of RRTs is not known, their implementation does require significant resources. OBJECTIVE: To test the effectiveness of a dedicated daytime/weekday intensive care unit (ICU) consult service without formal training of ward teams. METHODS: Pre- and postintervention study with weekends/nights during implementation period acting as a concurrent control. SETTING: An adult tertiary care university center in Montreal without an RRT. INTERVENTION: A daytime/weekday ICU consult service with a dedicated intensivist. RESULTS: Total hospital mortality rate did not differ between the control and the implementation period (6.65% vs 6.60%; P = .84). The hospital code blue rates also did not differ (1.21/1000 vs 1.14/1000 patient days; P = .58). In contrast, 30-day mortality of patients admitted to the ICU following an ICU consult decreased (39% vs 24% P = .01). Multivariate analysis confirmed this effect on 30 day mortality (odds ratio for implementation period: 0.53 [95% confidence interval: 0.33-0.85] P = .009). The 14-day ICU readmission rate was reduced with the intervention (5.1% vs 4.1%; P < .001). The effect on 30-day mortality and ICU readmissions were only present during daytime/weekdays. CONCLUSION: Implementation of an ICU consult service without any formal afferent limb training was associated with decreased mortality and 14-day readmission rates of patients admitted to the ICU. In contrast, hospital-wide mortality and code blue rates were unaffected. PMID- 25922387 TI - Does Social Health Insurance Close the Gap: The Case of Socioeconomic Status and Preterm Low-Birth-Weight Survival. AB - Using a retrospective cohort study design, we report empirical evidence on the effect of parental socioeconomic status, primary care, and health care expenditure associated with preterm or low-birth-weight (PLBW) babies on their mortality (neonatal, postneonatal, and under-5 mortality) under a universal health care system. A total of 4668 singleton PLBW babies born in Taiwan between January 1 and December 31, 2001, are extracted from a population-based medical claims database for a follow-up of up to 5 years. Multivariate survival models suggest the positive effect of higher parental income is significant in neonatal period but diminishes in later stages. Consistent inverse relationship is observed between adequate antenatal care and the three outcomes: neonatal hazard ratio (HR) = 0.494, 95% confidence interval (CI) = 0.312 to 0.783; postneonatal HR = 0.282, 95% CI = 0.102 to 0.774; and under-5 HR = 0.575, 95% CI = 0.386 to 0.857. Primary care services uptake should be actively promoted, particularly in lower income groups, to prevent premature PLBW mortality. PMID- 25922388 TI - Following the fate of bacterial cells experiencing sudden chromosome loss. AB - Chromosomal DNA is a constant source of information, essential for any given cell to respond and adapt to changing conditions. Here, we investigated the fate of exponentially growing bacterial cells experiencing a sudden and rapid loss of their entire chromosome. Utilizing Bacillus subtilis cells harboring an inducible copy of the endogenous toxin yqcG, which encodes an endonuclease, we induced the formation of a population of cells that lost their genetic information simultaneously. Surprisingly, these DNA-less cells, termed DLCs, did not lyse immediately and exhibited normal cellular morphology for a period of at least 5 h after DNA loss. This cellular integrity was manifested by their capacity to maintain an intact membrane and membrane potential and cell wall architecture similar to those of wild-type cells. Unlike growing cells that exhibit a dynamic profile of macromolecules, DLCs displayed steady protein and RNA reservoirs. Remarkably, following DLCs by time lapse microscopy revealed that they succeeded in synthesizing proteins, elongating, and dividing, apparently forming de novo Z rings at the midcell position. Taken together, the persistence of key cellular events in DLCs indicates that the information to carry out lengthy processes is harbored within the remaining molecular components. IMPORTANCE: Perturbing bacterial growth by the use of antibiotics targeting replication, transcription, or translation has been a subject of study for many years; however, the consequences of a more dramatic event, in which the entire bacterial chromosome is lost, have not been described. Here, we followed the fate of bacterial cells encountering an abrupt loss of their entire genome. Surprisingly, the cells preserved an intact envelope and functioning macromolecules. Furthermore, cells lacking their genome could still elongate and divide hours after the loss of DNA. Our data suggest that the information stored in the transient reservoir of macromolecules is sufficient to carry out complex and lengthy processes even in the absence of the chromosome. Based on our study, the formation of DNA-less bacteria could serve as a novel vaccination strategy, enabling an efficient induction of the immune system without the risk of bacterial propagation within the host. PMID- 25922389 TI - Cell Differentiation in a Bacillus thuringiensis Population during Planktonic Growth, Biofilm Formation, and Host Infection. AB - Bacillus thuringiensis (Bt) is armed to complete a full cycle in its insect host. During infection, virulence factors are expressed under the control of the quorum sensor PlcR to kill the host. After the host's death, the quorum sensor NprR controls a necrotrophic lifestyle, allowing the vegetative cells to use the insect cadaver as a bioincubator and to survive. Only a part of the Bt population sporulates in the insect cadaver, and the precise composition of the whole population and its evolution over time are unknown. Using fluorescent reporters to record gene expression at the single-cell level, we have determined the differentiation course of a Bt population and explored the lineage existing among virulent, necrotrophic, and sporulating cells. The dynamics of cell differentiation were monitored during growth in homogenized medium, biofilm formation, and colonization of insect larvae. We demonstrated that in the insect host and in planktonic culture in rich medium, the virulence, necrotrophism, and sporulation regulators are successively activated in the same cell. In contrast, in biofilms, activation of PlcR is dispensable for NprR activation and we observed a greater heterogeneity than under the other two growth conditions. We also showed that sporulating cells arise almost exclusively from necrotrophic cells. In biofilm and in the insect cadaver, we identified an as-yet uncharacterized category of cells that do not express any of the reporters used. Overall, we showed that PlcR, NprR, and Spo0A act as interconnected integrators to allow finely tuned adaptation of the pathogen to its environment. IMPORTANCE: Bt is an entomopathogen found ubiquitously in the environment and is a widely used biopesticide. Studies performed at the population level suggest that the infection process of Bt includes three successive steps (virulence, necrotrophism, and sporulation) controlled by different regulators. This study aimed to determine how these phenotypes are activated at the cellular level and if they are switched on in all cells. We used an insect model of infection and biofilms to decipher the cellular differentiation of this bacterium under naturalistic conditions. Our study reveals the connection and lineage existing among virulent, necrotrophic, and sporulating cells. It also shows that the complex conditions encountered in biofilms and during infection generate great heterogeneity inside the population, which might reflect a bet-hedging strategy to ameliorate survival. These data generate new insights into the role of regulatory networks in the adaptation of a pathogen to its host. PMID- 25922390 TI - Chromosomal "stress-response" domains govern the spatiotemporal expression of the bacterial virulence program. AB - Recent studies strongly suggest that the gene expression sustaining both normal and pathogenic bacterial growth is governed by the structural dynamics of the chromosome. However, the mechanistic device coordinating the chromosomal configuration with selective expression of the adaptive traits remains largely unknown. We used a holistic approach exploring the inherent relationships between the physicochemical properties of the DNA and the expression of adaptive traits, including virulence factors, in the pathogen Dickeya dadantii (formerly Erwinia chrysanthemi). In the transcriptomes obtained under adverse conditions encountered during bacterial infection, we explored the patterns of chromosomal DNA sequence organization, supercoil dynamics, and gene expression densities, together with the long-range regulatory impacts of the abundant DNA architectural proteins implicated in pathogenicity control. By integrating these data, we identified transient chromosomal domains of coherent gene expression featuring distinct couplings between DNA thermodynamic stability, supercoil dynamics, and virulence traits. IMPORTANCE: We infer that the organization of transient chromosomal domains serving specific functions acts as a fundamental device for versatile adjustment of the pathogen to environmental stress. We believe that the identification of chromosomal "stress-response" domains harboring distinct virulence traits and mediating the cellular adaptive behavior provides a breakthrough in understanding the control mechanisms of bacterial pathogenicity. PMID- 25922391 TI - Thinking globally, acting locally: harnessing the immune system to deal with recalcitrant pathogens. AB - Traditional approaches to harnessing the immune system to confront infectious diseases depend on vaccines, which have generally proven highly effective, but for many infections these either are not available or are of limited effectiveness. Although antibiotic therapy has been extremely successful in reducing the burden of bacterial disease, the emergence of resistance among several important pathogens threatens to undermine this accomplishment, and despite some successes chemotherapeutic treatments for viral, fungal, and parasitic infections are more limited. Understanding the mechanisms whereby pathogens manipulate the immune system to favor their survival, or exploit weaknesses in host immunity, can lead to novel approaches for the treatment of infections by redirecting host immune responses against the pathogen. Such treatments may be most effectively applied at the mucosal locations which are frequently the sites of initial infection and may also suggest new approaches for vaccine development. PMID- 25922392 TI - "Tolerance" of misused terminology? Enforcing standardized phenotypic definitions. PMID- 25922393 TI - Single nucleoprotein residue modulates arenavirus replication complex formation. AB - The Arenaviridae are enveloped, negative-sense RNA viruses with several family members that cause hemorrhagic fevers. This work provides immunofluorescence evidence that, unlike those of New World arenaviruses, the replication and transcription complexes (RTC) of lymphocytic choriomeningitis virus (LCMV) colocalize with eukaryotic initiation factor 4E (eIF4E) and that eIF4E may participate in the translation of LCMV mRNA. Additionally, we identify two residues in the LCMV nucleoprotein (NP) that are conserved in every mammalian arenavirus and are required for recombinant LCMV recovery. One of these sites, Y125, was confirmed to be phosphorylated by using liquid chromatography-tandem mass spectrometry (LC-MS/MS). NP Y125 is located in the N-terminal region of NP that is disordered when RNA is bound. The other site, NP T206, was predicted to be a phosphorylation site. Immunofluorescence analysis demonstrated that NP T206 is required for the formation of the punctate RTC that are typically observed during LCMV infection. A minigenome reporter assay using NP mutants, as well as Northern blot analysis, demonstrated that although NP T206A does not form punctate RTC, it can transcribe and replicate a minigenome. However, in the presence of matrix protein (Z) and glycoprotein (GP), translation of the minigenome message with NP T206A was inhibited, suggesting that punctate RTC formation is required to regulate viral replication. Together, these results highlight a significant difference between New and Old World arenaviruses and demonstrate the importance of RTC formation and translation priming in RTC for Old World arenaviruses. IMPORTANCE: Several members of the Arenaviridae cause hemorrhagic fevers and are classified as category A pathogens. Arenavirus replication-transcription complexes (RTC) are nucleated by the viral nucleoprotein. This study demonstrates that the formation of these complexes is required for virus viability and suggests that RTC nucleation is regulated by the phosphorylation of a single nucleoprotein residue. This work adds to the body of knowledge about how these key viral structures are formed and participate in virus replication. Additionally, the fact that Old World arenavirus complexes colocalize with the eukaryotic initiation factor 4E, while New World arenaviruses do not, is only the second notable difference observed between New and Old World arenaviruses, the first being the difference in the glycoprotein receptor. PMID- 25922394 TI - Reply to "'tolerance' of misused terminology? Enforcing standardized phenotypic definitions". PMID- 25922395 TI - Cyclic AMP Regulates Social Behavior in African Trypanosomes. AB - The protozoan parasite Trypanosoma brucei engages in surface-induced social behavior, termed social motility, characterized by single cells assembling into multicellular groups that coordinate their movements in response to extracellular signals. Social motility requires sensing and responding to extracellular signals, but the underlying mechanisms are unknown. Here we report that T. brucei social motility depends on cyclic AMP (cAMP) signaling systems in the parasite's flagellum (synonymous with cilium). Pharmacological inhibition of cAMP-specific phosphodiesterase (PDE) completely blocks social motility without impacting the viability or motility of individual cells. Using a fluorescence resonance energy transfer (FRET)-based sensor to monitor cAMP dynamics in live cells, we demonstrate that this block in social motility correlates with an increase in intracellular cAMP levels. RNA interference (RNAi) knockdown of the flagellar PDEB1 phenocopies pharmacological PDE inhibition, demonstrating that PDEB1 is required for social motility. Using parasites expressing distinct fluorescent proteins to monitor individuals in a genetically heterogeneous community, we found that the social motility defect of PDEB1 knockdowns is complemented by wild type parasites in trans. Therefore, PDEB1 knockdown cells are competent for social motility but appear to lack a necessary factor that can be provided by wild-type cells. The combined data demonstrate that the role of cyclic nucleotides in regulating microbial social behavior extends to African trypanosomes and provide an example of transcomplementation in parasitic protozoa. IMPORTANCE: In bacteria, studies of cell-cell communication and social behavior have profoundly influenced our understanding of microbial physiology, signaling, and pathogenesis. In contrast, mechanisms underlying social behavior in protozoan parasites are mostly unknown. Here we show that social behavior in the protozoan parasite Trypanosoma brucei is governed by cyclic-AMP signaling systems in the flagellum, with intriguing parallels to signaling systems that control bacterial social behavior. We also generated a T. brucei social behavior mutant and found that the mutant phenotype is complemented by wild-type cells grown in the same culture. Our findings open new avenues for dissecting social behavior and signaling in protozoan parasites and illustrate the capacity of these organisms to influence each other's behavior in mixed communities. PMID- 25922397 TI - Prevention of Clostridium difficile Infection With Probiotics. AB - Despite advances in the diagnosis and treatment of Clostridium difficile infection (CDI) and prevention efforts to reduce the spread of C. difficile, CDI remains a significant challenge to healthcare systems worldwide. Further advances in prevention of CDI may need to focus on those who continue to be exposed to the organism and who are susceptible. Interventions directed toward this susceptible population, particularly hospitalized patients who receive antibiotics, may be effective. There is moderate evidence on the effectiveness of probiotics to prevent primary CDI, but there are few data to support use in secondary prevention of recurrent CDI. This review discusses the literature available on the use of probiotics to prevent primary and secondary CDI. PMID- 25922396 TI - New approaches for bacteriotherapy: prebiotics, new-generation probiotics, and synbiotics. AB - The gut microbiota has a significant role in human health and disease. Dysbiosis of the intestinal ecosystem contributes to the development of certain illnesses that can be reversed by favorable alterations by probiotics. The published literature was reviewed to identify scientific data showing a relationship between imbalance of gut bacteria and development of diseases that can be improved by biologic products. The medical conditions vary from infectious and antibiotic-associated diarrhea to obesity to chronic neurologic disorders. A number of controlled clinical trials have been performed to show important biologic effects in a number of these conditions through administration of prebiotics, probiotics, and synbiotics. Controlled clinical trials have identified a limited number of prebiotics, probiotic strains, and synbiotics that favorably prevent or improve the symptoms of various disorders including inflammatory bowel disease, irritable bowel syndrome, infectious and antibiotic associated diarrhea, diabetes, nonalcoholic fatty liver disease, necrotizing enterocolitis in very low birth weight infants, and hepatic encephalopathy. Studies have shown that probiotics alter gut flora and lead to elaboration of flora metabolites that influence health through 1 of 3 general mechanisms: direct antimicrobial effects, enhancement of mucosal barrier integrity, and immune modulation. Restoring the balance of intestinal flora by introducing probiotics for disease prevention and treatment could be beneficial to human health. It is also clear that significant differences exist between different probiotic species. Metagenomics and metatranscriptomics together with bioinformatics have allowed us to study the cross-talk between the gut microbiota and the host, furthering insight into the next generation of biologic products. PMID- 25922399 TI - Lactobacillus acidophilus CL1285, Lactobacillus casei LBC80R, and Lactobacillus rhamnosus CLR2 (Bio-K+): Characterization, Manufacture, Mechanisms of Action, and Quality Control of a Specific Probiotic Combination for Primary Prevention of Clostridium difficile Infection. AB - A specific probiotic formulation composed of Lactobacillus acidophilus CL1285, Lactobacillus casei LBC80R, and Lactobacillus rhamnosus CLR2 (Bio-K+) has been marketed in North America since 1996. The strains and the commercial products have been evaluated for safety, identity, gastrointestinal survival, and stability throughout shelf life. The capacity of both the fermented beverages and the capsules to reduce incidences of antibiotic-associated diarrhea and Clostridium difficile infection (CDI) has been demonstrated in human clinical trials. Individual strains and the finished products have shown antimicrobial activity against C. difficile and toxin A/B neutralization capacity in vitro. The use of this specific probiotic formulation as part of a bundle of preventive measures to control CDI in healthcare settings is discussed. PMID- 25922398 TI - Risk and safety of probiotics. AB - Probiotics have been used safely for years. Safety outcomes are inconsistently reported in published clinical trials. In 2011, a report released by the Agency for Healthcare Research and Quality concluded that, although the existing probiotic clinical trials reveal no evidence of increased risk, "the current literature is not well equipped to answer questions on the safety of probiotics in intervention studies with confidence." Critics point out that the preponderance of evidence, including the long history of safe probiotic use as well as data from clinical trials, and animal and in vitro studies all support the assumption that probiotics are generally safe for most populations. Theoretical risks have been described in case reports, clinical trial results and experimental models, include systemic infections, deleterious metabolic activities, excessive immune stimulation in susceptible individuals, gene transfer and gastrointestinal side effects. More research is needed to properly describe the incidence and severity of adverse events related to probiotics. PMID- 25922400 TI - A Decade of Experience in Primary Prevention of Clostridium difficile Infection at a Community Hospital Using the Probiotic Combination Lactobacillus acidophilus CL1285, Lactobacillus casei LBC80R, and Lactobacillus rhamnosus CLR2 (Bio-K+). AB - In August 2003, the 284-bed community hospital Pierre-Le Gardeur (PLGH) in Quebec experienced a major outbreak associated with the Clostridium difficile NAP1/027/BI strain. Augmented standard preventive measures (SPMs) were not able to control this outbreak. It was decided in February 2004 to give to every adult inpatient on antibiotics, without any exclusion, a probiotic (Bio-K+: Lactobacillus acidophilus CL1285, Lactobacillus casei LBC80R, and Lactobacillus rhamnosus CLR2) within 12 hours of the antibiotic prescription. Augmented SPMs were continued. The use of the probiotic in addition to SPMs was associated with a marked reduction of C. difficile infection (CDI). During the 10 years of observation, 44 835 inpatients received Bio-K+, and the CDI rate at PLGH declined from 18.0 cases per 10,000 patient-days and remained at low mean levels of 2.3 cases per 10,000 patient-days. Additionally, 10-year data collected by the Ministry of Health in Quebec comparing the CDI rate between Quebec hospitals showed that CDI rates at PLGH were consistently and continuously lower compared with those at similar hospitals. Blood cultures were monitored at PLGH for Lactobacillus bacteremia through the 10 years' experience, and no Lactobacillus bacteremias were detected. Despite the limitation of an observational study, we concluded that the probiotic Bio-K+ was safe and effective in decreasing our primary CDI rate. PMID- 25922401 TI - Pathway to Prevention of Nosocomial Clostridium difficile Infection. AB - BACKGROUND: To address the significant morbidity and mortality rates associated with nosocomial Clostridium difficile-associated diarrhea (CDAD), a series of recommendations and a pathway to prevention were developed. METHODS: An expert panel of infectious disease (ID) specialists participated in a modified Delphi process with specific objectives: (1) conduct a review for CDAD and prevention; (2) develop statements based upon panel members' opinions; (3) hold a panel meeting during the 2012 IDWeek; and (4) review the final recommendations and prevention pathway prior to submission for publication. RESULTS: The panel voted on (1) antibiotic stewardship (7 of 8 panelists); (2) reduction of other potentially modifiable risk factors (variable); (3) utilization of specific probiotics to prevent C. difficile overgrowth (8/8); (4) staff education regarding CDAD preventive measures (8/8); (5) appropriate hand hygiene for everyone (7/8); (6) environmental cleaning (8/8); (7) medical equipment disinfection (7/8); (8) early detection of CDAD in symptomatic patients (7/8); (9) usage of protective clothing/gloves (8/8); (10) proper measures during outbreak (8/8); and (11) surveillance to monitor efficacy data of preventive measures (8/8). CONCLUSIONS: The panel members agreed with 11 of 17 recommendations presented. The additional recommendations by the panel were proton pump inhibitor use as a risk factor and the use of adjunctive therapy with specific probiotic, as it was approved by Health Canada for the risk reduction of CDAD in hospitalized patients. PMID- 25922402 TI - Reducing collateral damage associated with antibiotic treatment: do less harm. PMID- 25922403 TI - Current Trends in the Epidemiology and Outcomes of Clostridium difficile Infection. AB - Clostridium difficile is the most frequently identified cause of nosocomial diarrhea and has been associated with epidemics of diarrhea in hospitals and long term care facilities. The continued increase in C. difficile infection (CDI) suggests that it has surpassed other pathogens in causing healthcare-associated infections. The Centers for Disease Control and Prevention recently identified CDI as an "urgent threat" in its recent report on antibiotic resistance threats in the United States, highlighting the need for urgent and aggressive action to prevent this infection. The impact of antibiotics as a risk factor for new-onset CDI is well established; however, recognizing classes of antibiotics with the highest risks and reducing unnecessary antibiotic use are important strategies for prevention of CDI and subsequent recurrence. In addition, the recognition of the community as an important setting for onset of CDI presents a challenge and is an area for future research. PMID- 25922404 TI - Clostridium difficile Infection in Long-term Care Facilities: A Call to Action for Antimicrobial Stewardship. AB - Across the United States, the baby boomers are entering into their elderly years. As they are America's largest generation to do so to date, their need for care will greatly affect nursing homes, long-term care facilities, and long-term acute care hospitals (LTACHs). Unfortunately, the rise of Clostridium difficile infection (CDI), particularly in extended-care facilities, might become the biggest obstacle in their care. Elderly extended-care-facility residents are at an elevated risk of CDI simply due to their advanced age and the fact that they are receiving care in an extended-care facility. LTACHs experience a high incidence rate of CDI, and these infections can lead to major complications for a patient's health. Other factors that contribute to higher risk for CDI include receiving multiple courses of antibiotics, longer length of antibiotic treatment, and previous CDI. Although this obstacle to proper care is great, some simple solutions are available to healthcare providers. Probiotics may help improve natural immunity in patients, and strict adherence to antimicrobial stewardship standards could help reduce this serious bacterial threat. PMID- 25922405 TI - Determining the Long-term Effect of Antibiotic Administration on the Human Normal Intestinal Microbiota Using Culture and Pyrosequencing Methods. AB - The purpose of the study was to assess the effect of ciprofloxacin (500 mg twice daily for 10 days) or clindamycin (150 mg 4 times daily for 10 days) on the fecal microbiota of healthy humans for a period of 1 year as compared to placebo. Two different methods, culture and microbiome analysis, were used. Fecal samples were collected for analyses at 6 time-points. The interval needed for the normal microbiota to be normalized after ciprofloxacin or clindamycin treatment differed for various bacterial species. It took 1-12 months to normalize the human microbiota after antibiotic administration, with the most pronounced effect on day 11. Exposure to ciprofloxacin or clindamycin had a strong effect on the diversity of the microbiome, and changes in microbial composition were observed until the 12th month, with the most pronounced microbial shift at month 1. No Clostridium difficile colonization or C. difficile infections were reported. Based on the pyrosequencing results, it appears that clindamycin has more impact than ciprofloxacin on the intestinal microbiota. PMID- 25922406 TI - From yaks to yogurt: the history, development, and current use of probiotics. AB - The development of probiotics, which are living bacteria or yeasts used to confer a health benefit on the host, has paralleled our research in food preservation, microbiologic identification techniques, and our understanding of how the complex interactions in microbiota impact the host's health and recovery from disease. This review briefly describes the history of probiotics, where probiotic strains were originally isolated, and the types of probiotic products currently available on the global market. In addition, the uses or indications for these probiotics are described, along with the types of clinical investigations that have been done. Continuing challenges persist for the proper probiotic strain identification, regulatory pathways, and how healthcare providers can choose a specific strain to recommend to their patients. PMID- 25922407 TI - Differences of the Fecal Microflora With Clostridium difficile Therapies. AB - BACKGROUND: During treatment of Clostridium difficile infection (CDI), patterns of pathogen reduction in relationship to changes in components of the normal microbiota are hypothesized to be predictive of response to treatment and subsequent sustained cure. METHODS: At a single center, subjects enrolled into phase 2 and 3 C. difficile treatment clinical trials (2003-2008) provided fecal samples to assess killing of C. difficile and changes to components of the microbiome. Quantitative bacterial cultures, measurement of C. difficile toxin titers, quantitative polymerase chain reaction of fecal samples for Bacteroidetes, Clostridium clusters XIVa and IV, and C. difficile were performed. RESULTS: Quantitative bacterial cultures showed a mean log10 C. difficile count (colony-forming units [CFU]) of 6.7 +/- 2.0 at study entry; vancomycin treatment consistently reduced C. difficile counts to the limit of detection (2.0 log10 CFU/g), whereas metronidazole was associated with mean C. difficile counts 1.5-2 log10 higher at 10 days of treatment. In patients receiving tolevamer, C. difficile persisted in high counts during treatment; response to treatment was correlated with neutralization of toxin along with persistence of normal microbiota components. However, this was achieved in approximately half of subjects. Both vancomycin and metronidazole further suppressed microbiome components during treatment of CDI. Lactobacilli were observed to be a microbiome component that persisted during treatment of CDI. CONCLUSIONS: Differences of pathogen clearance and microbiome perturbation during treatment of CDI appear to explain treatment outcomes. The hypothesis that probiotic microbes could help prevent onset of CDI is supported by the observation of persistence of lactobacilli during and after treatment of CDI. PMID- 25922408 TI - Lactobacillus species: taxonomic complexity and controversial susceptibilities. AB - The genus Lactobacillus is a taxonomically complex and is composed of over 170 species that cannot be easily differentiated phenotypically and often require molecular identification. Although they are part of the normal human gastrointestinal and vaginal flora, they can also be occasional human pathogens. They are extensively used in a variety of commercial products including probiotics. Their antimicrobial susceptibilities are poorly defined in part because of their taxonomic complexity and are compounded by the different methods recommended by Clinical Laboratory Standards Institute and International Dairy Foundation. Their use as probiotics for prevention of Clostridium difficile infection is prevalent among consumers worldwide but raises the question of will the use of any concurrent antibiotic effect their ability to survive. Lactobacillus species are generally acid resistant and are able to survive ingestion. They are generally resistant to metronidazole, aminoglycosides and ciprofloxacin with L. acidophilus being susceptible to penicillin and vancomycin, whereas L. rhamnosus and L. casei are resistant to metronidazole and vancomycin. PMID- 25922409 TI - Towards High-throughput Immunomics for Infectious Diseases: Use of Next generation Peptide Microarrays for Rapid Discovery and Mapping of Antigenic Determinants. AB - Complete characterization of antibody specificities associated to natural infections is expected to provide a rich source of serologic biomarkers with potential applications in molecular diagnosis, follow-up of chemotherapeutic treatments, and prioritization of targets for vaccine development. Here, we developed a highly-multiplexed platform based on next-generation high-density peptide microarrays to map these specificities in Chagas Disease, an exemplar of a human infectious disease caused by the protozoan Trypanosoma cruzi. We designed a high-density peptide microarray containing more than 175,000 overlapping 15 mer peptides derived from T. cruzi proteins. Peptides were synthesized in situ on microarray slides, spanning the complete length of 457 parasite proteins with fully overlapped 15 mers (1 residue shift). Screening of these slides with antibodies purified from infected patients and healthy donors demonstrated both a high technical reproducibility as well as epitope mapping consistency when compared with earlier low-throughput technologies. Using a conservative signal threshold to classify positive (reactive) peptides we identified 2,031 disease specific peptides and 97 novel parasite antigens, effectively doubling the number of known antigens and providing a 10-fold increase in the number of fine mapped antigenic determinants for this disease. Finally, further analysis of the chip data showed that optimizing the amount of sequence overlap of displayed peptides can increase the protein space covered in a single chip by at least ~ threefold without sacrificing sensitivity. In conclusion, we show the power of high-density peptide chips for the discovery of pathogen-specific linear B-cell epitopes from clinical samples, thus setting the stage for high-throughput biomarker discovery screenings and proteome-wide studies of immune responses against pathogens. PMID- 25922410 TI - Validation of the 2014 European Society of Cardiology guidelines risk prediction model for the primary prevention of sudden cardiac death in hypertrophic cardiomyopathy. AB - BACKGROUND: The recently released 2014 European Society of Cardiology guidelines of hypertrophic cardiomyopathy (HCM) use a new clinical risk prediction model for sudden cardiac death (SCD), based on the HCM Risk-SCD study. Our study is the first external and independent validation of this new risk prediction model. METHODS AND RESULTS: The study population consisted of a consecutive cohort of 706 patients with HCM without prior SCD event, from 2 tertiary referral centers. The primary end point was a composite of SCD and appropriate implantable cardioverter-defibrillator therapy, identical to the HCM Risk-SCD end point. The 5-year SCD risk was calculated using the HCM Risk-SCD formula. Receiver operating characteristic curves and C-statistics were calculated for the 2014 European Society of Cardiology guidelines, and risk stratification methods of the 2003 American College of Cardiology/European Society of Cardiology guidelines and 2011 American College of Cardiology Foundation/American Heart Association guidelines. During follow-up of 7.7+/-5.3 years, SCD occurred in 42 (5.9%) of 706 patients (ages 49+/-16 years; 34% women). The C-statistic of the new model was 0.69 (95% CI, 0.57-0.82; P=0.008), which performed significantly better than the conventional risk factor models based on the 2003 guidelines (C-statistic of 0.55: 95% CI, 0.47-0.63; P=0.3), and 2011 guidelines (C-statistic of 0.60: 95% CI, 0.50-0.70; P=0.07). CONCLUSIONS: The HCM Risk-SCD model improves the risk stratification of patients with HCM for primary prevention of SCD, and calculating an individual risk estimate contributes to the clinical decision making process. Improved risk stratification is important for the decision making before implantable cardioverter-defibrillator implantation for the primary prevention of SCD. PMID- 25922413 TI - The impact of violence reduction initiatives on emergency department attendance. AB - BACKGROUND: Recent violence reduction initiatives in Glasgow have led to a reduction in recorded levels of violent crime.(1) This study evaluates the impact of these initiatives on assault-related emergency department attendances and admissions. METHODS: A retrospective observational study conducted in Glasgow Royal Infirmary's emergency department comparing assault-related emergency department attendances and hospital admissions over two 30-day study periods (April 2010 and April 2012). The primary outcome measure was the change in assault-related emergency department attendances. The secondary outcome measure was the impact on assault-related hospital and critical care admissions. RESULTS: In April 2010, there were 6098 emergency department attendances, 301 (4.9%) were due to assault. In April 2012, there were 7236 emergency department attendances, 263 (3.6%) were due to assault, representing a significant reduction in assault related attendances (p < 0.01). There were significant reductions in level 1 admissions 2010 n = 56 (19.2%), 2012 n = 36 (14.0%) p = 0.04 and critical care admissions, 2010 n = 5 (1.7%), 2012 n = 1 (0.4%) p = 0.04. CONCLUSIONS: Violence reduction initiatives in Glasgow have contributed to a reduction in assault related emergency department attendance at Glasgow Royal Infirmary. The reduction in hospital admissions, in particular critical care admissions, suggests a reduction in morbidity and cost to the National Health Service. PMID- 25922416 TI - China to halt using executed prisoners' organs for transplants: a step in the right direction in medical ethics. PMID- 25922417 TI - Underutilization of Radial Access in Patients Undergoing Percutaneous Coronary Intervention for ST-Segment-Elevation Myocardial Infarction: Insights From the Blue Cross Blue Shield of Michigan Cardiovascular Consortium. AB - BACKGROUND: The purpose of this study was to evaluate the frequency and temporal trends in use of transradial access (TRA) for percutaneous coronary intervention (PCI) in ST-segment-elevation myocardial infarction (STEMI). The use of TRA has been associated with less bleeding and improved clinical outcomes in patients undergoing PCI for STEMI. METHODS AND RESULTS: The frequency of TRA compared with transfemoral access for patients undergoing PCI for STEMI or other indications (non-ST-segment-elevation myocardial infarction, unstable angina, and non-acute coronary syndrome) in The Blue Cross Blue Shield of Michigan Cardiovascular Consortium database between 2010 and 2013 was evaluated. Propensity matching was used to assess the relationship of TRA with in-hospital clinical end points of major bleeding, transfusion, and death. The TRA cohort of patients was stratified into deciles based on their predicted bleeding risk and compared with PCI indication. Of 122,728 PCI procedures, 17,912 (14.6%) were via TRA. Among patients with STEMI cases, 8.3% of the PCI cases were performed via TRA. The use of TRA increased over the study period although the growth was slower for STEMI than for other indications, P<0.001. The use of TRA for PCI in STEMI was associated with a lower rate of bleeding (11.7% versus 20.0%; P<0.001) and vascular complications (0.7% versus 2.6%; P=0.001), but no mortality difference (1.25% versus 2.33%; P=0.175). There was a strong negative association between the predicted risk of bleeding and the use of TRA (P<0.001). CONCLUSIONS: The use of radial access for PCI in STEMI is increasing but at a slower pace than for patients with other indications. TRA was associated with a reduction in bleeding and transfusion, but there is a strong negative correlation between the predicted risk of bleeding and actual use of TRA in STEMI. PMID- 25922418 TI - Disrupting the mixed-species biofilm of Klebsiella pneumoniae B5055 and Pseudomonas aeruginosa PAO using bacteriophages alone or in combination with xylitol. AB - We investigated the potential of bacteriophages alone as well as in combination with xylitol for tackling mixed-species biofilm of Pseudomonas aeruginosa and Klebsiella pneumoniae. When mixed-species biofilm was established on polycarbonate discs, P. aeruginosa formed the base layer which was physically shielded on the top by K. pneumoniae. Thereafter, mixed-species biofilm was treated with bacteriophages. K. pneumoniae-specific depolymerase-producing phage KPO1K2 caused significant reduction in the count of Klebsiella. In contrast, P. aeruginosa-specific non-depolymerase-producing phage Pa29 failed to cause any reduction in the count of Pseudomonas. However, application of both phages together resulted in significant reduction in the count of both organisms. This suggests that depolymerase produced by phage KPO1K2 hydrolysed the top layer of K. pneumoniae and guided the entry of Pa29 to reach P. aeruginosa lying underneath. This phenomenon was confirmed when K. pneumoniae-specific non depolymerase-producing phage NDP was used along with Pa29. Pa29 could not penetrate and reach its host bacterium. Xylitol worked synergistically along with the phage, resulting in a significant decrease in counts of both organisms. Disruption of mixed species biofilm by phage and xylitol was confirmed on the basis of the amount of protein and DNA released. This phage-based approach to altering the structural pattern and disrupting the mixed species biofilm is the first of its kind. It can be used as a topical application, a coating for foreign bodies or for aerosol delivery to tackle infections where both pathogens coexist in a biofilm mode. PMID- 25922419 TI - Homozygous/Compound Heterozygous Triadin Mutations Associated With Autosomal Recessive Long-QT Syndrome and Pediatric Sudden Cardiac Arrest: Elucidation of the Triadin Knockout Syndrome. AB - BACKGROUND: Long-QT syndrome (LQTS) may result in syncope, seizures, or sudden cardiac arrest. Although 16 LQTS-susceptibility genes have been discovered, 20% to 25% of LQTS remains genetically elusive. METHODS AND RESULTS: We performed whole-exome sequencing child-parent trio analysis followed by recessive and sporadic inheritance modeling and disease-network candidate analysis gene ranking to identify a novel underlying genetic mechanism for LQTS. Subsequent mutational analysis of the candidate gene was performed with polymerase chain reaction, denaturing high-performance liquid chromatography, and DNA sequencing on a cohort of 33 additional unrelated patients with genetically elusive LQTS. After whole exome sequencing and variant filtration, a homozygous p.D18fs*13 TRDN-encoded triadin frameshift mutation was discovered in a 10-year-old female patient with LQTS with a QTc of 500 milliseconds who experienced recurrent exertion-induced syncope/cardiac arrest beginning at 1 year of age. Subsequent mutational analysis of TRDN revealed either homozygous or compound heterozygous frameshift mutations in 4 of 33 unrelated cases of LQTS (12%). All 5 TRDN-null patients displayed extensive T-wave inversions in precordial leads V1 through V4, with either persistent or transient QT prolongation and severe disease expression of exercise induced cardiac arrest in early childhood (<=3 years of age) and required aggressive therapy. The overall yield of TRDN mutations was significantly greater in patients <=10 years of age (5 of 10, 50%) compared with older patients (0 of 24, 0%; P=0.0009). CONCLUSIONS: We identified TRDN as a novel underlying genetic basis for recessively inherited LQTS. All TRDN-null patients had strikingly similar phenotypes. Given the recurrent nature of potential lethal arrhythmias, patients fitting this phenotypic profile should undergo cardiac TRDN genetic testing. PMID- 25922421 TI - European rating of drug harms. AB - BACKGROUND: The present paper describes the results of a rating study performed by a group of European Union (EU) drug experts using the multi-criteria decision analysis model for evaluating drug harms. METHODS: Forty drug experts from throughout the EU scored 20 drugs on 16 harm criteria. The expert group also assessed criteria weights that would apply, on average, across the EU. Weighted averages of the scores provided a single, overall weighted harm score (range: 0 100) for each drug. RESULTS: Alcohol, heroin and crack emerged as the most harmful drugs (overall weighted harm score 72, 55 and 50, respectively). The remaining drugs had an overall weighted harm score of 38 or less, making them much less harmful than alcohol. The overall weighted harm scores of the EU experts correlated well with those previously given by the UK panel. CONCLUSION: The outcome of this study shows that the previous national rankings based on the relative harms of different drugs are endorsed throughout the EU. The results indicates that EU and national drug policy measures should focus on drugs with the highest overall harm, including alcohol and tobacco, whereas drugs such as cannabis and ecstasy should be given lower priority including a lower legal classification. PMID- 25922420 TI - Intimate insight: MDMA changes how people talk about significant others. AB - RATIONALE: +/-3,4-methylenedioxymethamphetamine (MDMA) is widely believed to increase sociability. The drug alters speech production and fluency, and may influence speech content. Here, we investigated the effect of MDMA on speech content, which may reveal how this drug affects social interactions. METHOD: Thirty-five healthy volunteers with prior MDMA experience completed this two session, within-subjects, double-blind study during which they received 1.5 mg/kg oral MDMA and placebo. Participants completed a five-minute standardized talking task during which they discussed a close personal relationship (e.g. a friend or family member) with a research assistant. The conversations were analyzed for selected content categories (e.g. words pertaining to affect, social interaction, and cognition), using both a standard dictionary method (Pennebaker's Linguistic Inquiry and Word Count: LIWC) and a machine learning method using random forest classifiers. RESULTS: Both analytic methods revealed that MDMA altered speech content relative to placebo. Using LIWC scores, the drug increased use of social and sexual words, consistent with reports that MDMA increases willingness to disclose. Using the machine learning algorithm, we found that MDMA increased use of social words and words relating to both positive and negative emotions. CONCLUSIONS: These findings are consistent with reports that MDMA acutely alters speech content, specifically increasing emotional and social content during a brief semistructured dyadic interaction. Studying effects of psychoactive drugs on speech content may offer new insights into drug effects on mental states, and on emotional and psychosocial interaction. PMID- 25922422 TI - Midbrain raphe 5-HT1A receptor activation alters the effects of ghrelin on appetite and performance in the elevated plus maze. AB - Prior research suggests that midbrain serotonergic signaling and hypothalamic ghrelinergic signaling both play critical roles in appetitive and emotional behaviors. In the present study, we investigated the effects of median raphe nucleus (MRN) somatodentritic 5-HT1A receptor activation on the feeding-stimulant and anxiogenic action of paraventricular nucleus (PVN) ghrelin. In an initial experiment, adult male Sprague-Dawley rats were injected with either ghrelin (200 800 pmol) into the PVN or 8-OH-DPAT (2.5-10 nmol), a 5-HT1A receptor agonist, into the MRN. Performance on the elevated plus maze (EPM) was then assessed. In separate rats, MRN 8-OH-DPAT (2.5-5 nmol) was administered 5 min prior to PVN injection of ghrelin (400 pmol) followed by EPM testing. The orexigenic effects of MRN 8-OH-DPAT (0.1-1.6 nmol) paired with PVN ghrelin (50 pmol) were also examined. When administered alone into the PVN, ghrelin significantly decreased the number of entries and time spent in the open arms of the EPM. This anxiogenic effect was blocked if rats were allowed to eat immediately after ghrelin administration and then tested in the plus maze. MRN injections of 8-OH-DPAT were anxiolytic, and when rats were pretreated with 8-OH-DPAT prior to ghrelin, the anxiogenic action of the peptide was attenuated. In contrast, MRN administration of 8-OH-DPAT potentiated the eating-stimulant effect of PVN ghrelin. Overall, our findings demonstrate that ghrelinergic and serotonergic circuits interact in the neural control of eating and anxiety-like behaviors, with 5-HT1A receptor mechanisms potentiating the orexigenic action of ghrelin while inhibiting ghrelin induced anxiogenesis as measured via the EPM. PMID- 25922423 TI - Chronic ethanol exposure during adolescence through early adulthood in female rats induces emotional and memory deficits associated with morphological and molecular alterations in hippocampus. AB - There is increasing evidence that heavy ethanol exposure in early life may produce long-lasting neurobehavioral consequences, since brain structural maturation continues until adolescence. It is well established that females are more susceptible to alcohol-induced neurotoxicity and that ethanol consumption is increasing among women, especially during adolescence. In the present study, we investigated whether chronic ethanol exposure during adolescence through early adulthood in female rats may induce hippocampal histological damage and neurobehavioral impairments. Female rats were treated with distilled water or ethanol (6.5 g/kg/day, 22.5% w/v) by gavage from the 35(th)-90(th) day of life. Ethanol-exposed animals displayed reduced exploration of the central area and increased number of fecal boluses in the open field test indicative of anxiogenic responses. Moreover, chronic high ethanol exposure during adolescence induced marked impairments on short-term memory of female rats addressed on social recognition and step-down inhibitory avoidance tasks. These neurobehavioral deficits induced by ethanol exposure during adolescence through early adulthood were accompanied by the reduction of hippocampal formation volume as well as the loss of neurons, astrocytes and microglia cells in the hippocampus. These results indicate that chronic high ethanol exposure during adolescence through early adulthood in female rats induces long-lasting emotional and memory deficits associated with morphological and molecular alterations in the hippocampus. PMID- 25922424 TI - Modafinil in the treatment of crack-cocaine dependence in the Netherlands: Results of an open-label randomised controlled feasibility trial. AB - BACKGROUND: Crack-cocaine dependence is a serious disorder with no approved pharmacological treatment. Modafinil is a promising medication with increased cocaine abstinence and reduced craving in some previous studies. In the present study, we examined the acceptance, safety and potential benefits of modafinil as an add-on treatment to cognitive behavioural therapy (CBT) in crack-cocaine dependent patients. METHODS: Sixty-five crack-cocaine dependent outpatients participated in an open-label, randomised feasibility trial. Patients were randomised to receive either 12-week individual CBT plus 400 mg/day modafinil or 12-week individual CBT only. The primary outcome measure was CBT treatment retention. Secondary outcomes included modafinil adherence, tolerability and safety, use of cocaine and other substances, cocaine craving, health, social functioning and patient satisfaction. RESULTS: Modafinil adherence was low, with only 10% treatment completers. Intent-to-treat analyses showed that modafinil did not improve CBT treatment retention or any of the secondary cocaine-related outcomes. Both groups showed similar, large reductions in cocaine use during the study treatment. Post hoc exploratory analyses within the CBT plus modafinil group showed significantly larger baseline to week 12 reductions in cocaine use days in high (? 8 weeks) modafinil adherent patients. CONCLUSIONS: Acceptance and benefits of modafinil were not demonstrated in the present study. Since reduction in cocaine use was observed in high modafinil adherent patients, further research in the treatment of cocaine dependence, in which modafinil adherence is optimised, is warranted. PMID- 25922426 TI - Randomised clinical trial of the effects of prolonged-release melatonin, temazepam and zolpidem on slow-wave activity during sleep in healthy people. AB - Current pharmacological treatments for insomnia include benzodiazepine and non benzodiazepine hypnotics targeting gamma-aminobutyric acid (GABA)A receptors, as well as agonists of the melatonin receptors MT1 and MT2. Melatonin, temazepam and zolpidem are thought to exert their effect through different mechanisms of action, but whether this leads to differential effects on electroencephalogram (EEG) power spectra during sleep in middle-aged people is currently not known. To establish whether the effects of prolonged-release melatonin (2 mg) on the nocturnal sleep EEG are different to those of temazepam (20 mg) and zolpidem (10 mg). Sixteen healthy men and women aged 55-64 years participated in a double blind, placebo-controlled, four-way cross-over trial. Nocturnal sleep was assessed with polysomnography and spectral analysis of the EEG. The effects of single oral doses of prolonged-release melatonin, temazepam and zolpidem on EEG slow-wave activity (SWA, 0.75-4.5 Hz) and other frequencies during nocturnal non rapid eye movement (NREM) sleep were compared. In an entire night analysis prolonged-release melatonin did not affect SWA, whereas temazepam and zolpidem significantly reduced SWA compared with placebo. Temazepam significantly reduced SWA compared with prolonged-release melatonin. Prolonged-release melatonin only reduced SWA during the first third of the night compared with placebo. These data show that the effects of prolonged-release melatonin on the nocturnal sleep EEG are minor and are different from those of temazepam and zolpidem; this is likely due to the different mechanisms of action of the medications. PMID- 25922425 TI - The reinforcing effects of ethanol within the nucleus accumbens shell involve activation of local GABA and serotonin receptors. AB - Ethanol is reinforcing within the nucleus accumbens shell (NACsh), but the underlying mechanisms remain unclear. Ethanol can potentiate the function of the GABAA, GABAB, and serotonin-3 (5-HT3) receptors. Therefore, the current study tested the hypothesis that activation of these receptors would be involved in the reinforcing effects of ethanol in the NACsh. An intracranial self-administration (ICSA) procedure was used to assess the reinforcing effects of ethanol in the NACsh of alcohol preferring (P) rats. The ICSA consisted of seven sessions: four sessions to establish 150 mg% ethanol self-infusion into the NACsh; sessions 5 and 6 with co-infusion of ethanol plus one concentration of the GABAA antagonist bicuculline (10 or 100 uM), the GABAB antagonist SCH 50911 (50, 75 or 100 uM), or the 5-HT3 receptor antagonist zacopride (10 or 100 uM); and session 7 with 150 mg% ethanol alone. All groups self-infused ethanol into the NACsh and readily discriminated the active from inactive lever during the acquisition sessions. Co infusion of 100 uM, but not 10 uM, bicuculline or zacopride significantly decreased active responses during sessions 5 and 6. Co-infusion of 75 uM, but not 50 or 100 uM, SCH 50911 significantly attenuated responses for ethanol. Overall, the results suggest that the reinforcing effects of ethanol in the NACsh may be modulated by activation of local GABAA, GABAB and 5-HT3 receptors. PMID- 25922427 TI - Regulation of the pharmaceutical industry: promoting health or protecting wealth? PMID- 25922429 TI - Gene Expression Signatures Predictive of Bevacizumab/Erlotinib Therapeutic Benefit in Advanced Nonsquamous Non-Small Cell Lung Cancer Patients (SAKK 19/05 trial). AB - PURPOSE: We aimed to identify gene expression signatures associated with angiogenesis and hypoxia pathways with predictive value for treatment response to bevacizumab/erlotinib (BE) of nonsquamous advanced non-small cell lung cancer (NSCLC) patients. EXPERIMENTAL DESIGN: Whole-genome gene expression profiling was performed on 42 biopsy samples (from SAKK 19/05 trial) using Affymetrix exon arrays, and associations with the following endpoints: time-to-progression (TTP) under therapy, tumor-shrinkage (TS), and overall survival (OS) were investigated. Next, we performed gene set enrichment analyses using genes associated with the angiogenic process and hypoxia response to evaluate their predictive value for patients' outcome. RESULTS: Our analysis revealed that both the angiogenic and hypoxia response signatures were enriched within the genes predictive of BE response, TS, and OS. Higher gene expression levels (GEL) of the 10-gene angiogenesis-associated signature and lower levels of the 10-gene hypoxia response signature predicted improved TTP under BE, 7.1 months versus 2.1 months for low versus high-risk patients (P = 0.005), and median TTP 6.9 months versus 2.9 months (P = 0.016), respectively. The hypoxia response signature associated with higher TS at 12 weeks and improved OS (17.8 months vs. 9.9 months for low vs. high-risk patients, P = 0.001). CONCLUSIONS: We were able to identify gene expression signatures derived from the angiogenesis and hypoxia response pathways with predictive value for clinical outcome in advanced nonsquamous NSCLC patients. This could lead to the identification of clinically relevant biomarkers, which will allow for selecting the subset of patients who benefit from the treatment and predict drug response. PMID- 25922441 TI - Detection of IGF-1 protein variants by use of LC-MS with high-resolution accurate mass in routine clinical analysis. PMID- 25922428 TI - Myeloid-Derived Suppressor Cells as an Immune Parameter in Patients with Concurrent Sunitinib and Stereotactic Body Radiotherapy. AB - PURPOSE: The clinical effects of sunitinib on human myeloid-derived suppressor cell (MDSC) subsets and correlation of the T-cell-mediated immune responses and clinical outcomes in patients with oligometastases treated by stereotactic body radiotherapy (SBRT) have been evaluated. EXPERIMENTAL DESIGN: The numbers of granulocytic and monocytic MDSC subsets, effector T cells, and regulatory T cells in the peripheral blood were evaluated pre- and post-sunitinib treatment and concurrent with SBRT. Correlations between MDSC, Treg, and T-cell responses and clinical outcomes were analyzed. RESULTS: Patients with oligometastases of various cancer types had elevated granulocytic MDSC and certain subsets of monocytic MDSC population. Sunitinib treatment resulted in a significant reduction in monocytic MDSC, phosphorylated STAT3, and arginase levels in monocytic MDSC (CD33(+)CD14(+)CD16(+)), and an increase in T-cell proliferative activity in cancer patients. Interestingly, the effects of sunitinib on reducing the accumulation and immune-suppressive function of MDSC were significantly correlated with Treg reduction, in responders but not in nonresponding patients. SBRT synergized the therapeutic effects of sunitinib, especially as related to decreased numbers of monocytic MDSC, Treg, and B cells, and augmented Tbet expression in primary CD4 and CD8 T cells. These effects were not observed in patients receiving radiation therapy alone. Most interestingly, the responders, defined by sunitinib-mediated reduction in CD33(+)CD11b(+) myeloid cell populations, tend to exhibit improved progression-free survival and cause specific survival. CONCLUSIONS: Sunitinib treatment increased the efficacy of SBRT in patients with oligometastases by reversing MDSC and Treg-mediated immune suppression and may enhance cancer immune therapy to prevent tumor recurrence post-SBRT. PMID- 25922443 TI - Massively parallel ("next-generation") DNA sequencing. PMID- 25922442 TI - 24,25-Dihydroxyvitamin d3 and vitamin D status of community-dwelling black and white Americans. AB - BACKGROUND: 24,25-Dihydroxyvitamin D [24,25(OH)2D] is a metabolite of 25 hydroxyvitamin D (25D). Blacks frequently have low total 25D without manifestations of vitamin D deficiency, suggesting that total serum 25D may incorrectly reflect vitamin D status in different racial groups. The ratio of serum 24,25(OH)2D to 25D [vitamin D metabolite ratio (VMR)] represents a new candidate biomarker for vitamin D status. METHODS: We measured 24,25(OH)2D3 and 25D3 by mass spectrometry in a random community cohort of black (n = 212) and white (n = 164) Americans to evaluate VMR as a marker for vitamin D status. We measured parathyroid hormone concentrations by immunoassay to compare VMR and 25D3 against a physiological indicator of vitamin D deficiency. RESULTS: Serum 24,25(OH)2D3 strongly correlated with 25D3 in both black and white study participants (r = 0.90, P < 0.001 and r = 0.86, P < 0.001 respectively). Blacks had lower mean 25D3 than whites [17.0 (7.8) vs 27.5 (11.3) ng/mL; 42.4 (19.5) vs 68.6 (28.2) nmol/L, P < 0.001] and lower mean 24,25(OH)2D3 [2.1 (1.3) vs 3.6 (2.0) ng/mL; 5.1 (3.1) vs 8.7 (4.8) nmol/L, P < 0.001]. In contrast to total 25D3 concentrations, mean VMR values were similar in blacks and whites [11.9 (4.0) vs 12.5 (3.4), P = 0.16, respectively] and were negatively correlated with parathyroid hormone concentrations in both races (rs = -0.26, P < 0.001, and rs = -0.25, P < 0.001, respectively). CONCLUSIONS: Our results provide further evidence that measurement of total 25D for assessment of vitamin D status in patients of African descent deserves reevaluation and suggest that alternative measures such as VMR should be considered. PMID- 25922444 TI - Advance statements in the new Victorian Mental Health Act. AB - OBJECTIVE: There is growing recognition of the utility of advance statements in the area of mental health. The definition of advance statements and procedure for making and varying advance statements under the Victorian legislation is described. The implications for psychiatrists, mental health tribunals and the process should the psychiatrist vary their decision from that made in the advance statement are discussed. CONCLUSION: Advance statements being enshrined in legislation is another step in the direction of recovery-oriented service provision for persons with mental illness. The challenge for services will be to develop systems and processes that promote increased uptake of these instruments to empower persons with mental illness to participate in their treatment. PMID- 25922445 TI - Daily living skills in individuals with autism spectrum disorder from 2 to 21 years of age. AB - Daily living skills (DLS), such as personal hygiene, meal preparation, and money management, are important to independent living. Research suggests that many individuals with autism spectrum disorder exhibit impairments in daily living skills relative to their cognitive skills. This study examined predictors of daily living skills attainment and trajectories of daily living skills in a longitudinal sample referred for possible autism spectrum disorder and followed from 2 to 21 years of age. Consistent with previous studies, participants with autism spectrum disorder and nonspectrum diagnoses showed continual development of daily living skills throughout childhood and adolescence. Early childhood nonverbal mental age was the strongest predictor of daily living skills attainment for both diagnostic groups. Group-based modeling suggested two distinct trajectories of daily living skills development for participants with autism spectrum disorder. Skill levels for both groups of young adults with autism spectrum disorder remained considerably below age level expectations. Whereas the "High-DLS" group gained approximately 12 years in daily living skills from T2 to T21, the "Low-DLS" group's daily living skills improved 3-4 years over the 16- to 19-year study period. Nonverbal mental age, receptive language, and social-communication impairment at 2 years predicted High- versus Low-DLS group membership. Receiving greater than 20 h of parent-implemented intervention before age 3 was also associated with daily living skills trajectory. Results suggest that daily living skills should be a focus of treatment plans for individuals with autism spectrum disorder, particularly adolescents transitioning to young adulthood. PMID- 25922446 TI - A Review on Ethnobotanical and Therapeutic Uses of Fenugreek (Trigonella foenum graceum L). AB - Fenugreek with the scientific name of Trigonella foenum-graceum L and with leaves consisting of 3 small obovate to oblong leaflets is an annual herbaceous plant of the Fabaceae family. It is native to the eastern Mediterranean but is cultivated worldwide. This plant has medicinal alkaloids, steroid compounds, and sapogenins and many uses have been mentioned for this plant in traditional medicine. This plant has been used to ease childbirth, to aid digestion, and as a general tonic to improve metabolism. Trigonelline is considered as the most important metabolite of fenugreek, which is very effective in treating diabetes and decreasing blood cholesterol. Diaszhenin is another important compound in seeds of this plant, which is used in producing medicinal steroids like contraceptive pills. Many studies have been performed on the therapeutic effects and identification of chemical compounds of this plant. In this article, the most important biological effects and reported compounds about fenugreek seed are reviewed and its therapeutic applications are investigated. PMID- 25922447 TI - Fundamental questions in need of answers. PMID- 25922448 TI - The use of patient-reported outcomes after routine arthroplasty: beyond the whys and ifs. AB - The limitations and benefits of patient-reported outcome measures, in defining the merits of arthroplasty surgery, are discussed. PMID- 25922449 TI - Silver nanoparticles and their orthopaedic applications. AB - Implant-associated infection is a major source of morbidity in orthopaedic surgery. There has been extensive research into the development of materials that prevent biofilm formation, and hence, reduce the risk of infection. Silver nanoparticle technology is receiving much interest in the field of orthopaedics for its antimicrobial properties, and the results of studies to date are encouraging. Antimicrobial effects have been seen when silver nanoparticles are used in trauma implants, tumour prostheses, bone cement, and also when combined with hydroxyapatite coatings. Although there are promising results with in vitro and in vivo studies, the number of clinical studies remains small. Future studies will be required to explore further the possible side effects associated with silver nanoparticles, to ensure their use in an effective and biocompatible manner. Here we present a review of the current literature relating to the production of nanosilver for medical use, and its orthopaedic applications. PMID- 25922450 TI - Meniscal allograft transplantation: rationale for treatment. AB - The anatomy and microstructure of the menisci allow the effective distribution of load across the knee. Meniscectomy alters the biomechanical environment and is a potent risk factor for osteoarthritis. Despite a trend towards meniscus preserving surgery, many tears are irreparable, and many repairs fail. Meniscal allograft transplantation has principally been carried out for pain in patients who have had a meniscectomy. Numerous case series have reported a significant improvement in patient-reported outcomes after surgery, but randomised controlled trials have not been undertaken. It is scientifically plausible that meniscal allograft transplantation is protective of cartilage, but this has not been established clinically to date. PMID- 25922451 TI - A randomised trial comparing a short and a standard-length metaphyseal engaging cementless femoral stem using radiostereometric analysis. AB - This was a randomised controlled trial studying the safety of a new short metaphyseal fixation (SMF) stem. We hypothesised that it would have similar early clinical results and micromovement to those of a standard-length tapered Synergy metaphyseal fixation stem. Using radiostereometric analysis (RSA) we compared the two stems in 43 patients. A short metaphyseal fixation stem was used in 22 patients and a Synergy stem in 21 patients. No difference was found in the clinical outcomes pre- or post-operatively between groups. RSA showed no significant differences two years post-operatively in mean micromovement between the two stems (except for varus/valgus tilt at p = 0.05) (subsidence 0.94 mm (SD 1.71) vs 0.32 mm (SD 0.45), p = 0.66; rotation 0.96 degrees (SD 1.49) vs 1.41 degrees (SD 2.95), p = 0.88; and total migration 1.09 mm (SD 1.74) vs 0.73 mm (SD 0.72), p = 0.51). A few stems (four SMF and three Synergy) had initial migration > 1.0 mm but stabilised by three to six months, with the exception of one SMF stem which required revision three years post-operatively. For most stems, total micromovement was very low at two years (subsidence < 0.5 mm, rotation < 1.0 degrees , total migration < 0.5 mm), which was consistent with osseous ingrowth. The small sample makes it difficult to confirm the universal applicability of or elucidate the potential contraindications to the use of this particular new design of stem. PMID- 25922452 TI - The difference between the radiographic and the operative angle of inclination of the acetabular component in total hip arthroplasty: use of a digital protractor and the circumference of the hip to improve orientation. AB - A high radiographic inclination angle (RI) contributes to accelerated wear and has been associated with dislocation after total hip arthroplasty (THA). With freehand positioning of the acetabular component there is a lack of accuracy, with a trend towards a high radiographic inclination angle. The aim of this study was to investigate whether the use of a digital protractor to measure the operative inclination angle (OI) could improve the positioning of the acetabular component in relation to a 'safe zone'. We measured the radiographic inclination angles of 200 consecutive uncemented primary THAs. In the first 100 the component was introduced freehand and in the second 100 a digital protractor was used to measure the operative inclination angle. The mean difference between the operative and the radiographic inclination angles (?RI-OI) in the second cohort was 12.3 degrees (3.8 degrees to 19.8 degrees ). There was a strong correlation between the circumference of the hip and ?RI-OI. The number of RI outliers was significantly reduced in the protractor group (p = 0.002). Adjusting the OI, using a digital protractor and taking into account the circumference of the patient's hip, improves the RI significantly (p < 0.001) and does not require additional operating time. PMID- 25922453 TI - The reliability and accuracy of measuring anteversion of the acetabular component on plain anteroposterior and lateral radiographs after total hip arthroplasty. AB - There is no single standardised method of measuring the orientation of the acetabular component on plain radiographs after total hip arthroplasty. We assessed the reliability and accuracy of three methods of assessing anteversion of the acetabular component for 551 THAs using the PolyWare software and the methods of Liaw et al, and of Woo and Morrey. All measurements of the three methods had excellent intra- and inter-observer reliability. The values of the PolyWare software, which determines version of the acetabular component by edge detection were regarded as the reference standard. Although the PolyWare software and the method of Liaw et al were similarly precise, the method of Woo and Morrey was significantly less accurate (p < 0.001). The method of Liaw et al seemed to be more accurate than that of Woo and Morrey when compared with the measurements using the PolyWare software. If the qualified lateral radiograph was selected, anteversion measured using the method of Woo and Morrey was considered to be relatively reliable. PMID- 25922454 TI - A prospective comparative study of cementless total hip arthroplasty and hip resurfacing in patients under the age of 55 years: a ten-year follow-up. AB - The aim of this study was to evaluate the ten-year clinical and functional outcome of hip resurfacing and to compare it with that of cementless hip arthroplasty in patients under the age of 55 years. Between 1999 and 2002, 80 patients were enrolled into the study: 24 were randomised (11 to hip resurfacing, 13 to total hip arthroplasty), 18 refused hip resurfacing and chose cementless total hip arthroplasty with a 32 mm bearing, and 38 insisted on resurfacing. The mean follow-up for all patients was 12.1 years (10 to 14). Patients were assessed clinically and radiologically at one year, five years and ten years. Outcome measures included EuroQol EQ5D, Oxford, Harris hip, University of California Los Angeles and University College Hospital functional scores. No differences were seen between the two groups in the Oxford or Harris hip scores or in the quality of life scores. Despite a similar aspiration to activity pre-operatively, a higher proportion of patients with a hip resurfacing were running and involved in sport and heavy manual labour after ten years. We found significantly higher function scores in patients who had undergone hip resurfacing than in those with a cementless hip arthroplasty at ten years. This suggests a functional advantage for hip resurfacing. There were no other attendant problems. PMID- 25922455 TI - The prevalence of acetabular labral tears and associated pathology in a young asymptomatic population. AB - Acetabular labral tears and associated intra-articular pathology of the hip have been recognised as a source of symptoms. However, it is now appreciated that there is a relatively high prevalence of asymptomatic labral tears. In this study, 70 young asymptomatic adult volunteers with a mean age of 26 years (19 to 41) were recruited and underwent three tesla non-arthrographic MR scans. There were 47 women (67.1%) and 23 men (32.9%). Labral tears were found in 27 volunteers (38.6%); these were an isolated finding in 16 (22.9%) and were associated with other intra-articular pathology in the remaining 11 (15.7%) volunteers. Furthermore, five (7.1%) had intra-articular pathology without an associated labral tear. Given the high prevalence of labral pathology in the asymptomatic population, it is important to confirm that a patient's symptoms are due to the demonstrated abnormalities when considering surgery. PMID- 25922456 TI - Sustained five-year benefit of autologous matrix-induced chondrogenesis for femoral acetabular impingement-induced chondral lesions compared with microfracture treatment. AB - The repair of chondral lesions associated with femoroacetabular impingement requires specific treatment in addition to that of the impingement. In this single-centre retrospective analysis of a consecutive series of patients we compared treatment with microfracture (MFx) with a technique of enhanced microfracture autologous matrix-induced chondrogenesis (AMIC). Acetabular grade III and IV chondral lesions measuring between 2 cm(2) and 8 cm(2) in 147 patients were treated by MFx in 77 and AMIC in 70. The outcome was assessed using the modified Harris hip score at six months and one, two, three, four and five years post-operatively. The outcome in both groups was significantly improved at six months and one year post-operatively. During the subsequent four years the outcome in the MFx group slowly deteriorated, whereas that in the AMIC group remained stable. Six patients in the MFx group subsequently required total hip arthroplasty, compared with none in the AMIC group We conclude that the short term clinical outcome improves in patients with acetabular chondral damage following both MFx and AMIC. However, the AMIC group had better and more durable improvement, particularly in patients with large (>= 4 cm(2)) lesions. PMID- 25922458 TI - No statistically significant kinematic difference found between a cruciate retaining and posterior-stabilised Triathlon knee arthroplasty: a laboratory study involving eight cadavers examining soft-tissue laxity. AB - The aim of this study was to compare the maximum laxity conferred by the cruciate retaining (CR) and posterior-stabilised (PS) Triathlon single-radius total knee arthroplasty (TKA) for anterior drawer, varus-valgus opening and rotation in eight cadaver knees through a defined arc of flexion (0o to 110o). The null hypothesis was that the limits of laxity of CR- and PS-TKAs are not significantly different. The investigation was undertaken in eight loaded cadaver knees undergoing subjective stress testing using a measurement rig. Firstly the native knee was tested prior to preparation for CR-TKA and subsequently for PS-TKA implantation. Surgical navigation was used to track maximal displacements/rotations at 0o, 30o, 60o, 90o and 110 degrees of flexion. Mixed effects modelling was used to define the behaviour of the TKAs. The laxity measured for the CR- and PS-TKAs revealed no statistically significant differences over the studied flexion arc for the two versions of TKA. Compared with the native knee both TKAs exhibited slightly increased anterior drawer and decreased varus-valgus and internal-external roational laxities. We believe further study is required to define the clinical states for which the additional constraint offered by a PS-TKA implant may be beneficial. PMID- 25922457 TI - Reducing the risk of nerve injury during Bernese periacetabular osteotomy: a cadaveric study. AB - The modified Smith-Petersen and Kocher-Langenbeck approaches were used to expose the lateral cutaneous nerve of the thigh and the femoral, obturator and sciatic nerves in order to study the risk of injury to these structures during the dissection, osteotomy, and acetabular reorientation stages of a Bernese peri acetabular osteotomy. Injury of the lateral cutaneous nerve of thigh was less likely to occur if an osteotomy of the anterior superior iliac spine had been carried out before exposing the hip. The obturator nerve was likely to be injured during unprotected osteotomy of the pubis if the far cortex was penetrated by > 5 mm. This could be avoided by inclining the osteotome 45 degrees medially and performing the osteotomy at least 2 cm medial to the iliopectineal eminence. The sciatic nerve could be injured during the first and last stages of the osteotomy if the osteotome perforated the lateral cortex of ischium and the ilio-ischial junction by > 10 mm. The femoral nerve could be stretched or entrapped during osteotomy of the pubis if there was significant rotational or linear displacement of the acetabulum. Anterior or medial displacement of < 2 cm and lateral tilt (retroversion) of < 30 degrees were safe margins. The combination of retroversion and anterior displacement could increase tension on the nerve. Strict observation of anatomical details, proper handling of the osteotomes and careful manipulation of the acetabular fragment reduce the neurological complications of Bernese peri-acetabular osteotomy. PMID- 25922459 TI - Septic single-stage knee arthrodesis after failed total knee arthroplasty using a cemented coupled nail. AB - Knee arthrodesis is a potential salvage procedure for limb preservation after failure of total knee arthroplasty (TKA) due to infection. In this study, we evaluated the outcome of single-stage knee arthrodesis using an intramedullary cemented coupled nail without bone-on-bone fusion after failed and infected TKA with extensor mechanism deficiency. Between 2002 and 2012, 27 patients (ten female, 17 male; mean age 68.8 years; 52 to 87) were treated with septic single stage exchange. Mean follow-up duration was 67.1months (24 to 143, n = 27) (minimum follow-up 24 months) and for patients with a minimum follow-up of five years 104.9 (65 to 143,; n = 13). A subjective patient evaluation (Short Form (SF)-36) was obtained, in addition to the Visual Analogue Scale (VAS). The mean VAS score was 1.44 (SD 1.48). At final follow-up, four patients had recurrent infections after arthrodesis (14.8%). Of these, three patients were treated with a one-stage arthrodesis nail exchange; one of the three patients had an aseptic loosening with a third single-stage exchange, and one patient underwent knee amputation for uncontrolled sepsis at 108 months. All patients, including the amputee, indicated that they would choose arthrodesis again. Data indicate that a single-stage knee arthrodesis offers an acceptable salvage procedure after failed and infected TKA. PMID- 25922460 TI - Surgical outcomes of hip and knee arthroplasties for primary osteoarthritis in patients with Alzheimer's disease: a nationwide registry-based case-controlled study. AB - We compared the length of hospitalisation, rate of infection, dislocation of the hip and revision, and mortality following primary hip and knee arthroplasty for osteoarthritis in patients with Alzheimer's disease (n = 1064) and a matched control group (n = 3192). The data were collected from nationwide Finnish health registers. Patients with Alzheimer's disease had a longer peri-operative hospitalisation (median 13 days vs eight days, p < 0.001) and an increased risk for hip revision with a hazard ratio (HR) of 1.76 (95% confidence interval (CI) 1.03 to 3.00). Dislocation was the leading indication for revision. There was no difference in the rates of infection, dislocation of the hip, knee revision and short-term mortality. In long-term follow-up, patients with Alzheimer's disease had a higher mortality (HR 1.43; 95% CI 1.22 to 1.70), and only one third survived ten years post-operatively. Increased age and comorbidity were associated with longer peri-operative hospitalisation in patients with Alzheimer's disease. PMID- 25922461 TI - Evaluation of the foot and ankle outcome score in patients with osteoarthritis of the ankle. AB - The foot and ankle outcome score (FAOS) has been evaluated for many conditions of the foot and ankle. We evaluated its construct validity in 136 patients with osteoarthritis of the ankle, its content validity in 37 patients and its responsiveness in 39. Data were collected prospectively from the registry of patients at our institution. All FAOS subscales were rated relevant by patients. The Pain, Activities of Daily Living, and Quality of Life subscales showed good correlation with the Physical Component score of the Short-Form-12v2. All subscales except Symptoms were responsive to change after surgery. We concluded that the FAOS is a weak instrument for evaluating osteoarthritis of the ankle. However, some of the FAOS subscales have relative strengths that allow for its limited use while we continue to seek other satisfactory outcome instruments. PMID- 25922462 TI - Mid- to long-term outcome of 96 corrective hindfoot fusions in 84 patients with rigid flatfoot deformity. AB - Talonavicular and subtalar joint fusion through a medial incision (modified triple arthrodesis) has become an increasingly popular technique for treating symptomatic flatfoot deformity caused by posterior tibial tendon dysfunction. The purpose of this study was to look at its clinical and radiological mid- to long term outcomes, including the rates of recurrent flatfoot deformity, nonunion and avascular necrosis of the dome of the talus. A total of 84 patients (96 feet) with a symptomatic rigid flatfoot deformity caused by posterior tibial tendon dysfunction were treated using a modified triple arthrodesis. The mean age of the patients was 66 years (35 to 85) and the mean follow-up was 4.7 years (1 to 8.3). Both clinical and radiological outcomes were analysed retrospectively. In 86 of the 95 feet (90.5%) for which radiographs were available, there was no loss of correction at final follow-up. In all, 14 feet (14.7%) needed secondary surgery, six for nonunion, two for avascular necrosis, five for progression of the flatfoot deformity and tibiotalar arthritis and one because of symptomatic overcorrection. The mean American Orthopaedic Foot and Ankle Society Hindfoot score (AOFAS score) at final follow-up was 67 (between 16 and 100) and the mean visual analogue score for pain 2.4 points (between 0 and 10). In conclusion, modified triple arthrodesis provides reliable correction of deformity and a good clinical outcome at mid- to long-term follow-up, with nonunion as the most frequent complication. Avascular necrosis of the talus is a rare but serious complication of this technique. PMID- 25922463 TI - Intermittent pneumatic compression reduces the risk of deep vein thrombosis during post-operative lower limb immobilisation: a prospective randomised trial of acute ruptures of the Achilles tendon. AB - Deep vein thrombosis is a common complication of immobilising the lower limb after surgery. We hypothesised that intermittent pneumatic compression (IPC) therapy in outpatients who had undergone surgical repair of acute ruptures of the Achilles tendon could reduce the incidence of this problem. A total of 150 patients who had undergone surgical repair of the Achilles tendon were randomised to either treatment with IPC for six hours per day (n = 74) under an orthosis or treatment as usual (n = 74) in a plaster cast without IPC. At two weeks post operatively, the incidence of deep vein thrombosis was assessed using blinded, double-reported compression duplex ultrasound. At this point, IPC was discontinued and all patients were immobilised in an orthosis for a further four weeks. At six weeks post-operatively, a second compression duplex ultrasound scan was performed. At two weeks, the incidence of deep vein thrombosis was 21% in the treated group and 37% in the control group (p = 0.042). Age over 39 years was found to be a strong risk factor for deep vein thrombosis (odds ratio (OR) = 4.84, 95% confidence interval (CI) 2.14 to 10.96). Treatment with IPC, corrected for age differences between groups, reduced the risk of deep vein thrombosis at the two-week point (OR = 2.60; 95% CI 1.15 to 5.91; p =0.022). At six weeks, the incidence of deep vein thrombosis was 52% in the treated group and 48% in the control group (OR 0.94, 95% CI 0.49 to 1.83). IPC appears to be an effective method of reducing the risk of deep vein thrombosis in the early stages of post operative immobilisation of outpatients. Further research is necessary to elucidate whether it can confer similar benefits over longer periods of immobilisation and in a more heterogeneous group of patients. PMID- 25922464 TI - Mid-term clinical results of a modern convertible total elbow arthroplasty. AB - Unlinked, linked and convertible total elbow arthroplasties (TEAs) are currently available. This study is the first to report the clinical results of the convertible Latitude TEA. This was a retrospective study of a consecutive cohort of 63 patients (69 primary TEAs) with a mean age of 60 years (23 to 87). Between 2006 and 2008 a total of 19 men and 50 women underwent surgery. The mean follow up was 43 months (8 to 84). The range of movement, function and pain all improved six months post-operatively and either continued to improve slightly or reached a plateau thereafter. The complication rate is similar to that reported for other TEA systems. No loosening was seen. Remarkable is the disengagement of the radial head component in 13 TEAs (31%) with a radial head component implanted. Implantation of both the linked and the unlinked versions of the Latitude TEA results in improvement of function and decreased pain, and shows high patient satisfaction at mid-term follow-up. PMID- 25922465 TI - General versus spinal anaesthesia for patients aged 70 years and older with a fracture of the hip. AB - The aim of this study was to compare the operating time, length of stay (LOS), adverse events and rate of re-admission for elderly patients with a fracture of the hip treated using either general or spinal anaesthesia. Patients aged >= 70 years who underwent surgery for a fracture of the hip between 2010 and 2012 were identified from the American College of Surgeons National Surgical Quality Improvement Program (ACS-NSQIP) database. Of the 9842 patients who met the inclusion criteria, 7253 (73.7%) were treated with general anaesthesia and 2589 (26.3%) with spinal anaesthesia. On propensity-adjusted multivariate analysis, general anaesthesia was associated with slightly increased operating time (+5 minutes, 95% confidence interval (CI) +4 to +6, p < 0.001) and post-operative time in the operating room (+5 minutes, 95% CI +2 to +8, p < 0.001) compared with spinal anaesthesia. General anaesthesia was associated with a shorter LOS (hazard ratio (HR) 1.28, 95% CI 1.22 to 1.34, p < 0.001). Any adverse event (odds ratio (OR) 1.21, 95% CI 1.10 to 1.32, p < 0.001), thromboembolic events (OR 1.90, 95% CI 1.24 to 2.89, p = 0.003), any minor adverse event (OR 1.19, 95% CI 1.09 to 1.32, p < 0.001), and blood transfusion (OR 1.34, 95% CI 1.22 to 1.49, p < 0.001) were associated with general anaesthesia. General anaesthesia was associated with decreased rates of urinary tract infection (OR 0.73, 95% CI 0.62 to 0.87, p < 0.001). There was no clear overall advantage of one type of anaesthesia over the other, and surgeons should be aware of the specific risks and benefits associated with each type. PMID- 25922466 TI - Unstable paediatric pelvic injuries: the patho-anatomical patterns of pelvic ring failure and the role of avulsion of the iliac apophysis. AB - Unstable pelvic injuries in young children with an immature pelvis have different modes of failure from those in adolescents and adults. We describe the pathoanatomy of unstable pelvic injuries in these children, and the incidence of associated avulsion of the iliac apophysis and fracture of the ipsilateral fifth lumbar transverse process (L5-TP). We retrospectively reviewed the medical records of 33 children with Tile types B and C pelvic injuries admitted between 2007 and 2014; their mean age was 12.6 years (2 to 18) and 12 had an immature pelvis. Those with an immature pelvis commonly sustained symphyseal injuries anteriorly with diastasis, rather than the fractures of the pubic rami seen in adolescents. Posteriorly, transsacral fractures were more commonly encountered in mature children, whereas sacroiliac dislocations and fracture-dislocations were seen in both age groups. Avulsion of the iliac apophysis was identified in eight children, all of whom had an immature pelvis with an intact ipsilateral L5-TP. Young children with an immature pelvis are more susceptible to pubic symphysis and sacroiliac diastasis, whereas bony failures are more common in adolescents. Unstable pelvic injuries in young children are commonly associated with avulsion of the iliac apophysis, particularly with displaced SI joint dislocation and an intact ipsilateral L5-TP. PMID- 25922467 TI - Are two different projections of the inlet view necessary for the percutaneous placement of iliosacral screws? AB - We hypothesised that the anterior and posterior walls of the body of the first sacral vertebra could be visualised with two different angles of inlet view, owing to the conical shape of the sacrum. Six dry male cadavers with complete pelvic rings and eight dry sacrums with K-wires were used to study the effect of canting (angling the C-arm) the fluoroscope towards the head in 5 degrees increments from 10 degrees to 55 degrees . Fluoroscopic images were taken in each position. Anterior and posterior angles of inclination were measured between the upper sacrum and the vertical line on the lateral view. Three authors separately selected the clearest image for overlapping anterior cortices and the upper sacral canal in the cadaveric models. The dry bone and K-wire models were scored by the authors, being sure to check whether the K-wire was in or out. In the dry bone models the mean score of the relevant inlet position of the anterior or posterior inclination was 8.875 (standard deviation (sd) 0.35), compared with the inlet position of the opposite inclination of -5.75 (sd 4.59). We found that two different inlet views should be used separately to evaluate the borders of the body of the sacrum using anterior and posterior inclination angles of the sacrum, during placement of iliosacral screws. PMID- 25922468 TI - Can local recurrence of a sacral chordoma be treated by further surgery? AB - The purpose of this study was to evaluate the long-term outcome of patients with a sacral chordoma and the surgical management of locally recurrent disease. Between October 1990 and August 2013 we operated on 54 consecutive patients with a sacral chordoma. There were 34 men and 20 women with a mean age of 60 years (25 to 86). The mean maximum diameter of the tumour was 9.3 cm (3 to 20). The mean follow-up was 7.8 years (2 months to 23.4 years). The disease-specific survival was 82% at five years, 57% at ten years and 45% at 15 years. The local recurrence free survival was 49% at five years, 37% at ten years and 20% at 15 years. Local recurrence occurred in 30 patients (56%) at a mean of 3.8 years (3 months to 13 years) post-operatively. Survival after the treatment of recurrence was 89% at two years, 56% at five years and 19% at ten years. Of nine patients who had complete resection of a recurrence, one died after 72 months and eight remain disease-free. Incomplete resection of recurrent disease resulted in a survival of 54% at two years and 36% at five years. For 12 patients with a local recurrence who were treated palliatively, survival was 81% at two years and 31% at five years. A wide margin of resection gave the best chance of long-term survival and complete resection of local recurrence the best chance of control of disease. PMID- 25922469 TI - Is prematurity a risk factor for developmental dysplasia of the hip? : a prospective study. AB - The aim of this prospective study was to investigate prematurity as a risk factor for developmental dysplasia of the hip (DDH). The hips of 221 infants (88 female, 133 male, mean age 31.11 weeks; standard deviation (sd) 2.51) who were born in the 34th week of gestation or earlier, and those of 246 infants (118 female, 128 male, mean age 40.22 weeks; sd 0.36) who were born in the 40th week of gestation, none of whom had risk factors for DDH, were compared using physical examination and ultrasound according to the technique of Graf, within one week, after the correction of gestational age to the 40th week after birth or one week since birth, respectively. Both hips of all infants were included in the study. Ortolani's and Barlow's tests and restricted abduction were accepted as positive findings on examination. There was a statistically significant difference between pre- and full-term infants, according to the incidence of mature and immature hips (p < 0.001). The difference in the proportion of infants with an alpha angle < 60 degrees between the two groups was statistically significant (p < 0.001). The incidence of pathological dysplasia (alpha angle < 50 o) was not significantly different in the two groups (p = 1.000). The Barlow sign was present in two (0.5%) pre-term infants and in 14 (2.8%) full-term infants. These results suggests that prematurity is not a predisposing factor for DDH. PMID- 25922470 TI - Non-melanoma Skin Cancer in Canada Chapter 5: Management of Squamous Cell Carcinoma. AB - BACKGROUND: Squamous cell carcinoma (SCC) is the second-most common form of non melanoma skin cancer (NMSC). OBJECTIVE: To provide guidance to Canadian health care practitioners regarding management of SCCs. METHODS: Literature searches and development of graded recommendations were carried out as discussed in the accompanying introduction (chapter 1 of the NMSC guidelines). RESULTS: SCCs are sometimes confined to the epidermis, but they can also invade nearby tissues and, in some cases, metastasize to neighbouring lymph nodes or other organs. This chapter discusses the natural history, staging, prognosis, and management of SCC- a tumour type that is less common but typically more aggressive than BCC. For this reason, margin control is strongly preferred in treating SCCs. CONCLUSIONS: Although approaches such as cryosurgery and radiation therapy may be considered for some patients, surgical excision--sometimes coupled with radiation--remains the cornerstone of SCC management. Patients with high-risk SCC may also be considered for referral to an appropriate multidisciplinary clinic. PMID- 25922471 TI - Fifty moves a year: is there an association between joint physical custody and psychosomatic problems in children? AB - BACKGROUND: In many Western countries, an increasing number of children with separated parents have joint physical custody, that is, live equally much in their parent's respective homes. In Sweden, joint physical custody is particularly common and concerns between 30% and 40% of the children with separated parents. It has been hypothesised that the frequent moves and lack of stability in parenting may be stressful for these children. METHODS: We used data from a national classroom survey of all sixth and ninth grade students in Sweden (N=147839) to investigate the association between children's psychosomatic problems and living arrangements. Children in joint physical custody were compared with those living only or mostly with one parent and in nuclear families. We conducted sex-specific linear regression analyses for z-transformed sum scores of psychosomatic problems and adjusted for age, country of origin as well as children's satisfaction with material resources and relationships to parents. Clustering by school was accounted for by using a two-level random intercept model. RESULTS: Children in joint physical custody suffered from less psychosomatic problems than those living mostly or only with one parent but reported more symptoms than those in nuclear families. Satisfaction with their material resources and parent-child relationships was associated with children's psychosomatic health but could not explain the differences between children in the different living arrangements. CONCLUSIONS: Children with non-cohabitant parents experience more psychosomatic problems than those in nuclear families. Those in joint physical custody do however report better psychosomatic health than children living mostly or only with one parent. Longitudinal studies with information on family factors before and after the separation are needed to inform policy of children's postseparation living arrangements. PMID- 25922472 TI - Thalassaemia and risk of cancer: a population-based cohort study. AB - BACKGROUND: Studies that have investigated the epidemiological relationship between thalassaemia and cancers are scarce. Therefore, we conducted a longitudinal nationwide cohort study to determine whether patients with thalassaemia are at an increased risk of cancer. METHODS: We investigated the incidence and risk of cancer in 2655 patients diagnosed with thalassaemia between 1998 and 2010 by using data from the Taiwan Longitudinal Health Insurance Database. The comparison cohort comprised 10 620 people from the general population without thalassaemia. The follow-up period extended from the diagnostic date for thalassaemia to the date of a cancer diagnosis, censoring or 31 December 2011. We used Cox proportional hazard regression models to analyse the risks of cancer. RESULTS: The incidences of cancer were 3.96 and 2.60/1000 person-years for the thalassaemia and comparison cohorts, respectively. The overall incidence of cancer was 52% higher in the thalassaemia cohort than in the comparison cohort, with an adjusted HR (aHR) of 1.54 (95% CI 1.15 to 2.07). Patients with thalassaemia had a considerably higher risk of haematological malignancy (aHR=5.32, 95% CI 2.18 to 13.0) and abdominal cancer (aHR=1.96, 95% CI 1.22 to 3.15) than did the comparison cohort. Furthermore, patients with thalassaemia with transfusion exhibited a 9.31-fold risk for developing haematological malignancy and a 9.12-fold risk for developing abdominal cancer compared with those who did not receive transfusion. CONCLUSIONS: This nationwide retrospective cohort study indicates that patients with thalassaemia carried substantial risks of haematological malignancy and abdominal cancer compared with those of the general population. PMID- 25922473 TI - Carers' needs in advanced heart failure: A systematic narrative review. AB - BACKGROUND: Informal caregivers play a pivotal role in the care of people living with advanced heart failure, however, carers' needs have not been clearly identified. AIM: The aim of this study is to explore the evidence on palliative care needs expressed by carers of people with heart failure. METHODS: Five electronic databases (CINAHL PLUS, EMBASE, Medline, PsychInfo and SCOPUS) were systematically searched and articles published January 2003-June 2014 with a qualitative methodology focusing on the palliative care needs of carers of people living with heart failure were included. RESULTS: Data was systematically extracted from 15 articles using an inductive methodology for the thematic analysis. Ten broad categories emerged from which three key areas of support needs were identified; psychosocial support to maintain a sense of normalcy; support with daily living; support navigating the healthcare system. The articles were predominantly published in the UK and USA with a total sample size across all articles of 270, the majority of which were older female spouses. Results included a combination of carers, patients and professionals thoughts, however data was extracted for carers only. CONCLUSIONS: Carer's needs initiate when the patient is diagnosed and continue throughout the disease into bereavement. These needs are continuously prioritised and reprioritised depending on the patients' medical stability. A holistic approach is needed to support these carers, incorporating heart failure and palliative care specialties. Further research is warranted to explore different methods of delivering support and information and to evaluate whether these reduce carer burden. PMID- 25922474 TI - Feasibility of Day Surgery in Patients With Breast Conservation and Sentinel Node Biopsy: A Randomized Controlled Trial. AB - BACKGROUND AND AIMS: The aim of this study was to analyze feasibility of day surgery in breast cancer patients with breast conserving surgery and sentinel node biopsy. MATERIAL AND METHODS: The study was a randomized controlled trial comparing day surgery with one night hospital stay in breast cancer patients with breast conserving surgery and sentinel node biopsy. A total of 40 patients with ?3-cm tumor and clinically N0 were randomized to one night stay group and 38 patients to day surgery group. Within discharge, patients and their relatives were given questionnaires in order to evaluate their experience regarding the duration of hospital stay. RESULTS: Randomized groups were similar regarding patient age and tumor stage. A total of 18 (47%) day surgery group patients were discharged the same day. The most common reason for overnight hospital stay was axillary clearance, 9 (24%). None of the patients in the day surgery group, but 2 patients in the overnight hospital stay group had re-operation due to complications. Perception and preference results were analyzed both according to randomization and actual treatment groups. Patients in both groups had rather similar experiences on the first postoperative day. Also, spouse's or relative's perception after discharge was similar in both groups. CONCLUSION: Day surgery was well received by the patients and their relatives. Day surgery appears as feasible in patients with breast conservation and sentinel node biopsy. PMID- 25922475 TI - Responses of International Migrant Women to Abuse Associated With Pregnancy. AB - The current study aims to identify what newly arrived migrant women do, in the early months post-birth, to respond to abuse associated with pregnancy. Textual data from 59 migrant women were analyzed thematically to identify common responses to abuses. The most common response was to physically leave their countries of origin and move to Canada, or to move out of the shared dwelling. Other responses included taking legal action, remaining silent, reporting the abuse, seeking counseling, isolating themselves, and supporting anger management for the abuser. These results enhance our understanding of the decisions, including inaction, made by migrant women. PMID- 25922476 TI - Beyond the dyad: an assessment of sexual assault prevention education focused on social determinants of sexual assault among college students. AB - Sexual assault is prevalent in the United States, particularly among college women. Prevention programs are implemented to combat assault, yet rates have not changed for five decades. A course designed to deconstruct contextualized factors contributing to assault was developed as an alternative prevention initiative. The current study assessed the effectiveness of the course compared with a traditional program via in-depth interviews with students. Findings indicated that students in the course were more likely to acknowledge underlying determinants of sexual assault and articulate how such behaviors could lead to assault. The course could be an effective approach to sexual assault prevention education. PMID- 25922477 TI - Predicting the Accuracy of a Decision: A Neural Mechanism of Confidence. AB - The quantitative study of decision-making has traditionally rested on three key behavioral measures: accuracy, response time, and confidence. Of these, confidence--defined as the degree of belief, prior to feedback, that a decision is correct-is least well understood at the level of neural mechanism, although recent years have seen a surge in interest in the topic among theoretical and systems neuroscientists. Here we review some of these developments and highlight a particular candidate mechanism for assigning confidence in a perceptual decision. The mechanism is appealing because it is rooted in the same decision making framework--bounded accumulation of evidence--that successfully explains accuracy and reaction time in many tasks, and it is validated by neurophysiology and microstimulation experiments. PMID- 25922478 TI - Dynamic Hippocampal Circuits Support Learning- and Memory-Guided Behaviors. AB - The ability to learn spatial relationships and to modify stored representations when the world changes is essential for survival. In recent years, our understanding of the neural activity that underlie these learning and memory processes has improved considerably, in large part to an increase in the number of studies that use electrophysiological recordings as animals learn about their environments. In this review, we summarize some key findings from our laboratory, with a focus on recent discoveries that indicate that the rat hippocampus supports learning and decision-making behaviors via dynamic and smooth transitions in neural representation, internal processing state, and coupling with related brain structures. PMID- 25922479 TI - Frost trends and their estimated impact on yield in the Australian wheatbelt. AB - Radiant spring frosts occurring during reproductive developmental stages can result in catastrophic yield loss for wheat producers. To better understand the spatial and temporal variability of frost, the occurrence and impact of frost events on rain-fed wheat production was estimated across the Australian wheatbelt for 1957-2013 using a 0.05 degrees gridded weather data set. Simulated yield outcomes at 60 key locations were compared with those for virtual genotypes with different levels of frost tolerance. Over the last six decades, more frost events, later last frost day, and a significant increase in frost impact on yield were found in certain regions of the Australian wheatbelt, in particular in the South-East and West. Increasing trends in frost-related yield losses were simulated in regions where no significant trend of frost occurrence was observed, due to higher mean temperatures accelerating crop development and causing sensitive post-heading stages to occur earlier, during the frost risk period. Simulations indicated that with frost-tolerant lines the mean national yield could be improved by up to 20% through (i) reduced frost damage (~10% improvement) and (ii) the ability to use earlier sowing dates (adding a further 10% improvement). In the simulations, genotypes with an improved frost tolerance to temperatures 1 degrees C lower than the current 0 degrees C reference provided substantial benefit in most cropping regions, while greater tolerance (to 3 degrees C lower temperatures) brought further benefits in the East. The results indicate that breeding for improved reproductive frost tolerance should remain a priority for the Australian wheat industry, despite warming climates. PMID- 25922480 TI - Boron deficiency inhibits root cell elongation via an ethylene/auxin/ROS dependent pathway in Arabidopsis seedlings. AB - One of the earliest symptoms of boron (B) deficiency is the inhibition of root elongation which can reasonably be attributed to the damaging effects of B deprivation on cell wall integrity. It is shown here that exposure of wild-type Arabidopsis thaliana seedlings to B deficiency for 4h led to a drastic inhibition of root cell length in the transition between the elongation and differentiation zones. To investigate the possible mediation of ethylene, auxin, and reactive oxygen species (ROS) in the effect of B deficiency on root cell elongation, B deficiency was applied together with aminoethoxyvinylglycine (AVG, a chemical inhibitor of ethylene biosynthesis), silver ions (Ag(+), an antagonist of ethylene perception), alpha-(phenylethyl-2-oxo)-indoleacetic acid (PEO-IAA, a synthetic antagonist of TIR1 receptor function), and diphenylene iodonium (DPI, an inhibitor of ROS production). Interestingly, all these chemicals partially or fully restored cell elongation in B-deficient roots. To further explore the possible role of ethylene and auxin in the inhibition of root cell elongation under B deficiency, a genetic approach was performed by using Arabidopsis mutants defective in the ethylene (ein2-1) or auxin (eir1-4 and aux1-22) response. Root cell elongation in these mutants was less sensitive to B-deficient treatment than that in wild-type plants. Altogether, these results demonstrated that a signalling pathway involving ethylene, auxin, and ROS participates in the reduction of root cell elongation when Arabidopsis seedlings are subjected to B deficiency. A similar signalling process has been described to reduce root elongation rapidly under various types of cell wall stress which supports the idea that this signalling pathway is triggered by the impaired cell wall integrity caused by B deficiency. PMID- 25922481 TI - RNA processing in auxin and cytokinin pathways. AB - Auxin and cytokinin belong to the 'magnificent seven' plant hormones, having tightly interconnected pathways leading to common as well as opposing effects on plant morphogenesis. Tremendous progress in the past years has yielded a broad understanding of their signalling, metabolism, regulatory pathways, transcriptional networks, and signalling cross-talk. One of the rapidly expanding areas of auxin and cytokinin research concerns their RNA regulatory networks. This review summarizes current knowledge about post-transcriptional gene silencing, the role of non-coding RNAs, the regulation of translation, and alternative splicing of auxin- and cytokinin-related genes. In addition, the role of tRNA-bound cytokinins is also discussed. We highlight the most recent publications dealing with this topic and underline the role of RNA processing in auxin- and cytokinin-mediated growth and development. PMID- 25922482 TI - Imaging with the fluorogenic dye Basic Fuchsin reveals subcellular patterning and ecotype variation of lignification in Brachypodium distachyon. AB - Lignin is a complex polyphenolic heteropolymer that is abundant in the secondary cell walls of plants and functions in growth and defence. It is also a major barrier to the deconstruction of plant biomass for bioenergy production, but the spatiotemporal details of how lignin is deposited in actively lignifying tissues and the precise relationships between wall lignification in different cell types and developmental events, such as flowering, are incompletely understood. Here, the lignin-detecting fluorogenic dye, Basic Fuchsin, was adapted to enable comparative fluorescence-based imaging of lignin in the basal internodes of three Brachypodium distachyon ecotypes that display divergent flowering times. It was found that the extent and intensity of Basic Fuchsin fluorescence increase over time in the Bd21-3 ecotype, that Basic Fuchsin staining is more widespread and intense in 4-week-old Bd21-3 and Adi-10 basal internodes than in Bd1-1 internodes, and that Basic Fuchsin staining reveals subcellular patterns of lignin in vascular and interfascicular fibre cell walls. Basic Fuchsin fluorescence did not correlate with lignin quantification by acetyl bromide analysis, indicating that whole-plant and subcellular lignin analyses provide distinct information about the extent and patterns of lignification in B. distachyon. Finally, it was found that flowering time correlated with a transient increase in total lignin, but did not correlate strongly with the patterning of stem lignification, suggesting that additional developmental pathways might regulate secondary wall formation in grasses. This study provides a new comparative tool for imaging lignin in plants and helps inform our views of how lignification proceeds in grasses. PMID- 25922483 TI - OsAGSW1, an ABC1-like kinase gene, is involved in the regulation of grain size and weight in rice. AB - Grain shape and weight are two determining agronomic traits of rice yield. ABC1 (Activity of bc1 complex) is a newly found atypical kinase in plants. Here, we report on an ABC1 protein kinase gene, OsAGSW1 (ABC1-like kinase related to Grain size and Weight). Expression of OsAGSW1-GFP in rice revealed that OsAGSW1 is localized to the chloroplasts in rice. Analysis of OsAGSW1 promoter::beta glucuronidase transgenic rice indicated that this gene was highly expressed in vascular bundles in shoot, hull and caryopsis. Furthermore, OsAGSW1-RNAi and overexpressed transgenic rice lines were generated. Stable transgenic lines overexpressing OsAGSW1 exhibited a phenotype with a significant increase in grain size, grain weight, grain filling rate and 1000-grain weight compared with the wild-type and RNAi transgenic plants. Microscopy analysis showed that spikelet hulls just before heading were different in the OsAGSW1-overexpressed plants compared with wild-type and OsAGSW1 RNAi rice. Further cytological analysis showed that the number of external parenchyma cells in rice hulls of OsAGSW1 overexpressed plants increased, leading to wider and longer spikelet hulls than those of the wild-type and OsAGSW1-RNAi plants. The vascular cross-sectional area in lemma, carpopodium and ovules also strikingly increased and area of both xylem and phloem were enlarged in the OsAGSW1-overexpressed plants. Thus, our results demonstrated that OsAGSW1 plays an important role in seed shape and size of rice by regulating the number of external parenchyma cells and the development of vascular bundles, providing a new insight into the functions of ABC1 genes in plants. PMID- 25922484 TI - SRC2-1 is required in PcINF1-induced pepper immunity by acting as an interacting partner of PcINF1. AB - Elicitins are elicitors that can trigger hypersensitive cell death in most Nicotiana spp., but their underlying molecular mechanism is not well understood. The gene Phytophthora capsici INF1 (PcINF1) coding for an elicitin from P. capsici was characterized in this study. Transient overexpression of PcINF1 triggered cell death in pepper (Capsicum annuum L.) and was accompanied by upregulation of the hypersensitive response marker, Hypersensitive Induced Reaction gene 1 (HIR1), and the pathogenesis-related genes SAR82, DEF1, BPR1, and PO2. A putative PcINF1-interacting protein, SRC2-1, was isolated from a pepper cDNA library by yeast two-hybrid screening and was observed to target the plasma membrane. The interaction between PcINF1 and SRC2-1 was confirmed by bimolecular fluorescence complementation and co-immunoprecipitation. Simultaneous transient overexpression of SRC2-1 and PcINF1 in pepper plants triggered intensive cell death, whereas silencing of SRC2-1 by virus-induced gene silencing blocked the cell death induction of PcINF1 and increased the susceptibility of pepper plants to P. capsici infection. Additionally, membrane targeting of the PcINF1-SRC2-1 complex was required for cell death induction. The C2 domain of SRC2-1 was crucial for SRC2-1 plasma membrane targeting and the PcINF1-SRC2-1 interaction. These results suggest that SRC2-1 interacts with PcINF1 and is required in PcINF1 induced pepper immunity. PMID- 25922485 TI - The role of nodes in arsenic storage and distribution in rice. AB - Knowledge of arsenic (As) accumulation in rice (Oryza sativa L.) is important for minimizing As transfer to the food chain. The aim of this study was to investigate the role of rice nodes in As storage and distribution. Synchrotron MUX-ray fluorescence (MU-XRF) was used to map As distribution in the top node and internode of a lsi2 mutant defective in silicon/arsenite efflux carrier and its wild-type (WT) grown in soil. Lsi2 expression in different tissues during grain filling was investigated by quantitative RT-PCR. Arsenite or dimethylarsinic acid (DMA) was supplied to excised panicles to investigate the roles of Lsi2 and phytochelatins (PC) in As distribution. MU-XRF mapping revealed As storage in the phloem of different vascular bundles in the top node and internode. Soil-grown plants of lsi2 had markedly decreased As accumulation in the phloem compared with the WT. Lsi2 was strongly expressed, not only in the roots but also in the nodes. When excised panicles were exposed to As(III), the lsi2 mutant distributed more As to the node and flag leaf but less As to the grain compared with the WT, while there was no significant difference in DMA distribution. Inhibition of PC synthesis by l-buthionine-sulphoximine decreased As(III) deposition in the top node but increased As accumulation in the grain and flag leaf. The results suggest that rice nodes serve as a filter restricting As(III) distribution to the grain. Furthermore, Lsi2 plays a role in As(III) distribution in rice nodes and phytochelatins are important compounds for As(III) storage in the nodes. PMID- 25922486 TI - Enhanced acetyl-CoA production is associated with increased triglyceride accumulation in the green alga Chlorella desiccata. AB - Triglycerides (TAGs) from microalgae can be utilized as food supplements and for biodiesel production, but little is known about the regulation of their biosynthesis. This work aimed to test the relationship between acetyl-CoA (Ac CoA) levels and TAG biosynthesis in green algae under nitrogen deprivation. A novel, highly sensitive liquid chromatography mass spectrometry (LC-MS/MS) technique enabled us to determine the levels of Ac-CoA, malonyl-CoA, and unacetylated (free) CoA in green microalgae. A comparative study of three algal species that differ in TAG accumulation levels shows that during N starvation, Ac CoA levels rapidly rise, preceding TAG accumulation in all tested species. The levels of Ac-CoA in the high TAG accumulator Chlorella desiccata exceed the levels in the moderate TAG accumulators Dunaliella tertiolecta and Chlamydomonas reinhardtii. Similarly, malonyl-CoA and free CoA levels also increase, but to lower extents. Calculated cellular concentrations of Ac-CoA are far lower than reported K mAc-CoA values of plastidic Ac-CoA carboxylase (ptACCase) in plants. Transcript level analysis of plastidic pyruvate dehydrogenase (ptPDH), the major chloroplastic Ac-CoA producer, revealed rapid induction in parallel with Ac-CoA accumulation in C. desiccata, but not in D. tertiolecta or C. reinhardtii. It is proposed that the capacity to accumulate high TAG levels in green algae critically depends on their ability to divert carbon flow towards Ac-CoA. This requires elevation of the chloroplastic CoA pool level and enhancement of Ac-CoA biosynthesis. These conclusions may have important implications for future genetic manipulation to enhance TAG biosynthesis in green algae. PMID- 25922487 TI - Identification of a molecular dialogue between developing seeds of Medicago truncatula and seedborne xanthomonads. AB - Plant pathogenic bacteria disseminate and survive mainly in association with seeds. This study addresses whether seeds are passive carriers or engage a molecular dialogue with pathogens during their development. We developed two pathosystems using Medicago truncatula with Xanthomonas alfalfae subsp. alfalfae (Xaa), the natural Medicago sp. pathogen and Xanthomonas campestris pv. campestris (Xcc), a Brassicaceae pathogen. Three days after flower inoculation, the transcriptome of Xcc-infected pods showed activation of an innate immune response that was strongly limited in Xcc mutated in the type three secretion system, demonstrating an incompatible interaction of Xcc with the reproductive structures. In contrast, the presence of Xaa did not result in an activation of defence genes. Transcriptome profiling during development of infected seeds exhibited time-dependent and differential responses to Xcc and Xaa. Gene network analysis revealed that the transcriptome of Xcc-infected seeds was mainly affected during seed filling whereas that of Xaa-infected seeds responded during late maturation. The Xcc-infected seed transcriptome exhibited an activation of defence response and a repression of targeted seed maturation pathways. Fifty-one percent of putative ABSCISIC ACID INSENSITIVE3 targets were deregulated by Xcc, including oleosin, cupin, legumin and chlorophyll degradation genes. At maturity, these seeds displayed decreased weight and increased chlorophyll content. In contrast, these traits were not affected by Xaa infection. These findings demonstrate the existence of a complex molecular dialogue between xanthomonads and developing seeds and provides insights into a previously unexplored trade-off between seed development and pathogen defence. PMID- 25922489 TI - How endogenous plant cell-wall degradation mechanisms can help achieve higher efficiency in saccharification of biomass. AB - Cell-wall recalcitrance to hydrolysis still represents one of the major bottlenecks for second-generation bioethanol production. This occurs despite the development of pre-treatments, the prospect of new enzymes, and the production of transgenic plants with less-recalcitrant cell walls. Recalcitrance, which is the intrinsic resistance to breakdown imposed by polymer assembly, is the result of inherent limitations in its three domains. These consist of: (i) porosity, associated with a pectin matrix impairing trafficking through the wall; (ii) the glycomic code, which refers to the fine-structural emergent complexity of cell wall polymers that are unique to cells, tissues, and species; and (iii) cellulose crystallinity, which refers to the organization in micro- and/or macrofibrils. One way to circumvent recalcitrance could be by following cell-wall hydrolysis strategies underlying plant endogenous mechanisms that are optimized to precisely modify cell walls in planta. Thus, the cell-wall degradation that occurs during fruit ripening, abscission, storage cell-wall mobilization, and aerenchyma formation are reviewed in order to highlight how plants deal with recalcitrance and which are the routes to couple prospective enzymes and cocktail designs with cell-wall features. The manipulation of key enzyme levels in planta can help achieving biologically pre-treated walls (i.e. less recalcitrant) before plants are harvested for bioethanol production. This may be helpful in decreasing the costs associated with producing bioethanol from biomass. PMID- 25922488 TI - Mannans and endo-beta-mannanases (MAN) in Brachypodium distachyon: expression profiling and possible role of the BdMAN genes during coleorhiza-limited seed germination. AB - Immunolocalization of mannans in the seeds of Brachypodium distachyon reveals the presence of these polysaccharides in the root embryo and in the coleorhiza in the early stages of germination (12h), decreasing thereafter to the point of being hardly detected at 27h. Concurrently, the activity of endo-beta-mannanases (MANs; EC 3.2.1.78) that catalyse the hydrolysis of beta-1,4 bonds in mannan polymers, increases as germination progresses. The MAN gene family is represented by six members in the Brachypodium genome, and their expression has been explored in different organs and especially in germinating seeds. Transcripts of BdMAN2, BdMAN4 and BdMAN6 accumulate in embryos, with a maximum at 24-30h, and are detected in the coleorhiza and in the root by in situ hybridization analyses, before root protrusion (germination sensu stricto). BdMAN4 is not only present in the embryo root and coleorhiza, but is abundant in the de-embryonated (endosperm) imbibed seeds, while BdMAN2 and BdMAN6 are faintly expressed in endosperm during post-germination (36-42h). BdMAN4 and BdMAN6 transcripts are detected in the aleurone layer. These data indicate that BdMAN2, BdMAN4 and BdMAN6 are important for germination sensu stricto and that BdMAN4 and BdMAN6 may also influence reserve mobilization. Whether the coleorhiza in monocots and the micropylar endosperm in eudicots have similar functions, is discussed. PMID- 25922490 TI - Auxin-binding pocket of ABP1 is crucial for its gain-of-function cellular and developmental roles. AB - The plant hormone auxin is a key regulator of plant growth and development. Auxin levels are sensed and interpreted by distinct receptor systems that activate a broad range of cellular responses. The Auxin-Binding Protein1 (ABP1) that has been identified based on its ability to bind auxin with high affinity is a prime candidate for the extracellular receptor responsible for mediating a range of auxin effects, in particular, the fast non-transcriptional ones. Contradictory genetic studies suggested prominent or no importance of ABP1 in many developmental processes. However, how crucial the role of auxin binding to ABP1 is for its functions has not been addressed. Here, we show that the auxin-binding pocket of ABP1 is essential for its gain-of-function cellular and developmental roles. In total, 16 different abp1 mutants were prepared that possessed substitutions in the metal core or in the hydrophobic amino acids of the auxin binding pocket as well as neutral mutations. Their analysis revealed that an intact auxin-binding pocket is a prerequisite for ABP1 to activate downstream components of the ABP1 signalling pathway, such as Rho of Plants (ROPs) and to mediate the clathrin association with membranes for endocytosis regulation. In planta analyses demonstrated the importance of the auxin binding pocket for all known ABP1-mediated postembryonic developmental processes, including morphology of leaf epidermal cells, root growth and root meristem activity, and vascular tissue differentiation. Taken together, these findings suggest that auxin binding to ABP1 is central to its function, supporting the role of ABP1 as auxin receptor. PMID- 25922491 TI - A rare SNP mutation in Brachytic2 moderately reduces plant height and increases yield potential in maize. AB - Plant height has long been an important agronomic trait in maize breeding. Many plant height QTLs have been reported, but few of these have been cloned. In this study, a major plant height QTL, qph1, was mapped to a 1.6kb interval in Brachytic2 (Br2) coding sequence on maize chromosome 1. A naturally occurring rare SNP in qph1, which resulted in an amino acid substitution, was validated as the causative mutation. QPH1 protein is located in the plasma membrane and polar auxin transport is impaired in the short near-isogenic line RIL88(qph1). Allelism testing showed that the SNP variant in qph1 reduces longitudinal cell number and decreases plant height by 20% in RIL88(qph1) compared to RIL88(QPH1), and is milder than known br2 mutant alleles. The effect of qph1 on plant height is significant and has no or a slight influence on yield in four F2 backgrounds and in six pairs of single-cross hybrids. Moreover, qph1 could reduce plant height when heterozygous, allowing it to be easily employed in maize breeding. Thus, a less-severe allele of a known dwarf mutant explains part of the quantitative variation for plant height and has great potential in maize improvement. PMID- 25922492 TI - Internal efficiency of nutrient utilization: what is it and how to measure it during vegetative plant growth? AB - Efficient use of the resources required by plants to sustain crop production is considered an important objective in agriculture. In this context, the idea of developing crops with an enhanced ability to utilize mineral nutrients already taken up by roots has been proposed. In recent years powerful tools that allow the association of phenotypic variation with high-resolution genetic maps of crop plants have also emerged. To take advantage of these tools, accurate methods are needed to estimate the internal efficiency of nutrient utilization (ENU) at the whole-plant level, which requires using suitable conceptual and experimental approaches. Here we highlight some inconsistencies in the definitions of ENU commonly used for ENU 'phenotyping' at the vegetative stage and suggest that it would be convenient to adopt a dynamic definition. The idea that ENU should provide information about the relationship between carbon and mineral nutrient economies mainly during the period under which growth is actually affected by low internal nutrient concentration is here advocated as a guide for the selection of adequate operational ENU formulae for the vegetative stage. The desirability of using experimental approaches that allow removal of the influence of nutrient acquisition efficiency on ENU estimations is highlighted. It is proposed that the use of simulation models could help refine the conclusions obtained through these experimental procedures. Some potential limitations in breeding for high ENU are also considered. PMID- 25922493 TI - Genome-wide association mapping of growth dynamics detects time-specific and general quantitative trait loci. AB - Growth is a complex trait determined by the interplay between many genes, some of which play a role at a specific moment during development whereas others play a more general role. To identify the genetic basis of growth, natural variation in Arabidopsis rosette growth was followed in 324 accessions by a combination of top view imaging, high-throughput image analysis, modelling of growth dynamics, and end-point fresh weight determination. Genome-wide association (GWA) mapping of the temporal growth data resulted in the detection of time-specific quantitative trait loci (QTLs), whereas mapping of model parameters resulted in another set of QTLs related to the whole growth curve. The positive correlation between projected leaf area (PLA) at different time points during the course of the experiment suggested the existence of general growth factors with a function in multiple developmental stages or with prolonged downstream effects. Many QTLs could not be identified when growth was evaluated only at a single time point. Eleven candidate genes were identified, which were annotated to be involved in the determination of cell number and size, seed germination, embryo development, developmental phase transition, or senescence. For eight of these, a mutant or overexpression phenotype related to growth has been reported, supporting the identification of true positives. In addition, the detection of QTLs without obvious candidate genes implies the annotation of novel functions for underlying genes. PMID- 25922495 TI - Regulation of correlative inhibition of axillary bud outgrowth by basal branches varies with growth stage in Trifolium repens. AB - In Trifolium repens the decline in bud outgrowth that occurs with distance from basal root systems is due to correlative inhibition by the first-formed basal branches. The apical and axillary buds on these basal branches are the source of the inhibitory effect, but their mode of action is unclear. Inhibition might occur via basal branches being a sink for xylem-transported branching stimulants or alternatively by providing a source of inhibitory signals, or by both mechanisms. To distinguish between these mechanisms, four experiments were conducted on plants varying in initial growth stage from 10 to 19 nodes along their main stems to determine any variation in the relative importance of the operative mechanisms of correlative inhibition. Inhibitory signal exported into the main stem, detected as a branching response to girdling of basal branches, was relatively more significant in smaller (initially with 10-15 nodes on the main stem) than in larger (>19 nodes on main stem) plants. This signal was shown not to involve auxin fluxes, and is unidentified. However, across all stages of growth, the predominant mechanism driving correlative inhibition was the action of axillary and apical buds of basal branches as sinks for the stimulatory signal. This study indicates that the relative importance of the mechanisms regulating bud outgrowth in T. repens varies with growth stage and that, during intermediate stages, regulation has some similarity to that in Pisum. PMID- 25922494 TI - Phosphorus and magnesium interactively modulate the elongation and directional growth of primary roots in Arabidopsis thaliana (L.) Heynh. AB - A balanced supply of essential nutrients is an important factor influencing root architecture in many plants, yet data related to the interactive effects of two nutrients on root growth are limited. Here, we investigated the interactive effect between phosphorus (P) and magnesium (Mg) on root growth of Arabidopsis grown in pH-buffered agar medium at different P and Mg levels. The results showed that elongation and deviation of primary roots were directly correlated with the amount of P added to the medium but could be modified by the Mg level, which was related to the root meristem activity and stem-cell division. High P enhanced while low P decreased the tip-focused fluorescence signal of auxin biosynthesis, transport, and redistribution during elongation of primary roots; these effects were greater under low Mg than under high Mg. The altered root growth in response to P and Mg supply was correlated with AUX1, PIN2, and PIN3 mRNA abundance and expression and the accumulation of the protein. Application of either auxin influx inhibitor or efflux inhibitor inhibited the elongation and increased the deviation angle of primary roots, and decreased auxin level in root tips. Furthermore, the auxin-transport mutants aux1-22 and eir1-1 displayed reduced root growth and increased the deviation angle. Our data suggest a profound effect of the combined supply of P and Mg on the development of root morphology in Arabidopsis through auxin signals that modulate the elongation and directional growth of primary root and the expression of root differentiation and development genes. PMID- 25922496 TI - Woman with hypomagnesemia and hypocalcemia. PMID- 25922499 TI - Pregnant woman with markedly increased iron binding capacity. PMID- 25922500 TI - Red serum and urine samples. PMID- 25922501 TI - A Day in the Life of Dr. Bean and How the NIH Is Wasting $20 Billion per Year. PMID- 25922502 TI - Art and science of painting attributions: bernard berenson. PMID- 25922503 TI - Mitochondrial crisis in cerebrovascular endothelial cells opens the blood-brain barrier. AB - BACKGROUND AND PURPOSE: The blood-brain barrier (BBB) is a selectively permeable cerebrovascular endothelial barrier that maintains homeostasis between the periphery and the central nervous system. BBB disruption is a consequence of ischemic stroke and BBB permeability can be altered by infection/inflammation, but the complex cellular and molecular changes that result in this BBB alteration need to be elucidated to determine mechanisms. METHODS: Infection mimic (lipopolysaccharide) challenge on infarct volume, BBB permeability, infiltrated neutrophils, and functional outcomes after murine transient middle cerebral artery occlusion in vivo; mitochondrial evaluation of cerebrovascular endothelial cells challenged by lipopolysaccharide in vitro; pharmacological inhibition of mitochondria on BBB permeability in vitro and in vivo; the effects of mitochondrial inhibitor on BBB permeability, infarct volume, and functional outcomes after transient middle cerebral artery occlusion. RESULTS: We report here that lipopolysaccharide worsens ischemic stroke outcome and increases BBB permeability after transient middle cerebral artery occlusion in mice. Furthermore, we elucidate a novel mechanism that compromised mitochondrial function accounts for increased BBB permeability as evidenced by: lipopolysaccharide-induced reductions in oxidative phosphorylation and subunit expression of respiratory chain complexes in cerebrovascular endothelial cells, a compromised BBB permeability induced by pharmacological inhibition of mitochondrial function in cerebrovascular endothelial cells in vitro and in an in vivo animal model, and worsened stroke outcomes in transient middle cerebral artery occlusion mice after inhibition of mitochondrial function. CONCLUSIONS: We concluded that mitochondria are key players in BBB permeability. These novel findings suggest a potential new therapeutic strategy for ischemic stroke by endothelial cell mitochondrial regulation. PMID- 25922504 TI - Ischemia in intracerebral hemorrhage is associated with leukoaraiosis and hematoma volume, not blood pressure reduction. AB - BACKGROUND AND PURPOSE: Diffusion-weighted imaging (DWI) lesions have been identified both inside and outside the perihematoma region. We tested the hypotheses that larger hematoma volumes and blood pressure reduction are associated with DWI lesions. METHODS: Hematoma and perihematoma edema volumes were measured using planimetric techniques in 117 intracerebral hemorrhage (ICH) patients who underwent DWI. Perihematoma and remote DWI lesion volumes were measured using apparent diffusion coefficient thresholds for moderate (<730*10( 6) mm/s) and severe (<550*10(-6) mm/s) ischemia. Acute blood pressure change over the first 24 hours was calculated. RESULTS: The median (interquartile range) time to magnetic resonance imaging was 2 (1-5) days. Median hematoma volume was 9.8 (2.6-23.0) mL, and median perihematoma edema volume was 7.0 (2.9-18.6) mL. A small portion of the perihematoma region contained tissue below the thresholds for moderate (8.0 [2.9-14.5]%) and severe ischemia (1.1 [0.3-3.5]%). Ischemic perihematoma tissue volumes were correlated with hematoma volumes (R=0.52, P<0.001), but not maximal systolic blood pressure drop at 24 hours (R=-0.09, P=0.38). Remote DWI lesions were found in 17 (14.5%) patients (mean volume=0.44+/ 0.3 mL). Patients with remote DWI lesions had higher rates of antiplatelet use (P=0.01), prior ICH (P=0.03), lobar ICH (0.04), and larger leukoaraiosis volumes (P=0.02). Maximal systolic blood pressure drop at 24 hours was similar in patients with (-20.5 [-55, -10] mm Hg) and without remote DWI lesions (-27 [-46, 13] mm Hg, P=0.96). CONCLUSIONS: Small DWI lesions within and outside the perihematoma region are common in primary ICH. Perihematoma DWI lesions were independently associated with larger hematoma volumes. Remote DWI lesions may be an epiphenomenon associated with the underlying microvascular pathogenesis. These data do not support a hemodynamic mechanism of ischemic injury after primary ICH. PMID- 25922505 TI - Hypertension and brain health: setting limits: National Institute of Neurological Disorders and Stroke organizational update. PMID- 25922507 TI - Clinical predictors of accurate prehospital stroke recognition. AB - BACKGROUND AND PURPOSE: Prehospital activation of in-hospital stroke response hastens treatment but depends on accurate emergency medical services (EMS) stroke recognition. We sought to measure EMS stroke recognition accuracy and identify clinical factors associated with correct stroke identification. METHODS: Using EMS and hospital records, we assembled a cohort of EMS-transported suspect, confirmed, or missed ischemic stroke or transient ischemic attack cases. The sensitivity and positive predictive value (PPV) for EMS stroke recognition were calculated using the hospital discharge diagnosis as the gold standard. We used multivariable logistic regression analysis to determine the association between Cincinnati Prehospital Stroke Scale use and EMS stroke recognition. RESULTS: During a 12-month period, 441 EMS-transported patients were enrolled; of which, 371 (84.1%) were EMS-suspected strokes and 70 (15.9%) were EMS-missed strokes. Overall, 264 cases (59.9%) were confirmed as either ischemic stroke (n=186) or transient ischemic attack (n=78). The sensitivity of EMS stroke recognition was 73.5% (95% confidence interval, 67.7-78.7), and PPV was 52.3% (95% confidence interval, 47.1-57.5). Sensitivity (84.7% versus 30.9%; P<0.0001) and PPV (56.2% versus 30.4%; P=0.0004) were higher among cases with Cincinnati Prehospital Stroke Scale documentation. In multivariate analysis, Cincinnati Prehospital Stroke Scale documentation was independently associated with EMS sensitivity (odds ratio, 12.0; 95% confidence interval, 5.7-25.5) and PPV (odds ratio, 2.5; 95% confidence interval, 1.3-4.7). CONCLUSIONS: EMS providers recognized 3 quarters of the patients with ischemic stroke and transient ischemic attack; however, half of EMS-suspected strokes were false positives. Documentation of a Cincinnati Prehospital Stroke Scale was associated with higher EMS stroke recognition sensitivity and PPV. PMID- 25922506 TI - Myeloperoxidase is increased in human cerebral aneurysms and increases formation and rupture of cerebral aneurysms in mice. AB - BACKGROUND AND PURPOSE: Cerebral aneurysm (CA) affects 3% of the population and is associated with hemodynamic stress and inflammation. Myeloperoxidase, a major oxidative enzyme associated with inflammation, is increased in patients with CA, but whether myeloperoxidase contributes to CA is not known. We tested the hypotheses that myeloperoxidase is increased within human CA and is critical for formation and rupture of CA in mice. METHODS: Blood was drawn from the lumen of CAs and femoral arteries of 25 patients who underwent endovascular coiling of CA, and plasma myeloperoxidase concentrations were measured with ELISA. Effects of endogenous myeloperoxidase on CA formation and rupture were studied in myeloperoxidase knockout mice and wild-type (WT) mice using an angiotensin II elastase induction model of CA. In addition, effects of myeloperoxidase on inflammatory gene expression in endothelial cells were analyzed. RESULTS: Plasma concentrations of myeloperoxidase were 2.7-fold higher within CA than in femoral arterial blood in patients with CA. myeloperoxidase-positive cells were increased in aneurysm tissue compared with superficial temporal artery of patients with CA. Incidence of aneurysms and subarachnoid hemorrhage was significantly lower in myeloperoxidase knockout than in WT mice. In cerebral arteries, proinflammatory molecules, including tumor necrosis factor-alpha, cyclooxygenase-2 (COX2), chemokine (C-X-C motif) ligand 1 (CXCL1), chemokine (C motif) ligand (XCL1), matrix metalloproteinase (MMP) 8, cluster of differentiation 68 (CD68), and matrix metalloproteinase 13, and leukocytes were increased, and alpha-smooth muscle actin was decreased, in WT but not in myeloperoxidase knockout mice after induction of CA. Myeloperoxidase per se increased expression of vascular cell adhesion molecule-1 and intercellular adhesion molecule-1 in endothelial cells. CONCLUSIONS: These findings suggest that myeloperoxidase may contribute importantly to formation and rupture of CA. PMID- 25922508 TI - Immediate Hemorrhagic Transformation After Intravenous Tissue-Type Plasminogen Activator Injection in 2 Cocaine Users. PMID- 25922509 TI - Chronic Elevation of Tumor Necrosis Factor-alpha Mediates the Impairment of Leptomeningeal Arteriogenesis in db/db Mice. AB - BACKGROUND AND PURPOSE: Leptomeningeal collateral growth is a key factor that defines the severity of ischemic stroke. Patients with stroke generally have vascular risk factors, such as diabetes mellitus; however, consensus is lacking on how diabetes mellitus affects leptomeningeal arteriogenesis. We investigate the influence of diabetes mellitus on the leptomeningeal arteriogenesis. METHODS: We measured the vessel diameter of the leptomeningeal anastomoses 14 days after the common carotid artery occlusion in db/db, db/+, and streptozotocin-induced hyperglycemic mice. In another set of these mice, we measured the infarct volume attributed to subsequent middle cerebral artery occlusion 14 days after the common carotid artery occlusion. Mac-2-positive cells on the dorsal brain surface and the mRNA expression of several macrophage-related factors in the cerebral cortex were examined. Finally, we tested whether the leptomeningeal arteriogenesis could be restored by pharmaceutical intervention in the db/db mice. RESULTS: Cerebral hypoperfusion led to significant ipsilateral leptomeningeal collateral growth in db/+ mice and streptozotocin-induced hyperglycemic mice. The collateral growth contributed to reduced infarct volume. In contrast, leptomeningeal arteriogenesis was impaired in the db/db mice. The number of Mac-2-positive cells was increased and tumor necrosis factor-alpha mRNA expression was induced after common carotid artery occlusion in the db/+ mice. However, these responses were not observed in the db/db mice. Administration of the tumor necrosis factor-alpha inhibitor etanercept before common carotid artery occlusion restored the hypoperfusion-induced leptomeningeal collateral growth in db/db mice. CONCLUSIONS: These results indicate that leptomeningeal arteriogenesis is impaired in db/db mice and that suppression of the tumor necrosis factor-alpha response to hypoperfusion is the major contributing factor. PMID- 25922510 TI - Cancer in young adults with ischemic stroke. AB - BACKGROUND AND PURPOSE: Cancer is a risk factor for ischemic stroke. Little is known about cancer among young adults with ischemic stroke. We studied the frequency of cancer and its association with long-term risk of death among young patients with first-ever ischemic stroke. METHODS: 1002 patients aged 15 to 49 years, registered in the Helsinki Young Stroke Registry, and with a median follow up of 10.0 years (interquartile range 6.5-13.8) after stroke were included. Historical and follow-up data were derived from the Finnish Care Register and Statistics Finland. Survival between groups was compared with the Kaplan-Meier life-table method, and Cox proportional hazard models were used to identify factors associated with mortality. RESULTS: One or more cancer diagnosis was made in 77 (7.7%) patients, of whom 39 (3.9%) had cancer diagnosed prestroke. During the poststroke follow-up, 41 (53.2%) of the cancer patients died. Median time from prestroke cancer to stroke was 4.9 (1.0-9.5) years and from stroke to poststroke cancer was 6.7 (2.7-10.9) years. Poststroke cancer was associated with age>40 years, heavy drinking, and cigarette smoking. The cumulative mortality was significantly higher among the cancer patients (68.6%, 95% confidence interval 52.0%-85.3%) compared with patients without cancer (19.7%, 95% confidence interval 16.3%-23.2%). Active cancer at index stroke, melanoma, and lung/respiratory tract cancer had the strongest independent association with death during the follow-up when adjusted for known poststroke mortality prognosticators. CONCLUSIONS: Cancer, and especially active cancer and no other apparent cause for stroke, is associated with unfavorable survival among young stroke patients. PMID- 25922511 TI - Letter by Rutten et al Regarding Article, "Cysteine-Sparing CADASIL Mutations in NOTCH3 Show Proaggregatory Properties In Vitro". PMID- 25922512 TI - Response to Letter Regarding Article, "Cysteine-Sparing CADASIL Mutations in NOTCH3 Show Proaggregatory Properties In Vitro". PMID- 25922513 TI - Impact of alcohol consumption on the outcome of ischemic stroke and thrombolysis: role of the hepatic clearance of tissue-type plasminogen activator. AB - BACKGROUND AND PURPOSE: Tissue-type plasminogen activator (tPA) is the only acute treatment for ischemic stroke. Unfortunately, the benefit of tPA-driven thrombolysis is not systematic, and understanding the reasons for this is mandatory. The balance between beneficial and detrimental effects of tPA might explain the limited overall efficiency of thrombolysis. Here, we investigated whether this balance could be influenced by excessive alcohol intake. METHODS: We used a murine model of thromboembolic stroke, coupled to an array of biochemical assays, near-infrared or magnetic resonance imaging scans, 2-photon microscopy, hydrodynamic transfections, and immunohistological techniques. RESULTS: We found that 6 weeks of alcohol consumption (10% in drinking water) worsens ischemic lesions and cancels the beneficial effects of tPA-induced thrombolysis. We accumulate in vivo and in vitro evidence showing that this aggravation is correlated with a decrease in lipoprotein receptor-related protein 1-mediated hepatic clearance of tPA in alcohol-exposed mice. CONCLUSIONS: An efficient liver driven clearance of tPA might influence the safety of thrombolysis after stroke. PMID- 25922514 TI - Recovery to Preinterventional Functioning, Return-to-Work, and Life Satisfaction After Treatment of Unruptured Aneurysms. AB - BACKGROUND AND PURPOSE: The eventual goal of preventive treatment of unruptured intracranial aneurysms is to increase the number of life years with high life satisfaction. Insight in the time with reduced functioning, working capacity, and life satisfaction after aneurysm treatment is pivotal to balance the pros and cons of preventive aneurysm occlusion. METHODS: We sent a questionnaire on time to-recovery to preintervention functioning and return-to-work and life satisfaction to patients treated for an unruptured aneurysm between 2000 and 2013. Changes in life satisfaction before treatment, during recovery, and at follow-up were assessed with Wilcoxon signed-rank tests. RESULTS: The questionnaire was sent to 159 patients of whom 110 (69%) responded. The mean follow-up time after aneurysm treatment was 6 years (SD 4). Fifty-four patients had endovascular and 56 had microsurgical occlusion. Complete recovery to preintervention functioning was reported by 81% (95% confidence interval [CI], 74 88) of patients, with a median time-to-recovery of 3 months (range 0-48). Complete work recovery was reported by 78% (95% CI, 66-87) of patients. The proportion of patients with high life satisfaction reduced from 76% (95% CI, 67 84) before treatment to 52% (95% CI, 43-61) during the period of recovery (P<0.01) and restored largely at long-term follow-up (67% [95% CI, 59-76], P=0.08). CONCLUSION: Life satisfaction is significantly reduced during the period of recovery after treatment of unruptured aneurysms. In the long-term, ~1 out of 5 patients reports incomplete recovery. These treatment effects should be kept in mind when considering preventive aneurysm treatment. Prospective studies are needed to better compare these losses in patients treated for unruptured aneurysms with those who had subarachnoid hemorrhage. PMID- 25922515 TI - The Fossil Calibration Database-A New Resource for Divergence Dating. AB - Fossils provide the principal basis for temporal calibrations, which are critical to the accuracy of divergence dating analyses. Translating fossil data into minimum and maximum bounds for calibrations is the most important-often least appreciated-step of divergence dating. Properly justified calibrations require the synthesis of phylogenetic, paleontological, and geological evidence and can be difficult for nonspecialists to formulate. The dynamic nature of the fossil record (e.g., new discoveries, taxonomic revisions, updates of global or local stratigraphy) requires that calibration data be updated continually lest they become obsolete. Here, we announce the Fossil Calibration Database (http://fossilcalibrations.org), a new open-access resource providing vetted fossil calibrations to the scientific community. Calibrations accessioned into this database are based on individual fossil specimens and follow best practices for phylogenetic justification and geochronological constraint. The associated Fossil Calibration Series, a calibration-themed publication series at Palaeontologia Electronica, will serve as a key pipeline for peer-reviewed calibrations to enter the database. PMID- 25922517 TI - MOZ and BMI1 play opposing roles during Hox gene activation in ES cells and in body segment identity specification in vivo. AB - Hox genes underlie the specification of body segment identity in the anterior posterior axis. They are activated during gastrulation and undergo a dynamic shift from a transcriptionally repressed to an active chromatin state in a sequence that reflects their chromosomal location. Nevertheless, the precise role of chromatin modifying complexes during the initial activation phase remains unclear. In the current study, we examined the role of chromatin regulators during Hox gene activation. Using embryonic stem cell lines lacking the transcriptional activator MOZ and the polycomb-family repressor BMI1, we showed that MOZ and BMI1, respectively, promoted and repressed Hox genes during the shift from the transcriptionally repressed to the active state. Strikingly however, MOZ but not BMI1 was required to regulate Hox mRNA levels after the initial activation phase. To determine the interaction of MOZ and BMI1 in vivo, we interrogated their role in regulating Hox genes and body segment identity using Moz;Bmi1 double deficient mice. We found that the homeotic transformations and shifts in Hox gene expression boundaries observed in single Moz and Bmi1 mutant mice were rescued to a wild type identity in Moz;Bmi1 double knockout animals. Together, our findings establish that MOZ and BMI1 play opposing roles during the onset of Hox gene expression in the ES cell model and during body segment identity specification in vivo. We propose that chromatin-modifying complexes have a previously unappreciated role during the initiation phase of Hox gene expression, which is critical for the correct specification of body segment identity. PMID- 25922518 TI - CD169+ macrophages are sufficient for priming of CTLs with specificities left out by cross-priming dendritic cells. AB - Dendritic cells (DCs) are considered the most potent antigen-presenting cells (APCs), which directly prime or cross-prime MHC I-restricted cytotoxic T cells (CTLs). However, recent evidence suggests the existence of other, as-yet unidentified APCs also able to prime T cells. To identify those APCs, we used adenoviral (rAd) vectors, which do not infect DCs but selectively accumulate in CD169(+) macrophages (MPs). In mice that lack DCs, infection of CD169(+) MPs was sufficient to prime CTLs specific for all epitopes tested. In contrast, CTL responses relying exclusively on cross-presenting DCs were biased to selected strong MHC I-binding peptides only. When both DCs and MPs were absent, no CTL responses could be elicited. Therefore, CD169(+) MPs can be considered APCs that significantly contribute to CTL responses. PMID- 25922519 TI - IRBIT regulates CaMKIIalpha activity and contributes to catecholamine homeostasis through tyrosine hydroxylase phosphorylation. AB - Inositol 1,4,5-trisphosphate receptor (IP3R) binding protein released with IP3 (IRBIT) contributes to various physiological events (electrolyte transport and fluid secretion, mRNA polyadenylation, and the maintenance of genomic integrity) through its interaction with multiple targets. However, little is known about the physiological role of IRBIT in the brain. Here we identified calcium calmodulin dependent kinase II alpha (CaMKIIalpha) as an IRBIT-interacting molecule in the central nervous system. IRBIT binds to and suppresses CaMKIIalpha kinase activity by inhibiting the binding of calmodulin to CaMKIIalpha. In addition, we show that mice lacking IRBIT present with elevated catecholamine levels, increased locomotor activity, and social abnormalities. The level of tyrosine hydroxylase (TH) phosphorylation by CaMKIIalpha, which affects TH activity, was significantly increased in the ventral tegmental area of IRBIT-deficient mice. We concluded that IRBIT suppresses CaMKIIalpha activity and contributes to catecholamine homeostasis through TH phosphorylation. PMID- 25922520 TI - Convergent evolution toward an improved growth rate and a reduced resistance range in Prochlorococcus strains resistant to phage. AB - Prochlorococcus is an abundant marine cyanobacterium that grows rapidly in the environment and contributes significantly to global primary production. This cyanobacterium coexists with many cyanophages in the oceans, likely aided by resistance to numerous co-occurring phages. Spontaneous resistance occurs frequently in Prochlorococcus and is often accompanied by a pleiotropic fitness cost manifested as either a reduced growth rate or enhanced infection by other phages. Here, we assessed the fate of a number of phage-resistant Prochlorococcus strains, focusing on those with a high fitness cost. We found that phage resistant strains continued evolving toward an improved growth rate and a narrower resistance range, resulting in lineages with phenotypes intermediate between those of ancestral susceptible wild-type and initial resistant substrains. Changes in growth rate and resistance range often occurred in independent events, leading to a decoupling of the selection pressures acting on these phenotypes. These changes were largely the result of additional, compensatory mutations in noncore genes located in genomic islands, although genetic reversions were also observed. Additionally, a mutator strain was identified. The similarity of the evolutionary pathway followed by multiple independent resistant cultures and clones suggests they undergo a predictable evolutionary pathway. This process serves to increase both genetic diversity and infection permutations in Prochlorococcus populations, further augmenting the complexity of the interaction network between Prochlorococcus and its phages in nature. Last, our findings provide an explanation for the apparent paradox of a multitude of resistant Prochlorococcus cells in nature that are growing close to their maximal intrinsic growth rates. PMID- 25922521 TI - Animal models for studying neural crest development: is the mouse different? AB - The neural crest is a uniquely vertebrate cell type and has been well studied in a number of model systems. Zebrafish, Xenopus and chick embryos largely show consistent requirements for specific genes in early steps of neural crest development. By contrast, knockouts of homologous genes in the mouse often do not exhibit comparable early neural crest phenotypes. In this Spotlight article, we discuss these species-specific differences, suggest possible explanations for the divergent phenotypes in mouse and urge the community to consider these issues and the need for further research in complementary systems. PMID- 25922523 TI - Intrinsic and extrinsic mechanisms regulating satellite cell function. AB - Muscle stem cells, termed satellite cells, are crucial for skeletal muscle growth and regeneration. In healthy adult muscle, satellite cells are quiescent but poised for activation. During muscle regeneration, activated satellite cells transiently re-enter the cell cycle to proliferate and subsequently exit the cell cycle to differentiate or self-renew. Recent studies have demonstrated that satellite cells are heterogeneous and that subpopulations of satellite stem cells are able to perform asymmetric divisions to generate myogenic progenitors or symmetric divisions to expand the satellite cell pool. Thus, a complex balance between extrinsic cues and intrinsic regulatory mechanisms is needed to tightly control satellite cell cycle progression and cell fate determination. Defects in satellite cell regulation or in their niche, as observed in degenerative conditions such as aging, can impair muscle regeneration. Here, we review recent discoveries of the intrinsic and extrinsic factors that regulate satellite cell behaviour in regenerating and degenerating muscles. PMID- 25922524 TI - Transcription factors COUP-TFI and COUP-TFII are required for the production of granule cells in the mouse olfactory bulb. AB - Neural stem cells (NSCs) persist in the adult mammalian subventricular zone (SVZ) of the lateral ventricle. Primary NSCs generate rapidly dividing intermediate progenitor cells, which in turn generate neuroblasts that migrate along the rostral migratory stream (RMS) to the olfactory bulb (OB). Here, we have examined the role of the COUP-TFI and COUP-TFII orphan nuclear receptor transcription factors in mouse OB interneuron development. We observed that COUP-TFI is expressed in a gradient of low rostral to high caudal within the postnatal SVZ neural stem/progenitor cells. COUP-TFI is also expressed in a large number of migrating neuroblasts in the SVZ and RMS, and in mature interneurons in the OB. By contrast, very few COUP-TFII-expressing (+) cells exist in the SVZ-RMS-OB pathway. Conditional inactivation of COUP-TFI resulted in downregulation of tyrosine hydroxylase expression in the OB periglomerular cells and upregulation of COUP-TFII expression in the SVZ, RMS and OB deep granule cell layer. In COUP TFI/COUP-TFII double conditional mutant SVZ, cell proliferation was increased through the upregulation of the proneural gene Ascl1. Furthermore, COUP-TFI/II deficient neuroblasts had impaired migration, resulting in ectopic accumulation of calretinin (CR)+ and NeuN+ cells, and an increase in apoptotic cell death in the SVZ. Finally, we found that most Pax6+ and a subset of CR+ granular cells were lost in the OB. Taken together, these results suggest that COUP-TFI/II coordinately regulate the proliferation, migration and survival of a subpopulation of Pax6+ and CR+ granule cells in the OB. PMID- 25922522 TI - Sensory hair cell development and regeneration: similarities and differences. AB - Sensory hair cells are mechanoreceptors of the auditory and vestibular systems and are crucial for hearing and balance. In adult mammals, auditory hair cells are unable to regenerate, and damage to these cells results in permanent hearing loss. By contrast, hair cells in the chick cochlea and the zebrafish lateral line are able to regenerate, prompting studies into the signaling pathways, morphogen gradients and transcription factors that regulate hair cell development and regeneration in various species. Here, we review these findings and discuss how various signaling pathways and factors function to modulate sensory hair cell development and regeneration. By comparing and contrasting development and regeneration, we also highlight the utility and limitations of using defined developmental cues to drive mammalian hair cell regeneration. PMID- 25922525 TI - Lin28 promotes the proliferative capacity of neural progenitor cells in brain development. AB - Neural progenitor cells (NPCs) have distinct proliferation capacities at different stages of brain development. Lin28 is an RNA-binding protein with two homologs in mice: Lin28a and Lin28b. Here we show that Lin28a/b are enriched in early NPCs and their expression declines during neural differentiation. Lin28a single-knockout mice show reduced NPC proliferation, enhanced cell cycle exit and a smaller brain, whereas mice lacking both Lin28a alleles and one Lin28b allele display similar but more severe phenotypes. Ectopic expression of Lin28a in mice results in increased NPC proliferation, NPC numbers and brain size. Mechanistically, Lin28a physically and functionally interacts with Imp1 (Igf2bp1) and regulates Igf2-mTOR signaling. The function of Lin28a/b in NPCs could be attributed, at least in part, to the regulation of their mRNA targets that encode Igf1r and Hmga2. Thus, Lin28a and Lin28b have overlapping functions in temporally regulating NPC proliferation during early brain development. PMID- 25922526 TI - Lineage tracing of neuromesodermal progenitors reveals novel Wnt-dependent roles in trunk progenitor cell maintenance and differentiation. AB - In the development of the vertebrate body plan, Wnt3a is thought to promote the formation of paraxial mesodermal progenitors (PMPs) of the trunk region while suppressing neural specification. Recent lineage-tracing experiments have demonstrated that these trunk neural progenitors and PMPs derive from a common multipotent progenitor called the neuromesodermal progenitor (NMP). NMPs are known to reside in the anterior primitive streak (PS) region; however, the extent to which NMPs populate the PS and contribute to the vertebrate body plan, and the precise role that Wnt3a plays in regulating NMP self-renewal and differentiation are unclear. To address this, we used cell-specific markers (Sox2 and T) and tamoxifen-induced Cre recombinase-based lineage tracing to locate putative NMPs in vivo. We provide functional evidence for NMP location primarily in the epithelial PS, and to a lesser degree in the ingressed PS. Lineage-tracing studies in Wnt3a/beta-catenin signaling pathway mutants provide genetic evidence that trunk progenitors normally fated to enter the mesodermal germ layer can be redirected towards the neural lineage. These data, combined with previous PS lineage-tracing studies, support a model that epithelial anterior PS cells are Sox2(+)T(+) multipotent NMPs and form the bulk of neural progenitors and PMPs of the posterior trunk region. Finally, we find that Wnt3a/beta-catenin signaling directs trunk progenitors towards PMP fates; however, our data also suggest that Wnt3a positively supports a progenitor state for both mesodermal and neural progenitors. PMID- 25922527 TI - Sperm-inherited organelle clearance in C. elegans relies on LC3-dependent autophagosome targeting to the pericentrosomal area. AB - Macroautophagic degradation of sperm-inherited organelles prevents paternal mitochondrial DNA transmission in C. elegans. The recruitment of autophagy markers around sperm mitochondria has also been observed in mouse and fly embryos but their role in degradation is debated. Both worm Atg8 ubiquitin-like proteins, LGG-1/GABARAP and LGG-2/LC3, are recruited around sperm organelles after fertilization. Whereas LGG-1 depletion affects autophagosome function, stabilizes the substrates and is lethal, we demonstrate that LGG-2 is dispensable for autophagosome formation but participates in their microtubule-dependent transport toward the pericentrosomal area prior to acidification. In the absence of LGG-2, autophagosomes and their substrates remain clustered at the cell cortex, away from the centrosomes and their associated lysosomes. Thus, the clearance of sperm organelles is delayed and their segregation between blastomeres prevented. This allowed us to reveal a role of the RAB-5/RAB-7 GTPases in autophagosome formation. In conclusion, the major contribution of LGG-2 in sperm-inherited organelle clearance resides in its capacity to mediate the retrograde transport of autophagosomes rather than their fusion with acidic compartments: a potential key function of LC3 in controlling the fate of sperm mitochondria in other species. PMID- 25922528 TI - Relative Contributions of CYP1A2 and CYP2E1 to the Bioactivation and Clearance of 4-Aminobiphenyl in Adult Mice. AB - 4-Aminobiphenyl (ABP), a prototypical aromatic amine carcinogen in rodents and humans, requires bioactivation to manifest its toxic effects. A traditional model of ABP bioactivation, based on in vitro enzyme kinetic evidence, had postulated initial N-hydroxylation by the cytochrome P450 isoform CYP1A2. This is followed by phase 2 O-conjugation and hydrolysis to form a reactive nitrenium ion that covalently binds to DNA and produces tumor-initiating mutations. However, Cyp1a2( /-) mice still possess significant liver ABP N-hydroxylation activity, DNA damage, and incidence of ABP-induced liver tumors, and in vivo induction of CYP1A2 paradoxically reduces levels of ABP-induced DNA damage. Competing ABP detoxification pathways can include N-acetylation by arylamine N acetyltransferase 1 (NAT1) and/or NAT2; however, wild-type and Nat1/2(-/-) mice have similar in vivo ABP clearance rates. Together, these studies suggest the existence of novel ABP bioactivating and clearance/detoxification enzymes. In the present study, we detected similar reductions in Vmax for ABP N-hydroxylation by liver microsomes from Cyp1a2(-/-) and Cyp2e1(-/-) mice when compared with wild type mice. In addition, recombinant mouse CYP1A2 and CYP2E1 were both able to N hydroxylate ABP in mouse hepatoma cells. However, the in vivo clearance of ABP was significantly reduced in Cyp1a2(-/-) but not in Cyp2e1(-/-) mice. Our results support a significant role for CYP2E1 as a novel ABP N-oxidizing enzyme in adult mice, and suggest a more important contribution of CYP1A2 to the in vivo plasma clearance and thus detoxification of ABP. PMID- 25922529 TI - Ultrafast desorption of colloidal particles from fluid interfaces. AB - The self-assembly of solid particles at fluid-fluid interfaces is widely exploited to stabilize emulsions and foams, and in materials synthesis. The self assembly mechanism is very robust owing to the large capillary energy associated with particle adsorption, of the order of millions of times the thermal energy for micrometer-sized colloids. The microstructure of the interfacial colloid monolayer can also favor stability, for instance in the case of particle stabilized bubbles, which can be indefinitely stable against dissolution due to jamming of the colloid monolayer. As a result, significant challenges arise when destabilization and particle removal are a requirement. Here we demonstrate ultrafast desorption of colloid monolayers from the interface of particle stabilized bubbles. We drive the bubbles into periodic compression-expansion using ultrasound waves, causing significant deformation and microstructural changes in the particle monolayer. Using high-speed microscopy we uncover different particle expulsion scenarios depending on the mode of bubble deformation, including highly directional patterns of particle release during shape oscillations. Complete removal of colloid monolayers from bubbles is achieved in under a millisecond. Our method should find a broad range of applications, from nanoparticle recycling in sustainable processes to programmable particle delivery in lab-on-a-chip applications. PMID- 25922530 TI - Correction for Kaushal et al., Cryo-EM structure of the small subunit of the mammalian mitochondrial ribosome. PMID- 25922531 TI - Neural crest cell-derived VEGF promotes embryonic jaw extension. AB - Jaw morphogenesis depends on the growth of Meckel's cartilage during embryogenesis. However, the cell types and signals that promote chondrocyte proliferation for Meckel's cartilage growth are poorly defined. Here we show that neural crest cells (NCCs) and their derivatives provide an essential source of the vascular endothelial growth factor (VEGF) to enhance jaw vascularization and stabilize the major mandibular artery. We further show in two independent mouse models that blood vessels promote Meckel's cartilage extension. Coculture experiments of arterial tissue with NCCs or chondrocytes demonstrated that NCC derived VEGF promotes blood vessel growth and that blood vessels secrete factors to instruct chondrocyte proliferation. Computed tomography and X-ray scans of patients with hemifacial microsomia also showed that jaw hypoplasia correlates with mandibular artery dysgenesis. We conclude that cranial NCCs and their derivatives provide an essential source of VEGF to support blood vessel growth in the developing jaw, which in turn is essential for normal chondrocyte proliferation, and therefore jaw extension. PMID- 25922532 TI - Plastid-produced interorgannellar stress signal MEcPP potentiates induction of the unfolded protein response in endoplasmic reticulum. AB - Cellular homeostasis in response to internal and external stimuli requires a tightly coordinated interorgannellar communication network. We recently identified methylerythritol cyclodiphosphate (MEcPP) as a novel stress-specific retrograde signaling metabolite that accumulates in response to environmental perturbations to relay information from plastids to the nucleus. We now demonstrate, using a combination of transcriptome and proteome profiling approaches, that mutant plants (ceh1) with high endogenous levels of MEcPP display increased transcript and protein levels for a subset of the core unfolded protein response (UPR) genes. The UPR is an adaptive cellular response conserved throughout eukaryotes to stress conditions that perturb the endoplasmic reticulum (ER) homeostasis. Our results suggest that MEcPP directly triggers the UPR. Exogenous treatment with MEcPP induces the rapid and transient induction of both the unspliced and spliced forms of the UPR gene bZIP60. Moreover, compared with the parent background (P), ceh1 mutants are less sensitive to the ER-stress inducing agent tunicamycin (Tm). P and ceh1 plants treated with Tm display similar UPR transcript profiles, suggesting that although MEcPP accumulation causes partial induction of selected UPR genes, full induction is triggered by accumulation of misfolded proteins. This finding refines our perspective of interorgannellar communication by providing a link between a plastidial retrograde signaling molecule and its targeted ensemble of UPR components in ER. PMID- 25922533 TI - Architecture and migration of an epithelium on a cylindrical wire. AB - In a wide range of epithelial tissues such as kidney tubules or breast acini, cells organize into bidimensional monolayers experiencing an out-of-plane curvature. Cancer cells can also migrate collectively from epithelial tumors by wrapping around vessels or muscle fibers. However, in vitro experiments dealing with epithelia are mostly performed on flat substrates, neglecting this out-of plane component. In this paper, we study the development and migration of epithelial tissues on glass wires of well-defined radii varying from less than 1 um up to 85 um. To uncouple the effect of out-of-plane curvature from the lateral confinement experienced by the cells in these geometries, we compare our results to experiments performed on narrow adhesive tracks. Because of lateral confinement, the velocity of collective migration increases for radii smaller than typically 20 um. The monolayer dynamics is then controlled by front-edge protrusions. Conversely, high curvature is identified as the inducer of frequent cell detachments at the front edge, a phenotype reminiscent of the Epithelial Mesenchymal Transition. High curvature also induces a circumferential alignment of the actin cytoskeleton, stabilized by multiple focal adhesions. This organization of the cytoskeleton is reminiscent of in vivo situations such as the development of the trachea of the Drosophila embryo. Finally, submicron radii halt the monolayer, which then reconfigures into hollow cysts. PMID- 25922534 TI - Ominous projections for global antibiotic use in food-animal production. PMID- 25922535 TI - Genome-wide view of natural antisense transcripts in Arabidopsis thaliana. AB - Natural antisense transcripts (NATs) are endogenous transcripts that can form double-stranded RNA structures. Many protein-coding genes (PCs) and non-protein coding genes (NPCs) tend to form cis-NATs and trans-NATs, respectively. In this work, we identified 4,080 cis-NATs and 2,491 trans-NATs genome-widely in Arabidopsis. Of these, 5,385 NAT-siRNAs were detected from the small RNA sequencing data. NAT-siRNAs are typically 21nt, and are processed by Dicer-like 1 (DCL1)/DCL2 and RDR6 and function in epigenetically activated situations, or 24nt, suggesting these are processed by DCL3 and RDR2 and function in environment stress. NAT-siRNAs are significantly derived from PC/PC pairs of trans-NATs and NPC/NPC pairs of cis-NATs. Furthermore, NAT pair genes typically have similar pattern of epigenetic status. Cis-NATs tend to be marked by euchromatic modifications, whereas trans-NATs tend to be marked by heterochromatic modifications. PMID- 25922536 TI - Deploying QTL-seq for rapid delineation of a potential candidate gene underlying major trait-associated QTL in chickpea. AB - A rapid high-resolution genome-wide strategy for molecular mapping of major QTL(s)/gene(s) regulating important agronomic traits is vital for in-depth dissection of complex quantitative traits and genetic enhancement in chickpea. The present study for the first time employed a NGS-based whole-genome QTL-seq strategy to identify one major genomic region harbouring a robust 100-seed weight QTL using an intra-specific 221 chickpea mapping population (desi cv. ICC 7184 * desi cv. ICC 15061). The QTL-seq-derived major SW QTL (CaqSW1.1) was further validated by single-nucleotide polymorphism (SNP) and simple sequence repeat (SSR) marker-based traditional QTL mapping (47.6% R(2) at higher LOD >19). This reflects the reliability and efficacy of QTL-seq as a strategy for rapid genome wide scanning and fine mapping of major trait regulatory QTLs in chickpea. The use of QTL-seq and classical QTL mapping in combination narrowed down the 1.37 Mb (comprising 177 genes) major SW QTL (CaqSW1.1) region into a 35 kb genomic interval on desi chickpea chromosome 1 containing six genes. One coding SNP (G/A) carrying constitutive photomorphogenic9 (COP9) signalosome complex subunit 8 (CSN8) gene of these exhibited seed-specific expression, including pronounced differential up-/down-regulation in low and high seed weight mapping parents and homozygous individuals during seed development. The coding SNP mined in this potential seed weight-governing candidate CSN8 gene was found to be present exclusively in all cultivated species/genotypes, but not in any wild species/genotypes of primary, secondary and tertiary gene pools. This indicates the effect of strong artificial and/or natural selection pressure on target SW locus during chickpea domestication. The proposed QTL-seq-driven integrated genome-wide strategy has potential to delineate major candidate gene(s) harbouring a robust trait regulatory QTL rapidly with optimal use of resources. This will further assist us to extrapolate the molecular mechanism underlying complex quantitative traits at a genome-wide scale leading to fast-paced marker assisted genetic improvement in diverse crop plants, including chickpea. PMID- 25922537 TI - Dissecting the fungal biology of Bipolaris papendorfii: from phylogenetic to comparative genomic analysis. AB - Bipolaris papendorfii has been reported as a fungal plant pathogen that rarely causes opportunistic infection in humans. Secondary metabolites isolated from this fungus possess medicinal and anticancer properties. However, its genetic fundamental and basic biology are largely unknown. In this study, we report the first draft genome sequence of B. papendorfii UM 226 isolated from the skin scraping of a patient. The assembled 33.4 Mb genome encodes 11,015 putative coding DNA sequences, of which, 2.49% are predicted transposable elements. Multilocus phylogenetic and phylogenomic analyses showed B. papendorfii UM 226 clustering with Curvularia species, apart from other plant pathogenic Bipolaris species. Its genomic features suggest that it is a heterothallic fungus with a putative unique gene encoding the LysM-containing protein which might be involved in fungal virulence on host plants, as well as a wide array of enzymes involved in carbohydrate metabolism, degradation of polysaccharides and lignin in the plant cell wall, secondary metabolite biosynthesis (including dimethylallyl tryptophan synthase, non-ribosomal peptide synthetase, polyketide synthase), the terpenoid pathway and the caffeine metabolism. This first genomic characterization of B. papendorfii provides the basis for further studies on its biology, pathogenicity and medicinal potential. PMID- 25922538 TI - Corticosteroid sensitivity in gliomatosis cerebri delays diagnosis. PMID- 25922539 TI - Antithrombotic treatment and intracerebral haemorrhage: between Scylla and Charybdis. AB - In patients who have intracerebral haemorrhage while on antithrombotic treatment, there is no evidence from randomised clinical trials to support decisions with regard to antithrombotic medication. In the acute phase, we advise stopping all antithrombotic treatment with rapid reversal of antithrombotic effects of oral anticoagulants. After the acute phase, we discourage restarting oral anticoagulants in patients with a lobar haematoma caused by cerebral amyloid angiopathy because of the high risk of recurrent bleeding. In these patients, even treatment with platelet inhibitors needs careful weighing of the risks of bleeding and ischaemic stroke. In patients with non-lobar intracerebral haemorrhage, we suggest considering restarting optimal antithrombotic treatment. This includes treatment with oral anticoagulants for patients with atrial fibrillation and/or mechanical valve prosthesis. After intracerebral haemorrhage during oral anticoagulant therapy in patients with atrial fibrillation, direct anticoagulants may be better than vitamin K antagonists, but we await confirmation of this from ongoing trials. PMID- 25922540 TI - Cortical abnormalities on MRI: what a neurologist should know. AB - Cerebral cortical lesions develop in many disorders including vascular diseases, metabolic disorders, inflammatory diseases, tumours, infections and genetic disorders. In some diseases, the cortical involvement is typical and sometimes isolated, while in others the cortical lesions occur only occasionally (often alongside other typical extra-cortical lesions).In this review, we discuss mainly the MRI characteristics of cortical lesions encountered in different disorders. From a radiological perspective, identifying the origin of a cortical lesion depends on the exact localisation of signal changes, the presence of extra cortical lesions, the signal changes on different MRI sequences and the evolution of the radiological abnormalities over time. These must be interpreted in light of the history and clinical state of the patient, and other radiological and non radiological examinations. PMID- 25922541 TI - Comparison of Aerosol Delivery by Face Mask and Tracheostomy Collar. AB - BACKGROUND: The purpose of this study was to compare the performance of a tracheostomy collar, Wright mask, and aerosol mask attached to a jet nebulizer in facilitating aerosolized medication delivery to the lungs. We also compared albuterol delivery with open versus closed fenestration and determined the effect of inspiratory-expiratory ratio (I:E) on aerosol delivery. METHODS: Albuterol (2.5 mg/3 mL) was administered to an in vitro model consisting of an adult teaching mannequin extrathoracic and upper airway with stoma intubated with an 8 mm fenestrated tracheostomy tube. The cuff was deflated. A collecting filter at the level of the bronchi was connected to a breathing simulator at a tidal volume of 400 mL, breathing frequency of 20 breaths/min, and I:E of 2:1 and 1:2. A jet nebulizer was operated with O2 at 8 L/min. Each interface was tested in triplicate. The flow was discontinued at the end of nebulization. For each test, the nebulizer was attached to a tracheostomy collar with the fenestration open or closed, a Wright mask, or an aerosol mask. Drug was analyzed by spectrophotometry (276 nm). A paired t test and analysis of variance were performed (P < .05). RESULTS: The mean +/- SD percent albuterol dose delivered distal to the bronchi was greater with the tracheostomy collar with a closed fenestration (9.4 +/- 1.5%) compared with an open fenestration (7.0 +/- 0.8%). The doses delivered with the Wright mask (4.1 +/- 0.6%) and aerosol mask (3.5 +/- 0.04%) were both less than with the tracheostomy collar under either condition (P < .05). Increasing the I:E from 1:2 to 2:1 increased aerosol delivery by 2.5-4%, with significance for the tracheostomy collar with an open fenestration (11.6 +/- 1.4%), Wright mask (7.2 +/- 0.6%), and aerosol mask (6.1 +/- 0.5%). CONCLUSIONS: In an adult tracheostomy model, the tracheostomy collar delivered more aerosol to the bronchi than the Wright or aerosol mask. An I:E of 2:1 caused greater aerosol deposition compared with an I:E of 1:2. During aerosol administration via a tracheostomy collar, closing the fenestration improved aerosol delivery. PMID- 25922542 TI - Use of Online Self-Management Diaries in Asthma and COPD: A Qualitative Study of Subjects' and Professionals' Perceptions and Behaviors. AB - BACKGROUND: Online self-management diaries are used to support patients' self management skills and facilitate associated behavioral changes. Although web based diaries are well-known as a potential self-management tool, reasons that patients use (or do not use) self-management diaries, as well as perceptions and behaviors related to diary use, remain largely unknown. METHODS: Semistructured interviews (n = 30) were conducted with health-care professionals and subjects to understand perceptions and behaviors related to self-management diary use for asthma and COPD in 2 hospitals in Rotterdam, The Netherlands. RESULTS: Subjects in this study used self-management diaries to improve their knowledge of the disease, cope more consciously with their disease, feel in control, and discuss outcomes from the self-management diaries with their health-care professionals. Two subjects reported that they used the self-management diary to cope more effectively with their disease and recognized an exacerbation and acted by adjusting their medications. Both health-care professionals and subjects experienced practical barriers in integrating self-management diaries into their regular practices. Subjects' reasons for nonuse were related to the intervention, the disease, and subject-provider contact. CONCLUSIONS: Health-care professionals should help patients use self-management diaries by collaboratively developing an individual treatment plan and by showing patients how to use the diaries to recognize and act on an exacerbation. Together with the suggestions made for improving the self-management diaries, this will aid in the integration of self management diaries into regular health-care practice and enhance patients' self management of their disease. PMID- 25922543 TI - Takotsubo Cardiomyopathy and Subsequent Seizures Induced by Flexible Bronchoscopy. AB - Takotsubo cardiomyopathy is a transient left-ventricular dysfunction that typically occurs in elderly women due to emotional or physical stress. An 85-y old woman underwent flexible bronchoscopy to evaluate her malignant lymphoma. After flexible bronchoscopy, she experienced takotsubo cardiomyopathy diagnosed by left ventriculography and subsequent generalized tonic-clonic seizure diagnosed by electroencephalography. Magnetic resonance imaging of her brain after 1 d showed post-convulsive encephalopathy. We believe that these 2 consecutive incidents were caused by the physical stress of the flexible bronchoscopy. PMID- 25922545 TI - Successful Treatment of Severe Carbon Monoxide Poisoning and Refractory Shock Using Extracorporeal Membrane Oxygenation. AB - Carbon monoxide (CO) is the most common cause of poisoning and poisoning-related death in the United States. It is a tasteless and odorless poisonous gas produced from incomplete combustion of hydrocarbons, such as those produced by cars and heating systems. CO rapidly binds to hemoglobin to form carboxyhemoglobin, leading to tissue hypoxia, multiple-organ failure, and cardiovascular collapse. CO also binds to myocardial myoglobin, preventing oxidative phosphorylation in cardiac mitochondria and resulting in cardiac ischemia or stunning and cardiogenic pulmonary edema. Treatment of CO poisoning is mainly supportive, and supplemental oxygen remains the cornerstone of therapy, whereas hyperbaric oxygen therapy is considered for patients with evidence of neurological and myocardial injury. Extracorporeal membrane oxygenation (ECMO) has been utilized effectively in patients with respiratory failure and hemodynamic instability, but its use has rarely been reported in patients with CO poisoning. We report the successful use of venoarterial ECMO in a patient with severe CO poisoning and multiple-organ failure. PMID- 25922544 TI - 48-Hour Fluid Balance Does Not Predict a Successful Spontaneous Breathing Trial. AB - BACKGROUND: Both premature and delayed liberation from mechanical ventilation are associated with increased morbidity and mortality, and fluid balance could negatively influence extubation outcomes. We sought to determine the impact of fluid balance in the 48 h before a spontaneous breathing trial (SBT) on weaning outcomes in a mixed ICU population. METHODS: This was a prospective observational study in 2 adult medical-surgical ICUs. All enrolled subjects met eligibility criteria for weaning from mechanical ventilation. SBT failure was defined as inability to tolerate a T-piece trial for 30-120 min. Data on demographics, physiology, fluid balance in the 48 h preceding SBT (fluid input minus output over the 48-h period), lung ultrasound findings, and outcomes were collected. RESULTS: Of a total of 250 SBTs, SBT failure eventuated in 51 (20.4%). Twenty nine subjects (11.6%) had COPD, and 40 subjects (16%) were intubated due to respiratory sepsis. One-hundred eighty-nine subjects (75.6%) were extubated on the first attempt. Compared with subjects with SBT success, SBT failure subjects were younger (median of 66 vs. 75 y, P = .001) and had a higher duration of mechanical ventilation (median of 7 vs. 4 d, P < .001) and a higher prevalence of COPD (19.6 vs. 9.5%, P = .04). There were no statistically significant differences in 48-h fluid balance before SBT between groups (SBT failure, 1,201.65 +/- 2,801.68 mL; SBT success, 1,324.39 +/- 2,915.95 mL). However, in the COPD subgroup, we found a significant association between positive fluid balance in the 48 h before SBT and SBT failure (odds ratio of 1.77 [1.24-2.53], P = .04). CONCLUSIONS: Fluid balance should not delay SBT indication because it does not predict greater probability of SBT failure in the medical-surgical critically ill population. Notwithstanding, avoiding positive fluid balance in patients with COPD might improve weaning outcomes. (ClinicalTrials.gov registration NCT02022839.). PMID- 25922546 TI - Clinical and Pulmonary Function Markers of Respiratory Exacerbation Risk in Subjects With Quadriplegic Cerebral Palsy. AB - BACKGROUND: Although respiratory exacerbations are common in patients with quadriplegic cerebral palsy (CP), little is known about the factors that are related to increased exacerbation risk. This study aimed to identify the clinical and pulmonary function variables signaling risk of exacerbation in this type of patient. METHODS: Thirty-one children and young adults with quadriplegic CP underwent a comprehensive history, physical examination, and pulmonary function test, including arterial blood gas analysis, airway resistance using the interrupter technique, and home overnight SpO2 monitoring. Subjects were divided into 2 groups depending on the number of respiratory exacerbations reported during the year before study entry: frequent exacerbators (ie, >= 2 exacerbations) and infrequent exacerbators (ie, < 2 exacerbations). RESULTS: The frequent exacerbators were more likely to require hospitalization due to respiratory disorders compared with the infrequent exacerbators (13/14 vs 9/17, P = .02). Respiratory exacerbation was found to be associated with diagnosis of gastroesophageal reflux (adjusted odds ratio of 23.95 for subjects with confirmed diagnosis, P = .02) and higher PaCO2 levels (adjusted odds ratio of 12.60 for every 5-mm Hg increase in PaCO2 , P = .05). Subjects with PaCO2 >= 35 mm Hg showed an exacerbation odds ratio of 15.2 (95% CI 1.5-152.5, P = .01). CONCLUSIONS: Gastroesophageal reflux and increased PaCO2 can be considered simple, clinically useful markers of increased exacerbation risk in young subjects with quadriplegic CP. PMID- 25922547 TI - Computerized Assessment of Wheezing in Children With Respiratory Syncytial Virus Bronchiolitis Before and After Hypertonic Saline Nebulization. AB - BACKGROUND: Studies suggest an effect of nebulized hypertonic saline solution on air-flow limitation in subjects with respiratory syncytial virus (RSV) bronchiolitis, but results are based on subjective scores of clinical severity and are not clear. In this observational study, we used a noninvasive computerized tool to quantify wheezing before and after nebulization with hypertonic saline in children admitted for RSV infection. METHODS: Twenty-seven children (<= 24 months old) admitted to the pediatric ward of the Medical Center Leeuwarden with polymerase chain reaction-confirmed RSV bronchiolitis were included. Subjects were simultaneously assessed both clinically and by computerized acoustic monitoring before and 15 min after treatment with nebulized hypertonic saline solution. RESULTS: Clinical assessment, defined by the Respiratory Distress Assessment Instrument score, did not change after nebulization (n = 27, 5.0 vs 4.7, P = .17). Computerized acoustic monitoring showed no improvement in wheezing (n = 27, 3.4% vs 2.0%, P = .05) or inspiration/expiration ratio (0.85 vs 0.85, P = .93) after nebulization. CONCLUSIONS: Hypertonic saline nebulization does not improve air flow, as assessed by both clinical and computerized acoustic scores, in children admitted for RSV. PMID- 25922548 TI - Asymmetric dimethylarginine reflects cumulative inflammatory burden in rheumatoid arthritis. A novel mechanism of excessive cardiovascular morbidity? PMID- 25922549 TI - Effectiveness of biologic DMARDs in monotherapy versus in combination with synthetic DMARDs in rheumatoid arthritis: data from the Swiss Clinical Quality Management Registry. AB - OBJECTIVES: To determine the frequency of use of biologic DMARDs (bDMARDs) in monotherapy, to describe the baseline characteristics of patients treated with bDMARDs in monotherapy and to compare the effectiveness of bDMARDs in monotherapy with that of bDMARDs in combination with synthetic DMARDs (sDMARDs). METHODS: Using data from the Swiss RA (SCQM-RA) registry, bDMARD treatment courses (TCs) were classified either as monotherapy or as combination therapy, depending on the presence of concomitant sDMARDs. Prescription of bDMARD monotherapy was analysed using logistic regression. bDMARD retention was analysed using Kaplan-Meier and Cox models with the addition of time-varying covariate effects. Evolution of the DAS28 over time was analysed with mixed-effects models for longitudinal data. RESULTS: A total of 4218 TCs on bDMARDs from 3111 patients were included, of which 1136 TCs (27%) were initiated as monotherapy. bDMARD monotherapy was preferentially prescribed to older, co-morbid patients with longer disease duration, lower BMI, more active disease and more previous bDMARDs. After adjusting for potential confounding factors, drug retention was significantly lower in monotherapy [hazard ratio 1.15 (95% CI: 1.03, 1.30)]. Other factors such as type of bDMARD and calendar year of prescription were associated with a stronger effect on drug retention. Response to treatment in terms of DAS28 evolution was also slightly but significantly less favourable in monotherapy (P = 0.04). CONCLUSION: Our data suggest that bDMARD monotherapy is prescribed to more complex cases and is significantly less effective than bDMARD therapy in combination with sDMARDs, but to an extent that is clinically only marginally relevant. PMID- 25922550 TI - Investigation of the RbCa molecule: Experiment and theory. AB - We present a thorough theoretical and experimental study of the electronic structure of RbCa. The mixed alkali-alkaline earth molecule RbCa was formed on superfluid helium nanodroplets. Excited states of the molecule in the range of 13 000-23 000 cm-1 were recorded by resonance enhanced multi-photon ionization time of-flight spectroscopy. The experiment is accompanied by high level ab initio calculations of ground and excited state properties, utilizing a multireference configuration interaction method based on multiconfigurational self consistent field calculations. With this approach the potential energy curves and permanent electric dipole moments of 24 electronic states were calculated. In addition we computed the transition dipole moments for transitions from the ground into excited states. The combination of experiment and theory allowed the assignment of features in the recorded spectrum to the excited [Formula: see text], [Formula: see text], [Formula: see text], [Formula: see text], [Formula: see text], [Formula: see text], [Formula: see text], and [Formula: see text] states, where the experiment allowed to benchmark the calculation. This is the first experimental work giving insight into the previously unknown RbCa molecule, which offers great prospects in ultracold molecular physics due to its magnetic and electronic dipole moment in the [Formula: see text] ground state. PMID- 25922551 TI - Prognostic value of pentraxin-3 level in patients with STEMI and its relationship with heart failure and markers of oxidative stress. AB - OBJECTIVE: Pentraxin-3 (PTX3) appears to have a cardioprotective effect through a positive influence against postreperfusion damage. This study assesses the prognostic value of PTX3 level and its relationship with clinical parameters and markers of oxidative stress and nitric oxide metabolism in patients with ST elevation myocardial infarction (STEMI). METHODS: Plasma/serum levels of several biomarkers of inflammation and oxidative stress and nitrite/nitrate were assessed upon admission and 24 h after STEMI onset in patients treated by primary percutaneous coronary intervention. RESULTS: ROC analysis showed that plasma PTX3 at 24 h was a strong predictor of 30-day and 1-year mortality and independent predictor of combined end-point of left ventricle dysfunction or mortality in 1 year. The inflammatory response expressed by PTX3 had a significant relationship with age, heart failure, infarct size, impaired flow in the infarct-related artery, and renal function and positively correlated with neopterin, TNF-alpha, 8 hydroxy-2'-deoxyguanosine, and nitrite/nitrate. CONCLUSIONS: Plasma PTX3 at 24 h after STEMI onset is a strong predictor of 30-day and 1-year mortality. PTX3 as a single biomarker is comparable with currently used scoring systems (TIMI or GRACE) or B-type natriuretic peptide. PTX3 is also an independent predictor of combined end-point of left ventricle dysfunction or mortality in 1 year. PMID- 25922552 TI - Serum and urine biomarkers for human renal cell carcinoma. AB - Renal cell carcinoma (RCC) diagnosis is mostly achieved incidentally by imaging provided for unrelated clinical reasons. The surgical management of localized tumors has reported excellent results. The therapy of advanced RCC has evolved considerably over recent years with the widespread use of the so-called "targeted therapies." The identification of molecular markers in body fluids (e.g., sera and urine), which can be used for screening, diagnosis, follow-up, and monitoring of drug-based therapy in RCC patients, is one of the most ambitious challenges in oncologic research. Although there are some promising reports about potential biomarkers in sera, there is limited available data regarding urine markers for RCC. The following review reports some of the most promising biomarkers identified in the biological fluids of RCC patients. PMID- 25922553 TI - Overexpression of FRAT1 is associated with malignant phenotype and poor prognosis in human gliomas. AB - Glioma is the most common malignancy of the central nervous system. Approximately 40 percent of intracranial tumors are diagnosed as gliomas. Difficulties in treatment are associated closely with the malignant phenotype, which is characterized by excessive proliferation, relentless invasion, and angiogenesis. Although the comprehensive treatment level of brain glioma is continuously progressing, the outcome of this malignancy has not been improved drastically. Therefore, the identification of new biomarkers for diagnosis and therapy of this malignancy is of significant scientific and clinical value. FRAT1 is a positive regulator of the Wnt/beta-catenin signaling pathway and is overexpressed in many human tumors. In the present study, we investigated the expression status of FRAT1 in 68 patients with human gliomas and its correlation with the pathologic grade, proliferation, invasion, angiogenesis, and prognostic significance. These findings suggest that FRAT1 may be an important factor in the tumorigenesis and progression of glioma and could be explored as a potential biomarker for pathological diagnosis, an indicator for prognosis, and a target for biological therapy of malignancy. PMID- 25922554 TI - Long-term outcomes of hepatic resection versus living donor liver transplantation for hepatocellular carcinoma: a propensity score-matching study. AB - Hepatic resection (HR) and liver transplantation (LT) are surgical treatment options for hepatocellular carcinoma (HCC). However, it is clinically impossible to perform a randomized, controlled study to determine the usefulness of these treatments. The present study compared survival rates and recurrence rates of HR versus living donor LT (LDLT) for HCC by using the propensity score method. Between January 1999 and August 2012, 936 patients (732 HR, 204 LDLT) underwent surgical therapy for HCC in our center. Using the propensity score matching, 80 well-balanced patients were defined. The 1- and 5-year overall survival rates were 90% and 53% in the HR group and 82% and 63% in the LT group, respectively. They were not significantly different between the two groups. The odds ratio estimated using the propensity score matching analysis was 0.842 (P = 0.613). The 1- and 5-year recurrence rates were significantly lower in the LT group (9% and 21%) than in the HR group (43% and 74%) (P < 0.001), and the odds ratio was 0.214 (P = 0.001). In conclusion, HR should be considered a valid alternative to LDLT taking into consideration the risk for the living donor based on the results of this propensity score-matching study. PMID- 25922555 TI - Pelvic floor ultrasound imaging: are physiotherapists interchangeable in the assessment of levator hiatal biometry? AB - PURPOSE: To evaluate inter-examiner reliability in the ultrasound (US) assessment of levator hiatal dimensions when different physiotherapists perform independent data acquisition and analysis. METHODS: In this cross-sectional observational study, 14 asymptomatic nulliparous women were imaged at rest, during pelvic floor muscle contraction, and during Valsalva manoeuvre by two physiotherapists using three-dimensional (3D) and four-dimensional (4D) transperineal US. Examiners each measured the dimensions of the levator hiatus (area and antero-posterior and transverse diameters) from the US volumes they respectively acquired. Inter examiner reliability was determined using intra-class correlation coefficients (ICCs), and inter-examiner agreement was determined using Bland-Altman analyses. RESULTS: The ICC results demonstrated very good inter-examiner reliability (ICC=0.84-0.98); Bland-Altman results showed high inter-examiner agreement across all measurements. CONCLUSIONS: Trained examiners may be considered interchangeable in the US assessment of levator hiatal biometry. Overall, trained physiotherapists using transperineal US imaging to assess levator hiatal biometry can be confident when comparing their own clinical findings to those of their colleagues and to findings published in the literature. PMID- 25922556 TI - Characteristics of stabilizer muscles: a systematic review. AB - PURPOSE: To identify the main characteristics, based on available evidence, of stabilizer muscles to inform the development of a definition of stabilizer muscles. METHODS: Electronic databases were systematically searched for relevant literature from the databases' inception to June 2013 using keywords related to stability, muscles, and characteristics of stabilizer muscles. Studies that provided at least one characteristic of a stabilizer muscle were included. For the quality assessment, all included articles were categorized as either experimental or opinion-based studies. Methodological quality was assessed using a customized checklist, and data were analyzed with a narrative synthesis involving content analysis. The number of articles providing either direct evidence supporting a link between the characteristic and joint stability or indirect evidence that a muscle considered to be a stabilizer has that characteristic determined the level of significance of that characteristic for stabilizer muscles. RESULTS: A total of 77 studies met the inclusion criteria. The highest number of articles providing supporting evidence that a particular muscle characteristic plays a stabilizing role related to biomechanical characteristics (27 articles), followed by neurological characteristics (22 articles) and anatomical/physiological characteristics (4 articles). CONCLUSION: Based on a synthesis of supporting evidence from the literature, stabilizer muscles can be defined as muscles that contribute to joint stiffness by co contraction and show an early onset of activation in response to perturbation via either a feed-forward or a feedback control mechanism. These results may guide researchers to investigate which muscles exhibit these characteristics to determine whether particular muscles have a stabilizer rather than a prime mover role during normal functioning. PMID- 25922557 TI - No Differences in Outcomes in People with Low Back Pain Who Met the Clinical Prediction Rule for Lumbar Spine Manipulation When a Pragmatic Non-thrust Manipulation Was Used as the Comparator. AB - PURPOSE: To investigate differences in pain and disability between patients treated with thrust manipulation (TM) and those treated with non-thrust manipulation (NTM) in a group of patients with mechanical low back pain (LBP) who had a within-session response to an initial assessment and met the clinical prediction rule (CPR). METHODS: Data from 71 patients who met the CPR were extracted from a database of patients in a larger randomized controlled trial comparing TM and NTM. Treatment of the first two visits involved either TM or NTM (depending on allocation) and a standardized home exercise programme. Data analysis included descriptive statistics and a two-way ANOVA examining within- and between-groups effects for pain and disability, as well as total visits, total days in care, and rate of recovery. RESULTS: No between-group differences in pain or disability were found for NTM versus TM groups (p=0.55), but within subjects effects were noted for both groups (p<0.001). CONCLUSIONS: This secondary analysis suggests that patients who satisfy the CPR benefit as much from NTM as from TM. PMID- 25922558 TI - Barriers to and Facilitators of Access and Participation in Community-Based Exercise Programmes from the Perspective of Adults with Post-stroke Aphasia. AB - PURPOSE: To explore communication-related experiences with accessing and participating in community-based exercise programmes from the perspective of adults with post-stroke aphasia. METHODS: Adults with mild to severe post-stroke aphasia were recruited from the Aphasia Institute (AI), Toronto, Canada, for a qualitative descriptive study using semi-structured, in-depth one-on-one interviews. Participants were asked to identify facilitators of, barriers to, and strategies for joining and participating in exercise programmes. Interview data were analyzed using conventional content analysis. RESULTS: Ten adults with mild (40%), moderate (40%), or severe (20%) aphasia participated in this study. The majority of participants were men (60%) aged 60-69 years (40%). Participants experienced a combination of communication, environmental, and personal facilitators of and barriers to accessing and participating in community-based exercise programmes. Strategies to enhance participation can be applied at both programme and individual levels. CONCLUSIONS: Findings may inform clinical practice and programming to optimize access to and participation in community based exercise programmes for adults with post-stroke aphasia. PMID- 25922559 TI - Prevalence and characteristics of patients with a diagnosis of chronic obstructive pulmonary disease participating in non-pulmonary rehabilitation programmes: a brief report. AB - PURPOSE: To determine the prevalence of people with a diagnosis of chronic obstructive pulmonary disease (COPD) among those completing non-pulmonary rehabilitation (NPR) programmes and to describe their characteristics. METHODS: Electronic data of participants who completed an in-patient rehabilitation programme between July 1, 2010, and July 1, 2012 were retrospectively reviewed. Data extracted were month and year of birth, sex, height, weight, referral source, admission and discharge dates, programme admitted to, reason for admission, most responsible health condition, number of co-morbidities, referral agency on discharge, and Functional Independence Measure (FIM) scores on admission and discharge. RESULTS: The prevalence of COPD among participants who completed the NPR programmes was 7.5%. The most common reasons for admission were cardiac conditions (n=69, 20%), followed by post-unilateral hip replacement (n=40, 11%) and post-unilateral hip fracture (n=38, 11%). Patients were discharged after an average stay of 20 (SD 13) days. The mean FIM score was 91 (SD 11) at admission and 108 (SD 9) at discharge. CONCLUSIONS: The prevalence of a COPD diagnosis among participants in NPR programmes was 7.5%. COPD is a common comorbidity for people in rehabilitation programmes who have had amputations, have a cardiac condition, have undergone organ transplantation, or require complex care. PMID- 25922560 TI - Types and quality of physical therapy research publications: has there been a change in the past decade? AB - PURPOSE: To describe and compare the type and quality of evidence published in physical therapy (PT) journals during two time periods (2000-2002 vs. 2010-2012) and to explore scientific editors' opinions on changes in the types and quality of articles. METHODS: A quantitative, longitudinal, retrospective journal review was used to categorize and assess the methodological rigour of items published in four PT journals using the Hedges Project. A quantitative, descriptive, cross sectional survey explored the opinions of scientific editors. Percentages and frequencies of article types (as defined by the Hedges Project criteria), items passing rigour, and editor responses were calculated. Statistical significance of differences in article type and rigour between the two time periods was determined using Fisher's Exact Test. RESULTS: There was a significant increase in original studies and review articles from 2000-2002 to 2010-2012 (p<0.001, p=0.002, respectively). The overall pass rate for rigour was 33.3% in 2000-2002 and 42.5% in 2010-2012, showing a significant increase (p=0.019). The majority of editors reported an increase in systematic reviews, qualitative designs, and randomized controlled trials and believed that quality had improved by 2010-2012. CONCLUSION: From 2000-2002 to 2010-2012, the quality of articles published in PT journals improved and the proportion of original studies and review articles increased. PMID- 25922561 TI - Attitudes toward Master's and Clinical Doctorate Degrees in Physical Therapy. AB - Purpose : To examine the attitudes of a self-selected sample of Canadian physical therapists toward the transition from bachelor's to master's degrees and the implementation of clinical doctorate degrees in physical therapy (PT). Methods : A cross-sectional survey was conducted using a modified Dillman tailored approach. All eligible members of the Canadian Physiotherapy Association (CPA) were invited to participate. RESULTS: Of 1,397 Canadian physical therapists who responded to the survey, 45% favoured the transition from bachelor's to master's degrees, 21% did not, and 34% were neutral; 27% favoured a transition from a master's to a doctoral degree for entry into practice in PT, 53% did not favour this transition, and 20% were neutral. Finally, 56% favoured the implementation of a post-professional clinical doctorate (PPCD) in PT, 23% did not, and 21% were neutral. CONCLUSIONS: Overall, a self-selected sample of Canadian physical therapists supported the future implementation of a post-professional clinical doctorate degree in PT but did not support an entry-to-practice doctoral degree. However, these results must be interpreted with caution because of the study's small sample size. PMID- 25922562 TI - A lymphedema self-management programme: report on 30 cases. AB - PURPOSE: Compression therapy is the most important element in the treatment and long-term management of moderate and severe lymphedema, but it is not universally accessible in Canada. For those unable to access private lymphedema treatment, physiotherapists at the McGill University Health Centre (MUHC) Lymphedema Clinic began teaching patients and caregivers how to use compression bandages safely and effectively. METHODS: A retrospective chart review was combined with structured telephone or in-person interviews with 30 people who had attended a self bandaging clinic in the MUHC Lymphedema Clinic between 2011 and 2012. Patients were monitored weekly until limb volume plateaued, and a compression garment was then fitted for ongoing maintenance. Monthly or quarterly surveillance continued for 1 year. Follow-up interviews were conducted 3 to 18 months after patients had received their garments. RESULTS: The majority of participants had moderate to severe lymphedema; all achieved reduction of edema in the range of 48% to 92%. More than three-quarters of participants reported a global rate of change (GRC) of >=80%. Themes derived from the interviews included the importance of bandaging, the feeling of being in control, and difficulties with compression garments. Participants spontaneously expressed satisfaction about having tools to manage their condition themselves. CONCLUSION: For selected patients with lymphedema, a self-bandaging programme can be a route to lymphedema reduction, independence, and self-efficacy. PMID- 25922563 TI - Difficulties experienced in setting and achieving goals by participants of a falls prevention programme: a mixed-methods evaluation. AB - PURPOSE: To evaluate the ability of participants of a falls prevention programme to set and achieve goals. METHODS: The study used a prospective longitudinal design and a mixed-methods approach to data collection. Study participants were (1) 220 older adults participating in a 15-week combined exercise and education falls prevention programme and (2) 9 practitioners (3 home-care nurses, 5 community workers, and an exercise physiologist) involved in delivering the programme. Data from goal-setting forms were analyzed, and descriptive statistics were used to determine the number of appropriate goals set and achieved. Data were analyzed according to programme setting (home- or group-based) and whether or not participants were classified as being from a Culturally and Linguistically Diverse (CALD) background in the Australian context. Semi-structured interviews with programme practitioners were thematically analyzed. RESULTS: A total of 144 respondents (n=75 CALD group, n=41 non-CALD group, n=6 CALD home, n=22 non-CALD home) set 178 goals. Only 101 (57%) goals could be evaluated according to achievement, because participants set goals that focused on health state instead of behaviour, set goals not relevant to falls prevention, used inappropriate constructs to measure goal achievement, and either did not review their goals or dropped out of the programme before goal review. Of these 101 goals, 64 were achieved. Practitioners described their own difficulties in understanding the process of setting health behaviour goals along with communication, cultural, and logistic difficulties. CONCLUSIONS: Both CALD and non-CALD participants and those participating in both group- and home-based programmes experienced difficulty in setting and achieving goals to facilitate behaviour change for falls prevention. Data suggest that home-based participants had more difficulty in setting goals than their group-based counterparts and, to a lesser extent, that CALD participants experienced more difficulty in setting goals than their non-CALD counterparts. The use of a guided approach to goal setting and the need for more specific practitioner training and follow-up support regarding goal setting in the context of a falls prevention programme should be considered. PMID- 25922564 TI - Efficacy of anakinra for various types of crystal-induced arthritis in complex hospitalized patients: a case series and review of the literature. AB - BACKGROUND: There are few data on anakinra use after failure of conventional medications for crystal-induced peripheral arthritis and/or crowned dens syndrome among complex hospitalized patients. METHODS: We retrospectively analyzed the outcome of six patients affected with subacute crystal-induced arthritis who had received anakinra in second or third line therapy, including three patients with crowned dens syndrome and three others with gouty arthritis. Patients' comorbidities, reasons for anakinra use and associated drugs, and outcomes were recorded. RESULTS: All patients presented with elevated inflammatory syndrome, systemic symptoms with poly/oligoarthritis. Except for absolute contraindications, all patients were previously treated with full or decreased dose of NSAID, colchicine, and/or glucocorticoids, with unsatisfactory response. All three gouty patients exhibited complete responses in all acute involvements under anakinra within 3 to 5 days, including one of them who needed the reintroduction of colchicine treatment that was previously unsuccessful. Crowned dens syndrome patients, including two with pseudogout and one with subacute hydroxyapatite deposition disease, needed 9 to 11 days to achieve complete response. Tolerance to anakinra was good. CONCLUSION: In case series of complex hospitalized patients, anakinra showed good activity in crowned dens syndrome and associated crystal-induced peripheral arthritis, with longer treatment duration than in gouty arthritis. PMID- 25922565 TI - Systemic chemotherapy is modulated by platelet-activating factor-receptor agonists. AB - Chemotherapy is used to treat numerous cancers including melanoma. However, its effectiveness in clinical settings is often hampered by various mechanisms. Previous studies have demonstrated that prooxidative stressor-mediated generation of oxidized lipids with platelet-activating factor-receptor (PAF-R) agonistic activity induces systemic immunosuppression that augments the growth of experimental melanoma tumors. We have recently shown that treatment of murine B16F10 melanoma cells in vitro or tumors implanted into syngeneic mice and treated intratumorally with various chemotherapeutic agents generated PAF-R agonists in a process blocked by antioxidants. Notably, these intratumoral chemotherapy-generated PAF-R agonists augmented the growth of secondary (untreated) tumors in a PAF-R dependent manner. As both localized and systemic chemotherapies are used based on tumor localization/stage and metastases, the current studies were sought to determine effects of PAF-R agonists on systemic chemotherapy against experimental melanoma. Here, we show that systemic chemotherapy with etoposide (ETOP) attenuates the growth of melanoma tumors when given subsequent to the tumor cell implantation. Importantly, this ETOP-mediated suppression of melanoma tumor growth was blocked by exogenous administration of a PAF-R agonist, CPAF. These findings indicate that PAF-R agonists not only negatively affect the ability of localized chemotherapy but also compromise the efficacy of systemic chemotherapy against murine melanoma. PMID- 25922566 TI - Inflammatory mediators in vascular disease: identifying promising targets for intracranial aneurysm research. AB - Inflammatory processes are implicated in many diseases of the vasculature and have been shown to play a key role in the formation of intracranial aneurysms (IAs). Although the specific mechanisms underlying these processes have been thoroughly investigated in related pathologies, such as atherosclerosis, there remains a paucity of information regarding the immunopathology of IA. Cells such as macrophages and lymphocytes and their effector molecules have been suggested to be players in IA, but their specific interactions and the role of other components of the inflammatory response have yet to be determined. Drawing parallels between the pathogenesis of IA and other vascular disorders could provide a roadmap for developing a mechanistic understanding of the immunopathology of IA and uncovering useful targets for therapeutic intervention. Future research should address the presence and function of leukocyte subsets, mechanisms of leukocyte recruitment and activation, and the role of damage associated molecular patterns in IA. PMID- 25922568 TI - CNL Disease Resistance Genes in Soybean and Their Evolutionary Divergence. AB - Disease resistance genes (R-genes) encode proteins involved in detecting pathogen attack and activating downstream defense molecules. Recent availability of soybean genome sequences makes it possible to examine the diversity of gene families including disease-resistant genes. The objectives of this study were to identify coiled-coil NBS-LRR (= CNL) R-genes in soybean, infer their evolutionary relationships, and assess structural as well as functional divergence of the R genes. Profile hidden Markov models were used for sequence identification and model-based maximum likelihood was used for phylogenetic analysis, and variation in chromosomal positioning, gene clustering, and functional divergence were assessed. We identified 188 soybean CNL genes nested into four clades consistent to their orthologs in Arabidopsis. Gene clustering analysis revealed the presence of 41 gene clusters located on 13 different chromosomes. Analyses of the K s values and chromosomal positioning suggest duplication events occurring at varying timescales, and an extrapericentromeric positioning may have facilitated their rapid evolution. Each of the four CNL clades exhibited distinct patterns of gene expression. Phylogenetic analysis further supported the extrapericentromeric positioning effect on the divergence and retention of the CNL genes. The results are important for understanding the diversity and divergence of CNL genes in soybean, which would have implication in soybean crop improvement in future. PMID- 25922567 TI - The dietary flavonoid Kaempferol mediates anti-inflammatory responses via the Src, Syk, IRAK1, and IRAK4 molecular targets. AB - Even though a lot of reports have suggested the anti-inflammatory activity of kaempferol (KF) in macrophages, little is known about its exact anti-inflammatory mode of action and its immunopharmacological target molecules. In this study, we explored anti-inflammatory activity of KF in LPS-treated macrophages. In particular, molecular targets for KF action were identified by using biochemical and molecular biological analyses. KF suppressed the release of nitric oxide (NO) and prostaglandin E2 (PGE2), downregulated the cellular adhesion of U937 cells to fibronectin (FN), neutralized the generation of radicals, and diminished mRNA expression levels of inflammatory genes encoding inducible NO synthase (iNOS), TNF-alpha, and cyclooxygenase- (COX-) 2 in lipopolysaccharide- (LPS-) and sodium nitroprusside- (SNP-) treated RAW264.7 cells and peritoneal macrophages. KF reduced NF-kappaB (p65 and p50) and AP-1 (c-Jun and c-Fos) levels in the nucleus and their transcriptional activity. Interestingly, it was found that Src, Syk, IRAK1, and IRAK4 responsible for NF-kappaB and AP-1 activation were identified as the direct molecular targets of KF by kinase enzyme assays and by measuring their phosphorylation patterns. KF was revealed to have in vitro and in vivo anti inflammatory activity by the direct suppression of Src, Syk, IRAK1, and IRAK4, involved in the activation of NF-kappaB and AP-1. PMID- 25922569 TI - Synonymous Codon Usage Bias in the Plastid Genome is Unrelated to Gene Structure and Shows Evolutionary Heterogeneity. AB - Synonymous codon usage bias (SCUB) is the nonuniform usage of codons, occurring often in nearly all organisms. Our previous study found that SCUB is correlated with intron number, is unequal among exons in the plant nuclear genome, and mirrors evolutionary specialization. However, whether this rule exists in the plastid genome has not been addressed. Here, we present an analysis of SCUB in the plastid genomes of 25 species from lower to higher plants (algae, bryophytes, pteridophytes, gymnosperms, and spermatophytes). We found NNA and NNT (A- and T ending codons) are preferential in the plastid genomes of all plants. Interestingly, this preference is heterogeneous among taxonomies of plants, with the strongest preference in bryophytes and the weakest in pteridophytes, suggesting an association between SCUB and plant evolution. In addition, SCUB frequencies are consistent among genes with varied introns and among exons, indicating that the bias of NNA and NNT is unrelated to either intron number or exon position. Further, SCUB is associated with DNA methylation-induced conversion of cytosine to thymine in the vascular plants but not in algae or bryophytes. These data demonstrate that these SCUB profiles in the plastid genome are distinctly different compared with the nuclear genome. PMID- 25922570 TI - MicroRNA-Seq Data Analysis Pipeline to Identify Blood Biomarkers for Alzheimer's Disease from Public Data. AB - BACKGROUND: Alzheimer's disease (AD) is the most common cause of dementia with no curative therapy currently available. Establishment of sensitive and non-invasive biomarkers that promote an early diagnosis of AD is crucial for the effective administration of disease-modifying drugs. MicroRNAs (miRNAs) mediate posttranscriptional repression of numerous target genes. Aberrant regulation of miRNA expression is implicated in AD pathogenesis, and circulating miRNAs serve as potential biomarkers for AD. However, data analysis of numerous AD-specific miRNAs derived from small RNA-sequencing (RNA-Seq) is most often laborious. METHODS: To identify circulating miRNA biomarkers for AD, we reanalyzed a publicly available small RNA-Seq dataset, composed of blood samples derived from 48 AD patients and 22 normal control (NC) subjects, by a simple web-based miRNA data analysis pipeline that combines omiRas and DIANA miRPath. RESULTS: By using omiRas, we identified 27 miRNAs expressed differentially between both groups, including upregulation in AD of miR-26b-3p, miR-28-3p, miR-30c-5p, miR-30d-5p, miR-148b-5p, miR-151a-3p, miR-186-5p, miR-425-5p, miR-550a-5p, miR-1468, miR-4781 3p, miR-5001-3p, and miR-6513-3p and downregulation in AD of let-7a-5p, let-7e 5p, let-7f-5p, let-7g-5p, miR-15a-5p, miR-17-3p, miR-29b-3p, miR-98-5p, miR-144 5p, miR-148a-3p, miR-502-3p, miR-660-5p, miR-1294, and miR-3200-3p. DIANA miRPath indicated that miRNA-regulated pathways potentially downregulated in AD are linked with neuronal synaptic functions, while those upregulated in AD are implicated in cell survival and cellular communication. CONCLUSIONS: The simple web-based miRNA data analysis pipeline helps us to effortlessly identify candidates for miRNA biomarkers and pathways of AD from the complex small RNA-Seq data. PMID- 25922571 TI - The roles of neuregulin-1 in cardiac development, homeostasis, and disease. AB - Neuregulin-1 (NRG-1) and its signaling receptors, erythroblastic leukemia viral oncogene homologs (ErbB) 2, 3, and 4, have been implicated in both cardiomyocyte development and disease, as well as in homeostatic cardiac function. NRG-1/ErbB signaling is involved in a multitude of cardiac processes ranging from myocardial and cardiac conduction system development to angiogenic support of cardiomyocytes, to cardioprotective effects upon injury. Numerous studies of NRG 1 employ a variety of platforms, including in vitro assays, animal models, and human clinical trials, with equally varying and, sometimes, contradictory outcomes. NRG-1 has the potential to be used as a therapeutic tool in stem cell therapies, tissue engineering applications, and clinical diagnostics and treatment. This review presents a concise summary of the growing body of literature to highlight the temporally persistent significance of NRG-1/ErbB signaling throughout development, homeostasis, and disease in the heart, specifically in cardiomyocytes. PMID- 25922573 TI - An Interpretation of the Ancestral Codon from Miller's Amino Acids and Nucleotide Correlations in Modern Coding Sequences. AB - Purine bias, which is usually referred to as an "ancestral codon", is known to result in short-range correlations between nucleotides in coding sequences, and it is common in all species. We demonstrate that RWY is a more appropriate pattern than the classical RNY, and purine bias (Rrr) is the product of a network of nucleotide compensations induced by functional constraints on the physicochemical properties of proteins. Through deductions from universal correlation properties, we also demonstrate that amino acids from Miller's spark discharge experiment are compatible with functional primeval proteins at the dawn of living cell radiation on earth. These amino acids match the hydropathy and secondary structures of modern proteins. PMID- 25922572 TI - Gene delivery strategies to promote spinal cord repair. AB - Gene therapies hold great promise for the treatment of many neurodegenerative disorders and traumatic injuries in the central nervous system. However, development of effective methods to deliver such therapies in a controlled manner to the spinal cord is a necessity for their translation to the clinic. Although essential progress has been made to improve efficiency of transgene delivery and reduce the immunogenicity of genetic vectors, there is still much work to be done to achieve clinical strategies capable of reversing neurodegeneration and mediating tissue regeneration. In particular, strategies to achieve localized, robust expression of therapeutic transgenes by target cell types, at controlled levels over defined time periods, will be necessary to fully regenerate functional spinal cord tissues. This review summarizes the progress over the last decade toward the development of effective gene therapies in the spinal cord, including identification of appropriate target genes, improvements to design of genetic vectors, advances in delivery methods, and strategies for delivery of multiple transgenes with synergistic actions. The potential of biomaterials to mediate gene delivery while simultaneously providing inductive scaffolding to facilitate tissue regeneration is also discussed. PMID- 25922574 TI - CNS genes implicated in relapse. AB - Drug abuse is a condition that impacts not only the individual drug user, but society as a whole. Although prevention of initial drug use is the most effective way to prevent addiction, avoiding relapse is a crucial component of drug addiction recovery. Recent studies suggest that there is a set of genes whose expression is robustly and stably altered following drug use and ensuing abstinence. Such stable changes in gene expression correlate with ultrastructural changes in brain as well as alterations in behavior. As persistent molecular changes, these genes may provide targets for the development of therapeutics. Developing a list of well-characterized candidate genes and examining the effect of manipulating these genes will contribute to the ultimate goal of developing effective treatments to prevent relapse to drug use. PMID- 25922575 TI - Lower Cortisol Activity is Associated with First-Time Driving while Impaired. AB - Driving while impaired (DWI) is a grave and persistent high-risk behavior. Previous work demonstrated that DWI recidivists had attenuated cortisol reactivity compared to non-DWI drivers. This suggests that cortisol is a neurobiological marker of high-risk driving. The present study tested the hypothesis that this initial finding would extend to first-time DWI (fDWI) offenders compared to non-DWI drivers. Male fDWI offenders (n = 139) and non-DWI drivers (n = 31) were exposed to a stress task, and their salivary cortisol activity (total output and reactivity) was measured. Participants also completed questionnaires on sensation seeking, impulsivity, substance use, and engagement in risky and criminal behaviors. As hypothesized, fDWI offenders, compared to non DWI drivers, had lower cortisol reactivity; fDWI offenders also showed lower total output. In addition, cortisol activity was the most important predictor of group membership, after accounting for alcohol misuse patterns and consequences and other personality and problem behavior characteristics. The findings indicate that attenuated cortisol activity is an independent factor associated with DWI offending risk at an earlier stage in the DWI trajectory than previously detected. PMID- 25922576 TI - Altered Sirtuin 7 Expression is Associated with Early Stage Breast Cancer. AB - BACKGROUND: To evaluate sirtuin-7 (SirT7) mRNA expression status in breast cancer patients with different metastatic stages and survey SirT7 mRNA expression status in eight different types of cancer. METHODS: The expression of SirT7 in the commercially available TissueScan qPCR Breast Cancer Disease cDNA arrays containing 16 normal, 23 Stage I, 36 IIA, 22 IIB, 8 IIIA, 23 IIIA, 6 IIIB, 13 IIIC, and 5 IV were evaluated by quantitative real-time polymerase chain reaction (qRT-PCR) assay. Similar analysis was performed in TissueScan qPCR Cancer Survey cDNA array, which includes breast, colon, kidney, liver, lung, ovarian, prostate, and thyroid specimens. RESULTS: The mRNA expression levels of SirT7 were significantly higher in breast cancer samples compared to normal breast specimens (P < 0.001). Stratification of patients into groups according to metastatic stages indicated statistically significantly higher levels of SirT7 mRNA in CS-I, CS-II, and CS-III when compared to normal breast tissue (P < 0.05). Notably, SirT7 mRNA levels were higher in CS-I, CS-IIA, CS-IIB, and CS-IIIA (P < 0.05). Additionally, there were significantly lower SirT7 mRNA levels in thyroid carcinoma when compared to their corresponding normal tissue (P < 0.05). CONCLUSIONS: Our results indicate an increase in the mRNA expression level of SirT7 in breast cancer, particularly in CS-I, CS-IIA, CS-IIB, and CS-IIIA. The relationship of altered SirT7 with breast cancer progression and patient survival should be prospectively explored in future studies. PMID- 25922577 TI - Defining the survival benchmark for breast cancer patients with systemic relapse. AB - BACKGROUND: Our original paper, published in 1992, reported a median overall survival after first relapse in breast cancer of 26 months. The current retrospective review concentrates more specifically on patients with first systemic relapse, recognizing that subsets of patients with local recurrence are potentially curable. METHODS: Records of 5,168 patients from a largely breast cancer-specific oncology practice were reviewed to identify breast cancer patients with their first relapse between 1996 and 2006 after primary treatment. There were 189 patients diagnosed with metastatic disease within 2 months of being seen by our therapeutic team and 101 patients diagnosed with metastatic disease greater than 2 months. The patients were divided in order to account for lead-time bias than could potentially confound the analysis of the latter 101 patients. RESULTS: Median survival for our primary study population of 189 patients was 33 months. As expected, the median survival from first systemic relapse (MSFSR) for the 101 patients excluded because of the potential for lead time bias was better at 46 months. Factors influencing prognosis included estrogen receptor (ER) status, disease-free interval (DFI), and dominant site of metastasis. Compared with our original series, even with elimination of local regional recurrences in our present series, the median survival from first relapse has improved by 7 months over the past two decades. CONCLUSION: The new benchmark for MSFSR approaches 3 years. PMID- 25922578 TI - Safety and Efficacy of Gadobutrol for Contrast-enhanced Magnetic Resonance Imaging of the Central Nervous System: Results from a Multicenter, Double-blind, Randomized, Comparator Study. AB - PURPOSE: Contrast-enhanced magnetic resonance imaging (MRI) of the central nervous system (CNS) with gadolinium-based contrast agents (GBCAs) is standard of care for CNS imaging and diagnosis because of the visualization of lesions that cause blood-brain barrier breakdown. Gadobutrol is a macrocyclic GBCA with high concentration and high relaxivity. The objective of this study was to compare the safety and efficacy of gadobutrol 1.0 M vs unenhanced imaging and vs the approved macrocyclic agent gadoteridol 0.5 M at a dose of 0.1 mmol/kg bodyweight. MATERIALS AND METHODS: Prospective, multicenter, double-blind, crossover trial in patients who underwent unenhanced MRI followed by enhanced imaging with gadobutrol or gadoteridol. Three blinded readers assessed the magnetic resonance images. The primary efficacy variables included number of lesions detected, degree of lesion contrast-enhancement, lesion border delineation, and lesion internal morphology. RESULTS: Of the 402 treated patients, 390 patients received study drugs. Lesion contrast-enhancement, lesion border delineation, and lesion internal morphology were superior for combined unenhanced/gadobutrol-enhanced imaging vs unenhanced imaging (P < 0.0001 for all). Compared with gadoteridol, gadobutrol was non-inferior for all primary variables and superior for lesion contrast-enhancement, as well as sensitivity and accuracy for detection of malignant disease. The percentage of patients with at least one drug-related adverse event was similar for gadobutrol (10.0%) and gadoteridol (9.7%). CONCLUSION: Gadobutrol is an effective and well-tolerated macrocyclic contrast agent for MRI of the CNS. Gadobutrol demonstrates greater contrast-enhancement and improved sensitivity and accuracy for detection of malignant disease than gadoteridol, likely because of its higher relaxivity. PMID- 25922580 TI - Locoregional prostate cancer treatment pattern variation in independent cancer centers: policy effect, patient preference, or physician incentive? AB - Surveillance, Epidemiologic, and End Results (SEER) registry data abstracted from a priority 2 or higher reporting source from 2006 to 2008 were used to compare treatment patterns in 45-64-year old men diagnosed with locoregional prostate cancer (LRPC) across states with or without radiation therapy-directed certificate of need (CON) laws and across independent cancer centers (ICCs) compared to large multi-specialty groups (LMSGs). Adjusted treatment percentages for the five most common LRPC treatments (surgery, external beam radiation therapy (EBRT), combination brachytherapy with EBRT, brachytherapy, and observation) were compared using cross-sectional logistic regression between CON unregulated and -regulated states and between LMSGs and ICCs. LRPC EBRT rates were no different across CON regions, but are increased in ICCs compared to LMSGs (37.00% vs. 13.23%, P < 0.001). Variation in LRPC treatment patterns by reporting source merits further scrutiny under the Affordable Care Act of 2010, considering the intent of incentivized accountable care organizations (ACOs) established by the Patient Protection and Affordable Care Act of 2010 (PPACA) and the implications of early descriptions of these new healthcare provider organizations on prostate cancer treatment patterns. PMID- 25922579 TI - Mechanisms of Heightened Airway Sensitivity and Responses to Inhaled SO2 in Asthmatics. AB - Sulfur dioxide (SO2) is a problematic inhalable air pollutant in areas of widespread industrialization, not only in the United States but also in countries undergoing rapid industrialization, such as China, and it can be a potential trigger factor for asthma exacerbations. It is known that asthmatics are sensitive to the effects of SO2; however, the basis of this enhanced sensitivity remains incompletely understood. A PubMed search was performed over the course of 2014, encompassing the following terms: asthma, airway inflammation, sulfur dioxide, IL-10, mouse studies, and human studies. This search indicated that biomarkers of SO2 exposure, SO2 effects on airway epithelial cell function, and animal model data are useful in our understanding of the body's response to SO2, as are SO2-associated amplification of allergic inflammation, and potential promotion of neurogenic inflammation due to chemical irritant properties. While definitive answers are still being sought, these areas comprise important foci of consideration regarding asthmatic responses to inhaled SO2. Furthermore, IL-10 deficiency associated with asthma may be another important factor associated with an inability to resolve inflammation and mitigate oxidative stress resulting from SO2 inhalation, supporting the idea that asthmatics are predisposed to SO2 sensitivity, leading to asthma exacerbations and airway dysfunction. PMID- 25922581 TI - Detection and Molecular Characterization of Potentially Pathogenic Free-living Amoebae from Water Sources in Kish Island, Southern Iran. AB - Amoebic keratitis, a sight-threatening corneal infection, mainly occurs in contact lens wearers who wash their eyes with tap water. The present research was conducted to identify the occurrence of potentially pathogenic free-living amoebae (FLA) in tap water sources on Kish Island, a tourist region in Iran. Amoebae were detected using a culture-enriched method and by polymerase chain reaction (PCR)/sequencing of the diagnostic fragment 3 region of the 18S rRNA gene of Acanthamoeba. In the case of other free-living amoebae species, PCR/sequencing analysis of the 18S rDNA was conducted. Results of this study showed the presence of Acanthamoeba belonging to T3, T4, T5, and T11 genotypes in tap water sources. Additionally, Vermamoebae vermiformis was detected in three water samples. This is the first report of the Acanthamoeba genotypes T3, T4, T5, and T11 and V. vermiformis species in tap water sources in a tourist region in Iran. PMID- 25922582 TI - Tryptophan-ethylester, the false (unveiled) melatonin isomer in red wine. AB - Among the food plants, the presence of melatonin in grapes (Vitis vinifera L.) deserves particular attention because of the production of wine, an alcoholic beverage of economic relevance and with putative healthy effects. Furthermore, melatonin isomers have been detected in wine too. Recently, one of these isomers has been identified as tryptophan-ethylester, a compound with the same molecular weight of melatonin. In this Commentary, we briefly comment the source(s) of tryptophan-ethylester in wine and the putative nutritional role(s). PMID- 25922583 TI - Inhibition of Apoptosis and Efficacy of Pan Caspase Inhibitor, Q-VD-OPh, in Models of Human Disease. AB - Apoptosis is physiological cell death required for the cellular maintenance of homeostasis, and caspases play a major role in the execution of this process. Numerous disorders occur when levels of apoptosis within an organism are excessive, and several studies have explored the possibility of using caspase inhibitors to prevent these disorders. Q-VD-OPh (quinolyl-valyl-O-methylaspartyl [2,6-difluorophenoxy]-methyl ketone), a novel pan caspase inhibitor, has been used because of its efficacy to inhibit apoptosis at low concentrations, its ability to cross the blood-brain barrier, as well as being nontoxic in vivo. This review examines Q-VD-OPh's ability to inhibit apoptosis in several animal models of human disease. PMID- 25922584 TI - Evaluation of the 4-French Pulsar-18 Self-expanding Nitinol Stent in Long Femoropopliteal Lesions. AB - PURPOSE: To evaluate the patency and the freedom of target lesion revascularization of the 4-French Pulsar-18 self-expandable (SE) nitinol stent for the treatment of long femoropopliteal occlusive disease in a two-center, prospective, all-comers registry with a follow-up period of 12 months. METHODS: This registry enrolled 36 patients with symptomatic femoropopliteal long lesions for recanalization and implantation of the 4-French Pulsar-18 SE nitinol stent. Routine follow-up examination including duplex ultrasound was performed after 6 and 12 months. Primary patency was defined as no binary restenosis on duplex ultrasound (Peak systolic velocitiy ration (PSVR) <2.5) and no target lesion revascularization was performed within 12 months' follow-up. No drug-eluting devices were allowed in this registry. RESULTS: Average lesion length of the femoropopliteal segment was 182.3 +/- 51.8 mm. Mean stent implantation length was 181.5 +/- 35.4 mm. Total occlusion was present in 46 of the 48 (95.8%) treated lesions. Involvement of popliteal segment I-III was present in 3 (6.3%) lesions. The primary patency after 6 and 12 months was 87.5% and 85.4%, respectively. The clinically driven overall freedom from target lesion revascularization (fTLR) was 89.6% after 6 months and 87.5% after 12 months. ABI, pain-free walking distance and Rutherford category, all improved significantly (P < 0.001) after 6 and 12 months. The primary patency rate in patients with diabetes (P = 0.18) and renal insufficiency (P = 0.3) was not significantly lower as compared to the overall primary patency. CONCLUSIONS: In this two-center, all-comers registry, the use of the Pulsar-18 SE nitinol stent for endovascular intervention of femoropopliteal disease with a mean lesion length of 182.3 +/- 51.8 mm showed promising primary patency and fTLR rates after 6 and 12 months. Diabetes and renal insufficiency had no negative impact on the patency rate. PMID- 25922585 TI - Circulating Inflammatory and Hemostatic Biomarkers are Associated with All-Cause Death and Cancer Death in a Population of Community-Dwelling Japanese: the Tanushimaru Study. AB - BACKGROUND: In patients with cardiovascular diseases, inflammatory and hemostatic biomarkers are significant indicators of prognosis. We investigated whether circulating inflammatory and hemostatic biomarkers were predictive markers for all-cause death and cancer death in a population of community-dwelling Japanese. METHODS: We studied 1,920 healthy Japanese adults who underwent health examinations in 1999. Those who reported a history of inflammatory diseases and malignancy on a baseline questionnaire were excluded. Inflammatory and hemostatic biomarkers were measured in the remaining 1,862 participants, who were followed up periodically for 10 years. Multivariate proportional hazards regression analysis was used to estimate all-cause and cancer mortality. RESULTS: A total of 258 participants died during follow-up: 87 from cancer, 38 from cerebro cardiovascular diseases, and 133 from other diseases. Mean C-reactive protein (CRP) levels at baseline were significantly higher in decedents than in survivors. Mean von Willebrand factor (vWF) levels at baseline were significantly higher in decedents than in survivors. The Cox proportional hazards model after adjustments for age and sex showed that CRP (hazard ratio [HR], 1.26; 95% confidence interval [CI], 1.06-1.51) and vWF (HR, 1.01; 95% CI, 1.00-1.01) were independent predictors of all-cause death. CRP (HR, 1.40; 95% CI, 1.06-1.86) and vWF (HR, 1.01; 95% CI, 1.00-1.02) were also independent predictive markers for cancer death. CONCLUSIONS: Serum CRP and vWF were predictors of all-cause death and cancer death in the population of community dwelling Japanese. PMID- 25922586 TI - Clinical Significance of Late Enhancement and Regional Wall Remodeling Assessed by 3T Magnetic Resonance Imaging. AB - BACKGROUND: Clinical follow-up studies comparing left ventricular (LV) function and late gadolinium enhancement (LGE) by high-field 3T cardiac magnetic resonance (CMR) are of general interest due to the increased use of 3T scanners. In this study, the occurrence of LGE and LV regional wall remodeling (RWR) was assessed by 3T CMR in patients undergoing coronary angiography for suspected stable coronary artery disease (CAD). MATERIALS AND METHODS: Analysis of myocardial viability by LGE was performed at the segmental level. LVRWR was identified by a significant reduction (>=50%) of the wall thickness. Major adverse cardiovascular events (MACE) were registered during a median follow-up time of 58 (45-62) months. RESULTS: Of the 87 patients (59 +/- 9 years; 13 women) enrolled, nonviable myocardium was detected in 35 (40%) and significant CAD in 69 (79%). Nonviable myocardium was correlated to angiographic significant stenosis or occlusion. LVRWR was significantly related to a higher number of nonviable segments compared to those without LVRWR: ie, 6.0 +/- 3.2 segments versus 2.6 +/- 1.3; P < 0.001. In the nonviable group, LVEF was significantly reduced (P < 0.001) compared to the viable group: ie, 50 +/- 16% versus 61 +/- 8%, and LVEF was significantly correlated to the number of nonviable segments (r = -0.66, P < 0.001). The number of nonviable segments by LGE was significantly associated with MACE by an odds ratio of 1.25 (95% CI, 1.05-1.49; P = 0.013). CONCLUSION: The presence of nonviable myocardium as detected by LGE at 3T CMR is associated with angiographically significant CAD, and is associated with the development of LVRWR and reduced LVEF. Assessing the extent of nonviable myocardium by both LGE and LVRWR at the segmental level may therefore contribute to individualized risk stratification and treatment strategies. PMID- 25922587 TI - Diastolic function in heart failure. AB - Heart failure has reached epidemic proportions, and diastolic heart failure or heart failure with preserved ejection fraction (HFpEF) constitutes about 50% of all heart failure admissions. Long-term prognosis of both reduced ejection fraction heart failure and HFpEF are similarly dismal. No pharmacologic agent has been developed that actually treats or repairs the physiologic deficit(s) responsible for HFpEF. Because the physiology of diastole is both subtle and counterintuitive, its role in heart failure has received insufficient attention. In this review, the focus is on the physiology of diastole in heart failure, the dominant physiologic laws that govern the process in all hearts, how all hearts work as a suction pump, and, therefore, the elucidation and characterization of what actually is meant by "diastolic function". The intent is for the reader to understand what diastolic function actually is, what it is not, and how to measure it. Proper measurement of diastolic function requires one to go beyond the usual E/A, E/E', etc. phenomenological metrics and employ more rigorous causality (mathematical modeling) based parameters of diastolic function. The method simultaneously provides new physiologic insight into the meaning of in vivo "equilibrium volume" of the left ventricle (LV), longitudinal versus transverse volume accommodation of the chamber, diastatic "ringing" of the mitral annulus, and the mechanism of L-wave generation, as well as availability of a load-independent index of diastolic function (LIIDF). One important consequence of understanding what diastolic function is, is the recognition that all that current therapies can do is basically alter the load, rather than actually "repair" the functional components (chamber stiffness, chamber relaxation). If beneficial (biological/structural/metabolic) remodeling due to therapy does manifest ultimately as improved diastolic function, it is due to resumption of normal physiology (as in alleviation of ischemia) or activation of compensatory pathways already devised by evolution. In summary, meaningful quantitative characterization of diastolic function in any clinical setting, including heart failure, requires metrics based on physiologic mechanisms that quantify the suction pump attribute of the heart. This requires advancing beyond phenomenological global indexes such as E/A, E/E', Vp, etc. and employing causality (mathematical modeling) based parameters of diastolic function easily obtained via the parametrized diastolic function (PDF) formalism. PMID- 25922588 TI - Normalization of lung function following treatment of secondary usual interstitial pneumonia: a case report. AB - Usual interstitial pneumonia (UIP) is the most common idiopathic interstitial pneumonia (IIP) and is associated with a poor prognosis and poor responsiveness to immunosuppressive therapy. We present a case of a woman with steroid responsive biopsy-proven UIP with significant and sustained improvement in pulmonary function. A female in her 40s presented following a one-year history of progressive dyspnea, a 20 lb weight loss, and fatigue. Imaging of the chest with computed tomography (CT) showed bibasilar subpleural reticular opacities and minimal peripheral honeycombing. Comprehensive connective tissue disease (CTD) antibody testing was negative. Pulmonary function testing showed moderate impairment with reduction in forced vital capacity (FVC, 69% predicted), forced expiratory volume in one second (FEV1 73% predicted), and diffusing capacity for carbon monoxide (DLCO, 52% predicted). Surgical lung biopsy showed UIP with prominent inflammatory infiltrates. Following treatment with prednisone and azathioprine, the patient's symptoms resolved, while objective pulmonary function testing showed normalization of lung function, which is sustained at >4 years of follow-up. Improvement in lung function following immunosuppressive therapy is distinctly uncommon in either idiopathic or secondary UIP. This report suggests that occasionally, patients with secondary UIP occurring in the context of otherwise undefinable autoimmune clinical syndromes may be responsive to immunosuppressive therapy. PMID- 25922589 TI - Mimics of duplication cysts: intraperitoneal nodules in a 14-year-old boy. AB - Hemangiomas are the most common primary hepatic tumors, but there are few reports of their occurrence elsewhere in the abdomen. The concurrent existence of multiple fibrous nodules of the omentum, mesentery, and porta hepatis, along with a gastric hemangioma, in a child raises the question of syndromic association. Our search of the English literature revealed only rare mentions of hemangiomas involving the stomach and mesentery or omentum. These lesions have attracted clinical attention by symptoms of obstruction, gastrointestinal bleeding, intussusception, infection, perforation, or vague abdominal pain. Although some tumors exist unnoticed for many decades and are identified only incidentally, others present emergently and require immediate surgical attention. We report the case of a 14-year-old boy who presented with symptoms similar to those for appendicitis or duplication cyst, who was found to have a torsed gastric hemangioma and multiple benign fibrous nodules in the abdomen. The presence of multiple vascular or fibrous lesions is associated with genetic syndromes that can have lifelong and reproductive repercussions; so it is imperative that these tumors be recognized by diagnosticians. PMID- 25922590 TI - The Role of Uterine and Umbilical Arterial Doppler in High-risk Pregnancy: A Prospective Observational Study from India. AB - AIM: To study the role of Doppler imaging in prediction of high-risk pregnancies and their outcomes. METHODS AND MATERIAL: This prospective study in a setup of tertiary-level care center includes 500 high-risk pregnant women from rural and urban sectors and evaluates the predictive values of various Doppler indices. RESULTS: Out of 500 patients, 110 patients had abnormal Doppler among them, 70 patients had abnormal uterine artery Doppler, and 50 patients had abnormal umbilical artery Doppler flow indices. In all, 10 patients had both umbilical artery and uterine artery abnormal Doppler indices. When uterine artery was abnormal (70 patients), 20 patients had preeclampsia, 10 patients had pregnancy induced hypertension (PIH), and 25 patients had intrauterine growth restriction (IUGR). Systolic/diastolic (S/D) ratio and notch had sensitivity of 60% and positive predictive value of 33.3% and 37.5%, respectively. When umbilical artery was abnormal (50 patients), 10 had preeclampsia, 15 had PIH, and 15 had IUGR. S/D ratio had the highest positive predictive value of 40%; sensitivity is same for all. In uterine artery, combination of parameters had the best sensitivity of 80%, followed by notch and S/D ratio. In umbilical artery, combination of parameters, S/D ratio, and RI (resistance index) had sensitivity of 40%; specificity of all the indices was 91-96%. In all, 20 patients had bilateral notch, and among them 15 developed preeclampsia and 15 developed IUGR. When both uterine and umbilical artery Doppler were abnormal (10 patients), all patients had preeclampsia and IUGR. CONCLUSION: Therefore, Doppler study may be used for the prediction of preeclampsia and IUGR to reduce the maternal and perinatal morbidity and mortality. PMID- 25922591 TI - Successful prednisolone therapy in elderly patients with severe forms of henoch schonlein purpura nephritis. AB - INTRODUCTION: Recently, Henoch-Schonlein purpura (HSP) has been observed in elderly people, although it was believed to be uncommon in these subjects. The increased risks of developing end-stage renal disease (ESRD) in adults in comparison with children were highlighted by different studies; however, limited data are available on the treatment of HSP nephritis in adults. METHODS: Between 2002 and 2008, five elderly Japanese patients (>65 years old) (mean age, 68 years, ranging from 65 to 72) with severe forms of HSP nephritis were entered into a prospective study to evaluate prednisolone therapy on the outcome of nephropathy in terms of clinical symptoms and histopathological changes. The patients were considered at risk of developing chronic renal failure when they presented with a nephrotic syndrome and crescentic glomeruli. RESULTS: At the last follow-up, 4-10 years after initiation of the therapy, four patients had clinically recovered and one died of lung cancer. No patients developed ESRD. The clinical outcome seemed to be correlated with glomerular activity (massive proteinuria and crescent formation). In spite of a relatively large dose of prednisolone, a few adverse effects, such as insomnia and skin lesions, were observed. DISCUSSION: Our preliminary small study suggests that renal outcome as well as survival of elderly patients with severe forms of HSP might be altered by aggressive prednisolone therapy. PMID- 25922592 TI - Pentoxifylline reduces the inflammatory process in diabetic rats: relationship with decreases of pro-inflammatory cytokines and inducible nitric oxide synthase. AB - Studies suggest that inflammation is a key factor in the pathogenesis of diabetes mellitus. Pro-inflammatory cytokines, such as IL-6 and TNF-alpha, are produced by adipose tissue in large quantities, in obese and especially in diabetic individuals. Pentoxifylline (PTX) is a non-selective phosphodiesterase inhibitor with anti-inflammatory and antioxidant actions that may contribute to alleviate diabetes side effects, as neuropathy, retinopathy and nephropathy. This study aims to investigate PTX anti-inflammatory effects on the carrageenan-induced paw edema model, in alloxan-induced diabetic rats. Diabetic animals (male Wistar rats, 200-250 g) were daily treated with PTX (25, 50, 100 mg/kg, p.o.), glibenclamide (GLI, 5 mg/kg, p.o., as reference) or water, for 5 days. Afterwards, carrageenan-treated paws were dissected, their skin removed and the tissue used for preparation of homogenates and measurements of IL-6 and TNF-alpha by Elisa. Serum levels of nitrite were also determined and paw slices used for iNOS immunohistochemistry assays. We showed that diabetic rats presented an amplification of the inflammatory response, as related to non-diabetic rats, what was evident 48 h after the edema-induction. The PTX-treatment of diabetic rats reduced glycemia (as related to untreated-diabetic ones) and the paw edema. It also brought edema volumes to values similar to those of non-diabetic rats, at the same observation time. The increased TNF-alpha and IL-6 levels in paws of untreated-diabetic rats were reduced in diabetic animals after PTX treatments. Besides, the increased levels of nitrite in the serum of diabetic rats were also decreased by PTX. Furthermore, a higher number of iNOS immunostained cells was demonstrated in paw tissues from untreated-diabetic rats, as related to those of PTX-treated diabetic animals. Our results show that PTX reduces inflammatory parameters, as pro-inflammatory cytokines and iNOS expression, indicating the potential benefit of the drug for the treatment of diabetes and related pathologic conditions. PMID- 25922593 TI - Recent advances of vaccine adjuvants for infectious diseases. AB - Vaccines are the most effective and cost-efficient method for preventing diseases caused by infectious pathogens. Despite the great success of vaccines, development of safe and strong vaccines is still required for emerging new pathogens, re-emerging old pathogens, and in order to improve the inadequate protection conferred by existing vaccines. One of the most important strategies for the development of effective new vaccines is the selection and usage of a suitable adjuvant. Immunologic adjuvants are essential for enhancing vaccine potency by improvement of the humoral and/or cell-mediated immune response to vaccine antigens. Thus, formulation of vaccines with appropriate adjuvants is an attractive approach towards eliciting protective and long-lasting immunity in humans. However, only a limited number of adjuvants is licensed for human vaccines due to concerns about safety and toxicity. We summarize current knowledge about the potential benefits of adjuvants, the characteristics of adjuvants and the mechanisms of adjuvants in human vaccines. Adjuvants have diverse modes of action and should be selected for use on the basis of the type of immune response that is desired for a particular vaccine. Better understanding of current adjuvants will help exploring new adjuvant formulations and facilitate rational design of vaccines against infectious diseases. PMID- 25922594 TI - Adoptive Cell Therapy of Melanoma with Cytokine-induced Killer Cells. AB - Melanoma is the most aggressive skin cancer and its incidence is gradually increasing worldwide. Patients with metastatic melanoma have a very poor prognosis (estimated 5-year survival rate of <16%). In the last few years, several drugs have been approved for malignant melanoma, such as tyrosine kinase inhibitors and immune checkpoint blockades. Although new therapeutic agents have improved progression-free and overall survival, their use is limited by drug resistance and drug-related toxicity. At the same time, adoptive cell therapy of metastatic melanoma with tumor-infiltrating lymphocytes has shown promising results in preclinical and clinical studies. In this review, we summarize the currently available drugs for treatment of malignant melanoma. In addition, we suggest cytokine-induced killer (CIK) cells as another candidate approach for adoptive cell therapy of melanoma. Our preclinical study and several previous studies have shown that CIK cells have potent anti-tumor activity against melanomas in vitro and in an in vivo human tumor xenograft model without any toxicity. PMID- 25922595 TI - Circulating Levels of Adipokines Predict the Occurrence of Acute Graft-versus host Disease. AB - Currently, detecting biochemical differences before and after allogeneic stem cell transplantation (SCT) for improved prediction of acute graft-versus-host disease (aGVHD) is a major clinical challenge. In this pilot study, we analyzed the kinetics of circulating adipokine levels in patients with or without aGVHD before and after allogeneic SCT. Serum samples were obtained and stored at -80C within 3 hours after collection, prior to conditioning and at engraftment after transplantation. A protein array system was used to measure the levels of 7 adipokines of patients with aGVHD (n=20) and without aGVHD (n=20). The resistin level at engraftment was significantly increased (p<0.001) after transplantation, regardless of aGVHD occurrence. In the non-aGVHD group, the concentrations of the hepatocyte growth factor (HGF) (mean values+/-SD; 206.6+/-34.3 vs. 432.3+/-108.9 pg/ml, p=0.040) and angiopoietin-2 (ANG-2) (mean values+/-SD; 3,197.2+/-328.3 vs. 4,471.8+/-568.4 pg/ml, p=0.037) at engraftment were significantly higher than those of the pre-transplant period, whereas in the aGVHD group, the levels of adipokines did not change after transplantation. Our study suggests that changes in serum HGF and ANG-2 levels could be considered helpful markers for the subsequent occurrence of aGVHD. PMID- 25922596 TI - Caspase-1 independent viral clearance and adaptive immunity against mucosal respiratory syncytial virus infection. AB - Respiratory syncytial virus (RSV) infection is recognized by the innate immune system through Toll like receptors (TLRs) and retinoic acid inducible gene I. These pathways lead to the activation of type I interferons and resistance to infection. In contrast to TLRs, very few studies have examined the role of NOD like receptors in viral recognition and induction of adaptive immune responses to RSV. Caspase-1 plays an essential role in the immune response via the maturation of the proinflammatory cytokines IL-1beta and IL-18. However, the role of caspase 1 in RSV infection in vivo is unknown. We demonstrate that RSV infection induces IL-1beta secretion and that caspase-1 deficiency in bone marrow derived dendritic cells leads to defective IL-1beta production, while normal RSV viral clearance and T cell responses are observed in caspase-1 deficient mice following respiratory infection with RSV. The frequencies of IFN-gamma producing or RSV specific T cells in lungs from caspase-1 deficient mice are not impaired. In addition, we demonstrate that caspase-1 deficient neonatal or young mice also exhibit normal immune responses. Furthermore, we find that IL-1R deficient mice infected with RSV exhibit normal Th1 and cytotoxic T lymphocytes (CTL) immune responses. Collectively, these results demonstrate that in contrast to TLR pathways, caspase-1 might not play a central role in the induction of Th1 and CTL immune responses to RSV. PMID- 25922597 TI - Investigation of Immune Biomarkers Using Subcutaneous Model of M. tuberculosis Infection in BALB/c Mice: A Preliminary Report. AB - Evaluation and screening of vaccines against tuberculosis depends on development of proper cost effective disease models along with identification of different immune markers that can be used as surrogate endpoints of protection in preclinical and clinical studies. The objective of the present study was therefore evaluation of subcutaneous model of M.tuberculosis infection along with investigation of different immune biomarkers of tuberculosis infection in BALB/c mice. Groups of mice were infected subcutaneously with two different doses : high (2*10(6) CFU) and low doses (2*10(2) CFU) of M.tuberculosis and immune markers including humoral and cellular markers were evaluated 30 days post M.tuberculosis infections. Based on results, we found that high dose of subcutaneous infection produced chronic disease with significant (p<0.001) production of immune markers of infection like IFNgamma, heat shock antigens (65, 71) and antibody titres against panel of M.tuberculosis antigens (ESAT-6, CFP-10, Ag85B, 45kDa, GroES, Hsp-16) all of which correlated with high bacterial burden in lungs and spleen. To conclude high dose of subcutaneous infection produces chronic TB infection in mice and can be used as convenient alternative to aerosol models in resource limited settings. Moreover assessment of immune markers namely mycobacterial antigens and antibodies can provide us valuable insights on modulation of immune response post infection. However further investigations along with optimization of study protocols are needed to justify the outcome of present study and establish such markers as surrogate endpoints of vaccine protection in preclinical and clinical studies in future. PMID- 25922598 TI - Anti-herpes Activity of Vinegar-processed Daphne genkwa Flos Via Enhancement of Natural Killer Cell Activity. AB - Herpes simplex virus (HSV) is a common causative agent of genital ulceration and can lead to subsequent neurological disease in some cases. Here, using a genital infection model, we tested the efficacy of vinegar-processed flos of Daphne genkwa (vp-genkwa) to modulate vaginal inflammation caused by HSV-1 infection. Our data revealed that treatment with optimal doses of vp-genkwa after, but not before, HSV-1 infection provided enhanced resistance against HSV-1 infection, as corroborated by reduced mortality and clinical signs. Consistent with these results, treatment with vp-genkwa after HSV-1 infection reduced viral replication in the vaginal tract. Furthermore, somewhat intriguingly, treatment of vp-genkwa after HSV-1 infection increased the frequency and absolute number of CD3( )NK1.1(+)NKp46(+) natural killer (NK) cells producing interferon (IFN)-gamma and granyzme B, which indicates that vp-genkwa treatment induces the activation of NK cells. Supportively, secreted IFN-gamma was detected at an increased level in vaginal lavages of mice treated with vp-genkwa after HSV-1 infection. These results indicate that enhanced resistance to HSV-1 infection by treatment with vp genkwa is associated with NK cell activation. Therefore, our data provide a valuable insight into the use of vp-genkwa to control clinical severity in HSV infection through NK cell activation. PMID- 25922599 TI - 1-palmitoyl-2-linoleoyl-3-acetyl-rac-glycerol (EC-18) Modulates Th2 Immunity through Attenuation of IL-4 Expression. AB - Controlling balance between T-helper type 1 (Th1) and T-helper type 2 (Th2) plays a pivotal role in maintaining the biological rhythm of Th1/Th2 and circumventing diseases caused by Th1/Th2 imbalance. Interleukin 4 (IL-4) is a Th2-type cytokine and often associated with hypersensitivity-related diseases such as atopic dermatitis and allergies when overexpressed. In this study, we have tried to elucidate the function of 1-palmitoyl-2-linoleoyl-3-acetyl-rac-glycerol (EC-18) as an essential modulator of Th1/Th2 balance. EC-18 has showed an inhibitory effect on the production of IL-4 in a dose-dependent manner. RT-PCR analysis has proved EC-18 affect the transcription of IL-4. By analyzing the phosphorylation status of Signal transducer and activator of transcription 6 (STAT6), which is a transcriptional activator of IL-4 expression, we discovered that EC-18 induced the decrease of STAT6 activity in several stimulated cell lines, which was also showed in STAT6 reporter analysis. Co-treatment of EC-18 significantly weakened atopy-like phenotypes in mice treated with an allergen. Collectively, our results suggest that EC-18 is a potent Th2 modulating factor by regulating the transcription of IL-4 via STAT6 modulation, and could be developed for immune modulatory therapeutics. PMID- 25922600 TI - A Left-Sided Prevalence of Lentigo Maligna: A UK Based Observational Study and Review of the Evidence. AB - Skin cancer has been shown to present asymmetrically, prevalent on the left side of the body, more so in subtypes of cutaneous melanoma such as lentigo maligna. Biases have been linked to cumulative UV light exposure and automobile driving patterns. Though left-right ratios have previously correlated with the side men or women tend to position themselves or countries drive on, more recent trends indicate a consistent left-sided bias. To clarify reasons for changing trends, a review of the evidence base and LM's laterality in a UK cohort (99 cases 2000 2011) was conducted for the first time. The strong correlation of left-sided excess, found in both genders (ratios 1.381-1.5, P < 0.05 X (2) 0.841), is congruent with more recent findings. Though evidence indicates that driving position is no longer a risk factor for LM, due most likely to improved car window UV protection, it remains the most commonly attributed cause. Understanding phenomena such as UV lights "scatter effect" or that cumulative exposure may not be a significant risk factor helps rationalize older conclusions that would otherwise appear contradictory. The reasons for left-sided excess remain unclear but may be due to factors requiring further research such as the body's anatomical/embryological asymmetry. PMID- 25922602 TI - Clinical outcomes and quality of life in recipients of livers donated after cardiac death. AB - Donation after cardiac death (DCD) has expanded in the last decade in the US; however, DCD liver utilization has flattened in recent years due to poor outcomes. We examined clinical and quality of life (QOL) outcomes of DCD recipients by conducting a retrospective and cross-sectional review of patients from 2003 to 2010. We compared clinical outcomes of DCD recipients (n = 60) to those of donation after brain death (DBD) liver recipients (n = 669) during the same time period. DCD recipients had significantly lower rates of 5-year graft survival (P < 0.001) and a trend toward lower rates of 5-year patient survival (P = 0.064) when compared to the DBD cohort. In order to examine QOL outcomes in our cohorts, we administered the Short Form Liver Disease Quality of Life questionnaire to 30 DCD and 60 DBD recipients. The DCD recipients reported lower generic and liver-specific QOL. We further stratified the DCD cohort by the presence of ischemic cholangiopathy (IC). Patients with IC reported lower QOL when compared to DBD recipients and those DCD recipients without IC (P < 0.05). While the results are consistent with clinical experience, this is the first report of QOL in DCD recipients using standardized measures. These data can be used to guide future comparative effectiveness studies. PMID- 25922603 TI - The Utility of Capsule Endoscopy in Patients under 50 Years of Age with Recurrent Iron Deficiency Anaemia: Is the Juice Worth the Squeeze? AB - Background and Aims. The role of capsule endoscopy (CE) in the <50 years of age patients with iron deficiency anaemia (IDA) remains unclear. We aim to assess its utility in this cohort. Methods. All patients referred for CE for recurrent IDA were included retrospectively. Patients were divided into Group 1 (<50 years) and Group 2 (>=50 years). Results. There were 971 patients with recurrent IDA and 28% belonged to Group 1. The mean age was 40 years in this group with a DY of 28% (n = 76). Significant diagnoses included erosions and ulcers (26%; n = 71), small bowel (SB) angioectasia (AE) (10%; n = 27), SB tumours (3%; n = 7), Crohn's disease (3%; n = 7), SB bowel strictures (1%; n = 3), and SB varices (1%; n = 2). On logistic regression, the presence of diabetes (P = 0.02) and the use of warfarin (P = 0.049) was associated with increased DY. The DY in Group 2 was 38% which was significantly higher than in Group 1 (P = 0.02). While SB tumours were equally common in both groups, AE was commoner in Group 2 (P < 0.001). Conclusion. A significant proportion of patients <50 years are referred for CE. Although the DY is lower compared to those >=50 years, significant pathology is found in this age group. CE is advisable in patients <50 years old with recurrent IDA and negative bidirectional endoscopies. PMID- 25922601 TI - Molecular Pathogenesis of MALT Lymphoma. AB - Approximately 8% of all non-Hodgkin lymphomas are extranodal marginal zone B cell lymphoma of mucosa associated lymphoid tissue (MALT), also known as MALT lymphoma, which was first described in 1983 by Isaacson and Wright. MALT lymphomas arise at a wide range of different extranodal sites, with the highest frequency in the stomach, followed by lung, ocular adnexa, and thyroid, and with a low percentage in the small intestine. Interestingly, at least 3 different, apparently site-specific, chromosomal translocations and missense and frameshift mutations, all pathway-related genes affecting the NF-kappaB signal, have been implicated in the development and progression of MALT lymphoma. However, these genetic abnormalities alone are not sufficient for malignant transformation. There is now increasing evidence suggesting that the oncogenic product of translocation cooperates with immunological stimulation in oncogenesis, that is, the association with chronic bacterial infection or autoaggressive process. This review mainly discusses MALT lymphomas in terms of their genetic aberration and association with chronic infections and summarizes recent advances in their molecular pathogenesis. PMID- 25922604 TI - Necrosis of the ventral penile skin flap: a complication of hypospadias surgery in children. AB - Objectives. To review cases of hypospadias that were repaired with TIPU method and consequently resulted in the necrosis of ventral penile skin flaps. Methods. Eighty-three patients with hypospadias underwent TIPU procedure by two surgeons. Neourethra in all patients was covered with dartos flap prepared from the preputium or penile shaft. In cases where ventral skin could not be covered primarily, closure was ensured by using preputial Ombredanne or Byars' flaps to repair ventral defects. Results. The median age of patients was 4 years. Twenty five (30.12%) patients that underwent hypospadias repair had urethral opening at the coronal level, 33 (39.75%) at the distal penis, 10 (12.04%) at the midpenis, and 15 (18.07%) at the proximal penis. The ventral skin defect could not be primarily covered in 10 patients with penile shaft hypospadias. Consequently, Byars' method was used in 8 of these patients to cover the defect and the Ombredanne method was used in the remaining 2. Ventral skin flap necrosis developed in 5 patients (4 Byars and 1 Ombredanne). It was medically treated in 4 patients. Urethral fistula developed in the other patient whose necrosis was deeper. The mean hospital stay was 7 days for patients without necrosis, and 14 for those with necrosis. Conclusion. We are of the opinion that dartos flaps used in the TIPU method in order to cover neourethra and decrease the incidence of fistula development lead to necrosis in the Ombredanne or Byars' flaps by causing low blood supply to the preputium and thus extend hospital stay. PMID- 25922605 TI - The role of hyaluronan in innate defense responses of the intestine. AB - Hyaluronan is an abundant extracellular matrix component prevalent in the vertebrate intestinal tract. Here we discuss what is known about hyaluronan distribution during homeostasis and inflammatory diseases of the gut and discuss ways in which this glycosaminoglycan can participate in regulating innate host defense mechanisms. These natural responses include mechanisms promoting rapid leukocyte recruitment after bacterial challenge/colon tissue damage as well as promoting epithelial defense mechanisms in the intestine. PMID- 25922606 TI - Vertigo as a predominant manifestation of neurosarcoidosis. AB - Sarcoidosis is a granulomatous disease of unknown etiology that affects multiple organ systems. Neurological manifestations of sarcoidosis are less common and can include cranial neuropathies and intracranial lesions. We report the case of a 21 year-old man who presented with vertigo and uveitis. Extensive workup including brain imaging revealed enhancing focal lesions. A lacrimal gland biopsy confirmed the diagnosis of sarcoidosis. The patient was initially treated with prednisone, which did not adequately control his symptoms, and then was switched to methotrexate with moderate symptomatic improvement. Our patient had an atypical presentation with vertigo as the predominant manifestation of sarcoidosis. Patients with neurosarcoidosis typically present with systemic involvement of sarcoidosis followed by neurologic involvement. Vertigo is rarely reported as an initial manifestation. This case highlights the importance of consideration of neurosarcoidosis as an entity even in patients that may not have a typical presentation or systemic involvement of disease. PMID- 25922607 TI - Rash with DERMABOND PRINEO Skin Closure System Use in Bilateral Reduction Mammoplasty: A Case Series. AB - Background. Bilateral reduction mammoplasty is a common plastic surgery procedure that can be complicated by unfavorable scar formation along incision sites. Surgical adhesives can be utilized as an alternative or as an adjunct to conventional suture closures to help achieve good wound tension and provide an adequate barrier with excellent cosmesis. The recently introduced DERMABOND PRINEO Skin Closure System Skin Closure System combines the skin adhesive 2-octyl cyanoacrylate with a self-adhering polyester-based mesh. Proposed benefits of wound closure with DERMABOND PRINEO Skin Closure System, used with or without sutures, include its watertight seal, easy removal, microbial barrier, even distribution of tension, and reduction in wound closure time. Although allergic reactions to 2-octyl cyanoacrylate have been reported, few allergic reactions to DERMABOND PRINEO Skin Closure System have been noted in the literature. This case series describes three patients who experienced an allergic reaction to DERMABOND PRINEO Skin Closure System after undergoing elective bilateral reduction mammoplasties at our institution to further explore this topic. Methods. Retrospective chart review of bilateral reduction mammoplasty patients who received DERMABOND PRINEO Skin Closure System dressing at our institution was performed. Results. Three patients were identified as having a rash in reaction to DERMABOND PRINEO Skin Closure System after bilateral reduction mammoplasty. All three patients required systemic steroid treatment to resolve the rash. One patient was identified as having a prior adhesive reaction. Conclusions. DERMABOND PRINEO Skin Closure System has demonstrated its efficacy in optimizing scar healing and appearance. However, as we demonstrate these three allergic reactions to DERMABOND PRINEO Skin Closure System, caution must be utilized in its usage, namely, in patients with a prior adhesive allergy and in sites where moisture or friction may be apparent. PMID- 25922608 TI - Reprogramming with Small Molecules instead of Exogenous Transcription Factors. AB - Induced pluripotent stem cells (iPSCs) could be employed in the creation of patient-specific stem cells, which could subsequently be used in various basic and clinical applications. However, current iPSC methodologies present significant hidden risks with respect to genetic mutations and abnormal expression which are a barrier in realizing the full potential of iPSCs. A chemical approach is thought to be a promising strategy for safety and efficiency of iPSC generation. Many small molecules have been identified that can be used in place of exogenous transcription factors and significantly improve iPSC reprogramming efficiency and quality. Recent studies have shown that the use of small molecules results in the generation of chemically induced pluripotent stem cells from mouse embryonic fibroblast cells. These studies might lead to new areas of stem cell research and medical applications, not only human iPSC by chemicals alone, but also safe generation of somatic stem cells for cell based clinical trials and other researches. In this paper, we have reviewed the recent advances in small molecule approaches for the generation of iPSCs. PMID- 25922609 TI - Progression of autosomal dominant kidney disease: measurement of the stage transitions of chronic kidney disease. AB - BACKGROUND: Autosomal dominant polycystic kidney disease (ADPKD) is a progressive genetic disorder characterized by the development of numerous kidney cysts that result in kidney failure. Little is known regarding the key patient characteristics and utilization of healthcare resources for ADPKD patients along the continuum of disease progression. This observational study was designed to describe the characteristics of ADPKD patients and compare them with those of patients with other chronic kidney diseases. METHODS: This retrospective cohort study involved patients with a claim for ADPKD or PKD unspecified from 1/1/2000 2/28/2013 and >=6 months of previous continuous enrollment (baseline) within a large database of administrative claims in the USA. A random sample of chronic kidney disease (CKD) patients served as comparators. For a subset of ADPKD patients who had only a diagnosis code of unspecified PKD, abstraction of medical records was undertaken to estimate the proportion of patients who had medical chart-confirmed ADPKD. In patients with linked electronic laboratory data, the estimated glomerular filtration rate was calculated via serum creatinine values to determine CKD stage at baseline and during follow-up. Proportions of patients transitioning to another stage and the mean age at transition were calculated. RESULTS: ADPKD patients were, in general, younger and had fewer physician visits, but had more specific comorbidities at observation start compared with CKD patients. ADPKD patients had a longer time in the milder stages and longer duration before recorded transition to a more severe stage compared with CKD patients. Patients with ADPKD at risk of rapid progression had a shorter time-to end-stage renal disease than patients with CKD and ADPKD patients not at risk, but stage duration was similar between ADPKD patients at risk and those not at risk. CONCLUSIONS: These results suggest that distribution of patients by age at transition to next stage may be useful for identification of ADPKD patients at risk of rapid progression. The results also suggest that medical claims with diagnosis codes for "unspecified PKD", in absence of a diagnosis code for autosomal recessive polycystic kidney disease, may be a good proxy for ADPKD. PMID- 25922610 TI - Network pharmacology-based antioxidant effect study of zhi-zi-da-huang decoction for alcoholic liver disease. AB - Zhi-Zi-Da-Huang decoction (ZZDHD), a classic traditional Chinese medicine (TCM) formula, has been used for centuries to treat alcoholic liver disease. Reliable therapeutics of ZZDHD has also been validated in clinical practice. In this study, molecular docking and network analysis were carried out to explore the antioxidative mechanism of ZZDHD as an effective therapeutic approach to treat alcoholic liver disease. Multiple active compounds of ZZDHD were screened based on four key original enzymes (cytochrome P450 2E1, xanthine oxidase, inducible nitric oxide synthase, and cyclooxygenase-2) involved in ethanol-induced oxidative stress damage. A drug-target network was constructed through network pharmacology analysis, which predicted the relationships of active ingredients to the targets. Some results had been verified by the previous experimental pharmacological studies; meanwhile, it was first reported that xanthine oxidase and eriocitrin, neoeriocitrin, isorhoifolin, and poncirin had interactions. The network pharmacology strategy used provided a forceful tool for searching the mechanism of action of TCM formula and novel bioactive ingredients. PMID- 25922611 TI - Antioxidant and antimycotic activities of two native lavandula species from portugal. AB - The antioxidant and antimycotic activities of the essential oils and extracts of two native Portuguese Lavandula species, L. stoechas subsp. luisieri and L. pedunculata, were evaluated by in vitro assays. The total phenolics and flavonoids content were also determined. The antioxidant potential was assessed through DPPH radical scavenging, inhibition of lipid peroxidation (ILP), and DNA protection assays. All samples displayed a high DPPH scavenging activity, some of them showing concentration dependence. The majority of the samples were also able to inhibit lipid peroxidation. A strong correlation was observed between the results of DPPH and ILP assays and the flavonoids content of the samples. In the DNA protection assay, all the extracts were able to preserve DNA integrity. The antimycotic activity was performed against twelve fungi belonging to Basidiomycota and Ascomycota Divisions. L. stoechas subsp. luisieri exhibited the broadest activity spectra. L. pedunculata extracts were active against five fungi. Cryptococcus neoformans was the most sensitive, being inhibited by all the extracts. Our results led to the conclusion that L. stoechas subsp. luisieri and L. pedunculata can be useful as new sources of natural antioxidants and antimycotic agents, providing a possible valorization of the existing biodiversity and resources of Portuguese flora. PMID- 25922613 TI - Complementary and alternative medicine in cancer prevention and therapy. PMID- 25922612 TI - Changes of locoregional skin temperature in neonates undergoing laser needle acupuncture at the acupuncture point large intestine 4. AB - Laser acupuncture bears a potential risk for the skin surface, especially in neonates whose skin has histological and physiological peculiarities. We evaluated thermal changes of skin temperature in neonates during laser acupuncture by using a thermal camera (Flir i5, Flir Systems Inc., Portland, USA). Laserneedles (Laserneedle GmbH, Glienicke/Nordbahn, Germany) were fixed to the skin at Large Intestine 4 (LI 4, Hegu), bilaterally. Before application of laser acupuncture (685 nm, 15 mW, 500 MUm), as well as after 1, 5, and 10 min, thermographic pictures of both hands were taken. The measuring was carried out on the 23rd day after birth (20 neonates, mean postmenstrual gestational age 38 + 2, mean weight 2604 g). Compared to the initial temperature of 34.2 degrees C on the right hand, the skin temperature had increased to 35.3 degrees C (P < 0.05) after 5 min and up to 36.1 degrees C (P < 0.05) after 10 min of stimulation. Equally, on the left hand, an increase of the skin temperature from 34.5 degrees C to 35.9 degrees C (P < 0.05) and 35.9 degrees C (P < 0.05) was measured. The highest measured skin temperature after 10 min of stimulation amounted to 38.7 degrees C, without any clinically visible changes on the skin surface. PMID- 25922614 TI - Progressive muscle relaxation improves anxiety and depression of pulmonary arterial hypertension patients. AB - We explored the effects of progressive muscle relaxation (PMR) on anxiety, depression, and quality of life (QOL) in patients with pulmonary arterial hypertension (PAH). One hundred and thirty Han Chinese patients with PAH were randomly assigned to a PMR group (n = 65) and a control group (n = 65). In a 12 week study duration, the PMR group received hospital-based group and in-home PMR practice, while the control group received hospital-based mild group stretching and balance exercises. The control group and the PMR group were comparable at baseline. After 12 weeks of intervention, the PMR group showed significant improvement in anxiety, depression, overall QOL, and the mental component summary score of QOL (P < 0.05) but not the physical component summary score of QOL or the 6-minute walking distance. In contrast, the control group showed no significant improvement in any of the variables. Moreover, the PMR group showed significant improvement in all QOL mental health domains (P < 0.05) but not the physical health domains. In contrast, the control group showed no significant improvement in any QOL domain. In conclusion, this study suggests that PMR practice is effective in improving anxiety, depression, and the mental health components of QOL in patients with PAH. PMID- 25922615 TI - Acupuncture to Reduce HIV-Associated Inflammation. AB - Background. HIV infection is associated with systemic inflammation that can increase risk for cardiovascular events. Acupuncture has been shown to have immunomodulatory effects and to improve symptoms in persons with inflammatory conditions. Objective. To test the anti-inflammatory effects of an acupuncture protocol that targets the cholinergic anti-inflammatory pathway (CAIP), a neural mechanism whose activation has been shown to reduce the release of proinflammatory cytokines, in persons with HIV-associated inflammation. Design, Setting, Participants, and Interventions. Double-blind, placebo-controlled clinical trial conducted in an outpatient clinic located in a medically underserved urban neighborhood. Twenty-five clinically-stable HIV-infected persons on antiretroviral therapy were randomized to receive once weekly CAIP based acupuncture or sham acupuncture. Main Outcome Measures. Outcomes included plasma concentrations of high sensitivity C-reactive protein and D-dimer and fasting lipids. Results. Twenty-five participants completed the protocol (treatment group n = 12, control group n = 13). No adverse events related to the acupuncture protocol were observed. Compared to baseline values, the two groups did not significantly differ in any outcome measures at the end of the acupuncture protocol. Conclusions. CAIP-based acupuncture did not favorably modulate inflammatory or lipid parameters. Additional studies are warranted of CAIP-based protocols of different frequencies/durations. PMID- 25922616 TI - Benefits of WSES guidelines application for the management of intra-abdominal infections. AB - INTRODUCTION: The use of antibiotics is very high in the departments of Emergency and Trauma Surgery above all in the treatment of the intra-abdominal infections, to decrease morbidity and mortality rates; often the antimicrobial drugs are prescribed without a rationale and they are second-line antibiotics; this clinical practice increases costs without decreasing mortality. Aim of our study is to report the results in the application to the clinical practice of the World Society Emergency Surgeons (WSES) guidelines for the management of intra abdominal infections, at the department of Emergency and Trauma Surgery of the University Hospital of Parma (Italy) in 2012. METHODS: A retrospective observational analysis was carried out about patients admitted in the department of Emergency and Trauma Surgery of Parma (Italy), between January 2011 and December 2012. The data are expressed as percentages (%) and means (+/- SD). The results of the compared groups were analyzed using the Pearson's Chi-Square and Fisher's tests. For means involving continuous numerical data, the independent sample T test and the Mann-Whitney U-test were used for normally and abnormally distributed data, respectively (the data had been previously tested for normality using the Kolmogorov-Smirnov test). A p-value < 0.05 was considered statistically significant. RESULTS: Between January 2011 and December 2012, 2121 (968 in 2011 and 1153 in 2012) patients were admitted in the department of Emergency and Trauma Surgery (Italy) of Parma University Hospital with a diagnosis of acute IAI. Morbidity in 2012 was 10,2% compared to 22.7% in 2011 and mortality in 2012 was 1,1% compared to 3,2% in 2011 (p < 0,05). Costs for antibiotics in 2012 was 51392 euro, with a reduction of 31% compared to 2011. CONCLUSIONS: This study demonstrates that an inexpensive and easily application of guidelines based on medicine evidence in the use of antibiotics can lead to a significative reduction of hospital costs with outcomes improvement. PMID- 25922617 TI - Contribution of copy number variants (CNVs) to congenital, unexplained intellectual and developmental disabilities in Lebanese patients. AB - BACKGROUND: Chromosomal microarray analysis (CMA) is currently the most widely adopted clinical test for patients with unexplained intellectual disability (ID), developmental delay (DD), and congenital anomalies. Its use has revealed the capacity to detect copy number variants (CNVs), as well as regions of homozygosity, that, based on their distribution on chromosomes, indicate uniparental disomy or parental consanguinity that is suggestive of an increased probability of recessive disease. RESULTS: We screened 149 Lebanese probands with ID/DD and 99 healthy controls using the Affymetrix Cyto 2.7 M and SNP6.0 arrays. We report all identified CNVs, which we divided into groups. Pathogenic CNVs were identified in 12.1% of the patients. We review the genotype/phenotype correlation in a patient with a 1q44 microdeletion and refine the minimal critical regions responsible for the 10q26 and 16q monosomy syndromes. Several likely causative CNVs were also detected, including new homozygous microdeletions (9p23p24.1, 10q25.2, and 8p23.1) in 3 patients born to consanguineous parents, involving potential candidate genes. However, the clinical interpretation of several other CNVs remains uncertain, including a microdeletion affecting ATRNL1. This CNV of unknown significance was inherited from the patient's unaffected-mother; therefore, additional ethnically matched controls must be screened to obtain enough evidence for classification of this CNV. CONCLUSION: This study has provided supporting evidence that whole-genome analysis is a powerful method for uncovering chromosomal imbalances, regardless of consanguinity in the parents of patients and despite the challenge presented by analyzing some CNVs. PMID- 25922619 TI - Prothrombotic risk factors and antithrombotic therapy in children with ischemic stroke. AB - OBJECTIVE: Congenital and acquired prothrombotic disorders have been highlighted in a recent series of cerebrovascular stroke (CVS), with a controversial role in pathogenesis. The aim is to study some prothrombotic risk factors [activated protein C (APC) resistance, von Willebrand factor (vWF), anticardiolpin (ACL) antibodies and plasma homocysteine] in children with ischemic stroke, and to evaluate the role of aspirin and low molecular weight heparin (LMWH) in its management in relation to outcome. METHODS: A total of 37 cases aged from 1 month to 15 years ( mean +/- standard deviation 26.2 +/- 35.7 months), diagnosed as ischemic stroke (>24 hours) were recruited. Complete blood count, prothrombin time and concentration, partial thromboplastin time, serum electrolytes, random blood sugar, C-reactive protein, electrocardiogram and echocardiography were done. Levels of APC resistance, vWF, ACL antibodies [immunoglobulin G (IgG) and immunoglobulin M (IgM)] and plasma homocysteine were estimated. A total of 25 cases received aspirin 3-5 mg /kg/d and 12 patients received LMWH as initial dose at 75 international units (IU)/kg subcutaneously (SC) then 10-25 IU/kg/day for 15 days in a nonrandomized fashion. RESULTS: The levels of APC resistance, vWF, ACL antibodies (IgG and IgM) and plasma homocysteine were significantly higher in stroke cases than in controls. There was no significant difference between cases treated with aspirin and those with LMWH in all prothrombotic factors. Significant positive correlations were found between vWF and ACL antibodies (IgG and IgM) levels before treatment. Significant decrease in cognitive function was detected between cases treated with LMWH and those treated with aspirin. CONCLUSION: Ischemic CVS in children is multifactorial. Thrombophilia testing should be performed in any child with CVS. Early use of aspirin improves the prognosis and has less effect on cognitive function. PMID- 25922618 TI - Clinical, cytogenetic and molecular study of a case of ring chromosome 10. AB - Ring chromosome 10 is a rare cytogenetic finding. Only a few cases with molecular cytogenetic definition have been reported. We report here on a child with a ring chromosome 10, which is associated with prenatal and postnatal growth retardation, microcephaly, dysmorphic features, hypotonia, heart defect, severe pes equinovarus, and bronchial asthma. The chromosomal aberration was defined by chromosome microarray analysis, which revealed two deletions at 10pter (3.68 Mb) and 10qter (4.26 Mb). The clinical features are very similar to those reported in other clinical cases with ring chromosome 10, excluding bronchial asthma, which has not been previously reported in individuals with ring chromosome 10. PMID- 25922620 TI - Botulinum toxin in the management of blepharospasm: current evidence and recent developments. AB - Blepharospasm is a focal (although usually bilateral) dystonia of the orbicularis oculi muscles, producing excessive eye closure. This produces significant disability through functional blindness. Botulinum neurotoxins (BoNT) have become the treatment of choice for blepharospasm; the impressive response rate and the tolerable safety profile have been proven through multiple clinical studies. There are currently four BoNT approved in the United States for different indications - we review the data on blepharospasm for each of these drugs. Currently, incobotulinumtoxinA and onabotulinumtoxinA have the most evidence of benefit for patients with blepharospasm. Current evidence, recent development and future directions are discussed. PMID- 25922621 TI - The emerging role of tacrolimus in myasthenia gravis. AB - OBJECTIVE: To describe and evaluate the available evidence assessing the role of tacrolimus in the management of patients with myasthenia gravis (MG). DATA SOURCES: A literature search of MEDLINE (1946 to September 2014) and EMBASE (1947 to September 2014) was performed using the terms 'tacrolimus' and 'myasthenia gravis'. Citations of retrieved articles were examined for relevance. STUDY SELECTION AND DATA EXTRACTION: The search was limited to prospective clinical trials focused on clinical outcomes in patients with generalized MG. Case reports, retrospective evaluations and non-English articles were excluded. DATA SYNTHESIS: A total of 12 studies met inclusion criteria, of which seven articles evaluated tacrolimus in steroid-dependent patients and two examined the utility of tacrolimus in patients failing corticosteroids and cyclosporine. Other studies evaluated early initiation of tacrolimus after thymectomy, effectiveness of tacrolimus in de novo MG and the effectiveness of tacrolimus post-thymectomy in thymoma patients versus nonthymoma. A total of eight trials showed statistically significant improvements in quantitative MG score (QMGS) and postintervention status criteria - Myasthenia Gravis Foundation of America (PSC-MGFA). Of the trials examining steroid reduction with tacrolimus, two reported high rates of complete withdrawal; however, the most robust trial was unable to detect a difference in mean steroid dose. Long-term effects of tacrolimus (up to 5 years) were assessed in eight trials, which consistently showed positive effects on QMGS or reduction in adjunct therapies. CONCLUSIONS: There is limited yet promising information to suggest a beneficial role for tacrolimus in reducing QMGS and corticosteroid burden in patients with refractory symptoms or new-onset MG. Long term use appears to be safe in this population. PMID- 25922622 TI - Multi-faceted quantitative proteomics analysis of histone H2B isoforms and their modifications. AB - BACKGROUND: Histone isoforms and their post-translational modifications (PTMs) play an important role in the control of many chromatin-related processes including transcription and DNA damage. Variants of histones H2A and H3 have been studied in depth and have been found to have distinct functions. Although 13 somatic histone H2B isoforms have been identified by various biochemical and mass spectrometric (MS) approaches, the distinct roles of these isoforms within human cells are as yet unknown. Here, we have developed quantitative MS techniques to characterize isoform-specific H2B expression across the cell cycle, in differentiated myogenic cells, and in different cancer cell lines to illuminate potential functional roles. RESULTS: Using the MS strategies that we developed, we identified differences in H2B isoform levels between different cancer cell types, suggesting cancer or tissue-specific H2B isoform regulation. In particular, we found large variations in the levels of isoforms H2B1B and H2B1M across the panel of cell lines. We also found that, while individual H2B isoforms do not differ in their acetylation levels, trends in the acetylation on all H2B isoforms correlated with acetylation on other histone family members in the cancer cell line panel. We also used the MS strategies to study H2B protein expression across the cell cycle and determined that H2B isoforms that are alternatively spliced to carry a polyadenylation signal rather than the standard histone downstream element are expressed independently of the cell cycle. However, the level of protein produced from the polyadenylated transcripts does not contribute significantly to the total pool of H2B isoforms translated across the cell cycle or in non-cycling myogenic cells. CONCLUSIONS: Our results show that H2B isoforms are expressed at varying levels in different cells, suggesting isoform-specific, and possibly cell-type-specific, H2B gene regulation. The bottom-up mass spectrometry technique we developed for H2B quantification is compatible with the current standard histone H3 and H4 bottom-up 'one-pot' analysis platform so that H2B isoforms and their modifications can be studied in future experiments at the same time as histone H3 and H4 modifications. Therefore, we have expanded the histone landscape that can be interrogated in future experiments. PMID- 25922624 TI - Embolisation of internal carotid artery aneurysm using the double microcatheter technique - a case report. AB - BACKGROUND: A wide-necked aneurysm is defined as the one with a neck greater than 4 mm in diameter. Embolisation of wide-necked aneurysms is a great challenge for neuroradiologists. To overcome possible complications of endovascular treatment of this type of aneurysms, methods like intracranial stents, balloon remodelling, the double microcatheter and the microcatheter protective technique have been developed. CASE REPORT: We report a case of embolisation of a 63-year-old woman with a wide-necked aneurysm using the double microcatheter technique. Introduction of the second microcatheter into the aneurysm allowed for crossing two coils and prevented protrusion into the parent vessel, which resulted in successful treatment without postprocedural complications. Both postembolic and follow-up angiography showed complete exclusion of the aneurysm. CONCLUSIONS: The double microcatheter technique, owing to creation of a stable coil frame across the neck of the aneurysm, is suitable for treatment of aneurysms with an adverse dome-to-neck ratio. This technique is easy to perform for an experienced neuroradiologist. PMID- 25922623 TI - RNA-seq analysis of Macrobrachium rosenbergii hepatopancreas in response to Vibrio parahaemolyticus infection. AB - BACKGROUND: The Malaysian giant freshwater prawn, Macrobrachium rosenbergii, is an economically important crustacean worldwide. However, production of this prawn is facing a serious threat from Vibriosis disease caused by Vibrio species such as Vibrio parahaemolyticus. Unfortunately, the mechanisms involved in the immune response of this species to bacterial infection are not fully understood. We therefore used a high-throughput deep sequencing technology to investigate the transcriptome and comparative expression profiles of the hepatopancreas from this freshwater prawn infected with V. parahaemolyticus to gain an increased understanding of the molecular mechanisms underlying the species' immune response to this pathogenic bacteria. RESULT: A total of 59,122,940 raw reads were obtained from the control group, and 58,385,094 reads from the Vibrio-infected group. Via de novo assembly by Trinity assembler, 59,050 control unigenes and 73,946 Vibrio-infected group unigenes were obtained. By clustering unigenes from both libraries, a total of 64,411 standard unigenes were produced. The standard unigenes were annotated against the NCBI non-redundant, Swiss-Prot, Kyoto Encyclopaedia of Genes and Genome pathway (KEGG) and Orthologous Groups of Proteins (COG) databases, with 19,799 (30.73%), 16,832 (26.13%), 14,706 (22.83%) and 7,856 (12.19%) hits respectively, giving a final total of 22,455 significant hits (34.86% of all unigenes). A Gene Ontology (GO) analysis search using the Blast2GO program resulted in 6,007 unigenes (9.32%) being categorized into 55 functional groups. A differential gene expression analysis produced a total of 14,569 unigenes aberrantly expressed, with 11,446 unigenes significantly up regulated and 3,103 unigenes significantly down-regulated. The differentially expressed immune genes fall under various processes of the animal immune system. CONCLUSION: This study provided an insight into the antibacterial mechanism in M. rosenbergii and the role of differentially expressed immune genes in response to V. parahaemolyticus infection. Furthermore, this study has generated an abundant list of transcript from M.rosenbergii which will provide a fundamental basis for future genomics research in this field. PMID- 25922626 TI - A case of congenital uterine arterio-venous malformation managed by hysterectomy. AB - BACKGROUND: A uterine arteriovenous malformation (AVM) is a rare cause of uterine bleeding. It may have varied presentations ranging from being completely asymptomatic; to features of congestive heart failure to vaginal bleeding which may at times life be threatening. Clinical findings in such cases are often un reliable; requiring a high index of suspicion to make the diagnosis. Sonographic gray scale features are non-specific requiring confirmation with colour and spectral Doppler. CASE REPORT: We report a case of a 46-year-old lady who presented with heavy vaginal bleeding and ultrasound/colour Doppler evidence of uterine AVM managed by abdominal hysterectomy, describing the imaging features on ultrasound and Doppler. We also discuss in brief about this uncommon but serious condition which the radiologist/gynaecologist may encounter in thier practise. CONCLUSIONS: Uterine AV Malformation is a rare but potentially life-threatening cause of menorrhagia which must be kept in the differential diagnosis of sudden and massive vaginal bleeding. Ultrasound remains the modality of choice in diagnosing the condition which requires a high index of clinical suspicion. Color and spectral Doppler ultrasound should be used to supplement the findings and to confirm the diagnosis. PMID- 25922625 TI - The role of septal perforators and "myocardial bridging effect" in atherosclerotic plaque distribution in the coronary artery disease. AB - The distribution of atherosclerotic plaque burden in the human coronary arteries is not uniform. Plaques are located mostly in the left anterior descending artery (LAD), then in the right coronary artery (RCA), circumflex branch (LCx) and the left main coronary artery (LM) in a decreasing order of frequency. In the LAD and LCx, plaques tend to cluster within the proximal segment, while in the RCA their distribution is more uniform. Several factors have been involved in this phenomenon, particularly flow patterns in the left and right coronary artery. Nevertheless, it does not explain the difference in lesion frequency between the LAD and the LCx as these are both parts of the left coronary artery. Branching points are considered to be the risk points of atherosclerosis. In the LCx, the number of side branches is lower than in the LAD or RCA and there are no septal perforators with intramuscular courses like in the proximal third of the LAD and the posterior descending artery (PDA). We hypothesized that septal branches generate disturbed flow in the LAD and PDA in a similar fashion to the myocardial bridge (myocardial bridging effect). This coronary architecture determines the non-uniform plaque distribution in coronary arteries and LAD predisposition to plaque formation. PMID- 25922627 TI - [Massive vulval edema during pregnancy: report of a case]. PMID- 25922628 TI - Adult male with non-resolving opacity in the right hemithorax. AB - Pulmonary agenesis is a well-known but rare congenital anomaly of the respiratory system. It represents failure of development of the primitive lung bud. We are reporting bilobar agenesis of the right lung associated with multisystem involvement in an adult patient. PMID- 25922629 TI - [Wernicke encephalopathy complicating hyperemesis gravidarum and associated with pontine myelinolysis]. PMID- 25922630 TI - Distribution of new HIV infections among key risk population groups in Togo. AB - INTRODUCTION: Good data on the epidemiology of modes of transmission of HIV among population at risk are important for development of prevention strategies, and resource allocation for the implementation of the interventions. We sought to estimate new HIV infections among key risk groups in Togo. METHODS: We conducted a systematic review of epidemiological data on HIV and AIDS as part of the HIV control strategies in Togo from 2001 to 2012 following the PRISMA guidelines. We used the Mode of Transmission (MoT) modelling tool to estimate the incidence of new HIV infections in high risk groups. The MoT tool was developed and validated by UNAIDS and implemented by several countries using data on the HIV epidemic to estimate new HIV infections that will appear in the core groups. We used Epi-MoT tool to assess the availability and the quality of data. A score of availability of data over 50% and the quality over 1.5 were required to proceed to the MoT analysis. Uncertainty analysis to assess the reliability of the results was performed. RESULTS: Incidence of new HIV infections was estimated at 6,643 (95% CI = 5274, 9005) with an incidence rate of 203 per 1,000,000 inhabitants. The proportion of new HIV infections was 61.9% (95% CI = 46.2 to 71.7) in stable heterosexual couples compare to 14.01% (95% CI = 7.2 to 23.3) in people having casual sex. In high-risk groups new HIV infections accounted for 2.4% among sex workers (SWs) (95% CI = 1.2 - 4.1), 7.9% among clients of SWs (95% CI = 3.9-14.1) and 6.9% among men who have sex with men (MSM) (95% CI = 3.1 to 13.1). CONCLUSION: We describe the prediction of the HIV epidemic with a large contribution of stable heterosexual couples in the occurrence of new infections. But HIV incidence remains high in key risk populations. Innovative strategies for risk reduction should be strengthened to reduce the transmission especially in stable heterosexual couples. PMID- 25922631 TI - [Ischemic interventricular septal: report of a case observed in the cardiology department of the CHU-Yalgado Ouedraogo of Ouagadougou (Burkina Faso)]. PMID- 25922632 TI - [Hydatid cyst in costo-vertebral location]. PMID- 25922633 TI - [Stellar neuroretinitis revealing bartonellosis]. PMID- 25922634 TI - [Primitive essential Cutis verticis gyrata, a rare skin disease: case report and review of literature]. PMID- 25922635 TI - [Cancer developed in cystic dilatation of the bile duct: report of a case]. PMID- 25922636 TI - [Pulmonary tuberculosis mortality risk factors]. PMID- 25922637 TI - Spinal hydatidosis mimicking Guillain Barre syndrome: in case of doubt there is no rush to perform lumbar puncture. AB - Guillain Barre Syndrome (GBS) is a challenging pathology which diagnosis is based essentially on the clinical examination and the results of lumbar puncture. Differential diagnosis must be discussed if the clinical picture is not complete. We present the case of a patient who presented to the emergency department with symptoms evoking both GBS and spinal cord compression. The Radiology showed a diffused spinal hydatidosis. The lumbar puncture must be carefully considered. In this case, it would have exposed the patient to hydatid dissemination. PMID- 25922638 TI - Male involvement in family planning decision making in sub-Saharan Africa- what the evidence suggests. AB - The World Health Organization (WHO) estimated in 2012 that 287,000 maternal deaths occurred in 2010; sub-Saharan Africa (56%) and Southern Asia (29%) accounted for the global burden of maternal deaths. Men are also recognized to be responsible for the large proportion of ill reproductive health suffered by their female partners. Male involvement helps not only in accepting a contraceptive but also in its effective use and continuation. The objectives were to assess men's knowledge, attitude, and practice of modern contraceptive methods; determine the level of spousal communication about family planning decision making; and investigate the correlates of men's opinion about their roles in family planning decision making. We searched the following electronic databases from January 1995 to December 2013: Medline, Embase, CINAHL, LILAS, International Bibliography of Social Sciences, Social Services Abstracts, and Sociological Abstracts. Along with MeSH terms and relevant keywords, we used the Cochrane Highly Sensitive Search Strategy for identifying reports of articles in PubMed. There were no restrictions to language or publication status. Of 137 hits, 7 papers met the inclusion criteria. The concept of family planning was well known to men. In the Nigerian study, almost (99%) men were aware of the existence of modern contraceptives, and most of them were aware of at least two modern methods. Awareness of the condom was highest (98%). In the Malawi study, all of the participants reported that they were not using contraception before the intervention. In Ethiopia, above 90% of male respondents have supported and approved using and choosing family planning methods, but none of them practiced terminal methods. Generally, more male respondents disagreed than agreed that men should make decisions about selected family planning issues in the family. Decision-making dynamics around method choice followed a slightly different pattern. According to female participants, decisions regarding method choice were equally made by women or jointly, with male-dominated decisions falling last. There are many challenges to increase male involvement in family planning services. So far very few interventions addressing these challenges have been evaluated scientifically. Health education campaigns to improve beliefs and attitudes of men are absolutely needed. Additionally, improving accessibility, affordability, availability, accommodation and acceptability of family planning service venues will make them more attractive for male partners. PMID- 25922639 TI - Urticarial vasculitis induced by OTC diet pills: a case report. AB - BACKGROUND: Urticarial Vasculitis (UV) is in most of the cases idiopathic; however it has been associated with several conditions and drugs. Over the counter (OTC) diet pills are widely available, even on-line, but they are rarely regulated by pharmaceutical control. CASE PRESENTATION: We present the case of a 35-year-old female patient suffering of pruriginous and painful wheals more than 1 cm in diameter, with a burning sensation. The eruption lasted more than 24 hours and was accompanied by angioedema, headache and myalgia. No remarkable medical history was found, except for previous intake of OTC diet pills. UV diagnosis was confirmed by the skin biopsy of a lesion. CONCLUSION: OTC diet pills are widely available worldwide, and due to its widespread use, allergologists and dermatologist should be able to recognize symptoms and lesions of cutaneous vasculitis, which may be under reported. PMID- 25922640 TI - Epigallocatechin-3-gallate enhances the therapeutic effects of leptomycin B on human lung cancer a549 cells. AB - Our previous studies have shown Leptomycin B (LMB) is a promising antilung cancer drug. Epigallocatechin-3-gallate (EGCG) has antitumor properties but a debatable clinical application. The objective of this study is to evaluate the combination therapeutic effect of LMB and EGCG and its molecular mechanisms in human lung cancer A549 cells. Increased cytotoxicity was observed in LMB+EGCG-treated cells compared to LMB-treated cells. Elevated ROS was maximized 2 h after treatment, and LMB+EGCG-treated cells had higher ROS levels compared to LMB. N-Acetyl-L cysteine (NAC) studies confirmed the oxidative role of LMB and/or EGCG treatment. In comparison to the control, CYP3A4, SOD, GPX1, and p21 mRNA expression levels were increased 7.1-, 2.0-, 4.6-, and 13.1-fold in LMB-treated cells, respectively, while survivin was decreased 42.6-fold. Additionally, these increases of CYP3A4, SOD, and GPX1 were significantly reduced, while p21 was significantly increased in LMB+EGCG-treated cells compared to LMB-treated cells. The qRT-PCR results for p21 and survivin were further confirmed by Western blot. Our study first shows that LMB produces ROS and is possibly metabolized by CYP3A4, GPX1, and SOD in A549 cells, and combination treatment of LMB and EGCG augments LMB-induced cytotoxicity through enhanced ROS production and the modulation of drug metabolism and p21/survivin pathways. PMID- 25922641 TI - Antioxidative diet supplementation reverses high-fat diet-induced increases of cardiovascular risk factors in mice. AB - Obesity is a worldwide epidemic that is characterized not only by excessive fat deposition but also by systemic microinflammation, high oxidative stress, and increased cardiovascular risk factors. While diets enriched in natural antioxidants showed beneficial effects on oxidative stress, blood pressure, and serum lipid composition, diet supplementation with synthetic antioxidants showed contradictive results. Thus, we tested in C57Bl/6 mice whether a daily dosage of an antioxidative mixture consisting of vitamin C, vitamin E, L-arginine, eicosapentaenoic acid, and docosahexaenoic acid (corabion) would affect cardiovascular risk factors associated with obesity. Obese mice showed increased serum triglyceride and glucose levels and hypertension after eight weeks of being fed a high-fat diet (HFD). Importantly, corabion ameliorated all of these symptoms significantly. Oxidative stress and early signs of systemic microinflammation already developed after two weeks of high-fat diet and were significantly reduced by daily doses of corabion. Of note, the beneficial effects of corabion could not be observed when applying its single antioxidative components suggesting that a combination of various nutrients is required to counteract HFD-induced cardiovascular risk factors. Thus, daily consumption of corabion may be beneficial for the management of obesity-related cardiovascular complications. PMID- 25922642 TI - Quercetin affects Hsp70/IRE1alpha mediated protection from death induced by endoplasmic reticulum stress. AB - Relative to their normal counterparts, tumor cells generally exhibit a greater "stress phenotype" and express heat shock proteins (Hsp) that represent candidate targets for anticancer therapy. Here we investigated the role of Hsp70 in survival induced by endoplasmic reticulum (ER) stressors in human leukemia U937 cells. Quercetin, a major dietary flavonoid, or specific silencing affected the expression level of Hsp70 and did not allow the upregulation of inositol requiring kinase 1alpha (IRE1alpha), the prototype ER stress sensor regulating the unfolded protein response (UPR), that protects the cells against the stress of misfolded proteins in the ER. The reduction of Hsp70 prevented the upregulation of immunoglobulin heavy-chain binding protein (BiP), but not of CCAAT/enhancer-binding protein-homologous protein (CHOP), and induced apoptosis. Also specific silencing of IRE1alpha or inhibition of its endoribonuclease activity by 4MU8c hampered the upregulation of BiP, but not of CHOP, and induced apoptosis. These results suggest that drugs affecting the Hsp70-IRE1alpha axis, like quercetin, or affecting directly IRE1alpha may represent an effective adjuvant antileukemia therapy. PMID- 25922644 TI - Hepatic iron overload and fibrosis in patients with beta thalassemia major after hematopoietic stem cell transplantation: A pilot study. AB - Currently, hematopoietic stem cell transplantation (HSCT) is the only curative option for patients with beta-thalassemia major, but liver iron overload in these patients will not decrease and hepatic fibrosis may still progress despite successful HSCT. Liver biopsy samples were taken from 14 patients (Out of 25 patients) who underwent HSCT. All patients met three criteria: negative HCV antibody, liver fibrosis in samples before HSCT and lack of regular treatment for iron overload after HSCT (Because patients did not consent to phlebotomy or they had not regular follow-up). We evaluated liver fibrosis and liver iron overload by a semi quantitative method, Perls' Prussian blue staining, before and after HSCT. HSCT was successful in all the patients. Liver iron overload did not change after transplant (P=0.61), but hepatic fibrosis progressed after transplant (P=0.01). In patients with beta thalassemia major who previously had some degree of liver fibrosis, HSCT alone cannot reduce liver iron overload and liver fibrosis will increase. We recommend that regardless of the amount of iron overload in patients with beta thalassemia major that have shown some degree of fibrosis in their liver biopsy before transplantation, appropriate steps should be taken to reduce iron overload as soon as possible after successful transplantation. PMID- 25922645 TI - Study of Adrenal Functions using ACTH stimulation test in Egyptian children with Sickle Cell Anemia: Correlation with Iron Overload. AB - BACKGROUND: Sickle-cell anemia is characterized by defective hemoglobin synthesis with production of sickle hemoglobin. Sickle red blood cells become deformed and rigid with difficulty to pass through narrow capillaries and frequent clotting and thrombosis leading to repetitive vascular occlusions and progressive organ damage. We conducted this work to study some adrenal functions using ACTH stimulation test in Egyptian children with sickle cell anemia in correlation with iron overload. METHODS: This study was conducted on 60 children with sickle cell anemia who were attendants of Hematology unit, Pediatric department, Tanta university hospital in the period from April 2012 to May 2014 including 34 males and 26 females with their age ranging from 5-17 years and main age value of 13+/ 2.9 in comparison with 30 healthy children matched for age and sex as a control group. For all patients the following were done: Complete blood count, Hb electrophoresis, serum ferritin, iron, iron binding capacity, sodium and potassium, random blood glucose, thyroid functions , morning basal cortisol levels and adrenocorticotrophic hormone stimulation test. Results : There was significantly lower basal morning cortisol in patients than controls (mean value in patients were 8.78+/-3.53 ug/dl compared with 11.79+/-2.32 ug/dl in control group with p value of 0.021). No significant differences in adrenocorticotrophic hormone stimulation test between patients and controls were detected. (Mean value in patients were 23.078+/-3.709 ug/dl compared with 24.492+/-5.006 ug/dl in control group with p value of 0.389). Significant negative correlation was found between serum cortisol and ferritin in patients group (r= 0.625 and p value =0.003) CONCLUSION: There was significantly lower basal morning cortisol in sickle-cell anemia patients with significant negative correlation with iron overload so regular follow up to adrenal functions to detect any adrenal impairment, as SCD patients are vulnerable to adrenal hypo function, is recommended. PMID- 25922643 TI - Oxidative stress in myopia. AB - Myopia affected approximately 1.6 billion people worldwide in 2000, and it is expected to increase to 2.5 billion by 2020. Although optical problems can be corrected by optics or surgical procedures, normal myopia and high myopia are still an unsolved medical problem. They frequently predispose people who have them to suffer from other eye pathologies: retinal detachment, glaucoma, macular hemorrhage, cataracts, and so on being one of the main causes of visual deterioration and blindness. Genetic and environmental factors have been associated with myopia. Nevertheless, lack of knowledge in the underlying physiopathological molecular mechanisms has not permitted an adequate diagnosis, prevention, or treatment to be found. Nowadays several pieces of evidence indicate that oxidative stress may help explain the altered regulatory pathways in myopia and the appearance of associated eye diseases. On the one hand, oxidative damage associated with hypoxia myopic can alter the neuromodulation that nitric oxide and dopamine have in eye growth. On the other hand, radical superoxide or peroxynitrite production damage retina, vitreous, lens, and so on contributing to the appearance of retinopathies, retinal detachment, cataracts and so on. The objective of this review is to suggest that oxidative stress is one of the key pieces that can help solve this complex eye problem. PMID- 25922646 TI - The comparison of perceived stress in idiopathic thrombocytopenic purpura patients referred to Seyed Al-Shohada Hospital with healthy people in Isfahan, Iran, 2013. AB - BACKGROUND: Mental stress and daily crises comprise a part of physical and mental threats. Perceived stress is a physical and mental threat, as well. Perceived stress is a psychological process during which the individual considers his/ her physical and psychological welfare as being threatened. Since idiopathic thrombocytopenic purpura (ITP) is one of the chronic diseases being able to affect patients' perceived stress, this study was conducted to compare perceived stress in ITP patients and healthy people. MATERIALS AND METHODS: This is a descriptive-comparative study with control and case groups. In this study, 64 ITP patients referring Seyed Al-Shohada Hospital and the same number of healthy individuals from the patients' neighborhood, as the control group, were selected randomly and compared. The Kohen Perceived Stress Standard Questionnaire was used to collect the data. The data were analyzed by SPSS and Student's independent t test, chi-square, and Mann-Whitney test. Results : 64.1%, 59.4% and 53.1% of participants in case group were older than 35 years old, female and had elementary education. 78.1% of case group had severe perceived stress. 70.3% of participants in control group experienced mild perceived stress. Mann-Whitney test showed significant difference between two groups in level of stress (p<0.001). CONCLUSION: In ITP patients, perceived stress was considerable. Planning interventional measures to determine stress-making agents and subside or at least control them is very essential. PMID- 25922647 TI - Expansion of human cord blood hematopoietic stem/progenitor cells in three dimensional Nanoscaffold coated with Fibronectin. AB - BACKGROUND: Allogeneic hematopoietic stem cell transplantation is used in the treatment of patients suffering from hematologic and non-hematologic disorders, but the application is limited by the identification of a suitable donor. Umbilical cord blood (UCB) is an alternative source of hematopoietic stem cell (HSC) transplantation. Despite all advantages, the limited cell dose is one of the major obstacles. Ex-vivo expansion of HSC is an alternative way to overcome this problem. MATERIALS AND METHODS: In this study, polycaprolactone (PCL) scaffold coated with fibronectin (3D) is compared to routine cell culture system (two dimensional, 2D) used for cell culture.1*10(4) cord blood CD34+ cells isolated by MACS were seeded on PCL scaffold and allowed to expand for 10 days. Before and after this period, total cells, CD34(+) cells, CFC assay and CXCR4 expression were evaluated. RESULTS: Our findings demonstrated that 3D scaffold produced a 58-fold expansion of total cells compared to 2D cultures (38-fold expansion). Also CD34+ cells in 3D compare to 2D cell culture was 40-fold and 2.66 fold increased, respectively; this difference was statistically significant (p<0.05). Moreover, total number of colonies in the 3D scaffold was higher than those of 2D cell culture system, but no statistically significant difference was observed. Higher expression of CXCR4 in 3D compared to 2D showed better homing of cells that were cultured in 3D scaffold (p<0.05). CONCLUSION: PCL scaffold coated with fibronectin had higher number of total cells and CD34+cells than 2D routine culture system. Findings revealed that 3D is a proper cell culture system for hematopoietic stem cell expansion, compared to 2D. PMID- 25922648 TI - Association between Interlukin-6 (IL-6), Interlukin-10 (IL-10) and depression in patients undergoing Hematopoietic stem cell transplantation. AB - BACKGROUND: The release of pro-inflammatory cytokines is responsible for the variety of behavioral, neuro-endocrine and neuro-chemical alterations in psychiatric condition. In this study we evaluate relation between depression and IL-6 and IL-10 in patients undergoing hematopoietic stem cell transplantation (HSCT). MATERIALS AND METHODS: 66 patients in this cross-sectional study from July 2013 until August 2014 for HSCT interred the study and were assessed for depression using Hospital Anxiety and Depression Scale (HADS). Serum interleukin (IL)-6, (IL)-10 and high sensitive C-reactive protein (hs-CRP) were assessed on the same time. Association between these biomarkers with depression was evaluated using SPSS version 20. RESULTS: A total of 66 patients with the mean age of 41.18+13.92 and 41.95+12.35 years old in non depressed and depressed group respectively were enrolled in this study. Patients with depression showed significantly higher levels of serum IL-6 and the IL-6-to-IL-10 ratio compared to patients without depression (p<0.001).There was no statistically significant association between IL-10 and hs-CRP with depression in this group of the patients. CONCLUSIONS: High IL-6 level has significant association with depression in patients undergoing HSCT. In conclusion, since IL-6 can affect the outcomes after HSCT and depression was associated with increased serum IL-6 level, early identification of depression can be beneficial in these patients. PMID- 25922649 TI - Short view of leukemia diagnosis and treatment in iran. AB - BACKGROUND: Early diagnosis and treatment of leukemia patients remains a fundamental aim in clinical oncology, especially in developing country. Present study highlights the basic requirements of these patients in Iran. Better understanding of these issues may lead to improve the healthcare standards toward leukemia diagnosis and treatment. METHODS: This descriptive study included 101 specialists in hematology-oncology and pathology serving in oncology centers. The participants were then asked to fill out a standard questionnaire on the issues around diagnosis and treatment of blood malignancies. RESULTS: According to specialists, unfair distribution of facilities across the country, delayed diagnosis of disease, absence of psychological support for patients, and insufficient financial support were the main reasons of inappropriate diagnosis and treatment in leukemia patients. CONCLUSIONS: Our results show that making an amendment to health policies by preparing well-equipped medical centers in all provinces, improving the morale of patients through consultation during the process of treatment, and above all, subsiding leukemia patients' financial problems will promote the health standard regarding the leukemia diagnosis and treatment in Iran. PMID- 25922650 TI - Potential of Mesenchymal Stem Cell based application in Cancer. AB - Stem cell based treatments are being increasingly explored for their possible potential to treat various cancers. Mesenchymal stem cells believed to possess anti-tumor potential and are preferred for their properties like immune privileged nature, ability to migrate to the site of tumor and capability for multilineage differentiation. This tumor tropism property of MSCs could be utilized to deliver anti-tumor biological agents to the site of tumor. In a tumor micro-environment, MSCs are believed to play both, a pro-tumorigenic and an anti tumorigenic role. However, this is dependent on a host of factors like, types of MSCs, its source, type of cancer cell line under investigation, in vivo or in vitro conditions, factors secreted by MSCs and interactions between MSCs, host's immune cells and cancer cells. Among several cytokines secreted by MSCs, TRAIL (Tumor necrosis factor related apoptosis inducing ligand) is reported to be pro apoptotic for tumor cells. The MSCs from bone marrow and adipose tissue have been studied quite extensively. Deriving MSCs from sources such as umbilical cord blood and umbilical cord tissue is relatively easier. Umbilical cord tissue preferred for MSC derivation due to their abundant availability. These MSCs believed to up regulate TRAIL expression in MSC-cancer cell co-culture system resulting in induction of apoptosis in cancer cells. However, umbilical cord tissue derived MSCs needs to be studied for expression pattern of TRAIL in a co culture system. We present a review article on different studies reporting both, pro-tumorigenic and anti-tumorigenic properties of MSCs. PMID- 25922651 TI - Primary Ewing's Sarcoma of the temporal bone in an infant. AB - Introduction : Ewing's sarcoma is the second most common primary malignant tumor of bone found in children after Osteosarcoma. It accounts for 4-9% of primary malignant bone tumors and it affects bones of the skull or face in only 1-4% of cases. Hence it rarely affects the head and neck. Subject and Method : In this case report, we describe a case of primary Ewing's sarcoma occurring in the temporal bone. The tumor was surgically excised, and the patient underwent chemotherapy for ten months. Results : Neither recurrence nor distant metastasis was noted in these 10 months after surgery but about 18 months after surgery our patient was expired. Conclusion : Although the prognosis of Ewing's sarcoma is generally poor because of early metastasis to the lungs and to other bones, a review of the article suggested that Ewing's sarcoma occurring in the skull can often be successfully managed by intensive therapy with radical excision and chemotherapy. This result was supported by the case reported here. PMID- 25922652 TI - Published cases of adverse drug reactions: has the quality of reporting improved over time? AB - PURPOSE: A previous study of cases published approximately 10-30 years ago reveals that substantial improvement in the quality of adverse drug reaction (ADR) case reports is needed. Since that evaluation, recommendations are available concerning the content and formatting of case reports. OBJECTIVE: To compare the quality of recently published ADR case reports to a previously published study of the quality of ADR case reports from 10-30 years ago. A secondary objective is to determine the quality of reporting by specialty journal. METHODS: This was a two-phase study. Phase 1 included an assessment of the 23 patient, drug and ADR variables evaluated in the previous study to allow comparison with recently published case reports in specialty journals. Phase 2 mimicked the methods of Phase 1 with a random selection of available case reports in a 1-year period from a variety of journals. RESULTS: For Phase 1, 19 of the 23 variables had significant differences in reporting compared with the previous study. Reporting of active diseases, social history, weight, race, other drugs and dose had frequencies ranging from 25 to 80%, which was an improvement, but affording an opportunity for greater improvement. For Phase 2, 21 of the 23 variables had significant differences compared with the previous evaluation; however illicit drug use, mechanism for ADR and route of administration had significant reductions in reporting. CONCLUSION: Progress has been made in ADR case reporting quality for a variety of journals, but more improvement is required to ensure data are understandable and relatable to patient care. PMID- 25922654 TI - Bleeding risk with systemic thrombolytic therapy for pulmonary embolism: scope of the problem. AB - Acute pulmonary embolism represents a major complication of venous thromboembolism that is associated with high morbidity and mortality. Guidelines recommend the rapid initiation of anticoagulation and consideration of thrombolytic therapy in select patients, including those with hypotension or at high risk of developing hypotension. Evaluation for thrombolytic therapy should only be considered after assessment of contraindications and risk for major bleeding. The objective of this perspective article is to evaluate the bleeding risk associated with systemic thrombolytic therapy in the management of acute pulmonary embolism and discuss strategies to minimize this risk. Risk stratification of acute pulmonary embolism will be discussed to identify patient populations that warrant specific consideration of risk for major bleeding with thrombolytic therapy. In addition, the incidence, patient-specific risk factors, and pharmacologic characteristics, including concurrent anticoagulation and thrombolytic therapy, will be evaluated in the context of risk for major hemorrhage. Finally, supporting evidence for strategies to minimize risk of hemorrhage, including evaluation of contraindications, weight adjusted dosing, infusion strategy and catheter-directed thrombolytic administration will be evaluated. Despite published guidelines and review articles, select aspects to thrombolytic therapy for the management of pulmonary embolism remain controversial and under recognized, including risk of major hemorrhage. When making decisions about the role of thrombolytic therapy in pulmonary embolism, clinicians must be knowledgeable about the associated risks of thrombolytic therapy and individually evaluate patient risk factors prior to determining appropriate candidacy for thrombolytic therapy. For patients considered to be at high risk of major bleeding, strategies to minimize risk should be considered, including weight-adjusted doses and catheter directed therapy. Additional research is needed specific to the acute pulmonary embolism setting to validate risk factors and strategies to minimize major hemorrhage. PMID- 25922655 TI - Abuse-deterrent formulations: transitioning the pharmaceutical market to improve public health and safety. AB - This article evaluates abuse-deterrent formulations (ADFs) as a method to reduce prescription drug abuse while ensuring access to vital medications for individuals with legitimate need; assesses the pros and cons of ADFs and the current state of ADF adoption in the market; and develops policy recommendations to transition the market to ADFs. Although abuse-deterrent technology is still in its nascent stages, ADFs have been proven to reduce prescription drug abuse and its consequences, and even an incremental reduction in abuse can have a significant impact on the nation by reducing the costly social, physical, mental, and public health problems resulting from abuse. Federal ADF policy does not reflect the urgency of the prescription drug abuse epidemic and does not go far enough toward changing the status quo. Policies must be implemented to encourage innovation and a market shift toward ADFs by ensuring any generic medication that references a branded ADF demonstrates that it does not have abuse-deterrent properties inferior to the branded ADF product. Policies must also require federal prescription drug benefit plans to cover ADFs to ensure consumers have access to such medications. PMID- 25922653 TI - Menopausal hormone therapy and breast cancer mortality: clinical implications. AB - The Women's Health Initiative (WHI) has conducted two randomized, placebo controlled clinical trials to evaluate the influence of menopausal hormone therapy on chronic disease risk. Estrogen plus progestin was evaluated in 16,608 postmenopausal women without prior hysterectomy during 5.6 years' intervention. In that setting, combined hormone therapy use significantly increased breast cancer incidence and interfered with breast cancer detection. The breast cancers were not limited to estrogen receptor positive, favorable prognosis cancers and were identified at more advanced stage. As a result, deaths from breast cancer were significantly increased by estrogen plus progestin use. While the absolute breast cancer risk for relatively short term (2-4 years) use of combined hormone therapy is small, on a population basis a therapy which nearly doubles deaths from breast cancer requires cautious use. Estrogen alone was evaluated in 10,739 postmenopausal women with prior hysterectomy during 7.1 years' intervention. There was an overall reduction of breast cancer incidence seen with estrogen alone use and a suggestion that the effect on risk was more pronounced in women initiating hormone therapy further from menopause. Nonetheless, women with prior hysterectomy can be assured that short duration estrogen alone use for climacteric symptom management is relatively safe. Neither estrogen plus progestin nor estrogen alone should be used for chronic disease risk reduction. The safety of duration of use on chronic disease risk longer than in the WHI clinical trials is not defined. PMID- 25922657 TI - First line palliative chemotherapy in elderly patients with advanced soft tissue sarcoma. AB - BACKGROUND: The efficacy and toxicity of first line palliative chemotherapy for soft tissue sarcomas (STS) in the elderly is poorly described. METHODS: Patients over the age of 65 years receiving first line chemotherapy for advanced non-GIST STS January 1998 - January 2012 at the Royal Marsden Hospital were identified. Data regarding survival and predictive factors were collected retrospectively. RESULTS: 120 patients (52 females) with a median age of 72 (range 65-83) were treated. The most common histological subtypes were undifferentiated sarcoma (30%), leiomyosarcoma (27%), angiosarcoma (14%). 42% of patients had high grade tumours. 70% of patients had metastatic disease at presentation; lung metastasis being the most common disease site (72%). 80% received single agent chemotherapy, mostly with doxorubicin (60%). The median number of cycles was 2 (IQR 3). A partial response was reported in 20% of patients with disease stabilisation in a further 20%. 38% of patients were hospitalised for chemotherapy related toxicity. The median overall survival (OS) was 6.5 months (95% CI 4.7-8.3). Anaemia, lymphopenia, hypoalbuminemia, sarcoma subtype and co-morbidities were predictive for overall survival. CONCLUSION: The overall survival for elderly patients with STS is poor but several predictive factors have been identified. Hospital admissions for chemotherapy related toxicity are common. PMID- 25922656 TI - Testosterone modulates cardiac contraction and calcium homeostasis: cellular and molecular mechanisms. AB - The incidence of cardiovascular disease rises dramatically with age in both men and women. Because a woman's risk of cardiovascular disease rises markedly after the onset of menopause, there has been growing interest in the effect of estrogen on the heart and its role in the pathophysiology of these diseases. Much less attention has been paid to the impact of testosterone on the heart, even though the levels of testosterone also decline with age and low-testosterone levels are linked to the development of cardiovascular diseases. The knowledge that receptors for all major sex steroid hormones, including testosterone, are present on individual cardiomyocytes suggests that these hormones may influence the heart at the cellular level. Indeed, it is well established that there are male-female differences in intracellular Ca(2+) release and contraction in isolated ventricular myocytes. Growing evidence suggests that these differences arise from effects of sex steroid hormones on processes involved in intracellular Ca(2+) homeostasis. This review considers how myocardial contractile function is modified by testosterone, with a focus on the impact of testosterone on processes that regulate Ca(2+) handling at the level of the ventricular myocyte. The idea that testosterone regulates Ca(2+) handling in the heart is important, as Ca(2+) dysregulation plays a key role in the pathogenesis of a variety of different cardiovascular diseases. A better understanding of sex hormone regulation of myocardial Ca(2+) homeostasis may reveal new targets for the treatment of cardiovascular diseases in all older adults. PMID- 25922658 TI - Do human tumor-associated viruses play a role in the development of synovial sarcoma? AB - BACKGROUND: To date, the pathomechanism of soft tissue sarcomas such as synovial sarcoma remains unclear whereas even a viral etiology was suspected. Aim of this study was to analyze whether EBV, HHV-8 or HPV play a role in the development of synovial sarcomas. FINDINGS: In total 41 synovial sarcomas were included in this retrospective study. For detection of EBV 1/2 and HHV-8, resection specimens were analyzed with regard to virus-specific sequences using a SingleStep PCR. HPV analysis was carried out by an HPV-specific multiplex-PCR and subsequent array hybridization for HPV-typing. No virus-specific DNA of EBV, HHV-8 or HPV was detected. CONCLUSION: An involvement of these viruses in the etiology of synovial sarcoma was not detected but further studies are needed with different virus types and sarcoma entities. PMID- 25922659 TI - Activation of autophagy protects against cholestasis-induced hepatic injury. AB - BACKGROUND: Cholestasis is characterized by an abnormal accumulation of bile acids and causes hepatocellular injury. Recent studies show that autophagy is involved in the pathophysiology of many liver diseases. The potential role of autophagy in preventing cholestatic hepatotoxicity, however, has rarely been investigated. The aim of this study was to examine whether autophagy is involved in the cholestatic hepatotoxicity. RESULTS: We found that bile duct ligation (BDL) led to cholestatic liver injury and hepatocytic autophagy activation in the mice. Suppression of autophagy with Chloroquine (CQ) increased liver injury and hepatocytes apoptosis; while activation of autophagy by rapamycin reduced cholestasis hepatotoxicity. In L02 normal liver cells, Glycochenodeoxycholate (GCDC) treatment would induce autophagy. Inhibition of autophagy by CQ could promote GCDC-induced cell apoptosis. In contrast, rapamycin treatment could protect against GCDC-induced cell death. Furthermore, autophagy contributed to the liver cells survival via modulation of reactive oxygen species (ROS). CONCLUSIONS: These findings indicate that autophagy protects against cholestasis induced liver injury and hepatocyte apoptosis by eliminating ROS accumulation. Our data suggest that enhancement of autophagy may be a therapeutic strategy to mitigate cholestatic liver injury. PMID- 25922660 TI - SIRT1 expression is associated with lymphangiogenesis, lymphovascular invasion and prognosis in pN0 esophageal squamous cell carcinoma. AB - BACKGROUND: Sirtuin1 (SIRT1) is an NAD(+)-dependent type III histone deacetylase (HDAC). This research investigated the prevalence of SIRT1 protein expression and its prognostic influence with the aim of validating its potential role in lymphangiogenesis and lymphovascular invasion (LVI) in pN0 esophageal squamous cell carcinoma (ESCC). METHODS: A total of 206 patients were enrolled in this retrospective study. SIRT1 and VEGF-C protein expression was detected by immunohistochemical staining. Peritumoral lymphatic microvessel density (LVD) and LVI were evaluated by immunostaining for D2-40. Statistical analysis was then preformed to investigate the relevance of SIRT1 expression and various clinicopathologic features and to examine the effect of SIRT1 on tumor-induced lymphangiogenesis, LVI and prognosis. RESULTS: SIRT1 positive expression was identified in 95 cases in the nucleus and was significantly correlated with T status (P < 0.001), disease stage (P = 0.001), VEGF-C positive expression (P = 0.015), high LVD (P = 0.013) and positive LVI (P = 0.015). Patients with SIRT1 positive expression, high LVD and positive LVI had a significantly unfavorable 5 year disease free survival (P < 0.001, P = 0.030, and P < 0.001, respectively) and overall survival (P < 0.001, P = 0.017, and P < 0.001, respectively). However, based on multivariate Cox regression analysis, only SIRT1 positive expression and positive LVI were significant independent prognosticators of poor disease-free survival (P = 0.029 and 0.018, respectively) and overall survival (P = 0.045 and 0.031, respectively). CONCLUSIONS: SIRT1 positive expression was significantly associated with tumor progression, lymphangiogenesis, LVI and poor survival in pN0 ESCC patients. Our research shows a utilization of SIRT1 in prognosing poor survival and providing possible target for ESCC patients through inhibiting its lymphangiogenesis activity. PMID- 25922661 TI - Peptidylarginine deiminase IV promotes the development of chemoresistance through inducing autophagy in hepatocellular carcinoma. AB - BACKGROUND: Peptidylarginine deiminase IV (PADI4) is widely distributed in several tissues and the expression is correlated with many pathological processes. Chemotherapy remains a major treatment alternatively to surgery for a large number of patients at the advanced stage of hepatocellular carcinoma (HCC). However, the role of PADI4 in the chemoresistance of HCC has not been identified. METHODS: MTT and PI/Annexin V assay were employed to examine the proliferation and apoptosis of HCC cell lines. The expression of MDR1 is detected by Realtime PCR. GFP tagged LC3 expression vector and electron microscopy are utilized to demonstrate the occurrence of autophagy. RESULTS: We observed that the elevated PADI4 expression is associated with chemoresistance in HCC patients with TACE after surgery. In addition, we found that overexpression of PADI4 in HCC cell lines lead to the resistance to chemotherapeutic agents in vitro and in vivo. Interestingly, the HCC cells that overexpressed PADI4 were observed to undergo autophagy which was known as a protective mechanism for cells to resist the cell tosicity from chemotherapy. Autophagy inhibitor could effectively restore the sensitivity of HCC cells to chemotherapy in vitro and in vivo. CONCLUSIONS: These results indicate that PADI4 may induce chemoresistance in HCC cells by leading autophagy. PMID- 25922662 TI - The expression profile of Aedes albopictus miRNAs is altered by dengue virus serotype-2 infection. AB - BACKGROUND: Aedes albopictus is an important vector of Dengue virus (DENV) and it has quickly invaded the tropical and temperate environments worldwide. A few studies have shown that, microRNAs (miRNAs) regulate mosquito defense against pathogens. However, there is no systematic analysis of the impact of DENV infection on miRNA expression in Ae. albopictus. We conducted this study to investigate the miRNA expression of Ae. albopictus upon DENV-2 infection using Illumina RNA sequencing. RESULTS: A total of 103 known and 5 novel candidate miRNAs were identified in DENV-2 infected and non-infected adult female Ae. albopictus. Comparative analysis indicated that 52 miRNAs were significantly down regulated and 18 were up-regulated significantly after infection. Furthermore, RT qPCR validated the expression patterns of eleven of these differentially expressed miRNAs. Targets prediction and functional analysis of these regulated miRNAs suggested that miR-34-5p and miR-87 might be involved in the anti-pathogen and immune responses. CONCLUSION: This is the first systematic study on the impact of DENV infection on miRNA expression in Ae. albopictus. Complex changes in miRNA expression suggest a potential role of miRNAs in antiviral responses by regulating immune-related genes. This investigation provides information concerning DENV-induced miRNAs and offers clues for identifying potential candidates for vector based antiviral strategies. PMID- 25922663 TI - Decreased circulating and neutrophil mediated VEGF-A165 release in stable long term cardiac transplant recipients. AB - BACKGROUND: Vascular endothelial growth factor (VEGF) may play a role on the allograft remodelling following cardiac transplantation (CTx). We measured the circulating levels of VEGF-A165 concomitantly with the proinflammatory (Interleukin-8; IL-8), anti-inflammatory (IL-1 receptor antagonist; IL-1RA) and their release from neutrophils of CTx recipients. METHODS: Eighteen CTx recipients aged 49.6 +/- 3.1 years, being transplanted for 145 +/- 20 months were age-matched to 35 healthy control (HC) subjects. Concomitantly to plasma assessment, circulating neutrophils were isolated, purified and stimulated by vehicle (PBS), N-formyl-Met-Leu-Phe (fMLP, 10(-7) M), bacterial lipopolysaccharide (LPS, 1 MUg/mL), or tumour necrosis factor alpha (TNF-alpha, 10 ng/mL). RESULTS: Compared with HC, CTx recipients exhibited a decrease (-80%) in plasmatic levels of VEGF-A165 (225 +/- 42 (HC) vs 44 +/- 10 pg/mL (CTx); (p < 0.001). There were no differences in the levels of IL-8 and IL-1RA. Under basal or stimulated conditions, neutrophils from CTx patients exhibited a marked decrease ranging from -30 to -88% on their capacity to release VEGF-A165, IL-8 and IL-1RA upon stimulation. CONCLUSIONS: Long-term CTx recipients exhibit a marked reduction in the circulating levels of VEGF-A165, as well as neutrophil mediated release of VEGF-A165, IL-1RA and IL-8 compared to healthy volunteers. The mechanisms and physiological impacts of these findings deserve additional investigations. PMID- 25922664 TI - Antimicrobial use in Chinese swine and broiler poultry production. AB - BACKGROUND: Antimicrobial use for growth promotion in food animal production is now widespread. A major concern is the rise of antimicrobial resistance and the subsequent impact on human health. The antimicrobials of concern are used in concentrated animal feeding operations (CAFOs) which are responsible for almost all meat production including swine and poultry in the US. With global meat consumption rising, the CAFO model has been adopted elsewhere to meet this demand. One such country where this has occurred is China, and evidence suggests 70% of poultry production now occurs outside of traditional small farms. Moreover, China is now the largest aggregate consumer of meat products in the world. With this rapid rise in consumption, the Chinese production model has changed along with the use of antimicrobials in feeds. However, the specific antibiotic use in the Chinese food animal production sector is unclear. Additionally, we are aware of high quantities of antimicrobial use because of reports of high concentrations of antimicrobials in animal waste and surface waters surrounding animal feeding operations. METHODS: In this report, we estimate the volume of antibiotics used for swine and poultry production as these are the two meat sources with the highest levels of production and consumption in China. We adopt a model developed by Mellon et al. in the US for estimating drug use in feed for poultry and swine production to estimate overall antimicrobial use as well as antimicrobial use by class. RESULTS: We calculate that 38.5 million kg [84.9 million lbs] were used in 2012 in China's production of swine and poultry. By antibiotic class, the highest weights are tetracyclines in swine and coccidiostats in poultry. CONCLUSIONS: The volume of antimicrobial use is alarming. Although there are limitations to these data, we hope our report will stimulate further analysis and a sense of urgency in assessing the consequences of such high levels of utilization in terms of antibiotic resistance in the food supply and the environment. PMID- 25922666 TI - Genomic resolution of linkages in carbon, nitrogen, and sulfur cycling among widespread estuary sediment bacteria. AB - BACKGROUND: Estuaries are among the most productive habitats on the planet. Bacteria in estuary sediments control the turnover of organic carbon and the cycling of nitrogen and sulfur. These communities are complex and primarily made up of uncultured lineages, thus little is known about how ecological and metabolic processes are partitioned in sediments. RESULTS: De novo assembly and binning resulted in the reconstruction of 82 bacterial genomes from different redox regimes of estuary sediments. These genomes belong to 23 bacterial groups, including uncultured candidate phyla (for example, KSB1, TA06, and KD3-62) and three newly described phyla (White Oak River (WOR)-1, WOR-2, and WOR-3). The uncultured phyla are generally most abundant in the sulfate-methane transition (SMTZ) and methane-rich zones, and genomic data predict that they mediate essential biogeochemical processes of the estuarine environment, including organic carbon degradation and fermentation. Among the most abundant organisms in the sulfate-rich layer are novel Gammaproteobacteria that have genes for the oxidation of sulfur and the reduction of nitrate and nitrite. Interestingly, the terminal steps of denitrification (NO3 to N2O and then N2O to N2) are present in distinct bacterial populations. CONCLUSIONS: This dataset extends our knowledge of the metabolic potential of several uncultured phyla. Within the sediments, there is redundancy in the genomic potential in different lineages, often distinct phyla, for essential biogeochemical processes. We were able to chart the flow of carbon and nutrients through the multiple geochemical layers of bacterial processing and reveal potential ecological interactions within the communities. PMID- 25922665 TI - Maternal fucosyltransferase 2 status affects the gut bifidobacterial communities of breastfed infants. AB - BACKGROUND: Individuals with inactive alleles of the fucosyltransferase 2 gene (FUT2; termed the 'secretor' gene) are common in many populations. Some members of the genus Bifidobacterium, common infant gut commensals, are known to consume 2'-fucosylated glycans found in the breast milk of secretor mothers. We investigated the effects of maternal secretor status on the developing infant microbiota with a special emphasis on bifidobacterial species abundance. RESULTS: On average, bifidobacteria were established earlier and more often in infants fed by secretor mothers than in infants fed by non-secretor mothers. In secretor-fed infants, the relative abundance of the Bifidobacterium longum group was most strongly correlated with high percentages of the order Bifidobacteriales. Conversely, in non-secretor-fed infants, Bifidobacterium breve was positively correlated with Bifidobacteriales, while the B. longum group was negatively correlated. A higher percentage of bifidobacteria isolated from secretor-fed infants consumed 2'-fucosyllactose. Infant feces with high levels of bifidobacteria had lower milk oligosaccharide levels in the feces and higher amounts of lactate. Furthermore, feces containing different bifidobacterial species possessed differing amounts of oligosaccharides, suggesting differential consumption in situ. CONCLUSIONS: Infants fed by non-secretor mothers are delayed in the establishment of a bifidobacteria-laden microbiota. This delay may be due to difficulties in the infant acquiring a species of bifidobacteria able to consume the specific milk oligosaccharides delivered by the mother. This work provides mechanistic insight into how milk glycans enrich specific beneficial bacterial populations in infants and reveals clues for enhancing enrichment of bifidobacterial populations in at risk populations - such as premature infants. PMID- 25922667 TI - Mapping the cause-specific premature mortality reveals large between-districts disparity in Belgium, 2003-2009. AB - BACKGROUND: Reducing premature mortality is a crucial public health objective. The goal of this paper, beside updating previous mortality atlases with recent data, is to explore the relative between-districts disparity using a relative scale map design. METHODS: Causes of deaths and population data were provided by Statistics Belgium. All deaths occurring in the periods 1993-1999 and 2003-2009, in people aged 1-74 residing in Belgium were included. Age-adjusted rates by cause of death were computed for both periods; the 2003-2009 rates were classified using a relative scale with a 10% change between each level and represented on chloropleths maps with a green-to-red divergent colour scheme centred on the national mean. This particular design allows the comparability across all the maps since a same meaning is given to a specific colour. The variation coefficient and the decile ratio were calculated and compared between the 2 periods. RESULTS: A clear-cut regional divide at the disadvantage of Wallonia, and to some extent, of Brussels, was seen for all-cause, cardiovascular, cerebrovascular, diabetes, alcohol-related, mental and neurological diseases and non-transport accidents premature mortality. A NE-SW pattern parallel to the French border was observed for Lip, Oral Cavity, Pharynx, Larynx and oesophageal cancers, while various patterns are observed for the other cancers. The highest rates of road accident mortality are observed in the Southern districts. Many of those patterns are in continuity with earlier observations. However, the pattern of diabetes and mental and neurological diseases are new features. The variation coefficient and the decile ratios increased by 10% between the 1993-1997 and 2003-2009 periods. CONCLUSIONS: The use of a relative scale in the maps highlights the importance of the between districts disparity in premature mortality, with for most causes, a clear-cut regional divide at the disadvantage of Wallonia; this health gap results of complex interactions between various factors, including the socioeconomic context, cultural habits and environmental influences, as well as public health policies. It should be considered as a warning signal, warranting the attention of the policy makers. Meanwhile, these results also highlight the potential for improvement in the more disadvantaged regions. PMID- 25922668 TI - Life expectancy ranking of Canadians among the populations in selected OECD countries and its disparities among British Columbians. AB - BACKGROUND: Canada is among the world's leading nations with the longest life expectancy at birth (LE0), and British Columbia (BC) ranks top among Canadian provinces and territories for LE0 in both men and women. This paper examined recent data as well as projected trends in LE0 of Canadian men and women and explored the geographic and socioeconomic disparities in LE0 specific to BC. METHODS: Using retrospective data on LE0 and age-standardized mortality rates, Canada was compared to 11 other Organization for Economic Cooperation and Development (OECD) countries with the longest LE0. Projections were made using linear regression modelling to the year of 2023. The association between regional LE0 and regional socioeconomic status (SES) was examined for the province of BC using its Local Health Area (LHA) level data on SES and LE0. RESULTS: In 2009, Canadian men (LE0: 78.7 years) and women (LE0: 83.3 years) ranked 7(th) and 8(th), respectively among the 12 OECD nations under comparison. Significantly smaller annual gains in LE0 contributed to the losing of their top ranks in LE0 for Canadian men and women in recent years, which was projected to sustain. Higher mortality risks, particularly for lung cancer and external causes of mortality among women was found for Canada compared to leading countries on these measures. Geographic variations were evident in LE0 in BC, and there was a significant gap of 3.6 years in the average LE0 for BC's LHAs in the lowest SES tertile (78.6 years, 95% CI: 78.0-79.3) compared to those in the highest SES tertile (82.2 years, 95% CI: 81.6-82.8). CONCLUSIONS: Canada continues to remain one of the OECD countries with longest living population. With the highest LE0 in the country, British Columbia has an opportunity to address socio-economic disparities in LE0. PMID- 25922669 TI - Surveillance of Clostridium difficile infections in a long-term care psychogeriatric facility: outbreak analysis and policy improvement. AB - BACKGROUND: Following an exceptionally high Clostridium difficile infections (CDI) incidence (Spring 2011) in a psychogeriatric long-term care facility, a bidirectional study (2009-2012) was initiated to identify determinants (retrospectively) and to assess intervention measures taken (prospectively). METHODS: For every CDI patient (de novo cases, relapses, and recurrences), a control patient (patient in the opposite room) was selected and risk factor analysis performed. Following the epidemic peak a more stringent hygienic protocol and surveillance program were implemented, as well as uniform guidelines for metronidazole and vancomycin prescription. RESULTS: The nutritional state (total protein/prealbumine) significantly differed between the CDI group (poorer nutritional state at admission) and the control group, and also antibiotic use (general) could be confirmed as a risk factor. A multi-disciplinary nutritional team has been established in order to improve the nutritional balance of our patients. CONCLUSIONS: Aside from stringent hygiene and antibiotic prescription stewardship, malnutrition of patients is a factor to be taken into account to contain a CDI outbreak in a long term care facility (LTCF). PMID- 25922670 TI - Message from the editors: coeliac disease focused issue. PMID- 25922671 TI - Screening for celiac disease in the general population and in high-risk groups. AB - BACKGROUND: Celiac disease (CD) occurs in approximately 1% of the Western population. It is a lifelong disorder that is associated with impaired quality of life (QOL) and an excessive risk of comorbidity and death. OBJECTIVES: To review the literature on screening for CD in relation to the current World Health Organization (WHO) criteria for mass screening. METHODS: We performed a PubMed search to identify indexed papers on CD screening with a publication date from 1900 until 1 June 2014. When we deemed an abstract relevant, we read the corresponding paper in detail. RESULTS: CD fulfills several WHO criteria for mass screening (high prevalence, available treatment and difficult clinical detection), but it has not yet been established that treatment of asymptomatic CD may reduce the excessive risk of severe complications, leading to higher QOL nor that it is cost-effective. CONCLUSIONS: Current evidence is not sufficient to support mass screening for CD, but active case-finding may be appropriate, as we recognize that most patients with CD will still be missed by this strategy. Although proof of benefit is still lacking, screening for CD may be appropriate in high-risk groups. PMID- 25922672 TI - The gluten-free diet and its current application in coeliac disease and dermatitis herpetiformis. AB - BACKGROUND: A gluten-free diet (GFD) is currently the only available therapy for coeliac disease (CD). OBJECTIVES: We aim to review the literature on the GFD, the gluten content in naturally gluten-free (GF) and commercially available GF food, standards and legislation concerning the gluten content of foods, and the vitamins and mineral content of a GFD. METHODS: We carried out a PubMed search for the following terms: Gluten, GFD and food, education, vitamins, minerals, calcium, Codex wheat starch and oats. Relevant papers were reviewed and for each topic a consensus among the authors was obtained. CONCLUSION: Patients with CD should avoid gluten and maintain a balanced diet to ensure an adequate intake of nutrients, vitamins, fibre and calcium. A GFD improves symptoms in most patients with CD. The practicalities of this however, are difficult, as (i) many processed foods are contaminated with gluten, (ii) staple GF foods are not widely available, and (iii) the GF substitutes are often expensive. Furthermore, (iv) the restrictions of the diet may adversely affect social interactions and quality of life. The inclusion of oats and wheat starch in the diet remains controversial. PMID- 25922673 TI - Psychological morbidity of celiac disease: A review of the literature. AB - BACKGROUND: Celiac disease has been linked to decreased quality of life and certain mood disorders. The effect of the gluten free diet on these psychological aspects of the disease is still unclear. OBJECTIVES: The objective of this article is to review the literature on psychological morbidity of celiac disease. METHODS: We performed a PubMed search for the time period from 1900 until June 1, 2014, to identify papers on psychological aspects of celiac disease looking specifically at quality of life, anxiety, depression and fatigue. RESULTS: Anxiety, depression and fatigue are common complaints in patients with untreated celiac disease and contribute to lower quality of life. While aspects of these conditions may improve within a few months after starting a gluten-free diet, some patients continue to suffer from significant psychological morbidity. Psychological symptoms may affect the quality of life and the dietary adherence. CONCLUSION: Health care professionals need to be aware of the ongoing psychological burden of celiac disease in order to support patients with this disease. PMID- 25922675 TI - Non-coeliac gluten sensitivity: piecing the puzzle together. AB - The avoidance of wheat- and gluten-containing products is a worldwide phenomenon. While coeliac disease is well-established, much remains unknown about whether gluten can be a trigger of gastrointestinal and/or extra-intestinal symptoms in patients without coeliac disease. In this article, we discuss the latest scientific evidence and our current understanding for the possible mechanisms of this largely ambiguous group, termed 'non-coeliac gluten sensitive' (NCGS). We can conclude that NCGS should be regarded as an independent disease outside of coeliac disease and wheat allergy, and that the number of patients affected is likely to be limited. Many questions remain unanswered and it needs to be verified whether the elimination of dietary gluten alone is sufficient for the control of symptoms, and to understand the overlap with other components of wheat. PMID- 25922676 TI - Dental erosions and other extra-oesophageal symptoms of gastro-oesophageal reflux disease: Evidence, treatment response and areas of uncertainty. AB - Extra-oesophageal symptoms of gastro-oesophageal reflux disease (GORD) are often studied, but remain a subject of debate. It has been clearly shown that there is a relationship between the extra-oesophageal symptoms chronic cough, asthma, laryngitis and dental erosion and GORD. Literature is abundant concerning reflux related cough and reflux-related asthma, but much less is known about reflux related dental erosions. The prevalence of dental erosion in GORD and vice versa, the prevalence of GORD in patients with dental erosion is high but the exact mechanism of reflux-induced tooth wear erosion is still under review. PMID- 25922674 TI - Support for patients with celiac disease: A literature review. AB - BACKGROUND: Celiac disease (CD) is a lifelong disorder. Patients are at increased risk of complications and comorbidity. OBJECTIVES: We conducted a review of the literature on patient support and information in CD and aim to issue recommendations about patient information with regards to CD. METHODS: DATA SOURCE: We searched PubMed for English-language articles published between 1900 and June 2014, containing terms related to costs, economics of CD, or education and CD. STUDY SELECTION: Papers deemed relevant by any of the participating authors were included in the study. DATA SYNTHESIS: No quantitative synthesis of data was performed. Instead we formulated a consensus view of the information that should be offered to all patients with CD. RESULTS: There are few randomized clinical trials examining the effect of patient support in CD. Patients and their families receive information from many sources. It is important that health care personnel guide the patient through the plethora of facts and comments on the Internet. An understanding of CD is likely to improve dietary adherence. Patients should be educated about current knowledge about risk factors for CD, as well as the increased risk of complications. Patients should also be advised to avoid other health hazards, such as smoking. Many patients are eager to learn about future non-dietary treatments of CD. This review also comments on novel therapies but it is important to stress that no such treatment is available at present. CONCLUSION: Based on mostly observational data, we suggest that patient support and information should be an integral part of the management of CD, and is likely to affect the outcome of CD. PMID- 25922677 TI - Endoscopic mucosal resection of large colorectal adenomas: Only for expert centers? PMID- 25922678 TI - Gastro-oesophageal reflux is common in oligosymptomatic patients with dental erosion: A pH-impedance and endoscopic study. AB - BACKGROUND: Dental erosion is a complication of gastro-oesophageal reflux disease (GORD) according to the Montreal consensus statement. However, GORD has not been comprehensively characterized in patients with dental erosions and pH-impedance measures have not been reported. OBJECTIVES: Characterize GORD in patients with dental erosions using 24-h multichannel intraluminal pH-impedance measurements (pH-MII) and endoscopy. METHODS: This single-centre study investigated reflux in successive patients presenting to dentists with dental erosion using pH-MII and endoscopy. RESULTS: Of the 374 patients, 298 (80%) reported GORD symptoms <2 per week, 72 (19%) had oesophagitis and 59 (16%) had a hiatal hernia. In the 349 with pH-MII the mean percentage time with a pH <4 (95% CI) was 11.0 (9.3-12.7), and 34.4% (31.9-36.9) for a pH <5.5, a critical threshold for dental tissue. The mean numbers of total, acidic and weakly acidic reflux episodes were 71 (63-79), 43 (38-49) and 31 (26-35), respectively. Of the reflux episodes, 19% (17-21) reached the proximal oesophagus. In 241 (69%) patients reflux was abnormal using published normal values for acid exposure time and reflux episodes. No significant associations between the severity of dental erosions and any reflux variables were found. The presence of GORD symptoms and of oesophagitis or a hiatal hernia was associated with greater reflux, but not with increased dental erosion scores. CONCLUSIONS: Significant oligosymptomatic gastro-oesophageal reflux occurs in the majority of patients with dental erosion. The degree of dental erosion did not correlate with any of the accepted quantitative reflux indicators. Definition of clinically relevant reflux parameters by pH-MII for dental erosion and of treatment guidelines are outstanding. Gastroenterologists and dentists need to be aware of the widely prevalent association between dental erosion and atypical GORD. PMID- 25922679 TI - Incidence and distribution of coeliac disease in Campania (Italy): 2011-2013. AB - BACKGROUND: There exists a wide variation in the reported incidence of coeliac disease in recent decades. We aimed to evaluate the incidence rate of coeliac diagnoses performed in an Italian region, Campania, between 2011 and 2013 and its variation therein. METHODS: All coeliac diagnoses made from 2011 to 2013 and registered within the Campania coeliac disease register (CeliacDB) were identified. Incidence rates were analysed by sex, age and province of residence, with a Poisson model fitted to determine incidence rate ratios. RESULTS: We found 2049 coeliac disease diagnoses registered in the CeliacDB between 2011 and 2013; 1441 of these patients were female (70.4%) and 1059 were aged less than 19 years (51.7%). The overall incidence of coeliac disease in Campania was 11.8 per 100,000 person-years (95% CI 11.3-12.3) during the study period, with marked variation by age [27.4 per 100,000 person-years (95% CI 25.8-29.1) in children under 19 years of age and 7.3 per 100,000 (95% CI 6.8-7.8) in adults] and sex [16.1 per 100,000 person-years in females (95% CI 15.3-16.9) and 7.2 per 100,000 person-years in males (95% CI 6.6-7.8)]. Coeliac disease incidence was roughly similar in Naples, Salerno, Caserta and Avellino, but about half in Benevento. More than 80% of our study population was diagnosed by the combination of positive antitransglutaminase IgA and Marsh 3. More than half of the patients were symptomatic at the time of coeliac disease diagnosis (39.7% had a classical presentation and 21.1% a non-classical one according to the Oslo definition). CONCLUSIONS: Coeliac disease incidence was roughly similar among Campania provinces, except in Benevento where it was about half, probably due to less awareness of coeliac disease in this area. The incidence of coeliac disease in Campania appears to be lower than that reported by most of the previous literature, suggesting the necessity of new coeliac awareness programmes. PMID- 25922681 TI - How GI practice can benefit from social media. PMID- 25922682 TI - The past, present and future of gastroenterology in Europe and worldwide. PMID- 25922680 TI - Prevalence estimation of celiac disease in the general adult population of Latvia using serology and HLA genotyping. AB - BACKGROUND: Prevalence estimates for celiac disease (CD) depend on the method used. The role of deamidated gliadin peptide (DGP) and genetic testing in epidemiological studies and diagnostic settings of celiac disease (CD) has still to be established. OBJECTIVES: The objective of this article is to assess the prevalence of CD in Latvia by combining serological tests with DQ2.5/DQ8 testing. METHODS: A total of 1444 adults from a randomly selected cross-sectional general population sample were tested by ELISA for tTG IgA, DGP IgA and IgG antibodies (QUANTA Lite(r), Inova Diagnostics Inc). Samples with tTG IgA >=20U were tested for EMA IgA by indirect immunofluorescence assay, and all specimens with tTG IgA >=15U were tested by QUANTA-Flash(r) chemiluminescent assays (CIA) (Inova Diagnostics Inc) for tTG IgA, DGP IgA and IgG. DQ2.5/8 was detected in individuals with any positive ELISA test and a subgroup of controls. RESULTS: Forty-three individuals (2.98%; 95% CI: 2.10-3.86%) tested positive by at least one ELISA test; 41.86% of the serology-positive individuals (any test above the cutoff) were DQ positive. Six individuals (0.42%; 95% CI: 0.09-0.75%) were triple ELISA positive, and DQ2.5 or DQ8 was positive in all; 0.35% (95% CI: 0.05-0.65%) were tTG IgA and EMA positive. Two tTG IgA-negative cases were both DGP IgG and IgA positive, both being DQ positive; including them in the "serology-positive" group would increase the prevalence to 0.49% (95% CI: 0.13-0.85%). CIA tests revealed 2 tTG IgA-positive and EMA-negative cases with a positive genotype. DQ2.5 or DQ8 genotype was positive in 28.6% of the serology-negative population. CONCLUSIONS: Estimates of the prevalence of CD in Latvia based on the serogenetic testing approach range from 0.35% to 0.49% depending on the criteria used. There is a rationale for combining serological tests and DQ2.5/8 genotyping. PMID- 25922683 TI - UEG Week Barcelona 2015 - the place to be for clinicians and researchers. PMID- 25922684 TI - Vaccine development and new attempts of treatment for ragweed allergy. AB - Ragweeds are flowering plants in the genus Ambrosia in the aster family, Asteraceae. They are distributed in the tropical and subtropical regions of the New World, especially North America. Short ragweed is the most important weed. The ragweed flowering occurs late in the summer and the pollination period extends from the beginning of August to mid-October. Sensitization to ragweed pollen has risen in United States in the past decade and probably worldwide. The major allergenic compound in the pollen has been identified as Amb a 1. Ragweed allergies usually cause allergic rhinitis and asthma. Ragweed allergic patients may show signs of oral allergy syndrome caused by crossreactivity between ragweed allergens and food allergens. In the present article, an update about vaccine development and new knowledge for ragweed allergy is exhaustively revised. PMID- 25922685 TI - 4-chlorophenol removal from water using graphite and graphene oxides as photocatalysts. AB - Graphite and graphene oxides have been studied amply in the last decade, due to their diverse properties and possible applications. Recently, their functionality as photocatalytic materials in water splitting was reported. Research in these materials is increasing due to their band gap values around 1.8-4 eV, and therefore, these are comparable with other photocatalysts currently used in heterogeneous photocatalytic processes. Thus, this research reports the photocatalytic effectiveness of graphite oxide (GO) and graphene oxide (GEO) in the degradation of 4-chlorophenol (4-CP) in water. Under the conditions defined for this research, 92 and 97% of 4-CP were degraded with GO and GEO respectively, also 97% of total organic carbon was removed. In addition, by-products of 4-CP that produce a yellow solution obtained only using photolysis are eliminated by photocatalyst process with GO and GEO. The degradation of 4-CP was monitored by UV-Vis spectroscopy, High Performance Liquid Chromatography (HPLC) and Chemical Oxygen Demand (COD). Thus, photocatalytic activity to remove 4-CP from water employing GO and GEO without doping is successfully showed, and therefore, a new gate in research for these materials is opened. PMID- 25922686 TI - Prevalence and determinants of work related injuries among small and medium scale industry workers in Bahir Dar Town, north west Ethiopia. AB - OBJECTIVES: To assess the prevalence and determinants of work-related injuries among small and medium scale industrial workers in Bahir Dar town, northwest Ethiopia. METHOD: Cross sectional comparative study design was used. Purposive sampling method was used to choose the specific Kebele 14 of the study area, for its relatively high number of industries. The study units were stratified into small and medium scale industries. All workers who were available at the time of interview were included in the study. A pre-tested questionnaire was used to collect data. Data was analyzed using SPSS for windows 16.0. RESULT: A total of 328 and 655 workers from small and medium-scale industries respectively participated in the study. Seven hundred sixty nine (78.2%) were males. Three hundred thirty six workers (34.2%) reported that they had experienced work related injuries. Sex, monthly salary, age, work experience and use of personal protective equipment were found to be different in the small and medium industries (P < 0.05). CONCLUSION: There was a high prevalence of work related injuries. Sociodemographic, socioeconomic, personal work behavior and the working environment have contributed for the injuries. Work-related injuries are assumed to be preventable with the provision of occupational health programs in workplaces. Thus it is recommended that the owners of industries need to focus on training and installing safer work environment and Further studies with large scale coverage and prospective study designs are warranted. PMID- 25922687 TI - Should nephrologists take a larger role in interventional nephrology, and should central line insertion remain a requirement of nephrology residency training? A debate. AB - The Canadian Society of Nephrology must soon provide input concerning the future of procedural training in nephrology. While at one time, the ability to insert a central venous catheter (CVC) was an essential skill required by all nephrologists, in 2014, nephrology training and practice has changed in fundamental ways such that it would be both unreasonable, and impractical, to maintain this requirement. Indeed, survey evidence suggests that many current trainees are not achieving this competency. Amongst the reasons that this requirement should be withdrawn include: 1) Not all trainees have the procedural skills to safely learn to insert CVC's. 2) Most nephrologists in training and in practice are intellectually oriented, not procedurally oriented and are not seeking to perform lots of procedures. 3) In most practice settings, interventional radiologists and intensive care doctors perform dialysis line insertions using real time ultrasound guidance frequently, and offer timely, safer, and better service to patients. 4) Most trainees will not enter practice settings where CVC insertion ability is required. 5) Otherwise excellent future trainees may be denied a nephrology certificate of special competence only because they are unable to insert a CVC by the end of their fellowship. 6) Academic nephrology training programs that cannot provide adequate CVC insertion experience to fellows may lose their status as training centres. As a pragmatic way forward, Canadian nephrology training programs must encourage and offer only those nephrology trainees who have the ability and interest in procedural nephrology, a pathway through which they may be provided superb advanced training to become an expert. There is no longer a compelling reason to mandate this for all trainees. PMID- 25922688 TI - An education initiative modifies opinions of hemodialysis nurses towards home dialysis. AB - BACKGROUND: It has been shown that in-center hemodialysis (HD) nurses prefer in center HD for patients with certain characteristics; however it is not known if their opinions can be changed. OBJECTIVE: To determine if an education initiative modified the perceptions of in-center HD nurses towards home dialysis. DESIGN: Cross-sectional survey of in-center HD nurses before and after a three hour continuing nursing education (CNE) initiative. Content of the CNE initiative included a didactic review of benefits of home dialysis, common misconceptions about patient eligibility, cost comparisons of different modalities and a home dialysis patient testimonial video. SETTING: All in-center HD nurses (including those working in satellite dialysis units) affiliated with a single academic institution. MEASUREMENTS: Survey themes included perceived barriers to home dialysis, preferred modality (home versus in-center HD), ideal modality distribution in the local program, awareness of home dialysis and patient education about home modalities. METHODS: Paired comparisons of responses before and after the CNE initiative. RESULTS: Of the 115 in-center HD nurses, 100 registered for the CNE initiative and 89 completed pre and post surveys (89% response rate). At baseline, in-center HD nurses perceived that impaired cognition, poor motor strength and poor visual acuity were barriers to peritoneal dialysis and home HD. In-center HD was preferred for availability of multidisciplinary care and medical personnel in case of catastrophic events. After the initiative, perceptions were more in favor of home dialysis for all patient characteristics, and most patient/system factors. Home dialysis was perceived to be underutilized both at baseline and after the initiative. Finally, in-center HD nurses were more aware of home dialysis, felt better informed about its benefits and were more comfortable teaching in-center HD patients about home modalities after the CNE session. LIMITATIONS: Single-center study. CONCLUSIONS: CNE initiatives can modify the opinions of in-center HD nurses towards home modalities and should complement the multitude of strategies aimed at promoting home dialysis. PMID- 25922689 TI - Quadricuspid pulmonic valve found on well exam. AB - Quadricuspid pulmonic valve (QPV) is almost always a benign anomaly and is therefore usually discovered incidentally on radiographic studies or post-mortem at autopsy. Because of its rarity, the true extent of the physiology of QPV is not fully understood, and the few reported cases of it may underestimate its physiological consequences. In this case, we report on a young active-duty solider who presented for a well check-up and was discovered on imaging to have a QPV. We also review the most recent literature and provide recommendations regarding the most effective diagnostic modalities. PMID- 25922690 TI - A single-center experience in radioembolization as salvage therapy of hepatic metastases of uveal melanoma. AB - BACKGROUND: Overall survival (OS) of patients with hepatic metastases of uveal melanoma is strongly linked with hepatic tumor control. Due to the lack of an effective systemic chemotherapy, locoregional therapies like radioembolization should play an increasingly important role. PURPOSE: To report complications and response rates of radioembolization as salvage therapy for hepatic uveal melanoma metastases. MATERIAL AND METHODS: Between October 2006 and January 2014, eight patients (age, 59.1 +/- 15.3 years; 5 men) with histologically proven uveal melanoma and hepatic metastases received radioembolization with glass microspheres at a single center. All patients had been heavily pretreated with multiple systemic/locoregional therapies resulting in a long median interval between diagnosis of hepatic metastases and radioembolization (17.1 months; range, 6.4-23.2 months). Follow-up consisted of clinical assessment, laboratory tests and tri-phasic computed tomography (CT) before and 1, 3, 6, 9, and 12 months after radioembolization. Response to therapy was evaluated by CT using RECIST version 1.1 and by survival time. Safety (laboratory and clinical toxicity) was rated according to Common Terminology Criteria for Adverse Events 4.03. Using Kaplan-Meier analysis time to progression of hepatic metastases (hTTP) and OS were calculated. RESULTS: One month after radioembolization 50% of patients presented with stable and 50% with progressive disease. Median hTTP and OS after radioembolization were 4.3 weeks (range, 3.4-28.6 weeks) and 12.3 weeks (range, 3.7-62.6 weeks), respectively. Median OS after diagnosis of hepatic metastases was 19.9 months (range, 7.3-31.4 months). Radioembolization was tolerated well in all patients without toxicity higher than grade 2. CONCLUSION: Radioembolization is a safe salvage therapy even in heavily pretreated hepatic metastases of uveal melanoma. PMID- 25922691 TI - The growing fibroadenoma. AB - BACKGROUND: Fibroadenomas (FAs) are the most common tumors of the breast clinically and pathologically in adolescent and young women but may be discovered at any age. With increasing use of core biopsy rather than excision for diagnosis, it is now commonplace to follow these lesions with imaging. PURPOSE: To assess the incidence of epithelial abnormalities (atypia, in situ or invasive, ductal or lobular malignancies) in FAs diagnosed by core biopsy and to re evaluate the management paradigm for any growing FA. MATERIAL AND METHODS: A retrospective review of the senior author's pathology results over 19 years identified 2062 nodular FAs (biopsied by ultrasound or stereotactic guidance). Eighty-three core biopsied FAs were identified which subsequently enlarged. RESULTS: Twelve of 2062 of core biopsied nodules demonstrated atypia, in situ, or invasive malignancy (ductal or lobular) within or adjacent to the FA (0.58%). Eighty-three FAs enlarged and underwent either surgical excision (n = 65), repeat core biopsy (n = 9), or imaging follow-up (n = 9). The incidence of atypia, in situ or invasive malignancy was 0/83 (0%). Two enlarging FAs were subsequently surgically diagnosed as benign phyllodes tumors (PT). CONCLUSION: Malignancy in or adjacent to a core biopsied FA is rare. The risk of cancer in a growing FA is even rarer; none were present in our series. FAs with abnormal epithelial abnormalities require excision. Otherwise, FAs without epithelial abnormality diagnosed by core biopsy need no specific follow-up considering the negligible incidence of conversion to malignancy. The breast interventionalist must know how to manage discordant pathology results. PMID- 25922692 TI - Anti-angiogenic therapy in advanced non-small cell lung carcinoma (NSCLC): is there a role in subsequent lines of therapy? PMID- 25922693 TI - Epidermal growth factor receptor tyrosine kinase inhibitors in non-small cell lung cancer: a decade of progress and hopeful future. PMID- 25922694 TI - Clinical implications and future perspectives in testing non-small cell lung cancer (NSCLC) for anaplastic lymphoma kinase (ALK) gene rearrangements. PMID- 25922695 TI - Chemotherapy versus tyrosine kinase inhibitor in EGFR unselected population advanced non-small cell lung cancer still matter of debate?-An update incorporating the DELTA trial data. PMID- 25922696 TI - Second-line treatment in EGFR-unselected patients: is it time to close one arm of this river's DELTA? PMID- 25922697 TI - The challenge of using biomarkers and molecularly targeted drugs to improve cure rate in early stage non-small cell lung cancer. PMID- 25922698 TI - Individualizing adjuvant therapy for early stage non-small cell lung cancer: we see the destination, but we don't yet know the route. PMID- 25922699 TI - Accessing critical care big data: a step by step approach. PMID- 25922700 TI - Adjuvant chemotherapy after resection of N1 non-small cell lung cancer: differential impact of new evidence on physician and patient decisions. AB - BACKGROUND: Adjuvant cisplatin-based chemotherapy (ACT) after resection of stages II-IIIA non-small cell lung cancer (NSCLC) modestly increased survival in several clinical trials. This study evaluated the subsequent impact of those trials on ACT use in clinical practice. METHODS: Patients who underwent lobectomy or more extensive lung resection without induction chemotherapy for pathologically confirmed N1 positive NSCLC between 2000 and 2012 were reviewed. Referrals to medical oncology, oncologist recommendations for ACT, and initiation of ACT were evaluated. Because major trials supporting ACT were published in 2004 and 2005, analysis was stratified into two eras: 2000-2005 and 2006-2012. RESULTS: During the study period, 272 patients met inclusion criteria (110 in the 2000-2005 cohort, 162 in the 2006-2012 cohort). Referrals to medical oncology increased from 74.5% (n=82) in the 2000-2005 cohort to 90.1% (n=146) in the 2006-2012 cohort (P=0.002). Due to lack of referral or missed appointments, 35.5% (n=39) of the 2000-2005 patients and 17.9% (n=32) of the 2006-2012 patients did not have a documented conversation with an oncologist regarding ACT. The proportion of patients recommended for ACT increased from 61% (n=50) to 81.5% (n=119) between the eras (P<0.001). Of patients recommended for chemotherapy, 14% (7/50) in 2000 2005 and 13.4% (16/119) in 2006-2012 declined ACT (P=0.666). CONCLUSIONS: Publication of supporting evidence increased recommendations for ACT but did not change the percentage of patients who ultimately agreed to receive ACT. Additional research is needed to better understand patient decision-making in this situation. PMID- 25922701 TI - Diagnostic performance of cardiac magnetic resonance for the detection of acute cardiac allograft rejection: a systematic review and meta-analysis. AB - BACKGROUND: Several studies have addressed the diagnostic accuracy of cardiac magnetic resonance (CMR) to assess acute cardiac allograft rejection (ACAR) compared with endomyocardial biopsy (EMB). But the methodological heterogeneity limited the clinical application of CMR. Accordingly, we have sought a comprehensive, systematic literature review and meta-analysis for the purpose. METHODS: Studies prior to September 1, 2014 identified by Medline/PubMed, EMBASE and Cochrance search and citation tracking were examined by two independent reviewers. A study was included if a CMR was used as a diagnostic test for the detection of ACAR. RESULTS: Of the seven articles met the inclusion criteria. Only four studies using T2 relaxation time as a CMR parameter could be pooled results, because the number of studies using other parameters was less than three. By using DerSimonian-Laird random effects model, meta-analysis demonstrated a pooled sensitivity of 90% [95% confidence interval (CI), 79% to 97%], a pooled specificity of 83% (95% CI, 78% to 88%), and a pooled diagnostic odds ratio (DOR) of 61.66 (95% CI, 18.09 to 210.10). CONCLUSIONS: CMR seems to have a high sensitivity and moderate specificity in the diagnosis of ACAR. However, as a result of CMR for diagnostic ACAR should be comprehensively considered by physicians and imaging experts in the context of clinical presentations and imaging feature. Further investigations are still required to test different parameters and study condition. PMID- 25922702 TI - Accelerated radiotherapy and concurrent chemotherapy for patients with contralateral central or mediastinal lung cancer relapse after pneumonectomy. AB - BACKGROUND: Treatment options are very limited for patients with lung cancer who experience contralateral central or mediastinal relapse following pneumonectomy. We present results of an accelerated salvage chemoradiotherapy regimen. METHODS: Patients with localized contralateral central intrapulmonary or mediastinal relapse after pneumonectomy were offered combined chemoradiotherapy including concurrent weekly cisplatin (25 mg/m(2)) and accelerated radiotherapy [accelerated fractionated (AF), 60 Gy, 8*2 Gy per week] to reduce time for repopulation. Based on 4D-CT-planning, patients were irradiated using multifield intensity-modulated radiotherapy (IMRT) or helical tomotherapy. RESULTS: Between 10/2011 and 12/2012, seven patients were treated. Initial stages were IIB/IIIA/IIIB: 3/1/3; histopathological subtypes scc/adeno/large cell: 4/1/2. Tumour relapses were located in mediastinal nodal stations in five patients with endobronchial tumour in three patients. The remaining patients had contralateral central tumour relapses. All patients received 60 Gy (AF), six patients received concurrent chemotherapy. Median dose to the remaining contralateral lung, esophagus, and spinal cord was 6.8 (3.3-11.4), 8.0 (5.1-15.5), and 7.6 (2.8-31.2) Gy, respectively. With a median follow-up of 29 [17-32] months, no esophageal or pulmonary toxicity exceeding grade 2 [Common terminology criteria for adverse events (CTC-AE) v. 3] was observed. Median survival was 17.2 months, local in field control at 12 months 80%. Only two local recurrences were observed, both in combination with out-field metastases. CONCLUSIONS: This intensified accelerated chemoradiotherapy schedule was safely applicable and offers a curative chance in these pretreated frail lung cancer patients. PMID- 25922703 TI - CT features of lung scar cancer. AB - OBJECTIVE: To explore the CT features of lung scar cancer (LSC). METHODS: CT images of 41 LSCs and 66 non-LSCs were retrospectively compared in terms of location, size, shape, border, speculation, lobulation, pleural indentation, surrounding ground-glass opacification (sGGO), vessel convergence, vacuolation, calcification and satellite opacification. RESULTS: Thirty-eight LSCs were histopathologically identified as adenocarcinoma. The LSCs and non-LSCs were located 8.73+/-8.65 and 12.55+/-10.67 mm from the pleura, respectively. The mean lesion sizes (3-D ratios) in the initial LSC, pre-surgical LSC and non-LSC images were 24.28+/-6.29 (0.33+/-0.65), 32.23+/-8.14 (0.60+/-0.18) and 23.24+/-3.73 (0.35+/-0.61) mm, respectively. The initial and pre-surgical LSC images showed significant differences in speculation and sGGO (P<0.05). Significant differences were also noted in vacuolation, vessel convergence and sGGO between the pre surgical LSC and the non-LSC images (P<0.05) and in vacuolation between the initial LSC and the non-LSC images (P<0.05). CONCLUSIONS: Despite similar CT features of LSCs and non-LSCs, the early detection and diagnosis of LSCs is possible by studying scar-tissue changes such as enlargement and sGGO associated with well-defined lesion borders in follow-up CT images. PMID- 25922704 TI - Correlation between familial cancer history and epidermal growth factor receptor mutations in Taiwanese never smokers with non-small cell lung cancer: a case control study. AB - BACKGROUND: Lung cancer is a leading cause of cancer deaths in the world. Cigarette smoking remains a prominent risk factor, but lung cancer incidence has been increasing in never smokers. Genetic abnormalities including epidermal growth factor receptor (EGFR) mutations predominate in never smoking lung cancer patients. Furthermore, familial aggregations of patients with these mutations reflect heritable susceptibility to lung cancer. The correlation between familial cancer history and EGFR mutations in never smokers with lung cancer requires investigation. METHODS: This was a retrospective case-control study that evaluated the prevalence of EGFR mutations in lung cancer patients with familial cancer history. Never smokers with lung cancer treated at a hospital in Taiwan between April 2012 and May 2014 were evaluated. Inclusion criteria were never smokers with non-small cell lung cancer (NSCLC). Exclusion criteria involved patients without records of familial cancer history or tumor genotype. RESULTS: This study included 246 never smokers with lung cancer. The study population mainly involved never smoking women with a mean age of 60 years, and the predominant tumor histology was adenocarcinoma. Lung cancer patients with familial cancer history had an increased prevalence of EGFR mutations compared to patients without family history [odds ratio (OR): 5.9; 95% confidence interval (CI): 3.3-10.6; P<0.001]. Specifically, 57 out of 85 cancer patients (67%) with familial cancer history had these mutations, while 41 out of 161 patients (25%) without family history harbored mutations. Subgroup analysis also revealed that patients with familial lung cancer history had stronger association with EGFR mutations (OR: 7.5; 95% CI: 3.4-16.3; P<0.001) compared to patients with family history of non-pulmonary cancers (OR: 5.0; 95% CI: 2.5-10.0; P<0.001). CONCLUSIONS: The study demonstrated an increased prevalence of EGFR mutations in Taiwanese never smoking lung cancer patients with familial cancer history. Moreover, a sizable proportion of never smoking cancer patients harbored these mutations. These observations have implications for the treatment of lung cancer in never smokers. PMID- 25922705 TI - Effect of a combined anti-thrombotic therapy of thrombosis on prosthetic heart valves. AB - OBJECTIVE: To evaluate the curative effects and risks of a medical therapy with combined anti-thrombotic agents for thrombosis on prosthetic heart valves. METHODS: Twenty-two patients who suffered from thrombosis on prosthetic valves with stable hemodynamics were divided into the inpatient group and the outpatient group. Thrombosis on the valves were demonstrated by transesophageal echocardiographies (TEE). A combined anti-thrombotic therapy with clopidogrel and warfarin were prescribed for all the patients during the whole treatment. Low molecular weight heparin (LMWH) was given twice daily during the first 5 days for the inpatients. The patients accepted regular follow-ups for observation of the functions of prosthetic valves, changes of thrombi, coagulation status and general clinical status. RESULTS: There were 5 men and 17 women. Thirteen patients suffered from thrombosis on the mechanical mitral valves (MVs), five on the mechanical tricuspid valves (TVs), one on the mechanical aortic valve and tricuspid bio-prosthetic valve, one on the mechanical aortic valve, one on the mitral bio-prosthetic valve, and one on the tricuspid bio-prosthetic valve. After an average of 36.4+/-23.1 days' observation, 16 (73%) patients' valvular function recovered normal without TTE detectable thrombi, 6 (27%) patients' valvular function remained abnormal including three patients without TTE detectable thrombi during follow-ups. No significant differences of thrombi changes and period of thrombi disappearance were observed between the inpatient group and the outpatient group. For patients with mitral thrombosis, sizes of the left atriums (LAs) decreased an average of 4.1 mm after treatment (95% CI, 1.2-6.9 mm). No significant changes of other chambers and left ventricular ejection fractions (LVEF) were observed. For patients with tricuspid thrombosis, LVEF improved an average of 10.5% after treatment (95% CI, 0.1-17.9%). No significant changes of chambers were observed. None experienced major bleedings except for two cases of mild subcutaneous ecchymoses. CONCLUSIONS: The combined anti-thrombotic therapy based on clopidogrel and warfarin is a feasible treatment for thrombosis on prosthetic heart valves under a close monitoring. PMID- 25922706 TI - PET-CT guided curative conformal radiation therapy in limited stage small cell lung cancer. AB - BACKGROUND: The prognosis of small cell lung cancer (SCLC) has been improving with the advances in diagnostic and therapeutic modalities. Positron emission tomography/computed tomography (FDG-PET/CT) which has been studied in non-small cell lung cancer (NSCLC) for a long time, and it has only recently been applied to SCLC. Therefore we sought to observe firstly the prognostic importance of the FDG uptake in limited disease small cell lung cancer (LD-SCLC) patients and secondly the clinical outcomes and toxicity profiles of LD-SCLC patients treated with conformal radiation therapy (RT) using FDG-PET/CT simulation. METHODS: Between 2009 and 2011, 33 LD-SCLC patients with LD-SCLC underwent disease staging using FDG-PET/CT conformal RT. Thoracic radiation was administered at a daily fraction of 2 Gy. Total dose was prescribed according to the treatment protocol such as, concurrent or sequential chemotherapy and in some patients according to the response of CT. All patients underwent chemotherapy. Survival was estimated using the Kaplan-Meier method. RESULTS: The median age of the patients was 58 years (range, 38-77 years). The median follow-up time was 20 months (range, 6.6 47.6 months). The 3-year overall survival (OS) and locoregional control rates were 23% and 48%, respectively. CONCLUSIONS: There are few studies examining the impact of PET-CT and the prognostic significance of FDG-uptake on outcomes in patients with LD-SCLC. Higher RT doses in response to higher FDG uptake may be safely applied for the purpose of locoregional control. PMID- 25922707 TI - Circulating miR-499 are novel and sensitive biomarker of acute myocardial infarction. AB - BACKGROUND: miRNAs are known to play a crucial role in cardiac development, and the expression of miRNA is altered in the diseased heart. The aim of this study was to investigate the value of plasma microRNA-499 (miR-499) as a novel biomarker for early diagnosis of acute myocardial infarction (AMI). METHODS: Enrolled in this study were 227 patients with chest pain on presentation to the departments of emergency and cardiology of Wuxi Second People's Hospital between October 2011 and May 2014. Additional 100 healthy individuals who received physical examination in the same hospital during the same period were used as control. Plasma was collected at admission, and the abundance of miR-499 was measured using reverse transcriptase-polymerase chain reaction (RT-PCR). RESULTS: MiR-499 was significantly elevated in 142 patients diagnosed with AMI as compared with 85 patients in non-AMI group and 100 subjects in healthy control group. Plasma miR-499 were already detectable in the plasma as early as 1 h after onset of chest pain in AMI patients, and continued to increase gradually without any sign of decreasing tendency within 9 h in AMI patients. miR-499 was highly positively correlated with the serum creatine kinase-MB (CK-MB) and cTnI. The area under the curve (AUC) of miR-499 for the diagnosis of AMI was 0.86, with an optimal cut-off value of 4.79, sensitivity of 80%, and specificity of 80.28%. CONCLUSIONS: miR-499 was shown to substantially increase the diagnostic accuracy of CK-MB and cTnI in the diagnosis of AMI, and therefore it may prove to be a useful marker for early diagnosis of AMI. PMID- 25922708 TI - Therapy in stable chronic obstructive pulmonary disease patients with pulmonary hypertension: a systematic review and meta-analysis. AB - Pulmonary hypertension (PH) is a common complication of chronic obstructive pulmonary disease (COPD) without effective drugs to treat. We conducted a systematic review and meta-analysis in order to evaluate whether PH specific therapies were effective for stable COPD patients. Data were extracted from PubMed, Cochrane Central Register of Controlled Trials and China Knowledge Resource Integrated Database. Randomized controlled trials (RCTs) with PH specific therapy treated more than 4 weeks in COPD were selected. The main outcome was exercise capacity; meanwhile pulmonary arterial pressure (PAP), hypoxemia and health related life quality were also measured. We included nine trials involving 365 subjects, among which two were treated with bosentan and seven with sildenafil. The study time varied from 4 weeks to 18 months and mostly it was 12 weeks. In a pooled analysis of nine trials, exercise capacity of COPD patients was improved by PH-specific therapy [mean difference (MD) 66.39 m, 95% confidence intervals (CI): 59.44-73.34]. COPD with severe PH (mean PAP >35 mmHg by right heart catheterization or systolic PAP >50 mmHg by echocardiography) improved the exercise capacity (MD 67.24 m, 95% CI: 60.26-74.23), but COPD without PH at rest did not (MD -9.24 m, 95% CI: -75.08 to 56.31). Meanwhile PAP was decreased (MD -9.02 mmHg, 95% CI: -10.71 to -7.34 mmHg). Although hypoxemia and life quality were not improved, the dyspnea was alleviated or at least not aggravated (Borg dyspnea index, MD -0.86, 95% CI: -1.86 to 0.14). In conclusion, PH specific drugs (especially sildenafil) could improve exercise capacity and decrease PAP in COPD patients with severe PH. PMID- 25922709 TI - Efficacy and safety of endobronchial valves for advanced emphysema: a meta analysis. AB - OBJECTIVE: A meta-analysis was undertaken to evaluate the efficacy and safety of bronchoscopic lung volume reduction with endobronchial valves (EBV) for advanced emphysema. METHODS: A systematic search was performed from PubMed, EMBASE, CNKI, Cochrane Library database. Randomized control clinical trials on treatment of emphysema for 3-12 months with the EBV compared with standard medications and sham EBV were reviewed. Inclusion criteria were applied to select patients with advanced emphysema treated with EBV. The primary outcome was the percentage of the forced expiratory volume in the first second (FEV1%). Secondary outcomes included St George's Respiratory Questionnaire (SGRQ) score, the distance of the 6-minute walk (6MWD) test, the Modified Medical Research Council (MMRC) dyspnoea score, cycle ergometry workload, and the rate of the six major complications at 3 or 12 months. Fixed- or random-effects models were used and weighted mean differences (WMD), relative risks (RR) and 95% confidence intervals (CI) were calculated. RESULTS: Three trials (565 patients) were considered in the meta analysis. EBV patients yielded greater increases in FEV1% than standard medications (WMD =6.71; 95% CI, 3.31 to 10.10; P=0.0001), EBV patients also demonstrated a significant change for SGRQ score (WMD =-3.64; 95% CI, -5.93 to 1.34; P=0.002), MMRC dyspnoea score (WMD =-0.26; 95% CI, -0.44 to -0.08; P=0.004), and cycle ergometry workload (WMD =4.18; 95% CI, 2.14 to 6.22; P<0.0001). A similar level was evident for 6MWD (WMD =11.66; 95% CI, -3.31 to 26.64; P=0.13). EBV may increase the rate of hemoptysis (RR =5.15; 95% CI, 1.16 to 22.86; P=0.03), but didn't increase the adverse events including mortality, respiratory failure, empyema, pneumonia, pneumothrax. The overall rates for complications compared EBV with standard medications and sham EBV was not significant (RR =2.03; 95% CI, 0.98 to 4.21; P=0.06). CONCLUSIONS: EBV lung volume reduction for advanced emphysema showed superior efficacy and a good safety and tolerability compared with standard medications and sham EBV, further more randomized controlled trial (RCT) studies are needed to pay more attention to the long-term efficacy and safety of bronchoscopic lung volume reduction with EBV in advanced emphysema. PMID- 25922710 TI - Prognostic value of different scoring models in patients with multiple organ dysfunction syndrome associated with acute COPD exacerbation. AB - BACKGROUND AND OBJECTIVE: Chronic obstructive pulmonary disease (COPD) represents an increasing healthcare concern as a leading cause of morbidity and mortality worldwide. Our objective was to predict the outcome of COPD patients associated with multiple organ dysfunction syndrome (MODS) by scoring models. METHODS: A retrospective study was performed on severe COPD patients within 24 hours of the onset of MODS. The Acute Physiology and Chronic Health Evaluation (APACHE) II, APACHE III, Multiple Organ Dysfunction Score (MODS), Simplified Acute Physiology Score II (SAPS II), and Sepsis-related Organ Failure Assessment (SOFA) scores were calculated for patients. RESULTS: A total of 153 elderly patients were recruited. Compared to 30-day survivors, the number of failing organs and all of the scoring models were significantly higher in 30-day non-survivors. The SOFA showed the highest sensitivity and area under the curve (AUC) for predicting the prognosis of patients with MODS induced by acute exacerbation of COPD. The results of logistic regression indicated that factors that were correlated with the prognosis of COPD included the exacerbation history, SOFA score, number of failing organs, and duration of ICU stay. The value of exacerbation frequency for predicting the outcome of COPD was excellent (AUC: 0.892), with a sensitivity of 0.851 and a specificity of 0.797. CONCLUSIONS: The SOFA score, determined at the onset of MODS in elderly patients with COPD, was a reliable predictor of the prognosis. The exacerbation frequency, number of failing organs, and the SOFA score were risk factors of a poor prognosis, and the exacerbation frequency could also effectively predict the outcome of COPD. PMID- 25922711 TI - Impact of body mass index on survival of esophageal squamous carcinoma patients in southern China. AB - BACKGROUND: Although high body mass index (BMI) increases risk for developing esophageal adenocarcinoma (EAC), the prognostic influence of BMI is unknown in esophageal squamous carcinoma. METHODS: BMI was calculated using measured height and weight at the first diagnosis and categorized as overweight (25 to 29.9 kg/m(2)), normal (18.5 to 24.9 kg/m(2)) or underweight (<18.5 kg/m(2)). Survival was compared by using the log-rank test on the Kaplan-Meier life table. Multivariate Cox regression analysis was used to evaluate whether BMI was an independent prognostic factor for disease-specific survival (DSS). RESULTS: Among 1,176 esophageal squamous carcinoma patients, 146 (12.4%) were categorized as overweight, and 277 (23.6%) underweight. More patients in the underweight group had anemia (P=0.001), weight loss (P=0.035) and R1 resection (P<0.001). Less patients in the underweight group received adjuvant chemotherapy (P=0.01). Patients in the overweight group had a higher incidence rate of high blood pressure (P<0.001), diabetes (P<0.001) and coronary artery diseases (P<0.001). Moreover, more patients in the overweight group had a lower TNM stage (P=0.003). In the univariated analysis, high BMI was significantly associated with better DSS (P=0.013). CONCLUSIONS: After adjusting for covariates enrolled for study, high BMI was an independent prognostic factor in weight loss esophageal squamous carcinoma patients. PMID- 25922712 TI - Impact of metformin use on survival in locally-advanced, inoperable non-small cell lung cancer treated with definitive chemoradiation. AB - BACKGROUND: We investigated survival outcomes in diabetic patients with non-small cell lung cancer (NSCLC) treated with concurrent metformin and definitive chemoradiation. METHODS: This single-institution, retrospective cohort study included 166 patients with NSCLC who were treated definitively with chemoradiation between 1999 and 2013. Of 40 patients who had type II diabetes, 20 (50%) were on metformin, and 20 (50%) were not on metformin. The primary outcome was overall survival (OS), and secondary outcomes included progression-free survival (PFS), locoregional recurrence-free survival (LRRFS) and distant metastasis-free survival (DMFS). Kaplan Meier method and log-rank test were performed in survival analysis. Cox regression was utilized in univariate analysis of potential confounders. RESULTS: Median follow-up was 17.0 months. Compared with non-diabetic patients, diabetic patients on metformin demonstrated similar OS (16.3 vs. 14.3 mo, P=0.23), PFS (11.6 vs. 9.7 mo, P=0.26), LRRFS (14.1 vs. 11.9 mo, P=0.78), and DMFS (13.4 vs. 10.0 mo, P=0.69). Compared with diabetic patients not on metformin, diabetic patients on metformin also exhibited similar OS (14.3 vs. 19.2 mo, P=0.18), PFS (19.7 vs. 10.1 mo, P=0.38), LRRFS (11.9 vs. 15.5 mo, P=0.69), and DMFS (10.0 vs. 17.4 mo, P=0.12). Identified negative prognostic factors on included squamous cell histology, lower performance status, higher T stage, and non-caucasian ethnicity. CONCLUSIONS: No statistically significant differences in survival or patterns of failure were found among the three cohorts in this small set of patients. No statistically significant differences in survival or patterns of failure were found between the three cohorts in this small set of patients. Though it is possible that metformin use may in fact have no effect on survival in NSCLC patients treated with definitive RT, larger-scale retrospective and prospective studies are implicated for clarification. PMID- 25922713 TI - The efficacy and safety of prone positioning in adults patients with acute respiratory distress syndrome: a meta-analysis of randomized controlled trials. AB - BACKGROUND: Prone positioning for acute respiratory distress syndrome (ARDS) has no impact on mortality despite significant improvements in oxygenation. However, a recent trial demonstrated reduced mortality rates in the prone position for severe ARDS. We evaluated effects of prone position duration and protective lung strategies on mortality rates in ARDS. METHODS: We extensively searched MEDLINE, EMBASE, and the Cochrane Central Register of Controlled Trials to identify randomized controlled trials (RCTs) reporting on prone positioning during acute respiratory failure in adults for inclusion in our meta-analysis. RESULTS: Eight trials met our inclusion criteria, Totals of 1,099 and 1,042 patients were randomized to the prone and supine ventilation positions. The mortality rates associated with the prone and supine positions were 41% and 47% [risk ratio (RR), 0.90; 95% confidence interval (CI), 0.82-0.98, P=0.02], but the heterogeneity was moderate (P=0.01, I(2)=61%). In a subgroup analysis, the mortality rates for lung protective ventilation (RR 0.73, 95% CI, 0.62-0.86, P=0.0002) and duration of prone positioning >12 h (RR 0.75, 95% CI, 0.65-0.87, P<0.0001) were reduced in the prone position. Prone positioning was not associated with an increased incidence of cardiac events (RR 1.01, 95% CI, 0.87-1.17) or ventilator associated pneumonia (RR 0.88, 95% CI, 0.71-1.09), but it was associated with an increased incidence of pressure sores (RR 1.23, 95% CI, 1.07-1.41) and endotracheal dislocation (RR 1.33, 95% CI, 1.02-1.74). CONCLUSIONS: Prone positioning tends to reduce the mortality rates in ARDS patients, especially when used in conjunction with a lung protective strategy and longer prone position durations. Prone positioning for ARDS patients should be prioritized over other invasive procedures because related life-threatening complications are rare. However, further additional randomized controlled design to study are required for confirm benefit of prone position in ARDS. PMID- 25922714 TI - Antioxidant and lipid-regulating effects of probucol combined with atorvastatin in patients with acute coronary syndrome. AB - OBJECTIVE: To investigate the effects of probucol combined with atorvastatin on the serum oxidation index and lipid levels in patients diagnosed with acute coronary syndrome (ACS). METHODS: We randomly assigned 126 ACS patients (77 males and 49 females) to the control group (atorvastatin 20 mg/day, n=62) or the treatment group (atorvastatin 20 mg/day and probucol 750 mg/day, n=64). All the patients were followed up for 12 weeks. As oxidization indices, we measured the serum levels of total cholesterol (TC), low-density lipoprotein cholesterol (LDL C), high-density lipoprotein cholesterol (HDL-C), triglyceride (TG), oxidized LDL (ox-LDL), and paraoxonase-1 (PON1) before and after treatment. We also monitored the adverse effects of the drugs during the treatment. RESULTS: At baseline, there were no obvious differences (P>0.05) between the two groups (including age, gender, etc.). After 12 weeks of treatment, the ox-LDL levels in the treatment group were significantly lower while PON1 levels were significantly higher than those in the control group. There were no statistically significant difference between the two groups with respect to the side effects (P<0.05). CONCLUSIONS: The combined use of atorvastatin and probucol in ACS patients could reduce ox-LDL expression and increase PON1 expression more effectively than use atorvastatin alone. PMID- 25922715 TI - Epidemiology of carbapenem resistant Enterobacteriaceae (CRE) during 2000-2012 in Asia. AB - BACKGROUND: Over the past decade, the worldwide emergence of carbapenem resistance in Enterobacteriaceae has become a severe public health issue. This meta-analysis aims to describe the epidemiology of carbapenem resistant Enterobacteriaceae (CRE) during the years of 2000-2012 in Asian area. METHODS: PubMed and Embase databases were searched to identify the qualified papers. Random or fixed-effect model was used to deal with the data. RESULTS: Over all the 49 Asian countries (or regions), only 37.5% [19] of them contributed epidemiology data of CRE, and the rest ones provided either only case reports or no information at all. In Asia, the prevalence of CRE was still low during the study period with average resistance rates of 0.6% (95% CI, 0.6-0.8%, imipenem) and 0.9% (95% CI, 0.7-1.2%, meropenem). Resistance rates to imipenem and meropenem in Enterobacteriaceae exhibited stably escalating trend. Similar trend can also be observed among each Enterobacteriaceae genus, such as E. coli, Klebsiella spp. and Enterobacer spp. Klebsiella spp. accounted for the largest proportion among the isolates resistant to imipenem, and then followed by E. coli and Serratia. The rank order of resistance rates to imipenem among Enterobacteriaceae genus during the period of 2000-2012 was as follows: Serratia spp. (1.8%) > Proteus spp. (1.6%) > Klebsiella spp. (0.8%) = Citrobacter spp. (0.8%) > Enterobacer spp. (0.7%) > E. coli (0.2%). CONCLUSIONS: Given the fact that the prevalence of CRE was increasing during the past decade, it is urgent for us to establish regional surveillance worldwide, carry out more effective antibiotic stewardship and infection control measures to prevent further spread of carbapenem resistance in Enterobacteriaceae. PMID- 25922716 TI - Clinical characteristics and survival in idiopathic pulmonary fibrosis and connective tissue disease-associated usual interstitial pneumonia. AB - BACKGROUND: Previous studies have reported conflicting survival rates for connective tissue disease (CTD)-associated usual interstitial pneumonia (UIP) and idiopathic pulmonary fibrosis (IPF/UIP). This study investigated the differences in the clinical characteristics and prognoses of patients diagnosed with CTD-UIP and IPF/UIP. METHODS: A retrospective review of patients with IPF (n=88) and CTD UIP (n=67) from January 2008 to June 2013 was completed. We compared the demographics and clinical characteristics between the two groups. Survival rates were compared using a log-rank and Cox proportional hazard regression analysis. RESULTS: Undifferentiated-CTD (UCTD) accounted for 33% of the established CTD-UIP cases. No significant differences were identified in the demographic characteristics or physiological parameters between the UCTD and CTD patients (all P>0.05). However, the CTD-UIP patients were more likely to be young, female, and nonsmokers compared with the IPF/UIP group (all P<0.01). There was no difference in survival between the IPF/UIP and CTD-UIP patients [hazard ratio (HR), 1.74; 95% confidence interval (CI), 0.86-3.50; P=0.113]. However, the removal of the UCTD patients from the CTD group revealed that IPF/UIP was associated with a 2.47-fold increased risk of mortality compared with CTD-UIP (HR, 2.47; 95% CI, 1.01-6.09; P=0.049). CONCLUSIONS: Our findings indicate that the survival of CTD-UIP patients was similar compared with that of IPF/UIP patients. However, it appears that UCTD influences the survival rate of CTD-UIP patients. PMID- 25922717 TI - Assessment of the usefulness of video-assisted thoracoscopic surgery in patients with non-tuberculous thoracic empyema. AB - BACKGROUND: The purpose of this retrospective study was to investigate the effectiveness and the outcomes of video-assisted thoracic surgery (VATS) treatment and medical therapy (including chest tube drainage, antibiotic treatment) in empyema patients. METHODS: Thirty-two consecutive patients with thoracic empyema were treated by VATS or tube drainage from 2006 to 2011. An analysis reviewed outcomes between the operation group and the drainage group. In addition, the operation group was divided into two groups for analysis. RESULTS: The drainage period was 15.1+/-11.3 days in the drainage group and 8.3+/-4.6 days in the operation group. The length of hospital stay was 22.4+/-10.0 days in the drainage group and 16.3+/-5.0 days in the operation group. There were five in hospital deaths in the drainage group, but no in-hospital deaths in the operation groups. In addition, patients in the early operation group had a significantly shorter hospital stay and postintervention drainage period than patients in the late operation group. CONCLUSIONS: VATS for nontuberculous thoracic empyema was more effective than tube drainage and required a shorter hospital stay. The results also indicated that patients who receive early surgical treatment may show better outcomes with late surgical management. PMID- 25922718 TI - Ginsenoside metabolite compound K enhances the efficacy of cisplatin in lung cancer cells. AB - OBJECTIVE: To evaluate the potential of ginsenoside metabolite compound K (CK) in enhancing the anti-tumor effects of cisplatin against lung cancer cells, including cell proliferation and apoptosis, and the underlying mechanism. METHODS: Western blotting and p53 reporter assay were used to assess p53 expression and activity. MTT assay and TUNEL staining were employed to investigate the drug effects on cell growth and apoptosis, respectively. Combination index (CI) was calculated to determine synergism. RESULTS: We found that CK could significantly enhance cisplatin-induced p53 expression and activity in two lung cancer cell lines, H460 and A549. Consequently, synergistic inhibition of cell growth was observed when the cells were co-treated with CK and cisplatin compared to single treatment. In addition, the ability of cisplatin in apoptosis induction was similarly synergized by CK. Furthermore, by using p53 null lung cancer cells, we demonstrate that the synergy was p53 dependent. CONCLUSIONS: Conventional chemotherapies are often accompanied by development of drug resistance and severe side effects. Novel discoveries of low toxicity compounds to improve the outcome or enhance the efficacy of chemotherapies are of great interest. In the present study, our data provide the first evidence that CK could be potentially used as an agent to synergize the efficacy of cisplatin in lung cancer. PMID- 25922719 TI - Clinical outcomes of cyberknife stereotactic radiosurgery for lung metastases. AB - BACKGROUND: Cyberknife stereotactic radiosurgery is an emerging noninvasive technique for treating oligometastatic cancer. The aim of this study is to evaluate the efficacy and tolerability of cyberknife for the treatment of patients with lung metastases. MATERIALS AND METHODS: A total of 134 lung metastases in 95 patients were treated with cyberknife in the radiotherapy center of our hospital from March 2009 to March 2013. The number of lung metastases per patient ranged from one to four (single lesions in 63 patients, 66.3%). The average tumor volume was 14.6 cm(3) and the prescribed radiation dosage ranged from 30 to 60 Gy, fractionated one to five times with a 60% to 88% isodose line. The primary end point was local control (LC); secondary end points were survival and toxicity. RESULTS: The median follow-up was 17 months (ranging from 4 to 46 months). The 1-year LC rate was 97.6%, the 2-year LC rate was 90.6%, and the 3 year LC rate was 87.0%. The median survival time was 38.0 months and the median progression-free survival (PFS) time was 14.0 months. The 2-year PFS rate was 29.0% and the overall survival (OS) rate was 61.3%. No grade 4 or higher toxicity was encountered. CONCLUSIONS: Cyberknife is safe and effective treatment for patients with lung metastases. PMID- 25922720 TI - Effects of bronchoscopic lung volume reduction using transbronchial infusion of autologous blood and thrombin in patients with severe chronic obstructive pulmonary disease. AB - BACKGROUND: Existing medical treatments have limitations in the management of very severe chronic obstructive pulmonary disease (COPD). METHODS: We performed bronchoscopic lung volume reduction (BLVR) using transbronchial infusion of autologous blood and thrombin (BLVR with blood) in three patients with very severe COPD whose dyspnea could not be relieved by maximum medical management. Two patients underwent BLVR with blood in the left and right lungs at intervals of a half-year or a year, and one patient underwent this procedure in only the right lung. We assessed the changes in pulmonary function, exercise capacity and quality of life before and after BLVR with blood in a total of five procedures. RESULTS: The subjects were 58- to 74-year-old males. Their forced expiratory volume in one second (FEV1) percent predicted ranged from 14.8% to 23.4%. BLVR with blood achieved significant improvements as follows (values before -> after the procedure, mean +/- standard deviation): FEV1 0.45r the L -> 0.76r the L (P=0.004), inspiratory capacity 1.50cityo L -> 2.05+/-.05c L (P=0.015), 3-minute walk test 46.8nuteo m -> 89.6+/-34.5 m (P=0.004). Lung function peaked several months after BLVR with blood and returned to nearly the baseline level in 6 months, but exercise capacity was better than that at baseline for at least 12 months. St. George's Respiratory Questionnaire (SGRQ), measured in two patients before and 12 months after the procedure, showed remarkable improvements (-15.6 and -11.9 units). CONCLUSIONS: BLVR with blood is an effective palliative treatment for very severe COPD. PMID- 25922721 TI - Methylated APC and RASSF1A in multiple specimens contribute to the differential diagnosis of patients with undetermined solitary pulmonary nodules. AB - BACKGROUND: Inactivation of tumor-suppressor gene (TSG) by promoter hypermethylation has been reported in many tumor types, including lung cancer. This study was designed to determine the methylated APC and RASSF1A genes in tumor tissue, serum and plasma of patients with early stage lung cancer. METHODS: Eighty-nine patients with undetermined solitary pulmonary nodules detected upon CT-scan were recruited in this study. DNA samples were extracted from biopsy tissues, serum and plasma and QMSP of APC and RASSF1A was carried out after bisulfite conversion. The 89 patients consist of 58 stage I lung cancer patients and 31 benign lung disease according to pathological report. Twenty-six cancer patients had matched biopsy tumor tissue, serum and plasma samples. RESULTS: The methylation rates of APC and RASSF1A were 59.0% and 66.1% in biopsy tissues, 42.5% and 52.5% in serum, and 24.1% and 43.1% in plasma of cancer patients. For RASSF1A, different samples all showed a significant difference between cancer group and benign group (P<0.05). However, APC gene only explored the P value less than 0.05 in plasma result. Towards the 26 lung cancer patients with three matched samples, methylation rate in each sample type was more than 50.0% and displayed no difference. CONCLUSIONS: Evaluation of APC and RASSF1A promoter methylation by using QMSP appears to be very useful for the differential diagnosis of patients with undetermined solitary pulmonary nodules. Our results also suggested that plasma might be the best sample for clinical detection of early stage lung. PMID- 25922722 TI - Variability in the anti-tumor effect of tegafur-uracil depending on histologic types of lung cancer. AB - BACKGROUND: Tegafur-uracil (UFT) is an anticancer agent that inhibits thymidylate synthase (TS). The degree of TS expression in primary lung cancer (LC) is different according to histologic cell type. In this study, we examined the variability of the anti-tumor efficacy of UFT monotherapy depending on histological subtypes of LC. METHODS: In the current single-institution, retrospective study, we assigned the patients with LC to three histologic groups [the squamous (Sq) non-small cell lung cancer (NSCLC)] group, the non-Sq NSCLC group and the SCLC group] and then compared the clinical response to UFT monotherapy between the three groups. RESULTS: Our clinical series of 149 patients include 54 cases of Sq NSCLC, 67 cases of non-Sq NSCLC and 28 cases of SCLC. For Sq NSCLC, non-Sq NSCLC and SCLC group, the overall response rates (ORRs) were 1%, 1% and 0% (P=0.522), respectively. The disease control rates (DCRs) were 38.9%, 31.3% and 10.7% (P=0.012), respectively. The median progression-free survivals (PFSs) were 2.68, 2.25 and 1.46 months (P=0.004 for three groups and P=0.773 for two groups except for the SCLC group at the log-rank test), respectively. There was no significant difference between the groups in median overall survival (OS). CONCLUSIONS: Our results indicate that the degree of the anti-tumor effect of UFT was higher in patients with NSCLC as compared with SCLC. But it showed no significant difference between the patients with Sq NSCLC and those with non-Sq NSCLC. PMID- 25922723 TI - Utility of EBUS-TBNA for diagnosis of mediastinal tuberculous lymphadenitis: a multicentre Australian experience. AB - BACKGROUND: Endobronchial ultrasound (EBUS) transbronchial needle aspiration (TBNA) is an important diagnostic procedure for the interrogation of mediastinal lymph nodes. There is limited data describing the accuracy & safety of this technique for the diagnosis of tuberculous mediastinal lymphadenitis. METHODS: A multi-centre retrospective study of all EBUS-guided TBNA procedures that referred samples for mycobacteriology was performed. Results were correlated with post procedural diagnoses after a period of surveillance and cross-checked against relevant statewide tuberculosis (TB) registries, and sensitivity and specificity was calculated. In addition, nucleic acid amplification techniques (NAAT) were assessed, and sensitivity and specificity calculated using positive mycobacterial culture as the reference gold standard. RESULTS: One hundred and fifty-nine patients underwent EBUS-TBNA and had tissue referred for mycobacterial culture, of which 158 were included in the final analysis. Thirty-nine were ultimately diagnosed with TB (25%). Sensitivity of EBUS-TBNA for microbiologically confirmed tuberculous mediastinal lymphadenitis was 62% (24/39 cases). Specificity was 100%. Negative predictive value (NPV) and diagnostic accuracy for microbiologic diagnosis was 89% [95% confidence intervals (CI), 82-93%] and 91% (95% CI, 84 94%) respectively. For a composite clinicopathologic diagnosis of TB NPV and accuracy were 98% (95% CI, 93-99%) and 98% (95% CI, 95-99%) respectively. Sensitivity for NAAT was 38% (95% CI, 18-65%). CONCLUSIONS: EBUS-TBNA is a safe and well tolerated procedure in the assessment of patients with suspected isolated mediastinal lymphadenitis and demonstrates good sensitivity for a microbiologic diagnosis of isolated mediastinal lymphadenitis. When culture and histological results are combined with high clinical suspicion, EBUS-TBNA demonstrates excellent diagnostic accuracy and NPV for the diagnosis of mediastinal TB lymphadenitis. We suggest EBUS-TBNA should be considered the procedure of choice for patients in whom TB is suspected. PMID- 25922724 TI - Reconstruction techniques for hypopharyngeal and cervical esophageal carcinoma. AB - OBJECTIVE: To investigate the incidence of perioperative complications in patients with hypopharyngeal and cervical esophageal carcinoma who underwent three types of esophageal defect reconstruction procedures. METHODS: Clinical data from 105 patients with hypopharyngeal and cervical esophageal carcinoma who were treated at SUN YAT-SEN Memorial Hospital from January 2003 to February 2013 were retrospectively analyzed. Among these patients, 45 underwent a pectoral major muscle skin flap reconstruction following carcinoma resection (group A); 32 patients were treated with stomach replacement of the esophagus (group B), and 28 patients were treated with tube stomach replacement of the esophagus (group C). The incidences of perioperative complications were compared among these three groups. RESULTS: The incidences of anastomotic leakage, neck swelling, and incision infection were significantly lower in group C than in group A (P<0.05). The incidences of anastomotic leakage, reflux esophagitis, and thoracic stomach syndrome were significantly lower in group C than in group B (P<0.05). CONCLUSIONS: Tube stomach replacement of the esophagus in the setting of hypopharyngeal and cervical esophageal carcinoma reduced the incidence of complications; therefore, it is a reasonable procedure for the management of esophageal defects. PMID- 25922725 TI - Evaluation of the efficacy and safety of anti-PD-1 and anti-PD-L1 antibody in the treatment of non-small cell lung cancer (NSCLC): a meta-analysis. AB - BACKGROUND: Currently, blockade of the programmed cell death 1 (PD-1)/PD-1 ligand 1 (PD-L1) signaling pathway has been proved one of the most promising immunotherapeutic strategies against cancer. Several antibodies have been developed to either block the PD-1 or its ligand PD-L1 are under development. So far, a series of phase I trials on PD-1/PD-L1 antibodies for non-small cell lung cancer (NSCLC) have been completed, without reports of results from phase II studies. Thus, we sought to perform a meta-analysis incorporating all available evidences to evaluate the efficacy and safety of PD-1 or PD-L1 inhibition therapy. METHODS: Electronic databases were searched for eligible literatures. Data of objective respond rate (ORR) and rate of adverse effects (AEs) with 95% confidence interval (CI) evaluated by immunohistochemistry (IHC) was extracted. The outcomes were synthesized based on random-effect model. Subgroup analyses were proposed. RESULTS: In overall, ORR in the whole population with PD-1 blockage treatment is 22.5% (95% CI: 17.6% to 28.2%). Additionally, the rate of Grade 3-4 AEs is 16.7% (95% CI: 6.5% to 36.8%) and drug-related death rate is 2.5% (95% CI: 1.3% to 4.6%). As for patients with PD-L1 inhibition therapy, an overall ORR is 19.5% (95% CI: 13.2% to 27.7%). A higher rate of Grade 3-4 AEs (31.7%, 95% CI: 14.2% to 56.5%) is observed with a lower drug-related death rate (1.8%, 95% CI: 0.4% to 8.3%). In exploratory analyses of anti-PD-1 agents, we observed that greater ORR was presented in the median-dose cohort (3 mg/kg) than that of both low-dose (1 mg/kg) and high-dose (10 mg/kg) cohort (low-dose vs. median-dose: OR =0.12, P=0.0002; median-dose vs. high-dose: OR =1.47, P=0.18). CONCLUSIONS: Anti-PD-1 and anti PD-L1 antibodies showed objective responses in approximately one fourth NSCLC patients with a tolerable adverse-effect profile. In addition, median-dose (3 mg/kg) might be a preferential dosage of anti-PD-1 agents. PMID- 25922727 TI - Changes in peripheral CD19(+)Foxp3(+) and CD19(+)TGFbeta(+) regulatory B cell populations in rheumatoid arthritis patients with interstitial lung disease. AB - OBJECTIVE: Although the role of regulatory B cells (Bregs) in rheumatic disease has gained increasing attention, two lesser-known Breg subsets that express either Foxp3 or transforming growth factor beta (TGFbeta) are rarely examined in studies of rheumatic disease. This study investigates the association between the relative proportions of CD19(+)Foxp3(+) and CD19(+)TGFbeta(+) Bregs, and clinical indicators of disease severity in rheumatoid arthritis (RA) patients with or without interstitial lung disease (ILD). METHODS: A total of 31 RA patients (14 with and 17 without ILD) and 26 healthy control subjects were included. All subjects did not have other autoimmune disease except RA, tumor, active infection, or a history of related drug administration. Peripheral blood mononuclear cells (PBMCs) were isolated and analyzed by flow cytometry (FCM). The relationship between the relative proportions of CD19(+)Foxp3(+) and CD19(+)TGFbeta(+) Bregs and their associations to RA and ILD incidence, as well as disease severity assessed by common clinical indicators, were then examined. RESULTS: Our analyses revealed RA patients had significantly lower proportions of peripheral CD19(+)Foxp3(+) and CD19(+)TGFbeta(+) Bregs as compared to healthy controls. While no association was observed between CD19(+)Foxp3(+) Bregs and ILD incidence, patients with ILD had a substantially lower percentage of CD19(+)TGFbeta(+) Bregs compared to RA patients without ILD. In addition, CD19(+)Foxp3(+) Bregs were negatively correlated with erythrocyte sedimentation rate (ESR) and C-reactive protein (CRP) levels in RA patients, whereas CD19(+)TGFbeta(+) Bregs were only correlated with CRP in RA patients with ILD. Furthermore, there was a negative association between CD19(+)Foxp3(+) Bregs and disease severity scores, which was not found in analyses with CD19(+)TGFbeta(+) Bregs. CONCLUSIONS: The proportions CD19(+)Foxp3(+) and CD19(+)TGFbeta(+) Bregs were significantly decreased in RA patients, particularly in those with ILD complications, suggesting that Breg phenotypes may have different functions in the pathogenesis of RA and ILD. PMID- 25922726 TI - Clinicopathological and prognostic significance of programmed cell death ligand1 (PD-L1) expression in patients with non-small cell lung cancer: a meta-analysis. AB - OBJECTIVE: Programmed cell death 1 (PD-1) and one of its ligands, PD-L1, are key immune checkpoint proteins. Evidences showed PD-L1 is an emerging biomarker for immunotherapy by anti-PD-1 and anti-PD-L1 antibody in non-small cell lung cancer (NSCLC). To investigate the association of PD-L1 protein expression with clinicopathological features and its impact on survival outcome, we conducted a meta-analysis. METHODS: A comprehensive literature search of electronic databases (up to July 10, 2014) was performed. Correlation between PD-L1 expression and clinicopathological features and overall survival (OS) was analyzed by synthesizing the qualified data. Publication biases were examined. RESULTS: A total of 1,550 NSCLC patients from 9 studies were included. The pooled odds ratios (ORs) indicated high PD-L1 expression was associated with poor tumor differentiation [OR =0.53, 95% confidence interval (CI): 0.39-0.72, P<0.0001]. Whereas, none of other clinicopathological characteristics [gender, smoking status, histological type, invasive depth of tumor, status of lymph node metastasis and tumor node metastasis (TNM) stage] were correlated with PD-L1 expression in current analysis. The combined hazard ratio (HR) for OS showed high expression of PD-L1 impaired the OS in NSCLC (HRpositive/negative =1.47, 95% CI: 1.19-1.83, P=0.0004). CONCLUSIONS: Our meta-analysis indicated PD-L1 protein expression in NSCLC was not associated with common clinicopathological characteristics, except tumor differentiation. It was a poor prognostic biomarker for NSCLC. Further research should be performed to investigate the precise clinicopathological and prognostic significance of PD-L1 in NSCLC under uniform testing standard. PMID- 25922728 TI - A meta-analysis comparing hyperfractionated vs. conventional fractionated radiotherapy in non-small cell lung cancer. AB - BACKGROUND: Lung cancer is the leading cause of cancer-related mortality. Non small cell lung cancer (NSCLC) accounts for most lung cancer and carries a 5-year survival rate of 15%. The squamous cell carcinoma, large cell carcinoma, and adenocarcinoma are the most common types of NSCLC. The data on long term use of hyperfractionated radiotherapy (HRT) in NSCLC treatment is lacking. We performed a meta-analysis, based on published randomized trials to compare HRT [continuous hyperfractionated accelerated radiotherapy (CHART)/continuous hyperfractionated accelerated radiotherapy weekend less (CHARTWEL)] vs. conventional fractionated (CF) radiotherapy in the treatment of NSCLC. METHODS: A systematic search through the bibliographic databases, PubMed, Google Scholar and Cochrane Library was performed till December 2013. RESULTS: Of 63 studies identified, 3 studies were analyzed. All were randomized studies and included 1,005 patients in total. The pooled results of the studies showed that HRT did not improve overall survival (OS) of patients suffering from NSCLC compared to CF after 2 years (OR, 1.29; 95% CI, 0.98-1.71; P=0.16) and 3 years (OR, 0.55; 95% CI, 0.34-0.87; P=0.22) which was statistically significant. HRT was no better than CF in controlling tumour (OR, 1.40; 95% CI, 1.03-1.91). No significant difference in metastasis free survival (OR, 1.08; 95% CI, 0.83-1.39) and late dysphagia (OR, 1.48; 95% CI, 0.75 2.92) were observed between the two groups. CONCLUSIONS: The results of the present meta-analysis showed that HRT was not significantly better to conventional radiotherapy in NSCLC treatment. PMID- 25922729 TI - Thoracoscopic anatomical resection of congenital lung malformations in adults. AB - Congenital lung malformations (CLM) are a heterogeneous group of disorders that may require surgical resection to prevent complications. Thoracoscopic resection of CLM has been reported in infants. Our goal was to state whether it can also be a viable option in adults. Between 2007 and 2014, 11 patients had a thoracoscopic resection of a CLM (six lobectomies and five anatomic segmentectomies) with satisfactory results. Although being more challenging in adults due to infectious sequellae, this approach is safe. PMID- 25922730 TI - Video-assisted thoracic surgery resection of rib osteophytes. PMID- 25922731 TI - Uniportal video-assisted thoracoscopic left upper lobectomy under spontaneous ventilation. AB - Intubated general anesthesia with one-lung ventilation was traditionally considered necessary for thoracoscopic major pulmonary resections. However, non intubated thoracoscopic lobectomy can be performed by using conventional and uniportal video-assisted thoracoscopic surgery (VATS). These non-intubated procedures try to minimize the adverse effects of tracheal intubation and general anesthesia but these procedures must only be performed by experienced anesthesiologists and skilled thoracoscopic surgeons. Here we present a video of a uniportal VATS left upper lobectomy in a non-intubated patient, maintaining the spontaneous ventilation. PMID- 25922732 TI - Video-assisted thoracoscopic double sleeve lobectomy: a lived video in a nationwide academic conference. PMID- 25922734 TI - Etiology and management of spontaneous haemothorax. AB - Spontaneous haemothorax (SH) is a subcategory of haemothorax that involves the accumulation of blood within the pleural space in the abscence of trauma or other causes. The clinical presentation is variable and includes a rapid progression of symptoms of chest pain and dyspnea that can be life threatening when hemodynamic instability and hypovolemic shock occurs. Despite haemothorax, SH is much less common with data limited to case reports and case series. A literature review has been performed to identify and summarise all potentials causes leading to this clinical entity. PMID- 25922733 TI - Acute exacerbation of idiopathic pulmonary fibrosis-a review of current and novel pharmacotherapies. AB - Idiopathic pulmonary fibrosis (IPF) is a chronic and progressive form of lung disease of unknown etiology for which a paucity of therapies suggest benefit, and for which none have demonstrated improved survival. Acute exacerbation of IPF (AE IPF) is defined as a sudden acceleration of the disease or an idiopathic acute injury superimposed on diseased lung that leads to a significant decline in lung function. An AE-IPF is associated with a mortality rate as high as 85% with mean survival periods of between 3 to 13 days. Under these circumstances, mechanical ventilation (MV) is controversial, unless used a as a bridge to lung transplantation. Judicious fluid management may be helpful. Pharmaceutical treatment regimens for AE-IPF include the use of high dose corticosteroids with or without immunosuppressive agents such as cyclosporine A (CsA), and broad spectrum antibiotics, despite the lack of convincing evidence demonstrating benefit. Newer research focuses on abnormal wound healing as a cause of fibrosis and preventing fibrosis itself through blocking growth factors and their downstream intra-cellular signaling pathways. Several novel pharmaceutical approaches are discussed. PMID- 25922735 TI - Considerations for patients awaiting heart transplantation-Insights from the UK experience. AB - The nature and size of the heart transplant waiting list has changed over recent years, most obviously with a larger number of patients on the list with ventricular assist devices (VADs). Given the limited numbers of available donors it is time to re-evaluate who is actually placed on the list. Evidence suggests that many patients with stable ambulatory heart failure might have a limited survival benefit from heart transplantation, so these patients may be an obvious target when considering how to reduce the size of the list. How stable VAD patients or adult congenital heart disease patients with declining symptoms should be prioritized for transplantation is unclear. Nevertheless we do need effective and simple models that can predict which of these disparate groups would benefit from transplantation so that we can fairly distribute this scarce commodity to the sickest patients that would benefit the most from transplantation. PMID- 25922736 TI - Long-term continuous-flow left ventricular assist devices (LVAD) as bridge to heart transplantation. AB - Heart transplantation (HTx) is the treatment of choice for end-stage heart failure but the limited availability of heart's donors still represents a major issue. So long-term mechanical circulatory support (MCS) has been proposed as an alternative treatment option to assist patients scheduled on HTx waiting list bridging them for a variable time period to cardiac transplantation-the so-called bridge-to-transplantation (BTT) strategy. Nowadays approximately 90% of patients being considered for MCS receive a left ventricular assist device (LVAD). In fact, LVAD experienced several improvements in the last decade and the predominance of continuous-flow over pulsatile-flow technology has been evident since 2008. The aim of the present report is to give an overview of continuous flow LVAD utilization in the specific setting of the BTT strategy taking into consideration the most representative articles of the scientific literature and focusing the attention on the evolution, clinical outcomes, relevant implications on the HTx strategy and future perspectives of the continuous-flow LVAD technology. PMID- 25922737 TI - International collaboration and organ exchange in Switzerland. AB - BACKGROUND: Organ exchange among organ procurement organisations (OPOs) serves three main purposes: firstly, it reduces the loss of donor organs for which there is no suitable recipient on the waiting list of an OPO; secondly, it improves the odds of specific patient groups for receiving a matching donor organ; thirdly, it allows an optimised donor-recipient match, due to an expansion of the donor and recipient pool. However, only few published studies provide figures for the significance of international organ sharing. This study aims to assess the impact of organ imports on the Swiss transplant activity. METHODS: We retrospectively analysed the data related to international organ exchange and its impact on the Swiss transplant activity. Information about organs from deceased donors offered by foreign OPOs was extracted from the Swiss Organ Allocation System for the period from 1 January 2009 to 31 December 2013. RESULTS: During the study period, 1028 organs were offered by foreign OPOs for allocation to patients needing transplantation in Switzerland. Of all organs offered, 35.9% originated from the Agence de la Biomedecine (France) and 25.6% from the National Health Service Blood and Transplant (United Kingdom). Totally 137 organs (13.3%) were accepted by the Swiss transplant centres for transplantation. These imported organs account for 7.2% of the transplants performed between 2009 and 2013. The impact of imported organs on the transplant activity was largest for the liver (14.2%), followed by heart (8.9%), lung (6.3%) and kidney (4.0%). CONCLUSIONS: Our study showed that international organ exchange substantially contributed to the Swiss transplant activity during the period analysed. The collaboration between OPOs can be life-saving, especially for paediatric patients and selected adult transplant candidates. More patients might benefit from organ sharing if the standards for international collaboration could be further harmonised. PMID- 25922738 TI - Long-term outcome following heart transplantation: current perspective. AB - Heart transplantation keeps its leading position in the treatment of end-stage heart failure (HF). Survival rates and functional status following heart transplantation are excellent, particularly if compared to medical therapy. The process of acute and chronic transplant rejection, however, and the sequelae of immunosuppression, such as infection, malignancy and renal insufficiency, prevents even better results. Therapy with current mechanical circulatory support devices is associated with improving outcome and may become competitive to heart transplantation, at least in selected patients. But long-term results are not yet available. PMID- 25922740 TI - The use of correlation functions in thoracic surgery research. PMID- 25922739 TI - Pediatric heart transplantation. AB - Pediatric heart transplantation (pHTx) represents a small (14%) but very important and particular part in the field of cardiac transplantation. This treatment has lifelong impact on children. To achieve the best short and especially long-term survival with adequate quality of life, which is of crucial importance for this young patient population, one has to realize and understand the differences with adult HTx. Indication for transplantation, waitlist management including ABO incompatible (ABOi) transplantation and immunosuppression differ. Although young transplant recipients are ultimately likely to be considered for re-transplantation. One has to distinguish between myopathy and complex congenital heart disease (CHD). The differences in anatomy and physiology make the surgical procedure much more complex and create unique challenges. These recipients need a well-organized and educated team with pediatric cardiologists and intensivists, including a high skilled surgeon, which is dedicated to pHTx. Therefore, these types of transplants are best concentrated in specialized centers to achieve promising outcome. PMID- 25922741 TI - Selective polypharmacy for chronic obstructive pulmonary disease. PMID- 25922742 TI - Anaplastic lymphoma kinase-positive lung adenocarcinoma patient with development of sick sinus syndrome while on targeted treatment with crizotinib. AB - The anaplastic lymphoma kinase (ALK) positive non-small cell lung cancer (NSCLC) patients are younger and have never smoked, while pathologically are predominately adenocarcinomas. Crizotinib as an ALK inhibitor has been used in treating ALK positive NSCLC patients for several years and some adverse effects should be paid attention to. We now describe a case of ALK positive NSCLC patient with development of sick sinus syndrome (SSS) while on targeted treatment with crizotinib. A 46-year-old non-smoking woman with right hilar mass and underwent transesophageal endoscopic ultrasonography lymph node biopsy showed low differentiation adenocarcinoma, immunohistochemistry (IHC) of tumor samples revealed the ALK overexpression. The severe sinus bradycardia and RR interval prolongation were detected 3 months after crizotinib treatment, she underwent pacemaker implantation. Although the severe sinus bradycardia and RR interval prolongation were unusual adverse effects, physicians should be aware of these side effects when using crizotinib. PMID- 25922743 TI - Multivariate analysis in thoracic research. AB - Multivariate analysis is based in observation and analysis of more than one statistical outcome variable at a time. In design and analysis, the technique is used to perform trade studies across multiple dimensions while taking into account the effects of all variables on the responses of interest. The development of multivariate methods emerged to analyze large databases and increasingly complex data. Since the best way to represent the knowledge of reality is the modeling, we should use multivariate statistical methods. Multivariate methods are designed to simultaneously analyze data sets, i.e., the analysis of different variables for each person or object studied. Keep in mind at all times that all variables must be treated accurately reflect the reality of the problem addressed. There are different types of multivariate analysis and each one should be employed according to the type of variables to analyze: dependent, interdependence and structural methods. In conclusion, multivariate methods are ideal for the analysis of large data sets and to find the cause and effect relationships between variables; there is a wide range of analysis types that we can use. PMID- 25922744 TI - Successful removal of a giant pulmonary hamartoma coexisting with an anomalous common pulmonary venous trunk. AB - We present an extremely rare case of a giant pulmonary hamartoma (PH) coexisting with an anomalous common pulmonary venous trunk (ACPVT). An asymptomatic 39-year old man was referred for evaluation of a giant pulmonary lesion in his left thorax detected on chest X-ray during a routine medical examination. After clinical work-up, the patient underwent left exploratory thoracotomy. Since the extent of the tumor and coexistence of an ACPVT, a left pneumonectomy was performed. The specimen measured 28 cm * 18 cm * 17 cm and weighted for 2.1 kg. Histology revealed a blend of pieces of rounded cartilage separated by fibrous bands in which mature adipose tissue and cleft-like structures lined. The features were consistent with those of a chondromatous hamartoma. The patient made a satisfactory recovery and 10 months after the operation was asymptomatic. PMID- 25922745 TI - Primary pulmonary cancer colliding with metastatic choriocarcinoma. AB - Collision tumors are rare in nature. Although lung is one of the main organs where metastatic tumors may occur, collision neoplasms consisting of a primary lung cancer and metastatic choriocarcinoma have never been reported so far. Here we describe a case of primary squamous-cell lung carcinoma (SCC) colliding with metastatic choriocarcinoma in a 55-year-old woman. PMID- 25922746 TI - Aberrant aneurysm of adult-type pulmonary sequestration: report of a case. AB - Aberrant pulmonary artery exposed by high-blood pressure over a long period in adult-type pulmonary sequestration can be susceptible to arteriosclerotic change and aneurysmal formation. Dividing this aneurysmal artery has a risk of stump leakage and aneurysm. We herein report a 64-year-old man with an aberrant aneurysm of intralobar pulmonary sequestration. Thoracoscopic resection of the sequestrated lung was performed uneventfully by prior endovascular occlusion of the aberrant aneurysm. PMID- 25922747 TI - Malignant pheochromocytoma with lung metastasis after right adrenalectomy for pheochromocytoma eleven years ago. AB - A 30-year-old woman had multiple masses on right adrenalectomy site, posterior mediastinum, and left lung on computed tomography (CT) and positron emission tomography. She had a right adrenalectomy for pheochromocytoma eleven years ago. She received proper alpha and beta blocker and completed surgical resection. Pheochromocytoma was confirmed by histopathology. Here we report the case of metastatic malignant pheochromocytoma with very poor prognosis. PMID- 25922748 TI - Coinfection of Strongyloides stercoralis and Aspergillus found in bronchoalveolar lavage fluid from a patient with stubborn pulmonary symptoms. AB - We report a case involving coinfection with Strongyloides stercoralis (S. stercoralis) and Aspergillus found in the bronchoalveolar lavage fluid (BALF) of an elderly male patient who had a medical history of autoimmune pancreatitis (AIP) and who was treated with prednisone therapy 6 months previously. The patient presented with stubborn pulmonary symptoms and signs because of Aspergillus invasion and mechanical destruction caused by larval migration. We found S. stercoralis and Aspergillus in his BALF that provided diagnostic proof. PMID- 25922749 TI - Paravertebral mediastinal Mullerian cyst resected by video assisted thoracoscopic surgery. AB - Ever since Hattori et al. had described the mediastinal Mullerian cyst in 2005 there has been several new cases described in the literature. We report a 51-year old woman with an incidentally found 2 cm * 3 cm mass in her left paravertebral mediastinum. She underwent thoracoscopic removal with the impression of a neurogenic tumor and was unexpectedly found with a ciliated cyst of Mullerian origin. PMID- 25922750 TI - Double lung point in an 18-month-old child: a case report and literature review. AB - OBJECTIVE: Double lung point is a rare sign of pneumothorax in clinical practice. In this report I presented an 18-month-old child who presented with bilateral pneumothorax. DATA SYNTHESIS AND CASE PRESENTATION: Ultrasonography examination revealed conventional lung point sign on the right and double lung point on the left side. Thoracentesis was attempted and closed thoracic drainage was performed on the right side, but no gas was drawn on the left side. Clinical implication of double lung point sign found in chest ultrasonography is that the size of pneumothorax is limited and conservative treatment is enough. CONCLUSIONS: To the best of our knowledge, this is the first case of double lung point identified with ultrasonography in child. The strength of the case is that the double lung point sign is supported by computed tomography (CT). Furthermore, we propose that the presence of double lung point indicates limited pneumothorax and conservative management may well be attempted. PMID- 25922752 TI - Educational platform on thoracic surgery: further strategic possibilities. PMID- 25922751 TI - Flexible bronchoscopic excision of a tracheal mass under extracorporeal membrane oxygenation. AB - Tracheal tumor is a rare but life-threatening condition that can cause obstruction of the airway. Management of tracheal tumors is very challenging and includes surgical resection, radiotherapy, and therapeutic bronchoscopy. Herein, we present a very rare case of an 88-year-old female patient with a tracheal mass due to direct invasion of a mediastinal teratoma. We devised a new method for resection of the tracheal mass because management of her airway and the tracheal mass by conventional methods was impossible. We successfully resected the tracheal mass with flexible bronchoscopic electrocautery under extracorporeal membrane oxygenation (ECMO) without any complications. When management of a patient's airway and tracheal mass are impossible by conventional methods, this technique may be very useful. PMID- 25922753 TI - Exhaled nitric oxide and disease progression in chronic obstructive pulmonary disease. PMID- 25922754 TI - Comments to Dr. Yi-Xiang Wang's on training of young doctors under the current health care system in China. PMID- 25922755 TI - A long way ahead to improve the cost-effectiveness of biomedical research in China. PMID- 25922756 TI - Retraction: Application of piezoelectric nanogenerator in medicine: bio experiment and theoretical exploration. AB - [This retracts the article on p. 1300 in vol. 6, PMID: 25276373.]. PMID- 25922757 TI - A practical overview on probability distributions. AB - Aim of this paper is a general definition of probability, of its main mathematical features and the features it presents under particular circumstances. The behavior of probability is linked to the features of the phenomenon we would predict. This link can be defined probability distribution. Given the characteristics of phenomena (that we can also define variables), there are defined probability distribution. For categorical (or discrete) variables, the probability can be described by a binomial or Poisson distribution in the majority of cases. For continuous variables, the probability can be described by the most important distribution in statistics, the normal distribution. Distributions of probability are briefly described together with some examples for their possible application. PMID- 25922759 TI - Glaucomatous visual field defect severity and the prevalence of motor vehicle collisions in Japanese: a hospital/clinic-based cross-sectional study. AB - Purpose. This study examined the association between the severity of visual field defects and the prevalence of motor vehicle collisions (MVCs) in subjects with primary open-angle glaucoma (POAG). Methods. This is a cross-sectional study. Japanese patients who have had driver's licence between 40 and 85 years of age were screened for eligibility. Participants answered a questionnaire about MVCs experienced during the previous 5 years. Subjects with POAG were classified as having mild, moderate, or severe visual field defect. We evaluated associations between the severity of POAG and the prevalence of MVCs by logistic regression models. Results. The prevalence of MVCs was significantly associated with the severity of POAG categorized by worse eye MD (control: 30/187 = 16.0%; mild POAG: 17/92 = 18.5%; moderate POAG: 14/60 = 23.3%; severe POAG: 14/47 = 29.8%; P = 0.025, Cochran-Armitage trend test). Compared to the control group, the adjusted OR for MVC prevalence in subjects with mild, moderate, or severe POAG in the worse eye was 1.07 (95% CI: 0.55 to 2.10), 1.44 (95% CI: 0.68 to 3.08), and 2.28 (95% CI: 1.07 to 4.88). Conclusions. There is a significant association between the severity of glaucoma in the worse eye MD and the prevalence of MVCs. PMID- 25922760 TI - Comparison of United States and canadian glaucoma medication costs and price change from 2006 to 2013. AB - Objective. Compare glaucoma medication costs between the United States (USA) and Canada. Methods. We modelled glaucoma brand name and generic medication annual costs in the USA and Canada based on October 2013 Costco prices and previously reported bottle overfill rates, drops per mL, and wastage adjustment. We also calculated real wholesale price changes from 2006 to 2013 based on the Average Wholesale Price (USA) and the Ontario Drug Benefit Price (Canada). Results. US brand name medication costs were on average 4x more than Canadian medication costs (range: 1.9x-6.9x), averaging a cost difference of $859 annually. US generic costs were on average the same as Canadian costs, though variation exists. US brand name wholesale prices increased from 2006 to 2013 more than Canadian prices (US range: 29%-349%; Canadian range: 9%-16%). US generic wholesale prices increased modestly (US range: -23%-58%), and Canadian wholesale prices decreased (Canadian range: -38%-0%). Conclusions. US brand name glaucoma medications are more expensive than Canadian medications, though generic costs are similar (with some variation). The real prices of brand name medications increased more in the USA than in Canada. Generic price changes were more modest, with real prices actually decreasing in Canada. PMID- 25922758 TI - A review of collagen cross-linking in cornea and sclera. AB - Riboflavin/UVA cross-linking is a technique introduced in the past decades for the treatment of keratoconus, keratectasia, and infectious keratitis. Its efficacy and safety have been investigated with clinical and laboratory studies since its first clinical application by Wollensak for the treatment of keratoconus. Although its complications are encountered during clinical practice, such as infection inducing risk, minimal invasion merits a further investigation on its future application in clinical practice. Recently, collagen cross-linking in sclera shows a promising prospect. In present study, we summarized the representative studies describing the clinical and laboratory application of collagen cross-linking published in past decades and provided our opinion on the positive and negative results of cross-linking in the treatment of ophthalmic disorders. PMID- 25922761 TI - Fasting Blood Glucose Profile among Secondary School Adolescents in Ado-Ekiti, Nigeria. AB - Background. Over the past two decades there has been an increase in type 2 diabetes mellitus (T2DM) in children. Baseline data is needed to assess the impact of changing lifestyles on Ado-Ekiti, a previously semiurban community in Southwest Nigeria. This study was therefore conducted to assess the fasting blood glucose (FBG) of adolescents in Ado-Ekiti, Nigeria. Methodology. This was a cross sectional study involving 628 adolescents from three different secondary schools in Ado-Ekiti, Nigeria. With parental consent, volunteers completed a structured questionnaire, and an overnight FBG was measured. Results. There were 346 males and 282 females (male : female ratio = 1.2 : 1). Their ages ranged from 10 to 19 years (mean age: 14.2 +/- 1.7 years). Four hundred and forty-four (70.7%) had normal FBG, while 180 (28.7%) and 4 (0.6%) had FBG in the prediabetic and diabetic range, respectively. Female gender, age group 10-14 years, and family history of obesity were significantly associated with impaired FBG (P value <0.001, <0.001, and 0.045, resp.). Conclusion. Impaired FBG is common among secondary school adolescents and it is more prevalent among younger female adolescents (10-14 years) with positive family history of obesity. PMID- 25922762 TI - Is There Any Association between PEEP and Upper Extremity DVT? AB - Background. We hypothesized that positive end-exploratory pressure (PEEP) may promote venous stasis in the upper extremities and predispose to upper extremity deep vein thrombosis (UEDVT). Methods. We performed a retrospective case control study of medical intensive care unit patients who required mechanical ventilation (MV) for >72 hours and underwent duplex ultrasound of their upper veins for suspected DVT between January 2011 and December 2013. Results. UEDVT was found in 32 (28.5%) of 112 patients. Nineteen (67.8%) had a central venous catheter on the same side. The mean +/- SD duration of MV was 13.2 +/- 9.5 days. Average PEEP was 7.13 +/- 2.97 cm H2O. Average PEEP was >=10 cm H2O in 23 (20.5%) patients. Congestive heart failure (CHF) significantly increased the odds of UEDVT (OR 4.53, 95% CI 1.13-18.11; P = 0.03) whereas longer duration of MV (>=13 vs. <13 days) significantly reduced it (OR 0.29, 95% CI 0.11-0.8; P = 0.02). Morbid obesity showed a trend towards significance (OR 3.82, 95% CI 0.95-15.4; P = 0.06). Neither PEEP nor any of the other analyzed predictors was associated with UEDVT. Conclusions. There is no association between PEEP and UEDVT. CHF may predispose to UEDVT whereas the risk of UEDVT declines with longer duration of MV. PMID- 25922763 TI - Exploratory study of factors influencing job-related stress in Japanese psychiatric nurses. AB - This study explored the factor structure of psychiatric nurses' job-related stress and examined the specificity of the related stressors using the job stressor scale of the Brief Job Stress Questionnaire (BJSQ). The stressor scale of the BJSQ was administered to 296 nurses and assistant nurses. Answers were examined statistically. Exploratory factor analysis was performed to identify factor structures; two factors (overload and job environment) were valid. Confirmatory factor analysis was conducted to examine the two-factor structure and found 11 items with factor loadings of >0.40 (model 1), 13 items with factor loadings from 0.30 to <0.40 (model 2), and 17 items with factor loadings from 0.20 to <0.30 (model 3) for one factor; model 1 demonstrated the highest goodness of fit. Then, we observed that the two-factor structure (model 1) showed a higher goodness of fit than the original six-factor structure. This differed from subscales based on general workers' job-related stressors, suggesting that the factor structure of psychiatric nurses' job-related stressors is specific. Further steps may be necessary to reduce job-related stress specifically related to overload including attention to many needs of patients and job environment including complex ethical dilemmas in psychiatric nursing. PMID- 25922764 TI - Atrial Fibrillation in the Young: A Neurologist's Nightmare. AB - Atrial fibrillation (AF) is the most common sustained cardiac arrhythmia seen in clinical practice with prevalence in excess of 33 million worldwide. Although often asymptomatic and until recently considered a "benign" arrhythmia, it is now appreciated that thromboembolism resulting from AF results in significant morbidity and mortality predominantly due to stroke. Although an arrhythmia more commonly affecting the elderly, AF can also occur in the young. This review focuses on the impact of AF in the younger population and discusses the dilemmas of managing younger patients with AF. PMID- 25922765 TI - Parent-Child Agreement Using the Spence Children's Anxiety Scale and a Thermometer in Children with Autism Spectrum Disorder. AB - Children with Autism Spectrum Disorder (ASD) experience high anxiety which often prompts clinical referral and requires intervention. This study aimed to compare parent and child reports on the Spence Children's Anxiety Scale (SCAS) and a child-reported "worry thermometer" in 88 children aged 8-13 years, 44 with ASD and 44 age, gender, and perceptual IQ matched typically developing children. There were no gender differences in child report on the SCAS and worry thermometers. Results indicated generally good correlations between parent and child self-reported SCAS symptoms for typically developing children but poor agreement in parent-child ASD dyads. The worry thermometer child-report did not reflect child or parent reports on the SCAS. Findings suggest 8-13-year-old children with ASD may have difficulties accurately reporting their anxiety levels. The clinical implications were discussed. PMID- 25922766 TI - Gait deviations in children with autism spectrum disorders: a review. AB - In recent years, it has become clear that children with autism spectrum disorders (ASDs) have difficulty with gross motor function and coordination, factors which influence gait. Knowledge of gait abnormalities may be useful for assessment and treatment planning. This paper reviews the literature assessing gait deviations in children with ASD. Five online databases were searched using keywords "gait" and "autism," and 11 studies were found which examined gait in childhood ASD. Children with ASD tend to augment their walking stability with a reduced stride length, increased step width and therefore wider base of support, and increased time in the stance phase. Children with ASD have reduced range of motion at the ankle and knee during gait, with increased hip flexion. Decreased peak hip flexor and ankle plantar flexor moments in children with ASD may imply weakness around these joints, which is further exhibited by a reduction in ground reaction forces at toe-off in children with ASD. Children with ASD have altered gait patterns to healthy controls, widened base of support, and reduced range of motion. Several studies refer to cerebellar and basal ganglia involvement as the patterns described suggest alterations in those areas of the brain. Further research should compare children with ASD to other clinical groups to improve assessment and treatment planning. PMID- 25922767 TI - An online tool for nurse triage to evaluate risk for acute coronary syndrome at emergency department. AB - Background. To differentiate acute coronary syndrome (ACS) from other causes in patients presenting with chest pain at the emergency department (ED) is crucial and can be performed by the nurse triage. We evaluated the effectiveness of the ED nurse triage for ACS of the tertiary care hospital. Methods. We retrospectively enrolled consecutive patients who were identified as ACS at risk patients by the ED nurse triage. Patients were categorized as ACS and non-ACS group by the final diagnosis. Multivariate logistic analysis was used to predict factors associated with ACS. An online model predictive of ACS for the ED nurse triage was constructed. Results. There were 175 patients who met the study criteria. Of those, 28 patients (16.0%) were diagnosed with ACS. Patients with diabetes, patients with previous history of CAD, and those who had at least one character of ACS chest pain were independently associated with having ACS by multivariate logistic regression. The adjusted odds ratios (95% confidence interval) were 4.220 (1.445, 12.327), 3.333 (1.040, 10.684), and 12.539 (3.876, 40.567), respectively. Conclusions. The effectiveness of the ED nurse triage for ACS was 16%. The online tool is available for the ED triage nurse to evaluate risk of ACS in individuals. PMID- 25922769 TI - Incidental Finding of a Homozygous p.M348K Asymptomatic Italian Patient Confirms the Many Faces of Cystic Fibrosis. AB - Cystic fibrosis (CF; OMIM number 219700) is an autosomal recessive disease caused by mutations in the CFTR (cystic fibrosis transmembrane conductance regulator) gene, which results in abnormal viscous mucoid secretions in multiple organs and whose main clinical features are pancreatic insufficiency, chronic endobronchial infection, and male infertility. We report the case of a 47-year-old apparently normal male resulting in homozygosity for the mutation p.M348K from nonconsanguineous parents. The proband was screened using a standard panel of 70 different tested on NanoChip 400 platform. The massive parallel pyrosequencing on 454 JS machine allowed the second level analysis. The patient was firstly screened with two different platforms available in our laboratory, obtaining an ambiguous signal for the p.R347P mutation. For this reason we decided to clarify the discordant result of CFTR status by Next Generation Sequencing (NGS) using 454 Junior instrument. The patient is resulted no carrier of the p.R347P mutation, but NGS highlighted a homozygous substitution from T>A at position 1043 in the coding region, causing an amino acid substitution from methionine to lysine (p.M348K). Casual finding of p.M348K homozygote mutation in an individual, without any feature of classical or nonclassical CF form, allowed us to confirm that p.M348K is a benign rare polymorphism. PMID- 25922770 TI - Treatment of Acquired von Willebrand Syndrome and Prevention of Bleeding Postautologous Stem Cell Transplant during Severe Pancytopenia with IVIG. AB - The use of high dose chemotherapy followed by autologous hematopoietic stem cell transplantation for remission consolidation after initial induction represents standard of care for patients with multiple myeloma. Patients with myeloma and Acquired von Willebrand Syndrome (AVWS) undergoing autologous stem cell transplant (ASCT) are at significant risk of bleeding due to the profound thrombocytopenia, low Factor VIII levels, fever, and toxicities associated with the preparative regimen. We report a patient with AVWS associated with multiple myeloma who underwent autologous stem cell transplants as consolidation after initial induction and again at relapse. He was successfully treated with high dose intravenous immunoglobulin (IVIG) prior to each transplant with rapid resolution of AVWS. PMID- 25922768 TI - Altered theta oscillations and aberrant cortical excitatory activity in the 5XFAD model of Alzheimer's disease. AB - Alzheimer's disease (AD) is an age-related neurodegenerative disorder characterized by impairment of memory function. The 5XFAD mouse model was analyzed and compared with wild-type (WT) controls for aberrant cortical excitability and hippocampal theta oscillations by using simultaneous video electroencephalogram (EEG) monitoring. Seizure staging revealed that 5XFAD mice exhibited cortical hyperexcitability whereas controls did not. In addition, 5XFAD mice displayed a significant increase in hippocampal theta activity from the light to dark phase during nonmotor activity. We also observed a reduction in mean theta frequency in 5XFAD mice compared to controls that was again most prominent during nonmotor activity. Transcriptome analysis of hippocampal probes and subsequent qPCR validation revealed an upregulation of Plcd4 that might be indicative of enhanced muscarinic signalling. Our results suggest that 5XFAD mice exhibit altered cortical excitability, hippocampal dysrhythmicity, and potential changes in muscarinic signaling. PMID- 25922771 TI - Localized lymph node light chain amyloidosis. AB - Immunoglobulin-derived light chain amyloidosis can occasionally be associated with localized disease. We present a patient with localized lymph node light chain amyloidosis without an underlying monoclonal protein or lymphoproliferative disorder and review the literature of lymph node amyloidosis discussing work-up and risk factors for systemic progression. PMID- 25922772 TI - How an Opportunistic Infection Can Mess with Your Brain and Take Your Breath Away: A Rare Case of Simultaneous Lung and Brain Abscess due to Streptococcus anginosus. AB - Streptococcus anginosus (S. anginosus) is considered a friendly bug and is a one of many different bacteria that constitute the normal flora of the oral cavity. Nevertheless, it has been infrequently associated with more invasive infections, like lung abscess. It is extremely rare to have multisystemic involvement with S. anginosus group. We present a unique case of pulmonary and brain abscess due to S. anginosus in an immunocompetent patient. PMID- 25922773 TI - Unusual neurologic manifestations of a patient with cyanotic congenital heart disease after phlebotomy. AB - Secondary erythrocytosis in cyanotic congenital heart disease (CCHD) is a compensatory response to chronic hypoxia which should be managed with caution. CCHD patients, who have compensated erythrocytosis but do not manifest significant neurologic symptoms, may experience secondary life-threatening complications such as stroke in case of inappropriate phlebotomy. This study reports a young man with CCHD who developed frequently repeated transient neurologic deficits with various presentations after one session of phlebotomy. The symptoms resolved a few days after the hematocrit (Hct) level returned to the prephlebotomy level. PMID- 25922774 TI - Triplet Delivery following Unilateral Twin Salpingocyesis. AB - We present the case of a 36-year-old woman with primary infertility of six-year duration who had IVF/ICSI on account of male factor infertility. Transvaginal scanning done on the 30th day following embryo transfer revealed an empty uterine cavity with two gestational sacs containing active fetal echoes in the right adnexum. Patient reluctantly had right salpingectomy via open laparatomy. The patient had repeat embryo transfer eleven months afterwards that culminated in the delivery of living twins with a fetal papyraceous. PMID- 25922775 TI - Diagnostic challenges in primary hepatocellular carcinoma: case reports and review of the literature. AB - Hepatocellular carcinoma is the fifth most common malignancy and the third leading mortality cause worldwide. It typically develops secondarily to liver cirrhosis, due to hepatitis B or C infection, alcohol abuse, metabolic disease, and so forth. According to the American Association for the Study of Liver Diseases (AASLD) guidelines, which constitute diagnostic standards, the diagnosis of primary hepatocellular carcinoma (HCC) should be based on contrast-enhanced imaging. Lesion hyperenhancement should be observed throughout the arterial phase, followed by the washout during the venous phase. The diagnosis can also be based on the histopathological evaluation of liver biopsy specimen. Although the standards are clear, we often see patients with advanced HCC in clinical practice, who cannot be offered any effective treatment. Patients with chronic liver disease, presenting with inconclusive and changeable test results, constitute a separate problem. In such cases the diagnostic process is typically long-term and delayed. In this paper we present three case reports where the diagnosis could not be made promptly and the patients died as a result of a delayed diagnostic process. PMID- 25922776 TI - Long term follow-up of a successful lower limb replantation in a 3-year-old child. AB - Replantation of the lower extremity has controversial indications but nevertheless it may be considered in carefully selected patients who present early and are expected to show good functional recoveries. Here we present a successful replantation in a 3-year-old boy who has made excellent recovery with no functional deficit evident at 12 years of follow-up. He sustained a traumatic amputation at the level of distal tibia when he fell of a "Qing Qi" (motorcycle rickshaw). Replantation was attempted at 8 hours cold ischemia time with the tibia shortened 4 cm and all tendons, vessels, and nerves repaired. Patient required a second procedure during the same hospital stay for skin coverage. Patient made good recovery with ambulation without support at 6 months, less than 3 cm limb length discrepancy, plantar and dorsiflexion power 4/5, and recovery of sensation over the foot. Now at 12 years of follow-up patient has a normal gait and has integrated into society with no functional deficit. Considering the functional outcome of our case, replantation should be attempted whenever possible and feasible especially in children. PMID- 25922778 TI - Colorectal microcarcinoids in association with long-term exposure to urinary content: a case report and review of the literature. AB - Long-term exposure of colonic mucosa to urinary content and its association with increased risk of infection, mechanical and biochemical irritation, and malignancy have been described in the literature. Existing case reports and studies depict the low but distinct risk of malignancy in gastrointestinal segments which come in contact with urinary content as a result of surgical correction of urinary tract abnormalities. However, these reports are largely limited to colonic adenocarcinoma and urothelial cell carcinoma. Late urointestinal carcinoma in patients with ileal incorporation into the urinary tract has also been reported. To the best of our knowledge, however, there is only one case report documenting neuroendocrine (NE) cell hyperplasia in colonic mucosa after long-term cystoplasty. Our case is the first to describe microcarcinoids and diffuse NE hyperplasia occurring in a patient with congenital anorectal anomalies, resulting in long-term exposure of colonic mucosa to fecal stream and urinary content. This case, in conjunction with the reported cases in the literature, raises the distinct possibility of an association between exposure of colonic mucosa to urine and long-term development of malignancy, including NE neoplasms. PMID- 25922777 TI - Extrinsic subclavian vein compression after osteosynthesis of a midshaft clavicular fracture in an athlete. AB - Clavicle fractures are common injuries. Traditionally, nonsurgical management has been favored; however, recent evidence has emerged indicating that operative fixation produces lower nonunion rates, better functional outcomes, improved cosmesis, and greater patient satisfaction. Although clavicle fixation has been considered a safe procedure, several complications related to plate fixation have been reported. We report a case of a 21-year-old basketball player that had a vascular complication associated with internal fixation of a clavicle fracture. An external compression of the subclavian vein was attributed to a long screw of a precontoured clavicular plate. Although vascular complications associated with clavicle fixation are rare, they may be limb and even life threating. It is advisable that surgeons take measures to avoid them especially when placing the medial screws. PMID- 25922779 TI - New-onset panic, depression with suicidal thoughts, and somatic symptoms in a patient with a history of lyme disease. AB - Lyme Disease, or Lyme Borreliosis, caused by Borrelia burgdorferi and spread by ticks, is mainly known to cause arthritis and neurological disorders but can also cause psychiatric symptoms such as depression and anxiety. We present a case of a 37-year-old man with no known psychiatric history who developed panic attacks, severe depressive symptoms and suicidal ideation, and neuromuscular complaints including back spasms, joint pain, myalgias, and neuropathic pain. These symptoms began 2 years after being successfully treated for a positive Lyme test after receiving a tick bite. During inpatient psychiatric hospitalization his psychiatric and physical symptoms did not improve with antidepressant and anxiolytic treatments. The patient's panic attacks resolved after he was discharged and then, months later, treated with long-term antibiotics for suspected "chronic Lyme Disease" (CLD) despite having negative Lyme titers. He however continued to have subsyndromal depressive symptoms and chronic physical symptoms such as fatigue, myalgias, and neuropathy. We discuss the controversy surrounding the diagnosis of CLD and concerns and considerations in the treatment of suspected CLD patients with comorbid psychiatric diagnoses. PMID- 25922780 TI - Severe headache with eye involvement from herpes zoster ophthalmicus, trigeminal tract, and brainstem nuclei. AB - A 43-year-old female presented with severe sharp stabbing right-sided periorbital and retroorbital area headache, dull-aching unilateral jaw pain, eyelid swelling, ptosis, and tearing of the right eye but no rash. The pain episodes lasted five minutes to one hour and occurred 10-15 times per day with unremitting milder pain between the attacks. She later developed an erythematous maculopapular rash over the right forehead and therefore was treated with antivirals. MRI performed one month after the onset revealed small hypersignal-T2 in the right dorsolateral mid pons and from the right dorsolateral aspect of the pontomedullary region to the right dorsolateral aspect of the upper cervical cord, along the course of the principal sensory nucleus and spinal nucleus of the right trigeminal nerve. No definite contrast enhancement of the right brain stem/upper cervical cord was seen. Orbital imaging showed no abnormality of bilateral optic nerves/chiasm, extraocular muscles, and globes. Slight enhancement of the right V1, V2, and the cisterna right trigeminal nerve was detected. Our findings support the hypothesis of direct involvement by virus theory, reflecting rostral viral transmission along the gasserian ganglion to the trigeminal nuclei at brainstem and caudal spreading along the descending tract of CN V. PMID- 25922781 TI - Unexpected anal squamous cells carcinoma after open hemorrhoidectomy. AB - We report a case of unexpected anal squamous cells carcinoma found in hemorrhoidectomy specimen. The patient had a 3-year history of prolapsing hemorrhoids. A prolapsing hemorrhoid was present at eleven o'clock in lithotomy. Milligan-Morgan was performed and gross examination of the specimen was unremarkable. Histopathologic evaluation showed noninvasive squamous cells carcinoma. The present case report evidences the opportunity of routine histopathologic analysis of hemorrhoidal specimens particularly in case of long standing prolapse. Questions arise in the option of those techniques where no specimens are collected or tissue is excised far from deceased area. PMID- 25922782 TI - Ewing's Sarcoma of the Kidney Complicated by a Wunderlich Syndrome. AB - The Wunderlich syndrome found after the rupture of primitive renal Ewing's sarcoma is not a situation that we find often in everyday practice. The clinical findings are not specific, which is why the differential diagnosis must be made with a multitude of benign and malignant renal masses until the correct diagnosis can be made by the pathologist. The CT and MRI images are not characteristic. One treatment option is the multidisciplinary approach; however, the prognosis remains poor for patients with metastatic disease. PMID- 25922783 TI - Giant abdominoperineal malignant schwannoma: an unusual presentation and surgical challenge. AB - Schwannoma is a benign tumor arising from the Schwann cells of peripheral nerves. These are usually benign but malignant transformation can occur in larger lesions. The definitive diagnosis of malignancy can only be made after final histopathological report. The literature reports large pelvic and perineal schwannomas with few being malignant. We report the first case of such giant malignant abdominoperineal schwannoma which was benign on initial biopsy but final histopathology revealed it to be malignant. In view of proximity of perineal and pelvic tumors to urogenital organs and pelvic nerves, such cases represent a challenge to surgical excision. This case brings to highlight another atypical presentation of such tumors. PMID- 25922784 TI - Congenital midureteric stricture: challenges in diagnosis and management. AB - Background. Congenital midureteric stricture (MUS) is a rare malformation. We report our experience with five cases seen over a period of 4 years from 2010 to 2014. Materials and Methods. The study was based on the retrospective analysis of five patients diagnosed as having MUS. Diagnosis was suspected after fetal ultrasonography (USG) in one patient and magnetic resonance urography (MRU) in four patients. Retrograde pyelography (RGP) was performed on three patients. The final diagnosis was confirmed during surgical exploration in all the patients. Results. MRU was found to be a good investigation method. It showed the site of obstruction in the ureter in all instances. Intravenous urography detected proximal ureteric dilatation present in two of the patients. RGP delineates the level of stricture and the course of ureter, as shown in our cases. All patients had significant obstruction on the affected side. Four patients underwent ureteroureterostomy, all of whom had satisfactory results. In one patient, ureteric reimplantation was carried out due to distal small ureteric caliber. Conclusion. This rare entity is often misdiagnosed initially as pelviureteric junction obstruction. MRU is an excellent option for the anatomical location and functional assessment of the involved system. At the time of surgical correction of a ureteral obstruction, RGP is a useful adjunct for delineating the stricture level and morphology. PMID- 25922785 TI - Early postural changes in individuals with idiopathic Parkinson's disease. AB - Background and Objectives. Postural changes are frequent and disabling complications of Parkinson's disease (PD). Many contributing factors have been evident either related to disease pathology or to adaptive changes. This study aimed at studying the postural changes in subjects with Parkinson's disease and its relation to duration of illness and disease severity. Methods. Eighteen patients with PD and 18 healthy matched volunteers represented the sample of the study. The patients were at stage 1 or 1.5 according to the Modified Hoehn and Yahr Staging with duration of illness between 18 and 36 months. Three-dimensional analysis of the back surface was conducted to explore the postural changes in the sagittal and frontal planes in both the patients and the healthy subjects. Results. Kyphotic angle, lordotic angle, fleche cervicale, fleche lombaire, scoliotic angle, and associated vertebral rotation and pelvic obliquity were significantly increased in patients with PD compared to the healthy subjects (P <= 0.05). There was no association between the measured postural changes and duration of illness as well as the severity of the IPD (P <= 0.05). Conclusion. Postural changes start in the early stages of idiopathic PD and they have no relationship to the duration of illness and disease severity. PMID- 25922786 TI - Cognitive reserve in Parkinson's disease: the effects of welsh-english bilingualism on executive function. AB - Objective. Bilingualism has been shown to benefit executive function (EF) and delay the onset of Alzheimer's disease. This study aims at examining whether a bilingual advantage applies to EF in Parkinson's disease (PD). Method. In a cross sectional outpatient cohort of monolingual English (n = 57) and bilingual Welsh/English (n = 46) speakers with PD we evaluated the effects of bilingualism compared with monolingualism on performance on EF tasks. In bilinguals we also assessed the effects of the degree of daily usage of each language and the degree of bilingualism. Results. Monolinguals showed an advantage in performance of language tests. There were no differences in performance of EF tests in monolinguals and bilinguals. Those who used Welsh less in daily life had better performance on one test of English vocabulary. The degree of bilingualism correlated with one test of nonverbal reasoning and one of working memory but with no other tests of EF. Discussion. The reasons why the expected benefit in EF in Welsh-English bilinguals with PD was not found require further study. Future studies in PD should include other language pairs, analysis of the effects of the degree of bilingualism, and longitudinal analysis of cognitive decline or dementia together with structural or functional neuroimaging. PMID- 25922787 TI - Response surface optimization of a rapid ultrasound-assisted extraction method for simultaneous determination of tetracycline antibiotics in manure. AB - A rapid and cleanup-free ultrasound-assisted extraction method is proposed for the simultaneous extraction of oxytetracycline, tetracycline, chlortetracycline, and doxycycline in manure. The analytes were determined using high-performance liquid chromatography with ultraviolet detector. The influence of several variables on the efficiency of the extraction procedure was investigated by single-factor experiments. The temperature, pH, and amount of extraction solution were selected for optimization experiment using response surface methodology. The calibration curves showed good linearity (R (2) > 0.99) for all analytes in the range of 0.1-20 MUg/mL. The four antibiotics were successfully extracted from manure with recoveries ranging from 81.89 to 92.42% and good reproducibility (RSD, <4.06%) under optimal conditions, which include 50 mL of McIlvaine buffer extraction solution (pH 7.15) mixed with 1 g of manure sample, extraction temperature of 40 degrees C, extraction time of 10 min, and three extraction cycles. Method quantification limits of 1.75-2.32 mg/kg were obtained for the studied compounds. The proposed procedure demonstrated clear reductions in extraction time and elimination of cleanup steps. Finally, the applicability to tetracyclines antibiotics determination in real samples was evaluated through the successful determination of four target analytes in swine, cow manure, and mixture of animal manure with inorganic fertilizer. PMID- 25922788 TI - The influences of N-acetyl cysteine (NAC) on the cytotoxicity and mechanical properties of Poly-methylmethacrylate (PMMA)-based dental resin. AB - Objectives. This study aimed to investigate the influences of N-acetyl cysteine (NAC) on cytotoxicity and mechanical properties of Poly-methylmethacrylate (PMMA) dental resins. Methods. Experimental PMMA resin was prepared by incorporating various concentrations of NAC (0, 0.15, 0.3, 0.6 and 0.9 wt.%). MTT assay was performed to investigate viability of human dental pulp cells after exposure to extract of PMMA resin with or without NAC. Cell adhesion on resin specimens was examined with scanning electron microscopy. Degree of conversion was studied with Fourier Transform Infrared Spectroscopy (FTIR). Flexural strength, microhardness and surface roughness was evaluated using a universal testing machine, microhardness tester and optical profilometer, respectively. Results. Incorporation of NAC into PMMA resin significantly reduced its cytotoxicity and enhanced cell adhesion on its surface. NAC induced negative influences on the mechanical and physical properties of PMMA resin in a dose-dependent manner. The degree of conversion for all experimental PMMA resins reached as high as 72% after 24 h of polymerization. All the tested properties were maintained when the concentration of incorporated NAC was 0.15 wt.%. Conclusion. The addition of 0.15 wt.% NAC remarkably improved biocompatibility of PMMA resin without exerting significant negative influence on its mechanical and physical properties. PMID- 25922789 TI - Cyclic nucleotide binding and structural changes in the isolated GAF domain of Anabaena adenylyl cyclase, CyaB2. AB - GAF domains are a large family of regulatory domains, and a subset are found associated with enzymes involved in cyclic nucleotide (cNMP) metabolism such as adenylyl cyclases and phosphodiesterases. CyaB2, an adenylyl cyclase from Anabaena, contains two GAF domains in tandem at the N-terminus and an adenylyl cyclase domain at the C-terminus. Cyclic AMP, but not cGMP, binding to the GAF domains of CyaB2 increases the activity of the cyclase domain leading to enhanced synthesis of cAMP. Here we show that the isolated GAFb domain of CyaB2 can bind both cAMP and cGMP, and enhanced specificity for cAMP is observed only when both the GAFa and the GAFb domains are present in tandem (GAFab domain). In silico docking and mutational analysis identified distinct residues important for interaction with either cAMP or cGMP in the GAFb domain. Structural changes associated with ligand binding to the GAF domains could not be detected by bioluminescence resonance energy transfer (BRET) experiments. However, amide hydrogen-deuterium exchange mass spectrometry (HDXMS) experiments provided insights into the structural basis for cAMP-induced allosteric regulation of the GAF domains, and differences in the changes induced by cAMP and cGMP binding to the GAF domain. Thus, our findings could allow the development of molecules that modulate the allosteric regulation by GAF domains present in pharmacologically relevant proteins. PMID- 25922790 TI - Does the sex difference in competitiveness decrease in selective sub-populations? A test with intercollegiate distance runners. AB - Sex differences in some preferences and motivations are well established, but it is unclear whether they persist in selective sub-populations, such as expert financial decision makers, top scientists, or elite athletes. We addressed this issue by studying competitiveness in 1,147 varsity intercollegiate distance runners. As expected, across all runners, men reported greater competitiveness with two previously validated instruments, greater competitiveness on a new elite competitiveness scale, and greater training volume, a known correlate of competitiveness. Among faster runners, the sex difference decreased for one measure of competitiveness but did not decrease for the two other competitiveness measures or either measure of training volume. Across NCAA athletic divisions (DI, DII, DIII), the sex difference did not decrease for any competitiveness or training measure. Further analyses showed that these sex differences could not be attributed to women suffering more injuries or facing greater childcare responsibilities. However, women did report greater commitment than men to their academic studies, suggesting a sex difference in priorities. Therefore, policies aiming to provide men and women with equal opportunities to flourish should acknowledge that sex differences in some kinds of preferences and motivation may persist even in selective sub-populations. PMID- 25922791 TI - Transfer of intestinal bacterial components to mammary secretions in the cow. AB - Results from large multicentre epidemiological studies suggest an association between the consumption of raw milk and a reduced incidence of allergy and asthma in children. Although the underlying mechanisms for this association are yet to be confirmed, researchers have investigated whether bacteria or bacterial components that naturally occur in cow's milk are responsible for modulating the immune system to reduce the risk of allergic diseases. Previous research in human and mice suggests that bacterial components derived from the maternal intestine are transported to breast milk through the bloodstream. The aim of our study was to assess whether a similar mechanism of bacterial trafficking could occur in the cow. Through the application of culture-independent methodology, we investigated the microbial composition and diversity of milk, blood and feces of healthy lactating cows. We found that a small number of bacterial OTUs belonging to the genera Ruminococcus and Bifidobacterium, and the Peptostreptococcaceae family were present in all three samples from the same individual animals. Although these results do not confirm the hypothesis that trafficking of intestinal bacteria into mammary secretions does occur in the cow, they support the existence of an endogenous entero-mammary pathway for some bacterial components during lactation in the cow. Further research is required to define the specific mechanisms by which gut bacteria are transported into the mammary gland of the cow, and the health implications of such bacteria being present in milk. PMID- 25922792 TI - Similarity thresholds used in DNA sequence assembly from short reads can reduce the comparability of population histories across species. AB - Comparing inferences among datasets generated using short read sequencing may provide insight into the concerted impacts of divergence, gene flow and selection across organisms, but comparisons are complicated by biases introduced during dataset assembly. Sequence similarity thresholds allow the de novo assembly of short reads into clusters of alleles representing different loci, but the resulting datasets are sensitive to both the similarity threshold used and to the variation naturally present in the organism under study. Thresholds that require high sequence similarity among reads for assembly (stringent thresholds) as well as highly variable species may result in datasets in which divergent alleles are lost or divided into separate loci ('over-splitting'), whereas liberal thresholds increase the risk of paralogous loci being combined into a single locus ('under splitting'). Comparisons among datasets or species are therefore potentially biased if different similarity thresholds are applied or if the species differ in levels of within-lineage genetic variation. We examine the impact of a range of similarity thresholds on assembly of empirical short read datasets from populations of four different non-model bird lineages (species or species pairs) with different levels of genetic divergence. We find that, in all species, stringent similarity thresholds result in fewer alleles per locus than more liberal thresholds, which appears to be the result of high levels of over splitting. The frequency of putative under-splitting, conversely, is low at all thresholds. Inferred genetic distances between individuals, gene tree depths, and estimates of the ancestral mutation-scaled effective population size (theta) differ depending upon the similarity threshold applied. Relative differences in inferences across species differ even when the same threshold is applied, but may be dramatically different when datasets assembled under different thresholds are compared. These differences not only complicate comparisons across species, but also preclude the application of standard mutation rates for parameter calibration. We suggest some best practices for assembling short read data to maximize comparability, such as using more liberal thresholds and examining the impact of different thresholds on each dataset. PMID- 25922793 TI - The first occurrence of the enigmatic archosauriform Crosbysaurus Heckert 2004 from the Chinle Formation of southern Utah. AB - Originally identified as an ornithischian dinosaur, Crosbysaurus harrisae has been found in New Mexico, Arizona, and its type locality in Texas, as well as in North Carolina. The genus has been reassessed by other workers in light of reinterpretations about the postcrania of another putative Triassic ornithischian, Revueltosaurus. The understanding of Triassic dental faunas has become more complicated by the extreme convergence between pseudosuchian archosaurs and ornithischian dinosaur dental morphologies. We report here on a new specimen of Crosbysaurus (MNA V10666) from the Chinle Formation at Comb Ridge in southeastern Utah. This new specimen is assigned to Crosbysaurus sp. on the basis of the unique compound posterior denticles, labiolingual width, and curvature. While MNA V10666 does not help resolve the affinities of Crosbysaurus, it does represent the extension of the geographic range of this taxon for approximately 250 kilometers. This is the first record of the genus Crosbysaurus in Utah and as such it represents the northernmost known record of this taxon. This indicates that Crosbysaurus was not limited to the southern area of the Chinle/Dockum deposition but instead was widespread across the Late Triassic paleoriver systems of western Pangea. The reported specimen was found in close association with a typical Late Triassic Chinle fauna, including phytosaurs, metoposaurs, and dinosauromorphs. PMID- 25922794 TI - Validation of the Emotiv EPOC EEG system for research quality auditory event related potentials in children. AB - Background. Previous work has demonstrated that a commercial gaming electroencephalography (EEG) system, Emotiv EPOC, can be adjusted to provide valid auditory event-related potentials (ERPs) in adults that are comparable to ERPs recorded by a research-grade EEG system, Neuroscan. The aim of the current study was to determine if the same was true for children. Method. An adapted Emotiv EPOC system and Neuroscan system were used to make simultaneous EEG recordings in nineteen 6- to 12-year-old children under "passive" and "active" listening conditions. In the passive condition, children were instructed to watch a silent DVD and ignore 566 standard (1,000 Hz) and 100 deviant (1,200 Hz) tones. In the active condition, they listened to the same stimuli, and were asked to count the number of 'high' (i.e., deviant) tones. Results. Intraclass correlations (ICCs) indicated that the ERP morphology recorded with the two systems was very similar for the P1, N1, P2, N2, and P3 ERP peaks (r = .82 to .95) in both passive and active conditions, and less so, though still strong, for mismatch negativity ERP component (MMN; r = .67 to .74). There were few differences between peak amplitude and latency estimates for the two systems. Conclusions. An adapted EPOC EEG system can be used to index children's late auditory ERP peaks (i.e., P1, N1, P2, N2, P3) and their MMN ERP component. PMID- 25922795 TI - DCEMRI.jl: a fast, validated, open source toolkit for dynamic contrast enhanced MRI analysis. AB - We present a fast, validated, open-source toolkit for processing dynamic contrast enhanced magnetic resonance imaging (DCE-MRI) data. We validate it against the Quantitative Imaging Biomarkers Alliance (QIBA) Standard and Extended Tofts-Kety phantoms and find near perfect recovery in the absence of noise, with an estimated 10-20* speedup in run time compared to existing tools. To explain the observed trends in the fitting errors, we present an argument about the conditioning of the Jacobian in the limit of small and large parameter values. We also demonstrate its use on an in vivo data set to measure performance on a realistic application. For a 192 * 192 breast image, we achieved run times of <1 s. Finally, we analyze run times scaling with problem size and find that the run time per voxel scales as O(N (1.9)), where N is the number of time points in the tissue concentration curve. DCEMRI.jl was much faster than any other analysis package tested and produced comparable accuracy, even in the presence of noise. PMID- 25922796 TI - Association between rs7517847 and rs2201841 polymorphisms in IL-23 receptor gene and risk of ankylosing spondylitis: a meta-analysis. AB - To comprehensively evaluate the association between rs7517847 and rs2201841 polymorphisms in the Interleukin-23 (IL-23) receptor gene and ankylosing spondylitis (AS), a meta-analysis was performed. The Pubmed, Embase, MEDLINE, Cochrane, China National Knowledge Infrastructure (CNKI), VIP, Wanfang and China Biology Medicine disc (CBMdisc) databases were searched to identify eligible studies on rs7517847 and rs2201841 polymorphisms in the IL-23 receptor gene and AS that were published through September 2014. Data of interest were extracted from each study, and the meta-analysis was performed using STATA 12.0. Four studies were eligible for the meta-analysis and included a total patient population of 2,465. With regards to rs7517847, the current study showed that the genotype GG and allele G might play a protective role during AS (OR = 0.76, 95% CI [0.59-0.99]; OR = 0.88, 95% CI [0.78-0.99] for homozygote and allelic models, respectively). However, according to the meta-analysis, there was no statistical association between the genotype or allele of rs2201841 and an individual's susceptibility to AS in all genetic models. In conclusion, it was the IL-23 rs7517847 polymorphism rather than the rs2201841 polymorphism that had a statistical association with AS. Nevertheless, more evidence is needed to confirm this result. Consequently, it is necessary to carry out more high-quality studies to confirm the associations between these two single nucleotide polymorphisms and AS. PMID- 25922797 TI - Too packed to change: side-chain packing and site-specific substitution rates in protein evolution. AB - In protein evolution, due to functional and biophysical constraints, the rates of amino acid substitution differ from site to site. Among the best predictors of site-specific rates are solvent accessibility and packing density. The packing density measure that best correlates with rates is the weighted contact number (WCN), the sum of inverse square distances between a site's C alpha and the C alpha of the other sites. According to a mechanistic stress model proposed recently, rates are determined by packing because mutating packed sites stresses and destabilizes the protein's active conformation. While WCN is a measure of C alpha packing, mutations replace side chains. Here, we consider whether a site's evolutionary divergence is constrained by main-chain packing or side-chain packing. To address this issue, we extended the stress theory to model side chains explicitly. The theory predicts that rates should depend solely on side chain contact density. We tested this prediction on a data set of structurally and functionally diverse monomeric enzymes. We compared side-chain contact density with main-chain contact density measures and with relative solvent accessibility (RSA). We found that side-chain contact density is the best predictor of rate variation among sites (it explains 39.2% of the variation). Moreover, the independent contribution of main-chain contact density measures and RSA are negligible. Thus, as predicted by the stress theory, site-specific evolutionary rates are determined by side-chain packing. PMID- 25922798 TI - An experimental search strategy retrieves more precise results than PubMed and Google for questions about medical interventions. AB - Objective. We compared the precision of a search strategy designed specifically to retrieve randomized controlled trials (RCTs) and systematic reviews of RCTs with search strategies designed for broader purposes. Methods. We designed an experimental search strategy that automatically revised searches up to five times by using increasingly restrictive queries as long at least 50 citations were retrieved. We compared the ability of the experimental and alternative strategies to retrieve studies relevant to 312 test questions. The primary outcome, search precision, was defined for each strategy as the proportion of relevant, high quality citations among the first 50 citations retrieved. Results. The experimental strategy had the highest median precision (5.5%; interquartile range [IQR]: 0%-12%) followed by the narrow strategy of the PubMed Clinical Queries (4.0%; IQR: 0%-10%). The experimental strategy found the most high quality citations (median 2; IQR: 0-6) and was the strategy most likely to find at least one high quality citation (73% of searches; 95% confidence interval 68%-78%). All comparisons were statistically significant. Conclusions. The experimental strategy performed the best in all outcomes although all strategies had low precision. PMID- 25922799 TI - Diabetes screening: a pending issue in hypertense/obese patients. AB - The literature about possible cardiovascular consequences of diagnostic inertia in diabetes is scarce. We examined the influence of undetected high fasting blood glucose (FBG) levels on the cardiovascular risk and poor control of cardiovascular risk factors in hypertensive or obese patients, with no previous diagnosis of diabetes mellitus (i.e., diagnostic inertia). A cross-sectional study during a preventive program in a Spanish region was performed in 2003-2004. The participants were aged >=40 years and did not have diabetes but were hypertensive (n = 5, 347) or obese (n = 7, 833). The outcomes were high cardiovascular risk (SCORE >=5%), poor control of the blood pressure (>=140/90 mmHg) and class II obesity. The relationship was examined between FBG and the main parameters, calculating the adjusted odd ratios with multivariate models. Higher values of FBG were associated with all the outcomes. A more proactive attitude towards the diagnosis of diabetes mellitus in the hypertensive and obese population should be adopted. PMID- 25922800 TI - Test re-test reliability and construct validity of the star-track test of manual dexterity. AB - Objectives. We wished to determine test re-test reliability and construct validity of the star-track test of manual dexterity. Design. Test re-test reliability was examined in a controlled study. Construct validity was tested in a blinded randomized crossover study. Setting. The study was performed at a university hospital in Denmark. Participants. A total of 11 subjects for test re test and 20 subjects for the construct validity study were included. All subjects were healthy volunteers. Intervention. The test re-test trial had two measurements with 2 days pause in between. The interventions in the construct validity study included baseline measurement, intervention 1: fatigue, intervention 2: stress, and intervention 3: fatigue and stress. There was a 2 day pause between each intervention. Main outcome measure. An integrated measure of completion time and number of errors was used. Results. All participants completed the study (test re-test n = 11; construct validity n = 20). The test re testshowed a strong Pearson product-moment correlation (r = 0.90, n = 11, P < 0.01) with no sign of learning effect. The 20 subjects in the construct validity trial were randomized to the order of the four interventions, so that all subjects completed each intervention once. A repeated measures ANOVA determined that mean integrated measure differed between interventions (p = 0.002). Post hoc tests using Bonferroni correction revealed that compared with baseline all interventions had significantly higher integrated scores ranging from 47-59% difference in mean. Conclusion. The star track test of manual dexterity had a strong test re-test reliability, and was able to discriminate between a subject's normal manual dexterity and dexterity after exposure to fatigue and/or stress. PMID- 25922801 TI - Bayesian estimation of predator diet composition from fatty acids and stable isotopes. AB - Quantitative analysis of stable isotopes (SI) and, more recently, fatty acid profiles (FAP) are useful and complementary tools for estimating the relative contribution of different prey items in the diet of a predator. The combination of these two approaches, however, has thus far been limited and qualitative. We propose a mixing model for FAP that follows the Bayesian machinery employed in state-of-the-art mixing models for SI. This framework provides both point estimates and probability distributions for individual and population level diet proportions. Where fat content and conversion coefficients are available, they can be used to improve diet estimates. This model can be explicitly integrated with analogous models for SI to increase resolution and clarify predator-prey relationships. We apply our model to simulated data and an experimental dataset that allows us to illustrate modeling strategies and demonstrate model performance. Our methods are provided as an open source software package for the statistical computing environment R. PMID- 25922802 TI - New drugs for treating dyslipidemia: beyond statins. AB - Statins have been shown to be very effective and safe in numerous randomized clinical trials, and became the implacable first-line treatment against atherogenic dyslipidemia. However, even with optimal statin treatment, 60% to 80% of residual cardiovascular risk still exists. The patients with familial hypercholesterolemia which results in extremely high level of low density lipoprotein cholesterol (LDL-C) level and the patients who are intolerant or unresponsive to statins are the other hurdles of statin treatment. Recently, new classes of lipid-lowering drugs have been developed and some of them are available for the clinical practice. The pro-protein convertase subtilisin/kexintype 9 (PCSK9) inhibitor increases the expression of low density lipoprotein (LDL) receptor in hepatocytes by enhancing LDL receptor recycling. The microsomal triglyceride transport protein (MTP) inhibitor and antisense oligonucleotide against apolipoprotein B (ApoB) reduce the ApoB containing lipoprotein by blocking the hepatic very low density lipoprotein synthesis pathway. The apolipoprotein A1 (ApoA1) mimetics pursuing the beneficial effect of high density lipoprotein cholesterol and can reverse the course of atherosclerosis. ApoA1 mimetics had many controversial clinical data and need more validation in humans. The PCSK9 inhibitor recently showed promising results of significant LDL-C lowering in familial hypercholesterolemia (FH) patients from the long-term phase III trials. The MTP inhibitor and antisesnse oligonucleotide against ApoB were approved for the treatment of homozygous FH but still needs more consolidated evidences about hepatic safety such as hepatosteatosis. We would discuss the benefits and concerns of these new lipid-lowering drugs anticipating additional benefits beyond statin treatment. PMID- 25922803 TI - Current antiplatelet treatment strategy in patients with diabetes mellitus. AB - Patients with diabetes mellitus (DM) have accelerated atherosclerosis with an increased risk for atherothrombotic cardiovascular complications. A state of high platelet reactivity and activation, hypercoagulability (prothrombotic state) and a subdued response to standard antiplatelet agents may explain high rate of adverse cardiovascular events in patients with DM. Several antithrombotic treatment strategies have been developed to control the prothrombotic state in patients with DM: dose modification of commonly used agents; use of potent agents; and addition of a third antithrombotic drug (triple therapy) to commonly prescribed dual antiplatelet therapy of aspirin and a P2Y12 inhibitor. The present review aims to provide an overview of the current knowledge on platelet abnormalities in patients with DM, focusing on the challenges and perspectives of antiplatelet treatment strategies in this population. PMID- 25922804 TI - How can we easily measure glycemic variability in diabetes mellitus? PMID- 25922805 TI - The Insulin Resistance but Not the Insulin Secretion Parameters Have Changed in the Korean Population during the Last Decade. AB - BACKGROUND: This study aimed to compare the patterns of insulin secretion and resistance between Korean subjects in the 1990s and 2000s. METHODS: Insulin secretion and resistance indices were calculated from subjects who underwent 75-g oral glucose tolerance tests in the year 1997 to 1999 and 2007 to 2011 at the Seoul St. Mary's Hospital, Korea. RESULTS: A total of 578 subjects from the 1990s (mean age, 48.5 years) and 504 subjects from the 2000s (mean age, 50.2 years) were enrolled. Compared with the subjects from the 1990s, those from the 2000s exhibited increased insulin resistance (increased homeostatic model assessment for insulin resistance), and reduced insulin sensitivity (reduced Matsuda index and quantitative insulin sensitivity check index), regardless of their glucose tolerance status. However, insulinogenic index did not reveal significant differences between the 2 decades in subjects with or without diabetes. A distinct relationship was confirmed between Matsuda index and total area under the curve (insulin/glucose) in each glucose tolerance group. The mean product of the Matsuda index and the total area under the curve (insulin/glucose) as well as the oral disposition index, was lower in subjects with normal glucose tolerance from the 2000s than in those from the 1990s. CONCLUSION: After rapid economic growth and changes in lifestyle patterns, insulin resistance has worsened across the glucose tolerance status; however, the insulin secretory function remained unchanged, which resulted in an increase in the susceptibility to the development of type 2 diabetes mellitus among Korean subjects without diabetes. We could not rule out the potential selection bias and therefore, further studies in general Korean population are needed. PMID- 25922806 TI - Clinical features and causes of endogenous hyperinsulinemic hypoglycemia in Korea. AB - BACKGROUND: Endogenous hyperinsulinemic hypoglycemia (EHH) is characterized by an inappropriately high plasma insulin level, despite a low plasma glucose level. Most of the EHH cases are caused by insulinoma, whereas nesidioblastosis and insulin autoimmune syndrome (IAS) are relatively rare. METHODS: To evaluate the relative frequencies of various causes of EHH in Korea, we retrospectively analyzed 84 patients who were diagnosed with EHH from 1998 to 2012 in a university hospital. RESULTS: Among the 84 EHH patients, 74 patients (88%), five (6%), and five (6%) were diagnosed with insulinoma, nesidioblastosis or IAS, respectively. The most common clinical manifestation of EHH was neuroglycopenic symptoms. Symptom duration before diagnosis was 14.5 months (range, 1 to 120 months) for insulinoma, 1.0 months (range, 6 days to 7 months) for nesidioblastosis, and 2.0 months (range, 1 to 12 months) for IAS. One patient, who was diagnosed with nesidioblastosis in 2006, underwent distal pancreatectomy but was later determined to be positive for insulin autoantibodies. Except for one patient who was diagnosed in 2007, the remaining three patients with nesidioblastosis demonstrated severe hyperinsulinemia (157 to 2,719 uIU/mL), which suggests that these patients might have had IAS, rather than nesidioblastosis. CONCLUSION: The results of this study suggest that the prevalence of IAS may be higher in Korea than previously thought. Therefore, measurement of insulin autoantibody levels is warranted for EHH patients, especially in patients with very high plasma insulin levels. PMID- 25922807 TI - Selective immunoglobulin a deficiency in type 1 diabetes mellitus: a prevalence study in Western sicily (Italy). AB - BACKGROUND: The association between type 1 diabetes and immunoglobulin A deficiency (IgA-D) has long been recognized in many populations. The aim of this study was to assess the prevalence of IgA-D in patients with type 1 diabetes mellitus all coming from a defined geographical area and to investigate the clinical features of these subjects. METHODS: The records of 150 consecutive patients with type 1 diabetes mellitus referred in a period of one year were analyzed. A detailed history was obtained for each patient. Information was collected concerning age, gender, time of onset of diabetes, and presence of other autoimmune diseases. RESULTS: Out of 150 patients with type 1 diabetes, eight (5.3%) had a diagnosis of IgA-D. There were one female and seven male; all these patients were diagnosed by screening: none of them had history of recurrent infections. Autoimmune thyroiditis was coexisting in five patients (62%). Although other associated autoimmune disorders were found in a number of patients, there was no different prevalence rate in IgA deficient patients. CONCLUSION: This study shows the prevalence of IgA-D in Sicilian patients with type 1 diabetes as 5.3% which is much higher than reported in other Italian studies. Moreover, our data show a high prevalence of IgA-D in male gender and describe thyroiditis as the most frequent autoimmune disease present in these patients. Finally, in our case report, IgA-D diagnosis always followed routine IgA measurement when case finding for celiac disease with no history of recurrent infections in each patient. PMID- 25922808 TI - Low economic status is identified as an emerging risk factor for diabetes mellitus in korean men aged 30 to 59 years in korean national health and nutrition examination survey 2008 to 2010. AB - BACKGROUND: We compared the association between economic status and the prevalence of diabetes mellitus (DM) using large nationwide datasets covering the previous 10 years in Korea. METHODS: We analyzed the association between economic status and DM using Korean National Health and Nutrition Examination Survey (KNHANES) data from 2001 to 2010 weighted to represent the Korean population between 30 and 59 years of age. The economic status of participants was classified into quartiles according to monthly family income with an equivalence scale. RESULTS: In men, the prevalence of diabetes in the lowest income quartile (Q1) was significantly higher than that in the other quartiles in 2008 (age and body mass index-adjusted odds ratio [OR], 1.846; 95% confidence interval [CI], 1.126 to 3.027; P=0.015), 2009 (OR, 1.706; 95% CI, 1.094 to 2.661; P=0.019), and 2010 (OR, 1.560; 95% CI, 1.024 to 2.377; P=0.039) but not in 2001 or 2005. The data indicated that classification in the lowest economic status was an independent risk factor for diabetes even after adjusting for abdominal obesity, dyslipidemia, hypertension and education level in men of KNHANES 2008 to 2010. Although economic status was significantly associated with abdominal obesity, hypertriglyceridemia, and hypertension in women (P<0.001), there was no significant association between economic status and DM in women. CONCLUSION: Korean men between 30 and 59 years of age with the lowest economic status had a significantly higher prevalence of DM in 2008 to 2010 even after adjusting for other risk factors. PMID- 25922809 TI - Normal Glucose Tolerance with a High 1-Hour Postload Plasma Glucose Level Exhibits Decreased beta-Cell Function Similar to Impaired Glucose Tolerance. AB - BACKGROUND: Subjects with normal glucose tolerance (NGT) who have a high 1-hour postload plasma glucose level (>=155 mg/dL; NGT 1 hour-high) have been shown to be at higher risk for type 2 diabetes than subjects with NGT 1 hour-low postload plasma glucose level (<155 mg/dL). We compared beta-cell function in subjects with NGT 1 hour-high, NGT 1 hour-low, and impaired glucose tolerance (IGT). METHODS: We classified subjects into NGT 1 hour-low (n=149), NGT 1 hour-high (n=43), and IGT (n=52). The beta-cell function was assessed based on insulinogenic index (IGI), oral disposition index (DI), and insulin secretion sensitivity index-2 (ISSI-2). RESULTS: Insulin sensitivity was comparable between the subjects with NGT 1 hour-high and NGT 1 hour-low. The beta-cell function with/without adjusting insulin sensitivity was significantly different among the three groups. The IGI (pmol/mmol) was 116.8+/-107.3 vs. 64.8+/-47.8 vs. 65.8+/ 80.6 (P=0.141), oral DI was 3.5+/-4.2 vs. 1.8+/-1.4 vs. 1.8+/-3.1 (P<0.001), and ISSI-2 was 301.2+/-113.7 vs. 213.2+/-67.3 vs. 172.5+/-87.5 (P<0.001) in NGT 1 hour-low, NGT 1 hour-high, and IGT, respectively. Post hoc analyses revealed that oral DI and ISSI-2 were significantly different between NGT 1 hour-low and NGT 1 hour-high but comparable between NGT 1 hour-high and IGT. CONCLUSION: Among Korean subjects with NGT, those who have a higher 1-hour postload glucose level have a compromised insulin-sensitivity adjusted beta-cell function to a similar degree as IGT subjects. PMID- 25922810 TI - Intensive individualized reinforcement education is important for the prevention of hypoglycemia in patients with type 2 diabetes. AB - BACKGROUND: We investigated whether an intensive individualized reinforcement education program could influence the prevention of hypoglycemic events in patients with type 2 diabetes. METHODS: From March 2013 to September 2013, patients aged 35 to 75 years with type 2 diabetes who had not previously participated in diabetes education, and treated with insulin or a sulfonylurea containing regimen were included in the study. After structured group education, the patients assigned to the intensive individualized education group (IT) were requested to visit for reinforcement. All subjects in the IT were encouraged to self-manage dose adjustments. Participants in both groups (control group [CG, group education only; n=22] and IT [n=24]) attended follow-up visits at 2, 8, 12, and 24 weeks. At each visit, all patients were asked whether they had experienced hypoglycemia. RESULTS: The total study population consisted of 20 men (43.5%; mean age and diabetic duration of 55.9+/-11.0 and 5.1+/-7.3 years, respectively). At 24 weeks, there were no significant differences in hemoglobin A1c values between the CG and IT. The total number of hypoglycemic events per patient was 5.26+/-6.5 in the CG and 2.58+/-2.3 times in the IT (P=0.004). Adherence to lifestyle modification including frequency of exercise, self-monitoring of blood glucose, or dietary habit was not significantly different between the groups. However, adherence to hypoglycemia management, especially the dose adjustment of medication, was significantly higher in the IT compared with the CG. CONCLUSION: Compared with the structured group education, additional IT resulted in additional benefits in terms of avoidance of hypoglycemia and treating hypoglycemia in patients with type 2 diabetes. PMID- 25922812 TI - Letter: economic impact of combining metformin with dipeptidyl peptidase-4 inhibitors in diabetic patients with renal impairment in spanish patients (diabetes metab j 2015;39:74-81). PMID- 25922811 TI - 1,5-anhydroglucitol as a useful marker for assessing short-term glycemic excursions in type 1 diabetes. AB - BACKGROUND: Type 1 diabetes is associated with more severe glycemic variability and more frequent hypoglycemia than type 2 diabetes. Glycemic variability is associated with poor glycemic control and diabetic complications. In this study, we demonstrate the clinical usefulness of serum 1,5-anhydroglucitol (1,5-AG) for assessing changes in glycemic excursion in type 1 diabetes. METHODS: Seventeen patients with type 1 diabetes were enrolled in this study. A continuous glucose monitoring system (CGMS) was applied twice at a 2-week interval to evaluate changes in glycemic variability. The changes in serum glycemic assays, including 1,5-AG, glycated albumin and hemoglobin A1c (HbA1c), were also evaluated. RESULTS: Most subjects showed severe glycemic excursions, including hypoglycemia and hyperglycemia. The change in 1,5-AG level was significantly correlated with changes in the glycemic excursion indices of the standard deviation (SD), mean amplitude of glucose excursion (MAGE), lability index, mean postmeal maximum glucose, and area under the curve for glucose above 180 mg/dL (r=-0.576, -0.613, 0.600, -0.630, and -0.500, respectively; all P<0.05). Changes in glycated albumin were correlated with changes in SD and MAGE (r=0.495 and 0.517, respectively; all P<0.05). However, changes in HbA1c were not correlated with any changes in the CGMS variables. CONCLUSION: 1,5-AG may be a useful marker for the assessment of short-term changes in glycemic variability. Furthermore, 1,5-AG may have clinical implications for the evaluation and treatment of glycemic excursions in type 1 diabetes. PMID- 25922813 TI - Response: economic impact of combining metformin with dipeptidyl peptidase-4 inhibitors in diabetic patients with renal impairment in spanish patients (diabetes metab j 2015;39:74-81). PMID- 25922814 TI - Erratum: figure correction. A gut feeling to cure diabetes: potential mechanisms of diabetes remission after bariatric surgery. AB - [This corrects the article on p. 406 in vol. 38, PMID: 25541603.]. PMID- 25922815 TI - Paradigm shift regarding sinus augmentation. PMID- 25922817 TI - Validity of the vertical tube-shift method in determining the relationship between the mandibular third molar roots and the inferior alveolar nerve canal. AB - OBJECTIVES: To assess the validity of the vertical tube-shift method using intraoral periapical radiography (IOPAR) for determining the relationship between the mandibular third molar roots and the inferior alveolar nerve (IAN) canal in comparison with cone-beam computed tomography (CBCT). MATERIALS AND METHODS: Fifty impacted mandibular third molars were analyzed using the IOPAR vertical tube-shift method and CBCT. The relationship of the IAN canal to the impacted mandibular third molar was recorded as buccal, lingual or in line with the apex and was compared with CBCT findings. The sensitivity, specificity, positive predictive value (PPV), and negative predictive value (NPV) of the vertical tube shift method in depicting the relationship (buccal/lingual/in line with the apex) of the IAN canal to the third molar root apex was calculated. RESULTS: The sensitivity and specificity PPV and NPV of the IOPAR vertical tube-shift technique was found to be highest for a lingual relationship (100%) followed by buccal (94.4%, 92.3%, 97.1%, and 85.7%) and in line with the apex relationship (88.9%, 95.0%, 80.0%, and 97.4%) of the IAN canal with the third molar root apex, respectively. A statistically significant association was observed between the IOPAR vertical tube-shift method and the CBCT with a P-value <0.01. CONCLUSION: The vertical tube-shift method can be used as an effective diagnostic tool in assessing the relationship of the IAN canal to the third molar root apex with high sensitivity, specificity, PPV, and NPV. PMID- 25922818 TI - Infraorbital nerve transpositioning into orbital floor: a modified technique to minimize nerve injury following zygomaticomaxillary complex fractures. AB - OBJECTIVES: Transpositioning of the inferior alveolar nerve to prevent injury in lower jaw has been advocated for orthognathic, pre-prosthetic and for implant placement procedures. However, the concept of infra-orbital nerve repositioning in cases of mid-face fractures remains unexplored. The infraorbital nerve may be involved in trauma to the zygomatic complex which often results in sensory disturbance of the area innervated by it. Ten patients with infraorbital nerve entrapment were treated in similar way at our maxillofacial surgery centre. MATERIALS AND METHODS: In this article we are reporting three cases of zygomatico maxillary complex fracture in which intra-operative repositioning of infra orbital nerve into the orbital floor was done. This was done to release the nerve from fractured segments and to reduce the postoperative neural complications, to gain better access to fracture site and ease in plate fixation. This procedure also decompresses the nerve which releases it off the soft tissue entrapment caused due to trauma and the organized clot at the fractured site. RESULTS: There was no evidence of sensory disturbance during their three month follow-up in any of the patient. CONCLUSION: Infraorbital nerve transposition is very effective in preventing paresthesia in patients which fracture line involving the infraorbital nerve. PMID- 25922819 TI - Mandibular intraosseous squamous cell carcinoma lesion associated with odontogenic keratocyst: a case report. AB - Squamous cell carcinoma (SCC) is the most common malignant tumor in the oral cavity, and it accounts for about 90% of all oral cancers. Several risk factors for oral SCC have been identified; however, SCC associated with odontogenic keratocysts have rarely been reported. The present study describes the case of a 36-year-old man with SCC of the right ramus of the mandible, which was initially diagnosed as a benign odontogenic cyst. He underwent enucleation at another hospital followed by segmental mandibulectomy and fibular free flap reconstruction at our institution. In this case, we introduce a patient with oral cancer associated with odontogenic cyst on the mandible and report a satisfactory outcome with wide resection and immediate free flap reconstruction. PMID- 25922816 TI - Common risk factors for postoperative pain following the extraction of wisdom teeth. AB - The extraction of third molars is a common task carried out at dental/surgery clinics. Postoperative pain is one of the two most common complications of this surgery, along with dry socket. Knowledge of the frequent risk factors of this complication is useful in determining high-risk patients, planning treatment, and preparing the patients mentally. Since the risk factors for postoperative pain have never been summarized before while the risk factors for dry socket have been highly debated, this report summarizes the literature regarding the common predictors of postextraction pain. Except for surgical difficulty and the surgeon's experience, the influences of other risk factors (age, gender and oral contraceptive use) were rather inconclusive. The case of a female gender or oral contraceptive effect might mainly be associated with estrogen levels (when it comes to dry socket), which can differ considerably from case to case. Improvement in and unification of statistical and diagnostic methods seem necessary. In addition, each risk factor was actually a combination of various independent variables, which should instead be targeted in more comprehensive studies. PMID- 25922820 TI - A case report about the reconstruction procedures of the previously failed cylinderical implants site using distraction osteogenesis. AB - We report the eventually successful treatment of a huge bone defect and peri implantitis following reconstruction of a previously failed intra-mobile cylinder implant system (IMZ) implant site using distraction osteogenesis (DO). In the anterior mandible, two IMZ implants failed and surgical debridement was performed in accordance to the patient's needs. Thereafter, mobility and suppuration were decreased and the patient visited the dental clinic on a regular basis for oral health maintenance. However, the inflammation did not resolve, and the bone destruction around the implants progressed for 4 years. Finally, the implants failed and a severe bone defect remained after implant removal. To reconstruct the bone defects, we attempted bone graft procedures. Titanium mesh was unsuccessfully used to obtain bone volume regeneration. However, DO subsequently was used to obtain sufficient bone volume for implant placement. The new implants were then installed, followed by prosthetic procedures. In conclusion, progression of peri-implantitis could not be arrested despite surgical intervention and repeated maintenance care for 3 years. Reconstruction of the peri-implantitis site was complicated due to its horizontal and vertical bone defects. Lesions caused by implant failure require an aggressive regenerative strategy, such as DO. DO was successful in reconstruction of a peri-implantitis site that was complicated due to horizontal and vertical bone defects. PMID- 25922821 TI - Necrotizing fasciitis of the head and neck: a case report. AB - Necrotizing fasciitis (NF) is an infection that spreads along the fascial planes, causing subcutaneous tissue death characterized by rapid progression, systemic toxicity, and even death. NF often appears as a red, hot, painful, and swollen wound with an ill-defined border. As the infective process continues, local pain is replaced by numbness or analgesia. As the disease process continues, the skin initially becomes pale, then mottled and purple, and finally, gangrenous. The ability of NF to move rapidly along fascial planes and cause tissue necrosis is secondary to its polymicrobial composition and the synergistic effect of the enzymes produced by the bacteria. Treatment involves securing the airway, broad spectrum antimicrobial therapy, intensive care support, and prompt surgical debridement, repeated as needed. Reducing mortality rests on early diagnosis and prompt aggressive treatment. PMID- 25922822 TI - Salvage rapid maxillary expansion for the relapse of maxillary transverse expansion after Le Fort I with parasagittal osteotomy. AB - Maxillary transverse deficiency is one of the most common deformities among occlusal discrepancies. Typical surgical methods are segmental Le Fort I osteotomy and surgically-assisted rapid maxillary expansion (SARME). This patient underwent a parasagittal split with a Le Fort I osteotomy to correct transverse maxillary deficiency. During follow-up, early transverse relapse occurred and rapid maxillary expansion (RME) application with removal of the fixative plate on the constricted side was able to regain the dimension again. RME application may be appropriate salvage therapy for such a case. PMID- 25922823 TI - Unilateral intraoral vertical ramus osteotomy and sagittal split ramus osteotomy for the treatment of asymmetric mandibles. AB - In surgery for facial asymmetry, mandibles can be classified into two types, rotational and translational, according to the required mandibular movements for surgery. During surgery for rotational mandibular asymmetry, a bilateral sagittal split ramus osteotomy (BSSRO) may cause a large bone gap between the proximal and distal segments as well as condylar displacement, resulting in a relapse of the temporomandibular joint disorder, especially in severe cases. The intraoral vertical ramus osteotomy has an advantage, in this respect, because it causes less rotational displacement of the proximal segment on the deviated side and even displaced or rotated condylar segments may return to their original physiologic position. Unilateral intraoral vertical ramus osteotomy (UIVRO) on the short side combined with contralateral SSRO was devised as an alternative technique to resolve the spatial problems caused by conventional SSRO in cases of severe rotational asymmetry. A series of three cases were treated with the previously suggested protocol and the follow-up period was analyzed. In serial cases, UIVRO combined with contralateral SSRO may avoid mediolateral flaring of the bone segments and condylar dislocation, and result in improved condition of the temporomandibular joint. UIVRO combined with contralateral SSRO is expected to be a useful technique for the treatment of rotational mandibular asymmetry. PMID- 25922824 TI - An alternative treatment option for a bony defect from large odontoma using recycled demineralization at chairside. AB - Odontoma is the most common odontogenic benign tumor, and the treatment of choice is generally surgical removal. After excision, bone grafts may be necessary depending on the need for further treatment, or the size and location of the odontoma. Although the osteogenic capacity of a demineralized tooth was verified as early as 1967 by Urist and many other investigators, the cumbersome procedure, including a long demineralization time, may be less than comfortable for clinicians. A modified ultrasonic technology, with periodic negative pressure and temperature control, facilitated rapid and aseptic preparation of demineralized teeth for bone grafts. This approach reduces the demineralization time dramatically (<=80 minutes), so that the graft material can be prepared chairside on the same day as the extraction. The purpose of this article is to describe two cases of large compound odonotomas used as graft material prepared chairside for enucleation-induced bony defects. These two clinical cases showed favorable wound healing without complications, and good bony support for future dental implants or orthodontic treatment. Finally, this report will suggest the possibility of recycling the benign pathologic hard tissue as an alternative treatment option for conventional bone grafts in clinics. PMID- 25922825 TI - Discussion: An alternative treatment option for a bony defect from large odontoma using recycled demineralization at chairside. PMID- 25922827 TI - Age-dependent alteration of antioxidant defense system in hypertensive and type-2 diabetes patients. AB - BACKGROUND: The association between hypertension and diabetes has been linked to increased oxidative stress with age. This study was to examine the level of age dependent alterations in antioxidant defense system between patients having hypertension and/or type-2 diabetes. METHODS: The study was conducted at the Ahmadu Bello University Teaching Hospital, Zaria-Nigeria, using 200 Subjects recruited from the cardiology, endocrinology and outpatient clinics. They were divided into four groups of 50 subjects each, namely: Diabetic group (DG), hypertensive (HG) and hypertensive-diabetic group (HDG) as cases. The control group (CG) was non-diabetic normotensive subjects. They were all stratified into six age-ranges namely 20-29, 30-39, 40-49, 50-59, 60-69, 70-79 years. Oxidative stress markers (lipid peroxidation, antioxidant vitamins and elements, enzymatic and non-enzymatic antioxidant) were measured in the blood sample collected from all subjects in each age group within the study groups. RESULTS: The results in the DG, HG and HDG, showed that the percentage decrease in enzymatic antioxidants and antioxidant vitamins with age were significantly (P < 0.05) higher than 10.8% and 20.0% respectively when compared to the CG, whereas, the level of decrease in serum Selenium at same age range was significantly higher than 52.8%. The level of lipid peroxidation in the cases was observed to be significantly (P < 0.05) higher than 89.9% when compared to the mean reference values (2.94 +/- 0.05 nmol/ml) of the CG at same age range. Also, the decrease levels of endogenous antioxidants were observed to be directly related to aging. CONCLUSION: The result obtained demonstrates the percentage age-dependent alteration in oxidative stress markers. The percentage decrease in the antioxidant levels during aging could be an explanation to the possible link, underlying the complication of type 2 diabetes and hypertension in this locale. Hence, antioxidants supplements may be useful in the management of the diseases during aging. PMID- 25922828 TI - The relationship between glycemic control, beta2-microglobulin and inflammation in patients on maintenance dialysis treatment. AB - BACKGROUND: Hyperglycemia appears to play a significant role on the inflammatory cytokines production. Beta2-microglobulin (beta2M) is accumulated in the circulation of dialysis patients. We studied the relationship between glycemic control defined by glucose serum concentrations and insulin resistance, beta2M and markers of inflammation in patients on renal replacement therapies with or/and without diabetes mellitus. METHODS: We enrolled 96 dialyzed patients, 62 males and 34 females. The treatment modalities which were applied were : regular hemodialysis (HD, n = 34), predilution hemodiafiltration (HDF, n = 42) and peritoneal dialysis (PD, n = 20). Dialysis adequacy was defined by Kt/V for urea.Beta2M and insulin serum concentrations were measured by radioimmunoassays. hsCRP and TNF-alpha serum concentrations were measured by ELISA. Insulin resistance was calculated using the homeostasis model assessment of insulin resistance (HOMA-IR).We examined the association of elevated serum glucose with inflammatory factors and we built a multivariable model to investigate if glucose could be a potential determinant of beta2M serum levels. RESULTS: Serum glucose was positively correlated with beta2M and TNF-alpha (r = 0.320, p = 0.002 and r = 0.215, p = 0.03 respectively).We observed significant association between the patients with higher serum glucose concentrations and the patients with greater beta2MU concentrations (x(2) = 4.44, p = 0.03). Multivariable model showed that glucose acts as a significant independent determinant of beta2M adjusting for age, gender, dialysis modality and metabolic acidosis status. CONCLUSIONS: The elevated glucose concentrations were positively associated with both, greater beta2M serum concentrations and up-regulated inflammatory procedure in dialysis patients with or/and without diabetes mellitus. PMID- 25922829 TI - Corrigendum to "Semiphysiological versus Empirical Modelling of the Population Pharmacokinetics of Free and Total Cefazolin during Pregnancy". PMID- 25922830 TI - Wheeled mobility. PMID- 25922831 TI - Radial quantitative ultrasound and dual energy x-ray absorptiometry: intermethod agreement for bone status assessment in children. AB - Aim. To validate a radial quantitative ultrasound (QUS) system with dual energy X ray absorptiometry (DXA), a criterion technique in bone status assessment among children. Methods. Bone health was evaluated using a radial QUS system (Sunlight Omnisense 8000P) to measure the speed of sound (SOS) at one-third distal radius of the nondominant hand and DXA (Hologic QDR) was used to assess whole body bone mineral density (BMD). Results. Some 29.9% of the children were grossly misclassified according to quartiles of BMD and radial SOS. Poor agreement was observed between Z-scores of radial SOS and whole-body BMD (mean difference = 0.6 +/- 0.9; 95% limits of agreement = -1.4 to 2.6). With a cut-off value of -1.0, radial SOS yielded satisfactory sensitivity (80%) and specificity (93%) for the detection of children with low BMD. Conclusion. The observed poor agreement in the present study suggests that radial QUS and DXA are not comparable and hence are not interchangeable in evaluating bone status of the children. PMID- 25922832 TI - The Histone Acetyltransferase Gcn5 Regulates ncRNA-ICR1 and FLO11 Expression during Pseudohyphal Development in Saccharomyces cerevisiae. AB - Filamentous growth is one of the key features of pathogenic fungi during the early infectious phase. The pseudohyphal development of yeast Saccharomyces cerevisiae shares similar characteristics with hyphae elongation in pathogenic fungi. The expression of FLO11 is essential for adhesive growth and filament formation in yeast and is governed by a multilayered transcriptional network. Here we discovered a role for the histone acetyltransferase general control nonderepressible 5 (Gcn5) in regulating FLO11-mediated pseudohyphal growth. The expression patterns of FLO11 were distinct in haploid and diploid yeast under amino acid starvation induced by 3-amino-1,2,4-triazole (3AT). In diploids, FLO11 expression was substantially induced at a very early stage of pseudohyphal development and decreased quickly, but in haploids, it was gradually induced. Furthermore, the transcription factor Gcn4 was recruited to the Sfl1-Flo8 toggle sites at the FLO11 promoter under 3AT treatment. Moreover, the histone acetylase activity of Gcn5 was required for FLO11 induction. Finally, Gcn5 functioned as a negative regulator of the noncoding RNA ICR1, which is known to suppress FLO11 expression. Gcn5 plays an important role in the regulatory network of FLO11 expression via Gcn4 by downregulating ICR1 expression, which derepresses FLO11 for promoting pseudohyphal development. PMID- 25922833 TI - Identification of subgingival periodontal pathogens and association with the severity of periodontitis in patients with chronic kidney diseases: a cross sectional study. AB - BACKGROUND: The aim of our study was to assess the subgingival profile of 9 periodontal pathogens, by means of real-time PCR, in a group of predialysis chronic kidney disease patients with and without periodontal disease and to identify the risk factors associated with periodontal disease in these patients. MATERIAL AND METHODS: This is a single centre cross-sectional cohort study performed on 70 CKD patients. Patients received a full-mouth periodontal examination and the following parameters were assessed: periodontal pocket depth (PPD), clinical attachment level, bleeding on probing, and plaque index; subgingival biofilm samples were collected from the deepest periodontal pocket of each quadrant and were pooled in one transporting unit. Clinical data were drawn from the medical file of the patients. RESULTS: T. denticola (P = 0.001), T. forsythia (P < 0.001), and P. micros (P = 0.003) are significantly associated with periodontal disease in CKD subjects but in a multivariate model only age and T. forsythia remain independent risk factors for periodontal disease in patients with CKD. CONCLUSIONS: In our cohort, age and T. forsythia are independently associated with periodontitis in CKD patients. Within the limits of this study, CKD was not significantly associated with a particular subgingival periodontal pathogens profile in periodontitis patients. PMID- 25922834 TI - NOD-Like Receptor Signaling in Cholesteatoma. AB - Background. Cholesteatoma is a destructive process of the middle ear resulting in erosion of the surrounding bony structures with consequent hearing loss, vestibular dysfunction, facial paralysis, or intracranial complications. The etiopathogenesis of cholesteatoma is controversial but is associated with recurrent ear infections. The role of intracellular innate immune receptors, the NOD-like receptors, and their associated signaling networks was investigated in cholesteatoma, since mutations in NOD-like receptor-related genes have been implicated in other chronic inflammatory disorders. Results. The expression of NOD2 mRNA and protein was significantly induced in cholesteatoma compared to the external auditory canal skin, mainly located in the epithelial layer of cholesteatoma. Microarray analysis showed significant upregulation for NOD2, not for NOD1, TLR2, or TLR4 in cholesteatoma. Moreover, regulation of genes in an interaction network of the NOD-adaptor molecule RIPK2 was detected. In addition to NOD2, NLRC4, and PYCARD, the downstream molecules IRAK1 and antiapoptotic regulator CFLAR showed significant upregulation, whereas SMAD3, a proapoptotic inducer, was significantly downregulated. Finally, altered regulation of inflammatory target genes of NOD signaling was detected. Conclusions. These results indicate that the interaction of innate immune signaling mediated by NLRs and their downstream target molecules is involved in the etiopathogenesis and growth of cholesteatoma. PMID- 25922835 TI - Antiresistin RNA Oligonucleotide Ameliorates Diet-Induced Nonalcoholic Fatty Liver Disease in Mice through Attenuating Proinflammatory Cytokines. AB - The aim of this study was to determine whether inhibition of resistin by a synthetic antiresistin RNA (oligonucleotide) oligo ameliorates metabolic and histological abnormalities in nonalcoholic fatty liver disease (NAFLD) induced by high-fat diet (HFD) in mice. The antiresistin RNA oligo and a scrambled control oligo (25 mg/kg of body weight) were i.p. injected to HFD mice. Serum metabolic parameters and hepatic enzymes were measured after 4-week treatment. The treatment significantly reduced epididymal fat and attenuated the elevated serum resistin, cholesterol, triglycerides, glucose, and insulin with an improved glucose tolerance test. Antiresistin RNA oligo also normalized serum AST and ALT levels with improved pathohistology of NAFLD. Immunoblotting and qRT-PCR revealed that decreased protein and mRNA expression of resistin in fat and liver tissues of the treated mice were associated with reduction of adipose TNF-alpha and IL-6 expression and secretion into circulation. mRNA and protein expression of hepatic phosphoenolpyruvate carboxykinase (PEPCK) and sterol regulatory element-binding protein-1c (SREBP-1c) were also significantly decreased in the treated mice. Our results suggest that resistin may exacerbate NAFLD in metabolic syndrome through upregulating inflammatory cytokines and hepatic PEPCK and SREBP-1c. Antiresistin RNA oligo ameliorated metabolic abnormalities and histopathology of NAFLD through attenuating proinflammatory cytokines. PMID- 25922836 TI - Multiple sclerosis in older adults: the clinical profile and impact of interferon Beta treatment. AB - BACKGROUND: We examined (1) patient characteristics and disease-modifying drug (DMD) exposure in late-onset (LOMS, >=50 years at symptom onset) versus adult onset (AOMS, 18-<50 years) MS and (2) the association between interferon-beta (IFNbeta) and disability progression in older relapsing-onset MS adults (>=50 years). METHODS: This retrospective study (1980-2004, British Columbia, Canada) included 358 LOMS and 5627 AOMS patients. IFNbeta-treated relapsing-onset MS patients aged >=50 (regardless of onset age, 90) were compared with 171 contemporary and 106 historical controls. Times to EDSS 6 from onset and from IFNbeta eligibility were examined using survival analyses. RESULTS: LOMS patients (6%) were more likely to be male, with motor onset and a primary-progressive course, and exhibit faster progression and were less likely to take DMDs. Nonetheless, 57% were relapsing-onset, of which 31% were prescribed DMDs, most commonly IFNbeta. Among older relapsing-onset MS adults, no significant association between IFNbeta exposure and disability progression was found when either the contemporary (hazard ratio [HR]: 0.46; 95% CI: 0.18-1.22) or historical controls (HR: 0.54; 95% CI: 0.20-1.42) were considered. CONCLUSION: LOMS differed clinically from AOMS. One-third of older relapsing-onset MS patients were prescribed a DMD. IFNbeta exposure was not significantly associated with reduced disability in older MS patients. PMID- 25922837 TI - Survival of Mexican Children with Acute Lymphoblastic Leukaemia under Treatment with the Protocol from the Dana-Farber Cancer Institute 00-01. AB - Our aim in this paper is to describe the results of treatment of acute lymphoblastic leukaemia (ALL) in Mexican children treated from 2006 to 2010 under the protocol from the Dana-Farber Cancer Institute (DFCI) 00-01. The children were younger than 16 years of age and had a diagnosis of ALL de novo. The patients were classified as standard risk if they were 1-9.9 years old and had a leucocyte count <50 * 10(9)/L, precursor B cell immunophenotype, no mediastinal mass, CSF free of blasts, and a good response to prednisone. The rest of the patients were defined as high risk. Of a total of 302 children, 51.7% were at high risk. The global survival rate was 63.9%, and the event-free survival rate was 52.3% after an average follow-up of 3.9 years. The percentages of patients who died were 7% on induction and 14.2% in complete remission; death was associated mainly with infection (21.5%). The relapse rate was 26.2%. The main factor associated with the occurrence of an event was a leucocyte count >100 * 10(9)/L. The poor outcomes were associated with toxic death during induction, complete remission, and relapse. These factors remain the main obstacles to the success of this treatment in our population. PMID- 25922838 TI - Estradiol Valerate Pretreatment in Short Protocol GnRH-Agonist Cycles versus Combined Pretreatment with Oral Contraceptive Pills in Long Protocol GnRH-Agonist Cycles: A Randomised Controlled Trial. AB - The strategy of in vitro fertilization (IVF) procedures relies on the increasing pregnancy rate and decreasing the risk of premature ovulation and ovarian hyperstimulation syndrome. They are also designed to avoid weekend oocyte retrievals. Combined oral contraceptive (OC) pills are among the medicines used to accomplish these objectives. Alternatively, estradiol can be used instead of OC to obtain similar results. The aim of our study was to compare the differences in pregnancy rates (PRs), implantation rates, and miscarriage rates between a short agonist protocol with estradiol priming and a long protocol with combined OC. Of the 298 women who participated in this study, 134 achieved clinical pregnancies (45.0%). A higher PR (58.4%, n = 80, compared to 40.3%, n = 54) was achieved in the long protocol after OC pretreatment group. The implantation rate was also higher for this group (37.8% versus 28.0%; P = 0.03). The miscarriage rate was 15.0% (n = 12) for the long protocol after OC pretreatment group and 20.4% (n = 11) for the short agonist group (P = 0.81). The short agonist protocol required a 5.7% lower human menopausal gonadotropin (hMG) dosage than the long protocol but surprisingly the number of oocytes retrieved was also smaller. PMID- 25922839 TI - Kinematics of Rotation in Joints of the Lower Limbs and Pelvis during Gait: Early Results-SB ACLR Approach versus DB ACLR Approach. AB - It is difficult to find publications comparing rotation kinematics in large joints of the lower limbs and pelvis during gait in patients after single-bundle (SB) reconstruction of the anterior cruciate ligament (ACLR) with double-bundle (DB) ACLR of the knee. The aim of this study was to compare rotation kinematics in ankle, knee, and hip joints and the pelvis during gait in the 14th week after SB and DB ACLR. The subjects were males after SB (n = 10) and DB (n = 13) ACLR and a control group (n = 15). The values of kinematic parameters were recorded during internal (IR) and external (ER) rotation in the joints during gait using the BTS SMART. The SB ACLR group obtained significantly higher values of ER in the involved knee comparing to DB ACLR and controls and excessive IR in the hip comparing to controls. In the DB ACLR group, excessive ER was noted in the involved leg's foot. Comparing with the DB ACLR and control groups, SB ACLR subjects had more substantial disorders of rotation kinematics in the lower limb joints. However, in both ACLR groups, 14 weeks of postoperative physiotherapy were not enough to fully restore rotation kinematics in joints of the lower limbs during gait. PMID- 25922840 TI - Diagnostic Value of Subjective Memory Complaints Assessed with a Single Item in Dominantly Inherited Alzheimer's Disease: Results of the DIAN Study. AB - OBJECTIVE: We examined the diagnostic value of subjective memory complaints (SMCs) assessed with a single item in a large cross-sectional cohort consisting of families with autosomal dominant Alzheimer's disease (ADAD) participating in the Dominantly Inherited Alzheimer Network (DIAN). METHODS: The baseline sample of 183 mutation carriers (MCs) and 117 noncarriers (NCs) was divided according to Clinical Dementia Rating (CDR) scale into preclinical (CDR 0; MCs: n = 107; NCs: n = 109), early symptomatic (CDR 0.5; MCs: n = 48; NCs: n = 8), and dementia stage (CDR >= 1; MCs: n = 28; NCs: n = 0). These groups were subdivided by the presence or absence of SMCs. RESULTS: At CDR 0, SMCs were present in 12.1% of MCs and 9.2% of NCs (P = 0.6). At CDR 0.5, SMCs were present in 66.7% of MCs and 62.5% of NCs (P = 1.0). At CDR >= 1, SMCs were present in 96.4% of MCs. SMCs in MCs were significantly associated with CDR, logical memory scores, Geriatric Depression Scale, education, and estimated years to onset. CONCLUSIONS: The present study shows that SMCs assessed by a single-item scale have no diagnostic value to identify preclinical ADAD in asymptomatic individuals. These results demonstrate the need of further improvement of SMC measures that should be examined in large clinical trials. PMID- 25922841 TI - Magnetic resonance comparison of left-right heart volumetric and functional parameters in thalassemia major and thalassemia intermedia patients. AB - OBJECTIVES: To evaluate a population of asymptomatic thalassemia major (TM) and thalassemia intermedia (TI) patients using cardiovascular magnetic resonance (CMR). We supposed that TI group could be differentiated from the TM group based on T2(*) and that the TI group could demonstrate higher cardiac output. METHODS: A retrospective analysis of 242 patients with TM and TI was performed (132 males, 110 females; mean age 39.6 +/- 8 years; 186 TM, 56 TI). Iron load was assessed by T2(*) measurements; volumetric functions were analyzed using steady-state-free precession sequences. RESULTS: Significant difference in left-right heart performance was observed between TM with iron overload and TI patients and between TM with iron overload and TM without iron overload (P < 0.05); no significant differences were observed between TM without iron overload and TI patients. A significant correlation was observed between T2(*) and ejection fraction of right ventricle- (RV-) ejection fraction of left ventricle (LV); an inverse correlation was present among T2(*) values and end-diastolic volume of LV, end-systolic volume of LV, stroke volume of LV, end-diastolic volume of RV, end-systolic volume of RV, and stroke volume of RV. CONCLUSIONS: CMR is a leading approach for cardiac risk evaluation of TM and TI patients. PMID- 25922842 TI - Mechanical strain regulates osteogenic and adipogenic differentiation of bone marrow mesenchymal stem cells. AB - This study examined the effects of mechanical strain on osteogenic and adipogenic differentiation of cultured MSCs by stimulating MSCs cultured in general and adipogenic differentiation media using a mechanical strain device. Markers of osteogenic (Runx2, Osx, and I-collagen) and adipogenic (PPARgamma-2, C/EBPalpha, and lipid droplets) differentiation were examined using real-time PCR, western blot, immunocytochemical, or histochemical stain analyses. Levels of Runx2 and Osx gradually increased in MSC groups in general medium subject to strain stimulation, as compared with in unstrained groups. After adding the stress signal, I-collagen protein levels of expression were obviously promoted in cells in comparison to the controls. The levels of PPARgamma-2 and C/EBPalpha were decreased, and the emergence of lipid droplets was delayed in MSCs groups in adipogenic differentiation medium subject to strain stimulation, as compared with in unstrained groups. Mechanical strain can promote differentiation of MSCs into osteoblasts and can impede differentiation into adipocytes. These results clarify the mechanisms underlying the effects of exercise on bone repair and reconstruction and provide a more adequate scientific basis for the use of exercise therapy in the treatment of obesity and metabolic osteoporosis. PMID- 25922843 TI - Identification of Novel Mutations in ABCA4 Gene: Clinical and Genetic Analysis of Indian Patients with Stargardt Disease. AB - Stargardt disease (STGD) is the leading cause of juvenile macular degeneration associated with progressive central vision loss, photophobia, and colour vision abnormalities. In this study, we have described the clinical and genetic features of Stargardt patients from an Indian cohort. The next generation sequencing was carried out in five clinically confirmed unrelated patients and their family members using a gene panel comprising 184 retinal specific genes. Sequencing results were analyzed by read mapping and variant calling in genes of interest, followed by their verification and interpretation. Genetic analysis revealed ABCA4 mutations in all of the five unrelated patients. Among these, four patients were found with compound heterozygous mutations and another one had homozygous mutation. All the affected individuals showed signs and symptoms consistent with the disease phenotype. We report two novel ABCA4 mutations in Indian patients with STGD disease, which expands the existing spectrum of disease-causing variants and the understanding of phenotypic and genotypic correlations. Screening for causative mutations in patients with STGD using panel of targeted gene sequencing by NGS would be a cost effective tool, might be helpful in confirming the precise diagnosis, and contributes towards the genetic counselling of asymptomatic carriers and isolated patients. PMID- 25922844 TI - The association of soluble IGF2R and IGF2R gene polymorphism with type 2 diabetes. AB - The aim of this study is to investigate the insulin-like growth factor type 2 (IGF2R) gene and circulating soluble IGF2R in relation to type 2 diabetes (T2DM). Six hundred fifty-four subjects without history of diabetes were screened for diabetes by oral glucose tolerance test. In addition, 145 subjects with known diabetes were recruited from a local diabetes clinic. Circulating IGF2R levels were measured by ELISA method; plasma glucose was measured by colorimetric method; insulin levels were determined by chemiluminescent method; IGF2R gene rs416572 was genotyped using real-time PCR. The distributions of IGF2R genotypes were 69.2% CC, 27.8% CT, and 3.0% TT. The C allele was more commonly found in diabetes subjects, with a significant difference (P < 0.01). In the presence of the T allele, circulating IGF2R levels were significantly lower (P < 0.05). There was no significant difference in other potential confounders including age, sex, and BMI. Only circulating IGF2R, age, and BMI were independently associated with the degree of insulin resistance, as assessed by the HOMA model. It was found that age, sex, and BMI were associated with beta cell function. In conclusion, IGF2R gene polymorphism and circulating IGF2R are associated with T2DM. PMID- 25922845 TI - Liraglutide, a glucagon-like peptide-1 analog, increased insulin sensitivity assessed by hyperinsulinemic-euglycemic clamp examination in patients with uncontrolled type 2 diabetes mellitus. AB - AIMS: Glucagon-like peptide-1 (GLP-1) analog promotes insulin secretion by acting on pancreatic beta-cells. This antihyperglycemic treatment for type 2 diabetes mellitus (DM) has attracted increased clinical attention not only for its antihyperglycemic action but also for its potential extrapancreatic effects. We investigated whether liraglutide, a GLP-1 analog, could enhance insulin sensitivity as assessed by the hyperinsulinemic-euglycemic clamp in type 2 DM patients. MATERIALS: We prospectively enrolled 31 uncontrolled type 2 DM patients who were hospitalized and equally managed by guided diet- and exercise-therapies and then introduced to either liraglutide- or intensive insulin-therapy for 4 weeks. Insulin sensitivity was assessed by the glucose infusion rate (GIR) using hyperinsulinemic-euglycemic clamp before and after the therapies. RESULTS: Values of HbA1c, postprandial plasma glucose, and body mass index (BMI) were significantly decreased by hospitalized intensive insulin-therapy or liraglutide therapy. GIR was significantly increased by liraglutide-therapy but not by insulin-therapy, indicating that liraglutide-therapy significantly enhanced insulin sensitivity. BMI decreased during liraglutide-therapy but was not significantly correlated with changes in GIR. Multivariate logistic regression analysis demonstrated that liraglutide-therapy significantly correlated with increased insulin sensitivity in uncontrolled DM patients. CONCLUSIONS: Liraglutide may exhibit favorable effects on diabetes control for type 2 DM patients by increasing insulin sensitivity as an extrapancreatic action. Clinical trial registration Unique Identifier is UMIN000015201. PMID- 25922846 TI - Relationship between serum 25-hydroxyvitamin D and lower extremity arterial disease in type 2 diabetes mellitus patients and the analysis of the intervention of vitamin D. AB - The aim of this study was to explore the relationship between serum 25 hydroxyvitamin D [25(OH)D] concentrations and lower extremity arterial disease (LEAD) in type 2 diabetes mellitus (T2DM) patients and to investigate the intervention effect of vitamin D. 145 subjects were assigned to a control group (Group NC), T2DM group (Group DM1), and T2DM complicated with LEAD group (Group DM2); then Group DM2 were randomly divided into Group DM3 who received oral hypoglycemic agents and Group DM4 who received oral hypoglycemic drugs and vitamin D3 therapy. Compared to Group NC, 25(OH)D was significantly lower in Group DM2 and marginally lower in Group DM1. In contrast to baseline and Group DM3, 25(OH)D rose while low density lipoprotein (LDL), retinol binding protein 4 (RBP4), and HbA1c significantly lowered in Group DM4. Statistical analysis revealed that 25(OH)D had a negative correlation with RBP4, duration, HbA1c, homeostasis model assessment for insulin resistance (HOMA-IR), and fasting plasma glucose (FPG). LDL, systolic blood pressure (SBP), FPG, and smoking were risk factors of LEAD while high density lipoprotein (HDL) and 25(OH)D were protective ones. Therefore, we deduced that low level of 25(OH)D is significantly associated with the occurrence of T2DM complicated with LEAD. PMID- 25922847 TI - Impaired adipose tissue expandability and lipogenic capacities as ones of the main causes of metabolic disorders. AB - Obesity is considered a major health problem. However, mechanisms involved and its comorbidities are not elucidated. Recent theories concerning the causes of obesity have focused on a limit to the functional capacity of adipose tissue, comparing it with other vital organs. This assumption has been the central point of interest in our laboratory. We proposed that the failure of adipose tissue is initiated by the difficulty of this tissue to increase its cellularity due to excess in fat contribution, owing to genetic or environmental factors. Nevertheless, why the adipose tissue reduces its capacity to make new adipocytes via mesenchymal cells of the stroma has not yet been elucidated. Thus, we suggest that this tissue ceases fulfilling its main function, the storage of excess fat, thereby affecting some of the key factors involved in lipogenesis, some of which are reviewed in this paper (PPARgamma, ROR1, FASN, SCD1, Rab18, BrCa1, ZAG, and FABP4). On the other hand, mechanisms involved in adipose tissue expandability are also impaired, predominating hypertrophy via an increase in apoptosis and a decrease in adipogenesis and angiogenesis. However, adipose tissue failure is only part of this great orchestra, only a chapter of this nightmare. PMID- 25922848 TI - Low baseline interleukin-17A levels are associated with better treatment response at 12 weeks to tocilizumab therapy in rheumatoid arthritis patients. AB - T helper 17-related cytokines have been implicated in rheumatoid arthritis (RA) pathogenesis. The study aimed to identify cytokines associated with the treatment response of RA patients to tocilizumab (TCZ), a humanized monoclonal antibody against the interleukin- (IL-) 6 receptor. As an independent substudy of the 24 week, randomized, double-blinded CWP-TCZ301 trial of TCZ in RA patients with an inadequate response to disease-modifying antirheumatic drugs, serum levels of cytokines including tumor necrosis factor-alpha, IL-17A, IL-21, IL-23, IL-6, and soluble IL-6 receptor were measured. Baseline IL-17A levels were significantly lower in RA patients who achieved disease activity score 28 (DAS28) remission at 12 weeks of TCZ treatment, compared to patients not in remission. Patients were stratified into IL-17A low group and IL-17A high group. Significantly more patients in the IL-17A low group achieved remission as compared to the IL-17A high group (47.6 versus 17.4%, P = 0.032). DAS28 improvement was significantly better in the IL-17A low group than in the IL-17A high group at 12 weeks (P = 0.045) and 24 weeks (P = 0.046) after adjustment. Other baseline cytokines were not associated with treatment response to TCZ. The data demonstrate that low baseline IL-17A levels are associated with better clinical response to TCZ treatment in RA patients. PMID- 25922849 TI - Acceleration of wound healing by alpha-gal nanoparticles interacting with the natural anti-Gal antibody. AB - Application of alpha-gal nanoparticles to wounds and burns induces accelerated healing by harnessing the natural anti-Gal antibody which constitutes ~1% of human immunoglobulins. alpha-gal nanoparticles present multiple alpha-gal epitopes (Galalpha1-3Galbeta1-4GlcNAc-R), the carbohydrate ligand of anti-Gal. Studied alpha-gal nanoparticles were comprised of glycolipids with alpha-gal epitopes, phospholipids, and cholesterol. Binding of anti-Gal to alpha-gal nanoparticles in wounds activates the complement cascade, resulting in formation of chemotactic complement cleavage peptides that induce rapid recruitment of many macrophages. The Fc/Fcgamma receptors interaction between anti-Gal coating alpha gal nanoparticles and the recruited macrophages activates macrophages to produce cytokines/growth factors that promote wound healing and recruit stem cells. Studies of wound healing by alpha-gal nanoparticles were feasible in alpha1,3galactosyltransferase knockout mice and pigs. In contrast to other nonprimate mammals, these mice and pigs lack the alpha-gal epitope, and thus they are not immunotolerant to it and produce anti-Gal. Treatment of skin wounds and burns with alpha-gal nanoparticles resulted in 40-60% decrease in healing time in comparison with control wounds treated with saline. This accelerated healing is associated with increased recruitment of macrophages and extensive angiogenesis in wounds, faster regrowth of epidermis, and regeneration of the dermis. The accelerated healing further decreases and may completely eliminate fibrosis and scar formation in wounds. Since healing of internal injuries is mediated by mechanisms similar to those in external wound healing, it is suggested that alpha gal nanoparticles treatment may also improve regeneration and restoration of biological function following internal injuries such as surgical incisions, myocardial ischemia following infarction, and nerve injuries. PMID- 25922850 TI - Usage of neural network to predict aluminium oxide layer thickness. AB - This paper shows an influence of chemical composition of used electrolyte, such as amount of sulphuric acid in electrolyte, amount of aluminium cations in electrolyte and amount of oxalic acid in electrolyte, and operating parameters of process of anodic oxidation of aluminium such as the temperature of electrolyte, anodizing time, and voltage applied during anodizing process. The paper shows the influence of those parameters on the resulting thickness of aluminium oxide layer. The impact of these variables is shown by using central composite design of experiment for six factors (amount of sulphuric acid, amount of oxalic acid, amount of aluminium cations, electrolyte temperature, anodizing time, and applied voltage) and by usage of the cubic neural unit with Levenberg-Marquardt algorithm during the results evaluation. The paper also deals with current densities of 1 A . dm(-2) and 3 A . dm(-2) for creating aluminium oxide layer. PMID- 25922851 TI - Hybrid ontology for semantic information retrieval model using keyword matching indexing system. AB - Ontology is the process of growth and elucidation of concepts of an information domain being common for a group of users. Establishing ontology into information retrieval is a normal method to develop searching effects of relevant information users require. Keywords matching process with historical or information domain is significant in recent calculations for assisting the best match for specific input queries. This research presents a better querying mechanism for information retrieval which integrates the ontology queries with keyword search. The ontology based query is changed into a primary order to predicate logic uncertainty which is used for routing the query to the appropriate servers. Matching algorithms characterize warm area of researches in computer science and artificial intelligence. In text matching, it is more dependable to study semantics model and query for conditions of semantic matching. This research develops the semantic matching results between input queries and information in ontology field. The contributed algorithm is a hybrid method that is based on matching extracted instances from the queries and information field. The queries and information domain is focused on semantic matching, to discover the best match and to progress the executive process. In conclusion, the hybrid ontology in semantic web is sufficient to retrieve the documents when compared to standard ontology. PMID- 25922854 TI - Low Power Systolic Array Based Digital Filter for DSP Applications. AB - Main concepts in DSP include filtering, averaging, modulating, and correlating the signals in digital form to estimate characteristic parameter of a signal into a desirable form. This paper presents a brief concept of low power datapath impact for Digital Signal Processing (DSP) based biomedical application. Systolic array based digital filter used in signal processing of electrocardiogram analysis is presented with datapath architectural innovations in low power consumption perspective. Implementation was done with ASIC design methodology using TSMC 65 nm technological library node. The proposed systolic array filter has reduced leakage power up to 8.5% than the existing filter architectures. PMID- 25922853 TI - Lack of Association between rs2067474 Polymorphism in Histamine Receptor H2 Gene and Breast Cancer in Chinese Han Population. AB - Histamine H2 receptor (HRH2) was previously suggested to affect the proliferation of breast cancer cells and disease-free survival of breast cancer patients. Furthermore, a common polymorphism, rs2067474, was identified in an enhancer element of the HRH2 gene promoter and was reported to be associated with various diseases including cancer. However, the relationship between this polymorphism and breast cancer risk and malignant degree remains unclear. The aim of this study was to clarify the clinical association of rs2067474 polymorphism with breast cancer. A total of 201 unrelated Chinese Han breast cancer patients and 238 ethnicity-matched health controls were recruited and rs2067474 polymorphism was genotyped. Logistic regression analyses were performed to calculate the odds ratios (ORs) as a measure of association of genotype with breast cancer according to 3 genetic models (dominant, recessive, and additive). Although the percentage of hormone receptor negative cases tended to be higher in AA genotypes, we did not find any significant associations of rs2067474 polymorphism with breast cancer risk or with related clinicopathological parameters in the present study, which indicates that rs2067474 polymorphism of HRH2 gene might not be a risk factor in the development of breast cancer in Chinese Han population. PMID- 25922852 TI - L-lactic acid production by Lactobacillus rhamnosus ATCC 10863. AB - Lactic acid has been shown to have the most promising application in biomaterials as poly(lactic acid). L. rhamnosus ATCC 10863 that produces L-lactic acid was used to perform the fermentation and molasses was used as substrate. A solution containing 27.6 g/L of sucrose (main composition of molasses) and 3.0 g/L of yeast extract was prepared, considering the final volume of 3,571 mL (14.0% (v/v) inoculum). Batch and fed batch fermentations were performed with temperature of 43.4 degrees C and pH of 5.0. At the fed batch, three molasses feed were applied at 12, 24, and 36 hours. Samples were taken every two hours and the amounts of lactic acid, sucrose, glucose, and fructose were determined by HPLC. The sucrose was barely consumed at both processes; otherwise the glucose and fructose were almost entirely consumed. 16.5 g/L of lactic acid was produced at batch and 22.0 g/L at fed batch. Considering that lactic acid was produced due to the low concentration of the well consumed sugars, the final amount was considerable. The cell growth was checked and no substrate inhibition was observed. A sucrose molasses hydrolysis is suggested to better avail the molasses fermentation with this strain, surely increasing the L-lactic acid. PMID- 25922855 TI - Recent advances in combinatorial optimization. PMID- 25922856 TI - Fluorinated graphene dielectric films obtained from functionalized graphene suspension: preparation and properties. AB - In the present study, we have examined the interaction between a suspension of graphene in dimethylformamide and an aqueous solution of hydrofluoric acid, which was found to result in partial fluorination of suspension flakes. A considerable decrease in the thickness and lateral size of the graphene flakes (up to 1-5 monolayers in thickness and 100-300 nm in diameter) with increasing duration of fluorination treatment is found to be accompanied by a simultaneous transition of the flakes from the conducting to the insulating state. Smooth and uniform insulating films with a roughness of ~2 nm and thicknesses down to 20 nm were deposited from the suspension on silicon. The electrical and structural properties of the films suggest their use as insulating elements in thin-film nano- and microelectronic device structures. In particular, it was found that the films prepared from the fluorinated suspension display rather high breakdown voltages (field strength of (1-3) * 10(6) V cm(-1)), ultralow densities of charges in the film and at the interface with the silicon substrate in metal insulator-semiconductor structures (~(1-5) * 10(10) cm(-2)). Such excellent characteristics of the dielectric film can be compared only to well-developed SiO2 layers. The films from the fluorinated suspension are cheap, practically feasible and easy to produce. PMID- 25922857 TI - Mini-Cog for the diagnosis of Alzheimer's disease dementia and other dementias within a community setting. AB - BACKGROUND: Alzheimer's disease and related forms of dementia are becoming increasingly prevalent with the aging of many populations. The diagnosis of Alzheimer's disease relies on tests to evaluate cognition and discriminate between individuals with dementia and those without dementia. The Mini-Cog is a brief, cognitive screening test that is frequently used to evaluate cognition in older adults in various settings. OBJECTIVES: The primary objective of this review was to determine the diagnostic accuracy of the Mini-Cog for detecting Alzheimer's disease dementia and related dementias in a community setting.Secondary objectives included investigations of the heterogeneity of test accuracy in the included studies and potential sources of heterogeneity. These potential sources of heterogeneity included the baseline prevalence of dementia in study samples, thresholds used to determine positive test results, the type of dementia (Alzheimer's disease dementia or all causes of dementia), and aspects of study design related to study quality. Overall, the goals of this review were to determine if the Mini-Cog is a cognitive screening test that could be recommended to screen for cognitive impairment in community settings. SEARCH METHODS: We searched MEDLINE (OvidSP), EMBASE (OvidSP), PsycINFO (Ovid SP), Science Citation Index (Web of Science), BIOSIS previews (Web of Science), LILACS (BIREME), and the Cochrane Dementia Group's developing register of diagnostic test accuracy studies to March 2013. We used citation tracking (using the database's 'related articles' feature, where available) as an additional search method and contacted authors of eligible studies for unpublished data. SELECTION CRITERIA: We included all cross-sectional studies that utilized the Mini-Cog as an index test for the diagnosis of dementia when compared to a reference standard diagnosis of dementia using standardized dementia diagnostic criteria. For the current review we only included studies that were conducted on samples from community settings, and excluded studies that were conducted in primary care or secondary care settings. We considered studies to be conducted in a community setting where participants were sampled from the general population. DATA COLLECTION AND ANALYSIS: Information from studies meeting the inclusion criteria were extracted including information on the characteristics of participants in the studies. The quality of the studies was assessed using the QUADAS-2 criteria and summarized using risk of bias applicability and summary graphs. We extracted information on the diagnostic test accuracy of studies including the sensitivity, specificity, and 95% confidence intervals of these measures and summarized the findings using forest plots. Study specific sensitivities and specificities were also plotted in receiver operating curve space. MAIN RESULTS: Three studies met the inclusion criteria, with a total of 1620 participants. The sensitivities of the Mini-Cog in the individual studies were reported as 0.99, 0.76 and 0.99. The specificity of the Mini-Cog varied in the individual studies and was 0.93, 0.89 and 0.83. There was clinical and methodological heterogeneity between the studies which precluded a pooled meta-analysis of the results. Methodological limitations were present in all the studies introducing potential sources of bias, specifically with respect to the methods for participant selection. AUTHORS' CONCLUSIONS: There are currently few studies assessing the diagnostic test accuracy of the Mini-Cog in community settings. The limited number of studies and the methodological limitations that are present in the current studies make it difficult to provide recommendations for or against the use of the Mini-Cog as a cognitive screening test in community settings. Additional well-designed studies comparing the Mini Cog to other brief cognitive screening tests are required in order to determine the accuracy and utility of the Mini-Cog in community based settings. PMID- 25922858 TI - Treatment for preventing bleeding in people with haemophilia or other congenital bleeding disorders undergoing surgery. AB - BACKGROUND: In people with haemophilia or other congenital bleeding disorders undergoing surgical interventions, haemostatic treatment is needed in order to correct the underlying coagulation abnormalities and minimise the bleeding risk. This treatment varies according to the specific haemostatic defect, its severity and the type of surgical procedure. The aim of treatment is to ensure adequate haemostatic coverage for as long as the bleeding risk persists and until wound healing is complete. OBJECTIVES: To assess the effectiveness and safety of different haemostatic regimens (type, dose and duration, modality of administration and target haemostatic levels) administered in people with haemophilia or other congenital bleeding disorders for preventing bleeding complications during and after surgical procedures. SEARCH METHODS: We searched the Cochrane Cystic Fibrosis and Genetic Disorders Group's Coagulopathies Trials Register, compiled from electronic database searches and handsearching of journals and conference abstract books. We also searched the reference lists of relevant articles and reviews.Date of the last search: 20 November 2014. SELECTION CRITERIA: Randomised and quasi-randomised controlled trials comparing any hemostatic treatment regimen to no treatment or to another active regimen in children and adults with haemophilia or other congenital bleeding disorders undergoing any surgical intervention. DATA COLLECTION AND ANALYSIS: Two authors independently assessed trials (eligibility and risks of bias) and extracted data. Meta-analyses were performed on available and relevant data. MAIN RESULTS: Of the 16 identified trials, four (112 participants) were eligible for inclusion.Two trials evaluated 59 people with haemophilia A and B undergoing 63 dental extractions. Trials compared the use of a different type (tranexamic acid or epsilon-aminocaproic acid) and regimen of antifibrinolytic agents as haemostatic support to the initial replacement treatment. Neither trial specifically addressed mortality (one of this review's primary outcomes); however, in the frame of safety assessments, no fatal adverse events were reported. The second primary outcome of blood loss was assessed after surgery and these trials showed the reduction of blood loss and requirement of post-operative replacement treatment in people receiving antifibrinolytic agents compared with placebo. The remaining primary outcome of need for re-intervention was not reported by either trial.Two trials reported on 53 people with haemophilia A and B with inhibitors treated with different regimens of recombinant activated factor VII (rFVIIa) for haemostatic coverage of 33 major and 20 minor surgical interventions. Neither of the included trials specifically addressed any of the review's primary outcomes (mortality, blood loss and need for re-intervention). In one trial a high-dose rFVIIa regimen (90 MUg/kg) was compared with a low-dose regimen (35 MUg/kg); the higher dose showed increased haemostatic efficacy, in particular in major surgery, with shorter duration of treatment, similar total dose of rFVIIa administered and similar safety levels. In the second trial, bolus infusion and continuous infusion of rFVIIa were compared, showing similar haemostatic efficacy, duration of treatment and safety. AUTHORS' CONCLUSIONS: There is insufficient evidence from randomised controlled trials to assess the most effective and safe haemostatic treatment to prevent bleeding in people with haemophilia or other congenital bleeding disorders undergoing surgical procedures. Ideally large, adequately powered, and well-designed randomised controlled trials would be needed, in particular to address the cost effectiveness of such demanding treatments in the light of the increasing present economic constraints, and to explore the new challenge of ageing patients with haemophilia or other congenital bleeding disorders. However, performing such trials is always a complex task in this setting and presently does not appear to be a clinical and research priority. Indeed, major and minor surgeries are effectively and safely performed in these individuals in clinical practice, with the numerous national and international recommendations and guidelines providing regimens for treatment in this setting mainly based on data from observational, uncontrolled studies. PMID- 25922859 TI - Acupuncture for mumps in children. AB - BACKGROUND: Mumps is an acute, viral illness transmitted by respiratory droplets and saliva. A number of studies published in China have suggested that acupuncture is beneficial for children with mumps but the literature reporting the benefits or harms of acupuncture for mumps has not been systematically reviewed. OBJECTIVES: To determine the efficacy and safety of acupuncture for children with mumps. SEARCH METHODS: We searched CENTRAL (2014, Issue 11), MEDLINE (1950 to November week 3, 2014), EMBASE (1974 to December 2014), CINAHL (1981 to December 2014), AMED (1985 to December 2014), the Chinese BioMedical Literature Database (CBM) (1979 to November 2014), China National Knowledge Infrastructure (CNKI) (1979 to November 2014), Chinese Technology Periodical Database (CTPD) (1989 to November 2014) and Wanfang database (1982 to November 2014). We also handsearched a number of journals (from first issue to current issue). SELECTION CRITERIA: Randomised controlled trials comparing acupuncture with placebo acupuncture, no management, Chinese medication, Western medication or other treatments for mumps. Acupuncture included either traditional acupuncture or contemporary acupuncture, regardless of the source of stimulation (body, electro, scalp, fire, hand, fine needle, moxibustion). DATA COLLECTION AND ANALYSIS: Two review authors independently extracted data. We identified no trials for inclusion in this updated review. MAIN RESULTS: No study met our inclusion criteria. AUTHORS' CONCLUSIONS: We could not reach any conclusion about the efficacy and safety of acupuncture as we identified no trials for inclusion in this review. More high-quality research is needed. PMID- 25922860 TI - Antenatal lower genital tract infection screening and treatment programs for preventing preterm delivery. AB - BACKGROUND: Genital tract infection is associated with preterm birth (before 37 weeks' gestation). Screening for infections during pregnancy may therefore reduce the numbers of babies being born prematurely. However, screening for infections may have some adverse effects, such as increased antibiotic drug resistance and increased cost of treatment. OBJECTIVES: To assess the effectiveness of antenatal lower genital tract infection screening and treatment programs for reducing preterm birth and subsequent morbidity. SEARCH METHODS: We searched the Cochrane Pregnancy and Childbirth Group's Trials Register (30 November 2014), the Cochrane Central Register of Controlled Trials (The Cochrane Library 2014, Issue 7) and reference lists of retrieved reports. SELECTION CRITERIA: We included all published and unpublished randomised controlled trials in any language that evaluated any described methods of antenatal lower genital tract infection screening compared with no screening. DATA COLLECTION AND ANALYSIS: Two review authors independently assessed trials for inclusion and risk of bias, extracted data and checked for accuracy. MAIN RESULTS: One study (4155 women at less than 20 weeks' gestation) met the inclusion criteria. The intervention group (2058 women) received infection screening and treatment for bacterial vaginosis, trichomonas vaginalis and candidiasis; the control group (2097 women) also received screening, but the results of the screening program were not revealed and women received routine antenatal care. The rate of preterm birth before 37 weeks' gestation was significantly lower in the intervention group (3% versus 5% in the control group) with a risk ratio (RR) of 0.55 (95% confidence interval (CI) 0.41 to 0.75; the evidence for this outcome was graded as of moderate quality). The incidence of preterm birth for infants with a weight equal to or below 2500 g (low birthweight) and infants with a weight equal to or below 1500 g (very low birthweight) were significantly lower in the intervention group than in the control group (RR 0.48, 95% CI 0.34 to 0.66 and RR 0.34; 95% CI 0.15 to 0.75, respectively; both graded as moderate quality evidence). Based on a subset of costs for preterm births of < 1900 g, the authors reported that for each of those preterm births averted, EUR 60,262 would be saved. AUTHORS' CONCLUSIONS: There is evidence from one trial that infection screening and treatment programs for pregnant women before 20 weeks' gestation reduce preterm birth and preterm low birthweight. Infection screening and treatment programs are associated with cost savings when used for the prevention of preterm birth. Future trials should evaluate the effects of different types of infection screening programs. PMID- 25922861 TI - Antibiotic regimens for postpartum endometritis. AB - BACKGROUND: Postpartum endometritis occurs when vaginal organisms invade the endometrial cavity during the labor process and cause infection. This is more common following cesarean birth. The condition warrants antibiotic treatment. OBJECTIVES: Systematically, to review treatment failure and other complications of different antibiotic regimens for postpartum endometritis. SEARCH METHODS: We searched the Cochrane Pregnancy and Childbirth Group's Trials Register (30 November 2014) and reference lists of retrieved studies. SELECTION CRITERIA: We included randomized trials of different antibiotic regimens after cesarean birth or vaginal birth; no quasi-randomized trials were included. DATA COLLECTION AND ANALYSIS: Two review authors independently assessed trials for inclusion and risk of bias, extracted data and checked them for accuracy. MAIN RESULTS: The review includes a total of 42 trials, and 40 of these trials contributed data on 4240 participants.Regarding the primary outcomes, seven studies compared clindamycin plus an aminoglycoside versus penicillins and showed fewer treatment failures (risk ratio (RR) 0.65, 95% confidence interval (CI) 0.46 to 0.90). There were more treatment failures in those treated with an aminoglycoside plus penicillin when compared to those treated with gentamycin/clindamycin (RR 2.57, 95% CI 1.48 to 4.46). There were more treatment failures (RR 1.66, 95% CI 1.01 to 2.74) and wound infections (RR 1.88, 95% CI 1.08 to 3.28) in those treated with second or third generation cephalosporins (excluding cephamycins) versus those treated with clindamycin plus gentamycin. In four studies comparing once-daily with thrice daily dosing of gentamicin, there were fewer failures with once-daily dosing. There were more treatment failures (RR 1.94, 95% CI 1.38 to 2.72) and wound infections (RR 1.88, 95% CI 1.17 to 3.02) in those treated with a regimen with poor activity against penicillin-resistant anaerobic bacteria as compared to those treated with a regimen with good activity against penicillin-resistant anaerobic bacteria. There were no differences between groups with respect to severe complications and no trials reported any maternal deaths.Regarding the secondary outcomes, three studies that compared continued oral antibiotic therapy after intravenous therapy with no oral therapy, found no differences in recurrent endometritis or other outcomes. Four trials that compared clindamycin plus aminoglycoside versus cephalosporins identified fewer wound infections in those treated with clindamycin plus an aminoglycoside (RR 0.53, 95% CI 0.30 to 0.93). There were no differences between groups for the outcomes of allergic reactions. The overall risk of bias was unclear in the most of the studies. The quality of the evidence using GRADE comparing clindamycin and an aminoglycoside with another regimen (compared with cephalosporins or penicillins) was low to very low for therapeutic failure, severe complications, wound infection and allergic reaction. AUTHORS' CONCLUSIONS: The combination of clindamycin and gentamicin is appropriate for the treatment of endometritis. Regimens with good activity against penicillin-resistant anaerobic bacteria are better than those with poor activity against penicillin-resistant anaerobic bacteria. There is no evidence that any one regimen is associated with fewer side-effects. Following clinical improvement of uncomplicated endometritis which has been treated with intravenous therapy, the use of additional oral therapy has not been proven to be beneficial. PMID- 25922862 TI - Calcium supplementation (other than for preventing or treating hypertension) for improving pregnancy and infant outcomes. AB - BACKGROUND: Maternal nutrition during pregnancy is known to have an effect on fetal growth and development. It is recommended that women increase their calcium intake during pregnancy and lactation, although the recommended dosage varies among professionals. Currently, there is no consensus on the role of routine calcium supplementation for pregnant women other than for preventing or treating hypertension. OBJECTIVES: To determine the effect of calcium supplementation on maternal, fetal and neonatal outcomes (other than for preventing or treating hypertension) as well as any possible side effects. SEARCH METHODS: We searched the Cochrane Pregnancy and Childbirth Group's Trials Register (30th September 2014). SELECTION CRITERIA: We considered all published, unpublished and ongoing randomised controlled trials (RCTs) comparing maternal, fetal and neonatal outcomes in pregnant women who received calcium supplementation versus placebo or no treatment. Cluster-RCTs were eligible for inclusion but none were identified. Quasi-RCTs and cross-over studies were not eligible for inclusion. DATA COLLECTION AND ANALYSIS: Two review authors independently assessed trials for inclusion and risk of bias, extracted data and checked them for accuracy. MAIN RESULTS: Twenty-five studies met the inclusion criteria, but only 23 studies contributed data to the review. These 23 trials recruited 18,587 women, with 17,842 women included in final analyses. There were no statistically significant differences between women who received calcium supplementation and those who did not in terms of reducing preterm births less than 37 weeks' gestation (risk ratio (RR) 0.86, 95% confidence interval (CI) 0.70 to 1.05; 13 studies, 16,139 women; random-effects model) or less than 34 weeks' gestation (RR 1.04, 95% CI 0.80 to 1.36; four trials, 5669). Most studies were of low risk of bias. We conducted sensitivity analysis for the outcome of preterm birth less than 37 weeks by removing two trials with unclear risk of bias for allocation concealment; the results then favoured treatment with calcium supplementation (RR 0.80, 95% CI 0.65 to 0.99; 11 trials, 15,379 women). There was no significant difference in infant low birthweight between the two treatment groups (RR 0.93, 95% CI 0.81 to 1.07; six trials, 14,162 infants; random-effects model). However, when compared to the control group, women in the calcium supplementation group gave birth to slightly heavier birthweight infants (mean difference 56.40, 95% CI 13.55 to 99.25; 21 trials, 9202 women; random-effects model).Three outcomes were chosen for assessment with the GRADE software: preterm birth less than 37 weeks; preterm birth less than 34 weeks; and low birthweight less than 2500 g. Evidence for these outcomes was assessed as of moderate quality. AUTHORS' CONCLUSIONS: This review indicates that there are no clear additional benefits to calcium supplementation in prevention of preterm birth or low infant birthweight. While there was a statistically significant difference of 56 g identified in mean infant birthweight, there was significant heterogeneity identified, and the clinical significance of this difference is uncertain. PMID- 25922863 TI - Early versus late antiepileptic drug withdrawal for people with epilepsy in remission. AB - BACKGROUND: Epilepsy is a chronic neurological disorder which affects millions of people around the world. Antiepileptic drugs (AED) are the main interventions used to prevent seizures and control epilepsy. Although effective in most cases, AEDs are related to long-term adverse effects, such as cognitive and behavioural alterations. Thus when epilepsy is in remission, it may be in the individual's best interest to discontinue medication. However, the optimal timing of AED discontinuation is still unknown.This is an updated version of the original Cochrane review published in Issue 3, 2001. OBJECTIVES: (1) To quantify and compare risk of seizure recurrence, status epilepticus and mortality after early and late AED discontinuation in adult and pediatric epilepsy patients.(2) To assess which variables modify the risk of seizure recurrence.(3) To define a subpopulation in which early AED discontinuation is safe. SEARCH METHODS: We searched the Cochrane Epilepsy Group Specialised Register (June 2014); CENTRAL (Issue 5, The Cochrane Library, May 2014); MEDLINE (1946 to June 2014); CINAHL (23 June 2014); Scopus (1823 to June 2014); ClinicalTrials.gov (23 June 2014); and WHO International Clinical Trials Registry Platform (23 June 2014). We also checked the reference lists of studies found through the electronic searches. SELECTION CRITERIA: Randomised controlled trials that evaluate withdrawal of AEDs after varying periods of seizure remission in adults and children with epilepsy. Included studies compared an early AED discontinuation time (defined as a period of remission of seizures of less than two years) versus a late AED discontinuation time (defined as a period of remission of seizures of more than two years). DATA COLLECTION AND ANALYSIS: Two authors independently extracted data and assessed trial quality. Risk ratio (RR) with 95% confidence interval (CI) was calculated for each trial. Summary RRs and 95% CIs for dichotomous data were calculated using a fixed-effect model. A test of statistical heterogeneity was conducted for each pooled risk ratio calculation. Each included study underwent a 'Risk of bias' assessment, based on the Cochrane Handbook recommendations, and we examined the overall quality of information through the GRADE system, presented in two 'Summary of Findings' tables. MAIN RESULTS: Five trials were included in this review, representing 924 randomised children with epilepsy, all under 16 years of age at randomisation, with a median follow-up of 5.6 years. No eligible trial evaluated adults or assessed mortality or status epilepticus as outcomes. The pooled risk ratio for seizure relapse after AED withdrawal was 1.34 (95% CI 1.13 to 1.59, P = 0.0007). Conforming to this estimate, the number needed to harm, that is expose an individual to a higher risk of seizure relapse because of early withdrawal of AED, is 8 (95% CI 5 to 20). Early discontinuation was associated with greater relapse rates in people with partial seizures with a pooled risk ratio of 1.51 (95% CI 0.97 to 2.35, P = 0.07). Absence type epilepsy showed a lower risk of relapse. Variables associated with higher risk of seizure relapse were abnormal EEG findings (pooled RR 1.44, 95% CI 1.13 to 1.83, P = 0.003), especially epileptiform activity (RR 2.58, 95% CI 2.03 to 3.28, P < 0.0001); epilepsy onset before 2 years or after 10 years of age; history of status epilepticus; intellectual disability (IQ < 70); and high seizure frequency before and during treatment. Gender and family history did not show any significant influence over seizure relapse. Overall, the included trials were classified as low or unclear risk of bias where methodological information was not reported and could not be provided by original study authors. AUTHORS' CONCLUSIONS: There is evidence to support waiting for at least two seizure-free years before discontinuing AEDs in children, particularly if individuals have an abnormal EEG or partial seizures, or both. There is insufficient evidence to establish when to withdraw AEDs in children with generalised seizures. There is no evidence to guide the timing of withdrawal of AEDs in seizure-free adults. Further high-quality randomised controlled trials are needed, particularly recruiting adults and recruiting those with generalised seizure types, to identify the optimal timing of AED withdrawal and risk factors predictive of relapse. PMID- 25922864 TI - Effectiveness of the Valsalva Manoeuvre for reversion of supraventricular tachycardia. AB - BACKGROUND: People with the cardiac arrhythmia supraventricular tachycardia (SVT) frequently present to clinicians in the prehospital and emergency medicine settings. Restoring sinus rhythm by terminating the SVT involves increasing the refractoriness of atrioventricular nodal tissue within the myocardium by means of vagal manoeuvres, pharmacological agents, or electrical cardioversion. A commonly used first-line technique to restore the normal sinus rhythm (reversion) is the Valsalva Manoeuvre (VM). This is a non-invasive means of increasing myocardial refractoriness by increasing intrathoracic pressure for a brief period, thus stimulating baroreceptor activity in the aortic arch and carotid bodies, resulting in increased parasympathetic (vagus nerve) tone. OBJECTIVES: To assess the evidence of effectiveness of the VM in terminating SVT. SEARCH METHODS: We updated the electronic searches of the Cochrane Central Register of Controlled Trials (CENTRAL; 2014, Issue 7); MEDLINE Ovid (1946 to August week 3, 2014); EMBASE Classic and EMBASE Ovid (1947 to 27 August 2014); Web of Science (1970 to 27 August 2014); and BIOSIS Previews (1969 to 22 August 2014). We also checked trials registries, the Index to Theses, and the bibliographies of all relevant publications identified by these strategies. SELECTION CRITERIA: We included all randomised controlled trials (RCTs) that examined the effectiveness of VM in terminating SVT. DATA COLLECTION AND ANALYSIS: Two review authors independently extracted the data using a standardised form. We assessed each trial for internal validity, resolving any differences by discussion. We then extracted and entered data into Review Manager 5. MAIN RESULTS: In this update, we did not identify any new RCT studies for inclusion. We identified two RCT studies as ongoing that we are likely to include in future updates. Accordingly, our results are unchanged and include three RCTs with a total of 316 participants. All three studies compared the effectiveness of VM in reverting SVT with that of other vagal manoeuvres in a cross-over design. Two studies induced SVT within a controlled laboratory environment. Participants had ceased all medications prior to engaging in these studies. The third study reported on people presenting to a hospital emergency department with an episode of SVT. These participants were not controlled for medications or other factors prior to intervention.The two laboratory studies demonstrated reversion rates of 45.9% and 54.3%, whilst the clinical study demonstrated reversion success of 19.4%. This discrepancy may be due to methodological differences between studies, the effect of induced SVT versus spontaneous episodic SVT, and participant factors such as medications and comorbidities. We were unable to assess any of these factors, or adverse effects, further, since they were either not described in enough detail or not reported at all.Statistical pooling was not possible due to heterogeneity between the included studies. AUTHORS' CONCLUSIONS: We did not find sufficient evidence to support or refute the effectiveness of VM for termination of SVT. Further research is needed, and this research should include a standardised approach to performance technique and methodology. PMID- 25922865 TI - Group versus conventional antenatal care for women. AB - BACKGROUND: Antenatal care is one of the key preventive health services used around the world. In most Western countries, antenatal care traditionally involves a schedule of one-to-one visits with a care provider. A different way of providing antenatal care involves use of a group model. OBJECTIVES: 1. To compare the effects of group antenatal care versus conventional antenatal care on psychosocial, physiological, labour and birth outcomes for women and their babies.2. To compare the effects of group antenatal care versus conventional antenatal care on care provider satisfaction. SEARCH METHODS: We searched the Cochrane Pregnancy and Childbirth Group's Trials Register (31 October 2014), contacted experts in the field and reviewed the reference lists of retrieved studies. SELECTION CRITERIA: All identified published, unpublished and ongoing randomised and quasi-randomised controlled trials comparing group antenatal care with conventional antenatal care were included. Cluster-randomised trials were eligible, and one has been included. Cross-over trials were not eligible. DATA COLLECTION AND ANALYSIS: Two review authors independently assessed trials for inclusion and risk of bias and extracted data; all review authors checked data for accuracy. MAIN RESULTS: We included four studies (2350 women). The overall risk of bias for the included studies was assessed as acceptable in two studies and good in two studies. No statistically significant differences were observed between women who received group antenatal care and those given standard individual antenatal care for the primary outcome of preterm birth (risk ratio (RR) 0.75, 95% confidence interval (CI) 0.57 to 1.00; three trials; N = 1888). The proportion of low-birthweight (less than 2500 g) babies was similar between groups (RR 0.92, 95% CI 0.68 to 1.23; three trials; N = 1935). No group differences were noted for the primary outcomes small-for-gestational age (RR 0.92, 95% CI 0.68 to 1.24; two trials; N = 1473) and perinatal mortality (RR 0.63, 95% CI 0.32 to 1.25; three trials; N = 1943).Satisfaction was rated as high among women who were allocated to group antenatal care, but this outcome was measured in only one trial. In this trial, mean satisfaction with care in the group given antenatal care was almost five times greater than that reported by those allocated to standard care (mean difference 4.90, 95% CI 3.10 to 6.70; one study; N = 993). No differences in neonatal intensive care admission, initiation of breastfeeding or spontaneous vaginal birth were observed between groups. Several outcomes related to stress and depression were reported in one trial. No differences between groups were observed for any of these outcomes.No data were available on the effects of group antenatal care on care provider satisfaction.We used the GRADE (Grades of Recommendation, Assessment, Development and Evaluation) approach to assess evidence for seven prespecified outcomes; results ranged from low quality (perinatal mortality) to moderate quality (preterm birth, low birthweight, neonatal intensive care unit admission, breastfeeding initiation) to high quality (satisfaction with antenatal care, spontaneous vaginal birth). AUTHORS' CONCLUSIONS: Available evidence suggests that group antenatal care is positively viewed by women and is associated with no adverse outcomes for them or for their babies. No differences in the rate of preterm birth were reported when women received group antenatal care. This review is limited because of the small numbers of studies and women, and because one study contributed 42% of the women. Most of the analyses are based on a single study. Additional research is required to determine whether group antenatal care is associated with significant benefit in terms of preterm birth or birthweight. PMID- 25922866 TI - Full therapeutic engagement is less possible if patient stays are short--and getting shorter--and this conditions the kind of group on offer. PMID- 25922867 TI - Hand-held spectral-domain optical coherence tomography of small macular retinoblastoma in infants before and after chemotherapy. AB - PURPOSE: To demonstrate the utility of hand-held spectral-domain optical coherence tomography (SD-OCT) in assessing retinal structure in cases of macular retinoblastoma. METHODS: In this retrospective, observational case series, three young children with macular retinoblastoma were treated at a tertiary care hospital. At examination under anesthesia, each patient was evaluated with SD-OCT for analysis of retinal tumor and macula. The main outcomes were retinal morphology before and after chemotherapy. RESULTS: The mean patient age was 16 months (median: 9 months; range: 7 to 33 months). All patients had small exophytic macular retinoblastoma with subretinal fluid in the foveola. At presentation, the mean tumor thickness was 4.8 mm (range: 4.0 to 6.0 mm) and mean tumor base was 10.3 mm (range: 8.0 to 12.0 mm). SD-OCT documented tumor surface as smooth (n = 2) or irregular (n = 1), involvement of full-thickness retina (n = 3), and optical density as low (n = 3). The surrounding retina showed abrupt transition to tumor (n = 3), without intraretinal edema (n = 3), and with underlying subretinal fluid (n = 3). Following chemotherapy, all tumors showed regression with mean thickness of 2.6 mm (range: 2.2 to 3.0 mm). SD-OCT documented tumor surface as smooth (n = 1) or irregular (n = 2), and optical density as medium (n = 1) or high (n = 2). At the tumor site, the retina showed full-thickness disorganization but with abrupt transition to normal retina (n = 3). The foveola was anatomically intact (n = 1) or with outer retinal thinning (n = 2). Subretinal fluid was resolved in each case (n = 3). CONCLUSIONS: SD-OCT can provide precise anatomic monitoring of the macular region in infants and young children with small macular retinoblastoma. This may serve as a guide for visual potential in the preverbal child. PMID- 25922868 TI - Bilateral combined hamartomas of the retina and retinal pigment epithelium as the presenting feature of neurofibromatosis type 2 (Wishart Type). AB - An 8-week-old healthy female infant manifested leukocoria and reduced vision in the left eye. She was found to have bilateral combined hamartomas of the retina and retinal pigment epithelium. There were no other features of neurofibromatosis type 2 and brain imaging was normal. At 6 months of age, subtle posterior subcapsular lens opacity was noted in the right eye. Genetic testing for neurofibromatosis type 2 was advised but not performed. At 3 years of age, leg weakness with quadriceps atrophy led to neuroimaging and detection of multiple tumors, including bilateral vestibular schwannomas and cervical, thoracic, and lumbar paraspinal schwannomas. Molecular testing revealed a nonsense mutation in the neurofibromatosis type 2 gene. Bilateral combined hamartomas were the presenting feature of a severe phenotype of neurofibromatosis type 2. PMID- 25922869 TI - Atorvastatin treatment increases plasma bilirubin but not HMOX1 expression in stable angina patients. AB - BACKGROUND: In vitro and animal studies indicate that statins increase heme oxygenase-1 gene (HMOX1) expression, which then, presumably, increases plasma bilirubin concentration. However, clinical confirmation that statins concomitantly increase HMOX1 expression and plasma bilirubin concentration is lacking. We hypothesized that in patients with stable angina atorvastatin therapy (20 mg/day for 10 weeks) concomitantly increases total bilirubin concentration and HMOX1 expression, as assessed non-invasively by plasma analysis. METHODS: In 44 patients with stable angina plasma concentrations of total bilirubin, HMOX1 mRNA and HMOX1 protein were measured before and after the statin treatment, as well as plasma concentrations of oxidized low-density lipoprotein (OxLDL), malondialdehyde (MDA), monocyte chemoattractant protein (MCP-1) and C-reactive protein (CRP). RESULTS: Atorvastatin treatment increased total bilirubin concentration (median 6.95 MUmol/L vs. 8.55, + 23.02%; p < 0.001), but did not change plasma HMOX1 mRNA and HMOX1 protein concentrations. Plasma concentrations of OxLDL (- 31.85%, p < 0.001), MCP-1 (- 16.20%, p = 0.020) and CRP (- 7.32%, p = 0.010) were decreased but MDA was not decreased (15.32%, p = 0.107). Within subjects, increment of plasma bilirubin concentration did not correlate with the changes in HMOX1 mRNA and protein concentrations, but correlated with low-density lipoprotein cholesterol decrement (r = - 0.374, p = 0.012). Bilirubin increment did not correlate with the changes in oxidative and inflammatory markers. CONCLUSION: Our prospective observational trial finally confirms that atorvastatin (20 mg/day for 10 weeks) increases plasma total bilirubin concentration. However, it seems that this effect is HMOX1-independent. PMID- 25922870 TI - MnOx/Graphene for the Catalytic Oxidation and Adsorption of Elemental Mercury. AB - MnOx/graphene composites were prepared and employed to enhance the performance of manganese oxide (MnOx) for the capture of elemental mercury (Hg(0)) in flue gas. The composites were characterized using FT-IR, XPS, XRD, and TEM, and the results showed that the highly dispersed MnOx particles could be readily deposited on graphene nanosheets via hydrothermal process described here. Graphene appeared to be an ideal support for MnOx particles and electron transfer channels in the catalytic oxidation of Hg(0) at a high efficiency. Thus, MnOx/graphene-30% sorbents exhibited an Hg(0) removal efficiency of greater than 90% at 150 degrees C under 4% O2, compared with the 50% removal efficiency of pure MnOx. The mechanism of Hg(0) capture is discussed, and the main Hg(0) capture mechanisms of MnOx/graphene were catalytic oxidation and adsorption. Mn is the main active site for Hg(0) catalytic oxidation, during which high valence Mn (Mn(4+) or Mn(3+)) is converted to low valence Mn (Mn(3+) or Mn(2+)). Graphene enhanced the electrical conductivity of MnOx, which is beneficial for catalytic oxidation. Furthermore, MnOx/graphene exhibited an excellent regenerative ability, and is a promising sorbent for capturing Hg(0). PMID- 25922871 TI - Cardioprotective role of G-Protein Coupled Estrogen Receptor 1 (GPER1). AB - G-Protein Coupled Estrogen Receptor 1 (GPER1), also known as G-Protein Coupled Receptor 30 (GPR30) and initially considered an orphan receptor, has become one of the most important pharmacological targets in cardiovascular research. Since the gene encoding this putative receptor was cloned nearly 20 years ago, researchers have addressed its role in various aspects of physiology, including cardioprotection. Although extensive research has been carried out to understand the role of GPER1 as a pharmacological target to treat cardiovascular diseases, there are few current reviews addressing the overall cardioprotective benefits of this receptor and the signaling intermediates involved. This review considers the origins of GPER1, its cell biology, its physiological and pharmacological roles as a therapeutic target in cardiovascular disease, and what future research on GPER1 might entail. More specifically, the review focuses on GPER1 regulation of Angiotensin Type I Receptor (AT1R) and the role of estrogen receptors, epidermal growth factor receptor (EGFR) and matrix metalloproteinases (MMPs) in bringing about the cardioprotective effects of GPER1. Areas where improved knowledge of GPER1 biology is still needed to better understand the receptor's cardioprotective effects are also discussed. PMID- 25922872 TI - Analysis of the effect of design parameters and their interactions on the strength of dental restorations with endodontic posts, using finite element models and statistical analysis. AB - Many previous studies, both in vitro and with model simulations, have been conducted in an attempt to reach a full understanding of how the different design parameters of an endodontically restored tooth affect its mechanical strength. However, differences in the experimental set-up or modelling conditions and the limited number of parameters studied in each case prevent us from obtaining clear conclusions about the real significance of each parameter. In this work, a new approach is proposed for this purpose based on the combination of a validated three-dimensional parametric biomechanical model of the restored tooth and statistical analysis using full factorial analysis of variance. A two-step approach with two virtual tests (with, respectively, 128 and 81 finite element models) was used in the present work to study the effect of several design parameters on the strength of a restored incisor, using full factorial designs. Within the limitations of this study, and for cases where the parameters are within the ranges that were tested, the conclusions indicate that the material of the post is the most significant factor as far as its strength is concerned, the use of a low Young's modulus being preferable for this component. Once the post material has been chosen, the geometry of the post is of less importance than the Young's modulus selected for the core or, especially, for the crown. PMID- 25922873 TI - Stress and Spirituality on the Depressive Symptoms of Older Adults in Assisted Living: Gender Differences. AB - In this study the authors explore the effects of stress and spirituality on the depressive symptoms of 92 older adult men and 224 older adult women who reside in assisted living facilities. Hierarchical regression reveals that stress was related to increases in depressive symptoms. The stress of women was more strongly associated with depressive symptoms than found among men. In contrast, spiritual coping was associated with a decrease in depressive symptoms among all older adults in assisted living. The spiritual coping of older adult women was not a significant predictor of decreased depressive symptoms. Through this study the authors support the use of spiritual interventions to alleviate depressive symptoms experienced by older adults in assisted living. PMID- 25922878 TI - Cracking the Si Shell Growth in Hexagonal GaP-Si Core-Shell Nanowires. AB - Semiconductor nanowires have increased the palette of possible heterostructures thanks to their more effective strain relaxation. Among these, core-shell heterostructures are much more sensitive to strain than axial ones. It is now accepted that the formation of misfit dislocations depends both on the lattice mismatch and relative dimensions of the core and the shell. Here, we show for the first time the existence of a new kind of defect in core-shell nanowires: cracks. These defects do not originate from a lattice mismatch (we demonstrate their appearance in an essentially zero-mismatch system) but from the thermal history during the growth of the nanowires. Crack defects lead to the development of secondary defects, such as type-I1 stacking faults and Frank-type dislocations. These results provide crucial information with important implications for the optimized synthesis of nanowire-based core-shell heterostructures. PMID- 25922879 TI - A Pilot Study To Define Chemical Coping in Cancer Patients Using the Delphi Method. AB - BACKGROUND: "Chemical coping" is a commonly used term in the pain and palliative care literature, but is heterogeneously defined. We conducted a Delphi survey among palliative care and pain specialists internationally to identify a consensus definition for "chemical coping with opioids" and warning signs for chemical coping. METHODS: This Delphi survey consisted of two rounds on the following: (1) concepts and definition related to chemical coping, (2) warning signs for chemical coping, and (3) demographics. Consensus in this study was defined as agreement by a minimum of 70% of the experts. RESULTS: Participating in the first round were 14/19 (74%) physicians; 12/14 (86%) participated in the second round. The international experts reached the following consensus definition for chemical coping with opioids (92% agreement): "The use of opioids to cope with emotional distress, characterized by inappropriate and/or excessive opioid use." They also identified depression (consensus 93%); psychiatric disease (86%); a history of substance abuse (86%); a positive score for the Cut-down, Annoyed, Guilty, and Eye-opener (CAGE) alcoholism screening test (79%); a history of alcoholism (79%); and a history of smoking (71%) as important warning signs for chemical coping. CONCLUSION: Our expert panel reached a consensus definition for chemical coping and related warning signs, which may help clinicians and researchers to identify patients at risk of opioid misuse. PMID- 25922881 TI - Breast cancer diagnosis: biographical disruption, emotional experiences and strategic management in Thai women with breast cancer. AB - In this article we draw on Bury's theory of biographical disruption to discuss the meanings of, and emotional experiences related to, being diagnosed with breast cancer among southern Thai women. Qualitative methods, including in-depth interviewing and drawing methods, were used to collect data from 20 women with breast cancer. The women perceived breast cancer to be a rhok raai; an evil or dread disease. They believed that breast cancer would lead to death. The disruption in their biography occurred when they detected abnormalities indicating breast cancer. The women's narratives revealed their chaotic lives upon this diagnosis and the news precipitated in them shock, fear, anxiety and loss of hope. Although they experienced chaos and disruption, the women cultivated strategies that helped them cope with their experiences by accepting their fate and adhering to Buddhist beliefs and practices. Through their narratives of biographical disruption, the women in our study offer healthcare providers knowledge that could lead to an appreciation of their needs and concerns. This knowledge is crucial for health professionals who wish to provide emotional support to women who have been diagnosed with breast cancer in Thailand and elsewhere. PMID- 25922880 TI - Prevalence of HLA-B*57:01 allele in Argentinean HIV-1 infected patients. AB - Hypersensitivity reaction to abacavir (ABC hypersensitivity syndrome, AHS) is strongly associated with the presence of the HLA-B*57:01 allele. This study was designed to estimate the prevalence of HLA-B*57:01 allele in Argentinean HIV-1 infected patients. We analyzed the presence of HLA-B*57:01 allele in 1646 HIV-1 infected patients from different regions of Argentina. This allele was detected in 81 patients; most of them corresponded to patients living in the central region of the country. The prevalence of HLA-B*57:01 was 4.9%, similar to other Caucasian populations and higher than other data reported for South American populations. This strongly supports screening for the presence of HLA-B*57:01 in abacavir treatment of HIV-1 in our country. PMID- 25922882 TI - Susceptibility-weighted imaging in acute-stage pediatric convulsive disorders. AB - BACKGROUND: The aim of this preliminary study was to investigate the clinical use of acute-stage susceptibility-weighted imaging (SWI) in children with prolonged convulsive disorder. METHODS: Ten children with prolonged convulsive disorder who underwent SWI within 2 h after termination of seizure (acute-stage SWI group) and 15 control children who underwent SWI > 2 h after their seizures terminated or for other purposes were enrolled. The cerebral venous vasculature was compared between the groups. The acute-stage SWI group was further divided into three subgroups: normal group, those with regional low signals in the cerebral veins (regional group) and those with diffuse low signals in the cerebral veins (generalized group). Inter-ictal electroencephalography (EEG) and venous blood gas findings during seizure activity were compared between these subgroups. RESULTS: All patients in the acute-stage SWI group had low cerebral vein signal. Four patients were assigned to the regional group and six patients to the generalized group. Decrease of venous pH and the increase of venous pCO2 during seizure activity was more prominent in the regional group than in the generalized group. In the regional group, low-signal areas in the cerebral veins were consistent with abnormal areas on EEG; these low-signal areas resolved completely in all patients on follow-up SWI. Ten patients in the control group had normal SWI, and five had a generalized low signal. CONCLUSIONS: Acute-stage SWI may be a useful alternative for identifying lateralization of seizures in children with prolonged convulsive disorder. PMID- 25922883 TI - Rapid generation of endogenously driven transcriptional reporters in cells through CRISPR/Cas9. AB - CRISPR/Cas9 technologies have been employed for genome editing to achieve gene knockouts and knock-ins in somatic cells. Similarly, certain endogenous genes have been tagged with fluorescent proteins. Often, the detection of tagged proteins requires high expression and sophisticated tools such as confocal microscopy and flow cytometry. Therefore, a simple, sensitive and robust transcriptional reporter system driven by endogenous promoter for studies into transcriptional regulation is desirable. We report a CRISPR/Cas9-based methodology for rapidly integrating a firefly luciferase gene in somatic cells under the control of endogenous promoter, using the TGFbeta-responsive gene PAI 1. Our strategy employed a polycistronic cassette containing a non-fused GFP protein to ensure the detection of transgene delivery and rapid isolation of positive clones. We demonstrate that firefly luciferase cDNA can be efficiently delivered downstream of the promoter of the TGFbeta-responsive gene PAI-1. Using chemical and genetic regulators of TGFbeta signalling, we show that it mimics the transcriptional regulation of endogenous PAI-1 expression. Our unique approach has the potential to expedite studies on transcription of any gene in the context of its native chromatin landscape in somatic cells, allowing for robust high throughput chemical and genetic screens. PMID- 25922884 TI - Top-down Targeted Metabolomics Reveals a Sulfur-Containing Metabolite with Inhibitory Activity against Angiotensin-Converting Enzyme in Asparagus officinalis. AB - The discovery of bioactive natural compounds containing sulfur, which is crucial for inhibitory activity against angiotensin-converting enzyme (ACE), is a challenging task in metabolomics. Herein, a new S-containing metabolite, asparaptine (1), was discovered in the spears of Asparagus officinalis by targeted metabolomics using mass spectrometry for S-containing metabolites. The contribution ratio (2.2%) to the IC50 value in the crude extract showed that asparaptine (1) is a new ACE inhibitor. PMID- 25922885 TI - Occurrence of Bisphenol A Diglycidyl Ethers (BADGEs) and Novolac Glycidyl Ethers (NOGEs) in Archived Biosolids from the U.S. EPA's Targeted National Sewage Sludge Survey. AB - Epoxy resins incorporating bisphenol A diglycidyl ether (BADGE) and novolac glycidyl ether (NOGE) are used in a wide range of applications, including adhesives, structural and electrical laminates. However, little is known about the occurrence of BADGE, NOGE, and their derivatives in the environment. Using liquid chromatography-tandem mass spectrometry, BADGE, bisphenol F glycidyl ether (BFDGE), 3-ring NOGE, and eight of their derivatives (BADGE.2 H2O, BADGE.H2O, BADGE.HCl.H2O, BADGE.2 HCl, BADGE.HCl, BFDGE.2 H2O, and BFDGE.2 HCl) were determined in archived biosolid samples collected from 68 wastewater treatment plants (WWTPs) from the northeastern, midwestern, western, and southern regions of the USA. BADGE.2 H2O was the most frequently detected (DR = 99%) and the most abundant compound found (median: 93.6 ng/g dry weight [dw]) in this family. The highest total concentrations of target chemicals, ranging from 83.6 to 2490 ng/g dw, were found in biosolids collected from the northeastern United States. The sum of geometric mean (GM) concentration of BADGE, NOGE, and their derivatives in biosolids increased with the treatment capacity of WWTPs. Based on the measured concentrations in biosolids and predicted mass in wastewater, it was estimated that approximately 3.5% of the total production of BADGEs was emitted through WWTP discharges. PMID- 25922886 TI - International Collegium of Rehabilitative Audiology (ICRA) recommendations for the construction of multilingual speech tests. ICRA Working Group on Multilingual Speech Tests. AB - OBJECTIVE: To provide guidelines for the development of two types of closed-set speech-perception tests that can be applied and interpreted in the same way across languages. The guidelines cover the digit triplet and the matrix sentence tests that are most commonly used to test speech recognition in noise. They were developed by a working group on Multilingual Speech Tests of the International Collegium of Rehabilitative Audiology (ICRA). DESIGN: The recommendations are based on reviews of existing evaluations of the digit triplet and matrix tests as well as on the research experience of members of the ICRA Working Group. They represent the results of a consensus process. RESULTS: The resulting recommendations deal with: Test design and word selection; Talker characteristics; Audio recording and stimulus preparation; Masking noise; Test administration; and Test validation. CONCLUSIONS: By following these guidelines for the development of any new test of this kind, clinicians and researchers working in any language will be able to perform tests whose results can be compared and combined in cross-language studies. PMID- 25922888 TI - Molecular dynamics simulation study of the association of lidocainium docusate and its derivatives in aqueous solution. AB - Ionic liquid active pharmaceutical ingredients (IL APIs) are novel materials in which the ions themselves are APIs, but the pure salt is a liquid under ambient conditions. It has been found that IL APIs can have superior performance relative to their conventional salt analogues, but the mechanism for this is unclear. We have used molecular simulations to estimate the aqueous phase association constants of the IL API lidocainium docusate and their sodium and chloride counterparts. Lidocainium is the cationic form of lidocaine, a local anesthetic, while the docusate anion is an emollient. From strongest to weakest, the calculated association constants are 10.1 M(-1) (lidocainium docusate); 0.77 M( 1) (sodium chloride); 0.086 M(-1) (sodium docusate); and 0.065 M(-1) (lidocainium chloride). These results suggest that the experimentally observed enhanced efficacy of lidocainium docusate relative to the traditional drug formulation as a lidocaine hydrochloride salt could result from association of the ions in aqueous solution and at the cell membrane, leading to a synergistic activity effect. PMID- 25922889 TI - Loss of RNA-binding motif protein 3 expression is associated with right-sided localization and poor prognosis in colorectal cancer. AB - AIMS: RNA-binding motif protein 3 (RBM3) has recently been suggested as a prognostic biomarker in an array of human cancers. This study aimed to examine its effects in colorectal cancers. METHODS AND RESULTS: RBM3 expression was analysed by immunohistochemistry on a tissue microarray containing 1800 colorectal cancers (CRCs). Nuclear RBM3 immunohistochemical staining was found in 95.9% of all interpretable CRCs. Loss of RBM3 expression was linked to advanced tumour stage (P < 0.0001), right-sided tumour localization (P < 0.0001), and poor prognosis (P = 0.0003). In a multivariable analysis including RBM3 staining, tumour grade, tumour stage, and nodal status, only tumour stage and nodal status proved to be independent prognostic markers (P < 0.0001 each), whereas the prognostic impact of RBM3 staining was not significant (P = 0.2655). CONCLUSIONS: Our observations indicate that loss of RBM3 expression is an unfavourable prognostic marker in CRC, and is linked to right-sided tumour localization. PMID- 25922891 TI - Cardiopulmonary resuscitation and postresuscitation care 2015: saving more than 200 000 additional lives per year worldwide. PMID- 25922892 TI - Airway management during cardiopulmonary resuscitation. AB - PURPOSE OF REVIEW: This article evaluates the latest scientific evidence regarding airway management during in-hospital and out-of-hospital cardiopulmonary resuscitation (CPR). RECENT FINDINGS: In the in-hospital setting, observational research suggested that the quality of CPR using 'no flow ratio' as a surrogate marker was improved when advanced airway techniques were used. A registry study demonstrated that an initial failed intubation attempt was associated with an average delay of 3 min in time to return of spontaneous circulation. A prospective observational study showed that the Glide Scope videolaryngoscope was associated with a first-pass success rate of 93%, with no differences between less and more experienced physicians. In the out-of-hospital setting, a registry study suggested that intubation leads to a better outcome compared with supraglottic airway devices. However, no advanced airway devices showed a better outcome than basic airway techniques. An observational study reported that the i-gel supraglottic airway device offers a first-pass insertion success rate of 90%, and was easier to establish than the Portex Soft Seal laryngeal mask airway. Other out-of-hospital observational studies showed that the laryngeal tube offers a lower first-pass insertion success rate than expected, and complications of this device may influence later definitive airway management and the outcome as a whole. SUMMARY: Recent studies of airway management during CPR rely mostly on registry and observational designs. Prospective randomized trials are needed to determine the optimal approach to airway management during cardiac arrest, but have not yet been completed. PMID- 25922893 TI - Temperature management after cardiac arrest. AB - PURPOSE OF REVIEW: Temperature management for patients comatose after cardiac arrest has been an integral component of postcardiac arrest care for the last decade. In this review, we present recent findings and discuss implications for future trials. RECENT FINDINGS: The two largest trials on temperature management after cardiac arrest were recently presented. The first investigated prehospital induction of hypothermia using ice-cold intravenous saline in 1364 patients. The intervention gave a significant reduction in time from return of circulation to start of hypothermia and lower body temperature on admission to hospital. There was no difference in survival or neurological function between the study groups, but there were indications of possible harm in the group that received saline. The second trial investigated two actively controlled temperatures provided in intensive care units, randomizing 950 unconscious patients suffering out-of hospital cardiac arrest of a presumed cardiac cause to targeted temperature management at 33 and 36 degrees C. There was no difference in survival until end of trial or neurological function at 180 days. SUMMARY: Prehospital hypothermia induced by cold crystalloid infusion does not benefit cardiac arrest patients. For patients treated in an intensive care unit targeting a temperature of 36 degrees C provides similar results as targeting 33 degrees C. PMID- 25922895 TI - 'Kids save lives': why schoolchildren should train in cardiopulmonary resuscitation. AB - PURPOSE OF REVIEW: Quick initiation of basic life support (BLS) by laypersons is one of the most successful strategies in the fight against sudden cardiac death. In developed countries, cardiac arrest is still a major contributor to avoidable death, and despite the fact that more than 50% of all cardiac arrests are witnessed, layperson BLS is performed in less than 20%. To improve this situation, BLS training in schools has been established. RECENT FINDINGS: Cardiopulmonary resuscitation (CPR) instruction including the use of automatic external defibrillators (AEDs) has shown to be feasible even for young schoolchildren, and there is an indication that respective programmes are effective to enhance patient outcome on a population basis. Earlier training may even lead to more sustainable results; however, it is reasonable to implement adjusted curricula for different child ages. The programme 'Kids Save Lives' recently endorsed by the WHO will help promoting school-based BLS training worldwide demanding education on CPR for all pupils starting at least at age 12. SUMMARY: Resuscitation training in schools can help to increase the amount of BLS trained population. Social skills of pupils can be improved and training can be successfully implemented independently of the pupils' age and physique. PMID- 25922896 TI - The accuracy of noninvasive cardiac output and pressure measurements with finger cuff: a concise review. AB - PURPOSE OF REVIEW: The present review aims to summarize literature on the accuracy of the finger cuff method to measure cardiac output (CO) and blood pressure, its ability to track hemodynamic changes, and to predict fluid responsiveness. RECENT FINDINGS: Finger cuff is an easy-to-use hemodynamic monitoring technique. Different devices are currently available, which provide continuous arterial blood pressure (Finapress), whereas only ClearSight (previously known as Nexfin; BMEYE) provides an estimate of CO. In most studies, the criteria for clinical interchangeability (for CO) were not met, when compared with the currently used invasive monitoring systems such as uncalibrated CO via a radial artery line, and calibrated CO either via a pulmonary artery catheter or a femoral artery catheter connected to the PiCCO (Pulsion Medical Systems) or VolumeView (Edwards Lifesciences) devices. In particular, ClearSight obtained CO seems to be less accurate in patients with a low CO. However, in most patients, ClearSight is able to track hemodynamic changes induced by a fluid challenge or passive leg raising test. We will discuss in this review the relevant literature with regard to validation of the finger cuff technique for both arterial blood pressure and CO. SUMMARY: The finger cuff method provides a reasonable estimate of CO and blood pressure, which does not meet the criteria for clinical interchangeability with the currently used invasive devices. PMID- 25922898 TI - Nonlinear rheology of glass-forming colloidal dispersions: transient stress strain relations from anisotropic mode coupling theory and thermosensitive microgels. AB - Transient stress-strain relations close to the colloidal glass transition are obtained within the integration through transients framework generalizing mode coupling theory to flow driven systems. Results from large-scale numerical calculations are quantitatively compared to experiments on thermosensitive microgels, which reveals that theory captures the magnitudes of stresses semi quantitatively even in the nonlinear regime, but overestimates the characteristic strain where plastic events set in. The former conclusion can also be drawn from flow curves, while the latter conclusion is supported by a comparison to single particle motion measured by confocal microscopy. The qualitative picture, as previously obtained from simplifications of the theory in schematic models, is recovered by the quantitative solutions of the theory for Brownian hard spheres. PMID- 25922894 TI - Neurological prognostication after cardiac arrest. AB - PURPOSE OF REVIEW: Prediction of neurological prognosis in patients who are comatose after successful resuscitation from cardiac arrest remains difficult. Previous guidelines recommended ocular reflexes, somatosensory evoked potentials and serum biomarkers for predicting poor outcome within 72 h from cardiac arrest. However, these guidelines were based on patients not treated with targeted temperature management and did not appropriately address important biases in literature. RECENT FINDINGS: Recent evidence reviews detected important limitations in prognostication studies, such as low precision and, most importantly, lack of blinding, which may have caused a self-fulfilling prophecy and overestimated the specificity of index tests. Maintenance of targeted temperature using sedatives and muscle relaxants may interfere with clinical examination, making assessment of neurological status before 72 h or more after cardiac arrest unreliable. SUMMARY: No index predicts poor neurological outcome after cardiac arrest with absolute certainty. Prognostic evaluation should start not earlier than 72 h after ROSC and only after major confounders have been excluded so that reliable clinical examination can be made. Multimodality appears to be the most reasonable approach for prognostication after cardiac arrest. PMID- 25922899 TI - The theory behind, and the challenges of, conserving nature's stage in a time of rapid change. AB - Most conservation planning to date has focused on protecting today's biodiversity with the assumption that it will be tomorrow's biodiversity. However, modern climate change has already resulted in distributional shifts of some species and is projected to result in many more shifts in the coming decades. As species redistribute and biotic communities reorganize, conservation plans based on current patterns of biodiversity may fail to adequately protect species in the future. One approach for addressing this issue is to focus on conserving a range of abiotic conditions in the conservation-planning process. By doing so, it may be possible to conserve an abiotically diverse "stage" upon which evolution will play out and support many actors (biodiversity). We reviewed the fundamental underpinnings of the concept of conserving the abiotic stage, starting with the early observations of von Humboldt, who mapped the concordance of abiotic conditions and vegetation, and progressing to the concept of the ecological niche. We discuss challenges posed by issues of spatial and temporal scale, the role of biotic drivers of species distributions, and latitudinal and topographic variation in relationships between climate and landform. For example, abiotic conditions are not static, but change through time-albeit at different and often relatively slow rates. In some places, biotic interactions play a substantial role in structuring patterns of biodiversity, meaning that patterns of biodiversity may be less tightly linked to the abiotic stage. Furthermore, abiotic drivers of biodiversity can change with latitude and topographic position, meaning that the abiotic stage may need to be defined differently in different places. We conclude that protecting a diversity of abiotic conditions will likely best conserve biodiversity into the future in places where abiotic drivers of species distributions are strong relative to biotic drivers, where the diversity of abiotic settings will be conserved through time, and where connectivity allows for movement among areas providing different abiotic conditions. PMID- 25922901 TI - Cell signalling: Double duty for Dishevelled. PMID- 25922900 TI - Human umbilical cord mesenchymal stem cell transplantation restores damaged ovaries. AB - Ovarian injury because of chemotherapy can decrease the levels of sexual hormones and potentia generandi of patients, thereby greatly reducing quality of life. The goal of this study was to investigate which transplantation method for human umbilical cord mesenchymal stem cells (HUMSCs) can recover ovarian function that has been damaged by chemotherapy. A rat model of ovarian injury was established using an intraperitoneal injection of cyclophosphamide. Membrane-labelled HUMSCs were subsequently injected directly into ovary tissue or tail vein. The distribution of fluorescently labelled HUMSCs, estrous cycle, sexual hormone levels, and potentia generandi of treated and control rats were then examined. HUMSCs injected into the ovary only distributed to the ovary and uterus, while HUMSCs injected via tail vein were detected in the ovary, uterus, kidney, liver and lung. The estrous cycle, levels of sex hormones and potentia generandi of the treated rats were also recovered to a certain degree. Moreover, in some transplanted rats, fertility was restored and their offspring developed normally. While ovary injection could recover ovarian function faster, both methods produced similar results in the later stages of observation. Therefore, our results suggest that transplantation of HUMSCs by tail vein injection represents a minimally invasive and effective treatment method for ovarian injury. PMID- 25922902 TI - 'People form their own support systems - like forming their own families': the role of parents and friends in the first year at dental school. AB - Most students experience the transition from school to university as challenging. Students from backgrounds with little or no experience of higher education are most vulnerable in the transition, and most at risk of academic failure or early departure. This study examined the role that parents and friends play in the transition to university and in the first academic year. The study examines the mechanisms of this support so as to understand the ways in which support is provided. It examines whether - and if so, how - support mechanisms differed for first-generation students and those with family familiarity of university. Data were collected through focus group and individual interviews with dentistry students in their first and second academic years at a Faculty of Dentistry in South Africa. Concepts from psychology literature - attachment and friendship quality - provided the analytical framework. Findings from the study suggest that the social relationships which students have access to during the transition and the first academic year have the potential to provide emotional resources which ease transition and practical information about appropriate ways of being and doing at university. First-generation university students are less likely to have access to the latter because their parents have no experience of university. The study concludes with suggestions for ways in which universities and their teachers might provide support for all first-year students. PMID- 25922903 TI - Evaluation of the Efficacy, Safety, and Tolerability of 3 Dose Regimens of Topical Sodium Nitrite With Citric Acid in Patients With Anogenital Warts: A Randomized Clinical Trial. AB - IMPORTANCE: Anogenital warts are a common disorder associated with significant physical and mental distress and a substantial cause of health care costs. OBJECTIVE: To assess the efficacy of the topical application of nitric oxide delivered using acidified nitrite. DESIGN, SETTING, AND PARTICIPANTS: A multicenter, randomized, controlled, dose-ranging clinical trial was conducted in European genitourinary medicine clinics between December 20, 2001, and January 14, 2003. Analysis was by intent to treat for all individuals initiating therapy. Participants included male and female volunteers older than 18 years with between 2 and 50 external anogenital warts. A total of 299 individuals from 40 centers were randomized to a control arm and a treatment arm that received 3 doses of acidified nitrite applied topically for 12 weeks with an additional 12 weeks of follow-up, with the final follow-up visit on January 14, 2003. INTERVENTIONS: Placebo nitrite cream and placebo citric acid cream were applied twice daily. Active treatment was divided as low dose (sodium nitrite, 3%, with citric acid, 4.5%, creams applied twice daily), middle dose (sodium nitrite, 6%, with citric acid, 9%, creams applied once daily at night, with placebo applied in the morning), and high dose (sodium nitrite, 6%, with citric acid, 9%, creams applied twice daily). MAIN OUTCOMES AND MEASURES: The primary outcome was proportion of patients with complete clinical clearance of target warts; secondary outcomes were reduction in target wart area and safety. RESULTS: Complete clinical clearance at 12 weeks occurred in 10 of 74 patients (14%; 95% CI, 6%-21%) with placebo; 11 of 72 (15%; 95% CI, 7%-24%) with low-dose treatment; 17 of 74 (23%; 95% CI, 13%-33%) with middle-dose treatment; and 22 of 70 (31%; 95% CI, 21%-42%) with high-dose treatment (P = .01). Reduction in target wart area, time to clearance, and patient and investigator assessments supported the superiority of the high-dose therapy vs placebo. There were no systemic or serious adverse events associated with treatment. However, there was a dose-related increase in itching, pain, edema, and staining of the anogenital skin associated with the active treatment. Overall, 21 patients withdrew from active treatment because of adverse events compared with none using placebo. CONCLUSIONS AND RELEVANCE: Use of sodium nitrite, 6%, with citric acid, 9%, twice daily is more effective than placebo in the treatment of anogenital warts. Treatment was associated with local irritant adverse effects. TRIAL REGISTRATION: clinicaltrials.gov Identifier: NCT02015260. PMID- 25922904 TI - Hypertension guidelines: Evidence-based treatments for maintaining blood pressure control. AB - Approximately one in three adults in the United States has hypertension. This article provides an update on the latest JNC-8 guideline for treating hypertension in adults. Emphasis is placed on new and updated information and implications for primary care clinicians to help patients achieve and maintain better blood pressure control. PMID- 25922905 TI - Fall prevention in older adults. AB - Falls in older adults are a major public health concern and can often have fatal results. Practitioners need to be aware of assessment and diagnostic techniques to prevent falls in older adults. PMID- 25922906 TI - Anionic coordination complexes of C60 and C70 with cyclopentadienyl and pentamethylcyclopentadienyl molybdenum dicarbonyl. AB - Crystalline anionic coordination complexes (PPN(+)){CpMo(CO)2(eta(2)-C60)}(-) (), (PPN(+)){CpMo(CO)2(eta(2)-C70)}(-).0.5C6H14 () and (PPN(+)){Cp*Mo(CO)2(eta(2) C60)}(-).C6H5CN.C6H4Cl2 () containing cyclopentadienyl (, ) and pentamethylcyclopentadienyl () molybdenum dicarbonyl eta(2)-coordinated to fullerenes have been obtained by the reaction of the (PPN(+))(fullerene(-)) salt with the {Cp(*)Mo(CO)3(2)}2 dimers (PPN(+) is bis(triphenylphosphoranylidene)ammonium cation). The {CpMo(CO)2(eta(2)-C60(70))}( ) anions contain neutral C60 and C70. The optical properties and geometry of the CpMo(CO)2 moieties in and are similar to those in (PPN(+)){CpMo(0)(CO)3}(-). The analysis of optical data for shows that eta(2)-coordinated C60 molecules are more negatively charged in than in and . Complexes show weak EPR signals indicating that the major part of the samples is EPR silent and diamagnetic. Diamagnetism of the anions in is explained by the chemical bond formation between the initially paramagnetic CpMo(I)(CO)2 and (fullerene)(-) units. The DFT calculations for and support the diamagnetic singlet ground state for both complexes, in which the singlet-triplet energy gaps calculated at the M11/cc-pVTZ-PP/cc-pVDZ level of theory are about 1.27 and 0.95 eV, respectively. According to the calculations, C60 molecules are more negatively charged in than in and that can be explained by stronger back donation from the molybdenum moieties to fullerenes. PMID- 25922907 TI - Effect of BRAF mutational status on expression profiles in conventional papillary thyroid carcinomas. AB - BACKGROUND: Whereas 40 % to 70 % of papillary thyroid carcinomas (PTCs) are characterized by a BRAF mutation (BRAFmut), unified biomarkers for the genetically heterogeneous group of BRAF wild type (BRAFwt) PTCs are not established yet. Using state-of-the-art technology we compared RNA expression profiles between conventional BRAFwt and BRAFmut PTCs. METHODS: Microarrays covering 36,079 reference sequences were used to generate whole transcript expression profiles in 11 BRAFwt PTCs including five micro PTCs, 14 BRAFmut PTCs, and 7 normal thyroid specimens. A p-value with a false discovery rate (FDR) < 0.05 and a fold change > 2 were used as a threshold of significance for differential expression. Network and pathway utilities were employed to interpret significance of expression data. BRAF mutational status was established by direct sequencing the hotspot region of exon 15. RESULTS: We identified 237 annotated genes that were significantly differentially expressed between BRAFwt and BRAFmut PTCs. Of these, 110 genes were down- and 127 were upregulated in BRAFwt compared to BRAFmut PTCs. A number of molecules involved in thyroid hormone metabolism including thyroid peroxidase (TPO) were differentially expressed between both groups. Among cancer-associated molecules were ERBB3 that was downregulated and ERBB4 that was upregulated in BRAFwt PTCs. Two microRNAs were significantly differentially expressed of which miR492 bears predicted functions relevant to thyroid-specific molecules. The protein kinase A (PKA) and the G protein-coupled receptor pathways were identified as significantly related signaling cascades to the gene set of 237 genes. Furthermore, a network of interacting molecules was predicted on basis of the differentially expressed gene set. CONCLUSIONS: The expression study focusing on affected genes that are differentially expressed between BRAFwt and BRAFmut conventional PTCs identified a number of molecules which are connected in a network and affect important canonical pathways. The identified gene set adds to our understanding of the tumor biology of BRAFwt and BRAFmut PTCs and contains genes/biomarkers of interest. PMID- 25922908 TI - Contrasting spatial patterns and ecological attributes of soil bacterial and archaeal taxa across a landscape. AB - Even though recent studies have clarified the influence and hierarchy of environmental filters on bacterial community structure, those constraining bacterial populations variations remain unclear. In consequence, our ability to understand to ecological attributes of soil bacteria and to predict microbial community response to environmental stress is therefore limited. Here, we characterized the bacterial community composition and the various bacterial taxonomic groups constituting the community across an agricultural landscape of 12 km(2) , by using a 215 * 215 m systematic grid representing 278 sites to precisely decipher their spatial distribution and drivers at this scale. The bacterial and Archaeal community composition was characterized by applying 16S rRNA gene pyrosequencing directly to soil DNA from samples. Geostatistics tools were used to reveal the heterogeneous distribution of bacterial composition at this scale. Soil physical parameters and land management explained a significant amount of variation, suggesting that environmental selection is the major process shaping bacterial composition. All taxa systematically displayed also a heterogeneous and particular distribution patterns. Different relative influences of soil characteristics, land use and space were observed, depending on the taxa, implying that selection and spatial processes might be differentially but not exclusively involved for each bacterial phylum. Soil pH was a major factor determining the distribution of most of the bacterial taxa and especially the most important factor explaining the spatial patterns of alpha-Proteobacteria and Planctomycetes. Soil texture, organic carbon content and quality were more specific to a few number of taxa (e.g., beta-Proteobacteria and Chlorobi). Land management also influenced the distribution of bacterial taxa across the landscape and revealed different type of response to cropping intensity (positive, negative, neutral or hump-backed relationships) according to phyla. Altogether, this study provided valuable clues about the ecological behavior of soil bacterial and archaeal taxa at an agricultural landscape scale and could be useful for developing sustainable strategies of land management. PMID- 25922910 TI - Rational and Efficient Preparative Isolation of Natural Products by MPLC-UV-ELSD based on HPLC to MPLC Gradient Transfer. AB - In natural product research, the isolation of biomarkers or bioactive compounds from complex natural extracts represents an essential step for de novo identification and bioactivity assessment. When pure natural products have to be obtained in milligram quantities, the chromatographic steps are generally labourious and time-consuming. In this respect, an efficient method has been developed for the reversed-phase gradient transfer from high-performance liquid chromatography to medium-performance liquid chromatography for the isolation of pure natural products at the level of tens of milligrams from complex crude natural extracts. The proposed method provides a rational way to predict retention behaviour and resolution at the analytical scale prior to medium performance liquid chromatography, and guarantees similar performances at both analytical and preparative scales. The optimisation of the high-performance liquid chromatography separation and system characterisation allows for the prediction of the gradient at the medium-performance liquid chromatography scale by using identical stationary phase chemistries. The samples were introduced in medium-performance liquid chromatography using a pressure-resistant aluminium dry load cell especially designed for this study to allow high sample loading while maintaining a maximum achievable flow rate for the separation. The method has been validated with a mixture of eight natural product standards. Ultraviolet and evaporative light scattering detections were used in parallel for a comprehensive monitoring. In addition, post-chromatographic mass spectrometry detection was provided by high-throughput ultrahigh-performance liquid chromatography time-of flight mass spectrometry analyses of all fractions. The processing of all liquid chromatography-mass spectrometry data in the form of an medium-performance liquid chromatography x ultra high-performance liquid chromatography time-of-flight mass spectrometry matrix enabled an efficient localisation of the compounds of interest in the generated fractions. The methodology was successfully applied for the separation of three different plant extracts that contain many diverse secondary metabolites. The advantages and limitations of this approach and the theoretical chromatographic background that rules such as liquid chromatography gradient transfer are presented from a practical viewpoint. PMID- 25922909 TI - The preRC protein ORCA organizes heterochromatin by assembling histone H3 lysine 9 methyltransferases on chromatin. AB - Heterochromatic domains are enriched with repressive histone marks, including histone H3 lysine 9 methylation, written by lysine methyltransferases (KMTs). The pre-replication complex protein, origin recognition complex-associated (ORCA/LRWD1), preferentially localizes to heterochromatic regions in post replicated cells. Its role in heterochromatin organization remained elusive. ORCA recognizes methylated H3K9 marks and interacts with repressive KMTs, including G9a/GLP and Suv39H1 in a chromatin context-dependent manner. Single-molecule pull down assays demonstrate that ORCA-ORC (Origin Recognition Complex) and multiple H3K9 KMTs exist in a single complex and that ORCA stabilizes H3K9 KMT complex. Cells lacking ORCA show alterations in chromatin architecture, with significantly reduced H3K9 di- and tri-methylation at specific chromatin sites. Changes in heterochromatin structure due to loss of ORCA affect replication timing, preferentially at the late-replicating regions. We demonstrate that ORCA acts as a scaffold for the establishment of H3K9 KMT complex and its association and activity at specific chromatin sites is crucial for the organization of heterochromatin structure. PMID- 25922911 TI - HPLC-Based Activity Profiling for hERG Channel Inhibitors in the South African Medicinal Plant Galenia africana. AB - The human ether-a-go-go-related gene channel is a voltage-activated K(+) channel involved in cardiac action potential. Its inhibition can lead to QT prolongation, and eventually to potentially fatal arrhythmia. Therefore, it is considered a primary antitarget in safety pharmacology. To assess the risk of human ether-a-go go-related gene channel inhibition by medicinal plants, 700 extracts from different parts of 142 medicinal plants collected in Southern Africa were screened on Xenopus laevis oocytes. A CH2Cl2 extract from the stems and leaves of Galenia africana (Aizoaceae) reduced the peak tail human ether-a-go-go-related gene current by 50.4 +/- 5.5 % (n = 3) at a concentration of 100 ug/mL. By means of high-performance liquid chromatography-based activity profiling, nine flavonoids were identified in the active time windows. However, the human ether-a go-go-related gene channel inhibition of isolated compounds was less pronounced than that of extract and active microfractions (human ether-a-go-go-related gene inhibition between 10.1 +/- 5 and 14.1 +/- 1.6 at 100 uM). The two major constituents, 7,8-methylenedioxyflavone (1) and 7,8-dimethoxyflavone (13), were quantified (4.3 % and 9.4 %, respectively, in the extract). Further human ether-a go-go-related gene inhibition tests for compounds 1 and 13 at 300 uM showed a concentration-dependent inhibitory activity (33.2 +/- 12.4 and 30.0 +/- 7.4, respectively). In a detailed phytochemical profiling of the active extract, a total of 20 phenolic compounds, including six new natural products, were isolated and identified. PMID- 25922912 TI - Metabonomic Study of the Effects of Acanthopanax senticosus on Peripheral System of Rats. AB - Acanthopanax senticosus is extensively used to treat various nervous and cerebrovascular diseases in traditional medicinal systems in China and Russia. Ultrahigh-performance liquid chromatography-quadrupole time-of-flight-mass spectrometry coupled with pattern recognition methods was used to investigate the effects of A. senticosus on the peripheral system in rats. The analysis of possible pathways influenced by A. senticosus was performed with MetaboAnalyst and Cytoscape software. After treatment with A. senticosus, 21 modulated metabolites in heart tissue, 20 in liver tissue, 14 in spleen tissue, 17 in lung tissue, 16 in kidney tissue, and 12 in a serum sample were identified and considered potential biomarkers of A. senticosus treatments. The regulation of some endogenous metabolites by A. senticosus could be beneficial for the treatment of several peripheral system diseases, such as hypertension, cancer, and oxidative stress, etc. However, there were also some upregulated endogenous metabolites producing potential toxicity to the peripheral system. A metabonomic analysis revealed that protection and toxicity coexisted in the effects of A. senticosus on the peripheral system, which may be a practical guide for its safe use and beneficial to the expansion of its application. PMID- 25922913 TI - Evidence-Based Phytotherapy in Europe: Where Do We Stand? AB - Medicinal plants represent the oldest source of pharmacotherapy used by mankind. A considerable number of traditional systems of medicine (folk medicine) have emerged over the last millennia under different cultural conditions. Even nowadays, the majority of people in less developed countries have to rely on herbal remedies as primary health care. Based on scientific and technical progress, the options to produce high quality herbal medicinal products have been largely improved in the last decades. The acceptance of phytotherapy as a "natural and mild alternative" to synthetic drugs is very high within the general public in developed countries and, from a global perspective, sales figures of herbal medicines are constantly rising. However, we still face many issues in this field. In contrast to the popularity of herbal medicinal products, physicians and their respective societies often have a very critical view of them. Besides dogmatic obstacles, this is based on the frequently missing clinical trials that clearly demonstrate their efficacy and/or safety. This perspective discusses the reasons and implications of the lack of scientific evidence and also of the wrong understanding of the principles of rational phytotherapy. PMID- 25922914 TI - Expansion of myeloid-derived suppressor cells with arginase activity lasts longer in aged than in young mice after CpG-ODN plus IFA treatment. AB - As we age, the homeostatic function of many systems in the body, such as the immune function declines, which in turn contributes to augment susceptibility to disease. Here we describe that challenging aged mice with synthetic oligodeoxynucleotides containing unmethylated cytosine guanine motifs (CpG-ODN) emulsified in incomplete Freund's adjuvant (IFA), (CpG-ODN+IFA) an inflammatory stimulus, led to the expansion of CD11b+Gr1+ myeloid cells with augmented expression of CD124 and CD31. These myeloid cells lasted longer in the spleen of aged mice than in their younger counterparts after CpG-ODN+IFA treatment and were capable of suppressing T cell proliferative response by arginase induction. Myeloid cells from aged CpG-ODN+IFA-treated mice presented increased arginase-1 expression and enzyme activity. In addition, we found a different requirement of cytokines for arginase induction according to mice age. In myeloid cells from young treated mice, arginase-1 expression and activity is induced by the presence of each IL-4 or IL-6 in their extracellular medium, unlike myeloid cells from aged treated mice which need the presence of both IL-4 and IL-6 together for arginase induction and suppressor function. PMID- 25922915 TI - Total internal reflection fluorescence quantification of receptor pharmacology. AB - Total internal reflection fluorescence (TIRF) microscopy has been widely used as a single molecule imaging technique to study various fundamental aspects of cell biology, owing to its ability to selectively excite a very thin fluorescent volume immediately above the substrate on which the cells are grown. However, TIRF microscopy has found little use in high content screening due to its complexity in instrumental setup and experimental procedures. Inspired by the recent demonstration of label-free evanescent wave biosensors for cell phenotypic profiling and drug screening with high throughput, we had hypothesized and demonstrated that TIRF imaging is also amenable to receptor pharmacology profiling. This paper reviews key considerations and recent applications of TIRF imaging for pharmacology profiling. PMID- 25922917 TI - Pressure confinement effect in MoS2 monolayers. AB - With ever increasing interest in layered materials, molybdenum disulfide has been widely investigated due to its unique optoelectronic properties. Pressure is an effective technique to tune the lattice and electronic structure of materials such that high pressure studies can disclose new structural and optical phenomena. In this study, taking MoS2 as an example, we investigate the pressure confinement effect on monolayer MoS2 by in situ high pressure Raman and photoluminescence (PL) measurements. Our results reveal a structural deformation of monolayer MoS2 starting from 0.84 GPa, which is evidenced by the splitting of E(1)2g and A1g modes. A further compression leads to a transition from the 1H MoS2 phase to a novel structure evidenced by the appearance of two new peaks located at 200 and 240 cm(-1). This is a distinct feature of monolayer MoS2 compared with bulk MoS2. The new structure is supposed to have a distorted unit with the S atoms slided within a single layer like that of metastable 1T'-MoS2. However, unlike the non-photoluminescent 1T'-MoS2 structure, our monolayer shows a remarkable PL peak and a pressure-induced blue shift up to 13.1 GPa. This pressure-dependent behavior might enable the development of novel devices with multiple phenomena involving the strong coupling of the mechanical, electrical and optical properties of layered nanomaterials. PMID- 25922916 TI - The NOXA-MCL1-BIM axis defines lifespan on extended mitotic arrest. AB - Cell death on extended mitotic arrest is considered arguably most critical for the efficacy of microtubule-targeting agents (MTAs) in anticancer therapy. While the molecular machinery controlling mitotic arrest on MTA treatment, the spindle assembly checkpoint (SAC), appears well defined, the molecular components executing cell death, as well as factors connecting both networks remain poorly understood. Here we conduct a mini screen exploring systematically the contribution of individual BCL2 family proteins at single cell resolution to death on extended mitotic arrest, and demonstrate that the mitotic phosphorylation of BCL2 and BCLX represent a priming event for apoptosis that is ultimately triggered by NOXA-dependent MCL1 degradation, enabling BIM-dependent cell death. Our findings provide a comprehensive model for the initiation of apoptosis in cells stalled in mitosis and provide a molecular basis for the increased efficacy of combinatorial treatment of cancer cells using MTAs and BH3 mimetics. PMID- 25922918 TI - Development and evaluation of standardized narrative cases depicting the general surgery professionalism milestones. AB - PURPOSE: Residency programs now are required to use educational milestones, which has led to the need for new methods of assessment. The literature suggests that narrative cases are a promising tool to track residents' progress. This study demonstrates the process for developing and evaluating narrative cases representing the five levels of the professionalism milestones. METHOD: In 2013, the authors identified 28 behaviors in the Accreditation Council for Graduate Medical Education general surgery professionalism milestones. They modified previously published narrative cases to fit these behaviors. To evaluate the quality of these cases, the authors developed a 28-item, five-point scale instrument, which 29 interdisciplinary faculty completed. The authors compared the faculty ratings by narrative case and specialty with the authors' initial rankings of the cases by milestone level. They used t tests and analysis of variance to compare mean scores across specialties. RESULTS: The authors developed 10 narrative cases, 2 for each of the 5 milestone levels. Each case contained at least 20 of the 28 behaviors identified in the milestones. Mean faculty ratings matched the milestone levels. Reliability was good (G coefficient = 0.86, phi coefficient = 0.85), indicating consistency in raters' ability to determine the proper milestone level for each case. CONCLUSIONS: The authors demonstrate a process for using specialty-specific milestones to develop narrative cases that map to a spectrum of professionalism behaviors. This process can be applied to other competencies and specialties to facilitate faculty awareness of resident performance descriptors and provide a frame of reference for milestones assessment. PMID- 25922919 TI - Making meaning from sensory cues: a qualitative investigation of postgraduate learning in the operating room. AB - PURPOSE: The authors aimed to map and explicate what surgeons perceive they learn in the operating room. METHOD: The researchers used a grounded theory method in which data were iteratively collected through semistructured one-to-one interviews in 2010 and 2011 at four participating hospital sites. A four-person data analysis team from differing academic backgrounds qualitatively analyzed the content of the transcripts employing an immersion/crystallization approach. RESULTS: Participants were 22 UK surgeons, some of whom were in training at the time of the study and some of whom were attending surgeons. Major themes of learning in the operating room were perceived to be factual knowledge, motor skills, sensory semiosis, adaptive strategies, team working and management, and attitudes and behaviors. The analysis team classified 277 data points (short paragraphs or groups of sentences conveying meaning) under these major themes and subthemes. A key component of learning in the operating room that emerged from these data was sensory semiosis, defined as learning to make sense of visual and haptic cues. CONCLUSIONS: Although the authors found that learning in the operating room occurred across a wide range of domains, sensory semiosis was found to be an important theme that has not previously been fully acknowledged or discussed in the surgical literature. The discussion draws on the wider literature from the social sciences and cognitive psychology literature to examine how professionals learn to make meaning from "signs" making parallels with other medical specialties. PMID- 25922920 TI - How Do Medical Schools Identify and Remediate Professionalism Lapses in Medical Students? A Study of U.S. and Canadian Medical Schools. AB - PURPOSE: Teaching and assessing professionalism is an essential element of medical education, mandated by accrediting bodies. Responding to a call for comprehensive research on remediation of student professionalism lapses, the authors explored current medical school policies and practices. METHOD: In 2012 2013, key administrators at U.S. and Canadian medical schools accredited by the Liaison Committee on Medical Education were interviewed via telephone or e-mail. The structured interview questionnaire contained open-ended and closed questions about practices for monitoring student professionalism, strategies for remediating lapses, and strengths and limitations of current systems. The authors employed a mixed-methods approach, using descriptive statistics and qualitative analysis based on grounded theory. RESULTS: Ninety-three (60.8%) of 153 eligible schools participated. Most (74/93; 79.6%) had specific policies and processes regarding professionalism lapses. Student affairs deans and course/clerkship directors were typically responsible for remediation oversight. Approaches for identifying lapses included incident-based reporting and routine student evaluations. The most common remediation strategies reported by schools that had remediated lapses were mandated mental health evaluation (74/90; 82.2%), remediation assignments (66/90; 73.3%), and professionalism mentoring (66/90; 73.3%). System strengths included catching minor offenses early, emphasizing professionalism schoolwide, focusing on helping rather than punishing students, and assuring transparency and good communication. System weaknesses included reluctance to report (by students and faculty), lack of faculty training, unclear policies, and ineffective remediation. In addition, considerable variability in feedforward processes existed between schools. CONCLUSIONS: The identified strengths can be used in developing best practices until studies of the strategies' effectiveness are conducted. PMID- 25922921 TI - Diversity within unity. PMID- 25922922 TI - Introductory comment to Jay Greenberg's "Conversations with Oedipus". PMID- 25922923 TI - Conversations with oedipus. AB - As psychoanalysts engage with our patients in exploring their lives, we learn a great deal about the ways in which they express their own agency, and also about ways in which they respond to being the object of other people. But because of the particular history of psychoanalytic theorizing, we are more familiar with interpreting the patient's activity - the drives and wishes - than we are with dealing with the inevitable reversals between activity and passivity that characterize every life. This problem is explored by drawing parallels between clinical material and Sophocles' tragic rendering of the life of Oedipus the King. PMID- 25922924 TI - Anxiety and inhibition of panic attacks within translational and prospective research contexts. AB - Basic research involving animal models is an important tool to improve our understanding of clinical conditions related with anxiety and panic attacks. In fact, animal models have been used to study several paradigms on analogous and homologous elements of human anxiety phenomena. However, the direct transposition (translation) to clinical practice of the results obtained with animal models may be restricted by the different constructs used to describe and explain empirical evidence of anxiety phenomena among humans. We aimed to analyze whether theoretical assumptions on the potential inhibitory effects of anxiety on panic could be observed among humans in prospective studies designed to analyze the relationship between anxiety and panic. A systematic literature review including papers published in English language between 1997 and 2011 was undertaken on the MEDLINE database. The search yielded a total of 257 articles, of which 11 were included in the review. In three studies, the global dimension of the anxiety sensitivity construct worked as a facilitator of panic attacks. Six studies showed a positive correlation between the AS-Physical Concerns subfactor and the occurrence of panic attacks, whereas two studies found a greater effect of the AS Mental Incapacitation Concerns subfactor on panic. There was no evidence that anxiety might act as an inhibitor of panic attacks in humans, and there were no conclusive findings on the possibility that any anxiety construct could contribute toward inhibiting panic attacks. In sum, there seems to be a need for refining descriptions of anxious phenomena addressed both in basic preclinical research and in prospective-longitudinal studies involving humans. PMID- 25922925 TI - [Overgeneral autobiographical memory in depressive disorders]. AB - This article aims to review studies focusing on the relationship between overgeneral autobiographical memory and depressive disorders. Such characteristic has attracted attention because of its relationship with a poor ability to solve problems and to imagine the future, as well as with the maintenance and a poor prognosis of depression. Data were collected through a systematic search on LILACS, SciELO, MEDLINE, and IBECS databases, and also on the health sciences records of Portal de Periodicos da Coordenacao de Aperfeicoamento de Pessoal de Nivel Superior (CAPES), a Brazilian journal database, focusing on articles published between 2000 and 2010. The following keywords were used: memoria autobiografica, supergeneralizacao da memoria autobiografica, and memoria autobiografica e depressao in Portuguese; and autobiographical memory, overgeneral autobiographical memory, and autobiographical memory and depression in English. Following application of exclusion criteria, a total of 27 studies were reviewed. Overgeneral autobiographical memory has been investigated in several depressive disorders. However, further longitudinal studies are required to confirm the relevant role of this cognitive characteristic in anamnesis and in the treatment of mood disorders. PMID- 25922926 TI - Drug use and antisocial behavior among adolescents attending public schools in Brazil. AB - INTRODUCTION: Drug use is a social and a public health problem that has been related with antisocial behavior. The aim of this study was to evaluate the relationship between drug use and antisocial behavior among adolescents attending public schools in Brazil. METHOD: A total of 7,176 adolescents from low-income neighborhoods and public schools aged 14 to 19 years were assessed in five geographical regions in Brazil. Data on biosociodemographic characteristics and on drug use and antisocial behavior were assessed from complete answers to a national survey on risk and protective factors among adolescents. RESULTS: Over 80% of the adolescents who used alcohol and cigarettes were between 14 and 17 years old. The percentage of participants with antisocial behaviors was significantly higher among users of marijuana, cocaine, or crack than among adolescents who were not drug users. CONCLUSIONS: Prevention programs aimed at reducing substance use might help to decrease antisocial behaviors. PMID- 25922927 TI - Anxiety and depression symptoms in women with and without binge eating disorder enrolled in weight loss programs. AB - OBJECTIVES: 1) To investigate the association between binge eating scores, anxiety and depression symptoms, and body mass index (BMI), and 2) to assess the presence of differences in severity of anxiety symptoms, severity of depression symptoms, and BMI in women with and without binge eating disorder. METHOD: The sample comprised 113 women aged between 22 and 60 years (39.35+/-10.85) enrolled in weight loss programs in Porto Alegre, southern Brazil. The following instruments were used: structured interview, Brazilian Economic Classification Criteria, Beck Anxiety Inventory, Beck Depression Inventory, and Binge Eating Scale. Data were analyzed using descriptive and inferential statistics. RESULTS: A positive association was found between binge eating scores and the severity of anxiety symptoms (p < 0.001) and depression symptoms (p < 0.001). No significant association was observed between BMI and binge eating scores (p = 0.341). There were significant differences between women with and without binge eating disorder with regard to severity of anxiety symptoms (p < 0.001) and severity of depression symptoms (p < 0.001). Conversely, no significant differences were observed between the groups concerning BMI (p = 0.103). CONCLUSION: Our findings showed that binge eating is associated with symptoms of anxiety and depression, but not with BMI. PMID- 25922928 TI - Burnout syndrome and associated factors among health professionals of a public hospital. AB - OBJECTIVE: To identify the prevalence of burnout syndrome (BS) dimensions and their relationship with sociodemographic data, working variables, psychosocial variables, job satisfaction, hardiness, self-efficacy, and common mental disorders among health professionals of a public hospital. METHOD: This cross sectional study assessed 234 health professionals working at a public hospital in southern Brazil. Participants answered the Maslach Burnout Inventory, the Job Satisfaction Questionnaire, the Hardiness Scale, The General Self-Efficacy Scale, the Self-Reporting Questionnaire, and a questionnaire specifically designed for the present study to assess sociodemographic and variables related to work. Data were analyzed using descriptive and inferential statistics. RESULTS: An association was identified between the three dimensions of BS and sociodemographic data, variables related to work, psychosocial variables, hardy personality traits, and common mental disorders. CONCLUSION: The study allowed to define a risk profile for BS, namely male, young, undergraduate workers, with a low income, who see a large number of patients per day, physicians, government employees, absence of commitment, control and challenge (hardy personality traits), low self-efficacy, job dissatisfaction, presence of common mental disorders, and intention to change career, institution, or position at current institution. PMID- 25922929 TI - Application of the Rasch model in measuring personality disorders. AB - OBJECTIVE: To describe item and person parameters obtained with the Rasch model, one of the item response theory models, in the assessment of personality disorders based on Millon's theory. METHOD: A total of 350 people participated in the study. Age ranged from 18 to 67 years (mean +/- standard deviation = 27.02+/ 10.13), and 71.7% of the participants (n = 251) were female. Of the 350 individuals, 21.1% (n = 74) answered affirmatively about being under psychiatric treatment and taking psychiatric medications. The Personality Disorders Dimensional Inventory (PDDI), an instrument designed to assess personality disorders according to Millon's theory, was applied to all participants. Data were analyzed using the Rasch model. RESULTS: Overall, analysis with the Rasch model revealed that the PDDI has adequate psychometric properties for the assessment of personality disorders. CONCLUSION: Among the contributions of item response theory models for clinical instruments, the Rasch person-item map deserves to be highlighted as a successful attempt to improve the understanding of clinical scores obtained in response to particular test items. PMID- 25922930 TI - Non-medical use of methylphenidate: a review. AB - INTRODUCTION: Methylphenidate is a psychostimulant medication used for the treatment of attention deficit hyperactivity disorder and narcolepsy. However, it has also been used for non-medical purposes, e.g. to produce euphoria, to increase self-esteem, and to achieve the so-called neurocognitive enhancement, decreasing the feeling of tiredness and increasing focus and attention. OBJECTIVE: To describe, from theoretical and contextual points of view, the potential for abuse and non-medical use of methylphenidate. METHOD: The PubMed, SciELO and Cochrane databases were searched using the following keywords in Portuguese: metilfenidato, transtorno do deficit de atencao com hiperatividade, facilitadores dos processos cognitivos or agentes nootropicos, and abuso de substancias; and in English: methylphenidate, attention deficit disorder with hyperactivity, cognitive enhancement or nootropic agents, and substance abuse. Studies published between 1990 and 2010 were selected for review. RESULTS: Non medical use of methylphenidate is a relevant topic that raises important ethical and scientific questions in several areas, e.g. pharmacological and neurobiological characteristics, evidence of methylphenidate use, forms of non medical use of methylphenidate, mechanisms of action, and therapeutic application of methylphenidate. According to the review, methylphenidate can generally influence performance as a result of its stimulatory effect. Notwithstanding, evidence does not support the conclusion that it can enhance cognitive performance. CONCLUSION: Health professionals need to acquire expert knowledge and inform patients and their families on the methylphenidate potential for abuse when used with non-medical purposes. PMID- 25922931 TI - Determination of the positions and orientations of concentrated rod-like colloids from 3D microscopy data. AB - Confocal microscopy in combination with real-space particle tracking has proven to be a powerful tool in scientific fields such as soft matter physics, materials science and cell biology. However, 3D tracking of anisotropic particles in concentrated phases remains not as optimized compared to algorithms for spherical particles. To address this problem, we developed a new particle-fitting algorithm that can extract the positions and orientations of fluorescent rod-like particles from three dimensional confocal microscopy data stacks. The algorithm is tailored to work even when the fluorescent signals of the particles overlap considerably and a threshold method and subsequent clusters analysis alone do not suffice. We demonstrate that our algorithm correctly identifies all five coordinates of uniaxial particles in both a concentrated disordered phase and a liquid crystalline smectic-B phase. Apart from confocal microscopy images, we also demonstrate that the algorithm can be used to identify nanorods in 3D electron tomography reconstructions. Lastly, we determined the accuracy of the algorithm using both simulated and experimental confocal microscopy data-stacks of diffusing silica rods in a dilute suspension. This novel particle-fitting algorithm allows for the study of structure and dynamics in both dilute and dense liquid-crystalline phases (such as nematic, smectic and crystalline phases) as well as the study of the glass transition of rod-like particles in three dimensions on the single particle level. PMID- 25922932 TI - Coxiella burnetii Infections in Small Ruminants and Humans in Switzerland. AB - The recent Q fever epidemic in the Netherlands raised concerns about the potential risk of outbreaks in other European countries. In Switzerland, the prevalence of Q fever in animals and humans has not been studied in recent years. In this study, we describe the current situation with respect to Coxiella (C.) burnetii infections in small ruminants and humans in Switzerland, as a basis for future epidemiological investigations and public health risk assessments. Specific objectives of this cross-sectional study were to (i) estimate the seroprevalence of C. burnetii in sheep and goats, (ii) quantify the amount of bacteria shed during abortion and (iii) analyse temporal trends in human C. burnetii infections. The seroprevalence of C. burnetii in small ruminants was determined by commercial ELISA from a representative sample of 100 sheep flocks and 72 goat herds. Herd-level seroprevalence was 5.0% (95% CI: 1.6-11.3) for sheep and 11.1% (95% CI: 4.9-20.7) for goats. Animal-level seroprevalence was 1.8% (95% CI: 0.8-3.4) for sheep and 3.4% (95% CI: 1.7-6) for goats. The quantification of C. burnetii in 97 ovine and caprine abortion samples by real time PCR indicated shedding of >104 bacteria/g in 13.4% of all samples tested. To our knowledge, this is the first study reporting C. burnetii quantities in a large number of small ruminant abortion samples. Annual human Q fever serology data were provided by five major Swiss laboratories. Overall, seroprevalence in humans ranged between 1.7% and 3.5% from 2007 to 2011, and no temporal trends were observed. Interestingly, the two laboratories with significantly higher seroprevalences are located in the regions with the largest goat populations as well as, for one laboratory, with the highest livestock density in Switzerland. However, a direct link between animal and human infection data could not be established in this study. PMID- 25922933 TI - How feeling betrayed affects cooperation. AB - For a population of interacting self-interested agents, we study how the average cooperation level is affected by some individuals' feelings of being betrayed and guilt. We quantify these feelings as adjusted payoffs in asymmetric games, where for different emotions, the payoff matrix takes the structure of that of either a prisoner's dilemma or a snowdrift game. Then we analyze the evolution of cooperation in a well-mixed population of agents, each of whom is associated with such a payoff matrix. At each time-step, an agent is randomly chosen from the population to update her strategy based on the myopic best-response update rule. According to the simulations, decreasing the feeling of being betrayed in a portion of agents does not necessarily increase the level of cooperation in the population. However, this resistance of the population against low-betrayal-level agents is effective only up to some extend that is explicitly determined by the payoff matrices and the number of agents associated with these matrices. Two other models are also considered where the betrayal factor of an agent fluctuates as a function of the number of cooperators and defectors that she encounters. Unstable behaviors are observed for the level of cooperation in these cases; however, we show that one can tune the parameters in the function to make the whole population become cooperative or defective. PMID- 25922934 TI - MicroRNA-302a Suppresses Tumor Cell Proliferation by Inhibiting AKT in Prostate Cancer. AB - Micro (mi) RNAs are important regulators involved in various physical and pathological processes, including cancer. The miRNA-302 family has been documented as playing a critical role in carcinogenesis. In this study, we investigated the role of miRNA-302a in prostate cancer (PCa). MiRNA-302a expression was detected in 44 PCa tissues and 10 normal prostate tissues, and their clinicopathological significance was analyzed. Cell proliferation and cell cycle analysis were performed on PCa cells that stably expressed miRNA-302a. The target gene of miRNA-302a and the downstream pathway were further investigated. Compared with normal prostate tissues, miRNA-302a expression was downregulated in PCa tissues, and was even lower in PCa tissues with a Gleason score >=8. Overexpression of miRNA-302a induced G1/S cell cycle arrest in PCa cells, and suppressed PCa cell proliferation both in vitro and in vivo. Furthermore, miRNA 302a inhibits AKT expression by directly binding to its 3? untranslated region, resulting in subsequent alterations of the AKT-GSK3beta-cyclin D1 and AKT-p27Kip1 pathway. These results reveal miRNA-302a as a tumor suppressor in PCa, suggesting that miRNA-302a may be used as a potential target for therapeutic intervention in PCa. PMID- 25922935 TI - Extending the Functionality of Behavioural Change-Point Analysis with k-Means Clustering: A Case Study with the Little Penguin (Eudyptula minor). AB - We present a simple framework for classifying mutually exclusive behavioural states within the geospatial lifelines of animals. This method involves use of three sequentially applied statistical procedures: (1) behavioural change point analysis to partition movement trajectories into discrete bouts of same-state behaviours, based on abrupt changes in the spatio-temporal autocorrelation structure of movement parameters; (2) hierarchical multivariate cluster analysis to determine the number of different behavioural states; and (3) k-means clustering to classify inferred bouts of same-state location observations into behavioural modes. We demonstrate application of the method by analysing synthetic trajectories of known 'artificial behaviours' comprised of different correlated random walks, as well as real foraging trajectories of little penguins (Eudyptula minor) obtained by global-positioning-system telemetry. Our results show that the modelling procedure correctly classified 92.5% of all individual location observations in the synthetic trajectories, demonstrating reasonable ability to successfully discriminate behavioural modes. Most individual little penguins were found to exhibit three unique behavioural states (resting, commuting/active searching, area-restricted foraging), with variation in the timing and locations of observations apparently related to ambient light, bathymetry, and proximity to coastlines and river mouths. Addition of k-means clustering extends the utility of behavioural change point analysis, by providing a simple means through which the behaviours inferred for the location observations comprising individual movement trajectories can be objectively classified. PMID- 25922936 TI - Ultrasonographic Features of Hip Joints in Mucopolysaccharidoses Type I and II. AB - OBJECTIVES: The primary aim of this study was to assess the ultrasonographic features of hip joints in patients with mucopolysaccharidosis (MPS) type I and II in comparison with healthy population. The secondary aims were to correlate these features with clinical measures and to evaluate the utility of ultrasound in the diagnosis of MPS disease. MATERIALS AND METHODS: Sixteen MPS I (n = 3) and II (n = 13) patients were enrolled in the present study and underwent clinical and radiological evaluation, and bilateral high-resolution ultrasonography (US) of hip joints. The distance from the femoral neck to joint capsule (synovial joint space, SJS), joint effusion, synovial hyperthrophy, and local pathological vascularization were evaluated. The results were compared to the healthy population and correlated with clinical and radiological measures. RESULTS: 1. There was a difference in US SJS between children with MPS disease and the normative value for healthy population (7mm). Mean values of SJS were 15.81 +/- 4.08 cm (right hip joints) and 15.69 +/- 4.19 cm (left joints). 2. No inflammatory joint abnormalities were detected in MPS patients. 3. There was a clear correlation between US SJS and patients' age and height, while no clear correlation was observed between SJS and disease severity. CONCLUSIONS: 1. Patients with MPS I and II present specific features in hip joint ultrasonography. 2. The data suggests that ultrasonography might be effective in the evaluation of hip joint involvement in patients with MPS and might present a valuable tool in facilitating the diagnosis and follow up of the disease. PMID- 25922937 TI - Bilingualism and performance on two widely used developmental neuropsychological test batteries. AB - The present study investigated the effect of bilingualism on the two widely used developmental neuropsychological test batteries Wechsler Intelligence Scale for Children - Fourth Edition (WISC-IV) and A Developmental Neuropsychological Assessment, Second Edition (NEPSY-II) in children. The sample consisted of 100 Finland-Swedish children in two age groups. About half (n = 52) of the participants were early simultaneous bilinguals, and the other half (n = 48) were monolinguals. As no Finland-Swedish versions of the tests are available at the moment, both tests were translated and adapted to suit this population. The results revealed no difference in the performance between bilingual and monolingual children. This speaks against a cognitive advantage in bilingual children and indicates that development of separate norms for monolingual and bilingual children is not needed for clinical use. PMID- 25922938 TI - Hand in hand: public endorsement of climate change mitigation and adaptation. AB - This research investigated how an individual's endorsements of mitigation and adaptation relate to each other, and how well each of these can be accounted for by relevant social psychological factors. Based on survey data from two European convenience samples (N = 616 / 309) we found that public endorsements of mitigation and adaptation are strongly associated: Someone who is willing to reduce greenhouse gas emissions (mitigation) is also willing to prepare for climate change impacts (adaptation). Moreover, people endorsed the two response strategies for similar reasons: People who believe that climate change is real and dangerous, who have positive attitudes about protecting the environment and the climate, and who perceive climate change as a risk, are willing to respond to climate change. Furthermore, distinguishing between (spatially) proximal and distant risk perceptions suggested that the idea of portraying climate change as a proximal (i.e., local) threat might indeed be effective in promoting personal actions. However, to gain endorsement of broader societal initiatives such as policy support, it seems advisable to turn to the distant risks of climate change. The notion that "localising" climate change might not be the panacea for engaging people in this domain is discussed in regard to previous theory and research. PMID- 25922939 TI - Atypical antipsychotics as augmentation therapy in anorexia nervosa. AB - Anorexia nervosa (AN) is a life-threatening and difficult to treat mental illness with the highest mortality rates of any psychiatric disorder. We aimed to garner preliminary data on the real-world use of olanzapine and aripiprazole as augmentation agents of Selective Serotonin Reuptake Inhibitors (SSRIs) in adult inpatients affected by AN. We retrospectively evaluated the clinical charts of patients who were hospitalized between 2012 and 2014. Patients were evaluated upon admission and discharge. We investigated eating symptomatology, and both general and eating psychopathology using: Hamilton Rating Scale for Anxiety, Hamilton Rating Scale for Depression, and Yale-Brown-Cornell Eating Disorders Scale. The charts of 75 patients were included in this study. The sample resulted equally distributed among those receiving SSRIs and either aripiprazole or olanzapine in addition to SSRIs. Notwithstanding a few baseline clinical differences, upon discharge all groups were significantly improved on all measures. Interestingly, aripiprazole showed the greatest effectiveness in reducing eating-related preoccupations and rituals with a large effect size. The body of evidence on medication management in AN is in dismal condition. Augmentation therapy is a well-established approach to a variety of mental disorders and it is often used in every-day clinical practice with patients affected by AN as well. Nevertheless, to date very little data is available on this topic. Results from our sample yielded promising results on the effectiveness of aripiprazole augmentation in reducing eating-related obsessions and compulsions. Randomized controlled trials are warranted to confirm these encouraging findings. PMID- 25922940 TI - Identifying TF-MiRNA Regulatory Relationships Using Multiple Features. AB - MicroRNAs are known to play important roles in the transcriptional and post transcriptional regulation of gene expression. While intensive research has been conducted to identify miRNAs and their target genes in various genomes, there is only limited knowledge about how microRNAs are regulated. In this study, we construct a pipeline that can infer the regulatory relationships between transcription factors and microRNAs from ChIP-Seq data with high confidence. In particular, after identifying candidate peaks from ChIP-Seq data, we formulate the inference as a PU learning (learning from only positive and unlabeled examples) problem. Multiple features including the statistical significance of the peaks, the location of the peaks, the transcription factor binding site motifs, and the evolutionary conservation are derived from peaks for training and prediction. To further improve the accuracy of our inference, we also apply a mean reciprocal rank (MRR)-based method to the candidate peaks. We apply our pipeline to infer TF-miRNA regulatory relationships in mouse embryonic stem cells. The experimental results show that our approach provides very specific findings of TF-miRNA regulatory relationships. PMID- 25922941 TI - Treatment of iron deficiency anemia: practical considerations. AB - Iron deficiency anemia is a common problem worldwide, and doctors of all specialties need to be competent in its treatment. While most patients respond well to oral iron preparations, a substantial minority have side effects that make them adhere poorly to their treatment. For oral iron-intolerant patients, those responding poorly despite good adherence, and those with severe and/or symptomatic anemia, intravenous iron is an excellent alternative. It is, however, more expensive and carries a very small but potentially life-threatening risk of severe infusion-related hypersensitivity reactions. After outlining the main features of iron metabolism, in this review we compare the indications for therapy with oral and intravenous iron, and then focus on how to maximize the efficacy and safety of the two different routes. PMID- 25922943 TI - Correction: Interacted QTL Mapping in Partial NCII Design Provides Evidences for Breeding by Design. PMID- 25922942 TI - Misunderstanding of Front-Of-Package Nutrition Information on US Food Products. AB - Front-of-package nutrition symbols (FOPs) are presumably readily noticeable and require minimal prior nutrition knowledge to use. Although there is evidence to support this notion, few studies have focused on Facts Up Front type symbols which are used in the US. Participants with varying levels of prior knowledge were asked to view two products and decide which was more healthful. FOPs on packages were manipulated so that one product was more healthful, allowing us to assess accuracy. Attention to nutrition information was assessed via eye tracking to determine what if any FOP information was used to make their decisions. Results showed that accuracy was below chance on half of the comparisons despite consulting FOPs. Negative correlations between attention to calories, fat, and sodium and accuracy indicated that consumers over-relied on these nutrients. Although relatively little attention was allocated to fiber and sugar, associations between attention and accuracy were positive. Attention to vitamin D showed no association to accuracy, indicating confusion surrounding what constitutes a meaningful change across products. Greater nutrition knowledge was associated with greater accuracy, even when less attention was paid. Individuals, particularly those with less knowledge, are misled by calorie, sodium, and fat information on FOPs. PMID- 25922944 TI - Bats respond to very weak magnetic fields. AB - How animals, including mammals, can respond to and utilize the direction and intensity of the Earth's magnetic field for orientation and navigation is contentious. In this study, we experimentally tested whether the Chinese Noctule, Nyctalus plancyi (Vespertilionidae) can sense magnetic field strengths that were even lower than those of the present-day geomagnetic field. Such field strengths occurred during geomagnetic excursions or polarity reversals and thus may have played an important role in the evolution of a magnetic sense. We found that in a present-day local geomagnetic field, the bats showed a clear preference for positioning themselves at the magnetic north. As the field intensity decreased to only 1/5th of the natural intensity (i.e., 10 MUT; the lowest field strength tested here), the bats still responded by positioning themselves at the magnetic north. When the field polarity was artificially reversed, the bats still preferred the new magnetic north, even at the lowest field strength tested (10 MUT), despite the fact that the artificial field orientation was opposite to the natural geomagnetic field (P<0.05). Hence, N. plancyi is able to detect the direction of a magnetic field even at 1/5th of the present-day field strength. This high sensitivity to magnetic fields may explain how magnetic orientation could have evolved in bats even as the Earth's magnetic field strength varied and the polarity reversed tens of times over the past fifty million years. PMID- 25922945 TI - Functional Connectivity in MRI Is Driven by Spontaneous BOLD Events. AB - Functional brain signals are frequently decomposed into a relatively small set of large scale, distributed cortical networks that are associated with different cognitive functions. It is generally assumed that the connectivity of these networks is static in time and constant over the whole network, although there is increasing evidence that this view is too simplistic. This work proposes novel techniques to investigate the contribution of spontaneous BOLD events to the temporal dynamics of functional connectivity as assessed by ultra-high field functional magnetic resonance imaging (fMRI). The results show that: 1) spontaneous events in recognised brain networks contribute significantly to network connectivity estimates; 2) these spontaneous events do not necessarily involve whole networks or nodes, but clusters of voxels which act in concert, forming transiently synchronising sub-networks and 3) a task can significantly alter the number of localised spontaneous events that are detected within a single network. These findings support the notion that spontaneous events are the main driver of the large scale networks that are commonly detected by seed-based correlation and ICA. Furthermore, we found that large scale networks are manifestations of smaller, transiently synchronising sub-networks acting dynamically in concert, corresponding to spontaneous events, and which do not necessarily involve all voxels within the network nodes oscillating in unison. PMID- 25922946 TI - Auxin influx carriers control vascular patterning and xylem differentiation in Arabidopsis thaliana. AB - Auxin is an essential hormone for plant growth and development. Auxin influx carriers AUX1/LAX transport auxin into the cell, while auxin efflux carriers PIN pump it out of the cell. It is well established that efflux carriers play an important role in the shoot vascular patterning, yet the contribution of influx carriers to the shoot vasculature remains unknown. Here, we combined theoretical and experimental approaches to decipher the role of auxin influx carriers in the patterning and differentiation of vascular tissues in the Arabidopsis inflorescence stem. Our theoretical analysis predicts that influx carriers facilitate periodic patterning and modulate the periodicity of auxin maxima. In agreement, we observed fewer and more spaced vascular bundles in quadruple mutants plants of the auxin influx carriers aux1lax1lax2lax3. Furthermore, we show AUX1/LAX carriers promote xylem differentiation in both the shoot and the root tissues. Influx carriers increase cytoplasmic auxin signaling, and thereby differentiation. In addition to this cytoplasmic role of auxin, our computational simulations propose a role for extracellular auxin as an inhibitor of xylem differentiation. Altogether, our study shows that auxin influx carriers AUX1/LAX regulate vascular patterning and differentiation in plants. PMID- 25922947 TI - Scales tell a story on the stress history of fish. AB - Fish faced with stressful stimuli launch an endocrine stress response through activation of the hypothalamic-pituitary-interrenal (HPI-) axis to release cortisol into the blood. Scientifically validated biomarkers to capture systemic cortisol exposure over longer periods of time are of utmost importance to assess chronic stress in governmental, wildlife, aquaculture and scientific settings. Here we demonstrate that cortisol in scales of common carp (Cyprinus carpio L.) is the long-sought biomarker for chronic stress. Undisturbed (CTR) and daily stressed (STRESS) carp were compared. Dexamethasone (DEX) or cortisol (CORT) fed fish served as negative and positive controls, respectively. Scale cortisol was quantified with a validated ultra-performance liquid chromatography tandem mass spectrometry method. An increase in scale cortisol content was found in STRESS and CORT but not in CTR and DEX fish. Scale cortisol content reflects its accumulation in a stressor and time dependent manner and validates the scale cortisol content as biomarker for chronic stress. Plasma analyses confirmed that (i) CTR, DEX and CORT treatments were effective, (ii) plasma cortisol of STRESS fish showed no signs of chronic HPI-axis activation, and (iii) plasma cortisol is a poor predictor for chronic stress. The expression of HPI key genes crf, pomc, and star were up-regulated in STRESS fish in the absence of a plasma cortisol response, as was the target gene of cortisol encoding subunit alpha1 of the Na+/K+-ATPase in gills. When lost, scales of fish regenerate fast. Regenerated scales corroborate our findings, offering (i) unsurpassed time resolution for cortisol incorporation and as such for stressful events, and (ii) the possibility to investigate stress in a well defined and controlled environment and time frame creating novel opportunities for bone physiological research. We conclude that the cortisol content in ontogenetic and regenerated scales is an innovative biomarker for chronic stress offering ample applications in science and industry. PMID- 25922948 TI - A potential risk of overestimating apparent diffusion coefficient in parotid glands. AB - OBJECTIVES: To investigate transient signal loss on diffusion weighted images (DWI) and overestimation of apparent diffusion coefficient (ADC) in parotid glands using single shot echoplanar DWI (EPDWI). MATERIALS AND METHODS: This study enrolled 6 healthy subjects and 7 patients receiving radiotherapy. All participants received dynamic EPDWI with a total of 8 repetitions. Imaging quality of DWI was evaluated. Probability of severe overestimation of ADC (soADC), defined by an ADC ratio more than 1.2, was calculated. Error on T2WI, DWI, and ADC was computed. Statistical analysis included paired Student t testing and Mann-Whitney U test. A P value less than 0.05 was considered statistically significant. RESULTS: Transient signal loss was visually detected on some excitations of DWI but not on T2WI or mean DWI. soADC occurred randomly among 8 excitations and 3 directions of diffusion encoding gradients. Probability of soADC was significantly higher in radiotherapy group (42.86%) than in healthy group (24.39%). The mean error percentage decreased as the number of excitations increased on all images, and, it was smallest on T2WI, followed by DWI and ADC in an increasing order. CONCLUSIONS: Transient signal loss on DWI was successfully detected by dynamic EPDWI. The signal loss on DWI and overestimation of ADC could be partially remedied by increasing the number of excitations. PMID- 25922950 TI - An idiosyncratic history of burn scars. AB - The history of burn scars can best be found in military medical history. The care of wounded soldiers documented in the Illiad reflected the trauma of the weapons of war, arrow, spear, sword, and ax. The introduction of gunpowder in the 14th century, increasingly sophisticated explosives, and in modern times, petroleum driven vehicles, including airplanes, created a new subset of wounds requiring attention and post-survival scars challenging the quality of survival. This article selects from among a myriad of examples of modern military treatments as they relate to those survivors. Larrey, with Napolean's Grand Army, Sir Harold Gilles during and following World War I, and the Boston area preparation and response to the Cocoanut Grove Fire in 1942 are the principle topics examined. Recent modern interventions, related to the survival of horrific blast and burn injuries, with modern wound care and scar manipulation techniques provide context to the current ability to modify healing and scars. PMID- 25922949 TI - The Clostridium difficile Protease Cwp84 Modulates both Biofilm Formation and Cell-Surface Properties. AB - Clostridium difficile is responsible for 15-20% of antibiotic-associated diarrheas, and nearly all cases of pseudomembranous colitis. Among the cell wall proteins involved in the colonization process, Cwp84 is a protease that cleaves the S-layer protein SlpA into two subunits. A cwp84 mutant was previously shown to be affected for in vitro growth but not in its virulence in a hamster model. In this study, the cwp84 mutant elaborated biofilms with increased biomass compared with the parental strain, allowing the mutant to grow more robustly in the biofilm state. Proteomic analyses of the 630Deltaerm bacteria growing within the biofilm revealed the distribution of abundant proteins either in cell surface, matrix or supernatant fractions. Of note, the toxin TcdA was found in the biofilm matrix. Although the overall proteome differences between the cwp84 mutant and the parental strains were modest, there was still a significant impact on bacterial surface properties such as altered hydrophobicity. In vitro and in vivo competition assays revealed that the mutant was significantly impaired for growth only in the planktonic state, but not in biofilms or in vivo. Taken together, our results suggest that the phenotypes in the cwp84 mutant come from either the accumulation of uncleaved SlpA, or the ability of Cwp84 to cleave as yet undetermined proteins. PMID- 25922951 TI - Microstructural and molecular considerations in the treatment of scars with ablative fractional lasers. AB - Fractional ablative lasers have recently proven to be an effective modality for improving the clinical appearance and minimizing the morbidity associated with restrictivetype scars. Their tolerable safety profile on nonfacial sites and darker Fitzpatrick skin types provides an advantage over its fully ablative counterpart in treating facial rhytides, photodamaged skin, and acne scars. However, despite its increasing usage in clinical practice, the mechanism behind the observed clinical benefit remains complex and has yet to be fully elucidated. This paper reviews the work on the histological mechanism of action of ablative fractional lasers, and the molecular changes that occur posttreatment on restrictive scars, with an emphasis on mature burn and postsurgical scars. As the majority of research has been on the carbon dioxide laser, a natural focus on this wavelength is presented. PMID- 25922952 TI - Current trends and future considerations in scar treatment. AB - The goal of scar therapy is the restoration of the patient to their preinjury state. A combination of injected antimetabolites, surgery, laser, and laser assisted delivery of drugs is needed for minimally invasive surgical correction of scars. As a result, laser therapy is emerging as an essential treatment element. It has been noted that fractional lasers normalize both the clinical and histological appearance of scars. Laser- and light-based therapies complement existing approaches of surgery and physical therapy, resulting in significant gains with minimal associated morbidity. Emerging and future laser technologies are creating a new paradigm in the management of scar rehabilitation. PMID- 25922953 TI - Laser tratment of traumatic scars: a military perspective. AB - Advancements in medical treatment and transport over more than a decade of conflict have resulted in unprecedented survival rates for service members despite catastrophic injuries. Enhanced survival has created an unprecedented need for comprehensive rehabilitation and transition services. Though far from the exclusive domain of military dermatologists, military medicine has had a prominent role in integrating cutaneous procedural techniques into the rehabilitation of traumatically injured patients for a variety of reasons. The introduction of fractional laser technology in the mid-2000's has stimulated a revolution in scar treatment, and is gradually remodeling the fields of procedural dermatology and trauma rehabilitation both inside and outside of the military. This manuscript will provide a brief review of common cutaneous procedures applicable to rehabilitation, with an emphasis on ablative fractional laser resurfacing of scars and contractures. PMID- 25922954 TI - Multidisciplinary, multimodal approach for a child with a traumatic facial scar. AB - The treatment of disfiguring and disabling scars remains a field of active study, reinvigorated with recent advances in techniques and technologies. A variety of approaches can be utilized depending on scar characteristics, location, degree of tissue loss, and associated contractures. Just as traumatic scars can be complex and heterogeneous, the corresponding paradigm for treatment must also be flexible and multimodal for optimal improvement. This report describes a 3-year-old girl with a "mixed" (atrophic/hypertrophic), violaceous, contracted facial scar from a dog bite. It was treated with a novel approach utilizing a multidisciplinary pediatric scar team to combine autologous fat grafting, ablative fractional laser resurfacing, pulsed-dye laser, and laser-assisted delivery of a corticosteroid as concurrent, multimodal therapy to optimize the outcome. PMID- 25922955 TI - A review of scar assessment scales. AB - At our current level of understanding, scars are an unavoidable result of disruption of the integument following trauma and other sources of injury in the postnatal period. Millions of people worldwide suffer from diminished quality of life due to varying degrees of disfigurement, functional impairment, and psychosocial comorbidity. Scars also represent a significant financial burden to the healthcare system at large. Substantial momentum currently exists in scar research associated with innovative techniques and devices devoted to treating scars. In order to properly ascertain and compare responses to various therapies, accurate and reproducible qualitative and quantitative assessments are vital. At least 10 different scar assessment scales and tools have been created to date in an attempt to quantify scar severity. However, a "gold standard" scar scale still does not yet exist. A major limitation of most scar scales is their focus on a relatively narrow group of individual subjective and objective features, while failing to address the overall cosmetic, functional, and psychological sequelae. Herein, we provide a brief review of current scar assessment scales, discuss some of the major advantages and limitations of each, and introduce several characteristics that might be addressed in a new "gold standard" scar scale. The assessment and treatment of scars, particularly large traumatic scars, is frequently a multidisciplinary effort. The creation of an "ideal" scar scale will undoubtedly require input from therapists, surgeons, dermatologists, and other professionals alike. PMID- 25922956 TI - Treatment of ulcers with ablative fractional lasers. AB - Chronic, nonhealing ulcers are a frustrating therapeutic challenge and investigation of innovative therapies continues to be an important research pursuit. One unique and newly applied intervention is the use of ablative fractional lasers. This technology has recently been employed for the treatment of hypertrophic, disfiguring and function-limiting scars, and was first shown to induce healing of chronic wounds in patients with persistent ulcers and erosions within traumatic scars. Recent reports suggest it may be applicable for other types of chronic wounds as well. The mechanism of action for this modality remains to be elucidated but possible factors include laser-induced collagen remodeling, photomicrodebridement and disruption of biofilms, and induction of a proper wound healing cascade. PMID- 25922957 TI - Fractional epidermal grafting in combination with laser therapy as a novel approach in treating radiation dermatitis. AB - Radiation injury to the skin is a major source of dysfunction, disfigurement, and complications for thousands of patients undergoing adjunctive treatment for internal cancers. Despite the great potential for affecting quality of life, radiation injury has received little attention from dermatologists and is primarily being managed by radiation oncologists. During our volunteer work in Vietnam, we encountered numerous children with significant scarring and depigmentation of skin from the outdated use of radioactive phosphorus P32 in the treatment of hemangiomas. This dangerous practice has left thousands of children with significant fibrosis and disfigurement. Currently, there is no treatment for radiation dermatitis. Here, we report a case series using the combination of laser treatment, including pulsed-dye laser, fractional CO2 laser, and epidermal grafting to improve the appearance and function of the radiation scars in these young patients. We hope that by improving the appearance and function of these scars, we can improve the quality of life for these young patients and potentially open up a new avenue of treatment for cancer patients affected with chronic radiation dermatitis, potentially improving their range of motion, cosmesis, and reducing their risk of secondary skin malignancies. PMID- 25922958 TI - Letter of apology and notice of retraction. AB - Retraction of: Yazdan, P. Sem Cutan Med Surg. 2012 Dec;31(4):258-266 PMID: 21605090 [PubMed - indexed for MEDLINE]. PMID- 25922959 TI - Complete mitochondrial genome of the Swan Goose (Anser cygnoides L.) and its phylogenetic analysis. AB - In this study, we undertook the first complete the Swan Goose (Anser cygnoides L.) mitochondrial genome. The total length of the mitogenome is 16,739 bp. It contains the typical structure, including 13 protein-coding genes, 22 transfer RNA genes, two ribosomal RNA genes, and one D-loop region. The overall composition of the mitogenome is A (29.2%), G (15.8%), C (32.8%), and T (22.2%). Besides, the base preference of AT was not determined. Twenty-two kinds of tRNA were all typically cloverleaf structures. According to the phylogenetic analysis, A. cygnoides L. has a closer relationship with Anser anser. PMID- 25922960 TI - Complete mitochondrial genome of Paracobitis variegates and its phylogenetic analysis. AB - In this study, the complete mitochondrial genome sequence of the Paracobitis variegates was first reported. The total length of the mitogenome is 16,571 bp long with the A + T content of 55.6%. It contains the typical structure, including 13 protein-coding genes, 22 transfer RNA genes, two ribosomal RNA genes, and one D-loop region. The protein-coding genes start with the typical ATG codon, while COI gene uses GTG as the initiation codon. Most tRNA genes could form typical secondary structures except tRNA(ser), which had an absence of the DHU arm. There are 43 helices structures in 12S rRNA, and six domains, 53 helices structures in 16S rRNA. According to the phylogenetic analysis, Paracobitis variegates has a closer relationship with Barbatula toni. PMID- 25922961 TI - The complete mitochondrial genome sequence of Beaufortia szechuanensis (Cypriniformes, Balitoridae). AB - The Beaufortia szechuanensis is endemic to the upper reaches of Yangtze River in China. In this study, we successfully sequenced the mitochondrial genome of the B. szechuanensis, collected from the Qingyi River. The complete mitochondrial genome of B. szechuanensis was a circular molecule of 16,559 bp in length, containing 2 ribosomal RNA (rRNA) genes, 13 protein-coding genes, 22 transfer RNA (tRNA) genes, an origin of light-strand replication (OL) and a control region (D loop). It is the first complete mitochondrial DNA data in the genus Beaufortia. The cytochrome c oxidase subunit I (COI) sequence of 14 species in Balitoridae was used for phylogenetic analysis. The topology demonstrated that the Balitoridae can be classified into two subfamilies, and the B. szechuanensis belongs to the subfamily Gastromyzoninae. PMID- 25922963 TI - Correlated Protein Function Prediction via Maximization of Data-Knowledge Consistency. AB - Conventional computational approaches for protein function prediction usually predict one function at a time, fundamentally. As a result, the protein functions are treated as separate target classes. However, biological processes are highly correlated in reality, which makes multiple functions assigned to a protein not independent. Therefore, it would be beneficial to make use of function category correlations when predicting protein functions. In this article, we propose a novel Maximization of Data-Knowledge Consistency (MDKC) approach to exploit function category correlations for protein function prediction. Our approach banks on the assumption that two proteins are likely to have large overlap in their annotated functions if they are highly similar according to certain experimental data. We first establish a new pairwise protein similarity using protein annotations from knowledge perspective. Then by maximizing the consistency between the established knowledge similarity upon annotations and the data similarity upon biological experiments, putative functions are assigned to unannotated proteins. Most importantly, function category correlations are gracefully incorporated into our learning objective through the knowledge similarity. Comprehensive experimental evaluations on the Saccharomyces cerevisiae species have demonstrated promising results that validate the performance of our methods. PMID- 25922962 TI - The complete mitochondrial genome sequence of Aspergillus flavus. AB - Aspergillus flavus is a haploid filamentous fungus that is common in the environment and has been implicated in human infections. The complete mitochondrial genome of A. flavus has been determined by high-throughput sequencing technology in this work. Our study revealed that the mitochondrial genome of A. flavus is 31,602 bp long, with an A + T content of 74.83%, which consists of a usual set of mitochondrial proteins and RNA genes, including large and small ribosomal RNAs, 15 proteins, and 20 tRNA genes and contains two introns. Notably, it also contains two hypothetical proteins without obvious homology to any known proteins. All structural genes are located on one strand and are apparently transcribed in one direction. Codon usage analysis indicated that all protein coding genes employ the standard fungal mitochondrial start and stop codons; and the nucleotide bias toward AT was also reflected in the codon usage. The complete mitochondrial genomes of A. flavus would be useful for future investigation of the genetic, evolution, and clinical identification of Aspergillus species. PMID- 25922966 TI - Demographic and Environmental Factors Associated With Successful Day School Treatment Program Outcomes. AB - In this study the authors examine the impact of admission characteristics of 105 students admitted to a day school treatment program on outcomes. Those who graduated, earned a general education diploma (GED), or were returned to a regular classroom setting were categorized as successful and those placed in a more restrictive settings (including detention), dropped out, or left the program with no known outcome were unsuccessful. The sample was largely male (n = 78, 74.3%), Caucasian (64%, n = 67), poor (53.4%), and entered in middle school or high school (73%). The majority (53.3%) had 4 or more prior educational placements before entering. They stayed in the program on average 2.5 years (SD = 2.17) with a range from 6 days through 10 years. Forty-three (41%) students were successfully discharged. Unsuccessfully discharged students dropped out (31.4%), placed in residential programs (19%), or were psychiatrically hospitalized (5.7%). At intake, 56 (53.3%) had a history of truancy, 38 (37.1%) had a PINS and 28 (26.7%) had been on probation. African Americans were approximately 73% less likely to succeed and were more likely to be from families meeting federal poverty guidelines and to live in single family households. Those who entered the program in grades K-6 or 10-12 were over 3 times more likely to succeed than students admitted in grades 7-9. Using logistic regression to assess the bivariate relationships of the demographic characteristics with successful discharge, race, admission while in grades 7-9, having both parents at home, and number of days in the program were significantly associated with success. Having externalizing behaviors, 5 or more prior placements, history of truancy, and contact with the juvenile justice system were associated with unsuccessful outcomes. Students with a history of being in the juvenile justice system were 87% less likely to succeed in the program. Implications for school social workers are discussed. PMID- 25922967 TI - Molecular Insights into Ternary Surface Complexation of Arsenite and Cadmium on TiO2. AB - Insights from molecular-level mechanisms of arsenite [As(III)] and cadmium (Cd) co-adsorption on TiO2 can further our understanding of their synergistic removal in industrial wastewaters. The motivation for our study is to explore the interfacial interactions of neutrally charged As(III) and cationic Cd(2+) on nanocrystalline TiO2 using multiple complementary techniques. The results of adsorption edge, zeta potential, and surface complexation modeling suggest that coexistence of As(III) and Cd(2+) enhanced their synergistic adsorption on TiO2 and, consequently, resulted in the formation of a ternary surface complex. This ternary surface complex, in turn, inhibited the metal release into the aqueous phase and, therefore, facilitated the immobilization of the heavy metals. Our in situ flow-cell attentuated total reflectance Fourier transform infrared (ATR FTIR) spectroscopy and extended X-ray absorption fine structure (EXAFS) spectroscopy evidence showed that, regardless of the order of contact, As(III) was preferentially adsorbed on TiO2 rather than Cd. In agreement with our spectroscopic analysis, quantum chemistry calculations also illustrated that the Cd-As(III)-TiO2 ternary surface complex should be formed with the adsorbed As(III) as the bridging molecule. At high As(III) concentrations, the formation of the Cd-As(III)-TiO2 complex is responsible for the Cd removal. The simultaneous removal mechanisms will further our understanding of the removal of multiple pollutants in industrial wastewaters. PMID- 25922968 TI - Multiple sulphur and oxygen isotopes reveal microbial sulphur cycling in spring waters in the Lower Engadin, Switzerland. AB - Highly mineralized springs in the Scuol-Tarasp area of the Lower Engadin and in the Albula Valley near Alvaneu, Switzerland, display distinct differences with respect to the source and fate of their dissolved sulphur species. High sulphate concentrations and positive sulphur (delta(34)S) and oxygen (delta(18)O) isotopic compositions argue for the subsurface dissolution of Mesozoic evaporitic sulphate. In contrast, low sulphate concentrations and less positive or even negative delta(34)S and delta(18)O values indicate a substantial contribution of sulphate sulphur from the oxidation of sulphides in the crystalline basement rocks or the Jurassic sedimentary cover rocks. Furthermore, multiple sulphur (delta(34)S, Delta(33)S) isotopes support the identification of microbial sulphate reduction and sulphide oxidation in the subsurface, the latter is also evident through the presence of thick aggregates of sulphide-oxidizing Thiothrix bacteria. PMID- 25922969 TI - Probing molecular packing at engineered interfaces in organic field effect transistor and its correlation with charge carrier mobility. AB - Surface engineering of SiO2 dielectric using different self-assembled monolayer (SAM) has been carried out, and its effect on the molecular packing and growth behavior of copper phthalocyanine (CuPc) has been studied. A correlation between the growth behavior and performance of organic field effect transistors is examined. Depth profiling using positron annihilation and X-ray reflectivity techniques has been employed to characterize the interface between CuPc and the modified and/or unmodified dielectric. We observe the presence of structural defects or disorder due to disorientation of CuPc molecules on the unmodified dielectric and ordered arrangement on the modified dielectrics, consistent with the high charge carrier mobility in organic field effect transistors in the latter. The study also highlights the sensitivity of these techniques to the packing of CuPc molecules on SiO2 modified using different SAMs. Our study also signifies the sensitivity and utility of these two techniques in the characterization of buried interfaces in organic devices. PMID- 25922971 TI - Becoming "At Home" in Home Modifications: Professional Reasoning Across the Expertise Continuum. AB - Professional reasoning used by occupational therapists in home modifications as they develop from novice to expert was explored in this grounded theory study. Eight occupational therapists participated in multiple interviews and member checks about home modifications training and practice. Formal academic and experiential learning provided the foundation for reasoning systems and habits of practice. As therapists gained expertise, they were able to shift their primary focus from systematic reasoning steps to focus on the comprehensive, client centered, and contextual picture. Creative educational strategies support confidence in engaging in home modifications practice. PMID- 25922970 TI - Is Care for the Dying Improving in the United States? AB - BACKGROUND: Striking changes occurred in health care in the United States between 2000 and 2013, including growth of hospice and hospital-based palliative care teams, and changes in Medicare payment policies. OBJECTIVE: The aim of this study was to compare informants' reports and ratings of the quality of end-of-life care for decedents between 2000 and 2011-2013. METHODS: The study design comprised retrospective national surveys. Subjects were decedents age 65 years and older residing in the community from two time periods. Similar survey questions were asked at the two time periods. Bivariate and multivariate analyses were conducted, using appropriate survey weights to examine response differences between time periods, after adjusting for the decedent's age, race, pattern of functional decline, and the presence of a cancer diagnosis, as well as the respondent's relationship to the decedent. RESULTS: A total of 1208 informants were interviewed; 622 in 2000 and 586 in 2011-2013. Respondents from deaths in 2011-2013 were more likely to state that their loved ones experienced an unmet need for pain management (25.2% versus 15.5% in 2000, adjusted odds ratio [AOR] 1.9, 95% confidence interval [CI] 1.1-3.3). More respondents reported that religion and spirituality were addressed in the later time period (72.4% not addressed compared with 58.3%, AOR 1.4, 95% CI 1.1-1.9). High rates of unmet need for palliation of dyspnea and anxiety/depression remained. The overall rating of quality did not improve but decreased (with 56.7% stating care was excellent in 2000 and 47.0% in the later survey, AOR 0.70, 95% CI 0.52-0.95). CONCLUSIONS: Substantial unmet needs in end-of-life care remain. Continued efforts are needed to improve the quality of end-of-life care. PMID- 25922972 TI - Perinatal transmission of hepatitis C antigens: envelope 1, envelope 2 and non structural 4. AB - BACKGROUND: Perinatal exposure to hepatitis C virus (HCV) antigens during pregnancy may affect the developing immune system in the fetus. We aimed to study the perinatal transmission of HCV structural and non-structural antigens. METHODS: Sera from 402 pregnant mothers were tested for anti-HCV antibody and HCV RNA. HCV antigens were determined in sera from 101 HCV-infected mothers and their cord blood. RESULTS: In both serum and cord blood samples, HCV NS4 (non structural 4) at 27 kDa, E1 (envelope 1) at 38 kDa and E2 (envelope 2) at 40 kDa were identified, purified and quantified using western blotting, electroelution and ELISA. Maternal sera and neonate cord blood samples had similar detection rates for NS4 (94.1%), E1 (90.1%) and E2 (90.1%). The mean maternal serum levels (optical density, OD) of HCV NS4 (0.87 +/- 0.01), E1 (0.86 +/- 0.01) and E2 (0.85 +/- 0.01) did not differ significantly (p > 0.05) from those of neonatal cord blood (0.83 +/- 0.01, 0.87 +/- 0.01 and 0.85 +/- 0.01, respectively). Also, strong correlations (p < 0.0001) were shown between sera and cord blood sample levels of HCV NS4, r = 0.77; E1, r = 0.76 and E2, r = 0.80. The vertical transmission of these antigens in vaginal delivery did not differ significantly (p > 0.05) from those in caesarean section. CONCLUSIONS: These findings indicate that vertical transmission of HCV NS4, E1 and E2 antigens was very high. Thus, exposure to these antigens may influence the developing immune responses to natural infection or future vaccination. PMID- 25922973 TI - Longitudinal Forced Vital Capacity Monitoring as a Prognostic Adjunct after Lung Transplantation. AB - RATIONALE: After lung transplantation, spirometric values are routinely followed to assess graft function. FEV1 is used to characterize chronic allograft dysfunction, whereas the course of FVC change has been less acknowledged and rarely used. OBJECTIVES: To better understand the temporal relationship and prognostic ability of FEV1 and FVC decline after lung transplantation. METHODS: Serial FEV1 and FVC values were studied among 205 bilateral lung transplant recipients. Different decline patterns were characterized and evaluated for prognostic value via restricted mean modeling of mortality and times to other pertinent events. MEASUREMENTS AND MAIN RESULTS: Baseline FEV1 was achieved earlier than baseline FVC (median, 296 vs. 378 d; P < 0.0001). Decline in FEV1 or FVC from their respective post-transplant baselines occurred in 85 patients (41%). Fifty-nine of 85 (69%) had an isolated FEV1 decline, with 80% later meeting the FVC decline criterion. This subsequent FVC decline was associated with worsening FEV1 and lower median survival. Twenty-five of 85 patients (29%) demonstrated concurrent FEV1 and FVC decline. Patients with concurrent decline had higher 1- and 5-year mortality rates (1-yr, 53% vs. 18%, P < 0.0001; 5-yr, 61% vs. 48%, P = 0.001). These patients were more likely to have rapid-onset of spirometry decline (P = 0.05) and lower FEV1% predicted (P = 0.04) at presentation. CONCLUSIONS: FVC decline from its post-transplant baseline provides valuable prognostic information. Concurrent FEV1 and FVC decline identifies patients with fulminant, rapid deterioration and is the strongest clinical predictor of poor survival. Subsequent FVC decline in patients with an initial isolated FEV1 decline identifies disease progression and portends poor prognosis. PMID- 25922974 TI - Lattice-Matched InGaAs-InAlAs Core-Shell Nanowires with Improved Luminescence and Photoresponse Properties. AB - Core-shell nanowires (NW) have become very prominent systems for band engineered NW heterostructures that effectively suppress detrimental surface states and improve performance of related devices. This concept is particularly attractive for material systems with high intrinsic surface state densities, such as the low bandgap In-containing group-III arsenides, however selection of inappropriate, lattice-mismatched shell materials have frequently caused undesired strain accumulation, defect formation, and modifications of the electronic band structure. Here, we demonstrate the realization of closely lattice-matched radial InGaAs-InAlAs core-shell NWs tunable over large compositional ranges [x(Ga)~y(Al) = 0.2-0.65] via completely catalyst-free selective-area molecular beam epitaxy. On the basis of high-resolution X-ray reciprocal space maps the strain in the NW core is found to be insignificant (epsilon < 0.1%), which is further reflected by the absence of strain-induced spectral shifts in luminescence spectra and nearly unmodified band structure. Remarkably, the lattice-matched InAlAs shell strongly enhances the optical efficiency by up to 2 orders of magnitude, where the efficiency enhancement scales directly with increasing band offset as both Ga- and Al-contents increase. Ultimately, we fabricated vertical InGaAs-InAlAs NW/Si photovoltaic cells and show that the enhanced internal quantum efficiency is directly translated to an energy conversion efficiency that is ~3-4 times larger as compared to an unpassivated cell. These results highlight the promising performance of lattice-matched III-V core-shell NW heterostructures with significant impact on future development of related nanophotonic and electronic devices. PMID- 25922975 TI - Gene transcript accumulation and in situ mRNA hybridization of two putative glutamate dehydrogenase genes in etiolated Glycine max seedlings. AB - Glutamate dehydrogenase (EC 1.4.1.2) is a multimeric enzyme that catalyzes the reversible amination of alpha-ketoglutarate to form glutamate. We characterized cDNA clones of two Glycine max sequences, GmGDH1 and GmGDH2, that code for putative alpha- and beta-subunits, respectively, of the NADH dependent enzyme. Temporal and spatial gene transcript accumulation studies using semiquantitative RT-PCR and in situ hybridization have shown an overlapping gene transcript accumulation pattern with differences in relative gene transcript accumulation in the organs examined. Detection of NADH-dependent glutamate dehydrogenase activity in situ using a histochemical method showed concordance with the spatial gene transcript accumulation patterns. Our findings suggest that although the two gene transcripts are co-localized in roots of etiolated soybean seedlings, the ratio of the two subunits of the active holoenzyme may vary among tissues. PMID- 25922976 TI - Chemical synthesis and assembly of uniformly sized iron oxide nanoparticles for medical applications. AB - Magnetic iron oxide nanoparticles have been extensively investigated for their various biomedical applications including diagnostic imaging, biological sensing, drug, cell, and gene delivery, and cell tracking. Recent advances in the designed synthesis and assembly of uniformly sized iron oxide nanoparticles have brought innovation in the field of nanomedicine. This Account provides a review on the recent progresses in the controlled synthesis and assembly of uniformly sized iron oxide nanoparticles for medical applications. In particular, it focuses on three topics: stringent control of particle size during synthesis via the "heat up" process, surface modification for the high stability and biocompatibility of the nanoparticles for diagnostic purposes, and assembly of the nanoparticles within polymers or mesoporous silica matrices for theranostic applications. Using extremely small 3 nm sized iron oxide nanoparticles (ESION), a new nontoxic T1 MRI contrast agent was realized for high-resolution MRI of blood vessels down to 0.2 mm. Ferrimagnetic iron oxide nanoparticles (FION) that are larger than 20 nm exhibit extremely large magnetization and coercivity values. The cells labeled with FIONs showed very high T2 contrast effect so that even a single cell can be readily imaged. Designed assembly of iron oxide nanoparticles with mesoporous silica and polymers was conducted to fabricate multifunctional nanoparticles for theranostic applications. Mesoporous silica nanoparticles are excellent scaffolds for iron oxide nanoparticles, providing magnetic resonance and fluorescence imaging modalities as well as the functionality of the drug delivery vehicle. Polymeric ligands could be designed to respond to various biological stimuli such as pH, temperature, and enzymatic activity. For example, we fabricated tumor pH sensitive magnetic nanogrenades (termed PMNs) composed of self-assembled iron oxide nanoparticles and pH-responsive ligands. They were utilized to visualize small tumors (<3 mm) via pH-responsive T1 MRI and fluorescence imaging. Also, superior photodynamic therapeutic efficacy in highly drug-resistant heterogeneous tumors was observed. We expect that these multifunctional and bioresponsive nanoplatforms based on uniformly sized iron oxide nanoparticles will provide more unique theranostic approaches in clinical uses. PMID- 25922977 TI - Noninvasive visualization of tumoral fibrin deposition using a peptidic fibrin binding single photon emission computed tomography tracer. AB - Fibrin deposition plays an important role in the formation of mature tumor stroma and provides a facilitating scaffold for tumor angiogenesis. This study investigates the potential of the (111)In-labeled fibrin-binding peptide EPep for SPECT imaging of intratumoral fibrin deposition. (111)In-EPep and negative control (111)In-NCEPep were synthesized and characterized in vitro. In vivo SPECT images and ex vivo biodistribution profiles and autoradiographs were obtained in a fibrin-rich BT-20 breast cancer mouse model. Furthermore, biodistribution profiles were obtained in the fibrin-poor MDA-MD-231 model. In vitro, (111)In EPep displayed significantly more binding than (111)In-NCEPep toward human and mouse derived fibrin. SPECT/CT images displayed a marked SPECT signal in the tumor area for BT-20 tumor bearing mice injected with EPep but not for mice injected with NCEPep. Biodistribution profiles of BT-20 tumor bearing mice 3 h post-tracer injection showed significantly higher tumor uptake for EPep with respect to NCEPep (0.39 +/- 0.14 and 0.11 +/- 0.03% ID g(-1), respectively), whereas uptake in other organs was similar for EPep and NCEPep. Autoradiography of BT-20 tumor sections displayed a high signal for EPep which colocalized with intratumoral fibrin deposits. Histological evaluation of MDA-MB-231 tumor sections displayed no significant tumor stroma and only minute fibrin deposits. Biodistribution profiles in MDA-MB-231 tumor bearing mice 3 h post-injection showed EPep tumor uptake (0.14 +/- 0.04% ID g(-1)) which was significantly lower with respect to EPep BT-20 tumor uptake, indicating fibrin-specificity of EPep tumoral uptake. In conclusion, this work demonstrates the potential of EPep SPECT imaging for visualization of tumoral fibrin deposition. PMID- 25922978 TI - Naloxone added to bupivacaine or bupivacaine-fentanyl prolongs motor and sensory block during supraclavicular brachial plexus blockade: a randomized clinical trial. AB - BACKGROUND: In this study, the effect of naloxone on duration of supraclavicular brachial plexus block was evaluated. It was hypothesized that naloxone can increase the duration of neural blockade. METHODS: Sixty-eight patients scheduled for surgery under supraclavicular brachial plexus block were randomly assigned to receive 30 ml bupivacaine (Group C); 30 ml bupivacaine with 100 MUg of fentanyl (Group F); 30 ml bupivacaine with 100 ng naloxone (Group N); or 30 ml bupivacaine with 100 MUg of fentanyl and 100 ng naloxone (Group N + F). Sensory and motor blockade were recorded at 5, 15, and 30 min following the block, and every 10 min following the end of surgery. Duration of sensory and motor block was considered to be the time interval between the complete block and the first postoperative pain and complete recovery of motor functions. RESULTS: Sensory and motor onset times were the same in all groups. The duration of sensory and motor block in Group C (11.3 +/- 1.7 h and 4.56 +/- 1.0 h) and Group F (12.8 +/- 3.3 h and 5.1 +/- 2.0 h) were less than in the other groups (18.1 +/- 2.2 h and 6.18 +/- 1.0 h in Group N, and 15.8 +/- 2.9 h and 6.53 +/- 1.1 h in Group N + F, P < 0.0001). CONCLUSION: Addition of naloxone to bupivacaine in supraclavicular brachial plexus block prolonged the duration of the neural blockade. PMID- 25922979 TI - Nut clusters and crisps: atrocity stories and co-narration in interviews with approved mental health professionals. AB - The article explores the telling of co-narrated atrocity stories in accomplishing professional identity. Building on previous work, it is argued that group membership is a prerequisite for such stories to be told. Extracts from empirical data from interviews with social work approved mental health professionals are analysed using an ethnomethodological approach. The findings show how atrocity stories can be co-narrated, not only by longstanding colleagues, but also by two unacquainted persons who share the same professional identity. The article concludes that the ethnomethodological concepts of vulgar competency, unique adequacy, indexicality and the documentary method of interpretation are key to understanding the accomplishment of co-narrated atrocity stories. PMID- 25922980 TI - Prevalence and clinical characteristics of myelinated retinal nerve fibres: a cross-sectional study of Turkish individuals between 8 and 75 years. PMID- 25922981 TI - Dynamical phases of attractive particles sliding on a structured surface. AB - Inspired by experiments on quartz crystal microbalance setups, we study the mobility of a monolayer of Lennard-Jones particles driven over a hexagonal external potential. We pay special attention to the changes in the dynamical phases that arise when the lattice constant of the external substrate potential and the Lennard-Jones interaction are mismatched. We find that if the average particle separation is such that the particles repel each other, or interact harmonically, the qualitative behavior of the system is akin to that of a monolayer of purely repulsive Yukawa particles. On the other hand, if the particles typically attract each other, the ensuing dynamical states are determined entirely by the relative strength of the Lennard-Jones interaction with respect to that of the external potential. PMID- 25922982 TI - The effectiveness of marine reserve systems constructed using different surrogates of biodiversity. AB - Biological sampling in marine systems is often limited, and the cost of acquiring new data is high. We sought to assess whether systematic reserves designed using abiotic domains adequately conserve a comprehensive range of species in a tropical marine inter-reef system. We based our assessment on data from the Great Barrier Reef, Australia. We designed reserve systems aiming to conserve 30% of each species based on 4 abiotic surrogate types (abiotic domains; weighted abiotic domains; pre-defined bioregions; and random selection of areas). We evaluated each surrogate in scenarios with and without cost (cost to fishery) and clumping (size of conservation area) constraints. To measure the efficacy of each reserve system for conservation purposes, we evaluated how well 842 species collected at 1155 sites across the Great Barrier Reef seabed were represented in each reserve system. When reserve design included both cost and clumping constraints, the mean proportion of species reaching the conservation target was 20-27% higher for reserve systems that were biologically informed than reserves designed using unweighted environmental data. All domains performed substantially better than random, except when there were no spatial or economic constraints placed on the system design. Under the scenario with no constraints, the mean proportion of species reaching the conservation target ranged from 98.5% to 99.99% across all surrogate domains, whereas the range was 90-96% across all domains when both cost and clumping were considered. This proportion did not change considerably between scenarios where one constraint was imposed and scenarios where both cost and clumping constraints were considered. We conclude that representative reserve systems can be designed using abiotic domains; however, there are substantial benefits if some biological information is incorporated. PMID- 25922984 TI - 2015 american transplant congress abstracts. AB - To access the ATC 2015 abstracts, please visit http://www.atcmeetingabstracts.com/. PMID- 25922983 TI - Infectious disease outbreaks and increased complexity of care. AB - AIM: This study examined the effects of healthcare-associated infectious disease outbreaks on nurses' work in a large acute care hospital in Ontario, Canada. BACKGROUND: The incidence of healthcare-associated infections has increased. Previous research focuses on epidemiology, healthcare systems, and the economic burden of outbreaks. Few published studies focus on the impact of outbreaks on nurses' work in acute care facilities. INTRODUCTION: Since the severe acute respiratory syndrome epidemic in 2003, combating infectious diseases has become a key issue. Hospitals have implemented measures related to healthcare-associated infections. However, nurses experience challenges in preventing, controlling, and contending with outbreaks. METHODS: A retrospective exploratory case study approach was used. Data were collected over a 4-month period in 2012. The incidence rates of site-specific HAIs were analysed, and individual interviews were held with 23 bedside nurses and five nurse managers. FINDINGS: Five themes emerged from the interviews: comparison of healthcare-associated infections outbreaks; the nature of nurses' work; impact of outbreaks on patient care; innovation and quality control in clinical practice; and increased and expanded IPAC measures. The incidence rates of methicillin-resistant Staphylococcus aureus, Clostridium difficile and vancomycin-resistant enterococci at the study site decreased, but remained above provincial benchmarks. Nurses experienced workload challenges, time pressures and psychological effects stemming from outbreaks and developed various innovations in response. Patient care was also affected. CONCLUSION: Nurses' work has been impacted by healthcare-associated infectious disease outbreaks. Nursing workloads should be quantified to facilitate the development of guidelines for optimum nurse-patient ratio during outbreaks. IMPLICATIONS FOR NURSING AND/OR HEALTH POLICY: A strong evidence-based policy framework is required to address healthcare-associated infectious disease outbreaks. Infection prevention and control guidelines and procedures should be established provincially and nationally. An interdisciplinary approach is essential for the creation of comprehensive and innovative strategies. Nursing research has increased understanding of the implications of infectious diseases in hospitals. Building on the literature, findings from this study can be used to influence policies on the care of patients who have secondary infections. Nurse driven protocols are important and can lead to the creation of best practice guidelines that can be implemented across settings. PMID- 25922986 TI - Expression of CCL22 and Infiltration by Regulatory T Cells are Increased in the Decidua of Human Miscarriage Placentas. AB - PROBLEM: Regulatory T cells (Treg) are a T-cell subpopulation with suppressive capacities, specifically attracted by CCL22. We aimed to investigate whether CCL22 is expressed in human placentas and whether its presence, together with Treg infiltration, is associated with miscarriage conditions. METHOD OF STUDY: Paraffin samples were stained for CCL22 and for the Treg-specific transcription factor FoxP3. Expression levels were evaluated in a semi-quantitative manner. Double immunofluorescence was used for the identification of CCL22-producing cells. RESULTS: In all placentas, trophoblasts expressed CCL22. Interestingly, expression in the decidua was only observed in miscarriage conditions. Maternal stromal cells expressed CCL22. Correlation with a higher presence of Treg in the decidua of abortive tissues was observed. CONCLUSION: Our results demonstrate that CCL22 is expressed in human placenta. Decidual expression was only observed in miscarriage conditions and correlates with Treg infiltration. Thus, CCL22 plays a role in human pregnancy and may occur as a negative feedback response to pro-inflammatory events during miscarriage conditions. PMID- 25922985 TI - Bacterial diversity along a 2600 km river continuum. AB - The bacterioplankton diversity in large rivers has thus far been under-sampled despite the importance of streams and rivers as components of continental landscapes. Here, we present a comprehensive dataset detailing the bacterioplankton diversity along the midstream of the Danube River and its tributaries. Using 16S rRNA-gene amplicon sequencing, our analysis revealed that bacterial richness and evenness gradually declined downriver in both the free living and particle-associated bacterial communities. These shifts were also supported by beta diversity analysis, where the effects of tributaries were negligible in regards to the overall variation. In addition, the river was largely dominated by bacteria that are commonly observed in freshwaters. Dominated by the acI lineage, the freshwater SAR11 (LD12) and the Polynucleobacter group, typical freshwater taxa increased in proportion downriver and were accompanied by a decrease in soil and groundwater-affiliated bacteria. Based on views of the meta-community and River Continuum Concept, we interpret the observed taxonomic patterns and accompanying changes in alpha and beta diversity with the intention of laying the foundation for a unified concept for river bacterioplankton diversity. PMID- 25922987 TI - Regulation of flowering time by the histone deacetylase HDA5 in Arabidopsis. AB - The acetylation level of histones on lysine residues regulated by histone acetyltransferases and histone deacetylases plays an important but under-studied role in the control of gene expression in plants. With the aim of characterizing the Arabidopsis RPD3/HDA1 family histone deacetylase HDA5, we present evidence showing that HDA5 displays deacetylase activity. Mutants defective in the expression of HDA5 displayed a late-flowering phenotype. Expression of the flowering repressor genes FLC and MAF1 was up-regulated in hda5 mutants. Furthermore, the gene activation markers, histone H3 acetylation and H3K4 trimethylation on FLC and MAF1 chromatin were increased in hda5-1 mutants. Chromatin immunoprecipitation analysis showed that HDA5 binds to the chromatin of FLC and MAF1. Bimolecular fluorescence complementation assays and co immunoprecipitation assays showed that HDA5 interacts with FVE, FLD and HDA6, indicating that these proteins are present in a protein complex involved in the regulation of flowering time. Comparing gene expression profiles of hda5 and hda6 mutants by RNA-seq revealed that HDA5 and HDA6 co-regulate gene expression in multiple development processes and pathways. PMID- 25922988 TI - Yellow Fever Vaccination of a Primary Vaccinee During Adalimumab Therapy. AB - In this case report, we describe a 63-year-old female with Crohn's disease since age 16 years, and on adalimumab therapy, who inadvertently received a yellow fever vaccine (YFV) 4 days before her next dose of adalimumab. She had never received YFV. Her next dose of tumor necrosis factor (TNF) antagonist was held. She did not report any adverse effects referable to the vaccine. Reverse transcriptase-polymerase chain reaction (RT-PCR) for yellow fever (YF) viral RNA on days 12 and 18 postvaccination was negative. Neutralizing antibody to YF virus vaccine was immunoprotective on day 18 following vaccination, which further increased by day 26. A neutralizing antibody obtained 2 years following vaccination also remained immunoprotective. PMID- 25922989 TI - A Meta-Analysis of Cigarette Smoking Prevalence among Adolescents in China: 1981 2010. AB - BACKGROUND: Systematic data regarding adolescent smoking are needed at the national level to support evidence-based tobacco control in China. The goal of this study was to estimate smoking prevalence among Chinese adolescents using published data. METHODS: Published studies were located electronically from the commonly used databases in Chinese and English, complemented by manual searching. Forty-five studies were selected of the 9771 retrieved from the databases. These studies targeted adolescents aged 12-17 or middle/high school students, were conducted during the 1981-2010, and had adequate data for meta-analysis. The 45 selected studies covered 52 sites in different parts of China. Smoking rates were estimated using the sample-weighted and random effect method. RESULTS: The estimated prevalence rate of lifetime smoking (ever smoked) varied within a narrow range (39.04%-46.03%) for males and progressively increased from 2.47% in 1981-1985 to 19.72% in 2001-2005 for females. The prevalence rate of current (30 day) smoking for males declined from 26.62% in 1981-1985 to 10.86% in 1996-2000 before increasing again. The prevalence of current smoking for females increased from 0.29% in 1981-1985 to 3.26% in 2006-2010. CONCLUSIONS: The high levels of male smoking and the rapid increase in female smoking indicate growing burdens from tobacco-related diseases, underscoring the urgent need to strengthen adolescent tobacco control in China. PMID- 25922990 TI - Correction: Gravely, S., et al. Awareness, Trial, and Current Use of Electronic Cigarettes in 10 Countries: Findings from the ITC Project. Int. J. Environ. Res. Public Health 2014, 11, 11691-11704. AB - The authors wish to make the following amendments to their paper published in International Journal of Environmental Research and Public Health. PMID- 25922991 TI - Clicking for supper. AB - When close to prey, porpoises actively widen their sonar beam, which may make it harder for the prey to escape. PMID- 25922993 TI - Language impairment in bilingual children: from theory to practice. PMID- 25922992 TI - A simple biophysical model emulates budding yeast chromosome condensation. AB - Mitotic chromosomes were one of the first cell biological structures to be described, yet their molecular architecture remains poorly understood. We have devised a simple biophysical model of a 300 kb-long nucleosome chain, the size of a budding yeast chromosome, constrained by interactions between binding sites of the chromosomal condensin complex, a key component of interphase and mitotic chromosomes. Comparisons of computational and experimental (4C) interaction maps, and other biophysical features, allow us to predict a mode of condensin action. Stochastic condensin-mediated pairwise interactions along the nucleosome chain generate native-like chromosome features and recapitulate chromosome compaction and individualization during mitotic condensation. Higher order interactions between condensin binding sites explain the data less well. Our results suggest that basic assumptions about chromatin behavior go a long way to explain chromosome architecture and are able to generate a molecular model of what the inside of a chromosome is likely to look like. PMID- 25922994 TI - What Clinicians Need to Know about Bilingual Development. AB - Basic research on bilingual development suggests several conclusions that can inform clinical practice with children from bilingual environments. They include the following: (1) Dual language input does not confuse children. (2) It is not necessary for the two languages to be kept separate in children's experience to avoid confusion. (3) Learning two languages takes longer than learning one; on average, bilingual children lag behind monolingual children in single language comparisons. (4) A dominant language is not equivalent to an only language. (5) A measure of total vocabulary provides the best indicator of young bilingual children's language learning capacity. (6) Bilingual children can have different strengths in each language. (7) The quantity and quality of bilingual children's input in each language influence their rates of development in each language. (8) Immigrant parents should not be discouraged from speaking their native language to their children. (9) Bilingual environments vary enormously in the support they provide for each language, with the result that bilingual children vary enormously in their dual language skills. Empirical findings in support of each conclusion are presented. PMID- 25922995 TI - Phonological development in young bilinguals: clinical implications. AB - This article reviews recent research on bilingual phonological development and describes the nature of bilingual phonology, focusing on characteristics of cross linguistic influence on bilingual phonological abilities. There is evidence of positive and negative transfer (acceleration and deceleration) on children's phonological abilities. Several methodological issues limit the ability to generalize findings from previous research to larger groups of bilingual children (e.g., small sample size, lack of consideration of age of acquisition of each language, and language abilities of the participants). Sources of heterogeneity in language development are presented and discussed. Phonological abilities are related to language abilities in bilingual first language learners of English and Spanish. Empirical evidence from research in our laboratory supports this claim. We discuss implications of research findings and limitations for future research and clinical practice. We provide specific recommendations for bilingual research and for clinical assessment of young bilingual children. PMID- 25922996 TI - Speech Practice Effects on Bilingual Children's Fast Mapping Performance. AB - Learning a new word involves many subsystems and their interactions. The purpose of this study was to examine whether speech practice facilitates the subsequent fast mapping performance of bilingual preschool children. Participants were 18 typically developing preschoolers who learned Cantonese (L1) as a home language and English (L2) as a second language. Each participant was asked to repeat each of the four novel words after an auditory model (speech practice) before he or she was exposed to the novel word-objects in the subsequent fast mapping task. Significant speech practice and language effects on fast mapping production scores were found. These findings suggest a complex relationship between speech learning, fast mapping, and L1-L2 language skills. Our results suggest that clinical methods that facilitate bilingual children's production skills (e.g., repeat after a model) hold promise as a means of improving the initial stage of word learning in both languages. PMID- 25922997 TI - Taking account of both languages in the assessment of dual language learners. AB - This article addresses the issue of "adjusted" assessment of bilingual children, a practice that acknowledges that children who know two languages have distributed knowledge of those languages. In recent work, at least three procedures have become common for taking into account this distributed knowledge: a conceptual score, in which children are given credit for knowing some feature of language in either language; a combined or total score, which adds units of knowledge from each language together; and a best score, in which the performance in the better language is taken as the most appropriate measure. The article begins with a discussion of the rationale behind the varied scores. After reviewing a sample of studies that used each type, I will argue that vocabulary and morphosyntax are fundamentally different types of knowledge that may need distinct kinds of adjusted measurement. The value of each kind of adjusted assessment must be considered relative to its purpose: is it to gauge the child's readiness for schooling? Or is it to detect language disorders? Finally, a plea is made for more basic research to answer the many questions that are raised. PMID- 25922998 TI - Dual language intervention for bilinguals at risk for language impairment. AB - Selecting the initial language of intervention for bilingual children at risk for language impairment is challenging for clinicians, as both the home and academic languages are important for children's successful communication. In this project, six Spanish-English bilingual first graders at risk for language impairment participated in an 8-week intervention program targeting vocabulary, morphosyntax, narrative, and literacy skills in both Spanish and English. Children completed 24 small-group sessions (three times a week). One group received Spanish intervention first, then English, and another group received English first, then Spanish. The systematic use of both languages in intervention resulted in overall gains in vocabulary and narrative skills in this short-term intervention. Language condition groups differed in performance on oral narratives and semantics. Clinical recommendations for selecting the initial language of intervention are discussed. PMID- 25922999 TI - Parent programs for latino families with young children: social, cultural, and linguistic considerations. AB - It is likely that speech-language pathologists (SLPs) will be called upon to serve the growing numbers of children under age 5 from Latino families. Families are considered central to implementing language facilitation strategies at this age. These strategies must be both culturally informed and also focus on naturally occurring experiences in children's homes. However, few existing early intervention programs are specific to the cultural values and language learning experiences of young Latino children. This article reviews the current knowledge base on the early language learning experiences of these children and provides SLPs implementing family programs with suggestions on adapting family-centered language facilitation techniques to this population. PMID- 25923001 TI - Broken mirror. PMID- 25923000 TI - Preschool language interventions for latino dual language learners with language disorders: what, in what language, and how. AB - About a quarter of young children in the United States are dual language learners. The large majority are Latino children who are exposed to Spanish in their homes. The language needs of Latino dual language preschoolers are different from the needs of monolingual English-speaking children. As a group, they are likely to live in environments that put them at risk of delays in language development. This situation is direr for dual language preschoolers with language impairment. Recent findings from studies on interventions for Spanish English preschoolers with language impairment suggest that a bilingual approach does not delay English vocabulary and oral language learning and promotes Spanish maintenance. Targets and strategies for different language domains are described. The effects of pullout versus push-in interventions for this population are preliminarily explored. PMID- 25923002 TI - The selfish brain. PMID- 25923003 TI - The "selfish brain" hypothesis for metabolic abnormalities in bipolar disorder and schizophrenia. AB - Metabolic abnormalities are frequent in patients with schizophrenia and bipolar disorder (BD), leading to a high prevalence of diabetes and metabolic syndrome in this population. Moreover, mortality rates among patients are higher than in the general population, especially due to cardiovascular diseases. Several neurobiological systems involved in energy metabolism have been shown to be altered in both illnesses; however, the cause of metabolic abnormalities and how they relate to schizophrenia and BD pathophysiology are still largely unknown. The "selfish brain" theory is a recent paradigm postulating that, in order to maintain its own energy supply stable, the brain modulates energy metabolism in the periphery by regulation of both allocation and intake of nutrients. We hypothesize that the metabolic alterations observed in these disorders are a result of an inefficient regulation of the brain energy supply and its compensatory mechanisms. The selfish brain theory can also expand our understanding of stress adaptation and neuroprogression in schizophrenia and BD, and, overall, can have important clinical implications for both illnesses. PMID- 25923004 TI - Cross-cultural adaptation of the Operationalized Psychodynamic Diagnosis (OPD-2) in Portugal. AB - BACKGROUND: The Operationalized Psychodynamic Diagnosis (OPD-2) is internationally established as one of the major instruments available for clinical diagnosis and scientific research, being frequently used as an auxiliary tool in the selection of therapeutic interventions. AIMS: 1) To describe the methodological aspects of the adaptation of the OPD-2 into Portuguese (Portugal and Brazil). 2) To assess inter-rater agreement for the different axes of the instrument when scoring clinical interviews. METHOD: The cross-cultural adaptation involved translation of the instrument by different independent translators, whose versions were compared in discussion groups in order to develop a final Portuguese version. In the presence of discrepancies regarding the translation of original concepts, the authors of the original instrument were contacted for clarification. Five interviews were used to assess inter-rater agreement. Each subject participated in two interviews, conducted by an experienced clinical psychologist. The interviews were recorded, transcribed and then analyzed by the principal investigator and by three independent examiners. RESULTS: Axis IV (Structure) presented the highest inter-rater agreement (78%). Axes I (Experience of illness and prerequisites for treatment) and III (Conflict) showed the lowest inter-rater agreement results (66 and 57.7%, respectively). CONCLUSIONS: Our results point in the same direction as previous studies conducted in other countries. In our sample, the OPD-2 presented an acceptable inter-rater agreement; however, further studies are needed to assess the instrument's reliability. PMID- 25923005 TI - Problematic parent-infant relationships in two-parent families: prevalence and risk factors in a Brazilian neighborhood. AB - INTRODUCTION: Although the quality of parent-child relationships is known to be associated with the offspring's mental health, little is known about the prevalence of problematic relationships in this scenario. This cross-sectional study aims to investigate the prevalence and risk factors of different types of early parent-infant relationships in a Brazilian population group. METHODS: During 1 year, all families (n = 230) from an urban community of Porto Alegre, southern Brazil, with 4-month-old infants born in public hospitals were identified, and 148 were fully investigated by two family therapists. This study describes data on the 116 infants with two-parent families. Demographic, obstetric, and relational variables were collected through questionnaires and scales (Parent-Infant Relationship Global Assessment Scale, Global Assessment of Relational Functioning, and Self-Report Questionnaire). Prevalence ratios were calculated, and Poisson regression with robust variance was performed to adjust for covariates. RESULTS: Almost 10% of mothers and 12% of fathers showed at least a significantly perturbed relationship with their 4-month-old infants. Inadequate mother-infant bonding coincided with evidence of paternal mental disorder, poor maternal social network, and discontinuation of breastfeeding at 4 months. A problematic father-infant relationship was associated with a dysfunctional couple relationship and with low infant birth weight. CONCLUSIONS: There is a high prevalence of early parent-child relationship problems, suggesting a need for health system interventions. Parent-infant relational problems are prevalent very early in life and more associated with other relational problems than with socioeconomic burden. PMID- 25923006 TI - Brazilian Portuguese version of the Spence Children's Anxiety Scale (SCAS Brasil). AB - OBJECTIVE: To describe the cross-cultural adaptation of the Spence Children's Anxiety Scale (SCAS) for use in Brazil. METHODS: Cross-cultural adaptation followed a four-step process, based on specialized literature: 1) investigation of conceptual and item equivalence; 2) translation and back-translation; 3) pretest; and 4) investigation of operational equivalence. All these procedures were carried out for both the child and the parent versions of the SCAS. RESULTS: A final Brazilian version of the instrument, named SCAS-Brasil, was defined and is presented. CONCLUSION: The SCAS-Brasil instrument seems to be very similar to the original SCAS in terms of conceptual and item equivalence, semantics, and operational equivalence, suggesting that future cross-cultural studies may benefit from this early version. As a result, a new instrument is now available for the assessment of childhood anxiety symptoms in community, clinical, and research settings. PMID- 25923007 TI - Prevalence and profile of daily smokers seen at three primary health care units in Pelotas, southern Brazil. AB - OBJECTIVES: To estimate the prevalence of daily smoking among users of three primary health care units affiliated with a university hospital in the municipality of Pelotas, southern Brazil, and to identify factors associated with daily tobacco consumption. METHODS: This cross-sectional study included all individuals over 14 years of age who sought treatment at the health care units between June 29, 2009, and February 23, 2010, and lived in the area covered by the unit. Interviews were conducted during home visits to collect data on sociodemographic characteristics and health behaviors; the Mini International Neuropsychiatric Interview (MINI) was used to assess the presence of mood disorders; and a question from the Alcohol, Smoking and Substance Involvement Screening Test (ASSIST) on the daily use of tobacco in the past 3 months was used to assess smoking. RESULTS: The total sample comprised 1,848 individuals, mostly female (72.9%), aged between 46 and 60 years (28.5%), and belonging to socioeconomic class C (61%). The prevalence of daily smoking was 23.4% (n = 432), and there was a statistically significant difference between men and women: 27 vs. 22.1% (p < 0.050). CONCLUSION: Our findings confirm a high prevalence of smoking among users of primary health care units, underscoring the need for a more accurate process of diagnosis and treatment at these facilities. PMID- 25923009 TI - Use of antidepressants in the medical context. PMID- 25923008 TI - Low serum levels of 25-hydroxyvitamin D (25-OHD) in children with autism. AB - OBJECTIVE: To confirm previous evidence suggesting an association between autism and low vitamin D serum levels. METHODS: This preliminary exploratory study assessed the circulating levels of 25-hydroxyvitamin D (25-OHD) in pediatric patients with autism and in typically developing controls from Juiz de Fora, Brazil. RESULTS: Serum levels of 25-OHD were lower in children with autism (26.48 +/- 3.48 ng mL-1) when compared to typically developing subjects (40.52 +/- 3.13 ng mL-1) (p < 0.001). CONCLUSION: Our findings attest to the importance of vitamin supplementation during pregnancy and in the treatment of children with autism, who tend to present low vitamin D consumption rates. PMID- 25923010 TI - Can the self-propulsion of anisotropic microswimmers be described by using forces and torques? AB - The self-propulsion of artificial and biological microswimmers (or active colloidal particles) has often been modelled by using a force and a torque entering into the overdamped equations for the Brownian motion of passive particles. This seemingly contradicts the fact that a swimmer is force-free and torque-free, i.e. that the net force and torque on the particle vanish. Using different models for mechanical and diffusiophoretic self-propulsion, we demonstrate here that the equations of motion of microswimmers can be mapped onto those of passive particles with the shape-dependent grand resistance matrix and formally external effective forces and torques. This is consistent with experimental findings on the circular motion of artificial asymmetric microswimmers driven by self-diffusiophoresis. The concept of effective self propulsion forces and torques significantly facilitates the understanding of the swimming paths, e.g. for a microswimmer under gravity. However, this concept has its limitations when the self-propulsion mechanism of a swimmer is disturbed either by another particle in its close vicinity or by interactions with obstacles, such as a wall. PMID- 25923011 TI - Understanding Pig and Poultry Trade Networks and Farming Practices Within the Pacific Islands as a Basis for Surveillance. AB - Pacific Island countries have large pig and poultry populations. Yet little is known about patterns of contact between animals and how this influences disease spread in these islands. The objectives of this study were to examine farmer practices and the movements of pig and poultry within the Pacific Islands using questionnaires and social network analysis (SNA) tools to understand disease spread in the region. Questionnaire-based surveys were conducted in Fiji, Papua New Guinea (PNG), Solomon Islands and Vanuatu with interviews of 310 pig farmers and 491 poultry farmers. Pacific Island farmers were found to have few animals (median = 7 pigs/farm, IQR 4-12), (median = 50 chicken/farm, IQR 23-52), (median = 10 ducks/farm, IQR 4-25), (median = 12 Muscovy ducks/farm, IQR 7-28) and a diversified number of species. A large proportion of farmers (44.6-61.3%) do not implement any preventive or control measures, yet the majority (80.6-88%) did not experience any animal diseases over the past 12 months. Most farmers never ask for veterinary care, never engage in laboratory testing and do not report when their animals show clinical signs. Many pig farmers (31.8%) trade within their communities only and sell (24.5%) directly to consumers which reduces the risk of diseases spreading. Our results show an association between farmers that report having had disease on their farm in the past 12 months and movements of animals on and off their farms. The capitals of the studied provinces in PNG, Vanuatu and Solomon Islands were identified as the most connected nodes of both pig and poultry trade, while Fiji networks appeared much less connected. Our study found that farmer practices increased the risk of disease spread, but this was currently limited by trading practices. The SNA results serve as a basis for more targeted disease surveillance and better use of available resources for disease prevention and control. PMID- 25923012 TI - The challenges of research participation by children. PMID- 25923013 TI - SIRT7 inactivation reverses metastatic phenotypes in epithelial and mesenchymal tumors. AB - Metastasis is responsible for over 90% of cancer-associated mortality. In epithelial carcinomas, a key process in metastatic progression is the epigenetic reprogramming of an epithelial-to-mesenchymal transition-like (EMT) change towards invasive cellular phenotypes. In non-epithelial cancers, different mechanisms must underlie metastatic change, but relatively little is known about the factors involved. Here, we identify the chromatin regulatory Sirtuin factor SIRT7 as a key regulator of metastatic phenotypes in both epithelial and mesenchymal cancer cells. In epithelial prostate carcinomas, high SIRT7 levels are associated with aggressive cancer phenotypes, metastatic disease, and poor patient prognosis, and depletion of SIRT7 can reprogram these cells to a less aggressive phenotype. Interestingly, SIRT7 is also important for maintaining the invasiveness and metastatic potential of non-epithelial sarcoma cells. Moreover, SIRT7 inactivation dramatically suppresses cancer cell metastasis in vivo, independent of changes in primary tumor growth. Mechanistically, we also uncover a novel link between SIRT7 and its family member SIRT1, providing the first demonstration of direct interaction and functional interplay between two mammalian sirtuins. Together with previous work, our findings highlight the broad role of SIRT7 in maintaining the metastatic cellular phenotype in diverse cancers. PMID- 25923015 TI - Special Purpose Short Stop-Type Ammunitions (Hornet, Wasp, Mosquito)-Gelatin Model Investigation. AB - Short Stop-type .38 Mesko Special revolver ammunitions have been designed for incapacitation of humans without causing serious bodily injuries. Three types of those ammunitions differing in increasing amounts of gunpowder in the shell chamber and, consequently, increasing kinetic energy of the projectiles can be distinguished: Komar (Mosquito), Osa (Wasp), and Szerszen (Hornet), respectively.The aim of this study was to investigate the ballistic features of such projectiles in a gelatin model. Twenty percent gelatin blocks at 10 degrees C were shot at with a caliber .38 ROSSI Special revolver from 5-, 20-, 50-, and 100-cm distances.The deepest penetration was observed in the case of Hornet-type projectiles, which penetrated into the depth of 10 cm even when shot from 100-cm distance.The results of the research demonstrate that none of the projectiles shot at humans from firearms can be regarded as "safe" because the inflicted injuries do not depend solely on the construction of the bullet, but also on the shooting distance. The use of theoretically nonpenetrating Short Stop-type ammunitions at a distance not exceeding 1 m may cause serious injuries, at times even as extensive as those caused by penetrating projectiles. PMID- 25923016 TI - Effect of Macroscopic Grooves on Bone Formation and Osteoblastic Differentiation. AB - OBJECTIVES: The aim of this study is to investigate the effect of macroscopic grooves on bone formation in vivo and differentiation of human mesenchymal stem cells (hMSCs) in vitro. MATERIALS AND METHODS: The effects of macroscopic grooves on titanium alloy implants and disks were tested in rabbit tibiae and cultured hMSCs. The bone-to-implant contact (BIC) and bone area were evaluated in rabbit tibiae at 6 and 24 weeks after implant insertion. Osteoblastic differentiation was assessed by alkaline phosphatase (ALP) activity and real-time reverse transcription polymerase chain reaction (RT-PCR) on days 7, 14, and 21. All values were statically analyzed. RESULTS: BIC and bone area inside the grooves were significantly higher than those of control implants (P < 0.05). ALP activity was significantly higher for titanium disks with macroscopic grooves than without grooves on day 14 (P < 0.05). Real-time RT-PCR showed that the expression of osteogenic genes was significantly higher for disks with grooves on day 7 (P < 0.01). CONCLUSIONS: Macroscopic grooves accelerate osteoblastic differentiation in vitro and stimulate direct bone growth and deposition within the grooves in vivo. PMID- 25923014 TI - Correction of human phospholamban R14del mutation associated with cardiomyopathy using targeted nucleases and combination therapy. AB - A number of genetic mutations is associated with cardiomyopathies. A mutation in the coding region of the phospholamban (PLN) gene (R14del) is identified in families with hereditary heart failure. Heterozygous patients exhibit left ventricular dilation and ventricular arrhythmias. Here we generate induced pluripotent stem cells (iPSCs) from a patient harbouring the PLN R14del mutation and differentiate them into cardiomyocytes (iPSC-CMs). We find that the PLN R14del mutation induces Ca(2+) handling abnormalities, electrical instability, abnormal cytoplasmic distribution of PLN protein and increases expression of molecular markers of cardiac hypertrophy in iPSC-CMs. Gene correction using transcription activator-like effector nucleases (TALENs) ameliorates the R14del associated disease phenotypes in iPSC-CMs. In addition, we show that knocking down the endogenous PLN and simultaneously expressing a codon-optimized PLN gene reverses the disease phenotype in vitro. Our findings offer novel strategies for targeting the pathogenic mutations associated with cardiomyopathies. PMID- 25923017 TI - High-Level Macrolide-Resistant Moraxella catarrhalis and Development of an Allele Specific PCR Assay for Detection of 23S rRNA Gene A2330T Mutation: A Three-Year Study at a Chinese Tertiary Hospital. AB - Previous studies indicate that macrolide resistance in Moraxella catarrhalis isolates is less common in adults than in children. However, few studies have investigated M. catarrhalis macrolide resistance mechanisms in adult patients. In this study, 124 M. catarrhalis isolates were collected from adult patients in a Chinese tertiary hospital, between 2010 and 2013, and investigated for antimicrobial resistance. We found that only seven isolates were macrolide resistant and all exhibited high-level macrolide resistance (minimum inhibitory concentrations >256 MUg/ml). Multilocus sequence typing (MLST) suggested that M. catarrhalis has a diverse population; in particular, both pulsed-field gel electrophoresis and MLST revealed that all the seven high-level macrolide resistant M. catarrhalis belonged to different clones. A 934-bp 23S rRNA gene sequencing showed that only nine isolates (including all the seven macrolide resistant isolates) had mutations within the studied region, and only the seven macrolide-resistant isolates had mutation of A2330T. No other known macrolide resistance determinant genes (ermA, ermB, mefA, or mefE) were detected. These findings support previous studies in children on M. catarrhalis macrolide resistant isolates and suggest that the 23S rRNA gene A2330T mutation is responsible for the high M. catarrhalis macrolide resistance. The findings prompted us to successfully develop a simple allele-specific polymerase chain reaction assay for high-level macrolide-resistant 23S rRNA gene A2330T mutation for future clinical and further surveillance use. PMID- 25923018 TI - Multidisciplinary pediatric brain tumor clinics: the key to successful treatment? AB - Tumors of the CNS are the most common solid tumors diagnosed in childhood. As technology and research in cancer care are advancing, more specialties are involved in the diagnosis, treatment and follow-up of children with brain tumors. Multidisciplinary clinics have become the standard of care for cancer care throughout the USA, and specialty clinics focused on particular cancer types are gaining attention in improving the patient outcomes and satisfaction. We will discuss the role of multidisciplinary clinics, in an attempt to create preliminary guidelines on establishing and maintaining a multidisciplinary brain tumor clinic in order to optimize the care of the patients and their families. PMID- 25923020 TI - Extensive Tattoos Mimicking Lymphatic Metastasis on Positron Emission Tomography Scan in a Patient With Cervical Cancer. AB - BACKGROUND: Positron emission tomography (PET) fused with computed tomography (CT) imaging is common in the clinical assessment of patients with locally advanced cervical cancer. Limitations to the utilization and interpretation of PET-CT scans in patients with cervical cancer have been described, including false-positive findings secondary to tattoo ink. CASE: A 32-year-old woman presented with clinical stage 1B1 cervical cancer and extensive tattoos of the lower extremities. Preoperative PET-CT scan identified two ileac lymph nodes with increased fluorine-18-deoxyglucose uptake suspicious for metastatic disease. At the time of surgical resection, bilateral pigmented lymph nodes were identified with histologic examination showing deposition of tattoo ink and no malignant cells. CONCLUSION: Physicians should be cognizant of the possible effects of tattoos on PET-CT findings while counseling patients and formulating a treatment program. PMID- 25923019 TI - Structure and Dynamics of GeoCyp: A Thermophilic Cyclophilin with a Novel Substrate Binding Mechanism That Functions Efficiently at Low Temperatures. AB - Thermophilic proteins have found extensive use in research and industrial applications because of their high stability and functionality at elevated temperatures while simultaneously providing valuable insight into our understanding of protein folding, stability, dynamics, and function. Cyclophilins, constituting a ubiquitously expressed family of peptidyl-prolyl isomerases with a range of biological functions and disease associations, have been utilized both for conferring stress tolerances and in exploring the link between conformational dynamics and enzymatic function. To date, however, no active thermophilic cyclophilin has been fully biophysically characterized. Here, we determine the structure of a thermophilic cyclophilin (GeoCyp) from Geobacillus kaustophilus, characterize its dynamic motions over several time scales using an array of methodologies that include chemical shift-based methods and relaxation experiments over a range of temperatures, and measure catalytic activity over a range of temperatures to compare its structure, dynamics, and function to those of a mesophilic counterpart, human cyclophilin A (CypA). Unlike those of most thermophile/mesophile pairs, GeoCyp catalysis is not substantially impaired at low temperatures as compared to that of CypA, retaining ~70% of the activity of its mesophilic counterpart. Examination of substrate-bound ensembles reveals a mechanism by which the two cyclophilins may have adapted to their environments through altering dynamic loop motions and a critical residue that acts as a clamp to regulate substrate binding differentially in CypA and GeoCyp. Fast time scale (pico- to nanosecond) dynamics are largely conserved between the two proteins, in accordance with the high degree of structural similarity, although differences do exist in their temperature dependencies. Slower (microsecond) time scale motions are likewise localized to similar regions in the two proteins with some variability in their magnitudes yet do not exhibit significant temperature dependencies in either enzyme. PMID- 25923021 TI - Fumarate Hydratase Mutation in a Young Woman With Uterine Leiomyomas and a Family History of Renal Cell Cancer. AB - BACKGROUND: Heterozygous gene mutations in fumarate hydratase can result in a syndrome characterized by hereditary (cutaneous and uterine) leiomyomatosis and renal cell cancer. This disorder has been described in more than 200 families, but the prevalence of the disease is unknown. CASE: A 22 year-old woman of Bangladeshi lineage presented with menorrhagia and pelvic pain secondary to uterine leiomyomas and underwent an abdominal myomectomy. Because of a family history of renal cell cancer, she was tested for fumarate hydratase mutations and found to be a carrier. As a result of the risk of renal cell cancer associated with this mutation, an annual surveillance plan was initiated. CONCLUSION: Fumarate hydratase gene mutations should be considered in women presenting with leiomyomas and a family history of renal cancer. PMID- 25923022 TI - Paraneoplastic Cholestasis Associated With Ovarian Dysgerminoma. AB - BACKGROUND: Paraneoplastic syndromes are disorders caused by cancer that are not a direct result of the cancer mass itself or metastases to the affected organ. Paraneoplastic cholestasis is described with lymphoma and renal cell carcinoma. Unlike ovarian carcinoma, paraneoplastic syndromes are rarely seen in dysgerminoma. CASE: A 22-year-old woman presented with 3 days of jaundice and lower abdominal pain. Liver tests revealed marked cholestasis and high alkaline phosphatase and bilirubin levels. Imaging showed a normal-appearing liver, a large multiseptated ovarian cystic mass, ascites, and paraaortic lymphadenopathy. Debulking surgery found a dysgerminoma with metastasis to aortic lymph nodes. Hepatic dysfunction completely resolved within 4 weeks of surgery. CONCLUSION: Paraneoplastic syndrome should be considered in the differential diagnosis for patients with ovarian malignancies who present with cholestasis. PMID- 25923023 TI - Herpes Simplex Virus Cervicitis Mimicking Preterm Premature Rupture of Membranes. AB - BACKGROUND: The diagnosis of preterm premature rupture of membranes (PROM) is based on pooling, ferning, and Nitrazine tests; definitive diagnosis is made with a blue dye test. CASE: A 21-year-old woman, gravida 1 para 0, at 25 5/7 weeks of gestation was admitted for preterm PROM with positive findings of pooling, Nitrazine, and ferning. Her cervix was bluish with white plaques. Amniotic fluid volume was normal. On hospital day 8, her discharge ceased; examination was negative for pooling, Nitrazine, and ferning. A blue dye tampon test was negative. A Pap test result from her hospitalization returned consistent with herpes infection. CONCLUSION: The diagnosis of preterm PROM should be constantly reevaluated in the setting of a normal amniotic fluid volume. PMID- 25923024 TI - Management of Persistent Postpartum Hemorrhage Caused by Inner Myometrial Lacerations. AB - BACKGROUND: Postpartum hemorrhage management must involve rapid recognition of the source of bleeding. Inner myometrial laceration is an uncommonly recognized cause; most cases are demonstrated only by evaluation of peripartum hysterectomy specimens. The exact cause of this laceration is unknown; however, it can be identified by uterine cavity exploration and managed with conservative surgery that preserves fertility. CASE: Postpartum hemorrhage caused by inner myometrial lacerations is presented. We explored the uterine cavity through laparotomy and uterine hysterotomy to identify and repair the source of bleeding. CONCLUSION: In persistent hemorrhage that fails initial interventions, inner myometrial laceration should be considered. Uterine cavity exploration with laparotomy incision and hysterotomy to directly visualize the source are essential steps to manage postpartum hemorrhage while avoiding maternal morbidity, peripartum hysterectomy, and potential mortality. PMID- 25923025 TI - False-Positive Cystoscopic Diagnosis of Ureteral Obstruction After Hysterectomy Due to a Nonfunctional Kidney. AB - BACKGROUND: An estimated 0.2% of the population may have a unilateral nonfunctional kidney. This pre-existing condition may lead to the mistaken presumption that a ureteral injury has occurred when performing cystoscopy after hysterectomy. CASES: Two cases are presented in which cystoscopy to confirm ureteral patency after hysterectomy was performed in patients with pre-existing unknown nonfunctional kidneys. These false-positive findings resulted in additional operative time, additional cost, and unnecessary surgical exploration. CONCLUSION: Cystoscopy to confirm ureteral patency after hysterectomy may lead to an incorrect presumption of a ureteral injury in patients with a pre-existing nonfunctional kidney. PMID- 25923026 TI - Intrapartum Spontaneous Ureteral Rupture. AB - BACKGROUND: Although spontaneous rupture of the renal pelvis during pregnancy has been reported, albeit rarely, spontaneous ureteral rupture is extremely rare. CASE: We present the case of a 22-year-old nulliparous woman with spontaneous ureteral rupture after vaginal delivery diagnosed on contrast-enhanced computed tomography scan. Ureteroscopy revealed a rupture of her right midureter and a JJ stent was successfully placed. CONCLUSION: This case compels us to consider spontaneous ureteral rupture in the differential diagnosis for postpartum abdominal pain when common causes have been ruled out. We report this case to inform clinicians of this rare complication so that diagnosis is not delayed. Diagnosis can be made with contrast-enhanced computed tomography scan and cystoscopy, and ureteral stenting is a reasonable option for management. PMID- 25923028 TI - Pseudo Gitelman Syndrome Associated With Pregnancy. AB - BACKGROUND: Gitelman syndrome is a rare inherited renal tubulopathy associated with metabolic alkalosis and electrolyte disorders. Pseudo Gitelman syndrome presents with the same clinical characteristics as Gitelman syndrome, yet without genetic mutations in SLC12A3. CASE: A 32-year-old woman with no remarkable medical and family history developed hypokalemia at 32 weeks of gestation. Laboratory findings were consistent with Gitelman syndrome and potassium supplementation was initiated. The patient delivered a healthy neonate at 40 weeks of gestation and the electrolyte disorders drastically improved. After delivery, genomic analysis revealed no evidence of mutations in SLC12A3, and pseudo Gitelman syndrome was finally diagnosed. CONCLUSION: Pseudo Gitelman syndrome, presenting with Gitelman syndrome-like renal tubulopathy without mutations in SLC12A3, can cause a temporary electrolyte imbalance based on the physiologic changes of pregnancy. Although pregnant women with isolated hypokalemia need not be evaluated for Gitelman or pseudo Gitelman syndrome, if it is accompanied by metabolic alkalosis, hypocalciuria, hypomagnesia, and activation of the renin-angiotensin-aldosterone system without hypertension, this evaluation should be considered. PMID- 25923027 TI - Vacuum-Assisted Closure for Episiotomy Dehiscence. AB - BACKGROUND: Episiotomy dehiscence can result in a large vulvovaginal defect not amenable to delayed primary closure. CASE: A 26-year-old woman who underwent a forceps-assisted vaginal delivery with mediolateral episiotomy presented on postpartum day 5 with complete wound breakdown. Surgical exploration of the wound revealed a defect extending from the perineum into the vagina and deep into the ischiorectal fossa with poor tissue quality not amenable to a timely delayed primary closure. A vacuum-assisted closure device was used in lieu of traditional wound preparation and resulted in wound closure after 11 days of vacuum-assisted wound therapy. CONCLUSION: A vacuum-assisted closure device may be appropriate in cases of complex episiotomy breakdown and may expedite wound healing in the outpatient setting. PMID- 25923029 TI - Acquired Uterine Arteriovenous Malformation and Retained Placenta Increta. AB - BACKGROUND: Uterine arteriovenous malformations are rare and have been reported to occur after uterine trauma (eg, surgery, gestational trophoblastic disease, malignancy). CASE: A 33-year-old woman, gravida 3 para 3, presented 4 weeks post cesarean delivery with episodic profuse vaginal bleeding. Pelvic ultrasonography and magnetic resonance imaging revealed a left uterine arteriovenous malformation. After consideration of all treatment options, total laparoscopic hysterectomy was performed. CONCLUSION: Acquired uterine arteriovenous malformations and placental ingrowth into the myometrium are increasingly reported after surgical uterine procedures. This case of a postpartum patient with both uterine arteriovenous malformation and retained placenta increta suggests a correlation between the two complications. PMID- 25923030 TI - Fetoscopic Repair of Meningomyelocele. AB - BACKGROUND: Currently, maternal-fetal surgery for repair of myelomeningocele requires an upper-segment hysterotomy, which likely increases maternal postsurgical risks. If fetoscopic repair of myelomeningocele achieves similar or better fetal outcomes while decreasing maternal risks, it would be a better option. CASE: A patient with a fetus with a L3-S1 meningomyelocele underwent a laparotomy and fetoscopic repair using a two-port, in-CO2 approach at 23 2/7 weeks of gestation. The neonate was delivered at 30 6/7 weeks of gestation by lower segment cesarean delivery and required no further surgery, has not needed a shunt (5 months), and has normal, age-appropriate neurologic function. CONCLUSION: This innovative fetoscopic approach may offer an alternative to open fetal surgery and may prevent the need for hysterotomy and cesarean delivery in index and subsequent pregnancies. PMID- 25923031 TI - Pedicled lateral nasal wall flap for the reconstruction of the nasal septum perforation. A radio-anatomical study. AB - INTRODUCTION: The aim of this radio-anatomical study is to ensure that the potential donor area of the pedicled lateral nasal wall flap (PLNW) is adequate to reconstruct nasal perforation. MATERIAL AND METHODS: Analysis was conducted on 40 de-identified CT angiographies. The area and length of the PLNW, the septum, and the nasal floor were measured. In a cadaver study, 20 hemi-cranial sagittal sections were also analyzed. The anterior-posterior length of the PLNW flap and the distance between the sphenopalatine foramen and piriform aperture were measured. A clinical study with endoscopic closure of a large perforation was conducted in three patients. RESULTS: The CT angiographies demonstrated an average PLNW area of 10.80+/-1.13 cm2 and a nasal floor area of 3.78+/-0.58 cm2. The septal area (22.54+/-21.32 cm2) was significantly larger than the total PLNW flap area (14.59+/-1.21 cm2). The average length of the flap was 5.58+/-0.39 cm, while the septum was 6.66+/-0.42 cm; therefore the PLNW flap is insufficient to reconstruct the entire septum. The cadaver study showed that the length of the PLNW flap was 5.28+/-0.40 cm. These results demonstrate that measurements obtained from CT scans are reliable data and similar to those found in the radiological study. Complete closure was achieved in all three patients. CONCLUSION: The PLNW flap does not render enough tissue to reconstruct a total septal perforation; however, up to 84% of the septum could be repaired with a PLNW. The potential donor area obtained by CT scan and clinical practice support the approachability of PLNW to repair large septal perforation. PMID- 25923032 TI - Benzodiazepines in Anxiety Disorders. PMID- 25923033 TI - Controllable optical transitions of amorphous Mg and Mg-Ni films via electrochemical methods. AB - Amorphous Mg and MgNix (0.03 <= x <= 0.30) thin films capped with Pd were prepared by magnetron co-sputtering, and their hydrogen-induced optical transitions were investigated via electrochemical charging and discharging in KOH electrolyte solution. Repetitive transitions, up to dozens of times between the mirror state and transparent state, are achieved in these amorphous Mg and MgNix thin films even though some performance degeneration occurs during cycling. These deteriorations are mainly attributed to the breakdown of the film structure, which is caused by both a large change in film volume during cycling and the corrosive attack of the KOH electrolyte. In addition, calculations based on the electrochemical stripping method indicate that the hydrogen diffusion coefficient is significantly increased by amorphization; however, it is only slightly improved by the addition of Ni. Among the prepared amorphous films, MgNi0.09 film shows the largest hydrogen diffusion coefficient, namely, 2.64 * 10(-13) cm(2) s( 1). More importantly, the optical properties of the amorphous Mg and MgNix films are readily manipulated in the charging process, especially under a small charging current density, where there is a linear correlation between charging capacity and transmittance. The tunable optical properties obtained in the present study will greatly expand the application fields of Mg-based thin films. PMID- 25923034 TI - The contrarotational fluxionality of [3,3-(PMe2Ph)2-closo-3,1,2-PtC2B9H11] and related species. AB - DFT calculations allied with experimental crystallographic and NMR results elucidate the energetics and the geometrical and (11)B nuclear shielding changes in the contrarotational fluxionality of [3,3-(PMe2Ph)2-closo-3,1,2-PtC2B9H11] and confirm the identities of two stable rotational conformers. There is a relatively unhindered contrarotation of the {Pt(PR3)2} and nido-shaped carbons-together {C2B9H11} entities about an axis that contains the platinum atom, with a transition from trihapto to tetrahapto to pentahapto metal-to-cluster interaction as the rotation progresses from 0 degrees to 90 degrees , and a reversal as it progresses in turn through to 180 degrees , and thence through a similar cycle through to 360 degrees for a complete rotation. The overall energy minimum is the trihapto conformation, but there is also an island of stability for the tetrahapto conformation at slightly higher energy, corresponding to experimental observation of these two configurations. The highest-energy pentahapto mode constitutes a transition state, and its energy defines the activation energy for the complete contrarotation, which is matched by activation energies derived from NMR spectroscopy. The shallow minima and small energy differences suggest that ready cluster flexibility will be expected about the minima, again in accord with subtle rotamer angle differences seen in experimental results. Nuclear magnetic shielding criteria suggest significant changes in intracluster bonding as the rotation progresses. The trihapto bonding geometry and the corresponding electronic structure are favoured over quite a substantial arc (some 40 degrees ) of the rotation, before rapid changes ensue, and then, after progression through the tetrahapto conformation, the electronics and the bonding geometry then again remain similar within the pentahapto mode for a further 40 degrees or so of the rotational arc about this transition state. PMID- 25923035 TI - Whole-Exome Sequencing Reveals CLCNKB Mutations in a Case of Sudden Unexpected Infant Death. AB - Cases of sudden unexpected infant death (SUID) leave many families devastated, especially in those without an identified cause of death. Here, we describe the case of an apparently healthy 15-day-old infant who died suddenly and unexpectedly. Through whole-exome sequencing, the infant was posthumously found to have 2 mutations in the CLCNKB gene, leading to a molecular diagnosis of Bartter syndrome type III, the likely cause of death. This case illustrates the potential utility of exome sequencing in cases of SUID to suggest a diagnosis, with important implications for families, allowing them to come to closure over the cause of death, informing their future reproductive decisions, and minimizing the risk of recurrence. PMID- 25923036 TI - Coating lithium titanate with nitrogen-doped carbon by simple refluxing for high power lithium-ion batteries. AB - Nitrogen-doped carbon is coated on lithium titanate (Li4Ti5O12, LTO) via a simple chemical refluxing process, using ethylenediamine (EDA) as the carbon and nitrogen source. The process incorporates a carbon coating doped with a relatively high amount of nitrogen to form a conducting network on the LTO matrix. The introduction of N dopants in the carbon matrix leads to a higher density of C vacancies, resulting in improved lithium-ion diffusion. The uniform coating of nitrogen-doped carbon on Li4Ti5O12 (CN-LTO) enhances the electronic conductivity of a CN-LTO electrode and the corresponding electrochemical properties of the cell employing the electrode. The results of our study demonstrate that the CN-LTO anode exhibits higher rate capability and cycling performance over 100 cycles. From the electrochemical tests performed, the specific capacity of CN-LTO electrode at higher rates of 20 and 50 C are found to be 140.7 and 82.3 mAh g(-1), respectively. In addition, the CN-Li4Ti5O12 anode attained higher capacity retention of 100% at 1 C rate after 100 cycles and 92.9% at 10 C rate after 300 cycles. PMID- 25923039 TI - Regulation of Retinoic Acid Receptor Beta by Interleukin-15 in the Lung during Cigarette Smoking and Influenza Virus Infection. AB - Virus-induced exacerbations often lead to further impairment of lung function in chronic obstructive pulmonary disease. IL-15 is critical in antiviral immune responses. Retinoic acid (RA) signaling plays an important role in tissue maintenance and repair, particularly in the lung. We studied RA signaling and its relation to IL-15 in the lung during cigarette smoke (CS) exposure and influenza virus infection. In vivo studies show that RA signaling is diminished by long term CS exposure or influenza virus infection alone, which is further attenuated during infection after CS exposure. RA receptor beta (RARbeta) is specifically decreased in the lung of IL-15 transgenic (overexpression; IL-15Tg) mice, and a greater reduction in RARbeta is found in these mice compared with wild-type (WT) mice after infection. RARbeta is increased in IL-15 knockout (IL-15KO) mice compared with WT mice after infection, and the additive effect of CS and virus on RARbeta down-regulation is diminished in IL-15KO mice. IL-15 receptor alpha (IL 15Ralpha) is increased and RARbeta is significantly decreased in lung interstitial macrophages from IL-15Tg mice compared with WT mice. In vitro studies show that IL-15 down-regulates RARbeta in macrophages via IL-15Ralpha signaling during influenza virus infection. These studies suggest that RA signaling is significantly diminished in the lung by CS exposure and influenza virus infection. IL-15 specifically down-regulates RARbeta expression, and RARbeta may play a protective role in lung injury caused by CS exposure and viral infections. PMID- 25923040 TI - Postoperative Copeptin Concentration Predicts Diabetes Insipidus After Pituitary Surgery. AB - CONTEXT: Copeptin is a stable surrogate marker of vasopressin release; the peptides are stoichiometrically secreted from the neurohypophysis due to elevated plasma osmolality or nonosmotic stress. We hypothesized that following stress from pituitary surgery, patients with neurohypophyseal damage and eventual diabetes insipidus (DI) would not exhibit the expected pronounced copeptin elevation. OBJECTIVE: The objective was to evaluate copeptin's accuracy to predict DI following pituitary surgery. DESIGN: This was a prospective multicenter observational cohort study. SETTING: Three Swiss or Canadian referral centers were used. PATIENTS: Consecutive pituitary surgery patients were included. MEASUREMENTS: Copeptin was measured postoperatively daily until discharge. Logistic regression models and diagnostic performance measures were calculated to assess relationships of postoperative copeptin levels and DI. RESULTS: Of 205 patients, 50 (24.4%) developed postoperative DI. Post-surgically, median [25th-75th percentile] copeptin levels were significantly lower in patients developing DI vs those not showing this complication: 2.9 [1.9-7.9] pmol/L vs 10.8 [5.2-30.4] pmol/L; P < .001. Logistic regression analysis revealed strong association between postoperative copeptin concentrations and DI even after considering known predisposing factors for DI: adjusted odds ratio (95% confidence interval) 1.41 (1.16-1.73). DI was seen in 22/27 patients with copeptin <2.5 pmol/L (positive predictive value, 81%; specificity, 97%), but only 1/40 with copeptin >30 pmol/L (negative predictive value, 95%; sensitivity, 94%) on postoperative day 1. LIMITATIONS: Lack of standardized DI diagnostic criteria; postoperative blood samples for copeptin obtained during everyday care vs at fixed time points. CONCLUSIONS: In patients undergoing pituitary procedures, low copeptin levels despite surgical stress reflect postoperative DI, whereas high levels virtually exclude it. Copeptin therefore may become a novel tool for early goal-directed management of postoperative DI. PMID- 25923041 TI - Arrayed van der Waals Vertical Heterostructures Based on 2D GaSe Grown by Molecular Beam Epitaxy. AB - Vertically stacking two-dimensional (2D) materials can enable the design of novel electronic and optoelectronic devices and realize complex functionality. However, the fabrication of such artificial heterostructures on a wafer scale with an atomically sharp interface poses an unprecedented challenge. Here, we demonstrate a convenient and controllable approach for the production of wafer-scale 2D GaSe thin films by molecular beam epitaxy. In situ reflection high-energy electron diffraction oscillations and Raman spectroscopy reveal a layer-by-layer van der Waals epitaxial growth mode. Highly efficient photodetector arrays were fabricated, based on few-layer GaSe on Si. These photodiodes show steady rectifying characteristics and a high external quantum efficiency of 23.6%. The resultant photoresponse is super-fast and robust, with a response time of 60 MUs. Importantly, the device shows no sign of degradation after 1 million cycles of operation. We also carried out numerical simulations to understand the underlying device working principles. Our study establishes a new approach to produce controllable, robust, and large-area 2D heterostructures and presents a crucial step for further practical applications. PMID- 25923042 TI - (77)Se and (125)Te NMR spectroscopy on a selectivity study of organochalcogenanes with L-amino acids. AB - The hypervalent selenium- and tellurium-containing compounds (halo organoselenuranes and halo-organotelluranes) were treated with amino acids to evaluate their reactivity and chemoselectivity by (1)H, (13)C, (77)Se and (125)Te NMR spectroscopy. The study of forced thermal stability was performed and analyzed by NMR. The organotelluranes remained stable at temperatures around 60 degrees C but in the case of organoselenuranes, there was formation of new products at 37 degrees C as a result of halogen loss. (77)Se and (125)Te NMR spectroscopy has proved to be a very efficient and fast technique to evidence the high selectivity of organochalcogenanes against l-amino acids, specific to l cysteine. PMID- 25923043 TI - Cytoplasmic pH-Stat during Phenanthrene Uptake by Wheat Roots: A Mechanistic Consideration. AB - Dietary intake of plant-based foods is a major contribution to the total exposure of polycyclic aromatic hydrocarbons (PAHs). However, the mechanisms underlying PAH uptake by roots remain poorly understood. This is the first study, to our knowledge, to reveal cytoplasmic pH change and regulation in response to PAH uptake by wheat roots. An initial drop of cytoplasmic pH, which is concentration dependent upon exposure to phenanthrene (a model PAH), was followed by a slow recovery, indicating the operation of a powerful cytoplasmic pH regulating system. Intracellular buffers are prevalent and act in the first few minutes of acidification. Phenanthrene activates plasmalemma and tonoplast H(+) pump. Cytolasmic acidification is also accompanied by vacuolar acidification. In addition, phenanthrene decreases the activity of phosphoenolpyruvate carboxylase and malate concentration. Moreover, phenanthrene stimulates nitrate reductase. Therefore, it is concluded that phenanthrene uptake induces cytoplasmic acidification, and cytoplasmic pH recovery is achieved via physicochemical buffering, proton transport outside cytoplasm into apoplast and vacuole, and malate decarboxylation along with nitrate reduction. Our results provide a novel insight into PAH uptake by wheat roots, which is relevant to strategies for reducing PAH accumulation in wheat for food safety and improving phytoremediation of PAH-contaminated soils or water by agronomic practices. PMID- 25923045 TI - Effects of remifentanil on esophageal motility: a double-blind, randomized, cross over study in healthy volunteers. AB - BACKGROUND: Recent studies have shown that remifentanil increases the risk of aspiration and induces subjective swallowing difficulties. The mechanisms are not completely understood. Here, we investigated whether remifentanil impairs esophageal motility and hypothesized that this is one possible underlying mechanism. Naloxone was used to evaluate whether the effects of remifentanil are mediated through opioid receptors. We also examined subjective swallowing difficulties and the influence of metoclopramide on remifentanil-induced effects. METHODS: Fourteen healthy volunteers participated in a double-blind, randomized, cross-over trial at the University Hospital in Orebro, Sweden. They were studied on two different occasions, during which they were randomly assigned to receive either naloxone given as a bolus of 6 MUg/kg followed by an infusion of 0.1 MUg/kg/min, or saline 5 min before target-controlled infusions of remifentanil at three target-site concentrations: 1, 2, and 3 ng/ml. On both occasions, 0.2 mg/kg metoclopramide was given before the final measurement. Five swallows were performed during each measuring condition, and the metrics defining esophageal motility were measured by high-resolution manometry. Outcomes were differences in the metrics at baseline vs. during remifentanil infusion, with naloxone vs. placebo, and with remifentanil before and after metoclopramide administration. Differences in swallowing difficulties were also recorded. RESULTS: Remifentanil decreased swallow-evoked esophagogastric junction relaxation and the latency time of esophageal peristalsis. There were no significant effects of naloxone or metoclopramide on remifentanil-induced effects, and we detected no differences in swallowing difficulties. CONCLUSIONS: Remifentanil induces dysfunction of esophageal motility; this may contribute to the elevated risk of regurgitation and aspiration. PMID- 25923046 TI - Immunoexpression of intermediate filaments and morphological changes in the liver and bile duct of rats infected with Fasciola hepatica. AB - We investigated the immunoexpression of the intermediate filament proteins, cytokeratin and desmin, and the morphological changes in the liver of rats during experimental fasciolosis at 4, 7 and 10 weeks post-infection. Rats were infected with 30 Fasciola hepatica metacercariae. Paraffin sections of the liver were stained using H & E, PAS and azan stains. Immunohistochemical reactions were performed using antibodies against cytokeratin and desmin. The experimental F. hepatica infection led to fibrosis and cirrhosis of the liver, and to inflammation of the common bile ducts. The expression of cytokeratin was increased in the epithelial cells of both the liver bile ductules at 4, 7 and 10 weeks post-infection and in the common bile ducts at 7 and 10 weeks post infection compared to uninfected rats; expression in the common bile ducts was more intense. The myofibroblasts of the liver and smooth myocytes of the interlobular bile ducts and common bile ducts, showed a slight increase in desmin expression compared to the uninfected rats. The increased expression of cytokeratins in the hyperplastic rat common bile duct epithelium during the biliary phase of fasciolosis at 7 and 10 weeks post-infection may be explained by mechanical irritation by the parasite and an inflammatory reaction in the bile duct epithelium and in periductal fibrous tissue. PMID- 25923047 TI - Germ cell tumor-related lymphadenopathies caused acute pancreatitis. PMID- 25923048 TI - Fluorescent nucleoside derivatives as a tool for the detection of concentrative nucleoside transporter activity using confocal microscopy and flow cytometry. AB - The abundance and function of transporter proteins at the plasma membrane are likely to be crucial in drug responsiveness. Functional detection of human concentrative nucleoside transporters (hCNTs) is of interest for predicting drug sensitivity because of their ability to transport most nucleoside-derived drugs. In the present study, two fluorescent nucleoside analogues, uridine-furan and etheno-cytidine, were evaluated as tools to study in vivo nucleoside transporter related functions. These two molecules showed high affinity interactions with hCNT1 and hCNT3 and were shown to be substrates of both transporters. Both fluorescence microscopy and flow cytometry experiments showed that uridine-furan uptake was better suited for distinguishing cells that express hCNT1 or hCNT3. These data highlight the usefulness of fluorescent nucleoside derivatives, as long as they fulfill the requirements of confocal microscopy and flow cytometry, for in vivo analysis of hCNT-related function. PMID- 25923049 TI - A peptide nucleic acid-functionalized carbon nitride nanosheet as a probe for in situ monitoring of intracellular microRNA. AB - A novel probe for recognition of both cancer cells and intracellular microRNA (miRNA) is designed by functionalizing a carbon nitride nanosheet (f-CNNS) with a Cy5-labeled peptide nucleic acid (Cy5-PNA) and folate. The interaction between Cy5-PNA and CNNS quenches the fluorescence of Cy5, and the presence of folate endows the probe with good specificity to folate acceptor overexpressed cells. The probe can be specifically taken up by cancer cells with an incubation step. Upon the recognition of the PNA to complementary miRNA, the hybridization product is released from the CNNS surface, which leads to the fluorescence recovery and provides a specific method for sensing of miRNA. Thus, this probe can be used for cell-specific intracellular miRNA sensing with a confocal microscope. Using miRNA 18a as a target model, the dynamic changes of its expression level inside living cells can be monitored with the proposed method. This method possesses promising applications in the study of miRNA related bioprocesses and biomedicine. PMID- 25923050 TI - Candida albicans should be considered when managing keratitis in Atopic keratoconjunctivitis. PMID- 25923051 TI - Kinetic interfaces of patchy particles. AB - We study the irreversible adsorption of patchy particles on substrates in the limit of advective mass transport. Recent numerical results show that the interface roughening depends strongly on the particle attributes, such as, patch patch correlations, bond flexibility and strength of the interactions, uncovering new absorbing phase transitions. Here, we revisit these results and discuss in detail the transitions. In particular, we present new evidence that the tricritical point, observed in systems of particles with flexible patches, is in the tricritical directed percolation universality class. A scaling analysis of the time evolution of the correlation length for the aggregation of patchy particles with distinct bonding energies confirms that the critical regime is in the Kardar-Parisi-Zhang with quenched disorder universality class. PMID- 25923052 TI - Incorporating geodiversity into conservation decisions. AB - In a rapidly changing climate, conservation practitioners could better use geodiversity in a broad range of conservation decisions. We explored selected avenues through which this integration might improve decision making and organized them within the adaptive management cycle of assessment, planning, implementation, and monitoring. Geodiversity is seldom referenced in predominant environmental law and policy. With most natural resource agencies mandated to conserve certain categories of species, agency personnel are challenged to find ways to practically implement new directives aimed at coping with climate change while retaining their species-centered mandate. Ecoregions and ecological classifications provide clear mechanisms to consider geodiversity in plans or decisions, the inclusion of which will help foster the resilience of conservation to climate change. Methods for biodiversity assessment, such as gap analysis, climate change vulnerability analysis, and ecological process modeling, can readily accommodate inclusion of a geophysical component. We adapted others' approaches for characterizing landscapes along a continuum of climate change vulnerability for the biota they support from resistant, to resilient, to susceptible, and to sensitive and then summarized options for integrating geodiversity into planning in each landscape type. In landscapes that are relatively resistant to climate change, options exist to fully represent geodiversity while ensuring that dynamic ecological processes can change over time. In more susceptible landscapes, strategies aiming to maintain or restore ecosystem resilience and connectivity are paramount. Implementing actions on the ground requires understanding of geophysical constraints on species and an increasingly nimble approach to establishing management and restoration goals. Because decisions that are implemented today will be revisited and amended into the future, increasingly sophisticated forms of monitoring and adaptation will be required to ensure that conservation efforts fully consider the value of geodiversity for supporting biodiversity in the face of a changing climate. PMID- 25923054 TI - Implicit Measure of Life/Death Orientation Predicts Response of Suicidal Ideation to Treatment in Psychiatric Inpatients. AB - In this study, we set out to extend empirical research on the Life-Death Implicit Association Test (IAT) by administering the measure to an adult psychiatric inpatient population with suicidal ideation. We sought to examine its association with other suicide-relevant measures and to determine whether it adds predictive utility beyond that offered by other measures of suicide risk. The IAT was administered (N = 124) at biweekly intervals as part of an assessment battery at an inpatient facility for complex, treatment resistant psychiatric disorders (average length of stay: approximately 6 weeks). Multiple regression procedures were utilized to examine relationships among the measures and their predictive utility with respect to suicidal ideation at discharge. Consistent with prior research with other populations, significant associations were found between IAT performance and explicit (self-report and interview) measures of suicide risk. Moreover, the IAT was found to predict suicidal ideation at discharge above and beyond number of prior suicide attempts and admission scores on measures of depression, suicidal ideation, and hopelessness. Change in IAT performance over the course of treatment was observed. The IAT shows promise as an addition to explicit measures conventionally used to estimate suicide risk in psychiatric patients. These findings are consistent with a cognitive vulnerability model of suicide risk. PMID- 25923055 TI - Molecular adaptations of Herbaspirillum seropedicae during colonization of the maize rhizosphere. AB - Molecular mechanisms of plant recognition and colonization by diazotrophic bacteria are barely understood. Herbaspirillum seropedicae is a Betaproteobacterium capable of colonizing epiphytically and endophytically commercial grasses, to promote plant growth. In this study, we utilized RNA-seq to compare the transcriptional profiles of planktonic and maize root-attached H. seropedicae SmR1 recovered 1 and 3 days after inoculation. The results indicated that nitrogen metabolism was strongly activated in the rhizosphere and polyhydroxybutyrate storage was mobilized in order to assist the survival of H. seropedicae during the early stages of colonization. Epiphytic cells showed altered transcription levels of several genes associated with polysaccharide biosynthesis, peptidoglycan turnover and outer membrane protein biosynthesis, suggesting reorganization of cell wall envelope components. Specific methyl accepting chemotaxis proteins and two-component systems were differentially expressed between populations over time, suggesting deployment of an extensive bacterial sensory system for adaptation to the plant environment. An insertion mutation inactivating a methyl-accepting chemosensor induced in planktonic bacteria, decreased chemotaxis towards the plant and attachment to roots. In summary, analysis of mutant strains combined with transcript profiling revealed several molecular adaptations that enable H. seropedicae to sense the plant environment, attach to the root surface and survive during the early stages of maize colonization. PMID- 25923053 TI - Comparison of microarray expression profiles between follicular variant of papillary thyroid carcinomas and follicular adenomas of the thyroid. AB - BACKGROUND: Follicular variant of papillary thyroid carcinoma (FVPTC) and follicular adenoma (FA) are histologically closely related tumors and differential diagnosis remains challenging. RNA expression profiling is an established method to unravel molecular mechanisms underlying the histopathology of diseases. METHODS: BRAF mutational status was established by direct sequencing the hotspot region of exon 15 in six FVPTCs and seven FAs. Whole-transcript arrays were employed to generate expression profiles in six FVPTCs, seven FAs and seven normal thyroid tissue samples. The threshold of significance for differential expression on the gene and exon level was a p-value with a false discovery rate (FDR) < 0.05 and a fold change cutoff > 2. Two dimensional average linkage hierarchical clustering was generated using differentially expressed genes. Network, pathway, and alternative splicing utilities were employed to interpret significance of expression data on the gene and exon level. RESULTS: Expression profiling in FVPTCs and FAs, all of which were negative for a BRAF mutation, revealed 55 transcripts that were significantly differentially expressed, 40 of which were upregulated and 15 downregulated in FVPTCs vs. FAs. Amongst the most significantly upregulated genes in FVPTCs were GABA B receptor, 2 (GABBR2), neuronal cell adhesion molecule (NRCAM), extracellular matrix protein 1 (ECM1), heparan sulfate 6-O-sulfotransferase 2 (HS6ST2), and retinoid X receptor, gamma (RXRG). The most significantly downregulated genes in FVPTCs included interaction protein for cytohesin exchange factors 1 (IPCEF1), G protein coupled receptor 155 (GPR155), Purkinje cell protein 4 (PCP4), chondroitin sulfate N-acetylgalactosaminyltransferase 1 (CSGALNACT1), and glutamate receptor interacting protein 1 (GRIP1). Alternative splicing analysis detected 87 genes, 52 of which were also included in the list of 55 differentially expressed genes. Network analysis demonstrated multiple interactions for a number of differentially expressed molecules including vitamin D (1,25- dihydroxyvitamin D3) receptor (VDR), SMAD family member 9 (SMAD9), v-kit Hardy-Zuckerman 4 feline sarcoma viral oncogene homolog (KIT), and RXRG. CONCLUSIONS: This is one of the first studies using whole-transcript expression arrays to compare expression profiles between FVPTCs and FAs. A set of differentially expressed genes has been identified that contains valuable candidate genes to differentiate both histopathologically related tumor types on the molecular level. PMID- 25923056 TI - The effect of hemodialysis session on postural strategies in older end-stage renal disease patients. AB - Patients suffering from end-stage renal disease experience multiple disabilities, such as muscle wasting, weakness, higher postural sway, and fall rates compared with healthy population, which has a negative effect on physical functioning and autonomy. The vital treatment of hemodialysis is recognized to induce important post-hemodialysis fatigue, hypotension, cramps, and headache due to the rapid fluid redistribution, among others. Nevertheless, even the well-known negative effect of aforementioned consequences of hemodialysis treatment, its effect on physical function, especially postural balance, is unclear. Thus, this study hypothesized the adverse effect of hemodialysis treatment on postural sway in 12 end-stage renal disease patients (mean age 63.3 +/- 11 years) through the analysis of center-of-pressure (COP) trajectories recorded before and immediately after hemodialysis session. Evident postural alterations were observed at post hemodialysis balance assessment for COP position-based (Fs < 7.7, P < 0.02) and COP velocity-based variables (Fs > 2.33, P < 0.05), without changes in complexity of COP time series in anteroposterior and mediolateral directions. These results suggest that period after hemodialysis treatment is particularly unsafe, as evidenced by important disability in postural control, and highlight the importance of the medical support and falls-related prevention strategies of these older frail patients after hemodialysis treatment. PMID- 25923057 TI - The deterioration of Canadian immigrants' oral health: analysis of the Longitudinal Survey of Immigrants to Canada. AB - OBJECTIVE: To examine the effect of immigration on the self-reported oral health of immigrants to Canada over a 4-year period. METHODS: The study used Statistics Canada's Longitudinal Survey of Immigrants to Canada (LSIC 2001-2005). The target population comprised 3976 non-refugee immigrants to Canada. The dependent variable was self-reported dental problems. The independent variables were as follows: age, sex, ethnicity, income, education, perceived discrimination, history of social assistance, social support, and official language proficiency. A generalized estimation equation approach was used to assess the association between dependent and independent variables. RESULTS: After 2 years, the proportion of immigrants reporting dental problems more than tripled (32.6%) and remained approximately the same at 4 years after immigrating (33.3%). Over time, immigrants were more likely to report dental problems (OR = 2.77; 95% CI 2.55 3.02). An increase in self-reported dental problems over time was associated with sex, history of social assistance, total household income, and self-perceived discrimination. CONCLUSION: An increased likelihood of reporting dental problems occurred over time. Immigrants should arguably constitute an important focus of public policy and programmes aimed at improving their oral health and access to dental care in Canada. PMID- 25923058 TI - Nitric oxide donor s-nitroso-n-acetyl penicillamine (SNAP) alters meiotic spindle morphogenesis in Xenopus oocytes. AB - Nitric Oxide (NO) has been involved in both intra- and extra-cellular signaling pathways in a wide range of organisms, and can be detected in some reproductive tissues. Based upon previous results reporting that NO-donor SNAP (s-nitroso-n acetyl penicillamine) promoted the release from the metaphase II-anaphase II block in amphibian eggs, the aim of the present study was to assess the influence of SNAP on the activation of the molecular mechanisms triggering meiotic resumption of Xenopus oocytes, analogous to G2/M transition of the cell cycle. A high concentration of SNAP (2.5 mM) was found to inhibit the appearance of the white spot (meiotic resumption) and promoted alteration of spindle morphogenesis leading to atypical structures lacking bipolarity and correct chromosomes equatorial alignment. The medium acidification (pH = 4) promoted by SNAP specifically impacted the white spot occurrence. However, even when pH was restored to 7.4 in SNAP medium, observed spindles remained atypical (microtubule disorganization), suggesting SNAP impacted spindle assembly regardless of the pH. n-Acetyl-d,l-penicillamine disulfide, a degradation product of SNAP with the same molecular characteristics, albeit without release of NO, yielded spindle assemblies typical of metaphase II suggesting the specificity of NO action on meiotic spindle morphogenesis in Xenopus oocytes. PMID- 25923059 TI - Risk of initial and moderate caries lesions in primary teeth to progress to dentine cavitation: a 2-year cohort study. AB - AIM: To investigate the risk of sound surfaces, and initial and moderate caries lesions to progress to dentine cavitation in preschool children. DESIGN: A cohort study was designed with 639 children (12-59 months old) who had been examined by visual inspection during a survey in 2010. After 2 years, 469 children were re examined regarding the presence of dentine cavitations. The probability of progression was calculated for sound and carious (initial and moderate lesions) surfaces. Relative risk of progression and 95% confidence intervals for each condition compared with sound surfaces were calculated using multilevel Poisson regression analysis. Association with explanatory variables, including caries experience of the children, was also investigated. RESULTS: The higher the initial score attributed to the dental surface, the more likely was the progression. Moreover, children with severe lesions at baseline had higher risk of having a sound surface or a non-cavitated caries lesion progressing to cavitation when compared with caries-free children; however, this increased risk was not observed in children with only initial caries lesions. CONCLUSIONS: Initial caries lesions present a low frequency of progression. Moreover, sound surfaces and initial caries lesions in children already presenting cavitations are more likely to progress to more severe conditions. PMID- 25923060 TI - Multicenter Semiquantitative Evaluation of (123)I-FP-CIT Brain SPECT. AB - AIMS: The aims of this study were: (1) to cross-compare data from semiquantitative, software-assisted, and phantom-corrected evaluations of (123)I ioflupane [(123)I]N-omega-fluoropropyl-2beta-carbomethoxy-3beta-{4 iodophenyl}nortropane FP-CIT brain single-photon emission computed tomography (SPECT) acquired in three centers; (2) to assess the accuracy of semiquantitative evaluation; and (3) to identify the threshold with the best accuracy, sensitivity, and specificity in patients with suspected Parkinsonian Syndrome. MATERIAL AND METHODS: Two-hundred-twenty patients, acquired in three centers, were included. All of them underwent (123)I-FP-CIT brain SPECT. All examinations were analyzed with the freely available software, BasGan, and semiquantitative data were used to predict disease. Analysis was based on the values from the most deteriorated putamen and caudate, normalized for age, and corrected by anthropomorphic phantom data. Receiver operating characteristic (ROC) analysis was performed and areas under the curve (AUC) were estimated. RESULTS: Analysis showed high AUCs (.880, .866, .920, and .882 for each center and multicenter setting). Best thresholds were 1.53 and 1.56 for putamen and caudate, respectively. Thresholds of putamen data showed sensitivity and specificity of 86% and 89%, respectively, in the multicenter setting. Neither sensibility nor specificity showed significant differences among centers. CONCLUSION: A unique, accurate threshold for all centers, with high sensitivity and specificity was identified. Semiquantitative assessment of (123)I-FP-CIT brain SPECT among different centers resulted reliable, accurate, and potentially useful in clinical trials. PMID- 25923061 TI - Hypoelectrolytic isoosmotic solution for infusion prevents saline-induced ultrastuructural artifacts of renal biopsy specimens. AB - Artifacts in the process of specimen preparation are frequent in ultrastructural evaluation of renal biopsy. We hypothesized that the common practice of wrapping kidney biopsy specimens in saline-soaked gauze to prevent the drying of the specimens could be the major factor of artifacts. In this study, whole kidneys from two male Sprague-Dawley rats were used. Before fixation, fresh small cubes of kidney tissue were macerated in saline (Saline group) or hypoelectrolytic isoosmotic solution for infusion (HISI group) (Sorita T3 or SOLDEM 3A) for 10 or 30 min. Then, the specimens were processed by 1% OsO(4) in 0.1 M phosphate buffer (pH 7.4) and embedded by EPON 812 for ultramicroscopic analysis. In the Saline group, ultrastructural examination revealed swollen podocyte, swollen capillary protuberance of the mesangium into the glomerular capillary loop, tubular cells with swollen mitochondria and microvilli, and the smooth muscle cells in the arteriolar wall with marked vacuolar degeneration were detected after 10 min maceration in saline and these findings become more pronounced after 30 min maceration. However, in the HISI group, these artifacts were not identified or limited within 30 min. It is postulated that HISI solution could prevent the artifacts, and be used for soaking and wrapping instead of physiologic saline solution. PMID- 25923062 TI - Effect of exogenous xylanase on rumen in vitro gas production and degradability of wheat straw. AB - The objective of this study was to determine effects of xylanase on in vitro gas production (GP) and in sacco degradability of wheat straw. Rumen fluid was obtained from three Mongolian native goats fitted with permanent rumen cannulas. The trial consisted of five doses (0, 0.5, 1.0, 1.5, 2.0 MUL/g of substrate) of a commercial xylanase (Dyadic(r) xylanase PLUS, Dyadic International, Inc., Jupiter, FL, USA). For the in sacco degradability, different levels of xylanase enzyme were added directly onto 2 g of wheat straw in nylon bags and incubated in the rumen for 3, 6, 12, 24 and 48 h to estimate degradability of wheat straw. Total GP increased (P < 0.001) at all times of incubation at intermediate levels of xylanase. Methane production had a similar pattern at 3 and 12 h of incubation; increased linearly at 24 h of incubation, and was unaffected at 6 and 48 h of incubation. Rumen NH3 -N concentration increased linearly at 3 h and the highest values were observed with intermediate enzyme levels. All ruminal volatile fatty acids increased linearly with intermediate levels of the fibrolytic enzyme. The in sacco rate of dry matter degradation decreased linearly (P = 0.020) with increasing enzymes. Intermediate levels of xylanase improved rumen kinetic fermentation and degradability. The outcome of this research indicated that the application of xylanase enzyme could improve in vitro GP fermentation of wheat straw. PMID- 25923064 TI - Social minds. PMID- 25923063 TI - Musculoskeletal outcome in hemophilia: bleeds, joint structure and function, activity, and health-related fitness. AB - Treatment in hemophilia is designed to reduce bleed frequency, minimize joint damage, and maximize functional independence and quality of life. Therefore, success of a factor replacement protocol is usually gauged by its ability to produce near "normal joints"-without any significant pathology. The most commonly used outcome measurement tools are based on the radiological and clinical assessment of joint arthropathy. To improve the sensitivity to early changes, the clinical scores have been refined, and imaging based on magnetic resonance imaging and ultrasonography has been initiated. Although these scores are useful in assessing the structure and function of a joint, they do not consider the impact of arthropathy on overall musculoskeletal function. They are also not capable of assessing the efficacy of interventions on functional independence, participation in life activities, and quality of life. The development of functional scores such as the Functional Independence Score for Hemophilia, the pediatric Hemophilia Activities List, and some quality of life measurement tools have helped provide a more comprehensive assessment of health. This article describes the psychometric properties and limitations of the various clinimetric tools that are used to assess musculoskeletal outcome in hemophilia and suggests an algorithm for their use in clinical practice. PMID- 25923065 TI - Common mental disorders in mothers vs. infant and obstetric outcomes: a review. AB - INTRODUCTION: Pregnancy has been shown to increase women's vulnerability to mental disorders. Common mental disorders (CMDs) have been studied both in the general population and in pregnant vs. non-pregnant women. During pregnancy, CMDs have been considered a potential predictor of obstetric and infant outcomes. METHODS: A search was conducted on the PubMed/MEDLINE, LILACS, and SciELO databases to find relevant articles written in English, Spanish, and Portuguese. No limit was established for year of publication, but only studies involving human beings were included. RESULTS: A total of 25 articles were selected. There was a consensus among studies that the mean prevalence of CMD during pregnancy is 20%. There was also agreement that the occurrence of CMDs during pregnancy is a predictor of postpartum depression and anxiety disorders and that the disorder remains underdiagnosed and undertreated. As for the positive association between CMDs and obstetric and infant complications, results are still conflicting. In lower-income countries, frequently there is an association between CMD and perinatal changes. It is argued that some confounding factors, such as sociodemographic and cultural differences, health and maternal conditions, and type of instruments used, probably contribute to this lack of consensus. CONCLUSION: We believe that the conflicting results found in the literature are caused by differences in methodology and sociodemographic factors that influence the development of CMDs. Despite these differences, our findings underscore the need for depression and anxiety disorders during pregnancy to be studied and better identified by all professionals who provide antenatal care. PMID- 25923066 TI - Translation and adaptation of Theory of Mind tasks into Brazilian portuguese. AB - BACKGROUND: Theory of mind (ToM) is a field of social cognition that deals with the individual's cognitive ability to interpret or infer the mental states of others based on previous knowledge. Recently, research has shown that this ability is compromised in patients with some psychopathologies, e.g., schizophrenia and autistic disorder. Investigators have also shown that deficits in ToM have impacts on social functioning and, consequently, on quality of life. Even though ToM studies have recently grown in number, some problems still remain (e.g., the difficulty of standardized tools to assess ToM in different languages). OBJECTIVES: To describe the translation and adaptation into Brazilian Portuguese of two of the most important and widely used ToM tasks, namely, the Theory of Mind Stories and the Hinting Task. METHOD: The process included the following steps: 1) translation; 2) production of a single translated version and review by specialists; 3) back-translation into English; 4) review by an English speaking specialist; 5) adaptation of marked corrections; and 6) pilot application in a group representative of the target population (people with schizophrenia). RESULTS: A final translated version was obtained for each of the tasks. Both instruments were well understood by participants and can now be used in the Brazilian experimental setting. CONCLUSION: The availability of two major ToM tasks in Brazilian Portuguese facilitates the conduction of research on the topic in Brazil. In the future, this could help design clinical interventions aimed at people with social and cognitive difficulties. PMID- 25923067 TI - Stigmatizing attitudes in relatives of people with schizophrenia: a study using the Attribution Questionnaire AQ-27. AB - BACKGROUND: Family members of people with mental disorders can contribute to stigmatization. Because of the lack of adequate information and resources, and the fatigue resulting from daily care, the family can reinforce social exclusion of the mentally ill and disbelieve recovery. Furthermore, family members may also suffer from self-stigma, experiencing a decrease in their own self-esteem and self-worth. OBJECTIVE: To evaluate the presence of stigmatizing attitudes towards patients diagnosed with schizophrenia in a group of relatives of patients with this disorder. METHODS: In this exploratory study, we surveyed 40 family members of patients with schizophrenia seen at the Community Psychiatry Unit of the Psychiatry Department at Centro Hospitalar de Sao Joao (CHSJ), in Porto, Portugal, using a preliminary version of the Attribution Questionnaire AQ-27 in Portuguese. RESULTS: The questionnaire dimensions with the highest mean scores were help, pity, and coercion, followed by segregation, anger, avoidance, dangerousness, responsibility, and fear. These results suggest that relatives do not see people with schizophrenia as responsible for their illness and that they show concern and willingness to help. They avoid but do not fear people with schizophrenia and neither consider them dangerous. CONCLUSION: The participants expressed positive, little stigmatizing attitudes towards people with schizophrenia, probably as a result of their familiarity with severe mental disorder, an adequate attribution process, and low levels of perceived dangerousness. However, the high scores of coercion, pity, and segregation may reflect concealed stigmas that may influence the self-determination of the mentally ill, suggesting the need for psychoeducational interventions aimed at family members. PMID- 25923068 TI - Views on treatment adherence among psychoactive substance-dependent women in the outpatient setting: a qualitative study. AB - INTRODUCTION: In the female population, adherence to specialist clinical treatment for psychoactive substance dependence has peculiar characteristics in terms of therapeutic approaches available to addicts in general. A smaller number of women seek specialist treatment in comparison with men. Traditionally, most health care services specializing in chemical dependence provide similar therapies to both men or women, including the use of mixed-sex groups at some facilities. OBJECTIVE: To discuss the views or psychological meanings attributed by women with substance use disorders to phenomena associated with adherence to treatment at a specialist university outpatient clinic. METHODS: The qualitative clinical method was used, i.e., an approach characterized by the typically qualitative focus of human sciences adapted to health care settings. The semi structured interview technique with open questions was used for data collection, combined with observation of the women interviewed. Data were processed using qualitative content analysis. RESULTS: Three categories of treatment outcomes emerged: 1) significant motivations to seek and follow the treatment proposed; 2) symbolic meanings attributed to the drug; 3) psychological representations of lack of motivation to explain difficulties adhering to treatment. CONCLUSIONS: Our findings suggest that the motivations of addicted women to seek treatment vary, but highlight the fact that the substance used becomes perceived as something that causes significant losses and hinders the proper exercise of women's role in family and social contexts. A warm welcoming is considered essential for a patient to adhere to treatment, offsetting the strong physical pleasure associated with psychoactive substance use. PMID- 25923069 TI - Treatment dropout at a secondary mental health service. AB - OBJECTIVE: To investigate mental health dropout rates in secondary care and to identify possible associations between this variable and social, demographic, psychopathologic, and health care process-related variables. METHOD: This prospective, observational study included 994 patients referred to a secondary service by four primary care units and evaluated by a specialist mental health team between 2004 and 2008. The dependent variable was treatment dropout. Bivariate analyses investigated possible associations between treatment dropout and 57 independent variables. RESULTS: The overall dropout rate from specialist mental health treatment was relatively low (mean = 25.6%). Only four independent variables were associated with dropout: one socioeconomic, two psychopathological, and one health care process variable. All associations were marginally significant (p < 0.1). CONCLUSION: Our findings suggest that family members, patients, and health care professionals are well engaged in this mental health care system based on a model of primary care. The use of this mental health model of care should be extended to other regions of our country. PMID- 25923070 TI - Factor structure, internal consistency and reliability of the Posttraumatic Stress Disorder Checklist (PCL): an exploratory study. AB - INTRODUCTION: Posttraumatic stress disorder (PTSD) is an anxiety disorder resulting from exposure to traumatic events. The Posttraumatic Stress Disorder Checklist (PCL) is a self-report measure largely used to evaluate the presence of PTSD. OBJECTIVE: To investigate the internal consistency, temporal reliability and factor validity of the Portuguese language version of the PCL used in Brazil. METHODS: A total of 186 participants were recruited. The sample was heterogeneous with regard to occupation, sociodemographic data, mental health history, and exposure to traumatic events. Subjects answered the PCL at two occasions within a 15 days' interval (range: 5-15 days). RESULTS: Cronbach's alpha coefficients indicated high internal consistency for the total scale (0.91) and for the theoretical dimensions of the Diagnostic and Statistical Manual of Mental Disorders, 4th edition (DSM-IV) (0.83, 0.81, and 0.80). Temporal reliability (test-retest) was high and consistent for different cutoffs. Maximum likelihood exploratory factor analysis (EFA) was conducted and oblique rotation (Promax) was applied. The Kaiser-Meyer-Olkin (KMO) index (0.911) and Bartlett's test of sphericity (chi2 = 1,381.34, p < 0.001) indicated that correlation matrices were suitable for factor analysis. The analysis yielded three symptom clusters which accounted for 48.9% of the variance, namely, intrusions, avoidance, and numbing hyperarousal. CONCLUSION: Our findings provide additional data regarding the psychometric properties of the PCL, including internal consistency, test-retest reliability, and factor validity. Results are discussed in relation to PTSD theoretical models. PMID- 25923071 TI - Interdisciplinary lifestyle therapy improves binge eating symptoms and body image dissatisfaction in Brazilian obese adults. AB - INTRODUCTION: Obesity is related to numerous negative consequences for physical and mental health. It is often associated with the presence of binge eating disorder, body image dissatisfaction, and general psychopathology. OBJECTIVE: To assess the effects of an interdisciplinary lifestyle therapy on binge eating symptoms, depression, anxiety, body dissatisfaction, and quality of life in obese adults. METHODS: A total of 49 obese adults (body mass index = 37.35+/-5.82 kg/m2; age = 44.14+/-10.00 years) participated in a weight-loss program for 6 months. Symptoms suggestive of binge eating, body dissatisfaction, depression, anxiety, and quality of life were measured using self-reported questionnaires. Food intake was assessed using a 3-day dietary record. Data were analyzed using analysis of variance (ANOVA). RESULTS: ANOVA results showed a reduction in binge eating symptoms and in body dissatisfaction results. Depression and anxiety symptoms also decreased, and an increase was observed in quality of life scores. After therapy, a significant improvement was observed in dietary patterns, as well as significant weight loss. A positive correlation was found between variation of anxiety symptoms and lipid intake. Binge eating symptoms were associated with anxiety symptoms and body image dissatisfaction, and body image dissatisfaction correlated positively with anxiety symptoms in males only. In females, a positive correlation was observed between depression and binge eating symptoms. CONCLUSION: The interdisciplinary therapy was effective in promoting positive physical and psychological changes and in improving the quality of life of obese adults. PMID- 25923072 TI - Tobacco chippers seeking assistance for smoking cessation: a case series. AB - OBJECTIVE: To describe a series of cases of tobacco chippers (TCs) who sought assistance for smoking cessation. DESCRIPTION OF CASES: We describe the case of three TCs who participated in a free quit-smoking support group. Smokers answered self-administered questionnaires covering sociodemographic data, smoking history, nicotine dependence, perceived health status, and motivational stages. Of the 183 smokers enrolled in the program, three (1.6%) were considered TCs. All three were women and reported alcohol use, although at low frequencies. Two of them reported the presence of potentially tobacco-related disease. All TCs presented light nicotine dependence and reported difficulties quitting smoking. All dropped out after the first group meeting. COMMENTS: This study describes a subgroup of smokers not extensively described in the literature: TCs seeking assistance for smoking cessation, with some degree of nicotine dependence, and who do not adhere to regular group therapy. Interventions aimed at this population may be an interesting strategy for smoking cessation. PMID- 25923073 TI - The Ninth Liquid Matter Conference. PMID- 25923074 TI - Effects of mechanical stretching on the morphology and cytoskeleton of vaginal fibroblasts from women with pelvic organ prolapse. AB - Mechanical load and postmenopausal hypoestrogen are risk factors for pelvic organ prolapse (POP). In this study, we applied a 0.1-Hz uniaxial cyclic mechanical stretching (CS) with 10% elongation and 10-8 M 17-beta-estradiol to vaginal fibroblasts isolated from postmenopausal women with or without POP to investigate the effects of CS and estrogen on cell morphology and cytoskeletons of normal and POP fibroblasts. Under static culture condition, POP fibroblasts exhibited lower cell circularity and higher relative fluorescence intensities (RFIs) of F-actin, alpha-tubulin and vimentin. When cultured with CS, all fibroblasts grew perpendicular to the force and exhibited a decreased cell projection area, cell circularity and increased cell length/width ratio; normal fibroblasts exhibited increased RFIs of all three types of cytoskeleton, and POP fibroblasts exhibited a decreased RFI of F-actin and no significant differences of alpha-tubulin and vimentin. After being cultured with 17-beta-estradiol and CS, normal fibroblasts no longer exhibited significant changes in the cell projection area and the RFIs of F-actin and alpha-tubulin; POP fibroblasts exhibited no significant changes in cell circularity, length/width ratio and F-actin even with the increased RFIs of alpha-tubulin and vimentin. These findings suggest that POP fibroblasts have greater sensitivity to and lower tolerance for mechanical stretching, and estrogen can improve the prognosis. PMID- 25923075 TI - Induction of Nickel Accumulation in Response to Zinc Deficiency in Arabidopsis thaliana. AB - Excessive accumulation of nickel (Ni) can be toxic to plants. In Arabidopsis thaliana, the Fe2+ transporter, iron (Fe)-regulated transporter1 (IRT1), mediates Fe uptake and also implicates in Ni2+ uptake at roots; however, the underlying mechanism of Ni2+ uptake and accumulation remains unelucidated. In the present study, we found that zinc (Zn) deficient conditions resulted in increased accumulation of Ni in plants, particularly in roots, in A. thaliana. In order to elucidate the underlying mechanisms of Ni uptake correlating zinc condition, we traced 63Ni isotope in response to Zn and found that (i) Zn deficiency induces short-term Ni2+ absorption and (ii) Zn2+ inhibits Ni2+ uptake, suggesting competitive uptake between Ni and Zn. Furthermore, the Zrt/Irt-like protein 3 (ZIP3)-defective mutant with an elevated Zn-deficient response exhibited higher Ni accumulation than the wild type, further supporting that the response to Zn deficiency induces Ni accumulation. Previously, expression profile study demonstrated that IRT1 expression is not inducible by Zn deficiency. In the present study, we found increased Ni accumulation in IRT1-null mutant under Zn deficiency in agar culture. These suggest that Zn deficiency induces Ni accumulation in an IRT1-independen manner. The present study revealed that Ni accumulation is inducible in response to Zn deficiency, which may be attributable to a Zn uptake transporter induced by Zn deficiency. PMID- 25923076 TI - Nucleotide salvage deficiencies, DNA damage and neurodegeneration. AB - Nucleotide balance is critically important not only in replicating cells but also in quiescent cells. This is especially true in the nervous system, where there is a high demand for adenosine triphosphate (ATP) produced from mitochondria. Mitochondria are particularly prone to oxidative stress-associated DNA damage because nucleotide imbalance can lead to mitochondrial depletion due to low replication fidelity. Failure to maintain nucleotide balance due to genetic defects can result in infantile death; however there is great variability in clinical presentation for particular diseases. This review compares genetic diseases that result from defects in specific nucleotide salvage enzymes and a signaling kinase that activates nucleotide salvage after DNA damage exposure. These diseases include Lesch-Nyhan syndrome, mitochondrial depletion syndromes, and ataxia telangiectasia. Although treatment options are available to palliate symptoms of these diseases, there is no cure. The conclusions drawn from this review include the critical role of guanine nucleotides in preventing neurodegeneration, the limitations of animals as disease models, and the need to further understand nucleotide imbalances in treatment regimens. Such knowledge will hopefully guide future studies into clinical therapies for genetic diseases. PMID- 25923077 TI - A Quantum Chemical and Statistical Study of Cytotoxic Activity of Compounds Isolated from Curcuma zedoaria. AB - A series of 21 compounds isolated from Curcuma zedoaria was subjected to cytotoxicity test against MCF7; Ca Ski; PC3 and HT-29 cancer cell lines; and a normal HUVEC cell line. To rationalize the structure-activity relationships of the isolated compounds; a set of electronic; steric and hydrophobic descriptors were calculated using density functional theory (DFT) method. Statistical analyses were carried out using simple and multiple linear regressions (SLR; MLR); principal component analysis (PCA); and hierarchical cluster analysis (HCA). SLR analyses showed that the cytotoxicity of the isolated compounds against a given cell line depend on certain descriptors; and the corresponding correlation coefficients (R2) vary from 0%-55%. MLR results revealed that the best models can be achieved with a limited number of specific descriptors applicable for compounds having a similar basic skeleton. Based on PCA; HCA and MLR analyses; active compounds were classified into subgroups; which was in agreement with the cell based cytotoxicity assay. PMID- 25923078 TI - Relationship between Proinflammatory and Antioxidant Proteins with the Severity of Cardiovascular Disease in Type 2 Diabetes Mellitus. AB - Type 2 diabetes mellitus patients are at significant risk of cardiovascular disease, however, the pathophysiology of these complications is complex and incompletely known in this population. The aim of this study was to compare the serum proteome of patients with type 2 diabetes mellitus presenting or not presenting cardiovascular disease with non-diabetic subjects to find essential proteins related to these cardiovascular complications. This cross-sectional study compares the serum proteome by a combination of protein depletion with 2D DIGE (2-dimension Difference Gel Electrophoresis) methodology. The proteins differentially expressed were identified by MALDI TOF/TOF (Matrix-assisted laser desorption/ionization and Time-Of-Flight ion detector) or LC-MS/MS (Liquid Chromatography coupled to Mass-Mass Spectrometry). Type 2 diabetes mellitus patients with cardiovascular disease showed higher expression of plasma retinol binding protein and glutathione peroxidase-3 compared to those without cardiovascular disease and non-diabetic controls. These results show that proteins related to the inflammatory and redox state appear to play an important role in the pathogenesis of the cardiovascular disease in the type 2 diabetes mellitus patients. PMID- 25923079 TI - In Ovo Administration of Silver Nanoparticles and/or Amino Acids Influence Metabolism and Immune Gene Expression in Chicken Embryos. AB - Due to their physicochemical and biological properties, silver nanoparticles (NanoAg) have a wide range of applications. In the present study, their roles as a carrier of nutrients and an immunomodulator were tested in chicken embryos. Cysteine (Cys)+NanoAg injected embryos had smaller livers but heavier breasts on the 19th day of embryogenesis. Cys injected embryos had lower oxygen consumption compared to threonine (Thr) or NanoAg injected embryos. The energy expenditure in Thr+NanoAg, or NanoAg injected embryos was higher than Cys or Cys+NanoAg but was not different from uninjected control embryos. Relative expression of the hepatic insulin-like growth factor-I (IGF-I) gene was higher in Cys or NanoAg injected embryos after lipopolysaccharide (LPS) induction. The gene expression of hepatic tumour necrosis factor-alpha (TNF-alpha) and interleukin-6 (IL-6) did not differ among amino acids, NanoAg and uninjected controls in the non-LPS groups, but increased by many folds in the LPS treated NanoAg, Cys and Cys+NanoAg groups. In LPS treated spleens, TNF-alpha expression was also up-regulated by NanoAg, amino acids and their combinations, but interleukin-10 (IL-10) expression was down regulated in Thr, Cys or Thr+NanoAg injected embryos. Toll like receptor-2 (TLR2) expression did not differ in NanoAg or amino acids injected embryos; however, toll like receptor-4 (TLR4) expression was higher in all treated embryos, except for Cys+NanoAg, than in uninjected control embryos. We concluded that NanoAg either alone or in combination with amino acids did not affect embryonic growth but improved immunocompetence, indicating that NanoAg and amino acid complexes can act as potential agents for the enhancement of innate and adaptive immunity in chicken. PMID- 25923080 TI - An Exploratory Pilot Study of Genetic Marker for IgE-Mediated Allergic Diseases with Expressions of FcepsilonR1alpha and Cepsilon. AB - The high affinity immunoglobulin E (IgE) receptor-FcepsilonR1 is mainly expressed on the surface of effector cells. Cross-linking of IgE Abs bound to FcepsilonR1 by multi-valent antigens can induce the activation of these cells and the secretion of inflammatory mediators. Since FcepsilonR1 plays a central role in the induction and maintenance of allergic responses, this study aimed to investigate the association of FcepsilonR1 with the allergic phenotype of Cepsilon expression and cytokine and histamine release from peripheral leukocytes. Peripheral leukocytes from 67 allergic and 50 non-allergic subjects were used for genotyping analysis. Peripheral mononuclear cells (PBMCs) were used for Cepsilon expression and ELISpot analysis, while polymorphonuclear cells (PMNs) were used for histamine release. The association between genotype polymorphism of the FcepsilonR1alpha promoter region (rs2427827 and rs2251746) and allergic features of Cepsilon expression and histamine were analyzed, and their effects on leukocytes function were compared with wild type. The genotype polymorphisms of FcepsilonR1alpha promoter region with CT and TT in rs2427827 and TC in rs2251746 were significantly higher in allergic patients than in non allergic controls. Patients with single nucleotide polymorphism (SNP) of FcepsilonR1alpha promoter region had high levels of total IgE, mite-specific Der p 2 (Group 2 allergen of Dermatophagoides pteronyssinus)-specific IgE and IgE secretion B cells. The mRNA expression of FcepsilonR1alpha was significantly increased after Der p2 stimulation in PBMCs with SNPs of the FcepsilonR1alpha promoter region. Despite the increased Cepsilon mRNA expression in PBMCs and histamine release from PMNs and the up-regulated mRNA expression of interleukin (IL)-6 and IL-8 secretions after Der p2 stimulation, there was no statistically significant difference between SNPs of the FcepsilonR1alpha promoter region and the wild type. SNPs of FcepsilonR1alpha promoter region were associated with IgE expression, IgE producing B cells, and increased Der p2-induced FcepsilonR1alpha mRNA expression. These SNPs may be used as a disease marker for IgE-mediated allergic inflammation caused by Dermatophagoides pteronyssinus. PMID- 25923081 TI - Varicose veins of lower extremities, hemodynamics and treatment methods. AB - Chronic venous insufficiency is one of the most common disorders of the vascular system, affecting approximately 50% of adults. If left untreated it can lead to a number of complications, including venous ulceration and venous thrombosis. This review paper outlines the epidemiology and ethiopathogenesis of the disease with regard to hemodynamics and microcirculation disturbances. It describes the medical treatment as well as the traditional surgical approach to varicose veins (with several modifications of this technique), and its limitations and contraindications. Furthermore, it discusses a number of new, minimally invasive treatment methods, namely thermal in form (radiofrequency ablation, endovenous laser ablation, steam ablation) and nonthermal (sclerotherapy, echosclerotherapy, Clarivein, Sapheon). For each method, there is a brief historical overview, a description of its mechanism of action, and its indications and limitations. The results of comparative studies on individual treatment methods as well as meta analyses on this topic are briefly discussed. This paper highlights the progressive trend towards minimally invasive methods and attempts to predict the further development. PMID- 25923082 TI - Microbiological spectrum and susceptibility pattern of clinical isolates from the neonatal unit in a single medical center. AB - BACKGROUND: Infections are a frequent and significant cause of morbidity and mortality in neonatal units. The bacterial pathogens and their susceptibility patterns should be monitored in hospital settings. The aim of the study was to describe the distribution of the bacterial agents and their antibiotic resistant and susceptibility patterns in the Special Neonatal Care Unit (SNCU). MATERIAL AND METHODS: A retrospective analysis of results of microbiologically tested samples (blood, cerebrospinal fluid, urine, stool, eye excretions, external ear swabs, nasopharyngeal swabs and skin swabs) taken from newborns hospitalized in one SNCU in Warsaw (Poland) was conducted. The period analyzed was from July 1st, 2010 to December 31st, 2010. RESULTS: A total of 838 cultured samples were collected in the period analyzed. Three hundred seventy three of them (44.5%) were positive. The majority of the cultured microorganisms were classified as colonization: 338/373 (91%) strains. Gram negative bacteria were predominant colonizing flora: 227/338 (67%) strains. Gram positive bacteria were predominant causative agents in newborns with infections: 26/35 (74%) strains. 57.9% of Escherichia coli isolates were resistant to amoxicillin and ampicillin. 100% of Klebsiella pneumoniae were resistant to amikacin and netilmicin. Staphylococcus aureus methicillin resistant strains were cultured in 2.7% of cases. CONCLUSIONS: Gram negative species continue to be predominant agents of neonatal colonizing flora while gram positive bacteria remain important causative agents for symptomatic infections. Continuous monitoring of bacterial flora and its antibiotic susceptibility pattern is necessary to provide a successful antibiotic policy. Current results may be used for future national and international comparison. PMID- 25923084 TI - The impact of electromagnetic radiation of different parameters on platelet oxygen metabolism - in vitro studies. AB - BACKGROUND: Electromagnetic radiation emitted by a variety of devices, e.g. cell phones, computers and microwaves, interacts with the human body in many ways. Research studies carried out in the last few decades have not yet resolved the issue of the effect of this factor on the human body and many questions are left without an unequivocal answer. Various biological and health-related effects have not been fully recognized. Thus further studies in this area are justified. OBJECTIVES: A comparison of changes within catalase enzymatic activity and malondialdehyde concentration arising under the influence of the electromagnetic radiation emitted by car electronics, equipment used in physiotherapy and LCD monitors. MATERIAL AND METHODS: The suspension of human blood platelets at a concentration of 1 * 109/0.001 dm 3, obtained from whole blood by manual apheresis, was the study material. Blood platelets were exposed to an electromagnetic field for 30 min in a laboratory stand designed for the reconstruction of the electromagnetic radiation generated by car electronics, physiotherapy equipment and LCD monitors. The changes in catalase activity and malondialdehyde concentration were investigated after the exposure and compared to the control values (unexposed material). RESULTS: An increase in catalase activity and malondialdehyde concentration was observed after 30 min exposure of platelets to EMF regardless of the radiation source. The most significant changes determining the degree of oxidative stress were observed after exposure to the EMF generated by car electronics. CONCLUSIONS: The low frequency electromagnetic fields generated by car electronics, physiotherapy equipment and LCD monitors may be a cause of oxidative stress in the human body and may lead to free radical diseases. PMID- 25923083 TI - The effect of hemostatic agents and tissue adhesive on injured peripheral nerve healing in rats - Part I. Electrophysiological study. AB - BACKGROUND: In the practice of maxillofacial surgery, bleeding and nerve injury have common problems. In the control of bleeding, hemostatic agents and tissue adhesives have been frequently used. The effect of these hemostatic agents and tissue adhesives on the injured neural tissues has not been known. OBJECTIVES: In this study, we aimed to investigate the effects of hemostatic agents and tissue adhesive on injured nerve tissues. MATERIAL AND METHODS: Forty-two rats randomly divided into seven groups: Control, Oxidized Regenerated Cellulose (ORC), Gelatine Sponge (GS), Bovine Collagen (BC), Ankaferd BloodStopper (ABS), Glutaraldehyde Surgical Adhesive (BioGlue(r)) and N-butil-2 cyanoacrylate (Glubran(r)2). The left sciatic nerves were crushed and surrounded by hemostatic agents and tissue adhesives. At the end of 12 weeks, the surgical site was reopened and electrophysiological recordings were performed. RESULTS: In the ORC, GS, and BC groups, the compound action potential (CAP) values were lower compared to the control group (p < 0.05). Although the values of CAP in the ABS group were higher than in the control group while CAP values in the BioGlue and Glubran(r)2 groups were lower than the control group, there was no statistical significance between the experimental and control groups (p > 0.05). In the ORC, BC, GS, and Glubran(r)2 groups, the nerve conduction velocities (NCV) values were lower than in the control group (p < 0.05). In the ABS and BioGlue groups, NCV values were lower compared to the control group but no significant differences were found (p > 0.05). CONCLUSIONS: The present study provides evidence that ABS is the most suitable hemostatic agent due to its favorable effect on the healing of injured neural tissues. BioGlue is also a suitable surgical agent with no adverse effects. PMID- 25923085 TI - Expression of proapoptotic BAX and TP53 genes and antiapoptotic BCL-2 gene in MCF 7 and T-47D tumour cell cultures of the mammary gland after a photodynamic therapy with photolon. AB - BACKGROUND: Breast cancer is the most common malignant tumour in women in the whole world. Despite significant developments in the early diagnosis of breast cancer, there is no effective method which would assure total recovery of the patient. Currently available clinical data and laboratory tests indicate a possibility to introduce photodynamic therapy (PDT) to the supplementary treatment of breast cancer. OBJECTIVES: The aim of this study was to assess the influence of PDT with Photolon as a photosensibilizator on the expression of apoptosis associated genes (BCL-2, BAX, TP53) in human breast cancer cell lines, preceded by assessment of survivorship and proliferative activity in the tested cells after PDT. MATERIAL AND METHODS: In the present study human breast cancer cell lines MCF-7 and T-47D were used. Photolon (chlorin e6 complex: PVP 1:1) was used as a photosensitizer. Assessments of survivorship and proliferative activity of cells under the influence of PDT (WST-1 test) were conducted along with the expression of selected genes involved in the process of apoptosis: BCL-2, BAX, TP53 (RT-QPCR). RESULTS: PDT limited both survivorship and proliferative activity of breast cancer cells in the two tested lines. In case of T-47D cell line was found increase of BAX and BCL-2 genes expression after PDT and sustained activity of TP53 gene. Conversely, in MCF-7 cell line a decrease in expression was found for both BAX and TP53 genes, but also an increase of BCL-2 gene expression. CONCLUSIONS: A progressing decrease (24, 48 and 72 h after PDT) in the count of culture cells, which suggests the occurrence of apoptosis initiated by a photodynamic reaction with simultaneous increase of BCL-2/BAX index, indicates activation of a different endogenous apoptosis pathway than the one examined, namely pointing to suicidal death of cells after PDT. PMID- 25923086 TI - Hyperuricemia is an independent predictive factor for left ventricular diastolic dysfunction in patients with chronic kidney disease. AB - BACKGROUND: It has been reported that elevated serum uric acid (UA) levels is an independent factor of poor prognosis in patients with chronic heart failure and chronic kidney disease (CKD). OBJECTIVES: In our study, we assessed the potential impact of hyperuricemia on left ventricular (LV) diastolic dysfunction (DD) in patient with CKD. MATERIAL AND METHODS: The study group consisted of 50 patients with CKD, stages 2-5. Standard echocardiography and tissue Doppler imaging (TDI) were performed. The levels of UA and N-terminal prohormone brain natriuretic peptide (NT-proBNP) were determined. Patients were divided into two groups according to the results of peak mitral annular early diastolic velocity (EmLV): group with LV diastolic dysfunction (EmLV < 8 cm/s) DD (+) and group with normal LV diastolic function DD (-), when EmLV >= 8 cm/s. RESULTS: Patients DD (+) group, as compared to DD (-) patients were characterized by significantly higher serum UA levels [6.7 (4.4-14.3) mg/dL vs 5.8 (1.9-8.9) mg/dL, p = 0.004] respectively. The area under the receiver operating characteristic (ROC) curve was of serum UA levels for the detection of LV diastolic dysfunction was 0.734, 95% confidence interval (CI) 0.590-0.849, p = 0.001, whereas ROC derived UA value of > 6.0 mg/dL was characterized by a sensitivity of 76.9% and specificity of 62.5% for diagnosing LV diastolic dysfunction. The independent variable predicting LV diastolic dysfunction as measured by a multivariate logistic regression analysis was UA level > 6.0 mg/dL with odds ratio (OR) = 14.3 (95% CI 2.0-103.2), p = 0.006. CONCLUSIONS: Hyperuricemia is an independent predictive factor for LV diastolic dysfunction in patients with CKD. PMID- 25923087 TI - Cytotoxic activity of valproic acid on primary chronic lymphocytic leukemia cells. AB - BACKGROUND: Chronic lymphocytic leukemia (CLL) is the most common adult leukemia in western civilization. The accumulation of CD5+CD19+ B lymphocytes in peripheral blood is due to a defect in the apoptotic pathway rather than excessive proliferation in the bone marrow and lymph nodes. Despite a number of treatments, CLL remains an incurable disease. Valproic acid (VPA) activity, as a histone deacetylase inhibitor, could restore the epigenetic changes underlying the pathogenesis of CLL and thus induce cell death. OBJECTIVES: In the present study we hypothesized that VPA could induce CLL primary cells death through activation of apoptosis. MATERIAL AND METHODS: Peripheral blood samples were obtained from 53 CLL patients. Peripheral blood mononuclear cells were isolated through density gradient centrifugation and were the subject of a 24-hour cell culture with 10 mM of VPA. The cytotoxic effect of VPA was evaluated with an XTT test and thereafter confirmed using Annexin V-FITC/PI staining and flow cytometry techniques. RESULTS: In this study, a median VPA cytotoxicity of 13.88% with a range of 0-54.65% was observed. Annexin V/PI staining confirmed that the demonstrated cytotoxicity was caused by increased apoptosis in the VPA treated cells as compared to control cells. Statistical analysis showed that VPA's effect on CLL cells depends on lactate dehydrogenase serum levels, but is independent of all other prognostic markers. CONCLUSIONS: The results of the present experiments found that VPA at a clinically applicable concentration significantly induces apoptosis independently of the disease stage and might be a valuable therapeutic agent for all CLL patients. PMID- 25923088 TI - Porphobilinogen deaminase gene mutations in Polish patients with non-erythroid acute intermittent porphyria. AB - BACKGROUND: Acute intermittent porphyria (AIP) is an metabolic disorder characterized by a partial deficiency of the porphobilinogen deaminase, the enzyme of heme biosynthesis. The metabolic defect in AIP involves an approximately half-normal activity of porphobilinogen deaminase (PBGD, EC 4.3.1.8), the enzyme catalyzing condensation of four porphobilinogen molecules to hydroxymethylbilane. Due to tissue-specific alternative transcript splicing, the PBGD gene mutations within the range of exons 3-15 may lead to classical AIP involving erythrocytes and all the other tissues. Mutations within intron and exon 1 may result in the so-called non-erythroid AIP in which the PBGD activity is normal in erythrocytes and diminished in other tissues. OBJECTIVES: The aim of the present study was to characterise molecular errors in the PBGD gene in Polish patients with non-erythroid AIP and to evaluate the efficacy of the DNA sequencing method in the early diagnosis of this disorder. MATERIAL AND METHODS: Twenty five members of nine non-erythroid AIP families were assessed. In each of them DNA sequencing was performed using the Big Dye Terminator Cycle Sequencing Kit v.1.1 on the Hitachi 3730 Analyzer (Applied Biosystem, USA). RESULTS: Four mutations were detected in intron 1 of the PBGD gene, including one unreported novel mutation, 33+(4-12) del AGTGCTGAG, of an unknown biological mechanism, and three previously described mutations, i.e. 33+1 G > A, 33+2 T > C, 33+5 G > C, responsible for abnormal transcript splicing in the area of exon 1. Of 14 asymptomatic members of proband families in 6 subjects were diagnosed with AIP, and in 8 the AIP was excluded based on the DNA sequencing method. CONCLUSIONS: DNA sequencing based analysis is the only reliable method for correct diagnosis of asymptomatic non-erythroid AIP patients with normal urinary excretion of heme precursors. The mutations found in Polish patients with non-erythroid AIP represented those of splice defect and resulted in abnormal exon 1 splicing. PMID- 25923089 TI - Correlation of hepcidin level with insulin resistance and endocrine glands function in major thalassemia. AB - BACKGROUND: Hepcidin is a master regulator of iron metabolism that inhibits the transport of iron out of enterocytes and macrophages. Thalassemia major (TM) is associated with some of the endocrine disorders. However, studies have yet to be conducted on the correlation of hepcidin with hormone levels and insulin resistance (IR) in patients with TM. OBJECTIVES: In the present study, the correlation of hepcidin level with some endocrine and biochemical parameters was investigated to determine the factors that mainly affect hepcidin correlation in patients with thalassemia. These factors include hormones, iron status, and IR parameters. MATERIAL AND METHODS: Hepcidin and other measured biochemical parameters were compared between the TM patients (100) and healthy children (37). RESULTS: Serum thyroid-stimulating hormone (TSH) was positively correlated (p < 0.05) with hepcidin, iron, and ferritin. T4 hormone was correlated with ferritin only. Other hormones showed different correlation patterns with iron status parameters but were statistically insignificant (p > 0.05). The percentage of beta-cell function was the only parameter among the IR parameters that showed a significant difference between thalassemic and control groups. CONCLUSIONS: Thyroid and beta-cells dysfunctions are common in TM patients with frequent blood transfusions. In addition, hepcidin and TSH levels can be predicted significantly using the most correlated factors with hepcidin. These factors, including ferritin, insulin and TSH were used to construct predicting equations: S. Hepcidin = 0.003*Ferritin + 3.02*TSH + 0.12*Insulin + 16.85 (+/- 7.78) and TSH = 0.0083 * Insulin + 0.0042 * Ferritin + 0.0937 * Hepcidin + 1.91 (+/- 1.373). PMID- 25923090 TI - Prevalence of anti-thyroid peroxidase in adults with type 1 diabetes participating in Poznan Prospective Study. AB - BACKGROUND: Type 1 diabetes (DM 1) is frequently associated with autoimmune thyroid diseases (AITD). Screening for AITD in adults is rarely performed. The aim of this study was to evaluate the prevalence of anti-thyroid peroxidase (anti TPO) and thyroid function and their association with metabolic control in adults participating in Poznan Prospective Study (PoProStu). MATERIAL AND METHODS: The analysis included 74 patients (26 women and 48 men) aged 38.5 (IQR: 34.5-42.5), who have had diabetes for 15.0 (14-16) years. All patients have been treated with intensive functional insulin therapy (IFIT) from the onset of the disease. Anti TPO and thyroid-stimulating hormone (TSH) were determined. The concentration of anti-TPO >= 5.61 IU/mL was considered positive. Based on the levels of anti-TPO the patients were divided into two groups: anti-TPO positive and anti-TPO negative. Metabolic control was assessed by the level of glycated hemoglobin (HbA 1c). RESULTS: Anti-TPO was positive in 32 (43.2%) patients. Prevalence of autoantibodies was significantly higher in women (53% vs 21%; p = 0.009). There was no significant difference in HbA 1c levels [median (IQR): 7.6% (7.1-8.6) vs 7.6% (7.1-8.8); p = 0.82] and TSH levels [median (IQR): 2.05 uIU/mL (1.23-3.15) vs 1.62 uIU/mL (1.00-2.10); p = 0.06] between anti-TPO positive and negative patients. After excluding patients with a thyroid dysfunction, a significant difference in TSH levels between anti-TPO positive and negative group was found [median (IQR): 2.11 uIU/mL (1.29-3.31) vs 1.66 uIU/mL (1.29-3.31); p = 0.04]. CONCLUSIONS: High anti-TPO prevalence is found in adult patients with long standing DM 1, and autoantibodies occur more often in women. Therefore, screening for asymptomatic thyroid dysfunction should be performed in this group, as already recommended by the joint statement of Polish Society of Endocrinology and Diabetes Poland. PMID- 25923091 TI - Adiponectin levels in gestational diabetes mellitus and in pregnant women without glucose intolerance. AB - OBJECTIVES: The aim of the study was to determine serum adiponectin levels among patients with gestational diabetes mellitus (GDM) and normal pregnant women without glucose intolerance, and to investigate the relationship between these levels and clinical factors at the time of the diagnosis, at delivery and in the post-partum period. MATERIAL AND METHODS: The subjects' serum adiponectin concentration was measured using the enzyme-linked immunosorbent assay (ELISA) method at 24th-28th week of gestation, at delivery (in maternal circulation and the umbilical cord) and 24 h after delivery. The relationship between these groups' measurements and other established clinical-laboratory factors were investigated. RESULTS: Serum adiponectin concentrations were significantly lower (p = 0.02) in GDM patients compared with patients with normal glucose tolerance at 24th-28th week of gestation. During delivery, maternal serum adiponectin concentrations were significantly lower (p = 0.03) in GDM patients compared with patients with normal glucose tolerance. In the post-partum period, serum adiponectin concentrations were significantly higher (p = 0.009) in GDM patients compared with patients with normal glucose tolerance. Umbilical cord adiponectin concentrations were significantly lower (p = 0.005) in GDM patients compared with patients with normal glucose tolerance. CONCLUSIONS: Adiponectin concentrations in GDM patients' circulation were regulated by changes in glucose and insulin metabolism. A reduction in serum adiponectin levels seems to play a role in GDM patients' insulin resistance. PMID- 25923092 TI - Tissue factor and other hemostatic parameters in patients with advanced peripheral artery disease after endovascular revascularization - search for hemostatic factors which indicate restenosis. AB - BACKGROUND: In patients with peripheral artery disease (PAD) a hypercoagulable state and thromboembolic complications occur. Revascularization procedures increase this state, sometimes leading to restenosis. Restenosis following balloon angioplasty (PTA)and stent implantation is >= 50% of artery stenosis. OBJECTIVES: To determine the concentration of tissue factor (TF), tissue factor pathway inhibitor (TFPI), thrombin-antithrombin (TAT) complexes, fibrinogen and D dimers in the blood of patients with PAD after peripheral endovascular revascularization of the lower legs and in PAD patients with restenosis. MATERIAL AND METHODS: The study included 150 patients with PAD, 90 men and 60 women, aged 44-88 (mean 65.5) years, after successful peripheral angioplasty (PTA) and/or with stenting. During the 6 months after the revascularization procedures, restenosis occurred in 27 patients. The reference group consisted of 53 healthy persons (44 men and 9 women, aged 20-56 years). Blood was drawn in the morning into 3.2% natrium citrate at a ratio of 9 : 1. The concentration of TF, TFPI, TAT complexes and D-dimers were measured in plasma with commercial tests using an enzyme immunoassay. Fibrinogen was determined with coagulometer. RESULTS: In the plasma of patients with PAD after endovascular revascularization, the concentrations of TF, TAT complexes, fibrinogen and D-dimers were significantly higher compared to the reference group. During the six months of observation, 27 patients developed restenosis. The results of hemostatic factors in patients with restenosis were compared with the same patients before restenosis and the group of 123 PAD patients after endovascular revascularization. TF and fibrinogen levels in the 27 patients with restenosis were significantly higher than in the group of PAD patients before restenosis. CONCLUSIONS: Statistically significantly higher levels of tissue factor (TF) and fibrinogen in PAD patients with new restenosis, compared to those without restenosis after endovascular revascularization, indicate they can participate in the formation of restenosis. PMID- 25923093 TI - Analysis of skeletal maturity of children with cleft palate in terms of healthy children by the CVM method. AB - BACKGROUND: For many years, the analysis of bone age X-rays have been used for the hand and wrist, which were assessed on the basis of changes in the various centers of ossification. These images, however, do not constitute a diagnostic element of cleft defects, leading to additional exposure of the patient to X rays. The problem was solved by using lateral head films, which enabled the interpretation of the morphological changes in the cervical spine to evaluate skeletal development stages. OBJECTIVES: The objective of this work is to define the differences between the skeletal age and chronological age of children with malocclusion and congenital craniofacial disorders - primary and secondary palate cleft. MATERIAL AND METHODS: The study material comprised 90 lateral cephalometric radiographs of patients at the age of 7 to 16 (45 lateral head radiographs of patients with various occlusion disorders and 45 lateral head radiographs of patients with various types of primary and secondary palate cleft). Then, all the lateral cephalometric radiographs were analysed in terms of the shape of the 2nd, 3rd and 4th cervical vertebra in line with the Cervical Stage method (CS), developed by Baccetti et al. in 2005. RESULTS: Patients with malocclusions without malformations achieved various stages of bone development at an earlier chronological age compared with patients with primary and secondary palate. An exception was the phase CS 3 (early growth spurt) development disorders, in which patients with different types of cleft had lower chronological age compared with patients with malocclusion. CONCLUSIONS: The method that allows for an assessment of the development of skeletal maturity is the analysis of the shape of the cervical vertebrae in lateral head film. PMID- 25923095 TI - Glutathione S-transferase GSTM 1, null genotype may be associated with susceptibility to age-related cataract. AB - BACKGROUND: Age-related cataract (ARC) is the leading cause of visual disability and reversible blindness all over the world. The different expressions of GST isozymes among animals may explain the variations in the cataract formation caused by oxidative stress. OBJECTIVES: In this study, we evaluated the distribution of GST gene polymorphisms in ARC patients and the possible associations between the presence of ARC and GST gene polymorphisms. MATERIAL AND METHODS: The epidemiological data was collected by a standard questionnaire and blood samples were obtained from 130 ARC patients and 159 healthy controls. Data about smoking habits of the groups was recorded. Real-time polymerase chain reaction-based methods were used to detect genetic polymorphisms. RESULTS: The GSTM 1 null genotype was found to carry an increased risk for developing ARC (OR: 1.84, 95% CI: 1.13-2.99). The frequency of the GSTT 1 null genotype was not significantly different among the ARC patients and the controls (OR: 1.0, 95% CI: 0.64-1.6). The GSTP 1 Val/Val genotype was also not significantly different among the ARC patients and control groups (OR: 1.06, 95% CI: 0.50-2.23). GSTM 1 null genotype was highly frequent in non-smokers (OR: 3.25, 95% CI: 1.66-6.35) and moderately frequent in smokers (OR: 2.50, 95% CI: 1.28-4.86). Also, carrying the combined genotypes of GSTM 1 null, GSTT 1 and GSTP 1 105-Val allele was seen to have an increased risk of developing ARC (OR: 2.91, 95% CI: 1.31-6.44). CONCLUSIONS: This data may provide evidence that GSTM 1 gene polymorphisms may be associated with genetic susceptibility to develop ARC. Larger studies are warranted to verify these findings. PMID- 25923094 TI - Evaluation of the toxicity of anticancer chemotherapy in patients with colon cancer. AB - BACKGROUND: Modern anticancer chemotherapy can cause numerous adverse effects in the organism, whose functioning has already been disrupted by the neoplastic process itself. OBJECTIVES: The aim of the study was to evaluate and compare the frequency and severity of the toxicity of FOLFOX-4 and CLF-1 anticancer therapy in patients with colon cancer, and to analyze certain factors that might have increased the toxicity of the chemotherapy. MATERIAL AND METHODS: The study involved 64 patients suffering from generalized colon cancer, including 48 patients treated according to the FOLFOX-4 regimen and 16 patients treated according to the CLF-1 regimen. The toxicity of each regimen was analyzed on the basis of a confidential questionnaire formulated by the authors and laboratory research according to the extended WHO toxicity criteria. RESULTS: The analysis of the symptoms of toxicity symptoms associated with the use of the FOLFOX-4 and CLF-1 therapeutic regimens revealed that the most common side effects included nausea and vomiting, despite ondansetron premedication, and neurotoxicity. Disruption of the functioning of the nervous system under the FOLFOX-4 regimen statistically significant exacerbation that increased with the number of chemotherapy cycles administered; this was more common and more severe in women. Paresthesia was also revealed to be a neurotoxic effect of the FOLFOX-4 regimen after termination of therapy. A statistically significant relationship was observed between the use of vitamin supplements and the incidence and severity of the toxicity of the FOLFOX-4 regimen. CONCLUSIONS: The findings of the current study regarding the toxicity of the FOLFOX-4 and CLF-1 therapy regimens should be taken into consideration when monitoring chemotherapy safety in colon cancer. The patients' tolerance of the administered medication and the side effects reported by patients should be constantly evaluated, which will help prevent these side effects, apply appropriate therapy and contribute to the improvement of the patients' quality of life. The functioning of the central nervous system should be carefully evaluated when planning the anticancer therapy, especially if repeated administration of neurotoxic drugs is necessary in cases of a recurrence of the disease. Chemotherapy should be thoroughly monitored for safety, especially in women over 65 years of age suffering from coexisting diseases. Colon cancer patients and their families should be informed of the risks of nutritional supplements before the start of the anticancer chemotherapy, and may need to dispense with their use. PMID- 25923096 TI - Genotypic variations of virulent genes in Enterococcus faecium and Enterococcus faecalis isolated from three hospitals in Malaysia. AB - BACKGROUND: The genus Enterococcus is of increasing significance as a cause of nosocomial infections, and this trend is exacerbated by the development of antibiotic resistance. OBJECTIVES: The aim of the present study was to estimate the potential virulence factors in enterococci and to ascertain their prevalence in Malaysian hospitals. MATERIAL AND METHODS: The study comprised 222 enterococcal strains isolated from blood, urine, exudates, sputum, stool and body fluid. These strains were collected from patients staying in three referral hospitals in Malaysia. All isolates were identified to the species level, and their MIC of vancomycin was determined using E test strips. Specific primers were designed for detection of the five potential virulence genes (gelE, PAI, esp, ace, and sprE) by PCR assay. RESULTS: Different patterns and frequency of virulence determinants were found for the E. faecalis and E. faecium isolates. E. faecalis isolates had more virulence determinants than E. faecium isolates. Clinical enterococcal isolates were found to possess more virulence determinants than enterococci isolated from faecal samples. The esp gene is significantly more common (p = 0.049) in vancomycin-resistant strains (85.7%) than in vancomycin sensitive strains (44.2%). All of the vancomycin-resistant isolates were isolated from faecal samples. None of the classical virulence factors were found in 11% of enterococcal isolates, while all five virulence genes were found in 21% of enterococcal isolates. CONCLUSIONS: All the virulence genes considered in this study were important in the pathogenesis of enterococcal infections and further studies including more virulence genes and epidemiological data will be necessary in order to analyze the association and role of virulence genes in the pathogencity of enterococci. PMID- 25923097 TI - Validation of the Polish version of the oral health impact profile-14. AB - BACKGROUND: The Oral Health Impact Profile-14 (OHIP-14) is an example of a specific questionnaire used for assessing the quality of life in relation to oral health. OBJECTIVES: The aim of this study was to validate the Polish version of the original English Short-Form OHIP-14 questionnaire. MATERIAL AND METHODS: The Polish version of the OHIP-14 instrument had been prepared in accordance with generally accepted standards. The main study was conducted among a group of 150 subjects of both genders, aged from 35 to 91 who were randomly selected. Statistical analysis was made by STATISTICA software using the Cronbach alpha reliability test, Mann-Whitney U test, multiple comparison post-hoc test - LSD and Spearman's correlation coefficient. RESULTS: The total OHIP-14 score was 8.72 +/- 13.39, out of which the highest value was for item 4 (uncomfortable to eat 0.89 +/- 1.19). The value of the alpha Cronbach coefficient was above 0.9 for all 14 items of the OHIP-14 instrument indicating excellent internal consistency. Positive relationships between all items of the matrix of the inter-items correlation coefficients were found. The value of coefficients ranged from 0.56 to 0.90 at a significance level of p < 0.01. Construct validity was supported by the fact that oral health condition was correlated with total OHIP score. It was observed that there is a correlation between the quality of life evaluated with the OHIP-14 test and dental condition, dental needs, wearing removable dentures and self-assessment of general health and oral health condition. CONCLUSIONS: The obtained data indicated the reliability and validity of OHIP-14 instrument for the assessment of oral health-related quality of life for in Polish adult population. PMID- 25923098 TI - Quality of life in patients with type 2 diabetes in Poland - comparison with the general population using the EQ-5D questionnaire. AB - BACKGROUND: Complications of type 2 diabetes (T2D) lead to increased mortality and reduced quality of life (QOL). OBJECTIVES: The aim of the study was to compare health-related quality of life (HRQoL) in Polish patients with type 2 diabetes (T2D) and in a matched sample from the general population. MATERIAL AND METHODS: Data on HRQoL came from two non-interventional studies: a prospective study of patients with T2D and an EQ-5D study of Polish general population norms. The HRQoL analysis was conducted in four separate age groups: 32-44, 45-54, 55-64 and over 65 years old. We analyzed both subjective and objective assessment of HRQoL (EQ VAS and EQ-5D index) and the presence of restrictions within five dimensions of the EQ-5D descriptive part. RESULTS: A total of 274 patients with T2D and 214 representatives from the study of population norms were included. EQ VAS was systematically lower in diabetic patients as compared to the general population and decreased with age (68.2 vs 83.9, 62.4 vs 79.2; 54.9 vs 78.1, 50.2 vs 69.8 in consecutive age groups). A similar relationship was observed with the EQ-5D index. The largest mean differences were observed among subjects aged 55-64 years (EQ VAS: 23.2, EQ-5D index: 0.085). In three domains, i.e. self-care, usual activities and anxiety/depression, patients with diabetes who were over 45 years of age reported significantly more problems than respondents from the general population. CONCLUSIONS: Both subjective and objective HRQoL in patients with T2D was lower than in respondents similar in age from the general population. Compared with type 2 diabetic populations from other countries, Polish patients are characterized by relatively high HRQoL objective assessment and very low subjective assessment. PMID- 25923099 TI - Health-related quality of life of patients suffering from cystic fibrosis. AB - BACKGROUND: Cystic fibrosis (CF) is a particular example of a chronic disease with progressive course. Current statistical data shows that the life span of patients with CF has extended. Therefore, it is necessary to undertake interdisciplinary actions aiming at improving the efficiency of medical activities as well as minimalizing the influence of those interventions on the patients' quality of prolonged life. OBJECTIVES: The aim of the study was to depict the QoL of patients suffering from mucoviscidosis and show the differences in the assessment of patients' QoL depending on age and sex. MATERIAL AND METHODS: The study covered 30 patients with CF. Mean age of the respondent group was 24.83 +/- 6.98; mean age of females 25.8 +/- 7.27, whereas of males - 23.5 +/ 6.56. A specific questionnaire for testing cystic fibrosis quality of life (CFQoL) of patients was used in the study. RESULTS: Generally patients with CF evaluated their QoL as low. In the study with the use of a CFQoL questionnaire they evaluated their QoL as the lowest in a subscale: future concerns. In most domains women got lower mean values than men. A dependence between patients' QoL and their age was ascertained. The older the patient is, the lower QoL is in the case of subscales (CFQoL): physical, emotional and social functioning, chest symptoms, interpersonal relationships, body image, career concerns. CONCLUSIONS: Patients with CF generally evaluate their QoL as low; there are differences in the evaluation of QoL between women and men. There is a relation between patients' QoL their age. The older the patient is, the worse his QoL in most subscales is. PMID- 25923100 TI - Immunoglobulins and their use in children. AB - Immunoglobulin preparations are one of the products of the human plasma fractionation, where the plasma is obtained, in accordance with WHO guidelines from at least 1,000 donors. These preparations contain all IgG subclasses with various antigen characteristics. In clinical practice these drugs are used as replacement therapy in patients with primary and secondary immunodeficiencies as well as immunomodulatory therapy in many autoimmune diseases and systemic inflammatory diseases. Here we present characteristics of i.v. polyvalent, human immunoglobulin preparations available on the Polish market and the possibilities of their use in clinical practice, in children with hematological diseases. Considering the very low consumption of immunoglobulin preparations in our country as compared to other European countries, we would like to draw the attention of medical professionals, especially pediatricians and haematologists, to the benefits that stem from the use of these drugs in the therapy of children with haematological diseases. Our work will also facilitate the choice of an optimal polyvalent human immunoglobulin preparation for a particular patient. PMID- 25923101 TI - Neuroprotective effect of resveratrol against glutamate-induced excitotoxicity. AB - As the major neurotransmitter in the mammalian central nervous system (CNS), excessive extracellular glutamate (Glu) can activate the Glu receptors and neuronal calcium (Ca2+) overload, then produce neurotoxicity, which is a common pathway for neuronal injury or death, and is associated with acute and chronic neurodegenerative diseases. Therefore, it has been a therapeutic strategy to investigate neuroprotective effects against Glu-induced neurotoxicity for treating both acute and chronic forms of neurodegeneration. Resveratrol (Res), as a naturally occurring polyphenol mainly found in grapes and red wine, has shown a neuroprotective effect in a variety of experimental models for neurodegenerative diseases in vitro and in vivo. This review will focus on the neuroprotective effect of Res against Glu-induced excitotoxicity in neurodegenerative diseases by blocking different Glu receptors and Ca2+ ion channels. PMID- 25923102 TI - The quality of life and psychological, social and cognitive functioning of patients with acromegaly. AB - Acromegaly is a rare and chronic disease, most often caused by a pituitary adenoma. Excessive secretion of the growth hormone (GH) leads to hepatic secretion of insulin-like growth factor-1 (IGF-1), which in turn causes characteristic changes in the patient's appearance, many skeletal deformities and metabolic disorders. In addition to somatic symptoms, acromegalic patients demonstrate psychosocial and personality deficits, as well as common co occurrence of mental disorders. There are few studies investigating acromegaly in Poland. In recent years, the concept of quality of life has become fundamental to understanding health problems. Studies dealing with acromegaly likewise tend to include assessments of quality of life of patients suffering from this endocrinopathy. PMID- 25923103 TI - Remembrance of professor Tadeusz Marciniak - Lviv tradition in Wroclaw. AB - After the seizure of Lviv by the Soviets, in the years 1944-1946, Tadeusz Marciniak worked in the Descriptive Anatomy Department in the State-Medical Institute of Lviv and also performed the function of the dean of the Medical Faculty. On receiving a proposal to assume the Chair of the Anatomy Department in Wroclaw, he made the decision to leave Lviv. By July 2nd, 1946, prof. Tadeusz Marciniak had taken over the duties of full professor of the Descriptive Anatomy Department of the Medical Faculty of the University and the Technical College of Wroclaw. On taking his job in Wroclaw, prof. Marciniak undertook attempts to restore the worn out parts of the Anatomy Department building. Due to the lack of Polish manuals, he also took to the preparation of scripts for medical students. Professor Marciniak was a member of the Wroclaw Section of the Polish Anthropological Association and a regular member of the Wroclaw Association of Science. His main scientific interests referred to the morphogenesis of the central nervous system and urinary system. He concentrated on circulatory system and muscular system tetralogies. Professor Marciniak also actively participated in administrative work at the university. In the years 1947-1948, he held the office of associate dean of the Medical Faculty, and till 1950 was a member of the Senate of the University and Technical College of Wroclaw. In the years 1959 1962, he was a vice rector of the Medical University of Wroclaw. PMID- 25923104 TI - InAs/Si Hetero-Junction Nanotube Tunnel Transistors. AB - Hetero-structure tunnel junctions in non-planar gate-all-around nanowire (GAA NW) tunnel FETs (TFETs) have shown significant enhancement in 'ON' state tunnel current over their all-silicon counterpart. Here we show the unique concept of nanotube TFET in a hetero-structure configuration that is capable of much higher drive current as opposed to that of GAA NW TFETs.Through the use of inner/outer core-shell gates, a single III-V hetero-structured nanotube TFET leverages physically larger tunneling area while achieving higher driver current (ION) and saving real estates by eliminating arraying requirement. Numerical simulations has shown that a 10 nm thin nanotube TFET with a 100 nm core gate has a 5*normalized output current compared to a 10 nm diameter GAA NW TFET. PMID- 25923105 TI - Reducing sexual violence by increasing the supply of toilets in Khayelitsha, South Africa: a mathematical model. AB - BACKGROUND: Sexual violence is a major public health issue, affecting 35% of women worldwide. Major risk factors for sexual assault include inadequate indoor sanitation and the need to travel to outdoor toilet facilities. We estimated how increasing the number of toilets in an urban township (Khayelitsha, South Africa) might reduce both economic costs and the incidence and social burden of sexual assault. METHODS: We developed a mathematical model that links risk of sexual assault to the number of sanitation facilities and the time a woman must spend walking to a toilet. We defined a composite societal cost function, comprising both the burden of sexual assault and the costs of installing and maintaining public chemical toilets. By expressing total social costs as a function of the number of available toilets, we were able to identify an optimal (i.e., cost minimizing) social investment in toilet facilities. FINDINGS: There are currently an estimated 5600 toilets in Khayelitsha. This results in 635 sexual assaults and US$40 million in combined social costs each year. Increasing the number of toilets to 11300 would minimize total costs ($35 million) and reduce sexual assaults to 446. Higher toilet installation and maintenance costs would be more than offset by lower sexual assault costs. Probabilistic sensitivity analysis shows that the optimal number of toilets exceeds the original allocation of toilets in the township in over 80% of the 5000 iterations of the model. INTERPRETATION: Improving access to sanitation facilities in urban settlements will simultaneously reduce the incidence of sexual assaults and overall cost to society. Since our analysis ignores the many additional health benefits of improving sanitation in resource-constrained urban areas (e.g., potential reductions in waterborne infectious diseases), the optimal number of toilets identified here should be interpreted as conservative. PMID- 25923106 TI - Adoption Does Not Increase the Risk of Mortality among Taiwanese Girls in a Longitudinal Analysis. AB - Adopted children often experience health and well-being disadvantages compared to biological children remaining in their natal households. The degree of genetic relatedness is thought to mediate the level of parental investment in children, leading to poorer outcomes of biologically unrelated children. We explore whether mortality is related to adoption in a historical Taiwanese population where adoption rarely occurred among kin. Using Cox proportional hazards models in which adoption is included as a time-dependent covariate, we show that adoption of girls does not increase the risk of mortality, as previously suggested; in fact, it is either protective or neutral with respect to mortality. These results suggest that socio-structural variables may produce positive outcomes for adopted children, even compared to biological children who remain in the care of their parents. PMID- 25923107 TI - Systemic Delivery of scAAV8-Encoded MiR-29a Ameliorates Hepatic Fibrosis in Carbon Tetrachloride-Treated Mice. AB - Fibrosis refers to the accumulation of excess extracellular matrix (ECM) components and represents a key feature of many chronic inflammatory diseases. Unfortunately, no currently available treatments specifically target this important pathogenic mechanism. MicroRNAs (miRNAs) are short, non-coding RNAs that post-transcriptionally repress target gene expression and the development of miRNA-based therapeutics is being actively pursued for a diverse array of diseases. Because a single miRNA can target multiple genes, often within the same pathway, variations in the level of individual miRNAs can potently influence disease phenotypes. Members of the miR-29 family, which include miR-29a, miR-29b and miR-29c, are strong inhibitors of ECM synthesis and fibrosis-associated decreases in miR-29 have been reported in multiple organs. We observed downregulation of miR-29a/b/c in fibrotic livers of carbon tetrachloride (CCl4) treated mice as well as in isolated human hepatocytes exposed to the pro-fibrotic cytokine TGF-beta. Importantly, we demonstrate that a single systemic injection of a miR-29a expressing adeno-associated virus (AAV) can prevent and even reverse histologic and biochemical evidence of fibrosis despite continued exposure to CCl4. The observed therapeutic benefits were associated with AAV transduction of hepatocytes but not hepatic stellate cells, which are the main ECM producing cells in fibroproliferative liver diseases. Our data therefore demonstrate that delivery of miR-29 to the hepatic parenchyma using a clinically relevant gene delivery platform protects injured livers against fibrosis and, given the consistent fibrosis-associated downregulation of miR-29, suggests AAV-miR-29 based therapies may be effective in treating a variety of fibroproliferative disorders. PMID- 25923109 TI - Sea Surface Temperature Influence on Terrestrial Gross Primary Production along the Southern California Current. AB - Some land and ocean processes are related through connections (and synoptic-scale teleconnections) to the atmosphere. Synoptic-scale atmospheric (El Nino/Southern Oscillation [ENSO], Pacific Decadal Oscillation [PDO], and North Atlantic Oscillation [NAO]) decadal cycles are known to influence the global terrestrial carbon cycle. Potentially, smaller scale land-ocean connections influenced by coastal upwelling (changes in sea surface temperature) may be important for local to-regional water-limited ecosystems where plants may benefit from air moisture transported from the ocean to terrestrial ecosystems. Here we use satellite derived observations to test potential connections between changes in sea surface temperature (SST) in regions with strong coastal upwelling and terrestrial gross primary production (GPP) across the Baja California Peninsula. This region is characterized by an arid/semiarid climate along the southern California Current. We found that SST was correlated with the fraction of photosynthetic active radiation (fPAR; as a proxy for GPP) with lags ranging from 0 to 5 months. In contrast ENSO was not as strongly related with fPAR as SST in these coastal ecosystems. Our results show the importance of local-scale changes in SST during upwelling events, to explain the variability in GPP in coastal, water-limited ecosystems. The response of GPP to SST was spatially-dependent: colder SST in the northern areas increased GPP (likely by influencing fog formation), while warmer SST at the southern areas was associated to higher GPP (as SST is in phase with precipitation patterns). Interannual trends in fPAR are also spatially variable along the Baja California Peninsula with increasing secular trends in subtropical regions, decreasing trends in the most arid region, and no trend in the semi-arid regions. These findings suggest that studies and ecosystem process based models should consider the lateral influence of local-scale ocean processes that could influence coastal ecosystem productivity. PMID- 25923108 TI - A cluster of noncoding RNAs activates the ESR1 locus during breast cancer adaptation. AB - Estrogen receptor-alpha (ER)-positive breast cancer cells undergo hormone independent proliferation after deprivation of oestrogen, leading to endocrine therapy resistance. Up-regulation of the ER gene (ESR1) is critical for this process, but the underlying mechanisms remain unclear. Here we show that the combination of transcriptome and fluorescence in situ hybridization analyses revealed that oestrogen deprivation induced a cluster of noncoding RNAs that defined a large chromatin domain containing the ESR1 locus. We termed these RNAs as Eleanors (ESR1 locus enhancing and activating noncoding RNAs). Eleanors were present in ER-positive breast cancer tissues and localized at the transcriptionally active ESR1 locus to form RNA foci. Depletion of one Eleanor, upstream (u)-Eleanor, impaired cell growth and transcription of intragenic Eleanors and ESR1 mRNA, indicating that Eleanors cis-activate the ESR1 gene. Eleanor-mediated gene activation represents a new type of locus control mechanism and plays an essential role in the adaptation of breast cancer cells. PMID- 25923110 TI - Emergence of soft communities from geometric preferential attachment. AB - All real networks are different, but many have some structural properties in common. There seems to be no consensus on what the most common properties are, but scale-free degree distributions, strong clustering, and community structure are frequently mentioned without question. Surprisingly, there exists no simple generative mechanism explaining all the three properties at once in growing networks. Here we show how latent network geometry coupled with preferential attachment of nodes to this geometry fills this gap. We call this mechanism geometric preferential attachment (GPA), and validate it against the Internet. GPA gives rise to soft communities that provide a different perspective on the community structure in networks. The connections between GPA and cosmological models, including inflation, are also discussed. PMID- 25923112 TI - The local compressibility of liquids near non-adsorbing substrates: a useful measure of solvophobicity and hydrophobicity? AB - We investigate the suitability of the local compressibility chi(z) as a measure of the solvophobicity or hydrophobicity of a substrate. Defining the local compressibility as the derivative of the local one-body density rho(z) w.r.t. the chemical potential MU at fixed temperature T, we use density functional theory (DFT) to calculate chi(z) for a model fluid, close to bulk liquid-gas coexistence, at various planar substrates. These range from a 'neutral' substrate with a contact angle of theta~90 degrees , which favours neither the liquid nor the gas phase, to a very solvophobic, purely repulsive substrate which exhibits complete drying, i.e. theta = 180 degrees . We find that the maximum in the local compressibility chi(z), which occurs within one-two molecular diameters of the substrate, and the integrated quantity chi(ex) (the surface excess compressibility, defined below) both increase rapidly as theta increases and the substrate becomes more solvophobic. chi(z) provides a more pronounced indicator of solvophobicity than the density depletion in the vicinity of the surface which increases only weakly with increasing theta. For the limiting case of drying, theta = 180 degrees , we find lnchi(l) ~ l, where l is the thickness of the intruding film of gas which diverges in the approach to bulk coexistence MU -> MU(co). When the fluid is confined in a parallel slit with two identical solvophobic walls, or with competing solvophobic and solvophilic walls, chi(z) close to the solvophobic wall is altered little from that at the single substrate. We connect our results with simulation studies of water near to hydrophobic surfaces exploring the relationship between chi(z) and fluctuations in the local density and between chi(ex) and the mean-square fluctuation in the number of adsorbed molecules. PMID- 25923111 TI - Prostaglandin Transporter (PGT/SLCO2A1) Protects the Lung from Bleomycin-Induced Fibrosis. AB - Prostaglandin (PG) E2 exhibits an anti-fibrotic effect in the lung in response to inflammatory reactions and is a high-affinity substrate of PG transporter (SLCO2A1). The present study aimed to evaluate the pathophysiological relevance of SLCO2A1 to bleomycin (BLM)-induced pulmonary fibrosis in mice. Immunohistochemical analysis indicated that Slco2a1 protein was expressed in airway and alveolar type I (ATI) and II (ATII) epithelial cells, and electron microscopic immunohistochemistry further demonstrated cell surface expression of Slco2a1 in ATI cells in wild type (WT) C57BL/6 mice. PGE2 uptake activity was abrogated in ATI-like cells from Slco2a1-deficient (Slco2a1-/-) mice, which was clearly observed in the cells from WT mice. Furthermore, the PGE2 concentrations in lung tissues were lower in Slco2a1-/- than in WT mice. The pathological relevance of SLCO2A1 was further studied in mouse BLM-induced pulmonary fibrosis models. BLM (1 mg/kg) or vehicle (phosphate buffered saline) was intratracheally injected into WT and Slco2a1-/- mice, and BLM-induced fibrosis was evaluated on day 14. BLM induced more severe fibrosis in Slco2a1-/- than in WT mice, as indicated by thickened interstitial connective tissue and enhanced collagen deposition. PGE2 levels were higher in bronchoalveolar lavage fluid, but lower in lung tissues of Slco2a1-/- mice. Transcriptional upregulation of TGF-beta1 was associated with enhanced gene transcriptions of downstream targets including plasminogen activator inhitor-1. Furthermore, Western blot analysis demonstrated a significant activation of protein kinase C (PKC) delta along with a modest activation of Smad3 in lung from Slco2a1-/- mice, suggesting a role of PKCdelta associated with TGF-beta signaling in aggravated fibrosis in BLM-treated Slco2a1 /- mice. In conclusion, pulmonary PGE2 disposition is largely regulated by SLCO2A1, demonstrating that SLCO2A1 plays a critical role in protecting the lung from BLM-induced fibrosis. PMID- 25923113 TI - Therapeutic hypothermia modifies perinatal asphyxia-induced changes of the corpus callosum and outcome in neonates. AB - WHAT IS KNOWN ABOUT THIS SUBJECT?: Diffusion-weighted MRI has demonstrated changes in the corpus callosum of term neonates with perinatal asphyxia. The severity of cerebral changes demonstrated using diffusion-weighted MRI is difficult to assess without measuring values of the Apparent Diffusion Coefficient (ADC). WHAT IS NEW?: ADC values of the anterior part of the corpus callosum are slightly higher than of the posterior part in full term infants with perinatal asphyxia. Low ADC values of the corpus callosum were associated with an adverse outcome in infants with perinatal asphyxia. In infants treated with hypothermia lower ADC values than with normothermia were associated with a poor outcome, supporting neuroprotective effects of hypothermia. BACKGROUND: Using MRI, changes can be detected in the corpus callosum (CC) following perinatal asphyxia which are associated with later neurodevelopmental outcome. AIM: To study the association between the apparent diffusion coefficient of water (ADC) in the CC on MRI in neonates with perinatal asphyxia and neurodevelopmental outcome at 18 months of age. SUBJECTS, METHODS: Of 121 infants 32 (26%) died and 13 (11%) survived with an adverse neurological outcome. Sixty-five (54%) received therapeutic hypothermia. MRI was performed within 7 days after birth using a 1.5 T or 3.0 T system, and ADC values were measured in the anterior and posterior CC. The association between ADC and composite outcome (death or abnormal neurodevelopment) was analyzed for both normothermia and hypothermia cases using receiver operating characteristics. RESULTS: ADC values of the posterior CC were lower than of the anterior part (mean difference 0.050 x 10-3 mm2/s, p<0.001). Field strength did not affect ADC values. ADC values of the posterior part of the CC were significantly lower in infants with basal ganglia/thalamus or near total brain injury (p<0.001). Lower ADC values were associated with an adverse outcome, but cut-off levels were lower after hypothermia (1.024 x 10-3 mm2/s vs 0.969 x 10 3 mm2/s). CONCLUSION: Low ADC values of the posterior part of the corpus callosum are associated with an adverse outcome in term or near term neonates with perinatal asphyxia. Therapeutic hypothermia slightly modifies this association, showing that lower values were needed for an adverse outcome. PMID- 25923115 TI - Model for end-stage liver disease (MELD) score as a predictor and monitor of mortality in patients with Vibrio vulnificus necrotizing skin and soft tissue infections. AB - BACKGROUND: Vibrio vulnificus necrotizing skin and soft tissue infections (VNSSTIs) usually predispose patients with or without preexisting liver disease to septic shock, and then evolve to multiple organ dysfunction syndrome (MODS), thus resulting in high mortality in humans. However, clinicians do not have a valid prediction model to provide a reliable estimate of case-fatality rate when caring for these acutely and/or critically ill patients. METHODS/PRINCIPAL FINDINGS: We retrospectively analyzed 39 consecutive patients with VNSSTIs (mean age: 65.7 +/- 11.3 years) at our institution between 2007 and 2010. All patients were treated with the same protocol. Demographic and clinical characteristics, disease severity on admission, treatment details, and outcomes were collected for each patient and extracted for analyses. We studied the predictive value of the model for end-stage liver disease (MELD), modified MELD including sodium (MELD Na), and laboratory risk indicator for necrotizing fasciitis (LRINEC) scores for case-fatality. Logistic regression and receiver operating characteristic (ROC) curve analyses were performed. The mean MELD, MELD-Na and LRINEC scores on admission were 15.1 +/- 1.1, 17.7 +/- 1.1, and 3.4 +/- 0.4 points, respectively. After admission, these patients had temporary or progressive deterioration of nearly all their scores and lab values. The area under the ROC curve for the MELD and DeltaMELD scoring models were 0.929 (p = 0.002) and 0.897 (p = 0.005), respectively. An optimal MELD/DeltaMELD cutoff value >= 20/2 had a good sensitivity and specificity (all > 80%), with a 64/13-fold increased odds for case-fatality. Additionally, the development of severe forms of anemia (p = 0.014) and hypoalbuminemia (p = 0.019) were associated with an increased case fatality rate. DISCUSSION: The MELD/DeltaMELD scoring model is an effective risk stratification indicator at the time of admission and also an excellent condition monitor during hospitalization for medical care of acutely and/or critically ill patients with VNSSTIs. PMID- 25923114 TI - Field evaluation of a push-pull system to reduce malaria transmission. AB - Malaria continues to place a disease burden on millions of people throughout the tropics, especially in sub-Saharan Africa. Although efforts to control mosquito populations and reduce human-vector contact, such as long-lasting insecticidal nets and indoor residual spraying, have led to significant decreases in malaria incidence, further progress is now threatened by the widespread development of physiological and behavioural insecticide-resistance as well as changes in the composition of vector populations. A mosquito-directed push-pull system based on the simultaneous use of attractive and repellent volatiles offers a complementary tool to existing vector-control methods. In this study, the combination of a trap baited with a five-compound attractant and a strip of net-fabric impregnated with micro-encapsulated repellent and placed in the eaves of houses, was tested in a malaria-endemic village in western Kenya. Using the repellent delta undecalactone, mosquito house entry was reduced by more than 50%, while the traps caught high numbers of outdoor flying mosquitoes. Model simulations predict that, assuming area-wide coverage, the addition of such a push-pull system to existing prevention efforts will result in up to 20-fold reductions in the entomological inoculation rate. Reductions of such magnitude are also predicted when mosquitoes exhibit a high resistance against insecticides. We conclude that a push-pull system based on non-toxic volatiles provides an important addition to existing strategies for malaria prevention. PMID- 25923116 TI - Comparing Acute Effects of a Nano-TiO2 Pigment on Cosmopolitan Freshwater Phototrophic Microbes Using High-Throughput Screening. AB - Production of titanium-dioxide nanomaterials (nano-TiO2) is increasing, leading to potential risks associated with unintended release of these materials into aquatic ecosystems. We investigated the acute effects of nano-TiO2 on metabolic activity and viability of algae and cyanobacteria using high-throughput screening. The responses of three diatoms (Surirella angusta, Cocconeis placentula, Achnanthidium lanceolatum), one green alga (Scenedesmus quadricauda), and three cyanobacteria (Microcystis aeruginosa, Gloeocapsa sp., Synechococcus cedrorum) to short-term exposure (15 to 60 min) to a common nano-TiO2 pigment (PW6; average crystallite size 81.5 nm) with simulated solar illumination were assessed. Five concentrations of nano-TiO2 (0.5, 2.5, 5, 10, and 25 mg L-1) were tested and a fluorescent reporter (fluorescein diacetate) was used to assess metabolic activity. Algae were sensitive to nano-TiO2, with all showing decreased metabolic activity after 30-min exposure to the lowest tested concentration. Microscopic observation of algae revealed increased abundance of dead cells with nano-TiO2 exposure. Cyanobacteria were less sensitive to nano-TiO2 than algae, with Gloeocapsa showing no significant decrease in activity with nano-TiO2 exposure and Synechococcus showing an increase in activity. These results suggest that nanomaterial contamination has the potential to alter the distribution of phototrophic microbial taxa within freshwater ecosystems. The higher resistance of cyanobacteria could have significant implications as cyanobacteria represent a less nutritious food source for higher trophic levels and some cyanobacteria can produce toxins and contribute to harmful algal blooms. PMID- 25923117 TI - Single Genome Analysis for the Detection of Linked Multiclass Drug Resistance Mutations in HIV-1-Infected Children After Failure of Protease Inhibitor-Based First-Line Therapy. AB - The WHO recommends protease inhibitor (PI)-based antiretroviral therapy (ART) for vertically infected children after failed nevirapine (NVP) prophylaxis. Emergence of PI resistance on the backdrop of preexisting non-nucleoside reverse transcriptase inhibitor (NNRTI) resistance could compromise long-term treatment options in such children. We characterized multiclass drug resistance using single genome sequencing (SGS) in children with viremia while receiving PI-based ART. We applied SGS of HIV-1 protease (PR) and reverse transcriptase to longitudinal samples from a cohort of the Children with HIV Early Antiretroviral Therapy trial with viral loads >1000 copies per milliliter after 40 weeks of early ART. Bulk sequencing revealed NVP-selected resistance in 50% of these children, whereas SGS revealed NVP-selected resistance in 70%. Two children had baseline NRTI and PI mutations, suggesting previous maternal ART. Linked multiclass drug resistance after PI-based ART was detected by SGS in 2 of 10 children. In one child, the majority species contained M184V in reverse transcriptase linked to L10F, M46I/L, I54V, and V82A in PR and a triple-class drug-resistant variant with these mutations linked to the NNRTI mutation V108I. In the second child, the majority species contained M184V and V82A linked within viral genomes. We conclude that when PI-based ART is initiated soon after birth after single dose-NVP prophylaxis, PI and NRTI resistance can occur in the majority species as expected and also be selected on the same genomes as preexisting NNRTI-resistant mutations. These observations highlight a future therapeutic challenge for vertically infected children where antiretroviral drug classes are limited. PMID- 25923118 TI - So Many Brands and Varieties to Choose from: Does This Compromise the Control of Food Intake in Humans? AB - The recent rise in obesity is widely attributed to changes in the dietary environment (e.g., increased availability of energy-dense foods and larger portion sizes). However, a critical feature of our "obesogenic environment" may have been overlooked - the dramatic increase in "dietary variability" (the tendency for specific mass-produced foods to be available in numerous varieties that differ in energy content). In this study we tested the hypothesis that dietary variability compromises the control of food intake in humans. Specifically, we examined the effects of dietary variability in pepperoni pizza on two key outcome variables; i) compensation for calories in pepperoni pizza and ii) expectations about the satiating properties of pepperoni pizza (expected satiation). We reasoned that dietary variability might generate uncertainty about the postingestive effects of a food. An internet-based questionnaire was completed by 199 adults. This revealed substantial variation in exposure to different varieties of pepperoni pizza. In a follow-up study (n= 66; 65% female), high pizza variability was associated with i) poorer compensation for calories in pepperoni pizza and ii) lower expected satiation for pepperoni pizza. Furthermore, the effect of uncertainty on caloric compensation was moderated by individual differences in decision making (loss aversion). For the first time, these findings highlight a process by which dietary variability may compromise food-intake control in humans. This is important because it exposes a new feature of Western diets (processed foods in particular) that might contribute to overeating and obesity. PMID- 25923119 TI - Therapeutic Efficacy of Stem Cell-based Therapy in Peripheral Arterial Disease: A Meta-Analysis. AB - Several cell-based therapies for peripheral arterial disease (PAD) have been studied in multiple clinical trials; however, the outcome of this treatment remains controversial. The aim of this study was to perform a meta-analysis of the clinical trials on stem cell-based therapy after PAD. We searched for clinical trials that investigated the effect of stem cell-based therapy on patients with PAD and were published between January 2000 and October 2014. The outcomes of interest comprised all-cause mortality, amputation rate, ulcer healing, and ankle-brachial index (ABI). In addition, pooled odds ratios (ORs) and 95% confidence intervals (CIs) were calculated to assess the safety and efficacy of the stem cell-based therapies for PAD. Thirteen studies were retrieved from 261 citations for the analysis, and in total, 527 patients (mean age: 64.2 years; median follow up: 6 months) were included in the analysis. After synthesizing data, the meta-analysis showed significant improvement in the amputation rate (OR=0.33, 95%CI=0.22-0.51; P<0.001), ulcer healing (OR=6.11, 95%CI=3.04-12.28; P<0.001), and ABI (SMD=0.65, 95%CI=0.33-0.97; P<0.001) for the stem cell-based therapy group compared with the controls. Moreover, significant improvement in the amputation rate, ulcer healing, and ABI were also found based on the time point and stem cell source. In addition, no significant difference was found in the all-cause mortality (OR=0.80, 95%CI=0.39-1.641; P=0.546) between the stem cell-based therapy and control groups. Therefore, according to the results of our meta-analysis, stem cell-based therapy is safe and shows a beneficial outcome for patients with PAD, especially in the short term. PMID- 25923121 TI - An Unusual Complication of Stapes Surgery. PMID- 25923120 TI - Crystal Structure of Allophycocyanin from Marine Cyanobacterium Phormidium sp. A09DM. AB - Isolated phycobilisome (PBS) sub-assemblies have been widely subjected to X-ray crystallography analysis to obtain greater insights into the structure-function relationship of this light harvesting complex. Allophycocyanin (APC) is the phycobiliprotein always found in the PBS core complex. Phycocyanobilin (PCB) chromophores, covalently bound to conserved Cys residues of alpha- and beta- subunits of APC, are responsible for solar energy absorption from phycocyanin and for transfer to photosynthetic apparatus. In the known APC structures, heterodimers of alpha- and beta- subunits (known as alphabeta monomers) assemble as trimer or hexamer. We here for the first time report the crystal structure of APC isolated from a marine cyanobacterium (Phormidium sp. A09DM). The crystal structure has been refined against all the observed data to the resolution of 2.51 A to Rwork (Rfree) of 0.158 (0.229) with good stereochemistry of the atomic model. The Phormidium protein exists as a trimer of alphabeta monomers in solution and in crystal lattice. The overall tertiary structures of alpha- and beta- subunits, and trimeric quaternary fold of the Phormidium protein resemble the other known APC structures. Also, configuration and conformation of the two covalently bound PCB chromophores in the marine APC are same as those observed in fresh water cyanobacteria and marine red algae. More hydrophobic residues, however, constitute the environment of the chromophore bound to alpha-subunit of the Phormidium protein, owing mainly to amino acid substitutions in the marine protein. PMID- 25923122 TI - Subjective Visual Vertical Tilt Attraction to the Side of Rod Presentation: Effects of Age, Sex, and Vestibular Disorders. AB - OBJECTIVE: The aim of this study was to evaluate the effect of initial rod position on the subjective visual vertical (SVV) tilt and to investigate the effect of sex and age on the SVV tilt induced by this initial position. STUDY DESIGN: Prospective cross-sectional study. SETTING: Tertiary referral center. PATIENTS: The study included 6598 consecutive patients with a large range of vestibular disorders and 333 control subjects. The mean age was 55 years (range, 3-97), and the sex ratio was 0.6. INTERVENTION: SVV was measured by presenting a phosphorescent rod 12 times in total darkness with a 45-degree deviation from the vertical alternatively on the right and left. The patient was asked to replace the bar vertically with a remote control. RESULTS: On average, SVV at each iteration was tilted to the side of the rod presentation. It was stronger in female subjects, in younger individuals (<20 years) and seniors (>50). It was also higher in patients with a left vestibular loss in comparison to those with a right involvement. CONCLUSIONS: These effects suggest that short-term visual memory and multisensory cortical processing interfere with SVV measurements. PMID- 25923123 TI - Eccrine Poroma of the External Auditory Canal. PMID- 25923124 TI - Established disease-modifying treatments in relapsing-remitting multiple sclerosis. AB - PURPOSE OF REVIEW: The purpose of this review is to summarize mechanisms of action, efficacy and safety of established disease-modifying treatments (DMTs) that have been widely approved for use in relapsing-remitting multiple sclerosis (RRMS). RECENT FINDINGS: Established and widely used DMTs for the treatment of RRMS include the interferon-beta agents, glatiramer acetate, natalizumab, fingolimod, teriflunomide and dimethyl fumarate. These DMTs have quite different mechanisms of action, efficacy and safety and tolerability profiles, which are summarized concisely in the article below. SUMMARY: The treatment algorithm for RRMS is becoming increasingly complex with the ever-expanding armamentarium of DMTs. The choice of DMT will become an increasingly individual decision, based on a number of factors, including disease activity and severity, safety/tolerability profile and patient preference. Neurologists treating patients with multiple sclerosis (MS) will need a thorough knowledge of efficacy, safety and tolerability of the spectrum of DMTs available for treatment of RRMS to provide comprehensive clinical care. PMID- 25923125 TI - Migraine aura: new ideas about cause, classification, and clinical significance. AB - PURPOSE OF REVIEW: The migraine aura is a dramatic spontaneous change in brain activity resulting in a variety of transient neurological symptoms. The purpose of this review is to address recent advances in the understanding of aura and its role in migraine. RECENT FINDINGS: The formal classification of migraine aura is becoming both broader and more detailed. Traditionally viewed as a primary event that triggers a migraine attack, studies regarding the timing of aura relative to other symptoms of migraine indicate that it may not in fact play a primary role in initiating an attack. Careful recording and analysis of visual aura symptoms provides new insight into the initiation and propagation of the underlying brain phenomenon, and the different regions of visual cortex that produce different visual perceptions. Migraine with aura may have different responses to acute and preventive therapies. SUMMARY: There has been significant evolution of concepts regarding the causes of migraine aura, how it is best defined, and how it fits into the picture of the migraine disorder as a whole. Regardless of its exact role in the genesis of migraine, an increased understanding of aura has the potential to provide important new insight into not only migraine but also fundamental mechanisms of brain physiology. PMID- 25923126 TI - Psychiatric comorbidity and paediatric migraine: examining the evidence. AB - PURPOSE OF REVIEW: Psychiatric comorbidities are sometimes assumed in children with migraine. The goal of this review is to review the evidence for an association between psychiatric comorbidities and pediatric migraine. RECENT FINDINGS: Although depression or anxiety symptom scores may be higher in children with migraine who attend subspecialty clinics, the proportion of children with migraine who have clinically significant depression and anxiety is generally not elevated. In studies of children with migraine in the general population, the anxiety and depression scores are generally not elevated. Some of the scales used to measure anxiety and depression include questions about headaches and/or nausea, which makes them suboptimal tools for use in children with migraine as those are symptoms of migraine. Of note, depression was associated with incident development of chronic migraine in adolescents in one study. SUMMARY: The majority of children and adolescents with migraine do not have a comorbid psychiatric disorder. When a child with migraine does have a comorbid psychiatric disorder, it should be treated appropriately. PMID- 25923128 TI - Clinical update of Jakob-Creutzfeldt disease. AB - PURPOSE OF REVIEW: The present review discusses recent clinical data on diagnosis, new forms, and treatment of human prion diseases, and briefly summarizes research suggesting prion-like mechanisms in other neurodegenerative diseases. RECENT FINDINGS: When proper sequences are performed, MRI has high diagnostic utility in prion disease, but there are issues with interpretation of images. The spectrum of MRI's utility for diagnosis and understanding human prion disease is still being explored. Two recent diffusion tensor imaging studies quantified changes in the gray and white matter in sporadic Jakob-Creutzfeldt disease, with unexpected results. The diagnostic utility of cerebrospinal fluid biomarkers has been controversial. A few studies showed that amplification methods can detect prions in either cerebrospinal fluid, olfactory epithelium, blood and/or urine in various human prion diseases. Additional cases of variably protease-sensitive prionopathy have led to a broader understanding of this novel sporadic prion disease. A few new mutations causing genetic prion disease, one with a very atypical presentation, have been identified. Although recent human prion disease treatment trials did not show benefit, they have improved our understanding, and led to better quantification, of the progression of these disorders. Lastly, we briefly summarize the increasing evidence that many nonprion neurodegenerative proteinopathies might spread in the brain by a prion like mechanism. SUMMARY: New prion detection methods appear promising, but need to be replicated with larger sample sizes. Identification of novel forms of human prion disease might better elucidate the full spectrum of prion diseases and expand our understanding of their pathogenesis. PMID- 25923127 TI - A tale of two approaches: how metagenomics and proteomics are shaping the future of encephalitis diagnostics. AB - PURPOSE OF REVIEW: We highlight how metagenomics and proteomics-based approaches are being applied to the problem of diagnosis in idiopathic encephalitis. RECENT FINDINGS: Low cost, high-throughput next-generation sequencing platforms have enabled unbiased sequencing of biological samples. Rapid sequence-based computational algorithms then determine the source of all the nonhost (e.g., pathogen-derived) nucleic acids in a sample. This approach recently identified a case of neuroleptospirosis, resulting in a patient's dramatic clinical improvement with intravenous penicillin. Metagenomics also enabled the discovery of a neuroinvasive astrovirus in several patients. With regard to autoimmune encephalitis, advances in high throughput and efficient phage display of human peptides resulted in the discovery of autoantibodies against tripartite motif family members in a patient with paraneoplastic encephalitis. A complementary assay using ribosomes to display full-length human proteins identified additional autoantibody targets. SUMMARY: Metagenomics and proteomics represent promising avenues of research to improve upon the diagnostic yield of current assays for infectious and autoimmune encephalitis, respectively. PMID- 25923129 TI - Restricting Benzodiazepines to Short-Term Prescription. PMID- 25923130 TI - Analysis and significance of c-MET expression in adenoid cystic carcinoma of the salivary gland. AB - Adenoid cystic carcinoma (ACC), a rare salivary gland malignancy, is a histogenetic, morphologic, and clinical heterogeneous disease. Extensive efforts have been made to characterize molecular events associated with these tumors, including the identification of prognostic and predictive biomarkers. Increased copy number gain and amplification of c-Met, the cell surface receptor for hepatocyte growth factor, has been shown to enhance tumor growth and invasiveness and promote metastasis in certain tumor types. In this study, we evaluated the expression of c-Met by immunohistochemistry (IHC) in a large cohort of salivary gland ACCs and examined its clinicopathologic implications. Archival formalin fixed paraffin-embedded blocks from 200 ACC patients were used in this study. Pathologic patterns and phenotypic expression of c-Met were recorded and compared with clinical factors including gender, age, disease stage at diagnosis, and clinical outcomes. Correlations between c-MET expression and clinical characteristics were assessed by Pearson's chi-square test or by the 2-tailed Fisher exact test. Curves describing overall survival were generated by Kaplan Meier product limit method. Strong c-MET expression was seen in inner ductal and outer myoepithelial cells in 53.2% of the cases. There was no correlation between c-Met overexpression and clinicopathologic parameters or patient's overall survival ( p = .94074). In conclusion, c-MET expression is high in a significant subgroup of ACC patients. While c-MET expression is not a prognostic factor in ACC, its role as a predictive marker of benefit from MET inhibitors deserves further investigation. PMID- 25923131 TI - Electronic Band Structures and Native Point Defects of Ultrafine ZnO Nanocrystals. AB - Ultrafine ZnO nanocrystals with a thickness down to 0.25 nm are grown by a metalorganic chemical vapor deposition method. Electronic band structures and native point defects of ZnO nanocrystals are studied by a combination of scanning tunneling microscopy/spectroscopy and first-principles density functional theory calculations. Below a critical thickness of ~1 nm ZnO adopts a graphitic-like structure and exhibits a wide band gap similar to its wurtzite counterpart. The hexagonal wurtzite structure, with a well-developed band gap evident from scanning tunneling spectroscopy, is established for a thickness starting from ~1.4 nm. With further increase of the thickness to 2 nm, VO-VZn defect pairs are easily produced in ZnO nanocrystals due to the self-compensation effect in highly doped semiconductors. PMID- 25923132 TI - Aggregatibacter actinomycetemcomitans QseBC is activated by catecholamines and iron and regulates genes encoding proteins associated with anaerobic respiration and metabolism. AB - Aggregatibacter actinomycetemcomitans QseBC regulates its own expression and is essential for biofilm growth and virulence. However, the signal that activates the QseC sensor has not been identified and the qseBC regulon has not been defined. In this study, we show that QseC is activated by catecholamine hormones and iron but not by either component alone. Activation of QseC requires an EYRDD motif in the periplasmic domain of the sensor and site-specific mutations in EYRDD or the deletion of the periplasmic domain inhibits catecholamine/iron dependent induction of the ygiW-qseBC operon. Catecholamine/iron-dependent induction of transcription also requires interaction of the QseB response regulator with its binding site in the ygiW-qseBC promoter. Whole genome microarrays were used to compare gene expression profiles of A. actinomycetemcomitans grown in a chemically defined medium with and without catecholamine and iron supplementation. Approximately 11.5% of the A. actinomycetemcomitans genome was differentially expressed by at least two-fold upon exposure to catecholamines and iron. The expression of ferritin was strongly induced, suggesting that intracellular iron storage capacity is increased upon QseBC activation. Consistent with this, genes encoding iron binding and transport proteins were down-regulated by QseBC. Strikingly, 57% of the QseBC up-regulated genes (56/99) encode proteins associated with anaerobic metabolism and respiration. Most of these up-regulated genes were recently reported to be induced during in vivo growth of A. actinomycetemcomitans. These results suggest that detection of catecholamines and iron by QseBC may alter the cellular metabolism of A. actinomycetemcomitans for increased fitness and growth in an anaerobic host environment. PMID- 25923133 TI - TiO2 nanofibers resembling 'yellow bristle grass' in morphology by a soft chemical transformation. AB - We synthesized a uniquely shaped one-dimensional (1-D) TiO2 nanostructure having the morphology of yellow bristle grass with high surface area by the titanate route under mild reaction conditions. The electrospun TiO2-SiO2 composite nanofibers upon treatment with concentrated NaOH at 80 degrees C under ambient pressure for 24 h resulted in sodium titanate (Na2Ti3O7) nanostructures. The Na2Ti3O7 nanostructures have an overall 1-D fibrous morphology but the highly porous fiber surfaces were decorated with layered thorn-like features (a morphology resembling that of yellow bristle grass) resulting in high surface area (113 m(2) g(-1)) and porosity. The Na2Ti3O7 nanostructures were converted into TiO2 nanostructures of the same morphology by acidification (0.1 N HCl) followed by low temperature sintering (110 degrees C) processes. Dye-sensitized solar cells (DSCs) constructed out of the material (cells of area 0.20 cm(2) and thickness 12 MUm) showed a power conversion efficiency (eta) of 8.02% in comparison with commercial P-25 TiO2 (eta = 6.1%). PMID- 25923134 TI - Development and characterization of an effective food allergy model in Brown Norway rats. AB - BACKGROUND: Food allergy (FA) is an adverse health effect produced by the exposure to a given food. Currently, there is no optimal animal model of FA for the screening of immunotherapies or for testing the allergenicity of new foods. OBJECTIVE: The aim of the present study was to develop an effective and rapid model of FA in Brown Norway rats. In order to establish biomarkers of FA in rat, we compared the immune response and the anaphylactic shock obtained in this model with those achieved with only intraperitoneal immunization. METHODS: Rats received an intraperitoneal injection of ovalbumin (OVA) with alum and toxin from Bordetella pertussis, and 14 days later, OVA by oral route daily for three weeks (FA group). A group of rats receiving only the i.p. injection (IP group) were also tested. Serum anti-OVA IgE, IgG1, IgG2a, IgG2b and IgA antibodies were quantified throughout the study. After an oral challenge, body temperature, intestinal permeability, motor activity, and mast cell protease II (RMCP-II) levels were determined. At the end of the study, anti-OVA intestinal IgA, spleen cytokine production, lymphocyte composition of Peyer's patches and mesenteric lymph nodes, and gene expression in the small intestine were quantified. RESULTS: Serum OVA-specific IgG1, IgG2a and IgG2b concentrations rose with the i.p. immunization but were highly augmented after the oral OVA administration. Anti OVA IgE increased twofold during the first week of oral OVA gavage. The anaphylaxis in both IP and FA groups decreased body temperature and motor activity, whereas intestinal permeability increased. Interestingly, the FA group showed a much higher RMCP II serum protein and intestinal mRNA expression. CONCLUSIONS: These results show both an effective and relatively rapid model of FA assessed by means of specific antibody titres and the high production of RMCP II and its intestinal gene expression. PMID- 25923135 TI - Clotrimazole-cyclodextrin based approach for the management and treatment of Candidiasis - A formulation and chemistry-based evaluation. AB - Clotrimazole (CT) is a poorly soluble antifungal drug that is most commonly employed as a topical treatment in the management of vaginal candidiasis. The present work focuses on a formulation approach to enhance the solubility of CT using cyclodextrin (CD) complexation. A CT-CD complex was prepared by a co precipitation method. Various characterization techniques such as differential scanning calorimetry, infrared (IR) and X-ray spectroscopy, scanning electron microscopy and nuclear magnetic resonance (NMR) spectroscopy were performed to evaluate the complex formation and to understand the interactions between CT and CD. Computational molecular modeling was performed using the Schrodinger suite and Gaussian 09 program to understand structural conformations of the complex. The phase solubility curve followed an AL-type curve, indicating formation of a 1:1 complex. Molecular docking studies supported the data obtained through NMR and IR studies. Enthalpy changes confirmed that complexation was an exothermic and enthalpically favorable phenomenon. The CT-CD complexes were formulated in a gel and evaluated for release and antifungal activity. The in vitro release studies performed using gels demonstrated a sustained release of CT from the CT CD complex with the complex exhibiting improved release relative to the un complexed CT. Complexed CT-CD exhibited better fungistatic activity toward different Candida species than un-complexed CT. PMID- 25923136 TI - Curcumin-Zn(II) complex for enhanced solubility and stability: an approach for improved delivery and pharmacodynamic effects. AB - OBJECTIVE: The aim of present investigation was to prepare Curcumin-Zn(II) complex in a view to enhance solubility, stability and pharmacodynamic effect in experimentally induced ulcerative colitis. METHOD: Curcumin-Zn(II) complex was prepared by stirring curcumin with anhydrous zinc chloride at a molar ratio of 1:1. The prepared curcumin metallocomplex was characterized by TLC, FTIR, UV spectroscopy and (1)H NMR. In vitro kinetic degradation and solubility of Curcumin and Curcumin-Zn(II) complex was analyzed spectrophotometrically. Pharmacodynamic evaluation of curcumin and its metal complex was assessed in ulcerative colitis in mice. RESULTS: Curcumin showed chelation with zinc ion as confirmed by the TLC, FTIR, UV spectroscopy and (1)H NMR. The results of TLC [Rf value], IR Spectroscopy [shifting of stretching vibrations of upsilon(C=C) and upsilon(C=O)], UV spectra [deconvoluted with absorption band at 432-466.4 nm] of Curcumin-Zn(II) complex compared to curcumin confirmed the formation of metallocomplex. (1)HNMR spectra of Curcumin-Zn(II) showed the upfield shift of Ha and Hb. Kinetic stability studies showed metallocomplex with zinc exhibited good stability. In vivo study revealed significant reduction in severity and extent of colonic damage with Curcumin-Zn(II) which were further confirmed by histopathological study. CONCLUSION: This study recognizes higher solubility and stability of Curcumin-Zn(II) complex and suggested better pharmacodynamic effects. PMID- 25923137 TI - Correction: Phosphorus and Nitrogen Regulate Arbuscular Mycorrhizal Symbiosis in Petunia hybrida. PMID- 25923138 TI - Analysis of DNA methylation in plasma for monitoring hepatocarcinogenesis. AB - AIM: To explore whether the aberrant DNA methylation status in plasma could be used as a biomarker for hepatocellular carcinoma (HCC) screening among high-risk individuals. METHODS: The promoter methylation status of ELF, RASSF1A, p16, and GSTP1 was investigated by methylation-specific polymerase chain reaction (PCR) in 34 paired HCC and nontumor liver tissue from HCC patients and 10 tissues from patients with liver cirrhosis (LC). Plasma samples from 31 HCC patients, 10 LC patients as well as 7 patients with benign hepatic conditions were also collected and characterized using the same method. RESULTS: Among liver specimens, HCC tissues displayed a significantly higher methylation frequency of each gene compared with nontumor tissue (p<0.05). Moreover, the frequency was much higher in tumor tissues than in nontumor tissue, when the data from two or three genes were combined (p=0.001 and p<0.001, respectively). Among plasma samples, either the frequency of at least one methylated gene (p<0.001) or the average number of methylated genes (p<0.05) demonstrated a stepwise increase in patients with benign lesions, LC, and HCC. Furthermore, when positive results, that is, plasma methylation status of at least one gene were combined with the elevated AFP400 level (serum alpha-fetoprotein [AFP] level at a cutoff of 400 ng/mL), the diagnostic sensitivity of HCC could increase to 93.55%. CONCLUSIONS: These results suggested that the methylation of tumor suppressor genes may participate in the development and progression of HCC. Additionally, it may be useful to combine the plasma DNA methylation status of a panel of gene markers and the serum AFP for HCC screening. PMID- 25923139 TI - Hyperplasia of interstitial cells of cajal in sprouty homolog 4 deficient mice. AB - Gastrointestinal stromal tumors, which are thought to derive from interstitial cells of Cajal or their precursors, often harbor an oncogenic mutation of the KIT receptor tyrosine kinase. Sprouty homolog 4, a known negative regulator of ERK pathway, has been identified in the interstitial cells of Cajal in the KitK641E murine model of gastrointestinal stromal tumors. Sprouty homolog 4 was upregulated both at the mRNA and protein level in these cells, suggesting that Sprouty homolog 4 is downstream of oncogenic KIT activation and potentially engaged in the negative feedback loop of ERK activation in this model. Here, we used KitK641E heterozygous and Sprouty homolog 4 knock out animals to quantify interstitial cells of Cajal in situ, using quantitative immunofluorescence for the receptor tyrosine kinase Kit and for phosphodiesterase 3a (PDE3A). In the antrum of Sprouty homolog 4 knock out mice, hyperplasia of interstitial cells of Cajal was reminiscent of the KitK641E heterozygous mice antrum. Additionally, the density of interstitial cells of Cajal was higher in the colon of adult Sprouty homolog 4 knock out mice than in WT littermates, although hyperplasia seemed more severe in KitK641E heterozygous mice. Functional transit studies also show similarities between Sprouty homolog 4 knock out and KitK641E heterozygous mice, as the total transit time in 9 month old animals was significantly increased in both genotypes compared to WT littermates. We concluded that the lack of Sprouty homolog 4 expression leads to hyperplasia of the interstitial cells of Cajal and is functionally associated with a delayed transit time. PMID- 25923140 TI - Trends in the prevalence of autism spectrum disorder, cerebral palsy, hearing loss, intellectual disability, and vision impairment, metropolitan atlanta, 1991 2010. AB - This study examined the prevalence and characteristics of autism spectrum disorder (ASD), cerebral palsy (CP), hearing loss (HL), intellectual disability (ID), and vision impairment (VI) over a 15-20 year time period, with specific focus on concurrent changes in ASD and ID prevalence. We used data from a population-based developmental disabilities surveillance program for 8-year-olds in metropolitan Atlanta. From 1991-2010, prevalence estimates of ID and HL were stable with slight increases in VI prevalence. CP prevalence was constant from 1993-2010. The average annual increase in ASD prevalence was 9.3% per year from 1996-2010, with a 269% increase from 4.2 per 1,000 in 1996 to 15.5 per 1,000 in 2010. From 2000-2010, the prevalence of ID without ASD was stable; during the same time, the prevalence of ASD with and without co-occurring ID increased by an average of 6.6% and 9.6% per year, respectively. ASD prevalence increases were found among both males and females, and among nearly all racial/ethnic subgroups and levels of intellectual ability. Average annual prevalence estimates from 1991 2010 underscore the significant community resources needed to provide early intervention and ongoing supports for children with ID (13.0 per 1,000), CP, (3.5 per 1,000), HL (1.4 per 1,000) and VI (1.3 in 1,000), with a growing urgency for children with ASD. PMID- 25923141 TI - IFN-beta Therapy Regulates TLR7-Mediated Response in Plasmacytoid Dendritic Cells of Multiple Sclerosis Patients Influencing an Anti-Inflammatory Status. AB - Plasmacytoid dendritic cells (pDCs) display altered immune-phenotype in multiple sclerosis (MS) patients and are found actively recruited in postmortem MS brain lesions, implying that their immune regulation may represent an important aspect of MS pathogenesis. Because of the reported Toll-like receptor 7 (TLR7) implication in autoimmunity, in this study we characterized how IFN-beta therapy impacts on pDC activation to TLR7 triggering in MS patients, aspect only poorly investigated so far. In vivo IFN-beta administration regulates pDC functions in TLR7-treated peripheral blood mononuclear cell (PBMC) cultures differently from what is observed in isolated cells, suggesting that IFN-beta may activate inhibitory mechanisms in MS peripheral blood involved in turning off pDC response to dampen the ongoing inflammation. Indeed, IL-10, a key regulatory cytokine found increased upon TLR7 stimulation in in vivo IFN-beta-exposed PBMCs, directly reduced pDC-mediated IFN-alpha production. IFN-beta therapy also shaped T-cell responses by decreasing TLR7-induced pDC maturation and inducing T-cell inhibitory molecules. Accordingly, raised pDC-induced IL-27 and decreased IL-23 expression, together with high IL-10 level, contribute to inhibit Th17 cell differentiation. Our study uncovered a role for IFN-beta in the regulation of TLR7-mediated pDC responses in MS toward an anti-inflammatory phenotype opening new opportunities to better understand mechanisms of action of this drug in controlling MS immunopathogenesis. PMID- 25923144 TI - Recovery of Nickel and Cobalt from Laterite Tailings by Reductive Dissolution under Aerobic Conditions Using Acidithiobacillus Species. AB - Biomining of sulfidic ores has been applied for almost five decades. However, the bioprocessing of oxide ores such as laterites lags commercially behind. Recently, the Ferredox process was proposed to treat limonitic laterite ores by means of anaerobic reductive dissolution (AnRD), which was found to be more effective than aerobic bioleaching by fungi and other bacteria. We show here that the ferric iron reduction mediated by Acidithiobacillus thiooxidans can be applied to an aerobic reductive dissolution (AeRD) of nickel laterite tailings. AeRD using a consortium of Acidithiobacillus thiooxidans and Acidithiobacillus ferrooxidans extracted similar amounts of nickel (53-57%) and cobalt (55-60%) in only 7 days as AnRD using Acidithiobacillus ferrooxidans. The economic and environmental advantages of AeRD for processing of laterite tailings comprise no requirement for an anoxic atmosphere, 1.8-fold less acid consumption than for AnRD, as well as nickel and cobalt recovered in a ferrous-based pregnant leach solution (PLS), facilitating the subsequent metal recovery. In addition, an aerobic acid regeneration stage is proposed. Therefore, AeRD process development can be considered as environmentally friendly for treating laterites with low operational costs and as an attractive alternative to AnRD. PMID- 25923142 TI - Role of Krev Interaction Trapped-1 in Prostacyclin-Induced Protection against Lung Vascular Permeability Induced by Excessive Mechanical Forces and Thrombin Receptor Activating Peptide 6. AB - Mechanisms of vascular endothelial cell (EC) barrier regulation during acute lung injury (ALI) or other pathologies associated with increased vascular leakiness are an active area of research. Adaptor protein krev interaction trapped-1 (KRIT1) participates in angiogenesis, lumen formation, and stabilization of EC adherens junctions (AJs) in mature vasculature. We tested a role of KRIT1 in the regulation of Rho-GTPase signaling induced by mechanical stimulation and barrier dysfunction relevant to ventilator-induced lung injury and investigated KRIT1 involvement in EC barrier protection by prostacyclin (PC). PC stimulated Ras related protein 1 (Rap1)-dependent association of KRIT1 with vascular endothelial cadherin at AJs, with KRIT1-dependent cortical cytoskeletal remodeling leading to EC barrier enhancement. KRIT1 knockdown exacerbated Rho-GTPase activation and EC barrier disruption induced by pathologic 18% cyclic stretch and thrombin receptor activating peptide (TRAP) 6 and attenuated the protective effects of PC. In the two-hit model of ALI caused by high tidal volume (HTV) mechanical ventilation and TRAP6 injection, KRIT1 functional deficiency in KRIT1(+/-) mice increased basal lung vascular leak and augmented vascular leak and lung injury caused by exposure to HTV and TRAP6. Down-regulation of KRIT1 also diminished the protective effects of PC against TRAP6/HTV-induced lung injury. These results demonstrate a KRIT1 dependent mechanism of vascular EC barrier control in basal conditions and in the two-hit model of ALI caused by excessive mechanical forces and TRAP6 via negative regulation of Rho activity and enhancement of cell junctions. We also conclude that the stimulation of the Rap1-KRIT1 signaling module is a major mechanism of vascular endothelial barrier protection by PC in the injured lung. PMID- 25923143 TI - Epigenetically Modified Bone Marrow Stromal Cells in Silk Scaffolds Promote Craniofacial Bone Repair and Wound Healing. AB - Epigenetic regulation of gene expression is a central mechanism that governs cell stemness, determination, commitment, and differentiation. It has been recently found that PHF8, a major H4K20/H3K9 demethylase, plays a critical role in craniofacial and bone development. In this study, we hypothesize that PHF8 promotes osteoblastogenesis by epigenetically regulating the expression of a nuclear matrix protein, special AT-rich sequence-binding protein 2 (SATB2) that plays pivotal roles in skeletal patterning and osteoblast differentiation. Our results showed that expression levels of PHF8 and SATB2 in preosteoblasts and bone marrow stromal cells (BMSCs) increased simultaneously during osteogenic induction. Overexpressing PHF8 in these cells upregulated the expression of SATB2, Runx2, osterix, and bone matrix proteins. Conversely, knockdown of PHF8 reduced the expression of these genes. Furthermore, ChIP assays confirmed that PHF8 specifically bound to the transcription start site (TSS) of the SATB2 promoter, and the expression of H3K9me1 at the TSS region of SATB2 decreased in PHF8 overexpressed group. Implantation of the BMSCs overexpressing PHF8 with silk protein scaffolds promoted bone regeneration in critical-sized defects in mouse calvaria. Taken together, our results demonstrated that PHF8 epigenetically modulates SATB2 activity, triggering BMSCs osteogenic differentiation and facilitating bone formation and regeneration in biodegradable silk scaffolds. PMID- 25923145 TI - Do cinnamon supplements cause acute hepatitis? AB - BACKGROUND: The use of herbal medications to treat various diseases is on the rise. Cinnamon has been reported to improve glycolated hemoglobin and serum glucose levels. When patients consider the benefit of such substances, they are often not aware of potential adverse effects and drug interactions. Cinnamon, via coumarin, can cause liver toxicity. Therefore, its concomitant use with hepatotoxic drugs should be avoided. CASE REPORT: A 73-year-old woman was seen in the Emergency Department complaining of abdominal pain associated with vomiting and diarrhea after she started taking cinnamon supplements for about 1 week. The patient had been taking statin for coronary artery disease for many months. The laboratory workup and imaging studies confirmed the diagnosis of hepatitis. The detail workup did not reveal any specific cause. Cinnamon and statin were held. A few weeks after discharge, the statin was resumed without any further complications. This led to a diagnosis of cinnamon-statin combination-induced hepatitis. CONCLUSIONS: A combination of cinnamon supplement and statin can cause hepatitis, and it should be discouraged. PMID- 25923146 TI - Extracellular superoxide dismutase release by enoxaparin and sparing effect of heparin-grafted hemodialyzer. PMID- 25923147 TI - Imaging appearance of giant cell tumour of the spine above the sacrum. AB - Giant cell tumour (GCT) of the spine is rarely encountered in daily clinical practice. Most of the tumours occur at the sacrum instead of at the spine above the sacrum, which has been reported to account for 1.3-9.3% of all spine GCTs. This article is a review of our radiological experience of the diagnosis of spine GCT above the sacrum based on 34 patients at a single institution. The purpose of this pictorial review is to highlight the imaging findings of GCT and to provide clues that may distinguish it from other, more common neoplasms. PMID- 25923148 TI - A Meta-Analysis of the Relationship between Testicular Microlithiasis and Incidence of Testicular Cancer. AB - PURPOSE: There are many recent observational studies on testicular microlithiasis (TM) and risk of testicular cancer. Whether TM increases the risk of testicular cancer is still inconclusive. The objective of this updated meta-analysis was to synthesize evidence from clinical observational studies that evaluated the association between TM and testicular cancer. MATERIALS AND METHODS: We identified eligible studies by searching the PubMed, Embase and Cochrane Library before March 2014. Adjusted relative risks (RR) with 95% confidence interval (CI) were calculated using random-or fixed-model. RESULTS: A total of 14 studies involving 35,578 participants were included in the meta-analysis. On the basis of the Newcastle Ottawa Scale systematic review, eleven studies were identified as relatively high-quality. TM was strong association with an increased incidence of testicular cancer (RR = 12.70, 95% CI: 8.18-19.71, P < .001), with significant evidence of heterogeneity among these studies (P for heterogeneity < .001, I2 = 82.1%). The subgroup and sensitivity analysis confirmed the stability of the results and no publication bias was detected. CONCLUSION: The present meta analysis suggests that TM is significantly associated with risk of testicular cancer. More researches are warranted to clarify an understanding of the association between TM and risk of testicular cancer. PMID- 25923149 TI - Unfavorable anatomical factors influencing the success of retrograde intrarenal surgery for lower pole renal calculi. AB - PURPOSE: To determine the unfavorable factors, related to lower pole anatomical characteristics (LPACs), influencing the success of retrograde intrarenal surgery (RIRS) for lower pole renal calculi (LPC). MATERIALS AND METHODS: We reviewed the data of 36 patients who underwent RIRS for LPC between October 2012 and October 2013. The infundibulopelvic angle (IPA), infundibular length (IL) and infundibular width (IW) were measured on preoperative intravenous urographies. On follow-up stone-free status was defined as complete clearance at the first month kidney-ureter-bladder X-ray and computed tomography if necessary. RESULTS: The median stone size was 10 mm (range, 5-35). The stone-free rates according to LPACs at the first month follow-up were 100% (n = 17), 57.9% (n = 11), 90% (n = 18), 62.5% (n = 10), 90.5% (n = 19) and 60% (n = 9) for patients with IPA >= 70 degrees , IPA < 70o, IL < 3 cm, IL >= 3 cm, IW >= 5 mm and IW < 5 mm, respectively. While IPA and IW were associated with success of RIRS for LPC in multivariate analysis (P = .003 and P = .046, respectively), only IW was found to be a significant factor after applying multivariate analysis (P = .05). CONCLUSION: The results of our study demonstrated that only IW had a significant effect on the success rate of RIRS for LPC. PMID- 25923150 TI - Randomized double blinded placebo controlled trial comparing diclofenac and piroxicam in management of acute renal colic and its clinical implications. AB - PURPOSE: To compare the efficacy of sublingual piroxicam 40 mg with intramuscular diclofenac 75 mg in treatment of acute renal colic. The secondary objective was to look for factors that can affect the severity of the pain and pain relief in acute renal colic. MATERIALS AND METHODS: One hundred patients with acute renal colic were randomized into two groups. Group A (n = 50) received intramuscular diclofenac and sublingual methylcobalamin. Group B (n = 50) received sublingual piroxicam 40 mg and intramuscular distilled water. Pain severity was measured using Visual Analog Scale (VAS) and verbal and facial response scales. They were followed up for 3 h. Intramuscular injection of pentazocine 30 mg with promethazine 25 mg were used as rescue drugs. RESULTS: Both groups were comparable for age, sex distribution, body mass index (BMI), and pain duration before presentation. Significant pain relief was noticed in both groups. Sixteen percent in group A and 18% in group B had complete pain relief within 30 min (P = .75). Fifteen patients in group A and 13 patients in group B needed rescue drugs, 84% of group A and 76% of group B had complete pain relief at the end of 3 hours (P = .25). Decrease in pain by each scoring method was also comparable (P = .75). In multiple regression analysis, increasing age, positively affects the severity of pain and pain relief while increasing BMI negatively affect the initial pain relief. Acute renal colic seems to affect men more commonly than women, 81% of the study population were men. Patients with low initial pain score did not require any additional pain relief. Average pain duration before presenting to hospital is 260 min. Sixty percent of renal colics are due to stones below pelvic brim. CONCLUSION: The results show that sublingual piroxicam is as effective as intramuscular diclofenac. It can be easily self-administered and it overcomes the morbidity and time delay in getting intramuscular diclofenac. PMID- 25923151 TI - Laparoscopic upper pole heminephrectomy in adults for treatment of duplex kidneys. AB - PURPOSE: To present our results of laparoscopic upper pole heminephrectomy in adult patients with duplex kidney. MATERIALS AND METHODS: A total of 10 patients with an age range of 27 to 54 years old underwent laparoscopic upper pole heminephrectomy for complete duplication of the renal collecting system. The key point of the technique included the placement of a catheter in the normal ureter at the beginning of the procedure. The patient was positioned in a 45-90 degrees lateral decubitus position and a 4-port transperitoneal or 3-port retroperitoneal technique was applied followed by the mobilization of the upper pole ureter away from the renal hilum. Afterwards, the vasculature supplying the upper pole was precisely identified and ligated. Followed by transection of the ureter and its transposition cephalad to the hilum, the upper pole moiety was fully transected using the harmonic scalpel. RESULTS: Eight patients were operated on using the transperitoneal approach and 2 using the retroperitoneal technique. One patient required preoperative percutaneous drainage due to pyonephrosis. The operation time ranged between 150 to 350 min with minimal blood loss (0-200 mL). Hemostasis was achieved with an Argon laser in one patient. The lower pole calyceal system was perforated in one patient and repaired intracorporally. No major intraoperative complications occurred. All of the patients except two had their drains removed in 72 h after the operation and were generally discharged on postoperative day 3. CONCLUSION: Laparoscopic upper pole heminephrectomy for an ectopic ureter is safe and reproducible and offers benefits of laparoscopic surgery even in patients with complicated urinary tract infection. PMID- 25923152 TI - Prostate cancer: what about reproducibility of decision made at multidisciplinary team management? AB - PURPOSE: The prostate cancer (PCa) treatment is multimodal. Thus multidisciplinary team management (MDTM) decision-making process appears as a tool to answer all aspects of PCa treatment. Our aim was to evaluate the reproducibility of therapeutic decisions made at MDTM. MATERIALS AND METHODS: We compared therapeutic decisions of PCa by presenting the same file of patient under a fake identity after 6 to 12 months from the first presentation. Forty nine files of radical prostatectomy (RP) (28 pT2, 21 pT3) performed for clinical localized PCa were represented at MDTM which included urologist, oncologist, pathologist and radiologist. Analysis of therapeutic decisions comprised criteria such as: TNM stage, Gleason score, margin status and comorbidities. The reproducibility was assessed statistically by Kappa coefficient. RESULTS: Study subjects included 49 patients who underwent radical prostatectomy (RP). The mean age was similar in pT2 and pT3 groups (P = .09). The mean serum PSA value was 8.32 ng/mL (range, 3.56-19.5) in pT2 group and 9.4 ng/mL (range, 3.8-22) in pT3 group. The margin status in pT2 and pT3 groups was positive in 25.0% and 47.6%, respectively. The decisions made at first and second MDTM for pT2 group were the same in 100% of cases with a perfect kappa coefficient (k = 1). In the group of pT3 (n = 21), the decisions were different in 33% at the second MDTM in comparison to the first MDTM. Especially for pT3b only 29% were reproducible decision with a slight agreement (k = 0.1). Concerning pT3a, 86% of the decisions were reproducible with a substantial agreement (k = 0.74). CONCLUSION: We showed a reliability and reproducibility of decision made at MDTM when guidelines are well defined. The therapeutic attitudes were less reproducible in locally advanced PCa but decision concerning those cases should be made in the setting of guidelines. PMID- 25923153 TI - Anterior apical cores in the initial prostate biopsy does not increase detection of significant prostate cancer. AB - PURPOSE: To examine the effect of routine sampling anterior apical cores in the initial prostate biopsy among patients that 14-cores of prostate biopsy (PB) planned. MATERIALS AND METHODS: Five-hundred twenty-eight patients with increased prostate-specific antigen (PSA) levels and/or abnormal digital rectal examination underwent transrectal ultrasound and initial PB between November 2012 and October 2013. We performed routine 12-cores extended PB, plus 2 anterior apex samples that were taken from the junction of urethra and apex of the prostate. Site specific and unique cancer detection rate, tumor characteristics, the presence of clinically insignificant prostate cancer (PCa) (clinical stage <= T1, serum PSA level of < 10 ng/mL, biopsy Gleason score <= 6, number of positive biopsy cores <= 3 and no core with > 50% involvement) and biopsy-related pain were evaluated. RESULTS: PCa was detected in 147 of 451 patients (32.6%). The lateral base of the prostate was the most affected area with 128 of 451 patients (28.3%), followed by unique cancer detection, with 17 of 40 patients (43.5%). Anterior apex (n = 6) was in third place after the lateral apex (n = 8). The patients diagnosed by anterior apex cores were all clinically insignificant PCa. The cancer diagnosis rate would be 31% if 12-cores biopsy was used, but the rate was found to be 32.6% in 14-cores biopsy (P = .016). Average biopsy pain, right anterior apex biopsy pain, and left anterior apex biopsy pain were found to register at 0.61, 1.06 and 1.08 points in the visual analog scale pain score, respectively. When right and left anterior apex biopsy pain is compared to average biopsy pain, the pain level was found to be statistically significantly higher in the biopsies of right and left anterior apex (P = .040 and P = .042, respectively). CONCLUSION: The gold standard for the diagnosis of PCa is at least 8 cores PB. According to our results, although most PCa diagnosis is carried out with 14-cores PB, it should not be forgotten that these patients might have clinically insignificant PCa. PMID- 25923154 TI - Comparison of transobturator tape surgery using commercial and hand made slings in women with stress urinary incontinence. AB - PURPOSE: To compare the complications and success rates of hand-made sling with commercial sling used in transobturator tape (TOT) surgery. MATERIALS AND METHODS: From 2008 to 2010, hand-made slings were used in TOT surgery, whereas commercial slings were used from 2010 to 2013 in our clinic. Overall 102 patients were included in the study. Patients were categorized into 2 groups: group 1 had hand-made (polypropylene monofilament) slings, while group 2 had commercial slings (polypropylene monofilament). We retrospectively reviewed 1-year follow-up results of the whole cohort. Ages, body mass indexes, menopausal status, operation time, cost of sling, success of operation and complications were recorded. All these data were compared between the 2 groups. RESULTS: There were 41 patients (54.29 +/- 9.88 years) in group 1 and 61 patients (52.82 +/- 9.85 years) in group 2. Menopausal status and body mass index (28.1 vs. 29.2 kg/m2 respectively) were similar for both groups. Previous history of incontinence or pelvic organ prolapse surgery (P = .046), mean duration of the procedure (P = .001), and vaginal extrusion rate (P = .016) were significantly lower in group 2. The cost of the sling was higher in group 2 than in group 1. There was no significant difference in success of operation between the groups (P = .319). CONCLUSION: According to our results, hand-made mesh is a viable option in TOT surgery with similar efficacy, but surgeons should be careful in terms of vaginal extrusion. PMID- 25923155 TI - Penile Mondor's Disease: Primum Non Nocere! AB - PURPOSE: Penile Mondor's disease (superficial thrombophlebitis of the dorsal vein of the penis) is a rare clinical diagnosis. It is an easily diagnosed and treated disease. Nevertheless, when reviewing the literature, we considered that unnecessary tests are carried out for diagnosis. In this study, we aimed to indicate the redundancy of Doppler ultrasonography for diagnosis of penile Mondor's disease. MATERIALS AND METHODS: Seven patients with the clinical presentation of penile Mondor's disease were included in the study. In the first two patients, penile Doppler ultrasonography was performed for diagnostic purposes by applying a vasoactive intracavernosal agent. This diagnostic procedure was not implemented in the next five patients. RESULTS: Physical examinations revealed cord-like thickening lesions on dorsal and dorsolateral penis. In the first two patients, who penile Doppler ultrasonography with an intracavernosal vasoactive agent was used for diagnostic purposes, was developed priapism. We did not use penile Doppler for more patients as this would be unethical according to us. CONCLUSION: Recovery from penile Mondor's disease is usually spontaneous and smooth. A simple physical examination is sufficient for diagnosis, and palliative treatment is effective. For the diagnosis of this disease, unnecessary tests should be avoided so that patients are not harmed. PMID- 25923156 TI - The effect of fasting on erectile function and sexual desire on men in the month of Ramadan. AB - PURPOSE: To determine the effect of Ramadan intermittent fasting on erectile function (EF), sexual desire and serum hormone levels. MATERIALS AND METHODS: Eligible male participants completed the two domains of International Index of Erectile Function (IIEF) questionnaire for EF and sexual desire. They also provided information on any known disease, treatment taking, smoking habits and frequency of sexual intercourse. Frequency of sexual intercourse, two domains of IIEF questionnaire, serum hormone levels, body weight before and four-weeks after the end of month of Ramadan were also recorded. RESULTS: Overall, 45 men, with a mean age of 37 +/- 7.2 years, participated in the study. Frequency of sexual intercourse (P = .046), sexual desire (P = .002), body weight (P = .009) and serum follicle stimulating hormone (FSH) level (P = .016) decreased significantly at the end of month of Ramadan compared to baseline. No statistically significant differences were found on EF (P = .714), serum testosterone (P = .847), luteinizing hormone (P = .876), estradiol (P = .098) and dehydroepiandrosterone sulfate levels (P = .290). CONCLUSION: Ramadan intermittent fasting might be associated with decrease in sexual desire, frequency of sexual intercourse and serum FSH level. PMID- 25923157 TI - Re: The effect of fasting on erectile function and sexual desire on men in the of month Ramadan. PMID- 25923158 TI - Minimally Invasive Therapy Using Intralesional OnabotulinumtoxinA in Peyronie's Disease. AB - PURPOSE: To determine the effectiveness of intralesional administration of onabotulinumtoxinA in patients with Peyronie's disease (PD). MATERIALS AND METHODS: A prospective therapeutic cohort study was undertaken in patients aged >= 18 years with stable PD. Intervention included one-time intralesional application of 100 U of onabotulinumtoxinA. We included 22 patients who attended the urology clinic from October 1, 2011 to June 30, 2012. Primary outcome measure was degree of curvature. Secondary outcome measures were thickness of the fibrous plaque, improvement in erectile function and pain. Erectile function was evaluated using the International Index of Erectile Function (IIEF-5) questionnaire. The Visual Analog Scale (VAS) was used to measure pain during an erection. Statistical analyses were performed by Pearson's chi-squared test for categorical variables and student's t-test for quantitative variables. Any P value < .05 was considered statistically significant. RESULTS: The size of the fibrous plaque was reduced from 0.34 +/- 0.20 to 0.27 +/- 0.13 cm after treatment (P = .014). The curvature initially averaged 32.95 +/- 9.21 degrees , and improved to 25 +/- 9.38 degrees (P = .025). According to the Kelami classification, the curvature was < 30 degrees in 14 cases (63.6%) and was 30 degrees -60 degrees in eight cases (36.4%). At 16 weeks, the curvature was < 30 degrees in 19 cases (86.4%) and 30 degrees -60 degrees in three cases (13.6%). The IIEF-5 score was 16.18 +/- 4.46 before treatment and 18.22 +/- 4.55 after treatment (P = .002). Pain was reduced from 3.36 +/- 3.48 before treatment to 1.14 +/- 1.58 after treatment (P = .001). CONCLUSION: The administration of onabotulinumtoxinA may improve the clinical manifestations of PD resulting from fibrosis, thus improving sexual function in patients. PMID- 25923159 TI - Re: Minimally Invasive Therapy Using Intralesional OnabotulinumtoxinA in Peyronie's Disease. PMID- 25923161 TI - Idiopathic spontaneous bladder perforation: a rare case. PMID- 25923160 TI - Mitrofanoff cystolitholapaxy: an innovative method of stone clearance in a hostile abdomen with an inaccessible urethra. PMID- 25923162 TI - Giant bladder calculi: a case report. PMID- 25923163 TI - Re: Clinical application of computed tomography on prostate volume estimation in patients with lower urinary tract symptoms. PMID- 25923165 TI - Inorganic and organic trace mineral supplementation in weanling pig diets. AB - A study was conducted to evaluate the effects of dietary inorganic and organic trace minerals in two levels of supplementation regarding performance, diarrhea occurrence, hematological parameters, fecal mineral excretion and mineral retention in metacarpals and liver of weanling pigs. Seventy piglets weaned at 21 days of age with an average initial body weight of 6.70 +/- 0.38 kg were allotted in five treatments: control diet (no added trace mineral premix); 50% ITMP (control diet with inorganic trace mineral premix supplying only 50% of trace mineral requirements); 50% OTMP (control diet with organic trace mineral premix supplying only 50% of trace mineral requirements); 100% ITMP (control diet with inorganic trace mineral premix supplying 100% of trace mineral requirements); and 100% OTMP (control diet with organic trace mineral premix supplying 100% of trace mineral requirements). Feed intake and daily weight gain were not affected by treatments, however, piglets supplemented by trace minerals presented better gain:feed ratio. No differences were observed at calcium, phosphorus, potassium, magnesium, sodium and sulfur excreted in feces per kilogram of feed intake. Treatments did not affect calcium, phosphorus, magnesium, sulfur and iron content in metacarpals. Trace mineral supplementation, regardless of level and source, improved the performance of piglets. PMID- 25923166 TI - Lymphocyte subset reference intervals in blood donors from northeastern Brazil. AB - The reference intervals for leukocytes and lymphocytes currently used by most clinical laboratories present limitations as they are primarily derived from individuals of North American and European origin. The objective this study was to determine reference values for peripheral blood B lymphocytes, T lymphocyte subsets (CD4+, CD8+, naive, memory, regulatory, TCRalphabeta and TCRgammadelta+) and NK cells from blood donors in Salvador-Bahia, Brazil. RESULTS: The proportion of included male subjects was 73.7% and the median ages of males (34) and females (35) were found to be similar. Absolute counts total lymphocytes subsets to both gender was 1,956 (1,060-4,186) cells and relative values 34%. The T CD4+ and T CD8+ lymphocytes relative values was 51% (20-62) and 24% (9-28), respectively. The most statistically significant finding observed was a higher percentage of B lymphocytes (p=0.03) in females. Commonly cited subset reference intervals were found to be consistent with values in several populations from different geographic areas. PMID- 25923167 TI - Croton argenteus preparation inhibits initial growth, mitochondrial respiration and increase the oxidative stress from Senna occidentalis seedlings. AB - Senna ocidentalis is a weed, native to Brazil, considered to infest crops and plantations, and is responsible for yield losses of several crops, particularly soybean. The aim of this work was to evaluate if the Croton argenteus extract and fractions possess phytotoxic activity on S. ocidentalis. The crude ethanolic extract (CEE) and its hexanic (HF), chloroformic (CLF) and ethyl acetate (EAF) fractions were tested in germination, growth, oxidative stress increase, Adenosine triphosphate, L-malate and succinate synthesis. The crude extract and its fractions slowed down the germination of S. ocidentalis and decreased the final percentage of germination. Oxidative stress was also increased in the seedlings, by an increase of catalase, peroxidase, superoxide dismutase, glutathione reductase and lipid peroxidation; and it became clear that the ethyl acetate fraction was more phytotoxic. The results indicate that the crude extract and fractions of C. argenteus compromise the mitochondrial energy metabolism, by the inhibition of mitochondrial ATP production, with a decrease in the production of L-malate and succinate. The ethyl acetate fraction of C. argenteus showed high activity on germination and growth, and these effects take place by means of mitochondrial metabolism alterations and increase the oxidative stress, leading the seedling death. PMID- 25923168 TI - On Vastness and Variability: Cultural Transmission, Historicity, and the Paleoindian Record in Eastern South America. AB - Eastern South America, or what is today Brazilian territory, poses interesting questions about the early human occupation of the Americas. Three totally distinct and contemporaneous lithic technologies, dated between 11,000 and 10,000 14C BP, are present in different portions of the country: the Umbu tradition in the south, with its formal bifacial industry, with well-retouched scrapers and bifacial points; the Itaparica tradition in the central-west / northwest, totally unifacial, whose only formal artifacts are limaces; and the "Lagoa Santa" industry, completely lacking any formal artifacts, composed mainly of small quartz flakes. Our data suggests that these differences are not related to subsistence or raw-material constraints, but rather to different cultural norms and transmission of strongly divergent chaines operatoires. Such diversity in material culture, when viewed from a cultural transmission (CT) theory standpoint, seems at odds with a simple Clovis model as the origin of these three cultural traditions given the time elapsed since the first Clovis ages and the expected population structure of the early South American settlers. PMID- 25923169 TI - An Investigation of a Mathematical Model for the Internal Velocity Profile of Conical Diffusers Applied to DAWTs. AB - The Diffuser Augmented Wind Turbines (DAWTs) have been widely studied, since the diffusers improve the power coefficient of the wind turbine, particularly of small systems. The diffuser is a device which has the function of causing an increase on the flow velocity through the wind rotor plane due to pressure drop downstream, therefore resulting in an increase of the rotor power coefficient. This technology aids the turbine to exceed the Betz limit, which states that the maximum kinetic energy extracted from the flow is 59.26%. Thus, the present study proposes a mathematical model describing the behavior of the internal velocity for three conical diffusers, taking into account the characteristics of flow around them. The proposed model is based on the Biot-Savart's Law, in which the vortex filament induces a velocity field at an arbitrary point on the axis of symmetry of the diffusers. The results are compared with experimental data obtained for the three diffusers, and present good agreement. PMID- 25923170 TI - Selection in the host structures the microbiota associated with developing cod larvae (Gadus morhua). AB - Marine fish larvae are immature upon hatching, and share their environment with high numbers of bacteria. The microbial communities associated with developing fish larvae might be structured by other factors than those important in developing terrestrial animals. Here, we analysed the beta (beta)-diversity of the microbiota associated with developing cod larvae and compared it with the bacterial communities in water and live feed by applying pyrosequencing of bar coded v4 16S rDNA amplicons. A total of 15 phyla were observed in the cod larval microbiota. Proteobacteria was the most abundant, followed by Firmicutes, Bacteroidetes and Actinobacteria. The composition and diversity of the cod larval microbiota changed considerably with age. The temporal and spatial patterns of beta-diversity could not be explained by stochastic processes, and did not coincide with changes in the rearing conditions. Furthermore, the larval microbiota was highly distinct from the water and the live feed microbiota, particularly at early developmental stages. However, the similarity between larval and water microbiota increased with age. This study suggests that strong selection in the host structures the cod larval microbiota. The changes in community structure observed with increasing age can be explained by altered selection pressure due to development of the intestinal system. PMID- 25923171 TI - Development of an inhaled controlled release voriconazole dry powder formulation for the treatment of respiratory fungal infection. AB - The present research aimed to develop and characterize a sustained release dry powder inhalable formulation of voriconazole (VRZ) for invasive pulmonary aspergillosis. The developed formulations were studied for their in vitro release profile, aerosol, and physicochemical properties as well as interactions with lung epithelia in terms of toxicity and transport/uptake. VRZ and VRZ loaded poly lactide microparticles (VLM) were prepared by aqueous/organic cosolvent and organic spray drying, respectively. Powders were characterized using laser diffraction, differential scanning calorimetry (DSC), X-ray powder diffraction (XRPD), dynamic vapor sorption (DVS), and electron microscopy. Aerosol performance was evaluated using an RS01 dry powder inhaler and in vitro cascade impaction. Uptake across Calu-3 lung epithelia was studied, using aerosol deposition of the powder onto cells cultured in an air interface configuration, and compared to dissolution using a conventional dialysis membrane. Additionally, toxicity of VRZ and VLM and the potential impact of transmembrane proteins on uptake were investigated. The particle size and the aerosol performance of spray dried VRZ and VLM were suitable for inhalation purposes. VRZ exhibited a median volume diameter of 4.52 +/- 0.07 MUm while VLM exhibited 2.40 +/- 0.05 MUm. Spray dried VRZ was crystalline and VLM amorphous as evaluated by DSC and XRPD, and both powders exhibited low moisture sorption between 0 and 90% RH (<1.2% w/w) by DVS. The fine particle fraction (FPF) (% aerosol <5 MUm) for the VRZ was 20.86 +/ 1.98% while the VLM showed significantly improved performance (p < 0.01) with an FPF of 43.56 +/- 0.13%. Both VRZ and VLM were not cytotoxic over a VRZ concentration range of 1.2 nM to 30 MUM, and the VLM particles exhibited a sustained release over 48 h after being deposited on the Calu-3 cell line or via conventional dialysis-based dissolution measurements. Lastly, VRZ exhibited polarized transport across epithelia with basal to apical transport being slower than apical to basal. Influx and efflux transports may also play a role as transport was altered in the presence of a number of inhibitors. This study has established an inhalable and sustained release powder of VRZ for targeting invasive pulmonary aspergillosis. PMID- 25923172 TI - Dynamic Contrast-Enhanced Perfusion MRI of High Grade Brain Gliomas Obtained with Arterial or Venous Waveform Input Function. AB - BACKGROUND AND PURPOSE: The aim of this study was to evaluate the differences in dynamic contrast-enhanced (DCE) magnetic resonance imaging (MRI) perfusion estimates of high-grade brain gliomas (HGG) due to the use of an input function (IF) obtained respectively from arterial (AIF) and venous (VIF) approaches by two different commercially available software applications. METHODS: This prospective study includes 20 patients with pathologically confirmed diagnosis of high-grade gliomas. The data source was processed by using two DCE dedicated commercial packages, both based on the extended Toft model, but the first customized to obtain input function from arterial measurement and the second from sagittal sinus sampling. The quantitative parametric perfusion maps estimated from the two software packages were compared by means of a region of interest (ROI) analysis. The resulting input functions from venous and arterial data were also compared. RESULTS: No significant difference has been found between the perfusion parameters obtained with the two different software packages (P-value < .05). The comparison of the VIFs and AIFs obtained by the two packages showed no statistical differences. CONCLUSIONS: Direct comparison of DCE-MRI measurements with IF generated by means of arterial or venous waveform led to no statistical difference in quantitative metrics for evaluating HGG. However, additional research involving DCE-MRI acquisition protocols and post-processing would be beneficial to further substantiate the effectiveness of venous approach as the IF method compared with arterial-based IF measurement. PMID- 25923173 TI - Bandage and scleral contact lenses for ocular graft-versus-host disease after allogeneic haematopoietic stem cell transplantation. PMID- 25923174 TI - Correlation between crystalline order and vitrification in colloidal monolayers. AB - We investigate experimentally the relationship between local structure and dynamical arrest in a quasi-2d colloidal model system which approximates hard discs. We introduce polydispersity to the system to suppress crystallisation. Upon compression, the increase in structural relaxation time is accompanied by the emergence of local hexagonal symmetry. Examining the dynamical heterogeneity of the system, we identify three types of motion: 'zero-dimensional' corresponding to beta-relaxation, 'one-dimensional' or stringlike motion and '2D' motion. The dynamic heterogeneity is correlated with the local order, that is to say locally hexagonal regions are more likely to be dynamically slow. However, we find that lengthscales corresponding to dynamic heterogeneity and local structure do not appear to scale together approaching the glass transition. PMID- 25923175 TI - Evaluation of blood platelet count and function in patients with erectile dysfunction. AB - We evaluated and compared blood total platelet count, mean platelet volume (MPV) and platelet distribution width (PDW) values of patients with erectile dysfunction (ED) and control subjects. A total 57 male patients (mean age 49.7 +/ 12 years) with ED and 59 control men (mean age 49.7 +/- 10.7 years) were included in the study. All patients were evaluated using medical history with International Index of Erectile Function (IIEF) scores, physical examination and routine blood analysis. Total blood count, including white blood cell (WBC), total platelet counts, MPV and PDW parameters, were recorded in both groups. MPV values were detected to be significantly higher in patients with ED than control group: 10.7 +/- 1 and 9.72 +/- 1.5, respectively (P = 0.001). Similarly, PDW values were significantly higher in patients with ED than control group: 14.6 +/- 2.8 and 12.9 +/- 1.9, respectively (P = 0.001). However, mean platelet and mean WBC counts were similar in both groups (P = 0.45). We demonstrated that MPV and PDW values significantly increased in patients with ED compared with the control group. According to these findings, platelet function might play an important role in patients with ED that warrants further research. PMID- 25923176 TI - Determination of enantiomers by FESI-sweeping with an acid-labile sweeper in nonaqueous capillary electrophoresis. AB - In this work, a facile and highly efficient on-line concentration strategy based on a coupling of field enhanced sample injection (FESI) and sweeping was developed for the determination of trace enantiomers (propranolol, PL) by nonaqueous capillary electrophoresis (NACE). In this FESI-sweeping method, the use of a sample of high acidity and low conductivity (pH* = 2.5, 4.0 MUS cm(-1)) allowed for a large amount of analyte injection. Then, the concentration of the analytes was carried out by sweeping based on the interaction of an acid-labile anionic selector, di-n-butyl L-tartrate-boric acid complex acid, and cationic analytes. Simultaneously, the concentrated analytes were released and focused at the boundary of the acid sample solution and separation buffer due to the decomposition of the selector in the acid sample solution. Under the optimum conditions, a 21,000-fold sensitivity enhancement upon normal capillary zone electrophoresis (CZE) was achieved for PL enantiomers. The detection limits of R propranolol and S-propranolol were 0.26 ng mL(-1) and 0.31 ng mL(-1), respectively. Eventually, the FESI-sweeping method was applied to detect PL enantiomers in plasma, saliva, and urine. PMID- 25923177 TI - Advanced hair damage model from ultra-violet radiation in the presence of copper. AB - OBJECTIVE: Damage to hair from UV exposure has been well reported in the literature and is known to be a highly complex process involving initiation via absorption of UV light followed by formation and propagation of reactive oxygen species (ROS). The objective of this work was to understand these mechanisms, explain the role of copper in accelerating the formation of ROS and identify strategies to reduce the hair damage caused by these reactive species. METHODS: The location of copper in hair was measured by Transmission electron microscopy (TEM) X-ray energy dispersive spectroscopy (XEDS) and levels measured by ICP-OES. Protein changes were measured as total protein loss via the Lowry assay, and MALDI ToF was used to identify the biomarker protein fragments. TBARS assay was used to measure lipid peroxide formation. Sensory methods and dry combing friction were used to measure hair damage due to copper and UV exposure and to demonstrate the efficacy of N,N' ethylenediamine disuccinic acid (EDDS) and histidine chelants to reduce this damage. RESULTS: In this work, a biomarker protein fragment formed during UV exposure is identified using mass spectrometry. This fragment originates from the calcium-binding protein S100A3. Also shown is the accelerated formation of this peptide fragment in hair containing low levels of copper absorbed from hair during washing with tap water containing copper ions. Transmission electron microscopy (TEM) X-ray energy dispersive spectroscopy (XEDS) studies indicate copper is located in the sulphur-poor endo-cuticle region, a region where the S100A3 protein is concentrated. A mechanism for formation of this peptide fragment is proposed in addition to the possible role of lipids in UV oxidation. A shampoo and conditioner containing chelants (EDDS in shampoo and histidine in conditioner) is shown to reduce copper uptake from tap water and reduce protein loss and formation of S100A3 protein fragment. In addition, the long-term consequences of UV oxidation and additional damage induced by copper are illustrated in a four-month wear study where hair was treated with a consumer relevant protocol of hair colouring treatments, UV exposure and regular shampoo and conditioning. CONCLUSIONS: The role of copper in accelerating UV damage to hair has been demonstrated as well as the ability of chelants such as EDDS and histidine in shampoo and conditioner products to reduce this damage. PMID- 25923180 TI - Teamwork is our legacy. PMID- 25923178 TI - Exome Sequencing of Normal and Isogenic Transformed Human Colonic Epithelial Cells (HCECs) Reveals Novel Genes Potentially Involved in the Early Stages of Colorectal Tumorigenesis. AB - BACKGROUND: We have generated a series of isogenically derived immortalized human colonic epithelial cell (HCEC 1CT and HCEC 2CT) lines, including parental un immortalized normal cell strains. The CDK4 and hTERT immortalized colonic epithelial cell line (HCEC 1CT) is initially karyotypically normal diploid and expresses a series of epithelial cell markers including stem cell markers. Under stressful tissue culture conditions, a spontaneous aneuploidy event occurred in the HCEC 1CT line, resulting in a single chromosomal change leading to a stable trisomy 7 cell line (1CT7). Trisomy 7 occurs in about 40% of all benign human adenomas (polyps) and thus this specific chromosomal change in diploid HCEC 1CT cells appears to be non random. In addition, we have partially transformed the HCEC 1CT line by introducing stable knockdown of wild type APC and TP53, and ectopically introducing a mutant Krasv12 and a mutant version of APC (A1309), all commonly found mutations in colorectal cancer (CRC). METHODS: Whole exome sequencing and bioinformatic analyses were performed to comprehensively examine the genetic background of these isogenic cell lines. RESULTS: Exome sequencing of these experimentally progressed cell lines recapitulates a list of genes previously reported to be involved in CRC tumorigenesis. In addition, sequencing revealed a collection of novel genes specifically detected in 1CT7 and A1309 cells but not normal diploid 1CT cells. CONCLUSION: This study demonstrates the utility of using isogenic experimentally derived HCEC lines as a model to recapitulate CRC initiation and progression. Exome sequencing reveals a collection of novel genes that may play important roles in CRC tumorigenesis. PMID- 25923181 TI - Chronotype: a review of the advances, limits and applicability of the main instruments used in the literature to assess human phenotype. AB - The study of circadian typology differences has increased in the last few years. As a result, new instruments have been developed to estimate the individual circadian phase of temporal human behavior, also referred as chronotype. The current review was conducted to evaluate the differences among the questionnaires most frequently used to assess chronotype: the Morningness-Eveningness Questionnaire (MEQ), the Composite Scale of Morningness (CSM), and the Munich Chronotype Questionnaire (MCTQ). Each instrument evaluates a different aspect of chronotype. MEQ is considered to evaluate the phase preferences of individual behavior over a 24-hour day, while MCTQ measures the phase of sleep positions for both free and work days. CSM is similar to MEQ, but is more sensitive to measure shift work. The concept of chronotype has been used to refer to phase positions or phase preferences in the literature reviewed. Most of the time this is a consequence of different interpretations: it is not clear whether phase preferences are a direct manifestation of the individual's internal clock or a result of external cues, e.g., social interaction (including the alarm clock). Also, phase preferences are not uniform throughout life. Therefore, a single assessment, not taking age into consideration, will not accurately describe the sample. We suggest that MCTQ is the best instrument for investigators dealing with desynchronization and as an instrument for sleep phase. Conversely, if the goal is to assess characteristics that change under specific situations - chronotype -, the MEQ should be used. PMID- 25923182 TI - Is it all grist to the mill? Wandering between indications for psychoanalytic treatment and the analytic field. AB - Determining the indications and contraindications for psychoanalytic treatment seems crucial to achieve therapeutic success and improve treatment effectiveness. In reviewing the classic literature on the topic, aspects such as age, diagnosis, motivation for treatment, present moment in life, ability to gain insight, psychic suffering when seeking treatment, defensive behaviors, and frustration tolerance are clearly analyzed by therapists/analysts when indicating psychoanalytic treatments. However, traditionally, most criteria underlying such indications date back to a time when the therapeutic relationship was viewed merely as a therapist treating a patient, with no regard to the therapeutic relationship itself. The goal of this article was to critically review the relevance and current adequacy of indications for psychoanalytic treatment, in view of advancements in knowledge on the analytic field. Considering cases that do not evolve as expected according to the indications, patients who are better suited to certain therapists, and therapist-patient pairs that modify their interaction over the course of treatment, the main question remains on how to identify the necessary elements in evaluating a candidate patient for psychoanalytic treatment, as well as the significant elements of therapeutic action. PMID- 25923183 TI - Treating refractory obsessive-compulsive disorder: what to do when conventional treatment fails? AB - Obsessive-compulsive disorder (OCD) is a chronic and impairing condition. A very small percentage of patients become asymptomatic after treatment. The purpose of this paper was to review the alternative therapies available for OCD when conventional treatment fails. Data were extracted from controlled clinical studies (evidence-based medicine) published on the MEDLINE and Science Citation Index/Web of Science databases between 1975 and 2012. Findings are discussed and suggest that clinicians dealing with refractory OCD patients should: 1) review intrinsic phenomenological aspects of OCD, which could lead to different interpretations and treatment choices; 2) review extrinsic phenomenological aspects of OCD, especially family accommodation, which may be a risk factor for non-response; 3) consider non-conventional pharmacological approaches; 4) consider non-conventional psychotherapeutic approaches; and 5) consider neurobiological approaches. PMID- 25923184 TI - Treatment of female and male inpatient crack users: a qualitative study. AB - OBJECTIVE: To map treatment trajectories in a sample of male and female crack users through their narratives about the course of treatment seeking and their attempts to access health care services in Brazil. METHODS: Qualitative study of a purposive sample (five female and nine male hospitalized crack users) using semi-structured interviews. The interviews were transcribed and data explored using content analysis. RESULTS: Respondents reported difficulties getting access to hospitalization, relapse after discharge, and abandonment of treatment. There seems to be a peculiar model of behavior for women and men while dealing with craving for crack: while women got involved with prostitution and consequently became infected with HIV, every men of the sample reported criminal involvement. CONCLUSIONS: The relationship between relapse and a social environment conducive to consumption, associated with belief or disbelief in spiritual support, prostitution, and the legal complications arising from the use of crack, are relevant issues and should be taken into consideration in the development of preventive actions aimed at this specific population. PMID- 25923185 TI - Association between childhood trauma and loss of functionality in adult women with fibromyalgia. AB - OBJECTIVE: To investigate whether history of childhood trauma is associated with loss of functionality in adult women with fibromyalgia (FM). A secondary objective was to assess the presence of differences between depressed and non depressed adult women with FM in a regression model for functionality. METHODS: A total of 114 adult women with FM according to the American College of Rheumatology diagnostic criteria answered the Childhood Trauma Questionnaire and the Fibromyalgia Impact Questionnaire. All subjects were interviewed by trained psychiatrists and evaluated for depression using the Mini International Neuropsychiatric Interview (MINI) - Brazilian version 5.0.0. Correlation and regression models were used to investigate associations between childhood trauma and loss of functionality among patients with FM. The sample was stratified by presence and absence of clinical depression. RESULTS: Overall, childhood trauma was associated with of loss of functionality in adult women with FM. When stratified by depression, the regression model significantly increased the association among non-depressed patients, even after adjustment for age and use of psychotropic medications. CONCLUSIONS: Childhood trauma showed a clinically important association with loss of functionality among adult women with FM. The associations were more pronounced among subjects without comorbid depression. PMID- 25923186 TI - Sexual dysfunction, depression, and anxiety in young women according to relationship status: an online survey. AB - BACKGROUND: Sexual dysfunction is a common, still poorly understood problem among women. Being or not in a relationship seems to be a risk factor for sexual dysfunction. OBJECTIVES: To evaluate the presence of sexual problems, anxiety, and depression in young women and to correlate findings with current relationship status (single, in a committed relationship, or married). METHODS: Data were collected trough an online survey from a total of 155 women aged between 20 and 29 years. Sociodemographic data were collected, and both the Hospital Anxiety and Depression scale and the Female Sexual Function Index were applied. Data were statistically analyzed using the chi-square and Kruskal-Wallis tests, and groups were compared in 2 x 2 matrices using the Mann-Whitney test. RESULTS: Single women showed a significantly higher prevalence of problems in the lubrication (45.3%), orgasm (53.1%), satisfaction (67.2%), and pain (50%) domains and also in total Female Sexual Function Index scores (60.9%) in comparison with the other groups. Additionally, significantly higher depression scores were found among single women (5.89+/-3.3) in comparison to those in a committed relationship (4.05+/-2.83). Anxiety scores were similar in all groups. CONCLUSION: Our findings suggest that single women have a poorer sexual function and are more likely to have mood disorders in comparison to their peers involved in stable relationships. PMID- 25923187 TI - Translation and adaptation of the Bipolar Prodrome Symptom Scale-Retrospective: Patient Version to Brazilian portuguese. AB - BACKGROUND: Bipolar disorder (BD) is a chronic and often severe mental disease, associated with a significant burden in affected individuals. The characterization of a premorbid (prodromal) period and possible development of preventive interventions are recent advances in this field. Attempts to characterize high-risk stages in BD, identifying symptoms prior to the emergence of a first manic/hypomanic episode, have been limited by a lack of standardized criteria and instruments for assessment. The Bipolar Prodrome Symptom Scale Retrospective (BPSS-R), developed by Correll and collaborators, retrospectively evaluates symptoms that occur prior to a first full mood episode in individuals with BD. OBJECTIVE: To describe the translation and adaptation process of the BPSS-R to Brazilian Portuguese. METHOD: Translation was conducted as follows: 1) translation of the scale from English to Brazilian Portuguese by authors who have Portuguese as their first language; 2) merging of the two versions by a committee of specialists; 3) back-translation to English by a translator who is an English native speaker; 4) correction of the new version in English by the author of the original scale; 5) finalization of the new version in Brazilian Portuguese. RESULTS: All the steps of the translation process were successfully accomplished, resulting in a final version of the instrument. CONCLUSIONS: The Brazilian Portuguese version of the BPSS-R is a potentially useful instrument to investigate prodromal period of BD in Brazil. PMID- 25923188 TI - Fatty acid and phospholipase A2 plasma levels in children with autism. AB - OBJECTIVE: To evaluate fatty acid plasma levels, phospholipase A2 activity, and the developmental profiles of children with autism vs. control subjects. METHODS: Twenty four children with autism underwent laboratory analysis for fatty acid quantification using gas chromatography and PLA2 activity determination by fluorometric assay. RESULTS: No correlation was observed between the developmental quotient and fatty acid plasma levels. Phospholipase A2 activity was significantly higher among autistic children compared with controls. CONCLUSION: The study did not show a correlation between fatty acid and phospholipase A2 plasma levels and the developmental profile of children with autism. PMID- 25923189 TI - Impact of a near-death experience and religious conversion on the mental health of a criminal: case report and literature review. AB - OBJECTIVE: Near-death experiences have been defined as profound psychological events that may occur to a person while close to death or in a situation of extreme physical or emotional distress. These experiences seem to have an important effect on the patients' mental health and may occur in several situations despite their cultural and religious beliefs. CASE DESCRIPTION: The present case report describes the positive impact of a near-death experience (Greyson scale > 7) followed by religious conversion on the mental health of a former prisoner. COMMENTS: Investigation of the role of near-death experiences by the scientific community could shed light on the coping mechanisms and moral/ethical transformations that take place in these individuals. PMID- 25923190 TI - Incentive to retrogression is what the data suggest after 3 years. PMID- 25923191 TI - A review of selection-based tests of abiotic surrogates for species representation. AB - Because conservation planners typically lack data on where species occur, environmental surrogates--including geophysical settings and climate types--have been used to prioritize sites within a planning area. We reviewed 622 evaluations of the effectiveness of abiotic surrogates in representing species in 19 study areas. Sites selected using abiotic surrogates represented more species than an equal number of randomly selected sites in 43% of tests (55% for plants) and on average improved on random selection of sites by about 8% (21% for plants). Environmental diversity (ED) (42% median improvement on random selection) and biotically informed clusters showed promising results and merit additional testing. We suggest 4 ways to improve performance of abiotic surrogates. First, analysts should consider a broad spectrum of candidate variables to define surrogates, including rarely used variables related to geographic separation, distance from coast, hydrology, and within-site abiotic diversity. Second, abiotic surrogates should be defined at fine thematic resolution. Third, sites (the landscape units prioritized within a planning area) should be small enough to ensure that surrogates reflect species' environments and to produce prioritizations that match the spatial resolution of conservation decisions. Fourth, if species inventories are available for some planning units, planners should define surrogates based on the abiotic variables that most influence species turnover in the planning area. Although species inventories increase the cost of using abiotic surrogates, a modest number of inventories could provide the data needed to select variables and evaluate surrogates. Additional tests of nonclimate abiotic surrogates are needed to evaluate the utility of conserving nature's stage as a strategy for conservation planning in the face of climate change. PMID- 25923192 TI - Cost of treatment in patients with metastatic soft tissue sarcoma who respond favourably to chemotherpy. The SArcoma treatment and Burden of Illness in North America and Europe (SABINE) study. AB - Treatment of metastatic soft tissue sarcoma (mSTS) commonly includes multiple lines of chemotherapy, until a decline in performance status precludes further treatment. The primary objective of this study was to describe the lifetime healthcare resource utilisation and cost among mSTS patients with favourable response to chemotherapy. SABINE was a multi-centre (n = 25), multi-country (n = 9) retrospective chart review study of mSTS patients with favourable response to chemotherapy following 4 cycles. Healthcare resource utilisation was collected from first line until death or end of follow-up. Costs were analysed by health states (defined by treatment line, chemotherapy use and disease progression) and estimated by multiplying the mean weekly cost per health state by the expected number of weeks spent in each health state. Expected per-patient lifetime medical cost was ?65 616 (95% CI: ?51 454-?85 003); comprised of IV chemotherapy (31.7%), inpatient care (24.8%), concomitant medication (11.0%), oral chemotherapy (8.9%), outpatient visits (8.8%), radiotherapy (6.3%), hospice (4.0%), imaging (3.7%) and laboratory (0.7%). Weekly costs were 280-330% higher during chemotherapy treatment periods than off-chemotherapy, especially after disease progression. Per-patient costs were highest in the USA and lowest in the Netherlands and UK. The economic burden of mSTS is considerable and the amount of resources devoted to its treatment varies across countries. PMID- 25923193 TI - Engineering plants to reflect light: strategies for engineering water-efficient plants to adapt to a changing climate. AB - Population growth and globally increasing standards of living have put a significant strain on the energy-food-water nexus. Limited water availability particularly affects agriculture, as it accounts for over 70% of global freshwater withdrawals (Aquastat). This study outlines the fundamental nature of plant water consumption and suggests a >50% reduction in renewable freshwater demand is possible by engineering more reflective crops. Furthermore, the decreased radiative forcing resulting from the greater reflectivity of crops would be equivalent to removing 10-50 ppm CO2 from the atmosphere. Recent advances in engineering optical devices and a greater understanding of the mechanisms of biological reflectance suggest such a strategy may now be viable. Here we outline the challenges involved in such an effort and suggest three potential approaches that could enable its implementation. While the local benefits may be straightforward, determining the global externalities will require careful modelling efforts and gradually scaled field trials. PMID- 25923194 TI - Enhanced Resonant Tunneling in Symmetric 2D Semiconductor Vertical Heterostructure Transistors. AB - Tunneling transistors with negative differential resistance have widespread appeal for both digital and analog electronics. However, most attempts to demonstrate resonant tunneling devices, including graphene-insulator-graphene structures, have resulted in low peak-to-valley ratios, limiting their application. We theoretically demonstrate that vertical heterostructures consisting of two identical monolayer 2D transition-metal dichalcogenide semiconductor electrodes and a hexagonal boron nitride barrier result in a peak to-valley ratio several orders of magnitude higher than the best that can be achieved using graphene electrodes. The peak-to-valley ratio is large even at coherence lengths on the order of a few nanometers, making these devices appealing for nanoscale electronics. PMID- 25923196 TI - Instantaneous physico-chemical analysis of suspension-based nanomaterials. AB - High-throughput manufacturing of nanomaterial-based products demands robust online characterization and quality control tools capable of continuously probing the in-suspension state. But existing analytical techniques are challenging to deploy in production settings because they are primarily geared toward small batch ex-situ operation in research laboratory environments. Here we introduce an approach that overcomes these limitations by exploiting surface complexation interactions that emerge when a micron-scale chemical discontinuity is established between suspended nanoparticles and a molecular tracer. The resulting fluorescence signature is easily detectable and embeds surprisingly rich information about composition, quantity, size, and morphology of nanoparticles in suspension independent of their agglomeration state. We show how this method can be straightforwardly applied to enable continuous sizing of commercial ZnO nanoparticles, and to instantaneously quantify the anatase and rutile composition of multicomponent TiO2 nanoparticle mixtures pertinent to photocatalysis and solar energy conversion. PMID- 25923195 TI - Low dose of IGF-I increases cell size of skeletal muscle satellite cells via Akt/S6K signaling pathway. AB - The objective of this study was to investigate the effect of insulin growth factor-I (IGF-I) on the size of pig skeletal muscle satellite cells (SCs). Using microarray, real-time RT-PCR, radioimmunoassay analysis and western blot, we first showed that supplementation of low-dose of IGF-I in culture medium resulted in enlarged cell size of Lantang SCs, only Akt and S6K were up-regulated at both the mRNA and protein levels among almost all of the mTOR pathway key genes, but had no effect on cell number. To elucidate the signaling mechanisms responsible for regulating cell size under low-dose of IGF-I treatment, we blocked Akt and S6K activity with the specific inhibitors MK2206 and PF4708671, respectively. Both inhibitors caused a decrease in cell size. In addition, MK2206 lowered the protein level of p-Akt (Ser473), p-S6K (Thr389), and p-rpS6 (Ser235/236), whereas PF4708671 lowered the protein level of p-S6K (Thr389) and p-rpS6 (Ser235/236). However, low dose of IGF-I didn't affect the protein level of p-mTOR (Ser2448) and p-mTOR (Ser2481). When both inhibitors were applied simultaneously, the effect was the same as that of the Akt inhibition alone. Taken together, we report for the first time that low-dose of IGF-I treatment increases cell size via Akt/S6K signaling pathway. PMID- 25923197 TI - Quantum dot made in metal oxide silicon-nanowire field effect transistor working at room temperature. AB - We report the observation of an atomic like behavior from T = 4.2 K up to room temperature in n- and p-type Omega-gate silicon nanowire (NW) transistors. For that purpose, we modified the design of a NW transistor and introduced long spacers between the source/drain and the channel in order to separate the channel from the electrodes. The channel was made extremely small (3.4 nm in diameter with 10 nm gate length) with a thick gate oxide (7 nm) in order to enhance the Coulomb repulsion between carriers, which can be as large as 200 meV when surface roughness promotes charge confinement. Parasitic stochastic Coulomb blockade effect can be eliminated in our devices by choosing proper control voltages. Moreover, the quantum dot can be tuned so that the resonant current at T = 4.2 K exceeds that at room temperature. PMID- 25923198 TI - The Ninth Liquid Matter Conference. PMID- 25923199 TI - Maternal health phone line: saving women in papua new Guinea. AB - This paper presents the findings of a research project which has involved the establishment of a maternal health phone line in Milne Bay Province of Papua New Guinea (PNG). Mobile phones and landline phones are key information and communication technologies (ICTs). This research study uses the "ICTs for healthcare development" model to ascertain benefits and barriers to the successful implementation of the Childbirth Emergency Phone. PNG has a very high maternal mortality rate. The "three stages of delay" typology was developed by Thaddeus and Maine to determine factors that might delay provision of appropriate medical treatment and hence increase risk of maternal death. The "three stages of delay" typology has been utilised in various developing countries and also in the present study. Research undertaken has involved semi-structured interviews with health workers, both in rural settings and in the labour ward in Alotau. Additional data has been gathered through focus groups with health workers, analysis of notes made during phone calls, interviews with women and community leaders, observations and field visits. One hundred percent of interviewees (n = 42) said the project helped to solve communication barriers between rural health workers and Alotau Provincial Hospital. Specific examples in which the phone line has helped to create positive health outcomes will be outlined in the paper, drawn from research interviews. The Childbirth Emergency Phone project has shown itself to play a critical role in enabling healthcare workers to address life threatening childbirth complications. The project shows potential for rollout across PNG; potentially reducing maternal morbidity and maternal mortality rates by overcoming communication challenges. PMID- 25923200 TI - Demonstration of a quantum error detection code using a square lattice of four superconducting qubits. AB - The ability to detect and deal with errors when manipulating quantum systems is a fundamental requirement for fault-tolerant quantum computing. Unlike classical bits that are subject to only digital bit-flip errors, quantum bits are susceptible to a much larger spectrum of errors, for which any complete quantum error-correcting code must account. Whilst classical bit-flip detection can be realized via a linear array of qubits, a general fault-tolerant quantum error correcting code requires extending into a higher-dimensional lattice. Here we present a quantum error detection protocol on a two-by-two planar lattice of superconducting qubits. The protocol detects an arbitrary quantum error on an encoded two-qubit entangled state via quantum non-demolition parity measurements on another pair of error syndrome qubits. This result represents a building block towards larger lattices amenable to fault-tolerant quantum error correction architectures such as the surface code. PMID- 25923202 TI - Softening of edges of solids by surface tension. AB - Surface tension tends to minimize the area of interfaces between pieces of matter in different thermodynamic phases, be they in the solid or the liquid state. This can be relevant for the macroscopic shape of very soft solids and lead to a roughening of initially sharp edges. We calculate this effect for a Neo-Hookean elastic solid, with assumptions corresponding to actual experiments, namely the case where an initially sharp edge is rounded by the effect of surface tension felt when the fluid surrounding the soft solid (and so surface tension) is changed at the solid/liquid boundary. We consider two opposite limits where the analysis can be carried to the end, the one of a shallow angle and the one of a very sharp angle. Both cases yield a discontinuity of curvature in the state with surface tension although the initial state had a discontinuous slope. PMID- 25923201 TI - Metazoans evolved by taking domains from soluble proteins to expand intercellular communication network. AB - A central question in animal evolution is how multicellular animals evolved from unicellular ancestors. We hypothesize that membrane proteins must be key players in the development of multicellularity because they are well positioned to form the cell-cell contacts and to provide the intercellular communication required for the creation of complex organisms. Here we find that a major mechanism for the necessary increase in membrane protein complexity in the transition from non metazoan to metazoan life was the new incorporation of domains from soluble proteins. The membrane proteins that have incorporated soluble domains in metazoans are enriched in many of the functions unique to multicellular organisms such as cell-cell adhesion, signaling, immune defense and developmental processes. They also show enhanced protein-protein interaction (PPI) network complexity and centrality, suggesting an important role in the cellular diversification found in complex organisms. Our results expose an evolutionary mechanism that contributed to the development of higher life forms. PMID- 25923203 TI - Shifts in Symbiotic Endophyte Communities of a Foundational Salt Marsh Grass following Oil Exposure from the Deepwater Horizon Oil Spill. AB - Symbiotic associations can be disrupted by disturbance or by changing environmental conditions. Endophytes are fungal and bacterial symbionts of plants that can affect performance. As in more widely known symbioses, acute or chronic stressor exposure might trigger disassociation of endophytes from host plants. We tested this hypothesis by examining the effects of oil exposure following the Deepwater Horizon (DWH) oil spill on endophyte diversity and abundance in Spartina alterniflora - the foundational plant in northern Gulf coast salt marshes affected by the spill. We compared bacterial and fungal endophytes isolated from plants in reference areas to isolates from plants collected in areas with residual oil that has persisted for more than three years after the DWH spill. DNA sequence-based estimates showed that oil exposure shifted endophyte diversity and community structure. Plants from oiled areas exhibited near total loss of leaf fungal endophytes. Root fungal endophytes exhibited a more modest decline and little change was observed in endophytic bacterial diversity or abundance, though a shift towards hydrocarbon metabolizers was found in plants from oiled sites. These results show that plant-endophyte symbioses can be disrupted by stressor exposure, and indicate that symbiont community disassembly in marsh plants is an enduring outcome of the DWH spill. PMID- 25923204 TI - Neonatal Cortical Auditory Evoked Potentials Are Affected by Clinical Conditions Occurring in Early Prematurity. AB - PURPOSE: Cortical auditory evoked potentials may serve as an early indicator of developmental problems in the auditory cortex. The aim of the study was to determine the effect on neonatal cortical auditory processing of clinical conditions occurring in early prematurity. METHODS: Sixty-seven preterm infants born at 29 weeks mean gestational age (range, 23-34 weeks) were recorded at a mean postconception age of 35 weeks, before discharge from the third level neonatal intensive care unit. The average of 330 responses to standard 1000 Hz pure tones delivered in an oddball paradigm was recorded at frontal location. Data of 45 of 67 recruited premature infants were available for analysis. Mean amplitudes calculated from the data points of 30 milliseconds centered on P1 and N2 peaks in the waveforms of each subject were measured. The effect of perinatal clinical factors on cortical auditory evoked responses was evaluated. RESULTS: The amplitude of P1 component was significantly lower in infants with bronco pulmonary dysplasia (P = 0.004) and retinopathy of prematurity (P = 0.03). The multivariate analysis, done to evaluate the relative weight of gestational age and bronco-pulmonary dysplasia and/or retinopathy of prematurity on cortical auditory evoked potentials components, showed an effect of clinical factors on P1 (P = 0.005) and of gestational age on N2 (P = 0.02). CONCLUSIONS: Cortical auditory processing seems to be influenced by clinical conditions complicating extremely preterm birth. PMID- 25923205 TI - Climate impacts on extreme energy consumption of different types of buildings. AB - Exploring changes of building energy consumption and its relationships with climate can provide basis for energy-saving and carbon emission reduction. Heating and cooling energy consumption of different types of buildings during 1981-2010 in Tianjin city, was simulated by using TRNSYS software. Daily or hourly extreme energy consumption was determined by percentile methods, and the climate impact on extreme energy consumption was analyzed. The results showed that days of extreme heating consumption showed apparent decrease during the recent 30 years for residential and large venue buildings, whereas days of extreme cooling consumption increased in large venue building. No significant variations were found for the days of extreme energy consumption for commercial building, although a decreasing trend in extreme heating energy consumption. Daily extreme energy consumption for large venue building had no relationship with climate parameters, whereas extreme energy consumption for commercial and residential buildings was related to various climate parameters. Further multiple regression analysis suggested heating energy consumption for commercial building was affected by maximum temperature, dry bulb temperature, solar radiation and minimum temperature, which together can explain 71.5 % of the variation of the daily extreme heating energy consumption. The daily extreme cooling energy consumption for commercial building was only related to the wet bulb temperature (R2= 0.382). The daily extreme heating energy consumption for residential building was affected by 4 climate parameters, but the dry bulb temperature had the main impact. The impacts of climate on hourly extreme heating energy consumption has a 1-3 hour delay in all three types of buildings, but no delay was found in the impacts of climate on hourly extreme cooling energy consumption for the selected buildings. PMID- 25923206 TI - Insights from the metagenome of an acid salt lake: the role of biology in an extreme depositional environment. AB - The extremely acidic brine lakes of the Yilgarn Craton of Western Australia are home to some of the most biologically challenging waters on Earth. In this study, we employed metagenomic shotgun sequencing to generate a microbial profile of the depositional environment associated with the sulfur-rich sediments of one such lake. Of the 1.5 M high-quality reads generated, 0.25 M were mapped to protein features, which in turn provide new insights into the metabolic function of this community. In particular, 45 diverse genes associated with sulfur metabolism were identified, the majority of which were linked to either the conversion of sulfate to adenylylsulfate and the subsequent production of sulfide from sulfite or the oxidation of sulfide, elemental sulfur, and thiosulfate via the sulfur oxidation (Sox) system. This is the first metagenomic study of an acidic, hypersaline depositional environment, and we present evidence for a surprisingly high level of microbial diversity. Our findings also illuminate the possibility that we may be meaningfully underestimating the effects of biology on the chemistry of these sulfur-rich sediments, thereby influencing our understanding of past geobiological conditions that may have been present on Earth as well as early Mars. PMID- 25923207 TI - Recovery of native genetic background in admixed populations using haplotypes, phenotypes, and pedigree information--using Cika cattle as a case breed. AB - The aim of this study was to obtain unbiased estimates of the diversity parameters, the population history, and the degree of admixture in Cika cattle which represents the local admixed breeds at risk of extinction undergoing challenging conservation programs. Genetic analyses were performed on the genome wide Single Nucleotide Polymorphism (SNP) Illumina Bovine SNP50 array data of 76 Cika animals and 531 animals from 14 reference populations. To obtain unbiased estimates we used short haplotypes spanning four markers instead of single SNPs to avoid an ascertainment bias of the BovineSNP50 array. Genome-wide haplotypes combined with partial pedigree and type trait classification show the potential to improve identification of purebred animals with a low degree of admixture. Phylogenetic analyses demonstrated unique genetic identity of Cika animals. Genetic distance matrix presented by rooted Neighbour-Net suggested long and broad phylogenetic connection between Cika and Pinzgauer. Unsupervised clustering performed by the admixture analysis and two-dimensional presentation of the genetic distances between individuals also suggest Cika is a distinct breed despite being similar in appearance to Pinzgauer. Animals identified as the most purebred could be used as a nucleus for a recovery of the native genetic background in the current admixed population. The results show that local well adapted strains, which have never been intensively managed and differentiated into specific breeds, exhibit large haplotype diversity. They suggest a conservation and recovery approach that does not rely exclusively on the search for the original native genetic background but rather on the identification and removal of common introgressed haplotypes would be more powerful. Successful implementation of such an approach should be based on combining phenotype, pedigree, and genome-wide haplotype data of the breed of interest and a spectrum of reference breeds which potentially have had direct or indirect historical contribution to the genetic makeup of the breed of interest. PMID- 25923208 TI - A comparison of some organizational characteristics of the mouse central retina and the human macula. AB - Mouse models have greatly assisted our understanding of retinal degenerations. However, the mouse retina does not have a macula, leading to the question of whether the mouse is a relevant model for macular degeneration. In the present study, a quantitative comparison between the organization of the central mouse retina and the human macula was made, focusing on some structural characteristics that have been suggested to be important in predisposing the macula to stresses leading to degeneration: photoreceptor density, phagocytic load on the RPE, and the relative thinness of Bruch's membrane. Light and electron microscopy measurements from retinas of two strains of mice, together with published data on human retinas, were used for calculations and subsequent comparisons. As in the human retina, the central region of the mouse retina possesses a higher photoreceptor cell density and a thinner Bruch's membrane than in the periphery; however, the magnitudes of these periphery to center gradients are larger in the human. Of potentially greater relevance is the actual photoreceptor cell density, which is much greater in the mouse central retina than in the human macula, underlying a higher phagocytic load for the mouse RPE. Moreover, at eccentricities that correspond to the peripheral half of the human macula, the rod to cone ratio is similar between mouse and human. Hence, with respect to photoreceptor density and phagocytic load of the RPE, the central mouse retina models at least the more peripheral part of the macula, where macular degeneration is often first evident. PMID- 25923209 TI - Associations of Conflict-Related Trauma and Ongoing Stressors with the Mental Health and Functioning of West Papuan Refugees in Port Moresby, Papua New Guinea (PNG). AB - Documentation is limited in relation to the mental health of the people of West Papua, a territory that has been exposed to decades-long political persecution. We examined associations of traumatic events (TEs) and current stressors with mental disorder and functioning, amongst 230 West Papuan refugees residing in six settlements in Port Morseby, Papua New Guinea (PNG). We used culturally adapted modules to assess exposure to TEs and mental disorders. Current stressors and functioning were assessed using modifications of measures developed by the World Health Organization (WHO). 129 of 230 respondents (56%) reported exposure to at least one traumatic event (TE), including: political upheaval (36.5%), witnessing or hearing about family members tortured and murdered (33.9%), and not being able to access medical care for family members (33%). One fifth of respondents (47, 20.4%) experienced exposure to high levels of TEs (16 to 23). 211 (91.7%) endorsed at least one or more ongoing stressors, including: exposure to illicit substance use in the community (91.7%), problems with safety and the protection of women (89.6%), no access to legal rights and citizenship (88.3%), and lack of adequate shelter and facilities (85.2%). A quarter (26.9%) met criteria for one or more current mental disorder, and 69.1% reported functional impairment ranging from mild to extreme. Mental disorder was associated with being male (adjusted odds ratio=2.00; 95% CI=1.01-3.97), and exposure to the highest category of ongoing stressors (AOR=2.89; 95% CI=1.08-7.72). The TE count showed a dose response pattern in its relationship with functional impairment, the greatest risk (AOR=11.47; 95% CI=2.11-62.37) being for those experiencing the highest level of TE exposure (16-23 events). West Papuans living in settlements in Port Moresby reported a range of TEs, ongoing stressors and associated mental disorders characteristic of populations exposed to mass conflict and persecution, prolonged displacement, and ongoing conditions of extreme hardship. PMID- 25923210 TI - A household serosurvey to estimate the magnitude of a dengue outbreak in Mombasa, Kenya, 2013. AB - Dengue appears to be endemic in Africa with a number of reported outbreaks. In February 2013, several individuals with dengue-like illnesses and negative malaria blood smears were identified in Mombasa, Kenya. Dengue was laboratory confirmed and an investigation was conducted to estimate the magnitude of local transmission including a serologic survey to determine incident dengue virus (DENV) infections. Consenting household members provided serum and were questioned regarding exposures and medical history. RT-PCR was used to identify current DENV infections and IgM anti-DENV ELISA to identify recent infections. Of 1,500 participants from 701 households, 210 (13%) had evidence of current or recent DENV infection. Among those infected, 93 (44%) reported fever in the past month. Most (68, 73%) febrile infected participants were seen by a clinician and all but one of 32 participants who reportedly received a diagnosis were clinically diagnosed as having malaria. Having open windows at night (OR = 2.3; CI: 1.1-4.8), not using daily mosquito repellent (OR = 1.6; CI: 1.0-2.8), and recent travel outside of Kenya (OR = 2.5; CI: 1.1-5.4) were associated with increased risk of DENV infection. This survey provided a robust measure of incident DENV infections in a setting where cases were often unrecognized and misdiagnosed. PMID- 25923211 TI - New Information on Tataouinea hannibalis from the Early Cretaceous of Tunisia and Implications for the Tempo and Mode of Rebbachisaurid Sauropod Evolution. AB - The rebbachisaurid sauropod Tataouinea hannibalis represents the first articulated dinosaur skeleton from Tunisia and one of the best preserved in northern Africa. The type specimen was collected from the lower Albian, fluvio estuarine deposits of the Ain el Guettar Formation (southern Tunisia). We present detailed analyses on the sedimentology and facies distribution at the main quarry and a revision of the vertebrate fauna associated with the skeleton. Data provide information on a complex ecosystem dominated by crocodilian and other brackish water taxa. Taphonomic interpretations indicate a multi-event, pre-burial history with a combination of rapid segregation in high sediment supply conditions and partial subaerial exposure of the carcass. After the collection in 2011 of the articulated sacrum and proximalmost caudal vertebrae, all showing a complex pattern of pneumatization, newly discovered material of the type specimen allows a detailed osteological description of Tataouinea. The sacrum, the complete and articulated caudal vertebrae 1-17, both ilia and ischia display asymmetrical pneumatization, with the left side of vertebrae and the left ischium showing a more extensive invasion by pneumatic features than their right counterparts. A pneumatic hiatus is present in caudal centra 7 to 13, whereas caudal centra 14-16 are pneumatised by shallow fossae. Bayesian inference analyses integrating morphological, stratigraphic and paleogeographic data support a flagellicaudatan rebbachisaurid divergence at about 163 Ma and a South American ancestral range for rebbachisaurids. Results presented here suggest an exclusively South American Limaysaurinae and a more widely distributed Rebbachisaurinae lineage, the latter including the South American taxon Katepensaurus and a clade including African and European taxa, with Tataouinea as sister taxon of Rebbachisaurus. This scenario would indicate that South America was not affected by the end-Jurassic extinction of diplodocoids, and was most likely the centre of the rapid radiation of rebbachisaurids to Africa and Europe between 135 and 130 Ma. PMID- 25923212 TI - White Matter Differences Among Adolescents Reporting Psychotic Experiences: A Population-Based Diffusion Magnetic Resonance Imaging Study. AB - IMPORTANCE: Abnormal brain connectivity is thought to have a key role in the pathophysiology of schizophrenia and other psychotic disorders. White matter (WM) abnormalities have been reported in patients with schizophrenia and patients with prodromal syndromes. To our knowledge, no studies have yet reported on WM differences among adolescents who report psychotic experiences, a known vulnerability group for later severe psychopathology, including psychotic illness. OBJECTIVE: To study WM differences using diffusion-weighted imaging (whole-brain and tractography analyses) in adolescents who report psychotic experiences. DESIGN, SETTING, AND PARTICIPANTS: A population-based case-control study of 28 adolescents 13 to 16 years old who reported psychotic experiences and a matched sample of 28 adolescents who did not report psychotic experiences drawn from a sample of 212 young people recruited from primary schools in North Dublin and Kildare, Ireland. The study dates were 2008 to 2011. INTERVENTIONS: High angular resolution diffusion-weighted imaging data were used to conduct whole brain WM analysis using tract-based spatial statistics. Based on this exploratory analysis, a tractography-based approach with constrained spherical deconvolution was performed. RESULTS: Compared with control group participants, adolescents who reported psychotic experiences showed WM differences bilaterally in striatal regions in proximity to the putamen (increased fractional anisotropy, P = .01, false discovery rate corrected), and tractography identified significant WM differences bilaterally in the uncinate fasciculus (increased fractional anisotropy in the right [P = .001] and axial diffusivity in the left [P = .01] uncinate fasciculus, respectively). Similar patterns of WM differences between groups survived adjustment for other psychopathology, indicating some specificity for psychotic experiences. Exploratory along-tract analyses showed WM differences between groups in the frontal projections of the right inferior fronto-occipital fasciculus (reduced radial diffusivity in approximately 32% of the tract segment [P <= .0001] and increased fractional anisotropy in approximately 16% of the tract segment [P <= .0009]). CONCLUSIONS AND RELEVANCE: In a population-based study of adolescents reporting psychotic experiences, we found a number of WM differences in the region of the putamen located between the inferior fronto occipital fasciculus and the uncinate fasciculus and in the left parietal regions that include the fiber bundle of the superior longitudinal fasciculus. These findings suggest that subtle structural changes to WM microstructure are not merely a consequence of disorder but may index vulnerability to psychosis even at a very early age. PMID- 25923213 TI - Evolutionary Patterns among Living and Fossil Kogiid Sperm Whales: Evidence from the Neogene of Central America. AB - Kogiids are known by two living species, the pygmy and dwarf sperm whale (Kogia breviceps and K. sima). Both are relatively rare, and as their names suggest, they are closely related to the sperm whale, all being characterized by the presence of a spermaceti organ. However, this organ is much reduced in kogiids and may have become functionally different. Here we describe a fossil kogiid from the late Miocene of Panama and we explore the evolutionary history of the group with special attention to this evolutionary reduction. The fossil consists of cranial material from the late Tortonian (~7.5 Ma) Pina facies of the Chagres Formation in Panama. Detailed comparison with other fossil and extant kogiids and the results of a phylogenetic analysis place the Panamanian kogiid, herein named Nanokogia isthmia gen. et sp. nov., as a taxon most closely related to Praekogia cedrosensis from the Messinian (~6 Ma) of Baja California and to Kogia spp. Furthermore our results show that reduction of the spermaceti organ has occurred iteratively in kogiids, once in Thalassocetus antwerpiensis in the early-middle Miocene, and more recently in Kogia spp. Additionally, we estimate the divergence between extant species of Kogia at around the late Pliocene, later than previously predicted by molecular estimates. Finally, comparison of Nanokogia with the coeval Scaphokogia cochlearis from Peru shows that these two species display a greater morphological disparity between them than that observed between the extant members of the group. We hypothesize that this reflects differences in feeding ecologies of the two species, with Nanokogia being more similar to extant Kogia. Nanokogia shows that kogiids have been part of the Neotropical marine mammal communities at least since the late Miocene, and gives us insight into the evolutionary history and origins of one of the rarest groups of living whales. PMID- 25923214 TI - VRK1 chromatin kinase phosphorylates H2AX and is required for foci formation induced by DNA damage. AB - All types of DNA damage cause a local alteration and relaxation of chromatin structure. Sensing and reacting to this initial chromatin alteration is a necessary trigger for any type of DNA damage response (DDR). In this context, chromatin kinases are likely candidates to participate in detection and reaction to a locally altered chromatin as a consequence of DNA damage and, thus, initiate the appropriate cellular response. In this work, we demonstrate that VRK1 is a nucleosomal chromatin kinase and that its depletion causes loss of histones H3 and H4 acetylation, which are required for chromatin relaxation, both in basal conditions and after DNA damage, independently of ATM. Moreover, VRK1 directly and stably interacts with histones H2AX and H3 in basal conditions. In response to DNA damage induced by ionizing radiation, histone H2AX is phosphorylated in Ser139 by VRK1. The phosphorylation of H2AX and the formation of gammaH2AX foci induced by ionizing radiation (IR), are prevented by VRK1 depletion and are rescued by kinase-active, but not kinase-dead, VRK1. In conclusion, we found that VRK1 is a novel chromatin component that reacts to its alterations and participates very early in DDR, functioning by itself or in cooperation with ATM. PMID- 25923215 TI - Delivery of GM-CSF to Protect against Influenza Pneumonia. AB - BACKGROUND: Since adaptive immunity is thought to be central to immunity against influenza A virus (IAV) pneumonias, preventive strategies have focused primarily on vaccines. However, vaccine efficacy has been variable, in part because of antigenic shift and drift in circulating influenza viruses. Recent studies have highlighted the importance of innate immunity in protecting against influenza. METHODS: Granulocyte-macrophage colony stimulating factor (GM-CSF) contributes to maturation of mononuclear phagocytes, enhancing their capacity for phagocytosis and cytokine production. RESULTS: Overexpression of granulocyte macrophage-colony stimulating factor (GM-CSF) in the lung of transgenic mice provides remarkable protection against IAV, which depends on alveolar macrophages (AM). In this study, we report that pulmonary delivery of GM-CSF to wild type young and aged mice abrogated mortality from IAV. CONCLUSION: We also demonstrate that protection is species specific and human GM-CSF do not protect the mice nor stimulates mouse immunity. We also show that IAV-induced lung injury is the culprit for side-effects of GM-CSF in treating mice after IAV infection, and introduce a novel strategy to deliver the GM-CSF to and retain it in the alveolar space even after IAV infection. PMID- 25923216 TI - PTPN22 is associated with susceptibility to psoriatic arthritis but not psoriasis: evidence for a further PsA-specific risk locus. AB - OBJECTIVES: Psoriatic arthritis (PsA) is a chronic inflammatory arthritis associated with psoriasis; it has a higher estimated genetic component than psoriasis alone, however most genetic susceptibility loci identified for PsA to date are also shared with psoriasis. Here we attempt to validate novel single nucleotide polymorphisms selected from our recent PsA Immunochip study and determine specificity to PsA. METHODS: A total of 15 single nucleotide polymorphisms were selected (PImmunochip <1*10(-4)) for validation genotyping in 1177 cases and 2155 controls using TaqMan. Meta-analysis of Immunochip and validation data sets consisted of 3139 PsA cases and 11 078 controls. Novel PsA susceptibility loci were compared with data from two large psoriasis studies (WTCCC2 and Immunochip) to determine PsA specificity. RESULTS: We found genome wide significant association to rs2476601, mapping to PTPN22 (p=1.49*10(-9), OR=1.32), but no evidence for association in the psoriasis cohort (p=0.34) and the effect estimates were significantly different between PsA and psoriasis (p=3.2*10(-4)). Additionally, we found genome-wide significant association to the previously reported psoriasis risk loci; NOS2 (rs4795067, p=5.27*10(-9)). CONCLUSIONS: For the first time, we report genome-wide significant association of PTPN22 (rs2476601) to PsA susceptibility, but no evidence for association to psoriasis. PMID- 25923218 TI - Polymer Monoliths Containing Two-Photon Absorbing Phenylenevinylene Platinum(II) Acetylide Chromophores for Optical Power Limiting. AB - A series of platinum(II) acetylide complexes containing p-phenylenevinylene and moieties end-capped with triphenylamine groups have been incorporated into poly(methyl methacrylate) (PMMA) monoliths for optical power limiting applications. The one- and two-photon photophysical properties were investigated and compared to the photophysical properties in THF. The absolute two-photon absorption cross-section values for the monolith samples were measured and are comparable to the values obtained in solution. In the PMMA monoliths, the complexes retained the important two-photon absorption and reverse saturable absorption properties necessary for optical power limiting via dual mode mechanism, and their strong nonlinear absorption property was demonstrated by the open-aperture Z-scan method. Photostability studies of the p-phenylenevinylene platinum(II) acetylide complexes showed two photodegradation processes: a trans to-cis isomerization and a singlet-oxygen sensitized self-oxidative cleavage. The photostability of the least photostable complex TPV0 was increased upon incorporation into a PMMA matrix. PMID- 25923217 TI - Synovial CD4+ T-cell-derived GM-CSF supports the differentiation of an inflammatory dendritic cell population in rheumatoid arthritis. AB - OBJECTIVE: A population of synovial inflammatory dendritic cells (infDCs) has recently been identified in rheumatoid arthritis (RA) and is thought to be monocyte-derived. Here, we investigated the role and source of granulocyte macrophage-colony-stimulating factor (GM-CSF) in the differentiation of synovial infDC in RA. METHODS: Production of GM-CSF by peripheral blood (PB) and synovial fluid (SF) CD4+ T cells was assessed by ELISA and flow cytometry. In vitro CD4+ T cell polarisation experiments were performed with T-cell activating CD2/CD3/CD28 coated beads in the absence or presence of pro-Th1 or pro-Th17 cytokines. CD1c+ DC and CD16+ macrophage subsets were flow-sorted and analysed morphologically and functionally (T-cell stimulatory/polarising capacity). RESULTS: RA-SF CD4+ T cells produced abundant GM-CSF upon stimulation and significantly more than RA-SF mononuclear cells depleted of CD4+ T cells. GM-CSF-producing T cells were significantly increased in RA-SF compared with non-RA inflammatory arthritis SF, active RA PB and healthy donor PB. GM-CSF-producing CD4+ T cells were expanded by Th1-promoting but not Th17-promoting conditions. Following coculture with RA-SF CD4+ T cells, but not healthy donor PB CD4+ T cells, a subpopulation of monocytes differentiated into CD1c+ infDC; a process dependent on GM-CSF. These infDC displayed potent alloproliferative capacity and enhanced GM-CSF, interleukin-17 and interferon-gamma production by CD4+ T cells. InfDC with an identical phenotype to in vitro generated cells were significantly enriched in RA-SF compared with non-RA-SF/tissue/PB. CONCLUSIONS: We demonstrate a therapeutically tractable feedback loop of GM-CSF secreted by RA synovial CD4+ T cells promoting the differentiation of infDC with potent capacity to induce GM-CSF-producing CD4+ T cells. PMID- 25923219 TI - Distinct serum metabolomics profiles associated with malignant progression in the KrasG12D mouse model of pancreatic ductal adenocarcinoma. AB - BACKGROUND: Pancreatic ductal adenocarcinoma (PDAC) is the fourth leading cause of cancer deaths worldwide with less than a 6% 5-year survival rate. PDAC is associated with poor prognosis based on the late stage diagnosis of the disease. Current diagnostic tests lack the sensitivity and specificity to identify markers of early staging. Metabolomics has provided biomarkers for various diseases, stressors, and environmental exposures. In this study we utilized the p48-Cre/LSL KrasG12D mouse model with age-matched wild type mice. This model shows malignant progression to PDAC analogous to the human disease stages via early and late pancreatic intra-epithelial neoplasia (PanIN) lesions. RESULTS: Serum was collected from mice with early PanIN lesions (at 3-5 months) and with late PanIN or invasive PDAC lesions (13-16 months), as determined by histopathology. Metabolomics analysis of the serum samples was conducted through UPLC-TOFMS (Ultra Performance Liquid Chromatography coupled to Time-of-flight Mass Spectrometry). Multivariate data analysis revealed distinct metabolic patterns in serum samples collected during malignant progression towards invasive PDAC. Animals with early or late stage lesions were distinguished from their respective controls with 82.1% and 81.5% accuracy, respectively. This also held up for randomly selected subgroups in the late stage lesion group that showed less variability between animals. One of the metabolites, citrate, was validated through tandem mass spectrometry and showed increased levels in serum with disease progression. Furthermore, serum metabolite signatures from animals with early stage lesions identified controls and animals with late stage lesions with 81.5% accuracy (p<0.01) and vice-versa with 73.2% accuracy (p<0.01). CONCLUSIONS: We conclude that metabolomics analysis of serum samples can identify the presence of early and late stage pancreatic cancer. PMID- 25923221 TI - Correction: Two Classes of Bacterial IMPDHs according to Their Quaternary Structures and Catalytic Properties. PMID- 25923220 TI - Dexamethasone Treatment of Newborn Rats Decreases Cardiomyocyte Endowment in the Developing Heart through Epigenetic Modifications. AB - The potential adverse effect of synthetic glucocorticoid, dexamethasone therapy on the developing heart remains unknown. The present study investigated the effects of dexamethasone on cardiomyocyte proliferation and binucleation in the developing heart of newborn rats and evaluated DNA methylation as a potential mechanism. Dexamethasone was administered intraperitoneally in a three day tapered dose on postnatal day 1 (P1), 2 and 3 to rat pups in the absence or presence of a glucocorticoid receptor antagonist Ru486, given 30 minutes prior to dexamethasone. Cardiomyocytes from P4, P7 or P14 animals were analyzed for proliferation, binucleation and cell number. Dexamethasone treatment significantly increased the percentage of binucleated cardiomyocytes in the hearts of P4 pups, decreased myocyte proliferation in P4 and P7 pups, reduced cardiomyocyte number and increased the heart to body weight ratio in P14 pups. Ru486 abrogated the effects of dexamethasone. In addition, 5-aza-2'-deoxycytidine (5-AZA) blocked the effects of dexamethasone on binucleation in P4 animals and proliferation at P7, leading to recovered cardiomyocyte number in P14 hearts. 5 AZA alone promoted cardiomyocyte proliferation at P7 and resulted in a higher number of cardiomyocytes in P14 hearts. Dexamethasone significantly decreased cyclin D2, but not p27 expression in P4 hearts. 5-AZA inhibited global DNA methylation and blocked dexamethasone-mediated down-regulation of cyclin D2 in the heart of P4 pups. The findings suggest that dexamethasone acting on glucocorticoid receptors inhibits proliferation and stimulates premature terminal differentiation of cardiomyocytes in the developing heart via increased DNA methylation in a gene specific manner. PMID- 25923222 TI - Transcatheter Arterial Embolization with Ethanol Injection in Symptomatic Patients with Enlarged Polycystic Kidneys. AB - PURPOSE: To evaluate the safety and effectiveness of transcatheter arterial embolization (TAE) with ethanol in symptomatic patients with enlarged polycystic kidney disease. MATERIALS AND METHODS: This prospective study was institutional review board approved and was planned for patients with symptoms related to enlarged polycystic kidney disease, such as a markedly distended abdomen, gastroesophageal reflux, and abdominal pain. At the time of TAE, all patients were undergoing dialysis therapy for chronic renal failure, and their urinary volume had decreased to less than 500 mL per day. Bilateral renal TAE with absolute ethanol was performed, and changes in kidney volume, clinical symptoms, laboratory data, and complications were evaluated after TAE. The differences in patients' kidney volumes, clinical symptoms, abdominal circumference, and dry weights before and after TAE were analyzed with a mixed effect model. RESULTS: Fifteen patients (seven men and eight women; mean age, 57.7 years +/- 5.3 [standard deviation]) were treated. Among the 15 patients, the follow-up period was 24 months in 13 patients, 6 months in one patient, and 3 months in one patient. The mean kidney volume was 3380 mL before renal TAE, and at 3, 12, and 24 months after TAE, it significantly decreased to 60.9%, 39.8%, and 32.1% of the pretherapeutic value, respectively (P < .001). All patients reported improved clinical symptoms within 3 months after TAE (P < .001). Abdominal circumferences were significantly decreased after TAE (P < .001). The dry weights also continued to significantly decreased until 6 months after TAE (P < .001), at which point they began to slightly increase until 24 months after TAE. Abdominal pain, nausea, and inflammatory response developed in all patients after TAE, but these symptoms improved with conservative treatment. Abscess formation was found in one kidney, and drainage catheter placement was performed. No major complications related to TAE occurred in the remaining patients. CONCLUSION: Renal contraction therapy by TAE with ethanol injection appears to be a safe and effective treatment in patients with symptomatic enlarged polycystic kidney disease. PMID- 25923223 TI - Splenic Switch-off: A Tool to Assess Stress Adequacy in Adenosine Perfusion Cardiac MR Imaging. AB - PURPOSE: To investigate the pharmacology and potential clinical utility of splenic switch-off to identify understress in adenosine perfusion cardiac magnetic resonance (MR) imaging. MATERIALS AND METHODS: Splenic switch-off was assessed in perfusion cardiac MR examinations from 100 patients (mean age, 62 years [age range, 18-87 years]) by using three stress agents (adenosine, dobutamine, and regadenoson) in three different institutions, with appropriate ethical permissions. In addition, 100 negative adenosine images from the Clinical Evaluation of MR Imaging in Coronary Heart Disease (CE-MARC) trial (35 false and 65 true negative; mean age, 59 years [age range, 40-73 years]) were assessed to ascertain the clinical utility of the sign to detect likely pharmacologic understress. Differences in splenic perfusion were compared by using Wilcoxon signed rank or Wilcoxon rank sum tests, and true-negative and false-negative findings in CE-MARC groups were compared by using the Fisher exact test. RESULTS: The spleen was visible in 99% (198 of 200) of examinations and interobserver agreement in the visual grading of splenic switch-off was excellent (kappa = 0.92). Visually, splenic switch-off occurred in 90% of adenosine studies, but never in dobutamine or regadenoson studies. Semiquantitative assessments supported these observations: peak signal intensity was 78% less with adenosine than at rest (P < .001), but unchanged with regadenoson (4% reduction; P = .08). Calculated peak splenic divided by myocardial signal intensity (peak splenic/myocardial signal intensity) differed between stress agents (adenosine median, 0.34; dobutamine median, 1.34; regadenoson median, 1.13; P < .001). Failed splenic switch-off was significantly more common in CE-MARC patients with false-negative findings than with true-negative findings (34% vs 9%, P < .005). CONCLUSION: Failed splenic switch-off with adenosine is a new, simple observation that identifies understressed patients who are at risk for false-negative findings on perfusion MR images. These data suggest that almost 10% of all patients may be understressed, and that repeat examination of individuals with failed splenic switch-off may significantly improve test sensitivity. PMID- 25923224 TI - Wechsler Intelligence Scale for Children-V: Test Review. AB - Changes from the fourth edition of the Wechsler Intelligence Scale for Children (WISC) to the fifth edition are discussed, with particular emphasis on how the electronic administration facilitated assessment. The hierarchical organization and conceptualization of primary indices have been adjusted, based on recent theory and research on the construct of intelligence. Changes also include updates to psychometric properties and consideration of cultural bias. The scoring program allows intelligence scores to be linked statistically to achievement measures to aid in diagnoses of learning disabilities. Electronic assessment was clunky at times but overall delivered on its promise of quicker and more accurate administration and scoring. PMID- 25923225 TI - Ketamine-A Narrative Review of Its Uses in Medicine. AB - One of the most fascinating drugs in the anesthesiologist's armament is ketamine, an N-methyl-D-aspartate receptor antagonist with a myriad of uses. The drug is a dissociative anesthetic and has been used more often as an analgesic in numerous hospital units, outpatient pain clinics, and in the prehospital realm. It has been used to treat postoperative pain, chronic pain, complex regional pain syndrome, phantom limb pain, and other neuropathic conditions requiring analgesia. Research has also demonstrated its efficacy as an adjunct in psychotherapy, as a treatment for both depression and posttraumatic stress disorder, as a procedural sedative, and as a treatment for respiratory and neurologic conditions. Ketamine is not without its adverse effects, some of which can be mitigated with certain efforts. Such effects make it necessary for the clinician to use the drug only in situations where it will provide the greatest benefit with the fewest adverse effects. To the best of our knowledge, none of the reviews regarding ketamine have taken a comprehensive look at the drug's uses in all territories of medicine. This review will serve to touch on its chemical data, pharmacokinetics and pharmacodynamics, medical uses, and adverse effects while focusing specifically on the drugs usage in anesthesia and analgesia. PMID- 25923226 TI - Comparison of Efficacy and Tolerance of Automatic Continuous Positive Airway Pressure Devices With the Optimum Continuous Positive Airway Pressure. AB - Patients diagnosed with obstructive sleep apnea syndrome were randomly placed on automatic continuous positive airway pressure (ACPAP) for 2 hours followed by manual titration for the rest of the night. One hundred sixty-one patients entered the study, with at least 50 patients titrated with each of 3 ACPAP devices. The optimum continuous positive airway pressure (CPAP) was defined as the lowest pressure with an apnea-hypoxia index of <=5/hr, which ranged from 4 cm to 18 cm. Success with ACPAP was approximately 60%-80% when the optimum CPAP was 4-6 cm but fell to below 30% if the optimum CPAP was >=8 cm (P = 0.001). Average ACPAP ranged from 2 to 10 cm below the optimum level if the optimum CPAP was >=8 cm. Patients who responded to a low CPAP but deteriorated on higher pressures failed to respond to any of the automatic devices. We recommend that CPAP titration be performed manually before initiation of ACPAP in patients with obstructive sleep apnea. The basal pressure for ACPAP should be the optimum pressure obtained by manual titration. Limits on the upper level of ACPAP may be necessary for patients who deteriorate on higher positive pressures. PMID- 25923227 TI - Sudden Cardiac Arrest in a Patient With Apical Hypertrophic Cardiomyopathy: Case Report and a Brief Review of Literature. AB - Apical hypertrophic cardiomyopathy (HCM) is a phenotypic variant of nonobstructive HCM, in which hypertrophy of the myocardium predominantly involves the left ventricular apex. It is common in Japanese and other Asian populations but is rare in the United States. Apical HCM has a relatively benign prognosis in terms of cardiovascular mortality; however, morbid events such as ventricular aneurysms, apical thrombi, diastolic dysfunction, atrial fibrillation, and myocardial infarction are not uncommon. We report a case of an 18-year-old white man who presented to our hospital after an out-of-hospital cardiac arrest. The patient had a witnessed collapse while playing basketball in the field. He was found to be pulseless and unresponsive by his coach, and cardiopulmonary resuscitation was immediately started. Upon arrival of emergency medical services, an automated external defibrillator advised shock and he was defibrillated thrice. Return of spontaneous circulation was achieved in 15 minutes. He was intubated for airway protection and was brought to the hospital. Therapeutic hypothermia was initiated. He demonstrated good neurological status after active rewarming. Subsequent cardiac magnetic resonance imaging was suggestive of apical HCM with right ventricular involvement. The patient underwent an implantable cardioverter defibrillator placement for secondary prevention and was subsequently discharged. In conclusion, apical HCM can rarely be associated with adverse cardiovascular events. The diagnosis may be missed on transthoracic 2-dimensional cardiac echocardiogram, and cardiac magnetic resonance imaging should be considered to exclude apical HCM in young patients who present after sudden cardiac arrest. PMID- 25923229 TI - Comparison Between Sequential Therapy and Modified Bismuth-Included Quadruple Therapy for Helicobacter pylori Eradication in Chinese Patients. AB - To compare the efficacy and safety of sequential therapy and modified bismuth included quadruple therapy as a first-line Helicobacter pylori eradication in China. The patients were randomized to receive sequential therapy [n = 90; rabeprazole (20 mg twice daily) and amoxicillin (1 g twice daily) for 5 days, followed by rabeprazole (20 mg twice daily), tinidazole (500 mg twice daily) plus clarithromycin (500 mg twice daily) for another 5 days] or modified bismuth included quadruple therapy [n = 109; rabeprazole (20 mg twice daily), levofloxacin hydrochloride (400 mg twice daily), clarithromycin (500 mg twice daily), and colloidal bismuth pectin (200 mg 3 times a day) for 7 days]. A follow up urea breath test was applied 4 weeks later. A total of 199 patients were diagnosed with H. pylori infection. The intention-to-treat and per-protocol (PP) eradication rates were 91.7% and 92.6%, respectively, in the modified bismuth included quadruple therapy group, and 74.4% and 76.1%, respectively, in the sequential therapy group. The eradication rates were significantly higher in the modified bismuth-included quadruple therapy group, compared with the sequential therapy group (P = 0.001 for intention to treat and P = 0.001 for PP). Adverse effects were reported by patients from both groups, but the difference did not reach significant level (P = 0.280). The modified bismuth-included quadruple therapy seemed to be superior to the sequential therapy as the first-line regimen for H. pylori eradication in Chinese patients. PMID- 25923228 TI - Entecavir Combined With Adefovir Ameliorates Patients With Chronic Hepatitis B Who Fail to Respond to Nucleotide (Acid) Analog Monotherapy. AB - The aim of this study was to evaluate the efficacy and safety of entecavir (ETV) combined treatment with adefovir (ADV) on chronic hepatitic B (CHB) patients who failed to respond to nucleotide (acid) analog (NA) treatment. On this basis, the possible factors in the combined treatment of these patients will be analyzed. The safety, biochemical index, and the possible factors that might affect the ETV and ADV combined treatment at different points in time were retrospectively analyzed. The biochemical index included the following: virological response, hepatitis B virus (HBV) DNA decline, primary nonresponse, biochemical response, and the hepatitis B virus E antigen/hepatitis B virus E antibody seroconversion rate. There were 94 CHB patients and compensated liver cirrhosis patients who received ETV plus ADV treatment for over 12 weeks after failure of treatment with NAs. The authors have also investigated 76 CHB patients (80.9%) and 18 hepatitis B cirrhosis patients (19.1%) in this study. The HBV DNA baseline was 4.4 +/- 1.4 log10 IU/mL, and the positive rate of HBeAg before salvage treatment was 78.7% (74/94). The sample sizes were 94, 78, 42, 10, 6, and 1 for follow-up of 24, 48, 96, 144, 192, and 240 weeks, respectively. The virological responses (HBV DNA < 2 log10 IU/mL) and biochemical responses were 52.1%, 74.3%, and 90.4% and 63.1%, 61.6%, and 81.1%, respectively, at 24, 48, and 96 weeks, which showed significant differences (P < 0.001 and P < 0.005, respectively). The HBV DNA decline was presented as mean +/- SEM, which were 1.53 +/- 1.23, 1.75 +/- 1.37, 2.07 +/- 1.54, and 2.39 +/- 1.77 log10 IU/mL at 12, 24, 48, and 96 weeks, respectively. They showed significant differences compared with the baseline (chi = 8.084, P < 0.05). The rate of primary nonresponse was 30.9% (29/94), and the primary treatment failure rates were 26.6% (25/94), 24.4% (19/78), and 4.8% (2/42) at 24, 48, and 96 weeks, respectively. They all have statistical difference (P = 0.011 < 0.05). There were 23 patients who experienced virological breakthrough after the HBV DNA levels were undetectable, whereas after follow-up for 12-24 weeks, the HBV DNA levels were back to undetectable again. ETV plus ADV treatment is an efficient and safe treatment for CHB and compensated liver cirrhosis patients who experienced NA treatment failure. The high quantity of baseline HBV DNA level is a risk factor for poor efficacy of salvage treatment. PMID- 25923230 TI - Study of 27 Aqueous Humor Cytokines in Type 2 Diabetic Patients with or without Macular Edema. AB - The aim of the present study was to compare the changes in the levels of 27 aqueous humor cytokines between diabetic patients with macular edema (ME) and diabetic patients without ME. Undiluted aqueous humor samples were obtained from 68 consecutive type 2 diabetic patients without ME and 56 consecutive type 2 diabetic patients with ME. The concentrations of 27 cytokines in the aqueous humor samples were measured using a multiplex bead immunoassay. Compared with diabetic patients without ME, diabetic patients with ME had significantly higher concentrations of IL-1beta, IL-6, IL-8, IP-10, MCP-1, and VEGF in the aqueous humor. However, the concentrations of IL-10 and IL-12 were significantly lower in the diabetic patients with ME. The aqueous humor levels of IL-1beta, IL-6, IL-8, MCP-1, IP-10, and VEGF were closely correlated with retinal macular thickness, retinal macular volume and the severity of ME. In addition, the aqueous humor levels of IL-10 and IL-12 decreased with increasing the severity of ME. A variety of cytokines associated with inflammation and angiogenesis may contribute to the pathogenesis of diabetic macular edema, and both anti-inflammatory and antiangiogenic agents should be included in the treatment of ME simultaneously. PMID- 25923231 TI - Synthesis and catalytic application of magnesium complexes bearing pendant indolyl ligands. AB - Three novel indole-based ligand precursors [HIndPh(R), R = methoxy, HIndPh(OMe) (); thiomethoxy, HIndPh(SMe) (); and N,N'-dimethylamino, HIndPh(NMe2) ()] have been synthesized via Sonogashira and cyclization reactions with moderate to high yield. Reactions of these ligand precursors with 0.6 equivalent of Mg(n)Bu2 in THF afforded the magnesium bis-indolyl complexes , respectively. All the ligand precursors and related magnesium complexes have been characterized by NMR spectroscopy and elemental analyses. The molecular structures are reported for compounds and . Under optimized conditions, compound demonstrates efficient catalytic activities towards the ring opening polymerization of l-lactide and epsilon-caprolactone in the presence of BnOH. PMID- 25923232 TI - Correction: Assessing the Stability and Safety of Procedure during Endoscopic Submucosal Dissection According to Sedation Methods: A Randomized Trial. PMID- 25923233 TI - Money makes the (medical assessment) world go round: The cost of components of a summative final year Objective Structured Clinical Examination (OSCE). AB - INTRODUCTION: The widely used Objective Structured Clinical Examination (OSCE) is undoubtedly expensive. Cost-effectiveness is one of the components of the assessment utility index defining its usefulness. Our current financial climate demands increased transparency in the costs associated with medical education and it is now vital to ascertain how much is spent on assessments, such as the OSCE, and in particular costs associated with the different types of stations within the OSCE. METHODS: A retrospective case-study approach was used to identify all costs associated with the development, production, administration and post examination phases of the 2013 final year MBChB OSCE at the University of Aberdeen, Scotland. This 15 station OSCE was held over 2 days for 185 students. RESULTS: This OSCE cost L65,328 to run. Costs per station ranged from L3108 (prescribing) to L6577 (eye examination). The cost per student was L355. DISCUSSION: The costs of a "high stakes" OSCE are sobering. The bulk of costs identified are not modifiable in light of what is currently known about the metrics of OSCE utility, particularly reliability and validity. CONCLUSION: Providers, and funders, of medical education must be prepared to assign significant resource to OSCE assessment and centres should be encouraged to calculate precise costs associated with assessment to inform resource allocation decisions. PMID- 25923234 TI - Essential steps in developing best practices to assess reflective skill: A comparison of two rubrics. AB - PURPOSE: Medical education lacks best practices for evaluating reflective writing skill. Reflection assessment rubrics include the holistic, reflection theory based Reflection-on-Action and the analytic REFLECT developed from both reflection and narrative-medicine literatures. To help educators move toward best practices, we evaluated these rubrics to determine (1) rater requirements; (2) score comparability; and (3) response to an intervention. METHODS: One-hundred and forty-nine third-year medical students wrote reflections in response to identical prompts. Trained raters used each rubric to score 56 reflections, half written with structured guidelines and half without. We used Pearson's correlation coefficients to associate overall rubric levels and independent t tests to compare structured and unstructured reflections. RESULTS: Reflection-on Action training required for two hours; two raters attained an interrater reliability = 0.91. REFLECT training required six hours; three raters achieved an interrater-reliability = 0.84. Overall rubric correlation was 0.53. Students given structured guidelines scored significantly higher (p < 0.05) on both rubrics. CONCLUSIONS: Reflection-on-Action and REFLECT offer unique educational benefits and training challenges. Reflection-on-Action may be preferred for measuring overall quality of reflection given its ease of use. Training on REFLECT takes longer but it yields detailed data on multiple dimensions of reflection that faculty can reference when providing feedback. PMID- 25923235 TI - Designing an evaluation framework for WFME basic standards for medical education. AB - PURPOSE: To create an evaluation plan for the World Federation for Medical Education (WFME) accreditation standards for basic medical education. METHODS: We conceptualized the 100 basic standards from "Basic Medical Education: WFME Global Standards for Quality Improvement: The 2012 Revision" as medical education program objectives. Standards were simplified into evaluable items, which were then categorized as inputs, processes, outputs and/or outcomes to generate a logic model and corresponding plan for data collection. RESULTS: WFME standards posed significant challenges to evaluation due to complex wording, inconsistent formatting and lack of existing assessment tools. Our resulting logic model contained 244 items. Standard B 5.1.1 separated into 24 items, the most for any single standard. A large proportion of items (40%) required evaluation of more than one input, process, output and/or outcome. Only one standard (B 3.2.2) was interpreted as requiring evaluation of a program outcome. CONCLUSIONS: Current WFME standards are difficult to use for evaluation planning. Our analysis may guide adaptation and revision of standards to make them more evaluable. Our logic model and data collection plan may be useful to medical schools planning an institutional self-review and to accrediting authorities wanting to provide guidance to schools under their purview. PMID- 25923236 TI - Syntheses of 1-Bromo-8-methylnaphthalene and 1-Bromo-5-methylnaphthalene. AB - The Diels-Alder reaction between 2-methylfuran and 3-bromobenzyne (3), which was generated under mild conditions from 1,3-dibromobenzene and lithium diisopropylamide (LDA), gives a mixture of regioisomeric 1,4-dihydro-1,4 epoxynaphthalenes 4 and 5. A subsequent two-step deoxygenation affords the corresponding 1-bromo-8-methylnaphthalene (1) and 1-bromo-5-methylnaphthalene (2) in high yields. PMID- 25923237 TI - Identification of Critical Elements for Regulation of Inorganic Pyrophosphatase (PPA1) in MCF7 Breast Cancer Cells. AB - Cytosolic inorganic pyrophosphatase plays an important role in the cellular metabolism by hydrolyzing inorganic pyrophosphate (PPi) formed as a by-product of various metabolic reactions. Inorganic pyrophosphatases are known to be associated with important functions related to the growth and development of various organisms. In humans, the expression of inorganic pyrophosphatase (PPA1) is deregulated in different types of cancer and is involved in the migration and invasion of gastric cancer cells and proliferation of ovarian cancer cells. However, the transcriptional regulation of the gene encoding PPA1 is poorly understood. To gain insights into PPA1 gene regulation, a 1217 bp of its 5' flanking region was cloned and analyzed. The 5'-deletion analysis of the promoter revealed a 266 bp proximal promoter region exhibit most of the transcriptional activity and upon sequence analysis, three putative Sp1 binding sites were found to be present in this region. Binding of Sp1 to the PPA1 promoter was confirmed by Electrophoretic mobility shift assay (EMSA) and Chromatin immunoprecipitation (ChIP) assay. Importance of these binding sites was verified by site-directed mutagenesis and overexpression of Sp1 transactivates PPA1 promoter activity, upregulates protein expression and increases chromatin accessibility. p300 binds to the PPA1 promoter and stimulates Sp1 induced promoter activity. Trichostatin A (TSA), a histone deacetylase (HDAC) inhibitor induces PPA1 promoter activity and protein expression and HAT activity of p300 was important in regulation of PPA1 expression. These results demonstrated that PPA1 is positively regulated by Sp1 and p300 coactivates Sp1 induced PPA1 promoter activity and histone acetylation/deacetylation may contribute to a local chromatin remodeling across the PPA1 promoter. Further, knockdown of PPA1 decreased colony formation and viability of MCF7 cells. PMID- 25923238 TI - Modeling and Validation of Multilayer Poly(Lactide-Co-Glycolide) Scaffolds for In Vitro Directed Differentiation of Juxtaposed Cartilage and Bone. AB - Polymeric scaffolds, which release growth factors in a temporally controlled manner, have successfully directed the differentiation of stem cells into monolithic tissues of a single lineage. However, engineering precise boundaries in multilineage functional tissues, such as the juxtaposed cartilaginous and osseous tissue present in articulated joints, often remains a challenge. This work demonstrates a precise materials system for in vitro reconstruction of the three-dimensional architecture of these types of human tissues. Multilayer poly(lactide-co-glycolide) (PLG) scaffolds were used to produce spatiotemporal gradients to direct the differentiation of an initially uniform population of mesenchymal stem cells (MSCs) into juxtaposed cartilage and bone. Specifically, growth factors (chondrogenic transforming growth factor-beta3 and osteogenic bone morphogenetic protein-4) and their neutralizing antibodies were incorporated within distinct layers of the PLG scaffolds to create spatially segregated morphogen fields within the scaffold volume. The multilayer PLG scaffold designs were optimized by mathematical modeling, and generation of spatially segregated morphogen gradients was validated by assessing activity of luciferase reporter cell lines responsive to each growth factor. Scaffolds seeded with MSCs demonstrated production of juxtaposed cartilage and bone, as evaluated by biochemical staining and western blotting for tissue-specific matrix proteins. This work demonstrates a significant advance for the engineering of implantable constructs comprising tissues of multiple lineages, with potential applications in orthopedic regenerative medicine. PMID- 25923239 TI - Vasa previa: Another ultrasound sign and caution at cesarean section. PMID- 25923240 TI - Neonatal neuronal apoptosis after betamethasone administration in pregnant Wistar rats. AB - OBJECTIVE: To analyze the apoptosis of cortical and hippocampal neurons in newborn following the intramuscular administration of betamethasone in pregnant Wistar rats. METHODS: Betamethasone or placebo was administered to 10 pregnant rats. Subsequently, 98 newborns were analyzed in three different groups: therapeutic dose (TD, 20 mg/kg), triple therapeutic dose (3TD, 60 mg/kg), and nine times TD (9TD, 180 mg/kg). Forty-four newborns were injected with placebo (control subjects--CTR). Neuronal apoptosis was measured by immunofluorescence using the TUNEL assay. The one-way analysis of variance, Tukey-Kramer (parametric) test and Kruskal-Wallis (non-parametric) test were used for statistical analysis. RESULTS: The CA1 area of the hippocampus of TD and 3TD groups showed significant differences from that of the CTR group (p < 0.001). Compared to the CTR group, there was increased neuronal apoptosis in the dentate gyrus (DG) of animals in TD and 3TD groups (p < 0.0001). There were no significant differences in CA2 and CA3 regions as well as in amygdala and cortex. CONCLUSION: Prenatal administration of betamethasone leads to significant changes in neuronal apoptosis in CA1 and DG regions. PMID- 25923241 TI - Pregnancy outcomes among women with hemoglobin E trait. AB - OBJECTIVE: To compare the maternal and fetal outcomes between pregnant women complicated with hemoglobin E (HbE) trait and normal controls. PATIENTS AND METHODS: A retrospective cohort study was conducted by assessment of the database of maternal-fetal medicine units from January 2003 to December 2013 to identify singleton pregnant women complicated by HbE trait. Pregnancies with medical complications or fetal anomalies were excluded. The normal controls were low-risk pregnancies and were non-carrier status for thalassemia and hemoglobinopathy. RESULT: During the study period, 1073 women with HbE trait and 2146 normal controls were included. The baseline characteristics of the two groups were comparable except that the number of prenatal visit was statistically higher in study group (8.55 +/- 3.03 versus 7.85 +/- 4.33, p = <0.001). Most pregnancy outcomes were not significantly different. However, the rate of asymptomatic bacteriuria was minimally higher in the study group, 3.5% versus 2.3%; p = 0.042 (relative risk 1.19; 95%CI: 0.98-1.43). Note that the rates of gestational diabetes tend to be higher in the group of HbE trait (7.6% versus 6.8%), but did not reach a statistical level. CONCLUSION: The HbE trait does not significantly increase risk of common adverse pregnancy outcomes, except for minimal increase in asymptomatic bacteriuria. PMID- 25923242 TI - Streptococcus agalactiae in pregnancies complicated by preterm prelabor rupture of membranes. AB - OBJECTIVE: The main aim of this study was to evaluate the presence of Streptococcus agalactiae (S. agalactiae) in the vagina and the amniotic fluid in pregnancies complicated by preterm prelabor rupture of membranes (PPROM). The next aim was to evaluate the incidence of S. agalactiae early onset sepsis in newborns from PPROM pregnancies, with respect to the presence of S. agalactiae in the vagina and the amniotic fluid. METHODS: Singleton gestations with PPROM between 24 + 0 and 36 + 6 were included. A vaginal swab was obtained, and amniocentesis was performed at admission. The presence of S. agalactiae in the vagina and in the amniotic fluid was assessed by culture and by real-time polymerase chain reaction, respectively. RESULTS: In total, 336 women were included. The presence of S. agalactiae in the vaginal and amniotic fluid was found in 9% (31/336) and 1% (3/336) of women. One woman had S. agalactiae in the amniotic fluid but was negative for the presence of S. agalactiae in the vaginal fluid. Early onset neonatal sepsis developed in one newborn from pregnancies complicated by the presence of S. agalactiae in the amniotic fluid. CONCLUSION: The presence of S. agalactiae in the vagina and amniotic fluid complicated approximately each 10th and each 100th PPROM pregnancy. Cultivation-negative findings of S. agalactiae in the vagina did not exclude the positivity of the amniotic fluid for S. agalactiae and the development of early onset sepsis in newborns. PMID- 25923243 TI - Short and long-term effects of telaprevir on kidney function in patients with hepatitis C virus infection: a retrospective cohort study. AB - BACKGROUND: Recent reports suggest that telaprevir, a protease inhibitor used to treat hepatitis C infection, is associated with decline in kidney function during therapy, particularly in patients with baseline renal impairment. METHODS: Patients treated with telaprevir in a single healthcare network were retrospectively reviewed. Kidney function was determined at baseline, during therapy, and twelve weeks and twelve months after telaprevir discontinuation. Significant creatinine rise during therapy was defined as an increase in serum creatinine >= 0.3mg/dL from baseline during treatment with telaprevir. RESULTS: Between July 2011 to January 2013,seventy-eight patients began treatment. The majority completed the prescribed twelve weeks of telaprevir therapy; 32% discontinued due to side effects. The average rise in serum creatinine during therapy was 0.22mg/dL (standard deviation 0.22mg/dL). Thirty-one percent experienced a significant creatinine rise during therapy. Decline in estimated glomerular filtration rate (eGFR) was lower in those with baseline eGFR < 90 mL/min/1.73m2 compared to the group with baseline eGFR >= 90 mL/min/1.73m2 (12 vs. 18 mL/min/1.73m2, P = 0.047). Serum creatinine fully normalized by twelve weeks after cessation of telaprevir in 83% of patients, however experiencing a significant creatinine rise during telaprevir use was associated with a 6.6mL/min/1.73m2 decrease in estimated glomerular filtration rate at twelve months in an adjusted model. CONCLUSIONS: Decline in kidney function during therapy with telaprevir is common and is not associated with baseline eGFR < 90mL/min/1.73m2 as previously reported. PMID- 25923244 TI - Effects of transverse relationships between maxillary arch, mouth, and face on smile esthetics. AB - OBJECTIVE: To identify the ideal ratios between the widths of the maxillary arch, mouth, and face, respectively, and to determine the range of acceptable esthetic variations based on these ideal ratios. MATERIALS AND METHODS: A photograph of a young female with a harmonious smile was selected and digitally altered to produce two sets of images. The first image showed an altered intercanine width, while the second one showed an altered oral fissure breadth. These alterations were independently rated by judges, including 23 orthodontists and 30 undergraduates. The Mann-Whitney U-test was used to compare the scores given by male and female judges and those given by professional and nonprofessional judges. RESULTS: The following ideal transverse ratios were determined: intercanine width/oral fissure breadth, 0.638; oral fissure breadth/interparopia width: the distance between left and right paropia, 0.617; and intercanine width/face width at the level of the labial commissures, 0.300. A range of -10% to +10% was proposed as the thresholds of esthetic smile evaluations. It was shown that gender of the raters had no effect on the rating of photographs, nor were there any statistically significant differences between the professional and nonprofessional judges' ratings. CONCLUSIONS: Balanced transverse relationships in the facial region are important for smile esthetics, and there is a wide range of esthetically acceptable variations in the transverse relationships between the maxillary arch, mouth, and face. PMID- 25923245 TI - Three-dimensional evaluation of hybrid expander appliances: A pilot study. AB - OBJECTIVE: To evaluate transverse dimensional changes in dentoalveolar and skeletal structures caused by hybrid expander, using cone-beam computed tomography (CBCT). MATERIALS AND METHODS: The CBCT records of nine patients (five boys and four girls) (mean age 13.61 +/- 0.72 years) treated with hybrid expander were examined. CBCT images were taken at pretreatment and after the expansion. ELSA (point equidistant to both foramina spinosa) was determined as a reference point to compare the distances in all three dimensions. Nineteen transversal dimensions and four angles were measured for both right and left sides. Wilcoxon signed rank test was used for statistical comparison at P < .05 levels. RESULTS: A V-shaped expansion of suture was successfully achieved in all patients without teeth support. The amount of opening was greater in anterior than posterior and in inferior than superior. An 8.75-mm screw expansion was achieved for all patients. Expansion effects reverberated to maxillary central incisor, canine, first premolar, and first molar at 70%, 75%, 92%, and 89%, respectively. The molar teeth tipped buccally (right 3.06 degrees and left 3.24 degrees ) as did premolars (right 2.88 degrees and left 3.02 degrees ). CONCLUSION: The hybrid expander, minimally invasive expansion appliance that protects teeth by including bone support, can be used easily for rapid maxillary expansion treatment. PMID- 25923246 TI - Secular trends affect timing of emergence of permanent teeth. AB - OBJECTIVE: To examine the expression of possible secular trend in timing of the emergence of permanent teeth in Finnish children over the past few decades, considering the differences between genders. MATERIALS AND METHODS: Two age groups of Finnish children, one born in 1976-1985 (group 1980) and the other born in 1999-2002 (group 2000), were examined. Group 2000 comprised 483 children (235 girls and 248 boys) aged 6.4 to 8.5 years at the time of the examination, and the same children were examined at the age of 9.0 to 11.8 years. Altogether 405 children could be recalled, 196 girls and 209 boys. For comparison, matching age groups were selected from the group 1980 data (n = 1579), resulting in a sample of 312 children (155 girls and 157 boys) aged 6.4 to 8.5 years and 393 children aged 9.0 to 11.8 years. The emergence stage of each permanent tooth was determined clinically (Grades 0-3), based on which the subjects were furthermore divided according to the emergence stage of the dentition. RESULTS: Linear regression models showed that the permanent teeth of the first phase of the mixed dentition erupted earlier in group 2000 than in group 1980, but the teeth of the second phase of the mixed dentition erupted later in group 2000. Girls showed more advanced tooth eruption than boys. CONCLUSION: The longer duration of mixed dentition in group 2000 than in group 1980 makes the duration of combined follow up and active treatment longer, and should be considered in timing of efficient orthodontic treatment. PMID- 25923247 TI - Detection and Characterization of ZnO Nanoparticles in Surface and Waste Waters Using Single Particle ICPMS. AB - The increasing production of ZnO nanoparticles (nZnO) makes their analysis and characterization extremely important from an ecological risk perspective, especially at the low concentrations at which they are expected to be found in natural waters. Single particle ICPMS (SP-ICPMS) is one of the few techniques available to detect and characterize nanoparticles at environmentally relevant concentrations. Unfortunately, at the very low particle concentrations where SP ICPMS is performed, significant dissolution of the nZnO generally increases background levels of dissolved Zn to the point where measurements are not generally possible. By hyphenating SP-ICPMS with an ion-exchange resin, it was possible to characterize and quantify nZnO in order to gain insight into the nature of the nZnO in natural waters. Spiked and unspiked water samples were analyzed using a SP-ICPMS that was coupled to a column containing a strong metal binding resin (Chelex 100). In addition to the detection of ZnO nanoparticles and the determination of a size distribution in natural waters, it was possible to partition the dissolved Zn among free and/or labile and strongly bound Zn fractions. In two natural waters, a high proportion (ca. 93-100%) of dissolved Zn was measured, and the residual ZnO particles were mainly composed of small agglomerates (average sizes ranging from 133.6 to 172.4 nm in the surface water and from 167.6 to 216.4 nm in the wastewater effluent). Small numbers of small nanoparticles were also detected in nonspiked waters. PMID- 25923248 TI - Nickel-catalyzed hydroimination of alkynes. AB - A modular and atom-efficient synthesis of 2-aza-1,3-butadiene derivatives has been developed via nickel-catalyzed intermolecular coupling between internal alkynes and aromatic N-H ketimines. This novel alkyne hydroimination process is promoted by a catalyst system of a Ni(0) precursor ([Ni(cod)2]), N-heterocyclic carbene (NHC) ligand (IPr), and Cs2CO3 additive. The exclusive formation of (Z) enamine stereoisomers is consistent with a proposed anti-iminometalation of alkyne by pi-complexation with Ni(0) and subsequent attack by the N-H ketimine nucleophile. An NHC-ligated Ni(0) pi-imine complex, [(IPr)Ni(eta(1) HN?CPh2)(eta(2)-HN?CPh2)], was independently synthesized and displayed improved reactivity as the catalyst precursor. PMID- 25923249 TI - Association between decreased serum parathyroid hormone after total thyroidectomy and persistent hypoparathyroidism. AB - BACKGROUND: Postoperative hypocalcemia caused by hypoparathyroidism is one of the most common morbidities of total thyroidectomy. The aim of this study was to analyze the kinetics and factors affecting PTH levels after total thyroidectomy and central neck dissection (CND). MATERIAL/METHODS: We performed a retrospective study in 438 consecutive patients who underwent total thyroidectomy between January 2007 and December 2010. No patient had a history of thyroid or neck surgery. PTH and calcium levels were recorded 1 day before the operation, during the first 5 days, and during follow-up (2 weeks and 2, 6, and 12 months). RESULTS: PTH levels declined to 41.90% of its initial value on the first day after the operation. After surgery, PTH was correlated positively with calcium and inversely with phosphate levels from postoperative day 1 to 14. Based on clinical observation, using a PTH threshold of <7 ng/L on postoperative day 1 was predictive of persistent hypoparathyroidism, with sensitivity and negative predictive value 100%, but poor specificity (70.19%). CND increased the risk of transient hypoparathyroidism compared with total thyroidectomy alone. Patients with thyroiditis had an increased risk of permanent hypoparathyroidism compared with those without thyroiditis. Iatrogenic removal of the parathyroid glands increased the risk of permanent hypoparathyroidism compared with those without iatrogenic parathyroidectomy. CONCLUSIONS: PTH declined on the first day after thyroidectomy. PTH levels <7 ng/L on the first day after surgery might be associated with persistent hypoparathyroidism. CND, thyroiditis, and iatrogenic parathyroidectomy increased the risk of hypoparathyroidism. PMID- 25923250 TI - Parathyroidectomized patients have impaired capacity of peripheral vascular constriction during hemodialysis. AB - Parathyroidectomy (PTx) seems to improve cardiovascular outcomes and reduce blood pressure levels. However, the effect of PTx on hemodynamic changes during hemodialysis (HD) is still overlooked. This was a prospective cohort design. Patients with end-stage renal disease on maintenance HD were included. Diabetes and nonsinusal rhythm were exclusion criteria. History of PTx was recorded. Finometer monitor was used to access parameters immediately pre- and post-HD sessions. Cardiac index (CI) variation (DeltaCI) and peripheral arterial resistance variation (DeltaPAR) were the variables of interest. Biochemical and echocardiographic data were also obtained. PTx patients (n = 11) were matched to non-PTx patients (n = 20). DeltaPAR was lower in PTx group in comparison with non PTx group (P = 0.039), which was independent of parathyroid hormone (PTH) levels. Multiple regression analysis showed that PTx, DeltaCI, and dialysate calcium remained independently associated with PAR variation and even adjusted for ultrafiltration rate (adjusted r(2) = 0.64). In conclusion, parathyroidectomized patients have impaired capacity of vasoconstriction in response to ultrafiltration, an effect independent of serum PTH levels. Further studies are needed to elucidate mechanisms explaining the interaction between PTx and systemic vascular tonus. PMID- 25923251 TI - Photodegradation of Imidacloprid in Aqueous Solution by the Metal-Free Catalyst Graphitic Carbon Nitride using an Energy-Saving Lamp. AB - Imidacloprid has become a research hotspot, due to its high toxicity to bees and other nontarget organisms. Photodegradation is a common method for removing imidacloprid in an aquatic environment. Traditional methods of pesticide photodegradation have generally been confined by many factors, such as response to only high-energy ultraviolet light. Herein, the visible-light-driven photocatalyst graphitic carbon nitride (g-C3N4) was applied to the photodegradation of imidacloprid. Visible-light illumination (lambda >400 nm) resulted in nearly 90% substrate transformation in 5 h. With the illumination of an energy-saving lamp, imidacloprid has also been mostly removed. 1-((6 chloropyridin-3-yl)methylhydroxy)imidazolidin-2-ylidene nitramide) and 4,5 dihydro-N-nitro-1-(3-pyridinylmethyl)-1H-imidazol-2-amine were the main photoproducts identified by LC-MS analysis. The photocatalytic mechanism has also been discussed. This work could provide new perspective that g-C3N4, as a good visible-light photocatalyst could be applied to the cleanup of environmental pesticide pollution. PMID- 25923254 TI - Autofluorescence imaging in the differential diagnosis of optic disc melanocytoma. AB - PURPOSE: Optic disc melanocytoma (ODM) is a benign tumour that usually occurs on or adjacent to the optic nerve head. The aim of the study was to evaluate fundus autofluorescence (FAF) imaging as a diagnostic tool in ODM. METHODS: Retrospective comparative case series study of six patients with ODM and a comparing group of four patients with juxtapapillary choroidal nevus (JCN) and four with juxtapapillary uveal melanoma (JUM). Clinical examination was supplemented with ultrasound B-scan examination and spectral-domain optical coherence tomography. FAF images were obtained with the 532-nm laser (Optomap P200Tx) from all patients. RESULTS: Clinical examination in the ODM group revealed a dome-shaped, darkly pigmented tumour on or adjacent to the optic disc in all patients, with a mean tumour basal dimension 1.4 mm and mean tumour thickness by ultrasonography of 1.0 mm. FAF revealed a totally hypofluorescent mass with sharply demarcated, feathery edges. No hyperfluorescent changes due to orange pigment or subretinal fluid were seen. In contrast, patients with JCN and JUM manifested focal hyperfluorescence as well as larger hyperfluorescent areas at the tumour and its borders. CONCLUSION: Fundus autofluorescence imaging is a non-invasive adjuvant tool in the differential diagnosis of ODM characterized by lack of hyperfluorescence compared to JCN and JUM. PMID- 25923255 TI - Action of hyperbaric oxygenation in the rat skin flap. AB - PURPOSE: To evaluate the morphology, necrotic area and collagen content in skin flaps of rats subjected to hyperbaric oxygenation (HBO). METHODS: Forty adult rats were divided into four groups: GEC - epilated; GE/HBO - epilated subjected to HBO; GER - epilated submitted to skin flap (2 cm in width /8 cm length in the dorsal area) and GER/HBO - epilated, subjected to skin flap and HBO. HBO (2.4 ATA) was performed for two hours during seven consecutive days. In the eighth day, the rats were anesthetized and the skin flaps were removed and separated into three portions, relative to pedicle fixation. The material fixed in 10% formalin was processed for paraffin embedding; sections were stained by H.E and subjected to picrosirius-red method. The slides examined under light microscopy for evaluation of the collagen content in polarized light microscope and ImageLab(r) software (Bio-Rad). RESULTS: The data showed larger area of necrosis and lower levels of collagen in the three regions of the GER group, whereas in the GER/HBO group the collagen content was similar to the GEC and GE/HBO groups. CONCLUSION: Hyperbaric oxygenation reduced the area of necrosis and preserved the morphology and collagen content in skin flaps of rats. PMID- 25923256 TI - Evaluation of the anti-inflammatory and analgesic effects of green tea (Camellia sinensis) in mice. AB - PURPOSE: To evaluate the anti-inflammatory and analgesic effects of green tea (Camellia sinensis) in mice. METHODS: The anti-inflammatory effect of alcoholic extracts of green tea (AE) was evaluated in a cell migration assay with four groups of six Swiss mice receiving 0.07 g/Kg or 0.14 g/Kg EA (treatment groups), saline (negative control) or 10mg/Kg indomethacin (positive control) by gavage. One hour later 300 ug carrageen an was administered intraperitoneally or subcutaneously. The analgesic effect was evaluated using four groups of six animals receiving 0.07 g/Kg or 0.14 g/Kg EA, saline or 10mg/Kg indomethacin subcutaneously, followed 30 minutes later by 1% acetic acid. RESULTS: When administered subcutaneously at either dose (0.07 g/Kg and 0.14 g/Kg), AE inhibited carrageenan-induced cell migration (p<0.05). However, when administered by gavage, only the latter (0.14 g/Kg) was efficient (p<0.05). AE at both doses (0.07 g/Kg and 0.14 g/Kg) inhibited abdominal contortions (p<0.05), but the effect was not dose-dependent. CONCLUSION: Green tea was shown to have analgesic and anti-inflammatory properties and may constitute a natural treatment option in chronic inflammatory disorders. PMID- 25923252 TI - Sphingosine-1-phosphate metabolism: A structural perspective. AB - Sphingolipids represent an important class of bioactive signaling lipids which have key roles in numerous cellular processes. Over the last few decades, the levels of bioactive sphingolipids and/or their metabolizing enzymes have been realized to be important factors involved in disease development and progression, most notably in cancer. Targeting sphingolipid-metabolizing enzymes in disease states has been the focus of many studies and has resulted in a number of pharmacological inhibitors, with some making it into the clinic as therapeutics. In order to better understand the regulation of sphingolipid-metabolizing enzymes as well as to develop much more potent and specific inhibitors, the field of sphingolipids has recently taken a turn toward structural biology. The last decade has seen the structural determination of a number of sphingolipid enzymes and effector proteins. In these terms, one of the most complete arms of the sphingolipid pathway is the sphingosine-1-phosphate (S1P) arm. The structures of proteins involved in the function and regulation of S1P are being used to investigate further the regulation of said proteins as well as in the design and development of inhibitors as potential therapeutics. PMID- 25923257 TI - Does alfa lipoic acid prevent liver from methotrexate induced oxidative injury in rats? AB - PURPOSE: To determine the antioxidant and anti-inflammatory effects of alfa lipoic acid (ALA) on the liver injury induced by methotrexate (MTX) in rats. METHODS: Thirty two rats were randomly assigned into four equal groups; control, ALA, MTX and MTX with ALA groups. Liver injury was performed with a single dose of MTX (20 mg/kg) to groups 3 and 4. The ALA was administered intraperitonealy for five days in groups 2 and 4. The other rats received saline injection. At the sixth day the rats decapitated, blood and liver tissue samples were removed for TNF-alpha, IL-1beta, malondialdehyde, glutathione, myeloperoxidase and sodium potassium-adenosine triphosphatase levels measurement and histological examination. RESULTS: MTX administration caused a significant decrease in tissue GSH, and tissue Na+, K+ ATPase activity and which was accompanied with significant increases in tissue MDA and MPO activity. Moreover the pro inflammatory cytokines (TNF-alpha, IL- beta) were significantly increased in the MTX group. On the other hand, ALA treatment reversed all these biochemical indices as well as histopathological alterations induced by MTX. CONCLUSION: Alfa lipoic acid ameliorates methotrexate induced oxidative damage of liver in rats with its anti-inflammatory and antioxidant effects. PMID- 25923258 TI - Biocompatibility and osteogenesis of the castor bean polymer doped with silica (SiO2) or barium titanate (BaTiO3) nanoparticles. AB - PURPOSE: To evaluate the biocompatibility and osteogenesis of castor oil polymer doped with SiO2 or BaTiO3 nanoparticles. METHODS: Twenty four male rats Wistar were submitted to bone defect filled with castor oil polymer. The animals were distributed in two experimental groups had been formed with 12 animals each: Group 1 - Castor oil polymer doped with 0.30 grams of SiO2 replacing 0.30 grams of CaCO3. Group 2 - Castor oil polymer doped with 0.30 grams of BaTiO3 replacing 0.30 grams of CaCO3. Euthanasia occurred 30 and 60 days after surgery and the femurs were sent to histological analysis and MEV. RESULTS: The implants were biocompatible and allowed for progressive osteogenesis through osteoconduction in both observation periods. There was significant bone neoformation at 30 and 60 days in both groups within the histomorphometric evaluation, but group 1's osteogenesis was lesser in the 30 and 60-day periods observed when compared to the animals of group 2. The MEV morphometric evaluation evidenced a lesser percentage of osseous tissue filling within the BaTiO2-doped polymer. CONCLUSION: The castor oil polymer doped with SiO2 or BaTiO3 remained biocompatible and allowed for progressive osteogenesis in both observation periods. PMID- 25923259 TI - Micronucleus test in peripheral blood of rats treated with hyperbaric oxygen after subtotal splenectomy preserving the lower pole. AB - PURPOSE: To assess the mutagenic potential of the oxygen inhalation therapy (HBO), by means of the micronucleus test, performed in peripheral blood of rats that underwent subtotal splenectomy with lower pole preservation (ESTPI), after HBO sessions or simulations. METHODS: Eighteen male Wistar rats, were distributed into three groups of six animals: group 1 - submitted to ESTPI and HBO sessions; group 2 - submitted to ESTPI and HBO simulations; group 3 - underwent cyclophosphamide administration. In groups 1 and 2, blood samples from the animals' tails were collected before surgery (T0) and immediately after the 13th HBO session or simulation (T1). In group 3, tail blood samples were collected from animals before (T0) and 24 hours after (T1) cyclophosphamide (CP) delivery. The number of micronucleated normochromatic erythrocytes (MNNCE) was determined by blind counting 2000 normochromatic erythrocytes (NCE) per animal. RESULTS: Micronuclei average after CP delivery in group 3 was higher than before its use, thus confirming the mutagenic activity of this drug (p=0.01). In groups 1 and 2, no significant difference in the average of Micronuclei was observed when comparing it to blood samples before and after the 13th HBO session or simulation. CONCLUSION: The treatment protocol used in this study did not induce Micronucleus formation in animals submitted to ESTPI and HBO treatment or simulation. PMID- 25923260 TI - Parecoxib reduces renal injury in an ischemia/reperfusion model in rats. AB - PURPOSE: To evaluate the effect of parecoxib (an NSAID) on renal function by measuring plasma NGAL (serum neutrophil gelatinase-associated lipocalin) levels in an induced-ischemia rat model. METHODS: Forty male Wistar rats were randomly assigned to one of four groups: Ischemia (I), Ischemia/parecoxib (IP), No ischemia (NI), and No-ischemia/parecoxib (NIP). Body weight, mean arterial pressure, heart rate, body temperature, NGAL levels, and renal histology were compared across groups. RESULTS: The Ischemia (I) group, which did not receive parecoxib, showed the highest NGAL levels (p=0.001), while the IP group, which received the medication, had NGAL levels similar to those of the non-ischemic (NI and NIP) groups. CONCLUSION: Parecoxib resulted in renal protection in this experimental model. PMID- 25923261 TI - Renal biomarkers of male and female Wistar rats (Rattus norvegicus) undergoing renal ischemia and reperfusion. AB - PURPOSE: To investigate biomarkers of acute renal injury in Wistar rats, subjected to left renal ischemia for 10 minutes, and then compare reperfusion at 24 hours, and at 5, 7, 14 and 21 days after the procedure. METHODS: Eight female and male rats between 60 and 81 days old were used in the Central Animal Facility of the UFMS. Assessed biomarkers included urine protein, urea, creatinine, glucose, sodium, potassium, urine alkaline phosphatase and gamma-glutamyl transferase activities, and protein-to-creatinine ratio; and in serum: urea, creatinine, sodium and potassium, fractional excretion of sodium, potassium, urine flow and creatinine clearance. RESULTS: Greater variance was observed in the parameters at 24 hours and at five days (p<0.05) after reperfusion. On the 21st day, these parameters approximated those obtained for the control group. CONCLUSIONS: Renal ischemia for 10 minutes was sufficient to raise urine levels of protein, glucose, fractional excretion of potassium, urea, creatinine clearance, urine activity of gamma-glutamyltransferase and alkaline phosphatase enzymes in the first 24 hours, up to five days after reperfusion, which may indicate risk of acute kidney injury, according to the RIFLE classification. PMID- 25923263 TI - Biocompatibility of the bacterial cellulose hydrogel in subcutaneous tissue of rabbits. AB - PURPOSE: To evaluate the biocompatibility and local sensibility reaction to bacterial cellulose hydrogel (0.8%) implanted in subcutaneous tissue of rabbits. METHODS: Fifteen New Zeland rabbits were randomly allocated into three groups: T1, 7 days, T2, 21 days, and T3, 84 days. The new material was implanted in the subcutaneous tissue of the ear; on the scalp over the periosteum; and on the outer and inner surfaces of the thighs, in the aponeurosis of the muscle. At 7, 21 and 84 postoperative days, the material was collected for histological study. The clinical signs, inflammatory response, angiogenesis and fibrogenesis were variables used for analysis of the biocompatibility and biological reactivity to BCH. Analyses were performed with an AXIO(r) Imager. The statistical tests were performed using the GraphPad Prism 5.0 program(r) RESULTS: The intensity of the inflammatory infiltrate, considering the different cell types (PMN, LMN and GC), was statistically significant, with group T1 different from groups T2 and T3 (p = 0.0124 and p <0.0001, respectively) and T2 different from the T3 group (p = 0.0007). Fibrogenesis grade 1 was the most prevalent in groups T1 (55.4%) and T2 (44.6%). The formation of neovascularization in the group was identified in 84.4% of samples. CONCLUSION: Bacterial cellulose hydrogel (0.8%) is biocompatible, integrating with the subcutaneous tissue of rabbits and inducing tissue remodeling. PMID- 25923262 TI - Mast cell concentration and skin wound contraction in rats treated with Brazilian pepper essential oil (Schinus terebinthifolius Raddi). AB - PURPOSE: To evaluate wound contraction and the concentration of mast cells in skin wounds treated with 5% BPT essential oil-based ointment in rats. METHODS: Twenty rats, male, of adult age, were submitted to skin surgery on the right (RA) and left antimeres (LA) of the thoracic region. They were divided into two groups: control (RA - wounds receiving daily topical application of vaseline and lanolin) and treated (LA - wounds treated daily with the topical ointment). The skin region with wounds were collected at days 4, 7, 14 and 21 after surgery. Those were fixed in 10% formaldehyde and later processed for paraffin embedding. Sections were obtained and stained by H.E for histopathology analysis. The degree of epithelial contraction was measured and mast cell concentration were also evaluated. RESULTS: The treated group showed higher mast cell concentrations (p<0.05) associated with increased contraction at day 7 and 14 respectively. CONCLUSION: Ointment containing 5% Brazilian pepper tree oil increases mast cell concentration and promotes skin wound contraction in rats. PMID- 25923264 TI - Structural study of endopelvic fascia in prostates of different weights. Anatomic study applied to radical prostatectomy. AB - PURPOSE: To evaluate the structure of the endopelvic fascia in prostates of different weights. METHODS: We studied 10 patients with BPH (prostates> 90 g); 10 patients with prostate adenocarcinoma (PAC) (prostates< 60 g) and five young male cadavers (control group). During the surgery a small sample of endopelvic fascia was obtained. We analyzed elastic fibers, collagen and smooth muscle. The stereological analysis was done with the Image Pro and Image J programs. Means were statistically compared using the one-way ANOVA with the Bonferroni test and a p<0.05 was considered statistically significant. RESULTS: The mean of the prostate weight was 122 g in BPH patients, 53.1g in PAC patients and 18.6g in control group. Quantitative analysis documented that there are no differences (p=0.19) in Vv of elastic fibers and in Vv of type III collagen (p=0.88) between the three groups. There was a significant difference (p=0<0.0001) in the quantification of SMC in patients with prostates > 90 g (mean=9.61%) when compared to patients with prostates < 60 g (mean=17.92%) and with the control group (mean=33.35%). CONCLUSION: There are differences in endopelvic fascia structure in prostates> 90 g, which can be an additional factor for pre-operatory evaluation of radical prostatectomy. PMID- 25923265 TI - The myth of teaching styles: What medical educators need to know [Editorial]. PMID- 25923266 TI - Malignant otitis externa. PMID- 25923267 TI - Frontal recess polyp extending to the posterior choana-a frontal recess-choanal polyp. PMID- 25923268 TI - Bilateral true vocal fold atrophy. PMID- 25923269 TI - Giant Stensen duct calculus. PMID- 25923270 TI - Schneiderian papilloma of the sinonasal tract. PMID- 25923271 TI - Perineural spread of cutaneous squamous cell carcinoma along the great auricular nerve [corrected]. PMID- 25923272 TI - Unexpected cholesteatoma in a very young child with a congenital aural duplication anomaly. PMID- 25923273 TI - Distortion-product otoacoustic emissions testing in neonates treated with an aminoglycoside in a neonatal intensive care unit. AB - We evaluated the ototoxic effect of aminoglycosides on the outer hair cells of newborns in a neonatal intensive care unit (NICU) by means of distortion-product otoacoustic emissions (DPOAE) testing. Our study population was made up of 164 newborns who were divided into three groups: group A consisted of 105 infants who were given aminoglycoside therapy (either gentamicin or amikacin, or a combination of the two) as treatment for suspected or proven bacterial infection and septic states; group B included 30 newborns who were not given an antibiotic or who were given an antibiotic other than an aminoglycoside; group C, a control group, was made up of 29 healthy neonates who were hospitalized in the well-baby nursery. All the neonates underwent DPOAE testing in both ears (the f2 primary tone was presented at 2.0, 2.5, 3.2, and 4.0 kHz). We found that 41 patients in group A (39.0%) and 13 in group B (43.3%) failed the DPOAE test in one or both ears; the difference between these two groups was not statistically significant (p = 0.673). In group C, the DPOAE fail rate was 13.8% (4 newborns). In group A, there was no statistically significant association between the pass/fail rate and the specific aminoglycoside that was administered, or in the duration of antibiotic treatment, the number of doses, and the size of the mean daily dose and the mean total dose. In clinical practice, DPOAE testing is a sensitive method of evaluating the integrity of the outer hair cells in the basal turn of the cochlea after exposure to ototoxic drugs such as aminoglycosides. However, our study did not demonstrate that the aminoglycosides had any ototoxic effect on the hearing of neonates in the NICU. PMID- 25923274 TI - Is there a relationship between myeloperoxidase activity and conductive hearing loss in chronic otitis media complicated by cholesteatoma? AB - We conducted a prospective, controlled study of patients with chronic otitis media and cholesteatoma (1) to examine the expression of myeloperoxidase (MPO) using immunohistochemical staining techniques and (2) to investigate the relationship between MPO activity and the degree of conductive hearing loss in these patients. Our study population included 51 adults-26 men and 25 women, aged 18 to 58 years (mean: 37.5)-who had been diagnosed with chronic otitis media and cholesteatoma by physical examination and computed tomography (study group). Another 30 patients-13 men and 17 women, aged 18 to 52 years (mean: 32.7)-who had chronic otitis media without cholesteatoma served as the control group. Following audiometric evaluations, all patients underwent appropriate surgery. Postoperatively, cholesteatoma samples were analyzed by immunostaining for MPO positivity as a marker for acute inflammation. We found that MPO activity was present in all 51 study patients (100%) but in only 10 controls (33.3%); the difference was statistically significant (p< 0.01). In the study group, the degree of MPO activity was slight in 6 patients (11.8%), moderate in 24 patients (47.1%), and intense in 21 patients (41.2%), while in the control group, all 10 MPO-positive cases showed only a slight degree of activity. We also found a statistically significant association in the study group between the degree of MPO activity and the degree of conductive hearing loss (chi(2) = 13.518; p < 0.001). We encourage further study of all steps in the process of cholesteatoma formation. PMID- 25923275 TI - Prophylactic antibiotic therapy for fractures of the maxillary sinus. AB - We conducted a study to examine the incidence of acute sinusitis following maxillary sinus fractures, as well as the impact of antibiotics in the postinjury period. Fifty patients who presented to our institution with a fracture of the maxillary sinus were prospectively randomized to receive either a nasal saline spray and a 3-day course of antibiotics (either amoxicillin/clavulanate or levofloxacin) or nasal saline alone; there were 25 patients in each group. After a minimum of 3 days, all patients were assessed for acute sinusitis. Follow-up data were available on 17 patients (a total of 21 fractured sinuses) in the antibiotic group (68%) and 14 patients (17 fractured sinuses) in the control group (56%). The groups were balanced in terms of demographics, location of fractures, mechanism of fracture, and time to follow-up. After 3 days, 95.23% of the fractured sinuses in the antibiotic group and 88.23% of the fractured sinuses in the control group exhibited signs or symptoms consistent with or suggestive of acute sinusitis. Very few sinuses in either group showed no evidence of sinusitis: only 1 in the antibiotic group (4.76%) and 2 in the control group (11.76%); this difference was not significant (p = 0.5768). We conclude that while the clinical rate of acute sinusitis after maxillary sinus fractures is high, a 3-day course of antibiotics is not effective in preventing its symptoms in the postinjury period. PMID- 25923276 TI - Sinonasal undifferentiated carcinoma as a third primary neoplasm: A case report and review of the literature. AB - A 71-year-old man with a history of a pituitary prolactinoma and metastatic pancreatic carcinoma presented with epistaxis, visual changes, bilateral ophthalmoplegia, involuntary closure of the left eye, and ptosis of the right eye. The patient was found to have a soft-tissue mass in the posterior nasal cavity with extension through the floor of the sella turcica, the sphenoid sinuses, cavernous sinuses, and suprasellar region. The patient was subsequently taken to the operating room. Intraoperative frozen section of the sinonasal mass demonstrated carcinoma. The final pathology of the mass revealed sinonasal undifferentiated carcinoma (SNUC)-the patient's second skull base lesion and third primary neoplasm. SNUC is a rare neoplasm of the sinonasal cavities that rapidly progresses from symptom onset to mortality in the presence of aggressive multidimensional therapies. Given its poor prognosis and possibly devastating treatments, an open discussion of treatment options between physicians and the patient is of the utmost importance. Although SNUC is rare, it is important that practicing otolaryngologists, neurosurgeons, and skull base surgeons be familiar with this disease process-especially when caring for patients with a history of a benign skull base neoplasm and concern for possible recurrence, as was the case in this report. PMID- 25923277 TI - Potentially lethal pharyngolaryngeal edema with dyspnea in adult patients with mumps: A series of 5 cases. AB - In this article we describe 5 rare cases of mumps-associated pharyngolaryngeal edema. To the best of our knowledge, this report includes the first case of mumps associated pharyngolaryngeal edema in a patient who had previously received mumps vaccination, and these cases represent the sixth report of mumps-associated pharyngolaryngeal edema in the English literature. All 5 of our patients with mumps infection were adults and manifested airway stenosis due to pharyngolaryngeal edema. This edema responded favorably to steroid treatment without tracheotomy. We conclude that a pharyngolaryngeal examination is recommended for patients with mumps infection. Steroid treatment is usually effective against pharyngolaryngeal edema; however, in certain cases tracheotomy may be inevitable. PMID- 25923278 TI - Advanced airway management teaching in otolaryngology residency programs in Canada: A survey of residents. AB - We conducted a study to assess residents' levels of comfort with advanced airway management in Canadian otolaryngology residency programs. In October 2008, an electronic questionnaire was sent to all otolaryngology residents in Canada. Responses were voluntary and anonymous. The response rate was 64.8% (94 of 145 residents). Residents were asked about the amount of teaching they received and the amount they would like to receive each year in four areas: emergency surgical airway, pediatric airway, airway trauma, and management of complications during laryngoscopy/bronchoscopy. They were also asked how comfortable they were with their current level of knowledge in these areas. Overall, residents were not comfortable with difficult airway situations, scoring a mean of 3.08 on a 5-point Likert scale. Residents were most comfortable with the emergency airway and least comfortable with the pediatric airway. Overall, residents indicated that they had not received adequate teaching on advanced airway management, and they consistently desired more. With respect to the type of instruction, most residents requested more teaching via simulations, mannequins, and cadaver or animal models. Linear regression models revealed a positive relationship between their overall comfort with airway management and the number of airway teaching hours they received. Their consensus was that formal airway training should occur during postgraduate year (PGY) 2, with refresher courses offered every 2 years. This is the first wide-scale assessment of the status of airway teaching in otolaryngology residency programs in Canada. Overall, our findings suggest that otolaryngology residents in these programs are not comfortable with advanced airway management early in their training and feel they would benefit from a significant increase in airway teaching time. Comfort levels improved with increasing levels of training such that PGY5 residents indicated they were indeed comfortable with advanced airway management. PMID- 25923279 TI - The role of MMP-2, MMP-9, and TIMP-1 in the pathogenesis of nasal polyps: Immunohistochemical assessment at eight different levels in the epithelial, subepithelial, and deep layers of the mucosa. AB - We conducted a prospective study to investigate the role of matrix metalloproteinase-2 (MMP-2), matrix metalloproteinase-9 (MMP-9), and tissue inhibitor of metalloproteinase-1 (TIMP-1) in the pathogenesis of nasal polyps. Our study group consisted of 24 patients-21 men and 3 women, aged 23 to 70 years (mean: 45.97 +/- 11.60)-with nasal polyposis who underwent functional endoscopic sinus surgery. For comparison purposes, we assembled a control group of 11 patients-6 men and 5 women, aged 18 to 56 years (mean: 29.90 +/- 14.22)-without nasal polyps who underwent septoplasty and/or rhinoplasty. We analyzed 36 polyp specimens obtained from the study group (10 from the nasal cavity, 10 from the maxillary sinus, and 16 from the ethmoid sinus) and 11 tissue specimens from the control group (each control provided 1 specimen from the inferior turbinate). We then calculated the mean number of these cells in the epithelium, subepithelial layer of the lamina propria, and the deep paraglandular layer of the mucosa. In general, we found that MMP-2, MMP-9, and TIMP-1 values were higher in the nasal polyp group. These differences became less so as patients' ages and the duration of polyps increased. We conclude that the most important role that MMP-2 plays in polyp growth may be in terms of perivascular localization and an increase in vascular permeability, which causes inflammatory cell migration and edema in the extracellular matrix. An increase in MMP-2 in glandular tissue may lead to hydrolysis of tissue matrix components. The degraded extracellular matrix may result in fibrosis of the polyps. An increase of MMP-9 in the apical part of the epithelium in the polypoid tissue of the nasal cavity, maxillary sinus, and ethmoid sinus may facilitate the epithelial and endothelial cell migration that is observed during polyp development and growth. PMID- 25923280 TI - Guidelines for squamous cell carcinoma of the head and neck: A systematic assessment of quality. AB - We conducted a study to evaluate the quality of guidelines for squamous cell carcinoma of the head and neck (SCCHN) with the exception of nasopharyngeal cancer. Electronic searches were conducted of the U.S. National Guideline Clearinghouse, the Canadian Medical Association Infobase, the Guidelines International Network, the Scottish Intercollegiate Guidelines Network, the China Biology Medicine disc, PubMed, and Embase. Two independent reviewers assessed the eligible guidelines using the Appraisal of Guidelines for Research and Evaluation II (AGREE II) instrument. The degree of agreement among these sources was evaluated by using the intraclass correlation coefficient (ICC). A total of 514 articles were found to be clinical-guideline-related, and 49 guidelines were included in our analysis. Scores were assigned for each of the AGREE II domains: scope and purpose (mean: 71.63% +/- 2.80; median: 75%; ICC: 0.76), stakeholder involvement (mean: 43.37% +/- 2.96; median: 50%; ICC: 0.93), rigor of development (mean: 45.63% +/- 3.84; median: 42%; ICC: 0.83), clarity of presentation (mean: 68.08% +/- 2.53; median: 72%; ICC: 0.85), applicability (mean: 32.41% +/- 3.03; median: 29%; ICC: 0.92), and editorial independence (mean: 42.55% +/- 4.57; median: 42%; ICC: 0.95). We considered a domain score of greater than 60% to represent an acceptable level of quality. We conclude that, overall, the quality of SCCHN guidelines is moderate in relation to international averages. Greater efforts are needed to provide high-quality guidelines that serve as a useful and reliable tool for clinical decision making in this field. PMID- 25923281 TI - Massive myiasis in an advanced metastatic neck tumor. AB - Only a small number of cases of myiasis have been previously reported in patients with a head and neck malignancy; most of these occurred in patients with primary or metastatic skin cancer. We report a case of massive Lucilia sericata myiasis in the neck of a 57-year-old man with primary squamous cell carcinoma of the larynx and hypopharynx that metastasized to the neck lymph nodes. The neck disease manifested as necrosis and skin involvement. Clinical examination revealed an extensive wound within the neck tumor at levels II and V on the right that was heavily infested with maggot larvae. Removal of larvae clusters was performed, and the isolated larvae were subsequently identified as L sericata. To the best of our knowledge, this is the first report of an infestation of L sericata myiasis in a metastasis to the neck lymph nodes. PMID- 25923282 TI - Acinic cell carcinoma of the posterior wall of the pharynx. AB - Acinic cell carcinoma accounts for approximately 2 to 6% of all salivary gland tumors. It usually originates in the parotid gland; the minor salivary glands and the upper respiratory tract are involved only infrequently. We describe a case of acinic cell carcinoma of the posterior wall of the pharynx in a 21-year-old woman. To the best of our knowledge, this is the first case of this type of carcinoma at this location to be published in the literature. The mass was excised, and the patient was referred for postoperative radiation therapy to reduce the risk of local recurrence, but she did not keep her appointment and was lost to follow-up. PMID- 25923283 TI - Conidiobolus coronatus granuloma of the right inferior turbinate: A rare presentation. AB - Fungal infections are common in tropical countries such as India. Very few clinical cases caused by the Entomophthorales Zygomycetes have been reported. Rhinofacial infection is a rare form of zygomycosis in humans, and only limited information regarding optimal treatment is available. We report here a rare case of rhinofacial Conidiobolus coronatus infection in a previously healthy 18-year old man who presented with a fungal granuloma of the right inferior turbinate and face. Diagnosis was confirmed by microbiologic culture from a tissue biopsy. The infection was successfully treated with surgery and itraconazole therapy for 12 months. The clinical presentation and treatment of this rare, chronic, indolent form of fungal infection are highlighted in this article. PMID- 25923284 TI - Biphasic synovial sarcoma of the hypopharynx. AB - Synovial sarcoma is a malignant mesenchymal neoplasm usually involving the extremities of young adults. Localization in the head and neck region is rare. Histologically, these lesions have biphasic and monophasic variants, the latter being more rare and difficult to identify. Immunohistochemistry plays a crucial role in the diagnosis. We report a case of a biphasic synovial sarcoma arising in the hypopharynx with a review of the literature concerning this rare neoplasm. PMID- 25923285 TI - Use of the chorda tympani nerve in reconstruction of the ossicular chain. AB - We conducted a study to assess the use of the chorda tympani nerve in reconstruction of the ossicular chain. We retrospectively examined the medical records of 141 patients (154 ears) who had undergone middle ear surgery with 12 months of follow-up. The study population was made up of 58 males and 83 females, aged 9 to 83 years (mean: 45). These patients were divided into three groups based on the specific type of surgery they had undergone: in 35 patients, the chorda tympani nerve was used to spring and press the auricular bone prosthesis (CTN group); in 67 patients, the tympanic membrane was used to spring and press the auricular bone prosthesis (TM group); and in 39 patients, a gelatin sponge was used to support the auricular bone prosthesis (GS group). We compared pre- and postoperative air-bone gaps (ABGs) in each group, as well as the differences between these gaps among the three groups. We found significant differences between the pre- and postoperative ABGs in all three groups (all p < 0.01). These differences were also compared between the CTN and TM groups (t = 0.41; p > 0.05), between the CTN and GS groups (t = 2.07; p < 0.05), and between the TM and GS groups (t = 2.51; p < 0.05). In the CTN group, 1 patient experienced temporary postoperative hypogeusia, and another developed a mild case of delayed facial paralysis; both patients recovered within 2 weeks. We conclude that the chorda tympani nerve can be used to repair the ossicular chain to improve hearing without causing taste and facial nerve dysfunction and without the need for a second operation. PMID- 25923286 TI - Use of tragal cartilage grafts in rhinoplasty: An anatomic study and review of the literature. AB - We conducted a cadaveric study to determine the size of cartilage grafts that can be taken from the tragus without distorting tragal anatomy. Our subjects included 7 fresh cadavers-3 male and 4 female (age at death: 61 to 87 yr). Tragal cartilage grafts were harvested while leaving the lateral 3 mm of the tragal cartilage in situ to preserve the anatomic shape of the tragus. The grafts were measured and their dimensions recorded. The craniocaudal dimensions of the tragal cartilages ranged from 15 to 30 mm (mean: 21.6), and the width of each specimen ranged from 10 to 23 mm (mean: 15.3). The thickness of the cartilage was approximately 1 mm. The grafts were slightly curved along their long axis. We also review the literature regarding the dimensions of different grafts used in rhinoplasty, knowledge of which can help in preoperative planning. Tragal cartilage grafts have been used as shield, alar contour, alar batten, lateral crural onlay, dorsal onlay, and infratip lobule grafts. When a straight and/or thick graft is needed, two strips of tragal cartilage can be sutured in a mirror image configuration. PMID- 25923287 TI - Chronic discharging ear and multiple cranial nerve pareses: A sinister liaison. PMID- 25923288 TI - Large Haller cell mucocele leading to maxillary sinusitis. PMID- 25923290 TI - Long-range correlations in glasses and glassy fluids. AB - We argue that the existence of a non-decaying part of the self-intermediate scattering function implies a small wave-vector divergence of a four-point structure factor defined in terms of the microscopic self-intermediate scattering function. This divergence indicates long-range correlations of density fluctuations in direct space. We show that a signature of the divergence and the long-range correlations can be observed in computer simulations of glasses. Interestingly, remnants of this divergence can be easily observed in computer simulations of supercooled fluids. They manifest themselves as transient dynamic correlations with a very large correlation length; much larger than the correlation length characterizing the size of dynamic heterogeneities. PMID- 25923289 TI - Parathyroid localization using 4D-computed tomography. PMID- 25923291 TI - Alcohol and other substance use, mental health treatment use, and perceived unmet treatment need: Comparison between baby boomers and older adults. AB - BACKGROUND AND OBJECTIVE: As the baby boomers age, the number of older adults with comorbid substance use and mental disorders is projected to grow. Little research has examined the potential impact of substance use on older adults' mental health treatment use and unmet treatment need. This study examined these associations among the rapidly growing population of baby boomers and their older counterparts. METHODS: Data are from the 2008 to 2012 National Survey on Drug Use and Health (NSDUH) (N = 18,443 respondents aged 50-64 and 11,191 aged 65 +). Age combined and age-stratified logistic regression analyses were used to examine relationships between alcohol, illicit drug, and tobacco use and mental health problems, treatment use, and perceived unmet treatment need, with sociodemographic characteristics and health status as covariates. RESULTS: Heavy alcohol, illicit drug, and tobacco use increased the odds of having a mental health problem in both age groups. Compared to those who used alcohol on 1-99 days during the preceding year, lifetime abstainers had significantly lower odds of having received mental health treatment in both age groups. Poorer self-rated health and past-year mental health treatment use increased the odds of perceived unmet treatment need in both age groups, while lifetime abstention in the boomers decreased the odds. CONCLUSIONS AND SCIENTIFIC SIGNIFICANCE: This study's key finding is the lower likelihood of mental health treatment use among lifetime abstainers in both age groups. Further research may identify barriers to treatment use and ways to promote use among both age groups. PMID- 25923292 TI - Indoor air bacterial communities in Hong Kong households assemble independently of occupant skin microbiomes. AB - More than in any other habitat, humans exert a large influence on microbial communities indoors. Frequent contact between occupant skin and indoor surfaces causes indoor surface microbial communities to be largely assembled from and thus closely resemble occupant skin microbiomes. While indoor air and dust are known to also contain many human-associated taxa, household air communities have not yet been directly compared with occupant skin microbiomes. We sampled microorganisms from air, surfaces and occupant skin in 19 Hong Kong households and used Illumina sequencing of the V4 hypervariable region of the 16S rRNA gene to investigate the dispersal relationships between the bacterial communities at each site. Our results confirmed that indoor surfaces bear the 'bacterial fingerprint' of household occupant skin. However, while air communities contained abundant human-associated taxa and were household specific, air communities in each household did not resemble occupant skin from that household any more than occupant skin from other households. Our results suggest that, at least in Hong Kong, indoor air bacterial communities may be assembled largely from outdoor air and occupant body sites other than skin, and unlike surface communities do not harbour the occupants' skin 'bacterial fingerprint'. PMID- 25923293 TI - Nepalese primiparous mothers' knowledge of newborn care. AB - A cross-sectional study was carried out to explore the knowledge level of newborn care and to investigate the relationship between newborn-care knowledge and selected demographic variables among primiparous mothers. It was carried in outpatient department of a maternity and women's hospital in Kathmandu, Nepal with 276 primiparous mothers between 38 and 42 weeks of gestation. Data were collected during the antenatal period with using two instruments: the Newborn care Knowledge Questionnaire and State-Trait Anxiety Inventory for Adults. Participants had a moderate level of knowledge on newborn care (56%), and among its four components, participants had lowest knowledge in breastfeeding (44%) and adequate knowledge (78%) of immunization. Maternal education and socioeconomic status had a significant, positive association with newborn-care knowledge. Newborn-care knowledge was strongly predicted by anxiety. This is the first study to examine the maternal levels of knowledge of newborn care in Nepal. This study identified specific knowledge gaps in newborn care among primiparous mothers. Moreover, the results suggest the need of maternal-education programs in improving the health and well-being of mothers and newborns. PMID- 25923294 TI - Real-time direct cell concentration and viability determination using a fully automated microfluidic platform for standalone process monitoring. AB - The industrial production of cells has a large unmet need for greater process monitoring, in addition to the standard temperature, pH and oxygen concentration determination. Monitoring the cell health by a vast range of fluorescence cell based assays can greatly improve the feedback control and thereby ensure optimal cell production, by prolonging the fermentation cycle and increasing the bioreactor output. In this work, we report on the development of a fully automated microfluidic system capable of extracting samples directly from a bioreactor, diluting the sample, staining the cells, and determining the total cell and dead cells concentrations, within a time frame of 10.3 min. The platform consists of custom made stepper motor actuated peristaltic pumps and valves, fluidic interconnections, sample to waste liquid management and image cytometry based detection. The total concentration of cells is determined by brightfield microscopy, while fluorescence detection is used to detect propidium iodide stained non-viable cells. This method can be incorporated into facilities with bioreactors to monitor the cell concentration and viability during the cultivation process. Here, we demonstrate the microfluidic system performance by monitoring in real time the cell concentration and viability of yeast extracted directly from an in-house made bioreactor. This is the first demonstration of using the Dean drag force, generated due to the implementation of a curved microchannel geometry in conjunction with high flow rates, to promote passive mixing of cell samples and thus homogenization of the diluted cell plug. The autonomous operation of the fluidics furthermore allows implementation of intelligent protocols for administering air bubbles from the bioreactor in the microfluidic system, so that these will be guided away from the imaging region, thereby significantly improving both the robustness of the system and the quality of the data. PMID- 25923295 TI - Application of microencapsulated essential oils in cosmetic and personal healthcare products - a review. AB - Nowadays, the consumers around the world are increasingly focused on health and beauty. The renewed consumer interest in natural cosmetic products creates the demand for new products and reformulated others with botanical and functional ingredients. In cosmetic products, essential oils (EOs) play a major role as fragrance ingredients. They can optimize its proprieties and preservation, as well as the marketing image of the final product. Microencapsulation of EOs can protect and prevent the loss of volatile aromatic ingredients and improve the controlled release and stability of this core materials. The importance of EOs for cosmetic industry and its microencapsulation was reviewed in this study. Also a briefly introduction about the preparation of microparticles was presented. Some of the most important and usual microencapsulation techniques of EOs, as well as the conventional encapsulating agents, were discussed. Despite the fact that microencapsulation of EOs is a very promising and extremely attractive application area for cosmetic industry, further basic research needs to be carried out, for a better understanding of the biofunctional activities of microencapsulated EOs and its release modulation, as well as the effects of others cosmetic ingredients and the storage time in the microparticles properties. PMID- 25923298 TI - The "mental feature" in mental illness: difficulties that this reality poses for diagnosis and classification. AB - Four points are considered in this article. In the first place, it is argued that the "settings" of psychiatric care express the need to respond to the degree of decrease in personal freedom of the patient. Then, the issue of how "the mental feature" of the mental pathology has been recognized and categorized since the 18th century is examined, pointing out the difficulties involved in considering the mental nature of the subject of psychiatry. In the third place, the issue of how current systems of diagnosis and classification are posed regarding this reality is briefly looked at. Finally, the characteristics of a working hypothesis that allows organizing consistent clinical facts providing a heuristic perspective are analyzed. PMID- 25923299 TI - Systematic review of the prevalence of bipolar disorder and bipolar spectrum disorders in population-based studies. AB - This paper describes the findings of a systematic literature review aimed at providing an overview of the lifetime prevalence of bipolar disorder and bipolar spectrum disorders in population-based studies. Databases MEDLINE, ProQuest, Psychnet, and Web of Science were browsed for papers published in English between 1999 and May 2012 using the following search string: bipolar disorders OR bipolar spectrum disorders AND prevalence OR cross-sectional OR epidemiology AND population-based OR non-clinical OR community based. The search yielded a total of 434 papers, but only those published in peer-reviewed journals and with samples aged >= 18 years were included, resulting in a final sample of 18 papers. Results revealed rather heterogeneous findings concerning the prevalence of bipolar disorders and bipolar spectrum disorders. Lifetime prevalence of bipolar disorder ranged from 0.1 to 7.5%, whereas lifetime prevalence of bipolar spectrum disorders ranged from 2.4 to 15.1%. Differences in the rates of bipolar disorder and bipolar spectrum disorders may be related to the consideration of subthreshold criteria upon diagnosis. Differences in the prevalence of different subtypes of the disorder are discussed in light of diagnostic criteria and instruments applied. PMID- 25923296 TI - Use of both cumulus cells' transcriptomic markers and zona pellucida birefringence to select developmentally competent oocytes in human assisted reproductive technologies. AB - BACKGROUND: Selection of the best oocyte for subsequent steps of fertilization and embryo transfer was shown to be the crucial step in human infertility treatment procedure. Oocyte selection using morphological criteria mainly Zona pellucida (ZP) has been the gold standard method in assisted reproductive technologies (ART) clinics, but this selection approach has limitations in terms of accuracy, objectivity and constancy. Recent studies using OMICs-based approaches have allowed the identification of key molecular markers that quantitatively and non-invasively predict the oocyte quality for higher pregnancy rates and efficient infertility treatment. These biomarkers are a valuable reinforcement of the morphological selection criteria widely used in in vitro fertilization (IVF) clinics. In this context, this study was designed to investigate the relationship between transcriptomic predictors of oocyte quality found by our group and the conventional morphological parameters of oocyte quality mainly the ZP birefringence. RESULTS: Microarray data revealed that 48 and 27 differentially expressed candidate genes in cumulus cells (CCs) were respectively overexpressed and underexpressed in the ZGP (Zona Good Pregnant) versus ZBNP (Zona Bad Non Pregnant) groups. More than 70% of previously reported transcriptomic biomarkers of oocyte developmental competence were confirmed in this study. The analysis of possible association between ZP birefringence versus molecular markers approach showed an absence of correlation between them using the current set of markers. CONCLUSIONS: This study suggested a new integrative approach that matches morphological and molecular approaches used to select developmentally competent oocytes able to lead to successful pregnancy and the delivery of healthy baby. For each ZP birefringence score, oocytes displayed a particular CCs' gene expression pattern. However, no correlations were found between the 7 gene biomarkers of oocyte developmental potential and the ZP birefringence score. Further studies using larger lists of candidate markers are required to identify suitable genes that are highly correlated with the morphological criteria, and therefore able to reinforce the accuracy of oocyte selection and the effectiveness of infertility treatment. PMID- 25923300 TI - Association between anxiety symptoms and problematic alcohol use in adolescents. AB - BACKGROUND: Anxiety disorders are highly prevalent, affecting approximately 10% of individuals throughout life; its onset can be detected since early childhood or adolescence. Studies in adults have shown that anxiety disorders are associated with alcohol abuse, but few studies have investigated the association between anxiety symptoms and problematic alcohol use in early ages. OBJECTIVE: To evaluate if anxiety symptoms are associated with problematic alcohol use in young subjects. METHODS: A total of 239 individuals aged 10-17 years were randomly selected from schools located in the catchment area of Hospital de Clinicas de Porto Alegre. The Screen for Child Anxiety-Related Emotional Disorders (SCARED) was used to evaluate the presence of anxiety symptoms, and the Alcohol, Smoking and Substance Involvement Screening Test (ASSIST), to evaluate alcohol use. RESULTS: One hundred twenty-seven individuals (53.1% ) reported having already used alcohol. Of these, 14 individuals showed problematic alcohol use (5.8% ). There was no association between lifetime use of alcohol and anxiety symptoms, but mean SCARED scores in individuals with problematic alcohol use was higher if compared to those without problematic use, even after adjustment for age and gender (29.9+/-8.5 vs. 23.7+/-11.8, p < 0.001). CONCLUSIONS: Despite the limitation of a cross-sectional design, our study suggests that anxiety symptoms are associated with problematic alcohol use early in life. PMID- 25923301 TI - Impairment in psychosocial functioning in patients with different subtypes of eating disorders. AB - OBJECTIVE: To examine psychosocial functioning in eating disorder (ED) patients with restrictive and purgative subtypes. METHOD: Forty-four adult female patients with a diagnosis of ED were divided into restrictive (RP) and purgative (PP) groups according the presence of purgative symptoms. Functioning was assessed using the Functioning Assessment Short Test (FAST) and the Global Assessment of Functioning Scale (GAF). RESULTS: No differences were found in total FAST scores or in specific domains between the RP (39.58+/-11.92) and PP (45.75+/-11.75) groups (p = 0.19). However, PP showed more severe functional impairment than RP in the financial domain (p < 0.01). There were no differences in comorbidity with mood disorders, depressive symptoms, or general psychiatric symptoms between the two ED subtypes. CONCLUSIONS: The similarities found between PP and PR in overall functioning and in autonomy, cognition, work, interpersonal relationships, and leisure seem to reflect the use of an objective scale that corresponds to the clinical impression. In fact, the assessment of psychosocial functioning in ED patients using self-report instruments requires careful consideration because results may reflect the egosyntonic nature of symptoms commonly observed in these patients, particularly in the restrictive subtype. PMID- 25923302 TI - Prevalence of body image dissatisfaction and associated factors among physical education students. AB - OBJECTIVE: To determine the prevalence of and factors associated with body image dissatisfaction among physical education students enrolled in a public university. METHODS: This study evaluated 236 students and assessed body image perception (silhouette scale), sociodemographic variables (sex, age, parental education, marital status, university course, work, living arrangement, study shift, and income), physical activity level (International Physical Activity Questionnaire - Short Version), dietary habits, tobacco use, excessive intake of alcohol (questions from the tobacco, alcohol and drugs, and nutrition domains of the FANTASTIC instrument), and nutritional status (body mass index [BMI]). Descriptive analysis, the chi-square test, Fisher's exact test, and crude and adjusted multinomial regression were used. RESULTS: The prevalence of body image dissatisfaction was 69.5%; 44.1% were dissatisfied with excess weight. BMI >= 25.0 kg/m2 was associated with dissatisfaction with excess weight; factors associated with dissatisfaction with slimness were being male, eating an unhealthy diet, and smoking tobacco. CONCLUSION: Our findings suggest that female college students with a BMI >= 25.0 kg/m2 are more likely to present dissatisfaction with excess weight. Being male, eating an unhealthy diet, engaging in physical activity for < 739.61 min/week and smoking tobacco were the variables associated with dissatisfaction with thinness. PMID- 25923303 TI - Epidemiological profile of suicide in the Santa Catarina Coal Mining Region from 1980 to 2007. AB - BACKGROUND: Suicide is a public health problem worldwide. Estimates have indicated that over 1 million people commit suicide every year all over the world. Brazil has a moderate suicide death rate (4.1 per 100,000 inhabitants), but the fact that it is a large country leads to the coexistence of diverse characteristics and levels of development across the different Brazilian regions. In this sense, the South region has been shown to present suicide rates above the national average. OBJECTIVE: To estimate the profile of suicide in municipalities comprising the Santa Catarina Coal Mining Region from 1980 to 2007. METHODS: This ecological, time-series, descriptive study sought to characterize epidemiological aspects related to suicide method, marital status, sex, age, and occupation in the municipalities of the region in the years 1980 to 2007. RESULTS: A total of 474 suicides occurred in the period, yielding a mean death rate of 10.83 per 100,000 inhabitants. There was a predominance of males, at a 5:1 ratio, and a peak rate in the 55-64-year age group (11.31 per 100,000 inhabitants). The suicide method most commonly used was hanging (72%) and the most frequent occupation was hard labor work (11.60%); in relation to marital status, married subjects (48%) were the ones with the highest rates of suicide. CONCLUSIONS: The Santa Catarina Coal Mining Region has suicide mortality rates above the national average. This study highlights specific characteristics of suicide in the region and may contribute to the development of preventive measures. PMID- 25923304 TI - Transdiagnostic treatment using a unified protocol: application for patients with a range of comorbid mood and anxiety disorders. AB - OBJECTIVE: To evaluate the effectiveness of a unified cognitive-behavioral therapy protocol for group treatment of patients with a range of comorbid mood and anxiety disorders. METHODS: In this open-trial study, the unified protocol was followed for the psychotherapeutic treatment of 16 patients with comorbid mood and anxiety disorders, confirmed by the Mini International Neuropsychiatric Interview. Beck Depression and Anxiety Inventories, the World Health Organization Quality of Life evaluation instrument, and the ARIZONA scale of sexual function were used to evaluate progress in patients throughout the therapeutic process. RESULTS: All patients showed unipolar depressive disorder. Comorbidity with anxiety disorders was distributed as follows: generalized anxiety disorder, 13 (81.3%); panic disorder, 3 (18.8%); social anxiety disorder, 1 (6.3%); and post traumatic stress disorder, 1 (6.3%). Improvement was observed in the signs and symptoms of depression (F = 78.62, p < 0.001) and anxiety (F = 19.64, p < 0.001), overall quality of life (F = 39.72, p < 0.001), physical domain (F = 28.15, p < 0.001)), psychological variables (F = 9.90, p = 0.007), social functioning (F = 36.86, p < 0.001), environmental variables (F = 27.63, p < 0.001), and sexuality (F = 13.13; p < 0.005). All parameters showed highly significant correlations (p < 0.01). CONCLUSION: An effort to establish one unified treatment protocol for a whole family of emotional disorders (primarily mood and anxiety disorders) showed benefits in the field of clinical psychology and for the treatment of patients. No other data were found in the literature describing the implementation of the unified protocol in a transdiagnostic group. Our results revealed statistically significant improvement in all variables, suggesting that the protocol proposed can become an important tool to improve quality of life, sexuality, and anxiety/depression symptoms in patients with different diagnoses. PMID- 25923305 TI - Mood self-assessment in bipolar disorder: a comparison between patients in mania, depression, and euthymia. AB - BACKGROUND: Some studies indicate that mood self-assessment is more severely impaired in patients with bipolar disorder in a manic episode than in depression. OBJECTIVES: To investigate variations in mood self-assessment in relation to current affective state in a group of individuals with bipolar disorder. METHODS: A total of 165 patients with a diagnosis of bipolar disorder type I or type II had their affective state assessed using the Clinical Global Impressions Scale for use in bipolar illness (CGI-BP), the Positive and Negative Syndrome Scale (PANSS), and the Global Assessment of Functioning (GAF). In addition, participants completed a self-report visual analog mood scale (VAMS). Patients were divided into three groups (euthymia, mania, and depression) and compared with regard to VAMS results. RESULTS: Manic patients rated their mood similarly to patients in euthymia in 14 out of 16 items in the VAMS. By contrast, depressed patients rated only two items similarly to euthymic patients. CONCLUSION: Patients with bipolar disorder in mania, but not those in depression, poorly evaluate their affective state, reinforcing the occurrence of insight impairment in the manic syndrome. PMID- 25923306 TI - The use of antidepressants in medicine. PMID- 25923307 TI - Why geodiversity matters in valuing nature's stage. AB - Geodiversity--the variability of Earth's surface materials, forms, and physical processes-is an integral part of nature and crucial for sustaining ecosystems and their services. It provides the substrates, landform mosaics, and dynamic physical processes for habitat development and maintenance. By determining the heterogeneity of the physical environment in conjunction with climate interactions, geodiversity has a crucial influence on biodiversity across a wide range of scales. From a literature review, we identified the diverse values of geodiversity; examined examples of the dependencies of biodiversity on geodiversity at a site-specific scale (for geosites <1 km(2) in area); and evaluated various human-induced threats to geosites and geodiversity. We found that geosites are important to biodiversity because they often support rare or unique biota adapted to distinctive environmental conditions or create a diversity of microenvironments that enhance species richness. Conservation of geodiversity in the face of a range of threats is critical both for effective management of nature's stage and for its own particular values. This requires approaches to nature conservation that integrate climate, biodiversity, and geodiversity at all spatial scales. PMID- 25923308 TI - Poplar trees for phytoremediation of high levels of nitrate and applications in bioenergy. AB - The utilization of high amounts of nitrate fertilizers for crop yield leads to nitrate pollution of ground and surface waters. In this study, we report the assimilation and utilization of nitrate luxuriant levels, 20 times more than the highest N fertilizer application in Europe, by transgenic poplars overexpressing a cytosolic glutamine synthetase (GS1). In comparison with the wild-type controls, transgenic plants grown under high N levels exhibited increased biomass (171.6%) and accumulated higher levels of proteins, chlorophylls and total sugars such as glucose, fructose and sucrose. These plants also exhibited greater nitrogen-use efficiency particularly in young leaves, suggesting that they are able to translocate most of the resources to the above-ground part of the plant to produce biomass. The transgenic poplar transcriptome was greatly affected in response to N availability with 1237 genes differentially regulated in high N, while only 632 genes were differentially expressed in untransformed plants. Many of these genes are essential in the adaptation and response against N excess and include those involved in photosynthesis, cell wall formation and phenylpropanoid biosynthesis. Cellulose production in the transgenic plants was fivefold higher than in control plants, indicating that transgenic poplars represent a potential feedstock for applications in bioenergy. In conclusion, our results show that GS transgenic poplars can be used not only for improving growth and biomass production but also as an important resource for potential phytoremediation of nitrate pollution. PMID- 25923309 TI - Hierarchical graphene/metal grid structures for stable, flexible transparent conductors. AB - We report an experimental study on the fabrication and characterization of hierarchical graphene/metal grid structures for transparent conductors. The hierarchical structure allows for uniform and local current conductivity due to the graphene and exhibits low sheet resistance because the microscale silver grid serves as a conductive backbone. Our samples demonstrate 94% diffusive transmission with a sheet resistance of 0.6 Omega/sq and a direct current to optical conductivity ratio sigmadc/sigmaop of 8900. The sheet resistance of the hierarchical structure may be improved by over 3 orders of magnitude and with little decrease in transmission compared with graphene. Furthermore, the graphene protects the silver grid from thermal oxidation and better maintains the sheet resistance of the structure at elevated temperature. The graphene also strengthens the adhesion of the metal grid with the substrate such that the structure is more resilient under repeated bending. PMID- 25923310 TI - Cytokine stimulation of MUC4 expression in human female reproductive tissue carcinoma cell lines and endometrial cancer. AB - MUC4, a transmembrane glycoprotein, interferes with cell adhesion, and promotes EGFR signaling in cancer. Studies in rat models have demonstrated steroid hormonal regulation of endometrial MUC4 expression. In this study, qRT-PCR screening of mouse tissues determined that Muc4 mRNA also was robustly expressed in mouse uteri. Previous studies from our labs have demonstrated MUC4 mRNA was expressed at levels <1% of MUC1 mRNA in human endometrium and endometriotic tissue. Multiple human endometrial adenocarcinoma cell lines were assayed for MUC4 mRNA expression revealing extremely low basal expression in the Ishikawa, RL 95-2, AN3CA, and KLE lines. Moderate to high expression was observed in HEC50 and HEC-1A cells. MUC4 mRNA expression was not affected by progesterone and/or estrogen treatment, but was greatly stimulated at both mRNA and protein levels by proinflammatory cytokines (IFN-gamma and TNF-alpha), particularly when used in combination. In endometrial tissue, MUC4 mRNA levels did not change significantly between normal or cancerous samples; although, a subset of patients with grade 1 and 2 tumors displayed substantially higher expression. Likewise, immunostaining of human endometrial adenocarcinoma tissues revealed little to no staining in many patients (low MUC4), but strong staining in some patients (high MUC4) independent of cancer grade. In cases where staining was observed, it was heterogeneous with some cells displaying robust MUC4 expression and others displaying little or no staining. Collectively, these observations demonstrate that while MUC4 is highly expressed in the mouse uterus, it is not a major mucin in normal human endometrium. Rather, MUC4 is a potential marker of endometrial adenocarcinoma in a subset of patients. PMID- 25923311 TI - Peptide macrocycles featuring a backbone secondary amine: a convenient strategy for the synthesis of lipidated cyclic and bicyclic peptides on solid support. AB - A convenient strategy for the on-resin synthesis of macrocyclic peptides (3- to 13-mers) via intramolecular halide substitution by a diamino acid is described. The method is compatible with standard Fmoc/tBu SPPS and affords a tail-to-side chain macrocyclic peptide featuring an endocyclic secondary amine. This functional group is still reactive toward acylation, allowing for the continuation of the synthesis. An application to the synthesis of lipidated cyclic and bicyclic antimicrobial peptides is presented. PMID- 25923313 TI - Process-directed self-assembly of block copolymers: a computer simulation study. AB - The free-energy landscape of self-assembling block copolymer systems is characterized by a multitude of metastable minima and concomitant protracted relaxation times of the morphology. Tailoring rapid changes (quench) of thermodynamic conditions, one can reproducibly trap the ensuing kinetics of self assembly in a specific metastable state. To this end, it is necessary to (1) control the generation of well-defined, highly unstable states and (2) design the unstable state such that the ensuing spontaneous kinetics of structure formation reaches the desired metastable morphology. This process-directed self-assembly provides an alternative to fine-tuning molecular architecture by synthesis or blending, for instance, in order to fabricate complex network structures. Comparing our simulation results to recently developed free-energy techniques, we highlight the importance of non-equilibrium molecular conformations in the starting state and motivate the significance of the local conservation of density. PMID- 25923312 TI - Magnetoreception in the wood mouse (Apodemus sylvaticus): influence of weak frequency-modulated radio frequency fields. AB - The mammalian magnetic sense is predominantly studied in species with reduced vision such as mole-rats and bats. Far less is known about surface-dwelling (epigeic) rodents with well-developed eyes. Here, we tested the wood mouse Apodemus sylvaticus for magnetoreception using a simple behavioural assay in which mice are allowed to build nests overnight in a visually symmetrical, circular arena. The tests were performed in the ambient magnetic field or in a field rotated by 90 degrees . When plotted with respect to magnetic north, the nests were bimodally clustered in the northern and southern sectors, clearly indicating that the animals used magnetic cues. Additionally, mice were tested in the ambient magnetic field with a superimposed radio frequency magnetic field of the order of 100 nT. Wood mice exposed to a 0.9 to 5 MHz frequency sweep changed their preference from north-south to east-west. In contrast to birds, however, a constant frequency field tuned to the Larmor frequency (1.33 MHz) had no effect on mouse orientation. In sum, we demonstrated magnetoreception in wood mice and provide first evidence for a radical-pair mechanism in a mammal. PMID- 25923314 TI - Rapid responses of mesophyll conductance to changes of CO2 concentration, temperature and irradiance are affected by N supplements in rice. AB - Photosynthesis in C3 plants is significantly limited by mesophyll conductance (gm ), which can vary with leaf anatomical traits and nitrogen (N) supplements. Several studies have investigated the response of gm to N supplements; however, none examined the implications of N supplements on the response of gm to rapid environmental changes. Here we investigated the effect of N supplement on gm and the response of gm to change of CO2 , temperature and irradiance in rice. High N supplement (HN) increased mesophyll cell wall surface area and chloroplast surface area exposed to intercellular airspace per leaf area, and reduced cell wall thickness. These changes resulted in increased gm . The gm of leaves with HN was more sensitive to changes in CO2 concentration, temperature and irradiance. The difference in leaf structural features between low N supplement and HN indicates that a rapid change in gm is related to the regulation of diffusion through biological membranes rather than leaf structural features. These results will contribute to an understanding of the determinants of gm response to rapid changes in environmental factors. PMID- 25923316 TI - Influence of Amino Acid Compositions and Peptide Profiles on Antioxidant Capacities of Two Protein Hydrolysates from Skipjack Tuna (Katsuwonus pelamis) Dark Muscle. AB - Influence of amino acid compositions and peptide profiles on antioxidant capacities of two protein hydrolysates from skipjack tuna (Katsuwonus pelamis) dark muscle was investigated. Dark muscles from skipjack tuna were hydrolyzed using five separate proteases, including pepsin, trypsin, Neutrase, papain and Alcalase. Two hydrolysates, ATH and NTH, prepared using Alcalase and Neutrase, respectively, showed the strongest antioxidant capacities and were further fractionated using ultrafiltration and gel filtration chromatography. Two fractions, Fr.A3 and Fr.B2, isolated from ATH and NTH, respectively, showed strong radical scavenging activities toward 2,2-diphenyl-1-picrylhydrazyl radicals (EC50 1.08% +/- 0.08% and 0.98% +/- 0.07%), hydroxyl radicals (EC50 0.22% +/- 0.03% and 0.48% +/- 0.05%), and superoxide anion radicals (EC50 1.31% +/- 0.11% and 1.56% +/- 1.03%) and effectively inhibited lipid peroxidation. Eighteen peptides from Fr.A3 and 13 peptides from Fr.B2 were isolated by reversed phase high performance liquid chromatography, and their amino acid sequences were determined. The elevated antioxidant activity of Fr.A3 might be due to its high content of hydrophobic and aromatic amino acid residues (181.1 and 469.9 residues/1000 residues, respectively), small molecular sizes (3-6 peptides), low molecular weights (524.78 kDa), and amino acid sequences (antioxidant score 6.11). This study confirmed that a smaller molecular size, the presence of hydrophobic and aromatic amino acid residues, and the amino acid sequences were the key factors that determined the antioxidant activities of the proteins, hydrolysates and peptides. The results also demonstrated that the derived hydrolysates and fractions from skipjack tuna (K. pelamis) dark muscles could prevent oxidative reactions and might be useful for food preservation and medicinal purposes. PMID- 25923315 TI - Anti-Inflammatory and Analgesic Effects of the Marine-Derived Compound Excavatolide B Isolated from the Culture-Type Formosan Gorgonian Briareum excavatum. AB - In recent years, several marine-derived compounds have been clinically evaluated. Diterpenes are secondary metabolites from soft coral that exhibit anti inflammatory, anti-tumor and cytotoxic activities. In the present study, we isolated a natural diterpene product, excavatolide B, from cultured Formosan gorgonian Briareum excavatum and investigated its anti-inflammatory activities. We found that excavatolide B significantly inhibited the mRNA expression of the proinflammatory mediators, inducible nitric oxide synthase (iNOS) and cyclooxygenase-2 (COX-2), in lipopolysaccharide (LPS)-challenged murine macrophages (RAW 264.7). We also examined the anti-inflammatory and anti nociceptive effects of excavatolide B on intraplantar carrageenan-induced inflammatory responses. Excavatolide B was found to significantly attenuate carrageenan-induced nociceptive behaviors, mechanical allodynia, thermal hyperalgesia, weight bearing deficits and paw edema. In addition, excavatolide B inhibited iNOS, as well as the infiltration of immune cells in carrageenan induced inflammatory paw tissue. PMID- 25923317 TI - Functional diversity of anti-lipopolysaccharide factor isoforms in shrimp and their characters related to antiviral activity. AB - Anti-lipopolysaccharide factor (ALF) is a small protein with broad-spectrum antimicrobial activity, which has potential application in the disease control. Previously, we isolated seven ALF isoforms from the Chinese shrimp Fenneropenaeus chinensis. In the present study, their distributions in tissues of shrimp were analyzed and the data showed that different isoforms had different expression profiles, which suggested that they might have different functions. Then, the functions of different isoforms were studied by analyzing the antibacterial and antiviral activities of the functional domain of ALFs, the LPS-binding domain (LBD), which were synthesized by chemical methods. Different ALFs showed distinct antibacterial and antiviral activities, which were consistent with their diverse tissue distribution patterns. Sequence analysis on the LBD domain of different isoforms revealed that an identical lysine residue site was specifically conserved in peptides with anti-WSSV activity. In order to confirm whether this lysine residue is critical to the antiviral activity of the peptide, new peptides were synthesized by changing residues at this site. Changing the lysine residue at the specific site to other amino acid residue, the antiviral activity of the peptide apparently decreased. While replacing other residue with a lysine residue at this site in LBD peptide without anti-WSSV activity, the peptide will obtain the antiviral activity to WSSV. These results not only showed us a comprehensive understanding on the function of ALFs from F. chinensis, but also provided clues for the development of ALFs as potential therapeutic drugs to WSSV. PMID- 25923318 TI - Detecting bit-flip errors in a logical qubit using stabilizer measurements. AB - Quantum data are susceptible to decoherence induced by the environment and to errors in the hardware processing it. A future fault-tolerant quantum computer will use quantum error correction to actively protect against both. In the smallest error correction codes, the information in one logical qubit is encoded in a two-dimensional subspace of a larger Hilbert space of multiple physical qubits. For each code, a set of non-demolition multi-qubit measurements, termed stabilizers, can discretize and signal physical qubit errors without collapsing the encoded information. Here using a five-qubit superconducting processor, we realize the two parity measurements comprising the stabilizers of the three-qubit repetition code protecting one logical qubit from physical bit-flip errors. While increased physical qubit coherence times and shorter quantum error correction blocks are required to actively safeguard the quantum information, this demonstration is a critical step towards larger codes based on multiple parity measurements. PMID- 25923320 TI - 3D hydrodynamic interactions lead to divergences in 2D diffusion. AB - We investigate the influence of 3D hydrodynamic interactions on confined colloidal suspensions, where only the colloids are restricted to one or two dimensions. In the absence of static interactions among the colloids, i.e., an ideal gas of colloidal particles with a finite hydrodynamic radius, we find a divergent collective diffusion coefficient. The origin of the divergence is traced back to the dimensional mismatch of 3D hydrodynamic interactions and the colloidal particles moving only in 1D or 2D. Our results from theory are confirmed by Stokesian dynamics simulations and supported by light scattering observational data for particles at a fluid interface. PMID- 25923319 TI - Remodeling of RecG Helicase at the DNA Replication Fork by SSB Protein. AB - The RecG DNA helicase a key player in stalled replication fork rescue. The single stranded DNA binding protein (SSB) participates in this process, but its role in the interaction of RecG with the fork remains unclear. We used atomic force microscopy (AFM) to visualize the interaction of RecG with a fork DNA in the presence of SSB. We discovered that SSB enhances RecG loading efficiency onto the DNA fork by threefold. Additionally, SSB interacts with RecG leading to the RecG remodeling. As a result, RecG separates from the fork, but remains bound to the DNA duplex. Moreover, in this new binding mode RecG is capable of translocation along the parental duplex DNA. We propose a model of RecG interaction with the replication fork involving two RecG binding modes. SSB plays the role of a remodeling factor defining the mode of RecG binding to the fork mediated by the SSB C-terminus. In the translocating mode, RecG remains in the vicinity of the fork and is capable of initiating the fork regression. Our results afford novel mechanistic insights into RecG interaction with the replication fork and provide the basis for further structural studies. PMID- 25923321 TI - Aerobic Exercise Promotes a Decrease in Right Ventricle Apoptotic Proteins in Experimental Cor Pulmonale. AB - Pulmonary arterial hypertension is characterized by progressive increases in resistance and pressure in the pulmonary artery and Cor pulmonale. The effect of exercise on hydrogen peroxide-dependent signaling in the right ventricle (RV) of Cor pulmonale rats was analyzed. Rats were divided into sedentary control (SC), sedentary monocrotaline (SM), trained control (TC), and trained monocrotaline (TM) groups. Rats underwent exercise training (60% of VO2 max) for 5 weeks, with 3 weeks after monocrotaline injection (60 mg/kg intraperitoneally). Pulmonary resistance was enhanced in SM (2.0-fold) compared with SC. Pulmonary artery pressure was increased in SM (2.7-fold) and TM (2.6-fold) compared with their respective controls (SC and TC). RV hypertrophy indexes increased in SM compared with SC. Hydrogen peroxide was higher in SM (1.7-fold) than SC and was reduced by 47% in TM compared with SM. p-Akt was increased in TM (2.98-fold) compared with SM. The Bax/Bcl-2 ratio and caspase 3 were also increased (2.9-fold and 3.9-fold, respectively) in SM compared with SC. Caspase 3 was decreased in TM compared with SM (P < 0.05). Therefore, exercise training promoted a beneficial response by decreasing hydrogen peroxide concentrations, and consequently, apoptotic signaling in RV. PMID- 25923322 TI - Tripeptide SQL Inhibits Platelet Aggregation and Thrombus Formation by Affecting PI3K/Akt Signaling. AB - Centipede has been prescribed for the treatment of cardiovascular diseases in Asian countries for several hundred years. Previously, a new antiplatelet tripeptide SQL (H-Ser-Gln-Leu-OH) was isolated and characterized from centipede. In this study, we investigated its antithrombotic activities in vivo and underlying mechanism. It was found that SQL inhibited platelet aggregation induced by adenosine diphosphate, thrombin, epinephrine, and collagen and attenuated thrombus formation in both the ferric chloride-induced arterial thrombosis model and arteriovenous shunt thrombosis model in rats. It did not prolong the bleeding time in mice even at the dose of 10 mg/kg that showed potent antithrombosis effects. Molecular docking revealed that SQL binds PI3Kbeta with the binding free energy of -24.341 kcal/mol, which is close to that of cocrystallized ligand (-24.220 kcal/mol). Additionally, SQL displayed inhibition on the late (180 seconds) but did not influence the early (60 seconds) Akt Ser473 phosphorylation in the immunoblot assay. These results suggest that SQL inhibits thrombus formation in vivo and that SQL inhibits PI3K-mediated signaling or even the PI3K itself in platelets. This study may help elucidate the mechanism for centipede treating cardiovascular diseases. PMID- 25923323 TI - New Mechanism-based Approaches to Ablating Persistent AF: Will Drug Therapy Soon Be Obsolete? AB - Persistent atrial fibrillation (AF) represents a major public health and medical challenge. The progressive nature of the disease, high morbidity, and increasing health-economic costs ensure that it remains at the forefront of novel research into mechanisms and potential therapies. These are largely divided into pharmacological (drugs) and electrical (ablation) with patients often going from former to latter. AF ablation has improved sufficiently to be offered as first line for paroxysmal AF, but whether drug therapy will or be relegated. In this review, we shall outline the progress in mechanistic understanding of AF that may allow results from ablation to diverge dramatically from drug therapy and identify populations in whom drug therapy may become less relevant. We end by looking ahead to future developments that we hope will spur on therapeutic efficacy in both fields. PMID- 25923324 TI - The Past, Present, and Potential Future of Sodium Channel Block as an Atrial Fibrillation Suppressing Strategy. AB - Despite major advances in arrhythmia therapy, atrial fibrillation (AF) remains a challenge. A significant limitation in AF management is the lack of safe and effective drugs to restore and/or maintain sinus rhythm. The rational design of a new generation of AF-selective Na(+) channel blockers (NCBs) is emerging as a promising AF-suppressing strategy. Recent theoretical and experimental advances have generated insights into the mechanisms underlying AF maintenance and termination by antiarrhythmic drugs. Our understanding of antiarrhythmic drug induced proarrhythmia has also grown in sophistication. These discoveries have created new possibilities in therapeutic targeting and renewed interest in improved NCB antiarrhythmic drugs. Recently described differences in atrial versus ventricular electrophysiology can be exploited in the prospective design of atrial-selective NCBs. Furthermore, state-dependent block has been shown to be an important modulator of NCB rate selectivity. Together, differential atrial ventricular electrophysiological actions and state-dependent block form the backbone for the rational design of an AF-selective NCB. Synergistic combinations incorporating both NCB and block of K(+) currents may allow for further enhancement of AF selectivity. Future work on translating these basic research advances into the development of an optimized AF-selective NCB has the potential to provide safer and more effective pharmacotherapeutic options for AF, thereby fulfilling a major unmet clinical need. PMID- 25923325 TI - Females Choose Mates Based on Genetic Relatedness in a Small Dasyurid Marsupial, the Agile Antechinus (Antechinus agilis). AB - Females in a variety of taxa mate with more than one male during a single oestrus and exhibit mate preferences for genetically compatible males, but the influence of female mate choice on siring success is not clearly understood. Whether females choose to mate with more than one male or endure forced copulations is also often unknown. Here, we examined the effects of genetic relatedness on female mate choice and siring success in a small semelparous carnivorous marsupial, the agile antechinus (Antechinus agilis), during two consecutive breeding seasons. Experimental trials were conducted in captivity over periods of 72 hours using interconnected enclosures in which female antechinus could choose to access any of four separated males, but males were only able to access females that entered their quarters. Females had access to two genetically similar and two genetically dissimilar males simultaneously and all behavioural interactions were observed and scored from continuous video recordings. Genetic similarity between mates and paternity of young was determined by microsatellite analyses. Some females chose to enter and mate with more than one male during a single oestrus period. Although females investigated all males, they spent significantly more time visiting, and mated more times with, genetically dissimilar males. Males that were genetically dissimilar to the female sired 88% of subsequent offspring. Whilst males mated readily with most females, they rejected the advances of some receptive females, indicating a previously unexpected level of male mate choice. The results show that genetic relatedness between mates has a significant influence on mate choice, breeding and siring success in the agile antechinus. PMID- 25923326 TI - The impact of air pollutants on the brain. PMID- 25923327 TI - Trends in developed land cover adjacent to habitat for threatened salmon in Puget Sound, Washington, USA. AB - For widely distributed species at risk, such as Pacific salmon (Oncorhynchus spp.), habitat monitoring is both essential and challenging. Only recently have widespread monitoring programs been implemented for salmon habitat in the Pacific Northwest. Remote sensing data, such as Landsat images, are therefore a useful way to evaluate trends prior to the advent of species-specific habitat monitoring programs. We used annual (1986-2008) land cover maps created from Landsat images via automated algorithms (LandTrendr) to evaluate trends in developed (50-100% impervious) land cover in areas adjacent to five types of habitat utilized by Chinook salmon (O. tshawytscha) in the Puget Sound region of Washington State, U.S.A. For the region as a whole, we found significant increases in developed land cover adjacent to each of the habitat types evaluated (nearshore, estuary, mainstem channel, tributary channel, and floodplain), but the increases were small (<1% total increase from 1986 to 2008). For each habitat type, the increasing trend changed during the time series. In nearshore, mainstem, and floodplain areas, the rate of increase in developed land cover slowed in the latter portion of the time series, while the opposite occurred in estuary and tributary areas. Watersheds that were already highly developed in 1986 tended to have higher rates of development than initially less developed watersheds. Overall, our results suggest that developed land cover in areas adjacent to Puget Sound salmon habitat has increased only slightly since 1986 and that the rate of change has slowed near some key habitat types, although this has occurred within the context of a degraded baseline condition. PMID- 25923329 TI - Preventing introduction of livestock associated MRSA in a pig population- benefits, costs, and knowledge gaps from the Swedish perspective. AB - Antibiotic resistance is a growing concern in human, as well as in veterinary medicine. Part of the problem concerns how to respond to the risk presented by animal reservoirs of resistant bacteria with the potential of spreading to humans. One example is livestock associated methicillin-resistant Staphylococcus aureus (LA-MRSA). In countries where LA-MRSA is endemic in the pig population, people in contact with pigs have a higher risk of being colonised with LA-MRSA, and persons from this group are subjected to precautionary measures when visiting health care facilities. In the present study, it is assumed that, if LA-MRSA was introduced to the Swedish pig population, the prevalence in the risk groups would be the same as in Denmark or the Netherlands (two countries with low human prevalence that have implemented measures to detect, trace and isolate human LA MRSA cases and, therefore, have comprehensive data with good coverage regarding prevalence of LA-MRSA), and that similar interventions would be taken in Swedish health care facilities. It is also assumed that the Swedish pig population is free of MRSA or that the prevalence is very low. We analyse if it would be efficient for Sweden to prevent its introduction by testing imported live breeding pigs. Given that quarantining and testing at import will prevent introduction to the pig population, the study shows that the preventive measures may indeed generate a societal net benefit. Benefits are estimated to be between ? 870 720 and ? 1 233 511, and costs to ? 211 129. Still, due to gaps in knowledge, the results should be confirmed when more information become available. PMID- 25923328 TI - The hemiptera (insecta) of Canada: constructing a reference library of DNA barcodes. AB - DNA barcode reference libraries linked to voucher specimens create new opportunities for high-throughput identification and taxonomic re-evaluations. This study provides a DNA barcode library for about 45% of the recognized species of Canadian Hemiptera, and the publically available R workflow used for its generation. The current library is based on the analysis of 20,851 specimens including 1849 species belonging to 628 genera and 64 families. These individuals were assigned to 1867 Barcode Index Numbers (BINs), sequence clusters that often coincide with species recognized through prior taxonomy. Museum collections were a key source for identified specimens, but we also employed high-throughput collection methods that generated large numbers of unidentified specimens. Many of these specimens represented novel BINs that were subsequently identified by taxonomists, adding barcode coverage for additional species. Our analyses based on both approaches includes 94 species not listed in the most recent Canadian checklist, representing a potential 3% increase in the fauna. We discuss the development of our workflow in the context of prior DNA barcode library construction projects, emphasizing the importance of delineating a set of reference specimens to aid investigations in cases of nomenclatural and DNA barcode discordance. The identification for each specimen in the reference set can be annotated on the Barcode of Life Data System (BOLD), allowing experts to highlight questionable identifications; annotations can be added by any registered user of BOLD, and instructions for this are provided. PMID- 25923330 TI - Computel: computation of mean telomere length from whole-genome next-generation sequencing data. AB - Telomeres are the ends of eukaryotic chromosomes, consisting of consecutive short repeats that protect chromosome ends from degradation. Telomeres shorten with each cell division, leading to replicative cell senescence. Deregulation of telomere length homeostasis is associated with the development of various age related diseases and cancers. A number of experimental techniques exist for telomere length measurement; however, until recently, the absence of tools for extracting telomere lengths from high-throughput sequencing data has significantly obscured the association of telomere length with molecular processes in normal and diseased conditions. We have developed Computel, a program in R for computing mean telomere length from whole-genome next-generation sequencing data. Computel is open source, and is freely available at https://github.com/lilit-nersisyan/computel. It utilizes a short-read alignment based approach and integrates various popular tools for sequencing data analysis. We validated it with synthetic and experimental data, and compared its performance with the previously available software. The results have shown that Computel outperforms existing software in accuracy, independence of results from sequencing conditions, stability against inherent sequencing errors, and better ability to distinguish pure telomeric sequences from interstitial telomeric repeats. By providing a highly reliable methodology for determining telomere lengths from whole-genome sequencing data, Computel should help to elucidate the role of telomeres in cellular health and disease. PMID- 25923332 TI - Menstrual cycle phase does not predict political conservatism. AB - Recent authors have reported a relationship between women's fertility status, as indexed by menstrual cycle phase, and conservatism in moral, social and political values. We conducted a survey to test for the existence of a relationship between menstrual cycle day and conservatism. 2213 women reporting regular menstrual cycles provided data about their political views. Of these women, 2208 provided information about their cycle date, 1260 provided additional evidence of reliability in self-reported cycle date, and of these, 750 also indicated an absence of hormonal disruptors such as recent hormonal contraception use, breastfeeding or pregnancy. Cycle day was used to estimate day-specific fertility rate (probability of conception); political conservatism was measured via direct self-report and via responses to the "Moral Foundations" questionnaire. We also recorded relationship status, which has been reported to interact with menstrual cycle phase in determining political preferences. We found no evidence of a relationship between estimated cyclical fertility changes and conservatism, and no evidence of an interaction between relationship status and cyclical fertility in determining political attitudes. Our findings were robust to multiple inclusion/exclusion criteria and to different methods of estimating fertility and measuring conservatism. In summary, the relationship between cycle-linked reproductive parameters and conservatism may be weaker or less reliable than previously thought. PMID- 25923331 TI - Selective inhibition of esophageal cancer cells by combination of HDAC inhibitors and Azacytidine. AB - Esophageal cancers are highly aggressive tumors with poor prognosis despite some recent advances in surgical and radiochemotherapy treatment options. This study addressed the feasibility of drugs targeting epigenetic modifiers in esophageal squamous cell carcinoma (ESCC) and esophageal adenocarcinoma (EAC) cells. We tested inhibition of histone deacetylases (HDACs) by SAHA, MS-275, and FK228, inhibition of DNA methyltransferases by Azacytidine (AZA) and Decitabine (DAC), and the effect of combination treatment using both types of drugs. The drug targets, HDAC1/2/3 and DNMT1, were expressed in normal esophageal epithelium and tumor cells of ESCC or EAC tissue specimens, as well as in non-neoplastic esophageal epithelial (Het-1A), ESCC (OE21, Kyse-270, Kyse-410), and EAC (OE33, SK-GT-4) cell lines. In vitro, HDAC activity, histone acetylation, and p21 expression were similarly affected in non-neoplastic, ESCC, and EAC cell lines post inhibitor treatment. Combined MS-275/AZA treatment, however, selectively targeted esophageal cancer cell lines by inducing DNA damage, cell viability loss, and apoptosis, and by decreasing cell migration. Non-neoplastic Het-1A cells were protected against HDACi (MS-275)/AZA treatment. RNA transcriptome analyses post MS-275 and/or AZA treatment identified novel regulated candidate genes (up: BCL6, Hes2; down: FAIM, MLKL), which were specifically associated with the treatment responses of esophageal cancer cells. In summary, combined HDACi/AZA treatment is efficient and selective for the targeting of esophageal cancer cells, despite similar target expression of normal and esophageal cancer epithelium, in vitro and in human esophageal carcinomas. The precise mechanisms of action of treatment responses involve novel candidate genes regulated by HDACi/AZA in esophageal cancer cells. Together, targeting of epigenetic modifiers in esophageal cancers may represent a potential future therapeutic approach. PMID- 25923333 TI - Traditional chinese medicine Xuebijing treatment is associated with decreased mortality risk of patients with moderate paraquat poisoning. AB - Paraquat poisoning causes multiple organ injury and high mortality due to severe toxicity and lack of effective treatment. Xuebijing (XBJ) injection, a traditional Chinese medicine preparation of five Chinese herbs (Radix Salviae Miltiorrhiae, Rhizoma Chuanxiong, Flos Carthami, Angelica Sinensis and Radix Paeoniae Rubra), has an anti-inflammatory effect and is widely used in the treatment of sepsis. This retrospective study was designed to evaluate the effects of XBJ combined with conventional therapy on mortality risk of patients with acute paraquat poisoning. Out of 68 patients, 27 were treated with conventional therapy (control group) and 41 were treated with intravenous administration of XBJ (100 ml, twice a day, up to 7 days) plus conventional therapy (XBJ group). Vital organ function, survival time within 28 days and adverse events during the treatment were reviewed. Results indicated that XBJ treatment significantly increased median survival time among patients ingesting 10-30 ml of paraquat (P=0.02) compared with the control group. After adjustment for covariates, XBJ treatment was associated significantly with a lower mortality risk (adjusted HR 0.242, 95% CI 0.113 to 0.516, P=0.001) compared with the control group. Additionally, compared with Day 1, on Day 3 the value of PaO2/FiO2 was significantly decreased, and the values of serum alanine aminotransferase, creatinine and troponin T were significantly increased in the control group (all P<0.05), but these values were significant improved in the XBJ group (all P<0.05). Only one patient had skin rash with itch within 30 minutes after injection and no severe adverse events were found in the XBJ group. In conclusion, XBJ treatment is associated with decreased mortality risk of patients with moderate paraquat poisoning, which may be attributed to improved function of vital organs with no severe adverse events. PMID- 25923334 TI - Negative perceptions of aging and decline in walking speed: a self-fulfilling prophecy. AB - INTRODUCTION: Walking speed is a meaningful marker of physical function in the aging population. While it is a primarily physical measure, experimental studies have shown that merely priming older adults with negative stereotypes about aging results in immediate declines in objective walking speed. What is not clear is whether this is a temporary experimental effect or whether negative aging stereotypes have detrimental effects on long term objective health. We sought to explore the association between baseline negative perceptions of aging in the general population and objective walking speed 2 years later. METHOD: 4,803 participations were assessed over 2 waves of The Irish Longitudinal Study on Ageing (TILDA), a prospective, population representative study of adults aged 50+ in the Republic of Ireland. Wave 1 measures - which included the Aging Perceptions Questionnaire, walking speed and all covariates - were taken between 2009 and 2011. Wave 2 measures - which included a second measurement of walking speed and covariates - were collected 2 years later between March and December 2012. Walking speed was measured as the number of seconds to complete the Timed Up-And-Go (TUG) task. Participations with a history of stroke, Parkinson's disease or an MMSE < 18 were excluded. RESULTS: After full adjustment for all covariates (age, gender, level of education, disability, chronic conditions, medications, global cognition and baseline TUG) negative perceptions of aging at baseline were associated with slower TUG speed 2 years later (B=.03, 95% CI = .01 to 05, p< .05). CONCLUSIONS: Walking speed has previously been considered to be a consequence of physical decline but these results highlight the direct role of psychological state in predicting an objective aging outcome. Negative perceptions about aging are a potentially modifiable risk factor of some elements of physical decline in aging. PMID- 25923335 TI - Self-assembly with orthogonal-imposed stimuli to impart structure and confer magnetic function to electrodeposited hydrogels. AB - A magnetic nanocomposite film with the capability of reversibly collecting functionalized magnetic particles was fabricated by simultaneously imposing two orthogonal stimuli (electrical and magnetic). We demonstrate that cathodic codeposition of chitosan and Fe3O4 nanoparticles while simultaneously applying a magnetic field during codeposition can (i) organize structure, (ii) confer magnetic properties, and (iii) yield magnetic films that can perform reversible collection/assembly functions. The magnetic field triggered the self-assembly of Fe3O4 nanoparticles into hierarchical "chains" and "fibers" in the chitosan film. For controlled magnetic properties, the Fe3O4-chitosan film was electrodeposited in the presence of various strength magnetic fields and different deposition times. The magnetic properties of the resulting films should enable broad applications in complex devices. As a proof of concept, we demonstrate the reversible capture and release of green fluorescent protein (EGFP)-conjugated magnetic microparticles by the magnetic chitosan film. Moreover, antibody functionalized magnetic microparticles were applied to capture cells from a sample, and these cells were collected, analyzed, and released by the magnetic chitosan film, paving the way for applications such as reusable biosensor interfaces (e.g., for pathogen detection). To our knowledge, this is the first report to apply a magnetic field during the electrodeposition of a hydrogel to generate magnetic soft matter. Importantly, the simple, rapid, and reagentless fabrication methodologies demonstrated here are valuable features for creating a magnetic device interface. PMID- 25923336 TI - Genome wide analysis of novel copy number variations duplications/deletions of different epileptic patients in Saudi Arabia. AB - BACKGROUND: Epilepsy is genetically complex neurological disorder affecting millions of people of different age groups varying in its type and severity. Copy number variants (CNVs) are key players in the genetic etiology of numerous neurodevelopmental disorders and prior findings also revealed that chromosomal aberrations are more susceptible against the pathogenesis of epilepsy. Novel technologies, such as array comparative genomic hybridization (array-CGH), may help to uncover the pathogenic CNVs in patients with epilepsy. RESULTS: This study was carried out by high density whole genome array-CGH analysis with blood DNA samples from a cohort of 22 epilepsy patients to search for CNVs associated with epilepsy. Pathogenic rearrangements which include 6p12.1 microduplications in 5 patients covering a total region of 99.9kb and 7q32.3 microdeletions in 3 patients covering a total region of 63.9kb were detected. Two genes BMP5 and PODXL were located in the predicted duplicated and deleted regions respectively. Furthermore, these CNV findings were confirmed by qPCR. CONCLUSION: We have described, for the first time, several novel CNVs/genes implicated in epilepsy in the Saudi population. These findings enable us to better describe the genetic variations in epilepsy, and could provide a foundation for understanding the critical regions of the genome which might be involved in the development of epilepsy. PMID- 25923337 TI - Temperature-Tunable Nanoparticles for Selective Biointerface. AB - Drugs can be delivered by a temperature change-driven shrinking of the nanocarrier followed by the cargo release. This paper describes a different structural response to temperature, performed by nanoparticles of poly(N isopropylacrylamide) and hyaluronic acid. Around 35 degrees C, the hydrophobicity of the vinyl polymer drives a core-shell rearrangement with the acrylamide chains confined in the core and the polysaccharide moiety forming the shell. In this arrangement, the nanoparticles enable the active targeting of tumor cells, due to the specific interaction of hyaluronic acid with the CD44 receptors. When doxorubicin-loaded nanoparticles are up-taken, the polysaccharide part degrades in the cytoplasm and the cytotoxic effect of the anticancer drug in colon adenocarcinoma cells has a 2-fold increase with respect to healthy fibroblasts. These core-shell particles have hyaluronic acid as the key factor for the specific targeting of tumor cells and drug release with poly(N isopropylacrylamide) driving the transition. PMID- 25923338 TI - Passive acoustic monitoring of the temporal variability of odontocete tonal sounds from a long-term marine observatory. AB - The developments of marine observatories and automatic sound detection algorithms have facilitated the long-term monitoring of multiple species of odontocetes. Although classification remains difficult, information on tonal sound in odontocetes (i.e., toothed whales, including dolphins and porpoises) can provide insights into the species composition and group behavior of these species. However, the approach to measure whistle contour parameters for detecting the variability of odontocete vocal behavior may be biased when the signal-to-noise ratio is low. Thus, methods for analyzing the whistle usage of an entire group are necessary. In this study, a local-max detector was used to detect burst pulses and representative frequencies of whistles within 4.5-48 kHz. Whistle contours were extracted and classified using an unsupervised method. Whistle characteristics and usage pattern were quantified based on the distribution of representative frequencies and the composition of whistle repertoires. Based on the one year recordings collected from the Marine Cable Hosted Observatory off northeastern Taiwan, odontocete burst pulses and whistles were primarily detected during the nighttime, especially after sunset. Whistle usage during the nighttime was more complex, and whistles with higher frequency were mainly detected during summer and fall. According to the multivariate analysis, the diurnal variation of whistle usage was primarily related to the change of mode frequency, diversity of representative frequency, and sequence complexity. The seasonal variation of whistle usage involved the previous three parameters, in addition to the diversity of whistle clusters. Our results indicated that the species and behavioral composition of the local odontocete community may vary among seasonal and diurnal cycles. The current monitoring platform facilitates the evaluation of whistle usage based on group behavior and provides feature vectors for species and behavioral classification in future studies. PMID- 25923339 TI - Sex Differences and Self-Reported Attention Problems During Baseline Concussion Testing. AB - Amateur athletic programs often use computerized cognitive testing as part of their concussion management programs. There is evidence that athletes with preexisting attention problems will have worse cognitive performance and more symptoms at baseline testing. The purpose of this study was to examine whether attention problems affect assessments differently for male and female athletes. Participants were drawn from a database that included 6,840 adolescents from Maine who completed Immediate Postconcussion Assessment and Cognitive Testing (ImPACT) at baseline (primary outcome measure). The final sample included 249 boys and 100 girls with self-reported attention problems. Each participant was individually matched for sex, age, number of past concussions, and sport to a control participant (249 boys, 100 girls). Boys with attention problems had worse reaction time than boys without attention problems. Girls with attention problems had worse visual-motor speed than girls without attention problems. Boys with attention problems reported more total symptoms, including more cognitive-sensory and sleep-arousal symptoms, compared with boys without attention problems. Girls with attention problems reported more cognitive-sensory, sleep-arousal, and affective symptoms than girls without attention problems. When considering the assessment, management, and outcome from concussions in adolescent athletes, it is important to consider both sex and preinjury attention problems regarding cognitive test results and symptom reporting. PMID- 25923340 TI - Pain: cancer. PMID- 25923341 TI - Classification of neuropathic pain in cancer patients. AB - PURPOSE OF REVIEW: Neuropathic pain can affect up to 40% in patients with cancer, which could be related to the tumour, treatment or comorbid diseases. Effective assessment to diagnose neuropathic pain is crucial in order to choose the right treatment. RECENT FINDINGS: There is to date no systematic classification system; the Neuropathic Pain Special Interest Group of the International Association for the Study of Pain developed a neuropathic pain grading system intended to be used for both clinical and research purposes, and a recent review describes a step-by step process for applying the grading system in a clinical setting for cancer pain. SUMMARY: We have combined these recommendations to outline a clinically relevant process to classify neuropathic pain in patients with cancer. PMID- 25923342 TI - Could targeting epigenetic processes relieve chronic pain states? AB - PURPOSE OF REVIEW: Aberrations in the epigenetic landscape have previously been associated with human diseases such as cancer and schizophrenia, and drugs that target epigenetic processes are currently used as therapeutic agents. This article will review the evidence obtained from animal studies indicating that epigenetic processes might regulate long-term pain states and then discuss the possibility that targeting epigenetic mechanisms might be useful for the management of chronic pain. RECENT FINDINGS: Recent animal studies have reported injury-induced changes in epigenetic processes in the central nervous system. The picture that has emerged is that of very complex epigenetic programs that depend on the injury. However, some studies have reported the successful use of nonspecific epigenetic tools to improve the hypersensitivity that develops in animal models of long-term pain states. SUMMARY: The field of epigenetics and pain is rapidly emerging but further investigation is needed to fully comprehend the contribution of epigenetic processes to chronic pain states. Although therapeutic approaches targeting these mechanisms might seem worthwhile, we cannot assert that currently available global tools such as histone deacetylase inhibitors can be used successfully for the long-term treatment of chronic pain states. PMID- 25923344 TI - Impact of various emulsifiers on ALA bioavailability and chylomicron synthesis through changes in gastrointestinal lipolysis. AB - Formulating healthy food rich in omega 3 fatty acids requires prior knowledge of the parameters influencing their bioavailability and their metabolic fate. In this context, we studied the effects of various emulsifiers widely used in the food industry, on the gastrointestinal lipolysis of flaxseed oil emulsions in an in vitro model and on the intestinal absorption and lymphatic secretion of alpha linolenic acid (ALA) in rats. In vitro data showed that the emulsification of flaxseed oil with soya lecithin improved the gastric lipolysis of the oil (+30%), while the presence of Tween 80 or of sodium caseinate decreased it (-80% and 40%, respectively). The in vivo data demonstrated that the intestinal absorption and the lymphatic secretion of ALA were improved with soya lecithin (Cmax = 24 mg mL(-1)) and reduced in the presence of sodium caseinate (Cmax = 7 mg mL(-1)) compared to unemulsified flaxseed oil (Cmax = 16 mg mL(-1)); Tween 80 had no effect. In addition, the synthesized chylomicrons were notably larger and more numerous with soya lecithin whereas they were smaller in the presence of sodium caseinate (p < 0.05). This study shows that the intestinal bioavailability of ALA was increased by the emulsification of flaxseed oil with soya lecithin via an improved lipolysis, favouring the intestinal absorption of ALA and the secretion of many large chylomicrons in lymph. PMID- 25923346 TI - Preparation of substituted phenanthridines from the coupling of aryldiazonium salts with nitriles: a metal free approach. AB - A transition metal free approach for the synthesis of substituted phenanthridines from the coupling reaction of aryldiazonium tetrafluoroborates with nitriles has been developed. This operationally simple protocol proceeds through a substitution of aryldiazonium with nitriles followed by an intramolecular arylation to provide the corresponding phenanthridines in moderate to excellent yields. PMID- 25923347 TI - NanoTEST in a Nutshell. PMID- 25923345 TI - Whole genome sequencing of elite rice cultivars as a comprehensive information resource for marker assisted selection. AB - Current advances in sequencing technologies and bioinformatics revealed the genomic background of rice, a staple food for the poor people, and provided the basis to develop large genomic variation databases for thousands of cultivars. Proper analysis of this massive resource is expected to give novel insights into the structure, function, and evolution of the rice genome, and to aid the development of rice varieties through marker assisted selection or genomic selection. In this work we present sequencing and bioinformatics analyses of 104 rice varieties belonging to the major subspecies of Oryza sativa. We identified repetitive elements and recurrent copy number variation covering about 200 Mbp of the rice genome. Genotyping of over 18 million polymorphic locations within O. sativa allowed us to reconstruct the individual haplotype patterns shaping the genomic background of elite varieties used by farmers throughout the Americas. Based on a reconstruction of the alleles for the gene GBSSI, we could identify novel genetic markers for selection of varieties with high amylose content. We expect that both the analysis methods and the genomic information described here would be of great use for the rice research community and for other groups carrying on similar sequencing efforts in other crops. PMID- 25923348 TI - Suitability of human and mammalian cells of different origin for the assessment of genotoxicity of metal and polymeric engineered nanoparticles. AB - Nanogenotoxicity is a crucial endpoint in safety testing of nanomaterials as it addresses potential mutagenicity, which has implications for risks of both genetic disease and carcinogenesis. Within the NanoTEST project, we investigated the genotoxic potential of well-characterised nanoparticles (NPs): titanium dioxide (TiO2) NPs of nominal size 20 nm, iron oxide (8 nm) both uncoated (U Fe3O4) and oleic acid coated (OC-Fe3O4), rhodamine-labelled amorphous silica 25 (Fl-25 SiO2) and 50 nm (Fl-50 SiO) and polylactic glycolic acid polyethylene oxide polymeric NPs - as well as Endorem(r) as a negative control for detection of strand breaks and oxidised DNA lesions with the alkaline comet assay. Using primary cells and cell lines derived from blood (human lymphocytes and lymphoblastoid TK6 cells), vascular/central nervous system (human endothelial human cerebral endothelial cells), liver (rat hepatocytes and Kupffer cells), kidney (monkey Cos-1 and human HEK293 cells), lung (human bronchial 16HBE14o cells) and placenta (human BeWo b30), we were interested in which in vitro cell model is sufficient to detect positive (genotoxic) and negative (non-genotoxic) responses. All in vitro studies were harmonized, i.e. NPs from the same batch, and identical dispersion protocols (for TiO2 NPs, two dispersions were used), exposure time, concentration range, culture conditions and time-courses were used. The results from the statistical evaluation show that OC-Fe3O4 and TiO2 NPs are genotoxic in the experimental conditions used. When all NPs were included in the analysis, no differences were seen among cell lines - demonstrating the usefulness of the assay in all cells to identify genotoxic and non-genotoxic NPs. The TK6 cells, human lymphocytes, BeWo b30 and kidney cells seem to be the most reliable for detecting a dose-response. PMID- 25923350 TI - In vitro models of the human placental barrier--In regione caecorum rex est luscus. PMID- 25923349 TI - Towards an alternative testing strategy for nanomaterials used in nanomedicine: lessons from NanoTEST. AB - In spite of recent advances in describing the health outcomes of exposure to nanoparticles (NPs), it still remains unclear how exactly NPs interact with their cellular targets. Size, surface, mass, geometry, and composition may all play a beneficial role as well as causing toxicity. Concerns of scientists, politicians and the public about potential health hazards associated with NPs need to be answered. With the variety of exposure routes available, there is potential for NPs to reach every organ in the body but we know little about the impact this might have. The main objective of the FP7 NanoTEST project ( www.nanotest-fp7.eu ) was a better understanding of mechanisms of interactions of NPs employed in nanomedicine with cells, tissues and organs and to address critical issues relating to toxicity testing especially with respect to alternatives to tests on animals. Here we describe an approach towards alternative testing strategies for hazard and risk assessment of nanomaterials, highlighting the adaptation of standard methods demanded by the special physicochemical features of nanomaterials and bioavailability studies. The work has assessed a broad range of toxicity tests, cell models and NP types and concentrations taking into account the inherent impact of NP properties and the effects of changes in experimental conditions using well-characterized NPs. The results of the studies have been used to generate recommendations for a suitable and robust testing strategy which can be applied to new medical NPs as they are developed. PMID- 25923351 TI - Exploring the interactions of nanoparticles with multiple models of the maternal- fetal interface. PMID- 25923352 TI - Native Wolbachia from Aedes albopictus Blocks Chikungunya Virus Infection In Cellulo. AB - Wolbachia, a widespread endosymbiont of terrestrial arthropods, can protect its host against viral and parasitic infections, a phenotype called "pathogen blocking". However, in some cases Wolbachia may have no effect or even enhance pathogen infection, depending on the host-Wolbachia-pathogen combination. The tiger mosquito Aedes albopictus is naturally infected by two strains of Wolbachia, wAlbA and wAlbB, and is a competent vector for different arboviruses such as dengue virus (DENV) and chikungunya virus (CHIKV). Interestingly, it was shown in some cases that Ae. albopictus native Wolbachia strains are able to inhibit DENV transmission by limiting viral replication in salivary glands, but no such impact was measured on CHIKV replication in vivo. To better understand the Wolbachia/CHIKV/Ae. albopictus interaction, we generated a cellular model using Ae. albopictus derived C6/36 cells that we infected with the wAlbB strain. Our results indicate that CHIKV infection is negatively impacted at both RNA replication and virus assembly/secretion steps in presence of wAlbB. Using FISH, we observed CHIKV and wAlbB in the same mosquito cells, indicating that the virus is still able to enter the cell in the presence of the bacterium. Further work is needed to decipher molecular pathways involved in Wolbachia-CHIKV interaction at the cellular level, but this cellular model can be a useful tool to study the mechanism behind virus blocking phenotype induced by Wolbachia. More broadly, this put into question the ecological role of Wolbachia symbiont in Ae. albopictus, but also the ability of the CHIKV to counteract Wolbachia's antiviral potential in vivo. PMID- 25923353 TI - Endogenous Optical Signals Reveal Changes of Elastin and Collagen Organization During Differentiation of Mouse Embryonic Stem Cells. AB - Components of the extracellular matrix (ECM) have recently been shown to influence stem cell specification. However, it has been challenging to assess the spatial and temporal dynamics of stem cell-ECM interactions because most methodologies utilized to date require sample destruction or fixation. We examined the efficacy of utilizing the endogenous optical signals of two important ECM proteins, elastin (Eln), through autofluorescence, and type I collagen (ColI), through second harmonic generation (SHG), during mouse embryonic stem cell differentiation. After finding favorable overlap between antibody labeling and the endogenous fluorescent signal of Eln, we used this endogenous signal to map temporal changes in Eln and ColI during murine embryoid body differentiation and found that Eln increases until day 9 and then decreases slightly by day 12, while Col1 steadily increases over the 12-day period. Furthermore, we combined endogenous fluorescence imaging and SHG with antibody labeling of cardiomyocytes to examine the spatial relationship between Eln and ColI accumulation and cardiomyocyte differentiation. Eln was ubiquitously present, with enrichment in regions with cardiomyocyte differentiation, while there was an inverse correlation between ColI and cardiomyocyte differentiation. This work provides an important first step for utilizing endogenous optical signals, which can be visualized in living cells, to understand the relationship between the ECM and cardiomyocyte development and sets the stage for future studies of stem cell-ECM interactions and dynamics relevant to stem cells as well as other cell and tissue types. PMID- 25923354 TI - Effect of neoadjuvant chemotherapy on the serum levels of bone turnover markers in women with early-stage breast cancer. AB - BACKGROUND: To evaluate effects of neoadjuvant chemotherapy on the bone turnover markers of preoperational breast cancer patients. METHODS: Forty-one breast cancer patients (29 premenopausal and 12 postmenopausal) and 60 healthy women (30 premenopausal and 30 postmenopausal) aged 30-64 years, were evaluated for their bone status. Serum levels of the bone formation markers PINP and BAP, as well as the resorption markers ICTP and beta-Crosslaps in addition to E2, FSH, 25(OH)D and PTH were measured at the initial diagnosis and at 24 hours after each four chemotherapy cycles. BMD T-scores were determined in 12 patients 6 months after the neoadjuvant chemotherapies. RESULTS: The baseline levels of both bone formation and resorption markers in premenopausal patients were higher than in premenopausal healthy women (p<0.05), while no statistic difference was observed between postmenopausal patients and postmenopausal healthy women. Regardless of the menopausal status, chemotherapy increased the ICTP and beta-Crosslaps levels (p<0.05), but decreased the BAP and PINP levels (p<0.05), the later one significantly more with Taxane medication (p<0.01, p<0.05). Chemotherapy caused significant decreases of 25(OH)D levels in premenopausal (p<0.01) and postmenopausal (p<0.05) patients, however, did not affect the PTH concentrations. In premenopausal patients the E2 level decreased, while the FSH level increased after chemotherapy (p<0.05). Patients with pronounced ICTP and beta-Crosslaps combined with reduced BAP and PINP serum concentrations after neoadjuvant chemotherapies were prone to develop osteoporosis 6 month later. CONCLUSIONS: Neoadjuvant chemotherapy appeared to promote bone resorption and inhibit bone formation in both postmenopausal and premenopausal early-stage breast patients. PMID- 25923355 TI - Houttuynia cordata Extract Improves Physical Endurance Performance by Regulating Endothelial Production of Nitric Oxide. AB - Vascular function is mediated by various regulatory molecules, including endothelial nitric oxide (NO), which regulates the vasodilation of smooth muscle cells. We investigated whether standardized Houttuynia cordata extract (SHCE) could improve physical endurance performance by regulating the endothelial production of NO. For the standardization of Houttuynia cordata (HC) extract, its bioactive components were identified and quantified using ultraperformance liquid chromatography-mass spectrometry. Bioaccessibility and biological activity were measured by the in vitro digestion model system and free radical scavenging capacity, respectively. The vascular function in the endothelium was assessed by the phosphorylation of endothelial nitric oxide synthase (eNOS). A preliminary clinical trial was carried out to assess the physical endurance performance. HC extract was standardized to bioactive components, including chlorogenic acid, rutin, and quercitrin, with the concentration of 5.53, 6.09, and 16.15 mg from 1 g of dry weight, respectively. Bioaccessibility was 33.17%, 31.67%, and 11.18% for chlorogenic acid, rutin, and quercitrin, respectively. Antioxidant activities of SHCE were expressed as vitamin C equivalent antioxidant capacity in 55.81 and 17.23 mg/g of HC extract using ABTS and DPPH scavenging assay, respectively. In human aortic endothelial cells, insulin-mediated phosphorylation of eNOS was increased by SHCE in the presence of palmitate. However, the expression of blood pressure-regulating genes was not altered. The level of blood lactate concentration and the heart rate of subjects who drank SHCE were lower than those of subjects who drank plain water. Oxygen uptake from subjects drinking SHCE was slightly higher than that from those who drank plain water. This study demonstrated that SHCE decreased heart rate and blood lactate, increased oxygen uptake, and improved physical performance, presumably due to the increased NO production. PMID- 25923357 TI - Osmium and Platinum Decoupling in the Environment: Evidences in Intertidal Sediments (Tagus Estuary, SW Europe). AB - Catalytic converters in automobiles have significantly increased the input of platinum group elements (PGE) to the environment, and their coupled geochemical behavior has been proposed. To check this hypothesis, Pt and Os concentrations and (187)Os/(188)Os ratios were determined in sediment cores and interstitial waters from the Tagus Estuary (SW Europe) affected by different traffic pressure. Platinum concentration in surface sediments nearby the high traffic zone (up to 40 ng g(-1)) indicated severe contamination. Although lower than Pt, Os enrichment was also observed in surface sediments, with lower (187)Os/(188)Os ratios than in deeper layers. Dissolved Pt and Os in interstitial waters, 0.1-0.7 pg g(-1) and 0.03-0.10 pg g(-1), respectively, were higher than in typical uncontaminated waters. Results indicate two sources of Pt and Os into the Tagus Estuary salt marshes: a regional input associated with industrial activities, fossil fuel combustions, and regional traffic and a local source linked to nearby traffic density emissions. Estimations of Os and Pt released by catalytic converters support this two-source model. Differences in geochemical reactivity and range of dispersion from their sources lead to a decoupled behavior of Os and Pt, questioning the use of Os isotopes as proxies of PGE sources to the environment. PMID- 25923356 TI - Quantifying Distribution of Flow Cytometric TCR-Vbeta Usage with Economic Statistics. AB - Measuring changes of the T cell receptor (TCR) repertoire is important to many fields of medicine. Flow cytometry is a popular technique to study the TCR repertoire, as it quickly provides insight into the TCR-Vbeta usage among well defined populations of T cells. However, the interpretation of the flow cytometric data remains difficult, and subtle TCR repertoire changes may go undetected. Here, we introduce a novel means for analyzing the flow cytometric data on TCR-Vbeta usage. By applying economic statistics, we calculated the Gini TCR skewing index from the flow cytometric TCR-Vbeta analysis. The Gini-TCR skewing index, which is a direct measure of TCR-Vbeta distribution among T cells, allowed us to track subtle changes of the TCR repertoire among distinct populations of T cells. Application of the Gini-TCR skewing index to the flow cytometric TCR-Vbeta analysis will greatly help to gain better understanding of the TCR repertoire in health and disease. PMID- 25923358 TI - A perspective on web-based information for patients with chronic lung disease. AB - Although the majority of patients with a chronic disease obtain information about their condition from a health care professional, medical appointments may not allow sufficient time for educating patients and addressing questions. Internet resources can fill educational gaps and promote knowledge transformation. In a 2010 Pew Research Center report, the presence of a chronic disease increased the likelihood that a person would search online for health information. To provide the best medical care, it is important that health care providers are knowledgeable about medical information on the internet. This Perspective summarizes the major websites that present patient-focused medical information about three common lung diseases-asthma, chronic obstructive pulmonary disease, and idiopathic pulmonary fibrosis. These websites can be categorized as those sponsored by pharmaceutical companies, for-profit and nonprofit professional organizations, the National Health Lung and Blood Institute, health care organizations, and patient support groups. In addition, three novel websites about chronic obstructive pulmonary disease are described with the ostensible goal of providing user-friendly information with a focus on individual patients. One was developed as a public university-private partnership, whereas the other two were developed by individuals with interest and experience in respiratory diseases-a respiratory therapist and a pulmonologist. The websites described in this perspective, along with numerous other sources, provide medical information for patients with respiratory diseases that offer a marketplace for viewing. Health care professionals can recommend specific websites to patients to complement discussions during the office visit. PMID- 25923359 TI - Correction: Characterization of Cellulase Secretion and Cre1-Mediated Carbon Source Repression in the Potential Lignocellulose-Degrading Strain Trichoderma asperellum T-1. PMID- 25923360 TI - Meta-analysis on the curative effect of neoadjuvant chemotherapy for gastric cancer. AB - AIM: Aim of the study was to discuss the effectiveness of neoadjuvant chemotherapy for gastric cancer by meta-analysis. METHODS: Retrieve Chinese periodical full-text database, Medline, Wanfang database, Coehrane library, and preoperative neoadjuvant chemotherapy efficacy of gastric cancer in Embase. The keywords used were as follows: gastric carcinoma, retrieval effect, neoadjuvant chemoradiation with Chinese and English retrieval. The RevMan5.0 software was used to conducted the meta-analysis. RESULTS: A total of 16 articles were included. The study has a total of 1937 cases. The results of the neoadjuvant chemotherapy group showed that the survival and radical resection rate is higher than the traditional surgery group. The palliative resection rate is lower than the traditional surgery group (radical resection rate: odds ratio [OR]=1900, 95%CI 1.30 rese, P<0.0l, survival rate: OR=1.83, 95%CI 1.43 rate, P<0.01; palliative resection rate: OR=0.54, 95%CI 0.33, P=0.01). There was no significant difference between the pathological staging of the two groups (OR=1.03, 95%CI 0.623, P=0.90). CONCLUSION: The present clinical evidence shows that neoadjuvant chemotherapy can improve the survival rate of gastric cancer and the radical resection rate. PMID- 25923361 TI - Ultrasensitive near-infrared fluorescence-enhanced probe for in vivo nitroreductase imaging. AB - Nitroreductase (NTR) can be overexpressed in hypoxic tumors, thus the selective and efficient detection of NTR is of great importance. To date, although a few optical methods have been reported for the detection of NTR in solution, an effective optical probe for NTR monitoring in vivo is still lacking. Therefore, it is necessary to develop a near-infrared (NIR) fluorescent detection probe for NTR. In this study, five NIR cyanine dyes with fluorescence reporting structure decorated with different nitro aromatic groups, Cy7-1-5, have been designed and explored for possible rapid detection of NTR. Our experimental results presented that only a para-nitro benzoate group modified cyanine probe (Cy7-1) could serve as a rapid NIR fluorescence-enhanced probe for monitoring and bioimaging of NTR. The structure-function relationship has been revealed by theoretical study. The linker connecting the detecting and fluorescence reporting groups and the nitro group position is a key factor for the formation of hydrogen bonds and spatial structure match, inducing the NTR catalytic ability enhancement. The in vitro response and mechanism of the enzyme-catalyzed reduction of Cy7-1 have been investigated through kinetic optical studies and other methods. The results have indicated that an electro-withdrawing group induced electron-transfer process becomes blocked when Cy7-1 is catalytically reduced to Cy7-NH2 by NTR, which is manifested in enhanced fluorescence intensity during the detection process. Confocal fluorescence imaging of hypoxic A549 cells has confirmed the NTR detection ability of Cy7-1 at the cellular level. Importantly, Cy7-1 can detect tumor hypoxia in a murine hypoxic tumor model, showing a rapid and significant enhancement of its NIR fluorescence characteristics suitable for fluorescence bioimaging. This method may potentially be used for tumor hypoxia diagnosis. PMID- 25923363 TI - Accuracy of Three-Dimensional Printed Templates for Guided Implant Placement Based on Matching a Surface Scan with CBCT. AB - BACKGROUND: Reference elements are necessary to transfer a virtual planning into reality for guided implant placement. New systems allow matching optical scans with three-dimensional radiographic images. PURPOSE: To test whether digitally designed three-dimensional printed templates (D-temp) fabricated by matching surface scans and cone beam computed tomography (CBCT) images differ from the templates fabricated in-lab (L-temp) by using a physical transfer device for the positioning of the guiding sleeves. MATERIALS AND METHODS: L-temp were fabricated for eight human lower cadaver-jaws applying a digital planning software program (smop, Swissmeda AG, Zurich, Switzerland) using a Lego(r) (Lego Group, KIRKBI A/S, Billund, Denmark) brick as reference element and the respective transfer device (X1-table). Additionally, digital templates (D-temp) using the identical planning data sets and software were virtually designed and three-dimensional printed, after matching a surface scan with CBCT data. The accuracy of both templates for each planning was evaluated determining the estimated coronal, apical, and angular deviation if templates were used for implant placement. RESULTS: Mean coronal deviations for L-temp were 0.31 mm (mesial/distal), 0.32 mm (lingual/buccal), and 0.16 mm and 0.23 mm for D-temp, respectively. The mean apical deviations for L-temp were 0.50 mm (mesial/distal), 0.50 mm (lingual/buccal). and 0.25 mm and 0.34 mm for the D-temp, respectively. Differences between both devices were statistically significant (p < .05). CONCLUSIONS: A higher accuracy of implant placement can be achieved by using three-dimensional printed templates produced by matching a surface scan and CBCT as compared with templates which use physical elements transferring the virtual planning into reality. PMID- 25923362 TI - Detection of temporal changes in insect body reflectance in response to killing agents. AB - Computer vision and reflectance-based analyses are becoming increasingly important methods to quantify and characterize phenotypic responses by whole organisms to environmental factors. Here, we present the first study of how a non destructive and completely non-invasive method, body reflectance profiling, can be used to detect and time stress responses in adult beetles. Based on high resolution hyperspectral imaging, we acquired time series of average reflectance profiles (70 spectral bands from 434-876 nm) from adults in two beetle species, maize weevils (Sitophilus zeamais) and larger black flour beetles (Cynaus angustus). For each species, we acquired reflectance data from untreated controls and from individuals exposed continuously to killing agents (an insecticidal plant extract applied to maize kernels or entomopathogenic nematodes applied to soil applied at levels leading to ~100% mortality). In maize weevils (exposed to hexanic plant extract), there was no significant effect of the on reflectance profiles acquired from adult beetles after 0 and 12 hours of exposure, but a significant treatment response in spectral bands from 434 to 550 nm was detected after 36 to 144 hours of exposure. In larger black flour beetles, there was no significant effect of exposure to entomopathogenic nematodes after 0 to 26 hours of exposure, but a significant response in spectral bands from 434-480 nm was detected after 45 and 69 hours of exposure. Spectral bands were used to develop reflectance-based classification models for each species, and independent validation of classification algorithms showed sensitivity (ability to positively detect terminal stress in beetles) and specificity (ability to positively detect healthy beetles) of about 90%. Significant changes in body reflectance occurred at exposure times, which coincided with published exposure times and known physiological responses to each killing agent. The results from this study underscore the potential of hyperspectral imaging as an approach to non destructively and non-invasively quantify stress detection in insects and other animals. PMID- 25923364 TI - Prolonged pegylated liposomal doxorubicin treatment for recurrent pelvic cancers: a feasibility study. AB - We conducted a proof of concept study evaluating prolonged treatment with pegylated liposomal doxorubicin for recurrent ovarian, tubal and peritoneal carcinoma. Thirteen consecutive patients received an average of 22.6 cycles of pegylated liposomal doxorubicin, with an average cumulative dose of 1409 mg/m(2) . Progression-free survival at 18 months was 61.5%, and was longer than the previous progression-free survival in 10 of the 13 patients. Overall 5-year survival was 78.8%. Despite prolonged use and relatively large cumulative doses of pegylated liposomal doxorubicin, most of the patients had mild to moderate side-effects, none of the patients had detectable cardio-toxic side-effects, and a positive impact on the performance status was noticed. Thus, in our group of patients, continued pegylated liposomal doxorubicin treatment was associated with a longer progression-free interval and allowed improved performance status with manageable toxicity. PMID- 25923365 TI - In situ unravelling structural modulation across the charge-density-wave transition in vanadium disulfide. AB - A deep understanding of the relationship between electronic and structure ordering across the charge-density-wave (CDW) transition is crucial for both fundamental study and technological applications. Herein, using in situ X-ray absorption fine structure (XAFS) spectroscopy coupled with high-resolution transmission electron microscopy (HRTEM), we have illustrated the atomic-level information on the local structural evolution across the CDW transition and its influence on the intrinsic electrical properties in VS2 system. The structure transformation, which is highlighted by the formation of vanadium trimers with derivation of V-V bond length (DeltaR = 0.10 A), was clearly observed across the CDW process. Moreover, the corresponding influence of lattice variation on the electronic behavior was clearly characterized by experimental results as well as theoretical analysis, which demonstrated that vanadium trimers drive the deformation of space charge density distribution into ?3 *?3 periodicity, with the conductivity of a1g band reducing by half. These observations directly unveiled the close connection between lattice evolution and electronic property variation, paving a new avenue for understanding the intrinsic nature of electron lattice interactions in the VS2 system and other isostructural transition metal dichalcogenides across the CDW transition process. PMID- 25923366 TI - Empowering patients to link to care and treatment: qualitative findings about the role of a home-based HIV counselling, testing and linkage intervention in South Africa. AB - To explore the barriers and facilitators of linkage to and retention in care amongst persons who tested positive for HIV, qualitative research was conducted in a home-based HIV counselling and testing (HBCT) project with interventions to facilitate linkages to HIV care in rural KwaZulu-Natal, South Africa. The intervention tested 1272 adults for HIV in Vulindlela of whom 32% were HIV positive, received point-of-care (POC) CD4 testing and referral to local HIV clinics. Those testing positive also received follow-up visits from a counsellor to evaluate linkages to care. The study employed a qualitative methodology collecting data through in-depth semi-structured interviews. Respondents included 25 HIV-positive persons who had tested as part of HBCT project, 4 intervention research counsellors who delivered the HBCT intervention and 9 government clinic staff who received referrals for care. The results show that HBCT helped to facilitate linkage to care through providing education and support to help overcome fears of stigma and discrimination. The results show the perceived value of receiving a POC CD4 result during post-test counselling, both for those newly diagnosed and those previously diagnosed as HIV positive. The results also demonstrate that in-depth counselling creates an "educated consumer" facilitating engagement with clinical services. The study provides qualitative insights into the acceptability of confidential HBCT with same day POC CD4 testing and counselling as factors that influenced HIV-positive persons' decisions to link to care. This model warrants further evaluation in non-research settings to determine impact and cost-effectiveness relative to other HIV testing and referral strategies. PMID- 25923367 TI - Change in corneal hysteresis over time in normal, glaucomatous and diabetic eyes. AB - PURPOSE: Corneal hysteresis (CH) is lower in glaucomatous eyes. The aim of this study was to determine and compare the change in CH over time between normal, open angle glaucoma (POAG) and diabetic subjects. METHODS: We retrospectively analysed records of patients undergoing assessment with the Ocular Response Analyzer (Reichert, Corp., New York, NY, USA). Right eyes with at least 7 measurements were included. Patients with ocular pathology other than POAG were excluded. Two-sample t-tests, chi-squared and logistic regression were used to analyse data. RESULTS: A total of 1418 normal and 322 POAG patients were included. Patients with POAG were significantly older (70.73 +/- 11.33 vs. 61.59 +/- 16.56 years; p < 0.001), had a longer follow-up (4.14 +/- 1.34 vs. 2.72 +/- 1.49 years; p < 0.001) and had lower CH (9.58 +/- 2.17 vs. 9.95 +/- 2.19 mmHg p = 0.01), but there were no gender differences between groups (61.5 vs. 57.7% female; p = 0.21). We observed a significantly greater decrease in CH among patients with POAG (-0.11 +/- 0.73 vs. 0.07 +/- 2.31 mm Hg/year; p = 0.02). The relation between ?CH/year and diagnosis persisted after adjusting for age and follow-up time (OR 0.90; 95% CI 0.82, 0.99; p = 0.03). We found CH to be higher in diabetics vs. non-diabetics (10.34 +/- 2.04 vs. 9.88 +/- 2.19; p = 0.02), but ?CH/year was not different (0.07 +/- 1.27 vs. 0.03 +/- 2.10; p = 0.77). CONCLUSIONS: Patients with POAG in this study had a significantly greater rate of CH decline compared to normal. There was no significant difference in rate of CH change in diabetic and non-diabetic patients. PMID- 25923368 TI - Synthesis and evaluation of 1,2,4-triazolo[1,5-a]pyrimidines as antibacterial agents against Enterococcus faecium. AB - Rapid emergence of antibiotic resistance is one of the most challenging global public health concerns. In particular, vancomycin-resistant Enterococcus faecium infections have been increasing in frequency, representing 25% of enterococci infections in intensive care units. A novel class of 1,2,4-triazolo[1,5 a]pyrimidines active against E. faecium is reported herein. We used a three component Biginelli-like heterocyclization reaction for the synthesis of a series of these derivatives based on reactions of aldehydes, beta-dicarbonyl compounds, and 3-alkylthio-5-amino-1,2,4-triazoles. The resulting compounds were assayed for antimicrobial activity against the ESKAPE panel of bacteria, followed by investigation of their in vitro activities. These analyses identified a subset of 1,2,4-triazolo[1,5-a]pyrimidines that had good narrow-spectrum antibacterial activity against E. faecium and exhibited metabolic stability with low intrinsic clearance. Macromolecular synthesis assays revealed cell-wall biosynthesis as the target of these antibiotics. PMID- 25923376 TI - Cationic Polyrotaxanes as a Feasible Framework for the Intracellular Delivery and Sustainable Activity of Anionic Enzymes: A Comparison Study with Methacrylate Based Polycations. AB - We have developed cationic polyrotaxanes composed of N,N-dimethylaminoethyl (DMAE) group-modified alpha-cyclodextrins (alpha-CDs) threaded along a poly(ethylene glycol) (PEG) chain capped with a terminal bulky stopper (DMAE-PRX) for the intracellular delivery of proteins through the polyelectrolyte complexation. Herein, to ascertain the effect of supramolecular backbone structure of cationic polyrotaxanes, the physicochemical properties and biological activity of polyelectrolyte complex with anionic beta-galactosidase (beta-gal) were investigated in comparison to a cationic linear polymer, poly[2 (N,N-dimethylaminoethyl) methacrylate] (PDMAEMA). In the cellular experiments, the DMAE-PRX/beta-gal complexes exhibited higher intracellular uptake of beta-gal and sustainable enzymatic activity of delivered beta-gal than the PDMAEMA/beta gal complexes. It is considered that the cationic polyrotaxanes are promising supramolecular backbone structure for the intracellular protein delivery. PMID- 25923375 TI - Ontogeny of the Digestive System of Atlantic Salmon (Salmo salar L.) and Effects of Soybean Meal from Start-Feeding. AB - Despite a long history of rearing Atlantic salmon in hatcheries in Norway, knowledge of molecular and physiological aspects of juvenile development is still limited. To facilitate introduction of alternative feed ingredients and feed additives during early phases, increased knowledge regarding the ontogeny of the digestive apparatus in salmon is needed. In this study, we characterized the development of the gastrointestinal tract and accessory digestive organs for five months following hatch by using histological, biochemical and molecular methods. Furthermore, the effects of a diet containing 16.7% soybean meal (SBM) introduced at start-feeding were investigated, as compared to a fishmeal based control diet. Salmon yolk sac alevins and fry were sampled at 18 time points from hatch until 144 days post hatch (dph). Histomorphological development was investigated at 7, 27, 46, 54 and 144 dph. Ontogenetic expression patterns of genes encoding key digestive enzymes, nutrient transporters, gastrointestinal peptide hormones and T cell markers were analyzed from 13 time points by qPCR. At 7 dph, the digestive system of Atlantic salmon alevins was morphologically distinct with an early stomach, liver, pancreas, anterior and posterior intestine. About one week before the yolk sac was internalized and exogenous feeding was started, gastric glands and developing pyloric caeca were observed, which coincided with an increase in gene expression of gastric and pancreatic enzymes and nutrient transporters. Thus, the observed organs seemed ready to digest external feed well before the yolk sac was absorbed into the abdominal cavity. In contrast to post-smolt Atlantic salmon, inclusion of SBM did not induce intestinal inflammation in the juveniles. This indicates that SBM can be used in compound feeds for salmon fry from start-feeding to at least 144 dph and/or 4-5 g body weight. PMID- 25923377 TI - A string reaction coordinate for the folding of a polymer chain. AB - We investigate the crystallization mechanism of a single, flexible homopolymer chain with short range attractions. For a sufficiently narrow attractive well, the system undergoes a first-order like freezing transition from an expanded disordered coil to a compact crystalline state. Based on a maximum likelihood analysis of committor values computed for configurations obtained by Wang-Landau sampling, we construct a non-linear string reaction coordinate for the coil-to crystal transition. In contrast to a linear reaction coordinate, the string reaction coordinate captures the effect of different degrees of freedom controlling different stages of the transition. Our analysis indicates that a combination of the energy and the global crystallinity parameter Q6 provide the most accurate measure for the progress of the transition. While the crystallinity paramter Q6 is most relevant in the initial stages of the crystallization, the later stages are dominated by a decrease in the potential energy. PMID- 25923378 TI - The culturome of the human nose habitats reveals individual bacterial fingerprint patterns. AB - The complex anatomy of the human nose might offer distinct microbial niches. Microbiota composition may affect nose inflammatory diseases and Staphylococcus aureus carriage. Considering different nasal cavity locations, microbial colonization was analysed across individuals exhibiting chronic nasal inflammatory diseases (n = 18) and those without local inflammation signs (n = 16). Samples were collected systematically during surgery and examined by an extensive culture-based approach and, for a subset, by 16S rRNA gene community profiling. Cultivation yielded 141 taxa with members of Staphylococcus, Corynebacterium and Propionibacterium as most common isolates comprising the nasal core culturome together with Finegoldia magna. Staphylococcus aureus was most frequently found in association with Staphylococcus epidermidis and Propionibacterium acnes, and the posterior vestibules were redefined as S. aureus' principle habitat. Culturome analysis revealed host-specific bacterial 'fingerprints' irrespective of host-driven factors or intranasal sites. Comparisons between cultivable and molecular fingerprints demonstrated that only a small fraction of phylotypes (6.2%) was correlated. While the total number of different phylotypes was higher in the molecular dataset, the total number of identifications down to the species level was higher in the culturomic approach. To determine host-specific microbiomes, the advantages of molecular approaches should be combined with the resolution and reliability of species identification by culturomic analyses. PMID- 25923379 TI - Chemical analysis of multicellular tumour spheroids. AB - Conventional two dimensional (2D) monolayer cell culture has been considered the 'gold standard' technique for in vitro cellular experiments. However, the need for a model that better mimics the three dimensional (3D) architecture of tissue in vivo has led to the development of Multicellular Tumour Spheroids (MTS) as a 3D tissue culture model. To some extent MTS mimic the environment of in vivo tumours where, for example, oxygen and nutrient gradients develop, protein expression changes and cells form a spherical structure with regions of proliferation, senescence and necrosis. This review focuses on the development of techniques for chemical analysis of MTS as a tool for understanding in vivo tumours and a platform for more effective drug and therapy discovery. While traditional monolayer techniques can be translated to 3D models, these often fail to provide the desired spatial resolution and z-penetration for live cell imaging. More recently developed techniques for overcoming these problems will be discussed with particular reference to advances in instrument technology for achieving the increased spatial resolution and imaging depth required. PMID- 25923380 TI - Elucidating the effects of primary blast on the eye. PMID- 25923381 TI - Challenging glaucoma with a water-drinking test. PMID- 25923383 TI - Proceedings of the 21st European Pediatric Rheumatology (PReS) Congress. PMID- 25923386 TI - DSM-5: what is new and what is next? PMID- 25923384 TI - TGF-beta Blood Levels Distinguish Between Influenza A (H1N1)pdm09 Virus Sepsis and Sepsis due to Other Forms of Community-Acquired Pneumonia. AB - There is a strong interest in finding adequate biomarkers to aid in the diagnosis and prognosis of influenza A (H1N1)pdm09 virus infection. In this study, serum levels of inflammatory cytokines and laboratory markers were evaluated to assess their usefulness as biomarkers of influenza A (H1N1)pdm09 and their association with fatal cases. Serum samples of consecutive patients with a clinical presentation suggestive of influenza A (H1N1)pdm09 and progression to sepsis were evaluated. Serum inflammatory cytokines and routine laboratory tests were performed and correlated with positivity for influenza A (H1N1)pdm09 influenza by real time reverse transcription polymerase chain reaction and the results of three clinical severity scores (Sequential Organ Failure Assessment [SOFA], CURB 65, and Acute Physiology and Chronic Health Evaluation II [APACHE II]). High SOFA scores and some of its individual components, but not CURB-65 or APACHE II scores, correlate with fatal cases regardless of etiology. Total and unconjugated bilirubin, Ca(++), Cl(-), prothrombin times, and partial thromboplastin times discriminate influenza A (H1N1)pdm09 from other causes of community-acquired pneumonia. High levels of IL-8, IL-10, and IL-17 were increased in influenza A (H1N1)pdm09 patients when compared with controls (p<0.05). IL-6 levels were significantly elevated in influenza A (H1N1)pdm09 patients and non-(H1N1)pdm09 patients when compared with controls (p<0.05). TGF-beta serum levels discern between healthy controls, influenza A (H1N1)pdm09 patients, and patients with other causes of community-acquired pneumonia. TGF-beta levels were negatively correlated with SOFA on admission in influenza A (H1N1)pdm09 patients. TGF-beta levels are a useful tool for differentiating influenza A (H1N1)pdm09 from other causes of pneumonia progressing to sepsis. PMID- 25923387 TI - Atypical antipsychotics in the treatment of pathological aggression in children and adolescents: literature review and clinical recommendations. AB - OBJECTIVE: To review the literature about the use of atypical antipsychotics in the treatment of pathological aggression in children and adolescents. METHOD: The databases MEDLINE, SciELO, and LILACS were searched for publications in Portuguese or English from 1992 to August 2011 using the following keywords: mental disease, child, adolescent, treatment, atypical antipsychotic, aggressive behavior, aggression, and violent behavior. RESULTS: Sixty-seven studies of good methodological quality and clinical interest and relevance were identified. Studies including children and adolescents were relatively limited, because few atypical antipsychotics have been approved by the Food and Drug Administration (FDA). All the medications included in this review (risperidone, olanzapine, quetiapine, ziprasidone, aripiprazole and clozapine) have some effectiveness in treating aggression in children and adolescents, and choices should be based on clinical indications and side effects. CONCLUSIONS: There are few studies about the effectiveness and safety of atypical antipsychotics for the pediatric population, and further randomized controlled studies with larger groups of patients and more diagnostic categories, such as severe conduct disorder and oppositional defiant disorder, should be conducted to confirm the results reported up to date and to evaluate the impact of long-term use. PMID- 25923388 TI - The Iowa Gambling Task (IGT) in Brazil: a systematic review. AB - BACKGROUND: Decision-making is a complex, multidimensional cognitive function that requires the choice between two or more options and also the predictive analysis of its consequences. One of the tools most widely used to assess decision-making in neuropsychological research is the Iowa Gambling Task (IGT). OBJECTIVE: To conduct a systematic review of articles reporting empirical IGT studies based in Brazil. METHOD: Articles were obtained from multiple journal databases including ISI Web of Knowledge, Scopus, SciELO, LILACS, and Scholar Google. RESULTS: Thirty-six studies were included in this review and divided into four categories according to main subject matter (psychiatry & personality; demographic & cultural variables; medical/clinic; and psychometric properties & test administration standardization). In general, there was a significant growth in research employing IGT (Chi2 = 17.6, df = 5, p = 0.0003), but this growth was restricted to a few geographic areas of Brazil. The psychiatry & personality subject matter was the most abundant, accounting for 14 publications (39% of the total sample). CONCLUSION: Since its first adaptation to Brazilian Portuguese in 2006, a growing interest in decision-making as measured by the IGT can be observed, with psychiatry & personality topics representing a large portion of the scientific inquiry to date. Nevertheless, in order to extend the initial results of Brazilian IGT decision-making research, more studies are necessary - across a more diverse range of topics, including demographic & cultural variables, and psychometric properties & test administration standardization, the areas least studied -, as is the dissemination of the IGT to more regions of the country. PMID- 25923389 TI - Cross-cultural adaptation and preliminary psychometric properties of the Affective Reactivity Index in Brazilian Youth: implications for DSM-5 measured irritability. AB - OBJECTIVE: To describe the cross-cultural adaptation of the Affective Reactivity Index (ARI) to Brazilian Portuguese and to investigate preliminary psychometric properties of the adapted version. METHODS: Cross-cultural adaptation was based on the investigation of the theoretical and operational equivalences of the original ARI in the Brazilian context, followed by a process of translation, back translation, and review by a committee of experts. Data analysis was carried out in a community sample of 133 schoolchildren aged 8 to 17 years to investigate the following characteristics of the ARI: 1) factor structure; 2) internal consistency; 3) construct validity comparing differential relationships between irritability and anxiety dimensions and impairment; and 4) item response theory (IRT) parameters. RESULTS: A final Brazilian Portuguese version of the instrument was defined and is presented. Internal consistency was good, and our analysis supported the original single-factor structure of the ARI. Correlations of the ARI with distress-related anxiety dimensions were higher than with phobic-related anxiety dimensions, supporting its construct validity. In addition, higher ARI scores were associated with higher irritability-related impairment. IRT analysis underscored frequency of loss of temper as essential to inform about pathological states of irritability. CONCLUSION: The Brazilian Portuguese version of the ARI seems to be very similar to the original instrument in terms of conceptual, item, semantic, and operational equivalence. Our preliminary analysis replicates and extends previous evidence confirming promising psychometric properties for the ARI. PMID- 25923390 TI - Beginning and end of treatment of patients who dropped out of psychoanalytic psychotherapy. AB - INTRODUCTION: Even though it is expected that patients and therapist will agree on when to terminate psychotherapy, quite often patients discontinue treatment on their own. This study aims to better understand dropout in psychoanalytic psychotherapy (PP). METHOD: Baseline and post-treatment interviews were conducted with six adult women classified by their therapists as dropout patients at a PP outpatient clinic. Results were analyzed using Bardin's content analysis. RESULTS: Content analysis generated five categories (reasons for treatment, goals, readiness to change, previous treatment, transference) for the baseline interviews and three categories (change process, results, interruption) for post treatment interviews. Unclear treatment goals, low readiness to change, early signs of negative transference and resistance, and absence of recognition of their own participation in problems emerged in baseline interviews. In most cases, the patient's evaluation of the therapeutic relationship was not determinant of dropout. Therapeutic gains, dissatisfaction, and resistance during the psychotherapeutic process seemed to be associated with noncompliance. CONCLUSIONS: Decisions to initiate, continue, or quit PP depend on multiple factors, such as initial goals, readiness to change, insight capacity, awareness of personal problems, resistance, and transference. However, these factors should be considered in view of the methodological limitations of this study. Further investigation of PP dropout is still necessary. PMID- 25923391 TI - Cultural aspects in dementia: differences in the awareness of Brazilian caregivers. AB - OBJECTIVE: To explore differences in disease awareness in participants of a psychoeducational group designed for Latin American caregivers of people with dementia. METHOD: We assessed participants of a group developed at an outpatient unit for Alzheimer's disease. Interpretative phenomenological analysis was used to analyze differences in the caregivers' reports. RESULTS AND DISCUSSION: The participants, mostly spouses and daughters, presented moderate caregiver burden and different levels of awareness (aware, partially aware, or unaware). Disease awareness and the development of coping strategies were influenced by familism, religiosity, and duty. Becoming a caregiver was considered positive in some cases, due to religious convictions and beliefs related to the importance of caregiving. Caregiver unawareness may reflect an attempt to maintain integrity of the patient's identity. CONCLUSIONS: Our data allow some comparisons across cultures, which may be valuable in assessing the influence of different psychosocial environments on the knowledge about dementia. PMID- 25923392 TI - Translation, adaptation, and preliminary validation of the Brazilian version of the Behavior Problems Inventory (BPI-01). AB - INTRODUCTION: Children with atypical development often present behavior problems that impair their psychosocial adaptation. OBJECTIVE: To describe the cultural adaptation to Brazilian Portuguese of the Behavior Problems Inventory (BPI-01), as well as preliminary indicators of instrument reliability and validity. METHODS: The process involved translation, back-translation, and cultural adaptation of the instrument. Psychometric properties (reliability and validity) were assessed comparing scores obtained with the BPI-01, the Wechsler Intelligence Scales for Children and Adults, the Child Behavior Checklist for Ages 6-18 (CBCL/6-18), and the Autism Screening Questionnaire (ASQ). The sample comprised 60 children (30 typically developing and 30 atypically developing). RESULTS: The cultural adaptation process was considered adequate. Internal consistency of the BPI-01 was satisfactory, with a Cronbach's alpha of 0.65 for the self-injurious behavior scale, 0.82 for stereotyped behaviors, and 0.91 for aggressive/destructive behaviors. Considering a mean frequency of 0.5, the receiver operating characteristic (ROC) curve revealed 80% sensitivity and 3% specificity in the stereotyped behavior scale, 50 and 10% in aggressive/destructive behaviors, and 76 and 6% in self-injurious behaviors, respectively. Low-to-moderate correlations were observed between BPI-01, ASQ, and CBCL/6-18 scores. CONCLUSION: BPI-01 showed good psychometric properties, with satisfactory preliminary indicators of reliability, convergent validity, and sensitivity for the diagnosis of atypical development. PMID- 25923393 TI - Assessment of changes in nicotine dependence, motivation, and symptoms of anxiety and depression among smokers in the initial process of smoking reduction or cessation: a short-term follow-up study. AB - INTRODUCTION: The first days of a quit attempt represent an important challenge to long-term abstinence, especially because of the changes that take place over this period. OBJECTIVE: To examine whether smokers who have recently changed their smoking behavior show changes in the intensity of nicotine dependence, motivational stage, or symptoms of anxiety and depression relative to smokers without recent changes in smoking behavior. METHODS: Smokers attending a support group for smoking cessation in Porto Alegre, southern Brazil, were invited to participate. The program consisted of four weekly sessions. Smokers answered questionnaires covering intensity of nicotine dependence, stage of motivation, and symptoms of anxiety and depression at baseline and in the fourth week. Urine was collected at both time points, tested for cotinine concentration, and used to determine the final status of smokers. RESULTS: Of the 54 smokers included in the study, 20 (37%) stopped smoking or decreased tobacco use. Both smokers who stopped or reduced tobacco use and those who did not change their behavior presented a decrease in nicotine dependence scores (p = 0.001). Conversely, only the smokers who changed behavior presented an increase in scores in the maintenance stage (p < 0.001). CONCLUSION: When modifying tobacco use, smokers face a difficult process, marked by several changes. A better understanding of these changes and their implications for treatment are discussed. PMID- 25923394 TI - Who are the children and adolescent patients of a national referral service of eating disorders in Brazil?: a cross-sectional study of a clinical sample. AB - OBJECTIVES: To investigate the sociodemographic and clinical profile of patients receiving treatment at a specialized service for children and adolescents with eating disorders (ED) in Sao Paulo, Brazil, and to compare data with the relevant literature. METHODS: This cross-sectional study assessed male and female patients with ED up to 18 years of age. All data were collected upon admission. RESULTS: A total of 100 subjects were assessed. Mean age was 15.41+/-0.18 years, and mean age at ED onset was 13.5+/-0.19 years. Mean disease duration was 21.06 +/-1.67 months. Of the total sample, 82% of the patients were female, 84% were Caucasian, 64% came from A and B economic tiers. Moreover, in 60% ED started at 14 years of age or less, and 74% had psychiatric comorbidities. Anorexia nervosa was the most prevalent diagnosis (43%). Hospitalized patients had lower body mass index, longer ED duration, and more severe scores on the Children's Global Assessment Scale than outpatients (p < 0.05). CONCLUSIONS: Our young Brazilian patients with ED present epidemiological and symptomatic characteristics very similar to those found in the scientific literature, including a high prevalence of psychiatric comorbidities. The higher frequency of full syndrome ED, the predominance of cases with an early onset, the delay in beginning specialized treatment, and the more severe state of inpatients provide grounds for concern because these factors differ from what has been reported in reference studies and indicate greater ED severity. PMID- 25923395 TI - Twenty years of electroconvulsive therapy in a psychiatric unit at a university general hospital. AB - OBJECTIVE: To describe the sociodemographic and clinical profile of patients who underwent electroconvulsive therapy (ECT) at a university general hospital. METHOD: In this retrospective study, records from all patients undergoing ECT between January 1988 and January 2008 at the psychiatric unit of the general hospital of Universidade Estadual de Campinas (UNICAMP) were reviewed. Telephone contact was made with patients/relatives to collect follow-up data. RESULTS: A total of 200 charts were reviewed. The majority of patients were women, with a mean age of 39 years, and history of psychiatric hospitalization. The main indications for ECT were depression and catatonia. Complications were observed in less than half of the cases, and most were temporary and not severe. There was a good psychiatric outcome for 89.7% of the patients, especially for catatonic patients (100%, p = 0.02). Thirty-four percent of the cases were later contacted by telephone calls, at a mean of 8.5 years between the procedure and the contact. Among these, three (1.5%) reported persistent memory disorders and 73% considered ECT a good treatment. CONCLUSION: ECT has been performed according to international guidelines. In the vast majority of cases, undesirable effects were temporary and not severe. Response to ECT was positive in most cases, particularly in catatonic patients. PMID- 25923396 TI - Migrant and Seasonal Farmworker Food Insecurity: Prevalence, Impact, Risk Factors, and Coping Strategies. AB - In the United States, nearly 15% of the general population is considered food insecure; ethnic minorities, particularly Latinos, experience disproportionately higher rates. Food insecurity is particularly endemic among the migrant and seasonal farmworker population. This article systematically reviews current knowledge related to the prevalence of food insecurity among migrant and seasonal farmworkers. The impact, risk factors, and coping strategies of food insecurity are also presented. The authors argue for targeted social work efforts at mezzo- and macrolevels and make recommendations aimed at the prevention and amelioration of food insecurity. PMID- 25923397 TI - Evaluation of schistocyte analysis by a novel automated digital cell morphology application. AB - INTRODUCTION: The CellaVision Advanced Red Blood Cell (RBC) Software Application is a new software for advanced morphological analysis of RBC, which automatically performs a preliminary characterization and grouping of RBC into 21 morphological categories, including schistocytes. Upon automated classification, the software offers the possibility of reclassification of RBC by the operator. The aim of this study was to evaluate the schistocyte analysis by the CellaVision Advanced RBC Application. METHODS: Schistocyte counts were evaluated comparing the automated count on a CellaVision DM96, both before and after reclassification, with the reference manual microscopic method according to the ICSH criteria. Thirty-six samples of hospitalized patients and 40 samples of controls were analyzed. RESULTS: Within-run, between-run and between-observer coefficients of variation were lower when counted with the CellaVision compared to the manual microscopic count. The very high sensitivity but rather poor specificity implicates the need for reclassification by the operator, following automated analysis. After reclassification, method comparison studies revealed good agreement with the manual microscopic method, with however slightly higher values of schistocytes for the automated analysis. CONCLUSION: The CellaVision Advanced RBC Software Application provides a sensitive and reproducible measurement of schistocytes in peripheral blood, but still requires manual revision. Furthermore, it is an easy-to-use software and an excellent teaching tool that might contribute to standardization in the investigation of schistocyte-related conditions. PMID- 25923398 TI - Translation and validation of a Spanish version of the xerostomia inventory. AB - OBJECTIVE: The aim of this study was to validate a Spanish cross-cultural adaptation of the xerostomia inventory (XI). MATERIALS AND METHODS: The original English version of XI was translated into Spanish, cross-culturally adapted and field tested. The Spanish version of XI (XI-Sp) was tested with a sample of 41 patients with xerostomia. The reliability of the XI-Sp was determined through internal consistency and test-retest methods. The construct validity of XI-Sp was determined by means of correlation between XI-Sp scores and salivary flow measurements. RESULTS: Overall XI-Sp scores were 40.8 (SD = 10) for the first application and 40.2 (SD = 9.5) for the second. Cronbach's alpha value for the XI Sp was 0.89 and 0.87, respectively, while interitem correlation averages were r = 0.44 and r = 0.39 for each application. Interitem correlation and corrected total was rc >=0.30. The test-retest intraclass correlation coefficient value for the XI-Sp score was 0.59 and 0.91. Convergent validity for construct validity correlation with salivary flow showed a medium effect size (r2 = 0.10) for the first application but did not make a statistically significant prediction for the second (r2 = 0.7). CONCLUSIONS: This study provides evidence concerning the reliability of the XI-Sp, showing that it may be a useful tool for Spanish speaking xerostomia patients for both clinical and epidemiologic research. PMID- 25923399 TI - Response to Osofsky's "Misrepresentation by Citation". PMID- 25923400 TI - A petal-specific InMYB1 promoter from Japanese morning glory: a useful tool for molecular breeding of floricultural crops. AB - Production of novel transgenic floricultural crops with altered petal properties requires transgenes that confer a useful trait and petal-specific promoters. Several promoters have been shown to control transgenes in petals. However, all suffer from inherent drawbacks such as low petal specificity and restricted activity during the flowering stage. In addition, the promoters were not examined for their ability to confer petal-specific expression in a wide range of plant species. Here, we report the promoter of InMYB1 from Japanese morning glory as a novel petal-specific promoter for molecular breeding of floricultural crops. First, we produced stable InMYB1_1kb::GUS transgenic Arabidopsis and Eustoma plants and characterized spatial and temporal expression patterns under the control of the InMYB1 promoter by histochemical beta-glucuronidase (GUS) staining. GUS staining patterns were observed only in petals. This result showed that the InMYB1 promoter functions as a petal-specific promoter. Second, we transiently introduced the InMYB1_1 kb::GUS construct into Eustoma, chrysanthemum, carnation, Japanese gentian, stock, rose, dendrobium and lily petals by particle bombardment. GUS staining spots were observed in Eustoma, chrysanthemum, carnation, Japanese gentian and stock. These results showed that the InMYB1 promoter functions in most dicots. Third, to show the InMYB1 promoter utility in molecular breeding, a MIXTA-like gene function was suppressed or enhanced under the control of InMYB1 promoter in Arabidopsis. The transgenic plant showed a conspicuous morphological change only in the form of wrinkled petals. Based on these results, the InMYB1 promoter can be used as a petal specific promoter in molecular breeding of floricultural crops. PMID- 25923401 TI - Absolute and relative morbidity burdens attributable to various illnesses and injuries, non-service member beneficiaries of the Military Health System, 2014. PMID- 25923402 TI - Medical Surveillance Monthly Report: The first 20 years. PMID- 25923404 TI - Hospitalizations among members of the active component, U.S. Armed Forces, 2014. PMID- 25923403 TI - Absolute and relative morbidity burdens attributable to various illnesses and injuries, U.S. Armed Forces, 2014. PMID- 25923405 TI - Ambulatory visits among members of the active component, U.S. Armed Forces, 2014. PMID- 25923406 TI - Surveillance snapshot: Illness and injury burdens among reserve component service members, U.S. Armed Forces, 2014. PMID- 25923407 TI - Surveillance snapshot: Illness and injury burdens among U.S. military recruit trainees, 2014. PMID- 25923408 TI - MiR-25 suppresses 3T3-L1 adipogenesis by directly targeting KLF4 and C/EBPalpha. AB - In the past decade, miRNA emerges as a vital player in orchestrating gene regulation and maintaining cellular homeostasis. It is well documented that miRNA influences a variety of biological events, including embryogenesis, cell fate decision, and cellular differentiation. Adipogenesis is an organized process of cellular differentiation by which pre-adipocytes differentiate towards mature adipocytes. It has been shown that adipogenesis is tightly modulated by a number of transcription factors such as PPARgamma, KLF4, and C/EBPalpha. However, the molecular mechanisms underlying the missing link between miRNA and adipogenesis related transcription factors remain elusive. In this study, we unveiled that miR 25, a member of miR-106b-25 cluster, was remarkably downregulated during 3T3-L1 adipogenesis. Restored expression of miR-25 significantly impaired 3T3-L1 adipogenesis and downregulated the expression of serial adipogenesis-related genes. Further experiments presented that ectopic expression of miR-25 did not affect cell proliferation and cell cycle progression. Finally, KLF4 and C/EBPalpha, two key regulators of adipocyte differentiation, were experimentally identified as bona fide targets for miR-25. These data indicate that miR-25 is a novel negative regulator of adipocyte differentiation and it suppressed 3T3-L1 adipogenesis by targeting KLF4 and C/EBPalpha, which provides novel insights into the molecular mechanism of miRNA-mediated cellular differentiation. PMID- 25923409 TI - Nanoscale surface chemistry directs the tunable assembly of silver octahedra into three two-dimensional plasmonic superlattices. AB - A major challenge in nanoparticle self-assembly is programming the large-area organization of a single type of anisotropic nanoparticle into distinct superlattices with tunable packing efficiencies. Here we utilize nanoscale surface chemistry to direct the self-assembly of silver octahedra into three distinct two-dimensional plasmonic superlattices at a liquid/liquid interface. Systematically tuning the surface wettability of silver octahedra leads to a continuous superlattice structural evolution, from close-packed to progressively open structures. Notably, silver octahedra standing on vertices arranged in a square lattice is observed using hydrophobic particles. Simulations reveal that this structural evolution arises from competing interfacial forces between the particles and both liquid phases. Structure-to-function characterizations reveal that the standing octahedra array generates plasmonic 'hotstrips', leading to nearly 10-fold more efficient surface-enhanced Raman scattering compared with the other more densely packed configurations. The ability to assemble these superlattices on the wafer scale over various platforms further widens their potential applications. PMID- 25923410 TI - Investigation of surface charge density on solid-liquid interfaces by modulating the electrical double layer. AB - A solid surface in contact with water or aqueous solution usually carries specific electric charges. These surface charges attract counter ions from the liquid side. Since the geometry of opposite charge distribution parallel to the solid-liquid interface is similar to that of a capacitor, it is called an electrical double layer capacitor (EDLC). Therefore, there is an electrical potential difference across an EDLC in equilibrium. When a liquid bridge is formed between two conducting plates, the system behaves as two serially connected EDLCs. In this work, we propose a new method for investigating the surface charge density on solid-liquid interfaces. By mechanically modulating the electrical double layers and simultaneously applying a dc bias voltage across the plates, an ac electric current can be generated. By measuring the voltage drop across a load resistor as a function of bias voltage, we can study the surface charge density on solid-liquid interfaces. Our experimental results agree very well with the simple equivalent electrical circuit model proposed here. Furthermore, using this method, one can determine the polarity of the adsorbed state on the solid surface depending on the material used. We expect this method to aid in the study of electrical phenomena on solid-liquid interfaces. PMID- 25923411 TI - Optimizing hybrid spreading in metapopulations. AB - Epidemic spreading phenomena are ubiquitous in nature and society. Examples include the spreading of diseases, information, and computer viruses. Epidemics can spread by local spreading, where infected nodes can only infect a limited set of direct target nodes and global spreading, where an infected node can infect every other node. In reality, many epidemics spread using a hybrid mixture of both types of spreading. In this study we develop a theoretical framework for studying hybrid epidemics, and examine the optimum balance between spreading mechanisms in terms of achieving the maximum outbreak size. We show the existence of critically hybrid epidemics where neither spreading mechanism alone can cause a noticeable spread but a combination of the two spreading mechanisms would produce an enormous outbreak. Our results provide new strategies for maximising beneficial epidemics and estimating the worst outcome of damaging hybrid epidemics. PMID- 25923412 TI - A molecular-based approach to the thermodynamics of aqueous solutions: binary mixture of water and carbon dioxide. AB - A simple model and theory of molecular fluids is applied to a binary mixture of water and carbon dioxide. An approach based on the perturbation theory is followed using a reference system of so-called pseudo-hard bodies for water and hard triatomics for carbon dioxide. Pseudo-hard bodies bear the traits of the non additive nature of association supplementing the common excluded volume effect. The reference term is parametrized using Monte Carlo simulation data on the compressibility factor. After adding a simple mean-field term to the reference equation, fluid phase equilibria are qualitatively reproduced. PMID- 25923413 TI - The Core Pattern Analysis on Chinese Herbal Medicine for Sjogren's syndrome: A Nationwide Population-Based Study. AB - This large-scale survey aimed to evaluate frequencies and patterns of Chinese herbal medicine (CHM) used for Sjogren's syndrome (SS) in Taiwan by analyzing the National Health Insurance Research Database (NHIRD) for cases in which CHM was used as an alternative therapy to Western medicine for improving patients' discomforts. We analyzed cases of SS principal diagnosis (ICD-9:710.2) with a catastrophic illness certificate (CIC) in traditional Chinese medicine (TCM) outpatient clinics from three cohorts of the Longitudinal Health Insurance Database (LHID) in the NHIRD between 2002 and 2011. CHM prescription patterns for SS were evaluated from claimed visitation files and corresponding prescription files. There were 15,914 SS patients with CIC (SS/CIC), and we found only 130 SS/CIC cases visiting TCM clinics in LHID2000, 133 in LHID2005, and 126 in LHID2010. After removing duplicate data, 366 SS/CIC and 4,867 visits were analyzed. The 50-59 year age group showed the highest ratio (29.51%) in both women and men. "Qi-Ju-Di-Huang-Wan" and "Xuan-Shen" (Scrophularia ningpoensis Hemsl.) was the most commonly used formula and single herb, respectively. "Qi-Ju Di-Huang-Wan, Gan-Lu-Yin, Xuan-Shen, Mai-Men-Dong (Ophiopogon japonicus (L. f.) Ker-Gawl.), and Sheng-Di-Huang (raw Rehmannia glutinosa Libosch)" were the core pattern prescriptions in treating SS/CIC. PMID- 25923414 TI - Arabidopsis thaliana CML25 mediates the Ca(2+) regulation of K(+) transmembrane trafficking during pollen germination and tube elongation. AB - The concentration alteration of cytosolic-free calcium ([Ca(2+) ]cyt ) is a well known secondary messenger in plants and plays important roles during pollen grain germination and tube elongation. Here we demonstrate that CML25, a member of calmodulin-like proteins, has Ca(2+) -binding activity and plays a role in pollen grain germination, tube elongation and seed setting. CML25 transcript was abundant in mature pollen grains and pollen tubes, and its product CML25 protein was primarily directed to the cytoplasm. Two independent CML25 loss-of-function T DNA insertion mutants suffered a major reduction in both the rate of pollen germination and the elongation of the pollen tube. Also, pollen grains of cml25 mutants were less sensitive to the external K(+) and Ca(2+) concentration than wild-type pollen. The disruption of CML25 increased the [Ca(2+) ]cyt in both the pollen grain and the pollen tube, which in turn impaired the Ca(2+) -dependent inhibition of whole-cell inward K(+) currents in protoplasts prepared from these materials (pollen grain and pollen tube). Complementation of cml25-1 mutant resulted in the recovery of wild-type phenotype. Our findings indicate that CML25 is an important transducer in the Ca(2+) -mediated regulation of K(+) influx during pollen germination and tube elongation. PMID- 25923416 TI - Feasibility studies of concomitant administration of optimized formulation of probiotic-loaded Vancomycin hydrochloride pellets for colon delivery. AB - Objective of this study was to develop Vancomycin HCl pellets loaded with Saccharomyces boulardii (S.b.) for pH-dependent system and CODESTM for augmenting the efficacy of Vancomycin HCl in the treatment of colitis. Pellets were prepared by extrusion-spheronization. In the pH-dependent system, the pellets were coated with Eudragit FS 30D. These pellets exhibited spherical form and a uniform surface coating. The CODESTM system consisted of three components: core containing mannitol, drug and probiotic, an inner acid-soluble coating layer, and an outer layer of enteric coating material. Statistical factorial design was used to optimize both formulations. Scanning electron micrographs of coated pellets revealed uniform coating. In vitro drug release of these coated pellets was studied sequentially in various buffers with (2%) and without rat cecal content for a period of 12 h. From the optimized pH-dependent formulation, F6 (20% w/w coating level and 15% w/v concentration of polymer), higher amount of probiotic was released in earlier time phase (first 5 h) as compared to the CODESTM and so R5 [containing acid-soluble inner coating layer (15% w/w coating level and 12% w/v concentration of Eudragit E100), and an outer layer of enteric coating material (12% w/w coating level and 10% w/v concentration of Eudragit L100)] was considered as the best formulation after confirming in vivo X-ray studies conducted on rabbits, suggesting that Vancomycin HCl and S.b. may be co administered as pellets [CODESTM] to enhance the effectiveness of Vancomycin HCl in the treatment of colitis without its associated side effects, which can only be confirmed after clinical trials. PMID- 25923415 TI - Mathematical modelling of metabolic regulation in aging. AB - The underlying cellular mechanisms that characterize aging are complex and multifaceted. However, it is emerging that aging could be regulated by two distinct metabolic hubs. These hubs are the pathway defined by the mammalian target of rapamycin (mTOR) and that defined by the NAD+-dependent deacetylase enzyme, SIRT1. Recent experimental evidence suggests that there is crosstalk between these two important pathways; however, the mechanisms underpinning their interaction(s) remains poorly understood. In this review, we propose using computational modelling in tandem with experimentation to delineate the mechanism(s). We briefly discuss the main modelling frameworks that could be used to disentangle this relationship and present a reduced reaction pathway that could be modelled. We conclude by outlining the limitations of computational modelling and by discussing opportunities for future progress in this area. PMID- 25923417 TI - Characterization of silicone pressure-sensitive adhesive episcleral implant for drug delivery. AB - The development of an effective sustained ocular drug delivery system remains a challenging task. The objective of the present study was to characterize a silicone pressure sensitive adhesive (PSA) episcleral implant system for transscleral drug delivery. Silicone PSA implants for dexamethasone, atenolol, and bovine serum albumin (BSA) were prepared at different polymer-to-drug mass ratios. Implant adhesion to human cadaver sclera was measured. Drug release experiments were conducted in well-stirred containers in vitro. The results were then analyzed using a pharmacokinetic model and in vitro-in vivo data comparison from previous studies. The silicone PSA episcleral implants in the present study had an average diameter of 3.5 mm and a thickness of 0.8 mm. Drug release from the silicone PSA implants was influenced by drug solubility, implant polymer content, and implant coating. Drug release from the implants was observed to follow the receding boundary release mechanism and was solubility dependent with the higher water solubility drug showing higher release rate than the low solubility drug. Increasing polymer content in the implants led to a significant decrease in the drug release rate. Coated implants reduced the initial burst effect and provided lower release rates than the uncoated implants. These implants provided sustained drug release that could last up to several months in vitro and demonstrated the potential to offer drug delivery for chronic ocular diseases via the transscleral route. PMID- 25923418 TI - Differential DNA methylation in umbilical cord blood of infants exposed to mercury and arsenic in utero. AB - Mercury and arsenic are known developmental toxicants. Prenatal exposures are associated with adverse childhood health outcomes that could be in part mediated by epigenetic alterations that may also contribute to altered immune profiles. In this study, we examined the association between prenatal mercury exposure on both DNA methylation and white blood cell composition of cord blood, and evaluated the interaction with prenatal arsenic exposure. A total of 138 mother-infant pairs with postpartum maternal toenail mercury, prenatal urinary arsenic concentrations, and newborn cord blood were assessed using the Illumina Infinium Methylation450 array. White blood cell composition was inferred from DNA methylation measurements. A doubling in toenail mercury concentration was associated with a 2.5% decrease (95% CI: 5.0%, 1.0%) in the estimated monocyte proportion. An increase of 3.5% (95% CI: 1.0, 7.0) in B-cell proportion was observed for females only. Among the top 100 CpGs associated with toenail mercury levels (ranked on P-value), there was a significant enrichment of loci located in North shore regions of CpG islands (P = 0.049), and the majority of these loci were hypermethylated (85%). Among the top 100 CpGs for the interaction between arsenic and mercury, there was a greater than expected proportion of loci located in CpG islands (P = 0.045) and in South shore regions (P = 0.009) and all of these loci were hypermethylated. This work supports the hypothesis that mercury may be contributing to epigenetic variability and immune cell proportion changes, and suggests that in utero exposure to mercury and arsenic, even at low levels, may interact to impact the epigenome. PMID- 25923419 TI - Tailored interventions to address determinants of practice. AB - BACKGROUND: Tailored intervention strategies are frequently recommended among approaches to the implementation of improvement in health professional performance. Attempts to change the behaviour of health professionals may be impeded by a variety of different barriers, obstacles, or factors (which we collectively refer to as determinants of practice). Change may be more likely if implementation strategies are specifically chosen to address these determinants. OBJECTIVES: To determine whether tailored intervention strategies are effective in improving professional practice and healthcare outcomes. We compared interventions tailored to address the identified determinants of practice with either no intervention or interventions not tailored to the determinants. SEARCH METHODS: We conducted searches of The Cochrane Library, MEDLINE, EMBASE, PubMed, CINAHL, and the British Nursing Index to May 2014. We conducted a final search in December 2014 (in MEDLINE only) for more recently published trials. We conducted searches of the metaRegister of Controlled Trials (mRCT) in March 2013. We also handsearched two journals. SELECTION CRITERIA: Cluster-randomised controlled trials (RCTs) of interventions tailored to address prospectively identified determinants of practice, which reported objectively measured professional practice or healthcare outcomes, and where at least one group received an intervention designed to address prospectively identified determinants of practice. DATA COLLECTION AND ANALYSIS: Two review authors independently assessed quality and extracted data. We undertook qualitative and quantitative analyses, the quantitative analysis including two elements: we carried out 1) meta regression analyses to compare interventions tailored to address identified determinants with either no interventions or an intervention(s) not tailored to the determinants, and 2) heterogeneity analyses to investigate sources of differences in the effectiveness of interventions. These included the effects of: risk of bias, use of a theory when developing the intervention, whether adjustment was made for local factors, and number of domains addressed with the determinants identified. MAIN RESULTS: We added nine studies to this review to bring the total number of included studies to 32 comparing an intervention tailored to address identified determinants of practice to no intervention or an intervention(s) not tailored to the determinants. The outcome was implementation of recommended practice, e.g. clinical practice guideline recommendations. Fifteen studies provided enough data to be included in the quantitative analysis. The pooled odds ratio was 1.56 (95% confidence interval (CI) 1.27 to 1.93, P value < 0.001). The 17 studies not included in the meta-analysis had findings showing variable effectiveness consistent with the findings of the meta regression. AUTHORS' CONCLUSIONS: Despite the increase in the number of new studies identified, our overall finding is similar to that of the previous review. Tailored implementation can be effective, but the effect is variable and tends to be small to moderate. The number of studies remains small and more research is needed, including trials comparing tailored interventions to no or other interventions, but also studies to develop and investigate the components of tailoring (identification of the most important determinants, selecting interventions to address the determinants). Currently available studies have used different methods to identify determinants of practice and different approaches to selecting interventions to address the determinants. It is not yet clear how best to tailor interventions and therefore not clear what the effect of an optimally tailored intervention would be. PMID- 25923421 TI - Uniform Microparticles with Controllable Highly Interconnected Hierarchical Porous Structures. AB - A simple and versatile strategy is developed for one-step fabrication of uniform polymeric microparticles with controllable highly interconnected hierarchical porous structures. Monodisperse water-in-oil-in-water (W/O/W) emulsions, with methyl methacrylate, ethylene glycol dimethacrylate, and glycidyl methacrylate as the monomer-containing oil phase, are generated from microfluidics and used for constructing the microparticles. Due to the partially miscible property of oil/aqueous phases, the monodisperse W/O/W emulsions can deform into desired shapes depending on the packing structure of inner aqueous microdrops, and form aqueous nanodrops in the oil phase. The deformed W/O/W emulsions allow template syntheses of highly interconnected hierarchical porous microparticles with precisely and individually controlled pore size, porosity, functionality, and particle shape. The microparticles elaborately combine the advantages of enhanced mass transfer, large functional surface area, and flexibly tunable functionalities, providing an efficient strategy to physically and chemically achieve enhanced synergetic performances for extensive applications. This is demonstrated by using the microparticles for oil removal for water purification and protein adsorption for bioseparation. The method proposed in this study provides full versatility for fabrication of functional polymeric microparticles with controllable hierarchical porous structures for enhancing and even broadening their applications. PMID- 25923422 TI - Symptomatic Abdominal Mass. Gastric duplication. PMID- 25923424 TI - Epidemiological and Economic Impact of Monovalent and Pentavalent Rotavirus Vaccines in Low and Middle Income Countries: A Cost-effectiveness Modeling Analysis. AB - BACKGROUND: The competing choices of vaccination with either RV1 or RV5, the potential budget impact of vaccines on the EPI with different prices and new evidence make important an updated analysis for health decision makers in each country. The objective of this study is to assess cost-effectiveness of the monovalent and pentavalent rotavirus vaccines and impact on children deaths, inpatient and outpatient visits in 116 low and middle income countries that represent approximately 99% of rotavirus mortality. METHODS: A decision tree model followed hypothetical cohorts of children from birth up to 5 years of age for each country in 2010. Inputs were gathered from international databases and previous research on incidence and effectiveness of monovalent and pentavalent vaccines. Costs were expressed in 2010 international dollars. Outcomes were reported in terms of cost per disability-adjusted life-year averted, comparing no vaccination with either monovalent or pentavalent mass introduction. Vaccine price was assumed fixed for all world low-income and middle-income countries. RESULTS: Around 292,000 deaths, 3.34 million inpatient cases and 23.09 million outpatient cases would occur with no vaccination. In the base-case scenario, monovalent vaccination would prevent 54.7% of inpatient cases and 45.4% of deaths. Pentavalent vaccination would prevent 51.4% of inpatient cases and 41.1% of deaths. The vaccine was cost-effective in all world countries in the base-case scenario for both vaccines. Cost per disability-adjusted life-year averted in all selected countries was I$372 for monovalent, and I$453 for pentavalent vaccination. CONCLUSION: Rotavirus vaccine is cost-effective in most analyzed countries. Despite cost-effectiveness analysis is a useful tool for decision making in middle-income countries, for low-income countries health decision makers should also assess the impact of introducing either vaccine on local resources and budget impact analysis of vaccination. PMID- 25923423 TI - Transcriptomics profiling study of breast cancer from Kingdom of Saudi Arabia revealed altered expression of Adiponectin and Fatty Acid Binding Protein4: Is lipid metabolism associated with breast cancer? AB - BACKGROUND: Breast cancer incidence rates are increasing at an alarming rate among Saudi Arabian females. Most molecular genetic discoveries on breast cancer and other cancers have arisen from studies examining European and American patients. However, possibility of specific changes in molecular signature among cancer patients of diverse ethnic groups remains largely unexplored. We performed transcriptomic profiling of surgically-resected breast tumors from 45 patients based in the Western region of Saudi Arabia using Affymetrix Gene 1.0 ST chip. Pathway and biological function-based clustering was apparent across the tissue samples. RESULTS: Pathway analysis revealed canonical pathways that had not been previously implicated in breast cancer. Biological network analysis of differentially regulated genes revealed that Fatty acid binding protein 4, adipocyte (FABP4), adiponectin (ADIPOQ), and retinol binding protein 4 (RBP4) were most down regulated genes, sharing strong connection with the other molecules of lipid metabolism pathway. The marked biological difference in the signatures uncovered between the USA and Saudi samples underpins the importance of this study. Connectivity Map identified compounds that could reverse an observed gene expression signature CONCLUSIONS: This study describes, to our knowledge, the first genome-wide profiling of breast cancer from Saudi ethnic females. We demonstrate the involvement of the lipid metabolism pathway in the pathogenesis of breast cancer from this region. This finding also highlights the need for strategies to curb the increasing rates of incidence of this disease by educating the public about life-style risk factors such as unhealthy diet and obesity. PMID- 25923425 TI - Impact of Rotavirus Vaccination on Childhood Hospitalization for Seizures. AB - BACKGROUND: Rotavirus vaccine (RV) might reduce the risk of hospitalization due to childhood seizures (CS). We aimed to identify and assess variations in the incidence of hospitalizations for CS among children <5 years of age before and after RV introduction. METHODS: Annual hospitalization rates for any kind of CS, before and after RV introduction in 2007, were calculated using the official surveillance system for hospitalization data. RESULTS: Our study cohort totaled 6149 children <5 years of age admitted to the hospital between 2003 and 2013 with any kind of CS (780.3* + 779.0* + 333.2* + 345* ICD-9-CM code). The annual hospitalization rates for any kind of CS in children <5 years of age were correlated with RV coverage (r = -0.673; P = 0.033) and rotavirus acute gastroenteritis admission rates (rho = 0.506; P = 0.001), with decrease rates ranging from 16.2% (95% confidence interval: 8.3-23.5%) in 2007 to 34.0% (27.3 40.1%) in 2010, as compared with the median rate of the pre-vaccination period (2003 to 2006). Similarly, for convulsions (780.3*ICD-9-CM code), the decrease seen in children <5 years of age was significantly correlated with the increase in RV coverage (r = -0.747; P = 0.013) and rotavirus acute gastroenteritis admission rates (rho = 0.543; P < 0.001), with decrease rates ranging from 18.7% (9.6-26.8%) in 2007 to 42.5% (35.3-48.9%) in 2012. Significant results were also obtained for infants <12 months and infants 1-2 years of age. In the remaining age groups or diagnostic categories analyzed, changes were either not significant or not related to vaccination changes or rotavirus acute gastroenteritis admission rates. CONCLUSIONS: Our results show that rotavirus vaccination may have a significant impact in the decrease in seizure-related hospitalizations in childhood. This additional benefit of rotavirus vaccination seems more marked in the youngest infants. PMID- 25923426 TI - Bacterial and Respiratory Viral Interactions in the Etiology of Acute Otitis Media in HIV-infected and HIV-uninfected South African Children. AB - BACKGROUND: Bacteria and respiratory viruses are implicated in the pathogenesis of acute otitis media (AOM); however, data from low-middle income countries are sparse. We investigated the etiology of AOM in HIV-infected (HIV+), HIV uninfected (HIV-) and HIV-exposed clinically asymptomatic for HIV-infection (HEU) South African children. METHODS: Children >=3 months to <5 years of age with AOM were enrolled between May 2009 and April 2010 (NCT01031082). Middle ear fluid samples were cultured for bacteria; antibacterial susceptibility was done and serotyping undertaken for Streptococcus pneumoniae and Haemophilus influenzae. Nasopharyngeal aspirates were analyzed for respiratory viruses using immunofluorescence assay and polymerase chain reaction. RESULTS: Of 260 AOM episodes (HIV+:15; HIV-:182; HEU:63), bacteria were found in 54.6%, including Haemophilus influenzae (30.8%), 98.8% of which were nontypeable, and Streptococcus pneumoniae (20.4%), Staphylococcus aureus (15.8%), Moraxella catarrhalis (5.0%) and Streptococcus pyogenes (1.5%). Nonsusceptibility of Streptococcus pneumoniae to penicillin was 64.2%. Respiratory viruses were detected in 74.2% of cases. Human rhinovirus was most frequently detected (37.7%), followed by adenovirus (14.2%) and human bocavirus (11.5%) overall and irrespective of HIV status. Respiratory viruses were identified concurrently with S. pneumoniae, H. influenzae, M. catarrhalis (76.9-78.8%) and Staphylococcus aureus (63.4%) cultured from middle ear fluid, as well as in 72.0% of episodes negative for any bacteria. CONCLUSION: The study suggests that respiratory viruses and pathogenic bacteria play an important role in the development of AOM in children. A similar spectrum of pathogens was observed independently of HIV status. Vaccines targeting both nontypeable Haemophilus influenzae and S. pneumoniae may have a broad impact on AOM in South Africa. PMID- 25923427 TI - Clinical and Virological Characteristics of Early and Moderate Preterm Infants Readmitted With Viral Respiratory Infections. AB - BACKGROUND: Rehospitalization of children born prematurely (referred to as preterm children) caused by severe respiratory infections is common. Most studies have focused on respiratory syncytial virus infection. We designed a study to determine the virological and clinical characteristics of severe respiratory infections of children born early (<32 weeks) and moderate preterm (32 to 36 weeks), and compared them with full term (FT; >=37 weeks) children who were subsequently admitted with respiratory illness. METHODS: A 7-year observational prospective study was conducted on preterm and FT children, less than 14 years old hospitalized with respiratory infection. The presence of 16 respiratory viruses in nasopharyngeal aspirates was sought. Clinical and virological characteristics of subjects were compared among term and preterm children. RESULTS: We studied 411 respiratory hospital admissions of 262 preterm children who were compared with 2057 respiratory hospital admissions of term children. In 78.6% of preterm episodes, at least 1 respiratory virus was identified. The most frequent viruses were respiratory syncytial virus (29%), rhinovirus (25%) and human bocavirus (13%). Human metapneumovirus and parainfluenza virus were significantly more frequent in preterm than in term children (P < 0.001 and P = 0.017, respectively). Early preterm (EPT) infants admitted with bronchiolitis presented more hypoxia (P = 0.08), longer hospital stay (P = 0.05), more infiltrate on chest radiograph (P = 0.02) and more antibiotic treatment (P = 0.02) than moderate preterm (MPT) infants. Moreover, MPT needed more intensive care unit admission than FT infants (P < 0.001). Regarding wheezing episodes, EPT patients showed significantly more infiltrate/atelectasis (P < 0.001), longer oxygen therapy (P = 0.039) and longer hospital stay (P = 0.07) than MPT children, although similar percentage of intensive care unit admission was seen in both groups. MPT-wheezy children needed longer hospital stay than FT (P = 0.05). Previous bronchiolitis and EPT were independent factors associated with multiple wheezing admissions. CONCLUSION: Our results demonstrate that besides respiratory syncytial virus, other viruses mainly rhinovirus and human bocavirus are important pathogens in severe respiratory infections in preterm children. Human metapneumovirus and parainfluenza virus seem also to play a significant role in this group of children. There is increased medical resource utilization, not only among EPT but also in MPT hospitalized children with respiratory infections as many of them require more medical support than FT children. PMID- 25923428 TI - Mechanisms of glycosylation reactions studied by low-temperature nuclear magnetic resonance. PMID- 25923429 TI - Free Extracellular miRNA Functionally Targets Cells by Transfecting Exosomes from Their Companion Cells. AB - Lymph node and spleen cells of mice doubly immunized by epicutaneous and intravenous hapten application produce a suppressive component that inhibits the action of the effector T cells that mediate contact sensitivity reactions. We recently re-investigated this phenomenon in an immunological system. CD8+ T lymphocyte-derived exosomes transferred suppressive miR-150 to the effector T cells antigen-specifically due to exosome surface coat of antibody light chains made by B1a lymphocytes. Extracellular RNA (exRNA) is protected from plasma RNases by carriage in exosomes or by chaperones. Exosome transfer of functional RNA to target cells is well described, whereas the mechanism of transfer of exRNA free of exosomes remains unclear. In the current study we describe extracellular miR-150, extracted from exosomes, yet still able to mediate antigen-specific suppression. We have determined that this was due to miR-150 association with antibody-coated exosomes produced by B1a cell companions of the effector T cells, which resulted in antigen-specific suppression of their function. Thus functional cell targeting by free exRNA can proceed by transfecting companion cell exosomes that then transfer RNA cargo to the acceptor cells. This contrasts with the classical view on release of RNA-containing exosomes from the multivesicular bodies for subsequent intercellular targeting. This new alternate pathway for transfer of exRNA between cells has distinct biological and immunological significance, and since most human blood exRNA is not in exosomes may be relevant to evaluation and treatment of diseases. PMID- 25923430 TI - Transplantation of Human Neural Progenitor Cells Expressing IGF-1 Enhances Retinal Ganglion Cell Survival. AB - We have previously characterized human neuronal progenitor cells (hNP) that can adopt a retinal ganglion cell (RGC)-like morphology within the RGC and nerve fiber layers of the retina. In an effort to determine whether hNPs could be used a candidate cells for targeted delivery of neurotrophic factors (NTFs), we evaluated whether hNPs transfected with an vector that expresses IGF-1 in the form of a fusion protein with tdTomato (TD), would increase RGC survival in vitro and confer neuroprotective effects in a mouse model of glaucoma. RGCs co-cultured with hNPIGF-TD cells displayed enhanced survival, and increased neurite extension and branching as compared to hNPTD or untransfected hNP cells. Application of various IGF-1 signaling blockers or IGF-1 receptor antagonists abrogated these effects. In vivo, using a model of glaucoma we showed that IOP elevation led to reductions in retinal RGC count. In this model, evaluation of retinal flatmounts and optic nerve cross sections indicated that only hNPIGF-TD cells effectively reduced RGC death and showed a trend to improve optic nerve axonal loss. RT-PCR analysis of retina lysates over time showed that the neurotrophic effects of IGF 1 were also attributed to down-regulation of inflammatory and to some extent, angiogenic pathways. This study shows that neuronal progenitor cells that hone into the RGC and nerve fiber layers may be used as vehicles for local production and delivery of a desired NTF. Transplantation of hNPIGF-TD cells improves RGC survival in vitro and protects against RGC loss in a rodent model of glaucoma. Our findings have provided experimental evidence and form the basis for applying cell-based strategies for local delivery of NTFs into the retina. Application of cell-based delivery may be extended to other disease conditions beyond glaucoma. PMID- 25923431 TI - Ozone-Induced Rice Grain Yield Loss Is Triggered via a Change in Panicle Morphology That Is Controlled by ABERRANT PANICLE ORGANIZATION 1 Gene. AB - Rice grain yield is predicted to decrease in the future because of an increase in tropospheric ozone concentration. However, the underlying mechanisms are unclear. Here, we investigated the responses to ozone of two rice (Oryza Sativa L.) cultivars, Sasanishiki and Habataki. Sasanishiki showed ozone-induced leaf injury, but no grain yield loss. By contrast, Habataki showed grain yield loss with minimal leaf injury. A QTL associated with grain yield loss caused by ozone was identified in Sasanishiki/Habataki chromosome segment substitution lines and included the ABERRANT PANICLE ORGANIZATION 1 (APO1) gene. The Habataki allele of the APO1 locus in a near-isogenic line also resulted in grain yield loss upon ozone exposure, suggesting APO1 involvement in ozone-induced yield loss. Only a few differences in the APO1 amino acid sequences were detected between the cultivars, but the APO1 transcript level was oppositely regulated by ozone exposure: i.e., it increased in Sasanishiki and decreased in Habataki. Interestingly, the levels of some phytohormones (jasmonic acid, jasmonoyl-L isoleucine, and abscisic acid) known to be involved in attenuation of ozone induced leaf injury tended to decrease in Sasanishiki but to increase in Habataki upon ozone exposure. These data indicate that ozone-induced grain yield loss in Habataki is caused by a reduction in the APO1 transcript level through an increase in the levels of phytohormones that reduce leaf damage. PMID- 25923433 TI - Mesenchymal Stromal Cell Therapy in Hematology: From Laboratory to Clinic and Back Again. AB - There is currently major interest to use mesenchymal stromal cells (MSCs) for a very diverse range of therapeutic applications. This stems mainly from the immunosuppressive qualities and differentiation capacity of these cells. In this review, we focus on cell therapy applications for MSCs in hematology. In this domain, MSCs are used for the treatment or prevention of graft-versus-host disease, support of hematopoiesis, or repair of tissue toxicities after hematopoietic cell transplantation. We critically review the accumulating clinical data and elaborate on complications that might arise from treatment with MSCs. In addition, we assume that the real clinical benefit of using MSCs for these purposes can only be estimated by a better understanding of the influence of in vitro expansion on the biological properties of these cells as well as by more harmonization of the currently used expansion protocols. PMID- 25923432 TI - Peptides of presenilin-1 bind the amyloid precursor protein ectodomain and offer a novel and specific therapeutic approach to reduce beta-amyloid in Alzheimer's disease. AB - beta-Amyloid (Abeta) accumulation in the brain is widely accepted to be critical to the development of Alzheimer's disease (AD). Current efforts at reducing toxic Abeta40 or 42 have largely focused on modulating gamma-secretase activity to produce shorter, less toxic Abeta, while attempting to spare other secretase functions. In this paper we provide data that offer the potential for a new approach for the treatment of AD. The method is based on our previous findings that the production of Abeta from the interaction between the beta-amyloid precursor protein (APP) and Presenilin (PS), as part of the gamma-secretase complex, in cell culture is largely inhibited if the entire water-soluble NH2 terminal domain of PS is first added to the culture. Here we demonstrate that two small, non-overlapping water-soluble peptides from the PS-1 NH2-terminal domain can substantially and specifically inhibit the production of total Abeta as well as Abeta40 and 42 in vitro and in vivo in the brains of APP transgenic mice. These results suggest that the inhibitory activity of the entire amino terminal domain of PS-1 on Abeta production is largely focused in a few smaller sequences within that domain. Using biolayer interferometry and confocal microscopy we provide evidence that peptides effective in reducing Abeta give a strong, specific and biologically relevant binding with the purified ectodomain of APP 695. Finally, we demonstrate that the reduction of Abeta by the peptides does not affect the catalytic activities of beta- or gamma-secretase, or the level of APP. P4 and P8 are the first reported protein site-specific small peptides to reduce Abeta production in model systems of AD. These peptides and their derivatives offer new potential drug candidates for the treatment of AD. PMID- 25923434 TI - Effect of chemical stabilizers on the thermostability and infectivity of a representative panel of freeze dried viruses. AB - As a partner of the European Virus Archive (EVA) FP7 project, our laboratory maintains a large collection of freeze-dried viruses. The distribution of these viruses to academic researchers, public health organizations and industry is one major aim of the EVA consortium. It is known that lyophilization requires appropriate stabilizers to prevent inactivation of the virus. However, few studies have investigated the influence of different stabilizers and lyophilization protocols on the thermostability of different viruses. In order to identify optimal lyophilization conditions that will deliver maximum retention of viral infectivity titre, different stabilizer formulations containing trehalose, sorbitol, sucrose or foetal bovine serum were evaluated for their efficacy in stabilizing a representative panel of freeze dried viruses at different storage temperatures (-20 degrees C, +4 degrees C and +20 degrees C) for one week, the two latter mimicking suboptimal shipping conditions. The Tissue Culture Infectious Dose 50% (TCID50) assay was used to compare the titres of infectious virus. The results obtained using four relevant and model viruses (enveloped/non enveloped RNA/DNA viruses) still serve to improve the freeze drying conditions needed for the development and the distribution of a large virus collection. PMID- 25923436 TI - Anesthesia Workload Nationally During Regular Workdays and Weekends. AB - BACKGROUND: We analyze data from the American Society of Anesthesiologist's (ASA) Anesthesia Quality Institute (AQI) to report the U.S. anesthesia workload by time of day and day of the week. We consider the extent to which first case starts, rather than durations of workdays and weekend cases, influence the number of anesthesia providers nationally. METHODS: The ASA AQI data were from all the U.S. anesthesia groups that submitted cases to the National Anesthesia Clinical Outcomes Registry (NACOR) for all 12 months of 2013. For each of the n = 2,075,188 cases, we identified the local date and time of the start of anesthesia care, duration of anesthesia care, and the local time zone. Anesthesia workload was measured as the time from the start to the end of continuous anesthesia care. Data are reported as mean +/- SEM with 95% confidence intervals (CIs). RESULTS: Half (53.0% +/- 0.6%) of the ASA AQI-reported weekly anesthesia workload was completed by 1:00 PM, local time, on regular workdays. The busiest 8-hour interval was from 7:30 AM to 3:30 PM and accounted for 70.3% +/- 0.7% of anesthetic minutes. Although most facilities completed the majority of their weekly anesthesia workload in the mornings of regular workdays (P < 0.0001; 62.3%; CI, 58.6%-66.1%), just 24.4% of the University and large community hospitals did so (P = 0.0008 relative to half; CI, 13.8%-38.4%). CONCLUSIONS: The results are inconsistent with widespread use of surgical facilities (i.e., anesthesia providers) in mornings only, especially at University and large community hospitals. The observed national work hours match with what would be expected if most anesthesiologists work at least 8 hours on regular workdays. Opportunity for greater use of the capital (building and equipment) probably would involve the use of additional anesthesia providers representing a second shift or use of weekends. PMID- 25923435 TI - Reversal of Pipecuronium-Induced Moderate Neuromuscular Block with Sugammadex in the Presence of a Sevoflurane Anesthetic: A Randomized Trial. AB - BACKGROUND: Pipecuronium is a steroidal neuromuscular blocking agent. Sugammadex, a relaxant binding gamma-cyclodextrin derivative, reverses the effect of rocuronium, vecuronium, and pancuronium. We investigated whether sugammadex reverses moderate pipecuronium-induced neuromuscular blockade (NMB) and the doses required to achieve reversal. METHODS: This single-center, randomized, double blind, 5-group parallel-arm study comprised 50 patients undergoing general anesthesia with propofol, sevoflurane, fentanyl, and pipecuronium. Neuromuscular monitoring was performed with acceleromyography (TOF-Watch SX) according to international standards. When the NMB recovered spontaneously to train-of-four count 2, patients randomly received 1.0, 2.0, 3.0, or 4.0 mg/kg of sugammadex or placebo. Recovery time from sugammadex injection to normalized train-of-four (TOF) ratio 0.9 was the primary outcome variable. The recovery time from the sugammadex injection to final T1 was the secondary end point. Postoperative neuromuscular functions were also assessed. RESULTS: Each patient who received sugammadex recovered to a normalized TOF ratio of 0.9 within 5.0 minutes (95% lower confidence interval for the lowest dose 70.1%; for all doses 90.8%) and 79% of these patients reached a normalized TOF ratio 0.9 within 2.0 minutes (95% lower confidence interval for the lowest dose 26.7%; for all doses 63.7%). T1 recovered several minutes after the TOF ratio. No residual postoperative NMB was observed. CONCLUSIONS: Sugammadex adequately and rapidly reverses pipecuronium induced moderate NMB during sevoflurane anesthesia. Once the train-of-four count has spontaneously returned to 2 responses following pipecuronium administration, a dose of 2.0 mg/kg of sugammadex is sufficient to reverse the NMB. PMID- 25923437 TI - A single consent for serial anesthetics in burn surgery. AB - Obtaining anesthesia informed consent for a series of repetitive debridements in burn-injured patients requires a significant time investment for anesthesiologists and patient families. A single consent form was introduced that covered multiple related anesthetics in burn patients. The number of consents per patient before and after implementation was analyzed using Welch ANOVA; Tukey Kramer post hoc test, with 99% confidence intervals for mean differences was used to examine pairwise comparisons. The mean number of consents per patient was 4.5 +/- 2.8 and 1.6 +/- 0.51 (P < 0.001) before (2010) and after implementation (2013), respectively. The Multiple Related Anesthetics Consent Form in this population resulted in less time spent by anesthesia providers in obtaining consent for patients undergoing multiple related procedures while providing patient- and family-centric care. PMID- 25923438 TI - Chinese herbal therapy and Western drug use, belief and adherence for hypertension management in the rural areas of Heilongjiang province, China. AB - BACKGROUND: Traditional Chinese medicine (TCM) including Chinese herbal therapy has been widely practiced in China. However, little is known about Chinese herbal therapy use for hypertension management, which is one of the most prevalent chronic conditions in China. Thus we described Chinese herbal therapy and western drug users, beliefs, hypertension knowledge, and Chinese herbal and western drug adherence and determinants of Chinese herbal therapy use among patients with hypertension in rural areas of Heilongjiang Province, China. METHODOLOGY AND PRINCIPAL FINDINGS: This face-to-face cross sectional survey included 665 hypertensive respondents aged 30 years or older in rural areas of Heilongjiang Province, China. Of 665 respondents, 39.7% were male, 27.4% were aged 65 years or older. At the survey, 14.0% reported using Chinese herbal therapy and 71.3% reported using western drug for hypertension management. A majority of patients had low level of treatment adherence (80.6% for the Chinese herbal therapy users and 81.2% for the western drug users). When respondents felt that their blood pressure was under control, 72.0% of the Chinese herbal therapy users and 69.2% of the western drug users sometimes stopped taking their medicine. Hypertensive patients with high education level or better quality of life are more likely use Chinese herbal therapy. CONCLUSIONS AND SIGNIFICANCE: Majority of patients diagnosed with hypertension use western drugs to control blood pressure. Chinese herbal therapy use was associated with education level and quality of life. PMID- 25923439 TI - Different survival of Barcelona clinic liver cancer stage C hepatocellular carcinoma patients by the extent of portal vein invasion and the type of extrahepatic spread. AB - Portal vein invasion (PVI) and extrahepatic spread (ES) are two tumor-related factors that define advanced stage in the Barcelona Clinic Liver Cancer (BCLC) staging system (BCLC stage C), and the recommended first line therapy in this stage is sorafenib. However, the extent of PVI and the type of ES may affect patient prognosis as well as treatment outcome. This study analyzed survival of BCLC stage C HCC patients in order to see whether sub-classification of BCLC stage C is necessary. A total of 582 treatment naive, BCLC stage C HCC patients [age: 54.3 +/- 10.8 years, males = 494 (84.9%), hepatitis B virus (458, 78.7%)], defined by PVI and/or ES, were analyzed. Extent of PVI was divided into none, type I-segmental/sectoral branches, type II-left and/or right portal vein, and type III-main portal vein trunk. Type of ES was divided into nodal and distant metastasis. The extent of PVI and type of ES were independent factors for survival. When patients were sub-classified according to the extent of PVI and type of ES, the median survival was significantly different [11.7 months, 5.7 months, 4.9 months and 2.3 months for C1 (PVI-O/I without distant ES), C2 (PVI II/III without distant ES), C3 (PVI-0/I with distant ES), and C4 (PVI-II/III with distant ES), respectively, P = 0.01]. Patients' survival was different according to the treatment modality in each sub-stage. Sub-classification of BCLC stage C according to the extent of PVI and type of ES resulted in a better prediction of survival. Also, different outcome was observed by treatment modalities in each sub-stage. Sub-classification of BCLC stage C is required to minimize heterogeneity within the same tumor stage, that will help better predict survival and to select optimal treatment strategies. PMID- 25923440 TI - Analysis of GzmbCre as a Model System for Gene Deletion in the Natural Killer Cell Lineage. AB - The analysis of gene function in mature and activated natural killer cells has been hampered by the lack of model systems for Cre-mediated recombination in these cells. Here we have investigated the utility of GzmbCre for recombination of loxp sequences in these cells predicated on the observation that Gzmb mRNA is highly expressed in mature and activated natural killer cells. Using two different reporter strains we determined that gene function could be investigated in mature natural killer cells after GzmbCre mediated recombination in vitro in conditions that lead to natural killer cell activation such as in the cytokine combination of interleukin 2 and interleukin 12. We demonstrated the utility of this model by creating GzmbCre;Rosa26IKKbca mice in which Cre-mediated recombination resulted in expression of constitutively active IKKbeta, which results in activation of the NFkappaB transcription factor. In vivo and in vitro activation of IKKbeta in natural killer cells revealed that constitutive activation of this pathway leads to natural killer cell hyper-activation and altered morphology. As a caveat to the use of GzmbCre we found that this transgene can lead to recombination in all hematopoietic cells the extent of which varies with the particular loxp flanked allele under investigation. We conclude that GzmbCre can be used under some conditions to investigate gene function in mature and activated natural killer cells. PMID- 25923441 TI - Does the BRIEF-P Predict Specific Executive Function Components in Preschoolers? AB - The current study explored the association between the Behavior Rating Inventory of Executive Function-Preschool (BRIEF-P; Gioia, Espy, & Isquith, 2003 ) and a new battery of direct executive function (EF) measures designed for preschoolers. Forty-two typically developing 3- to 5-year-olds were given the Preschool Executive Function Battery (PEFB; Garon, Smith & Bryson, 2014); their mothers filled out the BRIEF-P. The findings support distinct associations between 3 BRIEF-P scales and corresponding direct EF measures. In particular, a strong association was found between the BRIEF-P Inhibition scale and children's performance on the PEFB Inhibition measure. The findings indicate that parent ratings of preschoolers' everyday EF behavior are related to performance on the PEFB, a laboratory measure. These findings have implications for early screening of children's EF difficulties as well as for future research. PMID- 25923443 TI - Air Oxidative Radical Oxysulfurization of Alkynes Leading to alpha-Thioaldehydes. AB - Air oxidative radical oxysulfurization of alkynes initiated by 0.5 mol % tert butyl hydroperoxide with arylthiols is described. The reaction proceeded at room temperature in the presence of 5% mol water to afford selective alpha thioaldehydes. PMID- 25923442 TI - Eag Domains Regulate LQT Mutant hERG Channels in Human Induced Pluripotent Stem Cell-Derived Cardiomyocytes. AB - Human Ether a go-go Related Gene potassium channels form the rapid component of the delayed-rectifier (IKr) current in the heart. The N-terminal 'eag' domain, which is composed of a Per-Arnt-Sim (PAS) domain and a short PAS-cap region, is a critical regulator of hERG channel function. In previous studies, we showed that isolated eag (i-eag) domains rescued the dysfunction of long QT type-2 associated mutant hERG R56Q channels, by substituting for defective eag domains, when the channels were expressed in Xenopus oocytes or HEK 293 cells.Here, our goal was to determine whether the rescue of hERG R56Q channels by i-eag domains could be translated into the environment of cardiac myocytes. We expressed hERG R56Q channels in human induced pluripotent stem cell-derived cardiomyocytes (hiPSC CMs) and measured electrical properties of the cells with whole-cell patch-clamp recordings. We found that, like in non-myocyte cells, hERG R56Q had defective, fast closing (deactivation) kinetics when expressed in hiPSC-CMs. We report here that i-eag domains slowed the deactivation kinetics of hERG R56Q channels in hiPSC-CMs. hERG R56Q channels prolonged the AP of hiPSCs, and the AP was shortened by co-expression of i-eag domains and hERG R56Q channels. We measured robust Forster Resonance Energy Transfer (FRET) between i-eag domains tagged with Cyan fluorescent protein (CFP) and hERG R56Q channels tagged with Citrine fluorescent proteins (Citrine), indicating their close proximity at the cell membrane in live iPSC-CMs. Together, functional regulation and FRET spectroscopy measurements indicated that i-eag domains interacted directly with hERG R56Q channels in hiPSC-CMs. These results mean that the regulatory role of i-eag domains is conserved in the cellular environment of human cardiomyocytes, indicating that i-eag domains may be useful as a biological therapeutic. PMID- 25923445 TI - Correction to ZnO/NiO Diode-Based Charge Trapping Layer for Flash Memory Featuring Low Voltage Operation. PMID- 25923444 TI - Chamaecyparis obtusa Essential Oil Inhibits Methicillin-Resistant Staphylococcus aureus Biofilm Formation and Expression of Virulence Factors. AB - The emergence of antibiotic-resistant bacteria has caused difficulty in treating infectious diseases. Methicillin-resistant Staphylococcus aureus (MRSA) is one of the most commonly recognized antibiotic-resistant bacteria. Novel antibiotics are urgently required to treat these bacteria. Raw materials derived from natural sources can be used for the development of novel antibiotics, such as Chamaecyparis obtusa (C. obtusa), which has been traditionally used in treating asthmatic disease. In this study, the antibacterial activity of the essential oil (EO) extracted from C. obtusa leaves against MRSA was investigated. MRSA growth and acid production from glucose metabolism were inhibited at concentrations greater than 0.1 mg/mL C. obtusa EO. MRSA biofilm formation was observed using scanning electron microscopy and safranin staining. C. obtusa EO inhibited MRSA biofilm formation at concentrations greater than 0.1 mg/mL. Using real-time polymerase chain reaction, mRNA expression of virulence factor genes, sea, agrA, and sarA, was observed. agrA expression was inhibited with C. obtusa EO concentrations greater than 0.2 mg/mL, whereas inhibition of sea and sarA expression was also observed at a concentration of 0.3 mg/mL. C. obtusa EO was analyzed by gas chromatography (GC) and GC coupled for mass spectrometry, which identified 59 constituents, accounting to 98.99% of the total EO. These findings suggest that C. obtusa EO has antibacterial effects against MRSA, which might be associated with the major components of C. obtusa EO, such as sabinene (19.06%), alpha-terpinyl acetate (16.99%), bornyl acetate (10.48%), limonene (8.54%), elemol (7.47%), myrcene (5.86%), gamma-terpinene (4.04%), and hibaene (3.01%). PMID- 25923446 TI - Model study of global mercury deposition from biomass burning. PMID- 25923447 TI - Health care utilization and costs of idiopathic pulmonary fibrosis in U.S. Medicare beneficiaries aged 65 years and older. AB - RATIONALE: Management of idiopathic pulmonary fibrosis (IPF) is resource intensive. Because an increasing prevalence of IPF was found among the elderly in the United States, it is important to understand the economic burden associated with the disease in this population. OBJECTIVES: To compare health care resource utilization and costs between patients with IPF and matched control subjects without IPF in Medicare, the largest U.S. payer covering the elderly. METHODS: Administrative claims from a 5% random sample of Medicare beneficiaries (aged 65+) from years 2000 to 2011 were analyzed. Incident patients with IPF were identified on the basis of International Classification of Diseases, ninth revision, Clinical Modification diagnosis codes, with at least 1 year of enrollment before (preindex) and after (postindex) the first diagnosis (index date). Up to five beneficiaries without IPF were matched to each patient with IPF, based on age, sex, race, and region. Annual health care resource utilization and medical costs (excluding outpatient drug costs) during the preindex and postindex periods were compared between patients with IPF and matched control subjects. MEASUREMENTS AND MAIN RESULTS: A total of 7,855 patients with IPF were matched to 38,856 control subjects. Compared with matched control subjects during the preindex period, patients with IPF had an 82% higher risk of hospitalization (28.8 vs. 15.8%), and 72% higher total medical costs ($10,124 vs. $5,888). Compared with matched control subjects during the postindex period, patients with IPF had a 134% higher risk of hospitalization (48.7 vs. 20.8%), similar increased risk of emergency room visits (39.6 vs. 17.5%), and 134% higher total medical costs ($20,887 vs. $8,932). CONCLUSIONS: In the U.S. Medicare population, patients with IPF incurred substantial health care resource utilization. The annual IPF-attributable medical cost to the U.S. health care system, excluding medication costs, is estimated at close to $2 billion. PMID- 25923448 TI - Influence of Age on Clinical Performance of Mandibular Two-Implant Overdentures: A 10-Year Prospective Comparative Study. AB - PURPOSE: The aim of this prospective comparative study was to assess whether age has influence on peri-implant health in patients treated with mandibular two implant overdentures during a 10-year evaluation period. MATERIALS AND METHODS: A prospective study was carried out with two groups of edentulous patients, viz a younger (n = 52; mean age 45 years, 35-50 years) and an older (n = 53; mean age 68 years, 60-80 years) group. In all patients, two dental implants were placed in the interforaminal region of the mandible and after a 3-month healing period overdentures were fabricated. Clinical and radiographic parameters were evaluated immediately after completion of the prosthetic treatment, and after 1, 5 and 10 years. Implant loss, plaque index, gingival index, bleeding index, and probing depth were assessed as clinical parameters. Peri-implant bone loss was assessed on dental radiographs made with a standardized long-cone technique with a direction device. RESULTS: Implant survival after 10 years was 97.1% and 93.4% in the younger and older group, respectively. Ten-year scores of plaque, gingiva, and bleeding were between 0 and 1 for both groups (possible scores 0-3), and mean probing depth was 3 mm in both groups. Mean peri-implant bone loss after 10 years was 1.2 and 1.4 mm in the younger and older patients, respectively. No significant differences were observed between the groups. CONCLUSION: Clinical performance of mandibular two-implant overdentures is equally successful in younger and older patients. PMID- 25923449 TI - Why Nature Uses Radical SAM Enzymes so Widely: Electron Nuclear Double Resonance Studies of Lysine 2,3-Aminomutase Show the 5'-dAdo* "Free Radical" Is Never Free. AB - Lysine 2,3-aminomutase (LAM) is a radical S-adenosyl-L-methionine (SAM) enzyme and, like other members of this superfamily, LAM utilizes radical-generating machinery comprising SAM anchored to the unique Fe of a [4Fe-4S] cluster via a classical five-membered N,O chelate ring. Catalysis is initiated by reductive cleavage of the SAM S-C5' bond, which creates the highly reactive 5' deoxyadenosyl radical (5'-dAdo*), the same radical generated by homolytic Co-C bond cleavage in B12 radical enzymes. The SAM surrogate S-3',4'-anhydroadenosyl-L methionine (anSAM) can replace SAM as a cofactor in the isomerization of L-alpha lysine to L-beta-lysine by LAM, via the stable allylic anhydroadenosyl radical (anAdo*). Here electron nuclear double resonance (ENDOR) spectroscopy of the anAdo* radical in the presence of (13)C, (2)H, and (15)N-labeled lysine completes the picture of how the active site of LAM from Clostridium subterminale SB4 "tames" the 5'-dAdo* radical, preventing it from carrying out harmful side reactions: this "free radical" in LAM is never free. The low steric demands of the radical-generating [4Fe-4S]/SAM construct allow the substrate target to bind adjacent to the S-C5' bond, thereby enabling the 5'-dAdo* radical created by cleavage of this bond to react with its partners by undergoing small motions, ~0.6 A toward the target and ~1.5 A overall, that are controlled by tight van der Waals contact with its partners. We suggest that the accessibility to substrate and ready control of the reactive C5' radical, with "van der Waals control" of small motions throughout the catalytic cycle, is common within the radical SAM enzyme superfamily and is a major reason why these enzymes are the preferred means of initiating radical reactions in nature. PMID- 25923452 TI - Pain severity, interference, and prescription analgesic use among depressed, low income homebound older adults. AB - OBJECTIVES: Disabled, homebound individuals tend to suffer both chronic pain and depression; however, low-income, homebound older adults have been underexposed in pain and depression research. We examined the extent of pain frequency, intensity, and interference; the relationship between pain and depressive symptoms; and prescription analgesic use and its association with use of antidepressant and anxiolytic medications among these older adults. METHOD: The data came from the baseline assessment of 215 homebound individuals aged 50+ who were referred to a clinical trial of depression treatment. Bivariate and multivariate analyses were used to examine the research questions. RESULTS: Almost 87% (n = 186) of the participants reported having had chronic pain in the preceding three months. Of the pain reporters, the mean frequency, intensity, and interference of pain were 8.65 +/- 2.05, 7.71 +/- 2.10, and 7.80 +/- 2.82, respectively, on a 1-10 scale, and 61% were taking a prescription analgesic. Analgesic users and nonusers did not differ in depressive symptoms and in pain frequency and intensity, but analgesic users reported higher pain interference than nonusers (8.22 +/- 2.46 vs. 7.14 +/- 3.22; t = 2.44, df = 184, p = .016). Pain frequency and interference were significantly associated with depressive symptoms, and pain interference was significantly associated with analgesic use in multivariate analysis. Anxiolytic medication use was also correlated with analgesic use. CONCLUSION: The findings underscore the significant pain-related problems in these vulnerable individuals and the need for recognizing and treating both pain and depression more effectively using both pharmacologic and nonpharmacologic interventions. PMID- 25923451 TI - Perceived food hypersensitivity relates to poor asthma control and quality of life in young non-atopic asthmatics. AB - BACKGROUND: The relationship between perceived food hypersensitivity in asthmatics, food allergen sensitization, asthma control and asthma-related quality of life has not been studied. OBJECTIVE: Our aim was to study the prevalence of perceived food hypersensitivity in a cohort of young asthmatics, its relation to food allergen sensitization, and any correlation to asthma control and asthma-related quality of life. METHODS: Perceived food hypersensitivity, as well as IgE sensitization to common food allergens, levels of exhaled nitric oxide (FeNO), and blood eosinophil counts (B-Eos) were assessed in 408 subjects (211 women) with asthma, aged (mean +/- SEM) 20.4 +/- 0.3 years. Subjects filled out the Asthma Control Test (ACT) and the Mini Asthma Quality of Life Questionnaire (Mini-AQLQ). Inflammation was assessed by means of FeNO and B Eos. RESULTS: Fifty-three per cent of subjects reported food hypersensitivity. A corresponding food allergen sensitization was found in 68% of these subjects. Non atopic subjects with perceived food hypersensitivity (n = 31) had lower ACT (19 (15 - 22) vs. 21 (20 - 23), p < 0.001) and Mini-AQLQ -scores (5.3 (4.3 - 6.1) vs. 6.1 (5.5 - 6.5), p < 0.001) than subjects with no food hypersensitivity (n = 190), despite lower levels of FeNO and B-Eos (p < 0.05). CONCLUSIONS AND CLINICAL RELEVANCE: Food hypersensitivity was commonly reported among young asthmatics. In a majority of cases, a corresponding food allergen sensitization was found. A novel and clinically important finding was that non-atopic subjects with perceived food hypersensitivity were characterized by poorer asthma control and asthma-related quality of life. PMID- 25923453 TI - Exposure to topical chloramphenicol during pregnancy and the risk of congenital malformations: a Danish nationwide cohort study. AB - PURPOSE: To investigate whether exposure to topical chloramphenicol in the first trimester of pregnancy is associated with congenital malformations. METHODS: The authors conducted a nationwide cohort study including all women giving live birth between 1997 and 2011 in Denmark. All women redeeming at least one prescription of chloramphenicol eye drops or eye ointment during the first 84 days of pregnancy were identified. Logistic regression was used to estimate the odds ratios of malformations among exposed women compared to non-exposed women. RESULTS: 966 372 births between 1997 and 2011 were included. A total of 6024 women were exposed to topical chloramphenicol in the first trimester. The rate of congenital malformations was 3.50% among offspring of exposed mothers and 3.49% among unexposed. Exposure to topical chloramphenicol in the first trimester was not associated with major congenital malformations (adjusted odds ratio = 1.06, 95% CI 0.91-1.22) or specific major malformations. The number of redeemed prescriptions decreased significantly during pregnancy as compared to before and after pregnancy (p < 0.0001). CONCLUSION: In this study, we found no association between dispensing of chloramphenicol eye drops or eye ointment in the first trimester of pregnancy and major congenital malformations. This is in accordance with a previous study analysing the risk of systemic chloramphenicol. PMID- 25923454 TI - Correlating molecular character of NIR imaging agents with tissue-specific uptake. AB - Near-infrared (NIR) fluorescent contrast agents are emerging in optical imaging as sensitive, cost-effective, and nonharmful alternatives to current agents that emit harmful ionizing radiation. Developing spectrally distinct NIR fluorophores to visualize sensitive vital tissues to selectively avoid them during surgical resection of diseased tissue is of great significance. Herein, we report the synthetic variation of pentamethine cyanine fluorophores with modifications of physicochemical properties toward prompting tissue-specific uptake into sensitive tissues (i.e., endocrine glands). Tissue-specific targeting and biodistribution studies revealed localization of contrast agents in the adrenal and pituitary glands, pancreas, and lymph nodes with dependence on molecular characteristics. Incorporation of hydrophobic heterocyclic rings, alkyl groups, and halogens allowed a fine-tuning capability to the hydrophobic character and dipole moment for observing perturbation in biological activity in response to minor structural alterations. These NIR contrast agents have potential for clinical translation for intraoperative imaging in the delineation of delicate glands. PMID- 25923455 TI - Mixed signals? Morphological and molecular evidence suggest a color polymorphism in some neotropical polythore damselflies. AB - The study of color polymorphisms (CP) has provided profound insights into the maintenance of genetic variation in natural populations. We here offer the first evidence for an elaborate wing polymorphism in the Neotropical damselfly genus Polythore, which consists of 21 described species, distributed along the eastern slopes of the Andes in South America. These damselflies display highly complex wing colors and patterning, incorporating black, white, yellow, and orange in multiple wing bands. Wing colors, along with some components of the male genitalia, have been the primary characters used in species description; few other morphological traits vary within the group, and so there are few useful diagnostic characters. Previous research has indicated the possibility of a cryptic species existing in P. procera in Colombia, despite there being no significant differences in wing color and pattern between the populations of the two putative species. Here we analyze the complexity and diversity of wing color patterns of individuals from five described Polythore species in the Central Amazon Basin of Peru using a novel suite of morphological analyses to quantify wing color and pattern: geometric morphometrics, chromaticity analysis, and Gabor wavelet transformation. We then test whether these color patterns are good predictors of species by recovering the phylogenetic relationships among the 5 species using the barcode gene (COI). Our results suggest that, while highly distinct and discrete wing patterns exist in Polythore, these "wingforms" do not represent monophyletic clades in the recovered topology. The wingforms identified as P. victoria and P. ornata are both involved in a polymorphism with P. neopicta; also, cryptic speciation may have taking place among individuals with the P. victoria wingform. Only P. aurora and P. spateri represent monophyletic species with a single wingform in our molecular phylogeny. We discuss the implications of this polymorphism, and the potential evolutionary mechanisms that could maintain it. PMID- 25923456 TI - Correction: Earliest stone-tipped projectiles from the Ethiopian Rift date to >279,000 years ago. PMID- 25923457 TI - Atomic healing of defects in transition metal dichalcogenides. AB - As-grown transition metal dichalcogenides are usually chalcogen deficient and therefore contain a high density of chalcogen vacancies, deep electron traps which can act as charged scattering centers, reducing the electron mobility. However, we show that chalcogen vacancies can be effectively passivated by oxygen, healing the electronic structure of the material. We proposed that this can be achieved by means of surface laser modification and demonstrate the efficiency of this processing technique, which can enhance the conductivity of monolayer WSe2 by ~400 times and its photoconductivity by ~150 times. PMID- 25923458 TI - Identification of 2-(ethylamino)-1-(4-methylphenyl)-1-pentanone (4-MEAP), a New "Legal High" Sold by an Internet Vendor as 4-Methyl Pentedrone. AB - Online vendors are offering a new legal high, 4-methylpentedrone (4-MPD). Information for potential users provided by internet vendors of 4-MPD includes incorrect structures and nonexistent CAS numbers. A sample of 4-MPD was obtained and analyzed using GC-MS, NMR, and LC-EIS. The fragmentation data from the GC-MS and LC-EIS produced an M-1 ion that suggested the molecular mass was 219 amu, rather than 205 amu as calculated for 4-methylpentedrone. The difference in molecular mass corresponded to the addition of a methyl group. Based on the mass and fragmentation pattern, two standards were synthesized, 2-(ethylamino)-1-(4 methylphenyl)-1-pentanone and 1-(4-methylphenyl)-2-(propylamino)-1-butanone. The synthesis involved bromination of the appropriate ketone followed by the reaction with ethylamine or propylamine. Based on the NMR data and unique fragmentation patterns produced by these molecules, the sample was identified as 2-(ethylamino) 1-(4-methylphenyl)-1-pentanone, not 4-methylpentedrone. PMID- 25923459 TI - The effects of 6-gingerol on proliferation, differentiation, and maturation of osteoblast-like MG-63 cells. AB - We investigated whether 6-gingerol affects the maturation and proliferation of osteoblast-like MG63 cells in vitro. Osteoblast-like MG63 cells were treated with 6-gingerol under control conditions, and experimental inflammation was induced by tumor necrosis factor-alpha (TNF-alpha). Expression of different osteogenic markers and cytokines was analyzed by real-time PCR, Western blotting, and enzyme linked immunosorbent assay. In addition, alkaline phosphatase (ALP) enzyme activity and biomineralization as markers for differentiation were measured. Treatment with 6-gingerol resulted in insignificant effects on the proliferation rate. 6-Gingerol induced the differentiation of osteoblast-like cells with increased transcription levels of osteogenic markers, upregulated ALP enzyme activity, and enhanced mineralized nodule formation. Stimulation with TNF-alpha led to enhanced interleukin-6 and nuclear factor-kappaB expression and downregulated markers of osteoblastic differentiation. 6-Gingerol reduced the degree of inflammation in TNF-alpha-treated MG-63 cells. In conclusion, 6 gingerol stimulated osteoblast differentiation in normal physiological and inflammatory settings, and therefore, 6-gingerol represents a promising agent for treating osteoporosis or bone inflammation. PMID- 25923460 TI - Treatment with 1,25(OH)2D3 induced HDAC2 expression and reduced NF-kappaB p65 expression in a rat model of OVA-induced asthma. AB - Recent evidence indicates that a deficiency of 1,25-dihydroxyvitamin D3 (1,25[OH]2D3) may influence asthma pathogenesis; however, its roles in regulating specific molecular transcription mechanisms remain unclear. We aimed to investigate the effect of 1,25(OH)2D3 on the expression and enzyme activity of histone deacetylase 2 (HDAC2) and its synergistic effects with dexamethasone (Dx) in the inhibition of inflammatory cytokine secretion in a rat asthma model. Healthy Wistar rats were randomly divided into 6 groups: control, asthma, 1,25(OH)2D3 pretreatment, 1,25(OH)2D3 treatment, Dx treatment, and Dx and 1,25(OH)2D3 treatment. Pulmonary inflammation was induced by ovalbumin (OVA) sensitization and challenge (OVA/OVA). Inflammatory cells and cytokines in the bronchoalveolar lavage (BAL) fluid and histological changes in lung tissue were examined. Nuclear factor kappa B (NF-kappaB) p65 and HDAC2 expression levels were assessed with Western blot analyses and quantitative reverse-transcriptase polymerase chain reaction (qRT-PCR). Enzyme activity measurements and immunohistochemical detection of HDAC2 were also performed. Our data demonstrated that 1,25(OH)2D3 reduced the airway inflammatory response and the level of inflammatory cytokines in BAL. Although NF-kappaB p65 expression was attenuated in the pretreatment and treatment groups, the expression and enzyme activity of HDAC2 were increased. In addition, 1,25(OH)2D3 and Dx had synergistic effects on the suppression of total cell infusion, cytokine release, and NF-kappaB p65 expression, and they also increased HDAC2 expression and activity in OVA/OVA rats. Collectively, our results indicated that 1,25(OH)2D3 might be useful as a novel HDAC2 activator in the treatment of asthma. PMID- 25923461 TI - IGF2, LEPR, POMC, PPARG, and PPARGC1 gene variants are associated with obesity related risk phenotypes in Brazilian children and adolescents. AB - Association studies of genetic variants and obesity and/or obesity-related risk factors have yielded contradictory results. The aim of the present study was to determine the possible association of five single-nucleotide polymorphisms (SNPs) located in the IGF2, LEPR, POMC, PPARG, and PPARGC1 genes with obesity or obesity related risk phenotypes. This case-control study assessed overweight (n=192) and normal-weight (n=211) children and adolescents. The SNPs were analyzed using minisequencing assays, and variables and genotype distributions between the groups were compared using one-way analysis of variance and Pearson's chi-square or Fisher's exact tests. Logistic regression analysis adjusted for age and gender was used to calculate the odds ratios (ORs) for selected phenotype risks in each group. No difference in SNP distribution was observed between groups. In children, POMC rs28932472(C) was associated with lower diastolic blood pressure (P=0.001), higher low-density lipoprotein (LDL) cholesterol (P=0.014), and higher risk in overweight children of altered total cholesterol (OR=7.35, P=0.006). In adolescents, IGF2 rs680(A) was associated with higher glucose (P=0.012) and higher risk in overweight adolescents for altered insulin (OR=10.08, P=0.005) and homeostasis model of insulin resistance (HOMA-IR) (OR=6.34, P=0.010). PPARG rs1801282(G) conferred a higher risk of altered insulin (OR=12.31, P=0.003), and HOMA-IR (OR=7.47, P=0.005) in overweight adolescents. PARGC1 rs8192678(A) was associated with higher triacylglycerols (P=0.005), and LEPR rs1137101(A) was marginally associated with higher LDL cholesterol (P=0.017). LEPR rs1137101(A) conferred higher risk for altered insulin, and HOMA-IR in overweight adolescents. The associations observed in this population suggested increased risk for cardiovascular diseases and/or type 2 diabetes later in life for individuals carrying these alleles. PMID- 25923463 TI - Silver Nanoparticle Coated Bioactive Glasses--Composites with Dex/CMC Hydrogels: Characterization, Solubility, and In Vitro Biological Studies. AB - Silver (Ag) coated bioactive glass particles (Ag-BG) were formulated and compared to uncoated controls (BG) in relation to glass characterization, solubility and microbiology. X-ray diffraction (XRD) confirmed a crystalline AgNP surface coating while ion release studies determined low Ag release (<2 mg/L). Cell culture studies presented increased cell viability (127 and 102%) with lower liquid extract (50 and 100 ml/ml) concentrations. Antibacterial testing of Ag-BG in E. coli, S. epidermidis and S. aureus significantly reduced bacterial cell viability by 60-90%. Composites of Ag-BG/CMC-Dex Hydrogels were formulated and characterized. Agar diffusion testing was conducted where Ag-BG/hydrogel composites produced the largest inhibition zones of 7 mm (E. coli), 5 mm (S. aureus) and 4 mm (S. epidermidis). PMID- 25923464 TI - Correction: Decreasing NF-kappaB Expression Enhances Odontoblastic Differentiation and Collagen Expression in Dental Pulp Stem Cells Exposed to Inflammatory Cytokines. PMID- 25923462 TI - Long-term, regular remote ischemic preconditioning improves endothelial function in patients with coronary heart disease. AB - Remote ischemic preconditioning (RIPre) can prevent myocardial injury. The purpose of this study was to assess the beneficial effects of long-term regular RIPre on human arteries. Forty patients scheduled for coronary artery bypass graft (CABG) surgery were assigned randomly to a RIPre group (n=20) or coronary heart disease (CHD) group (n=20). Twenty patients scheduled for mastectomy were enrolled as a control group. RIPre was achieved by occluding arterial blood flow 5 min with a mercury sphygmomanometer followed by a 5-min reperfusion period, and this was repeated 4 times. The RIPre procedure was repeated 3 times a day for 20 days. In all patients, arterial fragments discarded during surgery were collected to evaluate endothelial function by flow-mediated dilation (FMD), CD34(+) monocyte count, and endothelial nitric oxide synthase (eNOS expression). Phosphorylation levels of STAT-3 and Akt were also assayed to explore the underlying mechanisms. Compared with the CHD group, long-term regular RIPre significantly improved FMD after 20 days (8.5+/-2.4 vs 4.9+/-4.2%, P<0.05) and significantly reduced troponin after CABG surgery (0.72+/-0.31 and 1.64+/-0.19, P<0.05). RIPre activated STAT-3 and increased CD34(+) endothelial progenitor cell counts found in arteries. Long-term, regular RIPre improved endothelial function in patients with CHD, possibly due to STAT-3 activation, and this may have led to an increase in endothelial progenitor cells. PMID- 25923465 TI - Aerobic Exercise Training Prevents the Onset of Endothelial Dysfunction via Increased Nitric Oxide Bioavailability and Reduced Reactive Oxygen Species in an Experimental Model of Menopause. AB - OBJECTIVE: Previous studies have shown that estrogen deficiency, arising in postmenopause, promotes endothelial dysfunction. This study evaluated the effects of aerobic exercise training on endothelial dependent vasodilation of aorta in ovariectomized rats, specifically investigating the role of nitric oxide (NO) and reactive oxygen species (ROS). METHODS: Female Wistar rats ovariectomized (OVX - n=20) or with intact ovary (SHAM - n=20) remained sedentary (OVX and SHAM) or performed aerobic exercise training on a treadmill 5 times a week for a period of 8 weeks (OVX-TRA and SHAM-TRA). In the thoracic aorta the endothelium-dependent and -independent vasodilation was assessed by acetylcholine (ACh) and sodium nitroprusside (SNP), respectively. Certain aortic rings were incubated with L NAME to assess the NO modulation on the ACh-induced vasodilation. The fluorescence to dihydroethidium in aortic slices and plasma nitrite/nitrate concentrations were measured to evaluate ROS and NO bioavailability, respectively. RESULTS: ACh-induced vasodilation was reduced in OVX rats as compared SHAM (Rmax: SHAM: 86+/-3.3 vs. OVX: 57+/-3.0%, p<0.01). Training prevented this response in OVX-TRA (Rmax: OVX-TRA: 88+/-2.0%, p<0.01), while did not change it in SHAM-TRA (Rmax: SHAM-TRA: 80+/-2.2%, p<0.01). The L-NAME incubation abolished the differences in ACh-induced relaxation among groups. SNP induced vasodilation was not different among groups. OVX reduced nitrite/nitrate plasma concentrations and increased ROS in aortic slices, training as effective to restore these parameters to the SHAM levels. CONCLUSIONS: Exercise training, even in estrogen deficiency conditions, is able to improve endothelial dependent vasodilation in rat aorta via enhanced NO bioavailability and reduced ROS levels. PMID- 25923467 TI - Inclusions of a two dimensional fluid with competing interactions in a disordered, porous matrix. AB - The behavior of a fluid with competing interaction ranges adsorbed in a controlled pore size disordered matrix is studied by means of grand canonical Monte Carlo simulations in order to analyze the effects of confinement. The disordered matrix model is constructed from a two-dimensional non-additive hard sphere fluid (which shows close to its demixing critical point large fluctuations in the concentration), after a subsequent quenching of the particle positions and removal of one of the components. The topology of the porous network is analyzed by means of a Delaunay tessellation procedure. The porous cavities are large enough to allow for cluster formation, which is however somewhat hindered as a result of the confinement, as seen from the comparison of cluster size distributions calculated for the fluid under confinement and in the bulk. The occurrence of lamellar phases is impeded by the disordered nature of the porous network. Analysis of two-dimensional density maps of the adsorbed fluid for given matrix configurations shows that clusters tend to build up in specific locations of the porous matrix, so as to minimize inter-cluster repulsion. PMID- 25923466 TI - Impact of Toceranib/Piroxicam/Cyclophosphamide Maintenance Therapy on Outcome of Dogs with Appendicular Osteosarcoma following Amputation and Carboplatin Chemotherapy: A Multi-Institutional Study. AB - BACKGROUND: We hypothesized that the addition of toceranib to metronomic cyclophosphamide/piroxicam therapy would significantly improve disease-free interval (DFI) and overall survival (OS) in dogs with appendicular osteosarcoma (OSA) following amputation and carboplatin chemotherapy. METHODS AND FINDINGS: This was a randomized, prospective clinical trial in which dogs with OSA free of gross metastatic disease (n = 126) received carboplatin chemotherapy (4 doses) following amputation. On study entry, dogs were randomized to receive piroxicam/cyclophosphamide with or without toceranib (n = 63 each) after completing chemotherapy. Patient demographics were not significantly different between both groups. During or immediately following carboplatin chemotherapy, 32 dogs (n = 13 toceranib; n = 19 control) developed metastatic disease, and 13 dogs left the study due to other medical conditions or owner preference. Following carboplatin chemotherapy, 81 dogs (n = 46 toceranib; n = 35 control) received the metronomic treatment; 35 dogs (n = 20 toceranib; n = 15 control) developed metastatic disease during the maintenance therapy, and 26 dogs left the study due to other medical conditions or owner preference. Nine toceranib-treated and 11 control dogs completed the study without evidence of metastatic disease 1-year following amputation. Toceranib-treated dogs experienced more episodes of diarrhea, neutropenia and weight loss than control dogs, although these toxicities were low-grade and typically resolved with supportive care. More toceranib-treated dogs (n = 8) were removed from the study for therapy-associated adverse events compared to control dogs (n = 1). The median DFI for control and toceranib treated dogs was 215 and 233 days, respectively (p = 0.274); the median OS for control and toceranib treated dogs was 242 and 318 days, respectively (p = 0.08). The one year survival rate for control dogs was 35% compared to 38% for dogs receiving toceranib. CONCLUSIONS: The addition of toceranib to metronomic piroxicam/cyclophosphamide therapy following amputation and carboplatin chemotherapy did not improve median DFI, OS or the 1-year survival rate in dogs with OSA. PMID- 25923468 TI - Distinct mechanisms contribute to immunity in the lantibiotic NAI-107 producer strain Microbispora ATCC PTA-5024. AB - The investigation of self-resistance in antibiotic producers is important to understand the emergence of antibiotic resistance in pathogens and to improve antibiotic production. Lantibiotics are ribosomally synthesized antibiotics that mostly target peptidoglycan biosynthesis. The actinomycete Microbispora ATCC PTA 5024 produces the lantibiotic NAI-107, which interferes with peptidoglycan biosynthesis by binding bactoprenol-pyrophosphate-coupled peptidoglycan precursors. In order to understand how Microbispora counteracts the action of its own antibiotic, its peptidoglycan composition was analysed in detail. Microbispora peptidoglycan consists of muropeptides with D-Ala and Gly in similar proportion at the fourth position of the peptide stems and alternative 3-3 cross links besides the classical 4-3 cross-links. In addition, the NAI-107 biosynthetic gene cluster (mlb) was analysed for the expression of immunity proteins. We show that distinct immunity determinants are encoded in the mlb cluster: the ABC transporter MlbYZ acting cooperatively with the transmembrane protein MlbJ and the lipoprotein MlbQ. NMR structural analysis of MlbQ revealed a hydrophobic surface patch, which is proposed to bind the cognate lantibiotic. This study demonstrates that immunity in Microbispora is not only based on one determinant but on the action of the distinct immunity proteins MlbQ, MlbYZ and MlbJ. PMID- 25923469 TI - The 13th International Workshops on Opportunistic Protists (IWOP13). AB - The 13th International Workshops on Opportunistic Protists (IWOP-13) was held November 13-15, 2014 in Seville, Spain. The objectives of the IWOP meetings are to: (1) serve as a forum for exchange of new information among active researchers concerning the basic biology, molecular genetics, immunology, biochemistry, pathogenesis, drug development, therapy, and epidemiology of these immunodeficiency-associated pathogenic eukaryotic microorganisms that are seen in patients with AIDS and; (2) to foster the entry of new and young investigators into these underserved research areas. The IWOP meeting focuses on opportunistic protists; e.g. the free-living amoebae, Pneumocystis, Cryptosporidium, Toxoplasma, the Microsporidia, and kinetoplastid flagellates. This conference represents the major conference which brings together research groups working on these opportunistic pathogens. Progress has been achieved on understanding the biology of these pathogenic organisms, their involvement in disease causation in both immune deficient and immune competent hosts and is providing important insights into these emerging and reemerging pathogens. A continuing concern of the participants is the ongoing loss of scientific expertise and diversity in this research community. This decline is due to the small size of these research communities and an ongoing lack of understanding by the broader scientific community of the challenges and limitations faced by researchers working on these organisms, which makes these research communities very sensitive to declines in research funding. PMID- 25923471 TI - Single-virus force spectroscopy unravels molecular details of virus infection. AB - Virus infection is a multistep process that has significant effects on the structure and function of both the virus and the host cell. The first steps of virus replication include cell binding, entry and release of the viral genome. Single-virus force spectroscopy (SVFS) has become a promising tool to understand the molecular details of those steps. SVFS data complemented by biochemical and biophysical, including theoretical modeling approaches provide valuable insights into molecular events that accompany virus infection. Properties of virus-cell interaction as well as structural alterations of the virus essential for infection can be investigated on a quantitative level. Here we review applications of SVFS to virus binding, structure and mechanics. We demonstrate that SVFS offers unexpected new insights not accessible by other methods. PMID- 25923472 TI - Analysis of automated quantification of motor activity in REM sleep behaviour disorder. AB - Rapid eye movement (REM) sleep behaviour disorder (RBD) is characterized by dream enactment and REM sleep without atonia. Atonia is evaluated on the basis of visual criteria, but there is a need for more objective, quantitative measurements. We aimed to define and optimize a method for establishing baseline and all other parameters in automatic quantifying submental motor activity during REM sleep. We analysed the electromyographic activity of the submental muscle in polysomnographs of 29 patients with idiopathic RBD (iRBD), 29 controls and 43 Parkinson's (PD) patients. Six adjustable parameters for motor activity were defined. Motor activity was detected and quantified automatically. The optimal parameters for separating RBD patients from controls were investigated by identifying the greatest area under the receiver operating curve from a total of 648 possible combinations. The optimal parameters were validated on PD patients. Automatic baseline estimation improved characterization of atonia during REM sleep, as it eliminates inter/intra-observer variability and can be standardized across diagnostic centres. We found an optimized method for quantifying motor activity during REM sleep. The method was stable and can be used to differentiate RBD from controls and to quantify motor activity during REM sleep in patients with neurodegeneration. No control had more than 30% of REM sleep with increased motor activity; patients with known RBD had as low activity as 4.5%. We developed and applied a sensitive, quantitative, automatic algorithm to evaluate loss of atonia in RBD patients. PMID- 25923470 TI - Unmasking Novel Loci for Internal Phosphorus Utilization Efficiency in Rice Germplasm through Genome-Wide Association Analysis. AB - Depletion of non-renewable rock phosphate reserves and phosphorus (P) fertilizer price increases has renewed interest in breeding P-efficient varieties. Internal P utilization efficiency (PUE) is of prime interest because there has been no progress to date in breeding for high PUE. We characterized the genotypic variation for PUE present within the rice gene pool by using a hydroponic system that assured equal plant P uptake, followed by mapping of loci controlling PUE via Genome-Wide Association Studies (GWAS). Loci associated with PUE were mapped on chromosomes 1, 4, 11 and 12. The highest PUE was associated with a minor indica-specific haplotype on chromosome 1 and a rare aus-specific haplotype on chromosome 11. Comparative variant and expression analysis for genes contained within the chromosome 1 haplotype identified high priority candidate genes. Differences in coding regions and expression patterns between genotypes of contrasting haplotypes, suggested functional alterations for two predicted nucleic acid-interacting proteins that are likely causative for the observed differences in PUE. The loci reported here are the first identified for PUE in any crop that is not confounded by differential P uptake among genotypes. Importantly, modern rice varieties lacked haplotypes associated with superior PUE, and would thus benefit from targeted introgressions of these loci from traditional donors to improve plant growth in phosphorus-limited cropping systems. PMID- 25923473 TI - Fighting the Whole System: Dissociative Identity Disorder, Labeling Theory, and Iatrogenic Doubting. AB - This research examines how individuals diagnosed with dissociative identity disorder construe their experiences of being labeled with a contested diagnosis. Semistructured interviews were conducted in the United Kingdom with 5 women and 2 men diagnosed with dissociative identity disorder. A framework analysis was conducted. The analysis identified 2 overarching themes: diagnosis cross-examined and navigating care systems. The diagnosis appeared to be continually assessed by participants for its fit with symptoms, and the doubt among professionals seemed to be unhelpfully reflected in participants' attempts to understand and come to terms with their experiences. The findings are considered in light of labeling theory, the iatrogenic effects of professional doubt, and current debates concerning the reliability and validity of psychiatric diagnostic systems that have been reinvigorated by the publication of the Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition. PMID- 25923475 TI - Assessments of Motor Abnormalities on the Grid-Walking and Foot-Fault Tests From Undernutrition in Wistar Rats. AB - This study was designed to verify whether different lactation conditions influenced nervous system development. The authors used motor tasks to verify changes in exploratory activity and muscle strength of weaned rats from different litter sizes and evaluated the applicability of the grid-walking test for assessing motor abnormalities caused by undernutrition. Alterations in litter size during the suckling period perturbed the nutritional status of pups, which exhibited body weight differences between the groups. Large-litter (L) pups showed significant delays in achieving developmental milestones and neurological reflexes compared to the small-litter (S) and medium-litter (M) pups. The S, M, and L group pups exhibited similar exploratory responses and muscle strength. In the grid-walking and foot-fault tests, the L group pups traveled shorter distances and, consequently, had less footsteps. However, the percentages of foot faults in the L group were higher than S and M groups. These results reflect delayed maturation of structures responsible for sensorimotor responses, such as the cerebellum, because much cerebellar maturation takes place postnatally. This is the first study to report that early undernutrition in pups resulted in suboptimal performances on the grid-walking and foot-fault tests and that the former test was sensitive to alterations caused by nutritional deficiency. PMID- 25923474 TI - Influenza A virus-dependent remodeling of pulmonary clock function in a mouse model of COPD. AB - Daily oscillations of pulmonary function depend on the rhythmic activity of the circadian timing system. Environmental tobacco/cigarette smoke (CS) disrupts circadian clock leading to enhanced inflammatory responses. Infection with influenza A virus (IAV) increases hospitalization rates and death in susceptible individuals, including patients with Chronic Obstructive Pulmonary Disease (COPD). We hypothesized that molecular clock disruption is enhanced by IAV infection, altering cellular and lung function, leading to severity in airway disease phenotypes. C57BL/6J mice exposed to chronic CS, BMAL1 knockout (KO) mice and wild-type littermates were infected with IAV. Following infection, we measured diurnal rhythms of clock gene expression in the lung, locomotor activity, pulmonary function, inflammatory, pro-fibrotic and emphysematous responses. Chronic CS exposure combined with IAV infection altered the timing of clock gene expression and reduced locomotor activity in parallel with increased lung inflammation, disrupted rhythms of pulmonary function, and emphysema. BMAL1 KO mice infected with IAV showed pronounced detriments in behavior and survival, and increased lung inflammatory and pro-fibrotic responses. This suggests that remodeling of lung clock function following IAV infection alters clock-dependent gene expression and normal rhythms of lung function, enhanced emphysematous and injurious responses. This may have implications for the pathobiology of respiratory virus-induced airway disease severity and exacerbations. PMID- 25923476 TI - Assessment of a Self-Reported Drinks Diary for the Estimation of Drinks Intake by Care Home Residents: Fluid Intake Study in the Elderly (FISE). AB - OBJECTIVES: We evaluated the accuracy of a newly developed self-completed Drinks Diary in care home residents and compared it with direct observation and fluid intake charts. DESIGN: Observational study. SETTING: Residential care homes in Norfolk, UK. PARTICIPANTS: 22 elderly people (18 women, mean age 86.6 years SD 8.6, 12 with MMSE scores <27). MEASUREMENTS: Participants recorded their own drinks intake over 24 hours using the Drinks Diary while care staff used the homes' usual fluid intake chart to record drinks intake. These records were compared with drinks intake assessed by researcher direct observation (reference method), during waking hours (6am to 10pm), while drinks taken from 10pm to 6am were self-reported and checked with staff. RESULTS: Drinks intake assessed by the Drinks Diary was highly correlated with researcher direct observation (Pearson correlation coefficient r=0.93, p<0.001, mean difference -163ml/day) while few staff-completed fluid charts were returned and correlation was low (r=0.122, p=0.818, mean difference 702ml/day). The Drinks Diary classified 19 of 22 participants correctly as drinking enough or not using both the European Food Safety Authority and US recommendations. CONCLUSION: The Drinks Diary estimate of drinks intake was comparable with direct observation and more accurate (and reliably completed) than staff records. The Drinks Diary can provide a reliable estimate of drinks intake in elderly care home residents physically and cognitively able to complete it. It may be useful for researchers, care staff and practitioners needing to monitor drinks intake of elderly people, to help them avoid dehydration. PMID- 25923477 TI - Serum long-chain omega-3 polyunsaturated Fatty acids and future blood pressure in an ageing population. AB - OBJECTIVES: To investigate the associations of serum long-chain omega-3 polyunsaturated fatty acids (PUFA) and hair mercury with future blood pressure in an ageing population. DESIGN: Prospective study with baseline measurements in 1998-2001 and follow-up measurements in 2005-2008. The linear relationships (beta) of baseline serum fatty acids and hair mercury with future systolic and diastolic blood pressure and pulse pressure were analyzed with multiple linear regression models, using log-transformed values. PARTICIPANTS: 181 men and 200 women aged 53-73 y from the Kuopio Ischemic Heart Disease Risk Factor Study (KIHD) population in Eastern Finland, who were free of cardiovascular disease, diabetes or hypertension at baseline. MEASUREMENTS: Total serum esterified and nonesterified fatty acids and pubic hair mercury were used as markers for exposure. Anthropometric and other lifestyle and health-related data were collected. RESULTS: The mean serum concentrations were 1.67% (SD 0.92) for eicosapentaenoic acid (EPA), 0.79% (SD 0.16) for docosapentaenoic acid (DPA) and 2.78 (SD 0.92) for docosahexaenoic acid (DHA), of all serum fatty acids. The mean hair mercury concentration was 1.5 ug/g (SD 1.6). We did not find statistically significant associations between the baseline serum long-chain omega-3 PUFA concentrations or hair mercury content and future blood pressure. Hair mercury did not modify the associations with the long-chain omega-3 PUFAs, either. CONCLUSIONS: Higher serum long-chain omega-3 PUFA concentration, a biomarker of fish or fish oil consumption, may not have an impact on future blood pressure in an ageing population. PMID- 25923478 TI - Omega-3 dietary Fatty Acid status of healthy older adults in Tasmania, Australia: an observational study. AB - OBJECTIVES: To determine the dietary and supplement intake of omega-3 (n-3) polyunsaturated fatty acids (PUFA) of older Tasmanian adults; their plasma n-3 PUFA status and the relationship between n-3 PUFA intake and plasma status. DESIGN: Cross-sectional study. SETTING: Launceston and surrounding regions, Tasmania, Australia. PARTICIPANTS: Seventy-three community-dwelling older adults: 23 men aged 70 +/- 6.1 years and 50 women aged 70 +/- 6.7 years. MEASUREMENTS: A validated, semi-quantitative food frequency questionnaire estimated dietary PUFA intake. The plasma phospholipid fraction of venous blood samples was analysed for fatty acid content. Anthropometric data was recorded. RESULTS: Thirty-five participants (48%) regularly ingested a fish oil supplement. Their plasma n-3 PUFA profile contained significantly more eicosapentaenoic acid (EPA) (odds ratio 3.14; 95% CI 1.37% to 7.30%; p<0.05) and docosahexaenoic acid (DHA) (odds ratio 2.64; 95% CI 1.16% to 6.01%; p<0.05) than non-supplement users. Fish and meat were the main dietary sources of n-3 PUFAs. Participants most commonly consumed fish 3-4 times per week. Significant associations of dietary alpha-linolenic acid (ALA), EPA, docosapentaenoic acid (DPA) and DHA with plasma n-3 PUFAs were noted but not always between dietary and plasma counterparts. CONCLUSION: Without the use of fish oil supplements, most study participants were unable to meet the recommended daily intake of 0.5g EPA and DHA combined; however, the plasma n-3 PUFA profile of non-supplement-users was still robust compared to other Australian and overseas studies. PMID- 25923479 TI - Whey protein and high-volume resistance training in postmenopausal women. AB - OBJECTIVES: To examine the combined effects of whey protein supplementation and low intensity, high-volume resistance training in healthy postmenopausal women. DESIGN, SETTING AND SUBJECTS: Postmenopausal women (n=12; age: 57 +/- 4.7 years, weight: 75 +/- 17.4 kg, height: 163 +/- 5.5 cm, body mass index: 28.3 +/- 7.0) consumed whey protein (4 x 10 gram aliquots) or placebo (maltodextrin) during unilateral resistance training sessions 2 days per week (Monday, Thursday) and consumed the opposite beverage during training the other side of the body on alternating days (Tuesday, Friday) for 10 weeks. Participants performed 3 sets at 30% baseline 1-repetition maximum (1RM) to volitional muscle fatigue for 4 exercises (leg curl, biceps curl, leg extension, triceps extension). Prior to and following training, assessments were made for upper and lower limb lean tissue mass (dual energy x-ray absorptiometry), muscle thickness of the elbow and knee flexors and extensors (ultrasound) and muscle strength (1RM leg curl, biceps curl, leg extension, triceps extension). RESULTS: There was a significant increase over time for muscle strength (biceps curl, leg extension, triceps extension; P = 0.006) and muscle thickness (elbow flexors and extensors; P = 0.022) with no differences between whey protein and placebo. CONCLUSIONS: High volume resistance training is effective for improving some indices of muscle mass and strength in postmenopausal women, but the strategic ingestion of whey protein during training sessions does not augment this response. PMID- 25923480 TI - Assessment of energy intake in women with chronic obstructive pulmonary disease: a doubly labeled water method study. AB - OBJECTIVES: To maintain energy balance, reliable methods for assessing energy intake and expenditure should be used in patients with chronic obstructive pulmonary disease (COPD). The purpose of this study was to validate the diet history and 7-day food diary methods of assessing energy intake (EI) using total energy expenditure (TEE) with the doubly labeled water (DLW) method (TEEDLW) as the criterion method in outpatient women with COPD. METHODS: EI was assessed by diet history (EIDH) and a 7-day food diary (EIFD) in 19 women with COPD, using TEEDLW as the criterion method. The three methods were compared using intra-class correlation coefficients (ICC) and Bland-Altman analyses. The participants were classified according to their reporting status (EI/TEE) as valid-reporters 0.79 1.21, under-reporters < 0.79 or over-reporters > 1.21. RESULTS: Diet history underestimated reported EI by 28%, and 7-day food diary underestimated EI by approximately 20% compared with TEEDLW. The ICC analysis showed weak agreement between TEEDLW and EIDH (ICC=-0.01; 95%CI-0.10 to 0.17) and between TEEDLW and EIFD (ICC=0.11; 95%CI -0.16 to 0.44). The Bland-Altman plots revealed a slight systematic bias for both methods. For diet history, six women (32%) were identified as valid-reporters, and for the 7-day food diary, twelve women (63%) were identified as valid-reporters. The accuracy of reported EI was only related to BMI. CONCLUSION: The diet history and 7-day food diary methods underestimated energy intake in women with COPD compared with the DLW method. Individuals with higher BMIs are prone to underreporting. Seven-day food diaries should be used with caution in assessing EI in women with COPD. PMID- 25923481 TI - Effects of the daily consumption of protein enriched bread and protein enriched drinking yoghurt on the total protein intake in older adults in a rehabilitation centre: a single blind randomised controlled trial. AB - OBJECTIVES: To investigate the effects of protein enriched bread and drinking yoghurt, substituting regular products, on the total protein intake and the distribution of protein intake over the day in older adults. DESIGN: A single blind randomised controlled trial. SETTING: Rehabilitation centre. PARTICIPANTS: Older adults (>= 55 years) admitted to a rehabilitation centre after hospital discharge (n=34). INTERVENTION: Participants received a high protein diet (protein enriched bread and protein enriched drinking yoghurt; n=17) or a regular diet (regular bread and regular drinking yoghurt; n=17) for three consecutive weeks. MEASUREMENTS: Total protein intake and protein intake per meal, measured twice weekly over a three weeks period (six measurements per participant). RESULTS: Compared with controls, patients who received the protein enriched products had a significantly higher protein intake (115.3 g/d vs 72.5 g/d, P<0.001; 1.6 g/kg/d vs 1.1 g/kg/d, P<0.001). The intervention group consumed quantities over the recommended level (25-30 g/meal) during each of the three meals (32.5 g, 30.0 g, 34.8 g/meal), where the control group consumed quantities below the recommended level during breakfast (17.7 g) and lunch (18.4 g). CONCLUSIONS: The use of protein enriched products, replacing regular products, results in a significant increased daily protein intake in older adults. In addition, the daily consumption of protein enriched products improves protein distribution over the day. PMID- 25923482 TI - Effect of cysteine-rich whey protein (immunocal(r)) supplementation in combination with resistance training on muscle strength and lean body mass in non frail elderly subjects: a randomized, double-blind controlled study. AB - OBJECTIVES: The purpose of the present study was to examine the effect of a cysteine-rich whey protein (Immunocal(r)) supplementation in combination with resistance training on muscle strength and lean body mass (LBM) in elderly individuals. We hypothesized that the cysteine-rich whey protein (Immunocal(r)) group would experience a greater increase in muscle strength and lean body mass versus the control group (casein). DESIGN: Randomized double-blind controlled intervention study. SETTING: Institut de Recherches Cliniques de Montreal in Montreal, Canada. PARTICIPANTS: Ninety-nine non-frail elderly subjects were recruited. INTERVENTION: Participants were randomly assigned into two groups. The experimental group received a cysteine-rich whey protein isolate (Immunocal(r)) (20 g/day) and the control group received casein (20 g/day) during a 135-day period. In addition, both groups performed the same resistance training program (3 times per week). MEASUREMENTS: Body composition (DXA) and muscle strength (leg press) were measured. RESULTS: Of the 99 recruited participants, 84 completed the 135-day study period. Of these, 67 subjects (33 in the casein group and 34 in the Immunocal(r) group) complied and used at least 80 % of the study product and completed at least 80 % of their training sessions. Results in this selected group show an increase in all three muscle strength variables (absolute, normalized by BW and by LBM) by 31.0 %, 30.9 % and 30.0 %, respectively in the casein group as well as 39.3 %, 39.9 % and 43.3 %, respectively in the Immunocal(r) group after the intervention (p < 0.05). The increases in muscle strength favored Immunocal(r) versus casein by approximately 10 % when expressed in kg per kg BW and in kg per kg LBM (p < 0.05). No significant changes were found between pre-and-post intervention in both groups for total LBM. CONCLUSIONS: Our findings showed increases in muscle strength in both groups after resistance training, however, significant additional increases were observed in muscle strength with the addition of a cysteine-rich whey protein (Immunocal(r)) versus casein. PMID- 25923483 TI - Do calcium supplements increase serum and urine calcium levels in post-menopausal women? AB - OBJECTIVES: The frequent prescription of calcium supplements with vitamin D by health practitioners is a topic of concern globally. The present study was designed to find out whether the calcium supplements with vitamin D really affect serum and urinary calcium levels in post-menopausal women. DESIGN, SETTINGS AND PARTICIPANTS: The age-matched comparative study was performed among postmenopausal women who were already on and those who were not on calcium supplements with vitamin D for a period of time in relation to the estimation of the serum calcium and the urine calcium levels. Sixty healthy postmenopausal women were enrolled, with thirty among them forming the study group (SG) - who were on calcium supplements with vitamin D for a period of a month, three months, and up to twelve months - were studied and compared the results obtained with the age-matched control group (CG) of thirty post-menopausal women who were not on calcium supplements. MEASUREMENTS: The serum and the urinary calcium levels were estimated by using appropriate biochemical methods and the data were analysed using relevant statistical methods. RESULTS: The serum calcium levels did not vary significantly in SG in spite of consuming calcium supplements over a period of time, whereas the urinary calcium levels increased progressively (p value < 0.005) in those who have taken calcium supplements for a year compared to those who have taken for a month. CONCLUSION: Thus, the calcium supplements were of little significance on the serum calcium levels, but have a significant effect on the urinary calcium levels in post-menopausal women. PMID- 25923484 TI - Intake of antioxidants and subsequent decline in physical function in a racially/ethnically diverse population. AB - OBJECTIVES: Oxidative stress is considered a risk factor for physical function (PF) decline with aging. The objective of this study was to examine the relationship between antioxidant intake and change in PF over a 5-year period. DESIGN, SETTING, PARTICIPANTS: The Boston Area Community Health (BACH) Survey is a population-based longitudinal study including 5,502 racially/ethnically diverse and randomly selected participants aged 30-79 years. MEASUREMENTS: In total, 2828 persons aged 30-79 years completed the validated Block Food Frequency Questionnaire (FFQ) and participated in the follow-up study. Change in PF from baseline (2002-2005) to follow-up (2006-2010) was assessed using the validated SF 12 questionnaire. Linear models were used to examine the association between energy-adjusted quartiles of vitamins C, E and carotenoids and change in PF. RESULTS: A low intake (first quartile) of vitamin E was associated with a greater decline in PF compared with the highest quartile, with a mean difference in change in PF of -1.73 (95%CI:-3.31,-0.15). Notably, this mean difference was clinically meaningful as it was equivalent to the effect estimate we found for participants who were approximately 15 years apart in age in our cohort, as 1 year increase in age was associated with a mean difference in change in PF of 0.11 (95%CI:-0.16,-0.06). PF decline was not significantly different in the lowest compared with the highest quartile of vitamin C (mean difference=-1.29, 95%CI:-2.61, 0.03) or carotenoids (mean difference=-0.62, 95%CI:-2.22,0.99). CONCLUSIONS: Low intake of vitamin E was significantly associated with decline in PF with aging. These results are clinically meaningful, extend previous findings that oxidative stress contributes to PF decline, and may inform the development of future prevention strategies aimed at reducing this clinical and public health problem. PMID- 25923485 TI - Bilberry extract supplementation for preventing eye fatigue in video display terminal workers. AB - OBJECTIVES: To examine the effect of a dietary supplement containing bilberry extract (BE) on eye fatigue induced by acute video display terminal (VDT) loads. DESIGN AND SETTING: A prospective, randomized, double-blind, placebo-controlled study was performed from August 2012 to February 2013 in the Medical Corporation Jico-kai Yagi Hospital, and the Shinyokohama Shinoharaguchi Orthopedic Surgery and Dermatology Clinic, in Japan. PARTICIPANTS: Two hundred eighty-one office workers aged 20-40 years that used VDTs were screened by critical flicker fusion (CFF) and near point accommodation (NPA). INTERVENTION: The participants were randomized to either a BE (480 mg/day) or placebo (vehicle) group, and took allocated capsule, daily, for 8 weeks. MEASUREMENTS: The CFF, NPA, contrast visual acuity, functional visual acuity, keratoconjunctival epithelial damage, and fluorescein tear film break-up time were examined, and 18 subjective symptoms of eye fatigue were evaluated by questionnaire. Adverse events were reported via medical interviews. Data were collected both before and after VDT load at baseline, and 4, and 8 weeks after daily supplementation with either BE or placebo. RESULTS: Of 281 participants screened, 88 having relatively lower levels of CFF and NPA were enrolled in the study. Of these, 37 control and 43 BE group subjects completed the study. The VDT load-induced reduction in CFF was alleviated after 8 weeks of BE supplementation (95% confidence interval, 0.10 1.60; p=0.023), in contrast to placebo supplementation, while NPA variation was not. Of the subjective symptoms of eye fatigue, VDT load-induced ocular fatigue sensation, ocular pain, eye heaviness, uncomfortable sensation, and foreign body sensation were mitigated more in the BE group than in the control group, at week 8 (p<0.05). There were no severe adverse events in either group. CONCLUSIONS: BE supplementation improved some of the objective and subjective parameters of eye fatigue induced by VDT loads. PMID- 25923486 TI - The effects of substance p on tendinopathy are dose-dependent: an in vitro and in vivo model study. AB - OBJECTIVES: Substance P (SP) is known to be involved in neuropathic pain, chronic inflammation, and tendinopathy. The present study evaluated the effects of different doses of SP on tendon-derived stem cells (TDSCs) in vitro and tendons in vivo. METHODS: For the in vitro study, TDSCs cultured in growth medium with different concentrations of SP (negative control, 0.1 nM, and 1.0 nM). The effects of SP on TDSCs were examined with respect to their ability to proliferate and differentiate. For the in vivo study, we injected different doses of SP (saline control, 0.5 nmol, and 5.0 nmol) into rat patella tendons to investigate the effects of SP on tendons. RESULTS: Low and high doses SP significantly enhanced the proliferation ability of TDSCs. Low-dose of SP induced the expression of tenocyte-related genes; however, high-dose of SP induced the expression of non-tenocyte genes, which was evident by the high expression of PPARgamma and collagen type II. In the in vivo study, only high-doses of SP (5.0 nmol) induced the tendinosis-like changes in the patella tendon injection model. Low doses of SP (0.5 nmol) enhanced the tenogenesis compared with saline injection and the high-dose SP group. CONCLUSIONS: SP enhances the proliferation of TDSCs in vitro and the effects of SP on tendinopathy are dose-dependent in vivo. PMID- 25923487 TI - Fortification of Yogurts with Vitamin D and Calcium Enhances the Inhibition of Serum Parathyroid Hormone and Bone Resorption Markers: A Double Blind Randomized Controlled Trial in Women over 60 Living in a Community Dwelling Home. AB - OBJECTIVE: To evaluate whether fortification of yogurts with vitamin D and calcium exerts an additional lowering effect on serum parathyroid hormone (PTH) and bone resorption markers (BRM) as compared to iso-caloric and iso-protein dairy products in aged white women at risk of fragility fractures. DESIGN: A randomized double-blind controlled trial. SETTING: A community dwelling home. PARTICIPANTS: Forty-eight women over 60 years (mean age 73.4). INTERVENTION: Consumption during 84 days of two 125 g servings of either vitamin D and calcium fortified yogurts (FY) at supplemental levels of 10 ug vitamin D3/d and 520 mg/d of calcium (total=800 mg/d), or non fortified control yogurts (CY) providing 280 mg/d of calcium. MEASUREMENTS: Serum changes from baseline (D0) to D28, D56 and D84 in 25OHD, PTH and in two BRM: Tartrate-resistant-acid-phosphatase-isoform-5b (TRAP5b) and carboxy-terminal-cross-linked-telopeptide of type-I-collagen (CTX). RESULTS: The 10 years risk of major and hip fractures were 13.1 and 5.0%, and 12.9 and 4.2 %, in FY and CY groups, respectively. From D0 to D84, serum 25OHD increased (mean+/-SE) from 34.3+/-2.4 to 56.3+/-2.4 nmol/L in FY (n=24) and from 35.0+/-2.5 to 41.3+/-3.0 nmol/L in CY (n=24), (P=0.00001). The corresponding changes in PTH were from 64.1+/-5.1 to 47.4+/-3.8 ng/L in FY and from 63.5+/-4.6 to 60.7+/-4.2 ng/L in CY (P=0.0011). After D84, TRAP5b was reduced significantly (P=0.0228) and CTX fell though not significantly (P=0.0773) in FY compared to CY. CONCLUSION: This trial in aged white women living in a community dwelling home at risk for osteoporotic fractures confirms that fortification of dairy products with vitamin D3 and calcium should provide a greater prevention of secondary hyperparathyroidism and accelerated bone resorption as compared to non-fortified equivalent foods. PMID- 25923488 TI - Validation of the Mini Nutritional Assessment-Short Form in a Population of Frail Elders without Disability. Analysis of the Toulouse Frailty Platform Population in 2013. AB - OBJECTIVE: To assess the validity of the Mini Nutritional Assessment-Short Form (MNA-SF) in elderly patients from the Toulouse Frailty Platform. PARTICIPANTS: Overall, 267 patients aged 65 and over, without severe cognitive impairment (i.e. Mini Mental Status Examination > 20 and CDR<1), no physical disability (i.e. Activities of Daily Living >= 5) and no active cancer history (over the past 12 months) were included in 2013. MEASUREMENTS: Receiver operating characteristic (ROC) analyses were used to assess the predictive validity of the French version of the MNA-SF for good nutritional status (defined as a full MNA score>=24/30). Analyses were conducted in the overall sample and then in subgroups of frail and pre-frail subjects according to the frailty phenotype. Optimal cut-off points were determined to obtain the best sensitivity/specificity ratio and the highest number of correctly classified subjects. RESULTS: Among 267 patients, mean age=81.5+/-5.8; women=67.0%; 138 (51.7%) were frail, 98 (36.7%) were pre-frail and 31 (11.6%) were robust. Given their MNA-SF scores, 201 (75.3%) had a good nutritional status, 61 (22.8%) were at risk of malnutrition and 5 (1.9%) were malnourished. In the overall sample, but also in subgroups of pre-frail or frail elders, the areas under ROC curves were 0.954, 0.948 and 0.958 respectively. The 11 points cut-off provided the best correct classification ratio (91.4%); sensitivity=94.0%, specificity=83.3%. CONCLUSION: The MNA-SF appeared to be a validated and effective tool for malnutrition screening in frail elders. Implementing this tool in clinical routine should contribute to improving the screening of malnourished frail individuals. PMID- 25923489 TI - Determinants of Perceived Physical Environment Barriers among Community-Dwelling Elderly in Taiwan. AB - OBJECTIVES: To test the hypothesis that mobility, activities of daily living, and the interaction between them can play a key role in determining perceived physical environment barriers among community-dwelling elderly. DESIGN: Cross sectional. SETTING: Community. PARTICIPANTS: One hundred and ninety-seven community-dwelling elderly with more than 7 points on the Short Portable Mental State Questionnaire and less than 7 points on the Geriatric Depression Scale (15 items). INTERVENTION: None. MEASUREMENTS: Time Get-up and Go test (TUG), the subscales of basic activity of daily living (BADL)/instrumental activities of daily living (IADL) of the Hierarchy of Care Required (HCR), and the physical/structural subscale of the Craig Hospital Inventory of Environmental Factors in Community-dwelling Elderly in Taiwan were used to measure mobility, activities of daily living and perceived physical environment barriers, respectively. Hierarchical linear regression analyses were used to test the study hypothesis. RESULTS: Significant and positive relations were found to exist between perceived physical environment barriers and (1) the TUG time (beta=.300, p<.05), and (2) the IADL score for the HCR (beta=.322, p<.05), respectively. A significant and negative relation existed between perceived physical environment barriers and the interaction term (the TUG time and the IADL score for the HCR) (beta=-.211, p<.05). CONCLUSION: Mobility, IADL and the interaction between them are found to be significant determinants of perceived physical environment barriers in the community-dwelling elderly under consideration. Strategies targeting the enhancement of mobility among community-dwelling elderly are suggested to lead to improvements in the degree to which physical environment barriers are perceived. This beneficial effect could be greater in the case of elderly individuals with better IADL function. PMID- 25923490 TI - In-Hospital Haloperidol Use and Perioperative Changes in QTc-Duration. AB - OBJECTIVES: Haloperidol may prolong ECG QTc-duration but is often prescribed perioperatively to hip-fracture patients. We aimed to determine (1) how QTc duration changes perioperatively, (2) whether low-dose haloperidol-use influences these changes, and (3) which clinical variables are associated with potentially dangerous perioperative QTc-prolongation (PD-QTc; increase >50 ms or to >500 ms). DESIGN: Prospective cohort study. SETTING: Tertiary university teaching-hospital. PARTICIPANTS: Patients enrolled in a randomized controlled clinical trial of melatonin versus placebo on occurrence of delirium in hip-fracture patients. MEASUREMENTS: Data from ECGs made before and after hip surgery (1-3 days and/or 4 6 days post-surgery) were analyzed. QTc-duration was measured by hand, blinded for haloperidol and pre/post-surgery status. Clinical variables were measured at baseline. Mixed model analysis was used to estimate changes in QTc-duration. Risk factors for PD-QTc were estimated by logistic regression analysis. RESULTS: We included 89 patients (mean age 84 years, 24% male); 39 were treated with haloperidol. Patients with normal pre-surgery QTc-duration (male <=430 ms, female <=450 ms) had a significant increase (mean 12 ms, SD 28) in QTc-duration. A significant decrease (mean 19 ms, SD 34) occurred in patients with prolonged pre surgery QTc-duration (male >450ms, female >470 ms). Haloperidol-use did not influence the perioperative course of the QTc-interval (p=0.351). PD-QTc (n=8) was not associated with any of the measured risk-factors. CONCLUSION: QTc duration changed differentially, increasing in patients with normal, but decreasing in patients with abnormal baseline QTc-duration. PD-QTc was not associated with haloperidol-use or other risk-factors. Low-dose oral haloperidol did not affect perioperative QTc-interval. PMID- 25923491 TI - Change in Red Blood Cell Distribution width During the Last Years of Life in Geriatric Patients. AB - OBJECTIVES: Most of the studies that evaluate the association between red blood cell distribution width (RDW) and mortality assess it on a single occasion instead of doing so through serial measurements. Very few studies have investigated repeated measurements of RDW and its prognostic value, and most of them are focused on patients with cardiovascular diseases. RDW is a dynamic value so we aimed at determining the prognostic value of sequential RDW assessment in the last years of life in patients enrolled in a Department of Geriatrics. DESIGN: This work is part of a prospective study derived from a cohort of 122 patients over 75 years hospitalized in 2005 for the purpose of assessing the prognostic significance of several comorbidity and prognostic indices. SETTING: Patients were consecutively recruited for the study at admission in a tertiary hospital and then followed up for at least 5 years. PARTICIPANTS: A total of 55 patients with repeated RDW assessments during all the five years before their death were selected from the total cohort of 122 patients. RESULTS: We found a strong correlation between progressive rise in RDW and mortality risk, especially during the last year of life. There was a gradual significant increase in the RDW values along the last five years of life, with means growing up from 14,8 (95% CI: 13,98-15.62) to 16,37 (15,80-16,94). CONCLUSION: In our cohort of geriatric patients, RDW is a dynamic variable that is modified during the last five years of life, irrespective of their age, and especially during the last year. PMID- 25923492 TI - Increased Risk of Bacterial Infections among the Obese with Chronic Diseases. AB - OBJECTIVES: It has been well understood that cigarette smokers have an increased risk of infections; however, the association between obesity and infections has not been well explored in general population. METHODS: The analysis was based on data from the Canadian Community Health Survey - Healthy Aging (2008-2009), and included a total of 30 763 Canadians aged 45 years or older. Information on demographic data, body mass index (BMI), smoking status, chronic condition(s) and antibiotics use during the past month were collected. Logistic regression analysis was used to determine the associations of obesity and smoking with antibiotics use and adjusted for potential confounders. RESULTS: Overall, 6.6% used antibiotics in the previous month. Compared with those of normal weight, overweight and obese individuals were more likely to use antibiotics after adjustment for confounders, with odds ratios (ORs) of 1.28 (95% CI: 1.08, 1.50) and 1.25 (95% CI: 1.04, 1.50), respectively. When stratified by presence/absence of chronic condition(s), the associations were only significant among those with chronic condition(s) and the adjusted ORs were 1.30 (95% CI: 1.09, 1.55) for the overweight and 1.43 (95% CI: 1.18, 1.73) for the obese. Current smokers had an increased risk of antibiotics use when compared with non-smokers. The adjusted OR for smoking was similar for people with or without chronic condition(s), but was significant only for those with chronic condition(s) (OR 1.41, 95% CI: 1.16, 1.73). CONCLUSIONS: Overweight and obese Canadians aged 45 years or more, especially in those with chronic condition(s), had an increased risk of bacterial infections than their normal weight counterparts. The reasons for the modifying effect of chronic condition(s) on the association between body weight and infections were discussed. PMID- 25923493 TI - [The treatment of locally recurrent rectal cancer]. AB - Its incidence has decreased in recent decades due to advances in the treatment of patients with primary rectal cancer, but LRRC still occurs in 6-10% of these patients. LRRC is often accompanied by severe, progressive pain and has a major impact on quality of life. Curative treatment is possible based on surgical resection combined with chemoradiotherapy. Radical resection is the most important prognostic factor in curative treatment. Neo-adjuvant systemic therapy may further improve outcomes in LRRC patients. Many patients are not eligible for surgical treatment due to the presence of metastases or irresectability of the local recurrence. These patients should receive optimal palliative care for the disabling pain. Radiotherapy is effective against local pain in around 75% of patients but the duration of palliation is limited. PMID- 25923494 TI - [Burnout in Dutch medical students: prevalence and causes]. AB - OBJECTIVE: To investigate the prevalence and causes of burnout in Dutch medical students. DESIGN: Questionnaire survey. METHOD: All 14,570 student members of the KNMG (Royal Dutch Medical Association) were invited to fill in a digital survey. Burnout was determined with the Utrecht Burnout Scale (UBOS). Triggering and protective factors for burnout were also investigated . RESULTS: 2,739 medical students (18.8%) completed the survey and 14.5 per cent of all respondents met the burnout criteria. 17.8 per cent of the hospital interns who responded and 11.6 per cent of the preclinical students who responded met these criteria. Work home interference and high levels of emotional pressure had the strongest link to burn-out, while a sufficient amount of support from family, friends and peers reduced the risk of burnout in both undergraduates and hospital interns. CONCLUSION: Our exploratory research suggests that the prevalence of burnout is high, particularly among the hospital interns who responded. The most important contributory factors are high levels of emotional pressure and work-home interference. The low percentage of respondents makes it difficult to make any statement about the prevalence and causes of burnout among all Dutch medical students. PMID- 25923496 TI - [Prevention of injuries associated with horseback riding]. AB - Each year 9,900 equestrians present at Accident and Emergency Departments, 40% of them 10-19 year old females. The most common horse-riding injuries are to the head, brain, neck and face, torso and extremities. Because of the relatively larger head, children more often fall on their head. Wearing a helmet gives considerable protection. Despite the common use of a helmet by horseback riders, serious head injury still occurs regularly. Further research into improvement of the protective function of the helmet is indicated. The current safety vest (body protector) does not significantly reduce the risk of torso injury. Improvement of its protective function is necessary. Injury to the lower extremities is caused when they become trapped in the stirrup in a fall from or with the horse. Safety stirrups and sturdy footwear are possible preventive measures. Investment in the quality and promotion of preventive measures could reduce the frequency and severity of equestrian injuries. PMID- 25923497 TI - [Unexplained loss of consciousness: the diagnosis is never based on one symptom]. AB - Patients with transient loss of consciousness are often seen by a variety of specialists. Even if typical signs occur, it can be difficult to identify specific causes. We discuss two patients with complex presentations. The first patient was diagnosed with sleep syncope, a relatively unknown type of reflex syncope. The prodromal symptoms of discomfort and the subsequent loss of consciousness occurred while the patient was in bed or got up to go to the toilet due to abdominal symptoms. The onset in supine position was misleading, since this is a well-known alarm symptom of a possible cardiac cause. The second patient had vasovagal syncope followed by a psychogenic pseudosyncope. This resulted in frequent loss of consciousness of long duration with typical and atypical triggers and uncommon syncopal signs, including eye closure. These conflicting symptoms can be a pitfall and clinical expertise is required to identify the type of syncope. PMID- 25923498 TI - [Less need for prevention through better care? Towards an effective deployment of preventive and curative care]. AB - Scientists and politicians repeatedly call for more investment in prevention. Besides improving public health, this would reduce health care spending. This article discusses two mechanisms that are relevant to the debate regarding the efficiency of prevention. The first mechanism concerns the additional demand for health care as a result of increased life expectancy. The second mechanism concerns the impact that improvements in curative care have on the consequences of prevention. Both mechanisms show that prevention and curative care cannot be considered separately. Consequently, decisions on investments in preventive and curative care should ideally be based on the same decision-making framework. An effective deployment of prevention and care will benefit from economic evaluations that give as full a picture as possible of both the costs and benefits of new interventions. PMID- 25923499 TI - [A neonate with aganglionosis of the entire colon]. AB - BACKGROUND: 1 in every 5,000 children is born with Hirschsprung's disease (HD). Total colonic aganglionosis is an extended form of HD and is present in 2-13% of all patients with the disease. CASE DESCRIPTION: Paediatricians from a general hospital referred a 12-day-old male neonate on account of suspected abdominal obstruction and sepsis. An ileostomy was created and biopsies were taken during a laparotomy. Examination of the biopsies indicated total colonic aganglionosis. This diagnosis was unexpected because the symptoms of obstruction had occurred late and the radiological findings were not characteristic of Hirschsprung's disease. CONCLUSION: Persistent passage problems after delayed meconium passage are important alarm symptoms of Hirschsprung's disease. This diagnosis must be considered and ruled out in these patients in order to avoid an acute presentation of this disease. PMID- 25923500 TI - [LDL cholesterol lowering therapy: no target value but personalised treatment]. AB - We previously recommended that LDL cholesterol lowering therapy be based on the risk for (recurrent) coronary events, rather than on arbitrary targets for serum LDL cholesterol concentration. We also recommended refraining from therapy with ezetimibe until its efficacy in preventing cardiovascular events had been documented. At the American Heart Association scientific sessions 2014 the results of the IMPROVE-IT study were reported. In this large, randomised trial, a modest benefit of the combination of simvastatin plus ezetimibe over simvastatin alone was reported after 7 years of treatment. The efficacy of such combination therapy was similar to the efficacy of high-dose statin therapy, while the combination therapy is much more expensive. Comparing the efficacy and costs of different preventive therapies, we recommend first prescribing aspirin and a moderate dose of statin, secondly an ACE inhibitor. A high-dose statin should be considered in high-risk patients. The combination of simvastatin and ezetimibe should be prescribed only in high-risk patients (e.g. diabetics after myocardial infarction) who do not tolerate high-dose statins. PMID- 25923501 TI - [A woman with unilateral flushing of her face]. AB - A 42-year-old woman had symptoms of unilateral flushing and sweating of her face during exercise. The clinical diagnosis was 'harlequin syndrome'. This condition is caused by a defect of the sympathetic nervous system and is in most cases idiopathic. PMID- 25923502 TI - [The automated external defibrillator in the resuscitation chain. The importance of the AED examined]. AB - The survival rate for those suffering an out-of-hospital cardiac arrest (OHCA) is improving slowly, with > 90% of the survivors being discharged from hospital with cognitive function intact. A recent analysis of the ARREST (AmsteRdam Resuscitation Study) group documented an increase in survival rates with favourable neurological outcome from 16.2% in 2006 to 19.7% in 2012. Only those victims whose initial cardiac rhythm is 'shockable' (i.e. ventricular fibrillation or tachycardia) reap the benefits: their survival rate increased from 29.1% to 41.4%. The prognosis for those with a non-shockable rhythm remains grim (< 5% survival). A recent analysis of the ARREST database points to the increasing use of AEDs (by laypersons, but particularly by police officers and fire-fighters with a training in basic life support) as one of the main drivers of this improved prognosis. An AED is now used in 59% of OHCA in the greater Amsterdam area, and has become an essential link in the resuscitation chain. PMID- 25923503 TI - [Detecting inappropriate medication in older people: the revised STOPP/START criteria]. AB - The use of potentially inappropriate medications (PIMs) by older people and potential prescribing omissions (PPOs) represent a serious problem. It increases the risk of adverse drug reactions (ADRs), however it is susceptible to influence in a substantial number of cases. Use of the STOPP/START criteria developed in Ireland to optimise pharmacotherapy of older people reduces the number of ADRs and medication errors. Licensing of new drugs, the increased number of potentially inappropriate drugs, and the availability of new literature were grounds for an update of the first version of the STOPP/START criteria which was published in 2008. In order to develop a screening tool with a broader application, a consensus panel of experts in the field of pharmacotherapy of older people was selected from 14 European countries for the second version of the STOPP/START criteria, including two from the Netherlands. The translation of the second version of the STOPP/START criteria has been adapted to the situation in the Netherlands, partly by omitting drugs that are not licensed in the Netherlands. PMID- 25923504 TI - Misrepresentation by citation in Pooley et al. PMID- 25923506 TI - Sedimentation stacking diagram of binary colloidal mixtures and bulk phases in the plane of chemical potentials. AB - We give a full account of a recently proposed theory that explicitly relates the bulk phase diagram of a binary colloidal mixture to its phase stacking phenomenology under gravity (de las Heras and Schmidt 2013 Soft Matter 9 8636). As we demonstrate, the full set of possible phase stacking sequences in sedimentation-diffusion equilibrium originates from straight lines (sedimentation paths) in the chemical potential representation of the bulk phase diagram. From the analysis of various standard topologies of bulk phase diagrams, we conclude that the corresponding sedimentation stacking diagrams can be very rich, even more so when finite sample height is taken into account. We apply the theory to obtain the stacking diagram of a mixture of nonadsorbing polymers and colloids. We also present a catalog of generic phase diagrams in the plane of chemical potentials in order to facilitate the practical application of our concept, which also generalizes to multi-component mixtures. PMID- 25923505 TI - Seroprevalence of Toxoplasma gondii, rubella and Cytomegalovirus among pregnant females in north-western Turkey. AB - OBJECTIVE: To examine the sera-prevalence rates of Toxoplasma gondii, rubella and Cytomegalovirus (CMV) among pregnant women in different age groups in the context of a comparison with nationwide and international data previously reported. METHODS: Females of reproductive age attending to our hospital between 1 January 2012 and 1 January 2014 were included in this study. Antibodies against T gondii;~, rubella and CMV were assayed using chemiluminescence immunoassay methods. The test results.were evaluated retrospectively. RESULTS: Of the participants, 2.5 and 43.9% were seropositive for Toxoplasma lgM and lgG, respectively. The corresponding figures for rubella and CMV were 1.5 and 93.8%, and 2 and 91.5%, respectively. CONCLUSION: The high rates of immunity against rubella and CMV infections among pregnant females in our region call into question the routine screening of pregnant females for these two diseases. On the other hand, the high rate of seronegativity for T gondii warrants such a routine practice. PMID- 25923507 TI - Interference of blast cell fragments with automated platelet counting. AB - INTRODUCTION: Automated haematology analysers may inaccurately determine platelet counts in several circumstances. Spuriously elevated automated platelet counts have been reported in some acute leukaemia (AL) cases because of fragmentation of circulating blast cells (pseudoplatelets). Haemorrhagic diathesis is a common manifestation of AL, which is often caused by severe thrombocytopenia. Therefore, overestimation of the actual platelet count in patients with AL can affect its clinical management. We aimed to detect the frequency of pseudoplatelets in patients with AL. METHODS: Complete blood cell counts were performed on 86 AL patients with three automated analysers (ADVIA 2120, Coulter LH 750 and Sysmex XE 2100D). Platelet counts were also performed by quantitative flow cytometry (QFC). The platelet counts of the automatic analysers were compared to the platelet counts by QFC. Blood smears were checked for the presence of pseudoplatelets. RESULTS: The automated analysers overestimated the platelet count due to the presence of pseudoplatelets in patients with AL. Pseudoplatelets were observed in the blood smears of 11 patients (13%). Three of these patients were near the prophylactic platelet transfusion threshold. CONCLUSION: Spurious increases in automated platelet counts by blast cell fragments are little known but frequent artefacts that should be ruled out by careful examination of peripheral blood smears. PMID- 25923511 TI - Bulk and interfacial stresses in suspensions of soft and hard colloids. AB - We explore the influence of particle softness and internal structure on both the bulk and interfacial rheological properties of colloidal suspensions. We probe bulk stresses by conventional rheology, by measuring the flow curves, shear stress versus strain rate, for suspensions of soft, deformable microgel particles and suspensions of near hard-sphere-like silica particles. A similar behaviour is seen for both kinds of particles in suspensions at concentrations up to the random close packing volume fraction, in agreement with recent theoretical predictions for sub-micron colloids. Transient interfacial stresses are measured by analyzing the patterns formed by the interface between the suspensions and their solvent, due to a generalized Saffman-Taylor hydrodynamic instability. At odds with the bulk behaviour, we find that microgels and hard particle suspensions exhibit vastly different interfacial stress properties. We propose that this surprising behaviour results mainly from the difference in particle internal structure (polymeric network for microgels versus compact solid for the silica particles), rather than softness alone. PMID- 25923510 TI - Granulocyte macrophage colony-stimulating factor is required for aortic dissection/intramural haematoma. AB - Aortic dissection and intramural haematoma comprise an aortopathy involving separation of the aortic wall. Underlying mechanisms of the condition remain unclear. Here we show that granulocyte macrophage colony-stimulating factor (GM CSF) is a triggering molecule for this condition. Transcription factor Kruppel like factor 6 (KLF6)-myeloid-specific conditional deficient mice exhibit this aortic phenotype when subjected to aortic inflammation. Mechanistically, KLF6 downregulates expression and secretion of GM-CSF. Administration of neutralizing antibody against GM-CSF prevents the condition in these mice. Conversely, administration of GM-CSF in combination with aortic inflammation to wild-type mice is sufficient to induce the phenotype, suggesting the general nature of effects. Moreover, patients with this condition show highly increased circulating levels of GM-CSF, which is also locally expressed in the dissected aorta. GM-CSF is therefore a key regulatory molecule causative of this aortopathy, and modulation of this cytokine might be an exploitable treatment strategy for the condition. PMID- 25923512 TI - Disruption of the rice nitrate transporter OsNPF2.2 hinders root-to-shoot nitrate transport and vascular development. AB - Plants have evolved to express some members of the nitrate transporter 1/peptide transporter family (NPF) to uptake and transport nitrate. However, little is known of the physiological and functional roles of this family in rice (Oryza sativa L.). Here, we characterized the vascular specific transporter OsNPF2.2. Functional analysis using cDNA-injected Xenopus laevis oocytes revealed that OsNPF2.2 is a low-affinity, pH-dependent nitrate transporter. Use of a green fluorescent protein tagged OsNPF2.2 showed that the transporter is located in the plasma membrane in the rice protoplast. Expression analysis showed that OsNPF2.2 is nitrate inducible and is mainly expressed in parenchyma cells around the xylem. Disruption of OsNPF2.2 increased nitrate concentration in the shoot xylem exudate when nitrate was supplied after a deprivation period; this result suggests that OsNPF2.2 may participate in unloading nitrate from the xylem. Under steady-state nitrate supply, the osnpf2.2 mutants maintained high levels of nitrate in the roots and low shoot:root nitrate ratios; this observation suggests that OsNPF2.2 is involved in root-to-shoot nitrate transport. Mutation of OsNPF2.2 also caused abnormal vasculature and retarded plant growth and development. Our findings demonstrate that OsNPF2.2 can unload nitrate from the xylem to affect the root-to-shoot nitrate transport and plant development. PMID- 25923513 TI - 5-Methoxyquinoline Derivatives as a New Class of EZH2 Inhibitors. AB - A series of quinoline derivatives was synthesized and biologically evaluated as Enhancer of Zeste Homologue 2 (EZH2) inhibitors. Structure-activity relationship (SAR) studies led to the discovery of 5-methoxy-2-(4-methyl-1,4-diazepan-1-yl)-N (1-methylpiperidin-4-yl)quinolin-4-amine (5k), which displayed an IC50 value of 1.2 MUM against EZH2, decreased global H3K27me3 level in cells and also showed good anti-viability activities against two tumor cell lines. Due to the low molecular weight and the fact that no quinoline derivative has been reported as an EZH2 inhibitor, this compound could serve as a lead compound for further optimization. PMID- 25923514 TI - Lectin engineering, a molecular evolutionary approach to expanding the lectin utilities. AB - In the post genomic era, glycomics--the systematic study of all glycan structures of a given cell or organism--has emerged as an indispensable technology in various fields of biology and medicine. Lectins are regarded as "decipherers of glycans", being useful reagents for their structural analysis, and have been widely used in glycomic studies. However, the inconsistent activity and availability associated with the plant-derived lectins that comprise most of the commercially available lectins, and the limit in the range of glycan structures covered, have necessitated the development of innovative tools via engineering of lectins on existing scaffolds. This review will summarize the current state of the art of lectin engineering and highlight recent technological advances in this field. The key issues associated with the strategy of lectin engineering including selection of template lectin, construction of a mutagenesis library, and high-throughput screening methods are discussed. PMID- 25923516 TI - Does surgical menopause affect sexual performance differently from natural menopause? AB - INTRODUCTION: Hysterectomy is the most common major gynecologic operation, together with bilateral salpingo-oophorectomy in the majority of women over the age of 45. AIM: To investigate whether surgical menopause affects female sexual performance differently from natural menopause. METHODS: The study included 121 women who had undergone surgical menopause and 122 women who had undergone natural menopause. All the women had similar economic, sociocultural, and personal demographic profiles, had been postmenopausal for at least 1 year, and were between the ages of 45 and 65. The women were asked to complete a six question survey of sexual performance parameters (sexual desire, coital frequency, arousal, orgasm frequency, dyspareunia, and vaginal lubrication). These sexual performance parameters were compared between the surgical and natural menopause groups. RESULTS: With the exception of vaginal lubrication, sexual performance parameters were not statistically different between the two groups (P > 0.05). Vaginal lubrication in the surgically menopausal group was lower than in the naturally menopausal group (P < 0.05). Serum dehydroepiandrosterone sulphate, prolactin, and thyrotropin levels were not statistically different between the groups (P > 0.05), whereas serum estradiol and total testosterone levels in the surgically menopausal group were lower than those of the naturally menopausal group (P < 0.05). CONCLUSION: The results of this study showed that surgical menopause did not affect female sexual performance differently from natural menopause, with the exception of vaginal lubrication. PMID- 25923515 TI - Preclinical Validation of the Heparin-Reactive Peptide p5+14 as a Molecular Imaging Agent for Visceral Amyloidosis. AB - Amyloid is a complex pathologic matrix comprised principally of paracrystalline protein fibrils and heparan sulfate proteoglycans. Systemic amyloid diseases are rare, thus, routine diagnosis is often challenging. The glycosaminoglycans ubiquitously present in amyloid deposits are biochemically and electrochemically distinct from those found in the healthy tissues due to the high degree of sulfation. We have exploited this unique property and evaluated heparin-reactive peptides, such as p5+14, as novel agents for specifically targeting and imaging amyloid. Herein, we demonstrate that radiolabeled p5+14 effectively bound murine AA amyloid in vivo by using molecular imaging. Biotinylated peptide also reacted with the major forms of human amyloid in tissue sections as evidenced immunohistochemically. Furthermore, we have demonstrated that the peptide also binds synthetic amyloid fibrils that lack glycosaminoglycans implying that the dense anionic motif present on heparin is mimicked by the amyloid protein fibril itself. These biochemical and functional data support the translation of radiolabeled peptide p5+14 for the clinical imaging of amyloid in patients. PMID- 25923517 TI - An Excel tool for deriving key photosynthetic parameters from combined gas exchange and chlorophyll fluorescence: theory and practice. AB - Combined photosynthetic gas exchange and modulated fluorometres are widely used to evaluate physiological characteristics associated with phenotypic and genotypic variation, whether in response to genetic manipulation or resource limitation in natural vegetation or crops. After describing relatively simple experimental procedures, we present the theoretical background to the derivation of photosynthetic parameters, and provide a freely available Excel-based fitting tool (EFT) that will be of use to specialists and non-specialists alike. We use data acquired in concurrent variable fluorescence-gas exchange experiments, where A/Ci and light-response curves have been measured under ambient and low oxygen. From these data, the EFT derives light respiration, initial PSII (photosystem II) photochemical yield, initial quantum yield for CO2 fixation, fraction of incident light harvested by PSII, initial quantum yield for electron transport, electron transport rate, rate of photorespiration, stomatal limitation, Rubisco (ribulose 1.5-bisphosphate carboxylase/oxygenase) rate of carboxylation and oxygenation, Rubisco specificity factor, mesophyll conductance to CO2 diffusion, light and CO2 compensation point, Rubisco apparent Michaelis-Menten constant, and Rubisco CO2 saturated carboxylation rate. As an example, a complete analysis of gas exchange data on tobacco plants is provided. We also discuss potential measurement problems and pitfalls, and suggest how such empirical data could subsequently be used to parameterize predictive photosynthetic models. PMID- 25923518 TI - Lingering Questions on Choledochal Cysts. PMID- 25923519 TI - Variability of Suitable Habitat of Western Winter-Spring Cohort for Neon Flying Squid in the Northwest Pacific under Anomalous Environments. AB - We developed a habitat suitability index (HSI) model to evaluate the variability of suitable habitat for neon flying squid (Ommastrephes bartramii) under anomalous environments in the Northwest Pacific Ocean. Commercial fisheries data from the Chinese squid-jigging vessels on the traditional fishing ground bounded by 35 degrees -45 degrees N and 150 degrees -175 degrees E from July to November during 1998-2009 were used for analyses, as well as the environmental variables including sea surface temperature (SST), chlorophyll-a (Chl-a) concentration, sea surface height anomaly (SSHA) and sea surface salinity (SSS). Two empirical HSI models (arithmetic mean model, AMM; geometric mean model, GMM) were established according to the frequency distribution of fishing efforts. The AMM model was found to perform better than the GMM model. The AMM-based HSI model was further validated by the fishery and environmental data in 2010. The predicted HSI values in 1998 (high catch), 2008 (average catch) and 2009 (low catch) indicated that the squid habitat quality was strongly associated with the ENSO-induced variability in the oceanic conditions on the fishing ground. The La Nina events in 1998 tended to yield warm SST and favorable range of Chl-a concentration and SSHA, resulting in high-quality habitats for O. bartramii. While the fishing ground in the El Nino year of 2009 experienced anomalous cool waters and unfavorable range of Chl-a concentration and SSHA, leading to relatively low quality squid habitats. Our findings suggest that the La Nina event in 1998 tended to result in more favorable habitats for O. bartramii in the Northwest Pacific with the gravity centers of fishing efforts falling within the defined suitable habitat and yielding high squid catch; whereas the El Nino event in 2009 yielded less favorable habitat areas with the fishing effort distribution mismatching the suitable habitat and a dramatic decline of the catch of O. bartramii. This study might provide some potentially valuable insights into exploring the relationship between the underlying squid habitat and the inter annual environmental change. PMID- 25923520 TI - X-Ray Crystal Structure and Properties of Phanta, a Weakly Fluorescent Photochromic GFP-Like Protein. AB - Phanta is a reversibly photoswitching chromoprotein (PhiF, 0.003), useful for pcFRET, that was isolated from a mutagenesis screen of the bright green fluorescent eCGP123 (PhiF, 0.8). We have investigated the contribution of substitutions at positions His193, Thr69 and Gln62, individually and in combination, to the optical properties of Phanta. Single amino acid substitutions at position 193 resulted in proteins with very low PhiF, indicating the importance of this position in controlling the fluorescence efficiency of the variant proteins. The substitution Thr69Val in Phanta was important for supressing the formation of a protonated chromophore species observed in some His193 substituted variants, whereas the substitution Gln62Met did not significantly contribute to the useful optical properties of Phanta. X-ray crystal structures for Phanta (2.3 A), eCGP123T69V (2.0 A) and eCGP123H193Q (2.2 A) in their non-photoswitched state were determined, revealing the presence of a cis-coplanar chromophore. We conclude that changes in the hydrogen-bonding network supporting the cis-chromophore, and its contacts with the surrounding protein matrix, are responsible for the low fluorescence emission of eCGP123 variants containing a His193 substitution. PMID- 25923522 TI - In situ analysis of smoothelin-like 1 and calmodulin interactions in smooth muscle cells by proximity ligation. AB - The smoothelin-like 1 (SMTNL1) protein is the newest member of the smoothelin family of muscle proteins. Two calmodulin (CaM)-binding domains (CBD1 for Ca-CaM; CBD2 for apo-CaM) have been described for the SMTNL1 protein using in vitro assays. We now demonstrate in situ associations of SMTNL1 and CaM in A7r5 smooth muscle cells using the proximity ligation assay (PLA). We quantified CaM-SMTNL1 proximity events accurately after taking into account variations in protein expression levels. The refined method allows quantification of in situ proximity after transient transfection with an associated error of <10%. The proximity of SMTNL1 and CaM in A7r5 cells could be reduced by scrambling the amino acid sequence and mutation of large hydrophobic amino acids of CBD1. The truncation of CBD2 did not influence SMTNL1 proximity to CaM. Ultimately, we conclude that SMTNL1 forms complex interactions with CaM in smooth muscle cells, with a role for CBD1 and possibly the intrinsically disordered region. PMID- 25923521 TI - A higher level classification of all living organisms. AB - We present a consensus classification of life to embrace the more than 1.6 million species already provided by more than 3,000 taxonomists' expert opinions in a unified and coherent, hierarchically ranked system known as the Catalogue of Life (CoL). The intent of this collaborative effort is to provide a hierarchical classification serving not only the needs of the CoL's database providers but also the diverse public-domain user community, most of whom are familiar with the Linnaean conceptual system of ordering taxon relationships. This classification is neither phylogenetic nor evolutionary but instead represents a consensus view that accommodates taxonomic choices and practical compromises among diverse expert opinions, public usages, and conflicting evidence about the boundaries between taxa and the ranks of major taxa, including kingdoms. Certain key issues, some not fully resolved, are addressed in particular. Beyond its immediate use as a management tool for the CoL and ITIS (Integrated Taxonomic Information System), it is immediately valuable as a reference for taxonomic and biodiversity research, as a tool for societal communication, and as a classificatory "backbone" for biodiversity databases, museum collections, libraries, and textbooks. Such a modern comprehensive hierarchy has not previously existed at this level of specificity. PMID- 25923523 TI - CLUSTERED PRIMARY BRANCH 1, a new allele of DWARF11, controls panicle architecture and seed size in rice. AB - Panicle architecture and seed size are important agronomic traits that directly determine grain yield in rice (Oryza sativa L.). Although a number of key genes controlling panicle architecture and seed size have been cloned and characterized in recent years, their genetic and molecular mechanisms remain unclear. In this study, we identified a mutant that produced panicles with fascicled primary branching and reduced seeds in size. We isolated the underlying CLUSTERED PRIMARY BRANCH 1 (CPB1) gene, a new allele of DWARF11 (D11) encoding a cytochrome P450 protein involved in brassinosteroid (BR) biosynthesis pathway. Genetic transformation experiments confirmed that a His360Leu amino acid substitution residing in the highly conserved region of CPB1/D11 was responsible for the panicle architecture and seed size changes in the cpb1 mutants. Overexpression of CPB1/D11 under the background of cpb1 mutant not only rescued normal panicle architecture and plant height, but also had a larger leaf angle and seed size than the controls. Furthermore, the CPB1/D11 transgenic plants driven by panicle specific promoters can enlarge seed size and enhance grain yield without affecting other favourable agronomic traits. These results demonstrated that the specific mutation in CPB1/D11 influenced development of panicle architecture and seed size, and manipulation of CPB1/D11 expression using the panicle-specific promoter could be used to increase seed size, leading to grain yield improvement in rice. PMID- 25923524 TI - Percutaneous vertebroplasty for osteoporotic vertebral compression fracture. AB - BACKGROUND: Percutaneous vertebroplasty is widely used to treat acute and subacute painful osteoporotic vertebral fractures although recent placebo controlled trials have questioned its value. OBJECTIVES: To synthesise the available evidence regarding the benefits and harms of vertebroplasty for treatment of osteoporotic vertebral fractures. SEARCH METHODS: We searched CENTRAL, MEDLINE and EMBASE up to November 2014. We also reviewed reference lists of review articles, trials and trial registries to identify any other potentially relevant trials. SELECTION CRITERIA: We included randomised and quasi-randomised controlled trials (RCTs) including adults with painful osteoporotic vertebral fractures of any duration and comparing vertebroplasty with placebo (sham), usual care, or any other intervention. As it is least prone to bias, vertebroplasty compared with placebo was the primary comparison. Major outcomes were mean overall pain, disability, disease-specific and overall health-related quality of life, patient-reported treatment success, new symptomatic vertebral fractures and number of other serious adverse events. DATA COLLECTION AND ANALYSIS: At least two review authors independently selected trials for inclusion, extracted data, performed 'Risk of bias' assessment and assessed the quality of the body of evidence for the main outcomes using GRADE. MAIN RESULTS: Eleven RCTs and one quasi-RCT conducted in various countries were included. Two trials compared vertebroplasty with placebo (209 randomised participants), six compared vertebroplasty with usual care (566 randomised participants) and four compared vertebroplasty with kyphoplasty (545 randomised participants). Trial size varied from 34 to 404 participants, most participants were female, mean age ranged between 63.3 and 80 years, and mean symptom duration varied from a week to more than six months.Both placebo-controlled trials were judged to be at low overall risk of bias while other included trials were generally considered to be at high risk of bias across a range of criteria, most seriously due to lack of participant and study personnel blinding.Compared with placebo, there was moderate quality evidence based upon two trials that vertebroplasty provides no demonstrable benefits with respect to pain, disability, disease-specific or overall quality of life or treatment success. At one month, mean pain (on a scale 0 to 10, higher scores indicate more pain) was 5 points with placebo and 0.7 points better (1.5 better to 0.15 worse) with vertebroplasty, an absolute pain reduction of 7% (15% better to 1.5% worse) and relative reduction of 10% (21% better to 2% worse) (two trials, 201 participants). At one month, mean disability measured by the Roland Morris Disability Questionnaire (scale range 0 to 23, higher scores indicate worse disability) was 13.6 points in the placebo group and 1.1 points better (2.9 better to 0.8 worse) in the vertebroplasty group, absolute improvement in disability 4.8% (12.8% better to 3.3% worse), relative change 6.3% better (17.0% better to 4.4% worse) (two trials, 201 participants).At one month, disease-specific quality of life measured by the QUALEFFO (scale 0 to 100, higher scores indicating worse quality of life) was 2.4 points in the placebo group and 0.40 points worse (4.58 better to 5.38 worse) in the vertebroplasty group, absolute change: 0.4% worse (5% worse to 5% better), relative change 0.7% worse (9% worse to 8% better (based upon one trial, 73 participants). At one month overall quality of life measured by the EQ5D (0 = death to 1 = perfect health, higher scores indicate greater quality of life at one month was 0.27 points in the placebo group and 0.05 points better (0.01 worse to 0.11 better) in the vertebroplasty group, absolute improvement in quality of life 5% (1% worse to 11% better), relative change 18% better (4% worse to 39% better) (two trials, 201 participants). Based upon one trial (78 participants) at one month, 9/40 (or 225 per 1000) people perceived that treatment was successful in the placebo group compared with 12/38 (or 315 per 1000; range 150 to 664) in the vertebroplasty group, RR 1.40 (95% CI 0.67 to 2.95), absolute risk difference 9% more reported success (11% fewer to 29% more); relative change 40% more reported success (33% fewer to 195% more).Based upon moderate quality evidence from three trials (one placebo, two usual care, 281 participants) with up to 12 months follow-up, we are uncertain whether or not vertebroplasty increases the risk of new symptomatic vertebral fractures (28/143 observed in the vertebroplasty group compared with 19/138 in the control group; RR 1.47 (95% CI 0.39 to 5.50).Similary, based upon moderate quality evidence from two placebo-controlled trials (209 participants), we are uncertain about the exact risk of other adverse events (3/106 were observed in the vertebroplasty group compared with 3/103 in the placebo group; RR 1.01 (95% CI 0.21 to 4.85)). Notably, serious adverse events reported with vertebroplasty included osteomyelitis, cord compression, thecal sac injury and respiratory failure.Our subgroup analyses provided limited evidence that the effects did not differ according to duration of pain <= 6 weeks versus > 6 weeks. Including data from the six trials that compared vertebroplasty with usual care in a sensitivity analyses inconsistently altered the primary results, with all combined analyses displaying substantial to considerable heterogeneity. AUTHORS' CONCLUSIONS: Based upon moderate quality evidence, our review does not support a role for vertebroplasty for treating osteoporotic vertebral fractures in routine practice. We found no demonstrable clinically important benefits compared with a sham procedure and subgroup analyses indicated that results did not differ according to duration of pain <= 6 weeks versus > 6 weeks. Sensitivity analyses confirmed that open trials comparing vertebroplasty with usual care are likely to have overestimated any benefit of vertebroplasty. Correcting for these biases would likely drive any benefits observed with vertebroplasty towards the null, in keeping with findings from the placebo-controlled trials.Numerous serious adverse events have been observed following vertebroplasty. However due to the small number of events, we cannot be certain about whether or not vertebroplasty results in a clinically important increased risk of new symptomatic vertebral fractures and/or other serious adverse events. Patients should be informed about both the lack of high quality evidence supporting benefit of vertebroplasty and its potential for harm. PMID- 25923525 TI - Cathepsin Gene Family Reveals Transcriptome Patterns Related to the Infective Stages of the Salmon Louse Caligus rogercresseyi. AB - Cathepsins are proteases involved in the ability of parasites to overcome and/or modulate host defenses so as to complete their own lifecycle. However, the mechanisms underlying this ability of cathepsins are still poorly understood. One excellent model for identifying and exploring the molecular functions of cathepsins is the marine ectoparasitic copepod Caligus rogercresseyi that currently affects the Chilean salmon industry. Using high-throughput transcriptome sequencing, 56 cathepsin-like sequences were found distributed in five cysteine protease groups (B, F, L, Z, and S) as well as in an aspartic protease group (D). Ontogenic transcriptome analysis evidenced that L cathepsins were the most abundant during the lifecycle, while cathepsins B and K were mostly expressed in the larval stages and adult females, thus suggesting participation in the molting processes and embryonic development, respectively. Interestingly, a variety of cathepsins from groups Z, L, D, B, K, and S were upregulated in the infective stage of copepodid, corroborating the complexity of the processes involved in the parasitic success of this copepod. Putative functional roles of cathepsins were conjectured based on the differential expressions found and on roles previously described in other phylogenetically related species. Moreover, 140 single nucleotide polymorphisms (SNP) were identified in transcripts annotated for cysteine and aspartic proteases located into untranslated regions, or the coding region. This study reports for the first time the presence of cathepsin-like genes and differential expressions throughout a copepod lifecycle. The identification of cathepsins together with functional validations represents a valuable strategy for pinpointing target molecules that could be used in the development of new delousing drugs or vaccines against C. rogercresseyi. PMID- 25923526 TI - A Human Monoclonal Antibody against Hepatitis B Surface Antigen with Potent Neutralizing Activity. AB - We describe the production and characterization of human monoclonal antibodies (mAb) specific for the major hepatitis B virus (HBV) S protein. The mAbs, two IgG1kappa and one IgG1lambda, were secreted by B-cell clones obtained from peripheral blood mononuclear cells (PBMC) of one person convalescent from acute hepatitis B and one vaccinated individual. The former recognized a denaturation insensitive epitope within the p24 protein whereas the latter recognized a denaturation-sensitive, conformational epitope located within the HBsAg common "a" determinant. This mAb, denominated ADRI-2F3, displayed a very high protective titer of over 43,000 IU/mg mAb and showed an extremely potent neutralizing activity in the in vitro model of HBV infection using primary hepatocytes from Tupaia belangeri as target. Recombinant variable heavy and light domain sequences derived from mAb ADRI-2F3 were cloned into eukaryotic expression vectors and showed identical fine specificity and 1 log10 higher titer than the original IgG1lambda. It is envisaged that such mAb will be able to efficiently prevent HBV reinfection after liver transplantation for end-stage chronic HBV infection or infection after needle-stick exposure, providing an unlimited source of valuable protective anti-HBs antibody. PMID- 25923527 TI - High Molecular Weight Typing with MALDI-TOF MS - A Novel Method for Rapid Typing of Clostridium difficile. AB - Clostridium difficile strains were typed by a newly developed MALDI-TOF method, high molecular weight typing, and compared to PCR ribotyping. Among 500 isolates representing 59 PCR ribotypes a total of 35 high molecular weight types could be resolved. Although less discriminatory than PCR ribotyping, the method is extremely fast and simple, and supports for cost-effective screening of isolates during outbreak situations. PMID- 25923528 TI - Education about crying in normal infants is associated with a reduction in pediatric emergency room visits for crying complaints. AB - OBJECTIVE: The primary aim of this study was to determine whether there was any change in visits of 0- to 5-month old infants to the medical emergency room (MER) of a metropolitan pediatric hospital after province-wide implementation of a public health prevention program that teaches new parents about the properties of early crying in normal infants. METHODS: Free-text descriptions of Presenting Complaint and Final Diagnosis on electronic MER clinic visit files were used to classify infants as cases of infant crying not due to disease. Annual crying case visits as a percent of MER visits were analyzed pre- and post-introduction of the prevention program. RESULTS: Before the program, crying case visits represented 724 of 20,394 MER visits (3.5%). The age-specific pattern of MER visits for crying peaked at 6 weeks and was similar to the previously reported age-specific pattern of amounts of crying in the community. After program implementation, crying cases were reduced by 29.5% (p < .001). The most significant reductions were for crying visits in the first to third months of life. CONCLUSION: The findings imply that improved parental knowledge of the characteristics of normal crying secondary to a public health program may reduce MER use for crying complaints in the early months of life. PMID- 25923529 TI - Bullying in medically fragile youth: a review of risks, protective factors, and recommendations for medical providers. AB - Bullying is a common child and adolescent phenomenon that has concurrent and long term implications for victims' psychological, psychosomatic, social, and academic functioning. Youth with chronic illnesses are at increased risk for being bullied, but few studies have evaluated specific risk and protective factors for medically fragile youth. Despite recommendations by the American Academy of Pediatrics and the Society for Adolescent Medicine that pediatric health care providers should contribute to bullying prevention and intervention efforts, researchers also have yet to identify the best ways for providers to intervene with medically fragile youth. In this article, the authors review risk and protective factors for bullying among healthy samples. Then, the authors specifically address the ways in which these risk and protective factors are likely to apply to children with fragile medical conditions, and they provide summaries of extant bullying research for selected examples of medically fragile pediatric populations. Finally, the authors present recommendations for intervening with medically fragile youth and suggest several areas in which additional research is needed. PMID- 25923530 TI - When the adoption becomes termination. AB - CASE: Steven is an 11-year-old boy who was adopted from an orphanage in Eastern Europe 8 years ago, when he was 3 years old along with his biological sister who is 1 year older. You have cared for him in your practice since that time seeing them annually for well child care. His mother reports that the first 2 years after adoption were very difficult, and Steven has never really bonded with her or her husband. Currently, he is reported to steal possessions of family members and instigate arguments with his older sister and act defiantly. The parents have put locks on their bedroom door due to fears of violence, primarily by Steven's older sister. Steven's mother reports that she and her husband no longer attempt to "parent" the children and provide minimal supervision to avoid conflict. In school, Steven is reported to have symptoms of inattention and hyperactivity that improved with treatment with stimulant medication and some learning challenges, but otherwise he is described as a lovely boy who has good relationships with his teachers.They present to urgent care clinic when mom stated "We have had enough." That day both children were caught taking $10 from the mother's wallet. On further discussion, it was discovered that they had done this several times over the last month to buy ice cream for neighborhood friends to "welcome them" to the neighborhood. Steven's mother presents today stating that the family has exhausted therapy services and are experiencing financial hardship secondary to investing time and money into behavioral and psychiatric services for Steven and his sister. They want to dissolve the adoption and have the children removed from their home. They seek guidance on how to do this. What would be your initial approach with the parents? PMID- 25923531 TI - Characterization of Staphylococcus aureus Isolated from Non-Native Patients with Skin and Soft Tissue Infections in Shanghai. AB - BACKGROUND: Staphylococcus aureus is one predominant cause of skin and soft tissue infections (SSTIs), but little information exists regarding the characterization of S. aureus from non-native patients with SSTIs in China. METHODS: In this study, we enrolled 52 non-native patients with S. aureus SSTIs, and 65 native control patients with S. aureus SSTIs in Shanghai. 52 and 65 S. aureus isolates were collected from both groups, respectively. S. aureus isolates were characterized by antimicrobial susceptibility testing, toxin gene detection, and molecular typing with sequence type, spa type, agr group and SCCmec type. RESULTS: Methicillin-resistant S. aureus (MRSA) was detected in 8 non-native patients and 14 native patients with SSTIs. Overall, antimicrobial susceptibilities of S. aureus isolated from non-native patients were found higher than those from native patients. CC59 (ST338 and ST59) was found in a total of 14 isolates (4 from non-native patients; 10 from native patients), 9 of which were carrying lukS/F-PV (3 from non-native patients; 6 from native patients). ST7 was found in 12 isolates and all 12 isolates were found in native patients. The livestock-associated clone ST398 was found in 11 isolates (6 from non-native patients; 5 from native patients), and 5 ST398 lukS/F-PV-positive methicillin susceptible S. aureus (MSSA) were all discovered among non-native patients. The molecular epidemiology of S. aureus isolated from non-native patients was quite different from those from native patients. lukS/F-PV was more frequent in isolates originating from non-native patients with SSTIs compared to native patients (31 vs. 7, P <0.0001). CONCLUSIONS: CC59 was the most common clonal complex among patients with SSTIs in Shanghai. The other most common sequence types were ST7 and Livestock ST398. The molecular epidemiology of S. aureus isolated from non-native patients was quite different from those from native patients. S. aureus isolated from non-native patients was more likely to carry lukS/F-PV. PMID- 25923532 TI - DNA Electric Charge Oscillations Govern Protein-DNA Recognition. AB - The transcriptional activity of the serum response factor (SRF) protein is triggered by its binding to a 10-base-pair DNA consensus sequence designated the CArG box, which is the core sequence of the serum response element (SRE). Sequence-specific recognition of the CArG box by a core domain of 100 amino acid residues of SRF (core-SRF) was asserted to depend almost exclusively on the intrinsic SRE conformation and on the degree of protein-induced SRE bending. Nevertheless, this paradigm was invalidated by a temperature-dependent Raman spectroscopy study of 20-mer oligonucleotides involved in bonding interactions with core-SRF that reproduced both wild type and mutated c-fos SREs. Indeed, the SRE moieties that are complexed with core-SRF exhibit permanent interconversion dynamics between bent and linear conformers. Thus, sequence-specific recognition of the CArG box by core-SRF cannot be explained only in terms of the three dimensional structure of the SRE. A particular dynamic pairing process discriminates between the wild type and mutated complexes. Specific oscillations of the phosphate charge network of the SRE govern the recognition between both partners rather than an intrinsic set of conformations of the SRE. PMID- 25923533 TI - Modulation of inhibitory corticospinal circuits induced by a nocebo procedure in motor performance. AB - As recently demonstrated, a placebo procedure in motor performance increases force production and changes the excitability of the corticospinal system, by enhancing the amplitude of the motor evoked potentials (MEP) and reducing the duration of the cortical silent period (CSP). However, it is not clear whether these neurophysiological changes are related to the behavioural outcome (increased force) or to a general effect of expectation. To clarify this, we investigated the nocebo effect, in which the induced expectation decreases force production. Two groups of healthy volunteers (experimental and control) performed a motor task by pressing a piston with the right index finger. To induce a nocebo effect in the experimental group, low frequency transcutaneous electrical nerve stimulation (TENS) was applied over the index finger with instructions of its detrimental effects on force. To condition the subjects, the visual feedback on their force level was surreptitiously reduced after TENS. Results showed that the experimental group reduced the force, felt weaker and expected a worse performance than the control group, who was not suggested about TENS. By applying transcranial magnetic stimulation over the primary motor cortex, we found that while MEP amplitude remained stable throughout the procedure in both groups, the CSP duration was shorter in the experimental group after the nocebo procedure. The CSP reduction resembled previous findings on the placebo effect, suggesting that expectation of change in performance diminishes the inhibitory activation of the primary motor cortex, independently of the behavioural outcome. PMID- 25923534 TI - A Systematic Review of Hospital-to-School Reintegration Interventions for Children and Youth with Acquired Brain Injury. AB - OBJECTIVES: We reviewed the literature on interventions that aimed to improve hospital-to-school reintegration for children and youth with acquired brain injury (ABI). ABI is the leading cause of disability among children and youth. A successful hospital-to-school reintegration process is essential to the rehabilitative process. However, little is known about the effective components of of such interventions. METHODS AND FINDINGS: Our research team conducted a systematic review, completing comprehensive searches of seven databases and selected reference lists for relevant articles published in a peer-reviewed journal between 1989 and June 2014. We selected articles for inclusion that report on studies involving: a clinical population with ABI; sample had an average age of 20 years or younger; an intentional structured intervention affecting hospital-to-school transitions or related components; an experimental design; and a statistically evaluated health outcome. Two independent reviewers applied our inclusion criteria, extracted data, and rated study quality. A meta analysis was not feasible due to the heterogeneity of the studies reported. Of the 6933 articles identified in our initial search, 17 articles (reporting on 350 preadolescents and adolescents, aged 4-19, (average age 11.5 years, SD: 2.21) met our inclusion criteria. They reported on interventions varying in number of sessions (one to 119) and session length (20 minutes to 4 hours). The majority of interventions involved multiple one-to-one sessions conducted by a trained clinician or educator, homework activities, and parental involvement. The interventions were delivered through different settings and media, including hospitals, schools, and online. Although outcomes varied (with effect sizes ranging from small to large), 14 of the articles reported at least one significant improvement in cognitive, social, psychological, or behavioral functioning or knowledge of ABI. CONCLUSIONS: Cognitive, behavioral, and problem solving interventions have the potential to improve school reintegration for youth with ABI. However, more comprehensive interventions are needed to help link rehabilitation clinicians, educators, adolescents, and families. PMID- 25923535 TI - Delivery of Adipose-Derived Stem Cells Attenuates Adipose Tissue Inflammation and Insulin Resistance in Obese Mice Through Remodeling Macrophage Phenotypes. AB - Adipose-derived stem cells (ADSCs) have been used to control several autoimmune or inflammatory diseases due to immunosuppressive properties, but their role in obesity-associated inflammation remains unestablished. This study aims to evaluate the effects of ADSCs on obesity-induced white adipose tissue (WAT) inflammation and insulin resistance. We found that diet-induced obesity caused a remarkable reduction of ADSC fraction in mouse WAT. Delivery of lean mouse derived ADSCs, which could successfully locate into WAT of obese mice, substantially improved insulin action and metabolic homeostasis of obese mice. ADSC treatment not only reduced adipocyte hypertrophy but also attenuated WAT inflammation by reducing crown-like structures of macrophages and tumor necrosis factor (TNF)-alpha secretion. Importantly, ADSC treatment remodeled the phenotypes of adipose-resident macrophages from proinflammatory M1 toward anti inflammatory M2-like subtypes, as characterized by decreased MHC class II expressing but increased interleukin (IL)-10-producing macrophages together with low expression of TNF-alpha and IL-12. Coculture of ADSCs through the transwell or conditional medium with induced M1 macrophages also reproduced the phenotypic switch toward M2-like macrophages, which was substantiated by elevated arginase 1, declined inducible nitric oxide synthase, inhibition of NF-kappaB activity, and activation of STAT3/STAT6. Taken together, our data support that ADSC supplement in obese mice could sustain IL-10-producing M2-like macrophages in WAT through paracrine action, thereby suggesting the crucial role of ADSCs in resolving WAT inflammation, maintaining adipose homeostasis, and proposing a potential ADSC-based approach for the treatment of obesity-related diseases. PMID- 25923536 TI - Whole-exome analysis of foetal autopsy tissue reveals a frameshift mutation in OBSL1, consistent with a diagnosis of 3-M Syndrome. AB - BACKGROUND: We report a consanguineous couple that has experienced three consecutive pregnancy losses following the foetal ultrasound finding of short limbs. Post-termination examination revealed no skeletal dysplasia, but some subtle proximal limb shortening in two foetuses, and a spectrum of mildly dysmorphic features. Karyotype was normal in all three foetuses (46, XX) and comparative genomic hybridization microarray analysis detected no pathogenic copy number variants. RESULTS: Whole-exome sequencing and genome-wide homozygosity mapping revealed a previously reported frameshift mutation in the OBSL1 gene (c.1273insA p.T425nfsX40), consistent with a diagnosis of 3-M Syndrome 2 (OMIM #612921), which had not been anticipated from the clinical findings. CONCLUSIONS: Our study provides novel insight into the early clinical manifestations of this form of 3-M syndrome, and demonstrates the utility of whole exome sequencing as a tool for prenatal diagnosis in particular when there is a family history suggestive of a recurrent set of clinical symptoms. PMID- 25923537 TI - An aromatic cage is required but not sufficient for binding of Tudor domains of the Polycomblike protein family to H3K36me3. AB - Polycomblike (Pcl) proteins are important transcriptional regulators and components of the Polycomb Repressive Complex 2 (PRC2). The Tudor domains of human homologs PHF1 and PHF19 have been found to recognize trimethylated lysine 36 of histone H3 (H3K36me3); however, the biological role of Tudor domains of other Pcl proteins remains poorly understood. Here, we characterize the molecular basis underlying histone binding activities of the Tudor domains of the Pcl family. In contrast to a predominant view, we found that the methyl lysine binding aromatic cage is necessary but not sufficient for recognition of H3K36me3 by these Tudor domains and that a hydrophobic patch, adjacent to the aromatic cage, is also required. PMID- 25923538 TI - Good quality locally procured drugs can be as effective as internationally quality assured drugs in treating multi-drug resistant tuberculosis. AB - BACKGROUND: Owing toGiven the high costs of drugs to treat multi-drug resistant tuberculosis (MDR-TB), the Green Light Committee (GLC) initiative enables TB programs to procure quality-assured drugs at reduced prices. Despite price reductions, internationally quality assured (IQA) drugs can be more expensive than locally procured drugs. There is little evidence to inform decision-makers about whether IQA drugs are more effective than local drugs. This is the first study to compare outcomes between MDR-TB patients treated using IQA, and locally procured drugs in the same hospitals during the same time period. METHODS/FINDINGS: A retrospective cohort study was conducted in three hospitals across Pakistan. Data on baseline characteristics and treatment outcomes during the first six months of treatment were extracted from hospital records of adult culture-positive pulmonary MDR-TB patients starting treatment between January 2011 and June 2012. Two cohorts were defined: patients receiving IQA drugs, and patients receiving locally procured non-IQA drugs. Data were analysed using Kaplan-Meier curves and Cox proportional hazards regression. The primary outcome compared between cohorts was time to culture conversion. Of 231 patients, 90 were in the IQA and 141 in the non-IQA cohorts. Baseline characteristics were similar except for higher frequency of quinolone resistance in the IQA cohort. Overall, 193 patients (84%) culture converted. Culture conversion was not faster in the IQA cohort; the median time was 81 and 68 days in the IQA and non-IQA cohorts, respectively. Unadjusted and adjusted hazard ratios for culture conversion in IQA verses non-IQA cohorts were 0.82 (95%-CI, 0.62-1.10) and 0.95 (95%-CI, 0.66-1.36) respectively. CONCLUSIONS: Use of good quality, locally procured drugs can be effective in treating MDR-TB, may involve lower costs than using IQA drugs and could strengthen developing country drug quality assurance systems. This may be a suitable alternative in lieu of or whilst awaiting arrival of internationally procured medicines. PMID- 25923539 TI - Core-shell polymeric microcapsules with superior thermal and solvent stability. AB - A protective polydopamine (PDA) coating is applied to core-shell microcapsule surfaces by the polymerization of dopamine monomers. A neutral aqueous solution and the addition of an oxidant (i.e., ammonium persulfate) are crucial for microcapsule survival and the initiation of PDA polymerization, respectively. The resulting PDA coating is a dense and uniform layer approximately 50 nm thick. The PDA protective coating significantly increases capsule stability at an elevated temperature (180 degrees C) and in a variety of organic solvents and acidic/basic solutions that otherwise lead to deflation and loss of the core content of uncoated microcapsules. PMID- 25923541 TI - Biochar in co-contaminated soil manipulates arsenic solubility and microbiological community structure, and promotes organochlorine degradation. AB - We examined the effect of biochar on the water-soluble arsenic (As) concentration and the extent of organochlorine degradation in a co-contaminated historic sheep dip soil during a 180-d glasshouse incubation experiment. Soil microbial activity, bacterial community and structure diversity were also investigated. Biochar made from willow feedstock (Salix sp) was pyrolysed at 350 or 550 degrees C and added to soil at rates of 10 g kg-1 and 20 g kg-1 (representing 30 t ha-1 and 60 t ha-1). The isomers of hexachlorocyclohexane (HCH) alpha-HCH and gamma HCH (lindane), underwent 10-fold and 4-fold reductions in concentration as a function of biochar treatment. Biochar also resulted in a significant reduction in soil DDT levels (P < 0.01), and increased the DDE:DDT ratio. Soil microbial activity was significantly increased (P < 0.01) under all biochar treatments after 60 days of treatment compared to the control. 16S amplicon sequencing revealed that biochar-amended soil contained more members of the Chryseobacterium, Flavobacterium, Dyadobacter and Pseudomonadaceae which are known bioremediators of hydrocarbons. We hypothesise that a recorded short-term reduction in the soluble As concentration due to biochar amendment allowed native soil microbial communities to overcome As-related stress. We propose that increased microbiological activity (dehydrogenase activity) due to biochar amendment was responsible for enhanced degradation of organochlorines in the soil. Biochar therefore partially overcame the co-contaminant effect of As, allowing for enhanced natural attenuation of organochlorines in soil. PMID- 25923540 TI - Boceprevir or Telaprevir Based Triple Therapy against Chronic Hepatitis C in HIV Coinfection: Real-Life Safety and Efficacy. AB - BACKGROUND AND AIMS: Clinical trials of therapy against chronic hepatitis C virus (HCV) infection including boceprevir (BOC) or telaprevir (TVR) plus pegylated interferon and ribavirin (PR) have reported considerably higher response rates than those achieved with PR alone. This study sought to evaluate the efficacy and safety of triple therapy including BOC or TVR in combination with PR in HIV/HCV coinfected patients under real-life conditions. METHODS: In a multicentre study conducted in 24 sites throughout five European countries, all HIV/HCV-coinfected patients who initiated a combination of BOC or TVR plus PR and who had at least 60 weeks of follow-up, were analyzed. Sustained virologic response 12 weeks after the scheduled end of therapy date (SVR12) and the rate of discontinuations due to adverse events (AE) were evaluated. RESULTS: Of the 159 subjects included, 127 (79.9%) were male, 45 (34.4%) were treatment-naive for PR and 60 (45.4%) showed cirrhosis. SVR12 was observed in 31/46 (67.4%) patients treated with BOC and 69/113 (61.1%) patients treated with TVR. Overall discontinuations due to AE rates were 8.7% for BOC and 8% for TVR. Grade 3 or 4 hematological abnormalities were frequently observed; anemia 7%, thrombocytopenia 17.2% and neutropenia 16.4%. CONCLUSION: The efficacy and safety of triple therapy including BOC or TVR plus PR under real-life conditions of use in the HIV/HCV-coinfected population was similar to what is observed in clinical trials. Hematological side effects are frequent but manageable. PMID- 25923542 TI - Frozen-Density Embedding Strategy for Multilevel Simulations of Electronic Structure. PMID- 25923544 TI - Cybersecurity in Artificial Pancreas Experiments. AB - Medical devices have transformed modern health care, and ongoing experimental medical technology trials (such as the artificial pancreas) have the potential to significantly improve the treatment of several chronic conditions, including diabetes mellitus. However, we suggest that, to date, the essential concept of cybersecurity has not been adequately addressed in this field. This article discusses several key issues of cybersecurity in medical devices and proposes some solutions. In addition, it outlines the current requirements and efforts of regulatory agencies to increase awareness of this topic and to improve cybersecurity. PMID- 25923545 TI - Urinary kidney injury molecule-1 levels as a marker of early kidney injury in hypertensive patients. AB - BACKGROUND: Kidney injury molecule-1 (KIM-1) is a type 1 tubular cell transmembrane protein that is found in high levels in early stages of acute kidney injury and is stated to have predictive value in the early diagnosis of chronic kidney diseases. In this study, the hypothesis was that higher levels of KIM-1 would be detected in hypertensive patients for the early detection of nephropathy. With this goal, urinary KIM-1 levels of hypertensive cases were compared with those of healthy controls, and associations of KIM-1 levels with microalbuminuria and glomerular filtration rate (GFR) were investigated. METHODS: The study included a total of 80 patients aged >=20 years (55 male, 25 female, mean age: 57.21+/-9.12 years). The patient group consisted of 40 patients (28 males, 12 females, mean age: 57.58+/-8.79 years) who had had hypertension for at least 5 years, and the control group consisted of 40 healthy subjects (27 female, 13 male, mean age: 56.85+/-9.53 years). Groups were compared based on demographic, anthropometric and biochemical data, and urinary KIM-1 levels. Correlation analysis was made to assess the association of KIM-1 levels with microalbuminuria and GFR. Levels of urinary KIM-1 enzyme were measured using linked immunosorbent assay (ELISA). RESULTS: KIM-1 levels were found to be 0.86+/ 0.48 ng/mg creatinine in the patient, and 0.71+/-0.46 pg/mL in the control groups (P>0.05). A positive correlation was detected between KIM-1 levels and both systolic blood pressure and duration of disease (r=0.308, P=0.032 and r=0.339, P=0.032, respectively). CONCLUSIONS: While not supporting the hypothesis that KIM 1 levels may increase in hypertensive patients as an early indicator of hypertensive nephropathy, these findings suggested that this molecule might be associated with kidney injury in hypertensive nephropathy due to its positive correlation with the duration of hypertension. PMID- 25923546 TI - Why strategy matters now. PMID- 25923543 TI - Asthma, Airway Symptoms and Rhinitis in Office Workers in Malaysia: Associations with House Dust Mite (HDM) Allergy, Cat Allergy and Levels of House Dust Mite Allergens in Office Dust. AB - A prevalence study was conducted among office workers in Malaysia (N= 695). The aim of this study was to examine associations between asthma, airway symptoms, rhinitis and house dust mites (HDM) and cat allergy and HDM levels in office dust. Medical data was collected by a questionnaire. Skin prick tests were performed for HDM allergens (Dermatophagoides pteronyssinus, Dermatophagoides farinae) and cat allergen Felis domesticus. Indoor temperature and relative air humidity (RH) were measured in the offices and vacuumed dust samples were analyzed for HDM allergens. The prevalence of D. pteronyssinus, D. farinae and cat allergy were 50.3%, 49.0% and 25.5% respectively. Totally 9.6% had doctor diagnosed asthma, 15.5% had current wheeze and 53.0% had current rhinitis. The Der p 1 (from D. pteronyssinus) and Der f 1 (from D. farinae) allergens levels in dust were 556 ng/g and 658 ng/g respectively. Statistical analysis was conducted by multilevel logistic regression, adjusting for age, gender, current smoking, HDM or cat allergy, home dampness and recent indoor painting at home. Office workers with HDM allergy had more wheeze (p= 0.035), any airway symptoms (p= 0.032), doctor-diagnosed asthma (p= 0.005), current asthma (p= 0.007), current rhinitis (p= 0.021) and rhinoconjuctivitis (p< 0.001). Cat allergy was associated with wheeze (p= 0.021), wheeze when not having a cold (p= 0.033), any airway symptoms (p= 0.034), doctor-diagnosed asthma (p= 0.010), current asthma (p= 0.020) and nasal allergy medication (p= 0.042). Der f 1 level in dust was associated with daytime breathlessness (p= 0.033) especially among those with HDM allergy. Der f 1 levels were correlated with indoor temperature (p< 0.001) and inversely correlated with RH (p< 0.001). In conclusion, HDM and cat allergies were common and independently associated with asthma, airway symptoms and rhinitis. Der f 1 allergen can be a risk factor for daytime breathlessness. PMID- 25923547 TI - Virtual visits--confronting the challenges of telemedicine. PMID- 25923548 TI - U.S.-citizen international medical graduates--a boon for the workforce? PMID- 25923549 TI - AZD9291 in EGFR inhibitor-resistant non-small-cell lung cancer. AB - BACKGROUND: The EGFR T790M mutation is the most common mechanism of drug resistance to epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors in patients who have lung cancer with an EGFR mutation (EGFR-mutated lung cancer). In preclinical models, the EGFR inhibitor AZD9291 has been shown to be effective against both EGFR tyrosine kinase inhibitor-sensitizing and T790M resistance mutations. METHODS: We administered AZD9291 at doses of 20 to 240 mg once daily in patients with advanced lung cancer who had radiologically documented disease progression after previous treatment with EGFR tyrosine kinase inhibitors. The study included dose-escalation cohorts and dose-expansion cohorts. In the expansion cohorts, prestudy tumor biopsies were required for central determination of EGFR T790M status. Patients were assessed for safety, pharmacokinetics, and efficacy. RESULTS: A total of 253 patients were treated. Among 31 patients enrolled in the dose-escalation cohorts, no dose-limiting toxic effects occurred at the doses evaluated. An additional 222 patients were treated in five expansion cohorts. The most common all-cause adverse events were diarrhea, rash, nausea, and decreased appetite. The overall objective tumor response rate was 51% (95% confidence interval [CI], 45 to 58). Among 127 patients with centrally confirmed EGFR T790M who could be evaluated for response, the response rate was 61% (95% CI, 52 to 70). In contrast, among 61 patients without centrally detectable EGFR T790M who could be evaluated for response, the response rate was 21% (95% CI, 12 to 34). The median progression-free survival was 9.6 months (95% CI, 8.3 to not reached) in EGFR T790M-positive patients and 2.8 months (95% CI, 2.1 to 4.3) in EGFR T790M-negative patients. CONCLUSIONS: AZD9291 was highly active in patients with lung cancer with the EGFR T790M mutation who had had disease progression during prior therapy with EGFR tyrosine kinase inhibitors. (Funded by AstraZeneca; ClinicalTrials.gov number, NCT01802632.). PMID- 25923550 TI - Rociletinib in EGFR-mutated non-small-cell lung cancer. AB - BACKGROUND: Non-small-cell lung cancer (NSCLC) with a mutation in the gene encoding epidermal growth factor receptor (EGFR) is sensitive to approved EGFR inhibitors, but resistance develops, mediated by the T790M EGFR mutation in most cases. Rociletinib (CO-1686) is an EGFR inhibitor active in preclinical models of EGFR-mutated NSCLC with or without T790M. METHODS: In this phase 1-2 study, we administered rociletinib to patients with EGFR-mutated NSCLC who had disease progression during previous treatment with an existing EGFR inhibitor. In the expansion (phase 2) part of the study, patients with T790M-positive disease received rociletinib at a dose of 500 mg twice daily, 625 mg twice daily, or 750 mg twice daily. Key objectives were assessment of safety, side-effect profile, pharmacokinetics, and preliminary antitumor activity of rociletinib. Tumor biopsies to identify T790M were performed during screening. Treatment was administered in continuous 21-day cycles. RESULTS: A total of 130 patients were enrolled. The first 57 patients to be enrolled received the free-base form of rociletinib (150 mg once daily to 900 mg twice daily). The remaining patients received the hydrogen bromide salt (HBr) form (500 mg twice daily to 1000 mg twice daily). A maximum tolerated dose (the highest dose associated with a rate of dose-limiting toxic effects of less than 33%) was not identified. The only common dose-limiting adverse event was hyperglycemia. In an efficacy analysis that included patients who received free-base rociletinib at a dose of 900 mg twice daily or the HBr form at any dose, the objective response rate among the 46 patients with T790M-positive disease who could be evaluated was 59% (95% confidence interval [CI], 45 to 73), and the rate among the 17 patients with T790M-negative disease who could be evaluated was 29% (95% CI, 8 to 51). CONCLUSIONS: Rociletinib was active in patients with EGFR-mutated NSCLC associated with the T790M resistance mutation. (Funded by Clovis Oncology; ClinicalTrials.gov number, NCT01526928.). PMID- 25923553 TI - Inflammatory muscle diseases. PMID- 25923554 TI - Images in clinical medicine. Lindsay's nails in chronic kidney disease. PMID- 25923555 TI - Case records of the Massachusetts General Hospital. Case 14-2015. A 58-year-old woman with shortness of breath. PMID- 25923551 TI - A cluster-randomized trial to reduce cesarean delivery rates in Quebec. AB - BACKGROUND: In Canada, cesarean delivery rates have increased substantially over the past decade. Effective, safe strategies are needed to reduce these rates. METHODS: We conducted a cluster-randomized, controlled trial of a multifaceted 1.5-year intervention at 32 hospitals in Quebec. The intervention involved audits of indications for cesarean delivery, provision of feedback to health professionals, and implementation of best practices. The primary outcome was the cesarean delivery rate in the 1-year postintervention period. RESULTS: Among the 184,952 participants, 53,086 women delivered in the year before the intervention and 52,265 women delivered in the year following the intervention. There was a significant but small reduction in the rate of cesarean delivery from the preintervention period to the postintervention period in the intervention group as compared with the control group (change, 22.5% to 21.8% in the intervention group and 23.2% to 23.5% in the control group; odds ratio for incremental change over time, adjusted for hospital and patient characteristics, 0.90; 95% confidence interval [CI], 0.80 to 0.99; P=0.04; adjusted risk difference, -1.8%; 95% CI, -3.8 to -0.2). The cesarean delivery rate was significantly reduced among women with low-risk pregnancies (adjusted risk difference, -1.7%; 95% CI, -3.0 to -0.3; P=0.03) but not among those with high-risk pregnancies (P=0.35; P = 0.03 for interaction). The intervention group also had a reduction in major neonatal morbidity as compared with the control group (adjusted risk difference, -0.7%; 95% CI, -1.3 to -0.1; P=0.03) and a smaller increase in minor neonatal morbidity (adjusted risk difference, -1.7%; 95% CI, -2.6 to -0.9; P<0.001). Changes in minor and major maternal morbidity did not differ significantly between the groups. CONCLUSIONS: Audits of indications for cesarean delivery, feedback for health professionals, and implementation of best practices, as compared with usual care, resulted in a significant but small reduction in the rate of cesarean delivery, without adverse effects on maternal or neonatal outcomes. The benefit was driven by the effect of the intervention in low-risk pregnancies. (Funded by the Canadian Institutes of Health Research; QUARISMA Current Controlled Trials number, ISRCTN95086407.). PMID- 25923556 TI - Overcoming resistance to targeted therapy for lung cancer. PMID- 25923557 TI - Pulmonary alveolar proteinosis and macrophage transplantation. PMID- 25923558 TI - Progesterone in traumatic brain injury. PMID- 25923559 TI - Progesterone in traumatic brain injury. PMID- 25923560 TI - Progesterone in traumatic brain injury. PMID- 25923561 TI - Preexposure prophylaxis for HIV infection. PMID- 25923562 TI - V122I transthyretin variant in elderly black Americans. PMID- 25923563 TI - V122I transthyretin variant in elderly black Americans. PMID- 25923564 TI - V122I transthyretin variant in elderly black Americans. PMID- 25923565 TI - Surgical treatment of moderate ischemic mitral regurgitation. PMID- 25923552 TI - Intensive diabetes therapy and ocular surgery in type 1 diabetes. AB - BACKGROUND: The Diabetes Control and Complications Trial (DCCT) showed a beneficial effect of 6.5 years of intensive glycemic control on retinopathy in patients with type 1 diabetes. METHODS: Between 1983 and 1989, a total of 1441 patients with type 1 diabetes in the DCCT were randomly assigned to receive either intensive diabetes therapy or conventional therapy aimed at preventing hyperglycemic symptoms. They were treated and followed until 1993. Subsequently, 1375 of these patients were followed in the observational Epidemiology of Diabetes Interventions and Complications (EDIC) study. The self-reported history of ocular surgical procedures was obtained annually. We evaluated the effect of intensive therapy as compared with conventional therapy on the incidence and cost of ocular surgery during these two studies. RESULTS: Over a median follow-up of 23 years, 130 ocular operations were performed in 63 of 711 patients assigned to intensive therapy (8.9%) and 189 ocular operations in 98 of 730 patients assigned to conventional therapy (13.4%) (P<0.001). After adjustment for DCCT baseline factors, intensive therapy was associated with a reduction in the risk of any diabetes-related ocular surgery by 48% (95% confidence interval [CI], 29 to 63; P<0.001) and a reduction in the risk of all such ocular procedures by 37% (95% CI, 12 to 55; P=0.01). Forty-two patients who received intensive therapy and 61 who received conventional therapy underwent cataract extraction (adjusted risk reduction with intensive therapy, 48%; 95% CI, 23 to 65; P=0.002); 29 patients who received intensive therapy and 50 who received conventional therapy underwent vitrectomy, retinal-detachment surgery, or both (adjusted risk reduction, 45%; 95% CI, 12 to 66; P=0.01). The costs of surgery were 32% lower in the intensive therapy group. The beneficial effects of intensive therapy were fully attenuated after adjustment for mean glycated hemoglobin levels over the entire follow-up. CONCLUSIONS: Intensive therapy in patients with type 1 diabetes was associated with a substantial reduction in the long-term risk of ocular surgery. (Funded by the National Institute of Diabetes and Digestive and Kidney Diseases and others; DCCT/EDIC ClinicalTrials.gov numbers, NCT00360893 and NCT00360815.). PMID- 25923566 TI - Surgical treatment of moderate ischemic mitral regurgitation. PMID- 25923567 TI - Surgical treatment of moderate ischemic mitral regurgitation. PMID- 25923568 TI - Surgical treatment of moderate ischemic mitral regurgitation. PMID- 25923569 TI - Surgical treatment of moderate ischemic mitral regurgitation. PMID- 25923570 TI - Surgical treatment of moderate ischemic mitral regurgitation. PMID- 25923571 TI - Treatment of relapsed multiple myeloma. PMID- 25923572 TI - Treatment of relapsed multiple myeloma. PMID- 25923574 TI - Images in clinical medicine. Paraneoplastic neuromyotonia. PMID- 25923573 TI - Acute hydrophilic-polymer nephropathy and acute renal failure. PMID- 25923575 TI - Management of refractory hypoxemia during venovenous extracorporeal membrane oxygenation for ARDS. AB - Venovenous extracorporeal membrane oxygenation (VV ECMO) in acute respiratory distress syndrome (ARDS) is currently a widely used therapeutic strategy. However, patients are often still hypoxemic despite complete ECMO support. The major determinants of peripheral oxygen saturation (SpO2) during VV ECMO are pump flow, degree of recirculation, patient's systemic venous return and its oxygen saturation, hemoglobin concentration and residual lung function. Current guidelines state that the support can be considered adequate when the patient's SpO2 is equal or greater than 80%, but a possible objection could be that such a value of O2-tension may be too low and may worsen the patient's prognosis. Moving from the pathophysiology of hypoxemia during VV ECMO, this review focuses on recirculation of blood and on the possible strategies to minimize it, on the pharmacologic modulation of intrapulmonary shunt and on the questions related to management of ECMO flow and the risks and benefits of permissive hypoxemic states. Transfusional strategy during VV ECMO, administration of neuromuscular blocking agents and sedatives, therapeutic hypothermia, and prone positioning is also reviewed. The potential advantages of beta-blockers are discussed. Finally, transition from VV ECMO to venoarterial ECMO (VA ECMO) or a hybrid configuration is also examined. PMID- 25923577 TI - The effects of thermal and electric fields on the electronic structures of silicene. AB - We have investigated the effects of thermal and electric fields on the electronic properties of silicene. The effects were studied by a statistical analysis of canonical ensembles combined with the tight binding method. The tight binding parameters of silicene were obtained by fitting with the first principles results. We analysed the statistics of the gaps, the masses of the Dirac fermions and the effective speeds of light as a function of the cell dimension N. We show that the symmetry breaking caused by the buckling disorder in the thermal field alters the band structures of the silicene with small cells greatly. However, the buckling variation of any atom is compensated by other atoms in a large cell. Thus the band structure features near the Fermi energy in the pristine silicene are still protected by the sublattice symmetry in the thermal field. Moreover, the thermal field enhances the effect of the electric field to generate a band gap. The randomly buckled silicene needs a much smaller electric field than the pristine silicene. The higher temperature corresponds to a larger gap under the same electric field. All these features make silicene a better candidate for electronic devices at ambient temperature. PMID- 25923576 TI - Temporary left ventricular assist device through an axillary access is a promising approach to improve outcomes in refractory cardiogenic shock patients. AB - Cardiogenic shock (CS) causes significant morbidity and mortality and such patients can deteriorate rapidly. Temporary left ventricular assist devices (LVADs) are a promising approach to manage these patients. The following is a case series in which patients stabilized with a temporary LVAD for CS improvement were analyzed retrospectively. Between June 2011 and January 2014, 15 patients received temporary devices through an axillary approach (mean age: 53 +/- 15, 93% male). Mean survival time was 317.8 +/- 359.5 days (range: 6-936 days). During support there were no major bleeding events, infectious complications at the axillary access site, upper extremity edema, or emboli. The most of the patients recovered from CS (93%) were mobilized (67%) and were extubated (73%) while on temporary device support. Median times to extubation, intensive care unit discharge, and discontinuation of inotropic medications were: 1.63, 18, and 15 days, respectively. Four patients recovered to no device support and five received a long-term LVAD, all of whom remain alive. Therefore, implantation of a temporary LVAD through an axillary approach is a promising therapy for improving outcomes in patients needing mechanical circulatory support as a bridge to recovery or a definitive LVAD. PMID- 25923578 TI - Longitudinal cerebrovascular reactivity during pregnancy: a case study. AB - Normal cerebrovascular adaptation during pregnancy is poorly understood. We document a case study of progressively increased cerebrovascular reactivity to CO2, despite no change in resting blood flow, from prepregnancy to late gestation in a 36-year-old normotensive participant. Increased cerebral reactivity was related to progressive chronic respiratory alkalosis and specifically elevated pH and reduced HCO3(-). These novel data serve as important indicators of normative maternal cerebral adaptation and highlight novel areas of future study. PMID- 25923579 TI - Effect of fluoxetine treatment on mitochondrial bioenergetics in central and peripheral rat tissues. AB - Recent investigations have focused on the mitochondrion as a direct drug target in the treatment of metabolic diseases (obesity, metabolic syndrome). Relatively few studies, however, have explicitly investigated whether drug therapies aimed at changing behavior by altering central nervous system (CNS) function affect mitochondrial bioenergetics, and none has explored their effect during early neonatal development. The present study was designed to evaluate the effects of chronic treatment of newborn male rats with the selective serotonin reuptake inhibitor fluoxetine on the mitochondrial bioenergetics of the hypothalamus and skeletal muscle during the critical nursing period of development. Male Wistar rat pups received either fluoxetine (Fx group) or vehicle solution (Ct group) from the day of birth until 21 days of age. At 60 days of age, mitochondrial bioenergetics were evaluated. The Fx group showed increased oxygen consumption in several different respiratory states and reduced production of reactive oxygen species, but there was no change in mitochondrial permeability transition pore opening or oxidative stress in either the hypothalamus or skeletal muscle. We observed an increase in glutathione S-transferase activity only in the hypothalamus of the Fx group. Taken together, our results suggest that chronic exposure to fluoxetine during the nursing phase of early rat development results in a positive modulation of mitochondrial respiration in the hypothalamus and skeletal muscle that persists into adulthood. Such long-lasting alterations in mitochondrial activity in the CNS, especially in areas regulating appetite, may contribute to permanent changes in energy balance in treated animals. PMID- 25923580 TI - The effect of a carbohydrate mouth-rinse on neuromuscular fatigue following cycling exercise. AB - Carbohydrate (CHO) mouth-rinsing, rather than ingestion, is known to improve performance of high-intensity (>75% maximal oxygen uptake) short-duration (<=1 h) cycling exercise. Mechanisms responsible for this improvement, however, are unclear. The present study aimed to investigate the effect of a CHO mouth-rinse on cycling time-trial (TT) performance and mechanisms of fatigue. On 2 separate occasions, 9 male cyclists (mean +/- SD; maximal oxygen uptake, 61 +/- 5 mL.kg( 1).min(-1)) completed 45 min at 70% maximum power output (preload) followed by a 15-min TT. At 7.5-min intervals during the preload and TT, participants were given either a tasteless 6.4% maltodextrin mouth-rinse (CHO) or water (placebo (PLA)) in a double-blind, counterbalanced fashion. Isometric knee-extension force and electromyographic responses to percutaneous electrical stimulation and transcranial magnetic stimulation were measured before, after the preload, and after the TT. There were greater decreases in maximal voluntary contraction after the TT in PLA (20% +/- 10%) compared with the CHO (12% +/- 8%; P = 0.019). Voluntary activation was reduced following exercise in both trials, but did not differ between conditions (PLA -10% +/- 8% vs. CHO -5% +/- 4%; P = 0.150). The attenuation in the manifestation of global fatigue did not translate into a TT improvement (248 +/- 23 vs. 248 +/- 39 W for CHO and PLA, respectively). Furthermore, no differences in heart rate or ratings of perceived exertion were found between the 2 conditions. These data suggest that CHO mouth-rinsing attenuates neuromuscular fatigue following endurance cycling. Although these changes did not translate into a performance improvement, further investigation is required into the role of CHO mouth-rinse in alleviating neuromuscular fatigue. PMID- 25923581 TI - Access to Care, Treatment Ambivalence, Medication Nonadherence, and Long-Term Mortality Among Severely Hypertensive African Americans: A Prospective Cohort Study. AB - African Americans living in poor neighborhoods bear a high burden of illness and early mortality. Nonadherence may contribute to this burden. In a prospective cohort study of urban African Americans with poorly controlled hypertension, mortality was 47.6% over a median follow-up of 6.1 years. Patients with pill taking nonadherence were more likely to die (hazard ratio, 1.80; 95% confidence interval [CI], 1.18-2.76) after adjustment for potential confounders. With regard to factors related to nonadherence, poor access to care such as difficulty paying for medications was associated with prescription refill nonadherence (odds ratio [OR], 4.12; 95% CI, 1.88-9.03). Pill-taking nonadherence was not associated with poor access to care; however, it was associated with factors related to treatment ambivalence including lower hypertension knowledge (OR, 2.97; 95% CI, 1.39-6.32), side effects (OR, 3.44; 95% CI, 1.47-8.03), forgetfulness (OR, 3.62; 95% CI, 1.78 7.34), and feeling that the medications do not help (OR, 2.78; 95% CI, 1.09 7.09). These data suggest that greater access to care is a necessary but insufficient remedy to the disparities experienced by urban African Americans with hypertension. To achieve its full promise, health reform must also address treatment ambivalence. PMID- 25923583 TI - Dynamics and instantaneous normal modes in a liquid with density anomalies. AB - We investigate the relation between the dynamical features of a supercooled liquid and those of its potential energy landscape, focusing on a model liquid with density anomalies. We consider, at fixed temperature, pairs of state points with different density but the same diffusion constant and find that surprisingly they have identical dynamical features at all length and time scales. This is shown by the collapse of their mean square displacements and of their self intermediate scattering functions at different wavevectors. We then investigate how the features of the energy landscape change with density and establish that state points with equal diffusion constant have different landscapes. In particular, we find a correlation between the fraction of instantaneous normal modes connecting different energy minima and the diffusion constant, but unlike in other systems these two quantities are not in one-to-one correspondence with each other, showing that additional landscape features must be relevant in determining the diffusion constant. PMID- 25923582 TI - Resistance Training Reduces Force Tremor and Improves Manual Dexterity in Older Individuals With Essential Tremor. AB - Although symptoms of Essential Tremor (ET) are typically controlled with medication, it is of interest to explore additional therapies to assist with functionality. The purpose of this study was to determine if a generalized upper limb resistance training (RT) program improves manual dexterity and reduces force tremor in older individuals with ET. Ten Essential Tremor and 9 controls were recruited into a dual group, pretest-posttest intervention study. Participants performed 6 weeks of upper-limb RT, and battery of manual dexterity and isometric force tremor assessments were performed before and after the RT to determine the benefits of the program. The six-week, high-load, RT program produced strength increases in each limb for the ET and healthy older group. These changes in strength aligned with improvements in manual dexterity and tremor-most notably for the ET group. The least affected limb and the most affected limb exhibited similar improvements in functional assessments of manual dexterity, whereas reductions in force tremor amplitude following the RT program were restricted to the most affected limb of the ET group. These findings suggest that generalized upper limb RT program has the potential to improve aspects of manual dexterity and reduce force tremor in older ET patients. PMID- 25923584 TI - Male Sexual Behavior and Pheromone Emission Is Enhanced by Exposure to Guava Fruit Volatiles in Anastrepha fraterculus. AB - BACKGROUND: Plant chemicals can affect reproductive strategies of tephritid fruit flies by influencing sex pheromone communication and increasing male mating competitiveness. OBJECTIVE AND METHODOLOGY: We explored whether exposure of Anastrepha fraterculus males to guava fruit volatiles and to a synthetic blend of volatile compounds released by this fruit affects the sexual performance of wild and laboratory flies. By means of bioassays and pheromone collection we investigated the mechanism underlying this phenomenon. RESULTS: Guava volatile exposure enhanced male mating success and positively affected male calling behavior and pheromone release in laboratory and wild males. Changes in male behavior appear to be particularly important during the initial phase of the sexual activity period, when most of the mating pairs are formed. Exposure of laboratory males to a subset of guava fruit volatiles enhanced mating success, showing that the response to the fruit might be mimicked artificially. CONCLUSIONS: Volatiles of guava seem to influence male mating success through an enhancement of chemical and physical signals related to the communication between sexes. This finding has important implications for the management of this pest species through the Sterile Insect Technique. We discuss the possibility of using artificial blends to improve the sexual competitiveness of sterile males. PMID- 25923585 TI - Correction: Accurate Prediction of Severe Allergic Reactions by a Small Set of Environmental Parameters (NDVI, Temperature). PMID- 25923586 TI - Everyday life in the suburbs of Berlin: consequences for the social participation of aged men and women. AB - Against the background of demographic change, mobility issues are becoming crucial. Especially for the elderly, daily outdoor activities are essential for participation in social life. This article addresses the question of what extent older people, especially women, are threatened by limited social participation in Berlin's suburbia. The mobility of older women (70+) is characterized by the least number of trips, the shortest distances, and more than 50% walking trips. Besides, many older women are dissatisfied with their residential area. Given the lack of essential facilities, older women have to be considered as disadvantaged in terms of limited social participation. PMID- 25923587 TI - Paradoxical pinpoint pupils with asenapine. PMID- 25923588 TI - N,N'-Dioxide/Gadolinium(III)-Catalyzed Asymmetric Conjugate Addition of Nitroalkanes to alpha,beta-Unsaturated Pyrazolamides. AB - A highly efficient N,N'-dioxide/Gd(III) complex has been developed for the enantioselective conjugate addition of nitroalkanes to alpha,beta-unsaturated pyrazolamides. Under mild reaction conditions, a series of gamma nitropyrazolamides were obtained in good to excellent yields (up to 99%) with excellent enantioselectivities (up to 99% ee). What's more, the optically active products could be easily transformed into gamma-nitroesters which were key intermediates for the preparation of paroxetine, pregabalin and boclofen. PMID- 25923590 TI - Single-molecule junctions with epitaxial graphene nanoelectrodes. AB - On the way to ultraflat single-molecule junctions with transparent electrodes, we present a fabrication scheme based on epitaxial graphene nanoelectrodes. As a suitable molecule, we identified a molecular wire with fullerene anchor groups. With these two components, stable electrical characteristics could be recorded. Electrical measurements show that single-molecule junctions with graphene and with gold electrodes display a striking agreement. This motivated a hypothesis that the differential conductance spectra are rather insensitive to the electrode material. It is further corroborated by the assignment of asymmetries and spectral features to internal molecular degrees of freedom. The demonstrated open access graphene electrodes and the electrode-insensitive molecules provide a model system that will allow for a thorough investigation of an individual single molecule contact with additional probes. PMID- 25923589 TI - Ritonavir is the best alternative to ketoconazole as an index inhibitor of cytochrome P450-3A in drug-drug interaction studies. AB - AIMS: The regulatory prohibition of ketoconazole as a CYP3A index inhibitor in drug-drug interaction (DDI) studies has compelled consideration of alternative inhibitors. METHODS: The biomedical literature was searched to identify DDI studies in which oral midazolam (MDZ) was the victim, and the inhibitory perpetrator was either ketoconazole, itraconazole, clarithromycin, or ritonavir. The ratios (RAUC ) of total area under the curve (AUC) for MDZ with inhibitor divided by MDZ AUC in the control condition were aggregated across individual studies for each inhibitor. RESULTS: Mean (+/- SE) RAUC values were: ketoconazole (15 studies, 131 subjects), 11.5 (+/-1.2); itraconazole (five studies, 48 subjects), 7.3 (+/-1.0); clarithromycin (five studies, 73 subjects), 6.5 (+/ 10.9); and ritonavir (13 studies, 159 subjects), 14.5 (+/-2.0). Differences among inhibitors were significant (F = 5.31, P < 0.005). RAUC values were not significantly related to inhibitor dosage or to duration of inhibitor pre exposure prior to administration of MDZ. CONCLUSIONS: Ritonavir produces CYP3A inhibition equivalent to or greater than ketoconazole, and is the best index CYP3A inhibitor alternative to ketoconazole. Cobicistat closely resembles ritonavir in structure and function, and can also be considered. Itraconazole and clarithromycin are not suitable alternatives since they do not produce inhibition comparable with ketoconazole or ritonavir, and have other significant disadvantages as well. PMID- 25923591 TI - Ionizer assisted air filtration for collection of submicron and ultrafine particles-evaluation of long-term performance and influencing factors. AB - Previous research has demonstrated that unipolar ionization can enhance the filter performance to collect airborne particles, aeroallergens, and airborne microorganisms, without affecting the filter pressure drop. However, there is a lack of research on the long-term system performance as well as the influence of environmental and operational parameters. In this paper, both field and laboratory tests were carried out to evaluate the long-term particle collection efficiency of a synthetic filter of class M6 with and without ionization. The effect of air velocity, temperature, relative humidity, and particle concentration were further investigated in laboratory tests. Results showed that ionization enhanced the filtration efficiency by 40%-units during most of the operation time. When the ionization system was managed by periodically switching the ionizer polarity, the filtration efficiency against PM0.3-0.5 was maintained above 50% during half a year. Furthermore, the pressure drop of the ionizer assisted M6 filter was 25-30% lower than that of a filter of class F7. The evaluation of various influencing factors demonstrated that (1) air moisture reduced the increase of filtration efficiency; (2) higher upstream particle concentration and air velocity decreased the filtration efficiency; and (3) the air temperature had very limited effect on the filtration efficiency. PMID- 25923593 TI - A novel inorganic-organic nanohybrid material H4SiW12O40/pyridino-MCM-41 as efficient catalyst for the preparation of 1-amidoalkyl-2-naphthols under solvent free conditions. AB - A new inorganic-organic nanohybrid material H4SiW12O40/pyridino-MCM-41 was prepared and performed as an efficient, eco-friendly, and highly recyclable catalyst for the one-pot multi-component synthesis of different substituted 1 amidoalkyl-2-naphthols under solvent-free conditions. The nanohybrid catalyst was prepared through electrostatic anchoring of Keggin heteropolyacid H4SiW12O40 on the surface of MCM-41 nanoparticles modified by N-[3 (triethoxysilyl)propyl]isonicotinamide. The prepared material was characterized by XRD, SEM, EDX, UV-Vis, DTA-TGA, DLS, and FT-IR spectroscopy. Findings confirmed that the heteropolyacid is well dispersed on the surface of the solid support and its structure is preserved after immobilization on the TPI modified MCM-41 nanoparticles. The recovered catalyst was easily recycled for at least seven runs without considerable loss of catalytic activity. PMID- 25923592 TI - Why is aging conserved and what can we do about it? AB - The field of aging research has progressed rapidly over the past few decades. Genetic modulators of aging rate that are conserved over a broad evolutionary distance have now been identified. Several physiological and environmental interventions have also been shown to influence the rate of aging in organisms ranging from yeast to mammals. Here we briefly review these conserved pathways and interventions and highlight some key unsolved challenges that remain. Although the molecular mechanisms by which these modifiers of aging act are only partially understood, interventions to slow aging are nearing clinical application, and it is likely that we will begin to reap the benefits of aging research prior to solving all of the mysteries that the biology of aging has to offer. PMID- 25923594 TI - Photoreactivity of the linker region of two consecutive G-quadruplexes formed by human telomeric DNA. AB - We report the application of a photoreaction method for probing two consecutive G quadruplexes formed by human telomeric DNA. This method can discriminate the loop structure located between two consecutive G-quadruplexes formed by eight TTAGGG repeats in K(+) and Na(+) solutions. PMID- 25923595 TI - Extracellular haem peroxidases mediate Mn(II) oxidation in a marine Roseobacter bacterium via superoxide production. AB - Manganese (Mn) oxides are among the strongest sorbents and oxidants in environmental systems. A number of biotic and abiotic pathways induce the oxidation of Mn(II) to Mn oxides. Here, we use a combination of proteomic analyses and activity assays, to identify the enzyme(s) responsible for extracellular superoxide-mediated Mn oxide formation by a bacterium within the ubiquitous Roseobacter clade. We show that animal haem peroxidases (AHPs) located on the outer membrane and within the secretome are responsible for Mn(II) oxidation. These novel peroxidases have previously been implicated in direct Mn(II) oxidation by phylogenetically diverse bacteria. Yet, we show that in this Roseobacter species, AHPs mediate Mn(II) oxidation not through a direct reaction but by producing superoxide and likely also by degrading hydrogen peroxide. These findings point to a eukaryotic-like oscillatory oxidative-peroxidative enzymatic cycle by these AHPs that leads to Mn oxide formation by this organism. AHP expression appears unaffected by Mn(II), yet the large energetic investment required to produce and secrete these enzymes points to an as yet unknown physiological function. These findings are further evidence that bacterial peroxidases and secreted enzymes, in general, are unappreciated controls on the cycling of metals and reactive oxygen species (ROS), and by extension carbon, in natural systems. PMID- 25923596 TI - Hepatic safety in subjects with HIV-1 and hepatitis C and/or B virus: a randomized, double-blind study of maraviroc versus placebo in combination with antiretroviral agents. AB - BACKGROUND: One of the more clinically relevant co-morbidities in HIV-infected patients is the development of progressive liver disease due to hepatitis B virus (HBV) or hepatitis C virus (HCV). In addition, hepatotoxicity has been observed with prolonged use of antiretroviral agents. OBJECTIVE: To evaluate the hepatic safety of maraviroc in combination with other antiretroviral agents in HIV-1 infected subjects co-infected with HCV and/or HBV. METHODS: In this 148-week randomized, double-blind, placebo-controlled, multicentre study (NCT01327547), subjects received maraviroc twice daily (n = 70) or placebo (n = 67) in combination with other antiretroviral agents. PRIMARY ENDPOINT: the percentage at week 48 of subjects with Grade 3 and Grade 4 ALT abnormalities, defined as >5 * upper limit of normal (ULN) if baseline ALT <= ULN or >3.5 * baseline if baseline ALT>ULN in the maraviroc versus the placebo arm. RESULTS: At week 48, one subject in each group had met the primary endpoint definition. No subjects met protocol-defined liver stopping criteria and there were no cases of Hy's law or treatment-related hepatobiliary serious adverse events. No significant difference in change from baseline in enhanced liver fibrosis or hepatic elastography was observed between groups. Treatment-related hepatobiliary adverse events were reported in one and two subjects receiving maraviroc and placebo, respectively; discontinuations due to treatment-related AEs occurred in four and two subjects receiving maraviroc and placebo, respectively; two deaths were reported in the placebo group. CONCLUSIONS: The use of maraviroc does not increase hepatotoxicity in HIV-1-infected subjects co-infected with HCV and/or HBV through 48 weeks of treatment. PMID- 25923598 TI - Grafting Poly(OEGMA) Brushes from a Shape Memory Elastomer and Subsequent Wrinkling Behavior. AB - An azide-functionalized shape memory elastomer, poly(octylene diazoadipate-co octylene adipate), has been grafted with poly(oligoethylene glycol) methacrylate (poly(OEGMA)) brushes via aqueous ARGET (activators regenerated by electron transfer) ATRP. Sequential swelling of the substrate followed by a grafting-from reaction yielded an incompressible brush layer on the shape-memory substrate. Upon heating the substrate above the Tm to return to the primary shape, uniaxial wrinkles perpendicular to the direction of strain with sizes of 27-33 MUm appear in addition to micrometer-sized features formed on the temporary shape after grafting. Swelling equilibration time (t1) and grafting reaction time (t2) were varied to control wrinkle formation and size. In this manner, we were able to create unique, anisotropic hierarchical surface structures with different length scales and patterns. PMID- 25923597 TI - Enhanced anxiety in the male offspring of sires that self-administered cocaine. AB - We previously showed that paternal cocaine exposure reduced the reinforcing efficacy of cocaine in male offspring. Here, we sought to determine whether paternal cocaine experience could also influence anxiety levels in offspring. Male rats were allowed to self-administer cocaine (controls received saline passively) for 60 days and then were bred with naive females. Measures of anxiety and cocaine-induced anxiogenic effects were assessed in the adult offspring. Cocaine-sired male offspring exhibited increased anxiety-like behaviors, as measured using the novelty-induced hypophagia and defensive burying tasks, relative to saline-sired males. In contrast, sire cocaine experience had no effect on anxiety-like behaviors in female offspring. When challenged with an anxiogenic (but not anorectic) dose of cocaine (2.5 mg/kg, i.p.), anxiety-like behavior was enhanced in all animals to an equal degree regardless of sire drug experience. Since anxiety and depression are often co-morbid, we also assessed measures of depressive-like behavior. Sire cocaine experience had no effect on depression-like behaviors, as measured by the forced swim task, among male offspring. In a separate group of naive littermates, select neuronal correlates of anxiety were measured. Male offspring of cocaine-experienced sires showed increased mRNA and protein expression of corticotropin-releasing factor receptor 2 in the hippocampus. Together, these results indicate that cocaine-experienced sires produce male progeny that have increased baseline anxiety, which is unaltered by subsequent cocaine exposure. PMID- 25923599 TI - Papules in the Axillae of a Woman. PMID- 25923601 TI - Aorto-Left Atrial Fistula after Mitral Valve Surgery. PMID- 25923600 TI - Cyclopentadienyl-ruthenium(II) and iron(II) organometallic compounds with carbohydrate derivative ligands as good colorectal anticancer agents. AB - New ruthenium(II) and iron(II) organometallic compounds of general formula [(eta(5)-C5H5)M(PP)Lc][PF6], bearing carbohydrate derivative ligands (Lc), were prepared and fully characterized and the crystal structures of five of those compounds were determined by X-ray diffraction studies. Cell viability of colon cancer HCT116 cell line was determined for a total of 23 organometallic compounds and SAR's data analysis within this library showed an interesting dependency of the cytotoxic activity on the carbohydrate moiety, linker, phosphane coligands, and metal center. More importantly, two compounds, 14Ru and 18Ru, matched oxaliplatin IC50 (0.45 MUM), the standard metallodrug used in CC chemotherapeutics, and our leading compound 14Ru was shown to be significantly more cytotoxic than oxaliplatin to HCT116 cells, triggering higher levels of caspase-3 and -7 activity and apoptosis in a dose-dependent manner. PMID- 25923602 TI - Selective activation/coupling of polyhalogenated nucleophiles in ni/cr-mediated reactions: synthesis of c1-c19 building block of halichondrin bs. AB - The C1-C19 building block 46 of halichondrin Bs was synthesized via a selective activation/coupling of beta-bromoenone 34 with aldehyde 35 in a Ni/Cr-mediated reaction. The first phase of study was a method development to effect a coupling of a "naked" vinylogous anion with an aldehyde. The study with the coupling of 9 + 10 -> 11 revealed: (1) beta-bromoenone 9b is a better nucleophile than the corresponding beta-iodo- and beta-chloroenones 9a,c; (2) (Me)2Phen(OMe)2.NiCl2 13b is a better Ni-catalyst than (Me)2Phen(H)2.NiCl2 13a; and (3) a low Ni catalyst loading, for example, 0.05-0.1 mol % Ni-catalyst against 10 mol % Cr catalyst, is crucial for an effective coupling. The second phase of study was a method development to realize a selective activation/coupling of polyhalogenated nucleophiles such as 34. The competition experiment of 10 + 9b over 10 + 31a-c revealed: (1) (Me)2Phen(OMe)2.NiCl2 13b is more effective than (Me)2Phen(H)2.NiCl2 13a for the required selective activation/coupling; (2) a low Ni-catalyst loading, for example, 0.05-0.1 mol % Ni-catalyst against 10 mol % Cr catalyst, is crucial for discriminating beta-bromoenone 9b from the three types of vinyl iodides 31a-c. The third phase of study was an application of the developed method to execute the proposed coupling of 34 + 35 -> 36. For this application, a polyether-type Ni-catalyst 37c, readily soluble in the reaction medium, was introduced to achieve the selective activation/coupling with higher efficiency. With use of ion-exchange resin-based device, the coupling product 36 was transformed to the C1-C19 building block 46 of halichondrin Bs without purification/separation of the intermediates. PMID- 25923603 TI - Nutritional interventions in sarcopenia: a critical review. AB - The aim of the present paper is to critically review the details of the published nutrition intervention trials, with and without exercise, targeting sarcopenia. Sarcopenia is the loss of muscle mass, strength and/or performance with age. Since amino acids and energy are required for muscle synthesis it is possible that nutritional intake influences sarcopenia. Nutritional studies are challenging to carry out because of the complexity of modulating dietary intake. It is very difficult to change one nutrient without influencing many others, which means that many of the published studies are problematic to interpret. The studies included evaluate whole protein, essential amino acids and beta-hydroxyl beta-methylbutyrate (HMB). Whole-protein supplementation failed to show a consistent effect on muscle mass, strength or function. This can be explained by the variations in study design, composition of the protein supplement and the failure to monitor voluntary food intake, adherence and baseline nutritional status. Essential amino-acid supplements showed an inconsistent effect but there are only two trials that have significant differences in methodology and the supplement used. The HMB studies are suggestive of a beneficial effect on older adults, but larger well-controlled studies are required that measure outcomes relevant to sarcopenia, ideally in sarcopenic populations. The issues of timing and distribution of protein intake, and increased splanchnic amino-acid sequestration are discussed, and recommendations for future trials are made. PMID- 25923604 TI - Rules of engagement: turning recommendations into results in the diagnosis and management of gout. PMID- 25923605 TI - Biological agents and tuberculosis: risk estimates and screening strategies. PMID- 25923607 TI - Successful autologous hematopoietic stem cell transplantation for a patient with rapidly progressive localized scleroderma. AB - Autologous hematopoietic stem cell transplant (HSCT) for rapidly progressive disease has not been reported in localized scleroderma. Our patient, a 16-year old girl had an aggressive variant of localized scleroderma, mixed subtype (linear-generalized) with Parry Romberg syndrome, with no internal organ involvement, that was unresponsive to immunosuppressive therapy and was causing rapid disfigurement. She was administered autologous HSCT in June 2011 and has maintained drug-free remission with excellent functional status at almost 3.5 years of follow-up. PMID- 25923606 TI - Treatment of glucocorticoid-induced low bone mineral density in children: a systematic review. AB - AIMS: The aim of this systematic review was to evaluate, critically, the treatment options used in the management of bone loss associated with glucocorticoid (GC) use among children. METHODS: We performed a systematic search using PubMed, Cochrane clinical trial registry, Clinicaltiral.gov and Ovid databases (1 March, 2013). The search resulted in 34 eligible retrievals. Of them, seven clinical trials that fulfilled the inclusion and exclusion criteria were selected by two authors. RESULTS: Four studies have compared the effectiveness of bisphosphonates in the treatment of GC-induced low bone mineral density (BMD) in children. Remaining studies were on menatretenone + alfacacidol versus alfacalcidol alone, calcium + vitamin D versus placebo and alfacalcidol versus menatetrenone. In the four studies, bisphosphonates have shown the ability either to improve BMD or prevent bone loss associated with GC use in children. However, alendronate either in oral or intravenous routes and oral pamidronate were the only bisphosphnates that have been studied in children. Vitamin K2 (menatetrenone) combined with alfacalcidol has also preserved BMD in children on long-term GC therapy. Calcium combined with alfacalcidol has also prevented bone loss, greater than menatetrenone. Calcitriol together with Calcium in conventional doses has retarded bone loss, although the combination could not completely prevent the process. CONCLUSIONS: Vitamin D derivatives such as calcitriol or alfacalcidol together with adequate calcium can be considered suitable treatment options to be started simultaneously when long-term GC therapy is needed in children. For children who have been on GCs or have already lost BMD, either oral pamidronate or alendronate in oral/intravenous routes can be considered based on the availability. PMID- 25923609 TI - Addressing the commercial determinants is critical to emerging economies. PMID- 25923608 TI - Health literacy and diabetic foot ulcer healing. AB - The adherence by patients to diabetic foot ulcer therapy is often difficult. The goal of this study was to begin to understand how a patient's health literacy affects their foot ulcer management decisions. Initially using a cross-sectional study design, we evaluated diabetics with foot ulcers within 4 weeks of being asked to participate in a longitudinal study. We assessed health literacy using measures of general health literacy, diabetes health literacy, diabetes self efficacy, and diabetes numeracy. Individuals enrolled in the study had higher health literacy based on the Short Test of Functional Health Literacy in Adults [33.8 (SD 2.3) versus 27.3 (SD 9.6); p = 0.009] as compared to individuals who previously declined an invitation to enroll in the study. Furthermore, patients with lower Short Test of Functional Health Literacy in Adults scores had larger (p = 0.04) and older (p = 0.125) wounds (markers for poorer prognosis). Other measures of literacy showed similar results. In conclusion, those with diminished health literacy were less likely to enroll in an investigational study and had wounds that were less likely to heal. PMID- 25923610 TI - The stability of income inequality in Brazil, 2006-2012: an estimate using income tax data and household surveys. AB - OBJECT: the level and evolution of income inequality among adults in Brazil between 2006 and 2012. OBJECTIVES: to calculate the level of inequality, its trend over the years and the share of income growth appropriated by different social groups. METHODOLOGY: We combined tax data from the Annual Personal Income Tax Returns (Declaracao Anual de Ajuste do Imposto de Renda da Pessoa Fisica - DIRPF) and the Brazilian National Household Survey (Pesquisa Nacional por Amostra de Domicilios - PNAD) to construct a complete distribution of total income among adults in Brazil. We applied Pareto interpolations to income tax tabulations to arrive at the distribution within income groups. We tested the results, comparing the PNAD to the Brazilian Consumption and Expenditure Survey (Pesquisa de Orcamentos Familiares - POF) and to data from the Census Subsample Survey (Census. RESULTS: We found evidence that income inequality in Brazil is higher than previously thought and that it remained stable between 2006 and 2012; in making these findings, we thus diverged from most studies on the dynamics of inequality in Brazil.. There was income growth, but the top incomes have appropriated most of this growth. PMID- 25923611 TI - The individual, social justice and public health. AB - A theoretical reflection on public health from a standpoint of social justice, which does not overlook the individual, is presented. Based on a conceptualization of social justice, human rights and health in the framework of an epistemological analysis, a particular perspective on social justice and its implications for public health praxis, using a public health program as an example, is revealed. Some routes are identified in order to orient and put into practice the actions developed in public health programs. This requires a different way of understanding the scenarios and interchanges among people in the field of clinical practice. It is understood that these fields can also be seen as a suitable opportunity for the establishment of individuals and individualities committed to the political struggle for human rights, equity in health and recognition of a life worthy of human dignity. PMID- 25923612 TI - Relationship between gender, income and education and self-perceived oral health among elderly Mexicans. An exploratory study. AB - The aim of this study was to identify the relationship between sociodemographic factors and self-perceived oral health (SPOH) among the elderly. A cross sectional, exploratory examination of 150 elderly subjects whose ages ranged from 60-86 was conducted. These subjects used the Geriatric Oral Health Assessment Index (GOHAI) to assess their SPOH. In addition, sociodemographic data were collected from study participants. Data were analyzed using Student's t-test, the examination of odds ratio (OR) of logistic regression analysis, the chi-square test, and analysis of variance (ANOVA). The mean decayed, missing, and filled teeth (DMFT) index for the study participants was 20.1 +/- 5.8; 21.3% of subjects were edentulous, and 69.3% of subjects wore removable dentures. 62.7% of study participants had poor SPOH (defined as GOHAI score <44). Poor SPOH was significantly more frequent among males (OR = 2.72, 95% CI: 1.03-7.13, p < 0.05), low-income individuals (OR = 2.7, 95% CI: 1.3 -5.8, p < 0.01), and subjects with less education (OR = 2.26, 95% CI: 1.1-4.6, p < 0.05) than among the overall subject population. The findings suggest that gender (male), low income and low educational levels have a significant influence on the self-perceived oral health status of elderly individuals, irrespective of tooth loss. PMID- 25923613 TI - Trends in risk factors chronic diseases, according of health insurance, Brazil, 2008-2013. AB - This article aims to compare the trends for risk and protective factors for NCD in the population with and without health insurance. Analysis of temporal trends of the Vigitel phone survey, collected annually in adult population. Were used analyzed the temporal series of variables referent to risk and protective factors for NCD, from 2008 to 2013. Variables were compared according to the possession or not of health insurance using simple linear regression model. There was a reduction in the prevalence of smoking in the population with and without health insurance, in 0.72% and 0,69% per year respectively. The consumption of fruits and vegetables grew 0,8% and 0.72% per year respectively among the population with and without health insurance. Physical activity in leisure time increased 1.17% and 1.01% per year among population with and without health insurance. Excess weight increased in 1.03% and obesity in 0.74% p.y in the population with health insurance and 1.53% and 0.95% p.y without health insurance. Mammography increased 2.4% in the population without health insurance. Vigitel monitoring showed improvement in the indicators in the population with and without health insurance. PMID- 25923614 TI - [Deaths with leprosy as the underlying cause recorded in Brazil: use of data base linkage to enhance information]. AB - This study sought to describe the characteristics of deaths with leprosy as the underlying cause recorded in the Mortality Information System (SIM) and compare these characteristics with the groups of cases where the cause of death was reported, or failed to be reported, in the National Case Registration Database (Sinan). Deaths with leprosy as the underlying cause occurring in Brazil in the 2004-2009 period, and cases of leprosy from 1975 to 2010 were included. The probabilistic bases of SIM and Sinan were compared. Of the 1,463 deaths from leprosy recorded in SIM, 44.2% were not recorded in Sinan. Of the total number of deaths, the majority were men (72.5%), aged 60 or older (56.6%), occurring in hospitals (65.3%) and with due care (45.8%). Of the 820 deaths identified in Sinan, 92% were patients with multibacillary disease, 45.2% were discharged as cured by Sinan and 38.9% died. Deaths due to leprosy were found on SIM that were not notified to Sinan. The data base linkage enabled identification of ancillary records and inconsistencies between the systems. PMID- 25923615 TI - Global burden of diarrheal disease attributable to the water supply and sanitation system in the State of Minas Gerais, Brazil: 2005. AB - Advances have occurred in relation to the coverage of water supply and sanitation in Brazil, however inequalities are still observed in relation to the coverage of these services, reflecting the importance of diarrheal disease in the Brazilian epidemiological context. The aim of this study was to measure the impact of the water supply and sanitation system on diarrheal diseases among children aged under five. The global burden of diarrhea was calculated based on the attributable population fraction, using information on prevalence and relative risks from the 2000/2010 censuses and a study by Pruss et al. The north of the State of Minas Gerais, the Northeast and Jequitinhonha regions had the highest disability-adjusted life year (DALY) rates and ratios. The fraction of diarrhea attributable to the water supply and sanitation system was 83%, decreasing to 78.3% where sanitation had 100% coverage. An inverse relationship was found between DALY rates and attributable fractions and per capita GDP. Broadening the scope and coverage of services and improving the quality of water available in homes is an urgent requirement. These measures will bring economic and social benefits related to the reduction of diarrheal diseases and consequent improvement of the quality of life of children aged under five. PMID- 25923616 TI - Emergency room visits due to external causes and alcohol consumption--Capitals and the Federal District, Brazil, 2011. AB - The study objective was to describe the profile and factors related to alcohol consumption among emergency room visits by external causes. It is a cross sectional study with data from the Survey of Violence and Injuries in Emergency between September and October 2011, in 24 state capitals and the Federal District. Statistical analysis were performed for all cases treated in selected services, comparing the characteristics of the victims, according to the statement of alcohol consumption. 33,289 visits to emergency rooms by external causes in the population above 18 years of age were included. The prevalence of self-reported statement of alcohol consumption among these services was 14.9% for the 24 capitals and the Federal District, and was significantly higher among visits by violent causes than by accidents. For both accidents and violence the associated causes were victims male, black/brown, less educated, members of specific populations, occurrences on public roads. The results support global discussions on the importance of establishing policies and legal measures to restrict the consumption of alcohol and vehicular direction, control advertising of alcoholic beverages, and laws normalizing the functioning of sales points of alcoholic beverages. PMID- 25923617 TI - A review of Brazilian scientific output on crack--contributions to the political agenda. AB - OBJECT: scientific literature about crack abuse published in Brazilian journals indexed in SCIELO. OBJECTIVE: systematic review of literature treating findings as a framework for agenda-setting orienting policy decision makers. METHODOLOGY: SCIELO online journals research since 02/06/2013 on tag crack as "key word searched" and in indexes as "research amplitude". An amount of 199 references were identified and their abstracts were analyzed getting to a final group of 59 articles specifically studying crack issues in Brazil. ANALYSIS: institutional criteria (journal, subject area, and publishing time) and analytical categories created by the authors: "Social Risk", "Treatment", "Use/Abuse", "Profile", "Social Relations", and "Study". RESULTS: crack use impact Brazilian journals since 2011; health field is prominent; articles about "Associated Risk" and "Treatment" prevail; SUS cannot face demand;investment improvement in CAP and harm reduction; therapeutic communities need to match with SUS standards; youngers, black people and poor express users profile; rave style use; repressive policies were not well succeeded; and multidisciplinary approach are necessary. PMID- 25923618 TI - [Avoidable mortality in the states adjacent to the Mexico-United States border; 1999-2001 and 2009-2011]. AB - The scope of this article is to measure the effect of avoidable mortality in changes in life expectancy in the states adjacent to both sides of the US-Mexico border between 1999-2001 and 2009-2011. The data used were the records of mortality and population censuses from official sources in each country. Standardized mortality rates were estimated and the expected years of life lost were calculated. Both in 1999-2001 and in 2009-2011 the states belonging to the southern border of the United States had lower rates of avoidable mortality rates than those observed in the northern states of Mexico. In the border region avoidable deaths have seen an averageincrease of 0.19 years of life for America and a loss of 0.47 years of life for Mexico. The states of the US-Mexico border have common features in their health profiles that make it necessary to address some problemson a global basis and consider the particularities of each, in order to reduce gaps and enhance social equity through strategies involving independent national actions and othersby cross-border coordination. PMID- 25923619 TI - Quality of life of people living with HIV/AIDS treated by the specialized service in Vitoria-ES, Brazil. AB - The aim of this study is to establish the factors that influence the quality of life of people living with HIV/AIDS being treated at a specialized public service. The participants answered the questionnaire on sociodemographic conditions, issues related to HIV and daily habits. The quality of life was analyzed using the HIV/AIDS-targeted quality of life (HAT-QoL) instrument with 42 items divided into 9 fields: General Activity, Sexual Activity, Confidentiality Concerns, Health Concerns, Financial Concerns, HIV Awareness, Satisfaction with Life, Issues related to Medication and Trust in the Physician. Bivariate and multiple linear regressions were performed. Of the participants, 53.1% were women and had a mean age of 42 years. In analyzing the quality of life, the HAT-QoL domain with the lowest average was Financial Concerns (39.4), followed by Confidentiality Concerns (43.2), Sexual Activity (55.2) and Health Concerns (62. 88). There was an association between the variables: not being gainfully employed (p < 0.001), being mulatto or black (p = 0.045) and alcohol consumption (p = 0.041) with the worst quality of life scores. Inadequate socioeconomic and health conditions had a negative impact on the quality of life of people with HIV/AIDS. PMID- 25923620 TI - Prevalence of oral cancer self-examination among elderly people treated under Brazil's Unified Health System: household health survey. AB - The aim of this study was to examine the prevalence of oral cancer self examinationamong the elderly and confirm whether prevalence was higher among users of the dental services provided by Brazil's Unified Health System (SUS, acronym in Portuguese). A transversal study of elderly people aged between 65 and 74 years living in a large-sized Brazilian municipality was conducted using simple random sampling. Logistic regression was conducted and results were corrected for sample design and unequal weighting using the SPSS(r) software. The study assessed 740 individuals. A total of 492 met the inclusion criteria, of which 101 (22.4%) reported having performed an oral cancer self-examination. Prevalence was higher among users of the dental services provided by the SUS, higher-income individuals, people with higher levels of education, individuals that used a removable dental prosthesis, and people who had not experienced discomfort attributed to oral condition, and lower among people who sought regular and periodic dental treatment and individuals who did not have a drinking habit. This type of self-care should be encouraged by public health policies which respond to the needs of the elderly, with emphasis on users of private and philanthropic services, and other services outside the public health network. PMID- 25923621 TI - [Limits and possibilities of distance learning in continuing education in health: integrative review]. AB - This is a study on the use of distance learning (EaD, in Portuguese) as a teaching strategy in continuing health education (EPS, in Portuguese), which aimed to identify and analyze the limits and posibilities of using EaD in the EPS. Integrative Review Study. The result shows that EaD is an innovative, possible and potential strategy for EPS, facilitating the development of learning within or outside the health institution, although is evident the lack of research in the area. The limitations for the implementation of the programs are related to the time variable, preparation for dealing with the technologies and the importance of the tutor as a facilitator of learning. It concludes that the use of EaD has an important contribution to the development of human resources in health, is in the process of training and/or in the continuous knowledge process. PMID- 25923622 TI - The family's role as a support network for people living with HIV/AIDS: a review of Brazilian research into the theme. AB - The study of HIV transmission and the implementation of AIDS prevention actions recognize the importance of social networks in the transmission of the disease, the adherence to treatment and the quality of life of those infected. For this relevance there was a review of articles on social support networks to people living with HIV /AIDS available in the Virtual Health Library (VHL) were published in Brazil between 2002 and 2012. In this study 31 articles were used from journals covering the following areas: Nursing (n = 15), Psychology (n = 6) and Science Health / Biomedica (n = 6), were included, which some principal authors were affiliated to higher education public institutions (n = 17). In relation to the methodology used, priority wasgiven to conducting: qualitative research (n = 18), cross-sectional studies (n = 19) and studies that involved talking to people living with HIV/AIDS (n = 13). Particular importance was placed on analytic categories related to: adherence to treatment (n = 6), the family (n = 4), vulnerability (n = 3) and support from social networks (n = 5). Within this paper we argue for more investments into studies that focus on the family, carers and their households, as well as deepening the theoretical study of the themes discussed and the use of developed theories for the analysis of Social Networks. PMID- 25923623 TI - Family dynamics during the grieving process: a systematic literature review. AB - The loss of a loved one can affect family dynamics by changing the family system and creating the need for family members to reorganize. Good family functioning, which is characterized by open communication, expression of feelings and thoughts and cohesion among family members, facilitates adaptive adjustment to the loss. This study conducted a systematic review of the literature on family dynamics during the grieving process. A search was conducted in the EBSCO, Web of Knowledge and Bireme databases for scientific articles published from January 1980 to June 2013. Of the 389 articles found, only 15 met all the inclusion criteria. The selected studies provided evidence that dysfunctional families exhibit more psychopathological symptoms, more psychosocial morbidity, poorer social functioning, greater difficulty accessing community resources, lower functional capacity at work, and a more complicated grieving process. Family conflicts were also emphasized as contributing to the development of a complicated grieving process, while cohesion, expression of affection and good communication in families are believed to mitigate grief symptoms. PMID- 25923624 TI - Rodolfo dos Santos Mascarenhas: a pioneer of health history. AB - Studies on the work of Mascarenhas analyze his contribution to the history of health in Sao Paulo and the aspects of his work which place him in what is entitled the second generation of health workers of Sao Paulo state - being the first generation the one led by Emilio Ribas. This article recaptures these points and highlights his last works on preventive and community medicine. We argue that the conception of public health consolidated during his education was essential for his interest in the new model of medicine that was starting to spread in the country. PMID- 25923625 TI - Completeness of tuberculosis reporting forms for disease control in individuals with HIV/AIDS in priority cities of Bahia state. AB - The control of HIV / Tuberculosis (TB) co -infection remains a challenge for public health. Notification is mandatory for both diseases and the National Case Registry Database (Sinan) is responsible for the collection and processing of individual forms of reporting and monitoring. The adequate fulfillment of these fields chips (completeness) is essential to follow the dynamics of the disease and set priorities for intervention. The aim of this study was to evaluate the completeness of the notification forms of tuberculosis in the priority municipalities of Bahia (Camacari , Feira de Santana , Ilheus , Itabuna, Jequie, Lauro de Freitas , Porto Seguro , Teixeira de Freitas , Paulo Afonso, Barreiras and Salvador) to control the disease in individuals with HIV/AIDS using tabulations obtained from the Sinan in the period from 2001 to 2010. The results showed that despite the completeness of the field HIV be above 50 %, more than half the cases were met as "undone" or "being processed" in all municipalities assessed in the period. The low completeness of reporting forms may compromise the quality of surveillance of TB cases. The results suggest the need for greater availability of HIV testing in these individuals. PMID- 25923626 TI - Factors related to the performance of Specialized Dental Care Centers. AB - The Specialized Dental Care Centers (SDCC) have the mission to expand access to public medium complexity dental care and support the primary health care actions at this level of complexity. However, it is necessary to ensure the quality of services and to evaluate such services continuously to identify weaknesses and strengths that support the processes of leadership/management. Nevertheless, there is a dearth of studies on the assessment of oral health in specialized care that may indicate which factors should be investigated. Therefore, this integrated literature review sought to explore the plethora of publications on the evaluation of SDCC in the LILACS and MEDLINE data bases in October 2013 to identify factors possibly related to the performance of such health services. Thus, 13 references were included in this review pointing to forms of organization and management of work processes related to the creation of healthcare networks (operation of regulation centers and setting up of health consortiums). They include the contextual characteristics of the places where SDCCs are located (population size, Family Health Strategy coverage, Municipal Human Development Index, governance, governing capacity) were factors that influenced the SDCCs performance. PMID- 25923627 TI - Federalism, the economic-industrial health care complex and high-cost pharmaceutical assistance in Brazil. AB - Brazil has a relevant, although relatively unknown, special medicines programme that distributes high-cost products, such as drugs needed for cancer treatments. In 2009, the purchase of these medicines became the responsibility of the Brazilian Federal Government. Until then, there were no clear norms regarding the responsibilities, in terms of the management/financing of these medicines, of the Brazilian Federal Government and of the states themselves. This qualitative study analyses the policy process needed to transfer this programme to the central government. The study examines the reports of the Tripartite Commission between 2000 and 2012, and in-depth interviews with eleven key informants were conducted. The study demonstrates that throughout the last decade, institutional changes have been made in regard to the federal management of these programmes (such as recentralisation of the purchasing of medicines). It concludes that these changes can be explained because of the efficiency of the coordinating mechanisms of the Federal Government. These findings reinforce the idea that the Ministry of Health is the main driver of public health policies, and it has opted for the recentralisation of activities as a result of the development project implicit in the agenda of the Industrial and Economic Heal. PMID- 25923628 TI - The historic data series on AIDS in the state of Ceara, Brazil. AB - This study describes the historic records on AIDS in the Brazilian state of Ceara, with analysis by gender, age group and race. It is a descriptive, retrospective, ecological study, analyzing 7,896 notifications of cases of AIDS, of people aged 13 and above, resident in the Ceara, over the period 2001 through 2011. Percentage occurrences and other data were calculated based on the variables gender, age group and race. Average and comparison tests were made, considering p < 0.05 and the trend line. There is a progressive increase in the number of cases. The majority of cases are in men. The ratio between the sexes falls from 2003 through 2007, but the number of women is still lower overall in the period. Higher rates of occurrence were found between the ages of 30 and 39, and of those with black-white mixed-race skin color (80%). Based on the variables studied in the series that was analyzed, the results indicate a need for differentiated strategies in prevention and control of the disease in the state. PMID- 25923629 TI - Evaluation of knowledge of Oral Health of Community Health Agents connected with the Family Health Strategy. AB - The aim of this study was to evaluate the knowledge of Community Health Agents (CHA) about the oral health/disease process, and compare the results between those who work in Family Health Teams (FHT), with and without Oral Health Teams (OHT). The participants in this study were 162 subjects, representing 66% of the total number of CHA in the municipality, and 81 of them are connected with Family Health Units (FHU) with OHT, and 81 CHS with FHUs without OHT. Data were collected from October to December 2013, by application of a questionnaire, containing personal and professional data, and 12 validated questions about knowledge of the oral health/disease process. The Mann-Whitney test was applied to verify differences between the groups. Statistically significant differences were verified between the groups of CHA when the total scores of questions about the oral health/disease process were analyzed (p < 0.0021). It was concluded that knowledge about the oral health/disease process, of the CHAs connected with a FHU with an OHT was better when compared with that of CHAs connected with a FHU without an OHT. PMID- 25923630 TI - Prevalence of physical activity through the practice of sports among adolescents from Portuguese speaking countries. AB - This study evaluated the prevalence of physical activity through the practice of sports in adolescents from schools in two Brazilian cities and a Portuguese school, and its association with independent variables, such as gender and age. A cross-sectional study was conducted of schoolchildren from two cities in Brazil and one in Portugal. The total study sample was 3694 subjects (1622 males and 1872 females). Physical activity levels were assessed using Baecke's questionnaire. Body weight was measured on electronic scales and stature was measured with a portable wooden stadiometer. Numerical variables were expressed as mean, categorical variables were expressed as percentages and the chi-square test analyzed associations. The prevalence of no sport was high (39.7%), being higher in the Portuguese school than in the Brazilian schools (p < 0.001). Irrespective of being an adolescent in a Brazilian or Portuguese school, boys showed higher engagement in sports practice than girls (p < 0.001). In both, differences were identified between adolescents aged 13 to 15 (P = 0.001) and 16 to 17 (P = 0.001). The prevalence of physical inactivity among schoolchildren from two cities in Brazil and a school in Portugal was high, with the girls practicing less sport than the boys and with this imbalance likely to be higher in adolescents. PMID- 25923631 TI - Health and Labour from the Perspective of Railway Dock workers in Rio Grande do Sul, Brazil. AB - The main goal of this study is to understand and analyse the perspective of dockworkers on health and labour at the Railway Dry Port of the Municipality of Uruguaiana in the State of Rio Grande do Sul (RS), Brazil. Sixteen dockworkers participated in the study under the methodological approach of qualitative research. The fieldwork was conducted through individual interviews by applying a semi-structured research script with open-ended questions. For the data analysis, the "discourse analysis" method was adopted, leading to the definition of five thematic categories of interpretation. From the perspective of dockworkers, dock work differs in both the weight of toil, which is hard and intense, and the sense of satisfaction regarding the collaborative and collective aspect of labour, emphasising the human side of labour. Several reports on work accidents and the identification of hazards that may be avoided by implementing changes in the organisation and work conditions were also noted. PMID- 25923632 TI - Challenges in the coordination of children's healthcare. AB - This is a qualitative survey with a hermeneutic-dialectic frame of reference, designed to identify how parents and caregivers see the attribute 'coordination' in children's healthcare, in terms of resolving problems in children's health. The interview was held with 16 people responsible for care of children under one year of age, served in Emergency Care Units of a municipality in the south of Brazil, in 2010. With the thematic analysis, the central category was identified as: Effects and results of fragile coordination in Children's Primary Health Care, with the following themes: Divergences between different health units in the organization of care; functional barriers and delays obstructing access to technologies; absence of effective communication; absence of medical transport; need for healthcare on an individual basis; and coordination involving management of healthcare. It was concluded that the absence of coordination results in the absence of a solution-based approach in healthcare for children under one year old, showing gaps in the organization of the services and in health management, since communication, access to technologies, referral and counter-referral systems, and secure transport become essential for organizing primary care services and offering fully rounded care to the child. PMID- 25923633 TI - Prevalence and risk factors associated with traumatic dental injury among 12-year old schoolchildren in Montes Claros, MG, Brazil. AB - The scope of this study was to determine the prevalence of trauma in the permanent dentition of 12-year-old schoolchildren and assess associations with demographic factors such as gender and socioeconomic status and overjet and lip coverage clinical factors. A cross-sectional analysis was conducted using a representative sample of 638 students. Data were gathered by means of clinical examinations and self-administered questionnaires. Descriptive analysis was performed, followed by the use of the chi-square test and Poisson logistic regression model for the determination of significant associations. The prevalence of traumatic dental injury was 34.9%. Falls constituted the main etiological factor (49.7%), and occurred in the home (48.2%). The results of the Poisson regression analysis revealed that accentuated overjet (> 5 mm) remained associated with traumatic dental injury irrespective of the other variables [PR = 1.50 (95% CI: 1.41 to 1.61); p = 0.003]. Moreover, a statistically significant association was found between accentuated overjet and dental trauma. No significant associations were found between TDI and socioeconomic status. These findings highlight the need for prevention strategies and orthodontic correction at the onset of the permanent dentition. PMID- 25923634 TI - Association between the use of a baby's bottle and pacifier and the absence of breastfeeding in the second six months of life. AB - INTRODUCTION: The World Health Organization recommends breastfeeding for two years or more and advises against bottle feeding and pacifier use. OBJECTIVE: Investigate the association between bottle feeding and pacifier use, and breastfeeding in the second half-year of life. METHODS: Survey in a municipality of Rio de Janeiro state, in 2006, interviewing those responsible for 580 children aged 6-11 months. Bottle feeding and pacifier use, and variables which in the bivariate analysis were associated with the outcome 'absence of breastfeeding' (>= 0.20), were selected for multiple analysis. Adjusted prevalence ratios were obtained by a Poisson regression model. RESULTS: 40% of the children 6-11 months were not being breastfed, 47% used a pacifier and 57% used a bottle. Pacifier use (PR = 3.245; CI95%: 2.490-4.228) and bottle feeding (PR = 1.605; CI95%: 1.273 2.023) were shown to be strongly associated with the outcome, and also with: mother's low schooling (PR = 0.826; CI95%: 0.689-0.990); low birth weight (PR = 1.488; CI95%: 1.159-1.910); mother not being the baby carer (PR = 1.324; CI95%: 1.080-1.622); and increasing age of the baby in days (PR = 1.004; CI95%: 1.002 1.006). CONCLUSIONS: The use of pacifiers and bottles can reduce continued breastfeeding. Stronger discouragement of these artifacts should be adopted in public health policies. PMID- 25923635 TI - Effectiveness of the Live Births Information System in the Far-Western Brazilian Amazon. AB - The Live Birth Information System (SINASC) was implemented in 1990 for the purpose of providing information about the live-birth characteristics for the establishment of specific health indicators. This work evaluates the information quality of SINASC in relation to its data completeness and coverage for five municipalities from the State of Acre from 2005 to 2010. Lack of information (not filled out or stated as "unknown") was estimated for each variable. Coverage was estimated comparing the Civil Register office statistics in accordance with the mother's municipality of residence. An increase in incompleteness of the majority of variables was observed, and also a decrease in coverage between 2005 and 2010 in these municipalities. These findings do not tally with results from the majority of studies that use SINASC as a data source. The results of this work highlight the relevance of continuous capacity building and the incentive for accurate and complete data inclusion, as well as awareness of the importance of SINASC for public health policies. PMID- 25923636 TI - Undergraduate dental students' perspectives about experiences in primary care for their education in the field of health. AB - Supervised training periods in primary care have been used as spaces for teaching and extension in the area of health, making it feasible to include undergraduates in concrete teaching-learning scenarios. The aim of this study was to analyze the perceptions of dental students about the importance of supervised training periods in Family Health Units to their professional education. The sample consisted of 185 students who answered the question: What is your opinion about the importance of this training period in SUS to your professional education? Comment on this experience and its positive and negative aspects The responses were analyzed by the quali-quantitative Collective Subject Discourse (CSD) technique. The students appreciated learning through practice in the service; contact with professionals from other areas; opportunity for technical-operative improvement and demonstrated sensitivity in the face of social reality, although they appeared to be concerned about being absent from the faculty, arguing that they were being prejudiced as regards their intramural clinical productivity, exhaustively demanded of them. It was concluded that students placed value on the extramural experience, however, it was perceived that there was still a predominant influence of focus on intramural clinical training. PMID- 25923637 TI - Assessment of the management of the Family Health Strategy via the tool Assessment for Quality Improvement in municipalities of Minas Gerais, Brazil. AB - The self-assessment of the quality ofthe Family Health Strategy(FHS) was assessed in the context ofmanagement and its correlation with characteristics of FHS and of the municipality. Managers, coordinators and Family Health Unit managers of municipalities in the Northeast region of Minas Gerais replied with tools 1, 2 and 3 of the Assessment for Improving the Quality of Family Health Strategy (AIQ). Scores were defined for each subdimension, according to the number of features compliant with the standards of the AIQ. We tested the correlation of this score with coverage and the deployment time of the FHS, with the municipal population and the HDI (Human Development Index). The lowest scores were for Work Management, Permanent Education and Inputs, Immunobiologicals and Medicines. There was a positive correlation between the municipal population and Strengthening of Coordination, Support for Teams, Permanent Education Management and Standardization and a negative one with Infrastructure and Equipment. The use of the AIQ tools permitted the identification of subdimensions and municipalities which will require greater attention and intervention by the municipal management. PMID- 25923638 TI - Quality of primary health care: an analysis of avoidable hospitalizations in a Minas Gerais county, Brazil. AB - The aim of the study was to evaluate the quality of primary health care based on avoidable hospitalizations of men and women of all ages, from 2008 to 2012 in Alfenas County in the south of Minas Gerais state. This was an ecological study based on data from the Hospital Information System (HIS). The medical diagnoses selected for the study were pneumonia, diabetes mellitus and diseases of the circulatory system. There was a predominance of elderly males diagnosed with pneumonia, with an average hospital stay of five days. Admission rates for diseases of the circulatory system and diabetes mellitus tended to remain stable during the study period. While for pneumonia there was a tendency of growth that reached a plateau in early March 2009, bringing the average rate up from 2.01 to 3.51. The data suggest that primary health care is poorly organized to meet these diagnoses, particularly for pneumonia. PMID- 25923639 TI - [Prevalence and factors associated with Maternal Near Misses: a survey of the population in a capital city of the Brazilian Northeast]. AB - The scope of this study was to determine the prevalence of near misses and complications during pregnancy and the puerperal period, identifying the main clinical and intervention markers and socioeconomic and demographic factors associated with near misses. It involved a cross-sectional, population-based and probabilistic study with multi-stage complex sampling design conducted in Natal, State of Rio Grande do Norte, Brazil. A validated questionnaire was given to 848 women aged 15 to 49 identified in 8,227 households in 60 census sectors. In theanalysis of associations, the Chi-square test applied and calculated the prevalence ratio (PR) with Confidence Interval (CI) of 95% and 5% significance. The prevalence of maternal near misses was 41.1/1000LB, with hospitalization in an Intensive Care Unit (19.1/1000LB) and eclampsia (13.5/1000LB) being the most important markers. The prevalence of complications during pregnancy and the puerperal period was 21.2%. The highest prevalence of near misses was observed in older women, of black/brown race and low socioeconomic status. Conducting population surveys is feasible and may add important information to the study of near misses and the markers highlight the need for enhancing maternal care to reduce health inequality. PMID- 25923642 TI - [Early detection of breast cancer and the interpretation of results of survival studies]. PMID- 25923643 TI - Inhibition of cell-cell adhesion impairs directional epithelial migration on micropatterned surfaces. AB - The development of the vertebrate body plan with left-right (LR) asymmetry (also known as handedness and chirality) requires the emerging chiral morphogenesis of epithelial cells at specific embryonic stages. In this process, cell-cell adhesions coordinate cellular organization and collective cell migration, and are critical for the directional looping of developing embryonic organs. However, the underlying biophysical mechanism is not yet well understood. Here we modeled normal and delayed epithelial LR symmetry breaking with patterned epithelial chiral morphogenesis on microscale lines with various widths. The patterned cells exhibited biased migration wherein those on opposing boundaries migrated in different directions. Disrupting adherens junctions with ethylene glycol tetraacetic acid (EGTA) resulted in a decrease in velocity difference in opposing boundaries as well as the associated biased cell alignment, along with an increase in the overall random motion. Altering the distance between the opposing boundaries did not significantly alter alignment, but significantly disturbed the velocity profile of the cell migration field. Further examination of cell polarity indicated that disruption of adherens junctions did not affect cell polarization on the boundaries, but decreased the transmission of chiral bias into the interior region of the epithelial cell sheet. Overall, our results demonstrated the dependence of the scale of collective cell migration on the strength of cell-cell adhesion, and its effects on the chirality of a multicellular structure through mediating cell polarity in the vicinity of geometric boundaries. This study demonstrated that our 2D microscale system provides a simple yet effective tool for studying the influence of collective cell migration on LR symmetry breaking, and possibly for fetal drug screening to prevent birth defects related to alteration in cell-cell adhesion. PMID- 25923644 TI - Focusing Quality Improvement Efforts for Hemodialysis Access. PMID- 25923645 TI - Silencing a key gene of the common symbiosis pathway in Nicotiana attenuata specifically impairs arbuscular mycorrhizal infection without influencing the root-associated microbiome or plant growth. AB - While the biochemical function of calcium and calmodulin-dependent protein kinase (CCaMK) is well studied, and plants impaired in the expression of CCaMK are known not to be infected by arbuscular mycorrhizal fungi (AMF) in glasshouse studies, the whole-plant and ecological consequences of CCaMK silencing are not well understood. Here we show that three independently transformed lines of Nicotiana attenuata plants silenced in CCaMK (irCCaMK) are neither infected by Rhizophagus irregularis in the glasshouse nor by native fungal inoculum in the field. The overall fungal community of field-grown roots did not differ significantly among empty vector (EV) and the transgenic lines, and the bacterial communities only showed minor differences, as revealed by the alpha-diversity parameters of bacterial OTUs, which were higher in EV plants compared with two of the three transformed lines, while beta-diversity parameters did not differ. Furthermore, growth and fitness parameters were similar in the glasshouse and field. Herbivory inducible and basal levels of salicylic acid, jasmonic acid and abscisic acid did not differ among the genotypes, suggesting that activation of the classical defence pathways are not affected by CCaMK silencing. Based on these results, we conclude that silencing of CCaMK has few, if any, non-target effects. PMID- 25923646 TI - Cochlear supporting cell transdifferentiation and integration into hair cell layers by inhibition of ephrin-B2 signalling. AB - In mammals, cochlear sensory hair cells that are responsible for hearing are postmitotic and are not replaced after loss. One of the most promising strategies to regenerate hair cells is to identify and inhibit the factors preventing the conversion of adjacent non-sensory supporting cells into hair cells. Here we demonstrate that mammalian hair cells can be directly generated from supporting cells by inhibition of ephrin-B2 signalling. Using either ephrin-B2 conditional knockout mice, shRNA-mediated gene silencing or soluble inhibitors, we found that downregulation of ephrin-B2 signalling at embryonic stages results in supporting cell translocation into hair cell layers and subsequent switch in cell identity from supporting cell to hair cell fate. As transdifferentiation is here a result of displacement across boundary, this original finding presents the interest that newly generated hair cells directly integrate either hair cell layer, then would be likely more rapidly able to fit into functional circuitry. PMID- 25923649 TI - Solvent effects on the polar network of ionic liquid solutions. AB - Molecular dynamics simulations were used to probe mixtures of ionic liquids (ILs) with common molecular solvents. Four types of systems were considered: (i) 1 ethyl-3-methylimidazolium bis(trifluoromethylsulfonyl)imide plus benzene, hexafluorobenzene or 1,2-difluorobenzene mixtures; (ii) choline-based ILs plus ether mixtures (iii) choline-based ILs plus n-alkanol mixtures; and (iv) 1-butyl 3-methylimidazolium nitrate and 1-ethyl-3-methylimidazolium ethyl sulfate aqueous mixtures. The results produced a wealth of structural and aggregation information that highlight the resilience of the polar network of the ILs (formed by clusters of alternating ions and counter-ions) to the addition of different types of molecular solvent. The analysis of the MD data also shows that the intricate balance between different types of interaction (electrostatic, van der Waals, H bond-like) between the different species present in the mixtures has a profound effect on the morphology of the mixtures at a mesoscopic scale. In the case of the IL aqueous solutions, the present results suggest an alternative interpretation for very recently published x-ray and neutron diffraction data on similar systems. PMID- 25923650 TI - Contribution of the new XN-1000 parameters NEUT-RI and NEUT-WY for managing patients with immature granulocytes. PMID- 25923651 TI - Transverse excitations in liquid Fe, Cu and Zn. AB - Transverse acoustic (TA) excitation modes were observed in inelastic x-ray scattering spectra of liquid Fe, Cu and Zn. From the analysis of current correlation functions, we concluded that TA excitation modes can experimentally be detected through the quasi-TA branches in the longitudinal current correlation spectra in these liquid metals. The microscopic elastic constants are estimated and a characteristic difference from macroscopic polycrystalline value was found in Poisson's ratio of liquid Fe, which shows an extremely softer value of ~0.38 compared with the macroscopic value of ~0.275. The lifetime of the TA modes were determined to be ~0.45 ps for liquid Fe and Cu and ~0.55 ps for liquid Zn, reflecting different interatomic correlations between liquid transition metals and non-transition metals. The propagation length of the TA modes are ~0.85 nm in all of liquid metals, corresponding to the size of icosahedral or similar size of cages formed instantaneously in these liquid metals. PMID- 25923652 TI - Fetal calcifications are associated with chromosomal abnormalities. AB - OBJECTIVE: The biological importance of calcifications occasionally noted in fetal tissues (mainly liver) at autopsy or ultrasound is largely unexplored. Previous reports hint at an association to infection, circulatory compromise, malformations or chromosomal abnormalities. To identify factors associated with calcifications, we have performed a case-control study on the largest cohort of fetuses with calcifications described thus far. METHODS: One-hundred and fifty one fetuses with calcifications and 302 matched controls were selected from the archives of the Department of Pathology, Karolinska University Hospital. Chromosome analysis by karyotyping or quantitative fluorescence-polymerase chain reaction was performed. Autopsy and placenta reports were scrutinized for presence of malformations and signs of infection. RESULTS: Calcifications were mainly located in the liver, but also in heart, bowel, and other tissues. Fetuses with calcifications showed a significantly higher proportion of chromosomal abnormalities than controls; 50% vs. 20% (p<0.001). The most frequent aberrations among cases included trisomy 21 (33%), trisomy 18 (22%), and monosomy X (18%). A similar distribution was seen among controls. When comparing cases and controls with chromosomal abnormalities, the cases had a significantly higher prevalence of malformations (95% vs. 77%, p=0.004). Analyzed the other way around, cases with malformations had a significantly higher proportion of chromosomal abnormalities compared with controls, (66% vs. 31%, p<0.001). CONCLUSION: The presence of fetal calcifications is associated with high risk of chromosomal abnormality in combination with malformations. Identification of a calcification together with a malformation at autopsy more than doubles the probability of detecting a chromosomal abnormality, compared with identification of a malformation only. We propose that identification of a fetal tissue calcification at autopsy, and potentially also at ultrasound examination, should infer special attention towards co-existence of malformations, as this would be a strong indicator for a chromosomal abnormality. PMID- 25923653 TI - Si-rich SiNx based Kerr switch enables optical data conversion up to 12 Gbit/s. AB - Silicon photonic interconnection on chip is the emerging issue for next generation integrated circuits. With the Si-rich SiNx micro-ring based optical Kerr switch, we demonstrate for the first time the wavelength and format conversion of optical on-off-keying data with a bit-rate of 12 Gbit/s. The field resonant nonlinear Kerr effect enhances the transient refractive index change when coupling the optical data-stream into the micro-ring through the bus waveguide. This effectively red-shifts the notched dip wavelength to cause the format preserved or inversed conversion of data carried by the on-resonant or off resonant probe, respectively. The Si quantum dots doped Si-rich SiNx strengthens its nonlinear Kerr coefficient by two-orders of magnitude higher than that of bulk Si or Si3N4. The wavelength-converted and cross-amplitude-modulated probe data-stream at up to 12-Gbit/s through the Si-rich SiNx micro-ring with penalty of -7 dB on transmission has shown very promising applicability to all-optical communication networks. PMID- 25923654 TI - ?Kenyaichthyidae fam. nov. and ?Kenyaichthys gen. nov. - First Record of a Fossil Aplocheiloid Killifish (Teleostei, Cyprinodontiformes). AB - The extant Cyprinodontiformes (killifishes) with their two suborders Cyprinodontoidei and Aplocheiloidei represent a diverse and well-studied group of fishes. However, their fossil record is comparatively sparse and has so far yielded members of the Cyprinodontoidei only. Here we report on cyprinodontiform fossils from the upper Miocene Lukeino Formation in the Tugen Hills of the Central Rift Valley of Kenya, which represent the first fossil record of an aplocheiloid killifish. A total of 169 specimens - mostly extraordinarily well preserved - and a sample of ten extant cyprinodontiform species were studied on the basis of morphometrics, meristics and osteology. A phylogenetic analysis using PAUP was also conducted for the fossils. Both the osteological data and the phylogenetic analysis provide strong evidence for the assignment of the fossils to the Aplocheiloidei, and justify the definition of the new family ?Kenyaichthyidae, the new genus ?Kenyaichthys and the new species ?K. kipkechi sp. nov. The phylogenetic analysis unexpectedly places ?Kenyaichthys gen. nov. in a sister relationship to the Rivulidae (a purely Neotropical group), a probable explanation might be lack of available synapomorphies for the Rivulidae, Nothobranchiidae and Aplocheilidae. The specimens of ?K. kipkechi sp. nov. show several polymorphic characters and large overlap in meristic traits, which justifies their interpretation as a species flock in statu nascendi. Patterns of variation in neural and haemal spine dimensions in the caudal vertebrae of ?Kenyaichthys gen. nov. and the extant species studied indicate that some previously suggested synapomorphies of the Cyprinodontoidei and Aplocheiloidei need to be revised. PMID- 25923657 TI - Endotoxin-Binding Peptides Derived from Casein Glycomacropeptide Inhibit Lipopolysaccharide-Stimulated Inflammatory Responses via Blockade of NF-kappaB activation in macrophages. AB - Systemic low-grade inflammation and increased circulating lipopolysaccharide (LPS) contribute to metabolic dysfunction. The inhibitory effects and underlying molecular mechanisms of casein glycomacropeptide (GMP) hydrolysate on the inflammatory response of LPS-stimulated macrophages were investigated. Results showed that the inhibitory effect of GMP hydrolysates obtained with papain on nitric oxide (NO) production were obviously higher than that of GMP hydrolysates obtained with pepsin, alcalase and trypsin (p < 0.05), and the hydrolysate obtained with papain for 1 h hydrolysis (GHP) exhibited the highest inhibitory effect. Compared with native GMP, GHP markedly inhibited LPS-induced NO production in a dose-dependent manner with decreased mRNA level of inducible nitric oxide synthase (iNOS). GHP blocked toll-like receptor 4 (TLR4)/myeloid differentiation primary response 88 (MyD88)/nuclear factor-kappaB (NF-kappaB) signaling pathway activation, accompanied by downregulation of LPS-triggered significant upregulation of tumor necrosis factor (TNF)-alpha and interleukin (IL)-1beta gene expression. Furthermore, GHP could neutralize LPS not only by direct binding to LPS, but also by inhibiting the engagement of LPS with the TLR4/MD2 complex, making it a potential LPS inhibitor. In conclusion, these findings suggest that GHP negatively regulates TLR4-mediated inflammatory response in LPS-stimulated RAW264.7 cells, and therefore may hold potential to ameliorate inflammation-related issues. PMID- 25923656 TI - Selenium and its supplementation in cardiovascular disease--what do we know? AB - The trace element selenium is of high importance for many of the body's regulatory and metabolic functions. Balanced selenium levels are essential, whereas dysregulation can cause harm. A rapidly increasing number of studies characterizes the wide range of selenium dependent functions in the human body and elucidates the complex and multiple physiological and pathophysiological interactions of selenium and selenoproteins. For the majority of selenium dependent enzymes, several biological functions have already been identified, like regulation of the inflammatory response, antioxidant properties and the proliferation/differentiation of immune cells. Although the potential role of selenium in the development and progression of cardiovascular disease has been investigated for decades, both observational and interventional studies of selenium supplementation remain inconclusive and are considered in this review. This review covers current knowledge of the role of selenium and selenoproteins in the human body and its functional role in the cardiovascular system. The relationships between selenium intake/status and various health outcomes, in particular cardiomyopathy, myocardial ischemia/infarction and reperfusion injury are reviewed. We describe, in depth, selenium as a biomarker in coronary heart disease and highlight the significance of selenium supplementation for patients undergoing cardiac surgery. PMID- 25923658 TI - Acute phase IL-10 plasma concentration associates with the high risk sources of cardiogenic stroke. AB - BACKGROUND: Etiological assessment of stroke is essential for accurate treatment decisions and for secondary prevention of recurrence. There is evidence that interleukin-10 (IL-10) associates with ischemic stroke. The aim of this prospective study was to assess the levels of IL-10 in ischemic stroke with unknown or suspected cardiogenic etiology, and evaluate the correlation between IL-10 plasma concentration and the number of diagnosed high risk sources for cardioembolism. METHODS: A total of 141 patients (97 males; mean age 61+/-11 years) with acute ischemic stroke with unknown etiology or suspected cardiogenic etiology other than known atrial fibrillation (AF) underwent imaging investigations to assess high risk sources for cardioembolic stroke established by the European Association of Echocardiography (EAE). IL-10 was measured on admission to the hospital and on a three month follow-up visit. RESULTS: Acute phase IL-10 concentration was higher in patients with EAE high risk sources, and correlated with their number (p<0.01). In patients with no risk sources (n = 104), the mean IL-10 concentration was 2.7+/-3.1 ng/L (range 0.3-16.3 ng/L), with one risk source (n = 26) 3.7+/-5.5 ng/L (0.3-23.6 ng/L), with two risk sources (n = 10) 7.0+/-10.0 ng/L (1.29-34.8 ng/L) and with three risk sources (n = 1) 37.2 ng/L. IL-10 level was not significantly associated with cerebral infarct volume, presence of previous or recent myocardial infarction, carotid/vertebral artery atherosclerosis, paroxysmal AF registered on 24-hour ECG Holter monitoring or given intravenous thrombolytic treatment. CONCLUSION: IL-10 plasma concentration correlates independently with the number of EAE cardioembolic risk sources in patients with acute stroke. IL-10 may have potential to improve differential diagnostics of stroke with unknown etiology. PMID- 25923659 TI - Metabolic associations with archaea drive shifts in hydrogen isotope fractionation in sulfate-reducing bacterial lipids in cocultures and methane seeps. AB - Correlation between hydrogen isotope fractionation in fatty acids and carbon metabolism in pure cultures of bacteria indicates the potential of biomarker D/H analysis as a tool for diagnosing carbon substrate usage in environmental samples. However, most environments, in particular anaerobic habitats, are built from metabolic networks of micro-organisms rather than a single organism. The effect of these networks on D/H of lipids has not been explored and may complicate the interpretation of these analyses. Syntrophy represents an extreme example of metabolic interdependence. Here, we analyzed the effect of metabolic interactions on the D/H biosignatures of sulfate-reducing bacteria (SRB) using both laboratory maintained cocultures of the methanogen Methanosarcina acetivorans and the SRB Desulfococcus multivorans in addition to environmental samples harboring uncultured syntrophic consortia of anaerobic methane-oxidizing archaea (ANME) and sulfate-reducing Deltaproteobacteria (SRB) recovered from deep sea methane seeps. Consistent with previously reported trends, we observed a ~800/00 range in hydrogen isotope fractionation (epsilon(lipid-water)) for D. multivorans grown under different carbon assimilation conditions, with more D enriched values associated with heterotrophic growth. In contrast, for cocultures of D. multivorans with M. acetivorans, we observed a reduced range of epsilon(lipid-water) values (~360/00) across substrates with shifts of up to 610/00 compared to monocultures. Sediment cores from methane seep settings in Hydrate Ridge (offshore Oregon, USA) showed similar D-enrichment in diagnostic SRB fatty acids coinciding with peaks in ANME/SRB consortia concentration suggesting that metabolic associations are connected to the observed shifts in epsilon(lipid-water) values. PMID- 25923661 TI - Strange little flies in the big city: exotic flower-breeding drosophilidae (Diptera) in urban Los Angeles. AB - Urban landscapes are commonly considered too mundane and corrupted to be biotically interesting. Recent insect surveys employing 29 Malaise traps throughout Los Angeles, California, however, have uncovered breeding populations of two unexpected species of one of the most studied and familiar groups of organisms, Drosophila "fruit" flies. Unlike most introduced species of drosophilids, which breed in fresh or decaying fruits, these are specialized flower-breeders. A common species in the survey was Drosophila (Drosophila) gentica Wheeler and Takada, previously collected only once, in El Salvador. It belongs to the flavopilosa species group, all species of which have been known until now from central Chile, Argentina and Uruguay, to Veracruz, Mexico and the Caribbean, breeding in flowers of Cestrum ("jessamine") and Sessea (Solanaceae). The Los Angeles populations are probably breeding in a native and/or introduced Cestrum; in addition, populations in San Luis Obispo County were visiting ornamental Cestrum. Drosophila gentica occurs as far north as San Francisco, where it was found breeding in Cestrum aurantiacum. D. gentica is redescribed and figured in detail for diagnostic and identification purposes. Specimens from Jamaica previously identified as D. gentica are a distinct species but are not formally described in lieu of complete male specimens. Rare in the Malaise traps was Drosophila (Sophophora) flavohirta Malloch, a common species in Australia on the blossoms of native Myrtaceae, found on introduced Eucalyptus in South Africa and both Eucalyptus and Syzygium in Madagascar; adults feed on myrtaceous pollen and nectar, larvae breed in the flowers. It is also redescribed in detail, including its unusual egg. This is the first New World report of this species; DNA sequences confirm it is a morphologically highly aberrant member of the D. melanogaster species group. This study reveals how intensive field sampling can uncover remarkable biodiversity in even the most urbanized areas. PMID- 25923660 TI - Slow freezing, but not vitrification supports complete spermatogenesis in cryopreserved, neonatal sheep testicular xenografts. AB - The ability to spur growth of early stage gametic cells recovered from neonates could lead to significant advances in rescuing the genomes of rare genotypes or endangered species that die unexpectedly. The purpose of this study was to determine, for the first time, the ability of two substantially different cryopreservation approaches, slow freezing versus vitrification, to preserve testicular tissue of the neonatal sheep and subsequently allow initiation of spermatogenesis post-xenografting. Testis tissue from four lambs (3-5 wk old) was processed and then untreated or subjected to slow freezing or vitrification. Tissue pieces (fresh, n = 214; slow freezing, then thawing, n = 196; vitrification, then warming, n = 139) were placed subcutaneously under the dorsal skin of SCID mice and then grafts recovered and evaluated 17 wk later. Grafts from fresh and slow frozen tissue contained the most advanced stages of spermatogenesis, including normal tubule architecture with elongating spermatids in ~1% (fresh) and ~10% (slow frozen) of tubules. Fewer than 2% of seminiferous tubules advanced to the primary spermatocyte stage in xenografts derived from vitrified tissue. Results demonstrate that slow freezing of neonatal lamb testes was far superior to vitrification in preserving cellular integrity and function after xenografting, including allowing ~10% of tubules to retain the capacity to resume spermatogenesis and yield mature spermatozoa. Although a first for any ruminant species, findings also illustrate the importance of preemptive studies that examine cryo-sensitivity of testicular tissue before attempting this type of male fertility preservation on a large scale. PMID- 25923663 TI - Criteria-based audit of quality of care to women with severe pre-eclampsia and eclampsia in a referral hospital in Accra, Ghana. AB - OBJECTIVES: Severe pre-eclampsia and eclampsia are one of the major causes of maternal mortality globally. Reducing maternal morbidity and mortality demands optimizing quality of care. Criteria-based audits are a tool to define, assess and improve quality of care. The aim of this study was to determine applicability of a criteria-based audit to assess quality of care delivered to women with severe hypertensive disorders in pregnancy, and to assess adherence to protocols and quality of care provided at a regional hospital in Accra, Ghana. METHODS: Checklists for management of severe preeclampsia, hypertensive emergency and eclampsia were developed in an audit cycle based on nine existing key clinical care protocols. Fifty cases were audited to assess quality of care, defined as adherence to protocols. Analysis was stratified for complicated cases, defined as (imminent) eclampsia, perinatal mortality and/or one or more WHO maternal near miss C-criteria. RESULTS: Mean adherence to the nine protocols ranged from 15 85%. Protocols for 'plan for delivery' and 'magnesium sulphate administration' were best adhered to (85%), followed by adherence to protocols for 'eclampsia' (64%), 'severe pre-eclampsia at admission' (60%), 'severe pre-eclampsia ward follow-up' (53%) and 'hypertensive emergency' (53%). Protocols for monitoring were least adhered to (15%). No difference was observed for severe disease. Increased awareness, protocol-based training of staff, and clear task assignment were identified as contributors to better adherence. CONCLUSION: A criteria-based audit is an effective tool to determine quality of care, identify gaps in standard of care, and allow for monitoring and evaluation in a health facility, ultimately resulting in improved quality of care provided and reduced maternal morbidity and mortality. In our audit, good adherence was observed for plan for delivery and treatment with magnesium sulphate. Substandard adherence to a number of protocols was identified, and points towards opportunities for targeted improvement strategies. PMID- 25923662 TI - Dental and microbiological risk factors for hospital-acquired pneumonia in non ventilated older patients. AB - METHODS: We obtained a time series of tongue/throat swabs from 90 patients with lower limb fracture, aged 65-101 in a general hospital in the North East of England between April 2009-July 2010. We used novel real-time multiplex PCR assays to detect S. aureus, MRSA, E. coli, P. aeruginosa, S. pneumoniae, H. influenza and Acinetobacter spp. We collected data on dental/denture plaque (modified Quigley-Hein index) and outcomes of clinician-diagnosed HAP. RESULTS: The crude incidence of HAP was 10% (n = 90), with mortality of 80% at 90 days post discharge. 50% of cases occurred within the first 25 days. HAP was not associated with being dentate, tooth number, or heavy dental/denture plaque. HAP was associated with prior oral carriage with E. coli/S. aureus/P.aeruginosa/MRSA (p = 0.002, OR 9.48 95% CI 2.28-38.78). The incidence of HAP in those with carriage was 35% (4% without), with relative risk 6.44 (95% CI 2.04-20.34, p = 0.002). HAP was associated with increased length of stay (Fishers exact test, p=0.01), with mean 30 excess days (range -11.5-115). Target organisms were first detected within 72 hours of admission in 90% participants, but HAP was significantly associated with S. aureus/MRSA/P. aeruginosa/E. coli being detected at days 5 (OR 4.39, 95%CI1.73-11.16) or 14 (OR 6.69, 95%CI 2.40-18.60). CONCLUSIONS: Patients with lower limb fracture who were colonised orally with E. coli/ S. aureus/MRSA/P. aeruginosa after 5 days in hospital were at significantly greater risk of HAP (p = 0.002). PMID- 25923664 TI - The use of a chronic disease and risk factor surveillance system to determine the age, period and cohort effects on the prevalence of obesity and diabetes in South Australian adults--2003-2013. AB - BACKGROUND: Age, period and cohort (APC) analyses, using representative, population-based descriptive data, provide additional understanding behind increased prevalence rates. METHODS: Data on obesity and diabetes from the South Australian (SA) monthly chronic disease and risk factor surveillance system from July 2002 to December 2013 (n = 59,025) were used. Age was the self-reported age of the respondent at the time of the interview. Period was the year of the interview and cohort was age subtracted from the survey year. Cohort years were 1905 to 1995. All variables were treated as continuous. The age-sex standardised prevalence for obesity and diabetes was calculated using the Australia 2011 census. The APC models were constructed with ''apcfit'' in Stata. RESULTS: The age-sex standardised prevalence of obesity and diabetes increased in 2002-2013 from 18.6% to 24.1% and from 6.2% to 7.9%. The peak age for obesity was approximately 70 years with a steady increasing rate from 20 to 70 years of age. The peak age for diabetes was approximately 80 years. There were strong cohort effects and no period effects for both obesity and diabetes. The magnitude of the cohort effect is much more pronounced for obesity than for diabetes. CONCLUSION: The APC analyses showed a higher than expected peak age for both obesity and diabetes, strong cohort effects with an acceleration of risk after 1960s for obesity and after 1940s for diabetes, and no period effects. By simultaneously considering the effects of age, period and cohort we have provided additional evidence for effective public health interventions. PMID- 25923665 TI - Morphology, molecules, and monogenean parasites: an example of an integrative approach to cichlid biodiversity. AB - The unparalleled biodiversity of Lake Tanganyika (Africa) has fascinated biologists for over a century; its unique cichlid communities are a preferred model for evolutionary research. Although species delineation is, in most cases, relatively straightforward, higher-order classifications were shown not to agree with monophyletic groups. Here, traditional morphological methods meet their limitations. A typical example are the tropheine cichlids currently belonging to Simochromis and Pseudosimochromis. The affiliations of these widespread and abundant cichlids are poorly understood. Molecular work suggested that genus and species boundaries should be revised. Moreover, previous morphological results indicated that intraspecific variation should be considered to delineate species in Lake Tanganyika cichlids. We review the genera Simochromis and Pseudosimochromis using an integrative approach. Besides a morphometric study and a barcoding approach, monogenean Cichlidogyrus (Platyhelminthes: Ancyrocephalidae) gill parasites, often highly species-specific, are used as complementary markers. Six new species are described. Cichlidogyrus raeymaekersi sp. nov., C. muterezii sp. nov. and C. banyankimbonai sp. nov. infect S. diagramma. Cichlidogyrus georgesmertensi sp. nov. was found on S. babaulti and S. pleurospilus, C. franswittei sp. nov. on both S. marginatus and P. curvifrons and C. frankwillemsi sp. nov. only on P. curvifrons. As relatedness between Cichlidogyrus species usually reflects relatedness between hosts, we considered Simochromis monotypic because the three Cichlidogyrus species found on S. diagramma belonged to a different morphotype than those found on the other Simochromis. The transfer of S. babaulti, S. marginatus, S. pleurospilus and S. margaretae to Pseudosimochromis was justified by the similarity of their Cichlidogyrus fauna and the intermediate morphology of S. margaretae. Finally parasite data also supported the synonymy between S. pleurospilus and S. babaulti, a species that contains a large amount of geographical morphological variation. PMID- 25923666 TI - OLGA- and OLGIM-based staging of gastritis using narrow-band imaging magnifying endoscopy. AB - BACKGROUND AND AIM: As atrophic gastritis and intestinal metaplasia as a result of Helicobacter pylori are considered risk factors for gastric cancer, it is important to assess their severity. In the West, the operative link for gastritis assessment (OLGA) and operative link for gastric intestinal metaplasia assessment (OLGIM) staging systems based on biopsy have been widely adopted. In Japan, however, narrow-band imaging (NBI)-magnifying endoscopic diagnosis of gastric mucosal inflammation, atrophy, and intestinal metaplasia has been reported to be fairly accurate. Therefore, we investigated the practicality of NBI-magnifying endoscopy (NBI-ME) for gastritis staging. METHODS: We enrolled 55 patients, in whom NBI-ME was used to score the lesser curvature of the antrum (antrum) and the lesser curvature of the lower body (corpus). The NBI-ME score classification was established from images obtained beforehand, and then biopsy specimens taken from the observed areas were scored according to histological findings. The NBI-ME and histology scores were then compared. Furthermore, we assessed the NBI-ME and histology stages using a combination of scores for the antrum and corpus, and divided the stages into two risk groups: low and high. The degree to which the stage assessed by NBI-ME approximated that assessed by histology was then ascertained. RESULTS: Degree of correspondence between the NBI-ME and histology scores was 69.1% for the antrum and 72.7% for the corpus, and that between the high- and low-risk groups was 89.1%. CONCLUSION: Staging of gastritis using NBI ME approximates that based on histology, and would be a practical alternative to the latter. PMID- 25923667 TI - How a GNSS Receiver Is Held May Affect Static Horizontal Position Accuracy. AB - The static horizontal position accuracy of a mapping-grade GNSS receiver was tested in two forest types over two seasons, and subsequently was tested in one forest type against open sky conditions in the winter season. The main objective was to determine whether the holding position during data collection would result in significantly different static horizontal position accuracy. Additionally, we wanted to determine whether the time of year (season), forest type, or environmental variables had an influence on accuracy. In general, the F4Devices Flint GNSS receiver was found to have mean static horizontal position accuracy levels within the ranges typically expected for this general type of receiver (3 to 5 m) when differential correction was not employed. When used under forest cover, in some cases the GNSS receiver provided a higher level of static horizontal position accuracy when held vertically, as opposed to held at an angle or horizontally (the more natural positions), perhaps due to the orientation of the antenna within the receiver, or in part due to multipath or the inability to use certain satellite signals. Therefore, due to the fact that numerous variables may affect static horizontal position accuracy, we only conclude that there is weak to moderate evidence that the results of holding position are significant. Statistical test results also suggest that the season of data collection had no significant effect on static horizontal position accuracy, and results suggest that atmospheric variables had weak correlation with horizontal position accuracy. Forest type was found to have a significant effect on static horizontal position accuracy in one aspect of one test, yet otherwise there was little evidence that forest type affected horizontal position accuracy. Since the holding position was found in some cases to be significant with regard to the static horizontal position accuracy of positions collected in forests, it may be beneficial to have an understanding of antenna positioning within the receiver to achieve the greatest accuracy during data collection. PMID- 25923668 TI - Triplet state formation in photovoltaic blends of DPP-type copolymers and PC71 BM. AB - The exciton dynamics in pristine films of two structurally related low-bandgap diketopyrrolopyrrole (DPP)-based donor-acceptor copolymers and the photophysical processes in bulk heterojunction solar cells using DPP copolymer:PC71 BM blends are investigated by broadband transient absorption (TA) pump-probe experiments covering the vis-near-infrared spectral and fs-MUs dynamic range. The experiments reveal surprisingly short exciton lifetimes in the pristine poly-mer films in conjunction with fast triplet state formation. An in-depth analysis of the TA data by multivariate curve resolution analysis shows that in blends with fullerene as acceptor ultrafast exciton dissociation creates charge carriers, which then rapidly recombine on the sub-ns timescale. Furthermore, at the carrier densities created by pulsed laser excitation the charge carrier recombination leads to a substantial population of the polymer triplet state. In fact, virtually quantitative formation of triplet states is observed on the sub-ns timescale. However, the quantitative triplet formation on the sub-ns timescale is not in line with the power conversion efficiencies of devices indicating that triplet state formation is an intensity-dependent process in these blends and is reduced under solar illumination conditions, as free charge carriers can be extracted from the photoactive layer in devices. PMID- 25923669 TI - Chloroquine-enhanced efficacy of cisplatin in the treatment of hypopharyngeal carcinoma in xenograft mice. AB - Hypopharyngeal squamous cell carcinoma (HSCC) has the worst prognosis among head and neck cancers. Cisplatin (DDP)-based chemotherapy is an important part of multimodal treatments. However, resistance to DDP severely impairs the effectiveness of chemotherapy for HSCC. Chloroquine (CQ) has been reported to enhance the effectiveness of chemotherapy and radiotherapy in liver, pancreas, breast, prostate and colon tumors, but it is unclear whether CQ could increase the efficacy of DDP for treating HSCC. We inoculated BALB/c nude mice with a subcutaneous injection of human hypopharyngeal FaDu cells to generate our animal model. Mice were randomly divided into 4 groups and treated with vehicle control, CQ (60 mg/kg/day), DDP (5 mg/kg/6 days), or a combination of DDP and CQ. Tumor growth and survival of the mice were monitored. We found that CQ inhibited autophagy and increased DDP-induced apoptosis in the xenograft mouse model. CQ enhanced the efficacy of DDP, resulting in decreased tumor growth and prolonged survival of the mice. To test whether blocking autophagy enhanced the efficacy of DDP, FaDu cells were infected with lentiviral shRNA to Beclin-1 and inoculated into the flanks of nude mice. Inhibition of autophagy markedly enhanced the DDP induced antitumor effect. Our study suggests that the addition of CQ to DDP-based chemotherapy could be a potential therapeutic strategy for treating HSCC, and the inhibition of autophagy may contribute to chemotherapy sensitization in HSCC. PMID- 25923670 TI - Arrhythmogenic Biophysical Phenotype for SCN5A Mutation S1787N Depends upon Splice Variant Background and Intracellular Acidosis. AB - BACKGROUND: SCN5A is a susceptibility gene for type 3 long QT syndrome, Brugada syndrome, and sudden infant death syndrome. INa dysfunction from mutated SCN5A can depend upon the splice variant background in which it is expressed and also upon environmental factors such as acidosis. S1787N was reported previously as a LQT3-associated mutation and has also been observed in 1 of 295 healthy white controls. Here, we determined the in vitro biophysical phenotype of SCN5A-S1787N in an effort to further assess its possible pathogenicity. METHODS AND RESULTS: We engineered S1787N in the two most common alternatively spliced SCN5A isoforms, the major isoform lacking a glutamine at position 1077 (Q1077del) and the minor isoform containing Q1077, and expressed these two engineered constructs in HEK293 cells for electrophysiological study. Macroscopic voltage-gated INa was measured 24 hours after transfection with standard whole-cell patch clamp techniques. We applied intracellular solutions with pH7.4 or pH6.7. S1787N in the Q1077 background had WT-like INa including peak INa density, activation and inactivation parameters, and late INa amplitude in both pH 7.4 and pH 6.7. However, with S1787N in the Q1077del background, the percentages of INa late/peak were increased by 2.1 fold in pH 7.4 and by 2.9 fold in pH 6.7 when compared to WT. CONCLUSION: The LQT3-like biophysical phenotype for S1787N depends on both the SCN5A splice variant and on the intracellular pH. These findings provide further evidence that the splice variant and environmental factors affect the molecular phenotype of cardiac SCN5A-encoded sodium channel (Nav1.5), has implications for the clinical phenotype, and may provide insight into acidosis induced arrhythmia mechanisms. PMID- 25923671 TI - Potent Anti-HIV Chemokine Analogs Direct Post-Endocytic Sorting of CCR5. AB - G protein-coupled receptors (GPCRs) are desensitized and internalized following activation. They are then subjected to post-endocytic sorting (degradation, slow recycling or fast recycling). The majority of research on post-endocytic sorting has focused on the role of sequence-encoded address structures on receptors. This study focuses on trafficking of CCR5, a GPCR chemokine receptor and the principal entry coreceptor for HIV. Using Chinese Hamster Ovary cells stably expressing CCR5 we show that two different anti-HIV chemokine analogs, PSC-RANTES and 5P14 RANTES, direct receptor trafficking into two distinct subcellular compartments: the trans-Golgi network and the endosome recycling compartment, respectively. Our results indicate that a likely mechanism for ligand-directed sorting of CCR5 involves capacity of the chemokine analogs to elicit the formation of durable complexes of CCR5 and arrestin2 (beta-arrestin-1), with PSC-RANTES eliciting durable association in contrast to 5P14-RANTES, which elicits only transient association. PMID- 25923672 TI - Phylogenetic placement of metagenomic reads using the minimum evolution principle. AB - BACKGROUND: A central problem of computational metagenomics is determining the correct placement into an existing phylogenetic tree of individual reads (nucleotide sequences of varying lengths, ranging from hundreds to thousands of bases) obtained using next-generation sequencing of DNA samples from a mixture of known and unknown species. Correct placement allows us to easily identify or classify the sequences in the sample as to taxonomic position or function. RESULTS: Here we propose a novel method (PhyClass), based on the Minimum Evolution (ME) phylogenetic inference criterion, for determining the appropriate phylogenetic position of each read. Without using heuristics, the new approach efficiently finds the optimal placement of the unknown read in a reference phylogenetic tree given a sequence alignment for the taxa in the tree. In short, the total resulting branch length for the tree is computed for every possible placement of the unknown read and the placement that gives the smallest value for this total is the best (optimal) choice. By taking advantage of computational efficiencies and mathematical formulations, we are able to find the true optimal ME placement for each read in the phylogenetic tree. Using computer simulations, we assessed the accuracy of the new approach for different read lengths over a variety of data sets and phylogenetic trees. We found the accuracy of the new method to be good and comparable to existing Maximum Likelihood (ML) approaches. CONCLUSIONS: In particular, we found that the consensus assignments based on ME and ML approaches are more correct than either method individually. This is true even when the statistical support for read assignments was low, which is inevitable given that individual reads are often short and come from only one gene. PMID- 25923673 TI - Cervical vertebral fusion with anterior meningocele. AB - We present the first described case of cervical vertebral fusion associated with anterior meningocele and syringomyelia. A 45-year-old woman presented with minor trauma, and plain cervical spine radiographs highlighted a congenital deformity of the cervical vertebral bodies. She had a normal neurological examination; however, further imaging revealed a meningocele and syringomyelia. This case highlights the importance of thorough imaging investigation when presented with a congenital deformity in order to detect and prevent development of degenerative spinal cord pathologies. PMID- 25923674 TI - Reversible and Asymptomatic Gyral and Subarachnoid Contrast Enhancement after Carotid Stenting. AB - The presence of sulcal hyperdensity in patients after endovascular procedures is not necessarily attributable to hemorrhage. It may frequently indicate the absolute or concomitant extravasation of contrast material into the subarachnoid spaces.This case report describes the clinical case of an 84-year-old patient with 90% stenosis of the right internal carotid who presented with a diffuse gyral and sulcal hyperdensity in the right temporal-occipital and frontal lobes at routine post-carotid stenting (CAS) brain CT scan. The patient was asymptomatic and CT findings were interpreted as contrast enhancement hyperattenuation and no therapeutic decisions were made. A 24-hour follow-up brain CT demonstrated the complete resolution of the hyperdensity, confirming the diagnosis.In this patient we considered the concomitant presence of gyral and sulcal hyperdensity as the consequence of reversible damage to the blood-brain barrier (BBB) determining a transitory extravasation of contrast material. Asymptomatic gyral and subarachnoid contrast enhancement following CAS is generally indicative of benign and transitory damage to the BBB and is not to be misinterpreted as hemorrhage. PMID- 25923676 TI - Machine learning methods for the classification of gliomas: Initial results using features extracted from MR spectroscopy. AB - CONTEXT: With the advent of new imaging modalities, radiologists are faced with handling increasing volumes of data for diagnosis and treatment planning. The use of automated and intelligent systems is becoming essential in such a scenario. Machine learning, a branch of artificial intelligence, is increasingly being used in medical image analysis applications such as image segmentation, registration and computer-aided diagnosis and detection. Histopathological analysis is currently the gold standard for classification of brain tumors. The use of machine learning algorithms along with extraction of relevant features from magnetic resonance imaging (MRI) holds promise of replacing conventional invasive methods of tumor classification. AIMS: The aim of the study is to classify gliomas into benign and malignant types using MRI data. SETTINGS AND DESIGN: Retrospective data from 28 patients who were diagnosed with glioma were used for the analysis. WHO Grade II (low-grade astrocytoma) was classified as benign while Grade III (anaplastic astrocytoma) and Grade IV (glioblastoma multiforme) were classified as malignant. METHODS AND MATERIALS: Features were extracted from MR spectroscopy. The classification was done using four machine learning algorithms: multilayer perceptrons, support vector machine, random forest and locally weighted learning. RESULTS: Three of the four machine learning algorithms gave an area under ROC curve in excess of 0.80. Random forest gave the best performance in terms of AUC (0.911) while sensitivity was best for locally weighted learning (86.1%). CONCLUSIONS: The performance of different machine learning algorithms in the classification of gliomas is promising. An even better performance may be expected by integrating features extracted from other MR sequences. PMID- 25923675 TI - Cerebral Venous Sinus Thrombosis: Successful Treatment of Two Patients Using the Penumbra System and Review of Endovascular Approaches. AB - Cerebral venous sinus thrombosis (CVST) is an uncommon but potentially life threatening condition. When showing resistance to treatment or a malignant progression despite anticoagulant therapy, endovascular interventional treatment is of help. The Penumbra System (PS), a novel thrombectomy device specifically designed to remove the thrombus in acute ischemic stroke, also proved to be an effective device for mechanical recanalization of CVST. We first reported two cases successfully treated using the PS in the management of intractable CVST in Asia, and analyzed the technical differences of use of the device through a systematic review of the literature.One patient underwent mechanical thrombectomy of the thrombosed superior sagittal sinus using the 0.054-inch PS catheter when direct pharmacological thrombolysis failed. The other patient underwent mechanical thrombectomy using the 0.041-inch PS catheter with adjuvant local pharmacological thrombolysis. Literature reports on the use of the PS in patients with CVST were reviewed.Successful venous recanalization was achieved using the PS. The patients improved symptomatically following the intervention. Literature reports showed that the PS can be successfully applied for treatment of CVST, though the methods used previously were diverse.The PS has proved to be effective in the rapid recanalization of CVST, but different treatment techniques exist. The solution to these problems depends on more clinical trials as well as further improvements to devices. PMID- 25923678 TI - Inadvertent Detachment of a Retrievable Intracranial Stent: Review of Manufacturer and User Facility Device Experience. AB - Few systematic surveys have dealt with the potential procedural risks associated with the use of retrievable intracranial stents [Solitaire Flow Restoration (Solitaire FR)], which have become effective tools for recanalizing acutely occluded cerebral arteries. The aim of this study was to present the real-world experiences of Solitaire-FR-related adverse events by reviewing the MAUDE (Manufacturer and User Facility Device Experience) as published on the United States Food and Drug Administration website. In total, 85 adverse events related to the use of the Solitaire FR stent were reported between March 2012 and October 2014. In 80 patients these adverse events were attributable to inadvertent detachment of the device. Thirteen of these 80 patients (16%) died after the procedure. Morbidity data were available in 62 patients, among whom 11 (18%) had suffered a procedure-related injury. Detachment occurred at the first, second, and third pass in nine (21%), 21 (49%), and 13 (30%) of the 43 patients for whom this information was available, respectively. Resistance was perceived by the physician during retrieval of the device in 12 patients, and lesion characteristics were noted in 13. A rescue maneuver was reported in 20 (25%) of the 80 patients in whom the adverse event was attributable to detachment of the device, resulting in flow reestablishment in 13 (65%). The risk of inadvertent detachment during stent retrieval cannot be overemphasized in real-world scenarios, and careful consideration of the "dos and don'ts" is essential for the achievement of a safe procedure. PMID- 25923677 TI - Cerebral Blood Flow Changes in Glioblastoma Patients Undergoing Bevacizumab Treatment Are Seen in Both Tumor and Normal Brain. AB - Bevacizumab (BEV) is increasingly used to treat recurrent glioblastoma (GBM) with some reported improvement in neurocognitive function despite potential neurotoxicities. We examined the effects of BEV on cerebral blood flow (CBF) within recurrent GBM tumor and in the contralateral middle cerebral artery (MCA) territory.Post-chemoradiation patients with histologically confirmed GBM were treated with BEV and underwent routine, serial tumor imaging with additional pseudocontinuous arterial spin labeling (pcASL) following informed consent. Circular regions-of-interest were placed on pcASL images directly over the recurrent tumor and in the contralateral MCA territory. CBF changes before and during BEV treatment were evaluated in tumor and normal tissue. Linear mixed models were used to assess statistical significance.Fifty-three pcASL studies in 18 patients were acquired. Evaluation yielded lower mean tumoral CBF during BEV treatment compared with pre-treatment (45 +/- 27 vs. 65 +/- 27 ml/100 g/min, p = 0.002), and in the contralateral MCA territory during, compared with pre-BEV treatment (35 +/- 8.4 vs. 41 +/- 8.4 ml/100 g/min, p = 0.03). The decrease in mean CBF tended to be greater in the tumoral region than in the contralateral MCA, though the difference did not reach statistical significance (31% vs. 13%; p = 0.082). CONCLUSIONS: BEV administration results in statistically significant global CBF decrease with a potentially preferential decrease in tumor perfusion compared with normal brain tissue. PMID- 25923679 TI - Intraosseous Hemangioma of the Middle Turbinate: A Case Report of a Rare Entity and Literature Review. AB - Intraosseous hemangiomas arising from the nasal turbinate are exceedingly rare, with few reported cases in the literature. We describe a 61-year-old man found to have a nasal cavity mass on sinus computed tomograph (CT) and magnetic resonance imaging (MRI). Although an atypical site of occurrence, distinctive internal honeycomb bony trabeculations demonstrated on CT allowed the correct diagnosis of an intraosseous hemangioma to be prospectively proposed by the interpreting radiologist which had direct clinical and surgical impacts. PMID- 25923680 TI - MRI DWI/ADC signal predicts shrinkage of lumbar disc herniation after O2-O3 discolysis. AB - PURPOSE: Evaluate the discal morpho-structural changes as a predictive sign in the clinical outcome after ozone therapy in lumbar disc herniation using the T2 shine through effect in diffusion-weighted imaging (DWI). METHOD: One hundred and fifty-four patients suffering from lumbosciatica (89 men and 65 women; age range, 23-62 years) were included, previous MR study performed with FSE-T2 and T2-fat, SE-T1 and DWI sequences, and were randomly assigned to two groups. Seventy-seven patients (control group) underwent conservative treatment with intraforaminal injection of steroid and anaesthetic. The remaining 77 patients (study group) underwent the same treatment with the addition of oxygen-ozone (O2-O3). During the following six months, a MRI follow-up with the same sequences was performed. An intervertebral disc volumetric analysis (IDVA), DWI signal score and post treatment clinical outcome evaluation were performed for an assessment of hernia reduction. chi2 test, Student's t test and analysis of covariance were used for comparison of variables. RESULTS: In the study group, 58 of 77 patients had a successful outcome (responders). In the responders group, DWI T2-shine through effect was present during MRI follow-up and in particular in 53 of 77 patients in six months of follow-up (p < 0.05). Moreover, in the same group a statistically significant disc shrinkage was shown by IDVA in sixth months of follow-up (p < 0.05). CONCLUSIONS: T2-shine through effect in DWI is present before morphological disc reduction and moreover could be considered as a predictive sign of response to oxygen-ozone treatment. PMID- 25923681 TI - Double Origin of the Posterior Inferior Cerebellar Artery Diagnosed by MR Angiography: A Report of Two Cases. AB - The posterior inferior cerebellar artery (PICA) frequently arises from the fenestrated segment of the intracranial vertebral artery (VA), and this common variation can be misinterpreted as or confused with a PICA of double origin. Rarely, a PICA of true double origin occurs when two branches of the PICA arise separately from the intracranial VA and fuse to form an arterial ring. We discovered this rare variation incidentally while interpreting images of magnetic resonance (MR) angiography. This is the first report of MR angiographic findings of this rare variation. PMID- 25923682 TI - Novel finding of optic nerve central T2 hypointensity utilizing 3 Tesla MR imaging. AB - We sought to report a central T2 hypointensity within the optic nerve on 3 T MRI studies obtained as part of the NASA Flight Medicine Visual Impairment Intracranial Pressure Protocol that had not been described previously. Twenty-one astronauts, who had undergone MRI of both orbits with direct coronal T2 sequences between 2010 and 2012, were retrospectively included. Two of the astronauts did not have previous exposure to microgravity at the time of their scans. A central T2 hypointensity was observed in 100% of both right and left eyes. It was completely visualized throughout the nerve course in 15 right eyes (71.4%) and in 19 left eyes (90.5%).We describe a new finding seen in all study participants: a central T2 hypointensity in the epicenter of the optic nerve. We speculate that this T2 hypointensity may represent flow voids caused by the central retinal vessels. PMID- 25923683 TI - Three-dimensional stereotactic atlas of the extracranial vasculature correlated with the intracranial vasculature, cranial nerves, skull and muscles. AB - Our objective was to construct a 3D, interactive, and reference atlas of the extracranial vasculature spatially correlated with the intracranial blood vessels, cranial nerves, skull, glands, and head muscles.The atlas has been constructed from multiple 3T and 7T magnetic resonance angiogram (MRA) brain scans, and 3T phase contrast and inflow MRA neck scans of the same specimen in the following steps: vessel extraction from the scans, building 3D tubular models of the vessels, spatial registration of the extra- and intracranial vessels, vessel editing, vessel naming and color-coding, vessel simplification, and atlas validation.This new atlas contains 48 names of the extracranial vessels (25 arterial and 23 venous) and it has been integrated with the existing brain atlas.The atlas is valuable for medical students and residents to easily get familiarized with the extracranial vasculature with a few clicks; is useful for educators to prepare teaching materials; and potentially can serve as a reference in the diagnosis of vascular disease and treatment, including craniomaxillofacial surgeries and radiologic interventions of the face and neck. PMID- 25923684 TI - Neural loss aversion differences between depression patients and healthy individuals: A functional MRI investigation. AB - Neuroeconomics employs neuroscience techniques to explain decision-making behaviours. Prospect theory, a prominent model of decision-making, features a value function with parameters for risk and loss aversion. Recent work with normal participants identified activation related to loss aversion in brain regions including the amygdala, ventral striatum, and ventromedial prefrontal cortex. However, the brain network for loss aversion in pathologies such as depression has yet to be identified. The aim of the current study is to employ the value function from prospect theory to examine behavioural and neural manifestations of loss aversion in depressed and healthy individuals to identify the neurobiological markers of loss aversion in economic behaviour. We acquired behavioural data and fMRI scans while healthy controls and patients with depression performed an economic decision-making task. Behavioural loss aversion was higher in patients with depression than in healthy controls. fMRI results revealed that the two groups shared a brain network for value function including right ventral striatum, ventromedial prefrontal cortex, and right amygdala. However, the neural loss aversion results revealed greater activations in the right dorsal striatum and the right anterior insula for controls compared with patients with depression, and higher activations in the midbrain region ventral tegmental area for patients with depression compared with controls. These results suggest that while the brain network for loss aversion is shared between depressed and healthy individuals, some differences exist with respect to differential activation of additional areas. Our findings are relevant to identifying neurobiological markers for altered decision-making in the depressed. PMID- 25923685 TI - Unusual primary central nervous system lymphoma location involving the fourth ventricle and hypothalamus. AB - A previously healthy 65-year-old man presented with a two-week history of weight loss, headaches, blurred vision, asthenia and quickly worsening walking impairment. He denied photophobia, neck stiffness, fever, nausea or vomiting.Neurological examination showed global motor slowing, tendency to fall asleep during the clinical examination, generalized weakness against resistance to head and limbs, and osteotendon reflexes present in the upper limbs, but not evoked in the lower limbs. No sensitive deficit or focal neurologic sign was recognizable.Non-contrast multislice computed tomography (MSCT) of the head was performed in the emergency department, showing diffuse periventricular white matter and thalamic mild hyperdensity.Lumbar puncture, blood tests, including serology for HIV and other infections, were negative.On the third day the patient, showing decreased consciousness, underwent magnetic resonance imaging (MRI) with contrast medium injection. MRI revealed the presence of multiple pseudonodular avidly enhancing lesions, supra and infratentorial, crossing the midline, involving the ventricular system, including the fourth ventricle, with extension into the surrounding white matter, the corpus callosum, the thalamus and the hypothamalus.A stereotactic biopsy led to a diagnosis of diffuse large B cell lymphoma, primarily located in the central nervous system (PCNSL).After the completion of the first phase of treatment (immunotherapy with intravenous Rituximab and corticosteroid), the MRI showed a marked regression of tumor masses. PMID- 25923686 TI - The Xenopus laevis Atg4B Protease: Insights into Substrate Recognition and Application for Tag Removal from Proteins Expressed in Pro- and Eukaryotic Hosts. AB - During autophagy, members of the ubiquitin-like Atg8 protein family get conjugated to phosphatidylethanolamine and act as protein-recruiting scaffolds on the autophagosomal membrane. The Atg4 protease produces mature Atg8 from C terminally extended precursors and deconjugates lipid-bound Atg8. We now found that Xenopus laevis Atg4B (xAtg4B) is ideally suited for proteolytic removal of N terminal tags from recombinant proteins. To implement this strategy, an Atg8 cleavage module is inserted in between tag and target protein. An optimized xAtg4B protease fragment includes the so far uncharacterized C-terminus, which crucially contributes to recognition of the Xenopus Atg8 homologs xLC3B and xGATE16. xAtg4B-mediated tag cleavage is very robust in solution or on-column, efficient at 4 degrees C and orthogonal to TEV protease and the recently introduced proteases bdSENP1, bdNEDP1 and xUsp2. Importantly, xLC3B fusions are stable in wheat germ extract or when expressed in Saccharomyces cerevisiae, but cleavable by xAtg4B during or following purification. We also found that fusions to the bdNEDP1 substrate bdNEDD8 are stable in S. cerevisiae. In combination, or findings now provide a system, where proteins and complexes fused to xLC3B or bdNEDD8 can be expressed in a eukaryotic host and purified by successive affinity capture and proteolytic release steps. PMID- 25923688 TI - Correction: A nutrient-driven tRNA modification alters translational fidelity and genome-wide protein coding across an animal genus. AB - [This corrects the article DOI: 10.1371/journal.pbio.1002015.]. PMID- 25923687 TI - Borna disease virus phosphoprotein impairs the developmental program controlling neurogenesis and reduces human GABAergic neurogenesis. AB - It is well established that persistent viral infection may impair cellular function of specialized cells without overt damage. This concept, when applied to neurotropic viruses, may help to understand certain neurologic and neuropsychiatric diseases. Borna disease virus (BDV) is an excellent example of a persistent virus that targets the brain, impairs neural functions without cell lysis, and ultimately results in neurobehavioral disturbances. Recently, we have shown that BDV infects human neural progenitor cells (hNPCs) and impairs neurogenesis, revealing a new mechanism by which BDV may interfere with brain function. Here, we sought to identify the viral proteins and molecular pathways that are involved. Using lentiviral vectors for expression of the bdv-p and bdv-x viral genes, we demonstrate that the phosphoprotein P, but not the X protein, diminishes human neurogenesis and, more particularly, GABAergic neurogenesis. We further reveal a decrease in pro-neuronal factors known to be involved in neuronal differentiation (ApoE, Noggin, TH and Scg10/Stathmin2), demonstrating that cellular dysfunction is associated with impairment of specific components of the molecular program that controls neurogenesis. Our findings thus provide the first evidence that a viral protein impairs GABAergic human neurogenesis, a process that is dysregulated in several neuropsychiatric disorders. They improve our understanding of the mechanisms by which a persistent virus may interfere with brain development and function in the adult. PMID- 25923689 TI - Molecular Composite Coatings on Nafion Using Layer-by-Layer Self-Assembly. AB - Controlled growth of nanometer-scale multilayered coatings of negatively charged sulfonated poly(benzobisimidazole) (SPBI), complexed with positively charged poly(2-vinylpyridine) (P2VP) on quartz, and Nafion membrane as substrates has been explored. Both polymers, SPBI and P2VP, possess a net charge in methanol as a result of the dissolution of SPBI by complexation with triethylamine (TEA) and the protonation of P2VP with HCl, respectively, and thereby can form a multilayered molecular composite of alternating anionic SPBI and cationic P2VP via an electrostatic layer-by-layer (LbL) self-assembly. UV-vis absorption spectrophotometry was used to monitor the buildup and growth rate of such SPBI/P2VP multilayer films. Atomic force microscopy (AFM) was used to determine the roughness and thickness of the resulting SPBI/P2VP multilayers. As a result, it was found that a steady-state linear growth regime for the LbL self-assembled SPBI/P2VP multilayer films and coatings onto quartz and Nafion membranes was observed after completion of the first few deposition cycles, indicating the successful formation of the SPBI/P2VP multilayered assembly in methanol solutions. In addition, the SPBI/P2VP multilayer films in the perpendicular direction (flat view) demonstrated isotropic orientation distribution on the Nafion membrane, while the SPBI/P2VP multilayer films examined by X-ray scattering in the parallel direction (edge view) revealed anisotropic orientation, the combined observations indicating confinement of SPBI rods to the plane of the coating. We further found that the SPBI/P2VP multilayer coated Nafion possesses good thermal stability, as indicated by isothermal gravimetric analysis at 310 degrees C, and it was further observed that SPBI/P2VP multilayer coatings using the LbL self-assembly technique on Nafion membrane significantly increased the membrane stiffness, despite the small coating thickness employed. PMID- 25923690 TI - Systematic Review and Meta-Analysis of the Relationship between EPHX1 Polymorphisms and the Risk of Head and Neck Cancer. AB - AIM: To evaluate the association between the EPHX1 Tyr113His and His139Arg polymorphisms in the EPHX1 gene and the risk of head and neck cancer. MATERIALS AND METHODS: Studies on the association of EPHX1 Tyr113His and His139Arg polymorphisms with HNC performed up until June 1st, 2014, were identified using a predefined search strategy. Summary odds ratios (ORs) and 95% confidence intervals (CIs) were used to evaluate the strength of these associations. RESULTS: In this meta-analysis, 10 case-control studies, which included 9 studies of Tyr113His (1890 cases and 1894 controls) and 10 studies of His139Arg polymorphisms (1982 cases and 2024 controls), were considered eligible for inclusion. Overall, the pooled results indicated that the EPHX1 Tyr113His polymorphism was significantly associated with increased HNC risk (Tyr/His vs. Tyr/Tyr, OR = 1.26, 95%1.02-1.57;His/His+ Tyr/His vs. Tyr/Tyr, OR = 1.29, 95% I = 1.03-1.61). However, no significant association was found between the His139Arg polymorphism and HNC risk. In the subgroup analysis, a statistically significant association between the EPHX1 Tyr113His polymorphism and HNC was observed in population-based case-control studies (PCC), which involved less than 500 participants and genotype frequencies in HWE. This association showed minimal heterogeneity after excluding studies that were determined to contribute to heterogeneity. After categorizing the studies by publication time, a sensitivity analysis and cumulative meta-analysis of the two associations were conducted, and the results of the two analyses were consistent. CONCLUSION: Our meta-analysis suggests that EPHX1 Tyr113His polymorphism may be a risk factor for HNC, while the EPHX1 His139Arg polymorphism has no association with HNC risk. PMID- 25923691 TI - Household expenditure for dental care in low and middle income countries. AB - This study assessed the extent of household catastrophic expenditure in dental health care and its possible determinants in 41 low and middle income countries. Data from 182,007 respondents aged 18 years and over (69,315 in 18 low income countries, 59,645 in 15 lower middle income countries and 53,047 in 8 upper middle income countries) who participated in the WHO World Health Survey (WHS) were analyzed. Expenditure in dental health care was defined as catastrophic if it was equal to or higher than 40% of the household capacity to pay. A number of individual and country-level factors were assessed as potential determinants of catastrophic dental health expenditure (CDHE) in multilevel logistic regression with individuals nested within countries. Up to 7% of households in low and middle income countries faced CDHE in the last 4 weeks. This proportion rose up to 35% among households that incurred some dental health expenditure within the same period. The multilevel model showed that wealthier, urban and larger households and more economically developed countries had higher odds of facing CDHE. The results of this study show that payments for dental health care can be a considerable burden on households, to the extent of preventing expenditure on basic necessities. They also help characterize households more likely to incur catastrophic expenditure on dental health care. Alternative health care financing strategies and policies targeted to improve fairness in financial contribution are urgently required in low and middle income countries. PMID- 25923692 TI - High-Density Lipoprotein Prevents Endoplasmic Reticulum Stress-Induced Downregulation of Liver LOX-1 Expression. AB - Lectin-like oxidized low-density lipoprotein receptor-1 (LOX-1) is a specific cell-surface receptor for oxidized-low-density lipoprotein (ox-LDL). The impact of high-density lipoprotein (HDL) on endoplasmic reticulum (ER) stress-mediated alteration of the LOX-1 level in hepatocytes remains unclear. We aimed to investigate the impact on LOX-1 expression by tunicamycin (TM)-induced ER stress and to determine the effect of HDL on TM-affected LOX-1 expression in hepatic L02 cells. Overexpression or silencing of related cellular genes was conducted in TM treated cells. mRNA expression was evaluated using real-time polymerase chain reaction (PCR). Protein expression was analyzed by western blot and immunocytochemistry. Lipid uptake was examined by DiI-ox-LDL, followed by flow cytometric analysis. The results showed that TM induced the upregulation of ER chaperone GRP78, downregulation of LOX-1 expression, and lipid uptake. Knock down of IRE1 or XBP-1 effectively restored LOX-1 expression and improved lipid uptake in TM-treated cells. HDL treatment prevented the negative impact on LOX-1 expression and lipid uptake induced by TM. Additionally, 1-10 MUg/mL HDL significantly reduced the GRP78, IRE1, and XBP-1 expression levels in TM-treated cells. Our findings reveal that HDL could prevent the TM-induced reduction of LOX 1 expression via inhibiting the IRE1/XBP-1 pathway, suggesting a new mechanism for beneficial roles of HDL in improving lipid metabolism. PMID- 25923693 TI - Organelle-Specific Nitric Oxide Detection in Living Cells via HaloTag Protein Labeling. AB - Nitric oxide (NO) is a membrane-permeable signaling molecule that is constantly produced, transferred, and consumed in vivo. NO participates and plays important roles in multiple biological processes. However, spatiotemporal imaging of NO in living cells is challenging. To fill the gap in currently used techniques, we exploited the versatility of HaloTag technology and synthesized a novel organelle targetable fluorescent probe called HTDAF-2DA. We demonstrate the utility of the probe by monitoring subcellular NO dynamics. The developed strategy enables precise determination of local NO function. PMID- 25923694 TI - PPARalpha Protein Expression Was Increased by Four Weeks of Intermittent Hypoxic Training via AMPKalpha2-Dependent Manner in Mouse Skeletal Muscle. AB - Peroxisome proliferator-activated receptor alpha (PPARalpha) is critical for muscle endurance due to its role in the regulation of fatty acid oxidation. The 5'-AMP-activated protein kinase (AMPK) is an energy sensor in cells, but its role in PPARalpha regulation in vivo remains unknown. In this study, we examined PPARalpha expression in the skeletal muscle of AMPKalpha2 overexpression (OE), knockout (KO) and wild-type (WT) mice after four weeks of exercise under intermittent hypoxia. WT, OE and KO mice were used at 40 mice/strain and randomly subdivided into four subgroups: control (C), running (R), hypoxia (H), and running plus hypoxia (R+H) at 10 mice/group. The treadmill running was performed at the speed of 12 m/min, 60 min/day with a slope of 0 degree for four weeks. The hypoxia treatment was performed in daytime with normobaric hypoxia (11.20% oxygen, 8 hours/day). In the R+H group, the treadmill running was conducted in the hypoxic condition. AMPKalpha2, phosphor-AMPKalpha (p-AMPKalpha) (Thr172), nuclear PPARalpha proteins were measured by Western blot and the medium chain acyl coenzyme A dehydrogenase (MCAD) mRNA, the key enzyme for fatty acid oxidation and one of the PPARalpha target genes, was also measured in skeletal muscles after the interventions. The results showed that nuclear PPARalpha protein was significantly increased by R+H in WT muscles, the increase was enhanced by 41% (p<0.01) in OE mice, but was reduced by 33% (p<0.01) in KO mice. The MCAD mRNA expression was increased after four weeks of R+H intervention. The change in MCAD mRNA followed a similar trend as that of PPARalpha protein in OE and KO mice. Our data suggest that the increase in nuclear PPARalpha protein by four-week exercise training under the intermittent hypoxia was dependent on AMPK activation. PMID- 25923695 TI - Red squirrel middens influence abundance but not diversity of other vertebrates. AB - Some animals modify the environment in ways that can influence the resources available to other species. Because red squirrels (Tamiasciurus hudsonicus) create large piles of conifer-cone debris (middens) in which they store cones, squirrels concentrate resources that might affect biodiversity locally. To determine whether other animals are attracted to midden sites beyond their affinity for the same resources that attract red squirrels, we assessed associations between middens, mammals, and birds at population and community levels. We surveyed 75 middens where residency rates of red squirrels varied during the previous five years; sampling along this residency gradient permitted us to evaluate the influence of resources at middens beyond the influence of a resident squirrel. At each location, we quantified vegetation, landscape structure, abundance of conifer cones, and midden structure, and used capture recapture, distance sampling, and remote cameras to quantify presence, abundance, and species richness of mammals and birds. Red squirrels and the resources they concentrated at middens influenced mammals and birds at the population scale and to a lesser extent at the community scale. At middens with higher residency rates of red squirrels, richness of medium and large mammals increased markedly and species richness of birds increased slightly. After accounting for local forest characteristics, however, only species richness of medium-to-large mammals was associated with a red squirrel being resident during surveys. In areas where red squirrels were resident during surveys or in areas with greater amounts of resources concentrated by red squirrels, abundances of two of four small mammal species and two of four bird species increased. We conclude that the presence of this ecosystem modifier and the resources it concentrates influence abundance of some mammals and birds, which may have implications for maintaining biodiversity across the wide geographic range inhabited by red squirrels and other larderhoarding animals. PMID- 25923696 TI - Carbon (delta13C) and Nitrogen (delta15N) Stable Isotope Signatures in Bat Fur Indicate Swarming Sites Have Catchment Areas for Bats from Different Summering Areas. AB - Migratory patterns of bats are not well understood and traditional methods to study this, like capture-mark-recapture, may not provide enough detail unless there are many records. Stable isotope profiles of many animal species have been used to make inferences about migration. Each year Myotis lucifugus and M. septentrionalis migrate from summering roosts to swarming caves and mines in the fall, but the pattern of movement between them is not well understood. In this study, fur delta13C and delta15N values of 305 M. lucifugus and 200 M. septentrionalis were analyzed to make inferences about migration patterns between summering areas and swarming sites in Nova Scotia, Canada. We expected that there would be greater variability in delta13C and delta15N among individuals at swarming sites because it was believed that these sites are used by individuals originating from many summering areas. There was extensive overlap in the standard ellipse area, corrected for small sample sizes (SEAc), of bats at swarming sites and much less overlap in SEAc among groups sampled at summering areas. Meaningful inference could not be made on M. septentrionalis because their low variation in SEAc may have been the result of sampling only 3 summering areas. However, for M. lucifugus, swarming sites had larger SEAc than summering areas and predictive discriminant analysis assigned swarming bats to multiple summering areas, supporting the contention that swarming bats are mixed aggregations of bats from several summering areas. Together, these data support the contention that swarming sites have catchment areas for bats from multiple summering areas and it is likely that the catchment areas for swarming sites overlap. These data suggest that delta13C and delta15N profiling of bat fur offer some potential to make inferences about regional migration in bats. PMID- 25923697 TI - A Novel Function of CD82/KAI1 in Sialyl Lewis Antigen-Mediated Adhesion of Cancer Cells: Evidence for an Anti-Metastasis Effect by Down-Regulation of Sialyl Lewis Antigens. AB - We have recently elucidated a novel function for CD82 in E-cadherin-mediated homocellular adhesion; due to this function, it can inhibit cancer cell dissociation from the primary cancer nest and limit metastasis. However, the effect of CD82 on selectin ligand-mediated heterocellular adhesion has not yet been elucidated. In this study, we focused on the effects of the metastasis suppressor CD82/KAI1 on heterocellular adhesion of cancer cells to the endothelium of blood vessels in order to further elucidate the function of tetraspanins. The over-expression of CD82 in cancer cells led to the inhibition of experimentally induced lung metastases in mice and significantly inhibited the adhesion of these cells to human umbilical vein epithelial cells (HUVECs) in vitro. Pre-treatment of the cells with function-perturbing antibodies against sLea/x significantly inhibited the adhesion of CD82-negative cells to HUVECs. In addition, cells over-expressing CD82 exhibited reduced expression of sLea/x compared to CD82-negative wild-type cells. Significant down-regulation of ST3 beta-galactoside alpha-2, 3-sialyltransferase 4 (ST3GAL4) was detected by cDNA microarray, real-time PCR, and western blotting analyses. Knockdown of ST3GAL4 on CD82-negative wild-type cells inhibited expression of sLex and reduced cell adhesion to HUVECs. We concluded that CD82 decreases sLea/x expression via the down-regulation of ST3GAL4 expression and thereby reduces the adhesion of cancer cells to blood vessels, which results in inhibition of metastasis. PMID- 25923698 TI - Development of SSR Markers and Genetic Diversity in White Birch (Betula platyphylla). AB - In order to study genetic diversity of white birch (Betula platyphylla), 544 primer pairs were designed based on the genome-wide Solexa sequences. Among them, 215 primer pairs showed polymorphism between five genotypes and 111 primer pairs that presented clear visible bands in genotyping 41 white birch plants that were collected from 6 different geographical regions. A total of 717 alleles were obtained at 111 loci with a range of 2 to 12 alleles per locus. The results of statistic analysis showed that polymorphic frequency of the alleles ranged from 17% to 100% with a mean of 55.85%; polymorphism information content (PIC) of the loci was from 0.09 to 0.58 with a mean of 0.30; and gene diversity between the tested genotypes was from 0.01 to 0.66 with a mean of 0.36. The results also indicated that major allele frequency ranged from 0.39 to 1.00 with an mean of 0.75; expected heterozygosity from 0.22 to 0.54 with a mean of 0.46; observed heterozygosity from 0.02 to 0.95 with a mean of 0.26; Nei's index from 0.21 to 0.54 with a mean of 0.46; and Shannon's Information from 0.26 to 0.87 with a mean of 0.66. The 41 white birch genotypes at the 111 selected SSR loci showed low to moderate similarity (0.025-0.610), indicating complicated genetic diversity among the white birch collections. The UPGMA-based clustering analysis of the allelic constitution of 41 white birch genotypes at 111 SSR loci suggested that the six different geographical regions can be further separated into four clusters at a similarity coefficient of 0.22. Genotypes from Huanren and Liangshui provenances were grouped into Cluster I, genotypes from Xiaobeihu and Qingyuan provenances into Cluster II, genotypes from Finland provenance into Cluster III, and genotypes from Maoershan into Cluster IV. The information provided in this study could help for genetic improvement and germplasm conservation, evaluation and utilization in white birch tree breeding program. PMID- 25923699 TI - Normative database of retinal oximetry in Asian Indian eyes. AB - OBJECTIVE: To study the oxygen saturation profile in normal Asian Indian eyes. DESIGN: A cross sectional prospective study. SUBJECTS: Ninety eight consecutive patients presenting to our hospital with best corrected distance visual acuity (BCVA) of 20/20 and a normal ophthalmic examination were included in the study. Patients having any ocular or systemic disease were excluded from the study. MATERIALS AND METHODS: Oximetry was performed on all subjects with the Oxymap T1 retinal oximeter (Oxymap hf, Reykjavik, Iceland). MAIN OUTCOME MEASURES: The images were analysed for oxygen saturation and diameter. RESULTS: The mean age was 33 years (Range: 18-63; SD: 12.4). The average arteriolar saturation was 90.3 +/- 6.6% and the venous saturation was 56.9% +/- 6.3. The average A-V (arterio venous) difference was 33.2% +/- 5.2. There was an increase in arteriolar (R2 = 0.264; p=0.001) and venous saturation (R2 = 0.151; p=0.001) with age. There was no significant change in the arterio-venous saturation difference (AVSD). The inferotemporal quadrant had the lowest saturations. Age correlated positively with ocular perfusion pressure (OPP)(R2 = 0.07; p=0.007). OPP correlated positively with global arteriolar saturation (R2=0.057, p=0.018). CONCLUSION: This study provides the normative database for an Indian population and is comparable to previous studies. Age, vessel diameter and OPP were the significant factors that influenced the saturation. Arteriolar and venous saturations increased with age while the AVSD did not change significantly. PMID- 25923700 TI - Month 2 culture status and treatment duration as predictors of recurrence in pulmonary tuberculosis: model validation and update. AB - BACKGROUND: New regimens capable of shortening tuberculosis treatment without increasing the risk of recurrence are urgently needed. A 2013 meta-regression analysis, using data from trials published from 1973 to 1997 involving 7793 patients, identified 2-month sputum culture status and treatment duration as independent predictors of recurrence. The resulting model predicted that if a new 4-month regimen reduced the proportion of patients positive at month 2 to 1%, it would reduce to 10% the risk of a relapse rate >10% in a trial with 680 subjects per arm. The 1% target was far lower than anticipated. METHODS: Data from the 8 arms of 3 recent unsuccessful phase 3 treatment-shortening trials of fluoroquinolone-substituted regimens (REMox, OFLOTUB, and RIFAQUIN) were used to assess and refine the accuracy of the 2013 meta-regression model. The updated model was then tested using data from a treatment shortening trial reported in 2009 by Johnson et al. FINDINGS: The proportions of patients with recurrence as predicted by the 2013 model were highly correlated with observed proportions as reported in the literature (R2 = 0.86). Using the previously proposed threshold of 10% recurrences as the maximum likely considered acceptable by tuberculosis control programs, the original model correctly identified all 4 six-month regimens as satisfactory, and 3 of 4 four-month regimens as unsatisfactory (sensitivity = 100%, specificity = 75%, PPV = 80%, and NPV = 100%). A revision of the regression model based on the full dataset of 66 regimens and 11181 patients resulted in only minimal changes to its predictions. A test of the revised model using data from the treatment shortening trial of Johnson et al found the reported relapse rates in both arms to be consistent with predictions. INTERPRETATION: Meta-regression modeling of recurrence based on month 2 culture status and regimen duration can inform the design of future phase 3 tuberculosis clinical trials. PMID- 25923701 TI - STAT3 Decoy Oligodeoxynucleotides-Loaded Solid Lipid Nanoparticles Induce Cell Death and Inhibit Invasion in Ovarian Cancer Cells. AB - Recent advances in the synthesis of multi-functional nanoparticles have opened up tremendous opportunities for the targeted delivery of genes of interest. Cationic solid lipid nanoparticles (SLN) can efficiently bind nucleic acid molecules and transfect genes in vitro. Few reports have combined SLN with therapy using decoy oligodeoxynucleotides (ODN). In the present study, we prepared SLN to encapsulate STAT3 decoy ODN; then, the properties and in vitro behavior of SLN-STAT3 decoy ODN complexes were investigated. SLN-STAT3 decoy ODN complexes were efficiently taken up by human ovarian cancer cells and significantly suppressed cell growth. Blockage of the STAT3 pathway by SLN-STAT3 decoy ODN complexes resulted in an evident induction of cell death, including apoptotic and autophagic death. The mechanism involved the increased expression of cleaved caspase 3, Bax, Beclin-1 and LC3-II and reduced expression of Bcl-2, pro-caspase 3, Survivin, p-Akt and p mTOR. In addition, SLN-STAT3 decoy ODN complexes inhibited cell invasion by up regulating E-cadherin expression and down-regulating Snail and MMP-9 expression. These findings confirmed that SLN as STAT3 decoy ODN carriers can induce cell death and inhibit invasion of ovarian cancer cells. We propose that SLN represent a potential approach for targeted gene delivery in cancer therapy. PMID- 25923702 TI - Changes in the pulmonary function test after radioactive iodine treatment in patients with pulmonary metastases of differentiated thyroid cancer. AB - OBJECTIVE: Pulmonary function test (PFT) is a useful tool for an objective assessment of respiratory function. Impaired pulmonary function is critical for the survival and quality of life in patients with pulmonary metastases of solid cancers including thyroid cancer. This study aimed to evaluate clinical factors associated with severely impaired pulmonary function by serial assessment with PFT in patients with pulmonary metastasis of differentiated thyroid cancer (DTC) who received radioactive iodine treatment (RAIT). PATIENTS: This retrospective study enrolled 31 patients who underwent serial PFTs before and after RAIT for pulmonary metastasis of DTC. We evaluated the risk factors for severe impairment of pulmonary function. RESULTS: The median age of the patients was 44.1 years and 18 of them were female patients. Severe impairment of pulmonary function was observed in five patients (16%) after a median of three RAITs (cumulative I-131 activity = 20.4 GBq). These patients were older and more frequently had mild impairment of baseline pulmonary function, respiratory symptoms, or progressive disease compared with patients with stable pulmonary function. Neither cumulative dose nor number of RAIT was associated with decreased pulmonary function. Coexisting pulmonary diseases, presence of respiratory symptoms, and metastatic disease progression were significantly associated with severe decrease in forced vital capacity during follow-up (p =.047, p =.011, and p =.021, respectively). CONCLUSIONS: Pulmonary function was severely impaired during follow-up in some patients with pulmonary metastasis of DTC after a high-dose RAITs. Neither the number of RAIT nor the cumulative I-131 activity was associated with decreased pulmonary function. Serial PFT might be considered for some high-risk patients during follow-up. PMID- 25923703 TI - Three-Dimensional Gradients of Cytokine Signaling between T Cells. AB - Immune responses are regulated by diffusible mediators, the cytokines, which act at sub-nanomolar concentrations. The spatial range of cytokine communication is a crucial, yet poorly understood, functional property. Both containment of cytokine action in narrow junctions between immune cells (immunological synapses) and global signaling throughout entire lymph nodes have been proposed, but the conditions under which they might occur are not clear. Here we analyze spatially three-dimensional reaction-diffusion models for the dynamics of cytokine signaling at two successive scales: in immunological synapses and in dense multicellular environments. For realistic parameter values, we observe local spatial gradients, with the cytokine concentration around secreting cells decaying sharply across only a few cell diameters. Focusing on the well characterized T-cell cytokine interleukin-2, we show how cytokine secretion and competitive uptake determine this signaling range. Uptake is shaped locally by the geometry of the immunological synapse. However, even for narrow synapses, which favor intrasynaptic cytokine consumption, escape fluxes into the extrasynaptic space are expected to be substantial (>=20% of secretion). Hence paracrine signaling will generally extend beyond the synapse but can be limited to cellular microenvironments through uptake by target cells or strong competitors, such as regulatory T cells. By contrast, long-range cytokine signaling requires a high density of cytokine producers or weak consumption (e.g., by sparsely distributed target cells). Thus in a physiological setting, cytokine gradients between cells, and not bulk-phase concentrations, are crucial for cell-to-cell communication, emphasizing the need for spatially resolved data on cytokine signaling. PMID- 25923705 TI - Evidence for Patterns of Selective Urban Migration in the Greater Indus Valley (2600-1900 BC): A Lead and Strontium Isotope Mortuary Analysis. AB - Just as modern nation-states struggle to manage the cultural and economic impacts of migration, ancient civilizations dealt with similar external pressures and set policies to regulate people's movements. In one of the earliest urban societies, the Indus Civilization, mechanisms linking city populations to hinterland groups remain enigmatic in the absence of written documents. However, isotopic data from human tooth enamel associated with Harappa Phase (2600-1900 BC) cemetery burials at Harappa (Pakistan) and Farmana (India) provide individual biogeochemical life histories of migration. Strontium and lead isotope ratios allow us to reinterpret the Indus tradition of cemetery inhumation as part of a specific and highly regulated institution of migration. Intra-individual isotopic shifts are consistent with immigration from resource-rich hinterlands during childhood. Furthermore, mortuary populations formed over hundreds of years and composed almost entirely of first-generation immigrants suggest that inhumation was the final step in a process linking certain urban Indus communities to diverse hinterland groups. Additional multi disciplinary analyses are warranted to confirm inferred patterns of Indus mobility, but the available isotopic data suggest that efforts to classify and regulate human movement in the ancient Indus region likely helped structure socioeconomic integration across an ethnically diverse landscape. PMID- 25923704 TI - Sigma Factor SigB Is Crucial to Mediate Staphylococcus aureus Adaptation during Chronic Infections. AB - Staphylococcus aureus is a major human pathogen that causes a range of infections from acute invasive to chronic and difficult-to-treat. Infection strategies associated with persisting S. aureus infections are bacterial host cell invasion and the bacterial ability to dynamically change phenotypes from the aggressive wild-type to small colony variants (SCVs), which are adapted for intracellular long-term persistence. The underlying mechanisms of the bacterial switching and adaptation mechanisms appear to be very dynamic, but are largely unknown. Here, we analyzed the role and the crosstalk of the global S. aureus regulators agr, sarA and SigB by generating single, double and triple mutants, and testing them with proteome analysis and in different in vitro and in vivo infection models. We were able to demonstrate that SigB is the crucial factor for adaptation in chronic infections. During acute infection, the bacteria require the simultaneous action of the agr and sarA loci to defend against invading immune cells by causing inflammation and cytotoxicity and to escape from phagosomes in their host cells that enable them to settle an infection at high bacterial density. To persist intracellularly the bacteria subsequently need to silence agr and sarA. Indeed agr and sarA deletion mutants expressed a much lower number of virulence factors and could persist at high numbers intracellularly. SigB plays a crucial function to promote bacterial intracellular persistence. In fact, DeltasigB mutants did not generate SCVs and were completely cleared by the host cells within a few days. In this study we identified SigB as an essential factor that enables the bacteria to switch from the highly aggressive phenotype that settles an acute infection to a silent SCV-phenotype that allows for long-term intracellular persistence. Consequently, the SigB-operon represents a possible target to develop preventive and therapeutic strategies against chronic and therapy-refractory infections. PMID- 25923706 TI - Clinical features of children with pulmonary microscopic polyangiitis: report of 9 cases. AB - Kidneys and lungs are the most common organs involved in microscopic polyangiitis (MPA). A retrospective analysis of pediatric MPA patients with pulmonary lesions over the past 10 years was performed to investigate clinical features of MPA in children with pulmonary lesions. There were 9 patients enrolled in our study, including 2 boys and 7 girls, with a median age of 6.6 years at the time of disease onset and a median disease course of 2 months. All of the patients exhibited tachypnea, and 7 exhibited cough and hemoptysis. The most common presentation on pulmonary imaging was ground glass or patchy shadows, which were observed in 6 cases. Seven patients manifested with hematuria and proteinuria, with renal histopathology of fibrinoid necrosis/exudation of the glomerular capillaries. All of the patients presented with normocytic normochromic anemia. Of the 9 patients, 7 were positive for perinuclear antineutrophil cytoplasmic antibody (p-ANCA) and/or myeloperoxidase (MPO), and 2 were positive for p ANCA/MPO and cytoplasmic ANCA/proteinase 3. Eight patients had normal complement 3 (C3) levels, and one had an elevated C3 level. Five of the 9 patients were positive for antinuclear antibody ANA, and 4 were positive for double strand DNA (ds-DNA) antibody (3 were positive for both). The 7 patients who exhibited renal involvement received steroid plus cyclophosphamide (CTX) treatment. Of these patients, 4 achieved various degrees of remission, 2 were at the beginning of induction therapy, and one was lost to follow-up. Two patients with isolated pulmonary involvement received steroid plus leflunomide treatment and achieved complete remission. Diffuse alveolar hemorrhage was the most frequent presentation of lung involvement in children with MPA, and tachypnea, cough, hemoptysis and anemia were the common clinical symptoms. The majority of these patients exhibited hematuria, proteinuria and renal insufficiency. The efficacy of steroid plus CTX or leflunomide was evident in these patients. PMID- 25923707 TI - Isolation of Human Neural Stem Cells from the Amniotic Fluid with Diagnosed Neural Tube Defects. AB - Human neural stem cells (NSCs) are particularly valuable for the study of neurogenesis process and have a therapeutic potential in treating neurodegenerative disorders. However, current progress in the use of human NSCs is limited due to the available NSC sources and the complicated isolation and culture techniques. In this study, we describe an efficient method to isolate and propagate human NSCs from the amniotic fluid with diagnosed neural tube defects (NTDs), specifically, anencephaly. These amniotic fluid-derived NSCs (AF-NSCs) formed neurospheres and underwent long-term expansion in vitro. In addition, these cells showed normal karyotypes and telomerase activity and expressed NSC specific markers, including Nestin, Sox2, Musashi-1, and the ATP-binding cassette G2 (ABCG2). AF-NSCs displayed typical morphological patterns and expressed specific markers that were consistent with neurons, astrocytes, oligodendrocytes, and dopaminergic neurons after proper induction conditions. Furthermore, grafted AF-NSCs improved the physiological functions in a rat stroke model. The ability to isolate and bank human NSCs from this novel source provides a unique opportunity for translational studies of neurological disorders. PMID- 25923709 TI - A next generation semiconductor based sequencing approach for the identification of meat species in DNA mixtures. AB - The identification of the species of origin of meat and meat products is an important issue to prevent and detect frauds that might have economic, ethical and health implications. In this paper we evaluated the potential of the next generation semiconductor based sequencing technology (Ion Torrent Personal Genome Machine) for the identification of DNA from meat species (pig, horse, cattle, sheep, rabbit, chicken, turkey, pheasant, duck, goose and pigeon) as well as from human and rat in DNA mixtures through the sequencing of PCR products obtained from different couples of universal primers that amplify 12S and 16S rRNA mitochondrial DNA genes. Six libraries were produced including PCR products obtained separately from 13 species or from DNA mixtures containing DNA from all species or only avian or only mammalian species at equimolar concentration or at 1:10 or 1:50 ratios for pig and horse DNA. Sequencing obtained a total of 33,294,511 called nucleotides of which 29,109,688 with Q20 (87.43%) in a total of 215,944 reads. Different alignment algorithms were used to assign the species based on sequence data. Error rate calculated after confirmation of the obtained sequences by Sanger sequencing ranged from 0.0003 to 0.02 for the different species. Correlation about the number of reads per species between different libraries was high for mammalian species (0.97) and lower for avian species (0.70). PCR competition limited the efficiency of amplification and sequencing for avian species for some primer pairs. Detection of low level of pig and horse DNA was possible with reads obtained from different primer pairs. The sequencing of the products obtained from different universal PCR primers could be a useful strategy to overcome potential problems of amplification. Based on these results, the Ion Torrent technology can be applied for the identification of meat species in DNA mixtures. PMID- 25923710 TI - Revealing the Hierarchical Mechanical Strength of Single Cellulose Acetate Electrospun Filaments through Ultrasonic Breakage. AB - The tensile strength of single cellulose acetate electrospun fibers is determined through sonication-induced fragmentation in water using a model previously developed by Terentjev and co-workers. The fragmentation of the electrospun fibers results in a gradual shortening of their length until a constant modal length is achieved. A single electrospun CA fiber tensile strength of ~ 150 MPa (55-280 MPa) is determined based on fracture statistics. It is also observed that the fragmented fibers show bunches of nanofilaments at their ends with similar diameters to those of round structures observed in the cross-section of the initial electrospun fibers (~ 38 nm). The sonication of these nanofilaments gives rise to spherical particles with similar diameter dimensions, which allows the estimation of a value of the tensile strength of the order of 2 MPa for these nanostructures. The aggregation and the alignment of the nano filaments inside the electrospun fiber should be the source of its higher strength value. PMID- 25923708 TI - Blastocystis Isolates from Patients with Irritable Bowel Syndrome and from Asymptomatic Carriers Exhibit Similar Parasitological Loads, but Significantly Different Generation Times and Genetic Variability across Multiple Subtypes. AB - Blastocystis spp is a common intestinal parasite of humans and animals that has been associated to the etiology of irritable bowel syndrome (IBS); however, some studies have not found this association. Furthermore, many biological features of Blastocystis are little known. The objective of present study was to assess the generation times of Blastocystis cultures, from IBS patients and from asymptomatic carriers. A total of 100 isolates were obtained from 50 IBS patients and from 50 asymptomatic carriers. Up to 50 mg of feces from each participant were cultured in Barret's and in Pavlova's media during 48 h. Initial and final parasitological load were measured by microscopy and by quantitative PCR. Amplicons were purified, sequenced and submitted to GenBank; sequences were analysed for genetic diversity and a Bayesian inference allowed identifying genetic subtypes (ST). Generation times for Blastocystis isolates in both media, based on microscopic measures and molecular assays, were calculated. The clinical symptoms of IBS patients and distribution of Blastocystis ST 1, 2 and 3 in both groups was comparable to previous reports. Interestingly, the group of cases showed scarce mean nucleotide diversity (pi) as compared to the control group (0.011+/-0.016 and 0.118+/-0.177, respectively), whilst high gene flow and small genetic differentiation indexes between different ST were found. Besides, Tajima's D test showed negative values for ST1-ST3. No statistical differences regarding parasitological load between cases and controls in both media, as searched by microscopy and by qPCR, were detected except that parasites grew faster in Barret's than in Pavlova's medium. Interestingly, slow growth of isolates recovered from cases in comparison to those of controls was observed (p<0.05). We propose that generation times of Blastocystis might be easily affected by intestinal environmental changes due to IBS probably because virulent strains with slow growth may be selected, reducing their genetic variability. PMID- 25923711 TI - Ex situ conservation priorities for the wild relatives of potato (solanum L. Section petota). AB - Crop wild relatives have a long history of use in potato breeding, particularly for pest and disease resistance, and are expected to be increasingly used in the search for tolerance to biotic and abiotic stresses. Their current and future use in crop improvement depends on their availability in ex situ germplasm collections. As these plants are impacted in the wild by habitat destruction and climate change, actions to ensure their conservation ex situ become ever more urgent. We analyzed the state of ex situ conservation of 73 of the closest wild relatives of potato (Solanum section Petota) with the aim of establishing priorities for further collecting to fill important gaps in germplasm collections. A total of 32 species (43.8%), were assigned high priority for further collecting due to severe gaps in their ex situ collections. Such gaps are most pronounced in the geographic center of diversity of the wild relatives in Peru. A total of 20 and 18 species were assessed as medium and low priority for further collecting, respectively, with only three species determined to be sufficiently represented currently. Priorities for further collecting include: (i) species completely lacking representation in germplasm collections; (ii) other high priority taxa, with geographic emphasis on the center of species diversity; (iii) medium priority species. Such collecting efforts combined with further emphasis on improving ex situ conservation technologies and methods, performing genotypic and phenotypic characterization of wild relative diversity, monitoring wild populations in situ, and making conserved wild relatives and their associated data accessible to the global research community, represent key steps in ensuring the long-term availability of the wild genetic resources of this important crop. PMID- 25923712 TI - Hydrological response to land cover changes and human activities in arid regions using a geographic information system and remote sensing. AB - The hydrological response to land cover changes induced by human activities in arid regions has attracted increased research interest in recent decades. The study reported herein assessed the spatial and quantitative changes in surface runoff resulting from land cover change in the Al-Baha region of Saudi Arabia between 1990 and 2000 using an ArcGIS-surface runoff model and predicted land cover and surface runoff depth in 2030 using Markov chain analysis. Land cover maps for 1990 and 2000 were derived from satellite images using ArcGIS 10.1. The findings reveal a 26% decrease in forest and shrubland area, 28% increase in irrigated cropland, 1.5% increase in sparsely vegetated land and 0.5% increase in bare soil between 1990 and 2000. Overall, land cover changes resulted in a significant decrease in runoff depth values in most of the region. The decrease in surface runoff depth ranged from 25-106 mm/year in a 7020-km2 area, whereas the increase in such depth reached only 10 mm/year in a 243-km2 area. A maximum increase of 73 mm/year was seen in a limited area. The surface runoff depth decreased to the greatest extent in the central region of the study area due to the huge transition in land cover classes associated with the construction of 25 rainwater harvesting dams. The land cover prediction revealed a greater than twofold increase in irrigated cropland during the 2000-2030 period, whereas forest and shrubland are anticipated to occupy just 225 km2 of land area by 2030, a significant decrease from the 747 km2 they occupied in 2000. Overall, changes in land cover are predicted to result in an annual increase in irrigated cropland and dramatic decline in forest area in the study area over the next few decades. The increase in surface runoff depth is likely to have significant implications for irrigation activities. PMID- 25923713 TI - Improving the oxidative stability of a high redox potential fungal peroxidase by rational design. AB - Ligninolytic peroxidases are enzymes of biotechnological interest due to their ability to oxidize high redox potential aromatic compounds, including the recalcitrant lignin polymer. However, different obstacles prevent their use in industrial and environmental applications, including low stability towards their natural oxidizing-substrate H2O2. In this work, versatile peroxidase was taken as a model ligninolytic peroxidase, its oxidative inactivation by H2O2 was studied and different strategies were evaluated with the aim of improving H2O2 stability. Oxidation of the methionine residues was produced during enzyme inactivation by H2O2 excess. Substitution of these residues, located near the heme cofactor and the catalytic tryptophan, rendered a variant with a 7.8-fold decreased oxidative inactivation rate. A second strategy consisted in mutating two residues (Thr45 and Ile103) near the catalytic distal histidine with the aim of modifying the reactivity of the enzyme with H2O2. The T45A/I103T variant showed a 2.9-fold slower reaction rate with H2O2 and 2.8-fold enhanced oxidative stability. Finally, both strategies were combined in the T45A/I103T/M152F/M262F/M265L variant, whose stability in the presence of H2O2 was improved 11.7-fold. This variant showed an increased half-life, over 30 min compared with 3.4 min of the native enzyme, under an excess of 2000 equivalents of H2O2. Interestingly, the stability improvement achieved was related with slower formation, subsequent stabilization and slower bleaching of the enzyme Compound III, a peroxidase intermediate that is not part of the catalytic cycle and leads to the inactivation of the enzyme. PMID- 25923714 TI - Sequence Analysis of Insecticide Action and Detoxification-Related Genes in the Insect Pest Natural Enemy Pardosa pseudoannulata. AB - The pond wolf spider Pardosa pseudoannulata, an important natural predatory enemy of rice planthoppers, is found widely distributed in paddy fields. However, data on the genes involved in insecticide action, detoxification, and response are very limited for P. pseudoannulata, which inhibits the development and appropriate use of selective insecticides to control insect pests on rice. We used transcriptome construction from adult spider cephalothoraxes to analyze and manually identify genes enconding metabolic enzymes and target receptors related to insecticide action and detoxification, including 90 cytochrome P450s, 14 glutathione S-transferases (GSTs), 17 acetylcholinesterases (AChEs), 17 nicotinic acetylcholine receptors (nAChRs), and 17 gamma-aminobutyric acid (GABA) receptors, as well as 12 glutamate-gated chloride channel (GluCl) unigenes. Sequence alignment and phylogenetic analysis revealed the different subclassifications of P450s and GSTs, some important sequence diversities in nAChRs and GABA receptors, polymorphism in AChEs, and high similarities in GluCls. For P450s in P. pseudoannulata, the number of unigenes belonging to the CYP2 clade was much higher than that in CYP3 and CYP4 clades. The results differed from insects in which most P450 genes were in CYP3 and CYP4 clades. For GSTs, most unigenes belonged to the delta and sigma classes, and no epsilon GST class gene was found, which differed from the findings for insects and acarina. Our results will be useful for studies on insecticide action, selectivity, and detoxification in the spider and other related animals, and the sequence differences in target genes between the spider and insects will provide important information for the design of selective insecticides. PMID- 25923715 TI - Metabolic activity and functional diversity changes in sediment prokaryotic communities organically enriched with mussel biodeposits. AB - This experimental microcosm study reports the influence of organic enrichments by mussel biodeposits on the metabolic activity and functional diversity of benthic prokaryotic communities. The different biodeposit enrichment regimes created, which mimicked the quantity of faeces and pseudo-faeces potentially deposited below mussel farms, show a clear stimulatory effect of this organic enrichment on prokaryotic metabolic activity. This effect was detected once a certain level of biodeposition was attained with a tipping point estimated between 3.25 and 10 g day-1 m-2. Prokaryotic communities recovered their initial metabolic activity by 11 days after the cessation of biodeposit additions. However, their functional diversity remained greater than prior to the disturbance suggesting that mussel biodeposit enrichment may disturb the functioning and perhaps the role of prokaryotic communities in benthic ecosystems. This manipulative approach provided new information on the influence of mussel biodeposition on benthic prokaryotic communities and dose-response relationships and may support the development of carrying capacity models for bivalve culture. PMID- 25923717 TI - Fundamental measure theory for the electric double layer: implications for blue energy harvesting and water desalination. AB - Capacitive mixing (CAPMIX) and capacitive deionization (CDI) are promising candidates for harvesting clean, renewable energy and for the energy efficient production of potable water, respectively. Both CAPMIX and CDI involve water immersed porous carbon (supercapacitors) electrodes at voltages of the order of hundreds of millivolts, such that counter-ionic packing is important for the electric double layer (EDL) which forms near the surfaces of these porous materials. Thus, we propose a density functional theory (DFT) to model the EDL, where the White-Bear mark II fundamental measure theory functional is combined with a mean-field Coulombic and a mean spherical approximation-type correction to describe the interplay between dense packing and electrostatics, in good agreement with molecular dynamics simulations. We discuss the concentration dependent potential rise due to changes in the chemical potential in capacitors in the context of an over-ideal theoretical description and its impact on energy harvesting and water desalination. Compared to less elaborate mean-field models our DFT calculations reveal a higher work output for blue-energy cycles and a higher energy demand for desalination cycles. PMID- 25923716 TI - Corn Yield and Soil Nitrous Oxide Emission under Different Fertilizer and Soil Management: A Three-Year Field Experiment in Middle Tennessee. AB - BACKGROUND: A three-year field experiment was conducted to examine the responses of corn yield and soil nitrous oxide (N2O) emission to various management practices in middle Tennessee. METHODOLOGY/PRINCIPAL FINDINGS: The management practices include no-tillage + regular applications of urea ammonium nitrate (NT URAN); no-tillage + regular applications of URAN + denitrification inhibitor (NT inhibitor); no-tillage + regular applications of URAN + biochar (NT-biochar); no tillage + 20% applications of URAN + chicken litter (NT-litter), no-tillage + split applications of URAN (NT-split); and conventional tillage + regular applications of URAN as a control (CT-URAN). Fertilizer equivalent to 217 kg N ha(-1) was applied to each of the experimental plots. Results showed that no tillage (NT-URAN) significantly increased corn yield by 28% over the conventional tillage (CT-URAN) due to soil water conservation. The management practices significantly altered soil N2O emission, with the highest in the CT-URAN (0.48 mg N2O m(-2) h(-1)) and the lowest in the NT-inhibitor (0.20 mg N2O m(-2) h(-1)) and NT-biochar (0.16 mg N2O m(-2) h(-1)) treatments. Significant exponential relationships between soil N2O emission and water filled pore space were revealed in all treatments. However, variations in soil N2O emission among the treatments were positively correlated with the moisture sensitivity of soil N2O emission that likely reflects an interactive effect between soil properties and WFPS. CONCLUSION/SIGNIFICANCE: Our results indicated that improved fertilizer and soil management have the potential to maintain highly productive corn yield while reducing greenhouse gas emissions. PMID- 25923718 TI - Repetitive transcranial magnetic stimulation in cervical dystonia: effect of site and repetition in a randomized pilot trial. AB - Dystonia is characterized by abnormal posturing due to sustained muscle contraction, which leads to pain and significant disability. New therapeutic targets are needed in this disorder. The objective of this randomized, sham controlled, blinded exploratory study is to identify a specific motor system target for non-invasive neuromodulation and to evaluate this target in terms of safety and tolerability in the cervical dystonia (CD) population. Eight CD subjects were given 15-minute sessions of low-frequency (0.2 Hz) repetitive transcranial magnetic stimulation (rTMS) over the primary motor cortex (MC), dorsal premotor cortex (dPM), supplementary motor area (SMA), anterior cingulate cortex (ACC) and a sham condition with each session separated by at least two days. The Toronto Western Spasmodic Torticollis Rating Scale (TWSTRS) score was rated in a blinded fashion immediately pre- and post-intervention. Secondary outcomes included physiology and tolerability ratings. The mean change in TWSTRS severity score by site was 0.25 +/- 1.7 (ACC), -2.9 +/- 3.4 (dPM), -3.0 +/- 4.8 (MC), -0.5 +/- 1.1 (SHAM), and -1.5 +/- 3.2 (SMA) with negative numbers indicating improvement in symptom control. TWSTRS scores decreased from Session 1 (15.1 +/- 5.1) to Session 5 (11.0 +/- 7.6). The treatment was tolerable and safe. Physiology data were acquired on 6 of 8 subjects and showed no change over time. These results suggest rTMS can modulate CD symptoms. Both dPM and MC are areas to be targeted in further rTMS studies. The improvement in TWSTRS scores over time with multiple rTMS sessions deserves further evaluation. PMID- 25923719 TI - Assessment of robotic patient simulators for training in manual physical therapy examination techniques. AB - Robots that simulate patients suffering from joint resistance caused by biomechanical and neural impairments are used to aid the training of physical therapists in manual examination techniques. However, there are few methods for assessing such robots. This article proposes two types of assessment measures based on typical judgments of clinicians. One of the measures involves the evaluation of how well the simulator presents different severities of a specified disease. Experienced clinicians were requested to rate the simulated symptoms in terms of severity, and the consistency of their ratings was used as a performance measure. The other measure involves the evaluation of how well the simulator presents different types of symptoms. In this case, the clinicians were requested to classify the simulated resistances in terms of symptom type, and the average ratios of their answers were used as performance measures. For both types of assessment measures, a higher index implied higher agreement among the experienced clinicians that subjectively assessed the symptoms based on typical symptom features. We applied these two assessment methods to a patient knee robot and achieved positive appraisals. The assessment measures have potential for use in comparing several patient simulators for training physical therapists, rather than as absolute indices for developing a standard. PMID- 25923720 TI - Real-Time Observation of Morphological Transformations in II-VI Semiconducting Nanobelts via Environmental Transmission Electron Microscopy. AB - It has been observed that wurtzite II-VI semiconducting nanobelts transform into single-crystal, periodically branched nanostructures upon heating. The mechanism of this novel transformation has been elucidated by heating II-VI nanobelts in an environmental transmission electron microscope (ETEM) in oxidizing, reducing, and inert atmospheres while observing their structural changes with high spatial resolution. The interplay of surface reconstruction of high-energy surfaces of the wurtzite phase and environment-dependent anisotropic chemical etching of certain crystal surfaces in the branching mechanism of nanobelts has been observed. Understanding of structural and chemical transformations of materials via in situ microscopy techniques and their role in designing new nanostructured materials is discussed. PMID- 25923721 TI - Surfactant-adsorption-induced initial depinning behavior in evaporating water and nanofluid sessile droplets. AB - A surfactant-induced autophobic effect has been observed to initiate an intense depinning behavior at the initial stage of evaporation in both pure water and nanofluid sessile droplets. The cationic surfactant adsorbing to the negatively charged silicon wafer makes the solid surface more hydrophobic. The autophobing induced depinning behavior, leading to an enlarged contact angle and a shortened base diameter, takes place only when the surfactant concentration is below its critical micelle concentration (cmc). The initial spreading degree right before the droplet retraction, the retracting velocity of the contact line, and the duration of the initial droplet retraction are shown to depend negatively on the surfactant concentration below the cmc. An unexpected enhancement in the initial depinning has been found in the nanofluid droplets, possibly resulting from the hydrophilic interplay between the graphite nanoparticle deposition and the surfactant molecules. Such promotion of the initial depinning due to the nanoparticle deposition makes the droplet retract even at a surfactant concentration higher than the cmc (1.5 cmc). The resulting deposition formed in the presence of the depinning behavior has great enhancement for coffee-ring formation as compared to the one free of surfactant, implying that the formation of a coffee ring does not require the pinning of the contact line during the entire drying process. PMID- 25923722 TI - Carbon Dioxide Concentrations and Temperatures within Tour Buses under Real-Time Traffic Conditions. AB - This study monitored the carbon dioxide (CO2) concentrations and temperatures of three 43-seat tour buses with high-passenger capacities in a course of a three day, two-night school excursion. Results showed that both driver zones and passenger zones of the tour buses achieved maximum CO2 concentrations of more than 3000 ppm, and maximum daily average concentrations of 2510.6 and 2646.9 ppm, respectively. The findings confirmed that the CO2 concentrations detected in the tour buses exceeded the indoor air quality standard of Taiwan Environmental Protection Administration (8 hr-CO2: 1000 ppm) and the air quality guideline of Hong Kong Environmental Protection Department (1 hr-CO2: 2500 ppm for Level 1 for buses). Observations also showed that high-capacity tour bus cabins with air conditioning system operating in recirculation mode are severely lacking in air exchange rate, which may negatively impact transportation safety. Moreover, the passenger zones were able to maintain a temperature of between 20 and 25 degrees C during travel, which effectively suppresses the dispersion of volatile organic compounds. Finally, the authors suggest that in the journey, increasing the ventilation frequency of tour bus cabin, which is very beneficial to maintain the travel safety and enhance the quality of travel. PMID- 25923723 TI - Optineurin regulates the interferon response in a cell cycle-dependent manner. AB - Viral invasion into a host is initially recognized by the innate immune system, mainly through activation of the intracellular cytosolic signaling pathway and coordinated activation of interferon regulatory factor 3 (IRF3) and nuclear factor kappa B (NF-kappaB) transcription factors that promote type I interferon gene induction. The TANK-binding Kinase 1 (TBK1) phosphorylates and activates IRF3. Here, we show that Optineurin (Optn) dampens the antiviral innate immune response by targeting the deubiquitinating enzyme CYLD to TBK1 in order to inhibit its enzymatic activity. Importantly, we found that this regulatory mechanism is abolished at the G2/M phase as a consequence of the nuclear translocation of CYLD and Optn. As a result, we observed, at this cell division stage, an increased activity and phosphorylation of TBK1 that lead to its relocalization to mitochondria and to enhanced interferon production, suggesting that this process, which relies on Optn function, might be of major importance to mount a preventive antiviral response during mitosis. PMID- 25923725 TI - Discerning pig screams in production environments. AB - Pig vocalisations convey information about their current state of health and welfare. Continuously monitoring these vocalisations can provide useful information for the farmer. For instance, pig screams can indicate stressful situations. When monitoring screams, other sounds can interfere with scream detection. Therefore, identifying screams from other sounds is essential. The objective of this study was to understand which sound features define a scream. Therefore, a method to detect screams based on sound features with physical meaning and explicit rules was developed. To achieve this, 7 hours of labelled data from 24 pigs was used. The developed detection method attained 72% sensitivity, 91% specificity and 83% precision. As a result, the detection method showed that screams contain the following features discerning them from other sounds: a formant structure, adequate power, high frequency content, sufficient variability and duration. PMID- 25923724 TI - A stress-induced small RNA modulates alpha-rhizobial cell cycle progression. AB - Mechanisms adjusting replication initiation and cell cycle progression in response to environmental conditions are crucial for microbial survival. Functional characterization of the trans-encoded small non-coding RNA (trans sRNA) EcpR1 in the plant-symbiotic alpha-proteobacterium Sinorhizobium meliloti revealed a role of this class of riboregulators in modulation of cell cycle regulation. EcpR1 is broadly conserved in at least five families of the Rhizobiales and is predicted to form a stable structure with two defined stem loop domains. In S. meliloti, this trans-sRNA is encoded downstream of the divK pleD operon. ecpR1 belongs to the stringent response regulon, and its expression was induced by various stress factors and in stationary phase. Induced EcpR1 overproduction led to cell elongation and increased DNA content, while deletion of ecpR1 resulted in reduced competitiveness. Computationally predicted EcpR1 targets were enriched with cell cycle-related mRNAs. Post-transcriptional repression of the cell cycle key regulatory genes gcrA and dnaA mediated by mRNA base-pairing with the strongly conserved loop 1 of EcpR1 was experimentally confirmed by two-plasmid differential gene expression assays and compensatory changes in sRNA and mRNA. Evidence is presented for EcpR1 promoting RNase E dependent degradation of the dnaA mRNA. We propose that EcpR1 contributes to modulation of cell cycle regulation under detrimental conditions. PMID- 25923726 TI - Dietary and metabolic aspects of hypertension and hypertension-related organ damage. PMID- 25923727 TI - Endothelial dysfunction in hypertension: implications for treatment. PMID- 25923728 TI - Natriuretic peptides in the cross-talk of human cardiovascular and metabolic regulation. PMID- 25923729 TI - Blood pressure pharmacogenomics: gazing into a misty crystal ball. PMID- 25923730 TI - Frailty and the relationship between blood pressure and mortality in elderly patients with type 2 diabetes (Zwolle Outpatient Diabetes project Integrating Available Care-34). AB - OBJECTIVE: We aimed to investigate whether adjustment for frailty influences the relationship of blood pressure with mortality in elderly patients with type 2 diabetes mellitus (T2DM). METHODS: Patients aged 60 years and older (n = 858) were selected from a prospective observational cohort study of primary care patients with T2DM. Frailty was defined as a score less than 80 on the subscale 'physical functioning' of the RAND-36 questionnaire. After median follow-up for 14 years, multivariate Cox regression analyses were performed to evaluate the association between blood pressure and (cardiovascular) mortality. Analyses were performed in strata according to the frailty level ('physical functioning' score <80 and >=80) and were repeated for patients older than 75 years. RESULTS: Frailty was highly prevalent in our study population; 629 out of 858 patients (73%) fulfilled the criterion. For patients aged at least 60 years, the hazard ratios (95% confidence interval) of a 10 mmHg increase in SBP and DBP for cardiovascular mortality in nonfrail patients were 1.38 (1.15-1.68%) and 1.60 (1.07-2.37%), respectively. No relationship was observed for frail patients. For the oldest frail elderly, the hazard ratios of SBP and DBP for all-cause mortality were 0.92 (0.87-0.98%) and 0.83 (0.73-0.93%), respectively. For the oldest nonfrail elderly, a positive relationship between SBP and all-cause mortality was observed. CONCLUSIONS: Frailty modifies the relationship between blood pressure and mortality in elderly patients with T2DM. Higher blood pressure was related to increased cardiovascular mortality in nonfrail patients, even in the oldest elderly, and to lower all-cause mortality in frail patients. PMID- 25923731 TI - Renal denervation preserves renal function in patients with chronic kidney disease and resistant hypertension. AB - OBJECTIVES: Arterial hypertension and increased sympathetic activity are underlying pathogenetic mechanisms of the progressive loss of renal function in patients with chronic kidney disease (CKD). Meta-analyses have shown that impaired renal function is an independent cardiovascular risk factor. We hypothesized that renal denervation (RDN) decreases the decline of renal function in patients with CKD stages 3 and 4 and treatment-resistant hypertension. METHODS: We performed an observational study of 27 patients with CKD stages 3 and 4, office blood pressure (BP) >= 140/90 mmHg, while on at least three antihypertensive drug classes including diuretic, and diagnosis confirmed by 24-h ambulatory BP measurement >= 130/80 mmHg. All patients underwent catheter-based RDN using the Symplicity Flex RDN System (Medtronic Inc., Santa Rosa, California, USA). Renal function was evaluated for up to 3 years prior and 1 year after RDN. The change in estimated glomerular filtration rate (eGFR) was calculated by regression slope individually for each patient before and after RDN. The study was registered at http://www.clinicaltrials.gov (ID: NCT01442883). RESULTS: Mean baseline BP was 156 +/- 12/82 +/- 13 mmHg, despite treatment with 6.2 +/- 1.1 antihypertensive drugs. One year after RDN, office BP was reduced by 20 +/- 20 (P < 0.001)/8 +/- 14 mmHg (P = 0.005) and average 24-h ambulatory BP by 9 +/- 14 (P = 0.009)/4 +/- 7 mmHg (P = 0.019). Before RDN, eGFR declined by -4.8 +/- 3.8 ml/min per 1.73 m per year, and after RDN eGFR improved by +1.5 +/- 10 ml/min per 1.73 m at 12 months (P = 0.009). CONCLUSIONS: Our observational pilot study in patients with CKD stages 3 and 4 indicates that treatment of hypertension with RDN decreases BP and slows or even halts the decline of renal function. PMID- 25923732 TI - Phosphorylation of eIF4E Confers Resistance to Cellular Stress and DNA-Damaging Agents through an Interaction with 4E-T: A Rationale for Novel Therapeutic Approaches. AB - Phosphorylation of the eukaryotic translation initiation factor eIF4E is associated with malignant progression and poor cancer prognosis. Accordingly, here we have analyzed the association between eIF4E phosphorylation and cellular resistance to oxidative stress, starvation, and DNA-damaging agents in vitro. Using immortalized and cancer cell lines, retroviral expression of a phosphomimetic (S209D) form of eIF4E, but not phospho-dead (S209A) eIF4E or GFP control, significantly increased cellular resistance to stress induced by DNA damaging agents (cisplatin), starvation (glucose+glutamine withdrawal), and oxidative stress (arsenite). De novo accumulation of eIF4E-containing cytoplasmic bodies colocalizing with the eIF4E-binding protein 4E-T was observed after expression of phosphomimetic S209D, but not S209A or wild-type eIF4E. Increased resistance to cellular stress induced by eIF4E-S209D was lost upon knockdown of endogenous 4E-T or use of an eIF4E-W73A-S209D mutant unable to bind 4E-T. Cancer cells treated with the Mnk1/2 inhibitor CGP57380 to prevent eIF4E phosphorylation and mouse embryonic fibroblasts derived from Mnk1/2 knockout mice were also more sensitive to arsenite and cisplatin treatment. Polysome analysis revealed an 80S peak 2 hours after arsenite treatment in cells overexpressing phosphomimetic eIF4E, indicating translational stalling. Nonetheless, a selective increase was observed in the synthesis of some proteins (cyclin D1, HuR, and Mcl-1). We conclude that phosphorylation of eIF4E confers resistance to various cell stressors and that a direct interaction or regulation of 4E-T by eIF4E is required. Further delineation of this process may identify novel therapeutic avenues for cancer treatment, and these results support the use of modern Mnk1/2 inhibitors in conjunction with standard therapy. PMID- 25923734 TI - Improvement of biomass production and glucoamylase activity by Candida famata using factorial design. AB - To improve biomass production and glucoamylase activity (GA) by Candida famata, culture conditions were optimized. A 2(3) full factorial design (FFD) with a response surface model was used to evaluate the effects and interactions of pH (X1 ), time of cultivation (X2 ), and starch concentration (X3 ) on the biomass production and enzyme activity. A total of 16 experiments were conducted toward the construction of an empiric model and a first-order equation. It was found that all factors (X1 , X2 , and X3 ) and their interactions were significant at a certain confidence level (P < 0.05). Using this methodology, the optimum values of the three tested parameters were obtained as follows: pH 6; time of cultivation 24 H and starch concentration 7 g/L, respectively. Our results showed that the starch concentration (X3) has significantly influenced both dependent variables, biomass production and GA of C. famata. Under this optimized medium, the experimental biomass production and GA obtained were 1.8 +/- 0.54 g/L and 0.078 +/- 0.012 umol/L/Min, about 1.5- and 1.8-fold, respectively, higher than those in basal medium. The (R(2) ) coefficients obtained were 0.997 and 0.990, indicating an adequate degree of reliability in the model. Approximately 99% of validity of the predicted value was achieved. PMID- 25923733 TI - Metabolic and pancreatic effects of bone marrow mesenchymal stem cells transplantation in mice fed high-fat diet. AB - The purpose of this study was to investigate the effects of multiple infusions of allogeneic MSCs on glucose homeostasis and morphometry of pancreatic islets in high- fat diet (HFD) fed mice. Swiss mice were fed standard diet (C group) or HFD (HFD group). After 8 weeks, animals of HFD group received sterile phosphate buffered saline infusions (HFD-PBS) or four infusions of MSCs one week apart (HFD MSCs). Fasting glycemia (FG) was determined weekly and glucose (GTT) and insulin (ITT) tolerance tests were performed 4, 8, 12, and 16 weeks after the infusions of MSCs. The MSCs transplanted mice were classified as responder (FG < 180 mg/dL, 72.2% of transplanted mice) or non-responder (FG > 180mg/dL, 28.8%) Seven weeks after MSCs infusions, FG decreased in HFD-MSCs responder mice compared with the HFD-PBS group. Sixteen weeks post MSCs infusions, GTT and ITT areas under the curve (AUC) decreased in HFD-MSCs responder mice compared to HFD-PBS group. Serum insulin concentration was higher in HFD-PBS group than in control animals and was not different compared with the other groups. The relative volume of alpha-cells was significantly smaller in HFD-PBS group than in C group and significantly higher in HFD-MSCs-NR than in HFD-PBS and HFD-MSCs-R groups. Cell apoptosis in the islets was higher in HFD-PBS group than in C group, and lower in HFD-MSCs responder mice than in HFD-PBS group and non-responder animals. The results demonstrate the ability of multiple infusions of MSCs to promote prolonged decrease in hyperglycemia and apoptosis in pancreatic islets and increase in insulin sensitivity in HFD fed mice. PMID- 25923735 TI - Traumatic Brain Injury Impairs Soluble N-Ethylmaleimide-Sensitive Factor Attachment Protein Receptor Complex Formation and Alters Synaptic Vesicle Distribution in the Hippocampus. AB - Traumatic brain injury (TBI) impairs neuronal function and can culminate in lasting cognitive impairment. While impaired neurotransmitter release has been well established after experimental TBI, little is understood about the mechanisms underlying this consequence. In the synapse, vesicular docking and neurotransmitter release requires the formation of the soluble N-ethylmaleimide sensitive factor attachment protein receptor (SNARE) complex. Impairments in vesicle docking, and alterations in SNARE complex formation are associated with impaired neurotransmitter release. We hypothesized that TBI reduces SNARE complex formation and disrupts synaptic vesicle distribution in the hippocampus. To examine the effect of TBI on the SNARE complex, rats were subjected to controlled cortical impact (CCI) or sham injury, and the brains were assessed at 6 h, 1 d, one week, two weeks, or four weeks post-injury. Immunoblotting of hippocampal homogenates revealed significantly reduced SNARE complex formation at one week and two weeks post-injury. To assess synaptic vesicles distribution, rats received CCI or sham injury and the brains were processed for transmission electron microscopy at one week post-injury. Synapses in the hippocampus were imaged at 100k magnification, and vesicle distribution was assessed in pre synaptic terminals at the active zone. CCI resulted in a significant reduction in vesicle number within 150 nm of the active zone. These findings provide the first evidence of TBI-induced impairments in synaptic vesicle docking, and suggest that reductions in the pool of readily releasable vesicles and impaired SNARE complex formation are two novel mechanisms contributing to impaired neurotransmission after TBI. PMID- 25923736 TI - PKB-Mediated Thr649 Phosphorylation of AS160/TBC1D4 Regulates the R-Wave Amplitude in the Heart. AB - The Rab GTPase activating protein (RabGAP), AS160/TBC1D4, is an important substrate of protein kinase B (PKB), and regulates insulin-stimulated trafficking of glucose transporter 4. Besides, AS160/TBC1D4 has also been shown to regulate trafficking of many other membrane proteins including FA translocase/CD36 in cardiomyocytes. However, it is not clear whether it plays any role in regulating heart functions in vivo. Here, we found that PKB-mediated phosphorylation of Thr649 on AS160/TBC1D4 represented one of the major PAS-binding signals in the heart in response to insulin. Mutation of Thr649 to a non-phosphorylatable alanine increased the R-wave amplitude in the AS160Thr649Ala knockin mice. However, this knockin mutation did not affect the heart functions under both normal and infarct conditions. Interestingly, myocardial infarction induced the expression of a related RabGAP, TBC1D1, in the infarct zone as well as in the border zone. Together, these data show that the Thr649 phosphorylation of AS160/TBC1D4 plays an important role in the heart's electrical conduction system through regulating the R-wave amplitude. PMID- 25923737 TI - An assessment of the methodological quality of published network meta-analyses: a systematic review. AB - OBJECTIVE: To assess the methodological quality of published network meta analysis. DESIGN: Systematic review. METHODS: We searched the medical literature for network meta-analyses of pharmaceuticals. We assessed general study characteristics, study transparency and reproducibility, methodological approach, and reporting of findings. We compared studies published in journals with lower impact factors with those published in journals with higher impact factors, studies published prior to January 1st, 2013 with those published after that date, and studies supported financially by industry with those supported by non profit institutions or that received no support. RESULTS: The systematic literature search identified 854 citations. Three hundred and eighteen studies met our inclusion criteria. The number of network meta-analyses has grown rapidly, with 48% of studies published since January 2013. The majority of network meta-analyses were supported by a non-profit institution or received no support (68%). We found considerable inconsistencies among reviewed studies. Eighty percent reported search terms, 61% a network diagram, 65% sufficient data to replicate the analysis, and 90% the characteristics of included trials. Seventy percent performed a risk of bias assessment of included trials, 40% an assessment of model fit, and 56% a sensitivity analysis. Among studies with a closed loop, 69% examined the consistency of direct and indirect evidence. Sixty four percent of studies presented the full matrix of head-to-head treatment comparisons. For Bayesian studies, 41% reported the probability that each treatment was best, 31% reported treatment ranking, and 16% included the model code or referenced publicly-available code. Network meta-analyses published in higher impact factors journals and those that did not receive industry support performed better across the assessment criteria. We found few differences between older and newer studies. CONCLUSIONS: There is substantial variation in the network meta-analysis literature. Consensus among guidelines is needed improve the methodological quality, transparency, and consistency of study conduct and reporting. PMID- 25923738 TI - Why Small Is Beautiful: Wing Colour Is Free from Thermoregulatory Constraint in the Small Lycaenid Butterfly, Polyommatus icarus. AB - We examined the roles of wing melanisation, weight, and basking posture in thermoregulation in Polyommatus Icarus, a phenotypically variable and protandrous member of the diverse Polyommatinae (Lycaenidae). Under controlled experimental conditions, approximating to marginal environmental conditions for activity in the field (= infrequent flight, long duration basking periods), warming rates are maximised with fully open wings and maximum body temperatures are dependent on weight. Variation in wing melanisation within and between sexes has no effect on warming rates; males and females which differ in melanisation had similar warming rates. Posture also affected cooling rates, consistent with cooling being dependent on convective heat loss. We hypothesise that for this small sized butterfly, melanisation has little or no effect on thermoregulation. This may be a factor contributing to the diversity of wing colours in the Polyommatinae. Because of the importance of size for thermoregulation in this small butterfly, requirements for attaining a suitable size to confer thermal stability in adults may also be a factor influencing larval feeding rates, development time and patterns of voltinism. Our findings indicate that commonly accepted views of the importance of melanisation, posture and size to thermoregulation, developed using medium and large sized butterflies, are not necessarily applicable to small sized butterflies. PMID- 25923739 TI - A control chart based on cluster-regression adjustment for retrospective monitoring of individual characteristics. AB - The tendency for experimental and industrial variables to include a certain proportion of outliers has become a rule rather than an exception. These clusters of outliers, if left undetected, have the capability to distort the mean and the covariance matrix of the Hotelling's T2 multivariate control charts constructed to monitor individual quality characteristics. The effect of this distortion is that the control chart constructed from it becomes unreliable as it exhibits masking and swamping, a phenomenon in which an out-of-control process is erroneously declared as an in-control process or an in-control process is erroneously declared as out-of-control process. To handle these problems, this article proposes a control chart that is based on cluster-regression adjustment for retrospective monitoring of individual quality characteristics in a multivariate setting. The performance of the proposed method is investigated through Monte Carlo simulation experiments and historical datasets. Results obtained indicate that the proposed method is an improvement over the state-of art methods in terms of outlier detection as well as keeping masking and swamping rate under control. PMID- 25923740 TI - Suggestion-Induced Modulation of Semantic Priming during Functional Magnetic Resonance Imaging. AB - Using functional magnetic resonance imaging during a primed visual lexical decision task, we investigated the neural and functional mechanisms underlying modulations of semantic word processing through hypnotic suggestions aimed at altering lexical processing of primes. The priming task was to discriminate between target words and pseudowords presented 200 ms after the prime word which was semantically related or unrelated to the target. In a counterbalanced study design, each participant performed the task once at normal wakefulness and once after the administration of hypnotic suggestions to perceive the prime as a meaningless symbol of a foreign language. Neural correlates of priming were defined as significantly lower activations upon semantically related compared to unrelated trials. We found significant suggestive treatment-induced reductions in neural priming, albeit irrespective of the degree of suggestibility. Neural priming was attenuated upon suggestive treatment compared with normal wakefulness in brain regions supporting automatic (fusiform gyrus) and controlled semantic processing (superior and middle temporal gyri, pre- and postcentral gyri, and supplementary motor area). Hence, suggestions reduced semantic word processing by conjointly dampening both automatic and strategic semantic processes. PMID- 25923741 TI - HIV Viral Load Trends in Six Eastern Caribbean Countries Utilizing a Regional Laboratory Referral Service: Implications for Treatment as Prevention. AB - OBJECTIVE: Since 2009, seven countries in the Organization of Eastern Caribbean States (OECS), Antigua & Barbuda, Dominica, Grenada, Montserrat, St. Kitts & Nevis, Saint Lucia, and St. Vincent & the Grenadines, have been utilizing a laboratory referral service for HIV-1 viral load (VL) offered by The Ladymeade Reference Unit (LRU) Laboratory, Barbados. The objective of this study was to evaluate 5 year VL trends in the six larger OECS countries participating in this regional referral service. METHODS: Blood samples were collected in source countries and transported to Barbados as frozen plasma according to a standardized protocol. Plasma specimens were amplified by RT PCR on a Roche TaqMan 48 analyser (Roche Diagnostics, Panama City, Panama). VL was considered optimally suppressed below a threshold level of < 200 HIV-1 copies/mL of blood. The same threshold was used as a binary indicator in an analysis of the secular change in VL suppression. Montserrat was excluded due to insufficient number of samples. RESULTS: A steady rise in VL referrals from OECS countries was recorded, rising from 312 samples in 2009 to 1,060 samples in 2013. A total of 3,543 samples were tested, with a sample rejection rate (9.2%) mostly due to breaks in the cold chain. Aggregate VL data showed the odds of VL suppression in the Eastern Caribbean improved by 66% for each additional year after 2009 (Odds Ratio 1.66 [95% CI 1.46 to 1.88]; p<0.001). CONCLUSION: We demonstrate the feasibility of establishing a regional laboratory referral service for HIV VL monitoring in the Eastern Caribbean. Aggregate VL trends showed a significant year-on-year improvement in VL suppression, implying public health benefits through treatment as prevention in the OECS. VL provides a powerful monitoring & evaluation tool for strengthening HIV programs at country level among the small island states participating in this regional referral network. PMID- 25923743 TI - Brazilian Nephrology pays homage to Peter Brian Medawar. PMID- 25923744 TI - Renal replacement therapy in CKD: an update from the Latin American Registry of Dialysis and Transplantation. PMID- 25923745 TI - CKD in disadvantaged populations. PMID- 25923742 TI - Risk of bleeding and stroke with oral anticoagulation and antiplatelet therapy in patients with atrial fibrillation in Taiwan: a nationwide cohort study. AB - BACKGROUND: Data on the use of oral anticoagulation (OAC) and antiplatelet therapy and the risk of bleeding and stroke amongst Asian patients with atrial fibrillation (AF) are limited. We investigated the risks of bleeding and stroke with use of oral anticoagulation (OAC) and antiplatelet therapy as mono- or combination therapy, in patients with AF from a Chinese nationwide cohort study. METHODS: We studied a cohort of 10384 patients (57.2% men, age 67.8 +/- 13.2 yrs) between 1999 and 2010 from the National Health Insurance Research Database in Taiwan. Records of prescriptions were obtained during follow-up. The main outcome was a recurrent stroke during the follow-up period. Time-dependent Cox proportional hazards models were used for this analysis. RESULTS: We documented 1009 events for bleeding, as well as 224 hemorrhagic stroke and 1642 ischemic stroke events during a median 3.2 (interquartile range, 1.05-6.54) years' follow up. Compared with warfarin users, patients with antiplatelet therapy had a lower risk of bleeding (adjusted relative risk [RR], 0.59, 95% confidence interval [CI], 0.49-0.71, p<0.001) whilst combination therapy had a non-statistically significant higher bleeding risk (RR, 1.33, 95%, 0.91-1.94, p = 0.20). Patients on antiplatelet monotherapy had a similar risk for ischemic stroke compared with OAC (RR 1.05, 95% CI, 0.89-1.25, p = 0.50), whilst those on combination therapy had a significantly higher risk (RR 1.90, 95% CI, 1.34-2.70, p<0.001). CONCLUSION: In a national representative cohort, antiplatelet therapy had no significant difference in ischemic stroke risk to warfarin. For bleeding, aspirin had a lower risk compared to warfarin. This may reflect poor anticoagulation control, highlighting important missed opportunities for improved stroke prevention, especially in countries where anticoagulation management is suboptimal. PMID- 25923746 TI - Impact of social vulnerability on the outcomes of predialysis chronic kidney disease patients in an interdisciplinary center. AB - INTRODUCTION: Numerous studies examined the associations between socio demographic, economic and individual factors and chronic kidney disease (CKD) outcomes and observed that the associations were complex and multifactorial. Socioeconomic factors can be evaluated by a model of social vulnerability (SV). OBJECTIVE: To analyze the impact of SV on the outcomes of predialysis patients. METHODS: Demographic, clinical and laboratory data were collected from a cohort of patients with predialysis stage 3 to 5 who were treated by an interdisciplinary team (January 2002 and December 2009) in Minas Gerais, Brazil. Factor, cluster and discriminant analysis were performed in sequence to identify the most important variables and develop a model of SV that allowed for classification of the patients as vulnerable or non-vulnerable. Cox regression was performed to examine the impact of SV on the outcomes of mortality and need for renal replacement therapy (RRT). RESULTS: Of the 209 patients examined, 29.4% were classified as vulnerable. No significance difference was found between the vulnerable and non-vulnerable groups regarding either mortality (log rank: 0.23) or need for RRT (log rank: 0.17). In the Cox regression model, the hazard ratios (HRs) for the unadjusted and adjusted impact of SV on mortality were found to be 1.87 (confidence interval [CI]: 0.64-5.41) and 1.47 (CI: 0.35-6.0), respectively, and the unadjusted and adjusted impact of need for RRT to be 1.85 (CI: 0.71-4.8) and 2.19 (CI: 0.50-9.6), respectively. CONCLUSION: These findings indicate that SV did not influence the outcomes of patients with predialysis CKD treated in an interdisciplinary center. PMID- 25923747 TI - Contrast-induced nephropathy after computed tomography. AB - INTRODUCTION: Contrast induced nephropathy is the third most prevalent preventable cause of acute kidney injury in hospitalized patients. It defined as an absolute increase in serum creatinine >= 0.5 mg/dL and relative >= 25% increase. OBJECTIVE: We studied the risk factors to intravenous injection contrast nephropathy after computed tomography. METHODS: We studied 400 patients prospectively. RESULTS: The incidence of contrast induced nephropathy, with an absolute or a relative increase were 4.0% and 13.9%, respectively. Diabetes and cardiac failure were independent risk factors for CIN a relative increase de serum creatinine (O.R.: 3.5 [95% CI: 1.92-6.36], p < 0.01, 2.61 [95% CI: 1.14 6.03%], p < 0.05, respectively). CONCLUSIONS: We showed association between uses of intravenous injection contrast after computed tomography with acute injury renal, notably with diabetes and heart failure. PMID- 25923748 TI - Late nephrologist referral and mortality assotiation in dialytic patients. AB - INTRODUCTION: Chronic kidney disease is defined by the progressive loss of renal function. Interventions in early stages significantly improve the prognosis of patients with chronic kidney disease, reducing the mortality, and many studies show that early nephrologist referral reduces the mortality rate. OBJECTIVE: To analyze the characteristics of the patients in dialysis and the time between the first consultation in the dialysis clinic and the beginning of the dialytic program. METHODS: It was made a cohort retrospective study with two analysis axis: the social and epidemiological characteristics of the patients in hemodialysis and the time between the first consultation in the clinic and the beginning of the dialytic program. Analytical and descriptive methods where used to compare these data with the early referral and the mortality 12 months after the dialysis onset. RESULTS: One hundred and one patients were analyzed. The mortality rate of the early and lately referred patients was 47.8% and 20.5%, respectively (HR = 2.38; IC = 1.06-5.36; p = 0.035). Concerning the patients which initiated the dialysis with catheter and arteriovenous fistula, the mortality was respectively 51.4% and 10.3% (HR = 4.61; IC = 1,54-13,75; p = 0.006). CONCLUSION: The referral timing was predominantly late. The late referral was associated with a greater mortality. Other variables associated with a greater mortality were age of 70 or more, presence of diabetes and the use of catheter by the dialysis onset. PMID- 25923749 TI - Predictors of acute kidney injury and mortality in an Intensive Care Unit. AB - INTRODUCTION AND OBJECTIVES: To compare clinical characteristics and outcomes of patients with and without acute kidney injury (AKI), to evaluate the incidence and mortality of AKI and predictors of AKI and death in patients hospitalized in an Intensive Care Unit (ICU). METHODS: A retrospective study analyzed 152 patients admitted to a single ICU. We assessed age, gender, reason for hospitalization, risk factors for ARF, laboratory data, the need for renal therapy substitutive and mortality. Acute Physiology and Chronic Health Evaluation (APACHE II), Sequential Organ Failure Assessment (SOFA) and RIFLE were recorded on the day of ICU admission. We determined the incidence of AKI, mortality and the independent predictors of AKI and death using logistic regression model. RESULTS: Mean age was 57.1 +/- 20 years, ranging between 19 to 88 years, and 60.1% were male. Non-dialysis dependent AKI occurred in 81 patients (53.2%) while the ARF requiring dialysis occurred in 19 patients (12.4%). The overall mortality rate in the ICU was 35.9%, whereas the mortality rate in patients with non-dialysis dependent AKI was 43.2% and the IRA with dialysis of 84.2%. In multivariate analysis, invasive mechanical ventilation, elevated creatinine and urea at admission were independent risk factors for AKI, whereas clinical diagnosis, invasive mechanical ventilation, increased lactate and urea and hypernatremia were independent risk factors for ICU mortality. CONCLUSION: The incidence and mortality of AKI in ICU were high in this study, despite the advances that have been emerging in their management. PMID- 25923750 TI - Functional Capacity and Quality of Life in Patients with Chronic Kidney Disease In Pre-Dialytic Treatment and on Hemodialysis--A Cross sectional study. AB - INTRODUCTION: Chronic kidney disease (CKD) infers directly in functional capacity, independence and therefore quality of life (QOL). OBJECTIVE: To compare the physical fitness and quality of life of patients with chronic kidney disease submitted on hemodialysis (G1) and predialysis treatment (G2). METHODS: A cross sectional study, 54 patients with CKD, 27 of the G1 group (58.15 +/- 10.84 years), 27 of G2 group (62.04 +/- 16.56 years). There were cardiovascular risk factors, anthropometric measurements, respiratory muscle strength was measured by the inspiratory pressure (MIP) and expiratory (MEP) maximum measured in the manometer, six-minute walk (TC6'), cardiopulmonary exercise test, sit and stand one minute test (TSL1') and the Short-Form Questionary (SF-36) to assess QOL. The patients presented disease of stage between 2 and 5. It was applied the Kolmogorov-Smirnov normality test and used the t (Student) test or the U (Mann Whitney) test to compare the means of quantitative variables and the chi-square Pearson test and Fisher's exact test for qualitative variables. Pearson's or Spearman's test was used to identify correlations. RESULTS: No statistically significant difference was found between G1 and G2 in VO2peak (p = 0,259) in TC6' (p = 0,433) in the MIPmax (p = 0,158) and found only in the MEPmax (p = 0,024) to G1. The scores of the SF-36 in both groups showed a worse health status as evidenced by the low score in scores for QOL. CONCLUSION: Patients with CKD had reduced functional capacity and QOL, and hemodialysis, statistically, didn't have showed negative repercussions when compared with pre-dialysis patients. PMID- 25923751 TI - Hopelessness, suicide ideation, and depression in chronic kidney disease patients on hemodialysis or transplant recipients. AB - INTRODUCTION: Hopelessness, suicide ideation and depression symptoms affect life quality and expectancy of chronic kidney disease patients. OBJECTIVE: To verify whether there are differences in hopelessness, suicide ideation and depression symptoms between chronic kidney disease patients on hemodialysis or transplant recipients. We also analyzed the influence of sociodemographic factors in these symptoms. METHODS: Cross-sectional study in which 50 clinically stable chronic hemodialysis patients and 50 renal transplant patients matched by gender and age. Instruments-Beck Hopelessness Scale (BHS), Beck Scale for Suicide Ideation (BSI) and Beck Depression Inventory (BDI). RESULTS: BHS: 2% of each group scoring > 8 (p = 1.00). BSI: 4% in hemodialysis and 6% of the transplant patients scoring > 1 (p = 1.000). BDI: 20% in hemodialysis and 12% of transplant patients scoring > 14 (p = 0.275). Patients who did not have a labor activity presented more depressive symptoms (average BDI score: 10.5 vs. 7.3, p = 0.027). Transplant patients from deceased donor presented more depressive symptoms compared with those with transplant from living donors (average BDI score: 11.0 vs. 6.7, p = 0.042). CONCLUSION: There was no difference in the intensity of hopelessness, suicide ideation and depression symptoms between stable hemodialysis and transplant patients. Not performing a labor activity and receiving the transplant from deceased donor lead to more depressive symptoms. The high prevalence of depressive symptoms and the finding of suicide ideation in both modalities of renal replacement therapy point to the need to monitor and care for those patients. PMID- 25923752 TI - Survival of hemodialysis patients at a university hospital. AB - INTRODUCTION: Chronic Kidney Disease (CKD) is associated with high rates of morbidity and mortality, especially in dialyses population. OBJECTIVE: To determine the overall survival rate; the epidemiological and clinical profiles; the comorbidities and the variables associated with survival of the patients undergoing hemodialysis. METHODS: This is a longitudinal and descriptive study with 162 patients undergoing hemodialysis, at the University Hospital. The categorical variables were described by frequency and percentage; numerical variables by mean and standard-deviation. The analysis by Cox Regression model was used to study the influence of several clinical and demographic variables in survival rates. Kaplan Meyer model was used to construct the survival curves of the significant variables. RESULTS: The mean age was 48.09 years, and the monthly family income and level of education were reduced in most of the patients studied. Hypertension was the main comorbidity associated with CKD in this population, followed by Diabetes Mellitus. The variables that negatively influenced the survival rates were advanced age at the beginning of therapy and low hemoglobin and albumin levels. The overall survival was 84.41% and 63.32% in one and five years, respectively. CONCLUSION: The rate of survival was considered low compared others studies and was decreasing over the years, not representing improvements despite technological advances in diagnostic and therapeutic approaches. Advanced age, hypoalbuminemia and anemia are strong predictors of mortality. PMID- 25923753 TI - Prevalence of metabolic syndrome according to NCEP-ATP III and IDF criteria in patients on hemodialysis. AB - INTRODUCTION: Metabolic syndrome (MS) has a high prevalence in hemodialysis' patients and is a risk factor for cardiovascular disease, the leading cause of mortality in chronic kidney disease (CKD). Objectives To evaluate the prevalence of MS in patients on hemodialysis (HD) and the difference in its prevalence according to the NCEP-ATP III and IDF criteria. METHODS: We evaluated HD patients in two outpatient clinics in Fortaleza, with dialysis vintage of at least 3 months and aged 18 + years. The patients underwent measurement of waist circumference, blood pressure (BP), dosages of glucose, triglycerides and HDL cholesterol in fasting. RESULTS: 115 patients were included and the prevalence of MS was 41.7% according to the NCEP-ATP III and 42.6% according to the IDF. Among the 48 patients with a diagnosis of MS according to the NCEPATP III, 87.5% were diagnosed by the IDF. Among the 67 patients without MS by NCEP-ATP III, 89.5% were not diagnosed by means of the IDF. The variables of MS according to the NCEP which had a higher prevalence were abnormal HDL-chol in 83.4% of patients and BP altered or use of antihypertensive drugs in 81.3%. CONCLUSION: The prevalence of MS in the study population was high, regardless of the criteria used. The variables that contributed most to the diagnosis of MS were dyslipidemia and blood pressure. Routine assessment of the diagnosis of MS in HD should be implemented, since patients with MS have an increase in the number of hospitalizations and in the risk of cardiovascular events. PMID- 25923754 TI - Renal function and cognitive dysfunction: cross-sectional study of users enrolled at Ponte Family Health Unit. AB - INTRODUCTION: Recent studies show increased prevalence of Cognitive Dysfunction in patients with Chronic Kidney Disease. OBJECTIVE: To evaluate this association in users enrolled in the Family Health Unit Ponte. METHODS: We studied a sample of 246 elderly. We assessed cognitive function using the Mini Mental State Examination and the Glomerular Filtration Rate using the equation Modification of Diet in Renal Disease. The Glomerular Filtration Rate values obtained (ml/min/1,73 m2) were divided into three categories: < 60.00, 60 to 89.99 and >= 90. We collected additional variables from the Medical Support Service and studied the data using bivariate analyzes and logistic regression models. RESULTS: The groups with Glomerular Filtration Rate < 60 and >= 90 had a higher prevalence of Cognitive Dysfunction, irrespective of other factors. The odds ratios were, respectively, of 4.534 (95%CI: 1.257 to 16.356) and 3.302 (95% CI: 1.434 to 7.607). DISCUSSION: According to the literature, we found higher prevalence of Cognitive Dysfunction in the group with Glomerular Filtration Rate < 60. The high prevalence of Cognitive Dysfunction in users with GFR >= 90 is described in some studies and may be caused by situations that lead to overestimation of that rate, as the states of cachexia, or situations of glomerular hyperfiltration. CONCLUSION: The relationship between renal function and the prevalence of Cognitive Dysfunction was not linear, but rather in a parabolic shape. Further studies are needed to explain this relationship and to determine the need for monitoring Cognitive Dysfunction in patients with impaired renal function. PMID- 25923755 TI - Prevalence and factors associated with chronic kidney disease among hospitalized patients in a university hospital in the city of Sao Paulo, SP, Brazil. AB - INTRODUCTION: Chronic kidney disease (CKD) is a major public health problem worldwide. Nonetheless, little is known about its features in Brazil. OBJECTIVE: To identify prevalence and factors associated with CKD among hospitalized patients in a university hospital. METHODS: We randomly selected 826 medical records of patients admitted in 2009 in the medical inpatient unit. We defined CKD as the presence of medical diagnosis or personal history. We collected a number of clinical and demographic information and these variables were compared between patients with and without CKD. RESULTS: CKD prevalence was 12.7%. Patients with CKD differed from patients without (p < 0.05) regarding to: living with a partner (59.8% vs. 47.3%), older age (65.8 +/- 15.6 vs. 55.3 +/- 18.9 years-old), more comorbidities as hypertension (75.2% vs. 46.3%), diabetes (49.5% vs. 22.4%), dyslipidemia (23.8% vs. 14.9%), acute myocardial infarction (14.3% vs. 6.0%) and congestive heart failure (18.1% vs. 4.3%); length of hospitalization (11 (8-18) vs. 9 (6-12) days); and death occurrence (12.4% vs. 1.4%). The logistic regression analysis showed an independent association (OR, odds ratio, CI, confidence interval 95%) of CKD with age (OR 1.019, CI 1.003 to 1.036), hypertension (OR 2.032, CI 1.128 to 3.660), diabetes (OR 2.097, CI 1.232 to 3.570) and congestive heart failure (OR 2.665, CI 1.173 to 6.056). CONCLUSION: CKD prevalence among patients in a medical inpatient unit was high and CKD patients were more complex, as they were older and had a great number of co morbidities, reflecting a greater risk of death during hospitalization. PMID- 25923756 TI - Sarcopenia in chronic kidney disease. AB - Sarcopenia is a chronic condition associated with physiological aging process and is defined by the reduction of the mass, muscle strength and function. In Chronic Kidney Disease (CKD), sarcopenia is prevalent and is associated with increased morbidity and mortality and the occurrence of cardiovascular complications. By analyzing sarcopenia in patients with renal insufficiency, complex mechanisms that contribute to loss of muscle mass are highlighted, such as activation of mediators that stimulate the ubiquitin-proteasome system (SUP) ATP-dependent, inflammation, metabolic acidosis, angiotensin II and some hormonal factors. The therapeutic approach to sarcopenia in CKD includes exercises, correction of metabolic acidosis, hormone replacement therapy and insulin resistance. Thus, it is of paramount importance early recognition of sarcopenia in this population, in order to establish effective therapeutic interventions, thus avoiding the full range of complications associated with muscle wasting in CKD. PMID- 25923757 TI - Resveratrol plays important role in protective mechanisms in renal disease--mini review. AB - Resveratrol (RESV) is a polyphenolic compound found in various plants, including grapes, berries and peanuts, and its processed foods as red wine. RESV possesses a variety of bioactivities, including antioxidant, anti-inflammatory, cardioprotective, antidiabetic, anticancer, chemopreventive, neuroprotective, renal lipotoxicity preventative, and renal protective effects. Numerous studies have demonstrated that polyphenols promote cardiovascular health. Furthermore, RESV can ameliorate several types of renal injury in animal models, including diabetic nephropathy, hyperuricemic, drug-induced injury, aldosterone-induced injury, ischemia-reperfusion injury, sepsis-related injury, and endothelial dysfunction. In addition, RESV can prevent the increase in vasoconstrictors, such as angiotensin II (AII) and endothelin-1 (ET-1), as well as intracellular calcium, in mesangial cells. Together, these findings suggest a potential role for RESV as a supplemental therapy for the prevention of renal injury. PMID- 25923758 TI - The long-term outcome after acute kidney injury: a narrative review. AB - This review will focus on long-term outcomes after acute kidney injury (AKI). Surviving AKI patients have a higher late mortality compared with those admitted without AKI. Recent studies have claimed that long-term mortality in patients after AKI varied from 15% to 74% and older age, presence of previous co morbidities, and the incomplete recovery of renal function have been identified as risk factors for reduced survival. AKI is also associated with progression to chronic kidney (CKD) disease and the decline of renal function at hospital discharge and the number and severity of AKI episodes have been associated with progression to CKD. IN the most studies, recovery of renal function is defined as non-dependence on renal replacement therapy which is probably too simplistic and it is expected in 60-70% of survivors by 90 days. Further studies are needed to explore the long-term prognosis of AKI patients. PMID- 25923759 TI - [Collapsing variant of focal segmental glomerulosclerosis by parvovirus B19: case report]. AB - OBJECTIVE: To describe the clinical and laboratory profile of focal segmental glomerulosclerosis (FSGS) of the collapsing subtype in association with infection by parvovirus B19 (PVB19). CASE REPORT: Female patient, 37 years old, mulatto, developed pharyngalgia and fever with partial improvement after penicillin. After one week we observed reduced urinary output and lower limb edema. Smoker, family and personal history negative for hypertension, diabetes or kidney disease. Patient presented with olyguria, hypertension and edema, also hypochromic microcytic hypoproliferative anemia, nephritic range proteinuria, microscopic hematuria and renal dysfunction. All rheumatologic investigation, HIV and hepatitis serology were negative. Unremarkable renal ultrasound. PCR positive for PVB19 in bone marrow aspirate and blood and renal biopsy conclusive of collapsing FSGS subtype. Spontaneous remission occurred within two weeks of the profile. The blood PVB19 PCR was repeated within a month and resulted negative. This finding demonstrated PVB19 acute infection or viral reactivation in association with collapsing FSGS. CONCLUSION: There is demonstrated the temporal association of PVB19 viremia and collapsing FSGS, due primary infection or viral reactivation. The association of collapsing FSGS and PVB19 is described in the literature, demonstrating virus presence in kidney tissue, but the real relationship of virus in the pathogenesis of this glomerulopathy remains unclear. PMID- 25923760 TI - [Use of Eculizumab in atypical hemolytic uremic syndrome after renal transplantation]. AB - To report the use of Eculizumab in atypical hemolytic uremic syndrome (aHUS) after renal transplantation. A 16 year-old patient diagnosed with chronic kidney disease since 2010, due to aHUS, under dialysis. kidney transplantation by deceased donor: February/2012. She showed good clinical evolution until the 14th postoperative day, when he developed a fever, oliguria, worsening of renal function [serum creatinine (CRs): 4.0 mg/dl] and signs of hemolysis [platelets: 110,000 mm3; hemoglobin (Hb): 4.5 g/dL; LDH: 3366 U/L]. Renal biopsy of the graft: thrombotic microangiopathy. Treated with handling blood products (fresh plasma) and plasmapheresis, with improvement of renal function (serum creatinine: 1.46 mg/dl). A week after this complication, fever anemia, signs of hemolysis and ITU restarted then it was handled with ciprofloxacin, methylprednisolone pulse therapy and plasma transfusion (Platelets: 43,000 mm3; Hb: 6.0 mg/dl, reticulocytes; 1.3%, haptoglobin < 5.8 mg/dl, HDL: 1181 U/L). After clinical worsening, it was started a therapy with Eculizumab, 900 mg in every five days for two weeks. There was some progress with good clinical response, characterized by improved renal function, stabilization of aHUS and discharged in five days. Since then, she keeps using Eculizumab 900 mg each 15 days with the renal and haematological normalization (Platelets: 160,000 mm3; Hb: 11.4 g/dL). The use of Eculizumab was useful in controlling the ongoing manifestation of aHUS and transplant preservation. PMID- 25923761 TI - [Multibacillary leprosy in a renal recipient patient: a case report]. AB - Leprosy is still a public health concern in Brazil, where more than 30,000 new cases are detected every year. There are few reports of this mycobacteriosis in immunosuppressed patients, despite the increasing number of solid organ transplantation and the use of post-transplant drugs in this country. The authors describe a case of multibacillary leprosy in a renal transplant recipient, detected 12 years after the procedure, and discuss the therapy, adverse effects and management of leprosy reactions in patients immunosuppressed by drugs. PMID- 25923763 TI - Erratum. AB - Volume 36 Issue 4 -Oct/Nov/Dec 2014. Evaluation of food intake and excretion of metabolites in nephrolithiasis. Mauricio Carvalho was not cited as one of the authors in the original article published on the Brazilian Journal of Nephrology 36 (4), and Table 1 contained an error. The corrected version of the Table is printed below. PMID- 25923762 TI - [Nephrocalcinosis associated with the use of anabolic steroid]. AB - The anabolic steroid have been used as a therapeutic tool in various clinical conditions. However, indiscriminate use associated with other nutritional supplements has generated serious adverse effects. CASE REPORT: Male, 21 years old, admitted with nausea, fatigue, appetite loss, headache and hypertension. Blood tests showed Cr: 3.9 mg% U: 100 mg% and Total Calcium 14 mg/dl. Ultrasonography and renal biopsy were consistent with nephrocalcinosis. There has been gradual improvement in renal function and calcium levels after vigorous hydration and furosemide. However, after 1 year, renal calcium deposits persist, corticomedullary ratio reduced in ultrasound and stable creatinine of 1.4 mg/dl. Previous cases showed acute tubular necrosis and interstitial nephritis with little calcium deposits in the renal interstitium. In this case we found severe nephrocalcinosis associated with nephrosclerosis. Our objective is to report the occurrence of acute kidney Injury with nephrocalcinosis associated with use of anabolic steroid and provide a review of the matter. PMID- 25923764 TI - Erratum. AB - Volume 34 Issue 3 - July/Aug/Sept 2012. Nutritional and epidemiological aspects of patients with chronic renal failure undergoing hemodialysis from Brazil, 2010. The author's name Advisor Carmen Tzanno-Martins was highlighted in the incorrect place, the correct one is mentioned above. PMID- 25923765 TI - A theoretically-sufficient and computationally-practical technique for deterministic frequency seriation. AB - Frequency seriation played a key role in the formation of archaeology as a discipline due to its ability to generate chronologies. Interest in its utility for exploring issues of contemporary interest beyond chronology, however, has been limited. This limitation is partly due to a lack of quantitative algorithms that can be used to build deterministic seriation solutions. When the number of assemblages becomes greater than just a handful, the resources required for evaluation of possible permutations easily outstrips available computing capacity. On the other hand, probabilistic approaches to creating seriations offer a computationally manageable alternative but rely upon a compressed description of the data to order assemblages. This compression removes the ability to use all of the features of our data to fit to the seriation model, obscuring violations of the model, and thus lessens our ability to understand the degree to which the resulting order is chronological, spatial, or a mixture. Recently, frequency seriation has been reconceived as a general method for studying the structure of cultural transmission through time and across space. The use of an evolution-based framework renews the potential for seriation but also calls for a computationally feasible algorithm that is capable of producing solutions under varying configurations, without manual trial and error fitting. Here, we introduce the Iterative Deterministic Seriation Solution (IDSS) for constructing frequency seriations, an algorithm that dramatically constrains the search for potential valid orders of assemblages. Our initial implementation of IDSS does not solve all the problems of seriation, but begins to moves towards a resolution of a long-standing problem in archaeology while opening up new avenues of research into the study of cultural relatedness. We demonstrate the utility of IDSS using late prehistoric decorated ceramics from the Mississippi River Valley. The results compare favorably to previous analyses but add new details into the structure of cultural transmission of these late prehistoric populations. PMID- 25923766 TI - Straight, white teeth as a social prerogative. AB - A distinguishing feature of North American society is preoccupation with self image, as seen in the ritualistic nature of bodily practices aimed at constantly improving the body. Nowhere is this more apparent than in the prevailing fixation with straight, white teeth. While there is an ever-expanding literature on the sociology of body, very little has been written on teeth in this context. Using literature from anthropology, biology, dentistry, sociology and social psychology, this study attempts to answer: (1) Why have straight, white teeth become a beauty ideal in North American society? (2) What is the basis for this ideal? (3) How is this ideal propagated? It demonstrates that dental aesthetic tendencies are biologically, culturally and socially patterned. Concepts from the works of Pierre Bourdieu and Michel Foucault are used to illustrate how straight, white teeth contribute towards reinforcing class differences and how society exercises a disciplinary power on individuals through this ideal. It is concluded that modified teeth are linked to self and identity that are rooted in social structure. Moreover, teeth demonstrate the ways in which class differences are embodied and projected as symbols of social advantage or disadvantage. Implications on professional, public health, sociological and political levels are considered. PMID- 25923767 TI - DIDA: Distributed Indexing Dispatched Alignment. AB - One essential application in bioinformatics that is affected by the high throughput sequencing data deluge is the sequence alignment problem, where nucleotide or amino acid sequences are queried against targets to find regions of close similarity. When queries are too many and/or targets are too large, the alignment process becomes computationally challenging. This is usually addressed by preprocessing techniques, where the queries and/or targets are indexed for easy access while searching for matches. When the target is static, such as in an established reference genome, the cost of indexing is amortized by reusing the generated index. However, when the targets are non-static, such as contigs in the intermediate steps of a de novo assembly process, a new index must be computed for each run. To address such scalability problems, we present DIDA, a novel framework that distributes the indexing and alignment tasks into smaller subtasks over a cluster of compute nodes. It provides a workflow beyond the common practice of embarrassingly parallel implementations. DIDA is a cost-effective, scalable and modular framework for the sequence alignment problem in terms of memory usage and runtime. It can be employed in large-scale alignments to draft genomes and intermediate stages of de novo assembly runs. The DIDA source code, sample files and user manual are available through http://www.bcgsc.ca/platform/bioinfo/software/dida. The software is released under the British Columbia Cancer Agency License (BCCA), and is free for academic use. PMID- 25923768 TI - Anal Human Papillomavirus Genotyping among HIV-Positive Men Who Have Sex with Men in Xi'an, China. AB - BACKGROUND: Anal human papillomavirus (HPV) infection and its related diseases are relatively common in men who have sex with men (MSM), especially in those HIV positive. In China, molecular epidemiology of anal HPV infection among HIV positive MSM has been sparsely studied. METHODS: A cross-sectional study was conducted among HIV-positive MSM in Xi'an, China between April and July 2014. Anal swabs were collected for HPV genotyping. RESULTS: A total of 195 HIV positive MSM were included in this study. HPV genotyping showed that 99.0% (191/193) of participants were positive for at least one of the targeted 37 HPV genotypes. 183 (94.8%) of them were infected with multiple high-risk types and 154 (79.8%) of them with low-risk HPV types. HPV 18 was the most frequently identified high-risk type, followed by HPV 16 and HPV 51. As for low-risk types, HPV11, HPV 6 and HPV 81 were most commonly observe. High-risk HPV infection was found to be associated with the status of antiretroviral therapy (ART), the distribution of low-risk types was observed to be varied by CD4+ T cell level. CONCLUSION: Almost all HIV-positive MSM were anal HPV infected in our study. It is highly recommended to consider regular active screening and preventive intervention of HPV infection among this high risk population. PMID- 25923770 TI - Does the sole description of a tax authority affect tax evasion?--the impact of described coercive and legitimate power. AB - Following the classic economic model of tax evasion, taxpayers base their tax decisions on economic determinants, like fine rate and audit probability. Empirical findings on the relationship between economic key determinants and tax evasion are inconsistent and suggest that taxpayers may rather rely on their beliefs about tax authority's power. Descriptions of the tax authority's power may affect taxpayers' beliefs and as such tax evasion. Experiment 1 investigates the impact of fines and beliefs regarding tax authority's power on tax evasion. Experiments 2-4 are conducted to examine the effect of varying descriptions about a tax authority's power on participants' beliefs and respective tax evasion. It is investigated whether tax evasion is influenced by the description of an authority wielding coercive power (Experiment 2), legitimate power (Experiment 3), and coercive and legitimate power combined (Experiment 4). Further, it is examined whether a contrast of the description of power (low to high power; high to low power) impacts tax evasion (Experiments 2-4). Results show that the amount of fine does not impact tax payments, whereas participants' beliefs regarding tax authority's power significantly shape compliance decisions. Descriptions of high coercive power as well as high legitimate power affect beliefs about tax authority's power and positively impact tax honesty. This effect still holds if both qualities of power are applied simultaneously. The contrast of descriptions has little impact on tax evasion. The current study indicates that descriptions of the tax authority, e.g., in information brochures and media reports, have more influence on beliefs and tax payments than information on fine rates. Methodically, these considerations become particularly important when descriptions or vignettes are used besides objective information. PMID- 25923769 TI - Windpipe controls Drosophila intestinal homeostasis by regulating JAK/STAT pathway via promoting receptor endocytosis and lysosomal degradation. AB - The adult intestinal homeostasis is tightly controlled by proper proliferation and differentiation of intestinal stem cells. The JAK/STAT (Janus Kinase/Signal Transducer and Activator of Transcription) signaling pathway is essential for the regulation of adult stem cell activities and maintenance of intestinal homeostasis. Currently, it remains largely unknown how JAK/STAT signaling activities are regulated in these processes. Here we have identified windpipe (wdp) as a novel component of the JAK/STAT pathway. We demonstrate that Wdp is positively regulated by JAK/STAT signaling in Drosophila adult intestines. Loss of wdp activity results in the disruption of midgut homeostasis under normal and regenerative conditions. Conversely, ectopic expression of Wdp inhibits JAK/STAT signaling activity. Importantly, we show that Wdp interacts with the receptor Domeless (Dome), and promotes its internalization for subsequent lysosomal degradation. Together, these data led us to propose that Wdp acts as a novel negative feedback regulator of the JAK/STAT pathway in regulating intestinal homeostasis. PMID- 25923772 TI - Critical limits for urgent clinician notification at South African intensive care units. AB - BACKGROUND: Critical value policies are used by clinical laboratories to decide when to notify caregivers of life-threatening results. There, however, remains much debate regarding which tests should be included in critical value lists and clinically relevant limits. METHOD: An electronic survey was designed to determine the critical value policies of specialists for haematology tests in South African intensive care units. Data collected included a demographic component, critical value policies and critical value reporting. RESULTS: There were 68 respondents who represented a range of specialists from different disciplines. Four key critical values were identified, namely white cell count (WCC), haemoglobin, platelet count and international normalised ratio (INR). Median low and high adult and paediatric critical limits for the most frequently listed tests were as follows: haemoglobin <7 and >20 g/dL, platelet count <50 and >1000 * 10(9) /L, WCC < 2 and >20 * 10(9) /L and INR > 4. Specific critical limits for neonates were reported by 20 of the respondents. Of the respondents, 95.92% indicated that it was important to be contacted with first-time critical results and approximately half for repeat critical values. The majority preferred that the person notified of the critical value be the caregiver directly involved with the patient's care. CONCLUSION: It is important for critical value policies to be reviewed by each discipline to ensure cut-offs are clinically relevant. PMID- 25923771 TI - Serotonin and the search for the anatomical substrate of aggression. AB - All species of animals display aggression in order to obtain resources such as territories, mates, or food. Appropriate displays of aggression rely on the correct identification of a potential competitor, an evaluation of the environmental signals, and the physiological state of the animal. With a hard wired circuitry involving fixed numbers of neurons, neuromodulators like serotonin offer adaptive flexibility in behavioral responses without changing the "hard-wiring". In a recent report, we combined intersectional genetics, quantitative behavioral assays and morphological analyses to identify single serotonergic neurons that modulate the escalation of aggression. We found anatomical target areas within the brain where these neurons appear to form synaptic contacts with 5HT1A receptor-expressing neurons, and then confirmed the likelihood of those connections on a functional level. In this Extra View article, we offer an extended discussion of these recent findings and elaborate on how they can link a cellular and functional mapping of an aggression regulating circuit at a single-cell resolution level. PMID- 25923773 TI - Faculty Experiences of Merger and Organizational Change in a Social Work Program. AB - Social work programs are experiencing unprecedented organizational changes due to budget cuts, dwindling resources, global, and technological challenges. However, there is limited information in the literature about the merger experiences of faculty in social work programs. On one hand undergoing merger and reorganization provides the opportunity to reorganize, reprioritize, re-assess, develop strategies, and explore previously untapped opportunities for social work programs. Conversely, merger experiences have caused frustration, intention to quit, confusion, and loss of professional identity for social work faculty. In this article the authors utilize a journaling method and sense-making approach of the merger experiences of some of the faculty members of a social work program in the United States. The authors suggest a framework to understand how the faculty confronted the challenges, overcame the pitfalls, and maximized the opportunities offered during the merger and organizational change process. PMID- 25923774 TI - Unexpected interaction with dispersed crude oil droplets drives severe toxicity in Atlantic haddock embryos. AB - The toxicity resulting from exposure to oil droplets in marine fish embryos and larvae is still subject for debate. The most detailed studies have investigated the effects of water-dissolved components of crude oil in water accommodated fractions (WAFs) that lack bulk oil droplets. Although exposure to dissolved petroleum compounds alone is sufficient to cause the characteristic developmental toxicity of crude oil, few studies have addressed whether physical interaction with oil micro-droplets are a relevant exposure pathway for open water marine speices. Here we used controlled delivery of mechanically dispersed crude oil to expose pelagic embryos and larvae of a marine teleost, the Atlantic haddock (Melanogrammus aeglefinus). Haddock embryos were exposed continuously to two different concentrations of dispersed crude oil, high and low, or in pulses. By 24 hours of exposure, micro-droplets of oil were observed adhering and accumulating on the chorion, accompanied by highly elevated levels of cyp1a, a biomarker for exposure to aromatic hydrocarbons. Embryos from all treatment groups showed abnormalities representative of crude oil cardiotoxicity at hatch (5 days of exposure), such as pericardial and yolk sac edema. Compared to other species, the frequency and severity of toxic effects was higher than expected for the waterborne PAH concentrations (e.g., 100% of larvae had edema at the low treatment). These findings suggest an enhanced tissue uptake of PAHs and/or other petroleum compounds from attached oil droplets. These studies highlight a novel property of haddock embryos that leads to greater than expected impact from dispersed crude oil. Given the very limited number of marine species tested in similar exposures, the likelihood of other species with similar properties could be high. This unanticipated result therefore has implications for assessing the ecological impacts of oil spills and the use of methods for dispersing oil in the open sea. PMID- 25923775 TI - Combination proximal pulmonary artery coiling and distal embolization induces chronic elevations in pulmonary artery pressure in Swine. AB - Pulmonary hypertension (PH) is associated with aberrant vascular remodeling and right ventricular (RV) dysfunction that contribute to early mortality. Large animal models that recapitulate human PH are essential for mechanistic studies and evaluating novel therapies; however, these models are not readily accessible to the field owing to the need for advanced surgical techniques or hypoxia. In this study, we present a novel swine model that develops cardiopulmonary hemodynamics and structural changes characteristic of chronic PH. This percutaneous model was created in swine (n=6) by combining distal embolization of dextran beads with selective coiling of the lobar pulmonary arteries (2 procedures per lung over 4 weeks). As controls, findings from this model were compared with those from a standard weekly distal embolization model (n=6) and sham animals (n=4). Survival with the combined embolization model was 100%. At 8 weeks after the index procedure, combined embolization procedure animals had increased mean pulmonary artery pressure (mPA) and pulmonary vascular resistance (PVR) compared to the controls with no effect on left heart or systemic pressures. RV remodeling and RV dysfunction were also present with a decrease in the RV ejection fraction, increase in the myocardial performance index, impaired longitudinal function, as well as cardiomyocyte hypertrophy, and interstitial fibrosis, which were not present in the controls. Pulmonary vascular remodeling occurred in both embolization models, although only the combination embolization model had a decrease in pulmonary capacitance. Taken together, these cardiopulmonary hemodynamic and structural findings identify the novel combination embolization swine model as a valuable tool for future studies of chronic PH. PMID- 25923776 TI - Are cranial biomechanical simulation data linked to known diets in extant taxa? A method for applying diet-biomechanics linkage models to infer feeding capability of extinct species. AB - Performance of the masticatory system directly influences feeding and survival, so adaptive hypotheses often are proposed to explain craniodental evolution via functional morphology changes. However, the prevalence of "many-to-one" association of cranial forms and functions in vertebrates suggests a complex interplay of ecological and evolutionary histories, resulting in redundant morphology-diet linkages. Here we examine the link between cranial biomechanical properties for taxa with different dietary preferences in crown clade Carnivora, the most diverse clade of carnivorous mammals. We test whether hypercarnivores and generalists can be distinguished based on cranial mechanical simulation models, and how such diet-biomechanics linkages relate to morphology. Comparative finite element and geometric morphometrics analyses document that predicted bite force is positively allometric relative to skull strain energy; this is achieved in part by increased stiffness in larger skull models and shape changes that resist deformation and displacement. Size-standardized strain energy levels do not reflect feeding preferences; instead, caniform models have higher strain energy than feliform models. This caniform-feliform split is reinforced by a sensitivity analysis using published models for six additional taxa. Nevertheless, combined bite force-strain energy curves distinguish hypercarnivorous versus generalist feeders. These findings indicate that the link between cranial biomechanical properties and carnivoran feeding preference can be clearly defined and characterized, despite phylogenetic and allometric effects. Application of this diet-biomechanics linkage model to an analysis of an extinct stem carnivoramorphan and an outgroup creodont species provides biomechanical evidence for the evolution of taxa into distinct hypercarnivorous and generalist feeding styles prior to the appearance of crown carnivoran clades with similar feeding preferences. PMID- 25923778 TI - The influence of the environment and clothing on human exposure to ultraviolet light. AB - OBJECTION: The aim of this study is to determine the effect of clothing and the environment on human exposure to ultraviolet light. METHODS: The ultraviolet (ultraviolet A and ultraviolet B) light intensity was measured, and air quality parameters were recorded in 2014 in Beijing, China. Three types of clothing (white polyester cloth, pure cotton white T-shirt, and pure cotton black T-shirt) were individually placed on a mannequin. The ultraviolet (ultraviolet A and ultraviolet B) light intensities were measured above and beneath each article of clothing, and the percentage of ultraviolet light transmission through the clothing was calculated. RESULTS: (1) The ultraviolet light transmission was significantly higher through white cloth than through black cloth; the transmission was significantly higher through polyester cloth than through cotton. (2) The weather significantly influenced ultraviolet light transmission through white polyester cloth; transmission was highest on clear days and lowest on overcast days (ultraviolet A: P=0.000; ultraviolet B: P=0.008). (3) Air quality parameters (air quality index and particulate matter 2.5 and 10) were inversely related to the ultraviolet light intensity that reached the earth's surface. Ultraviolet B transmission through white polyester cloth was greater under conditions of low air pollution compared with high air pollution. CONCLUSION: Clothing color and material and different types of weather affected ultraviolet light transmission; for one particular cloth, the transmission decreased with increasing air pollution. PMID- 25923777 TI - Disposition of bisphenol AF, a bisphenol A analogue, in hepatocytes in vitro and in male and female Harlan Sprague-Dawley rats and B6C3F1/N mice following oral and intravenous administration. AB - 1. Bisphenol AF (BPAF) is used as a crosslinking agent for polymers and is being considered as a replacement for bisphenol A (BPA). 2. In this study, comparative clearance and metabolism of BPAF and BPA in hepatocytes and the disposition and metabolism of BPAF in rodents following oral administration of 3.4, 34 or 340 mg/kg [(14)C]BPAF were investigated. 3. BPAF was cleared more slowly than BPA in hepatocytes with the rate: rat > mouse > human. 4. [(14)C]BPAF was excreted primarily in feces by 72 h after oral administration to rats (65-80%) and mice (63-72%). Females excreted more in urine (rat, 15%; mouse, 24%) than males (rat, 1-4%; mouse, 10%). Residual tissue radioactivity was <2% of the dose at 72 h. Similar results were observed following intravenous administration. 5. In male rats, 52% of a 340 mg/kg oral dose was excreted in 24 h bile and was mostly comprised of BPAF glucuronide. However, >94% of fecal radioactivity was present as BPAF, suggesting extensive deconjugation in the intestine. 6. Metabolites identified in bile were BPAF-glucuronide, -diglucuronide, -glucuronide sulfate and -sulfate. 7. In conclusion, BPAF was well absorbed following gavage administration and highly metabolized and excreted mostly in the feces as BPAF. PMID- 25923779 TI - The Lao Experience in Deploying Influenza A(H1N1)pdm09 Vaccine: Lessons Made Relevant in Preparing for Present Day Pandemic Threats. AB - The Lao PDR, as did most countries of the Mekong Region, embarked on a pandemic vaccine initiative to counter the threat posed by influenza A(H1N1)pdm09. Overall, estimated vaccine coverage of the Lao population was 14%, with uptake in targeted health care workers and pregnant women 99% and 41%, respectively. Adverse Events Following Immunization accounted for only 6% of survey driven, reported vaccination experiences, with no severe consequences or deaths. Public acceptability of the vaccine campaign was high (98%). Challenges to vaccine deployment included: 1) no previous experience in fielding a seasonal influenza vaccine, 2) safety and efficacy concerns, and 3) late arrival of vaccine 10 months into the pandemic. The Lao success in surmounting these hurdles was in large measure attributed to the oversight assigned the National Immunization Program, and national sensitivities in responding to the avian influenza A(H5N1) crisis in the years leading up to the pandemic. The Lao "lessons learned" from pandemic vaccine deployment are made even more relevant four years on, given the many avian influenza strains circulating in the region, all with pandemic potential. PMID- 25923780 TI - Rivaroxaban use in patients with antiphospholipid syndrome and previous venous thromboembolism. PMID- 25923781 TI - Management of prosthetic valve thrombosis: what is the best dosage and administration route of thrombolytics. PMID- 25923782 TI - Transition metal complexes of phyllobilins - a new realm of bioinorganic chemistry. AB - Natural cyclic tetrapyrroles feature outstanding capacity for binding transition metal ions, furnishing Nature with the important metallo-porphyrinoid 'Pigments of Life', such as heme, chlorophyll (Chl) and vitamin B12. In contrast, linear tetrapyrroles are not generally ascribed a biologically relevant ability for metal-binding. Indeed, when heme or Chl are degraded to natural linear tetrapyrroles, their central Fe- or Mg-ions are set free. Some linear tetrapyrroles are, however, effective multi-dentate ligands and their transition metal complexes have remarkable chemical properties. The focus of this short review is centred on such complexes of the linear tetrapyrroles derived from natural Chl-breakdown, called phyllobilins. These natural bilin-type compounds are massively produced in Nature and in highly visible processes. Colourless non fluorescing Chl-catabolites (NCCs) and the related dioxobilin-type NCCs, which typically accumulate in leaves as 'final' products of Chl-breakdown, show low affinity for transition metal-ions. However, NCCs are oxidized in leaves to give less saturated coloured phyllobilins, such as yellow or pink Chl-catabolites (YCCs or PiCCs). YCCs and PiCCs are ligands for various biologically relevant transition metal-ions, such as Zn(ii)-, Ni(ii)- and Cu(ii)-ions. Complexation of Zn(ii)- and Cd(ii)-ions by the effectively tridentate PiCC produces blue metal complexes that exhibit an intense red fluorescence, thus providing a tool for the sensitive detection of these metal ions. Outlined here are fundamental aspects of structure and metal coordination of phyllobilins, including a comparison with the corresponding properties of bilins. This knowledge may be valuable in the quest of finding possible biological roles of the phyllobilins. Thanks to their capacity for metal-ion coordination, phyllobilins could, e.g., be involved in heavy-metal transport and detoxification, and some of their metal-complexes could act as sensitizers for singlet oxygen or as plant toxins against pathogens. PMID- 25923783 TI - Healthcare-associated infections are associated with insufficient dietary intake: an observational cross-sectional study. AB - BACKGROUND: Indicators to predict healthcare-associated infections (HCAI) are scarce. Malnutrition is known to be associated with adverse outcomes in healthcare but its identification is time-consuming and rarely done in daily practice. This cross-sectional study assessed the association between dietary intake, nutritional risk, and the prevalence of HCAI, in a general hospital population. METHODS AND FINDINGS: Dietary intake was assessed by dedicated dieticians on one day for all hospitalized patients receiving three meals per day. Nutritional risk was assessed using Nutritional Risk Screening (NRS)-2002, and defined as a NRS score >= 3. Energy needs were calculated using 110% of Harris-Benedict formula. HCAIs were diagnosed based on the Center for Disease Control criteria and their association with nutritional risk and measured energy intake was done using a multivariate logistic regression analysis. From 1689 hospitalised patients, 1024 and 1091 were eligible for the measurement of energy intake and nutritional risk, respectively. The prevalence of HCAI was 6.8%, and 30.1% of patients were at nutritional risk. Patients with HCAI were more likely identified with decreased energy intake (i.e. <= 70% of predicted energy needs) (30.3% vs. 14.5%, P = 0.002). The proportion of patients at nutritional risk was not significantly different between patients with and without HCAI (35.6% vs.29.7%, P = 0.28), respectively. Measured energy intake <= 70% of predicted energy needs (odds ratio: 2.26; 95% CI: 1.24 to 4.11, P = 0.008) and moderate severity of the disease (odds ratio: 3.38; 95% CI: 1.49 to 7.68, P = 0.004) were associated with HCAI in the multivariate analysis. CONCLUSION: Measured energy intake <= 70% of predicted energy needs is associated with HCAI in hospitalised patients. This suggests that insufficient dietary intake could be a risk factor of HCAI, without excluding reverse causality. Randomized trials are needed to assess whether improving energy intake in patients identified with decreased dietary intake could be a novel strategy for HCAI prevention. PMID- 25923784 TI - Baseline prevalence of abdominal aortic aneurysm, peripheral arterial disease and hypertension in men aged 65-74 years from a population screening study (VIVA trial). AB - BACKGROUND: Abdominal aortic aneurysm (AAA) screening has been introduced into some health systems and could easily be supplemented with broader vascular screening. The aim of this study was to evaluate the screening set-up and investigate combined screening for AAA, peripheral arterial disease (PAD) and possible hypertension (HT), and detection rates. METHODS: This observational study was based on the intervention arm of a screening trial in 25 083 Danish men aged 65-74 years. A combined screening programme for AAA, PAD and HT was offered at local hospitals. Participants with positive test results were offered secondary prophylaxis and/or referred to their general practitioner. The programme set-up included decentralized screening by three mobile teams at 14 venues. Diagnostic criteria were: aortic diameter at least 30 mm for AAA, ankle : brachial pressure index below 0.9 or above 1.4 for PAD, and BP exceeding 160/100 mmHg for HT. RESULTS: Overall, 18 749 men (uptake 74.7 per cent) attended the screening. An AAA was diagnosed in 3.3 (95 per cent c.i. 3.0 to 3.6) per cent, PAD in 10.9 (10.5 to 11.4) per cent and HT in 10.5 (10.0 to 10.9) per cent. Lipid lowering and/or antiplatelet treatment was initiated in 34.8 per cent of the participants. CONCLUSION: Preventive actions were started in one-third of the attenders. The long-term effect of this on morbidity and mortality is an important part of future analysis. The trial confirms that the prevalence of AAA in Denmark has decreased only slightly in the past decade, from 4.0 to 3.3 per cent, in contrast to other nations. PMID- 25923785 TI - The Impact of Patient Profiles and Procedures on Hospitalization Costs through Length of Stay in Community-Acquired Pneumonia Patients Based on a Japanese Administrative Database. AB - BACKGROUND: Community-acquired pneumonia is a common cause of patient hospitalization, and its burden on health care systems is increasing in aging societies. In this study, we aimed to investigate the factors that affect hospitalization costs in community-acquired pneumonia patients while considering the intermediate influence of patient length of stay. METHODS: Using a multi institutional administrative claims database, we analyzed 30,041 patients hospitalized for community-acquired pneumonia who had been discharged between April 1, 2012 and September 30, 2013 from 289 acute care hospitals in Japan. Possible factors associated with hospitalization costs were investigated using structural equation modeling with length of stay as an intermediate variable. We calculated the direct, indirect (through length of stay), and total effects of the candidate factors on hospitalization costs in the model. Lastly, we calculated the ratio of indirect effects to direct effects for each factor. RESULTS: The structural equation model showed that higher disease severities (using A-DROP, Barthel Index, and Charlson Comorbidity Index scores), use of mechanical ventilation, and tube feeding were associated with higher hospitalization costs, regardless of the intermediate influence of length of stay. The severity factors were also associated with longer length of stay durations. The ratio of indirect effects to direct effects on total hospitalization costs showed that the former was greater than the latter in the factors, except in the use of mechanical ventilation. CONCLUSIONS: Our structural equation modeling analysis indicated that patient profiles and procedures impacted on hospitalization costs both directly and indirectly. Furthermore, the profiles were generally shown to have greater indirect effects (through length of stay) on hospitalization costs than direct effects. These findings may be useful in supporting the more appropriate distribution of health care resources. PMID- 25923786 TI - From the bush to the bench: the annual Nothobranchius fishes as a new model system in biology. AB - African annual fishes from the genus Nothobranchius are small teleosts that inhabit temporary water bodies subject to annual desiccation due to the alternation of the monsoon seasons. Given their unique biology, these fish have emerged as a model taxon in several biological disciplines. Their increasing popularity stems from the extremely short lifespan that is the result of their specific life-history adaptations and is retained under laboratory conditions. Nothobranchius furzeri, the most popular laboratory species, is the vertebrate species with the shortest lifespan recorded in captivity. In the laboratory, adults of different Nothobranchius species and populations live between 3 and 18 months and, notably, there is a negative correlation between the captive lifespan of a species and the aridity of their habitat. Their short lifespan is coupled to rapid age-dependent functional decline and expression of cellular and molecular changes comparable to those observed in other vertebrates, including humans. The recent development of transgenesis in this species makes it possible to insert specific constructs into their genome, and the establishment of transgenic lines is facilitated by their very rapid generation time, which can be as short as 1 month. This makes Nothobranchius species particularly suited for investigating biological and molecular aspects of ageing and ageing-associated dysfunctions. At the same time, they also represent a unique model taxon to investigate the evolution of life-history adaptations and their genetic architecture. We review their natural history, including phylogenetic relationships, distribution in relation to habitat conditions and natural selection for differential longevity, population structure and demography, and life cycle with emphasis on diapause that may occur at three stages during embryonic development. We further critically evaluate their use as a laboratory model for understanding the evolution of a rapid ageing rate and its consequences for other life-history traits, for cellular, molecular and integrative traits associated with the ageing process, high incidence of neoplasias, their utility for genome-wide gene expression studies, and as a model for quantitative genetics. We summarize recent achievements in fostering Nothobranchius species as a widely applicable model system, including an annotated transcriptome, successful transgenesis, and existence of viable inbred lines. We compare the conditions they experience in the wild and in captivity and suggest that they are an ideal taxon to investigate natural genetic variation in a laboratory setting. We conclude that Nothobranchius species - and N. furzeri in particular - could become a unique model taxon that bridges interests in ecological and biomedical research. We hope that a conceptual and methodological integration of these two branches of biology will provide important new insights. PMID- 25923787 TI - Correction: A new large-bodied oviraptorosaurian theropod dinosaur from the latest Cretaceous of western North America. PMID- 25923788 TI - A real-time clinical endoscopic system for intraluminal, multiplexed imaging of surface-enhanced Raman scattering nanoparticles. AB - The detection of biomarker-targeting surface-enhanced Raman scattering (SERS) nanoparticles (NPs) in the human gastrointestinal tract has the potential to improve early cancer detection; however, a clinically relevant device with rapid Raman-imaging capability has not been described. Here we report the design and in vivo demonstration of a miniature, non-contact, opto-electro-mechanical Raman device as an accessory to clinical endoscopes that can provide multiplexed molecular data via a panel of SERS NPs. This device enables rapid circumferential scanning of topologically complex luminal surfaces of hollow organs (e.g., colon and esophagus) and produces quantitative images of the relative concentrations of SERS NPs that are present. Human and swine studies have demonstrated the speed and simplicity of this technique. This approach also offers unparalleled multiplexing capabilities by simultaneously detecting the unique spectral fingerprints of multiple SERS NPs. Therefore, this new screening strategy has the potential to improve diagnosis and to guide therapy by enabling sensitive quantitative molecular detection of small and otherwise hard-to-detect lesions in the context of white-light endoscopy. PMID- 25923789 TI - Reconfigurable Boolean logic using magnetic single-electron transistors. AB - We propose a novel hybrid single-electron device for reprogrammable low-power logic operations, the magnetic single-electron transistor (MSET). The device consists of an aluminium single-electron transistor with a GaMnAs magnetic back gate. Changing between different logic gate functions is realized by reorienting the magnetic moments of the magnetic layer, which induces a voltage shift on the Coulomb blockade oscillations of the MSET. We show that we can arbitrarily reprogram the function of the device from an n-type SET for in-plane magnetization of the GaMnAs layer to p-type SET for out-of-plane magnetization orientation. Moreover, we demonstrate a set of reprogrammable Boolean gates and its logical complement at the single device level. Finally, we propose two sets of reconfigurable binary gates using combinations of two MSETs in a pull-down network. PMID- 25923790 TI - Unified Synthesis of C1-C19 Building Blocks of Halichondrins via Selective Activation/Coupling of Polyhalogenated Nucleophiles in (Ni)/Cr-Mediated Reactions. AB - A unified synthesis of the C1-C19 building blocks 8-10 of halichondrins A-C was developed from the common synthetic intermediates 26a,b. Acetylenic ketones 26a,b were in turn synthesized via selective activation/coupling of polyhalogenated nucleophiles 23a,b with aldehyde 11 in a (Ni)/Cr-mediated coupling reaction. Compared with Ni/Cr-mediated couplings of vinyl iodides and aldehydes, this (Ni)/Cr-mediated coupling exhibited two unique features. First, the coupling was found to proceed with a trace amount or no added Ni-catalyst. Second, TES-Cl, a dissociating agent to regenerate the Cr-catalyst, was found to give a better yield than Zr(Cp)2Cl2. An adjustment of the oxidation state was required to transform acetylenic ketones 26a,b into C1-C19 building blocks 8 and 9 of halichondrins A and B, respectively. In the halichondrin B series, a hydroxyl directed (Me)4NBH(OAc)3 reduction of E- and Z-beta-alkoxy-enones 30 was found cleanly to achieve the required transformation, whereas a DMDO oxidation of E vinylogous ester 27 allowed to introduce the C13 hydroxyl group with a high stereoselectivity in the halichondrin A series. In the halichondrin C series, Hf(OTf)4 was used to convert the double oxy-Michael product 28 into C1-C19 building block 10. PMID- 25923804 TI - Single-cell kinetics of a repressilator when implemented in a single-copy plasmid. AB - Synthetic genetic clocks, such as the Elowitz-Leibler repressilator, will be key regulatory components of future synthetic circuits. We constructed a single-copy repressilator (SCR) by implementing the original repressilator circuit on a single-copy F-plasmid. After verifying its functionality, we studied its behaviour as a function of temperature and compared it with that of the original low-copy-number repressilator (LCR). Namely, we compared the period of oscillations, functionality (the fraction of cells exhibiting oscillations) and robustness to internal fluctuations (the fraction of expected oscillations that would occur). We found that, under optimal temperature conditions, the dynamics of the two systems differs significantly, although qualitatively they respond similarly to temperature changes. Exception to this is in the functionality, in which the SCR is higher at lower temperatures but lower at higher temperatures. Next, by adding IPTG to the medium at low and high concentrations during microscopy sessions, we showed that the functionality of the SCR is more robust to external perturbations, which indicates that the oscillatory behaviour of the LCR can be disrupted by affecting only a few of the copies in a cell. We conclude that the SCR, the first functional, synthetic, single-copy, ring-type genetic clock, is more robust to lower temperatures and to external perturbations than the original LCR. The SCR will be of use in future synthetic circuits, since it complements the array of tasks that the LCR can perform. PMID- 25923803 TI - Molecular Characterization of Enterotoxin-Producing Escherichia coli Collected in 2011-2012, Russia. AB - Enterotoxin-producing Escherichia coli (ETEC) are one of the main causative agents of diarrhea in children especially in developing countries and travel diarrhoea in adults. Pathogenic properties of ETEC associated with their ability to produce a heat-stable (ST) and/or heat-labile (LT) enterotoxins, as well as adhesins providing bacterial adhesion to intestinal epithelial cells. This study presents the molecular characterization of the ETEC isolates collected from the Central and Far-Eastern regions of Russia in 2011-2012. It was shown that all ETEC under study (n=18) had the heat-labile enterotoxin-coding operon elt, and had no the genes of the heat-stable enterotoxin operon est. DNA sequencing revealed two types of nucleotide exchanges in the eltB gene coding subunit B of LT in isolates collected from Cherepovets city (Central region, Russia) and Vladivostok city (Far-East region, Russia). Only one ETEC strain carried genes cfaA, cfaB, cfaC and cfaD coding adhesion factor CFA/I. Expression of LT in four ETEC isolates in the agglutination reaction was detected using a latex test system. The isolates were assigned to serogroups O142 (n = 6), O6 (n = 4), O25 (n = 5), O26 (n = 2), and O115 (n = 1). Genotyping showed that they belonged to an earlier described sequence-type ST4 (n = 3) as well as to 11 novel sequence-types ST1043, ST1312, ST3697, ST3707, ST3708, ST3709, ST3710, ST3755, ST3756, ST3757 and ST4509. The ETEC isolates displayed different levels of antimicrobial resistance. Eight isolates were resistant to only one drug, three isolates-to two drugs, one isolate-to three drugs, two isolates-to four antibacterials, and only one isolate to each of the five, six and ten antibacterials simultaneously. Genetic determinants of the resistance to beta-lactams and other classes of antibacterials on the ETEC genomes were identified. There are blaTEM (n = 10), blaCTX-M-15 (n = 1), class 1 integron (n = 3) carrying resistance cassettes to aminoglycosides and sulphonamides dfrA17-aadA5 and dfrA12-orfF-aadA2. One isolate ETEC_Ef-6 was found to be a multidrug-resistant (MDR) pathogen that carried both the beta-lactamase gene and class 1 integron. These data suggest the circulation of ETEC in Russia. Further investigations are necessary to study the spread of the revealed ETEC sequence types (STs) and serotypes. Their role in the etiology of diarrhea should be also estimated. PMID- 25923805 TI - Role of Nonmuscle Myosin II in Migration of Wharton's Jelly-Derived Mesenchymal Stem Cells. AB - It is the promise of regeneration and therapeutic applications that has sparked an interest in mesenchymal stem cells (MSCs). Following infusion, MSCs migrate to sites of injury or inflammation by virtue of their homing property. To exert optimal clinical benefits, systemically delivered MSCs need to migrate efficiently and in adequate numbers to pathological areas in vivo. However, underlying molecular mechanisms responsible for MSC migration are still not well understood. The Wharton's jelly (WJ) of the umbilical cord is an attractive source of MSCs for stem cell therapy because of its abundant availability and painless collection. In this study, we attempted to identify the role of nonmuscle myosin II (NMII), if any, in the migration of WJ-derived MSCs (WJ MSCs). Expression of NMII isoforms, NMIIA, and NMIIB was observed both at RNA and protein levels in WJ-MSCs. Inhibition of NMII or its regulator ROCK, by pharmacological inhibitors, resulted in significant reduction in the migration of WJ-MSCs as confirmed by the scratch migration assay and time-lapse microscopy. Next, trying to dissect the role of each NMII isoform in migration of WJ-MSCs, we found that siRNA-mediated downregulation of NMIIA, but not NMIIB expression, led to cells failing to retract their trailing edge and losing cell-cell cohesiveness, while exhibiting a nondirectional migratory pathway. Migration, moreover, is also dependent on optimal affinity adhesion, which would allow rapid attachment and release of cells and, hence, can be influenced by extracellular matrix (ECM) and adhesion molecules. We demonstrated that inhibition of NMII and more specifically NMIIA resulted in increased gene expression of ECM and adhesion molecules, which possibly led to stronger adhesions and, hence, decreased migration. Therefore, these data suggest that NMII acts as a regulator of cell migration and adhesion in WJ-MSCs. PMID- 25923806 TI - Trends of people using drugs and opioid substitute treatment recorded in England and wales general practice (1994-2012). AB - BACKGROUND: Illicit drug use is a multifaceted public-health problem with potentially serious impacts. The United Kingdom has one of the highest prevalence of illegal drug use in Europe. Reduction of overall illegal drug use in England and Wales has decreased from 11% to 8.2% (2012/13) over the past 10 years. People who use drugs often seek help from their family doctors. AIMS: To investigate General Practitioners (family doctors) first recording of drug use and opioid substitute treatment in primary care settings. DESIGN: A descriptive study design. Males and females (16-64 years old) were extracted from The Health Improvement Network (THIN) database. SETTING: England and Wales primary care. METHOD: The first recording of drug use and opioid substitution treatment in primary care was estimated for the period (1994-2012). Poisson regressions were conducted to estimate incidence risk ratios (IRR). RESULTS: We identified 33,508 first recordings of drug use and 10,869 individuals with prescriptions for opioid substitute treatment. Overall, males (IRR 2.02, 95% CI:1.97-2.07), people in the age-group; 16-24 (IRR 6.7, 95% CI:6.4-6.9) compared to those over 25 years and the most deprived (IRR 4.2, 95% CI:3.9-4.4) were more likely to have a recording of drug use. Males (IRR 1.2 95% CI:1.2-1.3), in the age-group; 25-34 (IRR 1.8 95% CI:1.7-1.9) and the most deprived (IRR 3.9 95% CI:3.6-4.3) were the groups more likely to have a opioid substitute treatment prescription. CONCLUSION: It is evident from this study that there is little recording of drug use and opioid substitute treatment in primary care. Most drug users do not receive treatment in primary care. PMID- 25923808 TI - Bacterial vaginosis. PMID- 25923807 TI - Transcriptome-Wide Identification of miRNAs and Their Targets from Typha angustifolia by RNA-Seq and Their Response to Cadmium Stress. AB - MicroRNAs (miRNAs) play important roles in plant responses to environmental stress. In this work, we used high-throughput sequencing to analyze transcriptome and small RNAs (sRNAs) in Typha angustifolia under cadmium (Cd) stress. 57,608,230 raw reads were obtained from deep sequencing of a pooled cDNA library. Sequence assembly and analysis yielded 102,473 unigenes. We subsequently sequenced two sRNA libraries from T. angustifolia with or without Cd exposure respectively. Based on transcriptome data of T. angustifolia, we catalogued and analyzed the sRNAs, resulting in the identification of 114 conserved miRNAs and 41 novel candidate miRNAs in both small RNA libraries. In silico analysis revealed 764 targets for 89 conserved miRNAs and 21 novel miRNAs. Statistical analysis on sequencing reads abundance and experimental validation revealed that 4 conserved and 6 novel miRNAs showed specific expression. Combined with function of target genes, these results suggested that miRNAs might play a role in plant Cd stress response. This study provided the first transcriptome-based analysis of miRNAs and their targets responsive to Cd stress in T. angustifolia, which provide a framework for further analysis of miRNAs and their role in regulating plant responses to Cd stress. PMID- 25923809 TI - Product development studies on sonocrystallized curcumin for the treatment of gastric cancer. AB - Curcumin suffers from the limitation of poor solubility and low dissolution that can lead to limited applications. The investigation was aimed to substantiate the potentiality of melt sonocrystallized gastroretentive tablets of curcumin. Melt sonocrystallized curcumin (MSC CMN) was developed and its therapeutic potential was validated by in vitro cytotoxicity studies against Human oral cancer cell line KB. MSC curcumin was then formulated as floating tablet and evaluated. MSC form of CMN exhibited 2.36-fold and 2.40-fold solubility enhancement in distilled water and phosphate buffer, pH 4.5, respectively, better flow properties and intrinsic dissolution rate (0.242 +/- 1.42 and 0.195 +/- 1.26 mg/cm2/min) in comparison to its original form. The GI50 value of MSC CMN was found to be less than 10, specifying inhibition of growth more effectively at its least concentration by 50%. The gastroretentive-floating tablet (Formulation F4) displayed controlled drug release (96.22% +/- 1.43%) for over 12 h. The present study revealed melt sonocrystallization can be used to produce particles with superior biopharmaceutical properties without the use of organic solvents or the addition of other excipients, and amenable to formulation in to a pharmaceutical dosage form. PMID- 25923810 TI - Diagnostic accuracy of computed tomography for chronic thromboembolic pulmonary hypertension: a systematic review and meta-analysis. AB - This study aimed to determine the diagnostic accuracy of computed tomography imaging for the diagnosis of chronic thromboembolic pulmonary hypertension (CTEPH). Additionally, the effect of test and study characteristics was explored. Studies published between 1990 and 2015 identified by PubMed, OVID search and citation tracking were examined. Of the 613 citations, 11 articles (n=712) met the inclusion criteria. The patient-based analysis demonstrated a pooled sensitivity of 76% (95% confidence interval [CI]: 69% to 82%), and a pooled specificity of 96% (95%CI: 93% to 98%). This resulted in a pooled diagnostic odds ratio (DOR) of 191 (95%CI: 75 to 486). The vessel-based analyses were divided into 3 levels: total arteries,main+ lobar arteries and segmental arteries. The pooled sensitivity were 88% (95%CI: 87% to 90%),95% (95%CI: 92% to 97%) and 88% (95%CI: 87% to 90%), respectively, with a pooled specificity of 90% (95%CI: 88% to 91%),96% (95%CI: 94% to 97%) and 89% (95% CI: 87% to 91%). This resulted in a pooled diagnostic odds ratio of 76 (95%CI: 23 to 254),751 (95%CI: 57 to 9905) and 189 (95%CI: 21 to 1072), respectively. In conclusion, CT is a favorable method to rule in CTEPH and to rule out pulmonary endarterectomy (PEA) patients for proximal branches. Furthermore, dual-energy and 320-slices CT can increase the sensitivity for subsegmental arterials, which are promising imaging techniques for balloon pulmonary angioplasty (BPA) approach. In the near future, CT could position itself as the key for screening consideration and for surgical and interventional operability. PMID- 25923812 TI - Development of a New Measure for Assessing Glucose Monitoring Device-Related Treatment Satisfaction and Quality of Life. AB - BACKGROUND: Many different devices are available to patients to measure glucose levels, but there is no validated method to assess treatment satisfaction with glucose monitoring devices and its impact on quality of life and other patient reported outcomes. To address this problem, we developed the Glucose Monitoring System Satisfaction Survey (GMSS). We describe the construction and validation of the GMSS and examine how key patient factors are associated with glucose device satisfaction. MATERIALS AND METHODS: Items were developed from interviews with 15 adults with either type 1 diabetes (T1D) or type 2 diabetes (T2D) and 10 diabetes healthcare professionals, resulting in an initial pool of 42 items. Separate exploratory factor analyses (EFAs) were conducted with adults with T1D (n=254) and with insulin-using T2D (n=206). Construct validity was established with overall well-being (World Health Organization-5), diabetes distress (Diabetes Distress Scale), attitudes toward glucose monitoring (Self-Monitoring of Blood Glucose Obstacles scale), and the previously validated Blood Glucose Monitoring System Rating Questionnaire. Regression analyses examined associations between total scale satisfaction and demographics, diabetes status, and glucose monitor use. RESULTS: The two EFAs resulted in two 15-item scales, one for T1D and one for T2D, and yielded four coherent and meaningful factors in each sample: three factors with the same items in common for both samples (Emotional Burden, Behavioral Burden, and Openness) and a fourth factor unique to each sample (Trust for T1D, Worthwhileness for T2D). The final EFA accounted for 66.5% of the variance in the T1D sample and 67.0% in the T2D sample. Validity was established by significant correlations with criterion variables. CONCLUSIONS: The GMSS is a reliable, valid measure of glucose device satisfaction in its T1D form and in its insulin-using T2D form. It provides a comprehensive profile of sources of device satisfaction for use in clinical care and research. PMID- 25923811 TI - A machine learning heuristic to identify biologically relevant and minimal biomarker panels from omics data. AB - BACKGROUND: Investigations into novel biomarkers using omics techniques generate large amounts of data. Due to their size and numbers of attributes, these data are suitable for analysis with machine learning methods. A key component of typical machine learning pipelines for omics data is feature selection, which is used to reduce the raw high-dimensional data into a tractable number of features. Feature selection needs to balance the objective of using as few features as possible, while maintaining high predictive power. This balance is crucial when the goal of data analysis is the identification of highly accurate but small panels of biomarkers with potential clinical utility. In this paper we propose a heuristic for the selection of very small feature subsets, via an iterative feature elimination process that is guided by rule-based machine learning, called RGIFE (Rule-guided Iterative Feature Elimination). We use this heuristic to identify putative biomarkers of osteoarthritis (OA), articular cartilage degradation and synovial inflammation, using both proteomic and transcriptomic datasets. RESULTS AND DISCUSSION: Our RGIFE heuristic increased the classification accuracies achieved for all datasets when no feature selection is used, and performed well in a comparison with other feature selection methods. Using this method the datasets were reduced to a smaller number of genes or proteins, including those known to be relevant to OA, cartilage degradation and joint inflammation. The results have shown the RGIFE feature reduction method to be suitable for analysing both proteomic and transcriptomics data. Methods that generate large 'omics' datasets are increasingly being used in the area of rheumatology. CONCLUSIONS: Feature reduction methods are advantageous for the analysis of omics data in the field of rheumatology, as the applications of such techniques are likely to result in improvements in diagnosis, treatment and drug discovery. PMID- 25923813 TI - CHOgenome.org 2.0: Genome resources and website updates. AB - Chinese hamster ovary (CHO) cells are a major host cell line for the production of therapeutic proteins, and CHO cell and Chinese hamster (CH) genomes have recently been sequenced using next-generation sequencing methods. CHOgenome.org was launched in 2011 (version 1.0) to serve as a database repository and to provide bioinformatics tools for the CHO community. CHOgenome.org (version 1.0) maintained GenBank CHO-K1 genome data, identified CHO-omics literature, and provided a CHO-specific BLAST service. Recent major updates to CHOgenome.org (version 2.0) include new sequence and annotation databases for both CHO and CH genomes, a more user-friendly website, and new research tools, including a proteome browser and a genome viewer. CHO cell-line specific sequences and annotations facilitate cell line development opportunities, several of which are discussed. Moving forward, CHOgenome.org will host the increasing amount of CHO omics data and continue to make useful bioinformatics tools available to the CHO community. PMID- 25923814 TI - Molecular Characterization of the Llamas (Lama glama) Casein Cluster Genes Transcripts (CSN1S1, CSN2, CSN1S2, CSN3) and Regulatory Regions. AB - In the present paper, we report for the first time the characterization of llama (Lama glama) caseins at transcriptomic and genetic level. A total of 288 casein clones transcripts were analysed from two lactating llamas. The most represented mRNA populations were those correctly assembled (85.07%) and they encoded for mature proteins of 215, 217, 187 and 162 amino acids respectively for the CSN1S1, CSN2, CSN1S2 and CSN3 genes. The exonic subdivision evidenced a structure made of 21, 9, 17 and 6 exons for the alphas1-, beta-, alphas2- and kappa-casein genes respectively. Exon skipping and duplication events were evidenced. Two variants A and B were identified in the alphas1-casein gene as result of the alternative out splicing of the exon 18. An additional exon coding for a novel esapeptide was found to be cryptic in the kappa-casein gene, whereas one extra exon was found in the alphas2-casein gene by the comparison with the Camelus dromedaries sequence. A total of 28 putative phosphorylated motifs highlighted a complex heterogeneity and a potential variable degree of post-translational modifications. Ninety-six polymorphic sites were found through the comparison of the lama casein cDNAs with the homologous camel sequences, whereas the first description and characterization of the 5'- and 3'-regulatory regions allowed to identify the main putative consensus sequences involved in the casein genes expression, thus opening the way to new investigations -so far- never achieved in this species. PMID- 25923815 TI - Design of highly potent urea-based, exosite-binding inhibitors selective for glutamate carboxypeptidase II. AB - We present here a structure-aided design of inhibitors targeting the active site as well as exosites of glutamate carboxypeptidase II (GCPII), a prostate cancer marker, preparing potent and selective inhibitors that are more than 1000-fold more active toward GCPII than its closest human homologue, glutamate carboxypeptidase III (GCPIII). Additionally, we demonstrate that the prepared inhibitor conjugate can be used for sensitive and selective imaging of GCPII in mammalian cells. PMID- 25923816 TI - Multicentre validation of manufacturers' weight-based recommendations for laryngeal mask airway size choice in anaesthetic practice: A retrospective analysis of 20,893 cases. AB - BACKGROUND: Manufacturers' weight-based recommendations for laryngeal mask airway (LMA) sizes are not scientifically founded and have never been validated clinically. OBJECTIVE: The validation of manufacturers' weight-based recommendations in clinical practice and whether other patient variables such as sex and age may influence LMA size choice. DESIGN: A retrospective study. SETTING: Four Israeli hospitals (two tertiary and two secondary hospitals). METHODS: Data on LMA use were retrieved from the Anaesthesia Information Management System (AIMS). Multinomial logistic regression analysis including weight, sex and age amongst adults, adolescents and children was used to identify predictors of LMA size used (development data set). Concordance between the size of LMA used and that predicted according to the model and the manufacturers' recommendations was assessed (validation data set). RESULTS: LMA insertions were analysed in 13,743 (65.8%) adults, 1807 (8.6%) adolescents and 5343 (25.6%) children. Suitability of manufacturers' recommendations was higher in children [4075/5343 (76.3%)] than adults [5200/13743 (37.8%)] or adolescents [885/1807 (49.0%); P < 0.001 for children vs. adults or adolescents]. Sex influenced LMA size in adults and adolescents, but not in children. Age had no influence. Amongst adults and adolescents, LMA size was better predicted by the regression model than by manufacturers' recommendations [adults: anaesthetists/model 61.7%, 95% confidence interval (95% CI) 60.1 to 63.2, anaesthetists/manufacturer 38.4%, 95% CI 36.0 to 39.0, P < 0.001; adolescents: anaesthetists/model 68.1%, 95% CI 64.1 to 72.0, anaesthetists/manufacturer 46.9%, 95% CI 42.7 to 51.1, P < 0.001]. In children, the regression model and manufacturers' weight-based recommendations performed equally (anaesthetists/model 78.0%, 95% CI 75.9 to 80.0, anaesthetists/manufacturer 75.7%, 95% CI 73.6 to 7.8, P = 0.126). CONCLUSION: Manufacturers' weight-based recommendations for LMA size reflect clinical practice in children, but not in adults and adolescents. In these age groups, choice of LMA size is influenced by sex and weight, although with wider ranges than those recommended by manufacturers. PMID- 25923817 TI - Private mitochondrial DNA variants in danish patients with hypertrophic cardiomyopathy. AB - Hypertrophic cardiomyopathy (HCM) is a genetic cardiac disease primarily caused by mutations in genes coding for sarcomeric proteins. A molecular-genetic etiology can be established in ~60% of cases. Evolutionarily conserved mitochondrial DNA (mtDNA) haplogroups are susceptibility factors for HCM. Several polymorphic mtDNA variants are associated with a variety of late-onset degenerative diseases and affect mitochondrial function. We examined the role of private, non-haplogroup associated, mitochondrial variants in the etiology of HCM. In 87 Danish HCM patients, full mtDNA sequencing revealed 446 variants. After elimination of 312 (69.9%) non-coding and synonymous variants, a further 109 (24.4%) with a global prevalence > 0.1%, three (0.7%) haplogroup associated and 19 (2.0%) variants with a low predicted in silico likelihood of pathogenicity, three variants: MT-TC: m.5772G>A, MT-TF: m.644A>G, and MT-CYB: m.15024G>A, p.C93Y remained. A detailed analysis of these variants indicated that none of them are likely to cause HCM. In conclusion, private mtDNA mutations are frequent, but they are rarely, if ever, associated with HCM. PMID- 25923818 TI - Cutaneous Sensory Block Area, Muscle-Relaxing Effect, and Block Duration of the Transversus Abdominis Plane Block: A Randomized, Blinded, and Placebo-Controlled Study in Healthy Volunteers. AB - BACKGROUND AND OBJECTIVES: The transversus abdominis plane (TAP) block is a widely used nerve block. However, basic block characteristics are poorly described. The purpose of this study was to assess the cutaneous sensory block area, muscle-relaxing effect, and block duration. METHODS: Sixteen healthy volunteers were randomized to receive an ultrasound-guided unilateral TAP block with 20 mL 7.5 mg/mL ropivacaine and placebo on the contralateral side. Measurements were performed at baseline and 90 minutes after performing the block. Cutaneous sensory block area was mapped and separated into a medial and lateral part by a vertical line through the anterior superior iliac spine. We measured muscle thickness of the 3 lateral abdominal muscle layers with ultrasound in the relaxed state and during maximal voluntary muscle contraction. The volunteers reported the duration of the sensory block and the abdominal muscle-relaxing effect. RESULTS: The lateral part of the cutaneous sensory block area was a median of 266 cm2 (interquartile range, 191-310 cm2) and the medial part 76 cm 2(interquartile range, 54-127 cm2). In all the volunteers, lateral wall muscle thickness decreased significantly by 9.2 mm (6.9-15.7 mm) during a maximal contraction. Sensory block and muscle-relaxing effect duration were 570 minutes (512-716 minutes) and 609 minutes (490-724 minutes), respectively. CONCLUSIONS: Cutaneous sensory block area of the TAP block is predominantly located lateral to a vertical line through the anterior superior iliac spine. The distribution is nondermatomal and does not cross the midline. The muscle-relaxing effect is significant and consistent. The block duration is approximately 10 hours with large variation. PMID- 25923819 TI - Prospective Observational Study of Patient-Controlled Intrathecal Analgesia: Impact on Cancer-Associated Symptoms, Breakthrough Pain Control, and Patient Satisfaction. AB - BACKGROUND AND OBJECTIVES: Although data exist for the efficacy of intrathecal therapy (ITT), there are no prospective data on patient-controlled intrathecal analgesia (PCIA) in refractory cancer pain. This study examines the effect of PCIA on cancer symptom scores, patient satisfaction, and analgesic efficacy with an emphasis on breakthrough pain (BTP). METHODS: Ninety-eight patients with refractory cancer pain prospectively completed questionnaires including the MD Anderson Symptom Inventory and a BTP survey before and after the implantation of an intrathecal pump. RESULTS: Fifty-eight patients were included in the study group. Average "worst" pain scores decreased from 8.32 (SD, 1.73) pre-ITT to 4.98 (SD, 2.92) post-ITT, P < 0.001. Severe pain (numerical rating score >=7) decreased from 84.2% to 35.2% (P < 0.001). Mean daily morphine equivalent dosing decreased from 805.3 mg/d to 128.2 mg/d, with 65.5% of patients discontinuing all nonintrathecal opioids. The mean MD Anderson Symptom Inventory symptom severity score decreased from 4.98 to 3.72 (P < 0.0001), and the symptom interference score from 6.53 to 4.37 (P < 0.001). Pain reduction was 46.8% with pre-ITT breakthrough medications and 65.2% with PCIA (P < 0.001). Median time to onset was 30 minutes with pre-ITT breakthrough medications and 10 minutes with PCIA (P < 0.001). Patient-controlled intrathecal analgesia, compared with conventional BTP medications, was "a lot better" in 60.7% and "a little better" in 28.6%. Overall pain control satisfaction was also improved, with 78.2% "a lot better" and 10.9% "I have no pain." CONCLUSIONS: In patients with poorly controlled cancer pain, PCIA is associated with improved pain control, improved cancer related symptoms, and high satisfaction. Compared with conventional BTP regimens, PCIA provides superior analgesia and a 3-fold faster onset of action. PMID- 25923820 TI - A Randomized Comparison Between Single- and Triple-Injection Subparaneural Popliteal Sciatic Nerve Block. AB - BACKGROUND AND OBJECTIVES: This prospective randomized trial compared ultrasound guided single-injection (SI) and triple-injection (TI) subparaneural popliteal sciatic nerve block. We hypothesized that multiple injections are not required when local anesthetic (LA) is deposited under the paraneurium because the latter entraps LA molecules, ensuring circumferential spread around the nerve. Therefore, in addition to comparable success rates, we also expected similar total anesthesia-related times (sum of performance and onset times) and designed this study as an equivalency trial. METHODS: Ultrasound-guided subparaneural posterior popliteal sciatic nerve block was carried out in 100 patients. In the SI group, LA was deposited at a single location between the tibial and peroneal nerves. In the TI group, LA was injected between the tibial and peroneal divisions, medial to the tibial nerve, and lateral to the common peroneal nerve. The total LA volume (15 mL) and mixture (lidocaine 1%-bupivacaine 0.25% epinephrine 5 MUg/mL) were identical in all subjects. The performance time, number of needle passes, and adverse events (paresthesia, neural edema) were recorded by the (nonblinded) investigator supervising the block. A blinded observer evaluated the success rate (sensorimotor composite score >=6/8 points at 30 minutes) as well as the onset time and contacted patients 7 days after the surgery to inquire about persistent numbness or motor deficit. RESULTS: Both techniques provided comparable success rates (92%) and total anesthesia-related times (17.1-19.7 minutes). Expectedly, the SI group required fewer needle passes (1 vs 3; P < 0.001) and a shorter needling time (3.0 +/- 2.3 minutes vs 4.0 +/- 2.3 minutes; P = 0.025). The TI group displayed a shorter onset time (12.5 +/- 7.9 minutes vs 15.8 +/- 7.9 minutes; P = 0.027). The performance time, procedural discomfort, and incidence of paresthesia (14%-20%) were similar between the 2 groups. Sonographic neural swelling was detected in 2 subjects in the SI group. In both cases, the needle was carefully withdrawn and the injection was completed uneventfully. Follow-up of the 100 subjects 1 week after surgery revealed no residual numbness or motor deficit. CONCLUSIONS: Ultrasound-guided SI and TI subparaneural popliteal sciatic nerve blocks result in comparable success rates and total anesthesia-related times. Expectedly, the SI technique requires fewer needle passes. PMID- 25923823 TI - Diseases, patients and the epistemology of practice: mapping the borders of health, medicine and care. AB - Last year saw the 20th anniversary edition of JECP, and in the introduction to the philosophy section of that landmark edition, we posed the question: apart from ethics, what is the role of philosophy 'at the bedside'? The purpose of this question was not to downplay the significance of ethics to clinical practice. Rather, we raised it as part of a broader argument to the effect that ethical questions - about what we should do in any given situation - are embedded within whole understandings of the situation, inseparable from our beliefs about what is the case (metaphysics), what it is that we feel we can claim to know (epistemology), as well as the meaning we ascribe to different aspects of the situation or to our perception of it. Philosophy concerns fundamental questions: it is a discipline requiring us to examine the underlying assumptions we bring with us to our thinking about practical problems. Traditional academic philosophers divide their discipline into distinct areas that typically include logic: questions about meaning, truth and validity; ontology: questions about the nature of reality, what exists; epistemology: concerning knowledge; and ethics: how we should live and practice, the nature of value. Any credible attempt to analyse clinical reasoning will require us to think carefully about these types of question and the relationships between them, as they influence our thinking about specific situations and problems. So, the answers to the question we posed, about the role of philosophy at the bedside, are numerous and diverse, and that diversity is illustrated in the contributions to this thematic edition. PMID- 25923821 TI - Calcitonin gene-related peptide in the joint: contributions to pain and inflammation. AB - Arthritis is the commonest cause of disabling chronic pain, and both osteoarthritis (OA) and rheumatoid arthritis (RA) remain major burdens on both individuals and society. Peripheral release of calcitonin gene-related peptide (CGRP) contributes to the vasodilation of acute neurogenic inflammation. Contributions of CGRP to the pain and inflammation of chronic arthritis, however, are only recently being elucidated. Animal models of arthritis are revealing the molecular and pathophysiological events that accompany and lead to progression of both arthritis and pain. Peripheral actions of CGRP in the joint might contribute to both inflammation and joint afferent sensitization. CGRP and its specific receptors are expressed in joint afferents and up-regulated following arthritis induction. Peripheral CGRP release results in activation of synovial vascular cells, through which acute vasodilatation is followed by endothelial cell proliferation and angiogenesis, key features of chronic inflammation. Local administration of CGRP to the knee also increases mechanosensitivity of joint afferents, mimicking peripheral sensitization seen in arthritic joints. Increased mechanosensitivity in OA knees and pain behaviour can be reduced by peripherally acting CGRP receptor antagonists. Effects of CGRP pathway blockade on arthritic joint afferents, but not in normal joints, suggest contributions to sensitization rather than normal joint nociception. CGRP therefore might make key contributions to the transition from normal to persistent synovitis, and the progression from nociception to sensitization. Targeting CGRP or its receptors within joint tissues to prevent these undesirable transitions during early arthritis, or suppress them in established disease, might prevent persistent inflammation and relieve arthritis pain. PMID- 25923824 TI - Assessment of Left Atrial Function in Patients with Celiac Disease. AB - BACKGROUND: There is some evidence suggesting increased risk of atrial fibrillation (AF) in patients with celiac disease (CD). Impaired left atrial function plays a significant role in the development of AF. This study aimed at assessing the electrical and mechanical functions of the left atrium in patients with CD. METHODS: A total of 71 patients with biopsy-proven, antibody-positive CD and 52 age-matched healthy controls were included in this prospective study. P wave dispersion (PWD) was measured to assess the electrical functions of the left atrium through the use of surface electrocardiography. A tissue Doppler echocardiography was performed to determine the atrial conduction and electromechanical delay (EMD) time. To evaluate the mechanical functions of the left atrium, maximum, minimum, and presystolic atrial volumes were estimated to calculate the contractile, conduit, and reservoir functions. RESULTS: In terms of transthoracic echocardiographic parameters, CD and control subjects were not significantly different. However, as compared to controls, patients with CD had significantly increased PWD (median 52 ms [interquartile range 46-58 ms] vs. 38 [36-40], P < 0.001). Also, significantly higher interatrial (49 ms [32-60] vs. 26 ms [22-28], P < 0.001), intra-left atrial (26 ms [17-44] vs. 14 ms [12-18], P < 0.001), and intra-right atrial (15 ms [8-22] vs. 10 ms [8-14], P < 0.001) EMD was found among CD subjects than controls. Despite an increase in the left atrial volume in patients with CD, conduit and reservoir functions were comparable. CONCLUSIONS: Although atrial mechanical functions are preserved in patients with CD, a slower electrical conduction was found, suggesting an increased risk of AF in this group of patients. PMID- 25923822 TI - Transcriptomic Analysis of Drought Stress Responses in Ammopiptanthus mongolicus Leaves Using the RNA-Seq Technique. AB - Ammopiptanthus mongolicus (Maxim. Ex Kom.) Cheng f., a relic tree of the Tertiary period, plays a critical role in maintaining desert ecosystems in the Mid-Asia region. Genome-scale gene expression profiling studies will provide deep insight into the molecular mechanism underlying the drought tolerance of A. mongolicus. In the present study, we investigated the transcriptional changes induced by drought treatment in A. mongolicus leaves by establishing a comprehensive transcriptome database and then performing a Digital Gene Expression (DGE) analysis using Solexa sequencing technology. A comprehensive transcriptome database was obtained by assembling the Illumina unigenes with expressed sequence tags (EST) available publicly, and other high throughput sequencing data. To analyze the dynamic and complicated gene regulation network during PEG6000 induced drought treatment in leaves of A. mongolicus, a time-course gene expression analysis was performed using tag-based DGE technology, which identified 437, 1,247 and 802 differentially expressed transcripts in 1, 24 and 72 h drought stress libraries, respectively. GO and KEGG analyses revealed hormone signal transduction and phenylpropanoid biosynthesis were enriched during drought treatment. A batch of drought-regulated transcription factor transcripts were identified, including the subsets of HD-ZIP, bZIP, WRKY, AP2/ERF and bHLH family members, which may play roles in drought response in A. mongolicus. The sequence collection assembled in the present study represents one of the most comprehensive transcriptome databases for A. mongolicus currently. The differentially expressed transcripts identified in our study provide a good start for identifying the key genes in stress response and performing functional analysis to reveal their roles in stress adaptation in planta. PMID- 25923825 TI - Tumour-derived exosomes: Tiny envelopes for big stories. AB - The discovery of exosomes, which are small, 30-100 nm sized extracellular vesicles that are released by virtual all cells, has initiated a rapidly expanding and vibrant research field. Current investigations are mainly directed toward the role of exosomes in intercellular communication and their potential value as biomarkers for a broad set of diseases. By horizontal transfer of molecular information such as micro RNAs, messenger RNAs or proteins, as well as by receptor-cell interactions, exosomes are capable to mediate the reprogramming of surrounding cells. Herein, we review how especially cancer cells take advantage of this mechanism to influence their microenvironment in favour of immune escape, therapy resistance, tumour growth and metastasis. Moreover, we provide a comprehensive microarray analysis (n > 1970) to study the expression patterns of genes known to be intimately involved in exosome biogenesis across 26 different cancer entities and a normal tissue atlas. Consistent with the elevated production of exosomes observed in cancer patient plasma, we found a significant overexpression especially of RAB27A, CHMP4C and SYTL4 in the corresponding cancer entities as compared to matched normal tissues. Finally, we discuss the immune modulatory and anti-tumorigenic functions of exosomes as well as innovative approaches to specifically target the exosomal circuits in experimental cancer therapy. PMID- 25923826 TI - Fluorescence Recovery after Photobleaching and Single-Molecule Tracking Measurements of Anisotropic Diffusion within Identical Regions of a Cylinder Forming Diblock Copolymer Film. AB - This work demonstrates ensemble and single-molecule diffusion measurements within identical regions of a cylinder-forming polystyrene-poly(ethylene oxide) diblock copolymer (PS-b-PEO) film using fluorescence recovery after photobleaching (FRAP) and single-molecule tracking (SMT). A PS-b-PEO film (~4 MUm thick) with aligned cylindrical PEO microdomains containing 10 MUM sulforhodamine B (SRB) was prepared by directional solvent-vapor penetration (SVP) of 1,4-dioxane. The ensemble diffusion behavior of SRB in the microdomains was assessed in FRAP studies of circular photobleached regions (~7 MUm in diameter). The SRB concentration was subsequently reduced by additional photobleaching, and the diffusion of individual SRB molecules was explored using SMT in the identical area (~16 * 16 MUm(2)). The FRAP data showed anisotropic fluorescence recovery, yielding the average microdomain orientation. The extent of fluorescence recovery observed (~90%) demonstrated long-range microdomain connectivity, while the recovery time dependence provided an ensemble measurement of the SRB diffusion coefficient within the cylindrical microdomains. The SMT data exhibited one dimensional diffusion of individual SRB molecules along the SVP direction across the entire film thickness, as consistent with the FRAP results. Importantly, the average of the single-molecule diffusion coefficients was close to the value obtained from FRAP in the identical area. In some cases, SMT offered smaller diffusion coefficients than FRAP, possibly due to contributions from SRB molecules confined within short PEO microdomains. The implementation of FRAP and SMT measurements in identical areas provides complementary information on molecular diffusion with minimal influence of sample heterogeneity, permitting direct comparison of ensemble and single-molecule diffusion behavior. PMID- 25923827 TI - Presentation and Clinical Outcomes of Choledochal Cysts in Children and Adults: A Multi-institutional Analysis. AB - IMPORTANCE: Choledochal cysts (CCs) are rare, with risk of infection and cancer. OBJECTIVE: To characterize the natural history, management, and long-term implications of CC disease. DESIGN, SETTING, AND PARTICIPANTS: A total of 394 patients who underwent resection of a CC between January 1, 1972, and April 11, 2014, were identified from an international multi-institutional database. Patients were followed up through September 27, 2014. Clinicopathologic characteristics, operative details, and outcome data were analyzed from May 1, 2014, to October 14, 2014. INTERVENTION: Resection of CC. MAIN OUTCOMES AND MEASURES: Management, morbidity, and overall survival. RESULTS: Among 394 patients, there were 135 children (34.3%) and 318 women (80.7%). Adults were more likely to present with abdominal pain (71.8% vs 40.7%; P < .001) and children were more likely to have jaundice (31.9% vs 11.6%; P < .001). Preoperative interventions were more commonly performed in adults (64.5% vs 31.1%; P < .001), including endoscopic retrograde pancreatography (55.6% vs 27.4%; P < .001), percutaneous transhepatic cholangiography (17.4% vs 5.9%; P < .001), and endobiliary stenting (18.1% vs 4.4%; P < .001)). Type I CCs were more often seen in children vs adults (79.7% vs 64.9%; P = .003); type IV CCs predominated in the adult population (23.9% vs 12.0%; P = .006). Extrahepatic bile duct resection with hepaticoenterostomy was the most frequently performed procedure in both age groups (80.3%). Perioperative morbidity was higher in adults (35.1% vs 16.3%; P < .001). On pathologic examination, 10 patients (2.5%) had cholangiocarcinoma. After a median follow-up of 28 months, 5-year overall survival was 95.5%. On follow-up, 13 patients (3.3%), presented with biliary cancer. CONCLUSIONS AND RELEVANCE: Presentation of CC varied between children and adults, and resection was associated with a degree of morbidity. Although concomitant cancer was uncommon, it occurred in 3.0% of the patients. Long-term surveillance is indicated given the possibility of future development of biliary cancer after CC resection. PMID- 25923828 TI - Studying Axonal Outgrowth and Regeneration of the Corticospinal Tract in Organotypic Slice Cultures. AB - Studies of axonal outgrowth and regeneration after spinal cord injury are hampered by the complexity of the events involved. Here, we present a simple and improved in vitro approach to investigate outgrowth, regeneration of the corticospinal tract, and intrinsic parenchymal responses. We prepared organotypic co-cultures using explants from the motor cortex of postnatal donor mice ubiquitously expressing green fluorescent protein and cervical spinal cord from wild type pups of the same age. Our data show that: a) motor-cortical outgrowth is already detectable after 1 d in culture and is source specific; b) treatment with neurotrophin-3 and C3 transferase from Clostridium botulinum significantly enhances axonal outgrowth during the course of cultivation; c) outgrowing axons form synaptic connections, as demonstrated by immunohistochemistry and calcium imaging; and d) migrating cells of motor-cortical origin can be reliably identified without previous tracing and are mostly neural precursors that survive and mature in the spinal cord parenchyma. Thus, our model is suitable for screening for candidate substances that enhance outgrowth and regeneration of the corticospinal tract and for studying the role of endogenous neural precursors after lesion induction. PMID- 25923829 TI - High temperature X-ray diffraction and thermo-gravimetrical analysis of the cubic perovskite Ba0.5Sr0.5Co0.8Fe0.2O3-delta under different atmospheres. AB - Ba(0.5)Sr(0.5)Co(0.8)Fe(0.2)O(3-delta) (BSCF) with the cubic perovskite structure is known to be metastable at low temperature under an oxidizing atmosphere. Here, the thermal and chemical expansion of BSCF were studied by in situ high temperature powder X-ray diffraction and thermo-gravimetrical analysis (TGA) in partial pressure of oxygen ranging from an inert atmosphere (~10(-4) bar) to 10 bar O(2). The BSCF powder, heat treated at 1000 degrees C and quenched to ambient temperature prior to the analysis, was shown to oxidize under an oxidizing atmosphere before thermal reduction took place. With decreasing partial pressure of oxygen the initial oxidation was suppressed and only reduction of Co/Fe and loss of oxygen were observed under an inert atmosphere. The thermal expansion of BSCF under different atmospheres was determined from the thermal evolution of the cubic unit cell parameter, demonstrating that the thermal expansion of BSCF depends on the atmosphere. Chemical expansion of BSCF was also estimated based on the diffraction data and thermo-gravimetrical analysis. A hexagonal perovskite phase, coexisting with the cubic BSCF polymorph, was observed to be formed above 600 degrees C during heating. The phase separation leading to the formation of the hexagonal polymorph was driven by oxidation, and the unit cell of the cubic BSCF was shown to decrease with increasing amounts of the hexagonal phase. The hexagonal phase disappeared upon further heating, accompanied with an expansion of the unit cell of the cubic BSCF. PMID- 25923831 TI - Intravascular carcinomatosis of central nervous system due to metastatic inflammatory breast cancer: A case report. AB - Central nervous system (CNS) involvement by metastatic cancer is well-recognized and typically presents with multifocal solid tumors within the brain parenchyma or leptomeningeal dissemination. We describe herein a histologically very rare case of CNS metastasis in a 52-year-old woman who presented with mental status changes. Post mortem examination revealed extensive CNS involvement by metastatic inflammatory breast carcinoma, characterized by the presence of single tumor cells diffusely present within capillaries without parenchymal or perivascular invasion, and acute ischemic changes/infarcts bilaterally involving multiple areas. The cancer cells were found predominantly in the cerebral cortices and deep gray matter structures. Pre-mortem magnetic resonance and CT imaging of the brain did not identify metastatic cancer; however, widespread ischemic changes (i.e. brain infarcts) were identified. Inflammatory breast carcinoma is well known to have a predilection for spread through lymphovascular spaces. Post mortem examination revealed tumor involvement of bilateral lungs, heart and bladder, with sinusoidal spread in the liver and lymph nodes and prominent involvement of the splenic red pulp in addition to extensive vascular involvement of the brain and spinal cord without a discrete mass, despite the presence of widely metastatic disease. The tumor cells in the CNS were strongly immunoreactive for pancytokeratin, E-cadherin, cytokeratin-7, epithelial membrane antigen and CAM 5.2. This unique histologic pattern of tumor spread is considered to represent "intravascular carcinomatosis" in the CNS, and most likely the cause of the patient's widespread ischemic injuries. PMID- 25923832 TI - Multiedge X-ray Absorption Spectroscopy Part II: XANES Analysis of Bridging and Terminal Chlorides in Hexachlorodipalladate(II) Complex. AB - X-ray absorption spectroscopy is a unique experimental technique that can provide ground state electronic structure information about transition metal complexes with unoccupied d-manifold. The quantitative treatments of pre-edge and rising edge features have already been developed for the sulfur- and chlorine-ligand K edge excitations. The complementarity of using multiple core excitation edges from hard, tender, and soft X-ray energy regions has been defined for the first paper of this series. The given study provides compelling evidence for the transferability of the empirical transition dipole integral from ligand K-edge to metal L-edge and back to ligand K-edge in the tender X-ray energy range. The case study was performed for a series of homoleptic chloropalladium compounds at the chlorine K- and palladium L-edges. We propose the method described here to be generally applicable for other core level excitations, where complementarity of ground state electronic structural information from XANES analysis can provide the complete electronic structure description. PMID- 25923830 TI - Paradoxical effect of dopamine medication on cognition in Parkinson's disease: relationship to side of motor onset. AB - Parkinson's disease (PD) is characterized by asymmetric motor symptom onset attributed to greater degeneration of dopamine neurons contralateral to the affected side. However, whether motor asymmetries predict cognitive profiles in PD, and to what extent dopamine influences cognition remains controversial. This study evaluated cognitive variability in PD by measuring differential response to dopamine replacement therapy (DRT) based on hemispheric asymmetries. The influence of DRT on cognition was evaluated in mild PD patients (n = 36) with left or right motor onset symptoms. All subjects were evaluated on neuropsychological measures on and off DRT and compared to controls (n = 42). PD patients were impaired in executive, memory and motor domains irrespective of side of motor onset, although patients with left hemisphere deficit displayed greater cognitive impairment. Patients with right hemisphere deficit responded to DRT with significant improvement in sensorimotor deficits, and with corresponding improvement in attention and verbal memory functions. Conversely, patients with greater left hemisphere dopamine deficiency did not improve in attentional functions and declined in verbal memory recall following DRT. These findings support the presence of extensive mild cognitive deficits in early PD not fully explained by dopamine depletion alone. The paradoxical effects of levodopa on verbal memory were predicted by extent of fine motor impairment and sensorimotor response to levodopa, which reflects extent of dopamine depletion. The findings are discussed with respect to factors influencing variable cognitive profiles in early PD, including hemispheric asymmetries and differential response to levodopa based on dopamine levels predicting amelioration or overdosing. PMID- 25923833 TI - Determining local geometrical features of grain boundaries from microscopy. AB - Grain boundaries are solid-solid interfaces whose dynamics is driven by their local curvature. As they are fluctuating interfaces and have a width comparable to the lattice spacing of the surrounding grains, the determination of their local geometrical characteristics is difficult. Here we present a method to determine the local normal direction, tangent plane and curvature of grain boundaries from microscopy images using point sampled surface analysis techniques. We apply our algorithm to study the boundary of a shrinking grain in a two-dimensional colloidal polycrystalline material. Our method is easily generalized to three dimensions, which makes it applicable to the wide range of interfaces encountered in soft matter. PMID- 25923834 TI - Radiation-driven lipid accumulation and dendritic cell dysfunction in cancer. AB - Dendritic cells (DCs) play important roles in the initiation and maintenance of the immune response. The dysfunction of DCs contributes to tumor evasion and growth. Here we report our findings on the dysfunction of DCs in radiation induced thymic lymphomas, and the up-regulation of the expression of the lipoprotein lipase (LPL) and the fatty acid binding protein (FABP4), and the level of triacylglycerol (TAG) in serum after total body irradiation, which contribute to DCs lipid accumulation. DCs with high lipid content showed low expression of co-stimulatory molecules and DCs-related cytokines, and were not able to effectively stimulate allogeneic T cells. Normalization of lipid abundance in DCs with an inhibitor of acetyl-CoA carboxylase restored the function of DCs. A high-fat diet promoted radiation-induced thymic lymphoma growth. In all, our study shows that dysfunction of DCs in radiation-induced thymic lymphomas was due to lipid accumulation and may represent a new mechanism in radiation-induced carcinogenesis. PMID- 25923835 TI - Involvement of Rho-Kinase/LIM Kinase/Cofilin Signaling Pathway in Corporal Fibrosis after Cavernous Nerve Injury in Male Rats. AB - INTRODUCTION: The molecular mechanism of corporal fibrosis leading to erectile dysfunction (ED) following cavernous nerve (CN) injury is poorly understood. AIM: To determine whether the LIMK2/cofilin pathway, the downstream effectors of ROCK1, was involved in ED and corporal fibrosis following bilateral CN injury in male rats. METHODS: Forty-eight 10-week-old male Sprague-Dawley rats were equally divided into three groups: sham surgery (S); bilateral CN crush injury (I); and bilateral CN resection (R). Within each groups, two subgroups were analyzed at 1 and 4 weeks postoperatively. MAIN OUTCOME MEASURES: Electrostimulation was performed to assess erectile function by the ratio of maximal intracavernous pressure to mean arterial pressure (ICP/MAP) and areas under the ICP curve to MAP (AUC/MAP). Penile tissue was processed for Masson's trichrome staining, Western blot (ROCK1, total LIMK2, phospho-LIMK2, total cofilin, phospho-cofilin), immunohistochemistry (alpha-SM actin [alpha-SMA]), and double immunofluorescent staining (ROCK1, phospho-LIMK2, vimentin). RESULTS: At each time point, both I and R groups showed a significantly lower percent of ICP/MAP and AUC, and decreased SM cell/collagen ratio and expression of alpha-SMA than S group. Densitometry revealed a significantly higher expression of ROCK1 in I and R groups compared with S group at all time points. The LIMK2 phosphorylation in I and R groups significantly increased at 1 week, but not at 4 weeks. The cofilin phosphorylation in R group significantly increased to that in S group starting at 1 week, while that in I group was increased significantly at 4 weeks. The double immunofluorescent staining noted that coexpression of vimentin with ROCK1 or phospho-LIMK2 in I and R groups was significantly increased mainly in the subtunical area at 1 week but not at 4 weeks. CONCLUSIONS: The ROCK1/LIMK2/cofilin pathway may be involved in ED related to corporal fibrosis, and it appears to be functional particularly in the early period after CN injury. PMID- 25923836 TI - 'The first pulse you take is your own' - but don't forget your colleagues'. Emotion teamwork in pre-hospital emergency medical services. AB - This article examines the way that intense emotions, both positive and negative, are collectively regulated at work by pre-hospital emergency teams. We analyse the collective strategies and solutions that are developed in daily medical work by teams and individuals with a view to furthering the action. After a review of the literature on emotion work in work collectives, we discuss the nature of pre hospital emergency work and the role of emotions in this work. We then examine the collective management of both disruptive and desired emotions by teams during interventions. The last section reflects on the long-term management of emotions at work using Randall Collins' concepts of interaction ritual and emotional energy. This study relies on fieldwork performed in emergency medical services in New York and Paris. PMID- 25923837 TI - Generalized Eruptive Histiocytosis Associated With FIP1L1-PDGFRA-Positive Chronic Eosinophilic Leukemia. AB - IMPORTANCE: Generalized eruptive histiocytosis (GEH) is a rare non-Langerhans cell histiocytosis with a benign, self-healing course. Neoplastic hematologic disorders of the myeloid lineage have been reported in association with GEH in 4 patients. A clonal association between GEH and the underlying leukemia was suspected in these patients but could only be confirmed in one patient. OBSERVATIONS: A male patient in his 20s presented with asymptomatic red to brown macules and papules. A skin biopsy confirmed a diagnosis of GEH. His blood cell count revealed hypereosinophilia. Morphologic and molecular analyses from bone marrow and blood samples revealed FIP1L1-PDGFRA-positive chronic eosinophilic leukemia. The patient was treated with imatinib and achieved complete clinical remission of his leukemia and the GEH. CONCLUSIONS AND RELEVANCE: To our knowledge, this is the first report of a patient with GEH associated with FIP1L1 PDGFRA-positive chronic eosinophilic leukemia. Generalized eruptive histiocytosis in association with a myeloid neoplasm may occur in 2 variants: a reactive condition or a clonal derivative of the underlying leukemia. In this case, both diseases responded well after initiation of treatment with imatinib. PMID- 25923838 TI - Food environments and childhood weight status: effects of neighborhood median income. AB - BACKGROUND: A key aspect of any intervention to improve obesity is to better understand the environment in which decisions are being made related to health behaviors, including the food environment. METHODS: Our aim was to examine the extent to which proximity to six types of food establishments is associated with BMI z-score and explore potential effect modification of this relationship. We used geographical information software to determine proximity from 49,770 pediatric patients' residences to six types of food establishments. BMI z-score obtained from the electronic health record was the primary outcome. RESULTS: In multivariable analyses, living in closest proximity to large (beta, -0.09 units; 95% confidence interval [CI], -0.13, -0.05) and small supermarkets (-0.08 units; 95% CI, -0.11, -0.04) was associated with lower BMI z-score; living in closest proximity to fast food (0.09 units; 95% CI, 0.03, 0.15) and full-service restaurants (0.07 units; 95% CI, 0.01, 0.14) was associated with a higher BMI z score versus those living farthest away. Neighborhood median income was an effect modifier of the relationships of convenience stores and full-service restaurants with BMI z-score. In both cases, closest proximity to these establishments had more of an adverse effect on BMI z-score in lower-income neighborhoods. CONCLUSIONS: Living closer to supermarkets and farther from fast food and full service restaurants was associated with lower BMI z-score. Neighborhood median income was an effect modifier; convenience stores and full-service restaurants had a stronger adverse effect on BMI z-score in lower-income neighborhoods. PMID- 25923839 TI - Clinical and technical feasibility of ultra-boost irradiation in Dominant Intraprostatic Lesion by Tomotherapy: preliminary experience and revision of literature. AB - BACKGROUND: The aim of this paper was to present our experience of dominant intraprostatic lesions (DIL) irradiation up to an EQD2 of 93,2 Gy with helical tomotherapy. METHODS: Between March 2012 and December 2014, 15 staged II-III patients with intermediate-high risk prostate cancer were enrolled in our protocol of DIL dose escalation by Tomotherapy. All patients were submitted to a multiparametric MRI (including DCE and DWI series), in order to visualize DILs. Considering a mean alpha/beta ratio of 3 for prostate cancer the prescribed doses were: 83.2 Gy in 32 fractions of 2.6 per fraction (EQD2=93.2 Gy) on the DILs, 75.2 Gy in 32 fractions of 2.35 Gy per fraction (EQD2=80.5 Gy) on the prostate gland and 67.2 Gy in 32 fraction of 2.1 (EQD2=68.5 Gy) on the seminal vesicles. RESULTS: With a mean follow-up of 16 months (range 2-39), no overall severe acute toxicities >G3 were observed; one patient out of 15 (6.6%) had acute gastrointestinal (GI) toxicity equal to G2, while two cases (13.3%) had G2 acute genitourinary (GU) toxicity. No >G2 late toxicity was observed. At last follow up, for all patients, the biochemical disease free survival was 100%. CONCLUSIONS: The irradiation of the whole prostate and seminal vesicles up to an EQD2 of 80.5 Gy and of DILs up to 93.2 Gy was clinically feasible and safe, without acute severe toxicity. Although with a short follow-up, late toxicities are currently absent and no patient relapsed. PMID- 25923840 TI - ZnRF3 induces apoptosis of gastric cancer cells by antagonizing Wnt and Hedgehog signaling. AB - AIM: The aim of this paper was to investigate the function an importance of E3 ubiquitin ligase ZnRF3 in the progression of cancer cell growth. METHODS: A total of 58 patients (44 males and 14 females) were enrolled in the study and their gastric tumors were removed surgically and were staged by the TNM approach. Among these patients, 43 patients died and 15 survived at the time of this study. The tumors and the paracancerous tissues were examined by immunohostochemistry for the expression of ZnRF3. We assessed the expression of ZnRF3 in gastric tumors and paracancerous tissues from our patients and related this to patient survival. RESULTS: A large proportion of malignant cancers of the stomach are gastric adenocarcinoma type. In spite of many studies, the molecular basis for this cancer is still unclear. Deregulated cell proliferative signaling via Wnt/beta catenin and Hedgehog pathways is considered important in the pathogenesis of many cancers including the gastric cancer. Recent studies identified ZnRF3 protein, which is a E3-ubiquitin ligase and which is either deleted or mutated in cancers, to inhibit Wnt signaling. However, the significance of ZnRF3 in the control of gastric cancer and whether it also regulates Hedgehog signaling pathway, is not known. ZnRF3 expression was much higher in tumors from aged patients. Male patients showed higher mortality than the females. Mechanistic studies using normal gastric cells (GES1) and gastric cancer cells (MGC-803) infected with either AdZnRF3 or AdGFP viral vectors, revealed that ZnRF3 overexpression causes significantly more apoptosis and lowered proliferation of cancer cells. ZnRF3 overexpression led to greatly reduced levels of Lgr5, a component of Wnt signaling and also Gli1, a component of Hedgehog signaling. Thus, ZnRF3 negatively influences both the Wnt and Hedgehog proliferative pathways and probably this way it negatively regulates cancer progression. These results suggest the importance of normal ZnRF3 function in checking the progression of cancer cell growth and indicate that a lack of this protein can lead to poorer clinical outcomes for gastric cancer patients. CONCLUSION: We observed a clear relationship between ZnRF3 expression in paracancerous tissue and tumor size. PMID- 25923841 TI - Demonstration of Confined Electron Gas and Steep-Slope Behavior in Delta-Doped GaAs-AlGaAs Core-Shell Nanowire Transistors. AB - Strong surface and impurity scattering in III-V semiconductor-based nanowires (NW) degrade the performance of electronic devices, requiring refined concepts for controlling charge carrier conductivity. Here, we demonstrate remote Si delta (delta)-doping of radial GaAs-AlGaAs core-shell NWs that unambiguously exhibit a strongly confined electron gas with enhanced low-temperature field-effect mobilities up to 5 * 10(3) cm(2) V(-1) s(-1). The spatial separation between the high-mobility free electron gas at the NW core-shell interface and the Si dopants in the shell is directly verified by atom probe tomographic (APT) analysis, band profile calculations, and transport characterization in advanced field-effect transistor (FET) geometries, demonstrating powerful control over the free electron gas density and conductivity. Multigated NW-FETs allow us to spatially resolve channel width- and crystal phase-dependent variations in electron gas density and mobility along single NW-FETs. Notably, dc output and transfer characteristics of these n-type depletion mode NW-FETs reveal excellent drain current saturation and record low subthreshold slopes of 70 mV/dec at on/off ratios >10(4)-10(5) at room temperature. PMID- 25923842 TI - Large-scale fabrication of commercially available, nonpolar linear polymer film with a highly ordered honeycomb pattern. AB - Highly ordered, hexagonally patterned poly(methyl methacrylate) (PMMA) thin film is successfully fabricated using an improved phase separation method. A mixture of chloroform and methanol, which is used as a volatile solvent/nonsolvent pair, effectively controls the surface morphology and sensitively determines the ordered pattern. In particular, the methanol accumulation, which induces the formation of a gel-like protective layer and enhances the lateral capillary force, is crucial in the formation of the highly ordered hexagonal pattern even when using a nonpolar polymer such as PMMA. The convergence of cost-effective and large-scale production of highly ordered micropatterned film has wide potential for application, and it can enable new prospects for the commercialization of future high-tech devices that require specific multifunctionality. PMID- 25923843 TI - Atomistic modeling to optimize composition and characterize structure of Ni-Zr-Mo metallic glasses. AB - An interatomic potential was constructed for the Ni-Zr-Mo ternary metal system with the newly proposed long-range empirical formulism, which has been verified to be applicable for fcc, hcp and bcc transition metals and their alloys. Applying the constructed potential, molecular dynamics simulations predict a hexagonal composition region within which metallic glass formation is energetically favored. Based on the simulation results, the driving force for amorphous phase formation is derived, and thus an optimized composition is pinpointed to Ni45Zr40Mo15, of which the metallic glass could be most stable or easiest to obtain. Further structural analysis indicates that the dominant interconnected clusters for Ni64Zr36-xMox MGs are <0, 0, 12, 0>, <0, 1, 10, 2>, <0, 2, 8, 2> and <0, 3, 6, 4>. In addition, it is found that the appropriate addition of Mo content could not only make a more ordered structure with a higher atomic packing density and a lower energy state, but also improve the glass formation ability of Ni-Zr-Mo alloys. Moreover, inherent hierarchical atomic configurations for ternary Ni-Zr-Mo metallic glasses are clarified via the short range, medium-range and further in the extended scale of the icosahedral network. PMID- 25923844 TI - Fungal effectors and plant susceptibility. AB - Plants can be colonized by fungi that have adopted highly diverse lifestyles, ranging from symbiotic to necrotrophic. Colonization is governed in all systems by hundreds of secreted fungal effector molecules. These effectors suppress plant defense responses and modulate plant physiology to accommodate fungal invaders and provide them with nutrients. Fungal effectors either function in the interaction zone between the fungal hyphae and host or are transferred to plant cells. This review describes the effector repertoires of 84 plant-colonizing fungi. We focus on the mechanisms that allow these fungal effectors to promote virulence or compatibility, discuss common plant nodes that are targeted by effectors, and provide recent insights into effector evolution. In addition, we address the issue of effector uptake in plant cells and highlight open questions and future challenges. PMID- 25923846 TI - An alternative approach in regulation of expression of a transgene by endogenous miR-145 in carcinoma and normal breast cell lines. AB - MicroRNAs are small noncoding RNAs that regulate gene expression by repressing translation of target cellular transcripts. Increasing evidences indicate that miRNAs have different expression profiles and play crucial roles in numerous cellular processes. Delivery and expression of transgenes for cancer therapy must be specific for tumors to avoid killing of healthy tissues. Many investigators have shown that transgene expression can be suppressed in normal cells using vectors that are responsive to microRNA regulation. To overcome this problem, miR 145 that exhibits downregulation in many types of cancer cells was chosen for posttranscriptional regulatory systems mediated by microRNAs. In this study, a psiCHECK-145T vector carrying four tandem copies of target sequences of miR-145 into 3'-UTR of the Renilla luciferase gene was constructed. Renilla luciferase activity from the psiCHECK-145T vector was 57% lower in MCF10A cells with high miR-145 expression as compared to a control condition. Additionally, overexpression of miR-145 in MCF-7 cells with low expression level of miR-145 showed more than 76% reduction in the Renilla luciferase activity from the psiCHECK-145T vector. Inclusion of miR-145 target sequences into the 3'-UTR of the Renilla luciferase gene is a feasible strategy for restricting transgene expression in a breast cancer cell line while sparing a breast normal cell line. PMID- 25923845 TI - Ablation of the p16(INK4a) tumour suppressor reverses ageing phenotypes of klotho mice. AB - The p16(INK4a) tumour suppressor has an established role in the implementation of cellular senescence in stem/progenitor cells, which is thought to contribute to organismal ageing. However, since p16(INK4a) knockout mice die prematurely from cancer, whether p16(INK4a) reduces longevity remains unclear. Here we show that, in mutant mice homozygous for a hypomorphic allele of the alpha-klotho ageing suppressor gene (kl(kl/kl)), accelerated ageing phenotypes are rescued by p16(INK4a) ablation. Surprisingly, this is due to the restoration of alpha-klotho expression in kl(kl/kl) mice and does not occur when p16(INK4a) is ablated in alpha-klotho knockout mice (kl(-/-)), suggesting that p16(INK4a) is an upstream regulator of alpha-klotho expression. Indeed, p16(INK4a) represses alpha-klotho promoter activity by blocking the functions of E2Fs. These results, together with the observation that the expression levels of p16(INK4a) are inversely correlated with those of alpha-klotho throughout ageing, indicate that p16(INK4a) plays a previously unrecognized role in downregulating alpha-klotho expression during ageing. PMID- 25923847 TI - Neuroimaging and neuropsychological consequences of cardiac arrest. PMID- 25923848 TI - A season of change for the journal of neuropsychiatry and clinical neurosciences. PMID- 25923849 TI - A Novel Anxiety and Affective Spectrum Disorder of Mind and Body-The ALPIM (Anxiety-Laxity-Pain-Immune-Mood) Syndrome: A Preliminary Report. AB - The authors describe a spectrum disorder comprising a core anxiety (A) disorder and four domains: joint laxity (L), chronic pain syndromes (P), immune disorders (I), and mood disorders (M)-dubbed the ALPIM syndrome. This study examined 76 consecutive outpatients with an anxiety disorder plus at least one somatic condition from three domains. More than 80% of the patients had panic attacks, fibromyalgia, and major depressive episodes. Associations were found between joint laxity and bipolar III, headache with bipolar II, and bipolar II with chronic fatigue syndrome. Significant relationships were demonstrated within and between domains, validating ALPIM as a syndrome. PMID- 25923851 TI - The impact of emotional distress on motor blocks and festination in Parkinson's disease. AB - Recent studies suggest that depression and anxiety in patients with Parkinson's disease may predispose them to freezing. Although festination is also frequent, the association with emotional disorders has not been examined. The aim of the authors was to clarify the association between freezing and festination with anxiety, depressive disorders, and emotional distress. The authors examined a consecutive series of 95 patients with Parkinson's disease using comprehensive psychiatric assessments and a new instrument specifically designed to assess the severity of freezing, festination, and emotional distress (Motor Blocks and Festination Scale). All patients were assessed with the Motor Blocks and Festination Scale, the Mini International Neuropsychiatric Interview, and scales to measure the severity of mood and anxiety disorders. A linear regression analysis showed that both motor blocks and festination were significantly associated with emotional distress and deficits on activities of daily living. Conversely, there was no significant association between motor blocks or festination and generalized anxiety disorder, panic disorder, agoraphobia, social phobia, or depression. Motor blocks and festination are significantly associated with emotional distress, but no significant associations were found with anxiety or affective disorders. PMID- 25923850 TI - Psychiatric disorders in children and adolescents 24 months after mild traumatic brain injury. AB - This study aimed to better understand the occurrence of novel psychiatric disorders (NPDs) in children with mild traumatic brain injury (mTBI) in relation to preinjury variables, injury-related variables, and concurrent neurocognitive outcome. Eighty-seven children aged 5-14 years who had experienced mTBI were studied from consecutive hospital admissions with semistructured psychiatric interviews soon after injury (baseline). Fifty-four children were reassessed 24 months postinjury. Standardized instruments were used to evaluate injury severity, lesion characteristics, preinjury variables (lifetime psychiatric disorder, family psychiatric history, family function, socioeconomic status, psychosocial adversity, adaptive function, and academic function), and finally, postinjury neurocognitive and adaptive function. At 24 months postinjury, NPDs had occurred in 17 of 54 (31%) participants. NPD at 24 months was related to frontal white matter lesions and was associated with estimated preinjury reading, preinjury adaptive function, and concurrent deficits in reading, processing speed, and adaptive function. These findings extend earlier reports that the psychiatric morbidity after mTBI in children is more common than previously thought, and moreover, it is linked to preinjury individual variables and injury characteristics and is associated with postinjury adaptive and neurocognitive functioning. PMID- 25923852 TI - A trial of d-cycloserine to treat the social deficit in older adolescents and young adults with autism spectrum disorders. AB - Autism spectrum disorders are difficult for older adolescents and young adults as impaired social communication affects the transition to adult life. d Cycloserine, a partial glycine agonist at the N-methyl-d-aspartic acid receptor, was tested in a double-blind randomized trial in 20 older adolescents and young adults with autism spectrum disorders using two dosing strategies (50 mg daily versus 50 mg weekly) for 8 weeks with a 2-week follow-up after discontinuation. d Cycloserine caused statistically and clinically significant improvement with no differentiation between dosing strategies on the Social Responsiveness Scale and the Aberrant Behavior Checklist before and after d-cycloserine administration. PMID- 25923853 TI - Man Versus Machine Part 2: Comparison of Radiologists' Interpretations and NeuroQuant Measures of Brain Asymmetry and Progressive Atrophy in Patients With Traumatic Brain Injury. AB - This study is an expanded version of an earlier study, which compared NeuroQuant measures of MRI brain volume with the radiologist's traditional approach in outpatients with mild or moderate traumatic brain injury. NeuroQuant volumetric analyses were compared with the radiologists' interpretations. NeuroQuant found significantly higher rates of atrophy (50.0%), abnormal asymmetry (83.3%), and progressive atrophy (70.0%) than the radiologists (12.5%, 0% and 0%, respectively). Overall, NeuroQuant was more sensitive for detecting at least one sign of atrophy, abnormal asymmetry, or progressive atrophy (95.8%) than the traditional radiologist's approach (12.5%). PMID- 25923854 TI - Higher-dose uses of zolpidem will increase the subsequent risk of developing benign brain tumors. AB - This study identified 37,810 patients with anxiety or sleep disorder (mean age=53.2 years, SD=16.0 years) who had zolpidem prescribed for at least 2 months from January 1, 2000 through December 31, 2009. Another non-zolpidem cohort was selected by 1:1 matching with the zolpidem cohort on the estimated probability (propensity score) of being treated. The zolpidem cohort had a higher incidence of benign brain tumors compared with the non-zolpidem cohort, particularly for elderly patients. The matched propensity score analysis showed that the highest risk of benign brain tumors occurred in participants with zolpidem exposure >=520 mg/year (hazard ratio=1.85, 95% confidence interval=1.21-2.82) compared with those not taking zolpidem. PMID- 25923855 TI - Confirmatory Factor Analysis of the Delirium Rating Scale Revised-98 (DRS-R98). AB - Principal components analysis applied to the Delirium Rating Scale-Revised-98 contributes to understanding the delirium construct. Using a multisite pooled international delirium database, the authors applied confirmatory factor analysis to Delirium Rating Scale-Revised-98 scores from 859 adult patients evaluated by delirium experts (delirium, N=516; nondelirium, N=343). Confirmatory factor analysis found all diagnostic features and core symptoms (cognitive, language, thought process, sleep-wake cycle, motor retardation), except motor agitation, loaded onto factor 1. Motor agitation loaded onto factor 2 with noncore symptoms (delusions, affective lability, and perceptual disturbances). Factor 1 loading supports delirium as a single construct, but when accompanied by psychosis, motor agitation's role may not be solely as a circadian activity indicator. PMID- 25923857 TI - ON-OFF Effects of Dopaminergic Therapy on Psychiatric Symptoms in Parkinson's Disease. AB - Psychiatric manifestations of Parkinson's disease (PD) are a cause of significant disability and the impact of dopaminergic medications is unclear. Using standardized rating scales, the authors tested the hypothesis that anxiety, depression, and apathy vary in the ON versus OFF states in PD in 33 PD patients and 29 healthy age- and education-matched controls. PD patients had significantly higher anxiety, depression, and apathy scores than control participants, regardless of ON-OFF state. Anxiety scores were higher in PD patients on relative to off dopaminergic medication. The ON-OFF difference in anxiety related to degree of improvement in motor function but not illness duration. PMID- 25923856 TI - Clinical correlates of superior temporal gyrus volume abnormalities in antipsychotic-naive schizophrenia. AB - In this study, the authors report superior temporal gyrus (STG) and Heschl's gyrus (HG) volume deficits in a large sample of medication-naive patients with schizophrenia (N=55) in comparison with healthy control subjects (N=45) with structural MRI using voxel-based morphometry. Patients had significantly smaller volumes of left HG [X=-41, Y=-22, Z=11; Brodmann's area (BA)-41), right HG (X=47, Y=-18, Z=11; BA-41), and left STG (X=-50, Y=-34, Z=11; BA-42] compared with healthy control subjects. In addition, Positive and Negative Syndrome Scale positive score had a significant negative correlation with left HG. Findings observed in a large sample of antipsychotic-naive patients with schizophrenia emphasize the role of HG and STG in the pathophysiology of schizophrenia. PMID- 25923858 TI - Tacrolimus neurotoxicity and the role of the Renin-Angiotensin system. PMID- 25923859 TI - Negative symptoms in neuropsychiatric systemic lupus erythematosus. PMID- 25923860 TI - Clonazepam needs to be taken care for refractory epilepsy: a rare case and review. PMID- 25923861 TI - Low doses of benzodiazepines for catatonia associated with systemic lupus erythematosus. PMID- 25923862 TI - Neurological and psychiatric findings of marchiafava-bignami disease in a nonalcoholic diabetic patient with high blood glucose levels. PMID- 25923863 TI - Man in the Mirror: Delusion of Misidentification in Down's Syndrome With Alzheimer's Disease. PMID- 25923864 TI - Anti-N-Methyl-D-Aspartate Receptor Encephalitis Presenting With Psychiatric Symptoms. PMID- 25923865 TI - Phonagnosia and inability to perceive time passage in right parietal lobe epilepsy. PMID- 25923866 TI - Reversible mirror clock drawing after acute right frontoparietal lobe infarct. PMID- 25923867 TI - Posttraumatic panhypopituitarism with depression. PMID- 25923868 TI - Acute pisa syndrome as a neurological emergency. PMID- 25923869 TI - Catatonia and kluver-bucy syndrome in a patient with acute disseminated encephalomyelitis. PMID- 25923870 TI - Improvement in athletic performance as an early symptom of behavioral variant frontotemporal dementia. PMID- 25923871 TI - Poststroke subcortical aphasia and neurobehavioral disturbances without motor or sensory deficits. PMID- 25923872 TI - Melancholia Associated With Severe Cognitive Disorders as the Expression of Late Onset Postpartum Anti-N-Methyl-d-Aspartic Acid Receptor Limbic Encephalitis. PMID- 25923873 TI - Enhanced Olfactory Cortex Connectivity in a Patient With PTSD With Olfactory Hallucinations. PMID- 25923874 TI - Unusual Case of Sporadic Creutzfeldt-Jakob Disease Subtype VV1. PMID- 25923875 TI - Differentiating frontotemporal dementia from catatonia: a complex neuropsychiatric challenge. PMID- 25923876 TI - Priming rTMS for Treatment Resistant Auditory Hallucinations in Schizophrenia. PMID- 25923878 TI - A case of sodium picosulphate-induced rhabdomyolysis. PMID- 25923879 TI - Empirically Supported Interventions for Sexual and Gender Minority Youth. AB - When empirically supported treatments (ESTs) are effectively adapted for use with minority populations, they may be more efficacious. As such, there is a need to adapt existing ESTs for use with diverse sexual and gender minority youth (SGMY). The unique bias-based challenges faced by SGMY require the integration of affirmative practices into ESTs to effectively address the specific needs of this underserved group of youth. The primary purpose of the authors in this article is to present a clearly articulated stakeholder driven model for developing an affirmative adapted version of cognitive behavioral therapy (CBT) for use with diverse SGMY. The authors' approach to adaptation follows the "adapt and evaluate" framework for enhancing cultural congruence of interventions for minority groups. A community based participatory research approach, consistent with a stakeholder driven process, is utilized to develop the intervention from the ground up through the voices of the target community. Researchers conducted 3 focus groups with culturally diverse SGMY to explore salient aspects of youths' cultural and SGM identities in order to inform the intervention and ensure its applicability to a wide range of SGMY. Focus group data is analyzed and integrated into an existing group-based CBT intervention. The following themes emerge as critical to affirmative work with diverse SGMY: (1) the interplay between cultural norms, gender norms, sexual orientation, and gender identity; (2) the complex role of religious community within the lives of SGMY; and (3) consideration of extended family and cultural community as youth navigate their SGM identities. PMID- 25923880 TI - Memory effects in schematic models of glasses subjected to oscillatory deformation. AB - We consider two schematic models of glasses subjected to oscillatory shear deformation, motivated by the observations, in computer simulations of a model glass, of a nonequilibrium transition from a localized to a diffusive regime as the shear amplitude is increased, and of persistent memory effects in the localized regime. The first of these schematic models is the NK model, a spin model with disordered multi-spin interactions previously studied as a model for sheared amorphous solids. The second model, a transition matrix model, is an abstract formulation of the manner in which occupancy of local energy minima evolves under oscillatory deformation cycles. In both of these models, we find a behavior similar to that of an atomic model glass studied earlier. We discuss possible further extensions of the approaches outlined. PMID- 25923881 TI - Magneto-responsive alginate capsules. AB - Upon incorporation of magnetic nanoparticles (mNPs) into gels, composite materials called ferrogels are obtained. These magneto-responsive systems have a wide range of potential applications including switches and sensors as well as drug delivery systems. In this article, we focus on the properties of calcium alginate capsules, which are widely used as carrier systems in medicine and technology. We studied the incorporation of different kinds of mNPs in matrix capsules and in the core and the shell of hollow particles. We found out that not all particle-alginate or particle-CaCl2 solution combinations were suitable for a successful capsule preparation on grounds of a destabilization of the nanoparticles or the polymer. For those systems allowing the preparation of switchable beads or capsules, we systematically studied the size and microscopic structure of the capsules, their magnetic behavior and mechanical resistance. PMID- 25923882 TI - Adenoviral delivery of recombinant soluble human tumor necrosis factor receptor 1 partially normalized mouse model of asthma. AB - BACKGROUND: Tumor necrosis factor alpha (TNF-alpha) is a proinflammatory cytokine that has been implicated in the airway pathology of asthma and result in resistance to hormone therapy. Tumor necrosis factor alpha inhibitors have become a major research focus in the treatment of asthma. METHODS: Recombinant adenovirus (Ad-sTNFR1-IgGFc) expressing a fusion protein (sTNFR1-IgGFc), which was consisted of the soluble extracellular region of TNF receptor 1 and Fc fragment of IgG (sTNFR1-IgGFc), was used to transduce primary human airway smooth muscle cells (HASMCs). Enzyme-linked immunosorbent assay, flow cytometry, and immunocytochemistry confirmed the expression of sTNFR1-IgGFc. MTT was used to test the effect of sTNFR1-IgGFc to antagonism TNF-alpha-induced proliferates of HASMCs. To investigate the in vivo effectiveness of sTNFR1-IgGFc, mouse model of asthma was established. Ad-sTNFR1-IgGFc was delivered to the lung via nasal spray. Expression of sTNFR1-IgGFc in the tissue was confirmed by in situ hybridization and immunohistochemistry. The 2 major cell types that are involved in the inflamed asthmatic airway, neutrophils and eosinophils, in bronchoalveolar lavage fluid were observed. RESULTS: The sTNFR1-IgGFc isolated from transduced HASMC culture supernatant was able to antagonize HASMC proliferation stimulated by TNF-alpha. Asthma-induced pathologies and alterations in the cell composition in bronchoalveolar lavage fluid were reduced in mice subjected to Ad-sTNFR1-IgGFc therapy. CONCLUSIONS: The soluble extracellular region of TNF receptor 1 and Fc fragment of IgG was able to functionally antagonize TNF-alpha in vitro and showed promise as a therapeutic agent for the localized treatment of severe refractory asthma. PMID- 25923883 TI - Modeling the carbon cycle in Lake Matano. AB - Lake Matano, Indonesia, is a stratified anoxic lake with iron-rich waters that has been used as an analogue for the Archean and early Proterozoic oceans. Past studies of Lake Matano report large amounts of methane production, with as much as 80% of primary production degraded via methanogenesis. Low delta(13)C values of DIC in the lake are difficult to reconcile with this notion, as fractionation during methanogenesis produces isotopically heavy CO2. To help reconcile these observations, we develop a box model of the carbon cycle in ferruginous Lake Matano, Indonesia, that satisfies the constraints of CH4 and DIC isotopic profiles, sediment composition, and alkalinity. We estimate methane fluxes smaller than originally proposed, with about 9% of organic carbon export to the deep waters degraded via methanogenesis. In addition, despite the abundance of Fe within the waters, anoxic ferric iron respiration of organic matter degrades <3% of organic carbon export, leaving methanogenesis as the largest contributor to anaerobic organic matter remineralization, while indicating a relatively minor role for iron as an electron acceptor. As the majority of carbon exported is buried in the sediments, we suggest that the role of methane in the Archean and early Proterozoic oceans is less significant than presumed in other studies. PMID- 25923884 TI - Specificity of Signal-Binding via Non-AHL LuxR-Type Receptors. AB - Quorum sensing is a typical communication system among Gram-negative bacteria used to control group-coordinated behavior via small diffusible molecules dependent on cell number. The key components of a quorum sensing system are a LuxI-type synthase, producing acyl-homoserine lactones (AHLs) as signaling molecules, and a LuxR-type receptor that detects AHLs to control expression of specific target genes. Six conserved amino acids are present in the signal binding domain of AHL-sensing LuxR-type proteins, which are important for ligand binding and -specificity as well as shaping the ligand-binding pocket. However, many proteobacteria possess LuxR-type regulators without a cognate LuxI synthase, referred to as LuxR solos. The two LuxR solos PluR and PauR from Photorhabdus luminescens and Photorhabdus asymbiotica, respectively, do not sense AHLs. Instead PluR and PauR sense alpha-pyrones and dialkylresorcinols, respectively, and are part of cell-cell communication systems contributing to the overall virulence of these Photorhabdus species. However, PluR and PauR both harbor substitutions in the conserved amino acid motif compared to that in AHL sensors, which appeared to be important for binding the corresponding signaling molecules. Here we analyze the role of the conserved amino acids in the signal-binding domain of these two non-AHL LuxR-type receptors for their role in signal perception. Our studies reveal that the conserved amino acid motif alone is essential but not solely responsible for ligand-binding. PMID- 25923885 TI - A meta-analysis of human disturbance impacts on Antarctic wildlife. AB - Evidence-based assessments are increasingly recognized as the best-practice approach to determine appropriate conservation interventions, but such assessments of the impact of human disturbance on wildlife are rare. Human disturbance comprises anthropogenic activities that are typically non-lethal, but may cause short- and/or longer-term stress and fitness responses in wildlife. Expanding human activity in the Antarctic region is of particular concern because it increases the scope and potential for increased human disturbance to wildlife in a region that is often thought of as relatively untouched by anthropogenic influences. Here, we use a meta-analytical approach to synthesise research on human disturbance to wildlife over the last three decades in the Antarctic and sub-Antarctic region. We combine data from 62 studies across 21 species on the behavioural, physiological and population responses of wildlife to pedestrian, vehicle and research disturbances. The overall effect size indicated a small, albeit statistically significant negative effect of disturbance (-0.39; 95% CI: 0.60 to -0.18). Negative effects were found for both physiological and population responses, but no evidence was found for a significant impact on wildlife behavioural responses. Negative effects were found across pedestrian, vehicle and research disturbances. Significant and high among-study heterogeneity was found in both disturbance and response sub-groups. Among species, it remains unclear to what extent different forms of disturbance translate into negative population responses. Most current guidelines to limit wildlife disturbance impacts in Antarctica recommend that approaches be tailored to animal behavioural cues, but our work demonstrates that behavioural changes do not necessarily reflect more cryptic, and more deleterious impacts, such as changes in physiology. In consequence, we recommend that pedestrian approach guidelines in the Antarctic region be revisited. Due to the high heterogeneity in effects, management guidelines for different sites and species will need to be developed on a case-by case basis, ideally in conjunction with carefully designed experiments. Guidelines to reduce the impact of research activities per se require development to reduce the potential impacts of conducting research. We identify research questions that, if answered, will further improve the evidence base for guidelines to manage human disturbance in Antarctica. PMID- 25923886 TI - Adaptive stress response pathways induced by environmental mixtures of bioaccumulative chemicals in dugongs. AB - To address the poorly understood mixture effects of chemicals in the marine mammal dugong, we coupled equilibrium-based passive sampling in blubber to a range of in vitro bioassays for screening mixtures of bioaccumulative chemicals. The modes of action included early effect indicators along important toxicity pathways, such as induction of xenobiotic metabolism, and some integrative indicators downstream of the molecular initiating event, such as adaptive stress responses. Activation of aryl hydrocarbon receptor (AhR) and Nrf2-mediated oxidative stress response were found to be the most prominent effects, while the p53-mediated DNA damage response and NF-kappaB-mediated response to inflammation were not significantly affected. Although polychlorinated dibenzo-p-dioxins (PCDDs) quantified in the samples accounted for the majority of AhR-mediated activity, PCDDs explained less than 5% of the total oxidative stress response, despite their known ability to activate this pathway. Altered oxidative stress response was observed with both individual chemicals and blubber extracts subject to metabolic activation by rat liver S9 fraction. Metabolic activation resulted in both enhanced and reduced toxicity, suggesting the relevance and utility of incorporating metabolic enzymes into in vitro bioassays. Our approach provides a first insight into the burden of toxicologically relevant bioaccumulative chemical mixtures in dugongs and can be applied to lipid tissue of other wildlife species. PMID- 25923887 TI - Toxoplasmosis in Mexico: epidemiological situation in humans and animals. AB - Toxoplasmosis is a parasitic disease widely distributed throughout the world, infecting a wide variety of animal species including humans. In Mexico, this parasite has been detected in different parts of the country, particularly in the tropical areas where the parasite can remain infective for long periods of time due to the environmental conditions (i.e. high temperature and humidity over the whole year). Several epidemiological studies have been conducted in both human and animal populations, but despite the wide distribution of the agent in the country, there is a significant lack of knowledge on the parasite transmission, treatment alternatives and control measures. The lack of feral cat populations and control measures in sites of meat production for human consumption are playing a role that has led to the wide spread of the disease in the country, particularly in tropical areas of Southeastern Mexico. For these reasons, this manuscript aims to review the published information on relevant epidemiological aspects of infection with T. gondii in humans and animals from Mexico. PMID- 25923888 TI - Discordance between body mass index and anthropometric measurements among HIV-1 infected patients on antiretroviral therapy and with lipoatrophy/lipohypertrophy syndrome. AB - INTRODUCTION: Highly Active Antiretroviral Therapy (HAART) has improved and extended the lives of thousands of people living with HIV/AIDS around the world. However, this treatment can lead to the development of adverse reactions such as lipoatrophy/lipohypertrophy syndrome (LLS) and its associated risks. OBJECTIVE: This study was designed to assess the prevalence of self-reported lipodystrophy and nutritional status by anthropometric measurements in patients with HIV/AIDS. METHODS: An observational study of 227 adult patients in the Secondary Immunodeficiencies Outpatient Department of Dermatology, Hospital das Clinicas, Faculty of Medicine, University of Sao Paulo (3002 ADEE-HCFMUSP). The sample was divided into three groups; Group 1 = 92 patients on HAART and with self-reported lipodystrophy, Group 2 = 70 patients on HAART without self-reported lipodystrophy and Group 3 = 65 patients not taking HAART. The nutritional status of individuals in the study sample was determined by body mass index (BMI) and percentage of body fat (% BF). The cardiovascular risk and diseases associated with abdominal obesity were determined by waist/hip ratio (WHR) and waist circumference (WC). RESULTS: The prevalence of self-reported lipoatrophy/lipohypertrophy syndrome was 33% among women and 59% among men. Anthropometry showed depletion of fat mass in the evaluation of the triceps (TSF) in the treatment groups with HAART and was statistically independent of gender; for men p = 0.001, and for women p = 0.007. Similar results were found in the measurement of skin folds of the upper and lower body (p = 0.001 and p = 0.003 respectively). In assessing the nutritional status of groups by BMI and % BF, excess weight and body fat were more prevalent among women compared to men (p = 0.726). The WHR and WC revealed risks for cardiovascular and other diseases associated with abdominal obesity for women on HAART and with self-reported LLS (p = 0.005) and (p = 0.011). CONCLUSIONS: Anthropometric measurements were useful in the confirmation of the prevalence of LLS. BMI alone does not appear to be a good parameter for assessing the nutritional status of HIV-infected patients on HAART and with LLS. Other anthropometric measurements are needed to evaluate patients with the lipoatrophy/lipohypertrophy syndrome. PMID- 25923889 TI - Preterm birth and fetal growth restriction in HIV-infected Brazilian pregnant women. AB - INTRODUCTION: Maternal HIV infection and related co-morbidities may have two outstanding consequences to fetal health: mother-to-child transmission (MTCT) and adverse perinatal outcomes. After Brazilian success in reducing MTCT, the attention must now be diverted to the potentially increased risk for preterm birth (PTB) and intrauterine fetal growth restriction (IUGR). OBJECTIVE: To determine the prevalence of PTB and IUGR in low income, antiretroviral users, publicly assisted, HIV-infected women and to verify its relation to the HIV infection stage. PATIENTS AND METHODS: Out of 250 deliveries from HIV-infected mothers that delivered at a tertiary public university hospital in the city of Vitoria, state of Espirito Santo, Southeastern Brazil, from November 2001 to May 2012, 74 single pregnancies were selected for study, with ultrasound validated gestational age (GA) and data on birth dimensions: fetal weight (FW), birth length (BL), head and abdominal circumferences (HC, AC). The data were extracted from clinical and pathological records, and the outcomes summarized as proportions of preterm birth (PTB, < 37 weeks), low birth weight (LBW, < 2500 g) and small (SGA), adequate (AGA) and large (LGA) for GA, defined as having a value below, between or beyond the +/- 1.28 z/GA score, the usual clinical cut-off to demarcate the 10th and 90th percentiles. RESULTS: PTB was observed in 17.5%, LBW in 20.2% and SGA FW, BL, HC and AC in 16.2%, 19.1%, 13.8%, and 17.4% respectively. The proportions in HIV-only and AIDS cases were: PTB: 5.9 versus 27.5%, LBW: 14.7% versus 25.0%, SGA BW: 17.6% versus 15.0%, BL: 6.0% versus 30.0%, HC: 9.0% versus 17.9%, and AC: 13.3% versus 21.2%; only SGA BL attained a significant difference. Out of 15 cases of LBW, eight (53.3%) were preterm only, four (26.7%) were SGA only, and three (20.0%) were both PTB and SGA cases. A concomitant presence of, at least, two SGA dimensions in the same fetus was frequent. CONCLUSIONS: The proportions of preterm birth and low birth weight were higher than the local and Brazilian prevalence and a trend was observed for higher proportions of SGA fetal dimensions than the expected population distribution in this small casuistry of newborn from the HIV-infected, low income, antiretroviral users, and publicly assisted pregnant women. A trend for higher prevalence of PTB, LBW and SGA fetal dimensions was also observed in infants born to mothers with AIDS compared to HIV-infected mothers without AIDS. PMID- 25923890 TI - Enterobacteriaceae isolates from the oral cavity of workers in a Brazilian oncology hospital. AB - The evaluation of workers as potential reservoirs and disseminators of pathogenic bacteria has been described as a strategy for the prevention and control of healthcare-associated infections (HAIs). The aim of this study was to evaluate the presence of Enterobacteriaceae in the oral cavity of workers at an oncology hospital in the Midwest region of Brazil, as well as to characterize the phenotypic profile of the isolates. Saliva samples of 294 workers from the hospital's healthcare and support teams were collected. Microbiological procedures were performed according to standard techniques. Among the participants, 55 (18.7%) were colonized by Enterobacteriaceae in the oral cavity. A total of 64 bacteria were isolated, including potentially pathogenic species. The most prevalent species was Enterobacter gergoviae (17.2%). The highest rates of resistance were observed for beta-lactams, and 48.4% of the isolates were considered multiresistant. Regarding the enterobacteria isolated, the production of ESBL and KPC was negative. Nevertheless, among the 43 isolates of the CESP group, 51.2% were considered AmpC beta-lactamase producers by induction, and 48.8% were hyper-producing mutants. The significant prevalence of carriers of Enterobacteriaceae and the phenotypic profile of the isolates represents a concern, especially due to the multiresistance and production of AmpC beta lactamases. PMID- 25923891 TI - Rickettsia typhi in rodents and R. felis in fleas in Yucatan as a possible causal agent of undefined febrile cases. AB - Rickettsia typhi is the causal agent of murine typhus; a worldwide zoonotic and vector-borne infectious disease, commonly associated with the presence of domestic and wild rodents. Human cases of murine typhus in the state of Yucatan are frequent. However, there is no evidence of the presence of Rickettsia typhi in mammals or vectors in Yucatan. The presence of Rickettsia in rodents and their ectoparasites was evaluated in a small municipality of Yucatan using the conventional polymerase chain reaction technique and sequencing. The study only identified the presence of Rickettsia typhi in blood samples obtained from Rattus rattus and it reported, for the first time, the presence of R. felis in the flea Polygenis odiosus collected from Ototylomys phyllotis rodent. Additionally, Rickettsia felis was detected in the ectoparasite Ctenocephalides felis fleas parasitizing the wild rodent Peromyscus yucatanicus. This study's results contributed to a better knowledge of Rickettsia epidemiology in Yucatan. PMID- 25923892 TI - Spatiotemporal trends of cases of pandemic influenza A(H1N1)pdm09 in Argentina, 2009-2012. AB - The aim of this paper was to analyze the spatiotemporal variations of cases of influenza A(H1N1)pdm09 in Argentina. A space-time permutation scan statistic was performed to test the non-randomness in the interaction between space and time in reported influenza A(H1N1)pdm09 cases. In 2009, two clusters were recorded in the east of Buenos Aires Province (May and June) and in the central and northern part of Argentina (July and August). Between 2011 and 2012, clusters near areas bordering other countries were registered. Within the clusters, in 2009, the high notification rates were first observed in the school-age population and then extended to the older population (15-59 years). From 2011 onwards, higher rates of reported cases of influenza A(H1N1)pdm09 occurred in children under five years in center of the country. Two stages of transmission of influenza A(H1N1)pdm09 can be characterized. The first stage had high rates of notification and a possible interaction with individuals from other countries in the major cities of Argentina (pattern of hierarchy), and the second stage had an increased interaction in some border areas without a clear pattern of hierarchy. These results suggest the need for greater coordination in the Southern Cone countries, in order to implement joint prevention and vaccination policies. PMID- 25923893 TI - Prevalence of intestinal parasites among food handlers of Sari, Northern Iran. AB - Parasitic infection is highly prevalent throughout the developing countries of the world. Food handlers are a potential source of infection for many intestinal parasites and other enteropathogenic infections as well. The aim of this study was to determine the prevalence of intestinal parasite carriers among food handlers attending the public health center laboratory in Sari, Northern Iran for annual check-up. The study was performed from August 2011 through February 2012. Stool samples were collected from 1041 male and female food handlers of different jobs aged between 18 to 63 years and were examined following standard procedures. Sociodemographic, environmental and behavioral data analysis of the food handlers were recorded in a separate questionnaire. Intestinal parasites were found in 161 (15.5%) of the studied samples. Seven species of protozoan or helminth infections were detected. Most of the participants were infected with Giardia lamblia (53.9%) followed by Blastocystis hominis (18%), Entamoeba coli (15.5%), Entamoeba histolytica/dispar (5.5%), Cryptosporidium sp. (3.1%), Iodamoeba butschlii (3.1%) and Hymenolepis nana (1.9%) as the only helminth infection. The findings emphasized that food handlers with different pathogenic organisms may predispose consumers to significant health risks. Routine screening and treatment of food handlers is a proper tool in preventing food-borne infections. PMID- 25923894 TI - Clinical and epidemiological profile of elderly patients with Chagas disease followed between 2005-2013 by pharmaceutical care service in Ceara State, Northeastern Brazil. AB - By controlling the transmission of Chagas disease, the challenge of providing assistance to millions of infected patients that reach old age arises. In this study, the socioeconomic, demographic and comorbidity records of all elderly chagasic patients followed at the Pharmaceutical Care Service of the Chagas Disease Research Laboratory were assessed. The information related to the clinical form of the disease was obtained from medical records provided by the Walter Cantidio University Hospital. The profile of the studied population was: women (50.5%); mean age of 67 years; retired (54.6%); married (51.6 %); high illiteracy rate (40.2%); and family income equal to the minimum wage (51.5%). The predominant clinical forms of Chagas disease were cardiac (65.3%) and indeterminate (14.7%). The main electrocardiographic changes were the right bundle branch block (41.0%), associated or not with the anterosuperior left bundle branch block (27.4%). The average number of comorbidities per patient was 2.23 +/- 1.54, with systemic arterial hypertension being the main one found (67.0%). It was found that the elderly comprise a vulnerable group of patients that associate aging with cardiac and/or digestive disorders resulting from the evolution of Chagas disease and other comorbidities, which requires special attention from health services to ensure more appropriate medical and social care. PMID- 25923895 TI - Predictive factors for the progression of chronic Chagas cardiomyopathy in patients without left ventricular dysfunction. AB - The identification of predictors for the progression of chronic Chagas cardiomyopathy (CCC) is essential to ensure adequate patient management. This study looked into a non-concurrent cohort of 165 CCC patients between 1985 and 2010 for independent predictors for CCC progression. The outcomes were worsening of the CCC scores and the onset of left ventricular dysfunction assessed by means of echo-Doppler cardiography. Patients were analyzed for social, demographic, epidemiologic, clinical and workup-related variables. A descriptive analysis was conducted, followed by survival curves based on univariate (Kaplan-Meier and Cox's univariate model) and multivariate (Cox regression model) analysis. Patients were followed from two to 20 years (mean: 8.2). Their mean age was 44.8 years (20-77). Comparing both iterations of the study, in the second there was a statistically significant increase in the PR interval and in the QRS duration, despite a reduction in heart rates (Wilcoxon < 0.01). The predictors for CCC progression in the final regression model were male gender (HR = 2.81), Holter monitoring showing pauses equal to or greater than two seconds (HR = 3.02) increased cardiothoracic ratio (HR = 7.87) and time of use of digitalis (HR = 1.41). Patients with multiple predictive factors require stricter follow-up and treatment. PMID- 25923897 TI - Antifungal activity of silver nanoparticles obtained by green synthesis. AB - Silver nanoparticles (AgNPs) are metal structures at the nanoscale. AgNPs have exhibited antimicrobial activities against fungi and bacteria; however synthesis of AgNPs can generate toxic waste during the reaction process. Accordingly, new routes using non-toxic compounds have been researched. The proposal of the present study was to synthesize AgNPs using ribose as a reducing agent and sodium dodecyl sulfate (SDS) as a stabilizer. The antifungal activity of these particles against C. albicans and C. tropicalis was also evaluated. Stable nanoparticles 12.5 +/- 4.9 nm (mean +/- SD) in size were obtained, which showed high activity against Candida spp. and could represent an alternative for fungal infection treatment. PMID- 25923898 TI - Effect of highly active antiretroviral therapy on vaginal Candida spp. isolation in HIV-infected compared to HIV-uninfected women. AB - Vulvovaginal candidiasis (VVC) in HIV-infected women contributed to the impairment of their quality of life. The aim of this study was to evaluate the effect of highly active antiretroviral therapy (HAART) use on the vaginal Candida spp. isolation in HIV-infected compared to HIV-uninfected women. This cross sectional study included 178 HIV-infected (HIV group) and 200 HIV-uninfected women (control) that were studied at the Specialized Assistance Service (SAE) for sexually transmitted diseases (STD)/AIDS of the city of Maringa, Brazil, from April 1 to October 30, 2011. The yeasts were isolated and identified by phenotypic and molecular methods. The in vitro antifungal susceptibility to fluconazole, itraconazole, nystatin and amphotericin B was tested by the reference microdilution method. Higher frequencies of total vaginal Candida spp. isolation were found in the HIV-infected group than in the control group. However, both groups showed a similar frequency of colonization and VVC. Although C. albicans was the most frequent and sensitive to azolics and polyenes in both HIV-infected and uninfected women, the emerging resistance of C. glabrata to amphotericin B in the HIV-infected women was observed. Although higher frequency of vaginal Candida spp. isolation had been observed in the HIV-infected than in HIV-uninfected women, colonization and VVC showed similar frequency in both groups, indicating that HAART appears to protect against vaginal colonization and VVC. PMID- 25923899 TI - Identification of Leishmania infantum in Puerto Iguazu, Misiones, Argentina. AB - The emergence of zoonotic visceral leishmaniasis (ZVL) in Latin America is a growing public health problem. The urbanization of ZVL has been observed in different countries around the world, and there are a growing number of reports drawing attention to the emergence of this infection in new locations, as well as its increase in previously established areas of endemicity. In the city of Posadas, Misiones province, Northeastern Argentina, the transmission of ZVL associated with canines and Lutzomyia longipalpis was first reported in 2006. In the city of Puerto Iguazu, also in Misiones province, the first human case of ZVL was reported in February 2014. From 209 surveyed dogs, 15 (7.17%) were identified as positive by serological and/or parasitological methods. Amplification was observed in 14 samples and in all cases the species implicated was Leishmania infantum. To the authors' knowledge, this is the first molecular characterization of L. infantum from dogs in this area. PMID- 25923900 TI - Detection of Leptospira spp. and Brucella abortus antibodies in free-living jaguars (Panthera onca) in two protected areas of northern Pantanal, Brazil. AB - This study aimed to assess the exposure of free-living jaguars (Panthera onca) to Leptospira spp. and Brucella abortus in two conservation units in the Pantanal of Mato Grosso, Brazil. The presence of antibodies in blood samples of eleven jaguars was investigated using autochthonous antigens isolated in Brazil added to reference antigen collection applied to diagnosis of leptospirosis by Microscopic Agglutination Test (MAT). The Rose Bengal test was applied for B. abortus antibodies. Two (18.2%) jaguars were seroreactive for the Leptospira spp. antigen and the serovar considered as most infective in both animals was a Brazilian isolate of serovar Canicola (L01). All jaguars were seronegative for B. abortus. These data indicate that the inclusion of autochthonous antigens in serological studies can significantly increase the number of reactive animals, as well as modify the epidemiological profile of Leptospira spp. infection. PMID- 25923901 TI - New wildlife hosts of Leptospira interrogans in Campeche, Mexico. AB - Leptospira interrogans has been identified to cause leptospirosis, a widespread zoonotic disease that has been identified in domestic and wild animals. This work analyzed kidneys from two species of wild rodents from the state of Campeche, Mexico. Analyses were made by PCR using specific primers for detection of Leptospira interrogans DNA. The rodent species that tested positive were Heteromys gaumeri and Ototylomys phyllotis, both of which are new hosts for the bacteria in Southeastern Mexico. These records provide new insights into the disease's transmission that should be studied carefully in order to identify other potential host species, including humans, which are at risk of becoming infected if they are in contact with infected wildlife. PMID- 25923902 TI - False-negative dengue cases. PMID- 25923903 TI - TLR5 expression in the small intestine depends on the adaptors MyD88 and TRIF, but is independent of the enteric microbiota. AB - In our recent article Hormann and coworkers have reported a role for epithelial cell-intrinsic TLR2 signaling for proliferation and renewal of the small intestinal epithelium. In this study, MyD88 and TRIF expression in the small intestine were affected by gut microbiota. Here, we report that in contrast to TLR2 and its co-receptor TLR1, TLR5 transcripts are not changed by presence of gut microbiota nor regulated through TLR2 or TLR4. Similar to TLR2 also TLR5 depends on MyD88 and TRIF adaptors. Our results indicate that TLR adaptor molecules could be determinants of TLR expression in the small intestine. PMID- 25923904 TI - Development of an Animal Model for Alcoholic Liver Disease in Zebrafish. AB - Alcoholic liver disease (ALD) continues to be a major cause of liver-related morbidity and mortality worldwide. To date, no zebrafish animal model has demonstrated the characteristic manifestations of ALD in the setting of chronic alcohol exposure. The aim of this study was to develop a zebrafish animal model for ALD. Male adult zebrafish were housed in a 1% (v/v) ethanol solution up to 3 months. A histopathological study showed the characteristic features of alcoholic liver steatosis and steatohepatitis in the early stages of alcohol exposure, including fat droplet accumulation, ballooning degeneration of the hepatocytes, and Mallory body formation. As the exposure time increased, collagen deposition in the extracellular matrix was observed by Sirius red staining and immunofluorescence staining. Finally, anaplastic hepatocytes with pleomorphic nuclei were arranged in trabecular patterns and formed nodules in the zebrafish liver. Over the time course of 1% ethanol exposure, upregulations of lipogenesis, fibrosis, and tumor-related genes were also revealed by semiquantitative and quantitative real-time reverse transcription-polymerase chain reaction. As these data reflect characteristic liver damage by alcohol in humans, this zebrafish animal model may serve as a powerful tool to study the pathogenesis and treatment of ALD and its related disorders in humans. PMID- 25923905 TI - Reference values for reticulocyte parameters and hypochromic RBC in healthy children. AB - INTRODUCTION: New erythrocyte and reticulocyte parameters available on modern hematology analyzers have shown to be useful markers in children. However, pediatric method-specific reference ranges for these indices are sparse. We aim to establish pediatric reference values for reticulocyte parameters and hypochromic red blood cells in healthy children with the ADVIA 2120 hematology analyzer. METHODS: Prospective study of 311 healthy children aged from 6 months to 18 years old with normal hematological parameters. ADVIA 2120 hematology analyzer (Siemens Healthcare Diagnostics, Amadora, Portugal) was used for whole blood hematological measures. The sample population was grouped according to age into three cohorts, and gender distribution was used for participants aged >=12 years. RESULTS: Age- and gender-specific reference limits of reticulocyte hemoglobin content (CHr or Ret-He), difference between the reticulocyte and erythrocyte hemoglobin content (Delta-He), immature reticulocyte fraction (IRF) and percentage of hypochromic red blood cells (%Hypo) are provided. Delta-He, IRF and %Hypo showed statistically significant gender differences in the 12-17 years group. CHr presented no significant gender variation within all age groups (median 30.8 +/- 1.7 pg). CONCLUSION: Establishing reliable pediatric reference intervals for these novel hematological parameters may offer valuable prospects for clinical practice and research in the pediatrics field. PMID- 25923906 TI - Enhanced Ag(+) Ion Release from Aqueous Nanosilver Suspensions by Absorption of Ambient CO2. AB - Nanosilver with closely controlled average particle diameter (7-30 nm) immobilized on nanosilica is prepared and characterized by X-ray diffraction, N2 adsorption, and transmission electron microscopy. The presence of Ag2O on the as prepared nanosilver surface is confirmed by UV-vis spectroscopy and quantified by thermogravimetric analysis and mass spectrometry. The release of Ag(+) ions in deionized water is monitored electrochemically and traced quantitatively to the dissolution of a preexisting Ag2O monolayer on the nanosilver surface. During this dissolution, the pH of the host solution rapidly increases, suppressing dissolution of the remaining metallic Ag. When, however, a nanosilver suspension is exposed to a CO2-containing atmosphere, like ambient air during its storage or usage, then CO2 is absorbed by the host solution decreasing its pH and contributing to metallic Ag dissolution and further leaching of Ag(+) ions. So the release of Ag(+) ions from the above closely sized nanosilver solutions in the absence and presence of CO2 as well as under synthetic air containing 200 1800 ppm of CO2 is investigated along with the solution pH and related to the antibacterial activity of nanosilver. PMID- 25923908 TI - Insights into the binding mode of curcumin to MD-2: studies from molecular docking, molecular dynamics simulations and experimental assessments. AB - Curcumin, a natural product, has been shown to possess notable anti-inflammatory activities and numerous studies have been carried out on its clinical applications. Recently, several reports mentioned that myeloid differentiation protein 2 (MD-2) may be the direct target of curcumin in the inhibition of lipopolysaccharide (LPS) signaling. However, the exact interaction between curcumin and MD-2 is still incompletely understood. In the present study, computational and experimental methods were employed to explore the underlying structural mechanism of curcumin binding to the MD-2 protein. Molecular docking and molecular dynamics (MD) simulation studies showed that curcumin could be embedded into the hydrophobic pocket of MD-2 and form stable hydrogen bonding interactions with residues R90 and Y102 of MD-2. Moreover, experimental results of curcumin binding to the MD-2(R90A/Y102A) mutant further confirmed that residues ARG-90 and TYR-102 contribute to the recognition process of curcumin binding to the MD-2 protein. In conclusion, we have explored the binding mechanism of curcumin to MD-2; more importantly, this work could offer useful references for designing novel analogs of curcumin as potential anti-inflammatory agents targeting the MD-2 protein. PMID- 25923907 TI - Probabilistic Decision Making with Spikes: From ISI Distributions to Behaviour via Information Gain. AB - Computational theories of decision making in the brain usually assume that sensory 'evidence' is accumulated supporting a number of hypotheses, and that the first accumulator to reach threshold triggers a decision in favour of its associated hypothesis. However, the evidence is often assumed to occur as a continuous process whose origins are somewhat abstract, with no direct link to the neural signals - action potentials or 'spikes' - that must ultimately form the substrate for decision making in the brain. Here we introduce a new variant of the well-known multi-hypothesis sequential probability ratio test (MSPRT) for decision making whose evidence observations consist of the basic unit of neural signalling - the inter-spike interval (ISI) - and which is based on a new form of the likelihood function. We dub this mechanism s-MSPRT and show its precise form for a range of realistic ISI distributions with positive support. In this way we show that, at the level of spikes, the refractory period may actually facilitate shorter decision times, and that the mechanism is robust against poor choice of the hypothesized data distribution. We show that s-MSPRT performance is related to the Kullback-Leibler divergence (KLD) or information gain between ISI distributions, through which we are able to link neural signalling to psychophysical observation at the behavioural level. Thus, we find the mean information needed for a decision is constant, thereby offering an account of Hick's law (relating decision time to the number of choices). Further, the mean decision time of s-MSPRT shows a power law dependence on the KLD offering an account of Pieron's law (relating reaction time to stimulus intensity). These results show the foundations for a research programme in which spike train analysis can be made the basis for predictions about behavior in multi alternative choice tasks. PMID- 25923909 TI - Modified MLVA for Genotyping Queensland Invasive Streptococcus pneumoniae. AB - BACKGROUND: Globally, over 800 000 children under five die each year from infectious diseases caused by Streptococcus pneumoniae. To understand genetic relatedness between isolates, study transmission routes, assess the impact of human interventions e.g. vaccines, and determine infection sources, genotyping methods are required. The 'gold standard' genotyping method, Multi-Locus Sequence Typing (MLST), is useful for long-term and global studies. Another genotyping method, Multi-Locus Variable Number of Tandem Repeat Analysis (MLVA), has emerged as a more discriminatory, inexpensive and faster technique; however there is no universally accepted method and it is currently suitable for short-term and localised epidemiology studies. Currently Australia has no national MLST database, nor has it adopted any MLVA method for short-term or localised studies. This study aims to improve S. pneumoniae genotyping methods by modifying the existing MLVA techniques to be more discriminatory, faster, cheaper and technically less demanding than previously published MLVA methods and MLST. METHODS: Four different MLVA protocols, including a modified method, were applied to 317 isolates of serotyped invasive S. pneumoniae isolated from sterile body sites of Queensland children under 15 years from 2007-2012. MLST was applied to 202 isolates for comparison. RESULTS: The modified MLVA4 is significantly more discriminatory than the 'gold standard' MLST method. MLVA4 has similar discrimination compared to other MLVA techniques in this study). The failure to amplify particular loci in previous MLVA methods were minimised in MLVA4. Failure to amplify BOX-13 and Spneu19 were found to be serotype specific. CONCLUSION: We have modified a highly discriminatory MLVA technique for genotyping Queensland invasive S. pneumoniae. MLVA4 has the ability to enhance our understanding of the pneumococcal epidemiology and the changing genetics of the pneumococcus in localised and short-term studies. PMID- 25923910 TI - Vorapaxar: A Protease-Activated Receptor Antagonist for the Prevention of Thrombotic Events. AB - Antiplatelet therapy reduces the risks for cardiovascular morbidity and mortality in patients with atherosclerotic disease, and it is also beneficial in managing peripheral arterial disease (PAD). These agents work through various therapeutic pathways to achieve antithrombotic effects. Although single- or two-drug regimens have been deployed to prevent vascular events, approximately 10% of the patients with acute coronary syndrome remain at risk for recurrent thrombotic events and may need a more aggressive preventative strategy. Vorapaxar offers a unique mechanism for platelet inhibition via the antagonism of protease-activated receptor-1. It is approved for the reduction of thrombotic cardiovascular events in patients with a history of myocardial infarction (MI) or PAD. This new drug approval was mainly based on the results from subgroup analyses from a large landmark trial (Thrombin Receptor Antagonist in Secondary Prevention of Atherothrombotic Ischemic Events-Thrombolysis in Myocardial Infarction 50), which found that vorapaxar reduces the rate of the combined end point of cardiovascular death, MI, stroke, and urgent coronary revascularization when used in addition to aspirin and/or clopidogrel in patients without a history of stroke. In this study, vorapaxar was discontinued in patients with a history of stroke due to excessive risk for intracranial hemorrhage after 2 years of therapy. As an adjunctive therapy to standard regimens, vorapaxar provides a greater net clinical benefit in MI patients who are at a lower risk for bleeding. In patients with PAD, it reduces the rates of recurrent acute limb ischemia with rehospitalization or peripheral revascularization. The most concerning adverse effect is bleeding. Vorapaxar should not be used in patients with a history of stroke, transient ischemic attack, intracranial hemorrhage, or active pathological bleeding. The risks and benefits of adding vorapaxar to intensify antiplatelet regimens should be assessed in individual patients to aim for additional therapeutic outcomes with minimal bleeding risks. PMID- 25923911 TI - Selection of Atmospheric Environmental Monitoring Sites based on Geographic Parameters Extraction of GIS and Fuzzy Matter-Element Analysis. AB - To effectively monitor the atmospheric quality of small-scale areas, it is necessary to optimize the locations of the monitoring sites. This study combined geographic parameters extraction by GIS with fuzzy matter-element analysis. Geographic coordinates were extracted by GIS and transformed into rectangular coordinates. These coordinates were input into the Gaussian plume model to calculate the pollutant concentration at each site. Fuzzy matter-element analysis, which is used to solve incompatible problems, was used to select the locations of sites. The matter element matrices were established according to the concentration parameters. The comprehensive correlation functions KA (xj) and KB (xj), which reflect the degree of correlation among monitoring indices, were solved for each site, and a scatter diagram of the sites was drawn to determine the final positions of the sites based on the functions. The sites could be classified and ultimately selected by the scatter diagram. An actual case was tested, and the results showed that 5 positions can be used for monitoring, and the locations conformed to the technical standard. In the results of this paper, the hierarchical clustering method was used to improve the methods. The sites were classified into 5 types, and 7 locations were selected. Five of the 7 locations were completely identical to the sites determined by fuzzy matter element analysis. The selections according to these two methods are similar, and these methods can be used in combination. In contrast to traditional methods, this study monitors the isolated point pollutant source within a small range, which can reduce the cost of monitoring. PMID- 25923912 TI - Correction: Drug synergy drives conserved pathways to increase fission yeast lifespan. PMID- 25923913 TI - Acyclovir Therapy Reduces the CD4+ T Cell Response against the Immunodominant pp65 Protein from Cytomegalovirus in Immune Competent Individuals. AB - Cytomegalovirus (CMV) infects the majority of the global population and leads to the development of a strong virus-specific immune response. The CMV-specific CD4+ and CD8+ T cell immune response can comprise between 10 and 50% of the T cell pool within peripheral blood and there is concern that this may impair immunity to other pathogens. Elderly individuals with the highest magnitude of CMV specific immune response have been demonstrated to be at increased risk of mortality and there is increasing interest in interventions that may serve to moderate this. Acyclovir is an anti-viral drug with activity against a range of herpes viruses and is used as long term treatment to suppress reactivation of herpes simplex virus. We studied the immune response to CMV in patients who were taking acyclovir to assess if therapy could be used to suppress the CMV-specific immune response. The T cell reactivity against the immunodominant late viral protein pp65 was reduced by 53% in people who were taking acyclovir. This effect was seen within one year of therapy and was observed primarily within the CD4+ response. Acyclovir treatment only modestly influenced the immune response to the IE-1 target protein. These data show that low dose acyclovir treatment has the potential to modulate components of the T cell response to CMV antigen proteins and indicate that anti-viral drugs should be further investigated as a means to reduce the magnitude of CMV-specific immune response and potentially improve overall immune function. PMID- 25923914 TI - Intracellular Adenosine Triphosphate Deprivation through Lanthanide-Doped Nanoparticles. AB - Growing interest in lanthanide-doped nanoparticles for biological and medical uses has brought particular attention to their safety concerns. However, the intrinsic toxicity of this new class of optical nanomaterials in biological systems has not been fully evaluated. In this work, we systematically evaluate the long-term cytotoxicity of lanthanide-doped nanoparticles (NaGdF4 and NaYF4) to HeLa cells by monitoring cell viability (mitochondrial activity), adenosine triphosphate (ATP) level, and cell membrane integrity (lactate dehydrogenase release), respectively. Importantly, we find that ligand-free lanthanide-doped nanoparticles induce intracellular ATP deprivation of HeLa cells, resulting in a significant decrease in cell viability after exposure for 7 days. We attribute the particle-induced cell death to two distinct cell death pathways, autophagy and apoptosis, which are primarily mediated via the interaction between the nanoparticle and the phosphate group of cellular ATP. The understanding gained from the investigation of cytotoxicity associated with lanthanide-doped nanoparticles provides keen insights into the safe use of these nanoparticles in biological systems. PMID- 25923915 TI - Regulation of Axolotl (Ambystoma mexicanum) Limb Blastema Cell Proliferation by Nerves and BMP2 in Organotypic Slice Culture. AB - We have modified and optimized the technique of organotypic slice culture in order to study the mechanisms regulating growth and pattern formation in regenerating axolotl limb blastemas. Blastema cells maintain many of the behaviors that are characteristic of blastemas in vivo when cultured as slices in vitro, including rates of proliferation that are comparable to what has been reported in vivo. Because the blastema slices can be cultured in basal medium without fetal bovine serum, it was possible to test the response of blastema cells to signaling molecules present in serum, as well as those produced by nerves. We also were able to investigate the response of blastema cells to experimentally regulated changes in BMP signaling. Blastema cells responded to all of these signals by increasing the rate of proliferation and the level of expression of the blastema marker gene, Prrx-1. The organotypic slice culture model provides the opportunity to identify and characterize the spatial and temporal co-regulation of pathways in order to induce and enhance a regenerative response. PMID- 25923916 TI - Global Developmental Gene Programing Involves a Nuclear Form of Fibroblast Growth Factor Receptor-1 (FGFR1). AB - Genetic studies have placed the Fgfr1 gene at the top of major ontogenic pathways that enable gastrulation, tissue development and organogenesis. Using genome-wide sequencing and loss and gain of function experiments the present investigation reveals a mechanism that underlies global and direct gene regulation by the nuclear form of FGFR1, ensuring that pluripotent Embryonic Stem Cells differentiate into Neuronal Cells in response to Retinoic Acid. Nuclear FGFR1, both alone and with its partner nuclear receptors RXR and Nur77, targets thousands of active genes and controls the expression of pluripotency, homeobox, neuronal and mesodermal genes. Nuclear FGFR1 targets genes in developmental pathways represented by Wnt/beta-catenin, CREB, BMP, the cell cycle and cancer related TP53 pathway, neuroectodermal and mesodermal programing networks, axonal growth and synaptic plasticity pathways. Nuclear FGFR1 targets the consensus sequences of transcription factors known to engage CREB-binding protein, a common coregulator of transcription and established binding partner of nuclear FGFR1. This investigation reveals the role of nuclear FGFR1 as a global genomic programmer of cell, neural and muscle development. PMID- 25923917 TI - 16S rRNA Amplicon Sequencing Demonstrates that Indoor-Reared Bumblebees (Bombus terrestris) Harbor a Core Subset of Bacteria Normally Associated with the Wild Host. AB - A MiSeq multiplexed 16S rRNA amplicon sequencing of the gut microbiota of wild and indoor-reared Bombus terrestris (bumblebees) confirmed the presence of a core set of bacteria, which consisted of Neisseriaceae (Snodgrassella), Orbaceae (Gilliamella), Lactobacillaceae (Lactobacillus), and Bifidobacteriaceae (Bifidobacterium). In wild B. terrestris we detected several non-core bacteria having a more variable prevalence. Although Enterobacteriaceae are unreported by non next-generation sequencing studies, it can become a dominant gut resident. Furthermore the presence of some non-core lactobacilli were associated with the relative abundance of bifidobacteria. This association was not observed in indoor reared bumblebees lacking the non-core bacteria, but having a more standardized microbiota compared to their wild counterparts. The impact of the bottleneck microbiota of indoor-reared bumblebees when they are used in the field for pollination purpose is discussed. PMID- 25923919 TI - Part III: Research on Intrapartum and Neonatal Care and Management. PMID- 25923920 TI - Characterization of familial breast cancer in Saudi Arabia. AB - BACKGROUND: The contribution of genetic factors to the development of breast cancer in the admixed and consanguineous population of the western region of Saudi Arabia is thought to be significant as the disease is early onset. The current protocols of continuous clinical follow-up of relatives of such patients are costly and cause a burden on the usually over-stretched medical resources. Discovering the significant contribution of BRCA1/2 mutations to breast cancer susceptibility allowed for the design of genetic tests that allows the medical practitioner to focus the care for those who need it most. However, BRCA1/2 mutations do not account for all breast cancer susceptibility genes and there are other genetic factors, known and unknown that may play a role in the development of such disease. The advent of whole-exome sequencing is offering a unique opportunity to identify the breast cancer susceptibility genes in each family of sufferers. The polymorphisms/mutations identified will then allow for personalizing the genetic screening tests accordingly. To this end, we have performed whole-exome sequencing of seven breast cancer patients with positive family history of the disease using the Agilent SureSelectTM Whole-Exome Enrichment kit and sequencing on the SOLiDTM platform. RESULTS: We have identified several coding single nucleotide variations that were either novel or rare affecting genes controlling DNA repair in the BRCA1/2 pathway. CONCLUSION: The disruption of DNA repair pathways is very likely to contribute to breast cancer susceptibility in the Saudi population. PMID- 25923921 TI - Dairy consumption and gastric cancer risk: a meta-analysis of epidemiological studies. AB - Studies investigating the association of dairy consumption with gastric cancer risk have reported inconsistent findings. We conducted this systematic review and meta-analysis to review and summarize the epidemiologic evidence on the relation of total dairy and milk consumption with risk of gastric cancer. We summarized the available literature on this topic using meta-analysis of relative risks (RR) associated with total dairy and milk intake. The total of 17 case-control and 6 cohort studies (3256 cases) were eligible for inclusion. When comparing the highest with the lowest category of total dairy intake, the results of cohort studies indicated that increased consumption of total dairy food was associated with a reduced risk of gastric cancer (RR = 0.76; 95% CI: 0.64-0.91), whereas case-control studies provided no association. In subgroup analysis, significantly inverse associations between total diary food consumption and gastric cancer risk were observed in Europe subgroup (RR = 0.73; 95% CI: 0.54-0.99), U.S. subgroup (RR = 0.78; 95% CI: 0.63-0.98) but not in Asia subgroup. However, milk consumption was not associated with gastric cancer risk no matter in main or subgroup analysis. The results of cohort studies, but not case-control studies, suggested that total dairy might be related to the reduction of gastric cancer risk. Milk consumption was not associated with gastric cancer risk. PMID- 25923924 TI - Correction: Uncovering the nutritional landscape of food. PMID- 25923923 TI - Investigating the Vascularization of Tissue-Engineered Bone Constructs Using Dental Pulp Cells and 45S5 Bioglass(r) Scaffolds. AB - Identification of a suitable cell source combined with an appropriate 3D scaffold is an essential prerequisite for successful engineering of skeletal tissues. Both osteogenesis and angiogenesis are key processes for bone regeneration. This study investigated the vascularization potential of a novel combination of human dental pulp stromal cells (HDPSCs) with 45S5 Bioglass(r) scaffolds for tissue-engineered mineral constructs in vivo and in vitro. 45S5 Bioglass scaffolds were produced by the foam replication technique with the standard composition of 45 wt% SiO2, 24.5 wt% Na2O, 24.5 wt% CaO, and 6 wt% P2O5. HDPSCs were cultured in monolayers and on porous 45S5 Bioglass scaffolds under angiogenic and osteogenic conditions for 2-4 weeks. HDPSCs expressed endothelial gene markers (CD34, CD31/PECAM1, and VEGFR2) under both conditions in the monolayer. A combination of HDPSCs with 45S5 Bioglass enhanced the expression of these gene markers. Positive immunostaining for CD31/PECAM1 and VEGFR2 and negative staining for CD34 supported the gene expression data, while histology revealed evidence of endothelial cell-like morphology within the constructs. More organized tubular structures, resembling microvessels, were seen in the constructs after 8 weeks of implantation in vivo. In conclusion, this study suggests that the combination of HDPSCs with 45S5 Bioglass scaffolds offers a promising strategy for regenerating vascularized bone grafts. PMID- 25923925 TI - Amphiphilic zinc phthalocyanine photosensitizers: synthesis, photophysicochemical properties and in vitro studies for photodynamic therapy. AB - Peripherally and non-peripherally tetra-substituted zinc(ii) phthalocyanines bearing 2-(2-{2-[3-(dimethylamino)phenoxy]ethoxy}ethoxy)ethoxy and 2-(2-{2-[3 (diethylamino)phenoxy]ethoxy}ethoxy)ethoxy groups (, , and ) were synthesized by cyclotetramerization of the corresponding phthalonitriles (, , and ). Their quaternized ionic derivatives (, , and ) were also synthesized by the reaction of them with methyl iodide. The novel compounds were characterized by using standard spectroscopic techniques such as FT-IR, (1)H NMR, (13)C NMR, UV-vis, mass and elemental analyses. The obtained quaternized phthalocyanines (, , and ) showed amphiphilic behaviour with excellent solubility in both organic and aqueous solutions, which makes them potential photosensitizers for use in photodynamic therapy (PDT) of cancer. The photophysical (fluorescence quantum yields and lifetimes) and photochemical (singlet oxygen and photodegradation quantum yields) properties of these novel phthalocyanines were studied in DMSO for both non-ionic and ionic quaternized derivatives. However, these properties were examined in both DMSO and phosphate buffer solution (PBS) for quaternized ionic phthalocyanines. The effects of the positions of substituents (peripheral or non peripheral) and the quaternization of the nitrogen atoms on the substituents about their photophysical and photochemical properties were also compared in this study. The bovine serum albumin (BSA) binding behaviours of the studied quaternized ionic zinc(ii) phthalocyanines were also described in PBS solutions. The quaternized phthalocyanines (, , and ) successfully displayed light-dependent photodamage in HeLa and HuH-7 cancer cells in photodynamic therapy treatment. The photosensitivity and the intensity of damage were found directly related to the concentration of the photosensitizers. PMID- 25923922 TI - Sp1 Mediates a Therapeutic Role of MiR-7a/b in Angiotensin II-Induced Cardiac Fibrosis via Mechanism Involving the TGF-beta and MAPKs Pathways in Cardiac Fibroblasts. AB - MicroRNA-7a/b (miR-7a/b) protects cardiac myocytes from apoptosis during ischemia/reperfusion injury; however, its role in angiotensin II (ANG II) stimulated cardiac fibroblasts (CFs) remains unknown. Therefore, the present study investigated the anti-fibrotic mechanism of miR-7a/b in ANG II-treated CFs. ANG II stimulated the expression of specific protein 1 (Sp1) and collagen I in a dose- and time-dependent manner, and the overexpression of miR-7a/b significantly down-regulated the expression of Sp1 and collagen I stimulated by ANG II (100 nM) for 24 h. miR-7a/b overexpression effectively inhibited MMP-2 expression/activity and MMP-9 expression, as well as CF proliferation and migration. In addition, miR 7a/b also repressed the activation of TGF-beta, ERK, JNK and p38 by ANG II. The inhibition of Sp1 binding activity by mithramycin prevented collagen I overproduction; however, miR-7a/b down-regulation reversed this effect. Further studies revealed that Sp1 also mediated miR-7a/b-regulated MMP expression and CF migration, as well as TGF-beta and ERK activation. In conclusion, miR-7a/b has an anti-fibrotic role in ANG II-treated CFs that is mediated by Sp1 mechanism involving the TGF-beta and MAPKs pathways. PMID- 25923926 TI - Development of Disease-specific, Context-specific Surveillance Models: Avian Influenza (H5N1)-Related Risks and Behaviours in African Countries. AB - Avian influenza virus (H5N1) is a rapidly disseminating infection that affects poultry and, potentially, humans. Because the avian virus has already adapted to several mammalian species, decreasing the rate of avian-mammalian contacts is critical to diminish the chances of a total adaptation of H5N1 to humans. To prevent the pandemic such adaptation could facilitate, a biology-specific disease surveillance model is needed, which should also consider geographical and socio cultural factors. Here, we conceptualized a surveillance model meant to capture H5N1-related biological and cultural aspects, which included food processing, trade and cooking-related practices, as well as incentives (or disincentives) for desirable behaviours. This proof of concept was tested with data collected from 378 Egyptian and Nigerian sites (local [backyard] producers/live bird markets/village abattoirs/commercial abattoirs and veterinary agencies). Findings revealed numerous opportunities for pathogens to disseminate, as well as lack of incentives to adopt preventive measures, and factors that promoted epidemic dissemination. Supporting such observations, the estimated risk for H5N1-related human mortality was higher than previously reported. The need for multidimensional disease surveillance models, which may detect risks at higher levels than models that only measure one factor or outcome, was supported. To develop efficient surveillance systems, interactions should be captured, which include but exceed biological factors. This low-cost and easily implementable model, if conducted over time, may identify focal instances where tailored policies may diminish both endemicity and the total adaptation of H5N1 to the human species. PMID- 25923927 TI - Preface: a special tribute to the memory of Dr. Sidney Nelson. PMID- 25923928 TI - Embedded ultrasonic transducers for active and passive concrete monitoring. AB - Recently developed new transducers for ultrasonic transmission, which can be embedded right into concrete, are now used for non-destructive permanent monitoring of concrete. They can be installed during construction or thereafter. Large volumes of concrete can be monitored for changes of material properties by a limited number of transducers. The transducer design, the main properties as well as installation procedures are presented. It is shown that compressional waves with a central frequency of 62 kHz are mainly generated around the transducer's axis. The transducer can be used as a transmitter or receiver. Application examples demonstrate that the transducers can be used to monitor concrete conditions parameters (stress, temperature, ...) as well as damages in an early state or the detection of acoustic events (e.g., crack opening). Besides application in civil engineering our setups can also be used for model studies in geosciences. PMID- 25923929 TI - Tidal volume estimation using the blanket fractal dimension of the tracheal sounds acquired by smartphone. AB - In this paper, we propose the use of blanket fractal dimension (BFD) to estimate the tidal volume from smartphone-acquired tracheal sounds. We collected tracheal sounds with a Samsung Galaxy S4 smartphone, from five (N = 5) healthy volunteers. Each volunteer performed the experiment six times; first to obtain linear and exponential fitting models, and then to fit new data onto the existing models. Thus, the total number of recordings was 30. The estimated volumes were compared to the true values, obtained with a Respitrace system, which was considered as a reference. Since Shannon entropy (SE) is frequently used as a feature in tracheal sound analyses, we estimated the tidal volume from the same sounds by using SE as well. The evaluation of the performed estimation, using BFD and SE methods, was quantified by the normalized root-mean-squared error (NRMSE). The results show that the BFD outperformed the SE (at least twice smaller NRMSE was obtained). The smallest NRMSE error of 15.877% +/- 9.246% (mean +/- standard deviation) was obtained with the BFD and exponential model. In addition, it was shown that the fitting curves calculated during the first day of experiments could be successfully used for at least the five following days. PMID- 25923930 TI - Novel monitoring techniques for characterizing frictional interfaces in the laboratory. AB - A pressure-sensitive film was used to characterize the asperity contacts along a polymethyl methacrylate (PMMA) interface in the laboratory. The film has structural health monitoring (SHM) applications for flanges and other precision fittings and train rail condition monitoring. To calibrate the film, simple spherical indentation tests were performed and validated against a finite element model (FEM) to compare normal stress profiles. Experimental measurements of the normal stress profiles were within -7.7% to 6.6% of the numerical calculations between 12 and 50 MPa asperity normal stress. The film also possessed the capability of quantifying surface roughness, an important parameter when examining wear and attrition in SHM applications. A high definition video camera supplied data for photometric analysis (i.e., the measure of visible light) of asperities along the PMMA-PMMA interface in a direct shear configuration, taking advantage of the transparent nature of the sample material. Normal stress over individual asperities, calculated with the pressure-sensitive film, was compared to the light intensity transmitted through the interface. We found that the luminous intensity transmitted through individual asperities linearly increased 0.05643 +/- 0.0012 candelas for an increase of 1 MPa in normal stress between normal stresses ranging from 23 to 33 MPa. PMID- 25923931 TI - A PDMS-Based 2-Axis Waterproof Scanner for Photoacoustic Microscopy. AB - Optical-resolution photoacoustic microscopy (OR-PAM) is an imaging tool to provide in vivo optically sensitive images in biomedical research. To achieve a small size, fast imaging speed, wide scan range, and high signal-to-noise ratios (SNRs) in a water environment, we introduce a polydimethylsiloxane (PDMS)-based 2 axis scanner for a flexible and waterproof structure. The design, theoretical background, fabrication process and performance of the scanner are explained in details. The designed and fabricated scanner has dimensions of 15 * 15 * 15 mm along the X, Y and Z axes, respectively. The characteristics of the scanner are tested under DC and AC conditions. By pairing with electromagnetic forces, the maximum scanning angles in air and water are 18 degrees and 13 degrees along the X and Y axes, respectively. The measured resonance frequencies in air and water are 60 and 45 Hz along the X axis and 45 and 30 Hz along the Y axis, respectively. Finally, OR-PAM with high SNRs is demonstrated using the fabricated scanner, and the PA images of micro-patterned samples and microvasculatures of a mouse ear are successfully obtained with high-resolution and wide-field of view. OR-PAM equipped with the 2-axis PDMS based waterproof scanner has lateral and axial resolutions of 3.6 MUm and 26 MUm, respectively. This compact OR-PAM system could potentially and widely be used in preclinical and clinical applications. PMID- 25923932 TI - A Self-Alignment Algorithm for SINS Based on Gravitational Apparent Motion and Sensor Data Denoising. AB - Initial alignment is always a key topic and difficult to achieve in an inertial navigation system (INS). In this paper a novel self-initial alignment algorithm is proposed using gravitational apparent motion vectors at three different moments and vector-operation. Simulation and analysis showed that this method easily suffers from the random noise contained in accelerometer measurements which are used to construct apparent motion directly. Aiming to resolve this problem, an online sensor data denoising method based on a Kalman filter is proposed and a novel reconstruction method for apparent motion is designed to avoid the collinearity among vectors participating in the alignment solution. Simulation, turntable tests and vehicle tests indicate that the proposed alignment algorithm can fulfill initial alignment of strapdown INS (SINS) under both static and swinging conditions. The accuracy can either reach or approach the theoretical values determined by sensor precision under static or swinging conditions. PMID- 25923933 TI - Smartphone applications with sensors used in a tertiary hospital-current status and future challenges. AB - Smartphones have been widely used recently to monitor heart rate and activity, since they have the necessary processing power, non-invasive and cost-effective sensors, and wireless communication capabilities. Consequently, healthcare applications (apps) using smartphone-based sensors have been highlighted for non invasive physiological monitoring. In addition, several healthcare apps have received FDA clearance. However, in spite of their potential, healthcare apps with smartphone-based sensors are mostly used outside of hospitals and have not been widely adopted for patient care in hospitals until recently. In this paper, we describe the experience of using smartphone apps with sensors in a large medical center in Korea. Among >20 apps developed in our medical center, four were extensively analyzed ("My Cancer Diary", "Point-of-Care HIV Check", "Blood Culture" and "mAMIS"), since they use smartphone-based sensors such as the camera and barcode reader to enter data into the electronic health record system. By analyzing the usage patterns of these apps for data entry with sensors, the current limitations of smartphone-based sensors in a clinical setting, hurdles against adoption in the medical center, benefits of smartphone-based sensors and potential future research directions could be evaluated. PMID- 25923934 TI - Reversible NO2 Optical Fiber Chemical Sensor Based on LuPc2 Using Simultaneous Transmission of UV and Visible Light. AB - In this paper, an NO2 optical fiber sensor is presented for pollution monitoring in road traffic applications. This sensor exploits the simultaneous transmission of visible light, as a measurement signal, and UV light, for the recovery of the NO2 sensitive materials. The sensor is based on a multimode fiber tip coated with a thin film of lutetium bisphthalocyanine (LuPc2). The simultaneous injection of UV light through the fiber is an improvement on the previously developed NO2 sensors and allows the simplification of the sensor head, rendering the external UV illumination of the film unnecessary. Coatings of different thicknesses were deposited on the optical fiber tips and the best performance was obtained for a 15 nm deposited thickness, with a sensitivity of 5.02 mV/ppm and a resolution of 0.2 ppb in the range 0-5 ppm. The response and recovery times are not dependent on thickness, meaning that NO2 does not diffuse completely in the films. PMID- 25923935 TI - Separation of radio-frequency sources and localization of partial discharges in noisy environments. AB - The detection of partial discharges (PD) can help in early-warning detection systems to protect critical assets in power systems. The radio-frequency emission of these events can be measured with antennas even when the equipment is in service which reduces dramatically the maintenance costs and favours the implementation of condition-based monitoring systems. The drawback of these type of measurements is the difficulty of having a reference signal to study the events in a classical phase-resolved partial discharge pattern (PRPD). Therefore, in open-air substations and overhead lines where interferences from radio and TV broadcasting and mobile communications are important sources of noise and other pulsed interferences from rectifiers or inverters can be present, it is difficult to identify whether there is partial discharges activity or not. This paper proposes a robust method to separate the events captured with the antennas, identify which of them are partial discharges and localize the piece of equipment that is having problems. The separation is done with power ratio (PR) maps based on the spectral characteristics of the signal and the identification of the type of event is done localizing the source with an array of four antennas. Several classical methods to calculate the time differences of arrival (TDOA) of the emission to the antennas have been tested, and the localization is done using particle swarm optimization (PSO) to minimize a distance function. PMID- 25923936 TI - A non-contact pulse automatic positioning measurement system for traditional Chinese medicine. AB - This study is to construct a non-contact pulse automatic positioning measurement system for Traditional Chinese Medicine (TCM) using optical triangulation measurements. The system consists of a linear laser, a CMOS image sensor and image analysis software. The linear laser is projected on the pulse beat location on the wrists; the CMOS image sensor records the process and the software analyzes the images. The program mainly uses the optical centroid and fast Fourier transform (FFT) principles to calculate centroid changes (pulse amplitude changes) from the images taken by the CMOS image sensor. It returns the positions of cun, guan and chi pulses automatically in terms of the amplitudes and the signals are then transformed from the time domain (time-amplitude) into the frequency domain (frequency-amplitude) via FFT to obtain the waveforms and frequencies of the cun, guan and chi pulses. It successfully extracts the data from the TCM pulse reading and can be a medical aid system for TCM. Combining the advantages of optical measurement and computer automation, this system provides a non-contact, easy to operate, fast in detection and low-cost equipment design. PMID- 25923937 TI - Development of a HIV-1 Virus Detection System Based on Nanotechnology. AB - Development of a sensitive and selective detection system for pathogenic viral agents is essential for medical healthcare from diagnostics to therapeutics. However, conventional detection systems are time consuming, resource-intensive and tedious to perform. Hence, the demand for sensitive and selective detection system for virus are highly increasing. To attain this aim, different aspects and techniques have been applied to develop virus sensor with improved sensitivity and selectivity. Here, among those aspects and techniques, this article reviews HIV virus particle detection systems incorporated with nanotechnology to enhance the sensitivity. This review mainly focused on four different detection system including vertically configured electrical detection based on scanning tunneling microscopy (STM), electrochemical detection based on direct electron transfer in virus, optical detection system based on localized surface plasmon resonance (LSPR) and surface enhanced Raman spectroscopy (SERS) using plasmonic nanoparticle. PMID- 25923938 TI - A High-Resolution Demodulation Algorithm for FBG-FP Static-Strain Sensors Based on the Hilbert Transform and Cross Third-Order Cumulant. AB - Static strain can be detected by measuring a cross-correlation of reflection spectra from two fiber Bragg gratings (FBGs). However, the static-strain measurement resolution is limited by the dominant Gaussian noise source when using this traditional method. This paper presents a novel static-strain demodulation algorithm for FBG-based Fabry-Perot interferometers (FBG-FPs). The Hilbert transform is proposed for changing the Gaussian distribution of the two FBG-FPs' reflection spectra, and a cross third-order cumulant is used to use the results of the Hilbert transform and get a group of noise-vanished signals which can be used to accurately calculate the wavelength difference of the two FBG-FPs. The benefit by these processes is that Gaussian noise in the spectra can be suppressed completely in theory and a higher resolution can be reached. In order to verify the precision and flexibility of this algorithm, a detailed theory model and a simulation analysis are given, and an experiment is implemented. As a result, a static-strain resolution of 0.9 nepsilon under laboratory environment condition is achieved, showing a higher resolution than the traditional cross correlation method. PMID- 25923939 TI - Fulminant presentation of autoimmune hepatitis: clinical features and early predictors of corticosteroid treatment failure. AB - BACKGROUND AND AIMS: Classical features of autoimmune hepatitis (AIH) may be altered during the abrupt onset of the disease. Corticosteroid therapy can be life-saving, but its use in the fulminant presentation of AIH (F-AIH) remains controversial. We aimed to assess the clinical features of patients with F-AIH and to describe the role of corticosteroids in this population. PATIENTS AND METHODS: We retrospectively analyzed 154 adult patients with fulminant hepatic failure who were admitted to six liver transplantation (LT) programs. The AIH simplified criteria were used to identify patients with F-AIH. RESULTS: We identified 40 (26%) patients with F-AIH. Compared with other etiologies, patients with F-AIH presented a longer interval from jaundice to encephalopathy (26 vs. 16 days, P=0.02) and a lower Model for End-Stage Liver Disease (MELD) score on admission (29 vs. 33, P=0.002). Overall, 25 (62%) patients with F-AIH underwent LT, eight (20%) patients survived, and seven (18%) died without LT. Seventeen patients received corticosteroids therapy, of whom seven (41%) survived without LT. Among the treated patients, higher MELD score and encephalopathy grade of 3 or more were associated significantly with corticosteroid failure. CONCLUSION: Patients with F-AIH have a more indolent presentation compared with the non-F-AIH population. Altogether, only eight (20%) patients presenting with F-AIH survived without LT. A subset of patients with F-AIH and an initial MELD score less than 27 and low-grade hepatic encephalopathy might benefit from administration of corticosteroids. PMID- 25923940 TI - Cardiac dysfunction in patients with cirrhosis: is the systolic component its main feature? AB - OBJECTIVE: To investigate the subclinical cardiac morphological and functional modifications in cirrhotic patients according to the stage of liver disease. PATIENTS AND METHODS: One hundred and thirteen cirrhotic patients underwent standard Doppler echocardiography and were compared with healthy individuals. Left ventricular (LV) geometry, systolic/diastolic function, and the main hemodynamic parameters were assessed according to current guidelines. RESULTS: Cirrhotic patients showed a reduction in the peripheral vascular resistance (PVR), a compensatory hyperdynamic syndrome, and a significant increase in cardiac index (CI), cardiac output (CO), and cardiac work, with a consequent increase in the prevalence of LV hypertrophy and associated diastolic dysfunction (DD). Age (P=0.005) and LV mass index (P=0.03) were the strongest predictors of DD. Even though all the systolic parameters assessed were similar between patients and controls, in patients with refractory ascites, the reduction of the PVR and mean blood pressure was not balanced by a further increase in cardiac work and therefore the CI and CO were supported only by the increase in heart rate. CONCLUSION: In cirrhotic patients, DD is strongly related to the increase in LV mass, not related to the stage of the liver disease, and can be correctly detectable only by the use of tissue Doppler imaging. For systolic dysfunction, along with the development and worsening of ascites, CO and CI do not increase further to compensate the continuous reduction of PVR and mean blood pressure, and their maintenance becomes critically dependent on the heart rate, thus suggesting a possible detrimental effect of beta-blockers in these patients. PMID- 25923941 TI - Measurements of serum procollagen-III peptide and M30 do not improve the diagnostic accuracy of transient elastography for the detection of hepatic fibrosis in patients with nonalcoholic fatty liver disease. AB - BACKGROUND: Transient elastography (TE) has recently emerged as an accurate noninvasive imaging method for the diagnosis of liver fibrosis in nonalcoholic fatty liver disease (NAFLD). Here, we tested whether adding serum measures of serum procollagen-III peptide (PIIIP) and caspase-cleaved cytokeratin 18 fragment (M30) to TE could improve its diagnostic accuracy in patients with biopsy-proven NAFLD. PATIENTS AND METHODS: TE was performed in 87 patients with NAFLD. Serum PIIIP and M30 levels were determined by enzyme-linked immunosorbent assay. Liver histology was considered the gold standard. The diagnostic accuracies were assessed by measuring the area under the receiver operating curve. RESULTS: At histopathological examination, 34 patients (39.1%) had significant fibrosis (F2 F4) and 19 patients (21.8%) had advanced fibrosis (F3-F4). Both TE and serum M30 levels were independent predictors of fibrosis, whereas no association was found with PIIIP. No significant differences in terms of sensitivity and specificity for both significant and advanced fibrosis were evident for TE, serum M30, or their combination. Moreover, the area under the receiver operating curves of serum M30 combined with TE did not differ significantly from those of either test alone. CONCLUSION: Both TE and serum M30 levels are accurate for the noninvasive diagnosis of fibrosis in NAFLD. However, their combination did not improve the overall diagnostic accuracy. PMID- 25923942 TI - Procoagulant imbalance aggravated with falling liver function reserve, but not associated with the presence of portal vein thrombosis in cirrhosis. AB - OBJECTIVES: Hypercoagulability, hemodynamic changes, and endothelial injury are the three major contributors to the development of thrombosis. However, the role of hypercoagulability in portal vein thrombosis (PVT) in liver cirrhosis is still controversial. The aim of this study is to elucidate the relationship between procoagulant imbalance and PVT in patients with liver cirrhosis. METHODS: This study included 151 patients with cirrhosis with (n=20) or without PVT (n=131). Levels of procoagulant factor (FVIII) and anticoagulants [protein C (PC), protein S (PS), and antithrombin (AT)] were measured. Procoagulant imbalance was also evaluated using a thrombin generation test with/without Protac and the results were expressed as Protac-induced coagulation inhibition percentage (PICI%). The lower the PICI% value, the greater the procoagulant imbalance. RESULTS: The levels of PC (P<0.001), PS (P<0.05), and AT (P<0.001) decreased progressively from Child-Pugh A to C in all patients, whereas the levels of FVIII did not alter with the severity of cirrhosis (P>0.05), which indicated the balance tilting toward procoagulation in liver cirrhosis. Similarly, the PICI% values decreased from Child-Pugh A to C (P<0.001). However, there were no differences in the levels of PC, PS, AT, FVIII or PICI% between patients with and without PVT (P>0.05), even after stratification by Child-Pugh classification (P>0.05). CONCLUSION: Procoagulant imbalance is not associated with the presence of PVT in patients with cirrhosis, although the imbalance worsens with the severity of cirrhosis. PMID- 25923943 TI - Hepatic steatosis in individuals living with HIV measured by controlled attenuation parameter: a cross-sectional study. AB - OBJECTIVES: Available data on the prevalence of hepatic steatosis in an unselected HIV-infected population are limited. The aim of this study was to determine the prevalence of hepatic steatosis and assess the associated factors in HIV-infected individuals. PATIENTS AND METHODS: One hundred and thirty-six HIV infected individuals were enrolled in this cross-sectional study. Patients underwent transient elastography and controlled attenuation parameter (CAP) measurements. We analyzed the associations between the CAP value and demographic, metabolic, and immunologic parameters. For the first time, in HIV-infected individuals, we used a continuous scale of CAP values to identify significant covariates of hepatic fat accumulation. As a result and compared with other methods, one of the main advantages of CAP was that the quantitative measurement of liver steatosis could be used for analysis. RESULTS: Using univariate analysis, CAP was significantly correlated with the following continuous variables: CD4 percentage (P=0.035), CD8 percentage (P=0.016), age (P<0.001), CD4/8 ratio (P=0.002), BMI (P<0.001), serum triglyceride (P<0.001), and serum cholesterol (P=0.004) levels, the length of known HIV positivity (P<0.001), and liver stiffness (P=0.041). With respect to categorical variables, a significant association was found for the presence of diabetes (P=0.006), hypertension (P<0.001), facial lipodystrophy (P=0.031), and the use of lopinavir (P=0.042). In multivariate analysis using linear regression, BMI (P<0.001), presence of diabetes (P=0.026), and hypertension (P=0.040) were identified as independent significant correlates. Darunavir therapy was associated negatively with the CAP value (P=0.032). CONCLUSION: Our findings reflect the importance of metabolic factors in hepatic steatosis. The strongest independent covariate was BMI. PMID- 25923944 TI - Tumor size is not a criterion for resection during the management of giant hemangioma of the liver. AB - BACKGROUND: Liver hemangiomas are the most common benign liver tumors. The management of giant (>=5 cm) hemangioma of the liver remains controversial. The aim of this study was to assess the influence of tumor size on postoperative outcomes after hepatectomy in patients with giant hemangioma of the liver. METHODS: Patients who were subjected to resection because of giant liver hemangioma between December 2006 and July 2012 were grouped by largest tumor size: 5-10 cm (group A) and 10-15 cm (group B). All patients underwent detailed preoperative assessments. Clinicopathologic features were analyzed, and univariate and multivariate analyses were used to determine risk factors that correlated independently with any complication, as well as the intraoperative red blood cell transfusion requirement. Long-term outcomes were assessed with a median follow-up of 56 months. RESULTS: One hundred and ninety patients, mean age 46 years, were included. The 146 patients with tumors 5-10 cm in size were compared with the remaining 44 patients with tumors 5-10 cm in size. The differences in postoperative morbidity (29.86 vs. 41.30%, P=0.150) and duration of hospitalization (11.06+/-7.02 vs. 12.17+/-7.74, P=0.465) between group A and group B did not reach statistical significance. Operation time, blood loss, and transfusion volume of group B were greater than those of group A. No perioperative deaths occurred and no recurrences were registered during follow-up in both groups. The results of univariate and multivariate analysis showed that diameter was not an independent risk factor of postoperative complications and intraoperative red blood cell transfusion. CONCLUSION: Giant hemangiomas should be monitored regularly. Asymptomatic tumors 5-10 cm in diameter can be managed conservatively even though they grow. When necessary, surgical treatment can be well justified because of low morbidity and mortality. PMID- 25923945 TI - Gastro-oesophageal reflux symptoms and coeliac disease: no role for routine duodenal biopsy. AB - BACKGROUND: Coeliac disease (CD) has been linked to gastro-oesophageal reflux disease (GORD). Previous studies have demonstrated an increased prevalence of reflux in patients with CD. However data on the risk for CD in patients presenting with reflux are conflicting. AIMS: The aim of this study was to establish the prevalence of CD in patients with GORD and to elucidate the mechanisms for reflux symptoms in newly diagnosed CD patients. METHODS: Group A: patients who had undergone routine duodenal biopsy were prospectively recruited between 2004 and 2014. Diagnostic yield was compared with that of a screening cohort. Group B: 32 patients with newly diagnosed CD who had undergone oesophageal manometry and 24-h pH studies were prospectively recruited. RESULTS: Group A: 3368 patients (58.7% female, mean age 53.4 years) underwent routine duodenal biopsy. Of these patients, 850 (25.2%) presented with GORD. The prevalence of CD among GORD patients was 1.3% (0.7-2.4%), which was not significantly higher than that in the general population (P=0.53). Within the context of routine duodenal biopsy at endoscopy (when corrected for concurrent symptoms, age and sex), reflux was found to be negatively associated with CD [adjusted odds ratio 0.12 (0.07-0.23), P<0.0001]. In group B, 34% of patients complained of reflux. On manometry, 9% had a hypotensive lower oesophageal sphincter and 40.6% had oesophageal motor abnormalities, with 25% significantly hypocontractile. On pH studies, 33% demonstrated reflux episodes. CONCLUSION: The prevalence of undiagnosed CD among GORD patients is similar to that in the general population, and routine duodenal biopsy cannot be recommended. A significant number of patients with newly diagnosed CD were found to have reflux and/or oesophageal dysmotility on pH/manometry studies; this may explain the high prevalence of reflux symptoms in CD. PMID- 25923946 TI - Liver steatosis is a risk factor for hepatotoxicity in patients with inflammatory bowel disease under immunosuppressive treatment. AB - OBJECTIVE: In inflammatory bowel disease (IBD), hepatic disorders are frequently due to nonalcoholic fatty liver disease and drug-induced hepatotoxicity. Immunosuppressive treatment is known to exert hepatotoxic side effects by a still unknown mode. The relevance of liver steatosis for the development of drug related hepatotoxicity in IBD is unknown. METHODS: The charts of 259 patients with IBD under immunosuppression with either azathioprine, 6-mercaptopurine, or methotrexate were reviewed. The prevalence of liver steatosis was assessed by means of ultrasound reports. Aspartate transaminase and alanine transaminase above the normal range were used to indicate liver abnormalities. RESULTS: Liver steatosis on the basis of ultrasound criteria was observed in 73 patients (28.2%). In patients with liver steatosis, the presence of elevated liver enzymes (ELE) was found to be significantly more prevalent (28.8 vs. 14.5%, P=0.0095). The finding of liver steatosis was associated with higher age (44.1 vs. 34.5 years, P<0.0001) and body weight (BMI 26.7 vs. 23.4 kg/m, P<0.0001). Development of ELE under immunosuppression was seen in 50 patients (19.3%). Of the patients who developed ELE, 44.0% (vs. 24.4%, P=0.0095) showed liver steatosis. Logistic regression analysis revealed that male individuals showed an increased likelihood of developing ELE associated with steatosis (P=0.0118, odds ratio=3.93) and that patients who received steroids less often developed ELE in association with liver steatosis (P=0.0414, odds ratio=0.31). CONCLUSION: This study suggests that fatty liver represents a risk factor for hepatotoxicity in patients with IBD under immunosuppressive treatment and should be routinely considered in treatment strategies. PMID- 25923947 TI - Circulating endothelial mediators in human pancreatitis-associated lung injury. AB - OBJECTIVES: To investigate the role of endothelial cell mediators, E-selectin (ES), intercellular adhesion molecule-1 (ICAM-1), tissue factor (TF), and von Willebrand factor (vWF), in the early phase of severe acute pancreatitis (SAP) complicated with respiratory failure [pancreatitis-associated lung injury (PALI)]. PATIENTS AND METHODS: This study included 30 patients with SAP and 39 patients with PALI. Blood samples were taken from SAP and PALI patients on presenting to the hospital (day 1), and days 2, 3, 5, and 10. The relationship between blood concentrations of the studied endothelial mediators and lung function tests was analyzed. RESULTS: PALI patients had significantly higher ES, ICAM-1, TF, and vWF blood levels than those with SAP as early as at admission and throughout the period studied. We found the highest concentration of ES on the second day, ICAM-1 and TF at admission, and vWF level on the fifth day. There were adverse correlations between ES, ICAM-1, TF, vWF concentrations, and the index of oxygenation--PaO2/FiO2 ratio (Rs=-0.385, Rs=-0.523, Rs=-0.505, Rs= 0.408, P<0.001, respectively). The most accurate prediction of PALI was provided by ICAM-1 and TF levels on the day of admission [areas under curve (AUCs): ES, 0.704; ICAM-1, 0.787; TF, 0.757; and vWF, 0.686]. CONCLUSION: Endothelium-related mediators ES, ICAM-1, TF, and vWF appear to participate in pancreatitis associated lung injury. In SAP, the measurement of endothelial mediator levels (especially ICAM-1 and TF) may be used as an early prognostic indicator that would predict the development of respiratory failure and to monitor the severity of lung dysfunction. PMID- 25923948 TI - In situ formed Bi/BiOBrxI1-x heterojunction of hierarchical microspheres for efficient visible-light photocatalytic activity. AB - Bi nanoparticles deposited in situ in BiOBrxI1-x hierarchical microspheres (Bi/BiOBrxI1-x heterojunction) were synthesized by a facile one-step solvothermal method. The as-prepared samples were characterized via XRD, SEM, TEM, XPS, UV-vis absorption spectroscopy and N2 adsorption-desorption. The hierarchical microspheres were composed of numerous nanosheets aggregated together compactly to form a spherical geometry. Results indicated that Bi nanoparticles were generated on the surface of BiOBrxI1-x microspheres via the in situ reduction of Bi(3+) by ethylene glycol. BiOBrxI1-x microspheres with deposited Bi nanoparticles were employed for the degradation of RhB under visible-light irradiation and the samples exhibited exceptionally enhanced photocatalytic activity. This immense enhancement in photocatalytic activity was attributed to the contribution of Bi nanoparticles to the efficient separation of electron-hole pairs and prolongation of the lifetime of charge carriers. The behavior of Bi nanoparticles as a cocatalyst for enhancing photocatalytic activity is similar to that of noble metals in photocatalysis. The as-prepared Bi/BiOBr0.266I0.734 sample exhibited highest photocatalytic activity, which exceeded those of other types of visible-light photocatalysts such as N-TiO2, Eu(3+)-BiOI, BiOBr, BiOBr0.2I0.8/graphene and even Ag/AgBr/BiOBr. The Bi/BiOBr0.266I0.734 sample displayed high photochemical stability under repeated visible-light irradiation, which is especially important for its practical application. The active species produced from Bi/BiOBrxI1-x under visible light were hydroxyl radicals. Bi/BiOBrxI1-x could generate more hydroxyl radicals due to the Bi nanoparticles, contributing to the enhance oxidation ability. This study demonstrated the high feasibility of utilizing low-cost Bi nanoparticles as a substitute for noble metals to enhance visible-light photocatalysis. PMID- 25923949 TI - Atg8 is involved in endosomal and phagosomal acidification in the parasitic protist Entamoeba histolytica. AB - Autophagy is one of two major bulk protein degradation systems and is conserved throughout eukaryotes. The protozoan Entamoeba histolytica, which is a human intestinal parasite, possesses a restricted set of autophagy-related (Atg) proteins compared with other eukaryotes and thus represents a suitable model organism for studying the minimal essential components and ancestral functions of autophagy. E. histolytica possesses two conjugation systems: Atg8 and Atg5/12, although a gene encoding Atg12 is missing in the genome. Atg8 is considered to be the central and authentic marker of autophagosomes, but recent studies have demonstrated that Atg8 is not exclusively involved in autophagy per se, but other fundamental mechanisms of vesicular traffic. To investigate this question in E. histolytica, we studied on Atg8 during the proliferative stage. Atg8 was constitutively expressed in both laboratory-maintained and recently established clinical isolates and appeared to be lipid-modified in logarithmic growth phase, suggesting a role of Atg8 in non-stress and proliferative conditions. These findings are in contrast to those for Entamoeba invadens, in which autophagy is markedly induced during an early phase of differentiation from the trophozoite into the cyst. The repression of Atg8 gene expression in En. histolytica by antisense small RNA-mediated transcriptional gene silencing resulted in growth retardation, delayed endocytosis and reduced acidification of endosomes and phagosomes. Taken together, these results suggest that Atg8 and the Atg8 conjugation pathway have some roles in the biogenesis of endosomes and phagosomes in this primitive eukaryote. PMID- 25923951 TI - Confusing borderline personality with severe bipolar illness. PMID- 25923950 TI - Studies on the ATP Binding Site of Fyn Kinase for the Identification of New Inhibitors and Their Evaluation as Potential Agents against Tauopathies and Tumors. AB - Fyn is a member of the Src-family of nonreceptor protein-tyrosine kinases. Its abnormal activity has been shown to be related to various human cancers as well as to severe pathologies, such as Alzheimer's and Parkinson's diseases. Herein, a structure-based drug design protocol was employed aimed at identifying novel Fyn inhibitors. Two hits from commercial sources (1, 2) were found active against Fyn with K(i) of about 2 MUM, while derivative 4a, derived from our internal library, showed a K(i) of 0.9 MUM. A hit-to-lead optimization effort was then initiated on derivative 4a to improve its potency. Slightly modifications rapidly determine an increase in the binding affinity, with the best inhibitors 4c and 4d having K(i)s of 70 and 95 nM, respectively. Both compounds were found able to inhibit the phosphorylation of the protein Tau in an Alzheimer's model cell line and showed antiproliferative activities against different cancer cell lines. PMID- 25923952 TI - Left Ventricular Dyssynchrony by Three-Dimensional Echocardiography: Current Understanding and Potential Future Clinical Applications. AB - Left ventricular mechanical dyssynchrony is an important prognostic factor for patients with symptomatic systolic heart failure and has emerged as a therapeutic target for cardiac resynchronization therapy (CRT). However, approximately one third of patients fail to improve after CRT based on current guideline recommendations and electrocardiographic criteria. Two-dimensional echocardiography and tissue Doppler-based techniques have shown variable results in assessment of left ventricular (LV) dyssynchrony and have limited value in clinical practice. Three-dimensional echocardiography (3DE) is an appealing novel imaging modality that has been recently used in quantitative evaluation of global and regional LV function. There is accumulating evidence that 3DE measurement of LV systolic dyssynchrony index may potentially play a role in predicting the short- and long-term response to CRT and further improve patient selection for CRT. New developments in 3DE speckle tracking technique and strain analysis may further improve the accuracy of LV mechanical dyssynchrony assessment in this population. In addition, recent studies suggest that mechanical dyssynchrony is present in patients with LV hypertrophy and diastolic heart failure. Three dimensional echocardiographic assessment of dyssynchrony may aid in diagnosis and in predicting long-term outcome in these patients. We will summarize current understanding of 3DE techniques and parameters in assessment of LV mechanical dyssynchrony in the population of patients with systolic heart failure, LV hypertrophy, and diastolic heart failure. A number of the novel 3DE techniques described in this review are early in their stage of development, and they will continue to evolve and need further testing in large multicenter studies. PMID- 25923953 TI - PREDICTIVE VALUE OF TNM CLASSIFICATION, INTERNATIONAL CLASSIFICATION, AND REESE ELLSWORTH STAGING OF RETINOBLASTOMA FOR THE LIKELIHOOD OF HIGH-RISK PATHOLOGIC FEATURES. AB - PURPOSE: To evaluate the predictive value of the seventh edition American Joint Committee on Cancer (AJCC/UICC) TNM classification, the International Classification of Retinoblastoma (ICRB), and Reese-Ellsworth staging for retinoblastoma for the likelihood of high-risk pathologic features. METHODS: A retrospective study of 50 primarily enucleated eyes from 49 retinoblastoma patients. Main outcome measures included demographics, TNM stage, ICRB group, Reese-Ellsworth stage, choroid, optic nerve, and anterior chamber invasion. RESULTS: The median age at enucleation was 30 months. High-risk pathologic features mandating adjuvant chemotherapy were seen in 5 of T2 eyes (22%), in 15 of T3 eyes (56%) (P = 0.021), in 1 of ICRB Group C eyes (13%), 8 of Group D eyes (33%), and 11 of Group E eyes (61%) (P = 0.035). High-risk pathologic features were 4.61 and 3.68 times more likely to be diagnosed at a more advanced T stage and ICRB group consecutively, whereas 0.133 time less likely to be diagnosed at a more advanced Reese-Ellsworth stage. At median follow-up of 40 months, no single case had metastasis or was dead. CONCLUSION: The higher tumor clinical TNM stage and the more advanced ICRB group at presentation are associated with higher frequency of high-risk pathologic features and may predict which patients should receive adjuvant chemotherapy. PMID- 25923954 TI - NEAR-INFRARED REFLECTANCE IMAGING IN EYES WITH ACUTE ZONAL OCCULT OUTER RETINOPATHY. AB - PURPOSE: To investigate the confocal scanning laser ophthalmoscopic images obtained with near-infrared (IR) light in eyes with acute zonal occult outer retinopathy (AZOOR). METHODS: Observational case series. The medical records of 12 eyes of 10 patients with AZOOR were reviewed. Scanning laser ophthalmoscopic images obtained from the AZOOR eyes were compared with images obtained by spectral-domain optical coherence tomography, by fundus autofluorescence, and by an adaptive optics fundus camera. RESULTS: In 8 of 12 eyes, abnormal hyporeflective areas were detected in the IR images, and the other 4 eyes did not have specific abnormalities in the IR images. The boundaries of the abnormal hyporeflective areas corresponded with the border of the irregularity of photoreceptor inner segment ellipsoid band in the spectral-domain optical coherence tomography images. The cone mosaics of the adaptive optics fundus image were disrupted in the abnormal hyporeflective area of the IR image. However, the areas of fundus autofluorescence abnormalities did not coincide with the hyporeflective areas in the IR images. CONCLUSION: The presence of hyporeflective areas in the IR images of patients with AZOOR suggests impairment of the photoreceptors area. The IR images would be useful to evaluate eyes with AZOOR. PMID- 25923955 TI - EFFECT OF PEGAPTANIB AND RANIBIZUMAB ON PLASMA AND VITREOUS HOMOCYSTEINE IN PATIENTS WITH EXUDATIVE AGE-RELATED MACULAR DEGENERATION. AB - PURPOSE: To investigate homocysteine (Hcy) concentration in the blood plasma and the vitreous in patients with exudative age-related macular degeneration receiving intravitreal anti-vascular endothelial growth factor therapy. METHODS: Plasma Hcy and vitreous Hcy levels were analyzed in 73 exudative age-related macular degeneration patients (50.7% received pegaptanib 0.3 mg and 50.3% received ranibizumab 0.5 mg) and compared with 80 controls and 40 patients with idiopathic epiretinal membranes, respectively. Homocysteine concentration was measured by immunonephelometric particle test, and it was determined before and after antiangiogenic therapy. RESULTS: The mean Hcy concentrations (+/- SD) of blood plasma and vitreous were 13.0 +/- 4.2 MUmol/L and 1.00 +/- 0.3 MUmol/L in patients treated with pegaptanib; in ranibizumab group, they were 12.8 +/- 2.5 MUmol/L and 1.4 +/- 0.6 MUmol/L, respectively. The results of plasma and vitreous Hcy indicated statistically significant differences between exudative age-related macular degeneration patients and control groups (P = 0.03 and P = 0.02). After 6 months with both intravitreal therapies, the plasma and vitreous Hcy concentrations did not change significantly (P = 0.1). CONCLUSION: Pegaptanib and ranibizumab did not increase the plasma or vitreous Hcy concentrations. PMID- 25923956 TI - WEDGE-SHAPED SUBRETINAL HYPOREFLECTIVITY IN GEOGRAPHIC ATROPHY. AB - PURPOSE: To describe wedge-shaped subretinal hyporeflectivity, a peculiar spectral domain optical coherence tomography finding in geographic atrophy (GA) areas of atrophic age-related macular degeneration. METHODS: We reviewed the charts of consecutive patients with GA who presented between January 2012 and December 2013. A standardized imaging protocol was performed in all patients, which included blue fundus autofluorescence, and spectral domain optical coherence tomography. RESULTS: Wedge-shaped subretinal hyporeflective lesions were found in 12 of 161 included eyes (11 of 94 consecutive patients, 6 males/5 females, mean age 79.6 +/- 9.3 years). On spectral domain optical coherence tomography, regions immediately adjacent to the wedge-shaped subretinal hyporeflective lesions were characterized by absence of the hyporeflective outer nuclear layer, the hyperreflective external limiting membrane, the ellipsoid zone, the interdigitation zone, and the retinal pigment epithelium. On "en face" images, they appeared as round-oval hyporeflectivities delimited by hyperreflective borders, which we interpreted as the outer plexiform layer. Mean GA area was significantly larger in eyes with as compared with eyes without wedge shaped subretinal hyporeflective lesions. Overall, the dimensions of the wedge shaped subretinal hyporeflective lesions did not change after a mean of ~ 15 months. CONCLUSION: Wedge-shaped subretinal hyporeflectivity, a previously unreported peculiar finding in GA areas of atrophic age-related macular degeneration eyes, appears delimited internally by the hyperreflective outer plexiform layer and externally by the hyperreflective Bruch membrane. These lesions, which are detected in eyes with large GA (even though stable over time), should be recognized and distinguished from subretinal fluid (and other exudative signs of age-related macular degeneration) because their presence should not require prompt treatment. PMID- 25923958 TI - LONG-TERM OUTCOMES FOR OPTIC DISK PIT MACULOPATHY AFTER VITRECTOMY. AB - PURPOSE: To evaluate the efficacy of pars plana vitrectomy for congenital optic disk pit maculopathy with various adjuvant techniques, including gas tamponade, internal limiting membrane peel, and temporal optic disk endolaser in a multicenter study with long-term follow-up. METHODS: A retrospective chart review was performed to identify eyes that underwent surgical repair for congenital optic disk pits and serous macular detachment with or without macular retinoschisis from four retinal centers across Canada from 2003 to 2013. Data collected included surgeries performed, preoperative and postoperative vision, central retinal thickness, and presence or absence of subretinal fluid. Optical coherence tomography was used to define anatomical success (i.e., foveal reattachment). RESULTS: Thirty-two eyes of 32 patients with optic disk pits and serous macular detachments were identified that had undergone surgical repair. All eyes underwent pars plana vitrectomy and induction of posterior vitreous detachment if one was not present. Additional procedures performed on occasion included internal limiting membrane peel (n = 8), temporal optic disk pits endolaser (n = 7), and gas tamponade (air, C3F8 or SF6; n = 31). After vitrectomy surgery, foveal attachment was achieved in 26 of 32 eyes (81.3%). The average number of surgeries required was 1.4 +/- 0.6, with a maximum of 3 vitrectomies (n = 2). Mean change in best-corrected visual acuity was -0.47 +/- 0.54 logMAR units, which corresponds to approximately 5 lines of visual improvement (P < 0.001). Median time to reattachment was 416 days. Preoperative vision, preoperative symptom days, and age were not associated with postoperative reattachment. Similarly, internal limiting membrane peel and temporal endolaser were not associated with postoperative reattachment, nor was there a difference between air and SF6 and C3F8 gas tamponade. Elevated preoperative central retinal thickness was associated with a lower chance of postoperative reattachment (P = 0.007) and was also the best prognostic indicator of success (P = 0.039). CONCLUSION: Vitrectomy for macular detachment due to optic disk pit has good long term success and results in an improvement in visual acuity. However, adjuvant techniques such as internal limiting membrane peel and temporal endolaser may not improve outcomes, nor does there seem to be a difference between short- and long acting gases. Patients should be made aware that it can take more than a year and multiple surgeries to achieve foveal reattachment and that increased baseline central retinal thickness is a poor prognostic sign. PMID- 25923957 TI - TOPOGRAPHIC CHANGES IN MACULAR GANGLION CELL-INNER PLEXIFORM LAYER THICKNESS AFTER VITRECTOMY WITH INDOCYANINE GREEN-GUIDED INTERNAL LIMITING MEMBRANE PEELING FOR IDIOPATHIC MACULAR HOLE. AB - PURPOSE: To evaluate the topographic changes in macular ganglion cell-inner plexiform layer (GCIPL) thickness after vitrectomy with indocyanine green-guided internal limiting membrane (ILM) peeling in eyes with idiopathic macular hole. METHODS: This is a retrospective analysis of 58 consecutive eyes with surgically closed macular hole after vitrectomy with indocyanine green-guided ILM peeling. Further, 31 eyes that had undergone vitrectomy without ILM peeling were used as the control group. The macular GCIPL thickness was measured with spectral domain optical coherence tomography before vitrectomy and at 1 month and 6 months after vitrectomy. RESULTS: The preoperative mean GCIPL thickness was 78.79 MUm and mean thickness at 1 month and 6 months after surgery significantly reduced progressively to 70.93 MUm and 67.64 MUm (P < 0.001 and P < 0.001, respectively). The postoperative mean GCIPL thickness was significantly lower than that of the group without ILM peeling at 1 month and 6 months postoperatively (P < 0.001, P < 0.001, respectively). The GCIPL thickness in the temporal area was significantly lower than in the nasal area at 1 month and 6 months postoperatively (P < 0.001, P < 0.001, respectively). CONCLUSION: A reduction of the macular GCIPL thickness was observed after vitrectomy with indocyanine green-guided ILM peeling for idiopathic macular hole, especially in the temporal area. PMID- 25923959 TI - SURGICAL OUTCOMES IN PATIENTS WITH MACULAR PUCKER AND GOOD PREOPERATIVE VISUAL ACUITY AFTER VITRECTOMY WITH MEMBRANE PEELING. AB - PURPOSE: To evaluate whether patients with macular pucker (epiretinal membrane [ERM]) and good preoperative visual acuity (20/50 or better) benefit from small gauge pars plana vitrectomy with membrane peeling. METHODS: Retrospective chart review of eyes undergoing small-gauge pars plana vitrectomy for ERM. Inclusion criterion was impaired visual acuity (20/50 or better) due to ERM. Exclusion criteria were preoperative visual acuity of 20/60 or worse, previous surgery (other than uncomplicated cataract surgery), and any documented evidence of macular or corneal disease that would limit visual potential. The main outcome measure was final visual acuity. Secondary outcomes included the role of internal limiting membrane peeling, and the effect of preoperative cystoid macular edema and internal limiting membrane peeling on visual acuity. RESULTS: One hundred and forty eyes met inclusion criteria of which 94% underwent 25-gauge vitrectomy (remainder had 23-gauge). There was a statistically significant improvement in final vision with the mean preoperative visual acuity of 0.305 logMAR (20/40) and 1-year visual acuity of 0.250 logMAR (20/35) (P = 0.0167). Cataract formation in phakic patients had a significant effect on the final visual outcome. Fifty-six of 63 patients (89%) in the phakic cohort developed a visually significant cataract by study end. The mean time to recommendation of cataract surgery was 8.4 months. Thirty-eight eyes (27%) had preoperative cystoid macular edema. Fifty nine eyes (42%) underwent internal limiting membrane peeling. Neither one of these secondary outcome measures had a significant effect on the final visual outcome. CONCLUSION: Pars plana vitrectomy is both efficacious and safe an option for patients with ERMs and good preoperative vision. Eyes with an ERM and vision 20/50 or better had a statistically significant improvement in the final visual outcome after small-gauge pars plana vitrectomy surgery. As with large-gauge vitrectomy, cataract formation occurred in most phakic eyes within the first year after surgery. PMID- 25923960 TI - Gene-gene and gene-environment interactions in meta-analysis of genetic association studies. AB - Extensive genetic studies have identified a large number of causal genetic variations in many human phenotypes; however, these could not completely explain heritability in complex diseases. Some researchers have proposed that the "missing heritability" may be attributable to gene-gene and gene-environment interactions. Because there are billions of potential interaction combinations, the statistical power of a single study is often ineffective in detecting these interactions. Meta-analysis is a common method of increasing detection power; however, accessing individual data could be difficult. This study presents a simple method that employs aggregated summary values from a "case" group to detect these specific interactions that based on rare disease and independence assumptions. However, these assumptions, particularly the rare disease assumption, may be violated in real situations; therefore, this study further investigated the robustness of our proposed method when it violates the assumptions. In conclusion, we observed that the rare disease assumption is relatively nonessential, whereas the independence assumption is an essential component. Because single nucleotide polymorphisms (SNPs) are often unrelated to environmental factors and SNPs on other chromosomes, researchers should use this method to investigate gene-gene and gene-environment interactions when they are unable to obtain detailed individual patient data. PMID- 25923961 TI - Measuring anticholinergic drug exposure in older community-dwelling Australian men: a comparison of four different measures. AB - AIMS: Anticholinergic drug exposure is associated with adverse outcomes in older people. While a number of tools have been developed to measure anticholinergic drug exposure, there is limited information about the agreement and overlap between the various scales. The aim of this study was to investigate the agreement and overlap between different measures of anticholinergic drug exposure in a cohort of community-dwelling older men. METHODS: A cross-sectional study was used to compare anticholinergic drug exposure calculated using the Anticholinergic Risk Scale (ARS), the Anticholinergic Drug Scale (ADS), the Anticholinergic Cognitive Burden (ACB) and the Drug Burden Index anticholinergic subscale (DBI-ACH) in a cohort of community-dwelling men aged 70 years and older (n = 1696). Statistical agreement, expressed as Cohen's kappa (kappa), between these measurements was calculated. RESULTS: Differences were found between the tools regarding the classification of anticholinergic drug exposure for individual participants. Thirteen percent of the population used a drug listed as anticholinergic on the ARS, 39% used a drug listed on the ADS and the ACB, and 18% of the population used one or more anticholinergic drugs listed on the DBI ACH. While agreement was good between the ACB and ADS (kappa = 0.628, 95% CI 0.593, 0.664), little agreement was found between remaining tools (kappa = 0.091 0.264). CONCLUSIONS: With the exception of the ACB and ADS, there was poor agreement regarding anticholinergic drug exposure among the four tools compared in this study. Great care should be taken when interpreting anticholinergic drug exposure using existing scales due to the wide variability between the different scales. PMID- 25923962 TI - Neuroprotective effects of fermented soybean products (Cheonggukjang) manufactured by mixed culture of Bacillus subtilis MC31 and Lactobacillus sakei 383 on trimethyltin-induced cognitive defects mice. AB - OBJECTIVES: This study aimed to investigate the beneficial effects of Cheonggukjang (CGK) manufactured by mixed culture of Bacillus subtilis MC31 and Lactobacillus sakei 383 on neurotoxic damages. METHODS: The specific aspects of brain functions were measured in Institute for Cancer Research (ICR) mice that had been pretreated for 4 weeks with three difference doses of CGK before trimethyltin (TMT) treatment. RESULTS: The short- and long-term memory loss induced by TMT treatment was significantly improved in the CGK-pretreated group in a dose-dependent manner. The number of dead cells in the granule cell layer of the dentate gyrus was decreased in the TMT/CGK-cotreated group relative to the TMT/vehicle-treated group, whereas significant suppression of acetylcholinesterase (AChE) activity was observed in the same group. Additionally, a dose-dependent increase in nerve growth factor (NGF) concentration, activation of the NGF receptor signaling pathway including the TrkA high affinity receptor and p75(NTR) low affinity receptor, and decline in Bax/Bcl-2 level was measured in all TMT/CGK-treated groups, although a decrease in the active form of caspase-3 was observed in the TMT/H-CGK-treated group. Furthermore, superoxide dismutase (SOD) activity was enhanced in the TMT/CGK treated group, whereas the level of malondialdehyde (MDA), a marker of lipid peroxidation, was 43-58% lower in the TMT/CGK-treated group than the TMT/vehicle treated group. DISCUSSION: These results demonstrate that CGK fermented by mixed culture of B. subtilis and L. sakei could exert a wide range of beneficial activities for neurodegenerative diseases, including Alzheimer, Parkinson, and Huntington disease. PMID- 25923963 TI - Ten-atom silver cluster signaling and tempering DNA hybridization. AB - Silver clusters with ~10 atoms are molecules, and specific species develop within DNA strands. These molecular metals have sparsely organized electronic states with distinctive visible and near-infrared spectra that vary with cluster size, oxidation, and shape. These small molecules also act as DNA adducts and coordinate with their DNA hosts. We investigated these characteristics using a specific cluster-DNA conjugate with the goal of developing a sensitive and selective biosensor. The silver cluster has a single violet absorption band (lambda(max) = 400 nm), and its single-stranded DNA host has two domains that stabilize this cluster and hybridize with target oligonucleotides. These target analytes transform the weakly emissive violet cluster to a new chromophore with blue-green absorption (lambda(max) = 490 nm) and strong green emission (lambda(max) = 550 nm). Our studies consider the synthesis, cluster size, and DNA structure of the precursor violet cluster-DNA complex. This species preferentially forms with relatively low amounts of Ag(+), high concentrations of the oxidizing agent O2, and DNA strands with ?20 nucleotides. The resulting aqueous and gaseous forms of this chromophore have 10 silvers that coalesce into a single cluster. This molecule is not only a chromophore but also an adduct that coordinates multiple nucleobases. Large-scale DNA conformational changes are manifested in a 20% smaller hydrodynamic radius and disrupted nucleobase stacking. Multidentate coordination also stabilizes the single-stranded DNA and thereby inhibits hybridization with target complements. These observations suggest that the silver cluster-DNA conjugate acts like a molecular beacon but is distinguished because the cluster chromophore not only sensitively signals target analytes but also stringently discriminates against analogous competing analytes. PMID- 25923964 TI - Monitoring VEGF levels with low-volume sampling in major vision-threatening diseases: age-related macular degeneration and diabetic retinopathy. AB - The purpose of this article is to demonstrate the capacity of paper-based ELISA (P-ELISA) to monitor VEGF in patients requiring treatment for vision-threatening diseases. The most commonly encountered vision-threatening diseases are age related macular degeneration (AMD) and diabetic retinopathy (DR), both of which may require short-term or life-long anti-VEGF injection treatment therapy. Accurate measurement of VEGF concentration in aqueous humor can provide significant and timely information to diagnose the disease state. Adequate and precise therapy may consequently be provided. At odds with conventional diagnostic approaches is the fact that a maximum of only 200 microliters of aqueous humor can be safely removed from the eye for testing. Fortunately, new diagnostic platforms, such as P-ELISA, require only minute volumes, i.e., approximately 2 microliters per test "well" and approximately 40 microliters total to quantify VEGF levels, and the testing process takes less than an hour. Thus, point-of-care (POC) diagnostics, such as P-ELISA, should be examined and improved upon as needed in order to develop an efficient tool for outpatient clinics and others to obtain semi-quantitative results that might facilitate accurate dosing of anti-VEGF treatment and delay or prevent the progression of AMD and DR. PMID- 25923965 TI - Importance of choline as essential nutrient and its role in prevention of various toxicities. AB - Choline is a water-soluble essential nutrient included as a member of the vitamin B12 group owing to its structural similarities with that of the other members of the group. Its roles and functions, however, extend much wider than that of the vitamins with which it is grouped. Choline is vital for maintenance of various key metabolic processes which play a role in the prevention or progression of various health impairments. The occurrence of diseases like neural tube defect (NTD) and Alzheimer's is prevented by the metabolic role of choline. It is also indispensable for mitigation of various forms of toxic contamination. While adequate level of choline in the body is essential, an excess of choline can result in various forms of disorder. To maintain the optimal level of choline in the body can be a challenge. The vital roles played by choline together with the range of contradictions and problems that choline presents make choline an interesting area of study. This paper attempts to summarize and review some recent publications on choline that have opened up new prospect in understanding the multiple role played by choline and in throwing light on the role played by this wonder essential nutrient in mitigating various forms of toxic contamination. PMID- 25923966 TI - Chicken and rabbit antibodies against porcine pepsinogen A. AB - Isolated porcine pepsinogen A was used for the preparation of polyclonal rabbit and polyclonal chicken anti-pepsinogen A antibodies. Immunochemical properties of both immunoglobulin fractions were compared. The rabbit anti-serum was further purified using immobilized porcine pepsinogen A on magnetic cellulose beads and the resulting anti-pepsinogen A fraction proved to be applicable for the separation and the determination of porcine pepsinogen A. In contrary, antibodies prepared from chicken eggs by the same way have been found not suitable for the evaluation of the pepsinogen A level. Unexpectedly, the pre-immune fraction of chicken antibodies showed reactivity against porcine pepsinogen A and the affinity separation of specific polyclonal chicken anti-pepsinogen A antibodies on immobilized porcine pepsinogen A did not result in an enrichment of anti pepsinogen A antibodies. PMID- 25923967 TI - Possible association between erectile dysfunction and osteoporosis in men. AB - Sexual dysfunction in general and erectile dysfunction (ED) in particular significantly affect men's quality of life. Some patients who have ED, also develop osteoporosis. So, in this study we investigated the relationship between erectile dysfunction and osteoporosis in men. 95 men with erectile dysfunction and 82 men with normal sexual function were included in the study. The men's sexual functions were evaluated by International Index of Erectile Function-5 items (IIEF-5). All men received a Dual Energy X-ray Absorptiometry (DEXA; Hologic) scan to measure bone mineral density (BMD) for osteoporosis. Chi-square test was used for statistical analysis. Mean age was 53.5 (38-69) in ED group and 50.1 (31-69) in control group. In ED group the men have lower T score levels than those of the control group. In conclusion, the men who have erectile dysfunction were at more risk for osteoporosis. The results of the present study demonstrate that the men with erectile dysfunction have low bone mineral density and they are at higher risk for osteoporosis. Because of easy and noninvasive evaluation of osteoporosis, patients with ED should be checked for bone mineral density and osteoporotic male subjects should be evaluated for ED. PMID- 25923968 TI - The effect of prenatal methamphetamine exposure on recognition memory in adult rats. AB - The use of methamphetamine (MA) among pregnant women is an increasing world-wide health problem. Prenatal MA exposure may cause changes in foetus but the exact effects have remained unclear. The aim of this study is to present the effect of prenatal MA exposure on recognition memory in adult rats. Adult female Wistar rats were injected daily with D-methamphetamine HCl (MA; 5 mg/kg, s.c.) during the entire gestation period. Control females were treated with saline in the same regime. Adult male offspring was administrated acutely by MA (1 mg/kg i.p.) or saline 30 minutes before beginning of an experiment. For testing recognition memory two tasks were chosen: Novel Object Recognition Test (NORT) and Object Location Test (OLT). Our results demonstrate that prenatally MA-exposed animals were worse in NORT independently on an acute administration of MA in adulthood. Prenatally MA-exposed rats did not deteriorate in OLT, but after acute administration of MA in adulthood, there was significant worsening compared to appropriate control. Prenatally saline-exposed offspring did not deteriorate in any test even after acute administration of MA. Our data suggest that prenatal MA exposure in rats cause impairment in recognition memory in adult offspring, but not in spatial memory. In addition, acute administration of MA to controls did not deteriorate either recognition or spatial memory. PMID- 25923969 TI - Daily profiles of dehydroepiandrosterone and its hydroxylated metabolites with respect to food intake. AB - Eight women of reproductive age with normal body mass index were given 5 standardised meals, and their hormonal milieu was determined during the course of the day. Plasma from 12 withdrawals was analysed for dehydroepiandrosterone and its 7- and 16-hydroxylated metabolites. Overall, there was a maximum in the levels of steroid hormones in the morning, followed by decreases throughout the day. There was also an additional significant decrease found for dehydroepiandrosterone and its 7alpha-hydroxyderivative in association with the consumption of main meals, but not for the 7beta-isomer or 16alpha hydroxyderivative. PMID- 25923970 TI - Unusual complication of bladder catheterization in child: catheterization of ureter. AB - Bladder probing is an invasive procedure that is often used by paediatric and other surgeons. We present a case who was ureter catheterized accidentally while placing a probe into the right ureter in an 18 months old female. If different catheter localization is determined during the examination, the process must be terminated immediately and the relevant specialist should be informed right away. PMID- 25923971 TI - Agenesis of the gallbladder diagnosed by magnetic resonance cholangiography: report of a case and review of the literature. AB - Gallbladder agenesis (GA) is a rare congenital anomaly of the biliary system often associated with other congenital abnormalities. Patients become symptomatic in 23% of cases (Richards et al., 1993). GA is often misinterpreted as other diseases, therefore, leading to unnecessary surgery. Many of these patients develop a typical symptomatology of cholelithiasis that leads them to operating theatre. If an operative procedure is done, it is better to remain at the level of laparoscopy because further surgical investigation may lead to detrimental biliary tract injuries (Waisberg et al., 2002). We present a case of GA, diagnosed by magnetic resonance with cholangiopancreatography. PMID- 25923972 TI - Successful use of extra-corporeal membrane oxygenation in a patient with streptococcal sepsis: a case report and review of literature. AB - A young patient with streptococcal sepsis due to the phlegmon of his left thigh was admitted to the general intensive care unit. He developed a multi-organ failure and septic cardiomyopathy with subsequent cardiogenic shock. This resulted in hemodynamic instability unresponsive to conservative medical treatment. We report a successful application of veno-arterial extra-corporeal membrane oxygenation, which was used to overcome the period of critically low cardiac output caused by severe septic myocardial dysfunction. PMID- 25923973 TI - Racial/Ethnic Disparities Associated With Initial Hemodialysis Access. AB - IMPORTANCE: Superior outcomes have been established with the use of an arteriovenous fistula (AVF) at first hemodialysis. However, considering the influence of comorbidities, medical insurance, and specialist care, racial/ethnic differences in the patterns of utilization of AVFs are unknown and deserve evaluation. OBJECTIVE: To assess national trends in initial hemodialysis access with respect to race/ethnicity stratified by comorbid disease, nephrology care, and medical insurance status within the US Renal Data System. DESIGN, SETTING, AND PARTICIPANTS: A retrospective analysis of all patients with end-stage renal disease in the US Renal Data System who initiated hemodialysis between January 1, 2006, and December 31, 2010. Univariable statistics (chi2 test and analysis of variance) and logistic regression were used to compare racial/ethnic groups (white vs black vs Hispanic). Multivariable logistic regression and propensity score-matching techniques were used to evaluate hemodialysis access rates between patients of different races/ethnicities with comparable characteristics. MAIN OUTCOMES AND MEASURES: Utilization rates of AVF, arteriovenous graft, and intravascular hemodialysis catheter. RESULTS: In this cohort of 396,075 patients, more white patients initiated hemodialysis with an AVF than black patients or Hispanic patients (18.3% vs 15.5% and 14.6%, respectively; P < .001). Black patients and Hispanic patients initiated hemodialysis with an AVF less frequently despite being younger and having less coronary artery disease, chronic obstructive pulmonary disease, and cancer than white patients with an AVF. When stratified by medical insurance status, black patients (odds ratios, 0.90 [95% CI, 0.82-0.98] for uninsured and 0.85 [95% CI, 0.84-0.87] for insured) and Hispanic patients (odds ratios, 0.72 [95% CI, 0.65-0.81] for uninsured and 0.81 [95% CI, 0.79-0.84] for insured) persistently initiated hemodialysis with an AVF less frequently than white patients (P < .05 for all). Arteriovenous fistula utilization at initial hemodialysis was lower among black patients (odds ratio, 0.81 [95% CI, 0.78-0.84]) and Hispanic patients (odds ratio, 0.86 [95% CI, 0.82 0.90]) compared with white patients within the category of patients who had nephrology care for longer than 1 year (P < .001 for all). CONCLUSIONS AND RELEVANCE: Black patients and Hispanic patients tend to initiate hemodialysis with an AVF less frequently than white patients despite being younger and having fewer comorbidities. These disparities persisted independent of factors that drive health access for fistula placement, such as medical insurance status and nephrology care. The sociocultural underpinnings of these disparities deserve investigation and redress to maximize the benefits of initiating hemodialysis via fistula in patients with end-stage renal disease irrespective of race/ethnicity. PMID- 25923974 TI - Seroepidemiology of human bocaviruses 1 and 2 in China. AB - Seroepidemiology studies had been used to research the newly discovered human bocaviruses (HBoVs). Antibodies against the HBoV1-4 VP2 protein virus-like particles (VLPs) were found to be cross-reactive. The aim of the present study was to characterize the seroprevalence of HBoV1 and 2 among healthy populations in China. Recombinant HBoV1 and 2 VLPs were used to establish enzyme-linked immunosorbent assays (ELISAs) for detection of cross-reactivity between HBoV1 and HBoV2 in 1391 serum samples collected from healthy individuals in China. Of these, 884 samples were collected from Beijing and 507 were from Nanjing. Infection with HBoV1 and 2 was prevalent in healthy Chinese people, with the seroprevalence of HBoV1 and 2 in Beijing at 69.2 (612/884) and 64.4% (569/884), respectively. Highest seroprevalence was observed in 3-5-year-olds. The seroprevalence of HBoV1 was significantly decreased between 10-13-year-olds (80.3%) and 14-20-year-olds (62.3%, p< 0.05). For individuals over 20 years, seroprevalence was relatively constant at about 60%. Similar trends were observed in children from Nanjing, with seroprevalence of HBoV1 and 2 for healthy children at 80.7% (409/507) and 81.3% (412/507), respectively. Moreover, both mouse and human antibodies against HBoV1 and HBoV2 VLPs were found to be cross-reactive and 58.4% (813/1391) serum samples were seropositive for both HBoV1 and HBoV2. This finding suggests HBoV is highly prevalent in China and the antibodies produced as a result of infection with either HBoV1 or HBoV 2 will offer future protection. The cross-reactivity between HBoVs is crucial for accurately determining HBoV seroepidemiology. PMID- 25923975 TI - Genetic Architecture of Ear Fasciation in Maize (Zea mays) under QTL Scrutiny. AB - MAIZE EAR FASCIATION: Knowledge of the genes affecting maize ear inflorescence may lead to better grain yield modeling. Maize ear fasciation, defined as abnormal flattened ears with high kernel row number, is a quantitative trait widely present in Portuguese maize landraces. MATERIAL AND METHODS: Using a segregating population derived from an ear fasciation contrasting cross (consisting of 149 F2:3 families) we established a two location field trial using a complete randomized block design. Correlations and heritabilities for several ear fasciation-related traits and yield were determined. Quantitative Trait Loci (QTL) involved in the inheritance of those traits were identified and candidate genes for these QTL proposed. RESULTS AND DISCUSSION: Ear fasciation broad-sense heritability was 0.73. Highly significant correlations were found between ear fasciation and some ear and cob diameters and row number traits. For the 23 yield and ear fasciation-related traits, 65 QTL were identified, out of which 11 were detected in both environments, while for the three principal components, five to six QTL were detected per environment. Detected QTL were distributed across 17 genomic regions and explained individually, 8.7% to 22.4% of the individual traits or principal components phenotypic variance. Several candidate genes for these QTL regions were proposed, such as bearded-ear1, branched silkless1, compact plant1, ramosa2, ramosa3, tasselseed4 and terminal ear1. However, many QTL mapped to regions without known candidate genes, indicating potential chromosomal regions not yet targeted for maize ear traits selection. CONCLUSIONS: Portuguese maize germplasm represents a valuable source of genes or allelic variants for yield improvement and elucidation of the genetic basis of ear fasciation traits. Future studies should focus on fine mapping of the identified genomic regions with the aim of map-based cloning. PMID- 25923977 TI - Progression of hypertension after partial nephrectomy in patients with renal tumors: A preliminary report. PMID- 25923976 TI - Screening and Treatment for Alcohol, Tobacco and Opioid Use Disorders: A Survey of Family Physicians across Ontario. AB - INTRODUCTION: As a primary point of contact within the health care system, family physicians are able to play a vital role in identifying individuals with substance use disorders and connecting them to the appropriate treatment. However, there is very little data available on whether family physicians are actively screening for and treating substance use disorders. The objective of the current survey was to assess whether family physicians in Ontario are screening for alcohol, opioid and tobacco use disorders, using validated tools and providing treatment. METHODS: An online survey consisting of a series of 38 primarily close-ended questions was circulated to family physicians in Ontario. Rates of screening for alcohol, opioid and tobacco dependence, use of validated tools for screening, providing treatment for dependent individuals and the current barriers to the prescription of pharmacotherapies for these drug dependences were assessed. RESULTS: The use of validated screening tools was limited for all three substances. Screening by family physicians for the substance use disorders among adolescents was much lower than screening among adults. Pharmacotherapy was more commonly used as an intervention for tobacco dependence than for alcohol and opioid dependence. This was explained by the lack of knowledge among family physicians on the pharmacotherapies for alcohol and opioid dependence. CONCLUSIONS: Findings from the current study suggest there is a need for family physicians to integrate screening for substance use disorders using validated tools into their standard medical practice. Furthermore, there is a need for increased knowledge on pharmacotherapies for alcohol and opioid use disorders. It is important to note that the low response rate is a major limitation to this study. One possible reason for this low response rate may be a lack of interest and awareness among family physicians on the importance of screening and treatment of substance use disorders in Ontario. PMID- 25923978 TI - Trihydrogen cation with neon and argon: structural, energetic, and spectroscopic data from quartic force fields. AB - The argonium cation, ArH(+), has been previously detected in nature for the first time. This cation is believed to form through the gas-phase reaction of Ar(+) and H2. In this work, quantum chemical techniques show that the reaction of Ar and H3(+) may be a viable alternative or contributor to the creation of ArH(+) corroborating previous analysis. In order to further evaluate this claim, highly accurate quartic force field computations are used to produce spectroscopic data and anharmonic vibrational frequencies for ArH3(+) in its 18 isotopologues. NeH3(+) is also analyzed but has a low Ne-H3(+) dissociation barrier. Therefore, it less likely to be observed. Consequently, NeH(+) is also unlikely to be formed from NeH3(+) as it was also not from NeH2(+). PMID- 25923979 TI - Surface conductivity measurements in nanometric to micrometric foam films. AB - Foam films (a liquid lamella in air covered by surfactants) are tools of choice for nanofluidic characterization as they are intrinsically nanometric. Their size is indeed fixed by a balance between external pressure and particular molecular interactions in the vicinity of interfaces. To probe the exact nature of these interfaces, different characterizations can be performed. Among them, conductivity in confined systems is a direct probe of the electrostatic environment in the vicinity of the surface. Therefore, we designed a dedicated experiment to measure this conductivity in a cylindrical bubble coupled to interferometry for film thickness characterization. We then show that this conductivity depends on the surfactant nature. These conductivity measurements have been performed in an extremely confined system, the so called Newton black foam films. Unexpectedly in this case, a conductivity close to surface conductivity is recovered. PMID- 25923980 TI - Sensorimotor transformation via sparse coding. AB - Sensorimotor transformation is indispensable to the accurate motion of the human body in daily life. For instance, when we grasp an object, the distance from our hands to an object needs to be calculated by integrating multisensory inputs, and our motor system needs to appropriately activate the arm and hand muscles to minimize the distance. The sensorimotor transformation is implemented in our neural systems, and recent advances in measurement techniques have revealed an important property of neural systems: a small percentage of neurons exhibits extensive activity while a large percentage shows little activity, i.e., sparse coding. However, we do not yet know the functional role of sparse coding in sensorimotor transformation. In this paper, I show that sparse coding enables complete and robust learning in sensorimotor transformation. In general, if a neural network is trained to maximize the performance on training data, the network shows poor performance on test data. Nevertheless, sparse coding renders compatible the performance of the network on both training and test data. Furthermore, sparse coding can reproduce reported neural activities. Thus, I conclude that sparse coding is necessary and a biologically plausible factor in sensorimotor transformation. PMID- 25923981 TI - Ruptures and sutures: time, audience and identity in an illness narrative. AB - First-person accounts of the illnesses experienced by sociologists have taken hybrid experimental forms. I add my voice to this growing tradition with a story about the discovery and treatment of a soft tissue sarcoma in my thigh, chronicled in a journal I kept over many months. The fragments scribbled in the journal became the basis of an extended illness narrative. I interrogate features of the narrative itself, including the handling of time and imagined audiences - those I was writing for. The illness narrative traces how cancer transformed the many identities I enact on a daily basis and how the invisible labour of particular health workers enabled the restoration of several prized identities. These workers - radiation, occupational and physical therapists - are typically subordinated in the medical hierarchy and the interactional work that they do with patients to restore and reconfigure ruptured identities after serious illness needs attention in medical sociology. PMID- 25923982 TI - Fitzpatrick Skin Type, Individual Typology Angle, and Melanin Index in an African Population: Steps Toward Universally Applicable Skin Photosensitivity Assessments. PMID- 25923983 TI - Oblivobesity: looking over the overweight that parents keep overlooking. PMID- 25923984 TI - High cardiovascular event rates occur within the first weeks of starting hemodialysis. AB - Early mortality is high in hemodialysis (HD) patients, but little is known about early cardiovascular event (CVE) rates after HD initiation. To study this we analyzed data in the AROii cohort of incident HD patients from over 300 European Fresenius Medical Care dialysis centers. Weekly rates of a composite of CVEs during the first year and monthly rates of the composite and its constituents (coronary artery, cerebrovascular, peripheral arterial, congestive heart failure, and sudden cardiac death) during the first 2 years after HD initiation were assessed. Of 6308 patients that started dialysis within 7 days, 1449 patients experienced 2405 CVEs over the next 2 years. The first-year CVE rate (30.2/100 person-years; 95% CI, 28.7-31.7) greatly exceeded the second-year rate (19.4/100; 95% CI, 18.1-20.8). Composite CVEs were highest during the first week with increased risk compared with the second year, persisting until the fifth month. Except for sudden cardiac death, temporal patterns of rates for all CVE categories were very similar, with highest rates during the first month and a high-risk period extending to 4 months. Higher or lower cumulative weekly dialysis dose, lower blood flow, and lower net ultrafiltration during dialysis were associated with CVE during the high-risk period, but not during the post high-risk period. Thus, the incidence of CVE in the first weeks after HD initiation is much higher than during subsequent periods which raises concerns that HD initiation may trigger CVEs. PMID- 25923986 TI - In Situ Temperature-Dependent Transmission Electron Microscopy Studies of Pseudobinary mGeTe.Bi2Te3 (m = 3-8) Nanowires and First-Principles Calculations. AB - Phase-change nanowires (NWs) have emerged as critical materials for fast switching nonvolatile memory devices. In this study, we synthesized a series of mGeTe.Bi2Te3 (GBT) pseudobinary alloy NWs-Ge3Bi2Te6 (m = 3), Ge4Bi2Te7 (m = 4), Ge5Bi2Te8 (m = 5), Ge6Bi2Te9 (m = 6), and Ge8Bi2Te11 (m = 8)-and investigated their composition-dependent thermal stabilities and electrical properties. As m decreases, the phase of the NWs evolves from the cubic (C) to the hexagonal (H) phase, which produces unique superlattice structures that consist of periodic 2.2 3.8 nm slabs for m = 3-8. In situ temperature-dependent transmission electron microscopy reveals the higher thermal stability of the compositions with lower m values, and a phase transition from the H phase into the single-crystalline C phase at high temperatures (400 degrees C). First-principles calculations, performed for the superlattice structures (m = 1-8) of GBT and mGeTe.Sb2Te3 (GST), show an increasing stability of the H phase (versus the C phase) with decreasing m; the difference in stability being more marked for GBT than for GST. The calculations explain remarkably the phase evolution of the GBT and GST NWs as well as the composition-dependent thermal stabilities. Measurement of the current voltage curves for individual GBT NWs shows that the resistivity is in the range 3-25 mOmega.cm, and the resistivity of the H phase is lower than that of the C phase, which has been supported by the calculations. PMID- 25923987 TI - Engineered biochar from biofuel residue: characterization and its silver removal potential. AB - A novel approach was used to prepare engineered biochar from biofuel residue (stillage from bagasse ethanol production) through slow pyrolysis. The obtained biochar was characterized for its physicochemical properties as well as silver sorption ability. Sorption experimental data showed that engineered biochar quickly and efficiently removed silver ion (Ag(+)) from aqueous solutions with a Langmuir maximum capacity of 90.06 mg/g. The high sorption of Ag(+) onto the biochar was attributed to both reduction and surface adsorption mechanisms. The reduction of Ag(+) by the biochar was confirmed with scanning electron microscopy, energy-dispersive X-ray spectroscopy, X-ray diffraction, and X-ray photoelectron spectroscopy analyses of the postsorption biochar, which clearly showed the presence of metallic silver nanoparticles on the surface of the carbon matrix. An antimicrobial ability test indicated that silver-laden biochar effectively inhibited the growth of Escherichia coli, while the original biochar without silver nanoparticles promoted growth. Thus, biochar, prepared from biofuel residue materials, could be potentially applied not only to remove Ag(+) from aqueous solutions but also to produce a new value-added nanocomposite with antibacterial ability. PMID- 25923985 TI - Executive summary of the KDIGO Controversies Conference on Supportive Care in Chronic Kidney Disease: developing a roadmap to improving quality care. AB - Patients with advanced chronic kidney disease (CKD) have a high burden of physical and psychosocial symptoms, poor outcomes, and high costs of care. Current paradigms of care for this highly vulnerable population are variable, prognostic and assessment tools are limited, and quality of care, particularly regarding conservative and palliative care, is suboptimal. The KDIGO Controversies Conference on Supportive Care in CKD reviewed the current state of knowledge in order to define a roadmap to guide clinical and research activities focused on improving the outcomes of people living with advanced CKD, including those on dialysis. An international group of multidisciplinary experts in CKD, palliative care, methodology, economics, and education identified the key issues related to palliative care in this population. The conference led to a working plan to address outstanding issues in this arena, and this executive summary serves as an output to guide future work, including the development of globally applicable guidelines. PMID- 25923989 TI - Global status of and prospects for protection of terrestrial geophysical diversity. AB - Conservation of representative facets of geophysical diversity may help conserve biological diversity as the climate changes. We conducted a global classification of terrestrial geophysical diversity and analyzed how land protection varies across geophysical diversity types. Geophysical diversity was classified in terms of soil type, elevation, and biogeographic realm and then compared to the global distribution of protected areas in 2012. We found that 300 (45%) of 672 broad geophysical diversity types currently meet the Convention on Biological Diversity's Aichi Target 11 of 17% terrestrial areal protection, which suggested that efforts to implement geophysical diversity conservation have a substantive basis on which to build. However, current protected areas were heavily biased toward high elevation and low fertility soils. We assessed 3 scenarios of protected area expansion and found that protection focused on threatened species, if fully implemented, would also protect an additional 29% of geophysical diversity types, ecoregional-focused protection would protect an additional 24%, and a combined scenario would protect an additional 42%. Future efforts need to specifically target low-elevation sites with productive soils for protection and manage for connectivity among geophysical diversity types. These efforts may be hampered by the sheer number of geophysical diversity facets that the world contains, which makes clear target setting and prioritization an important next step. PMID- 25923988 TI - Crystalline silica-induced leukotriene B4-dependent inflammation promotes lung tumour growth. AB - Chronic exposure to crystalline silica (CS) causes silicosis, an irreversible lung inflammatory disease that may eventually lead to lung cancer. In this study, we demonstrate that in K-ras(LA1) mice, CS exposure markedly enhances the lung tumour burden and genetic deletion of leukotriene B4 receptor-1 (BLT1(-/-)) attenuates this increase. Pulmonary neutrophilic inflammation induced by CS is significantly reduced in BLT1(-/-)K-ras(LA1) mice. CS exposure induces LTB4 production by mast cells and macrophages independent of inflammasome activation. In an air-pouch model, CS-induced neutrophil recruitment is dependent on LTB4 production by mast cells and BLT1 expression on neutrophils. In an implantable lung tumour model, CS exposure results in rapid tumour growth and decreased survival that is attenuated in the absence of BLT1. These results suggest that the LTB4/BLT1 axis sets the pace of CS-induced sterile inflammation that promotes lung cancer progression. This knowledge may facilitate development of immunotherapeutic strategies to fight silicosis and lung cancer. PMID- 25923991 TI - Correlation of structure and mechanical response in solid-like polymers. AB - Employing large scale molecular dynamics simulations, we measure the uniaxial tensile response of amorphous and semicrystalline states of a coarse-grained PVA bead-spring model. The response beyond the elastic limit encompasses strain softening and strain-hardening regimes. To understand the underlying mechanisms of plastic deformation, we analyse conformational and structural changes of polymers. In particular, we characterise the volume distribution of crystalline domains along the stress-strain curve. The strain-softening regime in semicrystalline samples is dominated by deformation of crystalline parts, while strain-hardening involves unfolding and alignment of chains in both amorphous and crystalline parts. Comparing the tensile response of semicrystalline and amorphous polymers, we find similar conformations of polymers for both systems in the strain-hardening regime. PMID- 25923990 TI - Novel use of terpenoids for treatment of dermatologic diseases: a systematic review of clinical trials. AB - BACKGROUND/OBJECTIVE: Terpenoids demonstrate pharmacologic activities that address important mechanisms underlying the pathogenesis of several cutaneous diseases. This review evaluated clinical trials of dermatology-specific terpenoid based treatments. METHODS: PubMed and EMBASE were reviewed on July 8, 2014. Two independent reviewers reviewed studies for inclusion and extracted data for studies meeting eligibility criteria. References were manually reviewed for potentially relevant studies. RESULTS: The search yielded 437 unique abstracts, of which 13 met inclusion and exclusion criteria. High-quality evidence suggests that ingenol mebutate may be effective in treating actinic keratosis. Limited available evidence indicates that terpenoids may benefit patients with nonmelanoma skin cancers, cutaneous candidiasis, hyperpigmentation, photoaging, and wounds. CONCLUSIONS: Terpenoids appear to be effective in treating specific dermatologic conditions. However, additional rigorously conducted clinical trials are needed to better ascertain efficacy. PMID- 25923992 TI - The management of obstetric anal sphincter injuries (OASIS): A national postal questionnaire survey in hospitals in the U.K. AB - Obstetric anal sphincter injuries (OASIS) represent a serious morbidity that can cause short- and long-term consequences. It has attracted attention leading to the development of a national guideline by the Royal College of Obstetricians and Gynaecologists (RCOG). The aim of this study was to establish the current management of these injuries in hospitals across the UK. An anonymous self construct questionnaire was posted to clinical directors/lead obstetricians in all hospitals in the UK and a total of 104 out of 233 (44.6%) questionnaires were returned. Over 90% of respondents' hospitals had protocols that required repair in theatre, as well as the prescription of laxatives and antibiotics and included these injuries in the risk management list. More than half of the respondents' hospitals did not have a dedicated perineal trauma clinic or used symptoms and quality of life questionnaires, endoanal scans or anal manometry routinely at follow-up. Over a third of respondents indicated that their units did not provide any training on repair of OASIS and did not have a multidisciplinary meeting involving colorectal surgeons. More effort is needed to improve all these aspects of care. PMID- 25923993 TI - Medical abortion: Teratogenic effects of misoprostol. PMID- 25923994 TI - Resilience and Healing Among Cambodian Survivors of the Khmer Rouge Regime. AB - In this article the author presents a qualitative study about resilience and healing among Cambodian survivors of the communist Khmer Rouge regime. The database of the Documentation Center of Cambodia (DC-Cam) was used to analyze 30 stories of people who survived but lost family members during the Khmer Rouge regime. The participants acted as civil parties in the Cambodian tribunal involving a trial of "Duch," the head of Tuol Sleng prison or (s21), where survivors' relatives were interrogated, tortured, and killed. Participation in the DC-Cam investigations and in the trial were seen as healing, resiliency factors. Resilience is a person-environment concept that addresses how people and societies overcome/recover from adverse or traumatic events. Resilience was revealed here through people's narratives of critical events that occurred at the personal, interpersonal, sociocultural, and societal levels. Thus, the participants' stories allow us to hear the "truth" of these experiences, how they have made meaning of them, and how they mustered their personal and environmental resources to deal with overwhelming demands (Gutheil & Congress, 2000). Findings suggest that participants attained closure and a sense of justice as a result of their interacting with DC-Cam staff and giving testimony to the tribunal. PMID- 25923995 TI - Power functional theory for the dynamic test particle limit. AB - For classical Brownian systems both in and out of equilibrium we extend the power functional formalism of Schmidt and Brader (2013 J. Chem. Phys. 138 214101) to mixtures of different types of particles. We apply the framework to develop an exact dynamical test particle theory for the self and distinct parts of the van Hove function, which characterize tagged and collective particle motion. The memory functions that induce non-Markovian dynamics are related to functional derivatives of the excess (over ideal) free power dissipation functional. The method offers an alternative to the recently found nonequilibrium Ornstein Zernike relation for dynamic pair correlation functions. PMID- 25923997 TI - Where Is the "Top of License" for the Psychiatrist? PMID- 25923996 TI - Lipid remodeling in Rhodopseudomonas palustris TIE-1 upon loss of hopanoids and hopanoid methylation. AB - The sedimentary record of molecular fossils (biomarkers) can potentially provide important insights into the composition of ancient organisms; however, it only captures a small portion of their original lipid content. To interpret what remains, it is important to consider the potential for functional overlap between different lipids in living cells, and how the presence of one type might impact the abundance of another. Hopanoids are a diverse class of steroid analogs made by bacteria and found in soils, sediments, and sedimentary rocks. Here, we examine the trade-off between hopanoid production and that of other membrane lipids. We compare lipidomes of the metabolically versatile alpha-proteobacterium Rhodopseudomonas palustris TIE-1 and two hopanoid mutants, detecting native hopanoids simultaneously with other types of polar lipids by electrospray ionization mass spectrometry. In all strains, the phospholipids contain high levels of unsaturated fatty acids (often >80%). The degree to which unsaturated fatty acids are modified to cyclopropyl fatty acids varies by phospholipid class. Deletion of the capacity for hopanoid production is accompanied by substantive changes to the lipidome, including a several-fold rise of cardiolipins. Deletion of the ability to make methylated hopanoids has a more subtle effect; however, under photoautotrophic growth conditions, tetrahymanols are upregulated twofold. Together, these results illustrate that the 'lipid fingerprint' produced by a micro-organism can vary depending on the growth condition or loss of single genes, reminding us that the absence of a biomarker does not necessarily imply the absence of a particular source organism. PMID- 25923998 TI - Resting State Dense Array Gamma Oscillatory Activity as a Response Marker for Cerebellar-Repetitive Transcranial Magnetic Stimulation (rTMS) in Schizophrenia. AB - BACKGROUND: As cerebellum and its abnormalities have been implicated in the pathophysiology of schizophrenia, repetitive transcranial magnetic stimulation (rTMS) of this alternate site has been suggested as a novel target for treating patients with this disorder. As resting state gamma activity measures functional brain connectivity, it could be used as a specific treatment marker. AIM: To investigate the effect of cerebellar-rTMS on resting state gamma activity, while studying its efficacy in recent onset schizophrenia patients. METHODS: This rater blinded prospective study was completed by 11 schizophrenia patients. They received 10 sessions of high-frequency (theta patterned) rTMS to midline cerebellum over 2 weeks. Resting state EEG was recorded using high (192-channel) resolution EEG at baseline and post rTMS. Gamma spectral power was calculated using fast Fourier transformation, Hanning window averaged over 8 scalp segments corresponding 8 lobes. Clinical improvement rated on the Positive and Negative Syndrome Scale and depressive symptoms assessed using the Calgary Depression Scale for Schizophrenia were other outcome variables. Nonparametric statistics were used. RESULTS: Over the treatment course, significant reduction was seen on negative syndrome and depression scores. Gamma spectral power in left frontal and temporal segments reduced significantly. Spearman correlation analysis showed that percentage reduction in psychopathology scores had significant positive correlation with percentage reduction in gamma spectral power. CONCLUSIONS: Cerebellar-rTMS might be an effective adjunct to treat intricate and lingering negative and affective symptoms. Resting state gamma spectral power in frontal and temporal regions might be used as a biomarker for treatment response. PMID- 25923999 TI - Olfactory navigation during spawning migrations: a review and introduction of the Hierarchical Navigation Hypothesis. AB - Migrations are characterized by periods of movement that typically rely on orientation towards directional cues. Anadromous fish undergo several different forms of oriented movement during their spawning migration and provide some of the most well-studied examples of migratory behaviour. During the freshwater phase of the migration, fish locate their spawning grounds via olfactory cues. In this review, we synthesize research that explores the role of olfaction during the spawning migration of anadromous fish, most of which focuses on two families: Salmonidae (salmonids) and Petromyzontidae (lampreys). We draw attention to limitations in this research, and highlight potential areas of investigation that will help fill in current knowledge gaps. We also use the information assembled from our review to formulate a new hypothesis for natal homing in salmonids. Our hypothesis posits that migrating adults rely on three types of cues in a hierarchical fashion: imprinted cues (primary), conspecific cues (secondary), and non-olfactory environmental cues (tertiary). We provide evidence from previous studies that support this hypothesis. We also discuss future directions of research that can test the hypothesis and further our understanding of the spawning migration. PMID- 25924000 TI - Multiwalled carbon nanotube dispersion methods affect their aggregation, deposition, and biomarker response. AB - To systematically evaluate how dispersion methods affect the environmental behaviors of multiwalled carbon nanotubes (MWNTs), MWNTs were dispersed in various solutions (e.g., surfactants, natural organic matter (NOM), and etc.) via ultrasonication (SON) and long-term stirring (LT). The two tested surfactants [anionic sodium dodecyl sulfate (SDS) and nonionic poly(ethylene glycol) poly(propylene glycol)-poly(ethylene glycol) (PEO-PPO-PEO) triblock copolymers (Pluronic)] could only disperse MWNTs via ultrasonication; while stable aqueous SON/MWNT and LT/MWNT suspensions were formed in the presence of the two model NOMs (Suwannee river humic acid and fulvic acid). Due to the inherent stochastic nature for both methods, the formed MWNT suspensions were highly heterogeneous. Their physicochemical properties, including surface charge, size, and morphology, greatly depended upon the dispersant type and concentration but were not very sensitive to the preparation methods. Aggregation and deposition behaviors of the dispersed MWNTs were controlled by van der Waal and electrostatic forces, as well as other non-DLVO forces (e.g., steric, hydrophobic forces, etc.). Unlike the preparation method-independent physicochemical properties, LT/NOM-MWNTs and SON/NOM-MWNTs differed in their fathead minnow epithelial cell metabolomics profiles. PMID- 25924005 TI - Non-inductive conditions expose the cryptic bract of flower phytomeres in Arabidopsis thaliana. AB - The aerial plant architecture is built by phytomeres which are metameric units, each composed of a stem segment (internode) and a leaf with axillary meristem (node). In Arabidopsis thaliana, fully developed flower phytomeres lack the leaf even if they temporarily exhibit a cryptic bract (CB) during early development. Recently, we demonstrated that the CB becomes more prominent under non-inductive short-day conditions. However, a full outgrowth as cauline leaf is prevented by Polycomb-group (Pc-G) proteins which silence the MADS gene FLOWERING LOCUS C (FLC) encoding a repressor of FLOWERING LOCUS T (FT). Also the loss of SHORT VEGETATIVE PHASE (SVP) supresses ectopic leaves at the base of Pc-G deficient pedicels. Here we present new expression data of flowering genes LEAFY (LFY) and TWIN SISTER OF FT (TSF) and the re-analysis of morphological changes in Pc-G deficient plants suggesting that the specifications of CB and floral meristem (FM) are separated in time. PMID- 25924006 TI - PM-IRRAS Determination of Molecular Orientation of Phosphonic Acid Self-Assembled Monolayers on Indium Zinc Oxide. AB - Self-assembled monolayers (SAMs) of phosphonic acids (PAs) on transparent conductive oxide (TCO) surfaces can facilitate improvement in TCO/organic semiconductor interface properties. When ordered PA SAMs are formed on oxide substrates, interface dipole and electronic structure are affected by the functional group properties, orientation, and binding modes of the modifiers. Choosing octylphosphonic acid (OPA), F13-octylphosphonic acid (F13OPA), pentafluorophenyl phosphonic acid (F5PPA), benzyl phosphonic acid (BnPA), and pentafluorobenzyl phosphonic acid (F5BnPA) as a representative group of modifiers, we report polarization modulation-infrared reflection-absorption spectroscopy (PM-IRRAS) of binding and molecular orientation on indium-doped zinc oxide (IZO) substrates. Considerable variability in molecular orientation and binding type is observed with changes in PA functional group. OPA exhibits partially disordered alkyl chains but on average the chain axis is tilted ~57 degrees from the surface normal. F13OPA tilts 26 degrees with mostly tridentate binding. The F5PPA ring is tilted 23 degrees from the surface normal with a mixture of bidentate and tridentate binding; the BnPA ring tilts 31 degrees from normal with a mixture of bidentate and tridentate binding, and the F5BnPA ring tilts 58 degrees from normal with a majority of bidentate with some tridenate binding. These trends are consistent with what has been observed previously for the effects of fluorination on orientation of phosphonic acid modifiers. These results from PM-IRRAS are correlated with recent results on similar systems from near-edge X-ray absorption fine structure (NEXAFS) and density functional theory (DFT) calculations. Overall, these results indicate that both surface binding geometry and intermolecular interactions play important roles in dictating the orientation of PA modifiers on TCO surfaces. This work also establishes PM-IRRAS as a routine method for SAM orientation determination on complex oxide substrates. PMID- 25924007 TI - Above 30% external quantum efficiency in green delayed fluorescent organic light emitting diodes. AB - Highly efficient green thermally activated delayed fluorescent organic light emitting diodes with an external quantum efficiency of 31.2% were investigated by using 3-(3-(carbazole-9-yl)phenyl) pyrido[3',2':4,5]furo[2,3-b]pyridine (3CzPFP) derived from carbazole and pyrido[3',2':4,5]furo[2,3-b]pyridine. The host material showed well-matched photoluminescence emission with absorption of the green dopant material, (4s,6s)-2,4,5,6-tetra(9H-carbazol-9-yl)isophthalonitrile (4CzIPN) and harvested all excitons of 4CzIPN. The 3CzPFP:4CzIPN film exhibited high photoluminescence quantum yield of 100%, and the green delayed fluorescence device employing the 3CzPFP host showed high maximum quantum efficiency of 31.2 +/- 0.5% at 1% doping after optimization of the device structure. PMID- 25924008 TI - The PI3K/AKT/mTOR interactive pathway. AB - The phosphatidylinositol 3-kinase (PI3K)/AKT/mammalian target of the rapamycin (mTOR) signalling pathway is hyperactivated or altered in many cancer types and regulates a broad range of cellular processes including survival, proliferation, growth, metabolism, angiogenesis and metastasis. The PI3K/AKT/mTOR pathway is regulated by a wide-range of upstream signalling proteins and it regulates many downstream effectors by collaborating with various compensatory signalling pathways, primarily with RAF/MEK/ERK pathway. Limited clinical success of the available targeted therapeutic agents and challenges mediated by tumour heterogeneity across different cancer types emphasize the importance of alterations in the PI3K/AKT/mTOR pathway in the design of effective personalized treatment strategies. Here we report a comprehensive PI3K/AKT/mTOR network that represents the intricate crosstalk between compensatory pathways, which can be utilized to study the AKT signalling mechanism in detail and improve the personalized combinatorial therapeutic strategies. PMID- 25924009 TI - Cost-Effectiveness of Screening and Treating Foreign-Born Students for Tuberculosis before Entering the United States. AB - INTRODUCTION: The Centers for Disease Control and Prevention is considering implementation of overseas medical screening of student-visa applicants to reduce the numbers of active tuberculosis cases entering the United States. OBJECTIVE: To evaluate the costs, cases averted, and cost-effectiveness of screening for, and treating, tuberculosis in United States-bound students from countries with varying tuberculosis prevalence. METHODS: Costs and benefits were evaluated from two perspectives, combined and United States only. The combined perspective totaled overseas and United States costs and benefits from a societal perspective. The United States only perspective was a domestic measure of costs and benefits. A decision tree was developed to determine the cost-effectiveness of tuberculosis screening and treatment from the combined perspective. RESULTS: From the United States only perspective, overseas screening programs of Chinese and Indian students would prevent the importation of 157 tuberculosis cases annually, and result in $2.7 million in savings. From the combined perspective, screening programs for Chinese students would cost more than $2.8 million annually and screening programs for Indian students nearly $440,000 annually. From the combined perspective, the incremental cost for each tuberculosis case averted by screening Chinese and Indian students was $22,187 and $15,063, respectively. Implementing screening programs for German students would prevent no cases in most years, and would result in increased costs both overseas and in the United States. The domestic costs would occur because public health departments would need to follow up on students identified overseas as having an elevated risk of tuberculosis. CONCLUSIONS: Tuberculosis screening and treatment programs for students seeking long term visas to attend United States schools would reduce the number of tuberculosis cases imported. Implementing screening in high-incidence countries could save the United States millions of dollars annually; however there would be increased costs incurred overseas for students and their families. PMID- 25924010 TI - Resolution of Benign and Malignant Sebaceous Neoplasms, in a Renal Transplant Patient Treated With Everolimus. AB - Nonmelanoma skin cancers are the most common malignancies in transplant recipients under immunosuppression; nevertheless, appendage tumors also may appear. The onset of several cutaneous neoplasms in transplant patients can cause deterioration in quality of life of these patients. A 62-year-old white woman patient developed several malignant and benign sebaceous neoplasms during an immunosuppressive treatment for a renal transplant. The genetic study showed a mutation in MSH6-eson 1 (c116G>A), without mutations in MLH1 gene and MSH2. A final diagnosis of multiple sebaceous tumors in an immunosuppressed patient without Muir -Torre syndrome was made. The spreading of further cutaneous neoplasms led to a change in immunosuppression: namely, that clinicians suspended tacrolimus and add everolimus. After 2 months, all tumor lesions on the face and on the limbs have disappeared, and no further lesions occurred. Everolimus could represent a valid therapeutical treatment for transplant patients at high risk for cutaneous tumors. A genetic consult and a consequent study of the genetic profile should be performed on each of these patients, to avoid risks of recurrent cutaneous tumors and negative effects on the quality of life. PMID- 25924011 TI - Resveratrol Induced Premature Senescence Is Associated with DNA Damage Mediated SIRT1 and SIRT2 Down-Regulation. AB - The natural polyphenolic compound resveratrol (3,4,5-trihydroxy-trans-stilbene) has broad spectrum health beneficial activities including antioxidant, anti inflammatory, anti-aging, anti-cancer, cardioprotective, and neuroprotective effects. Remarkably, resveratrol also induces apoptosis and cellular senescence in primary and cancer cells. Resveratrol's anti-aging effects both in vitro and in vivo attributed to activation of a (NAD)-dependent histone deacetylase family member sirtuin-1 (SIRT1) protein. In mammals seven members (SIRT1-7) of sirtuin family have been identified. Among those, SIRT1 is the most extensively studied with perceptive effects on mammalian physiology and suppression of the diseases of aging. Yet no data has specified the role of sirtuins, under conditions where resveratrol treatment induces senescence. Current study was undertaken to investigate the effects of resveratrol in human primary dermal fibroblasts (BJ) and to clarify the role of sirtuin family members in particular SIRT1 and SIRT2 that are known to be involved in cellular stress responses and cell cycle, respectively. Here, we show that resveratrol decreases proliferation of BJ cells in a time and dose dependent manner. In addition the increase in senescence associated beta-galactosidase (SA-beta-gal) activity and methylated H3K9-me indicate the induction of premature senescence. A significant increase in phosphorylation of gamma-H2AX, a surrogate of DNA double strand breaks, as well as in levels of p53, p21CIP1 and p16INK4A is also detected. Interestingly, at concentrations where resveratrol induced premature senescence we show a significant decrease in SIRT1 and SIRT2 levels by Western Blot and quantitative RT-PCR analysis. Conversely inhibition of SIRT1 and SIRT2 via siRNA or sirtinol treatment also induced senescence in BJ fibroblasts associated with increased SA beta-gal activity, gamma-H2AX phosphorylation and p53, p21CIP1 and p16INK4A levels. Interestingly DNA damaging agent doxorubicin also induced senescence in BJ fibroblasts associated with decreased SIRT1/2 levels. In conclusion our data reveal that resveratrol induced premature senescence is associated with SIRT1 and SIRT2 down regulation in human dermal fibroblasts. Here we suggest that the concomitant decline in SIRT1/2 expression in response to resveratrol treatment may be a cause for induction of senescence, which is most likely mediated by a regulatory mechanism activated by DNA damage response. PMID- 25924012 TI - Palladium-Catalyzed Oxirane-Opening Reaction with Arenes via C-H Bond Activation. AB - We achieved a palladium-catalyzed C-H activation/C-C coupling reaction between arenes with a pyridyl, aminoquinolinyl, imino, or amide directing group, and oxiranes. The reaction proceeded at room temperature without any additives and tolerated a wide variety of functional groups, and the products were obtained in good to excellent yields, even on gram scale. This is the first example of a transition-metal-catalyzed intermolecular direct coupling reaction between a C-H bond of aromatic compounds and a carbon atom of oxiranes via C-H bond activation. By using N-methoxybenzamide as a substrate, we obtained 3-substituted isochroman 1-ones in one pot. The coupling reaction proceeded with stereoretention. Kinetic isotope effect experiments suggested that C-H bond activation is the rate determining step. PMID- 25924013 TI - The pet factor--companion animals as a conduit for getting to know people, friendship formation and social support. AB - BACKGROUND: While companion animals have been previously identified as a direct source of companionship and support to their owners, their role as a catalyst for friendship formation or social support networks among humans has received little attention. This study investigated the indirect role of pets as facilitators for three dimensions of social relatedness; getting to know people, friendship formation and social support networks. METHODS: A telephone survey of randomly selected residents in four cities, one in Australia (Perth; n = 704) and three in the U.S. (San Diego, n = 690; Portland, n = 634; Nashville, n = 664) was conducted. All participants were asked about getting to know people within their neighborhood. Pet owners were asked additional questions about the type/s of pet/s they owned, whether they had formed friendships as a result of their pet, and if they had received any of four different types of social support from the people they met through their pet. RESULTS: Pet owners were significantly more likely to get to know people in their neighborhood than non-pet owners (OR 1.61; 95%CI: 1.30, 1.99). When analyzed by site, this relationship was significant for Perth, San Diego and Nashville. Among pet owners, dog owners in the three U.S. cities (but not Perth) were significantly more likely than owners of other types of pets to regard people whom they met through their pet as a friend (OR 2.59; 95%CI: 1.94, 3.46). Around 40% of pet owners reported receiving one or more types of social support (i.e. emotional, informational, appraisal, instrumental) via people they met through their pet. CONCLUSION: This research suggests companion animals can be a catalyst for several dimensions of human social relationships in neighborhood settings, ranging from incidental social interaction and getting to know people, through to formation of new friendships. For many pet owners, their pets also facilitated relationships from which they derived tangible forms of social support, both of a practical and emotionally supportive nature. Given growing evidence for social isolation as a risk factor for mental health, and, conversely, friendships and social support as protective factors for individual and community well-being, pets may be an important factor in developing healthy neighborhoods. PMID- 25924014 TI - Underlying Data for Sequencing the Mitochondrial Genome with the Massively Parallel Sequencing Platform Ion TorrentTM PGMTM. AB - BACKGROUND: Massively parallel sequencing (MPS) technologies have the capacity to sequence targeted regions or whole genomes of multiple nucleic acid samples with high coverage by sequencing millions of DNA fragments simultaneously. Compared with Sanger sequencing, MPS also can reduce labor and cost on a per nucleotide basis and indeed on a per sample basis. In this study, whole genomes of human mitochondria (mtGenome) were sequenced on the Personal Genome Machine (PGMTM) (Life Technologies, San Francisco, CA), the out data were assessed, and the results were compared with data previously generated on the MiSeqTM (Illumina, San Diego, CA). The objectives of this paper were to determine the feasibility, accuracy, and reliability of sequence data obtained from the PGM. RESULTS: 24 samples were multiplexed (in groups of six) and sequenced on the at least 10 megabase throughput 314 chip. The depth of coverage pattern was similar among all 24 samples; however the coverage across the genome varied. For strand bias, the average ratio of coverage between the forward and reverse strands at each nucleotide position indicated that two-thirds of the positions of the genome had ratios that were greater than 0.5. A few sites had more extreme strand bias. Another observation was that 156 positions had a false deletion rate greater than 0.15 in one or more individuals. There were 31-98 (SNP) mtGenome variants observed per sample for the 24 samples analyzed. The total 1237 (SNP) variants were concordant between the results from the PGM and MiSeq. The quality scores for haplogroup assignment for all 24 samples ranged between 88.8%-100%. CONCLUSIONS: In this study, mtDNA sequence data generated from the PGM were analyzed and the output evaluated. Depth of coverage variation and strand bias were identified but generally were infrequent and did not impact reliability of variant calls. Multiplexing of samples was demonstrated which can improve throughput and reduce cost per sample analyzed. Overall, the results of this study, based on orthogonal concordance testing and phylogenetic scrutiny, supported that whole mtGenome sequence data with high accuracy can be obtained using the PGM platform. PMID- 25924015 TI - Percutaneous microwave ablation of thyroid nodules: effects on thyroid function and antibodies. AB - PURPOSE: Microwave ablation (MWA) is a new minimally invasive method for thermal ablation of benign thyroid nodules with promising results. The aim of this study was to investigate whether MWA has an impact on thyroid function. MATERIALS AND METHODS: Thirty patients with a total of 34 benign thyroid nodules underwent MWA between January 2013 and July 2014. Serum levels of triiodothyronine (T3), thyroxine (T4), thyrotropin (TSH), thyroglobuline (Tg) and additionally antibodies against Tg (anti-Tg), thyrotropin receptors (TRAb) and thyroid peroxidase (anti-TPO) were measured at enrolment, 24 h after MWA, as well as at the 3-month and 6-month follow-up. Moreover, the nodule volume was evaluated to determine effectiveness. RESULTS: Serum TSH, T4, T3 and Tg levels did not change significantly at the 3-month or 6-month follow-up (p > 0.05); thyroid function was not affected by MWA. Antibody levels did not change significantly either; however, two patients developed antibodies after treatment. A volume reduction of 51.4% or 7.85 mL could be demonstrated after 3 months and a reduction of 55.8% or 14.0 mL after 6 months. Slight complications such as mild pain during the ablation or superficial haematomas emerged. The development of Graves' disease and mild Horner's syndrome were observed as more severe side effects. CONCLUSIONS: The data suggest MWA as an alternative for the treatment of benign thyroid nodules. While first results for preservation of thyroid function are positive, further measurements of laboratory data and especially antibodies are necessary. PMID- 25924016 TI - Dual applicator thermal ablation at 2.45 GHz: a numerical comparison and experiments on synchronous versus asynchronous and switched-mode feeding. AB - PURPOSE: This paper compares the results obtained with numerical simulations and ex vivo experiments involving a dual applicator microwave thermal ablation system operating at a 2.45 GHz frequency, both in synchronous and asynchronous modes. Our purpose was to demonstrate that at this frequency an asynchronous or switched mode system performs essentially as well as the synchronous one, in spite of the prevailing belief that coherence would assure better thermal (TH) synergy. Numerical analysis: The calculations of temperature fields were based on the Pennes bioheat equation, taking into account the effects of blood perfusion by means of a full-wave 3D simulator that allows numerical electromagnetic (EM) and TH analyses. MATERIALS AND METHODS: Experiments were done using a 100 W microwave (MW) power generator and a fast switched-mode sequential 'active' power splitter. By adding a further passive power splitter we arranged a test bed for an accurate experimental comparison of synchronous versus switched-mode TH ablations. RESULTS: The experimental ablation zones produced by a dual applicator array on ex vivo swine tissue corresponded well with the simulated ones, confirming that the simplifications assumed in the full-wave analysis were compatible with the aim of our work. CONCLUSIONS: Numerical simulations and experiments show that at a 2.45 GHz industrial, scientific and medical (ISM) frequency, synchronous, asynchronous and switched-mode multi-probe systems are substantially equivalent in terms of ablative performance. Moreover, the switched-mode solution offers simpler operation along with lesser sensitivity to the placement of applicators in the tissue. PMID- 25924017 TI - Spin crossover behaviour in one-dimensional Fe(II) compounds based on the [M(CN)4](2-) (M = Pd, Pt) units. AB - Four one-dimensional heterobimetallic coordination polymers {Fe(pic)2[M(CN)4]}n (M = Pd(II) () and Pt(II) (), pic = 2-picolylamine), and {Fe(pypz)2[M(CN)4]}n (M = Pd(II) () and Pt(II) (), pypz = 2-(1H-pyrazol-3-yl)pyridine) have been synthesized and characterized by infrared spectroscopy, X-ray diffraction, magnetic measurements and differential scanning calorimetry (DSC). Single-crystal X-ray analyses show that all the compounds are 1D neutral zigzag chain structures in which the planar [M(CN)4](2-) anion acts as a MU2-bridging ligand, and the two pic/pypz molecules as chelating coligands. Examination of the intermolecular contacts in compounds reveals the existence of the hydrogen bonding interactions involving the hydrogen donor groups of the pic and pypz ligands and the nitrogen atoms of the non-bridging cyanide groups of the [M(CN)4](2-) anions. Weak pi-pi interactions were also found to be important for the formation of the 3D structures of compounds and . The SCO properties of all compounds were confirmed by the detailed structural analyses of the coordination environments of the Fe(II) centres, DSC analyses, and magnetic susceptibility measurements. Compounds and exhibit complete SCO behaviour with very narrow thermal hysteresis loops centred near the room temperature (T1/2? = 270 K and T1/2? = 272 K for and T1/2? = 272 K and T1/2? = 274 K for ), whereas and exhibit abrupt SCO at 186 and 180 K, respectively. Compared to the mononuclear species of the pic and pypz ligands, the SCO temperatures are adjusted by the different ligand field strength of the [M(CN)4)](2-) units. The cooperativity from both the coordination bonds and supramolecular interaction leads to the observation of the hysteresis loops in the Fe-pic systems and the abrupt SCO transition in the Fe-pypz systems. Furthermore, the light-induced excited-spin-state trapping (LIESST) effect was observed for . PMID- 25924018 TI - Validation of the ICF Core Set for Vocational Rehabilitation from the perspective of patients with spinal cord injury using focus groups. AB - INTRODUCTION: The International Classification of Functioning, Disability and Health (ICF) Core Set for Vocational Rehabilitation is an application of the ICF of the World Health Organization with the purpose of identifying problems and resources relevant for people in a vocational rehabilitation given a health condition. OBJECTIVE: The objective of the study was to validate the Comprehensive ICF Core Set for Vocational Rehabilitation from the perspective of patients with spinal cord injury (SCI). The specific aims were to explore the aspects of functioning and health important to patients with SCI regarding return to work and to examine to what extent these aspects are represented by the current version of the Comprehensive ICF Core Set for Vocational Rehabilitation. METHODS: Focus group interviews were conducted. The sampling of patients followed the maximum variation strategy. Sample size satisfied saturation criterion. The focus groups were digitally recorded and transcribed verbatim. The meaning condensation procedure was used for the data analysis. After qualitative data analysis, the resulting concepts were linked to ICF categories according to established linking rules. RESULTS: Twenty-four SCI patients participated in seven focus groups. Sixty-three ICF categories out of 90 ICF categories contained in the Comprehensive ICF Core Set for Vocational Rehabilitation were reported by the patients. Forty-two additional categories that are not covered in the Comprehensive ICF Core Set for Vocational Rehabilitation were found but adding the health condition-specific ICF Core Set for SCI in long-term context, only 11 categories were not covered. CONCLUSIONS: The existing version of the Comprehensive ICF Core Set for Vocational Rehabilitation was confirmed almost entirely by the focus groups to explore the vocational situation of patients with SCI. Implications for Rehabilitation Validation of the ICF Core Set for Vocational Rehabilitation as a useful tool to facilitate social reintegration and rehabilitation of patients with SCI. Return to work is a key outcome in vocational rehabilitation of patients with SCI including those who are young with long-term employment prospects. The results of this study could provide a foundation in utilizing the ICF Core Set for Vocational Rehabilitation to guide rehabilitation goals, service planning and evaluation, and fostering an engaging relationship with employers in the context of SCI rehabilitation. SCI patients have specific needs, not entirely covered by the both ICF Core Set for SCI long term context and for Vocational Rehabilitation. Our results underline some of the second level categories, probably related to specific SCI impairment, which can be useful to plan specific rehabilitation programs to improve the return to work after SCI. PMID- 25924019 TI - Facilitating interprofessional evidence-based practice in paediatric rehabilitation: development, implementation and evaluation of an online toolkit for health professionals. AB - PURPOSE: Lack of time, competencies, resources and supports are documented as barriers to evidence-based practice (EBP). This paper introduces a recently developed web-based toolkit designed to assist interprofessional clinicians in implementing EBP within a paediatric rehabilitation setting. METHODS: EBP theory, models, frameworks and tools were applied or adapted in the development of the online resources, which formed the basis of a larger support strategy incorporating interactive workshops, knowledge broker facilitation and mentoring. RESULTS: The highly accessed toolkit contains flowcharts with embedded information sheets, resources and templates to streamline, quantify and document outcomes throughout the EBP process. Case examples relevance to occupational therapy and physical therapy highlight the utility and application of the toolkit in a clinical paediatric setting. Workshops were highly rated by learners for clinical relevance, presentation level and effectiveness. Eight evidence syntheses have been created and 79 interventions have been evaluated since the strategy's inception in January 2011. CONCLUSIONS: The toolkit resources streamlined and supported EBP processes, promoting consistency in quality and presentation of outputs. The online toolkit can be a useful tool to facilitate clinicians' use of EBP in order to meet the needs of the clients and families whom they support. Implications for Rehabilitation A comprehensive online EBP toolkit for interprofessional clinicians is available to streamline the EBP process and to support learning needs regardless of competency level. Multi method facilitation support, including interactive education, e-learning, clinical librarian services and knowledge brokering, is a valued but cost restrictive supplement to the implementation of online EBP resources. EBP resources are not one-size-fits-all; targeted appraisal tools, models and frameworks may be integrated to improve their utility for specific sectors, which may limit them for others. PMID- 25924020 TI - A simple approach for non-invasive transcranial optical vascular imaging (nTOVI). AB - In vivo imaging of cerebral vasculature is highly vital for clinicians and medical researchers alike. For a number of years non-invasive optical-based imaging of brain vascular network by using standard fluorescence probes has been considered as impossible. In the current paper controverting this paradigm, we present a robust non-invasive optical-based imaging approach that allows visualize major cerebral vessels at the high temporal and spatial resolution. The developed technique is simple to use, utilizes standard fluorescent dyes, inexpensive micro-imaging and computation procedures. The ability to clearly visualize middle cerebral artery and other major vessels of brain vascular network, as well as the measurements of dynamics of blood flow are presented. The developed imaging approach has a great potential in neuroimaging and can significantly expand the capabilities of preclinical functional studies of brain and notably contribute for analysis of cerebral blood circulation in disorder models. An example of 1 * 1.5 cm color-coded image of brain blood vessels of mouse obtained in vivo by transcranial optical vascular imaging (TOVI) approach through the intact cranium. PMID- 25924021 TI - The adaptation of a Danish version of the Pain Self-Efficacy Questionnaire: reliability and construct validity in a population of patients with fibromyalgia in Denmark. AB - The aim of this study was to translate, culturally adapt and evaluate the psychometric properties of the Pain Self-Efficacy Questionnaire (PSEQ) in a population of patients with fibromyalgia in Denmark. The study sample included 102 patients diagnosed with fibromyalgia referred to a specialist clinic. The PSEQ was translated and adapted to a Danish setting using a standard stepwise forward-backward translation procedure, followed by initial testing and focus group interview. Reliability was examined by analysing internal consistency and test-retest agreement. Construct validity was examined by investigating dimensionality, targeting, local independence, category functioning and differential item functioning (DIF). Reliability was high: Cronbach's alpha 0.88, test-retest correlation 0.93, intraclass correlation coefficient (ICC) 0.89 and item-total correlations 0.44-0.70. Factor analyses and item response (IRT) models indicated unidimensionality, and the PSEQ-DK was well targeted to the sample. High interitem correlation was observed between two items, indicating local dependence, and item misfit and DIF were observed for a few items. However, the overall fit of the scale to a single-factor model and IRT models supported acceptable construct validity. The PSEQ-DK showed acceptable psychometric properties and can therefore represent a reliable and valid measure for evaluating self-efficacy in patients with fibromyalgia in Denmark. PMID- 25924022 TI - Localization of serum resistance-associated protein in Trypanosoma brucei rhodesiense and transgenic Trypanosoma brucei brucei. AB - African trypanosomes infect a broad range of mammals, but humans and some higher primates are protected by serum trypanosome lytic factors that contain apolipoprotein L1 (ApoL1). In the human-infective subspecies of Trypanosoma brucei, Trypanosoma brucei rhodesiense, a gene product derived from the variant surface glycoprotein gene family member, serum resistance-associated protein (SRA protein), protects against ApoL1-mediated lysis. Protection against trypanosome lytic factor requires the direct interaction between SRA protein and ApoL1 within the endocytic apparatus of the trypanosome, but some uncertainty remains as to the precise mechanism and location of this interaction. In order to provide more insight into the mechanism of SRA-mediated resistance to trypanosome lytic factor, we assessed the localization of SRA in T. b. rhodesiense EATRO3 using a novel monoclonal antibody raised against SRA together with a set of well characterized endosomal markers. By three-dimensional deconvolved immunofluorescence single-cell analysis, combined with double-labelling immunoelectron microscopy, we found that ~ 50% of SRA protein localized to the lysosome, with the remaining population being distributed through the endocytic pathway, but apparently absent from the flagellar pocket membrane. These data suggest that the SRA/trypanolytic factor interaction is intracellular, with the concentration within the endosomes potentially crucial for ensuring a high efficiency. PMID- 25924023 TI - Hypermongones A-J, Rare Methylated Polycyclic Polyprenylated Acylphloroglucinols from the Flowers of Hypericum monogynum. AB - Hypermongones A-J (1-10), rare methylated polycyclic polyprenylated acylphloroglucinol derivatives, together with three known simple acylphloroglucinols (11-13) as their plausible biogenetic precursors, were identified from the flowers of Hypericum monogynum. The structures of 1-10 were elucidated by analysis of their 1D and 2D NMR spectroscopic data; the absolute configuration of their polycyclic skeleton was determined by the electronic circular dichroism exciton chirality method and was subsequently confirmed by an X-ray diffraction study of 1. The evaluation of their inhibitory effects on nitric oxide (NO) production in lipopolysaccharide-induced RAW264.7 cells revealed that compound 7 exhibited significant NO inhibition activity, with an IC50 value of 9.5 MUM. PMID- 25924024 TI - Plasma visfatin/nicotinamide phosphoribosyltransferase (visfatin/NAMPT) concentration in elderly subjects with metabolic syndrome. AB - INTRODUCTION: Visceral adipose tissue is the main source of circulating proinflammatory adipokine, visfatin/nicotinamide phosphoribosyltransferase (visfatin/NAMPT), whose role in the pathogenesis of metabolic syndrome (MS) components such as hypertension and carbohydrate and lipid disturbances is still uncertain, due to commonly used low specific C-terminal immunoassays to determine visfatin/NAMPT levels. OBJECTIVES: The aim of the study was to assess the association between the occurrence of MS components and circulating visfatin/NAMPT levels in elderly popula tion. PATIENTS AND METHODS: The analysis included 2174 elderly participants of the PolSenior study without heart failure, severe chronic kidney disease, cancer, and malnutrition. MS was defined according to the modified International Diabetes Federation criteria. Plasma visfatin/NAMPT concentrations were measured by a highly specific enzyme-linked immunosorbent assay. Additionally, high-sensitivity C-reactive protein (hsCRP), interleukin 6 (IL-6), and insulin levels were assessed, and the homeostasis model assessment for insulin resistance was calculated. RESULTS: Women were diagnosed with MS more often than men (71.2% vs 56.8%; P <0.001) and had a greater prevalence of all MS components except for type 2 diabetes. Women with MS had higher concentrations of hsCRP and IL-6 than those without MS. Visfatin/NAMPT concentrations were higher in women with MS than in those without MS (1.06 ng/ml [0.65-1.87] vs 0.85 ng/ml [0.54-1.40]; P <0.001), but no differences were observed in men (0.97 ng/ml [0.59 1.61] vs 0.90 ng/ml [0.56-1.60], respectively; P = 0.5). In women, there was a stronger association between the number of components of MS and increased plasma visfatin/NAMPT levels than in men. CONCLUSIONS: Plasma visfatin/NAMPT levels are increased only in elderly women with MS. It is difficult to distinguish the components of MS specifically associated wit h increased visfatin/NAMPT levels. PMID- 25924026 TI - Physiological Effects of Aquatic Exercise in Pregnant Women on Bed Rest. AB - This pilot study examined the effectiveness of an Aquatic Exercise Program (AEP) provided by an occupational therapist for pregnant women on hospitalized bed rest. Researchers conducted a retrospective analysis of medical records of hospitalized pregnant women comparing those who attended an AEP (n = 19) to a control group who received no AEP (n = 12). Statistical tests were used to assess evidence of differences in length of gestation as well as blood pressure and amniotic fluid index (AFI) at discharge. Women who received an AEP had increased AFI and length of gestation compared to the control group. This study supports the use of an AEP as an intervention for pregnant women on prescribed bed rest. Further research is recommended to validate these findings with a larger sample. PMID- 25924025 TI - Risk of hip/femur fractures during the initiation period of alpha-adrenoceptor blocker therapy among elderly males: a self-controlled case series study. AB - AIMS: This study aimed to evaluate the risk of hip/femur fractures during the initiation period of alpha-adrenoceptor blocker therapy using the National Health Insurance claims database, Taiwan, with a self-controlled case series design. METHODS: All male beneficiaries aged over 50 years as of 2007, who were incident users of alpha-adrenoceptor blockers and also had a diagnosis of hip/femur fracture within the 2007-2009 study period were identified. The first day when the alpha-adrenoceptor blocker was prescribed was set as the index date. We partitioned the initial 21 day period following the index date as the post exposure risk period 1, days 22-60 after the index date as the post-exposure risk period 2, the 21 day period prior to the index date as the pre-exposure risk period 1 and days 22-60 prior to the index date as the pre-exposure risk period 2. The remainder of the study period was defined as the unexposed period. The incidence rate ratio (IRR) of hip/femur fractures within each risk period compared with the unexposed period was estimated using a conditional Poisson regression model. RESULTS: A total of 5875 men were included. Compared with the unexposed period, the IRR of hip/femur fractures was 1.36 (95% confidence interval 1.06, 1.74, P = 0.017) within the post-exposure risk period 1 for patients without concomitant prescriptions of anti-hypertensive agents. CONCLUSIONS: Use of alpha-adrenoceptor blockers was associated with a small but significant increase in the risk of hip/femur fractures during the early initiation period in patients without concomitant prescriptions of anti hypertensive agents. PMID- 25924027 TI - Biosensor Enhancement Using Grooved Micromixers: Part II, Experimental Studies. AB - In this study we examine the experimental use of the staggered herringbone mixer (SHM) for the signal enhancement of a microfluidic surface plasmon resonance imaging (SPRi) affinity-based biosensor. We define the signal enhancement (Emix) as the ratio of the time-dependent slope of the sensor response of a SHM-based microfluidic channel and that of an unmixed channel; Emix is directly proportional to changes in the sensor sensitivity and inversely proportional to changes in the sensor limit of detection (LOD). Measurements were carried out for three SHM designs under a wide range of volumetric flow rates for two analytes: high diffusivity ssDNA and low diffusivity Escherichia coli bacteria. The experimental data collected in this study was found to exhibit a good match to that predicted by the numerical methods discussed in part I of this study. We found that Emix is dependent on the SHM groove geometry, the Peclet number Pe, and the overall microchannel length L; these dependencies are discussed in detail. For realistic experimental conditions, the enhancement that the SHM can provide is in the range of 1 < Emix < 5 (0% < improvement < 400%). PMID- 25924028 TI - Evidence-to-practice gaps in the management of community-dwelling Australian patients with ischaemic heart disease. AB - WHAT IS KNOWN AND OBJECTIVE: Ischaemic heart disease (IHD) is a major cause of death in developed countries. Patients with IHD are at greater risk of subsequent myocardial infarction (MI). International studies suggest that guideline recommended therapies proven to reduce this risk are underutilised. The objectives of this study were to review the use of guideline-recommended medications for the secondary prevention of IHD in Australians and identify patient characteristics influencing use of these medications. METHODS: The medication regimens of community dwelling Australians with documented IHD who received a Home Medicines Review (HMR) between January 2010 and September 2012 were extracted from a pharmacist decision support software database and retrospectively reviewed. Each patient's use of antithrombotics; angiotensin converting enzyme inhibitors (ACEIs) or angiotensin receptor blockers (ARBs); statins; and beta-blockers (BBs) or non-dihydropyridine calcium channel blockers (CCBs) was evaluated in conjunction with documented contraindications. Guideline concordance in all four categories was classified as 'Optimal Medical Therapy' (OMT). Univariate and multivariate analyses identified patient characteristics influencing OMT use. RESULTS AND DISCUSSION: Of the 5396 patient medication regimens reviewed, 24.3% demonstrated OMT. Guideline concordance was observed in 91.6%, 75.6%, 74.8%, and 42.4% of patients for antithrombotics, statins, ACEI/ARBs, and BB/CCBs, respectively. The independent predictors of not receiving OMT were age 75 years or over (adjusted odds ratio [AOR] 0.76; 95% confidence interval [CI] 0.67-0.87), asthma (AOR 0.69; 95% CI 0.57-0.84), and depression or anxiety (AOR 0.84; 95% CI 0.71-0.99). Diabetes (AOR 1.20; 95% CI 1.04-1.38), hypertension (AOR 1.56; 95% CI 1.36-1.79) and a high Charlson Comorbidity Index score (AOR 1.37; 95% CI 1.15-1.64) independently predicted receipt of OMT. WHAT IS NEW AND CONCLUSION: Only one quarter of community dwelling Australian patients with IHD receive antithrombotics, ACEI/ARBs, BB/CCBs and statins. The potential consequences of these evidence-to-practice gaps are exacerbated by Australia's increasing prevalence of IHD. Healthcare professionals must work to ensure that recommended therapies are prescribed and adhered to long-term, especially in the elderly and patients with asthma and mental health problems, to reduce IHD related mortality and morbidity and the consequent healthcare and financial impact. PMID- 25924029 TI - The Comparison between Minimally Invasive Coronary Bypass Grafting Surgery and Conventional Bypass Grafting Surgery in Proximal LAD Lesion. AB - BACKGROUND: Minimally invasive bypass grafting surgery has entered the clincal routine in several centers around the world, with an increasing popularity in the last decade. In our study, we aimed to make a comparison between minimally invasive coronary artery bypass grafting surgery and conventional bypass grafting surgery in isolated proximal left anterior descending artery (LAD) lesions. METHODS: Between January 2004 and December 2011, patients with proximal LAD lesions, who were treated with robotically assisted minimally invasive coronary artery bypass surgery and conventional bypass surgery, were included in the study. In Group 1, coronary bypass with cardiopulmonary bypass and complete sternotomy were applied to 35 patients and in Group 2, robotically assisted minimally invasive bypass surgery was applied to 35 patients. The demographic, preoperative, perioperative, and postoperative data were collected retrospectively. RESULTS: The mean follow-up time of the conventional bypass group was 5.7 +/- 1.7 years, whereas this ratio was 7.3 +/- 1.3 in the robotic group. There was no postoperative transient ischemic attack (TIA), wound infection, mortality, or need for intra-aortic balloon pump (IABP) in any of the patients. In the conventional bypass group, blood transfusion and ventilation time were significantly higher (P < .05) than in the robotic group. The intensive care unit (ICU) stay and hospital stay were remarkably shorter in the robotic group (P < .01). The postoperative pneumonia rate was significantly higher (20%) in the conventional bypass group (P < .01). Postoperative day 1 pain score was higher in the robotic group (P < .05), however, postoperative day 3 pain score in the conventional bypass group was higher (P < .05). Graft patency rate was 88.6% in the conventional bypass group whereas this ratio was 91.4% in the robotic bypass group, which was not clinically significant (P > .05). CONCLUSIONS: In isolated proximal LAD stenosis, robotic assisted minimally invasive coronary artery bypass grafting surgery requires less blood products, is associated with shorter ICU and hospital stay, and lesser pain in the early postoperative period in contrast to conventional surgery. The result of our studies, which showed similarities to the past studies, lead us to recognize the importance of minimally invasive interventions and the need to perform them more frequently in the future. PMID- 25924030 TI - Can preoperative erythrocyte sedimentation rate serve as an indicator for midterm adverse events after coronary bypass grafting? AB - OBJECTIVE: Erythrocyte sedimentation rate (ESR) may serve as a reasonably good indicator for coronary heart disease as usually ESR is elevated in these patients. The measurement of ESR is a very simple and cheap laboratory test that can be performed in routine blood examinations. In this study, we investigated the association between preoperative erythrocyte sedimentation rate and postoperative midterm adverse events after coronary artery bypass grafting (CABG). METHODS: In the study, only male patients were included. The patients were divided into two groups: group 1 (preoperative sedimentation rate [<20 mm/h] normal [n = 232, 63.9%]) and group 2 (preoperative sedimentation rate [>20 mm/h] above normal [n = 131, 36.1%]). The hemogram and biochemistry panel values were measured one day before operation, on the postoperative first day, on the postoperative seventh day, and on the postoperative third month. RESULTS: Among the laboratory values, there was a statistically significant difference between the two groups with respect to postoperative first-day ESR and postoperative third-month high-sensitivity C-reactive protein (P < .05). In terms of postoperative morbidity, there was also a statistically significant difference (P < .05) between the two groups with regard to pleural effusion, infection of the soft tissue over the sternum, pulmonary infection, return to the intensive care unit, rehospitalization, and mortality. CONCLUSIONS: Elevated preoperative sedimentation rate is associated with postoperative adverse events in patients who undergo CABG. For this purpose, we suggest that patients with higher sedimentation rates undergo detailed examination to prevent mortality and morbidity. PMID- 25924031 TI - Concomitant Transapical Transcatheter Valve Implantations: Edwards Sapien Valve for Severe Mitral Regurgitation in a Patient with Failing Mitral Bioprostheses and JenaValve for the Treatment of Pure Aortic Regurgitation. AB - Transcatheter valve implantation is a novel interventional technique, which was developed as an alternative therapy for surgical aortic valve replacement in inoperable patients with severe aortic stenosis. Despite limited experience in using transcatheter valve implantation for mitral and aortic regurgitation, transapical transcatheter aortic valve implantation and valve-in-valve implantation for degenerated mitral valve bioprosthesis can be performed in high risk patients who are not candidates for conventional replacement surgery. In this case, we present the simultaneous transcatheter valve implantation via transapical approach for both degenerated bioprosthetic mitral valve with severe regurgitation and pure severe aortic regurgitation. PMID- 25924032 TI - Aortic valve replacement in familial hypercholesterolemia: not an ordinary procedure. AB - Familial hypercholesterolemia is an inherited disorder with incidences of approximately 1:500 and 1:1,000,000 in heterozygous and homozygous form respectively. Affected patients usually show early coronary artery disease and severe aortic root calcification, despite optimization of therapy. We report a case of a 64-year-old woman affected by heterozygous familial hypercholesterolemia which presented dyspnea and anginal symptoms due to a severely calcified aortic root causing valve stenosis and narrowed sinotubular junction. Aortic valve replacement and aortic root enlargement were performed using the Manougian procedure. Even for experiences surgeons, this surgery could prove challenging for this group of patients due to aggressive degenerative tissue calcification of the aortic root, which often presents an extremely calcified aortic valve with a small annulus associated to a narrowed sinotubular junction. PMID- 25924033 TI - Early bioprosthesis failure: report of three cases and literature review. AB - BACKGROUND: We experienced three rare early bioprosthesis failure (EBF) cases. In this study, we analyze the causes and discuss the coping strategy of EBF. METHODS: We reviewed all cases of EBF in patients who received a bioprosthesis replacement in Changhai Hospital between January 2001 and January 2014, and reviewed related articles that were published between 1994 and 2014, searching for keywords in PubMed such as "bioprosthesis," "heart valve prosthesis," "early failure," and "bioprosthesis failure." RESULTS: Only three cases were found in Changhai Hospital during this time period. The reasons for EBF in these 3 cases were: native valve attachment, early calcification caused by metabolic syndrome, and early valve thrombosis. Literature review identified an additional 14 cases. The reasons for EBF in these 14 cases were as follows: native valve attachment in 6 cases; metabolic abnormalities in 3 cases; early valve thrombosis in 2 cases; chronic inflammation in 2 cases; and improper operation in 1 case. CONCLUSIONS: EBF is a rare but serious complication. The cause of EBF is complex. Appropriate preventive measures should be developed according to the condition of the patient. PMID- 25924034 TI - Clinical observation of postoperative warfarin anticoagulation in 300 patients undergoing mitral valve replacement with a carbomedics mechanical valve. AB - OBJECTIVE: The objective of this study was to evaluate the safety and efficacy of low-intensity warfarin treatment in Chinese patients after mitral valve replacement as well as the rationality of the INR standards of the hospital (The First People's Hospital of Jining City). METHODS: We retrospectively analyzed 270 cases in our hospital from January 2009 to December 2013; 239 patients completed the 5-year follow-up. There were 192 male and 78 female subjects, age 32-65 years old with a mean age 51.51 +/- 12.12 years old. All eligible candidates received a Carbomedics artificial mechanical valve replacement and were anticoagulated under this hospital's current guidelines for postoperative anticoagulant therapy mitral valve replacement (INR 1.8-2.5). We analyzed the patient's regularly recorded prothrombin times (PTs) and the occurrence of anticoagulation-related complications, such as bleeding, thrombosis, and embolism. RESULTS: A follow-up for 239 of 300 patients was performed for 3-60 months. Within this group, one patient died from cerebral hemorrhage, there was 1 case of subcutaneous bleeding, 1 case of epistaxis, 12 cases of gingival bleeding, in 15 menstrual quantity increased, and in 1 case we found cerebral infarction. CONCLUSIONS: In conclusion, low-intensity anticoagulation after mitral Carbomedics valve replacement is therapeutically effective and safe. There is room to improve the anticoagulation standard currently used, perhaps at a slightly lower level than this standard suggests. From our research we can formulate individualized treatment plans and effectively reduce the occurrence of complications. PMID- 25924035 TI - Cardiovascular Surgery with Cardiopulmonary Bypass in Patients with Preoperative Non-dialysis Dependent Renal Insufficiency. AB - BACKGROUND: Preoperative renal insufficiency is a predictor of acute renal injury in patients undergoing cardiovascular surgery with cardiopulmonary bypass. METHODS: From January 2010 to September 2012, 121 patients undergoing coronary bypass, valve replacement, or both were included in our retrospective study, using cardiopulmonary bypass. We compared the changes in renal function and clinical outcomes of 66 patients with a baseline serum creatinine level more than 1.5 mg/dL with 55 patients with normal serum creatinine levels. We analyzed the impact of cardiopulmonary bypass in patients with non-dialysis dependent renal insufficiency. RESULTS: In the group of patients with preoperative renal injury, the need for dialysis was greater, time of mechanical ventilation longer, and daily diuresis lesser compared with the group of patients with normal serum creatinine levels. Other clinical outcomes such as postoperative hemodynamic problems and organ dysfunction were similar. Prolonged time of cardiopulmonary bypass and cross-clamp affected postoperative renal injury. The study also showed intraoperative dopamine infusion at renal dose and ultrafiltration are not effective with protecting renal tubular function. Serum creatinine levels and glomerular filtration rate (GFR) were found to be useful parameters for renal injury. CONCLUSIONS: These results demonstrate the safety and trustworthiness of cardiopulmonary bypass in patients with non-dialysis dependent renal insufficiency. PMID- 25924036 TI - RIPC Remains a Promising Technique for Protection of the Myocardium during Open Cardiac Surgery: A Meta-Analysis and Systematic Review. AB - BACKGROUND: Remote ischemic preconditioning (RIPC) is the process of inducing brief ischemia in a tissue to prevent ischemic damage in another. This preconditioning can be induced simply by inflating a blood pressure cuff on a limb. Previous randomized controlled trials (RCT) have suggested that RIPC may infer myocardial protection during open cardiac surgery. One method of assessing the degree of myocardial damage incurred in these studies is to assay troponin concentration. Troponin is a cardiac enzyme released by damaged myocardiocytes. With the recent publication of several large RCTs in this area, a meta-analysis of the evidence was undertaken. METHODS: A systematic search of PubMed, EMBASE, and clinicaltrials.gov.uk was conducted using MeSH terms "ischaemic preconditioning" and "cardiac surgery." RCTs that examined post-surgery troponin concentrations were included in this review. The primary outcome investigated was troponin levels at six hours post-cardiac surgery. Secondary outcomes included six to eight hour and twenty-four hour troponin release. RESULTS: Thirteen RCTs, comprising 1398 participants, were identified for inclusion in this meta analysis. Twelve hour postoperative troponin was significantly reduced by RIPC, standardized mean difference 1.29 (95% CI 0.34-2.24). Six to eight and twenty four hour troponin were also significantly reduced, standardized mean differences 1.23 (95% CI 0.62-1.84) and 1.25 (95% CI 0.31-2.19) respectively. CONCLUSIONS: The reduction in troponin concentration suggests that RIPC reduces myocardial damage during open cardiac surgery, however, the degree of bias in the studies assessed may have had a significant impact on this result. PMID- 25924041 TI - [Patient with Parkinson's disease und unclear somnolence]. PMID- 25924042 TI - [Heart and diabetes: the number of high risk patients increases]. PMID- 25924043 TI - [Prevention of cardiovascular disease in patients with type 2 diabetes]. AB - The modern life style is often characterized by a lack of physical activity as well as unhealthy diet leading to a worldwide rise in obesity. This goes along with an increased incidence of type 2 diabetes, accompanied by an accelerated atherosclerosis. Life style changes and normalization of body weight therefore represent the cornerstones of diabetes prevention. In addition, a multi-factorial approach focusing on cardiovascular risk factors like dyslipidemia, hypertension and hyperglycemia enables an effective means for the prevention of micro- or macrovascular complications. PMID- 25924044 TI - [Glucose-lowering therapy in patients with cardiac comorbidities]. AB - The risk for cardiovascular events, congestive heart failure and cardiac arrhythmia is significantly increased in patients with diabetes. Although poor glycaemic control has been associated with an increased cardiovascular event rate, aggressive glucose-lowering strategies have failed to improve cardiovascular endpoints or mortality. Therefore, treatment-associated adverse effects, especially hypoglycaemia and weight gain, must be carefully outbalanced against the potential benefits of better glycaemic control. Furthermore, certain drug-specific aspects must be considered: Pioglitazone is contraindicated in patients with heart failure, and DPP-4 inhibitors have recently been associated with an increased heart failure rate. Heart rate may increase during treatment with GLP-1 analogues. Only with metformin a reduction in cardiovascular endpoint has been demonstrated in patients with diabetes. Insulin and sulphonylureas have yielded neutral results in the available endpoint trials. Endpoint studies with GLP-1 analogues or SGLT-2 inhibitors have not yet been completed. These various drug-specific actions in the cardiovascular system need to be born in mind for the choice of the optimal glucose-lowering strategy in patients with cardiac comorbidities. PMID- 25924045 TI - [Treatment of stable coronary artery disease in type II diabetes mellitus: drugs, coronary intervention and bypass surgery]. AB - The prognosis of patients with type 2 diabetes is reduced by coronary artery disease. The aim of treatment is therefore not only to treat angina symptoms but also improve the prognosis by medical and interventional treatment. LDL-lowering and coronary revascularisation have the largest beneficial impact on prognosis. PMID- 25924046 TI - [How to do: Blood culture]. AB - The detection of living microorganisms in the blood of a patient is of major diagnostic and prognostic importance. Blood cultures are the goldstandard in the diagnosis of BSIs (bloodstream infections). The "How to do: Blood culture collection" article provides a step-by-step approach to this method. The importance of obtaining blood cultures, indications and common pitfalls are explained in this teaching manuscript. PMID- 25924047 TI - [Rare cause of recurrent subileus]. AB - HISTORY AND CLINICAL FINDINGS: An 85-years-old woman with percutaneous endoscopic gastrostomy (PEG) presented at our emergency unit with repeating abdominal pain and changes in the consistency of the stool. The PEG was placed during a treatment of an oropharynxcarcinoma in the past, was replaced repeatedly and is still in use. INVESTIGATIONS: The initial clinical results were unobtrusive; the ultrasound of the abdomen showed mild distended loops of the small intestine, the x-ray of the abdomen was unsuspicious with diagnosis of subileus by constipation. The esophagogastroduodenoscopy was also without pathological findings and showed correct position of the PEG and normal aspect of the gastric tissue. An additional computerized tomography (ct-scan) of the abdomen demonstrated a foreign body nearly 2.5 cm in diameter in the distal part of the small intestine, the terminal ileum, differentiated as PEG retaining plate, also seen retrospectively in the initial x-ray. TREATMENT AND COURSE: Because the endoscopic salvage failed, the foreign body had to be removed surgically. The retaining plate was the cause for subtotal occlusion and also for the perforation of the small intestine. It was found nearly 15 cm before ileo-terminal valve. After operation the patient recovered soon. CONCLUSION: The history gave no hints of accidentally broken PEG-tube; presumably the retaining plate was cut off while the PEG was changed and let go on natural way. The aim of gastroenterologists should be removing PEG under endoscopic control. PMID- 25924048 TI - [Chronic inflammatory bowel disease: transition from pediatric to adult care]. AB - Children and adolescents with inflammatory bowel diseases (IBD) are a group of patients with increasingly special health care needs. Transition from a pediatric and adolescent healthcare system into an adult medicine setting may be difficult but nevertheless is very important to ensure physiological development of adolescent patients and of the continuity of their medical treatment. Transition has shown to be a challenge for pediatricians and adult doctors as well. In Germany within the healthcare system there are no special structures established to organize and optimize transition. The German Society for Pediatric Gastroenterology and Nutrition and the German Society of Internal Medicine have founded a working group to proceed the process of transition of young patients with IBD within the german health care. PMID- 25924049 TI - [The role of PET in lung cancer staging]. AB - The precise staging of lymph-node and distant metastases is pivotal for the choice of surgical procedures and overall therapy planning for patients with lung cancer. FDG-PET/CT plays a central role in the diagnostic algorithm of patients with potentially curable disease. In patients with histologically proven lung cancer, FDG-PET/CT provides a higher diagnostic accuracy in the staging of lymph node and distant metastases compared to staging with CT alone. Furthermore, as a whole body examination, FDG-PET/CT may replace further additional examinations. Prospective studies have also shown that the number of unnecessary thoracotomies and mediastinoscopies can be reduced by the inclusion of FDG-PET in the preoperative staging. PMID- 25924050 TI - [Gene therapy in Germany: from past to present]. AB - In 1994, the first clinical gene therapy trial was performed in Germany. Since then more than 2000 clinical gene therapy trials have been performed worldwide. After 20 years, a short resume is drawn here. PMID- 25924051 TI - [The doctor as manager]. PMID- 25924052 TI - [Prognosis of population-related morbidity for common cancers in Germany--Effects on health care]. AB - INTRODUCTION: The demand for outpatient and inpatient oncology care will rise in the next years. In this analysis, the number of new cases and the prevalence in 2020, the number of hospital days, types of treatment, sickness costs, and the number of oncology specialists are prognosed. METHODS: Projections of incidence and prevalence of cancer overall and of the three most common cancers were conducted with data from the German Population-Based Cancer Registries and from the German Federal Statistics Office. The average number of hospital days was extrapolated until 2020 on the basis of these population projections. Outpatient care was analyzed with billing data obtained from the WINHO. Projections of sickness costs in 2020 were calculated based on data from the German Federal Statistics Office under the assumption that cost per prevalent case remains constant within a given age group over the projection period. Numbers of specialists in hematology and oncology were taken from the database of the Association of Statutory Health Insurance Physicians. These forecasts are based on a series of assumptions. RESULTS: The number of new cancer cases will increase by about 67,000 cases until 2020 (reference year 2008). Prevalent cases will increase by about 176,000 cases. The needed number of hospital days will increase about 13% to 15.513 million days in 2020. An increase of 30% in cytoreductive and 23% in chemotherapy treatment of lung cancer was shown between 2008 and 2011. The number of contracted doctors with focus in hematology and oncology has increased in 2011 compared to 2005. Between 2002 and 2008, sickness costs increased by 52% in the outpatient sector and by 31% in the inpatient sector. In 2020, the increase of sickness costs is expected to reach about 1.7 billion EUR/year. CONCLUSIONS: Due to the increase of incident and prevalent cancer cases, the number of hospital days and sickness costs will increase. The results of the analyses show an increase of medical care services in the outpatient sector. PMID- 25924053 TI - [Is daytime sleepiness a sufficient predictor of sleep-disordered breathing during pre-anesthesia consultation?]. AB - BACKGROUND: Sleep-disordered breathing (SDB) is associated with increased rate of perioperative complications. Daytime sleepiness is a frequent symptom of SDB. Thus, aim of the present study was to evaluate whether preoperative assessment of daytime sleepiness would be eligible for sufficient prediction of SDB. METHODS: Patients before scheduled surgery were prospectively recruited and asked to answer a standardized sleep questionnaire (Epworth Sleepiness Scale; ESS). The night before surgery, sleep polygraphy was performed and the oxygen desaturation index 4% (ODI 4%) was calculated. RESULTS: Data of 363 patients (190 men and 173 women) were finally analyzed. Regarding risk assessment, 42 patients had ASA grade 1, 192 patients had ASA grade 2, 123 patients had ASA grade 3 and 6 patients had ASA grade 4. Mean Body Mass Index was 27.9 +/- 5.1 kg/m2, mean age was 59.2 +/- 13.3 years and mean ESS score was 5.7 +/- 3.4. Clinical relevant daytime sleepiness (ESS >= 11) was found in 32 patients (9%). In 11 patients (34%) with ESS >= 11, ODI 4% >= 5/h was calculated whereas in 21 patients with ESS >= 11 (66%), ODI 4% < 5/h was found. Odds ratio between ODI 4% >= 5/h and ESS >= 11 was 0.919 (CI 0.85-0.99, p = 0.038). CONCLUSION: In non-obese patients, daytime sleepiness is a rare event and is not associated with SDB. Thus, daytime sleepiness is not eligible for the preoperative SDB screening. PMID- 25924054 TI - Perforating granuloma annulare: a case report and literature review. PMID- 25924055 TI - Theoretical and experimental studies of the dechlorination mechanism of carbon tetrachloride on a vivianite ferrous phosphate surface. AB - Chlorinated organics are the principal and most frequently found contaminants in soil and groundwater, generating significant environmental problems. Over the past several decades, Fe-containing minerals naturally occurring in aquatic and terrestrial environments have been used as natural electron donors, which can effectively dechlorinate a variety of chlorinated organics. However, a full understanding of the reaction mechanism of the dechlorination pathway cannot be obtained by experimental investigations alone, due to the immeasurability of chemical species formed over a short reaction time. In this report, we describe experiments and density functional theory (DFT) calculations carried out to investigate the complex reduction pathway of carbon tetrachloride (CT) on a vivianite (Fe(II)3(PO4)2.8H2O) surface. Our results indicate that chloroform (HCCl3) and formate are the primary transformation products. The experimental results reveal that the reduction kinetics of CCl4 can be dramatically accelerated as the pH is increased from 3 to 11. On the basis of the DFT calculations, we found that HCCl3 can be formed by (*)CCl3 and :CCl3(-)* on a deprotonated vivianite surface (an adsorbate on vivianite is denoted using an asterisk). In addition, :CCl3(-)* can be nonreductively dechlorinated to form :CCl2* followed by sequential nucleophilic attack by OH(-)*, resulting in the formation of :CCl(OH)* and :C(OH)2*, which are responsible for production of CO and formate, respectively. The results obtained from this study can facilitate the modeling of systems of other halogenated species and minerals, which will provide fundamental insight into their corresponding reaction mechanisms. PMID- 25924056 TI - Interaction between colloidal particles on an oil-water interface in dilute and dense phases. AB - The interaction between micron-sized charged colloidal particles at polar/non polar liquid interfaces remains surprisingly poorly understood for a relatively simple physical chemistry system. By measuring the pair correlation function g(r) for different densities of polystyrene particles at the decane-water interface, and using a powerful predictor-corrector inversion scheme, effective pair interaction potentials can be obtained up to fairly high densities, and these reproduce the experimental g(r) in forward simulations, so are self consistent. While at low densities these potentials agree with published dipole-dipole repulsion, measured by various methods, an apparent density dependence and long range attraction are obtained when the density is higher. This condition is thus explored in an alternative fashion, measuring the local mobility of colloids when confined by their neighbors. This method of extracting interaction potentials gives results that are consistent with dipolar repulsion throughout the concentration range, with the same magnitude as in the dilute limit. We are unable to rule out the density dependence based on the experimental accuracy of our data, but we show that incomplete equilibration of the experimental system, which would be possible despite long waiting times due to the very strong repulsions, is a possible cause of artefacts in the inverted potentials. We conclude that to within the precision of these measurements, the dilute pair potential remains valid at high density in this system. PMID- 25924057 TI - Scaling behaviours in the growth of networked systems and their geometric origins. AB - Two classes of scaling behaviours, namely the super-linear scaling of links or activities, and the sub-linear scaling of area, diversity, or time elapsed with respect to size have been found to prevail in the growth of complex networked systems. Despite some pioneering modelling approaches proposed for specific systems, whether there exists some general mechanisms that account for the origins of such scaling behaviours in different contexts, especially in socioeconomic systems, remains an open question. We address this problem by introducing a geometric network model without free parameter, finding that both super-linear and sub-linear scaling behaviours can be simultaneously reproduced and that the scaling exponents are exclusively determined by the dimension of the Euclidean space in which the network is embedded. We implement some realistic extensions to the basic model to offer more accurate predictions for cities of various scaling behaviours and the Zipf distribution reported in the literature and observed in our empirical studies. All of the empirical results can be precisely recovered by our model with analytical predictions of all major properties. By virtue of these general findings concerning scaling behaviour, our models with simple mechanisms gain new insights into the evolution and development of complex networked systems. PMID- 25924058 TI - Seizure Outcome After Battery Depletion in Epileptic Patients Submitted to Deep Brain Stimulation. AB - OBJECTIVE: We studied patients treated with chronic DBS in whom there was depletion of the generator's battery, in order to get insight on the modulatory potential of chronic DBS in refractory epilepsy. MATERIAL: Nine adult patients with refractory epilepsy treated with at least three years of deep brain stimulation (DBS), and who were followed up for at least six months after battery depletion were studied. One patient was treated with hippocampal DBS (Hip-DBS), two to centro-median DBS (CM-DBS) and six to anterior nucleus stimulation (AN DBS). RESULTS: Two patients did not have seizure's frequency modification after battery depletion; the other seven patients had seizure frequency increase, including those three patients that were seizure-free. Five of those seven patients who had seizure frequency increase after battery's depletion had seizure's frequency lower than their pre-DBS baseline seizure frequency; two of such patients returned to their pre-DBS baseline seizure frequency. CONCLUSIONS: In the majority of the patients, three years of chronic DBS did not show a permanent effect on epileptogenesis. On the other hand, the post-battery depletion seizure's frequency was usually much lower than the baseline (pre-DBS) seizure's frequency, suggesting that there was actual network neuromodulation. PMID- 25924059 TI - Association between atherogenic dyslipidemia and recurrent stroke risk in patients with different subtypes of ischemic stroke. AB - BACKGROUND: The association between atherogenic dyslipidemia and stroke recurrence remains unclear, and may be influenced by different subtypes of ischemic stroke. AIMS: We aimed to investigate whether atherogenic dyslipidemia contributed to stroke recurrence in ischemic stroke patients and in those with certain subtypes of ischemic stroke. METHODS: We conducted a prospective hospital based study enrolling patients with acute ischemic stroke. Atherogenic dyslipidemia was defined as high-density lipoprotein cholesterol <40 mg/dl and triglycerides >=200 mg/dl. Ischemic stroke subtypes were classified according to the Trial of Org 10172 in Acute Stroke Treatment criteria. The patients were followed up at 3, 6, 12 and 24 months after stroke onset. The association between atherogenic dyslipidemia and stroke recurrence was analyzed by using multivariable Cox regression model. RESULTS: In the 510 ischemic stroke patients, 64 patients (12.5%) had atherogenic dyslipidemia, and 66 patients (12.9%) experienced stroke recurrence events within 24 months. Kaplan-Meier analysis revealed that stroke recurrence rate was significantly higher in patients with atherogenic dyslipidemia than those without in all the stroke patients (20.3% vs. 11.9%; P = 0.048), and more evident in those of large-artery atherosclerosis subtype (31.0% vs. 14.1%; P = 0.014), but not in the other subtypes. Multivariable Cox regression analysis revealed that atherogenic dyslipidemia was associated with higher stroke recurrence risk among stroke patients of large artery atherosclerosis subtype (hazard ratio, 2.79; 95% confidence interval, 1.24 6.28), but not significant in all the stroke patients (hazard ratio, 1.69; 95% confidence interval, 0.85-3.37). CONCLUSIONS: Atherogenic dyslipidemia is associated with higher risk of stroke recurrence in ischemic stroke patients. Such association might be more pronounced in large-artery atherosclerosis subtype and needs further investigation to establish such relationship. PMID- 25924060 TI - Janeway Lesions and Splinter Hemorrhages in a Patient With Eosinophilic Endomyocarditis. PMID- 25924061 TI - Differential Gene Expression Reveals Candidate Genes for Drought Stress Response in Abies alba (Pinaceae). AB - Increasing drought periods as a result of global climate change pose a threat to many tree species by possibly outpacing their adaptive capabilities. Revealing the genetic basis of drought stress response is therefore implemental for future conservation strategies and risk assessment. Access to informative genomic regions is however challenging, especially for conifers, partially due to their large genomes, which puts constraints on the feasibility of whole genome scans. Candidate genes offer a valuable tool to reduce the complexity of the analysis and the amount of sequencing work and costs. For this study we combined an improved drought stress phenotyping of needles via a novel terahertz water monitoring technique with Massive Analysis of cDNA Ends to identify candidate genes for drought stress response in European silver fir (Abies alba Mill.). A pooled cDNA library was constructed from the cotyledons of six drought stressed and six well-watered silver fir seedlings, respectively. Differential expression analyses of these libraries revealed 296 candidate genes for drought stress response in silver fir (247 up- and 49 down-regulated) of which a subset was validated by RT-qPCR of the twelve individual cotyledons. A majority of these genes code for currently uncharacterized proteins and hint on new genomic resources to be explored in conifers. Furthermore, we could show that some traditional reference genes from model plant species (GAPDH and eIF4A2) are not suitable for differential analysis and we propose a new reference gene, TPC1, for drought stress expression profiling in needles of conifer seedlings. PMID- 25924062 TI - Intrinsic Electron Mobility Exceeding 103 cm2/(V s) in Multilayer InSe FETs. AB - Graphene-like two-dimensional (2D) materials not only are interesting for their exotic electronic structure and fundamental electronic transport or optical properties but also hold promises for device miniaturization down to atomic thickness. As one material belonging to this category, InSe, a III-VI semiconductor, not only is a promising candidate for optoelectronic devices but also has potential for ultrathin field effect transistor (FET) with high mobility transport. In this work, various substrates such as PMMA, bare silicon oxide, passivated silicon oxide, and silicon nitride were used to fabricate multilayer InSe FET devices. Through back gating and Hall measurement in four-probe configuration, the device's field effect mobility and intrinsic Hall mobility were extracted at various temperatures to study the material's intrinsic transport behavior and the effect of dielectric substrate. The sample's field effect and Hall mobilities over the range of 20-300 K fall in the range of 0.1 2.0 * 10(3) cm(2)/(V s), which are comparable or better than the state of the art FETs made of widely studied 2D transition metal dichalcogenides. PMID- 25924064 TI - Th17 cells transdifferentiate into regulatory T cells during resolution of inflammation. AB - Inflammation is a beneficial host response to infection but can contribute to inflammatory disease if unregulated. The Th17 lineage of T helper (Th) cells can cause severe human inflammatory diseases. These cells exhibit both instability (they can cease to express their signature cytokine, IL-17A) and plasticity (they can start expressing cytokines typical of other lineages) upon in vitro re stimulation. However, technical limitations have prevented the transcriptional profiling of pre- and post-conversion Th17 cells ex vivo during immune responses. Thus, it is unknown whether Th17 cell plasticity merely reflects change in expression of a few cytokines, or if Th17 cells physiologically undergo global genetic reprogramming driving their conversion from one T helper cell type to another, a process known as transdifferentiation. Furthermore, although Th17 cell instability/plasticity has been associated with pathogenicity, it is unknown whether this could present a therapeutic opportunity, whereby formerly pathogenic Th17 cells could adopt an anti-inflammatory fate. Here we used two new fate mapping mouse models to track Th17 cells during immune responses to show that CD4(+) T cells that formerly expressed IL-17A go on to acquire an anti inflammatory phenotype. The transdifferentiation of Th17 into regulatory T cells was illustrated by a change in their signature transcriptional profile and the acquisition of potent regulatory capacity. Comparisons of the transcriptional profiles of pre- and post-conversion Th17 cells also revealed a role for canonical TGF-beta signalling and consequently for the aryl hydrocarbon receptor (AhR) in conversion. Thus, Th17 cells transdifferentiate into regulatory cells, and contribute to the resolution of inflammation. Our data suggest that Th17 cell instability and plasticity is a therapeutic opportunity for inflammatory diseases. PMID- 25924063 TI - Allogeneic IgG combined with dendritic cell stimuli induce antitumour T-cell immunity. AB - Whereas cancers grow within host tissues and evade host immunity through immune editing and immunosuppression, tumours are rarely transmissible between individuals. Much like transplanted allogeneic organs, allogeneic tumours are reliably rejected by host T cells, even when the tumour and host share the same major histocompatibility complex alleles, the most potent determinants of transplant rejection. How such tumour-eradicating immunity is initiated remains unknown, although elucidating this process could provide the basis for inducing similar responses against naturally arising tumours. Here we find that allogeneic tumour rejection is initiated in mice by naturally occurring tumour-binding IgG antibodies, which enable dendritic cells (DCs) to internalize tumour antigens and subsequently activate tumour-reactive T cells. We exploited this mechanism to treat autologous and autochthonous tumours successfully. Either systemic administration of DCs loaded with allogeneic-IgG-coated tumour cells or intratumoral injection of allogeneic IgG in combination with DC stimuli induced potent T-cell-mediated antitumour immune responses, resulting in tumour eradication in mouse models of melanoma, pancreas, lung and breast cancer. Moreover, this strategy led to eradication of distant tumours and metastases, as well as the injected primary tumours. To assess the clinical relevance of these findings, we studied antibodies and cells from patients with lung cancer. T cells from these patients responded vigorously to autologous tumour antigens after culture with allogeneic-IgG-loaded DCs, recapitulating our findings in mice. These results reveal that tumour-binding allogeneic IgG can induce powerful antitumour immunity that can be exploited for cancer immunotherapy. PMID- 25924066 TI - Cancer: Antibodies regulate antitumour immunity. PMID- 25924065 TI - Immunosuppressive plasma cells impede T-cell-dependent immunogenic chemotherapy. AB - Cancer-associated genetic alterations induce expression of tumour antigens that can activate CD8(+) cytotoxic T cells (CTLs), but the microenvironment of established tumours promotes immune tolerance through poorly understood mechanisms. Recently developed therapeutics that overcome tolerogenic mechanisms activate tumour-directed CTLs and are effective in some human cancers. Immune mechanisms also affect treatment outcome, and certain chemotherapeutic drugs stimulate cancer-specific immune responses by inducing immunogenic cell death and other effector mechanisms. Our previous studies revealed that B cells recruited by the chemokine CXCL13 into prostate cancer tumours promote the progression of castrate-resistant prostate cancer by producing lymphotoxin, which activates an IkappaB kinase alpha (IKKalpha)-BMI1 module in prostate cancer stem cells. Because castrate-resistant prostate cancer is refractory to most therapies, we examined B cell involvement in the acquisition of chemotherapy resistance. Here we focus on oxaliplatin, an immunogenic chemotherapeutic agent that is effective in aggressive prostate cancer. We show that mouse B cells modulate the response to low-dose oxaliplatin, which promotes tumour-directed CTL activation by inducing immunogenic cell death. Three different mouse prostate cancer models were refractory to oxaliplatin unless genetically or pharmacologically depleted of B cells. The crucial immunosuppressive B cells are plasmocytes that express IgA, interleukin (IL)-10 and programmed death ligand 1 (PD-L1), the appearance of which depends on TGFbeta receptor signalling. Elimination of these cells, which also infiltrate human-therapy-resistant prostate cancer, allows CTL-dependent eradication of oxaliplatin-treated tumours. PMID- 25924067 TI - Palaeontology: Dinosaur up in the air. PMID- 25924068 TI - Sequential cancer mutations in cultured human intestinal stem cells. AB - Crypt stem cells represent the cells of origin for intestinal neoplasia. Both mouse and human intestinal stem cells can be cultured in medium containing the stem-cell-niche factors WNT, R-spondin, epidermal growth factor (EGF) and noggin over long time periods as epithelial organoids that remain genetically and phenotypically stable. Here we utilize CRISPR/Cas9 technology for targeted gene modification of four of the most commonly mutated colorectal cancer genes (APC, P53 (also known as TP53), KRAS and SMAD4) in cultured human intestinal stem cells. Mutant organoids can be selected by removing individual growth factors from the culture medium. Quadruple mutants grow independently of all stem-cell niche factors and tolerate the presence of the P53 stabilizer nutlin-3. Upon xenotransplantation into mice, quadruple mutants grow as tumours with features of invasive carcinoma. Finally, combined loss of APC and P53 is sufficient for the appearance of extensive aneuploidy, a hallmark of tumour progression. PMID- 25924069 TI - A bizarre Jurassic maniraptoran theropod with preserved evidence of membranous wings. AB - The wings of birds and their closest theropod relatives share a uniform fundamental architecture, with pinnate flight feathers as the key component. Here we report a new scansoriopterygid theropod, Yi qi gen. et sp. nov., based on a new specimen from the Middle-Upper Jurassic period Tiaojishan Formation of Hebei Province, China. Yi is nested phylogenetically among winged theropods but has large stiff filamentous feathers of an unusual type on both the forelimb and hindlimb. However, the filamentous feathers of Yi resemble pinnate feathers in bearing morphologically diverse melanosomes. Most surprisingly, Yi has a long rod like bone extending from each wrist, and patches of membranous tissue preserved between the rod-like bones and the manual digits. Analogous features are unknown in any dinosaur but occur in various flying and gliding tetrapods, suggesting the intriguing possibility that Yi had membranous aerodynamic surfaces totally different from the archetypal feathered wings of birds and their closest relatives. Documentation of the unique forelimbs of Yi greatly increases the morphological disparity known to exist among dinosaurs, and highlights the extraordinary breadth and richness of the evolutionary experimentation that took place close to the origin of birds. PMID- 25924070 TI - Whole-brain functional imaging with two-photon light-sheet microscopy. PMID- 25924071 TI - MiXCR: software for comprehensive adaptive immunity profiling. PMID- 25924072 TI - PCR heads into the field. AB - Analyzing samples with PCR is routine in the lab. New approaches let researchers do this assay wherever they need. PMID- 25924073 TI - Non-invasive nuclear imaging for localization of viral reservoirs. PMID- 25924074 TI - Case studies of conservation plans that incorporate geodiversity. AB - Geodiversity has been used as a surrogate for biodiversity when species locations are unknown, and this utility can be extended to situations where species locations are in flux. Recently, scientists have designed conservation networks that aim to explicitly represent the range of geophysical environments, identifying a network of physical stages that could sustain biodiversity while allowing for change in species composition in response to climate change. Because there is no standard approach to designing such networks, we compiled 8 case studies illustrating a variety of ways scientists have approached the challenge. These studies show how geodiversity has been partitioned and used to develop site portfolios and connectivity designs; how geodiversity-based portfolios compare with those derived from species and communities; and how the selection and combination of variables influences the results. Collectively, they suggest 4 key steps when using geodiversity to augment traditional biodiversity-based conservation planning: create land units from species-relevant variables combined in an ecologically meaningful way; represent land units in a logical spatial configuration and integrate with species locations when possible; apply selection criteria to individual sites to ensure they are appropriate for conservation; and develop connectivity among sites to maintain movements and processes. With these considerations, conservationists can design more effective site portfolios to ensure the lasting conservation of biodiversity under a changing climate. PMID- 25924076 TI - Depression Literacy Among American Indian Older Adults. AB - Older American Indians experience high rates of depression and other psychological disorders, yet little research exist on the depression literacy of this group. Depression literacy is fundamental for individuals seeking help for depression in a timely and appropriate manner. In the present study the authors examine levels and predictors of knowledge of depression symptoms in a sample of rural older American Indians (N = 227) living in the Midwestern United States. Data from self-administered questionnaires indicate limited knowledge of depression and negative attitudes toward seeking help for mental health problems. Additional findings and implications for social work practice and policy are discussed. PMID- 25924077 TI - Supercooling and freezing processes in nanoconfined water by time-resolved optical Kerr effect spectroscopy. AB - Using heterodyne-detected optical Kerr effect (HD-OKE) measurements, we investigate the vibrational dynamics and the structural relaxation of water nanoconfined in Vycor porous silica samples (pore size ? 4 nm) at different levels of hydration and temperatures. At low levels of hydration corresponding to two complete superficial water layers, no freezing occurs and the water remains mobile at all the investigated temperatures with dynamic features similar, but not equal to, the bulk water. The fully hydrated sample shows the formation of ice at about 248 K. This process does not involve all the contained water; a part of it remains in a supercooled phase. The structural relaxation times measured from the decay of the time-dependent HD-OKE signal shows the temperature dependence largely affected by the hydration level; the low frequency (nu < 500 cm(-1)) vibrational spectra obtained by the Fourier transforms of the HD-OKE signal appear less affected by confinement. PMID- 25924079 TI - Automated Extraction of VTE Events From Narrative Radiology Reports in Electronic Health Records: A Validation Study. AB - BACKGROUND: Surveillance of venous thromboembolisms (VTEs) is necessary for improving patient safety in acute care hospitals, but current detection methods are inaccurate and inefficient. With the growing availability of clinical narratives in an electronic format, automated surveillance using natural language processing (NLP) techniques may represent a better method. OBJECTIVE: We assessed the accuracy of using symbolic NLP for identifying the 2 clinical manifestations of VTE, deep vein thrombosis (DVT) and pulmonary embolism (PE), from narrative radiology reports. METHODS: A random sample of 4000 narrative reports was selected among imaging studies that could diagnose DVT or PE, and that were performed between 2008 and 2012 in a university health network of 5 adult-care hospitals in Montreal (Canada). The reports were coded by clinical experts to identify positive and negative cases of DVT and PE, which served as the reference standard. Using data from the largest hospital (n=2788), 2 symbolic NLP classifiers were trained; one for DVT, the other for PE. The accuracy of these classifiers was tested on data from the other 4 hospitals (n=1212). RESULTS: On manual review, 663 DVT-positive and 272 PE-positive reports were identified. In the testing dataset, the DVT classifier achieved 94% sensitivity (95% CI, 88% 97%), 96% specificity (95% CI, 94%-97%), and 73% positive predictive value (95% CI, 65%-80%), whereas the PE classifier achieved 94% sensitivity (95% CI, 89% 97%), 96% specificity (95% CI, 95%-97%), and 80% positive predictive value (95% CI, 73%-85%). CONCLUSIONS: Symbolic NLP can accurately identify VTEs from narrative radiology reports. This method could facilitate VTE surveillance and the evaluation of preventive measures. PMID- 25924080 TI - Methanogenic archaea in marcellus shale: a possible mechanism for enhanced gas recovery in unconventional shale resources. AB - Marcellus Shale occurs at depths of 1.5-2.5 km (5000 to 8000 feet) where most geologists generally assume that thermogenic processes are the only source of natural gas. However, methanogens in produced fluids and isotopic signatures of biogenic methane in this deep shale have recently been discovered. This study explores whether those methanogens are indigenous to the shale or are introduced during drilling and hydraulic fracturing. DNA was extracted from Marcellus Shale core samples, preinjected fluids, and produced fluids and was analyzed using Miseq sequencing of 16s rRNA genes. Methanogens present in shale cores were similar to methanogens in produced fluids. No methanogens were detected in injected fluids, suggesting that this is an unlikely source and that they may be native to the shale itself. Bench-top methane production tests of shale core and produced fluids suggest that these organisms are alive and active under simulated reservoir conditions. Growth conditions designed to simulate the hydrofracture processes indicated somewhat increased methane production; however, fluids alone produced relatively little methane. Together, these results suggest that some biogenic methane may be produced in these wells and that hydrofracture fluids currently used to stimulate gas recovery could stimulate methanogens and their rate of producing methane. PMID- 25924078 TI - Prognostic role of cardiac power index in ambulatory patients with advanced heart failure. AB - BACKGROUND: Cardiac pump function is often quantified by left ventricular ejection fraction by various imaging modalities. As the heart is commonly conceptualized as a hydraulic pump, cardiac power describes the hydraulic function of the heart. We aim to describe the prognostic value of resting cardiac power index (CPI) in ambulatory patients with advanced heart failure. METHODS AND RESULTS: We calculated CPI in 495 sequential ambulatory patients with advanced heart failure who underwent invasive haemodynamic assessment with longitudinal follow-up of adverse outcomes (all-cause mortality, cardiac transplantation, or ventricular assist device placement). The median CPI was 0.44 W/m(2) (interquartile range 0.37, 0.52). Over a median of 3.3 years, there were 117 deaths, 104 transplants, and 20 ventricular assist device placements in our cohort. Diminished CPI (<0.44 W/m(2) ) was associated with increased adverse outcomes [hazard ratio (HR) 2.4, 95% confidence interval (CI) 1.8-3.1, P < 0.0001). The prognostic value of CPI remained significant after adjustment for age, gender, pulmonary capillary wedge pressure, cardiac index, pulmonary vascular resistance, left ventricular ejection fraction, and creatinine [HR 1.5, 95% CI 1.03-2.3, P = 0.04). Furthermore, CPI can risk stratify independently of peak oxygen consumption (HR 2.2, 95% CI 1.4-3.4, P = 0.0003). CONCLUSION: Resting cardiac power index provides independent and incremental prediction in adverse outcomes beyond traditional haemodynamic and cardio-renal risk factors. PMID- 25924081 TI - Genome wide gene expression analyses of Arabidopsis shoot stem cell niche cell populations. AB - The shoot apical meristem (SAM) of higher plants harbors stem cells at their tips. In the SAM, stem cell niches maintain the pluripotent nature of these cell types in the central zone (CZ) and allow them to enter in to differentiation pathways either in the peripheral zone (PZ) or rib meristem (RM). Apart from functional zones, SAM is also subdivided in to distinct cell layers termed as; L1 / epidermal, L2 / subepidermal and L3 / corpus cell layer. Thus, SAM is a complex structure made up of multiple cell types having discrete cell identities. In a recent study, we employed the fluorescent activated cell sorting approach to isolate the cell population of functional zones and cell layers and identified the cell population expressed genes (CPEGs). The Gene Ontology (GO) analysis revealed cellular functions of the identified CPEGs. The cell layers of the SAM are involved in pathogen defense, cell differentiation and photosynthesis. We found many genes in SAM CEPGs that responded to hormone treatment. These observations in the future will help researchers working in the area of shoot apex biology to elucidate the gene regulatory network involved in cell and tissue specialization. PMID- 25924082 TI - Spirituality Moderates Hopelessness, and Suicidal Ideation among Iranian Depressed Adolescents. AB - To examine the moderating role of spirituality between hopelessness, spirituality, and suicidal ideation, 202 Iranian depressed adolescent inpatients completed measures of patient health, suicidal ideation, hopelessness, and core spiritual experience. Structural equation modelling indicated that depressed inpatients high in hopelessness, but also high in spirituality, had less suicidal ideation than others. These findings reinforce the importance of spirituality as a protective factor against hopelessness and suicidal ideation. PMID- 25924083 TI - Photomechanically Controlled Encapsulation and Release from pH-Responsive and Photoresponsive Microcapsules. AB - Poly(acrylic acid)/azobenzene microcapsules were obtained through distillation precipitation polymerization and the selective removal of silica templates by hydrofluoric acid etching. The uniform, robust, and monodisperse microcapsules, confirmed by transmission electron microscopy and scanning electron microscopy, had reversible photoisomerization under ultraviolet (UV) and visible light. Under UV irradiation, azobenzene cross-linking sites in the main chain transformed from the trans to cis isomer, which induced the shrinkage of microcapsules. These photomechanical effects of azobenzene moieties were applied to the encapsulation and release of model molecules. After loading with rhodamine B (RhB), the release behaviors were completely distinct. Under steady UV irradiation, the shrinkage adjusted the permeability of the capsule, providing a novel way to encapsulate RhB molecules. Under alternate UV/visible light irradiation, a maximal release amount was reached due to the continual movement of shell networks by cyclic trans-cis photoisomerization. Also, microcapsules had absolute pH responsiveness. The diffusion rate and the final release percentage of RhB both increased with pH. The release behaviors under different irradiation modes and pH values were in excellent agreement with the Baker-Lonsdale model, indicating a diffusion controlled release behavior. Important applications are expected in the development of photocontrolled encapsulation and release systems as well as in pH sensitive materials and membranes. PMID- 25924084 TI - [The human being: light and shade]. PMID- 25924085 TI - New title: Trends in Psychiatry and Psychotherapy. PMID- 25924086 TI - [Brazilian norms for the Affective Norms for English Words]. AB - INTRODUCTION: The present study translated and adapted the Affective Norms for English Words (ANEW) to Brazilian Portuguese (ANEW-Br) and collected emotionality measures for a set of 1,046 words in Brazilian Portuguese. METHOD: A sample of 755 male and female undergraduate students used the valence and arousal scales of the Self-Assessment Manikin to judge the emotionality of 1,046 words in Brazilian Portuguese. RESULTS: Valence values ranged from 1.16 to 8.80, while arousal values ranged from 2.22 to 7.67. Further analyses indicated that both valence and arousal measures were reliable and suggested that the method used was appropriate for the collection of emotionality measures. CONCLUSION: The availability of Brazilian norms for the ANEW represents a methodological advancement for Brazilian investigators in the development of future studies about the effects of emotion on human cognition. PMID- 25924087 TI - [Interpersonal Measure of Psychopathy (IM-P): preliminary study in the Brazilian context]. AB - INTRODUCTION: The direct observation of interpersonal behaviors is an important resource in the description and diagnosis of the psychopathic personality. The Interpersonal Measure of Psychopathy (IM-P) is a psychometric instrument comprised of 21 items, designed to be applied in association with other instruments that also evaluate psychopaths. It focuses specifically on interpersonal and non-verbal behaviors that become evident during the interaction between the interviewer and individuals with psychopathic characteristics. OBJECTIVE: To describe preliminary results obtained in the assessment of interpersonal behaviors of psychopathic individuals using the IM-P, including instrument translation/adaptation and inter-rater reliability results, in a sample of Brazilian adolescents. METHOD: This was a cross-sectional, descriptive, correlation study conducted with a sample of 20 institutionalized male adolescents from the metropolitan area of Porto Alegre, state of Rio Grande do Sul, southern Brazil. Following instrument translation, interviewer training, and a pilot study conducted using a semi-structured interview, the IM-P was scored by three independent raters. RESULTS: The statistical results obtained using Kendall's coefficient of concordance revealed a high and satisfactory inter-rater agreement for IM-P total scores (W = 0.84; p < 0.001). Some items showed conflicting results and were therefore discussed and evaluated separately. CONCLUSION: The psychometric properties of the Brazilian Portuguese version of the IM-P, as assessed in this preliminary study, showed consistent inter-rater concordance, suggesting instrument reliability. Some study limitations are discussed, as are some relevant aspects that should be taken into consideration in future research involving the IM-P. PMID- 25924088 TI - [Translation and cross-cultural adaptation of the Recent-Onset Arthritis Disability (ROAD) index into Brazilian Portuguese]. AB - INTRODUCTION: The increasing search for the psychological treatment of patients with chronic diseases and with clinical indications for the control of physical and psychological capacities has revealed a need for instruments aimed at assessing these patients. Rheumatoid arthritis is a condition that has been widely studied with a focus on the development of new drugs and treatment approaches. However, psychometric instruments developed for this specific population are still rare. OBJECTIVE: To describe the translation and cross cultural adaptation into Brazilian Portuguese of the Recent-Onset Arthritis Disability (ROAD) index. METHODS: The process involved two translations and back translations performed by four independent translators, the assessment of all versions obtained, followed by the development of a synthetic version by specialists in the field. The process was completed with an experimental application of the instrument. RESULTS: All stages of the translation/adaptation process are described. No comprehension difficulties were reported by the participants, who had different education levels, ranging from elementary school to university level. CONCLUSION: At the end of the study, the final version of the ROAD index in Brazilian Portuguese is presented. The adapted instrument was considered adequate and equivalent in meaning to the original instrument. PMID- 25924089 TI - [Violence against women among urban area residents in Feira de Santana, Bahia, Brazil]. AB - OBJECTIVE: To analyze the occurrence of physical and/or psychological violence according to sociodemographic variables, lifestyle habits, and medical conditions in a Brazilian urban population. METHODS: This epidemiological, cross-sectional study was conducted with a representative sample of the urban population of Feira de Santana, state of Bahia, Brazil, aged > 15 years. We used a semistructured questionnaire to collect data on sociodemographic variables, lifestyle habits, medical conditions, and acts of victimization. RESULTS: Among the respondents, women presented an increased incidence of physical and/or psychological violence when compared with men. Violence against women showed to be related with the presence of comorbidities that adversely affect women's health. CONCLUSIONS: Health and safety policies in the municipality assessed should include actions aimed at preventing violence against women, in view of the high incidence of the problem and its strong impact on population health. PMID- 25924090 TI - [Temperament traits associated with bipolar affective disorder: an integrative literature review]. AB - Studies have suggested an association between temperament characteristics and adjustment and psychiatric disorders, describing them as different manifestations of vulnerability to psychopathology. The objective of this study was to conduct an integrative review of the literature on temperament traits typical of bipolar patients in relation to the general population. A systematic search was conducted on the MEDLINE, PsycINFO and LILACS databases, using the headings bipolar disorder, temperament and/or personality, between January 2000 and December 2010. The search was performed in January 2011. A total of 199 articles were identified for potential inclusion in the review. After application of the exclusion criteria, a total of 15 articles were selected and their full texts analyzed. Review of the selected studies revealed heterogeneity in terms of sample profile and specific temperament traits assessed with the appropriate instruments. Temperament traits in bipolar patients are identified based on different theoretical models. The results of five studies consistently showed that neuroticism is a distinct personality trait in the temperament profile of bipolar patients. Future reviews should use more specific keywords and limit the search to studies with a longitudinal design. PMID- 25924091 TI - [Cue exposure treatment and coping skills training as adjuvant therapies in the management of craving in a crack cocaine addict]. AB - OBJECTIVE: An increased prevalence of crack cocaine users has been observed in clinical samples over the past years, underscoring the need for conducting research and developing treatment strategies aimed at this population. The objective of this study was to describe the case of a crack cocaine addict (inpatient) submitted to cue exposure treatment (CET) and coping skills training (CS) as adjuvant approaches to the conventional addiction treatment. CASE DESCRIPTION: A male patient, 29 years old, single, with complete high school, was dependent on crack cocaine and marijuana and also had a diagnosis of harmful alcohol use. The patient had been hospitalized for 2 weeks and had undertaken a protocol comprising four motivational interview and relapse prevention sessions. Six sessions of CET and CS were carried out over 2 weeks, including both in vivo and imaginal exposure to stimuli evoking craving for crack cocaine, such as a crack pipe, a lighter, and simulated crack cocaine rocks (in vivo exposure), or remembering places and friends associated with drug use (imaginal exposure). The patient was also trained to use strategies for the management of craving. Three months after hospital discharge, toxicological screening was performed to assess abstinence. CET and CS were considered by the patient to be important techniques for the maintenance of abstinence and of a low level of craving 3 months after discharge. COMMENTS: These findings suggest that the two techniques may be useful as adjuvant therapies in the treatment of crack cocaine dependents. CET and CS should be assessed in clinical trials in order to demonstrate their real benefits. PMID- 25924092 TI - [Cinema e loucura: conhecendo os transtornos mentais atraves dos filmes]. PMID- 25924093 TI - A system level analysis of gastric cancer across tumor stages with RNA-seq data. AB - Gastric cancer is the third leading cause of cancer-related death in the world. Over the past few decades, with the development of high-throughput technologies and the application of various statistical tools, cancer research has witnessed remarkable advancements. However, no system level analysis has taken into account the cancer stages, which are known to be extremely important in prognosis and therapy. In this study, we aimed to carry out a system level analysis of the dynamics of the network structure across the normal phenotype and the four tumor stage phenotypes. We analyzed 276 samples of primary tumor tissues including normal and four tumor stage phenotypes to reveal the dynamics of the five phenotype-specific co-expression networks. Our analysis reveals that the structure of the normal network is dramatically different from that of a tumor network. The analysis of connectivity dynamics shows that hub genes present in the normal network but not in the tumor networks play important roles in tumorigenesis and hub genes unique to a tumor network are enriched in specific biological terms. Moreover, we found three interesting clusters of genes which possess specific dynamic features across the five phenotypes and are enriched in stage-specific biological terms. Integrating the results from the expression analysis and the connectivity analysis shows that the stages of tumor should be taken into consideration and a system level analysis serves as a complement to and a refinement of the traditional expression analysis. PMID- 25924094 TI - The Effectiveness of Noninvasive Interventions for Temporomandibular Disorders: A Systematic Review by the Ontario Protocol for Traffic Injury Management (OPTIMa) Collaboration. AB - OBJECTIVE: To determine the effectiveness and cost-effectiveness of noninvasive interventions for temporomandibular disorders (TMD). METHODS: We systematically searched MEDLINE, EMBASE, CINAHL, PsycINFO, and Cochrane Central register from 1990 to 2014 for effectiveness studies and the Cochrane Health Technology Assessment Database, EconLit, NHS Economic Evaluation Database, and Tufts Medical Center Cost-Effectiveness Analysis Register from 1990 to 2014 for cost effectiveness studies. Random pairs of independent reviewers critically appraised eligible studies using the Scottish Intercollegiate Guidelines Network criteria. Evidence from eligible studies was synthesized using best-evidence synthesis methodology. RESULTS: Our search for effectiveness studies yielded 16,995 citations; 31 were relevant and 7 randomized controlled trials (published in 8 articles) had a low risk of bias. We found no relevant cost-effectiveness studies. The evidence suggests that for persistent TMD: (1) cognitive-behavioral therapy and self-care management lead to similar improvements in pain and disability but cognitive-behavioral therapy is more effective for activity interference and depressive symptoms; (2) cognitive-behavioral therapy combined with usual treatment provides short-term benefits in pain and ability to control pain compared with usual treatment alone; (3) intraoral myofascial therapy may reduce pain and improve jaw opening; and (4) structured self-care management may be more effective than usual treatment. The evidence suggests that occlusal devices may not be effective in reducing pain and improving motion for TMD of variable duration. Evidence on the effectiveness of biofeedback is inconclusive. DISCUSSION: The available evidence suggests that cognitive-behavioral therapy, intraoral myofascial therapy, and self-care management are therapeutic options for persistent TMD. PMID- 25924095 TI - Chronic Pain and Heart Rate Variability in a Cross-Sectional Occupational Sample: Evidence for Impaired Vagal Control. AB - OBJECTIVES: The vagus nerve influences the modulation of pain. Chronic pain is associated with disturbance of the descendent inhibitory pathway (DIP). Heart rate variability (HRV) is a proxy measure for vagal activity and may reflect dysfunction of the DIP. We aimed to investigate the association of HRV and pain in individuals with and without chronic pain. MATERIALS AND METHODS: Drawing on cross-sectional data from 647 individuals, the present study explores the association of HRV and pain. The root mean square of successive differences (RMSSD), corresponding to parasympathetic regulation of the heart, was derived from 24-hour electrocardiogram recordings. Pain, demographic data, and health behaviors were assessed by self-administered questionnaires. Blood pressure was measured and inflammatory markers (white blood cell count, C-reactive protein, and fibrinogen) were analyzed from fasting blood samples. RESULTS: Those with chronic pain reported lower RMSSD. Results revealed a negative correlation of HRV and pain in multivariate-adjusted analysis only in respondents without chronic pain. DISCUSSION: Our results suggest that the DIP indexed by vagal activity operationalized as RMSSD is disturbed in persons with chronic pain. Furthermore, the correlations between RMSSD and pain are different between those without and those with chronic pain. The findings are discussed, emphasizing changes in brain activity and the comorbid dysregulation of emotion in patients with chronic pain, to provide implications for the treatment of chronic pain. PMID- 25924096 TI - Accuracy of Self-reported Prescribed Analgesic Medication Use: Linkage Between the Quebec Pain Registry and the Quebec Administrative Prescription Claims Databases. AB - OBJECTIVES: The validity of studies conducted with patient registries depends on the accuracy of the self-reported clinical data. As of now, studies about the validity of self-reported use of analgesics among chronic pain (CP) populations are scarce. The objective of this study was to assess the accuracy of self reported prescribed analgesic medication use. This was attained by comparing the data collected in the Quebec Pain Registry (QPR) database to those contained in the Quebec administrative prescription claims database (Regie de l'assurance maladie du Quebec [RAMQ]). METHODS: To achieve the linkage between the QPR and the RAMQ databases, the first 1285 patients who were consecutively enrolled in the QPR between October 31, 2008 and January 27, 2010 were contacted by mail and invited to participate in a study in which they had to provide their unique RAMQ health insurance number. Using RAMQ prescription claims as the reference standard, kappa coefficients, sensitivity, specificity, and their respective 95% confidence intervals were calculated for each therapeutic class of prescribed analgesic drugs that the participants reported taking currently and in the past 12 months. RESULTS: A total of 569 QPR patients responded to the postal mailing, provided their unique health insurance number, and gave informed consent for the linkage (response proportion=44%). Complete RAMQ prescription claims over the 12 months before patient enrollment into the QPR were available for 272 patients, who constituted our validated study population. Regarding current self-reported prescribed analgesic use, kappa coefficients measuring agreement between the 2 sources of information ranged from 0.66 to 0.78 for COX-2-selective nonsteroidal anti-inflammatory drugs, anticonvulsants, antidepressants, skeletal muscle relaxants, synthetic cannabinoids, opiate agonists/partial agonists/antagonists, and antimigraine agents therapeutic classes. For the past 12-month self-reported prescribed analgesic use, QPR patients were less accurate regarding anticonvulsants (kappa=0.59), opiate agonists/partial agonists/antagonists (kappa=0.57), and antimigraine agents use (kappa=0.39). DISCUSSION: Information about current prescribed analgesic medication use as reported by CP patients was accurate for the main therapeutic drug classes used in CP management. Accuracy of the past year self-reported prescribed analgesic use was somewhat lower but only for certain classes of medication, the concordance being good on all the others. PMID- 25924097 TI - Triggering Descending Pain Inhibition by Observing Ourselves or a Loved-One in Pain. AB - OBJECTIVES: Recent studies demonstrate that empathy-evoked brain responses include the activation of brainstem structures responsible for triggering descending pain inhibition. Unfortunately, direct evidence linking empathy for pain and descending inhibitory controls (conditioned pain modulation) is lacking. This study, therefore, aimed to determine if the observation of ourselves or a loved-one in pain could activate descending pain inhibition without exposure to a noxious stimulation; which is otherwise required. METHODS: Descending pain inhibition was triggered by immersing the right arm of participants (15 heterosexual couples; mean age+/-SE: 28.89+/-2.14) in a bath of cold water. The effects of empathy on descending pain inhibition were observed by immersing the right arm of participants in a bath of lukewarm water while having them watch a video of either themselves or their spouse during a previous nociceptive immersion. Immersion of the arm in a bath of lukewarm water without empathic (video) observation was also included as a control condition. RESULTS: A strong inhibitory response activated by the mere observation of the video of themselves or their spouse in pain without a nociceptive conditioning stimulus. Associative statistics also showed that strong pain catastrophizing responses while watching the video resulted in stronger pain inhibition. Moreover, high levels of empathy were associated with stronger pain inhibition, but only for women. DISCUSSION: This study showed that observing someone in pain triggers descending pain inhibition. Results also demonstrate how empathy and gender are affecting pain modulation mechanisms. PMID- 25924098 TI - Influence of Therapeutic Approach in the TENS-induced Hypoalgesia. AB - INTRODUCTION: The present study aimed to determine how the therapist's approach about intervention may influence transcutaneous electrical nerve stimulation (TENS)-induced hypoalgesia. METHODS: One hundred and sixty-one pain-free individuals agreed to participate in this study and had their demographics, perceived pain intensity, pressure pain threshold, anxiety level, and the state of anxiety inventory score measured. Subsequently, participants were randomly assigned into 6 study groups, 3 active and 3 placebo TENS associated with positive, negative, or neutral approaches about electrical stimulation, as given by the investigator. After the treatment, all parameters were reassessed. RESULTS: Active TENS-treated participants receiving either positive or neutral expectations about intervention showed a significant increase in pressure pain threshold (P<0.02) compared with pretreatment; however, this was not observed in the active TENS group when associated with negative expectations. The intensity of perceived pain was significantly reduced (P<0.02) only in the active TENS groups in association with either positive or neutral expectations. There was no significant difference in any of the variables assessed in the groups receiving placebo TENS intervention. DISCUSSION: The negative expectations induced prior to the proposed intervention promoted unfavorable outcomes with respect to the analgesic properties of TENS, suggesting that the approach taken by the physical therapist should be used to convey positive expectations and avoid those negatives, to promote more efficacious treatment. PMID- 25924099 TI - Light-triggered, self-immolative nucleic Acid-drug nanostructures. AB - The simultaneous intracellular delivery of multiple types of payloads, such as hydrophobic drugs and nucleic acids, typically requires complex carrier systems. Herein, we demonstrate a self-deliverable form of nucleic acid-drug nanostructure that is composed almost entirely of payload molecules. Upon light activation, the nanostructure sheds the nucleic acid shell, while the core, which consists of prodrug molecules, disintegrates via an irreversible self-immolative process, releasing free drug molecules and small molecule fragments. We demonstrate that the nanostructures exhibit enhanced stability against DNase I compared with free DNA, and that the model drug (camptothecin) released exhibits similar efficacy as free, unmodified drugs toward cancer cells. PMID- 25924100 TI - Kidney Stone Models for In Vitro Lithotripsy Research: A Comprehensive Review. PMID- 25924101 TI - Next generation sequencing of acute myeloid leukemia: influencing prognosis. AB - Acute myeloid leukemia (AML) is a clonal disorder of the blood forming cells characterized by accumulation of immature blast cells in the bone marrow and peripheral blood. Being a heterogeneous disease, AML has been the subject of numerous studies that focus on unraveling the clinical, cellular and molecular variations with the aim to better understand and treat the disease. Cytogenetic risk stratification of AML is well established and commonly used by clinicians in therapeutic management of cases with chromosomal abnormalities. Successive inclusion of novel molecular abnormalities has substantially modified the classification and understanding of AML in the past decade. With the advent of next generation sequencing (NGS) technologies the discovery of novel molecular abnormalities has accelerated. NGS has been successfully used in several studies and has provided an unprecedented overview of molecular aberrations as well as the underlying clonal evolution in AML. The extended spectrum of abnormalities discovered by NGS is currently under extensive validation for their prognostic and therapeutic values. In this review we highlight the recent advances in the understanding of AML in the NGS era. PMID- 25924102 TI - Analysis of the interrelationship of the pulmonary irritation and elicitation thresholds in rats sensitized with 1,6-hexamethylene diisocyanate (HDI). AB - This paper summarizes a range of experimental data central for developing a science-based approach for hazard identification of monomeric and polymeric aliphatic 1,6-hexamethylene diisocyanate (HDI). The dose-response curve of HDI induced pulmonary responses in naive or dermally sensitized rats after one or several inhalation priming exposures was examined in the Brown Norway (BN) rat asthma model. Emphasis was directed to demonstrate the need and the difficulty in selecting an appropriate pulmonary dose when much of the inhaled chemically reactive vapor may concentration dependently be retained in the upper airways of obligate nose-breathing rats. The course taken acknowledges the experimental challenges in identifying an elicitation threshold for HDI-monomer near or above the saturated vapor concentration or in the presence of a HDI-polymer aerosol. The inhalation threshold dose on elicitation was determined based on a fixed concentration (C) * variable exposure duration (t) protocol for improving inhalation dosimetry of the lower airways. Neutrophilic granulocytes (PMN) in bronchoalveolar lavage (BAL) fluid in equally inhalation primed naive and dermally sensitized rats were used to define the inhalation elicitation threshold C * t. Sensitized rats elaborated markedly increased PMN challenged sensitized rats relative to equally challenged naive rats at 5625 mg HDI/m(3) * min (75 mg/m(3) for 75 min). PMN were essentially indistinguishable at 900 mg HDI/m(3) * min. By applying adjustment factors accounting for both inter-species differences in inhalation dosimetry and intra-species susceptibility, the workplace human equivalent threshold C * t was estimated to be in the range of the current ACGIH TLV(r) of HDI. Thus, this rat "asthma" model was suitable to demonstrate elicitation thresholds for HDI-vapor after one or several inhalation priming exposures and seems to be suitable to derive occupational exposure values (OELs) for diisocyanates in general. PMID- 25924104 TI - Hippocampal Gene Expression Is Highly Responsive to Estradiol Replacement in Middle-Aged Female Rats. AB - In the hippocampus, estrogens are powerful modulators of neurotransmission, synaptic plasticity and neurogenesis. In women, menopause is associated with increased risk of memory disturbances, which can be attenuated by timely estrogen therapy. In animal models of menopause, 17beta-estradiol (E2) replacement improves hippocampus-dependent spatial memory. Here, we explored the effect of E2 replacement on hippocampal gene expression in a rat menopause model. Middle-aged ovariectomized female rats were treated continuously for 29 days with E2, and then, the hippocampal transcriptome was investigated with Affymetrix expression arrays. Microarray data were analyzed by Bioconductor packages and web-based softwares, and verified with quantitative PCR. At standard fold change selection criterion, 156 genes responded to E2. All alterations but 4 were transcriptional activation. Robust activation (fold change > 10) occurred in the case of transthyretin, klotho, claudin 2, prolactin receptor, ectodin, coagulation factor V, Igf2, Igfbp2, and sodium/sulfate symporter. Classification of the 156 genes revealed major groups, including signaling (35 genes), metabolism (31 genes), extracellular matrix (17 genes), and transcription (16 genes). We selected 33 genes for further studies, and all changes were confirmed by real-time PCR. The results suggest that E2 promotes retinoid, growth factor, homeoprotein, neurohormone, and neurotransmitter signaling, changes metabolism, extracellular matrix composition, and transcription, and induces protective mechanisms via genomic effects. We propose that these mechanisms contribute to effects of E2 on neurogenesis, neural plasticity, and memory functions. Our findings provide further support for the rationale to develop safe estrogen receptor ligands for the maintenance of cognitive performance in postmenopausal women. PMID- 25924105 TI - Refractory Dyslipidemia After Liver Transplant: Case Study With Successive Histologic Investigations. AB - Hyperlipidemia is not unusual in liver transplant recipients, but refractory severe hyperlipidemia is unusual. We treated a 39-year-old man who had severe dyslipidemia after liver transplant. The levels of blood lipids, liver enzymes, and essential indicators of liver pathology were monitored. The first serum sample was collected from the liver recipient 56 days after transplant surgery because samples could not be obtained sooner after the transplant. The levels of liver enzymes and blood lipids were improved with symptomatic treatment but had recurrent fluctuations. Tacrolimus and cyclosporine, even at low doses, may have been the dominant factor affecting the blood lipid levels in the recipient. PMID- 25924106 TI - Sr7.3Ca2.7(PO4)6F2:Eu(2+),Mn(2+): a novel single-phased white light-emitting phosphor for NUV-LEDs. AB - In this study, a series of novel single-phased white light-emitting phosphors, Sr(7.3-x/2-y/2)Ca(2.7-x/2-y/2)(PO4)6F2:xEu(2+),yMn(2+) (0 <= x <= 0.06, 0 <= y <= 0.9) (SCPF:xEu(2+),yMn(2+)), have been successfully prepared through a high temperature solid-state reaction. The crystal structure and photoluminescence have been measured and analyzed. The energy transfer mechanism is demonstrated to be a quadrupole-quadrupole interaction and the critical distance between the Eu(2+) and Mn(2+) has been calculated. Meanwhile, the efficiency eta of the energy transfer from Eu(2+) to Mn(2+) can reach 76%. The excitation spectra monitored at 457 nm ranges from 290 nm to 400 nm. Under excitation at 365 nm, the emission spectra include two broad bands peaked at 458 nm and 570 nm. By changing the ratio of Eu(2+)/Mn(2+), the emission color can change from blue to white. Furthermore, our results give the Commission International de L'Eclairage (CIE) chromaticity coordinates for the white LED as (0.334, 0.307) and a correlated color temperature of 3982 K, which indicates that the SCPF:Eu(2+),Mn(2+) phosphor is a very promising candidate for use as a near ultraviolet (NUV) white light emitting diode (WLED) phosphor. PMID- 25924103 TI - Central Fibroblast Growth Factor 21 Browns White Fat via Sympathetic Action in Male Mice. AB - Fibroblast growth factor 21 (FGF21) has multiple metabolic actions, including the induction of browning in white adipose tissue. Although FGF21 stimulated browning results from a direct interaction between FGF21 and the adipocyte, browning is typically associated with activation of the sympathetic nervous system through cold exposure. We tested the hypothesis that FGF21 can act via the brain, to increase sympathetic activity and induce browning, independent of cell-autonomous actions. We administered FGF21 into the central nervous system via lateral ventricle infusion into male mice and found that the central treatment increased norepinephrine turnover in target tissues that include the inguinal white adipose tissue and brown adipose tissue. Central FGF21 stimulated browning as assessed by histology, expression of uncoupling protein 1, and the induction of gene expression associated with browning. These effects were markedly attenuated when mice were treated with a beta-blocker. Additionally, neither centrally nor peripherally administered FGF21 initiated browning in mice lacking beta adrenoceptors, demonstrating that an intact adrenergic system is necessary for FGF21 action. These data indicate that FGF21 can signal in the brain to activate the sympathetic nervous system and induce adipose tissue thermogenesis. PMID- 25924107 TI - Closed loop tracked Doppler optical coherence tomography based heart monitor for the Drosophila melanogaster larvae. AB - This paper presents a novel instrument for biosciences, useful for studies of moving embryos. A dual sequential imaging/measurement channel is assembled via a closed-loop tracking architecture. The dual channel system can operate in two regimes: (i) single-point Doppler signal monitoring or (ii) fast 3-D swept source OCT imaging. The system is demonstrated for characterizing cardiac dynamics in Drosophila melanogaster larva. Closed loop tracking enables long term in vivo monitoring of the larvae heart without anesthetic or physical restraint. Such an instrument can be used to measure subtle variations in the cardiac behavior otherwise obscured by the larvae movements. A fruit fly larva (top) was continuously tracked for continuous remote monitoring. A heartbeat trace of freely moving larva (bottom) was obtained by a low coherence interferometry based doppler sensing technique. PMID- 25924108 TI - Avian Paramyxovirus: A Brief Review. AB - Avian paramyxoviruses (APMVs) have been reported from a wide variety of avian species around the world. Avian paramyxoviruses are economically significant because of the huge mortality and morbidity associated with it. Twelve different serotypes of APMV have been reported till date. Avian paramyxoviruses belong to the family Paramyxoviridae under genus Avulavirus. Newcastle disease virus (APMV 1) is the most characterized members among the APMV serotypes. Complete genome sequence of all twelve APMV serotypes has been published recently. In recent years, APMV-1 has attracted the virologists for its oncolytic activity and its use as a vaccine vector for both animals and humans. The recombinant APMV-based vaccine offers a pertinent choice for the construction of live attenuated vaccine due to its minimum recombination frequency, modular nature of transcription and lack of DNA phase during its replication. Although insufficient data are available regarding other APMV serotypes, our understanding about the APMV biology is expanding rapidly because of the availability of modern molecular biology tools and high-throughput complete genome sequencing. PMID- 25924109 TI - Recent national trends in acute myocardial infarction hospitalizations in Medicare: shrinking declines and growing disparities. PMID- 25924110 TI - Mental Health Impact of the Deepwater Horizon Oil Spill Among Wives of Clean-up Workers. PMID- 25924111 TI - Anti-parasitic Guanidine and Pyrimidine Alkaloids from the Marine Sponge Monanchora arbuscula. AB - HPLC-UV-ELSD-MS-guided fractionation of the anti-parasitic extract obtained from the marine sponge Monanchora arbuscula, collected off the southeastern coast of Brazil, led to the isolation of a series of guanidine and pyrimidine alkaloids. The pyrimidines monalidine A (1) and arbusculidine A (7), as well as the guanidine alkaloids batzellamide A (8) and hemibatzelladines 9-11, represent new minor constituents that were identified by analysis of spectroscopic data. The total synthesis of monalidine A confirmed its structure. Arbusculidine A (7), related to the ptilocaulin/mirabilin/netamine family of tricyclic guanidine alkaloids, is the first in this family to possess a benzene ring. Batzellamide A (8) and hemibatzelladines 9-11 represent new carbon skeletons that are related to the batzelladines. Evaluation of the anti-parasitic activity of the major known metabolites, batzelladines D (12), F (13), L (14), and nor-L (15), as well as of synthetic monalidine A (1), against Trypanosoma cruzi and Leishmania infantum is also reported, along with a detailed investigation of parasite cell-death pathways promoted by batzelladine L (14) and norbatzelladine L (15). PMID- 25924112 TI - Further call for PPI expertise in HEX. PMID- 25924113 TI - Resilience in physically abused children: protective factors for aggression. AB - Aggression continues to be a serious problem among children, especially those children who have experienced adverse life events such as maltreatment. However, there are many maltreated children who show resilient functioning. This study investigated potential protective factors (i.e., child prosocial skills, child internalizing well-being, and caregiver well-being) that promoted positive adaptation and increased the likelihood of a child engaging in the healthy, normative range of aggressive behavior, despite experiencing physical maltreatment. Logistic regression analyses were conducted using two waves of data from the National Survey of Child and Adolescent Well-Being (NSCAW-I). Children who were physically maltreated were more likely to exhibit clinical levels of aggressive behavior at Time 1 than children who were not physically maltreated. Children's internalizing well-being, children's prosocial behavior, and caregivers' well-being were associated with lower likelihood of clinical levels of aggressive behavior at Time 1. Children's internalizing well-being and children's prosocial behavior remained significantly associated with nonclinical aggression 18 months later. These findings highlight the role of protective factors in fostering positive and adaptive behaviors in maltreated children. Interventions focusing on preventing early aggression and reinforcing child prosocial skills, child internalizing well-being, and caregiver well-being may be promising in promoting healthy positive behavioral adjustment. PMID- 25924114 TI - Inhibiting or antagonizing glucagon: making progress in diabetes care. AB - Absolute or relative hyperglucagonaemia has been recognized for years in all experimental or clinical forms of diabetes. It has been suggested that excess secretion of glucagon by the islet alpha cells is a direct consequence of intra islet insulin secretory defects. Recent studies have shown that knockout of the glucagon receptor or administration of a monoclonal specific glucagon receptor antibody make insulin-deficient type 1 diabetic rodents thrive without insulin. These observations suggest that glucagon plays an essential role in the pathophysiology of diabetes and that targeting the alpha cell and glucagon are innovative approaches in the management of diabetes. Despite active research and identification of promising compounds, no one selective glucagon antagonist is presently used in the treatment of diabetes. Interestingly, besides insulin, several drugs used today in the management of diabetes appear to exert their effects, in part, by inhibiting glucagon secretion (glucagon-like peptide-1 receptor agonists, dipeptidyl peptidase-4 inhibitors, alpha-glucosidase inhibitors and, possibly, sulphonylureas) or glucagon action (metformin). The potential risks associated with total glucagon suppression include alpha-cell hyperplasia, increased mass of the pancreas, increased susceptibility to hepatosteatosis and hepatocellular injury and increased risk of hypoglycaemia, and these should be considered in the search and development of new compounds reducing glucagon receptor signalling. More than 40 years after its initial description, hyperglucagonaemia in diabetes can no longer be ignored or minimized, and its correction represents an attractive way to improve diabetes management. PMID- 25924116 TI - The state of medical education research: what can we learn from the outcomes of the UK Research Excellence Framework? PMID- 25924117 TI - Losing connectivity when using EHRs: a technological or an educational problem? PMID- 25924118 TI - Hold on one second: interrupting the intern year. PMID- 25924119 TI - The impact of programmatic assessment on student learning: what can the students tell us? PMID- 25924120 TI - When I say ... whole-task curricula. PMID- 25924121 TI - When I say ... realism. PMID- 25924122 TI - Reclaiming a theoretical orientation to reflection in medical education research: a critical narrative review. AB - CONTEXT: Reflection and reflective practice have become popular topics of scholarly dialogue in medical education. This popularity has given rise to checklists, portfolios and other tools to inspire and document reflection. We argue that some of the common ways in which reflection has been applied are influenced by broader discourses of assessment and evidence, and divorced from original theories of reflection and reflective practice. METHODS: This paper was developed using a critical narrative approach. First we present two theoretical lenses provided by theories of reflection. Next we present a summary of relevant literature, indexed in PubMed from 2004 to 2014, relating to the application of reflection or reflective practice to undergraduate and postgraduate medical education. We categorise these articles broadly by trends and problematise the trends relative to the two theoretical lenses of reflection. RESULTS: Two relevant theoretical orientations of reflection for medical education are: (i) reflection as epistemology of practice, and (ii) reflection as critical social inquiry. Three prevalent trends in the application of reflection to medical education are: (i) utilitarian applications of reflection; (ii) a focus on the self as the object of reflection, and (iii) reflection and assessment. These trends align with dominant epistemological positions in medicine, but not with those that underpin reflection. CONCLUSIONS: We argue for continued theorising of and theoretically informed applications of reflection, drawing upon epistemologies of practice and critical reflection as critical social inquiry. These directions offer medical education research broad and deep potential in theories of reflection, particularly in relation to knowledge creation within uncertain and complex situations, and challenging of dominant discourses and structures. Future work could explore how dominant epistemological positions and discourses in medicine influence theories from other disciplines when these theories are deployed in medical education. PMID- 25924123 TI - The impact of adopting EHRs: how losing connectivity affects clinical reasoning. AB - CONTEXT: As electronic health records (EHRs) are adopted by teaching hospitals, educators must examine how this change impacts trainee development. OBJECTIVES: We investigate this influence by studying clinician experiences of a hospital's move from paper charts to an EHR. We ask: how does each chart modality present conceptions of time and data interconnections? How do these conceptions affect clinical reasoning? METHODS: This two-phase, longitudinal study employed constructivist grounded theory. Data were collected at a paediatric teaching hospital before (Phase 1), during and after (Phase 2) the transition from a paper chart to an EHR system. Data collection consisted of field observations (146 hours involving 300 health care providers, 22 patients and 32 patient family members), think-aloud (n = 13) and think-after (n = 11) sessions, interviews (n = 39) and document retrieval (n = 392). Theories of rhetorical genre studies and visual rhetoric informed analysis. RESULTS: In the paper flowsheet, clinicians recorded and viewed patient data in chronologically organised displays that emphasised data interconnections. In the EHR flowsheet, clinicians viewed and recorded individual data points that were largely chronologically and contextually isolated. Clinicians reported that this change resulted in: (i) not knowing the patient's evolving status; (ii) increased cognitive workload, and (iii) loss of clinical reasoning support mechanisms. CONCLUSIONS: Understanding how patient data are interconnected is essential to clinical reasoning. The use of EHRs supports this goal because the EHR is a tool for collecting dispersed data; however, these collections often deconstruct data interconnections. Where the paper flowsheet emphasises chronology and interconnectedness, the EHR flowsheet emphasises individual data values that are largely independent of time and other patient data. To prepare trainees to work with EHRs, the ways of thinking and acting that were implicitly learned through the use of paper charts must be made explicit. To support clinical reasoning, medical educators should provide lessons in connectivity - the chronologically framed data interconnections upon which clinicians rely to provide patient care. PMID- 25924124 TI - The impact of programmatic assessment on student learning: theory versus practice. AB - CONTEXT: It is widely acknowledged that assessment can affect student learning. In recent years, attention has been called to 'programmatic assessment', which is intended to optimise both learning functions and decision functions at the programme level of assessment, rather than according to individual methods of assessment. Although the concept is attractive, little research into its intended effects on students and their learning has been conducted. OBJECTIVES: This study investigated the elements of programmatic assessment that students perceived as supporting or inhibiting learning, and the factors that influenced the active construction of their learning. METHODS: The study was conducted in a graduate entry medical school that implemented programmatic assessment. Thus, all assessment information, feedback and reflective activities were combined into a comprehensive, holistic programme of assessment. We used a qualitative approach and interviewed students (n = 17) in the pre-clinical phase of the programme about their perceptions of programmatic assessment and learning approaches. Data were scrutinised using theory-based thematic analysis. RESULTS: Elements from the comprehensive programme of assessment, such as feedback, portfolios, assessments and assignments, were found to have both supporting and inhibiting effects on learning. These supporting and inhibiting elements influenced students' construction of learning. Findings showed that: (i) students perceived formative assessment as summative; (ii) programmatic assessment was an important trigger for learning, and (iii) the portfolio's reflective activities were appreciated for their generation of knowledge, the lessons drawn from feedback, and the opportunities for follow-up. Some students, however, were less appreciative of reflective activities. For these students, the elements perceived as inhibiting seemed to dominate the learning response. CONCLUSIONS: The active participation of learners in their own learning is possible when learning is supported by programmatic assessment. Certain features of the comprehensive programme of assessment were found to influence student learning, and this influence can either support or inhibit students' learning responses. PMID- 25924125 TI - Portrait of a rural health graduate: exploring alternative learning spaces. AB - CONTEXT: Given that the staffing of rural facilities represents an international challenge, the support, training and development of students of rural origin at institutions of higher learning (IHLs) should be an integral dimension of health care provisioning. International studies have shown these students to be more likely than students of urban origin to return to work in rural areas. However, the crisis in formal school education in some countries, such as South Africa, means that rural students with the capacity to pursue careers in health care are least likely to access the necessary training at an IHL. In addition to challenges of access, throughput is relatively low at IHLs and is determined by a range of learning experiences. Insight into the storied educational experiences of health care professionals (HCPs) of rural origin has the potential to inform the training and development of rural-origin students. METHODS: Six HCPs of rural origin were purposively selected. Using a narrative inquiry approach, data were generated from long interviews and a range of arts-based methods to create and reconstruct the storied narratives of the six participants. Codes, categories and themes were developed from the reconstructed stories. Reid's four-quadrant model of learning theory was used to focus on the learning experiences of one participant. RESULTS: Alternative learning spaces were identified, which were made available through particular social spaces outwith formal lecture rooms. These offered opportunities for collaboration and for the reconfiguring of the participants' agency to be, think and act differently. Through the practices enacted in particular learning spaces, relationships of caring, sharing, motivating and mentoring were formed, which contributed to personal, social, academic and professional development and success. CONCLUSIONS: Learning spaces outwith the formal lecture theatre are critical to the acquisition of good clinical skills and knowledge in the development of socially accountable HCPs of rural origin. PMID- 25924127 TI - Really Good Stuff: Lessons learned through innovation in medical education. Introduction. PMID- 25924128 TI - An academic support programme for rural practitioners in India. PMID- 25924129 TI - Off to a good start. PMID- 25924130 TI - Concerns about raising concerns. PMID- 25924131 TI - Cultural competence lessons learned: the continuum model. PMID- 25924132 TI - Medical student nutrition and culinary training. PMID- 25924133 TI - The birth of scenario-oriented learning in ethics. PMID- 25924134 TI - Anaemia prevention in the community: students as change agents. PMID- 25924135 TI - The Professional Competencies Toolkit: teaching reflection with flash cards. PMID- 25924136 TI - Formative evaluation of a Master of Public Health curriculum. PMID- 25924137 TI - Setting short-answer question standards using borderline regression. PMID- 25924138 TI - Encouraging maximal learning with minimal effort using PeerWise. PMID- 25924139 TI - Introduction of an anatomy eBook enhances assessment outcomes. PMID- 25924140 TI - ABC of Research: experience of Indian medical undergraduates. PMID- 25924141 TI - Concept Walk: a novel method for introducing complex ideas. PMID- 25924142 TI - Medical students reintroduce basic science to residents. PMID- 25924143 TI - Using incident reporting to design authentic interprofessional education. PMID- 25924144 TI - Community health fair with follow-up. PMID- 25924145 TI - A multiprofessional paediatric society for undergraduates. PMID- 25924146 TI - History taking through virtual means. PMID- 25924147 TI - Low-cost model for teaching ophthalmoscopy. PMID- 25924148 TI - The future of conference posters: 'hipster and geek!'. PMID- 25924149 TI - Medical student lecture attendance versus iTunes U. PMID- 25924150 TI - Using Twitter to teach problem-based learning. PMID- 25924151 TI - The Virtual Human in team-based learning: assessing students' perceptions. PMID- 25924152 TI - Devising regional trainee initiatives to promote research. PMID- 25924153 TI - Mentor Match for physician-faculty: the search for 'Dr Right'. PMID- 25924154 TI - A workshop in feedback improves learning and changes the teaching culture. PMID- 25924155 TI - Feedforward interview: enhancing reflection for successful teachers. PMID- 25924156 TI - Using students' formative feedback to advocate reflective teaching. PMID- 25924157 TI - The teacher-student partnership: exploring the giving and receiving of feedback. PMID- 25924158 TI - Complaint management: taking quality assurance a step further. PMID- 25924159 TI - A mental health training programme for Chinese rural general practitioners. PMID- 25924160 TI - Demographic profiling of students: an advocacy tool for family medicine. PMID- 25924161 TI - Mentoring for female medical trainees in a dual-setting group. PMID- 25924162 TI - Faculty engagement in developing an internship entry test. PMID- 25924163 TI - A new model of reflection: are some elements missing from its design? PMID- 25924164 TI - On clinical reasoning research and applications: redefining expertise. PMID- 25924165 TI - Becoming professional: one physician's RRRRRRRRRReflections on professionalism. PMID- 25924166 TI - Bayesian predictive modeling based on multidimensional connectivity profiling. AB - Dysfunction of brain structural and functional connectivity is increasingly being recognized as playing an important role in many brain disorders. Diffusion tensor imaging (DTI) and functional magnetic resonance (fMR) imaging are widely used to infer structural and functional connectivity, respectively. How to combine structural and functional connectivity patterns for predictive modeling is an important, yet open, problem. We propose a new method, called Bayesian prediction based on multidimensional connectivity profiling (BMCP), to distinguish subjects at the individual level based on structural and functional connectivity patterns. BMCP combines finite mixture modeling and Bayesian network classification. We demonstrate its use in distinguishing young and elderly adults based on DTI and resting-state fMR data. PMID- 25924167 TI - Correlation of diffusion tensor imaging parameters in the canine brain. AB - The goal of this study was to determine the degree to which ex vivo diffusion tensor imaging (DTI) parameters correlate to one another in white matter regions on very high resolution MR scans. Specifically, we hypothesized that radial diffusivity (RD) and apparent diffusion coefficient (ADC) would correlate more closely than either would correlate with fractional anisotropy (FA). We performed post mortem DTI imaging on three canine brains on a 7 T MR scanner (TR = 100 ms, NEX = 1, gradient amplitude = 600 mT/m, b = 1492-1,565 s/mm2) and generated maps of FA, RD, and ADC. We measured RD, FA and ADC within 14 regions of interest representative of various portions of white matter. We compared the three combinations of values, i.e., FA vs ADC, FA vs RD and ADC vs RD, using linear regression models. Linear regression demonstrated that RD was significantly correlated with FA (p << 0.01; R2 = 0.3053) and also with ADC (p << 0.01; R2 = 0.6755), but to a much greater degree. However, ADC was not significantly correlated with FA (p = 0.526; R2 = 0.101). Our findings suggest that both RD and ADC reflect similar cytoarchitectural features, most likely that of myelination, whereas FA values likely reflect both myelination and additional microstructural features that constrain the diffusion of water in white matter. PMID- 25924169 TI - Neurovascular study of the trigeminal nerve at 3 t MRI. AB - This study aimed to show a novel visualization method to investigate neurovascular compression of the trigeminal nerve (TN) using a volume-rendering fusion imaging technique of 3D fast imaging employing steady-state acquisition (3D FIESTA) and coregistered 3D time of flight MR angiography (3D TOF MRA) sequences, which we called "neurovascular study of the trigeminal nerve". We prospectively studied 30 patients with unilateral trigeminal neuralgia (TN) and 50 subjects without symptoms of TN (control group), on a 3 Tesla scanner. All patients were assessed using 3D FIESTA and 3D TOF MRA sequences centered on the pons, as well as a standard brain protocol including axial T1, T2, FLAIR and GRE sequences to exclude other pathologies that could cause TN. Post-contrast T1 weighted sequences were also performed. All cases showing arterial imprinting on the trigeminal nerve (n = 11) were identified on the ipsilateral side of the pain. No significant relationship was found between the presence of an artery in contact with the trigeminal nerve and TN. Eight cases were found showing arterial contact on the ipsilateral side of the pain and five cases of arterial contact on the contralateral side. The fusion imaging technique of 3D FIESTA and 3D TOF MRA sequences, combining the high anatomical detail provided by the 3D FIESTA sequence with the 3D TOF MRA sequence and its capacity to depict arterial structures, results in a tool that enables quick and efficient visualization and assessment of the relationship between the trigeminal nerve and the neighboring vascular structures. PMID- 25924170 TI - Intracranial trigeminal schwannoma. AB - Intracranial trigeminal schwannomas are rare tumors. Patients usually present with symptoms of trigeminal nerve dysfunction, the most common symptom being facial pain. MRI is the imaging modality of choice and is usually diagnostic in the appropriate clinical setting. The thin T2-weighted CISS 3D axial sequence is important for proper assessment of the cisternal segment of the nerve. They are usually hypointense on T1, hyperintense on T2 with avid enhancement post gadolinium. CT scan is supplementary to MRI, particularly for tumors located in the skull base. Imaging plays a role in diagnosis and surgical planning. In this pictorial essay, we retrospectively reviewed imaging findings in nine patients with pathologically proven trigeminal schwannoma. Familiarity with the imaging findings of intracranial trigeminal schwannoma may help to diagnose this entity. PMID- 25924168 TI - Emerging techniques for evaluation of the hemodynamics of intracranial vascular pathology. AB - Advances in imaging modalities have improved the assessment of intracranial hemodynamics using non-invasive techniques. This review examines new imaging modalities and clinical applications of currently available techniques, describes pathophysiology and future directions in hemodynamic analysis of intracranial stenoses, aneurysms and arteriovenous malformations and explores how hemodynamic analysis may have prognostic value in predicting clinical outcomes and assist in risk stratification. The advent of new technologies such as pseudo-continuous arterial spin labeling, accelerated magnetic resonance angiography (MRA) techniques, 4D digital subtraction angiography, and improvements in clinically available techniques such as phase-contrast MRA may change the landscape of vascular imaging and modify current clinical practice guidelines. PMID- 25924171 TI - Neuromyelitis optica: atypical clinical and neuroradiological presentation. AB - The extreme variability of clinical and MRI findings in the suspicion of Devic's disease always requires the detection of specific antibodies (AQP4). MRI scans were performed with a high-field MRI scanner (1.5T General Electric Signa Horizon): the MRI protocol of the brain employed axial DP, T2, T1, FLAIR and DWI weighted images (wi) and coronal T2-wi. After intravenous administration of contrast medium axial and sagittal T1-weighted images of the brain were repeated. The spine protocol employed after contrast medium included sagittal T2-wi, T2-wi with fat suppression and T1-wi. In May 2004, a 64-year-old healthy Caucasian woman began to suffer loss of motor and thermal sensitivity in the left lower limb. MRI showed non-specific areas of abnormal signal intensity on the deep left frontal and right frontoparietal white matter with no pathological enhancement after contrast medium and a small intramedullary area of altered signal at metameric level C2-C4 with a diagnosis of post-viral transverse myelitis. The patient had two similar episodes years later so the neurologist decided to search for circulating IgG AQP4 with the definitive diagnosis of neuromyelitis optica. In this case, compared to a clinical presentation of atypical deficit neurological involvement, the neuroradiological results of a progressive diffuse involvement of the white matter were atypical. PMID- 25924172 TI - Supratentorial paraventricular schwannoma. AB - Intraventricular schwannoma in either infra or supratentorial location is an extremely rare tumor with less than 20 cases described in the literature to date. There is no consensus regarding the origin of this tumor. This paper describes an excised supratentorial schwannoma located on the wall of the left lateral ventricle. The relevant literature is reviewed. A 34-year-old man with no significant medical history presented with a recent episode of right focal motor seizures and weakness of the right lower extremity. Magnetic resonance imaging of the brain demonstrated a heterogeneous enhancing mass in the body of left lateral ventricle mass lesion with vasogenic edema in the adjacent brain parenchyma. The patient underwent a left frontoparietal parasagittal craniotomy with neuronavigational guidance to avoid damage to the primary motor cortex. The tumor originated from the ependymal layer and extended to the body of lateral ventricle. Complete surgical excision of the tumor was achieved. Intraventricular schwannomas are rare tumors amenable to complete surgical excision, having a good prognosis without the need for adjuvant therapy. The recognition of this benign and potentially curable neoplasm and its differentiation from other less favorable tumors is of obvious importance. PMID- 25924173 TI - Symmetric Basal Ganglia lesion in a diabetic dialysis patient: recurrence and pathogenesis. AB - This paper describes a diabetic dialysis patient presenting two episodes of symmetric basal ganglia lesions occurring 18 months apart, and discusses the MR imaging findings and the pathogenesis of this condition. PMID- 25924174 TI - MRI helps depict clinically undetectable risk factors in advanced stage retinoblastomas. AB - This study compared high-resolution MRI with histology in advanced stage retinoblastomas in which ophthalmoscopy and ultrasonography did not give an exhaustive depiction of the tumour and/or its extension. MRI of orbits and head in 28 retinoblastoma patients (28 eyes) treated with primary enucleation were evaluated. Iris neoangiogenesis, infiltrations of optic nerve, choroid, anterior segment and sclera suspected at MR and histology were compared. Abnormal anterior segment enhancement (AASE) was also correlated with histologically proven infiltrations. Brain images were also evaluated. Significant values were obtained for: prelaminar optic nerve (ON) sensitivity (0.88), positive predictive value (PPV) (0.75) and negative predictive value (NPV) (0.71); post-laminar ON sensitivity (0.50), specificity (0.83), PPV (0.50) and NPV (0.83); overall choroid sensitivity (0.82), and massive choroid NPV (0.69); scleral specificity (1), and NPV (1). AASE correlated with iris neoangiogenesis in 14 out of 19 eyes, and showed significant values for: overall ON PPV (0.65), prelaminar ON sensitivity (0.65), and PPV (0.61), post-laminar ON NPV (0.64); overall choroid sensitivity (0.77), PPV (0.59) and NPV (0.73); scleral NPV (0.83); anterior segment sensitivity (1), and NPV (1). Odds ratios (OR) and accuracy were significant in scleral and prelaminar optic nerve infiltration. Brain examination was unremarkable in all cases. High-resolution MRI may add important findings to clinical evaluation of advanced stage retinoblastomas. PMID- 25924175 TI - Inadvertent carotid artery occlusion due to a stent-related accordion effect: clinical experience with a retrievable stent to unfold the vascular wall and restore flow. AB - Inadvertent occlusion of an internal carotid artery (ICA) during stenting may be a catastrophic situation requiring a bailout operation to prevent permanent neurologic sequelae. The underlying mechanisms of ICA occlusion may include filter-related flow arrest, arterial dissection, vasospasm, and the accordion effect, and timely differential diagnosis is crucial for appropriate management. We present herein a case of stenting-related accordion effect that led to complete ICA occlusion, wherein temporary placement of a retrievable intracranial stent for rescue was successful in achieving flow restoration, but further complicated by engagement with the filter. The differential diagnosis, preventive measures, and management of the accordion effect are discussed. PMID- 25924176 TI - Spastic quadriparesis caused by anomalous vertebral artery compression of spinal cord at the cervico-medullary junction. AB - Vascular compression of medulla or spinal cord at the cervico-medullary junction has been commonly described in the literature and is often attributed to dolichoectasia of the vertebrobasilar arteries. We describe a case of anomalous course of the cervical segments of the bilateral vertebral arteries which were seen entering the spinal canal directly after exiting the transverse foramen of axis and causing significant cord compression at the cervico-medullary region leading to spastic quadriparesis. PMID- 25924177 TI - Vein of galen aneurysmal malformation: prognostic markers depicted on fetal MRI. AB - Fetal magnetic resonance imaging (MRI) serves a dual role in the prenatal diagnostic work up of a vein of Galen aneurysmal malformation (VGAM). First, it may confirm the prenatal ultrasound findings and secondly it may identify prognostically important secondary complications of the VGAM. Progressive heart failure with development of fetal hydrops and hemispheric white matter injuries are associated with a poor outcome in children with a VGAM. We present the prenatal findings using both ultrasound and MRI of a fetus with VGAM including bilateral injury of the cerebral hemispheres, severe dilatation of the jugular veins, cardiomegaly, and hydrops fetalis. The neonate died within 30 minutes after delivery. Moreover, fetal MRI revealed complete placenta praevia, uterine fibroids, and wrapping of the umbilical cord around the fetal neck. This additional information is unrelated to the fetal pathology, but could have been of importance to plan the delivery. PMID- 25924178 TI - Beware of the aneurysm in stealth mode! AB - Endovascular treatment is one of the treatment options considered for acute stroke in many primary stroke centers. Outcome from such treatment can be very successful and gratifying if the intervention is timely and patient selection is appropriate. There are however certain pitfalls that need to be kept in mind which, if the interventionalist is not careful, can adversely affect the outcome. We describe such a case where the patient presented with acute stroke due to basilar artery thrombosis but also had an aneurysm in the affected vessel. We also make certain recommendations to reduce the chances of complications arising during treatment of patients with such a condition. PMID- 25924179 TI - Employment of vasopressin receptor antagonists in management of hyponatraemia and volume overload in some clinical conditions. AB - WHAT IS KNOWN AND OBJECTIVE: Hyponatraemia, the most common electrolyte imbalance occurring in hospitalized subjects, is usually classified as hypovolaemic, euvolaemic or hypervolaemic. Hyponatraemia is a predictor of death among subjects with chronic heart failure and cirrhosis. The inappropriate secretion of the antidiuretic hormone (AVP) seems to be of pivotal importance in the decline of serum sodium concentration in these clinical conditions. The objective of this review was to summarize recent progress in management of hyponatraemia in SIADH, cirrhosis and heart failure. METHODS: Literature searches were conducted on the topics of hyponatraemia and vasopressin receptor antagonists, using PubMed, pharmaceutical company websites and news reports. The information was evaluated for relevance and quality, critically assessed and summarized. RESULTS AND DISCUSSION: The initial treatment of severe hyponatraemia is directed towards the prevention or management of neurological manifestations and consists of an intravenous infusion of hypertonic saline. Fluid restriction is indicated in oedematous states. Diuretics alone or in combination with other specific drugs remain the main strategy in the management of volume overload in heart failure. In resistant cases, ultrafiltration can lead to effective removal of isotonic fluid preventing new episodes of decompensation; however, aquapheresis is associated with increased costs and other limits. In several trials, the efficacy of vasopressin receptor antagonists in euvolaemic patients (inappropriate antidiuretic hormone secretion) or in hypervolaemic hyponatraemia (chronic heart failure, cirrhosis) has been evaluated. It was found that vaptans, which promote aquaresis, were superior to a placebo in raising and maintaining serum sodium concentrations in these subjects. WHAT IS NEW AND CONCLUSIONS: Combined with conventional therapy, vasopressin receptor antagonists (AVP-R antagonists) are able to increase the excretion of electrolyte-free water and the sodium concentration. Further studies are needed to assess efficacious outcomes of aquaresis compared with aquapheresis and with conventional therapy. PMID- 25924180 TI - Systematic Identification of a Panel of Strong Constitutive Promoters from Streptomyces albus. AB - Actinomycetes are important organisms for the biosynthesis of valuable natural products. However, only a limited number of well-characterized native constitutive promoters from actinomycetes are available for the construction and engineering of large biochemical pathways. Here, we report the discovery and characterization of 32 candidate promoters identified from Streptomyces albus J1074 by RNA-seq analysis. These 32 promoters were cloned and characterized using a streptomycete reporter gene, xylE, encoding catechol 2,3-dioxygenase. The strengths of the identified strong promoters varied from 200 to 1300% of the strength of the well-known ermE*p in MYG medium, and the strongest of these promoters was by far the strongest actinomycete promoter ever reported in the literature. To further confirm the strengths of these promoters, qPCR was employed to determine the transcriptional levels of the xylE reporter. In total, 10 strong promoters were identified and four constitutive promoters were characterized via a time-course study. These promoters were used in a plug-and play platform to activate a cryptic gene cluster from Streptomyces griseus, and successful activation of the target pathway was observed in three widely used Streptomyces strains. Therefore, these promoters should be highly useful in current synthetic biology platforms for activation and characterization of silent natural product biosynthetic pathways as well as the optimization of pathways for the synthesis of important natural products in actinomycetes. PMID- 25924181 TI - Gastroenteropancreatic neuroendocrine neoplasms: a 10-year experience of a single center. AB - INTRODUCTION: Gastroenteropancreatic neuroendocrine neoplasms (GEP-NENs) constitute a rare and heterogeneous group of tumors with varied biology. OBJECTIVES: The aim of this study was to establish the clinical characteristics of patients with GEP-NEN and identify factors influencing their 5-year survival. PATIENTS AND METHODS: The study included 122 patients living in Krakow or its administrative region, who were diagnosed with GEP-NEN between 2002 and 2011. RESULTS: The mean follow-up period was 4.9 +/-2.8 years. The most frequent primary site of the tumor was the small intestine (n = 25; 20%), followed by pancreas (n = 23; 19%), rectum (n = 23; 19%), stomach (n = 21; 17%), appendix (n = 19; 16%), and colon (n = 11; 9%). There were 84 tumors classified as NEN G1; 31, as NEN G2; 5, as neuroendocrine carcinoma; and 1, as mixed adenoneuroendocrine carcinoma. Most well-differentiated GEP-NENs (n = 57; 57%) were diagnosed at stage I according to the American Joint Committee on Cancer / Union for International Cancer Control (AJCC/UICC) classification; 77% of NEN G1 (n = 64) were diagnosed at stage I, but the majority of NEN G2-at stage IV (n = 18; 58%). Metastases at diagnosis were found in 38 patients (34%). In 90% of the cases (n = 101), tumors were hormonally nonfunctional. The overall 5-year survival was 85%. In the univariate analysis, NEN G2 (P = 0.003), higher stage according to the AJCC/UICC classification (P <0.001), and metastases at diagnosis (P <0.001) were associated with poorer prognosis. In standardized multivariate models, higher stage (P = 0.02) and metastases at diagnosis (P = 0.02) were independent risk factors for death. CONCLUSIONS: The most important factors affecting survival of patients with GEP-NENs are tumor stage and the presence of metastases at diagnosis. The analysis of single-center data improves identification of patients with poorer prognosis requiring a more aggressive approach. PMID- 25924182 TI - Considerations in the use of fluorescence in situ hybridization (FISH) and confocal laser scanning microscopy to characterize rumen methanogens and define their spatial distributions. AB - In this study, methanogen-specific coenzyme F420 autofluorescence and confocal laser scanning microscopy were used to identify rumen methanogens and define their spatial distribution in free-living, biofilm-, and protozoa-associated microenvironments. Fluorescence in situ hybridization (FISH) with temperature controlled hybridization was used in an attempt to describe methanogen diversity. A heat pretreatment (65 degrees C, 1 h) was found to be a noninvasive method to increase probe access to methanogen RNA targets. Despite efforts to optimize FISH, 16S rRNA methanogen-specific probes, including Arch915, bound to some cells that lacked F420, possibly identifying uncharacterized Methanomassiliicoccales or reflecting nonspecific binding to other members of the rumen bacterial community. A probe targeting RNA from the methanogenesis-specific methyl coenzyme M reductase (mcr) gene was shown to detect cultured Methanosarcina cells with signal intensities comparable to those of 16S rRNA probes. However, the probe failed to hybridize with the majority of F420-emitting rumen methanogens, possibly because of differences in cell wall permeability among methanogen species. Methanogens were shown to integrate into microbial biofilms and to exist as ecto- and endosymbionts with rumen protozoa. Characterizing rumen methanogens and defining their spatial distribution may provide insight into mitigation strategies for ruminal methanogenesis. PMID- 25924183 TI - RNAi-based glyconanoparticles trigger apoptotic pathways for in vitro and in vivo enhanced cancer-cell killing. AB - Gold glyconanoparticles (GlycoNPs) are full of promise in areas like biomedicine, biotechnology and materials science due to their amazing physical, chemical and biological properties. Here, siRNA GlycoNPs (AuNP@PEG@Glucose@siRNA) in comparison with PEGylated GlycoNPs (AuNP@PEG@Glucose) were applied in vitro to a luciferase-CMT/167 adenocarcinoma cancer cell line and in vivo via intratracheal instillation directly into the lungs of B6 albino mice grafted with luciferase CMT/167 adenocarcinoma cells. siRNA GlycoNPs but not PEGylated GlycoNPs induced the expression of pro-apoptotic proteins such as Fas/CD95 and caspases 3 and 9 in CMT/167 adenocarcinoma cells in a dose dependent manner, independent of the inflammatory response, evaluated by bronchoalveolar lavage cell counting. Moreover, in vivo pulmonary delivered siRNA GlycoNPs were capable of targeting c Myc gene expression (a crucial regulator of cell proliferation and apoptosis) via in vivo RNAi in tumour tissue, leading to an ~80% reduction in tumour size without associated inflammation. PMID- 25924184 TI - Spatially-resolved heterogeneous dynamics in a strong colloidal gel [corrected]. AB - We re-examine the classical problem of irreversible colloid aggregation, showing that the application of Digital Fourier Imaging (DFI), a class of optical correlation methods that combine the power of light scattering and imaging, allows one to pick out novel useful evidence concerning the restructuring processes taking place in a strong colloidal gel. In particular, the spatially resolved displacement fields provided by DFI strongly suggest that the temporally intermittent local rearrangements taking place in the course of gel ageing are characterized by very long-ranged spatial correlations. PMID- 25924185 TI - [Erratum for: Endoscopy of the Lacrimal Duct System in Children]. PMID- 25924186 TI - Erratum for: Predictive Factors for Intraocular Pressure Reduction after Phacoemulsification in Swiss Patients. PMID- 25924187 TI - Calculating when elective abdominal aortic aneurysm repair improves survival for individual patients: development of the Aneurysm Repair Decision Aid and economic evaluation. AB - BACKGROUND: Abdominal aortic aneurysm (AAA) repair aims to prevent premature death from AAA rupture. Elective repair is currently recommended when AAA diameter reaches 5.5 cm (men) and 5.0 cm (women). Applying population-based indications may not be appropriate for individual patient decisions, as the optimal indication is likely to differ between patients based on age and comorbidities. OBJECTIVE: To develop an Aneurysm Repair Decision Aid (ARDA) to indicate when elective AAA repair optimises survival for individual patients and to assess the cost-effectiveness and associated uncertainty of elective repair at the aneurysm diameter recommended by the ARDA compared with current practice. DATA SOURCES: The UK Vascular Governance North West and National Vascular Database provided individual patient data to develop predictive models for perioperative mortality and survival. Data from published literature were used to model AAA growth and risk of rupture. The cost-effectiveness analysis used data from published literature and from local and national databases. METHODS: A combination of systematic review methods and clinical registries were used to provide data to populate models and inform the structure of the ARDA. Discrete event simulation (DES) was used to model the patient journey from diagnosis to death and synthesised data were used to estimate patient outcomes and costs for elective repair at alternative aneurysm diameters. Eight patient clinical scenarios (vignettes) were used as exemplars. The DES structure was validated by clinical and statistical experts. The economic evaluation estimated costs, quality-adjusted life-years (QALYs) and incremental cost-effectiveness ratios (ICERs) from the NHS, social care provider and patient perspective over a lifetime horizon. Cost-effectiveness acceptability analyses and probabilistic sensitivity analyses explored uncertainty in the data and the value for money of ARDA-based decisions. The ARDA outcome measures include perioperative mortality risk, annual risk of rupture, 1-, 5- and 10-year survival, postoperative long term survival, median life expectancy and predicted time to current threshold for aneurysm repair. The primary economic measure was the ICER using the QALY as the measure of health benefit. RESULTS: The analysis demonstrated it is feasible to build and run a complex clinical decision aid using DES. The model results support current guidelines for most vignettes but suggest that earlier repair may be effective in younger, fitter patients and ongoing surveillance may be effective in elderly patients with comorbidities. The model adds information to support decisions for patients with aneurysms outside current indications. The economic evaluation suggests that using the ARDA compared with current guidelines could be cost-effective but there is a high level of uncertainty. LIMITATIONS: Lack of high-quality long-term data to populate all sections of the model meant that there is high uncertainty about the long-term clinical and economic consequences of repair. Modelling assumptions were necessary and the developed survival models require external validation. CONCLUSIONS: The ARDA provides detailed information on the potential consequences of AAA repair or a decision not to repair that may be helpful to vascular surgeons and their patients in reaching informed decisions. Further research is required to reduce uncertainty about key data, including reintervention following AAA repair, and assess the acceptability and feasibility of the ARDA for use in routine clinical practice. FUNDING: The National Institute for Health Research Health Technology Assessment programme. PMID- 25924188 TI - Expanding Lone Pair...pi Interactions to Nonaromatic Systems and Nitrogen Bases: Complexes of C2F3X (X = F, Cl, Br, I) and TMA-d9. AB - The molecular electrostatic potential surface of unsaturated, locally electron deficient molecules shows a positive region perpendicular to (a part of) the molecular framework. In recent years it has been shown both theoretically and experimentally that molecules are able to form noncovalent interactions with Lewis bases through this pi-hole. When studying unsaturated perfluorohalogenated molecules containing a higher halogen atom, a second electropositive region is also observed near the halogen atom. This region, often denoted as a sigma-hole, allows the molecules to interact with Lewis bases and form a halogen bond. To experimentally characterize the competition between both these noncovalent interactions, Fourier transform infrared and Raman spectra of liquefied noble gas solutions containing perfluorohalogenated ethylene derivatives (C2F3X; X = F, Cl, Br, or I) and trimethylamine(-d9) were investigated. Analysis of the spectra shows that in mixed solutions of trimethylamine(-d9) and C2F4 or C2F3Cl lone pair...pi complex is present, while evidence for halogen-bonded complex is found in solutions containing trimethylamine(-d9) and C2F3Cl, C2F3Br, or C2F3I. For all species observed, complexation enthalpies were determined, the values varying between -4.9(1) and -24.4 kJ mol(-1). PMID- 25924190 TI - Parthenium Dermatitis With Deck-Chair Sign. PMID- 25924191 TI - Assessing science. PMID- 25924189 TI - A novel brain stimulation technology provides compatibility with MRI. AB - Clinical electrical stimulation systems--such as pacemakers and deep brain stimulators (DBS)--are an increasingly common therapeutic option to treat a large range of medical conditions. Despite their remarkable success, one of the significant limitations of these medical devices is the limited compatibility with magnetic resonance imaging (MRI), a standard diagnostic tool in medicine. During an MRI exam, the leads used with these devices, implanted in the body of the patient, act as an electric antenna potentially causing a large amount of energy to be absorbed in the tissue, which can lead to serious heat-related injury. This study presents a novel lead design that reduces the antenna effect and allows for decreased tissue heating during MRI. The optimal parameters of the wire design were determined by a combination of computational modeling and experimental measurements. The results of these simulations were used to build a prototype, which was tested in a gel phantom during an MRI scan. Measurement results showed a three-fold decrease in heating when compared to a commercially available DBS lead. Accordingly, the proposed design may allow a significantly increased number of patients with medical implants to have safe access to the diagnostic benefits of MRI. PMID- 25924192 TI - Symposium overview: Raising standards. PMID- 25924193 TI - Q&A: Science regeneration. PMID- 25924194 TI - Evaluation: Moving away from metrics. PMID- 25924195 TI - Q&A: The numbers game. PMID- 25924196 TI - Q&A: Times are changing. PMID- 25924197 TI - Research impact: A tale of two systems. PMID- 25924198 TI - Q&A: China still rising. PMID- 25924199 TI - Perspective: Give youth a chance. PMID- 25924200 TI - Q&A: The global view. PMID- 25924201 TI - China's research & development spend. PMID- 25924202 TI - Amygdala-Hippocampal Connectivity Changes During Acute Psychosocial Stress: Joint Effect of Early Life Stress and Oxytocin. AB - Previous evidence shows that acute stress changes both amygdala activity and its connectivity with a distributed brain network. Early life stress (ELS), especially emotional abuse (EA), is associated with altered reactivity to psychosocial stress in adulthood and moderates or even reverses the stress attenuating effect of oxytocin (OXT). The neural underpinnings of the interaction between ELS and OXT remain unclear, though. Therefore, we here investigate the joint effect of ELS and OXT on transient changes in amygdala-centered functional connectivity induced by acute psychosocial stress, using a double-blind, randomized, placebo-controlled, within-subject crossover design. Psychophysiological interaction analysis in the placebo session revealed stress induced increases in functional connectivity between amygdala and medial prefrontal cortex, posterior cingulate cortex, putamen, caudate and thalamus. Regression analysis showed that EA was positively associated with stress-induced changes in connectivity between amygdala and hippocampus. Moreover, hierarchical linear regression showed that this positive association between EA and stress induced amygdala-hippocampal connectivity was moderated after the administration of intranasal OXT. Amygdala-hippocampal connectivity in the OXT session correlated negatively with cortisol stress responses. Our findings suggest that altered amygdala-hippocampal functional connectivity during psychosocial stress may have a crucial role in the altered sensitivity to OXT effects in individuals who have experienced EA in their childhood. PMID- 25924203 TI - Brain Rewarding Stimulation Reduces Extracellular Glutamate Through Glial Modulation in Medial Prefrontal Cortex of Rats. AB - Growing evidence implicates a critical involvement of prefrontal glial modulation of extracellular glutamate (GLU) in aversive behaviors. However, nothing is known about whether prefrontal glial cells modulate GLU levels in rewarding behaviors. To address this question, we measured GLU efflux in the medial prefrontal cortex (PFC) of rats associated with rewarding behaviors. We used intracranial self stimulation (ICSS) of the medial forebrain bundle (MFB) as the rewarding behavior. GLU was indirectly measured using microdialysis combined with on-line fluorometric detection of NADH resulting from the reaction of GLU and NAD(+) catalyzed by GLU dehydrogenase with a time resolution of 1 min. ICSS caused a minute-by-minute change of extracellular GLU in the medial PFC, with a slight decrease during the stimulation, followed by an increase afterward. This bidirectional change was tetrodotoxin insensitive and abolished by the gliotoxin fluorocitrate. To confirm and extend the previous studies of aversion-induced increase of extracellular GLU in the medial PFC, we also measured prefrontal GLU efflux associated with an aversive stimulation, immobilization stress. The temporal change in extracellular GLU caused by this stress was markedly different from that observed during ICSS. A rapid increase in GLU was detected during the aversive stimulation, followed by a large increase afterward. This bimodal change was tetrodotoxin insensitive, similar to that detected for ICSS. These findings indicate a bidirectional regulation of extracellular GLU by prefrontal glial cells associated with rat ICSS behavior, and reveal that glial modulation of GLU neurochemistry in the medial PFC contributes to rewarding as well as aversive behaviors in rats. PMID- 25924204 TI - Short Communication: Expression of APOBEC3G and Interferon Gamma in Pleural Fluid Mononuclear Cells from HIV/TB Dual Infected Subjects. AB - Sites of HIV/TB coinfection are characterized by increased HIV-1 replication and a TH1 profile. However, expression of HIV-1 restriction factors, such as APOBEC3G (A3G) in situ, is unknown. Using an RT-profiler focused on genes related to HIV-1 expansion, we examined pleural fluid mononuclear cells (PFMCs) from patients with HIV/TB coinfection in comparison to HIV-uninfected patients with TB disease. Significant expression of interferon (IFN)-gamma and restriction factors A3G and A3F and TRIM5alpha in PFMCs was found. Genes correlating significantly with the expression of IFN-gamma included A3G and A3F. However, pleural fluid HIV-1 viral load and HIV-1 gag/pol mRNA in PFMCs did not correlate with A3G activity. PMID- 25924205 TI - A 2.5-million-year perspective on coarse-filter strategies for conserving nature's stage. AB - Climate change will require novel conservation strategies. One such tactic is a coarse-filter approach that focuses on conserving nature's stage (CNS) rather than the actors (individual species). However, there is a temporal mismatch between the long-term goals of conservation and the short-term nature of most ecological studies, which leaves many assumptions untested. Paleoecology provides a valuable perspective on coarse-filter strategies by marshaling the natural experiments of the past to contextualize extinction risk due to the emerging impacts of climate change and anthropogenic threats. We reviewed examples from the paleoecological record that highlight the strengths, opportunities, and caveats of a CNS approach. We focused on the near-time geological past of the Quaternary, during which species were subjected to widespread changes in climate and concomitant changes in the physical environment in general. Species experienced a range of individualistic responses to these changes, including community turnover and novel associations, extinction and speciation, range shifts, changes in local richness and evenness, and both equilibrium and disequilibrium responses. Due to the dynamic nature of species responses to Quaternary climate change, a coarse-filter strategy may be appropriate for many taxa because it can accommodate dynamic processes. However, conservationists should also consider that the persistence of landforms varies across space and time, which could have potential long-term consequences for geodiversity and thus biodiversity. PMID- 25924206 TI - Structural characterisation of polycrystalline colloidal monolayers in the presence of aspherical impurities. AB - Impurities in crystalline materials introduce disorder into an otherwise ordered structure due to the formation of lattice defects and grain boundaries. The properties of the resulting polycrystal can differ remarkably from those of the ideal single crystal. Here we investigate a quasi-two-dimensional system of colloidal spheres containing a small fraction of aspherical impurities and characterise the resulting polycrystalline monolayer. We find that, in the vicinity of an impurity, the underlying hexagonal lattice is deformed due to a preference for five-fold co-ordinated particles adjacent to impurities. This results in a reduction in local hexagonal ordering around an impurity. Increasing the concentration of impurities leads to an increase in the number of these defects and consequently a reduction in system-wide hexagonal ordering and a corresponding increase in entropy as measured from the distribution of Voronoi cell areas. Furthermore, through both considering orientational correlations and directly identifying crystalline domains we observe a decrease in the average polycrystalline grain size on increasing the concentration of impurities. Our data show that, for the concentrations considered, local structural modifications due to the presence of impurities are independent of their concentration, while structure on longer lengthscales (i.e. the size of polycrystalline grains) is determined by the impurity concentration. PMID- 25924207 TI - Concentrations of Polybrominated Diphenyl Ethers, Hexabromocyclododecanes and Tetrabromobisphenol-A in Breast Milk from United Kingdom Women Do Not Decrease over Twelve Months of Lactation. AB - Conflicting evidence exists about whether concentrations of persistent organic chemicals in human milk decrease over the course of lactation. This has implications for the timing of sampling human milk for exposure assessment purposes. We examined this issue by measuring concentrations of polybrominated diphenyl ethers (PBDEs), hexabromocyclododecanes (HBCDs), the HBCD degradation products tetrabromocyclododecenes (TBCDs), and tetrabromobisphenol-A (TBBP-A) in human milk collected in 2010-2011 from 10 first-time mothers from Birmingham, UK. To evaluate whether concentrations varied significantly over the first 12 months postpartum, 12 samples were taken-one per month-from each mother, amounting to 120 samples overall. While concentrations of most of our target contaminants displayed no significant variation (p > 0.1) over the duration of our study, significant increases were detected in concentrations of ?TBCDs (p = 0.029, average increase 1.4%/month) and BDE-153 (p = 0.058, average increase 4.2%/month). When compared to data obtained from a different set of UK mothers from a related but geographically wider catchment area sampled contemporaneously to this study, the ratio of median concentrations of BDE-153 to BDE-99 was markedly lower in the current study (0.46 compared to 1.32). This may reflect unidentified differences in exposure of the participants in the two studies. PMID- 25924209 TI - Heart failure and brain failure: two of a kind? PMID- 25924208 TI - Validation of an International Classification of Diseases, Ninth Revision Code Algorithm for Identifying Chiari Malformation Type 1 Surgery in Adults. AB - BACKGROUND: The use of administrative billing data may enable large-scale assessments of treatment outcomes for Chiari Malformation type I (CM-1). However, to utilize such data sets, validated International Classification of Diseases, Ninth Revision (ICD-9-CM) code algorithms for identifying CM-1 surgery are needed. OBJECTIVE: To validate 2 ICD-9-CM code algorithms identifying patients undergoing CM-1 decompression surgery. METHODS: We retrospectively analyzed the validity of 2 ICD-9-CM code algorithms for identifying adult CM-1 decompression surgery performed at 2 academic medical centers between 2001 and 2013. Algorithm 1 included any discharge diagnosis code of 348.4 (CM-1), as well as a procedure code of 01.24 (cranial decompression) or 03.09 (spinal decompression, or laminectomy). Algorithm 2 restricted this group to patients with a primary diagnosis of 348.4. The positive predictive value (PPV) and sensitivity of each algorithm were calculated. RESULTS: Among 340 first-time admissions identified by Algorithm 1, the overall PPV for CM-1 decompression was 65%. Among the 214 admissions identified by Algorithm 2, the overall PPV was 99.5%. The PPV for Algorithm 1 was lower in the Vanderbilt (59%) cohort, males (40%), and patients treated between 2009 and 2013 (57%), whereas the PPV of Algorithm 2 remained high (>=99%) across subgroups. The sensitivity of Algorithms 1 (86%) and 2 (83%) were above 75% in all subgroups. CONCLUSION: ICD-9-CM code Algorithm 2 has excellent PPV and good sensitivity to identify adult CM-1 decompression surgery. These results lay the foundation for studying CM-1 treatment outcomes by using large administrative databases. PMID- 25924211 TI - Draining woofs. PMID- 25924210 TI - Characterization of zinc uptake by mouse primary cultured astrocytes and microglia. AB - To elucidate the regulatory mechanism for extracellular zinc in the CNS, we examined the zinc uptake characteristics in mouse astrocytes and microglia. Zinc was taken up into the two cell types time-dependently, and the cell-to-medium concentration (C/M) ratio in the initial uptake phase in astrocytes was significantly smaller than that in microglia, while in the steady state phase, there was no difference in their C/M ratios. In both astrocytes and microglia, the zinc uptake was mediated, at least in part, by high- and low-affinity systems. There were no differences for both in the Km values for zinc uptake between astrocytes and microglia, and those for the low-affinity system in both cell types were the same as that for mouse ZIP1 reported previously. On the other hand, the Vmax values for both systems were greater in microglia than in astrocytes. Among ZIP isoforms, expression of ZIP1 was high in astrocytes and microglia. Nickel, a competitive inhibitor of ZIP1, and ZIP1 knock-down decreased zinc uptake by both types of cells. Overall, it is demonstrated that astrocytes and microglia had a similar uptake system for zinc including ZIP1, and the differences found in their uptake profiles imply that they play different roles in the regulation of extracellular zinc to maintain brain homeostasis. PMID- 25924212 TI - Eating disorders: need for a broader assessment. PMID- 25924213 TI - Neuropsychological performance and menstrual cycle: a literature review. AB - Approximately 80% of all women of reproductive age experience psychological and physical changes associated with the premenstrual phase. Cognitive alterations are among the most common complaints. In this context, studies have assessed cognitive performance across the menstrual cycle in healthy women and also in women with premenstrual syndrome (PMS). The main objective of the present study was to review the literature on cognitive function in different phases of the menstrual cycle in women of reproductive age, both healthy and with PMS, in particular premenstrual dysphoric disorder (PMDD). We searched MEDLINE and LILACS databases. A total of 27 studies were selected. The studies used heterogeneous methodologies. Most studies suggested that healthy women show small fluctuations in cognitive performance across the menstrual cycle, with low performance scores in the luteal phase for visuospatial and motor skills, attention and concentration, verbal memory, visual memory, working memory, and reaction time. Among women with PMS or PMDD, low performance scores for visuospatial and motor skills, attention and concentration, verbal memory, working memory, reaction time and impulsivity were also detected in the luteal phase. Symptoms observed in PMS/PMDD patients showed low intensity, but greater when compared with healthy women. Evidence indicates fluctuations in cognitive performance in the different phases of the menstrual cycle in healthy and PMS women, with worse performance for women with PMS/PMDD in the luteal phase. However, methodological limitations prevent us from drawing solid conclusions. Further studies are needed to investigate the impact of these cognitive fluctuations on patients' daily activities. PMID- 25924214 TI - Psychological characteristics of mothers of patients with anorexia nervosa: implications for treatment and prognosis. AB - INTRODUCTION: The complexity of factors involved in anorexia nervosa (AN) and the recommendations of prominent health organizations underscore the importance of reflecting on therapeutic interventions aimed at patients' family members. OBJECTIVE: To expand knowledge about the mother-daughter relationship in AN, with a focus on developing a conceptual framework that is able to improve the treatment of the disorder, reduce factors that perpetuate it and improve prognosis. METHOD: A clinical method, anchored by psychodynamic references, was employed in a group of family members of patients with eating disorders. The group met weekly, and sessions were led by psychologists from the eating disorder outpatient clinic of a university hospital. RESULTS AND DISCUSSION: Common characteristics in the mother-daughter relationship in cases of AN were identified. The issue of mutual control, the dialectic between omnipotence and impotence, and the relationship of devotion, passion and annihilation between mothers and daughters are phenomena that form the basis of AN, with a direct influence on the severity of each case and on treatment success. CONCLUSION: Our findings allowed us to identify important aspects in the mother-daughter relationship in AN, which may improve the clinical interventions aimed at treating the disorder. PMID- 25924215 TI - Bullying and associated factors in adolescents aged 11 to 15 years. AB - INTRODUCTION: Bullying among adolescents has become the subject of extensive research due to its negative effects on attitude and behavior. However, Brazilian literature on the topic is scarce. OBJECTIVE: To assess bullying and associated factors among adolescents in a population-based sample in southern Brazil. METHOD: Population-based, cross-sectional study with adolescents aged 11 to 15 years living in the municipality of Pelotas, state of Rio Grande do Sul, Brazil. RESULTS: A total of 1,145 adolescents were included. Bullying behaviors and attitudes were found to be associated with the following factors: intentionally skipping classes, failing at school, using alcohol, smoking cigarettes, using illegal drugs, having engaged in sexual intercourse, carrying a weapon, being involved in an accident/being run over by any vehicle, and being involved in fights with physical aggression. CONCLUSION: Bullying is associated with several behaviors that pose risk to the adolescents' physical and psychological health. PMID- 25924216 TI - Stressors in attempted suicide by poisoning: a sex comparison. AB - OBJECTIVE: To identify stressors in attempted suicide by poisoning and to analyze differences between men and women. METHOD: This quantitative, comparative, cross sectional study evaluated 110 patients aged between 14 and 78 years. The following instruments used were: standardized Mini International Neuropsychiatric Interview (MINI) version 5.0.0 and an interview form specifically designed for the study. RESULTS: 70% of the suicide attempters were female; mean age was 28.1 years; 98.2% presented at least one psychiatric disorder. Among the stressors assessed, significant differences were observed between men and women for: not having a spouse, 72.7% among men and 54.5% among women; attempted suicide planning, 66.7% among men and 46.8% among women; being under the influence of alcohol during the attempted suicide, 51.5% among men and 26.0% among women; harmful use of alcohol, 42.4% in men and 22.1% in women; sexual abuse, 22.1% in women and 6.1% in men. CONCLUSIONS: Women presented a three times higher number of attempted suicides by poisoning. The identification of stressors with significant differences between sexes in the high-risk population here described can help define and organize strategies aimed at suicide prevention. Similar studies should be conducted in the general population. PMID- 25924217 TI - Translation and adaptation into Brazilian Portuguese of the Obsessional Beliefs Questionnaire (OBQ-44). AB - INTRODUCTION: The Obsessional Beliefs Questionnaire (OBQ-44) is a self administered instrument comprised of 44 items, designed to assess the beliefs of patients with obsessive compulsive disorder (OCD). The objective of this study was to describe the process of translation and adaption of the questionnaire into Brazilian Portuguese. METHOD: For the translation and adaptation of the OBQ-44, we first obtained authorization from the authors of the original scale to use the instrument. Subsequently, the scale was independently translated from English into Brazilian Portuguese by two health professionals with proficiency in English. Following comparison of the two translations, a preliminary version was obtained and tried out on a sample of 20 patients with a primary diagnosis of OCD. This pretest aimed to assess the patients' understanding of the items and to make any necessary language adaptations. Then, the scale was independently back translated by two psychiatrists, also with proficiency in English. Following comparison of the two back-translations, a final version in English was developed; this version was evaluated and approved by the authors of the original instrument. RESULTS: The Brazilian Portuguese version of the OBQ-44, after the process of translation and adaptation here described, showed to be of easy interpretation by patients with different educational levels. The instrument can therefore be used to assess patients from different Brazilian socioeconomic contexts. CONCLUSION: OBQ-44 is a self-administered instrument of easy application. Therefore, it can be useful in the identification of dysfunctional beliefs in OCD patients, contributing toward a better understanding of the role played by such beliefs in the onset and maintenance of the disorder. PMID- 25924218 TI - The concept of time in the perception of children and adolescents. AB - INTRODUCTION: Children and adolescents use different markers to elaborate the concept of time, and such markers change along their development. The objective of the present article was to analyze changes in time concepts in different age groups. METHODS: The study included 81 children and adolescents aged 6 to 17 years, attending elementary or high school at a public school in southern Brazil. Participants were asked to provide their definition of time, either orally (children) or in writing (older children and adolescents). RESULTS: Twenty-one words were identified as related with the definition of time. The term "hours" was the most frequently cited (24.7%), followed by "clock" and "family" (11.1% each). Among children aged 6 to 8 years, "family" was the term most frequently mentioned to refer to time. Between 9 to 11 years of age, the notion of time was essentially related to the use of a clock, and in the 12-17-year age group, time was mostly associated with the word "days." The word "family" appears to be a frequent temporal marker in childhood, but loses this function during adolescence, as new social relationships are established. CONCLUSION: The results of this study show that the concept of time varies according to age. Chronobiological studies should therefore take into consideration the temporal perception peculiar to each age group. PMID- 25924220 TI - [Psicoterapia dinamica das patologias leves de personalidade]. PMID- 25924219 TI - Schizophrenia and functional status. PMID- 25924222 TI - Fluorescent benzene-centered mono-, bis- and tris-triazapentadiene-boron complexes. AB - A series of novel benzene centered mono-, bis- and tris-1,3,5-triazapentadiene ligands was synthesized and investigated with respect to their reactivity towards triphenylborane. The resulting blue-fluorescent boron complexes with a six membered ring chelate structure show excellent thermal and chemical stability. All title compounds were completely characterized including X-ray diffraction studies for and . Whereas the absorption spectra of all three classes of compounds are similar, the fluorescence spectra show distinct differences. Thus, the emission spectra of show Stokes shifts of 4100-6700 cm(-1) with low quantum yields both in solution and in the solid state. However, the more bulky compounds show markedly larger molar extinction coefficients and smaller bathochromic shifts compared to . For all compounds, we observe significantly more intense red shifted fluorescence in the solid state compared to that in dichloromethane solutions. For the interpretation of the absorption properties TD-DFT studies were performed based on DFT geometry optimizations. PMID- 25924223 TI - Fiber probe for nonlinear imaging applications. AB - Over the past years it had been demonstrated that multimodal imaging combining the nonlinear modalities coherent anti-Stokes Raman scattering (CARS), two-photon excited auto-fluorescence (TPEF) and second harmonic generation (SHG) show a great potential for tissue diagnosis and tumor identification. To extend the applicability of this multimodal imaging approach for in-vivo tissue screening of difficult to access body regions the development of suitable fiber optic probes is required. Here we report about a novel CARS imaging fiber probe consisting of 10,000 coherent light guiding elements preserving the spatial relationship between the entrance and the output of the fiber. Therefore the scanning procedure can be shifted from the distal to the proximal end of the fiber probe and no moving parts or driving current are required to realize in-vivo CARS endoscopy. PMID- 25924225 TI - A new route toward light emission from Ge: tensile-strained quantum dots. AB - The tensile-strained Ge quantum dot (QD) is proposed as a new route for the realization of direct band gap conversion in Ge. Ge QDs were successfully grown on an InP substrate by molecular beam epitaxy. The strain field in the QDs were analyzed by high resolution transmission electron microscopy and simulated by the finite element method based on the measured geometries. The strain field in the QDs is found to be non-uniform and the shear component plays a significant role in the energy band structure, leading to larger required hydrostatic strain than that in the Ge thin films under biaxial strain to become a direct band gap. PMID- 25924224 TI - Structural and biochemical investigation of bacteriophage N4-encoded RNA polymerases. AB - Bacteriophage N4 regulates the temporal expression of its genome through the activity of three distinct RNA polymerases (RNAP). Expression of the early genes is carried out by a phage-encoded, virion-encapsidated RNAP (vRNAP) that is injected into the host at the onset of infection and transcribes the early genes. These encode the components of new transcriptional machinery (N4 RNAPII and cofactors) responsible for the synthesis of middle RNAs. Both N4 RNAPs belong to the T7-like "single-subunit" family of polymerases. Herein, we describe their mechanisms of promoter recognition, regulation, and roles in the phage life cycle. PMID- 25924226 TI - Comparative genomic identification and expression profiling of a novel ?-defensin gene cluster in the equine reproductive tract. AB - ?-defensins are small cationic proteins with potent immunoregulatory and antimicrobial activity. The number of genes encoding these peptides varies significantly between and within species but they have not been extensively characterised in the horse. Here, we describe a systematic search of the Equus caballus genome that identified a cluster of novel ?-defensin genes on Chromosome 22, which is homologous to a cluster on bovine Chromosome 13. Close genomic matches were found for orthologs of 13 of the bovine genes, which were named equine ?-defensins (eBD) 115, eBD116, eBD117, eBD119, eBD120, eBD122a, eBD123, eBD124, eBD125, eBD126, eBD127, eBD129 and eBD132. As expression of the homologous cluster in cattle was limited to the reproductive tract, tissue sections were obtained from the testis, caput, corpus and cauda epididymis and the vas deferens of three stallions and from the ovary, oviduct, uterine horn, uterus, cervix and vagina of three mares. Using a quantitative real-time polymerase chain reaction approach, each of the novel ?-defensin genes showed distinct region-specific patterns of expression. Preferential expression in the caput epididymis of these novel defensins in the stallion and in the oviduct in the mare suggests a possible role in immunoprotection of the equine reproductive tract or in fertility. PMID- 25924228 TI - Congenital megalourethra: a case report of an isolated delayed presentation. AB - Megalourethra is a diffuse dilatation of the anterior urethra due to lack of corpus spongiosum with or without corpora cavernosa; it usually presents as a dilatation of that part of the urethra. The absence of these structures causes a ballooning of the urethra despite there being no mechanical obstruction. A 7-year old boy presented with the complaints of weak stream, ballooning of the penis before and during voiding urine and post voiding dribbling. After examination and micturating urethrogram, he was diagnosed as having megalourethra, which was then corrected using reduction urethroplasty. These days megalourethra is diagnosed with prenatal ultrasonogram. This was a case of isolated delayed presentation of megalourethra without any associated anomaly. PMID- 25924229 TI - Underage drinking: does the minimum age drinking law offer enough protection? AB - Underage drinking is a significant problem in the US. It is responsible for several thousand mortalities and fatalities each year, both among minors and other members of society. Additionally, underage alcohol consumption produces a severe economic burden in the US. Introduction to alcohol in youth poses serious long-term risks for adolescents, including occupational, educational, and psychosocial impairments, and increases the risk for developing alcohol abuse disorders in adulthood. In order to address and mitigate this problem, the US has set a minimum age drinking law of 21 in all 50 states, and has implemented several supplementary laws limiting the possession and consumption of alcohol. Though these laws have successfully reduced underage drinking, several additional strategies are noteworthy, including preventative and intervention efforts incorporating environmental, individual, communal, and parental factors. The following literature review describes these concepts as they relate to underage drinking laws in the US. Directions for future research, interventions, and ongoing challenges related to the minimum drinking age in the US are also discussed. PMID- 25924230 TI - The role of serotonin in impulsive aggression, suicide, and homicide in adolescents and adults: a literature review. AB - This is a literature review discussing previous studies on the associations between impulsive aggression and the serotonergic system in adults, adolescents, and children. The review demonstrates that there is a clear association between low cerebrospinal fluid serotonin and impulsive aggression. However, studies on neurotransmitter receptor profiles, functional imaging, genetics, and epigenetics reviewed in this article suggest a more complicated picture that includes consideration of gene vs. environment in the evaluation of risk. Serotonin supplementation studies suggest that selective serotonin reuptake inhibitors may reduce impulsive aggression in some adults but are less effective in adults with pathological aggression and also in children and adolescents. Child and adolescent studies are less conclusive, in part due to the heterogeneous physiologic and psychosocial changes occurring over the course of development. The author thus concludes that psychiatrists can reduce risk in these special patient populations by creating safer environments in the form of changes in policy and increased support services. PMID- 25924227 TI - Id1 suppresses anti-tumour immune responses and promotes tumour progression by impairing myeloid cell maturation. AB - A central mechanism of tumour progression and metastasis involves the generation of an immunosuppressive 'macroenvironment' mediated in part through tumour secreted factors. Here we demonstrate that upregulation of the Inhibitor of Differentiation 1 (Id1), in response to tumour-derived factors, such as TGFbeta, is responsible for the switch from dendritic cell (DC) differentiation to myeloid derived suppressor cell expansion during tumour progression. Genetic inactivation of Id1 largely corrects the myeloid imbalance, whereas Id1 overexpression in the absence of tumour-derived factors re-creates it. Id1 overexpression leads to systemic immunosuppression by downregulation of key molecules involved in DC differentiation and suppression of CD8 T-cell proliferation, thus promoting primary tumour growth and metastatic progression. Furthermore, advanced melanoma patients have increased plasma TGFbeta levels and express higher levels of ID1 in myeloid peripheral blood cells. This study reveals a critical role for Id1 in suppressing the anti-tumour immune response during tumour progression and metastasis. PMID- 25924231 TI - Essential oil composition, phenolic content, antioxidant, and antimicrobial activity of cultivated Satureja rechingeri Jamzad at different phenological stages. AB - Satureja rechingeri is a rare endemic and endangered species found in Iran. Its propagation, variations in essential oil and phenolic content, as well as antioxidant and antimicrobial activities at different phenological stages are reported in this study. The chemical composition of essential oils obtained by hydro-distillation from the aerial parts were determined by GC and GC-MS. A total of 47 compounds were identified in the essential oils of S. rechingeri at different phenological stages. The major components of all oils were carvacrol (83.6%-90.4%), p-cymene (0.8%-2.9%) and gamma-terpinene (0.6%-2.4%). The total phenolic content and the antioxidant activity of methanolic extracts were determined with the Folin-Ciocalteau reagent and by the 2,2-diphenyl-1 picrylhydrazyl (DPPH) free radical scavenging and ferric reducing antioxidant power (FRAP) assay, respectively. Total phenols varied from 35.5 to 37.5 mg gallic acid equivalents/g dry weight (dw), and IC50 values in the radical scavenging assay ranged from 46.2 to 50.2 mg/mL, while those in the FRAP assay were between 49.6 and 52.5 MUM quercetin equivalents/g dw. By the disc diffusion method and by determination of the minimum inhibitory concentrations (MIC), the essentials oils of the various phenological stages were found to have high activities against four medically important pathogens. PMID- 25924232 TI - The effect of acupuncture on pain score after open kidney surgery. AB - BACKGROUND: The pain after nephrectomy, just as any other surgery, is one of the problems that surgeons confront. The aim of this study was to evaluate the relieving effect of acupuncture on the pain experienced after nephrectomy. METHODS: This was a clinical trial that was performed on 30 patients with mean age of 40.8 +/- 12.54 who were candidates for nephrectomy. After matching for gender and age, the patients were divided into either acupuncture or control group. In acupuncture group, four points were stimulated for 30 minutes, and in control group, other points were stimulated ineffectively for 30 min. Then, the pain experienced in the first six hours after the surgery was registered by a blind observer based on visual analog scale. Data were analyzed using SPSS software and the t-test. RESULTS: Our results showed that the severity of pain in the acupuncture group was significantly lower than that in the control group. Also, there were six patients who required opioids in the acupuncture group, but there were 12 such patients in the control group. The mean opiate used in the control group was significantly greater than the mean for the acupuncture group. CONCLUSIONS: Acupuncture can reduce the severity of pain and the demand for opioids in patients who have undergone nephrectomy. PMID- 25924233 TI - Erratum: Drug resistance in multiple myeloma: latest findings and new concepts on molecular mechanisms. PMID- 25924234 TI - Diet-induced hypercholesterolemia promotes androgen-independent prostate cancer metastasis via IQGAP1 and caveolin-1. AB - Obesity and metabolic syndrome are associated with several cancers, however, the molecular mechanisms remain to be fully elucidated. Recent studies suggest that hypercholesterolemia increases intratumoral androgen signaling in prostate cancer, but it is unclear whether androgen-independent mechanisms also exist. Since hypercholesterolemia is associated with advanced, castrate-resistant prostate cancer, in this study, we aimed to determine whether and how hypercholesterolemia affects prostate cancer progression in the absence of androgen signaling. We demonstrate that diet-induced hypercholesterolemia promotes orthotopic xenograft PC-3 cell metastasis, concomitant with elevated expression of caveolin-1 and IQGAP1 in xenograft tumor tissues. In vitro cholesterol treatment of PC-3 cells stimulated migration and increased IQGAP1 and caveolin-1 protein level and localization to a detergent-resistant fraction. Down regulation of caveolin-1 or IQGAP1 in PC-3 cells reduced migration and invasion in vitro, and hypercholesterolemia-induced metastasis in vivo. Double knock-down of caveolin-1 and IQGAP1 showed no additive effect, suggesting that caveolin-1 and IQGAP1 act via the same pathway. Taken together, our data show that hypercholesterolemia promotes prostate cancer metastasis independent of the androgen pathway, in part by increasing IQGAP1 and caveolin-1. These results have broader implications for managing metastasis of cancers in general as IQGAP1 and hypercholesterolemia are implicated in the progression of several cancers. PMID- 25924236 TI - Oncogenic mutations of thyroid hormone receptor beta. AB - The C-terminal frame-shift mutant of the thyroid hormone receptor TRbeta1, PV, functions as an oncogene. An important question is whether the oncogenic activity of mutated TRbeta1 is uniquely dependent on the PV mutated sequence. Using four C terminal frame-shift mutants-PV, Mkar, Mdbs, and AM-we examined that region in the oncogenic actions of TRbeta1 mutants. Remarkably, these C-terminal mutants induced similar growth of tumors in mouse xenograft models. Molecular analyses showed that they physically interacted with the p85alpha regulatory subunit of PI3K similarly in cells. In vitro GST-binding assay showed that they bound to the C-terminal Src-homology 2 (CSH2) of p85alpha with markedly higher avidity. The sustained association of mutants with p85alpha led to activation of the common PI3K-AKT-ERK/STAT3 signaling to promote cell proliferation and invasion and to inhibit apoptosis. Thus, these results argue against the oncogenic activity of PV being uniquely dependent on the PV mutated sequence. Rather, these four mutants could favor a C-terminal conformation that interacted with the CSH2 domain of p85alpha to initiate activation of PI3K to relay downstream signaling to promote tumorigenesis. Thus, we propose that the mutated C-terminal region of TRbeta1 could function as an "onco-domain" and TRbeta1 is a potential therapeutic target. PMID- 25924235 TI - Adrenomedullin blockade induces regression of tumor neovessels through interference with vascular endothelial-cadherin signalling. AB - The cellular and molecular mechanisms by which adrenomedullin (AM) blockade suppresses tumor neovessels are not well defined. Herein, we show that AM blockade using anti-AM and anti-AM receptors antibodies targets vascular endothelial cells (ECs) and vascular smooth muscle cells (VSMCs), and induces regression of unstable nascent tumor neovessels. The underlying mechanism involved, and shown in vitro and in vivo in mice, is the disruption of the molecular engagement of the endothelial cell-specific junctional molecules vascular endothelial-cadherin (VE-cadherin)/beta-catenin complex. AM blockade increases endothelial cell permeability by inhibiting cell-cell contacts predominantly through disruption of VE-cadherin/beta-catenin/Akt signalling pathway, thereby leading to vascular collapse and regression of tumor neovessels. At a molecular level, we show that AM blockade induces tyrosine phosphorylation of VE-cadherin at a critical tyrosine, Tyr731, which is sufficient to prevent the binding of beta-catenin to the cytoplasmic tail of VE-cadherin leading to the inhibition of cell barrier function. Furthermore, we demonstrate activation of Src kinase by phosphorylation on Tyr416, supporting a role of Src to phosphorylate Tyr731-VE-cadherin. In this model, Src inhibition impairs alphaAM and alphaAMR-induced Tyr731-VE-cadherin phosphorylation in a dose-dependent manner, indicating that Tyr731-VE-cadherin phosphorylation state is dependent on Src activation. We found that AM blockade induces beta-catenin phosphorylation on Ser33/Ser37/Thr41 sites in both ECs and VSMCs both in vitro and in vivo in mice. These data suggest that AM blockade selectively induces regression of unstable tumor neovessels, through disruption of VE-cadherin signalling. Targeting AM system may present a novel therapeutic target to selectively disrupt assembly and induce regression of nascent tumor neovessels, without affecting normal stabilized vasculature. PMID- 25924237 TI - Silencing of voltage-gated potassium channel KV9.3 inhibits proliferation in human colon and lung carcinoma cells. AB - Voltage-gated potassium (Kv) channels are known to be involved in cancer development and cancer cell proliferation. KV9.3, an electronically silent subunit, forms heterotetramers with KV2.1 in excitable cells and modulates its electrophysiological properties. However, the role of KV9.3 alone in non excitable cancer cells has not been studied. Here, we evaluated the effect of silencing KV9.3 on cancer cell proliferation in HCT15 colon carcinoma cells and A549 lung adenocarcinoma cells. We confirmed the expression of KV9.3 mRNA in HCT15 and A549 cells and showed that silencing KV9.3 using small interfering RNA caused G0/G1 cell cycle arrest and alterations in cell cycle regulatory proteins in both HCT15 and A549 cells without affecting apoptosis. Also, stable knockdown of KV9.3 expression using short-hairpin RNA inhibited tumor growth in SCID mouse xenograft model. Using a bioinformatics approach, we identified Sp1 binding sites in the promoter region of the gene encoding KV9.3. We further found that Sp1 bound to this region and showed that the Sp1 inhibitor, mithramycin A, induced a concentration-dependent decrease in KV9.3 expression. Taken together, these data suggest that knockdown of KV9.3 inhibits proliferation in colon carcinoma and lung adenocarcinoma cell lines and may be regulated by Sp1. PMID- 25924239 TI - Mathematical Models for Neglected Tropical Diseases: Essential Tools for Control and Elimination, Part A. PMID- 25924238 TI - Mitogen-activated protein kinase binding protein 1 (MAPKBP1) is an unfavorable prognostic biomarker in cytogenetically normal acute myeloid leukemia. AB - Mitogen-activated protein kinase binding protein 1 (MAPKBP1) is a key transcription factor in the NF-kappaB signalling pathway. In this study, associations between MAPKBP1 expression and molecular and clinical characteristics were evaluated by several microarray datasets. We found that MAPKBP1 was over-expressed in cytogenetically normal AML (CN-AML) patients compared to normal bone marrow. High MAPKBP1 expression (MAPKBP1high) was associated with significantly shorter event-free survival (EFS; P = 0.0004) and overall survival (OS; P = 0.0006) than low MAPKBP1 expression (MAPKBP1low) in a cohort of 157 CN-AML patients. In multivariable analyses, MAPKBP1high remained associated with shorter EFS (P = 0.003) and OS (P = 0.01). Validation in an independent cohort of 162 CN-AML patients further confirmed the prognostic value of MAPKBP1 (OS, P = 0.00172). Gene-expression profiling revealed that some important oncogenes, including MYCN, MYB, CDK6 and CCND2, etc, were up-regulated, while cell signalling pathways leading to apoptosis, antigen processing, and natural killer cell-mediated cytotoxicity were down-regulated in MAPKBP1high patients with CN-AML. MicroRNA expression profiling revealed thatsome oncogenic microRNAsincluding miR-155 and miR-126 were up-regulated, whilst anti-oncogenic microRNAsincluding miR-148a and miR-193a were down-regulated in MAPKBP1high patients with CN-AML, which may underlie the pathological processes in this malignancy. Taken together, these findings suggest MAPKBP1highis a novel, unfavourably prognostic biomarker for CN-AML risk-stratification. PMID- 25924240 TI - Authors' reply. PMID- 25924241 TI - Authors' reply. PMID- 25924242 TI - Authors' reply. PMID- 25924243 TI - Authors' reply. PMID- 25924244 TI - [Epidemiological investigation of the first human case infected with Streptococcus suis in Shandong]. PMID- 25924245 TI - One-stop shopping: efforts to integrate physical and behavioral health care in five California community health centers. AB - More than 70 percent of behavioral health conditions are first diagnosed in the primary care setting. Yet physical and behavioral health care are typically provided separately, compelling many vulnerable patients to navigate the complexities of two separate systems of care. This policy brief examines five community health centers (CHCs) in California that have taken preliminary steps toward creating "one-stop shopping" for both physical and behavioral health care. The steps taken to increase integration by the CHCs include employing behavioral health providers, using a single electronic health record that includes both physical and behavioral health data, transforming the physical space, and developing mechanisms for effective transition of patients between providers. The findings emphasize the importance of changes to Medi-Cal reimbursement policies to promote same-day visits, as well as the importance of cultural changes to integrate behavioral health. They also highlight the need for comprehensive tools to assess and promote integration and to identify solutions for the most challenging activities required to achieve full integration. PMID- 25924246 TI - [The future will tell you what the future has stored for us...]. PMID- 25924247 TI - [Percutaneous approaches to mitral valve disease]. AB - Percutaneous approaches to mitral valve disease consist in modifications of existing surgical techniques, aiming to replicate the favourable outcomes of surgery, with less procedure-related risk, due to their less invasive nature. While some of these techniques are clearly indicated for the management of certain valve diseases, other appear as possible alternatives to surgery among patients deemed at high-risk or considered inoperable, or are still under clinical investigation. Major development of these percutaneous approaches is expected within the future, thus hopefully allowing treatment of a larger proportion of patients with mitral valve disease. PMID- 25924248 TI - [Minimal invasive cardiac surgery]. AB - With the advent of cardiopulmonary bypass in 1953, complex intracardiac procedures were developed and a full sternotomy was established as the standard approach for these. With this technique, cardiac surgery achieved excellent immediate and long-term results that became the gold standard in a variety of cardiac pathologies, both congenital and acquired. By the late 90's, new techniques were developed, associated with less surgical trauma, decreased postoperative pain and faster functional recovery. Today, in specialized centres, minimally invasive cardiac surgery has been shown to achieve comparable and even better results than conventional surgery. It is rapidly becoming a new standard for valvular heart surgery. PMID- 25924249 TI - [Bioresorbable scaffolds - nobody is perfect (yet)]. AB - The new generation drug eluting stents have improved the results of coronary angioplasty by reducing the rate of instent restenosis and stent thrombosis compared to earlier devices, due to the thinner stent struts and improved or bioresorbable polymers. But permanent metallic stent struts may have some long term harmful effects such as inducing late thrombosis, neoatherosclerosis, restenosis and also impairing vasomotion and endothelial function. This was the rationale for introducing bioresorbable stents which offer radial support to the artery during the period needed (scaffolding) and then disappear, (liberating the vessels and restoring its physiological vasomotion. New randomized studies have shown their non-inferiority compared to new generation metallic drug eluting stents, but there are still some challenges to be overcome. PMID- 25924250 TI - [Early repolarization: when should one worry?]. AB - Early repolarization of the QRS complex on the surface ECG has long been considered to be a benign finding, but is now recognized as being associated with malignant ventricular arrhythmias and sudden death. This article overviews the literature on this subject, and includes illustrative clinical cases. PMID- 25924251 TI - [Periprocedural management of anticoagulation in patients undergoing atrial fibrillation ablation]. AB - Catheter ablation of atrial fibrillation (AF) has been increasingly performed and has become a standard of care treatment option for drug-refractory symptomatic patients. However, this procedure has been associated with major complications, like thromboembolic or bleeding events. Optimal periprocedural anticoagulation strategy is essential for minimizing these complications. In this article, we review current anticoagulation strategies, including use of oral anticoagulation with Vit-K-Antagonists, as well as use of direct oral anticoagulants in the periprocedural settings of AF ablation. PMID- 25924252 TI - [Lyme carditis]. AB - Untreated Lyme disease can affect the heart in up to 10% of patients. Its clinical outcome and severity vary, ranging from asymptomatic minor conduction disturbances to potentially fatal arrhythmias and severe heart failure. A history of a tick bite or a typical previous skin lesion (Erythema migrans) may be absent; clinicians should therefore keep a low threshold of suspicion when facing cardiac manifestations in a patient potentially exposed to the disease in endemic areas. We report the case of a patient with Lyme carditis expressed by variable degrees of atrio-ventricular block and review the literature. PMID- 25924253 TI - [Clinical scores for the venous thromboembolic disease: an aid for the diagnosis and the treatment?]. AB - The venous thromboembolic disease includes a wide range of conditions from well defined medical entities (pulmonary embolism, deep venous thrombosis), their diagnosis and prognosis, as well as the risk of developping a venous thromboembolic disease in association with hospitalisation for acute medical illness and with cancer. The assessment of the risk of treatment with anticoagulants is also itaken into account. For all these medical situations, numerous (approximately 50) clinical scores have been reported. They will be presented and critically analysed in the next series of 6 articles. PMID- 25924254 TI - [Ebola and favipiravir: when political preempts scientific communication]. PMID- 25924255 TI - [Good treatment and mistreatment]. PMID- 25924256 TI - [In February 2015 , miscellanea and electronic smoking]. PMID- 25924258 TI - [Pharmacotherapy of alcohol use -related disorders: inventory in France]. PMID- 25924257 TI - [What efficacy/side effects of oseltamivir in the treatment of influenza in adults?]. PMID- 25924259 TI - [The largest maternity in Switzerland will be in Geneva]. PMID- 25924260 TI - [One step from Switzerland to the therapeutic use of cannabis]. PMID- 25924261 TI - [Precision medicine, the new myth]. PMID- 25924263 TI - Building relationships with the media: how helping them helps you and the profession? PMID- 25924262 TI - FTC obtains a court order requiring the unwinding of a hospital system physician practice acquisition. PMID- 25924264 TI - Ready... or not? Stage 2 EHR vendor issues hardship exemption. PMID- 25924265 TI - Sports physical goal: reduce liability risks while assessing student fitness. PMID- 25924266 TI - Medical school curricula changing to align with new trends in health care delivery. PMID- 25924267 TI - Physicians need to be aware of haptenation & hypersensitivity disorders. PMID- 25924268 TI - Answering the call to serve physicians and country: Doctor Schroeder demonstrates what it means to be a leader. PMID- 25924270 TI - Are your adolescent patients up to date on all recommended vaccines? An update from the Michigan Department of Community Health. PMID- 25924269 TI - Electronic prescribing for controlled substances. PMID- 25924271 TI - 88 years and counting.... PMID- 25924272 TI - The time for physician leadership & vision is now. PMID- 25924273 TI - [Epidemiological alertness as a component of the malaria surveillance system]. AB - Malaria vigilance is a continuation of the functions of the malaria surveillance system in the countries that have achieved malaria elimination on their territories. The main function of the malaria vigilance during the post elimination period is a continuous monitoring and evaluation and implementation of necessary prevention measures against the possible re-establishment of local malaria transmission due to the importation of malaria from its endemic countries by residents and/or migrants. Various epidemiological aspects of malaria vigilance, such as standard identification of a malaria case during the post elimination period; notification procedures and reporting systems; training of personnel; free access to malaria diagnosis and treatment; mandatory laboratory confirmation of malaria diagnosis; and prompt efficacious treatment, are discussed. Other aspects include epidemiological classification of cases, seasonal pattern of imported cases, its territorial confinement, time-lag between the detection of a case, its diagnosis and treatment initiation, evaluation of the efficacy of individual chemoprophylaxis and treatment. PMID- 25924274 TI - [Molecular taxonomic identification of Trichinella spp. from the Arctic coasts of the Russian Federation]. AB - Epizootological surveys on the Arctic coasts of the Russian Federation revealed 8 terrestrial andmarine mammal species that were Trichinella carriers. The infection rate varied with the animal species from 1.6 to 92.8%. Analysis of the taxonomic affiliation of Trichinella isolated from the muscles of the terrestrial and marine mammals indicated that the Trichinella species T. nativa was widespread in the arctic areas of the Russian Federation. Analysis of sequences in the Cob gene of mtDNA revealed nucleotide differences between several isolates of this species. PMID- 25924275 TI - [The intensity of immune response to T. native antigen in the residents of coastal settlements in the Chukotka district, Chukotka Autonomous Okrug]. AB - Sixty-three (24.3%) out of 259 residents of coastal settlements were found to have a positive immune response to Trichinella antigen. All the seropositive cases were represented by people belonging to three ethnic groups: Chukchi (97.8%), Eskimos (1.2%), and Yakuts (1.0%). The antibody titers varied from 1:100 (32.8%) to 1:1600 (8.7%). The highest titer reactivity was observed in marine mammal hunters, retired persons, and non-manual employees. There was a direct relationship between the antibody titer values and the dietary habits of the respondents preferring traditional foods prepared from marine mammal meat. PMID- 25924277 TI - [Human dirofilariasis in the city of Khabarovsk]. PMID- 25924276 TI - [Parasitocenotic relationships in the marita micropopulations of Opisthorchis and opportunistic microorganisms (an in vitro model)]. AB - The purpose of this investigation was to determine the relation of exometabolites of Opisthorchis maritas and the bacteria Klebsiella pneumoniae and Staphylococcus aureus, by studying some physiological functions of mature Opisthorchis and the properties of bacteria in the artificial media during co-cultivation. Its modified procedure was used to examine tile hature of relationships in the micro- population of the parasite and opportunistic bacteria. The Opistorchis felineus maritas obtained from the liver of an infested animal were the object of helminthological examinations. Co-cultivation of the bacteria Klebsiella pneumoniae and Staphylococcus aureus with Opistorchis felineus maritas showed that the latter exerted some inhibitory effects on the growth and reproduction of bacteria; moreover, there were no changes in their biochemical processes, virulence factors; and antibiotic susceptibility. PMID- 25924278 TI - [Human granulocytic anaplasmosis and its concurrence with other tick-borne infections in the Republic of Altai]. AB - Human granulocytic anaplasmosis (HGA) cases occur everywhere in the Republic of Altai. Anaplasma phagocytophilum is transmitted to humans by at least three genera of ticks: Ixodes, Dermacentor, and Haemaphysalis. The risk of the infection is higher in the northern part of the republic. Most patients with HGA show serologic evidence of coinfection with North Asian tick typhus and other tick-borne diseases. The high probability of HGA concurrent with other tick-borne infections requires an integrated approach to preventing these diseases in the Republic of Altai. PMID- 25924279 TI - [Tropical malaria in children in the Republic of Tajikistan]. AB - The complications of tropical malaria were noted in 25 (9.4%) of 196 pediatric patients followed up. These included cerebral malaria in 8 (3%), severe hemolytic anemia in 15 (5.7%), hemoglobinuric fever in 1 (0.37%), and malarial hepatitis in 1 (0.37%). The occurrence of complications was associated with the late referral of patients to a health care facility and untimely treatment, as well as with preliminary misdiagnoses (acute respiratory viral infection, typhoid-parathyphoid fever, meningitis, acute enteric infection, viral hepatitis, sepsis). The main reasons for late diagnosis were the absence of malarial paroxysm at the onset of disease in infants and the wrong type of a temperature curve. PMID- 25924280 TI - [Trichinella autoinfection]. PMID- 25924281 TI - [Laboratory criteria for evaluating the degree of infestation in animals in blood parasitic diseases in relation to the time intervals and frequency of blood sampling]. PMID- 25924282 TI - [Role of helminth antigens in the abnormal mitosis of bone marrow cells in laboratory animals]. AB - The intraabdominal administration of somatic extracts of the cestodes Hydatigera taeniaformis Batsch 1786, Lamarck, 1816 and Diphyllobothrium latum Linnaeus, 1758 and the nematodes Anisakis simplex larva Rudolphi 1809, Toxocara canis Railliet et Henry, 1912 in albino mice proved that these helminths had a karyopathic effect on the bone marrow cells of the animals. The antigenic composition of these extracts was investigated using the agar gel immunodiffusion test. The antigenic composition of the parasites was ascertained to affect their karyopathic properties. The amount of antigens and their foreignness caused a marked karyopathic effect on the bone marrow cells of laboratory animals during intraabdominal administration. PMID- 25924283 TI - [Role of the mosquitoes Culex pipienis f. pipiens and Cx. pipiens f. molestus (Diptera, Culicidae) in the spread of West Nile virus in the south of Russia]. AB - Cx. pipiens is one of the major vectors of West Nile virus in the south of Russia and it is represented by the autogenic form, molestus, and the non-autogenic form, pipiens. The spatial distribution of its larvae and food preferences of females was investigated to assess the potential role of each form in the spread of the virus. The taxonomic status of the mosquitoes was determined from their capacity for autogenicity (543 specimens) and the type of mitochondrial DNA (348 specimens). The mosquitoes of the pipiens form were shown to develop in the open urban and rural reservoirs and the females were non-autogenic. Cx. pipiens form molestus was found only in the urban biotopes, mainly in the flooded basements and, in some years, also in the open reservoirs where it formed a mixed population with Cx. pipiens form pipiens. Both autogenic (85-95.2%) and non autogenic specimens were identified among the females with the mitotype in form molestus. Genetic analysis of Cx. pipiens females collected under the Berezantsev bell and in the trap with a bird showed that both forms were attracted to man and the bird. The findings suggest that Cx. pipiens form pipiens can transmit West Nile virus to humans both in the town and in its suburb and Cx. pipiens form molestus can only in urban areas. PMID- 25924284 TI - [Monitoring the natural foci of tularemia on Wrangel Island]. AB - Long-term annual monitoring of the natural foci of tularemia was first made on Wrangel Island. The objects of the investigation were pellets of birds-myophages, blood samples from rodents, and excrements from carnivorous mammals. A total of 2626 biological samples were examined in the period 2002 to 2011. A serological test was ascertained to be the most effective method for the detection of tularemia epizooties; polymerase chain reaction should be used as an additional technique to examine blood samples, as well as rodent tubular bone debris taken from the pellets. Tularemia epizooties were registered in the populations of two species of lemmings every year, except in 2003. An intensive diffuse tularemia epizooty was first detected in this area, which emerged in 2019, peaked by spring 2011, and covered most of the island. The antigen of tularemia pathogen was identified in 43.46% of the samples under examination,which is a high quantitative indicator of the intensity of an epizootic process. The fact that positive samples are annually found in the same areas of the island suggests that the causative agent is steadily and long preserved in the parasitic system. The availability of stable and active natural tularemia foci on Wrangel Island calls for preventive measures, particularly vaccination of risk groups coming to the island to conduct researches. PMID- 25924285 TI - [Disinvasive activity of Briz 25% e.c. against Toxocara canis eggs (experimental studies)]. AB - The insectoacaricid Briz 25% e.c. was tested for its effects on Toxocara canis eggs in pure culture. In the solar-illuminated laboratory at 22-23 degrees C, T. canis eggs of pure culture were destroyed on days 17-18 when in 1.25% aqueous emulsion of the insectoacaricid Briz 25% e.c. (0.313% with reference to the active ingredient cypermethrin). Within the egg, the parasite failed to die not only in the stage of protoblast (5-6 days), but also in the stages of semiformed (4 days) and mobile larva (7-8 days), i.e. for 16-17 days of the experiment. After eggshell destruction, T. canis larvae actively entered the working aqueous emulsion of Briz 25% e.c. and died within the first hours in the test agent. The working aqueous emulsion of Briz 25% e.c. (1.25% with reference to the agent or 0.313% to the active ingredient cypermethrin) exerted ovicidal and larvicidal activities against the pathogen of T. canis in the pure culture on days 17-18 at 22-23 degrees C. PMID- 25924286 TI - [The preparation of the salicylanilide MCT-24 and the investigation of its antihymenolepic activity]. PMID- 25924287 TI - [Acute toxicity of the antihelminthic mitranox]. PMID- 25924288 TI - [A case of alopecia in a patient with hydatid disease treated with Nemozole (albendazole)]. AB - The paper describes the development of alopecia with a patient with echinocccosis alveolaris during treatment with Nemozole (albandazole). To decide to continue or to discontinue Nemozole treatment in the development of alopecia, the patient should be given full information on the risk of alopecia to his life and quality of life as compared to the sequels of recurrent hydatid disease when Nemozole is discontinued. PMID- 25924289 TI - [Death cases from topical malaria in Russia (2009-2012)]. PMID- 25924290 TI - [An imported case of Chikungunya virus disease]. PMID- 25924292 TI - A special section on nanotechnology for sensing. PMID- 25924293 TI - Nanopillars for sensing. AB - Nanopillars have become a popular area of interest over the past few years because of their large surface area and their unique optical and electronic properties as 1D nano structures. They have proven useful for developing sensing devices. This minireview summarizes the sensing applications of nanopillars based on various sensing platforms. PMID- 25924291 TI - [The impact of climatic changes on Ixodes (Ixodidae) ticks and their related natural and focal infections]. PMID- 25924294 TI - Critical View on graphene oxide production and its transfer to surfaces aiming electrochemical applications. AB - Graphene and related materials has been studied aiming their use in several applications including electrochemical sensing systems for a large number of different analytes. However, there have been proportionally only a few studies discussing deeply the implications of the different variables that could be tuned in the preparations of these materials for the development of the electrochemical platforms. In this review it is discussed how the size, number of layers, crystallinity and purity of the graphite starting material affects the final graphene oxide (GO) and reduced graphene oxide (rGO) prepared by chemical exfoliation. The exfoliation process and the most frequently applied transfer methods used to prepare thin films of GO and rGO on surfaces/electrodes of sensing platforms are also discussed. The electrochemical behavior of these materials is evaluated as a role of surface organization and adsorption. Considering the parameters previously presented, it is outlined some of the most relevant sensors and biosensor systems, which employ graphene related materials and attempts to explore different possibilities of deposition. PMID- 25924295 TI - ZnO based potentiometric and amperometric nanosensors. AB - The existence of nanomaterials provides the solid platform for sensing applications due to owing of high sensitivity and a low concentration limit of detection. More likely used nanomaterials for sensing applications includes gold nanoparticles, carbon nanotubes, magnetic nanoparticles such as Fe3O4, quantum dots and metal oxides etc. Recently nanomaterial and biological detection becomes an interdisciplinary field and is very much focussed by the researchers. Among metal oxides ZnO is largely considered due to its less toxic nature, biocompatible, cheap and easy to synthesis. ZnO nanomaterial is highly used for the chemical sensing, especially electrochemical sensing due to its fascinating properties such as high surface to volume ratio, atoxic, biosafe and biocompatible. Moreover, ZnO nanostructures exhibit unique features which could expose a suitable nanoenviroment for the immobilization of proteineous material such as enzymes, DNA, antibodies, etc. and in doing so it retains the biological efficiency of the immobilized bio sensitive material. The following review describes the two different coatings (i.e., ionophore and enzyme) on the surface of ZnO nanorods for the chemical sensing of zinc ion detection, thallium (I) ion detection, and L-lactic acid and the measurement of galactose molecules. ZnO nanorods provide the excellent transducing properties in the generation of strong electrical signals. Moreover, this review is very much focused on the applications of ZnO nanostructures in the sensing field. PMID- 25924296 TI - Nanostructured conjugated polymers in chemical sensors: synthesis, properties and applications. AB - Conjugated polymers are organic materials endowed with a pi-electron conjugation along the polymer backbone that present appealing electrical and optical properties for technological applications. By using conjugated polymeric materials in the nanoscale, such properties can be further enhanced. In addition, the use of nanostructured materials makes possible miniaturize devices at the micro/nano scale. The applications of conjugated nanostructured polymers include sensors, actuators, flexible displays, discrete electronic devices, and smart fabric, to name a few. In particular, the use of conjugated polymers in chemical and biological sensors is made feasible owning to their sensitivity to the physicochemical conditions of its surrounding environment, such as chemical composition, pH, dielectric constant, humidity or even temperature. Subtle changes in these conditions bring about variations on the electrical (resistivity and capacitance), optical (absorptivity, luminescence, etc.), and mechanical properties of the conjugated polymer, which can be precisely measured by different experimental methods and ultimately associated with a specific analyte and its concentration. The present review article highlights the main features of conjugated polymers that make them suitable for chemical sensors. An especial emphasis is given to nanostructured sensors systems, which present high sensitivity and selectivity, and find application in beverage and food quality control, pharmaceutical industries, medical diagnosis, environmental monitoring, and homeland security, and other applications as discussed throughout this review. PMID- 25924297 TI - Bioelectrode applied to diagnosis of cardiac disease. AB - This paper describes the assembly of a bioelectrode based on poly(3-aminophenol) and anti-troponin T antibody for recognition of troponin T, which is a specific biomarker for diagnosis of acute myocardial infarction. This disease causes loss of cellular components, allowing the output of molecules such as troponin T. This proteic component acts as biomarker for diagnosis of acute myocardial infarction due to their high sensitivity and specificity. Poly(3-aminophenol) was electrodeposited onto fluorine doped tin oxide (FTO) coated glass and characterized by spectroscopic methods (UV-Visible, fluorescence, infrared), electrochemical methods (cyclic voltammetry and electrochemical impedance spectroscopy) and morphological methods (laser interferometry, field emission scanning electronic microscopy, and atomic force microscopy). UV/Vis analysis indicated that poly(3-aminophenol) presents extension of conjugation, in according with fluorescence studies. Electrochemical studies indicated that poly(3-aminophenol) electrodeposited in FTO is a material with passivating characteristics for anions and capacity of retaining cationic compounds. Laser interferometry showed that poly(3-aminophenol) covers the FTO surface with a thickness off 375 +/- 75 nm. Surface images by FE-SEM and AFM have shown a full coverage on the FTO by the polymer film. The incorporation of anti-troponin T antibody on FTO electrode modified with poly(3-aminophenol) allowed effective and selective detection of cardiac biomarker troponin T, by electrochemical impedance spectroscopy (label free) and by photoluminescence, based on CdSe/ZnS quantum dots. This research shows the step by step assembly of the bioelectrode, used for detection of troponin T by impedimetric and fluorescence methods, opening the opportunity for its use in the diagnosis of others diseases. PMID- 25924298 TI - Simultaneous determination of ascorbic acid, dopamine, uric acid, and tryptophan by nanocrystalline ZSM-5 modified electrodes. AB - Nanocrystalline ZSM-5 was prepared by using propyltriethoxysilane as an additive in the conventional ZSM-5 synthesis composition. Materials were characterized by a complementary combination of X-ray diffraction, nitrogen sorption, and Scanning electron microscopy. Transition metal ion exchanged nanocrystalline ZSM-5 (M-Nano ZSM-5, where M = Cu2+, Ni2+, Co2+, Fe2+, and Mn2+) modified electrodes were constructed for the simultaneous determination of ascorbic acid (AA), dopamine (DA), uric acid (UA), and tryptophan (Trp). Electrochemical studies were carried out by using cyclic voltammetry, linear sweep voltammetry, and chronoamperometry in buffer solution at pH 3.5. Fe-Nano-ZSM-5 modified electrode exhibited excellent electrocatalytic activity with well-separated oxidation peaks towards AA, DA, UA, and Trp in their simultaneous determination. Among the M-Nano-ZSM-5 and transition metal ion-exchanged ZSM-5 (M-ZSM-5) materials investigated in this study, Fe-Nano-ZSM-5 exhibited the highest catalytic activities towards the oxidation of AA, DA, UA, and Trp with good stability, sensitivity, and selectivity. The analytical performance of this sensor was demonstrated for the simultaneous determination of AA, DA, UA, and Trp in blood serum and UA concentration in urine samples. PMID- 25924299 TI - Gravimetric chemical sensors based on silica-based mesoporous organic-inorganic hybrids. AB - Silica-based mesoporous organic-inorganic hybrid material modified quartz crystal microbalance (QCM) sensors have been examined for their ability to achieve highly sensitive and selective detection. Mesoporous silica SBA-15 serves as an inorganic host with large specific surface area, facilitating gas adsorption, and thus leads to highly sensitive response; while the presence of organic functional groups contributes to the greatly improved specific sensing property. In this work, we summarize our efforts in the rational design and synthesis of novel sensing materials for the detection of hazardous substances, including simulant nerve agent, organic vapor, and heavy metal ion, and develop high-performance QCM based chemical sensors. PMID- 25924300 TI - Surface plasmon resonance biomolecular recognition nanosystem: influence of the interfacial electrical potential. AB - It is shown that the response of a surface plasmon resonance nanosystem designed according to Kretschmann geometry on the application of an external electric potential to the gold-electrolyte interface is well described by the proposed mathematical model, which takes into account the geometric surface imperfection and dependence of optical constants of the surface layer of gold film and capacitance of the electrical double layer on applied voltage. This model allows the appropriate correction for results of electrochemical surface plasmon resonance measurements. The dependence of a value of biomolecules adsorption in a surface plasmon resonance nanosystem on applied electric potential is shown for the first time. It is found that a shift of surface plasmon resonance angular position (Deltatheta(SPR)) and a change of capacitance of electrical double layer on the surface of gold (DeltaC(dl)) for the adsorption of proteins under applied voltage are related to the nonlinear dependence Deltatheta(SPR) = (a + b x DeltaC(dl))(-1). This phenomenon can be exploited in biochemical analysis to monitor the interaction of biomolecules, enhance response of biosensors, block unwanted adsorption, etc. PMID- 25924301 TI - Evaluation of coupling protocols to bind beta-glucosidase on magnetic nanoparticles. AB - Beta-Glucosidase has been chosen as a model biomolecule to establish a general protocol for binding enzymes on both ferromagnetic and superparamagnetic nano particles for sensing applications. Using EDC (1-(3-dimethyl-aminopropyl)-3 ethylcarbodiimide) or SMCC (Succinimidyl-4-(N-maleimidomethyl)cyclohexane-1 carboxylate) as coupling agents, we compared two different methods for the fabrication of enzyme-decorated magnetic nanoparticles. We identified the best conditions for the preparation of a responsive bioactive magnetic system comparing different covalent bio-grafting protocols. The enzymatic test has been performed using beta-Glucosidase. The systems were characterized using scanning electron microscopy, infrared spectroscopy, and the enzyme loading was measured by a glucose assay in the presence of the enzyme-decorated magnetic particles. Although the faster response of ferromagnetic particles to the magnetic field, the assay results suggested that the superparamagnetic particles are more efficient carriers. In fact, the best enzymatic activity was measured on superparamagnetic systems that have the further advantage of preventing aggregation induced by the residual magnetization. Hence, beta-Glucosidase coated magnetic nanospheres could provide an attractive system suitable for the cleavage and the rapid evaluation of glycoside levels in natural products, measuring the liberated glucose without the need for specialised instrumentation. Moreover, the magnetic particles allow the subsequent collection of enzymes for further analysis, such as its use in portable fast screening kits or devices. PMID- 25924302 TI - Simple electro-assisted immobilization of ciprofloxacin on carbon nanotube modified electrodes: its selective hydrogen peroxide electrocatalysis. AB - Ciprofloxacin (Cf) is a synthetic fourth generation fluoroquinolone class antibiotic used for the treatment of gram-positive, gram-negative and mycobacterium species infections. Electrochemical characteristic of the Cf antibiotic on carbon nanotube modified glassy carbon electrode (GCE/CNT) in pH 7 phosphate buffer solution has been investigated. Electrochemically oxidized radical byproduct of the Cf drug, which is formed as intermediate, gets immobilized on the GCE/CNT (GCE/Cf@CNT) and showed stable and well defined surface confined redox peak at -0.220 V versus Ag/AgCl. Control electrochemical experiment with unmodified GCE failed to show any such immobilization and redox features. Physicochemical characterizations of the Cf@CNT by transmission electron microscope, scanning electron microscope, infrared spectroscopy, UV-Vis and gas chromatography coupled mass spectroscopic analyses of Cf@CNT collectively revealed presence of native form of the Cf antibiotic molecule onto the CNT. The interaction between the Cf molecule and the CNT tubes are revealed from the decreased intensity in the Raman spectrum. The GCE/Cf@CNT showed excellent electrocatalytic response to hydrogen peroxide reduction reaction in pH 7 phosphate buffer solution. Amperometric i-t analysis for the detection of H2O2 showed a current linearity plot upto [H2O2] = 200 MUM at an applied potential - 0.1 V versus Ag/AgCl with a current sensitivity value 678 MUA mM(-1) cm(-2). No interferences were noticed with ascorbic acid, uric acid, cysteine and nitrite. The present study can be highly helpful to understand the interaction between the Cf and H2O2 in physiological systems and for the removal of Cf from the antibiotic polluted water samples especially in the aquaculture and agricultural systems. PMID- 25924303 TI - Layer-by-layer films based on carbon nanotubes and polyaniline for detecting 2 chlorophenol. AB - Electrochemical sensors made with layer-by-layer (LbL) films of functionalized multi-walled carbon nanotubes (MWCNTs-COO-) and polyaniline (PAni) deposited onto ITO substrates were used to detect 2-chlorophenol. Concentrations down to ppm level could be detected with square wave voltammetry (SWV), owing to synergistic effects between PAni and nanotubes, whose molecular-level interactions in the LbL films were inferred using FTIR and Raman spectroscopy. Significantly, the Raman spectra of MWCNTs-COO-/PAni LbL films indicated that the conducting properties of PAni were preserved upon adsorption on the ITO substrates, with homogeneous nanocomposites being formed according to Scanning Electron Microscopy (SEM) images. PMID- 25924304 TI - Highly stable polyaniline-poly(sodium 4-styrenesulfonate) nanoparticles for sensing of amines. AB - Sensing technology is the key of intelligent packaging. A variety of different sensing systems for indicating freshness through intelligent packaging have been presented. Polyaniline (PANI) can change its color reversibly through the acid base reaction with reactive compounds and has been widely used in different kinds of sensors. However, because PANI is insoluble in common organic solvents, this limits its practical usage in many applications. In this work, a highly stable polyaniline-poly(sodium 4-styrenesulfonate) (PANI:PSS) colloid has been developed as a facile colorimetric sensor of volatile amines. The results showed the PANI:PSS colloid is quite sensitive to changes in pH. When PANI:PSS colloids were homogenously deposited on filter paper, the paper are used as a sensor to detect triethylamine (TEA) vapor. The green color of the test paper changed to blue at a TEA concentration as low as 188 ppm. PMID- 25924305 TI - Synthesis of surface roughed Pt nanowires and their application as electrochemical sensors for hydrogen peroxide detection. AB - In this paper, platinum nanowires with roughed surface textures were fabricated by a galvanostatic electrodeposition method for electrochemical sensors toward hydrogen peroxide detection. The electrochemical behavior of the glassy carbon electrode modified with these nanowires has been studied for oxidation of hydrogen peroxide by using cyclic voltammetry and amperometry in phosphate buffer solution. Surface roughness was found to enhance the sensitivity of the Pt nanowire based electrochemical sensor towards H2O2. The Pt nanowires with rough surfaces displayed higher electrocatalytic response compared to nanowires with smooth surfaces, with a sensitivity of 171 MUA mM(-1) cm(-2), and linear dynamic range up to 35 mM. The nanowire concentration effect on the sensing behavior was investigated with the best sensitivity output found at a nanowire concentration of roughly 8.6 x 10(7) number of nanowires/cm2. The new sensor also showed good anti-interference property and exhibited high accuracy when a real water sample containing H2O2 was measured. PMID- 25924306 TI - Functionalized alkoxysilane mediated controlled synthesis of noble metal nanoparticles dispersible in aqueous and non-aqueous medium. AB - The synthesis of amphiphilic noble metal nanoparticles involving the functional role of 3-aminopropyltrimethoxysilane (3-APTMS) and 3-glycidoxypropyltrimethoxy silane (3-GPTMS) is reported herein. The mechanistic approach on the reactivity of these functional alkoxysilane for the typical controlled synthesis of AuNPs as evidenced from UV-visible spectroscopy and transmission electron microscopy (TEM) is reported. The experimental findings demonstrate the followings; (1) Methanolic solution of 3-GPTMS undergo interaction with 3-APTMS and the same is facilitated in the presence of 3-APTMS treated noble metal ions, (2) The molar ratio of 3 GPTMS/3-APTMS control the nanogeometry as well as the dispersibility of AuNPs in both aqueous and non-aqueous media, (3) the dispersion ability of nanoparticles is found to be based on the hydrophobic alkyl chain of the reaction product of 3 GPTMS and 3-APTMS, and (4) AuNPs shows absorption maxima as a function of polarity and refractive index of the medium. A typical application of as synthesized AuNPs as peroxidase mimetic is reported. PMID- 25924307 TI - Iron oxide nanostructured electrodes for detection of copper(II) ions. AB - Iron oxide nanostructured (ION) electrodes were assembled layer-by-layer onto ITO coated glass substrates and their structure, morphology, and electrochemical properties were investigated, the latter aiming at the development of a chemical sensor for Cu2+. The electrodes were built by immersing the substrate alternately into an aqueous colloidal suspension of positively charged magnetite nanoparticles (np-Fe3O4, 8 nm) and an aqueous solution of anionic sodium sulfonated polystyrene (PSS). The adsorbed amount of both materials was monitored ex-situ by UV-vis spectroscopy and it was found to increase linearly with the number of deposition cycles. The resulting films feature a densely-packed structure of magnetite nanoparticles, as suggested by AFM and Raman spectroscopy, respectively. Cyclic voltammograms of electrodes immersed in acetate buffer (pH 4.6) displayed three electrochemical events that were tentatively ascribed to the reduction of Fe(III) oxy-hydroxide to magnetite, reduction of maghemite to magnetite, and finally oxidation of magnetite to maghemite. The effect of np Fe3O4/PSS bilayers on the ION electrode performance was to increase the anodic and cathodic currents produced during electrochemical oxidation-reduction of the Fe(CN)(3-/4-) redox couple. With more bilayers, the ION electrode provided higher anodic/cathodic currents. Moreover, the redox couple exhibited a quasi-reversible behavior at the ION electrode as already observed with other working electrode systems. Fitting of voltammetry data provided the apparent electron transfer constants, which were found to be higher in ION electrodes for both redox couples (Fe(CN)(3-/4-) and Cu(2+/0)). By means of differential pulsed anodic stripping voltammetry, the ION electrodes were found to respond linearly to the presence of Cu2+ in aqueous samples in the range between 1.0 and 8.0 x 10(-6) mol x L(-1) and displayed a limit of detection of 0.3 x 10(-8) mol x L(-1). The sensitivity was - 0.6MUA/MUmol x L(-1). In standard addition and recovery experiments performed with tap water the recovery was about 102%-119%. In similar experiments conducted with ground and instant coffee samples the recovery was 92.5% and 103%, respectively. Furthermore, the ION electrodes were almost insensitive to the presence of common interfering ions, such as Zn2+, Mn2+, Ni2+, and Fe3+, even at concentrations ten times higher than that of Cu2+. PMID- 25924308 TI - Nanospherical aggregation of isothiouronium-terminated amphiphilic polythiophene: preparation and vapor-phase detection of volatile organic compounds. AB - Cationic isothiouronium-terminated amphiphilic poly(3-octylthiophene) IPOT has been synthesized by the reaction of bromoethylene-terminated poly(3 octylthiophene) with 1-(2-(2-methoxyethoxy)ethyl)-3-methylthiourea. By performing gel-permeation chromatography analysis, we estimated the number-average molecular weight (M(n)) and the polydispersity index (PDI) to be 1.07 x 10(4) and 1.48, respectively. The incorporation of an isothiouronium unit at the terminal position renders the polymer amphiphilic. Well-dispersed spherical aggregates were formed with increasing H2O content in the THF solution and were characterized by FE-SEM and powder XRD measurements. We thus proposed a core/shell-type micelle with a poly(3-octylthiophene) segment as the core and an isothiouronium segment as the shell, exposing the hydrophilic methoxyethoxy pendant. The change in morphology to a spherical shape led to a bathochromic shift of the absorption band with decreasing fluorescence intensity, enabling us to use it as a fluorimetric "off-on" sensor for volatile organic compounds (VOCs) where a quick response to THF was observed on the IPOT aggregate-coated TLC plate. PMID- 25924309 TI - Highly sensitive and selective fluoride ion sensors based on microcantilevers modified with hydrogels. AB - We have developed two microcantilever sensors, one modified with chitosan/gelatin hydrogels doped with CH3(OCH2CH2)3OTBDPS and another modified with chitosan OTBDPS/gelatin hydrogels, for the sensitive and selective detection of fluoride ions (F-) in aqueous solution. Upon exposure to F-, the microcantilevers underwent bending deflection due to the cleavage of Si-O bond on reacting with F- in the hydrogel. The results show that the maximum bending deflections are proportional to the concentrations of F-, and the limits of detection are 10(-8) M and 10(-9) M for the two microcantilevers, respectively. Other ions, such as Cl , Br-, NO3-, H2PO4-, HSO4-, and AcO- have little effect on the deflection of the microcantilevers. The results show that the microcantilever may be used for in situ quantitative detection of F- in an aqueous solution and the mechanism of the bending are discussed. PMID- 25924310 TI - Immunosensor for HIV-1 diagnostics based on immobilization of the antigenic peptide p24-3 into liposomes. AB - In this work we developed an immunosensor for HIV-1 diagnostics that exploits the biorecognition between the antibody anti-p24 and the antigenic peptide p24-3 (AMATLRAEQASQEVKNWMTETL- LVQNA) derived from the HIV-1 p24 protein. p24-3 was encapsulated in phospholipid liposomes and immobilized in layer-by-layer (LbL) films produced with polyethyleneimine (PEI). The incorporation of p24-3 into liposomes was investigated using circular dichroism (CD) spectroscopy, from which an increase in the alpha helix conformation could be noted. The maximum fluorescence emission for p24-3 occurred at 340 nm in solution, compatible with the tryptophan residue being exposed to the solvent, and at 335 and 322 nm when in liposomes and PEI/p24-3-liposome LbL films, respectively. This blue shift is consistent with the tryptophan being in a partially buried environment. With the preserved structure in the LbL films, p24-3 could recognize the anti-p24 antibody in impedance spectroscopy measurements. Therefore, LbL films containing p24-3 may be suitable for detecting HIV-1 in a low-cost, easy-to-use immunosensing assay. PMID- 25924311 TI - An electrochemical dopamine sensor based on the ZnO/CuO nanohybrid structures. AB - The selective detection of dopamine (DA) is of great importance in the modern medicine because dopamine is one of the main regulators in human behaviour. In this study, ZnO/CuO nanohybrid structures, grown on the gold coated glass substrate, have been investigated as a novel electrode material for the electrochemical detection of dopamine. Scanning electron microscopy (SEM), X-ray diffraction (XRD) and X-ray photoelectron spectroscopy (XPS) techniques were used for the material characterization and the obtained results are in good agreement. The selective determination of dopamine was demonstrated by cyclic voltammetry (CV) and amperometric experiments. The amperometric response was linear for dopamine concentrations between 1.0 x 10(-3) and 8.0 mM with a sensitivity of 90.9 MUA mM(-1) cm(-2). The proposed dopamine biosensor is very stable, selective over common interferents as glucose, uric acid and ascorbic acid, and also good reproducibility was observed for seven electrodes. Moreover, the dopamine sensor exhibited a fast response time of less than 10 s. The wide range and acceptable sensitivity of the presented dopamine sensor provide the possible application in analysing the dopamine from the real samples. PMID- 25924312 TI - Grazing angle photoluminescence of porous alumina as an analytical transducer for gaseous ethanol detection. AB - Porous alumina was used to build an optical sensor for gaseous ethanol detection. The photoluminescence collected in a grazing angle was used as a transducer signal. The photoluminescence detected with this optical setup shows well resolved Fabry-Perot type interference fringes at room temperature, whose position and shape are strongly dependent on the ethanol fraction adsorbed on the porous alumina surface. According to the surface porous morphology, different finesse and resolution between the emission fringes were observed. The analytical response of the sensor was tested in terms of spectral displacement of the fringes when in contact with gaseous ethanol. The sensor was tested for different temperatures and at 25 degrees C it presented the highest sensibility. The difference in the sensibility is a function of the temperature and can be related both to the modification of ethanol vapor pressure and the kinetics of adsorption processes at the walls of the glass cell and the porous alumina sample. PMID- 25924313 TI - Self-assembly of SiO2 nanoparticles for the potentiometric detection of neurotransmitter acetylcholine and its inhibitor. AB - The detection and quantification of neurotransmitter acetylcholine (ACh) are relevant because modifications in the ACh levels constitute a threat to human health. The biological regulator of this neurotransmitter is acetylcholinesterase (AChE), an enzyme that catalyzes the hydrolysis of ACh to choline and acetic acid. However, its activity is inhibited in the presence of organophosphate and carbamate pesticides, compromising the degradation of the neurotransmitter. There has been a growing interest in faster and more sensitive detection systems that include new methods and materials for the determination of the ACh concentration. This paper proposes a potentiometric biosensor for the detection of neurotransmitter ACh and its inhibitors, specifically organophosphate pesticide methamidophos. The biosensor is based on a self-assembled platform formed by poly(allylamine) hydrochloride (PAH) and silicon dioxide nanoparticles (SiO2-Np) that contains the immobilized enzyme AChE. First, the responses of the biosensor were investigated for different concentrations of ACh in buffer solutions. After quantifying ACh, the inhibition of AChE in the presence of methamidophos was determined, enabling the quantification of methamidophos expressed as the percentage of enzyme inhibition. The potential advantages of this biosensor include simplicity in building the electrode, possible production on an industrial scale, limited need for qualified personnel to operate the device and low processing cost. PMID- 25924314 TI - Controlled synthesis of layered Sn3O4 nanobelts by carbothermal reduction method and their gas sensor properties. AB - This paper reports both the controlled synthesis of Sn3O4 nanobelts by carbothermal reduction method and the gas sensor properties of these nanostructures. The synthesized material was characterized by X-ray diffraction, scanning electron microscopy, transmission electron microscopy, energy dispersive X-ray spectroscopy and gas sensor measurements. The results showed that the Sn3O4 nanobelts grow in a layered way and the careful control of experimental parameters is fundamental for stabilization of the correct phase. From the gas sensor measurements using oxygen as analyte gas, it was observed that the Sn3O4 nanobelts exhibit n-type behavior and both the sensitivity and the response time are dependent on the oxygen concentration. A model based on molecules adsorption was proposed to illustrate the mechanism of gas detection of these nanostructures. In summary, these results indicate that Sn3O4 nanobelts synthesized by carbothermal reduction method are promising to be applied as gas sensors. PMID- 25924315 TI - Avidin epoxy-graphite composite electrodes as platforms for genosensing and aptasensing. AB - This work presents two examples of biosensors that employ DNA as the recognition element. The transduction technique chosen is electrochemical impedance spectroscopy, which makes labeless detection possible. In the first case, a DNA probe was used to hybridize and detect a complementary DNA target; this principle may be used to construct biosensors to confirm a microbial, vegetal or animal species. The working example shown is the detection of enterohaemorragic Escherichia coli O104:H4 bacteria, blamed of an epidemic outbreak in vegetables in Germany in 2011. As a second example, a specific DNA aptamer able to interact with proteins, is used to develop a biosensor to detect thrombin, an important protein mediating in blood coagulation. Following the current trend in the field, these DNA biosensors have been prepared with help of nanocomponents in order to improve or to confirm and visualize the detection capabilities. PMID- 25924316 TI - Nanobiosensors exploiting specific interactions between an enzyme and herbicides in atomic force spectroscopy. AB - The development of sensitive methodologies for detecting agrochemicals has become important in recent years due to the increasingly indiscriminate use of these substances. In this context, nanosensors based on atomic force microscopy (AFM) tips are useful because they provide higher sensitivity with operation at the nanometer scale. In this paper we exploit specific interactions between AFM tips functionalized with the enzyme acetolactate synthase (ALS) to detect the ALS inhibitor herbicides metsulfuron-methyl and imazaquin. Using atomic force spectroscopy (AFS) we could measure the adhesion force between tip and substrate, which was considerably higher when the ALS-functionalized tip (nanobiosensor) was employed. The increase was approximately 250% and 160% for metsulfuron-methyl and imazaquin, respectively, in comparison to unfunctionalized probes. We estimated the specific enzyme-herbicide force by assuming that the measured force comprises an adhesion force according to the Johnson-Kendall-Roberts (JKR) model, the capillary force and the specific force. We show that the specific, biorecognition force plays a crucial role in the higher sensitivity of the nanobiosensor, thus opening the way for the design of similarly engineered tips for detecting herbicides and other analytes. PMID- 25924317 TI - Luminescent DNA- and agar-based membranes. AB - Luminescent materials containing europium ions are investigated for different optical applications. They can be obtained using bio-macromolecules, which are promising alternatives to synthetic polymers based on the decreasing oil resources. This paper describes studies of the DNA- and Agar-europium triflate luminescent membranes and its potential technological applications are expanded to electroluminescent devices. Polarized optical microscopy demonstrated that the samples are birefringent with submicrometer anisotropy. The X-ray diffraction analysis revealed predominantly amorphous nature of the samples and the atomic force microscopy images showed a roughness of the membranes of 409.0 and 136.1 nm for the samples of DNA10Eu and Agar1.11Eu, respectively. The electron paramagnetic resonance spectra of the DNA(n)Eu membranes with the principal lines at g ~ 2.0 and g ~ 4.8 confirmed uniform distribution of rare earth ions in a disordered matrix. Moreover, these strong and narrow resonance lines for the samples of DNA(n)Eu when compared to the Agar(n)Eu suggested a presence of paramagnetic radicals arising from the DNA matrix. The emission spectra suggested that the Eu3+ ions occupy a single local environment in both matrices and the excitation spectra monitored around the Eu emission lines pointed out that the Eu3+ ions in the Agar host were mainly excited via the broad band component rather than by direct intra-4f(6) excitation, whereas the opposite case occurred for the DNA-based sample. PMID- 25924318 TI - Pd nanoparticles/multiwalled carbon nanotubes electrode system for voltammetric sensing of tyrosine. AB - A facile and quick synthesis of palladium decorated multi-walled carbon nanotubes is presented in this work. The developed protocol allowed a quasi-homogeneous distribution of the metal nanoparticles on the surface of the nanotubes, and a controlled size of the nanoparticles in a range between 3.5 and 4.5 nm. After the characterization of the hybrid nanocomposite a first attempt on a possible application was made. The preliminary test, an ink-like nanocomposite as a modifier on the surface of a carbon screen-printed electrode, was performed in order to detect L-Tyrosine. Preliminary results are promising. A catalytic effect on the oxidation peak of the L-Tyrosine was shown and furthermore a low limit of detection, 1.46 x 10(-10) M, was reached. PMID- 25924319 TI - Development of a pH sensor using nanoporous nanostructures of NiO. AB - Glass is the conventional material used in pH electrodes to monitor pH in various applications. However, the glass-based pH electrode has some limitations for particular applications. The glass sensor is limited in the use of in vivo biomedical, clinical or food applications because of the brittleness of glass, its large size, the difficulty in measuring small volumes and the absence of deformation (inflexibility). Nanostructure-based pH sensors are very sensitive, reliable, fast and applicable towards in vivo measurements. In this study, nanoporous NiO nanostructures are synthesized on a gold-coated glass substrate by a hydrothermal route using poly(vinyl alcohol) (PVA) as a stabilizer. Scanning electron microscopy (SEM) and X-ray diffraction (XRD) techniques were used for the morphological and crystalline studies. The grown NiO nanostructures are uniform and dense, and they possess good crystallinity. A pH sensor based on these NiO nanostructures was developed by testing the different pH values from 2 12 of phosphate buffered saline solution. The proposed pH sensor showed robust sensitivity of -43.74 +/- 0.80 mV/pH and a quick response time of less than 10 s. Moreover, the repeatability, reproducibility and stability of the presented pH sensor were also studied. PMID- 25924320 TI - A potentiometric biosensor for the detection of notch 3 using functionalized ZnO nanorods. AB - The notch signalling plays a vital and radical role for the activity of cellular proliferation, differentiation and apoptosis. In this study, for the first time a particular biosensor is developed for the detection of notch 3. ZnO nanorods were fabricated on the gold coated glass substrate by hydrothermal method and afterwards were decorated with the gold nanoparticles by electrodepositing technique. Scanning electron microscopy (SEM) has shown the perpendicular to the substrate growth pattern of ZnO nanorods. X-ray diffraction (XRD) studies showed the c-axis oriented growth direction with wurtzite crystal structure of ZnO nanorods. X-ray Photoelectron Spectroscopy (XPS) and energy dispersive X-ray (EDX) techniques have shown the presence of Zn, O and Au atoms in the prepared functional material. Furthermore, the anti-notch 3 was physically adsorbed on the gold nanoparticles functionalized ZnO nanorods. The developed potentiometric immunosensor has shown response to the wide range of notch 3 molecules. The detected range included 1.00 x 10(-5)-1.50 x 10(0 ) MUg/mL with a sensitivity of 23.15 +/- 0.31 mV/decade. The analytical parameters including reproducibility, stability, and selectivity were also investigated and the observed results indicate the acceptable performance of the notch 3 biosensor. Moreover, the proposed notch 3 biosensor exhibited a fast response time of 10 s. PMID- 25924321 TI - Hydrothermal growth of CuO nanoleaf structures, and their mercuric ion detection application. AB - Mercury is the hazardous heavy metal ion for the environment and the human being therefore its determination is very important and herein we describe the development of mercury ion sensor on the CuO nanoleaf like nanostructures using cetyltrimethylammonium bromide (CTAB) surfactant as template for the growth by hydrothermal growth method. Scanning electron microscopy and X-ray diffraction study has shown high density and good crystal quality of the fabricated CuO nanostructures respectively. The presented mercury ion sensor has detected the wide range of 1.0 x 10(-7) to 1.0 x 10(-1) M mercury ion concentrations with an acceptable Nernstian behaviour and a sensitivity of 30.1 +/- 0.6 mV/decade. The proposed mercury ion sensor exhibited low detection limit of 1.0 x 10(-8) M and also a fast response time of less than 5 s. In addition, the presented mercury ion sensor has shown an excellent repeatability, reproducibility, stability and selectivity. Moreover, the mercury ion selective electrode based on CuO nanoleaves was tested as an indicator electrode in the potentiometric titration. PMID- 25924322 TI - Microcantilever sensors coated with a sensitive polyaniline layer for detecting volatile organic compounds. AB - This paper describes a silicon cantilever sensor coated with a conducting polymer layer. The mechanical response (deflection) of the bimaterial (the coated microcantilever) was investigated under the influence of several volatile compounds-methanol, ethanol, acetone, propanol, dichloroethane, toluene and benzene. The variations in the deflection of the coated and uncoated microcantilevers when exposed to volatile organic compounds were evaluated, and the results indicated that the highest sensitivity was obtained with the coated microcantilever and methanol. The uncoated microcantilever was not sensitive to the volatile organic compounds. An increase in the concentration of the volatile organic compound resulted in higher deflections of the microcantilever sensor. The sensor responses were reversible, sensible, rapid and proportional to the volatile concentration. PMID- 25924323 TI - A selective potentiometric copper (II) ion sensor based on the functionalized ZnO nanorods. AB - In this work, ZnO nanorods were hydrothermally grown on the gold-coated glass substrate and characterized by field emission scanning electron microscopy (FESEM) and X-ray diffraction (XRD) techniques. The ZnO nanorods were functionalized by two different approaches and performance of the sensor electrode was monitored. Fourier transform infrared spectroscopy (FTIR) was carried out for the confirmation of interaction between the ionophore molecules and ZnO nanorods. In addition to this, the surface of the electrode was characterized by X-ray photoelectron spectroscopy (XPS) showing the chemical and electronic state of the ionophore and ZnO nanorod components. The ionophore solution was prepared in the stabilizer, poly vinyl chloride (PVC) and additives, and then functionalized on the ZnO nanorods that have shown the Nernstian response with the slope of 31 mV/decade. However, the Cu2+ ion sensor was fabricated only by immobilizing the selective copper ion ionophore membrane without the use of PVC, plasticizers, additives and stabilizers and the sensor electrode showed a linear potentiometric response with a slope of 56.4 mV/decade within a large dynamic concentration range (from 1.0 x 10(-6) to 1.0 x 10(-1) M) of copper (II) nitrate solutions. The sensor showed excellent repeatability and reproducibility with response time of less than 10 s. The negligible response to potentially interfering metal ions such as calcium (Ca2+), magnesium (Mg2+), potassium (K+), iron (Fe3+), zinc (Zn2+), and sodium (Na+) allows this sensor to be used in biological studies. It may also be used as an indicator electrode in the potentiometric titration. PMID- 25924324 TI - Discrimination of mercuric ions in piezoelectric sensors with a conjugated polymeric active layer. AB - The synthetic conjugated poly(1,4-arylene-2,5-thienylene) containing benzo[c][2,1,3]thiadiazole monomeric units (Bz-PAT) is proposed as active layer for the selective detection of mercuric ions. The Bz-PAT polymer chemical structure induces the formation of a disordered film with numerous vacancies and the size of these defects could be exploited for a reversible trapping of mercuric ions. For these reasons the Langmuir-Schaefer (LS) deposition method has been employed for transferring Bz-PAT layers with the desired accurate bi dimensional organization control of the layer and with a high control of the deposition parameters. In this contribution, the frequency variation of quartz crystal microbalances functionalized with 10, 20, 30 and 40 LS runs of Bz-PAT have been investigated in response to the injection of aqueous solutions of HgCl2, Pb(NO3)2, NiCl2, CdCl2 and ZnSO4 at different concentrations (0.5 mM, 1 mM, 5 mM). An almost linear dependence on the number of the LS layers and hence on the film thickness, measured by means of ellipsometric spectroscopy, has been found in terms of sensor response to concentration of Hg2+ ions fluxed. By means of UV-Vis spectroscopy, the variations in the pi-pi* absorption band of the polymer, attributed to the thiophene segment, induced by HgCl2 injection has been analyzed and explained as a consequence of the electron transfer from the mercuric ion to the polymer solid film. These results, together with the linear relation found between the number of deposited layers and LS film thickness, suggest that the sensing mechanism can be explained both by an electron interaction between active layer and analyte and a diffusion mechanism of Hg2+ into the solid film that reaches an asymptotic value at 30 runs (about 80 nm), then a higher number of layers does not influence the sensor sensibility. PMID- 25924326 TI - Novel solid-state route to nanostructured tin, zinc and cerium oxides as potential materials for sensors. AB - Solid-state sensor nanostructured materials (SnO2, ZnO and CeO2) have been prepared by pyrolysis of macromolecular complexes: PSP-co-4-PVP x (SnCl2)n, PSP co-4-PVP x (ZnCl2)n and PSP-co-4-PVP x (Ce(NO3)3)n in several molar ratios under air at 800 degrees C. The as-prepared nanostructured SnO2 exhibits morphologies and particle sizes which are dependent upon the molar ratio of the SnCl2:PSP-co-4 PVP. When a larger weight fraction of the inorganic salt in the precursor mixture is used (1:10 > 1:5 > 1.1) larger crystalline crystals are found for each oxide. For ZnO and CeO2 agglomerates of morphologies from the respective hexagonal and cubic structures were observed with typical sizes of 30-50 nm in both cases for a precursor mixture ratio of 1:1. PMID- 25924325 TI - Electrochemical DNA sensors based on nanostructured organic dyes/DNA/polyelectrolyte complexes. AB - Polyelectrolyte complexes based on electropolymerized phenothiazine dyes (Methylene Blue and Methylene Green), poly(allylamine hydrochloride), polystyrene sulfonate and native DNA from salmon sperm have been for the first time obtained by self-assembling on the glassy carbon electrode using the layer-by-layer assembly and characterized using direct current voltammetry and electrochemical impedance spectroscopy. The changes in the charge transfer resistance and capacitance are attributed to the charge separation and the regularity of the layers depending on the number of layers and the position of DNA within the complex. Fenton reagent increases the resistance of the outer interface of the modifier with the maximal effect for the coatings including polymeric form of Methylene Green based coatings and direct contact of the DNA and polyphenothiazines. Meanwhile the selectivity of the response was found higher for the coatings based on poly(Methylene Blue). The difference in the behavior of the polyelectrolyte complex including different components makes it possible to distinguish the response related to the DNA damage and changes in the redox status of polyphenothiazines. PMID- 25924327 TI - Structural and electrochemical properties of lutetium bis-octachloro phthalocyaninate nanostructured films. Application as voltammetric sensors. AB - Thin films of the bis[2,3,9,10,16,17,23,24-octachlorophthalocyaninate] lutetium(III) complex (LuPc2Cl32) have been prepared by the Langmuir-Blodgett and the Langmuir-Schaefer (LS) techniques. The influence of the chlorine substituents in the structure of the films and in their spectroscopic, electrochemical and sensing properties has been evaluated. The pi-A isotherms exhibit a monolayer stability greater than the observed in the unsubstituted analogue (LuPc2), being easily transferred to solid substrates, also in contrast to LuPc2. The LB and LS films present a linear growth forming stratified layers, monitored by UV-VIS absorption spectroscopy. The latter also revealed the presence of LuPc2Cl32 in the form of monomers and aggregates in both films. The FTIR data showed that the LuPc2Cl32 molecules present a non-preferential arrangement in both films. Monolayers of LB and LS were deposited onto 6 nm Ag island films to record surface-enhanced resonance Raman scattering (SERRS), leading to enhancement factors close to 2 x 10(3). Finally, LB and LS films deposited onto ITO glass have been successfully used as voltammetric sensors for the detection of catechol. The improved electroactivity of the LB and LS films has been confirmed by the reduction of the overpotential of the oxidation of catechol. The enhancement of the electrocatalytic effect observed in LB and LS films is the result of the nanostructured arrangement of the surface which increases the number of active sites. The sensors show a limit of detection in the range of 10( 5) mol/L. PMID- 25924328 TI - Carbohydrate-based amphiphilic diblock copolymers with pyridine for the sensitive detection of protein binding. AB - Glycopolymers are useful macromolecules for presenting carbohydrates in multivalent form. Here, amphiphilic block copolymers consisting of hydrophilic lactose and hydrophobic pyridine were synthesized via reversible addition fragmentation chain transfer polymerization (RAFT). RAFT polymerization of 2-O methacryloyloxyethyl-(beta-D-lactoseheptaacetate) (2-O-MALac) was performed using cumyl dithiobenzoate (CDB) as the chain transfer agent to give well-defined glycopolymers. The livingness of the process was further demonstrated by successfully chain-extending one of obtained glycopolymers with 4-pyridyl methyl methacrylate affording narrow dispersed diblocks. With the obtained block copolymers, a glycosurface was generated on the gold surface of quartz crystal microbalance (QCM) through self-assembled strategy by the use of gold affinitive pyridine functional group. Furthermore, the resulting glycosurface was used to detect the binding of lactose specific lectin, ricinus communis agglutinin (RCA120) without non-specific protein adsorption. PMID- 25924329 TI - Amphiphilic copolymer of poly(ethylene glycol)-block-polypyridine; synthesis, physicochemical characterization, and adsorption onto silica nanoparticle. AB - In this study, we newly synthesized amphiphilic block copolymers composed of hydrophilic poly(ethylene glycol) (PEG) and hydrophobic pyridine segments (PEG-b Py). Chain transfer agent terminated PEG was subsequently chain-extended with 3 (4-pyridyl)-propyl acrylate to obtain PEG-b-Py by reversible additional fragmentation chain transfer (RAFT) polymerization. Particularly, the effect of varying PEG molecular weight (M(n)) of the block copolymers (M(n) = 2000 (2k), and 5000 (5k)) was investigated in terms of critical micelle concentration (cmc), pyrene solubilization, micelle size distribution, and association number per micelle. Based on the amphiphilic balance, PEG-b-Pys formed core-shell type polymer micelle. The cmc value of PEG2k-b-Py was lower than that of PEG5k-b-Py, suggesting the degree of phase separation was strongly depended on PEG M(n). Furthermore, the adsorption of PEG-b-Py copolymer onto silica nanoparticles as dispersant was studied to estimate the effect of PEG M(n) in the copolymers and their solubility in the medium on the adsorption. Adsorbed density of PEG2k-b-Py copolymer onto silica nanoparticle was higher than that of PEG5k-b-Py, which was significantly correlated with the degree of phase-separation based on the amphiphilic balance. The adsorbed amount of copolymer was further changed as a function of solvent polarity, phase separation predicting the presence of the acid-base interaction between Py and silanol group existed on silica nanoparticles. The resultant dispersion stability was highly correlated with the graft density of copolymer onto silica surface. As a result, PEG2k-b-Py coated silica nanoparticles in aqueous media (with high solvent polarity) showed high dispersion stability. These fundamental investigations for the surface modification of the nanoparticle provide the insight into the highly stable colloidal dispersion as well as the design of dispersant molecular structure. PMID- 25924330 TI - Comparing conjugated polymer thin film and electrospun nanofiber sensing elements for detection of explosives. AB - We report sensitive detection of explosive materials via fluorescence quenching mechanism of a conjugated polymer Poly[(9,9-dioctylfluorenyl-2,7-diyl)-co (bithiophene)]. The polymer used in this investigation is highly fluorescent and can be easily processed into thin films or nanostructured fibers. We have shown that a thin film of the polymer can detect TNT and DNT easily at ambient condition and in vapor phase. The detection limit for TNT is less than 5 parts per billion (ppt) at 25 degrees C and ambient conditions. Additionally, we have also carried out a comparative study to investigate the role of nanostructures on sensitivity. Towards this, a sensing element of fluorescent nanofibers was fabricated using electrospinning and quenching efficiency was tested. In general, nanostructure improves sensitivity by enhancing the surface area but in case of conjugated polymer we noticed that it did not add much value as far sensitivity is concern. PMID- 25924331 TI - Perylenetetracarboxylic diimide (PTCDI) nanowires for sensing ethyl acetate in wine. AB - We report the application of perylenetetracarboxylic diimide (PTCDI) nanowires for sensing ethyl acetate. The conductivity of the crystalline nano/microwires increases quickly and selectively in the presence of ethyl acetate vapor, but not with water, acid and alcohol vapors, suggesting that the nanowires of PTCDI may be used for monitoring ethyl acetate during a wine manufacturing process. PMID- 25924332 TI - A special section on nanocatalysis and their applications. PMID- 25924333 TI - Promotion effect of Pd on TiO2 for visible light photocatalytic degradation of gaseous formaldehyde. AB - TiO2 and Pd doped TiO2 (Pd/TiO2) nanoparticles were prepared by sol gel method. Pd/TiO2 material was characterized by XRD, TEM, TPR, XPS and BET. From XRD data, the crystalline type of TiO2 is known to as Anatase type. TiO2 and Pd/TiO2 were in the order of 9-10 nm and 10-13 nm respectively. The photocatalytic activities of the TiO2 and Pd/TiO2 nanomaterials were evaluated and compared for the photodegradation of formaldehyde (HCHO). HCHO degradation on Pd/TiO2 catalyst, at 60 min, the degradation rate of gaseous HCHO is 95%. Using Pd/TiO2, the rate was faster than TiO2 or doped with other metals (Au/TiO2; Ag/TiO2; Pt/TiO2). PMID- 25924334 TI - Wide bandgap Bi2O2CO3-coupled Bi2MoO6 heterostructured hollow microspheres: one pot synthesis and enhanced visible-light photocatalytic activity. AB - Hierarchical Bi2O2CO3/Bi2MoO6 heterostructured photocatalysts composed of nanoplatelets of Bi2O2CO3 and Bi2MoO6 were successfully prepared by a facile template-free solvothermal process. The microsphere-like Bi2O2CO3/Bi2MoO6 composites exhibited superior visible light photocatalytic activity towards degradation of rhodamine B. The highest degradation efficiency was observed on the material with the Bi/Mo molar ratio of 2.88/1, which can degrade 99% rhodamine B within 90 min, while only 44% rhodamine B was degraded over the pure Bi2MoO6 microspheres and 2% over the Bi2O2CO3 nanoplatelets. The dramatic enhancement in their photocatalytic performance of the Bi2O2CO3/Bi2MoO6 photocatalysts can be attributed to the high surface area and the effective separation of the photoinduced carriers at the interfaces and in the semiconductors. The photo-generated h+(VB) in the Bi2O2CO3/Bi2MoO6 photocatalysts turn out to be the dominant active species in the photocatalytic reaction. Importantly, Bi2O2CO3/Bi2MoO6 displayed visible-light photocatalytic activity for the destruction of E. coli (the percent kill is 99.09 in 60 min). In addition, the Bi2O2CO3/Bi2MoO6 composite was very stable during the reaction and can be used repeatedly. These features mean the present heterostructured photocatalyst can be applied in environmental remediation, and waste water disinfection. PMID- 25924335 TI - Synthesis, characterization and photocatalytic activity of Ag/AgCl/graphite-like C3N4 under visible light irradiation. AB - A new type of Ag/AgCl/g-C3N4 composite could be facilely fabricated. The techniques of X-ray diffraction (XRD), transmission electron microscopy (TEM), X ray photoelectron spectroscopy (XPS), UV-vis diffuse reflectance spectroscopy (DRS), Fourier transform infrared spectra (FT-IR) were used to characterize the phase and structure of the samples. The activity of the Ag/AgCl/g-C3N4 composites for photodegradation of methyl orange (MO) was higher than that of either the pure g-C3N4 or Ag/AgCl. DRS of Ag/AgCl/g-C3N4 composites exhibited strong absorbance in the visible region due to the localized surface plasmon resonance (LSPR) absorption of metal Ag nanomaterial. The enhancement of photocatalytic activity of the Ag/AgCI/g-C3N4 composites was attributed to the effective charge transfer from plasmon-excited Ag to AgCI, which suppressed the charge recombination during photocatalytic reaction process. PMID- 25924336 TI - Preparation, characterization and photocatalytic activity of AgBr/BiVO4 composite photocatalyst. AB - The AgBr/BiVO4 heterostructure were synthesized. The heterostructure materials were characterized by XRD, DRS, SEM-EDS, TEM, XPS and TG-DSC. In order to investigate the photocatalytic activity of AgBr/BiVO4 heterostructures, the methylene blue (MB) dye was used as a model compound. The result suggested that under visible light irradiation, the degradation efficiency of AgBr/BiVO4 reached 83.1% within 2.5 h, which was higher than that of the pure BiVO4. The presence of AgBr significantly increased the photocatalytic activity of the composites. The photocatalytic mechanism was also discussed. PMID- 25924337 TI - Surfactant anchoring and aggregate structure at silica nanoparticles: a persuasive facade for the adsorption of azo dye. AB - Nanotechnology's aptitude to silhouette matter at the scale of the nanometer has unlocked the flap to new inventions of applications in material science and nanomedicine. Engineered silica nanoparticles are key actor of this strategy. The amphitheatre of silica nanoparticles is inexplicably bilateral. Silica particles play essential function in everyday commercial purposes for instance energy storage, chemical and biological sensors, food processing and catalysis. One of the most appealing applications to emerge in the recent years is the use of silica particles for cleaning up contaminants in groundwater, soil and sediments. Herein this work, surfactant modified silica nanoparticles with unique surface and pore properties as well as high surface areas have been extensively investigated as an alternative for the dye removal. The physical and chemical characterizations of adsorbent have been studied using FTIR and scanning electron microscopy. The present investigation aims to explore the comparative effect of different surfactants during the formation of the target composite materials. The effects of various parameters like pH, adsorbent doses, dye concentration, addition of salt have also been investigated. These findings indicate that the nano silica particles are effective materials for dye removal and can be used to alleviate environmental problems. PMID- 25924338 TI - Preparation for Mn/nanographite materials and study on electrochemical degradation of phenol by Mn/nanographite cathodes. AB - Mn/nanographite (nano-G) materials were got by chemical redox reaction and using nano-G, potassium permanganate and manganese acetate as raw materials. The microstructures and properties of nano-G and Mn/nano-G sheets were characterized by means of SEM, XPS, XRD and Raman. The results showed that manganese oxide nanoscale rod inlaid on the graphite layer surface, the manganese valence of Mn/nano-G was +4 and existed in the form of the mix crystal of alpha-MnO2 and gamma-MnO2. Moreover, Mn/nano-G represented the preferable electro-catalysis performance. The electrolysis of phenol was conducted by using self-made cathode and the Ti/IrO2/RuO2 anode in the diaphragm cell. In the diaphragm electrolysis system with the aeration conditions, under 120 min's electrolysis, the degradation rate of 100 mg/L phenol of Mn/nano-G cathode reached 97.2%. Compared with the nano-G cathode, the Mn/nano-G had higher catalytic activity and better degradation rate of phenolic organics. PMID- 25924339 TI - Development of Ni-Mo/Al2O3 catalyst for reverse water gas shift (RWGS) reaction. AB - In the present study, Mo/Al2O3 catalyst was prepared using impregnation method. Then it was promoted with Ni ions to produce Ni-Mo/Al2O3 catalyst. The structures of the catalysts were studied using X-ray diffraction (XRD), Energy dispersive X ray (EDAX), Brunauer-Emmett-Teller (BET), X-ray photoelectron spectroscopy (XPS), CO chemisorption, temperature programmed reduction of hydrogen (H2-TPR) and scanning electron microscope (SEM) techniques. Catalytic performances of the two catalysts were investigated in a fixed-bed reactor for RWGS reaction. The results indicated that addition of nickel promoter to Mo/Al2O3 catalyst enhances its activity. It is reasonable for the electron deficient state of the Ni species and existence of NiMoO4 phase to possess high activity in RWGS reaction. Stability test of Ni-Mo/Al2O3 catalyst was carried out in a fixed bed reactor and a high CO2 conversion for 60 h time on stream was demonstrated. This study introduces a new catalyst, Ni-Mo/Al2O3, with high activity and stability for RWGS reaction. PMID- 25924340 TI - Ultrasound assisted synthesis and physicochemical characterizations of fluorine modified CoMo/Al2O3 nanocatalysts used for hydrodesulfurization of thiophene. AB - A series of CoMo/F-Al2O3 nanocatalysts with different fluorine loadings of 0, 0.4, 0.8 and 1 wt% were successfully synthesized by a sonochemical method and used for catalytic hydrodesulfurization (HDS) of thiophene. The nanocatalysts were characterized with X-ray diffraction analysis (XRD), Field Emission Scanning Electron Microscopy (FESEM), BET nitrogen adsorption Brunauer-Emmett-Teller (BET) analysis, Fourier Transform Infrared Spectroscopy (FTIR) and temperature programmed desorption of ammonia (TPD-NH3) techniques. The XRD results showed a high dispersion of the molybdenum species on the gamma-Al2O3 support due to the application of sonochemical method along with fluorine addition. The CoMo/F-Al2O3 nanocatalysts had a particle size less than 100 nm. The specific surface area of the samples was slightly decreased with increasing the fluorine content. The FTIR results confirmed that with the increase of fluorine amount in the CoMo/Al2O3 nanocatalysts, it would generate more active sites. Moreover, the TPD results showed that the fluorinated nanocatalysts had higher acidity than the promoter free nanocatalysts, because of the formation of new strong acid sites on the gamma-Al2O3 support by the promoter. The catalytic activity for thiophene HDS reaction was investigated in a stirred slurry-tank reactor in the atmospheric pressure to determine the effect of fluorine amount on the nanocatalyst performance. The results of thiophene HDS reaction showed that the fluorinated nanocatalysts were more active than fluorine-free nanocatalysts and consequently, they were able to remove nearly 100% of thiophene in the initial solution. Furthermore, the nanocatalyst with the fluorine content of 0.8 wt% had the highest activity in HDS of thiophene. However, further addition of fluorine led to decrease in catalytic activity which could be attributed to the agglomerated particles formed on the nanocatalyst surface. PMID- 25924341 TI - An improved chromatographic method to determine the propane diffusivity in CHA/AEI-SAPO zeolite. AB - Diffusion limitations may quick arise in small pore zeolite. Since each zeolite has its specific pore structure, much effort need to be put in meauring and understanding the mass transport phenomena in these systems. A 3-zone-column chromatographic model that includes the effects of system non-ideal behavior, the pressure drop of the packed bed, the particle size distribution, and nonlinear adsorption equilibrium for the measurement of diffusivities in nanopores was solved numerically in the time domain. A CHA/AEI intergrowth SAPO zeolite was successfully synthesized using hydrothermal method and characterized by X-ray diffraction (XRD), scanning electron microscopy (SEM), physisorption analyzer and Malvern Mastersizer etc. The diffusion behavior of propane in the CHA/AEI-SAPO zeolite was systematically studied to obtain diffusion coefficient. The apparent diffusivity at 100 degrees C is 3.1 +/- 0.5 x 10(-16) m2/s and the activation energy is 35 +/- 4 kJ/mol. This provides reliable data to obtain anticipated product selectivity by controlling the diffusion rates of specific gases in the nanopores. PMID- 25924342 TI - Mo-doped TiO2 with enhanced visible light photocatalytic activity: a combined experimental and theoretical study. AB - In this paper, the effects of Mo doping on the geometrical, electronic, optical, and photocatalytic properties of TiO2 have been investigated theoretically and experimentally. The density functional theory based calculations show that Mo doping creates impurity states (Mo 4d) below the conduction band of TiO2 and the Fermi level is pinned inside the conduction band verifying n-type doping nature of the Mo in TiO2, which enhances its visible light absorption. Anatase TiO2 particles with Mo contents of 0.08, 0.1, 0.5, 1.0, 1.5 and, 2.0 at.% were synthesized by hydrothermal method without any post heat treatment for crystallization. Experiment results show that Mo ions have been successfully doped into the TiO2 lattice. The morphology of TiO2 particles is nearly spherical and the grain size is uniformly distributed as about 10 nm. Synthesized sample with 0.1 at.% Mo doping concentration shows the best visible light photocatalytic activity due to the reduced band gap and improved electron-hole pairs separation. However, the photocatalytic activity of the sample with 2.0 at.% Mo is relatively low although its visible light absorption is the best among the samples. The enhanced recombination of electron-hole pairs caused by the excessive Mo doping concentration may account for it. PMID- 25924343 TI - Improved catalytic activity of laser generated bimetallic and trimetallic nanoparticles. AB - We report synthesis of silver nanoparticles, bimetallic (Al2O3@Ag) nanoparticles and trimetallic (Al2O3@AgAu) nanoparticles by nanosecond pulse laser ablation (PLA) in deionized water. Two-step laser ablation methodologies were adopted for the synthesis of bi- and tri-metallic nanoparticles. In this method a silver or gold target was ablated in colloidal solution of gamma-alumina nanoparticles prepared by PLA. The TEM image analysis of bimetallic and trimetallic particles reveals deposition of fine silver particles and Ag-Au alloy particles, respectively, on large alumina particles. The laser generated nanoparticles were tested for catalytic reduction of 4-nitrophenol to 4-aminophenol and showed excellent catalytic behaviour. The catalytic rate was greatly improved by incorporation of additional metal in silver nanoparticles. The catalytic efficiency of trimetallic Al2O3@AgAu for reduction of 4-nitrophenol to 4 aminophenol was remarkably enhanced and the catalytic reaction was completed in just 5 sec. Even at very low concentration, both Al2O3@Ag nanoparticles and Al2O3@AgAu nanoparticles showed improved rate of catalytic reduction than monometallic silver nanoparticles. Our results demonstrate that alumina particles in the solution not only provide the active sites for particle dispersion but also improve the catalytic activity. PMID- 25924344 TI - Electrochemical performance of La2O3/Li2O/TiO2 nano-particle coated cathode material LiFePO4. AB - Cathode material, LiFePO4 was modified by coating with a thin layer of La2O3/Li2O/TiO2 nano-particles for improving its performance for lithium ion batteries. The morphology and structure of the modified cathode material were characterized by powder X-ray diffraction, scanning electron microcopy and AES. The performance of the battery with the modified cathode material, including cycling stability, C-rate discharge was examined. The results show that the battery composed of the coated cathode materials can discharge at a large current density and show stable cycling performance in the range from 2.5 to 4.0 V. The rate of Li ion diffusion increases in the battery with the La2O3/Li2O/TiO2-coated LiFePO4 as a cathode and the coating layer may acts as a faster ion conductor (La(2/3-x)Li(3x)TiO3). PMID- 25924345 TI - Revisiting the CO oxidation reaction on various Au/TiO2 catalysts: roles of the surface OH groups and the reaction mechanism. AB - This work aims to understand the influence of TiO2 surface structure in Au/TiO2 catalysts on CO oxidation. Au nanoparticles (3 wt%) in the range of 4 to 8 nm were loaded onto four kinds of TiO2 surfaces, which had different surface structures and were synthesized by calcining hydrogen titanate nanotubes at various temperatures and in different atmospheres. The Au catalyst supported on anatase nanorods exhibited the highest activity in CO oxidation at 30 degrees C among all the five Au/TiO2 catalysts including the reference catalyst of Au/TiO2 P25. X-ray photoelectron spectroscopy (XPS) and infrared emission spectra (IES) results indicate that the anatase nanorods have the most active surface on which water molecules can be strongly adsorbed and OH groups can be formed readily. Theoretical calculation indicates that the surface OH can facilitate the O2 adsorption on the anatase surface. Such active surface features are conducive to the O2 activation and CO oxidation. PMID- 25924346 TI - Enhancement of acetylene hydrogenation activity over Ni-Zn bimetallic catalyst by doping with Au. AB - A series of modified Ni-Zn bimetallic catalysts were prepared by depositing different kinds of 4 wt% metals (Ir, Pt, Au, Cu, Ag) on the Ni-Zn-Al hydrotalcite (NZAH) and tested in the selective hydrogenation of acetylene. The activity was enhanced by 3-fold over the 4 wt% Au/NZAH, meanwhile, the yield of C2H4 was also increased more than 4 times compared with the NZAH. Characterization by means of H2-TPR, XRD, SEM, and TEM revealed that Au was highly dispersed on the catalyst, and the ternary Au-Ni-Zn alloy was formed during the H2 reduction at 500 degrees C. Doping Au in Ni-Zn bimetallic catalyst weakens the adsorption of acetylene and also hinders the coke deposition on the catalyst, which leads to the enhanced activity in acetylene hydrogenation. PMID- 25924347 TI - Ultra-dispersed Pt nanoparticles on SAPO-34/gamma-Al2O3 support for efficient propane dehydrogenation. AB - Ultra-dispersed precious metal nanoparticles with good thermal stability are highly required for heterogeneous catalysis. However, the efficient and effective strategy to disperse ultra-fine precious metal nanoparticles at high reaction temperature is still not fully understood yet. In this contribution, a family of catalysts with ultra-small Pt nanoparticles were prepared using impregnation method by adjusting the zeolite content in the SAPO-34 and gamma-Al2O3 mixed support. The effect of Pt nanoparticle size on the catalytic activity, selectivity, and stability was investigated in the propane dehydrogenation reaction. Catalyst with smaller Pt particles exhibits better catalytic performance. Both the highest Pt dispersion and the best catalytic activity can be achieved by using SAPO-34 and gamma-Al2O3 mixed support with 70 wt.% of SAPO 34. The size and structure of the Pt nanoparticles on the optimal catalyst were characterized by transmission electron microscopy. Pt nanoparticles with an average size of 1.32 nm were observed. There were stronger metal-support interactions between the oxidized tin species and Pt particles on SAPO-34 support compared to that on gamma-Al2O3 catalyst. These lead to high Pt dispersion and consequently good catalytic performance. PMID- 25924348 TI - Preparation and characterization of MWCNT-graft-PCA-Pt electrode fabricated by electrospray deposition method for proton exchange membrane fuel cell. AB - In this paper, the development and application of a novel carbon nanotube/Polycitric acid (MWCNT-graft-PCA-Pt) nanocomposite as an efficient nanocatalyst for PEM fuel cell is reported. Covalent attachment to PCA agents is the main method for the modification of CNTs with polymers. By this method electrocatalysts with a narrow particle-size distribution and good dispersion have been produced. Carbon nanotube (CNT) film electrodes have been fabricated by a novel process involving the electrostatic spray deposition (ESD) of a CNT solution. The CNT film electrodes have shown well-entangled and interconnected porous structures with good adherence to the substrate. Cyclic voltammograms (CV) of catalysts using the spongy thin layer electrode technique were obtained for the catalysts surface at evaluation and for Methanol Oxidation reaction (MOR). CV results have demonstrated that the current density and MOR activity of the MWCNT graft-PCA-Pt is respectively higher than of the MWCNT-Pt nanocatalyst. PMID- 25924349 TI - A facile route to preparation of high purity nanoporous silica from acid-leached residue of serpentine. AB - As the current cost of mineral carbonation is too high for an economically viable industrial process, it is desirable to produce value-added products from CO2 mineralization process. In this work, a facile and cost-effective process was developed for the production of high purity SiO2 from acid-leached serpentine residue. The Si extraction rate is fast even under ambient conditions due to the highly defective structure of the residue. The reaction kinetics were studied and it was found that the Si extraction rate was under a combination of chemical reaction control and film diffusion control. The SiO2 sample prepared has high purity with a nanoporous structure, which renders it a potential candidate for applications such as an adsorbent and a catalyst support. PMID- 25924350 TI - Photochemical synthesis, characterization and enhanced visible light induced photocatalysis of Ag modified TiO2 nanocatalyst. AB - Nanocomposite of titania (TiO2) and silver (Ag) has been synthesized by a photochemical deposition method. We investigated the simultaneous enhancement of visible light sensitivity and photocatalytic activities of as-prepared Ag-TiO2 nanocomposite photocatalyst. The resulting Ag-TiO2 nanomaterials were characterized by various analytical techniques including X-ray diffraction (XRD), energy-dispersive X-ray spectroscopy (EDS), transmission electron microscopy (TEM), UV-Vis diffuse reflectance spectroscopy (DRS), X-ray photoelectron spectroscopy (XPS) and photoluminescence (PL). Photocatalytic activity was evaluated by decomposition of methylene blue (MB) dye solution under simulated visible light irradiation. Ag nanoparticles were well dispersed on the surface of TiO2 and composite nanoparticles were effectively enhanced in visible light induced photocatalytic activity compared to that of Ag free TiO2. It was found that the enhanced activity is result from simultaneous effects of nano-Ag deposits by increasing the absorption capacity in visible region and by acting as electron trappers to promote charge separation of photoinduced electrons (e-) and holes (h+). The effect of the amount of Ag nanoparticles on its photoactivity under simulated visible light was also investigated. PMID- 25924351 TI - Carbon-embedded carbon nanotubes as supports of polymer electrolyte membrane fuel cell catalysts. AB - Carbon shells embedded carbon nanotubes can facilitate Pt nanoparticles loading and dispersing on the core-shell nanostructural support. Carbon shells are prepared by coating polyaniline layers on the core (carbon nanotubes) with in situ polymerization and subsequent carbonization. The carbon shell embedded carbon nanotube supported Pt catalyst reveals high electrochemical active surface area and mass activity, which are the factors of 1.4 times and 2.2 times higher than that of the pristine carbon nanotube supported Pt, respectively. In addition, the carbon shell embedded carbon nanotube supported Pt catalyst has a higher stability than the carbon nanotube supported Pt catalyst. The improved catalytic activity and stability of our new catalyst can be ascribed to the improved dispersion of Pt nanoparticles on surfaces of carbon nanotubes and the interaction between Pt nanoparticles and carbon shells. PMID- 25924352 TI - Synthesis of three-dimensional (3D) hierarchical titanate nanoarchitectures from Ti particles and their photocatalytic degradation of tetracycline hydrochloride under visible-light irradiation. AB - Three-dimensional (3D) titanates hierarchical macro/nano-architectures constructed by one-dimensional (1D) nanobelts are successfully synthesized by a hydrothermal-calcining process using metal Ti particles as a precursor. Their morphology and structure are characterized, and their photocatalytic reactivity to tetracycline hydrochloride (TC) is evaluated under visible-light irradiation. The results show that the 1D nanobelts are formed through hydrothermal reaction, and then those 1D nanobelts encircle the metal Ti particles precursor to form 3D macro/nano-architectures. The products with different phase composition, from hydrated titanium oxides to sodium titanates, are obtained by increasing the post calcining temperatures from 200 degrees C to 800 degrees C. The photocatalytic degradation of TC is observed for all samples under visible-light irradiation, and the sample calcined at 600 degrees C achieves the best photocatalytic reactivity. The visible-light performance of as-synthesized catalysts is considered as a charge-transfer mechanism initiated by the photoexcitation of the surface-complex between TC molecules and titanates, and then followed by the photosensitization mechanism. Two intermediates are identified in the photodegradation process using liquid chromatography combined with mass spectrometry. In addition, the as-synthesized titanates are stable and can be used repeatedly, showing their promising prospect in the practical applications. PMID- 25924353 TI - Nanoscale Fe(0) particles for pentachlorophenol removal from aqueous solution: temperature effect and particles transformation. AB - Pentachlorophenol (PCP), as an important contaminant which was toxic and intractable, has received extensive attention. In this paper, the temperature effect during the transformation of PCP using nanoscale Fe(0) particles was studied, and the transformation processes of PCP and iron particles was explained. The results revealed that the removal processes of PCP followed pseudo first-order kinetics. The scale of dechlorination to the transformation of PCP increased with the increase of temperature, though the transformation rate decreased after reacting for 2 h under the experimental condition. However, the initial apparent transformation rate constants were calculated to be 0.312-0.536 h(-1) at the temperature of 20-50 degrees C, which showed an increase of transformation rate along with the increase of temperature. And the surface-area normalized rate constants were calculated to be 9.50 x 10-3-1.63 x 10-2 L . h-1 . m-2. The experimental activation energy was calculated to be 15.0 kJ x mol(-1) from these rate constants using Arrhenius equation. A phenomenon observed at 50 degrees C indicated that more than one chlorine atom was removed from PCP and suggested beta-elimination might be the major pathway for transformation. Sorption experiments showed that the sorption process on the surface of particles could be ignored in the kinetics and thermodynamics models. The changes of morphologies of nanoparticles before and after reaction indicated the transformation process of iron particles, and could be used to explain the changes of activity of nanoparticles. Magnetite (Fe3O4) and/or maghemite (Fe2O3) and lepidocrocite (gamma-FeOOH) were corrosion products of iron. And along with the increase of temperature, the increased intensity of XRD peaks revealed the related a better crystallizing. PMID- 25924354 TI - Yb-doped ZnSe nanoparticles: synthesis, physical properties and photocatalytic activity. AB - In this study, Yb-doped ZnSe nanoparticles were synthesized by co-reduction method at 150 degrees C and pH = 12 for 24 h. The obtained materials were characterized by X-ray diffraction (XRD), UV-Vis diffuse reflectance spectroscopy (DRS), scanning electron microscopy (SEM) and transmission electron microscopy (TEM). Powder XRD patterns indicated that the Yb(x)Zn(1-x)Se crystals (x = 0.00 0.10) are isostructural with ZnSe. SEM and TEM images confirmed doping of Yb3+ into the lattice of ZnSe nanoparticles. The UV-Vis diffuse reflectance characteristics of the Yb-doped ZnSe samples were quite similar to that of the undoped sample and showed a strong photoabsorption at visible light range. The electrical conductivity of Yb-doped ZnSe nanomaterials was higher than pure ZnSe at room temperature, and increased with temperature. The photocatalytic activity of synthesized nanoparticles was investigated by the degradation of Orange II solution under visible light irradiation. It was observed that the color removal efficiency of Yb-doped ZnSe catalyst was much higher than that of pure ZnSe (26.28 and 77.10% after 120 min of treatment for ZnSe and Yb(0.06)Zn(0.94)Se, respectively). The results demonstrated the good photocatalytic ability of synthesized nanoparticles under visible light. Also, it was revealed that the decolorization efficiency of Orange II over Yb-doped ZnSe increased with increasing Yb loading up to 6 mol% and then decreased. PMID- 25924355 TI - Facile synthesis and characterization of PtCu core-shell and alloy nanoparticles. AB - A facile technique for the synthesis of PtCu core-shell nanoparticles (Pt@Cu and Cu@Pt) of size 10-15 nm by successive and co-reduction method is reported in this study. Optical studies such as UV-Vis and PL emission confirmed the formation of core-shell nanoparticles. The influence of particle segregation on alloy formation was studied. XRD studies revealed that the alloy formed after annealing of the core-shell nanoparticles was PtCu and PtCu3 and their average particle size was calculated to be 18 and 20 nm, respectively. The electrochemical studies of the core-shell and alloy nanoparticles revealed the segregation pattern and their stability. PMID- 25924356 TI - Preparation and characterization of Zr-N-codoped TiO2 nano-photocatalyst and its activity enhanced-mechanism. AB - Zr-N-codoped TiO2 nano-photocatalyst was prepared through sol-gel method using ammonia water and zirconium nitrate as the source of N and Zr, respectively. The resulting materials were characterized by X-ray diffraction (XRD), transmission electron microscopy (TEM), X-ray photoelectron spectroscopy (XPS) and ultraviolet visible diffuse reflectance spectroscopy (UV-vis DRS). XRD results showed that codoping with Zr and N elements could greatly inhibit the phase transformation of TiO2 from anatase to rutile. XPS analysis indicated that Zr4+ was incorporated into the lattice of TiO2 through substituting titanium atoms. Meanwhile, N was also incorporated into the lattice of TiO2 through substituting oxygen atoms and existed in the form of N-Ti-O. DRS revealed that the light absorption edge of Zr N-TiO2 was significantly red-shifted to visible region, leading to a narrower band gap and higher visible photocatalytic activity. The enhanced visible activity was attributed to the well anatase crystallite, intense light absorbance in visible region and narrow band gap. PMID- 25924357 TI - Excellent performance for preferential CO oxidition over porous carbon supported IrFe catalysts. AB - By employing mesoporous carbon (MC), active carbon (AC), XC-72 and CMK-3 as the supports, we report carbon supported IrFe catalysts in the application of preferential oxidation of CO for the first time. The optimal activity was obtained over IrFe/MC, with a CO conversion of 83.5% at 80 degrees C. This activity became even better in the second run and achieved a CO conversion of 89.5% at 60 degrees C. The as-prepared catalysts have been characterized by N2 sorption isotherms, X-ray diffraction, high-resolution scanning electron microscopy, transmission electron microscopy, Mossbauer spectroscopy, X-ray photoelectron spectroscopy and H2 temperature programmed reduction. The promising PROX performance over the IrFe/MC can be attributed to the intrinsic surface properties of MC and its specific interaction with metal species. PMID- 25924358 TI - Preparation of platinum nanoparticle catalyst for propane dehydrogenation. AB - Supported Pt nanoparticle catalysts were prepared by combing a chemical reduction method with an ultrasonic sonication loading method. Several techniques including transmission electron microscopy (TEM), nitrogen sorption technique and pyridine adsorption Fourier-transform infrared (Py-IR) were applied to characterize the physicochemical properties of these catalysts. The catalytic performance of catalysts was evaluated in the dehydrogenation of propane. The influence of the preparation method of Pt nanoparticles, the ratio of Polyvinyl Pyrrolidone (PVP) to Pt, loading method and different supports on the catalytic performance was investigated. PVP is useful for controlling the size of Pt nanoparticles and a PVP/Pt ratio of 15 is favorable to achieve a good catalytic performance. NaBH4 reduction is better than ethanol refluxing in preparing Pt nanoparticles. The ultrasonic sonication is effective to load the Pt nanoparticles onto the support channels. The mesoporous alumina proved to be a good catalyst support due to its high surface area and unique pore structure. PMID- 25924359 TI - Heating activated red mud catalytic ozonation for degradation nitrobenzene from aqueous solution: performance and influence of preparation factors. AB - Red mud (RM), a waste residue of alumina refinery, has been used to develop an effective catalyst to enhance nitrobenzene (NB) removal from aqueous solution by ozonation. The result showed that the development of catalytic activity of RM was obtained by heating activation. The effects of different factors (heating temperature and time) have been examined in batch experiments. Sample prepared by heating RM at 400 degrees C for 4 h showed the highest activity in catalytic ozonation of NB. The temperature exhibited a significant effect on the performance of both NB removal and ozone decomposition. However, the effect of the heating time was insignificant. Experiments of both catalytic ozone decomposition and hydroxyl radical (*OH) inhibiting confirmed the existence of *OH in heated RM catalytic ozonation. According to the XRD pattern, the change of mineral content was the key reason for the development of catalytic activity, especially for hematite and magnetite. PMID- 25924360 TI - Removal of ofloxacin from aqueous phase using Ni-doped TiO2 nanoparticles under solar irradiation. AB - Ni-doped TiO2 nanoparticles were prepared using hydrothermal method and characterized by means of XRD, TEM, and TGA. The detailed characterization results revealed that the catalyst possessed spherical morphology and excellent crystalline and thermal properties. Photocatalytic capability of Ni-doped TiO2 nanoparticles was estimated by means of ofloxacin degradation under solar light. About 70% degradation of ofloxacin (25 mg/L, natural pH) was obtained with 1 g/L catalyst dose. The microbiological analysis was carried by examining its antibacterial activity against E. coli culture on agar plate. The results indicated a decrease in antibacterial activity of drug solution with increase in irradiation time, which further supported the excellent catalytic behavior of the prepared Ni-doped TiO2. PMID- 25924361 TI - Preparation and photocatalytic properties of core-shell nano-TiO2 @ alpha-Al2O3 microspheres. AB - Core-shell nano-TiO2@a-Al2O3 microspheres of 5-20 MUm were prepared by the heterogeneous precipitation method combined with the hydro-thermal and calcination process using alpha-Al2O3 microspheres as substrate. Their morphologies, microstructure and crystalline phase were characterized by SEM and XRD respectively. The photocatalytic activity was evaluated by degradation of methyl orange. The as-prepared 10 wt.% nano-TiO2@alpha -Al2O3 microspheres possess alpha core-shell structure with a monolayer of nano-TiO2 particles less than 30 nm on the surface of alpha-Al2O3 microspheres. Their photocatalytic properties are largely influenced by the calcination temperature and the sample calcined at 800 degrees C for 2 h has the best photocatalytic activity. This high photocatalytic activity can be attributed to the synergetic effects of the unique structure of nano-TiO2 @alpha-Al2O3 microspheres, quantum size effect, composition of crystalline phase and crystallinity of nano-TiO2. These nano TiO2@alpha-Al2O3 microspheres may be conveniently separable and useful in practical treatment of organic waste waters due to the large particle size and high photocatalytic properties. PMID- 25924362 TI - Synthesis, features and solar-light-driven photocatalytic activity of TiO2 nanotube arrays loaded with SnO2. AB - In the present study TiO2 nanotube arrays (TNTs) were loaded with a post transition metal oxide particles namely SnO2 via incipient wet impregnation method by varying its concentration (1.59 wt%, 2.25 wt% and 2.84 wt%). The photocatalytic activity of the prepared photocatalyst was evaluated for the degradation of methylene blue (MB) in presence of natural solar light irradiation. The morphological analyses revealed that the prepared TNTs had average inner diameter of 109 nm, wall thickness of 15 nm and tube length of 7-10 MUm, respectively, while the crystalline phase and Raman spectra confirmed the 100% anatase mineral form of TiO2. Further, the presence of SnO2 in TNTs was confirmed by high resolution transmission electron microscopy (HRTEM) and X-ray photoelectron spectroscopy (XPS). The visible light absorption properties of TNTs improved drastically with increasing SnO2 loadings. The coupling effect of SnO2 and TiO2 significantly enhanced degradation efficiency of MB. An 84% degradation of MB was achieved in 6 h of irradiation under clear sky condition. PMID- 25924363 TI - Synthesis of novel magnetic cellulose-chitosan composite microspheres and their application in laccase immobilization. AB - Novel magnetic cellulose-chitosan composite microspheres were prepared by sol-gel transition method using ionic liquids as solvent for dissolution and regeneration. Subsequently, the composite microspheres activated by glutaradehyde to immobilize enzyme. Which of their structure, properties and morphology were studied by scanning electron microscopy, transmission electron microscopy, Fourier transform infrared spectroscopy, X-ray diffraction, and vibrating-sample magnetometer showed Fe3O4 nanoparticles with mean size of -10 nm were successfully embedded in the composite microspheres. The microshpheres were examined to be with the mean size of 20 MUm and good magnetic property with saturation magnetization of 30.1 emu g(-1). The effect of pH and temperature on the immobilization of laccase was also investigated. Compared with free laccase, the pH, thermal and operational stabilities of the immobilized laccase were improved and the activity recovery of immobilized laccase reached 80.6%. Immobilized laccase retained 88.9% activity after 12 reaction cycles. Therefore, the cellulose-chitosan composite microspheres were expected to be a novel support for enzyme immobilization. PMID- 25924365 TI - Cr2O3 nanoparticles modified TiO2 nanotubes for enhancing visible photoelectrochemical performance. AB - TiO2 nanotube arrays modified by nanoparticles Cr2O3 with high sensibility in the visible spectrum were prepared by annealing the anodic TiO2 nanotube arrays pre loaded with Cr(NO3)3 solution which was uniformly clung to the TiO2 nanotube arrays. The influence of the dipping time on the microstructure of the Cr2O3/TiO2 nanotubes was investigated. The microstructure and the elemental analysis were characterized by scanning electron microscope (SEM) and Energy dispersive X-ray (EDX). The photoelectrochemical performances of the as-prepared composite nanotubes were determined by measuring the photogenerated current and voltage under illumination of ultraviolet-visible (UV-vis)/visible light. The TiO2 nanotube arrays modified by Cr2O3 showed higher photocurrent values than those of unmodified TiO2 nanotube arrays. The enhanced photoelectrochemical behaviors can be attributed to the modified Cr2O3 which increases the probability of charge carrier separation and extends the range of the TiO2 photoresponse from UV to visible region due to the low band gap of 2.3 eV of Cr2O3. PMID- 25924364 TI - Effect of multi-walled carbon nanotubes and conducting polymer on capacitance of mesoporous carbon electrode. AB - Porous carbon is the most widely used electrode materials in energy storage devices. It is generally accepted that in such electrodes, mesoporosity is more desired in supercapacitor than microporosity for the ions tranportation. However, the relatively poor conductivity of porous carbon often leads to low capacitance. To improve the capacity of mesoporous carbon based electrode, we designed a composite film composed of mesoporous carbon, multiwalled carbon nanotubes (MWNTs) and conducting polymer, Poly-3,4 ethylenedioxythiophene/poly(styrenesulfonate) (PEDOT-PSS), and hoped that each component in the composed film could contribute synergetically to improve electrochemical properties. The electrochemical performance of the film was evaluated by cyclic voltammetry and constant current charge/discharge method. With the assistance of MWNTs and conducting polymer, the specific capacitance of the mesoporous carbon based electrode was amplified six times. The electrode also presented excellent charge/discharge rate and good cycling stability, retaining about 94% of its initial capacitance after 1000 cycles. The results demonstrated that mesoporous carbon is more effectively utilized with assistance of MWNTs and conducting polymer in the electrode. Such method is very promising for the future applications of the porous carbon in electrode materials for high performance electrochemical supercapacitors. PMID- 25924366 TI - Electrochemical durability of heat-treated carbon nanospheres as catalyst supports for proton exchange membrane fuel cells. AB - Carbon nanospheres is wildly used to support noble metal nanocatalysts in proton exchange membrane (PEM) fuel cells, however they show a low resistance to electrochemical corrosion. In this study, the N-doped treatment of carbon nanospheres (Vulcan XC-72) is carried out in ammonia gas. The effect of heating treatment (up to 1000 degrees C) on resistances to electrochemical oxidation of the N-doped carbon nanospheres (HNC) is investigated. The resistance to electrochemical oxidation of carbon supports and stability of the catalysts are investigated with potentiostatic oxidation and accelerated durability test by simulating PEM fuel cell environment. The HNC exhibit a higher resistance to electrochemical oxidation than traditional Vulcan XC-72. The results show that the N-doped carbon nanospheres have a great potential application in PEM fuel cells. PMID- 25924367 TI - Electrodeposition of polyaniline onto TiO2 nanoparticles/multiwalled carbon nanotubes for visible light photoelectrocatalysis. AB - In this study, polyaniline (PANI) was coated onto TiO2 nanoparticles/multiwalled carbon nanotubes (TiO2/MWCNTs) hybrid by electrochemical polymerization. Modification of TiO2/MWCNTs with PANI endows the resulted hybrid with visible light activity. The PANI/TiO2/MWCNTs hybrid shows remarkable photoelectrocatalytic activity for the degradation of RhB under visible light irradiation. The enhanced photocatalytic activity of the PANI/TiO2/MWCNTs hybrid originates from the effective charge transfer properties of the heterojunctions of PANI-TiO2 and TiO2-MWCNTs. The efficient charge transportation and high photoelectrocatalytic activity towards degradation of rhodamine B make this novel hybrid material promising for photocatalysis and for the development of photoelectrical devices. PMID- 25924368 TI - LiNi0.5Mn1.5O4 nanorod clusters as cathode material for high energy and high power lithium-ion batteries. AB - High tap density LiNi0.5Mn1.5O4 nanorod clusters composed of well-crystallined LiNi0.5Mn1.5O4 nanorods with diameter of about 150 nm and length of about 1 MUm were synthesized by a template method. beta-MnO2 nanorods synthesized by a hydrothermal method were used as the template. LiNi0.5.Mn1.5O4 nanorod clusters were then synthesized by solid-state reaction of a mixture containing beta-MnO2 nanorods, nickel acetate, and lithium hydroxide. It is found that a preheat treatment and grinding of the precursor for the solid state reaction is critical to form pure phase ordered LiNi0.5Mn1.5O4 and the nanorod cluster structure. LiNi0.5Mn1.5O4 nanorod clusters can deliver charge and discharge capacities as high as 140.61 mA h g(-1) and 128.42 mA h g(-1), respectively, at a 0.1 C rate between 3.0 and 4.9 V versus Li/Li+. Moreover, the nanorod clusters exhibit high power capability, maintaining capacities of 105.90 and 98.05 mA h g(-1) at 2 C and 5 C rates, respectively. PMID- 25924369 TI - Synthesis, characterisation and application of copper modified brookite titania photocatalyst activated by visible light. AB - Brookite titania nanomaterials modified with Copper Nanoparticles (NPs) Cu-TiO2 were prepared in this research. Hydrothermal method was used to prepare Brookite Titania whiles, copper NPs were loaded on its surface by consecutive ion adsorption and photoreduction. The photocatalyst was characterised by Transmission electron microscopy (TEM), X-ray diffraction (XRD), X-ray Photoelectron spectroscopy (XPS), UV-Vis diffuse reflectance Spectrum (UV-vis DRS) and Inductively Coupled Plasma-Atomic Emission spectroscopy (ICP-AES). The photocatalytic activity of the prepared composite was also determined by photodecolorisation of organic pollutants under visible light. Crystal Violet dye (CV) was used as a model organic pollutant. The optimum loading ratio of Cu/Ti which resulted in the best photodecolorisation efficiency was also determined. The results revealed that the sample Cu-TiO2 (Cu/Ti = 2% molar ratio) with copper particle size of 3 nm had the best photocatalytic decolorisation efficiency of 98% after 50 min of irradiation under visible light. The decolorisation efficiency of the sample Cu-TiO2 (2%) was also higher than that of commercial P25 (38%). PMID- 25924370 TI - Multi walled carbon nanotubes as sorbent for removal of crystal violet. AB - Carbon nanotubes (CNTs) possess high surface active site to volume ratio as well as controlled pore size distribution that make them high profile material with an exceptional sorption capability and high sorption efficiency compared to conventional adsorbents. In the present paper, multi walled carbon nanotubes were synthesized by chemical vapor deposition (CVD) method and were further used for the removal of dye crystal violet. Microscopic and spectroscopic techniques were used for characterization. The systematic assessments of the pH and effect of adsorbent on different concentrations of dye with respect to contact time were examined. Langmuir and Temkin models were used to describe the isotherm studies. PMID- 25924371 TI - Synthesis and characterization of LiFePO4/C cathode materials by sol-gel method. AB - The carbon coated LiFePO4 cathode materials (LiFePO4/C) were successfully synthesized by sol-gel method with glucose, citric acid and PEG-4000 as dispersant and carbon source, respectively. The microstructure and grain size of LiFePO4/C composite were characterized by X-ray diffraction, Raman spectroscopy, transmission electron microscopy. The results showed that the carbon source and calcination temperature had important effect on the graphitization degree of carbon; the carbon decomposed by citric acid had higher graphitization degree; with calcination temperature rising, the graphitization degree of carbon increased and the particles size increased. The graphitization degree and grain size were very important for improving the electrochemical performance of LiFePO4 cathode materials, according to the experimental results, the sample LFP-700 (LFP C) which was synthesized with citric acid as dispersant at 700 degree C had lower polarization and larger discharge capacity. PMID- 25924372 TI - Improved photovoltaic performance of multiple carbon-doped ZnO nanostructures under UV and visible light irradiation. AB - We report synthesis of multiple carbon-doped ZnO nanostructures by using carbon cloth as substrates to obtain multiple hollow ZnO microtube-nanowire structures. X-ray diffraction, X-ray photoelectron spectroscopy, and transmission electron microscopy analysis clearly show that carbon is doped into ZnO through substitution of carbon for oxygen in the growth and annealing processes. Upon exposure to 633-nm red laser, a distinct photoresponse can be observed, which indicates that carbon doping in ZnO can well extend its light harvesting to visible light region. Furthermore, a prototype of photovoltaic cell was fabricated to demonstrate the photovoltaic performance of multiple carbon-doped ZnO nanostructures under UV and visible light irradiation. This result shows that carbon-doped ZnO can act as effective photoactive materials for photoelectric components. PMID- 25924373 TI - Preparation of hollow titania spheres and their photocatalytic activity under visible light. AB - Hollow titania spheres with different shell thicknesses were facilely prepared starting from TiCl4 and using ploystyrene methyl acrylic acid latexes as the sacrificial templates. The average diameters of the hollow titania spheres ranging from 294 to 340 nm were tuned by changing the weight ratios of TiO2 to ploystyrene methyl acrylic acid latex from 0.8:1 to 1.4:1. The hollow titania spheres were constructed by the small-sized anatase TiO2 nanoparticles with the average diameter of ca. 18 nm (SEM). In addition to UV light absorption caused by the primary anatase TiO2 nanoparticles, the hollow titania spheres also had visible light absorption performance. Photocatalytic results showed that all the hollow titania spheres had higher photocatalytic activity for the degradation of phenol under visible light irradiation than the commercial TiO2 nanoparticles (P25). The photocatalytic activity of the hollow titania spheres increased with the increase in sell thickness, being consistent with their visible light absorbance. The visible light photocatalytic activity was probably due to the presence of additional energy levels between valence and conduction bands, which were caused by the formation of oxygen bridging bonds between the primary TiO2 nanoparticles. PMID- 25924374 TI - Density functional theory studies of the palladium-silver(211) stepped surfaces. AB - Twenty-five kinds of Palladium-silver alloy stepped surface models are established based on the pure Pd(211) stepped surface system. The surface energies, work function, d-band center and the d-band local density of states (d LDOS) on these different Palladium-silver alloy stepped surface configurations were investigated using the generalized gradient approximation (GGA) of density functional theory (DFT). The calculation results show that both the concentration and position of the doped Ag atoms have effect on these four surface parameters. The surface stability is weakened with increase of the concentration of the doped Ag atoms. The work function is more sensitive to the position of Ag atoms than the Ag concentration, while the surface energy is more depended on the Ag concentration. The substitution of Pd atoms by Ag on the pure Pd(211) stepped surface leads to the reduction of the work function. On the other hand, the d band center of the surface Pd atoms shifts to the Fermi energy level when the Ag atoms substitute the Pd atoms in the third layer. Furthermore, the magnitude of the surface Pd d-band center increases with the content of Ag atoms from the bottom to the top along the stepped surface, and the bonding activity of the surface Pd atoms enhances. The further d-LDOS analysis shows that the Pd d electronic structure changed with the substitution by Ag atoms on the stepped surface. PMID- 25924375 TI - Catalytic soot oxidation over Ce- and Cu-doped hydrotalcites-derived mesoporous mixed oxides. AB - Ce- and Cu-doped hydrotalcites derived mixed oxides were prepared through co precipitation and calcination method, and their catalytic activities for soot oxidation with O2 and O2/NO were investigated. The solids were characterized by XRD, TG-DTG, BET, H2-TPR, in situ FTIR and TPO techniques. All the catalysts precursors showed the typical diffraction patterns of hydrotalcite-like materials having layered structure. The derived mixed oxides exhibited mesoporous properties with specific surface area of 45-160 m2/g. After both Ce and Cu incorporated, mixed crystalline phases of CuO (tenorite), CeO2 (fluorite) and MgAl2O4 (spinel) were formed. As a result, the NO(x) adsorption capacity of this catalyst was largely increased to 201 MUmol/g, meanwhile, it was also the most effective to convert NO into NO2 in the sorption process due to the enhanced reducibility. The in situ FTIR spectra revealed that NO(x) were stored mainly as chelating bidentate and monodentate nitrate. The interaction effect between Cu and Ce in the mixed oxide resulted in different NO(x) adsorption behavior. Compared with the non-catalyzed soot oxidation, soot conversion curves over the mixed oxides catalysts shift to low temperature in O2. The presence of NO in the gas phase significantly enhanced the soot oxidation activity with ignition temperature decreased to about 320 degrees C, which is due to NO conversion to NO2 over the catalyst followed by the reaction of NO2 with soot. This explains the cooperative effect of Ce and Cu in the mixed oxide on soot oxidation with high activity and 100% selectivity to CO2 formation. PMID- 25924376 TI - Electrocatalytic reduction of CO2 to formic acid on palladium-graphene nanocomposites gas-diffusion electrode. AB - Palladium-graphene nanocomposites catalysts for the conversion of CO2 to formic acid were prepared by means of sodium borohydride reduction of K2PdCl4 in a graphite oxide suspension, and characterized by X-ray diffraction (XRD), scanning electron microscopy (SEM), transmission electron microscopy (TEM) and cyclic voltammetry (CV) technologies. The characterization results showed that graphene with a d-spacing of 3.82 A was fabricated, and palladium nanoparticles with an average size of 3.8 nm were highly dispersed in the graphene sheets with amorphous structure. The cyclic voltammogram analyses indicated palladium graphene nanocomposites catalysts posed high catalytic activity for the CO2 reduction and the rate-determining step was the CO2 diffusion process from bulk solution to electrode surface. Then the electrocatalytic reduction of CO2 was investigated in a diaphragm electrolysis device, using Pd/graphene gas-diffusion electrode as a cathode and a Ti/RuO2 net anode. The reduction process was optimized by the application of factorial design 2(3) (voltage, reaction time and electrolyte concentration) and response surface methodology (RSM). Optimum conditions for the production of formic acid were given as following: voltage: 5.1 V, reaction time: 50.4 min and electrolyte concentration: 0.5 mol L(-1). The yield of formic acid formation was 3157.7 mg L(-1) and Faraday efficiency was 86.9% under the optimum operation condition. PMID- 25924377 TI - Nickel cobalt oxide nanowire-reduced graphite oxide composite material and its application for high performance supercapacitor electrode material. AB - In this paper, we report a facile synthesis method of mesoporous nickel cobalt oxide (NiCo2O4) nanowire-reduced graphite oxide (rGO) composite material by urea induced hydrolysis reaction, followed by sintering at 300 degrees C. P123 was used to stabilize the GO during synthesis, which resulted in a uniform coating of NiCo2O4 nanowire on rGO sheet. The growth mechanism of the composite material is discussed in detail. The NiCo2O4-rGO composite material showed an outstanding electrochemical performance of 873 F g(-1) at 0.5 A g(-1) and 512 F g(-1) at 40 A g(-1). This method provides a promising approach towards low cost and large scale production of supercapacitor electrode material. PMID- 25924378 TI - Role of interfacial strain in fiber-shaped solar cell based on TiO2 nanotube arrays. AB - This study reports the first equivalent circuit model for all-solid, fiber shaped, dye-sensitized solar cell (DSSC), in order to reveal the internal catalytic reaction mechanism in this new type of solar cells. The counter electrode of the winding structure leads to negative impedance under high frequency, which is consistent with the model. The study further investigates the strain of the TiO2 nanotube (TNT) arrays and its influence on interfacial mechanism. As a unique characteristic of fiber-shaped DSSC, the strain of the TNT arrays strengthens the permeation of the electrolyte. The permeation not only improves the efficiency of interfacial photochemical reactions, but also magnifies the probability of the side reactions on the electrolyte/Ti interfaces. Therefore, both the variation of impedance and overall conversion efficiency exhibit similar inflection points. Different from that of traditional plate-type device, the interfacial impedance in the equivalent circuit of fiber-shaped devices should be treated as a variable for changes in TiO2 and CuI layers. PMID- 25924379 TI - Theoretical study of the catalytic CO oxidation by Pt catalyst supported on Ge doped grapheme. AB - The geometry, electronic structure and catalytic properties of the anchored Pt atom on the Ge-doped graphene (Pt/Ge-graphene) substrates are investigated using the first-principles computations. It is found that Ge atoms can form strong covalent bonds with the carbon atoms at the vacancy site on the defective graphene. The Ge-graphene as substrate can effectively anchored Pt atoms and form supported Pt catalyst, which exhibits good catalytic activity for CO oxidation with a two-step route, starting with the Langmuir-Hinshelwood (LH) reaction followed by the Eley-Rideal (ER) reaction. The Ge dopant in graphene plays a vital role in enhancing the substrate-adsorbate interaction through facilitating the charge redistribution at their interfaces. The Ge-graphene can be used as the reactive support to control the stability and activity of the Pt catalysts. This work provides valuable guidance on fabricating carbon-based catalysts for CO oxidation, and validates the reactivity of single-atom catalyst for designing atomic-scale catalysts. PMID- 25924380 TI - Promotion effect of Au on N/TiO2 for hydrogen generation from water splitting. AB - A series of N/TiO2 were prepared by sol gel method, which was acted as photocatalysts. These photocatalysts were characterized by Transmission Electronic Microscopy (TEM), Reflective UV-Visible spectra and X-ray diffraction (XRD). The photocatalysts were applied for hydrogen gas generation from the water splitting reaction under visible light. Various N/Ti addition ratios could change the hydrogen generation rate. For the addition ratios N/Ti = 10 of N/TiO2, we obtained the maximum hydrogen production rate is about 38 MUmol h(-1) g(-1). By loading the Au into the N/TiO2, the hydrogen generation rate was increased. We could get the best hydrogen production rate of 0.05 wt% Au/N/TiO2 is about 517 MUmol h(-1) g(-1). PMID- 25924381 TI - Effect of sulfuric acid on textural properties and catalytic performance of ruthenium-containing ordered mesoporous carbon prepared via a direct RuCl3/SBA-15 hard templated method. AB - Ruthenium-containing ordered mesoporous carbon (Ru-OMC) catalysts with highly dispersed Ru nanoparticles semi-embedded in carbon framework were prepared via a direct RuCl3/SBA-15 hard templated method. The effect of sulfuric acid on the texture structure and catalytic performance of Ru-OMC were studied. The status of Ru nanoparticles and mesoporous structure of Ru-OMC catalysts were characterized by X-ray diffraction (XRD), X-ray fluorescence (XRF), nitrogen sorption, scanning electron microscopy (SEM), high resolution transmission electron microscopy (HRTEM) and CO chemisorption techniques. The addition of appropriate amount of sulfuric acid is necessary to improve the ordered mesoporous structure of Ru-OMC catalysts. The framework of carbon structure shrinks with the increase in sulfur acid contents, which is proved by a slight decrease in surface area and increase in pore diameters for Ru-OMC with different sulfur contents. The turnover frequency (TOF) for Ru-OMC reaches the highest up to 3.98 s(-1) in benzene hydrogenation with optimized sulfur acid content of 0.08 mmol/g sucrose. PMID- 25924382 TI - Lanthanum and zirconium co-doped ZnO nanocomposites: synthesis, characterization and study of photocatalytic activity. AB - Nanocomposits of zinc oxide co-doped with lanthanum and zirconium were prepared using the modified sol-gel method. The samples were characterized by X-ray diffraction (XRD), transmission electron microscopy (TEM), energy dispersive spectroscopy (EDS), diffuse reflectance spectroscopy (DRS), and BET surface area measurement. For comparison, the La and Zr mono doped ZnO have also been prepared under the same conditions. The XRD results revealed that all the materials showed a hexagonal wurtzite crystal structure. It was found that the particle size of La Zr-doped ZnO is much smaller as compared to that of pure ZnO. The effect of operational parameters such as, doping concentration, catalyst loading, pH and initial concentration of methylene blue on the extent of degradation was investigated. The photocatalytic activity of the undoped ZnO, mono-doped and La Zr-ZnO photocatalysts was evaluated by the photocatalytic degradation of methylene blue in aqueous solution. The presence of lanthanium and/or zirconium causes a red shift in the absorption band of ZnO. The results show that the photocatalytic activity of the La-Zr-ZnO photocatalyst is much higher than that of undoped and mono-doped ZnO, resulting from the La and Zr synergistic effect. The co-operation of the lanthanum and zirconium ion leads to the narrowing of the band gap and greatly improves the photocatalytic activity. The photocatalyst co doped with lanthanum and zirconium 4 mol% shows the best photoactivity and photodecomposition efficiencies were improved by 92% under UV-Vis irradiation at the end of 30 min, compared with the pure and mono doped samples. PMID- 25924383 TI - Ion-exchangeable titanate nanotubes with visible light responsive photocatalytic activities for dyes degradation. AB - Sn(2+)- and Pb(2+)-substituted NaHTi3O7 nanotubes were prepared by a hydrothermal synthesis method followed by ion-exchange reaction. The samples were characterized by XRD, SEM, TEM, XPS and UV-visible diffuse reflectance spectroscopy. The photocatalytic activities were investigated for the photodegradation of methylene orange (MO) and methylene blue (MB) under visible light irradiation. The results indicate that Sn2+ and Pb2+ substitutions could have significant impacts on the optical properties and photocatalytic activities of samples. Both Sn(2+)- and Pb(2+)-substituted NaHTi3O7 nanotubes show activities for methylene orange and methylene blue photodegradation under visible light irradiation. With better absorption of visible light, the Sn-NaHTi3O7 sample showed higher activity than Pb-NaHTi3O7. PMID- 25924384 TI - Removal of Congo red dye molecules by MnO2 nanorods. AB - Uniform MnO2 nanorods were synthesized successfully via a facile and effective hydrothermal approach. Scanning electron microscope images showed that the average diameter of the as-synthesized nanorod is about 30 nm and the length of that is about 5 MUm, respectively. Photocatalytic experimental results indicate that Congo red can be degraded nearly completely (over 97%) after visible light irradiation of 120 min, demonstrating potential applications of such nanorod structures for wastewater purification. PMID- 25924385 TI - Photocatalytic degradation of direct red-23 dye with ZnO nanoparticles. AB - This work reports a facile and large-scale synthesis of ZnO nanoparticles by simple self-propagating solution combustion method using dextrose as fuel and their effective use as a photocatalyst for photocatalytic degradation of Direct Red-23 (DR-23) dye in an immersion well type photo-reactor. The prepared ZnO nanoparticles were characterized by various analytical tools using field emission scanning electron microscopy (FESEM) attached with energy dispersive spectroscopy (EDS), X-ray diffraction (XRD) pattern, Fourier transform infrared (FTIR) spectroscopy and UV-Vis. spectroscopy measurements. The detailed characterizations confirmed that the prepared ZnO nanoparticles are pure, well crystalline and possessing wurtzite hexagonal phase. Almost complete photo degradation of the DR-23 was observed in 110 min. under UV irradiation in presence of ZnO nanoparticle photocatalyst. This study reveals that simply prepared ZnO nanomaterials are effective photocatalyst for the photocatalytic degradation of various toxic chemicals and pollutants. PMID- 25924386 TI - Hierarchical alpha-Fe2O3 hollow spheres: facile synthesis, formation mechanism and their application in Cr(VI) removal. AB - In this paper, a simple and efficient route had been developed for the synthesis of hierarchical alpha-Fe2O3 hollow microspheres with open pores on the shells. All chemicals used were low-cost compounds and environmentally benign. The as prepared samples were characterized by field emission scanning electron microscope (FESEM), X-ray diffraction (XRD) and Brunauer-Emmett-Teller (BET) gas sorptometry. The results showed that the chelating ligand SSA and the initial pH value of the solution played important roles in the morphological control of the alpha-Fe2O3 nanostructures. A possible formation mechanism was described based on the experimental results. The obtained alpha-Fe2O3 hollow spheres exhibited an excellent adsorption capacity for Cr(VI) ions because of their high surface area and a good ability to preserve the accessible surface. PMID- 25924387 TI - Surface acidity effects of Al-SBA-15 mesoporous materials on adsorptive desulfurization. AB - SBA-15 and Aluminum-substituted SBA-15 with Si/Al molar ratio 10 (Al-SBA-15(10)) mesoporous materials were directly synthesized by a hydrolysis approach and characterized by a powder X-ray diffraction (XRD), N2 physisorption analysis and Fourier transform infrared (FTIR) etc. The relative number of hydroxyl groups was investigated by in situ FTIR systematically. The acid type and acid strength of the adsorbents were monitord by FTIR at 423 K and 673 K, respectively, utilizing pyridine as a probe. Desulfurization performances of the adsorbents were investigated via static adsorption experiment. Gas chromatography-sulfur chemiluminescence detector (GC-SCD) was employed to detect the sulfur compounds in model fuels before and after treated by the adsorbents. The calcined Al-SBA 15(10) material shows well-ordered hexagonal mesostructure and strong Lewis acid sites (L acid) and weak Bronsted acid sites (B acid). The number of hydroxy on the surface of the Al-SBA-15(10) is more than that of SBA-15, which is beneficial to further modifications such as spontaneous monolayer dispersion. Desulfurization performance of the adsorbents is affected by surface acidity of adsorbents and the constituent of model fuels (olefins, arene, etc.). The thiophene and olefins adsorbed on the B acid site of the adsorbent may occur subsequently alkylation reactions, which may block the pores of the adsorbents and thus cause the reduction of desulfurization capacity. PMID- 25924388 TI - Influence of calcination temperature on the properties of titanium oxide sulfur recovery catalysts. AB - To study the effect of calcination temperatures on the sulfur recovery catalysts, titanium oxide (TiO2), as sulfur recovery catalysts, were treated at four calcination temperatures of 300 degrees C, 500 degrees C, 700 degrees C and 900 degrees C. The structure of the catalysts were characterized by X-ray powder diffraction (XRD), Raman, transmission electron microscopy (TEM), Scanning electron microscopy (SEM), temperature thermogravimetry (TG) and differential scanning calorimetry (DSC). The results showed that with the calcination temperature increasing, the particle size of the TiO2 catalysts increases but the surface area and total pore volume decrease. The extent of reduction was more serious after calcination at 500 degrees C. Rutile phase were formed at calcination temperature about 700 degrees C. On the basis of these results, a scheme for the change of TiO2 with increasing calcination temperatures was proposed. The Claus catalytic activity of the TiO2 catalysts was evaluated in the traditional conditions. It was found that the Claus catalytic activity, which decreased a little when the calcination temperature was no more than 500 degrees C but much once the calcination temperature was more than 500 degrees C, was not only related to the surface area and pore volume, but also the phase of the TiO2. The activity of rutile was less than the anatase and a possible reaction pathway to reveal this mechanism was proposed. PMID- 25924389 TI - Microwave-assisted synthesis of gold, silver, platinum and palladium nanostructures and their use in electrocatalytic applications. AB - Microwave-assisted ionic liquid method was used for synthesis of various noble metals, such as gold, silver, platinum and palladium nanomaterials. This route does not employ any template agent, surface capping agents or reducing agents. The process is fast, simple and of high yield. Different metal precursors in various ionic liquids media (1-butyl-3-methylimidazolium tetrafluoroborate, octyl pyridinium hexaflurophosphate and 1-octyl-3-methylimidazolium hexaflurophosphate) were applied to produce metal nanomaterials. Silver, platinium and palladium nanoparticles exhibit spherical morphology while nanosheets with high aspect ratio were obtained for gold. These metal nanostructures were incorporated into a carbon ionic liquid electrode to investigate their electrocatalytic properties. It was found that synthesis in different ionic liquids result in different activity. Excellent electrocatalytic effects toward adenine, hydrazine, formaldehyde and ethanol were observed for the modified electrodes with different nanoparticles synthesized in 1-butyl-3-methylimidazolium tetrafluoroborate. The high conductivity, large surface-to-volume ratio and active sites of nanosized metal particles are responsible for their electrocatalytic activity. In contrast, the carbon ionic liquid electrode modified with synthesized metal nanoparticles in octyl pyridinium hexaflurophosphate and 1-octyl-3-methylimidazolium hexaflurophosphate showed negligible activity for detection of these probes. PMID- 25924390 TI - Catalytic performance and kinetics of wire-mesh honeycomb catalyst for reduction of NO with NH3. AB - V2O5/TiO2/Al2O3 catalysts with wire-mesh honeycomb (WMH) structure were prepared with three sequent steps: anode oxidation, sol-gel process and impregnation, and used for selective catalytic reduction (SCR) of nitric oxide (NO) with ammonia (NH3). According to the results of BET specific surface area (S(BET)), X-ray diffraction (XRD), and energy-dispersive X-ray analysis (EDX), the effective V2O5/TiO2/Al2O3 structure was formed on the surface of aluminum mesh. The catalytic activity was examined, and the results showed that the excellent treatment efficiency of WMH catalyst was obtained when the temperature was in the range of 473 to 673 K. The NO conversion rate was 86% at 673 K when the space volocity (SV) was 5000 h(-1), the NO conversion rate was both enhanced when increasing NH3/NO ratio or influent NO concentration. The kinetic analysis showed that the catalytic reaction followed pseudo-first-order kinetic model, the SCR reaction depended on chemical kinetics at low temperature (T < 493 K) and mass transfer at high temperature (T > 513 K). PMID- 25924391 TI - Study on biomass based nanofibers preparation by electrospinning. AB - The electrospinnability of lignin was improved by blending in a solution of polyacrylonitrile (PAN) resulting in the reduction of the nanofiber cost. The compositions containing low concentration of the lignin shows good spinnability. The influences of main process parameters, such as flow rate, voltage and concentration on the nanofibers morphology were studied by scanning electron microscope (SEM). The results indicated that by changing parameters, nanofibers with good morphology were obtained. According to the study, when other parameters were kept unchanged, the parameters to prepare ideal nanofibers are as follows: flow rate is 0.04 mm/h; the voltage is 25 kV and the lignin amount is 2 wt.%. The results of this work showed that this novel method is a quite promising technique for preparation of biomass based carbon nanofiber precursors. PMID- 25924392 TI - Hydrothermal synthesis and photocatalytic performance of uniform alpha-Fe2O3 nanocubes. AB - In this paper, large scale uniform alpha-Fe2O3 nanocubes are synthesized through a facile and effective hydrothermal route. The structure and morphology of the resultant products are characterized by X-ray diffraction (XRD), and scanning electron microscope (SEM). A possible growth mechanism for alpha-Fe2O3 nanocubes is proposed based on the experimental results. Photocatalytic test reveals that Congo red can be degraded nearly completely (over 95%) after visible light irradiation of 40 min. In addition, methyl orange and methylene blue aqueous solution degradation experiments also are conducted in the same condition, revealing the versatile potential applications of the product in wastewater purifications. PMID- 25924393 TI - Hydrogen production by partial oxidation of methanol over gold supported on Fe2O3. AB - Partial oxidation of methanol (POM) to produce hydrogen was investigated over Au/Fe2O3 catalysts. The catalysts were prepared by inverse co-precipitation method. The influence of catalyst synthesis parameters such as precipitant, gold loading, calcination temperature and reaction parameter such as reaction temperature on POM reaction to produce hydrogen were investigated. The catalysts have been characterized by means of TGA, BET, XRD, TEM, SEM-EDS and XPS analyses. TGA and DTGA profiles clearly indicate that minimum decomposition temperature required to obtain Fe2O3 in Au/Fe2O3 catalysts is 660 K. SEM-EDS analysis confirms that Au and Fe in Au/Fe2O3 are homogeneously distributed over the agglomerate. A detailed microstuctural characterization of Au/Fe2O3 sample by XRD, TEM and XPS analyses has shown that nanometer sized gold particles with oxidized gold species is in predominant amount in the uncalcined catalysts sample. The mean particle size and metallic state of gold particles increase with increasing calcination temperature. A highly active Au/Fe2O3 catalyst is obtained by using Na2CO3 as precipitant with lower gold loading and calcination at 673 K. The catalytic behavior of the Au/Fe2O3 catalyst is related not only to the gold but also to the chemical state of the support. The effect of reaction temperature on the catalytic performance of the Au/Fe2O3 catalysts was studied in the temperature range of 423 to 523 K. Oxygen conversion was complete through out the examined temperature range. Methanol conversion increased with rise in temperature and attains 100% at 503 K; Hydrogen selectivity increased with rise in reaction temperature up to 523 K and then dropped off. The overall reactions involved are methanol combustion, partial oxidation, steam reforming and decomposition. CO produced by methanol decomposition and/or by reverse water gas shift is subsequently transformed into CO2 and H2 by the water gas shift and/or CO oxidation. PMID- 25924394 TI - Visible light driven alpha-Fe2O3 nanorod photocatalyst. AB - alpha-Fe2O3 nanorods are controlled prepared by a facile hydrothermal process followed by a calcination treatment. The experiment results indicate that the morphology of the as-obtained product depends greatly on the quantity of NaOH. The photocatalytic performances of the as-prepared samples were evaluated by photocatalytic decolorization of Congo red solution at ambient temperature. The results indicate that the photocatalytic activity of the alpha-Fe2O3 nanorods is superior to alpha-Fe2O3 nanoparticles and microplates, revealing the versatile potential applications of the product in wastewater purifications. PMID- 25924395 TI - Preparation of micro/nanostructure TiO2 spheres by controlling pollen as hard template and soft template. AB - In this paper, micro/nanostructure TiO2 spheres were synthesized by a sunflower pollen induced and self-assembly mineralization process, in which a titania precursor and pollen reacted in one-pot at normal pressure. In this paper, the bio-template advantage, as hard and soft template is fully demonstrated. The superiority of our synthesis is that we not only can control pollen as hard template, but also can control it as soft template only by changing reactions temperature. Under 80 degrees C of water bath, TiO2 microspheres which replicated the morphology of pollen were prepared by controlling pollen as hard template. Under 100 degrees C, hierarchical TiO2 spheres with complicated morphology, different from pollen template, were synthesized by using pollen as soft template. At the same time, judicious choice of the amount of pollen affords the synthesis of hierarchical structures spheres with adjustable morphology and crystal structure. The morphology can be tuned from microspheres constructed from TiO2 nanorods to nanospheres constructed from TiO2 nanoparticles, and the crystal structure can be tuned from rutile to anatase. More over this anatase phase can be keep better even at high temperature of 1000 degrees C. The as-prepared micro/nano structure photocatalysts not only have high photocatalytic activities, but also have good separability and reuse performance. PMID- 25924396 TI - Synthesis and characterization of Co-SBA-15 via rapid ultrasonic technique and their catalytic properties. AB - The rapid preparation of SBA-15 with cobalt (Co) introduction was performed via the ultrasonic irradiation in combination with "pH-adjusting" method. The catalytic properties of the synthesized Co-SBA-15 were investigated by examining the oxidation of styrene with hydrogen peroxide. The effect of pH values on the textural properties were extensively investigated using small-angle X-ray Diffraction (XRD), N2 adsorption-desorption isotherms and Transmission Electron Microscipy (TEM). The characterization results showed that the incorporation of Co by ultrasonic method did not destroy the mesoporous structure of SBA-15. The Co-SBA-15 catalyst with Co/Si (the molar ratio of 0.03) at pH of 7.5 exhibited a well-ordered hexagonal mesoporous structure with higher surface area and pore volume. This catalyst had excellent styrene conversion and selectivity to benzaldehyde of 21.8% and 92.3%, respectively. The physicochemical properties and catalytic activity of the Co-SBA-15 catalysts via ultrasonic technique possessed the comparable characteristics as those prepared via conventional hydrothermal method. PMID- 25924397 TI - Electrocatalytic oxidation of four low-carbon alcohols at Pd nanoparticle modified indium tin oxide electrode. AB - A Pd nanoparticle modified indium tin oxide (Pd NPs/ITO) electrode was prepared by cyclic voltammetry (CV) methods. The surface morphology of the modified electrode was characterized by scanning electron microscopy (SEM). The Pd NPs/ITO electrode exhibits excellent electrocatalytic activity towards the oxidation of four low-carbon alcohols including methanol, ethanol, propanol and isopropanol in alkaline electrolyte at room temperature. The effects of reactant concentration and scan rate on the alcohols electrocatalytic oxidation at the Pd NPs/ITO electrode were discussed in detail and the electrocatalytic oxidations of four alcohols are confirmed as diffusion-controlled process from their similar CV characteristic. These low-carbon alcohols or their dissociation products are adsorbed on the surface of Pd NPs/ITO electrode, and simultaneously inhibit the adsorption and desorption of hydrogen, leading to the dominant of alcohol oxidation. The oxidation processes of four low-carbon alcohols are irreversible on Pd NPs/ITO electrode. The activity order of alcohol oxidation on Pd NPs/ITO electrode is identified as ethanol > propanol > methanol > isopropanol. The four alcohols can be easily identified from their positions of oxidation peak. PMID- 25924398 TI - Hydrothermal synthesis of flower-like MoS2 nanospheres for electrochemical supercapacitors. AB - Flower-like MoS2 nanospheres were synthesized by a hydrothermal route. The structure and surface morphology of the as-prepared MoS2 was characterized by X ray diffraction (XRD) and scanning electron microscopy (SEM). The supercapacitive behavior of MoS2 in 1 M KCl electrolyte was studied by means of cyclic voltammetry (CV), constant current charge-discharge cycling (CD) and electrochemical impedance spectroscopy (EIS). The XRD results indicate that the as-prepared MoS2 has good crystallinity. SEM images show that the MoS2 nanospheres have uniform sizes with mean diameter about 300 nm. Many nanosheets growing on the surface make the MoS2 nanospheres to be a flower-like structure. The specific capacitance of MoS2 is 122 F x g(-1) at 1 A x g(-1) or 114 F x g(-1) at 2 mv s(-1). All the experimental results indicate that MoS2 is a promising electrode material for electrochemical supercapacitors. PMID- 25924399 TI - Study on the electrochemical behavior of nanostructure S-doping manganese oxide as a novel supercapacitor material. AB - A nanostructure S-doping manganese oxide (MnO(x)S(y)) amorphous powder was prepared by a homogeneous coprecipitation method for supercapacitor application. The structure and surface morphology of the as-prepared MnO(x)S(y) powder were characterized by X-ray diffraction (XRD), scanning electron microscopy (SEM), elemental analysis and X-ray photoelectron spectroscopy (XPS). The as-prepared nanostructure S-doping manganese oxide powder was confirmed with a chemical composition of MnO1.26S0.23 by elemental analysis, in which the average oxidation state of manganese is about 3.1. The supercapacitive behavior of the as-prepared MnO1.26S0.23 was studied by means of cyclic voltammetry (CV) and constant current charge-discharge cycling (CD) experiments in 1 mol L(-1) Na2SO4 electrolyte. A maximum specific capacitance of 181 F g(-1) was obtained for MnO1.26S0.23. Furthermore, the specific capacitance remained 97.3% of the original value after 500 cycles. The superior capacitive behavior and better cycling stability indicate that the amorphous nanostructure MnO(x)S(y) maybe a promising electrode material for electrochemical capacitors. PMID- 25924400 TI - Catalytic mechanism of cationic red GTL at wide pH using the Mo-Zn-Al-O nanocatalyst under room conditions. AB - Catalytic mechanism of cationic red GTL at wide pH using the Mo-Zn-Al-O nanocatalyst under room conditions was investigated. The experimental results indicate that initial pH significantly affected the removal of cationic red GTL, the removal of COD, the pH value and residual oxygen in the reaction. In the range of pH value from 4 to 10, decolorization of cationic red GTL was almost above 90%. COD removal efficiency was enhanced with the decrease of pH in CWAO process and 79% of the COD was removed at pH 4.0, whereas only 57% COD removal was observed at pH 10.0. The terminal pH was in the range of 5.0-6.0 and the highest terminal concentrations of aqueous oxygen with 5.5 mg/L were observed at pH = 4.0. The radical inhibition experiments also carried out and the generation of *OH and 1O2 in catalytic wet air oxidation process were detected. It was found that the degradation of cationic red GTL occurs mainly via oxidation by 1O2 radical generated by Mo-Zn-Al-O nanocatalyst under acid conditions and *OH radical under alkaline conditions. PMID- 25924401 TI - Removal performance and mechanism of ibuprofen from water by catalytic ozonation using sludge-corncob activated carbon as catalyst. AB - To discover the catalytic activity of sludge-corncob activated carbon in catalytic ozonation of Ibuprofen, the performance of sludge-corncob activated carbon and three selected commercial activated carbons as catalysts in catalytic ozonation was investigated. The observation indicates the degradation rate of Ibuprofen increases significantly in the presence of sludge-corncob activated carbon and the catalytic activity of sludge-corncob activated carbon is much higher than that of the other three commercial activated carbons. Ibuprofen's removal rate follows pseudo-first order kinetics model well. It is also found that the adsorption removal of Ibuprofen by sludge-corncob activated carbon is less than 30% after 40 min. And the removal efficiency of Ibuprofen in the hybrid ozone/sludge-corncob activated carbon system is higher than the sum of sludge corncob activated carbon adsorption and ozonation alone, which is a supportive evidence for catalytic reaction. In addition, the results of radical scavenger experiments demonstrate that catalytic ozonation of Ibuprofen by sludge-corncob activated carbon follows a hydroxyl radical reaction pathway. During ozonation of Ibuprofen in the presence of activated carbon, ozone could be catalytically decomposed to form hydrogen peroxide, which can promote the formation of hydroxyl radical. The maximum amount of hydrogen peroxide occurs in the presence of sludge corncob activated carbon, which can explain why sludge-corncob activated carbon has the best catalytic activity among four different activated carbons. PMID- 25924402 TI - Adsorption kinetics of benzotriazole and its derivatives by nano Zn-Al-O. AB - Benzotriazole and its derivatives are important industrial auxiliaries, which are serious pollution sources in the natural aquatic environment. Benzotriazole and its derivatives adsorption by a novel nano absorbent (nano Zn-Al-O binary metal oxide, named as ZAO) being explored as an effective water treatment method, was carried out in this study. Results showed that benzotriazole and its derivatives were all effectively adsorbed from water by ZAO. Removal efficiencies of benzotriazole, 5-methyl-benzotriazol and 5,6-dimethyl-benzotriazole with 5 g/L adsorbent dosage achieved 89%, 81% and 92%, respectively. The adsorption kinetics and isotherm models were used to express the adsorption process and discuss the adsorption mechanism. The adsorption kinetics well followed pseudo-second-order model, indicating that chemical adsorption dominated the adsorption. Adsorption isotherm was well expressed by Freundlich model. Structure characteristics of benzotriazole and its derivatives had great effect on their adsorption. Hydrogen bond interaction was considered as the main mechanism for the surface adsorption. However, hydrophobic interactions played an important role in 5,6-dimethyl benzotriazole adsorption due to its weak polarity. PMID- 25924403 TI - Synthesis of Pd nanoparticles decorated with graphene and their application in electrocatalytic degradation of 4-chlorophenol. AB - Pd/graphene catalysts were prepared in situ from graphite oxide and palladium salts by the hydrogen-reduction method and were then used for the construction of Pd/graphene gas-diffusion electrodes (GDE). The prepared catalysts were characterized by X-ray diffraction (XRD), transmission electron microscopy (TEM) and differential pulse voltammetry (DPV) techniques. In the Pd/graphene catalysts, Pd particles, with an average size of 3.6 nm and an amorphous structure, were highly dispersed in the graphene. The Pd/graphene catalysts accelerated the two-electron reduction of O2 to H2O2 by feeding air, which favors the production of hydroxyl radicals (HO*). In the electrolytic system, HO* was determined in the reaction mixture by the electron spin resonance spectrum (ESR). The dechlorination degree of 4-chlorophenol reached approximately 90.5% after 80 min, and the removal efficiency and the average removal efficiency of 4 chlorophenol, in terms of total organic carbon (TOC) after 120 min, reached approximately 93.3% and 85.1%, respectively. Furthermore, based on the analysis of electrolysis intermediates by high performance liquid chromatography (HPLC) and ion chromatography (IC), a reaction scheme was proposed for the Pd/grapheme GDE catalytic degradation of 4-chlorophenol. PMID- 25924404 TI - TiO2/bi A-SPAES(Ds 1.0) composite membranes for proton exchange membrane in direct methanol fuel cell (DMFC). AB - A series of TiO2/bi A-SPAES(Ds 1.0) composite membranes with various contents of nano-sized TiO2 particles were prepared through sol-gel method. Scanning electron microscopy (SEM) images indicated the TiO2 particles were well dispersed within polymer matrix. These membranes were used for proton exchange membrane (PEM) for performance evaluation in direct methanol fuel cell (DMFC). These composite membranes showed good thermal stability and mechanical strength. It was found that the water uptake of these membranes enhanced with the TiO2 amount increasing in these composite membranes. Meanwhile, the introduction of TiO2 particles increased the proton conductivity and reduced the methanol permeability. The proton conductivities of these composite membranes with 8% TiO2 particles (0.120 S/cm and 0.128 S/cm) were higher than those of Nafion 117 membrane (0.114 S/cm and 0.117 S/cm) at 80 degrees C and 100 degrees C. Specially, the methanol diffusion coefficient (1.2 x 10(-7) cm2/s) of the composite membrane with 8% TiO2 content was much lower than that of Nafion 117 membrane (2.1 x 10(-6) cm2/s). As a result, the TiO2/bi A-SPAES composite membrane was considered as a promising material for PEM in DMFC. PMID- 25924405 TI - Characterization and catalytic performance of heteropoly acid H4SiW12O40 supported on nanoporous materials. AB - Heteropoly acid H4SiW12O40 (SiW) has been supported on different nanoporous materials and characterized by powder X-ray diffraction (XRD), FTIR, HRTEM, N2 physisorption, and thermal analysis. No SiW diffraction peaks are observed after loading 33-50 wt% of SiW on various mesoporous materials (pore size: -30 A) except for siliceous MCM-48. In contrast, the SiW diffraction peaks appear at 14 wt% loading on zeolite EMT with micropore size of ca. 7.4 x 6.5 A. Supported SiW retains the Keggin structure on mesopore surface. The cubic mesostructure of MCM 48 is stable while MCM-41 loses its regular hexagonal mesostructure upon loading SiW. Several factors account for different behaviours of various supports, including pore size, curvature of mesopore interface and interaction between SiW and aluminium sites in the framework. The resulting 33-50 wt% SiW/MCM-48 solid acid catalysts have large surface area (- 550 m2/g), regular pore arrangement with uniform pore size (- 25 A), finely dispersed SiW and good thermal stability. They exhibit significantly improved activity in acid-catalyzed cracking of long chain hydrocarbons in comparison with bulk SiW and SiW/MCM-41. PMID- 25924406 TI - Synthesis, characterization and catalytic activity of nano-spherical MCM-41 modified with vanadium. AB - Vanadium modified MCM-41 nanospheres were synthesized by the impregnation and sol gel super-molecular method respectively. Structure and morphology of the obtained materials were characterized using X-ray diffraction (XRD), inductively coupling plasma (ICP), Fourier transform infrared (FT-IR), scanning electron microscopy (SEM) and N2-adsorption-desorption techniques. The influence of particle sizes on their catalytic activities in styrene oxidation and benzene hydroxylation was investigated. Results revealed that all the samples had regular sphere shape and adjustable particle size within 40-160 nm, and exhibited high catalytic activities in the oxidation of styrene and hydroxylation of benzene. The smaller the particle size is, the higher the activity becomes. Meanwhile, the catalysts synthesized by the sol-gel method are more effective than that synthesized via impregnation method, indicating the vanadium species in the mesoporous framework are probably the catalytic active sites. PMID- 25924407 TI - The UV/Fenton degradation of tetrabromobisphenol A catalyzed by nanocrystalline chromium substituted magnetite. AB - The heterogeneous UV/Fenton degradation of tetrabromobisphenol A (TBBPA) catalyzed by nanocrystalline Fe3O4 and Fe2.04Cr0.96O4 was investigated, with focus on the influence of UV light and initial pH, degradation pathways and effect of Cr substation. The catalysts were prepared by a precipitation-oxidation method and characterized by chemical analysis, XRD, XAFS, TG-DSC, BET surface area and magnetometer. At pH 6.7 and under UV irradiation, almost complete degradation of TBBPA by Fe2.04Cr0.96O4 was accomplished within 240 min, and the leaching Fe ions were negligible. The substitution of chromium greatly increased the BET specific surface area and surface hydroxyl amount, which improved the heterogeneous UV/Fenton catalytic activity of magnetite. Moreover, Cr3+ on the octahedral sites enhanced the electron transfer process in the magnetite structure to accelerate the *OH generation. The produced *OH radicals preferentially attacked the C-Br bonds of TBBPA and then beta-cleavaged the C-C bonds between benzene rings and isopropyl groups. The above results are of great significance for well understanding the effect of transition metal substitution on the UV/Fenton catalytic activity of magnetite and prospecting the application of magnetite minerals in environmental purification. PMID- 25924408 TI - Catalytic dechlorination of carbon tetrachloride in liquid phase with methanol as H-donor over Ag/C catalyst. AB - Catalytic hydrodechlorination of carbon tetrachloride (CCl4) is an effective measure to remove CCl4 due to its pollutant character. The dechlorination of CCl4 to dichloromethane (CH2Cl2) and chloroform (CHCl3) with a molar ratio of 3:2 was catalyzed by carbon-supported silver (Ag/C) catalyst in methanol solution. It was proposed from the catalytic results and characterization (X-ray diffraction, transmission electron microscopy and X-ray photoelectron spectroscopy) data that, the chloride ion is abstracted from adsorbed CCl4 by Ag to form CCl3 and CCI2 radicals and silver chloride (AgCl), and meanwhile the dehydrogenation of methanol over Ag domains intrigues initial active Ag-H species and formaldehyde (HCHO); then the CCI3 and CCI, radicals are combined with Ag-H to generate reaction products (CHCl3 and CH2Cl2) and Ag, and the dehydrogenated product HCHO facilitates the regeneration of formed AgCl to Ag with formation of carbon monoxide and hydrogen chloride. The catalyst can be recovered and recycled, and there was no significant decrease in catalytic activity and selectivity after 4th recycling. PMID- 25924409 TI - Nanoscale Ni-B electrocatalyst prepared from nickel ethylenediamine complex for direct ethanol electrocatalytic oxidation. AB - Ni-B/Cu electrode prepared by the electroless deposition technique of chemical reduction of nickel ethylenediamine complex with BH4- was characterized by SEM, XRD and XPS techniques, respectively, and evaluated using ethanol electrocatalytic oxidation by the method of cyclic voltammetry. The as-prepared Ni-B/Cu electrode exhibited much higher electrocatalytic activity than the Ni B/Cu electrode obtained via direct reduction of nickel metallic ions. The effects of the nickel ethylenediamine complex can be attributed to both the structural effect and electronic effect. The nickel ethylenediamine complex can not only make an electroless deposition stable and highly dispersed, but also facilitate the formation of more nanoscale microcrystalline Ni on the electrode surface, which increased the electrochemical oxidation activity. Moreover, ethylenediamine influenced the electronic states of Ni and B on the electrode surface, more electrons transfer from the B to Ni that the Ni active sites became more highly unsaturated, which could promote the form of adsorbed active ethanol. PMID- 25924410 TI - Photo-catalyzed p-nitrophenol degradation in aqueous dispersions of ferrihydrite and H2O2. AB - Nitrophenols are hazardous and toxic to living organisms. For this study, ferrihydrite was prepared to test its capabilities for p-nitrophenol degradation. A ferrihydrite particle prepared in neutral environmental conditions is sphere like with a diameter of 2-4 nm and its total surface area is approximately 229 m2 x g(-1). The combination of ferrihydrite and trace H2O2 is effective for the degradation of p-nitrophenol under simulated sunlight irradiation. Hydroquinone, the initial intermediate of p-nitrophenol decomposition, autocatalyses the subsequent degradation of p-nitrophenol because it accelerates the photo reductive dissolution of ferrihydrite. The effect of key operating parameters such as ferrihydrite dosage, initial solution pH and H2O2 dosage were also studied on the photocatalytic degradation of p-nitrophenol. The results indicate that the combination of 0.2 g x L(-1) ferrihydrite, 0.45 mmol x L(-1) H2O2 is highly efficient for the degradation of p-nitrophenol (0.15 mmol x L(-1)) at pH 2.5-3.0. A ferrihydrite was reused several times, still keeping its original photocatalysis. PMID- 25924411 TI - Quantum dots of ZnSe(S) doped with copper as nanophotocatalyst in the degradation of organic dyes. AB - Copper-doped quantum dots of ZnSe(S) synthesized via microwave-heating conditions were used as photocatalyst in the photo-degradation of methylene blue (MB), methyl violet (MV) and victoria blue (VB) under UV irradiation (302 nm) in aqueous phase and at pH 6.5. Quantum dots were characterized by High Resolution Transmission Electron Microscopy (HR-TEM), X-ray diffraction (XRD), UV-Vis, photoluminescence and Fourier transform infrared (FT-IR) spectroscopy. The degradation of MB, MV and VB were monitored using High Performance Liquid Chromatography (HPLC) at 660 nm, 590 nm and 610 nm, respectively. Degradations percentages of 46%, 88% and 90% of MB, MV and VB, respectively, were achieved in presence of 1000 mg/L of quantum dots and 6 hours of UV-irradiation. Cu-doped ZnSe(S) QDs evidenced a remarkable capability to degrade cationic organic dyes as single components and in mixtures. PMID- 25924412 TI - A novel synthesis and characterization of ordered meso/macroporous alumina with hierarchical and adjustable pore size. AB - The sub-micron polystyrene (PS) microspheres with adjustable size were firstly synthesized using emulsion polymerization method by adding only a small amount of emulsifier. Then, three dimensionally ordered macroporous alumina with mesoporous walls and adjustable macropore size was facilely prepared by the colloidal template method. The alumina and PS spheres were characterized by nanoparticle size analyzer, SEM, XRD and N2 adsorption. The results show that the polystyrene microsphere has adjustable single-sized pore with diameter in the range of 100 350 nm and the yield is higher than that prepared by soap free emulsion polymerization. The alumina materials as prepared using the PS colloidal crystals as the template, had ordered meso-macroporous structures and adjustable apertures. The mesopores (about 3.6 nm) in gamma-alumina were formed by controlling the heat treatment of alumina precursor. BET surface area and pore volume of the hierarchical alumina as obtained can reach to 241.3 m2/g and 0.33 cm3/g, respectively. PMID- 25924413 TI - Photocatalytic oxidation of phenolic pollutants and hydrophobic organic compounds in industrial wastewater using modified nonosize titanium silicate-1 thin film technology. AB - Nanocrystalline Titanium Silicate-1 (TS-1) with attractive physical and chemical properties is being explored for the degradation of phenol. A fully dispersible nanocrystalline zeolite TS-1 was prepared. The catalyst was characterized by DLS, XRD, TEM and BET analyses. XRD analysis confirmed that the diffraction pattern of the NPs (CP-0) was very similar to that of amorphous silica and the aged concentrated precursor sample CP-48 showed peaks characteristic of MFI. TEM analysis confirmed that the size of the crystal is about 30 nm. The photocatalytic oxidation of phenol was studied over nanocrystalline Titanium silicate-1 thin film flow reactor. The experimental parameters such as aeration, flow rate, solution pH and phenol concentration were optimized. The degradation efficiency of choro-substituted phenols are compared at optimum conditions. In addition, photocatalytic degradation efficiency of simulated phenolic waste water was studied. The results are significant, as the method adopted here can be extended for the treatment and purification of waste water and air using nanocrystalline Titanium silicate-1 thin film flow reactor. PMID- 25924414 TI - Some observations on the synthesis of fully-dispersible nanocrystalline zeolite ZSM-5. AB - A facile method for the rapid synthesis of fully-dispersible ZSM-5 (Si/Al = 100) of about 30 nm size in high yield (about 91%) is described. The method comprises three steps, viz., concentration of an initial clear solution, low-temperature (80 degrees C) ageing of concentrated sol, and high-temperature (175 degrees C) hydrothermal treatment or microwave heating (175 degrees C) of aged concentrated sol. A simple vacuum-concentration method was used for the extraction of pure NPs of ZSM-5 in solution. XRD, FT-IR, TGA and ASAP characterizations showed that the NPs were partially crystalline. The concentration step accelerated the aggregation of primary units, which helps in the production of a large number of nucleation centers protected by TPA+ ions against aggregation. During low temperature ageing, the number of critical sized nuclei increases, growing into zeolite. The high-temperature heating results in the complete growth of unreacted silica, giving high yields. A key factor for generating small non-aggregated zeolite crystals is the amount of water in the synthesis sol. The three-step method presented here produces a target material of small and uniform sized, non aggregated ZSM-5 of about 30 nm in a short reaction time. The results are significant, as the synthesis method adopted here produces much uniform, non aggregated nanocrystalline ZSM-5 in a shorter time with high yield. PMID- 25924415 TI - Promoting family farming to feed the world. PMID- 25924416 TI - Phenomenological study on experience of care givers of patients with dementia in rural Kerala. AB - A phenomenological study was carried out to know the experience of 10 care givers of patients with dementia in a costal rural community in Thrissur district of Kerala (India). A qualitative approach with survey design using unstructured questionnaire was employed to collect the data. After establishing rapport with the care givers, they were asked to describe what it was like a caregiver of a patient with diagnosed dementia. Interviews were recorded and transcribed verbatim before analysis by personal reflections on Giorgi's method. The study revealed that caregivers of clients with dementia in rural settings have concerns related to caring and outcome. They expressed being overwhelmed, isolated and helpless with this deteriorating condition. PMID- 25924417 TI - Nursing informatics: the future now. AB - Technological advancements in the health care field have always impacted the health care practices. Nursing practice has also been greatly influenced by the technology. In the recent years, use of information technology including computers, handheld digital devices, internet has advanced the nursing by bridging the gap from nursing as an art to nursing as science. In every sphere of nursing practice, nursing research, nursing education and nursing informatics play a very important role. If used properly it is a way to save time, helping to provide quality nursing care and increases the proficiency of nursing personnel. PMID- 25924418 TI - Effect of structured teaching programme on VIA test for early detection and diagnosis of cervical cancer. AB - The conceptual framework of the study, undertaken in select health centres of New Delhi, was based on General System Model. The research approach was evaluative with one group pre-test and post-test design. The study population comprised of Community Health Workers working in selected centres in Najafgarh, Delhi. Purposive sampling technique was used to select a sample of 30 Community Health Workers. A structured knowledge questionnaire was developed to assess the knowledge of subjects. A Structured Teaching Programme was developed to enhance the knowledge of Community Health Workers. Pre-test was given on day 1 and Structured Teaching Programme administered on same day. Post-test was conducted on day 7. Most of the Community Health Workers were in the age group of 21-30 years with academic qualification up to Higher Secondary level. Maximum Community Health Workers had professional qualification as ANM/MPHW (female). Majority of the Community Health Workers had experience up to 5 years. Initially there was deficit in scores of knowledge of Community Health Workers regarding Visual Inspection with Acetic Acid (VIA) test. Mean post-test knowledge scores of Community Health Workers were found to be signifi- cantly higher than their mean pre-test knowledge score. The Community Health Workers after expo- sure to Structured Teaching Programme gained a significant positive relationship between post-test knowledge scores. The study reveals the efficacy of Structured Teaching Programme in enhancing the knowledge of Community Health Workers regarding VIA test and a need for conducting a regular and well planned health teaching programme on VIA test for improving their knowledge on VIA test for the early detection and diagnosis of cervical cancer. PMID- 25924419 TI - Effect of acharya technique upon back pain among industrial workers. AB - Back pain is a universal problem affecting people from all regions of the world. Since relief using modern systems of medicine is hardly forthcoming, the efficacy of indigenously developed Acharya Technique was assessed. Using purposive sampling, data was collected from 30 industrial workers from Erode (TN). It was found that while 36.7 percent participants had complete discomfort in back pain before resorting to Acharya Technique, after its administration, 40percent had only mild discomfort in back pain, thus showing the effectiveness of this technique. It is suggested to include Acharya Technique in continuing educational programmes on wider scale. PMID- 25924420 TI - Assessing the effect of self instructional module on knowledge of menopause & hormone replacement therapy for menopausal women in Moradabad (UP). AB - Objectives of the study were to identify the problems faced by menopausal women and to find out the remedial measures adopted by them, to assess the knowledge of menopausal women regarding menopause & hormone replacement therapy (HRT) before and after administration of self-instructional module (SIM) and to find out the acceptability and utility of the SIM. An evaluative research approach, with pre experimental one group pre-test post-test design was adopted. Purposive sampling technique was used to obtain an adequate size of the sample. The sample comprised of 100 menopausal women living in selected community of Moradabad (UP). A knowledge questionnaire and opinionnaire were administered, and SIM on menopause and HRT administered. It was found that there was deficit in knowledge of menopausal women regarding menopause and HRT. Mean post-test knowledge scores were significantly higher than mean pre-test knowledge scores. SIM was found highly acceptable and useful by menopausal women. PMID- 25924421 TI - Effect of acupressure vs reflexology on pre-menstrual syndrome among adolescent girls--a pilot study. AB - Premenstrual syndrome is the most common of gynaecologic complaints. It affects half of all female adolescents today and represents the leading cause of college/school absenteeism among that population. It was sought to assess the effectiveness of acupressure Vs reflexology on premenstrual syndrome among adolescents. Two-group pre-test and post-test true experimental design was adopted for the study. Forty adolescent girls from Government Girls Secondary School, Erode with pre- menstrual syndrome fulfilling the inclusion criteria were selected by simple random sampling. A pre-test was conducted by using premenstrual symptoms assessment scale. Immediately after pre-test acupressure Vs reflexology was given once a week for 6 weeks and again post-test was conducted to assess the effectiveness of treatment. Collected data was analysed by using descriptive and inferential statistics. In post-test, the mean score of the experimental group I sample was 97.3 (SD = 2.5) and the group II mean score was 70:8 (SD = 10.71) with paired 't' value of 19.2 and 31.9. This showed that the reflexology was more effective than acupressure in enhancing the practice of the sample regarding pre-menstrual syndrome. Statistically no significant association was found between the post-test scores of the sample with their demographic variables. The findings imply the need for educating adolescent girls on effective management of pre-menstrual syndrome. PMID- 25924422 TI - [4-amino-1,8-naphthalimide on the Sensitive effect of arsenic trioxide in hepatocellular carcinoma cells]. AB - OBJECTIVE: To study the effect and mechanism of 4-amino-1, 8-naphthalimide (4-AN) on the sensitive effect of arsenic trioxide (ATO) in hepatocellular carcinoma cells. METHODS: Hepatocellular carcinoma HepG2 cells were divided into two groups according to whether they were treated with 4-AN or not. Cell viability was evaluated by MTT assay, population doubling experiment and colony formation assay; genic mechanism was explored by 8-OH-dG assay, single cell gel electrophoresis (comet assay) and microriucleus test. RESULTS: At 2-10 micromol/L concentration of ATO, the cell viability and colony formation efficiency of the combinatio group (4-AN+ATO) were significantly lower than that of the ATO group (P<0.05); moreover, the tail-length (L-Tail) and olive tail moment (OTM) in comet assay were notablely higher than that of the ATO group (P<0.05). At 2-20 micromol/L concentration of ATO, the population doubling time and 8-OH-dG in combination group were significantly higher than that of ATO group (P<0.05). Results from DNA damage repair assay showed that the efficiency of DNA damage repair in combination group was remarkably lower than that of ATO group (P<0.05). At 5-20 micromol/L concentration of ATO, the frequency of micronucleated cells in combination group was significantly higher than that of ATO group (P<0.05). CONCLUSION: 4-AN can significantly increase the sensitivity of ATO in treatment with hepatocellular carcinoma cells and prevent DNA damage repair may be a primary mechanism for this effect. PMID- 25924423 TI - [The cytotoxic effect and the effect of permeability with OmpA like protein Loa22 from Leptospira interrogans serovar]. AB - OBJECTIVE: To study the toxic effect and the change of permeability on human umbilical vein endothelia (HUVE) of the Loa22 protein from virulent serovar Lai. Leptaspira interrogans by expressing its protein. METHODS: In this study, the pGEX-Loa22 peptide prokaryotic recombinant plasmid of Leptospira interrogans serovar Lai preserved in our laboratory was used to express Loa22 fusion protein with GST lable. Then the target fusion protein was obtained by using affinity chromatography with the GST-Trap FF Column. The purified Loa22 fusion protein was detected by SDS-PAGE and confirmed by Western blot assay using the mouse anti-GST tag monoclonal anti-body. pGEX-Loa22 protein was administered to culture with human umbilical vein endothelial cells (HUVEC) to elucidate the cytotoxic role and the change of permeability of leptospiral outer membrane proteins. RESULTS: The recombiant plasmid with Loa22 mature peptide was expressed successfully and the protein was purfied. Significant higher level of apoptosis ratio, lower CCK-8 aborntion, and increasing permeability on HUVEC were observed after treated the HUVEC with the expressed fusion protein. CONCLUSION: The purified Loa22 fusion protein have obvious toxic effects on vascular endothelial cells, and also it can increase permeability of HUVEC. PMID- 25924424 TI - [Cordycepin protects podocytes from injury mediated by complements complex C5b 9]. AB - OBJECTIVE: To explore the protective effect of Cordycepin (3'-deoxyadenosine), a bioactive compound of Cordyceps Sinensis, on injury of podocytes. METHODS: C5b-9 induced podocyte injury was used as a model of membranous nephropathy in vitro. This model was established using mouse podocyte cell line--MPC5. Cordycepin was given as an intervention. Ultra-micro morphological changes were observed by electron microscope. F-actin cytoskeleton and expression of nephrin were observed by fluorescence microscope. The phosphorylation of mitogen-activated protein kinase (MAPK) was measured by Western blot. RESULTS: Stimulated by C5b-9 for 3 h, MPC5 showed secondary foot processes, with cytoskeleton structure damaged, nephrin relocated from the cell surface to the cytoplasm, and cell signal pathway p38, JNK and ERK activated. Cordycepin protected foot processes and cytoskeleton structures of podocytes, suppressed the redistribution of nephrin, and inhibited p38/JNK action. CONCLUSION: Cordycepin can protect podocyte from C5b-9-induced injury partly through inhibiting the activation of p38/JNK signaling pathway. PMID- 25924425 TI - [The effect of edaravone on MAPKs signal pathway associated with Abeta(25-35) treatment in PC12 cells]. AB - OBJECTIVE: To explore whether edaravone protects cells damage via mitogen activated protein kinases (MAPKs) signal pathway, and which procedure of p38 be affected so as to add theories for AD pathogenesis and treatments. METHODS: According to different drugs treated, PC12 cells in vitro were divided into four groups. Negative control group: cells were treated with media alone. AD model group: cells were treated with 30 pmol/L Abeta(25-35). Inhibitor control group: cells were treated with 10 micromol/L SB203580 Cp38 mitogen-activated protein kinase (p38) inhibitor], 10 micromol/L SP600125 [c-Jun NH2 terminal kinase (JNK) inhibitor], or 10 micromol/L PD98059 extracelular signal regulated kinase (ERK) inhibitor]. Low-dose, middle-dose and high-dose edaravone group: cells plated for 24 hours treated with 30 micromol/L Abeta(25-35) and co-treated with 20, 40, 80 micromol/L edaravone 3 hours, respectively. The morphology of the treated cells were observed, the p-p38, p-JNK and p-ERK proteins in each group were tested by the Western blot. The p38 mRNA were tested in each group above (only add SB203580 10 micromol/L in third group) by the real time PCR. RESULTS: (1) The p-p38 protein was significantly increased in model control group compared with that in negative control group (P<0.05). The p-p38 protein in the inhibitor group and edaravone groups was decreased significantly (P<0.05) when compared with that in model control group. The p-p38 proteins were significantly increased in the three edaravone groups compared with that in inhibiter control group (P<0.05). The p p38 protein in middle-dose edaravone group was decreased compared with that in low-dose edaravone group (P<0.05). There was no relationship in dose-dependent manner about edaravone. Compared with three edaravone groups, the p-p38 protein was lower than it in high-dose edaravone & inhibiter group (P<0.05). (2) The p JNK protein was significantly increased in model control group compared with that in negative control group (P<0.05). The p-JNK protein in the inhibitor group was decreased compared with that in model control group (P<0.05). (3) No significantly difference of p-ERK protein concentration was observed in other groups when compared with that in negative control group (P>0.05 each). (4) Compared with negative control group, the p38 mRNA in model control group was significantly increased, and it was significantly decreased in inhibitor control group (P<0.05 each). In 40 micromol/L and 80 micromol/L edaravone groups, the p38 mRNA was significantly decreased compared with that in model control group, and it still was decreased compared with that in inhibitor control group (P<0.05). The p38 mRNA in 40 micromol/L edaravone group was the lowest among three edaravone groups, and it was obviously different from that in 20 micromol/L and 80 micromol/L edaravone groups (P<0.05). CONCLUSION: Abeta(25-35) could increase the p-p38 and p-JNK protein expression in cultured PC12 cells, but there was no obviously expression of p-ERK protein. These indicated that Abeta(25-35) might activate MAPKs signal pathway, especially p38 and JNK, and lead to PC12 cell damage. Edaravone could decrease p38 mRNA induced-Abeta(25-35), which indicated edaravone could protect PC12 cell damage via blocking p38 signal pathway in mRNA stage and protein stage simultaneously. Hence, it is promising that edaravone would be a new medicine for AD. PMID- 25924426 TI - [Investigate the clonal origin of different phenotypic tumor-like cells in the epidermis and dermis of skin lesions in lymphomatoid papulosis]. AB - OBJECTIVE: To explore the correlation of the clone sources of MF-like cells in the epidermis and RS-like cells in the dermis of lymphomatoid papulosis (LyP), a compartive study of this two type cells in 8 LyP cases was carried out. METHODS: 8 cases of LyP (4 type A cases and 4 type C cases) were detected the immunophenotype first, and then comparative study between the MF-like cells and RS-like cells was conducted on T-cell receptor (TCR) gamma-chain gene rearrangement by combinating laser capture microdissectinon (LCM) and PCR. PCR products of one patient which had positive bands were selected randomly for sequencing and sequence alignment analysis. RESULTS: Monoclonal TCRgamma gene rearrangement was detected in 6 cases (75%) of the 8 cases. Detection rates of LyP type A and type C were 50% (2/4) and 100% (4/4), respectively. The rates of MF-like cells and RS-like cells were 75% (6/8) and 75% (6/8), respectively. Homology of the products with positive stripes in both MF-like cells and RS-like cells in one randomly selected case was compared and analyzed, and the results showed the homology of them was 106/108 (98%). CONCLUSION: The MF-like cells in the epidermis and the RS-like cells in the dermis of LyP may be from the same clone. PMID- 25924427 TI - [The study of increased immunogenicity of UCMSC Stimulated by TLR7 agonist CL264]. AB - OBJECTIVE: To study the change of immune status of umbilical cord mesenchymal stem cells (UCMSC) stimulated by toll like receptor 7 (TLR7) agonist CL264. METHODS: TLR7 specific ligand CL264 was used to stimulate the UCMSC. Flow cytometry was conducted to assay the expression of co-stimulators [human leukocyte antigen (HLA)-E, CD80 and CD86] and surface markers of stem cells (CD29, CD59 and CD90). Quantitative PCR was applied to measure the expression variation of immune-related molecules and stem cell markers. Cell differentiation experiment was used to study the change of differentiation ability of UCMSC upon CL264 stimulation. Peripheral blood mononuclear cells (PBMC) were isolated from healthy human and then cocultured with UCMSC in the presence of CL264. Cytotoxicity assay was used to measure the attack of PBMC to UCMSC. RESULTS: Expression of cotimulatory molecules CD86 and HLA-E were enhanced in UCMSC upon CL264 stimulation. Real-time PCR indicated that many pro-inflammatory molecules [interleukin (IL)-1beta, IL-6, IL-8, IL-10, interferon (IFN)-beta, IFN-gamma, nuclear factor-KB (NF-kappaB), transforming growth factor-beta (TGF-beta)] were induced in the presence of CL264 while the expression of stem cells markers were inhibited [Kruppel-like factor-4 (Klf4), Nestin, SRY-related high-mobility-group box protein-2 (Sox2), Lin28]. Activation of TLR7 also increased the immune attack of PBMC on UCMSC. Our study also indicated that the treatment of CL264 did not influence the differentiation ability of UCMSC. CONCLUSION: TLR7 agonist CL264 could increase the immunogenicity of UCMSC. PMID- 25924428 TI - [Gender-dependent expression of ERalpha in arsenic exposed mice offspring's lung tissue]. AB - OBJECTIVE: To observe theexpression variations of estrogen receptor alpha (ERalpha) in different periods of mice offspring and the gender-dependent differences in the lung tissue with parental arsenic exposure. METHODS: Parental female mice were exposed to arsenic by gavage from gestational day 8th to offspring infancy, and offspring were exposed to arsenic by drinking water after infancy. The expression level of ERalpha mRNA and protein in lung tissue of the male and female offspring in different developmental periods and different doses (low, middle, high) of sodium arsenite exposure were detected by real-time PCR and Western blot. RESULTS: ERalpha mRNA expression in female lung tissue was lower than male in embryonic period (P<0.05); ERalpha mRNA expression in female lung tissue was higher than that of male in infant and adult periods (middle dose of infancy P<0.05, middle and high doses of adulthood P<0.05); No statistical significances were observed in embryo, infancy and adulthood control groups. ERalpha mRNA expression in female lung tissue of infancy and adulthood was higher than that in embryonic period (low, middle and high dose groups P<0.05). ERa protein expression in arsenic exposed female lung tissue was higher than that of male in infant and adult periods, it was also increased by compared with corresponding control groups (P<0.05). The expression level of ERalpha protein in exposed adult female and male offspring were higher than that of infancy. CONCLUSION: Arsenic infected during pregnancy can increase the lung tissue's ERalpha expression level of female offspring in infancy and adulthood. This result is significant to elucidate the role of environment pollutants in gender difference of lung cancer's occurrence. PMID- 25924429 TI - [Protective effects of levetiracetam and simvastatin on pilocarpine-induced epilepsy in rat models]. AB - OBJECTIVE: TO determine neuroprotective properties of levetiracetam and simvastatin using rats with pilocaroine-induced epilepsy. METHODS: Epileptic rat models were randomly divided into 4 groups, each being exposed to saline, simvastatin, levetiracetam, or levetiracetam + simvastatin. Brain tissues of the rats were examined. Nissl staining was used to determine pilocarpine-induced neuronal loss in CA1 and CA3 of hippocampus. Western blot was used to detect calpain-1 expression of hippocampus. RESULTS: Severe cell death was found 24 h after seizures, with a level significantly higher than the controls. Compared with the saline-treated cells, simvastatin did not decrease severe cell death (P>0.05), but levetiracetam and levetiracetam+simvastatin decreased severe cell death 24 h after seizures (P<0.05). No significant differences were found between those treated with levetiracetam and those with levetiracetam+simvastatin. Compared with controls, overexpressed calpain-1 was found in the rats 24 h after seizures, which indicates that calpain-1 may be involved in the pathophysiological mechanisms of epilepsy. Compared with those treated with pilocarpine + saline, simvastatin, levetiracetam and levetiracetam + simvastatin reduced the level of calpain-1 24 h after seizures (P<0.05). CONCLUSION: Levetiracetam, not simvastatin, possesses neuroprotective properties, through changing calpain-1 expression levels. But levetiracetam plus simvastatin treatment does not have advantages over the choice of monotherapy. Simvastain does not possess neuroprotective properties at the early stage of epilepsy. PMID- 25924430 TI - [Estrogen induced rapid increase of intracellular calcium plays important role in the implantation of mouse blastocysts]. AB - OBJECTIVE: To study the roles of the increased intracellular calcium induced rapidly by estrogen in the implantation of mouse blastocysts. METHODS: The mouse blastocysts were collected from the female mice on the pregnant day 4, divided into 3 groups: control, E2-BSA and BAPTA +E2-BSA. Immunofluorescence staining, confocal microscopy, embryo and endometrial epithenial cells co-culture and embryo transfer were used to investigate the effect of increased intracellular calcium induced by E2-BSA on the expression and localization of integrins in blastocysts and their adhesion to endometrial epithenial calls (EECs) and implantation into the endometrium. RESULTS: The increase of intracellular calcium induced rapidly by estrogen could cause the cluster and relocation of integrin av and beta3, and BAPTA might block this effect, the adhesion rate of blastocysts in contol group was 35.5%, BAPTA +E2-BSA group was 26.7% and significantly lower than 65.6% of E2-BSA group (P<0.05), and the implantation rate in BAPTA+E2-BSA group was 11.8%, which was significantly lower than 52.9% of E2-BSA group (P<0.05). CONCLUSION: The rapid increase of intracellular calcium induced by estrogen may cause the relocalization of integrin in blastocysts and their adhesion to ECCs, which is important in the process of implantation. PMID- 25924431 TI - [Effects of altered IFNAR expression on CD4+ CD25+ treg cell dysfunction in patients with systemic lupus erythematosus]. AB - OBJECTIVE: To explore the role of type I interferon (IFNalpha) on the function of CD4+ CD25+ regulatory T (Treg) cells in patients with systemic lupus erythematosus (SLE). METHODS: Twenty patients with newly-onset active SLE and 20 healthy controls were recruited in this study. The expressions of type I interferon a receptor (IFNAR) on Treg cells were analyzed using flow cytometry. CD4+ CD25+ Treg cells were purified by magnetic-activated cell sorter (MACS). The function of these cells was assessed in vitro with or without IFNalpha (500 U/mL). The effect of exogenous IFNalpha on the apoptosis of Treg cells and the expression level of FOXP3, CTLA-4, and pAKT in Treg cells were analyzed using flow cytometry. Results The expression levels of IFNAR1 on CD4+ CD25+ Treg cells were significantly higher in the SLE patients than in the healthy controls (P=0.0006). There was a positive correlation between the expression levels of IFNAR on Treg cells and the SLEDAI scores in the SLE patients. Exogenous IFNalpha impaired the suppressive capacity of Treg cells in the SLE patients. However, neither the apoptosis of Treg cells nor the expression levels of FOXP3 and CTLA-4 on Treg cells were influenced by IFNalpha stimulation. IFNalpha enhanced AKT phosphorylation in Treg cells in the SLE patients. CONCLUSION: Altered IFNAR expression may contribute to Treg cell dysfunction in SLE patients through enhancing AKT phosphorylation in Treg cells. PMID- 25924432 TI - [The sedative-hypnotic effects and safety of oral administrated propofol prodrugs hx0969w and fospropofol disodiun in comparison with propofol emulsion in rats]. AB - OBJECTIVE: To estimate the median effective dose (EDs0) of oral administrated HX0969w, fospropofol disodium and propofol emulsion in rats, and to compare the sedative-hypnotic effects and safety of the three drugs. METHODS: The ED50 of the three drugs were determined using sequential method. Thirty healthy adult Sprague Dawley rats were divided into three groups randomly, being orally administered with HX0969w (n=10), fospropofol disodium (n=10) and propofol emulsion (n=10), respectively. The neurobehavioral performance of the rats was observed. The time of loss of forepaw righting reflex (LRR) and the time of recovery of forepaw righting reflex (RRR) were recorded. RESULTS: The ED50 of oral HX0969w, fospropofol disodium and propofol emulsion were 96.5 mg/kg, 130.0 mg/kg and 113.8 mg/kg, respectively. HX0969w, fospropofol disodium and propofol emulsion had a mean LRR of (10.0 +/- 2.9) min,(7.5 +/- 2.8) min and (16.0 +/- 5.9) min; respectively; and a mean RRR of (66.9 +/- 21.5) min, (131.9 +/- 32.7) min and (198.9 +/- 110.0) min, respectively. CONCLUSION: HX0969w, fospropofol disodium and propofol emulsion can produce sedative-hypnotic effects and they are safe when administered by oral route. The two propofol prodrugs HX0969w and fospropofol disodium have shorter LRR than propofol emulsion. HX0969w also has a shorter RRR than fospropofol disodium and propofol emulsion. PMID- 25924433 TI - [CecropinA-magainin, a new hybrid antibacterial peptide against meticillin resistant Staphylococcus aureus]. AB - OBJECTIVE: To study the mechanism of cecropinA-mangainin treatment on the meticillin-resistant Staphylococcus anreus biofilms. METHODS: The activity of the hybrid antibacterial peptide against Staphylococcus anreus was evaluated by the minimum inhibitory concentration (MIC) test and its effect on the bacteria membrane changes were observed through transmission electron microscope. The concentration of K+ of the tested bacterial liquid after interact with antibacterial peptide was detected with atomic absorption spectrometer. The changes of the treated bacteria biofilm was also evaluated by using flow cytometry. RESULTS: The results demonstrated that the MIC of the peptide against Staphylococcus aureus was 64 microg/mL. The ultrastructure changes of the meticillin-resistant Staphylococcus anreus membrane and the rising concentration of intracellular K+ were observed. And increased number of PI positive cells was also observed after hybrid antibacterial peptide treatmennt. CONCLUSION: The hybrid antibacterial peptide could kill the meticillin-resistant Staphylococcus anreus by damage the treated bacteria membrane. PMID- 25924434 TI - [Influence of healing process of extraction on related growth factors in microscrew-bone interface of implanted titanium microscrews near the extraction wounds]. AB - OBJECTIVE: To detect the expression of growth factors relating to bone reconstructions in microscrew-bone interface of implanted titanium microscrews near the extraction wounds, and to determine the influence of healing process on the growth factors. METHODS: Eight male Beagle dogs (age 18 months) were divided into experimental and control groups. Titanium microscrews were implanted near an extraction wound in the dogs in the experimental group, while the controls had implantation without extraction wounds. The dogs were sacrificed at 1, 3, 8, 12 weeks, respectively. Immunohistochemistry and in situ hybridization sections were performed to detect the expression of TGF-beta, TNF-alpha, osteocalcin (OC) protein and Cbfal mRNA. RESULTS: The experimental group had higher levels of expression of TGF-beta, TNF-alpha protein and Cbfa1 mRNA than the controls, with significant differences appearing at week one for TNF-alpha (P<0.05), week three for TGF-beta and TNF-alpha (P<0.05), and week eight for Cbfa1 mRNA (P<0.05). The expression of OC increased over time and reached peak at week eight (P<0.05). CONCLUSION: Microscrews implanted near extraction wounds can maintain stability. Severe inflammation occurs in the early stage of healing, but does not sustain. Bone remodeling remains active over the healing process. But prolonged healing phase without force loading could weaken the remodeling. PMID- 25924435 TI - [Expression of fatty acid synthase and adipocyte fatty acid-binding protein and the relationship with the clinicopathological characteristics in human infiltrating ductal breast cancer]. AB - OBJECTIVE: To study the expression of fatty acid synthase (FASN) and adipocyte fatty acid-binding protein (A-FABP) in human infiltrating ductal breast cancer (IDC) tissues and hunman breast cancer cells and the relationship with the clinicopathogical characteristics. To further explore the relationship between FASN and A-FABP, and the relevance of the invasion in cancer cell. METHODS: The expression of FASN and A-FABP was detected in 58 cases of human infiltrating ductal breast cancer and 12 cases of human normal breast tissues by immunohistochemistry technique, calculated positive expression percentage according to the number of positive cells percentage and the staining degree of positive sediment. The cell wound-healing assay was applied to detect the invasion of SKBR3 and MCF-7 cells. Western blot was used to detect the expression of FASN and A-FABP in MCF-7 and SKBR3 cells. RESULTS: The positive rates of FASN and A-FABP were 8.3% (1/12) and 16.7% (1/6) respectively in 12 cases of normal breast tissues by immunohistochemistry. In 58 cases of IDC tissues, the positive rates of FASN and A-FABP were 72.4% (42/58) and 79.3% (46/58) respectively. The differences of the positive rates of FASN and A-FABP in normal breast and IDC tissues were statistically significant (P<0.01, P2 cm) when compared with lymph node metastasis negative group or the diameter < or =2 cm group, the differences were statistically significant (P<0.01). In IDC group, the expression of FASN correlated with A-FABP (r=0.797, P<0.001), The migration rate of SKBR3 was significantly higher than MCF-7 cell at 12, 24 h (P<0.05), FASN expression in SKBR3 was higher than that in MCF-7. CONCLUSION: FASN and A-FABP might associated with the lymph node metastasis and tumor size, and there was correlation between FASN and A-FABP in human IDC tissues. FASN may associated with the invasion and metastasis in breast cancer cells. PMID- 25924436 TI - [Clinical significances of plasma interleukin-6,C-reaction protein and tumor necrosis factor-alpha in patients with aortic dissection]. AB - OBJECTIVE: To investigate the clinical significances of plasma IL-6, CRP and TNF alpha concentration changes in aortic dissection. METHODS: Plasma concentrations of IL-6, TNF-alpha and CRP were determined in 68 aortic dissection patients,50 patients with essential hypertensionand 50 healthy volunteers. The changes of plasma IL-6, CRP and TNF-alpha concentration were analyzed in aortic group along with the progression of the disease which was divided into 9 differenttime courses. RESULTS: Compared with essential hypertension and healthy control group, significantly elevated CRP, IL-6 and TNF-alpha concentrations were detected in aortic dissection patients (P<0.05, respectively). All the concentrations of CRP, IL-6 and TNF-alpha reached the peak in acute phase of aortic dissection and then gradually declined in subacute and chronic phase. CONCLUSION: Increased plasma inflammatory factors were significantly associated with aortic dissection. PMID- 25924437 TI - [Study on the oxidative stress in the ovaries of a rat model of polycystic ovary]. AB - OBJECTIVE: To establish a pathological animal model of polycystic ovary (PCO) by letrozole in rats. Investigate whether PCO were mediated by the effect of oxidative stress by measuring oxidative stress levels in this cohort of rats with PCO, and proceed a new way of treatment for polycystic ovary syndrom (PCOS). METHODS: 90 SD female rats aged 6 weeks were randomly divided into two groups, including a control group of 45 rats that received vehicle only [19% aqueous solution of carboxmethlycellulose (CMC), 1 mL/d] once daily orally (p.o.), and an experimental group of 45 rats, which were administered letrozole at concentrations of 1 mg/kg p.o. dissolved in 1% CMC (1 mL/d) once daily. The treatment period was 28 d. During this period, vaginal smears were collected daily for estrus cycle determination and body masses were measured every 7 d. On the day subsequent to the last letrozole dose administration, rats were killed; Uteri and ovaries were then excised and weighed for the calculation of organ indexes. Serum hormone levels, SHBG and histologic changes in the ovaries were examined. Then testosterone free index (FAD) was calculated. Oxidant status was evaluated by determination of ovarian total oxidant status (TOS), malondialdehyde (MDA) concentration and intracellular reactive oxygen species (ROS) level, while antioxidant status was evaluated by determination of total antioxidant status (TAS) and superoxide dismutase (SOD) concentration. RESULTS: Vaginal smear test showed the estrus cycle began to disappear from day 12 to day 15. A statistically significant difference in growth curves, ovarian weights, uterine weights and organ indexes between the groups were also observed. In rats with PCO serum testosterone (T), follicle-stimulating hormone (FSH) concentrations and free androgen index (FADI) were significantly increased compared with the control group (rats without PCO). However, rats with PCO had decreased levels of estrogen (E2), luteinizing hormone (LH), and progesterone (P) compared with the control group. In a rat model of PCO achieved via letrozole, it was found that the levels of TOS, MDA, oxidative stress index (OSI) and intracellular ROS were significantly increased, while the TAS level, SOD content were significantly decreased in the ovary homogenates (P<0.05). The results indicated that the PCOS pathological process significantly increased the oxidative stress production. CONCLUSION: PCO rat model successfully induced via letrozole, and it is a suitable model for study of ovarian lesions. Oxidative stress also contributes to the PCO rat model, the protective effect of antioxidant might provide a new insight into the potential therapeutic solution to PCOS. PMID- 25924438 TI - [Changes in health-related quality of life in incipient stroke survivors]. AB - OBJECTIVE: To assess the long-term changes in quality of life of stroke patients. METHODS: A total of 467 stroke survivors were recruited for this study. The participants completed the 12-Item Short Form Health Survey (SF-12) at a three month interval over two years. Multi-level modelling was performed to identify the trend of changes and associated demographic characteristics. RESULTS: The participants had (31.50 +/- 10.49) PCS and (51.92 +/- 10.03) MCS at the baseline survey. Overall, PCS and MCS scores increased over time, but MCS scores declined slightly 15 months later. Men had higher PCS scores than women. The multi-level model revealed similar trends of PCS changes in those with different gender and education. Older patients had slower changes in quality of life over time (beta9 = -0.013, P = 0.03) compared with their younger counterparts. The trends of MCS changes were similar among those with different age, gender and education. CONCLUSION: Support should be strengthened for female stroke survivors and those with older age and lower levels of education. PMID- 25924439 TI - [Prognostic determinants of adrenocortical carcinoma in adults]. AB - OBJECTIVE: To investigate the clinical features and prognostic determinants of adrenocortical carcinoma (ACC) in adult patients. METHODS: All adult patients (aged > or =18 years old) who were admitted to West China Hospital, Sichuan University from 1st Jan., 2000 to 31st Jan., 2013 with a pathologically diagnosed ACC were included in this study. Data about the demographics, clinical characteristics, laboratory examinations and outcomes of those patients were extracted and analyzed. RESULTS: A total of 52 cases were identified, with a median follow-up of 26 months (3-159 months). The patients had a median survival time of 29 months (1-156 months), with a 1-year, 3-year; and 5-year survival rate of 71.0%, 47.0%, and 42.7%, respectively. In the univariate analysis, aged >45 years old at diagnosis (P = 0.017), advanced stage (III-IV stage, P<0.001), incomplete resection (P = 0.011), symptomatic (P = 0.017), hypoalbuminemia (P = 0.003), and elevated lactate dehydrogenase (LDH) (P = 0.017) were associated with poor prognosis of ACC. The multivariate analysis confirmed that hypoalbuminemia Chazard ratio (HR) = 5.306; 95% confidence interval (95% CI: 1.975, 14.258; P = 0.001), female (HR = 4.020; 95% CI: 1.610, 10.038; P = 0.003), advanced stage (HR = 7.405; 95% CI: 2.561, 21.410; P < 0.001), and older age (HR = 4.628; 95% CI: 1.791, 11.959; P = 0.002) were predictors of poor prognosis of ACC. CONCLUSION: Hypoalbuminemia, female, older age, and advanced stage are independent risk factors associated with poor prognosis of ACC.in adult patients. PMID- 25924440 TI - [Immune function and catch-up growth of 6-month infants with intrauterine growth retardation]. AB - OBJECTIVE: To explore the influence of "developmental programming" on immunity function and the correlation between immunologic changes and physical growth. METHODS: Sixty singleton pregnancies with intrauterine growth retardation (IUGR) and twenty normal pregnant women were enrolled in this study at their third trimester of pregnancy. Birth weight, birth length, mode of delivery, complication of newborn were measured and/or recorded at the moment of delivery. Physical development of the infants was measured every month up to six months old using weight and length as indicators. The deviation of physical growth was evaluated by Z score. Blood samples were taken from the infants at the sixth month. Lymphocyte subpopulations were anaLyzed using flow cytometry. Humoral immunity were measured using immunoturbidimetry. RESULTS: About 27.27% and 29.09% of IUGR infants were found to have small for gestational age (SGA) and neonatal complications. They had lower birth body masses and birth lengths than those of controls (P<0.05). After correcting for gestational age, the IUGR boys had lower body masses at birth and one months old, as well as lower lengths at 0-6 months compared with the controls. The IUGR girls had lower weights at 0, 1, 3, 4, and 6 months, as well as lower lengths at 0, 3, 4, 5, and 6 months. The IUGR infants without intrauterine-catch-up growth had lower proportion of B lymphocyte than those with intrauterine-catch-up growth (P<0.05). The IUGR infants without extrauterine-catch-up growth had higher numbers of B lymphocyte and lower IgG than those of normal controls (P<0.05). CONCLUSION: IUGR infants without intrauterine-catch-up and extrauterine-catch-up have impaired immunity function. The theory of "development program" needs proof of studies with a large sample size and long-term follow-up. PMID- 25924441 TI - [Risk factors associated with chronic obstructive pulmonary disease: a comparison between urban and rural populations in Chengdu]. AB - OBJECTIVE: To determine risk factors associated with the prevalence of chronic obstructive pulmonary disease (COPD) in urban and rural populations in Chengdu. METHODS: A multistage random cluster sampling method was adopted to select participants from four communities in Chengdu. All residents aged 40-70 yr. were eligible to participate in this study, which involved a questionnaire survey, physical examination and portable spirometry. Those with airflow limitations were also given post-bronchodilator testing 15 min after inhalation of a dose of 200 microg salbutamol. We defined a forced expiratory volume in one second/forced vital capacity (FEV1/FVC) of less than 70% as COPD. Logistic regression models were performed to identify risk factors of COPD. RESULTS: Of a total of 1931 eligible participants, 1579 (81.77%) completed the questionnaire and spirometry. About 8.35% were identified with COPD: 7.69% in urban vs. 12.37% in rural (P<0.05). The prevalence of COPD increased with age (P<0.05) in the male and total populations. Rural COPD patients had a higher level of smoking rate and use of coal as fuel for cooking than their urban counterparts (P<0.05). But rural COPD patients had a lower level of BMI, waist circumference, literacy, and average household income per capita than their urban counterparts (P<0.05). The multivariate analysis showed that tobacco smoking index (pack-year), education, age and BMI were predictors of COPD for male patients; whereas, coal fuel usage, income and BMI were predictors of COPD for female patients. CONCLUSION: COPD prevalence is higher in rural areas than in urban Chengdu. Major risk factors of COPD include smoking, coal fuels and BMI. PMID- 25924442 TI - [Decreased maternal plasma urocortin level in intrahepatic cholestasis of pregnancy]. AB - OBJECTIVE: To measure the plasma level of urocortin and the placenta expression of its receptor corticotropin-releasing hormone receptor (CRHR)-2 in the patients with intrahepatic cholestasis of pregnancy (ICP). METHODS: This study enrolled 20 patients with ICP and 20 normal pregnant women (control group). The plasma level of urocortin at different gestational age (34-37 weeks) was measured by enzyme linked immunosorbent assay (ELISA), and the placenta expression of CRHR-2 was investigated by immunohistochemical technique. RESULTS: The plasma urocortin levels at different gestational age in normal pregnany were (79.47 +/- 11.35) pg/mL at 34 weeks, (83.00 +/- 12.67) pg/mL at 35 weeks, (80.28 +/- 11.48) pg/mL at 36 weeks, and (84.24 +/- 13.62) pg/mL at 37 weeks, respectively. No upward tendency was observed along with the increase of gestational age (F= 0.67, P>0.05). Compared with normal pregnany, ICP patients had novel down trend of the plasma urocortin levels (F = 6.78, P<0.05), which were (68.53 +/- 16.95) pg/mL at 34 weeks, (64. 19+22. 50) pg/mL at 35 weeks, (50.06 +/- 13.98) pg/mL at 36 weeks, (47.91 +/- 15.65) pg/mL at 37 weeks, CRHR-2 staining was found in syncytiotrophoblast and feto-placental vascular endothelium cells of placenta, and there was no statistical differences found for integral optical density value of CRHR-2 staining between control (101.09 +/- 27.21) and ICP (111.83 +/- 35.02) groups (P>0.05). CONCLUSION: The urocortin-mediated stress compensation insufficiency may be involved in the fetal outcomes in ICP. PMID- 25924443 TI - [Immune mediated inflammatory pathogenesis and assessment of disease activity in rheumatoid arthritis]. AB - Rheumatoid arthritis (RA) is a systemic chronic inflammatory disease with synovitis and pannus formation as its basic pathologic features. Immune mediated inflammation is the core event in the occurrence and development of RA, but the inflammatory mechanism in RA pathogenesis remains unclear and needs more research to be illustrated. T cells, B cells, proinflammatory cytokine network and chemokines were confirmed to be involved in the process. In addition, the cells related to the structure of bone and joint, such as synovial cells, osteoblasts and osteoclasts, also participate in the inflammation progression of RA acting as the effector cells of immune regulation. The severity of inflammation of RA is closely related to disease activity. There are many kinds of tools for the assessment of disease activity of RA, The rationale use and optimization of these assessment tools will be helpful to make the treatment decision and improve the prognosis of RA. PMID- 25924444 TI - [CCL19/IL-1beta positive feedback loop involved in the progress of inflammation in rheumatoid arthritis]. AB - OBJECTIVE: To explore the function and mechanism of CCL19 in the pathogenesis of rheumatoid arthritis. METHODS: Synovial fibroblasts were collected from 5 cases of rheumatoid arthritis. Peripheral blood mononuclear cells (PBMCs) were obtained from 5 healthy people by Ficoll-Hypaque density gradien centrifugation. The cells were stimulated with IL-1beta, TNF-alpha, IL-17 and other cytokines, and then the expression of CCL19 was detected by RT-PCR. The cells also were treated with different concentration of CCL19, then the expressions of IL-1beta, TNF-alpha were detected by RT-PCR, the expressions of p-ERK, p-p38 were detected by western blot. RESULTS: IL-1beta promoted the CCL19/CCR7 expression in both synovial fibroblasts and PBMCs. CCL19 upregulated the expression of IL-10 in both synovial fibroblasts and PBMCs. The stimulation of CCL19 also increased its receptor CCR7 expression. CCL19 activated p-ERK and p-p38 in PBMCs. CONCLUSION: The positive feedback loop between CCL19 and IL-1 participate in the development of rheumatoid arthritis. PMID- 25924445 TI - [Correlation of RANKL/OPG, dickkopf-1 and bone marrow edema in rheumatoid arthritis with the complaint of knee pain]. AB - OBJECTIVE: To investigate the correlation of the receptor activator of nuclear factor kappa-B ligand (RANKL)/serum osteoprotegerin (OPG) system, Dickkopf-1 (DKK 1) and bone marrow edema (BME) in rheumatoid arthritis (RA) with the complaint of knee pain. METHODS: The clinical data of 50 cases of RA with the complaint of knee pain were collected. According to MRI finding, half of them (25 cases) had bone marrow edema (BME). Each patient received the measurement of serum OPG, RANKL, DKK-1, C-reactive protein (CRP), erythrocyte sedimentation rate (ESR), anti cyclic citrullinated peptide antibody (CCP), rheumatoid factort(RF). The clinical symptoms, disease activity score 28 (DAS28), were compared between BME and non-BME griups, and the correlation between RANKL/OPG system, DKK-1 and BME of RA was analyzed. RESULTS: Compared with non BME group, BME group had shorter course (P=0.000), higher DAS28 score (P=0.009), CRP (P=0:000), RF (P=0.033) and CCP (P=0.012). lower level of serum OPG (P=0.000), higher level of RANKL (P=0.000), RANKL/OPG (P=0.000), and DKK-1 (P=0.001). The severity of bone marrow edema was correlated with the serum RANKL (volume r(s)=0.31, P=0.027; degree r(s)=0.33, P=0.022), RANKL/OPG (volume r(s)=0.29, P=0.039; degree r(s)=0.28, P=0.043), DKK-1 (volume r(s)=0.33, P=0.021; degree r(s)=0.34, P=0.019). CONCLUSION: BME is one of the early signs of bone erosion in RA, there were more active inflammation, autoantibodies, and osteocasts in RA patients with BME. PMID- 25924446 TI - [Comparison of four assessment criteria for disease activity of rheumatoid arthritis]. AB - OBJECTIVE: To compare of the efficacy of four assessment criteria for evaluating disease activity in rheumatoid arthritis. METHODS: Clinical data were collected from 172 patients ofrheumatoid arthritis. Disease activity was evaluated by four assessment criteria, which are disease activity score 28-C-reactive protein (DAS28-CRP), disease activity score 28-erythrocyte sedimentation rate (DAS28 ESR), simplified disease activity index (SDAI) and clinical disease activity index (CDAI). The patients were divided into four groups which were remission, low, middle and high disease activity. The correlations and consistencies among four methods were compared. RESULTS: Disease activities evaluated by four methods in 172 RA patients were significantly positive correlated (P<0.01). It was significantly consistent between SDAI and CDAI, also between DAS28-ESR and DAS28 CRP, the Kappa values were 0.949 and 0.862 respectively. The differences of the four methods in remission and high disease activity groups were no statistical significance. The proportion of the patients in low disease activity and middle disease activity groups evaluated by DAS28-ESR and DAS28-CRP were statistical different from that evaluated by CDAI and SDAI (P<0.05). CONCLUSION: Strong correlation was observed between the four methods. CDAI could be used to evaluate whether RA is remission or activity. For disease activity assessment, DSA28-ESR and DAS28-CRP seems superior to CDAI and SDAI. PMID- 25924447 TI - [Clinical value of MDHAQ for disease activity assessment in patients with rheumatoid arthritis]. AB - OBJECTIVE: To evaluate the clinical value of the mutidimensional health assessment questionnaire (MDHAQ) for disease activity assessment in patients with rheumatoid arthritis (RA). METHODS: A total of 100 RA patients were recruited in this study and completed the MDHAQ. Clinical data and involved joint function assessment were also collected. Routine assessment of patient index data 3 (RAPID3) was calculated using the MDHAQ. The correlations between RAPID3 and disease activity score 28 (DAS28), simplified disease activity index (CDAI), simplified disease activity index (SDAI) and clinical characteristics were analyzed. RESULTS: RAPID3 was correlated with erythrocyte sedimentation rate (ESR), C-reactive protein (CRP), swollen joints count, tender joints count and overall physician rating (P<0.05). The MDHAQ had a Cronbach's alpha coefficient of 0.821 and a KMO of 0.576. Bartlett's test of sphericity showed P<0.001. RAPID3 was also correlated with DAS28, CDAI and SDAI, with a coefficient of 0.743, 0.697 and 0.640 (P<0.001), respectively. CONCLUSION: MDHAQ is a reliable instrument for disease activity assessment in patients with RA. It is easy to administer in busy clinical settings. PMID- 25924448 TI - [Disease activity and therapeutic strategy of patients with late-onset rheumatoid arthritis]. AB - OBJECTIVE: To compare the disease activity and therapeutic strategy of late-onset rheumatoid arthritis (LORA) with young-onset rheumatoid arthritis (YORA). METHODS: Medical records of 259 patients with rheumatoid arthritis (RA) were reviewed retrospectively. The cut-off between LORA and YORA was operationally set at 60 years of age at disease onset. Gender ratio, disease duration, feature of involved joint, extra-articular features, laboratory features, disease activity score and treatment strategy were compared between LORA and YORA. RESULTS: The LORA patients had a gender ratio (male/female) of 1/1.88, which was approaching 1/1 in the older age group. It took longer for LORA to be diagnosed than YORA (P<0.001). LORA had more frequent involvement of shoulders (P < 0.001), while elbow, wrist, metacarpophalangeal joint ( MCP), proximal interphalangeal joint (PIP) and ankle joints were more common in YORA (P<0.001). LORA patients were more likely to have anemia than YORA patients (P<0.05). No significant differences were found between LORA and YORA in specific serologic index, including rheumatoid factor and anticyclic citrullinated peptide antibody, and disease activity score 28-C-reactive protein (DAS28-CRP) and clinical disease activity index (CDAI). But LORA had a higher simplified disease activity index (SDAI) (P=0.002). Glucorcoticoid was used in 67.4% LORA patients, compared with 29.3% in YORA patients (P<0.001). In contrast, disease-modifying anti-rheumatic drugs (DMARDs) were used in 73.7% LORA patients, compared with 97.6% in YORA patients (P<0.001). CONCLUSION: Delayed diagnose of LORA is common due to atypical presentation at disease onset. RA should be considered in elderly patients with large joints for differential diagnosis. LORA is more likely to have anemia than YORA, albeit no significant differences in serological index and extraarticular presentations. LORA patients should be treated with DMARDs as aggressively as YORA patients, if their comorbidities allow to do so. PMID- 25924449 TI - [Clinical characteristics of rheumatoid arthritis with cold pattern knee pain]. AB - OBJECTIVE: To investigate the clinical characteristic of rheumatoid arthritis associated with cold pattern knee joint pain. METHODS: The study enrolled 60 patients of RA with the complaint of knee pain, 30 cases with cold pattern and 30 cases without cold pattern. The clinical symptoms, DAS28 score, cold knee score were collected, and serum hypoxia inducible factor-1alpha (HIF-1alpha) erythrocyte sedimentation rate (ESR), C-reactive protein (CRP) and thermal texture maps (TTM) of knee temperature were measured. The difference between two groups was compared to analyze the clinical characteristics of RA with cold pattern knee pain. RESULTS: There were differences between the two groups in the course (t=5.932, P=0.000), DAS28 score (t=2.716, P=0.007), knee (delta TTM) (t=7.731, P=0.000), absolute difference of thermal texture maps between popliteal fossia and front district in knee (ATTM) (t=14.295, P=0.000), CRP (t=5.684, P=0.000), ESR (t=4.506, P=0.000), HIF-1alpha (t=4.817, P=0.000). CONCLUSION: RA patients with cold pattern knee pain show the clinical characteristics with longer course of disease, lower level of local inflammation, lower disease activity. PMID- 25924450 TI - [Acetabular morphological analysis in patients with high dislocated DDH using three-dimensional surface reconstruction technique]. AB - OBJECTIVE: To simulate acetabular morphology and perform acetabular quantitative analysis in high dislocated developmental dysplasia of the hip (DDH) patients using three-dimensional (3D) surface reconstruction technique, in order to understand the acetabular anatomic features and develop operative strategies for acetabular reconstruction. METHODS: 3D pelvic images were reconstructed by Mimics software from CT data of 13 patients (13 hips) with high developmental DDH and 13 normal persons (26 hips). True acetabular superior-inferior diameter, anterior posterior diameter, acetabular depth, medial wall thickness, abduction angle and anteversion angle were measured and compared between the two groups of participants. RESULTS: Irregular acetabular shape was found in high dislocated group, showing a triangle with wide upper and narrow lower. The acetabular quantitative analysis revealed (38.29 +/- 2.71) mm superior-inferior diameter, (21.74 +/- 5.33) mm anterior-posterior diameter, (15.50 +/- 2.93) mm acetabular depth, (6.80 +/- 2.97) mm medial wall thickness, (49.29 +/- 7.40) degrees abduction angle and (23.82 +/- 11.21) degrees anteversion angle in high dislocated patients. The superior-inferior diameter, anterior-posterior diameter and acetabular depth of high dislocated patients were significantly smaller than those of the normal contirols (P<0.05). However, the medial wall thickness, abduction angle and anteversion angle of high dislocated patients were significantly bigger than those of the normal controls (P<0.05). CONCLUSION: 3D reconstruction technique can restore true acetabular morphology and perform quantitative analysis. Compared with normal controls, high dislocated DDH patients have acetabular features: irregular shape, lower opening, higher medial wall and bigger abduction and anteversion angles. Joint arthroplasty surgery in high dislocated DDH patients needs to look at these acetabular features. PMID- 25924451 TI - [Research for a better method of neonatal rat cardiac myocytes, primary culture and purification]. AB - OBJECTIVE: To seek a simple and effective approach through probing method about primary culture and purification of neonatal rat cardiac myocytes. METHODS: Twenty neonatal rats were randomly divided into 2 groups. Group A: the cardiac myocytes were gained by means of enzymic digestion and tubularis-blowing; Group B: the cardiac myocytes were gained by means of enzymic digestion and rotator stirring. The cardiac myocytes in both groups were purified by means of differential attachment technique and BrdU inhibition and were identified with immunofluorescence staining. Viability was assessed with trypan blue staining and pulsation was assessed under microscope. RESULTS: The rates of cardiac myocyte's viability, pulsation and purity in group A were (89.90 +/- 2.92)%, (91.30 +/- 2.00)% and (94.90 +/- 1.79)% respectively; The corresponding rates in group B were (94.70 +/- 2.31)%, (95.00 +/- 1.24)% and (95.60 +/- 1.43)% respectively. The rates of cardiac myocyte's viability, pulsation in group B were significantly higher than that of group A, which was statistically different (P>0.05). The rate of cardiac myocytes purity in group B was a bit higher than group A, but which wasn't statistically different (P<0.05). Fibroblasts cultured with BrdU grew weaker and less than those without BrdU. CONCLUSION: The method of rotator stirring and enzymic digestion was better than that of tubularis-blowing and enzymic digestion, which helped to gain cardiac myocyte effectively. BrdU helped to purify cardiac myocytes. PMID- 25924452 TI - [Early human papillomavirus testing predicts residual/recurrent disease after LEEP risk factors for predicting residual disease in high-grade squamous cervical intraepithelial neoplasia following LEEP conization]. AB - OBJECTIVE: To explore the risk factors for residual/recurrent disease of cervical intraepithelial neoplasia (CIN) 2 or worse after loop electrosurgical excision procedure (LEEP) and the timing point for postoperative follow-up. METHODS: 428 patients with CIN 2 or CIN 3 who were treated with LEEP were retrospectively reviewed. Postoperative follow-up was performed by Pap smear and human papillomavirus (HPV) hybrid capture 2 (HC2) testing. The definition of persistent/recurrent disease was biopsy-proven CIN 2 or worse. RESULTS: 296 patients were CIN 2 and 132 were CIN 3 among 428 patients. The positive rate of HPV HC2 before LEEP was 86.7% (371/428). During follow-up, 26 patients (6.1%) had residual/recurrent disease, the positive LEEP margin, especially the cone top status, was a significant risk factor for persistent/recurrent disease. Other factors such as age, HPV viral load [> or =100 relative light units (RLU)], and HPV typing (type 16/18 vs. other types) did not predict recurrence. HPV HC2 test at 3 months after LEEP can find all the residual/recurrent disease, the sensitivity and negative predictive value of the HPV HC2 test for residual/recurrent disease were both 100% at 3 and 6 months. CONCLUSION: The positive margin of LEEP specimen especially the cone top status was a significant risk factor for residual/recurrent disease after LEEP. HPV test at 3 months during follow-up can offer timely information about residual/recurrent disease and help for the risk control in treatment selection. PMID- 25924453 TI - [Gynecologic cancers in a hospital: a retrospective analysis of admission data over ten years]. AB - OBJECTIVE: To investigate admission patterns of patients with gynecologic cancers over a ten year period, which will provide a basis for further epidemiological studies. METHODS: We reviewed medical records of patients with gynecologic cancers who were admitt d to the West China Second University Hospital of Sichuan University from 2003 to 2012. Their clinicopathological data were extracted and analysed. RESULTS: The number of admitted patients increased over the years, with cervical, uterine and ovary cancers as the top three gynaecological cancers. They accounted for 92.13% of total gynaecological cancers. The peak age of gynaecological cancers was 40-49 years, which accounted for 34.02% (3132/9207) of all patients, followed by 50-59 years (26.64%, 2453/9207). Most (72.46%, 3062/4226) cervical cancer patients aged 30-49 years, compared with 40-59 years for uterine cancers (69.77%, 1768/2534) and 40-59 years for ovarian cancers (58.30%, 1004/1722). Patients in their 20th account for 4.43% (408/9 207) of total cancers, with in which cervical and ovarian cancers as the most common pathological type. Patients under 20 years of age accounted for only 0.98% (90/9207) of total cancers, with ovarian cancers as the most common pathological type. Patients over 60 years accounted for 12.90% (1188/9207) of total cancers, with uterine and ovarian cancers as the most common pathological type. Most patients were at an early stage of cancers when they were admitted to the hospital. CONCLUSION: Hospitalized patients with gynecologic cancers increase over years. Cervical, uterine and ovary cancers remain to be a focus of treatment. Peak age of those cancers varies. PMID- 25924454 TI - [Values of short-term anti-tuberculosis treatment in differential diagnosis of Crohn's disease and intestinal tuberculosis]. AB - OBJECTIVE: To determine the values of short-term anti-tuberculosis treatment in the differential diagnosis of Crohn's disease (CD) and intestinal tuberculosis (ITB). METHODS: A review of cases (from January 2009 to October 2013) with a 2-3 month therapeutic trial of anti-tuberculosis was performed. The clinical manifestation and endoscopic findings of the patients, and the accuracy, sensitivity and specificity of the short term anti-tuberculosis trial for differential diagnosis of ITB and CD were analysed. RESULTS: Sixty-four cases entered into study, with 33 diagnosed with ITB and 31 with CD. In the ITB patients, 31 had significant improvement in their clinical and endoscopic manifestations, with decreased erythrocyte sedimentation rate (ESR) and C reactive portein (CRP) (P<0.05) and increased hemoglobin (HGB) (P<0.05). On the contrary, only three CD patients showed improvement in their disease activity (CDAI). The accuracy of short-term anti-tuberculosis treatment in the differential diagnosis was 92.19%, with a sensitivity and specificity of 93.94% and 90.32%, respectively. There was no significant difference in CDAI scores in the CD patients prior to and after 2-3 months trial of anti-tuberculosis treatment. CONCLUSION: Short term trial of anti-tuberculosis treatment is valuable and feasible in the differential diagnosis of ITB and CD. PMID- 25924455 TI - [Trans-lumbar-and-peritoneally joint approach for laparoscopic removal of large adrenal neoplasms]. AB - OBJECTIVE: To explore the safety and efficacy of translumbar-and-peritoneally joint (TLPJ) approach for laparoscopic dissection of large neoplasms from adrenal glands. METHODS: Sixty patients with diameters > or = 6.0 cm adrenal neoplasms were recruited in this study. Of the participants, 30 were given transperitoneally laparoscopic adenectomy and 30 were given TLPJ approach. We compared the basic characteristics of the patients, as well as their conditions during and after operations. RESULTS: The two groups of patients had similar characteristics. No significant differences were found between the two approaches in terms of conversion to open surgery, estimated blood loss, transfusion, operating time, side injury, fluctuations of heart rate and blood pressure, and vascular accidents (P>0.05), although slight, but not significant, advantages were shown in the TLPJ patients on starting food intake and physical activities. Similar results were also found .in drainage volume, time to remove drainage, length of hospital stay, usage of analgesic, fever incidence, infection and intestinal obstruction etc (P>0.05). Above all, no significant differences were found between the two groups in recurrence, metastasis and overall survival rates (P>0.05). CONCLUSION: Laparoscopic surgery with TLPJ approach, translumbar combined with entirely side peritoneum opened, is safe and efficient compared with the traditional transperitoneal approach for patients with large adrenal neoplasms. PMID- 25924457 TI - [Energy and nutrient reference values]. PMID- 25924458 TI - [Reference values of energy for the Venezuelan population]. AB - The project of updating the Venezuelan energy reference values respond to the recommendations made by an FAO experts committee, several decades ago for the countries assuming this work. Because of the dramatic changes experienced globally regarding energy intake/expenditure and particularly variations on the Venezuelan nutritional scenario with the presence of "the double burden of malnutrition" it a review of Energy Reference Values (VRE) from a more integral approach is pertinent. This report follows the methodology proposed by FAO/WHO/UNU 2004 experts committee and energy reference values were established by group of age and gender, also average energy values for Venezuelan population were obtained. For calculation of these requirements, the energy expenditure was included by taking into account Basal Metabolic Rate and physical activity level for some specific groups. The score average values updated in 2012 of 2.200 kcal/dia reported to be lower than those of 2000 at all ages for masculine gender except for the 16-17 age group and for feminine gender just until ages 10-12 years and from there are slightly above the values obtained in 2000. PMID- 25924459 TI - [Reference values of proteins for the Venezuelan population]. AB - This study presents the reference values for protein requirements. The consumption of the Venezuelan population was obtained according to the Food Consumption Monitoring Survey (ESCA) 2010-2012. The diet provided good quality proteins, combining animal and vegetable foods in an approximate ratio of 1:1. The reference values were calculated based on the safe levels of protein intake recommended by WHO/FAO/UN 2007, with an adjustment for protein supply depending on age, weight, and contribution to the caloric formula of proteins for light physical activity. The reference values for protein requirements recommended as safe levels of intake in g/kg/day are 1.14 to 1.80 for males and females less than one-year-old, from 1 to 3 years, 0.90 to 1.14; from 4 to 6 years old, 0.86 to 0.89; and from 7 to 10 years old, 0.91 to 0.92. For adolescents, the average is 0.88 and 1.07 for males and females, respectively. In adults from 20 to 59 years old, 0.83 for men and women is recommended, and for older adults, 1.00 for men and women. In pregnant women, additional consumptions are recommended according to gestation time. Adolescent pregnant women must consume additional 1.2 to 1.7 g/kg/day to normal requirement. In breastfeeding women, the values differ between the first six months postnatal period and after six months of breastfeeding. The reference values for protein in this update were lower than the values of the 2000 version. PMID- 25924460 TI - [Reference values of fats for the Venezuelan population]. AB - The present work is a review of the available intormation in the scientific literature in food and human nutrition related to fats and oils, in order to bring a range of guidance on nutritional requirements in pregnancy, infancy, childhood and adulthood, in improving the health and nutritional well-being. Topics include: Characteristics of fatty acids, nomenclature, requirements and recommendations regarding their consumption and its impact on the health situation in Venezuela and recommendations. We present recommendations for total fat requirements and the different fatty acids for different age groups and biological conditions. It was noted that depending on the distribution of fat intake by food of the Venezuelan population energy intake (28.84%) is in line with the recommendations of the FAO/WHO, 2010. Vegetable fats contribute about 62.60% of the total fat where the main source are oils (83.97%) followed by cereals (21.47%) the rest is contributed by vegetables, legumes, vegetables and others. While animal fats represent a 36.84%. Total chiffon, where milk and dairy products account for the highest percentage (47.43%) followed by meat and fish (41.07%), and a lower contribution from eggs (2.07%). This suggests a high ratio n-6/n-3 in feeding conditions Venezuelan general, being necessary to consider ways in which diminish this relationship, in order to prevent cardiovascular disease. PMID- 25924461 TI - [Reference values of carbohydrates for the Venezuelan population]. AB - An update of the nutritional recommendations for carbohydrate intake to the Venezuelan population was performed. For this work the concepts, data and methodology followed by other countrie's or groups of countries to obtain and document their own reference, in order to provide basic information to facilitate the establishment of reference values can be revised to better adapt to the Venezuelan population. The data correspond to healthy populations and taken as reference the recommendations of the Food and Nutrition Board of the U.S., the Committees of Experts on Energy and Protein FAO/WHO, among others. As a result of the literature review, the historical caloric formula of population and dietary patterns of Venezuela was propose the consumption of total carbohydrate intake between 50 and 60% of total caloric intake and simple sugars do not exceed 10% of intake. It is suggested to increase the consumption of vegetables, whole grains, legumes, vegetables and whole tropical fruits. PMID- 25924462 TI - [Reference values of folic acid for the Venezuelan population]. AB - The review on folic acid requirements for Venezuela comprise the definitions adopted worldwide known as Dietary Reference Intakes (DRIs) that include Recommended Dietary Allowance (RDA), Estimated Average Requirement (EAR), Adequate Intake (AI) and Tolerable Upper Intake Levels (UL). In contrast with the situation in some countries, that required adjustments in fortification policies in order to avoid excessive folic acid consumption, in Venezuela several studies show an elevated prevalence of deficiency. National evidence at this point is insufficient to establish the recommendation, and as in the 2000 review of the Venezuelan RDAs, the actual recommendations are based on the reported for the United States population. The Recommended Dietary Allowances for Venezuela are 65 80 microg/day for infants less than 1 year old, 150-300 microg/day for children and 400 microg/day for adolescents and adults, increasing to 600 microg/day during pregnancy and to 500 microg/day during lactation. The estimated average requirement is 120-250 microg/day for children, 330 microg/day for adolescents, 320 microg/day for adults, 520 microg/day for pregnancy and 450 microg/day during lactation. The tolerable upper intake levels for folic acid are 300-600 microg/day for children, 800 microg/day for adolescents and 1000 microg/day for adults. During pregnancy and lactation the UL is 800 microg/day for pregnant and lactating women between 14 and 18 years of age, and 1000 microg/day for older pregnant and lactating women. The continuous evaluation of folic acid status is important to design adequate and efficient policies to control both, the deficiency and the excess of folic acid consumption. PMID- 25924463 TI - [Reference values of vitamin A for the Venezuelan population]. AB - Vitamin A deficiency is one of the most prevalent nutritional deficiencies worldwide, mainly affecting children and women. The cause of vitamin A deficiency is insufficient intake, especially in presence of infection and the consequences of the deficiency are xerophthalmia, night blindness, anemia, increased susceptibility to infections and the still controversial increase in infant mortality. National evidence at this point is insufficient to establish the recommendation, and as in the 2000 review of the Venezuelan RDAs, the actual recommendations are based on the reported for the United States population. The Recommended Dietary Allowances (RDA) for Venezuela are 400-500 RE/day for infants, 300-400 RE/day for children 600 RE/day for adolescents, 900 RE/day for men and 700 RE/day for women, increasing to 750 RE/day for pregnancy and to 1200 1300 RE/day during lactation, depending on the age. The estimated average requirement (EAR) is between 210 and 275 RE/day for children, 445 RE/day for male adolescents, 420 RE/day for female adolescents, 630 RE/day for men and 485 RE/day for women, increasing to 530-550 and 885-900 RE/ day during pregnancy and lactation, respectively. The tolerable upper intake levels (UL) for vitamin A are 600 RE/day for children, 1700 a 2800 RE/day for adolescents and 3000 RE/day for adults, males and females. PMID- 25924464 TI - [Reference values of niacin for the Venezuelan population]. AB - Niacin is a water soluble vitamin, also known as nicotinic acid or Vitamin B3. Nicotinamide is a derivative of niacin (amide of nicotinic acid), and is used by the body to produce the coenzyme nicotinamide adenine dinucleotide (NAD) and nicotinamide adenine dinucleotide phosphate (NADP), In preparing this review about the niacin requirements for Venezuela, it was found that there is not enough national data to establish recommendations, therefore, as in the 2000 review of the Venezuelan Recommended Dietary Allowances (RDAs), the actual recommendations for intake of niacin, are based on those reported for the United States population. The RDAs for Venezuela are: 2-4 mg/day for infants less than 1 year old, 6-8 mg/day for children between 1 and 8 years, 12 mg/day for children between 9 and 13 years, 14 mg/day for adolescents and female adults, 16 mg/day for adolescents and adult males, 18 mg/day during pregnancy and 17 mg/day during lactation. The estimated average requirement (EAR) is: 6-9 mg/day for children, 11 mg/ day for adolescents and female adults and 12 mg/day for adolescents and adult males, increasing to 14 mg/day during pregnancy and to 13 mg/day during lactation. The niacin Tolerable Upper Intake Levels (UL) are: 10 mg/day for children between 1 and 3 years, 15 mg/day for children between 4 and 8 years, 20 mg/day for children between 9 and 13 years, 30 mg/day for adolescents and 35 mg/day for adults. It is necessary to perform studies where the nutritional status of this vitamin is evaluated for different population groups, including not only the estimation of consumption, but the use of biochemical indicators, such as measuring the levels of the coenzymes NAD and NADP in erythrocytes or whole blood and determination of the major urinary metabolites of the vitamin. PMID- 25924465 TI - [Reference values of iron, iodine, zinc, selenium, copper, molybdenum, vitamin C, vitamin E, vitamin K, carotenoids and polyphenols for the Venezuelan population]. AB - The review on iron, iodine, zinc, selenium, copper, molybdenum, vitamin C, vitamin E, vitamin K, carotenoids and polyphenols recommendations for Venezuela comprise the definitions adopted worldwide known as Dietary Reference Intakes (DRIs) that include Recommended Dietary Allowance (RDA), Estimated Average Requirement (EAR), Adequate Intake (AI) and Tolerable Upper Intake Levels (UL). The RDA for iron: 11 mg/day for infants < 1 year of age, 7-10 mg/day for children, 8-11 mg/day for males, 8-18 mg/day for females and 27 mg/day during pregnancy. RDA for iodine: 110-130 microg/day for infants, 90-120 microg/ day for children and adolescents, 150 microg/day for adults, 220 microg/ day for pregnancy and 290 microg/day during lactation. RDA Zinc: 2-3 mg/day for infants, 3-5 mg/day for children, 8-11 mg/day for male adolescents and adults, 8-9 mg/day for female adolescents and adults, 12 mg/day during pregnancy and 13 mg/day for lactation. RDA Vitamin C: 40-50 mg/day for infants, 15-45 mg/ day for children, 75 mg/day for male adolescents, 65 mg/day for female adolescents, 90 mg/day for adult males, 75 mg/day for adult females, 80-85 mg/day during pregnancy and 115 120 mg/day during lactation. Recommendations for copper, selenium, molybdenum, vitamins E, K, carotenoids and polyphenols are also presented. These recommendations will help to design adequate and efficient policies that could help to avoid or to treat the consequences derived from the deficiency or the excess of these nutrients. PMID- 25924466 TI - [Reference values of calcium, vitamin D, phosphorus, magnesium and fluoride for the Venezuelan population]. AB - The following micronutrients were considered together for their role in bone health: calcium, vitamin D, phosphorus, magnesium and fluoride. Calcium: not enough is known to change current recommendations. In adolescents and adults, limited data suggest that consuming the recommended level is associated with normal bone mass. In older adults, the limited data reported low consumption and a high rate of fractures but there is no information on whether the current values are adequate. Vitamin D: the limited data reported high deficiency in older adults, which was related to osteoporosis. Given the recent increase in North American recommendation for their contribution to bone health, we proposed to increase the recommendation to 400-600 IU/d for Venezuela. Phosphorus, magnesium and fluoride: the lack of local data does not support changing the latest recommendations. Therefore, it highlights the lack of local studies to assess current recommendations. Studies are needed to estimate the intake of these micronutrients in the population and evaluate their interaction and their relation to bone and overall health. Information of the adequacy of these nutrients in human milk for infants is needed. Alto, it is necessary to implement an effective nutrition surveillance system and implement interventions that maximize bone health from an early stage, including the design and implementation of a dairy policy that leads to an increase in production and consumption by the population. PMID- 25924467 TI - [Progress in the treatment of diabetic wound healing via stem cells transplant]. AB - The morbidity of diabetes has been increasing rapidly in recent years. Delayed wound healing has become a common complication in diabetes, which seriously affects the orthobiosis of patients. Exploring and finding the molecular mechanisms of diabetic wound healing and the effective therapies to promote wound healing have important clinical significances. Stem cells transplant has become a research hotspot in accelerating diabetic wound healing. This article reviewed the present approaches concerning stem cells transplant in diabetic wound healing both at domestic and abroad, and looked forward the clinical therapy of stem cells on diabetic wound healing. PMID- 25924468 TI - [Histone deacetylase 6: structure, functions and development of selective inhibitors]. AB - Histone deacetylase 6 (HDAC6) is an unique subtype of histone deacetylases with two tandem deacetylase domains and substrate specificity for non-histone proteins. It is involved in many important physiological and pathological processes and has become a promising therapeutic target in recent decades. Different kinds of potent HDAC6-selective inhibitors have been reported around the world. This paper reviews the progress in the study of structure and functions of HDAC6 as well as the development of HDAC6-selective inhibitors. PMID- 25924469 TI - [Recent advances and perspective in the study of the nano-reinforcing materials for molecular imprinting of proteins]. AB - Molecular imprinting technique (MIT) involves the synthesis of polymer in the presence of a template to produce complementary binding sites in terms of its size, shape and functional group orientation. Such kind of polymer possesses specific recognition ability towards its template molecule. Despite the rapid development of MIT over the years, the majority of the template molecules that have been studied are small molecules, while molecular imprinting of proteins remains a significant yet challenging task due to their large size, structural flexibility and complex conformation. This review, we summarized the research findings over the past years, and discussed the nano-reinforcing materials used to prepare molecular imprinting of proteins and the perspective of these nano reinforcing materials. PMID- 25924470 TI - [Effect of huangqin tang on the regulatory NF-kappaB p65 signal pathway in rats with ulcerative colitis]. AB - To investigate the effect of huangqin tang on expression of cytokines and NF kappaB p65 in rats with ulcerative colitis (UC), and to probe into its underlying mechanisms of action. The mode of UC rats with cell immunoreactivity was made using compound method (trinitrobenzene sulfonic acid and ethanol). Rats were randomly divided into control group, model group, SASP group and high dose, middle dose and low dose of huangqin tang group. The food intake, body weight and microscopic damage of rats in each group were evaluated after being treated for five days. The blood and colon tissue were also collected. Production of NO was detected by Griess assay, the expression levels of IL-6, TNF-alpha, PGE2 were detected by ELISA. ICH method was undertaken to determine the expression of NF kappaB p65 protein in colon tissue. The food intake and body weight of model group rats were lower than that of control group. The expression levels of NO, IL 6, TNF-alpha, PGE2 in serum and NF-kappaB p65 protein of colon tissue in model group were higher than that of control group. The above indexes were ameliorated in high and middle dose of huangqin tang groups. But there was no significant difference with SASP group. NF-kappaB p65 may be involved in the pathogenesis of UC, and huangqin tang can inhibit the relative activity of NF-kappaB p65, and decrease the expression levels of NO, IL-6, TNF-alpha and PGE2. PMID- 25924471 TI - [The idiosyncratic hepatotoxicity of Polygonum multiflorum based on endotoxin model]. AB - The liver injury induced by Polygonum multiflorum Thunb. (PM) was investigated based on idiosyncratic hepatotoxicity model co-treated with lipopolysaccharide (LPS) at a non-hepatotoxic dose. Sprague-Dawley (SD) rats were intragastrically administered with three doses (18.9, 37.8, 75.6 g crude drug per kg body weight) of 50% alcohol extracts of PM alone or co-treated with non-toxic dose of LPS (2.8 mg.kg(-1)) via tail vein injection. The plasma alanine aminotransferase (ALT) and aspartate aminotransferase (AST) activities were assayed and the isolated livers were evaluated for histopathological changes. The dose-toxicity relationships of single treatment of PM or co-treatment of LPS were investigated comparatively to elucidate the idiosyncratic hepatotoxicity of PM. The results showed that no significant alterations of plasma ALT and AST activities were observed in the groups of solo-administration of LPS (2.8 mg.kg(-1), i.v.) or different dosage (18.9, 37.8 and 75.6 g.kg(-1), i.g.) of PM, compared to normal control group (P > 0.05); while significant elevations were observed in the co-administration groups of PM and LPS. Treatment with LPS alone caused slight infiltration of inflammatory cells in portal area but no evident hepatocytes injury. Co-treatment with LPS and PM (75.6 g.kg(-1), i.g.) caused hepatocyte focal necrosis, loss of central vein intima and a large number of inflammatory cell infiltration in portal areas. When further reduce the dosage of PM, significant increases of plasma ALT and AST activities (P < 0.05) were still observed in co-administration groups of LPS and PM (1.08 or 2.16 g.kg(-1)), but not in LPS or PM solo administration groups. Nevertheless, the co-treatment of low dosage of PM (0.54 g.kg(-1)) with LPS did not induce any alteration of plasma ALT and AST. In conclusion, intragastric administration with 75.6 g.kg(-1) of PM did not induce liver injury in normal rats model; while the 2 folds of clinical equivalent dose of PM (1.08 g.kg(-1)) could result in liver injury in the LPS-based idiosyncratic hepatotoxicity model, which could be used to evaluate the idiosyncratic hepatotoxicity of PM. PMID- 25924472 TI - [Effects of crocetin on VCAM-1 expression in human umbilical vein endothelial cells and monocyte-endothelial cell adhesion]. AB - Crocetin, a naturally occurring carotenoid, possesses antioxidant and antiatherosclerotic properties, of which the underlying mechanism remains unclear. In the present study, we examined the effects of crocetin (0.1, 1, 10 MUmol.L(-1)) on angiotensin II (Ang II, 0.1 MUmol.L(-1)) induced expression of vascular cell adhesion molecule-1 (VCAM-1) in human umbilical vein endothelial cells (HUVECs) and monocyte-endothelial cell adhesion. The effects of crocetin on the activation of nuclear factor kappa B (NF-kappaB) and intracellular reactive oxygen species (ROS) were also observed. The results demonstrated that crocetin notably suppressed Ang II induced NF-kappaB activation (P<0.01) and VCAM-1 expression (P<0.05, P<0.01) in HUVECs, accompanied by a markedly reduced monocyte endothelial cell adhesion (P<0.05, P<0.01). In addition, preincubation with crocetin resulted in a significant enhancement of cellular antioxidant capacity (P<0.05, P<0.01), while Ang II induced intracellular ROS decreased markedly (P<0.05, P<0.01). These results indicated that crocetin was capable of suppressing Ang II induced VCAM-1 expression and monocyte-endothelial cell adhesion by suppression of NF-kappaB activation, which might be derived from the enhancement of antioxidant capacity and subsequent reduction of intracellular ROS. PMID- 25924473 TI - [Effect of allitridum on remodeling of the transient outward potassium current of ventricular myocytes of spontaneously hypertensive rats]. AB - We aimed to study the effect of allitridum (All) on the transient outward potassium current (Ito) of ventricular myocytes of spontaneously hypertensive rats (SHR). Totally 30 male SHRs were randomly divided into three groups: low dose All group (7.5 mg.kg(-1)), high-dose All group (15.0 mg.kg(-1)) and normal saline group. The other 10 sex and age matched Wistar-kyoto rats (WKY) were also taken as control group (WKY group). All animals received i.p. administration for 8 weeks. The dual enzymatic method was used to separate single ventricular myocyte from animals. Patch-clamp technique was used to record Ito and analyze the effect of All on the current. It was shown that the left ventricular hypertrophy of SHR was reversed significantly by All. Furthermore, the density of Ito was recovered in both high and low dose All groups. The peak current densities of Ito were enhanced from 18.23+/-3.64 to 25.17+/-2.86 pA/pF (P<0.01) and 36.47+/-5.42 pA/pF (P<0.01) at +50 mV by All 7.5 mg.kg(-1) and 15.0 mg.kg( 1), respectively, which was not significantly different with WKY group. The effect was associated with positive shift of the steady-state, close-state inactivation, and shortened recovery from inactivation of Ito. It is concluded that All decreases the remodeling of Ito of ventricular hypertrophic myocytes of SHR. PMID- 25924474 TI - [Effect of ethyl gallate on invasion abilities and its mechanism of breast cancer MDA-MB-231 cells]. AB - This study is to investigate the effect of ethyl gallate on invasion capabilities and its mechanism of breast cancer MDA-MB-231 cells. Using cell adhesion and transwell assay, separately, the effects of ethyl gallate on the invasion of MDA MB-231 cells were measured. The Akt-NF-kappaB signal pathway protein expressions were analyzed with Western blot. Also, the mRNA levels of MMP-9 and MMP-2 were analyzed by RT-PCR. Ethyl gallate inhibited the abilities of motility, adhesion and invasion of breast cancer MDA-MB-231 cells in vitro (P<0.05), inhibited the mRNA levels of MMP-9, MMP-2, phosphorylation of AKt and protein expression of NF kappaB. It is concluded that ethyl gallate can inhibit the abilities of invasion of breast cancer in vitro by inhibiting the mRNA levels of MMP-9/MMP-2, phosphorylation of Akt and protein expression of NF-kappaB. PMID- 25924475 TI - [The in vitro HAART pharmacodynamics study with dolutegravir as the "anchor"]. AB - This study is to evaluate the HAART pharmacodynamics with dolutegravir as the "anchor" in vitro. A nucleoside reverse transcriptase inhibitors (NRTIs) resistant recombinant virus model (VSVG/HIV-1(RT-D67N,K70R,T215F)) and an integrase inhibitors (INIs) resistant recombinant virus model (VSVG/HIV-1(IN G140S,QI48H)) were constructed and established. The anti-viral pharmacodynamics was evaluated with drug combinations including two NRTIs along with one INI or one NNRTI. The results showed that the combination with an INI gave a stronger synergism on wild type HIV-1 replication comparing to that with an NNRTI. Comparing the two INIs as the "anchor" for HAART, DTG exhibited an equivalent CI to that of RAL on wild type HIV-1 replication; but a greater synergy than RAL on INI-resistant HIV-1 replication. Besides of the pharmacodynamics results of DTG based drug combination, the results may contribute to clinical antiviral therapy. PMID- 25924476 TI - [Design and synthesis of photoaffinity biotin labelled 2'-O-propargyl-guanosine]. AB - Photoaffinity labeling is widely applied to demonstrate targets of small molecule ligands. In this paper, biotin photoaffinity labeled molecule with propargyl group 1 has been designed and synthesized, followed it's labeling of N2-acetyl-2' O-propargyl guanosine 9 by "click chemistry". This technology presents delight development potential in labeling of second messenger cyclic nucleotide, antisense oligonucleotide or siRNA. PMID- 25924477 TI - [Design, synthesis and evaluation of 5-aminobenzimidazolone derivatives as acetylcholinesterase inhibitors]. AB - The target compounds were prepared from 5-aminobenzimidazolone by two steps reaction, and their AChE inhibitory activities were measured by Ellman method in vitro. The AChE inhibitory activity of compound 4d is the best of them, and its IC50 value is equal to 7.2 MUmol.L(-1), which is better than that of rivastigmine; moreover the 4d had no inhibitory activities to BuChE. Therefore, the inhibitory activities of 5-aminobenzimidazolone derivatives to acetylcholinesterase are worth further researching. PMID- 25924478 TI - [Chemical constituents of Taxus chinensis var. mairei cell cultures]. AB - The chemical constituents of Taxus chinensis var. mairei cell cultures were investigated by chromatographic methods, including silica gel column chromatography, Sephadex LH-20 and preparative HPLC. Thirteen compounds were isolated from the 80% ethanol extract of cultured cells and their structures were elucidated by spectral data and physicochemical properties, which were identified as 2alpha,4alpha,7beta,9alpha,10beta-pentaacetoxy-14beta-hydroxytax-11-ene (1), 2alpha,4alpha,7beta,9alpha,10beta-pentaacetoxytax-11-ene (2), 1beta-deoxybaccatin VI (3), 2alpha-acetoxytaxusin (4), taxuyunnanine C (5), yunnanxane (6), 2alpha,5alpha,10beta-triacetoxy-14beta-propionyloxy-4 (20), 11-taxadiene (7), 2alpha,5alpha,10beta-triacetoxy-14beta-isobutyryloxy-4 (20), 11-taxadiene (8), 2alpha,5alpha,10beta-triacetoxy-14beta-(2'-methyl)butyryloxy-4 (20), 11-taxadiene (9), 13-dehydroxylbaccatin III (10), 13-dehydroxy-10-deacetylbaccatin III (11), paclitaxel (12) and (13) beta-sitosterol. Among them, compound 1 is a new compound, and compounds 2, 4, 10 and 11 are isolated from the cell culture of Taxus chinensis var. mairei for the first time. PMID- 25924479 TI - [Characterization and comparison of interferon reference standards using UPLC MS]. AB - The study aims to characterize and compare interferon reference standards from 5 manufacturers. By testing molecular mass and trypsin-digested peptide mass mapping, the amino acid sequence was verified and post-translational modifications such as disulfide bond were identified. Results show that the molecular mass and amino acid sequence were consistent with theory; the disulfide bonds of 4 lots of interferon were Cys1-Cys98/Cys29-Cys138, 1 lot was Cys29 Cys139/Cys86-Cys99; N-terminal "+Met", acetyl N-terminal and Met oxidation were identified in part of the sample. UPLC-MS can be used to characterize and compare interferon reference standards from different manufacturers. PMID- 25924480 TI - [Determination of 10 mycotoxin contaminants in Panax notoginseng by ultra performance liquid chromatography-tandem mass spectrometry]. AB - To ensure the quality and safety of Panax notoginseng, a method for the simultaneous determination of 10 mycotoxins in Panax notoginseng was developed using ultra performance liquid chromatography tandem mass spectrometry (UPLC MS/MS). The sample was extracted with acetonitrile and purified by HLB multifunction cleanup column. The separation was performed on a Phenomenex Kinetex XB-C18 column by gradient elution using methanol and 5 mmol.L(-1) ammonium acetate as mobile phase. The targeted compounds were detected in MRM mode by mass spectrometry with electrospray ionization (ESI) source operated in both positive and negative ionization modes. The linear relationships of the 10 mycotoxins were good in their respective linear ranges. The correlation coefficients (r) ranged from 0.9981 to 1.0000. The LOQs of the 10 mycotoxins were between 0.15 and 8.6 MUg.kg(-1). The average recoveries ranged from 73.8% to 107.0% with relative standard deviations (RSDs) of 0.10%-10.9%. The results demonstrated that the proposed method was sensitive and accurate, and suitable for the mycotoxins quantification in Panax notoginseng. PMID- 25924481 TI - [The effective parts of liangxue tongyu prescription on cooling-blood and activating-blood and analysis of chemical constituents by HPLC-MS and GC-MS]. AB - In order to clarify material basis of effective parts of liangxue tongyu prescription, blood-heat and blood-stasis rat model induced by dry yeast was established. The changes of rectal temperature, blood viscosity and plasma viscosity were used to evaluate the cooling-blood and activating-blood effects of liangxue tongyu prescription and its parts. Compared with the model group, the extract from liangxue tongyu prescription, its volatile oil and n-butanol part could significantly reduce rectal temperature (P<0.01), and also reduce blood viscosity and plasma viscosity to various degrees (P<0.01 or P<0.05). So volatile oil and n-butanol part were primarily identified as effective parts of liangxue tongyu prescription. By using GC-MS with normalization method of area to analyze volatile oil of liangxue tongyu prescription, 70 compounds were identified, accounting for about 92.54%, mainly as beta-asarone, paeonol, alpha-asarone and shyobunone. 42 compounds such as peony glycosides, tannins, and iridoid glycosides were identified by HPLC-MS techniques and standard comparison. The study determined the effective parts of liangxue tongyu prescription and clarified the chemical composition providing the foundation for further studies on material basis of liangxue tongyu prescription. PMID- 25924482 TI - [Development of a novel reporter gene method for determination of ADCC potency of anti-CD20 monoclonal antibody]. AB - The biological activity of ADCC by anti-CD20 monoclonal antibody was determined by BioGloTM Luciferase Assay System using Jurkat/NFAT-luc+FcgammaRIIIa cell line as effector cell and WIL2-S cell line as target cell. The developed method was verified for specificity, precision and accuracy. Anti-CD20 monoclonal antibody showed a dose-response mode by the developed method, and the determination result complied with the following four-parameter equation: y = (A-D)/[1 + (X/C)(B)] + D. The optimized parameters of the method were determined including the antibodies diluted concentration (18,000 ng.mL(-1)), dilution rate (1:5), the ratio of effector cell and target cell (6:1), and induction time (6 h). The values of eight independent tests have passed a statistical test for curve regression analysis, linear or parallelism, which showed the method possessed good specificity. Four different dilute groups of recovery rates sample were determined for 3 times, and the result showed mean relative potencies of (44.39+/ 3.93)%, (72.74+/-2.78)%, (128.28+/-7.01)% and (168.19+/-2.70)% respectively, with a variation coefficient of less than 10%, and the recoveries of (88.78+/-7.85)%, (96.99+/-3.70)%, (102.63+/-5.61)% and (112.12+/-1.80)% respectively. A novel reporter gene method for determination of biological activity of ADCC by anti CD20 monoclonal antibody was successfully developed, which showed strong specificity, good reproducibility and high accuracy, and might be used routinely. PMID- 25924483 TI - [Ultrasonic microbubbles for glioma-targeted drug delivery]. AB - Ultrasonic microbubbles were used to open blood-brain barriers (BBB) with a reversed and limited behavior feature in the study, which could improve the brain targeted delivery of anti-tumor drugs. The glioma rat model was prepared. Low frequency ultrasound was combined with microbubbles to affect the permeability of BBB compared with the permeability of independently administered Evans blue (EB) crossing BBB. Time point and length of ultrasound were investigated whether they affect the permeability of BBB and the damage of brain tissue. The effect of the growth time of glioma on BBB permeability was explored. Only glioma had a very little impact on BBB permeability. However, ultrasonic microbubbles opened the BBB with the features of temporary, limited and reversed behavior and improved EB and magnetic resonance imaging contrast agent penetrating BBB. A length of 30 s ultrasound is appropriate for opening BBB and no damage of brain tissue. Drugs should be injected before ultrasound so that they enter into brain as BBB opening. Ultrasonic microbubbles can open BBB effectively and safely, which improve drugs penetrating BBB under proper time point and length. PMID- 25924484 TI - [Cell penetrating peptide TAT and brain tumor targeting peptide T7 dual modified liposome preparation and in vitro targeting evaluation]. AB - The purpose of this study is to prepare T7 and TAT dual modified liposomes (T7 TAT-LIP) to penetrate through blood brain barrier and target to brain tumor cells. The liposomes were prepared with CFPE, T7 modified PEG-DSPE, TAT modified PEG-DSPE, soybean phospholipid, PEG-DSPE and cholesterol. The CFPE was used to track the cellular uptake efficiency. The density of T7 and TAT and the length of PEG were optimized, and then the liposomes were characterized by particle size, zeta potential, morphology and stability. Afterwards, the cellular uptake by bEnd.3 and C6 cells were evaluated. The results showed that the optimized parameters were 6% of T7, 0.5% of TAT, the molecular weight of PEG for T7 was 2000 and the molecular weight of PEG for TAT was 1000. After optimization, the particle size of T7-TAT-LIP was 118 nm, the zeta potential was -6.32 mV and the particles were spherical. The turbidity and particle size of liposomes were not obviously changed after 24 h incubation in PBS at 37 degrees C. The particle size and polydispersity index were also stable during 1 month incubation at 4-8 degrees C. The cellular uptake by both bEnd.3 and C6 cells of T7-TAT-LIP was higher than that of T7 or TAT modified liposomes, suggesting dual modified liposomes possessed better blood brain barrier targeting ability and brain tumor targeting ability than the single ligand modified liposomes. PMID- 25924485 TI - [The expression of SQS1 gene and the content of glycyrrhizic acid of Glycyrrhiza uralensis Fisch. in different concentrations of Mn2+]. AB - The transplants of one-year-old Glycyrrhiza uralensis Fisch. were subjected to five concentrations of MnSO4-H2O (0, 1.81, 18.1, 36.2 and 54.3 mg.L(-1)) culturing in vermiculite. qRT-PCR and HPLC were respectively used to measure the relative expression of SQS1 gene and the content of glycyrrhizic acid of G. uralensis in different concentrations of MnSO4.H2O. This is to explore discuss the effects of the expression of SQS1 gene and the accumulation of glycyrrhizic acid by Mn treatment. The results showed both the expression of SQS1 gene and the content of glycyrrhzic acid of G. uralensis tended to rise after the fall of the first with the increase of concentration of Mn treatment. And they were of very significant positive correlation (P<0.01, r=0.737). Relative expression of SQS1 gene reached the highest 7.90 under 18.1 mg.L(-1) MnSO4.H2O treatment. It was very significantly different between 18.1 mg.L(-1) concentration of MnSO4.H2O treatment and CK (0 mg.L(-1)), 1.81, 36.2 and 54.3 mg.L(-1) (P<0.01), and 1.75, 1.37, 1.37, 2.33 times respectively. The content of glycyrrhizic acid reached the highest under 1.81 and 18.1 mg.L(-1) MnSO4.H2O treatment, and there were not significant difference (P>0.05). It was very significantly different between them and other concentrations of MnSO4.H2O treatment (P<0.01). This study suggests the appropriate concentration of Mn treatment could certain promote the expression of SQS1 gene and the accumulation of glycyrrhizic acid of G. uralensis. PMID- 25924486 TI - [Downregulation of lanosterol synthase gene expression by antisense RNA technology in Saccharomyces cerevisiae]. AB - The cyclization of 2,3-oxidosqualene is the key branch point of ergosterol and triterpenoid biosynthesis. Downregulation of 2,3-oxidosqualene metabolic flux to ergosterol in Saccharomyces cerevisiae may redirect the metabolic flux toward the triterpenoid synthetic pathway. In our study, primers were designed according to erg7 gene sequence of S. cerevisiae. Three fragments including 5' long fragment, 5' short fragment and erg7 coding region fragment were amplified by PCR. 5' long fragment consists of the promoter and a part of erg7 coding region sequence. 5' short fragment consists of a part of promoter and a part of erg7 coding region sequence. These fragments were inserted reversely into pESC-URA to construct antisense expression plasmids. The recombinant plasmids were transformed into S. cerevisiae INVSc1 and recombinant strains were screened on the nutritional deficient medium SD-URA. The erg7 expression level of recombinant strains, which harbored antisense expression plasmid of erg7 coding region, was similar to that of INVScl by semi-quantitative PCR detection. But erg7 expression level of recombinant strains, which harbored 5' long antisense fragment and 5' short antisense fragment, was significantly lower than that of the control. The results of TLC and HPLC showed that the ergosterol content of recombinant strains, which harbored 5' long antisense fragment, decreased obviously. The ergosterol contents of the others were almost equal to that of INVSc1. Lanosterol synthase gene expression was downregulated by antisense RNA technology in S. cerevisiae, which lays a foundation for reconstructing triterpenoid metabolic pathway in S. cerevisiae by synthetic biology technology. PMID- 25924487 TI - [Choice and thinking of treatment of clavicle fractures]. PMID- 25924488 TI - [Therapeutic effects of titanium elastic nails for the treatment of clavicular fractures in elder children]. AB - OBJECTIVE: To research the application and clinical effect of titanium elastic nails (TEN) for the treatment of closed clavicular fracture in elder children. METHODS: From October 2010 to December 2012,16 elderly children with clavicular fracture of elder children were treated with internal fixation, including 9 boys and 7 girls with an average age of 14.2 yeats old ranging from 9 to 17 years. The mean time between injury and surgery was 2 to 6 days. Thirteen patients had a transverse fractures; 3 patients had a oblique fractures, excluding the long oblique patients. Neer function score after 3 months follow-up and the shoulder activity degree after 3 weeks followed were compared respectively between the injured side and healthy side. Fracture reduction and healing were followed up by X-rays to analyze internal fixation with TEN technique. RESULTS: All patients were healed well after surgery. There were 2 cases with soft tissue irritation. No cases of infection, TEN broken, delayed healing or skin bursting were observed. All patients were followed up for 3 to 10 months,with an average of 7.2 months. There were no significant differences (t=2.12, P>0.05) between the healthy side (98.75+/-2.70) and injured side(96.69+/-6.22)of Neer score at 3 months during followed up. The shoulder activity at 3 weeks during followed up was different between both sides (P<0.05). The intramedullary nail was removed after X-rays at 12-18 weeks during followed up showed good bone healing,and the shoulder function was recovered well. CONCLUSION : Internal fixation with TEN for the treatment of clavicular fracture has advantages of a limited invasion, beauty, safety and reliability. This technique provides an ideal fixation option for the treatment of clavicular fracture in elder children. PMID- 25924489 TI - [AO elastic intramedullary nailing for the treatment of clavicle fractures]. AB - OBJECTIVE: To evaluate the outcome of Titanium elastic intramedullary nailing (TEN) for the treatment of displaced midclavicular fractures. METHODS: Between February 2010 and February 2013, 62 patients with displaced midclavicular fractures were treated by TEN, including 27 males and 35 females with an average age of 37.6 years old ranging from 15 to 67 years. The course of disease was from 1 to 9 days (means 2.7 days). Thirty-nine cases were treated by closed reduction and 23 cases by assistant small incision. Based on OTA (the Orthopaedic Trauma Association classification) classification, 31 cases of simple fractures involved 5 cases of 06-A1,15 cases of 06-A2,11 cases of 06-A3; 31 cases of wedge fractures involved 4 cases of 06-B1,12 cases of 06-B2,15 cases of 06-B3. Postoperative pain relief were evaluated by VAS score,and operation time,fracture healing time were recorded. After 6 weeks and after removing internal fixation shoulder joint function was evaluated by Constant score, and shoulder joint function were assessed by Herscovici score after 6 weeks. RESULTS: Except 2 cases were lost to follow-up, 2 cases did not remove internal fixation, 3 cases' fractures were nonunion, the remaining 55 patients received follow-up for an average time of 11.4 months. The average preoperative VAS score was 5.20+/-0.71, and it turned to be 1.550.59 at 3 days after operation. The average operative duration was 40 min (15 to 65 min). The average bone healing time was (2.71+/-0.54) months (2 to 5 months). No difference about bone healing time was found between simple fractures and wedge fractures,and between the patients treated by closed reduction and assistant small incision. According to Herscovici standard, the shoulder function was excellent in 49 cases, good in 4, fair in 1, and poor in 1. Simple fractures achieved better Constant score than wedge fractures at 6 weeks postoperatively, whereas no difference was found at 4 weeks after fixation removal. CONCLUSION: Titanium elastic nails (TEN) for treatment of displaced midclavicular fractures has advantages of good clinical effect,rapid pain relief,fast recovery of shoulder joint function. For OTA classification type B patients with comminuted fracture can replace steel to achieve very good effect, but to grasp the appropriate. PMID- 25924490 TI - [Comparison the effects between anatomical locked plate in combination with coracoclavicular ligament reconstruction and clavicular hook plate for the treatment of Neer II b distal clavicle fractures]. AB - OBJECTIVE: To compare the therapeutic effects between anatomical locked plate combined with coracoclavicular ligament reconstruction and clavicular hook plate for treatment of distal clavicle fracture of Neer type II b. METHODS: From August 2010 to August 2013, 42 patients with Neer II b distal clavicle fractures were randomly divided into two groups as group A and group B. In group A, there were 22 cases including 14 males and 8 females with an average age of (44.2+/-11.6) years old. In group B, there were 20 cases including 11 males and 9 females with an average of (45.6+/-12.4) years old. The patients of group A were treated with anatomical locked plate combined with coracoclavicular ligament reconstruction,the patients of group B were treated with hook plate. All fractures were fresh, the time between injuries and operation was 24 hours to 7 days (mean,72 h). General information between the two groups was comparable before operation(P>0.05). Postoperative radiographic were followed up to observe the fracture healing,internal fixation and to measure coracoclavicular distance of two groups. Shoulder function after operation was evaluated by Constant-Murley score system. RESULTS: All patients were followed up with an average of 16.8 months (ranging 12 to 24 months). There was no nonunion,infection and other complications between two groups. The clavicular stress fracture occurred in 1 clavicular hook patient at 6 months after the operation. According to the Constant-Murley score system, that the scores of group A were 90.6+/-6.2, 91.8+/ 4.8, 94.7+/-3.6 and 97.8+/-1.2 at 1st, 3rd, 6 month and last follow-up after operation were higher than those of group B 74.8+/-3.4, 78.4+/-4.4, 82.2+/-2.8 and 94.6+/-3.6 (P 0.05). The fracture healing time of group A (21.6+/-2.2) weeks was shorter than that of group B (25.8+/-2.5) weeks (P 0.05). There were no statistically significant differences between two groups in coracoclavicular distance at last follow-up (P>0.05). CONCLUSION: The anatomical locked plate combined with coracoclavicular ligament reconstruction need not expose shoulder and can reduce the incidence of postoperative pain and limited activity of shoulder, with fewer complication, it is advantageous to the shoulder joint function early recovery. PMID- 25924491 TI - [Comparison of the efftec between eccentric fixation and intramedullary fixation for treatment of intertrochanteric fractures]. AB - OBJECTIVE: To compare the efficacy between eccentric fixation and internal fixation for treatment of intertrochanteric fractures of femur,to provide a theoretical basis for the selection of the treatment method of the intertrochanteric fractures of femur. METHODS: From February 2007 to January 2010,82 patients with femoral intertrochanteric fracture were treated by internal fixation including 39 cases of eccentric fixation involving 23 males and 6 females, aged from 41 to 81 years old with an average of (62.68+/-10.69), using the DHS or proximal femoral locking plate; 43 cases of intramedullary fixation involving 15 males, 28 females,aged from 43 to 78 years old with an average of (62.60+/-8.37),using PFN or PFNA fixed. The surgical incision length, operative time, blood loss and postoperative Harris score between two groups were compared. RESULTS: The wound of two groups were primary healing without operative complications. All cases received follow-up for an average time of 18.3 months (12 to 28 months). The incision length, operative time and blood loss had a statistically significant difference between two groups (P<0.05). Harris scores of hip joint function at 1 month after operation had statistically significant difference between two groups (P<0.05), and Harris scores at 12 months after operation had no statistical significance difference between two groups. The rate of excellent and good was 89.7% in eccentric fixation group and 90.7% in intramedullary fixation group,the difference was not statistically significant (t=0.0613, P>0.05). In eccentric fixation group, there was 1 case of fracture nonunion with DHS loose and ensuing hip varus deformity. In intramedullary nail fixation group, there was no anti-rotation out,distal intramedullary nail of femoral refracture occurred in 1 case. CONCLUSION: Two treatment methods for the treatment of femoral fractures had a good therapeutic effect,but the intramedullary fixation had shorter operative time and less blood loss than the eccentric fixation,it prior to apply to osteoporosis and unstable femoral intertrochanteric fractures. PMID- 25924492 TI - [Comparison of effect between early and delayed in primary intramedullary nailing combined with locked plate fixation for the treatment of multi-segments tibial fractures of type]. AB - OBJECTIVE: To compare the clinical results of early and delayed intramedullary nailing and locked plating for the treatment of multi-segments tibial fractures of type AO/ASIF-42C2. METHODS: Between January 2010 and January 2013,45 patients with multi-segments closed tibial fractures of AO/ASIF-42C2 were treated by early primary intramedullary nailing and locked plating in 20 cases as early group and delayed in 25 cases as delayed group. In early group,20 cases included 13 males and 7 females with an average age of (37.9+/-14.3) years old ranging from 20 to 56 years;according to soft tissue injury Tscherne classification, 8 fractures were frade I,12 were grade II. In delayed group, 25 cases included 17 males and 8 females with an average age of (38.7+/-17.2) years old ranging from 24 to 55 years,4 fractures were grade I ,19 were grade II ,2 were grade III. The operative time, blood loss, hospital stay,fracture healing time and complications were recorded. At final follow-up, the Johner-Wruhs score were used to evaluate functional efficacy, and the posterior-anterior and lateral X-ray to evaluate fracture reduction and alignment. RESULTS: All the patients were followed up for (12.5+/-2.5) months in early group and (13.2+/-2.8) months in delayed group (P>0.05). No wounds infections were happened. At the last follow-up, the mean range of knee joint was 10 degrees -0 degrees -120 degrees . According to Johner Wruhs scoring,there were 15 cases in excellent,3 in good,fair in 2 in early group; 21 in excellent,2 in good,2 in fair. The average operative time,blood loss had no significant differences between two groups (P>0.05), but hospital stay in early group was significantly shorter than those in delayed group(P<0.05). Average fracture healing time of early group and delayed group were (5.3+/-2.6) months and (6.0+/-2.9) months, respectively (P>0.05). CONCLUSION: For multi segments tibial fractures of type AO/ASIF-42C2 with preoperative minor soft tissue injuries lighter of Tscherne grade I or II, early primary intramedullary nailing and locked plating does not significantly increase the postoperative incidence of soft tissue complications for patients. The early and delayed primary intramedullary nailing and locked plating for treatment of AO/ASIF-42C2 proximal third tibial fractures can get similar curative effect. PMID- 25924493 TI - [Application of the pedicle screw in the subaxial cervical spine]. AB - OBJECTIVE: To research the clinical application of lower cervical pedicle screw fixation procedure. METHODS: From September 2011 to July 2013,32 patients underwent posterior pedicle screw-rod system fixation were retrospective analyzed includinig 20 males and 12 females with an average age of 56.4 years old ranging from 21 to 78 years. Among them, 10 patients were traumatic cervical spinal injury, 9 patients were cervical spinal canal tumors, 7 cases were posterior longitudinal ligament ossification of cervical vertebrae, 6 cases were multiple segmental cervical spondylopathy. Preoperatively, X-ray, computed tomography, magnetic resonance imaging and magnetic resonance angiography of the vertebral artery were performed in all patients. After the operation and during the follow up,X-ray and computed tomography were performed to confirm the pedicle screw position. The accuracy of the pedicle screw placement was evaluated by 4 grades classification from Lee. The spinal cord function was assessed by ASIA impairment scale for traumatic patients and JOA score for non traumatic patients. RESULTS: Totally 144 pedicle screws performed on 32 patients from C3 to C7 involving 132 screws of grade 0,5 screws of grade 1,5 of screws grade 2 and 2 screws of grade 3 according to postoperative CT. There were 12 screws penetrating the pedicle cortex including 8 screws at lateral,2 screws at caudal, 1 screw at medial and 1 screw at cranial. The follow-up time was 12 to 33 months with an average of (21.0+/-1.5) months. The spinal cord function was not improved in 6 complete cervical spinal cord injury patients,but their paraplegic level descended 1 to 3 segments. Four incomplete cervical spinal cord injury patients' ASIA impairment scale was increased by 1 to 2 grades in average. The JOA score of 22 atraumatic patients increased from preoperative 11.5+/-0.8 to 15.9+/-0.6 of postoperative at 6 months (P<0.01). There were no screw loosening,screw pullout and screw-rod breakage. CONCLUSION: The lower cervical pedicle screw fixation can provide excellent 3D stability of the vertebral column. The operation risk and Complication could be minimized by adequate preoperative evaluation for appropriate cases and individual pedicle screw placement. It deserved the clinical expansion. PMID- 25924494 TI - [Annlication of external fixator combined with damage control treatment for open fracture of the extremities]. AB - OBJECTIVE: To investigate the application and effects of external fixator under the guidance of damage control therapy in limb open fracture. METHODS: From May 2008 to January 2013,72 cases with severe limb open fractures (Unincor- porated shock) were divided into control group and observation group (36 cases in each group). In observation group, 36 patients (including 22 males and 14 females) were treated by external fixator at stage I, as soon as possible after waiting for patients physiology conditions being stable,the stage II fracture operation was performed. In control group, 36 patients (24 males and 12 females) were treated by the first stage open reduction. The hospital admission time, open fracture severity score (OFSS),operation duration,operative blood loss,X-ray expose times, callus appear time, fracture healing time, postoperative infection rate, complications and Johner-Wruhs accceccment were recorded and evaluated. RESULTS: All patients were followed up for 8 to 12 months (10.4 in averaged). The mean operation duration, operative blood loss, callus appear time, fracture healing time the mean operation duration reespectively were (56.79+/-8.87) min, (216.16+/-18.21) ml, (5.32+/-0.71) weeks, (12.79+/-2.52) weeks in observation group,and (104.53+/-9.28) min, (439.93+/-14.65) ml, (4.97+/-1.26) weeks, (14.81+/ 2.63) weeks in control group. According to Johner-Wruhs acccecement,there were were 33 cases in excellent,2 in good,and 1 in poor in observation group,non-union of fracture in 1 case,local infection occurred in 1 cases; in control group 25 cases in excellent,6 in good, and 5 in poor, non-union of fracture in 1 case,local infection occurred in 8 cases. There were significant differences in operation duration, operative blood loss, callus appear time, fracture healing time, postoperative infection rate, complications (P<0.05). There were no significant differences in hospital admission time, open fracture severity score and X-ray expose times (P>0.05). CONCLUSION: Under the guidance of damage control therapy,using external fixator measures to treat patients with open fractures of limbs is worth popularizing in clinical application because it can shorten the operation time, less blood loss, reduce the infection rate and complications, improve the success rate of surgery and recovery rate. PMID- 25924495 TI - [Comparative study of less invasive stabilization system (LISS) and the condylar support plates for the treatment of AO type C distal femoral fractures in adults]. AB - OBJECTIVE: To summarize the complications and the early clinical effect of less invasive stabilization system and the femoral condylar support plates in the treatment of AO type C distal femoral fractures. METHODS: From September 2007 to February 2012, 46 patients with AO type C distal femoral fractures were retrospectively studied. Of all patients 25 were treated with less invasive stabilization system including 14 males and 11 females with a mean age of (56.3+/ 4.2) years old; according to AO classification, there were 14 cases of C1, 8 cases of C2 and 3 cases of C3 with a mean hospital stay of (15.6+/-1.7) days. While 21 cases were treated with femoral condylar support plates fixation including 12 males and 9 females with a mean age of (53.8+/-5.1) years old;there were 13 cases of C1, 6 cases of C2 and 2 cases of C3 with a mean hospital stay of (17.8+/-2.2) days. Comparative analysis was performed from the operation related index,postoperative complications and Evanich score of the knee joint function between the two groups at follow-up. RESULTS: All 46 patients were followed up from 13 to 38 months with a mean time of 19.6 months after surgery. Complications included 1 case with infection,3 cases with internal fixation failure, 1 case with nonunion and 1 case with activity limitation of the affected knee. The differences in the incision length, blood loss, fracture healing time were significant between two groups (P<0.05), while there was no significant difference in the duration of operations, hospital stays and the incidence of postoperative complications between two groups (P>0.05). The statistical significance was also found in the Evanich score at last follow-up between two groups (P<0.05). CONCLUSION: Patients with less invasive stabilization system fixation had the characteristics of less trauma, shorter fracture healing time and better functional recovery. Less invasive stabilization system had became one of the ideal internal fixations in the treatment of AO type C distal femoral fractures. PMID- 25924496 TI - [Hamstring tendon transplantation embedding reconstruction of medial patellofemoral ligament for the treatment of recurrent patellar dislocation]. AB - OBJECTIVE: To explore the effectiveness of hamstring tendon graft embedding reconstruction of medial patellofemoral ligament for the treatment of recurrent dislocation of the patella. METHODS: From March 2008 to June 2013,67 patients with recurrent dislocation of patella were treated, including 28 males, 39 females with an average age of 22 years ranging from 10 to 42 years old. The clinical manifestations involved knee joint instability,"giving way", sense of patellar dislocation, anterior knee pain. All 67 patients underwent arthroscopic hamstring tendon graft embedding reconstruction of the medial patellofemoral ligament. The curative effect were evaluated by preoperative and postoperative Lysholm score and Q angle changes. RESULTS: All cases were followed up after operation and the mean follow-up time was(27.5+/-13.4) months(4 to 69 months). Postoperative incision were healed well and no patellar dislocation or subluxation occurred. Lysholm score improved from preoperative 76.35+/-2.86 to 82.71+/-2.29 postoperatively; Q angle decreased from preoperative (18.75+/-2.33) degrees to postoperative(13.28+/-1.75) degrees . CONCLUSION: The method for the reconstruction of medial patellofemoral ligament can provide enough tension, patellar stability.imoroving the function of knee ioint. PMID- 25924497 TI - [Treatment of equinovarus accompanied with ulcer using Ilizarov technology and limited operation]. AB - OBJECTIVE: To explore the surgical method and clinical curative effect of Ilizarov technique combined with limited surgical treatment for neurotrophic malnutrition equinovarus accompanied with weight-bearing area ulcer. METHODS: From July 2004 to December 2011, 21 cases of neurological disorders equinovarus with skin ulcer in weight-bearing area were treated including 14 males and 7 females with an average age of 21.3 years old ranging from 8 to 32 years. Among them,19 cases with talipes equinovarus were on account of spina bifid and 2 cases on account of spinal cord injury of lumbar sacral segment. Nine cases were on the left foot and 12 cases were right foot. The ulcer area in out-below side of the fifth metatarsal bone was in 6 cases, in basement of the fifth metatarsal bone in 5 cases,in lateral of calcaneocuboid joint 2 cases, and in lateral of subtalar joint in 8 cases. Surgical procedure included plantar medial release technique, tendo-chilles lengthenning, and three-joint partial osteotomy. During operation,the skin and soft tissue of ulcer were resected and the incision was sutured when the ulcer was in the lateral of subtalar joint, and ankle Ilizarov external fixation for extension was installed after correcting talipes equinovarus partially. For the legacy skin ulcer in weight-bearing area,the Shenrg-ji cream (Chinese characters) was used after operation for one time per day until the wound healed. Adjusting Ilizarov external fixation for correcting residual deformity until it is satisfaction. During this process weight-bearing walking was keeping. RESULTS: All cases were followed up from 6 to 52 months with an average of 28 months. All ulcers were healing and no recurrence. The ulcer healing time was 14 to 36 days postoperative (26 days in average). Eighteen deformity feet were corrected satisfactorily, and recovered fully plantar foot, 3 feet appeared mild deformity after 1 year. Ankle joint activity appeared limited in 15 cases and got completely rigidity in 6 cases. The AOFAS increased from preoperative 34.0+/-7.2 to 86.0+/-8.5 postoperatively; 8 feet got excellent, 10 good,3 fair. CONCLUSION: The clinical effect of Ilizarov technique combined with limited operation and the Sheng-ji cream in correction of the talipes equinovarus with skin ulcer in weigh-bearing area on account of neurotrophic malnutrition is satisfactory, the surgical method is simple and the treating course in security, and serious complications can be avoided. PMID- 25924498 TI - [Myogenic elephant skin cream combined with Vacuum sealing drainage (VSD) for the treatment of bedsores]. AB - OBJECTIVE: To discuss the efficacy of the myogenic elephant skin cream combining with VSD for treating severe bedsores. METHODS: Twenty-nine cases of III and IV degree bedsores were treated from June 2009 to June 2013. Among them, 15 cases were treated by myogenic elephant skin cream combined with VSD (VSD group) including 7 males and 8 females with an average age of (69.0+/-5.3) years old ranging from 17 to 96 years;other 14 cases were treated by the treatment of conventional dressing change (control group) including 6 males and 8 females with an average age of (71.0+/-4.2) years old ranging from 40 to 86 years. At 7, 14, 21, 28 d after treatments, specimens of wound two groups were respectively taken to examine immunohistochemical CD34 adopted SABC, the number of wild vascular cross were observed as capillary density value under high magnification microscope. It was used to assess the hyperplasia of granulation tissue of wound. The capillary density value and the visual wound observation were indicators for evaluation of clinical efficacy. RESULTS: Seventeen of 19 cases got complete data of specimens of wound at 7, 14, 21, 28 d,included 9 cases of VSD group,8 of control group. In the microscope view, the capillary density of VSD group was higher than that of control group significantly (P<0.05), it showed the application of VSD technology improved hyperplasia of granulation tissue much faster than conventional dressing change. In VSD group, 13 cases with 15 wounds healed, 2 cases with 3 wounds improved; in control group,3 cases with 3 wounds healed,7 cases with 9 wounds improved, 4 cases with 5 wounds were unhealed. CONCLUSION: Using the VSD technology with continuous high pressure suction to clean the drainage of wound and lacuna thoroughly can effectively control infection,promote the growth of granulation tissue, and then applying myogenic elephant skin cream to improve partial blood supply while prompting rapid growth of new granulation tissue and epithelial cell. The risk of this treatment is low,and the course of treatment is short, this provides a safe and effective method for treating bedsores. PMID- 25924499 TI - [Diagnosis and treatment of non-ossifying fibroma: a case report]. PMID- 25924500 TI - [Forefoot plantar pressure changes of the first tarsometatarsal joint fracture dislocation fixation by different internal fixations]. AB - OBJECTIVE: To measure the changes of plantar pressure of the first tarsometatarsal joint fracture and dislocation by three different implants to provide experimental reference in selecting implants. METHODS: Eight fresh foot specimens were made into the models of the first tarsometatarsal joint fracture and dislocation, which were fixed with 3.5 mm cortical screw, 1/4 tubular plate and compressive staple in turn. After the loading of 600 N, the changes of the plantar pressure in forefoot were measured by the method of the F-scan plantar pressure system. RESULTS: After first tarsometatarsal joint fracture and dislocation, the peak pressure under the first metatarsal head would decrease, while the pressure under the second metatarsal head would increased,whose differences were statistically significant (P<0.05). When the first tarsometatarsal joint was fixed with screw or plate respectively; the peak pressure under the two metatarsal heads would tend to be normal. However,the staple fixation showed the statistical significant difference compared with normal state, although the peak pressure under the first and second metatarsal heads were recovered in some extent(P<0.05). CONCLUSION: After the first tarsometatarsal joint fracture-dislocation, the plantar pressure might be compensated partly by the adjacent metatarsal heads according to the regulation of the load transfer mechanism. While the first tarsometatarsal joint fracture dislocation was fixated by screw or plate, the plantar pressure of the forefoot would return to the normal state. However,if the joint was fixated by the staple, it would still be difficult to return the plantar pressure to be normal. PMID- 25924501 TI - [Femoral tunnel positioning in posterior cruciate ligament double-bundle reconstruction by computer aided design]. AB - OBJECTIVE: To study mechanical affect of knee joint of reasonable positioning of femoral tunnel during knee posterior cruciate ligament (PCL) double-bundle reconstruction and graft fixation after reconstruction by virtual reality interactive technology and evaluate the biomechanical response of knee after reconstruction by finite element analysis. METHODS: Knee specimens from five fresh frozen cadavers were used. Computer simulations and biomechanical experiments were used in this study. Experiments on flexion and extension movements of the knee joint were performed on specimens of fresh human knee joint. Laser three dimensional scanning was used to record and calculate the indexes of movements. Three-dimensional models of knee joint bone structure were then reconstructed on computer with the experimental data. Simulations of flexion and extension movements were carried out on the models to show the spatial positions of femur and tibia and label the attachment sites of PCL. Ten test points in the anterior,posterior, proximal, distal at the femoral attachment area of anterior and lateral bundle (ALB) and postoperior medial bundle (PMB) were selected and the central points of tibial en attachment areat anchored. The distance btween each two points of two article surface was calculated and contacted by software of Geomagic. Model was import software Ansys, adopting the tetrahedron unit a finite element model of complex tibial and femoral was set up to simulat human walking in one leg,on this condition the the joint surface force of model under weight impact load were analyzed. RESULTS: The three-dimensional models could demonstrate the spatial positions of the bone structure of the knee in different flexions and extensions. The models could be used to measure the spatial distance between 2 points on the femoral and tibial planes by software Geomagic. There was significantly difference among the length changes of anterolateral bundle and posteromedial bundle at every fixed point with different flexion angles (P<0.05), so the fixed angle with different points. The length changes of anterior lateral bundle's A2, A1 and posterior medial bundle's B3, B1 points were (1.35+/-0.19) mm, (5.41+/-1.22) mm, (1.95+/-0.04) mm and (5.23+/ 2.21) mm, respectively. The A2 and B3 points' length changes were the less, and that of the Al and B1 points were the more. It had no significant difference between the length changes of anterior lanteral bundle's A2 and A3 point (P=0.913>0.05). All of the maximal length changes of anterior lateral bundle's A2, A3 and postterior medial bundle's B3 points were less than 2 mm. CONCLUSION: The models of knee joint were builded through computer technology and it can be measure the lenth of cruciate ligament with software Geomagic exactly. The femoral tunnel for the PCL double-bundle reconstruction should be located as follows: ALB at the middle point of upper edge of femoral attachment site (proximal point),while PMB at the middle point of femoral attachment site (proximal point). This model provides a satisfactory method for the evaluation of the biomechanical response of knee after cruciate ligament reconstruction. PMID- 25924502 TI - [An abnormal deeper lateral femoral notch is an indirect evidence for anterior cruciate ligament tear]. AB - OBJECTIVE: To investigate the relationship between degree of abnormal deeper lateral femoral notch between anterior cruciate ligament tear. METHODS: The radiograph and MRI image material of 16 patients with anterior cruciate ligament injury from January 2013 to November 2013 were reviewed including 14 males and 2 females with an average age of 28.3 years old ranging from 18 to 52 years. Eleven cases was on right side and 5 on left. Survey tool of PASC imaging system was used to measure the depth of lateral femoral notch in patients with abnormal indicated by lateral X-ray view or sagittal view of MRI in knee joint,while clinical data,physical examination,image material in arthroscopy of these patients were retrospective researched. RESULTS: Four patients had an abnormal lateral femoral notch with the depth of 2 mm on lateral X-ray and sagittal MRI, while positive anterior drawer sign and Lachman test as well as anterior cruciate ligament tears on MRI, and completed tears were comfirmed on the operation of arthroscopy. Two patients without abnomal lateral femoral notch on lateral view of X-ray while with the depth of 1 mm on sagittal view of MRI were also coupled with positive anterior drawer sign and Lachman test as well as anterior cruciate ligament tears on MRI, and one of them were comfirmed completed anterior cruciate ligament tears on the arthroscopy operation and completed tear could not comfirmed on another one because of disagreed with arthroscopy operation. CONCLUSION: There appears to be an association between abnormal lateral femoral notch on lateral view of knee with anterior cruciate ligament tears. An abnormal deeper lateral femoral notch is an indirect evidence for anterior cruciate ligament tears. PMID- 25924503 TI - [Surgical treatment for Lisfranc injuries accompanied by the base crashing of the second metatarsal bone]. AB - OBJECTIVE: To discuss the clinical effects of open reduction and internal fixation (ORIF) for treatment of patients with Lisfranc injury combined the second metatarsal base comminuted fracture. METHODS: From March 2007 to June 2012, 7 patients with Lisfranc injury combined the second metatarsal base comminuted fracture were treated including 5 males and 2 female aged from 22 to 51 years old (means 42 years), 4 of sprain and 3 of traffic injury. According Myerson classification, there was 1 case of type A, 3 of type B and 3 of type C. Kirschner wire was used to fix Lisfranc ligament placing from the medial cuneiform bone to the second metatarsal base during the operation. After the operation American Orthopaedic Foot and Ankle Society (AOFAS) criteria system were applied to evaluate the foot and ankle function. Preoperative and postoperative AP, lateral and oblique X-ray and CT scan were collected for radiographic evaluation. RESULTS: All patients were followed up from 12 to 20 months (16.8 months in average). According to AOFAS criteria system, 3 cases were excellent result,3 good, 1 fair. All the wounds were primary healing without skin necrosis, infection, Kirschner loose,broken, or other complications. CONCLUSION: Kirschner wire had good clinical efficacy for fixing Lisfranc ligament injury with the second metatarsal base comminuted fracture, and could avoid arthrodesis. PMID- 25924504 TI - [Treatment of nonunion of femoral shaft fracture after initial locked intramedullary fixation with plate and xenogenic bony plate]. AB - OBJECTIVE: To investigate the clinical effects of plate and xenogenic bony plate for the treatment of nonunion of femoral shaft fracture after initial fixation with locked intramedullary nailing. METHODS: From February 2006 to June 2013, 21 cases with nonunion of femoral shaft fracture after initial fixation with locked intramedullary nailing were treated with femoral plate and contralateral xenogenic bony plate. There were 12 males and 9 females with an average age of 34.8 years old (ranging from 18 to 62 years). The time of nonunion was 9 to 18 months (averaged 12.8 months). The clinical outcomes of the treatment were evaluated by Merchan assessment. RESULTS: All of the patients were primary healing, and on complications such as infection,fat embolism, internal fixation breaking or rotational deformity, shortening were occurred. All the cases were followed up for 13.2 months (ranging from 8 to 24 months). Nineteen cases were bone healed,the time of union averaged 6.2 months (ranging from 4 to 9 months). Two cases appeared delayed union and gained bony union after 7 to 13 months' observation. According to the criterion of Merchan,the results were excellent in 13 cases, good in 6 cases, poor in 2 cases. CONCLUSION: Treatment of nonunion of femoral shaft fracture after initial locked intramedullary fixation with plate and xenogenic bony plate has advantages of high curative rate and low complications, good postoperative function recovery, it is a reliable treatment to elevate the stability of fixation and promote the osteogenesis. PMID- 25924505 TI - [Clinical characteristics and stage I operation of anterior and posterior approaches for the treatment of cervicothoracic junction (C7T1) fracture dislocation]. AB - OBJECTIVE: To summary the characteristics of cervicothoracic junction (C7T1) fracture-dislocation,and explore the surgical treatment of combined anterior posterior procedure. METHODS: From January 2005 to March 2010,8 cases of cervicothoracic junction (C7T1) fracture-dislocation were treated by stage I operation through anterior and posterior approacheg, supplemented by non structural bone graft. All patients were male with a mean age of 45.0 years old ranging from 32 to 68 years. Six cases were diagnosed clearly by CT scan but with normal cervical spine X-ray film at admission. According to AO classification, 4 cases were of type B, 4 cases of type C, with unilateral locked articular process in 2 cases, bilateral in 2 cases. Preoperative MRI showed intervertebral disc injury in 6 cases. RESULTS: The average operation time was 246.3 min ranging from 150 to 320 min. The blood loss was with an average of 307.5 ml (150 to 600 ml). One patient got hoarseness but recovered without special treatment 6 months later; No other complications happened. One patient of preoperative Frankel grade A died, the remaining patients were followed up from 12 to 63 months (38.6 months in average). These fracture-dislocations were completely reduction after operation, healed with bony union 12 months later, and no pseudoarthrosis. The function of the spinal cord improved obviously at the final follow-up, 1 patient of preoperative grade A had died,and the spinal cord function of the other one had no significant changes,the 2 cases of grade B recovered to C and D respectively, 1case recovered from grade C to D, and 3 case recovered from D to E. CONCLUSION: Cervicothoracic junction (C7T1) fracture-dislocation is a rare clinical spine trauma, and missed easily. The CT is a necessary complement to these patients highly suspected C7T1 fracture-dislocation but with negative cervical spine X-ray film. The patients diagnosed clearly could receive stage I operation of anterior and posterior approaches, supplemented with non-structural bone graft. PMID- 25924506 TI - [Research progress on Drynaria fortunei naringin on inflammation and bone activity]. AB - Flavonoid naringin is widely distributed in various types of plants and is an important component of herbal Drynaria. In previous studies, Drynaria has been demonstrated to have inhibitory effects on inflammatory responses and bone destruction and exert anabolic effects on bone, has been widely used in the clinical treatment. Naringin, was in the stage of experimental yet. The experimental results have confirmed that naringin suppressed inflammation including arthritis by lowering the expression of inflammatory cytokines, and the mechanism can be explained as reducing the expression of NF-kappaB. Naringin has been shown to increase osteoblast proliferation by increasing the expression of BMP-2, inhibit osteoclast activity by reducing the expression of RANKL. In animal experimental, naringin was useful for osteoporosis, and the mechanisms are in depth studies. Research in the field of traditional Chinese medicine and orthopedics, naringin as a explicit material structure in the components of Drynaria, has been concerned about the experimental studies, it is not only prosperity the development of traditional Chinese medicine research,but also ready for clinical studies anti-inflammatory and bone effects of naringin in the future. PMID- 25924507 TI - [X-ray performance of melorheostosis in right foot:report of one case]. PMID- 25924508 TI - [Surgical treatment strategy for flatfoot related with accessory navicular]. AB - Accessory navicular source flatfoot is one of the foot deformity of clinical common disease,its treatment method is more controversial, differences in clinical efficacy of different surgical methods, according to accessory navicular source flatfoot symptoms of surgical treatment,there is no uniform standard, around a pair of accessory navicular excision how to reconstruct the arch produced a series of operation methods, the clinical curative effect of different operative methods produce also different, how to develop the operation strategy, choose operation method, and after acessory navicular excision whether to rebuild posterior tibial tendon, how to rebuild, the problems such as how to rebuild is the research hotspot and difficulty, looking forward to further research. PMID- 25924509 TI - Extraction of pinocembrin from leaves of different species of Eucalyptus and its quantitative analysis by qNMR and HPTLC. AB - Pinocembrin, a flavanone with a variety of biological activities was isolated from Eucalyptus sieberi leaves and quantified in several other Eucalyptus species using qNMR and HPTLC densitometry. The effect of different extraction procedures on the extraction of the compound from Eucalyptus sieberi was also studied. The methods were validated in terms ofselectivity, specificity, linearity, recovery, precision and repeatability. PMID- 25924510 TI - Anti-inflammatory compounds from Ampelopsis cantoniensis. AB - Many natural products have been shown to have an inhibitory effect on nitric oxide (NO), and are used as chemotherapy agents for inflammation disease. The current study was designed to evaluate the anti-inflammatory activity of chemical components from the leaves of Ampelopsis cantoniensis. Sixteen compounds (1-16) were isolated and identified. Phloretin (5) and 5,7,3',5'-tetrahydroxyflavanone (16) inhibited nitric oxide (NO) production with IC50 values of 5.2, and 18.5 MUM, respectively. The inhibitory effect of compounds 5 and 16 were accompanied by dose-dependent decreases in LPS-induced nitric oxide synthase (iNOS) in RAW 264.7 cells, respectively. This study investigated the significant anti inflammatory properties of isolated compounds from the leaves of A. cantoniensis for the first time. The findings demonstrate that A. cantoniensis could be used beneficially in the treatment of inflammation disease. PMID- 25924511 TI - Convergent synthesis of moslosooflavone, isowogonin and norwogonin from chrysin. AB - A convergent synthesis route of moslooflavone, isowogonin and norwogoninis reported,starting from chrysin, an easily available flavone, by methylation, bromination, methoxylation and demethylation procedures. This synthetic route is convenient and can give the three rare flavones in good yield. PMID- 25924512 TI - Tangeretin triggers melanogenesis through the activation of melanogenic signaling proteins and sustained extracellular signal- regulated kinase in B16/F10 murine melanoma cells. AB - In order to test the effectiveness of tangeretin at ameliorating melanoma and melanoma-associated depigmentation, western blotting was used to assess the melanin content of treated melanoma cells. Tangeretin, a 4',5,6,7,8 pentamethoxyflavone, was found to trigger intracellular melanin production in a concentration-dependent manner in B16/F10 murine melanoma cells. Melanin content increased 1.74-fold in response to treatment with 25 MUM of tangeretin, compared to that in non-treated cells. Examination of melanogenic protein expression showed that tyrosinase, tyrosinase-related protein (TRP)-1, and extracellular signal-regulated kinase (ERK) 1/2 levels increased in a dose-dependent manner. Furthermore, the expression of cyclic adenosine monophosphate response element binding protein (CREB) and microphthalmia transcription factor (MITF) was increased by tangeretin in 1 h and 4 h, respectively. Tangeretin- upregulated melanogenesis was suppressed by ERK 1/2 inhibitor and not by ERK1 inhibitor. These results suggest that tangeretin has therapeutic potential for melanoma and melanoma-associated depigmentation because it can induce hyperpigmentation through the activation of melanogenic signaling proteins and initiation of sustained ERK2 expression. PMID- 25924513 TI - Flavonoids from Artocarpus anisophyllus and their bioactivities. AB - Two new prenylated flavonoids, 4',5-dihydroxy-6,7-(2,2-dimethylpyrano)-2'-methoxy 8-gamma,gamma-dimethylallylflavone 1 and 3'-hydroxycycloartocarpin 2 along with six known flavonoids, 5,7-dihydroxy-4'-methoxy-8-prenylflavanone 3, isobavachalcone 4, pyranocycloartobiloxanthone A 5, artocarpin 6, chaplashin 7 and cycloartocarpin 8 were isolated for the first time from the leaves and the heartwoods of Artocarpus anisophyllus Miq. The structures of isolated flavonoids were elucidated spectroscopically using 1D and 2D NMR, FTIR, MS, UV and also by comparison with literature data. These flavonoids were screened for their antioxidant and tyrosinase inhibitory activities. The dichloromethane and ethyl acetate crude extracts together with 3'-hydroxycycloartocarpin 2, pyranocycloartobiloxanthone A 5 and artocarpin 6 showed DPPH (2,2-diphenyl-l picrylhydrazyl) radical scavenging activity with SC50 values of 80.2, 40.0, 152.9, 20.2 and 140.0 MUg/mL in 30 min, respectively. Pyranocycloartobiloxanthone A 5 exhibited significant tyrosinase inhibitory activity against tyrosinase from mushroom with IC50 values of 60.5 MUg/mL. PMID- 25924514 TI - Chrysanthemum indicum attenuates cisplatin-induced nephrotoxicity both in vivo and in vitro. AB - Chrysanthemum indicum Linne has been used in traditional medicine to treat various inflammatory diseases in East Asia. The aim of the present study was to investigate the protective effect of C. indicum ethanol extract (CILE) against cisplatin-induced nephrotoxicity. An HPLC-photodiode array method was used for fingerprint analysis of the CILE and ten major constituents were quantitatively analyzed. The protective effect of CILE on cisplatin-induced nephrotoxicity was assessed using both in vitro (porcine kidney cell; PK15 cell) and in vivo (Sprague Dawley rat) experiments. In the in vitro study, CILE enhanced PK15 cell viability after cisplatin treatment with recovered antioxidant status. Moreover, the increased p53 expression after cisplatin treatment was decreased in the CILE pretreated cells. In the in vivo study, SD rats were treated for 28 consecutive days with CILE (0, 100, 300 and 500 mg/kg). On day 23, a single dose of cisplatin (5 mg/kg) was injected to induce nephrotoxicity. The CILE pretreated group showed recovered serum renal function index with ameliorated oxidative stress. Histopathological alterations and apoptosis in the kidney were also decreased in CILE pretreated rats. Taken together, CILE could attenuate cisplatin-induced nephrotoxicity and might be a beneficial agent for acute renal failure management. PMID- 25924515 TI - Foliar flavonoids from Tanacetum vulgare var. boreale and their geographical variation. AB - Foliar flavonoids of Tanacetum vulgare var. boreale were isolated. Eight flavonoid glycosides, 7-O-glucosides of apigenin, luteolin, scutellarein and 6- hydroxyluteolin, and 7-O-glucuronides of apigenin, luteolin, chrysoeriol and eriodictyol were identified. Moreover, eight flavonoid aglycones, apigenin, luteolin, hispidulin, nepetin, eupatilin, jaceosidin, pectolinarigenin and axillarin were also isolated and identified. The flavonoid composition of two varieties of T. vulgare, i.e. var. boreale and var. vulgare, were compared. All samples of var. boreale and one sample of var. vulgare had the same flavonoid pattern, and could be distinguished from almost all the samples of var. vulgare. Thus, the occurrence of chemotypes, which are characterized by either the presence or absence of scutellarein 7-O-glucoside, eriodictyol 7-O-glucuronide and pectolinarigenin was shown in T. vulgare sensu lato. PMID- 25924516 TI - Altitudinal variation of flavonoid content in the leaves of Fallopia japonica and the needles of Larix kaempferi on Mt. Fuji. AB - Ultraviolet-B radiation is harmful to plants, and its intensity increases at altitude. So plants growing at high altitude possess UV protection systems. Flavonoid is known as a major UV protectant because it absorbs UV radiation and scavenges UV-induced free radicals in plant tissues. Japanese knotweed (Fallopia japonica) and Japanese larch (Larix kaempferi) grow at a wide range of altitudes on Mt. Fuji, the highest mountain in Japan, while the two plants harbor a homogeneous genetic structure. In the present study, a total of 14 flavonol 3-O glycosides were isolated from both species. Furthermore, quantitative HPLC analyses revealed that flavonoid levels in the leaves of F. japonica and the needles of L. kaempferi increased with increasing altitude of their growing sites. The altitudinal trend of UV-absorbing antioxidants of herbal and woody plants was simultaneously revealed for the first time. These results suggest that both species have chemically acclimatized to high altitude regions, in which severe environmental conditions such as higher UV radiation exist. PMID- 25924517 TI - Quantitative flavonoid variation accompanied by change of flower colors in Edgeworthia chrysantha, Pittosporum tobira and Wisteria floribunda. AB - The flavonoids in the flowers of Edgeworthia chrysantha, Pittosporum tobira and Wisteria floribunda were isolated and identified. Quercetin and kaempferol 3-O glucosides and 3-O-rutinosides were found in E. chrysantha, and quercetin 3-O rutinoside, 3-O-glucoside and 3-O-pentosylrhamnosylglucoside, kaempferol 3-O robinobioside, 3-O-rutinoside, 3-O-glucoside and 3-O-pentosylrhamnosylglucoside, and isorhamnetin 3-O-rutinoside were isolated from P. tobira. Ten flavonoids, quercetin 3-O-sophoroside, 3-O-rutinoside, 3-O-glucoside, kaempferol 3-O sophoroside and 3-O-glucoside, luteolin 5-O-glucoside, 7- O-glucoside and 7-O hexoside, and apigenin 7-O-glucoside and 4'-O-hexoside were isolated from W floribunda. The major pigments of E. chrysantha were carotenoids. Their content decreased with the change in flower color to white from yellow via cream, and total flavonoid content also slightly decreased by ca. 0.8 in cream and ca. 0.9 fold in white flowers. In contrast with E. chrysantha, white flowers of P. tobira turn to cream and then yellow in which the major pigments are also carotenoids. In this species, both carotenoid and flavonoid contents are gradually increased from white to yellow flowers. Though the petal color of Wisteria floribunda is mauve, due to anthocyanin pigments, the yellow areas are due to carotenoids; these turn to white in the late flowering stage. However, their flavonoid contents were essentially the same among the yellow, cream and white spots of flags. Thus, it was shown by HPLC analysis of the flower flavonoids of E. chrysantha, P. tobira and W. floribunda, although the visible pigments such as carotenoids and anthocyanins are quantitatively varied, the quantitative variation in UV-absorbing substances, such as flavones and flavonols, differs with plant species. PMID- 25924518 TI - New kaempferol 3,7-diglycosides from Asplenium ruta-muraria and Asplenium altajense. AB - A flavonoid was isolated from the fronds of Asplenium ruta-muraria and A. altajense (Aspleniaceae) collected in the Altai Mountains and adjacent area. The compound was identified as kaempferol 3-O-beta-[(6'''-E-caffeoylglucopyranosyl) (1-->3)-glucopyranoside]-7-O-beta-glucopyranoside (1) by UV, 1H and 13C NMR spectroscopy, LC-MS, and acid and alkaline hydrolyses. Another flavonoid (2) was isolated from A. altajense, as a minor compound, together with 1 and identified as deacylated compound 1, i.e. kaempferol 3-O-laminaribioside-7-O-glucoside. They were found in nature for the first time. PMID- 25924519 TI - New flavonol glycosides from the leaves and flowers of Primula sieboidii. AB - Three flavonol glycosides were isolated from the leaves of Primula sieboldii. They were identified as quercetin 3-O-beta-[xylopyranosyl-(1-->2)-beta- glucopyranosyl-(1-->6)-beta-glucopyranoside] (1), kaempferol 3-O-beta [glucopyranosyl-(1-->2)-beta-glucopyranosyl-(1-->6)-beta-glucopyranoside] (2) and kaempferol 3- O-beta-[xylopyranosyl-(1-->2)-beta-glucopyranosyl-(1-->6)-beta glucopyranoside] (3). Their chemical structures were determined by UV, 1H and 13C NMR spectroscopy, LC-MS and acid hydrolysis. Compounds 1 and 3 are found in nature for the first time. They were also detected in the flowers, together with two anthocyanins, malvidin 3,5-di-O-glucoside and a minor petunidin dihexoside. PMID- 25924520 TI - Flavone C-glucosides responsible for yellow pigmentation induced by low temperature in bracts of Zantedeschia aethiopica. AB - We aimed to identify the main compounds responsible for low temperature-induced yellow pigmentation of the bracts of Zantedeschia aethiopica 'Wedding March'. On the basis of the area ratios estimated from absorbance at 400 nm in HPLC analyses, we identified two flavonoids, isoorientin and swertiajaponin, as such compounds. We also identified two additional flavonoids, isovitexin and swertisin, which do not contribute considerably to the yellow pigmentation. Flavonoids of Zantedeschia bracts seem to belong to the class of flavone C glycosides. PMID- 25924521 TI - Flavonoids and their qualitative variation in Calystegia soldanella and related species (Convolvulaceae). AB - Coastal species are exposed to severe environmental stresses, e.g. salt and UV-B. The plants adapt themselves to such harsh environment by controlling morphological features and chemical defense systems. Flavonoids are known as efficient anti-stress polyphenols produced by plants. Most flavonoids show antioxidant activity, and their properties are important for plants to survive under high-stress conditions such as those in a coastal area. Among the compounds, ortho-dihydroxylated flavonoids act as strong antioxidants. In this survey, we elucidated the flavonoid composition of a seashore species Calystegia soldanella, which is distributed not only on the seashore, but also by the inland freshwater lake, Lake Biwa. Seven flavonol glycosides, i.e. quercetin 3-0- rutinoside, 3-O-glucoside, 3-O-rhamnoside and 3-O-apiosyl-(1-->2)-[rhamnosyl-(1- >6)-glucoside], and kaempferol 3-O-rutinoside, 3-O-glucoside and 3-0- rhamnoside were isolated from the leaves of C. soldanella. In addition, it was shown that the quercetin (Qu) to kaempferol (Km) ratio of coastal populations was higher than that of lakeshore populations. In general, these differences of Qu/Km ratio depend on flavonoid 3'-hydroxylase (F3'H) transcription. RT-PCR analysis suggested that F3'H of C. soldanella is regulated translationally or post translationally, but not transcriptionally. Furthermore, quantitative and qualitative differences in flavonoid composition occurred among three Calystegia species, C. soldanella, C. japonica and C. hederacea. PMID- 25924522 TI - A new triglycosyl flavonoid isolated from leaf juice of Kalanchoe gastonis bonnieri (Crassulaceae). AB - Kalanchoe gastonis-bonnieri R. Hamet & H. Perrier (Crassulaceae) is a succulent species empirically used as a vaginal contraceptive as well as to heal genitourinary infections. A phytochemical study of leaf juice prepared from specimens collected in the flowering season resulted in the isolation of the new flavonoid quercetin 3-O-alpha-rhamnopyranoside-7-O-beta-D-glucopyranosyl-(1-->3) alpha-L-rhamnopyranoside, as well as the already known 6-C-beta-D-glucopyranosyl- 8-C-beta-D-glucopyranosylapigenin (vicenin-2). The NMR spectra of this flavonoid at room temperature exhibited broad and duplicated signals, suggesting the existence of rotameric conformers, which was confirmed by coalescence of the signals at 40 degrees C. The structural elucidation was based on 1H and 13C NMR (HMQC and HMBC) analyses and MS data. This is the first report of a C-glycosyl flavonoid (vicenin-2) in the Crassulaceae family. Additionally, this is the first study in which atropoisomerism has been shown for vicenin-2. PMID- 25924523 TI - Flavonoids from Stellaria nemorum and Stellaria holostea. AB - Stellaria nemorum L. and S. holostea L. (Caryophyllaceae) were investigated for their flavonoids. The new flavonoid 6-C-[(alpha-arabinopyranosyl)-( 1-->2)-O-beta xylopyranosyl]apigenin (1) and the four known C-glycosides, 6-C-[(alpha arabinopyranosyl)-(1-->2)-O-beta-glucopyranosyl]apigenin (2), apigenin 6-C-beta- galactopyranoside-8-C-beta-glucopyranoside (3), apigenin 6-C-beta-glucopyranoside 8-C-alpha-arabinopyranoside (4), and apigenin 6-C-beta-glucopyranoside-8-C-beta- xylopyranoside (5) were isolated from the aerial parts of S. nemorum for the first time. Furthemore, five known flavonoids, 3,5,7-trihydroxy-3',5'- dimethoxyflavone (9), diosmetin 6-C-beta-glucopyranoside (8), schaftoside (4), isoorientin (6) and orientin (7) were obtained from the aerial parts of S. holostea. Compounds 4, 8 and 9 are reported for the first time from this species. The structures of all isolated compounds were unambiguously elucidated by one- and two- dimensional NMR and mass spectral analysis, by acid hydrolysis, as well as by comparison with literature data. The crude extracts of the investigated species exhibited antimicrobial activity against Staphylococcus aureus, while none of the isolated compounds was found to be active. PMID- 25924524 TI - Novel C-xylosylflavones from the leaves and flowers of Iris gracilipes. AB - Two new C-glycosylflavones, apigenin 7,4'-dimethyl ether 6-C-beta-[(4"'-acetyl-L rhamnopyranosyl)-(1-->2)-xylopyranoside] (1) and apigenin 7,4'-dimethyl ether 6-C beta-L-rhamnopyranosyl-(1-->2)-xylopyranoside (2) were isolated from the leaves of Iris gracilipes (Iridaceae), along with two known flavonoids, swertiajaponin (3) and swertisin (4). C-Xylosylflavones 1 and 2 were elucidated by UV and NMR spectroscopy, mass spectrometry, and acid and alkaline hydrolyses. These novel compounds were also presented in the flowers. PMID- 25924525 TI - Constituents of the leaves of Verbascum blattaria. AB - Phytochemical investigation of the dried leaves of Verbascum blattaria L. (Scrophulariaceae) led to the isolation and identification of five known compounds, E-harpagoside, laterioside, kaempferol 3-O-beta-D-glucopyranoside, bis(2-ethylhexyl)phthalate, and (2S)-liquiritigenin. The structures of these compounds were determined by physical and spectroscopic data analysis. All compounds were isolated from V blattaria for the first time. PMID- 25924526 TI - Anthocyanins and other flavonoids as flower pigments from eleven Centaurea species. AB - Anthocyanins and other flavonoids were isolated from the flowers of eleven Centaurea species, C. macrocephala, C. rupestotilis and C. suaveolens, which produce yellow flowers, and C. achtarovii, C. dealbata, C. montana, C. nigra, C. scabiosa, C. simplicicaulis, C. hypoleuca and C. triumfetti, which have cyanic flowers. Four anthocyanins, cyanidin 3,5-di-O-glucoside, cyanidin 3-O-(6" malonylglucoside)-5-O-glucoside, cyanidin 3-O-(6"-succinylglucoside)-5- O glucoside and cyanidin glycoside, were detected in the cyanic flowers of seven Centaurea species. Of these anthocyanins, the first two were found as major anthocyanins. In the cyanic species, four other flavonoids, apigenin 7-O glucuronide-4'-O-glucoside, malonylated apigenin 7,4'-di-O-glucoside, apigenin 7 0- glucuronide and kaempferol glycoside, were also isolated. On the other hand, nine flavonols and four flavones were isolated from the three yellow-flowered species, and identified as quercetagetin, quercetagetin 7-O-glucoside, quercetagetin 3'-methyl ether 7-O-glucoside, patuletin, patuletin 7-O-glucoside, quercetin 7-O-glucoside, kaempferol 3-methyl ether, kaempferol 3-methyl ether 4' O-glucuronide and isorhamnetin 3-O-galactoside, and apigenin, apigenin 7- O glucuronide, luteolin 7-O-glucoside and apigenin 6,8-di-C-glucoside (vicenin-2). Of these flavonoids, the former five flavonols are "yellow flavonols", and it was shown that their flower colors are due to these compounds. PMID- 25924527 TI - Flower color changes in three Japanese hibiscus species: further quantitative variation of anthocyanin and flavonols. AB - One anthocyanin and four flavonols were detected from the petals of Hibiscus hamabo, H. tiliaceus and H. glaber. They were identified as cyanidin 3-0- sambubioside, gossypetin 3-O-glucuronide-8-O-glucoside, quercetin 7-O-rutinoside, gossypetin 3-O-glucoside and gossypetin 8-O-glucuronide by UV spectra, LC-MS, acid hydrolysis and HPLC. The flavonoid composition was essentially the same among the petals ofH. hamabo, H. tiliaceus and H. glaber, and there was little quantitative variation, except for cyanidin 3-O-sambubioside, the content of which in the petals ofH. tiliaceus and H. glaber was much higher than in that of H. hamabo. Flower colors of H. tiliaceus and H. glaber change from yellow to red, and that of H. hamabo changes from yellow to orange. These changes were caused by contents of anthocyanin and flavonols, which increased after flowering of H. hamabo, H. tiliaceus and H. glaber. PMID- 25924528 TI - Anthocyanins in the bracts of Curcuma species and relationship of the species based on anthocyanin composition. AB - Five anthocyanins, delphinidin 3-O-rutinoside, cyanidin 3-O-rutinoside, petunidin 3-O-rutinoside, malvidin 3-O-glucoside and malvidin 3-O-rutinoside, were identified. Three anthocyanins, delphinidin 3-O-glucoside, cyanidin 3-O-glucoside and pelargonidin 3-O-rutinoside, were putatively identified based on C18 HPLC retention time, absorption spectrum, including lambdamax, and comparisons with those of corresponding standard anthocyanins, as the compounds responsible for the pink to purple-red pigmentation of the bracts of Curcuma alismatifolia and five related species. Cluster analysis based on four major anthocyanins formed two clusters. One consisted of only one species, C. alismatifolia, and the other consisted of five. Each cluster further formed sub-clusters depending on either species or habitats. PMID- 25924529 TI - Acylated cyanidin 3-sophoroside-5-glucoside in purple-violet flowers of Moricandia arvensis (Brassicaceae). AB - A new acylated anthocyanin was isolated as a major pigment, along with a known anthocyanin (Moricandia arvensis anthocyanin 1: MAA-1), from a strain of Moricandia arvensis (Code No. MOR-ARV-3) with purple-violet flowers, and identified as cyanidin 3-O-[2-O-(2-O-(4-O-(6-O-(4-O-(beta-glucopyranosyl)-trans caffeoyl)-beta-glucopyranosyl)-trans-sinapoyl)-beta-glucopyranoside]-5-O-[6-O (malonyl)-beta-glucopyranoside]. PMID- 25924530 TI - Molecular structures of the stem tuber anthocyanins of colored potatoes and their coloring effects on the tubers. AB - This paper summarized the important achievements about the general characteristics of the molecular structures of the stem tuber anthocyanins of Colored potatoes and the basic coloring effects of the anthocyanins on the tubers. The various coloration patterns of the skins and/or flesh of Colored potato tubers result from the accumulation of the anthocyanins in the periderms, phelloderms and/or peripheral cortices of the tubers, and the tuber colors are fundamentally determined by the matching profiles of the six naturally occurring anthocyanidins, i.e., cyanidin, delphinidin, malvidin, pelargonidin, peonidin and petunidin. Generally, the tuber anthocyanidins hold an O-glycosidic bond-linked rutinosyl at the C3 site, and either a glucosyl linked by an O-glycosidic bond or no substituent group may exist at the C5 site simultaneously. Furthermore, an E monoacyl frequently exists at the C3-rutinosyls or at the C5-glucosyls of most tuber anthocyanins, and the phenolic acids acylating the tuber anthocyanins are often p-coumaric, ferulic and caffeic acids. The popular names of the p- coumaric acid derivatives of the malvidin, pelargonidin, peonidin and petunidin of the tubers are Malvanin, Pelanin, Peonanin and Petanin, respectively. This review provides a reference for the exploration of the mechanism of the tuber coloration and the identification of the molecular structures of the stem tuber anthocyanins of Colored potatoes. PMID- 25924531 TI - Biological activity of the methanol and water extracts of the fruits of anthocyanin-rich plants grown in south-west Poland. AB - In this study we focused on the chemical composition, antioxidant, anti inflammatory and antibacterial properties of methanol and water extracts of fruits of six species grown in south-west Poland: blackberry, blackcurrant, chokeberry, cherry, gooseberry and raspberry. No general correlation could be drawn between extract chemical properties (i.e. antioxidant and free radical scavenging) and observed biological effects. However, blackcurrant and blackberry extracts (both methanol and water) appeared to be good antioxidants and free radical scavengers, as well as effective inhibitors of E. coli adhesion to the uroepithelial cells. On the other hand, the poorest antioxidants and free radical scavengers, cherry and gooseberry extracts, also poorly affected bacterial growth, swimming ability and adhesion to epithelial cells. Surprisingly, gooseberry extracts, which showed generally weak effects, appearedto be the most effective inhibitor of bacterial biofilm formation. Additionally, most of the studied extracts showed reasonably strong anti-inflammatory properties. PMID- 25924532 TI - Investigation into the antioxidant and antidiabetic potential of Moringa stenopetala: identification of the active principles. AB - The fresh leaves of Moringa stenopetala (family, Moringaceae) are commonly eaten as cabbage while dried leaves are used as nutritional supplement and for treating a variety of disease conditions including diabetes. The present investigation into the therapeutic potential of the leaves and seeds of the plant revealed no inhibitory effect against alpha-glucosidase enzyme up to the concentration of 200 MUg/mL but the leaves extract displayed potent DPPH (1,1-diphenyl-2- picrylhydrazyl) radical scavenging effect (IC50, 59.5 +/- 4.1 MUg/mL). An activity directed fractionation and isolation procedure resulted in the identification of the major antioxidant compound as rutin and minor active component, neochlorogenic acid. Both the crude extract (0.8-200 MUg/mL) and rutin (0.8-200 MUM) but not neochlorogenic acid displayed a concentration-dependent protection of human pancreatic beta-cells (1.4E7 cells) from oxidant-induced cell death. The identification of these compounds along with their potential role in the nutritional and medicinal significance of the plant is discussed. PMID- 25924533 TI - Polyphenolic compounds and antioxidant activities of the leaves of Glochidion hypoleucum. AB - Bioassay-guided fractionation of the methanol extract of Glochidion hypoleucum (Miq.) Boerl leaves led to the isolation of five polyphenolic compounds, methyl gallate, gallic acid, apigenin-8-C-beta-D-glucopyranoside (vitexin), luteolin-8-C beta-D-glucopyranoside (orientin), and luteolin-6-C-beta-D-glucopyranoside (isoorientin). The chemical structures of the isolated compounds were determined using spectroscopic (NMR, UV-Vis, IR) and mass spectrometric techniques. The antioxidative properties of the methanol extract and isolated polyphenols were evaluated using 1,1-diphenyl-2-picrylhydrazyl (DPPH) for radical scavenging activity and 2',7'-dichlorodihydrofluorescein diacetate (DCFH-DA) to measure the level of reactive oxygen species (ROS). With the exception of vitexin, the crude methanol extract and the polyphenolic compounds inhibited DPPH radicals with IC50 values ranging from 2.46 +/- 0.05 to 40.0 +/- 0.3 MUg/mL. In addition, the crude methanol extract attenuated H202-induced intracellular ROS production in a dose dependent manner in HEK-293 cells. Gallic acid and isoorientin significantly reduced the ROS level in HEK-293 cells at a concentration of 20 MUM. PMID- 25924534 TI - Evaluation of antioxidant activity, and quantitative estimation of flavonoids, saponins and phenols in crude extract and dry fractions of Medicago lupulina aerial parts. AB - This study was designed to evaluate the flavonoid, saponin (TSC) and phenolic (TPC) contents and in vitro antioxidant activity of the crude (CME) and dry extracts and fractions of Medicago lupulina L. aerial parts. A validated RP-HPLC method led to quantitation of flavonols (kaempferol, quercetin and myricetin) and flavones (apigenin and luteolin) in the hydrolyzed extract. TSC and TPC were assayed spectrophotometrically at 560 and 760 nm, respectively. The antioxidant activity of the CME and the dry fractions were followed in vitro by DPPH free radical and ferric reducing antioxidant power (FRAP) methods. The flavonoid content of CME was 1.27 mg/g dw. The prevailing flavonoids were luteolin and myricetin, at concentrations of 0.37 and 0.36 mg/g dw, respectively. TSC and TPC were detected in CME at the level of 90.4 mg ESE/g dw, and 12.9 mg GAE/g dw, respectively. In the DPPH and FRAP tests, the CME exhibited antioxidant capacity with TEAA and FRAP values of 45.4 MUmol Trolox(r)/g dw and 0.2 mmol Fe2+/g dw, respectively. The diethyl ether dry fraction was the most valuable one, showing the highest antioxidant activity (TEAA = 726.1 MUmol Trolox(r)/g dw, FRAP = 2349.4 MUmol Fe2+/g dw) that was in accordance with its high TPC (162.4 mg/g dw). PMID- 25924535 TI - Dual excitatory and smooth muscle-relaxing effect of Sideritis montana extract on guinea-pig ileum. AB - The neuronal and smooth muscle effects of a methanol extract prepared from the air-dried flowering aerial parts of Sideritis montana L. (SME) was tested in vitro on Guinea-pig ileum. The chemical composition of the investigated extract was analysed by HPLC-MS, and chrysoeriol, chlorogenic acid and caffeic acid were detected as main constituents. The isolated organ assay showed that S. montana extract caused an immediate contraction and a more slowly developing inhibitory response in the ileum. The SME-induced contractions were strongly inhibited by the acetylcholine muscarinic receptor antagonist atropine (0.5 MUM), but not by either the Na+ channel blocker tetrodotoxin (TTX; 0.5 MUM) or the histamine H1 receptor antagonist chloropyramine (0.5 MUM). Selective desensitization of capsaicin-sensitive neurons by the sensory neuron stimulant and blocker capsaicin did not influence the contractile effect of SME. As to the spasmolytic effect, SME inhibited the effects of electrical field stimulation, exogenous acetylcholine, and histamine. These smooth muscle-relaxing effects were reversible in 40 min by repeated renewals of the bathing solution. PMID- 25924536 TI - Phenolic constituents of Carex vulpinoidea seeds and their tyrosinase inhibitory activities. AB - Two new phenolics, a stilbenoid, vulpinoideol A (1), and a chalcone, vulpinoideol B (2), along with ten known compounds (3-12) were isolated from Carex vulpinoidea Michx. seeds. The structures of compounds 1-12 were elucidated based on spectrometric and spectroscopic analyses including HRESIMS, 1D and 2D NMR data. All compounds were evaluated for their tyrosinase enzyme inhibitory activities. PMID- 25924537 TI - Analysis of active compounds and antioxidant activity assessment of six popular Chinese Juhua teas. AB - Chrysanthemum is an important traditional Chinese medicine and is drunk daily as a herbal tea. Chlorogenic acids and flavonoids are generally considered as the bioactive compounds. In this work, six kinds of Juhua Tea were analyzed and their active compounds and antioxidant activities were compared. In total, 32 phenolic compounds were profiled and identified using HPLC-DAD/ESI-MSn, composed of chlorogenic acids (10), flavones (8), chalcones (8), flavanones (4) and flavonols (2). Chalcones were the main flavonoids in Kunlun Xueju (Coreopsis tinctoria) extract, while flavones and chlorogenic acids were dominant in the five Chrysanthemum teas. Total chlorogenic acids content (TCA) was highest in Tai Ju (Chrysanthemum morifolium cv. 'Tai Ju') (8.59 +/- 0.87 mg/g DW), and total flavonoids content (TF) was highest in Kunlun Xueju (87.2 +/- 7.0 mg/g DW), which were both lowest in Ganye Ju (Chrysanthemum eticuspe) (TCA 0.86 +/- 0.26 mg/g DW, TF 1.43 +/- 0.41 mg/g DW). Huangin Ju (Anthemis tinctoria) possessed the most flavones (19.7 +/- 0.6 mg/g DW). Antioxidant capacity of each drink, assessed by Folin-Ciocalteu, DPPH, ABTS and FRAP assays, consistently showed that Kunlun Xueju extract possessed stronger antioxidant activity than the other five, suggesting that the flavonoids content accounted for the free radical scavenging. The present work provides a method for the characterization and quality control of Juhua Tea. Moreover, it is a guideline for consuming choice, due to the different biological functions resulting from chalcones, chlorogenic acids, and flavones. PMID- 25924538 TI - Two new isoflavanones from the roots of Erythrina variegata. AB - Two new isoflavanones, eryvarins Y (1) and Z (2), together with three known compounds (3-5) were isolated from the roots of Erythrina variegata. The structures of 1 and.2 were established on the basis of spectroscopic data. The new compounds are peculiar isoflavanones, possessing both a 3-methylbut-2-en- 1 yl group and a 2-hydroxy-3-methylbut-3-en-1-yl group. Among the isolates, orientanol E (5) exhibited potent antibacterial activity against methicillin- resistant Staphylococcus aureus (MRSA) strains. PMID- 25924539 TI - Crocetenone, a new rotenoid with an unusual trans-fused ring system from Iris crocea. AB - Crocetenone, a new rotenoid (1), along with five known compounds apocyanin (2), tectorigenin (3), 5,2',3'-trihydroxy-7-methoxy flavanone (4), tectoridin (5) and tectoridin glycoside (6), were isolated from the methanolic extract of the root of Iris crocea. The structure of compounds was elucidated on the basis of 1D- and 2D-NMR spectroscopic and MS analysis. Antibacterial and antioxidant activities of compounds 1-6 were evaluated. Crocetenone (1) showed a prominent antibacterial activity. PMID- 25924540 TI - Wood colors and their coloring matters: a review. AB - A number of colored specialty woods, such as ebony, rosewood, mahogany and amboyna, and commercially important woods, such as morus, logwood, Brazilwood, Japanese yellowwood, blackwood, kwila, red beech and myrtle beech, exhibit a wide range of colors from black, violet, dark red, reddish brown, to pale yellow. These colors are not only due to colored pigments contained in extractives from those woods but also to insoluble polymers. Wood and bark from many species of both hardwood and softwood trees contain many types of flavonoid compounds. Research on flavonoids has been conducted mainly from two points of view. The first is chemotaxonomy with flavonoid compounds as taxonomic markers, and the second relates to the utilization of woods for pulp and paper and the use of tannins from bark for wood adhesives. Most chemotaxonomic studies have been conducted on flavonoids in the extracts from softwoods such as Podocarpus, Pinus, Pseudotsuga, Larix, Taxus, Libocedrus, Tsuja, Taxodium, Sequoia, Cedrus, Tsuga, Abies and Picea. Hardwood chemotaxonomic studies include those on Prunus and Eucalyptus species. Studies on flavonoids in pulp and paper production were conducted on Eucalyptus woods in Australia and woods from Douglas fir in the USA and larch in Japan. Flavonoids as tannin resources from black wattle tannin and quebracho tannin have been used commercially as wood adhesives. Flavonoids in the bark from radiata pine and southern pine, from western and eastern hemlock, southern red oak and Quercus dentata are also discussed. In addition, the distribution of flavonoids among tree species is described, as is the first isolation of rare procyanidin glycosides in nature. PMID- 25924541 TI - Utilization of flavonoid compounds from bark and wood: a review. AB - Flavonoid compounds, which are extracted from bark and wood and used commercially, are flavan 3-ols as monomers and their polymers, which are called "condensed tannins". Reactions of the condensed tannins with formaldehyde are the basis for wood adhesives. In the late 1940s, tannin research for wood adhesives was begun and the world-first commercial use of wattle tannin from black wattle (Acacia mearnsii) bark as wood adhesives occurred in Australia in the 1960s. In addition, wattle tannin-based adhesives were further developed in South Africa and the uses of these adhesives have been continuing to date. The success of wattle tannin in wood adhesives is demonstrated by the collaboration of the ACIAR with the CAF in the early 1990s. Although radiata pine bark (Pinus radiata) could be a useful resource for the production of wood adhesives, three problems prevented its use in this application: low extractive yields from the bark, variable quality of the tannin extracts and excessive viscosity of the formulated tannin adhesives. In order to overcome these problems, various extraction methods have been proposed. Studies on tannin adhesives from bark of other pine species are also described. Furthermore, the use of the tannin in the bark without extraction is described as "bark adhesives" from radiata pine and black wattle. The use of radiata tannin without formaldehyde for moulded wood products is also described. Owing to the strong antioxidant activity of flavonoid compounds, bark extracts from French maritime pine (Pinus pinaster, synonym P. maritima) and radiata pine have been commercialized as nutritional supplements: Pycnogenol and Enzogenol, respectively. The background and the development of Pycnogenol and the basic difference in the preparation processes between Pycnogenol and Enzogenol are described. On the basis of the discovery that the SOSA value for wattle tannin is approximately 10 times that of extracts from pine bark supplements (Pycnogenol and Enzogenol), chemical, biochemical and clinical studies on wattle tannin were conducted. Results from these studies are outlined. Wattle tannin has been developed as a nutritional supplement and marketed as Acapolia in Japan. PMID- 25924542 TI - Flavonoids in foods: a review. AB - The flavonoids in edible plants and foods are surveyed. The food materials rich in flavonoids, such as grape, tea, and cocoa receive particular attention. Also, the ingestion of flavonoids, the absorption and the bioavailability in vivo are discussed. Flavonoids have antioxidant and other living-body modulating activities. When expressing these functionalities, interactions between flavonoids and proteins are important. The interactions with various enzymes and receptors are described. Moreover, as an example of a processed food containing flavonoids, fermented red vinegar that we have investigated is highlighted. The structural determination, antioxidant activity and the generation mechanism of the new acylated polyphenols in red vinegar are described. PMID- 25924543 TI - Contribution to flower colors of flavonoids including anthocyanins: a review. AB - Flavonoids are one of the major pigments in higher plants, together with chlorophylls and carotenoids. Though ca. 8,000 kinds of flavonoids have been reported in nature, anthocyanins, chalcones, aurones and some flavonols act as major flower pigments. Flavonoids are present as major components in many flowers. On the other hand, flavones and flavonols, which are colorless or extremely pale yellow, function as copigment substances. Moreover, expression of the flower colors is diversified by inter-molecular and intra-molecular copigmentation, metal chelation, pH change and so on. In this review, I describe the distribution of the flavonoids which act as the pigments, and contribution to flower colors, e.g., yellow, scarlet, red, red-purple, violet, purple, blue and so on, of flavonoids, especially anthocyanins, chalcones, aurones and flavonols. PMID- 25924544 TI - Use of placental growth factor and uterine artery doppler pulsatility index in pregnancies involving intrauterine fetal growth restriction or preeclampsia to predict perinatal outcomes. AB - AIM: The potential of uterine artery (UA) Doppler pulsatility index (PI) and maternal serum placental growth factor (PlGF) level to predict perinatal outcome was explored in pregnancies complicated by intrauterine fetal growth restriction (IUGR) or preeclampsia (PE). METHODS: This longitudinal, prospective, and case controlled study was conducted over a period of 24 months. At-risk pregnancies involving small-for-gestational-age (SGA) fetuses, IUGR, gestational hypertension (GH), or PE were investigated, analyzing UA Doppler PI findings and maternal PlGF levels determined at the time of diagnosis (third trimester). RESULTS: UA Doppler PI and maternal serum PlGF values differed significantly in pregnancies complicated by IUGR and/or PE (vs. SGA or GH, p < 0.01). In the context of IUGR or PE, both parameters also differed significantly by perinatal outcome (adverse vs. normal, p < 0.01), although no predictive advantage over UA Doppler PI alone was conferred by adding a PlGF assay. CONCLUSION: UA Doppler PI and maternal serum PlGF determinations in the third trimester help identify pregnancies at the highest risk of adverse perinatal outcomes due to IUGR and/or PE. Although joint testing confers no predictive benefit over UA Doppler PI alone, the two diagnostics are interchangeable for this purpose. PMID- 25924545 TI - Single versus double flap approach in periodontal regenerative treatment. AB - AIM: to compare the outcomes of a regenerative strategy based on recombinant human platelet-derived growth factor-BB (rhPDGF-BB, 0.3 mg/ml) and beta tricalcium phosphate (beta-TCP) in the treatment of intraosseous defects accessed with the Single Flap Approach (SFA) versus Double Flap Approach based on papilla preservation techniques (DFA). MATERIALS AND METHODS: Fifteen and 13 defects, randomly assigned to SFA or DFA, respectively, were grafted with rhPDGF-BB + beta TCP. Probing parameters were assessed before and 6 months after surgery. Pain (VAS(pain)) was self-reported using a visual analogue scale. RESULTS: Twelve SFA sites and DFA 6 sites showed complete flap closure at 2 weeks post-surgery. No significant differences in 6-month changes in probing parameters and radiographic defect fill were found between groups. Significantly lower VAS(pain) was observed in SFA group compared to DFA group at day +1, +2 and +6. A significantly greater number of analgesics were consumed in the DFA group compared to the SFA group at day +1. CONCLUSIONS: When combined with rhPDGF-BB and beta-TCP, the SFA may result in similar clinical outcomes, better quality of early wound healing, and lower pain and consumption of analgesics during the first postoperative days compared to the DFA. PMID- 25924546 TI - Pregnancy outcomes of women with coexisting systemic lupus erythematosus flare and preeclampsia. AB - OBJECTIVES: Systemic lupus erythematosus (SLE) flare and preeclampsia are difficult to differentiate from each other and occasionally coexist; This study aimed to analyze cases requiring termination of pregnancy due to SLE flare or preeclampsia and to elucidate the association between these two conditions; Methods. Out of 71 pregnancies in 60 women managed for SLE-complicated pregnancies who delivered at or after 22 weeks' gestation at a tertiary center, 7 pregnancies were terminated due to uncontrollable severe SLE flare or severe preeclampsia We retrospectively analyzed the clinical courses and laboratory findings of these 7 cases to determine whether their pathological conditions were attributable to SLE flare alone, preeclampsia alone, or the coexistence of these two conditions. RESULTS: One of the 7 cases had preeclampsia alone, two had SLE alone, and four had both conditions. The coexistence of preeclampsia and SLE was thus the most common condition. In cases with both conditions, SLE flare had preceded preeclampsia, thereby making treatment after delivery difficult. CONCLUSION: Severe SLE flare often preceded severe preeclampsia and worsened after delivery. When differentiating severe SLE flare from severe preeclampsia is difficult during pregnancy, women should be regarded as having SLE flare rather than preeclampsia and aggressively treated. PMID- 25924547 TI - Glatiramer acetate: long-term safety and efficacy in relapsing-remitting multiple sclerosis. AB - Glatiramer acetate (GA) is approved for relapsing-remitting multiple sclerosis in 57 countries worldwide, with more than 2 million patient-years of exposure and over 20 years of continuous clinical use without new safety concerns. GA has an overall favorable risk-benefit profile: 30% reduced annual relapse rate and decreased brain lesion activity. In clinically definite MS or clinically isolated syndrome, GA slows brain atrophy, which may be related to its unique anti inflammatory and neuroprotective mechanisms of action. Early treatment with GA delays the onset of clinically definite MS more effectively than late treatment in clinically isolated syndrome. GA is not associated with immunosuppression, autoimmune disease, infections or development of neutralizing antibodies. A new three-times-weekly formulation of GA is available to potentially reduce the incidence of injection-related side effects. Other safety advantages of GA include its pregnancy rating (Category B) and limited uncontrolled data suggesting that tolerability is similar in children with MS. PMID- 25924548 TI - Syntheses, Characterization, and Optical Properties of Centrosymmetric Ba3(BS3)1.5(MS3)0.5 and Noncentrosymmetric Ba3(BQ3)(SbQ3). AB - The most advanced UV-vis and IR NLO materials are usually borates and chalcogenides, respectively. But thioborates, especially thio-borometalates, are extremely rare. Here, four new such compounds are discovered by solid state reactions representing 0D structures constructed by isolated BQ3 trigonal planes and discrete MQ3 pyramids with Ba(2+) cations filling among them, centrosymmetric monoclinic P21/c Ba3(BS3)1.5(MS3)0.5 (M = Sb, Bi) 1, 2 with a = 12.9255(9), 12.946(2) A; b = 21.139(2), 21.170(2)A; c = 8.4194(6), 8.4207(8) A; beta = 101.739(5), 101.688(7) degrees ; V = 2252.3(3), 2259.9(3) A(3) and noncentrosymmetric hexagonal P62m Ba3(BQ3)(SbQ3) (Q = S, Se) 3, 4 with a = b = 17.0560(9), 17.720(4) A; c = 10.9040(9), 11.251(3) A; V = 2747.1(3), 3060(2) A(3). 3 exhibits the strongest SHG among thioborates that is about three times that of the benchmark AgGaS2 at 2.05 MUm. 1 and 3 also show an interesting structure relationship correlated to the size mismatching of the anionic building units that can be controlled by the experimental loading ratio of B:Sb. Syntheses, structure characterizations, and electronic structures based on the density functional theory calculations are reported. PMID- 25924550 TI - Using information to deliver safer care: a mixed-methods study exploring general practitioners' information needs in North West London primary care. AB - BACKGROUND: The National Health Service in England has given increasing priority to improving inter-professional communication, enabling better management of patients with chronic conditions and reducing medical errors through effective use of information. Despite considerable efforts to reduce patient harm through better information usage, medical errors continue to occur, posing a serious threat to patient safety. OBJECTIVES: This study explores the range, quality and sophistication of existing information systems in primary care with the aim to capture what information practitioners need to provide a safe service and identify barriers to its effective use in care pathways. METHOD: Data were collected through semi-structured interviews with general practitioners from surgeries in North West London and a survey evaluating their experience with information systems in care pathways. RESULTS: Important information is still missing, specifically discharge summaries detailing medication changes and changes in the diagnosis and management of patients, blood results ordered by hospital specialists and findings from clinical investigations. Participants identified numerous barriers, including the communication gap between primary and secondary care, the variable quality and consistency of clinical correspondence and the inadequate technological integration. CONCLUSION: Despite attempts to improve integration and information flow in care pathways, existing systems provide practitioners with only partial access to information, hindering their ability to take informed decisions. This study offers a framework for understanding what tools should be in place to enable effective use of information in primary care. PMID- 25924549 TI - Impact of tacrolimus and mycophenolate mofetil regimen vs. a conventional therapy with steroids on cardiovascular risk in liver transplant patients. AB - The aim of this study was to evaluate the impact of a steroid-free regimen with tacrolimus and mycophenolate mofetil (modified therapy) vs. a standard regimen of tacrolimus and steroids on the cardiovascular risk score of liver transplant recipients. Patients who received a liver transplant were randomized to a modified therapy (n = 58) or a standard regimen (n = 59). Both groups were balanced at baseline, except for a higher prevalence of diabetes mellitus (DM) (p < 0.01) and a higher serum creatinine concentration (p < 0.05) in the modified therapy group. After 12 months, the prevalence of new-onset DM, arterial hypertension, hypercholesterolemia, hypertriglyceridemia, and changes in cardiovascular risk factors was similar in both groups. The increase in serum creatinine (mg/dL) compared to baseline at one yr post-transplantation was numerically lower in the modified therapy group (0.22 +/- 0.42) than in the standard regimen group (0.41 +/- 0.67) (p = 0.068). Although estimated cardiovascular risk score did not vary significantly compared to baseline in either group, there was a slight reduction in the modified regimen (-0.27 +/- 2.87) vs. a mild increase (0.17 +/- 2.94) in the standard regimen (p = 0.566). In conclusion, a steroid-free regimen with tacrolimus and mycophenolate mofetil was associated with a trend toward better preservation of kidney function and reduction of cardiovascular risk score. PMID- 25924551 TI - Characteristics of electronic patient-provider messaging system utilisation in an urban health care organisation. AB - INTRODUCTION: Research suggests that electronic messaging can improve patient engagement. Studies indicate that a 'digital divide' may exist, where certain patient populations may be using electronic messaging less frequently. This study aims to determine which patient characteristics are associated with different levels of usage of an electronic patient-provider messaging system in a diverse urban population. METHODS: Cross-sectional electronic health record data were extracted for patients 10 years of age or older who live in New York City and who visited a set of clinics between 1 July 2011 and 30 June 2012. Regression analyses determined which participant characteristics were associated with the sending of electronic messages. RESULTS: Older, female, English-speaking participants of white race who received more messages, had any diagnoses, more office visits and a provider who sent messages were more likely to send more messages. Non-Millennial, non-white participants who received fewer messages, had more office visits, any diagnoses, a provider who saw fewer patients with patient portal accounts, lived in a low socioeconomic status neighbourhood, and did not have private insurance were more likely to send zero messages. CONCLUSION: This study found significant differences in electronic messaging usage based on demographic, socioeconomic and health-related patient characteristics. Future studies are needed to support these results and determine the causes of observed associations. PMID- 25924552 TI - Using the Internet as a source of information and support: a discussion paper on the risks and benefits for children and young people with long-term conditions. AB - Children and young people who have long-term conditions are likely to seek health related information via the Internet. Because of their continuing contact with children with such conditions, primary care practitioners may be well placed to discuss with them and their families the risks and benefits of accessing information online. This includes not only the relative merits of particular sites but also more general online safety issues. To achieve this, it may be helpful for primary care practitioners to consider how they view risk in general, the risks associated with the Internet and the vulnerabilities of children and young people, particularly those with long-term conditions. PMID- 25924553 TI - Unleashing the power of e-Health requires the development of an evidence base for interventions that improve care. PMID- 25924554 TI - Journal of Innovation in Health Informatics: building on the 20-year history of a BCS Health peer review journal. AB - After 20-years as Informatics in Primary Care the journal is renamed Journal of Innovation in Health Informatics. The title was carefully selected to reflect that: (1) informatics provides the opportunity to innovate rather than simply automates; (2) implementing informatics solutions often results in unintended consequences, and many implementations fail and benefits and innovations may go unrecognised; (3) health informatics is a boundary spanning discipline and is by its very nature likely to give rise to innovation. Informatics is an innovative science, and informaticians need to innovate across professional and discipline boundaries. PMID- 25924555 TI - A simple clinical coding strategy to improve recording of child maltreatment concerns: an audit study. AB - BACKGROUND: Recording concerns about child maltreatment, including minor concerns, is recommended by the General Medical Council (GMC) and National Institute for Health and Clinical Excellence (NICE) but there is evidence of substantial under-recording. AIM: To determine whether a simple coding strategy improved recording of maltreatment-related concerns in electronic primary care records. DESIGN AND SETTING: Clinical audit of rates of maltreatment-related coding before January 2010-December 2011 and after January-December 2012 implementation of a simple coding strategy in 11 English family practices. The strategy included encouraging general practitioners to use, always and as a minimum, the Read code 'Child is cause for concern'. A total of 25,106 children aged 0-18 years were registered with these practices. We also undertook a qualitative service evaluation to investigate barriers to recording. METHOD: Outcomes were recording of 1) any maltreatment-related codes, 2) child protection proceedings and 3) child was a cause for concern. RESULTS: We found increased recording of any maltreatment-related code (rate ratio 1.4; 95% CI 1.1-1.6), child protection procedures (RR 1.4; 95% CI 1.1-1.6) and cause for concern (RR 2.5; 95% CI 1.8-3.4) after implementation of the coding strategy. Clinicians cited the simplicity of the coding strategy as the most important factor assisting implementation. CONCLUSION: This simple coding strategy improved clinician's recording of maltreatment-related concerns in a small sample of practices with some 'buy-in'. Further research should investigate how recording can best support the doctor-patient relationship. HOW THIS FITS IN: Recording concerns about child maltreatment, including minor concerns, is recommended by the General Medical Council (GMC) and National Institute for Health and Clinical Excellence (NICE), but there is evidence of substantial under-recording. We describe a simple clinical coding strategy that helped general practitioners to improve recording of maltreatment-related concerns. These improvements could improve case finding of children at risk and information sharing. PMID- 25924556 TI - Examining the symptom of fatigue in primary care: a comparative study using electronic medical records. AB - BACKGROUND: The symptom of fatigue is one of the top five most frequently presented health complaints in primary care, yet it remains underexplored in the Canadian primary care context. OBJECTIVE: The objective of this study was to examine the prevalence and impact of patients presenting with fatigue in primary care, using the only known electronic database in Canada to capture patient reported symptoms. METHODS: Data were extracted from the Deliver Primary Healthcare Information (DELPHI) database, an electronic medical record database located in Ontario, Canada. Patients were identified using the International Classification of Primary Care, Revised Second Edition coding system. Two groups of patients (fatigue or non-fatigue symptom) were followed for one year and compared. Both descriptive and multivariable analyses were conducted. RESULTS: A total of 103 fatigue symptom patients, and 103 non-fatigue symptom patients, were identified in the DELPHI database. The period prevalence of fatigue presentation was 8.2%, with the majority of patients being female and over 60 years of age. These patients experienced numerous co-occurring morbidities, in addition to the fatigue itself. During the one year follow-up period, fatigue symptom patients had significantly higher rates of subsequent visits (IRR = 1.19, p = 0.038) and investigations (IRR = 1.68, p < 0.001), and markedly high levels of referrals following their index visit. CONCLUSIONS: This research used an electronic database to examine the symptom, fatigue. Using these data, fatigue symptom patients were found to have higher rates of health care utilisation, compared to non-fatigue symptom patients. PMID- 25924557 TI - Exploiting the information revolution: call for independent evaluation of the latest English national experiment. AB - BACKGROUND: The English National Health Service (NHS) has a long history of national experiments with information technology; some successful, others less so. The NHS England Five Year Forward View aspires to 'Exploit the information revolution' through the transformational work of the National Information Board (NIB). NIB has published a 'Framework for Action' that promotes citizen empowerment, information availability, transparency, public trust, innovation, informatics skills and societal value. ISSUE: The framework sets out many laudable and common sense ambitions, but is light on evidence to support its aspirations, or plans for its evaluation. Considerable resource was invested in evaluation studies in the later stages of the National Programme for IT in England, but the analyses do not seem to have been included. Most of the cited evidence is from an unpublished report by management consultants rather than independent peer-reviewed work. RECOMMENDATION: National experiments of this importance should be evidence based and properly evaluated so that each iteration of 'information revolution' produces an evidence base to inform subsequent generations of care provision models and technology innovation. Evaluation should be planned from the very start rather than added in as an afterthought. Like any good business plan there should be defined critical success factors for health and social care, and a declaration of how they might be measured. Unintended consequences should be qualitatively explored. Evaluation should also consider critical-interpretive social perspectives to understand the human factors in technology deployment and should seek a theoretically informed insight into the mechanisms of change. CONCLUSIONS: The NHS Five Year Forward View and the NIB framework set out challenging ambitions based on transformative use of information technology and collaborative partnerships with commissioners and providers. The framework stands up very well against the Hayes principles, but the learning opportunities associated with this programme should not be missed. PMID- 25924558 TI - Minimally disruptive medicine is needed for patients with multimorbidity: time to develop computerised medical record systems to meet this requirement. AB - BACKGROUND: Minimally disruptive medicine (MDM) is proposed as a method for more appropriately managing people with multiple chronic disease. Much clinical management is currently single disease focussed, with people with multimorbidity being managed according to multiple single disease guidelines. Current initiatives to improve care include education about individual conditions and creating an environment where multiple guidelines might be simultaneously supported. The patient-centred medical home (PCMH) is an example of the latter. However, educational programmes and PCMH may increase the burden on patients. PROBLEM: The cumulative workload for patients in managing the impact of multiple disease-specific guidelines is only relatively recently recognised. There is an intellectual vacuum as to how best to manage multimorbidity and how informatics might support implementing MDM. There is currently no alternative to multiple single-condition- specific guidelines and a lack of certainty, should the treatment burden need to be reduced, as to which guideline might be 'dropped'. ACTION: The best information about multimorbidity is recorded in primary care computerised medical record (CMR) systems and in an increasing number of integrated care organisations. CMR systems have the potential to flag individuals who might be in greatest need. However, CMR systems may also provide insights into whether there are ameliorating factors that might make it easier for them to be resilient to the burden of care. Data from such CMR systems might be used to develop the evidence base about how to better manage multimorbidity. CONCLUSIONS: There is potential for these information systems to help reduce the management burden on patients and clinicians. However, substantial investment in research driven CMR development is needed if we are to achieve this. PMID- 25924560 TI - Eleven Years of Data on the Jefferson Scale of Empathy-Medical Student Version (JSE-S): Proxy Norm Data and Tentative Cutoff Scores. AB - OBJECTIVE: This study was designed to provide typical descriptive statistics, score distributions and percentile ranks of the Jefferson Scale of Empathy Medical Student version (JSE-S) of male and female medical school matriculants to serve as proxy norm data and tentative cutoff scores. SUBJECTS AND METHODS: The participants were 2,637 students (1,336 women and 1,301 men) who matriculated at Sidney Kimmel (formerly Jefferson) Medical College between 2002 and 2012, and completed the JSE at the beginning of medical school. Information extracted from descriptive statistics, score distributions and percentile ranks for male and female matriculants were used to develop proxy norm data and tentative cutoff scores. RESULTS: The score distributions of the JSE tended to be moderately skewed and platykurtic. Women obtained a significantly higher mean score (116.2 +/- 9.7) than men (112.3 +/- 10.8) on the JSE-S (t2,635 = 9.9, p < 0.01). It was suggested that percentile ranks can be used as proxy norm data. The tentative cutoff score to identify low scorers was <= 95 for men and <= 100 for women. CONCLUSIONS: Our findings provide norm data and cutoff scores for admission decisions under certain conditions and for identifying students in need of enhancing their empathy. PMID- 25924561 TI - Label-free water sensors using hybrid polymer-dielectric mid-infrared optical waveguides. AB - A chip-scale mid-IR water sensor was developed using silicon nitride (SiN) waveguides coated with poly(glycidyl methacrylate) (PGMA). The label-free detection was conducted at lambda=2.6-2.7 MUm because this spectral region overlaps with the characteristic O-H stretch absorption while being transparent to PGMA and SiN. Through the design of a hybrid waveguide structure, we were able to tailor the mid-IR evanescent wave into the PGMA layer and the surrounding water and, consequently, to enhance the light-analyte interaction. A 7.6 times enhancement of sensitivity is experimentally demonstrated and explained by material integration engineering as well as waveguide mode analysis. Our sensor platform made by polymer-dielectric hybrids can be applied to other regions of the mid-IR spectrum to probe other analytes and can ultimately achieve a multispectral sensor on-a-chip. PMID- 25924562 TI - Amphiphilic fullerene/ZnO hybrids as cathode buffer layers to improve charge selectivity of inverted polymer solar cells. AB - Two types of novel fullerene derivative/ZnO hybrids were prepared by physically blending amphiphilic fullerene-end-capped poly(ethylene glycol) (C60-PEG) with ZnO nanocrystals (ZnO/C60-PEG) and by in situ grown ZnO from C60-PEG (ZnO@C60 PEG) at relatively low temperatures. The C60-PEG could act as n-doping on the ZnO while the PEG side chain of C60-PEG could passivate the defects of the ZnO at the same time, consequently increasing the lowest unoccupied molecular orbital (LUMO) level. Compared with the ZnO/C60-PEG by the physical blend approach, the ZnO@C60 PEG by the growth approach showed a more favorable morphology and higher electron mobility by developing a homogeneous network. As a consequence, the efficiency of the inverted polymer solar cells based on thieno[3,4-b] thiophene/benzodithiophene (PTB7):[6,6]-phenyl C71-butyric acid methyl ester (PC71BM) is raised to 8.0% for the ZnO@C60-PEG cathode buffer layer and to 7.5% for the ZnO/C60-PEG cathode buffer layer with improved long-term stability. PMID- 25924563 TI - Functional topography of the thalamocortical system in human. AB - Various studies have indicated that the thalamus is involved in controlling both cortico-cortical information flow and cortical communication with the rest of the brain. Detailed anatomy and functional connectivity patterns of the thalamocortical system are essential to understanding the cortical organization and pathophysiology of a wide range of thalamus-related neurological and neuropsychiatric diseases. The current study used resting-state fMRI to investigate the topography of the human thalamocortical system from a functional perspective. The thalamus-related cortical networks were identified by performing independent component analysis on voxel-based thalamic functional connectivity maps across a large group of subjects. The resulting functional brain networks were very similar to well-established resting-state network maps. Using these brain network components in a spatial regression model with each thalamic voxel's functional connectivity map, we localized the thalamic subdivisions related to each brain network. For instance, the medial dorsal nucleus was shown to be associated with the default mode, the bilateral executive, the medial visual networks; and the pulvinar nucleus was involved in both the dorsal attention and the visual networks. These results revealed that a single nucleus may have functional connections with multiple cortical regions or even multiple functional networks, and may be potentially related to the function of mediation or modulation of multiple cortical networks. This observed organization of thalamocortical system provided a reference for studying the functions of thalamic sub-regions. The importance of intrinsic connectivity-based mapping of the thalamocortical relationship is discussed, as well as the applicability of the approach for future studies. PMID- 25924564 TI - On the relationship between lower extremity muscles activation and peak vertical and posterior ground reaction forces during single leg drop landing. AB - AIM: Anterior cruciate ligament (ACL) injury continues to be an important medical issue for athletes participating in sports. Vertical and posterior ground reaction forces have received considerable attention for their potential influence on ACL injuries. The purpose of this study was to examine the relationship between electromyographic activity of lower extremity muscles and the peak vertical and posterior ground reaction forces during single leg drop landing. METHODS: Thirteen physical education male students participated in this correlation study. Electromyographic activities of gluteus medius, biceps femoris, medial gastrocnemius, soleus as well as anterior tibialis muscles along with ground reaction forces were measured. Participants performed single-leg landing from a 0.3 m height on to a force platform. Landing was divided into two phases: 100 ms preceding ground contact and 100 ms proceeding ground contact. Pearson correlation test was used to determine the relationships between these muscles activity and peak vertical and posterior ground reaction forces. RESULTS: The results of the study indicated that the activity of soleus and tibialis anterior in pre-landing phase were positively correlated with peak vertical ground reaction force ([P<=0.04], [P<=0.008], respectively). However, no significant correlation was found between the activities of other muscles in pre landing phase and peak vertical as well as peak posterior ground reaction forces. Also, no significant correlation was found between the activities of muscles in post-landing phase and peak vertical as well as peak posterior ground reaction forces. CONCLUSION: Soleus loading shifts the proximal tibia posterior at the knee joint and tibialis anterior prevent hyperporonation of the ankle, a mechanisms of ACL injury. Hence, neuromuscular training promoting preparatory muscle activity in these muscles may reduce the incidence of ACL injuries. PMID- 25924565 TI - Accuracy of self-perception and Body Mass Index compared to actual body fat percentage in athletes and non-athletes. AB - BACKGROUND: The purpose of this study was to examine the accuracy of self reported weight status compared to weight status based on actual body fat percentage in athletes and non-athletes. METHODS: Adult athletes (N.=76; 43 female and 33 male) and non-athletes (N.=80; 43 female and 37 male) participated in this cross-sectional study. Participants were asked to identify their perceived weight status. Height and weight were measured, and BMI was calculated. Body fat percentage was assessed using BOD POD. Cross-tabs analyses were used to determine agreement between perceived weight status, weight status based on body fat percentage, and weight status based on BMI. RESULTS: Overall, agreement between perceived weight status and actual weight status based on body fat percentage was fair. Of the 43 overweight/obese participants, 42% under-estimated weight status, thinking they were normal weight. Of the 114 normal weight participants, 6% over-estimated their weight status, thinking they were overweight. Although there were lower rates of overweight/obesity among athletes, 50% of overweight/obese athletes thought they were normal weight, while 39% of overweight/obese non-athletes thought they were normal weight. None of the normal weight athletes (N.=56) over-estimated their weight status. In contrast, 20% of male non-athletes, and 9% of female non-athletes who were normal weight thought they were overweight. CONCLUSIONS: Similar to trends observed in recent studies, results from the current study indicate that a high proportion of overweight/obese adults underestimate their weight status, and athletes may not be immune to this trend. Reasons as to why this phenomenon may be occurring and future directions are discussed. PMID- 25924566 TI - Physiological characteristics of elite snowboarders. AB - BACKGROUND: The aim of this study was to profile the physiological qualities of elite snowboarders and quantified the relationships with snowboarding performance. METHODS: Ten alpine (ALP, mean+/-SD age: 25.6+/-4.4 yrs; body mass 78.1+/-12.1; height 178.4+/-9.8 cm; sum of 7 skinfolds 74.8+/-19.4 mm; body fat 13.8+/-3.7%) and ten snowboard cross (SBX, mean+/-SD age: 23.5+/-4.3 yrs; body mass 77.2+/-9.2; height 181.0+/-4.9 cm; sum of 7 skinfolds 70.1+/-21.1 mm; body fat 11.9+/-3.5%) elite male athletes undertook aerobic power (cycle ergometer maximum oxygen uptake), muscular isometric strength (maximal isometric voluntary contraction, MVC), and muscle-power (vertical jumps), as well as ALP (parallel giant slalom [PGS] and parallel slalom [PSL]) and SBX simulated competitions. Associations between measurements were assessed by correlation analysis. RESULTS: Absolute (ALP 383.1+/-38.0 W, P<0.01; SBX 339.7+/-41.3 W, P<0.05) and relative (ALP, 4.6+/-0.5 W.kg-1, P<0.01; SBX 4.5+/-0.3 W.kg-1, P<0.05) power output, power at the first (ALP 196.0+/-53.7 W, P<0.01; SBX 192.8+/-24.3, P<0.01) and second (ALP 285.4+/-60.6 W, P<0.01; SBX 280.4+/-20.3 W, P<0.01) ventilatory threshold, MVC (ALP 731.9+/-181.9 N.m-1, P<0.001; SBX 680.1+/-76.8 N.m-1, P<0.001) and leg stiffness (ALP 31.4+/-4.8 N.m-1.kg-1, P<0.01; SBX 25.4+/-3.0 N.m-1.kg-1, P<0.01) were highly correlated with PGS (r=-0.88 to -0.97), PSL (r=-0.84 to -0.94), and SBX (r=-0.89 to -0.93) performance times. CONCLUSIONS: To meet the demands of snowboarding competition, elite snowboarders require highly developed muscular strength and power. This study provides criteria for the selection of appropriate physiological variables for the longitudinal monitoring of relevant parameters in snowboarding. PMID- 25924567 TI - Effects of kinesio taping on anaerobic power and capacity results. AB - BACKGROUND: Kinesio taping is a therapeutic method used by physiotherapists during musculoskeletal and neuromuscular disorders. Efficacy of the kinesio taping implementation on sport performance is inconsistent. The purpose of this study was to determine the effects of kinesio taping on 30 second-repeated jump power, wingate anaerobic power and wingate anaerobic capacity results. METHODS: Thirty one healthy male athletes volunteered to participate in this study. The subjects were randomly assigned to one of two groups: a kinesio taping group (16 subjects; X age: 21.87+/-2.02 years) and a without kinesio taping group (15 subjects; X age: 21.66+/-1.67 years). The Kinesio taping group was taped with a Y shaped kinesio tape at the quadriceps muscles according to the Kenzo Kase's Kinesio taping manual. RESULTS: A dependent t-test was used to compare the anaerobic power and capacity measurements before and after the kinesio taping application. CONCLUSIONS: No significant differences were found for absolute wingate anaerobic power, relative wingate anaerobic power, absolute wingate anaerobic capacity, relative wingate anaerobic capacity and 30 second-repeated jump power outputs after the kinesio taping application (P>0.05). PMID- 25924568 TI - Brain development in male rats subjected to early weaning and treated with diet containing flour or flaxseed oil after 21 days until 60 days. AB - The precocious interruption of lactation is a prime factor for developmental plasticity. Here we analyzed whether flour or flaxseed oil treatment contributes to body and brain mass in male rats subjected to early weaning. Pups were weaned for separation from their mother at 14 (early weaning, EW) and 21 days (control, C). At 21 days, some of the pups were evaluated (C21 v. EW21). After 21 days, control pups (C60) were fed a control diet. EW pups were divided into those fed a control diet (EWC60), those given flaxseed flour (EWFF60), and those given flaxseed oil (EWFO60) until 60 days. EW21 showed lower body and absolute brain mass and higher relative brain mass. At 60 days, EWC60 and EWFO60 had lower body mass. With regard to relative brain mass, EWC60 was heavier; EWFO60 had lower values compared with EWC60 and higher values compared with C60 and EWFF60. These results indicated that flaxseed flour, in comparison with flaxseed oil, contributes to brain development after EW. PMID- 25924569 TI - Regenerative Skin Wound Healing in Mammals: State-of-the-Art on Growth Factor and Stem Cell Based Treatments. AB - Mammal skin has a crucial function in several life-preserving processes such as hydration, protection against chemicals and pathogens, initialization of vitamin D synthesis, excretion and heat regulation. Severe damage of the skin may therefore be life-threatening. Skin wound repair is a multiphased, yet well orchestrated process including the interaction of various cell types, growth factors and cytokines aiming at closure of the skin and preferably resulting in tissue repair. Regardless various therapeutic modalities targeting at enhancing wound healing, the development of novel approaches for this pathology remains a clinical challenge. The time-consuming conservative wound management is mainly restricted to wound repair rather than restitution of the tissue integrity (the so-called "restitutio ad integrum"). Therefore, there is a continued search towards more efficacious wound therapies to reduce health care burden, provide patients with long-term relief and ultimately scarless wound healing. Recent in vivo and in vitro studies on the use of skin wound regenerative therapies provide encouraging results, but more protracted studies will have to determine whether the effect of observed effects are clinically significant and whether regeneration rather than repair can be achieved. For all the aforementioned reasons, this article reviews the emerging field of regenerative skin wound healing in mammals with particular emphasis on growth factor- and stem cell-based therapies. PMID- 25924570 TI - From silos to systems: an integrated approach to neuroscience innovation. AB - The Ontario Brain Institute manages a network of partnerships among researchers, clinicians, industry representatives and patients to maximize their collective impact on developing better treatment and care for those living with brain disorders. PMID- 25924571 TI - Drug developers reboot anti-NGF pain programmes. PMID- 25924572 TI - March of the synthesis machines. PMID- 25924576 TI - Patent watch: Have the biosimilar floodgates been opened in the United States? PMID- 25924577 TI - Changes in clinical trial length. PMID- 25924578 TI - Regulation of B-cell-activating factor expression on the basophil membrane of allergic patients. AB - BACKGROUND: To investigate the modulation of B-cell-activating factor (BAFF) expression on the basophil membrane of allergic patients. BAFF is an important regulator of B-cell activation, proliferation and immunoglobulin production, which may play a role in respiratory allergic diseases in promoting the production of IgE by B cells. METHODS: Peripheral blood samples of 10 patients with allergic rhinitis, 3 with severe asthma and fungal sensitization (SAFS), 3 with allergic bronchopulmonary aspergillosis (ABPA) and 11 healthy controls were assessed regarding BAFF (CD257) expression using the basophil activation test before and after stimulation with IgE and allergens, as well IgE-independent stimuli, like fMLP, lipotheichoic acid from Staphylococcus aureus (LTA-SA) and lipopolysaccharide (LPS). RESULTS: BAFF membrane expression did not change after IgE and allergen stimulation both in patients and controls, while it was upregulated by Aspergillus stimulation, both in sensitized patients and controls. In both patients and controls, BAFF expression was significantly upregulated following LTA-SA and beta-1,3-glucan exposure (toll-like receptor-2 ligands), but not following LPS stimulation. CONCLUSIONS: Basophils from allergic and healthy subjects constitutively express membrane BAFF, which is not upregulated by IgE or specific allergens but by TLR-2 ligands (LTA-SA and beta-1,3-glucan). Aspergillus fumigatus stimulation was able to upregulate BAFF expression on the basophils of sensitized asthmatic patients, but not via IgE-dependent mechanisms, since results did not differ between the patient and control groups. These findings suggest that basophils may contribute to the polyclonal production of IgE commonly observed in patients with SAFS and ABPA. PMID- 25924579 TI - Structural views of quinone oxidoreductase from Mycobacterium tuberculosis reveal large conformational changes induced by the co-factor. AB - Energy generation, synthesis of biomass and detoxification of synthetic compounds are driven by electron transfer in all living organisms. Soluble quinone oxidoreductases (QORs) catalyze transfer of electrons from NADPH to substrates. The open reading frame Rv1454c of Mycobacterium tuberculosis (Mtb) encodes a NADPH-dependent QOR that is known to catalyze one-electron reduction of quinones to produce semiquinones. Here, we report the crystal structures of the apo-enzyme of MtbQOR and its binary complex with NADPH determined at 1.80 and 1.85 A resolutions, respectively. The enzyme is bi-modular. Domain I binds the substrate, while domain II folds into a typical Rossmann fold for tethering NADPH. Binding of NADPH induces conformational changes. Among the known structures of QORs, MtbQOR exhibits the largest conformational change. Movement of Phe41 to stack against Ala244 results in partial closure of the active site. Comparison of the structure with homologs suggests a conserved topology. However, differences are observed in the region around the site of hydride transfer, highlighting differences in substrate specificities amongst the homologs. Unliganded as well as NADPH-bound MtbQOR crystallized as a dimer. Dimerization is mediated by homotypic intermolecular interactions involving main chain Calpha as well as side-chain atoms of residues. The results of analytical ultracentrifugation analysis revealed that MtbQOR exists as a dimer in solution. Enzymatic assays indicate that MtbQOR prefers 9,10-phenanthrenequinone over 1,4 benzoquinone as a substrate. The ability to reduce quinones probably assists Mtb in detoxification of a range of harmful chemicals encountered in the host during invasion. DATABASE: The coordinates and structure factors for apo- and NADPH bound MtbQOR have been deposited in the Protein Data Bank under accession codes 4RVS and 4RVU, respectively. PMID- 25924580 TI - The accessory coracobrachialis muscle: ultrasound and MR features. AB - OBJECTIVE: To present the prevalence, clinical relevance, and ultrasound (US) and magnetic resonance imaging (MRI) appearances of the accessory coracobrachialis (ACB) muscle. MATERIALS AND METHODS: We present an US prospective study of the ACB muscle over a 2-year period. Five of the eight patients with suspected ACB on US were subsequently examined by MRI. RESULTS: An ACB muscle was demonstrated by US in eight patients (eight shoulders), including seven females, one male, with mean age 39 years, over 770 (664 patients) consecutive shoulder US examinations referred to our institution yielding a prevalence of 1.04%. In dynamic US assessment, one case of subcoracoid impingement secondary to a bulky ACB was diagnosed. No thoracic outlet syndrome was encountered in the remaining cases. MRI confirmed the presence of the accessory muscle in five cases. CONCLUSIONS: ACB muscle is a rarely reported yet not uncommon anatomic variation of the shoulder musculature encountered only in eight of 664 patients referred for shoulder US study. Its US and MRI appearance is described. One of our patients presented with subcoracoid impingement related to the presence of an ACB. PMID- 25924581 TI - Late Abdominal Pregnancies (>=20 Weeks Gestation): A Review from 1965 to 2012. AB - BACKGROUND: Information about the diagnosis and management of late abdominal pregnancies (>=20 weeks gestation) is limited to case reports and small case series. METHODS: We performed a literature review of abdominal pregnancies >=20 weeks gestation from 1965 to November 2012. Excluded were abdominal ectopic pregnancies that did not primarily implant in the peritoneal cavity, including tubal, ovarian, and intraligamentary pregnancies, and those prior to 20 weeks gestation. RESULTS: The 31 cases identified were at 30.4 +/- 7.4 weeks at diagnosis and 33 +/- 8.3 weeks at delivery. The most common sites of placental implantation were uterus or adnexa (47.8%), bowel (30%), and the potential spaces surrounding the uterus (8.7%). There were 5 cases of an intra-abdominal abscess in the 14 patients in whom the placenta had been left in situ. Maternal outcomes were documented in 26 cases with 7 deaths; 27 fetal outcomes were documented in 22 cases with 3 fetal deaths (13.6%). CONCLUSION: An abdominal ectopic pregnancy is an uncommon but serious event and should be considered in all patients until intrauterine gestation is confirmed. Management should be undertaken by an experienced surgical team in a tertiary care facility. PMID- 25924582 TI - Cationic Titanocene(III) Complexes for Catalysis in Single-Electron Steps. AB - By exploiting solvent and anion effects, [Cp2Ti](+) complexes for atom-economical catalysis in single-electron steps were developed and applied for the first time. These complexes constitute remarkably stable and active catalysts for radical arylations. The reaction kinetics and catalyst composition were studied by cyclic voltammetry and in situ IR spectroscopy. PMID- 25924583 TI - Sleep duration and cancer risk in women. AB - PURPOSE: The objective was to conduct an analysis of sleep duration and risk of selected site-specific and groups of cancer among a large prospective cohort of California women. METHODS: The study population was comprised of 101,609 adult females participating in the California Teachers Study. All sites of invasive cancer prospectively diagnosed from baseline (1995-1996) through 2011 were identified through linkage to the California Cancer Registry (n = 12,322). Site specific analyses focused on the following cancers: breast (n = 5,053), colorectal (n = 983), lung (n = 820), melanoma (n = 749), and endometrial (n = 957). Additionally, we evaluated a group of estrogen-mediated cancers consisting of breast, endometrial, and ovarian cancer (n = 6,458). Sleep duration was based on self-report of average time sleeping in the year prior to baseline. Cox proportional hazard models were used to calculate adjusted hazard ratios and 95 % confidence intervals (HRs, 95 % CI). RESULTS: Point estimates for all sites and site-specific cancers generally were near or below one for short sleepers (<6 h/night) and above one for long sleepers (10+ h/night); confidence intervals, however, were wide and included unity. Compared to average sleepers (7-9 h/night), long sleepers had an increased risk of the group of estrogen-mediated cancers (HR 1.22, 95 % CI 0.97-1.54, p (trend) = 0.04). CONCLUSIONS: These analyses suggest that longer sleep may be associated with increased risks of estrogen-mediated cancers. Further studies with more refined measures of sleep duration and quality are warranted. PMID- 25924584 TI - Even anti-tobacco studies must be held to basic scientific standards. A response to: Smoking intensity and intent to continue smoking among menthol and non menthol adolescent smokers in Canada. PMID- 25924585 TI - Erratum to: Use of the Persuasive Health Message framework in the development of a community-based mammography promotion campaign. PMID- 25924586 TI - Erratum to: Breast and cervical cancers diagnosed and stage at diagnosis among women served through the National Breast and Cervical Cancer Early Detection Program. PMID- 25924587 TI - Erratum to: Provider management of equivocal cervical cancer screening results among underserved women, 2009-2011: follow-up of atypical squamous cells of undetermined significance. PMID- 25924588 TI - Efficacy of Insulin Pump Therapy on Diabetes Treatment Satisfaction and Glycemic Control Among Patients with Type 1 Diabetes Mellitus in Saudi Arabia: A Prospective Study. AB - INTRODUCTION: The aim of this study was to explore the impact of insulin pump therapy on diabetes treatment satisfaction and glycemic control among patients with type 1 diabetes mellitus (T1DM) in Saudi Arabia. METHODS: A 6-month, prospective study was conducted among 47 patients (aged 17-24 years) with T1DM who attended the Insulin Pump Clinic at Prince Sultan Military Medical City, Riyadh, Saudi Arabia, between April 2014 and November 2014. The respondents were purposively and conveniently selected and were interviewed using the Arabic version of the Diabetes Treatment Satisfaction Questionnaire at baseline, 3, and 6 months. Demographics and clinical variables including hemoglobin A1c (HbA1c) were also collected. RESULTS: The mean (+/-standard deviation) age of the study cohort was 19.1 +/- 1.93 years. Seventeen patients were male (36.2%) and 30 were female (63.8%). Compared to baseline, significant positive differences were found in treatment satisfaction among female patients and patients with long-standing T1DM at 6 months. Frequency of hyperglycemia and hypoglycemia declined significantly in female patients at 6 months and in patients who had a shorter duration of T1DM. Furthermore, significant positive differences were found in HbA1c levels among female patients and among those who had a shorter duration of T1DM compared to baseline. Both female and male patients and those with a shorter duration of T1DM showed a significant decline in insulin necessity at 6 months when compared to baseline. CONCLUSION: Although multiple daily injections is a feasible preference for insulin supply, insulin pumps should also be considered for patients with T1DM as it appears to increase patients' treatment satisfaction, decrease the frequency of hypoglycemia, hyperglycemia, and reduce HbA1c levels. PMID- 25924589 TI - Structure-charge relationship - the case of hematite (001). AB - We present a multidisciplinary study on the hematite (001)-aqueous solution interface, in particular the relationship between surface structure (studied via surface diffraction in a humid atmosphere) and the macroscopic charging (studied via surface- and zeta-potential measurements in electrolyte solutions as a function of pH). Upon aging in water changes in the surface structure are observed, that are accompanied by drastic changes in the zeta-potential. Surprisingly the surface potential is not accordingly affected. We interpret our results by increasing hydration of the surface with time and enhanced reactivity of singly-coordinated hydroxyl groups that cause the isoelectric point of the surface to shift to values that are reminiscent of those typically reported for hematite particles. In its initial stages after preparation the hematite surface is very flat and only weakly hydrated. Our model links the entailing weak water structure with the observed low isoelectric point reminiscent of hydrophobic surfaces. The absence of an aging effect on the surface potential vs. pH curves is interpreted as domination of the surface potential by the doubly coordinated hydroxyls, which are present on both surfaces. PMID- 25924590 TI - HMGB1 Enhances the AGE-Induced Expression of CTGF and TGF-beta via RAGE-Dependent Signaling in Renal Tubular Epithelial Cells. AB - BACKGROUND/AIMS: Advanced glycation end products (AGEs) induce epithelial mesenchymal transition (EMT) in renal proximal tubular epithelial cells (PTECs) by promoting the two EMT regulators, transforming growth factor beta (TGF-beta) and connective tissue growth factor (CTGF). However, the exact signaling mechanism remains largely unclear. METHODS: We investigated the promotion to high mobility group box 1 (HMGB1) in renal tubular epithelial HK-2 cells by AGE-BSA with quantitative PCR and western blot assay, and then determined the regulatory role of HMGB1 in the AGE-BSA-induced CTGF and TGF-beta. In addition, the dependence of the receptor of advanced glycation end products (RAGE) was also examined in the CTGF and TGF-beta promotion by AGEs and HMGB1 in HK-2 cells using the RNAi method. RESULTS: It was demonstrated that AGEs induced translocation and release of HMGB1 from tubular epithelial HK-2 cells, and the released HMGB1 enhanced the promotion to CTGF and TGF-beta by AGEs in HK-2 cells. On the other side, the HMGB1 knockdown by siRNA attenuated the AGE-BSA-induced expression of TGF-beta. Moreover, the CTGF and TGF-beta promotion in HK-2 cells by AGEs and HMGB1 was RAGE-dependent. CONCLUSION: Our results indicated that AGEs induced HMGB-1 and promoted the CTGF and TGF-beta in renal epithelial HK-2 cells RAGE dependently. And there was a synergism between AGEs and HMGB1 in the RAGE signaling activation. The in vitro data suggested that the AGE-RAGE and HMGB-1 RAGE signaling might play an important role in the promotion of CTGF and TGF-beta in the renal fibrosis process of diabetic nephropathy. PMID- 25924591 TI - THE APPARENT NON-SIGNIFICANCE OF SEX IN CHILD UNDERNUTRITION IN INDIA. AB - The lack of significance of sex in the determination of child nutrition in India, as revealed from the analysis of data from the entire population, is misleading and perplexing. Given that child nutrition is affected by all channels through which sex bias operates, scholars have sought to explain its inconclusive evidence, looking at child-specific household-level factors such as birth order and sex composition of surviving older siblings. The paper points out that sex inequality needs to be examined in the context of its intersection with other consequential social identities such as religious membership, economic status and caste group affiliation. Sex disparity in child stunting is found to be prevalent particularly among upper caste Hindus. However, the relative advantage that poor tribal girls enjoy is reversed with improvement in wealth status. Thus, children in different social settings need customized policy focus. PMID- 25924592 TI - A store-based intervention to increase fruit and vegetable consumption: The El Valor de Nuestra Salud cluster randomized controlled trial. AB - INTRODUCTION: Most evidence-based interventions to improve fruit and vegetable (FV) consumption target individual behaviors and family systems; however, these changes are difficult to sustain without environmental support. This paper describes an innovative social and structural food store-based intervention to increase availability and accessibility of FVs in tiendas (small- to medium-sized Latino food stores) and purchasing and consumption of FVs among tienda customers. METHODS: Using a cluster randomized controlled trial with 16 tiendas pair-matched and randomized to an intervention or wait-list control condition, this study will evaluate a 2-month intervention directed at tiendas, managers, and employees followed by a 4-month customer-directed food marketing campaign. The intervention involves social (e.g., employee trainings) and structural (e.g., infrastructure) environmental changes. Three hundred sixty-nine customers (approximately 23 per tienda) serve on an evaluation cohort and complete assessments (interviews and measurements of weight) at 3 time points: baseline, 6-months post-baseline, and 12-months post-baseline. The primary study outcome is customer-reported daily consumption of FVs. Manager interviews and monthly tienda audits and collection of sales data will provide evidence of tienda-level intervention effects, our secondary outcomes. Process evaluation methods assess dose delivered, dose received, and fidelity. RESULTS: Recruitment of tiendas, managers, employees, and customers is complete. Demographic data shows that 30% of the customers are males, thus providing a unique opportunity to examine the effects of a tienda based intervention on Latino men. CONCLUSIONS: Determining whether a tienda-based intervention can improve customers' FV purchasing and consumption will provide key evidence for how to create healthier consumer food environments. PMID- 25924593 TI - A coumarin-based fluorescent turn-on probe for detection of biothiols in vitro. AB - A novel fluorescent probe (CA-N) was designed and synthesized for detection of biothiols. CA-N displayed a strong fluorescence in the presence of biothiols with high sensitivity, and the mechanism for detection biothiols was based on the Michael addition reaction of a thiol group to alpha,beta-unsaturated ketones. CA N showed low detection limit for cysteine (Cys), homocysteine (Hcy), and glutathione (GSH), which were calculated as 3.16, 0.19 and 5.15 MUM, respectively. At the same time, CA-N exhibited high selectivity toward biothiols compared with other biological amino acids. In vitro cell experiments proved that CA-N had no cytotoxicity, high cell permeability and could be employed in living cell imaging for biothiols. PMID- 25924594 TI - Drug metabolism by cytochrome p450 enzymes: what distinguishes the pathways leading to substrate hydroxylation over desaturation? AB - Cytochrome P450 enzymes are highly versatile biological catalysts in our body that react with a broad range of substrates. Key functions in the liver include the metabolism of drugs and xenobiotics. One particular metabolic pathway that is poorly understood relates to the P450 activation of aliphatic groups leading to either hydroxylation or desaturation pathways. A DFT and QM/MM study has been carried out on the factors that determine the regioselectivity of aliphatic hydroxylation over desaturation of compounds by P450 isozymes. The calculations establish multistate reactivity patterns, whereby the product distributions differ on each of the spin-state surfaces; hence spin-selective product formation was found. The electronic and thermochemical factors that determine the bifurcation pathways were analysed and a model that predicts the regioselectivity of aliphatic hydroxylation over desaturation pathways was established from valence bond and molecular orbital theories. Thus, the difference in energy of the O?H versus the O?C bond formed and the pi-conjugation energy determines the degree of desaturation products. In addition, environmental effects of the substrate binding pocket that affect the regioselectivities were identified. These studies imply that bioengineering P450 isozymes for desaturation reactions will have to include modifications in the substrate binding pocket to restrict the hydroxylation rebound reaction. PMID- 25924596 TI - The Relationship Between Problem-Solving Ability and Self-Harm Amongst People with Mild Intellectual Disabilities. AB - BACKGROUND: The purpose of this study was to investigate the relationship between depression, hopelessness, problem-solving ability and self-harming behaviours amongst people with mild intellectual disabilities (IDs). METHODS: Thirty-six people with mild IDs (77.9% women, Mage = 31.77, SD = 10.73, MIQ = 62.65, SD = 5.74) who had a history of self-harm were recruited. Participants were asked to complete measures of depression, hopelessness and problem-solving ability. RESULTS: Cutting was most frequently observed, and depression was prevalent amongst the sample. There was a significant positive relationship between depression and hopelessness, while there was no significant relationship between self-harm and depression or hopelessness. Problem-solving ability explained 15% of the variance in self-harm scores. CONCLUSIONS: Problem-solving ability appears to be associated with self-harming behaviours in people with mild IDs. PMID- 25924595 TI - Identification of genes involved in biosynthesis of mannan polysaccharides in Dendrobium officinale by RNA-seq analysis. AB - Dendrobium officinale is a traditional Chinese medicinal plant. The stems of D. officinale contain mannan polysaccharides, which are promising bioactive polysaccharides for use as drugs. However, the genes involved in the biosynthesis of mannan polysaccharides in D. officinale have not yet been identified. In this study, four digital gene expression profiling analyses were performed on developing stems of greenhouse-grown D. officinale to identify such genes. Based on the accumulation of mannose and on gene expression levels, eight CELLULOSE SYNTHASE-LIKE A genes (CSLA), which are highly likely to be related to the biosynthesis of bioactive mannan polysaccharides, were identified from the differentially expressed genes database. In order to further analyze these DoCSLA genes, a full-length cDNA of each was obtained by RACE. The eight genes, belonging to the CSLA family of the CesA superfamily, contain conserved domains of the CesA superfamily. Most of the genes, which were highly expressed in the stems of D. officinale, were related to abiotic stress. Our results suggest that the CSLA family genes from D. officinale are involved in the biosynthesis of bioactive mannan polysaccharides. PMID- 25924597 TI - Outcomes of a Long-term Case Review Program during the On-site Training of Pharmacy Students. AB - This study sought to determine whether a long-term case review (LTCR) program helped pharmacy students develop their abilities as pharmacists, and how their level of satisfaction changed. LTCRs were comprised of four elements: self learning, one-on-one bedside training with advising pharmacists, daily group sessions including three members, and weekly plenary sessions (case conferences). This program conducted on-site training in a hospital for 21 fifth-year students. The students were divided into 7 groups. One member of each group was assigned to a ward for bedside training for three weeks, while other member(s) of the central pharmacy provided support through daily group sessions. Each week, students training in the wards delivered case presentations in the case conference. All students, advising pharmacists, and teachers participated in these weekly case conferences. Upon conclusion of the on-site training, a survey was conducted on the program's efficacy. Through information sharing during group discussions, and in case conferences, continuous patient follow up was possible regardless of students' training schedules in wards or in the central pharmacy. After introducing the LTCR, the mean satisfaction level for case conferences (as scored using a 5-point Likert-type scale) increased from 3.4 to 4.3. Students' levels of understanding also improved. Statistically significant increases in students' self-evaluation scores on professional awareness, presentation skills, and logical thinking were also observed. We concluded that the program helped students to gain practical experience, made them more aware of clinical issues, and improved their presentation skills. Through this program, the students gained clinical competency through a deep understanding of the clinical courses of diseases and patient-oriented pharmaceutical care. PMID- 25924598 TI - Astaxanthin attenuates adriamycin-induced focal segmental glomerulosclerosis. AB - BACKGROUND/AIM: Focal segmental glomerulosclerosis (FSGS) is a specific pattern of chronic renal injury with progressive glomerular scarring. The phenotypic alterations that contribute to FSGS include inflammatory response and oxidative stress. Astaxanthin (ATX) has a broad range of biological functions, particularly antioxidant and anti-inflammatory ones. This study was designed to evaluate the renoprotective effect of ATX treatment on Adriamycin-induced FSGS. METHODS: In Balb/c mice, Adriamycin nephropathy was induced by Adriamycin (10 mg/kg body weight, diluted in normal saline) via a tail vein on day 0. Then the mice were treated with ATX (50 mg/kg body weight) once daily by oral gavage, again starting on the day of Adriamycin injection and continued for 6 weeks. At 6 weeks, the mice were sacrificed; kidneys and blood samples were collected for further analysis. RESULTS: Animals that underwent intermittent exposure to ATX treatment exhibited significant improvements in renal functional parameters as well as in glomerular and interstitial fibrosis compared to those undergoing saline treatment in FSGS mouse models. ATX treatment exerted anti-inflammatory and antioxidant effects by promoting Nrf2 expression and suppressing renal nucleotide binding oligomerization domain-like receptor protein 3 inflammasome activation. CONCLUSION: ATX might offer a ray of hope for ameliorating FSGS. PMID- 25924599 TI - Multitarget Therapeutic Leads for Alzheimer's Disease: Quinolizidinyl Derivatives of Bi- and Tricyclic Systems as Dual Inhibitors of Cholinesterases and beta Amyloid (Abeta) Aggregation. AB - Multitarget therapeutic leads for Alzheimer's disease were designed on the models of compounds capable of maintaining or restoring cell protein homeostasis and of inhibiting beta-amyloid (Abeta) oligomerization. Thirty-seven thioxanthen-9-one, xanthen-9-one, naphto- and anthraquinone derivatives were tested for the direct inhibition of Abeta(1-40) aggregation and for the inhibition of electric eel acetylcholinesterase (eeAChE) and horse serum butyrylcholinesterase (hsBChE). These compounds are characterized by basic side chains, mainly quinolizidinylalkyl moieties, linked to various bi- and tri-cyclic (hetero)aromatic systems. With very few exceptions, these compounds displayed inhibitory activity on both AChE and BChE and on the spontaneous aggregation of beta-amyloid. In most cases, IC50 values were in the low micromolar and sub micromolar range, but some compounds even reached nanomolar potency. The time course of amyloid aggregation in the presence of the most active derivative (IC50 =0.84 MUM) revealed that these compounds might act as destabilizers of mature fibrils rather than mere inhibitors of fibrillization. Many compounds inhibited one or both cholinesterases and Abeta aggregation with similar potency, a fundamental requisite for the possible development of therapeutics exhibiting a multitarget mechanism of action. The described compounds thus represent interesting leads for the development of multitarget AD therapeutics. PMID- 25924600 TI - Evolving role of FNA biopsy in diagnosing lymphoma: past, present, and future. PMID- 25924601 TI - Association of sweet taste receptor gene polymorphisms with dental caries experience in school children. AB - Sweet taste is a powerful factor influencing food acceptance. The peripheral taste response to sugar is mediated by the TAS1R2/TAS1R3 taste receptors. The aim of the study was to determine the relationship between TAS1R2 (rs35874116 or rs9701796) and/or TAS1R3 (rs307355) single nucleotide polymorphisms with dental caries experience in schoolchildren. A total of 184 schoolchildren aged between 7 and 12 years (101 girls, 83 boys) were included in the study. Genomic DNA was extracted from saliva samples and the genotypes were identified by qPCR. The genotype frequencies were as follows: 6.6% for homozygous wild type, 41.8% for heterozygous and 51.6% for homozygous polymorphic genotype carriers of TAS1R2 gene rs35874116; 27.8% for heterozygous and 72.2% for homozygous polymorphic genotype carriers of TAS1R2 gene rs9701796, and 83.1% for homozygous wild type and 16.9% for heterozygous genotype carriers of TAS1R3 gene rs307355 polymorphism. A significant association was observed between total caries experience (dft + DMFT - decayed filled primary teeth + decayed, missing and filled permanent teeth) and TAS1R2 rs35874116 (p = 0.008) and TAS1R3 rs307355 (p = 0.04) gene polymorphisms but not for TAS1R2 gene rs9701796 polymorphism. TAS1R3 gene rs307355 polymorphism has been found to be an independent risk factor for dental caries experience by logistic regression analysis and to have increased the risk of caries. Moderate caries experience (4-7 caries) was found to be associated with TAS1R3 rs307355 heterozygous genotype, whereas high-risk caries experience (>8 caries) was found to be associated with TAS1R2 rs35874116 homozygous polymorphic genotype. PMID- 25924602 TI - Dose-Dense Neoadjuvant Chemotherapy plus Radical Surgery in Locally Advanced Cervical Cancer: A Phase II Study. AB - OBJECTIVE: To assess the efficacy and toxicity profile of dose-dense cisplatin based neoadjuvant chemotherapy (NACT) followed by radical surgery in patients affected by locally advanced cervical cancer. METHODS: Patients affected by carcinoma of the uterine cervix FIGO (International Federation of Obstetrics and Gynecology) stage IB2-IIIB were enrolled into the study. The treatment schedule consisted of 5 cycles of intravenous paclitaxel 60 mg/m(2) plus cisplatin 60 mg/m(2) every 10 days; patients were then submitted to radical hysterectomy and pelvic lymphadenectomy. RESULTS: From January 2011 to March 2013, 22 patients were enrolled. Median age was 47 (26-83) years. FIGO stages included 1 IIA, 15 IIB, 1 IIIA, and 5 IIIB. Ninety-one percent of patients completed all the 5 planned cycles of NACT. Three patients experienced allergic reactions to paclitaxel. Grade 3-4 hematological toxicity was observed in 18% of cases. In 3 cases, grade 3-4 extra-hematological adverse and life-threatening events were reported (1 ototoxicity, 1 transient ischemic attack, and 1 myocardial infarction). No treatment-related death occurred. The operability rate was 86.4%. The overall response rate was 52.6%: 5 patients (26.3%) experienced clinical complete response, and 5 (26.3%) showed a clinical partial response. Stable disease was observed in 47.4% of patients, with no progressive disease recorded. Pathological response was observed in 57.9% of cases. Six out of 19 (31.6%) patients were submitted to adjuvant treatment. CONCLUSION: Dose-dense cisplatin based NACT showed a response rate in approximately half of patients. However, in consideration of the reported extra-hematological toxicity, further studies on and new strategies with dose-dense platinum-based NACT are required to improve outcome in cervical cancer patients. PMID- 25924603 TI - Backbone assignment of the three dimers of HU from Escherichia coli at 293 K: EcHUalpha2, EcHUbeta2 and EcHUalphabeta. AB - HU is one of the major nucleoid-associated proteins involved in bacterial chromosome structure and in all DNA-dependent cellular activities. Similarly to eukaryotic histones, this small dimeric basic protein wraps DNA in a non-sequence specific manner, promoting DNA super-structures. In most bacteria, HU is a homodimeric protein encoded by a single gene. However, in enterobacteria such as Escherichia coli, the presence of two genes coding for two peptidic chains, HUalpha and HUbeta, lead to the coexistence of three forms: two homodimers EcHUalpha2 and EcHUbeta2, as well as a heterodimer EcHUalphabeta. Genetic and biochemical investigation suggest that each EcHU dimer plays a specific physiological role in bacteria. Their relative abundance depends on the environmental conditions and is driven by an essential, yet unknown, fast outstanding chain-exchange mechanism at physiological temperature. Our goal is to understand this fundamental mechanism from a structural and kinetics standpoint using NMR. For this purpose, the first steps are the assignment of each dimer in their native and intermediate states. Here, we report the backbone assignment of each HU dimers from E. coli at 293 K in their native state. PMID- 25924604 TI - An estrogen-associated dietary pattern and breast cancer risk in the Swedish Mammography Cohort. AB - High endogenous hormone levels have been associated with breast cancer and dietary factors have the potential to influence breast cancer risk through effects on hormone levels. Dietary patterns derived from reduced rank regression provide a way to identify food groups correlated with hormones and subsequently examine food patterns that may be associated with breast cancer risk. We investigated whether a dietary pattern previously correlated with estradiol and estrone sulfate was associated with breast cancer in the prospective Swedish Mammography Cohort. Among 37,004 primarily postmenopausal women diet was assessed with a food frequency questionnaire. Cox proportional hazard models were used to calculate hazard ratios (HRs) and 95% confidence intervals (95% CIs). During 15 years of follow-up 1,603 cases of breast cancer were identified. A higher estrogen dietary pattern score was associated with an increased risk of breast cancer. Women in the highest quartile of estrogen pattern score had a 29% (95% CI = 1.08-1.55) increased risk of breast cancer compared to women in the lowest quartile (p(trend) = 0.006). When the association was examined by estrogen receptor status, it was only significant for those with estrogen-receptor positive tumors; however, in the competing risk analysis there were no significant differences in the effect estimates by receptor subtype (p(heterogeneity) = 0.65). Our findings suggest that a dietary pattern associated with higher estrogen levels may increase breast cancer risk. However, whether the influence of this dietary pattern is through a direct effect on estrogen levels deserves further study. PMID- 25924605 TI - Anatomical features of skull base and oral cavity: a pilot study to determine the accessibility of the sella by transoral robotic-assisted surgery. AB - The role of transoral robotic surgery (TORS) in the skull base emerges and represents the natural progression toward miniinvasive resections in confined spaces. The accessibility of the sella via TORS has been recently described on fresh human cadavers. An anatomic study is mandatory to know if this approach would be feasible in the majority of patients regardless of their oral morphological features. From 30 skull base CT scans from patients who were asked to open their mouth as wide as they can, we measured specific dimensions of the oral cavity and the skull base, such as length of the palate, mouth opening and distance from the sella to the palate. All data were acquired on a sagittal midline plane and on a 25 degrees rotation plane, which simulated the axis of the robotic instruments. Looking at the projection of the dental palatine line on the sella, we studied possible predictive factors of sellar accessibility and tried to bring objective data for surgical feasibility. We also proposed an angle alpha to study the working angle at the skull base. We observed that the maximal mouth opening was a good predictive factor of sellar accessibility by TORS (p < 0.05). The mouth aperture threshold value for a good sensitivity, over 80 %, was comparable to the mean value of mouth opening in our series, 38.9 and 39.4 mm respectively. Moreover, we showed a statistically significant increase of the working angle alpha at the skull base comparing the lateral access to the midline one (p < 0.05). This seemed to quantitatively demonstrate that the robotic arms placed at the labial commissure of the mouth can reach the sella. From these anatomical features and previous cadaveric dissections, we assume that TORS may be feasible on a majority of patients to remove pituitary adenomas. PMID- 25924606 TI - A priority health index identifies the top six priority risk and related factors for non-communicable diseases in Brazilian cities. AB - BACKGROUND: In Brazil, 72% of all deaths in 2007 were attributable to non communicable diseases (NCD). We used a risk and related factor based index to prioritize NCD prevention programs in the combined 26 capital cities and the federal district (i.e., Brasilia) of Brazil. METHODS: We used 2006-2011 data (adults) from census and Brazil's surveillance of 12 NCD risk factors and 74 disease group mortality. The risk and related factors were: smoking, physical inactivity, overweight-obesity, low fruits and vegetables intake, binge drinking, insufficient Pap smear screening (women aged 25 to 59 years), insufficient mammography screening (women aged 50 to 69 years), insufficient blood pressure screening, insufficient blood glucose screening, diagnosis of hypercholesterolemia, diagnosis of hypertension and diagnosis of diabetes. We generated six indicators: intervention reduction of the risk factor prevalence, intervention cost per person, prevalence of risk factor, deaths attributable to risk factor, risk factor prevalence trend and ratio of risk factor prevalence between people with and without a high school education. We transformed risk and related factor indicators into priority scores to compute a priority health index (PHI). We implemented sensitivity analysis of PHI by computing it with slightly altered formulas and altering values of indicators under the assumption of bias in their estimation. We ranked risk factors based on PHI values. RESULTS: We found one intermediate (i.e., overweight-obesity) and six top risk and related factors priorities for NCD prevention in Brazil's large urban areas: diagnosed hypertension, physical inactivity, blood pressure screening, diagnosed hypercholesterolemia, smoking and binge drinking. CONCLUSION: Brazil has already prioritized the six top priorities (i.e., hypertension, physical inactivity, blood pressure screening, hypercholesterolemia, smoking and binge drinking) and one intermediate priority (i.e., overweight-obesity) for NCD prevention identified in this report. Because effective interventions to reduce disease burden associated with each of the six priority risk factors are available, strategies based on these interventions need to be sustained in order to reduce NCD burden in Brazil. PHI can be used to track NCD prevention and health promotion actions at the local and national level in Brazil and in countries with similar public health surveillance systems. PMID- 25924607 TI - Tribological changes in the articular cartilage of a human femoral head with avascular necrosis. AB - The present study evaluated the tribological properties of the articular cartilage surface of the human femoral head with postcollapse stage avascular necrosis (AVN) using atomic force microscopy. The cartilage surface in the postcollapse stage AVN of the femoral head was reported to resemble those of disuse conditions, which suggests that the damage could be reversible and offers the possibilities of success of head-sparing surgeries. By comparing the tribological properties of articular cartilage in AVN with that of osteoarthritis, the authors intended to understand the cartilage degeneration mechanism and reversibility of AVN. Human femoral heads with AVN were explanted from the hip replacement surgery of four patients (60-83 years old). Nine cylindrical cartilage samples (diameter, 5 mm and height, 0.5 mm) were sectioned from the weight-bearing areas of the femoral head with AVN, and the cartilage surface was classified according to the Outerbridge Classification System (AVN0, normal; AVN1, softening and swelling; and AVN2, partial thickness defect and fissuring). Tribological properties including surface roughness and frictional coefficients and histochemistry including Safranin O and lubricin staining were compared among the three groups. The mean surface roughness Rq values of AVN cartilage increased significantly with increasing Outerbridge stages: Rq = 137 +/ 26 nm in AVN0, Rq = 274 +/- 49 nm in AVN1, and Rq = 452 +/- 77 nm in AVN2. Significant differences in Rq were observed among different Outerbridge stages in all cases (p < 0.0001). The frictional coefficients (MU) also increased with increasing Outerbridge stages. The frictional coefficient values were MU = 0.115 +/- 0.034 in AVN0, MU = 0.143 +/- 0.025 in AVN1, and MU = 0.171 +/- 0.039 in AVN2. Similarly to the statistical analysis of surface roughness, significant statistical differences were detected between different Outerbridge stages in all cases (p < 0.05). Both surface roughness and frictional coefficient of cartilage, which were linearly correlated, increased with increasing Outerbridge stages in postcollapse AVN. The underlying mechanism of these results can be related to proteoglycan loss within the articular cartilage that is also observed in osteoarthritis. With regard to the tribological properties, the cartilage degeneration mechanism in AVN was similar to that of osteoarthritis without reversibility. PMID- 25924608 TI - Clinical characteristics and beta cell function in Chinese patients with newly diagnosed type 2 diabetes mellitus with different levels of serum triglyceride. AB - BACKGROUND: To explore clinical characteristics and beta cell function in Chinese patients with newly diagnosed drug naive type 2 diabetes mellitus (T2DM) with different levels of serum triglyceride (TG). METHODS: Patients with newly diagnosed T2DM (n = 624) were enrolled and divided into different groups according to levels of serum TG. All patients underwent oral glucose tolerance tests and insulin releasing tests. Demographic data, lipid profiles, glucose levels, and insulin profiles were compared between different groups. Basic insulin secretion function index (homeostasis model assessment for beta cell function index, HOMA-beta), modified beta cell function index (MBCI), glucose disposition indices (DI), and early insulin secretion function index (insulinogenic index, IGI) were used to evaluate the beta cell function. RESULTS: Patients of newly diagnosed T2DM with hypertriglyceridemia were younger, fatter and had worse lipid profiles, glucose profiles, and high insulin levels than those with normal TG. There is no difference in early phase insulin secretion among groups of newly diagnosed T2DM patients with different TG levels. The basal beta cell function (HOMA-beta and MBCI) initially increased along rising TG levels and then decreased as the TG levels rose further. The insulin sensitivity was relatively high in patients with a low level of TG and low with a high level of TG. CONCLUSIONS: Hypertriglyceridemia influences clinical characteristics and beta cell function of Chinese patients with newly diagnosed T2DM. A better management of dyslipidemia may, to some extent, reduce the effect of lipotoxicity, thereby improving glucose homeostasis in patients with newly diagnosed T2DM. PMID- 25924609 TI - Cloning-free CRISPR/Cas system facilitates functional cassette knock-in in mice. AB - Although the CRISPR/Cas system has enabled one-step generation of knockout mice, low success rates of cassette knock-in limit its application range. Here we show that cloning-free, direct nuclear delivery of Cas9 protein complex with chemically synthesized dual RNAs enables highly efficient target digestion, leading to generation of knock-in mice carrying a functional cassette with up to 50% efficiency, compared with just 10% by a commonly used method consisting of Cas9 mRNA and single guide RNA. Our cloning-free CRISPR/Cas system facilitates rapid one-step generation of cassette knock-in mice, accelerating functional genomic research by providing various in vivo genetic tools. PMID- 25924610 TI - Transcriptional profiling of PRKG2-null growth plate identifies putative down stream targets of PRKG2. AB - BACKGROUND: Kinase activity of cGMP-dependent, type II, protein kinase (PRKG2) is required for the proliferative to hypertrophic transition of growth plate chondrocytes during endochondral ossification. Loss of PRKG2 function in rodent and bovine models results in dwarfism. The objective of this study was to identify pathways regulated or impacted by PRKG2 loss of function that may be responsible for disproportionate dwarfism at the molecular level. METHODS: Microarray technology was used to compare growth plate cartilage gene expression in dwarf versus unaffected Angus cattle to identify putative downstream targets of PRGK2. RESULTS: Pathway enrichment of 1284 transcripts (nominal p < 0.05) was used to identify candidate pathways consistent with the molecular phenotype of disproportionate dwarfism. Analysis with the DAVID pathway suite identified differentially expressed genes that clustered in the MHC, cytochrome B, WNT, and Muc1 pathways. A second analysis with pathway studio software identified differentially expressed genes in a host of pathways (e.g. CREB1, P21, CTNNB1, EGFR, EP300, JUN, P53, RHOA, and SRC). As a proof of concept, we validated the differential expression of five genes regulated by P53, including CEBPA, BRCA1, BUB1, CD58, and VDR by real-time PCR (p < 0.05). CONCLUSIONS: Known and novel targets of PRKG2 were identified as enriched pathways in this study. This study indicates that loss of PRKG2 function results in differential expression of P53 regulated genes as well as additional pathways consistent with increased proliferation and apoptosis in the growth plate due to achondroplastic dwarfism. PMID- 25924611 TI - The most used and most helpful facilitators for patient-centered medical home implementation. AB - BACKGROUND: Like other transformative healthcare initiatives, patient-centered medical home (PCMH) implementation requires substantial investments of time and resources. Even though PCMH and PCMH-like models are being implemented by multiple provider practices and health systems, little is known about what facilitates their implementation. The purpose of this study was to assess which PCMH-implementation resources are most widely used, by whom, and which resources primary care personnel find most helpful. METHODS: This study is an analysis of data from a cross-sectional survey of primary care personnel in the Veterans Health Administration in 2012, in which respondents were asked to rate whether they were aware of and accessed PCMH-implementation resources, and to rate their helpfulness. Logistic regression was used to produce odds ratios for the outcomes (1) resource use and (2) resource helpfulness. Respondents were nested within clinics, nested, in turn, within 135 parent hospitals. RESULTS: Teamlet huddles were the most widely accessed (80.4% accessed) and most helpful (90.4% rated helpful) resource; quality-improvement methods to conduct small tests of change were the least frequently accessed (42.4% accessed) resource though two-thirds (66.7%) of users reported as helpful. Supervisors were significantly more likely (ORs, 1.46 to 1.86) to use resources than non-supervisors but were less likely to rate the majority (8 out of 10) of resources as "somewhat/very helpful" than non supervisors (ORs, 0.72 to 0.84). Longer-tenured employees tended to rate resources as more helpful. CONCLUSIONS: These findings are the first in the PCMH literature that we are aware of that systematically assesses primary care staff's access to and the helpfulness of PCMH implementation resources. Supervisors generally reported greater access to resources, relative to non-supervisors, but rated resources as less helpful, suggesting that information about them may not have been optimally disseminated. Knowing what resources primary care staff use and find helpful can inform administrators' and policymakers' investments in PCMH implementation resources. The implications of our model extend beyond just PCMH implementation but also to considerations when providing implementation resources for other complex quality-improvement initiatives. PMID- 25924612 TI - Sigma-1 receptor directly interacts with Rac1-GTPase in the brain mitochondria. AB - BACKGROUND: Small Rho-GTPases are critical mediators of neuronal plasticity and are involved in the pathogenesis of several psychiatric and neurological disorders. Rac-GTPase forms a multiprotein complex with upstream and downstream regulators that are essential for the spatiotemporal transmission of Rac signaling. The sigma-1 receptor (Sig1R) is a ligand-regulated membrane protein chaperone, and multiprotein complex assembly is essential to sigma-receptor function. RESULTS: Using immunoprecipitation techniques, we have shown that in mitochondrial membranes Sig1R could directly interact with Rac1. Besides Rac1, the Sig1R forms complexes with inositol 1,4,5-trisphosphate receptor and Bcl2, suggesting that mitochondrial associated membranes (MAM) are involved in this macromolecular complex formation. Assembly of this complex is ligand-specific and depends on the presence of sigma agonist/antagonist, as well as on the presence of GTP/GDP. Treatment of mitochondrial membranes with (+)-pentazocine leads to the (+)-pentazocine-sensitive phosphorylation of Bad and the pentazocine sensitive NADPH-dependent production of ROS. CONCLUSION: We suggest that Sig1R through Rac1 signaling induces mild oxidative stress that possibly is involved in the regulation of neuroplasticity, as well as in the prevention of apoptosis and autophagy. PMID- 25924613 TI - Comparison of amyloid deposition in human kidney biopsies as predictor of poor patient outcome. AB - BACKGROUND: Amyloidosis leads to deposition of abnormal protein with beta-pleated sheet structure in specific compartments of the affected organs. The histological localization of these amyloid deposits determines the overall survival of the patient. METHODS: In this study we have assessed the histological localization and severity of amyloid deposition in 35 patients with biopsy-proven renal amyloidosis and have compared those to clinical parameters, histo-pathological injury criteria and respective patient outcome. Comparisons were statistically analyzed using thus comparison between the different study groups, which was done using Student t-test and analysis of variance. RESULTS: We find that the glomerulus is by far the most commonly and most severely affected renal compartment and patients with severe glomerular amyloidosis advance faster towards end stage renal disease (ESRD) and death, compared to those patients without glomerular amyloid deposits. Patients with severe glomerular amyloidosis showed higher serum creatinine and urine protein levels, while patients with severe vascular amyloidosis showed higher levels of interstitial inflammatory infiltrate. CONCLUSION: In kidneys affected by amyloidosis, the amyloid proteins are predominantly deposited along vessels, especially the small vessels including glomerular capillary loops. The severity of glomerular amyloid deposition enhances the risk of developing ESRD and increases the risk for premature death. PMID- 25924614 TI - Distribution of glutamate receptors in the posterodorsal medial amygdala of adult male rats. AB - The rat posterodorsal medial amygdala (MePD) has a remarkable neuronal plasticity and responds to olfactory/pheromonal stimuli to modulate emotional and reproductive behaviors. Glutamate is locally released by incoming sensorial pathways to establish and enforce synaptic inputs. Here, we combined DiI dye and immunolabeling procedure under confocal microscopy to describe the presence and distribution of glutamate receptors on neurons of the MePD of adult male rats. Western blot analysis interrogated binding specificity. Both AMPA (GluA1-4 subunits) and NMDA (GluN1 subunit) receptors were immunolabeled on cell bodies and along proximal and distal dendritic shafts. AMPA receptors were mainly observed on mushroom and stubby/wide spines, whereas NMDA receptors were found on thin spines. Colocalization of AMPA and NMDA receptors occurred in some spines. Filopodium did not show immunolabeled puncta on it. Our results are different from the distribution of glutamate receptors in the amygdaloid lateral nucleus, an upstream area involved with emotional processing, and suggest a region specific excitatory transmission at proximal and distal dendritic branches. Altogether, these data provide new information for synaptic processing in the MePD likely related to the modulation of social behavior in rats. PMID- 25924615 TI - Can Anyone Hear Me? Does Anyone See Me? A Qualitative Meta-Analysis of Women's Experiences of Heart Disease. AB - Female heart patients are underdiagnosed and undertreated. The purpose of this qualitative meta-data-analysis was to explain how societal expectations related to gender and the treatment environment influence women's experiences and can inform optimal care. The authors used grounded theory methodology and a social constructionist gender lens to analyze 43 studies (1993-2012) of women's experiences of heart disease. The analysis illustrates how social expectations within both medical and relational contexts led to women experiencing barriers to diagnosis and treatment and inadvertent minimization of their experience and knowledge. Women's descriptions of their experiences suggest three kinds of health care strategies that have the potential to increase women's engagement with heart disease treatment and rehabilitation: (a) support give and take in relational connections, (b) identify and acknowledge unique health-promoting behavior, and (c) focus on empowerment. These findings have interdisciplinary implications for practice with women with heart disease. PMID- 25924617 TI - Junior doctor dementia champions in a district general hospital (innovative practice). AB - Dementia is a common condition in the UK with around 25% of patients in acute hospitals having dementia. In the UK, there is national guidance on the assessment of cognitive impairment in acute hospitals. This article is a qualitative study of junior doctors' experiences as part of a dementia and delirium team involved in changing the care of patients with dementia in a hospital in the UK. It draws on data from a focus group and follow-up questionnaire in two hospital trusts. We examine what drives doctors to become involved in such projects and the effects of this experience upon them. We suggest a typology for getting junior doctors involved in projects generating change when working with patients with dementia. Being more actively involved in caring for and developing services for patients with dementia may represent the crossing of an educational threshold for these junior doctors. PMID- 25924616 TI - ATP-Binding Cassette Transporter Structure Changes Detected by Intramolecular Fluorescence Energy Transfer for High-Throughput Screening. AB - Multidrug resistance protein 1 (MRP1) actively transports a wide variety of drugs out of cells. To quantify MRP1 structural dynamics, we engineered a "two-color MRP1" construct by fusing green fluorescent protein (GFP) and TagRFP to MRP1 nucleotide-binding domains NBD1 and NBD2, respectively. The recombinant MRP1 protein expressed and trafficked normally to the plasma membrane. Two-color MRP1 transport activity was normal, as shown by vesicular transport of [(3)H]17beta estradiol-17-beta-(D-glucuronide) and doxorubicin efflux in AAV-293 cells. We quantified fluorescence resonance energy transfer (FRET) from GFP to TagRFP as an index of NBD conformational changes. Our results show that ATP binding induces a large-amplitude conformational change that brings the NBDs into closer proximity. FRET was further increased by substrate in the presence of ATP but not by substrate alone. The data suggest that substrate binding is required to achieve a fully closed and compact structure. ATP analogs bind MRP1 with reduced apparent affinity, inducing a partially closed conformation. The results demonstrate the utility of the two-color MRP1 construct for investigating ATP-binding cassette transporter structural dynamics, and it holds great promise for high-throughput screening of chemical libraries for unknown activators, inhibitors, or transportable substrates of MRP1. PMID- 25924618 TI - Leading academics condemn government undermining of NICE. PMID- 25924619 TI - Acoustic Liquid Handling for Rapid siRNA Transfection Optimization. AB - Gene knockdown by small interfering RNA (siRNA) has been used extensively to investigate the function of genes in targeted and genome-wide studies. One of the primary challenges of siRNA studies of any scale is to achieve sufficient gene knockdown to produce the biological changes that lead to measurable phenotypes. Reverse, lipid-based transfection efficiency minimally requires the optimization of the following parameters: cell number, knockdown duration, siRNA oligonucleotide concentration, type/brand of transfection lipid, and transfection lipid concentration. In this study, we describe a methodology to utilize the flexibility and low-volume range of the Echo acoustic liquid handler to rapidly screen a matrix of transfection conditions. The matrix includes six different transfection lipids from three separate vendors across a broad range of concentrations. Our results validate acoustic liquid transfer for the delivery of siRNAs and transfection reagents. Finally, this methodology is applied to rapidly optimize transfection conditions across many tissue culture cell lines derived from various originating tissues. PMID- 25924620 TI - Oral agents in multiple sclerosis. AB - Multiple sclerosis (MS) is a complex autoimmune disease of the central nervous system. Disease-modifying drugs licensed for MS treatment have been developed to reduce relapse rates and halt disease progression. The majority of current MS drugs involve regular, parenteral administration, affecting long-term adherence and thus reducing treatment efficacy. Over the last two decades great progress has been made towards developing new MS therapies with different modes of action and biologic effects. In particular, oral drugs have generated much interest because of their convenience and positive impact on medication adherence. Fingolimod was the first launched oral treatment for relapsing-remitting MS; recently, Teriflunomide and Dimethyl fumarate have also been approved as oral disease-modifying agents. In this review, we summarize and discuss the history, pharmacodynamics, efficacy, and safety of oral agents that have been approved or are under development for the selective treatment of MS. PMID- 25924621 TI - Induction of cardioprotection by small netrin-1-derived peptides. AB - We have shown that netrin-1 induces potent cardioprotection via extracellular signal-regulated kinases 1 and 2 (ERK1/2)-dependent endothelial nitric oxide synthase (eNOS)/NO activation. The present study investigated cardioprotective effects of small netrin-1-derived peptides. We synthesized three laminin (Lam) V peptides and found those time dependently increased phosphorylation of ERK1/2 and eNOSs1179 in endothelial cells at the same molar concentration used for netrin-1. Preperfusion with Lam V peptides induced a substantial reduction in infarct size (control 39.3 +/- 0.2% vs. 14.6 +/- 2.3%, 23.0 +/- 2.8%, and 18.8 +/- 0.8% for V1, V2, and V3, respectively). Furthermore, reperfusion with all three also induced potent cardioprotection (control 37.6 +/- 1.3% vs. 17.6 +/- 3.2%, 20.6 +/ 1.7%, and 15.8 +/- 2.0% for V1, V2, and V3, respectively), implicating that these peptides are consistently beneficial whenever they are delivered to the heart. Based on the sequence alignment, we found a region of high sequence homology and synthesized smaller peptides [V1-9 amino acid (aa), V2-10aa, and V3 11aa]. These smaller peptides markedly reduced infarct size during reperfusion (V1-9aa 16.8 +/- 2.2%, V2-10aa 18.6 +/- 1.7%, and V3-11aa 16.7 +/- 3.0% vs. control 37.6 +/- 1.3%). A negative control V3-16aa with no sequence homology failed to protect the heart. Of note, the core area has the characteristic sequence of: Cx(1-2)Cx(3-4)Tx(0-1)G. Furthermore, all three smaller peptides induced NO production in endothelial cells that could in turn diffuse to cardiomyocytes to promote survival. Combined applications of V1-9aa and V2-10aa synergistically induced more NO production. Taken together, these data strongly suggest that small netrin-1-derived peptides are highly effective in protecting the heart against myocardial ischemia-reperfusion injury and has the potential to be developed into peptide drugs directly applicable to the treatment of myocardial infarction. PMID- 25924623 TI - Is Immediate Radical Cystectomy Necessary for All Patients with Non-Muscle Invasive Micropapillary Bladder Cancer? AB - INTRODUCTION: We aim to review the outcomes of micropapillary urothelial carcinoma (MPUC) of the bladder from a single institution. The hypothesis is that non-muscle-invasive (NMI) MPUC may have a heterogeneous prognosis, and detailed pathological analysis may identify patients that could be managed without immediate cystectomy. PATIENTS AND METHODS: This is a retrospective analysis of patients presenting with MPUC in a primary transurethral resection specimen (n = 40). The pattern of micropapillary (MP) differentiation [surface/non-invasive (sMP) or invasive (iMP)], extent of MP differentiation and lymphovascular invasion (LVI) were correlated with overall survival (OS), recurrence-free survival and upstaging at re-resection. RESULTS: Sixteen of 40 patients died after a median follow-up of 37 months. Tumour stage was strongly predictive of OS (p < 0.0001). LVI was associated with increased mortality (hazard ratio 12.4, 95% CI: 3.5-44.5, p = 0.0001), higher pathological stage (p = 0.001), lymph node involvement (p = 0.001) and iMP differentiation (p = 0.006). In NMI patients not undergoing cystectomy (n = 17), NMI-sMP compared with NMI-iMP differentiation was associated with an improved OS when compared with iMP (63 vs. 47 months, p = 0.05). CONCLUSIONS: MPUC is an aggressive variant of urothelial carcinoma (UC). Similar to conventional UC, LVI associated with MPUC is an adverse prognostic indicator. iMP is a morphological marker for LVI. Histopathological reports should distinguish between sMP and iMP differentiation. PMID- 25924622 TI - Exon 4-encoded sequence is a major determinant of cytotoxicity of apolipoprotein L1. AB - The apolipoprotein L1 (APOL1) gene (APOL1) product is toxic to kidney cells, and its G1 and G2 alleles are strongly associated with increased risk for kidney disease progression in African Americans. Variable penetrance of the G1 and G2 risk alleles highlights the significance of additional factors that trigger or modify the progression of disease. In this regard, the effect of alternative splicing in the absence or presence of G1 or G2 alleles is unknown. In this study we investigated whether alternative splicing of non-G1, non-G2 APOL1 (APOL1 G0) affects its biological activity. Among seven APOL1 exons, exons 2 and 4 are differentially expressed in major transcripts. We found that, in contrast to APOL1 splice variants B3 or C, variants A and B1 demonstrate strong toxicity in human embryonic kidney (HEK293T) cells. Subsequently, we established that exon 4 is a major determinant of toxicity of variants A and B1 and that extracellular release of these variants is dispensable for their cytotoxicity. Although only variants A and B1 induced nuclear translocation of transcription factor EB (TFEB), a master regulator of lysosomal biogenesis and autophagy, exon 4-positive and -negative APOL1 variants stimulated perinuclear accumulation of unprocessed autophagosomes. Knockdown of endogenous TFEB did not attenuate APOL1 cytotoxicity, indicating that nuclear translocation of TFEB is dispensable for APOL1 toxicity. Our findings that a human podocyte cell line expresses exon 4 positive and -negative APOL1 transcripts suggest that these variants may play a differential role in podocyte pathology. In summary, we have identified exon 4 as a major determinant of APOL1 G0 cytotoxicity. PMID- 25924624 TI - Cyclic mechanical stretching induces autophagic cell death in tenofibroblasts through activation of prostaglandin E2 production. AB - BACKGROUND/AIMS: Autophagic cell death has recently been implicated in the pathophysiology of tendinopathy. Prostaglandin E2 (PGE2), a known inflammatory mediator of tendinitis, inhibits tenofibroblast proliferation in vitro; however, the underlying mechanism is unclear. The present study investigated the relationship between PGE2 production and autophagic cell death in mechanically loaded human patellar tendon fibroblasts (HPTFs) in vitro. METHODS: Cultured HPTFs were subjected to exogenous PGE2 treatment or repetitive cyclic mechanical stretching. Cell death was determined by flow cytometry with acridine orange/ethidium bromide staining. Induction of autophagy was assessed by autophagy markers including the formation of autophagosomes and autolysosomes (by electron microscopy, AO staining, and formation of GPF-LC3-labeled vacuoles) and the expression of LC3-II and BECN1 (by western blot). Stretching-induced PGE2 release was determined by ELISA. RESULTS: Exogenous PGE2 significantly induced cell death and autophagy in HPTFs in a dose-dependent manner. Blocking autophagy using inhibitors 3-methyladenine and chloroquine, or small interfering RNAs against autophagy genes Becn-1 and Atg-5 prevented PGE2-induced cell death. Cyclic mechanical stretching at 8% and 12% magnitudes for 24 h significantly stimulated PGE2 release by HPTFs in a magnitude-dependent manner. In addition, mechanical stretching induced autophagy and cell death. Blocking PGE2 production using COX inhibitors indomethacin and celecoxib significantly reduced stretching induced autophagy and cell death. CONCLUSION: Taken together, cyclic mechanical stretching induces autophagic cell death in tenofibroblasts through activation of PGE2 production. PMID- 25924625 TI - Is the Duration of Dual Antiplatelet Therapy after Implantation of Drug-Eluting Stents the Longer the Better? PMID- 25924626 TI - A Novel Multipeptide Microarray for the Specific and Sensitive Mapping of Linear IgE-Binding Epitopes of Food Allergens. AB - BACKGROUND: The identification of B-cell epitopes of food allergens can possibly lead to novel diagnostic tools and therapeutic reagents for food allergy. We sought to develop a flexible, low-tech, cost-effective and reproducible multipeptide microarray for the research environment to enable large-scale screening of IgE epitopes of food allergens. METHODS: Overlapping peptides (15 mer, 4 amino acid offset) covering the primary sequence of either peanut allergen Ara h 1 or all 3 subunits of the soybean allergen Gly m 5 were simultaneously synthesized in-house on a porous cellulose matrix. Identical peptide microarrays created with up to 384 duplicate peptide-cellulose microspots each were investigated for specificity and sensitivity in IgE immunodetection and in direct experimental comparison to the formerly established SPOTTM membrane technique. RESULTS: The in-house microarray identified with 98% reproducibility the same IgE binding peptides as the SPOTTM membrane technique. Additional IgE-binding peptides were identified using the microarray. While the sensitivity was increased between 2- and 20-fold, the amount of human serum required was reduced by at least two thirds over the SPOTTM membrane technique using the microarray. After subtraction of the potential background, we did not observe non-specific binding to the presented peptides on microarray. CONCLUSIONS: The novel peptide microarray allows simple and cost-effective screening for potential epitopes of large allergenic legume seed storage proteins, and it could be adapted for other food allergens as well, to study allergenic epitopes at the individual subject level in large paediatric and adult study groups of food allergic subjects. PMID- 25924627 TI - Neuromagnetic cortical activation during initiation of optokinetic nystagmus: an MEG pilot study. AB - PURPOSE: To investigate the spatiotemporal evolution of cortical activation during the initiation of optokinetic nystagmus using magnetoencephalography. BACKGROUND: Previous imaging studies of optokinetic nystagmus in humans using positron emission tomography and functional magnetic resonance imaging discovered activation of a large set of cortical and subcortical structures during steady state optokinetic stimulation, but did not provide information on the temporal dynamics of the initial response. Imaging studies have shown that cortical areas responsible for vision in occipital and temporo-occipital areas are involved, i.e. cortical areas control optokinetic stimulation in humans. Magnetoencephalography provides measures that reflect neural ensemble activity in the millisecond time scale, allowing the identification of early cortical components of visuomotor integration. DESIGN/METHODS: We studied neuromagnetic cortical responses during the initiation of optokinetic nystagmus in 6 right handed healthy subjects. Neuromagnetic activity was recorded with a whole-head magnetoencephalograph, consisting of 143 planar gradiometers. RESULTS: The mean (+/-SD) latency between stimulus onset and initiation of optokinetic nystagmus was 177.7 +/- 59 ms. Initiation of optokinetic nystagmus evoked an early component in the primary visual cortex starting at 40-90 ms prior to the onset of the slow phase of nystagmus. Almost simultaneously an overlapping second component occurred bilaterally in the temporo-occipital area (visual motion areas), pronounced in the right hemisphere, starting at 10-60 ms prior to the slow-phase onset. Both components showed long-duration activity lasting for up to 100 ms after slow-phase onset. CONCLUSIONS: Our findings suggest that the initiation of optokinetic nystagmus induces early cortical activation in the occipital cortex and almost simultaneously bilaterally in the temporo-occipital cortex. These cortical regions might represent essential areas for the monitoring of retinal slip. PMID- 25924628 TI - Prevalence and factors associated with isolation of Aspergillus and Candida from sputum in patients with non-cystic fibrosis bronchiectasis. AB - BACKGROUND: Information on the role of fungi in non-cystic fibrosis (CF) bronchiectasis is lacking. OBJECTIVES: Our aim was to determine the prevalence of and factors associated with the isolation and persistence of fungi from sputum in these patients. METHODS: We performed a multicenter observational study comprising adult patients with non-CF bronchiectasis. Persistence of Aspergillus spp. and Candida albicans was defined as the presence of >=2 positive sputum cultures taken at least 6 months apart within a period of 5 years. RESULTS: A total of 252 patients (62.7% women with a mean +/- SD age of 55.3 +/- 16.7 years) were included in the study. All patients had at least 1 sputum sample cultured for fungi, with a mean +/- SD of 7 +/- 6 cultures per patient. Eighteen (8.7%) and 71 (34.5%) patients had persistent positive cultures for Aspergillus spp. and C. albicans, respectively. Patients with persistence of Aspergillus spp. and C. albicans were older and had more daily purulent sputum. In addition, patients with persistent C. albicans had worse postbronchodilator forced expiratory volume in the first second (FEV1), more frequent cystic bronchiectasis, and more hospital-treated exacerbations. They were also more frequently treated with long term antibiotics. Multivariate analysis showed that daily purulent sputum (OR = 3.75, p = 0.045) and long-term antibiotics (OR = 2.37, p = 0.005) were independently associated with persistence of Aspergillus spp. and C. albicans, respectively. CONCLUSIONS: Isolation and persistence of Aspergillus spp. and C. albicans are frequent in patients with non-CF bronchiectasis. Daily purulent sputum and chronic antibiotic treatment were associated with persistence of Aspergillus spp. and C. albicans, respectively. PMID- 25924629 TI - The 350th anniversary of scientific publishing: van Leeuwenhoek, the most prolific author of the Philosophical Transactions of the Royal Society. PMID- 25924632 TI - Genetic polymorphisms and function of the organic anion-transporting polypeptide 1A2 and its clinical relevance in drug disposition. AB - The solute carrier organic anion-transporting polypeptides (OATPs) are a family of transporter proteins that have been extensively recognized as key determinants of absorption, distribution, metabolism and excretion of various drugs because of their broad substrate specificity and wide tissue distribution as well as the involvement of drug-drug interaction. Human OATP1A2 is a drug uptake transporter known for its broad substrate specificity, including many drugs in clinical use. OATP1A2 expression has been detected in the intestine, liver, brain and kidney. A considerable number of single nucleotide polymorphisms have been found for the OATP1A2 gene. A number of studies have shown that the cellular uptake and pharmacokinetic behavior of some drugs may be impaired in the case of certain OATP1A2 variants. Interestingly, some studies show that the mRNA expression of OATP1A2 is nearly 10-fold higher in breast cancer compared with adjacent healthy breast tissues. This review is, therefore, focused on the genetic polymorphisms, function and clinical relevance of OATP1A2 as well as on the substrates transported by it. PMID- 25924630 TI - Nonlinear ionizing radiation-induced changes in eye lens cell proliferation, cyclin D1 expression and lens shape. AB - Elevated cataract risk after radiation exposure was established soon after the discovery of X-rays in 1895. Today, increased cataract incidence among medical imaging practitioners and after nuclear incidents has highlighted how little is still understood about the biological responses of the lens to low-dose ionizing radiation (IR). Here, we show for the first time that in mice, lens epithelial cells (LECs) in the peripheral region repair DNA double strand breaks (DSB) after exposure to 20 and 100 mGy more slowly compared with circulating blood lymphocytes, as demonstrated by counts of gammaH2AX foci in cell nuclei. LECs in the central region repaired DSBs faster than either LECs in the lens periphery or lymphocytes. Although DSB markers (gammaH2AX, 53BP1 and RAD51) in both lens regions showed linear dose responses at the 1 h timepoint, nonlinear responses were observed in lenses for EdU (5-ethynyl-2'-deoxy-uridine) incorporation, cyclin D1 staining and cell density after 24 h at 100 and 250 mGy. After 10 months, the lens aspect ratio was also altered, an indicator of the consequences of the altered cell proliferation and cell density changes. A best-fit model demonstrated a dose-response peak at 500 mGy. These data identify specific nonlinear biological responses to low (less than 1000 mGy) dose IR-induced DNA damage in the lens epithelium. PMID- 25924631 TI - From Animaculum to single molecules: 300 years of the light microscope. AB - Although not laying claim to being the inventor of the light microscope, Antonj van Leeuwenhoek (1632-1723) was arguably the first person to bring this new technological wonder of the age properly to the attention of natural scientists interested in the study of living things (people we might now term 'biologists'). He was a Dutch draper with no formal scientific training. From using magnifying glasses to observe threads in cloth, he went on to develop over 500 simple single lens microscopes (Baker & Leeuwenhoek 1739 Phil. Trans. 41, 503-519. (doi:10.1098/rstl.1739.0085)) which he used to observe many different biological samples. He communicated his finding to the Royal Society in a series of letters (Leeuwenhoek 1800 The select works of Antony Van Leeuwenhoek, containing his microscopical discoveries in many of the works of nature, vol. 1) including the one republished in this edition of Open Biology. Our review here begins with the work of van Leeuwenhoek before summarizing the key developments over the last ca 300 years, which has seen the light microscope evolve from a simple single lens device of van Leeuwenhoek's day into an instrument capable of observing the dynamics of single biological molecules inside living cells, and to tracking every cell nucleus in the development of whole embryos and plants. PMID- 25924633 TI - Biomimetic remineralization of human enamel in the presence of polyamidoamine dendrimers in vitro. AB - Poly(amidoamine) (PAMAM) dendrimers, known as artificial proteins, have unique and well-defined molecular size and structure. It has previously been used to mimic protein-crystal interaction during biomineralization. In this study, generation 4.5 (4.5G) PAMAM with carboxylic acid (PAMAM-COOH) was synthesized and utilized to remineralize the surface of etched enamel in vitro. Using confocal laser scanning microscopy, Fourier transform infrared spectroscopy, X-ray diffraction analysis and scanning electron microscopy we observed that 4.5G PAMAM COOH can be absorbed on the etched enamel surface and that it can induce the formation of hydroxyapatite crystals with the same orientation as that of the enamel prisms on longitudinal and transversal enamel surfaces. The self-assembly behavior of PAMAM in the mineralization solution was also investigated and the result showed that 4.5G PAMAM can assemble to microribbon structure similar to the behavior of amelogenins. Therefore, we concluded that 4.5G PAMAM-COOH assemblies can act as the organic template on enamel surface and in mineralization solution to control the nucleation site and morphology of new grown crystals to form the biomimetic structure of human enamel, which may open a new way for repairing damaged enamel. PMID- 25924635 TI - Setaria digitata in advancing our knowledge of human lymphatic filariasis. AB - Setaria digitata is a filarial parasite that causes fatal cerebrospinal nematodiasis in goats, sheep and horses, resulting in substantial economic losses in animal husbandry in the tropics. Due to its close resemblance to Wuchereria bancrofti, this nematode is also frequently used as a model organism to study human lymphatic filariasis. This review highlights numerous insights into the morphological, histological, biochemical, immunological and genetic aspects of S. digitata that have broadened our understanding towards the control and eradication of filarial diseases. PMID- 25924634 TI - HPSE2 mutations in urofacial syndrome, non-neurogenic neurogenic bladder and lower urinary tract dysfunction. AB - BACKGROUND: Urofacial syndrome (UFS) is characterised by congenital bladder dysfunction accompanied by a characteristic abnormal grimace upon smiling and crying. In recent years, biallelic mutations of HPSE2 and LRIG2 have been reported in UFS patients. Non-neurogenic neurogenic bladder (NNNB) has a bladder identical to UFS without typical facial features. The aim of this study was to analyse HPSE2 mutations in patients with UFS and NNNB or severe lower urinary tract dysfunction (LUTD) without abnormal facial expression. METHODS: Patients with UFS, NNNB and severe LUTD were enrolled in the study. We examined a total of 35 patients from 33 families. There were seven UFS patients from five different families, 21 patients with NNNB and seven with LUTD. HPSE2 gene mutation analysis was performed using the polymerase chain reaction protocol followed by Sanger sequencing in these patients. RESULTS: A twin pair with UFS was found to be homozygous for c.457C>T (p.Arg153*) mutation. No other pathogenetic variant was detected. CONCLUSION: HPSE2 mutations were found in one UFS family but not detected in patients with NNNB and severe LUTD. Considering the increasingly recognised cases of NNNB that were diagnosed in early childhood period, genetic factors appear to be responsible. Thus, further genetic studies are needed to discover novel associated gene variants in these bladder anomalies. PMID- 25924636 TI - Perspective in predicting the effect of pleurodesis in the treatment of malignant pleural effusions. AB - BACKGROUND: Pleurodesis with talc has been used for many years. No objective criteria of inflammatory symptoms are known in order to use them to predict the effect of therapy and selection of patients. PURPOSE OF THE STUDY: To objectify the course of local inflammatory changes in the pleural cavity, quantify their dynamics in a clinically used procedure, and to determine specific predictors of inflammation as perspective markers of selection of patients suitable for talcage. MATERIAL AND METHOD: A total of 114 patients were retrospectively divided into Group A (n1 = 98) of patients without relapse and Group B (n2 = 16) of patients with relapse of exudate. The need for repeated thoracic punctures or drainages over the course of a 12-month monitoring period was the criterion of treatment failure. RESULTS: The groups were not different as for the baseline values of sTLR-2 (p0 = 0.638). Group A showed a marked growth during the monitoring period in 2 hours following talcage (p2= 0.002) and in 24 hours (p24 = 0.016). Group B showed higher sCD-163 levels (p0 < 0.001). The initial sTREM-1 values and those after two hours were similar in both groups (p0 = 0.146; p2 < 0.0641). In 24 hours, Group A had markedly higher values (p24 < 0.001). CONCLUSION: The sTLR-2, sCD-163 and sTREM-1 values can be prospectively determined. High sCD-163 values predict unsuitable selection of a candidate for talcage. The degree of inflammatory response can be evaluated using sTLR-2 or sTREM-1. Talcage using an inserted thoracic drain can be repeated at low levels. The cost of ELISA examination is approximately 18 euros (Tab. 1, Fig. 4, Ref. 20). PMID- 25924637 TI - Avascular necrosis of bone in childhood cancer patients: a possible role of genetic susceptibility. AB - With the increasing number of paediatric cancer patients and with their prolonged survival, the evidence of a number of serious complications induced by anticancer therapy is rising. Osteonecrosis (ON) of bone is one of these treatment-related effects with a multifactorial pathogenesis. In the past few years, several polymorphisms of candidate genes with possible role in development of this disorder were studied.We summarized potential risk factors leading to increased susceptibility to osteonecrosis of bone development in cancer patients during childhood and to present current knowledge in the field of genetic aspects of this condition (Ref. 86). PMID- 25924638 TI - The decrease in NKG2D+ Natural Killer cells in peripheral blood of patients with metastatic colorectal cancer. AB - BACKGROUND: Natural killer (NK) cells play important roles in the immune defense against tumors such as colorectal cancer. In humans, NKG2D is an activating immune receptor constitutively expressed in most cytotoxic lymphocytes including NK and CD8+ T cells. In this study, the expression of NKG2D molecule was investigated in peripheral blood NK cells from colorectal cancer patients and compared with healthy subjects. METHODS: We studied 21 non-metastatic (low grade), 17 non-metastatic (high-grade), 16 metastatic colorectal cancer patients, and 24 healthy controls. Peripheral blood samples were obtained to isolate peripheral blood mononuclear cells (PBMCs) and the percentage of peripheral blood NKG2D+CD3-CD56+ NK cells was analyzed by flow cytometry. The expression of NKG2D at mRNA level was also measured by real-time PCR in both, patients and control subjects. RESULTS: The results showed a significant reduction in the percentage of NKG2D+NK cells as well as NKG2D mRNA expression in peripheral blood of metastatic colon cancer patients. CONCLUSION: This result suggests that decreased expression of activating NKG2D receptor in metastatic colorectal cancer might compromise NK cell function and allow tumor to evade immunity (Tab. 3, Fig. 4, Ref. 33). PMID- 25924639 TI - Assessment of complications depending on the sliding screw position - finite element method analysis. AB - OBJECTIVES: The study was aimed at the assessment of specific complications depending on the sliding hip screw position. BACKGROUND: The finite element method in the biomechanical analysis of this implant may be used to predict the mechanical failure due to the screw position. METHODS: 380 sliding screw osteosyntheses for stable pertrochanteric fractures of 365 patients were included in the study. We divided and analysed the osteosyntheses with five various screw positions and focused on the specific complications development. For the construction of the finite element model of the femur, the program ABAQUS 6.9 was used. Analyses were performed with evaluation of the bone response to the different screw locations (strain and stress) with maximum low-cycle high stress loading. RESULTS: The specific complication rate was 10 %, with the re-operation rate of 4.2 %. If placing the screw in the middle third of the neck it reduced significantly strain patterns of the plate and screw. A screw position in the superior third of the neck significantly increased the strain of the plate and screw by more than 63 %. CONCLUSIONS: The conformity in the clinical and biomechanical analyses was observed. The finite element model can be considered as valid in predicting sliding screw failures (Tab. 4, Fig. 8, Ref. 30). PMID- 25924640 TI - Polycystic ovary syndrome - a risk factor of pre-eclampsia after in vitro fertilisation. AB - AIM: Taking into account an increasing number of pregnancies after the assisted reproduction, we tried to evaluate the risk of pre-eclampsia for mono-foetal pregnancy after IVF and to determine the degree of risk factors. MATERIAL AND METHODS: The study included 16,400 patients, while 15,874 of them were after spontaneous conception and 526 after conception using assisted reproductive technologies. For the basic statistical analysis, we used frequency tables and basic statistical characteristics for numeric and ordinary variables. To verify the statistical dependence, we used contingency tables, Fisher exact test and the odds ratio. RESULTS: In the group of women after in vitro fertilisation, a higher incidence of pre-eclampsia was recorded than in the group of women after spontaneous conception. Conception via in vitro fertilisation represents the 3.4 fold risk of pre-eclampsia development (OR 3.404 95% CI 2.407-4.8). CONCLUSION: The major causes of a higher incidence of pre-eclampsia in case of assisted reproduction include: polycystic ovary syndrome, insulin resistance, subfertility, age and obesity of patients. Assisted reproductive technologies are not the cause of a higher incidence of pre-eclampsia in case of the assisted reproduction (Tab. 4, Fig. 2, Ref. 22). PMID- 25924641 TI - Generation and characterization of chicken egg yolk antibodies (IgY) against TNFR1. AB - TNF is from a big family of cytokines with different activities in different parts of the body. Among the various activities of TNFR1, induction of apoptosis by a receptor appears to be an attractive and promising one. This can be achieved through the death domain of the receptor in cells that are stimulated by ligand, to induce apoptosis. Activation of the receptor occurs through its occupation by ligands or its antagonists such as antibodies. Several kinds of antibodies, including antibodies of mammals and birds are used in the research and therapy field. Avian antibodies are highly regarded which is due to the many positive characteristics they have. Firstly, total protein of TNFR1 was cloned. Blood sampling was performed, white blood cell separation, extraction of RNA and at cDNA synthesis. After making sure from synthesis of cDNA, it was used as template for PCR reaction. The cloned fragment in the prokaryotic expression vector, pET28a, transferred to prokaryotic host, BL21(DE3) and the protein (TNFR1) expressed. After protein purification by affinity column were injected to immunize the chickens. Interestingly, antibodies purified from egg yolk of immunized chickens, in ELISA assay showed sufficient specificity. Such antibodies could able to ensure quick and immediate protection against several biotargets (Fig. 4, Ref. 37). PMID- 25924642 TI - Morphometric and stereological assessment of the effects of zinc oxide nanoparticles on the mouse testicular tissue. AB - OBJECTIVE: To evaluate the effects of zinc oxide nanoparticles (ZNPs) on morphometric and stereological parameters of mouse testis. BACKGROUND: ZNPs are increasingly used in sunscreens, biosensors, food additives, pigments, rubber manufacture, and electronic materials. However, the potential toxicity of these nanoparticles is not well understood. METHODS: Experimental Groups (ZNP-1, ZNP-2 and ZNP-3) received one of the following treatments daily for 35 days: 5, 50 and 300 mg/kg ZNPs respectively. Right testis from each animal was fixed in bouin's solution for measurement of total volume of testis, total volume of seminiferous tubules, total volume of interstitial tissue and total number of Leydig cells by stereological methods. Seminiferous tubule diameter and seminiferous epithelium height were assessed by morphometrical method. The left testicles were homogenized for measurement of testosterone concentration. RESULTS: There was a significant decrease in the weight of testicles in ZNP-3 groups. The stereological and morphometrical parameters were significantly changed in ZNP-2 and ZNP-3 groups. ZNP-2 and ZNP-3 groups also showed a significant decrease in testosterone concentrations (p < 0.05). CONCLUSION: This study demonstrated that ZNPs can change stereological and morphometrical parameters of the seminiferous tubules and reduce the number of Leydig cells (Tab. 3, Fig. 3, Ref. 36). PMID- 25924643 TI - The effect of Nesfatin-1 on heart L-type Ca2+ channel alpha1c subunit in rats subjected to chronic restraint stress. AB - BACKGROUND: Elevated L-type Ca2+channel expression level increases Ca2+ influx. This can cause hypertrophy and pathological remodeling of the heart especially under stress conditions. Nesfatin-1 can activate hypothalamic L, P and Q type Ca2+ channels and increase insulin secretion in pancreatic islet beta cells via activation of L-type Ca2+ channels. On the other hand, the effect of nesfatin-1 on cardiac L-type Ca2+ channels has not been studied yet. OBJECTIVES: We aimed to identify the effect of peripheral chronic Nesfatin-1 application on cardiac L type Ca2+ channel alpha1c subunit expression level in normal rats and those subjected to chronic restraint stress. METHODS: Three-month aged Wistar albino rats were randomly divided into 4 groups (n = 7) as Control, Stress, Control+Nesfatin-1, and Nesfatin-1+Stress. Rats in groups subjected to restraint stress were placed in a specially built size-manipulable cabin for 2 h/day (between 10:00 and 12:00 a.m.) for 10 consecutive days without allowing water and food intake. Nesfatin-1 segment (0.25 nmol/g bw intraperitoneally) was applied during the 10 consecutive days. Western blot analyses were performed to determine the expression level of L-type Ca2+ channel alpha1c subunit protein in rat cardiac extracts. RESULTS: Cardiac L-type Ca2+ channel alpha1c subunit protein expression levels were increased significantly after chronic peripheral Nesfatin 1 application in rats subjected to restraint stress (p = 0.032). CONCLUSION: We can conclude that Nesfatin-1 can cause cardiac failures during clinical treatments by elevating cardiac L-type Ca2+ channel alpha1c subunit protein expression level (Fig. 2, Ref. 26). PMID- 25924644 TI - The effects of some tumor markers on human erythrocyte (HCA-I and HCA-II), bovine erythrocyte (BCA) and bovine lung (CA-IV) carbonic anhydrase enzyme activities in vitro. AB - OBJECTIVE: The influence of prostatic acid phosphatase (PAP) and human chorionic gonadotropin (HCG), tumor markers have been investigated on human erythrocyte carbonic anhydrase (HCA-I and HCA-II) and bovine erythrocyte (BCA) and bovine lung carbonic anhydrase (CA-IV) in vitro. BACKGROUND: Tumor markers are substances that can often be detected in higher-than-normal amounts in the blood, urine, or body tissues of some patients with certain types of cancer. Tumor markers are produced either by the tumor itself or by the body in response to the presence of cancer or certain benign (noncancerous) conditions. In addition to their role in cancer diagnosis, some tumor marker levels are measured before treatment to help doctors plan appropriate therapy. RESULTS AND CONCLUSION: All of the tumor markers were determined to have inhibition effect, on human CA-I, CA II, bovine erythrocyte CA (BCA) and bovine lung CA-IV isoenzymes. The effect of each tumor marker on CA was investigated by Wilbur-Andersen method modified by Rickly et al Inhibition effects of two different tumor markers on human CA-I, CA II, bovine erythrocyte CA (BCA) and bovine lung CA-IV isoenzymes were determined by using the CO2-Hydratase method by plotting activity % vs (tumor markers). I50 values of tumor markers exhibiting inhibition effects were found by means of these graphs (Tab.1, Fig. 2, Ref. 20). PMID- 25924645 TI - Interventional effects of squid ink polysaccharides on cyclophosphamide associated testicular damage in mice. AB - Cyclophosphamide (CP) is a commonly used antitumour and immunosuppressive drug, but it is inevitable that the chemotherapeutic agent may cause long-term or permanent reproductive damage on young male patients through inducing oxidative stress in the testes. Squid ink polysaccharides (SIP), a newly found marine glycosaminoglycon have been proved to have antioxidant capabilities and chemotherapy-protective activities on model animals in our recent investigations. This study was conducted to assess whether or not SIP could protect male mice against gonadotoxicity during CP exposure. Sexually mature male Kunming mice were allocated to one of four groups. CP was abdominally administered at dose of 15 mg/kg body weight to two groups of mice for ten weeks, once a week, one group of mice received SIP at dose of 80 mg/kg body weight by gavage for ten weeks, once a day. The other two groups comprised a vehicle treated group and an SIP treated group. Toxicity of CP and protective activity of SIP on the testes were assessed by: sperm parameters, organ index, testicular antioxidant ability, activities of marker enzymes, sex hormone content, and histopathological features. Data showed CP-induced, serious negative changes on murine sperm parameters, organ index, testicular antioxidant ability, activities of marker enzymes, sexual hormone contents, and histopathological features which were all significantly impaired by SIP. This study found that SIP were demonstrated to offer protective effects against CP-induced toxicity on testes in mice (Tab. 2, Fig. 3, Ref. 29). PMID- 25924646 TI - Our own method of fixation of biodegradable tracheal stent. AB - The authors present their own unique original method of fixation polydioxan biodegradable stents in the treatment of tracheal stenosis documented by pictures and video (Fig. 3, Ref. 12). PMID- 25924647 TI - The place of D-dimer and L-lactate levels in the early diagnosis of acute mesenteric ischemia. AB - INTRODUCTION: Acute mesenteric ischemia (AMI) is an abdominal-vascular emergency which is rare and has high mortality rates (60-80 %) due to late diagnosis (1-3). Although it is known that extravascular reasons like intestinal intussusception, volvulus, strangulated hernias and obstructions can cause intestinal gangrene, these are rarely the cause of AMI (1). MATERIALS AND METHODS: In this study, we used male Wistar-Albino rats weighing 250-300 grams obtained from Pamukkale University Experimental Research Laboratory. Animals were exposed to light-dark cycles for 12 hours and had free access to food and water. They were kept in cages for 7 days to stabilise their intestinal flora. In animals of group I, nothing was made other than taking 0.5 ml blood intracardially. In other animals, abdomen was reached with midline laparotomy and superior mesenteric artery (SMA) was located. In group II (operative control group), SMA was isolated and manipulated but was not ligated. In Group III (intestinal ischemia group), SMAwas isolated and ligated with 3/0 silk tie distally to the aorta. After this process, intestinal ischemia was achieved which was confirmed by paleness and pulselessness of intestines, caecum and right colon. Later on, abdomen was closed with double 3/0 polyglactin sutures. At postoperative 1st, 4th and 6th hours 0.5 ml blood was taken intracardially from the animals in groups II and III in order to quantify D-dimer and L-lactate levels. LABORATORY TESTS: D-dimer: Blood samples which were put into tubes containing sodium citrate, were seperated from plasma with centrifugation at 4000 rpm for 7 minutes.L-lactate: Blood L-lactate levels were determined from blood taken into capillary tubes with the help of immobilised enzyme electrode technology using YSI 1500 Sport portative lactate analyzer (Yellow Springs Instruments Inc., Ohio-USA). HISTOPATHOLOGIC VERIFICATION: Two cm long intestinal samples were taken from animals in which SMA was ligated in order to achieve mesenteric ischemia and these samples were fixed in 10 % formol. DISCUSSION: As a result, in rats with SMA occlusion serum D-dimer levels were not increased significantly when compared either in the group or with the basal values of the control group and values in operative control group. Therefore, it is concluded that D-dimer is not a useful marker for early diagnosis of AMI. On the other hand, it is revealed that blood L-lactate levels began to increase significantly following 4th hour of mesenteric ischemia and it is shown that this increase continued at the 6th hour. In addition, considering the utmost importance of the early diagnosis in patients with the clinical suspicion of AMI, L-lactate seems to be a suitable marker to use in emergency departments because it is achieved with a portable device that gives fast and accurate results. Nevertheless, our results are need to be supported by clinical studies with larger patient series (Tab. 2, Fig. 11, Ref. 39). PMID- 25924649 TI - A Rationale for Mineralocorticoid Supplementation in Classic Congenital Adrenal Hyperplasia. PMID- 25924648 TI - Progesterone or progestogen-releasing intrauterine systems for heavy menstrual bleeding. AB - BACKGROUND: Heavy menstrual bleeding (HMB) is an important cause of ill health in women and it accounts for 12% of all gynaecology referrals in the UK. Heavy menstrual bleeding is clinically defined as greater than or equal to 80 mL of blood loss per menstrual cycle. However, women may complain of excessive bleeding when their blood loss is less than 80 mL. Hysterectomy is often used to treat women with this complaint but medical therapy may be a successful alternative.The intrauterine device was originally developed as a contraceptive but the addition of progestogens to these devices resulted in a large reduction in menstrual blood loss. Case studies of two types of progesterone or progestogen-releasing systems, Progestasert and Mirena, reported reductions of up to 90% and improvements in dysmenorrhoea (pain or cramps during menstruation). Insertion, however, may be regarded as invasive by some women, which affects its acceptability as a treatment. Frequent intermenstrual bleeding and spotting is also likely during the first few months after commencing treatment. OBJECTIVES: To determine the effectiveness, acceptability and safety of progesterone or progestogen-releasing intrauterine devices in achieving a reduction in heavy menstrual bleeding. SEARCH METHODS: All randomised controlled trials of progesterone or progestogen releasing intrauterine devices for the treatment of heavy menstrual bleeding were obtained by electronic searches of The Cochrane Library, the specialised register of MDSG, MEDLINE (1966 to January 2015), EMBASE (1980 to January 2015), CINAHL (inception to December 2014) and PsycINFO (inception to January 2015). Additional searches were undertaken for grey literature and for unpublished trials in trial registers. Companies producing progestogen-releasing intrauterine devices and experts in the field were contacted for information on published and unpublished trials. SELECTION CRITERIA: Randomised controlled trials in women of reproductive age treated with progesterone or progestogen-releasing intrauterine devices versus no treatment, placebo, or other medical or surgical therapy for heavy menstrual bleeding within primary care, family planning or specialist clinic settings were eligible for inclusion. Women with postmenopausal bleeding, intermenstrual or irregular bleeding, or pathological causes of heavy menstrual bleeding were excluded. DATA COLLECTION AND ANALYSIS: Potential trials were independently assessed by at least two review authors. The review authors extracted the data independently and data were pooled where appropriate. Risk ratios (RRs) were estimated from the data for dichotomous outcomes and mean differences (MD) for continuous outcomes. The primary outcomes were reduction in menstrual blood loss and satisfaction; in addition, rate of adverse effects, changes in quality of life, failure of treatment and withdrawal from treatment were also assessed. MAIN RESULTS: We included 21 RCTs (2082 women). The included trials mostly assessed the levonorgestrel-releasing intrauterine device (LNG IUS) (no conclusions could be reached from one small study assessing Progestasert which was discontinued in 2001) and so conclusions are based only on LNG IUS. Comparisons were made with placebo, oral medical treatment, endometrial destruction techniques and hysterectomy. Ratings for the overall quality of the evidence for each comparison ranged from very low to high. Limitations in the evidence included inadequate reporting of study methods and inconsistency.Seven studies compared the LNG IUS with oral medical therapy: either norethisterone acetate (NET) administered over most of the menstrual cycle, medroxyprogesterone acetate (MPA) (administered for 10 days), the oral contraceptive pill, mefenamic acid or usual medical treatment where participants could choose the oral treatment that was most suitable. The LNG IUS was more effective at reducing HMB as measured by the alkaline haematin method (MD 66.91 mL, 95% CI 42.61 to 91.20; two studies, 170 women; I(2) = 81%, low quality evidence) or by Pictorial Bleeding Assessment Chart (PBAC) scores (MD 55.05, 95% CI 27.83 to 82.28; three studies, 335 women; I(2) = 79%, low quality evidence), improving quality of life and a greater number of women continued with their treatment at two years when compared with oral treatment. Although substantial heterogeneity was identified for the bleeding outcomes, the direction of effect consistently favoured the LNG IUS. There was insufficient evidence to reach conclusions on satisfaction. Minor adverse effects (such as pelvic pain, breast tenderness and ovarian cysts) were more common with the LNG IUS.Ten studies compared the LNG IUS with endometrial destruction techniques: three with transcervical resection, one with rollerball ablation and six with thermal balloon ablation. Evidence was inconsistent and very low quality with respect to reduction in bleeding outcomes and satisfaction was comparable between treatments (low and moderate quality evidence). Improvements in quality of life were experienced with both types of treatment. Minor adverse events were more common with the LNG IUS overall, but it appeared more cost effective compared to thermal ablation within a two-year time frame in one study.Three studies compared the LNG IUS with hysterectomy. The LNG IUS was not as successful at reducing HMB as hysterectomy (high quality evidence). The women in these studies reported improved quality of life, regardless of treatment. In spite of the high rate of surgical treatment in those having LNG IUS within 10 years, the LNG IUS was more cost effective than hysterectomy. AUTHORS' CONCLUSIONS: The levonorgestrel-releasing intrauterine device (LNG IUS) is more effective than oral medication as a treatment for heavy menstrual bleeding (HMB). It is associated with a greater reduction in HMB, improved quality of life and appears to be more acceptable long term but is associated with more minor adverse effects than oral therapy.When compared to endometrial ablation, it is not clear whether the LNG IUS offers any benefits with regard to reduced HMB and satisfaction rates and quality of life measures were similar. Some minor adverse effects were more common with the LNG IUS but it appeared to be more cost effective than endometrial ablation techniques.The LNG IUS was less effective than hysterectomy in reducing HMB. Both treatments improved quality of life but the LNG IUS appeared more cost effective than hysterectomy for up to 10 years after treatment. PMID- 25924650 TI - Pre-Eclampsia-Associated Reduction in Placental Growth Factor Impaired Beta Cell Proliferation Through PI3k Signalling. AB - BACKGROUND/AIM: Reduction in serum placental growth factor (PLGF) frequently co occurs with preeclampsia (PE) and gestational diabetes mellitus (GDM). Recently, we reported that impairment in gestational beta-cell mass growth may result from PE-associated reduction in PLGF and lead to development of GDM. Here, we studied the underlying mechanisms. METHODS: We co-cultured primary mouse beta cells with mouse islet endothelial cells (MS1), with or without PLGF. We also cultured beta cells in conditioned media from PLGF-treated MS1. Specific signal-pathway inhibitors were applied to cultured beta cells in conditioned media from PLGF treated MS1. We analysed beta-cell proliferation by BrdU incorporation. We analysed changes in cell number by a MTT assay. We analysed protein levels of cell-cycle regulators in beta cells by Western blot. RESULTS: PLGF itself failed to induce beta-cell proliferation, but significantly augmented proliferation of beta cells co-cultured with MS1, which resulted in significant increases in cell number. Conditioned media from the PLGF-treated MS1 cells similarly induced beta cell proliferation, which was abolished by inhibition of PI3k/Akt signalling, but not by inhibition of either ERK/MAPK or JNK signalling. The induction of beta cell proliferation by PLGF-treated MS1 cells appeared to involve decreases in cell-cycle inhibitors p21 and p27, and increases in cell-cycle activators CDK4 and CyclinD1. CONCLUSION: Gestational PLGF may target islet endothelial cells to release growth factors that activate PI3k/Akt signalling in beta cells to increase their proliferation. PE-associated reduction in PLGF impairs these processes to result in GDM. PMID- 25924652 TI - The histamine H4 receptor regulates chemokine production in human natural killer cells. AB - BACKGROUND: Natural killer (NK) cells have been detected in the lesional skin of patients with inflammatory skin diseases, where high levels of histamine are also present. Therefore, we investigated the effect of histamine, in particular via the histamine H4 receptor (H4R), on gene expression levels in human NK cells. METHODS: Comprehensive microarray-based mRNA expression profiling was performed to assess the gene expression levels in human NK cells in response to H4R stimulation in an unbiased approach. The expression of selected cytokines and chemokines was quantified by real-time PCR and enzyme-linked immunosorbent assay. RESULTS: The microarray analysis identified only few genes which were differentially regulated upon H4R stimulation. In follow-up studies, a significant upregulation of CCL3 and CCL4 at the mRNA level and in addition for CCL3 also at the protein level via the H4R was observed. CONCLUSION: The elevated expression levels of chemokines in response to H4R stimulation might foster the inflammation in allergic skin diseases and characterize the H4R as a promising therapeutic target. PMID- 25924653 TI - Towards prospective trial registration in Human Reproduction: step 2 of 3. PMID- 25924651 TI - Human Cytokine-Induced Memory-Like Natural Killer Cells. AB - Natural killer (NK) cells are innate lymphoid cells that are important for host defense against infection and mediate antitumor responses. Recent reports from several laboratories have identified that NK cells can remember a prior activation event and consequently respond more robustly when restimulated, a property termed innate NK cell memory. NK cell memory has now been identified following hapten exposure, viral infection, and combined cytokine preactivation with IL-12, IL-15, and IL-18. Many questions in the field remain regarding the cellular and molecular mechanisms regulating memory NK cells and their responses, as well as their formation and function in mice and humans. Here we review our current understanding of cytokine-induced memory-like (CIML) NK cells that are generated by combined preactivation with IL-12, IL-15, and IL-18. These cells exhibit enhanced NK cell effector functions weeks after the initial cytokine preactivation. Further, we highlight the preclinical rationale and ongoing therapeutic application of CIML NK cells for adoptive immunotherapy in patients with hematologic malignancies. PMID- 25924654 TI - Many women undergoing fertility treatment make poor lifestyle choices that may affect treatment outcome. AB - STUDY QUESTION: What are the lifestyle choices and dietary aspects of women about to undergo fertility treatment in New Zealand? SUMMARY ANSWER: A considerable proportion of women about to undergo fertility treatment make poor lifestyle choices, including the consumption of alcohol and caffeine. WHAT IS KNOWN ALREADY: Women undergoing fertility treatment are highly motivated to achieve pregnancy, but there are relatively few published data on their lifestyle, lifestyle changes or dietary aspects. STUDY DESIGN, SIZE, DURATION: This was a cross-sectional study of 250 women aged 20-43 years, taking place between March 2010 and August 2011. PARTICIPANTS/MATERIALS, SETTING, METHODS: Women about to undergo IVF or ICSI treatment in two large fertility clinics in Auckland and Hamilton, New Zealand. Lifestyle and dietary intake questionnaires were individually administered once to each participant 35 days (SD = 22) prior to fertility treatment initiation. Outcome measures included incidence of smoking, consumption of alcohol and caffeinated beverages, BMI, detailed intake of dietary supplements and fertility treatment success. Consumption of certain nutrient supplements was compared with the general female New Zealand population. MAIN RESULTS AND THE ROLE OF CHANCE: There were high rates of alcohol (50.8%) and caffeine (86.8%) consumption. Most women (82.8%) reported at least one lifestyle change in preparation for fertility treatment, but less than half of women who consumed alcohol regularly reduced their intake and 60% did not change consumption of caffeinated beverages. Similarly, the majority of women did not change their exercise levels (64.4%) or BMI (83.6%) ahead of fertility treatment. Coffee intake appeared unrelated to treatment outcome, but women who consumed caffeinated herbal tea (36.4% of the study population consumed green tea) had lower odds of becoming pregnant (odds ratio, OR 0.52; P = 0.041 versus those not consuming caffeinated herbal tea). Women who abstained from drinking or reduced alcohol intake had twice the odds of becoming pregnant than those who maintained their drinking habits prior to fertility treatment (OR 2.27; P = 0.049). While 93.2% of women took a folic acid supplement, 16.8% had an inadequate intake compared with the current New Zealand prenatal recommendation of 800 mcg/day. Women who held a university degree or higher qualification had twice the odds of becoming pregnant as women with lower levels of education (OR 2.08; P = 0.017), though this finding appeared to be unrelated to lifestyle or dietary habits. LIMITATIONS, REASONS FOR CAUTION: The study involved self-reported behaviours that might have been misrepresented by respondents. In addition, our questionnaires covered the period following the first clinical assessment but ~5 weeks prior to fertility treatment initiation, so that we cannot ascertain whether dietary intakes and lifestyle choices persisted over the course of treatment itself. WIDER IMPLICATIONS OF THE FINDINGS: Many women about to undergo fertility treatment make poor lifestyle choices that may negatively affect their chances of becoming pregnant. These findings may be more widely applicable to other women attempting to become pregnant. Specific advice for women regarding healthy lifestyle choices while undergoing fertility treatment is warranted. STUDY FUNDING/COMPETING INTERESTS: A.A.G. received financial support from Abbott Nutrition Research & Development Asia-Pacific Center; J.C.P. is a shareholder of Fertility Associates; the other authors have no financial or non-financial conflicts of interest to disclose. PMID- 25924655 TI - Risk of hypertensive disorders in pregnancies following assisted reproductive technology: a cohort study from the CoNARTaS group. AB - STUDY QUESTION: Is the risk of hypertensive disorders in pregnancies conceived following specific assisted reproductive technology (ART) procedures different from the risk in spontaneously conceived (SC) pregnancies? SUMMARY ANSWER: ART pregnancies had a higher risk of hypertensive disorders, in particular following cryopreservation, with the highest risk seen in twin pregnancies following frozen thawed cycles. WHAT IS KNOWN ALREADY: The risk of hypertensive disorders is higher in ART pregnancies than in SC pregnancies. The increased risk may be partly explained by multiple pregnancies and underlying infertility, but a contribution from specific ART procedures has not been excluded. STUDY DESIGN, SIZE, DURATION: Population-based cohort study, including sibling design with nationwide data from health registers in Sweden, Denmark and Norway. PARTICIPANTS/MATERIALS, SETTING, METHODS: All registered ART pregnancies and a sample of SC pregnancies with gestational age >=22 weeks from 1988 to 2007 were included. ART singleton pregnancies (n = 47 088) were compared with SC singleton pregnancies (n = 268 599), matched on parity and birth year. ART twin pregnancies (n = 10 918) were compared with SC twin pregnancies (46 674). We used logistic regression to estimate adjusted odds ratios and risk differences for hypertensive disorders in pregnancies following IVF, ICSI and fresh or frozen-thawed cycles. We also compared fresh and frozen-thawed cycles within mothers who had conceived following both procedures using conditional logistic regression (sibling analysis). MAIN RESULTS AND THE ROLE OF CHANCE: Hypertensive disorders were reported in 5.9% of ART singleton and 12.6% of ART twin pregnancies. Comparing singleton pregnancies, the risk of hypertensive disorders was higher after all ART procedures. The highest risk in singleton pregnancies was seen after frozen thawed cycles [risk 7.0%, risk difference 1.8%, 95% confidence interval (CI) 1.2 2.8]. Comparing twin pregnancies, the risk was higher after frozen-thawed cycles (risk 19.6%, risk difference 5.1%, 95% CI 3.0-7.1), but not after fresh cycles. In siblings, the risk was higher after frozen-thawed cycles compared with fresh cycles within the same mother (odds ratio 2.63, 95% CI 1.73-3.99). There were no clear differences in risk for IVF and ICSI. LIMITATIONS, REASONS FOR CAUTION: The number of ART siblings in the study was limited. Residual confounding cannot be excluded. In addition, we did not have information on all SC pregnancies in each woman's history, and could therefore not compare risk in ART versus SC pregnancies in the same mother. WIDER IMPLICATIONS OF THE FINDINGS: Pregnancies following frozen-thawed cycles have a higher risk of hypertensive disorders, also when compared with fresh cycle pregnancies by the same mother. The safety aspects in frozen-thawed cycles merit further attention. STUDY FUNDING/COMPETING INTERESTS: Funding was received from the European Society for Human Reproduction and Embryology, the University of Copenhagen, the Danish Agency for Science, Technology and Innovation, the Nordic Federation of Societies of Obstetrics and Gynecology and the Liaison Committee between the Central Norway Regional Health Authority and the Norwegian University of Science and Technology. None of the authors has any competing interests to declare. PMID- 25924656 TI - Melamine negatively affects oocyte architecture, oocyte development and fertility in mice. AB - STUDY QUESTION: Does melamine have a toxic effect on oocyte development and fertility in vivo? SUMMARY ANSWER: Melamine had toxic effects on oocyte quality and fertility due to its effects on the oocyte cytoskeleton, apoptosis and autophagy induction, and epigenetic modifications in an in vivo mouse model. WHAT IS KNOWN ALREADY: Melamine is a chemical compound that is widely used during the manufacture of amino resins and plastics. In 2008, melamine was reported to adulterate milk and infant formulas in China, which sparked food safety concerns worldwide. Ingesting melamine may result in reproductive damage, and bladder or kidney stones, which can lead to bladder cancer. STUDY DESIGN, SIZE, DURATION: Mice were randomly assigned to three groups and fed a diet that included melamine (0, 10 and 50 mg/kg/day) for 8 weeks. The in vivo effect of melamine on female reproduction was examined. PARTICIPANTS/MATERIALS, SETTING, METHODS: We used immunofluorescent staining, western blotting and qRT-PCR to examine the effect of melamine on oocyte quality. MAIN RESULTS AND THE ROLE OF CHANCE: Our results showed the following effects of this melamine-containing diet. (i) Ovary weights were reduced in melamine fed mice. Oocyte developmental competence was also reduced, as shown by reduced polar body extrusion rates. (ii) Melamine feeding resulted in abnormal oocyte cytoskeletons, as shown by increased rates of aberrant spindles and reduced actin microfilament expression. (iii) Melamine exposed oocytes had higher rates of abnormal mitochondrial distributions and early stage apoptosis/autophagy, which were shown by increased microtubule associated protein 1 light chain 3 (LC3) protein expression level and caspase 9, autophagy-related protein 14 (atg14), and lc3 mRNA levels. (iv) Fluorescence intensity analysis showed that DNA methylation levels were reduced in the oocytes of melamine fed mice. Histone methylation levels were also altered, as Di-methyl Histone H3 (Lys4) (H3K4me2) level was increased and Tri-methyl-Histone H3 (Lys9) (H3K9me3), Di-methyl-Histone H3 (Lys9) (H3K9me2), and Tri-methyl-Histone H3 (Lys27) (H3K27me3) levels were reduced in oocytes from melamine fed mice. (v) The litter sizes of melamine fed mice were significantly reduced when compared with those of controls. LIMITATIONS, REASONS FOR CAUTION: Although we examined the possible effects of melamine on oocyte quality and fertility, we did not determine the effect of melamine on offspring development. WIDER IMPLICATIONS OF THE FINDINGS: Our findings indicate that melamine plays a major role in oocyte quality and fertility. This information could contribute to a better understanding of melamine toxicity in female reproduction. STUDY FUNDING/COMPETING INTERESTS: This study was supported by the National Basic Research Program of China (2014CB138503) and the Natural Science Foundation of Jiangsu Province (BK20140030). The authors have no conflict of interest to disclose. PMID- 25924657 TI - Concurrent exome-targeted next-generation sequencing and single nucleotide polymorphism array to identify the causative genetic aberrations of isolated Mayer-Rokitansky-Kuster-Hauser syndrome. AB - STUDY QUESTION: Can the use of whole-exome sequencing (WES) together with single nucleotide polymorphism (SNP) array help to identify novel causative genes of isolated Mayer-Rokitansky-Kuster-Hauser (MRKH) syndrome? SUMMARY ANSWER: OR4M2 (olfactory receptor, family 4, subfamily M, member 2) and PDE11A (phosphodiesterase 11A) gene loss-of-function variants as well as deletions at 15q11.2, 19q13.31, 1p36.21, and 1q44 were identified as possible commonly altered regions in patients with type 1 MRKH. WHAT IS KNOWN ALREADY: The isolated form of Mullerian aplasia is the most common subtype of MRKH syndrome, which invariably leads to difficulties producing offspring in affected women. However, there is little information currently available to allow for genetic testing and counseling to be performed for those affected by this syndrome. STUDY DESIGN, SIZE AND DURATION: This was a case-series genetic study. A total of seven consecutive unrelated women with type 1 MRKH were enrolled. The enrollment and experimental procedures were performed over a 2-year period. PARTICIPANTS/MATERIALS, SETTING, METHODS: Whole exome-targeted next-generation sequencing and SNP array (Affymetrix Genome-Wide Human SNP Array 6.0) were performed on the first five unrelated women with type 1 MRKH syndrome. The data were combined, and the '3-hit principal' was applied on a genome-wide scale to search for the common causative genes. Quantitative PCR (qPCR) and Sanger sequencing were used to validate the identified genomic copy number losses and variants. Replication tests using direct Sanger sequencing and qPCR were performed on the remaining two women with type 1 MRKH syndrome to support the credibility of the potential candidate genes and deletions. MAIN RESULTS AND THE ROLE OF CHANCE: A total of 3443 damaging variants based on WES were shown to intersect with 1336 copy number variations (deletions) derived from the SNP array. Four highly recurrent deletions at 15q11.2 (80%), 19q13.31 (40%), 1p36.21 (40%) and 1q44 (40%) were identified in the first five women with type 1 MRKH syndrome and were considered to be novel candidate aberrations. A previously reported 1q21.1 deletion was also recurrent in two of the first five women with type 1 MRKH syndrome. The 1q44 and 19q13.31 deletions were present in at least one of the two additional patients. Damaging variants were detected in HNRNPCL1 (heterogeneous nuclear ribonucleoprotein C-like 1), OR2T2 (olfactory receptor, family 2, subfamily T, member 2), OR4M2, ZNF816 (zinc finger protein 816), and PDE11A in several of the initial five patients. Among these, the damaging variants of OR4M2 (located at 15q11.2) and PDE11A were found in at least one of the two additional patients with type 1 MRKH. LIMITATIONS, REASONS FOR CAUTION: In this study, we only searched for the deletions or damaging variants causing loss-of-function of genes in at least three of the initial five patients (3-hit criteria). Therefore, the study was designed to only detect common causative genes. Genomic duplications and/or rare individual mutations that may have also contributed to MRKH syndrome were not investigated. WIDER IMPLICATIONS OF THE FINDINGS: This study demonstrated the feasibility of the use of combined data from both WES and SNP arrays for the identification of possible common causative genetic aberrations in patients with type 1 MRKH syndrome on a genome-wide scale. Further validation of our found causative genes is required before applying on genetic testing and counseling. STUDY FUNDING/COMPETING INTERESTS: The study was supported by grants from the National Science Council of Taiwan (NSC98-2314-B002 105-MY3 and NSC 100-2314-B002-027-MY3). The funding sources had no involvement in the design or analysis of the study. The authors have no competing interests to declare. TRIAL REGISTRATION NUMBER: Not applicable. PMID- 25924658 TI - High Cytotoxicity and Apoptotic Effects of Natural Bioactive Benzofuran Derivative on the MCF-7 Breast Cancer Cell Line. AB - This study was focused on evaluation of the cytotoxicity and apoptotic affects of benzofuran derivative on MCF-7 breast cancer cell line. This effective compound was isolated from the root of Petasites hybridus plant. For experiments, the MCF 7 cells were treated with several concentrations (0-500MUM) of 1-(6-hydroxy-2- isopropenyl-1-benzofuran-5-yl)-1-ethanone 1 at different times. In this study, test of neutral red was also employed for cytotoxicity assay and quantity of P53, P21. Bax genes expression was analyzed using Real-Time PCR and ELISA techniques. Results show that compound 1 has cytotoxicity and apoptotic effects on Human breast cancer (Michigan Cancer Foundation-7) MCF-7 cells. PMID- 25924659 TI - Screening for Potential Bioactive Components in Ginkgo biloba Extract by the Rat Renal Tubular Epithelial Cell Extraction and LC-MS/MS. AB - Rat renal tubular epithelial cell (RTEC) cultured with high glucose has been used to observe the protective effect of Ginkgo biloba extract (GBE) against diabetic nephropathy (DN). The compounds in GBE binding with cell membrane or entering into cell are still unknown, which may be potential bioactive components. In this paper, a powerful method for screening and analyzing the potential bioactive components from GBE was developed using cell extraction coupled with high performance liquid chromatography tandem mass spectrometry (LC-MS/MS). 8 prototype compounds and 5 metabolites were obtained, among which 6 prototype compounds and 1 metabolite were identified or tentatively characterized as rutin, bilobalide, ginkgolide B, ginkgolide C, genkwanin, apigenin and diosmetin by comparing their retention times and MS spectra with those of authentic standards or literature data. The 6 prototype compounds were further quantitatively analyzed using electrospray ionization in negative mode multiple reaction monitoring (MRM). The results showed that high glucose changed the Tmax, MRT(0 t), Cmax and AUC(0-t) of all observed compounds and decreased the t1/2 of genkwanin and apigenin, significantly. The overall findings indicate that 8 prototype compounds may be the potential bioactive components of GBE with preventive effect against DN and the method of RTEC extraction coupled with LC MS/MS technology screening method we developed is a feasible, rapid, and useful tool for screening and analyzing potential bioactive components. PMID- 25924660 TI - Mixed colloids and acute kidney injury: a case of selection bias? PMID- 25924661 TI - The Association of Leisure Activities in Middle Adulthood with Cognitive Performance in Old Age: The Moderating Role of Educational Level. AB - BACKGROUND: One of the fundamental challenges for gerontological research is how to maintain and promote intact cognitive functioning in old age. Previous research revealed that high educational level, good health status, and an active lifestyle during adulthood seem to be protective against cognitive impairment in old age. However, up to now, a detailed examination of the interaction of these relations based on a broader variety of activities and considering past and current activities is missing. OBJECTIVE: The present study set out to extend the literature by investigating in more detail the interactions of educational level and health status with a broad variety of past and current leisure activities in their association with cognitive functioning in a large sample of older adults with a wide age range. METHODS: A total of 2,812 older adults (aged 65-101 years) served as the sample for the present study. A test on verbal abilities and one on processing speed were applied. In addition, individuals were retrospectively interviewed regarding their educational level, current general health status, and 18 leisure activities (in terms of currently performed activities and those that had been carried out at the age of 45 years). RESULTS: Regressions indicated that engaging in more current activities and in more activities at the age of 45 years (both analyzed as an overall activity measure) was related to better cognitive performance in old age (r values up to 0.39, p values <0.001). These associations were more pronounced in individuals with a low (compared to a high) educational level. CONCLUSION: Present results suggest that an active lifestyle during middle adulthood may be related to better cognitive functioning in old age, particularly in individuals with a low educational level. These findings are discussed with respect to models of cognitive aging. PMID- 25924662 TI - Fibrocalculous pancreatic diabetes: a case report. AB - BACKGROUND: Diabetes is now becoming a major cause of morbidity and mortality in both developing and developed countries. Even though type 1 and type 2 are the commonest, diabetes mellitus due to secondary causes have been identified. Fibrocalculous Pancreatic Diabetes is a unique entity wherein pancreatic calcification and chronic inflammation lead to exocrine and endocrine failure of the pancreas. This form of non-alcoholic pancreatopathy is exclusively seen among the young, with a male preponderance and commonly in tropical countries where malnutrition and poverty go hand in hand. Whereas, interestingly this case has a late presentation in a female, unlike in other reported cases. For the best of our knowledge this is the first such documented case reported in Sri Lanka. CASE PRESENTATION: A 57 year old non-alcoholic Sinhalese female from Sri Lanka, presented with a history of chronic pancreatitis of nine years duration, after which she had developed severe Insulin Dependent Diabetes Mellitus. Imaging of the abdomen showed typical pancreatic calcifications, and this presentation accords with the criteria for Fibrocalculous pancreatic diabetes. CONCLUSION: This case report demonstrates a rare form of secondary diabetes in a middle aged female, without a childhood history of abdominal pain suggestive of pancreatitis, indicating late onset disease. Therefore a high index of suspicion is necessary even though the diagnostic criteria indicates the presence of childhood onset of disease. PMID- 25924663 TI - Hearing aid or tinnitus masker: which one is the best treatment for blast-induced tinnitus? The results of a long-term study on 974 patients. AB - The aim of this longitudinal study was to explore whether a hearing aid or noise generator would be an effective audiological treatment for blast-induced chronic tinnitus. The amount of satisfaction from different hearing devices (hearing aid, noise generator, or both) during different time periods (1, 6, 12 and 24 months after fitting) was assessed. The 974 subjects enrolled in this study were Iran Iraq war veterans, suffering from tinnitus for at least 2 years. About 84% of the subjects preferred just a hearing aid. Only 2.7% chose the noise generator, and the others preferred to use both devices. There were no significant differences between the hearing thresholds of the 3 groups. The satisfaction score for the hearing aid and combined devices increased by time but decreased for the noise generator. There was no correlation between the satisfaction score and parameters such as hearing thresholds, audiogram configuration and tinnitus pitch. We concluded that, compared with a noise generator, the most long-lasting treatment for blast-induced tinnitus is a hearing aid. The possible cause for such a performance is probably the recovery of the auditory function and neuroplasticity through the hearing aid. PMID- 25924664 TI - Time for a standardized system of reporting sites of genomic methylation. AB - The authors argue that the lack of a widely used, systematic way to report sites of DNA methylation is a often a barrier to reproducibility and therefore holds back research. PMID- 25924665 TI - Fat intake and the development of type 2 diabetes. AB - The increase in the number of patients with diabetes has become a worldwide healthcare issue, with numbers predicted to reach approximately 600 million by 2035. In Asia-Pacific region, the prevalence of type 2 diabetes has increased dramatically in recent decades, of which the major causes are believed to be modern lifestyle changes, e.g., Western dietary pattern and reduced physical activity, on their genetic basis of lower insulin secretory capacity. Particularly, in East Asian countries, the amount of fat intake has increased nearly three-fold over this half of century; dietary fat appears to be the major culprit of type 2 diabetes pandemic in East Asia. However, convincing evidence has not yet been provided as to whether high-fat diet causes type 2 diabetes in epidemiological cohort studies. Here, we summarize clinical studies regarding fat intake and type 2 diabetes, and animal studies on high-fat diet-induced diabetes including our recent works on the novel mouse lines (selectively bred diet induced glucose intolerance-prone [SDG-P] and -resistant [SDG-R]) to address the etiology of high-fat diet-induced diabetes. These epidemiological and experimental findings would provide further insight into the etiology of type 2 diabetes under the modern nutritional environment, namely in the context of increased fat intake. PMID- 25924666 TI - Endothelial dysfunction, insulin resistance and inflammation in congenital hypogonadism, and the effect of testosterone replacement. AB - Patients with hypogonadism have poor cardiovascular and metabolic outcomes, and the effect of testosterone replacement therapy (TRT) is not clear. We investigated the presence of inflammation, insulin resistance and endothelial dysfunction in an unconfounded population of congenital hypogonadotrophic hypogonadism (CHH) and the effect of TRT on these subjects. A total of 60 patients with CHH (mean age 21.82+/-2.22 years) and 70 healthy control subjects (mean age 21.32+/-1.13 years) were enrolled. The demographic parameters, Asymmetric dimethylarginine (ADMA), TNF-like weak inducer of apoptosis (TWEAK), high sensitive C reactive protein (hs-CRP) and homeostatic model assessment of insulin resistance (HOMA-IR) levels were measured before and after TRT. The patients had higher Waist Circumferences (WC) (p=0.009), Diastolic Blood Pressures (p=0.02), Triglycerides (p=0.03), ADMA, insulin and HOMA-IR levels (p<0.001 for all) and lower TWEAK levels (p<0.001), compared to the healthy controls. After 5.56 +/- 2.04 months of TRT, the patients had significantly elevated systolic blood pressures (p=0.01), body mass indexes and WC (p<0.001 and p=0.001 respectively) and decreased total and HDL cholesterol levels (p=0.032 and p<0.001 respectively). ADMA levels significantly increased (p=0.003), while the alterations in TWEAK, hsCRP and HOMA-IR were not significant. The results of the present study show that endothelial dysfunction, inflammation and insulin resistance are prevalent even in the very young subjects with CHH, who have no metabolic or cardiac problems at present. This increased cardiometabolic risk however, do not improve but even get worse after six months of TRT. Long term follow-up studies are warranted to investigate the unfavorable cardiometabolic effects of TRT. PMID- 25924667 TI - Passive Immunization against Congenital Cytomegalovirus Infection: Current State of Knowledge. AB - Primary infection with the human cytomegalovirus (CMV) occurs in 1-4% of pregnancies. The rates of maternal-fetal CMV transmissions are around 25, 36, 41, and 66%, for infections occurring in the peri-conceptional weeks, first, second, and third trimester of pregnancy, respectively. On the other hand, the severity of fetal organ damage and dysfunction diminishes with increasing gestational age. Congenitally CMV-infected newborns may have neurosensory impairments like mental retardation, cerebral palsy, epilepsy, progressive hearing loss or visual defects, or even may have a fatal outcome. In in-vitro experiments, CMV specific neutralizing IgG antibodies - which are abundant in CMV specific hyperimmune globulin (HIG) products - inhibited the entry of the virus into target cells and hampered viral cell-to-cell spread. This article provides a brief overview on the epidemiology and diagnostic tools in congenital CMV infection. It also concisely summarizes the currently available study results on the safety and effectiveness of HIG treatment. Accordingly, in clinical studies HIG administration to expectant mothers following primary CMV infection (prophylactic use) was shown to lower the risk of maternal-fetal transmission of CMV compared to untreated controls. HIG was also able to ameliorate the disease sequelae in evidently infected fetuses (therapeutic use), as demonstrated by the regression or even resolution of sonographic pathologies including placental inflammation. PMID- 25924668 TI - Early ART initiation among HIV-positive pregnant women in central Mozambique: a stepped wedge randomized controlled trial of an optimized Option B+ approach. AB - BACKGROUND: Despite effective prevention strategies and increasing investments in global health, maternal to child transmission (MTCT) of HIV remains a significant problem globally, especially in sub-Saharan Africa. In 2012, there were 94,000 HIV-positive pregnant women in Mozambique. Approximately 15% of these women transmitted HIV to their newborn infants, resulting in nearly 14,000 new pediatric HIV infections that year. To address this issue, in 2013, the Mozambican Ministry of Health implemented the World Health Organization recommended "Option B+" strategy in which all newly diagnosed HIV-positive pregnant women are counseled to initiate combination anti-retroviral therapy (ART) immediately upon diagnosis regardless of CD4 count and to continue treatment for life. Given the limited experience with Option B+ in sub-Saharan Africa, few rigorous pragmatic trials have studied this new treatment strategy. METHODS: This study utilizes an initial formative research process involving patient and health care provider interviews and focus groups, workforce assessments, value stream mapping, and commodity utilization assessments to understand the strengths and weaknesses in the current Option B+ care cascade. The formative research is intended to guide identification and prioritization of key workflow modifications and the development of an enhanced adherence and retention package. These two components are bundled into a defined intervention implemented and evaluated across six health facilities utilizing a stepped wedge randomized controlled trial study design. The overall objective of this trial is to develop and test a pilot intervention in central Mozambique to implement the new Option B+ guidelines with high fidelity and increase the proportion of HIV positive pregnant women in target antenatal clinics (ANC) who start ART prior to delivery and are retained in care. DISCUSSION: This pragmatic study utilizes research strategies that have the potential to meaningfully improve the Option B+ care cascade in central Mozambique and to decrease the MTCT of HIV. This trial is designed to identify critical low-cost improvement strategies that can be bundled into a defined intervention. If this intervention has a measurable impact, it can be rapidly scaled up to other ANC in Mozambique and sub-Saharan Africa. TRIAL REGISTRATION: ClinicalTrials.gov: NCT02371265. PMID- 25924669 TI - Cross-sectional associations between residential environmental exposures and cardiovascular diseases. AB - BACKGROUND: Prior research examining neighbourhood effects on cardiovascular diseases (CVDs) has focused on the impact of neighbourhood socio-economic status or a few selected environmental variables. No studies of cardiovascular disease outcomes have investigated a broad range of urban planning related environmental factors. This is the first study to combine multiple neighbourhood influences in an integrated approach to understanding the association between the built and social environment and CVDs. By modeling multiple neighbourhood level social and environmental variables simultaneously, the study improved the estimation of effects by accounting for potential contextual confounders. METHODS: Data were collected using a cross-sectional survey (n = 2411) across 87 census tracts (CT) in Toronto, Canada, and commercial and census data were accessed to characterize the residential environment. Multilevel regressions were used to estimate the associations of neighbourhood factors on the risk of CVD. RESULTS: Exposure to violent crimes, environmental noise, and proximity to a major road were independently associated with increased odds of CVDs (p < 0.05) in the fully adjusted model. While reduced access to food stores, parks/recreation, and increased access to fast food restaurants were associated with increased odds of CVDs in partially adjusted models (p < 0.05), these associations were fully attenuated after adjusting for BMI and physical activity. Housing disrepair was not associated with CVD risk. CONCLUSIONS: These findings illustrate the importance of measuring and modeling a broad range of neighborhood factors- exposure to violent crimes, environmental noise, and traffic, and access to food stores, fast food, parks/recreation areas--to identify specific stressors in relation to adverse health outcomes. Further research to investigate the temporal order of events is needed to better understand the direction of causation for the observed associations. PMID- 25924670 TI - Comparative clinical study testing the effectiveness of school based oral health education using experiential learning or traditional lecturing in 10 year-old children. AB - BACKGROUND: School based oral health education through traditional lecturing has been found successful only in improving oral health knowledge, while has low effectiveness in oral hygiene and gingival health. The aim of this study was to evaluate the effectiveness of experiential learning (EL) oral health education to traditional lecturing (TL), on enhancing oral health knowledge, attitude and behavior as well as oral hygiene, gingival health and caries of 10-year-old children. METHODS: Eighty-four children were recruited for the EL and 100 for the TL group from 3 locations in Greece. Data regarding oral health knowledge, attitude and behavior were collected via questionnaires. Data regarding dental plaque, gingivitis and caries were collected by clinical examination. The evaluation using questionnaires and clinical examination was assessed at baseline and 6 and 18 months afterwards. Two calibrated pediatric dentists examined the students using a periodontal probe and artificial light. Modified hygiene index (HI) was used for dental plaque recording, the simplified gingival index (GI-S) was used for gingivitis and DMFT, based on BASCD criteria, for dental caries. Based on a dedicated manual, the teacher applied in the classroom the oral health educational program using EL. RESULTS: EL group had statistically significant better hygiene than the TL at 6 months (p < 0.05). Within the same group, both groups had enhanced oral health knowledge at 6 and 18 months (p < 0.05) and improved oral health behavior (p > 0.05) and attitude (p > 0.05) at 6 months in comparison to baseline. CONCLUSION: EL program was found more successful than TL in oral hygiene improvement. Both oral health education programs improved the oral health knowledge, attitude and behavior of children. TRIAL REGISTRATION: ClinicalTrials.gov (NCT02320162). PMID- 25924671 TI - Novel insights into the insect trancriptome response to a natural DNA virus. AB - BACKGROUND: Little is known about invertebrate responses to DNA viruses. Here, we infect a commercially important pest moth species Plodia interpunctella with its naturally infecting DNA virus. We sequenced, assembled and annotated the complete transcriptome of the moth, and a partial transcriptome of the virus. We then tested for differential gene expression between moths that were exposed to the virus and controls. RESULTS: We found 51 genes that were differentially expressed in moths exposed to a DNA baculovirus compared to controls. Gene set enrichment analysis revealed that cuticle proteins were significantly overrepresented in this group of genes. Interestingly, 6 of the 7 differentially expressed cuticle proteins were downregulated, suggesting that baculoviruses are able to manipulate its host's response. In fact, an additional 29 of the 51 genes were also downregulated in exposed compared with control animals, including a gram-negative binding protein. In contrast, genes involved in transposable element movement were upregulated after infection. CONCLUSIONS: We present the first experiment to measure genome-wide gene expression in an insect after infection with a natural DNA virus. Our results indicate that cuticle proteins might be key genes underpinning the response to DNA viruses. Furthermore, the large proportion of genes that were downregulated after viral exposure suggests that this virus is actively manipulating the insect immune response. Finally, it appears that transposable element activity might increase during viral invasion. Combined, these results provide much needed host candidate genes that respond to DNA viral invaders. PMID- 25924672 TI - Giant solitary fibrous tumor of the pelvis successfully treated with preoperative embolization and surgical resection: a case report. AB - Solitary fibrous tumors (SFTs) rarely develop in the pelvis. When they do arise, they are usually treated using surgery, although SFTs are often very large by the time of diagnosis, which makes surgical excision difficult. We report a case of a 63-year-old man who was referred to our hospital for the treatment of a giant tumor of the pelvis. Computed tomography (CT) revealed a 30 * 25 * 19 cm sized hypervascular tumor that almost completely filled the pelvic cavity. The diagnosis of SFT was made by CT-assisted needle biopsy. The feeding arteries of the tumor were embolized twice. The first embolization aimed to reduce the tumor volume, while the second one was planned a day prior to the surgery to obtain hematostasis during the operation. Tumor resection was then performed. The blood loss during the operation was 440 ml, and there was no uncontrollable bleeding. The postoperative course was uneventful. No recurrence of SFT was observed during a 2-year follow-up. PMID- 25924673 TI - Infinitely Adaptive Transition-Metal Ordering in Ln2O2MSe2-Type Oxychalcogenides. AB - A number of Ln2O2MSe2 (Ln = La and Ce; M = Fe, Zn, Mn, and Cd) compounds, built from alternating layers of fluorite-like [Ln2O2](2+) sheets and antifluorite-like [MSe2](2-) sheets, have recently been reported in the literatures. The available MSe4/2 tetrahedral sites are half-occupied, and different compositions display different ordering patterns: [MSe2](2-) layers contain MSe4/2 tetrahedra that are exclusively edge-sharing (stripe-like), exclusively corner-sharing (checkerboard like), or mixtures of both. This paper reports 60 new compositions in this family. We reveal that the transition-metal arrangement can be systematically controlled by either Ln or M doping, leading to an "infinitely adaptive" structural family. We show how this is achieved in La2O2Fe1-xZnxSe2, La2O2Zn1 xMnxSe2, La2O2Mn1-xCdxSe2, Ce2O2Fe1-xZnxSe2, Ce2O2Zn1-xMnxSe2, Ce2O2Mn1-xCdxSe2, La2-yCeyO2FeSe2, La2-yCeyO2ZnSe2, La2-yCeyO2MnSe2, and La2-yCeyO2CdSe2 solid solutions. PMID- 25924674 TI - Finding My Way: protocol of a randomised controlled trial evaluating an internet self-help program for cancer-related distress. AB - BACKGROUND: A cancer diagnosis elicits greater distress than any other medical diagnosis, and yet very few studies have evaluated the efficacy of structured online self-help therapeutic programs to alleviate this distress. This study aims to assess the efficacy over time of an internet Cognitive Behaviour Therapy (iCBT) intervention ('Finding My Way') in improving distress, coping and quality of life for individuals with a recent diagnosis of early stage cancer of any type. METHODS/DESIGN: The study is a multi-site Randomised Controlled Trial (RCT) seeking to enrol 188 participants who will be randomised to either the Finding My Way Intervention or an attention-control condition. Both conditions are delivered online; with 6 modules released once per week, and an additional booster module released one month after program-completion. Participants complete online questionnaires on 4 occasions: at baseline (immediately prior to accessing the modules); post-treatment (immediately after program-completion); then three and six months later. Primary outcomes are general distress and cancer-specific distress, with secondary outcomes including Health-Related Quality of Life (HRQoL), coping, health service utilisation, intervention adherence, and user satisfaction. A range of baseline measures will be assessed as potential moderators of outcomes. Eligible participants are individuals recently diagnosed with any type of cancer, being treated with curative intent, aged over 18 years with sufficient English language literacy, internet access and an active email account and phone number. Participants are blinded to treatment group allocation. Randomisation is computer generated and stratified by gender. DISCUSSION: Compared to the few prior published studies, Finding My Way will be the first adequately powered trial to offer an iCBT intervention to curatively treated patients of heterogeneous cancer types in the immediate post-diagnosis/treatment period. If found efficacious, Finding My Way will assist with overcoming common barriers to face-to-face therapy in a cost-effective and accessible way, thus helping to reduce distress after cancer diagnosis and consequently decrease the cancer burden for individuals and the health system. TRIAL REGISTRATION: Australian New Zealand Clinical Trials Registry ACTRN12613000001796 16.10.13. PMID- 25924676 TI - A model of professional self-identity formation in student doctors and dentists: a mixed method study. AB - BACKGROUND: Professional self-identity [PSI] can be defined as the degree to which an individual identifies with his or her professional group. Several authors have called for a better understanding of the processes by which healthcare students develop their professional identities, and suggested helpful theoretical frameworks borrowed from the social science and psychology literature. However to our knowledge, there has been little empirical work examining these processes in actual healthcare students, and we are aware of no data driven description of PSI development in healthcare students. Here, we report a data driven model of PSI formation in healthcare students. METHODS: We interviewed 17 student doctors and dentists who had indicated, on a tracking questionnaire, the most substantial changes in their PSI. We analysed their perceptions of the experiences that had influenced their PSI, to develop a descriptive model. Both the primary coder and the secondary coder considered the data without reference to the existing literature; i.e. we used a bottom up approach rather than a top down approach. RESULTS: The results indicate that two overlapping frames of reference affect PSI formation: the students' self perception and their perception of the professional role. They are 'learning' both; neither is static. Underpinning those two learning processes, the following key mechanisms operated: [1] When students are allowed to participate in the professional role they learn by trying out their knowledge and skill in the real world and finding out to what extent they work, and by trying to visualise themselves in the role. [2] When others acknowledge students as quasi professionals they experience transference and may respond with counter transference by changing to meet expectations or fulfil a prototype. [3] Students may also dry-run their professional role (i.e., independent practice of professional activities) in a safe setting when invited. CONCLUSIONS: Students' experiences, and their perceptions of those experiences, can be evaluated through a simple model that describes and organises the influences and mechanisms affecting PSI. This empirical model is discussed in the light of prevalent frameworks from the social science and psychology literature. PMID- 25924675 TI - Systemic inflammation in early neonatal mice induces transient and lasting neurodegenerative effects. AB - BACKGROUND: The inflammatory mediator lipopolysaccharide (LPS) has been shown to induce acute gliosis in neonatal mice. However, the progressive effects on the murine neurodevelopmental program over the week that follows systemic inflammation are not known. Thus, we investigated the effects of repeated LPS administration in the first postnatal week in mice, a condition mimicking sepsis in late preterm infants, on the developing central nervous system (CNS). METHODS: Systemic inflammation was induced by daily intraperitoneal administration (i.p.) of LPS (6 mg/kg) in newborn mice from postnatal day (PND) 4 to PND6. The effects on neurodevelopment were examined by staining the white matter and neurons with Luxol Fast Blue and Cresyl Violet, respectively. The inflammatory response was assessed by quantifying the expression/activity of matrix metalloproteinases (MMP), toll-like receptor (TLR)-4, high mobility group box (HMGB)-1, and autotaxin (ATX). In addition, B6 CX3CR1(gfp/+) mice combined with cryo immunofluorescence were used to determine the acute, delayed, and lasting effects on myelination, microglia, and astrocytes. RESULTS: LPS administration led to acute body and brain weight loss as well as overt structural changes in the brain such as cerebellar hypoplasia, neuronal loss/shrinkage, and delayed myelination. The impaired myelination was associated with alterations in the proliferation and differentiation of NG2 progenitor cells early after LPS administration, rather than with excessive phagocytosis by CNS myeloid cells. In addition to disruptions in brain architecture, a robust inflammatory response to LPS was observed. Quantification of inflammatory biomarkers revealed decreased expression of ATX with concurrent increases in HMGB1, TLR-4, and MMP-9 expression levels. Acute astrogliosis (GFAP(+) cells) in the brain parenchyma and at the microvasculature interface together with parenchymal microgliosis (CX3CR1(+) cells) were also observed. These changes preceded the migration/proliferation of CX3CR1(+) cells around the vessels at later time points and the subsequent loss of GFAP(+) astrocytes. CONCLUSION: Collectively, our study has uncovered a complex innate inflammatory reaction and associated structural changes in the brains of neonatal mice challenged peripherally with LPS. These findings may explain some of the neurobehavioral abnormalities that develop following neonatal sepsis. PMID- 25924677 TI - Ectoparasites of murids in peninsular Malaysia and their associated diseases. AB - A considerable number of rat-borne ectoparasite studies have been conducted since the early 1930s in the Malayan Peninsula (now known as peninsular Malaysia). The majority of studies were field surveys and collections of specimens across the region, and were conducted primarily to catalogue the ectoparasite host distribution and discover novel species. This has generated a signification amount of information, particularly on the diversity and host distribution; other aspects such as morphology, host distribution and medical significance have also been investigated. Amongst the four main groups (mites, fleas, ticks, lice), rat borne mites have received the most attention with a particular emphasis on chiggers, due to their medical importance. More recent studies have examined the distribution of ectoparasites in rats from different habitat type simplicating a high prevalence of zoonotic species infesting rat populations. Despite being capable of transmitting dangerous pathogens to human, the health risks of rat borne ectoparasites appear to be small with no serious outbreaks of diseases recorded. Although an extensive number of works have been published, there remain gaps in knowledge that need to be addressed, such as, the distribution of under studied ectoparasite groups (listrophorids and myobiids), determining factors influencing infestation, and understanding changes to the population distribution over time. PMID- 25924678 TI - The etiology and outcome of non-traumatic coma in critical care: a systematic review. AB - BACKGROUND: Non-traumatic coma (NTC) is a serious condition requiring swift medical or surgical decision making upon arrival at the emergency department. Knowledge of the most frequent etiologies of NTC and associated mortality might improve the management of these patients. Here, we present the results of a systematic literature search on the etiologies and prognosis of NTC. METHODS: Two reviewers independently performed a systematic literature search in the Pubmed, Embase and Cochrane databases with subsequent reference and citation checking. Inclusion criteria were retrospective or prospective observational studies on NTC, which reported on etiologies and prognostic information of patients admitted to the emergency department or intensive care unit. RESULTS: Eventually, 14 studies with enough data on NTC, were selected for this systematic literature review. The most common causes of NTC were stroke (6-54%), post-anoxic coma (3 42%), poisoning (<1-39%) and metabolic causes (1-29%). NTC was also often caused by infections, especially in African studies affecting 10-51% of patients. The NTC mortality rate ranged from 25 to 87% and the mortality rate continued to increase long after the event had occurred. Also, 5-25% of patients remained moderately-severely disabled or in permanent vegetative state. The mortality was highest for stroke (60-95%) and post-anoxic coma (54-89%) and lowest for poisoning (0-39%) and epilepsy (0-10%). CONCLUSION: NTC represents a challenge to the emergency and the critical care physicians with an important mortality and moderate-severe disability rate. Even though, included studies were very heterogeneous, the most common causes of NTC are stroke, post anoxic, poisoning and various metabolic etiologies. The best outcome is achieved for patients with poisoning and epilepsy, while the worst outcome was seen in patients with stroke and post-anoxic coma. Adequate knowledge of the most common causes of NTC and prioritizing the causes by mortality ensures a swift and adequate work-up in diagnosis of NTC and may improve outcome. PMID- 25924680 TI - Prevalence and diversity of Plasmodium and Haemoproteus parasites in the globally threatened Aquatic Warbler Acrocephalus paludicola. AB - The diversity and prevalence of malaria parasites of the genera Plasmodium and Haemoproteus were determined in the globally-threatened Aquatic Warbler Acrocephalus paludicola. Birds were sampled during migration in Portugal and at the wintering quarters in Senegal and parasites were detected using molecular methods. Only three generalist parasite lineages (Plasmodium) were found. There were no significant differences in the prevalence of parasites between sexes in Europe, but adults had higher prevalence than first-year birds, and birds in Europe had higher prevalence than those captured in Africa. When comparing with other Acrocephalus species and taking sample size into account, Aquatic Warblers had the lowest prevalence and, together with another threatened species, the Seychelles Warbler Acrocephalus sechellensis, the lowest diversity of malaria parasites. We hypothesize that the low diversity of parasites and absence of specialist lineages of Aquatic Warblers are caused by its small population size and fragmented distribution. Furthermore, Aquatic Warblers' extreme habitat specialization may decrease their exposure to malaria parasites, but other explanations such as high mortality (which would constraint the sampling of infected birds) or, in contrast, very efficient immunological system in clearing the infections cannot be ruled out. This study contributes to explain variation in prevalence and diversity of malaria parasites among hosts. PMID- 25924681 TI - Side Chain Influence on the Morphology and Photovoltaic Performance of 5-Fluoro-6 alkyloxybenzothiadiazole and Benzodithiophene Based Conjugated Polymers. AB - Three conjugated polymers (P1-P3) with benzodithiophene derivatives as the donor unit, 5-fluoro-6-(2-hexyldecyloxy)-4,7-di(thiophen-2-yl)benzo[c][1,2,5] thiadiazole as the acceptor unit and thiophene as the spacer were designed, synthesized, and used as donor materials for polymer solar cells (PSCs). The influence of side chains at the benzodithiophene unit on the performance of PSCs was investigated. PSCs with the blend of P2:PC71BM (1:2, by weight) as the active layer show the highest power conversion efficiency (PCE) of 6.88%, with an open circuit voltage (Voc) of 0.76 V, a short circuit current (Jsc) of 14.67 mA/cm(2), and a fill factor (FF) of 0.62. Our research revealed that the variation of side chains had a great influence on the morphology of blend films, which is crucial to the performance of PSCs. As indicated by transmission electron microscopy, the blends of P1:PC71BM (1:2) and P2:PC71BM (1:2) formed nanofibers, whereas the blends of P3:PC71BM (1:2) formed spherical domains. Therefore, we concluded that formation of a more interpenetrating phase-separated donor-acceptor network with a larger interfacial area and proper percolation in the blends from P1 to P2 is mainly responsible for better performance in the corresponding devices. PMID- 25924679 TI - What is the impact of chronic kidney disease stage and cardiovascular disease on the annual cost of hospital care in moderate-to-severe kidney disease? AB - BACKGROUND: Reliable estimates of the impacts of chronic kidney disease (CKD) stage, with and without cardiovascular disease, on hospital costs are needed to inform health policy. METHODS: The Study of Heart and Renal Protection (SHARP) randomized trial prospectively collected information on kidney disease progression, serious adverse events and hospital care use in a cohort of patients with moderate-to-severe CKD. In a secondary analysis of SHARP data, the impact of participants' CKD stage, non-fatal cardiovascular events and deaths on annual hospital costs (i.e. all hospital admissions, routine dialysis treatments and recorded outpatient/day-case attendances in United Kingdom 2011 prices) were estimated using linear regression. RESULTS: 7,246 SHARP patients (2,498 on dialysis at baseline) from Europe, North America, and Australasia contributed 28,261 years of data. CKD patients without diabetes or vascular disease incurred annual hospital care costs ranging from L403 (95% confidence interval: 345-462) in CKD stages 1-3B to L525 (449-602) in CKD stage 5 (not on dialysis). Patients in receipt of maintenance dialysis incurred annual hospital costs of L18,986 (18,620-19,352) in the year of initiation and L23,326 (23,231-23,421) annually thereafter. Patients with a functioning kidney transplant incurred L24,602 (24,027-25,178) in hospital care costs in the year of transplantation and L1,148 (978-1,318) annually thereafter. Non-fatal major vascular events increased annual costs in the year of the event by L6,133 (5,608-6,658) for patients on dialysis and by L4,350 (3,819-4,880) for patients not on dialysis, and were associated with increased costs, though to a lesser extent, in subsequent years. CONCLUSIONS: Renal replacement therapy and major vascular events are the main contributors to the high hospital care costs in moderate-to-severe CKD. These estimates of hospital costs can be used to inform health policy in moderate-to severe CKD. PMID- 25924682 TI - Building a Prediction Model for Vacuum-Assisted Operative Vaginal Delivery Risk. AB - AIM: The objective of this study was to evaluate the risk factors for operative vaginal delivery and to propose a new nomogram for predicting the risk. METHODS: We retrospectively analyzed the data of 1,955 pregnancies that occurred in our clinic between the years 2007 and 2008. Included were singleton pregnancies with labor diagnosis after the 36th gestational week in which spontaneous or operative vaginal deliveries occurred. In this study, the operative delivery was carried out exclusively by vacuum extraction. RESULTS: After univariate analysis and multivariate logistic regression stepwise model selection, maternal age, nulliparity, medically assisted procreation, gestational age at birth, male fetus, epidural analgesia and medical induction of labor were found to be the most predictive variables for operative vaginal delivery. Considering these factors we propose a new nomogram for an objectified determination of the risk of operative vaginal delivery. CONCLUSIONS: The new nomogram we propose could be an important tool for an objectified determination of the risk of operative vaginal delivery by vacuum extraction in individualized patient counseling. PMID- 25924683 TI - Antipsychotic drug exposure and risk of pulmonary embolism: a population-based, nested case-control study. AB - BACKGROUND: Only three observational studies investigated whether exposure to antipsychotics is associated with an increased risk of pulmonary embolism, with conflicting results. This study was therefore carried out to establish the risk of pulmonary embolism associated with antipsychotic drugs, and to ascertain the risk associated with first- and second-generation antipsychotic drugs, and with exposure to individual drugs. METHODS: We identified 84,253 adult individuals who began antipsychotic treatment in a large Italian health care system. Cases were all cohort members who were hospitalized for non-fatal or fatal pulmonary embolism during follow-up. Up to 20 controls for each case were extracted from the study cohort using incidence density sampling and matched by age at cohort entry and gender. Each individual was classified as current, recent or past antipsychotic user. The occurrence non-fatal or fatal pulmonary embolism was the outcome of interest. RESULTS: Compared to past use, current antipsychotic use more than double the risk of pulmonary embolism (odds ratio 2.31, 95% confidence interval 1.16 to 4.59), while recent use did not increase the risk. Both conventional and atypical antipsychotic exposure was associated with an increase in risk, and the concomitant use of both classes increased the risk of four times (odds ratio 4.21, 95% confidence interval 1.53 to 11.59). CONCLUSIONS: Adding the results of this case-control study to a recent meta-analysis of three observational studies substantially changed the overall estimate, which now indicates that antipsychotic exposure significantly increases the risk of pulmonary embolism. PMID- 25924684 TI - Oral fluoride levels 1 h after use of a sodium fluoride rinse: effect of sodium lauryl sulfate. AB - Increasing the concentration of free fluoride in oral fluids is an important goal in the use of topical fluoride agents. Although sodium lauryl sulfate (SLS) is a common dentifrice ingredient, the influence of this ion on plaque fluid and salivary fluid fluoride has not been examined. The purpose of this study was to investigate the effect of SLS on these parameters and to examine the effect of this ion on total (or whole) plaque fluoride, an important source of plaque fluid fluoride after a sufficient interval following fluoride administration, and on total salivary fluoride, a parameter often used as a surrogate measure of salivary fluid fluoride. Ten subjects accumulated plaque for 48 h before rinsing with a 12 mmol/l NaF (228 ug/g F) rinse containing or not containing 0.5% (w/w) SLS. SLS had no statistically significant effect on total plaque and total saliva fluoride but significantly increased salivary fluid and plaque fluid fluoride (by 147 and 205%, respectively). These results suggest that the nonfluoride components of topical agents can be manipulated to improve the fluoride release characteristics from oral fluoride reservoirs and that statistically significant change may be observed in plaque fluid and salivary fluid fluoride concentrations that may not be observed in total plaque and total saliva fluoride concentrations. PMID- 25924685 TI - Beyond greenspace: an ecological study of population general health and indicators of natural environment type and quality. AB - BACKGROUND: Many studies suggest that exposure to natural environments ('greenspace') enhances human health and wellbeing. Benefits potentially arise via several mechanisms including stress reduction, opportunity and motivation for physical activity, and reduced air pollution exposure. However, the evidence is mixed and sometimes inconclusive. One explanation may be that "greenspace" is typically treated as a homogenous environment type. However, recent research has revealed that different types and qualities of natural environments may influence health and wellbeing to different extents. METHODS: This ecological study explores this issue further using data on land cover type, bird species richness, water quality and protected or designated status to create small-area environmental indicators across Great Britain. Associations between these indicators and age/sex standardised prevalence of both good and bad health from the 2011 Census were assessed using linear regression models. Models were adjusted for indicators of socio-economic deprivation and rurality, and also investigated effect modification by these contextual characteristics. RESULTS: Positive associations were observed between good health prevalence and the density of the greenspace types, "broadleaf woodland", "arable and horticulture", "improved grassland", "saltwater" and "coastal", after adjusting for potential confounders. Inverse associations with bad health prevalence were observed for the same greenspace types, with the exception of "saltwater". Land cover diversity and density of protected/designated areas were also associated with good and bad health in the predicted manner. Bird species richness (an indicator of local biodiversity) was only associated with good health prevalence. Surface water quality, an indicator of general local environmental condition, was associated with good and bad health prevalence contrary to the manner expected, with poorer water quality associated with better population health. Effect modification by income deprivation and urban/rural status was observed for several of the indicators. CONCLUSIONS: The findings indicate that the type, quality and context of 'greenspace' should be considered in the assessment of relationships between greenspace and human health and wellbeing. Opportunities exist to further integrate approaches from ecosystem services and public health perspectives to maximise opportunities to inform policies for health and environmental improvement and protection. PMID- 25924686 TI - Effects of Pulmonary Rehabilitation in Patients with Non-Cystic Fibrosis Bronchiectasis: A Retrospective Analysis of Clinical and Functional Predictors of Efficacy. AB - BACKGROUND: International guidelines recommend the inclusion of patients with bronchiectasis in pulmonary rehabilitation (PR) to improve exercise capacity and health-related quality of life (HRQoL). At present, the effect of PR in these patients has been poorly investigated. OBJECTIVE: The aim of our retrospective analysis was to evaluate the effects and predictors of success for a PR program in patients with bronchiectasis not related to cystic fibrosis (non-CF bronchiectasis). METHODS: One hundred and thirty-five non-CF bronchiectasis inpatients, allocated to a 3-week PR program, were retrospectively evaluated. Exercise capacity (6-min walk distance, 6MWD), dyspnea (Baseline/Transition Dyspnea Index, BDI/TDI), and HRQoL [EuroQol visual analogue scale (EQ-VAS)] were assessed before and after PR. The relationship between baseline parameters and changes in outcome measures after PR was assessed. Both univariate and multiple logistic analyses were performed to evaluate the presence of independent predictors of the efficacy of PR. RESULTS: One hundred and eight patients [49 males, mean age 71 years, mean forced expiratory volume in 1 s (FEV1) 76% predicted] were included. After PR, there was a significant improvement in 6MWD, TDI, and EQ-VAS score (p < 0.001). Changes in 6MWD and EQ-VAS score correlated with baseline FEV1, FEV1/vital capacity (VC), residual volume, transfer factor of the lung for carbon monoxide, and the number of exacerbations in the previous year. Both univariate and multivariate logistic regression analyses showed that male gender, baseline FEV1/VC <70%, and >2 exacerbations in the previous year were independent predictors of PR efficacy in terms of an improvement in 6MWD. CONCLUSIONS: Our study supports the inclusion of patients with bronchiectasis in PR programs. Clinical and functional baseline findings partially predict the response to PR in terms of exercise tolerance. Further prospective, randomized, controlled trials are needed. PMID- 25924687 TI - Clinical relevance of cluster analysis in phenotyping allergic rhinitis in a real life study. AB - BACKGROUND: Disease stratification, using phenotypic characterization performed either by hypothesis- or data-driven methods, was developed to improve clinical decisions. However, cluster analysis has not been used for allergic rhinitis. OBJECTIVE: To define clusters in allergic rhinitis and to compare them with ARIA (Allergic Rhinitis and Its Impact on Asthma), a hypothesis-driven approach. METHODS: A French observational prospective multicenter study (EVEIL: Echelle visuelle analogique dans la rhinite allergique) was carried out on 990 patients consulting general practitioners for allergic rhinitis and treated as per clinical practice. In this study, changes in symptom scores, visual analogue scales and quality of life were measured at baseline and after 14 days of treatment. A post hoc analysis was performed to identify clusters of patients with allergic rhinitis - using Ward's hierarchical method - and to define their clinical relevance at baseline and after 14 days of treatment. The cluster approach was compared to the ARIA approach. RESULTS: Patients were clustered into 4 phenotypes which partly followed the ARIA classes. These phenotypes differed in their disease severity including symptoms and quality of life. Physicians in real life practice prescribed medication regardless of the phenotype and severity, with the exception of patients with ocular symptoms. Prescribed treatments were comparable in hypothesis- and data-driven analyses. The prevalence of uncontrolled patients during treatment was similar in the 4 clusters, but was significantly different according to the ARIA classes. CONCLUSION: Cluster analysis using demographic and clinical parameters only does not appear to add relevant information for disease stratification in allergic rhinitis. PMID- 25924688 TI - HIF-1alpha as a Regulator of BMP2-Induced Chondrogenic Differentiation, Osteogenic Differentiation, and Endochondral Ossification in Stem Cells. AB - BACKGROUND/AIMS: Joint cartilage defects are difficult to treat due to the limited self-repair capacities of cartilage. Cartilage tissue engineering based on stem cells and gene enhancement is a potential alternative for cartilage repair. Bone morphogenetic protein 2 (BMP2) has been shown to induce chondrogenic differentiation in mesenchymal stem cells (MSCs); however, maintaining the phenotypes of MSCs during cartilage repair since differentiation occurs along the endochondral ossification pathway. In this study, hypoxia inducible factor, or (HIF)-1alpha, was determined to be a regulator of BMP2-induced chondrogenic differentiation, osteogenic differentiation, and endochondral bone formation. METHODS: BMP2 was used to induce chondrogenic and osteogenic differentiation in stem cells and fetal limb development. After HIF-1alpha was added to the inducing system, any changes in the differentiation markers were assessed. RESULTS: HIF 1alpha was found to potentiate BMP2-induced Sox9 and the expression of chondrogenesis by downstream markers, and inhibit Runx2 and the expression of osteogenesis by downstream markers in vitro. In subcutaneous stem cell implantation studies, HIF-1alpha was shown to potentiate BMP2-induced cartilage formation and inhibit endochondral ossification during ectopic bone/cartilage formation. In the fetal limb culture, HIF-1alpha and BMP2 synergistically promoted the expansion of the proliferating chondrocyte zone and inhibited chondrocyte hypertrophy and endochondral ossification. CONCLUSION: The results of this study indicated that, when combined with BMP2, HIF-1alpha induced MSC differentiation could become a new method of maintaining cartilage phenotypes during cartilage tissue engineering. PMID- 25924689 TI - Clinical characteristics of concomitant nephrotic IgA nephropathy and minimal change disease in children. AB - BACKGROUND: IgA nephropathy (IgAN) is the most common primary glomerulonephritis in children and adolescents worldwide. Meanwhile, minimal change disease (MCD) is the most common cause of nephrotic syndrome in children. Recently, several case reports have revealed that IgAN can be complicated by MCD in adults. Here, we report our experience concerning the features of such patients in pediatrics. METHODS: The clinical manifestations and pathological features of 197 children who presented with IgAN from December 2007 to November 2013 were analyzed retrospectively based on the criteria for nephrotic syndrome and MCD. RESULTS: Among the 197 children diagnosed with primary IgAN, 25 (12.7%) patients presented with nephrotic syndrome, and 7 patients (2.8%) presented with MCD-like pathological features and nephrotic syndrome simultaneously. The cohort of 7 patients included 5 boys, and the median age was 8.9. All of the patients who were diagnosed with primary nephrotic syndrome were treated initially with corticosteroids. Except for 1 patient with steroid resistance who was lost to follow-up, the other 6 cases presented were steroid sensitive and remained in complete remission for the last follow-up, with median and mean follow-up durations of 30.5 and 34.5 months, respectively (range 10-65 months). CONCLUSIONS: This study revealed that IgAN and MCD may also coexist in children. Moreover, most of these patients who presented with nephrotic syndrome responded well to steroids and had a favorable prognosis. Large-scale studies are required, and careful attention should be paid to such complicated cases. PMID- 25924690 TI - Normal-Appearing Endometrial Cells in Pap Tests of Women Aged Forty Years or Older and Cytohistological Correlates. AB - OBJECTIVE: The Bethesda System 2001 for reporting cervical cytology recommends reporting benign-appearing, exfoliated endometrial cells in women aged 40 years or older. The objective of this study was to determine the significance of normal endometrial cells in conventional Papanicolaou (Pap) tests of women aged 40 years and older and to correlate this finding with histological follow-up. STUDY DESIGN: Over a period of 5 years, all Pap tests showing endometrial cells in women aged >= 40 years were identified. Histological follow-up and outcome were evaluated. RESULTS: Out of 17,275 Pap tests, 199 (1.15%) showed benign endometrial cells. Forty-seven of these 199 patients had subsequent tissue sampling by surgical procedures including endometrial curettage (n = 31), lower genital tract biopsy (n = 30) and hysterectomy (n = 2). Overall, out of 47 cases, 3 (6.4%) had significant endometrial pathology including 2 simple hyperplasias without atypia and 1 complex hyperplasia with atypia. CONCLUSION: The incidence of clinically significant endometrial lesions associated with the presence of endometrial cells in Pap tests of women aged 40 years and older was very low. Considering this finding, women aged between 40 and 50 years with benign endometrial cells in a Pap test should undertake endometrial sampling only when additional clinical indicators are recognized. PMID- 25924691 TI - The Effect of Oral Morphine on Pain-Related Brain Activation - An Experimental Functional Magnetic Resonance Imaging Study. AB - Knowledge about cerebral mechanisms underlying pain perception and effect of analgesic drugs is important for developing methods for diagnosis and treatment of pain. The aim was to explore altered brain activation before and after morphine treatment using functional magnetic resonance imaging recorded during experimental painful heat stimulation. Functional magnetic resonance imaging data were recorded and analysed in 20 healthy volunteers (13 men and 7 women, 24.9 +/- 2.6 years) in a randomized, double-blind, placebo-controlled, cross-over study. Painful stimulations were applied to the right forearm using a contact heat evoked potential stimulator (CHEPS) before and after treatment with 30 mg oral morphine and placebo. CHEPS stimulations before treatment induced activation in the anterior cingulate cortex, secondary somatosensory cortex/insula, thalamus and cerebellum (n = 16, p < 0.05). In response to morphine treatment, the spatial extent of these pain-specific areas decreased (n = 20). Reduced pain-induced activation was seen in the right insula, anterior cingulate cortex and inferior parietal cortex after morphine treatment compared to before treatment (n = 16, p < 0.05), and sensory ratings of pain perception were significantly reduced after morphine treatment (p = 0.02). No effect on pain-induced brain activation was seen after placebo treatment compared to before treatment (n = 12, p > 0.05). In conclusion, heat stimulation activated areas in the 'pain matrix' and a clinically relevant dose of orally administered morphine revealed significant changes in brain areas where opioidergic pathways are predominant. The method may be useful to investigate the mechanisms of analgesics. PMID- 25924692 TI - A multinomial model for comorbidity in England of long-standing cardiovascular disease, diabetes and obesity. AB - Comorbidity has been found to be significantly related to increased levels of mortality, decreased functional status and quality of life, increasing dependence on health services and an increased risk of mental and social problems. Previous research into comorbidity has mainly focused on identifying the most common groupings of illnesses found among elderly healthcare users. In contrast, this paper pools data from the Health Survey for England from 2008 to 2012 to form a representative sample of individuals in private households in England to explore the risk of comorbidity among the general population; and to take account of not only the demographic but also the socioeconomic and area-level determinants of comorbidity. Using a multinomial logistic model, this research confirms that age and gender are significant predictors of cardiovascular disease, diabetes and obesity, whether examined singly or in any comorbidity combination. Across the seven possible disease combinations, the odds ratios are lowest for those individuals with a high income (6 of 7), home-owning (5 of 7), degree educated (7 of 7) and living in the least deprived area (6 of 7), when controlling for demographic and smoking characteristics. The important influence of socioeconomic factors associated with comorbidity risk indicates that healthcare policy needs to move from a focus on age profiles to take better account of individual and local area socioeconomic circumstances. PMID- 25924693 TI - Outcome analysis of laparoscopic incisional hernia repair and risk factors for hernia recurrence in liver transplant patients. AB - INTRODUCTION: Incisional hernia is a common complication after liver transplantation (LT). Immunosuppression, obesity, and use of steroids are known risk factors. The purpose of the retrospective study was to summarize and evaluate experiences and results of laparoscopic intraperitoneal onlay mesh (IPOM) hernia repair. METHODS: We reviewed our liver transplant patients over a seven-yr period with laparoscopic incisional hernia repair (LIHR) to direct our attention on risk factors for hernia recurrence after hernia repair. RESULTS: Fifty-four patients after LT with incisional hernia were treated with laparoscopic repair, 42 male and 12 female patients of overall mean age of 58 +/- 9 yr and body mass index (BMI) of 25 +/- 4 kg/m(2) . A total of 755 LTs were performed at our institution in this time period, resulting in 7.15% of patients undergoing laparoscopic hernia repair. The mean postoperative hospital stay after was nine d. During the follow-up, nine recurrent hernias were noted (17%). BMI (p = 0.001) and sirolimus as immunosuppressive therapy were significantly associated with hernia recurrence (p = 0.014). CONCLUSION: LIHR is a safe and feasible method to treat hernias after LT. BMI and sirolimus as immunosuppressive therapy are risk factors for recurrence of hernia after laparoscopic hernia repair. PMID- 25924694 TI - Potent Inhibitory Effect of Chinese Dietary Spices on Fatty Acid Synthase. AB - Dietary spices have been adopted in cooking since ancient times to enhance flavor and also as food preservatives and disease remedies. In China, the use of spices and other aromatic plants as food flavoring is an integral part of dietary behavior, but relatively little is known about their functions. Fatty acid synthase (FAS) has been recognized as a remedy target, and its inhibitors might be applied in disease treatment. The present work was designed to assess the inhibitory activities on FAS of spices extracts in Chinese menu. The in vitro inhibitory activities on FAS of 22 extracts of spices were assessed by spectrophotometrically monitoring oxidation of NADPH at 340 nm. Results showed that 20 spices extracts (90.9 %) exhibited inhibitory activities on FAS, with half inhibition concentration (IC(50)) values ranging from 1.72 to 810.7 MUg/ml. Among them, seven spices showed strong inhibitory effect with IC(50) values lower than 10 MUg/ml. These findings suggest that a large proportion of the dietary spices studied possess promising inhibitory activities on FAS, and subsequently might be applied in the treatment of obesity and obesity-related human diseases. PMID- 25924695 TI - Periodontal status and pathogenic bacteria after gastric bypass: a cohort study. AB - AIM: The aim this study was to evaluate the influence of gastric bypass surgery (GBS) on periodontal disease and quantify the periodontopathogenic bacteria in patients undergoing this surgery. MATERIAL AND METHODS: This prospective study was composed of 50 patients who underwent bariatric surgery and the data collection was performed in three periods pre-operative, 6 (6M) and 12 months (12 M) postoperative. The oral clinical examination to assess periodontal disease; gingival fluid sample collection for quantification of the periodontopathogenic bacteria Porphyromonas gingivalis, Tannerella forsythia, Treponema denticola, and Prevotella intermedia using q-PCR; body mass index (BMI) and for collection of the individual's health-related data from medical files. RESULTS: There was a significant reduction in serum C-reactive protein (CRP) and glucose levels after surgery. The mean probing pocket depth (PPD) and clinical attachment level (CAL) increased significantly in the postoperative period of 6 months (p = 0.001). In the same period, the amount of P. gingivalis increased (p = 0.028) and the other bacteria decreased slightly (p > 0.050). In the presence of P. gingivalis, T. forsythia, T. denticola and P. intermedia, a poor periodontal condition was observed. CONCLUSION: The periodontal disease increased in severity and P. gingivalis increased after GBS. A systemic inflammation resolution due to bariatric surgery in obese subjects does not seem to affect the course of periodontal disease. PMID- 25924696 TI - Facial Contouring Surgery with Custom Silicone Implants Based on a 3D Prototype Model and CT-Scan: A Preliminary Study. AB - BACKGROUND: From perspectives of differences in anatomic and cultural characteristics from Caucasians, Asians have been considered to undergo facial bone contouring surgery of the zygoma and mandible and fat grafting in the anterior mimetic area of midface. We have sought to develop more ready-to-use methods for increasing the applicability of custom facial implants in the field of esthetic surgery. PATIENTS AND METHODS: We performed insertion of custom silicone implants after taking a clinical history and photographs in a total of seven patients (n = 7) between March 2008 and July 2014. Our clinical series of patients comprises two men and five women, whose mean age was 41.6 +/- 21.6-years old (range 23-82 years). In addition, the patients were followed up during a mean period of 11.43 +/- 6.68 months (range 3-24 months). In the current study, we evaluated treatment outcomes of custom silicone implants using polyvinyl alcohol (PVA) in facial contouring surgery by reviewing seven cases. RESULTS: There were no abnormalities of the soft tissue or bone due to the use of custom silicone implants. Moreover, we found that custom silicone implants were advantageous in predicting treatment outcomes. All the patients were satisfied with treatment outcomes. CONCLUSION: Custom silicone implants based on the PVA clay on the 3D RP model will play a prominent role in facial contouring surgery but its full potential deserves further studies. LEVEL OF EVIDENCE IV: This journal requires that authors assign a level of evidence to each article. For a full description of these Evidence-Based Medicine ratings, please refer to the Table of Contents or the online Instructions to Authors www.springer.com/00266 . PMID- 25924697 TI - Preoperative magnetic resonance imaging-based breast volumetry for immediate breast reconstruction. AB - BACKGROUND: Preoperative breast magnetic resonance imaging (MRI) is a routine test for oncologic evaluation. However, determining breast volume using a preoperative MRI obtained as a part of oncologic evaluation has not yet been attempted for immediate breast reconstruction. The study introduces the benefit of MRI-based volumetry, not only in autologous breast reconstruction but also in implant-based breast reconstruction. METHODS: Forty patients preparing for autologous breast reconstruction with a deep inferior epigastric artery perforator (DIEP) flap and 30 patients for implant-based breast reconstruction from June 2011 to June 2012 were included in this study. In every DIEP case, we collected data about actual resected breast tissue weight during mastectomy and final flap weight inserted intraoperatively. Computed tomography (CT) was for preoperative CT angiography for microsurgical breast reconstruction, whereas MRI was performed for oncologic evaluation. In every implant-based reconstruction case, MRI-based breast volume was measured in the same way for DIEP patients and resected breast tissue weight was measured intraoperatively. In addition, we also added or subtracted the breast volume by any modification, such as reduction and augmentation on the ipsilateral or contralateral side. To determine the accuracy of MRI-based volumetry, Pearson correlation coefficients were calculated to quantify the correlation between CT and MRI-based volumetry data and intraoperative volume measurements. RESULTS: For DIEP patients, the mean resected breast tissue weight during mastectomy was more closely related to the mean estimated breast volume using MRI than to the mean estimated breast volume using CT (Pearson coefficient 0.928 and 0.782; p = 0.001). MRI gave a closer correlation to final flap weight than CT (Pearson correlation coefficient 0.959 and 0.873; p = 0.001). For implant-based reconstruction patients, the breast volume measured by MRI correlated closely with the actual mean weight of resected breast specimens (0.937; p = 0.001). Mean net implanted volume was more closely related to mean estimated breast volume using MRI than to mean resected breast tissue weight during mastectomy (0.893 and 0.880; p = 0.001). CONCLUSIONS: Reliable volumetric information can be obtained using MRI for breast implant volume and autologous tissue needed in optimizing symmetry in breast reconstruction. LEVEL OF EVIDENCE IV: This journal requires that authors assign a level of evidence to each article. For a full description of these Evidence-Based Medicine ratings, please refer to the Table of Contents or the online Instructions to Authors www.springer.com/00266 . PMID- 25924698 TI - The efficacy of radio-frequency ablation for metastatic lung or liver tumors of male germ cell tumors as an alternative minimally invasive therapy after salvage chemotherapy. AB - BACKGROUND: The aim of this study was to assess the efficacy of radio-frequency ablation (RFA) for metastatic lung or liver tumors of germ cell tumors (GCTs) after chemotherapy. METHODS: RFA with computed tomography guidance and monitoring was performed in 24 patients with 48 metastatic lung or liver tumors of GCTs. Group A consisted of 9 patients with tumor marker normalization after salvage chemotherapy and group B consisted of 15 patients without tumor marker normalization in spite ofintensive treatment. RESULTS: Out of 48 tumors, 41 tumors in 21 patients were evaluated for the efficacy of the RFA treatment. Of the 41 tumors, successful ablation was achieved in 34 (82.9 %). The patients in group A had significantly better survival than the patients in group B (p = 0.0003). In group A, all 9 patients are still alive with no evidence of disease (NED). Patients with a solitary tumor had significantly better survival than those with multiple tumors (p = 0.0247). In group B, 2 patients are alive with NED, 1 patient is alive with disease, and the remaining 12 patients have died a tumor-related death. Three cases of pneumothorax requiring intubation were observed. CONCLUSIONS: RFA is less invasive than surgery and is an effective treatment option for curative and palliative therapy as an alternative to invasive salvage surgery for post-chemotherapeutic metastatic lung or liver lesions from GCT. PMID- 25924699 TI - Systemic delivery of nanoparticle formulation of novel tubulin inhibitor for treating metastatic melanoma. AB - Clinical translation of tubulin inhibitors for treating melanoma is limited by multidrug efflux transporters, poor aqueous solubility, and dose-limiting peripheral toxicities. Tubulin inhibitors with efficacy in taxane-resistant cancers are promising drug candidates and can be used as single agent or in conjunction with other chemotherapy. Systemic therapy of such a novel tubulin inhibitor, 2-(1H-indol-5-yl)thiazol-4-yl)3,4,5-trimethoxyphenyl methanone (abbreviated as LY293), is limited by its poor aqueous solubility. The objective of this study was to design a polymeric nanocarrier for systemic administration of LY293 to improve tumor accumulation and reduce side effects of tubulin inhibitor in a lung metastasis melanoma mouse model. Methoxy polyethylene glycol b-poly(carbonate-co-lactide) (mPEG-b-P(CB-co-LA)) random copolymer was synthesized and characterized by 1H NMR and gel permeation chromatography (GPC). Polymeric nanoparticles were formulated using oil/water (o/w) emulsification method with a mean particle size of 150 nm and loading efficiency of 7.40%. Treatment with LY293-loaded nanoparticles effectively inhibited the proliferation of melanoma cells in vitro and exhibited concentration-dependent cell cycle arrest in G2/M phase. Mitotic arrest activated the intrinsic apoptotic machinery by increasing the cellular levels of cleaved poly ADP ribose polymerase (PARP) and fraction of sub-G1 cells. In vivo, LY293-loaded nanoparticles significantly inhibited the proliferation of highly aggressive metastasized melanoma in a syngeneic lung metastasis melanoma mouse model without toxicity to vital organs. In conclusion, we have designed a promising polymeric nanocarrier for systemic delivery of LY293 for treating metastatic melanoma while minimizing the toxicity associated with the administration of cosolvents. PMID- 25924700 TI - Expression of matrix metalloproteinases in bovine luteal cells induced by prostaglandin F2alpha, interferon gamma and tumor necrosis factor alpha. AB - We recently demonstrated that luteal cells flow out from the ovary via lymphatic vessels during luteolysis. However, the regulatory mechanisms of the outflow of luteal cells are not known. Matrix metalloproteinases (MMPs) can degrade the extracellular matrix and basal membrane, and tissue inhibitors of matrix metalloproteinases (TIMPs) inhibit the activity of MMPs. To test the hypothesis that MMP expression in luteal cells is regulated by luteolytic factors, we investigated the effects of prostaglandin F2alpha (PGF), interferon gamma (IFNG) and tumor necrosis factor alpha (TNF) on the mRNA expression of MMPs and TIMPs in cultured luteal cells. Luteal cells obtained from the CL at the mid-luteal stage (days 8-12 after ovulation) were cultured with PGF (0.01, 0.1, 1 MUM), IFNG (0.05, 0.5, 5 nM) and TNF (0.05, 0.5, 0.5 nM) alone or in combination for 24 h. PGF and IFNG significantly increased the expression of MMP-1 mRNA. In addition, 1 MUM PGF in combination with 5 nM IFNG stimulated MMP-1 and MMP-9 mRNA expression significantly more than either treatment alone. In contrast, IFNG significantly decreased the level of MMP-14 mRNA. The mRNA expression of TIMP-1, which preferentially inhibits MMP-1, was suppressed by 5 nM INFG. One MUM PGF and 5 nM IFNG suppressed TIMP-2 mRNA expression. These results suggest a new role of MMPs: luteal MMPs stimulated by PGF and IFNG break down the extracellular matrix surrounding luteal cells, which accelerates detachment from the CL during luteolysis, providing an essential prerequisite for outflow of luteal cells from the CL to lymphatic vessels. PMID- 25924701 TI - Osteochondroma of the Hyoid Bone: A Previously Unrecognized Location and Review of the Literature. AB - Osteochondroma is a benign cartilaginous neoplasm and the most common benign tumor of bone. Osteochondromas occur primarily in the axial skeleton with a predilection for the distal femur, and relatively few cases occur in the head and neck region. The majority of cases of osteochondromas in the head and neck region affect the mandibular condyle, with fewer cases reported in the skull base and the neck. To our knowledge, there is no reported case of osteochondroma of the hyoid bone documented in the English literature. We thus report the first case of a hyoid bone osteochondroma, presenting as an asymptomatic mass in a young woman. PMID- 25924702 TI - Prognostic value of CD56 in patients with acute myeloid leukemia: a meta analysis. AB - PURPOSE: Extensive studies have investigated the prognostic value of CD56 for patients with acute myeloid leukemia (AML), but the results remained inconclusive. The aim of this meta-analysis is to resolve this controversial issue. METHODS: A systematic search of PubMed, Embase, Cochrane Library, and CBM was performed to identify studies that assessed the prognostic value of CD56 in AML patients. Pooled hazard ratios (HRs) with 95 % confidence intervals (CIs) for overall survival (OS) and disease-free survival (DFS) and pooled odds ratio (OR) with 95 % CIs for complete remission rate (CRR) and relapse rate (RR) were calculated. RESULTS: Totally, 32 studies with 4074 patients were included. For AML with t(8;21) translocation, CD56 overexpression was associated with shorter OS (HR 2.22; 95 % CI 1.30-3.78) and DFS (HR 2.63; 95 % CI 1.10-6.29) and increased RR (OR 3.29; 95 % CI 1.67-6.48), but did not affect CRR (OR 0.94; 95 % CI 0.49-1.80). For AML with t(15;17) translocation, CD56 overexpression was associated with shorter OS (HR 2.43; 95 % CI 1.66-3.57) and DFS (HR 4.27; 95 % CI 1.15-15.78), increased RR (OR 3.11; 95 % CI 2.01-4.81), and decreased CRR (OR 0.42; 95 % CI 0.25-0.72). For AML as a whole, CD56 overexpression was associated with shorter OS (HR 1.74; 95 % CI 1.38-2.19) and DFS (HR 2.38; 95 % CI 1.87 3.02), increased RR (OR 5.19; 95 % CI 2.84-9.48), and decreased CRR (OR 0.62; 95 % CI 0.41-0.96). CONCLUSIONS: This meta-analysis indicated that CD56 overexpression may be an adverse prognostic factor for AML. PMID- 25924703 TI - [Tropical and travel-related dermatomycoses : Part 2: cutaneous infections due to yeasts, moulds, and dimorphic fungi]. AB - Besides dermatophytoses, a broad range of cutaneous infections due to yeasts and moulds may occur in subtropical and tropical countries where they can affect travellers. Not to be forgotten are endemic occurring dimorphic or biphasic fungi in countries with hot climate, which cause systemic and secondary cutaneous infections in immunosuppressed and immunocompetent people. In the tropics, the prevalence of pityriasis versicolor, caused by the lipophilic yeast Malassezia spp., is about 30-40 %, in distinct areas even 50 %. Increased hyperhidrosis under tropical conditions and simultaneously humidity congestion have to be considered as significant disposing factors for pityriasis versicolor. In tropical countries, therefore, an exacerbation of a preexisting pityriasis versicolor in travellers is not rare. Today, mostly genital yeast infections due to the new species Candida africana can be found worldwide. Due to migration from Africa this yeast pathogen has reached Germany and Europe. Eumycetomas due to mould fungi are rarely diagnosed in Europe. These deep cutaneous mould infections are only found in immigrants from African countries. The therapy of eumycetoma is protracted and often not successful. Cutaneous cryptococcoses due to the yeast species Cryptococcus neoformans and Cryptococcus gattii occur worldwide; however, they are found more frequently in the tropics. Immunosuppressed patients, especially those with HIV/AIDS, are affected by cryptococcoses. Furthermore, Cryptococcus gattii also causes infections in immunocompetent hosts in Central Africa, Australia, California, and Central America.Rarely found are infections due to dimorphic fungi after travel to countries where these fungal pathogens are endemic. In individual cases, cutaneous or lymphogenic transferred sporotrichosis due to Sporothrix schenkii can occur. Furthermore, scarcely known is secondary cutaneous coccidioidomycosis due to Coccidioides immitis after travelling to desert-like endemic regions in southwestern states of the United States and in Latin America, where primary respiratory infection due to this biphasic fungus can be acquired. The antifungal agent itraconazole is the treatment of choice for sporotrichosis and coccidioidomycosis. Talaromyces marneffei-until recently known as Penicillium marneffei-is only found in Southeastern Asia. Mycosis due to this dimorphic fungus has to be considered as an AIDS-defining opportunistic infection. After hematogeneous spread, Talaromyces marneffei affects the skin and mucous membranes of the mouth. Amphotericin B and itraconazole can be used for therapy. PMID- 25924704 TI - Upregulation of Homer1a Promoted Retinal Ganglion Cell Survival After Retinal Ischemia and Reperfusion via Interacting with Erk Pathway. AB - Retinal ischemia and reperfusion (I/R) is extensively involved in ocular diseases, causing retinal ganglion cell (RGCs) death resulting in visual impairment and blindness. Homer1a is considered as an endogenous neuroprotective protein in traumatic brain injury. However, the roles of Homer1a in RGCs I/R injury have not been elucidated. The present study investigated the changes in expression and effect of Homer1a in RGCs both in vitro and in vivo after I/R injury using Western blot, TUNEL assay, gene interference and overexpression, and gene knockout procedures. The levels of Homer1a and phosphorylated Erk (p-Erk) increased in RGCs and retinas after I/R injury. Upregulation of Homer1a in RGCs after I/R injury decreased the level of p-Erk, and mitigated RGCs apoptosis. Conversely, downregulation of Homer1a increased the level of p-Erk, and augmented RGCs apoptosis. Furthermore, inhibition of the p-ERK reduced RGCs apoptosis, and increased the expression of Homer 1a after I/R injury. Finally, the retinas of Homer1a KO mice treated with I/R injury had significantly less dendrites and RGCs, compared with Homer1a WT mice. These findings demonstrated that Homer1a may contribute to RGCs survival after I/R injury by interacting with Erk pathway. PMID- 25924705 TI - Effect of CYP2C9 Genetic Polymorphism in a Chinese Population on the Metabolism of Mestranol in vitro. AB - BACKGROUND: Mestranol is a widely used estrogen, which is converted into its active metabolite ethinyl estradiol by cytochrome P450 (CYP) 2C9. To comprehensively examine the enzymatic activity of reported CYP2C9 variants in Chinese individuals in response to mestranol, wild-type CYP2C9*1 and 35 allelic variants were highly expressed in Sf21 insect cell microsomes and used for the detection of their enzymatic values in vitro. These results showed that the majority of tested variants exhibited decreased clearance values compared to wild type, except for CYP2C9*40 and *36. METHOD: Insect microsomes expressing the 36 CYP2C9 variants were incubated with 0.25-8 MUmol/l mestranol for 30 min at 37 degrees C. Then, the production of the metabolite of mestranol, ethinyl estradiol, was analyzed using high-performance liquid chromatography. RESULTS: Most CYP-catalyzed reactions were sufficiently described by classical Michaelis Menten kinetic parameters (e.g., Km and Vmax), while 9 variants exhibited atypical or non-Michaelis-Menten kinetic values, which were largely due to the self-inhibitory effect in response to mestranol. CONCLUSION: This is the first report of these rare alleles for mestranol metabolism, which provides fundamental data for further clinical studies on CYP2C9 alleles for mestranol metabolism. PMID- 25924706 TI - The influence of cochlear implant electrode position on performance. AB - OBJECTIVES: To study the relation between variables related to cochlear implant electrode position and speech perception performance scores in a large patient population. DESIGN: The study sample consisted of 203 patients implanted with a CII or HiRes90K implant with a HiFocus 1 or 1J electrode of Advanced Bionics. Phoneme and word score averages for the 1- and 2-year follow-up were calculated for 41 prelingually deaf and 162 postlingually deaf patients. Analyses to reveal correlations between these performance outcomes and 6 position-related variables (angle of most basal electrode contact, surgical insertion angle, surgical insertion, wrapping factor, angular insertion depth, linear insertion depth) were executed. The scalar location, as an indication for the presence of intracochlear trauma, and modiolus proximity beyond the basal turn were not evaluated in this study. In addition, different patient-specific variables (age at implantation, age at onset of hearing loss, duration of deafness, preoperative phoneme and word scores) were tested for correlation with performance. RESULTS: The performance scores of prelingual patients were correlated with age at onset of hearing loss, duration of deafness and preoperative scores. For the postlingual patients, performance showed correlations with all 5 patient-specific variables. None of the 6 position-related variables influenced speech perception in cochlear implant patients. CONCLUSIONS: Although several patient-specific variables showed correlations with speech perception outcomes, not one of the studied angular and linear position-related variables turned out to have a demonstrable influence on performance. PMID- 25924707 TI - Clinicopathological features and outcomes of IgA nephropathy with hematuria and/or minimal proteinuria. AB - BACKGROUND/AIMS: Information regarding the clinical and histological prognostic factors of IgA nephropathy (IgAN) is mostly derived from patients in whom diagnostic renal biopsies were performed because their proteinuria levels were higher than 1-2 g/d. The clinicopathological features and outcomes of IgAN patients presenting with normal blood pressure, normal renal function, hematuria and minimal or no proteinuria are not well described. We therefore conducted a study of the clinicopathological features and outcomes in IgAN patients with these characteristics. METHODS: The clinical, laboratory, and pathological manifestations and long-term outcomes of all IgAN patients with the above mentioned characteristics were collected. The relationships between renal pathology, injury, long-term outcomes and clinical factors were studied, and the risk factors of IgAN were analyzed using multivariate logistic regression. RESULTS: Of all of the renal biopsy cases, IgAN with the above features accounted for 8.9%. Among these patients, 67.2% (253) showed simultaneous hematuria and proteinuria, 23.1% (87) showed only hematuria, and 9.7% (36) showed only proteinuria. Additionally, 33.8% (127) patients showed macroscopic hematuria and 65.1% (245) had a prodromal infection. Regarding renal pathological changes, 45.5% (171) of the patients were unexpectedly classified as Grade II to IV (Hass classification). Proteinuria at the time of renal biopsy was an independent predictor of more severe renal pathological injury. After a median follow-up of 75 months, 61 (16.2%) patients experienced adverse events. Among these patients, 28 (7.45%) exhibited hypertension, 22 (5.85%) presented proteinuria levels >1 g/24 h, and 11 (2.9%) developed impaired renal function. CONCLUSIONS: Severe renal histological injury may be observed in some IgAN patients with benign clinical characteristics. Proteinuria is an independent predictor of severe renal pathological injury in IgAN patients with mild proteinuria. More severe pathological injury (> Grade II, Hass classification) are predictors of poor prognosis. PMID- 25924708 TI - WITHDRAWN: Zinc for the common cold. PMID- 25924709 TI - Is fever control or improved survival the 'risk factor' for ventilator-associated pneumonia? PMID- 25924710 TI - Pneumopyopericardium mimicking an inferior ST elevation myocardial infarction with regional electrocardiogram changes: a case report. AB - BACKGROUND: Pneumopyopericardium is a rare disease with poor prognosis. The usual presentation is with fever, shortness of breath and haemodynamic compromise. The Electrocardiogram changes associated with this disease entity would be similar to pericarditis such as concave shaped ST elevations in all leads with PR sagging. Pneumopyopericardium mimicking an acute ST Elevation Myocardial Infarction, with regional Electrocardiogram changes has hitherto not been described in world literature. CASE PRESENTATION: We describe the case of a 48 year old native Sri Lankan man, presenting with chest pain and Electrocardiogram changes compatible with an Acute ST Elevation Myocardial Infarction, subsequently found to have Pneumopyopericardium secondary to an oesophageal tear. Retrospective history revealed repetitive vomiting due to heavy alcohol consumption, prior to presentation. It unfortunately led to a fatal outcome. CONCLUSION: Pneumopyopericardium may mimic an acute ST elevation myocardial infarction with associated regional Electrocardiogram changes. A high degree of suspicion should be maintained and an adequate history should always be obtained prior to any intervention in all ST Elevation Myocardial Infarction patients. PMID- 25924711 TI - High genetic risk individuals benefit less from resistance exercise intervention. AB - OBJECTIVES: Genetic factors have an important role in body mass index (BMI) variation, and also likely have a role in the weight loss and body composition response to physical activity/exercise. With the recent identification of BMI associated genetic variants, it is possible to investigate the interaction of these genetic factors with exercise on body composition outcomes. METHODS: In a block-randomized clinical trial of resistance exercise among women (n=148), we examined whether the putative effect of exercise on weight and dual-energy x-ray absorptiometry-derived body composition measurements differs according to genetic risk for obesity. Approximately one-half of the sample was randomized to an intervention consisting of a supervised, intensive, resistance exercise program, lasting 1 year. Genetic risk for obesity was defined as a genetic risk score (GRS) comprised of 21 single-nucleotide polymorphisms (SNPs) known to be associated with BMI variation. We examined the interaction of exercise intervention and the GRS on anthropometric and body composition measurements after 1 year of the exercise intervention. RESULTS: We found statistically significant interactions for body weight (P=0.01), body fat (P=0.01), body fat % (P=0.02) and abdominal fat (P=0.02), whereby the putative effect of exercise is greater among those with a lower level of genetic risk for obesity. No single SNP appears to be a major driver of these interactions. CONCLUSIONS: The weight-loss response to resistance exercise, including changes in body composition, differs according to an individual's genetic risk for obesity. PMID- 25924712 TI - Objective measures are complementary to, rather than a replacement for, self reported methods. PMID- 25924714 TI - Nutritional epidemiology data should be analyzed by nutritional epidemiologists. PMID- 25924713 TI - Response to 'Energy balance measurement: when something is not better than nothing'. PMID- 25924715 TI - Signal peptide peptidase-mediated nuclear localization of heme oxygenase-1 promotes cancer cell proliferation and invasion independent of its enzymatic activity. PMID- 25924716 TI - An intergenic regulatory region mediates Drosophila Myc-induced apoptosis and blocks tissue hyperplasia. PMID- 25924717 TI - Photochemical Synthesis of Ultrafine Cubic Boron Nitride Nanoparticles under Ambient Conditions. AB - Cubic boron nitride (c-BN) is a super-hard material whose hardness increases dramatically with decreasing size. However, c-BN nanoparticles (NPs) with sizes less than 10 nm have never been obtained. Herein we report a simple strategy towards the synthesis of ultrafine c-BN NPs with an average size of 3.5 nm. The method, under ambient conditions, exploits a laser-induced photochemical effect and employs dioxane solution of ammonia borane (AB) as a liquid target. Meanwhile, total dehydrogenation of AB is realized by laser irradiation. Therefore, this approach shows great potential for the preparation of super-hard NPs as well as controllable dehydrogenation. PMID- 25924718 TI - Identification of Recurrent Clostridium difficile Infection Using Administrative Codes: Accuracy and Implications for Surveillance. AB - OBJECTIVE: To develop an algorithm using administrative codes, laboratory data, and medication data to identify recurrent Clostridium difficile infection (CDI) and to examine the sensitivity, specificity, positive and negative predictive values, and performance of this algorithm. METHODS: We identified all patients with 2 or more International Classification of Diseases, Ninth Edition, Clinical Modification (ICD-9-CM) codes for CDI (008.45) from January 1 through December 31, 2013. Information on number of diagnosis codes, stool toxin assays (enzyme immunoassay or polymerase chain reaction), and unique prescriptions for metronidazole and vancomycin was identified. Logistic regression was used to identify independent predictors of recurrent CDI and a predictive model was developed. RESULTS: A total of 591 patients with at least 2 ICD-9 codes for CDI were included (median age, 66 years). The derivation cohort consisted of 157 patients among whom 43 (27%) had recurrent CDI. Presence of 3 or more ICD-9 codes for CDI (odds ratio, 2.49), 2 or more stool tests (odds ratio, 2.88), and 2 or more prescriptions for vancomycin (odds ratio, 5.87) were independently associated with confirmed recurrent CDI. A classifier incorporating 2 or more prescriptions for vancomycin and either 2 or more stool tests or 3 or more ICD-9 CM codes had a positive predictive value of 41% and negative predictive value of 90%. The area under the receiver operating characteristic curve for this combined classifier was modest (0.69). CONCLUSION: Identification of recurrent episodes of CDI in administrative data poses challenges. Accurate assessment of burden requires individual case review to confirm diagnosis. PMID- 25924719 TI - Malignant risk stratification of thyroid FNA specimens with indeterminate cytology based on molecular testing. AB - BACKGROUND: Fine-needle aspiration (FNA) has been employed for many years for examining thyroid nodules, and the cytology of aspirates is the primary determinant for whether thyroidectomy is indicated. Fifteen to thirty percent of thyroid nodules, not being clearly benign or malignant, fall into an indeterminate category. The main goals of molecular diagnostics for thyroid nodules are to prevent unnecessary surgery in patients with benign nodules and to stop patients with malignant nodules from being subjected to repeated operations. METHODS: This study was designed to evaluate the diagnostic utility of 4 markers in thyroid FNA cytology via testing for the BRAF V600E mutation and the expression of microRNA-221, microRNA-222, and galectin-3 protein in FNA samples with indeterminate cytology. RESULTS: A predictor model distinguishing benign samples from malignant samples on the basis of the 4 aforementioned markers was formulated. This decision model provided a sensitivity of 73.5%, a specificity of 89.8%, and a diagnostic accuracy of 75.7%. The positive predictive value was 80.6%, and the negative predictive value was 85.5%; this suggested that the prediction had good reliability. CONCLUSIONS: One hundred twenty FNA samples were examined, and 62 nodules were classified as benign with the proposed diagnostic algorithm. This resulted in a reduction of the initial 120 patients to 58 and thus decreased by half the number of persons undergoing surgery. PMID- 25924720 TI - Domain atrophy creates rare cases of functional partial protein domains. AB - BACKGROUND: Protein domains display a range of structural diversity, with numerous additions and deletions of secondary structural elements between related domains. We have observed a small number of cases of surprising large-scale deletions of core elements of structural domains. We propose a new concept called domain atrophy, where protein domains lose a significant number of core structural elements. RESULTS: Here, we implement a new pipeline to systematically identify new cases of domain atrophy across all known protein sequences. The output of this pipeline was carefully checked by hand, which filtered out partial domain instances that were unlikely to represent true domain atrophy due to misannotations or un-annotated sequence fragments. We identify 75 cases of domain atrophy, of which eight cases are found in a three-dimensional protein structure and 67 cases have been inferred based on mapping to a known homologous structure. Domains with structural variations include ancient folds such as the TIM-barrel and Rossmann folds. Most of these domains are observed to show structural loss that does not affect their functional sites. CONCLUSION: Our analysis has significantly increased the known cases of domain atrophy. We discuss specific instances of domain atrophy and see that there has often been a compensatory mechanism that helps to maintain the stability of the partial domain. Our study indicates that although domain atrophy is an extremely rare phenomenon, protein domains under certain circumstances can tolerate extreme mutations giving rise to partial, but functional, domains. PMID- 25924722 TI - Association between Oxidative Stress and Frailty in an Elderly German Population: Results from the ESTHER Cohort Study. AB - BACKGROUND: Oxidative stress (OS) and inflammatory biomarkers have been postulated to be important factors in the development of age-related diseases. While causes of frailty are complex and multidimensional based on the interaction of genetic, biological, physical, and environmental factors, the biological basis of frailty has been difficult to establish. OBJECTIVE: In this study, we aimed to assess the possible association between different OS and inflammatory biomarkers and frailty. METHODS: This cross-sectional analysis was performed among 2,518 subjects participating in a large population-based cohort study on aging conducted in Germany. Frailty was assessed as proposed by Fried et al. [J Gerontol A Biol Sci Med Sci 2001;56:M146-M156]. OS biomarkers, biological antioxidant potential (BAP), derivate of reactive oxygen metabolites (d-ROM) and total thiol levels (TTL), and an established biomarker of inflammation C-reactive protein (CRP) were measured by spectrophotometry and immunoturbidimetry. Logistic regression models were performed to assess the relationship between the OS biomarkers and frailty status. Odds ratios (OR) and 95% confidence intervals (CI) were calculated to quantify the associations. RESULTS: Mean levels of d-ROM, TTL, and CRP differed between frail and non-frail participants (p values <0.0001). Comparing highest and lowest quartiles of the biomarkers, statistically significant positive associations with frailty were observed for d-ROM (OR: 2.02, 95% CI: 1.25-3.25) and CRP (OR: 3.15, 95% CI: 2.00-4.96), respectively, after controlling for age and sex. An inverse statistically significant association with frailty was observed for TTL (OR: 0.42, 95% CI: 0.25-0.69). CONCLUSION: The strong associations with OS biomarkers and CRP support a major role of OS and inflammation in the development of frailty, which should be followed up in further longitudinal studies on frailty. PMID- 25924721 TI - Bridging the Gap: using an interrupted time series design to evaluate systems reform addressing refugee maternal and child health inequalities. AB - BACKGROUND: The risk of poor maternal and perinatal outcomes in high-income countries such as Australia is greatest for those experiencing extreme social and economic disadvantage. Australian data show that women of refugee background have higher rates of stillbirth, fetal death in utero and perinatal mortality compared with Australian born women. Policy and health system responses to such inequities have been slow and poorly integrated. This protocol describes an innovative programme of quality improvement and reform in publically funded universal health services in Melbourne, Australia, that aims to address refugee maternal and child health inequalities. METHODS/DESIGN: A partnership of 11 organisations spanning health services, government and research is working to achieve change in the way that maternity and early childhood health services support families of refugee background. The aims of the programme are to improve access to universal health care for families of refugee background and build organisational and system capacity to address modifiable risk factors for poor maternal and child health outcomes. Quality improvement initiatives are iterative, co-designed by partners and implemented using the Plan Do Study Act framework in four maternity hospitals and two local government maternal and child health services. Bridging the Gap is designed as a multi-phase, quasi-experimental study. Evaluation methods include use of interrupted time series design to examine health service use and maternal and child health outcomes over a 3-year period of implementation. Process measures will examine refugee families' experiences of specific initiatives and service providers' views and experiences of innovation and change. DISCUSSION: It is envisaged that the Bridging the Gap program will provide essential evidence to support service and policy innovation and knowledge about what it takes to implement sustainable improvements in the way that health services support vulnerable populations, within the constraints of existing resources. PMID- 25924723 TI - The application of the Palliative Prognostic Index, charlson comorbidity index, and Glasgow Prognostic Score in predicting the life expectancy of patients with hematologic malignancies under palliative care. AB - BACKGROUND: The clinical course for hematologic malignancy varies widely and no prognostic tool is available for patients with a hematologic malignancy under palliative care. To assess the application of the Palliative Prognostic Index (PPI), Charlson Comorbidity Index (CCI), and Glasgow Prognostic Score (GPS) as prognostic tools in patients with hematologic malignancies under palliative care. METHODS: We included 217 patients with pathologically proven hematologic malignancies under palliative care consultation service (PCCS) between January 2006 and December 2012 at a single medical center in Taiwan. Patients were categorized into subgroups by PPI, CCI, and GPS for survival analysis. RESULTS: The median survival was 16 days (interquartile range, 4-47.5 days) for all patients and 204 patients (94%) died within 180 days after PCCS. There was a significant difference in survival among patients categorized using the PPI (median survival 49, 15, and 7 days in patients categorized into a good, intermittent, and poor prognostic group, respectively) and the GPS (median survival 66 and 13 days for GPS 0 and 1, respectively). There was no difference in survival between patients with a GPS score of 0 versus 2, or a CCI score of 0 versus >=1. The survival time was significantly discriminated after stratifying patients with a good PPI score based on the CCI (median survival 102 and 41 days in patients with a CCI score of 0 and >=1, respectively) from those with a poor PPI score by using the GPS (median survival 47 and 7 days in patients with GPS scores of 0 and 1-2, respectively). CONCLUSIONS: PPI is a useful prognosticator of life expectancy in terminally ill patients under palliative care for a hematologic malignancy. Concurrent use of the GPS and CCI improved the accuracy of prognostication using the PPI. PMID- 25924724 TI - Total laparoscopic nerve-sparing radical parametrectomy for occult early-stage cervical cancer: surgical technique and postoperative bladder function. AB - Surgery and radiotherapy are both regarded as standard treatments for occult cervical cancers. Surgery has several theoretical advantages over radiotherapy; therefore, such cancers, especially in their early stages, are commonly treated with radical parametrectomy. However, postoperative bladder dysfunction is an important potential complication of this type of surgery. This is a case report of total laparoscopic nerve-sparing radical parametrectomy for an occult cervical cancer using our original surgical concept based on detailed anatomical investigation of pelvic nerve networks in a fresh cadaver. We evaluated the validity of our nerve-sparing technique by assessing postoperative bladder function using urodynamic studies. PMID- 25924726 TI - Modular synthesis of a dual metal-dual semiconductor nano-heterostructure. AB - Reported is the design and modular synthesis of a dual metal-dual semiconductor heterostructure with control over the dimensions and placement of its individual components. Analogous to molecular synthesis, colloidal synthesis is now evolving into a series of sequential synthetic procedures with separately optimized steps. We detail the challenges and parameters that must be considered when assembling such a multicomponent nanoparticle, and their solutions. This multicomponent nanosystem, Ru-CdSe@CdS-Pt, was designed to achieve charge carrier separation and directional transfer across different interfaces toward two separate redox catalysts. This heterostructure may potentially serve as a nanometric closed circuit photoelectrochemical cell. PMID- 25924725 TI - Multivariate meta-analysis of prognostic factor studies with multiple cut-points and/or methods of measurement. AB - A prognostic factor is any measure that is associated with the risk of future health outcomes in those with existing disease. Often, the prognostic ability of a factor is evaluated in multiple studies. However, meta-analysis is difficult because primary studies often use different methods of measurement and/or different cut-points to dichotomise continuous factors into 'high' and 'low' groups; selective reporting is also common. We illustrate how multivariate random effects meta-analysis models can accommodate multiple prognostic effect estimates from the same study, relating to multiple cut-points and/or methods of measurement. The models account for within-study and between-study correlations, which utilises more information and reduces the impact of unreported cut-points and/or measurement methods in some studies. The applicability of the approach is improved with individual participant data and by assuming a functional relationship between prognostic effect and cut-point to reduce the number of unknown parameters. The models provide important inferential results for each cut point and method of measurement, including the summary prognostic effect, the between-study variance and a 95% prediction interval for the prognostic effect in new populations. Two applications are presented. The first reveals that, in a multivariate meta-analysis using published results, the Apgar score is prognostic of neonatal mortality but effect sizes are smaller at most cut-points than previously thought. In the second, a multivariate meta-analysis of two methods of measurement provides weak evidence that microvessel density is prognostic of mortality in lung cancer, even when individual participant data are available so that a continuous prognostic trend is examined (rather than cut-points). PMID- 25924727 TI - MS565: A SPECT Tracer for Evaluating the Brain Penetration of BAF312 (Siponimod). AB - BAF312 (siponimod) is a sphingosine-1-phosphate (S1P) receptor modulator in clinical development for the treatment of multiple sclerosis, with faster organ/tissue distribution and elimination kinetics than its precursor FTY720 (fingolimod). Our aim was to develop a tracer to better quantify the penetration of BAF312 in the human brain, with the potential to be labeled for positron emission tomography (PET) or single-photon emission computed tomography (SPECT). Although the PET radioisotopes (11)C and (18)F could have been introduced in BAF312 without modifying its structure, they do not have decay kinetics compatible with the time required for observing the drug's organ distribution in patients. In contrast, the SPECT radioisotope (123) I has a longer half-life and would suit this purpose. Herein we report the identification of an iodinated derivative of BAF312, (E)-1-(4-(1-(((4-cyclohexyl-3-iodobenzyl)oxy)imino)ethyl)-2 ethylbenzyl)azetidine-3-carboxylic acid (18, MS565), as a SPECT tracer candidate with affinity, S1P receptor selectivity, overall physicochemical properties, and blood pharmacokinetics similar to those of the original molecule. A whole-body autoradiography study performed with [(14)C]MS565 subsequently confirmed that its organ distribution is similar to that of BAF312. This validates the selection of MS565 for (123)I radiolabeling and for use in imaging studies to quantify the brain penetration of BAF312. PMID- 25924728 TI - Association of Abnormal Liver Function Parameters with HIV Serostatus and CD4 Count in Antiretroviral-Naive Rwandan Women. AB - We determined the associations of HIV infection/CD4 count with markers of hepatocellular damage [elevated aspartate aminotransferase (AST) and alanine aminotransferase (ALT)] and liver synthetic function (decreased albumin) in HIV infected (HIV(+)) antiretroviral therapy (ART)-naive and uninfected (HIV(-)) Rwandan women. In 2005, 710 HIV(+) ART-naive and 226 HIV(-) women enrolled in the Rwanda Women's Interassociation Study and Assessment. Liver enzymes were measured with abnormality defined as either AST or ALT >=1.25 times the upper limit of normal. Low serum albumin level was defined as <3.5 g/dl. Multivariable logistic regression analysis identified independent predictors of elevated AST/ALT and low serum albumin. HIV(-) women had the lowest prevalence (6.6%) of abnormal AST/ALT, with the highest prevalence (16.4%) in HIV(+) women with CD4 <200 cells/MUl (p=0.01). The odds of having serum albumin <3.5 g/dl was 5.7-fold higher in HIV(+) than HIV(-) women (OR=5.68, 95% CI: 3.32-9.71). The risk of low albumin decreased from low to high CD4 count, with OR=2.62, 95% CI: 1.66, 4.14 and OR=1.57, 95% CI: 1.01, 2.43 in HIV(+) women with a CD4 count <200 and 200-350 cells/MUl, respectively vs. HIV(+) with CD4 >350 (p<0.001 and p<0.05 for all comparisons). Our findings suggest that HIV-associated liver damage may occur in ART-naive patients. Although liver abnormality prevalences in this cohort of HIV infected Rwandan women are less than reported in developed countries, caution is needed for risk assessment measures to monitor and screen HIV-infected patients pre- and post-ART initiation in African clinical settings to curtail potential risks associated with HIV infection. PMID- 25924729 TI - Biophysical probing of the binding properties of a Cu(II) complex with G quadruplex DNA: an experimental and computational study. AB - Telomerase inhibition through G-quadruplex stabilization by small molecules is of great interest as a novel anticancer therapeutic strategy. Here, we show that newly synthesized Cu-complex binds to G-quadruplex DNA and induces changes in its stability. This biophysical interaction was investigated in vitro using spectroscopic, voltammetric and computational techniques. The binding constant for this complex to G-quadruplex using spectroscopic and electrochemical methods is in the order of 10(5) . The binding stoichiometry was investigated using spectroscopic techniques and corresponded to a ratio of 1: 1. Fluorescence titration results reveal that Cu-complex is quenched in the presence of G quadruplex DNA. Analysis of the fluorescence emission at different temperatures shows that DeltaH degrees > 0, DeltaS degrees > 0 and DeltaG degrees < 0, and indicates that hydrophobic interactions played a major role in the binding processes. MD simulation results suggested that this ligand could stabilize the G quadruplex structure. An optimized docked model of the G-quadruplex-ligand mixture confirmed the experimental results. Based on the results, we conclude that Cu-complex as an anticancer candidate can bind and stabilize the G quadruplex DNA structure. PMID- 25924730 TI - Reduction of CO2 by Pyridine Monoimine Molybdenum Carbonyl Complexes: Cooperative Metal-Ligand Binding of CO2. AB - [((Ar) PMI)Mo(CO)4 ] complexes (PMI=pyridine monoimine; Ar=Ph, 2,6-di-iso propylphenyl) were synthesized and their electrochemical properties were probed with cyclic voltammetry and infrared spectroelectrochemistry (IR-SEC). The complexes undergo a reduction at more positive potentials than the related [(bipyridine)Mo(CO)4 ] complex, which is ligand based according to IR-SEC and DFT data. To probe the reaction product in more detail, stoichiometric chemical reduction and subsequent treatment with CO2 resulted in the formation of a new product that is assigned as a ligand-bound carboxylate, [( iPr 2PhPMI)Mo(CO)3 (CO2 )](2-) , by NMR spectroscopic methods. The CO2 adduct [( iPr 2PhPMI)Mo(CO)3 (CO2 )](2-) could not be isolated and fully characterized. However, the C-C coupling between the CO2 molecule and the PDI ligand was confirmed by X-ray crystallographic characterization of one of the decomposition products of [( iPr 2PhPMI)Mo(CO)3 (CO2 )](2-) . PMID- 25924731 TI - Change in self-rated general health is associated with perceived illness burden: a 1-year follow up of patients newly diagnosed with type 2 diabetes. AB - BACKGROUND: Diabetic patients' lifestyle adaptations to improve glycaemic control are not always followed by improvements in self-rated general health (SRH). The perceived impact of diabetes on patients' daily lives may influence changes in their SRH. This paper examines the association of illness severity, treatment, behavioural, and coping-related factors with changes in SRH from diagnosis of type 2 diabetes until one year later, in a population-based sample of 599 patients aged 40 years or over who were treated in general practice. METHODS: Change in SRH was estimated by a cumulative probit model with the inclusion of covariates related to SRH (e.g. illness severity at diagnosis, behaviour, treatment, and the perceived impact of diabetes on patients' daily lives one year later). RESULTS: At diagnosis, 11.6% of patients reported very good, 35.1% good, 44.6% fair and 8.5% poor SRH. Physical inactivity, many diabetes-related symptoms, and cardiovascular disease were related to lower SRH ratings. On average SRH improved by 0.46 (95% CI: 0.37; 0.55) during the first year after diagnosis without inclusion of covariates. Mental and practical illness burden was the only factor associated with change in SRH, independent of patients' diabetes severity and medical treatment (p = 0.03, multivariate analysis). Compared to otherwise similar patients without illness burden, increase in SRH was marginally smaller among patients who expressed minor illness burden, but much smaller among patients with more pronounced illness burden. CONCLUSIONS: Much as one would expect, many patients increased their SRH during the first year after diabetes diagnosis. This increase in SRH was not associated with indicators of illness severity or factors reflecting socio-demographic circumstances, but patients experiencing illness burden had a smaller increase than those who reported no illness burden. We suggest that during the diabetes consultation, general practitioners explore further how patients manage their illness burden. We further suggest that diabetes guidelines extend their current focus on clinical and social aspects of diabetes to include questions on patient's perceived illness burden and SRH. PMID- 25924732 TI - Formulation and evaluation of different floating tablets containing metronidazole to target stomach. AB - The purpose of this study is to formulate and develop tablets dosage form containing Metronidazole which has swelling and floating properties as a gastroretentive controlled-release drug delivery system to improve drug bioavailability. Fifteen different formulations of effervescence-forming floating systems were designed using HPMC K15M, xanthan gum, co-povidone, Eudragit(r) RL PO, pluronic(r) F-127 and/or polypropylene foam powder as swelling agents and sodium bicarbonate with/ without citric acid as gas-forming agents at different compositions. Six out of these 15 formulations which have satisfactory tablet floating behaviour were further studied with the incorporation of Metronidazole. The tablets were evaluated based on tablet physicochemical properties, floating behaviour, swelling ability and drug dissolution studies which were carried out using 0.1M HCl at 37 degrees C for 8 hours. Furthermore, evaluation of the powder mixtures using Fourier transform infrared (FT-IR) spectroscopy, differential scanning calorimetry (DSC) and scanning electron microscope (SEM) were investigated. Most of the tablets show good physicochemical properties except for F11 which contains pluronic(r) F-127 as its release-retarding matrix-forming polymer. Other formulations show high swelling capacity, ability to float for at least 8 hours in vitro and have sustained drug release characteristics. Data obtained indicated that F3 which contains HPMC (12.5%w/w), xanthan gum (25%w/w), co-povidone (12.5%w/w) and sodium bicarbonate (31.7%w/w) is a suitable formulation with short floating lag time, good floating behaviour and sustained drug release for at least 8 hours in vitro with a zero order kinetic. Combinations of HPMC K15M and xanthan gum as swelling agents show synergistic effect in retarding drug release and are suitable in providing the most sustained drug release system. PMID- 25924734 TI - Long-term low intensity physical exercise attenuates heart failure development in aging spontaneously hypertensive rats. AB - BACKGROUND: Physical exercise is a strategy to control hypertension and attenuate pressure overload-induced cardiac remodeling. The influence of exercise on cardiac remodeling during uncontrolled hypertension is not established. We evaluated the effects of a long-term low intensity aerobic exercise protocol on heart failure (HF) development and cardiac remodeling in aging spontaneously hypertensive rats (SHR). METHODS: Sixteen month old SHR (n=50) and normotensive Wistar-Kyoto (WKY, n=35) rats were divided into sedentary (SED) and exercised (EX) groups. Rats exercised in treadmill at 12 m/min, 30 min/day, 5 days/week, for four months. The frequency of HF features was evaluated at euthanasia. STATISTICAL ANALYSES: ANOVA and Tukey or Mann-Whitney, and Goodman test. RESULTS: Despite slightly higher systolic blood pressure, SHR-EX had better functional capacity and lower HF frequency than SHR-SED. Echocardiography and tissue Doppler imaging showed no differences between SHR groups. In SHR-EX, however, left ventricular (LV) systolic diameter, larger in SHR-SED than WKY-SED, and endocardial fractional shortening, lower in SHR-SED than WKY-SED, had values between those in WKY-EX and SHR-SED not differing from either group. Myocardial function, assessed in LV papillary muscles, showed improvement in SHR-EX over SHR SED and WKY-EX. LV myocardial collagen fraction and type I and III collagen gene expression were increased in SHR groups. Myocardial hydroxyproline concentration was lower in SHR-EX than SHR-SED. Lysyl oxidase gene expression was higher in SHR SED than WKY-SED. CONCLUSION: Exercise improves functional capacity and reduces decompensated HF in aging SHR independent of elevated arterial pressure. Improvement in functional status is combined with attenuation of LV and myocardial dysfunction and fibrosis. PMID- 25924733 TI - Long-Term Exposure to House Dust Mite Leads to the Suppression of Allergic Airway Disease Despite Persistent Lung Inflammation. AB - BACKGROUND: Allergic asthma is a major cause of worldwide morbidity and results from inadequate immune regulation in response to innocuous, environmental antigens. The need exists to understand the mechanisms that promote nonreactivity to human-relevant allergens such as house dust mite (HDM) in order to develop curative therapies for asthma. The aim of our study was to compare the effects of short-, intermediate- and long-term HDM administration in a murine asthma model and determine the ability of long-term HDM exposure to suppress allergic inflammation. METHODS: C57BL/6 mice were intranasally instilled with HDM for short-term (2 weeks), intermediate-term (5 weeks) and long-term (11 weeks) periods to induce allergic airway disease (AAD). The severity of AAD was compared across all stages of the model via both immunological and pulmonary parameters. RESULTS: Short- and intermediate-term HDM exposure stimulated the development of AAD that included eosinophilia in the bronchoalveolar lavage fluid (BALF), pronounced airway hyperreactivity (AHR) and evidence of lung inflammation. Long term HDM exposure promoted the suppression of AAD, with a loss of BALF eosinophilia and AHR despite persistent mononuclear inflammation in the lungs. Suppression of AAD with long-term HDM exposure was associated with an increase in both Foxp3+ regulatory T cells and IL-10-positive alveolar macrophages at the site of inflammation. CONCLUSIONS: This model recapitulates the key features of human asthma and may facilitate investigation into the mechanisms that promote immunological tolerance against clinically relevant aeroallergens. PMID- 25924735 TI - Hippocampal Subfield Atrophy in Multi-Domain but Not Amnestic Mild Cognitive Impairment. AB - BACKGROUND/AIMS: To investigate differences in hippocampal (HP) subfields and the adjoining perirhinal and entorhinal cortices (PRC and ERC) between amnestic mild cognitive impairment (aMCI) and multi-domain amnestic MCI (mdMCI) patients, and controls. METHODS: Nineteen patients characterized as aMCI were compared with 24 mdMCI patients and 31 controls by means of an automatic HP segmentation procedure. RESULTS: We found significant atrophy of the PRC and ERC in aMCI relative to controls, whereas a more pronounced pattern of atrophy in most subfields, including total HP volume, was found in the mdMCI group. The mdMCI group also had a significant cornu ammonis sector 4 region with dentate gyrus, subiculum and total HP atrophy relative to aMCI. CONCLUSION: The aMCI group showed atrophy in the PRC and ERC, whereas significantly more affection of the HP subfields was evident in mdMCI. The mdMCI group may thus represent clinical progression relative to aMCI coupled with HP subfield affection. PMID- 25924736 TI - Lower lung cancer rates in Jewish smokers in Israel and the USA. AB - Lung cancer rates in Israeli Jews have remained stable over the last five decades and are much lower than in most developed countries despite high historical smoking rates. We compared lung cancer risk in Jews and non-Jews in Israel and in the United States. Data were derived from a population-based, case-control study in Israel (638 cases, 496 controls) to estimate lung cancer risk associated with smoking. Data were also acquired from a case-control study in the United States with information on religious affiliation (5,093 cases, 4,735 controls). Smoking was associated with lung cancer risk in all religion/gender groups in both studies. However, major differences in risk magnitude were noted between Jews and non-Jews; ever smoking was associated with a moderately elevated risk of lung cancer in Jewish men and women in Israel (OR = 4.61, 2.90-7.31 and OR = 2.10, 1.36-3.24, respectively), and in Jewish men and women in the United States (OR = 7.63, 5.34-10.90 and OR = 8.50, 5.94-12.17) but were significantly higher in Israeli non-Jewish men (OR = 12.96, 4.83-34.76) and US non-Jewish men and women (OR = 11.33, 9.09-14.12 and OR = 12.78, 10.45-15.63). A significant interaction between smoking and religion was evident in light, moderate and heavy male and female smokers. The differences in risk level between Israeli Jews and non-Jews could not be explained by lung cancer genetic risk variants which were identified in GWAS (genes in the CHRNA5, TERT and CLPTM1L regions). Data from the two studies support the notion of a reduced risk of lung cancer in Jewish compared to non-Jewish smokers in different areas of the world. PMID- 25924738 TI - Valuable guidance on frailty. PMID- 25924737 TI - Efficacy and Safety of Intravitreal Dexamethasone Implant in Patients with Diabetic Macular Edema. AB - PURPOSE: To evaluate the efficacy and safety of intravitreal implant of dexamethasone (Ozurdex(r)) in diabetic macular edema (DME). METHODS: This was a retrospective multicenter noncomparative study. Seventy-eight patients with DME followed for at least 6 months were included (P1.5 Network). Best-corrected visual acuity (BCVA), central retinal thickness (CRT), intraocular pressure (IOP) and cataract progression were studied at baseline and then at 1, 2, 4 and 6 months. RESULTS: The mean CRT decrease from baseline was 145.2 um at 6 months. The mean BCVA improvement from baseline was 6.7 at 6 months. An increase in IOP was observed for 11.7% of patients, and all patients were managed by topical treatment. No glaucoma or cataract surgery was necessary, and no endophthalmitis was reported. CONCLUSIONS: One injection of Ozurdex has an anatomical and functional effectiveness for the treatment of DME. Side effects were rare and manageable in our practice. (c) 2015 S. Karger AG, Basel. PMID- 25924740 TI - Obese people are less likely to develop dementia, finds study. PMID- 25924741 TI - Commission asks for ideas to create integrated service. PMID- 25924742 TI - Acute hospitals recognised for quality of end of life care. PMID- 25924743 TI - Trusts urged to extend visiting hours for 'partners in care'. PMID- 25924744 TI - Role play masterclass for sensitive conversations. PMID- 25924745 TI - Befriending service puts best practice in the spotlight. PMID- 25924749 TI - Get the right connections. PMID- 25924755 TI - Practice question. Collaborative working with patients and their families. PMID- 25924756 TI - Developing the evidence base for hygiene and emollient practices. AB - Maintaining skin integrity is an essential part of ensuring health and wellbeing in older people, and personal hygiene and emollient practices are central in achieving this aim. As nurses we are expected to deliver evidence-based care. However, there is a significant lack of evidence about how best we should provide day-to-day care that promotes skin health for older people. This article briefly examines the concept of evidence-based practice, reveals the gap in knowledge on skin hygiene and emollient practices for older people and justifies the need for a systematic review in this area. Finally it introduces a Cochrane protocol for a review that will collate and review existing knowledge and identify areas for future research. The application to practice of the new evidence generated either by the Cochrane review or by subsequent research is examined. PMID- 25924757 TI - Diagnosis and management of patients with hypercalcaemia. AB - Hypercalcaemia is a common biochemical abnormality in the blood that can be caused by malignancy, hyperparathyroidism, medications or underlying medical conditions. Initial signs and symptoms are often vague, however, if someone has severe hypercalcaemia it is treated as an emergency, requiring prompt management to prevent life-threatening complications such as dehydration, cardiac arrhythmias or coma. Understanding the pathophysiology, signs and symptoms of hypercalcaemia enables effective diagnosis and holistic management of the patient with complex health needs. PMID- 25924758 TI - Methods for managing residents with dysphagia. AB - Nurses working in nursing homes will care for residents who have dysphagia, or difficulty swallowing, on a regular basis. Clear, evidence-based guidelines are necessary for all staff to be able to meet the needs of these residents safely and efficiently. A multidisciplinary approach is important to ensure accurate assessment, devise appropriate care and achieve specific goals. Equipment such as valved beakers, rimmed plates and non-slip mats will help maintain safety during mealtimes. Prescription items, such as fluid thickeners and anticholinergic medication, help to manage the condition and provide comfort during mealtimes and in between. Robust education and training should be in place for all nursing and care staff who care for residents with the condition. PMID- 25924759 TI - Improving communication when caring for acutely ill patients with dementia. AB - People living with dementia have complex needs, which may be compounded when they develop an acute illness. It is vital to recognise any deterioration in a patient and respond appropriately to prevent serious complications and, in some cases, mortality. It is necessary for all healthcare professionals to develop assessment skills that take account of potential communication difficulties. This article reviews the literature on communicating with people with dementia, and considers the main issues involved in managing patients with an acute illness who are already living with dementia. The aim is to ensure that nurses consider how they communicate in these situations and to recognise the benefits that can be gained by healthcare professionals and patients from enhanced communication. PMID- 25924760 TI - Live life to the full. PMID- 25924761 TI - Dysregulation of serum gamma interferon levels in vascular chronic Q Fever patients provides insights into disease pathogenesis. AB - A large community outbreak of Q fever occurred in the Netherlands in the period 2007 to 2010. Some of the infected patients developed chronic Q fever, which typically includes pathogen dissemination to predisposed cardiovascular sites, with potentially fatal consequences. To identify the immune mechanisms responsible for ineffective clearance of Coxiella burnetii in patients who developed chronic Q fever, we compared serum concentrations of 47 inflammation associated markers among patients with acute Q fever, vascular chronic Q fever, and past resolved Q fever. Serum levels of gamma interferon were strongly increased in acute but not in vascular chronic Q fever patients, compared to past resolved Q fever patients. Interleukin-18 levels showed a comparable increase in acute as well as vascular chronic Q fever patients. Additionally, vascular chronic Q fever patients had lower serum levels of gamma interferon-inducible protein 10 (IP-10) and transforming growth factor beta (TGF-beta) than did acute Q fever patients. Serum responses for these and other markers indicate that type I immune responses to C. burnetii are affected in chronic Q fever patients. This may be attributed to an affected immune system in cardiovascular patients, which enables local C. burnetii replication at affected cardiovascular sites. PMID- 25924762 TI - Loss of Immunization-Induced Epitope-Specific CD4 T-Cell Response following Anaplasma marginale Infection Requires Presence of the T-Cell Epitope on the Pathogen and Is Not Associated with an Increase in Lymphocytes Expressing Known Regulatory Cell Phenotypes. AB - We have shown that in cattle previously immunized with outer membrane proteins, infection with Anaplasma marginale induces a functionally exhausted CD4 T-cell response to the A. marginale immunogen. Furthermore, T-cell responses following infection in nonimmunized cattle had a delayed onset and were sporadic and transient during persistent infection. The induction of an exhausted T-cell response following infection presumably facilitates pathogen persistence. In the current study, we hypothesized that the loss of epitope-specific T-cell responses requires the presence of the immunizing epitope on the pathogen, and T-cell dysfunction correlates with the appearance of regulatory T cells. In limited studies in cattle, regulatory T cells have been shown to belong to gammadelta T cell subsets rather than be CD4 T cells expressing forkhead box protein P3 (FoxP3). Cattle expressing the DRB3*1101 haplotype were immunized with a truncated A. marginale major surface protein (MSP) 1a that contains a DRB3*1101 restricted CD4 T-cell epitope, F2-5B. Cattle either remained unchallenged or were challenged with A. marginale bacteria that express the epitope or with A. marginale subsp. centrale that do not. Peripheral blood and spleen mononuclear cells were monitored for MSP1a epitope F2-5B-specfic T-cell proliferative responses and were stained for gammadelta T-cell subsets or CD4(+) CD25(+) FoxP3(+) T cells before and during infection. As hypothesized, the induction of T cell exhaustion occurred only following infection with A. marginale, which did not correlate with an increase in either CD4(+) CD25(+) FoxP3(+) T cells or any gammadelta T-cell subset examined. PMID- 25924763 TI - Evaluation of the Salmonella enterica Serovar Pullorum Pathogenicity Island 2 Mutant as a Candidate Live Attenuated Oral Vaccine. AB - Salmonella enterica serovar Pullorum (S. Pullorum) is a highly adapted pathogen that causes pullorum disease (PD), an important systemic disease of poultry that causes severe economic losses in developing countries. In the interests of developing a safe and immunogenic oral vaccine, the efficacy of a Salmonella pathogenicity island 2 (SPI2)-deleted mutant of S. Pullorum (S06004DeltaSPI2) was evaluated in chickens. S06004DeltaSPI2 was severely less virulent than the parental wild-type strain S06004 as determined by the 50% lethal dose (LD50) for 3-day-old chickens when injected intramuscularly. Two-day-old chickens immunized with a single oral dose of S06004DeltaSPI2 showed no differences in body weight or clinical symptoms compared with those in the negative-control group. S06004DeltaSPI2 bacteria were not isolated from livers or spleens of immunized chickens after a short period of time, and specific humoral and cellular immune responses were significantly induced. Immunized chickens were challenged with S. Pullorum strain S06004 and Salmonella enterica serovar Gallinarum (S. Gallinarum) strain SG9 at 10 days postimmunization (dpi), and efficient protection against the challenges was observed. None of the immunized chickens died, the clinical symptoms were slight and temporary following challenge in immunized chickens compared with those in the control group, and these chickens recovered by 3 to 5 dpi. Overall, these results demonstrate that S06004DeltaSPI2 can be used as a live attenuated oral vaccine. PMID- 25924764 TI - Antiviral Innate Immune Activation in HIV-Infected Adults Negatively Affects H1/IC31-Induced Vaccine-Specific Memory CD4+ T Cells. AB - Tuberculosis (TB) remains a global health problem, with vaccination being a necessary strategy for disease containment and elimination. A TB vaccine should be safe and immunogenic as well as efficacious in all affected populations, including HIV-infected individuals. We investigated the induction and maintenance of vaccine-induced memory CD4(+) T cells following vaccination with the subunit vaccine H1/IC31. H1/IC31 was inoculated twice on study days 0 and 56 among HIV infected adults with CD4(+) lymphocyte counts of >350 cells/mm(3). Whole venous blood stimulation was conducted with the H1 protein, and memory CD4(+) T cells were analyzed using intracellular cytokine staining and polychromatic flow cytometry. We identified high responders, intermediate responders, and nonresponders based on detection of interleukin-2 (IL-2), tumor necrosis factor alpha (TNF-alpha), and gamma interferon (IFN-gamma) expressing central (TCM) and effector memory CD4(+) T cells (TEM) 182 days after the first immunization. Amplicon-based transcript quantification using next-generation sequencing was performed to identify differentially expressed genes that correlated with vaccine induced immune responses. Genes implicated in resolution of inflammation discriminated the responders from the nonresponders 3 days after the first inoculation. The volunteers with higher expression levels of genes involved in antiviral innate immunity at baseline showed impaired H1-specific TCM and TEM maintenance 6 months after vaccination. Our study showed that in HIV-infected volunteers, expression levels of genes involved in the antiviral innate immune response affected long-term maintenance of H1/IC31 vaccine-induced cellular immunity. (The clinical trial was registered in the Pan African Clinical Trials Registry [PACTR] with the identifier PACTR201105000289276.). PMID- 25924765 TI - A Combination of Three Fully Human Toxin A- and Toxin B-Specific Monoclonal Antibodies Protects against Challenge with Highly Virulent Epidemic Strains of Clostridium difficile in the Hamster Model. AB - Clostridium difficile infection (CDI) is the principal cause of nosocomial diarrhea and pseudomembranous colitis associated with antibiotic therapy. Recent increases in the number of outbreaks attributed to highly virulent antibiotic resistant strains underscore the importance of identifying efficacious alternatives to antibiotics to control this infection. CDI is mediated by two large exotoxins, toxins A and B. Strong humoral toxin-specific immune responses are associated with recovery and a lack of disease recurrence, whereas insufficient humoral responses are associated with recurrent CDI. Multiple approaches targeting these toxins, including intravenous immunoglobulin, neutralizing polymers, active vaccines, and, most recently, monoclonal antibodies (MAbs), have been explored, with various degrees of success. In this study, we describe the characterization of the first MAbs isolated from healthy human donors using a high-throughput B-cell cloning strategy. The MAbs were selected based on their ability to inhibit the actions of toxins A and B in vitro and because of their in vivo efficacy in a hamster challenge model. A potent 2-MAb cocktail was identified and then further potentiated by the addition of a second anti-toxin B MAb. This 3-MAb combination protected animals against mortality and also reduced the severity and duration of diarrhea associated with challenge with highly virulent strains of C. difficile toxinotypes 0 and III. This highly efficacious cocktail consists of one MAb specific to the receptor binding domain of toxin A and two MAbs specific to nonoverlapping regions of the glucosyltransferase domain of toxin B. This MAb combination offers great potential as a nonantibiotic treatment for the prevention of recurrent CDI. PMID- 25924767 TI - Development and Evaluation of a Multiplex Microsphere Assay for Quantitation of IgG and IgA Antibodies against Neisseria meningitidis Serogroup A, C, W, and Y Polysaccharides. AB - We developed and evaluated a rapid and simple multiplex microsphere assay for the quantification of specific IgG and IgA antibodies against meningococcal serogroup A, C, W, and Y capsular polysaccharides in serum and saliva. Meningococcal polysaccharides were conjugated to distinct magnetic carboxylated microspheres, and the performance of the assay was assessed using the CDC1992 standard meningococcal reference serum and a panel of serum and saliva samples. The standard curve was linear over an eight 3-fold dilution range in the IgG assay and a seven 3-fold dilution range in the IgA assay. No cross-reactivity was discovered, and the assay showed high specificity with >=91% homologous inhibition and <=11% heterologous inhibition for all serogroups and immunoglobulin classes. Lower limits of detections were <=280 pg/ml for IgG and <=920 pg/ml for IgA antibodies. The assay was reproducible, with a mean coefficient of variation of <=5% for intra-assay duplicates, a mean coefficient of variation of <=20% for interassay repeated analysis with different conjugations of microspheres, and a mean coefficient of variation within 25.8% for interoperator variation. The assay showed good correlation to the standard meningococcal polysaccharide enzyme-linked immunosorbent assay (ELISA) for detection of serum antibodies. This multiplex assay is robust and reliable and requires less sample volume, and less time and workload are needed than for ELISA, making this method highly relevant for serological and salivary investigations on the effect of meningococcal vaccines and for immunosurveillance studies. PMID- 25924766 TI - Stable Expression of Lentiviral Antigens by Quality-Controlled Recombinant Mycobacterium bovis BCG Vectors. AB - The well-established safety profile of the tuberculosis vaccine strain, Mycobacterium bovis bacille Calmette-Guerin (BCG), makes it an attractive vehicle for heterologous expression of antigens from clinically relevant pathogens. However, successful generation of recombinant BCG strains possessing consistent insert expression has encountered challenges in stability. Here, we describe a method for the development of large recombinant BCG accession lots which stably express the lentiviral antigens, human immunodeficiency virus (HIV) gp120 and simian immunodeficiency virus (SIV) Gag, using selectable leucine auxotrophic complementation. Successful establishment of vaccine stability stems from stringent quality control criteria which not only screen for highly stable complemented BCG DeltaleuCD transformants but also thoroughly characterize postproduction quality. These parameters include consistent production of correctly sized antigen, retention of sequence-pure plasmid DNA, freeze-thaw recovery, enumeration of CFU, and assessment of cellular aggregates. Importantly, these quality assurance procedures were indicative of overall vaccine stability, were predictive for successful antigen expression in subsequent passaging both in vitro and in vivo, and correlated with induction of immune responses in murine models. This study has yielded a quality-controlled BCG DeltaleuCD vaccine expressing HIV gp120 that retained stable full-length expression after 10(24) fold amplification in vitro and following 60 days of growth in mice. A second vaccine lot expressed full-length SIV Gag for >10(68)-fold amplification in vitro and induced potent antigen-specific T cell populations in vaccinated mice. Production of large, well-defined recombinant BCG DeltaleuCD lots can allow confidence that vaccine materials for immunogenicity and protection studies are not negatively affected by instability or differences between freshly grown production batches. PMID- 25924768 TI - Comparison of Two Commercial Tick-Borne Encephalitis Virus IgG Enzyme-Linked Immunosorbent Assays. AB - Despite the availability of protective vaccines, tick-borne encephalitis virus (TBEV) infections have been increasingly reported to the European Centre for Disease Prevention and Control in the past 2 decades. Since the diagnosis of TBEV exposure relies on serological testing, we compared two commercial enzyme-linked immunosorbent assays (ELISAs), i.e., Immunozym FSME IgG assay (ELISA-1) and Euroimmun FSME Vienna IgG assay (ELISA-2). Both assays use whole TBEV antigens, but they differ in viral strains (Neudoerfl for ELISA-1 and K23 for ELISA-2) and cutoff values. In testing of samples from 398 healthy blood donors, ELISA-1 showed higher reactivity levels than ELISA-2 (P < 0.001), suggesting different assay properties. This finding was supported by Bland-Altman analysis of the optical density at 450 nm (OD450) (mean bias, +0.32 [95% limits of agreement, 0.31 to +0.95]) and persisted after transformation into Vienna units. Concordant results were observed for 276 sera (69%) (44 positive and 232 negative results). Discordant results were observed for 122 sera (31%); 15 were fully discordant, all being ELISA-1 positive and ELISA-2 negative, and 107 were partially discordant (101 being ELISA-1 indeterminate and ELISA-2 negative and 6 having positive or indeterminate reactivity in both ELISAs). Neutralization testing at a 1:10 dilution yielded positive results for 33 of 44 concordant positive sera, 1 of 15 fully discordant sera, and 1 of 33 partially discordant sera. Indirect immunofluorescence testing revealed high antibody titers of >=100 for yellow fever virus in 18 cases and for dengue virus in one case, suggesting that cross reactivity contributed to the ELISA-1 results. We conclude that (i) cross reactivity among flaviviruses remains a limitation of TBEV serological testing, (ii) ELISA-2 revealed reasonable sensitivity and specificity for anti-TBEV IgG population screening of human sera, and (iii) neutralization testing is most specific and should be reserved for selective questions. PMID- 25924769 TI - Circulating miRNAs miR-34a and miR-150 associated with colorectal cancer progression. AB - BACKGROUND: Screening for the early detection of colorectal cancer is important to improve patient survival. The aim of this study was to investigate the potential of circulating cell-free miRNAs as biomarkers of CRC, and their efficiency at delineating patients with polyps and benign adenomas from normal and cancer patient groups. METHODS: The expression of 667 miRNAs was assessed in a discovery set of 48 plasma samples comprising normal, polyp, adenoma, and early and advanced cancer samples. Three miRNAs (miR-34a, miR-150, and miR-923) were further examined in a validation cohort of 97 subjects divided into the same five groups, and in an independent public dataset of 40 CRC samples and paired normal tissues. RESULTS: High levels of circulating miR-34a and low miR-150 levels distinguished groups of patients with polyps from those with advanced cancer (AUC = 0.904), and low circulating miR-150 levels separated patients with adenomas from those with advanced cancer (AUC = 0.875). In addition, the altered expression of miR-34a and miR-150 in an independent public dataset of forty CRC samples and paired normal tissues was confirmed. CONCLUSION: We identified two circulating miRNAs capable of distinguishing patient groups with different diseases of the colon from each other, and patients with advanced cancer from benign disease groups. PMID- 25924770 TI - Rehabilitation in Patients before and after Lung Transplantation. AB - Lung transplantation is an established treatment for patients with end-stage lung disease. It has been observed that despite near-normal lung function, exercise intolerance and reductions in quality of life (QOL) often persist up to years after transplantation. Several modifiable pre- and posttransplant factors are known to contribute to these persisting impairments. Physiological changes associated with severe and chronic lung disease, limb muscle dysfunction, inactivity/deconditioning, and nutritional depletion can affect exercise capacity and physical functioning in candidates for lung transplantation. After transplantation, extended hospital and intensive care unit stay, prolonged sedentary time, persisting inactivity, immunosuppressant medications and episodes of organ rejection may all impact lung recipients' recovery. Available evidence will be reviewed and content will be proposed (both evidence and experience based) for rehabilitation interventions prior to transplantation, during hospitalization after transplantation, and in both the immediate (<=12 months after hospital discharge) and long-term (>12 months after hospital discharge) posttransplant phase. Outpatient rehabilitation programs including supervised exercise training have been shown to be effective in improving limb muscle dysfunction, exercise capacity, and QOL both before and after transplantation if offered appropriately. Unmet research needs included the absence of sufficiently powered randomized controlled trials measuring the effects of rehabilitation interventions on crucial long-term outcomes such as sustained improvements in QOL, participation in daily activity, survival, incidence of morbidities and cost effectiveness. Remotely monitored (telehealth) home-based exercise or pedometer based walking interventions might be interesting alternatives to supervised outpatient rehabilitation interventions in the long-term posttransplant phase and warrant further investigation. PMID- 25924771 TI - A single dose of a neuron-binding human monoclonal antibody improves brainstem NAA concentrations, a biomarker for density of spinal cord axons, in a model of progressive multiple sclerosis. AB - BACKGROUND: Intracerebral infection of susceptible mouse strains with Theiler's murine encephalomyelitis virus (TMEV) results in chronic demyelinating disease with progressive axonal loss and neurologic dysfunction similar to progressive forms of multiple sclerosis (MS). We previously showed that as the disease progresses, a marked decrease in brainstem N-acetyl aspartate (NAA; metabolite associated with neuronal integrity) concentrations, reflecting axon health, is measured. We also demonstrated stimulation of neurite outgrowth by a neuron binding natural human antibody, IgM12. Treatment with either the serum-derived or recombinant human immunoglobulin M 12 (HIgM12) preserved functional motor activity in the TMEV model. In this study, we examined IgM-mediated changes in brainstem NAA concentrations and central nervous system (CNS) pathology. FINDINGS: (1)H-magnetic resonance spectroscopy (MRS) showed that treatment with HIgM12 significantly increased brainstem NAA concentrations compared to controls in TMEV-infected mice. Pathologic analysis demonstrated a significant preservation of axons in the spinal cord of animals treated with HIgM12. CONCLUSIONS: This study links drug efficacy of slowing deficits with axon preservation and NAA concentrations in the brainstem in a model of progressive MS. HIgM12-mediated changes of NAA concentrations in the brainstem are a surrogate marker of axon injury/preservation throughout the spinal cord. This study provides proof-of-concept that a neuron-reactive human IgM can be therapeutic and provides a biomarker for clinical trials. PMID- 25924772 TI - Biological and nonbiological complex drugs for multiple sclerosis in Latin America: regulations and risk management. AB - Biological drugs and nonbiological complex drugs with expired patents are followed by biosimilars and follow-on drugs that are supposedly similar and comparable with the reference product in terms of quality, safety and efficacy. Unlike simple molecules that can be copied and reproduced, biosimilars and follow on complex drugs are heterogeneous and need specific regulations from health and pharmacovigilance agencies. A panel of 14 Latin American experts on multiple sclerosis from nine different countries met to discuss the recommendations regarding biosimilars and follow-on complex drugs for treating multiple sclerosis. Specific measures relating to manufacturing, therapeutic equivalence assessment and pharmacovigilance reports need to be implemented before commercialization. Physical, chemical, biological and immunogenic characterizations of the new product need to be available before clinical trials start. The new product must maintain the same immunogenicity as the original. Automatic substitution of biological and complex drugs poses unacceptable risks to the patient. PMID- 25924773 TI - A thermodynamic gauge for mobile counter-ions from colloids and nanoparticles. AB - A thermodynamic equilibrium sensor is proposed that measures the ratio of the number of elementary charges z to the mass m of charged solutes such as charged colloids and nanoparticles. The sensor comprises a small, membrane-encapsulated salt solution volume that absorbs neutral salt molecules in response to the release of mobile counter-ions by charge carriers in the surrounding suspension. The sensor state emerges as a limiting case of the equilibrium salt imbalance, and the ensuing osmotic pressure difference, between arbitrary salt and suspension volumes. A weight concentration of charge carriers c is predicted to significantly increase the sensor's salt number density from its initial value rhos,0 to rhoRs, according to the relation (rhoRs/rhos,0)(2)-1=zc/mrhos,0, under the assumption that the mobile ions involved in the thermodynamic sensor suspension equilibrium are ideal and homogeneously distributed. PMID- 25924774 TI - Tunable optical activity of plasmonic dimers assembled by DNA origami. AB - We investigate the optical response of gold nanorod (AuNR) dimers assembled in parallel on a DNA origami template. Plasmonic circular dichroism (CD) was found to be highly dependent on the orientation of the dimers relative to the DNA axis and the inter-rod distances. Dipole-dipole distances play a critical role in the induced plasmonic chirality. The orientation dependence of induced CD was further verified by AuNR/Au nanosphere (AuNS) heterodimers. The experimental results of the plasmonic CD agreed well with theoretical calculations. PMID- 25924775 TI - A DFT-based genetic algorithm search for AuCu nanoalloy electrocatalysts for CO2 reduction. AB - Using a DFT-based genetic algorithm (GA) approach, we have determined the most stable structure and stoichiometry of a 309-atom icosahedral AuCu nanoalloy, for potential use as an electrocatalyst for CO2 reduction. The identified core-shell nano-particle consists of a copper core interspersed with gold atoms having only copper neighbors and a gold surface with a few copper atoms in the terraces. We also present an adsorbate-dependent correction scheme, which enables an accurate determination of adsorption energies using a computationally fast, localized LCAO basis set. These show that it is possible to use the LCAO mode to obtain a realistic estimate of the molecular chemisorption energy for systems where the computation in normal grid mode is not computationally feasible. These corrections are employed when calculating adsorption energies on the Cu, Au and most stable mixed particles. This shows that the mixed Cu135@Au174 core-shell nanoalloy has a similar adsorption energy, for the most favorable site, as a pure gold nano-particle. Cu, however, has the effect of stabilizing the icosahedral structure because Au particles are easily distorted when adding adsorbates. PMID- 25924776 TI - Effects of propofol versus thiopental on Apgar scores in newborns and peri operative outcomes of women undergoing emergency cesarean section: a randomized clinical trial. AB - BACKGROUND: General and regional anesthesia are the two main techniques used in cesarean section. Regional anesthesia is preferred, but under certain circumstances, such as by patient request and in patients with back deformities, general anesthesia is the only option. Commonly used induction agents include thiopental, ketamine, and propofol, depending on availability and the maternal clinical condition. The objective of this study was to investigate the effects of thiopental and propofol on the neonatal Apgar score and maternal recovery time following emergency cesarean section in order to determine the superior agent for mothers and neonates. METHODS: This single-blinded randomized clinical trial included 150 ASA I and II patients block-randomized equally between the two study arms. Pregnant women at term scheduled to undergo cesarean section and their neonates were enrolled. The primary outcomes were the Apgar scores through 10-min postpartum, resuscitation requirement, and admission to the neonatal intensive care unit. The secondary outcome was the maternal recovery times. RESULTS: At 0 min (umbilical cord clamp time), 43 (57.3%) neonates in the propofol group had an Apgar score < 7 compared with 31 (41.3%) neonates in the thiopental group (p = 0.05). The maternal recovery time was shorter in the propofol group than in the thiopental group (25 min vs. 31 min, respectively, p = 0.003). CONCLUSION: Apgar scores do not differ significantly whether thiopental or propofol is used for anesthetic induction in women undergoing general anesthesia for an emergency cesarean section. TRIAL REGISTRATION: Pan-African Clinical Trial Registry (#PACTR201306000536344) http://www.pactr.org/ATMWeb/appmanager/atm/atmregistry?_nfpb=true&_pageLabel=atm_ ortal_page_mytrials. PMID- 25924777 TI - Interactive format is favoured in case conference. AB - BACKGROUND: Follow-up case presentation (FCP), a staple of emergency medicine residency conference curricula nationwide, has traditionally been delivered using PowerPoint(TM) (PP). The sole use of the PP lecture format may limit audience participation. In light of existing literature supporting chalkboard and morning report formats, we changed FCP to an interactive chalkboard format with limited PP slides. We hypothesised that this change will enhance the perceived educational impact of FCP on learners. METHODS: To examine learners' perceptions regarding the PP-based and 'chalkboard talk' discussion formats, we conducted a time-series investigation with pre- and post-intervention questionnaires using the five-point Likert scale. After obtaining Institutional Review Board exemption, 60 emergency medicine residents (post graduate years 1-4) were recruited through e-mail to complete the pre-intervention questionnaire. The post intervention questionnaire was administered following a run-in period of nine post-intervention FCPs. The questionnaires were compared using Mantel-Haenszel chi-square tests. RESULTS: The pre- and post-intervention questionnaire completion rates were 83.3 per cent (50/60) and 65 per cent (39/60), respectively. The chalkboard format was perceived by learners to be significantly more effective than PP-based FCPs at educating the learner regarding the topics covered (3.5 versus 4.0, pre- versus post-, respectively, p = 0.003), teaching practical knowledge (3.4 versus 3.8, p = 0.014), stimulating self-knowledge assessment (3.4 versus 3.8, p = 0.023), encouraging the generation of broad differential diagnoses (3.4 versus 3.9, p = 0.008), and promoting an interactive learning environment (3.1 versus 4.1, p < 0.0001). CONCLUSIONS: The implementation of chalkboard format with interactive discussion is perceived by learners to be the superior didactic educational medium, compared with the exclusive use of PP slides for FCPs. The chalkboard format was perceived by learners to be significantly more effective. PMID- 25924778 TI - MID2 can substitute for MID1 and control exocytosis of lytic granules in cytotoxic T cells. AB - We have recently shown that the E3 ubiquitin ligase midline 1 (MID1) is upregulated in murine cytotoxic lymphocytes (CTL), where it controls exocytosis of lytic granules and the killing capacity. Accordingly, CTL from MID1 knock-out (MID1(-/-)) mice have a 25-30% reduction in exocytosis of lytic granules and cytotoxicity compared to CTL from wild-type (WT) mice. We wondered why the MID1 gene knock-out did not affect exocytosis and cytotoxicity more severely and speculated whether MID2, a close homologue of MID1, might partially compensate for the loss of MID1 in MID1(-/-) CTL. Here, we showed that MID2, like MID1, is upregulated in activated murine T cells. Furthermore, MID1(-/-) CTL upregulated MID2 two-twenty-fold stronger than CTL from WT mice, suggesting that MID2 might compensate for MID1. In agreement, transfection of MID2 into MID1(-/-) CTL completely rescued exocytosis of lytic granules in MID1(-/-) CTL, and vice versa, knock-down of MID2 inhibited exocytosis of lytic granules in both WT and MID1(-/ ) CTL, demonstrating that both MID1 and MID2 play a central role in the regulation of granule exocytosis and that functional redundancy exists between MID1 and MID2 in CTL. PMID- 25924779 TI - Decreased expression of microRNA-124 is an independent unfavorable prognostic factor for patients with breast cancer. AB - BACKGROUND: MicroRNA-124 (miR-124) has been reported to be downregulated in breast cancer. However, its clinical significance and prognostic value in breast cancer have not been extensively studied. METHODS: The tissue expression levels of miR-124 were measured using quantitative real-time PCR in 133 breast cancer patients. The correlation between the miR-124 levels and the clinicopathological factors of the patients was also analyzed. Survival and Cox proportional-hazards regression analyses were performed to determine the correlation between miR-124 expression levels and prognosis in the patients. RESULTS: Quantitative real-time PCR analysis showed that miR-124 had lower expression in breast cancer specimens than that in matched adjacent normal breast tissues (0.39 +/- 0.16 vs. 1.00 +/- 0.39; P < 0.05). Low miR-124 expression level was significantly associated with advanced TNM stage (P = 0.011), lymph node metastasis (P = 0.012), and poorer pathological differentiation (P = 0.023). A significant difference was found that breast cancer patients with low miR-124 expression level had distinctly shorter overall survival than patients with high miR-124 expression level (63.8% vs. 35.2%, P = 0.03). Furthermore, multivariate analysis of the prognosis factors with a Cox proportional hazards model confirmed that low miR-124 expression was a significant independent predictor of poor survival in breast cancer (HR = 3.16, 95% CI: 1.79-9.13, P = 0.017). CONCLUSION: These findings proved that the decreased expression of miR-124 might be associated with tumor progression and poor prognosis in patients with breast cancer. VIRTUAL SLIDES: The virtual slide(s) for this article can be found here: http://www.diagnosticpathology.diagnomx.eu/vs/3752603721493544. PMID- 25924780 TI - Factors determining renal impairment in unilateral ureteral colic secondary to calcular disease: a prospective study. AB - OBJECTIVE: To evaluate all possible risk factors that can cause impairment of overall renal function in patients with unilateral ureteral calculus and a normal contralateral kidney. METHODS: This is a prospective study of 90 patients who presented to our institute complaining of renal colic secondary to unilateral ureteral calculus. All patients were evaluated with a thorough history, physical examination, and laboratory and radiological investigations including renal function testing, urine analysis, non-contrast computed topography, and radionucleotide scan. Patients were divided into two groups according to their calculated creatinine clearance using the Modification of Diet in Renal Disease (MDRD) formula. Group I (favorable group) had a creatinine clearance >60 ml/min, while group II (unfavorable group) had a creatinine clearance <60 ml/min. RESULTS: The patients' mean age +/- SD was 38.8 +/- 11.4 years. Group I included 54 patients (60 %), while group II included 36 patients (40 %). On univariate analysis, factors that were associated with overall renal function impairment were patients' age, urea-to-creatinine ratio (UCR), use of nonsteroidal anti inflammatory drugs, stone location, and presence of obstruction. However, using binary logistic regression analysis, only patients' age, UCR, and presence of obstruction sustained statistical significance in association with renal function impairment. CONCLUSION: The study of factors that help explain the presence of renal impairment in patients with unilateral ureteral calculus is important in the clinical setting. Patients' age, urea-to-creatinine ratio, and degree of obstruction seem to be significantly associated with overall renal function impairment. PMID- 25924781 TI - Impact of continuous positive airway pressure (CPAP) on the respiratory capacity of chronic kidney disease patients under hemodialysis treatment. AB - PURPOSE: Chronic kidney disease (CKD) patients on long-term dialysis present changes in pulmonary function and respiratory muscle strength, negatively influencing physical capacity. OBJECTIVE: To analyze the impact of a continuous positive airway pressure (CPAP) protocol on the respiratory capacity of CKD patients under hemodialysis. METHODS: A randomized clinical trial was conducted involving 40 CKD patients 19-83 years old divided into two groups: control (n = 20) and CPAP (n = 20). Subjects were assessed on the respiratory muscle function test, maximal respiratory pressures, peak flow and 6-min walk test, at baseline and again at the 2-month follow-up. CPAP group patients were submitted to CPAP protocol (PEEP: 5 cm H2O, flow: 15 L/min, FiO2: 33 %) three times per week during hemodialysis sessions. RESULTS: The CPAP group showed higher forced vital capacity, forced expiratory volume in one second, peak expiratory flow, maximal inspiratory pressure, peak flow, as well as lower systolic blood pressure, heart rate, respiratory rate and Borg scale, in addition to a longer distance travelled on the 6-min walk test, compared with the control group. CONCLUSION: The introduction of a CPAP protocol during hemodialysis sessions had a positive impact on pulmonary function and physical capacity in CKD patients. PMID- 25924782 TI - Urine chemokines indicate pathogenic association of obesity with BPH/LUTS. AB - OBJECTIVES: High prevalence of lower urinary tract symptoms (LUTS) consistent with benign prostate hyperplasia (BPH) is associated with obesity and prostatic inflammation. Here, we investigated whether chemokines associated with obesity and prostatic inflammation can be measured in normally voided urine of BPH/LUTS patients to demonstrate the mechanistic association between obesity and BPH/LUTS. METHODS: Frozen urine specimens of BPH/LUTS patients enrolled in the Nashville Men's Health Study were sent for blinded analysis to University of Pittsburgh. Thirty patients were blocked by their AUA-SI (>7 or <=7) and prostatic enlargement (<40, 40-60, >60 cc). Clinical parameters including age, prostate size, and medications were derived from chart review. CXC chemokines (CXCL-1, CXCL-8, and CXCL-10), CC chemokines (CCL2 and CCL3), and sIL-1ra were measured in thawed urine using LuminexTM xMAP((r)) technology and ELISA for NGF. RESULTS: Urinary CCL2 levels were several fold higher compared with the other six proteins, of which CCL3 was detectable in less than one-fourth of patients. Urine levels of sIL-1ra and CXCL-8 were significantly associated with increasing BMI and waist circumference in BPH patients. CXCL-8 showed a marginal association with overall AUA-SI scores, as well as obstructive (p = 0.08) symptom subscores. Prostate volume was inversely and marginally associated with urinary CXCL-10 (p = 0.09). CONCLUSIONS: Urine levels of CXCL-8, CXCL-10, and sIL-1ra were associated with varying degrees with LUTS severity, prostate size, and obesity, respectively. These findings in urine are consistent with past studies of chemokine levels from expressed prostatic secretions and demonstrate the potential of noninvasively measured chemokine in urine to objectively classify BPH/LUTS patients. PMID- 25924783 TI - BMP2 response pattern in human lung fibroblasts predicts outcome in lung adenocarcinomas. AB - BACKGROUND: Bone morphogenetic proteins play important roles in development, morphogenesis and cancer. With this study we aimed to characterize the response of lung stromal fibroblasts to BMPs and their antagonists on a genome wide level and investigate its potential role in human lung adenocarcinomas. METHODS: We used an ex vivo culture model and measured gene expression changes in human lung fibroblasts after stimulation with BMPs and their antagonists using HEEBO microarrays. The in vitro data were correlated with in vivo observations in published expression datasets of human lung adenocarcinomas. RESULTS: We have systematically analyzed the response to BMP2, BMP4, BMP7 and their antagonists, Gremlin and Noggin, to define common and specific gene expression patterns. A BMP2 induced gene expression signature was defined, which is specific for stromal fibroblasts. Gene expression profiles from lung adenocarcinoma biopsies were analyzed to determine the prognostic significance of the "Fibroblast specific BMP2 induced gene list". This gene list successfully segregated patients with different prognostic outcome in 3 datasets. In a small dataset (Garber et al.) there was a strong trend for a worse prognosis of patients with adenocarcinomas of all stages over-expressing the "Fibroblast specific BMP2 induced gene list". In two larger datasets with stage I adenocarcinomas we observed a significantly worse disease-free (p = 0.002, Lee et al. and p = 0.002, Bhattacharjee et al.) and overall survival (p = 0.0002). CONCLUSIONS: The effects of BMPs and their antagonists are heterogeneous in different cell types. The gene expression pattern induced by BMP2 in primary lung fibroblasts may predict outcomes of patients with lung adenocarcinomas. PMID- 25924784 TI - Using films as a psychoeducation tool for patients with schizophrenia: a pilot study using a quasi-experimental pre-post design. AB - BACKGROUND: Relapses and, subsequently, readmissions are common in patients with schizophrenia. Psychoeducation has been shown to reduce the number and duration of readmissions. Yet, only little more than 20% of psychiatric patients in German speaking countries receive psychoeducation. Among other reasons, costs may be considered too high by hospitals. The objective of the present study was to test the feasibility of a new cost-efficient approach in the psychoeducation of patients with schizophrenia. In this study, films were used to impart knowledge about the illness to inpatients. METHODS: A total of 113 participants were initially included in the study, eleven of which were not included in the final analyses. Six films about the symptoms, diagnosis, causes, warning signs, treatment of schizophrenia and about the influence of family members and friends were shown in a group setting in the presence of nursing staff. All films combined facts, expert opinions, and personal experiences of peers. As the main outcome criterion of this feasibility pilot study, we measured the effects on knowledge. Secondary outcome measures included compliance, insight into illness, side effects, and quality of life. Data were collected directly after the intervention and about half a year afterwards. The number and the duration of readmissions to the hospital were recorded and compared to the number and duration of prior admissions. Patients were also asked to state their subjective opinion about the films. Main data analyses were done using paired t-tests and Wilcoxon signed-rank tests. Secondary analyses also involved ANOVAs and ANCOVAs. RESULTS: One hundred and two inpatients were included in the data analyses. Showing the films in the tested setting was shown to be feasible. Knowledge about schizophrenia (p < .001), compliance (ps < .01), insight into illness (p < .01), and quality of life (p < .001) all increased significantly after patients had watched the films and remained stable for at least half a year. A vast majority (84.9%) of the patients found the films to be interesting and informative. CONCLUSIONS: Using films to educate inpatients about schizophrenia is a feasible method that is cost- and time-efficient and well received by the patients. PMID- 25924785 TI - Multibranched acquired periungual fibrokeratomas with confounding histopathologic findings resembling papillomavirus infection: a report of two cases. AB - Acquired periungual fibrokeratomas are benign fibrous tissue tumors and are considered as the topographical variant of acquired digital fibrokeratoma. They usually present as solitary tumors. In some instance, the entity may appear in multibranched fashion. The main histopathologic features consist of acanthosis, thick collagen bundles mainly oriented in a vertical axis forming a central core, and numerous proliferating fibroblasts. In this article, we present two cases of acquired multibranched periungual fibrokeratoma and depict their varying clinical features over time. Binucleation and perinuclear halos of keratinocytes mimicking human papillomavirus (HPV) infection were detected microscopically, but there was no reactivity with HPV immunostaining. In context, anti-HPV immunostaining may be helpful in the differentiation of fibrokeratomas from HPV infection. On the other hand, it should be kept in mind that these histopathologic findings may be found in acral biopsies independent of viral effects. PMID- 25924786 TI - A Multi-module Approach to Calculation of Oyster (Crassostrea virginica) Environmental Benefits. AB - Environmental benefits are one of the motivations for management restoration of depleted bivalve populations. We describe a series of linked modules for benefits calculation. The modules include: oyster (Crassostrea virginica) bioenergetics, materials transport via the tidal prism, and benefits quantification. Quantified benefits include carbon, nitrogen, and phosphorus removal and shell production. The modules are demonstrated through application to the Great Wicomico River, a tributary of Chesapeake Bay, USA. Oysters on seven reefs (total area 2.8 * 10(5) m(2)) are calculated to remove 15.2, 6.2, and 0.2 tons per annum of carbon, nitrogen, and phosphorus, respectively, from the Great Wicomico. Oyster mortality contributes 108 tons per annum dry weight shell to the reefs. PMID- 25924787 TI - A Coupled SD and CLUE-S Model for Exploring the Impact of Land Use Change on Ecosystem Service Value: A Case Study in Baoshan District, Shanghai, China. AB - Most of the cities in developing countries are experiencing rapid urbanization. Land use change driven by urban sprawl, population growth, and intensified socio economic activities have led to a steep decline of ecosystem service value (ESV) in rapid urbanization areas, and decision-makers often ignore some valuable ecosystem service functions and values in land use planning. In this paper, we attempt to build a modeling framework which integrated System Dynamics model with Conversion of Land Use and its Effects at Small Extent model to simulate the dynamics of ESV of landscape and explore the potential impacts of land use change on ESV. We take Baoshan district of Shanghai as an example which is a fast urbanization area of metropolitan in China. The results of the study indicate that: (1) The integrated methodology can improve the characterization and presentation of the dynamics of ESV, which may give insight into understanding the possible impacts of land use change on ESV and provide information for land use planning. (2) Land use polices can affect the magnitude and location of ESV both directly and indirectly. Land use changes tend to weaken and simplify ecosystem service functions and values of landscape at urban rural fringe where land use change is more intensive. (3) The application of the methodology has proved that the integration of currently existing models within a single modeling framework could be a beneficial exploration, and should be encouraged and enhanced in the future research on the changing dynamics of ESV due to the complexity of ecosystem services and land use system. PMID- 25924788 TI - Statistical Dimensioning of Nutrient Loading Reduction: LLR Assessment Tool for Lake Managers. AB - Implementation of the EU Water Framework Directive (WFD) has set a great challenge on river basin management planning. Assessing the water quality of lakes and coastal waters as well as setting the accepted nutrient loading levels requires appropriate decision supporting tools and models. Uncertainty that is inevitably related to the assessment results and rises from several sources calls for more precise quantification and consideration. In this study, we present a modeling tool, called lake load response (LLR), which can be used for statistical dimensioning of the nutrient loading reduction. LLR calculates the reduction that is needed to achieve good ecological status in a lake in terms of total nutrients and chlorophyll a (chl-a) concentration. We show that by combining an empirical nutrient retention model with a hierarchical chl-a model, the national lake monitoring data can be used more efficiently for predictions to a single lake. To estimate the uncertainties, we separate the residual variability and the parameter uncertainty of the modeling results with the probabilistic Bayesian modeling framework. LLR has been developed to answer the urgent need for fast and simple assessment methods, especially when implementing WFD at such an extensive scale as in Finland. With a case study for an eutrophic Finnish lake, we demonstrate how the model can be utilized to set the target loadings and to see how the uncertainties are quantified and how they are accumulating within the modeling chain. PMID- 25924789 TI - A Fish-Based Index of Biotic Integrity for the Assessment of Streams Located in a Sugarcane-Dominated Landscape in Southeastern Brazil. AB - A multimetric, fish-based Index of Biotic Integrity (IBI) was developed and tested to assess the ecological status of streams with different riparian conditions in the Piracicaba River Basin. Nine streams with three categories of riparian zone preservation were selected: native forest (NF) with preserved forest, secondary forest (SF) with forest in an advanced state of regeneration and surrounded by sugarcane plantations, and sugarcane (SC) without riparian vegetation and surrounded by SC crops. A continuous scoring system was employed, and candidate metrics were tested for range, responsiveness, and redundancy, resulting in the selection of eight metrics to compose the index. The final IBI score was positively correlated with an Environmental Index both in the dry (Spearman's rho = 0.76; P = 0.01) and rainy seasons (Spearman's rho = 0.66; P = 0.04), suggesting that this IBI is a suitable tool for the assessment of the biological conditions of these streams. The highest IBI values were observed in the rainy season at the NF and SF sites, with significant differences between the NF and SC sites (Kruskal-Wallis test: P = 0.03). The results indicated some variability in the biological integrity at SF and SC sites, suggesting a relationship with the intensity of the management of this crop. Patterns were consistent with other studies that have shown the effects of agriculture on the environmental quality of streams, which indicate the importance of the riparian zone to the maintenance of ecosystem integrity and supports the use of the IBI for biological monitoring in similar regions. PMID- 25924790 TI - Prioritizing Urban Habitats for Connectivity Conservation: Integrating Centrality and Ecological Metrics. AB - Connectivity among fragmented areas of habitat has long been acknowledged as important for the viability of biological conservation, especially within highly modified landscapes. Identifying important habitat patches in ecological connectivity is a priority for many conservation strategies, and the application of 'graph theory' has been shown to provide useful information on connectivity. Despite the large number of metrics for connectivity derived from graph theory, only a small number have been compared in terms of the importance they assign to nodes in a network. This paper presents a study that aims to define a new set of metrics and compares these with traditional graph-based metrics, used in the prioritization of habitat patches for ecological connectivity. The metrics measured consist of "topological" metrics, "ecological metrics," and "integrated metrics," Integrated metrics are a combination of topological and ecological metrics. Eight metrics were applied to the habitat network for the fat-tailed dunnart within Greater Melbourne, Australia. A non-directional network was developed in which nodes were linked to adjacent nodes. These links were then weighted by the effective distance between patches. By applying each of the eight metrics for the study network, nodes were ranked according to their contribution to the overall network connectivity. The structured comparison revealed the similarity and differences in the way the habitat for the fat-tailed dunnart was ranked based on different classes of metrics. Due to the differences in the way the metrics operate, a suitable metric should be chosen that best meets the objectives established by the decision maker. PMID- 25924791 TI - Genome-wide association mapping of preharvest sprouting resistance in a diversity panel of European winter wheats. AB - Global wheat production will benefit from cultivars showing genetic resistance to preharvest sprouting (PHS). Working on PHS resistance is still challenging due to the lack of simple protocols for the provocation of symptoms for appropriate trait differentiation under highly variable environmental conditions. Therefore, the availability of molecular markers for enhancing PHS resistance in breeding lines is of utmost importance. Genome-wide association mapping was performed to unravel the genetics of PHS resistance in a diversity panel of 124 winter wheat genotypes using both random and targeted marker locus approaches. Data for grain germination tests, spike wetting treatments, and field sprouting damage measurements of grains were collected in 11, 12, and four environments, respectively. Twenty-two quantitative trait loci (QTL) linked with 40 markers were detected for the three traits commonly used for assessing the PHS resistance of cultivars. All but five QTL on chromosomes 1B, 1D (two QTL), 3D, and 5D showed locations similar to previous studies, including prominent QTL on chromosomes 2BS, 3AS, and 4AL. The highest retrieval rate across environments was found for QTL on chromosomes 1D, 2BS, 3D, 4AL, and 7B. The study identified genomic signatures useful for marker-assisted improvement of PHS resistance not only in European breeding programs, but of global significance. PMID- 25924792 TI - The burden of primary headache disorders in Zambia: national estimates from a population-based door-to-door survey. AB - BACKGROUND: Three headache disorders - migraine, tension-type headache (TTH) and medication-overuse headache (MOH) - are major contributors to population ill health. Policy-makers need local knowledge of these to guide priority-setting. Earlier we reported the prevalence of these disorders in Zambia; here we describe the burdens attributable to them. METHODS: This was a cross-sectional population based survey of adults aged 18-65 years, selected by cluster-randomized sampling in the mostly urban Lusaka Province and mostly rural Southern Province. Interviewers visiting households used a structured questionnaire. Diagnoses made algorithmically applied ICHD-II criteria. Burden enquiry focused on the previous 3 months and the day before interview. Disability was estimated by applying disability weights (DWs) from the Global Burden of Disease Survey 2010. RESULTS: From 1,134 households, 1,085 unrelated adults (450 male, 635 female) were interviewed (refusal rate 4.3%). The gender- and habitation-adjusted 1-year prevalence of migraine was 22.9%, of TTH 22.8%, of headache on >=15 days/month 11.5%, of probable MOH (pMOH) 7.1%. Reported mean intensity of migraine attacks was 2.7, representing severe pain. People with migraine spent 10.0% of their time in the ictal state (DW: 0.433); they were therefore 4.3% disabled overall. Disability from TTH was much lower. People with pMOH (time with headache: 37.5%; DW: 0.220) were 8.3% disabled overall. Average lost productive time in the preceding 3 months for migraine was 4.1 days from work (6.3% loss) and 4.2 days (4.7% loss) from household work. Losses for pMOH were 4.8 days (7.4% loss) from work and 4.5 days (5.0% loss) from household work. In the population aged 18-65 years (effectively the working population), estimated disability from migraine was 0.98%, with 1.4% of workdays lost, and from pMOH was 0.59%, with 0.53% of workdays lost. Headache yesterday was reported by 28.3% of participants, whose average productivity yesterday was 55.9% of expectation. CONCLUSIONS: Zambia loses 1.93% of GDP to headache, and action is required to mitigate this loss and the associated suffering. Structured headache services with their basis in primary care are the most efficient, effective, affordable and equitable solution. They could be implemented within the existing health-care infrastructure of Zambia. These matters require urgent political attention. PMID- 25924793 TI - New records of species of Saemundssonia (Insecta: Phthiraptera: Philopteridae) infesting breeding terns in the Arabian Peninsula, with notes on their phylogeny and ecology. AB - Six species of terns, which breed on the Arabian Peninsula, were examined for head chewing lice of the genus Saemundssonia in four different islands around the coasts of Saudi Arabia, both in the Red Sea and in the Arabian Gulf. Four louse species were collected: Saemundssonia laticaudata, Saemundssonia melanocephalus, Saemundssonia meridiana and Saemundssonia sternae, of which three are recorded for the first time from this region. Also, we record three new host-louse associations for the world-Saemundssonia laticaudata and Saemundssonia sternae from white-cheeked terns and Saemundssonia melanocephalus from Saunders's terns including a host-switch event of Saemundssonia laticaudata on white-cheeked terns in the Karan Island population. Gene bank data for the COI gene from seven species of Saemundssonia that infest marine birds were used to propose evolutionary trees using two different statistical methods: maximum parsimony (MP) and neighbour joining (NJ). The result indicated that the tree which was produced by NJ is likely to be more accurate as it appeared more compatible with hosts' phylogeny. The trees indicate relationships between tern Saemundssonia and congeneric species from other marine birds, especially from gulls. An ANOVA was also conducted to test the mean parasite load for each tern species studied, and results indicate that there is a relation between louse loads and colonization behaviour of the hosts. Data from lice examined and illustrations of lice and their hosts are also included. PMID- 25924794 TI - MJD and OTU deubiquitinating enzymes in Schistosoma mansoni. AB - The ubiquitination and deubiquitination of proteins can alter diverse cellular processes, such as proteolysis, trafficking, subcellular localisation, DNA repair, apoptosis and signal transduction. Deubiquitinating enzymes (DUBs) are responsible for removing ubiquitin from their target proteins. Previous reports have shown the presence of two subfamilies of DUBs in Schistosoma mansoni: Ub carboxyl-terminal hydrolase (UCH) and Ub-specific protease (USP). In this study, we analysed the ovarian tumour (OTU) and Machado-Joseph disease protein domain (MJD) proteases found in the Schistosoma mansoni genome database. An in silico analysis identified two different MJD subfamily members, SmAtaxin-3 and SmJosephin, and five distinct OTU proteases, SmOTU1, SmOTU3, SmOTU5a, SmOTU6b and SmOtubain. The phylogenetic analysis showed the evolutionary conservation of these proteins. Furthermore, the 3D structures confirmed the similarity of these proteins with human proteins. In addition, we performed quantitative reverse transcription-polymerase chain reaction (qRT-PCR) and observed distinct expression profiles for all of the investigated transcripts between the cercariae, schistosomula and adult worm stages. Taken together, our data suggest that MJD and OTU subfamily members contribute to regulating the activity of the Ub-proteasome system during the life cycle of this parasite. PMID- 25924795 TI - Evaluation of ImmunoCard STAT test and ELISA versus light microscopy in diagnosis of giardiasis and cryptosporidiosis. AB - This study was designed to evaluate ImmunoCard STAT Cryptosporidium/Giardia rapid assay and ELISA copro-antigen assays in detecting Giardia lamblia and Cryptosporidium species in fecal samples in comparison to microscopy. Both ImmunoCard STAT and ELISA assays were evaluated with 90 stool specimens that were tested by the standard ova and parasite examination including staining with both iron hematoxylin stain and modified Ziehl Neelson stains. Counting the number of Giardia cysts and Cryptosporidia oocysts in the positive stool samples was done in order to quantify the lower limit of parasite number that was able to be detected by all included assays. Both ImmunoCard STAT and ELISA assays were compared on the basis of the attributes which are number of detected cases, sensitivity, specificity, time required for the procedure and screening, ease of performance and interpretation, and cost. Microscopic examination revealed that 13.3% of the samples were positive for Giardia and 2.2% for Cryptosporidium. By ELISA, 16.7% of the samples were infected with Giardia and 3.3% with Cryptosporidium, while by ImmunoCard STAT, 17.8 and 4.45% of the samples were positive for Giardia and Cryptosporidium, respectively. There is no statistically significant difference between the results of ELISA and ImmunoCard STAT assays. The lowest concentration detected in the stool samples was 10.50 +/- 1.05 Giardia cysts and 2.83 +/- 1.72 Cryptosporidium oocysts. The ImmunoCard STAT was extremely easy to read, thus requiring much less time, but its cost was much higher than ELISA. We concluded that although the overall ranking of both assays was high, the ImmunoCard STAT rapid assay was a more desirable test despite its higher cost. PMID- 25924796 TI - In vitro acaricidal activity of 1,8-cineole against Sarcoptes scabiei var. cuniculi and regulating effects on enzyme activity. AB - 1,8-Cineole found in many essential oils is a monoterpene and acts as a repellent against Sarcoptes scabiei var. cuniculi. In the present study, the acaricidal activity of 1,8-cineole against S. scabiei var. cuniculi was evaluated and the acaricidal mechanism was also investigated by assaying enzyme activities. The results showed that the lethal concentration of 50% (LC50) value (95% confidence limit (CL)) and the lethal time of 50% (LT50) value (95% CL) of 1,8-cineole were 2.77 mg/mL and 3.606 h, respectively. The pathological changes under transmission electron microscopy showed that the morphology of the mitochondria was abnormal, the cell nuclear membrane was damaged, and the nuclear chromatin was dissoluted. The activities of superoxide dismutase (SOD), glutathione-s-transferases (GSTs), monoamine oxidase (MAO), nitric oxide synthase (NOS), and acetylcholinesterase (AChE) were significantly changed after treatment with 1,8-cineole for 4, 8, 12, and 24 h. SOD and GSTs are associated with the protection mechanism of scabies mites. And, the activities of SOD and GSTs were increased as compared with the control group. MAO, AChE, and NOS are associated with the nervous system of scabies mites. The activity of MAO was increased whereas the AChE was suppressed. The activity of NOS was suppressed in the high-dose group whereas increased in the middle-dose group and low-dose group. These results indicated that the mechanism of 1,8-cineole mainly attributed to the changes of these enzyme activities related to the nervous system of scabies mites. PMID- 25924797 TI - Dynamic left ventricular outflow tract obstruction secondary to hypovolemia in a German Shepard dog with splenic hemangiosarcoma. AB - Dynamic left ventricular outflow tract obstruction (DLVOTO) is a common condition in cats and humans. In this case report, a dog is described with DLVOTO secondary to severe intra-abdominal hemorrhage caused by a hemangiosarcoma. The dog was a 9 year-old, 35.7-kg, spayed female German Shepard dog that presented with a history of tachypnea and collapse. A Levine II/VI systolic murmur was present at the heart base. Abdominal ultrasonography revealed a splenic mass and a large amount of ascites. Echocardiography showed a reduced left ventricular diameter and an increased aortic velocity caused by systolic anterior motion (SAM) of the mitral valve apparatus. The heart murmur and the SAM were resolved after treatment including a splenectomy and a blood transfusion. PMID- 25924798 TI - Erratum to: New Directions in Qualitative Research in Psychology. PMID- 25924800 TI - Introducing Female Black Swiss Mice: Minimal Effects of Sex in a Strain-Specific Battery of Tests for Mania-Like Behavior and Response to Lithium. AB - Black Swiss (BS) mice were shown to be an advantageous strain to model behavioral domains of mania, but to date only male mice were tested, whereas bipolar disorder (BPD) is equally prevalent in women and men. This study was therefore designed to examine the possibility of using both male and female BS mice in future studies. Groups of male and female BS mice were compared with each other, with or without lithium treatment, in tests for domains of mania-like behavior including activity in an open field, sweet solution preference, elevated plus maze, forced swim and amphetamine-induced hyperactivity. The results indicate mostly a similarity between female and male BS mice, both naive and after chronic lithium treatment. The results are discussed in the context of the deficiency in utilizing female mice in animal models research and suggest that both male and female BS mice can be used to model domains of mania-like behavior. PMID- 25924799 TI - [Medical treatment of pulmonary hypertension: what's new?]. AB - Pulmonary hypertension (PH) is a chronic progressive disease of the pulmonary circulation of multifactorial causes. The current diagnostic classification of PH distinguishes five main groups, which have as a common feature an increased pulmonary arterial pressure and pulmonary resistance. The classification differentiates pulmonary arterial hypertension (PAH), PH due to left heart disease, PH in lung diseases and/or hypoxia, chronic thromboembolic pulmonary hypertension (CTEPH), and PH with unclear/multifactorial mechanisms. Recent advances in basic research with the approval of new drugs and the establishment of therapeutic strategies, mainly in PAH and CTEPH, require a differentiated view of the disease, a careful diagnosis and initiation of therapy, and regular follow ups. In this article, we provide an overview of the complex drug therapy currently available for PAH patients. PMID- 25924801 TI - Variation in heterostylous breeding systems in neighbouring populations of Oxalis alpina (Oxalidaceae). AB - The heterostylous reproductive system of Oxalis alpina in the Galiuro Mts. of Arizona was investigated using field surveys, controlled crosses in the greenhouse and measurements of reproductive morphs. Although populations in the Pinaleno Mts. to the immediate east and in the Santa Catalina Mts. to the immediate west have derived distylous reproductive systems, tristyly, the ancestral reproductive system in O. alpina, has been retained in the Galiuro Mts. POPULATION: Tristylous incompatibility relationships in the Galiuro population are modified from the ancestral condition, with significant loss of incompatibility differentiation between stamen whorls of both short- and long styled morphs. Morphological adjustments of anther positions in the Galiuro population of O. alpina match those expected in light of incompatibility modification, with divergence of the mid-level anthers away from the position of the mid stigmas of the mid-styled morph. The occurrence of tristyly in an area of Arizona where distyly is found in adjacent mountain ranges is particularly remarkable, and indicates both the isolation of populations restricted to the upper elevations of these mountain ranges and variation in the tempo of evolution over short geographic distances. PMID- 25924802 TI - Nidogen 1 and Nuclear Protein 1: novel targets of ETV5 transcription factor involved in endometrial cancer invasion. AB - Endometrial cancer is the most frequent malignancy of the female genital tract in western countries. Our group has previously characterized the upregulation of the transcription factor ETV5 in endometrial cancer with a specific and significant increase in those tumor stages associated with myometrial invasion. We have shown that ETV5 overexpression in Hec1A endometrial cancer cells induces epithelial to mesenchymal transition resulting in the acquisition of migratory and invasive capabilities. In the present work, we have identified Nidogen 1 (NID1) and Nuclear Protein 1 (NUPR1) as direct transcriptional targets of ETV5 in endometrial cancer cells. Inhibition of NID1 and NUPR1 in ETV5 overexpressing cells reduced cell migration and invasion in vitro and reduced tumor growth and dissemination in an orthotopic endometrial cancer model. Importantly, we confirmed a significant increase of NUPR1 and NID1 protein expression in the invasion front of the tumor compared to their paired superficial zone, concomitant to ETV5 overexpression. Altogether, we conclude that NID1 and NUPR1 are novel targets of ETV5 and are actively cooperating with ETV5 at the invasion front of the tumor in the acquisition of an invasive phenotype to jointly drive endometrial cancer invasion. PMID- 25924803 TI - Effect of corticosteroids on facial function after cerebellopontine angle tumor removal: a double-blind study versus placebo. AB - The aim of this study was to assess the effect of corticosteroids administered intra- and postoperatively on the occurrence of facial palsy after a cerebellopontine angle (CPA) tumor resection, and to investigate pre- and intraoperative prognostic factors. A multicenter, prospective, randomized, double blind and versus-placebo study was conducted between 2006 and 2010. Three hundred and ten patients operated on for a CPA tumor (96% vestibular schwannomas, 4% miscellaneous) were included by five participating centers. The population was stratified into patients with small (<=15 mm CPA on axial MRI views) and large tumors. In each group, patients were randomized to receive corticosteroid (1 mg/kg/day i.v. methylprednisolone intraoperatively and at postoperative days 1-5) or placebo. Steroids did not affect the facial function at postoperative days 1, 8 and 30 in patients with small or large tumors as evaluated by House and Brackmann grading. PMID- 25924804 TI - Voluntary emergence and water detection in a newly recognized amphibious fish. AB - Galaxias 'nebula', a small fish which has adaptations for air-breathing but is not known to be amphibious, voluntarily emerged from water and, in an unfamiliar environment, moved preferentially towards an alternative water source. Nebula may thus be considered one of the few truly amphibious fishes, and their ability to detect water provides a selective advantage which aids their survival in unpredictable natural environments. PMID- 25924805 TI - Barrier agents for adhesion prevention after gynaecological surgery. AB - BACKGROUND: Pelvic adhesions can form as a result of inflammation, endometriosis or surgical trauma. During pelvic surgery, strategies to reduce pelvic adhesion formation include placing barrier agents such as oxidised regenerated cellulose, polytetrafluoroethylene or fibrin sheets between the pelvic structures. OBJECTIVES: To evaluate the effects of barrier agents used during pelvic surgery on rates of pain, live birth and postoperative adhesions in women of reproductive age. SEARCH METHODS: We searched the following databases in February 2015: the Menstrual Disorders and Subfertility Group (MDSG) Specialised Register of Controlled Trials, MEDLINE, EMBASE, CINAHL, PsycINFO, the Cochrane Central Register of Controlled Trials (CENTRAL) and trial registries. We handsearched relevant journals, conference proceedings and grey literature sources and we contacted pharmaceutical companies for information. SELECTION CRITERIA: Randomised controlled trials (RCTs) of the use of barrier agents compared with other barrier agents, placebo or no treatment for the prevention of adhesions in women undergoing gynaecological surgery. DATA COLLECTION AND ANALYSIS: Two review authors independently assessed trials for eligibility and risk of bias and extracted the data. We calculated odds ratios (ORs) or mean differences (MD) with 95% confidence intervals (CIs) using a fixed effect model. The overall quality of the evidence was assessed using GRADE (Grades of Recommendation, Assessment, Development and Evaluation) methods. MAIN RESULTS: Eighteen RCTs (1262 women) were included. Six RCTs randomised women; the remainder randomised pelvic organs. Laparoscopy (eight RCTs) and laparotomy (10 RCTs) were the primary surgical techniques. Indications for surgery included myomectomy (six RCTs), ovarian surgery (five RCTs), pelvic adhesions (five RCTs), endometriosis (one RCT) and mixed (one RCT). The sole indication for surgery in three of the RCTs was infertility. Twelve RCTs reported commercial funding; the rest did not state their source of funding.No studies reported either of our primary outcomes of pelvic pain and live birth. Oxidised regenerated cellulose (Interceed) versus no treatment at laparoscopy or laparotomy (13 RCTs)At second-look laparoscopy oxidised regenerated cellulose at laparoscopy was associated with reduced incidence of de novo adhesions (OR 0.50, 95% CI 0.30 to 0.83, three RCTs, 360 participants, I(2) = 75%, very low-quality evidence) and of re-formed adhesions (OR 0.17, 95% CI 0.07 to 0.41, three RCTs, 100 participants, I(2) = 36%, low quality evidence).At second-look laparoscopy no evidence was found of any difference between the groups in the incidence of de novo adhesions after laparotomy (OR 0.72, 95% CI 0.42 to 1.25, one RCT, 271 participants, I(2) = 41%, low-quality evidence). However, the incidence of re-formed adhesions was lower in the intervention group (OR 0.38, 95% CI 0.27 to 0.55, six RCTs, 554 participants, moderate-quality evidence). Expanded polytetrafluoroethylene (Gore-Tex) versus no treatment at gynaecological surgery (one RCT) The evidence suggested that at second-look laparoscopy expanded polytetrafluoroethylene was associated with a reduction in new adhesion formation (OR 0.17, 95% CI 0.03 to 0.94, one RCT, 42 participants, low-quality evidence). Expanded polytetrafluoroethylene (Gore-Tex) versus oxidised regenerated cellulose (Interceed) at gynaecological surgery (two RCTs)One RCT found no difference between the groups at second-look laparoscopy in the incidence of de novo adhesions (OR 0.93, 95% CI 0.26 to 3.41, 38 participants, very low-quality evidence). A second RCT suggested that the expanded polytetrafluoroethylene group had a lower adhesion score (out of 11) (MD -3.79, 95% CI -5.12 to -2.46, 62 participants, very low-quality evidence) and a lower risk of re-formed adhesions (OR 0.13, 95% CI 0.02 to 0.80, 23 participants, very low-quality evidence). This last finding was sensitive to choice of effect estimate and no longer suggested a difference between the groups when a risk ratio was calculated (RR 0.36, 95% CI 0.13 to 1.01). Sodium hyaluronate and carboxymethylcellulose (Seprafilm) versus no treatment at gynaecological surgery (one RCT)Sodium hyaluronate and carboxymethylcellulose was associated with a lower adhesion score (out of 4) at second-look laparoscopy (MD 0.49, 95% CI 0.53 to 0.45, one RCT, 127 participants, moderate-quality evidence). Fibrin sheet versus no treatment at laparoscopic myomectomy (one RCT)There was no evidence of a difference between the groups in the incidence of de novo adhesions at second look laparoscopy (OR 1.20, 95% CI 0.42 to 3.41, one RCT, 62 participants) or in adhesion score (out of 4) (MD 0.14, 95% CI -0.67 to 0.39, one RCT, 48 participants, low-quality evidence).Fourteen of the 18 RCTs reported adverse events. No events directly attributed to adhesion agents were reported. AUTHORS' CONCLUSIONS: We found no evidence on the effects of barrier agents used during pelvic surgery on either pain or fertility outcomes in women of reproductive age.Low quality evidence suggests that oxidised regenerated cellulose (Interceed), expanded polytetrafluoroethylene (Gore-Tex) and sodium hyaluronate with carboxymethylcellulose (Seprafilm) may all be more effective than no treatment in reducing the incidence of adhesion formation following pelvic surgery. There is no conclusive evidence on the relative effectiveness of these interventions. There is no evidence to suggest that fibrin sheet is more effective than no treatment. No adverse events directly attributed to the adhesion agents were reported. The quality of the evidence ranged from very low to moderate. The most common limitations were imprecision and poor reporting of study methods. Most studies were commercially funded, and publication bias could not be ruled out. PMID- 25924806 TI - Clinical symptoms, signs and tests for identification of impending and current water-loss dehydration in older people. AB - BACKGROUND: There is evidence that water-loss dehydration is common in older people and associated with many causes of morbidity and mortality. However, it is unclear what clinical symptoms, signs and tests may be used to identify early dehydration in older people, so that support can be mobilised to improve hydration before health and well-being are compromised. OBJECTIVES: To determine the diagnostic accuracy of state (one time), minimally invasive clinical symptoms, signs and tests to be used as screening tests for detecting water-loss dehydration in older people by systematically reviewing studies that have measured a reference standard and at least one index test in people aged 65 years and over. Water-loss dehydration was defined primarily as including everyone with either impending or current water-loss dehydration (including all those with serum osmolality >= 295 mOsm/kg as being dehydrated). SEARCH METHODS: Structured search strategies were developed for MEDLINE (OvidSP), EMBASE (OvidSP), CINAHL, LILACS, DARE and HTA databases (The Cochrane Library), and the International Clinical Trials Registry Platform (ICTRP). Reference lists of included studies and identified relevant reviews were checked. Authors of included studies were contacted for details of further studies. SELECTION CRITERIA: Titles and abstracts were scanned and all potentially relevant studies obtained in full text. Inclusion of full text studies was assessed independently in duplicate, and disagreements resolved by a third author. We wrote to authors of all studies that appeared to have collected data on at least one reference standard and at least one index test, and in at least 10 people aged >= 65 years, even where no comparative analysis has been published, requesting original dataset so we could create 2 x 2 tables. DATA COLLECTION AND ANALYSIS: Diagnostic accuracy of each test was assessed against the best available reference standard for water-loss dehydration (serum or plasma osmolality cut-off >= 295 mOsm/kg, serum osmolarity or weight change) within each study. For each index test study data were presented in forest plots of sensitivity and specificity. The primary target condition was water-loss dehydration (including either impending or current water loss dehydration). Secondary target conditions were intended as current (> 300 mOsm/kg) and impending (295 to 300 mOsm/kg) water-loss dehydration, but restricted to current dehydration in the final review.We conducted bivariate random-effects meta-analyses (Stata/IC, StataCorp) for index tests where there were at least four studies and study datasets could be pooled to construct sensitivity and specificity summary estimates. We assigned the same approach for index tests with continuous outcome data for each of three pre-specified cut-off points investigated.Pre-set minimum sensitivity of a useful test was 60%, minimum specificity 75%. As pre-specifying three cut-offs for each continuous test may have led to missing a cut-off with useful sensitivity and specificity, we conducted post-hoc exploratory analyses to create receiver operating characteristic (ROC) curves where there appeared some possibility of a useful cut off missed by the original three. These analyses enabled assessment of which tests may be worth assessing in further research. A further exploratory analysis assessed the value of combining the best two index tests where each had some individual predictive ability. MAIN RESULTS: There were few published studies of the diagnostic accuracy of state (one time), minimally invasive clinical symptoms, signs or tests to be used as screening tests for detecting water-loss dehydration in older people. Therefore, to complete this review we sought, analysed and included raw datasets that included a reference standard and an index test in people aged >= 65 years.We included three studies with published diagnostic accuracy data and a further 21 studies provided datasets that we analysed. We assessed 67 tests (at three cut-offs for each continuous outcome) for diagnostic accuracy of water-loss dehydration (primary target condition) and of current dehydration (secondary target condition).Only three tests showed any ability to diagnose water-loss dehydration (including both impending and current water-loss dehydration) as stand-alone tests: expressing fatigue (sensitivity 0.71 (95% CI 0.29 to 0.96), specificity 0.75 (95% CI 0.63 to 0.85), in one study with 71 participants, but two additional studies had lower sensitivity); missing drinks between meals (sensitivity 1.00 (95% CI 0.59 to 1.00), specificity 0.77 (95% CI 0.64 to 0.86), in one study with 71 participants) and BIA resistance at 50 kHz (sensitivities 1.00 (95% CI 0.48 to 1.00) and 0.71 (95% CI 0.44 to 0.90) and specificities of 1.00 (95% CI 0.69 to 1.00) and 0.80 (95% CI 0.28 to 0.99) in 15 and 22 people respectively for two studies, but with sensitivities of 0.54 (95% CI 0.25 to 0.81) and 0.69 (95% CI 0.56 to 0.79) and specificities of 0.50 (95% CI 0.16 to 0.84) and 0.19 (95% CI 0.17 to 0.21) in 21 and 1947 people respectively in two other studies). In post-hoc ROC plots drinks intake, urine osmolality and axillial moisture also showed limited diagnostic accuracy. No test was consistently useful in more than one study.Combining two tests so that an individual both missed some drinks between meals and expressed fatigue was sensitive at 0.71 (95% CI 0.29 to 0.96) and specific at 0.92 (95% CI 0.83 to 0.97).There was sufficient evidence to suggest that several stand-alone tests often used to assess dehydration in older people (including fluid intake, urine specific gravity, urine colour, urine volume, heart rate, dry mouth, feeling thirsty and BIA assessment of intracellular water or extracellular water) are not useful, and should not be relied on individually as ways of assessing presence or absence of dehydration in older people.No tests were found consistently useful in diagnosing current water-loss dehydration. AUTHORS' CONCLUSIONS: There is limited evidence of the diagnostic utility of any individual clinical symptom, sign or test or combination of tests to indicate water-loss dehydration in older people. Individual tests should not be used in this population to indicate dehydration; they miss a high proportion of people with dehydration, and wrongly label those who are adequately hydrated.Promising tests identified by this review need to be further assessed, as do new methods in development. Combining several tests may improve diagnostic accuracy. PMID- 25924807 TI - Adolescent age moderates genetic and environmental influences on parent adolescent positivity and negativity: Implications for genotype-environment correlation. AB - We examined how genotype-environment correlation processes differ as a function of adolescent age. We tested whether adolescent age moderates genetic and environmental influences on positivity and negativity in mother-adolescent and father-adolescent relationships using parallel samples of twin parents from the Twin and Offspring Study in Sweden and twin/sibling adolescents from the Nonshared Environment in Adolescent Development Study. We inferred differences in the role of passive and nonpassive genotype-environment correlation based on biometric moderation findings. The findings indicated that nonpassive gene environment correlation played a stronger role for positivity in mother- and father-adolescent relationships in families with older adolescents than in families with younger adolescents, and that passive gene-environment correlation played a stronger role for positivity in the mother-adolescent relationship in families with younger adolescents than in families with older adolescents. Implications of these findings for the timing and targeting of interventions on family relationships are discussed. PMID- 25924808 TI - Interaction Networks in Protein Folding via Atomic-Resolution Experiments and Long-Time-Scale Molecular Dynamics Simulations. AB - The integration of atomic-resolution experimental and computational methods offers the potential for elucidating key aspects of protein folding that are not revealed by either approach alone. Here, we combine equilibrium NMR measurements of thermal unfolding and long molecular dynamics simulations to investigate the folding of gpW, a protein with two-state-like, fast folding dynamics and cooperative equilibrium unfolding behavior. Experiments and simulations expose a remarkably complex pattern of structural changes that occur at the atomic level and from which the detailed network of residue-residue couplings associated with cooperative folding emerges. Such thermodynamic residue-residue couplings appear to be linked to the order of mechanistically significant events that take place during the folding process. Our results on gpW indicate that the methods employed in this study are likely to prove broadly applicable to the fine analysis of folding mechanisms in fast folding proteins. PMID- 25924809 TI - Variability in Early Ahmarian lithic technology and its implications for the model of a Levantine origin of the Protoaurignacian. AB - This paper re-examines lithic technological variability of the Early Ahmarian, one of the early Upper Palaeolithic cultural entities in the Levant, which has often been regarded as a precursor of the Protoaurignacian (the early Upper Palaeolithic in Europe) in arguments for the occurrence of a cultural spread in association with the dispersal of Homo sapiens from the Levant to Europe. Using quantitative data on several lithic techno-typological attributes, we demonstrate that there is a significant degree of variability in the Early Ahmarian between the northern and southern Levant, as previously pointed out by several researchers. In addition, we suggest that the technology similar to the southern Early Ahmarian also existed in the northern Levant, i.e., the Ksar Akil Phase 4 group (the KA 4 group), by introducing new Upper Palaeolithic assemblages from Wadi Kharar 16R, inland Syria. We then review currently available stratigraphic records and radiocarbon dates (including a new date from Wadi Kharar 16R), with special attention to their methodological background. As a result, we propose alternative chronological scenarios, including one that postulates that the southern Early Ahmarian and the KA 4 group appeared later than the northern Early Ahmarian with little or no overlap. On the basis of the alternative scenarios of chronological/geographical patterns of the Early Ahmarian variability, we propose four possible relationships between the Protoaurignacian and the Early Ahmarian, including a new scenario that the appearance of the Protoaurignacian preceded those of similar technological entities in the Levant, i.e., the southern Early Ahmarian and the KA 4 group. If the last hypothesis is substantiated, it requires us to reconsider the model of a Levantine origin of the Protoaurignacian and its palaeoanthropological implications. PMID- 25924810 TI - Radiation-induced bronchiolitis obliterans organizing pneumonia (BOOP) syndrome in breast cancer patients is associated with age. AB - BACKGROUND: Radiation-induced bronchiolitis obliterans organizing pneumonia (BOOP) syndrome is a rarely observed phenomenon characterized by infiltration of the lungs outside of the radiation field, differentiating it from radiation pneumonitis (RP).The risk factors for radiation-induced BOOP (RT-BOOP) remain unclear and controversial. We retrospectively analyzed the incidence and risk factors for RT-BOOP associated with radiation therapy (RT) after breast conserving surgery (BCS) and post-mastectomy radiation therapy (PMRT). METHODS AND MATERIALS: We analyzed 1,176 breast cancer patients treated with RT after BCS or PMRT between March 2005 and September2008 at the cancer institute hospital of the Japanese foundation for cancer research. Chest radiographs were routinely obtained every three to six months for at least 12 months after surgery, as well as when the patients experienced respiratory symptoms or fever. RESULTS: RT-BOOP syndrome was diagnosed in 16patients (1.4%), including12BCS patients (1.3%) and four PMRT patients (1.8%). An older age (>=52 years old) was significantly associated with the incidence of RT-BOOP syndrome in a univariate analysis (p =0.023). The type of treatment (BCS or PMRT) and irradiated lung volume at 20 Gy (V20) were not significantly associated with the incidence of RT-BOOP syndrome in the entire patient cohort. In the multivariate analysis, age and smoking were the significant factor associated with RT-induced BOOP syndrome (p =0.044 and 0.049, respectively). CONCLUSIONS: RT-BOOP syndrome was a rarity, and the incidence for BCT cases was similar to that for PMRT cases. The irradiated lung volume was not significantly associated with RT-BOOP syndrome. An older age can predict the incidence of RT-BOOP syndrome. PMID- 25924811 TI - Clinical applications of cortisol measurements in hair. AB - Cortisol measurements in blood, saliva and urine are frequently used to examine the hypothalamus-pituitary-adrenal (HPA) axis in clinical practice and in research. However, cortisol levels are subject to variations due to acute stress, the diurnal rhythm and pulsatile secretion. Cortisol measurements in body fluids are not always a reflection of long-term cortisol exposure. The analysis of cortisol in scalp hair is a relatively novel method to measure cumulative cortisol exposure over months up to years. Over the past years, hair cortisol concentrations (HCC) have been examined in association with a large number of somatic and mental health conditions. HCC can be used to evaluate disturbances of the HPA axis, including Cushing's syndrome, and to evaluate hydrocortisone treatment. Using HCC, retrospective timelines of cortisol exposure can be created which can be of value in diagnosing cyclic hypercortisolism. HCC have also been shown to increase with psychological stressors, including major life events, as well as physical stressors, such as endurance exercise and shift work. Initial studies show that HCC may be increased in depression, but decreased in general anxiety disorder. In posttraumatic stress disorder, changes in HCC seem to be dependent on the type of traumatic experience and the time since traumatization. Increased hair cortisol is consistently linked to obesity, metabolic syndrome and cardiovascular disease. Potentially, HCC could form a future marker for cardiovascular risk stratification, as well as serve as a treatment target. PMID- 25924812 TI - Influence of transport and time on blood variables commonly measured for the athlete biological passport. AB - Some recent studies have characterized the stability of blood variables commonly measured for the Athlete Biological Passport. The aim of this study was to characterize the impact of different shipments conditions and the quality of the results returned by the haematological analyzer. Twenty-two healthy male subjects provided five EDTA tubes each. Four shipment conditions (24, 36, 48, 72 h) under refrigerated conditions were tested and compared to a set of samples left in the laboratory also under refrigerated conditions (group control). All measurements were conducted using two Sysmex XT-2000i analyzers. Haemoglobin concentration, reticulocytes percentage, and OFF-score numerical data were the same for samples analyzed just after collection and after a shipment under refrigerated conditions up to 72 h. Detailed information reported especially by the differential (DIFF) channel scatterplot of the Sysmex XT-2000i indicated that there were signs of blood deterioration, but were not of relevance for the variables used in the Athlete Biological Passport. As long as the cold chain is guaranteed, the time delay between the collection and the analyses of blood variables can be extended. PMID- 25924814 TI - Why the Queen's Speech on 19 May should include a bill to reinstate the NHS in England. PMID- 25924813 TI - Suppression of skeletal muscle signal using a crusher coil: A human cardiac (31) p-MR spectroscopy study at 7 tesla. AB - PURPOSE: The translation of sophisticated phosphorus MR spectroscopy ((31)P-MRS) protocols to 7 Tesla (T) is particularly challenged by the issue of radiofrequency (RF) heating. Legal limits on RF heating make it hard to reliably suppress signals from skeletal muscle that can contaminate human cardiac (31)P spectra at 7T. We introduce the first surface-spoiling crusher coil for human cardiac (31)P-MRS at 7T. METHODS: A planar crusher coil design was optimized with simulations and its performance was validated in phantoms. Crusher gradient pulses (100 MUs) were then applied during human cardiac (31)P-MRS at 7T. RESULTS: In a phantom, residual signals were 50 +/- 10% with BISTRO (B1 -insensitive train to obliterate signal), and 34 +/- 8% with the crusher coil. In vivo, residual signals in skeletal muscle were 49 +/- 4% using BISTRO, and 24 +/- 5% using the crusher coil. Meanwhile, in the interventricular septum, spectral quality and metabolite quantification did not differ significantly between BISTRO (phosphocreatine/adenosine triphosphate [PCr/ATP] = 2.1 +/- 0.4) and the crusher coil (PCr/ATP = 1.8 +/- 0.4). However, the specific absorption rate (SAR) decreased from 96 +/- 1% of the limit (BISTRO) to 16 +/- 1% (crusher coil). CONCLUSION: A crusher coil is an SAR-efficient alternative for selectively suppressing skeletal muscle during cardiac (31)P-MRS at 7T. A crusher coil allows the use of sequence modules that would have been SAR-prohibitive, without compromising skeletal muscle suppression. PMID- 25924815 TI - Moving towards an enhanced community palliative support service (EnComPaSS): protocol for a mixed method study. AB - BACKGROUND: The challenge of an ageing population and consequential increase of long term conditions means that the number of people requiring palliative care services is set to increase. One UK hospice is introducing new information and communication technologies to support the redesign of their community services; improve experiences of existing patients; and allow efficient and effective provision of their service to more people. Community Palliative Care Nurses employed by the hospice will be equipped with a mobile platform to improve communication, enable accurate and efficient collection of clinical data at the bedside, and provide access to clinical records at the point of care through an online digital nursing dashboard. It is believed that this will ensure safer clinical interventions, enable delegated specialist care deployment, support the clinical audit of patient care and improve patient safety and patient/carer experience. Despite current attempts to evaluate the implementation of such technology into end of life care pathways, there is still limited evidence supporting the notion that this can be sustained within services and implemented to scale. This study presents an opportunity to carry out a longitudinal evaluation of the implementation of innovative technology to provide evidence for designing more efficient and effective community palliative care services. METHODS: A mixed methods approach will be used to understand a wide range of organisational, economic, and patient-level factors. The first stage of the project will involve the development of an organisational model incorporating proposed changes resulting from the introduction of new novel mobile technologies. This model will guide stage two, which will consist of gathering and analysing primary evidence. Data will be collected using interviews, focus groups, observation, routinely collected data and documents. DISCUSSION: The implementation of this new approach to community-based palliative care delivery will require significant changes to established working patterns. This new service delivery model is being developed by the Hospice in collaboration with a team of international academic, industry, and clinical commissioning service improvement specialists. The findings from this initial evaluation will provide valuable baseline evidence regarding the delivery of palliative and end-of-life care services. PMID- 25924816 TI - Management of traumatic popliteal vascular injuries in a level I trauma center: A 6-year experience. AB - INTRODUCTION: Popliteal vascular trauma remains a challenging entity, and carries the greatest risk of limb loss among the lower extremity vascular injuries. Operative management of traumatic popliteal vascular injuries continues to evolve. We aim at describing our experience with such complex injuries, with associated patterns of injury, diagnostic and therapeutic challenges, and outcomes. METHODS: From January 2006 to September 2011, 191 adult trauma patients presented to an urban level I trauma center in Miami, Florida with traumatic lower extremity vascular injuries. Variables collected included age, gender, mechanism of injury, and clinical status at presentation. Surgical data included vessel injury, technical aspects of repair, associated complications and outcomes. RESULTS: Forty-seven (24.6%) patients were diagnosed with traumatic popliteal vascular injuries. Mean age was 38.1 +/- 16.1 years, and the majority of patients were males (43 patients, 91.4%). There were 21 (44.7%) penetrating injuries, and 26 (55.3%) blunt injuries. Vascular repair with saphenous venous interposition graft and PTFE (polytetrafluoroethylene) grafting were performed in 36 (70.7%) and 2 (3.9%) patients, respectively. Blunt popliteal injuries were significantly more associated with major tissue loss, and length of hospital and intensive care unit (ICU) stays. The risk for amputation is increased with longer ICU stays and the use of PTFE grafting for vascular repair. The overall mortality rate in this series was 8.5%. CONCLUSIONS: Blunt popliteal vascular injuries are associated with increased morbidity compared to penetrating trauma. Early restoration of blood perfusion, frequent use of interposition grafts with autogenous saphenous vein, and liberal use of fasciotomies play important role to achieve acceptable outcomes. PMID- 25924817 TI - The effects of sulforaphane on the liver and remote organ damage in hepatic ischemia-reperfusion model formed with pringle maneuver in rats. AB - BACKGROUND: The purpose of this study was to investigate the effect of Sulforaphane on ischemia/ reperfusion (IR) injury of the liver and distant organs resulting from liver blood flow arrest. MATERIALS AND METHODS: Fourty Wistar rats were assigned into four groups, each included 10 rats were used. Group I as only laparatomy, Group II laparatomy and Sulforaphane application, Group III hepatic IR; and Group IV as hepatic IR and Sulforaphane application group. Animals were subjected to liver ischemia for 30 min and then reperfusion is started. 5 mg/kg Sulforaphane was applied via oral lavage 15 minutes before initiating the experimental study. Blood samples were taken from the animals for biochemical analysis at 60th minutes of the experiment in the first and second groups; 30 minutes after beginning reperfusion in the third and forth groups. Simultaneously, liver, lung and kidney tissues were sampled for biochemical and histopathological examinations. RESULTS: The administration of sulforaphane significantly reduced the serum TOA and liver TOA levels, increased the serum TAC and liver TAC levels and also decreased The OSI and liver OSI levels. In the histopathologic examination, the injury was reduced by the administration of sulforaphane. Administration of sulforaphane did not lead to any significant changes in any parameter including histopathological parameters in both the kidney and the lung. CONCLUSIONS: Sulforaphane reduced the liver oxidative stress from I/R injury. A histological injury in liver was reduced by sulforaphane administration. However, there were no significant effects of sulforaphane on the remote organ injuries induced by IR. PMID- 25924818 TI - Household illness, poverty and physical and emotional child abuse victimisation: findings from South Africa's first prospective cohort study. AB - BACKGROUND: Physical and emotional abuse of children is a large scale problem in South Africa, with severe negative outcomes for survivors. Although chronic household illness has shown to be a predictor for physical and emotional abuse, no research has thus far investigated the different pathways from household chronic illness to child abuse victimisation in South Africa. METHODS: Confidential self-report questionnaires using internationally utilised measures were completed by children aged 10-17 (n = 3515, 56.7% female) using door-to-door sampling in randomly selected areas in rural and urban locations of South Africa. Follow-up surveys were conducted a year later (96.7% retention rate). Using multiple mediation analyses, this study investigated direct and indirect effects of chronic household illness (AIDS or other illness) on frequent (monthly) physical and emotional abuse victimisation with poverty and extent of the ill person's disability as hypothesised mediators. RESULTS: For children in AIDS-ill families, a positive direct effect on physical abuse was obtained. In addition, positive indirect effects through poverty and disability were established. For boys, a positive direct and indirect effect of AIDS-illness on emotional abuse through poverty were detected. For girls, a positive indirect effect through poverty was observed. For children in households with other chronic illness, a negative indirect effect on physical abuse was obtained. In addition, a negative indirect effect through poverty and positive indirect effect through disability was established. For boys, positive and negative indirect effects through poverty and disability were found respectively. For girls, a negative indirect effect through poverty was observed. CONCLUSIONS: These results indicate that children in families affected by AIDS-illness are at higher risk of child abuse victimisation, and this risk is mediated by higher levels of poverty and disability. Children affected by other chronic illness are at lower risk for abuse victimisation unless they are subject to higher levels of household disability. Interventions aiming to reduce poverty and increase family support may help prevent child abuse in families experiencing illness in South Africa. PMID- 25924819 TI - Potent Gastric Acid Inhibition Over 24 Hours by 4-Times Daily Dosing of Esomeprazole 20 mg. AB - BACKGROUND: When administered at a standard dose, proton pump inhibitors (PPIs) do not always provide sufficient acid inhibition for all subjects, particularly in extensive metabolizers (EMs) of CYP2C19. Whether esomeprazole at a dose of 20 mg four times daily dosing (q.i.d.) can attain sufficient acid inhibition throughout 24 h in EMs remains unclear. We therefore investigated the efficacy of esomeprazole q.i.d. for acid inhibition. METHODS: In a randomized cross-over design, 30 Helicobacter pylori-negative healthy young Japanese volunteers received esomeprazole at a dose of 20 mg two times a day (b.i.d.) or q.i.d. for 7 days. A pH monitoring was conducted before the trial as a control and on day 7 of both regimens. RESULTS: Median pH values in the q.i.d. regimen were significantly higher than those with the b.i.d. regimen in EMs (b.i.d.: 5.3, q.i.d.: 6.6, p = 0.022), intermediate metabolizer (IM) (b.i.d.: 5.5, q.i.d.: 6.8, p = 0.005) and poor metabolizer (PM) (b.i.d.: 6.2, q.i.d.: 7.0, p = 0.047), respectively. Median pH with the b.i.d. regimen differed significantly by CYP2C19 genotypes (p = 0.004), but not the q.i.d. regimen (p = 0.384). CONCLUSION: Esomeprazole q.i.d. achieved potent acid inhibition in all Helicobacter pylori-negative subjects, irrespective of CYP2C19 genotype, which might be one of the rescue regimens for patients' refractory to PPI treatment. PMID- 25924820 TI - Signal detection in FDA AERS database using Dirichlet process. AB - In the recent two decades, data mining methods for signal detection have been developed for drug safety surveillance, using large post-market safety data. Several of these methods assume that the number of reports for each drug-adverse event combination is a Poisson random variable with mean proportional to the unknown reporting rate of the drug-adverse event pair. Here, a Bayesian method based on the Poisson-Dirichlet process (DP) model is proposed for signal detection from large databases, such as the Food and Drug Administration's Adverse Event Reporting System (AERS) database. Instead of using a parametric distribution as a common prior for the reporting rates, as is the case with existing Bayesian or empirical Bayesian methods, a nonparametric prior, namely, the DP, is used. The precision parameter and the baseline distribution of the DP, which characterize the process, are modeled hierarchically. The performance of the Poisson-DP model is compared with some other models, through an intensive simulation study using a Bayesian model selection and frequentist performance characteristics such as type-I error, false discovery rate, sensitivity, and power. For illustration, the proposed model and its extension to address a large amount of zero counts are used to analyze statin drugs for signals using the 2006 2011 AERS data. PMID- 25924821 TI - Unwinding of the C-Terminal Residues of Neuropeptide Y is critical for Y2 Receptor Binding and Activation. AB - Despite recent breakthroughs in the structural characterization of G-protein coupled receptors (GPCRs), there is only sparse data on how GPCRs recognize larger peptide ligands. NMR spectroscopy, molecular modeling, and double-cycle mutagenesis studies were integrated to obtain a structural model of the peptide hormone neuropeptide Y (NPY) bound to its human G-protein-coupled Y2 receptor (Y2R). Solid-state NMR measurements of specific isotope-labeled NPY in complex with in vitro folded Y2R reconstituted into phospholipid bicelles provided the bioactive structure of the peptide. Guided by solution NMR experiments, it could be shown that the ligand is tethered to the second extracellular loop by hydrophobic contacts. The C-terminal alpha-helix of NPY, which is formed in a membrane environment in the absence of the receptor, is unwound starting at T(32) to provide optimal contacts in a deep binding pocket within the transmembrane bundle of the Y2R. PMID- 25924823 TI - Designing Dual-functionalized Gels for Self-reconfiguration and Autonomous Motion. AB - Human motion is enabled by the concerted expansion and contraction of interconnected muscles that are powered by inherent biochemical reactions. One of the challenges in the field of biomimicry is eliciting this form of motion from purely synthetic materials, which typically do not generate internalized reactions to drive mechanical action. Moreover, for practical applications, this bio-inspired motion must be readily controllable. Herein, we develop a computational model to design a new class of polymer gels where structural reconfigurations and internalized reactions are intimately linked to produce autonomous motion, which can be directed with light. These gels contain both spirobenzopyran (SP) chromophores and the ruthenium catalysts that drive the oscillatory Belousov-Zhabotinsky (BZ) reaction. Importantly, both the SP moieties and the BZ reaction are photosensitive. When these dual-functionalized gels are exposed to non-uniform illumination, the localized contraction of the gel (due to the SP moieties) in the presence of traveling chemical waves (due to the BZ reaction) leads to new forms of spontaneous, self-sustained movement, which cannot be achieved by either of the mono-functionalized networks. PMID- 25924822 TI - Small mosquitoes, large implications: crowding and starvation affects gene expression and nutrient accumulation in Aedes aegypti. AB - BACKGROUND: Environmental factors such as temperature, nutrient availability, and larval density determine the outcome of postembryonic development in mosquitoes. Suboptimal temperatures, crowding, and starvation during the larval phase reduce adult mosquito size, nutrient stores and affect vectorial capacity. METHODS: In this study we compared adult female Aedes aegypti, Rockefeller strain, raised under standard laboratory conditions (Large) with those raised under crowded and nutritionally deprived conditions (Small). To compare the gene expression and nutritional state of the major energy storage and metabolic organ, the fat body, we performed transcriptomics using Illumina based RNA-seq and metabolomics using GC/MS on females before and 24 hours following blood feeding. RESULTS: Analysis of fat body gene expression between the experimental groups revealed a large number of significantly differentially expressed genes. Transcripts related to immunity, reproduction, autophagy, several metabolic pathways; including amino acid degradation and metabolism; and membrane transport were differentially expressed. Metabolite profiling identified 60 metabolites within the fat body to be significantly affected between small and large mosquitoes, with the majority of detected free amino acids at a higher level in small mosquitoes compared to large. CONCLUSIONS: Gene expression and metabolites in the adult fat body reflect the individual post-embryonic developmental history of a mosquito larva. These changes affect nutritional storage and utilization, immunity, and reproduction. Therefore, it is apparent that changes in larval environment due to weather conditions, nutrition availability, vector control efforts, and other factors can affect adult vectorial capacity in the field. PMID- 25924824 TI - Correlation of Aurora-A expression with the effect of chemoradiation therapy on esophageal squamous cell carcinoma. AB - BACKGROUND: Chemoradiation therapy (CRT) is one of the most useful treatments for esophageal squamous cell carcinoma (ESCC). However, because some patients respond well to CRT and others do not, it is important to be able to predict response to CRT before beginning treatment by using markers. Aurora-A encodes a cell cycle regulated serine/threonine kinase that has essential functions in centrosome maturation and chromosome segregation. In this study, we investigated the relationship between the expression of Aurora-A and the response to CRT in patients with ESCC. METHODS: We immunohistochemically investigated the expression of Aurora-A in biopsy specimens of untreated primary tumors of 78 patients with ESCC and determined the relationship between Aurora-A levels and patient responses to CRT, which consisted of 5-fluorouracil plus cisplatin and 40 Gy of radiation. RESULTS: Tumors were judged as Aurora-A positive when more than 10% of the cancer cells displayed a distinct positive nuclear anti-Aurora-A immunoreaction by immunohistochemical evaluation. The tumors of 46 of 78 patients (58.9%) displayed positive expression of Aurora-A. In terms of clinical response the percentage of patients showing complete response (CR), incomplete response/stable disease of primary lesion (IR/SD), and progressive disease (PD) was 19.2, 69.2, and 11.5%, respectively. In terms of histological response the tumor grade of the 41 patients who underwent surgery was as follows: grade 1, 48.8%; grade 2, 29.2%; grade 3, 22.0%. CRT was effective for patients who had Aurora-A (+) tumors (clinically: P = 0.0003, histologically: P = 0.036). CONCLUSIONS: Our results suggest that Aurora-A expression in biopsy specimens of primary tumors is associated with CRT efficacy in patients with ESCC. Assessment of Aurora-A expression in biopsy specimens maybe useful for regarding the potential utility of CRT therapy for patients with ESCC before treatment. PMID- 25924825 TI - Engineering a mobile health tool for resource-poor settings to assess and manage cardiovascular disease risk: SMARThealth study. AB - BACKGROUND: The incidence of chronic diseases in low- and middle-income countries is rapidly increasing both in urban and rural regions. A major challenge for health systems globally is to develop innovative solutions for the prevention and control of these diseases. This paper discusses the development and pilot testing of SMARTHealth, a mobile-based, point-of-care Clinical Decision Support (CDS) tool to assess and manage cardiovascular disease (CVD) risk in resource constrained settings. Through pilot testing, the preliminary acceptability, utility, and efficiency of the CDS tool was obtained. METHODS: The CDS tool was part of an mHealth system comprising a mobile application that consisted of an evidence-based risk prediction and management algorithm, and a server-side electronic medical record system. Through an agile development process and user centred design approach, key features of the mobile application that fitted the requirements of the end users and environment were obtained. A comprehensive analytics framework facilitated a data-driven approach to investigate four areas, namely, system efficiency, end-user variability, manual data entry errors, and usefulness of point-of-care management recommendations to the healthcare worker. A four-point Likert scale was used at the end of every risk assessment to gauge ease-of-use of the system. RESULTS: The system was field-tested with eleven village healthcare workers and three Primary Health Centre doctors, who screened a total of 292 adults aged 40 years and above. 34% of participants screened by health workers were identified by the CDS tool to be high CVD risk and referred to a doctor. In-depth analysis of user interactions found the CDS tool feasible for use and easily integrable into the workflow of healthcare workers. Following completion of the pilot, further technical enhancements were implemented to improve uptake of the mHealth platform. It will then be evaluated for effectiveness and cost-effectiveness in a cluster randomized controlled trial involving 54 southern Indian villages and over 16000 individuals at high CVD risk. CONCLUSIONS: An evidence-based CVD risk prediction and management tool was used to develop an mHealth platform in rural India for CVD screening and management with proper engagement of health care providers and local communities. With over a third of screened participants being high risk, there is a need to demonstrate the clinical impact of the mHealth platform so that it could contribute to improved CVD detection in high risk low resource settings. PMID- 25924826 TI - The Psychological Impact of a Colorectal Cancer Diagnosis Following a Negative Fecal Occult Blood Test Result. AB - BACKGROUND: Screening using fecal occult blood testing (FOBt) reduces colorectal cancer mortality, but the test has low sensitivity. A "missed" cancer may cause psychologic harms in the screened population that partially counteract the benefits of early detection. METHODS: Three hundred and eleven people diagnosed with colorectal cancer (i) after a negative FOBt result (interval cancer), (ii) a positive result (screen-detected cancer), or (iii) in regions where screening was not offered, completed questions on quality of life (FACT-C), depression (CES-D), perceived diagnostic delay, and trust in the results of FOBt screening. Fifteen withheld consent to data matching with medical records, leaving a sample size of 296. RESULTS: Controlling for demographic and clinical variables, patients with an interval cancer reported poorer quality of life (difference in means = 6.16, P = 0.03) and more diagnostic delay (OR, 0.37; P = 0.02) than patients with screen detected disease, with no differences in depression. No differences were observed between the interval cancer group and the group not offered screening on these measures. Patients with an interval cancer reported the lowest levels of trust in FOBt. CONCLUSIONS: An interval cancer has adverse effects on trust in FOBt, but does not result in worse psychologic outcomes compared with people diagnosed in areas with no screening program. People with an interval cancer report poorer quality of life than people with screen-detected disease. IMPACT: Improvements in test sensitivity could improve quality of life among people who complete an FOB test over and above any benefits already conferred by earlier detection. PMID- 25924827 TI - Posttranslational modifications of intact proteins detected by NMR spectroscopy: application to glycosylation. AB - Posttranslational modifications (PTMs) are an integral part of the majority of proteins. The characterization of structure and function of PTMs can be very challenging especially for glycans. Existing methods to analyze PTMs require complicated sample preparations and suffer from missing certain modifications, the inability to identify linkage types and thus chemical structure. We present a direct, robust, and simple NMR spectroscopy method for the detection and identification of PTMs in proteins. No isotope labeling is required, nor does the molecular weight of the studied protein limit the application. The method can directly detect modifications on intact proteins without sophisticated sample preparation. This approach is well suited for diagnostics of proteins derived from native organisms and for the quality control of biotechnologically produced therapeutic proteins. PMID- 25924828 TI - Multitarget-directed tricyclic pyridazinones as G protein-coupled receptor ligands and cholinesterase inhibitors. AB - By following a multitarget ligand design approach, a library of 47 compounds was prepared, and they were tested as binders of selected G protein-coupled receptors (GPCRs) and inhibitors of acetyl and/or butyryl cholinesterase. The newly designed ligands feature pyridazinone-based tricyclic scaffolds connected through alkyl chains of variable length to proper amine moieties (e.g., substituted piperazines or piperidines) for GPCR and cholinesterase (ChE) molecular recognition. The compounds were tested at three different GPCRs, namely serotoninergic 5-HT1A, adrenergic alpha1A, and dopaminergic D2 receptors. Our main goal was the discovery of compounds that exhibit, in addition to ChE inhibition, antagonist activity at 5-HT1A because of its involvement in neuronal deficits typical of Alzheimer's and other neurodegenerative diseases. Ligands with nanomolar affinity for the tested GPCRs were discovered, but most of them behaved as dual antagonists of alpha1A and 5-HT1A receptors. Nevertheless, several compounds displaying this GPCR affinity profile also showed moderate to good inhibition of AChE and BChE, thus deserving further investigations to exploit the therapeutic potential of such unusual biological profiles. PMID- 25924829 TI - The Efficacies and Toxicities of Antidepressant Drugs in Clinics, Building the Relationship between Chemo-Genetics and Socio-Environments. AB - Antidepressants generally relief human depressive symptoms and help depressed people. Nevertheless, some undesired clinical events, such as suicide have been emerging more recently. In order to improve and promote antidepressant utilizations in clinics, new researches are focusing on reevaluation of the relationship between efficacy and toxicities of antidepressants in China and US. These researches speed up quickly. Many creative ideas and discoveries have been made, including predictions of the efficacies and toxicities of antidepressants under the same evaluating systems (pharmacogenetics and bioinformatics), genome wide associate study (GWAS) of the relationship between individual genetic factors and therapeutic outcomes of different types of antidepressants and socio environmental factors. Hopefully, therapeutic efficacies and outcomes by different types of antidepressant treatments for patients can be improved in clinical trials in the near future. PMID- 25924830 TI - Longitudinal changes in resting-state brain activity in a capsular infarct model. PMID- 25924832 TI - Home Therapy with Plasma-Derived C1 Inhibitor: A Strategy to Improve Clinical Outcomes and Costs in Hereditary Angioedema. AB - BACKGROUND: Attacks of hereditary angioedema with C1 inhibitor deficiency (C1-INH HAE) are commonly treated in the emergency department. Self-administration is emerging as an effective treatment option. In this study, we assessed the impact of home therapy with plasma-derived C1 esterase inhibitor (pdC1-INH) concentrate on treatment outcomes and costs. METHODS: This is an observational study in C1 INH-HAE patients who switched to home therapy with pdC1-INH (Berinert(r)) after learning intravenous self-infusion in a training course at a center in Southern Italy. Before starting home therapy and after the first year of home therapy, patients were interviewed about their treatment and outcomes during the prior 12 months. Annual costs were analyzed by cost minimization from the Italian health care payer perspective and the societal perspective. Outcomes and costs before and after the switch to home therapy were compared. RESULTS: The training course was attended by 36 participants, 17 (47.2%) of whom decided to switch to home therapy. This therapy was associated with a significant decrease in the mean annual number of hospitalizations (16.8 vs. 2.1, p = 0.003) and missed work/school days (20.3 vs. 7.1, p = 0.037) compared to conventional treatment. The times from symptom onset to treatment administration and from treatment administration to symptom improvement/resolution were not significantly different between the two strategies. The mean annual per-patient costs decreased with home therapy from EUR 30,010.57 to EUR 26,621.16 (11.3% saving) and from EUR 29,309.34 to EUR 26,522.04 (9.5% saving) from the societal and payer perspective, respectively. CONCLUSIONS: Home therapy with pdC1-INH is a feasible strategy for the management of C1-INH-HAE and may result in cost savings. PMID- 25924831 TI - Design and methods of the NiCK study: neurocognitive assessment and magnetic resonance imaging analysis of children and young adults with chronic kidney disease. AB - BACKGROUND: Chronic kidney disease is strongly linked to neurocognitive deficits in adults and children, but the pathophysiologic processes leading to these deficits remain poorly understood. The NiCK study (Neurocognitive Assessment and Magnetic Resonance Imaging Analysis of Children and Young Adults with Chronic Kidney Disease) seeks to address critical gaps in our understanding of the biological basis for neurologic abnormalities in chronic kidney disease. In this report, we describe the objectives, design, and methods of the NiCK study. DESIGN/METHODS: The NiCK Study is a cross-sectional cohort study in which neurocognitive and neuroimaging phenotyping is performed in children and young adults, aged 8 to 25 years, with chronic kidney disease compared to healthy controls. Assessments include (1) comprehensive neurocognitive testing (using traditional and computerized methods); (2) detailed clinical phenotyping; and (3) multimodal magnetic resonance imaging (MRI) to assess brain structure (using T1 weighted MRI, T2-weighted MRI, and diffusion tensor imaging), functional connectivity (using functional MRI), and blood flow (using arterial spin labeled MRI). Primary analyses will examine group differences in neurocognitive testing and neuroimaging between subjects with chronic kidney disease and healthy controls. Mechanisms responsible for neurocognitive dysfunction resulting from kidney disease will be explored by examining associations between neurocognitive testing and regional changes in brain structure, functional connectivity, or blood flow. In addition, the neurologic impact of kidney disease comorbidities such as anemia and hypertension will be explored. We highlight aspects of our analytical approach that illustrate the challenges and opportunities posed by data of this scope. DISCUSSION: The NiCK study provides a unique opportunity to address key questions about the biological basis of neurocognitive deficits in chronic kidney disease. Understanding these mechanisms could have great public health impact by guiding screening strategies, delivery of health information, and targeted treatment strategies for chronic kidney disease and its related comorbidities. PMID- 25924833 TI - Recombinant Human Growth Hormone Therapy in Children with Chromosome 15q26 Deletion. AB - BACKGROUND: The insulin-like growth factor 1 receptor (IGF IR) gene is located on chromosome 15q26.3. Heterozygous 15q26 deletions involving the IGFIR gene are rare, resulting in intrauterine and postnatal growth retardation, developmental delay and microcephaly. Limited evidence exists on the effect of growth hormone (GH) therapy in these cases. METHODS: We report a series of cases with 15q26 deletions, including response to GH treatment. RESULTS: Seven children (2 males) presented with short stature [median height standard deviation score (SDS) of 4.8 (range -3.0 to -5.6)]. GH was started at a median age of 5 years (range 1.8 to 12.4) for a median duration of 5.8 years (range 1.0 to 12.4). Median height SDS increased by +0.6 (range 0.1 to 1.0), +1.3 (range 0.1 to 2.4) and +1.4 (range 0.8 to 3.3) after 1 (n = 7), 5 (n = 4) and 10 years (n = 3) of GH treatment, respectively. Four patients reached final height after 5.8 to 12.4 years of GH with a median change in height SDS of +1.1 (range 0 to 3.3). CONCLUSION: This study demonstrates a moderate, though variable, response to GH therapy, suggesting that GH resistance caused by heterozygous IGFIR deletions can be partially overcome by GH therapy. The first-year response was moderate, and whilst long-term treatment improved height SDS, the final adult height remained reduced. Therefore, an individual trial of GH therapy may be appropriate in these patients. (c) 2015 S. Karger AG, Basel. PMID- 25924835 TI - Global surgery--going beyond the Lancet Commission. PMID- 25924834 TI - Global Surgery 2030: evidence and solutions for achieving health, welfare, and economic development. PMID- 25924836 TI - Finding surgery's place on the global health agenda. PMID- 25924837 TI - Surgical palliative care in resource-limited settings. PMID- 25924838 TI - John Meara: helping to make surgery truly global. PMID- 25924839 TI - Right-Sided Diverticulosis and Disparities from Left-Sided Diverticulosis in the Vietnamese Population Living in Boston, Mass., USA: A Retrospective Cohort Study. AB - OBJECTIVE: To report the prevalence, clinical differences and complications of right-sided diverticulosis (RD) and to investigate the potential disparities from left-sided diverticulosis (LD) in the Vietnamese population. SUBJECTS AND METHODS: A retrospective cohort study was conducted using medical records of Vietnamese-born patients from 2000 to 2013 in a community teaching hospital in Boston, Mass., USA. By simple randomization, a randomized control group of 299 Caucasian patients was also selected from the same time frame [167 males (M) and 132 females (F)]. Colonoscopy reports were reviewed for demographics (age and gender), indication and anatomical location of the colonic diverticulosis (CD), concomitant colonic findings, symptoms, and endoscopic complications. RESULTS: A total of 207 patients were included in the Vietnamese cohort (mean age 61.6 +/- 8.9 years). The mean age at first screening colonoscopy was 58.2 +/- 7.2 years (114 F/92 M, 55.7/44.4%). Our study identified 104 (50.5%) patients with LD (57 M/47 F), 65 (31.1%) with RD (35 M/30 F) and 38 (18.4%) with both LD and RD (23 M/15 F); 133 (64%) were asymptomatic. A total of 21 (33%) patients with RD were symptomatic. The mean age of the control group was 61.6 +/- 8.1 years. The average age at first screening colonoscopy was 52.8 +/- 6.4 years. Of the 299 in the Caucasian group, 254 (84.9%) had LD (114 M/140 F), 9 (3.0%) had RD (2 M/7 F) and 36 (12%) had both LD and RD (16 M/20 F); 225 (75%) were asymptomatic and came in for screening colonoscopies. A total of 2 patients (22%) with RD were symptomatic. CONCLUSION: RD was common in this Vietnamese population, and the prevalence was higher than in the Caucasian control group. PMID- 25924840 TI - Laboratory and field evaluations of camptothecin sodium salt against phytophagous mites. AB - BACKGROUND: Camptothecin (CPT), a monoterpene indole alkaloid from Camptotheca acuminate (Nyssaceae), is toxic to some insect pests but insoluble in water. Here we show that an aqueous CPT-Na(+) solution can kill the phytophagous mites Tetranychus urticae (TU), Acaphylla theae (AT) and Brevipalpus obovatus (BO) under laboratory and field conditions. RESULTS: Modelling of 10 day time concentration-mortality responses of female adults to 2 mL tower sprays of three CPT-Na(+) dilutions generated LC50 and LT50 values that decreased over post-spray days and sprayed amounts respectively. CPT-Na(+) sprays required to kill 50% BO, TU and AT were 35, 41 and 124 ug mL(-1) on day 1 post-spray, but rapidly decreased to 2.2, 2.5 and 3.6 ug mL(-1) on day 5, and to 0.69, 0.77 and 1.17 ug mL(-1) on day 7 respectively. In summer field trials, a spray rate of 7.5 g CPT Na(+) ha(-1) provided better control efficacy against TU (81-85%) on cotton or AT (90-93%) and BO (83-88%) in tea gardens than aramite (commercial acaricide) at the labelled rate of 56.25 g ha(-1) . Half of the CPT-Na(+) rate controlled the mites as effectively as aramite. CONCLUSION: Water-soluble CPT-Na(+) is a promising plant-sourced acaricide to combat wide-spectrum pest mites. PMID- 25924842 TI - Soft-patchy nanoparticles: modeling and self-organization. AB - We consider a novel class of patchy particles inspired by polymer-based complex units where the limited valence in bonding is accompanied by soft interactions and incessant fluctuations of the patch positions, possibly leading to reversible modifications of the patch number and size. We introduce a simple model that takes into account the aforementioned features and we focus on the role played by the patch flexibility on the self-organization of our patchy units in the bulk, with particular attention to the connectivity properties and the morphology of the aggregated networks. PMID- 25924843 TI - A register-based study of variations in services received among dental care attenders. AB - OBJECTIVES: To investigate whether receipt of dental services, among attenders, reflects variations in dental health or whether and to what degree it is associated with socioeconomic status, with irregular or regular dental attendance and with the availability of dentists in residential areas. MATERIALS AND METHODS: This retrospective register-based study followed two Danish cohorts, aged 25 and 40, with a dental examination in 2009 (n = 32,351). The dental service data were registered during 2005-2009. The number of dental examinations, individual preventive services (IPS), tooth extractions, root fillings and composite fillings were analyzed in relation to socioeconomic status, irregular/regular dental attendance, inhabitant/dentist ratio and to DMFT at age 15 (DMFT15) and change in DMFT (DeltaDMFT) from age 15 to age 25 and age 40, respectively. Poisson regression and negative binomial regression analyses were used. RESULTS: The variations in number of services received in the study population were small (SD = 0.2-2.7). However, with a few exceptions, high levels of DMFT15 and DeltaDMFT were associated with receipt of more dental services. Socioeconomically-privileged individuals received more dental examinations but fewer tooth extractions, root fillings and composite fillings compared to disadvantaged persons, when controlled for dental health levels. Irregular attenders received fewer IPS and composite fillings but had more extractions compared to regular attenders. CONCLUSIONS: Variations in dental care services were found to reflect variations in dental health, but the variations were also related to individual socioeconomic status, residential area and dental attendance patterns. PMID- 25924841 TI - HIV-1 Tat immunization restores immune homeostasis and attacks the HAART resistant blood HIV DNA: results of a randomized phase II exploratory clinical trial. AB - BACKGROUND: The phase II multicenter, randomized, open label, therapeutic trial (ISS T-002, Clinicaltrials.gov NCT00751595) was aimed at evaluating the immunogenicity and the safety of the biologically active HIV-1 Tat protein administered at 7.5 or 30 MUg, given 3 or 5 times monthly, and at exploring immunological and virological disease biomarkers. The study duration was 48 weeks, however, vaccinees were followed until the last enrolled subject reached the 48 weeks. Reported are final data up to 144 weeks of follow-up. The ISS T-002 trial was conducted in 11 clinical centers in Italy on 168 HIV positive subjects under Highly Active Antiretroviral Therapy (HAART), anti-Tat Antibody (Ab) negative at baseline, with plasma viremia <50 copies/mL in the last 6 months prior to enrollment, and CD4(+) T-cell number >=200 cells/MUL. Subjects from a parallel observational study (ISS OBS T-002, Clinicaltrials.gov NCT0102455) enrolled at the same clinical sites with the same criteria constituted an external reference group to explore biomarkers of disease. RESULTS: The vaccine was safe and well tolerated and induced anti-Tat Abs in most patients (79%), with the highest frequency and durability in the Tat 30 MUg groups (89%) particularly when given 3 times (92%). Vaccination promoted a durable and significant restoration of T, B, natural killer (NK) cells, and CD4(+) and CD8(+) central memory subsets. Moreover, a significant reduction of blood proviral DNA was seen after week 72, particularly under PI-based regimens and with Tat 30 MUg given 3 times (30 MUg, 3x), reaching a predicted 70% decay after 3 years from vaccination with a half-life of 88 weeks. This decay was significantly associated with anti Tat IgM and IgG Abs and neutralization of Tat-mediated entry of oligomeric Env in dendritic cells, which predicted HIV-1 DNA decay. Finally, the 30 MUg, 3x group was the only one showing significant increases of NK cells and CD38(+)HLA DR(+)/CD8(+) T cells, a phenotype associated with increased killing activity in elite controllers. CONCLUSIONS: Anti-Tat immune responses are needed to restore immune homeostasis and effective anti-viral responses capable of attacking the virus reservoir. Thus, Tat immunization represents a promising pathogenesis driven intervention to intensify HAART efficacy. PMID- 25924844 TI - Appropriate sevoflurane concentration to stabilize autonomic activity during intubation with rocuronium in infants: a randomized controlled trial. AB - BACKGROUND: In infants, sevoflurane is commonly used for induction of anesthesia, following which a muscle relaxant is administered to facilitate tracheal intubation. When rocuronium is used as the muscle relaxant, intubation may be performed before reaching an adequate depth of anesthesia because of its rapid onset. The purpose of this study was to investigate the optimal sevoflurane concentration that would minimize the impact of intubation on hemodynamics and autonomic nervous system (ANS) activity in infants. METHODS: Sixty-one infants aged 1-6 months, undergoing cleft lip repair, were enrolled. Patients were randomly assigned to three end-tidal sevoflurane concentration (E'Sevo) groups, 3%, 4% and 5%. Anesthesia was induced with 5% sevoflurane with 100% oxygen, and rocuronium (0.6 mg/kg) was administered. The concentration of sevoflurane was adjusted to the predetermined concentration in each group. Mechanical pressure control ventilation via a face mask was commenced. Five minutes after E'Sevo became stable at the predetermined concentration, tracheal intubation was performed. Immediately after tracheal intubation, ventilation was restarted at the same ventilator settings and continued for 150 seconds. Heart rate (HR) and mean arterial pressure (MAP) were measured 5 times in the 150 seconds after intubation. Normalized units (nu) of high frequency (HF: 0.04-0.15 Hz) and the ratio of low frequency (LF: 0.15-0.4 Hz) to HF components (LF/HF) of HR variability were calculated by MemCalc/Tonam2CTM. Normalized units of HF (HFnu) and LF/HF reflect cardiac parasympathetic and sympathetic activity, respectively. RESULTS: After intubation, HR increased slightly in all groups and MAP increased by 9.2% in the E'Sevo-3% group. LF/HF increased (p < 0.01) and HFnu decreased (p < 0.01) in all groups 30 seconds after intubation. HFnu was lower (p < 0.001) and LF/HF was higher (p = 0.007) in the E'Sevo-3% group than in E'Sevo-5% group. ANS responses to intubation were reduced in a dose-dependent manner. CONCLUSIONS: Sympathomimetic and parasympatholytic responses to intubation in the E'Sevo-3% group were much greater than those in the E'Sevo-5% group. During tracheal intubation in infants, 4% or 5% sevoflurane is appropriate for prevention of sympathetic hyperactivation and maintenance of ANS balance as compared to 3% sevoflurane, when a muscle relaxant is co-administered. TRIAL REGISTRATION: The study was registered at UMIN-CTR ( UMIN000009933). PMID- 25924845 TI - Nrp1, a Neuronal Regulator, Enhances DDR2-ERK-Runx2 Cascade in Osteoblast Differentiation via Suppression of DDR2 Degradation. AB - BACKGROUND: Osteoblastogenesis is under delicate control by multiple factors and hormones. Recent reports indicated the involvement of immunological and neuronal regulators. However, the role of neuropilin 1 (Nrp1) in osteoblastogenesis remains obscure. METHODS: Real-time PCR was carried out to detect the mRNA of osteoblastic markers, Nrp1, and discoidin domain receptor 2 (DDR2). Immunoblot was performed to test the protein of Nrp1 and DDR2. Osteogenic differentiation was evaluated by mRNA analysis of osteogenic markers, and determination of ALP activity and OCN secretion. The intercellular signaling effectors were examined by immunoblot. Immunofluorescent assays were performed to detect the localization of Nrp1 and DDR2. Half-life determination assay was executed to test the DDR2 stability. RESULTS: The expression of Nrp1 paralleled with that of DDR2 during osteoblastogensis. Nrp1 overexpression enhanced DDR2-induced stimulation of osteoblastogensis, whereas Nrp1 silencing caused attenuation. Nrp1 overexpression increased the phosphorylation of DDR2, ERK1/2 and Runx2. Nrp1 co-localized with DDR2 in the cellular membrane of differentiated MC3T3-E1. Enhanced or attenuated Nrp1 expression did not alter the mRNA transcript of DDR2. Nrp1 overexpression prolonged the half-life of DDR2 protein. CONCLUSION: Our results originally demonstrated the stimulatory role of Nrp1 in DDR2-induced osteoblast differentiation, providing molecular evidence for exploiting Nrp1 and DDR2 as targets to treat bone-related disease. PMID- 25924847 TI - Chiral Iminophosphoranes-An Emerging Class of Superbase Organocatalysts. AB - Chiral Bronsted base catalysis is a fascinating and highly explored field of research. For many years catalysts based on chincona alkaloid chiral scaffolds have constituted privileged systems widely employed in numerous base-promoted organic transformations. Recently, a novel group of chiral base catalysts has been successfully introduced. The application of organosuperbases, namely cyclopropenimines, guanidines, and iminophosphoranes, as chiral catalysts is receiving increasing attention. The aim of this Concept article is to summarize recent progress in the field of chiral iminophosphorane superbase organocatalysis. Catalysts design, different approaches to their synthesis, and applications in asymmetric synthesis are outlined and discussed in detail. PMID- 25924846 TI - Improving the differential diagnosis between myelodysplastic syndromes and reactive peripheral cytopenias by multiparametric flow cytometry: the role of B cell precursors. AB - BACKGROUND: Immunophenotyping is a valuable ancillary technique for the differential diagnosis between myelodysplastic syndromes (MDS) with low bone marrow (BM) blast counts and a normal karyotype, and reactive peripheral (PB) cytopenias. Our aim was to search for the most important variables for this purpose. We also analyzed the age variation of BM B-cell precursors (BCP) and its differences in reactive and clonal cytopenias. METHODS: Immunophenotypic analyzes were performed in BM of 54 patients with MDS (76% with BM blasts <5%) and 35 cases of reactive cytopenias. Healthy allogeneic BM transplantation donors (n = 41) were used as controls. We used a four-color panel of antibodies analyzing 9 granulocytic, 8 monocytic and 6 CD34(+) cell features. RESULTS: Asynchronous shift to the left in maturing granulocytes and increase in CD16(+) monocytes were also found in reactive PB cytopenias, but the most important aberrancies in MDS were seen in myeloid CD34(+) cells. Decrease in BCP, that is a hallmark of MDS, could also be found in reactive cytopenias, especially in patients >55 years. % BM BCP could be calculated by the formula: (-7.97 * log age) + (4.24 * log % CD34 (+) cells) - (0.22 x nr. alterations CD34 (+) cells) + 0.577. Corrected R(2) = 0.467. CONCLUSION: Analysis of myelomonocytic precursors and CD34(+) cells was satisfactory for the differential diagnosis between reactive PB cytopenias and MDS. The most specific alterations were found in CD34(+) cells. Comparison of the values obtained with those of normal age-matched controls is recommended. VIRTUAL SLIDES: The virtual slide(s) for this article can be found here: http://www.diagnosticpathology.diagnomx.eu/vs/1975931809154663. PMID- 25924848 TI - Diaphragm Pacing without Tracheostomy in Congenital Central Hypoventilation Syndrome Patients. AB - BACKGROUND: Congenital central hypoventilation syndrome (CCHS) is a rare disorder affecting central control of breathing. Thus, patients require lifelong assisted ventilation. Diaphragm pacing (DP) may permit decannulation in those who are ventilator dependent only during sleep. OBJECTIVE: The purpose of this study is to determine if patients with CCHS can be successfully ventilated by DP without tracheostomy. METHODS: We reviewed the records of 18 CCHS patients (mean age 19.5 +/- 10.1 years; 44% female) who were ventilated by DP only during sleep. RESULTS: Prior to diaphragm pacer implantation surgery, 14 CCHS patients had been using home portable positive pressure ventilation (PPV) via tracheostomy, 1 had been on PPV via endotracheal tube, and 3 had been using noninvasive PPV (NPPV). Of the patients with tracheostomy prior to DP (n = 15), 11 (73%) were decannulated and ventilated successfully by DP without tracheostomy. Of all the patients reviewed (n = 18), 13 (72%) were successfully ventilated by DP without tracheostomy. Obesity prevented successful DP without tracheostomy in 1 patient, and upper airway obstruction prevented success in another patient. Snoring and/or obstructive apneas were present in some patients, but they were improved by diaphragm pacer changes, adenotonsillectomy, and/or use of nasal steroids. CONCLUSIONS: DP without tracheostomy can be successfully achieved in patients with CCHS. Snoring and obstructive apneas, when present, can be managed by diaphragm pacer changes and medical therapies. Obesity can pose a challenge to successful DP. PMID- 25924849 TI - Modular design of SPIRO-OMeTAD analogues as hole transport materials in solar cells. AB - We predict the ionisation potentials of the hole-conducting material SPIRO-OMeTAD and twelve methoxy isomers and polymethoxy derivatives. Based on electronic and economic factors, we identify the optimal compounds for application as p-type hole-selective contacts in hybrid halide perovskite solar cells. PMID- 25924851 TI - Rethinking agency and medical adherence technology: applying Actor Network Theory to the case study of Digital Pills. AB - Much literature surrounding medical technology and adherence posits that technology is a mechanism for social control. This assumes that the medical establishment can take away patients' agency. Although power relationships and social control can play a key role, medical technology can also serve as an agentive tool to be utilized. We (1) offer the alternative framework of Actor Network Theory to view medical technology, (2) discuss the literature on medication adherence and technology, (3) delve into the ramifications of looking at adherence as a network and (4) use Digital Pills as a case study of dispersed agency. PMID- 25924850 TI - MiR-320a acts as a prognostic factor and Inhibits metastasis of salivary adenoid cystic carcinoma by targeting ITGB3. AB - BACKGROUND: Salivary Adenoid cystic carcinoma (SACC) patients with local invasion and lung metastasis are often resistant to conventional therapy such as operation, chemotherapy and radiotherapy. To explore the underling mechanisms, we studied the roles of miRNA in regulating invasiveness of SACC cells. METHODS: MicroRNA profiling was done in SACC cells with microarray. MiRNA mimics or antisense oligonucleotide was transfected and invasiveness of SACC cells was evaluated by adhesion assay and transwell assay. The target gene of miRNA was identified by luciferase reporter assay and "rescue" experiment. Tumor metastasis was evaluated by BALB/c-nu mice xenografts. MiRNA and its target gene expression were identified by in-situ hybridization and immunohistochemistry respectively, in 302 patients from affiliated hospitals of Sun Yat-sen University and in 148 patients from affiliated hospitals of Central South University, and correlated to the clinicopathological status of the patients. RESULTS: MiR-320a was down regulated in high lung metastatic ACCM and SACC-LM cells compared with the corresponding low metastatic ACC2 and SACC-83 cells, and inhibited adhesion, invasion and migration of SACC cells by targeting integrin beta 3 (ITGB3). In vivo, enforced miR-320a expression suppressed metastasis of SACC xenografts. In the two independent sets, miR-320a was downregulated in primary SACCs with metastasis compared to those without metastasis, and low expression of this miRNA predicts poor patient survival and rapid metastasis. Multivariate analysis showed that miR-320a expression was an independent indicator of lung metastasis. CONCLUSIONS: MiR-320a inhibits metastasis in SACCs by targeting ITGB3 and may serve as a therapeutic target and prognostic marker in salivary cancers. PMID- 25924852 TI - A dual-specific anti-IGF-1/IGF-2 human monoclonal antibody alone and in combination with temsirolimus for therapy of neuroblastoma. AB - The insulin-like growth factors (IGFs), IGF-1 and IGF-2, have been implicated in the growth, survival and metastasis of a broad range of malignancies including pediatric tumors. They bind to the IGF receptor type 1 (IGF-1R) and the insulin receptor (IR) which are overexpressed in many types of solid malignancies. Activation of the IR by IGF-2 results in increased survival of tumor cells. We have previously identified a novel human monoclonal antibody, m708.5, which binds with high (pM) affinity to both human IGF-1 and IGF-2, and potently inhibits phosphorylation of the IGF-1R and the IR in tumor cells. m708.5 exhibited strong antitumor activity as a single agent against most cell lines derived from neuroblastoma, Ewing family of tumor, rhabdomyosarcoma and osteosarcoma. When tested in neuroblastoma cell lines, it showed strong synergy with temsirolimus and synergy with chemotherapeutic agents in vitro. In xenograft models, the combination of m708.5 and temsirolimus significantly inhibited neuroblastoma growth and prolonged mouse survival. Taken together, these results support the clinical development of m708.5 for pediatric solid tumors with potential for synergy with chemotherapy and mTOR inhibitors. PMID- 25924854 TI - Solvent selection causes remarkable shifts of the "Ouzo region" for poly(lactide co-glycolide) nanoparticles prepared by nanoprecipitation. AB - Polymer nanoparticles (NPs) offer versatile novel biological features of interest for drug delivery applications. "Ouzo diagrams" allowed for a systematic manufacture of specified colloidal formulations by the widely used nanoprecipitation process. Surprisingly, despite the well-documented relevance of the applied organic solvent for nanoprecipitation, its effect on the actual status of the "Ouzo region" was so far not studied. Herein, investigations were undertaken to account for the potential impact of the solvent type on the "Ouzo diagrams" for poly(lactide-co-glycolide) (PLGA) and tetrahydrofuran (THF), 1,4 dioxane, acetone and dimethyl sulfoxide (DMSO). The "Ouzo region" shifted considerably to higher polymer fractions upon solvent change (rank order: THF < 1,4-dioxane < acetone < DMSO). Assuming a one-to-one transformation of detached PLGA-bearing solvent droplets (droplet diameter for THF: ~800 nm, 1,4-dioxane: ~700 nm, acetone: ~500 nm and DMSO: ~300 nm) into non-divisible polymer aggregates upon solvent displacement, facilitated to predict the size of NPs found within the "Ouzo region" (size range: 40-200 nm). In conclusion, application of "Ouzo diagrams" is a valuable tool for drug delivery research and will most-likely replace the "trial-and-error"-approach to identify the operating window for the production of stable colloidal formulations by the nanoprecipitation technique. PMID- 25924853 TI - High-throughput bone and cartilage micropellet manufacture, followed by assembly of micropellets into biphasic osteochondral tissue. AB - Engineered biphasic osteochondral tissues may have utility in cartilage defect repair. As bone-marrow-derived mesenchymal stem/stromal cells (MSC) have the capacity to make both bone-like and cartilage-like tissues, they are an ideal cell population for use in the manufacture of osteochondral tissues. Effective differentiation of MSC to bone-like and cartilage-like tissues requires two unique medium formulations and this presents a challenge both in achieving initial MSC differentiation and in maintaining tissue stability when the unified osteochondral tissue is subsequently cultured in a single medium formulation. In this proof-of-principle study, we used an in-house fabricated microwell platform to manufacture thousands of micropellets formed from 166 MSC each. We then characterized the development of bone-like and cartilage-like tissue formation in the micropellets maintained for 8-14 days in sequential combinations of osteogenic or chondrogenic induction medium. When bone-like or cartilage-like micropellets were induced for only 8 days, they displayed significant phenotypic changes when the osteogenic or chondrogenic induction medium, respectively, was swapped. Based on these data, we developed an extended 14-day protocol for the pre-culture of bone-like and cartilage-like micropellets in their respective induction medium. Unified osteochondral tissues were formed by layering 12,000 osteogenic micropellets and 12,000 chondrogenic micropellets into a biphasic structure and then further culture in chondrogenic induction medium. The assembled tissue was cultured for a further 8 days and characterized via histology. The micropellets had amalgamated into a continuous structure with distinctive bone-like and cartilage-like regions. This proof-of-concept study demonstrates the feasibility of micropellet assembly for the formation of osteochondral-like tissues for possible use in osteochondral defect repair. PMID- 25924855 TI - A Randomized Controlled Trial of Crown Therapy in Young Individuals with Amelogenesis Imperfecta. AB - Amelogenesis imperfecta (AI) is a rare, genetically determined defect in enamel mineralization. Existing treatment recommendations suggest resin-composite restorations until adulthood, although such restorations have a limited longevity. New crown materials allow for minimal preparation techniques. The aim of this study was to compare the quality and longevity of 2 crown types-Procera and IPS e.max Press-in adolescents and young adults with AI. A secondary aim was to document adverse events. We included 27 patients (11 to 22 y of age) with AI in need of crown therapy in a randomized controlled trial using a split-mouth technique. After placing 119 Procera crowns and 108 IPS e.max Press crowns following randomization, we recorded longevity, quality, adverse events, and tooth sensitivity. After 2 y, 97% of the crowns in both crown groups had excellent or acceptable quality. We found no significant differences in quality between Procera and IPS e.max Press crowns. Tooth sensitivity was significantly reduced after crown therapy (P < 0.001). Endodontic complications occurred in 3% of crowns. The results show that it is possible to perform crown therapy with excellent results and without severe complications in young patients with AI. The study is registered at http://www.controlled-trials.com (ISRCTN70438627). PMID- 25924856 TI - Insulin Response Genes in Different Stages of Periodontal Disease. AB - Bacterial infections are known to alter glucose metabolism within tissues via mechanisms of inflammation. We conducted this study to examine whether insulin response genes are differentially expressed in gingival tissues, comparing samples from experimental gingivitis and periodontitis subjects to those from healthy individuals. Total RNA was extracted from gingival biopsies from 26 participants: 8 periodontally healthy, 9 experimental gingivitis, and 9 periodontitis subjects. Gene expression patterns were evaluated with a polymerase chain reaction array panel to examine 84 candidate genes involved with glucose metabolism, insulin resistance, and obesity. Array data were evaluated with a t test adjusted by the false discover rate (P < 0.05), and ingenuity pathway analysis was performed for statistical testing of pathways. Although tissue samples were not sufficient to enable protein quantification, we confirmed the upregulation of the key gene using lipopolysaccharide-stimulated primary gingival epithelial cells by Western blot. The mRNA expression patterns of genes that are associated with insulin response and glucose metabolism are markedly different in experimental gingivitis subjects compared with healthy controls. Thirty-two genes are upregulated significantly by at least 2-fold, adjusted for false discover rate (P < 0.05). Periodontitis subjects show similar but attenuated changes in gene expression patterns, and no genes meet the significance criteria. Ingenuity pathway analysis demonstrates significant activation of the carbohydrate metabolism network in experimental gingivitis but not in periodontitis. G6PD protein increases in response to lipopolysaccharide stimulation in primary gingival epithelial cells, which is in the same direction as upregulated mRNA in tissues. Acute gingival inflammation may be associated with tissue metabolism changes, but these changes are not evident in chronic periodontitis. This study suggests that acute gingival inflammation may induce localized changes that modify tissue insulin/glucose metabolism. PMID- 25924858 TI - Frozen section diagnosis for non-melanoma skin cancers: correlation with permanent section diagnosis. AB - Frozen section pathology is routinely used for margin assessment of non-melanoma skin cancer (NMSC). Frozen section can also be used for the primary diagnosis of several skin lesions. Limited data exist on the accuracy of frozen section in the diagnosis of NMSC. We performed a retrospective chart review of 300 cases in which frozen section diagnoses were compared with permanent section diagnoses of NMSC. Frozen section and permanent section pathology were concordant 83.3% of the time, with the highest concordance rates noted for basal cell carcinoma (145/153, 95%). Our results show a high level of concordance between frozen section and corresponding permanent section pathology diagnosis for NMSC. The rapidity of frozen section tissue processing and pathology reporting makes this technique useful in dermatologic practice for immediate diagnosis and management of NMSC. Further studies should explore strategies to decrease or eliminate discrepancies between frozen and permanent section diagnosis. PMID- 25924857 TI - Long-Term Fluoride Release from Dental Resins Affects STRO-1+ Cell Behavior. AB - Fluoride-releasing restorative dental materials can be beneficial to remineralize dentin and help prevent secondary caries. However, the effects of fluoride release from dental materials on the activity of dental pulp stem cells are not known. Here we investigate whether different fluoride release kinetics from dental resins supplemented with modified hydrotalcite (RK-F10) or fluoride-glass filler (RK-FG10) could influence the behavior of a human dental pulp stem cell subpopulation (STRO-1(+) cells) known for its ability to differentiate toward an odontoblast-like phenotype. The 2 resins, characterized by similar physicochemical properties and fluoride content, exhibited different long-term fluoride release kinetics. Our data demonstrate that long-term exposure of STRO 1(+) cells to a continuous release of a low amount of fluoride by RK-F10 increases their migratory response to transforming growth factor beta1 (TGF beta1) and stromal cell-derived factor 1 (SDF-1), both important promoters of pulp stem cell recruitment. Moreover, the expression patterns of dentin sialoprotein (dspp), dentin matrix protein 1 (dmp1), osteocalcin (ocn), and matrix extracellular phosphoglycoprotein (mepe) indicate a complete odontoblast like cell differentiation only when STRO-1(+) cells were cultured on RK-F10. On the contrary, RK-FG10, characterized by an initial fluoride release burst and reduced lifetime of the delivery, did not elicit any significant effect on both STRO-1(+) cell migration and differentiation. Taken together, our results highlight the importance of taking into account fluoride release kinetics in addition to fluoride concentration when designing new fluoride-restorative materials. PMID- 25924859 TI - The importance of good history taking: a case report. AB - INTRODUCTION: Early comprehensive geriatric assessment (CGA) with good history taking is essential in assessing the older adult. CASE PRESENTATION: Our patient, a 75-year-old Caucasian woman, was originally admitted to hospital for investigation of iron deficiency anemia. During admission, she developed pneumonia and new intermittent atrial fibrillation in association with a right sided weakness, which was felt to be new at the time. Following this episode, she was treated for a further chest infection and, despite clinical improvement, her inflammatory markers failed to settle satisfactorily. She was transferred to her local hospital for a period of rehabilitation where further neurological findings made the diagnosis of solely stroke questionable; these findings prompted further history-taking, investigations and input from other disciplines, thereby helping to arrive at a working diagnosis of vasculitic neuropathy. CONCLUSIONS: The case aims to highlight the importance of taking a good history and performing an early comprehensive assessment in the older adult. PMID- 25924860 TI - Undergraduate cardiac arrest team training. AB - BACKGROUND AND OBJECTIVES: Health profession students are traditionally educated within their discipline with little to no interaction with other health professionals, but are expected to function as integral members of the health care team after graduation. Health profession educators must bridge this disconnect by providing interprofessional learning experiences for students. We sought to evaluate the impact of interdisciplinary team-based (ITB) versus individual discipline-based (DB) learning with multiple health care disciplines during a simulated cardiac arrest. METHODS: We performed a randomised trial with trainees from radiologic science (RS), physician assistant (PA) and nursing programmes (RN), taught by ITB and DB methods. Teams assessed a simulated patient experiencing a cardiac arrest before and after being educated using the First 5 Minutes((r)) Curriculum (First-5). Knowledge and subjective evaluations were collected on each participant both before and after the educational intervention. The data were analysed using generalised estimating equations to account for correlated data. RESULTS: We enrolled 29 subjects: 15 ITB (4 PA, 5 RN, 6 RS) and 14 DB (3 PA, 5 RN, 6 RS). Knowledge improved more in the ITB group than in the DB group: with a median change of 2 (IQR 0-2) versus 1 (IQR 0-2), respectively (p = 0.014). Subjectively, participants overwhelmingly responded that working and learning with other disciplines was a valuable experience, and that more opportunities for interdisciplinary learning should be integrated into the curriculum. More opportunities for interdisciplinary learning should be integrated into the curriculum DISCUSSION: In our pilot study using a simulated model and the First-5, ITB education appears to improve trainees' knowledge over DB education, and was subjectively preferred by the learner. PMID- 25924861 TI - Perforation of Meckel's diverticulum by an intact fish bone: a case report and literature review. PMID- 25924862 TI - Synergy and pinning effects in a monatomic liquid film in confined conditions. AB - The freezing behavior of a monatomic liquid film in confined conditions during rapid cooling was studied by molecular dynamics simulations. We illustrated the synergy and pinning effects of the local icosahedral order during freezing. Our results show that the icosahedron contributes to nucleation through the synergy with other short-range ordered structures and participates in crystal growth via assimilation, but the pinning effect should be overcome when crystals grow. Furthermore, a semi-ordered morphology with maze-like nano-patterns emerged due to the cooperation between the synergy effect and the pinning effect. Our findings shed light on the correlation between the local icosahedral order and the crystalline medium-range order, providing a better understanding of the rapid solidification. PMID- 25924863 TI - NHS is over-reliant on temporary staff, King's Fund warns. PMID- 25924864 TI - Recent advances of microRNA-based molecular diagnostics to reduce false-positive lung cancer imaging. AB - Lung cancer is the leading cause of cancer deaths in the world. Advances in early detection crucial to enable timely curative surgery have been made in recent years. Cost-benefit profiles of lung cancer screening in smokers by low-dose computed tomography are still under evaluation. In particular, the high false positive rates of low-dose computed tomography, together with the issue of overdiagnosis and the overall costs of screening, prompted a focus on the development of noninvasive complementary biomarkers to implement lung cancer screening. MicroRNA are a new class of blood-based biomarkers useful for early lung cancer detection and prognosis definition. Here, we discuss the seminal publications that reported circulating microRNA signatures with the greatest potential to impact clinical activity and patient care. PMID- 25924865 TI - Regional distribution of physicians: the role of comprehensive private health insurance in Germany. AB - OBJECTIVE: In recent years, the co-existence in Germany of two parallel comprehensive insurance systems-statutory health insurance (SHI) and private health insurance (PHI)-has been posited as a possible cause of a persistent unequal regional distribution of physicians. The present study investigates the effect of the proportion of privately insured patients on the density of SHI licensed physicians, while controlling for regional variations in the average income from SHI patients. METHODS: The proportion of residents in a district with private health insurance is estimated using complete administrative data from the SHI system and the German population census. Missing values are estimated using multiple imputation techniques. All models control for the estimated average income ambulatory physicians generate from treating SHI insured patients and a well-defined set of covariates on the level of districts in Germany in 2010. RESULTS: Our results show that every percentage change in the proportion of residents with private health insurance is associated with increases of 2.1 and 1.3 % in the density of specialists and GPs respectively. Higher SHI income in rural areas does not compensate for this effect. CONCLUSION: From a financial perspective, it is rational for a physician to locate a new practice in a district with a high proportion of privately insured patients. From the perspective of patients in the SHI system, the incentive effects of PHI presumably contribute to a concentration of health care services in wealthy and urban areas. To date, the needs-based planning mechanism has been unable to address this imbalance. PMID- 25924866 TI - Comparison of milk oligosaccharides pattern in colostrum of different horse breeds. AB - Colostrum oligosaccharides are known to exhibit prebiotic and immunomodulatory properties. Oligosaccharide composition is species-specific, and equine colostrum has been reported to contain unique oligosaccharides. Therefore, equine oligosaccharides (EMOS) from colostrum from different horse breeds were analyzed by CE-LIF, CE-MS(n), HILIC-MS(n), and exoglycosidase degradation. Sixteen EMOS were characterized and quantified, of which half were neutral and half were acidic. EMOS showed about 63% structural overlap with human milk oligosaccharides, known for their bioactivity. Seven EMOS were not reported before in equine oligosaccharides literature: neutral Gal(beta1-4)HexNAc, Gal(beta1-4)Hex-Hex, beta4'-galactosyllactose, and lactose-N-hexaose, as well as acidic 6'-Sialyl-Hex-Ac-HexNAc, sialyllacto-N-tetraose-a, and disialylacto-N tetraose (isomer not further specified). In all colostrum samples, the average oligosaccharide concentration ranged from 2.12 to 4.63 g/L; with beta 6'and 3'- galactosyllactose, 3'-sialyllactose, and disialyllactose as the most abundant of all oligosaccharides (27-59, 16-37, 1-8, and 1-6%, respectively). Differences in presence and in abundance of specific EMOS were evident not only between the four breeds but also within the breed. PMID- 25924867 TI - The current trends of mortality following congenital heart surgery: the Japan Congenital Cardiovascular Surgery Database. AB - OBJECTIVES: Whereas surgical outcomes of congenital heart surgery have improved during the past two decades, there are still measurable postoperative mortalities in this field. This study is aimed at evaluating the current situation of mortality following congenital heart surgery. METHODS: Data on all registered 28 810 patients in The Japan Congenital Cardiovascular Surgery Database (JCCVSD) between 2008 and 2012 were analysed, except for patients with degenerative cardiomyopathy including dilated, restrictive and hypertrophic cardiomyopathy, and pathologically or histologically malignant cardiac tumours. The number of registered cases increased every year, and reached ~9000 cases in 2012. The median age at surgery was 0.8 years (range, 0-82). More than half of the patients (54%) who underwent surgery were <1 year old, and 6.0% of all patients were over 18 years old (adults). In this study, all mortalities within 90 days after the operation and mortality at discharge beyond 90 days of hospitalization were defined as '90-day and in-hospital mortality'. RESULTS: The 30-, 90-day and in hospital mortality rates were 2.3, 3.5 and 4.5%, respectively. The mean and median durations from surgery to death were 61 +/- 89 and 28 days (range, 0-717), respectively. Whereas 658 mortalities (51%) occurred within 30 days of surgery, 265 (21%) occurred later than 90 days after surgery. A total of 3630 patients (13%) were hospitalized for more than 90 days after the operation; of those, 3365 patients survived at discharge (93%). Cardiac problems were the most frequent causes of death after the surgery at any point in time, and 7.1 per 1000 patients died at over 30 days after the operation due to solely cardiac. CONCLUSIONS: The investigation of JCCVSD revealed that about a half of mortalities occurred later than 30 days; hence 90-day and in-hospital mortality would be a good discriminator that accurately represented the current situation of mortality after congenital heart surgery. Mortalities long after the operation due to post cardiotomy heart failure without any other lethal complications were still not rare. PMID- 25924868 TI - Should computed tomography angiography supersede invasive coronary angiography for the evaluation of graft patency following coronary artery bypass graft surgery? AB - Invasive coronary angiography (ICA) has long been the established gold standard in assessing graft patency following coronary artery bypass graft (CABG). Over the past decade or so however, improvements in computed tomography angiography (CTA) technology have allowed its emergence as a useful clinical tool in graft assessment. The recent introduction of 64-slice and now 128-slice scanners into widespread distribution, and the development of 320-detector row technology allowing volumetric imaging of the entire heart at single points in time within one cardiac cycle, has increased the potential of CTA to supersede ICA in this capacity. This study sought to examine the evidence surrounding this potential. A best evidence topic was constructed according to a structured protocol. The enquiry: In [patients who have undergone coronary artery bypass graft surgery] is [computed tomography angiography or invasive coronary angiography] superior in terms of [graft patency assessment, stenosis detection, radiation exposure and complication rate]? Four hundred and twenty-four articles were identified from the search strategy. Four additional articles were identified from references of key articles. Seventeen articles selected as best evidence were tabulated. The reliability of CTA as a tool in the detection of graft patency and stenosis has continued to improve with each successive generation of multislice technology. The latest 64- and 128-slice CTA techniques are able to detect graft patency and stenosis with very high sensitivities and specificities comparable with ICA, while remaining non-invasive procedures associated with fewer complications (ICA carries a 0.08% risk of myocardial infarction and 0.7% risk of minor complications in clinically stable patients). Present limitations of the technology include the accurate visualization of distal anastomoses and clip artefacts. In addition, the capacity of diagnostic ICA to be combined simultaneously with percutaneous coronary interventions is an important advantage and a further limitation of CTA alone. Recent developments, however, including the derivation of fractional flow reserve and perfusion assessment from CTA as functional measures of stenosis severity have given CTA at present the capacity to become a first-line tool in the assessment of patients with suspected graft dysfunction. Novel computer-automated diagnostic software, though currently in infancy, has shown promise in facilitating and speeding image interpretation. With further improvements in scanning technologies, CTA is likely to supersede ICA for graft assessment in the near future. PMID- 25924869 TI - Recurrence of primary spontaneous pneumothorax in young adults and children. AB - OBJECTIVES: Although better nutritional support has improved the growth rates in children, the occurrence of primary spontaneous pneumothorax has also been increasing in children. The current study attempts to investigate the occurrence and recurrence of primary spontaneous pneumothorax and the efficacy of surgery for primary spontaneous pneumothorax in young adults and children. METHODS: A total of 840 patients were treated for pneumothorax at our hospital from January 2006 to December 2010. Exclusion criteria for this study were age >25 or secondary, traumatic or iatrogenic pneumothorax, and a total of 517 patients were included. Patients were classified into three groups according to age at the first episode of primary spontaneous pneumothorax: Group A: <=16 years; Group B: 17-18 years and Group C: >=19 years. RESULTS: The study group was composed of 470 male and 47 female patients. There were 234 right-sided, 279 left-sided and 4 bilateral primary spontaneous pneumothoraces. Wedge resection by video-assisted thoracic surgery was performed in 285 patients, while 232 were managed by observation or closed thoracostomy. In the wedge resection group, 51 patients experienced recurrence. The recurrence rates after wedge resection were 27.9% in Group A, 16.5% in Group B and 13.2% in Group C (P = 0.038). The recurrence rates after observation or closed thoracostomy were 45.7% in Group A, 51.9% in Group B and 47.7% in Group C (P = 0.764). CONCLUSIONS: In the present study, postoperative recurrence rates were higher than those in the literature. Intense and long-term follow-up was probably one reason for the relatively high recurrence rate. The recurrence rate after wedge resection in patients aged <=16 years was higher than that in older patients. There was no difference between the recurrence rates after observation or closed thoracostomy, regardless of age. These results suggest that wedge resection might be delayed in children. PMID- 25924870 TI - Spatiotemporally resolved black carbon concentration, schoolchildren's exposure and dose in Barcelona. AB - At city level, personal monitoring is the best way to assess people's exposure. However, it is usually estimated from a few monitoring stations. Our aim was to determine the exposure to black carbon (BC) and BC dose for 45 schoolchildren with portable microaethalometers and to evaluate the relationship between personal monitoring and fixed stations at schools (indoor and outdoor) and in an urban background (UB) site. Personal BC concentra-tions were 20% higher than in fixed stations at schools. Linear mixed-effect models showed low R(2) between personal measurements and fixed stations at schools (R(2) <= 0.28), increasing to R(2) >= 0.70 if considering only periods when children were at schools. For the UB station, the respective R(2) were 0.18 and 0.45, indicating the importance of the distance to the monitoring station when assessing exposure. During the warm season, the fixed stations agreed better with personal measurements than during the cold one. Children spent 6% of their time on commuting but received 20% of their daily BC dose, due to co-occurrence with road traffic rush hours and the close proximity to the source. Children received 37% of their daily integrated BC dose at school. Indoor environments (classroom and home) were responsible for the 56% BC dose. PMID- 25924871 TI - Systematic review of model-based cervical screening evaluations. AB - BACKGROUND: Optimising population-based cervical screening policies is becoming more complex due to the expanding range of screening technologies available and the interplay with vaccine-induced changes in epidemiology. Mathematical models are increasingly being applied to assess the impact of cervical cancer screening strategies. METHODS: We systematically reviewed MEDLINE(r), Embase, Web of Science(r), EconLit, Health Economic Evaluation Database, and The Cochrane Library databases in order to identify the mathematical models of human papillomavirus (HPV) infection and cervical cancer progression used to assess the effectiveness and/or cost-effectiveness of cervical cancer screening strategies. Key model features and conclusions relevant to decision-making were extracted. RESULTS: We found 153 articles meeting our eligibility criteria published up to May 2013. Most studies (72/153) evaluated the introduction of a new screening technology, with particular focus on the comparison of HPV DNA testing and cytology (n = 58). Twenty-eight in forty of these analyses supported HPV DNA primary screening implementation. A few studies analysed more recent technologies - rapid HPV DNA testing (n = 3), HPV DNA self-sampling (n = 4), and genotyping (n = 1) - and were also supportive of their introduction. However, no study was found on emerging molecular markers and their potential utility in future screening programmes. Most evaluations (113/153) were based on models simulating aggregate groups of women at risk of cervical cancer over time without accounting for HPV infection transmission. Calibration to country-specific outcome data is becoming more common, but has not yet become standard practice. CONCLUSIONS: Models of cervical screening are increasingly used, and allow extrapolation of trial data to project the population-level health and economic impact of different screening policy. However, post-vaccination analyses have rarely incorporated transmission dynamics. Model calibration to country-specific data is increasingly common in recent studies. PMID- 25924872 TI - WHO European Childhood Obesity Surveillance Initiative: associations between sleep duration, screen time and food consumption frequencies. AB - BACKGROUND: Both sleep duration and screen time have been suggested to affect children's diet, although in different directions and presumably through different pathways. The present cross-sectional study aimed to simultaneously investigate the associations between sleep duration, screen time and food consumption frequencies in children. METHODS: The analysis was based on 10 453 children aged 6-9 years from five European countries that participated in the World Health Organization European Childhood Obesity Surveillance Initiative. Logistic multilevel models were used to assess associations of parent-reported screen time as well as sleep duration (exposure variables) with consumption frequencies of 16 food items (outcome variables). All models were adjusted for age, sex, outdoor play time, maximum educational level of parents and sleep duration or screen time, depending on the exposure under investigation. RESULTS: One additional hour of screen time was associated with increased consumption frequencies of 'soft drinks containing sugar' (1.28 [1.19;1.39]; odds ratio and 99% confidence interval), 'diet/light soft drinks' (1.21 [1.14;1.29]), 'flavoured milk' (1.18 [1.08;1.28]), 'candy bars or chocolate' (1.31 [1.22;1.40]), 'biscuits, cakes, doughnuts or pies' (1.22 [1.14;1.30]), 'potato chips (crisps), corn chips, popcorn or peanuts' (1.32 [1.20;1.45]), 'pizza, French fries (chips), hamburgers'(1.30 [1.18;1.43]) and with a reduced consumption frequency of 'vegetables (excluding potatoes)' (0.89 [0.83;0.95]) and 'fresh fruits' (0.91 [0.86;0.97]). Conversely, one additional hour of sleep duration was found to be associated with increased consumption frequencies of 'fresh fruits' (1.11 [1.04;1.18]) and 'vegetables (excluding potatoes)' (1.14 [1.07;1.23]). CONCLUSION: The results suggest a potential relation between high screen time exposure and increased consumption frequencies of foods high in fat, free sugar or salt whereas long sleep duration may favourably be related to children's food choices. Both screen time and sleep duration are modifiable behaviours that may be tackled in childhood obesity prevention efforts. PMID- 25924873 TI - Hypothalamic-Pituitary Axis in Non-Functioning Pituitary Adenomas: Focus on the Prevalence of Isolated Central Hypoadrenalism. AB - INTRODUCTION: Non-functioning pituitary adenomas (NFPA) account for about 40% of pituitary tumors. Pituitary deficiencies are present at diagnosis in 60-80% of NFPA, and, classically, growth hormone (GH) secretion is lost first, while adrenocorticotropic hormone is expected to disappear last. The aim of this study was to evaluate the incidence of multiple or isolated pituitary deficiencies in a large series of NFPA. MATERIALS AND METHODS: We retrospectively analyzed data on 218 NFPA cases (59% females, 59% with macroadenomas, average age: 50.2 +/- 17 years) followed up at our center from 1990 to 2013. At diagnosis all patients had a complete evaluation of pituitary function in basal conditions and provocative tests for the hypothalamic-pituitary-adrenal axis, while tests for GH deficiency (GHD) were carried out in 38%. RESULTS: 52.3% of patients (65.6% of macroadenomas, 33.3% of microadenomas) presented at least 1 pituitary deficiency: isolated deficiency in 29.8%, multiple deficiencies in 30% and panhypopituitarism in 9%. Isolated deficiencies were hypogonadism in 11.5% of patients (8% in micro , 14% in macroadenomas), hypoadrenalism in 10.1% (14% in micro-, 7% in macroadenomas) and GHD in 8.3% (8.9% in micro-, 7.8% in macroadenomas). About 30% of microadenomas had at least 1 pituitary deficiency at diagnosis, independently of tumor localization within the sellar region. CONCLUSIONS: The presence of isolated hypoadrenalism suggests that the order of appearance of hypopituitarism does not always follow the one expected. Given the relatively high prevalence of isolated hypoadrenalism even in microadenomas, we suggest a full assessment of basal and dynamic pituitary function in all NFPA regardless of tumor size. PMID- 25924875 TI - A Theoretical Method for Characterizing Nonlinear Effects in Paul Traps with Added Octopole Field. AB - In comparison with numerical methods, theoretical characterizations of ion motion in the nonlinear Paul traps always suffer from low accuracy and little applicability. To overcome the difficulties, the theoretical harmonic balance (HB) method was developed, and was validated by the numerical fourth-order Runge Kutta (4th RK) method. Using the HB method, analytical ion trajectory and ion motion frequency in the superimposed octopole field, epsilon, were obtained by solving the nonlinear Mathieu equation (NME). The obtained accuracy of the HB method was comparable with that of the 4th RK method at the Mathieu parameter, q = 0.6, and the applicable q values could be extended to the entire first stability region with satisfactory accuracy. Two sorts of nonlinear effects of ion motion were studied, including ion frequency shift, Deltabeta, and ion amplitude variation, Delta(C(2n)/C0) (n ? 0). New phenomena regarding Deltabeta were observed, although extensive studies have been performed based on the pseudo potential well (PW) model. For instance, the |Deltabeta| at epsilon = 0.1 and epsilon = -0.1 were found to be different, but they were the same in the PW model. This is the first time the nonlinear effects regarding Delta(C(2n)/C0) (n ? 0) are studied, and the associated study has been a challenge for both theoretical and numerical methods. The nonlinear effects of Delta(C(2n)/C0) (n ? 0) and Deltabeta were found to share some similarities at q < 0.6: both of them were proportional to epsilon, and the square of the initial ion displacement, z(0)(2). PMID- 25924874 TI - Germline PRKACA amplification causes variable phenotypes that may depend on the extent of the genomic defect: molecular mechanisms and clinical presentations. AB - OBJECTIVE: We have recently reported five patients with bilateral adrenocortical hyperplasia (BAH) and Cushing's syndrome (CS) caused by constitutive activation of the catalytic subunit of protein kinase A (PRKACA). By doing new in-depth analysis of their cytogenetic abnormality, we attempted a better genotype phenotype correlation of their PRKACA amplification. DESIGN: This study is a case series. METHODS: Molecular cytogenetic, genomic, clinical, and histopathological analyses were performed in five patients with CS. RESULTS: Reinvestigation of the defects of previously described patients by state-of-the-art molecular cytogenetics showed complex genomic rearrangements in the chromosome 19p13.2p13.12 locus, resulting in copy number gains encompassing the entire PRKACA gene; three patients (one sporadic case and two related cases) were observed with gains consistent with duplications, while two sporadic patients were observed with gains consistent with triplications. Although all five patients presented with ACTH-independent CS, the three sporadic patients had micronodular BAH and underwent bilateral adrenalectomy in early childhood, whereas the two related patients, a mother and a son, presented with macronodular BAH as adults. In at least one patient, PRKACA triplication was associated with a more severe phenotype. CONCLUSIONS: Constitutional chromosomal PRKACA gene amplification is a recently identified genetic defect associated with CS, a trait that may be inherited in an autosomal dominant manner or occur de novo. Genomic rearrangements can be complex and can result in different copy number states of dosage-sensitive genes, e.g., duplication and triplication. PRKACA amplification can lead to variable phenotypes clinically and pathologically, both micro- and macro-nodular BAH, the latter of which we speculate may depend on the extent of amplification. PMID- 25924876 TI - Activity of drugs and components of natural origin in the severe myoclonic epilepsy of infancy (Dravet syndrome). AB - The sea anemones (Cnidaria) produce neurotoxins, polypeptides active on voltage gated sodium channels, which induce a non-inactivating condition, with consequent seizures and paralysis in zebrafish (Danio rerio). In humans, severe myoclonic epilepsy of infancy (SMEI) is due to SCN1A gene mutation, which causes a non inactivating sodium channels condition with seizures. Some symptoms, such as age of first seizure, repetitive events, frequent status epilepticus, scarce responsiveness to antiepileptic drugs (AEDs), may be due to superimposed environmental causes. The authors report a case of SMEI treated for years with benzodiazepines and subsequently with valproate. The attenuation of the frequency of epileptic events and of time in seizing, but no change in burst duration and EEG events was observed. These results are similar to those reported in the literature about zebrafish scn1Lab mutant, which recapitulates the SCN1A symptoms and AED resistance occurring in humans. During seizures the production of polypeptides similar to sea anemones neurotoxins, causing repetitive seizures, status epilepticus, and AED resistance can be hypothesized in subjects with SCN1A mutation. PMID- 25924877 TI - An improved odor bait for monitoring populations of Aedes aegypti-vectors of dengue and chikungunya viruses in Kenya. AB - BACKGROUND: Effective surveillance and estimation of the biting fraction of Aedes aegypti is critical for accurate determination of the extent of virus transmission during outbreaks and inter-epidemic periods of dengue and chikungunya fever. Here, we describe the development and use of synthetic human odor baits for improved sampling of adult Ae. aegypti, in two dengue and chikungunya fevers endemic areas in Kenya; Kilifi and Busia counties. METHODS: We collected volatiles from the feet and trunks of two female and two male volunteers aged between 25 and 45 years. We used coupled gas chromatography- electroantennographic detection (GC/EAD) analysis to screen for antennally-active components from the volatiles and coupled GC-mass spectrometry (GC/MS) to identify the EAD-active components. Using randomized replicated designs, we compared the efficacies of Biogents (BG) sentinel traps baited with carbon dioxide plus either single or blends of the identified compounds against the BG sentinel trap baited with carbon dioxide plus the BG commercial lure in trapping Ae. aegypti. The daily mosquito counts in the different traps were subjected to negative binomial regression following the generalized linear models procedures. RESULTS: A total of ten major EAD-active components identified by GC/MS as mainly aldehydes and carboxylic acids, were consistently isolated from the human feet and trunk volatiles from at least two volunteers. Field assays with synthetic chemicals of the shared EAD-active components identified from the feet and trunk gave varying results. Ae. aegypti were more attracted to carbon dioxide baited BG sentinel traps combined with blends of aldehydes than to similar traps combined with blends of carboxylic acids. When we assessed the efficacy of hexanoic acid detected in odors of the BG commercial lure and volunteers plus carbon dioxide, trap captures of Ae. aegypti doubled over the trap baited with the commercial BG lure. However, dispensing aldehydes and carboxylic acids together in blends, reduced trap captures of Ae. aegypti by ~45%-50%. CONCLUSIONS: Our results provide evidence for roles of carboxylic acids and aldehydes in Ae. aegypti host attraction and also show that of the carboxylic acids, hexanoic acid is a more effective lure for the vector than the BG commercial lure. PMID- 25924879 TI - To explain the variation of OGTT dynamics by biological mechanisms: a novel approach based on principal components analysis in women with history of GDM. AB - Early reexamination of carbohydrate metabolism via an oral glucose tolerance test (OGTT) is recommended after pregnancy with gestational diabetes (GDM). In this report, we aimed to assess the dominant patterns of dynamic OGTT measurements and subsequently explain them by meanings of the underlying pathophysiological processes. Principal components analysis (PCA), a statistical procedure that aims to reduce the dimensionality of multiple interrelated measures to a set of linearly uncorrelated variables (the principal components) was performed on OGTT data of glucose, insulin and C-peptide in addition to age and body mass index (BMI) of 151 women (n = 110 females after GDM and n = 41 controls) at 3-6 mo after delivery. These components were explained by frequently sampled intravenous glucose tolerance test (FSIGT) parameters. Moreover, their relation with the later development of overt diabetes was studied. Three principal components (PC) were identified, which explained 71.5% of the variation of the original 17 variables. PC1 (explained 47.1%) was closely related to postprandial OGTT levels and FSIGT-derived insulin sensitivity (r = 0.68), indicating that it mirrors insulin sensitivity in the skeletal muscle. PC2 (explained 17.3%) and PC3 (explained 7.1%) were shown to be associated with beta-cell failure and fasting (i.e., hepatic) insulin resistance, respectively. All three components were related with diabetes progression (occurred in n = 25 females after GDM) and showed significant changes in long-term trajectories. A high amount of the postpartum OGTT data is explained by principal components, representing pathophysiological mechanisms on the pathway of impaired carbohydrate metabolism. Our results improve our understanding of the underlying biological processes to provide an accurate postgestational risk stratification. PMID- 25924878 TI - Angiotensin II receptor blockade or deletion of vascular endothelial ACE does not prevent vascular dysfunction and remodeling in 20-HETE-dependent hypertension. AB - Increased vascular 20-HETE is associated with hypertension and activation of the renin-angiotensin system (RAS) through induction of vascular angiotensin converting enzyme (ACE) expression. Cyp4a12tg mice, whose Cyp4a12-20-HETE synthase expression is under the control of a tetracycline (doxycycline, DOX) promoter, were used to assess the contribution of ACE/RAS to microvascular remodeling in 20-HETE-dependent hypertension. Treatment of Cyp4a12tg mice with DOX increased systolic blood pressure (SBP; 136 +/- 2 vs. 102 +/- 1 mmHg; P < 0.05), and this increase was prevented by administration of 20-HEDGE, lisinopril, or losartan. DOX-induced hypertension was associated with microvascular dysfunction and remodeling of preglomerular microvessels, which was prevented by 20-HEDGE, a 20-HETE antagonist, yet only lessened, but not prevented, by lisinopril or losartan. In ACE 3/3 mice, which lack vascular endothelial ACE, administration of 5alpha-dihydrotestosterone (DHT), a known inducer of 20-HETE production, increased SBP; however, the increase was about 50% of that in wild type (WT) mice (151 +/- 1 vs. 126 +/- 1 mmHg). Losartan and 20-HEDGE prevented the DHT-induced increase in SBP in WT and ACE 3/3 mice. DHT treatment increased 20-HETE production and microvascular remodeling in WT and ACE 3/3 mice; however, remodeling was attenuated in the ACE 3/3 mice as opposed to WT mice (15.83 +/- 1.11 vs. 22.17 +/- 0.92 MUm; P < 0.05). 20-HEDGE prevented microvascular remodeling in WT and ACE 3/3 mice, while losartan had no effect on microvascular remodeling in ACE 3/3. Taken together, these results suggest that RAS contributes to 20-HETE-mediated microvascular remodeling in hypertension and that 20-HETE driven microvascular remodeling independent of blood pressure elevation does not fully rely on ACE activity in the vascular endothelium. PMID- 25924880 TI - Forearm cutaneous vascular and sudomotor responses to whole body passive heat stress in young smokers. AB - The purpose of this study was to compare smokers and nonsmokers' sudomotor and cutaneous vascular responses to whole body passive heat stress. Nine regularly smoking (SMK: 29 +/- 9 yr; 10 +/- 6 cigarettes/day) and 13 nonsmoking (N-SMK: 27 +/- 8 yr) males were passively heated until core temperature (TC) increased 1.5 degrees C from baseline. Forearm local sweat rate (LSR) via ventilated capsule, sweat gland activation (SGA), sweat gland output (SGO), and cutaneous vasomotor activity via laser-Doppler flowmetry (CVC) were measured as mean body temperature increased (DeltaTb) during passive heating using a water-perfused suit. Compared with N-SMK, SMK had a smaller DeltaTb at the onset of sweating (0.52 +/- 0.19 vs. 0.35 +/- 0.14 degrees C, respectively; P = 0.03) and cutaneous vasodilation (0.61 +/- 0.21 vs. 0.31 +/- 0.12 degrees C, respectively; P < 0.01). Increases in LSR and CVC per degrees C DeltaTb (i.e., sensitivity) were similar in N-SMK and SMK (LSR: 0.63 +/- 0.21 vs. 0.60 +/- 0.40 Deltamg/cm(2)/min/ degrees C DeltaTb, respectively, P = 0.81; CVC: 82.5 +/- 46.2 vs. 58.9 +/- 23.3 Delta%max/ degrees C DeltaTb, respectively; P = 0.19). However, the plateau in LSR during whole body heating was higher in N-SMK vs. SMK (1.00 +/- 0.13 vs. 0.79 +/- 0.26 mg.cm( 2).min(-1); P = 0.03), which was likely a result of higher SGO (8.94 +/- 3.99 vs. 5.94 +/- 3.49 MUg.gland(-1).min(-1), respectively; P = 0.08) and not number of SGA (104 +/- 7 vs. 121 +/- 9 glands/cm(2), respectively; P = 0.58). During whole body passive heat stress, smokers had an earlier onset for forearm sweating and cutaneous vasodilation, but a lower local sweat rate that was likely due to lower sweat output per gland. These data provide insight into local (i.e., forearm) thermoregulatory responses of young smokers during uncompensatory whole body passive heat stress. PMID- 25924881 TI - Long-term pathological consequences of prenatal infection: beyond brain disorders. AB - Prenatal immunological adversities such as maternal infection have been widely acknowledged to contribute to an increased risk of neurodevelopmental brain disorders. In recent years, epidemiological and experimental evidence has accumulated to suggest that prenatal exposure to immune challenges can also negatively affect various physiological and metabolic functions beyond those typically associated with primary defects in CNS development. These peripheral changes include excessive accumulation of adipose tissue and increased body weight, impaired glycemic regulation and insulin resistance, altered myeloid lineage development, increased gut permeability, hyperpurinergia, and changes in microbiota composition. Experimental work in animal models further suggests that at least some of these peripheral abnormalities could directly contribute to CNS dysfunctions, so that normalization of peripheral pathologies could lead to an amelioration of behavioral deficits. Hence, seemingly unrelated central and peripheral effects of prenatal infection could represent interrelated pathological entities that emerge in response to a common developmental stressor. Targeting peripheral abnormalities may thus represent a valuable strategy to improve the wide spectrum of behavioral abnormalities that can emerge in subjects with prenatal infection histories. PMID- 25924882 TI - Profiling of the fetal and adult rat liver transcriptome and translatome reveals discordant regulation by the mechanistic target of rapamycin (mTOR). AB - The mechanistic target of rapamycin (mTOR) integrates growth factor signaling, nutrient abundance, cell growth, and proliferation. On the basis of our interest in somatic growth in the late gestation fetus, we characterized the role of mTOR in the regulation of hepatic gene expression and translation initiation in fetal and adult rats. Our strategy was to manipulate mTOR signaling in vivo and then characterize the transcriptome and translating mRNA in liver tissue. In adult rats, we used the nonproliferative growth model of refeeding after a period of fasting and the proliferative model of liver regeneration following partial hepatectomy. We also studied livers from preterm fetal rats (embryonic day 19) in which fetal hepatocytes are asynchronously proliferating. All three models employed rapamycin to inhibit mTOR signaling. Analysis of the transcriptome in fasted-refed animals showed rapamycin-mediated induction of genes associated with oxidative phosphorylation. Genes associated with RNA processing were downregulated. In liver regeneration, rapamycin induced genes associated with lysosomal metabolism, steroid metabolism, and the acute phase response. In fetal animals, rapamycin inhibited expression of genes in several functional categories that were unrelated to effects in the adult animals. Translation control showed marked fetal-adult differences. In both adult models, rapamycin inhibited the translation of genes with complex 5' untranslated regions, including those encoding ribosomal proteins. Fetal translation was resistant to the effects of rapamycin. We conclude that the mTOR pathway in liver serves distinct physiological roles in the adult and fetus, with the latter representing a condition of rapamycin resistance. PMID- 25924884 TI - UrQt: an efficient software for the Unsupervised Quality trimming of NGS data. AB - BACKGROUND: Quality control is a necessary step of any Next Generation Sequencing analysis. Although customary, this step still requires manual interventions to empirically choose tuning parameters according to various quality statistics. Moreover, current quality control procedures that provide a "good quality" data set, are not optimal and discard many informative nucleotides. To address these drawbacks, we present a new quality control method, implemented in UrQt software, for Unsupervised Quality trimming of Next Generation Sequencing reads. RESULTS: Our trimming procedure relies on a well-defined probabilistic framework to detect the best segmentation between two segments of unreliable nucleotides, framing a segment of informative nucleotides. Our software only requires one user-friendly parameter to define the minimal quality threshold (phred score) to consider a nucleotide to be informative, which is independent of both the experiment and the quality of the data. This procedure is implemented in C++ in an efficient and parallelized software with a low memory footprint. We tested the performances of UrQt compared to the best-known trimming programs, on seven RNA and DNA sequencing experiments and demonstrated its optimality in the resulting tradeoff between the number of trimmed nucleotides and the quality objective. CONCLUSIONS: By finding the best segmentation to delimit a segment of good quality nucleotides, UrQt greatly increases the number of reads and of nucleotides that can be retained for a given quality objective. UrQt source files, binary executables for different operating systems and documentation are freely available (under the GPLv3) at the following address: https://lbbe.univ-lyon1.fr/ UrQt-.html . PMID- 25924883 TI - Cross-sectional analysis of serum calcium levels for associations with left ventricular hypertrophy in normocalcemia individuals with type 2 diabetes. AB - BACKGROUND: Left ventricular hypertrophy (LVH) is prevalent in patients with type 2 diabetes mellitus (T2DM). Recent studies show that an increase in albumin adjusted serum calcium level is associated with an elevated risk of T2DM. We speculate that increased serum calcium levels in T2DM patients are related to LVH prevalence. METHODS: In this echocardiographic study, 833 normocalcemia and normophosphatemia patients with T2DM were enrolled. The associations between serum calcium and metabolic parameters, left ventricular mass index (LVMI), as well as the rate of LVH were examined using bivariate linear correlation, multivariate linear regression and logistic regression, respectively. The predictive performance of serum calcium for LVH was evaluated using the area under the receiver operating characteristic curve (AUC). RESULTS: Patients with LVH have significantly higher serum calcium than those without LVH. Serum calcium was positively associated with total cholesterol, triglycerides, low-density lipoprotein cholesterol, serum uric acid, HOMA-IR and fasting plasma glucose. Multivariate linear regression analysis demonstrated that serum calcium was independently associated with LVMI (p < 0.001). In comparison with patients in the lowest serum calcium quartile, the odds ratio (OR) for LVH in patients in the highest quartile was 2.909 (95% CI 1.792-4.720; p < 0.001). When serum calcium was analyzed as a continuous variable, per 1 mg/dl increase, the OR (95% CI) for LVH was [2.400 (1.552-3.713); p < 0.001]. Serum calcium can predict LVH (AUC = 0.617; 95% CI (0.577-0.656); p < 0.001). CONCLUSIONS: Albumin-adjusted serum calcium is associated with an increased risk of LVH in patients with T2DM. PMID- 25924885 TI - Single-step bioassays in serum and whole blood with a smartphone, quantum dots and paper-in-PDMS chips. AB - The development of nanoparticle-based bioassays is an active and promising area of research, where point-of-care (POC) diagnostics are one of many prospective applications. Unfortunately, the majority of nanoparticle-based assays that have been developed to date have failed to address two important considerations for POC applications: use of instrumentation amenable to POC settings, and measurement of analytes in biological sample matrices such as serum and whole blood. To address these considerations, we present design criteria and demonstrate proof-of-concept for a semiconductor quantum dot (QD)-based assay format that utilizes smartphone readout for the single-step, Forster resonance energy transfer (FRET)-based detection of hydrolase activity in serum and whole blood, using thrombin as a model analyte. Important design criteria for assay development included (i) the size and emission wavelength of the QDs, which had to balance brightness for smartphone imaging, optical transmission through blood samples, and FRET efficiency for signaling; (ii) the wavelength of a light emitting diode (LED) excitation source, which had to balance transmission through blood and the efficiency of excitation of QDs; and (iii) the use of an array of paper-in-polydimethylsiloxane (PDMS)-on-glass sample chips to reproducibly limit the optical path length through blood to ca. 250 MUm and permit multiplexing. Ultimately, CdSe/CdS/ZnS QDs with peak emission at 630 nm were conjugated with Alexa Fluor 647-labeled peptide substrates for thrombin and immobilized on paper test strips inside the sample cells. This FRET system was sensitive to thrombin activity, where the recovery of QD emission with hydrolytic loss of FRET permitted kinetic assays in buffer, serum and whole blood. Quantitative results were obtained in less than 30 min with a limit of detection 18 NIH units mL(-1) of activity in 12 MUL of whole blood. Proof-of-concept for a competitive binding assay was also demonstrated with the same platform. Overall, this work demonstrates that the integration of QDs with smartphones and other consumer electronics can potentiate bioassays that are highly amenable to future point-of care diagnostic applications. PMID- 25924886 TI - Separating chemical and excluded volume interactions of polyethylene glycols with native proteins: Comparison with PEG effects on DNA helix formation. AB - Small and large PEGs greatly increase chemical potentials of globular proteins (MU2), thereby favoring precipitation, crystallization, and protein-protein interactions that reduce water-accessible protein surface and/or protein-PEG excluded volume. To determine individual contributions of PEG-protein chemical and excluded volume interactions to MU2 as functions of PEG molality m3 , we analyze published chemical potential increments MU23 = dMU2/dm3 quantifying unfavorable interactions of PEG (PEG200-PEG6000) with BSA and lysozyme. For both proteins, MU23 increases approximately linearly with the number of PEG residues (N3). A 1 molal increase in concentration of PEG -CH2 OCH2 - groups, for any chain-length PEG, increases MUBSA by ~2.7 kcal/mol and MUlysozyme by ~1.0 kcal/mol. These values are similar to predicted chemical interactions of PEG -CH2 OCH2 - groups with these protein components (BSA ~3.3 kcal/mol, lysozyme ~0.7 kcal/mol), dominated by unfavorable interactions with amide and carboxylate oxygens and counterions. While these chemical effects should be dominant for small PEGs, larger PEGS are expected to exhibit unfavorable excluded volume interactions and reduced chemical interactions because of shielding of PEG residues in PEG flexible coils. We deduce that these excluded volume and chemical shielding contributions largely compensate, explaining why the dependence of MU23 on N3 is similar for both small and large PEGs. PMID- 25924887 TI - Development and Fit-for-Purpose Validation of a Soluble Human Programmed Death-1 Protein Assay. AB - Programmed death-1 (PD-1) protein is a co-inhibitory receptor which negatively regulates immune cell activation and permits tumors to evade normal immune defense. Anti-PD-1 antibodies have been shown to restore immune cell activation and effector function-an exciting breakthrough in cancer immunotherapy. Recent reports have documented a soluble form of PD-1 (sPD-1) in the circulation of normal and disease state individuals. A clinical assay to quantify sPD-1 would contribute to the understanding of sPD-1-function and facilitate the development of anti-PD-1 drugs. Here, we report the development and validation of a sPD-1 protein assay. The assay validation followed the framework for full validation of a biotherapeutic pharmacokinetic assay. A purified recombinant human PD-1 protein was characterized extensively and was identified as the assay reference material which mimics the endogenous analyte in structure and function. The lower limit of quantitation (LLOQ) was determined to be 100 pg/mL, with a dynamic range spanning three logs to 10,000 pg/mL. The intra- and inter-assay imprecision were <=15%, and the assay bias (percent deviation) was <=10%. Potential matrix effects were investigated in sera from both normal healthy volunteers and selected cancer patients. Bulk-prepared frozen standards and pre-coated Streptavidin plates were used in the assay to ensure consistency in assay performance over time. This assay appears to specifically measure total sPD-1 protein since the human anti-PD 1 antibody, nivolumab, and the endogenous ligands of PD-1 protein, PDL-1 and PDL 2, do not interfere with the assay. PMID- 25924889 TI - [Surgery for intracerebral hemorrhage? Pro]. PMID- 25924888 TI - Effect of Type 2 Diabetes Mellitus and Diabetic Nephropathy on IgG Pharmacokinetics and Subcutaneous Bioavailability in the Rat. AB - The objective of this research was to assess the effects of type 2 diabetes mellitus (T2DM) and diabetic nephropathy (DN) on the pharmacokinetics of human IgG (hIgG), an antibody isotype, in Zucker diabetic fatty (ZDF) rats. Furthermore, the specific role of T2DM in the altered disposition of hIgG was evaluated by treating diabetic rats with pioglitazone, while the role of chronic kidney disease (CKD) was assessed using 5/6 nephrectomized Sprague Dawley rats. ZDF male (lean non-diabetic control and obese diabetic) and pioglitazone-treated ZDF rats were studied at ages 12-13 weeks (only DM was present), and at ages 29 30 weeks (progression to DN). All animals were dosed with 1 mg/kg of hIgG intravenously (IV) or subcutaneously (SC). ZDF rats had significantly higher blood glucose concentrations and urinary albumin excretion compared to control rats. Significant increases in total clearance (2.5-fold) and renal clearance (100-fold) of hIgG were observed; however the major increase in total clearance was due to increased non-renal clearance. Greater changes in urinary albumin excretion and total and renal clearances of IgG (3.5-fold and 300-fold, respectively) were observed with progression to DN. SC bioavailability of hIgG in all animal groups was similar (>84%). With pioglitazone-treatment, diabetic animals remained euglycemic and treatment was able to reverse the clearance changes, although incompletely. In the CKD group, no difference in hIgG clearance was observed when compared with controls. In conclusion, the increased clearance of hIgG in ZDF diabetic animals, reversal by pioglitazone treatment and lack of effect of CKD, demonstrate the influence of T2DM on hIgG pharmacokinetics. PMID- 25924891 TI - A Bayesian mixture of semiparametric mixed-effects joint models for skewed longitudinal and time-to-event data. AB - In longitudinal studies, it is of interest to investigate how repeatedly measured markers in time are associated with a time to an event of interest, and in the mean time, the repeated measurements are often observed with the features of a heterogeneous population, non-normality, and covariate measured with error because of longitudinal nature. Statistical analysis may complicate dramatically when one analyzes longitudinal-survival data with these features together. Recently, a mixture of skewed distributions has received increasing attention in the treatment of heterogeneous data involving asymmetric behaviors across subclasses, but there are relatively few studies accommodating heterogeneity, non normality, and measurement error in covariate simultaneously arose in longitudinal-survival data setting. Under the umbrella of Bayesian inference, this article explores a finite mixture of semiparametric mixed-effects joint models with skewed distributions for longitudinal measures with an attempt to mediate homogeneous characteristics, adjust departures from normality, and tailor accuracy from measurement error in covariate as well as overcome shortages of confidence in specifying a time-to-event model. The Bayesian mixture of joint modeling offers an appropriate avenue to estimate not only all parameters of mixture joint models but also probabilities of class membership. Simulation studies are conducted to assess the performance of the proposed method, and a real example is analyzed to demonstrate the methodology. The results are reported by comparing potential models with various scenarios. PMID- 25924890 TI - Orbital dermatofibrosarcoma protuberans with intracranial extension preceded by recurrent leiomyoma of the orbit: a case report. AB - INTRODUCTION: Dermatofibrosarcoma protuberans is a rare, locally aggressive cutaneous tumor of intermediate to low-grade malignancy. COL1A1-PDGFbeta translocation is specific to dermatofibrosarcoma protuberans, where the abnormally fused COL1A1-PDGFbeta gene directs formation of an abnormal combined (fusion) protein that researchers believe to ultimately function like the platelet-derived growth factor-beta protein. CASE PRESENTATION: In this report, we present a case of a 63-year-old Asian man with dermatofibrosarcoma protuberans of the right orbit with intracranial extension. He had a prior history of recurrent leiomyomas at the identical site. He underwent near-total en bloc resection of the tumor through a wide craniectomy with a 6 cm rim of the frontal scalp, allowing the tumor to be resected en bloc, leaving negative margins. Microscopically, the tumor comprised spindle cells with mild nuclear atypia and a low mitotic index embedded in a spiraling pattern of decussating fascicles consistent with dermatofibrosarcoma protuberans. The lesion was positive for CD34 and BCL2. Following resection, the patient was started on imatinib mesylate therapy (800 mg/day). CONCLUSIONS: We propose that platelet-derived growth factor, which has been implicated in the progression of leiomyomas by augmenting mitogenesis, may have acted in an autocrine manner to cause cell division, which may have led to the development of dermatofibrosarcoma protuberans in our patient. Further research is imperative to find certain molecular associations between the discussed soft tissue tumors. Also important is the effective utilization of platelet-derived growth factor receptor kinase inhibitors to prevent transformation to any platelet-derived growth factor-driven tumor, which in our patient was a dermatofibrosarcoma protuberans. PMID- 25924892 TI - Erratum. PMID- 25924893 TI - What information do parents need when facing end-of-life decisions for their child? A meta-synthesis of parental feedback. AB - BACKGROUND: The information needs of parents facing end-of-life decisions for their child are complex due to the wide-ranging dimensions within which such significant events unfold. While parents acknowledge that healthcare professionals are their main source of information, they also turn to a variety of additional sources of written information in an attempt to source facts, discover solutions, and find hope. Much has been written about the needs of parents faced with end-of-life decisions for their child but little is known about the written information needs such parents have. Research in the adult intensive care context has shown that written resources impact positively on the understanding of medical facts, including diagnoses and prognoses, communication between families and healthcare professionals, and the emotional wellbeing of families after their relative's death. METHODS: A meta-synthesis of predominantly empirical research pertaining to features which assist or impede parental end-of life decisions was undertaken to provide insight and guidance in our development of written resources (short print and online comprehensive version) for parents. RESULTS: The most prominently cited needs in the literature related to numerous aspects of information provision; the quantity, quality, delivery, and timing of information and its provision impacted not only on parents' ability to make end of-life decisions but also on their emotional wellbeing. The meta-synthesis supports the value of written materials, as these provide guidance for both parents and healthcare professionals in pertinent content areas. CONCLUSIONS: Further research is required to determine the impact that written resources have on parental end-of-life decision-making and on parents' wellbeing during and after their experience and time in the hospital environment. PMID- 25924894 TI - Epinephrine reversed high-concentration bupivacaine-induced inhibition of calcium channels and transient outward potassium current channels, but not on sodium channel in ventricular myocytes of rats. AB - BACKGROUND: Epinephrine is a first-line drug for cardiopulmonary resuscitation, but its efficacy in the treatment of bupivacaine-induced cardiac toxicity is still in question. We hypothesized that epinephrine can reverse cardiac inhibition of bupivacaine by modulating ion flows through the ventricular myocyte membrane channels of rats. The aim of this study was to observe and report the effects of epinephrine on high-concentration bupivacaine-induced inhibition of sodium (INa), L-type calcium (ICa-L), and transient outward potassium (Ito) currents in the ventricular myocytes of rats. METHODS: The ventricular myocytes were isolated from Sprague-Dawley rats (250-300 g) by acute enzymatic dissociation. The whole-cell patch clamp technique was used to record the ion channel currents in single ventricular myocytes both before and after administration of medications. RESULT: Administration of bupivacaine 100 MUmol/L significantly reduced INa, (P < 0.05). However, administration of bupivacaine 100 MUmol/L in conjunction with epinephrine 0.15 MUg/ml had no effect in restoring INa to its previous state. Similarly, a sharp decline of ICa-L and Ito was observed after administration of bupivacaine 100 MUmol/L (P < 0.05). In contrast to INa, ICa-L and Ito were significantly improved after the administration of the aforementioned combination of bupivacaine and epinephrine (P < 0.05). CONCLUSION: Epinephrine can reverse high-concentration bupivacaine induced inhibition of ICa L and Ito, but not INa. Thus, epinephrine's effectiveness in reversal of bupivacaine-induced cardiac toxicity secondary to sodium channel inhibition may be limited. PMID- 25924897 TI - Time to end the political rhetoric on health tourism. PMID- 25924895 TI - Impaired Th17 polarization of phenotypically naive CD4(+) T-cells during chronic HIV-1 infection and potential restoration with early ART. AB - BACKGROUND: Depletion of mucosal Th17 cells during HIV/SIV infections is a major cause for microbial translocation, chronic immune activation, and disease progression. Mechanisms contributing to Th17 deficit are not fully elucidated. Here we investigated alterations in the Th17 polarization potential of naive-like CD4(+) T-cells, depletion of Th17-commited subsets during HIV pathogenesis, and Th17 restoration in response to antiretroviral therapy (ART). RESULTS: Peripheral blood CD4(+) T-cells expressing a naive-like phenotype (CD45RA(+)CCR7(+)) from chronically HIV-infected subjects receiving ART (CI on ART; median CD4 counts 592 cells/MUl; viral load: <50 HIV-RNA copies/ml; time since infection: 156 months) compared to uninfected controls (HIV-) were impaired in their survival and Th17 polarization potential in vitro. In HIV- controls, IL-17A-producing cells mainly originated from naive-like T-cells with a regulatory phenotype (nTregs: CD25(high)CD127(-)FoxP3(+)) and from CD25(+)CD127(+)FoxP3(-) cells (DP, double positive). Th17-polarized conventional naive CD4(+) T-cells (nT: CD25( )CD127(+)FoxP3(-)) also produced IL17A, but at lower frequency compared to nTregs and DP. In CI on ART subjects, the frequency/counts of nTreg and DP were significantly diminished compared to HIV- controls, and this paucity was further associated with decreased proportions of memory T-cells producing IL-17A and expressing Th17 markers (CCR6(+)CD26(+)CD161(+), mTh17). nTregs and DP compared to nT cells harbored superior levels of integrated/non-integrated HIV-DNA in CI on ART subjects, suggesting that permissiveness to integrative/abortive infection contributes to impaired survival and Th17 polarization of lineage-committed cells. A cross-sectional study in CI on ART subjects revealed that nTregs, DP and mTh17 counts were negatively correlated with the time post-infection ART was initiated and positively correlated with nadir CD4 counts. Finally, a longitudinal analysis in a HIV primary infection cohort demonstrated a tendency for increased nTreg, DP, and mTh17 counts with ART initiation during the first year of infection. CONCLUSIONS: These results support a model in which the paucity of phenotypically naive nTregs and DP cells, caused by integrative/abortive HIV infection and/or other mechanisms, contributes to Th17 deficiency in HIV-infected subjects. Early ART initiation, treatment intensification with integrase inhibitors, and/or other alternative interventions aimed at preserving/restoring the pool of cells prone to acquire Th17 functions may significantly improve mucosal immunity in HIV-infected subjects. PMID- 25924896 TI - Association of C5aR1genetic polymorphisms with coronary artery disease in a Han population in Xinjiang, China. AB - BACKGROUND: Complement 5a receptor (C5aR) was demonstrated a receptor of complement 5a (C5a) which is involved in many inflammatory diseases. The functional responses attributed to C5a results from its interaction with its receptors C5aR, which stimulates food intake, plays a role in increasing the inflammatory response in adipose tissue as well as the cardiovascular and neural systems. However, There are unknown associations between the SNPs of C5aR1 gene and coronary artery disease (CAD). METHODS: We examined the role of the tagging single nucleotide polymorphisms (SNPs) of C5aR1 gene for CAD using a case-control design, and determined the prevalence of C5aR1 genotypes in 505 CAD patients and 469 age and sex-matched healthy control subjects of Han population. RESULTS: The rs10853784 was found to be associated with CAD in dominant model (CC vs TT + CT, P = 0.004). The difference remained statistically significant after multivariate adjustment (OR = 1.430, 95% CI: 1.087 ~ 1.882, P = 0.011). There was no significant difference in genotype distributions of rs4577202 and rs7250152 between CAD patients and control subjects. The frequency of the haplotype (A-T-C) was significantly higher in the CAD patients than in the controls (P = 0.035), and the haplotype (A-C-T) was significantly lower in the CAD patients than in the control subjects in Chinese Han population (P = 0.002). CONCLUSION: The results of this study indicate that rs10853784 of C5aR1 gene are associated with CAD in Han population of China, and A-C-T haplotypes may be protective genetic marker and the A-T-C may be risk genetic marker for CAD in Chinese Han population. VIRTUAL SLIDES: The virtual slide(s) for this article can be found here: http://www.diagnosticpathology.diagnomx.eu/vs/2054871241495194 . PMID- 25924898 TI - Correlation Between Timed Barium Esophagogram and Esophageal Transit Scintigraphy Results in Achalasia. AB - BACKGROUND: Timed barium esophagogram (TBE) and esophageal transit scintigraphy (ETS) have been adopted as useful ways to evaluate achalasia patients. TBE has merit as a simple, non-invasive, and convenient method. AIMS: The study sought to compare the results of these two tests and verify their usefulness in evaluating treatment response. In addition, we assessed whether TBE could effectively replace ETS through correlation analysis. METHODS: The medical records of 50 achalasia patients treated between September 2011 and June 2014 were reviewed retrospectively. The height and width of the barium column at 1, 2, and 5 min were measured by TBE. Half-life (T 1/2, min) and R 30 (percentage of remaining radioactivity 30 s after radioisotope ingestion) were measured by ETS. Both tests were performed before and after treatment, and the tests were carried out 1 and 2 days after procedures. And we analyzed the correlation between the parameters from the two tests. RESULTS: The parameters of TBE and ETS were improved after treatment (p < 0.05). Before treatment, the height and width results at 5 min from TBE positively correlated with the T 1/2 parameter from ETS (correlation coefficients of 0.59 and 0.75, respectively). After treatment, the correlation coefficients between the 5-min height and width of the barium column by TBE and T 1/2 by ETS were 0.55 and 0.46, respectively. CONCLUSIONS: Both TBE and ETS are useful modalities in assessing esophageal emptying and response to achalasia treatment. TBE and ETS results have a statistically significant correlation both pre- and post-treatment. We suggest that TBE could effectively replace ETS for the assessment of achalasia. PMID- 25924899 TI - Rapid Growth Rates of Suspected Pancreatic Cyst Branch Duct Intraductal Papillary Mucinous Neoplasms Predict Malignancy. AB - BACKGROUND: The majority of branch duct intraductal papillary mucinous neoplasms (BD-IPMNs) are recommended for surveillance imaging based on consensus guidelines. However, growth rates that should prompt concern for malignant transformation of BD-IPMN are unknown. AIMS: To determine whether BD-IPMN growth can predict an increased risk of malignancy and define growth rates concerning for malignant BD-IPMN. METHODS: The study is a retrospective, multicenter study of suspected BD-IPMN patients undergoing imaging surveillance. All patients underwent EUS evaluation followed by surveillance imaging. RESULTS: Two hundred and eighty-four patients with suspected BD-IPMN without worrisome features or high-risk stigmata were followed for a median 56 months and underwent a median of four imaging studies. Nine patients (3.2 %) developed malignant BD-IPMN. Malignant BD-IPMN grew at a faster rate (18.6 vs. 0.8 mm/year; P = 0.05) compared to benign BD-IPMN. BD-IPMN growth rate between 2 and 5 mm/year was associated with an increased risk of malignancy with hazard ratio (HR) of 11.4 (95 % CI 2.2 58.6) when compared to subjects with BD-IPMN growth rate <2 mm/year (P = 0.004). BD-IPMN growth rate >=5 mm/year had a hazard ratio of 19.5 (95 % CI 2.4-157.8) (P = 0.005). BD-IPMN growth rate of 2 mm/year had a sensitivity of 78 %, specificity of 90 %, and accuracy of 88 % to identify malignancy. Total BD-IPMN growth was also associated with increased risk of malignancy (P = 0.003) with all malignant IPMNs growing at least 10 mm prior to cancer diagnosis. CONCLUSIONS: BD-IPMN growth rates >=2 mm/year and total growth of >=10 mm should be considered worrisome features for BD-IPMN at increased risk of malignancy. PMID- 25924900 TI - DNA Polymerases as targets for gene therapy of hepatocellular carcinoma. AB - BACKGROUND: Hepatocyte carcinoma (HCC) is one of the most common malignancies worldwide. Despite many achievements in diagnosis and treatment, HCC mortality remains high due to the malignant nature of the disease. Novel approaches, especially for targeted therapy, are being extensively explored. Gene therapy is ideal for such purpose for its specific expression of exogenous genes in HCC cells driven by tissue-specific promoter. However strategies based on correction of mutations or altered expressions of genes responsible for the development/progression of HCC have limitations because these aberrant molecules are not presented in all cancerous cells. In the current work, we adopted a novel strategy by targeting the DNA replication step which is essential for proliferation of every cancer cell. METHODS: A recombinant adenovirus with alpha fetoprotein (AFP) promoter-controlled expressions of artificial microRNAs targeting DNA polymerases alpha, delta, epsilon and recombinant active Caspase 3, namely Ad/AFP-Casp-AFP-amiR, was constructed. RESULTS: The artificial microRNAs could efficiently inhibit the expression of the target polymerases in AFP positive HCC cells at both RNA and protein levels, and HCC cells treated with the recombinant virus Ad/AFP-Casp-AFP-amiR exhibited significant G0/1 phase arrest. The proliferation of HCC cells were significantly inhibited by Ad/AFP-Casp-AFP amiR with increased apoptosis. On the contrary, the recombinant adenovirus Ad/AFP Casp-AFP-amiR did not inhibit the expression of DNA polymerases alpha, delta or epsilon in AFP-negative human normal liver cell HL7702, and showed no effect on the cell cycle progression, proliferation or apoptosis. CONCLUSIONS: Inhibition of DNA polymerases alpha, delta and epsilon by AFP promoter-driven artificial microRNAs may lead to effective growth arrest of AFP-positive HCC cells, which may represent a novel strategy for gene therapy by targeting the genes that are essential for the growth/proliferation of cancer cells, avoiding the limitations set by any of the individually altered gene. PMID- 25924902 TI - [Biologic therapies in autoimmune diseases]. PMID- 25924901 TI - The homeoprotein DLX4 controls inducible nitric oxide synthase-mediated angiogenesis in ovarian cancer. AB - BACKGROUND: Homeobox genes encode transcription factors that control patterning of virtually all organ systems including the vasculature. Tumor angiogenesis is stimulated by several homeobox genes that are overexpressed in tumor cells, but the mechanisms of these genes are poorly understood. In this study, we investigated the mechanisms by which DLX4, a homeobox gene that is associated with increased tumor microvessel density, stimulates ovarian tumor angiogenesis. METHODS: Expression of DLX4 and nitric oxide synthases was analyzed in publicly available transcriptional profiles of ovarian cancer clinical specimens. Levels of inducible nitric oxide synthase (iNOS) were evaluated by quantitative RT-PCR, flow cytometry and nitric oxide assays using ovarian cancer cell lines in which DLX4 was overexpressed or knocked down. Signal Transducer and Activator of Transcription 1 (STAT1) expression and activity were evaluated by luciferase reporter assays, immunofluorescence staining, Western blot and immunoprecipitation. Endothelial cell growth and tumor angiogenesis were evaluated in in vitro assays and xenograft models. RESULTS: We identified that DLX4 induces expression of iNOS, an enzyme that stimulates angiogenesis by generating nitric oxide. Analysis of datasets of two independent patient cohorts revealed that high DLX4 expression in ovarian cancer is strongly associated with elevated expression of iNOS but not of other nitric oxide synthases. Studies using STAT1-expressing and STAT1-deficient cells revealed that DLX4 interacts with STAT1 and induces iNOS expression in part by stimulating STAT1 activity. Expression of DLX4 in ovarian cancer cells stimulated endothelial cell growth in vitro and increased microvessel density in xenograft models, and these stimulatory effects of DLX4 were abrogated when its induction of iNOS was inhibited. CONCLUSION: These findings indicate that DLX4 promotes ovarian tumor angiogenesis in part by stimulating iNOS expression. PMID- 25924903 TI - [Asthma and comorbidity]. PMID- 25924904 TI - [T-cell senescence and autoimmune diseases]. PMID- 25924905 TI - [PM2.5 and allergic diseases]. PMID- 25924906 TI - [Short-term effects of air pollutants on pulmonary function in adolescent with a history of asthma or allergies]. AB - BACKGROUND: Transboundary pollution including airborne fine particulate matter (PM(2.5)) has been attracting attention in recent years and its health effects are concerned. We evaluated the short-term effects of air pollutants on pulmonary function among young students. METHODS: Forced expiratory volume in 1 second (FEV1) and peak expiratory flow (PEF) were examined every morning for 1 month in 37 students who attend a school in a remote island of the Seto Inland Sea. The concentrations of fine and coarse particles (PM(2.5) and PM(10-2.5)), optical black carbon (OBC) and nitrogen dioxide (NO2) were measured on the rooftop of the school. RESULTS: The change in PEF was significantly associated with an increase in the prior 24-h average concentration of PM(2.5) among subjects with a history of asthma (-42.5 L/min [95% confidence interval (CI): -77.0, -8.1], for an interquartile rage increase of 17.6 MUg/m3). Negative associations between pulmonary function and the concentrations of NO2and OBC were observed as well. On the other hand, among the subjects with a history of allergy other than asthma and those without such history, negative association between air pollutants and pulmonary function was not observed. CONCLUSIONS: Subjects with a history of asthma are considered to be more affected by short-term exposure to air pollutants. PMID- 25924907 TI - [Utility of the allerport(r) HRT in the diagnosis of hen's egg allergy: a pediatric multicenter challenge study]. AB - Purpose This study aimed to evaluate the utility of the Allerport(r) HRT in the diagnosis of hen's egg allergy. Method We enrolled 51 subjects who underwent the Allerport(r) HRT before an oral food challenge (OFC) consisting of heated egg. Blood samples were collected within three months prior to OFC to measure histamine release (HR) and specific IgE antibody titers. We examined whether the Allerport(r) HRT was useful as a means of diagnosing hen's egg allergy and predicting severity of induced symptoms. Of 51 subjects, three whose OFC results were not valid**1** and 13 who were classified as "low responders" to the Allerport(r) HRT (%HR due to anti-IgE below 20%) were excluded. Of the remaining 35 subjects (average age: 4 years), 23 showed positive reactions to the OFC. Quantities of histamine released in spontaneous HR and egg white (EW)- and ovomucoid (OVM)-induced HR were significantly higher in patients with positive reactions. In our receiver operating characteristic analysis, the area under the curve for %HR against 6 ng/ml of EW was 0.9601 and that against 3 ng/ml of OVM was 0.9022. The cutoff value was 15.0% for EW and 3.7% for OVM. The sensitivity was 95.7% for EW and 91.3% for OVM, and the specificity was 83.3% for EW and 58.3% for OVM. %HR correlated well with the severity of induced symptoms in the OFC. Conclusion Allerport(r) HRT is useful for the diagnosis of hen's egg allergy, and may also aid in predicting the severity of induced symptoms. PMID- 25924908 TI - [A case of food-dependent exercise-induced anaphylaxis caused by ingestion of orange]. AB - The patient was a 10-year-old girl who presented with a history of anaphylactic episodes on three occasions, that developed in association with exercise after she ate citrus fruit. She underwent tolerance tests, as food-dependent exercise induced anaphylaxis (FDEIA) induced by citrus fruit was suspected. The result of the test for the combination of intake of oranges and exercise was negative. The patient presented with swollen eyelid and wheezing following combined intake of orange and aspirin, based on which she was diagnosed as having FDEIA. Many patients developing an allergic reaction to fruit are diagnosed as having oral allergy syndrome (OAS), and only few cases of FDEIA are reported. Immunoblot tests revealed antigens of 9 kDa, 39 kDa and 53 kDa in this patient, and an inhibition study with oranges revealed that the 39 kDa and 53 kDa antigens were probably antigen-specific allergens. Although the studied patient showed a strongly positive result for IgE antibodies specifically directed at cedar pollen, no common antigenicity with cedar pollen could be recognized. The final diagnosis was a type of FDEIA caused by 39 kDa and 53 kDa proteins, which are different from antigens previously identified in patients with citrus fruits allergy. It should be the first report of such a case. PMID- 25924909 TI - Increased total mortality as a function of 24-h pulse pressure dipping. AB - Elevated pulse pressure (PP) as a difference between systolic and diastolic blood pressure is a significant risk factor of cardiovascular (CV) diseases. The goal of our study was to determine the association between PP and major adverse CV events (MACEs), and all-cause and CV mortality in the different age groups of patients with coronary artery disease (CAD) confirmed by angiography. To the PROGNOSIS study, finally there were included 891 subjects with CAD. An analysis of the receiver operating characteristic was used for predicting PP dipping among the age groups of patients. A COX proportional hazards model was used to examine the association between PP and PP dipping and risk of MACE, revascularization, CV and total mortality after adjusting for sex, diabetes, smoking and low-density lipoprotein cholesterol. The median follow-up period was 8.3 years (interquartile range: 5.3-9.0 years). There were 245 (27%) all-cause deaths including 114 (13%) CV deaths during the follow-up period. MACE occurred in 442 (50%) subjects, but coronary artery interventions (percutaneous coronary intervention or coronary artery bypass grafting) were performed in 578 subjects (65%). A Cox proportional regression analysis confirmed the relationship between PP dipping as well as PP dipping thresholds points and risk of MACE and total mortality only in the group of the oldest subjects. In contrast to younger CAD patients, PP dipping is related to MACE, CV and total mortality in very elderly CAD subjects. Nocturnal PP values tend to be higher than diurnal PP values in the oldest CAD individuals. In conclusion, in contrast to younger CAD patients, PP dipping is related to MACE, CV and total mortality in very elderly CAD subjects. Nocturnal PP values tend to be higher than diurnal PP values in the oldest CAD individuals. PMID- 25924910 TI - Effects of heart rate variability biofeedback on cardiovascular responses and autonomic sympathovagal modulation following stressor tasks in prehypertensives. AB - Autonomic dysfunction is implicated in prehypertension, and previous studies have suggested that therapies that improve modulation of sympathovagal balance, such as biofeedback and slow abdominal breathing, are effective in patients with prehypertension at rest. However, considering that psychophysiological stressors may be associated with greater cardiovascular risk in prehypertensives, it is important to investigate whether heart rate variability biofeedback (HRV-BF) results in equivalent effects on autonomic cardiovascular responses control during stressful conditions in prehypertensives. A total of 32 college students with prehypertension were enrolled and randomly assigned to HRV-BF (n=12), slow abdominal breathing (SAB, n=10) or no treatment (control, n=10) groups. Then, a training experiment consisting of 15 sessions was employed to compare the effect of each intervention on the following cardiovascular response indicators before and after intervention: heart rate (HR); heart rate variability (HRV) components; blood volume pulse amplitude (BVPamp); galvanic skin response; respiration rate (RSP); and blood pressure. In addition, the cold pressor test and the mental arithmetic challenge test were also performed over two successive days before and after the invention as well as after 3 months of follow-up. A significant decrease in HR and RSP and a significant increase in BVPamp were observed after the HRV-BF intervention (P<0.001). For the HRV analysis, HRV-BF significantly reduced the ratio of low-frequency power to high-frequency power (the LF/HF ratio, P<0.001) and increased the normalized high-frequency power (HFnm) (P<0.001) during the stress tests, and an added benefit over SAB by improving HRV was also observed. In the 3-month follow-up study, similar effects on RSP, BVPamp, LF/HF and HFnm were observed in the HRV-BF group compared with the SAB group. HRV-BF training contributes to the beneficial effect of reducing the stress-related cardiovascular response in prehypertensives by improving autonomic sympathovagal modulation. PMID- 25924911 TI - Changing dietary patterns and associated risk factors on trends in blood pressure levels in middle-aged Irish adults: a population-based study. PMID- 25924913 TI - Multimodality imaging of a primary cardiac diffuse large B-cell lymphoma. PMID- 25924912 TI - Differential diagnosis of depression and Alzheimer's disease with the Addenbrooke's Cognitive Examination-Revised (ACE-R). AB - BACKGROUND: One of the usual problems psychologists and clinicians face in clinical practice is differential diagnostics of Alzheimer's disease and depression. It has been reported that the ACE and ACE-R could discriminate the cognitive dysfunctions due to depression from that due to dementia, although this is not uniform in all studies. The current study aimed to evaluate the utility of the ACE-R to differentiate late-life onset depression (with severe episode) from mild-moderate Alzheimer's Disease (AD). METHODS: This study received approval from the Lithuanian Bioethics Committee. All participants were older than 50 years (mean age = 66.52 (+/-8.76) years). The study sample consisted of 295 individuals: 117 with severe depression, 85 with mild-moderate Alzheimer's disease (AD), and 94 age, gender and education matched participants of control group. RESULTS: The ACE-R had high sensitivity (100%) and specificity (81%) at detecting cognitive impairments related to AD. Patients with late-life onset depression (ACE-R mean 76.82, SD = 7.36) performed worse than controls (ACE-R mean 85.08, SD = 7.2), but better than the AD group (ACE-R mean 54.74, SD = 12.19). Participants with late-life onset depression were differentiated by mild impairment in the ACE-R total score with mild memory (13.79, SD = 6.29) and greater deficits in letter fluency (3.65, SD = 1.21) than in semantic fluency (4.68, SD = 1.23). Participants with AD were differentiated by severely impaired performance on attention and orientation (11.80, SD = 2.93), memory (8.25, SD = 3.47) and language subtests (17.21, SD = 4.04), and moderately impaired performance on verbal fluency (6.07, SD = 2.74). CONCLUSIONS: ACE-R has diagnostic accuracy in detecting people with AD and can be used in differential diagnostics of late-life onset depression (severe episode) and AD. Diagnostic accuracy may be improved by analyzing the neuropsychological profiles and using lower cutoffs for different age groups. PMID- 25924914 TI - Comparative methylome analysis in solid tumors reveals aberrant methylation at chromosome 6p in nasopharyngeal carcinoma. AB - Altered patterns of DNA methylation are key features of cancer. Nasopharyngeal carcinoma (NPC) has the highest incidence in Southern China. Aberrant methylation at the promoter region of tumor suppressors is frequently reported in NPC; however, genome-wide methylation changes have not been comprehensively investigated. Therefore, we systematically analyzed methylome data in 25 primary NPC tumors and nontumor counterparts using a high-throughput approach with the Illumina HumanMethylation450 BeadChip. Comparatively, we examined the methylome data of 11 types of solid tumors collected by The Cancer Genome Atlas (TCGA). In NPC, the hypermethylation pattern was more dominant than hypomethylation and the majority of de novo methylated loci were within or close to CpG islands in tumors. The comparative methylome analysis reveals hypermethylation at chromosome 6p21.3 frequently occurred in NPC (false discovery rate; FDR=1.33 * 10(-9) ), but was less obvious in other types of solid tumors except for prostate and Epstein Barr virus (EBV)-positive gastric cancer (FDR<10(-3) ). Bisulfite pyrosequencing results further confirmed the aberrant methylation at 6p in an additional patient cohort. Evident enrichment of the repressive mark H3K27me3 and active mark H3K4me3 derived from human embryonic stem cells were found at these regions, indicating both DNA methylation and histone modification function together, leading to epigenetic deregulation in NPC. Our study highlights the importance of epigenetic deregulation in NPC. Polycomb Complex 2 (PRC2), responsible for H3K27 trimethylation, is a promising therapeutic target. A key genomic region on 6p with aberrant methylation was identified. This region contains several important genes having potential use as biomarkers for NPC detection. PMID- 25924915 TI - Corticotropin releasing factor receptor expression in painful human dental pulp. AB - BACKGROUND: Our objective was to correlate the presence of symptoms and dental pulp injury with the amount of a subtype of corticotropin releasing factor receptor (CRF-R) in symptomatic and asymptomatic human teeth. We hypothesized that patients diagnosed with irreversible pulpitis have increased levels of CRF R. MATERIALS AND METHODS: Dental history, diagnosis and radiographs were obtained from treatment records following extractions. Teeth were diagnosed as asymptomatic or symptomatic demonstrated by clinical and radiographic evaluation. Tissue sections from tooth pulp were immunoreacted with antibodies directed against CRF receptor 2 (CRF-R2) and neurofilament protein and examined to correlate CRF-R expression with pulpal diagnosis. RESULTS: Our results indicated that symptomatic pulps demonstrated significantly greater expression of CRF-R2. The increased expression was localized on distinct cellular profiles throughout the pulp and was not directly correlated with neurofilament expression. CONCLUSIONS: Our findings suggest that the analgesic effects of endogenously produced CRF may be enhanced via upregulation of CRF-R2 expression, and may explain the occurrence of reduced pain symptoms in some patients with irreversible pulpitis. The application of CRF-R agonists may be a feasible strategy in reducing pain associated with irreversible pulpitis. PMID- 25924917 TI - Oligonucleotide aptamers for glioma targeting: an update. AB - Malignant glioma is the most prevalent and lethal primary brain tumor. Due to molecular heterogeneity and organ-specific clinical manifestations, it is essential to improve glioma treatment by shifting from conventional cytotoxic chemotherapy to more targeted therapies. Hence, innovative approaches based on ligands able to specifically detect and measure mutated proteins associated to a specific tumor phenotype are needed in order to refine diagnosis and therapy of glioma. To date, antibody- based approaches have been developed for in vivo applications but, in most cases, they show toxicity, do not reach adequate sensitivity and have a low permeability across the blood-brain-barrier. Single stranded nucleic acid aptamers, generated by the SELEX (Systematic Evolution of Ligands by EXponential enrichment) process, have been shown as a valuable alternative to protein antibodies because may couple the advantages of their chemical nature to the high specific binding of antibodies to their proper targets. The simplicity of aptamers selection and derivatization with other molecules (nanocarriers, tracers for imaging, drugs) combined to low immunogenicity and toxicity, render them a versatile tool for identification of new biomarkers, in vitro diagnosis, in vivo imaging and targeted therapy. Aim of this review article is to discuss contemporary applications of aptamers as innovative tools for glioma diagnosis and therapy. We will describe promising new approaches for the identification of aptamers targeting proteins with a crucial role in glioma, including SELEX protocols against living glioma cells and brain tumor-initiating cells. Additionally, we will review recently proposed aptamer based strategies for site-targeted controlled delivery of therapeutics and imaging agents to the brain. Summarizing, we hope that this article will provide an updated overview of perspectives and challenges for aptamer-based glioma treatment in the near future. PMID- 25924916 TI - Mutations upstream of fabI in triclosan resistant Staphylococcus aureus strains are associated with elevated fabI gene expression. AB - BACKGROUND: The enoyl-acyl carrier protein (ACP) reductase enzyme (FabI) is the target for a series of antimicrobial agents including novel compounds in clinical trial and the biocide triclosan. Mutations in fabI and heterodiploidy for fabI have been shown to confer resistance in S. aureus strains in a previous study. Here we further determined the fabI upstream sequence of a selection of these strains and the gene expression levels in strains with promoter region mutations. RESULTS: Mutations in the fabI promoter were found in 18% of triclosan resistant clinical isolates, regardless the previously identified molecular mechanism conferring resistance. Although not significant, a higher rate of promoter mutations were found in strains without previously described mechanisms of resistance. Some of the mutations identified in the clinical isolates were also detected in a series of laboratory mutants. Microarray analysis of selected laboratory mutants with fabI promoter region mutations, grown in the absence of triclosan, revealed increased fabI expression in three out of four tested strains. In two of these strains, only few genes other than fabI were upregulated. Consistently with these data, whole genome sequencing of in vitro selected mutants identified only few mutations except the upstream and coding regions of fabI, with the promoter mutation as the most probable cause of fabI overexpression. Importantly the gene expression profiling of clinical isolates containing similar mutations in the fabI promoter also showed, when compared to unrelated non-mutated isolates, a significant up-regulation of fabI. CONCLUSIONS: In conclusion, we have demonstrated the presence of C34T, T109G, and A101C mutations in the fabI promoter region of strains with fabI up-regulation, both in clinical isolates and/or laboratory mutants. These data provide further observations linking mutations upstream fabI with up-regulated expression of the fabI gene. PMID- 25924918 TI - Autologous Olfactory Lamina Propria Transplantation for Chronic Spinal Cord Injury: Three-Year Follow-Up Outcomes From a Prospective Double-Blinded Clinical Trial. AB - We did a clinical trial to determine whether olfactory mucosa lamina propria (OLP) transplants promote regeneration and functional recovery in chronic human spinal cord injury (SCI). The trial randomized 12 subjects to OLP transplants (n = 8) or control sham surgery (n = 4). The subjects received magnetic resonance imaging (MRI), electromyography (EMG), urodynamic study (UDS), American Spinal Injury Association impairment scale (AIS), and other functional assessments. OLP transplanted subjects recovered more motor, sensory, and bladder function compared to sham-operated subjects. At 3 years after OLP transplant, one patient improved from AIS A to C and another recovered from AIS A to B, two recovered more than three segmental sensory levels, two had less spasticity, two had altered H-reflexes and SSEP, two regained bladder and anorectal sensation and had improved bladder compliance on UDS. OLP-treated patients had partial or complete tissue bridges at the injury site compared to cavitary gaps in sham-operated patients. The limited recovery suggests that OLP transplants alone do not have significant benefits but may provide a rationale for larger randomized trials or combination therapies. PMID- 25924919 TI - Utilization of a genetically modified muscle flap for local BMP-2 production and its effects on bone healing: a histomorphometric and radiological study in a rat model. AB - AIM OF THE STUDY: We developed an experimental rat model to explore the possibility of enhancing the healing of critical-size bone defects. The aim of this study was to demonstrate the feasibility of this concept by achieving high local BMP-2 expression via a transduced muscle flap that would facilitate bony union while minimizing systemic sequelae. METHODS: The transduction potential of the adenoviral vector encoding for BMP-2 was tested in different cell lines in vitro. In vivo experiments consisted of harvesting a pedicled quadriceps femoris muscle flap with subsequent creation of a critical-size defect in the left femur in Sprague-Dawley rats. Next, the pedicled muscle flap was perfused with high titers of Ad.BMP-2 and Ad.GFP virus, respectively. Twelve animals were divided into three groups comparing the effects of Ad.BMP-2 transduction to Ad.GFP and placebo. Bone healing was monitored radiologically with subsequent histological analysis post-mortem. RESULTS: The feasibility of this concept was demonstrated by successful transduction in vitro and in vivo as evidenced by a marked increase of BMP-2 expression. The three examined groups only showed minor difference regarding bone regeneration; however, one complete bridging of the defect was observed in the Ad.BMP-2 group. No evidence of systemic viral contamination was noted. CONCLUSIONS: A marked increase of local BMP-2 expression (without untoward systemic sequelae) was detected. However, bone healing was not found to be significantly enhanced, possibly due to the small sample size of the study. PMID- 25924920 TI - Angioimmunoblastic T-cell lymphomas presenting as autoimmune hemolytic anemias: clinical manifestations and circulating cytokine features. PMID- 25924921 TI - The extent of local tumor invasion predicts prognosis in stage IE nasal natural killer/T-cell lymphoma: a novel T staging system for risk stratification. AB - A heterogeneous treatment response and prognosis exists among patients with Ann Arbor stage IE natural killer/T-cell lymphoma (NKTCL), and further risk stratification is required to identify high-risk patients. Here, we assessed the extent of local tumor invasion (LTI) in 185 patients with Ann Arbor stage IE primary nasal NKTCL and proposed a novel four-level T staging system. We found that a more advanced T stage was associated with a significantly lower rate of complete remission (CR) after chemotherapy and a marginally lower rate of CR after radiotherapy. While patients with no LTI (T1) or mild LTI (T2) presented with similar 5-year overall survival (OS; 83.6 % vs. 86.0 %, P = 0.990), those with moderately or highly advanced local disease (T3 or T4) had significantly worse survival (5-year OS was 63.3 % and 35.1 %, respectively). A more advanced T stage (T3 or T4) was an independent prognostic factor for both OS and progression free survival (PFS) in the Cox regression model. In addition, patients with T3 or T4 disease experienced locoregional failure more frequently than those with T1 or T2 disease, and patients with T4 disease had a significantly higher risk of distant failure. Our data demonstrated that the T staging system, based on the extent of LTI, could serve as an effective clinical parameter for further risk stratification among patients with primary nasal Ann Arbor stage IE NKTCL. PMID- 25924922 TI - Endostatin, Cathepsin S, and Cathepsin L, and Their Association with Inflammatory Markers and Mortality in Patients Undergoing Hemodialysis. AB - BACKGROUND/AIMS: Although both endostatin and cathepsins S have been associated with higher mortality, data in patients with end-stage renal disease (ESRD) are scarce. METHODS: A longitudinal cohort study of 207 prevalent patients undergoing hemodialysis. RESULTS: Cathepsins S and L were associated with soluble receptors for tumor necrosis factor (sTNFR1 and sTNFR2, rho between 0.28 and 0.43, p < 0.001 for all). Weaker or absent associations between endostatin, cathepsins S and L were seen with other inflammatory biomarkers, that is, CRP, interleukin 6, pentraxin 3, and TNF. In Cox and Laplace regression models adjusted for age, sex, dialysis vintage, and diabetes: standard deviation increments of endostatin was associated with a lower mortality (hazard ratio 0.75, 95% confidence interval (CI) 0.57-0.98), and with 6.8 months longer median survival. CONCLUSIONS: The high levels of endostatin, cathepsins S and L, and their associations with sTNFR1 and sTNFR2 warrant further studies exploring mortality, and the angiogenic and inflammatory pathways in ESRD. PMID- 25924923 TI - Tumor and Patient Characteristics of Individuals with Mismatch Repair Deficient Colorectal Cancer. AB - AIMS: To investigate tumor and patient characteristics of individuals with mismatch repair (MMR)-deficient colorectal carcinomas. METHODS: We immunhistochemically investigated tissue samples of 307 consecutive patients with colorectal cancer for defects in DNA MMR proteins (hMLH1, hMSH2, hMSH6, hPMS2) and those with mutations further for microsatellite instability (MSI) and BRAF V600E mutations. RESULTS: 32/308 (10.4%) tumors showed MMR deficiency. Seventy five percent (n = 24) had loss of hMLH1 and hPMS2 expression, 3% (n = 1) of hPMS2 alone, 18.8% (n = 6) of hMSH6 and hMSH2, 3% (n = 1) of hMSH2 alone. All MMR deficient tumors showed high MSI. These tumors occurred preferably in the right sided colon, in women and showed specific histological features. We obtained the family history of 18/32 patients; 2 (11.1%) met Amsterdam Criteria, 5 (27.8%) Bethesda Guidelines and 6 (33.3%) revised Bethesda Guidelines. BRAF V600E mutations were found in 16 (67%) of hMLH1 and none of the hMSH2 deficient tumors. CONCLUSION: We suggest using immunhistochemical testing of tumor tissues with subsequent MSI analysis, which may be justified as a screening method for MMR deficiency in colorectal cancer, since it identifies patients with possibly hereditary defects and unalike response to chemotherapy. PMID- 25924924 TI - Systematic discovery of drug interaction mechanisms. AB - Drug combinations are increasingly important in disease treatments, for combating drug resistance, and for elucidating fundamental relationships in cell physiology. When drugs are combined, their individual effects on cells may be amplified or weakened. Such drug interactions are crucial for treatment efficacy, but their underlying mechanisms remain largely unknown. To uncover the causes of drug interactions, we developed a systematic approach based on precise quantification of the individual and joint effects of antibiotics on growth of genome-wide Escherichia coli gene deletion strains. We found that drug interactions between antibiotics representing the main modes of action are highly robust to genetic perturbation. This robustness is encapsulated in a general principle of bacterial growth, which enables the quantitative prediction of mutant growth rates under drug combinations. Rare violations of this principle exposed recurring cellular functions controlling drug interactions. In particular, we found that polysaccharide and ATP synthesis control multiple drug interactions with previously unexplained mechanisms, and small molecule adjuvants targeting these functions synthetically reshape drug interactions in predictable ways. These results provide a new conceptual framework for the design of multidrug combinations and suggest that there are universal mechanisms at the heart of most drug interactions. PMID- 25924926 TI - Processes for non-destructive transfer of graphene: widening the bottleneck for industrial scale production. AB - The exceptional charge-transport, mechanical, and barrier properties of graphene are well known. High-quality films of single-layer graphene produced over large areas, however, are extremely expensive. The high cost of graphene precludes its use in industries-such as transparent electrodes and flexible packaging-that might take full advantage of its properties. This minireview presents several strategies for the transfer of graphene from the substrates used for growth to substrates used for the final application. Each strategy shares the characteristic of being non-destructive: that is, the growth substrate remains reusable for further synthesis of new graphene. These processes have the potential to lower significantly the costs of manufacturing graphene, to increase production yields, and to minimize environmental impact. This article is divided into sections on (i) the synthesis of high-quality single-layer graphene and (ii) its non-destructive transfer to a host substrate. Section (ii) is further divided according to the substrate from which graphene is transferred: single-crystalline wafers or flexible copper foils. We also comment, wherever possible, on defects produced as a result of the transfer, and potential strategies to mitigate these defects. We conclude that several methods for the green synthesis and transfer of graphene have several of the right characteristics to be useful in industrial scale production. PMID- 25924925 TI - Factors associated with stunting among children according to the level of food insecurity in the household: a cross-sectional study in a rural community of Southeastern Kenya. AB - BACKGROUND: Chronic malnutrition or stunting among children under 5 years old is affected by several household environmental factors, such as food insecurity, disease burden, and poverty. However, not all children experience stunting even in food insecure conditions. To seek a solution at the local level for preventing stunting, a cross-sectional study was conducted in southeastern Kenya, an area with a high level of food insecurity. METHODS: The study was based on a cohort organized to monitor the anthropometric status of children. A structured questionnaire collected information on the following: demographic characteristics, household food security based on the Household Food Insecurity Access Scale (HFIAS), household socioeconomic status (SES), and child health status. The associations between stunting and potential predictors were examined by bivariate and multivariate stepwise logistic regression analyses. Furthermore, analyses stratified by level of food security were conducted to specify factors associated with child stunting in different food insecure groups. RESULTS: Among 404 children, the prevalence of stunting was 23.3%. The percentage of households with severe food insecurity was 62.5%. In multivariative analysis, there was no statistically significant association with child stunting. However, further analyses conducted separately according to level of food security showed the following significant associations: in the severely food insecure households, feeding tea/porridge with milk (adjusted Odds Ratio [aOR]: 3.22; 95% Confidence Interval [95% CI]: 1.43-7.25); age 2 to 3 years compared with 0 to 5 months old (aOR: 4.04; 95% CI: 1.01-16.14); in households without severe food insecurity, animal rearing (aOR: 3.24; 95% CI: 1.04-10.07); SES with lowest status as reference (aOR range: from 0.13 to 0.22). The number of siblings younger than school age was not significantly associated, but was marginally associated in the latter household group (aOR: 2.81; 95% CI: 0.92-8.58). CONCLUSIONS: Our results suggest that measures against childhood stunting should be optimized according to food security level observed in each community. PMID- 25924927 TI - Incentives for non-physician health professionals to work in the rural and remote areas of Mozambique--a discrete choice experiment for eliciting job preferences. AB - BACKGROUND: Successfully motivating and retaining health workers is critical for the effective performance of health systems. In Mozambique, a shortage of health care professionals and low levels of staff motivation in rural and remote areas pose challenges to the provision of equitable health care delivery. This study provides quantitative information on the job preferences of non-physician health professionals in Mozambique, examining how different aspects of jobs are valued and how health professionals might respond to policy options that would post them to district hospitals in rural areas. METHODS: The study used a discrete choice experiment (DCE) to elicit the job preferences of non-physician health professionals. Data collection took place in four Mozambique provinces: Maputo City, Maputo Province, Sofala and Nampula. DCE questionnaires were administered to 334 non-physician health professionals with specialized or university training ('mid-level specialists' and N1 and N2 categories). In addition, questionnaires were administered to 123 N1 and N2 students to enable comparison of the results for those with work experience with those without and determine how new N1 and N2 graduates can be attracted to rural posts. RESULTS: The results indicate that the provision of basic government housing has the greatest impact on the probability of choosing a job at a public health facility, followed by the provision of formal education opportunities and the availability of equipment and medicine at a health facility. The sub-group analysis suggests that job preferences vary according to stage of life and that incentive packages should vary accordingly. Recruitment strategies to encourage non-clinical professionals to work in rural/remote areas should also consider birthplace, as those born in rural/remote areas are more willing to work remotely. CONCLUSION: The study was undertaken within an overarching project that aimed to develop incentive packages for non physician health professionals assigned to work in remote/rural areas. Based on the DCE results, the project team, together with the Mozambique Ministry of Health, has developed a range of health workforce retention strategies focusing on the provision of housing benefits and professional development opportunities to be utilized when assigning non-physician health professionals to rural/remote areas. PMID- 25924928 TI - Validation of the modified Ranson versus Glasgow score for pancreatitis in a Singaporean population. AB - BACKGROUND: The characteristics of patients with acute pancreatitis in multi ethnic Singapore differ from that of the populations used in formulating the modified Ranson and Glasgow scores. The use of these scoring systems has not previously been validated in the Singaporean setting. This study aims to validate and compare the prognostic use of the modified Ranson and Glasgow scores, and to determine the superiority of one score over the other in predicting the outcome for acute pancreatitis in the Singaporean population. METHODS: This is a 3-year retrospective study of patients diagnosed with acute pancreatitis at our centre. Patients with chronic pancreatitis, acute on chronic pancreatitis, iatrogenic pancreatitis, pancreatic cancer as well as those with incomplete Ranson or Glasgow scores were excluded from the study. Case notes and computer records were reviewed for local complications of pancreatitis and organ failure. Receiver operator characteristic (ROC) curves of the Ranson and Glasgow scores were plotted for the prediction of severity and mortality. RESULTS: Between January 2010 and December 2012, 230 cases were diagnosed with acute pancreatitis. A majority of the patients had mild pancreatitis (n = 194, 84.3%), and the overall 30-day mortality rate was 3.5% (n = 8). ROC of the Ranson and Glasgow scoring systems for mortality showed an area under curve (AUC) of 0.854 (P = 0.001) and 0.776 (P = 0.008), respectively. For severity, the AUC for the modified Ranson and Glasgow score was calculated to be 0.694 and 0.668, respectively. CONCLUSIONS: The ROC curves of Ranson and Glasgow scores for mortality are comparable with that published in earlier studies. In a Singaporean population, the Ranson score is more accurate in the prediction of mortality. However, both scoring systems are poor predictors for severity of acute pancreatitis. PMID- 25924929 TI - Influenza vaccine efficacy trials: a simulation approach to understand failures from the past. AB - The success of a seasonal influenza vaccine efficacy trial depends not only upon the design but also upon the annual epidemic characteristics. In this context, simulation methods are an essential tool in evaluating the performances of study designs under various circumstances. However, traditional methods for simulating time-to-event data are not suitable for the simulation of influenza vaccine efficacy trials because of the seasonality and heterogeneity of influenza epidemics. Instead, we propose a mathematical model parameterized with historical surveillance data, heterogeneous frailty among the subjects, survey-based heterogeneous number of daily contact, and a mixed vaccine protection mechanism. We illustrate our methodology by generating multiple-trial data similar to a large phase III trial that failed to show additional relative vaccine efficacy of an experimental adjuvanted vaccine compared with the reference vaccine. We show that small departures from the designing assumptions, such as a smaller range of strain protection for the experimental vaccine or the chosen endpoint, could lead to smaller probabilities of success in showing significant relative vaccine efficacy. PMID- 25924930 TI - Increased B7H4 tissue expression correlates with high CA19.9 serum levels and a worse prognosis of pancreatic adenocarcinoma. AB - Pancreatic cancer (PC) is a leading cause of cancer death worldwide, especially in Western societies. Its aggressive nature and poor prognosis increase the need for identifying new and more accurate diagnostic and prognostic tools. We studied 41 patients who had undergone radical surgical resection for PC, investigated B7H4 protein expression in the PC tissue specimens of these patients by immunohistochemistry and analyzed several clinical and pathological features. The positive expression of the B7H4 antigen was associated with a negative impact of chemotherapy with gemcitabine on patient survival and also correlated with high CA19.9 serum levels and poorly differentiated tumors. Moreover, patients that overexpressed B7H4 antigen had worse prognosis compared to the ones that did not overexpress B7H4. B7H4 antigen is a negative prognostic marker for PC patients and also seems to express resistance of PC patients to chemotherapy with gemcitabine. PMID- 25924931 TI - plethy: management of whole body plethysmography data in R. AB - BACKGROUND: Characterization of respiratory phenotypes can enhance complex trait and genomic studies involving allergic/autoimmune and infectious diseases. Many aspects of respiration can be measured using devices known as plethysmographs that can measure thoracic movement. One such approach (the Buxco platform) performs unrestrained whole body plethysmography on mice which infers thoracic movements from pressure differences from the act of inhalation and exhalation. While proprietary software is available to perform basic statistical analysis as part of machine's bundled software, it is desirable to be able to incorporate these analyses into high-throughput pipelines and integrate them with other data types, as well as leverage the wealth of analytic and visualization approaches provided by the R statistical computing environment. RESULTS: This manuscript describes the plethy package which is an R/Bioconductor framework for pre processing and analysis of plethysmography data with emphasis on larger scale longitudinal experiments. The plethy package was designed to facilitate quality control and exploratory data analysis. We provide a demonstration of the features of plethy using a dataset assessing the respiratory effects over time of SARS and Influenza infection in mice. CONCLUSION: The plethy package provides functionality for users to import, perform quality assessment and exploratory data analysis in a manner that allows interoperability with existing modelling tools. Our package is implemented in R and is freely available as part of the Bioconductor project http://www.bioconductor.org/packages/release/bioc/html/plethy.html . PMID- 25924933 TI - The state of Veterans Affairs sleep medicine programs: 2012 inventory results. AB - PURPOSE: The Veterans Health Administration (VHA) represents one of the largest integrated health-care systems in the country. In 2012, the Veterans Affairs Sleep Network (VASN) sought to identify available sleep resources at VA medical centers (VAMCs) across the country through a national sleep inventory. METHODS: The sleep inventory was administered at the annual 2012 VA Sleep Practitioners meeting and by email to sleep contacts at each VAMC. National prosthetics contacts were used to identify personnel at VAMCs without established sleep programs. Follow-up emails and telephone calls were made through March 2013. RESULTS: One hundred eleven VA medical centers were included for analysis. Thirty nine programs did not respond, and 10 were considered "satellites," referring all sleep services to a larger neighboring VAMC. Sleep programs were stratified based on extent of services offered (i.e., in-lab and home testing, sleep specialty clinics, cognitive behavioral therapy for insomnia (CBT-i)): 28 % were complex sleep programs (CSPs), 46 % were intermediate (ISPs), 9 % were standard (SSPs), and 17 % offered no formal sleep services. Overall, 138,175 clinic visits and 90,904 sleep testing encounters were provided in fiscal year 2011 by 112.1 physicians and clinical psychologists, 100.4 sleep technologists, and 115.3 respiratory therapists. More than half of all programs had home testing and CBT-i programs, and 26 % utilized sleep telehealth. CONCLUSIONS: The 2012 VA sleep inventory suggests considerable variability in sleep services within the VA. Demand for sleep services is high, with programs using home testing, sleep telehealth, and a growing number of mid-level providers to improve access to care. PMID- 25924932 TI - A rare case of intravascular epithelioid hemangioendothelioma of the cephalic vein treated with surgery and postoperative radiation therapy: a case report and review of the literature. AB - INTRODUCTION: Epithelioid hemangioendothelioma (EHE) is a rare endothelial tumor with an intermediate grade of malignancy. Few cases of primary vascular hemangioendothelioma have been described in the literature. Surgery is the treatment of choice, but radiation therapy and chemotherapy should also be considered in particular cases. CASE PRESENTATION: We present the case of a 44 year-old Caucasian woman affected by EHE of the cephalic vein, treated by complete surgical removal of the mass and postoperative local radiation therapy. At 5-year follow-up, our patient is alive, with no signs of local or distant relapse and with no late radiation-related effects. CONCLUSIONS: Postoperative radiotherapy may play a role in cases in which tumor margins are close or cannot be assessed or when high-risk features are present. PMID- 25924934 TI - Comparison of the upper airway dynamics of oronasal and nasal masks with positive airway pressure treatment using cine magnetic resonance imaging. AB - PURPOSE: It is known that oronasal masks are not as effective at opening the upper airway compared to nasal only continuous positive airway pressure (CPAP) masks in patients with sleep-disordered breathing. However, the physiological mechanism for this difference in efficacy is not known; although, it has been hypothesized to involve the retroglossal and/or retropalatal region of the upper airway. The objective of this study was to investigate differences in retroglossal and retropalatal anterior-posterior space with the use of oronasal vs. nasal CPAP masks using real-time cine magnetic resonance imaging (cMRI). METHODS: Ten subjects (eight men, two women) with obstructive sleep apnea (OSA) were given cMRI with both nasal and oronasal CPAP masks. Each subject was imaged with each interface at pressures of 5, 10, and 15 cm of H2O, while in the supine position along the sagittal plane. RESULTS: The oronasal mask produced significantly less airway opening in the retropalatal region of the upper airway compared to the nasal mask interface. During exhalation, mask style had a significant effect on anterior-posterior distance p = 0.016. No differences were found in the retroglossal region between mask styles. CONCLUSIONS: Our study confirmed previous findings showing differences in treatment efficacy between oronasal and nasal mask styles. We have shown anatomic evidence that the nasal mask is more effective in opening the upper airway compared to the oronasal mask in the retropalatal region. PMID- 25924935 TI - Properties of Hemoglobin Decolorized with a Histidine-Specific Protease. AB - This study investigated the application of Aspergilloglutamic peptidase (AGP) on porcine hemoglobin decolorization. AGP from fungus Aspergillus niger is identified to possess a high preference towards the histidine residues. As histidine residues in hemoglobin are known to coordinate the heme group within the globin molecule, we therefore hypothesized that incubating hemoglobin with a histidine-specific protease would efficiently separate the non-heme peptides from the heme-enriched peptides with a minimum degree of hydrolysis. AGP-decolored porcine hemoglobin hydrolysates were assessed on their functional (for example, color, emulsification, foaming, and water binding) and sensory properties. The results were compared with commercially available blood-derived proteins (subtilisin-decolored hemoglobin hydrolysates and plasma protein). It was observed that AGP is able to effectively decolor hemoglobin. The degree of hydrolysis (DH) increased less than 3% using AGP to achieve 90% color reduction of hemoglobin, whereas a DH increase of more than 20% is needed using subtilisin. The AGP-decolored hemoglobin hydrolysates (AGP-Hb) possess good emulsification, foaming, and water binding properties, which are better or comparable with the plasma protein, and much better than the subtilisin-decolored hemoglobin hydrolysates (subtilisin-Hb). The model canned meat with addition of AGP-Hb showed the highest value in hardness, springiness, and chewiness from the texture analysis. Furthermore, the canned meat with AGP-Hb was found to have a better sensory profile than the ones with addition of subtilisin-Hb and plasma protein. PMID- 25924937 TI - Temozolomide in Advanced Neuroendocrine Neoplasms: Pharmacological and Clinical Aspects. AB - Alkylating agents, such as streptozocin and dacarbazine, have been reported as active in neuroendocrine neoplasms (NENs). Temozolomide (TMZ) is an oral, potentially less toxic derivative of dacarbazine, which has shown activity both as a single agent and in combination with other drugs. Nevertheless, its role in NENs has not been well defined. Several retrospective and prospective phase I-II studies have been published describing its use in a variety of NENs. In a retrospective series, the combination of capecitabine and TMZ was reported to be associated with a particularly high tumour response in pancreatic NENs as a first line treatment. Although in NENs, determination of the O6-methylguanine-DNA methyltransferase (MGMT) status has been suggested as a predictive biomarker of response, its role still remains investigational, awaiting validation along with the establishment of the optimal detection method. Metronomic schedules have been reported to potentially overcome MGMT-related drug resistance. Toxicity is manageable if well monitored. We reviewed the literature regarding pharmacological and clinical aspects of TMZ, focusing on specific settings of NENs, different schedules, toxicity and safety profiles, and potential predictive biomarkers of response. PMID- 25924936 TI - Tissue Transglutaminase, Not Lysyl Oxidase, Dominates Early Calcium-Dependent Remodeling of Fibroblast-Populated Collagen Lattices. AB - Cell-populated collagen gels have provided significant insight into the cellular contractile mechanisms and cell-matrix interactions that are necessary for compacting and remodeling extant matrix. Nevertheless, little research has been devoted towards determining how cells entrench these deformations that contribute to establishing a preferred mechanical state. To this end, we examined the roles of two covalent matrix cross-linkers, i.e. tissue transglutaminase and lysyl oxidase, during global remodeling of the free-floating fibroblast-populated collagen lattice. Inhibition of tissue transglutaminase resulted in a reduced rate of compaction compared to controls during early remodeling (up to 2 days). In contrast, inhibition of lysyl oxidase did not alter the early compaction of these lattices, but it reduced the compaction after 2 days of culture. Acute inhibition of different contractile mechanisms suggested further that calcium dependent contractility may have dominated during the initial remodeling of the collagen lattice before giving way to calcium-independent contractility at later times. In summary, these findings suggest that early remodeling of the free floating collagen lattice is facilitated by calcium-dependent cell contraction while entrenchment is dominated by a tissue transglutaminase-mediated cross linking of the extant matrix. As remodeling continues, however, lysyl oxidase increases its contribution, perhaps by consolidating de novo collagen fibrils into fibers to continue the remodeling while the cells transition to a more sustained, calcium-independent contractility. These results promise to influence future tissue engineering studies as well as computational simulations aimed at understanding matrix remodeling in complex in vivo situations. PMID- 25924938 TI - A small molecule walks along a surface between porphyrin fences that are assembled in situ. AB - An on-surface bimolecular system is described, comprising a simple divalent bis(imidazolyl) molecule that is shown to "walk" at room temperature via an inchworm mechanism along a specific pathway terminated at each end by oligomeric "fences" constructed on a monocrystalline copper surface. Scanning tunneling microscopy shows that the motion of the walker occurs along the [110] direction of the Cu surface with remarkably high selectivity and is effectively confined by the orthogonal construction of covalent porphyrin oligomers along the [001] surface direction, which serve as barriers. Density functional theory shows that the mobile molecule walks by attaching and detaching the nitrogen atoms in its imidazolyl "legs" to and from the protruding close-packed rows of the metal surface and that it can transit between two energetically equivalent extended and contracted conformations by overcoming a small energy barrier. PMID- 25924939 TI - Maternal hypomagnesemia causes placental abnormalities and fetal and postnatal mortality. AB - INTRODUCTION: Magnesium (Mg(2+)) is essential for cellular growth and the maintenance of normal cellular processes. However, little is known about how maternal hypomagnesemia during pregnancy affects fetal growth and development. This study investigated the effects of maternal hypomagnesemia on the late gestation placenta and fetus, and postnatal outcomes until weaning. METHODS: Female CD1 mice consumed a control (0.2% w/w Mg(2+)), moderately Mg(2+) deficient (MMD; 0.02% w/w Mg(2+)) or severely Mg(2+) deficient (SMD; 0.005% w/w Mg(2+)) diet for 4 weeks prior to mating and throughout pregnancy. Dams were killed at E18.5 for embryonic studies or allowed to litter naturally and the offspring studied up to postnatal day 21. RESULTS: At E18.5, both Mg(2+) deficient diets decreased maternal plasma and bone Mg(2+) but only the SMD diet decreased fetal plasma Mg(2+). Maternal hypomagnesemia led to fetal loss and fetal growth restriction. Maternal Mg(2+) deficiency increased placental glycogen cell area and decreased spongiotrophoblast cell area while upregulating mRNA expression of the MagT1 Mg(2+) transporter in spongiotrophoblast cells. The SMD animals also displayed instances of gross placental abnormalities. After birth, pups in the SMD group had increased early postnatal mortality and failed to thrive. Pups in the MMD group underwent catch-up growth but remained shorter than controls at PN21 and were hypomagnesemic and hypoglycemic. CONCLUSIONS: These changes suggest that maternal Mg(2+) deficiency during pregnancy impairs placental development and fetal growth, which may have long-term health consequences for offspring. Collectively, these results have important implications for women who are Mg(2+) deficient during pregnancy. PMID- 25924940 TI - Awareness and knowledge regarding of cervical cancer, Pap smear screening and human papillomavirus infection in Gabonese women. AB - BACKGROUND: Cervical cancer is the commonest cancer and the leading cause of cancer mortality in women in Gabon. The age-standardized incidence of cervical cancer is 19.9 per 100 000 women and the mortality rate is 8.4 per 100 000. Various international studies have identified the lack of awareness and knowledge about cervical cancer as barriers to use preventive methods. This article assesses the awareness and knowledge about cervical cancer, Pap smear testing and its use and HPV among women living in Libreville, Gabon. METHODS: This study was conducted in October 2014 in Libreville. A total of 452 women aged 16 years and above were recruited from different town locations. Logistic regression analysis was used to identify the effect of demographic characteristics on the level of knowledge about cervical cancer, Pap smear testing and HPV. Odds ratio and 95% confidence intervals were used to identify the strength of association. Associations were considered statistically significant at p < 0.05. RESULTS: Of all the women interviewed, 91.6% (414/452) had heard about cervical cancer and only 27.9% (126/452) had heard of Pap smear test. Of these 126 women, only 65.1% (82/126) had done cervical cancer screening and 68.3% (56/82) on the suggestion of a doctor. The most common reason for not undergoing Pap smear testing was neglect (50%, 22/44) followed by lack of financial resources (13.6%, 6/44), fear of discovering a serious disease (13.6%, 6/44) and deeming it unimportant (13.6%, 6/44). Only 8% (40/452) of the participants had heard about HPV and their knowledge of HPV was fair. There is a very poor level of knowledge about cervical cancer among Gabonese women. CONCLUSION: This study demonstrates a very low level of knowledge about cervical cancer, Pap smear testing and HPV in a sample of Gabonese women. There is a critical need for Gabonese women to be informed about cervical cancer and the Pap smear test to improve the use of this preventive method. The implication of health staff and Gabonese media should be included as a centerpiece in the effort to inform the population in order to reduce the burden of cervical cancer in Gabon and save women lives. PMID- 25924941 TI - A highly sensitive homogeneous electrochemical assay for alkaline phosphatase activity based on single molecular beacon-initiated T7 exonuclease-mediated signal amplification. AB - Alkaline phosphatase (ALP), a class of enzymes that catalyzes the dephosphorylation of a variety of substrates, is one of the most commonly assayed enzymes in routine clinical practice, and an important biomarker related to many human diseases. Herein, a facile and highly sensitive homogeneous electrochemical biosensing strategy was proposed for the ALP activity detection based on single molecular beacon-initiated T7 exonuclease-assisted signal amplification. One 3' phosphorylated and 5'-methylene blue (MB) labeled hairpin probe (HP) is ingeniously designed. In the presence of ALP, the dephosphorylation of HP, the subsequent Klenow fragment (KF) polymerase-catalyzed elongation and T7 exonuclease-catalyzed digestion of the duplex stem of HP take place, releasing MB labeled mononucleotides and the trigger DNA (tDNA). tDNA then hybridizes with another HP and initiates the subsequent cycling cleavage process. As a result, a large amount of MB-labeled mononucleotides are released, generating a significantly amplified electrochemical signal toward the ALP activity assay. A directly measured detection limit as low as 0.1 U L(-1) is obtained, which is comparable to that of the fluorescence method and up to three orders of magnitude lower than that of the immobilization-based electrochemical strategy previously reported. In addition to high sensitivity and good selectivity, the as-proposed strategy also exhibits the advantages of simplicity and convenience, because the assay is carried out in the homogeneous solution phase and sophisticated electrode modification processes are avoided. Therefore, the homogeneous electrochemical method we proposed here is an ideal candidate for ALP activity detection in biochemical research and clinical practices. PMID- 25924942 TI - Factors Influencing the Reliability of Thyroid Fine-Needle Aspiration: Analysis of Thyroid Nodule Size, Guidance Mode for Aspiration and Preparation Method. AB - OBJECTIVE: We aimed to clarify the influence of ThinPrep preparation, nodule size and guidance mode on the accuracy of thyroid fine-needle aspiration (FNA). METHODS: A total of 1,240 thyroid FNAs were reviewed and 489 cases with histological correlations were enrolled in this study. RESULTS: Of the 489 total cases examined, 101 were processed with both ThinPrep and conventional preparation and 388 entirely with ThinPrep. The overall nondiagnostic rate, sensitivity and accuracy of FNA were 2.0, 91.0 and 89.4%, respectively. The cases with a preoperative ultrasound (n = 469) were grouped according to nodule size. The nondiagnostic rate, sensitivity and accuracy of FNA did not differ significantly with nodule size (p1 = 0.339, p2 = 0.179, p3 = 0.119). A total of 101 resections were performed with palpation-guided FNA and 388 were performed with ultrasound-guided FNA. The nondiagnostic rates, sensitivity and accuracy of FNA were similar in these two groups. CONCLUSIONS: The ThinPrep technique is a valid method for thyroid FNA and is effective for thyroid nodules >= 0.5 cm. The reliability of FNA results is not reduced with larger nodules. The use of palpation-guided FNA for palpable solid nodules is also effective. PMID- 25924943 TI - Key determinants of target DNA recognition by retroviral intasomes. AB - BACKGROUND: Retroviral integration favors weakly conserved palindrome sequences at the sites of viral DNA joining and generates a short (4-6 bp) duplication of host DNA flanking the provirus. We previously determined two key parameters that underlie the target DNA preference for prototype foamy virus (PFV) and human immunodeficiency virus type 1 (HIV-1) integration: flexible pyrimidine (Y)/purine (R) dinucleotide steps at the centers of the integration sites, and base contacts with specific integrase residues, such as Ala188 in PFV integrase and Ser119 in HIV-1 integrase. Here we examined the dinucleotide preference profiles of a range of retroviruses and correlated these findings with respect to length of target site duplication (TSD). RESULTS: Integration datasets covering six viral genera and the three lengths of TSD were accessed from the literature or generated in this work. All viruses exhibited significant enrichments of flexible YR and/or selection against rigid RY dinucleotide steps at the centers of integration sites, and the magnitude of this enrichment inversely correlated with TSD length. The DNA sequence environments of in vivo-generated HIV-1 and PFV sites were consistent with integration into nucleosomes, however, the local sequence preferences were largely independent of target DNA chromatinization. Integration sites derived from cells infected with the gammaretrovirus reticuloendotheliosis virus strain A (Rev-A), which yields a 5 bp TSD, revealed the targeting of global chromatin features most similar to those of Moloney murine leukemia virus, which yields a 4 bp duplication. In vitro assays revealed that Rev-A integrase interacts with and is catalytically stimulated by cellular bromodomain containing 4 protein. CONCLUSIONS: Retroviral integrases have likely evolved to bend target DNA to fit scissile phosphodiester bonds into two active sites for integration, and viruses that cut target DNA with a 6 bp stagger may not need to bend DNA as sharply as viruses that cleave with 4 bp or 5 bp staggers. For PFV and HIV-1, the selection of signature bases and central flexibility at sites of integration is largely independent of chromatin structure. Furthermore, global Rev-A integration is likely directed to chromatin features by bromodomain and extraterminal domain proteins. PMID- 25924944 TI - Comparison of the effects of moderate and severe hypercapnic acidosis on ventilation-induced lung injury. AB - BACKGROUND: We have proved that hypercapnic acidosis (a PaCO2 of 80-100 mmHg) protects against ventilator-induced lung injury in rats. However, there remains uncertainty regarding the appropriate target PaCO2 or if greater CO2 "doses" (PaCO2 > 100 mmHg) demonstrate this effect. We wished to determine whether severe acute hypercapnic acidosis can reduce stretch-induced injury, as well as the role of nuclear factor-kappaB (NF-kappaB) in the effects of acute hypercapnic acidosis. METHODS: Fifty-four rats were ventilated for 4 hours with a pressure controlled ventilation mode set at a peak inspiratory pressure (PIP) of 30 cmH2O. A gas mixture of carbon dioxide with oxygen (FiCO2 = 4-5%, FiCO2 = 11-12% or FiCO2 = 16-17%; FiO2 = 0.7; balance N2) was immediately administered to maintain the target PaCO2 in the NC (a PaCO2 of 35-45 mmHg), MHA (a PaCO2 of 80-100 mmHg) and SHA (a PaCO2 of 130-150 mmHg) groups. Nine normal or non-ventilated rats served as controls. The hemodynamics, gas exchange and inflammatory parameters were measured. The role of NF-kappaB pathway in hypercapnic acidosis-mediated protection from high-pressure stretch injury was then determined. RESULTS: In the NC group, high-pressure ventilation resulted in a decrease in PaO2/FiO2 from 415.6 (37.1) mmHg to 179.1 (23.5) mmHg (p < 0.001), but improved by MHA (379.9 +/ 34.5 mmHg) and SHA (298.6 +/- 35.3 mmHg). The lung injury score in the SHA group (7.8 +/- 1.6) was lower than the NC group (11.8 +/- 2.3, P < 0.05) but was higher than the MHA group (4.4 +/- 1.3, P < 0.05). Compared with the NC group, after 4 h of high pressure ventilation, the MHA and SHA groups had decreases in MPO activity of 67% and 33%, respectively, and also declined the levels of TNF-alpha (58% versus 72%) and MIP-2 (76% versus 60%) in the BALF. Additionally, both hypercapnic acidosis groups reduced stretch-induced NF-kappaB activation (p < 0.05) and significantly decreased lung ICAM-1 expression (p < 0.05). CONCLUSIONS: Moderate hypercapnic acidosis (PaCO2 maintained at 80-100 mmHg) has a greater protective effect on high-pressure ventilation-induced inflammatory injury. The potential mechanisms may involve alterations in NF-kappaB activity. PMID- 25924945 TI - Uncovering a missing demographic in trauma registries: epidemiology of trauma among American Indians and Alaska Natives in Washington State. AB - BACKGROUND: The objectives of this study were to evaluate racial misclassification in a statewide trauma registry and to describe the epidemiology of trauma among the Washington American Indian and Alaska Native (AI/AN) population. METHODS: We performed probabilistic record linkage between the Washington Trauma Registry (2005-2009) and Northwest Tribal Registry, a dataset of known AI/AN. AI/AN patients were compared with caucasians on demographic, injury and clinical outcome factors. A multivariable model estimated odds of mortality. RESULTS: Record linkage increased ascertainment of AI/AN cases in the trauma registry 71%, from 1777 to 3039 cases. Compared with caucasians, AI/AN trauma patients were younger (mean age=36 vs 47 years, p<0.001) and more commonly male (66.5% vs 61.2%, p<0.001). AI/AN experienced more intentional injuries (suicide or homicide: 20.1% vs 6.7%, p<0.001), a higher proportion of severe traumatic brain injury (20.7% vs 16.8%, p=0.004) and were less likely than caucasians to use safety equipment such as seat belts/airbags (53.9% vs 76.7%, p<0.001). ISSs were similar (ISS >15: 21.4% vs 20.5%, p=0.63), and no difference was observed in mortality after adjustment for covariates (p=0.58). CONCLUSIONS: Linkage to a state trauma registry improved data quality by correcting racial misclassification, allowing for a comprehensive description of injury patterns for the AI/AN population. AI/AN sustained more severe injuries with similar postinjury outcomes to caucasians. Future efforts should focus on primary prevention for this population, including increased use of seat belts and child safety seats and reduction of interpersonal violence and suicide. PMID- 25924947 TI - NMR data visualization, processing, and analysis on mobile devices. AB - Touch-screen computers are emerging as a popular platform for many applications, including those in chemistry and analytical sciences. In this work, we present our implementation of a new NMR 'app' designed for hand-held and portable touch controlled devices, such as smartphones and tablets. It features a flexible architecture formed by a powerful NMR processing and analysis kernel and an intuitive user interface that makes full use of the smart devices haptic capabilities. Routine 1D and 2D NMR spectra acquired in most NMR instruments can be processed in a fully unattended way. More advanced experiments such as non uniform sampled NMR spectra are also supported through a very efficient parallelized Modified Iterative Soft Thresholding algorithm. Specific technical development features as well as the overall feasibility of using NMR software apps will also be discussed. All aspects considered the functionalities of the app allowing it to work as a stand-alone tool or as a 'companion' to more advanced desktop applications such as Mnova NMR. PMID- 25924946 TI - PKCalpha promotes the mesenchymal to amoeboid transition and increases cancer cell invasiveness. AB - BACKGROUND: The local invasion of tumor cells into the surrounding tissue is the first and most critical step of the metastatic cascade. Cells can invade either collectively, or individually. Individual cancer cell invasion can occur in the mesenchymal or amoeboid mode, which are mutually interchangeable. This plasticity of individual cancer cell invasiveness may represent an escape mechanism for invading cancer cells from anti-metastatic treatment. METHODS: To identify new signaling proteins involved in the plasticity of cancer cell invasiveness, we performed proteomic analysis of the amoeboid to mesenchymal transition with A375m2 melanoma cells in a 3D Matrigel matrix. RESULTS: In this screen we identified PKCalpha as an important protein for the maintenance of amoeboid morphology. We found that the activation of PKCalpha resulted in the mesenchymal amoeboid transition of mesenchymal K2 and MDA-MB-231 cell lines. Consistently, PKCalpha inhibition led to the amoeboid-mesenchymal transition of amoeboid A375m2 cells. Next, we showed that PKCalpha inhibition resulted in a considerable decrease in the invading abilities of all analyzed cancer cell lines. CONCLUSIONS: Our results suggest that PKCalpha is an important protein for maintenance of the amoeboid morphology of cancer cells, and that downregulation of PKCalpha results in the amoeboid to mesenchymal transition. Our data also suggest that PKCalpha is important for both mesenchymal and amoeboid invasiveness, making it an attractive target for anti-metastatic therapies. PMID- 25924948 TI - Moisture damage in home associates with systemic inflammation in children. AB - This study investigated the association between confirmed moisture damage in homes and systemic subclinical inflammation in children. Home inspections were performed in homes of 291 children at the age of 6 years. Subclinical inflammation at the age of 6 years was assessed by measuring the circulating levels of C-reactive protein (CRP) and leukocytes in peripheral blood and fractional exhaled nitric oxide (FeNO). Proinflammatory cytokines interleukin (IL)-1beta and IL-6 and tumor necrosis factor (TNF)-alpha were measured in unstimulated, and in phorbol 12-myristate 13-acetate and ionomycin (PI), lipopolysaccharide (LPS), or peptidoglycan (PPG)-stimulated whole blood. Major moisture damage in the child's main living areas (living room, kitchen, or child's bedroom) and moisture damage with mold in the bathroom were associated with increased levels of CRP and stimulated production of several proinflammatory cytokines. There were no significant associations between moisture damage/visible mold and leukocyte or FeNO values. The results suggest that moisture damage or mold in home may be associated with increased systemic subclinical inflammation and proinflammatory cytokine responsiveness. PMID- 25924950 TI - Ubiquitin-Proteasome System Inhibition Promotes Long-Term Depression and Synaptic Tagging/Capture. AB - A balance of protein synthesis and degradation is critical for the dynamic regulation and implementation of long-term memory storage. The role of the ubiquitin-proteasome system (UPS) in regulating the plasticity at potentiated synapses is well studied, but its roles in depressed synaptic populations remain elusive. In this study, we probed the possibility of regulating the UPS by inhibiting the proteasome function during the induction of protein synthesis independent form of hippocampal long-term depression (early-LTD), an important component of synaptic plasticity. Here, we show that protein degradation is involved in early-LTD induction and interfering with this process facilitates early-LTD to late-LTD. We provide evidence here that under the circumstances of proteasome inhibition brain-derived neurotrophic factor is accumulated as plasticity-related protein and it drives the weakly depressed or potentiated synapses to associativity. Thus, UPS inhibition promotes LTD and establishes associativity between weakly depressed or potentiated synapses through the mechanisms of synaptic tagging/capture or cross-capture. PMID- 25924949 TI - A multi-scale approach to designing therapeutics for tuberculosis. AB - Approximately one third of the world's population is infected with Mycobacterium tuberculosis. Limited information about how the immune system fights M. tuberculosis and what constitutes protection from the bacteria impact our ability to develop effective therapies for tuberculosis. We present an in vivo systems biology approach that integrates data from multiple model systems and over multiple length and time scales into a comprehensive multi-scale and multi compartment view of the in vivo immune response to M. tuberculosis. We describe computational models that can be used to study (a) immunomodulation with the cytokines tumor necrosis factor and interleukin 10, (b) oral and inhaled antibiotics, and PMID- 25924951 TI - Exploring the Early Organization and Maturation of Linguistic Pathways in the Human Infant Brain. AB - Linguistic processing is based on a close collaboration between temporal and frontal regions connected by two pathways: the "dorsal" and "ventral pathways" (assumed to support phonological and semantic processing, respectively, in adults). We investigated here the development of these pathways at the onset of language acquisition, during the first post-natal weeks, using cross-sectional diffusion imaging in 21 healthy infants (6-22 weeks of age) and 17 young adults. We compared the bundle organization and microstructure at these two ages using tractography and original clustering analyses of diffusion tensor imaging parameters. We observed structural similarities between both groups, especially concerning the dorsal/ventral pathway segregation and the arcuate fasciculus asymmetry. We further highlighted the developmental tempos of the linguistic bundles: The ventral pathway maturation was more advanced than the dorsal pathway maturation, but the latter catches up during the first post-natal months. Its fast development during this period might relate to the learning of speech cross modal representations and to the first combinatorial analyses of the speech input. PMID- 25924952 TI - Discrete Neural Signatures of Basic Emotions. AB - Categorical models of emotions posit neurally and physiologically distinct human basic emotions. We tested this assumption by using multivariate pattern analysis (MVPA) to classify brain activity patterns of 6 basic emotions (disgust, fear, happiness, sadness, anger, and surprise) in 3 experiments. Emotions were induced with short movies or mental imagery during functional magnetic resonance imaging. MVPA accurately classified emotions induced by both methods, and the classification generalized from one induction condition to another and across individuals. Brain regions contributing most to the classification accuracy included medial and inferior lateral prefrontal cortices, frontal pole, precentral and postcentral gyri, precuneus, and posterior cingulate cortex. Thus, specific neural signatures across these regions hold representations of different emotional states in multimodal fashion, independently of how the emotions are induced. Similarity of subjective experiences between emotions was associated with similarity of neural patterns for the same emotions, suggesting a direct link between activity in these brain regions and the subjective emotional experience. PMID- 25924953 TI - Cross-correlation spin noise spectroscopy of heterogeneous interacting spin systems. AB - Interacting multi-component spin systems are ubiquitous in nature and in the laboratory. As such, investigations of inter-species spin interactions are of vital importance. Traditionally, they are studied by experimental methods that are necessarily perturbative: e.g., by intentionally polarizing or depolarizing one spin species while detecting the response of the other(s). Here, we describe and demonstrate an alternative approach based on multi-probe spin noise spectroscopy, which can reveal inter-species spin interactions--under conditions of strict thermal equilibrium--by detecting and cross-correlating the stochastic fluctuation signals exhibited by each of the constituent spin species. Specifically, we consider a two-component spin ensemble that interacts via exchange coupling, and we determine cross-correlations between their intrinsic spin fluctuations. The model is experimentally confirmed using "two-color" optical spin noise spectroscopy on a mixture of interacting Rb and Cs vapors. Noise correlations directly reveal the presence of inter-species spin exchange, without ever perturbing the system away from thermal equilibrium. These non invasive and noise-based techniques should be generally applicable to any heterogeneous spin system in which the fluctuations of the constituent components are detectable. PMID- 25924954 TI - Cleavage of a P-N Bond in a Urea-Containing (Ph2 P(R)PPh2 )-Bridged Dinuclear Gold(I) Thiolate Complex by Fluoride and a Mechanistic Insight. AB - A urea-containing, (Ph2 P(R)PPh2 )-bridged, dinuclear, gold(I) thiolate complex, [Au2 {Ph2 PN(C6 H4 OMe-4)PPh2 }(SC6 H4 NHCONHC6 H5 )2 ] (1) was designed and synthesized and its photophysical and anion recognition properties studied. The results show that 1 has a high selectivity toward F(-) . Upon addition of F(-) , the yellow solution was decolorized, and drastic changes of emission and (1) H and (31) P{(1) H} NMR signals were observed. Interestingly, these changes are attributed to fluoride-assisted P-N bond hydrolysis, instead of the expected hydrogen-bonding interactions with the urea receptor. Similar changes were observed for two other basic anions, AcO(-) and H2 PO4 (-) , but to a much lesser extent; and these anions were found to bind to the urea receptor at the same time. On the other hand, Cl(-) was found to only bind to the urea moiety through hydrogen-bonding interactions. Further studies with the control complex [Au2 {Ph2 PN(C6 H4 OMe-4)PPh2 }Cl2 ] (2) indicate that F(-) assists the hydrolysis process via cleavage of the P-N bond. DFT calculations were performed to study the reaction mechanism for the fluoride-assisted P-N bond hydrolysis of 2; these provide a better insight into the role of fluoride in the hydrolysis. PMID- 25924956 TI - A step-wise approach towards introduction of an alcohol based hand rub, and implementation of front line ownership- using a, rural, tertiary care hospital in central India as a model. AB - BACKGROUND: Appropriate hand hygiene is a gold standard to combat healthcare associated infections (HAIs). The World Health Organization (WHO) has recommended alcohol based hand rub (ABHR) as the most effective tool to maintain hand hygiene. In resource poor settings commercially available ABHR is not "economically accessible". The objectives of this study were to assess the acceptability of, and to build confidence for an in-house prepared (based on WHO guidelines) alcohol based hand rub among healthcare workers (HCWs) using a rural, tertiary care hospital in central India as an example. METHODS: A series of activities were developed and conducted based on the Precede-Proceed model, the Trans Theoretical model of behaviour change, Front line ownership and Social marketing. A modified WHO-ABHR formulation, the 'test product' and 'WHO product evaluation form' were used for self assessment of acceptability of the 'test product'. Confidence building activities, as finger tip culture, visual portrayal method and handmade posters, were used in high-risk wards for HAIs, to build confidence for the 'test product' in removing transient flora from the hands. A locally developed feedback from was used to evaluate the impact of the activities conducted. RESULTS: Overall 183 HCWs were enrolled for the assessment of the 'test product' (130- doctors and 53 nurses). Out of these 83% (108/130) doctors and 94% (50/53) nurses were satisfied with the 'test product'. The confidence building activity was conducted with 116 participants (49 doctors). After single use of the 'test product', overall a significant reduction was observed for the CFUs on the blood agar plates (0.77 Log(10), p < 0.001). A complete reduction (100%) in colony forming units on incubated blood agar plates was seen for 13% (15/116) participants. Eighty two percent (95/116) participants expressed their confidence in the 'test product'. CONCLUSION: The self reported acceptance level for the 'test product' was high. The use of finger tip culture coupled with the visual portrayal was perceived as a convincing and highly effective way to develop confidence in HCWs. Thus, is the foremost step towards successful introduction of ABHR and can be seen as a model for similar settings. PMID- 25924957 TI - Identification and antimicrobial activity detection of lactic Acid bacteria isolated from corn stover silage. AB - A total of 59 lactic acid bacteria (LAB) strains were isolated from corn stover silage. According to phenotypic and chemotaxonomic characteristics, 16S ribosomal DNA (rDNA) sequences and recA gene polymerase chain reaction amplification, these LAB isolates were identified as five species: Lactobacillus (L.) plantarum subsp. plantarum, Pediococcus pentosaceus, Enterococcus mundtii, Weissella cibaria and Leuconostoc pseudomesenteroides, respectively. Those strains were also screened for antimicrobial activity using a dual-culture agar plate assay. Based on excluding the effects of organic acids and hydrogen peroxide, two L. plantarum subsp. plantarum strains ZZU 203 and 204, which strongly inhibited Salmonella enterica ATCC 43971(T), Micrococcus luteus ATCC 4698(T) and Escherichia coli ATCC 11775(T) were selected for further research on sensitivity of the antimicrobial substance to heat, pH and protease. Cell-free culture supernatants of the two strains exhibited strong heat stability (60 min at 100 degrees C), but the antimicrobial activity was eliminated after treatment at 121 degrees C for 15 min. The antimicrobial substance remained active under acidic condition (pH 2.0 to 6.0), but became inactive under neutral and alkaline condition (pH 7.0 to 9.0). In addition, the antimicrobial activities of these two strains decreased remarkably after digestion by protease K. These results preliminarily suggest that the desirable antimicrobial activity of strains ZZU 203 and 204 is the result of the production of a bacteriocin-like substance, and these two strains with antimicrobial activity could be used as silage additives to inhibit proliferation of unwanted microorganism during ensiling and preserve nutrients of silage. The nature of the antimicrobial substances is being investigated in our laboratory. PMID- 25924958 TI - Choline Essentiality and Its Requirement in Diets for Juvenile Parrot Fish (Oplegnathus fasciatus). AB - A 12-wk feeding trial was conducted to evaluate the essentiality of choline supplementation in diets for parrot fish. Five isonitrogenous and isocaloric diets were supplemented with 0 (as control), 500, 1,000, and 2,000 mg choline per kg diet, and a positive control diet without choline contained 0.3% of 2-amino-2 methyl-1-propanol as choline biosynthesis inhibitor (designated as Con, C500, C1000, C2000 and Con(+), respectively). Triplicate groups of fish (body weight, 8.8+/-0.01 g) were fed one of the experimental diets at a rate of 4% body weight twice daily. The fish fed Con(+) diet revealed significantly lower growth performance and feed utilization efficiency than other fish groups. Supplementation of choline to the basal diet did not significantly influence fish growth. The highest liver lipid content was observed in fish fed the Con(+) diet and inversely correlated with liver choline concentration although the differences were not significant. Also, significantly higher liver linoleic, eicosapentaenoic and docosahexaenoic acid contents were found in fish fed the Con(+) diet. Innate immune parameters including respiratory burst and myeloperoxidase activities were not significantly affected by dietary choline levels. The findings in this study conclude that choline concentration of approximately 230 mg kg(-1) diet meets the requirement of parrot fish. PMID- 25924959 TI - Effects of ripening duration and rosemary powder addition on salchichon modified sausage quality. AB - The ripening durations and ingredients for the Salchichon sausages were modified to increase pork rear leg consumption by Korean consumers. The salchichon, a ripened pork sausage, was produced to evaluate the efficacy of two different ripening durations with and without rosemary powder on salchichon sausage quality, and the treatments were: i) 45 days of ripening without rosemary, ii) 60 days of ripening without rosemary, iii) 45 days of ripening with 0.05% rosemary, and iv) 60 days of ripening with 0.05% rosemary. Significant differences were observed in both moisture and fat content for ripening durations, with the highest moisture and least fat content observed in salchichon modified sausage (SMS) ripened for 45 days. Ripening duration and rosemary addition appeared to influence water activity (aw) of salchichon sausages. The aw of SMS ripened for 45 days was 0.80, whereas the other had aw values <0.80. Lactic acid bacteria were predominant, as Korean traditional fermented red pepper paste was added to sausages; however, the Bacillus cereus population was significantly affected by rosemary powder addition. Chewiness and gumminess decreased significantly due to the addition of rosemary powder compared to SMS without rosemary powder, and both 45 days of ripening and rosemary powder addition influenced the hardness of SMS. In conclusion, ripening duration of SMS for 45 days in the presence of rosemary powder provided superior SMS quality with an economical ripening duration compared to that of ripening with rosemary powder or ripening for 60 days. PMID- 25924960 TI - Molecular Characterization and Expression Analysis of Adrenergic Receptor Beta 2 (ADRB2) Gene before and after Exercise in the Horse. AB - The adrenergic receptor beta 2 (ADRB2) plays a role in various physiological responses of the muscle to exercise, such as contraction and relaxation. Given its important role in muscle function, we investigated the structure of the horse ADRB2 gene and its expression pattern after exercise to determine if it can serve as a putative biomarker for recovery. Evolutionary analyses using synonymous and non-synonymous mutation ratios, were compared with other species (human, chimpanzee, mouse, rat, cow, pig, chicken, dog, and cat), and revealed the occurrence of positive selection in the horse ADRB2 gene. In addition, expression analyses by quantitative polymerase chain reaction exhibited ubiquitous distribution of horse ADRB2 in various tissues including lung, skeletal muscle, kidney, thyroid, appendix, colon, spinal cord and heart, with the highest expression observed in the lung. The expression of ADRB2 in skeletal muscle was significantly up-regulated about four folds 30 minutes post-exercise compared to pre-exercise. The expression level of ADRB2 in leukocytes, which could be collected with convenience compared with other tissues in horse, increased until 60 min after exercise but decreased afterward until 120 min, suggesting the ADRB2 expression levels in leukocytes could be a useful biomarker to check the early recovery status of horse after exercise. In conclusion, we identified horse ADRB2 gene and analyzed expression profiles in various tissues. Additionally, analysis of ADBR2 gene expression in leukocytes could be a useful biomarker useful for evaluation of early recovery status after exercise in racing horses. PMID- 25924961 TI - Quality evaluation of five commercial enzyme linked immunosorbent assay kits for detecting aflatoxin b1 in feedstuffs. AB - The objective of this study was to evaluate the quality of five commercial enzyme linked immunosorbent assay (ELISA) kits (A, B, C, D, and E) from different suppliers for detecting aflatoxin B1 (AFB1). AFB1-free corn samples supplemented with different levels of AFB1 (5, 10, and 20 MUg/kg) were used as positive controls and 6 replicates of each control sample were tested to evaluate the accuracy and precision of these kits. In addition, we also evaluated the performance of these ELISA kits for AFB1 in 30 feed samples, including corn, distillers dried grains with soluble, wheat samples, soybean meal, and poultry feed, which were verified by high performance liquid chromatography. Results showed that the coefficients of variation ranged from 1.18% to 16.22% in intra plate and 2.85% to 18.04% in inter-plate for the determination of AFB1. The half maximal inhibitory concentration for five kits ranged from 3.72 to 7.22 MUg/kg. The quantitation limits of AFB1 were all under the legal limit in China but somewhat inconsistent with kit instructions. Although the recovery rate of four of the five kits were either less than 90% or more than 110%, all these values were acceptable in practice. Two kits had high false positive rates (C and E). In conclusion, our results revealed that the qualities of five tested ELISA kits were significantly different. PMID- 25924962 TI - Molecular Characterization and Expression Analysis of the Peroxisome Proliferator Activated Receptor Delta (PPARdelta) Gene before and after Exercise in Horse. AB - While athletic abilities such as speed, endurance and recovery are important in the horse, genes related to these abilities have not been extensively investigated. Here, we characterized the horse peroxisome proliferator-activated receptor delta (PPARdelta) gene and analyzed the expression of PPARdelta during exercise. PPARdelta is a known regulator of beta-oxidation, muscle fiber transformation, and running endurance. Through evolutionary analysis using the synonymous and non-synonymous mutation ratio, it was revealed that positive selection occurred in the horse PPARdelta gene. Two important domains related to nuclear hormone receptors, C4 zinc finger and ligand binding domain, were also found to be conserved well in horse PPARdelta. Horse PPARdelta was expressed ubiquitously in many tissues, but the expression level was various depending on the tissues. In the skeletal muscle, PPARdelta increased about 2.5 folds after 30 min of exercise. Unlike in muscle, the increase of PPARdelta expression was observed at 60 min but not 30 min of exercise in leukocytes. This finding might be useful for testing the endurance of horse using blood samples. Conclusively, the horse PPARdelta gene is evolutionarily conserved well and can be used as a biomarker of endurance in horse. PMID- 25924963 TI - Modelling Pasture-based Automatic Milking System Herds: Grazeable Forage Options. AB - One of the challenges to increase milk production in a large pasture-based herd with an automatic milking system (AMS) is to grow forages within a 1-km radius, as increases in walking distance increases milking interval and reduces yield. The main objective of this study was to explore sustainable forage option technologies that can supply high amount of grazeable forages for AMS herds using the Agricultural Production Systems Simulator (APSIM) model. Three different basic simulation scenarios (with irrigation) were carried out using forage crops (namely maize, soybean and sorghum) for the spring-summer period. Subsequent crops in the three scenarios were forage rape over-sown with ryegrass. Each individual simulation was run using actual climatic records for the period from 1900 to 2010. Simulated highest forage yields in maize, soybean and sorghum- (each followed by forage rape-ryegrass) based rotations were 28.2, 22.9, and 19.3 t dry matter/ha, respectively. The simulations suggested that the irrigation requirement could increase by up to 18%, 16%, and 17% respectively in those rotations in El-Nino years compared to neutral years. On the other hand, irrigation requirement could increase by up to 25%, 23%, and 32% in maize, soybean and sorghum based rotations in El-Nino years compared to La-Nina years. However, irrigation requirement could decrease by up to 8%, 7%, and 13% in maize, soybean and sorghum based rotations in La-Nina years compared to neutral years. The major implication of this study is that APSIM models have potentials in devising preferred forage options to maximise grazeable forage yield which may create the opportunity to grow more forage in small areas around the AMS which in turn will minimise walking distance and milking interval and thus increase milk production. Our analyses also suggest that simulation analysis may provide decision support during climatic uncertainty. PMID- 25924965 TI - Type 2 diabetes is more common among Indians who stay in India than in those who migrate to US, study finds. PMID- 25924964 TI - Selenium in pig nutrition and reproduction: boars and semen quality-a review. AB - Selenium plays an important role in boar nutrition via participating in selenoprotein synthesis. It seems likely that selenoproteins are central for antioxidant system regulation in the body. Se-dependent enzyme glutathione peroxidase (GSH-Px) is the most studied selenoprotein in swine production. However, roles of other selenoproteins in boar semen production and maintenance of semen quality also need to be studied. Boar semen is characterised by a high proportion of easily oxidized long chain polyunsaturated fatty acids and requires an effective antioxidant defense. The requirement of swine for selenium varies depending on many environmental and other conditions and, in general, is considered to be 0.15 to 0.30 mg/kg feed. It seems likely that reproducing sows and boars are especially sensitive to Se deficiency, and meeting their requirements is an important challenge for pig nutritionists. In fact, in many countries there are legal limits as to how much Se may be included into the diet and this restricts flexibility in terms of addressing the Se needs of the developing and reproducing swine. The analysis of data of various boar trials with different Se sources indicates that in some cases when background Se levels were low, there were advantages of Se dietary supplementation. It is necessary to take into account that only an optimal Se status of animals is associated with the best antioxidant protection and could have positive effects on boar semen production and its quality. However, in many cases, background Se levels were not determined and therefore, it is difficult to judge if the basic diets were deficient in Se. It can also be suggested that, because of higher efficacy of assimilation from the diet, and possibilities of building Se reserves in the body, organic selenium in the form of selenomethionine (SeMet) provided by a range of products, including Se-Yeast and SeMet preparations is an important source of Se to better meet the needs of modern pig genotypes in commercial conditions of intensive pig production. PMID- 25924966 TI - Elevated blood lipids are uncommon in patients with post-polio syndrome--a cross sectional study. AB - BACKGROUND: The post-polio syndrome occurs in people who previously have had poliomyelitis. After the initial recovery, new or increasing neurologic symptoms occur. Inflammation and dyslipidaemia may play an important role in the development of atherosclerotic complications, for example myocardial infarction and angina pectoris. Previous studies on cardiovascular risk factors in the post polio syndrome have found a higher prevalence of hypertension, ischemic heart disease, hyperlipidaemia, and stroke in these patients. The present study was undertaken in order to evaluate whether post-polio patients have elevated lipid values, and if blood lipid abnormalities could be correlated to signs of inflammation. METHODS: Cross-sectional study of 89 consecutive post-polio patients, (53 women, mean age 65 years) from the Post-Polio Outpatient Clinic, Danderyd University Hospital, Stockholm, Sweden. The lipid profiles of post-polio patients were compared to age and sex matched reference values from two earlier studies. Statistical analyses were performed by the Student's t-test, and linear regression analyses were assessed by Pearson's correlation coefficient. RESULTS: Mean total cholesterol levels (5.7 mmol/L) were low or normal in post-polio patients, whereas low density lipoprotein levels (3.6 mmol/L) were normal, and high density lipoprotein (1.5 mmol/L) and triglycerides (1.4 mmol/L) lower than reference values. The prevalence of diabetes (7%), hypertension (38%), concomitant cardiovascular disease, (including angina pectoris, myocardial infarction, heart failure, atrial fibrillation and stroke) (7%), and calculated 10 year risk of coronary heart disease according to Framingham risk score algorithm (8%) was not increased in post-polio patients. CONCLUSIONS: Compared to reference populations, post-polio patients in Sweden appear to have low or normal total cholesterol and low density lipoprotein levels, whereas high density lipoprotein and triglyceride levels are low. Hence, a possible persisting inflammatory process in post-polio syndrome does not seem to be associated with increased lipids and an increased risk for coronary heart disease events. PMID- 25924967 TI - Saccharification of sunflower stalks using lignocellulases from a fungal consortium comprising Pholiota adiposa and Armillaria gemina. AB - Lignocellulases from Armillaria gemina and Pholiota adiposa are efficient in hydrolyzing aspen and poplar biomass, respectively. In the present study, lignocellulosic enzymes obtained from a fungal consortium comprising P. adiposa and A. gemina were used for the saccharification of sunflower stalks. Sunflower stalks were thermochemically pretreated using 2 % NaOH at 50 degrees C for 24 h. The saccharification process parameters including substrate concentration, enzyme loading, pH, and temperature were optimized using response surface methodology to improve the saccharification yield. The highest enzymatic hydrolysis (84.3 %) was obtained using the following conditions: enzyme loading 10 FPU/g-substrate, substrate 5.5 %, temperature 50 degrees C, and pH 4.5. The hydrolysis yield obtained using the enzymes from the fungal consortium was equivalent to that obtained using a mixture of commercial enzymes Celluclast and Novozyme beta glucosidase. Addition of up to 500 ppm of heavy metal ions (As, Cu, Fe, Mn, Ni, Pb, and Zn) during saccharification did not significantly affect the saccharification yield. Thus, the biomass grown for phytoremediation of heavy metals can be used for the production of reducing sugars followed by ethanol fermentation. PMID- 25924968 TI - Immobilization of beta-galactosidase from Lactobacillus plantarum HF571129 on ZnO nanoparticles: characterization and lactose hydrolysis. AB - beta-Galactosidase from Lactobacillus plantarum HF571129 was immobilized on zinc oxide nanoparticles (ZnO NPs) using adsorption and cross-linking technique. Immobilized beta-galactosidase showed broad-spectrum pH optima at pH 5-7.5 and temperature 50-60 degrees C. Fourier transform infrared spectroscopy (FTIR) and field emission scanning electron microscopy (FESEM) showed that beta galactosidase successfully immobilized onto supports. Due to the limited diffusion of high molecular weight substrate, K m of immobilized enzyme slightly increased from 6.64 to 10.22 mM, while V max increased from 147.5 to 192.4 umol min(-1) mg(-1) as compared to the soluble enzyme. The cross-linked adsorbed enzyme retained 90 % activity after 1-month storage, while the native enzyme showed only 74 % activity under similar incubation conditions. The cross-linked beta-galactosidase showed activity until the seventh cycle and maintained 88.02 % activity even after the third cycle. The activation energy of thermal deactivation from immobilized biocatalyst was 24.33 kcal/mol with a half-life of 130.78 min at 35 degrees C. The rate of lactose hydrolysis for batch and packed bed was found to be 0.023 and 0.04 min(-1). PMID- 25924969 TI - Impact of hand-foot skin reaction on treatment outcome in patients receiving capecitabine plus erlotinib for advanced pancreatic cancer: a subgroup analysis from AIO-PK0104. AB - BACKGROUND: Drug-induced skin toxicity may correlate with treatment efficacy in cancer patients receiving chemotherapy or biological agents. The correlation of the capecitabine-associated hand-foot skin reaction (HFS) on outcome parameters in pancreatic cancer (PC) has not yet been investigated. METHODS: Within the multicentre phase III AIO-PK0104 trial, patients with confirmed advanced PC were randomly assigned to first-line treatment with either capecitabine plus erlotinib (150 mg/day, arm A) or gemcitabine plus erlotinib (150 mg/day, arm B). A cross over to either gemcitabine (arm A) or capecitabine (arm B) was performed after failure of the first-line regimen. Data on skin toxicity were correlated with efficacy study endpoints using uni- and multivariate analyses. To control for guarantee-time bias (GTB), we focused on subgroup analyses of patients who had completed two and three or more treatment cycles. RESULTS: Of 281 randomised patients, skin toxicity data were available for 255 patients. Median time to capecitabine-attributed HFS was two cycles, 36 of 47 (77%) HFS events had been observed by the end of treatment cycle three. Considering HFS during first-line treatment in 101 patients treated with capecitabine for at least two cycles within the capecitabine plus erlotinib arm, time to treatment failure after first and second-line therapy (TTF2) and overall survival (OS) both were significantly prolonged for the 44 patients (44%) with HFS compared to 57 patients without HFS (56%) (TTF2: 7.8 vs. 3.8 months, HR 0.50, p = 0.001; OS: 10.4 vs. 5.9 months, HR 0.55, p = 0.005). A subgroup analysis of 70 patients on treatment with capecitabine for at least three cycles showed similar results (TTF2: 8.3 vs. 4.4 months, HR 0.53, p = 0.010; OS: 10.4 vs. 6.7 months, HR 0.62, p = 0.056). CONCLUSION: The present subgroup analysis from AIO-PK0104 suggests that HFS may serve as an independent clinical predictor for treatment outcome in capecitabine treated patients with advanced PC. PMID- 25924970 TI - Nationwide improvement of rectal cancer treatment outcomes in Norway, 1993-2010. AB - BACKGROUND: The Norwegian Rectal Cancer Project was initated in 1993 with the aims of improving surgery, decreasing local recurrence rates, improving survival, and establishing a national rectal cancer registry. Here we present results from the Norwegian Colorectal Cancer Registry (NCCR) from 1993 to 2010. MATERIAL AND METHODS: A total of 15 193 patients were diagnosed with rectal cancer in Norway 1993-2010, and were registered with clinical data regarding diagnosis, treatment, locoregional recurrences and distant metastases. Of these, 10 796 with non metastatic disease underwent tumour resection. The results were stratified into five time periods, and the treatment outcomes were compared. Recurrence rates are presented for the 9785 patients who underwent curative major resection (R0/R1). RESULTS: Among all 15 193 patients, relative five-year survival increased from 54.1% in 1993-1997 to 63.4% in 2007-2010 (p < 0.001). Among the 10 796 patients with stage I-III disease who underwent tumour resection, from 1993-1997 to 2007 2010, relative five-year survival improved from 71.2% to 80.6% (p < 0.001). An increasing proportion of these patients underwent surgery at large-volume hospitals; and 30- and 100-day mortality rates, respectively, decreased from 3.0% to 1.4% (p < 0.001) and from 5.1% to 3.0% (p < 0.011). Use of preoperative chemoradiotherapy increased from 6.5% in 1993 to 39.0% in 2010 (p < 0.001). Estimated local recurrence rate after major resection (R0/R1) decreased from 14.5% in 1993-1997 to 5.0% in 2007-2009 (p < 0.001), and distant recurrence rate decreased from 26.0% to 20.2% (p < 0.001). CONCLUSION: Long-term outcomes from a national population-based rectal cancer registry are presented. Improvements in rectal cancer treatment have led to decreased recurrence rates of 5% and increased survival on a national level. PMID- 25924971 TI - Diagnostic imaging of intra-abdominal cyst in heifer using the computed tomography. AB - A 10-month-old Japanese black heifer was diagnosed as having an intra-abdominal cyst using computed tomography (CT). Through a posterior ventral midline incision, the cyst was removed, and the heifer completely recovered after the surgery. CT scans enabled detection of the intra-abdominal cyst and measurements of the diameter of the cyst before the surgery. PMID- 25924972 TI - A molecular material based on electropolymerized cobalt macrocycles for electrocatalytic hydrogen evolution. AB - An electrocatalytic material for the H2 evolution reaction (HER) in acidic aqueous solution has been prepared by electropolymerization of Co(ii) dibenzotetraaza[14] annulene (CoTAA). Chemical analysis by X-ray photoelectron spectroscopy (XPS) confirms that the structural integrity of the [Co(II)-N4] motif is preserved in the poly-CoTAA film. In acetate buffer solution at pH 4.6, an overpotential eta = -0.57 V is required to attain a catalytic current density ik = 1 mA cmgeom(-2). The faradaic efficiency of poly-CoTAA for the HER is 90% over a period of one hour of electrolysis, but there is a decrease of the apparent concentration of Co sites after prolonged H2 production, which we ascribe to partial demetallation of the poly-CoTAA film at negative potentials. PMID- 25924973 TI - Silica-based liquid marbles as microreactors for the silver mirror reaction. AB - Little attention has been paid to the participation of the shell of silica particle-based liquid marbles and their influence on chemical reactions. The fabrication of liquid marbles with the encapsulating particle shells not only act as protecting layers to provide a confined environment, but also provide the reactive substrate surfaces to regulate the classical silver mirror reaction. Fabrication of silver mirrors with different morphologies was achieved by modifying particle surface properties, which could further lead to Janus liquid marbles. The different evaporation behavior of microreactors was demonstrated. Micrometer-sized silica particles were used for the preparation of monolayer stabilized liquid marbles, which show great potential in fabricating Janus particles from superhydrophobic particles that are not attainable from Pickering emulsions. PMID- 25924974 TI - Assessment of Small Airways with Computed Tomography: Mosaic Attenuation or Lung Density? AB - BACKGROUND: Computed tomography (CT) assessment of air trapping has been considered useful as a measure of small airway disease. Mean lung density (MLD) and the percentage of the lung field occupied by low attenuation area (LAA%) can be evaluated automatically, and their expiratory/inspiratory (E/I) ratios correlate with asthma severity and spirometry parameters. However, mosaic attenuation, another indicator of air trapping, has been assessed visually, and its functional relevance remains controversial. OBJECTIVES: This retrospective study was conducted to correlate mosaic attenuation, which was assessed visually and automatically, and the E/I ratios of MLD and LAA% (defined as areas <-960 Hounsfield units) with clinical and physiological variables, including impulse oscillometry (IOS) indices. MATERIAL AND METHODS: In 36 nonsmoking patients with stable asthma, the lungs were scanned at full inspiration and full expiration. Mosaic attenuation was measured visually and automatically, by counting areas with CT values higher than the surrounding areas. MLD and LAA% were measured using our validated method. Spirometry, IOS, exhaled NO and the sputum eosinophil count were evaluated. RESULTS: The automatic results and visual scores of mosaic attenuation correlated well on expiratory scans (r = 0.894) and to a lesser degree on inspiratory scans (r = 0.629; p < 0.0001 for both). However, only the E/I ratios of MLD and LAA% correlated with forced expiratory volume in 1 s/forced vital capacity of spirometry and the IOS indices of resistance from 5 to 20 Hz and the integrated area of low-frequency reactance. CONCLUSIONS: Our automatic method for analysis of mosaic attenuation is likely useful, but the results themselves may not be reflecting small airway involvement of asthma, unlike the E/I ratios of MLD and LAA%. PMID- 25924975 TI - Incorporation of individual-patient data in network meta-analysis for multiple continuous endpoints, with application to diabetes treatment. AB - Availability of individual patient-level data (IPD) broadens the scope of network meta-analysis (NMA) and enables us to incorporate patient-level information. Although IPD is a potential gold mine in biomedical areas, methodological development has been slow owing to limited access to such data. In this paper, we propose a Bayesian IPD NMA modeling framework for multiple continuous outcomes under both contrast-based and arm-based parameterizations. We incorporate individual covariate-by-treatment interactions to facilitate personalized decision making. Furthermore, we can find subpopulations performing well with a certain drug in terms of predictive outcomes. We also impute missing individual covariates via an MCMC algorithm. We illustrate this approach using diabetes data that include continuous bivariate efficacy outcomes and three baseline covariates and show its practical implications. Finally, we close with a discussion of our results, a review of computational challenges, and a brief description of areas for future research. PMID- 25924977 TI - Medicinal Chemists of the 21(st) Century--Who Are We and Where to Go? AB - Many recent articles have dealt with the future challenges in medicinal chemistry. Here, I discuss my concerns over the future of medicinal chemists, who have to be skilled and knowledgeable in many different fields, particularly in the context of the ever-growing requirements, the request for even broader diversification, and the substantial structural change in industrial drug discovery. In my opinion, we have to do the following in order to ensure sustained high quality and achievements: 1) to focus on superior design without excluding complex structures a priori; 2) to proactively shape the future of our discipline; 3) to discuss specialization; 4) to intensify exchange between academia and industry; and 5) to remodel education of the next generation of medicinal chemists. By providing my opinion on these aspects, I hope to stimulate discussions and change within the community. PMID- 25924976 TI - Predicting childhood effortful control from interactions between early parenting quality and children's dopamine transporter gene haplotypes. AB - Children's observed effortful control (EC) at 30, 42, and 54 months (n = 145) was predicted from the interaction between mothers' observed parenting with their 30 month-olds and three variants of the solute carrier family C6, member 3 (SLC6A3) dopamine transporter gene (single nucleotide polymorphisms in intron8 and intron13, and a 40 base pair variable number tandem repeat [VNTR] in the 3' untranslated region [UTR]), as well as haplotypes of these variants. Significant moderating effects were found. Children without the intron8-A/intron13-G, intron8 A/3'-UTR VNTR-10, or intron13-G/3'-UTR VNTR-10 haplotypes (i.e., haplotypes associated with the reduced SLC6A3 gene expression and thus lower dopamine functioning) appeared to demonstrate altered levels of EC as a function of maternal parenting quality, whereas children with these haplotypes demonstrated a similar EC level regardless of the parenting quality. Children with these haplotypes demonstrated a trade-off, such that they showed higher EC, relative to their counterparts without these haplotypes, when exposed to less supportive maternal parenting. The findings revealed a diathesis-stress pattern and suggested that different SLC6A3 haplotypes, but not single variants, might represent different levels of young children's sensitivity/responsivity to early parenting. PMID- 25924978 TI - Population Growth and Allergen Content of Cultured Euroglyphus maynei House Dust Mites. AB - BACKGROUND: The house dust mite, Euroglyphus maynei, occurs in homes worldwide and is an important source of many allergens. Many patients sensitive to Dermatophagoides farinae and D. pteronyssinus are also sensitive to E. maynei. Extracts to detect sensitivity to E. maynei and reagents to detect E. maynei allergens in the environment or in cultures are not readily available. Information for the culture of E. maynei and for the determination of allergen and endotoxin levels in cultures is limited. METHOD: We mass cultured E. maynei at 23 and 30 degrees C and determined the population growth profiles from inoculation until cultures could be harvested for the production of extracts. We also developed an ELISA to measure Eur m 1 and Eur m 2 allergens using mouse monoclonal antibodies directed at cross-reacting epitopes of group 1 and group 2 allergens of D. farinae and D. pteronyssinus. RESULTS: The E. maynei populations grew exponentially at both 23 and 30 degrees C; however, the cultures matured more rapidly at 23 degrees C. The Eur m 1 and Eur m 2 allergen concentrations in culture extracts changed independently as the cultures grew and matured. At both temperatures, the Eur m 1 concentrations increased as the cultures matured, while the Eur m 2 concentrations did not. The endotoxin levels in these cultures were low. CONCLUSION: We report here that E. maynei can be cultured at 23 and 30 degrees C. Monoclonal antibodies directed at cross-reacting epitopes on Dermatophagoides allergens can be used to measure the associated E. maynei allergen levels in these cultures. PMID- 25924979 TI - The economic impact of amyotrophic lateral sclerosis: a systematic review. AB - Amyotrophic lateral sclerosis (ALS) is a devastating neurological disease for which there is no cure, and the associated economic burden is considerable. In this review, the authors summarize the existing body of literature pertaining to the costs associated with ALS to demonstrate the scale and scope of the economic burden of this paralyzing disease. Twelve studies from eight countries published between January 2001 and January 2015 met the inclusion criteria and were included in this review. Direct and indirect costs varied significantly across countries. Standardized to the 2015 US$, the annual total cost per patient ranged from US$ 13,667 in Denmark to as high as US$ 69,475 in the USA, with the national economic burden of ALS estimated at US$ 279-472 million in the USA. Costs associated with ALS were greater than that of other neurological diseases, indicating a continued need for medical advances and financial support for patients and families. Regional cost analyses are necessary to determine how best to spend funds that have been raised globally from the ice bucket phenomenon. PMID- 25924981 TI - CD20-Positive nodal natural killer/T-cell lymphoma with cutaneous involvement. AB - CD20-positive natural killer (NK)/T-cell lymphoma is extremely rare. We describe a case of a CD20-positive nodal NK/T-cell lymphoma with cutaneous involvement in a 32-year-old man. The patient presented with fever, night sweats, right inguinal lymphadenopathy and multiple violaceous to erythematous nodules and plaques on the back and bilateral legs. Immunohistochemical analysis showed diffusely and strongly positive staining for CD3, CD3 epsilon, CD43, CD56, TIA-1 and CD20 but negative staining for other B-cell markers, including CD79a and PAX-5 and T-cell markers CD5 and CD7. The tumor cell nuclei were diffusely positive for Epstein Barr virus-encoded RNA in situ hybridization. A partial clinical response was observed after chemotherapy, indicated by the decreased size of the lymph nodes and skin lesions. It is a diagnostic challenge to deal with lymphoma cells that present with the surface proteins of both T- and B-cells. PMID- 25924980 TI - Treatment of osteonecrosis of the femoral head with focal anatomic-resurfacing implantation (HemiCAP): preliminary results of an alternative option. AB - BACKGROUND: The optimal treatment of osteonecrosis of the femoral head has not been established yet. The aim of this study was to report preliminary clinical results of focal anatomic-resurfacing implantation for the treatment of osteonecrosis of the femoral head. METHODS: Five patients (four male, one female) with seven surgical procedures, ages between 37 and 52 with an average age of 45.2 (+/- 7.2), diagnosed as femoral head avascular necrosis and who were unresponsive to conservative management or had failed previous surgical treatments were treated with a focal anatomic femoral head resurfacing between the years 2011-2012 and were retrospectively reviewed. Five patients with at least two years of follow-up, one left hip, two right hips, and two patients with bilateral hip surgery were included in this review. After safe surgical dislocation of the hip, full exposure of the femoral head was established. A focal-resurfacing implant matching patient anatomy and femoral head curvature was performed accordingly. Neither intraoperative or postoperative complications nor revision ensued. Visual analogue scores and Harris Hip Scores were recorded both preoperatively and at postoperative 2 years for all seven surgeries. RESULTS: The mean follow-up period was 26.6 +/- 3.8 months, with a range between 24-33 months. The mean visual analogue scores were 8.9 +/- 0.9 preoperatively and 2.3 +/- 1.0 postoperatively at year two (p = 0.017). Harris Hip Scores at postoperative follow-up were found to improve significantly from good to excellent scores (86.0 +/- 7.9), compared with preoperative poor scores (26.7 +/- 11.8) (p = 0.018). The clinical improvements in visual analogue scores (VAS) and Harris Hip Scores were also found to correlate with each other (p < 0.05). CONCLUSIONS: In the present study, the alternative technique of focal anatomic hip resurfacing with HemiCAP(r) yielded preliminary successful results for the treatment of osteonecrosis of the femoral head. To the best of our knowledge, this is the first case series in the literature, reporting functional clinical results with the use of a focal anatomic-resurfacing implant for the treatment of focal femoral head osteonecrosis. PMID- 25924982 TI - Proline-poor hydrophobic domains modulate the assembly and material properties of polymeric elastin. AB - Elastin is a self-assembling extracellular matrix protein that provides elasticity to tissues. For entropic elastomers such as elastin, conformational disorder of the monomer building block, even in the polymeric form, is essential for elastomeric recoil. The highly hydrophobic monomer employs a range of strategies for maintaining disorder and flexibility within hydrophobic domains, particularly involving a minimum compositional threshold of proline and glycine residues. However, the native sequence of hydrophobic elastin domain 30 is uncharacteristically proline-poor and, as an isolated polypeptide, is susceptible to formation of amyloid-like structures comprised of stacked beta-sheet. Here we investigated the biophysical and mechanical properties of multiple sets of elastin-like polypeptides designed with different numbers of proline-poor domain 30 from human or rat tropoelastins. We compared the contributions of these proline-poor hydrophobic sequences to self-assembly through characterization of phase separation, and to the tensile properties of cross-linked, polymeric materials. We demonstrate that length of hydrophobic domains and propensity to form beta-structure, both affecting polypeptide chain flexibility and cross-link density, play key roles in modulating elastin mechanical properties. This study advances the understanding of elastin sequence-structure-function relationships, and provides new insights that will directly support rational approaches to the design of biomaterials with defined suites of mechanical properties. PMID- 25924984 TI - Effects of donor age, long-term passage culture, and cryopreservation on tonsil derived mesenchymal stem cells. AB - OBJECTIVES: Human mesenchymal stem cells (MSCs) are efficacious in various cellular therapeutic applications and have been isolated from several tissues. Recent studies have reported that human tonsil tissue contains a new source of progenitor cells, potentially applicable for cell-based therapies. Information about the effects of donor age, long-term passage and cryopreservation are essential for clinical applications and cell-based therapies. Therefore, the authors investigated how the morphology, cell-surface markers, proliferation potential and differentiation capacity of tonsil-derived MSCs (T-MSCs) were affected by donor age, long-term passage, and cryopreservation. MATERIALS AND METHODS: T-MSCs were isolated from tonsillar tissue of 20 patients undergoing tonsillectomy. Authors evaluated the effects of donor-age, long-term passage, and cryopreservation on the morphology, surface markers, proliferation potential and differentiation capacities of T-MSCs. RESULTS: T-MSCs exhibited a fibroblast like, spindle-shaped appearance. There were no significant morphological differences according to donor age, long-term passage or cryopreservation. T-MSCs isolated from donors of various ages were positive for markers CD90, CD44, and CD73, but negative for CD45, CD31, and HLA-DR. There were no significant differences in the expression of positive and negative surface markers as a function of donor age, long-term passage and cryopreservation. T-MSCs from different donor age groups showed similar proliferation potentials after passage 2. After long-term passage and cryopreservation, there were no significant morphological differences. Cryopreservation did not affect the proliferation potential of T-MSCs, but there was a significant decrease in the proliferation potential in long-term passage T-MSCs (passage 15). The effect of donor age, long term passage and cryopreservation on the in vitro adipogenic, osteogenic, and chondrogenic differentiation potential of T-MSCs was not significant. CONCLUSION: The effect of donor age, long-term passage culture, and cryopreservation on T-MSC properties are negligible, except for the proliferation capacity of long-term cultured T-MSCs. Therefore, T-MSCs are considered to be promising MSCs that can be used as future alternative sources for autologous or allogenic MSCs. PMID- 25924985 TI - An easy 'Filter-and-Separate' method for enantioselective separation and chiral sensing of substrates using a biomimetic homochiral polymer. AB - We present a polyfluorene appended with protected l-glutamic acid that exhibited a reversible alpha-helix/beta-sheet-like conformation and helical porous fibrous morphology mimicking the super-structure of proteins. The new homochiral polymer probe enabled efficient heterogeneous enantioselective separation and chiral sensing of a wide variety of substrates from their aqueous racemic mixture using an easy 'Filter-and-Separate' method. PMID- 25924983 TI - Transciptome analysis reveals flavonoid biosynthesis regulation and simple sequence repeats in yam (Dioscorea alata L.) tubers. AB - BACKGROUND: Yam (Dioscorea alata L.) is an important tuber crop and purple pigmented elite cultivar has recently become popular because of associated health benefits. Identifying candidate genes responsible for flavonoid biosynthesis pathway (FBP) will facilitate understanding the molecular mechanism of controlling pigment formation in yam tubers. Here, we used Illumina sequencing to characterize the transcriptome of tubers from elite purple-flesh cultivar (DP) and conventional white-flesh cultivar (DW) of yam. In this process, we also designed high quality molecular markers to assist molecular breeding for tuber trait improvement. RESULTS: A total of 125,123 unigenes were identified from the DP and DW cDNA libraries, of which about 49.5% (60,020 unigenes) were annotated by BLASTX analysis using the publicly available protein database. These unigenes were further annotated functionally and subject to biochemical pathway analysis. 511 genes were identified to be more than 2-fold (FDR < 0.05) differentially expressed between the two yam cultivars, of which 288 genes were up-regulated and 223 genes were down-regulated in the DP tubers. Transcriptome analysis detected 61 unigenes encoding multiple well-known enzymes in the FBP. Furthermore, the unigenes encoding chalcone isomerase (CHS), flavanone 3-hydroxylase (F3H), flavonoid 3'-monooxygenase (F3'H), dihydroflavonol 4-reductase (DFR), leucoanthocyanidin dioxygenase (LDOX), and flavonol 3-O-glucosyltransferase (UF3GT) were found to be significantly up-regulated in the DP, implying that these genes were potentially associated with tuber color formation in this elite cultivar. The expression of these genes was further confirmed by qRT-PCR. Finally, 11,793 SSRs were successfully identified with these unigenes and 6,082 SSR markers were developed using Primer 3. CONCLUSIONS: This study provides the first comprehensive transcriptomic dataset for yam tubers, which will significantly contribute to genomic research of this and other related species. Some key genes associated with purple-flesh trait were successfully identified, thus providing valuable information about molecular process of regulating pigment accumulation in elite yam tubers. In the future, this information might be directly used to genetically manipulate the conventional white-fleshed tuber cultivars to enable them to produce purple flesh. In addition, our SSR marker sets will facilitate identification of QTLs for various tuber traits in yam breeding programs. PMID- 25924986 TI - Increased metabolic risk in adolescent offspring of mothers with type 1 diabetes: the EPICOM study. AB - AIMS/HYPOTHESIS: We aimed to investigate metabolic risk factors, insulin sensitivity and insulin secretion in adolescent offspring of mothers with type 1 diabetes compared with offspring of non-diabetic mothers. METHODS: During 1993 1999, pregnancies of women with type 1 diabetes in Denmark were prospectively reported to a central registry in the Danish Diabetes Association. Data included information on maternal demography, diabetes status and pregnancy outcome. We invited 746 eligible children from this cohort (index offspring) to a follow-up examination. Control offspring were identified through The Danish Central Office of Civil Registration and matched with respect to date of birth, sex and postal code. Anthropometric measurements and blood sampling for metabolic characterisation, including an oral glucose tolerance test, were performed. RESULTS: We examined 278 index offspring (mean age 16.7 years; range 13.0-19.8 years) and 303 control offspring (mean age 16.8 years; range 13.5-20.4 years). Index offspring had higher BMI SD score (0.44: 95% CI 0.21, 0.66) compared with controls, after adjustments for pubertal development and maternal pre-pregnancy BMI. Furthermore, index offspring had a higher prevalence of components included in metabolic syndrome and prediabetes (impaired fasting glucose and/or impaired glucose tolerance), with reduced insulin sensitivity and relative insulin secretion deficiency, compared with controls. Maternal HbA1c levels in pregnancy were not directly associated with offspring metabolic outcomes. CONCLUSIONS/INTERPRETATION: Adolescent offspring of mothers with type 1 diabetes had a less favourable metabolic profile and higher frequency of prediabetes than the background population. Significant associations between these outcomes and maternal HbA1c levels in pregnancy could not be demonstrated. TRIAL REGISTRATION: ClinicalTrials.gov NCT01559181. PMID- 25924987 TI - Incidence and remission of type 2 diabetes in relation to degree of obesity at baseline and 2 year weight change: the Swedish Obese Subjects (SOS) study. AB - AIMS/HYPOTHESIS: The aim of this work was to analyse the rates of incidence and remission of type 2 diabetes in relation to baseline BMI and weight change in the prospective, controlled Swedish Obese Subjects (SOS) study. METHODS: Three thousand four-hundred and eighty-five obese individuals receiving bariatric surgery or conventional treatment were grouped into four baseline BMI categories (<35, 35-40, 40-45 or >= 45 kg/m(2)) and five weight-change categories according to their BMI at 2 years (increase [>= 1 BMI unit increase], no change [less than 1 BMI unit change], minor reduction [-1 to -9 BMI units], medium reduction [-10 to -14 BMI units] and major reduction [< -15 BMI units]). The incidence and remission of diabetes at 2 years was assessed. RESULTS: Among individuals with no weight change, diabetes incidence rates were 5.5%, 7.4%, 8.3% and 5.2%, in the four baseline BMI categories, respectively. In those with an initial BMI of 35 40, 40-45 and >= 45 kg/m(2) who attained a minor reduction in weight, the corresponding rates were 1.3%, 1.2% and 3.4%, respectively. In both the medium- and major-weight-reduction groups, diabetes incidence was <= 0.5%. Among individuals with diabetes at baseline, the remission rates were 15.3-26.9% in the no-weight-change groups, and 48.1-70% for individuals who attained a minor weight reduction. In the medium- and major-weight-reduction groups, the remission rate was 77-97%. There were no differences in 2 year incidence and remission rates between different baseline BMI groups that achieved the same degree of weight reduction. CONCLUSIONS/INTERPRETATION: In obese individuals, the favourable effect of weight reduction on type 2 diabetes incidence and remission is independent of initial BMI. Trial registration ClinicalTrials.gov number NCT01479452. PMID- 25924988 TI - Established and Potential Predictive Biomarkers in Gastrointestinal Cancer--c Kit, Her2, Ras and Beyond. AB - BACKGROUND: Gastrointestinal cancers are among the leading causes of cancer related deaths worldwide. In different tumor types, personalized systemic treatment strategies based upon biomarker-selection were established over the last years. Although there is a flood of targeted agents in clinical development, only a few targeted agents with a predictive biomarker could be established for the treatment of patients with gastrointestinal cancer patients so far. SUMMARY: Currently, predictive biomarkers for gastrointestinal cancers include Her2 overexpression or amplification (gastroesophageal adenocarcinoma), c-Kit overexpression (gastrointestinal stromal tumors) and RAS wild-type (colorectal cancer). Selection of patients based on these biomarkers allows the efficient use of targeted agents. The presence of a BRAF mutation and/or high microsatellite instability is prognostic and rather a predictive marker in CRC. Promising candidate markers in advanced clinical development are MET amplification in gastroesophageal adenocarcinoma, Met overexpression and high AFP serum levels in hepatocellular carcinoma. KEY MESSAGE: Biomarker-guided systemic treatment is established in a subset of patients with gastrointestinal cancer. Ongoing clinical trials and further advances in high-throughput technologies will hopefully result in more personalized systemic treatment strategies for these patients in the near future. PMID- 25924989 TI - Identification and Characterization of Terpene Synthases Potentially Involved in the Formation of Volatile Terpenes in Carrot (Daucus carota L.) Roots. AB - Plants produce an excess of volatile organic compounds, which are important in determining the quality and nutraceutical properties of fruit and root crops, including the taste and aroma of carrots (Daucus carota L.). A combined chemical, biochemical, and molecular study was conducted to evaluate the differential accumulation of volatile terpenes in a diverse collection of fresh carrots (D. carota L.). Here, we report on a transcriptome-based identification and functional characterization of two carrot terpene synthases, the sesquiterpene synthase, DcTPS1, and the monoterpene synthase, DcTPS2. Recombinant DcTPS1 protein produces mainly (E)-beta-caryophyllene, the predominant sesquiterpene in carrot roots, and alpha-humulene, while recombinant DcTPS2 functions as a monoterpene synthase with geraniol as the main product. Both genes are differentially transcribed in different cultivars and during carrot root development. Our results suggest a role for DcTPS genes in carrot aroma biosynthesis. PMID- 25924990 TI - Inhaled beta-agonist does not modify sympathetic activity in patients with COPD. AB - BACKGROUND: Neurohumoral activation is present in COPD and might provide a link between pulmonary and systemic effects, especially cardiovascular disease. Because long acting inhaled beta-agonists reduce hyperinflation, they could reduce sympathoexcitation by improving the inflation reflex. We aimed to evaluate if inhaled therapy with salmeterol reduces muscle sympathetic nerve activity (MSNA) evaluated by microneurography. METHODS: MSNA, heart rate, blood pressure, and respiration were continually measured. After baseline recording of 20 minutes, placebo was administered; after further 45 minutes salmeterol (50 MUg) was administered which was followed by a further 45 minutes of data recording. Additionally, lung function, plasma catecholamine levels, arterial pulse wave velocity, heart rate variability, and baroreflex sensitivity were evaluated. Following 4 weeks of treatment with salmeterol 50 MUg twice daily, measurements were repeated without placebo administration. RESULTS: A total of 32 COPD patients were included. Valid MSNA signals were obtained from 18 patients. Change in MSNA (bursts/100 heart beats) following acute administration of salmeterol did not differ significantly from the change following placebo (-1.96 +/- 9.81 vs. 0.65 +/- 9.07; p = 0.51) although hyperinflation was significantly reduced. Likewise, no changes in MSNA or catecholamines were observed after 4 weeks. Heart rate increased significantly by 3.8 +/- 4.2 (p < 0.01) acutely and 3.9 +/- 4.3 bpm (p < 0.01) after 4 weeks. Salmeterol treatment was safe and well tolerated. CONCLUSIONS: By using microneurography as a gold standard to evaluate sympathetic activity we found no change in MSNA following salmeterol inhalation. Thus, despite an attenuation of hyperinflation, the long acting beta-agonist salmeterol does not appear to reduce nor incite sympathoexcitation. TRIAL REGISTRATION: This study was registered with the European Clinical Trials Database (EudraCT No. 2011 001581-18) and ClinicalTrials.gov ( NCT01536587 ). PMID- 25924991 TI - Phase I study of ipilimumab in phased combination with paclitaxel and carboplatin in Japanese patients with non-small-cell lung cancer. AB - BACKGROUND: Ipilimumab is an antibody that targets the cytotoxic T-lymphocyte antigen-4 to potentiate an antitumor response. Adding ipilimumab 10 mg/kg to paclitaxel (PTX) and carboplatin (CBDCA) in a phased schedule improved progression-free survival in a phase II non-small-cell lung cancer (NSCLC) study. METHODS: This dose-escalating, phase I study was designed to identify the recommended dose of ipilimumab (3 or 10 mg/kg) by evaluating dose-limiting toxicity (DLT; Cycles 3 and 4) in phased combination with PTX (175 mg/m(2)) and CBDCA (area under the curve = 6) in Japanese patients with advanced NSCLC. Treatment was administered intravenously every 3 weeks initially, followed by some eligible patients receiving maintenance ipilimumab once every 12 weeks. Additional endpoints included safety, tumor response, pharmacokinetics, and immunogenicity. RESULTS: Fifteen patients were enrolled and 12 received ipilimumab (n = 6, 3 mg/kg; n = 6, 10 mg/kg) in combination with PTX and CBDCA. DLTs occurred in 2 patients (ipilimumab 3 mg/kg) and 1 patient (ipilimumab 10 mg/kg). The most common grade 3/4 adverse events (AEs) were decreased hemoglobin, leukopenia, and neutropenia. The most common immune-related AEs affected the skin, gastrointestinal, and nervous system. The safety profile was similar in both cohorts. Three patients in each cohort achieved a partial response. The pharmacokinetic (PK) profile of ipilimumab in Japanese patients was similar to that observed in previous studies in non-Japanese patients. Conclusions The recommended dose of ipilimumab in phased combination with PTX and CBDCA in Japanese patients with NSCLC was identified as 10 mg/kg. The safety profile was consistent with the previously defined AE profile. PMID- 25924992 TI - Oncogenic viruses and cancer. PMID- 25924994 TI - Recent advances in the study of Kaposi's sarcoma-associated herpesvirus replication and pathogenesis. AB - It has now been over twenty years since a novel herpesviral genome was identified in Kaposi's sarcoma biopsies. Since then, the cumulative research effort by molecular biologists, virologists, clinicians, and epidemiologists alike has led to the extensive characterization of this tumor virus, Kaposi's sarcoma associated herpesvirus (KSHV; also known as human herpesvirus 8 (HHV-8)), and its associated diseases. Here we review the current knowledge of KSHV biology and pathogenesis, with a particular emphasis on new and exciting advances in the field of epigenetics. We also discuss the development and practicality of various cell culture and animal model systems to study KSHV replication and pathogenesis. PMID- 25924993 TI - Model systems to study the life cycle of human papillomaviruses and HPV associated cancers. AB - The prevalent human papillomaviruses (HPVs) infect either cutaneous or mucosal epithelium. Active Infections lead to epithelial hyperprolifeation and are usually cleared in healthy individuals within a year. Persistent infections in the anogenital tracts by certain high-risk genotypes such as HPV-16, HPV-18 and closely related types, can progress to high grade dysplasias and carcinomas in women and men, including cervical, vulva, penile and anal cancers. A significant fraction of the head and neck cancers are also caused by HPV-16. The viral oncogenes responsible for neoplastic conversion are E6 and E7 that disrupt the pathways controlled by the two major tumor suppressor genes, p53 and members of pRB family. Because HPV cannot be propagated in conventional submerged monolayer cell cultures, organotypic epithelial raft cultures that generate a stratified and differentiated epithelium have been used to study the viral life cycle. This article describes several systems to examine aspects of the viral productive phase, along with the advantages and limitations. Animal model systems of HPV carcinogenesis are also briefly described. PMID- 25924996 TI - Plasma Pentraxin 3 Is Closely Associated with Peripheral Arterial Disease in Hemodialysis Patients and Predicts Clinical Outcome: A 6-Year Follow-Up. AB - BACKGROUND: The aim of this study is to investigate the value of plasma PTX3 level for assessing peripheral artery disease (PAD) and clinical outcome in hemodialysis (HD) patients. METHODS: The ankle-brachial index (ABI) was measured in HD patients. PTX3 levels in 116 HD patients were measured by ELISA. RESULTS: Overall, 116 HD patients were enrolled; 21 (18%) patients had PAD. Using the ROC curve analysis for PAD, PTX3 (cut-off value 4.06 ng/ml, AUC 0.901, p < 0.0001) showed a significantly better positive predictive value than hsCRP (cut-off value 3.33 ng/ml, AUC 0.640, p < 0.05). During follow-up (mean 57 +/- 26 months), 40 deaths (34%) occurred. Kaplan-Meier analysis found that those patients with elevated PTX3 had a significantly poor outcome (p < 0.0001), and Cox analysis further confirmed that PTX3 was an independent predictor of overall mortality (HR, 1.105, p = 0.03). For prediction of overall mortality, the AUC for PTX3 (cut off value 3.22 ng/ml, AUC 0.690, p < 0.0001) was close to hsCRP (cut-off value 5.84 ng/ml, AUC 0.620, p < 0.001). CONCLUSIONS: For the prediction of PAD in HD patients, the diagnostic sensitivity and specificity of PTX3 were higher than those of hsCRP. Furthermore, PTX3 was also a predictor of all-cause mortality in HD patients. PTX3 may be considered a novel biomarker of inflammation in HD patients. PMID- 25924997 TI - Laboratory, clinical and therapeutic features of respiratory panic disorder subtype. AB - OBJECTIVE: It is our aim to elaborate on the new developments in regard to the respiratory subtype (RS) of panic disorder (PD) since it was first described. We will present psychopathological features, diagnostic criteria, genetic and physiopathological hypotheses, as well as therapeutic and prognostic characteristics. METHOD: Two searches were performed in the Thomson Reuters Web of Knowledge (http://wokinfo.com/): 1 - search terms: "panic disorder" AND ("respiratory symptom" OR "respiratory symptoms" OR "respiratory subtype" OR "respiratory panic" OR "cardiorespiratory"); 2 - all articles citing Briggs and colleagues' 1993 article "Subtyping of Panic Disorder by Symptom Profile" (Br J Psychiatry 1993;163: 201-9). Only those articles involving human subjects and written English were included. RESULTS: In comparison with patients of the non respiratory subtype (NRS), RS patients showed greater familial history of PD, and higher comorbidity rates for anxiety disorders and depressive disorders. These patients were also more sensitive to CO2, hyperventilation and caffeine. CONCLUSION: Certain characteristics, such as heightened sensitivity to CO2 and the higher incidence of a family history of PD, clearly distinguished the Respiratory Subtype patients from the Non-Respiratory. Nonetheless, some studies failed to demonstrate differential responses to pharmacological treatment and CBT across the subtypes. RS patients seem to respond faster than NRS to pharmacological treatment with antidepressants and benzodiazepines, but more studies are needed to confirm this finding. PMID- 25924995 TI - Reduced risk of breast cancer associated with recreational physical activity varies by HER2 status. AB - Convincing epidemiologic evidence indicates that physical activity is inversely associated with breast cancer risk. Whether this association varies by the tumor protein expression status of the estrogen receptor (ER), progesterone receptor (PR), human epidermal growth factor receptor 2 (HER2), or p53 is unclear. We evaluated the effects of recreational physical activity on risk of invasive breast cancer classified by the four biomarkers, fitting multivariable unconditional logistic regression models to data from 1195 case and 2012 control participants in the population-based Women's Contraceptive and Reproductive Experiences Study. Self-reported recreational physical activity at different life periods was measured as average annual metabolic equivalents of energy expenditure [MET]-hours per week. Our biomarker-specific analyses showed that lifetime recreational physical activity was negatively associated with the risks of ER-positive (ER+) and of HER2-negative (HER2-) subtypes (both Ptrend <= 0.04), but not with other subtypes (all Ptrend > 0.10). Analyses using combinations of biomarkers indicated that risk of invasive breast cancer varied only by HER2 status. Risk of HER2-breast cancer decreased with increasing number of MET-hours of recreational physical activity in each specific life period examined, although some trend tests were only marginally statistically significant (all Ptrend <= 0.06). The test for homogeneity of trends (HER2- vs. HER2+ ) reached statistical significance only when evaluating physical activity during the first 10 years after menarche (Phomogeneity = 0.03). Our data suggest that physical activity reduces risk of invasive breast cancers that lack HER2 overexpression, increasing our understanding of the biological mechanisms by which physical activity acts. PMID- 25924998 TI - Poly(ADP-Ribose)Polymerase 1 (PARP-1) Activation and Ca(2+) Permeable alpha-Amino 3-Hydroxy-5-Methyl-4-Isoxazolepropionic Acid (AMPA) Channels in Post-Ischemic Brain Damage: New Therapeutic Opportunities? AB - A significant number of laboratories observed that poly (ADP-ribose) polymerase (PARP) inhibitors, administered a few hours after ischemic or traumatic brain injury, may drastically reduce the subsequent neurological damage. It has also been shown that PARP inhibitors, administered for 24 hours to rats with permanent middle cerebral artery occlusion (MCAO), may reduce the number of dying neurons for a long period after surgery, thus suggesting that these agents could reduce the delayed brain damage and the neurological and cognitive impairment (dementia) frequently observed a few months after a stroke. In organotypic hippocampal slices exposed to N-methyl-N'-nitro-N'-nitrosoguanidine (MNNG), an alkylating agent able to activate PARP, a selective and delayed degeneration of the CA1 pyramidal cells which was anatomically similar to that observed after a short period of oxygen and glucose deprivation (OGD) has been described. Biochemical and electrophysiological approaches showed that MNNG exposure caused an increased expression and function of the calcium permeable alpha-amino- 3-hydroxy-5-methyl 4-isoxazolepropionic acid (AMPA) channels in the CA1 but not in the CA3 hippocampal region. PARP inhibitors prevented this increase and reduced CA1 cell death. The AMPA receptor antagonist 2,3-dihydroxy-6- nitro-7-sulfamoyl benzo[f]quinoxaline-2,3-dione or the selective Ca(2+) permeable AMPA channel blocker 1-Naphthyl acetyl spermine (NASPM), also reduced the MNNG-induced CA1 pyramidal cell death. Since activation of PARP-1 facilitate the expression of Ca(2+) permeable channels and the subsequent delayed cell death, PARP inhibitors administered a few hours after a stroke may not only reduce the early post ischemic brain damage but also the late neuronal death frequently occurring after severe stroke. PMID- 25924999 TI - A retrospective, multi-center cohort study evaluating the severity- related effects of cerebrolysin treatment on clinical outcomes in traumatic brain injury. AB - Traumatic brain injury (TBI) is a leading cause of death and disability for which there is currently no effective drug therapy available. Because drugs targeting a single TBI pathological pathway have failed to show clinical efficacy to date, pleiotropic agents with effects on multiple mechanisms of secondary brain damage could represent an effective option to improve brain recovery and clinical outcome in TBI patients. In this multicenter retrospective study, we investigated severity-related efficacy and safety of the add-on therapy with two concentrations (20 ml/day or 30 ml/day) of Cerebrolysin (EVER Neuro Pharma, Austria) in TBI patients. Adjunctive treatment with Cerrebrolysin started within 48 hours after TBI and clinical outcomes were ranked according to the Glasgow Outcome Scale and the Modified Rankin Disability Score at 10 and 30 days post TBI. Analyses of efficacy were performed separately for subgroups of patients with mild, moderate or severe TBI according to Glasgow Coma Scale scores at admission. Compared to standard medical care alone (control group), both doses of Cerebrolysin were associated with improved clinical outcome scores at 10 days post-TBI in mild patients and at 10 and 30 days in moderate and severe cases. A dose-dependent effect of Cerebrolysin on TBI recovery was supported by the dose related differences and the significant correlations with treatment duration observed for outcome measures. The safety and tolerability of Cerebrolysin in TBI patients was very good. In conclusion, the results of this large retrospective study revealed that early Cerebrolysin treatment is safe and is associated to improved TBI outcome. PMID- 25925000 TI - Lower uric Acid linked with cognitive dysfunction in the elderly. AB - Uric acid has been associated as a risk factor for cardiovascular disease. Recently, however, there is growing evidence that uric acid plays a role as antioxidant in the brain. In cognitive dysfunction, vascular and oxidative stress mechanisms play a role, but the link remains unknown. Therefore, we investigated the link between serum uric acid-levels and cognitive function in 62 elderly subjects. The statistical analysis was adjusted to age, sex and cardiovascular risk factors. Here, we found that lower serum uric acid levels are linked to cognitive dysfunction. In a Mexican population, higher levels of uric acid are associated with a decreased risk of dementia. PMID- 25925001 TI - A phase II study of pemetrexed monotherapy in chemo-naive Eastern Cooperative Oncology Group performance status 2 patients with EGFR wild-type or unknown advanced non-squamous non-small cell lung cancer (HANSHIN Oncology Group 002). AB - PURPOSE: The aim of our study was to investigate the efficacy and safety of pemetrexed monotherapy in chemo-naive Eastern Cooperative Oncology Group (ECOG) performance status (PS) 2 patients with epidermal growth factor receptor (EGFR) wild-type or unknown advanced non-squamous non-small cell lung cancer (NSCLC). METHODS: Pemetrexed was administered at 500 mg/m(2) triweekly until progression with supplementations in chemo-naive ECOG PS 2 patients with EGFR wild-type or unknown advanced non-squamous NSCLC. RESULTS: Between September 2009 and April 2013, twenty-eight patients were enrolled. Median age was 75 (range 59-89). Nineteen (68 %) of 28 were ever smoker, and 18 (64 %) had pulmonary emphysema. Sixteen (57 %) had comorbidities such as hypertension, heart disease, and/or diabetes. In 26 eligible patients, the overall response rate, disease control rate, median PFS, and median overall survival were 11.5, 53.8 %, 3.0 [95 % confidence interval (CI) 1.9-5.7] months and 9.5 (95 % CI 3.3-12.5) months, respectively. Median administered course number was 3 (range 1-14). Median duration of PS maintenance <=2 was 4.9 (95 % CI 1.3-9.7) months. Common (>=10 %) grade 3/4 toxicities included 7 (27 %) neutropenia, 7 (27 %) leukopenia, 4 (15 %) fatigue, and 3 (12 %) thrombocytopenia. Febrile neutropenia and interstitial lung disease were not observed. There were no treatment-related deaths. CONCLUSION: Pemetrexed monotherapy demonstrated moderate efficacy and good safety in chemo naive PS 2 patients with EGFR wild-type or unknown non-squamous NSCLC. It can be a therapeutic option in "frail" PS 2 non-squamous NSCLC patients without the indication of combination regimens, if the patient is EGFR wild-type. PMID- 25925002 TI - Docetaxel in combination with octreotide shows synergistic apoptotic effect by increasing SSTR2 and SSTR5 expression levels in prostate and breast cancer cell lines. AB - PURPOSE: Docetaxel (DTX) is widely used for the treatment of metastatic prostate and breast cancers. Despite the clinical success of DTX, drug-related cumulative toxicity restricts its clinical use in cancer therapy. Thus, there is an urgent need for new therapeutic options. Octreotide (OCT) is a synthetic somatostatin analog that induces apoptosis in different cancer cell lines in vitro. In this study, we investigated the possible synergistic apoptotic effects of DTX in combination with OCT in prostate and breast cancer cell lines. METHODS: The XTT cell viability assay was used to determine cytotoxicity. Apoptosis was evaluated by Cell Death Detection ELISA(Plus) Kit. The expression levels of apoptotic proteins were assessed by human apoptosis antibody array. Levels of SSTR2 and SSTR5 proteins were determined by western blot analysis. RESULTS: DTX and OCT combination induced apoptosis in both breast and prostate cancer cells in a concentration- and time-dependent manner. Moreover, combination treatment resulted in inhibition of anti-apoptotic proteins such as Bcl-2 and Bcl-xL and induction of pro-apoptotic proteins Bax, Cytochrome c and IAPs in all of the tested cancer cell lines. SSTR2 and SSTR5 protein levels were induced as compared to any agent alone. CONCLUSIONS: These results indicate that this combination treatment is a significant inducer of apoptosis in a synergistic manner in breast and prostate cancer cells. This strong synergism helps to lower the dose of DTX in both types of cancers, thus letting DTX to be used for longer periods by delaying resistance development and lesser side effects. PMID- 25925003 TI - Genetic abnormalities in adolescents and young adults with neuroblastoma: A report from the Italian Neuroblastoma group. AB - BACKGROUND: Less than 5% of neuroblastomas (NB) occur in adolescents and young adults (AYA), in whom the disease has an indolent and fatal course. PROCEDURE: We studied the genomic profile and histological characteristics of 34 NBs from AYA patients enrolled in the Italian Neuroblastoma Registry (INBR) between 1979 and 2009. RESULTS: Disease was disseminated in 20 patients and localized in 14; 30/34 tumors were classified as NB and 4/34 as nodular ganglioneuroblastoma (nGNB). Segmental Chromosome Aberrations (SCAs) were observed in 29 tumors (85%) namely 1p imbalance (58%), 17q gain (52%), 9p loss (32%), 11q loss (30%), 1q gain (17%), 7q gain (17%), 2p gain (14%), 3p loss (14%), and 4p loss (7%). MYCN amplification and MYCN gain were detected in 3 (10%) and 2 cases (7%) respectively. An anaplastic lymphoma receptor tyrosine kinase (ALK) gene mutation study on the available cases from this cohort revealed 4/25 (16%) mutated cases. In parallel, alpha thalassaemia/mental retardation syndrome X linked (ATRX) gene mutations were also sought, a novel mutation being detected in 1/21 (4,7%) cases. CONCLUSION: This study confirmed the low incidence of MYCN amplification in AYA and recorded a high frequency of 17q gain and 9p and 11q loss independently from the stage of the disease. The presence of 1q gain, which identifies patients with particularly aggressive disease, relapse and poor survival, was also detected. Furthermore, the frequency of ALK mutations suggests that a target-based therapy with ALK inhibitors might be effective in this subset of patients. PMID- 25925004 TI - Limitations of the linear and the projection approximations in three-dimensional transmission electron microscopy of fully hydrated proteins. AB - We establish expressions for the linear and quadratic terms in the series expansion of the phase and the phase and amplitude object description of imaging thin specimens by transmission electron microscopy. Based on these expressions we simulate the corresponding contributions to images of unstained protein complexes of varying thickness and arrive at an estimate for how much each term contributes to the contrast of the image. From this we can estimate a maximum specimen thickness for which the weak phase and the weak amplitude and phase object approximation (and therefore linear imaging) is still reasonably accurate. When discussing thick specimens it is also necessary to consider limitations due to describing the image as a filtered projection of the specimen, since the different layers of the specimen are not imaged with the same defocus value. We therefore compared simulations based on the projection approximation with the more accurate multislice model of image formation. However, we find that the errors due to nonlinear image contributions are greater than those due to the defocus gradient for the defocus values chosen for the simulations. Finally, we study how the discussed nonlinear image contributions and the defocus gradient affect the quality of three-dimensional reconstructions. We find that three dimensional reconstructions reach high resolution when at the same time exhibiting localized systematic structural errors. PMID- 25925005 TI - Clinical manifestations and risk factors of anastomotic leakage after low anterior resection for rectal cancer. AB - BACKGROUND: Anastomotic leakage is a common complication that can be associated with catastrophic consequences. However, the risk factors and incidence of anastomotic leakage vary considerably among clinical studies because of the lack of a standardized definition, clinical course and appropriate treatment options. The aim of this study was to identify and classify the clinical manifestations and treatment of anastomotic leakage and analyse the possible risk factors after low anterior resection. METHODS: From January 2009 to June 2010, 632 patients underwent low anterior resection for primary colorectal cancer at Samsung Medical Center. Patients with only one colorectal anastomosis were included from this prospectively collected medical database. RESULTS: The overall leakage rate was 6.0% (n = 38). In cases of generalized leakage, the patients that selected surgical management, regardless of having protective enterostomy and time of occurrence, had better outcomes. Protective enterostomy did not have a preventive effect and was not associated with a lower rate of anastomotic leakage. However, protective enterostomy confined the inflammation to only the pelvic cavity (P = 0.045) and no surgical intervention was initially needed. Male gender (P = 0.021, relative risk (RR) = 2.680, 95% confidence interval (CI) = 1.164-6.171) and side to-end/J pouch-to-end anastomosis (P = 0.012, RR = 2.696, 95% CI = 1.249-5.818) were significant risk factors that affected anastomotic leakage. CONCLUSION: Surgical management is the best choice for generalized leakage. A protective enterostomy diminished the occurrence of generalized leakage and consequent surgical management; therefore, fragile patients at high risk for anastomotic leakage are recommended to undergo protective enterostomy. PMID- 25925006 TI - Eliminating the isoleucine biosynthetic pathway to reduce competitive carbon outflow during isobutanol production by Saccharomyces cerevisiae. AB - BACKGROUND: Isobutanol is an important biorefinery target alcohol that can be used as a fuel, fuel additive, or commodity chemical. Baker's yeast, Saccharomyces cerevisiae, is a promising organism for the industrial manufacture of isobutanol because of its tolerance for low pH and resistance to autolysis. It has been reported that gene deletion of the pyruvate dehydrogenase complex, which is directly involved in pyruvate metabolism, improved isobutanol production by S. cerevisiae. However, the engineering strategies available for S. cerevisiae are immature compared to those available for bacterial hosts such as Escherichia coli, and several pathways in addition to pyruvate metabolism compete with isobutanol production. RESULTS: The isobutyrate, pantothenate or isoleucine biosynthetic pathways were deleted to reduce the outflow of carbon competing with isobutanol biosynthesis in S. cerevisiae. The judicious elimination of these competing pathways increased isobutanol production. ILV1 encodes threonine ammonia-lyase, the enzyme that converts threonine to 2-ketobutanoate, a precursor for isoleucine biosynthesis. S. cerevisiae mutants in which ILV1 had been deleted displayed 3.5-fold increased isobutanol productivity. The DeltaILV1 strategy was further combined with two previously established engineering strategies (activation of two steps of the Ehrlich pathway and the transhydrogenase-like shunt), providing 11-fold higher isobutanol productivity as compared to the parent strain. The titer and yield of this engineered strain was 224 +/- 5 mg/L and 12.04 +/- 0.23 mg/g glucose, respectively. CONCLUSIONS: The deletion of competitive pathways to reduce the outflow of carbon, including ILV1 deletion, is an important strategy for increasing isobutanol production by S. cerevisiae. PMID- 25925007 TI - Using theory and formative research to design interventions to improve community health worker motivation, retention and performance in Mozambique and Uganda. AB - BACKGROUND: Community health workers (CHWs) are increasingly being used in low income countries to address human resources shortages, yet there remain few effective, evidence-based strategies for addressing the enduring programmatic constraints of worker motivation, retention and performance. This paper describes how two interventions were designed by the Innovations at Scale for Community Access and Lasting Effects (inSCALE) project to address these constraints in Uganda and Mozambique drawing on behavioural theory and formative research results. METHODS: A review of the work motivation and CHW motivation literature- incorporating influences on retention and performance--was conducted on articles sourced through electronic web searches. Formative research with a focus on the barriers and facilitators to CHW motivation, retention and performance was conducted with community health workers and key stakeholders in Uganda and Mozambique. An analytical induction approach to the thematic analysis of transcripts from 98 in-depth interviews and 26 focus group discussions was adopted across the country settings. RESULTS: From the theoretical review, it was determined that the interventions should promote CHWs as members of a collective by highlighting a sense of shared experience, focus on alignment between worker and programme goals, and emphasise the actions that lead to good performance. The Social Identity Approach was selected as the theory most likely to lead to the development of effective, scalable and sustainable interventions by addressing the identified gap in the literature of the influence of CHW working context. The formative research indicated that CHWs value feedback and feeling connected to the health system and their community, are motivated by status and community standing, and want to be provided with the necessary tools to perform. Two interventions based on these results were developed: a participatory, local community approach and an information communication technology (ICT) approach. CONCLUSIONS: Drawing on contextual data and theory that is sensitive to context can potentially lead to the development of appropriate and effective interventions when aiming to improve the motivation, retention and performance of CHWs in Uganda and Mozambique and other comparable settings. Evaluation of the developed interventions is crucial to assess this potential. PMID- 25925008 TI - Targeting intracellular bacteria with an extended cationic amphiphilic polyproline helix. AB - An extended cationic and amphiphilic polyproline helix (CAPH) is described with a dual mode of action: effective cell penetration of human macrophages, and potent antimicrobial activity in vitro against both Gram-positive and negative pathogens, including Acinetobacter baumannii, Escherichia coli O157 and Bacillus anthracis. This dual action was successfully combined to clear pathogenic bacteria (Brucella and Salmonella) residing within macrophages. PMID- 25925009 TI - Profile Likelihood-Based Confidence Intervals and Regions for Structural Equation Models. AB - Structural equation models (SEM) are widely used for modeling complex multivariate relationships among measured and latent variables. Although several analytical approaches to interval estimation in SEM have been developed, there lacks a comprehensive review of these methods. We review the popular Wald-type and lesser known likelihood-based methods in linear SEM, emphasizing profile likelihood-based confidence intervals (CIs). Existing algorithms for computing profile likelihood-based CIs are described, including two newer algorithms which are extended to construct profile likelihood-based confidence regions (CRs). Finally, we illustrate the use of these CIs and CRs with two empirical examples, and provide practical recommendations on when to use Wald-type CIs and CRs versus profile likelihood-based CIs and CRs. OpenMx example code is provided in an Online Appendix for constructing profile likelihood-based CIs and CRs for SEM. PMID- 25925010 TI - A Finite Mixture of Nonlinear Random Coefficient Models for Continuous Repeated Measures Data. AB - Nonlinear random coefficient models (NRCMs) for continuous longitudinal data are often used for examining individual behaviors that display nonlinear patterns of development (or growth) over time in measured variables. As an extension of this model, this study considers the finite mixture of NRCMs that combine features of NRCMs with the idea of finite mixture (or latent class) models. The efficacy of this model is that it allows the integration of intrinsically nonlinear functions where the data come from a mixture of two or more unobserved subpopulations, thus allowing the simultaneous investigation of intra-individual (within-person) variability, inter-individual (between-person) variability, and subpopulation heterogeneity. Effectiveness of this model to work under real data analytic conditions was examined by executing a Monte Carlo simulation study. The simulation study was carried out using an R routine specifically developed for the purpose of this study. The R routine used maximum likelihood with the expectation-maximization algorithm. The design of the study mimicked the output obtained from running a two-class mixture model on task completion data. PMID- 25925011 TI - CTisus iQuiz App Review. PMID- 25925012 TI - Ventriculobiliary Shunts, Another Option. AB - The basic management of hydrocephalus includes shunts to the peritoneum and atrium. However, there are particularly complex patients in whom it is necessary to look for atypical places for implanting the distal catheter. Since 2000, 1,325 shunts have been implanted in pediatric patients. Only 3 patients required a ventriculobiliary shunt. We report 3 cases: a 7-year-old boy with a surgically treated complex heart disease, a 16-month-old girl with hydrocephalus secondary to a brain tumor and multiple bacteremias secondary to an infection of the central venous reservoir, and a 4-year-old girl with nonreabsorptive hydrocephalus caused by intraventricular bleeding due to premature birth, necrotizing enterocolitis and shunt infections with abdominal pseudocysts, which caused multiple abdominal septations and, finally, a nonreabsorptive peritoneum. At present, cases 1 [45 months after ventriculobiliary shunt (VBS)] and 3 (27 months after VBS) are symptom free, while case 2 (14 months after VBS) died of infectious respiratory complications. The gold standard for the treatment of nonreabsorptive hydrocephalus is a ventriculoperitoneal shunt, the second option is a ventriculoatrial shunt, and the third option is uncertain. In our short experience, a ventriculo-gallbladder shunt is a good option when there is no abdominal hypertension. PMID- 25925014 TI - Cumulative Effects of Foraging Behavior and Social Dominance on Brain Development in a Facultatively Social Bee (Ceratina australensis). AB - In social insects, both task performance (foraging) and dominance are associated with increased brain investment, particularly in the mushroom bodies. Whether and how these factors interact is unknown. Here we present data on a system where task performance and social behavior can be analyzed simultaneously: the small carpenter bee Ceratina australensis. We show that foraging and dominance have separate and combined cumulative effects on mushroom body calyx investment. Female C. australensis nest solitarily and socially in the same populations at the same time. Social colonies comprise two sisters: the social primary, which monopolizes foraging and reproduction, and the social secondary, which is neither a forager nor reproductive but rather remains at the nest as a guard. We compare the brains of solitary females that forage and reproduce but do not engage in social interactions with those of social individuals while controlling for age, reproductive status, and foraging experience. Mushroom body calyx volume was positively correlated with wing wear, a proxy for foraging experience. We also found that, although total brain volume did not vary among reproductive strategies (solitary vs. social nesters), socially dominant primaries had larger mushroom body calyx volumes (corrected for both brain and body size variation) than solitary females; socially subordinate secondaries (that are neither dominant nor foragers) had the least-developed mushroom body calyces. These data demonstrate that sociality itself does not explain mushroom body volume; however, achieving and maintaining dominance status in a group was associated with mushroom body calyx enlargement. Dominance and foraging effects were cumulative; dominant social primary foragers had larger mushroom body volumes than solitary foragers, and solitary foragers had larger mushroom body volumes than nonforaging social secondary guards. This is the first evidence for cumulative effects on brain development by dominance and task performance. PMID- 25925013 TI - Estrogens Suppress Spinal Endomorphin 2 Release in Female Rats in Phase with the Estrous Cycle. AB - BACKGROUND/AIMS: Male and female rats differ in their ability to utilize spinal endomorphin 2 (EM2; the predominant mu-opioid receptor ligand in spinal cord) and in the mechanisms that underlie spinal EM2 analgesic responsiveness. We investigated the relevance of spinal estrogen receptors (ERs) to the in vivo regulation of spinal EM2 release. METHODS: ER antagonists were administered directly to the lumbosacral spinal cord of male and female rats, intrathecal perfusate was collected, and resulting changes in EM2 release were quantified using a plate-based radioimmunoassay. RESULTS: Intrathecal application of an antagonist of either estrogen receptor-alpha (ERalpha) or the ER GPR30 failed to alter spinal EM2 release. Strikingly, however, the concomitant blockade of ERalpha and GPR30 enhanced spinal EM2 release. This effect was sexually dimorphic, being absent in males. Furthermore, the magnitude of the enhancement of spinal EM2 release in females was dependent upon estrous cycle stage, suggesting a relationship with circulating levels of 17beta-estradiol. The rapid onset of enhanced EM2 release following intrathecal application of ERalpha/GPR30 antagonists (within 30-40 min) suggests mediation via ERs in the plasma membrane, not the nucleus. Notably, both ovarian and spinally synthesized estrogens are essential for membrane ER regulation of spinal EM2 release. CONCLUSION: These findings underscore the importance of estrogens for the regulation of spinal EM2 activity and, by extension, endogenous spinal EM2 antinociception in females. Components of the spinal estrogenic mechanism(s) that suppress EM2 release could represent novel drug targets for improving utilization of endogenous spinal EM2, and thereby pain management in women. PMID- 25925015 TI - White-light emission strategy of a single organic compound with aggregation induced emission and delayed fluorescence properties. AB - A novel white-light-emitting organic molecule, which consists of carbazolyl- and phenothiazinyl-substituted benzophenone (OPC) and exhibits aggregation-induced emission-delayed fluorescence (AIE-DF) and mechanofluorochromic properties was synthesized. The CIE color coordinates of OPC were directly measured with a non doped powder, which presented white-emission coordinates (0.33, 0.33) at 244 K to 252 K and (0.35, 0.35) at 298 K. The asymmetric donor-acceptor-donor' (D-A-D') type of OPC exhibits an accurate inherited relationship from dicarbazolyl substituted benzophenone (O2C, D-A-D) and diphenothiazinyl-substituted benzophenone (O2P, D'-A-D'). By purposefully selecting the two parent molecules, that is, O2C (blue) and O2P (yellow), the white-light emission of OPC can be achieved in a single molecule. This finding provides a feasible molecular strategy to design new AIE-DF white-light-emitting organic molecules. PMID- 25925016 TI - Visual analysis of biological data-knowledge networks. AB - BACKGROUND: The interpretation of the results from genome-scale experiments is a challenging and important problem in contemporary biomedical research. Biological networks that integrate experimental results with existing knowledge from biomedical databases and published literature can provide a rich resource and powerful basis for hypothesizing about mechanistic explanations for observed gene phenotype relationships. However, the size and density of such networks often impede their efficient exploration and understanding. RESULTS: We introduce a visual analytics approach that integrates interactive filtering of dense networks based on degree-of-interest functions with attribute-based layouts of the resulting subnetworks. The comparison of multiple subnetworks representing different analysis facets is facilitated through an interactive super-network that integrates brushing-and-linking techniques for highlighting components across networks. An implementation is freely available as a Cytoscape app. CONCLUSIONS: We demonstrate the utility of our approach through two case studies using a dataset that combines clinical data with high-throughput data for studying the effect of beta-blocker treatment on heart failure patients. Furthermore, we discuss our team-based iterative design and development process as well as the limitations and generalizability of our approach. PMID- 25925017 TI - Association between muscle trigger points, ongoing pain, function, and sleep quality in elderly women with bilateral painful knee osteoarthritis. AB - OBJECTIVE: The objectives of this study were to investigate if referred pain elicited by active trigger points (TrPs) reproduced the symptoms in individuals with painful knee osteoarthritis (OA) and to determine the relationship between the presence of active TrPs, intensity of ongoing pain, function, quality of life, and sleep quality in individuals with painful knee OA. METHODS: Eighteen women with bilateral painful knee OA, aged 79 to 90 years, and 18 matched controls participated. Muscle TrPs were bilaterally explored in several muscles of the lower extremity. Trigger points were considered active if the elicited referred pain reproduced knee symptoms, and TrPs were considered latent if the elicited pain did not reproduce symptoms. Pain was collected with a numerical pain rate scale (0-10), function was assessed with Western Ontario and McMaster Universities, quality of life was assessed with the Medical Outcomes Study Short Form 36 questionnaire, and sleep quality was determined with the Pittsburgh Sleep Quality Index. RESULTS: Women with knee OA exhibited a greater number of active TrPs (mean, 1 +/- 1; P < .001) but similar number of latent TrPs (mean, 4 +/- 2) than healthy women (mean, 4 +/- 3; P = .613). A greater number of active TrPs were associated with higher intensity of ongoing pain (r = 0.605; P = .007). Higher intensity of ongoing knee pain was associated with lower physical function (P < .05). CONCLUSIONS: The referred pain elicited by active TrPs in the lower extremity muscles contributed to pain symptoms in painful knee OA. A higher number of active TrPs was associated with higher intensity of ongoing knee pain. PMID- 25925018 TI - Reliability of 2 protocols for assessing pressure pain threshold in healthy young adults. AB - OBJECTIVE: The purposes of this study were to determine whether there were differences in mean values or reliability for 2 frequently used protocols for pressure pain threshold (PPT) and to calculate how large a difference in PPT is necessary to be 95% confident that a real change has occurred. METHODS: Thirteen participants (8 females) aged 22.3 (+/-2.3) years from a university community were included. Two testers evaluated participants using 2 protocols, in which PPT was measured 3 times at 8 different body locations. The "cluster protocol" consisted of 3 successive measurements at each location with a 30-second rest between each measurement. The "circuit protocol" consisted of 1 measurement taken at each anatomical location until "the circuit" was complete and then repeated a total of 3 times. RESULTS: A 2-way analysis of variance did not reveal significant differences between protocols at any body location (P = .46-.98). Intertester reliability was good to excellent for all locations (intraclass correlation coefficient, 0.84-0.96), and limits of agreement ranged from 108 to 223 kPa. CONCLUSIONS: Either the cluster or circuit protocol can be used to measure PPT in clinical or research setting. A difference of 160 kPa is considered sufficient to indicate a real difference between repeated measures of PPT regardless of protocol used for testing. PMID- 25925019 TI - Effect of upper thoracic manipulation on mouth opening and electromyographic activity of masticatory muscles in women with temporomandibular disorder: a randomized clinical trial. AB - OBJECTIVE: The purpose of this study was to assess the effect of upper thoracic manipulation on vertical mouth opening (VMO) and electromyographic activity of the masticatory muscles in women with temporomandibular disorder (TMD). METHODS: A randomized, controlled, blinded study involving 32 women (mean age of 24.78 +/- 5.41 years) diagnosed with TMD was performed. Subjects were randomly allocated to an experimental group (n = 16) or a sham manipulation (placebo) group (n = 16). A single session of manipulation was administered to the T1 vertebral area. Electromyography was used to determine activity of masticatory muscles with the mandible at rest and during isometric contraction. Vertical mouth opening was measured using a ruler. Measurements were made before manipulation, immediately after manipulation, and at the short-term follow-up (2 to 4 days after manipulation). RESULTS: No significant differences were found in any of the comparisons of mandibular VMO or electromyographic activity of the masticatory muscles at rest or during isometric contraction of mandibular elevator muscles (P > .05). Regarding isometric contraction of the mandibular depressors, an immediate increase in muscle activity was found in the suprahyoid (P = .014) and left masseter (P = .005) muscles. CONCLUSION: In the present study, no significant differences were found regarding VMO between the experimental and placebo groups or among the different evaluations times in each group. Moreover, Cohen d test revealed no clinical effect of the technique. Therefore, based upon the findings of this study, manipulation administered to the T1 vertebral area appears to have no effect on VMO and electromyographic activity of the masticatory muscles in women with TMD. PMID- 25925020 TI - Learning spinal manipulation: the effect of expertise on transfer capability. AB - OBJECTIVE: Transfer capability represents the changes in performance in one task that result from practice or experience in other related tasks. Increased transfer capability has been associated with expertise in several motor tasks. The purpose of this study was to investigate if expertise in spinal manipulation therapy, assessed in groups of trainees and experienced chiropractors, is associated with increased transfer capabilities. METHODS: Forty-nine chiropractic students (fifth- and sixth-year students) and experienced chiropractors were asked to perform blocks of 10 thoracic spine manipulations in 3 different conditions: preferred position and table setting, increased table height, and unstable support surface. Spinal manipulations were performed on a computer connected device developed to emulate a prone thoracic spine manipulation. Thrust duration, thrust force rate of force application, and preload force were obtained for each trial and compared across groups and conditions. RESULTS: Results indicated that both expertise and performance conditions modulated the biomechanical parameters of spinal manipulation. Decreased thrust duration and increased rate of force application were observed in experienced clinicians, whereas thrust force and thrust rate of force application were significantly decreased when task difficulty was increased. Increasing task difficulty also led to significant increases in performance variability. CONCLUSION: Overall, this study suggests that when instructed to perform spinal manipulation in a challenging context, trainees and experts choose to modulate force to optimize thrust duration, a characteristic feature of high-velocity, low-amplitude spinal manipulation. Given its known association with motor proficiency, transfer capability assessments should be considered in spinal manipulative therapy training. PMID- 25925021 TI - Assessment of dissociation among combat-exposed soldiers with and without posttraumatic stress disorder. AB - BACKGROUND: Dissociation is a disruption of and/or discontinuity in the normal, subjective integration of one or more aspects of psychological functioning, including memory, identity, consciousness, perception, and motor control. A limited number of studies investigated combat-related dissociation. OBJECTIVE: The primary aim of this study was to evaluate the relationship between dissociative symptoms and combat-related trauma. METHOD: This study included 184 individuals, including 84 patients who were exposed to combat and diagnosed with posttraumatic stress disorder (PTSD) (Group I), 50 subjects who were exposed to combat but were not diagnosed with PTSD (Group II), and 50 healthy subjects without combat exposure (Group III). The participants were evaluated using the Dissociative Experiences Scale (DES) to determine their total and sub-factor (i.e., amnesia, depersonalization/derealization, and absorption) dissociative symptom levels. In addition, Group I and Group II were compared with respect to the relationship between physical injury and DES scores. RESULTS: The mean DES scores (i.e., total and sub-factors) of Group I were higher than those of Group II (p<0.001), and Group II's mean DES scores (i.e., total and sub-factors) were higher than those of Group III (p<0.001). Similarly, the number of subjects with high total DES scores (i.e.,>30) was highest in Group I, followed by Group II and Group III. When we compared combat-exposed subjects with high total DES scores, Group I had higher scores than Group II. In contrast, no relationship between the presence of bodily injury and total DES scores could be demonstrated. In addition, our results demonstrated that high depersonalization/derealization factor scores were correlated with bodily injury in PTSD patients. A similar relationship was found between high absorption factor scores and bodily injury for Group II. CONCLUSIONS: Our results demonstrated that the level of dissociation was significantly higher in subjects with combat-related PTSD than in subjects without combat-related PTSD. In addition, combat-exposed subjects without PTSD also had higher dissociation levels than healthy subjects without combat experience. PMID- 25925023 TI - A Battery Made from a Single Material. AB - A single-material battery is prepared using Li10GeP2S12 as the electrolyte, anode, and cathode, based on the Li-S and Ge-S components in Li10GeP2S12 acting as the active centers for its cathode and anode performance, respectively. The single-Li10GeP2S12 battery exhibits a remarkably low interfacial resistance due to the improvement of interfacial contact and interactions, and the suppression of interfacial strain/stress. PMID- 25925025 TI - Energetic salts based on furazan-functionalized tetrazoles: routes to boost energy. AB - Based on the backbone of the furazan-tetrazole structure, routes were developed to improve the properties of energetic materials. Two types of high-density energetic salts were designed, prepared, and fully characterized. Single-crystal X-ray analyses support the structural characteristics for two amino salts. A majority of the salts exhibited good detonation properties, high thermal stabilities, and relatively low impact and friction sensitivities. Hydroxylammonium and hydrazinium salts, 1-3 and 1-4, which have relatively high densities (1.84 and 1.74 g cm(-3,) , respectively), acceptable impact and friction sensitivities (14 J, 160 N and 28 J, 360 N), and good detonation pressures (38.3 and 32.2 GPa) and velocities (9323 and 9094 m s(-1) ), have performance properties superior to 1,3,5-trinitro-1,3,5-triazinane (RDX) and triaminotrinitrobenzene (TATB). PMID- 25925024 TI - SMIFH2 has effects on Formins and p53 that perturb the cell cytoskeleton. AB - Formin proteins are key regulators of the cytoskeleton involved in developmental and homeostatic programs, and human disease. For these reasons, small molecules interfering with Formins' activity have gained increasing attention. Among them, small molecule inhibitor of Formin Homology 2 domains (SMIFH2) is often used as a pharmacological Formin blocker. Although SMIFH2 inhibits actin polymerization by Formins and affects the actin cytoskeleton, its cellular mechanism of action and target specificity remain unclear. Here we show that SMIFH2 induces remodelling of actin filaments, microtubules and the Golgi complex as a result of its effects on Formins and p53. We found that SMIFH2 triggers alternated depolymerization repolymerization cycles of actin and tubulin, increases cell migration, causes scattering of the Golgi complex, and also cytotoxicity at high dose. Moreover, SMIFH2 reduces expression and activity of p53 through a post-transcriptional, proteasome-independent mechanism that influences remodelling of the cytoskeleton. As the action of SMIFH2 may go beyond Formin inhibition, only short-term and low dose SMIFH2 treatments minimize confounding effects induced by loss of p53 and cytotoxicity. PMID- 25925026 TI - Minimum effective concentration of bupivacaine for axillary brachial plexus block guided by ultrasound. AB - INTRODUCTION: The use of ultrasound in regional anesthesia allows reducing the dose of local anesthetic used for peripheral nerve block. The present study was performed to determine the minimum effective concentration (MEC90) of bupivacaine for axillary brachial plexus block. METHODS: Patients undergoing hand surgery were recruited. To estimate the MEC90, a sequential up-down biased coin method of allocation was used. The bupivacaine dose was 5 mL for each nerve (radial, ulnar, median, and musculocutaneous). The initial concentration was 0.35%. This concentration was changed by 0.05% depending on the previous block; a blockade failure resulted in increased concentration for the next patient; in case of success, the next patient could receive or reduction (0.1 probability) or the same concentration (0.9 probability). Surgical anesthesia was defined as driving force <= 2 according to the modified Bromage scale, lack of thermal sensitivity and response to pinprick. Postoperative analgesia was assessed in the recovery room with numeric pain scale and the amount of drugs used within 4h after the blockade. RESULTS: MEC90 was 0.241% [R(2): 0.978, confidence interval: 0.20 0.34%]. No patient, with successful block, reported pain after 4h. CONCLUSION: This study demonstrated that ultrasound guided axillary brachial plexus block can be performed with the use of low concentration of local anesthetics, increasing the safety of the procedure. Further studies should be conducted to assess blockade duration at low concentrations. PMID- 25925027 TI - Influence of preoperative propranolol on cardiac index during the anhepatic phase of liver transplantation. AB - INTRODUCTION: Liver transplantation is the best therapeutic option for end-stage liver disease. Non-selective beta-blocker medications such as propranolol act directly on the cardiovascular system and are often used in the prevention of gastrointestinal bleeding resulting from HP. The effects of propranolol on cardiovascular system of cirrhotic patients during liver transplantation are not known. OBJECTIVE: Evaluate the influence of propranolol used preoperatively on cardiac index during the anhepatic phase of liver transplantation. METHOD: 101 adult patients (73 male [72.2%]) who underwent cadaveric donor orthotopic liver transplantation by piggyback technique with preservation of the retrohepatic inferior vena cava performed at Hospital das Clinicas, Federal University of Minas Gerais were evaluated. There was no difference in severity between groups by the MELD system, p=0.70. The preoperative use of propranolol and the cardiac index outcome were compared during the anhepatic phase of liver transplantation in 5 groups (I: increased cardiac index, II: cardiac index reduction lower than 16%, III: cardiac index reduction equal to or greater than 16% and less than 31%, IV: cardiac index reduction equal to or greater than 31% and less than 46%, V: cardiac index reduction equal to or greater than 46%). RESULTS: Patients in group I (46.4%) who received propranolol preoperatively were statistically similar to groups II (60%), III (72.7%), IV (50%) and V (30.8%), p=0.57. CONCLUSION: The use of propranolol before transplantation as prophylaxis for gastrointestinal bleeding may be considered safe, as it was not associated with worsening of cardiac index in anhepatic phase of liver transplantation. PMID- 25925028 TI - Anatomical basis for sciatic nerve block at the knee level. AB - BACKGROUND AND OBJECTIVES: Recently, administration of sciatic nerve block has been revised due to the potential benefit for postoperative analgesia and patient satisfaction after the advent of ultrasound. The aim of this study was to describe the anatomical relations of the sciatic nerve in the popliteal fossa to determine the optimal distance the needle must be positioned in order to realize the sciatic nerve block anterior to its bifurcation into the tibial and common fibular nerve. METHOD: The study was conducted by dissection of human cadavers' popliteal fossa, fixed in 10% formalin, from the Laboratory of Human Anatomy and Morphology Departments of the Universidade Federal de Alagoas and Universidade de Ciencias da Saude de Alagoas. Access to the sciatic nerve was obtained. RESULTS: 44 popliteal fossa were analyzed. The bifurcation of the sciatic nerve in relation to the apex of the fossa was observed. There was bifurcation in: 67.96% below the apex, 15.90% above the apex, 11.36% near the apex, and 4.78% in the gluteal region. CONCLUSIONS: The sciatic nerve bifurcation to its branches occurs at various levels, and the chance to succeed when the needle is placed between 5 and 7 cm above the popliteal is 95.22%. PMID- 25925029 TI - Bacterial colonization due to increased nurse workload in an intensive care unit. AB - INTRODUCTION: The rates of multiresistant bacteria colonization or infection (MRB+) development in intensive care units are very high. The aim of this study was to determine the possible association between the risk of development of nosocomial infections and increased daily nurse workload due to understaffing in intensive care unit. METHODS: We included 168 patients. Intensity of workload and applied procedures to patients were scored with the Project de Recherche en Nursing and the Omega scores, respectively. The criteria used for infections were those defined by the Centers for Disease Control. RESULTS: Of the 168 patients, 91 (54.2%) were female and 77 (45.8%) were male patients. The mean age of female and male was 64.9 +/- 6.2 years and 63.1 +/- 11.9 years, respectively. The mean duration of hospitalization in intensive care unit was 18.4 +/- 6.1 days. Multiresistant bacteria were isolated from cultures of 39 (23.2%) patients. The development of MRB+ infection was correlated with length of stay, Omega 1, Omega 2, Omega 3, Total Omega, daily PRN, and Total PRN (p < 0.05). There was no correlation between development of MRB+ infection with gender, age and APACHE-II scores (p > 0.05). CONCLUSION: The risk of nosocomial infection development in an intensive care unit is directly correlated with increased nurse workload, applied intervention, and length of stay. Understaffing in the intensive care unit is an important health problem that especially affects care-needing patients. Nosocomial infection development has laid a heavy burden on the economy of many countries. To control nosocomial infection development in the intensive care unit, nurse workload, staffing level, and working conditions must be arranged. PMID- 25925030 TI - Local analgesic effect of tramadol is not mediated by opioid receptors in early postoperative pain in rats. AB - BACKGROUND AND OBJECTIVES: Tramadol is known as a central acting analgesic drug, used for the treatment of moderate to severe pain. Local analgesic effect has been demonstrated, in part due to local anesthetic-like effect, but other mechanisms remain unclear. The role of peripheral opioid receptors in the local analgesic effect is not known. In this study, we examined role of peripheral opioid receptors in the local analgesic effect of tramadol in the plantar incision model. METHODS: Young male Wistar rats were divided into seven groups: control, intraplantar tramadol, intravenous tramadol, intravenous naloxone intraplantar tramadol, intraplantar naloxone-intraplantar tramadol, intravenous naloxone-intravenous tramadol, and intravenous naloxone. After receiving the assigned drugs (tramadol 5mg, naloxone 200 MUg or 0.9% NaCl), rats were submitted to plantar incision, and withdrawal thresholds after mechanical stimuli with von Frey filaments were assessed at baseline, 10, 15, 30, 45 and 60 min after incision. RESULTS: Plantar incision led to marked mechanical hyperalgesia during the whole period of observation in the control group, no mechanical hyperalgesia were observed in intraplantar tramadol group, intraplantar naloxone-intraplantar tramadol group and intravenous naloxone-intraplantar tramadol. In the intravenous tramadol group a late increase in withdrawal thresholds (after 45 min) was observed, the intravenous naloxone-intravenous tramadol group and intravenous naloxone remained hyperalgesic during the whole period. CONCLUSIONS: Tramadol presented an early local analgesic effect decreasing mechanical hyperalgesia induced by plantar incision. This analgesic effect was not mediated by peripheral opioid receptors. PMID- 25925031 TI - Opioid-free total intravenous anesthesia with propofol, dexmedetomidine and lidocaine infusions for laparoscopic cholecystectomy: a prospective, randomized, double-blinded study. AB - BACKGROUND AND OBJECTIVES: Intraoperative use of opioids may be associated with postoperative hyperalgesia and increased analgesic consumption. Side effects due to perioperative use of opioids, such as postoperative nausea and vomiting may delay discharge. We hypothesized that total intravenous anesthesia consisting of lidocaine and dexmedetomidine as an opioid substitute may be an alternative technique for laparoscopic cholecystectomy and would be associated with lower fentanyl requirements in the postoperative period and less incidence of postoperative nausea and vomiting. METHODS: 80 Anesthesiologists I-II adults were scheduled for elective laparoscopic cholecystectomy. Patients were randomly allocated into two groups to have either opioid-free anesthesia with dexmedetomidine, lidocaine, and propofol infusions (Group DL) or opioid-based anesthesia with remifentanil, and propofol infusions (Group RF). All patients received a standard multimodal analgesia regimen. A patient controlled analgesia device was set to deliver IV fentanyl for 6h after surgery. The primary outcome variable was postoperative fentanyl consumption. RESULTS: Fentanyl consumption at postoperative 2nd hour was statistically significantly less in Group DL, compared with Group RF, which were 75 +/- 59 MUg and 120 +/- 94 MUg respectively, while it was comparable at postoperative 6th hour. During anesthesia, there were more hypotensive events in Group RF, while there were more hypertensive events in Group DL, which were both statistically significant. Despite higher recovery times, Group DL had significantly lower pain scores, rescue analgesic and ondansetron need. CONCLUSION: Opioid-free anesthesia with dexmedetomidine, lidocaine and propofol infusions may be an alternative technique for laparoscopic cholecystectomy especially in patients with high risk for postoperative nausea and vomiting. PMID- 25925032 TI - Frequency of colonization and isolated bacteria from the tip of epidural catheter implanted for postoperative analgesia. AB - BACKGROUND AND OBJECTIVE: The increased use of epidural analgesia with catheter leads to the need to demonstrate the safety of this method and know the incidence of catheter colonization, inserted postoperatively for epidural analgesia, and the bacteria responsible for this colonization. METHODS: From November 2011 to April 2012, patients electively operated and maintained under epidural catheter for postoperative analgesia were evaluated. The catheter tip was collected for semiquantitative and qualitative microbiological analysis. RESULTS: Of 68 cultured catheters, six tips (8.8%) had positive cultures. No patient had superficial or deep infection. The mean duration of catheter use was 43.45 h (18 118) (p=0.0894). The type of surgery (contaminated or uncontaminated), physical status of patients, and surgical time showed no relation with the colonization of catheters. Microorganisms isolated from the catheter tip were Staphylococcus aureus, Pseudomonas aeruginosa and Sphingomonas paucimobilis. CONCLUSION: Postoperative epidural catheter analgesia, under these study conditions, was found to be low risk for bacterial colonization in patients at surgical wards. PMID- 25925033 TI - Intravenous lidocaine for postmastectomy pain treatment: randomized, blind, placebo controlled clinical trial. AB - BACKGROUND AND OBJECTIVE: Postoperative pain treatment in mastectomy remains a major challenge despite the multimodal approach. The aim of this study was to investigate the analgesic effect of intravenous lidocaine in patients undergoing mastectomy, as well as the postoperative consumption of opioids. METHODS: After approval by the Human Research Ethics Committee of the Instituto de Medicina Integral Prof. Fernando Figueira in Recife, Pernambuco, a randomized, blind, controlled trial was conducted with intravenous lidocaine at a dose of 3mg/kg infused over 1h in 45 women undergoing mastectomy under general anesthesia. One patient from placebo group was. RESULTS: Groups were similar in age, body mass index, type of surgery, and postoperative need for opioids. Two of 22 patients in lidocaine group and three of 22 patients in placebo group requested opioid (p=0.50). Pain on awakening was identified in 4/22 of lidocaine group and 5/22 of placebo group (p=0.50); in the post-anesthetic recovery room in 14/22 and 12/22 (p=0.37) of lidocaine and placebo groups, respectively. Pain evaluation 24h after surgery showed that 2/22 and 3/22 patients (p=0.50) of lidocaine and placebo groups, respectively, complained of pain. CONCLUSION: Intravenous lidocaine at a dose of 3mg/kg administered over a period of an hour during mastectomy did not promote additional analgesia compared to placebo in the first 24h, and has not decreased opioid consumption. However, a beneficial effect of intravenous lidocaine in selected and/or other therapeutic regimens patients cannot be ruled out. PMID- 25925034 TI - Evaluation of brachial plexus fascicles involvement on infraclavicular block: unfixed cadaver study. AB - BACKGROUND AND OBJECTIVES: This study shows how the diffusion of the anesthetic into the sheath occurs through the axillary infraclavicular space and hence proves the efficacy of the anesthetic block of the brachial plexus, and may thereby allow a consolidation of this pathway, with fewer complications, previously attached to the anesthesia. MATERIALS AND METHODS: 33 armpits of adult cadavers were analyzed and unfixed. We injected a solution of neoprene with latex dye in the infraclavicular space, based on the technique advocated by Gusmao et al., and put the corpses in refrigerators for three weeks. Subsequently, the specimens were thawed and dissected, exposing the axillary sheath along its entire length. RESULTS AND DISCUSSION: Was demonstrated involvement of all fasciculus of the plexus in 51.46%. In partial involvement was 30.30%, 18.24% of cases the acrylic was located outside the auxiliary sheath involving no issue. CONCLUSIONS: The results allow us to establish the infraclavicular as an effective and easy way to access plexus brachial, because the solution involved the fascicles in 81.76% partially or totally, when it was injected inside the axillary sheath. We believe that only the use of this pathway access in practice it may demonstrate the efficiency. PMID- 25925035 TI - Influence of different body positions in vital capacity in patients on postoperative upper abdominal. AB - RATIONALE: The changes in body position can cause changes in lung function, and it is necessary to understand them, especially in the postoperative upper abdominal surgery, since these patients are susceptible to postoperative pulmonary complications. OBJECTIVE: To assess the vital capacity in the supine position (head at 0 degrees and 45 degrees ), sitting and standing positions in patients in the postoperative upper abdominal surgery. METHODS: A cross-sectional study conducted between August 2008 and January 2009 in a hospital in Salvador/BA. The instrument used to measure vital capacity was analogic spirometer, the choice of the sequence of positions followed a random order obtained from the draw of the four positions. Secondary data were collected from the medical records of each patient. RESULTS: The sample consisted of 30 subjects with a mean age of 45.2 +/- 11.2 years, BMI 20.2 +/- 1.0 kg/m(2). The position on orthostasis showed higher values of vital capacity regarding standing (mean change: 0.15 +/- 0.03 L; p=0.001), the supine to 45 (average difference: 0.32 +/- 0.04 L; p = 0.001) and 0 degrees (0.50 +/- 0.05 L; p = 0.001). There was a positive trend between the values of forced vital capacity supine to upright posture (1.68 +/- 0.47; 1.86 +/- 0.48; 2.02 +/- 0.48 and 2.18 +/- 0.52 L; respectively). CONCLUSION: Body position affects the values of vital capacity in patients in the postoperative upper abdominal surgery, increasing in postures where the chest is vertical. PMID- 25925036 TI - Comparison of interscalene brachial plexus block and intra-articular local anesthetic administration on postoperative pain management in arthroscopic shoulder surgery. AB - BACKGROUND AND OBJECTIVES: In this study, the aim was to compare postoperative analgesia effects of the administration of ultrasound-guided interscalene brachial plexus block and intra-articular bupivacaine carried out with bupivacaine. METHODS: In the first group of patients 20 mL 0.25% bupivacaine and ultrasound-guided interscalene brachial plexus block (ISPB) were applied, while 20 mL 0.25% bupivacaine was given via intra-articular (IA) administration to the second group patients after surgery. Patients in the third group were considered the control group and no block was performed. Patient-controlled analgesia (PCA) with morphine was used in all three groups for postoperative analgesia. RESULTS: In the ISPB group, morphine consumption in the periods between 0-4, 6-12 and 12 24 postoperative hours and total consumption within 24h was lower than in the other two groups. Morphine consumption in the IA group was lower than in the control group in the period from 0 to 6h and the same was true for total morphine consumption in 24h. Postoperative VASr scores in the ISPB group were lower than both of the other groups in the first 2h and lower than the control group in the 4th and 6th hours (p<0.05). In the IA group, VASr and VASm scores in the 2nd, 4th and 6th hours were lower than in the control group (p<0.05). CONCLUSION: Interscalene brachial plexus block was found to be more effective than intra articular local anesthetic injection for postoperative analgesia. PMID- 25925037 TI - Does ultrasonographic volume of the thyroid gland correlate with difficult intubation? An observational study. AB - BACKGROUND AND OBJECTIVES: Preoperative ultrasonographic evaluation of the thyroid gland done by surgeons could let us foresee airway management challenges. The aim of this observational study was to evaluate the effects of thyroid related parameters assessed preoperatively by surgeons via ultrasonography and chest X-ray on intubation conditions. METHODS: Fifty patients undergoing thyroid surgery were enrolled. Thyromental distance, Mallampati score, neck circumference and range of neck movement were evaluated before the operation. Thyroid volume, signs of invasion or compression and tracheal deviation on chest X-ray were also noted. The intubation conditions were assessed with Cormack and Lehane score and the intubation difficulty scale. Statistical analyses were done with SPSS 15.0 software. RESULTS: The mean thyroid volume of the patients was 26.38 +/- 14 mL. The median intubation difficulty scale was 1 (0-2). Thyromental distance (p = 0.011; r = 0.36; 95% CI 0.582-0.088), Mallampati score (p = 0.041; r = 0.29; 95% CI 0.013-0.526), compression or invasion signs (p = 0.041; r = 0.28; 95% CI 0.006 0.521) and tracheal deviation on chest X-ray (p = 0.041; r = 0.52; 95% CI 0.268 0.702) were correlated with intubation difficulty scale. Also patients were classified into two groups related to their intubation difficulty scale (Group I, n = 19: intubation difficulty scale = 0; Group II, n = 31: 1< intubation difficulty scale <= 5) and difficult intubation predictors and thyroid-related parameters were compared. Only Mallampati score was significantly different between groups (p = 0.025). CONCLUSION: The thyroid volume is not associated with difficult intubation. However clinical assessment parameters may predict difficult intubation. PMID- 25925038 TI - What is missing for difficult airway management in the 21st century. PMID- 25925039 TI - The glomerular permeability factors in idiopathic nephrotic syndrome. AB - It is currently postulated that steroid-sensitive idiopathic nephrotic syndrome (SSNS) and steroid-resistant idiopathic nephrotic syndrome (SRNS), which are not related to the mutation of a gene coding for podocyte structures or for glomerular basement membrane proteins, result from a circulating factor affecting podocyte shape and function. T lymphocytes have for a long time been suspected to be involved in the pathophysiology of these diseases. The successful treatment of steroid-dependant nephrotic syndrome with rituximab suggests a potential role for B lymphocytes. Clinical and experimental data indicate roles for cytokines IL-13, TNFalpha, circulating cardiotrophin-like cytokine factor 1 (member of the IL-6 family), circulating hemopexin, radical oxygen species, and the soluble urokinase type plasminogen activator receptor (suPAR) in the development of nephrotic syndrome. Podocyte metabolism modifications-leading to the overexpression of the podocyte B7-1antigen (CD 80), hypoactivity of the podocyte enzyme sphingomyelin phosphodiesterase acid-like 3 b (SMPDL3b), and to the podocyte production of a hyposialylated form of the angiopoietin-like 4 (Angptl4)-are mechanisms possibly involved in the changes in the podocyte cytoskeleton leading to SSNS and or SRNS. Different multifactorial pathophysiological mechanisms can be advocated for SSNS and SRNS. The present paper reviews the experimental and clinical data upon which the different hypotheses are based and reports their possible clinical applications. PMID- 25925040 TI - Proteinuria 1 year after renal transplantation is associated with impaired graft survival in children. AB - BACKGROUND: Proteinuria is a common manifestation of chronic kidney disease (CKD), and there is a high incidence of CDK and its complications following renal transplantation. However, little data are available on the association between proteinuria and graft/patient survival in the paediatric transplant population. The primary aim of this study was to investigate the associations between posttransplant proteinuria and graft/patient survival in children after renal transplantation. METHODS: In this retrospective study, we screened all 91 children receiving renal allografts at a single institution between 1997 and 2007. The inclusion criteria were a functioning graft at 1 year posttransplant, data availability and no recurrence of focal-segmental glomerulosclerosis. The final cohort included 75 patients. Proteinuria was considered to be pathologic if the urinary protein/creatinine ratio was >30 mg/mmol. Donor and recipient characteristics, data on proteinuria, estimated glomerular filtration rate (eGFR) and rejection episodes were analysed. The most recent of the biopsies performed during the follow-up after 1 year posttransplant were analysed separately in the proteinuric group and the non-proteinuric group. RESULTS: Proteinuria at 1-year posttransplant was pathologic in 35 % of patients. The 5-year graft survival rate was significantly lower in the proteinuric group than in the non-proteinuric group (77 vs. 100 %; p < 0.001). Proteinuria at 1 year posttransplant was associated with reduced long-term graft survival independent of other risk factors, including decreased eGFR or episodes of acute corticosensitive and corticoresistant rejection. The most frequent histologic finding in the proteinuric group was chronic rejection. There was no significant difference in the 5-year patient survival rate between the proteinuric group and the non proteinuric group. CONCLUSION: This study emphasizes the importance of proteinuria as a prognostic factor of renal allograft survival in children. PMID- 25925041 TI - High expression of Talin-1 is associated with poor prognosis in patients with nasopharyngeal carcinoma. AB - BACKGROUND: Talin-1 is a cytoskeletal protein that plays an important role in tumourgenesis, migration and metastasis in several malignant tumors. The aim of this study was to evaluate the expression and prognostic value of Talin-1 in nasopharyngeal carcinoma (NPC). METHODS: Talin-1 mRNA and protein expression were examined in NPC cell lines and clinical nasopharyngeal tissues by quantitative RT PCR, agarose gel electrophoresis and western blotting. The expression of Talin-1 was analyzed by immunohistochemical staining in 233 paraffin-embedded NPC specimens with clinical follow-up data and cox regression analysis was used to identify independent prognostic factors. The functional role of Talin-1 in NPC cell lines was evaluated by small interfering RNA-mediated depletion of the protein followed by the wound healing and transwell invasion assays. RESULTS: The expression of Talin-1 was significantly upregulated in most NPC cell lines and clinical tissues at both the mRNA and protein levels. High expression of Talin-1 was significantly associated with distant metastasis (P = 0.001) and patient death (P = 0.001). In addition, high expression of Talin-1 was associated with significantly poorer overall survival (OS: HR, 2.15; 95% CI, 1.28-3.63; P = 0.003) and poorer distant metastasis-free survival (DMFS: HR, 2.39; 95% CI, 1.38 4.15; P = 0.001). Cox regression analysis indicated that high expression of Talin 1 and TNM stage were independent prognostic indicators (both P < 0.05). Stratified analysis demonstrated that high expression of Talin-1 was associated with significantly poorer survival in patients with advanced stage disease (stage III-IV, HR, 1.91; 95% CI, 1.09-3.35; P = 0.02 for OS and HR, 2.22; 95% CI, 1.24 3.99; P = 0.006 for DMFS). Furthermore, the depletion of Talin-1 suppressed the migratory and invasive ability of NPC cells in vitro. CONCLUSIONS: Our data demonstrate that high expression of Talin-1 is associated with significantly poorer OS and poorer DMFS in NPC and depletion of Talin-1 expression inhibited NPC cell migration and invasion. Talin-1 may serve as novel prognostic biomarker in NPC. PMID- 25925043 TI - [In Process Citation]. PMID- 25925042 TI - Functional outcome of prolonged refractory status epilepticus. AB - INTRODUCTION: To characterize etiology, clinical course and outcomes of patients in prolonged refractory status epilepticus (PRSE) and looking for prognostic factors. METHODS: Retrospective study conducted in patients hospitalized from January 1, 2001 to December 31, 2011 in 19 polyvalent intensive care units in French university and general hospitals. Patients were adults with a generalized convulsive refractory status epilepticus that lasted more than seven days, despite treatment including an anesthetic drug and mechanical ventilation. Patients with anoxic encephalopathy were excluded. Follow-up phone call was used to determine functional outcome using modified Rankin Scale (mRS) with mRS 0-3 defining good and mRS 4-6 poor outcome. RESULTS: 78 patients (35 female) were included. Median age was 57 years. Causes of status epilepticus were various, mainly including prior epilepsy (14.1%), CNS infection (12.8%), and stroke (12.8%). No etiology was found in 27 (34.6%) patients. PRSE was considered controlled in only 53 (67.9%) patients after a median duration of 17 (IQR 12-26) days. The median length of ICU stay was 28 (19-48) days. Forty-one (52.5%) patients died in the ICU, 26 from multiple organ failure, 8 from care withdrawal, 2 from sudden cardiac arrest, 1 from brain death and 4 from unknown causes. PRSE was previously resolved in 20 patients who died in the ICU. At one-year follow up, there were 12 patients with good outcome and 58 with poor outcome and 8 lost of follow-up. On multivariate analysis, only vasopressor use was a predictor of poor outcome (OR 6.54; 95%CI 1.09-39.29; p = 0.04). CONCLUSION: Poor outcome was observed in about 80% of this population of PRSE. Most patients died from systemic complications linked to their ICU stay. Some patients can recover satisfactorily over time though we did not identify any robust factor of good outcome. PMID- 25925044 TI - [Role of VEGF in diseases of the retina]. AB - Angiogenesis is the process through which new blood vessels are formed, based on preexisting vessels, and is the paradigm of diseases such as cancer and exudative ageassociated macular degeneration (ARMD). Several proangiogenic factors have been identified, such as vascular endothelial growth factor (VEGF), especially VEGF-A, which activates endothelial cells and promotes cell proliferation, migration, and an increase in vascular permeability. VEGF is also involved in the etiopathogenesis of other retinal diseases, such as diabetic macular edema and macular edema secondary to retinal vein occlusion. Likewise, there is increasing evidence that placental growth factor (PIGF) acts recepsynergetically with VEGF in promoting these diseases. Currently, the main treatment for these diseases are the anti-VEGF drugs, aflibercept, ranibizumab and bevacizumab. These agents differ in their molecular structure and mechanism of action. PMID- 25925045 TI - [Aflibercept. An approach to pharmacology]. AB - Aflibercept is a fusion protein whose chemical structure combines the constant fraction of any IgG with a variable fraction constructed with fundamental parts of VEGF receptors. Consequently, it is able to bind to various VEGF as well as to placental growth factor (PIGF), which has been related to a possible synergistic effect in efficacy. The affinity of this drug is higher than that of ranibizumab and bevacizumab. Moreover, it has an intraocular antiinflammatory effect. Intravitreal administration leads to the presence of traces of the drug in plasma but the concentrations are so reduced that the presence of systemic adverse effects, including arterial hypertension, is practically nil. Because of its prolonged intraocular elimination half-life and high affinity, the drug can be administered in convenient regimens, since, after an initial monthly injection for the first three doses, the interval between injections is increased to one every two months and, after the first 12 months, the dosing will depend on the visual and anatomical results. PMID- 25925046 TI - [New perspectives in the approach to age-related macular degeneration]. AB - The approval of aflibercept for the neovascular form of age-related macular degeneration has opened up the possibility of treating patients with fewer injections, since the drug can be administered once every two months. Aflibercept can also be used as rescue therapy in patients with suboptimal response to other antiangiogenic treatments. The present study reviews the scientific evidence on aflibercept, both in treatment-naive patients and in those with an unsatisfactory response to conventional treatments. PMID- 25925047 TI - [New perspectives in the approach to central retinal vein occlusion]. AB - OBJECTIVE: The COPERNICUS and GALILEO trials were designed to evaluate the safety and efficacy of intravitreal injection of 2mg of aflibercept in the treatment of macular edema secondary to central retinal vein occlusion. MATERIAL AND METHOD: Two phase III randomized, double-masked trials: COPERNICUS in North America (188 patients) and galileo in Europe and Asia (177 patients). In COPERNICUS, the patients in the treatment group received monthly injections of 2mg aflibercept for 6 months and later continued with strict PRN treatment with monthly follow-up every 6 months and with a minimum of 3-monthly follow up for 1 year. Patients in the placebo group could receive treatment after the sixth month, with similar treatment regimens and follow-up to the treatment group. In contrast, in galileo, the placebo group received no PRN treatment until 1 year of follow-up and during the first 6 months, followup visits were bi-monthly. RESULTS: The treatment group in COPERNICUS showed a mean improvement of 13 letters versus the placebo group (1.5 letters) at week 100 of follow-up. In galileo, the mean best corrected visual acuity at 76 weeks were 13.7 and 6.6 in the treatment and placebo groups, respectively. CONCLUSIONS: Early treatment with intravitreal afliberceptin achieves better results than when treatment is delayed by 6 months or 1 year. The visual benefits obtained with the drug are affected by the reduction in the frequency of monitoring during follow-up. PMID- 25925048 TI - [New perspectives in the approach to diabetic macular edema. Aflibercept therapy]. AB - The VISTA and VIVID trials were conducted to compare the safety and efficacy of two intravitreal injection (IVI) regimens of aflibercept versus macular laser photocoagulation for the treatment of diabetic macular edema (DME). These double masked, phase III clinical trials randomized (461/402) patients with DME to receive either 2mg aflibercept IVI every 4 weeks (2q4) or 2mg aflibercept IVI every 8 weeks (2q8) after 5 initial monthly doses vs macular laser photocoagularion. The primary efficacy endpoint was the mean change in best corrected visual acuity (BCVA) from baseline to week 52. Secondary efficacy endpoints were the change in central retinal thickness (CRT), the proportion of patients who gained >=10 amd >=15 Early Treatment Diabetic Retinopathy Study (ETDRS) letters, and the change in the National Eye Institute Visual Function Questionnaire (NEI VFQ-25) in near and distance vision. The mean BCVA gains in the 2q4 and 2q8 groups versus the laser group were 12.5 and 10.7 versus 0.2 letters (p<0.0001) in VISTA, and 10.5 and 10.7 versus 1.2 letters (p<0.0001) in VIVID. The proportions of patients gaining >= 15 letters and the proportion of patients with an improvement of > 2 levels in the severity of diabetic retinopathy was significant in the treatment groups versus the laser group. Mean reductions in CRT in the 2q4 and 2q8 groups vs the laser group were 185.9 and 183.1 versus 73.3 MUm (p<0.0001) in VISTA, and 195.0 and 192.4 versus 66.2 MUm (p<0.0001) in VIVID. The incidences of ocular and nonocular adverse events were similar in all groups. In conclusion, IIV aflibercept demonstrated statistically significant superiority in improvement in BCVA and reduction in DME over laser, with similar efficacy in the 2q4 and 2q8 groups in VISTA and VIVID. PMID- 25925049 TI - [Management of aflibercept in routine clinical practice]. AB - Aflibercept is a new anti-vegf drug that, unlike ranibizumab and bevacizumab blocks both vegf-A and placental growth factor. Moreover, it binds with much greater strength and affinity to human VEGF-A165 than other endogenous vegf receptors, conferring it with a more extended effect and allowing a lower frequency of intravitreal injections. This facilitates the adoption of fixed treatment regimens other than monthly or individual regimens such as "treat and extend". Aflibercept is indicated for the treatment of neovascular (exudative) age-related macular degeneration (ARMD), visual alteration due to macular edema secondary to central retinal vein occlusion (CRVO) and visual alteration due to diabetic macular edema (DME). The present article reviews the management of aflibercept in routine clinical practice, based on the specifications of its new core data sheet, which includes all the therapeutic indications in which its use has been approved and evaluating the distinct alternatives and treatment regimens after the initial loading doses. PMID- 25925050 TI - Prevalence of plasma small dense LDL is increased in obesity in a Thai population. AB - BACKGROUND: Plasma low density lipoprotein (LDL) particles vary in size, density, electrical charge and chemical composition. An increased presence of small dense LDL (sdLDL), along with raised triglyceride concentrations and decreased high density lipoprotein (HDL) cholesterol concentrations is commonly known as the atherogenic triad and has been observed in some cases of obesity, principally in Europe and America. This study examines the prevalence of sdLDL in the plasma of an obese (BMI>=25 kg/m2) Thai population. METHODS: Plasma from fasted obese (n=48) and non-obese (n=16) Thai participants was subjected to density gradient ultracentrifugation in iodixanol to separate lipoproteins. Gradients were unloaded top-to-bottom into 20 fractions which were assayed for cholesterol, triglyceride, apo B and apo A-1 to identify lipoprotein types and subtypes. RESULTS: LDL cholesterol was subfractionated into LDL I+II (fractions 3-6, rho=1.021-1.033 g/ml) which was considered to represent large buoyant LDL (lbLDL), LDL III (fractions 7-9, rho=1.036-1.039 g/ml) which was considered to represent sdLDL, and, LDL IV (fractions 10-12, rho=1.044-1.051 g/ml) which was considered to represent very sdLDL. Concentrations of LDL III and IV were increased by 15-20% in obese participants whilst that of LDL I+II was concomitantly decreased by 10%. This was accompanied by a 50% increase in plasma triglyceride concentrations and 15% decrease in HDL cholesterol concentrations. Only 3/16 (19%) non-obese participants had a pattern B LDL cholesterol profile (peak density of >1.033 g/ml), whilst 28/48 (58%) obese participants were pattern B. When expressed as a fraction of the LDL concentration, total sdLDL (i.e. LDL III+IV) showed highly significant correlations to plasma triglyceride concentrations and the triglyceride/HDL cholesterol ratio. CONCLUSIONS: The prevalence of sdLDL is increased in obesity in a Thai population such that they demonstrate a similar atherogenic triad to that previously observed in European and American populations. PMID- 25925051 TI - Treating fever in children under 5 years of age: caregiver perceptions of community health worker services in Dangme West district, Ghana. AB - BACKGROUND: Integrated community case management of childhood illnesses is a key strategy to help reduce mortality in children under 5 years; particularly those with difficult access to treatment. However, the success of such strategies depends on community utilization of services. This study assessed community utilization, perceptions and related factors of community health worker services. METHODS: Data were gathered from a cross-sectional survey among 562 caregivers and focus group discussions among 84 caregivers. Factors related to utilization of community health workers (CHWs) for management of childhood fevers were analyzed using logistic regression and focus group discussions to explore caregiver perceptions of CHW activities. RESULTS: Utilization of CHWs for management of fever in under-5s was 59.4%. Caregivers who were exposed to the communication intervention were about four times more likely to use the services of the CHWs compared to those who were not exposed (OR 3.79; 95% CI: 2.62-5.49; p<0.001). Farmers were 84% more likely to use CHW services for children sick with fever compared to those who were unemployed (OR 1.84; 95% CI: 1.00-3.39; p=0.05). Caregiver perceptions of the program were generally positive; most caregivers expressed satisfaction with the CHW services, citing prompt treatment, friendliness and free medicines. Male involvement in the CHW program was comparatively low. CONCLUSIONS: Dissemination of information among priority groups can enhance utilization of CHW services. Exploring the perspective of both men and women to gain in-depth understanding on their views on male involvement will be useful for planning appropriate strategies to get more males involved in community-based child health programs. PMID- 25925052 TI - A wild bootstrap approach for the selection of biomarkers in early diagnostic trials. AB - BACKGROUND: In early diagnostic trials, particularly in biomarker studies, the aim is often to select diagnostic tests among several methods. In case of metric, discrete, or even ordered categorical data, the area under the receiver operating characteristic (ROC) curve (denoted by AUC) is an appropriate overall accuracy measure for the selection, because the AUC is independent of cut-off points. METHODS: For selection of biomarkers the individual AUC's are compared with a pre defined threshold. To keep the overall coverage probability or the multiple type I error rate, simultaneous confidence intervals and multiple contrast tests are considered. We propose a purely nonparametric approach for the estimation of the AUC's with the corresponding confidence intervals and statistical tests. This approach uses the correlation among the statistics to account for multiplicity. For small sample sizes, a Wild-Bootstrap approach is presented. It is shown that the corresponding intervals and tests are asymptotically exact. RESULTS: Extensive simulation studies indicate that the derived Wild-Bootstrap approach keeps and exploits the nominal type-I error at best, even for high accuracies and in case of small samples sizes. The strength of the correlation, the type of covariance structure, a skewed distribution, and also a moderate imbalanced case control ratio do not have any impact on the behavior of the approach. A real data set illustrates the application of the proposed methods. CONCLUSION: We recommend the new Wild Bootstrap approach for the selection of biomarkers in early diagnostic trials, especially for high accuracies and small samples sizes. PMID- 25925053 TI - Polymorphisms in the Perilipin Gene May Affect Carcass Traits of Chinese Meat type Chickens. AB - Improved meat quality and greater muscle yield are highly sought after in high quality chicken breeding programs. Past studies indicated that polymorphisms of the Perilipin gene (PLIN1) are highly associated with adiposity in mammals and are potential molecular markers for improving meat quality and carcass traits in chickens. In the present study, we screened single nucleotide polymorphisms (SNPs) in all exons of the PLIN1 gene with a direct sequencing method in six populations with different genetic backgrounds (total 240 individuals). We evaluated the association between the polymorphisms and carcass and meat quality traits. We identified three SNPs, located on the 5' flanking region and exon 1 of PLIN1 on chromosome 10 (rs315831750, rs313726543, and rs80724063, respectively). Eight main haplotypes were constructed based on these SNPs. We calculated the allelic and genotypic frequencies, and genetic diversity parameters of the three SNPs. The polymorphism information content (PIC) ranged from 0.2768 to 0.3750, which reflected an intermediate genetic diversity for all chickens. The CC, CT, and TT genotypes influenced the percentage of breast muscle (PBM), percentage of leg muscle (PLM) and percentage of abdominal fat at rs315831750 (p<0.05). Diplotypes (haplotype pairs) affected the percentage of eviscerated weight (PEW) and PBM (p<0.05). Compared with chickens carrying other diplotypes, H3H7 had the greatest PEW and H2H2 had the greatest PBM, and those with diplotype H7H7 had the smallest PEW and PBM. We conclude that PLIN1 gene polymorphisms may affect broiler carcass and breast muscle yields, and diplotypes H3H7 and H2H2 could be positive molecular markers to enhance PEW and PBM in chickens. PMID- 25925054 TI - Multiple Genes Related to Muscle Identified through a Joint Analysis of a Two stage Genome-wide Association Study for Racing Performance of 1,156 Thoroughbreds. AB - Thoroughbred, a relatively recent horse breed, is best known for its use in horse racing. Although myostatin (MSTN) variants have been reported to be highly associated with horse racing performance, the trait is more likely to be polygenic in nature. The purpose of this study was to identify genetic variants strongly associated with racing performance by using estimated breeding value (EBV) for race time as a phenotype. We conducted a two-stage genome-wide association study to search for genetic variants associated with the EBV. In the first stage of genome-wide association study, a relatively large number of markers (~54,000 single-nucleotide polymorphisms, SNPs) were evaluated in a small number of samples (240 horses). In the second stage, a relatively small number of markers identified to have large effects (170 SNPs) were evaluated in a much larger number of samples (1,156 horses). We also validated the SNPs related to MSTN known to have large effects on racing performance and found significant associations in the stage two analysis, but not in stage one. We identified 28 significant SNPs related to 17 genes. Among these, six genes have a function related to myogenesis and five genes are involved in muscle maintenance. To our knowledge, these genes are newly reported for the genetic association with racing performance of Thoroughbreds. It complements a recent horse genome-wide association studies of racing performance that identified other SNPs and genes as the most significant variants. These results will help to expand our knowledge of the polygenic nature of racing performance in Thoroughbreds. PMID- 25925055 TI - Genetic effects of polymorphisms in myogenic regulatory factors on chicken muscle fiber traits. AB - The myogenic regulatory factors is a family of transcription factors that play a key role in the development of skeletal muscle fibers, which are the main factors to affect the meat taste and texture. In the present study, we performed candidate gene analysis to identify single-nucleotide polymorphisms in the MyoD, Myf5, MyoG, and Mrf4 genes using polymerase chain reaction-single strand conformation polymorphism in 360 Erlang Mountain Chickens from three different housing systems (cage, pen, and free-range). The general linear model procedure was used to estimate the statistical significance of association between combined genotypes and muscle fiber traits of chickens. Two polymorphisms (g.39928301T>G and g.11579368C>T) were detected in the Mrf4 and MyoD gene, respectively. The diameters of thigh and pectoralis muscle fibers were higher in birds with the combined genotypes of GG-TT and TT-CT (p<0.05). Moreover, the interaction between housing system and combined genotypes has no significant effect on the traits of muscle fiber (p>0.05). Our findings suggest that the combined genotypes of TT-CT and GG-TT might be advantageous for muscle fiber traits, and could be the potential genetic markers for breeding program in Erlang Mountain Chickens. PMID- 25925056 TI - Proteomic Analysis of Bovine Pregnancy-specific Serum Proteins by 2D Fluorescence Difference Gel Electrophoresis. AB - Two dimensional-fluorescence difference gel electrophoresis (2D DIGE) is an emerging technique for comparative proteomics, which improves the reproducibility and reliability of differential protein expression analysis between samples. The purpose of this study was to investigate bovine pregnancy-specific proteins in the proteome between bovine pregnant and non-pregnant serum using DIGE technique. Serums of 2 pregnant Holstein dairy cattle at day 21 after artificial insemination and those of 2 non-pregnant were used in this study. The pre electrophoretic labeling of pregnant and non-pregnant serum proteins were mixed with Cy3 and Cy5 fluorescent dyes, respectively, and an internal standard was labeled with Cy2. Labeled proteins with Cy2, Cy3, and Cy5 were separated together in a single gel, and then were detected by fluorescence image analyzer. The 2D DIGE method using fluorescence CyDye DIGE flour had higher sensitivity than conventional 2D gel electrophoresis, and showed reproducible results. Approximately 1,500 protein spots were detected by 2D DIGE. Several proteins showed a more than 1.5-fold up and down regulation between non-pregnant and pregnant serum proteins. The differentially expressed proteins were identified by MALDI-TOF mass spectrometer. A total 16 protein spots were detected to regulate differentially in the pregnant serum, among which 7 spots were up-regulated proteins such as conglutinin precursor, modified bovine fibrinogen and IgG1, and 6 spots were down-regulated proteins such as hemoglobin, complement component 3, bovine fibrinogen and IgG2a three spots were not identified. The identified proteins demonstrate that early pregnant bovine serum may have several pregnancy specific proteins, and these could be a valuable information for the development of pregnancy-diagnostic markers in early pregnancy bovine serum. PMID- 25925057 TI - Milk Yield, Composition, and Fatty Acid Profile in Dairy Cows Fed a High concentrate Diet Blended with Oil Mixtures Rich in Polyunsaturated Fatty Acids. AB - To evaluate the effects of feeding linseed oil or/and sunflower oil mixed with fish oil on milk yield, milk composition and fatty acid (FA) profiles of dairy cows fed a high-concentrate diet, 24 crossbred primiparous lactating dairy cows in early lactation were assigned to a completely randomized design experiment. All cows were fed a high-concentrate basal diet and 0.38 kg dry matter (DM) molasses per day. Treatments were composed of a basal diet without oil supplement (Control), or diets of (DM basis) 3% linseed and fish oils (1:1, w/w, LSO-FO), or 3% sunflower and fish oils (1:1, w/w, SFO-FO), or 3% mixture (1:1:1, w/w) of linseed, sunflower, and fish oils (MIX-O). The animals fed SFO-FO had a 13.12% decrease in total dry matter intake compared with the control diet (p<0.05). No significant change was detected for milk yield; however, the animals fed the diet supplemented with SFO-FO showed a depressed milk fat yield and concentration by 35.42% and 27.20%, respectively, compared to those fed the control diet (p<0.05). Milk c9, t11-conjugated linoleic acid (CLA) proportion increased by 198.11% in the LSO-FO group relative to the control group (p<0.01). Milk C18:3n-3 (ALA) proportion was enhanced by 227.27% supplementing with LSO-FO relative to the control group (p<0.01). The proportions of milk docosahexaenoic acid (DHA) were significantly increased (p<0.01) in the cows fed LSO-FO (0.38%) and MIX-O (0.23%) compared to the control group (0.01%). Dietary inclusion of LSO-FO mainly increased milk c9, t11-CLA, ALA, DHA, and n-3 polyunsaturated fatty acids (PUFA), whereas feeding MIX-O improved preformed FA and unsaturated fatty acids (UFA). While the lowest n-6/n-3 ratio was found in the LSO-FO, the decreased atherogenecity index (AI) and thrombogenicity index (TI) seemed to be more extent in the MIX-O. Therefore, to maximize milk c9, t11-CLA, ALA, DHA, and n-3 PUFA and to minimize milk n-6/n-3 ratio, AI and TI, an ideal supplement would appear to be either LSO-FO or MIX-O. PMID- 25925058 TI - Gas Exchanges and Dehydration in Different Intensities of Conditioning in Tifton 85 Bermudagrass: Nutritional Value during Hay Storage. AB - The present study aimed at evaluating the intensity of Tifton 85 conditioning using a mower conditioner with free-swinging flail fingers and storage times on dehydration curve, fungi presence, nutritional value and in vitro digestibility of Tifton 85 bermudagrass hay dry matter (DM). The dehydration curve was determined in the whole plant for ten times until the baling. The zero time corresponded to the plant before cutting, which occurred at 11:00 and the other collections were carried out at 8:00, 10:00, 14:00, and 16:00. The experimental design was randomised blocks with two intensities of conditioning (high and low) and ten sampling times, with five replications. The high and low intensities related to adjusting the deflector plate of the free iron fingers (8 and 18 cm). In order to determine gas exchanges during Tifton 85 bermudagrass dehydration, there were evaluations of mature leaves, which were placed in the upper middle third of each branch before the cutting, at every hour for 4 hours. A portable gas analyser was used by an infrared IRGA (6400xt). The analysed variables were photosynthesis (A), stomatal conductance (gs), internal CO2 concentration (Ci), transpiration (T), water use efficiency (WUE), and intrinsic water use efficiency (WUEi). In the second part of this study, the nutritional value of Tifton 85 hay was evaluated, so randomised blocks were designed in a split plot through time, with two treatments placed in the following plots: high and low intensity of cutting and five different time points as subplots: cutting (additional treatment), baling and after 30, 60, and 90 days of storage. Subsequently, fungi that were in green plants as well as hay were determined and samples were collected from the grass at the cutting period, during baling, and after 30, 60, and 90 days of storage. It was observed that Tifton 85 bermudagrass dehydration occurred within 49 hours, so this was considered the best time for drying hay. Gas exchanges were more intense before cutting, although after cutting they decreased until ceasing within 4 hours. The lowest values of acid detergent insoluble nitrogen were obtained with low conditioning intensity after 30 days of storage, 64.8 g/kg DM. The in vitro dry matter of Tifton 85 bermudagrass did not differ among the storage times or the conditioning intensities. There was no fungi present in the samples collected during the storage period up to 90 days after dehydration, with less than 30 colony forming units found on plate counting. The use of mower conditioners in different intensities of injury did not speed up the dehydration time of Tifton 85. PMID- 25925059 TI - Aerobic Stability and Effects of Yeasts during Deterioration of Non-fermented and Fermented Total Mixed Ration with Different Moisture Levels. AB - The present experiment evaluated the influence of moisture level and anaerobic fermentation on aerobic stability of total mixed ration (TMR). The dynamic changes in chemical composition and microbial population that occur after air exposure were examined, and the species of yeast associated with the deterioration process were also identified in both non-fermented and fermented TMR to deepen the understanding of aerobic deterioration. The moisture levels of TMR in this experiment were adjusted to 400 g/kg (low moisture level, LML), 450 g/kg (medium moisture level, MML), and 500 g/kg (high moisture level, HML), and both non-fermented and 56-d-fermented TMR were subjected to air exposure to determine aerobic stability. Aerobic deterioration resulted in high losses of nutritional components and largely reduced dry matter digestibility. Non fermented TMR deteriorated during 48 h of air exposure and the HML treatment was more aerobically unstable. On dry matter (DM) basis, yeast populations significantly increased from 10(7) to 10(10) cfu/g during air exposure, and Candida ethanolica was the predominant species during deterioration in non fermented TMR. Fermented TMR exhibited considerable resistance to aerobic deterioration. Spoilage was only observed in the HML treatment and its yeast population increased dramatically to 10(9) cfu/g DM when air exposure progressed to 30 d. Zygosaccharomyces bailii was the sole yeast species isolated when spoilage occurred. These results confirmed that non-fermented and fermented TMR with a HML are more prone to spoilage, and fermented TMR has considerable resistance to aerobic deterioration. Yeasts can trigger aerobic deterioration in both non-fermented and fermented TMR. C. ethanolica may be involved in the spoilage of non-fermented TMR and the vigorous growth of Z. bailii can initiate aerobic deterioration in fermented TMR. PMID- 25925060 TI - Effects of benzoic Acid and thymol on growth performance and gut characteristics of weaned piglets. AB - A total of 144 weaned crossed pigs were used in a 42-d trial to explore the effects of different concentrations/combinations of benzoic acid and thymol on growth performance and gut characteristics in weaned pigs. Pigs were randomly allotted to 4 dietary treatments: i) control (C), basal diet, ii) C+1,000 mg/kg benzoic acid+100 mg/kg thymol (BT1), iii) C+1,000 mg/kg benzoic acid+200 mg/kg thymol (BT2) and, iv) C+2,000 mg/kg benzoic acid+100 mg/kg thymol (BT3). Relative to the control, pigs fed diet BT3 had lower diarrhoea score during the overall period (p<0.10) and improved feed to gain ratio between days 1 to 14 (p<0.05), which was accompanied by improved apparent total tract digestibility of ether extract, Ca and crude ash (p<0.05), and larger lipase, lactase and sucrose activities in the jejunum (p<0.05) at d 14 and d 42. Similarly, relative to the control, pigs fed diet BT3 had higher counts for Lactobacillus spp in digesta of ileum at d 14 (p<0.05), and pigs fed diets BT1, BT2, or BT3 also had higher counts of Bacillus spp in digesta of caecum at d 14 (p<0.05), and lower concentration of ammonia nitrogen in digesta of caecum at d 14 and d 42 (p<0.05). Finally, pigs fed diet BT3 had higher concentration of butyric acid in digesta of caecum at d 42 (p<0.05), and a larger villus height:crypt depth ratio in jejunum and ileum at d 14 (p<0.05) than pigs fed the control diet. In conclusion, piglets fed diet supplementation with different concentrations/combinations of benzoic acid and thymol could improve feed efficiency and diarrhoea, and improve gut microfloral composition. The combination of 2,000 mg/kg benzoic acid+100 mg/kg thymol produced better effects than other treatments in most measurements. PMID- 25925061 TI - Effects of dietary corticosterone on yolk colors and eggshell quality in laying hens. AB - The objective of this study was to investigate the effects of dietary corticosterone on egg quality. For 2 weeks hens received either control or experimental diet containing corticosterone at 30 mg/kg diet. Feed intake and egg production were monitored daily, and body weight measured weekly. Egg weights and egg quality were measured daily. Corticosterone treatment resulted in a remarkable increase in feed intake and sharp decrease in egg production compared with control (p<0.05) whereas body weight remained unchanged. Decreased albumen height, but no changes in egg weight, led to decreased Haugh unit (p<0.05). Corticosterone caused elevated eggshell thickness (p<0.05) without altering weight and strength, suggesting possible changes in shell structure. Yolk color and redness were increased by corticosterone (p<0.05) but lightness and yellowness were either not changed or inconsistent over the time period of measurements. Increased concentrations in plasma were also found for corticosterone, glucose, cholesterol, creatinine, uric acid, albumin, aspartate aminotransferase, creatine kinase, lactate dehydrogenase, total protein, and amylase (p<0.05), suggesting that corticosterone increased protein breakdown, renal dysfunctions and pancreatitis. Together, the current results imply that dietary corticosterone affects egg quality such as yolk colors and shell thickness, in addition to its effects on feed intake and egg production. PMID- 25925062 TI - Effects of inclusion levels of wheat bran and body weight on ileal and fecal digestibility in growing pigs. AB - The objective of this study was to determine the effects of graded inclusions of wheat bran (0%, 9.65%, 48.25% wheat bran) and two growth stages (from 32.5 to 47.2 kg and 59.4 to 78.7 kg, respectively) on the apparent ileal digestibility (AID), apparent total tract digestibility (ATTD) and hindgut fermentation of nutrients and energy in growing pigs. Six light pigs (initial body weight [BW] 32.5+/-2.1 kg) and six heavy pigs (initial BW 59.4+/-3.2 kg) were surgically prepared with a T-cannula in the distal ileum. A difference method was used to calculate the nutrient and energy digestibility of wheat bran by means of comparison with a basal diet consisting of corn-soybean meal (0% wheat bran). Two additional diets were formulated by replacing 9.65% and 48.25% wheat bran by the basal diet, respectively. Each group of pigs was allotted to a 6*3 Youden square design, and pigs were fed to three experimental diets during three 11-d periods. Hindgut fermentation values were calculated as the differences between ATTD and AID values. For the wheat bran diets, the AID and ATTD of dry matter (DM), ash, organic matter (OM), carbohydrates (CHO), gross energy (GE), and digestible energy (DE) decreased with increasing inclusion levels of wheat bran (p<0.05). While only AID of CHO and ATTD of DM, ash, OM, CHO, GE, and DE content differed (p<0.05) when considering the BW effect. For the wheat bran ingredient, there was a wider variation effect (p<0.01) on the nutrient and energy digestibility of wheat bran in 9.65% inclusion level due to the coefficient of variation (CV) of the nutrient and energy digestibility being higher at 9.65% compared to 48.25% inclusion level of wheat bran. Digestible energy content of wheat bran at 48.25% inclusion level (4.8 and 6.7 MJ/kg of DM, respectively) fermented by hindgut was significantly higher (p<0.05) than that in 9.65% wheat bran inclusion level (2.56 and 2.12 MJ/kg of DM, respectively), which was also affected (p<0.05) by two growth stages. This increase in hindgut fermentation caused the difference in ileal DE (p<0.05) to disappear at total tract level. All in all, increasing wheat bran levels in diets negatively influences the digestibility of some nutrients in pigs, while it positively affects the DE fermentation in the hindgut. PMID- 25925063 TI - Estimation of pork quality traits using exsanguination blood and postmortem muscle metabolites. AB - The current study was designed to estimate the pork quality traits using metabolites from exsanguination blood and postmortem muscle simultaneously under the Korean standard pre- and post-slaughter conditions. A total of 111 Yorkshire (pure breed and castrated male) pigs were evaluated under the Korean standard conditions. Measurements were taken of the levels of blood glucose and lactate at exsanguination, and muscle glycogen and lactate content at 45 min and 24 h postmortem. Certain pork quality traits were also evaluated. Correlation analysis and multiple regression analysis including stepwise regression were performed. Exsanguination blood glucose and lactate levels were positively correlated with each other, negatively related to postmortem muscle glycogen content and positively associated with postmortem muscle lactate content. A rapid and extended postmortem glycolysis was associated with high levels of blood glucose and lactate, with high muscle lactate content, and with low muscle glycogen content during postmortem. In addition, these were also correlated with paler meat color and reduced water holding capacity. The results of multiple regression analyses also showed that metabolites in exsanguination blood and postmortem muscle explained variations in pork quality traits. Especially, levels of blood glucose and lactate and content of muscle glycogen at early postmortem were significantly associated with an elevated early glycolytic rate. Furthermore, muscle lactate content at 24 h postmortem alone accounted for a considerable portion of the variation in pork quality traits. Based on these results, the current study confirmed that the main factor influencing pork quality traits is the ultimate lactate content in muscle via postmortem glycolysis, and that levels of blood glucose and lactate at exsanguination and contents of muscle glycogen and lactate at postmortem can explain a large portion of the variation in pork quality even under the standard slaughter conditions. PMID- 25925064 TI - Molecular Analysis of Alternative Transcripts of the Equine Cordon-Bleu WH2 Repeat Protein-Like 1 (COBLL1) Gene. AB - The purpose of this study was to investigate the alternative splicing in equine cordon-bleu WH2 repeat protein-like 1 (COBLL1) gene that was identified in horse muscle and blood leukocytes, and to predict functional consequences of alternative splicing by bioinformatics analysis. In a previous study, RNA-seq analysis predicted the presence of alternative spliced isoforms of equine COBLL1, namely COBLL1a as a long form and COBLL1b as a short form. In this study, we validated two isoforms of COBLL1 transcripts in horse tissues by the real-time polymerase chain reaction, and cloned them for Sanger sequencing. The sequencing results showed that the alternative splicing occurs at exon 9. Prediction of protein structure of these isoforms revealed three putative phosphorylation sites at the amino acid sequences encoded in exon 9, which is deleted in COBLL1b. In expression analysis, it was found that COBLL1b was expressed ubiquitously and equivalently in all the analyzed tissues, whereas COBLL1a showed strong expression in kidney, spinal cord and lung, moderate expression in heart and skeletal muscle, and low expression in thyroid and colon. In muscle, both COBLL1a and COBLL1b expression decreased after exercise. It is assumed that the regulation of COBLL1 expression may be important for regulating glucose level or switching of energy source, possibly through an insulin signaling pathway, in muscle after exercise. Further study is warranted to reveal the functional importance of COBLL1 on athletic performance in race horses. PMID- 25925065 TI - Biocomputational characterization and evolutionary analysis of bubaline dicer1 enzyme. AB - Dicer, an ribonuclease type III type endonuclease, is the key enzyme involved in biogenesis of microRNAs (miRNAs) and small interfering RNAs (siRNAs), and thus plays a critical role in RNA interference through post transcriptional regulation of gene expression. This enzyme has not been well studied in the Indian water buffalo, an important species known for disease resistance and high milk production. In this study, the primary coding sequence (5,778 bp) of bubaline dicer (GenBank: AB969677.1) was determined and the bubaline Dicer1 biocomputationally characterized to determine the phylogenetic signature among higher eukaryotes. The evolutionary tree revealed that all the transcript variants of Dicer1 belonging to a specific species were within the same node and the sequences belonging to primates, rodents and lagomorphs, avians and reptiles formed independent clusters. The bubaline dicer1 is closely related to that of cattle and other ruminants and significantly divergent from dicer of lower species such as tapeworm, sea urchin and fruit fly. Evolutionary divergence analysis conducted using MEGA6 software indicated that dicer has undergone purifying selection over the time. Seventeen divergent sequences, representing each of the families/taxa were selected to study the specific regions of positive vis-a-vis negative selection using different models like single likelihood ancestor counting, fixed effects likelihood, and random effects likelihood of Datamonkey server. Comparative analysis of the domain structure revealed that Dicer1 is conserved across mammalian species while variation both in terms of length of Dicer enzyme and presence or absence of domain is evident in the lower organisms. PMID- 25925066 TI - Molecular Phylogenetic Diversity and Spatial Distribution of Bacterial Communities in Cooling Stage during Swine Manure Composting. AB - Polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) and subsequent sub-cloning and sequencing were used in this study to analyze the molecular phylogenetic diversity and spatial distribution of bacterial communities in different spatial locations during the cooling stage of composted swine manure. Total microbial DNA was extracted, and bacterial near full-length 16S rRNA genes were subsequently amplified, cloned, RFLP-screened, and sequenced. A total of 420 positive clones were classified by RFLP and near-full-length 16S rDNA sequences. Approximately 48 operational taxonomic units (OTUs) were found among 139 positive clones from the superstratum sample; 26 among 149 were from the middle-level sample and 35 among 132 were from the substrate sample. Thermobifida fusca was common in the superstratum layer of the pile. Some Bacillus spp. were remarkable in the middle-level layer, and Clostridium sp. was dominant in the substrate layer. Among 109 OTUs, 99 displayed homology with those in the GenBank database. Ten OTUs were not closely related to any known species. The superstratum sample had the highest microbial diversity, and different and distinct bacterial communities were detected in the three different layers. This study demonstrated the spatial characteristics of the microbial community distribution in the cooling stage of swine manure compost. PMID- 25925067 TI - Nitrogen Removal from Milking Center Wastewater via Simultaneous Nitrification and Denitrification Using a Biofilm Filtration Reactor. AB - Milking center wastewater (MCW) has a relatively low ratio of carbon to nitrogen (C/N ratio), which should be separately managed from livestock manure due to the negative impacts of manure nutrients and harmful effects on down-stream in the livestock manure process with respect to the microbial growth. Simultaneous nitrification and denitrification (SND) is linked to inhibition of the second nitrification and reduces around 40% of the carbonaceous energy available for denitrification. Thus, this study was conducted to find the optimal operational conditions for the treatment of MCW using an attached-growth biofilm reactor; i.e., nitrogen loading rate (NLR) of 0.14, 0.28, 0.43, and 0.58 kg m(-3) d(-1) and aeration rate of 0.06, 0.12, and 0.24 m(3) h(-1) were evaluated and the comparison of air-diffuser position between one-third and bottom of the reactor was conducted. Four sand packed-bed reactors with the effective volume of 2.5 L were prepared and initially an air-diffuser was placed at one third from the bottom of the reactor. After the adaptation period of 2 weeks, SND was observed at all four reactors and the optimal NLR of 0.45 kg m(-3) d(-1) was found as a threshold value to obtain higher nitrogen removal efficiency. Dissolved oxygen (DO) as one of key operational conditions was measured during the experiment and the reactor with an aeration rate of 0.12 m(3) h(-1) showed the best performance of NH4-N removal and the higher total nitrogen removal efficiency through SND with appropriate DO level of ~0.5 mg DO L(-1). The air-diffuser position at one third from the bottom of the reactor resulted in better nitrogen removal than at the bottom position. Consequently, nitrogen in MCW with a low C/N ratio of 2.15 was successfully removed without the addition of external carbon sources. PMID- 25925068 TI - Modelling Pasture-based Automatic Milking System Herds: System Fitness of Grazeable Home-grown Forages, Land Areas and Walking Distances. AB - To maintain a predominantly pasture-based system, the large herd milked by automatic milking rotary would be required to walk significant distances. Walking distances of greater than 1-km are associated with an increased incidence of undesirably long milking intervals and reduced milk yield. Complementary forages can be incorporated into pasture-based systems to lift total home grown feed in a given area, thus potentially 'concentrating' feed closer to the dairy. The aim of this modelling study was to investigate the total land area required and associated walking distance for large automatic milking system (AMS) herds when incorporating complementary forage rotations (CFR) into the system. Thirty-six scenarios consisting of 3 AMS herds (400, 600, 800 cows), 2 levels of pasture utilisation (current AMS utilisation of 15.0 t dry matter [DM]/ha, termed as moderate; optimum pasture utilisation of 19.7 t DM/ha, termed as high) and 6 rates of replacement of each of these pastures by grazeable CFR (0%, 10%, 20%, 30%, 40%, 50%) were investigated. Results showed that AMS cows were required to walk greater than 1-km when the farm area was greater than 86 ha. Insufficient pasture could be produced within a 1 km distance (i.e. 86 ha land) with home grown feed (HGF) providing 43%, 29%, and 22% of the metabolisable energy (ME) required by 400, 600, and 800 cows, respectively from pastures. Introduction of pasture (moderate): CFR in AMS at a ratio of 80:20 can feed a 400 cow AMS herd, and can supply 42% and 31% of the ME requirements for 600 and 800 cows, respectively with pasture (moderate): CFR at 50:50 levels. In contrast to moderate pasture, 400 cows can be managed on high pasture utilisation (provided 57% of the total ME requirements). However, similar to the scenarios conducted with moderate pasture, there was insufficient feed produced within 1-km distance of the dairy for 600 or 800 cows. An 800 cow herd required 140 and 130 ha on moderate and high pasture-based AMS system, respectively with the introduction of pasture: CFR at a ratio of 50:50. Given the impact of increasing land area past 86 ha on walking distance, cow numbers could be increased by purchasing feed from off the milking platform and/or using the land outside 1-km distance for conserved feed. However, this warrants further investigations into risk analyses of different management options including development of an innovative system to manage large herds in an AMS farming system. PMID- 25925069 TI - Classification of agents using Syrian hamster embryo (SHE) cell transformation assay (CTA) with ATR-FTIR spectroscopy and multivariate analysis. AB - The Syrian hamster embryo (SHE) cell transformation assay (pH 6.7) has a reported sensitivity of 87% and specificity of 83%, and an overall concordance of 85% with in vivo rodent bioassay data. To date, the SHE assay is the only in vitro assay that exhibits multistage carcinogenicity. The assay uses morphological transformation, the first stage towards neoplasm, as an endpoint to predict the carcinogenic potential of a test agent. However, scoring of morphologically transformed SHE cells is subjective. We treated SHE cells grown on low-E reflective slides with 2,6-diaminotoluene, N-nitroso-N-ethylnitroguanidine, N nitroso-N-methylurea, N-nitroso-N-ethylurea, EDTA, dimethyl sulphoxide (DMSO; vehicle control), methyl methanesulfonate, benzo[e]pyrene, mitomycin C, ethyl methanesulfonate, ampicillin or five different concentrations of benzo[a]pyrene. Macroscopically visible SHE colonies were located on the slides and interrogated using attenuated total reflection Fourier-transform infrared (ATR-FTIR) spectroscopy acquiring five spectra per colony. The acquired IR data were analysed using Fisher's linear discriminant analysis (LDA) followed by principal component analysis (PCA)-LDA cluster vectors to extract major and minor discriminating wavenumbers for each treatment class. Each test agent vs. DMSO and treatment-induced transformed cells vs. corresponding non-transformed were classified by a unique combination of major and minor discriminating wavenumbers. Alterations associated with Amide I, Amide II, lipids and nucleic acids appear to be important in segregation of classes. Our findings suggest that a biophysical approach of ATR-FTIR spectroscopy with multivariate analysis could facilitate a more objective interrogation of SHE cells towards scoring for transformation and ultimately employing the assay for risk assessment of test agents. PMID- 25925070 TI - Association between age and repair of oxidatively damaged DNA in human peripheral blood mononuclear cells. AB - It has been hypothesised that positive associations between age and levels of oxidative stress-generated damage to DNA may be related to an age-dependent decline in DNA repair activity. The objective of this study was to investigate the association between age and repair activity of oxidatively damaged DNA in peripheral blood mononuclear cells (PBMCs). We isolated PBMCs from subjects aged 18-83 years, as part of a health survey of the Danish population that focussed on lifestyle factors. The level of DNA repair activity was measured as incisions on potassium bromate-damaged DNA by the comet assay. There was an inverse association between age and DNA repair activity with a 0.65% decline in activity per year from age 18 to 83 (95% confidence interval: 0.16-1.14% per year). Univariate regression analysis also indicated inverse associations between DNA repair activity and waist-hip ratio (P < 0.05) and plasma concentrations of glycosylated hemoglobin (P = 0.07). However, multivariate regression analysis only showed an inverse association between age and DNA repair activity (P < 0.05), indicating that the decline in repair activity was not mediated by metabolic risk factors. In summary, the results show an inverse association between age and DNA repair activity of oxidatively damaged DNA. PMID- 25925071 TI - Evaluation of tubomanometry as a routine diagnostic tool for chronic obstructive Eustachian tube dysfunction. AB - OBJECTIVE: The objective of this study was to demonstrate the reliability of tubomanometry (TMM) described by Esteve in the diagnosis of chronic obstructive Eustachian tube (ET) dysfunction. STUDY DESIGN: Combined prospective and retrospective clinical study. SETTING: Tertiary referral centre, affiliated to university. METHODS: Two hundred and fifteen healthy subjects were examined once, 25 healthy subjects underwent TMM weekly for 6 weeks, and six healthy subjects were tested three times a day on at least three different days. The results of tubomanometry in healthy subjects were compared to data obtained from 171 patients with chronic obstructive ET dysfunction. RESULTS: In healthy subjects, there was an immediate opening of the ET at 30-50 mbar with an R-value <= 1 in at least 94% of the cases. In patients with chronic ET dysfunction, an opening of the ET could be registered in only 42% of patients at 30 mbar and in 58% at 50 mbar. The average of the R-value in these subjects always indicated towards a delayed opening (R > 1). When measurements are repeated in the same subject with a weekly interval, the intraclass correlation (ICC) was 0.49 for the TMM with 30 mbar, 0.51 for the TMM with 40 mbar and 0.52 for the TMM with 50 mbar in healthy people. For the patients with symptoms of ET dysfunction, the ICC for up to four repeated measures was 0.50 for the TMM with 30 mbar, 0.53 for the TMM with 40 mbar and 0.54 for the TMM with 50 mbar. A complete agreement of the results in repeated measurements within seconds was present in 86% for 30 and 40 mbar and in 79% for 50 mbar. The ICC was 0.61 for the TMM with 50 mbar, 0.62 for the TMM with 40 mbar and 0.68 for the TMM with 30 mbar. CONCLUSIONS: Tubomanometry can support the diagnosis of ET dysfunction. An R-value <= 1 indicates a regular function of the ET, an R-value >1 indicates a delayed opening of the ET, and no definable R value means no detectable opening of the ET. TMM is a reliable and valid instrument to support the diagnosis of chronic obstructive ET dysfunction. PMID- 25925072 TI - Parotidectomy combined with identification and preservation procedures of the great auricular nerve. AB - CONCLUSIONS: We found that the great auricular nerve (GAN) passes at the median (m) point between the tips of the mandibular angle and mastoid process. We also established the GAN definitive line using this point for rapid identification of the trunk of the GAN and systematic parotidectomy combined with procedures for identification of the GAN, elevation of the skin flap, and exposure of the parotid capsule, which showed a high rate of preservation of the nerve and the lobular branch. OBJECTIVE: The aim of this study was to improve parotidectomy and the rate of preservation of the GAN. METHODS: This study comprised 74 consecutive patients who were scheduled to have parotidectomy for benign tumors at our department between November 2011 and April 2014. We examined whether our GAN definitive line including the m point was useful to identify the trunk of the GAN and whether anterograde dissection of the nerve could be performed simultaneously with skin flap elevation and exposure of the parotid capsule and contributed to preservation of the trunk to the lobular branch. RESULTS: The trunk was identified under the GAN definitive line drawn preoperatively in 97.3% of cases (72/74). Combined surgery was successfully performed with a 95.9% (71/74) preservation rate of the GAN including the lobular branch. PMID- 25925074 TI - [Study on Extraction Conditions of Water-Soluble Substances-Purity Test (4) for Polyvinylpolypyrrolidone Listed in Japan's Specifications and Standards for Food Additives]. AB - The food additive polyvinylpolypyrrolidone is approved for use as a filter aid. The water-soluble substances test of polyvinylpolypyrrolidone often shows poor reproducibility. The instruction "boil gently while stirring using a stirrer" was considered critical, and so this issue was examined. The results showed that the use of a combination of both an oil bath and a stirrer provided good reproducibility without decomposition or other problems. PMID- 25925073 TI - Acute fatal posthypoxic leukoencephalopathy following benzodiazepine overdose: a case report and review of the literature. AB - BACKGROUND: Among the rare neurological complications of substances of abuse is the selective cerebral white matter injury (leukoencephalopathy). Of which, the syndrome of delayed post hypoxic encephalopathy (DPHL) that follows an acute drug overdose, in addition to "chasing the dragon" toxicity which results from chronic heroin vapor inhalation remain the most commonly described syndromes of toxic leukoencephalopathy. These syndromes are reported in association with opioid use. There are very few cases in the literature that described leukoencephalopathy following benzodiazepines, especially with an acute and progressive course. In this paper, we present a patient who developed an acute severe fatal leukoencephalopathy following hypoxic coma and systemic shock induced by benzodiazepine overdose. CASE PRESENTATION: A 19-year-old male was found comatose at home and brought to hospital in a deep coma, shock, hypoxia, and acidosis. Brain magnetic resonant imaging (MRI) revealed a strikingly selective white matter injury early in the course of the disease. The patient remained in a comatose state with no signs of neurologic recovery until he died few weeks later following an increase in the brain edema and herniation. CONCLUSION: Toxic leukoencephalopathy can occur acutely following an overdose of benzodiazepine and respiratory failure. This is unlike the usual cases of toxic leukoencephalopathy where there is a period of lucidity between the overdose and the development of white matter disease. Unfortunately, this syndrome remains of an unclear pathophysiology and with no successful treatment. PMID- 25925075 TI - [Basic principles of interpretation of hepatocellular hypertrophy in risk assessment in Japan]. AB - This article provided a scientific basis for determining whether liver hypertrophy, a common change in the liver induced by xenobiotics in toxicological studies, is an adaptive or adverse event. To maintain homeostasis in the whole organism, the liver frequently responds to xenobiotic exposure by increasing metabolic capacity via nuclear receptor activation. The resuiting hepatic adaptive responses (hepatocellular hypertrophy and increased relative liver weight) are potentially beneficial to the organism in providing increased capacity to respond to chemical-induced stress. However, excessive responses should be recognized as adverse. Practically, hepatocellular hypertrophy leading to the following alterations should be considered adverse: 1) hepatocellular degeneration/ necrosis, whether or not accompanied with inflammatory reaction, 2) changes indicating damage to biliary tracts, 3) disruption of fat metabolism, 4) pigmentation, 5) deviation from typical localization or morphological features of hypertrophied hepatocytes. PMID- 25925076 TI - [Surveillance of radioactive cesium in domestic foods on the Japanese market (Fiscal Years 2012 and 2013)]. AB - We surveyed the concentration of radioactive cesium in foods purchased at markets in areas where possible contamination has been a concern after the Fukushima accident. In fiscal years 2012 and 2013, we surveyed 1,735 and 1,674 foods, respectively, using a NaI (Tl) scintillation spectrometer for the screening test and a gamma-ray spectrometer with a germanium semiconductor detector for the final test. Only 3 and 4 samples (0.2% of our total samples) exceeded the regulatory limit (100 Bq/kg) for radioactive cesium in fiscal years 2012 and 2013, respectively. Our surveillance indicates that the pre-shipment monitoring of foods by local governments has been working effectively. PMID- 25925077 TI - [Interlaboratory study on migration test of antimony and germanium for food contact polyethylene terephthalate]. AB - An interlaboratory study was performed to evaluate a migration test method of antimony (Sb) and germanium (Ge), based on the Japanese Food Sanitation Law for food- contact polyethylene terephthalate. Eighteen laboratories participated, and quantified Sb and Ge in three test solutions as blind duplicates using graphite furnace atomic absorption spectrometry (GF-AAS), inductively coupled plasma optical emission spectrometry (ICP-OES) or induced coupled plasma-mass spectrometry (ICP-MS). Statistical analysis revealed that the trueness, repeatability and reproducibility were 98-107%, 1.7-7.5% and 2.0-18.8% by using GF-AAS and ICP-OES. The performance of these methods is sufficient for testing the specifications. The performance parameters of ICP-MS were 99-106%, 0.7-2.2% and 2.2-10.5%, respectively. ICP-MS is available as an alternative measuring method. However, in some laboratories, the quantitative values of Sb were higher than the addition levels. We found that Sb in working solutions is absorbed on glass vessels. Careful control of concentration in working solutions is required for Sb analysis. PMID- 25925078 TI - Characterizing gaseous peptide structure with action-EET and simulated annealing. AB - Evaluation of biomolecular structure in the gas phase is challenging, but worthwhile due to advantages in sensitivity and speed relative to traditional condensed phase approaches. Herein, we demonstrate that a recently developed method utilizing energy transfer to establish distance constraints can be combined with molecular dynamics calculations to rapidly and accurately reveal gaseous peptide structures. Three peptides in various charge states are examined. The influence of increasing charge state on peptide structure is easily observed. The presence of multiple conformations can be detected. Furthermore, the method is demonstrated to aid the assignment of charge, which is frequently nontrivial for peptides containing numerous acidic and basic residues that could adopt a variety of conformers of equal charge state. Comparison with ion mobility reveals that many low energy structures that are distinguishable by distance constraints would not be resolvable by collision cross section. Action-EET is demonstrated to be a powerful new tool for structure elucidation. PMID- 25925079 TI - Tailoring supramolecular nanotubes by bile salt based surfactant mixtures. AB - An approach for tailoring self-assembled tubular structures is described. By controlling the relative composition of a two-component surfactant mixture comprising the natural bile salt lithocholate and its bolamphiphilic derivative, it was possible to finely tune the nanotube cross-section of the mixed tubular aggregates that self-associated spontaneously in aqueous solution at pH 12. The diameter was found to vary up to 50% when the stoichiometric ratio of the two bile salts was changed. The tuning of supramolecular nanochannels with such remarkable precision is of significant interest for technological applications of these materials. PMID- 25925081 TI - Does the UK civil service code stifle reporting on health and science? PMID- 25925080 TI - H2O2-Activated Mitochondrial Phospholipase iPLA2gamma Prevents Lipotoxic Oxidative Stress in Synergy with UCP2, Amplifies Signaling via G-Protein-Coupled Receptor GPR40, and Regulates Insulin Secretion in Pancreatic beta-Cells. AB - AIMS: Pancreatic beta-cell chronic lipotoxicity evolves from acute free fatty acid (FA)-mediated oxidative stress, unprotected by antioxidant mechanisms. Since mitochondrial uncoupling protein-2 (UCP2) plays antioxidant and insulin regulating roles in pancreatic beta-cells, we tested our hypothesis, that UCP2 mediated uncoupling attenuating mitochondrial superoxide production is initiated by FA release due to a direct H2O2-induced activation of mitochondrial phospholipase iPLA2gamma. RESULTS: Pro-oxidant tert-butylhydroperoxide increased respiration, decreased membrane potential and mitochondrial matrix superoxide release rates of control but not UCP2- or iPLA2gamma-silenced INS-1E cells. iPLA2gamma/UCP2-mediated uncoupling was alternatively activated by an H2O2 burst, resulting from palmitic acid (PA) beta-oxidation, and it was prevented by antioxidants or catalase overexpression. Exclusively, nascent FAs that cleaved off phospholipids by iPLA2gamma were capable of activating UCP2, indicating that the previously reported direct redox UCP2 activation is actually indirect. Glucose-stimulated insulin release was not affected by UCP2 or iPLA2gamma silencing, unless pro-oxidant activation had taken place. PA augmented insulin secretion via G-protein-coupled receptor 40 (GPR40), stimulated by iPLA2gamma cleaved FAs (absent after GPR40 silencing). INNOVATION AND CONCLUSION: The iPLA2gamma/UCP2 synergy provides a feedback antioxidant mechanism preventing oxidative stress by physiological FA intake in pancreatic beta-cells, regulating glucose-, FA-, and redox-stimulated insulin secretion. iPLA2gamma is regulated by exogenous FA via beta-oxidation causing H2O2 signaling, while FAs are cleaved off phospholipids, subsequently acting as amplifying messengers for GPR40. Hence, iPLA2gamma acts in eminent physiological redox signaling, the impairment of which results in the lack of antilipotoxic defense and contributes to chronic lipotoxicity. PMID- 25925082 TI - Hypercalciuria in familial hyperkalemia and hypertension with KLHL3 mutations. AB - BACKGROUND: Familial hyperkalemia and hypertension (FHHt) is a rare genetic disorder manifested by hyperkalemia and early hypertension. Hypercalciuria is another accompanying feature. Mutations in WNK4 and WNK1 were found initially, and recently additional mutations were found in two genes, KLHL3 and CUL3, which are components of the Ubiquitin system. It was not reported whether these latter mutations are accompanied by hypercalciuria. METHODS: We compared urinary calcium excretion (UCa) in affected subjects with FHHt and KLHL3 mutations, and in their unaffected family members, and in affected subjects with FHHt and WNK4 Q565E mutation. RESULTS: Two new families with FHHt including a total number of 23 subjects, 10 of them affected, in whom previously described mutations in KLHL3 (Q309R and R528H) were identified. Presenting features were short stature in the first family, and transient tachypnea of the newborn (TTN) in the second. Affected subjects had hypercalciuria. UCa levels in affected subjects in the two families were significantly higher than in unaffected subjects (0.608 +/- 0.196 vs. 0.236 +/- 0.053 mmol Ca per mmol creatinine, respectively (p < 0.0001)). Hypercalciuria in FHHt with KLHL3 mutations is less severe than that observed in FHHt with the Q565E WNK4 mutation (0.608 +/- 0.196 (n = 10) mmol Ca per mmol creatinine versus 0.860 +/- 0.295 (n = 29), respectively (p = 0.0168)). CONCLUSIONS: FHHt caused by KLHL3 mutations is accompanied by hypercalciuria as well as hyperkalemia and hypertension. The similar phenomena observed for FHHt caused by WNK4 mutations fits the other evidence that WNK4 mutations are activating, and the aberrant mechanism of calcium handling by the kidney in FHHt. PMID- 25925084 TI - A Rapid Novel HPLC Method for Estimation of Eight Related Compounds in Azilsartan Kamedoxomil and Identification of Degradation Compounds by Using LC-MS. AB - A novel, rapid, specific and stability-indicating reverse-phase high-performance liquid chromatography method was developed for the quantitative determination of related compounds, obtained from two different synthetic routes and degradation products of Azilsartan kamedoxomil (AZL). The method was developed by using a YMC Pack pro C18 (150 * 4.6 mm, 3 um) column with a mobile phase containing a gradient mobile phase combination. The eluted compounds were measured at wavelength 220 nm. The developed method run time was 25 min, within which AZL and its eight impurities were well separated with minimum 3.0 resolution. The drug substance was subjected to stress conditions of hydrolysis (acid, base and water), oxidation, photolysis, sunlight, 75% relative humidity and thermal degradation as per International Conference on Harmonization (ICH) prescribed stress conditions to ascertain the stability-indicating power of the method. Significant degradation was observed during acid, base, peroxide, water hydrolysis and 75% relative humidity studies. The mass balance of AZL was close to 100% in all the stress condition. The developed method was validated as per the ICH guidelines with respect to specificity, linearity, limit of detection, limit of quantification, accuracy, precision and robustness. PMID- 25925083 TI - Negative emotional reactivity as a marker of vulnerability in the development of borderline personality disorder symptoms. AB - Negative emotionality is a distinguishing feature of borderline personality disorder (BPD). However, this person-level characteristic has not been examined as a marker of vulnerability in the development of this disorder. The current study utilized a multimethod approach to examine the interplay between negative emotional reactivity and cumulative exposure to family adversity on the development of BPD symptoms across 3 years (ages 16-18) in a diverse, at-risk sample of adolescent girls (N = 113). A latent variable of negative emotional reactivity was created from multiple assessments at age 16: self-report, emotion ratings to stressors from ecological assessments across 1 week, and observer rated negative affectivity during a mother-daughter conflict discussion task. Exposure to family adversity was measured cumulatively between ages 5 and 16 from annual assessments of family poverty, single parent household, and difficult life circumstances. The results from latent growth curve models demonstrated a significant interaction between negative emotional reactivity and family adversity, such that exposure to adversity strengthened the association between negative emotional reactivity and BPD symptoms. In addition, family adversity predicted increasing BPD symptoms during late adolescence. These findings highlight negative emotional reactivity as a marker of vulnerability that ultimately increases risk for the development of BPD symptoms. PMID- 25925085 TI - High-Performance Liquid-Chromatographic Analysis of Plasma Iohexol Concentrations. AB - In this study, a high-performance liquid-chromatographic (HPLC) method using photodiode array detection and isocratic conditions was developed for the analysis of plasma iohexol concentrations. Plasma proteins were precipitated with 1:1 volume of plasma and acetonitrile-ethanol-water (60:38.4:1.6, v/v/v). Iohexol concentrations in the supernatant phase were analyzed on a Waters Symmetry C-18 reversed-phase column under isocratic conditions at 245 nm. The extraction recoveries of iohexol from plasma were >95% and the plasma iohexol calibration curves were linear (R(2) >= 0.9998) from 10 to 1500 ug/mL. The within-day coefficients of variation (CVs) at plasma iohexol concentrations of 100, 375, 750 and 1500 ug/mL were 5.1, 3.5, 1.3 and 2.5%, respectively; the between-day CVs at 100, 375, 750 and 1500 ug/mL were 8.6, 4.2, 4.0 and 3.7%, respectively. The day to-day accuracies of the method at plasma iohexol concentrations of 50, 100, 375, 750 and 1500 ug/mL were 89.0, 99.4, 108.4, 103.6 and 101.2%, respectively (n = 5). The lower limit of plasma iohexol quantitation was 10 ug/mL and no interferences >9 ug/mL were found in over 75 pre-dose porcine plasma samples. The applicability of the method was demonstrated by determining the glomerular filtration rates of iohexol in the porcine (Sus scrofa) model. PMID- 25925086 TI - Commentary: How useful is 'burden of disease' to set public health priorities for infectious diseases? AB - For many infectious diseases, a low burden of disease does not equate to reduced potential public health importance. Many zoonotic infectious diseases have the potential for human-to-human transmission with potentially devastating consequences as currently seen with Ebola. Policymakers should not be lulled into thinking that the best use of resources is to allocate them only to the most obvious current problems. PMID- 25925087 TI - Controlling Nipah virus encephalitis in Bangladesh: Policy options. AB - Nipah virus (NiV) encephalitis is endemic in Bangladesh, with yearly seasonal outbreaks occurring since 2003. NiV has a notable case fatality rate, 75-100 per cent depending on the strain. In Bangladesh, primary transmission to humans is believed to be because of consumption of bat-contaminated date palm sap (DPS). Both the disease and the virus have been investigated extensively, however efforts to implement preventive strategies have met social and cultural challenges. Here we present a variety of community approaches to control the spread of Nipah encephalitis, along with advantages and disadvantages of each. This information may be useful to health workers and policymakers in potential NiV outbreak areas in Southeast Asia. PMID- 25925088 TI - Atopic Dermatitis in Early Life: Evidence for at Least Three Phenotypes? Results from the GUSTO Study. AB - BACKGROUND: Atopic dermatitis (AD) has been highlighted as a likely first step in the 'atopic march', emphasizing the need to define predisposing factors. METHODS: We evaluated AD risk factors and phenotypes in an Asian mother-offspring cohort . We defined three phenotypes of doctor-diagnosed AD based on the time of onset of the disease: early AD occurring within the first 6 months of life, AD occurring between 6 and 12 months and late-onset AD starting after the age of 12 months. RESULTS: Maternal allergic history was associated with an increased risk of developing early-onset AD (adjusted odds ratio (aOR) 20.46, 95% confidence interval (CI) 2.73-153.15, p < 0.01). Maternal allergic history and attendance at a daycare centre increased the odds of the development of AD between 6 and 12 months (aOR 4.19, 95% CI 1.01-17.45, p = 0.049 and aOR 11.42, 95% CI 1.49-87.50, p = 0.02, respectively). Risk factors associated with increased odds of late onset AD from 12 months were the consumption of probiotics between the age of 9 and 12 months and antibiotic treatment in the first 6 months of life (aOR 4.32, 95% CI 1.07-17.45, p = 0.04 and aOR 3.11, 95% CI 1.10-8.76, p = 0.03, respectively). Early-onset AD was associated with an increased risk of developing allergic sensitization (aOR 46.51, 95% CI 3.44-628.81, p < 0.01). CONCLUSION: We found that early-onset AD was mainly associated with familial factors, while late onset AD was associated with the consumption of antibiotics or probiotics. The findings support the concept that different phenotypes of AD exist in young children. PMID- 25925090 TI - Down-Regulation of MiR-1294 is Related to Dismal Prognosis of Patients with Esophageal Squamous Cell Carcinoma through Elevating C-MYC Expression. AB - AIMS: Changes in the expression of microRNAs (miRNAs) have been found in many cancers. This study aimed to investigate the expression of miR-1294 in patients with esophageal squamous cell carcinoma (ESCC) and its effect on prognosis. The underlying mechanism was explored as well. METHODS: We examined the expression of miRNA in human ESCC cancer tissues and adjacent non-tumor controls using quantitative reverse transcription polymerase chain reaction (qRT-PCR). And the relationship between expressions of miR-1294 and ESCC prognosis was analyzed in this study. Over-expression and knock-down methods were used to investigate the biological functions of miRNA-1294. The effect of miRNA-1294 on cell proliferation was evaluated by MTT. Besides, the function of miR-1294 on cell migration and invasion were evaluated by transwell assays. RESULTS: MiR-1294 was significantly down-regulated in human ESCC tissues compared with the non-tumor controls tissues (P=0.014). And patients with low miR-1294 expression had a significantly poorer prognosis than those with a high miR-1294 expression (P=0.040). Negative association was defined between the expression of miR-1294 and the c-MYC expression in ESCC patients (Pearson correlation, r=-0.299, P=0.0079). Additionally, it was found that miR-1294 suppress esophageal cancer cells proliferation, migration and invasion capacity through targeting c-MYC in vitro. CONCLUSIONS: Down-regulation of miR-1294 correlates with poor prognosis of ESCC. It's partially due to the reduced function of c-MYC. This study may give insight into the understanding of pathogenesis of esophageal cancer and provide evidence for diagnosis and treatment of esophageal cancer. PMID- 25925089 TI - [Personality and comorbidity: are there "difficult patients" in hip arthroplasty?]. AB - BACKGROUND: Concomitant disorders at the time of surgery in addition to psychological and socioeconomic patient characteristics may influence treatment outcomes in hip arthroplasty. OBJECTIVES: To describe the impact of these factors on perioperative complications and postoperative results in terms of function, quality of life, and patient satisfaction. MATERIALS AND METHODS: Review of relevant clinical studies, meta-analyses, and presentation of our own results. RESULTS: Comorbidities in general, especially in combination, increase the perioperative risk profile. Socioeconomic factors (education, professional qualifications, social deprivation) in addition to psychological variables (depression, distressed personality) can have a major impact on postoperative functional outcomes and patient satisfaction. CONCLUSIONS: It is of crucial importance to avoid inequalities in the provision of joint replacement for patients with hip osteoarthritis and co-existing risk factors. Preventive strategies should be implemented to reduce the negative impact of comorbidities on treatment outcome. Personalized communication and education may be helpful in avoiding unrealistic patient expectations before hip replacement. PMID- 25925091 TI - Application of ATR-FTIR spectroscopy to the study of thermally induced changes in secondary structure of protein molecules in solid state. AB - FTIR spectroscopy in combination with ATR sampling technique is the most accessible analytical technique to study secondary structure of proteins both in solid and aqueous solution. Although several studies have demonstrated the applications of ATR-FTIR to study conformational changes of solid dried proteins due to dehydration, there are no reports that demonstrate the application of ATR FTIR in the study of thermally induced changes of secondary structure of biomolecules directly on the solid state. In this study, four biomolecules of pharmaceutical interest, lysozyme, myoglobine, chymotripsin and human growth hormone (hGH), were studied on the solid state before and after different thermal treatments in order to relate changes of secondary structure to partial or total thermal denaturation processes. The results obtained provide experimental evidence that protein thermal denaturation in the solid state can be detected by displacement of carbonyl bands which correspond to conformational transformations between alpha-helix to beta-sheet or intermolecular beta-sheet; the molecules studied undergo this transformation when exposed to a temperature close to their denaturation temperature which may become irreversible depending on the extent of the heating treatment. These findings demonstrate that ATR-FTIR is an effective and time efficient technique that allows the monitoring of the protein thermal denaturation process of solid samples without further reconstitution or prior sample preparation. PMID- 25925092 TI - The potential clinical impact of the tissue-based map of the human proteome. AB - Since the first draft of the human genome sequence was published, several attempts have been made to map the human proteome, the functional representation of the genome. One such initiative is the Human Protein Atlas project, which recently released a tissue-based map of the human proteome. The Human Protein Atlas is based on the combination of transcriptomics and antibody-based proteomics for mapping the human proteome down to the single cell level. The comprehensive publicly available database contains more than 13 million unique immunohistochemistry images and provides an excellent resource for exploration and investigation of future drug targets and disease biomarkers. PMID- 25925094 TI - Anti-CCP Antibodies and Rheumatological Findings in Brazilian Patients with Crohn's Disease. AB - BACKGROUND/AIMS: Arthropathy is the most common extraintestinal manifestation observed in patients with Crohn's disease (CD). The present study aimed to screen rheumatoid arthritis (RA) using anti-CCP antibodies and rheumatoid factor (RF) in CD patients from Southern Brazil. Additionally, the presence of arthralgia and spondyloarthritis (SpA) was evaluated. CD patients, previously diagnosed using clinical data, imaging tests, endoscopic and histological findings, were included consecutively. METHODS: A total of 100 patients participated in the study, of which 60% were female, with a mean age of 41.9 +/- 12.04 (16-83 years). As controls, sera from 100 healthy individuals from the same geographic area were analyzed. RESULTS: Arthralgias were present in 55% of the patients, being more frequent in women (65.5%; 36/55), than in males (34.5%). No association was found between arthralgia and the treatment method used. Six patients (6/100) had SpA previously diagnosed. In the CD group, anti-CCP was positive only in one patient, while RF was positive in 7 patients (7%; 7/100). The anti-CCP positive patient (woman, 38 years old, RF positive), fulfilled the ACR criteria and was diagnosed as RA. In the control group, anti-CCP antibodies were detected in 1% (1/100) and RF was positive in 6 of the samples (6%). CONCLUSION: Our data showed low frequency of anti-CCP antibodies and RF in Brazilian patients with CD. Additionally, we found a high prevalence of arthralgia in these patients, with 6% of them diagnosed with SpA. PMID- 25925093 TI - Herpes simplex virus type 1 infection in neurons leads to production and nuclear localization of APP intracellular domain (AICD): implications for Alzheimer's disease pathogenesis. AB - Several data indicate that neuronal infection with herpes simplex virus type 1 (HSV-1) causes biochemical alterations reminiscent of Alzheimer's disease (AD) phenotype. They include accumulation of amyloid-beta (Abeta), which originates from the cleavage of amyloid precursor protein (APP), and hyperphosphorylation of tau protein, which leads to neurofibrillary tangle deposition. HSV-1 infection triggers APP processing and drives the production of several fragments including APP intracellular domain (AICD) that exerts transactivating properties. Herein, we analyzed the production and intracellular localization of AICD following HSV-1 infection in neurons. We also checked whether AICD induced the transcription of two target genes, neprilysin (nep) and glycogen synthase kinase 3beta (gsk3beta), whose products play a role in Abeta clearance and tau phosphorylation, respectively. Our data indicate that HSV-1 led to the accumulation and nuclear translocation of AICD in neurons. Moreover, results from chromatin immunoprecipitation assay showed that AICD binds the promoter region of both nep and gsk3beta. Time course analysis of NEP and GSK3beta expression at both mRNA and protein levels demonstrated that they are differently modulated during infection. NEP expression and enzymatic activity were initially stimulated but, with the progression of infection, they were down-regulated. In contrast, GSK3beta expression remained nearly unchanged, but the analysis of its phosphorylation suggests that it was inactivated only at later stages of HSV-1 infection. Thus, our data demonstrate that HSV-1 infection induces early upstream events in the cell that may eventually lead to Abeta deposition and tau hyperphosphorylation and further suggest HSV-1 as a possible risk factor for AD. PMID- 25925095 TI - Renal Cell Carcinoma: Delayed Metachronous Metastases to Parotid and Cerebellum. AB - PURPOSE: The purpose of this report is to describe a rare case of delayed metachronous isolated metastases of renal cell carcinoma (RCC) to the parotid gland and the cerebellum. The metastases occurred more than a decade after treatment of the primary tumor without any other systemic involvement. In addition, the potential differential diagnosis of the parotid mass based on presentation and imaging is discussed. MATERIALS AND METHODS: An 83-year-old man presented for evaluation and treatment of a rapidly growing mass at the right parotid region. He had a history of RCC resection 10 years before this presentation and had no evidence of persistent disease at the primary site. The diagnosis of metastatic RCC was made after fine-needle aspiration biopsy examination of the mass. The patient underwent superficial parotidectomy for resection of the tumor. Approximately 1.5 years later, he complained of loss of balance. Further investigation disclosed a cerebellar mass that at biopsy examination was found to represent RCC. He underwent stereotactic ablation of the mass. He currently remains free of disease at the primary site and the parotid and without further known brain metastases. RESULTS: This report presents the 29th case of a solitary parotid mass consistent with metastatic RCC 10 years after successful treatment of the primary RCC. Approximately 1.5 years later, the patient presented with new-onset loss of balance. Further investigation disclosed a mass to the cerebellum consistent with metastatic RCC. This case is unique because the brain involvement occurred extremely late, 11.5 years after successful treatment of primary RCC and 1.5 years after resection of a metastatic RCC to the parotid, and without any evidence of other metastases. CONCLUSIONS: Late distant metastases of RCC are not uncommon and patients require life surveillance follow-up, but such late presentation of metachronous metastases without systemic disease progression is unique. The patterns of metastases of RCC are not clearly defined and this diagnosis should be considered, especially in patients with relevant history. PMID- 25925096 TI - Number of genes controlling a quantitative trait in a hybrid zone of the aposematic frog Ranitomeya imitator. AB - The number of genes controlling mimetic traits has been a topic of much research and discussion. In this paper, we examine a mimetic, dendrobatid frog Ranitomeya imitator, which harbours extensive phenotypic variation with multiple mimetic morphs, not unlike the celebrated Heliconius system. However, the genetic basis for this polymorphism is unknown, and not easy to determine using standard experimental approaches, for this hard-to-breed species. To circumvent this problem, we first develop a new protocol for automatic quantification of complex colour pattern phenotypes from images. Using this method, which has the potential to be applied in many other systems, we define a phenotype associated with differences in colour pattern between different mimetic morphs. We then proceed to develop a maximum-likelihood method for estimating the number of genes affecting a quantitative trait segregating in a hybrid zone. This method takes advantage of estimates of admixture proportions obtained using genetic data, such as microsatellite markers, and is applicable to any other system where a phenotype has been quantified in an admixture/introgression zone. We evaluate the method using extensive simulations and apply it to the R. imitator system. We show that probably one or two, or at most three genes, control the mimetic phenotype segregating in a R. imitator hybrid zone identified using image analyses. PMID- 25925098 TI - Chordate phylogeny and the meaning of categorial ranks in modern evolutionary biology. PMID- 25925097 TI - Homoploid hybrid speciation and genome evolution via chromosome sorting. AB - Genomes of numerous diploid plant and animal species possess traces of interspecific crosses, and many researches consider them as support for homoploid hybrid speciation (HHS), a process by which a new reproductively isolated species arises through hybridization and combination of parts of the parental genomes, but without an increase in ploidy. However, convincing evidence for a creative role of hybridization in the origin of reproductive isolation between hybrid and parental forms is extremely limited. Here, through studying Agrodiaetus butterflies, we provide proof of a previously unknown mode of HHS based on the formation of post-zygotic reproductive isolation via hybridization of chromosomally divergent parental species and subsequent fixation of a novel combination of chromosome fusions/fissions in hybrid descendants. We show that meiotic segregation, operating in the hybrid lineage, resulted in the formation of a new diploid genome, drastically rearranged in terms of chromosome number. We also demonstrate that during the heterozygous stage of the hybrid species formation, recombination was limited between rearranged chromosomes of different parental origin, representing evidence that the reproductive isolation was a direct consequence of hybridization. PMID- 25925099 TI - Social evolution in the shadow of asymmetrical relatedness. AB - The persistence of altruism and spite remains an enduring problem of social evolution. It is well known that selection for these actions depends on the structure of the population-that is, on actors' genetic relationships to recipients and to the 'neighbourhood' upon which the effects of their actions redound. Less appreciated, however, is that population structure can cause genetic asymmetries between partners whereby the relatedness (defined relative to the neighbourhood) of an individual i to a partner j will differ from the relatedness of j to i. Here, we introduce a widespread mechanism of kin recognition to a model of dispersal in subdivided populations. In so doing, we uncover three remarkable consequences of asymmetrical relatedness. First, altruism directed at phenotypically similar partners evolves more easily among migrant than native actors. Second, spite directed at dissimilar partners evolves more easily among native than migrant actors. Third, unlike migrants, natives can evolve to pay costs that far outstrip those they spitefully impose on others. We find that the frequency of natives relative to migrants amplifies the asymmetries between them. Taken together, our results reveal differentiated patterns of 'phenocentrism' that readily arise from asymmetries of relatedness. PMID- 25925100 TI - Functional role of phenylacetic acid from metapleural gland secretions in controlling fungal pathogens in evolutionarily derived leaf-cutting ants. AB - Fungus-farming ant colonies vary four to five orders of magnitude in size. They employ compounds from actinomycete bacteria and exocrine glands as antimicrobial agents. Atta colonies have millions of ants and are particularly relevant for understanding hygienic strategies as they have abandoned their ancestors' prime dependence on antibiotic-based biological control in favour of using metapleural gland (MG) chemical secretions. Atta MGs are unique in synthesizing large quantities of phenylacetic acid (PAA), a known but little investigated antimicrobial agent. We show that particularly the smallest workers greatly reduce germination rates of Escovopsis and Metarhizium spores after actively applying PAA to experimental infection targets in garden fragments and transferring the spores to the ants' infrabuccal cavities. In vitro assays further indicated that Escovopsis strains isolated from evolutionarily derived leaf-cutting ants are less sensitive to PAA than strains from phylogenetically more basal fungus-farming ants, consistent with the dynamics of an evolutionary arms race between virulence and control for Escovopsis, but not Metarhizium. Atta ants form larger colonies with more extreme caste differentiation relative to other attines, in societies characterized by an almost complete absence of reproductive conflicts. We hypothesize that these changes are associated with unique evolutionary innovations in chemical pest management that appear robust against selection pressure for resistance by specialized mycopathogens. PMID- 25925101 TI - Suffixation influences receivers' behaviour in non-human primates. AB - Compared to humans, non-human primates have very little control over their vocal production. Nonetheless, some primates produce various call combinations, which may partially offset their lack of acoustic flexibility. A relevant example is male Campbell's monkeys (Cercopithecus campbelli), which give one call type ('Krak') to leopards, while the suffixed version of the same call stem ('Krak oo') is given to unspecific danger. To test whether recipients attend to this suffixation pattern, we carried out a playback experiment in which we broadcast naturally and artificially modified suffixed and unsuffixed 'Krak' calls of male Campbell's monkeys to 42 wild groups of Diana monkeys (Cercopithecus diana diana). The two species form mixed-species groups and respond to each other's vocalizations. We analysed the vocal response of male and female Diana monkeys and overall found significantly stronger vocal responses to unsuffixed (leopard) than suffixed (unspecific danger) calls. Although the acoustic structure of the 'Krak' stem of the calls has some additional effects, subject responses were mainly determined by the presence or the absence of the suffix. This study indicates that suffixation is an evolved function in primate communication in contexts where adaptive responses are particularly important. PMID- 25925102 TI - Sexual selection's impacts on ecological specialization: an experimental test. AB - In many species, individuals specialize on different resources, thereby reducing competition. Such ecological specialization can promote the evolution of alternative ecomorphs-distinct phenotypes adapted for particular resources. Elucidating whether and how this process is influenced by sexual selection is crucial for understanding how ecological specialization promotes the evolution of novel traits and, potentially, speciation between ecomorphs. We evaluated the population-level effects of sexual selection (as mediated by mate choice) on ecological specialization in spadefoot toad tadpoles that express alternative ecomorphs. We manipulated whether sexual selection was present or reversed by mating females to their preferred versus non-preferred males, respectively. We then exposed their tadpoles to resource competition in experimental mesocosms. The resulting distribution of ecomorphs was similar between treatments, but sexual selection generated poorer trait integration in, and lower fitness of, the more specialized carnivore morph. Moreover, disruptive and directional natural selection were weaker in the sexual selection present treatment. Nevertheless, this effect on disruptive selection was smaller than previously documented effects of ecological opportunity and competitor density. Thus, sexual selection can inhibit adaptation to resource competition and thereby hinder ecological specialization, particularly when females obtain fitness benefits from mate choice that offset the cost of producing competitively inferior offspring. PMID- 25925103 TI - Is diversification in male reproductive traits driven by evolutionary trade-offs between weapons and nuptial gifts? AB - Many male animals have evolved exaggerated traits that they use in combat with rival males to gain access to females and secure their reproductive success. But some male animals invest in nuptial gifts that gains them access to females. Both these reproductive strategies are costly in that resources are needed to produce the weapon or nuptial gift. In closely related species where both weapons and nuptial gifts are present, little is known about the potential evolutionary trade off faced by males that have these traits. In this study, we use dobsonflies (order Megaloptera, family Corydalidae, subfamily Corydalinae) to examine the presence and absence of enlarged male weapons versus nuptial gifts within and among species. Many dobsonfly species are sexually dimorphic, and males possess extremely enlarged mandibles that they use in battles, whereas in other species, males produce large nuptial gifts that increase female fecundity. In our study, we show that male accessory gland size strongly correlates with nuptial gift size and that when male weapons are large, nuptial gifts are small and vice versa. We mapped weapons and nuptial gifts onto a phylogeny we constructed of 57 species of dobsonflies. Our among-species comparison shows that large nuptial gift production evolved in many species of dobsonfly but is absent from those with exaggerated weapons. This pattern supports the potential explanation that the trade-off in resource allocation between weapons and nuptial gifts is important in driving the diversity of male mating strategies seen in the dobsonflies, whereas reduced male-male competition in the species producing large spermatophores could be an alternative explanation on their loss of male weapons. Our results shed new light on the evolutionary interplay of multiple sexually selected traits in animals. PMID- 25925104 TI - A hybrid behavioural rule of adaptation and drift explains the emergent architecture of antagonistic networks. AB - Ecological processes that can realistically account for network architectures are central to our understanding of how species assemble and function in ecosystems. Consumer species are constantly selecting and adjusting which resource species are to be exploited in an antagonistic network. Here we incorporate a hybrid behavioural rule of adaptive interaction switching and random drift into a bipartite network model. Predictions are insensitive to the model parameters and the initial network structures, and agree extremely well with the observed levels of modularity, nestedness and node-degree distributions for 61 real networks. Evolutionary and community assemblage histories only indirectly affect network structure by defining the size and complexity of ecological networks, whereas adaptive interaction switching and random drift carve out the details of network architecture at the faster ecological time scale. The hybrid behavioural rule of both adaptation and drift could well be the key processes for structure emergence in real ecological networks. PMID- 25925105 TI - Sex allocation theory reveals a hidden cost of neonicotinoid exposure in a parasitoid wasp. AB - Sex allocation theory has proved to be one the most successful theories in evolutionary ecology. However, its role in more applied aspects of ecology has been limited. Here we show how sex allocation theory helps uncover an otherwise hidden cost of neonicotinoid exposure in the parasitoid wasp Nasonia vitripennis. Female N. vitripennis allocate the sex of their offspring in line with Local Mate Competition (LMC) theory. Neonicotinoids are an economically important class of insecticides, but their deployment remains controversial, with evidence linking them to the decline of beneficial species. We demonstrate for the first time to our knowledge, that neonicotinoids disrupt the crucial reproductive behaviour of facultative sex allocation at sub-lethal, field-relevant doses in N. vitripennis. The quantitative predictions we can make from LMC theory show that females exposed to neonicotinoids are less able to allocate sex optimally and that this failure imposes a significant fitness cost. Our work highlights that understanding the ecological consequences of neonicotinoid deployment requires not just measures of mortality or even fecundity reduction among non-target species, but also measures that capture broader fitness costs, in this case offspring sex allocation. Our work also highlights new avenues for exploring how females obtain information when allocating sex under LMC. PMID- 25925106 TI - The AVRDC - The World Vegetable Center mungbean (Vigna radiata) core and mini core collections. AB - BACKGROUND: Large ex situ germplasm collections generally harbor a wide range of crop diversity. AVRDC--The World Vegetable Center is holding in trust the world's second largest mungbean (Vigna radiata) germplasm collection with more than 6,700 accessions. Screening large collections for traits of interest is laborious and expensive. To enhance the access of breeders to the diversity of the crop, mungbean core and mini core collections have been established. RESULTS: The core collection of 1,481 entries has been built by random selection of 20% of the accessions after geographical stratification and subsequent cluster analysis of eight phenotypic descriptors in the whole collection. Summary statistics, especially the low differences of means, equal variance of the traits in both the whole and core collection and the visual inspection of quantile-quantile plots comparing the variation of phenotypic traits present in both collections indicated that the core collection well represented the pattern of diversity of the whole collection. The core collection was genotyped with 20 simple sequence repeat markers and a mini core set of 289 accessions was selected, which depicted the allele and genotype diversity of the core collection. CONCLUSIONS: The mungbean core and mini core collections plus their phenotypic and genotypic data are available for distribution to breeders. It is expected that these collections will enhance the access to biodiverse mungbean germplasm for breeding. PMID- 25925107 TI - Specificity of dermal mucin in the diagnosis of lupus erythematosus: comparison with other dermatitides and normal skin. AB - Increased dermal mucin is a feature of lupus erythematosus (LE); however, its amount and distribution have not been well characterized. The differentiation of LE from other forms of dermatitis can be challenging when other features of LE are subtle or equivocal. One hundred and thirty-five skin specimens showing LE, graft vs. host disease, erythema multiforme/fixed drug eruption, lichen planus, polymorphous light eruption (PMLE), urticaria, eczematous dermatitis and psoriasis and normal skin with and without photodamage were collected. The amounts of mucin in the papillary, superficial reticular and deep reticular dermis were scored from 0 to 3 on hematoxylin-eosin (H&E) and alcian blue (AB) stains, and compared between groups. The mean scores in the reticular dermis were significantly higher in LE than in other categories except PMLE and eczematous dermatitis. A combined H&E + AB score of >=5 in the superficial reticular dermis gave an overall specificity of 85.7% for LE. Mucin in the papillary dermis failed to distinguish among entities. Normal photodamaged skin showed significantly more mucin in the superficial reticular dermis compared to non-photodamaged skin. While LE is associated with increased mucin deposition, scant to moderate amount of mucin alone has limited specificity and is common in other dermatitides or photodamaged skin. PMID- 25925108 TI - Use of fluoride-containing water for the irrigation of soil-plant systems. AB - Many groundwaters used for irrigation contain elevated concentrations of F, but much remains unknown regarding how this F behaves within soils and plants. The present study investigated the adsorption and desorption of F from several soils in short- to medium-term irrigation systems and related foliar F concentrations in three forage plant species to the maximum tolerable level (MTL) in the diets of grazing animals (being 1.8 MUmol/g for young cattle, for example). Although adsorption isotherms could be successfully used to predict the behavior (adsorption and desorption) of F within the soil, this was not related to the subsequent accumulation of F in plant foliage. In addition, the extent to which F accumulated in the foliage depended on the plant species. Regardless, F generally did not accumulate in plant foliage to levels exceeding the MTL when used at rates equivalent to irrigation for 25 years. In addition to uptake by roots, F may accumulate in foliar tissues directly due to retention from overhead irrigation. The data presented here regarding the behavior of F in soils and plants will assist in the rigorous regulation of F-containing irrigation water to ensure maximum plant growth while simultaneously minimizing potential harm. PMID- 25925110 TI - Topical delivery of drugs for the effective treatment of fungal infections of skin. AB - The prevalence of fungal infections of skin has increased rapidly, affecting approximately 40 million people across the globe. A wide variety of antifungal drugs has been utilized in the effective management of numerous dermatological infections. Topical treatment of fungal infections has proved to be quite advantageous due to various factors like targeting the site of infection, minimizing systemic side effects, enhanced efficacy of treatment, and improved patient compliance. In spite the fact that these agents are therapeutically active on topical application, these have restricted drug delivery across the skin resulting in insufficient therapeutic index and may exert local as well as systemic side effects. The accomplishment of topical drug delivery needs to pacify two anomalous aspects, first the barrier nature of stratum corneum, and second, deposition of drug within the skin should be ideally achieved with limited percutaneous absorption. Thus, to facilitate the delivery of antifungal drugs and improve the treatment aspects, various novel delivery carriers have been developed. This article attempts to provide an in-depth knowledge of nanoparticulate and vesicular carriers. This article focuses on the different aspects of fungal infections and their effective treatment with antifungal drugs. Efficacy of various carrier systems (nanoparticulate and vesicular carriers) in delivering antifungal drugs topically has also been discussed. Besides, compiling various research reports, this article also includes formulation considerations inclusive of regulatory aspects of excipients used, the mechanisms of penetration, and patents reported. PMID- 25925111 TI - Proniosomes in transdermal drug delivery. AB - Proniosomes are liquid crystalline-compact niosomal hybrid that can be hydrated to form niosomal dispersion instantly before use. It is a promising drug carrier with better physical and chemical stability than niosomes. Proniosomes have the potential to be scaled up for industrial purposes. They have been remarkably considered for transdermal drug delivery because of their competences, including the penetration enhancing ability of surfactants and their non-toxic characteristics. This review offers current approaches in the research and development of proniosomal formulations for the transdermal delivery of drugs with a focus on therapeutic applications. PMID- 25925112 TI - Enhancing topical analgesic administration: review and prospect for transdermal and transbuccal drug delivery systems. AB - Topical administration is an appealing method for drug delivery due to its non invasiveness, self-controlled application, avoidance of first-pass metabolism in the liver and reduction of systemic side effects compared to other conventional routes such as oral and parenteral. However, topical administration must overcome the permeable barriers that skin and mucosa represent for the drug to achieve its desired therapeutic effect. Penetration of drugs through human skin is mainly impaired by the stratum corneum- the uppermost keratinized skin layer. In contrast, the stratified squamous epithelium (a nonkeratinized tissue) represents the major physical barrier for transbuccal drug administration in humans. Different technologies have been studied to enhance the bioavailability or local effects of drugs administered through skin and buccal mucosa. Those technologies involve the use of physical or chemical enhancers and new dosage forms such as vesicles, cyclodextrins, nanoparticles and other complex systems. Combinations of these technologies may further increase drug delivery in some cases. As analgesia is one of the main therapeutic effects sought through topical administration, this paper focuses on the review of drug delivery systems to improve the topical and transdermal/transbuccal drug delivery of substances with known analgesic action. A discussion of their possibilities and limitations is also included. PMID- 25925113 TI - Nanocarriers and their Actions to Improve Skin Permeability and Transdermal Drug Delivery. AB - Transdermal drug delivery is impeded by the natural barrier of epidermis namely stratum corneum. This limits the route to transport of drugs with a log octanol water partition coefficient of 1 to 3, molecular weight of less than 500 Da and melting point of less than 200 degrees C. Nanotechnology has received widespread investigation as nanocarriers are deemed to be able to fluidize the stratum corneum as a function of size, shape, surface charges, and hydrophilicity hydrophobicity balance, while delivering drugs across the skin barrier. This review provides an overview and update on the latest designs of liposomes, ethosomes, transfersomes, niosomes, magnetosomes, oilin- water nanoemulsions, water-in-oil nanoemulsions, bicontinuous nanoemulsions, covalently crosslinked polysaccharide nanoparticles, ionically crosslinked polysaccharide nanoparticles, polyelectrolyte coacervated nanoparticles and hydrophobically modified polysaccharide nanoparticles with respect to their ability to fuse or fluidize lipid/protein/tight junction regimes of skin, and effect changes in skin permeability and drug flux. Universal relationships of nanocarrier size, zeta potential and chemical composition on transdermal permeation characteristics of drugs will be developed and discussed. PMID- 25925114 TI - Recent advances in physical delivery enhancement of topical drugs. AB - The skin has evolved to resist the penetration of foreign substances and particles. Effective topical drug delivery into and/or through the skin is hindered by these epidermal barriers. A range of physical enhancement methods has been developed to selectively overcome this barrier. This review discusses recent advances in physical drug delivery by broadly separating the techniques into two main areas; indirect and direct approaches. Indirect approaches consist of electrical, vibrational or laser instrumentation that creates pores in the skin followed by application of the drug. Direct approaches consist of mechanical disruption of the epidermis using techniques such as microdermabrasion, biolistic injectors and microneedles. Although, in general, physical techniques are yet to be established in a clinical setting, the potential gains of enhancing delivery of compounds through the skin is of great significance and will no doubt continue to receive much attention. PMID- 25925115 TI - Lipid nanoparticles for dermal drug delivery. AB - Lipid based drug delivery systems have been widely studied and reported over the past decade and offer a useful alternative to other colloidal drug delivery systems. Skin is a popular route of drug delivery for locally and systemically acting drugs and nanoparticles are reported as a potential formulation strategy for dermal delivery. Although the skin acts as a natural physical barrier against penetration of foreign materials, including particulates, opportunities exist for the delivery of therapeutic nanoparticles, especially in diseased and damaged skin and via appendageal routes such as the openings of hair follicles. The extent and ability of nanoparticles to penetrate into the underlying viable tissue is still the subject of debate although recent studies have identified the follicular route as the most likely route of entry; this influences the potential applications of these dosage forms as a drug delivery strategy. This paper reviews present state of art of lipid-based nanocarriers focussing on solid lipid nanoparticles, nanostructured lipid carriers and nanoemulsions, their production methods, potential advantages and applications in dermal drug delivery. PMID- 25925116 TI - Potential of peptide-based enhancers for transdermal delivery. AB - The skin presents several advantages as an administration route, including the possibility of localizing drugs in the tissue and overcoming the first-pass effect. However, its use is limited by the barrier function of the tissue, which is provided mainly (but not exclusively) by the stratum corneum. Various strategies to overcome this layer, have been considered over the years, ranging from the use of physical methods such as iontophoresis to wellknown conventional chemical penetration enhancers like oleic acid and DMSO. However, delivery of hydrophilic and large compounds remains a challenge. More recently, selected groups of peptides have attracted increasing attention due to their ability to penetrate into the skin promoting the transport of small and large molecules, including nanodispersed systems. Here, we will discuss the properties and application to cutaneous (into the skin) and transdermal (across the skin) delivery of three groups of peptides, namely protein-transduction domains, phage displayed peptides and antimicrobial peptides. PMID- 25925117 TI - A review of polymeric colloidal nanogels in transdermal drug delivery. AB - Nanogel nanoparticles loaded with active compounds are referred to as Drug-loaded polymeric colloidal nanogels (DPCNs). These nanogels are emerging as promising carriers for transdermal drug delivery applications. Much interest has been directed towards the potential use of DPCNs to deliver a variety of drugs for either controlled or sustained drug delivery systems. Transdermal drug delivery systems (TDDS) have shown a number of beneficial properties such as improving patients compliance as they are conveniently dosed compared to intravenous and oral therapy. The use of TDDS depends on the effectiveness of the drug formulation to accumulate in sufficient concentrations at the specific targeted sites, hence the therapeutic significance of DPCNs in TDDS. Nanogels have a high drug loading capacity, biodegradability and biocompatibility, which are the key points in designing an efficient TDDS. The advanced development of DPCN has led to stimuli responsive drug delivery systems that release the entrapped drug under variable environmental incentives. The development of these drug delivery systems has created room for further research to characterize the physical and chemical properties of theses nanogels as well as their in vitro and in vivo behavior. Therefore this review presents an insight on the basic fabrication methods, advanced developments, limitations and therapeutic significance of the DPCN in TDDS as well as forthcoming potential applications. Despite these numerous positive scientific findings, efficient TDDS remains a challenge for pharmaceutical scientists and significant amount of research is still directed toward the development of superior TDDS. PMID- 25925118 TI - Dendritic nanoparticles for cutaneous drug delivery--testing in human skin and reconstructed human skin. AB - Dendritic nanoparticles have been developed with auspicious properties like high loading capacity for guest molecules, low polydispersity and tunable end groups. Demonstrating increased cellular uptake and bypassed efflux transporters, dendritic nanoparticles may offer new treatment options for therapy-resistant diseases. New core-shell architectures address the drawbacks of initial approaches. Especially tecto-dendrimers, bearing low-radii dendrimers on the surface of a bigger dendrimer, as well as the core-multishell architectures with an alkyl inner shell and a monomethylpoly(ethylene glycol) outer shell, gained interest for dermatotherapy. Moreover, the integration of e.g. pH labile groups into dendritic nanoparticles may offer triggered drug release. However, before declaring dendritic nanoparticles as an ultimate drug delivery system for skin penetration, dendritic nanoparticles need to prove their efficacy and safety in non-clinical, and subsequently in clinical studies. Here, we review major characteristics of human skin, and thus target structures for topical drug delivery systems. Focusing on the use as in vitro test system, we summarize the features of reconstructed human skin. Since drug delivery systems are intended to be applied to diseased skin, we additionally review latest insights into disease related changes in the highly prevalent skin diseases such as atopic dermatitis, and cutaneous squamous cell carcinoma, as well as in their respective human cell based skin disease models. We will conclude with the proposal of an integrated test strategy to promote the introduction of dendritic nanoparticles into medicinal products. PMID- 25925119 TI - Current pharmaceutical design on adhesive based transdermal drug delivery systems. AB - Drug-in-adhesive transdermal drug delivery matrix exploits intimate contact of the carrier with stratum corneum, the principal skin barrier to drug transport, to deliver the actives across the skin and into the systemic circulation. The main application challenges of drug-in-adhesive matrix lie in the physicochemical properties of skin varying with age, gender, ethnicity, health and environmental condition of patients. This in turn poses difficulty to design a universal formulation to meet the intended adhesiveness, drug release and drug permeation performances. This review focuses on pressure-sensitive adhesives, and their adhesiveness and drug release/permeation modulation mechanisms as a function of adhesive molecular structure and formulation attributes. It discusses approaches to modulate adhesive tackiness, strength, elasticity, hydrophilicity, molecular suspension capability and swelling capacity, which contribute to the net effect of adhesive on skin bonding, drug release and drug permeation. PMID- 25925120 TI - Vesicular carriers for skin drug delivery: the PheroidTM technology. AB - The skin remains an attractive area for drug delivery. The skin, however, often limits the ingress of drugs, because of its very low permeability. Much research, focusing on employing a variety of physical and chemical methods, aimed at reversibly altering skin permeability in favour of compounds, has been reported. Of the many chemical approaches that exist, one comprises the use of vesicular carriers for delivering drugs into and possibly through the skin. This review offers an overview of various vesicles that have been investigated during dermal and transdermal drug delivery research in recent years, with special emphasis on a relatively new carrier, namely the PheroidTM. The progress made to date by our research group with regards to the use of the PheroidTM as transdermal delivery vector, is also discussed in detail. PMID- 25925121 TI - Cutaneous delivery of natural antioxidants: the enhancement approaches. AB - Topically applied natural antioxidants can be an effective treatment for inhibiting oxidative damage and photoaging of the skin. Due to the barrier function of the stratum corneum (SC), it is necessary to use an enhancement approach to promote the cutaneous absorption of natural antioxidants. Some factors that should be considered when developing delivery systems for natural antioxidants include increased solubility, enhanced storage stability, improved permeability and bioavailability, skin targeting, and minimal side effects. This review describes the skin delivery systems for natural antioxidant permeation that have been developed during the last decade. The antioxidants introduced include vitamins, polyphenols, and carotenoids. Various types of formulations are employed to improve the skin penetration of the antioxidants, such as hydrogels, cyclodextrin, microemulsions, nanoparticles, liposomes and niosomes. This review focuses on the introduction of natural antioxidants used in skin protection, the mechanisms of antioxidant activity on the skin, and formulation designs for enhancing absorption and efficacy. PMID- 25925122 TI - Supersaturation as a tool for skin penetration enhancement. AB - Supersaturated systems have attracted interest to enhance the skin penetration because of the low cost and reduced risks of irritation with respect to other approaches. The mechanism is simply based on the increased drug driving force for transit out of the dosage form and penetrate the stratum corneum. Supersaturated systems can be obtained by preparation of solvent/non-solvent mixtures; or mixtures containing a skin penetrating solvent or a volatile solvent, and quenching. All methods are described to obtain solutions or semisolid preparations; meanwhile the solvent evaporation and quenching can be used in the transdermal patch production. The adopted formulative strategies can increase the drug concentration in the vehicle 5-fold the solubility and the corresponding increment of the thermodynamic activity determines a significant increase of the drug flux through the skin, according to the Fick's law. The main limitation of supersaturated systems is related to their thermodynamic instability that, leading to drug crystallization in the vehicle, affects the drug skin penetration. Among the possible strategies to avoid or retard this issue the use of polymeric materials appears the most efficacious. However, the crystallization of a drug during storage and/or application on the skin is driven by so many factors that the stability of supersaturated systems is unpredictable. This paper offers a comprehensive review of the literature with the aim to underline the "pros and cons" of the application of supersaturation in transdermal delivery in the light of the theoretical aspects. PMID- 25925123 TI - Recent developments in skin mimic systems to predict transdermal permeation. AB - In recent years there has been a drive to create experimental techniques that can facilitate the accurate and precise prediction of transdermal permeation without the use of in vivo studies. This review considers why permeation data is essential, provides a brief summary as to how skin acts as a natural barrier to permeation and discusses why in vivo studies are undesirable. This is followed by an in-depth discussion on the extensive range of alternative methods that have been developed in recent years. All of the major 'skin mimic systems' are considered including: in vitro models using synthetic membranes, mathematical models including quantitative structure-permeability relationships (QSPRs), human skin equivalents and chromatographic based methods. All of these model based systems are ideally trying to achieve the same end-point, namely a reliable in vitro-in vivo correlation, i.e. matching non-in vivo obtained data with that from human clinical trials. It is only by achieving this aim, that any new method of obtaining permeation data can be acknowledged as a potential replacement for animal studies, for the determination of transdermal permeation. In this review, the relevance and potential applicability of the various models systems will also be discussed. PMID- 25925124 TI - Breaking the skin barrier: achievements and future directions. AB - Skin delivery is more advantageous for drug administration than other routes since it is more compliant and can avoid the first-pass metabolic effect. More importantly, it can ensure stable blood level of transdermal drugs for a long period of time, avoiding fluctuation and reducing side effects. However, it is restricted by the barrier function of the stratum corneum. Therefore, significant attention has been paid to developing methods to modify the kinetics of skin drug delivery and expand the range of drugs that can be used for transdermal delivery. Novel mechanisms of increasing the intercellular and appendages penetration pathways have also been developed. This review focuses on chemical penetration enhancers, physical permeabilization (sonophoresis, iontophoresis and microneedles) and novel nanocarriers for skin delivery. Recent developments on skin delivery are also discussed. PMID- 25925125 TI - Overcoming the skin permeation barrier: challenges and opportunities. AB - Stratum corneum (SC), the outermost layer of the skin, constitutes an excellent protective physiological barrier, and is the main challenge in transdermal drug delivery. Many approaches have been used to enhance the penetration of drugs through this layer, covering passive and active methods or the combination of both. This opens the opportunity to broaden the spectrum of drugs that can be administered through the skin, providing alternatives to existing products, and filling gaps that conventional routes failed to occupy. In this review, an overview of the different permeation enhancing methodologies is carried out, focusing on the combination of lipid nanoparticles with conventional chemical enhancers, as a proof-of-concept of a successful development strategy. PMID- 25925127 TI - Synthesis of hollow and trimetallic nanostructures by seed-mediated co-reduction. AB - Coupling seed-mediated co-reduction with galvanic replacement for the first time provides a route to trimetallic (Ag-Au-Pd) nanostructures with hollow interiors. Moreover, manipulating the synthetic conditions can suppress galvanic replacement and facilitate formation of trimetallic core@shell (Ag@Au-Pd) nanostructures. These results illustrate the role of seed composition in the synthesis of architecturally defined multimetallic nanostructures by seed-mediated co reduction. PMID- 25925126 TI - Homoharringtonine, a clinically approved anti-leukemia drug, sensitizes tumor cells for TRAIL-induced necroptosis. AB - BACKGROUND: One hallmark of cancer cells is their ability to evade physiologic signals causing regulated cell death (RCD). Correspondingly, TRAIL-based therapies to eliminate human cancer cells via enforced induction of apoptosis have been established and represent a promising approach in anti-cancer research. However, due to frequently appearing intrinsic or acquired resistances of tumor cells against apoptosis, TRAIL-based apoptotic strategies for the treatment of cancer patients have shown limited efficacy. As a potential alternative, regulated necrosis (and necroptosis triggered e.g. by TRAIL receptors 1/2) has recently gained considerable attention. Regulated necrosis represents a mode of RCD molecularly distinct from apoptosis whose potential in anti-cancer therapy is almost uncharacterized. Since in most cancer cells survival pathways counteract the effects of TRAIL-induced RCD, sensitizers such as cycloheximide (CHX) are frequently added in cell culture to overcome this problem. Unfortunately, those sensitizers are cytotoxic and therefore not suitable for the treatment of cancer patients. Here, we have alternatively employed homoharringtonine (HHT), a plant alkaloid which was recently approved by the U. S. Food and Drug Administration to treat patients with chronic myeloid lymphoma. RESULTS: We show that HHT is an efficient sensitizer for TRAIL-induced necroptosis in multiple human cancer cell lines. In addition, HHT-enhanced TRAIL-mediated necroptosis occurs via the same signaling pathways (involving RIPK1/RIPK3/MLKL) as CHX-enhanced necroptosis. Importantly, consecutive treatment schedules of necroptosis and apoptosis in either combination revealed remarkable additive effects not reached by repetitive apoptotic treatments alone. CONCLUSIONS: Taken together, our data demonstrate that HHT can replace harmful substances such as CHX to sensitize human cancer cells to TRAIL-induced necroptosis. Thus, HHT represents a promising enhancer in TRAIL-based necroptotic anti-cancer therapies also in patients. PMID- 25925129 TI - Base or nucleophile? DFT finally elucidates the origin of the selectivity between the competitive reactions triggered by MeLi or LDA on propanal. AB - The competition between basicity and nucleophilicity of two standard organolithium reagents was studied using DFT. Comparing the reactivity of solvated (MeLi)2 and (LDA)2 toward propanal finally explains why methyllithium adds onto the carbonyl while LDA deprotonates the alpha-position, in accord with experiment and Ireland's deprotonation TS. PMID- 25925128 TI - Single-Step Assembly of Multimodal Imaging Nanocarriers: MRI and Long-Wavelength Fluorescence Imaging. AB - Magnetic resonance imaging (MRI)- and near-infrared (NIR)-active, multimodal composite nanocarriers (CNCs) are prepared using a simple one-step process, flash nanoprecipitation (FNP). The FNP process allows for the independent control of the hydrodynamic diameter, co-core excipient and NIR dye loading, and iron oxide based nanocrystal (IONC) content of the CNCs. In the controlled precipitation process, 10 nm IONCs are encapsulated into poly(ethylene glycol) (PEG) stabilized CNCs to make biocompatible T2 contrast agents. By adjusting the formulation, CNC size is tuned between 80 and 360 nm. Holding the CNC size constant at an intensity weighted average diameter of 99 +/- 3 nm (PDI width 28 nm), the particle relaxivity varies linearly with encapsulated IONC content ranging from 66 to 533 * 10(-3) m(-1) s(-1) for CNCs formulated with 4-16 wt% IONC. To demonstrate the use of CNCs as in vivo MRI contrast agents, CNCs are surface functionalized with liver-targeting hydroxyl groups. The CNCs enable the detection of 0.8 mm(3) non-small cell lung cancer metastases in mice livers via MRI. Incorporating the hydrophobic, NIR dye tris-(porphyrinato)zinc(II) into CNCs enables complementary visualization with long-wavelength fluorescence at 800 nm. In vivo imaging demonstrates the ability of CNCs to act both as MRI and fluorescent imaging agents. PMID- 25925130 TI - Reducing diarrhoea deaths in South Africa: costs and effects of scaling up essential interventions to prevent and treat diarrhoea in under-five children. AB - BACKGROUND: Diarrhoea is one of the leading causes of morbidity and mortality in South African children, accounting for approximately 20% of under-five deaths. Though progress has been made in scaling up multiple interventions to reduce diarrhoea in the last decade, challenges still remain. In this paper, we model the cost and impact of scaling up 13 interventions to prevent and treat childhood diarrhoea in South Africa. METHODS: Modelling was done using the Lives Saved Tool (LiST). Using 2014 as the baseline, intervention coverage was increased from 2015 until 2030. Three scale up scenarios were compared: by 2030, 1) coverage of all interventions increased by ten percentage points; 2) intervention coverage increased by 20 percentage points; 3) and intervention coverage increased to 99%. RESULTS: The model estimates 13 million diarrhoea cases at baseline. Scaling up intervention coverage averted between 3 million and 5.3 million diarrhoea cases. In 2030, diarrhoeal deaths are expected to reduce from an estimated 5,500 in 2014 to 2,800 in scenario one, 1,400 in scenario two and 100 in scenario three. The additional cost of implementing all 13 interventions will range from US$510 million (US$9 per capita) to US$960 million (US$18 per capita), of which the health system costs range between US$40 million (less than US$1 per capita) and US$170 million (US$3 per capita). CONCLUSION: Scaling up 13 essential interventions could have a substantial impact on reducing diarrhoeal deaths in South African children, which would contribute toward reducing child mortality in the post-MDG era. Preventive measures are key and the government should focus on improving water, sanitation and hygiene. The investments required to achieve these results seem feasible considering current health expenditure. PMID- 25925131 TI - An overview of the BIOASQ large-scale biomedical semantic indexing and question answering competition. AB - BACKGROUND: This article provides an overview of the first BIOASQ challenge, a competition on large-scale biomedical semantic indexing and question answering (QA), which took place between March and September 2013. BIOASQ assesses the ability of systems to semantically index very large numbers of biomedical scientific articles, and to return concise and user-understandable answers to given natural language questions by combining information from biomedical articles and ontologies. RESULTS: The 2013 BIOASQ competition comprised two tasks, Task 1a and Task 1b. In Task 1a participants were asked to automatically annotate new PUBMED documents with MESH headings. Twelve teams participated in Task 1a, with a total of 46 system runs submitted, and one of the teams performing consistently better than the MTI indexer used by NLM to suggest MESH headings to curators. Task 1b used benchmark datasets containing 29 development and 282 test English questions, along with gold standard (reference) answers, prepared by a team of biomedical experts from around Europe and participants had to automatically produce answers. Three teams participated in Task 1b, with 11 system runs. The BIOASQ infrastructure, including benchmark datasets, evaluation mechanisms, and the results of the participants and baseline methods, is publicly available. CONCLUSIONS: A publicly available evaluation infrastructure for biomedical semantic indexing and QA has been developed, which includes benchmark datasets, and can be used to evaluate systems that: assign MESH headings to published articles or to English questions; retrieve relevant RDF triples from ontologies, relevant articles and snippets from PUBMED Central; produce "exact" and paragraph-sized "ideal" answers (summaries). The results of the systems that participated in the 2013 BIOASQ competition are promising. In Task 1a one of the systems performed consistently better from the NLM's MTI indexer. In Task 1b the systems received high scores in the manual evaluation of the "ideal" answers; hence, they produced high quality summaries as answers. Overall, BIOASQ helped obtain a unified view of how techniques from text classification, semantic indexing, document and passage retrieval, question answering, and text summarization can be combined to allow biomedical experts to obtain concise, user understandable answers to questions reflecting their real information needs. PMID- 25925132 TI - Double-well dynamics of noise-driven control activation in human intermittent control: the case of stick balancing. AB - When facing a task of balancing a dynamic system near an unstable equilibrium, humans often adopt intermittent control strategy: Instead of continuously controlling the system, they repeatedly switch the control on and off. Paradigmatic example of such a task is stick balancing. Despite the simplicity of the task itself, the complexity of human intermittent control dynamics in stick balancing still puzzles researchers in motor control. Here we attempt to model one of the key mechanisms of human intermittent control, control activation, using as an example the task of overdamped stick balancing. In doing so, we focus on the concept of noise-driven activation, a more general alternative to the conventional threshold-driven activation. We describe control activation as a random walk in an energy potential, which changes in response to the state of the controlled system. By way of numerical simulations, we show that the developed model captures the core properties of human control activation observed previously in the experiments on overdamped stick balancing. Our results demonstrate that the double-well potential model provides tractable mathematical description of human control activation at least in the considered task and suggest that the adopted approach can potentially aid in understanding human intermittent control in more complex processes. PMID- 25925133 TI - Detection of wood cell wall porosity using small carbohydrate molecules and confocal fluorescence microscopy. AB - A novel approach to nanoscale detection of cell wall porosity using confocal fluorescence microscopy is described. Infiltration of cell walls with a range of nitrophenyl-substituted carbohydrates of different molecular weights was assessed by measuring changes in the intensity of lignin fluorescence, in response to the quenching effect of the 4-nitrophenyl group. The following carbohydrates were used in order of increasing molecular weight; 4-nitrophenyl beta-D-glucopyrano side (monosaccharide), 4-nitrophenyl beta-D-lactopyranoside (disaccharide), 2 chloro-4-nitrophenyl beta-D-maltotrioside (trisaccharide), and 4-nitrophenyl alpha-D-maltopentaoside (pentasaccharide). This technique was used to compare cell wall porosity in wood which had been dewatered to 40% moisture content using supercritical CO2, where cell walls remain fully hydrated, with kiln dried wood equilibrated to 12% moisture content. Infiltration of cell walls as measured by fluorescence quenching, was found to decrease with increasing molecular weight, with the pentasaccharide being significantly excluded compared to the monosaccharide. Porosity experiments were performed on blocks and sections to assess differences in cell wall accessibility. Dewatered and kiln dried wood infiltrated as blocks showed similar results, but greater infiltration was achieved by using sections, indicating that not all pores were easily accessible by infiltration from the lumen surface. In wood blocks infiltrated with 4 nitrophenyl alpha-D-maltopentaoside, quenching of the secondary wall was quite variable, especially in kiln dried wood, indicating limited connectivity of pores accessible from the lumen surface. PMID- 25925134 TI - Demographics and trends in the acute presentation of diverticular disease: a national study. AB - BACKGROUND: Diverticular disease (DD) is a major health problem in the Western world. The aim of this study was to describe demographics and trends in acute DD admissions in New Zealand. METHODS: Information pertaining to acute hospital admissions between January 2000 and June 2012 for a primary diagnosis of large bowel DD was retrieved from a national database. RESULTS: There were 25,167 admissions for acute DD. Mean age of presentation decreased from 65.9 years in 2000 to 64.1 years in 2012 (P < 0.001). Mean age was lower in men than women (61.4 versus 67.4 years, P < 0.001). Although men comprised 45.2% of the cohort they were over-represented in the 18-44 years stratum (68.6 versus 31.4%; P < 0.001). Europeans accounted for 84.8% of admissions and presented at an older age (65.8 years) than Maori (56.2 years), Pacific Islanders (58.4 years) or Asians (58.9 years) (P < 0.001). Acute DD admissions were higher in more deprived populations (P < 0.001). Mean length of hospital stay (LOS) reduced from 5.8 days in 2000 to 4.1 days in 2012 (P < 0.001). LOS increased with age (P < 0.001) and deprivation (P = 0.013), but did not differ between ethnicities (P = 0.088). Computed tomography scanning of acute admissions doubled from 2000 to 2012 (29.7 59.2%; P < 0.001) with a halving in the use of acute in-patient colonoscopy (26.1 13.2%; P < 0.001) and emergent surgery (14.8-7.2%; P < 0.001). Percutaneous drain use increased from 0.6% in 2000 to 1.1% in 2012 (P = 0.003). CONCLUSION: Acute DD is a source of considerable morbidity in New Zealand and there have been significant changes in its admission demographics and trends over the last decade. PMID- 25925135 TI - Natural killer cell therapy in children with relapsed leukemia. AB - BACKGROUND: Novel therapies are needed for children with relapsed or refractory leukemia. We therefore tested the safety and feasibility of haploidentical natural killer cell therapy in this patient population. PROCEDURE: Twenty-nine children who had relapsed or refractory leukemia were treated with chemotherapy followed by the infusion of haploidentical NK cells. Cohort 1 included 14 children who had not undergone prior allogeneic hematopoietic cell transplantation (HCT), whereas Cohort 2 included 15 children with leukemia that had relapsed after HCT. RESULTS: Twenty-six (90%) NK donors were KIR mismatched (14 with one KIR and 12 with 2 KIRs). The peak NK chimerism levels were >10% donor in 87% of the evaluable recipients. In Cohort 1, 10 had responsive disease and 12 proceeded to HCT thereafter. Currently, 5 (36%) are alive without leukemia. In Cohort 2, 10 had responsive disease after NK therapy and successfully proceeded to second HCT. At present, 4 (27%) are alive and leukemia free. The NK cell infusions and the IL-2 injections were well-tolerated. CONCLUSIONS: NK cell therapy is safe, feasible, and should be further investigated in patients with chemotherapy-resistant leukemia. PMID- 25925137 TI - Rhenium-catalyzed dehydrogenative olefination of C(sp(3))-H bonds with hypervalent iodine(III) reagents. AB - A dehydrogenative olefination of C(sp(3))-H bonds is disclosed here, by merging rhenium catalysis with an alanine-derived hypervalent iodine(III) reagent. Thus, cyclic and acyclic ethers, toluene derivatives, cycloalkanes, and nitriles are all successfully alkenylated in a regio- and stereoselective manner. PMID- 25925136 TI - Interleukin-1 Gene Cluster Polymorphisms and its Haplotypes may Predict the Risk to Develop Cervical Cancer in Tunisia. AB - Our study aimed to evaluate the association between IL-1alpha (4845 G/T), IL 1beta (-511C/T) and IL-1RN (VNTR) polymorphisms and risk of cervical cancer. This case-control study investigates three polymorphisms in 130 patients and 260 controls by PCR-restriction fragment length polymorphism (RFLP). The IL-1RN (VNTR) A1/A3 genotype appear as a cervical cancer risk factor (p = 0.048; OR = 2.92; 95 % CI = 1.00-8.74), moreover, the L/2* decreased the risk (p = 0.011; OR = 0.47; 95 % CI = 0.25-0.88) and may be a protective factor against this pathology. Stratified analysis according to the FIGO stage subgroup revealed that the IL-1beta-511 T/T genotype and T allele may be a protective factors against cervical cancer development for patients with early stage (p = 0.030; OR = 0.46; 95 % CI = 0.22-0.96) (p = 0.020; OR = 0.68; 95 % CI = 0.48-0.97). However, for the patients with advanced FIGO stage, IL-1RN-VNTR L/2* genotype appear as a protective factor for this pathology (p = 0.023; OR = 0.29; 95 % CI = 0.08-0.99). The (G-T-L) haplotype showed a significant decreased frequency in cervical cancer patients as compared to controls (p = 0.032; OR = 0.53; 95 % CI = 0.29-0.95). In contrast, the (T-T-2*) combination appear a risk factor for the development of cervical cancer (p = 0.018; OR = 1.57; 95 % CI = 1.07-2.30). Our study suggested that IL1 cluster polymorphisms and haplotypes may be a genetic risk factor for cervical cancer. PMID- 25925139 TI - Retraction Statement. Paper by Takai et al.: Oncology 2006;70:97-105, (DOI: 10.1159/000092585). PMID- 25925138 TI - Interfacing microbial styrene production with a biocompatible cyclopropanation reaction. AB - The introduction of new reactivity into living organisms is a major challenge in synthetic biology. Despite an increasing interest in both the development of small-molecule catalysts that are compatible with aqueous media and the engineering of enzymes to perform new chemistry in vitro, the integration of non native reactivity into metabolic pathways for small-molecule production has been underexplored. Herein we report a biocompatible iron(III) phthalocyanine catalyst capable of efficient olefin cyclopropanation in the presence of a living microorganism. By interfacing this catalyst with E. coli engineered to produce styrene, we synthesized non-natural phenyl cyclopropanes directly from D-glucose in single-vessel fermentations. This process is the first example of the combination of nonbiological carbene-transfer reactivity with cellular metabolism for small-molecule production. PMID- 25925140 TI - Effect from low-level exposure of oxytetracycline on abundance of tetracycline resistance genes in arable soils. AB - To evaluate the effect from low-level exposure of antibiotics on the abundance of antibiotic resistance genes, unpolluted arable soils were treated with oxytetracycline (OTC)-containing manure, with OTC (0, 2, 20, or 70 MUg kg(-1)) added every 2 weeks on 10 occasions. Six tetracycline resistance genes [TRGs tet(A), tet(L), tet(M), tet(Q), tet(O), and tet(W)] and the 16S ribosomal RNA (rRNA) gene were monitored using real-time quantitative polymerase chain reaction. The relative abundance of tet(A), tet(L), tet(M), and tet(Q) genes in soil increased 10-1000 times after application of OTC-containing manure. Tet(A) abundance per unit of residual OTC on day 140 was 1.53-4.42 times higher than that on day 28, while tet(L) abundance was 1.04-1.74 times higher. Treatment with >40 MUg kg(-1) OTC significantly increased abundance of tet(A) and tet(L), while tet(M) and tet(Q) abundance was positively correlated (R (2) = 0.965 and 0.932, p < 0.01) with residual OTC concentrations. There was a significant accumulation of TRGs associated with low-level OTC exposure in arable soils. Besides OTC residual, the effects from exposure time and application frequencies should also be considered to limit the increase in abundance of tet(A) and tet(L). PMID- 25925141 TI - Reducing dioxin formation by adding hydrogen in simulated fly ash. AB - In this study, simulated fly ash containing CuO/CuCl2 was heated at 350 degrees C in a flow of N2 and also in a nitrogen flow containing 10 vol% H2, to evaluate the influence of hydrogen adding on dioxin formation. The total polychlorinated dibenzo-p-dioxins and dibenzofurans (PCDD/F) output derived from the CuO sample under N2 and 10 % H2 was 7.382 and 0.708 ng/g, respectively. As for CuCl2, it was 589 and 46.1 ng/g, respectively. The results show that the hydrogen adding has a good inhibition effect on PCDD/F formation; the inhibition rate was higher than 90 % for PCDD/Fs. HCl and NH3 were detected by Gasmet in the flue gas; the probable inhibition mechanism of hydrogen reaction was proposed, based on our measurements and others' researches. PMID- 25925142 TI - Potential toxic effects of aircraft de-icers and wastewater samples containing these compounds. AB - One of the major problems of airport operation is the impact of pollution caused by runoff waters. Runoff waters at an airport may contain high concentrations of different contaminants resulting from various activities of its operation. High quantities of aircraft de-icing/anti-icing fluids are used annually at airports worldwide. Aircraft de-icers and anti-icers may have negative environmental impacts, but their effects on aquatic organisms are virtually unknown. In order to address this issue, aircraft de-icers, pavement de-icers and wastewater samples were obtained from a regional airport. To evaluate the toxicity of wastewater samples and aircraft de-icing/anti-icing fluids (ADAFs), two bio-tests were performed: the Lemna growth inhibition test according to OECD guideline 221 and the luminescent bacteria test according to ISO guideline 11348-2. In the Lemna growth inhibition test, phytotoxicity was assessed using the endpoints frond number and frond area. The luminescent bacteria test involved the marine bacterium Vibrio fischeri. The estimates of effective concentrations (EC50) values were determined using the free software R and the "drc" library. Aquatic plants and marine bacteria showed a higher sensitivity towards ADAFs than to wastewater samples. Experiments showed that aircraft de-icing/anti-icing fluids and wastewater samples were relatively more toxic towards Lemna gibba L. in comparison to V. fischeri. PMID- 25925143 TI - Physiological and biochemical responses of Suaeda fruticosa to cadmium and copper stresses: growth, nutrient uptake, antioxidant enzymes, phytochelatin, and glutathione levels. AB - Environmental pollution by trace metal elements (TMEs) is a serious problem worldwide, increasing in parallel with the development of human technology. The present research aimed to examine the response of halophytic species Suaeda fruticosa to oxidative stress posed by combined abiotic stresses. Plants have been grown for 1 month with an irrigation solution supplemented with 200 mM NaCl and 400 MUM Cd(2+) or 400 MUM Cu(2+). The level of glutathione (GSH), phytochelatins (PCs), and antioxidant enzyme activities [ascorbate peroxidase (APX), guaiacol peroxidase (GPX), and catalase (CAT)] as well as lipid peroxidation was studied to see the stress exerted by the TME and the level of tolerance and detoxification strategy adopted by S. fruticosa. Relative growth rate (RGR) decreased under Cd(2+) stress in this species, whereas Cu(2+) did not have any impact on S. fruticosa performance. Cd(2+) or Cu(2+) enhanced malondialdehyde, suggesting reactive oxygen species-induced disruption of membrane integrity and oxidative stress in S. fruticosa. On the other hand, the activities of the antioxidant enzymes CAT, APX, and GPX diminished and mineral nutrition was disturbed by metal stress. S. fruticosa was able to synthesize PCs in response to TME toxicity. However, data indicate that GSH levels underwent a significant decrease in roots and leaves of S. fruticosa stressed by Cd(2+) or Cu(2+). The GSH depletion accompanied by the increase of phytochelatin concentration suggests the involvement of GSH in the synthesis of phytochelatins. PMID- 25925144 TI - Characterization of VOC sources in an urban area based on PTR-MS measurements and receptor modelling. AB - In this study, the concentrations of volatile organic compounds were measured by the use of proton transfer reaction mass spectrometry, together with NO x , NO, NO2, SO2, CO and PM10 and meteorological parameters in an urban area of Belgrade during winter 2014. The multivariate receptor model US EPA Unmix was applied to the obtained dataset resolving six source profiles, which can be attributed to traffic-related emissions, gasoline evaporation/oil refineries, petrochemical industry/biogenic emissions, aged plumes, solid-fuel burning and local laboratories. Besides the vehicle exhaust, accounting for 27.6 % of the total mixing ratios, industrial emissions, which are present in three out of six resolved profiles, exert a significant impact on air quality in the urban area. The major contribution of regional and long-range transport was determined for source profiles associated with petrochemical industry/biogenic emissions (40 %) and gasoline evaporation/oil refineries (29 %) using trajectory sector analysis. The concentration-weighted trajectory model was applied with the aim of resolving the spatial distribution of potential distant sources, and the results indicated that emission sources from neighbouring countries, as well as from Slovakia, Greece, Poland and Scandinavian countries, significantly contribute to the observed concentrations. PMID- 25925145 TI - Characterization and source apportionment of particle number concentration at a semi-urban tropical environment. AB - Principal component analysis (PCA) and correlation have been used to study the variability of particle mass and particle number concentrations (PNC) in a tropical semi-urban environment. PNC and mass concentration (diameter in the range of 0.25->32.0 MUm) have been measured from 1 February to 26 February 2013 using an in situ Grimm aerosol sampler. We found that the 24-h average total suspended particulates (TSP), particulate matter <=10 MUm (PM10), particulate matter <=2.5 MUm (PM2.5) and particulate matter <=1 MUm (PM1) were 14.37 +/- 4.43, 14.11 +/- 4.39, 12.53 +/- 4.13 and 10.53 +/- 3.98 MUg m(-3), respectively. PNC in the accumulation mode (<500 nm) was the most abundant (at about 99 %). Five principal components (PCs) resulted from the PCA analysis where PC1 (43.8 % variance) predominates with PNC in the fine and sub-microme tre range. PC2, PC3, PC4 and PC5 explain 16.5, 12.4, 6.0 and 5.6 % of the variance to address the coarse, coarser, accumulation and giant fraction of PNC, respectively. Our particle distribution results show good agreement with the moderate resolution imaging spectroradiometer (MODIS) distribution. PMID- 25925146 TI - Selenium, nickel, and calcium levels in cancerous and non-cancerous prostate tissue samples and their relation with some parameters. AB - In the present study, tissue samples of patients with cancerous and non-cancerous prostate were analyzed for their Se, Ni, and Ca contents. Possible relationship between Se, Ni, and Ca concentrations and some parameters including preoperative prostate-specific antigen (PSA) levels, histopathological neurovascular invasion, extra-capsular extension, seminal vesicle invasion, positive surgical margins, PSA relapse after radical prostatectomy, and total Gleason scores were obtained. Inductively coupled plasma (ICP) optical emission spectrometry and ICP-mass spectrometry instruments were used for the determination of analytes interested. All the system parameters in digestion and measurement steps were optimized to obtain efficient digestion and sensitive measurements. There was no statistically meaningful difference observed in the concentration of selenium in cancerous and benign prostatic tissues (p = 0.347) while nickel levels in cancerous tissues were observed as significantly lower than benign tissues (p < 0.001). In addition, calcium concentration in cancerous tissue samples were found to be statistically lower than those in benign tissues (p < 0.001) with mean values of 657 and 1,431 mg/kg, respectively. PMID- 25925147 TI - Ecophysiological and antioxidant traits of Salvia officinalis under ozone stress. AB - Ecophysiological and antioxidant traits were evaluated in sage (Salvia officinalis) plants exposed to 120 ppb of ozone for 90 consecutive days (5 h day( 1)). At the end of fumigation, plants showed slight leaf yellowing that could be considered the first visual symptom of leaf senescence. Ozone-stressed leaves showed (1) reduced photosynthetic activity (-70 % at the end of exposure), (2) chlorophyll loss (-59 and -56 % of chlorophyll a and b concentrations, starting from 30 days from the beginning of exposure), and (3) cellular water deficit (-12 % of the relative water content at the end of the fumigation). These phenomena are indicative of oxidative stress in the chloroplasts (as confirmed by the strong degradation of beta-carotene) despite the photoprotection conferred by xanthophyll cycle [as demonstrated by the significant rise of de-epoxidation index, reaching the maximum value at the end of the treatment (+69 %)], antioxidant compounds [as confirmed by the increase of phenols (in particular caffeic acid and rosmarinic acid)], and water-soluble carbohydrates (especially monosaccharides). By means of combined ecophysiological and biochemical approaches, this study demonstrates that S. officinalis is able to activate an adaptive survival mechanism allowing the plant to complete its life cycle even under oxidative stressful conditions. PMID- 25925148 TI - Evaluation of radiological risks due to natural radioactivity around Lynas Advanced Material Plant environment, Kuantan, Pahang, Malaysia. AB - Understanding the public awareness concerning the Lynas Advanced Material Plant (LAMP), an Australian rare earths processing plant located in Malaysia, a radiological study in soil and water samples collected at random surrounding the LAMP environment was undertaken using HPGe gamma-ray spectrometry. The mean soil activities for (226)Ra, (232)Th, and (40)K were found to be 6.56 +/- 0.20, 10.62 +/- 0.42, and 41.02 +/- 0.67 Bq/kg, respectively, while for water samples were 0.33 +/- 0.05, 0.18 +/- 0.04, and 4.72 +/- 0.29 Bq/l, respectively. The studied areas show typical local level of radioactivity from natural background radiation. The mean gamma absorbed dose rate in soils at 1 m above the ground was found to be 11.16 nGy/h. Assuming a 20 % outdoor occupancy factor, the corresponding annual effective dose showed a mean value of 0.014 mSv year(-1), significantly lower than the worldwide average value of 0.07 mSv year(-1) for the annual outdoor effective dose as reported by UNSCEAR (2000). Some other representative radiation indices such as activity utilization index (AUI), H ex, H in, excess lifetime cancer risk (ELCR), and annual gonadal dose equivalent (AGDE) were derived and also compared with the world average values. Statistical analysis performed on the obtained data showed a strong positive correlation between the radiological variables and (226)Ra and (232)Th. PMID- 25925149 TI - Use of a porcine dermal collagen implant for contaminated abdominal wall reconstruction in a 105-year-old woman: a case report and review of the literature. AB - INTRODUCTION: Repair of contaminated abdominal wall defect in a geriatric patient is a challenge for the surgeon. We present the case of the oldest patient (105 years old) to successfully undergo a single-stage repair of a contaminated abdominal wall defect with a PermacolTM implant. CASE PRESENTATION: A 105-year old Caucasian woman presented to our emergency room with a clinical and radiological diagnosis of small bowel obstruction due to prior operative adhesions. She underwent laparotomy with small bowel resection and primary closure of her abdomen. There was total eventration of her bowel through the suture line 9 days after surgery. She underwent a second laparotomy that revealed no signs of peritonitis or turbid fluid. Her abdomen was closed with a 15 * 10 cm PermacolTM implant sutured sublay with prolene sutures. Her postoperative period was unremarkable. After a follow-up period of 3 years and 2 months, there was no sign of recurrent hernia or wound contamination. CONCLUSION: We suggest that PermacolTM mesh can be considered an efficient alternative to primary closure or synthetic mesh in geriatric patients with contaminated abdominal wall defects. PMID- 25925150 TI - Evaluation of a New Automated Processing System (TACASTM Pro) for Liquid-Based Procedures. AB - OBJECTIVE: To evaluate a fully automated processing system (TACASTM Pro) for liquid-based procedures (LBPs). METHODS AND MATERIALS: Materials were 3,483 and additionally 502 specimens that were taken at Kanagawa Health Service Association. Specimens obtained with a Cervex-Brush(r) were first smeared to glass slides using one side of the brush and then processed to TACAS Pro. RESULTS: (1) The microscopy watching time per normal case was 3.65 +/- 0.85 min in the conventional procedure, whereas in the LBP it was 1.95 +/- 0.60 min, and the latter reduced workload to 53%. (2) The handling time of TACAS Pro per day was 2 h and 25.8 min. The workload at a laboratory offset it and revealed the work saving to be 63.8%. (3) Unsatisfactory rates were 0% in the conventional procedure, whereas in the LBP it was 1.88% at first. The latter rate decreased to 0.5% after system improvement. (4) Specimens which may disturb microscopy analysis were found in 1.06%, including 3 cases of possible carry-over of cells to the following slides. An additional study with the revised system confirmed no carry-over. (5) Incidences of abnormal cytology were consistent between the two methods. CONCLUSIONS: The revised automated processing system TACAS Pro is a feasible and useful LBP and reduces the workload of cytology laboratories. PMID- 25925151 TI - Peritoneal Dialysis Catheter Placement Using an Ultrasound-Guided Transversus Abdominis Plane Block. AB - BACKGROUND: Peritoneal dialysis (PD) catheter placement is usually performed using general or local anesthesia. We present our PD catheter placement experience using an ultrasound-guided transversus abdominis plane (TAP) block, which is a regional anesthesia technique. METHODS: In this study, we analyzed 33 patients from our center with ESRD who underwent PD catheter placement using a TAP block between June 2011 and April 2014. RESULTS: The TAP block was successful for 29/33 (87.9%) patients. Four patients (12.1%) had pain at the incision site and required general anesthesia. There were no anesthesia-, surgery- or catheter related complications. CONCLUSION: ESRD patients have a substantial number of comorbidities that can be negatively influenced by general anesthesia. Because regional anesthesia has no systemic effect, this procedure could be recommended for this group of patients. A TAP block is an effective, safe method and can be used as the principal anesthesia technique for PD catheter placement. PMID- 25925152 TI - Differential Gene Expression in Gonadotropin-Releasing Hormone Neurons of Male and Metestrous Female Mice. AB - BACKGROUND: Gonadotropin-releasing hormone (GnRH) neurons play a pivotal role in the regulation of the hypothalamic-pituitary gonadal axis in a sex-specific manner. We hypothesized that the differences seen in reproductive functions of males and females are associated with a sexually dimorphic gene expression profile of GnRH neurons. METHODS AND RESULTS: We compared the transcriptome of GnRH neurons obtained from intact metestrous female and male GnRH-green fluorescent protein transgenic mice. About 1,500 individual GnRH neurons from each sex were sampled with laser capture microdissection followed by whole transcriptome amplification for gene expression profiling. Under stringent selection criteria (fold change >1.6, adjusted p value 0.01), Affymetrix Mouse Genome 430 PM array analysis identified 543 differentially expressed genes. Sexual dimorphism was most apparent in gene clusters associated with synaptic communication, signal transduction, cell adhesion, vesicular transport and cell metabolism. To validate microarray results, 57 genes were selected, and 91% of their differential expression was confirmed by real-time PCR. Similarly, 88% of microarray results were confirmed with PCR from independent samples obtained by patch pipette harvesting and pooling of 30 GnRH neurons from each sex. We found significant differences in the expression of genes involved in vesicle priming and docking (Syt1, Cplx1), GABAergic (Gabra3, Gabrb3, Gabrg2) and glutamatergic (Gria1, Grin1, Slc17a6) neurotransmission, peptide signaling (Sstr3, Npr2, Cxcr4) and the regulation of intracellular ion homeostasis (Cacna1, Cacnb1, Cacng5, Kcnq2, Kcnc1). CONCLUSION: The striking sexual dimorphism of the GnRH neuron transcriptome we report here contributes to a better understanding of the differences in cellular mechanisms of GnRH neurons in the two sexes. PMID- 25925153 TI - Photodynamic Inactivation Mediated by Erythrosine and its Derivatives on Foodborne Pathogens and Spoilage Bacteria. AB - The purpose of the present study was to evaluate the efficacy of photodynamic inactivation (PDI) mediated by erythrosine (ERY) and its ester derivatives erythrosine methyl ester (ERYMET) and erythrosine butyl ester (ERYBUT) on foodborne pathogens and spoilage bacteria. We evaluated Staphylococcus aureus ATCC 25923, Aeromonas hydrophila ATCC 7966, Salmonella enterica serotype Typhimurium ATCC 14028, Escherichia coli ATCC 25922, and Pseudomonas aeruginosa ATCC 27853. The toxicity of all of the compounds was assessed in VERO cells. PDI mediated by ERY and its derivatives combined with a light-emitting diode was performed at different concentrations and exposure times. S. aureus was more photosensitive than Gram-negative bacteria to ERY, ERYMET, and ERYBUT. The ERY mediated PDI of S. aureus induced a significant reduction of 4.0 log CFU/ml at a light dose of 40 J/cm(2). ERYMET and ERYBUT at lower light doses than ERY completely eradicated S. aureus. When photoirradiated with ERY at light doses of 156 and 234 J/cm(2), A. hydrophila was completely eradicated. ERYBUT was more efficient in the PDI of A. hydrophila than ERYMET, even at 1 x 10(-5) M and lower light doses. Salmonella Typhimurium, E. coli, and P. aeruginosa required higher concentrations of photosensitizers to reduce cell survival. ERYBUT and ERY may be promising photosensitizing agents against A. hydrophila and S. aureus. They were effective at reducing bacterial counts at nontoxic concentrations. The photoinactivation rate of the evaluated bacteria decreased in the following order: S. aureus > A. hydrophila > E. coli > S. Typhimurium > P. aeruginosa. PMID- 25925154 TI - Reproductive strategies and seasonal changes in the somatic indices of seven small-bodied fishes in Atlantic Canada in relation to study design for environmental effects monitoring. AB - Small-bodied fishes are more commonly being used in environmental effects monitoring (EEM) studies. There is a lack of understanding of the biological characteristics of many small-bodied species, which hinders study designs for monitoring studies. For example, 72% of fish population surveys in Canada's EEM program for pulp and paper mills that used small-bodied fishes were conducted outside of the reproductive period of the species. This resulted in an inadequate assessment of the EEM program's primary effect endpoint (reproduction) for these studies. The present study examined seasonal changes in liver size, gonad size, and condition in seven freshwater and estuarine small-bodied fishes in Atlantic Canada. These data were used to examine differences in reproductive strategies and patterns of energy storage among species. Female gonadal recrudescence in all seven species began primarily in the 2-month period in the spring before spawning. Male gonadal development was concurrent with females in five species; however, gonadal recrudescence began in the fall in male three-spined stickleback (Gasterosteus aculeatus) and slimy sculpin (Cottus cognatus). The spawning period for each species was estimated from the decline in relative ovary size after its seasonal maximum value in spring. The duration of the spawning period reflected the reproductive strategy (single vs multiple spawning) of the species. Optimal sampling periods to assess reproductive impacts in each species were determined based on seasonal changes in ovary size and were identified to be during the prespawning period when gonads are developing and variability in relative gonad size is at a minimum. PMID- 25925155 TI - Retraction Note to: Composite use of numerical groundwater flow modeling and geoinformatics techniques for monitoring Indus Basin aquifer, Pakistan. PMID- 25925156 TI - Dissipation and residue of 2,4-D in citrus under field condition. AB - The dissipation, residues, and risks of 2,4-dicholrophenoxyacetic acid (2,4-D) in citrus under field condition were investigated based on a simple ultra performance LC (UPLC)-MS/MS method. The results indicated that the residue level of 2,4-D in citrus did not degrade gradually with sampling time under field condition. At pre-harvest intervals (PHI) of 20-40 days, 2,4-D residues were 0.021-0.269 mg/kg in citrus flesh, 0.028-0.337 mg/kg in whole citrus, and 0.028 0.376 mg/kg in citrus peel, all bellow the China maximum residue limit in citrus (1 mg/kg). Risks of 2,4-D were assessed by calculation of risk quotient, and the results revealed no significant health risks after consumption of citrus. PMID- 25925157 TI - Degradation of three fungicides following application on strawberry and a risk assessment of their toxicity under greenhouse conditions. AB - The health risk to humans of pesticide application on minor crops, such as strawberry, requires quantification. Here, the dissipation and residual levels of three fungicides (pyraclostrobin, myclobutanil, and difenoconazole) were studied for strawberry under greenhouse conditions using high-performance liquid chromatography (HPLC)-tandem mass spectrometry after Quick, Easy, Cheap, Effective, Rugged, and Safe extraction. This method was validated using blank samples, with all mean recoveries of these three fungicides exceeding 80%. The residues of all three fungicides dissipated following first-order kinetics. The half-lives of pyraclostrobin, myclobutanil, and difenoconazole were 1.69, 3.30, and 3.65 days following one time application and 1.73, 5.78, and 6.30 days following two times applications, respectively. Fungicide residue was determined by comparing the estimated daily intake of the three fungicides against the acceptable daily intake. The results indicate that the potential health risk of the three fungicides was not significant in strawberry when following good agricultural practices (GAP) under greenhouse conditions. PMID- 25925158 TI - Input strategy analysis for an air quality data modelling procedure at a local scale based on neural network. AB - In recent years, a significant part of the studies on air pollutants has been devoted to improve statistical techniques for forecasting the values of their concentrations in the atmosphere. Reliable predictions of pollutant trends are essential not only for setting up preventive measures able to avoid risks for human health but also for helping stakeholders to take decision about traffic limitations. In this paper, we present an operating procedure, including both pollutant concentration measurements (CO, SO2, NO2, O3, PM10) and meteorological parameters (hourly data of atmospheric pressure, relative humidity, wind speed), which improves the simple use of neural network for the prediction of pollutant concentration trends by means of the integration of multivariate statistical analysis. In particular, we used principal component analysis in order to define an unconstrained mix of variables able to improve the performance of the model. The developed procedure is particularly suitable for characterizing the investigated phenomena at a local scale. PMID- 25925159 TI - Development of a hybrid pollution index for heavy metals in marine and estuarine sediments. AB - Heavy metal pollution of sediments is a growing concern in most parts of the world, and numerous studies focussed on identifying contaminated sediments by using a range of digestion methods and pollution indices to estimate sediment contamination have been described in the literature. The current work provides a critical review of the more commonly used sediment digestion methods and identifies that weak acid digestion is more likely to provide guidance on elements that are likely to be bioavailable than other traditional methods of digestion. This work also reviews common pollution indices and identifies the Nemerow Pollution Index as the most appropriate method for establishing overall sediment quality. Consequently, a modified Pollution Index that can lead to a more reliable understanding of whole sediment quality is proposed. This modified pollution index is then tested against a number of existing studies and demonstrated to give a reliable and rapid estimate of sediment contamination and quality. PMID- 25925160 TI - High pressure induced charge transfer in 3d-4f bimetallic photomagnetic materials. AB - Pressure-induced crystal color change of photo-magnetic materials [Ln(DMF)4(H2O)3(MU-CN)M(CN)5].H2O, Ln = Y, M = Fe (1), Ln = Y, M = Co (2), Ln = Nd, M = Fe (3) (DMF = N,N-dimethyl formamide) are investigated using variable pressure X-ray Absorption Near-Edge Structure (XANES) spectroscopy and X-ray diffraction. For 1 the effect is caused by ligand-to-metal charge transfer (LMCT) on the iron site. PMID- 25925161 TI - Thin Film Thermoelectric Metal-Organic Framework with High Seebeck Coefficient and Low Thermal Conductivity. PMID- 25925162 TI - Patient Perception of Imiquimod Treatment for Actinic Keratosis and Superficial Basal Cell Carcinoma in 202 Patients. AB - OBJECTIVE: To document the impact on patient-reported outcomes and health-related quality of life (HRQoL) of treatment with imiquimod cream in patients with actinic keratosis (AK) and superficial basal cell carcinoma (sBCC). METHODS: This open-label, multicenter study included AK and sBCC patients eligible for treatment with imiquimod 5% cream. HRQoL was measured by the Skindex-17 and the Skin Cancer Index (SCI) and treatment satisfaction by the Treatment Satisfaction Questionnaire for Medication. RESULTS: 118 AK patients and 84 patients with sBCC were included. Low baseline HRQoL impairment was found on both questionnaires, which remained low after treatment, except for a small dip at the end of the application period. CONCLUSION: Imiquimod 5% cream treatment has no clinically relevant HRQoL impact in AK and sBCC patients according to the Skindex-17 and SCI. The effect of imiquimod treatment on HRQoL may be limited or these questionnaires do not fully capture relevant issues, such as fear of recurrence. PMID- 25925163 TI - Nickel N-heterocyclic carbene catalyzed C-C bond formation: a new route to aryl ketones. AB - A novel nickel N-heterocyclic carbene catalyzed cross-coupling reaction of aryl aldehydes with boronic esters for the synthesis of aryl ketones was developed. This reaction provides a mild, practical method toward aryl ketones, which are versatile intermediates and building blocks in organic synthesis. PMID- 25925164 TI - Retrospective evaluation of the incidental finding of 403 papillary thyroid microcarcinomas in 2466 patients undergoing thyroid surgery for presumed benign thyroid disease. AB - BACKGROUND: The aim of our study was to investigate the incidence of papillary thyroid microcarcinoma (PTMC) in patients operated for benign thyroid diseases (BTD) and its relation to age, sex, extent of surgery and type of BTD. METHODS: Retrospective study of 2466 patients who underwent thyroid surgery for BTD from 2008 to 2013. To determine independent predictors for PTMC we used three separate multivariate logistic regression models (MLR). RESULTS: There were 2128 (86.3%) females and 338 (13.7%) males. PTMC was diagnosed in 345 (16.2%) females and 58 (17.2%) males. Age ranged from 14 to 85 years (mean 54 years). Sex and age were not related to the incidence of PTMC. The overall incidence of PTMC was 16.3%. The highest incidence was in Hashimoto thyroiditis (22.7%, chi(2) = 10.80, p < 0.001); and in patients with total/near-total thyroidectomy (17.7%, chi(2) = 7.05, p < 0.008). The lowest incidence (6.6%, chi(2) = 9.96, p < 0.001) was in a solitary hyperfunctional thyroid nodule (SHTN). According to MLR, Hashimoto thyroiditis (OR 1.54, 95% CI 1.15-2.05, p < 0.003) and SHTN (OR 0.43, 95% CI 0.21 0.87, p < 0.019) are independent predictors. Since the extent of surgery was an independent predictor (OR 1.45, 95% CI 1.10-1.92, p = 0.009) for all BTD, and sex and age were not; when the MLR model was adjusted for them, Graves disease (OR 0.72, 95% CI 0.53-0.99, p < 0.041) also proved to be an independent predictor. CONCLUSIONS: Sex and age are not statistically related to the incidence of PTMC in BTD. The incidence of PTMC is higher in Hashimoto thyroiditis and patients with total/near-total thyroidectomy; and lower in patients with a SHTN and Graves disease. PMID- 25925165 TI - When do confounding by indication and inadequate risk adjustment bias critical care studies? A simulation study. AB - INTRODUCTION: In critical care observational studies, when clinicians administer different treatments to sicker patients, any treatment comparisons will be confounded by differences in severity of illness between patients. We sought to investigate the extent that observational studies assessing treatments are at risk of incorrectly concluding such treatments are ineffective or even harmful due to inadequate risk adjustment. METHODS: We performed Monte Carlo simulations of observational studies evaluating the effect of a hypothetical treatment on mortality in critically ill patients. We set the treatment to have either no association with mortality or to have a truly beneficial effect, but more often administered to sicker patients. We varied the strength of the treatment's true effect, strength of confounding, study size, patient population, and accuracy of the severity of illness risk-adjustment (area under the receiver operator characteristics curve, AUROC). We measured rates in which studies made inaccurate conclusions about the treatment's true effect due to confounding, and the measured odds ratios for mortality for such false associations. RESULTS: Simulated observational studies employing adequate risk-adjustment were generally able to measure a treatment's true effect. As risk-adjustment worsened, rates of studies incorrectly concluding the treatment provided no benefit or harm increased, especially when sample size was large (n = 10,000). Even in scenarios of only low confounding, studies using the lower accuracy risk-adjustors (AUROC < 0.66) falsely concluded that a beneficial treatment was harmful. Measured odds ratios for mortality of 1.4 or higher were possible when the treatment's true beneficial effect was an odds ratio for mortality of 0.6 or 0.8. CONCLUSIONS: Large observational studies confounded by severity of illness have a high likelihood of obtaining incorrect results even after employing conventionally "acceptable" levels of risk-adjustment, with large effect sizes that may be construed as true associations. Reporting the AUROC of the risk-adjustment used in the analysis may facilitate an evaluation of a study's risk for confounding. PMID- 25925166 TI - Partial skull base tumour resection in combination with radiosurgery: an escape procedure or a reasonable solution of treatment? AB - Despite advancement in microsurgical techniques for skull base tumour surgery, approaches of this kind still represent a significant challenge for neurosurgeons due to the size of the tumour and its interference and proximity to important neural and vascular structures. After incomplete resection, gamma knife radiosurgery is becoming an alternative or adjunctive treatment option. In this article, some examples of our experience in combined treatment of the skull base tumours with surgical procedure and gamma knife therapy for the remaining tumour tissue are presented. PMID- 25925167 TI - OsTCP19 influences developmental and abiotic stress signaling by modulating ABI4 mediated pathways. AB - Class-I TCP transcription factors are plant-specific developmental regulators. In this study, the role of one such rice gene, OsTCP19, in water-deficit and salt stress response was explored. Besides a general upregulation by abiotic stresses, this transcript was more abundant in tolerant than sensitive rice genotypes during early hours of stress. Stress, tissue and genotype-dependent retention of a small in-frame intron in this transcript was also observed. Overexpression of OsTCP19 in Arabidopsis caused upregulation of IAA3, ABI3 and ABI4 and downregulation of LOX2, and led to developmental abnormalities like fewer lateral root formation. Moreover, decrease in water loss and reactive oxygen species, and hyperaccumulation of lipid droplets in the transgenics contributed to better stress tolerance both during seedling establishment and in mature plants. OsTCP19 was also shown to directly regulate a rice triacylglycerol biosynthesis gene in transient assays. Genes similar to those up- or downregulated in the transgenics were accordingly found to coexpress positively and negatively with OsTCP19 in Rice Oligonucleotide Array Database. Interactions of OsTCP19 with OsABI4 and OsULT1 further suggest its function in modulation of abscisic acid pathways and chromatin structure. Thus, OsTCP19 appears to be an important node in cell signaling which crosslinks stress and developmental pathways. PMID- 25925168 TI - Amount of hepatic fat predicts cardiovascular risk independent of insulin resistance among Hispanic-American adolescents. AB - BACKGROUND: Nonalcoholic fatty liver disease (NAFLD) has emerged as the major pediatric chronic liver disease, and it is estimated to affect more than one third of obese children in the U.S. Cardiovascular complications are a leading cause of increased mortality in adults with NAFLD and many adolescents with NAFLD already manifest signs of subclinical atherosclerosis including increased carotid intima-media thickness. METHODS: Volume of intrahepatic fat was assessed in 50 Hispanic-American, overweight adolescents, using Magnetic Resonance Spectroscopy. Lipoprotein compositions were measured using Nuclear Magnetic Resonance. RESULTS: Plasma triglycerides (TG) (p=0.003), TG/HDL ratio (p=0.006), TG/apoB ratio (p=0.011), large VLDL concentration (p=0.019), VLDL particle size (p=0.012), as well as small dense LDL concentration (p=0.026) progressively increased across higher levels of hepatic fat severity, while large HDL concentration progressively declined (p=0.043). This pattern of associations remained even after controlling for gender, BMI, visceral fat, and insulin resistance. CONCLUSIONS: Our findings suggest that increased hepatic fat is strongly associated with peripheral dyslipidemia and the amount of fat in the liver may influence cardiovascular risk. Further studies are needed to longitudinally monitor dyslipidemia in children with NAFLD and to examine whether the reduction of hepatic fat would attenuate their long-term CVD risk. PMID- 25925169 TI - Meta-analysis of incidence rate data in the presence of zero events. AB - BACKGROUND: When summary results from studies of counts of events in time contain zeros, the study-specific incidence rate ratio (IRR) and its standard error cannot be calculated because the log of zero is undefined. This poses problems for the widely used inverse-variance method that weights the study-specific IRRs to generate a pooled estimate. METHODS: We conducted a simulation study to compare the inverse-variance method of conducting a meta-analysis (with and without the continuity correction) with alternative methods based on either Poisson regression with fixed interventions effects or Poisson regression with random intervention effects. We manipulated the percentage of zeros in the intervention group (from no zeros to approximately 80 percent zeros), the levels of baseline variability and heterogeneity in the intervention effect, and the number of studies that comprise each meta-analysis. We applied these methods to an example from our own work in suicide prevention and to a recent meta-analysis of the effectiveness of condoms in preventing HIV transmission. RESULTS: As the percentage of zeros in the data increased, the inverse-variance method of pooling data shows increased bias and reduced coverage. Estimates from Poisson regression with fixed interventions effects also display evidence of bias and poor coverage, due to their inability to account for heterogeneity. Pooled IRRs from Poisson regression with random intervention effects were unaffected by the percentage of zeros in the data or the amount of heterogeneity. CONCLUSION: Inverse-variance methods perform poorly when the data contains zeros in either the control or intervention arms. Methods based on Poisson regression with random effect terms for the variance components are very flexible offer substantial improvement. PMID- 25925170 TI - Toll-like receptor 9 trafficking and signaling for type I interferons requires PIKfyve activity. AB - Toll-like receptors (TLRs) traffic to distinct membranes for signaling. TLR7 and TLR9 recognize viral nucleic acids in the endosomes and induce robust anti-viral program. Signaling from these TLRs bifurcate at the level of distinct endosomal compartments, namely VAMP3(+) and LAMP(+) endosomes, to mediate the induction of cytokine and type I interferon (IFN) genes, respectively. The formation of the TLR9 endosome competent for IFNs induction requires AP-3. Phosphoinositides (PIs) mark distinct subcellular membranes and control membrane trafficking. However, their role in TLR trafficking and signaling in different dendritic cell (DC) subsets remains unclear. Here, we examined the role of phosphatidylinositol 3P 5 kinase, PIKfyve, in TLR9 trafficking and signaling. We demonstrate that inhibition of PIKfyve activity preferentially blocks TLR9 signaling for type I IFN induction in FLT3L-bone marrow-derived DCs. By confocal microscopy using RAW264.7 cells, we show that trafficking of both TLR9 and CpG to the LAMP1(+) compartment was blocked by PIKfyve inhibitor treatment, whereas their trafficking to the VAMP3(+) endosome remained intact. Further, AP-3 recruitment to TLR9 endosomes was impaired by PIKfyve inhibition. These data indicate that PIKfyve provides critical PIs necessary for the formation of endosome from which TLR9 signals to induce type I IFNs. PMID- 25925171 TI - Multiple intracranial arterial stenosis influences the long-term prognosis of symptomatic middle cerebral artery occlusion. AB - BACKGROUND: Large intracranial occlusive vascular disease is a major contributor to the incidence of stroke worldwide, especially when it involves the middle cerebral artery (MCA). The data on the prognosis of symptomatic atherosclerotic MCA occlusions (MCAO) with concomitant intracranial arterial disease (MCAO-AIS) are limited. MCAO-AIS may reflect the extent of the atherosclerotic intracranial disease, we hypotheses that coexisting intracranial arterial disease influenced the prognosis of MCAO. METHODS: Patients having survived at least one month after the initial ischemic stroke who suffered from atherosclerotic occlusion of the MCA were enrolled. According to their concomitant atherosclerotic intracranial arterial disease, the patients were assigned to one of two groups: the MCAO or the MCAO-AIS. All of the patients' cerebrovascular risk factors were recorded. Recurrent ischemic stroke and death were the end-point events during the follow up. RESULTS: A total of 232 patients (mean age 57.68 +/- 9.50 years; 69% male) were analyzed. The mean follow-up time was 17.65 months. The end-point events occurred in 35 (15.09%) patients, resulting in an annual rate of 10.26%. The presence of MCAO- AIS was an independent risk factor associated with the patient's prognosis in the cohort (OR = 3.426, 95% CI 1.261 to 9.308; p = 0.016), as well as gender and diabetes mellitus. The MCAO-AIS were more likely to experience ipsilateral ischemic strokes, but the difference was not statistically significant. CONCLUSION: Concomitant intracranial arterial disease may influence the prognosis of patients with atherosclerotic MCAO. The result warrants further research in larger sample population. PMID- 25925172 TI - Internal Amplification Control for a Cryptosporidium Diagnostic PCR: Construction and Clinical Evaluation. AB - Various constituents in clinical specimens, particularly feces, can inhibit the PCR assay and lead to false-negative results. To ensure that negative results of a diagnostic PCR assay are true, it should be properly monitored by an inhibition control. In this study, a cloning vector harboring a modified target DNA sequence (~375 bp) was constructed to be used as a competitive internal amplification control (IAC) for a conventional PCR assay that detects ~550 bp of the Cryptosporidium oocyst wall protein (COWP) gene sequence in human feces. Modification of the native PCR target was carried out using a new approach comprising inverse PCR and restriction digestion techniques. IAC was included in the assay, with the estimated optimum concentration of 1 fg per reaction, as duplex PCR. When applied on fecal samples spiked with variable oocysts counts, ~2 oocysts were theoretically enough for detection. When applied on 25 Cryptosporidium-positive fecal samples of various infection intensities, both targets were clearly detected with minimal competition noticed in 2-3 samples. Importantly, both the analytical and the diagnostic sensitivities of the PCR assay were not altered with integration of IAC into the reactions. When tried on 180 randomly collected fecal samples, 159 were Cryptosporidium-negatives. Although the native target DNA was absent, the IAC amplicon was obviously detected on gel of all the Cryptosporidium-negative samples. These results imply that running of the diagnostic PCR, inspired with the previously developed DNA extraction protocol and the constructed IAC, represents a useful tool for Cryptosporidium detection in human feces. PMID- 25925173 TI - Pathogenicity of Five Strains of Toxoplasma gondii from Different Animals to Chickens. AB - Toxoplasma gondii is a protozoan parasite with a broad range of intermediate hosts. Chickens as important food-producing animals can also serve as intermediate hosts. To date, experimental studies on the pathogenicity of T. gondii in broiler chickens were rarely reported. The objective of the present study was to compare the pathogenicity of 5 different T. gondii strains (RH, CN, JS, CAT2, and CAT3) from various host species origin in 10-day-old chickens. Each group of chickens was infected intraperitoneally with 5*10(8), 1*10(8), 1*10(7), and 1*10(6) tachyzoites of the 5 strains, respectively. The negative control group was mockly inoculated with PBS alone. After infection, clinical symptoms and rectal temperatures of all the chickens were checked daily. Dead chickens during acute phage of the infection were checked for T. gondii tachyzoites by microscope, while living cases were checked for T. gondii infection at day 53 post-inoculation (PI) by PCR method. Histopathological sections were used to observe the pathological changes in the dead chickens and the living animals at day 53 PI. No significant differences were found in survival periods, histopathological findings, and clinical symptoms among the chickens infected with the RH, CN, CAT2, and CAT3 strains. Histopathological findings and clinical symptoms of the JS (chicken origin) group were similar to the others. However, average survival times of infected chickens of the JS group inoculated with 5*10(8) and 1*10(8) tachyzoites were 30.0 and 188.4 hr, respectively, significantly shorter than those of the other 4 mammalian isolates. Chickens exposed to 10(8) of T. gondii tachyzoites and higher showed acute signs of toxoplasmosis, and the lesions were relatively more severe than those exposed to lower doses. The results indicated that the pathogenicity of JS strain was comparatively stronger to the chicken, and the pathogenicity was dose-dependent. PMID- 25925174 TI - Seroprevalence and Potential Risk Factors Associated with Neospora spp. Infection among Asymptomatic Horses in Jordan. AB - This study aimed to determine the seroprevalence and to identify risk factors associated with Neospora spp. infection in horses in Jordan. Management related data were collected from each farm and individual horses. Sera from 227 horses from 5 of 6 climatic regions in Jordan were analyzed for the presence of antibodies to Neospora spp. by ELISA kit. The study was performed during spring of 2010. The association between seropositivity and risk factors was analyzed. A total of 7 (3%) of 227 sera had antibodies for Neospora spp. There was a significant regional difference (P=0.018) between the 5 climatic regions. Positive cases were located in Amman and Irbid, while the other regions (Zarqa, Jordan Valley, and Wadi Mousa) had zero prevalence. The use of anthelmintics at least once a year resulted in a significant reduction of the seroprevalence to Neospora spp. (1.6% vs 9.8%). However, this might be a phenomenon by chance and a better hygiene since owners can invest in anthelmintics. Other risk factors such as age, gender, breed, usage, body condition score, grazing, presence of other animals mixed with the horses in the same property, and a history of previous diseases were not significantly associated with the seroprevalence to Neospora spp. infection. This is the first study to report on the presence of Neospora seropositive horses in Jordan. Further studies are warranted to better understand the role of certain risk factors in the transmission of Neospora spp. among horse population and to determine which Neospora spp. are responsible for the infection. PMID- 25925175 TI - Relationship between Antibody-Positive Rate against Plasmodium vivax Circumsporozoite Protein and Incidence of Malaria. AB - The relationship between anti- Plasmodium vivax circumsporozoite protein (CSP) antibody levels and the prevalence of malaria in epidemic areas of South Korea was evaluated. Blood samples were collected from inhabitants of Gimpo-si (city), Paju-si, and Yeoncheon-gun (county) in Gyeonggi-do (province), as well as Cheorwon-gun in Gangwon-do from November to December 2004. Microscopic examinations were used to identify malaria parasites. ELISA was used to quantitate anti-circumsporozoite protein (CSP) antibodies against P. vivax. A total of 1,774 blood samples were collected. The overall CSP-ELISA-positive rate was 7.7% (n=139). The annual parasite incidences (APIs) in these areas gradually decreased from 2004 to 2005 (1.09 and 0.80, respectively). The positive rate in Gimpo (10.4%, 44/425) was the highest identified by CSP-ELISA. The highest API was found in Yeoncheon, followed by Cheorwon, Paju, and Gimpo in both years. The positive rates of CSP-ELISA were closely related to the APIs in the study areas. These results suggest that seroepidemiological studies based on CSP may be helpful in estimating the malaria prevalence in certain areas. In addition, this assay can be used to establish and evaluate malaria control and eradication programs in affected areas. PMID- 25925176 TI - Allelic Diversity and Geographical Distribution of the Gene Encoding Plasmodium falciparum Merozoite Surface Protein-3 in Thailand. AB - Merozoite surface proteins (MSPs) of malaria parasites play critical roles during the erythrocyte invasion and so are potential candidates for malaria vaccine development. However, because MSPs are often under strong immune selection, they can exhibit extensive genetic diversity. The gene encoding the merozoite surface protein-3 (MSP-3) of Plasmodium falciparum displays 2 allelic types, K1 and 3D7. In Thailand, the allelic frequency of the P. falciparum msp-3 gene was evaluated in a single P. falciparum population in Tak at the Thailand and Myanmar border. However, no study has yet looked at the extent of genetic diversity of the msp-3 gene in P. falciparum populations in other localities. Here, we genotyped the msp 3 alleles of 63 P. falciparum samples collected from 5 geographical populations along the borders of Thailand with 3 neighboring countries (Myanmar, Laos, and Cambodia). Our study indicated that the K1 and 3D7 alleles coexisted, but at different proportions in different Thai P. falciparum populations. K1 was more prevalent in populations at the Thailand-Myanmar and Thailand-Cambodia borders, whilst 3D7 was more prevalent at the Thailand-Laos border. Global analysis of the msp-3 allele frequencies revealed that proportions of K1 and 3D7 alleles of msp-3 also varied in different continents, suggesting the divergence of malaria parasite populations. In conclusion, the variation in the msp-3 allelic patterns of P. falciparum in Thailand provides fundamental knowledge for inferring the P. falciparum population structure and for the best design of msp-3 based malaria vaccines. PMID- 25925177 TI - Low Fetal Weight is Directly Caused by Sequestration of Parasites and Indirectly by IL-17 and IL-10 Imbalance in the Placenta of Pregnant Mice with Malaria. AB - The sequestration of infected erythrocytes in the placenta can activate the syncytiotrophoblast to release cytokines that affect the micro-environment and influence the delivery of nutrients and oxygen to fetus. The high level of IL-10 has been reported in the intervillous space and could prevent the pathological effects. There is still no data of Th17 involvement in the pathogenesis of placental malaria. This study was conducted to reveal the influence of placental IL-17 and IL-10 levels on fetal weights in malaria placenta. Seventeen pregnant BALB/C mice were divided into control (8 pregnant mice) and treatment group (9 pregnant mice infected by Plasmodium berghei). Placental specimens stained with hematoxylin and eosin were examined to determine the level of cytoadherence by counting the infected erythrocytes in the intervillous space of placenta. Levels of IL-17 and IL-10 in the placenta were measured using ELISA. All fetuses were weighed by analytical balance. Statistical analysis using Structural Equation Modeling showed that cytoadherence caused an increased level of placental IL-17 and a decreased level of placental IL-10. Cytoadherence also caused low fetal weight. The increased level of placental IL-17 caused low fetal weight, and interestingly low fetal weight was caused by a decrease of placental IL-10. It can be concluded that low fetal weight in placental malaria is directly caused by sequestration of the parasites and indirectly by the local imbalance of IL-17 and IL-10 levels. PMID- 25925178 TI - Prevalence and Associated Risk Factors of Toxocara vitulorum Infections in Buffalo and Cattle Calves in Three Provinces of Central Cambodia. AB - The prevalence and associated risk factors of Toxocara vitulorum infection in buffalo and cattle calves was studied in 3 provinces in central Cambodia. Fecal samples were collected from 517 calves between the age of 1-15 weeks and processed for nematode egg counts by a modified McMaster method. A total of 64 calves were found to excrete T. vitulorum eggs in their feces (12.4%; 95% exact CI: 9.7-15.5). The mean fecal egg count was 2,798 EPG (SD=16,351; range=0 224,400). A multivariable generalized linear mixed model showed higher odds of T. vitulorum infection for buffalo versus cattle, for animals aged 4-8 weeks versus younger and older ones, and for animals with strongyle infection. There was no association with fecal consistency. Farmers should be aware of the potential impact of T. vitulorum , and treat their calves at the age of 2-3 weeks with anthelmintics such as benzimidazoles or pyrantel. PMID- 25925179 TI - Developmental and Phylogenetic Characteristics of Stellantchasmus falcatus (Trematoda: Heterophyidae) from Thailand. AB - This study aimed to investigate the infection status, worm development, and phylogenetic characteristics of the intestinal trematode, Stellantchasmus falcatus. The metacercariae of S. falcatus were detected only in the half-beak (Dermogenus pusillus) out of the 4 fish species examined. Their prevalence was 90.0%, and the intensity of infection was 919 metacercariae on average. Worms were recovered from 33 (97.1%) of 34 chicks that were experimentally infected with 200 S. falcatus metacercariae each, and the average recovery rate was 43.0%. The body size and inner organs of S. falcatus quickly increased in the experimental chicks over days 1-2 post-infection (PI). In addition, ITS2 sequence data of this parasite were analyzed to examine the phylogenetic relationships with other trematodes using the UPGMA method. The results indicated that the ITS2 sequence data recorded from trematodes in the family Heterophyidae appeared to be monophyletic. This study concluded that D. pusillus serves as a compatible second intermediate host of S. falcatus in Thailand and that S. falcatus can develop rapidly in the experimental chicks. Data collected from this study can help to close the gap in knowledge regarding the epidemiology, biology, and phylogenetic characteristics of S. falcatus in Thailand. PMID- 25925180 TI - Zoonotic Intestinal Trematodes in Stray Cats (Felis catus) from Riverside Areas of the Republic of Korea. AB - The present study was performed to survey the infection status of zoonotic intestinal trematode (ZIT) in stray cats from 5 major riverside areas in the Republic of Korea. Total 400 stray cats were captured with live-traps in riverside areas of Seomjingang ('gang' means river) (203 cats) from June to October 2010, and of Yeongsangang (41), Nakdonggang (57), Geumgang (38), and Hangang (61 cats) from June to October 2011, respectively. Small intestines resected from cats were opened with a pair of scissors in a beaker with 0.85% saline and examined with naked eyes and under a stereomicroscope. More than 16 ZIT species were detected in 188 (92.6%) cats from Seomjingang areas, and the number of worms recovered was 111 per cat infected. In cats from riverside areas of Yeongsangang, Nakdonggang, Geumgang, and Hangang, more than 9, 8, 3, and 5 ZIT species were recovered, and the worm burdens were 13, 42, 11, and 56 specimens per infected cat, respectively. As the members of family Heterophyidae, more than 10 species, i.e., Metagonimus spp., Pygidiopsis summa, Heterophyes nocens, Stellantchasmus falcatus, Heterophyopsis continua, Acanthotrema felis, Centrocestus armatus, Procerovum varium, Cryptocotyle concava, and Stictodora lari, were recovered. More than 5 species of echinostomes, i.e., Echinostoma hortense, Echinochasmus japonicus, Echinochasmus sp., Echinoparyphium sp., and unidentified larval echinostomes, were collected. Plagiorchis spp. were detected in cats from areas of Seomjin-gang and Yeongsangang. From the above results, it has been confirmed that stray cats in 5 major riverside areas of Korea are highly infected with various species of ZITs. PMID- 25925181 TI - Spontaneous splenic rupture in a vivax malaria case treated with transcatheter coil embolization of the splenic artery. AB - An enlarged spleen is considered one of the most common signs of malaria, and splenic rupture rarely occurs as an important life-threatening complication. Splenectomy has been recommended as the treatment of choice for hemodynamically unstable patients. However, a very limited number of splenic rupture patients have been treated with transcatheter coil embolization. Here we report a 38-year old Korean vivax malaria patient with ruptured spleen who was treated successfully by embolization of the splenic artery. The present study showed that angiographic embolization of the splenic artery may be an appropriate option to avoid perioperative harmful effects of splenectomy in malaria patients. PMID- 25925182 TI - An outbreak of trichinellosis by consumption of raw soft-shelled turtle meat in Korea. AB - Trichinellosis transmission to humans via the consumption of reptile meat is rare worldwide. In Korea, however, 2 such outbreaks, possibly via consumption of soft shelled turtle meat, have occurred in 2 successive years. In 17 August 2014, 6 patients were admitted to Wonju Severance Christian Hospital complaining of myalgia, fever, and headache. Eosinophilia was the indication of the initial laboratory results, and they were eventually diagnosed as trichinellosis by ELISA. All of the patients worked at the same company and had eaten raw soft shelled turtle meat at a company dinner 10 days prior to their admission. They were treated with albendazole for 2 weeks, upon which all of their symptoms disappeared. This is the 8th report on human trichinellosis in Korea, and the second implicating raw soft-shelled turtle meat. PMID- 25925183 TI - Strongyloidiasis in a diabetic patient accompanied by gastrointestinal stromal tumor: cause of eosinophilia unresponsive to steroid therapy. AB - We report here a case of strongyloidiasis in a 72-year-old diabetic patient (woman) accompanied by gastrointestinal stromal tumor receiving imatinib therapy, first diagnosed as hypereosinophilic syndrome and treated with steroids for uncontrolled eosinophilia. She suffered from lower back pain and intermittent abdominal discomfort with nausea and diagnosed with gastrointestinal stromal tumor. After post-operative imatinib treatment eosinophilia persisted, so that steroid therapy was started under an impression of hypereosinophilic syndrome. In spite of 6 months steroid therapy, eosinophilia persisted. Stool examination was performed to rule out intestinal helminth infections. Rhabditoid larvae of Strongyloides stercoralis were detected and the patient was diagnosed as strongyloidiasis. This diagnosis was confirmed again by PCR. The patient was treated with albendazole for 14 days and her abdominal pain and diarrhea improved. This case highlights the need for thorough investigation, including molecular approaches, to test for strongyloidiasis before and during steroid therapies. PMID- 25925184 TI - Genetic Polymorphisms in Plasmodium vivax Dihydrofolate Reductase and Dihydropteroate Synthase in Isolates from the Philippines, Bangladesh, and Nepal. AB - Genetic polymorphisms of pvdhfr and pvdhps genes of Plasmodium vivax were investigated in 83 blood samples collected from patients in the Philippines, Bangladesh, and Nepal. The SNP-haplotypes of the pvdhfr gene at the amino acid positions 13, 33, 57, 58, 61, 117, and 173, and that of the pvdhps gene at the positions 383 and 553 were analyzed by nested PCR-RFLP. Results suggest diverse polymorphic patterns of pvdhfr alone as well as the combination patterns with pvdhps mutant alleles in P. vivax isolates collected from the 3 endemic countries in Asia. All samples carried mutant combination alleles of pvdhfr and pvdhps. The most prevalent combination alleles found in samples from the Philippines and Bangladesh were triple mutant pvdhfr combined with single mutant pvdhps allele and triple mutant pvdhfr combined with double wild-type pvdhps alleles, respectively. Those collected from Nepal were quadruple mutant pvdhfr combined with double wild-type pvdhps alleles. New alternative antifolate drugs which are effective against sulfadoxine-pyrimethamine (SP)-resistant P. vivax are required. PMID- 25925185 TI - Seroprevalence of Trichinella sp. in Wild Boars (Sus scrofa) from Yanggu-gun, Gangwon-do, Korea. AB - A total 7 outbreaks of trichinellosis have occurred in Korea, mostly as a result of consumption of raw wild boar (Sus scrofa) meat. Since only 1 serological survey on wild boars had yet been performed in Korea, the present study aimed to estimate the prevalence of trichinellosis in wild boars and some species of rodents by artificial digestion and serological examinations in Yanggu-gun, Gangwon-do, the endemic area of trichinellosis. Both the wild boar and rodent muscle samples revealed no Trichinella larvae by direct examination and artificial digestion method. However, serological examinations revealed that 4 wild boar sera samples out of 118 (3.4%) were positive to Trichinella antigen. Although the recovery of Trichinella larvae ended in a failure, it is proved for the first time that the sylvatic cycle of Trichinella has been maintained in wild boars of Gangwon-do, Korea. PMID- 25925186 TI - Ancient mitochondrial DNA analyses of ascaris eggs discovered in coprolites from joseon tomb. AB - Analysis of ancient DNA (aDNA) extracted from Ascaris is very important for understanding the phylogenetic lineage of the parasite species. When aDNAs obtained from a Joseon tomb (SN2-19-1) coprolite in which Ascaris eggs were identified were amplified with primers for cytochrome b (cyt b) and 18S small subunit ribosomal RNA (18S rRNA) gene, the outcome exhibited Ascaris specific amplicon bands. By cloning, sequencing, and analysis of the amplified DNA, we obtained information valuable for comprehending genetic lineage of Ascaris prevalent among pre-modern Joseon peoples. PMID- 25925187 TI - Infection status of endoparasites in foreigner workers living in Cheonan City, Chungnam Province, Korea. AB - At present, more than 500,000 foreigner workers, most of them from Asian countries with high parasitic infection rates, are working in Korea. Since investigation into the prevalence of parasitic infections in foreigner workers has not yet been conducted in Korea, the present study was performed to determine the parasitic infection status of foreigner workers living in Cheonan City, Chungcheongnam-do (Chungnam Province) and to plan, on that basis, effective control measures. From October to December 2013, the parasitic infection status of 231 foreigner workers employed at selected Cheonan-si small businesses was investigated by both stool examination and ELISA. A total of 60 individuals (26.0%) were found to be infected with parasites. The stool examination detected 14 positive cases (6.1%), and ELISA revealed 50 positive people (21.6%), for at least a kind of parasitic disease. The most common infection was cysticercosis (8.7%), followed by toxocariasis (7.8%) and clonorchiasis (7.4%). Since it was proved that parasitic infections were prevalent among foreigner workers living in Cheonan City, more comprehensive study is urgently needed in order to understand the nationwide status of parasitic infections in foreigner workers. PMID- 25925188 TI - On cilia, flagella, and pulmonary pseudoprotozoa. PMID- 25925189 TI - The role of biological processes in reducing both odor impact and pathogen content during mesophilic anaerobic digestion. AB - Mesophilic anaerobic digestion (MAD) produces renewable energy, but it also plays a role in reducing the impact of digestates, both by reducing odor and pathogen content. Ten full-scale biogas plants characterized by different plant designs (e.g. single digesters, parallel or serial digesters), plant powers (ranging from 180 to 999 kWe), hydraulic retention time (HRT) (ranging between 20 to 70 days) and feed mixes were monitored and odors and pathogens were observed in both ingestates and digestates. Results obtained indicated that MAD reduced odors (OU) from, on average, OUingestate=99,106+/-149,173 OU m(-2) h(-1) (n=15) to OU digestate=1106+/-771 OU m(-2) h(-1) (n=15). Pathogens were also reduced during MAD both because of ammonia production during the process and competition for substrate between pathogens and indigenous microflora, i.e. Enterobacteriaceae from 6.85*10(3)+/-1.8*10(1) to 1.82*10(1)+/-3.82*10(1); fecal Coliform from 1.82*10(4)+/-9.09 to 2.45*10(1)+/-3.8*10(1); Escherichia coli from 8.72*10(3)+/ 2.4*10(1) to 1.8*10(1)+/-2.94*10(1); Clostridium perfringens from 6.4*10(4)+/-7.7 to 5.2*10(3)+/-8.1 (all data are expressed as CFU g(-1) ww). Plants showed different abilities to reduce pathogen indicators, depending on the pH value and toxic ammonia content. PMID- 25925190 TI - Deletion of 4.4 Mb at 2q33.2q33.3 May Cause Growth Deficiency in a Patient with Mental Retardation, Facial Dysmorphic Features and Speech Delay. AB - A patient with a rare interstitial deletion of chromosomal band 2q33.2q33.3 is described. The clinical features resembled the 2q33.1 microdeletion syndrome (Glass syndrome), including mental retardation, facial dysmorphism, high-arched narrow palate, growth deficiency, and speech delay. The chromosomal aberration was characterized by whole genome BAC aCGH. A comparison of the current patient and Glass syndrome features revealed that this case displayed a relatively mild phenotype. Overall, it is suggested that the deleted region of 2q33 causative for Glass syndrome may be larger than initially suggested. PMID- 25925191 TI - Reversible Hydrophobic-Hydrophilic Transition of Ionic Liquids Driven by Carbon Dioxide. AB - Ionic liquids (ILs) with a reversible hydrophobic-hydrophilic transition were developed, and they exhibited unique phase behavior with H2O: monophase in the presence of CO2, but biphase upon removal of CO2 at room temperature and atmospheric pressure. Thus, coupling of reaction, separation, and recovery steps in sustainable chemical processes could be realized by a reversible liquid-liquid phase transition of such IL-H2O mixtures. Spectroscopic investigations and DFT calculations showed that the mechanism behind hydrophobic-hydrophilic transition involved reversible reaction of CO2 with anion of the ILs and formation of hydrophilic ammonium salts. These unique IL-H2O systems were successfully utilized for facile one-step synthesis of Au porous films by bubbling CO2 under ambient conditions. The Au porous films and the ILs were then separated simultaneously from aqueous solutions by bubbling N2, and recovered ILs could be directly reused in the next process. PMID- 25925192 TI - HIV-related knowledge, perceptions, attitudes, and utilisation of HIV counselling and testing: a venue-based intercept commuter population survey in the inner city of Johannesburg, South Africa. AB - BACKGROUND: HIV counselling and testing (HCT) and knowledge about HIV have been key strategies utilised in the prevention and control of HIV/AIDS worldwide. HIV knowledge and uptake of HCT services in sub-Saharan Africa are still low. This study was conducted to determine factors associated with HCT and HIV/AIDS knowledge levels among a commuter population in Johannesburg, South Africa. OBJECTIVE: To identify the factors associated with HCT uptake among the commuter population. DESIGN: A simple random sampling method was used to select participants in a venue-based intercept survey at a taxi rank in the Johannesburg Central Business District. Data were collected using an electronic questionnaire. Logistic regression analysis assessed factors associated with HIV testing stratified by gender. RESULTS: 1,146 respondents were interviewed, the maority (n=579, 50.5%) were females and (n=780, 68.1%) were over 25 years of age. Overall HCT knowledge was high (n=951, 83%) with more females utilising HCT facilities. There was a significant difference in HIV testing for respondents living closer to and further away from health facilities. Slightly more than half of the respondents indicated stigma as one of the barriers for testing (n=594, 52%, p value=0.001). For males, living with a partner (aOR: 1.68, 95% CI: 1.02-2.78, p value: 0.041) and possessing a post-primary education were positively associated with testing (aOR: 2.00, 95% CI: 1.15-3.47, p-value: 0.014), whereas stigma and discrimination reduced the likelihood of testing (aOR: 0.40, 95% CI: 0.31-0.62, p value: <0.001). For females, having one sexual partner (aOR: 2.65, 95% CI: 1.19 5.90, p-value: 0.017) and a low perceived benefit for HIV testing (aOR: 0.54, 95% CI: 0.30-0.96, p-value: 0.035) were associated with HIV testing. CONCLUSION: The overall HIV/AIDS knowledge was generally high. Gender-specific health education and HIV intervention programmes are needed for improved access to HCT services. One favourable intervention would be the use of home-based HCT programmes. PMID- 25925193 TI - Health insurance and child mortality in rural Burkina Faso. AB - BACKGROUND: Micro health insurance schemes have been implemented across developing countries as a means of facilitating access to modern medical care, with the ultimate aim of improving health. This effect, however, has not been explored sufficiently. OBJECTIVE: We investigated the effect of enrolment into community-based health insurance on mortality in children under 5 years of age in a health and demographic surveillance system in Nouna, Burkina Faso. DESIGN: We analysed the effect of health insurance enrolment on child mortality with a Cox regression model. We adjusted for variables that we found to be related to the enrolment in health insurance in a preceding analysis. RESULTS: Based on the analysis of 33,500 children, the risk of mortality was 46% lower in children enrolled in health insurance as compared to the non-enrolled children (HR=0.54, 95% CI 0.43-0.68) after adjustment for possible confounders. We identified socioeconomic status, father's education, distance to the health facility, year of birth, and insurance status of the mother at time of birth as the major determinants of health insurance enrolment. CONCLUSIONS: The strong effect of health insurance enrolment on child mortality may be explained by increased utilisation of health services by enrolled children; however, other non-observed factors cannot be excluded. Because malaria is a main cause of death in the study area, early consultation of health services in case of infection could prevent many deaths. Concerning the magnitude of the effect, implementation of health insurance could be a major driving factor of reduction in child mortality in the developing world. PMID- 25925194 TI - Comparison of the effects of BPA and BPAF on oocyte spindle assembly and polar body release in mice. AB - Bisphenol AF (BPAF), a homolog of bisphenol A (BPA), is a widely used environmental chemical that has adverse effects on reproduction. The aim of this study was to analyse the effects of BPA and BPAF exposure on oocyte maturation in vitro. Oocytes were cultured in the presence of BPA or BPAF (2, 20, 50 or 100 MUg/ml) for 18 h. At concentrations of 50 and 100 MUg/ml, BPA and BPAF inhibited oocyte maturation, with BPAF treatment causing a sharp decrease in the number of oocytes reaching maturity. Oocytes were exposed to BPA or BPAF at 2 MUg/ml and cultured for different durations (6, 9, 12, 15 or 18 h). Both BPAF and BPA caused a cell cycle delay under these conditions. Oocytes cultured in the presence of BPA or BPAF (50 MUg/ml) for 21 h were tested for the localization of alpha tubulin and MAD2 using immunofluorescence. High concentrations of BPAF induced cell cycle arrest through the activation of the spindle assembly checkpoint. After 12 h of culture in BPAF (50 MUg/ml), oocytes were transferred to control medium for 9 h. Only 63.3% oocytes treated in this manner progressed to metaphase II (MII). Oocytes exposed to high doses of BPA experienced a cell cycle delay, but managed to progress to MII when the culture period was prolonged. In addition, MAD2 was localized in the cytoplasm of these oocytes. In conclusion, both BPAF and BPA exposure affected oocyte maturation, however BPAF and BPA have differential effects on SAC activity. PMID- 25925195 TI - The efficacy of superselective intra-arterial infusion with concomitant radiotherapy for adenoid cystic carcinoma of the head and neck. AB - CONCLUSIONS: Superselective intra-arterial cisplatin infusion with concomitant radiotherapy (RADPLAT) is considered to be one of the treatments of choice for patients with adenoid cystic carcinoma (ACC) who prefer not to undergo radical surgery. OBJECTIVE: To evaluate the efficacy of RADPLAT for patients with ACC of the head and neck. PATIENTS AND METHODS: Between 2001-2010, nine patients with untreated ACC were given superselective intra-arterial infusion of cisplatin (100 120 mg/m(2)/week) with simultaneous intravenous infusion of thiosulfate to neutralize cisplatin toxicity and radiotherapy (65-70 Gy). RESULTS: Five patients had tumors arising in the base of the tongue, two in the maxillary sinus, and the remaining two in the nasopharynx. The median follow-up period was 9 years 7 months (9;7) (range = 4;6-12;5), and the 5-year local control (LC), overall survival (OS), and disease-free survival rates were 88.9%, 88.9%, and 55.6%, respectively. The 10-year OS rate was 57.1%, but all patients who remained alive for over 10 years are still alive with disease. Primary tumor recurrence was observed in five of the nine patients, with the median time to recurrence being 6 years (range = 4-9 years). Five of the nine patients had distant metastasis, and of these three patients also had primary recurrence. PMID- 25925196 TI - A small region of porcine hemagglutinating encephalomyelitis virus spike protein interacts with the neural cell adhesion molecule. AB - OBJECTIVE: The spike (S) protein of porcine hemagglutinating encephalomyelitis virus (PHEV) may mediate infection by binding to a cellular neural cell adhesion molecule (NCAM). This study aimed to identify the crucial domain of the S1 subunit of the S protein that interacts with NCAM. METHODS: Three truncated segments (S(1-291), S(277-794) and S(548-868)) of the S gene of PHEV and the NCAM gene were cloned individually into the Escherichia coli expression vectors and yeast two-hybrid expression vectors. The interaction between S(1-291), S(277 794), S(548-868) and NCAM were detected by a GST pull-down experiment and yeast two-hybrid assay. RESULTS: Three fusion proteins (S(1-291), S(277-794) and S(548 868)) were screened for their interactions with NCAM by protein-protein interaction assays. The results of these assays clarified that S(277-794) interacted with NCAM, while S(1-291) and S(548-868) did not. CONCLUSIONS: A small fragment (258-amino-acid fragment, residues 291-548) on the PHEV S protein was posited to be the minimum number of amino acids necessary to interact with NCAM. This fragment may be the receptor-binding domain that mediates PHEV binding to NCAM. PMID- 25925197 TI - Single-molecule spectroscopy and femtosecond transient absorption studies on the excitation energy transfer process in ApcE(1-240) dimers. AB - ApcE(1-240) dimers with one intrinsic phycocyanobilin (PCB) chromophore in each monomer that is truncated from the core-membrane linker (ApcE) of phycobilisomes (PBS) in Nostoc sp. PCC 7120 show a sharp and significantly red-shifted absorption. Two explanations either conformation-dependent Forster resonance energy transfer (FRET) or the strong exciton coupling limit have been proposed for red-shifted absorption. This is a classic example of the special pair in the photosynthetic light harvesting proteins, but the mechanism of this interaction is still a matter of intense debate. We report the studies using single-molecule and transient absorption spectra on the interaction in the special pair of ApcE dimers. Our results demonstrate the presence of conformation-dependent FRET between the two PCB chromophores in ApcE dimers. The broad distributions of fluorescence intensities, lifetimes and polarization difference from single molecule measurements reveal the heterogeneity of local protein-pigment environments in ApcE dimers, where the same molecular structures but different protein environments are the main reason for the two PCB chromophores with different spectral properties. The excitation energy transfer rate between the donor and the acceptor about (110 ps)(-1) is determined from transient absorption measurements. The red-shifted absorption in ApcE dimers could result from more extending conformation, which shows another type of absorption redshift that does not depend on strong exciton coupling. The results here stress the importance of conformation-controlled spectral properties of the chemically identical chromophores, which could be a general feature to control energy/electron transfer, widely existing in the light harvesting complexes. PMID- 25925198 TI - L-arginine exacerbates experimental cerebral malaria by enhancing pro inflammatory responses. AB - L-Arginine (L-Arg), the substrate for nitric oxide (NO) synthase, has been used to treat malaria to reverse endothelial dysfunction in adults. However, the safety and efficacy of L-Arg remains unknown in malaria patients under the age of five, who are at the greatest risk of developing cerebral malaria (CM), a severe malaria complication. Here, we tested effects of L-Arg treatment on the outcomes of CM using a mouse model. Experimental cerebral malaria (ECM) was induced in female C57BL/6 mice infected with Plasmodium berghei ANKA, and L-Arg was administrated either prophylactically or after parasite infection. Surprisingly, both types of L-Arg administration caused a decline in survival time and raised CM clinical scores. L-Arg treatment increased the population of CD4(+)T-bet(+)IFN gamma(+) Th1 cells and the activated macrophages (F4/80(+)CD36(+)) in the spleen. The levels of pro-inflammatory cytokines, IFN-gamma and TNF-alpha, in splenocyte cultures were also increased by L-Arg treatment. The above changes were accompanied with a rise in the number of dendritic cells (DCs) and an increase in their maturation. However, L-Arg did not affect the population of regulatory T cells or the level of IL-10 in the spleen. Taken together, these data suggest that L-Arg may enhance the Th1 immune response, which is essential for a protective response in uncomplicated malaria but could be lethal in CM patients. Therefore, the prophylactic use of L-Arg to treat CM, based on the assumption that restoring the bioavailability of endothelial NO improves the outcome of CM, may need to be reconsidered especially for children. PMID- 25925199 TI - Visible Light-Driven Atom Transfer Radical Addition to Olefins using Bi2 O3 as Photocatalyst. AB - Bismuth oxide, an inexpensive and non-toxic semiconductor, has been successfully used as a visible light photocatalyst for the atom transfer radical addition (ATRA) reaction of organobromides to diversely functionalized terminal olefins. The reaction takes place under very mild conditions, in the absence of any additive, and with low catalyst loading (1 mol %). The corresponding ATRA products are obtained with moderate to excellent yields (up to 95 %). PMID- 25925200 TI - Microbial granulation for lactic acid production. AB - This work investigated the formation of microbial granules to boost the productivity of lactic acid (LA). The flocculated form of LA-producing microbial consortium, dominated by Lactobacillus sp. (91.5% of total sequence), was initially obtained in a continuous stirred-tank reactor (CSTR), which was fed with 2% glucose and operated at a hydraulic retention time (HRT) of 12 h and pH 5.0 +/- 0.1 under a thermophilic condition (50 degrees C). The mixed liquor in the CSTR was then transferred to an up-flow anaerobic sludge blanket reactor (UASB). The fermentation performance and granulation process were monitored with a gradual decrease of HRT from 8.0 to 0.17 h, corresponding to an increase in the substrate loading from 60 to 2,880 g glucose L(-1) d(-1) . As the operation continued, the accumulation of biomass in the UASB was clearly observed, which changed from flocculent to granular form with decrease in HRT. Up to the HRT decrease to 0.5 h, the LA concentration was maintained at 19-20 g L(-1) with over 90% of substrate removal efficiency. However, further decrease of HRT resulted in a decrease of LA concentration with increase in residual glucose. Nevertheless, the volumetric LA productivity continuously increased, reaching 67 g L-fermenter (-1) h(-1) at HRT 0.17 h. The size of LA-producing granules and hydrophobicity gradually increased with decrease in HRT, reaching 6.0 mm and 60%, respectively. These biogranules were also found to have high settling velocities and low porosities, ranging 2.69-4.73 cm s(-1) and 0.39-0.92, respectively. PMID- 25925201 TI - Integrin beta1, Osmosensing, and Chemoresistance in Mouse Ehrlich Carcinoma Cells. AB - BACKGROUND/AIMS: Altered expression of the integrin family of cell adhesion receptors has been associated with initiation, progression, and metastasis of solid tumors as well as in the development of chemoresistance. Here, we investigated the role of integrins, in particular integrin beta1, in cell volume regulation and drug-induced apoptosis in adherent and non-adherent Ehrlich ascites cell lines. METHODS: Adhesion phenotypes were verified by colorimetric cell-adhesion-assay. Quantitative real-time PCR and western blot were used to compare expression levels of integrin subunits. Small interfering RNA was used to silence integrin beta1 expression. Regulatory volume decrease (RVD) after cell swelling was studied with calcein-fluorescence-self-quenching and Coulter counter analysis. Taurine efflux was estimated with tracer technique. Caspase assay was used to determine apoptosis. RESULTS: We show that adherent cells have stronger fibronectin binding and a significantly increased expression of integrin alpha5, alphav, and beta1 at mRNA and protein level, compared to non-adherent cells. Knockdown of integrin beta1 reduced RVD of the adherent but not of the non adherent cells. Efflux of taurine was unaffected. In contrast to non-adherent, adherent cells exhibited chemoresistance to chemotherapeutic drugs (cisplatin and gemcitabine). However, knockdown of integrin beta1 promoted cisplatin-induced caspase activity in adherent cells. CONCLUSION: Our data identifies integrin beta1 as a part of the osmosensing machinery and regulator of cisplatin resistance in adherent Ehrlich cells. PMID- 25925202 TI - Ten reasons to be more attentive to patients when setting the ventilator. PMID- 25925204 TI - Immanuel Kant's categorical imperative and the brain-dead patient. PMID- 25925203 TI - Intravenous amino acid therapy for kidney function in critically ill patients: a randomized controlled trial. AB - IMPORTANCE: Acute kidney injury (AKI) is characterized by severe loss of glomerular filtration rate (GFR) and is associated with a prolonged intensive care unit (ICU) stay and increased risk of death. No interventions have yet been shown to prevent AKI or preserve GFR in critically ill patients. Evidence from mammalian physiology and small clinical trials suggests higher amino acid intake may protect the kidney from ischemic insults and thus may preserve GFR during critical illness. OBJECTIVE: To determine whether amino acid therapy, achieved through daily intravenous (IV) supplementation with standard amino acids, preserves kidney function in critically ill patients. DESIGN, SETTING, AND PARTICIPANTS: Multicenter, phase II, randomized clinical trial conducted between December 2010 and February 2013 in the ICUs of 16 community and tertiary hospitals in Australia and New Zealand. Participants were adult critically ill patients expected to remain in the study ICU for longer than 2 days. INTERVENTIONS: Random allocation to receive a daily supplement of up to 100 g of IV amino acids or standard care. MAIN OUTCOMES AND MEASURES: Duration of renal dysfunction (primary outcome); estimated GFR (eGFR) derived from creatinine; eGFR derived from cystatin C; urinary output; renal replacement therapy (RRT) use; fluid balance and other measures of renal function. RESULTS: 474 patients were enrolled and randomized (235 to standard care, 239 to IV amino acid therapy). At time of enrollment, patients allocated to receive amino acid therapy had higher APACHE II scores (20.2 +/- 6.8 vs. 21.7 +/- 7.6, P = 0.02) and more patients had pre-existing renal dysfunction (29/235 vs. 44/239, P = 0.07). Duration of renal dysfunction after enrollment did not differ between groups (mean difference 0.21 AKI days per 10 patient ICU days, 95 % CI -0.27 to 1.04, P = 0.45). Amino acid therapy significantly improved eGFR (treatment group * time interaction, P = 0.004), with an early peak difference of 7.7 mL/min/1.73 m(2) (95 % CI 1.0-14.5 mL/min/1.73 m(2), P = 0.02) on study day 4. Daily urine output was also significantly increased (+300 mL/day, 95 % CI 145-455 mL, P = 0.0002). There was a trend towards increased RRT use in patients receiving amino acid therapy (13/235 vs. 25/239, P = 0.062); however, this trend was not present after controlling for baseline imbalance (P = 0.21). CONCLUSION AND RELEVANCE: Treatment with a daily IV supplement of standard amino acids did not alter our primary outcome, duration of renal dysfunction. TRIAL REGISTRATION: anzctr.org.au Identifier: ACTRN12609001015235. PMID- 25925205 TI - HAUSP regulates c-MYC expression via de-ubiquitination of TRRAP. AB - PURPOSE: The de-ubiquitinase HAUSP has been reported to exhibit various biological roles implicated in the development of cancer and other pathologies. The dual nature of HAUSP (i.e., oncogenic and tumor suppressive) makes the protein even more versatile. The major aims of this study were to reveal the effect of HAUSP over-expression on the overall proteome and to identify bona fide substrates of HAUSP. In addition, we aimed to unravel the functionality and physiological relevance of the de-ubiquitinating activity of HAUSP on one of its newly identified substrates, TRRAP. METHODS: An overall proteome analysis was performed after exogenous HAUSP over-expression in HEK293 cells, followed by 2 dimensional gel electrophoresis (2-DE). Interacting proteins were subsequently isolated using immunoprecipitation and 1-dimensional gel electrophoresis (1-DE). Both were followed by tandem MALDI-TOF/TOF mass spectrometry and gene ontology based analyses. To validate the functionality of one of the identified substrates (TRRAP), Western blotting, immunocytochemistry, immunoprecipitation, in vivo de ubiquitination, quantitative real-time PCR and luciferase assays were performed. RESULTS: The substrate screening indicated that HAUSP may be involved in tumorigenesis, cytoskeletal organization and transport, and chaperone systems. One candidate substrate, TRRAP, was found to physically interact and co-localize with HAUSP. As TRRAP regulates c-MYC expression, and in order to validate the effect of HAUSP on TRRAP, c-MYC protein and mRNA expression levels were analyzed after exogenous HAUSP over-expression. Both were found to be up-regulated. We also found that c-MYC transactivation increased upon exogenous HAUSP over expression. By using a luciferase reporter assay, we found that a c-MYC responsive promoter exhibited increased activity, which was subsequently abrogated upon TRRAP knockdown. CONCLUSIONS: From our results we conclude that HAUSP may act as an oncogenic protein that can modulate c-MYC expression via TRRAP. Our results provide a new context in which HAUSP may play a role in cancer cell signalling. PMID- 25925207 TI - The Neurologist in Dante's Inferno. AB - The year 2015 marks the 750th birth anniversary of the Italian poet Dante Alighieri (1265-1321). It is less known that Dante had a sound level of medical knowledge, probably derived by his academic studies. In his works, medieval notions of neuroanatomy and neurophysiology (e.g. the connection between brain and spinal cord, function of optic nerve and peripheral nerves, knowledge of vegetative nervous system) and descriptions of neurological disorders (e.g. epileptic seizures, effects on nervous system by metal intoxication, and narcolepsy) may be found, specially in the Inferno, the first part of his masterpiece, the Divine Comedy. These accurate descriptions have led some authors to believe that the poet himself may have suffered from a neurological disease (epilepsy or hypersomnia). Damned souls of the Inferno seem to be also afflicted by psychiatric disorders, such as melancholia and depression. The analysis of Dante's works confirms that poetry - as well as literature in general - may be an important source of information for historians of neurology. PMID- 25925206 TI - The BMI1 polycomb protein represses cyclin G2-induced autophagy to support proliferation in chronic myeloid leukemia cells. AB - The BMI1 polycomb protein regulates self-renewal, proliferation and survival of cancer-initiating cells essentially through epigenetic repression of the CDKN2A tumor suppressor locus. We demonstrate here for the first time that BMI1 also prevents autophagy in chronic myeloid leukemia (CML) cell lines, to support their proliferation and clonogenic activity. Using chromatin immunoprecipitation, we identified CCNG2/cyclin G2 (CCNG2) as a direct BMI1 target. BMI1 downregulation in CD34+ CML cells by PTC-209 pharmacological treatment or shBMI1 transduction triggered CCNG2 expression and decreased clonogenic activity. Also, ectopic expression of CCNG2 in CD34+ CML cells strongly decreased their clonogenicity. CCNG2 was shown to act by disrupting the phosphatase 2A complex, which activates a PKCzeta-AMPK-JNK-ERK pathway that engages autophagy. We observed that BMI1 and CCNG2 levels evolved inversely during the progression of CML towards an acute deadly phase, and therefore hypothesized that BMI1 could support acute transformation of CML through the silencing of a CCNG2-mediated tumor-suppressive autophagy response. PMID- 25925208 TI - Recent findings from the Human Proteome Project: opening the mass spectrometry toolbox to advance cancer diagnosis, surveillance and treatment. AB - The Human Proteome Project stands to eclipse the Human Genome Project in terms of scope, content and interpretation. Its outputs, in conjunction with recent developments across the proteomics community, provide new tools for cancer research with the potential of providing clinically relevant insights into the disease. These collectively may guide the development of future diagnosis, surveillance and treatment strategies. Having established a robust organizational framework within the international community, the Human Proteome Organization and the proteomics community at large have made significant advances in biomarker discovery, detection, molecular imaging and in exploring tumor heterogeneity. Here, the authors discuss some developments in cancer proteomics and how they can be implemented to reduce the global burden of the disease. PMID- 25925209 TI - Differential expressions of cancer-associated genes and their regulatory miRNAs in colorectal carcinoma. AB - Colorectal cancer is one of the frequently seen malignancies in the world. To date, several oncogenes and tumor suppressor genes have been identified and linked to colorectal cancer pathogenesis. Although recent advances in the diagnosis and therapy of colorectal cancer are promising, identifying novel genetic contributors is still high priority. In the present study, expression profile of some cancer-related genes and their regulatory miRNA molecules were evaluated by using a high-throughput real-time PCR method. For the study, a total of 54 patients diagnosed with CRC and normal colon tissue samples of 42 healthy controls were included. For the expression analysis, total RNA was extracted from FFPE tissue samples and converted to cDNA. All expression analyses were assessed by using Fluidigm Microfluidic Dynamic Array chips for 96 samples and the reactions were held in Fluidigm BioMarkTM HD System Real-Time PCR. As a result of the study, expression of the ADAMTS1, FHIT, RUNX1, RUNX3 and WWOX genes was shown to be significantly altered in CRC tissues in contrast to normal tissue samples. Moreover, miR-378a-3p, miR-155-5p, miR-193b-3p, miR-96-5p, miR-17-5p, miR-27a-3p, miR-133b, miR-203a, miR-205-5p, miR-34c-5p, miR-130a-3p, miR-301a-3p, miR-132-3p, miR-222-3p, miR-34a-5p, miR-21-5p, miR-29a-3p and miR-29b-3p were found to be significantly deregulated in CRC. Consequently, results of the current study strongly suggest the involvement of novel cancer-related genes and their regulatory miRNAs in CRC physiopathology. PMID- 25925210 TI - Henry Marsh: Thinking fast and slow. PMID- 25925211 TI - Genital soft tissue tumors. AB - Mesenchymal neoplasms of the vulvovaginal and inguinoscrotal regions are among the most diagnostically challenging specimens in the pathology laboratory owing largely to their unique intersection between general soft tissue tumors and relatively genital-specific mesenchymal tumors. Genital stromal tumors are a unique subset of soft tissue tumors encountered at this location, and this group includes fibroepithelial stromal polyp, superficial (cervicovaginal) myofibroblastoma, cellular angiofibroma, mammary-type myofibroblastoma, angiomyofibroblastoma and aggressive angiomyxoma. Aside from the striking morphologic and immunophenotypic similarity that is seen with these entities, there is evidence that a subset of genital stromal tumors may be linked genetically. This review will focus on simplifying this group of tumors and provide the pathologist or dermatopathologist with practical management information. Smooth muscle tumors of the external genitalia will also be discussed. PMID- 25925212 TI - A Processable Shape Memory Polymer System for Biomedical Applications. AB - Polyurethane shape memory polymers (SMPs) with tunable thermomechanical properties and advanced processing capabilities are synthesized, characterized, and implemented in the design of a microactuator medical device prototype. The ability to manipulate glass transition temperature (Tg ) and crosslink density in low-molecular weight aliphatic thermoplastic polyurethane SMPs is demonstrated using a synthetic approach that employs UV catalyzed thiol-ene "click" reactions to achieve postpolymerization crosslinking. Polyurethanes containing varying C=C functionalization are synthesized, solution blended with polythiol crosslinking agents and photoinitiator and subjected to UV irradiation, and the effects of number of synthetic parameters on crosslink density are reported. Thermomechanical properties are highly tunable, including glass transitions tailorable between 30 and 105 degrees C and rubbery moduli tailorable between 0.4 and 20 MPa. This new SMP system exhibits high toughness for many formulations, especially in the case of low crosslink density materials, for which toughness exceeds 90 MJ m(-3) at select straining temperatures. To demonstrate the advanced processing capability and synthetic versatility of this new SMP system, a laser-actuated SMP microgripper device for minimally invasive delivery of endovascular devices is fabricated, shown to exhibit an average gripping force of 1.43 +/- 0.37 N and successfully deployed in an in vitro experimental setup under simulated physiological conditions. PMID- 25925213 TI - Aortic valve haematoma as a complication after coronary angiography: a clinical case with spontaneous resolution. PMID- 25925214 TI - An auscultatory conundrum: severe mitral stenosis with a third heart sound? PMID- 25925215 TI - Impacts of lesion angle on incidence and distribution of acute vessel wall injuries and strut malapposition after drug-eluting stent implantation assessed by optical coherence tomography. AB - AIMS: To investigate the impact of lesion angle on the incidence and distribution of acute vessel wall injuries and incomplete stent apposition (ISA) following second-generation drug-eluting stent (DES) implantation using optical coherence tomography (OCT). Several ex vivo studies demonstrated that angled arterial walls are exposed to imbalanced mechanical stress from deployed stents. METHODS AND RESULTS: We included 243 lesions treated with a single DES (148 everolimus eluting stent and 95 zotarolimus-eluting stent). Angled lesions were defined as lesions with angle >=45 degrees on an angiogram (n = 58). The vessel wall injuries and ISA were evaluated by OCT. The results were compared with non-angled lesions (<45 degrees , n = 185). The incidence of instent dissection, thrombus, and ISA was significantly higher in the angled group than in the non-angled group (84.5 vs. 63.2%, P < 0.01; 55.2 vs. 35.1%, P < 0.01; 75.9 vs. 44.9%, P < 0.001, respectively). In the angled group, the normalized tissue protrusion volume around the centre of angle (6.59 +/- 6.81, mm(3) * 10(2)) was higher than in the distal sub-segment (2.21 +/- 2.87, mm3 * 10(2), P < 0.001), in the proximal sub segment (4.14 +/- 5.34, mm3 * 10(2), P = 0.02), and in the non-angled group (3.30 +/- 2.81, mm3 * 10(2), P < 0.001). The incidence of major adverse cardiac events within 12 months was similar between the groups. CONCLUSIONS: Angled coronary lesions had a higher incidence rate of OCT-detected vessel wall injuries and ISA compared with non-angled lesions following second-generation DES implantation. Further studies are needed to understand the long-term clinical significance of these findings. PMID- 25925216 TI - 3-D transoesophageal echocardiography guidance in percutaneous closure of three distant atrial septal defects. PMID- 25925217 TI - Limitations of coronary computed tomographic angiography for delineating the lumen and vessel contours of coronary arteries in patients with stable angina. AB - AIMS: We sought to evaluate whether coronary computed tomographic angiography (CCTA) could accurately and reproducibly delineate the lumen and vessel contours of coronary arteries. METHODS AND RESULTS: One hundred coronary stenotic lesions representing 91 patients with stable angina who received both CCTA and intravascular ultrasound (IVUS) were analysed. Three segments with minimal lumen cross-sectional area (CSA), proximal reference, and distal reference on IVUS images were selected for each lesion. Five observers measured lumen and vessel CSAs at three matching segments on CCTA images. These CSAs were compared with the IVUS-measured CSAs as a reference standard. All five observers underestimated lumen CSA at the three selected segments by CCTA. The minimal lumen CSA assessed by CCTA exhibited very weak correlations with those obtained by IVUS (r =0.23, 0.24, 0.15, 0.25, and 0.28, respectively). In contrast to the lumen CSA, the vessel CSA at the three segments was overestimated by all observers when assessed by CCTA. At the segment with minimal lumen CSA, the vessel CSA obtained by CCTA showed weak correlations with those assessed by IVUS (r = 0.43, 0.33, 0.44, 0.37, and 0.42, respectively). Moreover, intra-class correlation coefficients ranged from 0.44 to 0.73 among the five observers for lumen or vessel CSA measurements by CCTA at the segment with minimal lumen CSA. CONCLUSION: CCTA has potential limitations in the accurate delineation of lumen and vessel contours in patients with angina, as there was a high level of discordance with the IVUS-measured lumen and vessel CSAs and high inter-observer variability. PMID- 25925218 TI - Diagnosis of extensive myocardial, pericardial, and coronary calcification in Weber-Christian disease. PMID- 25925219 TI - Optical coherence tomography can visualize the pulmonary artery in Williams Beuren syndrome. PMID- 25925220 TI - Echocardiographic parameters of left ventricular size and function as predictors of symptomatic heart failure in patients with a left ventricular ejection fraction of 50-59% treated with anthracyclines. AB - AIMS: The aim of this study was to assess whether baseline echocardiographic measures of left ventricular (LV) size and function predict the development of symptomatic heart failure or cardiac death (major adverse cardiac events, MACE) in patients treated with anthracyclines who have a pre-chemotherapy left ventricular ejection fraction (LVEF) between 50 and 59%. METHODS AND RESULTS: Patients with an LVEF between 50 and 59% before anthracyclines were selected. In these patients, LV volumes, LVEF, and peak longitudinal strain (GLS) were measured. Individuals were followed for MACE and all-cause mortality over a median of 659 days (range: 3-3704 days). Of 2234 patients undergoing echocardiography for pre-anthracycline assessment, 158 (7%) had a resting ejection fraction of 50-59%. Their average LV end-diastolic volume (LVEDV) was 101 +/- 22 mL, LVEF was 54 +/- 3%, and global longitudinal strain (GLS) was -17.7 +/- 2.6%. Twelve patients experienced a MACE (congestive heart failure) at a median of 173 days (range: 15-530). Age, diabetes, previous coronary artery disease, LVEDV, indexed LVEDV, LVESV, indexed LVESV, and GLS were all predictive of MACE (P = 0.012, 0.039, 0.0029, 0.012, and 0.0065 for LVEDV, LVEDVI, LVESV, LVESVI, and GLS, respectively). Indexed LVEDV and GLS remained predictive of MACE when adjusted for age. Age and GLS were also predictive of overall mortality (P < 0.0001 and 0.0105, respectively). CONCLUSION: In patients treated with anthracyclines with an LVEF of 50-59%, both baseline EDV and GLS predict the occurrence of MACE. These parameters may help target patients who could benefit from closer cardiac surveillance and earlier initiation of cardioprotective medical therapy. PMID- 25925222 TI - Presence of Pseudomonas aeruginosa influences biofilm formation and surface protein expression of Staphylococcus aureus. AB - Although Staphylococcus aureus and Pseudomonas aeruginosa can individually colonize and infect their hosts, the commensalistic effect of the two is more tenacious and lethal. In this study, it was shown that in co-culture with P. aeruginosa, a sub-population of S. aureus exhibited improved resistance to kanamycin by selection of small colony variant (SCV) phenotype. Additionally, biofilm formation by the two bacteria was denser in the co-culture, compared with biofilm formed in individual pure cultures. Using Atomic Force Microscope (AFM) force spectroscopy for single cells, it was demonstrated that S. aureus cultured in the presence of P. aeruginosa bound more tenaciously to substrates. Surface shaved peptides were isolated and identified using ultra-performance liquid chromatography-quadrupole-time of flight and a homology search program spider. Results indicated that serine-rich adhesin, extracellular matrix binding protein and other putative adhesion proteins could be responsible for the enhanced attachment of S. aureus in the co-culture. Besides, several other proteins were differentially expressed, indicating the occurrence of a range of other interactions. Of particular interest was a multidrug resistant protein named ABC transporter permease which is known to expel xenobiotics out of the cells. Positive regulation of this protein could be involved in the SCV selection of S. aureus in the co-culture. PMID- 25925221 TI - Fungal artificial chromosomes for mining of the fungal secondary metabolome. AB - BACKGROUND: With thousands of fungal genomes being sequenced, each genome containing up to 70 secondary metabolite (SM) clusters 30-80 kb in size, breakthrough techniques are needed to characterize this SM wealth. RESULTS: Here we describe a novel system-level methodology for unbiased cloning of intact large SM clusters from a single fungal genome for one-step transformation and expression in a model host. All 56 intact SM clusters from Aspergillus terreus were individually captured in self-replicating fungal artificial chromosomes (FACs) containing both the E. coli F replicon and an Aspergillus autonomously replicating sequence (AMA1). Candidate FACs were successfully shuttled between E. coli and the heterologous expression host A. nidulans. As proof-of-concept, an A. nidulans FAC strain was characterized in a novel liquid chromatography-high resolution mass spectrometry (LC-HRMS) and data analysis pipeline, leading to the discovery of the A. terreus astechrome biosynthetic machinery. CONCLUSION: The method we present can be used to capture the entire set of intact SM gene clusters and/or pathways from fungal species for heterologous expression in A. nidulans and natural product discovery. PMID- 25925223 TI - Making EBSD on water ice routine. AB - Electron backscatter diffraction (EBSD) on ice is a decade old. We have built upon previous work to select and develop methods of sample preparation and analysis that give >90% success rate in obtaining high-quality EBSD maps, for the whole surface area (potentially) of low porosity (<15%) water ice samples, including very fine-grained (<10 MUm) and very large (up to 70 mm by 30 mm) samples. We present and explain two new methods of removing frost and providing a damage-free surface for EBSD: pressure cycle sublimation and 'ironing'. In general, the pressure cycle sublimation method is preferred as it is easier, faster and does not generate significant artefacts. We measure the thermal effects of sample preparation, transfer and storage procedures and model the likelihood of these modifying sample microstructures. We show results from laboratory ice samples, with a wide range of microstructures, to illustrate effectiveness and limitations of EBSD on ice and its potential applications. The methods we present can be implemented, with a modest investment, on any scanning electron microscope system with EBSD, a cryostage and a variable pressure capability. PMID- 25925224 TI - [The Malady of Emperor Frederick III. and Virchow's diagnostic role]. AB - Crownprince Frederick Wilhelm of Prussia was once the hope of the liberal movement in Germany. He embodied and lived a humanistic ideal based on the spirit of the enlightenment. Starting in January 1887 the passionate pipe smoker suffered on an unusual long hoarseness. A polyp of the vocal cord was diagnosed. Although this diagnosis seemed harmless, an odyssee was launched that made history. Rudolf Virchow-the foremost pathologist of that time-was involved in the following histological diagnosis. His role and that of the sprouting histopathology will be presented in this essay. PMID- 25925225 TI - Anti-proliferative activity of hop-derived prenylflavonoids against human cancer cell lines. AB - Flavonoids form a substantial group of secondary plant metabolites that display several health-promoting effects. Therefore, prenylflavonoids, a subclass of flavonoids, have attracted increasing attention. Here, we investigated the possible anti-cancer potential of 6-prenylnaringenin (6-PN) and 8 prenylnaringenin (8-PN), two prenylflavonoids present in hops and beer and demonstrate an unexpectedly pronounced, dose-dependent reduction of cellular proliferation of human PC-3 prostate cancer and UO.31 renal carcinoma cells upon treatment. Based on these findings 6-PN and 8-PN are currently further clinically evaluated in detail. PMID- 25925226 TI - HOME Plus: Program design and implementation of a family-focused, community-based intervention to promote the frequency and healthfulness of family meals, reduce children's sedentary behavior, and prevent obesity. AB - BACKGROUND: Involvement in meal preparation and eating meals with one's family are associated with better dietary quality and healthy body weight for youth. Given the poor dietary quality of many youth, potential benefits of family meals for better nutritional intake and great variation in family meals, development and evaluation of interventions aimed at improving and increasing family meals are needed. This paper presents the design of key intervention components and process evaluation of a community-based program (Healthy Home Offerings via the Mealtime Environment (HOME) Plus) to prevent obesity. METHODS: The HOME Plus intervention was part of a two-arm (intervention versus attention-only control) randomized-controlled trial. Ten monthly, two-hour sessions and five motivational/goal-setting telephone calls to promote healthy eating and increasing family meals were delivered in community-based settings in the Minneapolis/St. Paul, MN metropolitan area. The present study included 81 families (8-12 year old children and their parents) in the intervention condition. Process surveys were administered at the end of each intervention session and at a home visit after the intervention period. Chi-squares and t tests were used for process survey analysis. RESULTS: The HOME Plus program was successfully implemented and families were highly satisfied. Parents and children reported that the most enjoyable component was cooking with their families, learning how to eat more healthfully, and trying new recipes/foods and cooking tips. Average session attendance across the ten months was high for families (68%) and more than half completed their home activities. CONCLUSIONS: Findings support the value of a community-based, family-focused intervention program to promote family meals, limit screen time, and prevent obesity. TRIAL REGISTRATION: NCT01538615. PMID- 25925227 TI - Interventions targeting absences increase adherence and reduce abandonment of childhood cancer treatment in El Salvador. AB - BACKGROUND: In El Salvador, about 200 new cases of pediatric cancer are diagnosed each year, and survival rates approach 70%. Although treatment is available at no cost, abandonment of therapy has remained at a steady yearly rate of 13% during the past decade. A time sensitive adherence tracking procedure (TS-ATP) was recently implemented to detect missed appointments, identify their causes, and intervene promptly. Procedure The study team was informed daily of patient/family failure to attend medical appointments in the pediatric oncology unit; the families were contacted and interviewed to ascertain and address the reasons. Patients who did not return after this initial contact were contacted again through local health clinics and municipalities. Law enforcement was a last resort for patients undergoing frontline treatment with a good prognosis., The system was adapted to clinical urgency: families of patients undergoing induction therapy were contacted within 24 hr, those in other therapy phases, within 48 hr, and those who had completed treatment, within one week. Reasons for absence were obtained by telephone or in person. RESULTS: The annual rate of abandonment was reduced from 13-3% during the 2 years period. There were 1,111 absences reported and 1,472 contacts with caregivers and institutions. The three main reasons for absences were financial needs (165, 23%), unforeseen barriers (116, 16%), and domestic needs (86, 12%). CONCLUSIONS: Use of the treatment adherence tracking system to locate and communicate with patients/families after missed appointments and the allocated aid stemming from these interviews substantially reduced abandonment and non-adherence. PMID- 25925228 TI - Bone Recuperation After rhBMP-2 Insertion in Alcoholic Animals-Experimental Study. AB - BACKGROUND: Alcoholism affects bone repair and this study evaluated the recombinant human BMP-2 (rhBMP-2)/collagen sponge association aiming to improve the bone healing process. The aim of this study was to investigate the action of alcoholism and its effect on the repair of bone defects (BD) performed on rat calvaria after the application of rhBMP-2, either pure or combined with a collagen matrix, using radiographic, histological and immunohistochemical methods. METHODS: We used 80 rats divided into two groups and these into 4 subgroups, each with a waiting period for sacrifice of four and six weeks after the BD (5mm). The groups were divided into: Veh-X) vehicle+BD, Veh-BMP) water+BD+5ug rhBMP-2, Veh-ACS) water+ BD+absorbable collagen sponge, Veh-BMP/ACS) water+BD+5ug rhBMP-2/absorbable collagen sponge, EtOH-X) ethanol+BD, EtOH-BMP) ethanol+BD+5ugrhBMP-2, EtOH-ACS) ethanol+BD+absorbable collagen sponge, and EtOH BMP/ACS) ethanol+ BD+5ug of rhBMP-2/ absorbable collagen sponge. RESULTS: Radiographically, it was found that after six weeks, for the groups treated with rhBMP-2, independent of the carrier use and ethanol administration, there was more new bone formation (p<0.05). For immunohistochemical analysis, osteocalcin and bone sialoprotein were found to be predominant in groups treated with rhBMP 2. For quantitative stereology, which aims to calculate the volume of new bone, higher values for the groups treated with rhBMP-2 pure or combined with the carrier were found; but for the groups treated with ethanol, a higher bone formation in the groups treated with rhBMP-2 associated with the carrier in the periods of four and six weeks (p<0.001) was found. CONCLUSION: It was concluded that the carrier was effective for rhBMP-2 delivery, even in the presence of ethanol. PMID- 25925229 TI - Role of alternative interventional procedures when endo- and epicardial catheter ablation attempts for ventricular arrhythmias fail. AB - BACKGROUND: Ventricular tachycardia (VT) refractory to antiarrhythmic drugs and standard percutaneous catheter ablation techniques portends a poor prognosis. We characterized the reasons for ablation failure and describe alternative interventional procedures in this high-risk group. METHODS AND RESULTS: Sixty seven patients with VT refractory to 4+/-2 antiarrhythmic drugs and 2+/-1 previous endocardial/epicardial catheter ablation attempts underwent transcoronary ethanol ablation, surgical epicardial window (Epi-window), or surgical cryoablation (OR-Cryo; age, 62+/-11 years; VT storm in 52%). Failure of endo/epicardial ablation attempts was because of VT of intramural origin (35 patients), nonendocardial origin with prohibitive epicardial access because of pericardial adhesions (16), and anatomic barriers to ablation (8). In 8 patients, VT was of nonendocardial origin with a coexisting condition also requiring cardiac surgery. Transcoronary ethanol ablation alone was attempted in 37 patients, OR-Cryo alone in 21 patients, and a combination of transcoronary ethanol ablation and OR-Cryo (5 patients), or transcoronary ethanol ablation and Epi-window (4 patients), in the remainder. Overall, alternative interventional procedures abolished >=1 inducible VT and terminated storm in 69% and 74% of patients, respectively, although 25% of patients had at least 1 complication. By 6 months post procedures, there was a significant reduction in defibrillator shocks (from a median of 8 per month to 1; P<0.001) and antiarrhythmic drug requirement although 55% of patients had at least 1 VT recurrence, and mortality was 17%. CONCLUSIONS: A collaborative strategy of alternative interventional procedures offers the possibility of achieving arrhythmia control in high-risk patients with VT that is otherwise uncontrollable with antiarrhythmic drugs and standard percutaneous catheter ablation techniques. PMID- 25925230 TI - Differentiation of papillary muscle from fascicular and mitral annular ventricular arrhythmias in patients with and without structural heart disease. AB - BACKGROUND: Idiopathic left ventricular arrhythmias (VAs) and those caused by structural heart disease can originate from the papillary muscles, fascicles, and mitral annulus. Differentiation of these arrhythmias can be challenging because they present with a right bundle branch block morphology by electrocardiography. We sought to identify clinical, electrocardiographic, and electrophysiological features that distinguish these left VAs in patients with and without structural heart disease. METHOD AND RESULTS: Patients undergoing catheter ablation for papillary muscle, fascicular, or mitral annular VAs were studied. Demographic data and electrocardiographic and electrophysiological findings were analyzed. Fifty-two VAs in 51 patients (32 [63%] male; mean age 61+/-15 years) with papillary muscle (n=18), fascicular (n=15), and mitral annular (n=19) origins were studied. Patients with papillary muscle VAs were older and had higher prevalence of left ventricular dysfunction (67% versus 13% of fascicular VA patients [P=0.009]) and coronary artery disease (78% versus 37% of mitral annular VA patients [P=0.036]). Papillary muscle VAs were distinguished electrocardiographically from fascicular VAs by longer QRS durations and lower prevalence of r= 18 years. The WHO STEPS questionnaire was used to document the demographics, history of previous medical check-up or screening, anthropometric and biochemical measurements of the participants. Average income level and educational status were indicators used to assess the impact of SES. Multivariate analyses were performed to assess any difference between the geographical locations and SES indicators, and prevalence of CVD risk factors and access to CVD risk screening. RESULTS: The 422 participants (273 females and 149 males) [corrected] had mean age (+/- standard deviation) of 38.3 +/- 20.5 and 42.9 +/- 20.7 years, respectively. Only total cholesterol (p = 0.001), triglyceride (p = 0.005), high density lipoprotein cholesterol (HDL) (p < 0.0001), body mass index (BMI) (p = 0.03) and average income rate (p = 0.01) showed significant difference between gender groups. Overall prevalence of prediabetes (4.9%), diabetes (5.4%), hypertension (35.7%), low HDL (17.8%), hypertriglyceridemia (23.2%), hypercholesterolemia (38.1%) and central obesity of 52.2% was recorded. Except between total cholesterol (p = 0.042) and HDL (p = 0.017), other CVD risk factors did not show a statistical significance across income levels. Participants with 'university and postgraduate education' had higher access to blood pressure and blood glucose screening compared to other educational groups; and this showed a statistical significance. CONCLUSION: This study has shown that a significant number of modifiable CVD risk factors exist in the rural and urban migrants of an adult Nigerian population. While income level did not affect the CVD risk factor prevalence, it did affect accessibility to CVD risk screening. There is a need for access to diagnosis of modifiable risk factors at all levels of society. PMID- 25925239 TI - Geriatric Nutritional Risk Index Is a Simple Predictor of Mortality in Chronic Hemodialysis Patients. AB - BACKGROUND: Malnutrition is common in hemodialysis (HD) patients, and it is associated with increasing risk of mortality. The geriatric nutritional risk index (GNRI) has been developed as a tool to assess the nutritional risk. The aim of this study was to examine the reliability of the GNRI as a mortality predictor in a Japanese HD cohort. METHODS: We prospectively examined the GNRI of 332 maintenance HD patients aged 65.4 +/- 13.2, 213 males, and followed up on them for 36 months. The patients were divided into quartiles (Q) according to GNRI values (Q1: <91.6, Q2: 91.7-97.0, Q3: 97.1-102.2, Q4: >102.3). Predictors for all cause mortality were examined using Kaplan-Meier and Cox proportional-hazards analyses. RESULTS: The GNRI presented a normal distribution. During the follow-up period of 36 months, 76 patients died. The overall mortality at the end of the 3 year observational period was 22.3%. At the 3-year follow-up period, Kaplan-Meier survival rates for all-cause mortality were 72.3, 79.3, 84.9 and 92.6% in Q1, Q2, Q3, and Q4, respectively (p = 0.0067). Multivariate Cox proportional-hazards analysis demonstrated that the GNRI was a significant predictor of adjusted all cause mortality (HR 0.958; 95% CI 0.929-0.989, p = 0.0073). CONCLUSIONS: The results of the present study demonstrate that the GNRI is a strong predictor of overall mortality in HD patients. However, cardiovascular mortality was not associated with GNRI values, and did not differ among the GNRI quartiles. The GNRI score can be considered a simple and reliable marker of predictor for mortality risk in Japanese HD patients. PMID- 25925240 TI - Glucose and Fat Metabolism in Acromegaly: From Mice Models to Patient Care. AB - Patients with active acromegaly are frequently insulin resistant, glucose intolerant, and at risk for developing overt type 2 diabetes. At the same time, these patients have a relatively lean phenotype associated with mobilization and oxidation of free fatty acids. These features are reversed by curative surgical removal of the growth hormone (GH)-producing adenoma. Mouse models of acromegaly share many of these characteristics, including a lean phenotype and proneness to type 2 diabetes. There are, however, also species differences with respect to oxidation rates of glucose and fat as well as the specific mechanisms underlying GH-induced insulin resistance. The impact of acromegaly treatment on insulin sensitivity and glucose tolerance depends on the treatment modality (e.g. somatostatin analogs also suppress insulin secretion, whereas the GH antagonist restores insulin sensitivity). The interplay between animal research and clinical studies has proven useful in the field of acromegaly and should be continued in order to understand the metabolic actions of GH. PMID- 25925241 TI - Ancestries of a recombining diploid population. AB - We derive the exact one-step transition probabilities of the number of lineages that are ancestral to a random sample from the current generation of a bi parental population that is evolving under the discrete Wright-Fisher model with n diploid individuals. Our model allows for a per-generation recombination probability of r . When r = 1, our model is equivalent to Chang's (Adv Appl Probab 31:1002-1038, 1999) model for the karyotic pedigree. When r = 0, our model is equivalent to Kingman's (Stoch Process Appl 13:235-248, 1982) discrete coalescent model for the cytoplasmic tree or sub-karyotic tree containing a DNA locus that is free of intra-locus recombination. When 0 < r < 1 our model can be thought to track a sub-karyotic ancestral graph containing a DNA sequence from an autosomal chromosome that has an intra-locus recombination probability r . Thus, our family of models indexed by r ? [0, 1] connects Kingman's discrete coalescent to Chang's pedigree in a continuous way as r goes from 0 to 1. For large populations, we also study three properties of the ancestral process corresponding to a given r ? (0, 1): the time Tn to a most recent common ancestor (MRCA) of the population, the time Un at which all individuals are either common ancestors of all present day individuals or ancestral to none of them, and the fraction of individuals that are common ancestors at time Un. These results generalize the three main results of Chang's (Adv Appl Probab 31:1002-1038, 1999). When we appropriately rescale time and recombination probability by the population size, our model leads to the continuous time Markov chain called the ancestral recombination graph of Hudson (Theor Popul Biol 23:183-201, 1983) and Griffiths (The two-locus ancestral graph, Institute of Mathematical Statistics 100-117, 1991). PMID- 25925242 TI - Can treatment increase the epidemic size? AB - Antiviral treatment is one of the key pharmacological interventions against many infectious diseases. This is particularly important in the absence of preventive measures such as vaccination. However, the evolution of drug-resistance in treated patients and its subsequent spread to the population pose significant impediments to the containment of disease epidemics using treatment. Previous models of population dynamics of influenza infection have shown that in the presence of drug-resistance, the epidemic final size (i.e., the total number of infections throughout the epidemic) is affected by the treatment rate. These models, through simulation experiments, illustrate the existence of an optimal treatment rate, not necessarily the highest possible rate, for minimizing the epidemic final size. However, the conditions for the existence of such an optimal treatment rate have never been found. Here, we provide these conditions for a class of models covered in the literature previously, and investigate the combination effect of treatment and transmissibility of the drug-resistant pathogen strain on the epidemic final size. For the first time, we obtain the final size relations for an epidemic model with two strains of a pathogen (i.e., drug-sensitive and drug-resistant). We also discuss this model with specific functional forms of de novo resistance emergence, and illustrate the theoretical findings with numerical simulations. PMID- 25925243 TI - BAG3: a new player in the heart failure paradigm. AB - BAG3 is a cellular protein that is expressed predominantly in skeletal and cardiac muscle but can also be found in the brain and in the peripheral nervous system. BAG3 functions in the cell include: serving as a co-chaperone with members of the heat-shock protein family of proteins to facilitate the removal of misfolded and degraded proteins, inhibiting apoptosis by interacting with Bcl2 and maintaining the structural integrity of the Z-disk in muscle by binding with CapZ. The importance of BAG3 in the homeostasis of myocytes and its role in the development of heart failure was evidenced by the finding that single allelic mutations in BAG3 were associated with familial dilated cardiomyopathy. Furthermore, significant decreases in the level of BAG3 have been found in end stage failing human heart and in animal models of heart failure including mice with heart failure secondary to trans-aortic banding and in pigs after myocardial infarction. Thus, it becomes relevant to understand the cellular biology and molecular regulation of BAG3 expression in order to design new therapies for the treatment of patients with both hereditary and non-hereditary forms of dilated cardiomyopathy. PMID- 25925244 TI - Impact of pre-implant amiodarone exposure on outcomes in cardiac transplant recipients. AB - Amiodarone remains one of the preferred antiarrhythmic medications for patients with advanced heart failure awaiting cardiac transplant. However, the long half life and rapid redistribution of this agent into donor myocardium expose heart transplant recipients to potential adverse outcomes. In reviewing the current body of literature, we found that pre-operative amiodarone exposure can increase the risk of bradycardia post-transplant; however, this is unlikely to require permanent pacemaker implant. Further, amiodarone has several serious drug-drug interactions with calcineurin inhibitors. Clinicians should therefore consider empiric reduction in initial dosing for tacrolimus or cyclosporine, and carefully monitor blood levels for at least 3 months post-transplant. Although the evidence is conflicting, amiodarone exposure pre-operatively may increase the risk of early graft failure and mortality. Amiodarone use should be minimized whenever possible; if amiodarone cannot practically be discontinued in the pre-transplant phase, judicious monitoring for QTc prolongation and ventricular arrhythmia should be implemented after transplant. As most of the studies included in this review suffered from small sample sizes and limited follow-up, additional research in this area is warranted. PMID- 25925245 TI - Toward Enhanced Photocatalytic Oxygen Evolution: Synergetic Utilization of Plasmonic Effect and Schottky Junction via Interfacing Facet Selection. PMID- 25925246 TI - The Prevalence of Human Bocavirus, Human Coronavirus-NL63, Human Metapneumovirus, Human Polyomavirus KI and WU in Respiratory Tract Infections in Kuwait. AB - OBJECTIVE: The aim of this study was to investigate the prevalence of human coronavirus (HCoV)-NL63, human metapneumovirus (hMPV), human bocavirus (Boca), human polyomavirus KI (KIV) and human polyomavirus WU (WUV) in respiratory tract infections (RTI) in Kuwait. MATERIALS AND METHODS: Respiratory samples from 735 hospitalized patients with RTI from September 2010 to April 2013 were evaluated for the presence of HCoV-NL63, hMPV, Boca, KIV and WUV using molecular assays, polymerase chain reaction (PCR) and reverse-transcription PCR. RESULTS: Of the 735 patients, 285 (38.8%) were diagnosed with viral RTI. The distribution of respiratory viruses was hMPV: 15 (5.3%), Boca: 14 (4.9%), WUV: 10 (3.5%) and KIV: 4 (1.4%). HCoV-NL63 was not detected in any of the samples. CONCLUSIONS: These newly discovered viruses were associated with the development of RTI in Kuwait. The rapid identification of these viral infections could aid in the control of nosocomial transmission, reduce the use of antibiotics and improve treatment and management strategies. PMID- 25925247 TI - Lithium Storage in Heat-Treated SnF2 /Polyacrylonitrile Anode. AB - Tin(II) fluoride (SnF2 ) has a high Li-storage capacity because it stores lithium first by a conversion reaction and then by a Li/Sn alloying/dealloying reaction. A polyacrylonitrile (PAN)-bound SnF2 electrode was heat-treated to enhance the integral electrical contact and the mechanical strength through its cross-linked framework. The heat-treated SnF2 electrode showed reversible capacities of 1047 mAh g(-1) in the first cycle and 902 mAh g(-1) after 100 cycles. Part of the excess capacity is due to lithium storage at the Sn/LiF interface, and the other part is assumed to correspond to the presence of reduced SnF2 with protons released during the thermal cross-linking of PAN. PMID- 25925248 TI - Therapeutic limited bronchoalveolar lavage with fiberoptic bronchoscopy as a bridging procedure prior to total lung lavage in a patient with pulmonary alveolar proteinosis: a case report. AB - INTRODUCTION: Therapeutic total lung lavage under general anesthesia is the current mainstay of treatment for pulmonary alveolar proteinosis, which is a rare lung disease characterized by alveolar accumulation of surfactant. Therapeutic limited bronchoalveolar lavage is considered an alternative treatment to conventional total lung lavage. CASE PRESENTATION: A 61-year-old, previously healthy, Sri Lankan Moor woman presented to our facility with progressively worsening difficulty in breathing and persistent dry cough for one year. Her respiratory examination revealed bibasal fine end-inspiratory crepitations. A chest radiograph showed bilateral mid and lower zone alveolar interstitial shadows and a high-resolution computed tomography scan of her chest revealed septal thickening with ground-glass shadows more on mid and lower zones bilaterally. A diagnostic bronchoalveolar lavage fluid analysis revealed diastase resistant protein clumps in periodic acid Schiff stain. The diagnosis was made as pulmonary alveolar proteinosis. An arterial blood gas analysis performed prior to intervention revealed a significant hypoxia (partial pressure of oxygen - 64 mmHg) with alveolar-arterial gradient was 35.4 mmHg. Therapeutic limited bronchoalveolar lavage was arranged and her right and her left lung were lavaged separately in two sessions done two weeks apart under local anesthesia. Our patient had significant clinical improvement and resolution of the bilateral septal thickening with minimal resolution of the ground-glass opacities in a repeat high-resolution computed tomography scan done two weeks later. Subsequently, a total lung lavage under general anesthesia was also done, which improved her dyspnea and arterial hypoxemia. CONCLUSIONS: Therapeutic limited bronchoalveolar lavage can be successfully performed as an interval bridging procedure, as a 'prewash', prior to conventional total lung lavage for pulmonary alveolar proteinosis. PMID- 25925249 TI - The accuracy of 3D fluoroscopy-navigated screw insertion in the upper and subaxial cervical spine. AB - PURPOSE: Due to better primary stability and repositioning options, pedicle screws are increasingly used during posterior stabilization of the cervical spine. However, the serious risks generally associated with the insertion of screws in the cervical spine remain. The purpose of this study is to examine the accuracy of pedicle screw insertion with the use of 3D fluoroscopy navigation systems, also accounting for various spine levels. METHODS: Data of 64 patients were collected during and after screw implantation (axial and subaxial) in the cervical spine. 207 screws were implanted from C1 to C7 and analyzed for placement accuracy according to postoperative CT scans and following the modified Gertzbein and Robbins classification. RESULTS: The accuracy of most of the inserted screws was assessed as grade 2 according to the modified Gertzbein and Robbins classification. 93.9% of the screws implanted at C1 or C2, and 78.51% of the screws implanted at levels C3-C7 showed placement accuracy grade 2 or better, indicating pedicle wall perforation of <2 mm. Overall, seven complications were observed. In three cases, the vertebral artery was affected, leading to one fatality. Surgical revision was necessary once because of Magerl screw misplacement and three times due to impaired wound healing. No radicular symptoms resulted from screw malposition. CONCLUSION: Axial and subaxial screws can be inserted with a high grade of accuracy using 3D fluoroscopy-based navigation systems. Nevertheless, while this useful innovation helps to minimize the risks of misplacement, the surgery is still a challenge, as arising complications remain severe. PMID- 25925250 TI - Functional MRI detects perfusion impairment in renal allografts with delayed graft function. AB - Delayed graft function (DGF) after kidney transplantation is not uncommon, and it is associated with long-term allograft impairment. Our aim was to compare renal perfusion changes measured with noninvasive functional MRI in patients early after kidney transplantation to renal function and allograft histology in biopsy samples. Forty-six patients underwent MRI 4-11 days after transplantation. Contrast-free MRI renal perfusion images were acquired using an arterial spin labeling technique. Renal function was assessed by estimated glomerular filtration rate (eGFR), and renal biopsies were performed when indicated within 5 days of MRI. Twenty-six of 46 patients had DGF. Of these, nine patients had acute rejection (including borderline), and eight had other changes (e.g., tubular injury or glomerulosclerosis). Renal perfusion was significantly lower in the DGF group compared with the group with good allograft function (231 +/- 15 vs. 331 +/ 15 ml.min(-1).100 g(-1), P < 0.001). Living donor allografts exhibited significantly higher perfusion values compared with deceased donor allografts (P < 0.001). Renal perfusion significantly correlated with eGFR (r = 0.64, P < 0.001), resistance index (r = -0.57, P < 0.001), and cold ischemia time (r = 0.48, P < 0.01). Furthermore, renal perfusion impairment early after transplantation predicted inferior renal outcome and graft loss. In conclusion, noninvasive functional MRI detects renal perfusion impairment early after kidney transplantation in patients with DGF. PMID- 25925251 TI - Muc1 is protective during kidney ischemia-reperfusion injury. AB - Ischemia-reperfusion injury (IRI) due to hypotension is a common cause of human acute kidney injury (AKI). Hypoxia-inducible transcription factors (HIFs) orchestrate a protective response in renal endothelial and epithelial cells in AKI models. As human mucin 1 (MUC1) is induced by hypoxia and enhances HIF-1 activity in cultured epithelial cells, we asked whether mouse mucin 1 (Muc1) regulates HIF-1 activity in kidney tissue during IRI. Whereas Muc1 was localized on the apical surface of the thick ascending limb, distal convoluted tubule, and collecting duct in the kidneys of sham-treated mice, Muc1 appeared in the cytoplasm and nucleus of all tubular epithelia during IRI. Muc1 was induced during IRI, and Muc1 transcripts and protein were also present in recovering proximal tubule cells. Kidney damage was worse and recovery was blocked during IRI in Muc1 knockout mice compared with congenic control mice. Muc1 knockout mice had reduced levels of HIF-1alpha, reduced or aberrant induction of HIF-1 target genes involved in the shift of glucose metabolism to glycolysis, and prolonged activation of AMP-activated protein kinase, indicating metabolic stress. Muc1 clearly plays a significant role in enhancing the HIF protective pathway during ischemic insult and recovery in kidney epithelia, providing a new target for developing therapies to treat AKI. Moreover, our data support a role specifically for HIF-1 in epithelial protection of the kidney during IRI as Muc1 is present only in tubule epithelial cells. PMID- 25925252 TI - Effect of dietary protein restriction on renal ammonia metabolism. AB - Dietary protein restriction has multiple benefits in kidney disease. Because protein intake is a major determinant of endogenous acid production, it is important that net acid excretion change in parallel during protein restriction. Ammonia is the primary component of net acid excretion, and inappropriate ammonia excretion can lead to negative nitrogen balance. Accordingly, we examined ammonia excretion in response to protein restriction and then we determined the molecular mechanism of the changes observed. Wild-type C57Bl/6 mice fed a 20% protein diet and then changed to 6% protein developed an 85% reduction in ammonia excretion within 2 days, which persisted during a 10-day study. The expression of multiple proteins involved in renal ammonia metabolism was altered, including the ammonia generating enzymes phosphate-dependent glutaminase (PDG) and phosphoenolpyruvate carboxykinase (PEPCK) and the ammonia-metabolizing enzyme glutamine synthetase. Rhbg, an ammonia transporter, increased in expression in the inner stripe of outer medullary collecting duct intercalated cell (OMCDis-IC). However, collecting duct-specific Rhbg deletion did not alter the response to protein restriction. Rhcg deletion did not alter ammonia excretion in response to dietary protein restriction. These results indicate 1) dietary protein restriction decreases renal ammonia excretion through coordinated regulation of multiple components of ammonia metabolism; 2) increased Rhbg expression in the OMCDis-IC may indicate a biological role in addition to ammonia transport; and 3) Rhcg expression is not necessary to decrease ammonia excretion during dietary protein restriction. PMID- 25925253 TI - Caffeine-induced diuresis and natriuresis is independent of renal tubular NHE3. AB - Caffeine is one of the most widely consumed behavioral substances. We have previously shown that caffeine- and theophylline-induced inhibition of renal reabsorption causes diuresis and natriuresis, an effect that requires functional adenosine A1 receptors. In this study, we tested the hypothesis that blocking the Gi protein-coupled adenosine A1 receptor via the nonselective adenosine receptor antagonist caffeine changes Na(+)/H(+) exchanger isoform 3 (NHE3) localization and phosphorylation, resulting in diuresis and natriuresis. We generated tubulus specific NHE3 knockout mice (Pax8-Cre), where NHE3 abundance in the S1, S2, and S3 segments of the proximal tubule was completely absent or severely reduced (>85%) in the thick ascending limb. Consumption of fluid and food, as well as glomerular filtration rate, were comparable in control or tubulus-specific NHE3 knockout mice under basal conditions, while urinary pH was significantly more alkaline without evidence for metabolic acidosis. Caffeine self-administration increased total fluid and food intake comparably between genotypes, without significant differences in consumption of caffeinated solution. Acute caffeine application via oral gavage elicited a diuresis and natriuresis that was comparable between control and tubulus-specific NHE3 knockout mice. The diuretic and natriuretic response was independent of changes in total NHE3 expression, phosphorylation of serine-552 and serine-605, or apical plasma membrane NHE3 localization. Although caffeine had no clear effect on localization of the basolateral Na(+)/bicarbonate cotransporter NBCe1, pretreatment with DIDS inhibited caffeine-induced diuresis and natriuresis. In summary, NHE3 is not required for caffeine-induced diuresis and natriuresis. PMID- 25925256 TI - Perspectives: From Bedside to Bench. PMID- 25925254 TI - Renal NCC is unchanged in the midpregnant rat and decreased in the late pregnant rat despite avid renal Na+ retention. AB - Pregnancy is characterized by plasma volume expansion due to Na(+) retention, driven by aldosterone. The aldosterone-responsive epithelial Na(+) channel is activated in the kidney in pregnancy. In the present study, we investigated the aldosterone-responsive Na(+)-Cl(-) cotransporter (NCC) in mid- and late pregnant rats compared with virgin rats. We determined the abundance of total NCC, phosphorylated NCC (pNCC; pT53, pS71 and pS89), phosphorylated STE20/SPS-1 related proline-alanine-rich protein kinase (pSPAK; pS373), and phosphorylated oxidative stress-related kinase (pOSR1; pS325) in the kidney cortex. We also measured mRNA expression of NCC and members of the SPAK/NCC regulatory kinase network, serum and glucocorticoid-regulated kinase (SGK)1, total with no lysine kinase (WNK)1, WNK3, and WNK4. Additionally, we performed immunohistochemistry for NCC kidneys from virgin and pregnant rats. Total NCC, pNCC, and pSPAK/OSR1 abundance were unchanged in midpregnant versus virgin rats. In late pregnant versus virgin rats, total NCC and pNCC were decreased; however, pSPAK/OSR1 was unchanged. We detected no differences in mRNA expression of NCC, SGK1, total WNK1, WNK3, and WNK4. By immunohistochemistry, NCC was mainly localized to the apical region in virgin rats, and density in the apical region was reduced in late pregnancy. Therefore, despite high circulating aldosterone levels in pregnancy, the aldosterone-responsive transporter NCC is not increased in total or activated (phosphorylated) abundance or in apical localization in midpregnant rats, and all are reduced in late pregnancy. This contrasts to the mineralocorticoid-mediated activation of the epithelial Na(+) channel, which we have previously reported. Why and how NCC escapes aldosterone activation in pregnancy is not clear but may relate to regional differences in aldosterone sensitivity the increased K(+) intake or other undefined mechanisms. PMID- 25925257 TI - Defective renal dopamine function and sodium-sensitive hypertension in adult ovariectomized Wistar rats: role of the cytochrome P-450 pathway. AB - We have previously shown that ovariectomy in adult Wistar rats under normal sodium (NS) intake results in an overexpression of the total Na(+)-K(+)-ATPase (NKA) alpha1-subunit (Di Ciano LA, Azurmendi PJ, Toledo JE, Oddo EM, Zotta E, Ochoa F, Arrizurieta EE, Ibarra FR. Clin Exp Hypertens 35: 475-483, 2013). Upon high sodium (HS) intake, ovariectomized (oVx) rats developed defective NKA phosphorylation, a decrease in sodium excretion, and an increment in mean blood pressure (MBP). Since NKA phosphorylation is modulated by dopamine (DA), the aim of this study was to compare the intracellular response of the renal DA system leading to NKA phosphorylation upon sodium challenge in intact female (IF) and oVx rats. In IF rats, HS caused an increase in urinary DA and sodium, in NKA phosphorylation state, in cytochrome P-4504A (CYP4A) expression, and in 20-HETE production, while MBP kept normal. Blockade of the D1 receptor (D1R) with the D1 like receptor antagonist SCH 23390 in IFHS rats shifted NKA into a more dephosphorylated state, decreased sodium excretion by 50%, and increased MBP. In oVxNS rats, D1R expression was reduced and D3R expression was increased, and under HS intake sodium excretion was lower and MBP higher than in IFHS rats (both P < 0.05), NKA was more dephosphorylated than in IFHS, and CYP4A expression or 20 HETE production did not change. Blockade of D1R in oVxHS rats changed neither NKA phosphorylation state nor sodium excretion or MBP. D2R and PKCalpha expression did not vary among groups. The alteration of the renal DA system produced by ovariectomy could account for the defective NKA phosphorylation, the inefficient excretion of sodium load, and the development of salt-sensitive hypertension. PMID- 25925258 TI - ENaC inhibition stimulates HCl secretion in the mouse cortical collecting duct. I. Stilbene-sensitive Cl- secretion. AB - Inhibition of the epithelial Na(+) channel (ENaC) reduces Cl(-) absorption in cortical collecting ducts (CCDs) from aldosterone-treated rats and mice. Since ENaC does not transport Cl(-), the purpose of the present study was to explore how ENaC modulates Cl(-) absorption in mouse CCDs perfused in vitro. Therefore, we measured transepithelial Cl(-) flux and transepithelial voltage in CCDs perfused in vitro taken from mice that consumed a NaCl-replete diet alone or the diet with aldosterone administered by minipump. We observed that application of an ENaC inhibitor [benzamil (3 MUM)] to the luminal fluid unmasks conductive Cl( ) secretion. During ENaC blockade, this Cl(-) secretion fell with the application of a nonselective Cl(-) channel blocker [DIDS (100 MUM)] to the perfusate. While single channel recordings of intercalated cell apical membranes in split-open CCDs demonstrated a Cl(-) channel with properties that resemble the ClC family of Cl(-) channels, ClC-5 is not the primary pathway for benzamil-sensitive Cl(-) flux. In conclusion, first, in CCDs from aldosterone-treated mice, most Cl(-) absorption is benzamil sensitive, and, second, benzamil application stimulates stilbene-sensitive conductive Cl(-) secretion, which occurs through a ClC-5 independent pathway. PMID- 25925259 TI - Expansion of prostate epithelial progenitor cells after inflammation of the mouse prostate. AB - Prostatic inflammation is a nearly ubiquitous pathological feature observed in specimens from benign prostate hyperplasia and prostate cancer patients. The microenvironment of the inflamed prostate is highly reactive, and epithelial hyperplasia is a hallmark feature of inflamed prostates. How inflammation orchestrates epithelial proliferation as part of its repair and recovery action is not well understood. Here, we report that a novel epithelial progenitor cell population is induced to expand during inflammation. We used sphere culture assays, immunofluorescence, and flow cytometry to show that this population is increased in bacterially induced inflamed mouse prostates relative to naive control prostates. We confirmed from previous reports that this population exclusively possesses the ability to regrow entire prostatic structures from single cell culture using renal grafts. In addition, putative progenitor cells harvested from inflamed animals have greater aggregation capacity than those isolated from naive control prostates. Expansion of this critical cell population requires IL-1 signaling, as IL-1 receptor 1-null mice exhibit inflammation similar to wild-type inflamed animals but exhibit significantly reduced progenitor cell proliferation and hyperplasia. These data demonstrate that inflammation promotes hyperplasia in the mouse prostatic epithelium by inducing the expansion of a selected epithelial progenitor cell population in an IL-1 receptor-dependent manner. These findings may have significant impact on our understanding of how inflammation promotes proliferative diseases such as benign prostatic hyperplasia and prostate cancer, both of which depend on expansion of cells that exhibit a progenitor-like nature. PMID- 25925260 TI - Protein- and diabetes-induced glomerular hyperfiltration: role of glucagon, vasopressin, and urea. AB - A single protein-rich meal (or an infusion of amino acids) is known to increase the glomerular filtration rate (GFR) for a few hours, a phenomenon known as "hyperfiltration." It is important to understand the factors that initiate this upregulation because it becomes maladaptive in the long term. Several mediators and paracrine factors have been shown to participate in this upregulation, but they are not directly triggered by protein intake. Here, we explain how a rise in glucagon and in vasopressin secretion, directly induced by protein ingestion, might be the initial factors triggering the hepatic and renal events leading to an increase in the GFR. Their effects include metabolic actions in the liver and stimulation of sodium chloride reabsorption in the thick ascending limb. Glucagon is not only a glucoregulatory hormone. It is also important for the excretion of nitrogen end products by stimulating both urea synthesis in the liver (along with gluconeogenesis from amino acids) and urea excretion by the kidney. Vasopressin allows the concentration of nitrogenous end products (urea, ammonia, etc.) and other protein-associated wastes in a hyperosmotic urine, thus allowing a very significant water economy characteristic of all terrestrial mammals. No hyperfiltration occurs in the absence of one or the other hormone. Experimental results suggest that the combined actions of these two hormones, along with the complex intrarenal handling of urea, lead to alter the composition of the tubular fluid at the macula densa and to reduce the intensity of the signal activating the tubuloglomerular feedback control of GFR, thus allowing GFR to raise. Altogether, glucagon, vasopressin, and urea contribute to set up the best compromise between efficient urea excretion and water economy. PMID- 25925262 TI - Impact of real-time ultrasound guidance on complications of percutaneous dilatational tracheostomy: a propensity score analysis. AB - INTRODUCTION: Recent studies have demonstrated the feasibility of real-time ultrasound guidance during percutaneous dilatational tracheostomy, including in patients with risk factors such as coagulopathy, cervical spine immobilization and morbid obesity. Use of real-time ultrasound guidance has been shown to improve the technical accuracy of percutaneous dilatational tracheostomy; however, it is unclear if there is an associated reduction in complications. Our objective was to determine whether the peri-procedural use of real-time ultrasound guidance is associated with a reduction in complications of percutaneous dilatational tracheostomy using a propensity score analysis. METHODS: This study reviewed all percutaneous dilatational tracheostomies performed in an 8-year period in a neurocritical care unit. Percutaneous dilatational tracheostomies were typically performed by trainees under guidance of the attending intensivist. Bronchoscopic guidance was used for all procedures with addition of real-time ultrasound guidance at the discretion of the attending physician. Real-time ultrasound guidance was used to guide endotracheal tube withdrawal, guide tracheal puncture, identify guidewire entry level and confirm bilateral lung sliding. The primary outcome was a composite of previously defined complications including (among others) bleeding, infection, loss of airway, inability to complete procedure, need for revision, granuloma and early dislodgement. Propensity score analysis was used to ensure that the relationship of not using real-time ultrasound guidance with the probability of an adverse outcome was examined within groups of patients having similar covariate profiles. Covariates included were age, gender, body mass index, diagnosis, Acute Physiology and Chronic Health Evaluation II score, timing of tracheostomy, positive end-expiratory pressure and presence of risk factors including coagulopathy, cervical spine immobilization and prior tracheostomy. RESULTS: A total of 200 patients underwent percutaneous dilatational tracheostomy during the specified period, and 107 received real-time ultrasound guidance. Risk factors for percutaneous dilatational tracheostomy were present in 63 (32%). There were nine complications in the group without real-time ultrasound guidance: bleeding (n = 4), need for revision related to inability to ventilate or dislodgement (n = 3) and symptomatic granuloma (n = 2). There was one complication in the real-time ultrasound guidance group (early dislodgement). The odds of having an adverse outcome for patients receiving real-time ultrasound guidance were significantly lower (odds ratio = 0.08; 95% confidence interval, 0.009 to 0.811; P = 0.032) than for those receiving a standard technique while holding the propensity score quartile fixed. CONCLUSIONS: The use of real-time ultrasound guidance during percutaneous dilatational tracheostomy was associated with a significant reduction in procedure-related complications. PMID- 25925263 TI - Serious adverse events and reactions in organ transplantation; a web-net tool based nationwide system for reporting and monitoring. AB - Organ transplantation is vulnerable to serious adverse reactions and events, which require a system for their monitoring and management, as required of EU Member States by Directive 2010/53/EU. A management system was implemented in Poland using modern network technologies through the following steps: 1) the development of a catalogue of events and reactions, 2) the preparation and implementation of the network module, 3) the operational procedures, 4) the evaluation system. The catalogue consists of reactions and events in recipients and living donors related to organ procurement. A referral system was introduced as a module of a web tool www.rejestry.net (400 participated institutions). Notification includes information regarding the location, type, description, analysis, and measures taken to resolve and prevent problems. During the period 2012-2013, 17 serious adverse events and 112 reactions were documented among 3223 transplanted organs (events in 0.5% and reactions in 3.4% of the cases). The major cases included: transplantation from a donor with neoplasia, early recipient death, early graft loss, and transmission of severe infection. Evaluation revealed underestimated number of notifications of "death of recipient within 30 post-transplant days", which reported 74 of the 92 reactions (80%) occurring in reality. The system is a platform for self-assessment and the dissemination of information regarding the potential dangers, including alarms in cases in which an event/reaction in one center is accessible to others. However, the system is not punitive, because the fear of disclosing failures in the transplant centers plays an important role in the monitoring process. PMID- 25925261 TI - FGF9 from cancer-associated fibroblasts is a possible mediator of invasion and anti-apoptosis of gastric cancer cells. AB - BACKGROUND: Cancer-associated fibroblasts (CAFs), which reside around tumor cells, are suggested to play a pivotal role in tumor progression. Here we performed microarray analyses to compare gene expression profiles between CAFs and non-cancerous gastric fibroblasts (NGFs) from a patient with gastric cancer and found that fibroblast growth factor 9 (FGF9) was a novel growth factor overexpressed in CAFs. We then examined the biological effects of FGF9 during progression of gastric cancer. METHODS: Expression of FGF9 in CAFs and NGFs, and their secreted products, were examined by Western blotting. The effects of FGF9 on AGS and MKN28 gastric cancer cells in terms of proliferation, invasion and anti-apoptosis were assessed by WST-1 assay, invasion chamber assay and FACS, respectively. Furthermore, the intracellular signaling by which FGF9 exerts its biological roles was examined in vitro. RESULTS: FGF9 was strongly expressed in CAFs in comparison with NGFs, being compatible with microarray data indicating that FGF9 was a novel growth factor overexpressed in CAFs. Treatment with FGF9 promoted invasion and anti-apoptosis through activation of the ERK and Akt signaling pathways in AGS and MKN28 cells, whereas these effects were attenuated by treatment with anti-FGF9 neutralizing antibody. In addition, FGF9 treatment significantly enhanced the expression of matrix metalloproteinase 7 (MMP7) in both cell lines. CONCLUSIONS: FGF9 is a possible mediator secreted by CAFs that promotes the anti-apoptosis and invasive capability of gastric cancer cells. PMID- 25925264 TI - Clinical manifestations and frequency of hypocalcemia in 22q11.2 deletion syndrome. AB - BACKGROUND: This study investigated the evolution of hypocalcemia with age and its associated risk factors in patients with 22q11.2 deletion syndrome (22qDS) and congenital heart defects. METHOD: A retrospective review of the medical records of 16 22qDS patients (nine female, seven male; age range, 20.5-43 years) was performed. The frequency of hypocalcemia, as well as the clinical course of the disease and the presence of other phenotypes, were investigated. RESULTS: Ten of the 16 patients (62.5%) had a history of hypocalcemia. Among the 10 patients, the first onset of hypocalcemia occurred in the following developmental periods: neonatal stage, n = 1; early childhood, n = 3; late childhood, n = 2; adolescence, n = 2; and adulthood, n = 2. Neonatal hypocalcemia was observed in one patient, but it was transient. Two patients had sustained hypocalcemia after cardiac surgery. Hypocalcemia in one patient was transient following cardiac surgery, but it recurred during early adulthood. One patient developed hypocalcemia at 43 years of age. Thymus defect tended to be correlated with history of hypocalcemia (P = 0.09). This condition was often transient (60%) and was triggered by physical stress, such as intracardiac surgery. CONCLUSION: In 22qDS patients, hypocalcemia was often mild and transient during childhood, but it may recur in adulthood. Routine clinical measurement of serum calcium is recommended, particularly in 22qDS patients with thymic defect or in patients who are under physical stress. PMID- 25925265 TI - Induction of neutralizing antibodies specific for the envelope proteins of the koala retrovirus by immunization with recombinant proteins or with DNA. AB - BACKGROUND: The koala retrovirus (KoRV) is the result of a transspecies transmission of a gammaretrovirus with fatal consequences for the new host. Like many retroviruses, KoRV induces lymphoma, leukemia and an immunodeficiency that is associated with opportunistic infections in the virus-infected animals. We recently reported the induction of neutralizing antibodies by immunization with the recombinant ectodomain of the transmembrane envelope protein p15E of KoRV. Since the neutralization titers of the p15E-specific sera were only moderate, we investigated the use of the surface envelope protein gp70 to induce neutralizing antibodies. FINDINGS: We immunized rats and goats with the recombinant gp70 protein of the KoRV, an unglycosylated protein of 52kD (rgp70/p52) or with the corresponding DNA. In parallel we immunized with recombinant rp15E or with a combination of rp15E and rgp70/p52. In all cases binding and neutralizing antibodies were induced. The gp70-specific sera had titers of neutralizing antibodies that were 15-fold higher than the p15E-specific sera. Combining rp15E and rgp70/p52 did not significantly increase neutralizing titers compared to rgp70/p52 alone. High titers of neutralizing antibodies specific for gp70 were also induced by immunization with DNA. Since KoRV and PERV are closely related, we investigated cross-neutralization of the antisera. The antisera against p15E and gp70 of PERV and KoRV inhibited infection by both viruses. CONCLUSION: The envelope proteins of the KoRV may therefore form the basis of an effective preventive vaccine to protect uninfected koalas from infection and possibly an immunotherapeutic treatment for those already infected. PMID- 25925266 TI - Seasonal changes in infaunal community structure in a hypertrophic brackish canal: Effects of hypoxia, sulfide, and predator-prey interaction. AB - We conducted a one-year survey of macrozoobenthic community structure at 5 stations in a eutrophic canal in inner Tokyo Bay, focusing on the impacts of hypoxia, sediment H2S, and species interaction in the littoral soft-bottom habitats. Complete defaunation or decreasing density of less-tolerant taxa occurred under hypoxia during warmer months, especially at subtidal or sulfidic stations; this was followed by rapid recolonization by opportunistic polychaetes in fall-winter. Sedimentary H2S increased the mortality of macroinvertebrates under hypoxia or delayed population recovery during recolonization. The density of several polychaetes (e.g., Pseudopolydora reticulata) declined in winter, coincident with immigration of the predator Armandia lanceolata. This suggests that absence of A. lanceolata under moderate hypoxia enabled the proliferation of prey taxa. We conclude that oxygen concentration, sediment H2S, and hypoxia induced changes in species interactions are potential drivers for spatiotemporal changes in macrozoobenthic assemblage structure in hypoxia-prone soft-bottom communities. PMID- 25925267 TI - The earliest trough concentration predicts the dose of tacrolimus required for remission induction therapy in ulcerative colitis patients. AB - BACKGROUND: Oral tacrolimus therapy is effective for refractory ulcerative colitis (UC), but dose adjustment according to the trough concentrations which varies largely among individuals, is required. This study aimed to identify factors to predict the tacrolimus dose required for achieving the target trough level for remission induction of UC. METHODS: Forty-seven consecutive UC patients who were treated with tacrolimus were retrospectively analyzed. Tacrolimus doses were adjusted every 2 or 3 days to achieve trough concentrations of 10-15 ng/mL. The dose required for reaching the target trough level was analyzed based on disease characteristics, course of trough concentrations, and gene polymorphism related to tacrolimus metabolism. RESULTS: Median daily dose of tacrolimus required for achieving the target trough level was 0.19 (0.07-0.42) mg/kg, and patients were divided into high or low dose group (< 0.2 mg/kg or > 0.2 mg/kg). The value of initial trough concentration/starting dose was higher in the low dose group than in the high dose group (1.35 ng/mL/mg vs. 0.78 ng/mL/mg, p < 0.0001). Although presence of CYP3A5 *1 was more frequently observed in the high dose group, initial trough concentration was the only significant factor for determining requirement of high dose of tacrolimus (OR = 28.0, 95% confidence interval 3.20 - 631). CONCLUSIONS: The most practical predictor of the dose required for achieving the target trough concentration was the trough concentration measured 2 or 3 days after starting tacrolimus therapy. Our findings would make tarcolimus administration for UC safer, easier and more effective. PMID- 25925268 TI - Sibship size, birth order and risk of nasopharyngeal carcinoma and infectious mononucleosis: a nationwide study in Sweden. AB - BACKGROUND: The aetiology of nasopharyngeal carcinoma (NPC) remains enigmatic in endemic and non-endemic areas. Early-life infection with Epstein-Barr virus (EBV) may predispose to NPC development, whereas delayed primary infection with EBV may cause infectious mononucleosis (IM). METHODS: We used Swedish population and health registers to investigate whether potential indicators of early EBV infection, such as birth order, sibship size, maternal age and paternal age, are related to the subsequent risks for NPC and IM. We conducted two nested case control studies, one for each health outcome, based on 251 NPC case patients, 11 314 IM case patients and five population control subjects per case matched by birth year and sex. We used conditional logistic regression modelling to estimate odds ratios (ORs) and their 95% confidence intervals (CIs) for NPC and IM. RESULTS: The multivariate-adjusted ORs of developing NPC increased with number of siblings; the ORs associated with having one, two and three or more siblings, compared with none, were 1.59 (95% CI = 0.97, 2.62), 1.94 (95% CI = 1.17, 3.22), and 2.03 (95% CI = 1.23, 3.35), respectively (Ptrend = 0.006). This increased risk of NPC was explained mainly by having older rather than younger siblings. In contrast, lower risks of IM were observed among individuals with an increasing number of older siblings, younger siblings and total siblings. CONCLUSIONS: Early life social environment, possibly related to EBV infection, contributes to NPC pathogenesis in non-endemic areas. This hypothesis is further supported by the clearly contrasting findings between NPC and IM. PMID- 25925269 TI - Autobiographical deficits correlate with gray matter volume in depressed and high risk participants. AB - Autobiographical memory (AM) overgenerality is a consistent neuropsychological feature of major depressive disorder (MDD) and is present in individuals at high familial risk (HR) of developing MDD. Structural changes have been found in brain regions implicated in AM recall in MDDs and HRs. However, the relationship between selective regional gray matter volume (GMV) differences and AM recall deficits has not been examined. We examined this relationship in 27 HR, 43 unmedicated MDD and 47 low-risk healthy control participants as they completed an AM task during functional magnetic resonance imaging. FreeSurfer was used for automated anatomical image processing and volumetric quantification. Anatomical regions of interest for GMV analysis were selected based on regions most commonly activated in controls as they recall specific AMs according to a recent meta analysis. Pearson correlations were calculated among volumetric and AM recall data. In HRs and MDDs, left hippocampal volume correlated positively with specific (HRs r = 0.42; MDDs r = 0.60) and inversely with categorical AM recall (HRs r = -0.51; MDDs r = -0.35). In MDDs, left precuneus volume also correlated positively with specific (r = 0.49) and inversely with categorical (r = -0.35) AM recall. Our results suggest selective GMV alterations within the AM network may contribute to AM impairments observed in both HR and MDD individuals. PMID- 25925270 TI - Sending mixed signals: worry is associated with enhanced initial error processing but reduced call for subsequent cognitive control. AB - Worry is reliably associated with overactive action-monitoring processes as measured by the error-related negativity (ERN). However, worry is not associated with error-related behavioral adjustments which are typically used to infer increased cognitive control following errors. We hypothesized that this disconnect between overactive action monitoring and unimproved post-error adjustments in worriers is the result of reduced functional integration between medial and lateral prefrontal regions during generation of the ERN, understood to have an important role in mediating controlled processing. To test this, we examined ERN amplitude and interchannel phase synchrony extracted from scalp recorded electroencephalographic data during error processing in 77 undergraduates who performed a Flankers task. Correlational and path analytic results demonstrated that worry was related to both an enlarged ERN and reduced phase synchrony. Although not directly related to post-error behavioral adjustments, results also revealed that worry was indirectly related to poor post error adjustments through its association with reduced phase synchrony. Therefore, worry seems to affect multiple components of the action-monitoring system. It is related not just with the initial response to the error, but also with the transmission of information between networks involved in cognitive control processes. PMID- 25925271 TI - Emotion and goal-directed behavior: ERP evidence on cognitive and emotional conflict. AB - Cognitive control supports goal-directed behavior by resolving conflict among opposing action tendencies. Emotion can trigger cognitive control processes, thus speeding up conflict processing when the target dimension of stimuli is emotional. However, it is unclear what role emotionality of the target dimension plays in the processing of emotional conflict (e.g. in irony). In two EEG experiments, we compared the influence of emotional valence of the target (emotional, neutral) in cognitive and emotional conflict processing. To maximally approximate real-life communication, we used audiovisual stimuli. Participants either categorized spoken vowels (cognitive conflict) or their emotional valence (emotional conflict), while visual information was congruent or incongruent. Emotional target dimension facilitated both cognitive and emotional conflict processing, as shown in a reduced reaction time conflict effect. In contrast, the N100 in the event-related potentials showed a conflict-specific reversal: the conflict effect was larger for emotional compared with neutral trials in cognitive conflict and smaller in emotional conflict. Additionally, domain general conflict effects were observed in the P200 and N200 responses. The current findings confirm that emotions have a strong influence on cognitive and emotional conflict processing. They also highlight the complexity and heterogeneity of the interaction of emotion with different types of conflict. PMID- 25925272 TI - Social decisions affect neural activity to perceived dynamic gaze. AB - Gaze direction, a cue of both social and spatial attention, is known to modulate early neural responses to faces e.g. N170. However, findings in the literature have been inconsistent, likely reflecting differences in stimulus characteristics and task requirements. Here, we investigated the effect of task on neural responses to dynamic gaze changes: away and toward transitions (resulting or not in eye contact). Subjects performed, in random order, social (away/toward them) and non-social (left/right) judgment tasks on these stimuli. Overall, in the non social task, results showed a larger N170 to gaze aversion than gaze motion toward the observer. In the social task, however, this difference was no longer present in the right hemisphere, likely reflecting an enhanced N170 to gaze motion toward the observer. Our behavioral and event-related potential data indicate that performing social judgments enhances saliency of gaze motion toward the observer, even those that did not result in gaze contact. These data and that of previous studies suggest two modes of processing visual information: a 'default mode' that may focus on spatial information; a 'socially aware mode' that might be activated when subjects are required to make social judgments. The exact mechanism that allows switching from one mode to the other remains to be clarified. PMID- 25925273 TI - Phylogenetic Diversity of Peltigera Cyanolichens and Their Photobionts in Southern Chile and Antarctica. AB - The lichen genus Peltigera has been mainly revised in the Northern Hemisphere, with most species being recorded in Europe and North America. This study assessed the phylogenetic diversity of the mycobionts and cyanobionts of Peltigera cyanolichens collected in Southern Chile and Antarctica, areas in which lichens are extremely diverse but poorly studied. The operational taxonomic units (OTUs) of each symbiont were defined by analyzing the genetic diversity of the LSU and SSU rDNA of the mycobionts and cyanobionts, respectively, and a phylogenetic approach was used to relate these OTUs with sequences previously reported for Peltigera and Nostoc. Among the 186 samples collected, 8 Peltigera and 15 Nostoc OTUs were recognized, corresponding to sections Peltigera, Horizontales, and Polydactylon, in the case of the mycobionts, and to the Nostoc clade II, in the case of the cyanobionts. Since some of the OTUs recognized in this study had not previously been described in these areas, our results suggest that the diversity of Peltigera reported to date in the regions studied using traditional morphological surveys has underestimated the true diversity present; therefore, further explorations of these areas are recommended. PMID- 25925274 TI - Nephrogenic Syndrome of Inappropriate Antidiuresis in a Female Neonate: Review of the Clinical Presentation in Females. AB - BACKGROUND: Nephrogenic syndrome of inappropriate antidiuresis (NSIAD) is a rare X-linked disease due to gain-of-function mutations in the AVP V2 receptor gene. Hemizygous males present with recurrent episodes of severe hyponatremia in infancy. Heterozygous females are usually asymptomatic. CASE REPORT: We report on a 23-day-old female neonate, born at term with 3,260 g that presented with recurrent hyponatremia (Na between 124 and 134 mmol/l) due to NSIAD. She was a heterozygous carrier of the c.409 C>T mutation in the AVPR2 gene. CONCLUSIONS: This is the first report of a female neonate presenting with hyponatremia due to NSIAD. The diagnosis of NSIAD should not be limited to male infants and should also be considered in female infants with the clinical picture of inappropriate antidiuresis. PMID- 25925275 TI - The effect of pre-maturation culture using phosphodiesterase type 3 inhibitor and insulin, transferrin and selenium on nuclear and cytoplasmic maturation of bovine oocytes. AB - This study aims to evaluate if a pre-maturation culture (PMC) using cilostamide as a meiotic inhibitor in combination with insulin, transferrin and selenium (ITS) for 8 or 24 h increases in vitro embryo production. To evaluate the effects of PMC on embryo development, cleavage rate, blastocyst rate, embryo size and total cell number were determined. When cilostamide (20 MUM) was used in PMC for 8 or 24 h, 98% of oocytes were maintained in germinal vesicles. Although the majority of oocytes resumed meiosis after meiotic arrest, the cleavage and blastocyst rates were lower than the control (P 0.05) to the control. The deleterious effect of 20 MUM cilostamide treatment for 24 h on a PMC was confirmed by lower cumulus cell viability, determined by trypan blue staining, in that group compared with the other groups. A lower concentration (10 MUM) and shorter exposure time (8 h) minimized that effect but did not improve embryo production. More studies should be performed to determine the best concentration and the arresting period to increase oocyte competence and embryo development. PMID- 25925276 TI - Non-alternant non-benzenoid kekulenes: the birth of a new kekulene family. AB - "Kekulene" is a doughnut-like shaped polycyclic aromatic hydrocarbon consisting of cyclically arrayed benzene rings. It has attracted a great deal of theoretical interest because it is regarded as an ideal model to study conjugation circuits of pi electrons, i.e. whether they delocalize locally in benzene rings or globally throughout the molecule. Though kekulene was synthesized in 1978, it was the only known compound of this class of compounds for a long time. Recently, new kekulene-related molecules, septulene, which is a non-alternant benzenoid hydrocarbon, and a tetracyclopentatetraphenylene (TCPTP) derivative belonging to non-alternant non-benzenoid hydrocarbons, were synthesized. This article presents theoretical and experimental aspects of kekulene-related molecules focusing on the viewpoint of conjugation circuits by classifying them into three types: benzenoid kekulenes including kekulene itself and septulene, yet unknown anti kekulene and non-alternant non-benzenoid kekulenes represented by TCPTP. PMID- 25925277 TI - Impact of enrichment conditions on cross-species capture of fresh and degraded DNA. AB - By combining high-throughput sequencing with target enrichment ('hybridization capture'), researchers are able to obtain molecular data from genomic regions of interest for projects that are otherwise constrained by sample quality (e.g. degraded and contamination-rich samples) or a lack of a priori sequence information (e.g. studies on nonmodel species). Despite the use of hybridization capture in various fields of research for many years, the impact of enrichment conditions on capture success is not yet thoroughly understood. We evaluated the impact of a key parameter--hybridization temperature--on the capture success of mitochondrial genomes across the carnivoran family Felidae. Capture was carried out for a range of sample types (fresh, archival, ancient) with varying levels of sequence divergence between bait and target (i.e. across a range of species) using pools of individually indexed libraries on Agilent SureSelect(TM) arrays. Our results suggest that hybridization capture protocols require specific optimization for the sample type that is being investigated. Hybridization temperature affected the proportion of on-target sequences following capture: for degraded samples, we obtained the best results with a hybridization temperature of 65 degrees C, while a touchdown approach (65 degrees C down to 50 degrees C) yielded the best results for fresh samples. Evaluation of capture performance at a regional scale (sliding window approach) revealed no significant improvement in the recovery of DNA fragments with high sequence divergence from the bait at any of the tested hybridization temperatures, suggesting that hybridization temperature may not be the critical parameter for the enrichment of divergent fragments. PMID- 25925278 TI - Comparison of digital volume tomography and high-resolution computed tomography in detecting superior semicircular canal dehiscence--a temporal bone study. AB - CONCLUSION: In detecting a thin bony coverage of a superior semicircular canal (SSC), digital volume tomography (DVT) scans in Poeschl projection seem to be superior to high-resolution computed tomography (CT) scans. Still, a definite diagnosis of SSC dehiscence (SSCD) is not possible with any radiologic imaging technique. OBJECTIVE: To compare CT and DVT to find out whether DVT is equal, better or worse in showing a thin bony layer on top of an SCC. METHODS: In 11 human temporal bone specimens, the SSC was microscopically blue-lined leaving a thin bony coverage on top of it. All specimens were assessed with both high resolution CT and DVT. After reconstructing the images in Stenvers and Poeschl projections, all images were evaluated by five independent examiners experienced in radiologic imaging of the temporal bone using a four-point ordinal scale, from 1 (distinct dehiscence) to 4 (distinct coverage). RESULTS: The mean score for all CT scans was 2.58 compared with 3.22 for DVT scans (p = 0.000). Poeschl projection showed a mean score of 3.25 compared with 2.55 for Stenvers projection (p = 0.000). The best imaging modality was found to be DVT scans in Poeschl projections, with a mean score of 3.60. PMID- 25925279 TI - Efficient Synthesis of Amides and Esters from Alcohols under Aerobic Ambient Conditions Catalyzed by a Au/Mesoporous Al2 O3 Nanocatalyst. AB - An efficient heterogeneous Au/mesoporous alumina nanocatalyst has been successfully developed for the synthesis of amides and esters from simple building blocks of readily available alcohols and amines. The processes were simple and were performed at room temperature and atmospheric pressure of O2 to form the desired products with up to 97 % isolated yield. The ability of Au/mesoporous alumina to catalyze these reactions under ambient conditions further enhances the sustainability of these chemical processes. Furthermore, the nanocatalyst was stable to air and water and could be recovered and reused easily. The enhanced catalytic activity of Au/mesoporous alumina might be attributed to the presence of negatively charged Au nanoparticles that could promote oxidation processes as well as the stability of the mesoporous alumina support calcined at a high temperature of 800 degrees C. PMID- 25925280 TI - Monkeys and Rats Are Not Susceptible to Ferret Hepatitis E Virus Infection. AB - Ferret hepatitis E virus (HEV), a novel hepatitis E-like virus, has been identified in ferrets in the Netherlands, Japan, and the US. To determine whether ferret HEV transmits to other animals, we inoculated laboratory rats (Wistar), nude rats (Long-Evans-rnu/rnu), and cynomolgus monkeys with ferret HEV (F4351) by intravenous injection. None of the animals demonstrated a positive sign for virus replication, indicating that rats and monkeys are not susceptible to ferret HEV. PMID- 25925281 TI - Composite faces are not processed holistically: evidence from the Garner and redundant target paradigms. AB - Composite faces fuse the top half of one face with the bottom half of another. These stimuli inflict a strong illusion of a novel face on their viewers, and are often considered to be processed holistically. The current study challenges this holistic view. Here I present provocative evidence from various classic attention paradigms such as the Garner (1974) and the redundant target (Miller, Cognitive Psychology, 14, 247-279, 1982; Townsend & Nozawa, Journal of Mathematical Psychology, 39, 321-359, 1995) tasks showing that face parts are perceived and processed in an analytic rather than holistic fashion. In Experiment 1, composite faces failed to exhibit Garner interference, indicating perfect selective attention to the constituent parts. In Experiments 2 and 3, composite faces failed to exhibit super-capacity with same-identity composites, demonstrating limited or unlimited capacity. This pattern is consistent with analytic perception. Taken together, the results cast serious doubts on the validity of the holistic processing approach. In many respects, the study proposes disillusionment from the composite face illusion. In addition, the study highlights the importance of converging operations, model testability, and individual differences in the study of faces. PMID- 25925282 TI - Accelerated increase and decrease in subjective age as a function of changes in loneliness and objective social indicators over a four-year period: results from the health and retirement study. AB - OBJECTIVES: The study examined the role of changes in loneliness and objective social indicators in the formation of changes in subjective age over a four-year period. METHODS: The Health and Retirement Study is a US nationally representative study of older adults over 50 and their spouse of any age. We restricted the sample to individuals, 65 years of age and older (n = 2591). An accelerated increase in subjective age was defined as an increase in subjective age over the two waves greater than five years. An accelerated decrease in subjective age was defined as a difference that was lower than three years. These were examined against a change in subjective age in the range of three to five years (i.e., change consistent with the passage of time). RESULTS: For 23.4% of the sample, changes in subjective age were consistent with the passage of time. A total of 38.3% had an accelerated decrease in subjective age, whereas 38.3% had an accelerated increase. A decrease in loneliness over the two waves resulted in an accelerated decrease in subjective age, whereas an increase in depressive symptoms resulted in an accelerated increase in subjective age. Changes in objective social indicators, physical difficulties or medical comorbidity did not predict changes in subjective age. CONCLUSIONS: This is one of very few studies that examined changes in subjective age over time. Changes in subjective age represent an important construct that corresponding to other changes in subjective experiences. PMID- 25925283 TI - Dynamic gas-inclusion in a single crystal. AB - In solid-state science, most changing phenomena have been mysterious. Furthermore, the changes in chemical composition should be added to mere physical changes to also cover the chemical changes. Here, the first success in characterizing the nature of gas inclusion in a single crystal is reported. The gas inclusion process has been thoroughly investigated by in situ optical microscopy, single-crystal X-ray diffraction analyses, and gas adsorption measurements. The results demonstrated an inclusion action of a first-order transition behavior induced by a critical concentration on the phase boundary. The transfer of phase boundary and included gas are strongly related. This relationship can generate the dynamic features hidden in the inclusion phenomena, which can lead to the guest capturing and transfer mechanism that can apply to spatiotemporal inclusion applications by using host solids. PMID- 25925285 TI - A cautionary note on the immunohistochemical detection of BRAF v600e mutations in serrated lesions of the colon. PMID- 25925286 TI - Cancer testis antigen expression in testicular germ cell tumors and in intratubular germ cell neoplasia. PMID- 25925287 TI - Chloroquine Inhibits Ca(2+) Signaling in Murine CD4(+) Thymocytes. AB - BACKGROUND/AIMS: Bitter-tasting chloroquine can suppress T cell activation by inhibiting Ca(2+) signaling. However, the mechanism of inhibition remains largely unclear. METHODS: In this study, CD4(+) T cells were isolated from the thymus, and the calcium content of CD4(+) thymocytes was measured using fura-2 AM and a TILL imaging system. Pyrazole-3 (Pyr3), thapsigargin (TG), and caffeine were used to assess the effects of chloroquine on the intracellular Ca(2+) content of CD4(+) T cells. RESULTS: In murine CD4(+) thymocytes, chloroquine decreased the TG-triggered intracellular Ca(2+) increase in a dose-dependent manner. In the absence of chloroquine under Ca(2+)-free conditions (0 mM Ca(2+) and 0.5 mM EGTA), TG induced a transient Ca(2+) increase. After restoration of the extracellular Ca(2+) concentration to 2 mM, a dramatic Ca(2+) increase occurred. This elevation was completely blocked by chloroquine and was markedly inhibited by Pyr3, a selective antagonist of transient receptor potential C3 (TRPC3) channel and stromal interaction molecule (STIM)/Orai channel. Furthermore, the TG induced transient Ca(2+) increase under Ca(2+)-free conditions was eliminated in the presence of chloroquine. Chloroquine also blocked the dialyzed inositol-1,4,5 trisphosphate (IP3)-induced intracellular Ca(2+) increase. However, chloroquine was not able to decrease the caffeine-induced Ca(2+) increase. CONCLUSION: These data indicate that chloroquine inhibits the elevation of intracellular Ca(2+) in thymic CD4(+) T cells by inhibiting IP3 receptor-mediated Ca(2+) release from intracellular stores and TRPC3 channel-mediated and/or STIM/Orai channel-mediated Ca(2+) influx. PMID- 25925288 TI - Functional assessment of the liver with gadolinium-ethoxybenzyl diethylenetriamine penta-acetate-enhanced MRI in living-donor liver transplantation. AB - BACKGROUND: A precise estimation of the capacity of the remnant liver following partial liver resection is important. In this study, the regional function of the liver in patients undergoing living-donor liver transplantation was evaluated by gadolinium-ethoxybenzyl-diethylenetriamine penta-acetic acid (EOB)-enhanced MRI, with special reference to the congested region. METHODS: EOB-MRI analysis was performed before hepatectomy in donors, and 7 days after surgery in the donor and recipient. In the hepatocyte phase, from images obtained 15 min after Primovist(r) injection, the signal intensity in each liver segment was measured and divided by the signal intensity of the erector spinae muscle (liver to muscle ratio, LMR) for standardization. Inter-regional differences in LMRs were analysed in donors and recipients. RESULTS: Thirty-two living donors and 31 recipients undergoing living-donor liver transplantation were enrolled. In donors, the LMRs of the remnant left lobe were almost equivalent among the liver segments. In the remnant right lobe without the middle hepatic vein, the mean(s.d.) LMR for congested segments (S5 and S8) was significantly lower than that for non congested segments (S6 and S7): 2.60(0.52) versus 3.64(0.56) respectively (P < 0.001). After surgery, values in the non-congested region were almost identical to those in the preoperative donor liver. LMR values in the left and right lobe graft were significantly lower than those in the corresponding segment before donor surgery (P < 0.001). CONCLUSION: The function of the congested region secondary to outflow obstruction in the remnant donor liver was approximately 70 per cent of that in the non-congested region. EOB-MRI is a promising tool to assess regional liver function, with good spatial resolution. PMID- 25925289 TI - Visual Attention and Saccadic Oculomotor Control in Parkinson's Disease. AB - BACKGROUND: In patients with Parkinson's disease (PD) we aimed at differentiating the relation between selective visual attention, deficits of programming and dynamics of saccadic eye movements while searching for a target and hand-reaction time as well as hand-movement time. Visual attention is crucial for concentrating selectively on one aspect of the visual field while ignoring other aspects. Eye movements are anatomically and functionally related to mechanisms of visual attention. Saccadic dysfunction might confound selective visual attention in PD. METHODS: We studied visual selective attention in 22 medicated PD patients (clinical ON status, mild to moderate disease severity) and 22 age matched controls. We looked for possible interferences through oculomotor deficits. Two tasks were compared: free viewing of photographs and time optimal visual search of a hidden target. Visual search times (VST), task related dynamics of saccades, and hand-reaction and hand-movement times were analyzed. RESULTS: In the free viewing task mild to moderately affected PD patients did not differ statistically from healthy subjects with respect to saccade dynamics. However, patients differed significantly from healthy subjects in the time optimal visual search task with 25% lower rates of successful searches. Hand movement reaction time did not differ in both groups, whereas hand movement execution time was significantly prolonged in PD patients. CONCLUSION: Saccadic oculomotor control and hand movement reaction times were intact, whereas in our less severely affected treated PD patients, visual selective attention was not. The highly reduced successful search rate might be related to disturbed programming and delayed execution of saccades during time optimal visual search due to decreased execution of serial-order sequential generation of saccades. PMID- 25925290 TI - Endocrine mucin-producing sweat gland carcinoma: a study of three cases and CK8, CK18 and CD5/6 immunoexpression. AB - Endocrine mucin-producing sweat gland carcinoma is a cutaneous adnexal tumor that is rarely reported in the literature. We identified only 29 previously reported cases. All these cases share some clinical morphologic and immunohistochemical features. Among the immunohistochemical markers, cytokeratins 5/6, 8 and 18 (CK5/6, CK8 and CK18) had not been previously studied in this tumor. Although studies with cytokeratin Cam5.2 exist, we know at present that this marker does not correspond to antibodies CK8/18, but rather to CK7 and CK8. We studied three examples of endocrine mucin-producing sweat gland carcinoma with 18 immunostains. Our cases showed an immunoprofile CK8+, CK18+, CK5/6- (or only focally positive), CK7+, GCDFP-15+ (2 cases), estrogen receptor+, progesterone receptor+, HER2-, neuron-specific enolase + (2 cases), anti-synaptophysin+, chromogranin A +, CD56 variable (1 case +, 1 case-), CD57-, anti-human D2-40- (two cases), p63- or focally positive, smooth muscle actin + with variable pattern of expression and smooth muscle myosin heavy chain expressed in a peripheral discontinuous layer in some nodules, but absent in most. PMID- 25925291 TI - Long-term survival of patients with recurrent endometrial stromal sarcoma: a multicenter, observational study. AB - OBJECTIVE: The aim of this study was to evaluate the clinical behavior and management outcome of recurrent endometrial stromal sarcoma (ESS). METHODS: A retrospective review of charts of 10 patients with recurrent ESS was performed and relapse-free interval, relapse site, treatment, response to treatment, duration of follow-up and clinical outcome extracted. Survival outcome measures used were post-relapse survival which was defined as the time from first evidence of relapse to death from any cause. Living patients were censored at the date of last follow-up. RESULTS: The median age and median relapse-free interval at the time of initial relapse were 51.5 years and 66.5 months, respectively. The number of relapses ranged from one to five. Sixteen surgical procedures for recurrent disease included nine (56.0%) complete resections. There was no statistically significant difference between initial recurrent tumors and second/subsequent recurrent tumors in the rate of complete surgery (44.4% vs. 71.4%, respectively, p=0.36). Of the eleven evaluable occasions when hormonal therapy was used for recurrent disease, disease control was achieved in eight (72.7%). There was no difference between initial recurrent tumors and second/subsequent recurrent tumors in disease control rate by hormonal therapy (85.7% vs. 50.0%, respectively, p=0.49). The 10-year post-relapse survival rate was 90.0% and the overall median post-relapse survival 119 months (range, 7 to 216 months). CONCLUSION: Post-relapse survival of patients with ESS can be expected to be >10 years when treated by repeated surgical resection and hormonal therapy or both. PMID- 25925292 TI - Cost-effectiveness of para-aortic lymphadenectomy before chemoradiotherapy in locally advanced cervical cancer. AB - OBJECTIVE: To evaluate the cost-effectiveness of nodal staging surgery before chemoradiotherapy (CRT) for locally advanced cervical cancer in the era of positron emission tomography/computed tomography (PET/CT). METHODS: A modified Markov model was constructed to evaluate the cost-effectiveness of para-aortic staging surgery before definite CRT when no uptake is recorded in the para-aortic lymph nodes (PALN) on PET/CT. Survival and complication rates were estimated based on the published literature. Cost data were obtained from the Korean Health Insurance Review and Assessment Service. Strategies were compared using an incremental cost-effectiveness ratio (ICER). Sensitivity analyses were performed, including estimates for the performance of PET/CT, postoperative complication rate, and varying survival rates according to the radiation field. RESULTS: We compared two strategies: strategy 1, pelvic CRT for all patients; and strategy 2, nodal staging surgery followed by extended-field CRT when PALN metastasis was found and pelvic CRT otherwise. The ICER for strategy 2 compared to strategy 1 was $19,505 per quality-adjusted life year (QALY). Under deterministic sensitivity analyses, the model was relatively sensitive to survival reduction in patients who undergo pelvic CRT alone despite having occult PALN metastasis. A probabilistic sensitivity analysis demonstrated the robustness of the case results, with a 91% probability of cost-effectiveness at the willingness-to-pay thresholds of $60,000/QALY. CONCLUSION: Nodal staging surgery before definite CRT may be cost-effective when PET/CT imaging shows no evidence of PALN metastasis. Prospective trials are warranted to transfer these results to guidelines. PMID- 25925293 TI - Isolated tumor cells and micrometastases in regional lymph nodes in stage I to II endometrial cancer. AB - OBJECTIVE: The aim of this study was to clarify the clinical significance of isolated tumor cells (ITCs) or micrometastasis (MM) in regional lymph nodes in patients with International Federation of Gynecology and Obstetrics (FIGO) stage I to II endometrial cancer. METHODS: In this study, a series of 63 patients with FIGO stage I to II were included, who had at least one of the following risk factors for recurrence: G3 endometrioid/serous/clear cell adenocarcinomas, deep myometrial invasion, cervical involvement, lympho-vascular space invasion, and positive peritoneal cytology. These cases were classified as intermediate-risk endometrial cancer. Ultrastaging by multiple slicing, staining with hematoxylin and eosin and cytokeratin, and microscopic examination was performed on regional lymph nodes that had been diagnosed as negative for metastases. RESULTS: Among 61 patients in whom paraffin-embedded block was available, ITC/MM was identified in nine patients (14.8%). Deep myometrial invasion was significantly associated with ITC/MM (p=0.028). ITC/MM was an independent risk factor for extrapelvic recurrence (hazard ratio, 17.9; 95% confidence interval [CI], 1.4 to 232.2). The 8-year overall survival (OS) and recurrence-free survival (RFS) rates were more than 20% lower in the ITC/MM group than in the node-negative group (OS, 71.4% vs. 91.9%; RFS, 55.6% vs. 84.0%), which were statistically not significant (OS, p=0.074; RFS, p=0.066). Time to recurrence tended to be longer in the ITC/MM group than in the node-negative group (median, 49 months vs. 16.5 months; p=0.080). CONCLUSIONS: It remains unclear whether ITC/MM have an adverse influence on prognosis of intermediate-risk endometrial cancer. A multicenter cooperative study is needed to clarify the clinical significance of ITC/MM. PMID- 25925295 TI - Behaviour change. PMID- 25925294 TI - Role of vaginal pallor reaction in predicting late vaginal stenosis after high dose-rate brachytherapy in treatment-naive patients with cervical cancer. AB - OBJECTIVE: To assess actual rates of late vaginal stenosis and identify predisposing factors for complications among patients with previously untreated cervical cancer following high-dose-rate brachytherapy. METHODS: We performed longitudinal analyses of 57 patients using the modified Dische score at 6, 12, 18, 24, 36, and 60 months after treatment, which consisted of 15 interstitial brachytherapys and 42 conventional intracavitary brachytherapys, with a median follow-up time of 36 months (range, 6 to 144 months). RESULTS: More than half of the patients developed grade 1 (mild) vaginal stenosis within the first year of follow-up, and grade 2 (97.5%, moderate) to grade 3 (severe) stenosis gradually increased with time. Actual stenosis rates for grade 1, 2, and 3 were 97.5% (95% confidence interval [CI], 92.7 to 97.5), 60.7% (95% CI, 42.2 to 79.3), and 7.4% (95% CI, 0 to 18.4) at 3 years after treatment. Pallor reaction grade 2-3 at 6 months was only a statistically significant predisposing factor for grade 2-3 late vaginal stenosis 3 years or later with a hazard ratio of 3.48 (95% CI, 1.32 to 9.19; p=0.018) by a multivariate Cox proportional hazard model. Patients with grade 0-1 pallor reaction at 6 months showed a grade >=2 vaginal stenosis rate of 53%, whereas the grade 2-3 pallor reaction group achieved a grade >=2 vaginal stenosis rate at 3 years at 100% (p=0.001). CONCLUSION: High-dose-rate brachytherapy was associated with high incidence of late vaginal stenosis. Pallor reaction grade 2-3 at 6 months was predictive of late grade 2-3 vaginal stenosis at 3 years after treatment. These findings should prove helpful for patient counseling and preventive intervention. PMID- 25925296 TI - New report highlights diversity across health trainer services. PMID- 25925297 TI - Breastfeeding could be linked to higher IQ. PMID- 25925298 TI - Governing the RSPH in 2015 and beyond. PMID- 25925299 TI - Smarter running: shaping the behavioral change interventions of the future! PMID- 25925300 TI - Lifebuoy: help a child reach 5. PMID- 25925301 TI - What would your future self say? Using motivational interviewing to affect behaviour change. PMID- 25925302 TI - Behaviour change. Change behaviour. PMID- 25925303 TI - Prevention is better than cure: tackling non-communicable diseases in developing countries by focusing on prevention. PMID- 25925304 TI - The Knee High Design Challenge: taking a different approach to early years. PMID- 25925305 TI - Rethink Cancer: cancer education in schools. PMID- 25925306 TI - Chimpshop and alcohol reduction - using technology to change behaviour. PMID- 25925307 TI - National child measurement programme: does it work? PMID- 25925308 TI - Health trainers making a difference to mental health and wellbeing. AB - This short report explores the key findings from a review(1) of information on health trainers in 2013/2014 which had a particular focus on mental health and wellbeing. After summarising the key findings of the review, it focuses on mental health, briefly exploring the links between mental and physical health before discussing what differences engagement with a health trainer made to people's sense of self-efficacy and wellbeing. Health trainers are a non-clinical workforce introduced in 2004,(2) who receive training in competencies to enable them to support people in disadvantaged communities to improve their health.(3) The population groups or settings that health trainers focus on varies from service to service, but all work one-to-one, most spending at least an hour with a client at their first appointment, supporting and enabling them to decide what they want to do. The emphasis is on the client determining their own priorities and how to achieve them. Generally, health trainers see clients for a total of six sessions, where how to achieve goals and progress towards them is discussed. The Data Collection and Reporting System (DCRS) is used by approximately 60% of Health Trainer Services to record monitoring data. Around 90% of Health Trainer Services using DCRS record ethnographic data on health trainers and clients, plus the issues clients worked on and the progress they made. There is also a wide range of other data which can be recorded, including before and after mental health and wellbeing scores. We were given access to aggregate data in order to conduct an analysis. Descriptive statistics were generated to calculate percentage change pre- to post-intervention. A total of 1,377 (= 919 full time equivalents) health trainers were recorded in the DCRS system as working with 97,248 clients in England during 2013/2014. The health trainer model embodies the principle of lay support,(4) and services aim to recruit a high proportion of their staff from similar backgrounds to their clients. They have been reasonably successful with 32% of health trainers coming from the most deprived areas (Quintile 1),(i) with a further 20% from Quintile 2. In all, 40% percent of health trainers lived in the same areas as their clients. PMID- 25925309 TI - Exploring the experiences of pregnant women using an NHS stop smoking service: a qualitative study. AB - AIM: The purpose of this article was to explore women's experiences of attempting to stop smoking while pregnant using National Health Service (NHS) support. METHOD: A qualitative methodological approach was adopted to enable the researcher to develop an understanding of the women's experiences. Six individual semi-structured interviews were conducted with women who accessed an NHS stop smoking service while pregnant. The data were analysed using comparative analysis. RESULTS: Five themes were identified: health risks, motivations to stop smoking, influences on smoking behaviour, feelings about smoking and experiences of using NHS stop smoking support. Motivation to stop smoking was predominantly due to concerns about their unborn baby's health, and knowledge of health risks was generally good. Limited information relating to the associated health risks of continued smoking in pregnancy from healthcare professionals appeared to be a common experience. External pressures both positively and negatively influenced the smoking status of the women. Stress was cited by all the women as a significant challenge to smoking cessation and something which they all struggled with. The women's experiences of using NHS support while pregnant was varied; some felt it adequately met their needs, while others felt that their expectations were not met. CONCLUSION: Continued smoking in pregnancy is complex, and it appears that successful smoking cessation is related to a number of internal and external factors which present significant challenges for expectant mothers who smoke. Stress was found to be a major contributor in continued smoking; therefore, NHS stop smoking services should incorporate stress management techniques into stop smoking interventions. In addition, services should be flexible, adapting service provision to meet women's needs. PMID- 25925310 TI - Intake of diet fizzy drinks directly linked to obesity. PMID- 25925311 TI - Translating clinical proteomics: the importance of study design. AB - Mass spectrometry-based clinical proteomics approaches were introduced into the biomedical field more than two decades ago. Despite recent developments both in the field of mass spectrometry and bioinformatics, the gap between proteomics results and their translation into clinical practice still needs to be closed, as implementation of proteomics results in the clinic appears to be scarce. An extra focus on the importance of the experimental design is therefore of crucial importance. PMID- 25925312 TI - The efficacy and safety of the Chinese herbal medicine Di-Tan decoction for treating Alzheimer's disease: protocol for a randomized controlled trial. AB - BACKGROUND: Alzheimer's disease (AD) is the most common type of dementia in the elderly. It is estimated that the global prevalence of dementia will rise from 24.3 million in 2005 to 81.1 million in 2040. AD has a devastating impact on sufferers, caregivers, their communities and the healthcare system in general. "Di-tan decoction" (DTD) is a traditional Chinese medicine (TCM) formula frequently used to treat symptoms that are now defined as AD in clinical treatment. However, the existing evidence for recommending DTD in clinical practice derives from studies that were methodologically flawed. In this study, we aim to determine the efficacy and safety of DTD in AD patients based on a rigidly randomized controlled trial. It will provide critical information on sample size and treatment regimen for conducting a full-scale clinical trial of DTD later. METHODS/DESIGN: This study will be a double-blind, randomized, placebo controlled, add-on trial. After a 2-week run-in period, eligible patients with mild to moderate AD will be recruited and given either DTD or placebo twice daily for 24 weeks with follow-up 6 weeks after the last treatment. An increase of four points or greater on the scores of Alzheimer's Disease Assessment Scale-cognitive subscale (ADAD-cog) will be considered as a positive primary outcome. Total scores of the ADAD-cog, the Chinese version of Mini-Mental State Examination (C MMSE), and the Chinese version of the Disability Assessment for Dementia (C-DAD) score will be used as secondary outcomes. Adverse events will also be reported. DISCUSSION: This randomized trial will be the first rigorous empirical study on the efficacy of DTD for treating cognitive symptoms in AD patients. Its success will justify and warrant a large-scale clinical trial to further consolidate the evidence for DTD's efficacy in treating AD. TRIAL REGISTRATION: Chinese Clinical Trial Registry ( ChiCTR-TRC-12004548 , Date of registration: 22 November 2012). PMID- 25925313 TI - Reduced levels of circulating progenitor cells in juvenile idiopathic arthritis are counteracted by anti TNF-alpha therapy. AB - BACKGROUND: Endothelial progenitor cells (EPC) promote angiogenesis and vascular repair. Though reduced EPC levels have been shown in rheumatoid arthritis, no study has so far evaluated EPCs in children with juvenile idiopathic arthritis (JIA). We aimed to study circulating EPCs in children with JIA, their relation to disease activity, and effects of anti TNF-alpha treatment. METHODS: Circulating EPCs were quantified by flow cytometry based on CD34, CD133 and KDR expression in peripheral blood of 22 patients with oligoarticular JIA and 29 age-matched controls. EPCs were re-assessed in children with methotrexate-resistant oligo extended JIA before and up to 12 month after initiation of anti-TNF-alpha therapy. Plasma concentrations of inflammatory and EPC-regulating factors were measured using a multiplex array. Confocal immunofluorescence was used to demonstrate EPCs in synovial tissues. RESULTS: Children with active JIA showed a significant reduction of relative and absolute counts of circulating progenitor cells and EPCs compared to age-matched healthy controls. CD34(+) cell levels were modestly and inversely correlated to disease activity. A strong inverse correlation was found between serum TNF-alpha and EPC levels. In 8 patients treated with anti TNF-alpha agents, the number of EPCs rose to values similar to healthy controls. CD34(+)KDR(+) EPCs were found in the synovial tissue of JIA children, but not in control. CONCLUSIONS: Children with JIA have reduced levels of the vasculoprotective and proangiogenic EPCs. While EPCs may contribute to synovial tissue remodelling, EPC pauperization may indicate an excess cardiovascular risk if projected later in life. PMID- 25925314 TI - A letter to the next secretary of state for health. PMID- 25925315 TI - Infrared Spectroscopy During Electrocatalytic Turnover Reveals the Ni-L Active Site State During H2 Oxidation by a NiFe Hydrogenase. AB - A novel in situ IR spectroscopic approach is demonstrated for the characterization of hydrogenase during catalytic turnover. E. coli hydrogenase 1 (Hyd-1) is adsorbed on a high surface-area carbon electrode and subjected to the same electrochemical control and efficient supply of substrate as in protein film electrochemistry during spectral acquisition. The spectra reveal that the active site state known as Ni-L, observed in other NiFe hydrogenases only under illumination or at cryogenic temperatures, can be generated reversibly in the dark at ambient temperature under both turnover and non-turnover conditions. The observation that Ni-L is present at all potentials during turnover under H2 suggests that the final steps in the catalytic cycle of H2 oxidation by Hyd-1 involve sequential proton and electron transfer via Ni-L. A broadly applicable IR spectroscopic technique is presented for addressing electrode-adsorbed redox enzymes under fast catalytic turnover. PMID- 25925316 TI - Activation and regulation of the granulation tissue derived cells with stemness related properties. AB - INTRODUCTION: Skin as the largest and easily accessible organ of the body represents an abundant source of adult stem cells. Among them, dermal stem cells hold great promise in tissue repair and the skin granulation tissue has been recently proposed as a promising source of dermal stem cells, but their biological characteristics have not been well investigated. METHODS: The 5-bromo 2'-deoxyuridine (BrdU) lineage tracing approach was employed to chase dermal stem cells in vivo. Granulation tissue derived cells (GTCs) were isolated and their in vitro proliferation, self-renewing, migration, and multi-differentiation capabilities were assessed. Combined radiation and skin wound model was used to investigate the therapeutic effects of GTCs. MicroRNA-21 (miR-21) antagomir was used to antagonize miR-21 expression. Reactive oxygen species (ROS) were scavenged by N-acetyl cysteine (NAC). RESULTS: The quiescent dermal stem/progenitor cells were activated to proliferate upon injury and enriched in granulation tissues. GTCs exhibited enhanced proliferation, colony formation and multi-differentiation capacities. Topical transplantation of GTCs into the combined radiation and skin wound mice accelerated wound healing and reduced tissue fibrosis. Blockade of the miR-21 expression in GTCs inhibited cell migration and differentiation, but promoted cell proliferation and self-renewing at least partially via a ROS dependent pathway. CONCLUSIONS: The granulation tissue may represent an alternative adult stem cell source in tissue replacement therapy and miR-21 mediated ROS generation negatively regulates the stemness related properties of granulation tissue derived cells. PMID- 25925317 TI - Why do movements drift in the dark? Passive versus active mechanisms of error accumulation. AB - When vision of the hand is unavailable, movements drift systematically away from their targets. It is unclear, however, why this drift occurs. We investigated whether drift is an active process, in which people deliberately modify their movements based on biased position estimates, causing the real hand to move away from the real target location, or a passive process, in which execution error accumulates because people have diminished sensory feedback and fail to adequately compensate for the execution error. In our study participants reached back and forth between two targets when vision of the hand, targets, or both the hand and targets was occluded. We observed the most drift when hand vision and target vision were occluded and equivalent amounts of drift when either hand vision or target vision was occluded. In a second experiment, we observed movement drift even when no visual target was ever present, providing evidence that drift is not driven by a visual-proprioceptive discrepancy. The observed drift in both experiments was consistent with a model of passive error accumulation in which the amount of drift is determined by the precision of the sensory estimate of movement error. PMID- 25925318 TI - Gain and phase of perceived virtual rotation evoked by electrical vestibular stimuli. AB - Galvanic vestibular stimulation (GVS) evokes a perception of rotation; however, very few quantitative data exist on the matter. We performed psychophysical experiments on virtual rotations experienced when binaural bipolar electrical stimulation is applied over the mastoids. We also performed analogous real whole body yaw rotation experiments, allowing us to compare the frequency response of vestibular perception with (real) and without (virtual) natural mechanical stimulation of the semicircular canals. To estimate the gain of vestibular perception, we measured direction discrimination thresholds for virtual and real rotations. Real direction discrimination thresholds decreased at higher frequencies, confirming multiple previous studies. Conversely, virtual direction discrimination thresholds increased at higher frequencies, implying low-pass filtering of the virtual perception process occurring potentially anywhere between afferent transduction and cortical responses. To estimate the phase of vestibular perception, participants manually tracked their perceived position during sinusoidal virtual and real kinetic stimulation. For real rotations, perceived velocity was approximately in phase with actual velocity across all frequencies. Perceived virtual velocity was in phase with the GVS waveform at low frequencies (0.05 and 0.1 Hz). As frequency was increased to 1 Hz, the phase of perceived velocity advanced relative to the GVS waveform. Therefore, at low frequencies GVS is interpreted as an angular velocity signal and at higher frequencies GVS becomes interpreted increasingly as an angular position signal. These estimated gain and phase spectra for vestibular perception are a first step toward generating well-controlled virtual vestibular percepts, an endeavor that may reveal the usefulness of GVS in the areas of clinical assessment, neuroprosthetics, and virtual reality. PMID- 25925319 TI - Feedback to distal dendrites links fMRI signals to neural receptive fields in a spiking network model of the visual cortex. AB - The blood oxygenation level-dependent (BOLD) response has been strongly associated with neuronal activity in the brain. However, some neuronal tuning properties are consistently different from the BOLD response. We studied the spatial extent of neural and hemodynamic responses in the primary visual cortex, where the BOLD responses spread and interact over much longer distances than the small receptive fields of individual neurons would predict. Our model shows that a feedforward-feedback loop between V1 and a higher visual area can account for the observed spread of the BOLD response. In particular, anisotropic landing of inputs to compartmental neurons were necessary to account for the BOLD signal spread, while retaining realistic spiking responses. Our work shows that simple dendrites can separate tuning at the synapses and at the action potential output, thus bridging the BOLD signal to the neural receptive fields with high fidelity. PMID- 25925320 TI - 5-HT2A receptor activation is necessary for CO2-induced arousal. AB - Hypercapnia-induced arousal from sleep is an important protective mechanism pertinent to a number of diseases. Most notably among these are the sudden infant death syndrome, obstructive sleep apnea and sudden unexpected death in epilepsy. Serotonin (5-HT) plays a significant role in hypercapnia-induced arousal. The mechanism of 5-HT's role in this protective response is unknown. Here we sought to identify the specific 5-HT receptor subtype(s) involved in this response. Wild type mice were pretreated with antagonists against 5-HT receptor subtypes, as well as antagonists against adrenergic, cholinergic, histaminergic, dopaminergic, and orexinergic receptors before challenge with inspired CO2 or hypoxia. Antagonists of 5-HT(2A) receptors dose-dependently blocked CO2-induced arousal. The 5-HT(2C) receptor antagonist, RS-102221, and the 5-HT1A receptor agonist, 8 OH-DPAT, attenuated but did not completely block CO2-induced arousal. Blockade of non-5-HT receptors did not affect CO2-induced arousal. None of these drugs had any effect on hypoxia-induced arousal. 5-HT2 receptor agonists were given to mice in which 5-HT neurons had been genetically eliminated during embryonic life (Lmx1b(f/f/p)) and which are known to lack CO2-induced arousal. Application of agonists to 5-HT(2A), but not 5-HT(2C), receptors, dose-dependently restored CO2 induced arousal in these mice. These data identify the 5-HT(2A) receptor as an important mediator of CO2-induced arousal and suggest that, while 5-HT neurons can be independently activated to drive CO2-induced arousal, in the absence of 5 HT neurons and endogenous 5-HT, 5-HT receptor activation can act in a permissive fashion to facilitate CO2-induced arousal via another as yet unidentified chemosensor system. PMID- 25925321 TI - Accessory stimulus modulates executive function during stepping task. AB - When multiple sensory modalities are simultaneously presented, reaction time can be reduced while interference enlarges. The purpose of this research was to examine the effects of task-irrelevant acoustic accessory stimuli simultaneously presented with visual imperative stimuli on executive function during stepping. Executive functions were assessed by analyzing temporal events and errors in the initial weight transfer of the postural responses prior to a step (anticipatory postural adjustment errors). Eleven healthy young adults stepped forward in response to a visual stimulus. We applied a choice reaction time task and the Simon task, which consisted of congruent and incongruent conditions. Accessory stimuli were randomly presented with the visual stimuli. Compared with trials without accessory stimuli, the anticipatory postural adjustment error rates were higher in trials with accessory stimuli in the incongruent condition and the reaction times were shorter in trials with accessory stimuli in all the task conditions. Analyses after division of trials according to whether anticipatory postural adjustment error occurred or not revealed that the reaction times of trials with anticipatory postural adjustment errors were reduced more than those of trials without anticipatory postural adjustment errors in the incongruent condition. These results suggest that accessory stimuli modulate the initial motor programming of stepping by lowering decision threshold and exclusively under spatial incompatibility facilitate automatic response activation. The present findings advance the knowledge of intersensory judgment processes during stepping and may aid in the development of intervention and evaluation tools for individuals at risk of falls. PMID- 25925322 TI - Effect of enriching the diet with menhaden oil or daily treatment with resolvin D1 on neuropathy in a mouse model of type 2 diabetes. AB - The purpose of this study was to determine the effect of supplementing the diet of a mouse model of type 2 diabetes with menhaden (fish) oil or daily treatment with resolvin D1 on diabetic neuropathy. The end points evaluated included motor and sensory nerve conduction velocity, thermal sensitivity, innervation of sensory nerves in the cornea and skin, and the retinal ganglion cell complex thickness. Menhaden oil is a natural source for n-3 polyunsaturated fatty acids, which have been shown to have beneficial effects in other diseases. Resolvin D1 is a metabolite of docosahexaenoic acid and is known to have anti-inflammatory and neuroprotective properties. To model type 2 diabetes, mice were fed a high fat diet for 8 wk followed by a low dosage of streptozotocin. After 8 wk of hyperglycemia, mice in experimental groups were treated for 6 wk with menhaden oil in the diet or daily injections of 1 ng/g body wt resolvin D1. Our findings show that menhaden oil or resolvin D1 did not improve elevated blood glucose, HbA1C, or glucose utilization. Untreated diabetic mice were thermal hypoalgesic, had reduced motor and sensory nerve conduction velocities, had decreased innervation of the cornea and skin, and had thinner retinal ganglion cell complex. These end points were significantly improved with menhaden oil or resolvin D1 treatment. Exogenously, resolvin D1 stimulated neurite outgrowth from primary cultures of dorsal root ganglion neurons from normal mice. These studies suggest that n-3 polyunsaturated fatty acids derived from fish oil could be an effective treatment for diabetic neuropathy. PMID- 25925323 TI - Cooperative vocal control in marmoset monkeys via vocal feedback. AB - Humans adjust speech amplitude as a function of distance from a listener; we do so in a manner that would compensate for such distance. This ability is presumed to be the product of high-level sociocognitive skills. Nonhuman primates are thought to lack such socially related flexibility in vocal production. Using predictions from a simple arousal-based model whereby vocal feedback from a conspecific modulates the drive to produce a vocalization, we tested whether another primate exhibits this type of cooperative vocal control. We conducted a playback experiment with marmoset monkeys and simulated "far-away" and "nearby" conspecifics using contact calls that differed in sound intensity. We found that marmoset monkeys increased the amplitude of their contact calls and produced such calls with shorter response latencies toward more distant conspecifics. The same was not true in response to changing levels of background noise. To account for how simulated conspecific distance can change both the amplitude and timing of vocal responses, we developed a model that incorporates dynamic interactions between the auditory system and limbic "drive" systems. Overall, our data show that, like humans, marmoset monkeys cooperatively control the acoustics of their vocalizations according to changes in listener distance, increasing the likelihood that a conspecific will hear their call. However, we propose that such cooperative vocal control is a system property that does not necessitate any particularly advanced sociocognitive skill. At least in marmosets, this vocal control can be parsimoniously explained by the regulation of arousal states across two interacting individuals via vocal feedback. PMID- 25925324 TI - Frequency of gamma oscillations in humans is modulated by velocity of visual motion. AB - Gamma oscillations are generated in networks of inhibitory fast-spiking (FS) parvalbumin-positive (PV) interneurons and pyramidal cells. In animals, gamma frequency is modulated by the velocity of visual motion; the effect of velocity has not been evaluated in humans. In this work, we have studied velocity-related modulations of gamma frequency in children using MEG/EEG. We also investigated whether such modulations predict the prominence of the "spatial suppression" effect (Tadin D, Lappin JS, Gilroy LA, Blake R. Nature 424: 312-315, 2003) that is thought to depend on cortical center-surround inhibitory mechanisms. MEG/EEG was recorded in 27 normal boys aged 8-15 yr while they watched high-contrast black-and-white annular gratings drifting with velocities of 1.2, 3.6, and 6.0 degrees /s and performed a simple detection task. The spatial suppression effect was assessed in a separate psychophysical experiment. MEG gamma oscillation frequency increased while power decreased with increasing velocity of visual motion. In EEG, the effects were less reliable. The frequencies of the velocity specific gamma peaks were 64.9, 74.8, and 87.1 Hz for the slow, medium, and fast motions, respectively. The frequency of the gamma response elicited during slow and medium velocity of visual motion decreased with subject age, whereas the range of gamma frequency modulation by velocity increased with age. The frequency modulation range predicted spatial suppression even after controlling for the effect of age. We suggest that the modulation of the MEG gamma frequency by velocity of visual motion reflects excitability of cortical inhibitory circuits and can be used to investigate their normal and pathological development in the human brain. PMID- 25925325 TI - Blockade of in vitro ictogenesis by low-frequency stimulation coincides with increased epileptiform response latency. AB - Low-frequency stimulation, delivered through transcranial magnetic or deep-brain electrical procedures, reduces seizures in patients with pharmacoresistant epilepsy. A similar control of ictallike discharges is exerted by low-frequency electrical stimulation in rodent brain slices maintained in vitro during convulsant treatment. By employing field and "sharp" intracellular recordings, we analyzed here the effects of stimuli delivered at 0.1 or 1 Hz in the lateral nucleus of the amygdala on ictallike epileptiform discharges induced by the K(+) channel blocker 4-aminopyridine in the perirhinal cortex, in a rat brain slice preparation. We found that 1) ictal events were nominally abolished when the stimulus rate was brought from 0.1 to 1 Hz; 2) this effect was associated with an increased latency of the epileptiform responses recorded in perirhinal cortex following each stimulus; and 3) both changes recovered to control values following arrest of the 1-Hz stimulation protocol. The control of ictal activity by 1-Hz stimulation and the concomitant latency increase were significantly reduced by GABAB receptor antagonism. We propose that this frequency-dependent increase in latency represents a short-lasting, GABAB receptor-dependent adaptive mechanism that contributes to decrease epileptiform synchronization, thus blocking seizures in epileptic patients and animal models. PMID- 25925327 TI - A highly polarized excitable cell separates sodium channels from sodium-activated potassium channels by more than a millimeter. AB - The bioelectrical properties and resulting metabolic demands of electrogenic cells are determined by their morphology and the subcellular localization of ion channels. The electric organ cells (electrocytes) of the electric fish Eigenmannia virescens generate action potentials (APs) with Na(+) currents >10 MUA and repolarize the AP with Na(+)-activated K(+) (KNa) channels. To better understand the role of morphology and ion channel localization in determining the metabolic cost of electrocyte APs, we used two-photon three-dimensional imaging to determine the fine cellular morphology and immunohistochemistry to localize the electrocytes' ion channels, ionotropic receptors, and Na(+)-K(+)-ATPases. We found that electrocytes are highly polarized cells ~ 1.5 mm in anterior-posterior length and ~ 0.6 mm in diameter, containing ~ 30,000 nuclei along the cell periphery. The cell's innervated posterior region is deeply invaginated and vascularized with complex ultrastructural features, whereas the anterior region is relatively smooth. Cholinergic receptors and Na(+) channels are restricted to the innervated posterior region, whereas inward rectifier K(+) channels and the KNa channels that terminate the electrocyte AP are localized to the anterior region, separated by >1 mm from the only sources of Na(+) influx. In other systems, submicrometer spatial coupling of Na(+) and KNa channels is necessary for KNa channel activation. However, our computational simulations showed that KNa channels at a great distance from Na(+) influx can still terminate the AP, suggesting that KNa channels can be activated by distant sources of Na(+) influx and overturning a long-standing assumption that AP-generating ion channels are restricted to the electrocyte's posterior face. PMID- 25925326 TI - Abnormal neuronal activity in Tourette syndrome and its modulation using deep brain stimulation. AB - Tourette syndrome (TS) is a common childhood-onset disorder characterized by motor and vocal tics that are typically accompanied by a multitude of comorbid symptoms. Pharmacological treatment options are limited, which has led to the exploration of deep brain stimulation (DBS) as a possible treatment for severe cases. Multiple lines of evidence have linked TS with abnormalities in the motor and limbic cortico-basal ganglia (CBG) pathways. Neurophysiological data have only recently started to slowly accumulate from multiple sources: noninvasive imaging and electrophysiological techniques, invasive electrophysiological recordings in TS patients undergoing DBS implantation surgery, and animal models of the disorder. These converging sources point to system-level physiological changes throughout the CBG pathway, including both general altered baseline neuronal activity patterns and specific tic-related activity. DBS has been applied to different regions along the motor and limbic pathways, primarily to the globus pallidus internus, thalamic nuclei, and nucleus accumbens. In line with the findings that also draw on the more abundant application of DBS to Parkinson's disease, this stimulation is assumed to result in changes in the neuronal firing patterns and the passage of information through the stimulated nuclei. We present an overview of recent experimental findings on abnormal neuronal activity associated with TS and the changes in this activity following DBS. These findings are then discussed in the context of current models of CBG function in the normal state, during TS, and finally in the wider context of DBS in CBG-related disorders. PMID- 25925328 TI - Transcutaneous spinal direct current stimulation modulates human corticospinal system excitability. AB - This study aimed to assess the effects of thoracic anodal and cathodal transcutaneous spinal direct current stimulation (tsDCS) on upper and lower limb corticospinal excitability. Although there have been studies assessing how thoracic tsDCS influences the spinal ascending tract and reflexes, none has assessed the effects of this technique over upper and lower limb corticomotor neuronal connections. In 14 healthy subjects we recorded motor evoked potentials (MEPs) elicited by transcranial magnetic stimulation (TMS) from abductor hallucis (AH) and hand abductor digiti minimi (ADM) muscles before (baseline) and at different time points (0 and 30 min) after anodal or cathodal tsDCS (2.5 mA, 20 min, T9-T11 level). In 8 of the 14 subjects we also tested the soleus H reflex and the F waves from AH and ADM before and after tsDCS. Both anodal and cathodal tsDCS left the upper limb MEPs and F wave unchanged. Conversely, while leaving lower limb H reflex unchanged, they oppositely affected lower limb MEPs: whereas anodal tsDCS increased resting motor threshold [(mean +/- SE) 107.33 +/- 3.3% increase immediately after tsDCS and 108.37 +/- 3.2% increase 30 min after tsDCS compared with baseline] and had no effects on MEP area and latency, cathodal tsDCS increased MEP area (139.71 +/- 12.9% increase immediately after tsDCS and 132.74 +/- 22.0% increase 30 min after tsDCS compared with baseline) without affecting resting motor threshold and MEP latency. Our results show that tsDCS induces polarity-specific changes in corticospinal excitability that last for >30 min after tsDCS offset and selectively affect responses in lower limb muscles innervated by lumbar and sacral motor neurons. PMID- 25925329 TI - Facilitation of cutaneous inputs during the planning phase of gait initiation. AB - It has been shown that during the planning of a voluntary movement the transmission of cutaneous afferent inputs to the somatosensory cortex is attenuated shortly before the motor output as well as during movement execution. However, it is not known whether the sensory suppression observed during the planning phase (i.e., before any movement execution) is a systemic phenomenon or whether it is dependent on movement context. For example, movements such as step initiation are controlled based on information received from cutaneous receptors in the feet. Because afferent information emerging from these receptors is critical for movement initiation, we hypothesized that suppression of these inputs may not occur during the planning phase prior to gait initiation. To examine this hypothesis we measured the cortical response to somatosensory stimulation during the planning phase of step initiation and during movement execution. Sensitivity to cutaneous stimulation was assessed by measuring the amplitude of the cortical somatosensory-evoked potential (SEP, over the Cz electrode) following electrical stimulations of the plantar sole of one foot. Two stimulations were provided during the planning phase of a step movement and two stimulations during movement execution. It was found that the P50-N80 SEP was facilitated in the early planning phase (-700 ms before motor execution) compared with when participants remained still (control standing task). This mechanism might contribute to an enhanced perception of cutaneous input leading to a more accurate setting of the forces to be exerted onto the ground to shift the body's weight toward the supporting side prior to foot-off. PMID- 25925330 TI - Insights into the All-trans-Retinoic Acid and Arsenic Trioxide Combination Treatment for Acute Promyelocytic Leukemia: A Meta-Analysis. AB - BACKGROUND: This study aimed to compare the curative effects of the combination therapy of all-trans-retinoic acid (ATRA) and arsenic trioxide (ATO, As2O3) with ATRA monotherapy on newly diagnosed acute promyelocytic leukemia (APL). METHODS: The studies were retrieved from PubMed, EMBASE, Cochrane Library, ChinaInfo and China National Knowledge Infrastructure (CNKI) databases from the inception to June 20, 2014. Thereafter, the eligible studies were selected based on the predefined criteria, and the literature quality was assessed. The meta-analysis was conducted using Review Manager 5.2 software. The pooled effect size was relative risk (RR) and its 95% confidence interval (CI). RESULTS: A total of 8 studies containing 480 cases were included, among which 264 were assigned to the ATRA + ATO group and the other 216 to the ATRA group. The meta-analysis showed that ATRA + ATO combination therapy significantly improved the complete remission (CR) rate (RR = 1.09, 95% CI = 1.03-1.16, p = 0.004), decreased the early mortality rate (RR = 0.42, 95% CI = 0.20-0.9, p = 0.03) and relapse rate (RR = 0.17, 95% CI = 0.07-0.42, p < 0.0001), but increased the high risk of liver dysfunction (RR = 2.43, 95% CI = 1.72-3.41, p < 0.00001), comparing with ATRA monotherapy. CONCLUSIONS: The ATRA + ATO combination therapy may be more effective for newly diagnosed APL with a higher CR rate but lower early mortality rate and relapse rate. However, the risks of liver damage should be of concern. PMID- 25925331 TI - Advances in understanding of the pathogenesis of acute respiratory distress syndrome. AB - The clinical syndrome of acute lung injury (ALI) occurs as a result of an initial acute systemic inflammatory response. This can be consequent to a plethora of insults, either direct to the lung or indirect. The insult results in increased epithelial permeability, leading to alveolar flooding with a protein-rich oedema fluid. The resulting loss of gas exchange leads to acute respiratory failure and typically catastrophic illness, termed acute respiratory distress syndrome (ARDS), requiring ventilatory and critical care support. There remains a significant disease burden, with some estimates showing 200,000 cases each year in the USA with a mortality approaching 50%. In addition, there is a significant burden of morbidity in survivors. There are currently no disease-modifying therapies available, and the most effective advances in caring for these patients have been in changes to ventilator strategy as a result of the ARDS network studies nearly 15 years ago. Here, we will give an overview of more recent advances in the understanding of the cellular biology of ALI and highlight areas that may prove fertile for future disease-modifying therapies. PMID- 25925332 TI - Controlled self-assembly of a pyrene-based bolaamphiphile by acetate ions: from nanodisks to nanofibers by fluorescence enhancement. AB - In this paper, a pyrene moiety is incorporated into a bolaamphiphile to form a novel molecule denoted PRB. Above the critical micelle concentration, PRB forms nanodisks in the aqueous solution. The addition of acetate ions induces a morphological change in self-assembled aggregates, which convert into nanofibers with a diameter of several nanometers. More interestingly, along with the morphological change, the fluorescence of the assemblies was enhanced concomitantly, which can be attributed to the binding effect of acetate ions on pyridinium head groups of PRB. PMID- 25925333 TI - Out-of-focus background subtraction for fast structured illumination super resolution microscopy of optically thick samples. AB - We propose a structured illumination microscopy method to combine super resolution and optical sectioning in three-dimensional (3D) samples that allows the use of two-dimensional (2D) data processing. Indeed, obtaining super resolution images of thick samples is a difficult task if low spatial frequencies are present in the in-focus section of the sample, as these frequencies have to be distinguished from the out-of-focus background. A rigorous treatment would require a 3D reconstruction of the whole sample using a 3D point spread function and a 3D stack of structured illumination data. The number of raw images required, 15 per optical section in this case, limits the rate at which high resolution images can be obtained. We show that by a succession of two different treatments of structured illumination data we can estimate the contrast of the illumination pattern and remove the out-of-focus content from the raw images. After this cleaning step, we can obtain super-resolution images of optical sections in thick samples using a two-beam harmonic illumination pattern and a limited number of raw images. This two-step processing makes it possible to obtain super resolved optical sections in thick samples as fast as if the sample was two-dimensional. PMID- 25925334 TI - Mathematical Modeling of Different Molecule Removal on On-Line Haemodiafiltration: Influence of Dialysis Duration and Infusion Flow. AB - BACKGROUND: In a previous study on a nocturnal, every-other-day online haemodiafiltration scheme, different removal patterns were observed for urea, creatinine, beta2-microglobulin, myoglobin and prolactin. The aim of this study was to evaluate the influence of dialysis duration and infusion flow (Qi) on the removal of different molecular weight (MW) solutes, and to quantify the effect of the different treatments on the kinetics of the solutes by using a classical two compartment model. METHODS: This prospective, in-center study was carried out in 10 patients on a nocturnal, every-other-day online post-dilution haemodiafiltration program. Each patient received four dialysis sessions with different conditions, two 4-h sessions (with infusion flows of 50 or 100 ml/min) and two 8-h sessions (with infusion flows of 50 or 100 ml/min). To analyze the solute kinetics, blood samples were obtained hourly during the dialysis treatments and in the first 3 h post-dialysis. RESULTS: Removal patterns differed in the molecules studied, which were quantified by means of the two-compartment mathematical model. The main results show the impact of dialysis duration on the removal of low molecular weight molecules (urea and creatinine), while the impact of Qi is clearly shown for high molecular weight molecules (myoglobin and prolactin). For middle molecular weight solutes, such as beta2-microglobulin, both factors (duration and Qi) enhance the removal efficiency of the dialyzer. CONCLUSIONS: Our study evaluates experimentally and mathematically how treatment time and infusion flow affect the filtration of solutes of different MW during post-dilution haemodiafiltration. The results provided by the present study should help physicians to select and individualise the most appropriate schedules to deliver an optimum diffusive and convective dialysis dose for each patient. PMID- 25925335 TI - Health Economics and Nutrition: Atopic Dermatitis. Editorial. PMID- 25925336 TI - Atopic dermatitis: global epidemiology and risk factors. AB - Atopic dermatitis (AD) is a chronic inflammatory skin disease posing a significant burden on health-care resources and patients' quality of life. It is a complex disease with a wide spectrum of clinical presentations and combinations of symptoms. AD affects up to 20% of children and up to 3% of adults; recent data show that its prevalence is still increasing, especially in low-income countries. First manifestations of AD usually appear early in life and often precede other allergic diseases such as asthma or allergic rhinitis. Individuals affected by AD usually have genetically determined risk factors affecting the skin barrier function or the immune system. However, genetic mutations alone might not be enough to cause clinical manifestations of AD, and it is merely the interaction of a dysfunctional epidermal barrier in genetically predisposed individuals with harmful effects of environmental agents which leads to the development of the disease. AD has been described as an allergic skin disease, but today, the contribution of allergic reactions to the initiation of AD is challenged, and it is proposed that allergy is rather a consequence of AD in subjects with a concomitant underlying atopic constitution. Treatment at best achieves symptom control rather than cure; there is thus a strong need to identify alternatives for disease prevention. PMID- 25925337 TI - Treatment of childhood atopic dermatitis and economic burden of illness in Asia Pacific countries. AB - Atopic dermatitis (AD) is a common chronic inflammatory skin condition in children. In Asia, the prevalence of AD is increasing, which is largely attributed to environmental and socioeconomic factors including family income, parental education, lifestyle and metropolitan living. Current clinical guidelines recommend a stepped approach in the management of eczema in children, with treatment steps tailored to the severity of the eczema. To address the skin barrier dysfunction, skin hydration and the application of emollients is essential. There is evidence supporting the use of bleach baths as an antimicrobial therapy against Staphylococcus aureus. In patients in whom topical treatment fails, wet wrap therapy may be considered as a treatment option before considering systemic therapies. In the second part of this article, the economic burden of AD is addressed. AD not only negatively impacts the child's quality of life but also that of the whole family and is associated with a burden on health care costs and society. AD in an infant will lead to frequent additional visits to the pediatrician, to additional and partially expensive treatment costs and, in rare cases, to hospitalization. It is thus of utmost importance to define efficient strategies to not only treat AD but also to decrease the risk of developing the disease. PMID- 25925338 TI - Cost-effectiveness of partially hydrolyzed whey protein formula in the primary prevention of atopic dermatitis in high-risk urban infants in Southeast Asia. AB - BACKGROUND: Atopic dermatitis (AD) is one of the most common skin conditions among infants. Proteins found in cow's milk formula (CMF) have been found to be attributable to heightened AD risk, particularly in infants with familial AD heredity. Previous studies have suggested that intervention with partially hydrolyzed formula in nonexclusively breastfed infants can have a protective effect against AD development. OBJECTIVE: The aim of the present study was to compare the estimates of the economic impact of reducing the AD incidence by feeding a partially hydrolyzed whey-based formula (PHF-W) instead of a standard CMF to high-risk nonexclusively breastfed urban infants for the first 17 weeks of life in the Philippines, Malaysia, and Singapore. METHODS: In each country, a mathematical model simulated AD incidence and burden from birth to 6 years of age of using PHF-W versus CMF in the target population using data from the German Infant Nutritional Intervention study. The models integrated literature, current cost and market data, and expert clinician opinion. Modeled outcomes included AD risk reduction, time spent after AD diagnosis, AD symptom-free days, quality adjusted life years (QALYs), and costs (direct and indirect). Outcomes were discounted at 3% per year. Costs were expressed in USD. RESULTS: Feeding high risk infants PHF-W instead of CMF resulted in an estimated absolute 14% (95% CI 1 24) AD risk reduction, a 0.69-year (95% CI 0.25-1.13) reduction in the time spent after AD diagnosis per child, reductions of 16-38 AD days, and gains in 0.02-0.04 QALYs, depending on the country. The per-child AD-related 6-year cost-saving estimates of feeding high-risk infants with PHF-W versus CMF were USD 739 in Singapore, USD 372 in Malaysia, and USD 237 in the Philippines. PMID- 25925339 TI - The impact of atopic dermatitis on quality of life. AB - Approximately 5-20% of children worldwide suffer from atopic dermatitis (AD), a kind of dermatitis characterized as an inflammatory, relapsing, noncontagious and itchy skin disorder. Children often develop AD during their first year of life. An increased rate of sensitization to both food and aeroallergens has been shown to coexist in patients with AD. Sensitization to well-known allergens such as cow's milk protein can occur on average in 50% of children with AD. In general, quality of life (QoL) is perceived as the quality of an individual's daily life, that is, an assessment of their well-being or lack thereof. QoL is a broad concept that includes such things as standard of living, community, and family life. Patients with skin diseases experience a wide range of symptoms ranging from trivial problems to major handicaps which affect their lives. The misery of living with AD cannot be overstated for it may have a profoundly negative effect on the health-related QoL of children and their families in many cases. Physicians taking care of children with AD should consult parents on how their child's illness has impacted their lifestyle and recommend professional intervention if deemed necessary. PMID- 25925340 TI - Policies and Livestock Systems Driving Brucellosis Re-emergence in Kazakhstan. AB - Brucellosis is a considerable public health and economic burden in many areas of the world including sub-Saharan Africa, the Middle East and former USSR countries. The collapse of the USSR has been cited as a driver for re-emergence of diseases including brucellosis, and human incidence rates in the former Soviet republics have been estimated as high as 88 per 100,000 per year. The aim of this paper is to examine the historical trends in brucellosis in Kazakhstan and to explore how livestock systems, veterinary services and control policies may have influenced them. In conclusion, a brucellosis epidemic most likely began before the collapse of the USSR and high livestock densities may have played an important role. Changes to the livestock systems in Kazakhstan, as well as other factors, are likely to have an impact on the success of brucellosis policies in the future. Incentives and practicalities of different policies in smallholder settings should be considered. However, the lack of reliable estimates of brucellosis prevalence and difficulties in understanding exactly how policy is being applied in Kazakhstan, which is a vast country with low population density, prevent firm conclusions from being drawn. PMID- 25925341 TI - Pocket-sized Ultrasound for Physical Diagnosis. PMID- 25925342 TI - The ACA's 65th Birthday Challenge: Moving from Medicaid to Medicare. AB - The Affordable Care Act (ACA) expanded Medicaid to millions of low-income near elderly Americans, facilitating access to health care services, but did not change income eligibility for Medicaid for those 65 years and older. Therefore, following the ACA's coverage expansion, many newly-insured older enrollees will face a complex insurance transition on their 65th birthday: they will lose Medicaid coverage and transition from Medicaid to Medicare as their primary insurer. This transition in primary health insurance coverage includes changes to benefits, patient cost-sharing, and provider reimbursement, which could have profound consequences on the use of health services and associated health outcomes for low-income seniors. Using data from 2012, we estimate that 1.6 million current Medicaid beneficiaries and an additional 1.6 to 2.9 million low income individuals who will gain Medicaid coverage under the ACA will be likely to make this transition in the next decade. Primary care physicians and policymakers can help mitigate the potential consequences of this insurance transition by preparing patients for Medicare's more restrictive insurance coverage, encouraging patients to sign up for available low-income subsidies, and understanding how the loss of Medicaid coverage impacts out-of-pocket costs. PMID- 25925343 TI - FDG-PET in the Evaluation of Brain Metabolic Changes Induced by Cognitive Stimulation in aMCI Subjects. AB - Cognitive training has reported to improve cognitive performance in Mild Cognitive Impairment (MCI) as well as in older healthy subjects. 18F-FDG-PET is widely used in the diagnoses of dementia for its ability to identify early metabolic changes. This study was aimed to assess the effect of cognitive stimulation on brain metabolic network and clinical cognitive performance. Thirty aMCI subjects were enrolled in the study and allocated in two groups matched for cognitive profile, sex and schooling and then randomly assigned to the training arm or to the placebo arm. All subjects underwent neuropsychological assessment and PET imaging before and after intervention. We found significant association between brain metabolism and cognitive stimulation in treated aMCI subjects. Brain metabolic changes included Brodmann areas reported to be involved in working memory and attentive processes as well as executive functions. Our study shows that metabolic changes occur earlier than possible clinical changes related to the intervention. 18F-FDG-PET could provide a useful biomarker of response to identify a population of aMCI suitable to respond to treatment, according to most recent data on default network mode and its adaptivity to external stimuli. PMID- 25925344 TI - A new phenolic glycoside from Spiraea prunifolia var. simpliciflora twigs. AB - The phytochemical investigation of the methanol extract from the twigs of Spiraea prunifolia var. simpliciflora (Rosaceae) using column chromatography led to the isolation of a new phenol glycoside, 1-O-(E)-caffeoyl-2-O-p-(E)-coumaroyl-beta-D glucopyranose (1), together with 16 known phenolic compounds (2-17). The structure of this new compound was elucidated by analysis of spectroscopic data including 1D, 2D nuclear magnetic resonance and HR-FAB-MS data. The isolated compounds were tested for cytotoxicity against four human tumor cell lines in vitro using the sulforhodamine B bioassay. PMID- 25925345 TI - Live birth rates in the different combinations of the Bologna criteria poor ovarian responders: a validation study. AB - PURPOSE: to compare the baseline characteristics and chance of live birth in the different categories of poor responders identified by the combinations of the Bologna criteria and establish whether these groups comprise a homogenous population. METHODS: database containing clinical and laboratory information on IVF treatment cycles carried out at the Mother-Infant Department of the University Hospital of Modena between year 2007 and 2011 was analysed. This data was collected prospectively and recorded in the registered database of the fertility centre. Eight hundred and thirty women fulfilled the inclusion/ exclusion criteria of the study and 210 women fulfilled the Bologna criteria definition for poor ovarian response (POR). Five categories of poor responders were identified by different combinations of the Bologna criteria. RESULTS: There were no significant differences in female age, AFC, AMH, cycle cancellation rate and number of retrieved oocytes between the five groups. The live birth rate ranged between 5.5 and 7.4 % and was not statistically different in the five different categories of women defined as poor responders according to the Bologna criteria. CONCLUSION: The study demonstrates that the different groups of poor responders based on the Bologna criteria have similar IVF outcomes. This information validates the Bologna criteria definition as women having a uniform poor prognosis and also demonstrates that the Bologna criteria poor responders in the various subgroups represent a homogenous population with similar pre-clinical and clinical outcomes. PMID- 25925346 TI - Prognostic value of growth of 4-cell embryos on the day of transfer in fresh IVF ET cycles. AB - PURPOSE: To investigate the prognostic value of growth of 4-cell embryos on the day of transfer in determining clinical pregnancy and live birth rates after fresh in vitro fertilization (IVF)-embryo transfer (ET) cycles. METHODS: Retrospective cohort study of all patients between January 2008 and January 2013 initiating fresh IVF-ET cycles resulting in embryos that were not more than 4 cells 72 h after oocyte retrieval in the morning of their transfer. Patients were stratified into 2 groups based on whether embryos did or did not grow more than the 4-cell stage on the afternoon of ET. The odds of clinical pregnancy and live birth were considered as primary outcomes. Student's t-tests and Chi-square (chi2) tests were used as indicated, with logistic regression controlling for maternal age and number of embryos transferred. RESULTS: Three hundred forty three patients were identified for inclusion: 165 and 178 patients had 4-cell embryos with and without growth on the afternoon of ET, respectively. The demographic and baseline IVF cycle characteristics of the study cohort were comparable. Patients with embryo growth had higher clinical pregnancy (13.9 % vs. 4.49 %) and live birth (10.9 % vs. 3.37 %) rates compared to patients without embryo growth. This represented an overall increased odds of clinical pregnancy [Odds ratio (OR) = 3.44; 95 % Confidence Intervals (CI) 1.49-7.93; P = 0.004)] and live birth (OR = 3.51; 95 % CI 1.36-9.07; P = 0.01). The increased odds remained unchanged after adjusting for maternal age and number of embryos transferred. CONCLUSIONS: Transfer of 4-cell embryos 3 days after oocyte retrieval can result in clinical pregnancies and live births, albeit at a low rate. Growth of an embryo more than the 4-cell stage on the afternoon of ET may serve as a positive prognostic factor for IVF-ET cycle outcome. PMID- 25925347 TI - Expression of interleukin-22 in decidua of patients with early pregnancy and unexplained recurrent pregnancy loss. AB - PURPOSE: Researchers have hypothesized that an imbalance of immune cells in the uterine decidua and a dysfunction in cytokines they produce may contribute to recurrent pregnancy loss (RPL). The objective of this study was to determine if IL-22, IL-23 and IL-17 are expressed abnormally in the decidua of patients with RPL compared to those women with a normal pregnancy. We also sought to confirm that uterine natural killer (uNK) cells are lower in the decidua of patients with RPL, as well as identify IL-22 expression by uNK cells. METHODS: After meeting strict inclusion criteria, maternal decidua of nine patients with unexplained RPL and a confirmed euploid fetal loss, and 11 gestational age-matched patients undergoing elective pregnancy termination were included in our analysis. Quantitative real time-polymerase chain reaction (qRT-PCR) was performed to quantify RNA expression, Western blot was performed to quantify protein expression and immunohistochemistry (IHC) was performed to identify IL-22 and uNK cells. RESULTS: We found that women with unexplained RPL and a euploid fetal loss had significantly less gene and protein expression of IL-22 in the decidua. Additionally, we found that IL-22 is primarily expressed by uNK cells in the decidua. CONCLUSIONS: In conclusion, our results suggest that lower levels of IL 22 in the uterine decidua in patients with unexplained RPL may contribute to a disruption of decidual homeostasis and ultimately lead to early pregnancy loss. PMID- 25925348 TI - Deposition of the spermatozoon in the human oocyte at ICSI: impact on oocyte survival, fertilization and blastocyst formation. AB - PURPOSE: To evaluate whether the deposition of the spermatozoon in the human oocyte at ICSI has any effect on oocyte survival, fertilization, blastocyst development and quality. METHODS: In a prospective study, including 78 ICSI cycles, sibling oocytes were injected with "no intention" (group A, standard ICSI, n = 393) or "intention" to deposit the spermatozoon under the cortex (group B, n = 354). Outcome parameters were oocyte survival and fertilization, as well as blastocyst formation and quality. RESULTS: Depositing the sperm under the cortex of the oocyte was not always successful for its final position, therefore, group B was divided into three subgroups: B1 successful deposition (119 oocytes, 33.6 % of oocytes in group B); B2 initially successful but spermatozoon spontaneously relocated after 2 min (136 oocytes, 38.4 %); and B3 unsuccessful deposition (99 oocytes, 28.0 %). Group A and B were compared on an intention-to treat basis. Additionally, A, B1, B2 and B3 were also compared. The oocyte survival and fertilization, blastocyst and top-quality blastocyst developmental rates were not significantly different. CONCLUSIONS: The procedure of depositing the spermatozoon intentionally under the oocyte cortex demanded high technical skills. Successful positioning was only obtained in 34 % of the attempts. We obtained no evidence of improved oocyte survival and fertilization, blastocyst formation and quality when the spermatozoon was permanently positioned under the oocyte cortex. Taken together, depositing the spermatozoon under the oocyte cortex is not recommended for routine ICSI application. PMID- 25925349 TI - Androgen receptor (AR) gene CAG trinucleotide repeat length associated with body composition measures in non-syndromic obese, non-obese and Prader-Willi syndrome individuals. AB - PURPOSE: Total body mass impacts reproductive health and infertility which has increased in the United States with rising rates of obesity. Overlapping genetic and environmental factors contribute to obesity and infertility including the androgen receptor (AR), a steroid hormone-activated transcription factor that is key in regulating androgen activity and sensitivity to sex hormones, weight and body composition in both males and females. The AR gene which is X-linked contains a polymorphic CAG trinucleotide repeat which varies in length and inversely correlated with gene expression. METHODS: We examined the AR gene CAG repeat length and measures of weight and body mass index (BMI) in 27 non syndromic obese and 33 lean controls and for the first time compared with 28 individuals with Prader-Willi syndrome (PWS), a rare obesity-related genetic disorder with natural sex hormone deficits to examine the effects of AR gene CAG repeat length on androgen-mediated response and obesity-related factors relevant to human infertility and reproduction. RESULTS: Mean CAG repeat length in base pairs (278 +/- 7.9) did not significantly differ by subject group (F = 2.6, p = 0.08) but was strongly positively correlated with height standard deviation (SD) among males (r = 0.31, p < 0.05), mainly lean and obese, but not PWS (r = 0.02, p = 0.94). A negative correlation was observed for weight SD among females (r = 0.29, p < 0.04) when grouped together. CONCLUSIONS: The results were consistent with an androgen-mediated effect on height and weight negligible in PWS and supporting the role of sex hormones and AR gene interaction in obesity and infertility, both cardinal features of PWS. CAG repeat length of the AR gene is a marker for increased androgen sensitivity with shorter lengths predicting smaller stature in non-PWS adult males possibly due to accelerating fusion of bone growth plates and reducing the growth phase. Increased androgen effects from shorter CAG repeat lengths in non-PWS females could impact pregnancy-related weight gain and pregnancy outcomes. PMID- 25925350 TI - Ratio of progesterone-to-number of follicles as a prognostic tool for in vitro fertilization cycles. AB - PURPOSE: To establish a ratio of the P level to the number of follicles (P/F ratio) on the day of human chorionic gonadotropin (hCG) administration and to evaluate whether this ratio is associated with in vitro fertilization (IVF) outcome. METHODS: This study was conducted between January 2012 and June 2013. A total of 337 patients with cleavage-stage day-3 fresh embryo transfer with P levels <=1.5 ng/mL on the day of hCG administration were included in the study. The main outcome was ongoing pregnancy rate. RESULT(S): The P/F ratio was calculated according to the equation (P[ng/mL]/number of follicles) on the day of final oocyte maturation. Using ROC, we established a cut-off level of 0.075 for the P/F ratio. The area under the curve (AUC) (0.756; 95 % confidence interval [CI]: 0.704-0.807) indicated that it was a good prognostic test. In group 1 (patients under 36 years old), the ongoing pregnancy rates were 57 and 30 % for patients with P/F ratios <= .075 and > .075, respectively, (p = 0.003). In group 2 (patients between 36 and 39 years old), the ongoing pregnancy rates were 58 % and 17 % (p = 0.001) for patients with P/F ratios <= .075 and > .075, respectively. In group 3 (patients >= 40 years old), the ongoing pregnancy rates were 41.7 and 10.9 % (p = 0.001) for patients with P/F ratios <= .075 and > .075, respectively. CONCLUSIONS: The P/F ratio is a good prognostic test for predicting IVF outcome that can correlate the P level with ovarian response. PMID- 25925351 TI - Unaltered timing of embryo development in women with polycystic ovarian syndrome (PCOS): a time-lapse study. AB - PURPOSE: Polycystic ovarian syndrome (PCOS) is a common cause of female infertility. Factors other than anovulation, such as low embryo quality have been suggested to contribute to the infertility in these women. This 2-year retrospective study used timelapse technology to investigate the PCOS-influence on timing of development in the pre-implantation embryo (primary endpoint). The secondary outcome measure was live birth rates after elective single-embryo transfer. METHODS: In total, 313 embryos from 43 PCOS women, and 1075 embryos from 174 non-PCOS women undergoing assisted reproduction were included. All embryos were monitored until day 6. Differences in embryo kinetics were tested in a covariance regression model to account for potential confounding variables: female age, BMI, fertilization method and male infertility. RESULTS: Time to initiate compaction and reach the morula stage as well as the duration of the 4th cleavage division was significantly shorter in PCOS embryos compared with non PCOS embryos. No other kinetic differences were found at any time-points annotated. The proportion of multi-nucleated cells at the 2-cell stage was significantly higher in PCOS embryos compared with non-PCOS embryos. The live birth rates were comparable between the two groups. CONCLUSION: The findings suggest that the causative factor for subfertility in PCOS is not related to timing of development in the pre-implantation embryo. PMID- 25925352 TI - E-selectin, resistin and reactive oxygen species levels in GnRH -agonist and antagonist protocols in IVF/ICSI: a prospective cohort study. AB - PURPOSE: To compare E-selectin, resistin and reactive oxygen species (ROS) levels in serum and follicular fluid (FF) of subfertile women undergoing Controlled Ovarian Hyperstimulation (COH) during IVF/ICSI cycles, using GnRH-agonist and antagonist protocols. METHODS: In this prospective cohort study, 85 subfertile women undergoing IVF/ICSI were included. Participants underwent the GnRH-agonist and -antagonist protocols; and blood samples were collected at three time points: basic (at start of COH), on the day of hCG and at oocyte retrieval (OR); and from the FF from the first follicle aspirate. Clinical and IVF cycle characteristics, were compared between groups, together with the levels of E-selectin, resistin and ROS in serum and FF, through ELISA. Their prognostic value on pregnancy outcomes was examined. RESULT(S): Examining molecules levels are increasing in serum, from start of COH until OR, irrespectively of the protocol used; FF levels at OR were similar to those in serum at that day. Resistin FF levels were lower in GnRH agonists, compared with the antagonist protocol. Resistin levels at start of COH were associated with clinical pregnancy rates, and this remained significant following adjustment for age, BMI and IVF protocol used, while values of >13.5 ng/ml were associated with a six times greater odd of a pregnancy. CONCLUSION: E-selectin, resistin and ROS levels are increasing during COH, reaching their highest values at OR, with comparable values measured in the FF at that time. Resistin values >13.5 ng/ml are linked with a 6-fold increase on the odds of a pregnancy. PMID- 25925353 TI - Principal component analysis-based unsupervised feature extraction applied to in silico drug discovery for posttraumatic stress disorder-mediated heart disease. AB - BACKGROUND: Feature extraction (FE) is difficult, particularly if there are more features than samples, as small sample numbers often result in biased outcomes or overfitting. Furthermore, multiple sample classes often complicate FE because evaluating performance, which is usual in supervised FE, is generally harder than the two-class problem. Developing sample classification independent unsupervised methods would solve many of these problems. RESULTS: Two principal component analysis (PCA)-based FE, specifically, variational Bayes PCA (VBPCA) was extended to perform unsupervised FE, and together with conventional PCA (CPCA)-based unsupervised FE, were tested as sample classification independent unsupervised FE methods. VBPCA- and CPCA-based unsupervised FE both performed well when applied to simulated data, and a posttraumatic stress disorder (PTSD)-mediated heart disease data set that had multiple categorical class observations in mRNA/microRNA expression of stressed mouse heart. A critical set of PTSD miRNAs/mRNAs were identified that show aberrant expression between treatment and control samples, and significant, negative correlation with one another. Moreover, greater stability and biological feasibility than conventional supervised FE was also demonstrated. Based on the results obtained, in silico drug discovery was performed as translational validation of the methods. CONCLUSIONS: Our two proposed unsupervised FE methods (CPCA- and VBPCA-based) worked well on simulated data, and outperformed two conventional supervised FE methods on a real data set. Thus, these two methods have suggested equivalence for FE on categorical multiclass data sets, with potential translational utility for in silico drug discovery. PMID- 25925354 TI - Prognostic value of epicardial fat volume measurements by computed tomography: a systematic review of the literature. AB - OBJECTIVES: To perform a systematic review of the growing body of literature evaluating the prognostic value of epicardial fat volume (EFV) quantified by cross-sectional imaging. METHODS: Two independent reviewers performed systematic searches on both PubMed and Scopus using search terms developed with a medical librarian. Peer-reviewed articles were selected based on the inclusion of outcome data, utilization of epicardial fat volume and sufficient reporting for analysis. RESULTS: A total of 411 studies were evaluated with nine studies meeting the inclusion criteria. In all, the studies evaluated 10,252 patients. All nine studies were based on CT measurements. Seven studies evaluated the prognostic value of EFV unadjusted for calcium score, and six of these studies found a significant association between EFV and clinical outcomes. Seven studies evaluated the incremental value of EFV beyond calcium scoring, and six of these studies found a significant association. CONCLUSIONS: The majority of studies suggest that EFV quantification is significantly associated with clinical outcomes and provides incremental prognostic value over coronary artery calcium scoring. Future research should use a binary cutoff of 125 mL for evaluation of EFV to provide consistency with other research. KEY POINTS: * Epicardial fat volume (EFV) has prognostic value for adverse cardiac events * Establishment of standardized quantitative categories for EFV is needed * Quantification of EFV could improve risk assessment with calcium scoring. PMID- 25925355 TI - Performance of Automated Software in the Assessment of Segmental Left Ventricular Function in Cardiac CT: Comparison with Cardiac Magnetic Resonance. AB - OBJECTIVE: To evaluate the accuracy, reliability and time saving potential of a novel cardiac CT (CCT)-based, automated software for the assessment of segmental left ventricular function compared to visual and manual quantitative assessment of CCT and cardiac magnetic resonance (CMR). METHODS: Forty-seven patients with suspected or known coronary artery disease (CAD) were enrolled in the study. Wall thickening was calculated. Segmental LV wall motion was automatically calculated and shown as a colour-coded polar map. Processing time for each method was recorded. RESULTS: Mean wall thickness in both systolic and diastolic phases on polar map, CCT, and CMR was 9.2 +/- 0.1 mm and 14.9 +/- 0.2 mm, 8.9 +/- 0.1 mm and 14.5 +/- 0.1 mm, 8.3 +/- 0.1 mm and 13.6 +/- 0.1 mm, respectively. Mean wall thickening was 68.4 +/- 1.5 %, 64.8 +/- 1.4 % and 67.1 +/- 1.4 %, respectively. Agreement for the assessment of LV wall motion between CCT, CMR and polar maps was good. Bland-Altman plots and ICC indicated good agreement between CCT, CMR and automated polar maps of the diastolic and systolic segmental wall thickness and thickening. The processing time using polar map was significantly decreased compared with CCT and CMR. CONCLUSION: Automated evaluation of segmental LV function with polar maps provides similar measurements to manual CCT and CMR evaluation, albeit with substantially reduced analysis time. KEY POINTS: * Cardiac computed tomography (CCT) can accurately assess segmental left ventricular wall function. * A novel automated software permits accurate and fast evaluation of wall function. * The software may improve the clinical implementation of segmental functional analysis. PMID- 25925356 TI - FDG-PET/CT and FLT-PET/CT for differentiating between lipid-poor benign and malignant adrenal tumours. AB - OBJECTIVE: To compare F-18-fluorodeoxyglucose (FDG) and F-18-fluorothymidine (FLT) PET/CT examinations for differentiating between benign and malignant adrenal tumours. METHODS: Thirty lipid-poor benign and 11 malignant tumours of 40 patients were included. FDG- and FLT-based indices including visual score, maximum standardized uptake value (SUVmax) and FDG adrenal lesion/liver SUVmax (A/L SUVmax) or FLT adrenal lesion/back muscle SUVmax (A/B SUVmax) ratio were compared between benign and malignant tumours using the Mann-Whitney's U or Wilcoxon signed-rank test, and their diagnostic performances were evaluated by means of the area under the curve (AUC) values derived from the receiver operating characteristic analysis. RESULTS: All indices were significantly higher in malignant than benign tumours on both images (p < 0.05 each). On FDG-PET/CT, the sensitivity, specificity, and accuracy were 91 %, 63 % and 71 % for visual score, 91 %, 67 % and 73 % for SUVmax, and 100 %, 70 % and 78 % for A/L SUVmax ratio, respectively. On FLT-PET/CT, they were 100 %, 97 % and 98 % for visual score, SUVmax and A/B SUVmax ratio, respectively. All FLT indices were significantly higher than those of FDG in AUC (p < 0.05 each). CONCLUSION: FLT PET/CT may be superior to FDG-PET/CT in differentiating lipid-poor benign from malignant adrenal tumours because of higher specificity and accuracy. KEY POINTS: * All FDG indices were significantly higher in malignant than in benign tumours. * All FLT indices were significantly higher in malignant than in benign tumours. * All FLT indices were significantly higher than those of FDG in AUC. PMID- 25925357 TI - Anastomotic leakage after colorectal surgery: diagnostic accuracy of CT. AB - OBJECTIVES: To evaluate the diagnostic accuracy of CT in postoperative colorectal anastomotic leakage (AL). METHODS: Two independent blinded radiologists reviewed 153 CTs performed for suspected AL within 60 days after surgery in 131 consecutive patients, with (n = 58) or without (n = 95) retrograde contrast enema (RCE). Results were compared to original interpretations. The reference standard was reoperation or consensus (a radiologist and a surgeon) regarding clinical, laboratory, radiological, and follow-up data after medical treatment. RESULTS: AL was confirmed in 34/131 patients. For the two reviewers and original interpretation, sensitivity of CT was 82 %, 87 %, and 71 %, respectively; specificity was 84 %, 84 %, and 92 %. RCE significantly increased the positive predictive value (from 40 % to 88 %, P = 0.0009; 41 % to 92 %, P = 0.0016; and 40 % to 100 %, P = 0.0006). Contrast extravasation was the most sensitive (reviewers, 83 % and 83 %) and specific (97 % and 97 %) sign and was significantly associated with AL by univariate analysis (P < 0.0001 and P < 0.0001). By multivariate analysis with recursive partitioning, CT with RCE was accurate to confirm or rule out AL with contrast extravasation. CONCLUSIONS: CT with RCE is accurate for diagnosing postoperative colorectal AL. Contrast extravasation is the most reliable sign. RCE should be performed during CT for suspected AL. KEY POINTS: * CT accurately diagnosed clinically suspected colorectal AL and showed good interobserver agreement * Contrast extravasation was the most sensitive and specific CT sign * Retrograde contrast enema during CT improved positive predictive value * Retrograde contrast enema decreased false negative or indeterminate original CT interpretations. PMID- 25925358 TI - Normal thymus in adults: appearance on CT and associations with age, sex, BMI and smoking. AB - OBJECTIVE: To investigate CT appearance and size of the thymus in association with participant characteristics. MATERIALS AND METHODS: 2540 supposedly healthy participants (mean age 58.9 years, 51 % female) were evaluated for the CT appearance of thymic glands with four-point scores (according to the ratio of fat and soft tissue), size and morphology. These were correlated with participants' age, sex, BMI and smoking history. RESULTS: Of 2540 participants, 1869 (74 %) showed complete fatty replacement of the thymus (Score 0), 463 (18 %) predominantly fatty attenuation (Score 1), 172 (7 %) half fatty and half soft tissue attenuation (Score 2) and 36 (1 %) solid thymic gland with predominantly soft-tissue attenuation (Score 3). Female participants showed less fatty degeneration of the thymus with higher thymic scores within age 40-69 years (P < 0.001). Participants with lower thymic scores showed higher BMI (P < 0.001) and were more likely to be former smokers (P < 0.001) with higher pack-years (P = 0.04). CONCLUSIONS: Visual assessment with four-point thymic scores revealed a sex difference in the fatty degeneration of the thymus with age. Women show significantly higher thymic scores, suggesting less fat content of the thymus, during age 40-69 years. Cigarette smoking and high BMI are associated with advanced fatty replacement of the thymus. KEY POINTS: 74% of participants (mean age 58.9 years) demonstrated complete fatty thymus. Women show less fatty thymus compared to men at ages 40-69 years. Smoking and high BMI are associated with advanced fatty degeneration in thymus. PMID- 25925359 TI - Improvement of the accuracy of liver lesion DCEUS quantification with the use of automatic respiratory gating. AB - OBJECTIVES: To evaluate the efficiency of automatic respiratory gating (ARG) in reducing respiratory motion-induced artefacts from dynamic contrast-enhanced ultrasound (DCEUS) acquisitions and to assess the impact of ARG on DCEUS quantification parameters in patients with liver malignancies. METHODS: Twenty five patients with liver metastasis were imaged with DCEUS. The lognormal indicator dilution model was fitted on time-intensity curves extracted from hepatic lesions with and without the use of ARG and DCEUS quantification parameters were extracted. The goodness of fit was assessed using the coefficient of determination (R (2) LN ). The effect respiration had on the data was assessed using the respiration amplitude (RA) metric. Pearson's correlation coefficient (r) was used to assess the correlation between R (2) LN and RA with and without the use of ARG. RESULTS: The RA parameter was strongly correlated with R (2) LN (r = -0.96, P = 7.412 * 10(-15)) and this correlation became weaker with ARG (r = -0.64, P = 5.449 * 10(-4)). ARG significantly influenced the values of the quantification parameters extracted (P <= 0.05). The RA was significantly decreased when ARG was used (P = 1.172 * 10(-6)). CONCLUSIONS: ARG has a significant impact on the quantification parameters extracted and it has been shown to improve the accuracy of liver lesion DCEUS. KEY POINTS: * ARG has a significant impact on DCEUS quantification parameters. * ARG can improve the modelling of liver lesion haemodynamics using DCEUS quantification. * ARG significantly reduces the respiration amplitude of DCEUS lesion time-intensity curves. PMID- 25925360 TI - CT perfusion assessment of Moyamoya syndrome before and after direct revascularization (superficial temporal artery to middle cerebral artery bypass). AB - PURPOSE: To evaluate the utility of CT perfusion (CTP) for the assessment of superficial temporal artery-middle cerebral artery (STA-MCA) anastomosis in patients with Moyamoya syndrome (MMS). SUBJECTS AND METHODS: Twenty-four consecutive MMS patients, who underwent unilateral STA-MCA bypass surgery, received CTP before and after surgery. The relative perfusion parameter values of surgical hemispheres before treatment were compared with post-treatment values. All patients underwent CT angiography (CTA) before and after surgery in order to confirm the patency of bypass. RESULTS: The follow-up CTA after surgery clearly demonstrated 20 (20/24, 83.3 %) bypass arteries, whereas four (16.7 %) bypass arteries were occluded or very small. Postoperative rMTT and rTTP values (P < 0.05) of the surgical side were significantly lower than pre-operation. In patients (n = 20) with bypass patency, postoperative rCBF, rMTT and rTTP values (P < 0.05) of the surgical side were significantly improved. However, the differences of all parameters were not significant (P > 0.05) in the patients (n = 4) without bypass patency after revascularization. CONCLUSION: This study demonstrates that CTP can provide a crucial quantitative assessment of cerebral haemodynamic changes in MMS before and after STA-MCA anastomosis. KEY POINTS: Twenty-four MMS patients undergoing STA-MCA bypass received CTP pre- and post surgery. Cerebral haemodynamics improved on the surgical side post-surgery on CTP maps. rCBF might have a better correlation with patency of the bypass artery. CTP can evaluate cerebral perfusion changes in MMS patients after cerebral revascularization. PMID- 25925361 TI - Molecular MRI differentiation between primary central nervous system lymphomas and high-grade gliomas using endogenous protein-based amide proton transfer MR imaging at 3 Tesla. AB - OBJECTIVES: To show the ability of using the amide proton transfer-weighted (APTW) MRI signals as imaging biomarkers to differentiate primary central nervous system lymphomas (PCNSLs) from high-grade gliomas (HGGs). METHODS: Eleven patients with lymphomas and 21 patients with HGGs were examined. Magnetization transfer (MT) spectra over an offset range of +/- 6 ppm and the conventional MT ratio (MTR) at 15.6 ppm were acquired. The APTW signals, total chemical-exchange saturation-transfer signal (integral between 0 and 5 ppm, CEST total), and MTR signal were obtained and compared between PCNSLs and HGGs. The diagnostic performance was assessed with the receiver operating characteristic (ROC) curve analysis. RESULTS: The PCNSLs usually showed more homogeneous APTW hyperintensity (spatially compared to normal brain tissue) than the HGGs. The APTW max, APTW max min and CEST total signal intensities were significantly lower (P < 0.05, 0.001 and 0.05, respectively), while the APTW min and MTR were significantly higher (both P < 0.01) in PCNSL lesions than in HGG lesions. The APTW values in peritumoral oedema were significantly lower for PCNSLs than for HGGs (P < 0.01). APTW max-min had the highest area under the ROC curve (0.963) and accuracy (94.1 %) in differentiating PCNSLs from HGGs. CONCLUSIONS: The protein-based APTW signal would be a valuable MRI biomarker by which to identify PCNSLs and HGGs presurgically. KEY POINTS: PCNSLs overall showed more homogeneous APTW hyperintensity than HGGs. Maximum APTW signals were lower in PCNSL lesions than in HGG lesions. MTR signals were higher in PCNSLs than in HGGs. APTW heterogeneity had the highest accuracy in differentiating PCNSLs from HGGs. PMID- 25925367 TI - Crystalline Cyclic (Alkyl)(amino)carbene-tetrafluoropyridyl Radical. AB - A stable cyclic (alkyl)(amino)carbene (CAAC) 1 inserts into the para-CF bond of pentafluoropyridine, and after fluoride abstraction, the iminium-pyridyl adduct [3](+) was isolated. A cyclic voltammetry study shows a reversible three-state redox system involving [3](+) , [3](?) , and [3](-) . The CAAC-pyridyl radical [3](?) , obtained by reduction of [3](+) with magnesium, has been spectroscopically and crystallographically characterized. In contrast to the lack of pi communication between the CAAC and the pyridine units in cation [3](+) , the unpaired electron of [3](?) is delocalized over an extended pi system involving both heterocycles. PMID- 25925366 TI - Cystic Fibrosis from Laboratory to Bedside: The Role of A20 in NF-kappaB-Mediated Inflammation. AB - Cystic fibrosis (CF) is a lifelong, inflammatory multi-organ disease and the most common lethal, genetic condition in Caucasian populations, with a median survival rate of 41.5 years. Pulmonary disease, characterized by infective exacerbations, bronchiectasis and increasing airway insufficiency is the most serious manifestation of this disease process, currently responsible for over 80% of CF deaths. Chronic dysregulation of the innate immune and host inflammatory response has been proposed as a mechanism central to this genetic condition, primarily driven by the nuclear factor kappaB (NF-kappaB) pathway. Chronic activation of this transcription factor complex leads to the production of pro-inflammatory cytokines and mediators such as IL-6, IL-8 and TNF-alpha. A20 has been described as a central and inducible negative regulator of NF-kappaB. This intracellular molecule negatively regulates NF-kappaB-driven pro-inflammatory signalling upon toll-like receptor activation at the level of TRAF6 activation. Silencing of A20 increases cellular levels of p65 and induces a pro-inflammatory state. We have previously shown that A20 expression positively correlates with lung function (FEV1%) in CF. Despite improvement in survival rates in recent years, advancements in available therapies have been incremental. We demonstrate that the experimental use of naturally occurring plant diterpenes such as gibberellin on lipopolysaccharide-stimulated cell lines reduces IL-8 release in an A20 dependent manner. We discuss how the use of a novel bio-informatics gene expression connectivity-mapping technique to identify small molecule compounds that similarly mimic the action of A20 may lead to the development of new therapeutic approaches capable of reducing chronic airway inflammation in CF. PMID- 25925368 TI - Automatic representation of a visual stimulus relative to a background in the right precuneus. AB - Our brains represent the position of a visual stimulus egocentrically, in either retinal or craniotopic coordinates. In addition, recent behavioral studies have shown that the stimulus position is automatically represented allocentrically relative to a large frame in the background. Here, we investigated neural correlates of the 'background coordinate' using an fMRI adaptation technique. A red dot was presented at different locations on a screen, in combination with a rectangular frame that was also presented at different locations, while the participants looked at a fixation cross. When the red dot was presented repeatedly at the same location relative to the rectangular frame, the fMRI signals significantly decreased in the right precuneus. No adaptation was observed after repeated presentations relative to a small, but salient, landmark. These results suggest that the background coordinate is implemented in the right precuneus. PMID- 25925369 TI - Bone geometry of the hip is associated with obesity and early structural damage- a 3.0 T magnetic resonance imaging study of community-based adults. AB - INTRODUCTION: The mechanism by which obesity increases the risk of hip osteoarthritis is unclear. One possibility may be by mediating abnormalities in bony geometry, which may in turn be associated with early structural abnormalities, such as cartilage defects and bone marrow lesions. METHODS: One hundred and forty one older adults with no diagnosed hip osteoarthritis had weight and body mass index measured between 1990 and 1994 and again in 2009 to 2010. Acetabular depth and lateral centre edge angle, both measures of acetabular over-coverage, as well as femoral head cartilage volume, cartilage defects and bone marrow lesions were assessed with 3.0 T magnetic resonance imaging performed in 2009 to 2010. RESULTS: Current body mass index, weight and weight gain were associated with increased acetabular depth and lateral centre edge angle (all P <= 0.01). For every 1 mm increase in acetabular depth, femoral head cartilage volume reduced by 59 mm(3) (95% confidence interval (CI) 20 mm(3) to 98 mm(3), P < 0.01). Greater acetabular depth was associated with an increased risk of cartilage defects (odds ratio (OR) 1.22, 95% CI 1.03 to 1.44, P = 0.02) and bone marrow lesions (OR 1.29, 95% CI 1.01 to 1.64, P = 0.04) in the central region of the femoral head. Lateral centre edge angle was not associated with hip structure. CONCLUSIONS: Obesity is associated with acetabular over-coverage. Increased acetabular depth, but not the lateral centre edge angle, is associated with reduced femoral head cartilage volume and an increased risk of cartilage defects and bone marrow lesions. Minimising any deepening of the acetabulum (for example, through weight management) might help to reduce the incidence of hip osteoarthritis. PMID- 25925370 TI - Plasma resistant atypical hemolytic uremic syndrome associated with a CFH mutation treated with eculizumab: a case report. AB - INTRODUCTION: Thrombotic microangiopathies are a group of diseases presenting as microangiopathic hemolytic anemia, thrombocytopenia and end-organ dysfunction. As the role of the complement system was elucidated in atypical hemolytic uremic syndrome pathogenesis, eculizumab was successfully introduced into clinical practice. We present a large pedigree with multiple individuals carrying a functionally significant novel factor H mutation. We describe the proband's presentation following a presumed infectious trigger requiring plasma exchange and hemodialysis. CASE PRESENTATION: A 32-year-old Caucasian woman presented with pyrexia and headache lasting one week to our Emergency Department. She gave no history of diarrhea or other symptoms to account for her high temperature. She was not taking any medication. She was pyrexial (38 degrees C), tachycardic (110 bpm) and hypertensive (160/110 mmHg). Her fundoscopy revealed grade IV hypertensive retinopathy. She had mild pretibial and periorbital edema, with oliguria (450 mL/day). She had a pregnancy one year previously, during which she had hypertension, proteinuria and edema, with successful delivery at term. Her mother had died in her early 30s with a clinical picture consistent with thrombotic microangiopathy. Her laboratory evaluation showed microangiopathic hemolytic anemia. After 22 sessions of plasma exchange, her lactate dehydrogenase levels started to climb. As a result, she was classified as plasma resistant and eculizumab therapy was instituted. Her lactate dehydrogenase level and platelet count normalized, and her renal function recovered after three months of dialysis. CONCLUSIONS: We demonstrate that, even in patients with atypical hemolytic uremic syndrome and prolonged dialysis dependence, recovery of renal function can be seen with eculizumab treatment. We suggest a treatment regime of at least three months prior to evaluation of efficacy. PMID- 25925371 TI - Effects of JWA, XRCC1 and BRCA1 mRNA expression on molecular staging for personalized therapy in patients with advanced esophageal squamous cell carcinoma. AB - BACKGROUND: DNA damage repair genes JWA, XRCC1 and BRCA1 were associated with clinical outcomes and could convert the response to the cisplatin-based therapy in some carcinomas. The synergistic effects of JWA, XRCC1 and BRCA1 mRNA expression on personalized therapy remain unknown in advanced esophageal squamous cell carcinoma (ESCC). METHODS: We employed quantitative real-time polymerase chain reaction (qPCR) to determine the expression of JWA, XRCC1 and BRCA1 mRNA in paraffin-embedded specimen from 172 patients with advanced ESCC who underwent the first-line cisplatin-or docetaxel-based treatments. RESULTS: High JWA or XRCC1mRNA expression was correlated with longer median overall survival (mOS) in all the patients (both P<0.001) or in subgroups with different regimens (all P<0.05), but not correlated with response rate (RR, all P>0.05). Multivariate analysis revealed that high JWA (HR 0.22; 95% CI 0.13-0.37; P<0.001) or XRCC1 (HR 0.36; 95% CI 0.21-0.63; P<0.001) mRNA expression emerged as the independent prognostic factors for ESCC patients in this cohort. But no significant difference in prognostic efficacy was found between JWA plus XRCC1 and JWA alone through ROC analysis. Further subgroup analysis showed cisplatin-based treatments could improve mOS of patients with low JWA expression (P<0.05), especially in those with low BRCA1 expression simultaneously (P<0.001); while in patients with high JWA expression, high BRCA1 mRNA expression was correlated with increased mOS in docetaxel-based treatments (P=0.044). CONCLUSION: JWA, XRCC1and BRCA1 mRNA expression could be used as predictive markers in molecular staging for personalized therapy in patients with advanced ESCC who received first-line cisplatin- or docetaxel-based treatments. PMID- 25925373 TI - Different Impacts of Time From Collapse to First Cardiopulmonary Resuscitation on Outcomes After Witnessed Out-of-Hospital Cardiac Arrest in Adults. AB - BACKGROUND: It is well known that cardiopulmonary resuscitation (CPR) should be attempted as early as possible after out-of-hospital cardiac arrest (OHCA). However, it is unclear about the impact of time to CPR on OHCA outcome by first documented rhythm (pulseless ventricular tachycardia/ventricular fibrillation [pVT/VF], pulseless electric activity [PEA], and asystole). METHODS AND RESULTS: We enrolled 257,354 adult witnessed OHCA patients between 2007 and 2012 from a prospective nationwide population-based cohort database in Japan. We evaluated relationships between time from collapse to first CPR and neurologically favorable 1-month survival defined as Glasgow-Pittsburg cerebral performance category 1 or 2 by first documented rhythm after witnessed OHCA. We used logistic model for the estimation of prognosis. The number of OHCA patients with pVT/VF, PEA, and asystole were 38,661, 96,906, and 121,787, respectively. The overall neurologically favorable 1-month survival rates were 21.3% in patients with pVT/VF, 2.7% PEA, and 0.6% asystole. The proportion of asystole increased as the time from collapse to CPR delayed, whereas those of pVT/VF and PEA decreased (trend P<0.001). Estimated incidences of end-point after OHCA became lower as first CPR delayed irrespective of type of first documented rhythm, but were different by the rhythm. The average percentage point decreases in neurologically favorable 1-month survival probability for each incremental minute of CPR delay were 8.3%, 4.4%, and 6.4% for patients with pVT/VF, PEA, and asystole, respectively. CONCLUSIONS: The OHCA outcome differed by time to first CPR and first documented rhythm. Shortening of time to first CPR is crucial for improving the OHCA outcome. PMID- 25925372 TI - Incidence and predictors of cognitive decline in patients with left ventricular assist devices. AB - BACKGROUND: After left ventricular assist device (LVAD) placement for advanced heart failure, increased cerebral perfusion should result in improved cognitive function. However, stroke (a well-known LVAD complication) and subclinical cerebral ischemia may result in transient or permanent cognitive decline. We sought to describe the incidence and predictors of cognitive decline after LVAD using a valid, sensitive assessment tool. METHODS AND RESULTS: Among 4419 patients in the Interagency Registry for Mechanically Assisted Circulatory Support who underwent LVAD implantation between May 2012 and December 2013, cognitive function was assessed in 1173 patients with the Trail Making B Test before LVAD and at 3, 6, and 12 months. The test detects several forms of cognitive impairment, including subclinical stroke. Cognitive decline was defined as a clinically important increase during follow-up using a moderate Cohen d effect size of 0.5*baseline SD (32 s). The cumulative incidence of cognitive decline in the year after LVAD implantation, treating death and transplantation as competing risks, was 29.2%. In adjusted analysis, older age (>=70 versus <50 years; hazard ratio, 2.24; 95% confidence interval 1.46-3.44; P(trend)<0.001) and destination therapy (hazard ratio, 1.42; 95% confidence interval, 1.05-1.92) were significantly associated with greater risk of cognitive decline. CONCLUSIONS: Cognitive decline occurs commonly in patients in the year after LVAD and is associated with older age and destination therapy. These results could have important implications for patient selection and improved communication of risks before LVAD implantation. Additional studies are needed to explore the association between cognitive decline and subsequent stroke, health status, and mortality in patients after LVAD. PMID- 25925374 TI - Exuberant squamous metaplasia of the gastric mucosa in a patient with gastric adenocarcinoma. AB - BACKGROUND: The presence of squamous epithelium in the stomach is only occasionally encountered and is associated with prolonged mucosal injury. Squamous metaplasia in patients with cancer is relatively rare and only four cases have been reported in the stomach, all of which have been associated with squamous cell carcinomas. We present the first case of exuberant squamous metaplasia in a patient with gastric adenocarcinoma of the cardia. CASE PRESENTATION: A 56-year-old woman presented with epigastric pain and weight loss. Endoscopy showed an irregular depressed hyperemic lesion covered with a whitish plaque on the cardia. A total gastrectomy was performed and the tumor in the subcardia was found to extend up to the proximal stomach with diffuse squamous metaplasia in the surface of the tumor and proximal gastric mucosa in contiguity with the esophageal squamous epithelium. It is believed that the squamous extension from the esophagus to the proximal stomach and the gastric adenocarcinoma occurred at the same time. CONCLUSIONS: Synchronous squamous metaplasia and underlying adenocarcinoma in the stomach is extremely rare. Recognition of this entity would be beneficial for clinicians to avoid unnecessary treatment. VIRTUAL SLIDES: The virtual slide(s) for this article can be found here: http://www.diagnosticpathology.diagnomx.eu/vs/1035146445160150 . PMID- 25925375 TI - The Catalytic Subunit of DNA-Dependent Protein Kinase Coordinates with Polo-Like Kinase 1 to Facilitate Mitotic Entry. AB - DNA-dependent protein kinase catalytic subunit (DNA-PKcs) is the key regulator of the non-homologous end joining pathway of DNA double-strand break repair. We have previously reported that DNA-PKcs is required for maintaining chromosomal stability and mitosis progression. Our further investigations reveal that deficiency in DNA-PKcs activity caused a delay in mitotic entry due to dysregulation of cyclin-dependent kinase 1 (Cdk1), the key driving force for cell cycle progression through G2/M transition. Timely activation of Cdk1 requires polo-like kinase 1 (Plk1), which affects modulators of Cdk1. We found that DNA PKcs physically interacts with Plk1 and could facilitate Plk1 activation both in vitro and in vivo. Further, DNA-PKcs-deficient cells are highly sensitive to Plk1 inhibitor BI2536, suggesting that the coordination between DNA-PKcs and Plk1 is not only crucial to ensure normal cell cycle progression through G2/M phases but also required for cellular resistance to mitotic stress. On the basis of the current study, it is predictable that combined inhibition of DNA-PKcs and Plk1 can be employed in cancer therapy strategy for synthetic lethality. PMID- 25925376 TI - The Differential Effects of Anti-Diabetic Thiazolidinedione on Prostate Cancer Progression Are Linked to the TR4 Nuclear Receptor Expression Status. AB - The insulin sensitizers, thiazolidinediones (TZDs), have been used as anti diabetic drugs since the discovery of their ability to alter insulin resistance through transactivation of peroxisome proliferator-activated receptors (PPARs). However, their side effects in hepatitis, cardiovascular diseases, and bladder cancer resulted in some selling restrictions in the USA and Europe. Here, we found that the potential impact of TZDs on the prostate cancer (PCa) progression might be linked to the TR4 nuclear receptor expression. Clinical surveys found that 9% of PCa patients had one allele TR4 deletion in their tumors. TZD increased cell growth and invasion in PCa cells when TR4 was knocked down. In contrast, TZD decreased PCa progression in PCa cells with wild type TR4. Mechanism dissection found that the Harvey Rat Sarcoma (HRAS) oncogene increased on TZD treatment of the TR4 knocked-down CWR22Rv1 and C4-2 cells, and interruption with HRAS inhibitor resulted in reversal of TZD-induced PCa progression. Together, these results suggest that TZD treatment may promote PCa progression depending on the TR4 expression status that may be clinically relevant since extra caution may be needed for those diabetic PCa patients receiving TZD treatment who have one allele TR4 deletion. PMID- 25925377 TI - Widespread Non-Canonical Epigenetic Modifications in MMTV-NeuT Breast Cancer. AB - Breast tumors in (FVB * BALB-NeuT) F1 mice have characteristic loss of chromosome 4 and sporadic loss or gain of other chromosomes. We employed the Illumina GoldenGate genotyping platform to quantitate loss of heterozygosity (LOH) across the genome of primary tumors, revealing strong biases favoring chromosome 4 alleles from the FVB parent. While allelic bias was not observed on other chromosomes, many tumors showed concerted LOH (C-LOH) of all alleles of one or the other parent on sporadic chromosomes, a pattern consistent with cytogenetic observations. Surprisingly, comparison of LOH in tumor samples relative to normal unaffected tissues from these animals revealed significant variegated (stochastic) deviations from heterozygosity (V-LOH) in every tumor genome. Sequence analysis showed expected changes in the allelic frequency of single nucleotide polymorphisms (SNPs) in cases of C-LOH. However, no evidence of LOH due to mutations, small deletions, or gene conversion at the affected SNPs or surrounding DNA was found at loci with V-LOH. Postulating an epigenetic mechanism contributing to V-LOH, we tested whether methylation of template DNA impacts allele detection efficiency using synthetic oligonucleotide templates in an assay mimicking the GoldenGate genotyping format. Methylated templates were systematically over-scored, suggesting that the observed patterns of V-LOH may represent extensive epigenetic DNA modifications across the tumor genomes. As most of the SNPs queried do not contain standard (CpG) methylation targets, we propose that widespread, non-canonical DNA modifications occur during Her2/neuT driven tumorigenesis. PMID- 25925378 TI - IGF-1R Inhibition Activates a YES/SFK Bypass Resistance Pathway: Rational Basis for Co-Targeting IGF-1R and Yes/SFK Kinase in Rhabdomyosarcoma. AB - The insulin-like growth factor 1 receptor (IGF-1R) has surfaced as a significant target in multiple solid cancers due to its fundamental roles in pro-survival and anti-apoptotic signaling. However, development of resistance to IGF-1R blockade represents a significant hindrance and limits treatment efficacy in the clinic. In this study, we identified acquired resistance to IGF-1R blockade with R1507, an antibody against IGF-1R, and with BMS-754807, a small molecular inhibitor of IGF-1R/insulin receptor (IR). We showed that treatment with an IGF-IR antibody, R1507, or an IR/IGF-IR kinase inhibitor, BMS-754807, was associated with increased activation of YES/SRC family tyrosine kinase (SFK) in rhabdomyosarcoma (RMS). Combining anti-IGF-1R agents with SFK inhibitors resulted in blockade of IGF-1R inhibition-induced activation of YES/SFK and displayed advantageous antitumor activity in vitro and in vivo. Our data provide evidence that IGF-1R blockade results in activation of the YES/SRC family kinase bypass resistance pathway in vitro and in vivo. This may be of particular clinical relevance since both Yes and IGF components are overexpressed in RMS. Increased YES/SFK activation might serve as a clinical biomarker for predicting tumor resistance to IGF-1R inhibition. Dual inhibition of IGF-1R and SFK may have a broader and enhanced clinical benefit for patients with RMS. PMID- 25925379 TI - Dysregulation of AKT Pathway by SMYD2-Mediated Lysine Methylation on PTEN. AB - Phosphatase and tensin homologue (PTEN), one of the well-characterized tumor suppressor proteins, counteracts the phosphatidylinositol 3-kinase-AKT pathway through its unique lipid phosphatase activity. The functions of PTEN are regulated by a variety of posttranslational modifications such as acetylation, oxidation, ubiquitylation, phosphorylation, and SUMOylation. However, methylation of PTEN has not been reported so far. In this study, we demonstrated that the oncogenic protein lysine methyltransferase SET and MYND domain containing 2 (SMYD2) methylates PTEN at lysine 313 in vitro and in vivo. Knockdown of SMYD2 suppressed the cell growth of breast cancer cells and attenuated phosphorylation levels of AKT, indicating that SMYD2-mediated methylation negatively regulates PTEN tumor suppressor activity and results in activation of the phosphatidylinositol 3-kinase-AKT pathway. Furthermore, PTEN protein with lysine 313 substitution diminished phosphorylation of PTEN at serine 380, which is known to inactivate tumor suppressor functions of PTEN. Taken together, our findings unveil a novel mechanism of PTEN dysregulation regulated by lysine methylation in human cancer. PMID- 25925380 TI - Macrophage Ablation Reduces M2-Like Populations and Jeopardizes Tumor Growth in a MAFIA-Based Glioma Model. AB - Monocytes/macrophages are an influential component of the glioma microenvironment. However, understanding their diversity and plasticity constitute one of the most challenging areas of research due to the paucity of models to study these cells' inherent complexity. Herein, we analyzed the role of monocytes/macrophages in glioma growth by using a transgenic model that allows for conditional ablation of this cell population. We modeled glioma using intracranial GL261-bearing CSF-1R-GFP(+) macrophage Fas-induced apoptosis (MAFIA) transgenic mice. Conditional macrophage ablation was achieved by exposure to the dimerizer AP20187. Double immunofluorescence was used to characterize M1- and M2 like monocytes/macrophages during tumor growth and after conditional ablation. During glioma growth, the monocyte/macrophage population consisted predominantly of M2 macrophages. Conditional temporal depletion of macrophages reduced the number of GFP(+) cells, targeting mainly the repopulation of M2-polarized cells, and altered the appearance of M1-like monocytes/macrophages, which suggested a shift in the M1/M2 macrophage balance. Of interest, compared with control-treated mice, macrophage-depleted mice had a lower tumor mitotic index, microvascular density, and reduced tumor growth. These results demonstrated the possibility of studying in vivo the role and phenotype of macrophages in gliomas and suggested that transitory depletion of CSF-1R(+) population influences the reconstitutive phenotypic pool of these cells, ultimately suppressing tumor growth. The MAFIA model provides a much needed advance in defining the role of macrophages in gliomas. PMID- 25925381 TI - Development and validation of a scalable next-generation sequencing system for assessing relevant somatic variants in solid tumors. AB - Next-generation sequencing (NGS) has enabled genome-wide personalized oncology efforts at centers and companies with the specialty expertise and infrastructure required to identify and prioritize actionable variants. Such approaches are not scalable, preventing widespread adoption. Likewise, most targeted NGS approaches fail to assess key relevant genomic alteration classes. To address these challenges, we predefined the catalog of relevant solid tumor somatic genome variants (gain-of-function or loss-of-function mutations, high-level copy number alterations, and gene fusions) through comprehensive bioinformatics analysis of >700,000 samples. To detect these variants, we developed the Oncomine Comprehensive Panel (OCP), an integrative NGS-based assay [compatible with <20 ng of DNA/RNA from formalin-fixed paraffin-embedded (FFPE) tissues], coupled with an informatics pipeline to specifically identify relevant predefined variants and created a knowledge base of related potential treatments, current practice guidelines, and open clinical trials. We validated OCP using molecular standards and more than 300 FFPE tumor samples, achieving >95% accuracy for KRAS, epidermal growth factor receptor, and BRAF mutation detection as well as for ALK and TMPRSS2:ERG gene fusions. Associating positive variants with potential targeted treatments demonstrated that 6% to 42% of profiled samples (depending on cancer type) harbored alterations beyond routine molecular testing that were associated with approved or guideline-referenced therapies. As a translational research tool, OCP identified adaptive CTNNB1 amplifications/mutations in treated prostate cancers. Through predefining somatic variants in solid tumors and compiling associated potential treatment strategies, OCP represents a simplified, broadly applicable targeted NGS system with the potential to advance precision oncology efforts. PMID- 25925383 TI - Quantum dot assisted tracking of the intracellular protein Cyclin E in Xenopus laevis embryos. AB - BACKGROUND: Luminescent semiconductor nanocrystals, also known as quantum dots (QD), possess highly desirable optical properties that account for development of a variety of exciting biomedical techniques. These properties include long-term stability, brightness, narrow emission spectra, size tunable properties and resistance to photobleaching. QD have many promising applications in biology and the list is constantly growing. These applications include DNA or protein tagging for in vitro assays, deep-tissue imaging, fluorescence resonance energy transfer (FRET), and studying dynamics of cell surface receptors, among others. Here we explored the potential of QD-mediated labeling for the purpose of tracking an intracellular protein inside live cells. RESULTS: We manufactured dihydrolipoic acid (DHLA)-capped CdSe-ZnS core-shell QD, not available commercially, and coupled them to the cell cycle regulatory protein Cyclin E. We then utilized the QD fluorescence capabilities for visualization of Cyclin E trafficking within cells of Xenopus laevis embryos in real time. CONCLUSIONS: These studies provide "proof-of-concept" for this approach by tracking QD-tagged Cyclin E within cells of developing embryos, before and during an important developmental period, the midblastula transition. Importantly, we show that the attachment of QD to Cyclin E did not disrupt its proper intracellular distribution prior to and during the midblastula transition. The fate of the QD after cyclin E degradation following the midblastula transition remains unknown. PMID- 25925384 TI - Knowledge translation tool to improve pregnant women's awareness of gestational weight gain goals and risks of gaining outside recommendations: a non-randomized intervention study. AB - BACKGROUND: There is an urgent need to prevent excessive pregnancy weight gain, a contributor to both maternal and child obesity. However, the majority of women had reported not being counseled to gain an appropriate amount of gestational weight by their health care providers. We developed a knowledge translation (KT) tool designed to facilitate the clinical interaction between pregnant women and their health care providers (HCPs). We piloted the tool on the impact on women's knowledge of gestational weight gain (GWG) goals, and evaluated its potential in promoting appropriate knowledge about GWG within the 2009 Institute of Medicine guidelines. METHODS: We conducted a prospective cohort study, comparing women's knowledge about GWG after the KT tool to women from the same clinics and care providers the year prior. Our primary outcome was the proportion of women who reported receiving an appropriate GWG recommendation from their care provider. We evaluated knowledge on a survey conducted at enrollment in the cohort at <= 20 weeks gestation and evaluated participant satisfaction with the KT tool in the third trimester. We performed univariate and multivariable logistic regression analyses for differences in outcomes with historical controls from the same clinics. Our a priori sample size calculation required 130 participants to demonstrate a 15% increase in reported counseling about gestational weight gain. RESULTS: One hundred and forty-six women were recruited and 131 (90%) completed the enrollment survey. Women who received the KT tool were more likely to report receiving a specific GWG recommendation from their HCP (adjusted odds ratio [AOR] 3.45, 95% confidence interval [CI] 2.22-5.37) and discussing GWG topics with their HCP (AOR 7.96, 95% CI 4.41-14.37), and believing that there were risks to their infants with inadequate GWG (AOR 2.48, 95% CI 1.14-5.37). Half of women (49.5%) indicated that they would recommend the tool to a friend. CONCLUSIONS: Women who received the KT tool reported receiving more counseling on GWG from their HCPs and were more aware of the risks of gaining outside appropriate GWG recommendations. The association between GWG education and GWG requires further research. PMID- 25925382 TI - Updates in the perioperative and emergency management of non-vitamin K antagonist oral anticoagulants. AB - Perioperative management of patients treated with the non-vitamin K antagonist oral anticoagulants is an ongoing challenge. Due to the lack of good clinical studies involving adequate monitoring and reversal therapies, management requires knowledge and understanding of pharmacokinetics, renal function, drug interactions, and evaluation of the surgical bleeding risk. Consideration of the benefit of reversal of anticoagulation is important and, for some low risk bleeding procedures, it may be in the patient's interest to continue anticoagulation. In case of major intra-operative bleeding in patients likely to have therapeutic or supra-therapeutic levels of anticoagulation, specific reversal agents/antidotes would be of value but are currently lacking. As a consequence, a multimodal approach should be taken which includes the administration of 25 to 50 U/kg 4-factor prothrombin complex concentrates or 30 to 50 U/kg activated prothrombin complex concentrate (FEIBA(r)) in some life threatening situations. Finally, further studies are needed to clarify the ideal therapeutic intervention. PMID- 25925385 TI - Crystal structures reveal transient PERK luminal domain tetramerization in endoplasmic reticulum stress signaling. AB - Stress caused by accumulation of misfolded proteins within the endoplasmic reticulum (ER) elicits a cellular unfolded protein response (UPR) aimed at maintaining protein-folding capacity. PERK, a key upstream component, recognizes ER stress via its luminal sensor/transducer domain, but the molecular events that lead to UPR activation remain unclear. Here, we describe the crystal structures of mammalian PERK luminal domains captured in dimeric state as well as in a novel tetrameric state. Small angle X-ray scattering analysis (SAXS) supports the existence of both crystal structures also in solution. The salient feature of the tetramer interface, a helix swapped between dimers, implies transient association. Moreover, interface mutations that disrupt tetramer formation in vitro reduce phosphorylation of PERK and its target eIF2alpha in cells. These results suggest that transient conversion from dimeric to tetrameric state may be a key regulatory step in UPR activation. PMID- 25925387 TI - What are hospital nurses' strengths and weaknesses in patient safety competence? Findings from three Korean hospitals. AB - OBJECTIVE: To examine hospital nurses' patient safety competencies and the association between these competencies and safety climate. DESIGN: Cross sectional questionnaire survey. SETTING: Three teaching hospitals in Seoul, Korea. PARTICIPANTS: In total, 459 nurses from general adult nursing care units, intensive care units or operating rooms (response rate = 87.4%). METHOD: Self administered questionnaires were distributed to measure patient safety competency. Multiple regression analyses were performed to examine relationships between patient safety competency and safety climate. MAIN OUTCOME MEASURE S: Patient safety competency scores ('teamwork', 'communication', 'managing safety risks', 'human and environmental factors', 'adverse event recognition' and 'safety culture' dimensions) and perceived safety climate. RESULTS: The mean patient safety competency score was 3.3 (SD = 0.4) out of 5.0; 396 nurses (86.3%) rated their competency as above average. Among subscales, 'managing safety risks' scores were the highest, and 'teamwork' scores were the lowest. Patient safety competency differed significantly by participants' age, educational level, clinical experience and position. Patient safety competency was higher in older nurses with master's or higher degrees and clinical experience of longer duration. Nurse managers' scores were higher than those of staff nurses. Safety climate was perceived as moderate. After adjusting for other individual and organizational characteristics, patient safety competency was positively associated with safety climate perception. CONCLUSIONS: Nurses' safety competency was rated as moderate. In particular, nurses lacked confidence in teamwork. Nurses with higher safety competency perceived safety climate more positively. Efforts emphasizing teamwork to enhance nurses' safety competency should be prioritized, thereby contributing to improvement of safety climates. PMID- 25925388 TI - History of Recreational Physical Activity and Survival After Breast Cancer: The California Breast Cancer Survivorship Consortium. AB - Recent epidemiologic evidence suggests that prediagnosis physical activity is associated with survival in women diagnosed with breast cancer. However, few data exist for racial/ethnic groups other than non-Latina whites. To examine the association between prediagnosis recreational physical activity and mortality by race/ethnicity, we pooled data from the California Breast Cancer Survivorship Consortium for 3 population-based case-control studies of breast cancer patients (n=4,608) diagnosed from 1994 to 2002 and followed up through 2010. Cox proportional hazards models provided estimates of the relative hazard ratio for mortality from all causes, breast cancer, and causes other than breast cancer associated with recent recreational physical activity (i.e., in the 10 years before diagnosis). Among 1,347 ascertained deaths, 826 (61%) were from breast cancer. Compared with women with the lowest level of recent recreational physical activity, those with the highest level had a marginally decreased risk of all cause mortality (hazard ratio=0.88, 95% confidence interval: 0.76, 1.01) and a statistically significant decreased risk of mortality from causes other than breast cancer (hazard ratio=0.63, 95% confidence interval: 0.49, 0.80), and particularly from cardiovascular disease. No association was observed for breast cancer-specific mortality. These risk patterns did not differ by race/ethnicity (non-Latina white, African American, Latina, and Asian American). Our findings suggest that physical activity is beneficial for overall survival regardless of race/ethnicity. PMID- 25925386 TI - Probing disorders of the nervous system using reprogramming approaches. AB - The groundbreaking technologies of induced pluripotency and lineage conversion have generated a genuine opportunity to address fundamental aspects of the diseases that affect the nervous system. These approaches have granted us unrestricted access to the brain and spinal cord of patients and have allowed for the study of disease in the context of human cells, expressing physiological levels of proteins and under each patient's unique genetic constellation. Along with this unprecedented opportunity have come significant challenges, particularly in relation to patient variability, experimental design and data interpretation. Nevertheless, significant progress has been achieved over the past few years both in our ability to create the various neural subtypes that comprise the nervous system and in our efforts to develop cellular models of disease that recapitulate clinical findings identified in patients. In this Review, we present tables listing the various human neural cell types that can be generated and the neurological disease modeling studies that have been reported, describe the current state of the field, highlight important breakthroughs and discuss the next steps and future challenges. PMID- 25925389 TI - Lifestyle, family history, and risk of idiopathic Parkinson disease: a large Danish case-control study. AB - The relationship between Parkinson disease (PD) and smoking has been examined in several studies, but little is known about smoking in conjunction with other behaviors and a family history of PD. Using unconditional logistic regression analysis, we studied individual and joint associations of these factors with idiopathic PD among 1,808 Danish patients who were diagnosed in 1996-2009 and matched to 1,876 randomly selected population controls. Although there was a downward trend in duration of smoking, this was not observed for daily tobacco consumption. A moderate intake of caffeine (3.1-5 cups/day) was associated with a lower odds ratio for PD (0.45, 95% confidence interval: 0.34, 0.62), as was a moderate intake of alcohol (3.1-7 units/week) (odds ratio = 0.60, 95% confidence interval: 0.58, 0.84); a higher daily intake did not reduce the odds further. When these behaviors were studied in combination with smoking, the odds ratios were lower than those for each one alone. Compared with never smokers with no family history of PD, never smokers who did have a family history had an odds ratio of 2.81 (95% confidence interval: 1.91, 4.13); for smokers with a family history, the odds ratio was 1.60 (95% confidence interval: 1.15, 2.23). In conclusion, duration of smoking seems to be more important than intensity in the relationship between smoking and idiopathic PD. The finding of lower risk estimates for smoking in combination with caffeine or alcohol requires further confirmation. PMID- 25925390 TI - Simultaneous detection of novel H7N9 and other influenza A viruses in poultry by multiplex real-time RT-PCR. AB - BACKGROUND: A novel reassortant H7N9 influenza A virus has crossed the species barrier from poultry to cause human infections in China in 2013 and 2014. Rapid detection of the novel H7N9 virus is important to detect this virus in poultry and reduce the risk of an epidemic in birds or humans. FINDINGS: In this study, a multiplex real-time RT-PCR (rRT-PCR) assay for rapid detection of H7N9 and other influenza A viruses was developed. To evaluate the assay, various influenza A viruses, other avian respiratory viruses, and 1,070 samples from poultry were tested. Fluorescence signals corresponding to H7 and N9 subtypes were detected only when H7 and N9 subtypes were present, while the fluorescence signal for the influenza A M gene was detected in all specimens with influenza A strains. The fluorescent signal can be detected in dilutions as low as 56 copies per reaction for the H7, N9 and M genes. Intra- and inter-assay variability tests showed a reliable assay. In poultry samples, a comparison of rRT-PCR with virus isolation showed a high level of agreement. CONCLUSIONS: The multiplex rRT-PCR assay in this study has good specificity, sensitivity and reproducibility, and will be useful for laboratory surveillance and rapid diagnosis of H7N9 and other influenza A viruses. PMID- 25925391 TI - Carbon benefits of wolfberry plantation on secondary saline land in Jingtai oasis, Gansu--A case study on application of the CBP model. AB - The largest global source of anthropogenic CO2 emissions comes from the burning of fossil fuel and approximately 30% of total net emissions come from land use and land use change. Forestation and reforestation are regarded worldwide as effective options of sequestering carbon to mitigate climate change with relatively low costs compared with industrial greenhouse gas (GHG) emission reduction efforts. Cash trees with a steady augmentation in size are recognized as a multiple-beneficial solution to climate change in China. The reporting of C changes and GHG emissions for sustainable land management (SLM) practices such as afforestation is required for a variety of reasons, such as devising land management options and making policy. The Carbon Benefit Project (CBP) Simple Assessment Tool was employed to estimate changes in soil organic carbon (SOC) stocks and GHG emissions for wolfberry (Lycium barbarum L.) planting on secondary salinized land over a 10 year period (2004-2014) in the Jingtai oasis in Gansu with salinized barren land as baseline scenario. Results show that wolfberry plantation, an intensively managed ecosystem, served as a carbon sink with a large potential for climate change mitigation, a restorative practice for saline land and income stream generator for farmers in soil salinized regions in Gansu province. However, an increase in wolfberry production, driven by economic demands, would bring environmental pressures associated with the use of N fertilizer and irrigation. With an understanding of all of the components of an ecosystem and their interconnections using the Drivers-Pressures-State-Impact Response (DPSIR) framework there comes a need for strategies to respond to them such as capacity building, judicious irrigation and institutional strengthening. Cost benefit analysis (CBA) suggests that wolfberry cultivation was economically profitable and socially beneficial and thus well-accepted locally in the context of carbon sequestration. This study has important implications for Gansu as it helps to understand the role cash trees can play in carbon emission reductions. Such information is necessary in devising management options for sustainable land management (SLM). PMID- 25925392 TI - The Vicious Cycle of Family Atmosphere, Interpersonal Self-concepts, and Paranoia in Schizophrenia-A Longitudinal Study. AB - Recent cognitive models of paranoid delusions highlight the role of self-concepts in the development and maintenance of paranoia. Evidence is growing that especially interpersonal self-concepts are relevant in the genesis of paranoia. In addition, negative interpersonal life-experiences are supposed to influence the course of paranoia. As dysfunctional family atmosphere corresponds with multiple distressing dyadic experiences, it could be a risk factor for the development and maintenance of paranoia. A total of 160 patients with a diagnosis of schizophrenia were assessed twice within 12 months. Standardized questionnaires and symptom rating scales were used to measure interpersonal self concepts, perceived family atmosphere, and paranoia. Data were analyzed using longitudinal cross-lagged structural equation models. Perceived negative family atmosphere was associated with the development of more pronounced negative interpersonal self-concepts 12 months later. Moreover, paranoia was related to negative family atmosphere after 12 months as well. As tests revealed that reversed associations were not able to explain the data, we found evidence for a vicious cycle between paranoia, family atmosphere, and interpersonal self concepts as suggested by theoretical/cognitive model of paranoid delusions. Results suggest that broader interventions for patients and their caretakers that aim at improving family atmosphere might also be able to improve negative self concepts and paranoia. PMID- 25925393 TI - New Targets for Prevention of Schizophrenia: Is It Time for Interventions in the Premorbid Phase? AB - A number of influences have converged that make this Special Theme Issue timely: "A New Direction: Considering Developmentally Sensitive Targets for Very Early Intervention in Schizophrenia". These factors include: 1. the substantial knowledge about premorbid developmental vulnerabilities to psychosis, especially regarding schizophrenia; 2. the promising results emerging from interventions during the clinical high-risk (CHR) phase of psychosis and; 3. the recognition that the CHR period is a relatively late phase of developmental derailment. These factors have together led to a perspective that even earlier intervention is warranted. This paper briefly summarizes the articles comprising the Special Theme including new data on early neurocognitive development, proposed potential targets for psychosocial and psychopharmacological interventions during the premorbid period as early as pregnancy, and ethical challenges. These thought experiments must be empirically tested, and the ethical challenges overcome as posed by the various interventions, which range from relatively low risk, supportive, psychosocial to higher risk, experimental, pharmacological interventions. All of the interventions proposed require careful study of ethics, safety, potential stigma, feasibility, efficacy and tolerability, and the meaning to the people involved. PMID- 25925395 TI - The field evaluation of a push-pull system to control malaria vectors in northern Belize, Central America. AB - BACKGROUND: Campaigns for the continued reduction and eventual elimination of malaria may benefit from new and innovative vector control tools. One novel approach being considered uses a push-pull strategy, whereby spatial repellents are used in combination with outdoor baited traps. The desired effect is the behavioural manipulation of mosquito populations to elicit movement of vectors away from people and into traps. METHODS: Here, a prototype push-pull intervention was evaluated using an experimental hut methodology to test proof-of principle for the strategy against two natural vector populations, Anopheles albimanus and Anopheles vestitipennis, in Belize, Central America. A Latin square study design was used to compare mosquito entry into experimental huts and outdoor traps across four different experimental conditions: 1) control, with no interventions; 2) pull, utilizing only outdoor traps; 3) push, utilizing only an indoor spatial repellent; and 4) push-pull, utilizing both interventions simultaneously. RESULTS: For An. vestitipennis, the combined use of an indoor repellent and outdoor baited traps reduced average nightly mosquito hut entry by 39% (95% CI: [0.37-0.41]) as compared to control and simultaneously increased the nightly average densities of An. vestitipennis captured in outdoor baited traps by 48% (95% CI: [0.22-0.74]), compared to when no repellent was used. Against An. albimanus, the combined push-pull treatment similarly reduced hut entry, by 54% (95% CI: [0.40-0.68]) as compared to control; however, the presence of a repellent indoors did not affect overall outdoor trap catch densities for this species. Against both anopheline species, the combined intervention did not further reduce mosquito hut entry compared to the use of repellent alone. CONCLUSIONS: The prototype intervention evaluated here clearly demonstrated that push-pull strategies have potential to reduce human-vector interactions inside homes by reducing mosquito entry, and highlighted the possibility for the strategy to simultaneously decrease human-vector interactions outside of homes by increasing baited trap collections. However, the variation in effect on different vectors demonstrates the need to characterize the underlying behavioral ecology of target mosquitoes in order to drive local optimization of the intervention. PMID- 25925396 TI - Pharmacological justification of use of Solena heterophylla Lour. in gastrointestinal, respiratory and vascular disorders. AB - BACKGROUND: Solena heterophylla Lour. has traditionally been used in the management of diseases pertaining to gastrointestinal, respiratory and vascular system and present study was undertaken to validate its traditional uses. METHODS: The aqueous ethanolic extract of Solena heterophylla Lour (Sh.Cr) was tested in-vitro on isolated rabbit jejunum, tracheal and aorta preparations. The responses of tissues were recorded using isotonic transducers coupled with PowerLab data acquisition system. RESULTS: The aqueous ethanolic extract of Solena heterophylla Lour (Sh.Cr) (0.03-1.0 mg/ml) on application to spontaneous contractions in isolated rabbit jejunum preparation exerted relaxant effect through decrease in magnitude and frequency of contractions, caused relaxation of K(+)(80 mM)-induced contractions and shifted the Ca(2+) concentration response curves toward right in isolated rabbit jejunum preparations in a manner similar to verapamil (a standard Ca(2+) channel blocker), thus confirming its Ca(2+) channel blocking activity. The Sh.Cr also caused relaxation of carbachol (1 MUM)- and K(+)(80 mM)-induced contractions in isolated rabbit tracheal preparations in a manner comparable to dicyclomine. CONCLUSIONS: The observed relaxant effect may be outcome of anti-muscarinic and Ca(2+) channel blocking activities. The Sh.Cr (0.03-1.0 mg/ml) against phenyephrine (1 MUM)- and K(+)(80 mM)-induced contractions in isolated rabbit aortic preparations exerted a relaxant effect, possibly through Ca(2+) channel blocking activity. These findings provide a rationale for the folkloric uses of the plant in the management of ailments pertaining to gastrointestinal, respiratory and vascular system. PMID- 25925397 TI - Customised fragments libraries for protein structure prediction based on structural class annotations. AB - BACKGROUND: Since experimental techniques are time and cost consuming, in silico protein structure prediction is essential to produce conformations of protein targets. When homologous structures are not available, fragment-based protein structure prediction has become the approach of choice. However, it still has many issues including poor performance when targets' lengths are above 100 residues, excessive running times and sub-optimal energy functions. Taking advantage of the reliable performance of structural class prediction software, we propose to address some of the limitations of fragment-based methods by integrating structural constraints in their fragment selection process. RESULTS: Using Rosetta, a state-of-the-art fragment-based protein structure prediction package, we evaluated our proposed pipeline on 70 former CASP targets containing up to 150 amino acids. Using either CATH or SCOP-based structural class annotations, enhancement of structure prediction performance is highly significant in terms of both GDT_TS (at least +2.6, p-values < 0.0005) and RMSD ( 0.4, p-values < 0.005). Although CATH and SCOP classifications are different, they perform similarly. Moreover, proteins from all structural classes benefit from the proposed methodology. Further analysis also shows that methods relying on class-based fragments produce conformations which are more relevant to user and converge quicker towards the best model as estimated by GDT_TS (up to 10% in average). This substantiates our hypothesis that usage of structurally relevant templates conducts to not only reducing the size of the conformation space to be explored, but also focusing on a more relevant area. CONCLUSIONS: Since our methodology produces models the quality of which is up to 7% higher in average than those generated by a standard fragment-based predictor, we believe it should be considered before conducting any fragment-based protein structure prediction. Despite such progress, ab initio prediction remains a challenging task, especially for proteins of average and large sizes. Apart from improving search strategies and energy functions, integration of additional constraints seems a promising route, especially if they can be accurately predicted from sequence alone. PMID- 25925398 TI - Peanut oral immunotherapy in adolescents: study protocol for a randomized controlled trial. AB - BACKGROUND: Peanut allergy is an increasingly common health problem. Current treatment guidelines are based on strict avoidance. However, in the last few years, oral immunotherapy protocols have shown promising results yielding increased tolerance to peanut in allergic children. Adolescence is particularly at risk. METHODS/DESIGN: We have designed a randomized, double-blind, placebo controlled, multicenter study to investigate the efficacy and safety of peanut oral escalating immunotherapy in a 12- to 18-year-old population with proved allergy to peanut. Patients are selected when the threshold of peanut intake is over 100 mg and 2 cumulated g on the first double-blind, placebo-controlled oral food challenge (DBPCOFC). During the build-up placebo-controlled blinded phase, doses containing peanut or placebo will be administered by gradual up-dosing from 10 mg to 2 g with 2-weekly increments. After this first randomized phase, the desensitized participants will continue to intake native peanut in an unblinded process during 13 or 37 weeks following a second randomization. Adverse events are picked up and managed throughout the entire protocol. The main endpoint is the percentage of patients with negative DBPCOFC at the threshold of 2 g of cumulative peanut at the end of the build-up phase of 24 weeks. Secondary endpoints include: (1) desensitization 6 weeks and 6 months after the end of the maintenance phase; (2) adverse effects during the build-up phase; (3) immunological profile confirming peanut desensitization. Immunologic assays will be carried out at every DBPCOFC and at the middle of the build-up phase to evaluate the peanut immunologic profile modifications. DISCUSSION: This double blind, placebo-controlled study will be, to our knowledge, the first evaluation of a peanut oral immunotherapy protocol in teenagers in the purpose to reduce severe reactions after unexpected intake and to improve quality of life. TRIAL REGISTRATION: ClinicalTrial.gov: NCT02046083 (23 January 2014). PMID- 25925399 TI - The association between physical activity and healthcare costs in children- results from the GINIplus and LISAplus cohort studies. AB - BACKGROUND: Physical inactivity in children is an important risk factor for the development of various morbidities and mortality in adulthood, physical activity already has preventive effects during childhood. The objective of this study is to estimate the association between physical activity, healthcare utilization and costs in children. METHODS: Cross-sectional data of 3356 children aged 9 to 12 years were taken from the 10-year follow-up of the birth cohort studies GINIplus and LISAplus, including information on healthcare utilization and physical activity given by parents via self-administered questionnaires. Using a bottom-up approach, direct costs due to healthcare utilization and indirect costs resulting from parental work absence were estimated for the base year 2007. A two-step regression model compared effects on healthcare utilization and costs for a higher (>= 7 h/week) versus a lower (<7 h/week) level of moderate-to-vigorous physical activity (MVPA) adjusted for age, gender, BMI, education and income of parents, single parenthood and study region. Recycled predictions estimated adjusted mean costs per child and activity group. RESULTS: The analyses for the association between physical activity, healthcare utilization and costs showed no statistically significant results. Different directions of estimates were noticeable throughout cost components in the first step as well as the second step of the regression model. For higher MVPA (>= 7 h/week) compared with lower MVPA (< 7 h/week) total direct costs accounted for 392 EUR (95% CI: 342-449 EUR) versus 398 EUR (95% CI: 309-480 EUR) and indirect costs accounted for 138 EUR (95% CI: 124-153 EUR) versus 127 EUR (95% CI: 111-146 EUR). CONCLUSIONS: The results indicate that childhood might be too early in life, to detect significant preventive effects of physical activity on healthcare utilization and costs, as diseases attributable to lacking physical activity might first occur later in life. This underpins the importance of clarifying the long-term effects of physical activity as it may strengthen the promotion of physical activity in children from a health economic perspective. PMID- 25925400 TI - Comparing methods of determining Legionella spp. in complex water matrices. AB - BACKGROUND: Legionella testing conducted at environmental laboratories plays an essential role in assessing the risk of disease transmission associated with water systems. However, drawbacks of culture-based methodology used for Legionella enumeration can have great impact on the results and interpretation which together can lead to underestimation of the actual risk. Up to 20% of the samples analysed by these laboratories produced inconclusive results, making effective risk management impossible. Overgrowth of competing microbiota was reported as an important factor for culture failure. For quantitative polymerase chain reaction (qPCR), the interpretation of the results from the environmental samples still remains a challenge. Inhibitors may cause up to 10% of inconclusive results. This study compared a quantitative method based on immunomagnetic separation (IMS method) with culture and qPCR, as a new approach to routine monitoring of Legionella. RESULTS: First, pilot studies evaluated the recovery and detectability of Legionella spp using an IMS method, in the presence of microbiota and biocides. The IMS method results were not affected by microbiota while culture counts were significantly reduced (1.4 log) or negative in the same samples. Damage by biocides of viable Legionella was detected by the IMS method. Secondly, a total of 65 water samples were assayed by all three techniques (culture, qPCR and the IMS method). Of these, 27 (41.5%) were recorded as positive by at least one test. Legionella spp was detected by culture in 7 (25.9%) of the 27 samples. Eighteen (66.7%) of the 27 samples were positive by the IMS method, thirteen of them reporting counts below 10(3) colony forming units per liter (CFU l(-1)), six presented interfering microbiota and three presented PCR inhibition. Of the 65 water samples, 24 presented interfering microbiota by culture and 8 presented partial or complete inhibition of the PCR reaction. So the rate of inconclusive results of culture and PCR was 36.9 and 12.3%, respectively, without any inconclusive results reported for the IMS method. CONCLUSION: The IMS method generally improved the recovery and detectability of Legionella in environmental matrices, suggesting the possibility to use IMS method as valuable indicator of risk. Thus, this method may significantly improve our knowledge about the exposure risk to these bacteria, allowing us to implement evidence-based monitoring and disinfection strategies. PMID- 25925401 TI - Non-invasive respiratory volume monitoring identifies opioid-induced respiratory depression in an orthopedic surgery patient with diagnosed obstructive sleep apnea: a case report. AB - INTRODUCTION: Obstructive sleep apnea and opioid-induced respiratory depression can unpredictably threaten respiratory competence in the post-anesthesia care unit. Current respiratory monitoring relies heavily on respiratory rate and oxygen saturation, as well as subjective clinical assessment. These assessments have distinct limitations, and none provide a real-time, objective, quantitative direct measurement of respiratory status. A novel, non-invasive respiratory volume monitor uses bioimpedance to provide accurate, quantitative measurements of minute ventilation, tidal volume and respiratory rate continuously in real time, providing a direct measurement of ventilation. CASE PRESENTATION: The case describes an orthopedic surgery patient (54-year-old Caucasian man, body mass index 33.7 kg/m(2)) with diagnosed obstructive sleep apnea in whom the respiratory volume monitor data depicted persistent apneic behavior undetected by other monitoring. The monitor was able to detect a sudden reduction in minute ventilation after initial opioid administration in the post-anesthesia care unit. The patient had sustained low minute ventilation until discharge. Neither respiratory rate data from the hospital monitor nor oxygen saturation readings reflected the respiratory decompensation, remaining within normal limits even during sustained low minute ventilation. CONCLUSIONS: The events of this case illustrate the limitations of current respiratory rate monitoring and pulse oximetry in the evaluation of post-surgical respiratory status. Our patient displayed stable respiratory rate and no evidence of desaturation, despite sustained low minute ventilation, and he received opioids in the post-anesthesia care unit despite already compromised ventilation. Because the available monitoring did not indicate the patient's true respiratory status, he was treated with additional opioids, markedly increasing his risk for further respiratory decline. PMID- 25925402 TI - Ethnoveterinary plants and practices used for ecto-parasite control in semi-arid smallholder farming areas of Zimbabwe. AB - BACKGROUND: The inclusion of traditional plant-based ecto-parasite control methods in primary health care of livestock is increasingly becoming an important intervention for improving livestock productivity in resource-challenged smallholder farming areas. In this study, commonly used plants used for the control of cattle ticks and other pests were identified through a survey in four semi-arid districts of Zimbabwe. METHODS: A standard structured questionnaire with details of demographics, socioeconomic status of households, livestock parasites, control practices and list of ethnoveterinary plants used was used to interview 233 knowledgeable smallholder farmers in four districts. Focus group discussions with community members further provided insights on how the plants were being used and other issues surrounding ecto-parasite control and indigenous knowledge systems in the study areas. RESULTS: The older generation (>40 years) of the respondents were knowledgeable about ethnoveterinary plants and practices. Overall, 51 plant species were reportedly effective against cattle ticks and other livestock parasites. The most frequently mentioned plants were in descending order, Cissus quadrangularis (30.1%), Lippia javanica (19.6%), Psydrax livida (14.9%) and Aloe sp (14.9%). Most of the plant materials were prepared by crushing and soaking in water and spraying the extract on animals. Despite the knowledge of these useful pesticidal plants, the preferred animal health care for cattle and other highly ranked livestock species is still the use of commercial acaricides. Cattle dipping services were reported sporadic by 48% of the respondents. Traditional knowledge and plants are considered only as an alternative in the absence of conventional synthetic products. CONCLUSIONS: Livestock farming communities know of plant species used for livestock ecto parasite control. The plant species are mostly used to complement commercial products. More work, is required to confirm the acaricidal properties claimed by the farmers in order to optimize and promote sustainable use of these plants. PMID- 25925403 TI - Predicting the risk of death following coronary artery bypass graft made simple: a retrospective study using the American College of Surgeons National Surgical Quality Improvement Program database. AB - INTRODUCTION: Risk models to predict 30-day mortality following isolated coronary artery bypass graft is an active area of research. Simple risk predictors are particularly important for cardiothoracic surgeons who are coming under increased scrutiny since these physicians typically care for higher risk patients and thus expect worse outcomes. The objective of this study was to develop a 30-day postoperative mortality risk model for patients undergoing CABG using the American College of Surgeons National Surgical Quality Improvement Program database. MATERIAL AND METHODS: Data was extracted and analyzed from the American College of Surgeons National Surgical Quality Improvement Program Participant Use Files (2005-2010). Patients that had ischemic heart disease (ICD9 410-414) undergoing one to four vessel CABG (CPT 33533-33536) were selected. To select for acquired heart disease, only patients age 40 and older were included. Multivariate logistic regression analysis was used to create a risk model. The C statistic and the Hosmer-Lemeshow goodness-of-fit test were used to evaluate the model. Bootstrap-validated C-statistic was calculated. RESULTS: A total of 2254 cases met selection criteria. Forty-nine patients (2.2%) died within 30 days. Six independent risk factors predictive of short-term mortality were identified including age, preoperative sodium, preoperative blood urea nitrogen, previous percutaneous coronary intervention, dyspnea at rest, and history of prior myocardial infarction. The C-statistic for this model was 0.773 while the bootstrap-validated C-statistic was 0.750. The Hosmer-Lemeshow test had a p-value of 0.675, suggesting the model does not overfit the data. CONCLUSIONS: The American College of Surgeons National Surgical Quality Improvement Program risk model has good discrimination for 30-day mortality following coronary artery bypass graft surgery. The model employs six independent variables, making it easy to use in the clinical setting. PMID- 25925405 TI - Alcohol Abuse and Pancreatic Diseases: An Overview. AB - BACKGROUND: Alcohol is one of the etiological factors of chronic pancreatitis and there is evidence that acute pancreatitis is the first episode of preexisting chronic pancreatitis and is sometimes not evident from a clinical point of view. The diagnosis of acute pancreatitis is based on the presence of abdominal pain, serum increase of pancreatic enzymes or their presence in urine and/or the presence of alterations of the pancreas imaging. AIMS: To revise actual knowledge on the relationship between alcohol use and pancreatic diseases benign as well as malignant. RESULTS: In occasional drinkers, levels of serum amylase were found to be abnormally high in approximately 13% of subjects, while pancreatic isoamylase and lipase were found to be abnormally high in serum in only 2%. The reason might be related to the fact that alcohol can affect the salivary glands. In chronic alcoholics without abdominal pain, amylase and lipase in serum are elevated in 14% of subjects and, in patients with alcoholic acute pancreatitis, pancreatic amylase and isoamylase are elevated in 94% of cases and lipase is generally more sensitive (100% of cases). CONCLUSIONS: Chronic abuse of alcohol, but not occasional alcoholic intoxication, causes pancreatic damage. Regarding pancreatic neoplasms, the role of alcohol is under debate in ductal pancreatic adenocarcinoma as well as in pancreatic neuroendocrine tumors. Few relevant patents are also described in this review. PMID- 25925404 TI - Effect of preoperative neuromuscular training (NEMEX-TJR) on functional outcome after total knee replacement: an assessor-blinded randomized controlled trial. AB - BACKGROUND: Improving functional status preoperatively through exercise may improve postoperative outcome. Previous knowledge on preoperative exercise in knee osteoarthritis is insufficient. The aim of the study was to compare the difference in change between groups in lower extremity function from baseline to 3 months after Total Knee Replacement (TKR) following a neuromuscular exercise programme (NEMEX-TJR) plus a knee school educational package (KS) or KS alone. METHODS: 45 patients (55-83 years, 53% male, waiting for TKR) were randomized to receive a minimum of 8 sessions of NEMEXTJR plus 3 sessions of KS or 3 sessions of KS alone. Function was assessed with the Chair Stand Test (CST, primary endpoint) and the Knee Injury and Osteoarthritis Outcome Score (KOOS) subscales focusing on daily living function (ADL) and pain (secondary endpoints). Assessments were performed immediately before and after the intervention, and at 6 weeks, 3 months and 12 months after surgery by a physiotherapist, blinded to group allocation. RESULTS: After intervention before surgery we observed a small improvement for primary and secondary endpoints in both groups, which did not differ significantly between groups: comparing the exercise to the control group the treatment effect for the CST was -1.5 seconds (95% CI: -5.3, 2.2), for KOOS ADL and KOOS pain the treatment effect was 1.3 points (-10.1, 12.8) and -2.3 ( 12.4, 7.9) respectively. At 3 months after surgery we observed a small improvement in the primary endpoint in the control group and a significant improvement in the secondary endpoints in both exercise and control groups, which did not differ significantly between groups: comparing the exercise group to the control group the treatment effect in the CST was 2.0 seconds (-1.8, 5.8), for KOOS ADL and KOOS pain the treatment effect was -4.9 points (-16.3, 6.5) and -3.3 points (-13.5, 6.8) respectively. CONCLUSIONS: A median (IQR) of 10 (8, 14) exercise sessions before surgery showed an additional small but non-significant improvement in all functional assessments compared to patient education alone. These benefits were not sustained after TKR. Our trial doesn't give a conclusive answer to whether additional preoperative exercise on postoperative functional outcomes is beneficial. PMID- 25925406 TI - Examining the usefulness of a Family Empowerment Program guided by the Illness Beliefs Model for families caring for a child with thalassemia. AB - The purpose of this pilot study was to design, implement, and evaluate a Family Empowerment Program (FEP), guided by the Illness Beliefs Model. Participants included 25 Thai family members who were the primary caregivers of a child with thalassemia. In Phase I, data were collected from participants using individual in-depth interviews and focus groups before involvement in the FEP. In Phase II, 12 hr of FEP sessions were offered to groups of participants. Content analysis of the audiotaped FEP sessions is reported in this article. Family caregivers reported that the FEP helped them share beliefs and experiences related to caring for their child with thalassemia, make decisions related to families' problems/needs and beliefs, provide each other mutual social support, and develop increased ability to manage care for their chronically ill child through sharing information and learning from other family caregivers about family functioning, family management, and family relationships. Future research is needed to examine the FEP intervention under more controlled conditions with measures that include family functioning and child health outcomes. PMID- 25925408 TI - Waiting time and the psychosocial consequences of false-positive mammography: cohort study. AB - BACKGROUND: There is wide variation in the psychosocial response to false positive mammography. We aimed to assess whether women having to wait longer to exclude cancer had increased psychosocial consequences that persisted after cancer was ruled out. FINDINGS: We selected women with false-positive mammography (n = 272), screened for breast cancer in Copenhagen and Funen (Denmark) over a 1 year period. We measured psychosocial consequences immediately before women attended their recall visit and 1, 6, 18 and 36 months after women received their final diagnosis. After women were told that cancer had been ruled out, adverse psychosocial consequences decreased with time. We found no statistically significant differences between women who had cancer ruled out immediately at the recall visit (waiting time of 0) and women who had to wait longer before cancer was ruled out (waiting times 1-30, 30-120 and > 120 days), when psychosocial consequences were measured via a condition-specific questionnaire (Consequences of Screening in Breast Cancer) at 5 time points (0, 1, 6, 18 and 36 months after cancer exclusion). CONCLUSION: We did not confirm that waiting time was associated with worse long-term psychosocial consequences but type II error (failure to detect a true difference) might be a plausible explanation for our results. PMID- 25925407 TI - Impact of a community-based perinatal and newborn preventive care package on perinatal and neonatal mortality in a remote mountainous district in Northern Pakistan. AB - BACKGROUND: There is limited evidence from community-based interventions to guide the development of effective maternal, perinatal and newborn care practices and services in developing countries. We evaluated the impact of a low-cost package of community-based interventions implemented through government sector lady health workers (LHWs) and community health workers (CHWs) of a NGO namely Aga Khan Health Services on perinatal and neonatal outcomes in a sub-population of the remote mountainous district of Gilgit, Northern Pakistan. METHODS: The package was evaluated using quasi experimental design included promotion of antenatal care, adequate nutrition, skilled delivery and healthy newborn care practices. Control areas continued to receive the routine standard health services. The intervention areas received intervention package in addition to the routine standard health services. Outcome measures included changes in maternal and newborn-care practices and perinatal and neonatal mortality rates between the intervention and control areas. RESULTS: The intervention was implemented in a population of 283324 over a 18 months period. 3200 pregnant women received the intervention. Significant improvements in antenatal care (92% vs 76%, p < .001), TT vaccination (67% vs 47%, p < .001), institutional delivery (85% vs 71%, p < .001), cord application (51% vs 71%, p < .001), delayed bathing (15% vs 43%, p < .001), colostrum administration (83% vs 64%, p < .001), and initiation of breastfeeding within 1 hour after birth (55% vs 40%, p < .001) were seen in intervention areas compared with control areas. Our results indicate significant reductions in mortality rates in intervention areas as compared to control areas from baseline in perinatal mortality rate (from 47.1 to 35.3 per 1000 births, OR 0.62; 95% CI: 0.56-0.69; P 0.02) and neonatal mortality rates (from 26.0 to 22.8 per 1000 live births, 0.58; 95% CI: 0.48-0.68; P 0.03). CONCLUSIONS: The implementation of a set of low cost community-based intervention package within the health system settings in a mountainous region of Pakistan was found to be both feasible and beneficial. The interventions had a significant impact in reduction of the burden of perinatal and neonatal mortality. TRIAL REGISTRATION: This study is registered, ClinicalTrial.gov NCT02412293 . PMID- 25925409 TI - Polyimide dendrimers containing multiple electron donor-acceptor units and their unique photophysical properties. AB - A high-yielding synthesis of a series of polyimide dendrimers, including decacyclene- and perylene-containing dendrimer D6, in which two types of polyimide dyes are present, is reported. In these constructs, the branching unit is represented by trisphenylamine, and the solubilizing chains by N-9 heptadecanyl-substituted perylene diimides. The photophysical properties of the dendrimers have been studied by absorption, steady-state, and time-resolved emission spectroscopy and pump-probe transient absorption spectroscopy. Photoinduced charge-separated (CS) states are formed on the femtosecond timescale upon visible excitation. In particular, in D6, two different CS states can be formed, involving different subunits that decays independently with different lifetimes (ca. 10-100 ps). PMID- 25925410 TI - Transient elevation of glycolysis confers radio-resistance by facilitating DNA repair in cells. AB - BACKGROUND: Cancer cells exhibit increased glycolysis for ATP production (the Warburg effect) and macromolecular biosynthesis; it is also linked with therapeutic resistance that is generally associated with compromised respiratory metabolism. Molecular mechanisms underlying radio-resistance linked to elevated glycolysis remain incompletely understood. METHODS: We stimulated glycolysis using mitochondrial respiratory modifiers (MRMs viz. di-nitro phenol, DNP; Photosan-3, PS3; Methylene blue, MB) in established human cell lines (HEK293, BMG 1 and OCT-1). Glucose utilization and lactate production, levels of glucose transporters and glycolytic enzymes were investigated as indices of glycolysis. Clonogenic survival, DNA repair and cytogenetic damage were studied as parameters of radiation response. RESULTS: MRMs induced the glycolysis by enhancing the levels of two important regulators of glucose metabolism GLUT-1 and HK-II and resulted in 2 fold increase in glucose consumption and lactate production. This increase in glycolysis resulted in resistance against radiation-induced cell death (clonogenic survival) in different cell lines at an absorbed dose of 5 Gy. Inhibition of glucose uptake and glycolysis (using fasentin, 2-deoxy-D-glucose and 3-bromopyruvate) in DNP treated cells failed to increase the clonogenic survival of irradiated cells, suggesting that radio-resistance linked to inhibition of mitochondrial respiration is glycolysis dependent. Elevated glycolysis also facilitated rejoining of radiation-induced DNA strand breaks by activating both non-homologous end joining (NHEJ) and homologous recombination (HR) pathways of DNA double strand break repair leading to a reduction in radiation-induced cytogenetic damage (micronuclei formation) in these cells. CONCLUSIONS: These findings suggest that enhanced glycolysis generally observed in cancer cells may be responsible for the radio-resistance, partly by enhancing the repair of DNA damage. PMID- 25925411 TI - Nicotine pre-exposure reduces stroke-induced glucose transporter-1 activity at the blood-brain barrier in mice. AB - BACKGROUND: With growing electronic cigarette usage in both the smoking and nonsmoking population, rigorous studies are needed to investigate the effects of nicotine on biological systems to determine long-term health consequences. We have previously shown that nicotine exerts specific neurovascular effects that influence blood brain barrier (BBB) function in response to stroke. In this study, we investigated the effects of nicotine on carrier-mediated glucose transport into ischemic brain. Specifically, the present study investigates glucose transporter-1 (GLUT1) function and expression at the BBB in a focal brain ischemia model of mice pre-exposed to nicotine. METHODS: Nicotine was administrated subcutaneously by osmotic pump at the dose of 4.5 mg/kg/day for 1, 7, or 14 days to reflect the plasma levels seen in smokers. Ischemic-reperfusion (IR) injury was induced by 1 h transient middle cerebral artery occlusion (tMCAO) and 24 h reperfusion. Glucose transport was estimated using an in situ brain perfusion technique with radiolabeled glucose and brain vascular GLUT1 expression was detected with immunofluorescence. RESULTS: The nicotine pre-exposure (1, 7 & 14 day) resulted in significant reduction in D-glucose influx rate (K in ) across the BBB, with a 49% reduction in 14 day nicotine-infused animals. We observed a 41% increase in carrier-mediated glucose transport across the BBB in saline infused tMCAO animals compared to saline-infused sham animals. Interestingly, in the tMCAO group of animals pre-exposed to nicotine for 14 days had significantly attenuated increased glucose transport by 80% and 38% compared to saline-infused tMCAO and sham animals respectively. Furthermore, immunofluorescence studies of GLUT1 protein expression in the brain microvascular endothelium confirmed that GLUT1 was also induced in saline-infused tMCAO animals and this protein expression induction was reduced significantly (P < 0.01) with 14 day nicotine pre-exposure in tMCAO animals. CONCLUSIONS: Nicotine pre-exposure reduced the IR enhanced GLUT1 transporter function and expression at the BBB in a focal brain ischemia mouse model. These studies suggest that nicotine exposure prior to stroke could create an enhanced glucose deprived state at the neurovascular unit (NVU) and could provide an additional vulnerability to enhanced stroke injury. PMID- 25925412 TI - The association between time to antibiotics and relevant clinical outcomes in emergency department patients with various stages of sepsis: a prospective multi center study. AB - INTRODUCTION: In early sepsis stages, optimal treatment could contribute to prevention of progression to severe sepsis. Therefore, we investigated if there was an association between time to antibiotics and relevant clinical outcomes in hospitalized emergency department (ED) patients with mild to severe sepsis stages. METHODS: This is a prospective multicenter study in three Dutch EDs. Patients were stratified into three categories of illness severity, as assessed by the predisposition, infection, response, and organ failure (PIRO) score: PIRO score 1 to 7, 8 to 14 and >14 points, reflected low, intermediate, and high illness severity, respectively. Consecutive hospitalized ED patients with a suspected infection who were treated with intravenous antibiotics were eligible to participate in the study. The primary outcome measure was the number of surviving days outside the hospital at day 28 which was used as an inverse measure of hospital length of stay (LOS). The secondary outcome measure was 28 day mortality, taking into account the time to mortality. Multivariable Cox regression analysis was used to estimate the association between time to antibiotics and the primary and secondary outcome measures corrected for confounders, including appropriateness of antibiotics and initial ED resuscitation, in three categories of illness severity. RESULTS: Of the 1,168 included patients, 112 died (10%), while 85% and 95% received antibiotics within three and six hours, respectively. No association between time to antibiotics and surviving days outside the hospital or mortality was found. Only in PIRO group 1 to 7 was delayed administration of antibiotics (>3 hours) associated with an increase in surviving days outside the hospital at day 28 (hazard ratio: 1.46, 95% confidence interval: 1.05 to 2.02 after correction for potential confounders). CONCLUSIONS: In ED patients with mild to severe sepsis who received antibiotics within six hours after ED presentation, a reduction in time to antibiotics was not found to be associated with an improvement in relevant clinical outcomes. PMID- 25925414 TI - How can we promote patient recall of information from medical consultations? PMID- 25925413 TI - Mallotus philippinensis Muell. Arg fruit glandular hairs extract promotes wound healing on different wound model in rats. AB - BACKGROUND: Mallotus philippinensis Muell. Arg (MP, Euphorbiaceae) are widely distributed perennial shrub or small tree in tropical and subtropical region in outer Himalayas regions. Since, Mallotus philippinensis have been shown to have a number of medicinal values. Hence our present study was to investigate the healing potential of fruit extract in rat wound models. METHODS: The study includes acute toxicity and wound healing potential of 50% ethanol extract of MP fruit glandular hair (MPE). MPE (200 mg/kg) was administered orally, once daily for 10 days (incision and dead space wound) and 22 days (excision wound). MPE was found safe when given to rats upto 10 times of optimal effective dose. Wound breaking strength (WBS) in Incision wound and rate of contraction, period of epithelization and scar area in Excision wound were evaluated. Granulation tissue free radicals (nitric oxide and lipid peroxidation), antioxidants (catalase, superoxide dismutase, and reduced glutathione), acute inflammatory marker (myeloperoxidase), connective tissue markers (hydroxyproline, hexosamine, and hexuronic acid), and deep connective tissue histology were studied in Dead space wound. RESULTS: MPE significantly increased WBS and enhanced wound contraction, and decreased both epithelization period and scar area compared with control group. MPE was found to decrease free radicals (50.8 to 55.2%, P<0.001) and myeloperoxidase (44.0%, P<0.001) but enhanced antioxidants (41.1 to 54.5%, P<0.05 to P<0.001) and connective tissue markers (39.5 to 67.3%, P<0.05 to P<0.01). Histopathological evaluation revealed more density of collagen formation with minimal inflammatory cells in deeper tissues. CONCLUSION: Thus, the study revealed Mallotus philippinensis fruit hair extract, safe and effective in wound healing and the healing effects seemed to be due to decrease in free radical generated tissue damage, promoting effects on antioxidant status and faster collagen deposition as evidenced biochemically and histology. PMID- 25925416 TI - Targeted design of a cubic boron imidazolate cage with sensing and reducing functions. AB - A cubic cationic cage is rationally designed by using tridentate boron imidazolate ligands to link tetrahedral metal Zn(ii) centers, which displays excellent properties in the Cr2O7(2-) exchange and can reduce Au(3+) ions into Au nanoparticles directly. PMID- 25925417 TI - The changing epidemiology of dengue in China, 1990-2014: a descriptive analysis of 25 years of nationwide surveillance data. AB - BACKGROUND: Dengue has been a notifiable disease in China since 1 September 1989. Cases have been reported each year during the past 25 years of dramatic socio economic changes in China, and reached a historical high in 2014. This study describes the changing epidemiology of dengue in China during this period, to identify high-risk areas and seasons and to inform dengue prevention and control activities. METHODS: We describe the incidence and distribution of dengue in mainland China using notifiable surveillance data from 1990-2014, which includes classification of imported and indigenous cases from 2005-2014. RESULTS: From 1990-2014, 69,321 cases of dengue including 11 deaths were reported in mainland China, equating to 2.2 cases per one million residents. The highest number was recorded in 2014 (47,056 cases). The number of provinces affected has increased, from a median of three provinces per year (range: 1 to 5 provinces) during 1990 2000 to a median of 14.5 provinces per year (range: 5 to 26 provinces) during 2001-2014. During 2005-2014, imported cases were reported almost every month and 28 provinces (90.3%) were affected. However, 99.8% of indigenous cases occurred between July and November. The regions reporting indigenous cases have expanded from the coastal provinces of southern China and provinces adjacent to Southeast Asia to the central part of China. Dengue virus serotypes 1, 2, 3, and 4 were all detected from 2009-2014. CONCLUSIONS: In China, the area affected by dengue has expanded since 2000 and the incidence has increased steadily since 2012, for both imported and indigenous dengue. Surveillance and control strategies should be adjusted to account for these changes, and further research should explore the drivers of these trends. PMID- 25925418 TI - The role of histone demethylase KDM4B in Myc signaling in neuroblastoma. AB - BACKGROUND: Epigenetic alterations, such as histone methylation, modulate Myc signaling, a pathway central to oncogenesis. We investigated the role of the histone demethylase KDM4B in N-Myc-mediated neuroblastoma pathogenesis. METHODS: Spearman correlation was performed to correlate MYCN and KDM4B expression. RNA interference, microarray analysis, gene set enrichment analysis, and real-time polymerase chain reaction were used to define the functions of KDM4B. Immunoprecipitation and immunofluorescence were used to assess protein-protein interactions between N-Myc and KDM4B. Chromatin immunoprecipitation was used to assess the binding of Myc targets. Constitutive and inducible lentiviral-mediated KDM4B knockdown with shRNA was used to assess the effects on tumor growth. Kaplan Meier survival analysis was used to assess the prognostic value of KDM4B expression. All statistical tests were two-sided. RESULTS: KDM4B and MYCN expression were found to be statistically significantly correlated in a variety of cancers, including neuroblastoma (R = 0.396, P < .001). Functional studies demonstrated that KDM4B regulates the Myc pathway. N-Myc was found to physically interact with and recruit KDM4B. KDM4B was found to regulate neuroblastoma cell proliferation and differentiation in vitro and xenograft growth in vivo (5 mice/group, two-tailed t test, P <= 0.001). Finally, together with MYCN amplification, KDM4B was found to stratify a subgroup of poor-prognosis patients (122 case patients, P < .001). CONCLUSIONS: Our findings provide insight into the epigenetic regulation of Myc via histone demethylation and proof-of-concept for inhibition of histone demethylases to target Myc signaling in cancers such as neuroblastoma. PMID- 25925421 TI - Carbonaceous materials and their advances as a counter electrode in dye sensitized solar cells: challenges and prospects. AB - Dye-sensitized solar cells (DSSCs) serve as low-costing alternatives to silicon solar cells because of their low material and fabrication costs. Usually, they utilize Pt as the counter electrode (CE) to catalyze the iodine redox couple and to complete the electric circuit. Given that Pt is a rare and expensive metal, various carbon materials have been intensively investigated because of their low costs, high surface areas, excellent electrochemical stabilities, reasonable electrochemical activities, and high corrosion resistances. In this feature article, we provide an overview of recent studies on the electrochemical properties and photovoltaic performances of carbon-based CEs (e.g., activated carbon, nanosized carbon, carbon black, graphene, graphite, carbon nanotubes, and composite carbon). We focus on scientific challenges associated with each material and highlight recent advances achieved in overcoming these obstacles. Finally, we discuss possible future directions for this field of research aimed at obtaining highly efficient DSSCs. PMID- 25925420 TI - Electroencephalogram valid rate in simple reaction time task as an easy index of children's attention functions. AB - BACKGROUND: Electroencephalogram (EEG) signal artifacts occur often in children, but an EEG valid rate (VR), constructed by excluding the artifacts, might be meaningful to evaluate children's neuropsychological functions. The aim of this study was to develop an easy screening index, the EEGVR, and to investigate attention function in children using this index. METHODS: The EEG was carried out during a 4 min simple reaction time (SRT) task as standard procedure in 50 children, consisting of 26 with attention-deficit-hyperactivity disorder (ADHD; mean age, 9.8 years; range, 8-11.3 years) and 24 without (mean age, 10.1 years; range, 7.8-12 years). An easy index was derived from the valid rate (VR) of EEG using area under the receiver operating characteristic curve. The index was applied to regroup the 50 children into high VR (HVR) and low VR (LVR) groups, while the Comprehensive Non-verbal Attention Test (CNAT) and four behavioral questionnaires were compared between the two groups in order to investigate the validity of this index. RESULTS: The EEGVR at 75% was optimal to identify HVR and LVR (sensitivity, 0.769; specificity, 0.792). The LVR group had significantly lower scores on both CNAT and the behavioral questionnaires, although the demographic variables and full-scale intelligence quotient (FSIQ) were similar between the two groups. CONCLUSIONS: The EEGVR in an SRT task might be an easy and effective index to screen the attention function of children, and could consequently contribute to the early diagnosis of ADHD. PMID- 25925419 TI - US assessment of HPV types in cancers: implications for current and 9-valent HPV vaccines. AB - BACKGROUND: This study sought to determine the prevaccine type-specific prevalence of human papillomavirus (HPV)-associated cancers in the United States to evaluate the potential impact of the HPV types in the current and newly approved 9-valent HPV vaccines. METHODS: The Centers for Disease Control and Prevention partnered with seven US population-based cancer registries to obtain archival tissue for cancers diagnosed from 1993 to 2005. HPV testing was performed on 2670 case patients that were fairly representative of all participating cancer registry cases by age and sex. Demographic and clinical data were evaluated by anatomic site and HPV status. Current US cancer registry data and the detection of HPV types were used to estimate the number of cancers potentially preventable through vaccination. RESULTS: HPV DNA was detected in 90.6% of cervical, 91.1% of anal, 75.0% of vaginal, 70.1% of oropharyngeal, 68.8% of vulvar, 63.3% of penile, 32.0% of oral cavity, and 20.9% of laryngeal cancers, as well as in 98.8% of cervical cancer in situ (CCIS). A vaccine targeting HPV 16/18 potentially prevents the majority of invasive cervical (66.2%), anal (79.4%), oropharyngeal (60.2%), and vaginal (55.1%) cancers, as well as many penile (47.9%), vulvar (48.6%) cancers: 24 858 cases annually. The 9-valent vaccine also targeting HPV 31/33/45/52/58 may prevent an additional 4.2% to 18.3% of cancers: 3944 cases annually. For most cancers, younger age at diagnosis was associated with higher HPV 16/18 prevalence. With the exception of oropharyngeal cancers and CCIS, HPV 16/18 prevalence was similar across racial/ethnic groups. CONCLUSIONS: In the United States, current vaccines will reduce most HPV associated cancers; a smaller additional reduction would be contributed by the new 9-valent vaccine. PMID- 25925422 TI - Evaluation of the egg transmission and pathogenicity of Mycoplasma gallisepticum isolates genotyped as ts-11. AB - Live Mycoplasma gallisepticum vaccines are used for the control of respiratory disease, egg production losses and egg transmission associated with M. gallisepticum infection in long-lived poultry. The first field case of apparent increased virulence and vertical transmission of ts-11, a live M. gallisepticum vaccine, has been reported. In that study a M. gallisepticum isolate from the broiler progeny of ts-11-vaccinated breeders was genotyped as ts-11 by sequence analysis of four different genetic targets and Random Amplified Polymorphic DNA and found to be significantly more virulent than ts-11 vaccine. The objective of the current study was to evaluate the rate of egg transmission and pathogenicity of ts-11 vaccine and isolates recovered from ts-11-vaccinated breeders (K6222B) and their broiler progeny (K6216D) which had been genotyped as ts-11. Groups of 28-week-old specific pathogen-free chickens at 87% average weekly egg production were inoculated with sterile broth media (negative controls), ts-11 vaccine, K6222B, K6216D or R strain (positive controls) by eye-drop and aerosol. K6216D transmitted via the egg at an average rate of 4.0% in the third and fourth weeks post-infection, while egg transmission of K6222B and ts-11 vaccine was not detected. M. gallisepticum was isolated from the air sacs, ovaries and oviducts of hens infected with K6216D and K6222B, but not from those infected with ts-11 vaccine. K6216D and K6222B both induced respiratory signs and significantly more tracheal colonization and more severe tracheal and air sac lesions than ts-11 vaccine (P <= 0.05). There were no substantial differences in the egg production of ts-11, K6216D and K6222B infected groups. These results provide the first conclusive evidence of transovarian transmission of an isolate genotyped as ts-11 and indicate that isolates genotyed as ts-11 vary in their virulence and ability to transmit via the egg. PMID- 25925423 TI - The hyper-reactive malarial splenomegaly: a systematic review of the literature. AB - BACKGROUND: The hyper-reactive malarial splenomegaly syndrome (HMS) is a leading cause of massive splenomegaly in malaria-endemic countries. HMS is caused by a chronic antigenic stimulation derived from the malaria parasite. Classic Fakunle's major criteria for case definition are: persistent gross splenomegaly, elevated anti-malarial antibodies, IgM titre >2 SD above the local mean value and favourable response to long-term malaria prophylaxis. The syndrome is fatal if left untreated. The aim of this study is to systematically review the literature about HMS, particularly focussing on case definition, epidemiology and management. METHODS: The search strategy was based on the following database sources: Pubmed, EmBase, Scopus. Search was done in March, 2014 and limited to English, Spanish, Italian, French, and Portuguese. RESULTS: Papers detected were 149, of which 89 were included. Splenomegaly was variably defined and the criterion of increased IgM was not always respected. The highest prevalence was reported in Papua New Guinea (up to 80%). In different African countries, 31 to 76% of all splenomegalies were caused by HMS. Fatality rate reached 36% in three years. The most frequent anti-malarial treatments administered were weekly chloroquine or daily proguanil from a minimum of one month to lifelong. In non endemic countries, a few authors opted for a single, short anti-malarial treatment. All treated patients with no further exposure improved. Cases not completely fulfilling Fakunle's criteria and therefore untreated, subsequently evolved into HMS. It seems thus appropriate to treat incomplete or 'early' HMS, too. CONCLUSIONS: For patients not re-exposed to endemic areas, a short course of treatment is sufficient, showing that eradicating the infection is sufficient to cure HMS. Longer (probably lifelong) courses, or intermittent treatments, are required for those who remain exposed. Splenectomy, associated with high mortality, should be strictly limited to cases not responding to medical treatment. PMID- 25925424 TI - Identifying Opportunities for Virtual Reality Simulation in Surgical Education: A Review of the Proceedings from the Innovation, Design, and Emerging Alliances in Surgery (IDEAS) Conference: VR Surgery. AB - OBJECTIVES: To conduct a review of the state of virtual reality (VR) simulation technology, to identify areas of surgical education that have the greatest potential to benefit from it, and to identify challenges to implementation. BACKGROUND DATA: Simulation is an increasingly important part of surgical training. VR is a developing platform for using simulation to teach technical skills, behavioral skills, and entire procedures to trainees and practicing surgeons worldwide. Questions exist regarding the science behind the technology and most effective usage of VR simulation. A symposium was held to address these issues. METHODS: Engineers, educators, and surgeons held a conference in November 2013 both to review the background science behind simulation technology and to create guidelines for its use in teaching and credentialing trainees and surgeons in practice. RESULTS: Several technologic challenges were identified that must be overcome in order for VR simulation to be useful in surgery. Specific areas of student, resident, and practicing surgeon training and testing that would likely benefit from VR were identified: technical skills, team training and decision making skills, and patient safety, such as in use of electrosurgical equipment. CONCLUSIONS: VR simulation has the potential to become an essential piece of surgical education curriculum but depends heavily on the establishment of an agreed upon set of goals. Researchers and clinicians must collaborate to allocate funding toward projects that help achieve these goals. The recommendations outlined here should guide further study and implementation of VR simulation. PMID- 25925425 TI - Significance of Velamentous Cord Insertion for Twin-Twin Transfusion Syndrome. AB - INTRODUCTION: The objective of this study was to evaluate the actual association between velamentous cord insertion (VCI) and twin-twin transfusion syndrome (TTTS) in the native cohort concerning the natural history of monochorionic twin pregnancies. MATERIAL AND METHODS: All monochorionic diamniotic twin pregnancies who received prenatal care from <16 weeks of gestation until delivery at our center between 2004 and 2013 were included in this retrospective cohort study. Macroscopically defined cord insertion site was recorded as velamentous, marginal, or central. The effects of VCI on TTTS and a composite of adverse outcomes, including abortion, death, and neurological morbidities <=28 days of age, were evaluated with a multiple logistic regression model. RESULTS: A total of 357 monochorionic diamniotic twin pregnancies were analyzed. VCI in both twins was noted in 2.5% of cases and VCI in at least one twin was noted in 22.1% of cases. The incidence of TTTS was 8.4%; the incidence of a composite of adverse outcomes in at least one twin was 9.8%. There was no correlation between VCI and TTTS as well as a composite of adverse outcomes. DISCUSSION: VCI in monochorionic twin pregnancies was not a risk factor for TTTS and severe perinatal morbidities. PMID- 25925427 TI - PI3K signaling in the locus coeruleus: a new molecular pathway for ADHD research. PMID- 25925426 TI - Meniscus repair using mesenchymal stem cells - a comprehensive review. AB - The menisci are a pair of semilunar fibrocartilage structures that play an essential role in maintaining normal knee function. Injury to the menisci can disrupt joint stability and lead to debilitating results. Because natural meniscal healing is limited, an efficient method of repair is necessary. Tissue engineering (TE) combines the principles of life sciences and engineering to restore the unique architecture of the native meniscus. Mesenchymal stem cells (MSCs) have been investigated for their therapeutic potential both in vitro and in vivo. This comprehensive review examines the English literature identified through a database search using Medline, Embase, Engineering Village, and SPORTDiscus. The search results were classified based on MSC type, animal model, and method of MSC delivery/culture. A variety of MSC types, including bone marrow derived, synovium-derived, adipose-derived, and meniscus-derived MSCs, has been examined. Research results were categorized into and discussed by the different animal models used; namely murine, leporine, porcine, caprine, bovine, ovine, canine, equine, and human models of meniscus defect/repair. Within each animal model, studies were categorized further according to MSC delivery/culture techniques. These techniques included direct application, fibrin glue/gel/clot, intra-articular injection, scaffold, tissue-engineered construct, meniscus tissue, pellets/aggregates, and hydrogel. The purpose of this review is to inform the reader about the current state and advances in meniscus TE using MSCs. Future directions of MSC-based meniscus TE are also suggested to help guide prospective research. PMID- 25925428 TI - MiR-132 Regulates Rem Expression in Cardiomyocytes During Long-Term beta Adrenoceptor Agonism. AB - AIMS: To characterize the effects of long-term beta-adrenergic receptor stimulation on Rem protein and mRNA expression in rat heart and possible involvement of miR-132. METHODS: Adult rats were treated with isoproterenol (ISO, 150 ug.kg.h(-1)) for 2 d and Rem, miR-132, and alpha1c (the principal subunit of Cav1.2 channels) were measured at protein and mRNA levels with western blot and quantitative reverse transcriptase polymerase chain reaction (qRT-PCR) experiments, respectively. Ca(2+) currents and intracellular Ca(2+) signals were evaluated in isolated cardiomyocytes. RESULTS: Systemic administration of ISO led to decreases in Rem protein and mRNA levels (down to 49%). Furthermore, levels of the microRNAs (miRs) miR-132 and miR-214 were upregulated 5- and 9-fold, respectively. Transfection of miR-132, but not miR-214, into HEK293 cells reduced the expression of a luciferase reporter gene controlled by a conserved 3' untranslated region (UTR) of Rem by half. Chronic ISO administration also led to a 25% decrease in the amplitude of peak L-type Ca(2+) currents, a 40% decrease in alpha1c subunit protein abundance at the membrane level, and a 60% decrease in expression of alpha1c channel subunit mRNA. CONCLUSIONS: These results suggest that Rem expression is down-regulated posttranscriptionally by miR-132 in response to long-term activation of beta-adrenergic signaling, but this down regulation does not produce a larger Ca(2+) influx through Cav1.2 channels. PMID- 25925429 TI - miR-487b, miR-3963 and miR-6412 delay myogenic differentiation in mouse myoblast derived C2C12 cells. AB - BACKGROUND: Skeletal muscle differentiation is a multistep, complex pathway in which several important signaling molecules are involved. Recently, microRNAs (miRNAs), endogenous non-coding small RNAs that regulate mRNAs, have been proposed to be involved in skeletal muscle differentiation. In this study, we identified skeletal muscle differentiation-associated miRNAs by comparing miRNA expression profiles between C2C12 cells and Wnt4 over-expressing C2C12 cells (W4 08), which can spontaneously differentiate into myotubes. RESULTS: We identified miR-206, miR-133a, and miR-133b as up-regulated miRNAs and miR-487b, miR-3963 and miR-6412 as down-regulated miRNAs in differentiating cells. We focused on the down-regulated miRNAs because their functions were largely unknown. Transfection of mimics of these miRNAs into C2C12 cells resulted in significantly reduced expression of myogenic differentiation markers, including troponin T and myosin heavy chain fast type and slow type, but did not affect the expression of the myogenic transcription factors, MyoD and myogenin. CONCLUSIONS: These miRNAs were characterized as new myogenic differentiation-associated miRNAs which may delay late myogenic differentiation or maturation. PMID- 25925430 TI - Natalizumab as a Disease-Modifying Therapy in Chronic Inflammatory Demyelinating Polyneuropathy - A Report of Three Cases. AB - BACKGROUND: Several treatments are available to treat the immune-mediated chronic inflammatory demyelinating polyneuropathy (CIDP). Among these treatments, intravenous immunoglobulins, corticosteroids and plasma exchanges are validated and widely used. A few immunosuppressive drugs have been tried, but they had little efficiency. METHODS: We describe three CIDP patients treated by Natalizumab (acting against cellular adhesion and T-cell migration) after a failure of the validated treatments. RESULTS: We observed a long-term improvement in one patient, a dramatic improvement over a significant duration in another patient and stabilization in the last one. CONCLUSION: This open label study provides evidence for the value of Natalizumab as second-line treatment for individual patients with a high dependency on waning efficacy of first-line therapies. CIDP is characterized by heterogeneity of clinical phenotypes, electrophysiological and pathological features, and various variable courses types of evolution. The different responses to drugs of our patients are consistent with some reported cases and may reflect the spectrum of lesional mechanisms and the molecular dysfunctions in CIDP. PMID- 25925415 TI - Regular wine consumption in chronic heart failure: impact on outcomes, quality of life, and circulating biomarkers. AB - BACKGROUND: Moderate, regular alcohol consumption is generally associated with a lower risk of cardiovascular events but data in patients with chronic heart failure are scarce. We evaluated the relations between wine consumption, health status, circulating biomarkers, and clinical outcomes in a large Italian population of patients with chronic heart failure enrolled in a multicenter clinical trial. METHODS AND RESULTS: A brief questionnaire on dietary habits was administered at baseline to 6973 patients enrolled in the Gruppo Italiano per lo Studio della Sopravvivenza nell'Insufficienza Cardiaca-Heart Failure (GISSI-HF) trial. The relations between wine consumption, fatal and nonfatal clinical end points, quality of life, symptoms of depression, and circulating biomarkers of cardiac function and inflammation (in subsets of patients) were evaluated with simple and multivariable-adjusted statistical models. Almost 56% of the patients reported drinking at least 1 glass of wine per day. After adjustment, clinical outcomes were not significantly different in the predefined 4 groups of wine consumption. However, patients with more frequent wine consumption had a significantly better perception of health status (Kansas City Cardiomyopathy Questionnaire score, adjusted P<0.0001), less frequent symptoms of depression (Geriatric Depression Scale, adjusted P=0.01), and lower plasma levels of biomarkers of vascular inflammation (osteoprotegerin and C-terminal proendothelin 1, adjusted P<0.0001, and pentraxin-3, P=0.01) after adjusting for possible confounders. CONCLUSIONS: We show for the first time in a large cohort of patients with chronic heart failure that moderate wine consumption is associated with a better perceived and objective health status, lower prevalence of depression, and less vascular inflammation, but does not translate into more favorable clinical 4-year outcomes. CLINICAL TRIAL REGISTRATION: URL: http://www.clinicaltrials.gov. Unique identifier: NCT0033633. PMID- 25925431 TI - BiClamp(r) forcep liver transection versus clamp crushing technique for liver resection: study protocol for a randomized controlled trial. AB - BACKGROUND: Blood loss and the requirement of blood transfusions during liver transection have been shown to correlate well with higher morbidity and mortality rates and a worse prognosis. Various devices for liver parenchymal transection have been developed to reduce intraoperative blood loss. The goal of this study is to evaluate the safety and effectiveness of BiClamp(r) forcep transection compared to a clamp crushing technique in patients undergoing liver resection. METHODS/DESIGN: This study will include patients 18 years and older scheduled for hepatectomy with hepatic vascular exclusion who give informed consent. A sample size of 48 patients in each randomization arm will be calculated to detect a difference in the reduction of blood loss of approximately 200 ml (90% power and alpha = 0.05 (two-tailed)). The primary efficacy endpoint of the trial will be the total intraoperative blood loss based on the randomized dissection technique. The statistical analysis is based on the intention-to-treat population. Patients will be followed up on for three months for complications and adverse events. DISCUSSION: This prospective, single-center, randomized controlled, single blinded, two-group parallel trial is designed to assess the efficacy and safety of BiClamp forcep hepatectomy versus clamp crushing for parenchymal transection during elective hepatic resection. TRIAL REGISTRATION: This trial was registered with Clinicaltrials.gov (identifier: NCT02197481 ) on 15 July 2014. PMID- 25925432 TI - Intramolecular hydrogen bonds quench photoluminescence and enhance photocatalytic activity of carbon nanodots. AB - Understanding the photoluminescence (PL) and photocatalytic properties of carbon nanodots (CNDs) induced by environmental factors such as pH through surface groups is significantly important to rationally tune the emission and photodriven catalysis of CNDs. Through adjusting the pH of an aqueous solution of CNDs, it was found that the PL of CNDs prepared by ultrasonic treatment of glucose is strongly quenched at pH 1 because of the formation of intramolecular hydrogen bonds among the oxygen-containing surface groups. The position of the strongest PL peak and its corresponding excitation wavelength strongly depend on the surface groups. The origins of the blue and green emissions of CNDs are closely related to the carboxyl and hydroxyl groups, respectively. The deprotonated COO( ) and CO(-) groups weaken the PL peak of the CNDs and shift it to the red. CNDs alone exhibit photocatalytic activity towards degradation of Rhodamine B at different pH values under UV irradiation. The photocatalytic activity of the CNDs is the highest at pH 1 because of the strong intramolecular hydrogen bonds formed among the oxygen-containing groups. PMID- 25925435 TI - Thank you for sharing. PMID- 25925434 TI - Hearing abilities and sound reception of broadband sounds in an adult Risso's dolphin (Grampus griseus). AB - While odontocetes do not have an external pinna that guides sound to the middle ear, they are considered to receive sound through specialized regions of the head and lower jaw. Yet odontocetes differ in the shape of the lower jaw suggesting that hearing pathways may vary between species, potentially influencing hearing directionality and noise impacts. This work measured the audiogram and received sensitivity of a Risso's dolphin (Grampus griseus) in an effort to comparatively examine how this species receives sound. Jaw hearing thresholds were lowest (most sensitive) at two locations along the anterior, midline region of the lower jaw (the lower jaw tip and anterior part of the throat). Responses were similarly low along a more posterior region of the lower mandible, considered the area of best hearing in bottlenose dolphins. Left- and right-side differences were also noted suggesting possible left-right asymmetries in sound reception or differences in ear sensitivities. The results indicate best hearing pathways may vary between the Risso's dolphin and other odontocetes measured. This animal received sound well, supporting a proposed throat pathway. For Risso's dolphins in particular, good ventral hearing would support their acoustic ecology by facilitating echo detection from their proposed downward oriented echolocation beam. PMID- 25925436 TI - A hard sell. PMID- 25925437 TI - More on unicorns. PMID- 25925433 TI - Current techniques for high-resolution mapping of behavioral circuits in Drosophila. AB - Understanding behavior requires unraveling the mysteries of neurons, glia, and their extensive connectivity. Drosophila has emerged as an excellent organism for studying the neural basis of behavior. This can be largely attributed to the extensive effort of the fly community to develop numerous sophisticated genetic tools for visualizing, mapping, and manipulating behavioral circuits. Here, we attempt to highlight some of the new reagents, techniques and approaches available for dissecting behavioral circuits in Drosophila. We focus on detailing intersectional strategies such as the Flippase-induced intersectional Gal80/Gal4 repression (FINGR), because of the tremendous potential they possess for mapping the minimal number of cells required for a particular behavior. The logic and strategies outlined in this review should have broad applications for other genetic model organisms. PMID- 25925438 TI - China's scientific progress hinges on access to data. PMID- 25925450 TI - Embryo editing sparks epic debate. PMID- 25925451 TI - Gene editing poses challenges for journals. PMID- 25925452 TI - Canadian budget pushes applied research. PMID- 25925453 TI - Vatican hosts climate meeting. PMID- 25925454 TI - Gene-testing firms set sights on drug development. PMID- 25925455 TI - Bone DNA reveals humanity's trek into South America. PMID- 25925456 TI - Correction. PMID- 25925457 TI - Collateral damage: How a case of misconduct brought a leading Japanese biology institute to its knees. PMID- 25925458 TI - Science in turmoil: After the Arab Spring. PMID- 25925459 TI - Personalized medicine: Time for one-person trials. PMID- 25925460 TI - Statistics: P values are just the tip of the iceberg. PMID- 25925468 TI - Iran: Lift sanctions now to save public health. PMID- 25925469 TI - Fisheries: Better policing for fishy catch data. PMID- 25925470 TI - Publishing: Double-blind peer review a double risk. PMID- 25925471 TI - Germline edits: Trust ethics review process. PMID- 25925472 TI - Germline edits: Heat does not help debate. PMID- 25925473 TI - Immunology: Stillbirth prevented by signal blockade. PMID- 25925474 TI - Palaeoclimate: Northern push for the bipolar see-saw. PMID- 25925475 TI - Materials science: Semiconductors grown large and thin. PMID- 25925477 TI - Extended hard-X-ray emission in the inner few parsecs of the Galaxy. AB - The Galactic Centre hosts a puzzling stellar population in its inner few parsecs, with a high abundance of surprisingly young, relatively massive stars bound within the deep potential well of the central supermassive black hole, Sagittarius A* (ref. 1). Previous studies suggest that the population of objects emitting soft X-rays (less than 10 kiloelectronvolts) within the surrounding hundreds of parsecs, as well as the population responsible for unresolved X-ray emission extending along the Galactic plane, is dominated by accreting white dwarf systems. Observations of diffuse hard-X-ray (more than 10 kiloelectronvolts) emission in the inner 10 parsecs, however, have been hampered by the limited spatial resolution of previous instruments. Here we report the presence of a distinct hard-X-ray component within the central 4 * 8 parsecs, as revealed by subarcminute-resolution images in the 20-40 kiloelectronvolt range. This emission is more sharply peaked towards the Galactic Centre than is the surface brightness of the soft-X-ray population. This could indicate a significantly more massive population of accreting white dwarfs, large populations of low-mass X-ray binaries or millisecond pulsars, or particle outflows interacting with the surrounding radiation field, dense molecular material or magnetic fields. However, all these interpretations pose significant challenges to our understanding of stellar evolution, binary formation, and cosmic-ray production in the Galactic Centre. PMID- 25925478 TI - High-mobility three-atom-thick semiconducting films with wafer-scale homogeneity. AB - The large-scale growth of semiconducting thin films forms the basis of modern electronics and optoelectronics. A decrease in film thickness to the ultimate limit of the atomic, sub-nanometre length scale, a difficult limit for traditional semiconductors (such as Si and GaAs), would bring wide benefits for applications in ultrathin and flexible electronics, photovoltaics and display technology. For this, transition-metal dichalcogenides (TMDs), which can form stable three-atom-thick monolayers, provide ideal semiconducting materials with high electrical carrier mobility, and their large-scale growth on insulating substrates would enable the batch fabrication of atomically thin high-performance transistors and photodetectors on a technologically relevant scale without film transfer. In addition, their unique electronic band structures provide novel ways of enhancing the functionalities of such devices, including the large excitonic effect, bandgap modulation, indirect-to-direct bandgap transition, piezoelectricity and valleytronics. However, the large-scale growth of monolayer TMD films with spatial homogeneity and high electrical performance remains an unsolved challenge. Here we report the preparation of high-mobility 4-inch wafer scale films of monolayer molybdenum disulphide (MoS2) and tungsten disulphide, grown directly on insulating SiO2 substrates, with excellent spatial homogeneity over the entire films. They are grown with a newly developed, metal-organic chemical vapour deposition technique, and show high electrical performance, including an electron mobility of 30 cm(2) V(-1) s(-1) at room temperature and 114 cm(2) V(-1) s(-1) at 90 K for MoS2, with little dependence on position or channel length. With the use of these films we successfully demonstrate the wafer scale batch fabrication of high-performance monolayer MoS2 field-effect transistors with a 99% device yield and the multi-level fabrication of vertically stacked transistor devices for three-dimensional circuitry. Our work is a step towards the realization of atomically thin integrated circuitry. PMID- 25925479 TI - Precise interpolar phasing of abrupt climate change during the last ice age. AB - The last glacial period exhibited abrupt Dansgaard-Oeschger climatic oscillations, evidence of which is preserved in a variety of Northern Hemisphere palaeoclimate archives. Ice cores show that Antarctica cooled during the warm phases of the Greenland Dansgaard-Oeschger cycle and vice versa, suggesting an interhemispheric redistribution of heat through a mechanism called the bipolar seesaw. Variations in the Atlantic meridional overturning circulation (AMOC) strength are thought to have been important, but much uncertainty remains regarding the dynamics and trigger of these abrupt events. Key information is contained in the relative phasing of hemispheric climate variations, yet the large, poorly constrained difference between gas age and ice age and the relatively low resolution of methane records from Antarctic ice cores have so far precluded methane-based synchronization at the required sub-centennial precision. Here we use a recently drilled high-accumulation Antarctic ice core to show that, on average, abrupt Greenland warming leads the corresponding Antarctic cooling onset by 218 +/- 92 years (2sigma) for Dansgaard-Oeschger events, including the Bolling event; Greenland cooling leads the corresponding onset of Antarctic warming by 208 +/- 96 years. Our results demonstrate a north-to-south directionality of the abrupt climatic signal, which is propagated to the Southern Hemisphere high latitudes by oceanic rather than atmospheric processes. The similar interpolar phasing of warming and cooling transitions suggests that the transfer time of the climatic signal is independent of the AMOC background state. Our findings confirm a central role for ocean circulation in the bipolar seesaw and provide clear criteria for assessing hypotheses and model simulations of Dansgaard-Oeschger dynamics. PMID- 25925480 TI - A circuit mechanism for differentiating positive and negative associations. AB - The ability to differentiate stimuli predicting positive or negative outcomes is critical for survival, and perturbations of emotional processing underlie many psychiatric disease states. Synaptic plasticity in the basolateral amygdala complex (BLA) mediates the acquisition of associative memories, both positive and negative. Different populations of BLA neurons may encode fearful or rewarding associations, but the identifying features of these populations and the synaptic mechanisms of differentiating positive and negative emotional valence have remained unknown. Here we show that BLA neurons projecting to the nucleus accumbens (NAc projectors) or the centromedial amygdala (CeM projectors) undergo opposing synaptic changes following fear or reward conditioning. We find that photostimulation of NAc projectors supports positive reinforcement while photostimulation of CeM projectors mediates negative reinforcement. Photoinhibition of CeM projectors impairs fear conditioning and enhances reward conditioning. We characterize these functionally distinct neuronal populations by comparing their electrophysiological, morphological and genetic features. Overall, we provide a mechanistic explanation for the representation of positive and negative associations within the amygdala. PMID- 25925482 TI - Glottic airway gain after 'suture arytenoid laterofixation' in bilateral vocal cord paralysis. AB - CONCLUSION: This method is an easy, non-expensive, and effective technique in bilateral vocal cord paralysis to improve glottic airway and clinical performance. OBJECTIVE: To evaluate the effectiveness of 'suture arytenoid laterofixation' surgery in bilateral vocal cord paralysis. MATERIALS AND METHODS: A retrospective analysis of patients' medical history undergoing 'suture arytenoid laterofixation' surgery for bilateral vocal cord paralysis. This technique was applied under general anesthesia with both microlaryngoscopy and video-monitoring. Two 16 g needles and one 1/0 nylon thread were used for the procedure with 1 cm skin incision; no tracheotomy or tissue excision was required. Pre-post-operative photographs of the glottic region were taken from the endoscopic records, and the areas of rima glottis openings were calculated with the Image-J programme. RESULTS: Forty-seven patients were analyzed. The mean pre-post-operative rima glottis areas were 1.11 +/- 0.56 and 2.24 +/- 0.93 mm(2), respectively (p < 0.001). Five patients with previous tracheotomy were decannulated within a few days after the operation. In three patients, mild complications developed in the early post-operative period (two laryngeal edemas, one submucosal hematoma). Tracheotomy was performed to only one pregnant patient in the post-operative first day. None of the patients had granulation formation or synechia. PMID- 25925483 TI - Additional Support for Consolidative Radiotherapy for Diffuse Large B Cell Lymphoma in the Modern Rituximab Era. PMID- 25925484 TI - Is foxglove effective in heart failure? AB - BACKGROUND: Digoxin is the oldest known treatment for heart failure (HF) and has been demonstrated to reduce admissions for worsening heart failure in a large randomized trial recruiting patients in sinus rhythm with heart failure and ejection fraction <45%. This study forms the basis for current international guidelines recommending that digoxin should be considered in patients with symptomatic HF despite optimal doses of angiotensin-converting enzyme inhibitors/angiotensin receptor blockers, beta-blockers, and mineralocorticoid receptor antagonists in addition to device therapy, if indicated. However, digoxin predates mortality reducing HF therapies, and this article reviews the historical and recent data. METHODS: Multiple PubMed searches were performed including, but not limited to, the search terms "digoxin," "heart failure," "efficacy," "treatment," "side-effects," "morbidity," "mortality," and "arrythmia." Articles were excluded if not relevant, not in English or without abstract. Reference lists of relevant articles were manually searched for further references. Due to the large number of articles retrieved, a selection was reviewed based on the authors' best judgement. RESULTS: Three randomized controlled trials and three large contemporary observational reports of digoxin therapy in heart failure and sinus rhythm were retrieved. Other studies were noted that included patients with heart failure and atrial fibrillation, which were also reviewed. CONCLUSION: Definitive randomized evidence of digoxin efficacy as add-on therapy in HF is lacking because most landmark trials of modern HF disease modifying agents postdate the randomized studies of digoxin. Furthermore, questions remain regarding the optimum dose of digoxin and there are signals that digoxin may be harmful in some patients with HF. All contemporary data for digoxin in HF are derived from observational studies and the findings are conflicting. Despite two centuries of experience using cardiac glycosides to treat HF, fundamental questions regarding the efficacy and safety of digoxin in HF remain unanswered. PMID- 25925485 TI - Prevalence of "complicated" stress urinary incontinence in female patients: can urodynamics provide more information in such patients? AB - INTRODUCTION AND HYPOTHESIS: The role of urodynamic investigation has been recently questioned on the basis of data from a selected population of patients with stress urinary incontinence defined as uncomplicated. The aim of this study was to determine the proportion of patients who underwent urodynamic investigation in our centre in whom the stress urinary incontinence could be defined as uncomplicated. The secondary aim was to assess the number of women in whom the urodynamic investigation added information to the preurodynamic assessment. METHODS: This was a retrospective single-centre study. The data from female patients who underwent urodynamic evaluation prior to surgery for stress urinary incontinence between 2008 and 2012 were considered. Patients were categorized as presenting with uncomplicated or complicated stress urinary incontinence according to the definitions used in the ValUE trial. Urodynamic observations were then compared with preurodynamic data. RESULTS: Data from 244 female patients were considered. Due to incomplete data, 33 of these patients were excluded from the evaluation. Only 47 patients (22.3 %) were considered to have uncomplicated stress urinary incontinence according to the definition used in the ValUE trial. The remaining 164 patients (77.7 %) were considered to have complicated stress urinary incontinence. Urodynamic observations differed from the preurodynamic data in 134 of 211 patients (63.5 %). A diagnosis of voiding dysfunction was obtained in 25.6 % of patients. CONCLUSIONS: The majority of our patients had complicated stress urinary incontinence. In a relevant percentage of these patients, a urodynamic test added some new information, including a diagnosis of voiding dysfunction. The role of urodynamic investigation needs to be explored in this patient group. PMID- 25925486 TI - Evaluation of the single-incision Elevate system to treat pelvic organ prolapse: follow-up from 15 to 45 months. AB - INTRODUCTION AND HYPOTHESIS: The aim of this study was to assess the 2-year clinical outcomes of pelvic reconstructive surgery with the single-incision Elevate system (American Medical Systems, Minnetonka, MN, USA). METHODS: This retrospective study was conducted from November 2010 to August 2013, and included 210 patients with pelvic organ prolapse stage 3 or 4 who underwent pelvic reconstructive surgery with an Elevate system and were followed for 1 to 3 years postoperatively. Assessments included pre- and postoperative Pelvic Organ Prolapse Quantification (POP-Q) stage, Urogenital Distress Inventory (UDI-6), Incontinence Impact Questionnaire (IIQ-7) and multi-channel urodynamic examinations. Anatomical success was defined as postoperative POP-Q stage 0 or I. RESULTS: The anatomical success rates were 95 % for the anterior vaginal wall, 99 % for the posterior vaginal wall and 94 % for the apical vaginal wall after a median 27 months of follow-up. POP-Q, UDI-6 and IIQ-7 scores, maximal flow rate and post-voiding residual urine all improved significantly after surgery. Complications included 1 case of internal bleeding, 4 cases of mesh exposure, 5 cases of recurrent prolapse that required salvage operations, and 3 cases of urine retention that required intermittent catheterization. There were no bladder or bowel injuries during surgery. CONCLUSIONS: Pelvic reconstructive surgery with the Elevate system yielded good anatomical outcomes and symptom improvement after 2 years of follow-up. PMID- 25925487 TI - Virtual reality: a proposal for pelvic floor muscle training. AB - INTRODUCTION AND HYPOTHESIS: This video's proposal was to present one of the pelvic floor muscle (PFM) training programs, used in our research, that we designed as a virtual reality intervention protocol and investigated its effects on PFM contractility. METHODS: Two clinical, controlled and prospective studies were conducted, one with 19 nulliparous women without urinary symptoms, who were evaluated by both electromyography and digital palpation (DP) and another with 27 postmenopausal women with mixed urinary symptoms (assessed by both ICIQ UI-SF and ICIQ-OAB), evaluated by vaginal dynamometry and DP, with a total of 46 women in both studies. This protocol was designed so that the participant would play a video game, seated on a pressure base platform, while commanding it through her pelvic movements. Using a virtual reality game, five activities were performed during 30 min, twice a week, with a total of 10 sessions. RESULTS: A significant increase in PFM strength was found in both the nulliparous (p = 0.0001) and the postmenopausal (p = 0.0001) groups of women, as ascertained by DP. A significant increase in postmenopausal women's muscle strength and endurance assessed by dynamometry (p = 0.05) and a concomitant decrease in their urinary symptoms, were observed. CONCLUSION: This virtual reality program promoted an increase in PFM contractility and a decrease in postmenopausal urinary symptoms. PMID- 25925488 TI - Therapeutic bronchoscopy improves spirometry, quality of life, and survival in central airway obstruction. AB - BACKGROUND: Central airway obstruction (CAO) occurs in patients with primary or metastatic lung malignancy and nonmalignant pulmonary disorders and results in significant adverse effects on respiratory function and quality of life. OBJECTIVES: The objective of this study was to assess the effect of therapeutic bronchoscopic interventions on spirometry, dyspnea, quality of life, and survival in patients with CAO. METHODS: We prospectively studied patients who underwent therapeutic rigid bronchoscopy for CAO. Spirometry, San Diego Shortness of Breath questionnaire (SOBQ), and SF-36 questionnaire responses were obtained before the procedure and at follow-up 6-8 weeks after the procedure. RESULTS: Fifty-three patients (24 malignant and 29 nonmalignant CAO), who underwent successful rigid bronchoscopic intervention, were enrolled. Airway stent placement and various debulking techniques including mechanical debridement and heat therapy were used. After bronchoscopy, there was a significant increase in forced vital capacity (2.2 +/- 0.91 l before, 2.7 +/- 0.80 l after, p = 0.009) and forced expiratory volume at 1 s (1.4 +/- 0.60 l before, 1.8 +/- 0.67 l after, p = 0.002). The SOBQ score improved from 55.8 +/- 30.1 before the procedure to 37.9 +/- 27.25 after the procedure (p = 0.002). In the SF-36, there was an improvement in almost all domains, with statistically significant improvement seen in several domains. Benefits were seen independent of the etiology of CAO, site of intervention or stent placement. The patients with malignant CAO, in whom airway patency could not be achieved, had a poor survival. CONCLUSIONS: Alleviation of CAO with therapeutic rigid bronchoscopy results in improvement in spirometry, shortness of breath, quality of life, and survival. PMID- 25925489 TI - Generation of large pig and bovine blastocysts by culturing in human induced pluripotent stem cell medium. AB - We investigated the effect of human induced pluripotent stem cell (hiPS) medium on porcine somatic cell nuclear transfer and bovine in vitro fertilized early blastocysts, in comparison with North Carolina State University (NCSU)-37 medium and in vitro culture (IVC)-II medium. After 2 days of culture, the diameter of the portion of the blastocyst that was extruded from the zona pellucid dramatically differed between porcine blastocysts cultured in hiPS medium and those cultured in NCSU-37 medium (221.47 +/- 38.94 MUm versus 481.87 +/- 40.61 MUm, P < 0.01). Moreover, the diameter of the portion of the blastocyst significantly differed between bovine blastocysts cultured in hiPS medium and those cultured in IVC-II medium (150.30 +/- 29.49 MUm versus 195.58 +/- 41.59 MUm, P < 0.01). Furthermore, the total number of cells per porcine and bovine blastocyst was more than two-fold higher in blastocysts cultured in hiPS medium than in those cultured in NCSU-37 medium (44.33 +/- 5.28 and 143.33 +/- 16.05, P < 0.01) or IVC-II medium (172.12 +/- 45.08 and 604.83 +/- 242.64, P < 0.01), respectively. These results indicate that hiPS medium markedly improves the quality of porcine and bovine blastocysts. PMID- 25925490 TI - Lateral posterior parietal activity during reality monitoring discriminations of memories of high and low perceptual vividness. AB - Regions of the lateral posterior parietal cortex (PPC) tend to be more active during recognition of previously studied items compared to correct rejection of unstudied items. Previously, we demonstrated that this effect is source-specific. While items that were encoded through visual perception elicited robust successful retrieval activity in the lateral PPC during a subsequent source memory test, items that were visually imagined did not elicit this effect. Memories of perceived events typically contain more perceptually-based contextual details than memories of imagined events. Therefore, source-based differences in lateral parietal activity might be due to a difference in the perceptual vividness of memories of perceived and imagined events. The goal of the present study was to test this hypothesis. Participants perceived and imagined items in both high and low perceptual vividness conditions. Experiment 1 demonstrated that memories for items encoded in the high vividness conditions contained significantly greater visual detail than memories encoded in the low vividness conditions. In Experiment 2, participants were scanned while they made source memory judgments about items that were previously perceived and imagined in high and low vividness conditions. Consistent with previous findings, the left lateral PPC was more active during retrieval of perceived compared to imagined events. However, lateral PPC activity did not vary according to vividness, suggesting that source effects in this region cannot be explained by a difference in the perceptual vividness of memories encoded through perception versus imagination. PMID- 25925491 TI - Increased Prevalence of Sleep Apnea in Children with Pseudohypoparathyroidism Type 1a. AB - BACKGROUND/AIMS: Pseudohypoparathyroidism type 1a (PHP1a) is a rare genetic disorder. This study aimed to determine the prevalence of sleep apnea in children with PHP1a. METHODS: Nineteen patients with PHP1a between the age of 2 and 21 years were enrolled prospectively using online advertisements. Parents completed a medical history and surveys to assess sleep behavior. Polysomnography records were obtained when available. In addition, 18 subjects were identified in a retrospective chart review of de-identified medical records with 2.3 million patient charts. RESULTS: Parents reported sleep disturbance (94%) and daytime somnolence (81%) in their children with PHP1a. In the retrospective chart review, 39% had a history of sleep apnea versus 8.8% of a similarly obese control group. In the combined analysis (n = 31), 52% had a history of snoring and 45% had a diagnosis of sleep apnea. Patients were obese with a mean BMI z-score of 2.20 +/- 0.59. Patients with sleep apnea were significantly younger than those without a diagnosis (8.1 +/- 5.4 vs. 12.8 +/- 5.0 years, p = 0.02). CONCLUSIONS: Children with PHP1a have a 4.4-fold greater relative risk of sleep apnea than similarly obese children. Screening for sleep apnea in this population may be warranted to prevent adverse health outcomes. PMID- 25925492 TI - Molecular profiling of tumour budding implicates TGFbeta-mediated epithelial mesenchymal transition as a therapeutic target in oral squamous cell carcinoma. AB - Although tumour budding is an adverse prognostic factor for many cancer types, the molecular mechanisms governing this phenomenon are incompletely understood. Therefore, understanding the molecular basis of tumour budding may provide new therapeutic and diagnostic options. We employ digital image analysis to demonstrate that the number of tumour buds in cytokeratin-stained sections correlates with patients having lymph node metastases at diagnosis. The tumour bud count was also a predictor of overall survival, independent of TNM stage. Tumour buds and paired central tumour areas were subsequently collected from oral squamous cell carcinoma (OSCC) specimens, using laser capture microdissection, and examined with RNA sequencing and miRNA-qPCR arrays. Compared with cells from the central parts of the tumours, budding cells exhibited a particular gene expression signature, comprising factors involved in epithelial-mesenchymal transition (EMT) and activated TGFbeta signalling. Transcription factors ZEB1 and PRRX1 were up-regulated concomitantly with the decreased expression of mesenchymal-epithelial (MET) transcription factors (eg OVOL1) in addition to Kruppel-like factors and Grainyhead-like factors. Moreover, miR-200 family members were down-regulated in budding tumour cells. We used immunohistochemistry to validate five markers of the EMT/MET process in 199 OSCC tumours, as well as in situ hybridization in 20 OSCC samples. Given the strong relationship between tumour budding and the development of lymph node metastases and an adverse prognosis, therapeutics based on inhibiting the activation of TGFbeta signalling may prove useful in the treatment of OSCC. PMID- 25925493 TI - Molecular imaging of tumors with nanobodies and antibodies: Timing and dosage are crucial factors for improved in vivo detection. AB - The utility of nanobodies and conventional antibodies for in vivo imaging is well known, but optimum dosing and timing schedules for one versus the other have not been established. We aimed to improve specific tumor imaging in vivo with nanobodies and conventional antibodies using near-infrared fluorescence (NIRF) imaging. We used ARTC2 expressed on lymphoma cells as a model target antigen. ARTC2-specific nanobody s+16a and conventional antibody Nika102 were labeled with NIRF-dye AF680. In vivo NIRF-imaging of ARTC2-positive and ARTC2-negative xenografts was performed over 24 h post-injection of 5, 10, 25, or 50 ug of each conjugate. Specific target-binding and tissue-penetration were verified by NIRF imaging ex vivo, flow cytometry and fluorescence microscopy. NIRF-imaging of s+16a(680) in vivo revealed a six times faster tumor accumulation than of Nika102(680). Using 50 ug of s+16a(680) increased the specific signals of ARTC2 positive tumors without increasing background signals, allowing a tumor-to background (T/B) ratio of 12.4 +/- 4.2 within 6 h post-injection. Fifty micrograms of Nika102(680) increased specific signals of ARTC2-positive tumors but also of ARTC2-negative tumors and background, thereby limiting the T/B ratio to 6.1 +/- 2.0. Ten micrograms of Nika102(680) only slightly reduced specific tumor signals but dramatically reduced background signals. Ex vivo analyses confirmed a faster and deeper tumor penetration with s+16a(680). Using nanobody s+16a allowed same-day imaging with a high T/B ratio, whereas antibody Nika102 gave optimal imaging results only 24 h post injection. Nanobody s+16a required a high dose, whereas antibody Nika102 had the best T/B-ratio at a low dose. Therefore, timing and dosage should be addressed when comparing nanobodies and conventional antibodies for molecular imaging purposes. PMID- 25925494 TI - Contact force and impedance decrease during ablation depends on catheter location and orientation: insights from pulmonary vein isolation using a contact force sensing catheter. AB - PURPOSE: Contact force (CF) sensing during radiofrequency (RF) ablation allows controlling lesion size. The aim of this study was to analyze the impact of catheter tip location and orientation on the association of CF and impedance decrease. METHODS: We retrospectively analyzed RF applications from 32 patients undergoing catheter ablation for paroxysmal atrial fibrillation using a force sensing catheter and 3D mapping system. CF, catheter location and orientation relative to the tissue during ablation as well as the absolute impedance decrease during the first 20 s of ablation as a surrogate for lesion effectiveness were analyzed for 791 RF applications. RESULTS: While a higher CF was achieved around the right pulmonary veins (12.5 vs. 11.4 g, p = 0.045), a lower median absolute impedance decrease within the first 20 s was seen around the right veins compared to the left veins (9.3 vs. 10.2 Omega, p = 0.02). With different catheter orientations relative to the tissue, higher CF and impedance decrease was seen when the catheter was orientated parallel or oblique to the tissue (30 degrees 145 degrees ) as compared perpendicularly (0-30 degrees ) with a median CF of 13.2 vs. 8.0 g (p < 0.001) and a median impedance decrease during the first 20 s of 11 vs. 7 Omega (p < 0.001). Importantly, achieved CF, baseline impedance, catheter orientation and location all independently predicted the initial absolute and relative impedance decrease in a multivariable linear regression model (p < 0.05). CONCLUSIONS: The effectiveness of RF ablation lesions, as assessed by the initial impedance decrease, is not only dependent on the achieved catheter CF but also on catheter orientation and location. PMID- 25925495 TI - Tissue characteristics and evolution after steam pop. PMID- 25925496 TI - Chimerical pyrene-based [7]helicenes as twisted polycondensed aromatics. AB - Chimerical pyrene-based dibenzo[7]helicene rac-1 and 2H-pyran[7]helicene (M,R,R) (-)-2, in which two pyrene subunits are fused to the [7]helicene/[7]heterohelicene scaffold, were synthesised by means of Ni(0) - or Co(I) -mediated [2+2+2] cycloisomerisation of dipyrenyl-acetylene-derived triynes. Pyrene-based dibenzo[7]helicene 1 was obtained in enantioenriched form by enantioselective cycloisomerisation under Ni(0) /QUINAP catalysis (57 % ee) or in enantiopure form by racemate resolution by liquid chromatography on a chiral column. 1,3-Allylic-type strain-controlled diastereoselective cycloisomerisation was employed in the synthesis of enantiopure (M,R,R)-(-)-2. Physicochemical properties of 1 and 2 encompassing the helicity assignment, stability to racemisation, X-ray crystal structure, UV/Vis, experimental/calculated electronic circular dichroism and fluorescence spectra were studied. Accordingly, comparison of the X-ray crystal structure of (M,R,R)-(-)-2 with calculated structures (DFT: B3LYP/cc-pVDZ, B97D/cc-pVDZ) indicated that its helical backbone is slightly over flattened owing to intramolecular dispersion forces between tert-butylated pyrene subunits. Both 1 and 2 are fluorescent (with quantum yields in dichloromethane of PhiF =0.10 and 0.17, respectively) and are suggested to form intramolecular excimer states upon excitation, which are remarkably stabilised and exhibit large Stokes shifts (296 and 203 nm, respectively). PMID- 25925497 TI - From Association to Function in the Post-GWAS Era. PMID- 25925498 TI - The Contribution of Osteoprogenitor Cells to Arterial Stiffness and Hypertension. AB - Hypertension, the major cause of cardiovascular disease, is bidirectionally linked to arterial stiffness. Evidence shows that vascular calcification, either medial or intimal, induces arterial stiffening further worsening hypertension parallel to substantially increasing cardiovascular risk. The disturbance in the bone-vascular axis that leads to the increase of calcium deposition in the arterial wall may be the result of a shift in the functionality of bone marrow derived circulating stem cells with a calcifying potential, namely osteoprogenitor cells. These cells deposit bone matrix proteins in the vascular wall that can subsequently become mineralized. The current notion is that these cells derive from diverse cell lines. The present review summarizes the current knowledge on the role of progenitor cells with a calcifying potential on arterial calcification, stiffness and hypertension. PMID- 25925499 TI - Towards a Paradigm Shift in Cholesterol Treatment. A Re-examination of the Cholesterol Issue in Japan. PMID- 25925500 TI - Ring Tension Applied to Thiol-Mediated Cellular Uptake. AB - The objective of the study was to explore the potential of ring tension in cyclic disulfides for thiol-mediated cellular uptake. Fluorescent probes that cannot enter cells were equipped with cyclic disulfides of gradually increasing ring tension. As demonstrated by flow cytometry experiments, uptake into HeLa Kyoto cells increased with increasing tension. Differences in carbon-sulfur-sulfur carbon (CSSC) dihedral angles as small as 8 degrees caused significant changes in uptake efficiency. Uptake with high ring tension was better than with inactivated or activated linear disulfides or with thiols. Conversion of thiols on the cell surface into sulfides and disulfides decreased the uptake. Reduction of exofacial disulfides into thiols increased the uptake of transporters with disulfides and inactivated controls with thiols. These results confirm the occurrence of dynamic covalent disulfide-exchange chemistry on cell surfaces. Mechanistic and colocalization studies indicate that endocytosis does not fully account for this cellular uptake with ring tension. PMID- 25925501 TI - Metformin versus insulin for gestational diabetes mellitus: a meta-analysis. AB - The aim of the present meta-analysis was to determine the efficacy and safety of metformin for the treatment of women with gestational diabetes mellitus (GDM). We searched databases, including PubMed, Embase and the Cochrane Central Register of Controlled Trials, for randomized controlled trials (RCTs) comparing metformin and insulin treatments in women with GDM. We carried out statistical analyses using RevMan 2011 and used the Grading of Recommendations, Assessment, Development, and Evaluations profiler to rate the quality of evidence of the primary outcomes. We analysed eight studies involving 1592 subjects. Meta analysis of the RCTs showed that metformin had statistically significant effects on pregnancy-induced hypertension [PIH; risk ratio (RR) 0.54; 95% confidence interval (CI) 0.31, 0.91]. However, its effects on neonatal hypoglycaemia (RR 0.80; 95% CI 0.62, 1.02), rate of large-for-gestational age infants (RR 0.77; 95% CI 0.55, 1.08), respiratory distress syndrome (RR 1.26; 95% CI 0.67, 2.37), phototherapy (RR 0.94; 95% CI 0.67, 1.31) and perinatal death (RR 1.01; 95% CI 0.11, 9.53) were not significant. Our analyses suggest that there is no clinically relevant difference in efficacy or safety between metformin and insulin; however, metformin may be a good choice for GDM because of the lower risk of PIH. The advantages of metformin in terms of glycaemic control, PIH incidence and gestational age at birth are unclear, and should be verified in further trials. PMID- 25925502 TI - Characterization of motility and piliation in pathogenic Neisseria. AB - BACKGROUND: The type IV pili (Tfp) of pathogenic Neisseria (i.e., N. gonorrhoeae and N. meningitidis) are essential for twitching motility. Tfp retraction, which is dependent on the ATPase PilT, generates the forces that move bacteria over surfaces. Neisseria motility has mainly been studied in N. gonorrhoeae whereas the motility of N. meningitidis has not yet been characterized. RESULTS: In this work, we analyzed bacterial motility and monitored Tfp retraction using live-cell imaging of freely moving bacteria. We observed that N. meningitidis moved over surfaces at an approximate speed of 1.6 MUm/s, whereas N. gonorrhoeae moved with a lower speed (1.0 MUm/s). An alignment of the meningococcal and gonococcal pilT promoters revealed a conserved single base pair variation in the -10 promoter element that influence PilT expression. By tracking mutants with altered pilT expression or pilE sequence, we concluded that the difference in motility speed was independent of both. Live-cell imaging using total internal reflection fluorescence microscopy demonstrated that N. gonorrhoeae more often moved with fewer visible retracting filaments when compared to N. meningitidis. Correspondingly, meningococci also displayed a higher level of piliation in transmission electron microscopy. Nevertheless, motile gonococci that had the same number of filaments as N. meningitidis still moved with a lower speed. CONCLUSIONS: These data reveal differences in both speed and piliation between the pathogenic Neisseria species during twitching motility, suggesting a difference in Tfp-dynamics. PMID- 25925503 TI - Edible and medicinal termites: a global overview. AB - Termites are mainly known for damage caused to human beings, both in urban and rural areas. However, these insects play an important role in the decomposition of organic matter in tropical regions and are important natural resources, which are widely used in traditional medicine and are also consumed by human populations in several parts of the world. This study aimed to catalogue termite species used worldwide through a literature review, characterizing them by its human populations' use. The results showed that at least 45 species of termites, belonging to four families, are used in the world, with 43 species used in human diet and/or in livestock feeding. Nine termite species are used as a therapeutic resource. There is an overlapping use of seven species. The use of termites was registered in 29 countries over three continents. Africa is the continent with the highest number of records, followed by America and Asia. The results suggest that, in addition to their ecological importance, termites are a source of medicinal and food resources to various human populations in various locations of the world, showing their potential for being used as an alternative protein source in human or livestock diets, as well as a source for new medicines. PMID- 25925504 TI - Salt-induced counterion condensation and related phenomena in sodium carboxymethylcellulose-sodium halide-methanol-water quaternary systems. AB - Polyion-counterion interactions in sodium carboxymethylcellulose (NaCMC) in methanol-water media have been investigated conductometrically with reference to their variations with polyelectrolyte concentration, relative permittivity and the type and concentration of added electrolytes. The specific conductance data in polyelectrolyte-salt solutions were analyzed using an equation recently developed by us following the scaling description for the configuration of a polyion chain according to Dobrynin et al. Excellent quantitative agreement between the experimental results and those obtained with the new equation developed was observed. The results demonstrate that approximately 43-59% of the counterions remain free and that there has been a suppression of counterion dissociation in the presence of a salt in any given mixed solvent medium, the extent of which increases with increasing salt concentration. NaCl was found to be slightly more efficient than NaBr in suppressing the counterion-condensation in NaCMC-methanol-water systems. An increase in the amount of methanol in the media causes a reduction in the fraction of free counterions. The results further demonstrate that the monomer units experience more frictional resistance as the methanol content of the mixture increases or as the concentration of the added electrolytes increases. The results were discussed in terms of various interactions prevailing in these systems. PMID- 25925505 TI - Initiation of renal replacement therapy in the intensive care unit in Vicenza (IRRIV) score. AB - INTRODUCTION: One of the top research priorities in acute kidney injury is related to the timing of renal replacement therapy (RRT) initiation. The purpose was to develop an index that might serve as a standardized concept of timing of initiation of RRT. METHODS: A previously described database was used. We applied a multivariable Cox regression model with backward selection to characterize parameters present in those patients who received RRT compared with those who did not receive RRT. RESULTS: We studied 590 patients. We identified independent risk factors for RRT and a risk score was devised. The Area Under the Curve of the receiver operating characteristic curve was 0.81 (95% CI 0.74-0.86) for predicting the need for RRT. CONCLUSIONS: We have developed a simple Score (IRRIV Score) to identify patients at high risk of requiring RRT. This score may serve as a standardized definition of the timing of initiation of RRT. PMID- 25925507 TI - 2015 Annual meeting Official Proceedings volume XVI. PMID- 25925506 TI - Translation and validation of the Persian version of the STarT Back Screening Tool in patients with nonspecific low back pain. AB - OBJECTIVE: To translate the STarT Back Screening Tool (SBT) into Persian and to investigate the psychometric properties of the new version in a group of patients with Non-Specific Low Back Pain (NSLBP). BACKGROUND: The STarT is a validated questionnaire used for subgrouping LBP patients at three levels of low-, medium-, and high-risk, based on the risk of chronicity. It has previously been translated and validated in different languages. METHODS: The translation and validation of the original questionnaire were carried out in accordance with the standard guidelines. To approve the construct validity, 295 patients with NSLBP completed a questionnaire package. The package comprised of the STarT, Roland-Morris Disability questionnaire (RMDQ), Tampa Scale for Kinesiophobia (TSK), Coping Strategies Questionnaire (CSQ), and Hospital Anxiety and Depression Scale (HADS). To evaluate test-retest reliability, 35 randomly selected NSLBP patients completed the STarT questionnaire within min. 24-hour interval. RESULTS: Factor analysis confirmed two subscales of the STarT. The Cronbach alpha was .83 and .81 for the STarT and the subscale, respectively. This questionnaire showed excellent test-retest reliability (ICC = .85) (p < 0.01). The correlations between the STarT and RMDQ, CSQ, TSK, and the two subscales of HADS were estimated to be .81, .70, .71, .74, and .71, respectively. The Area under the Curve was also calculated for 6 items and the range was between .734 and .860. CONCLUSIONS: The Persian version of the STarT is reliable and valid, and consistent with the original questionnaire. Therefore, clinicians to subgroup Persian-speaking NSLBP patients can use it. PMID- 25925508 TI - Histomorphological evaluation of atherosclerotic lesions in patients with peripheral artery occlusive disease. AB - PURPOSE: Peripheral arterial occlusive disease (PAOD) is mainly caused by atherosclerosis of the vessel wall. These pathological changes are classified into different stages and are well described for carotid and coronary vessels, but not for PAOD. The aim of our study was to analyze plaque morphology of femoral arteries in patients with intermittent claudication and critical limb ischemia. PATIENTS AND METHODS: In this retrospective study 85 atherosclerotic plaques (common and superficial femoral artery) of 71 patients with a clinical symptomatic PAOD were analyzed, by histology (01/2009-07/2010). Atherosclerotic lesions were classified according to Stary (type I-VIII). For further characterization, plaques were evaluated for the presence of collagen, elastin, calcifications, smooth muscle cells, macrophages, leucocytes, and cellularity. RESULTS: The majority (91%) of atherosclerotic lesions were of advanced types according to Stary (V-VII). Atherosclerotic lesion type VI was associated with significant higher amount of inflammatory cells in comparison to all other atherosclerotic plaque types (CD45: p<0.001; CD68: p=0.013). In addition, atherosclerotic plaques with a pronounced neovascularization contained a higher amount of CD45 (p=0.015; rho=0.273) and CD68 (p=0.016; rho=0.275) positive cells. CONCLUSION: Atherosclerotic lesions of femoral arteries show similar morphological changes as coronary or carotid arteries. But inflammatory cells had a higher impact on plaque progression and destabilization than any other factor. PMID- 25925509 TI - The limitations of using insurance data for research. PMID- 25925510 TI - Dental practice structure. PMID- 25925511 TI - Author's response. PMID- 25925512 TI - Denture quality. PMID- 25925513 TI - More about denture quality. PMID- 25925514 TI - Response from the ADA Science Institute. PMID- 25925515 TI - Implants and pain. PMID- 25925516 TI - Infant care. PMID- 25925518 TI - Authors' response. PMID- 25925519 TI - More about pain. PMID- 25925520 TI - Authors' response. PMID- 25925521 TI - Visits to US emergency departments by 20- to 29-year-olds with toothache during 2001-2010. AB - BACKGROUND: Visits to emergency departments (EDs) for dental symptoms are on the rise, yet reliance on EDs for dental care is far from ideal. ED toothache visits represent opportunities to improve access to professional dental care. METHODS: This research focuses on 20- to 29-year-olds, who account for more ED toothache visits than do other age groups. The authors analyzed publicly available ED visit data from the National Hospital Ambulatory Medical Care Survey (NHAMCS) from 2001 through 2010. They assessed trends in ED toothache visit rates compared with back pain and all cause ED visits during the past decade. The authors used NHAMCS data for years 2009 and 2010 to characterize the more recent magnitude, relative frequency, and independent risk factors for ED toothache visits. Statistical analyses accounted for the complex sampling design. RESULTS: The average annual increase in ED visit rates among 20- to 29-year-olds during 2001-2010 was 6.1% for toothache, 0.3% for back pain, and 0.8% for all causes of ED visits. In 2009 and 2010, 20- to 29-year-olds made an estimated 1.27 million ED visits for toothaches and accounted for 42% of all ED toothache visits. Toothache was the fifth most common reason for any ED visit and third most common for uninsured ED visits by 20- to 29-year-olds. Independent risk factors for ED toothache visits were being uninsured or Medicaid-insured. CONCLUSIONS: Younger adults increasingly rely on EDs for toothaches-likely because of barriers to accessing professional dental care. Expanding dental coverage and access to affordable dental care could increase options for timely dental care and decrease ED use for dental symptoms. PRACTICAL IMPLICATIONS: Though additional research is needed to better understand why younger adults disproportionately use the ED for toothaches, findings from this study suggest the importance of maintaining access to a dental home from childhood through adolescence and subsequently into early adulthood. PMID- 25925522 TI - Clopidogrel is not associated with increased bleeding complications after full mouth extraction: A retrospective study. AB - BACKGROUND: To the authors' knowledge, the effect of clopidogrel on bleeding complications during full-mouth extraction has not been studied. The authors aimed to determine the safety of continued use of clopidogrel during full-mouth extraction. METHODS: The authors performed a retrospective study of consecutive patients undergoing full-mouth extraction who were taking aspirin, clopidogrel, a combination of aspirin and clopidogrel, or neither. The main study outcomes in the 4 study groups were estimated blood loss, transfusion requirements, and complications. The authors also examined the correlation between the number of teeth extracted and estimated blood loss in various groups. RESULTS: Seventy-one patients underwent full-mouth extraction with removal of an average of 19 teeth. The authors excluded 3 patients owing to lack of data regarding blood loss. Of the remaining 68 patients, 25 were using aspirin, 12 were using clopidogrel, 9 were using both aspirin and clopidogrel, and 22 had discontinued the use of antiplatelets. There was no significant difference in the number of teeth extracted (P = .283) and estimated blood loss (P = .111) among the 4 groups. The authors found a significant moderate correlation between the number of teeth extracted and estimated blood loss in the group using aspirin (r = 0.537; P = .006) and in the group using clopidogrel, whether alone or in combination with aspirin (r = 0.535; P = .012), but not in the group who discontinued the use of antiplatelets. There was no need for blood transfusion in any patient. CONCLUSIONS: The results of this study provide limited evidence to suggest that continuation of clopidogrel during full-mouth extraction and preprosthetic surgery may be safe and does not appear to be associated with a significant risk of bleeding. PRACTICAL IMPLICATIONS: Clopidogrel therapy during full-mouth extraction is not associated with significant bleeding complications and may be continued in patients who have a high risk of experiencing a cardiac event. PMID- 25925523 TI - Assessing the standards of online oral hygiene instructions for patients with fixed orthodontic appliances. AB - BACKGROUND: The authors conducted this study to assess the quality of the information available on the Web about oral hygiene for patients with fixed orthodontic appliances. METHODS: The authors entered the search terms "cleaning braces," "brushing braces," and "oral hygiene and braces" into Google, Yahoo, and Bing search engines. They analyzed Web sites satisfying the inclusion criteria from the first 20 hits of each search for accessibility, usability, and reliability by using the LIDA instrument; for readability by using the Flesch Reading Ease (FRE) score; and for the completeness of oral hygiene instructions. RESULTS: Sixty-two Web sites met the inclusion criteria. The mean total LIDA score of 71.2 indicated the moderate quality of the design of the reviewed Web sites. The mean (standard deviation [SD]) values of LIDA scores for accessibility, usability, and reliability were 85.9 (7.0), 63.4 (16.1), and 48.0 (10.4), respectively. The mean (SD) FRE Score of 68.6 (9.7) applied to standard reading skills. The completeness of information (mean [SD] = 67.1 [27.8]) presented the highest variability. CONCLUSIONS: Overall, the authors found that the standards of online oral hygiene materials for orthodontic patients with fixed appliances exhibited modest scores. Readability appeared to be appropriate for young adolescents, whereas the comprehensiveness of the displayed information was highly variable. Further improvement of the infrastructure of electronic health information (that is, e-health) in orthodontics is necessary to meet patients' needs. PRACTICAL IMPLICATIONS: Given the moderate quality of oral hygiene instruction available on the Web for patients with fixed appliances, orthodontic patients and caregivers should be cautious when browsing the Internet for relevant information. Dental professionals should refer patients to valid Web based educational materials. PMID- 25925524 TI - Lessons learned from dental patient safety case reports. AB - BACKGROUND: Errors are commonplace in health care, including dentistry. It is imperative for dental professionals to intercept errors before they lead to an adverse event and to mitigate their effects when an adverse event occurs. This requires a systematic approach at both the profession level, encapsulated in the Agency for Healthcare Research and Quality's patient safety initiative framework, as well as at the practice level, in which crew resource management is a tested paradigm. Supporting patient safety at both the profession and dental practice levels relies on understanding the types and causes of errors, which have not been well studied. METHODS: The authors performed a retrospective review of dental adverse events reported in the literature. Electronic bibliographic databases were searched, and data were extracted on background characteristics, incident description, case characteristics, clinic setting where adverse event originated, phase of patient care that adverse event was detected, proximal cause, type of patient harm, degree of harm, and recovery actions. RESULTS: The authors identified 182 publications (containing 270 cases) through their search. Delayed treatment, unnecessary treatment, or disease progression after misdiagnosis was the largest type of harm reported. Of the reviewed cases, 24.4% of those patients involved in an adverse event experienced permanent harm. One of every 10 case reports reviewed (11.1%) reported that the adverse event resulted in the death of the affected patient. CONCLUSIONS: Published case reports provide a window into understanding the nature and extent of dental adverse events; however, the overall dearth of publications on adverse events in the dental literature points to the need for more study. PRACTICAL IMPLICATIONS: Siloed and incomplete contributions to dentistry's understanding of adverse events in the dental office are threats to dental patients' safety. Publishing more, and more comprehensive, case reports on adverse events is recommended for dental practitioners. PMID- 25925525 TI - A practical approach to evidence-based dentistry: VII: How to use patient management recommendations from clinical practice guidelines. AB - BACKGROUND AND OVERVIEW: Clinical practice guidelines represent highly processed evidence with associated recommendations to inform clinical practice and optimize patient care. Appropriately developed, evidence-based recommendations will integrate the best evidence regarding benefits and harms, the certainty of the evidence, patients' values and preferences, and resource utilization. PRACTICAL IMPLICATIONS: The authors provide a structure for clinicians to critically appraise clinical practice guidelines to determine whether the guidelines offer trustworthy recommendations. PMID- 25925526 TI - Rash around the mouth: What is it? PMID- 25925527 TI - Adjunct local antimicrobials provide statistically significant benefits over subgingival debridement alone in patients with chronic periodontitis. PMID- 25925528 TI - Rethinking dentist shortages. PMID- 25925529 TI - Developing greater business intelligence. PMID- 25925530 TI - Keeping skills current. PMID- 25925531 TI - Antibiotic use in US hospitals: quantification, quality measures and stewardship. AB - A majority of patients hospitalized in the US hospitals receive an antibiotic during their hospitalization. Furthermore, up to half of antibiotics prescribed in hospitals are inappropriate. In the setting of continued emergence of antibiotic-resistant pathogens and a limited pipeline of new antimicrobials, attention to optimizing antibiotic use in healthcare settings is essential. We review the measures of antibiotic consumption in the USA, the evolving metrics for comparing antibiotic use (known as benchmarking), trends in antibiotic use, the structure and outcome measures of Antimicrobial Stewardship Programs and interventions to optimize antimicrobial use. PMID- 25925532 TI - Infectious episodes lead to the oxidative stress response after lung transplantation. AB - BACKGROUND: Reactive oxygen species function as key metabolites that can impair biological processes. In lung transplantation, severe oxidative stress is expected when ischemia/reperfusion injury, acute allograft rejection, and various infections occur. CASE REPORT: Two clinical cases in which serial measurements of the oxidative stress response (levels of diacron-reactive oxygen metabolites) were taken during hospitalization using a Free Radical Elective Evaluator are reported. In the first case, a 30-year-old man underwent right single lung transplantation for juvenile pulmonary emphysema. Immunosuppression was maintained using tacrolimus, mycophenolate mofetil, and steroid. The oxidative stress response fluctuated significantly (p<0.01) during the infections caused by bronchial stenosis compared to the stable condition. No acute rejection was seen during hospitalization. In the second case, a 44-year-old woman underwent right single lung transplantation for lymphangioleiomyomatosis. Immunosuppression was maintained by the same regimen as in case 1. The patient's postoperative course was uneventful, and there was no allograft rejection or infection. The oxidative stress response remained at the non-stress level. CONCLUSIONS: The oxidative stress response was measured by the levels of diacron-reactive oxygen metabolites in lung transplantation. High oxidative stress responses were seen during exposure to infections. This might become a non-invasive marker of complications after transplantation. PMID- 25925533 TI - [A dreamed cooperation: Stakeholder query in Flemish Limburg concerning cooperation in the field of mental healthcare for older people]. AB - This study is an extensive stakeholder query on cooperation in the field of mental healthcare for older people. Cooperation is a key theme in the current policy on mental healthcare in Flanders which is an application of the socialisation of care. The consultative platform SPIL recruited representatives of the primary healthcare through local consultative platforms (POP) and other relevant actors. This qualitative study used the appreciative inquiry in focus groups. There were 12 focus groups with a total of 110 participants, asked to dream of an ideal cooperation. Results show a great willingness to work together effectively with a central role for the patient. Participants seek knowledge, expertise and practical support from each other. They request a consult feature to know where to turn to. The main premise to cooperation is knowing each other, for which time and space is needed. A joint patient record is another request. CONCLUSION: No great new projects are requested. Focus must go to further elaboration of working together. PMID- 25925534 TI - The classic P300 encodes a build-to-threshold decision variable. AB - The P300 component of the human event-related potential has been the subject of intensive experimental investigation across a five-decade period, owing to its apparent relevance to a wide range of cognitive functions and its sensitivity to numerous brain disorders, yet its exact contribution to cognition remains unresolved. Here, we carry out key analyses of the P300 elicited by transient auditory and visual targets to examine its potential role as a 'decision variable' signal that accumulates evidence to a decision bound. Consistent with the latter, we find that the P300 reaches a stereotyped amplitude immediately prior to response execution and that its rate of rise scales with target detection difficulty and accounts for trial-to-trial variance in RT. Computational simulations of an accumulation-to-bound decision process faithfully captured P300 dynamics when its parameters were set by model fits to the RT distributions. Thus, where the dominant explanatory accounts have conceived of the P300 as a unitary neural event, our data reveal it to be a dynamically evolving neural signature of decision formation. These findings place the P300 at the heart of a mechanistically principled framework for understanding decision making in both the typical and atypical human brain. PMID- 25925535 TI - Swine flu: how well did India respond? PMID- 25925536 TI - Invited commentary. PMID- 25925537 TI - Results of transcaval embolization for sac expansion from type II endoleaks after endovascular aneurysm repair. AB - OBJECTIVE: Management of type II endoleaks after endovascular aneurysm repair can be problematic. This study reports our experience with a relatively novel strategy to treat this complication, transcaval coil embolization (TCCE) of the aneurysm sac. METHODS: We reviewed 29 consecutive patients undergoing TCCE from 2010 to 2013. Demographics, operative details, and outcomes were assessed. RESULTS: Since 2006, 29 TCCEs have been performed at our institution in 26 patients for sac expansion from type II endoleaks. Patients were male (83%) and former or current smokers (88%), with an average age of 78 +/- 7.1 years. TCCE was performed a mean of 4.2 +/- 4 years after initial endovascular aneurysm repair. Endoleaks resulted in a mean sac growth of 1.2 +/- 1 cm in diameter and 37% +/- 32% by volume. Forty-six percent had prior procedures (5 translumbar, 3 transarterial, 3 transcaval, 1 aortic cuff, and 1 iliac limb extension). Two patients had no flow identified in the aneurysm sac after puncture was successful, and one was found to have a hygroma rather than arterial flow. An additional two patients had ultimate embolization from sac access between the endograft iliac limb and arterial wall after transcaval puncture failed, for a 90% procedural success (83% for transcaval technical success). Mean fluoroscopy time was 27 +/- 13 minutes with 29 +/- 21 mL of contrast material used and a median of 10 coils per case. Additional adjuncts included thrombin injection (17%), intravascular ultrasound (14%), sac pressure measurements (28%), and on table integrated computed tomography (17%). Median length of stay was 1 day (range, 0-5 days). There were no procedural adverse events. Reintervention was required in five cases (three repeated TCCEs, two graft relinings). One-year freedom from reintervention was 95%. At a mean 16.5 months of follow-up, 70% experienced no further endoleak and had stable or decreasing sac diameters. There have been no ruptures during follow-up. CONCLUSIONS: In this series, TCCE for treatment of aneurysm enlargement due to type II endoleaks was safe and relatively effective despite prior failed interventions in nearly half of the cases. TCCE is a useful alternative in cases in which the anatomy makes other approaches difficult or impossible. PMID- 25925538 TI - Discussion. PMID- 25925539 TI - A comparison of results with eversion versus conventional carotid endarterectomy from the Vascular Quality Initiative and the Mid-America Vascular Study Group. AB - OBJECTIVE: Carotid endarterectomy (CEA) is usually performed with eversion (ECEA) or conventional (CCEA) technique. Previous studies report conflicting results with respect to outcomes for ECEA and CCEA. We compared patient characteristics and outcomes for ECEA and CCEA. METHODS: Deidentified data for CEA patients were obtained from the Society for Vascular Surgery Vascular Quality Initiative (SVS VQI) database for years 2003 to 2013. Second (contralateral) CEA, reoperative CEA, CEA after previous carotid stenting, or CEA concurrent with cardiac surgery were excluded, leaving 2365 ECEA and 17,155 CCEA for comparison. Univariate analysis compared patients, procedures, and outcomes. Survival analysis was also performed for mortality. Multivariate analysis was used selectively to examine the possible independent predictive value of variables on outcomes. RESULTS: Groups were similar with respect to sex, demographics, comorbidities, and preoperative neurologic symptoms, except that ECEA patients tended to be older (71.3 vs 69.8 years; P < .001). CCEA was more often performed with general anesthesia (92% vs 80%; P < .001) and with a shunt (59% vs 24%; P < .001). Immediate perioperative ipsilateral neurologic events (ECEA, 1.3% vs CCEA, 1.2%; P = .86) and any ipsilateral stroke (ECEA, 0.8% vs CCEA, 0.9%; P = .84) were uncommon in both groups. ECEA tended to take less time (median 99 vs 114 minutes; P < .001). However, ECEA more often required a return to the operating room for bleeding (1.4% vs 0.8%; P = .002), a difference that logistic regression analysis showed was only partly explained by differential use of protamine. Life-table estimated 1-year freedom from any cortical neurologic event was similar (96.7% vs 96.7%). Estimated survival was similar comparing ECEA with CCEA at 1 year (96.7% vs 95.9%); however, estimated survival tended to decline more rapidly in ECEA patients after ~2 years. Cox proportional hazards modeling confirmed that independent predictors of mortality included age, coronary artery disease, chronic obstructive pulmonary disease, and smoking, but also demonstrated that CEA type was not an independent predictor of mortality. The 1-year freedom from recurrent stenosis >50% was lower for ECEA (88.8% vs 94.3%, P < .001). However, ECEA and CCEA both had a very high rate of freedom from reoperation at 1 year (99.5% vs 99.6%; P = .67). CONCLUSIONS: ECEA and CCEA appear to provide similar freedom from neurologic morbidity, death, and reintervention. ECEA was associated with significantly shorter procedure times. Furthermore, ECEA obviates the expenses, including increased operative time, associated with use of a patch in CCEA, and a shunt, more often used in CCEA in this database. These potential benefits may be reduced by a slightly greater requirement for early return to the operating room for bleeding. PMID- 25925540 TI - Effect of perioperative complications after endovascular therapy in patients with peripheral artery disease due to femoropopliteal lesions. AB - OBJECTIVE: Despite wide use, high initial success, and acceptable durability of endovascular therapy (EVT) for femoropopliteal (FP) lesions, the frequency of 30 day perioperative complications (POCs) and their effect on clinical outcomes have not been systematically evaluated, which is the subject of this study. METHODS: We used a multicenter database of 2145 consecutive patients (70% male; overall mean age, 73 +/- 9 years) who successfully underwent EVT for FP lesions to investigate independent predictors of POCs (logistic regression analysis) and effect of POCs on prognostic outcomes (Cox proportional regression). RESULTS: POCs were observed in 209 patients (10%). In multivariate logistic regression analysis, body mass index <18.5 kg/m(2), critical limb ischemia, and TransAtlanic Inter-Society Consensus for the Management of Peripheral Arterial Disease class D lesions were independently associated with POCs (adjusted odds ratios [95% confidence intervals], 2.0 [1.3-2.9], 2.5 [1.9-3.3], and 1.6 [1.2-2.1], respectively). After risk stratification of POCs according to the number of these risk factors, the incidence of POCs was higher in the groups with higher scores. Follow-up for >30 days (mean, 2.3 +/- 1.8 years) was available for 2079 of 2145 patients. A Cox hazard regression model adjusted for baseline clinical characteristics showed POCs were negatively and independently associated with future occurrence of major adverse limb events (defined as major amputation and major reintervention) or death (hazard ratio [95% confidence interval], 1.6 [1.2 2.1]; P < .05). CONCLUSIONS: Body mass index <18.5 kg/m(2), critical limb ischemia, and TransAtlantic Inter-Society Consensus for the Management of Peripheral Arterial Disease class D lesion were positively associated with POCs after EVT for FP lesions. The occurrence of POCs may adversely affect clinical outcomes in the chronic phase. PMID- 25925541 TI - High-output heart failure resulting from a traumatic arteriovenous fistula. PMID- 25925542 TI - Aortic arch repair for complex coarctation of the aorta with aberrant bilateral subclavian artery. PMID- 25925543 TI - The role of cost-effectiveness for vascular surgery service provision in the United Kingdom. AB - OBJECTIVE: The cost of health care is increasingly becoming an international issue, with many health care systems requiring evaluation of cost when agreeing to fund health care. In the United Kingdom (UK), for example, the National Institute for Health and Care Excellence highlights the importance of using cost effectiveness analyses to facilitate the effective use of resources. This study evaluates the use of cost-effectiveness analyses and the provision of vascular surgery. METHODS: A systematic review of published literature was performed. UK based studies assessing cost-effectiveness or cost-utility of superficial venous interventions, abdominal aortic aneurysm (AAA) repair, and carotid endarterectomy (CEA) were included. All included studies were quality assessed to determine the overall strength of UK economic evidence for each intervention. RESULTS: Four superficial venous, six AAA, and two CEA studies met the inclusion criteria. After quality assessment, the UK evidence supporting the cost-effectiveness of superficial venous intervention was graded strong. The economic evidence for asymptomatic and symptomatic CEA was graded limited and insufficient, respectively, owing to a paucity of UK literature in this field. There was strong UK economic evidence affirming that endovascular aneurysm repair (EVAR) is unlikely to be a cost-effective alternative to open repair. CONCLUSIONS: There is strong economic evidence for symptomatic superficial venous intervention. However, funding for varicose vein treatments remains controversial. Future economic analyses are required for symptomatic and asymptomatic CEA to better advise national policy. Despite strong economic evidence, current UK guidance is for EVAR over open repair in the elective setting, with the majority of elective AAA repairs being EVAR. PMID- 25925544 TI - The future of vascular surgery. PMID- 25925545 TI - Reply: To PMID 24877855. PMID- 25925546 TI - Regarding "Predicted shortfall in open aneurysm experience for vascular surgery trainees". PMID- 25925547 TI - Regarding "The role of atropine in carotid stenting of recurrent stenosis after eversion endarterectomy". PMID- 25925548 TI - Reply: To PMID 25088741. PMID- 25925550 TI - A central role for the acid sphingomyelinase/ceramide system in neurogenesis and major depression. AB - Major depressive disorder is a severe and chronic illness with high lifetime prevalence and a high incidence of suicide as the cause of death for patients with this diagnosis. Major depressive disorder is often treated with anti depressants. Although these drugs have been used for many years, their exact mode of action is still unknown. It has been suggested that many anti-depressants act by increasing the concentrations of serotonergic transmitters in the synaptic space. However, recent studies have examined the effects of anti-depressants on neurogenesis in the hippocampus, the restoration of hippocampal neuronal networks that may be affected by major depression, and the regulation of the hypothalamic pituitary-adrenal axis by immature neurons in the hippocampus. Here, we present and discuss a novel hypothesis suggesting that these events are regulated by the concentrations of sphingolipids, in particular ceramide, in the hippocampus. These concepts suggest that the acid sphingomyelinase/ceramide system plays a central role in the pathogenesis of major depression and may be a novel target for anti-depressants. PMID- 25925549 TI - Risk factors of acute and overuse musculoskeletal injuries among young conscripts: a population-based cohort study. AB - BACKGROUND: Military service in Finland is compulsory for all male citizens and annually about 80% of 19-year-old men enter into the service. The elevated risk for many chronic diseases and loss of function among those who are inactive and unfit can be often detected already in youth. On the other hand, activity-induced injuries among young are true public health issue. The purpose of the present prospective cohort follow-up study was to evaluate predictive associations between acute or overuse injuries and their various intrinsic risk factors. METHODS: Four successive cohorts of conscripts who formed a representative sample of Finnish young men were followed for 6 months. At the beginning of the service, the risk factors of injuries were measured and recorded and then the acute and overuse injuries treated at the garrison clinic were identified. Predictive associations between injuries and their risk factors were examined by multivariate Cox's proportional hazard models. RESULTS: Of the 1411 participants, 27% sustained an acute injury and 51% suffered from overuse injury. Concerning acute injuries, highest risk for severe injuries were detected among conscripts with low fitness level in both the standing long-jump and push-up tests (hazard rate, HR=5.9; 95% CI: 1.6-21.3). A history of good degree in school sports was not a protective factor against acute injuries. High waist circumference and, on the other hand, being underweight according to BMI increased the HR for overuse injuries. Brisk leisure time physical activity before military entry was a protective factor against overuse injuries. Poor result in Cooper's test was a warning signal of elevated risk of overuse injuries. CONCLUSION: We confirmed previous findings that low level of physical fitness is predictor for musculoskeletal injuries during intensive physical training. The U-shaped relationship between body composition and overuse injuries was noticed indicating that both obesity and underweight are risk factors for overuse injuries. Persons with excellent sports skills according to their earlier degrees in school sports had similar HR for acute injuries than those with poorer degrees. This indicates that school-age sports skills and fitness do not carry far and therefore preventive programmes are needed to prevent activity-induced injuries. PMID- 25925551 TI - Crystalline hetero-stereocomplexed polycarbonates produced from amorphous opposite enantiomers having different chemical structures. AB - Stereocomplexation is the stereoselective interaction between two opposite enantiomeric polymers through an interlocked orderly assembly. Most studies focus on the stereocomplex formation from the crystalline opposite enantiomers having the identical structure; nevertheless, rare examples were reported regarding the crystalline stereocomplexes from enantiomeric polymers having different chemical structures. Herein we show a strategy for polymer orderly assembly through the formation of crystalline hetero-stereocomplexed polymeric materials by the cocrystallization of amorphous isotactic polycarbonates with different chemical structures and opposite configurations. The behaviors in the crystalline state are significantly different from that of the component enantiomeric polymers or their homo-stereocomplexes. This study is expected to open up a new way to prepare various semicrystalline materials having a wide variety of physical properties and degradability. PMID- 25925552 TI - Community-based primary health care for older adults: a qualitative study of the perceptions of clients, caregivers and health care providers. AB - BACKGROUND: Older persons are often poorly served by existing models of community based primary health care (CBPHC). We sought input from clients, informal caregivers, and health care providers on recommendations for system improvements. METHODS: Focus group interviews were held with clients, informal caregivers, and health care providers in mid-sized urban and rural communities in Ontario. Data were analyzed using a combination of directed and emergent coding. Results were shared with participants during a series of feedback sessions. RESULTS: An extensive list of barriers, facilitators, and recommended health system improvements was generated. Barriers included poor system integration and limited access to services. Identified facilitators were person and family-focused care, self-management resources, and successful collaborative practice. Recommended system improvements included expanding and integrating care teams, supports for system navigation, and development of standardized information systems and care pathways. CONCLUSIONS: Older adults still experience frustrating obstacles when trying to access CBPHC. Identified barriers and facilitators of improved system integration aligned well with current literature and Wagner's Chronic Care Model. Additional work is needed to implement the recommended improvements and to discern their impact on patient and system outcomes. PMID- 25925553 TI - Platinum and platinum based nanoalloys synthesized by wet chemistry. AB - Platinum nanocrystals and their derivatives with palladium and cobalt are of fundamental interest due to their wide field of application in chemistry and physics. Their properties are strongly dependent on their shape and composition. However the chemical route is far from allowing control of both shape and composition. In this paper, we show both experimentally and theoretically the important role of the interaction of small adsorbed molecules on the shape but also on the composition. This has been studied by comparing the case of pure palladium and platinum nanocrystals and the case of PtPd and PtCo nanoalloys synthesized by the liquid-liquid phase transfer method. PMID- 25925554 TI - Headteachers' prior beliefs on child health and their engagement in school based health interventions: a qualitative study. AB - BACKGROUND: Schools play an important role in promoting the health of children. However, little consideration is often given to the influence that headteachers' and school staff's prior beliefs have on the implementation of public health interventions. This study examined primary school headteachers' and school health co-ordinators' views regarding child health in order to provide greater insights on the school's perspective for those designing future school-based health interventions. METHODS: A qualitative study was conducted using 19 semi structured interviews with headteachers, deputy headteachers and school health co ordinators in the primary school setting. All transcripts were analysed using thematic analysis. RESULTS: Whilst many participants in this study believed good health was vital for learning, wide variance was evident regarding the perceived health of school pupils and the magnitude of responsibility schools should take in addressing child health behaviours. Although staff in this study acknowledged the importance of their role, many believed the responsibility placed upon schools for health promotion was becoming too much; suggesting health interventions need to better integrate school, parental and societal components. With mental health highlighted as an increasing priority in many schools, incorporating wellbeing outcomes into future school based health interventions is advocated to ensure a more holistic understanding of child health is gained. CONCLUSION: Understanding the health beliefs of school staff when designing interventions is crucial as there appears to be a greater likelihood of interventions being successfully adopted if staff perceive a health issue as important among their pupils. An increased dependability on schools for addressing health was expressed by headteachers in this study, highlighting a need for better understanding of parental, child and key stakeholder perspectives on responsibility for child health. Without this understanding, there is potential for certain child health issues to be ignored. PMID- 25925555 TI - Epidemiology, clinical profile and treatment patterns of venous thromboembolism in cancer patients in Taiwan: a population-based study. AB - BACKGROUND: Venous thromboembolism (VTE) is a clinically significant complication that is well documented among Caucasian cancer patients. However, evidence regarding VTE incidence and treatment among Asian cancer patients is very limited. The objective of this study is to investigate the incidence, risk factors and management of VTE among Taiwanese cancer patients. METHODS: Using Taiwan's National Health Insurance Research Database, we identified 43,855 newly diagnosed cancer patients between 2001 and 2008. Two alternative algorithms for identifying VTE event were explored to better quantify a range of incidence rates of VTE in our cancer patients. Multivariable logistic regression models were used to explore VTE risk factors. RESULTS: The incidence rates of VTE were 9.9 (algorithm 1) and 3.4 (algorithm 2) per 1,000 person-years, respectively. The incidence rates were higher in certain cancers, particularly liver, pancreas, and lung. Significant risk factors for VTE were site of cancer, prior history of VTE, chemotherapy and major surgeries. Long-term anticoagulant therapy was initiated in 64.1% patients with VTE and 72.2% of them received warfarin alone. Approximately two-thirds of patients with VTE received <= 3 months of anticoagulant therapy. CONCLUSION: Incidence of cancer-related VTE is lower among Taiwanese compared to Caucasian populations. Nevertheless, risk factors for cancer-related VTE found in our study were consistent with current literature. PMID- 25925556 TI - Ceramic Lithium Ion Conductor to Solve the Anode Coking Problem of Practical Solid Oxide Fuel Cells. AB - For practical solid oxide fuel cells (SOFCs) operated on hydrocarbon fuels, the facile coke formation over Ni-based anodes has become a key factor that limits their widespread application. Modification of the anodes with basic elements may effectively improve their coking resistance in the short term; however, the easy loss of basic elements by thermal evaporation at high temperatures is a new emerging problem. Herein, we propose a new design to develop coking-resistant and stable SOFCs using Li(+) -conducting Li0.33 La0.56 TiO3 (LLTO) as an anode component. In the Ni/LLTO composite, any loss of surface lithium can be efficiently compensated by lithium diffused from the LLTO bulk under operation. Therefore, the SOFC with the Ni/LLTO anode catalyst layer yields excellent power outputs and operational stability. Our results suggest that the simple adoption of a Li(+) conductor as a modifier for Ni-based anodes is a practical and easy way to solve the coking problem of SOFCs that operate on hydrocarbons. PMID- 25925557 TI - Association between retinal vein occlusion, axial length and vitreous chamber depth measured by optical low coherence reflectometry. AB - BACKGROUND: Results of ocular biometric measurements in retinal vein occlusion (RVO) eyes are still inconclusive and controversial. The aim of this study was to evaluate the association between ocular axial length (AL), vitreous chamber depth (VCD) and both central (CRVO) and branch retinal vein occlusions (BRVO) using optical low coherence reflectometry (OLCR). METHODS: Both eyes of 37 patients with unilateral CRVO (mean age: 66 +/- 14 years, male:female - 21:16) and 46 patients with unilateral BRVO (mean age: 63 +/- 12 years, male:female - 24:22) were enrolled in this study. The control group consisted of randomly selected single eyes of 67 age and gender matched volunteers without the presence or history of RVO (mean age: 64 +/- 14 years, male:female - 34:33). Optical biometry was performed by OLCR biometer (LenStar LS 900). Average keratometry readings, central corneal thickness (CCT), anterior chamber depth (ACD), lens thickness (LT), AL and VCD of eyes with RVO were compared with those of fellow eyes using paired t-tests and with those of control eyes using independent t-tests. RESULTS: Mean CCT, ACD and LT, average keratometry readings of affected RVO eyes, unaffected fellow eyes and control eyes was not statistically different in either groups. In eyes with CRVO mean AL and VCD of affected eyes were significantly shorter than those of control eyes (p < 0.001, p < 0.05), mean difference in AL and VCD between the affected and control eyes was 0.56 +/- 0.15 mm and 0.45 +/- 0.19 mm, respectively. In eyes with BRVO, mean AL of the affected eyes was significantly shorter with a mean difference of 0.57 +/- 0.15 mm (p < 0.001) and the VCD was significantly shorter with a mean difference of 0.61 +/- 0.15 mm (p < 0.001) comparing with the control eyes. CONCLUSION: Shorter AL and VCD might be a potential anatomical predisposing factor for development either of CRVO or BRVO. PMID- 25925558 TI - Antibacterial and Anti-inflammatory Activities of Ppc-1, Active Principle of the Cellular Slime Mold Polysphondylium pseudo-candidum. AB - The diisopentenyloxy quinolobactin derivative 3-methylbut-2-enyl-4-methoxy-8-[(3 methylbut-2-enyl)oxy] quinoline-2-carboxylate, also named as Ppc-1, has been initially isolated from the fruiting bodies of the cellular slime mold Polysphondylium pseudo-candidum. Given that few data are available in the literature concerning the biological properties of this compound, this study was undertaken to evaluate its antibacterial and anti-inflammatory properties. Ppc-1 exerted antibacterial activity on the Gram negative periodontopathogen Porphyromonas gingivalis, while it had no such effect on the other bacterial species tested. The antibacterial activity of Ppc-1 appeared to result from its ability to permeate the cell membrane. Using the U937-3xkappaB-LUC human monocytic cell line, Ppc-1 was found to dose-dependently inhibit the lipopolysaccharide-induced NF-kappaB activation, a signaling pathway that has been associated with inflammatory mediator secretion. In conclusion, Ppc-1, by exhibiting a dual mode of action including antibacterial and anti-inflammatory activities, may represent a promising targeted therapeutic agent for periodontal diseases. PMID- 25925559 TI - Roles of Natural Compounds from Medicinal Plants in Cancer Treatment: Structure and Mode of Action at Molecular Level. AB - Every year, cancer takes the life of millions of people. Conventional treatments have produced unsatisfactory results for some types of cancer, and the side effects are extensive, leading to a shift in the focus of treatment towards alternative medicines. Indeed, medicinal plants have long been investigated by scientists for their anti-cancer properties. Some phytochemicals that are important active constituents of plants, including catechins, ursolic acid, silymarin, glycyrrhizin, ellagic acid, gallic acid and various types of flavonoids, have shown promise in future cancer management. The current review covers various aspects of cancer treatment based on medicinal plants at molecular level and sheds light on their structures and modes of action. PMID- 25925560 TI - Maternal Anxiety and the Second-Trimester Prenatal Screening: A Prospective Cohort Study. AB - OBJECTIVE: Assessing the effects of maternal anxiety on the markers and results of quadruple screening and on maternal anxiety after receiving positive results. METHODS: This prospective cohort study evaluated 1,595 pregnant women referred for prenatal visits. Maternal state/trait anxiety levels were measured, then quadruple screening was performed by measuring serum alpha-fetoprotein (AFP), beta-human chorionic gonadotropin, inhibin A, and unconjugated estriol (UE3). After receiving the results, the state/trait anxiety was remeasured. Amniocentesis was performed for screening-positive mothers. RESULTS: High prescreening maternal anxiety was associated with lower rates of elevated AFP (OR, 0.27; 95% CI, 0.1-0.74) and elevated inhibin A (OR, 0.38; 95% CI, 0.15 0.98). High maternal anxiety was associated with higher rates of decreased UE3 (OR, 1.8; 95% CI, 1.06-3.08). There were no significant associations between prescreening maternal anxiety and the final screening or amniocentesis results. Among the screening-positive mothers, those who had high state/trait anxiety before screening had higher anxiety scores after receiving positive results compared to those with low prescreening anxiety levels (52.9 +/- 10.8 vs. 43.7 +/ 10.3). CONCLUSION: High prescreening maternal anxiety is associated with lower rates of elevated AFP and inhibin A and higher rates of decreased UE3. However, maternal anxiety does not affect the final screening or amniocentesis result. High maternal state/trait anxiety before screening is associated with significantly higher maternal anxiety after the receipt of positive results. PMID- 25925561 TI - Prevalence and molecular characterization of avian infectious bronchitis virus in poultry flocks in Morocco from 2010 to 2014 and first detection of Italy 02 in Africa. AB - The aim of this study was to investigate the prevalence and diversity of infectious bronchitis virus (IBV) genotypes in poultry flocks in 16 areas of Morocco between 2010 and 2014. A total of 360 chicken flocks suspected of being infected by IBV were screened for the IBV N gene using real-time reverse transcriptase-polymerase chain reaction (RT-PCR). Flocks were classified into four groups according to their IBV vaccination programme. Group 1 contained unvaccinated birds. Group 2 received a single application of live H120 vaccine. Groups 3 and 4 birds received one or two booster vaccination(s), respectively, mostly using the H120 vaccine. The real-time RT-PCR results showed that 51.7% of the flocks were positive for the IBV genome with geographical disparities. Molecular characterization of IBV was performed on 50 RT-PCR positive samples by partially sequencing the S1 gene, including the hypervariable regions (nucleotides 705-1097). Two predominant genotypes were detected, with the Massachusetts type dominating (66%), among which 25% of the samples were identical to the H120 vaccine. The second most common genotype (present in 32% of the flocks) was surprisingly Italy 02, revealing the first detection of this genotype in Morocco and also in Africa. 793B, the predominant genotype in the late 1990s in Morocco, was only detected on one occasion and was identical to the 4/91 vaccine strain. This study highlights the high prevalence of IBV in poultry farms in Morocco and confirms its continuous dynamic changes and evolution. PMID- 25925562 TI - Comparison of the Brain Volume in Essential Tremor and Parkinson's Disease Tremor Using an Automated Segmentation Method. AB - BACKGROUND: Essential tremor (ET) and Parkinson's disease (PD) are common neurological disorders in elderly people, and some features of ET and PD may overlap. Quantitative analysis of brain atrophy may be useful in differentiating neurodegenerative disorders. The aim of this study was to identify the volumetric differences of subcortical structures in patients with ET and PD tremor using an automated segmentation method. METHODS: Volumetric MRIs were obtained in 45 patients with ET, 45 patients with PD tremor, and 45 age- and sex-matched control subjects. The volume of the different brain structures was measured by the automated segmentation method (FreeSurfer). RESULTS: Volumetric data obtained with automated segmentation of cerebral regions showed a significant atrophy of the cerebellum in patients with ET. Cerebellar atrophy of ET patients was more significant in the white matter than in the grey matter, and it was noted only in patients with ET having a head tremor. No volumetric differences were found between the PD group and the control group. CONCLUSION: Our study suggests that volumetric differences in subcortical structures using whole brain segmentation method may help to differentiate ET from PD tremor. PMID- 25925563 TI - p38MAPK Signaling Enhances Glycolysis Through the Up-Regulation of the Glucose Transporter GLUT-4 in Gastric Cancer Cells. AB - BACKGROUND/AIMS: Previous studies have shown that p38MAPK is involved in gastric cancer, yet the underlying mechanism remains unclear. METHODS: q-PCR, Western blot and immunohistochemistry were used to explore the expression of PP2A and the phosphorylation of p38MAPK in gastric cancer tissues and normal gastric tissues. Activated p38MAPK in the gastric cancer cell line MKN45 using activator, then q PCR, glucose uptake assay and colony formation assay were performed to determine whether p38MAPK promotes gastric cancer through the enhancement of glycolysis. After transfection of p38MAPK dominant negative mutation (p38DN) into MKN45 cells or MKN45 cells treated with an inhibitor of p38MAPK, Western blot was performed to detect the expression of GLUT-4. The knock down of MEF2alpha in MKN45 cells by siRNA was followed by Western blot and luciferase reporter assay to investigate the underlying mechanism of the role of p38MAPK in the promotion of gastric cancer. Finally, q-PCR, Western blot and immunohistochemistry were performed to examine GLUT-4 expression in gastric cancer tissues and normal gastric tissues. RESULTS: We found that p38MAPK activation significantly increases GLUT-4 expression and promotes glucose uptake and cell growth in gastric cancer cells. Inhibition of p38MAPK abrogates the up-regulation of GLUT-4. MEF2alpha knockdown abolishes p38MAPK-mediated GLUT-4 up-regulation. PP2A, an inhibitor of p38MAPK, is down-regulated in gastric cancer tissues, which might contribute to the activation of p38MAPK. CONCLUSIONS: Our data indicate that the abnormal activation of p38MAPK promotes glycolysis within gastric cancer cells through the upregulation of GLUT-4 in a MEF2a-dependent manner. PMID- 25925564 TI - Nitrate Anion Recognition in Organic-Aqueous Solvent Mixtures by a Bis(triazolium)acridine-Containing [2]Rotaxane. AB - The synthesis of a novel [2]rotaxane host system containing a bis(triazolium)acridine-based axle component is reported. (1)H NMR anion-binding titrations reveal that the rotaxane is able to recognise selectively the NO3(-) anion over a range of more basic oxoanions (AcO(-), HCO3(-) and H2PO4(-)) in a competitive organic-aqueous solvent mixture. PMID- 25925565 TI - TET1 is controlled by pluripotency-associated factors in ESCs and downmodulated by PRC2 in differentiated cells and tissues. AB - Ten-eleven translocation (Tet) genes encode for a family of hydroxymethylase enzymes involved in regulating DNA methylation dynamics. Tet1 is highly expressed in mouse embryonic stem cells (ESCs) where it plays a critical role the pluripotency maintenance. Tet1 is also involved in cell reprogramming events and in cancer progression. Although the functional role of Tet1 has been largely studied, its regulation is poorly understood. Here we show that Tet1 gene is regulated, both in mouse and human ESCs, by the stemness specific factors Oct3/4, Nanog and by Myc. Thus Tet1 is integrated in the pluripotency transcriptional network of ESCs. We found that Tet1 is switched off by cell proliferation in adult cells and tissues with a consequent genome-wide reduction of 5hmC, which is more evident in hypermethylated regions and promoters. Tet1 downmodulation is mediated by the Polycomb repressive complex 2 (PRC2) through H3K27me3 histone mark deposition. This study expands the knowledge about Tet1 involvement in stemness circuits in ESCs and provides evidence for a transcriptional relationship between Tet1 and PRC2 in adult proliferating cells improving our understanding of the crosstalk between the epigenetic events mediated by these factors. PMID- 25925566 TI - Translation initiation factor eIF3 promotes programmed stop codon readthrough. AB - Programmed stop codon readthrough is a post-transcription regulatory mechanism specifically increasing proteome diversity by creating a pool of C-terminally extended proteins. During this process, the stop codon is decoded as a sense codon by a near-cognate tRNA, which programs the ribosome to continue elongation. The efficiency of competition for the stop codon between release factors (eRFs) and near-cognate tRNAs is largely dependent on its nucleotide context; however, the molecular mechanism underlying this process is unknown. Here, we show that it is the translation initiation (not termination) factor, namely eIF3, which critically promotes programmed readthrough on all three stop codons. In order to do so, eIF3 must associate with pre-termination complexes where it interferes with the eRF1 decoding of the third/wobble position of the stop codon set in the unfavorable termination context, thus allowing incorporation of near-cognate tRNAs with a mismatch at the same position. We clearly demonstrate that efficient readthrough is enabled by near-cognate tRNAs with a mismatch only at the third/wobble position. Importantly, the eIF3 role in programmed readthrough is conserved between yeast and humans. PMID- 25925567 TI - Argonaute of the archaeon Pyrococcus furiosus is a DNA-guided nuclease that targets cognate DNA. AB - Functions of prokaryotic Argonautes (pAgo) have long remained elusive. Recently, Argonautes of the bacteria Rhodobacter sphaeroides and Thermus thermophilus were demonstrated to be involved in host defense. The Argonaute of the archaeon Pyrococcus furiosus (PfAgo) belongs to a different branch in the phylogenetic tree, which is most closely related to that of RNA interference-mediating eukaryotic Argonautes. Here we describe a functional and mechanistic characterization of PfAgo. Like the bacterial counterparts, archaeal PfAgo contributes to host defense by interfering with the uptake of plasmid DNA. PfAgo utilizes small 5'-phosphorylated DNA guides to cleave both single stranded and double stranded DNA targets, and does not utilize RNA as guide or target. Thus, with respect to function and specificity, the archaeal PfAgo resembles bacterial Argonautes much more than eukaryotic Argonautes. These findings demonstrate that the role of Argonautes is conserved through the bacterial and archaeal domains of life and suggests that eukaryotic Argonautes are derived from DNA-guided DNA interfering host defense systems. PMID- 25925568 TI - A novel sigma factor reveals a unique regulon controlling cell-specific recombination in Mycoplasma genitalium. AB - The Mycoplasma genitalium MG428 protein shows homology to members of the sigma-70 family of sigma factors. Herein, we found that MG428 activates transcription of recA, ruvA and ruvB as well as several genes with unknown function. Deletion of MG_428 or some of the up-regulated unknown genes led to severe recombination defects. Single cell analyses revealed that activation of the MG428-regulon is a rare event under laboratory growth conditions. A conserved sequence with sigma-70 promoter architecture (TTGTCA-N(18/19)-ATTWAT) was identified in the upstream region of all of the MG428-regulated genes or operons. Primer extension analyses demonstrated that transcription initiates immediately downstream of this sigma70 type promoter in a MG428-dependent manner. Furthermore, mutagenesis of the conserved -10 and -35 elements corroborated the requirement of these regions for promoter function. Therefore, a new mycoplasma promoter directs transcription of a unique recombination regulon. Additionally, MG428 was found to interact with the RNAP core enzyme, reinforcing the predicted role of this protein as an alternative sigma factor. Finally, our results indicate that MG428 contributes to the generation of genetic diversity in this model organism. Since recombination is an important mechanism to generate antigenic variation, MG428 emerges as a novel factor contributing to M. genitalium virulence. PMID- 25925569 TI - NGL Viewer: a web application for molecular visualization. AB - The NGL Viewer (http://proteinformatics.charite.de/ngl) is a web application for the visualization of macromolecular structures. By fully adopting capabilities of modern web browsers, such as WebGL, for molecular graphics, the viewer can interactively display large molecular complexes and is also unaffected by the retirement of third-party plug-ins like Flash and Java Applets. Generally, the web application offers comprehensive molecular visualization through a graphical user interface so that life scientists can easily access and profit from available structural data. It supports common structural file-formats (e.g. PDB, mmCIF) and a variety of molecular representations (e.g. 'cartoon, spacefill, licorice'). Moreover, the viewer can be embedded in other web sites to provide specialized visualizations of entries in structural databases or results of structure-related calculations. PMID- 25925570 TI - The ribonuclease DIS3 promotes let-7 miRNA maturation by degrading the pluripotency factor LIN28B mRNA. AB - Multiple myeloma, the second most frequent hematologic tumor after lymphomas, is an incurable cancer. Recent sequencing efforts have identified the ribonuclease DIS3 as one of the most frequently mutated genes in this disease. DIS3 represents the catalytic subunit of the exosome, a macromolecular complex central to the processing, maturation and surveillance of various RNAs. miRNAs are an evolutionarily conserved class of small noncoding RNAs, regulating gene expression at post-transcriptional level. Ribonucleases, including Drosha, Dicer and XRN2, are involved in the processing and stability of miRNAs. However, the role of DIS3 on the regulation of miRNAs remains largely unknown. Here we found that DIS3 regulates the levels of the tumor suppressor let-7 miRNAs without affecting other miRNA families. DIS3 facilitates the maturation of let-7 miRNAs by reducing in the cytoplasm the RNA stability of the pluripotency factor LIN28B, a inhibitor of let-7 processing. DIS3 inactivation, through the increase of LIN28B and the reduction of mature let-7, enhances the translation of let-7 targets such as MYC and RAS leading to enhanced tumorigenesis. Our study establishes that the ribonuclease DIS3, targeting LIN28B, sustains the maturation of let-7 miRNAs and suggests the increased translation of critical oncogenes as one of the biological outcomes of DIS3 inactivation. PMID- 25925571 TI - GenoLIB: a database of biological parts derived from a library of common plasmid features. AB - Synthetic biologists rely on databases of biological parts to design genetic devices and systems. The sequences and descriptions of genetic parts are often derived from features of previously described plasmids using ad hoc, error-prone and time-consuming curation processes because existing databases of plasmids and features are loosely organized. These databases often lack consistency in the way they identify and describe sequences. Furthermore, legacy bioinformatics file formats like GenBank do not provide enough information about the purpose of features. We have analyzed the annotations of a library of ~2000 widely used plasmids to build a non-redundant database of plasmid features. We looked at the variability of plasmid features, their usage statistics and their distributions by feature type. We segmented the plasmid features by expression hosts. We derived a library of biological parts from the database of plasmid features. The library was formatted using the Synthetic Biology Open Language, an emerging standard developed to better organize libraries of genetic parts to facilitate synthetic biology workflows. As proof, the library was converted into GenoCAD grammar files to allow users to import and customize the library based on the needs of their research projects. PMID- 25925572 TI - PolySearch2: a significantly improved text-mining system for discovering associations between human diseases, genes, drugs, metabolites, toxins and more. AB - PolySearch2 (http://polysearch.ca) is an online text-mining system for identifying relationships between biomedical entities such as human diseases, genes, SNPs, proteins, drugs, metabolites, toxins, metabolic pathways, organs, tissues, subcellular organelles, positive health effects, negative health effects, drug actions, Gene Ontology terms, MeSH terms, ICD-10 medical codes, biological taxonomies and chemical taxonomies. PolySearch2 supports a generalized 'Given X, find all associated Ys' query, where X and Y can be selected from the aforementioned biomedical entities. An example query might be: 'Find all diseases associated with Bisphenol A'. To find its answers, PolySearch2 searches for associations against comprehensive collections of free-text collections, including local versions of MEDLINE abstracts, PubMed Central full-text articles, Wikipedia full-text articles and US Patent application abstracts. PolySearch2 also searches 14 widely used, text-rich biological databases such as UniProt, DrugBank and Human Metabolome Database to improve its accuracy and coverage. PolySearch2 maintains an extensive thesaurus of biological terms and exploits the latest search engine technology to rapidly retrieve relevant articles and databases records. PolySearch2 also generates, ranks and annotates associative candidates and present results with relevancy statistics and highlighted key sentences to facilitate user interpretation. PMID- 25925573 TI - The 9-1-1 checkpoint clamp coordinates resection at DNA double strand breaks. AB - DNA-end resection, the generation of single-stranded DNA at DNA double strand break (DSB) ends, is critical for controlling the many cellular responses to breaks. Here we show that the conserved DNA damage checkpoint sliding clamp (the 9-1-1 complex) plays two opposing roles coordinating DSB resection in budding yeast. We show that the major effect of 9-1-1 is to inhibit resection by promoting the recruitment of Rad9(53BP1) near DSBs. However, 9-1-1 also stimulates resection by Exo1- and Dna2-Sgs1-dependent nuclease/helicase activities, and this can be observed in the absence of Rad9(53BP1). Our new data resolve the controversy in the literature about the effect of the 9-1-1 complex on DSB resection. Interestingly, the inhibitory role of 9-1-1 on resection is not observed near uncapped telomeres because less Rad9(53BP1) is recruited near uncapped telomeres. Thus, 9-1-1 both stimulates and inhibits resection and the effects of 9-1-1 are modulated by different regions of the genome. Our experiments illustrate the central role of the 9-1-1 checkpoint sliding clamp in the DNA damage response network that coordinates the response to broken DNA ends. Our results have implications in all eukaryotic cells. PMID- 25925574 TI - i-cisTarget 2015 update: generalized cis-regulatory enrichment analysis in human, mouse and fly. AB - i-cisTarget is a web tool to predict regulators of a set of genomic regions, such as ChIP-seq peaks or co-regulated/similar enhancers. i-cisTarget can also be used to identify upstream regulators and their target enhancers starting from a set of co-expressed genes. Whereas the original version of i-cisTarget was focused on Drosophila data, the 2015 update also provides support for human and mouse data. i-cisTarget detects transcription factor motifs (position weight matrices) and experimental data tracks (e.g. from ENCODE, Roadmap Epigenomics) that are enriched in the input set of regions. As experimental data tracks we include transcription factor ChIP-seq data, histone modification ChIP-seq data and open chromatin data. The underlying processing method is based on a ranking-and recovery procedure, allowing accurate determination of enrichment across heterogeneous datasets, while also discriminating direct from indirect target regions through a 'leading edge' analysis. We illustrate i-cisTarget on various Ewing sarcoma datasets to identify EWS-FLI1 targets starting from ChIP-seq, differential ATAC-seq, differential H3K27ac and differential gene expression data. Use of i-cisTarget is free and open to all, and there is no login requirement. Address: http://gbiomed.kuleuven.be/apps/lcb/i-cisTarget. PMID- 25925575 TI - Molecular insights into HSD10 disease: impact of SDR5C1 mutations on the human mitochondrial RNase P complex. AB - SDR5C1 is an amino and fatty acid dehydrogenase/reductase, moonlighting as a component of human mitochondrial RNase P, which is the enzyme removing 5' extensions of tRNAs, an early and crucial step in tRNA maturation. Moreover, a subcomplex of mitochondrial RNase P catalyzes the N(1)-methylation of purines at position 9, a modification found in most mitochondrial tRNAs and thought to stabilize their structure. Missense mutations in SDR5C1 cause a disease characterized by progressive neurodegeneration and cardiomyopathy, called HSD10 disease. We have investigated the effect of selected mutations on SDR5C1's functions. We show that pathogenic mutations impair SDR5C1-dependent dehydrogenation, tRNA processing and methylation. Some mutations disrupt the homotetramerization of SDR5C1 and/or impair its interaction with TRMT10C, the methyltransferase subunit of the mitochondrial RNase P complex. We propose that the structural and functional alterations of SDR5C1 impair mitochondrial RNA processing and modification, leading to the mitochondrial dysfunction observed in HSD10 patients. PMID- 25925576 TI - Why weight? Modelling sample and observational level variability improves power in RNA-seq analyses. AB - Variations in sample quality are frequently encountered in small RNA-sequencing experiments, and pose a major challenge in a differential expression analysis. Removal of high variation samples reduces noise, but at a cost of reducing power, thus limiting our ability to detect biologically meaningful changes. Similarly, retaining these samples in the analysis may not reveal any statistically significant changes due to the higher noise level. A compromise is to use all available data, but to down-weight the observations from more variable samples. We describe a statistical approach that facilitates this by modelling heterogeneity at both the sample and observational levels as part of the differential expression analysis. At the sample level this is achieved by fitting a log-linear variance model that includes common sample-specific or group specific parameters that are shared between genes. The estimated sample variance factors are then converted to weights and combined with observational level weights obtained from the mean-variance relationship of the log-counts-per million using 'voom'. A comprehensive analysis involving both simulations and experimental RNA-sequencing data demonstrates that this strategy leads to a universally more powerful analysis and fewer false discoveries when compared to conventional approaches. This methodology has wide application and is implemented in the open-source 'limma' package. PMID- 25925577 TI - Balancing acts of SRI and an auto-inhibitory domain specify Set2 function at transcribed chromatin. AB - Set2-mediated H3K36 methylation ubiquitously functions in coding regions in all eukaryotes. It has been linked to the regulation of acetylation states, histone exchange, alternative splicing, DNA repair and recombination. Set2 is recruited to transcribed chromatin through its SRI domain's direct association with phosphorylated Pol II. However, regulatory mechanisms for histone modifying enzymes like Set2 that travel with elongating Pol II remain largely unknown beyond their initial recruitment events. Here, by fusing Set2 to RNA Pol II, we found that the SRI domain can also recognize linker DNA of chromatin, thereby controlling Set2 substrate specificity. We also discovered that an auto inhibitory domain (AID) of Set2 primarily restricts Set2 activity to transcribed chromatin and fine-tunes several functions of SRI. Finally, we demonstrated that AID mutations caused hyperactive Set2 in vivo and displayed a synthetic interaction with the histone chaperone FACT. Our data suggest that Set2 is intrinsically regulated through multiple mechanisms and emphasize the importance of a precise temporal control of H3K36 methylation during the dynamic transcription elongation process. PMID- 25925578 TI - Structural and functional analysis reveals that human OASL binds dsRNA to enhance RIG-I signaling. AB - The oligoadenylate synthetase (OAS) enzymes are cytoplasmic dsRNA sensors belonging to the antiviral innate immune system. Upon binding to viral dsRNA, the OAS enzymes synthesize 2'-5' linked oligoadenylates (2-5As) that initiate an RNA decay pathway to impair viral replication. The human OAS-like (OASL) protein, however, does not harbor the catalytic activity required for synthesizing 2-5As and differs from the other human OAS family members by having two C-terminal ubiquitin-like domains. In spite of its lack of enzymatic activity, human OASL possesses antiviral activity. It was recently demonstrated that the ubiquitin like domains of OASL could substitute for K63-linked poly-ubiquitin and interact with the CARDs of RIG-I and thereby enhance RIG-I signaling. However, the role of the OAS-like domain of OASL remains unclear. Here we present the crystal structure of the OAS-like domain, which shows a striking similarity with activated OAS1. Furthermore, the structure of the OAS-like domain shows that OASL has a dsRNA binding groove. We demonstrate that the OAS-like domain can bind dsRNA and that mutating key residues in the dsRNA binding site is detrimental to the RIG-I signaling enhancement. Hence, binding to dsRNA is an important feature of OASL that is required for enhancing RIG-I signaling. PMID- 25925579 TI - Hamartoma of the optic nerve in a young child-case report and review of the literature. AB - PURPOSE: Hamartomas are well described but yet incompletely understood sporadic benign lesions that can arise in various locations. Hypothalamic hamartomas of infancy are often associated with severe developmental disturbances. We present a case of an infant boy with a hamartoma that arises from the optic nerve and lead to progressive unspecific seizure activity, behavioral problems and precautious puberty. METHODS: A 1-year-old male patient was presented with horizontal nystagmus and developmental retardation. Magnetic resonance imaging (MRI) with contrast revealed an isointense mass ventral of the chiasm consistent with a hamartoma. Soon after the MRI, the mother of the patient reported gelastic-like seizures. The patient was evaluated by an interdisciplinary team, and surgery was recommended. Intraoperatively, a firm attachment to the optic nerve was recognized and a thin remnant layer of tissue was left behind. RESULTS: After an uncomplicated near total resection, the patient improved significantly. After 6 months, the frequency of seizures reoccurred, which were again unresponsive to antiepileptic medication. In a second operation, a complete resection of the remnants was performed, and the patient showed lasting clinical improvement. CONCLUSION: We conclude that hamartomas mimicking hypothalamic symptoms can also arise from the optic pathway and that a reoperation, if feasible, of even small remnants is essential in order to achieve lasting symptom relieve. PMID- 25925580 TI - Transporter-mediated L-glutamate elimination from cerebrospinal fluid: possible involvement of excitatory amino acid transporters expressed in ependymal cells and choroid plexus epithelial cells. AB - BACKGROUND: L-Glutamate (L-Glu) is the major excitatory neurotransmitter in the CNS, and its level in cerebrospinal fluid (CSF) is reported to be increased in neuroexcitatory diseases such as epilepsy. Since L-Glu concentration in the CSF is reported to be lower than that in plasma, it has been proposed that some mechanisms of L-Glu clearance from the CSF operate in the brain. The purpose of this study was to elucidate the major pathway of L-Glu elimination from rat CSF and the transporters responsible. METHODS: Protein expression and localization of excitatory amino acid transporters were examined by immunohistochemical analysis using specific antibodies. In vivo elimination of L-Glu from rat CSF was evaluated by intracerebroventricular administration. An L-Glu uptake study by using primary-cultured rat ependymal cells and isolated rat choroid plexus was performed to characterize L-Glu transport mechanisms. RESULTS: An immunohistochemical analysis has shown that excitatory amino acid transporter (EAAT) 1 and EAAT3, which are D-aspartate-sensitive and kainate-insensitive L-Glu transporters, are localized on the CSF-side of rat ependymal cells and choroid plexus epithelial cells, respectively. In contrast, the kainate-sensitive L-Glu transporter, EAAT2, is not expressed in these cells. In vivo L-Glu elimination clearance from the rat CSF (189 MUL/(min . rat)) was 23-fold higher than the CSF bulk flow rate, indicating that facilitative process(es) are involved in L-Glu elimination from the CSF. The in vivo [(3)H]L-Glu elimination from the CSF was significantly inhibited by unlabeled L-Glu and D-aspartate, but not kainate. Moreover, unlabeled L-Glu and D-aspartate inhibited [(3)H]L-Glu uptake by rat ependymal cells and choroid plexus epithelial cells, whereas kainate had little effect. CONCLUSION: It is suggested that EAAT1 in ependymal cells and EAAT3 in choroid plexus epithelial cells participate in L-Glu elimination from the CSF. PMID- 25925581 TI - Projecting the benefits and harms of mammography using statistical models: proof or proofiness? PMID- 25925583 TI - A modular tethering complex for endosomal recycling. AB - How proteins migrate through the interconnected organelles of the endolysosomal system is poorly understood. A piece of the puzzle has been added with the identification of a complex of tethering factors that functions in the recycling of proteins towards the cell surface. PMID- 25925582 TI - E-cadherin junctions as active mechanical integrators in tissue dynamics. AB - During epithelial morphogenesis, E-cadherin adhesive junctions play an important part in mechanically coupling the contractile cortices of cells together, thereby distributing the stresses that drive cell rearrangements at both local and tissue levels. Here we discuss the concept that cellular contractility and E-cadherin based adhesion are functionally integrated by biomechanical feedback pathways that operate on molecular, cellular and tissue scales. PMID- 25925584 TI - Linking primary and metastatic tumour re-initiation. AB - Whether the cancer cells responsible for the growth of primary tumours are also able to re-initiate tumour growth after seeding to distant organs is unclear. The characterization of breast cancer cells with both of these attributes now identifies the functional and molecular determinants necessary to mediate primary tumour formation and re-initiation at the secondary site. PMID- 25925585 TI - AMBRA1 links autophagy to cell proliferation and tumorigenesis by promoting c-Myc dephosphorylation and degradation. PMID- 25925586 TI - The Role of Consolidative Radiotherapy after a Complete Response to Chemotherapy in the Treatment of Diffuse Large B-Cell Lymphoma in the Rituximab Era: Results from a Systematic Review with a Meta-Analysis. AB - BACKGROUND: The current standard therapy for patients with diffuse large B-cell lymphoma (DLBCL) is rituximab plus cyclophosphamide, doxorubicin, vincristine and prednisone (RCHOP). The role of radiotherapy (RT) after complete response (CR) to RCHOP in patients with DLBCL remains unclear. This systematic review with a meta analysis is an attempt to evaluate this role. METHODS: Studies that evaluated RT versus no-RT after CR to RCHOP for DLBCL patients were searched in databases. Hazard ratios (HR) with their respective 95% confidence intervals (CI) were calculated using a random-effects model. RESULTS: A total of 4 qualified retrospective studies (633 patients) were included in this review. The results suggested that RT improved overall survival (OS; HR 0.33, 95% CI 0.14-0.77) and progression-free/event-free survival (PFS/EFS; HR 0.24, 95% CI 0.11-0.50) in all patients compared with no-RT. In a subgroup analysis of patients with stage III IV DLBCL, RT improved PFS/EFS (HR 0.19, 95% CI 0.07-0.51) and local control (HR 0.12, 95% CI 0.03-0.44), with a trend of improving OS (HR 0.35, 95% CI 0.12 1.05). CONCLUSION: Consolidation RT could significantly improve outcomes of DLBCL patients who achieved a CR to RCHOP. However, the significance of these results was limited by these retrospective data. Further investigation of the role of consolidation RT in the rituximab era is needed. PMID- 25925587 TI - Endothelial alpha-parvin controls integrity of developing vasculature and is required for maintenance of cell-cell junctions. AB - RATIONALE: Angiogenesis and vessel integrity depend on the adhesion of endothelial cells (ECs) to the extracellular matrix and to adjacent ECs. The focal adhesion protein alpha-parvin (alpha-pv) is essential for vascular development. However, the role of alpha-pv in ECs in vivo is not known. OBJECTIVE: To determine the function of alpha-pv in ECs during vascular development in vivo and the underlying mechanisms. METHODS AND RESULTS: We deleted the alpha-pv gene specifically in ECs of mice to study its role in angiogenesis and vascular development. Here, we show that endothelial-specific deletion of alpha-pv in mice results in late embryonic lethality associated with hemorrhages and reduced vascular density. Postnatal-induced EC-specific deletion of alpha-pv leads to retinal hypovascularization because of reduced vessel sprouting and excessive vessel regression. In the absence of alpha-pv, blood vessels display impaired VE-cadherin junction morphology. In vitro, alpha-pv deficient ECs show reduced stable adherens junctions, decreased monolayer formation, and impaired motility, associated with reduced formation of integrin mediated cell-extracellular matrix adhesion structures and an altered actin cytoskeleton. CONCLUSIONS: Endothelial alpha-pv is essential for vessel sprouting and for vessel stability. PMID- 25925589 TI - Ureteric vasculitis, an unusual presentation of polyarteritis nodosa: a case report. AB - A 22 year old female presented with vasculitic skin rash. She was incidentally found to be hypertensive and had proteinuria. Skin biopsy showed leuco cytoclastic vasculitis. On Imaging, there was left hydronephrosis, hydroureter with bilateral multiple foci of ureteric stenosis and micro-aneurysms in relation to interlobar arteries of kidney. A diagnosis of classical Polyarteritis Nodosa (cPAN) with multi-level ureteric stenosis was made. She was treated with Glucocorticoids, Cyclophosphamide, following which Azathioprine was given. PMID- 25925588 TI - Comprehensive molecular characterization of human adipocytes reveals a transient brown phenotype. AB - BACKGROUND: Functional brown adipose tissue (BAT), involved in energy expenditure, has recently been detected in substantial amounts in adults. Formerly overlooked BAT has now become an attractive anti-obesity target. METHODS AND RESULTS: Molecular characterization of human brown and white adipocytes, using a myriad of techniques including high-throughput RNA sequencing and functional assays, showed that PAZ6 and SW872 cells exhibit classical molecular and phenotypic markers of brown and white adipocytes, respectively. However, the pre-adipocyte cell line SGBS presents a versatile phenotype. A transit expression of classical brown markers such as UCP1 and PPARgamma peaked and declined at day 28 post-differentiation initiation. Conversely, white adipocyte markers, including Tcf21, showed reciprocal behavior. Interestingly, leptin levels peaked at day 28 whereas the highest adiponectin mRNA levels were detected at day 14 of differentiation. Phenotypic analysis of the abundance and shape of lipid droplets were consistent with the molecular patterns. Accordingly, the oxidative capacity of SGBS adipocytes peaked on differentiation day 14 and declined progressively towards differentiation day 28. CONCLUSIONS: Our studies have unveiled a new phenotype of human adipocytes, providing a tool to identify molecular gene expression patterns and pathways involved in the conversion between white and brown adipocytes. PMID- 25925590 TI - Pedobacter edaphicus sp. nov. isolated from forest soil in South Korea. AB - A Gram-negative, yellow-colored, rod-shaped, strictly aerobic, motile bacterium was isolated from forest soil in Gyeongsang Province, South Korea. The strain was designated as THG-DA2.1(T). Cells of strain THG-DA2.1(T) grew optimally at pH 7.0, at temperature 28 degrees C and in the presence of 0.5 % NaCl. Based on 16S rRNA gene sequence, strain THG-DA2.1(T) was shown to belong to the genus Pedobacter and shares highest sequence similarity with Pedobacter ginsengisoli KCTC 12576(T). The DNA G+C content was determined to be 42.3 mol %. The predominant isoprenoid quinone was identified as menaquinone MK-7. The major cellular fatty acids of strain THG-DA2.1(T) were iso-C15:0 and C16:1 omega6c and/or C16:1 omega7c (summed feature 3*). Strain THG-DA2.1(T) contains phosphatidylethanolamine as major polar lipid, but an unidentified aminolipid, two unidentified phospholipids and two unidentified lipids were also detected. On the basis of the data obtained from polyphasic taxonomy in this study, strain THG DA2.1(T) is considered to represent a novel species of the genus Pedobacter, for which the name Pedobacter edaphicus sp. nov. is proposed. The type strain is THG DA2.1(T) (=KCTC 42232(T) =JCM 30351(T)). PMID- 25925591 TI - Influence of Morphine on Pharmacokinetics and Pharmacodynamics of Ticagrelor in Patients with Acute Myocardial Infarction (IMPRESSION): study protocol for a randomized controlled trial. AB - BACKGROUND: Ticagrelor is an oral platelet P2Y12 receptor antagonist which is recommended for patients suffering from myocardial infarction, both with and without persistent ST segment elevation. Morphine is the first choice drug in pain alleviation in the same clinical subset. Recently a possible negative influence of morphine on the pharmacokinetics and antiplatelet effects of P2Y12 receptor blockers has been postulated. METHODS/DESIGN: The IMPRESSION study is a phase IV, single center, randomized, double-blind, placebo-controlled clinical trial that is designed to assess the influence of morphine on the pharmacokinetics and pharmacodynamics of ticagrelor in patients with myocardial infarction. The study is planned to include up to 100 patients with myocardial infarction who will be randomized into one of two arms in a 1:1 ratio. Subjects in the intervention arm prior to the loading dose of ticagrelor (180 mg) will receive morphine (5 mg) intravenously, whereas patients in the control arm will receive a placebo prior to the loading dose of ticagrelor (180 mg). The pharmacokinetics of ticagrelor and its active metabolite (AR-C124910XX) will be assessed by liquid chromatography mass spectrometry. Platelet function testing in each patient will be performed using up to four different methods (platelet vasodilator-stimulated phosphoprotein assay, multiple electrode aggregometry, VerifyNow, and light transmission aggregometry). DISCUSSION: This study is expected to provide essential evidence-based data on the impact of morphine on the absorption of ticagrelor in patients with myocardial infarction as well as to shed some light on the suspected connection between morphine use and antiplatelet activity of ticagrelor in the same group of patients. TRIAL REGISTRATION: ClinicalTrials.gov identifier: NCT02217878 (14 August 2014). PMID- 25925593 TI - The Cultural and Linguistic Adaptation to Brazilian Portuguese and Content Validity of the Patient Expectations and Satisfaction With Prenatal Care Instrument. AB - BACKGROUND: Patient satisfaction reflects how an individual's expectations, goals, and preferences are met by health care providers or services. Most research on patient expectations and satisfaction has been conducted in developed countries; there was no Portuguese language instrument to measure pregnant women's expectations and satisfaction with prenatal care. PURPOSE: To adapt and test the Patient Expectations and Satisfaction with Prenatal Care (PESPC) instrument for use in Brazil. DESIGN: We conducted a systematic cultural and linguistic adaptation of the PESPC into Brazilian Portuguese and tested the validity of the adapted instrument. RESULTS: Implementation of this rigorous methodological process resulted in a valid, reliable, culturally, and linguistically appropriate instrument. IMPLICATIONS FOR PRACTICE: We recommend further assessment of the Brazilian Portuguese PESPC with more diverse samples of Portuguese-speaking pregnant women in Brazil and other countries. Application of this structured approach to cultural and linguistic instrument adaptation is one way to further transcultural nursing research. PMID- 25925592 TI - Antigenicity and immunogenicity of PvRALP1, a novel Plasmodium vivax rhoptry neck protein. AB - BACKGROUND: Proteins secreted from the rhoptry in Plasmodium merozoites are associated with the formation of tight junctions and parasitophorous vacuoles during invasion of erythrocytes and are sorted within the rhoptry neck or bulb. Very little information has been obtained to date about Plasmodium vivax rhoptry associated leucine (Leu) zipper-like protein 1 (PvRALP1; PVX_096245), a putative rhoptry protein. PvRALP1 contains a signal peptide, a glycine (Gly)/glutamate (Glu)-rich domain, and a Leu-rich domain, all of which are conserved in other Plasmodium species. METHODS: Recombinant PvRALP1s were expressed as full-length protein without the signal peptide (PvRALP1-Ecto) and as truncated protein consisting of the Gly/Glu- and Leu-rich domains (PvRALP1-Tr) using the wheat germ cell-free expression system. The immunoreactivity to these two fragments of recombinant PvRALP1 protein in serum samples from P. vivax-infected patients and immunized mice, including analysis of immunoglobulin G (IgG) subclasses, was evaluated by enzyme-linked immunosorbent assay or protein microarray technology. The subcellular localization of PvRALP1 in blood stage parasites was also determined. RESULTS: Recombinant PvRALP1-Ecto and PvRALP1-Tr proteins were successfully expressed, and in serum samples from P. vivax patients from the Republic of Korea, the observed immunoreactivities to these proteins had 58.9% and 55.4% sensitivity and 95.0% and 92.5% specificity, respectively. The response to PvRALP1 in humans was predominantly cytophilic antibodies (IgG1 and IgG3), but a balanced Th1/Th2 response was observed in mice. Unexpectedly, there was no significant inverse correlation between levels of parasitaemia and levels of antibody against either PvRALP1-Ecto (R2=0.11) or PvRALP1-Tr (R2=0.14) antigens. PvRALP1 was localized in the rhoptry neck of merozoites, and this was the first demonstration of the localization of this protein in P. vivax. CONCLUSIONS: This study analysed the antigenicity and immunogenicity of PvRALP1 and suggested that PvRALP1 may be immunogenic in humans during parasite infection and might play an important role during invasion of P. vivax parasites. PMID- 25925594 TI - Efavirenz alters mitochondrial respiratory function in cultured neuron and glial cell lines. AB - BACKGROUND: The NNRTI efavirenz is among the most widely employed antiretroviral drugs. Although it is considered safe, efavirenz has been linked with several adverse effects including neurological manifestations, which appear in the majority of the patients on efavirenz-containing regimens. The molecular mechanisms responsible for these manifestations are not understood, but mounting evidence points to altered brain bioenergetics. METHODS: We evaluated the effect of short-term efavirenz treatment on the mitochondrial respiratory function of cultured glioblastoma and differentiated neuroblastoma cell lines using a Seahorse Extracellular Flux Analyzer. RESULTS: Incubation with efavirenz provoked a significant and concentration-dependent decrease in basal respiration and specifically in ATP production-coupled O2 consumption in both SH-SY5Y and U-251MG cells, with the effect being more pronounced in the latter. In contrast, efavirenz did not alter mitochondrial proton leakage in either of the cell types. Efavirenz led to a decrease in the respiratory control ratio as well as to a reduction in the maximal respiration rate and spare respiratory capacity in both U-251MG and SH-SY5Y cells, the former cells being more susceptible. CONCLUSIONS: These findings reveal that efavirenz specifically alters mitochondrial respiration, which is of relevance for a better understanding of the molecular mechanisms responsible for the efavirenz-associated neurological effects that have been recorded in clinical situations. PMID- 25925596 TI - Recurrence of dual-strain Clostridium difficile infection in an in vitro human gut model. AB - BACKGROUND: Clostridium difficile infection (CDI) is still a major challenge to healthcare facilities. The detection of multiple C. difficile strains has been reported in some patient samples during initial and recurrent CDI episodes. However, the behaviour of individual strains and their contribution to symptomatic disease is unclear. METHODS: An in vitro human gut model was used to investigate the germination and proliferation of two distinct C. difficile strains during initial and recurrent simulated CDI, as well as their response to vancomycin treatment. The gut model was inoculated with a pooled human faecal emulsion and indigenous gut microbiota, C. difficile populations (vegetative and spore forms), cytotoxin levels and antimicrobial activity were monitored throughout the experiment. RESULTS: Both C. difficile strains germinated and proliferated in response to ceftriaxone instillation, with cytotoxin detected during the peak vegetative growth. Vancomycin instillation resulted in a rapid decline in the vegetative forms of both strains, with only spores remaining 2 days after the start of dosing. A recrudescence of both strains occurred following the cessation of vancomycin installation, although this was observed more quickly, and to a greater extent, in one strain than the other. CONCLUSIONS: Within a human gut model, multiple C. difficile strains are able to germinate and proliferate concurrently in response to antibiotic challenge (the onset of simulated CDI). Similarly, more than one strain can proliferate during simulated recurrent CDI, although with differences in germination and growth rate and timing. It appears probable that multiple strains can contribute to CDI within an individual patient, with possible implications for management and bacterial transmission. PMID- 25925595 TI - Incidence and nature of adverse reactions to antibiotics used as endocarditis prophylaxis. AB - OBJECTIVES: Antibiotic prophylaxis (AP) administration prior to invasive dental procedures has been a leading focus of infective endocarditis prevention. However, there have been long-standing concerns about the risk of adverse drug reactions as a result of this practice. The objective of this study was to identify the incidence and nature of adverse reactions to amoxicillin and clindamycin prophylaxis to prevent infective endocarditis. METHODS: We obtained AP prescribing data for England from January 2004 to March 2014 from the NHS Business Services Authority, and adverse drug reaction data from the Medicines and Healthcare Products Regulatory Agency's Yellow Card reporting scheme for prescriptions of the standard AP protocol of a single 3 g oral dose of amoxicillin or a single 600 mg oral dose of clindamycin for those allergic to penicillin. RESULTS: The reported adverse drug reaction rate for amoxicillin AP was 0 fatal reactions/million prescriptions (in fact 0 fatal reactions for nearly 3 million prescriptions) and 22.62 non-fatal reactions/million prescriptions. For clindamycin, it was 13 fatal and 149 non-fatal reactions/million prescriptions. Most clindamycin adverse drug reactions were Clostridium difficile infections. CONCLUSIONS: AP adverse drug reaction reporting rates in England were low, particularly for amoxicillin, and lower than previous estimates. This suggests that amoxicillin AP is comparatively safe for patients without a history of amoxicillin allergy. The use of clindamycin AP was, however, associated with significant rates of fatal and non-fatal adverse drug reactions associated with C. difficile infections. These were higher than expected and similar to those for other doses, durations and routes of clindamycin administration. PMID- 25925597 TI - Estimation of Detection Rates of Aneuploidy in High-Risk Pregnancy Using an Approach Based on Nuchal Translucency and Non-Invasive Prenatal Testing: A Cohort Study. AB - OBJECTIVES: The aim was to investigate aneuploidy detection using an approach based on nuchal translucency (NT) and non-invasive prenatal testing (NIPT). METHODS: This was a cohort study including 5,306 high-risk pregnancies with NT measurements and chorionic villus samples (CVS) tested for full karyotype. RESULTS: The fetal karyotype was normal in 4,172 (78.6%) cases and abnormal in 1,134 (21.4%), including 1,009 with a likely clinically significant adverse outcome. Universal CVS with full karyotyping would lead to the diagnosis of all clinically significant abnormalities. A policy of relying solely on NIPT would have led to the diagnosis of 88.9% of clinically significant abnormalities. A strategy whereby NIPT is the main method, with CVS reserved for cases with NT >=3.0 mm, would require CVS in 21.7% of cases, identify 94.8% of significant abnormalities and avoid miscarriage in 41 pregnancies compared to CVS for all. CONCLUSIONS: A policy of NIPT for increased-risk cases and CVS with full karyotype if the NT was >=3.0 mm reduced the risk of miscarriage yet still identified 95% of clinically significant aneuploidy. PMID- 25925598 TI - Validation of the geriatric anxiety inventory in a duloxetine clinical trial for elderly adults with generalized anxiety disorder. AB - BACKGROUND: The Generalized Anxiety Inventory (GAI) has been developed for use in the assessment of anxiety symptoms in older adults (>= 65 years), but previous validation work has not examined the psychometric qualities of the instrument in relation to treatment. The objective of this study was to examine the performance of the GAI for its internal reliability, convergent and divergent validity, and its sensitivity to treatment. METHODS: Elderly patients with generalized anxiety disorder (GAD) participated in a 10-week double-blind study of duloxetine treatment for patients with GAD. Anxiety symptoms were assessed with the Hamilton Anxiety Rating Scale (HAMA), the Hospital Anxiety and Depression Scale (HADS) anxiety and depression subscales, and the GAI. Internal reliability of the GAI was assessed with Cronbach's alpha. Correlations among the HAMA, HADS, and GAI scores were analyzed to determine convergent and divergent validity. Patients were also compared on remission status using recommended cut-off scores for the GAI. RESULTS: Patients with GAD, who were at least 65 years of age, were randomly assigned to double-blind treatment with either duloxetine (N = 151) or placebo (N = 140) for 10 weeks acute therapy. The mean change on the GAI was significantly greater with duloxetine compared with placebo treatment (-8.36 vs. -4.96, respectively, p <= 0.001). The GAI demonstrated good internal consistency, good convergent and divergent validity, but suggested cut-off values for caseness with the GAI did not correspond to remission status as measured by the HAMA. CONCLUSIONS: Within an elderly patient population with GAD, the GAI demonstrated sound psychometric qualities and sensitivity to change with treatment. PMID- 25925599 TI - Development and validation of the Penn Arthralgia Aging Scale among breast cancer survivors. AB - BACKGROUND: Breast cancer survivors on aromatase inhibitors often experience joint pain as a side effect of their treatment; qualitative investigations suggest that this arthralgia may cause women to feel that they are aging faster than they should be. To facilitate further study of this experience, the Penn Arthralgia Aging Scale (PAAS) was developed. This report describes the development and validation of the PAAS in a racially diverse sample of breast cancer survivors suffering from joint pain. METHODS: The items of the scale were developed from a content analysis of interviews with patients. The scale was pilot-tested, and modifications were made on the basis of patient feedback. Subsequently, 596 breast cancer survivors who endorsed joint pain completed the 8 item PAAS. The factor structure (with exploratory factor analysis), the internal consistency, and the convergent, divergent, and incremental validity were examined. RESULTS: The resulting scale had a 1-factor structure with strong internal consistency (Cronbach's alpha = .94) and demonstrated both convergent and divergent validity: the PAAS was significantly correlated with joint pain severity (rs = 0.55, P < .01) and had a small and nonsignificant correlation with actual age (rs = -0.07, P = .10). The PAAS was also found to explain incremental variance in anxiety, depression, and pain interference outcomes. CONCLUSIONS: These findings suggest that the PAAS produces reliable and valid scores that capture perceptions of aging due to arthralgia among breast cancer survivors. With further research, the PAAS may advance our understanding of how perceptions of aging may affect breast cancer survivors' emotional, behavioral, and clinical outcomes. PMID- 25925600 TI - Confusing what you heard with what you did: False action-memories from auditory cues. AB - Creating a mental image of one's own performance, observing someone else performing an action, and viewing a photograph of a completed action all can lead to the illusory recollection that one has performed this action. While there are fundamental differences in the nature of these three processes, they are aligned by the fact that they involve primarily or solely the visual modality. According to the source-monitoring framework, the corresponding visual memory traces later can be mistakenly attributed to self-performance. However, when people perform actions, they do not only engage vision, but also other modalities, such as auditory and tactile systems. The present study focused on the role of audition in the creation of false beliefs about performing an action and explored whether auditory cues alone-in the absence of any visual cues-can induce false beliefs and memories for actions. After performing a series of simple actions, participants listened to the sound of someone performing various actions, watched someone perform the actions, or simultaneously both heard and saw someone perform them. Some of these actions had been performed earlier by the participants and others were new. A later source-memory test revealed that all three types of processing (hearing, seeing, or hearing plus seeing someone perform the actions) led to comparable increases in false claims of having performed actions oneself. The potential mechanisms underlying false action-memories from sound and vision are discussed. PMID- 25925601 TI - A novel human model of the neurodegenerative disease GM1 gangliosidosis using induced pluripotent stem cells demonstrates inflammasome activation. AB - GM1 gangliosidosis (GM1) is an inherited neurodegenerative disorder caused by mutations in the lysosomal beta-galactosidase (beta-gal) gene. Insufficient beta gal activity leads to abnormal accumulation of GM1 gangliosides in tissues, particularly in the central nervous system, resulting in progressive neurodegeneration. Here, we report an in vitro human GM1 model, based on induced pluripotent stem cell (iPSC) technology. Neural progenitor cells differentiated from GM1 patient-derived iPSCs (GM1-NPCs) recapitulated the biochemical and molecular phenotypes of GM1, including defective beta-gal activity and increased lysosomes. Importantly, the characterization of GM1-NPCs established that GM1 is significantly associated with the activation of inflammasomes, which play a critical role in the pathogenesis of various neurodegenerative diseases. Specific inflammasome inhibitors potently alleviated the disease-related phenotypes of GM1 NPCs in vitro and in vivo. Our data demonstrate that GM1-NPCs are a valuable in vitro human GM1 model and suggest that inflammasome activation is a novel target pathway for GM1 drug development. PMID- 25925602 TI - Effect of Leukocyte Concentration on the Efficacy of Platelet-Rich Plasma in the Treatment of Knee Osteoarthritis. AB - BACKGROUND: Leukocyte-poor platelet-rich plasma (LP-PRP) is hypothesized to be more suitable for intra-articular injection than leukocyte-rich PRP (LR-PRP) in the treatment of knee osteoarthritis. PURPOSE: To compare clinical outcomes and rates of adverse reactions between LP-PRP and LR-PRP for this application. STUDY DESIGN: Meta-analysis. METHODS: The MEDLINE, EMBASE, and Cochrane databases were reviewed. The primary outcome was the incidence of local adverse reactions. Secondary outcomes were the changes in International Knee Documentation Committee (IKDC) subjective score and Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC) score between baseline and final follow-up measurements. A Bayesian network meta-analysis was performed, with a post hoc meta-regression to correct for baseline differences in WOMAC scores. Treatment rankings were based on surface under the cumulative ranking (SUCRA) probabilities. RESULTS: Included in the analysis were 6 randomized controlled trials (evidence level 1) and 3 prospective comparative studies (evidence level 2) with a total of 1055 patients. Injection of LP-PRP resulted in significantly better WOMAC scores than did injection of hyaluronic acid (mean difference, 21.14; 95% CI, -39.63 to -2.65) or placebo (mean difference, -17.84; 95% CI, 34.95 to -0.73). No such difference was observed with LR-PRP (mean difference, 14.28; 95% CI, -44.80 to 16.25). All treatment groups resulted in equivalent IKDC subjective scores. The SUCRA analysis showed that LP-PRP was the highest ranked treatment for both measures of clinical efficacy (WOMAC and IKDC). Finally, PRP injections resulted in a higher incidence of adverse reactions than hyaluronic acid (odds ratio, 5.63; 95% CI, 1.38-22.90), but there was no difference between LR-PRP and LP-PRP (odds ratio, 0.78; 95% CI, 0.05-11.93). These reactions were nearly always local swelling and pain, with a single study reporting medical side effects including syncope, dizziness, headache, gastritis, and tachycardia (17/1055 total patients). CONCLUSION: LP-PRP results in improved functional outcome scores compared with hyaluronic acid and placebo when used for treatment of knee osteoarthritis. LP-PRP and LR-PRP have similar safety profiles, although both induce more transient reactions than does hyaluronic acid. Adverse reactions to PRP may not be directly related to leukocyte concentration. PMID- 25925603 TI - Prevalence of Ulnar Collateral Ligament Surgery in Professional Baseball Players. AB - BACKGROUND: While the high rate of ulnar collateral ligament (UCL) injuries in professional baseball is widely discussed in the media and medical literature, the actual prevalence of UCL reconstruction has not been documented. HYPOTHESIS: The prevalence of UCL reconstruction will be higher among pitchers than nonpitchers, and Major League Baseball (MLB) pitchers will have a higher prevalence than will minor league pitchers. STUDY DESIGN: Descriptive epidemiology study. METHODS: An online questionnaire was distributed to all 30 MLB organizations. Certified athletic trainers from each team administered the questionnaire to all players in the organization, including major league players and 6 levels of minor league players. Demographic data were compared between major and minor league players. Continuous variables (age, years of professional baseball, country of origin, etc) were compared with Student t tests (P < .05). Categorical variables (level, position, etc) were compared using chi-square analysis (P < .05). RESULTS: A total of 5088 professional baseball players (722 major league and 4366 minor league) participated in the survey. Pitchers represented 53% of all players, and 497 players reported at least 1 UCL reconstruction, demonstrating a prevalence rate of 10% (497 of 5088). Pitchers reported a significantly higher prevalence of UCL reconstruction (16%; 437 of 2706) than nonpitchers (3%; 60 of 2382; P < .001). Among major league pitchers, 25% (96 of 382) had a history of UCL reconstruction, while minor league pitchers showed a 15% (341 of 2324) prevalence (P < .001). Major league pitchers were also significantly older (28.8 +/- 3.9 years) than minor league pitchers (22.8 +/- 3.0; P < .001). The majority of major leaguers (86%) had their UCL reconstruction as professional pitchers, whereas the majority of minor league pitchers (61%) underwent their UCL reconstruction during high school and college (P < .001). The rates of UCL revision, prior elbow surgery, prior shoulder surgery, and types of UCL graft were similar between the major league and minor league pitchers. No difference in prevalence was shown between pitchers born in the United States versus Latin American countries. CONCLUSION: Pitchers have a high prevalence of UCL reconstruction in professional baseball, with 25% of major league pitchers and 15% of minor league pitchers having a history of the surgery. PMID- 25925604 TI - Is the Chain of Oxidation and Reduction Process Reversible in Luminescent Graphene Quantum Dots? AB - Graphene-based quantum dots (QDs) have received a tremendous amount of attention as a new type of light-emitting materials. However, their luminescence origins remain controversial due to extrinsic states of the impurities and disorder structures. Especially, the function of oxygen-contents should be understood and controlled as a crucial element for tuning the optical properties of graphene based QDs. Herein, a series of graphene oxide QDs (GOQDs) with different amounts of oxygen-contents are first synthesized via a direct oxidation route of graphite nanoparticle and thoroughly compared with a series of reduced GOQDs (rGOQDs) prepared by the conventional chemical reduction. Irreversible emission and different carrier dynamics are observed between the GOQDs and rGOQDs, although both routes show a similar tendency with regard to the variation of oxygen functional components. Their luminescence mechanisms are closely associated with different atomic structures. The mechanism for the rGOQDs can be associated with a formation of small sp(2) nanodomains as luminescent centers, whereas those of GOQDs may be composed of oxygen-islands with difference sizes depending on oxidation conditions surrounded by a large area of sp(2) bonding. Important insights for understanding the optical properties of graphene-based QDs and how they are affected by oxygen-functional groups are shown. PMID- 25925605 TI - "Suddenly Having two Positive People who are Carriers is a Whole New Thing" - Experiences of Couples Both Identified as Carriers of Cystic Fibrosis Through a Population-Based Carrier Screening Program in Australia. AB - A population-based CF carrier screening program was implemented in Victoria, Australia in 2006. This study explored the experiences of couples when both partners were identified as CF carriers. Between January 2006 and December 2010, 10 carrier couples were identified and invited to undertake a semi-structured interview. Nine interviews were conducted, seven couple interviews and two individual interviews. One couple declined to participate due to the recent termination of an affected pregnancy. Interviews were analyzed using inductive content analysis. All couples experienced surprise on learning their carrier couple result. The couples who were pregnant at the time of screening chose to have prenatal diagnosis, with the majority considering it to be the "next step." The two couples who had an affected pregnancy reported feelings of devastation and grief upon receiving their prenatal diagnosis result and terminated the pregnancy. All carrier couples were offered free genetic counseling, with only one couple declining the offer. Couples were unprepared for a positive carrier couple result. However, all the couples changed their reproductive behavior as a result of their carrier status. The results of this study have been used to inform the program and service offered to CF carrier couples particularly with respect to genetic counseling for reproductive decision making. PMID- 25925606 TI - Genetics and Personal Insurance: the Perspectives of Canadian Cancer Genetic Counselors. AB - Genetic discrimination in the context of genetic testing has been identified as a concern for symptomatic and asymptomatic individuals for more than three decades. Genetic counselors are often the health care professionals who discuss risks and benefits of genetic testing with patients, thereby making them most appropriate to address patient concerns about genetics and personal insurance (i.e., life, life as related to mortgage or group insurance, disability, critical illness and travel). A pilot study was conducted to ascertain the current practices of Canadian cancer genetic counselors in regard to their discussions with patients about genetic testing and access to personal insurance. Among the 36 counselors surveyed, 100 % reported discussing the issue of genetic testing and personal insurance with their patients. Several factors influenced the content, depth and length of these discussions including age, cancer status, family members, and patients' current and future insurance needs. Counselors reported discussing with patients the possible impact of genetic test results on access to personal insurance, possible access and use of patient genetic information by insurance companies, and whom patients should contact if they have additional questions. The most commonly reported inquiries from patients included questions about the possible impact of genetic testing on their ability to obtain insurance, and the insurability of family members. While 28 % of counselors reported having been contacted by an insurer requesting access to patient information, only one counselor was aware of or could recall the outcome of such a request. This pilot study revealed that issues concerning genetics and personal insurance are commonly discussed in Canadian cancer genetic counseling sessions. Counselors furthermore expressed a need for additional educational resources on the topic of genetics and personal insurance for themselves and their patients. PMID- 25925607 TI - Attitudes and Knowledge of Maternal-Fetal Medicine Fellows Regarding Noninvasive Prenatal Testing. AB - Using cell-free DNA in maternal serum to detect fetal aneuploidy has been shown to have high sensitivity and specificity. The purpose of this study was to assess attitudes and knowledge of Maternal-Fetal Medicine (MFM) fellows regarding noninvasive prenatal testing (NIPT). A 13 question survey was sent via listserv to US-based MFM fellows. One hundred sixteen fellows responded, a 42.3% response rate, with >75% reporting they are comfortable ordering NIPT. Most (82%) preferred that a patient discuss options with a provider or genetic counselor. Three common methods used to learn about NIPT were: formal educational activities (n = 78, 69%), self-review of the literature (n = 76, 67%), and discussions with peers (n = 73, 65%). On questions related to trisomy 21, accuracy was >70%. However, accuracy was lower regarding use in twin pregnancies (42%) and monosomy X screening (50%). PMID- 25925608 TI - From-core and from-end direct C-H arylations: a step-saving new synthetic route to thieno[3,4-c]pyrrole-4,6-dione (TPD)-incorporated D--pi-A-pi-D functional oligoaryls. AB - In contrast to the traditional multistep synthesis, herein an efficient and fewer steps new synthetic strategy is demonstrated for the facile preparation of organic-electronically important D-pi-A-pi-D-type oligoaryls through sequential direct C?H arylations. This methodology has shown that the synthesis of thieno[3,4-c]pyrrole-4,6-dione (TPD)- or furano[3,4-c]pyrrole-4,6-dione (FPD) centred target molecules could be accessed step-economically either from the core structure (acceptor) or from the end structure (donor), which supplied a more flexible and succinct new synthetic alternative to the preparation of the pi functional small-molecule semiconducting materials. In addition, optical and electrochemical properties of the synthesized oligoaryls were examined. PMID- 25925609 TI - Effect of Preterm Birth on Postnatal Apolipoprotein and Adipocytokine Profiles. AB - BACKGROUND: Critical metabolic changes preparing for ex utero life may occur at the fetal age of approximately 28-32 weeks, and preterm birth <28 weeks postmenstrual age (PMA) may affect these pathways. Children born <28 weeks often have poorer outcomes possibly due to a major shift in metabolism, including nutritional supply and a shift in lipid-transporting particles and lipid profile. This shift may occur in apolipoprotein and adipocytokine levels, which may influence metabolism. OBJECTIVE: To determine whether there is a shift in apolipoprotein and adipocytokine levels in neonates born at a gestational age (GA) of 28 and 32 weeks, respectively. METHODS: Blood samples from 47 infants (GA 32 weeks, n = 30 and GA 28 weeks, n = 17) were collected at birth and, in the GA28 group, also at PMA 32 weeks. Apolipoproteins A-1, A-2, B, C-2, C-3, and E were analyzed, as well as adiponectin and leptin levels. RESULTS: Serum levels of apolipoproteins A-1, C-2, C-3, and E were lower at birth in the GA28 group compared to the GA32 group. Adiponectin and leptin levels were low at birth in the GA28 group. In the GA28 group 4 weeks after birth, leptin levels were still low, whereas adiponectin levels had increased to levels similar to those found at birth in the GA32 group. Apolipoprotein A-1, C-2, C-3, and E levels were negatively correlated with days receiving total parenteral nutrition. CONCLUSION: There are significant differences in apolipoprotein and adipocytokine levels, which can be associated with GA and birth weight. The impact of these changes on neonatal and future morbidity remains to be determined. PMID- 25925611 TI - Erratum. PMID- 25925610 TI - Filamin B Enhances the Invasiveness of Cancer Cells into 3D Collagen Matrices. AB - Numerous types of cancer cells migrate into extracellular tissues. This phenomenon is termed invasion, and is associated with poor prognosis in cancer patients. In this study, we demonstrated that filamin B (FLNb), an actin-binding protein, is highly expressed in cancer cell lines that exhibit high invasiveness, with a spindle morphology, into 3D collagen matrices. In addition, we determined that knockdown of FLNb in invasive cancer cells converts cell morphology from spindle-shaped, which is associated with high invasiveness, to round-shaped with low invasiveness. Furthermore, di-phosphorylation of myosin regulatory light chain (MRLC) and phosphorylation of focal adhesion kinase (FAK) are inhibited in FLNb-knockdown cancer cells. These results suggest that FLNb enhances invasion of cancer cells through phosphorylation of MRLC and FAK. Therefore, FLNb may be a new therapeutic target for invasive cancers. PMID- 25925612 TI - The Short-Term Remission of Diabetic Nephropathy After Roux-en-Y Gastric Bypass in Chinese Patients of T2DM with Obesity. AB - The study aimed to examine the effect of gastric bypass on diabetic nephropathy (DN) in Chinese patients. A retrospective study of 101 samples with DN stages I to IV underwent Roux-en-Y gastric bypass. Anthropometric and biochemical parameters were assessed during a 1-year follow-up. Binary logistic regression analysis was used for predictors and ROC for cutoff points. There was significant reduction of medication for diabetes and hypertension. Overall remission of T2DM was 80.2 %. Preoperative albumin/creatinine ratio (ACR) and serum creatinine (SCr) levels could be predictors for DN remission, and the cutoff points were 126 mg/g cr and 57 MUmol/L, respectively. Gastric bypass showed improvement of T2DM and DN. Gastric bypass may be more beneficial for those with lower preoperative ACR and SCr. PMID- 25925613 TI - The role of bone marrow biopsy and FDG-PET/CT in identifying bone marrow infiltration in the initial diagnosis of high grade non-Hodgkin B-cell lymphoma and Hodgkin lymphoma. Accuracy in a multicenter series of 372 patients. AB - Bone marrow infiltration (BMI), categorized as an extra-nodal site, affects stage and is associated with poor prognosis in newly diagnosed lymphoma patients. We have evaluated the accuracy of PET/CT and bone marrow biopsy (BMB) to assess BMI in 372 lymphoma patients [140 Hodgkin Lymphoma (HL) and 232 High Grade B-cell non Hodgkin Lymphoma (HG B-NHL), among them 155 Diffuse Large B-Cell Lymphoma (DLCL)]. For HL cases, and taking into account PET/CT, sensitivity, negative predictive value (NPV) and accuracy were 96.7, 99.3, and 99.3% while those of BMB were 32.3, 83.8, and 85%, respectively. For HG B-NHL and considering PET/CT, sensitivity, NPV, and accuracy were 52.7, 81.7, and 84.1%, while those of BMB were 77.6, 90.2, and 90.7%, respectively. In the HG B-NHL group, 25 patients would have been under-staged without BMB. These results lead us to recommend PET/CT and the avoidance of BMB to assess BMI in HL. In the case of HG B-NHL, bone marrow status should be assessed firstly by means of PET/CT; only in either focal or diffuse PET/CT with low borderline SUV max values or in negative cases, should BMB be carried out afterwards. In the HG B-NHL setting and at the present moment, both techniques are complementary. PMID- 25925614 TI - A Fluxional Copper Acetylide Cluster in CuAAC Catalysis. AB - A molecularly defined copper acetylide cluster with ancillary N-heterocyclic carbene (NHC) ligands was prepared under acidic reaction conditions. This cluster is the first molecular copper acetylide complex that features high activity in copper-catalyzed azide-alkyne cycloadditions (CuAAC) with added acetic acid even at -5 degrees C. Ethyl propiolate protonates the acetate ligands of the dinuclear precursor complex to release acetic acid and replaces one out of four ancillary ligands. Two copper(I) ions are thereby liberated to form the core of a yellow dicationic C2-symmetric hexa-NHC octacopper hexaacetylide cluster. Coalescence phenomena in low-temperature NMR experiments reveal fluxionality that leads to the facile interconversion of all of the NHC and acetylide positions. Kinetic investigations provide insight into the influence of copper acetylide coordination modes and the acetic acid on catalytic activity. The interdependence of "click" activity and copper acetylide aggregation beyond dinuclear intermediates adds a new dimension of complexity to our mechanistic understanding of the CuAAC reaction. PMID- 25925616 TI - Success/Failure Prediction of Noninvasive Mechanical Ventilation in Intensive Care Units. Using Multiclassifiers and Feature Selection Methods. AB - OBJECTIVES: This paper addresses the problem of decision-making in relation to the administration of noninvasive mechanical ventilation (NIMV) in intensive care units. METHODS: Data mining methods were employed to find out the factors influencing the success/failure of NIMV and to predict its results in future patients. These artificial intelligence-based methods have not been applied in this field in spite of the good results obtained in other medical areas. RESULTS: Feature selection methods provided the most influential variables in the success/failure of NIMV, such as NIMV hours, PaCO2 at the start, PaO2 / FiO2 ratio at the start, hematocrit at the start or PaO2 / FiO2 ratio after two hours. These methods were also used in the preprocessing step with the aim of improving the results of the classifiers. The algorithms provided the best results when the dataset used as input was the one containing the attributes selected with the CFS method. CONCLUSIONS: Data mining methods can be successfully applied to determine the most influential factors in the success/failure of NIMV and also to predict NIMV results in future patients. The results provided by classifiers can be improved by preprocessing the data with feature selection techniques. PMID- 25925615 TI - Adjuvant therapy following surgery in non-small cell lung cancer (NSCLC). AB - Non-small cell lung cancer (NSCLC) accounts for 80-90 % of cases of primary lung cancer. Although surgery is recommended as the primary treatment for early-stage NSCLC, the prognosis is unsatisfactory even when complete resection is achieved. Recent clinical trials have shown that postoperative adjuvant chemotherapy with cytotoxic agents, namely uracil-tegafur (UFT) for stage IA (>2 cm in diameter)-IB patients or cisplatin-based regimens for stage II-IIIA patients, improves the prognosis, and adjuvant chemotherapy is recommended as the "standard treatment of care." However, adjuvant chemotherapy provides only a modest 5-year survival benefit of 4 % and may sometimes be fatal. To improve the risk-benefit balance of adjuvant chemotherapy, targeting agents such as antibodies against vascular endothelial growth factor (VEGF) and tyrosine-kinase inhibitors of epidermal growth factor receptor (EGFR-TKIs) are being evaluated in ongoing adjuvant trials. Another promising approach may be the individualization of adjuvant chemotherapy based on biomarkers that may predict the prognosis or benefits associated with adjuvant chemotherapy. The current status and future perspectives of adjuvant chemotherapy for NSCLC are reviewed and discussed. PMID- 25925617 TI - Implications of female sex on stroke risk factors, care, outcome and rehabilitation: an Asian perspective. AB - BACKGROUND: Stroke affects 16.9 million people annually and the greatest burden of stroke is in low- and middle-income countries, where 69% of all strokes occur. Stroke risk factors, mortality and outcomes differ in developing countries as compared to the developed world. We performed a literature review of 28 articles pertaining to epidemiology of stroke in Asian women, stroke risk factors, gender related differences, and stroke outcomes. SUMMARY: Asian women differ from women worldwide due to differences in stroke awareness, risk factor profile, stroke subtypes, and social issues that impact stroke care. While Asian men have a higher incidence of stroke as compared to women overall, the long- and short-term outcomes in Asian women tend to be poorer. Both conventional and gender-specific risk factors contribute to stroke risk. Oral contraceptive use and addictions such as tobacco and alcohol are less prevalent among Asian women due to socio cultural differences. There is however, a much higher preponderance of pregnancy related stroke and cardio-embolic stroke secondary to rheumatic heart disease and heavy use of chewing tobacco. The overall outcome is poor due to poor access to health care and lack of resources. Key Messages: Our review exposed the gaps in our knowledge about stroke risk factors and differences in stroke care provided to Asian women. While there are sociocultural barriers that impede the provision of immediate care to these stroke patients, much needs to be done by way of prevention of recurrent stroke and treatment of risk factors. PMID- 25925618 TI - Antibody-drug conjugates in non-Hodgkin lymphoma. PMID- 25925620 TI - Spine surgical research: searching for absolute truth in the era of "big data". PMID- 25925619 TI - Safety and activity of the anti-CD79B antibody-drug conjugate polatuzumab vedotin in relapsed or refractory B-cell non-Hodgkin lymphoma and chronic lymphocytic leukaemia: a phase 1 study. AB - BACKGROUND: Patients with relapsed or refractory B-cell non-Hodgkin lymphoma (NHL) have an unfavourable prognosis with few treatment options. Polatuzumab vedotin is an antibody-drug conjugate containing an anti-CD79B monoclonal antibody conjugated to the microtubule-disrupting agent monomethyl auristatin E. We aimed to assess the safety and clinical activity of polatuzumab vedotin in relapsed or refractory B-cell NHL and chronic lymphocytic leukaemia (CLL). METHODS: In this phase 1, multicentre, open-label study, we enrolled patients with documented NHL or CLL expected to express CD79B (confirmation of CD79B expression was not required) and for whom no suitable therapy of curative intent or higher priority existed from 13 centres. The primary endpoints of the study were to assess safety and tolerability, determine the maximum tolerated dose, and identify the recommended phase 2 dose of polatuzumab vedotin as a single agent and in combination with rituximab. A 3 + 3 dose-escalation design was used in which we treated patients with polatuzumab vedotin (0.1-2.4 mg/kg every 21 days) in separate dose-escalation cohorts for NHL and CLL. After determination of the recommended phase 2 dose, we enrolled patients with relapsed or refractory diffuse large B-cell lymphoma and relapsed or refractory indolent NHL into indication-specific cohorts. We also enrolled patients with relapsed or refractory NHL into an additional cohort to assess the feasibility of the combination of polatuzumab vedotin and rituximab 375 mg/m(2). Patients who received any dose of polatuzumab vedotin were available for safety analyses. This study is registered with ClinicalTrials.gov, number NCT01290549. FINDINGS: Between March 21, 2011, and Nov 30, 2012, we enrolled 95 patients (34 to the NHL dose-escalation cohort, 18 to the CLL dose-escalation cohort, 34 with NHL to the expansion cohort at the recommended phase 2 dose, and nine with NHL to the rituximab combination cohort; no expansion cohort of CLL was started due to lack of activity in the dose-escalation cohort). The recommended phase 2 dose in NHL was 2.4 mg/kg as a single agent and in combination with rituximab; the maximum tolerated dose in CLL was 1.0 mg/kg as a result of dose-limiting toxic effects reported in two of five patients given 1.8 mg/kg. Grade 3-4 adverse events were reported in 26 (58%) of 45 patients with NHL treated at the single-agent recommended phase 2 dose, and the most common grade 3-4 adverse events were neutropenia (18 [40%] of 45), anaemia (five [11%]), and peripheral sensory neuropathy (four [9%]). Serious adverse events were reported in 17 (38%) of 45 patients, and included diarrhoea (two patients), lung infection (two patients), disease progression (two patients), and lung disorder (two patients). Seven (77%) of nine patients in the rituximab combination cohort had a grade 3-4 adverse event, with neutropenia (five [56%]), anaemia (two [22%]), and febrile neutropenia (two [22%]) reported in more than one patient. 11 (12%) of 95 patients died during the study: eight with relapsed or refractory diffuse large B cell lymphoma (due to progressive disease in four patients, infections in three patients [two treatment related], and treatment-related worsening ascites in one patient) and three with relapsed or refractory CLL (due to progressive disease, pulmonary infection, and pneumonia; none thought to be treatment-related). At the recommended phase 2 dose, objective responses were noted in 23 of 42 activity evaluable patients with NHL given single-agent polatuzumab vedotin (14 of 25 with diffuse large B-cell lymphoma, seven of 15 with indolent NHL, and two with mantle cell lymphoma) and seven of nine patients treated with polatuzumab vedotin combined with rituximab. No objective responses were observed in patients with CLL. INTERPRETATION: Polatuzumab vedotin has an acceptable safety and tolerability profile in patients with NHL but not in those with CLL. Its clinical activity should be further assessed in NHL. FUNDING: Genentech. PMID- 25925621 TI - Spine fellowships, ESPN rankings, and the AP Top 25. PMID- 25925622 TI - Re: Evaniew N, Yarascavitch B, Madden K, Ghert M, Drew B, Bhandari M, et al. Atlantoaxial instability in acute odontoid fractures is associated with nonunion and mortality. Spine J 2015;15:910-7. PMID- 25925623 TI - A novel approach to patients with acute odontoid fractures: atlantoaxial instability as a prognostic variable. AB - COMMENTARY ON: Liu S, Liu L. Re: Evaniew N, Yarascavitch B, Madden K, Ghert M, Drew B, Bhandari M, et al. Atlantoaxial instability in acute odontoid fractures is associated with nonunion and mortality. Spine J 2015;15:1160 (in this issue). PMID- 25925624 TI - Ten-year follow-up in pregnancy and lactation-associated osteoporosis: sequential therapy with strontium ranelate and ibandronate. PMID- 25925625 TI - Letter to the editor regarding: "Evaluation of topical application and systemic administration of rosuvastatin in preventing epidural fibrosis in rats" by Bora Gurer et al. PMID- 25925627 TI - Laparoscopic hysterectomy: weigh harms, but do not dismiss benefits. PMID- 25925626 TI - Radiotherapeutic and surgical management for newly diagnosed brain metastasis(es): An American Society for Radiation Oncology evidence-based guideline. AB - PURPOSE: To systematically review the evidence for the radiotherapeutic and surgical management of patients newly diagnosed with intraparenchymal brain metastases. METHODS AND MATERIALS: Key clinical questions to be addressed in this evidence-based Guideline were identified. Fully published randomized controlled trials dealing with the management of newly diagnosed intraparenchymal brain metastases were searched systematically and reviewed. The U.S. Preventative Services Task Force levels of evidence were used to classify various options of management. RESULTS: The choice of management in patients with newly diagnosed single or multiple brain metastases depends on estimated prognosis and the aims of treatment (survival, local treated lesion control, distant brain control, neurocognitive preservation). Single brain metastasis and good prognosis (expected survival 3 months or more): For a single brain metastasis larger than 3 to 4 cm and amenable to safe complete resection, whole brain radiotherapy (WBRT) and surgery (level 1) should be considered. Another alternative is surgery and radiosurgery/radiation boost to the resection cavity (level 3). For single metastasis less than 3 to 4 cm, radiosurgery alone or WBRT and radiosurgery or WBRT and surgery (all based on level 1 evidence) should be considered. Another alternative is surgery and radiosurgery or radiation boost to the resection cavity (level 3). For single brain metastasis (less than 3 to 4 cm) that is not resectable or incompletely resected, WBRT and radiosurgery, or radiosurgery alone should be considered (level 1). For nonresectable single brain metastasis (larger than 3 to 4 cm), WBRT should be considered (level 3). Multiple brain metastases and good prognosis (expected survival 3 months or more): For selected patients with multiple brain metastases (all less than 3 to 4 cm), radiosurgery alone, WBRT and radiosurgery, or WBRT alone should be considered, based on level 1 evidence. Safe resection of a brain metastasis or metastases causing significant mass effect and postoperative WBRT may also be considered (level 3). Patients with poor prognosis (expected survival less than 3 months): Patients with either single or multiple brain metastases with poor prognosis should be considered for palliative care with or without WBRT (level 3). It should be recognized, however, that there are limitations in the ability of physicians to accurately predict patient survival. Prognostic systems such as recursive partitioning analysis, and diagnosis-specific graded prognostic assessment may be helpful. CONCLUSIONS: Radiotherapeutic intervention (WBRT or radiosurgery) is associated with improved brain control. In selected patients with single brain metastasis, radiosurgery or surgery has been found to improve survival and locally treated metastasis control (compared with WBRT alone). PMID- 25925628 TI - A validated prediction model for IVF: is it clinically applicable? PMID- 25925629 TI - Antibiotic prophylaxis in obstetrics. PMID- 25925630 TI - Molluscs as models for translational medicine. AB - This paper describes the advantages of adopting a molluscan model for studying the biological basis of some central nervous system pathologies affecting humans. In particular, we will focus on the freshwater snail Lymnaea stagnalis, which is already the subject of electrophysiological studies related to learning and memory, as well as ecotoxicological studies. The genome of L. stagnalis has been sequenced and annotated but the gene characterization has not yet been performed. We consider the characterization of the gene networks that play crucial roles in development and functioning of the central nervous system in L. stagnalis, an important scientific development that comparative biologists should pursue. This important effort would add a new experimental model to the limited number of invertebrates already used in studies of translational medicine, the discipline that seeks to improve human health by taking advantage of knowledge collected at the molecular and cellular levels in non-human organisms. PMID- 25925631 TI - Two pentasaccharide resin glycosides from Argyreia acuta. AB - Two new compounds of acutacosides 1 and 2, pentasaccharide resin glycosides were isolated from the aerial parts of Argyreia acuta. The core of the two compounds was operculinic acid A, and they were esterfied at the same position, just one substituent group was linked at C-2 of Rha. The absolute configuration of the aglycone in the two compounds was established by Mosher's method, which was (11S) hydroxyhexadecanoic acid (jalapinolic acid). Their structures were established by a combination of spectroscopic and chemical methods. PMID- 25925632 TI - Verifying the Indonesian version of the Child Behavior Checklist. AB - BACKGROUND: The Child Behavior Checklist for Ages 6-18 (CBCL/6-18) is widely used to assess emotional and behavioral problems in children in the USA and Europe. Given that Indonesia has a more traditional culture that is different from the USA and Europe, it is possible that the CBCL is not effective in assessing the emotional and behavioral problems of Indonesian children, due to a difference in culture. Moreover, the validity and reliability of the Indonesian version of the CBCL/6-18 have not been tested. The purpose of this study was therefore to test the validity and reliability of the Indonesian version of the CBCL/6-18. METHODS: Three hundred and eight mothers of children attending public primary schools participated in this study by completing the self-administered questionnaire. RESULTS: All items of the CBCL were positively correlated with total score (0.15 0.59), and total problems score had high internal consistency (r = 0.94). The correlations between questionnaire items and the eight subscales of the CBCL ranged from 0.10 to 0.74 and from 0.12 to 0.64 for the internalizing and externalizing scales, respectively (P < 0.01). The eight subscales of the CBCL had good internal consistency (0.61-0.87). CONCLUSIONS: The CBCL/6-18 is a valid and reliable instrument to measure emotional and behavioral problems in Indonesian children aged 6-12 years. PMID- 25925634 TI - Perioperative risk factors for acute kidney injury after liver resection surgery: an historical cohort study. AB - PURPOSE: This study aimed to identify the incidence and risk factors for acute kidney injury (AKI) after liver resection surgery and to clarify the relationship between postoperative AKI and outcome. METHODS: We conducted a historical cohort study of patients who underwent liver resection surgery with sevoflurane anesthesia from January 2004 to October 2011. Acute kidney injury was diagnosed based on the Acute Kidney Injury Network classification within 72 hr after the surgery. Patient data, surgical and anesthetic data, and laboratory data were extracted manually from the patients' electronic charts. Multivariable logistic regression analysis was used to identify perioperative risk factors for postoperative AKI. RESULTS: Acute kidney injury was diagnosed in 78 of 642 patients (12.1%; 95% confidence interval [CI]: 9.7 to 14.9). Multivariable analysis showed an independent association between postoperative AKI and preoperative estimated glomerular filtration rate (adjusted odds ratio [aOR] 0.74; 95% CI: 0.64 to 0.85), preoperative hypertension (aOR 2.10; 95% CI: 1.11 to 3.97), and intraoperative red blood cell transfusion (aOR 1.04; 95% CI: 1.01 to 1.07). Development of AKI within 72 hr after liver resection surgery was associated with increased hospital mortality, prolonged length of stay, and increased rates of mechanical ventilation, reintubation, and renal replacement therapy. CONCLUSION: Perioperative risk factors for AKI after liver resection surgery are similar to those established for other surgical procedures. Further studies are needed to establish causality and to determine whether interventions on modifiable risk factors can reduce the incidence of postoperative AKI and improve patient outcome. This study was registered at the University Hospital Medical Information Network (UMIN) Center (UMIN 000008089). PMID- 25925635 TI - Modelling socioeconomic determinants for cultivation and in-situ conservation of Vitex doniana Sweet (Black plum), a wild harvested economic plant in Benin. AB - BACKGROUND: Cultivation is the most appropriate management option when both demand and harvesting of wild plant species increase beyond natural production levels. In the current study we made the assumption that, besides the intrinsic biological and ecological characteristics of the species, the decision to cultivate and/or to conserve an overharvested wild plant species is triggered by the socioeconomic factors such as land tenure and size, origin of respondents, gender, and users' knowledge of the plant phenology. METHODS: We carried out semi structured interviews with 178 informants involved in V. doniana exploitation. The data collected were related to socio-demographic characteristics of informants' household situation, knowledge of the biology and propagation of the species, willingness to cultivate the species, in-situ maintenance of populations, and costs associated with management of the species. According to data types we used Student's t, Spearman correlation, Kruskal-Wallis, Fisher's exact and chi2 tests to test the effects of land tenure, origin of respondents, gender and users' knowledge of plant phenology on the decision making process. Conditional inference tree models and generalized additive models were also used to identify variables which were significantly determinant in the decision to cultivate and/or to conserve the species in-situ. RESULTS: We found that men were more willing to cultivate the species than women and this is conditioned by land area available. The willingness to conserve the species in-situ depends mainly on the total land area available, the number of trees within the landscape, accessibility of the trees, land tenure, gender, location, seedling cost, and trade-off cost for conservation. People who offered more than one US dollar to acquire a seedling of V. doniana, landowners, and those who own a total land area in excess of 6.5 ha were most willing to conserve the species in-situ. CONCLUSIONS: From our findings we conclude that future management and conservation initiatives for V. doniana should first target specific user groups for sustainable exploitation of the species. Also, the Cultivation Opportunity Ratio is an important indicator for quick determination of the likelihood of farmers to engage into cultivation and conservation of the species. PMID- 25925636 TI - 5-hydroxytryptamine medications for the treatment of obesity. AB - The central 5-hydroxytryptamine (5-HT; serotonin) system represents a fundamental component of the brain's control of energy homeostasis. Medications targeting the 5-HT pathway have been at the forefront of obesity treatment for the past 15 years. Pharmacological agents targeting 5-HT receptors (5-HTR), in combination with genetic models of 5-HTR manipulation, have uncovered a role for specific 5 HTRs in energy balance and reveal the 5-HT2 C R as the principal 5-HTR mediating this homeostatic process. Capitalising on this neurophysiological machinery, 5 HT2 C R agonists improve obesity and glycaemic control in patient populations. The underlying therapeutic mechanism has been probed using model systems and appears to be achieved primarily through 5-HT2 C R modulation of the brain melanocortin circuit via activation of pro-opiomelanocortin neurones signalling at melanocortin4 receptors. Thus, 5-HT2 C R agonists offer a means to improve obesity and type 2 diabetes, which are conditions that now represent global challenges to human health. PMID- 25925637 TI - Internet Use by First-Time Mothers for Infant Feeding Support. AB - BACKGROUND: Optimal nutrition during infancy has benefits to individuals and to society. Australian women actively seek health and nutrition information from a wide variety of sources and have extensive access to the Internet, but its efficacy in supporting recommendation-consistent infant feeding is unknown. OBJECTIVES: The objectives of this study were to evaluate sources of infant feeding information used by first-time mothers and to describe breast and formula feeding patterns 6 months post birth associated with successful use of the Internet for breastfeeding support. METHODS: Healthy women between 18 and 40 years of age in their first pregnancy were recruited to the Feeding Queensland Babies Study by convenience sampling in Brisbane, Australia, between June 2010 and March 2011. Participants completed a questionnaire online when their infants were 6 months of age and a demographic questionnaire. RESULTS: Health care providers, books, general Internet searches, family, and friends were common sources of breastfeeding information for women during infants' first 6 months. Information sources for infant formula were less often accessed. Of mothers who sought breastfeeding assistance on the Internet, those who found it unhelpful had lower odds of giving breast milk at 6 months (odds ratio [OR] = 0.3; 95% confidence interval [CI], 0.1-0.5) and higher odds of giving formula (OR = 3.3; 95% CI, 1.7-6.5) compared with those who found the help they needed, adjusted for age and socioeconomic status. CONCLUSION: Professional, print, and interpersonal information resources for infant feeding are widely accessed by mothers. Online breastfeeding information and support may help women to meet their breastfeeding intentions and to minimize formula use. PMID- 25925633 TI - Matrotrophy and placentation in invertebrates: a new paradigm. AB - Matrotrophy, the continuous extra-vitelline supply of nutrients from the parent to the progeny during gestation, is one of the masterpieces of nature, contributing to offspring fitness and often correlated with evolutionary diversification. The most elaborate form of matrotrophy-placentotrophy-is well known for its broad occurrence among vertebrates, but the comparative distribution and structural diversity of matrotrophic expression among invertebrates is wanting. In the first comprehensive analysis of matrotrophy across the animal kingdom, we report that regardless of the degree of expression, it is established or inferred in at least 21 of 34 animal phyla, significantly exceeding previous accounts and changing the old paradigm that these phenomena are infrequent among invertebrates. In 10 phyla, matrotrophy is represented by only one or a few species, whereas in 11 it is either not uncommon or widespread and even pervasive. Among invertebrate phyla, Platyhelminthes, Arthropoda and Bryozoa dominate, with 162, 83 and 53 partly or wholly matrotrophic families, respectively. In comparison, Chordata has more than 220 families that include or consist entirely of matrotrophic species. We analysed the distribution of reproductive patterns among and within invertebrate phyla using recently published molecular phylogenies: matrotrophy has seemingly evolved at least 140 times in all major superclades: Parazoa and Eumetazoa, Radiata and Bilateria, Protostomia and Deuterostomia, Lophotrochozoa and Ecdysozoa. In Cycliophora and some Digenea, it may have evolved twice in the same life cycle. The provisioning of developing young is associated with almost all known types of incubation chambers, with matrotrophic viviparity more widespread (20 phyla) than brooding (10 phyla). In nine phyla, both matrotrophic incubation types are present. Matrotrophy is expressed in five nutritive modes, of which histotrophy and placentotrophy are most prevalent. Oophagy, embryophagy and histophagy are rarer, plausibly evolving through heterochronous development of the embryonic mouthparts and digestive system. During gestation, matrotrophic modes can shift, intergrade, and be performed simultaneously. Invertebrate matrotrophic adaptations are less complex structurally than in chordates, but they are more diverse, being formed either by a parent, embryo, or both. In a broad and still preliminary sense, there are indications of trends or grades of evolutionarily increasing complexity of nutritive structures: formation of (i) local zones of enhanced nutritional transport (placental analogues), including specialized parent-offspring cell complexes and various appendages increasing the entire secreting and absorbing surfaces as well as the contact surface between embryo and parent, (ii) compartmentalization of the common incubatory space into more compact and 'isolated' chambers with presumably more effective nutritional relationships, and (iii) internal secretory ('milk') glands. Some placental analogues in onychophorans and arthropods mimic the simplest placental variants in vertebrates, comprising striking examples of convergent evolution acting at all levels-positional, structural and physiological. PMID- 25925638 TI - The 100 people most influencing the specialty of orthodontics, 1915-2014. PMID- 25925639 TI - A century of influence: Part 1. Orthodontic pioneers. AB - The story of orthodontics during the first 100 years of Journal publication can be told through the people who lived it. As part of the American Journal of Orthodontics and Dentofacial Orthopedics' Centennial Celebration, we present 100 people who most influenced the specialty during the last 100 years. Part 1 describes the orthodontic pioneers who were born in the 1800 s. They were broadly educated in the sciences, and most studied orthodontics with Angle, Dewey, or Lischer. They were innovators and inventors, and they laid the foundation of the specialty during the early years of the 20th century. PMID- 25925640 TI - A journal by any other name. PMID- 25925641 TI - Ethics in orthodontics. A proud tradition of ethics in a proud specialty. PMID- 25925642 TI - Charles H. Tweed, 1895-1970. PMID- 25925643 TI - I remember Charlie Tweed. PMID- 25925644 TI - Orthodontics 2015: What's happening now? PMID- 25925645 TI - The decade ahead: Finding a better way. PMID- 25925646 TI - Through a glass darkly: Orthodontics in the 21st century. PMID- 25925647 TI - Reflections on mentorship. PMID- 25925648 TI - What do the teeth say? PMID- 25925649 TI - Incorporating 3-dimensional models in online articles. AB - INTRODUCTION: The aims of this article are to introduce the capability to view and interact with 3-dimensional (3D) surface models in online publications, and to describe how to prepare surface models for such online 3D visualizations. METHODS: Three-dimensional image analysis methods include image acquisition, construction of surface models, registration in a common coordinate system, visualization of overlays, and quantification of changes. Cone-beam computed tomography scans were acquired as volumetric images that can be visualized as 3D projected images or used to construct polygonal meshes or surfaces of specific anatomic structures of interest. The anatomic structures of interest in the scans can be labeled with color (3D volumetric label maps), and then the scans are registered in a common coordinate system using a target region as the reference. The registered 3D volumetric label maps can be saved in .obj, .ply, .stl, or .vtk file formats and used for overlays, quantification of differences in each of the 3 planes of space, or color-coded graphic displays of 3D surface distances. RESULTS: All registered 3D surface models in this study were saved in .vtk file format and loaded in the Elsevier 3D viewer. In this study, we describe possible ways to visualize the surface models constructed from cone-beam computed tomography images using 2D and 3D figures. The 3D surface models are available in the article's online version for viewing and downloading using the reader's software of choice. These 3D graphic displays are represented in the print version as 2D snapshots. Overlays and color-coded distance maps can be displayed using the reader's software of choice, allowing graphic assessment of the location and direction of changes or morphologic differences relative to the structure of reference. The interpretation of 3D overlays and quantitative color coded maps requires basic knowledge of 3D image analysis. CONCLUSIONS: When submitting manuscripts, authors can now upload 3D models that will allow readers to interact with or download them. Such interaction with 3D models in online articles now will give readers and authors better understanding and visualization of the results. PMID- 25925650 TI - Combined surgical-orthodontic treatment: how did it evolve and what are the best practices now? AB - It has been 50 years since the landmark presentation by Hugo Obwegeser at Walter Reed Army Hospital. At that conference, Professor Obwegeser offered American surgeons techniques to correct facial skeletal deformities with access through intraoral incisions. As important advances in surgical technique and anesthesia evolved for the surgical procedures, a major contribution by American orthodontists in collaboration with surgeons was the creation of a common diagnostic, planning, and treatment scheme for use by both clinician groups in the treatment of dentofacial deformities, the skeletal and dental problems of the most severely affected 5% of the population. This article summarizes what American orthodontists and surgeons have learned in the late 20th and early 21st centuries, and forecasts what might be the future of treatment for patients with dentofacial deformities. PMID- 25925651 TI - Evolution of occlusion and temporomandibular disorder in orthodontics: Past, present, and future. AB - Occlusion has been an important consideration in orthodontics since the beginning of the discipline. Early emphasis was placed on the alignment of the teeth, the stability of the intercuspal position, and the esthetic value of proper tooth positioning. These factors remain important to orthodontists, but orthopedic principles associated with masticatory functions must also be considered. Orthopedic stability in the masticatory structures should be a routine treatment goal to help reduce risk factors associated with developing temporomandibular disorders. PMID- 25925652 TI - Orthodontic material applications over the past century: Evolution of research methods to address clinical queries. AB - The advances in the field of materials as they relate to orthodontics can be divided into the actual evolution of materials applied to daily practice and the changes in research methods to study the performance and the biologic properties of the materials. Although it is evident that new materials have saturated the market during the past century, the basic concepts of attaching one appliance to the enamel to use as a grip and inserting wires into that to control the spatial orientation of a tooth are identical to the original concepts. In contrast to that, the numbers of treatises about those subjects and the complexity of instrumentation and analytic tools used in published research have advanced tremendously and at a frenetic pace. This highly specialized pattern of research may effectively raise boundaries across research areas, since the complexity of the issues allows researchers to comprehend the content of journal articles in a narrow spectrum of disciplines. The purposes of this article were to review the advances in the research methods for investigating the various properties of orthodontic materials and to assist the reader in navigating this topic. A synopsis of the materials is also provided, listing future applications that already exist at the experimental stage or are yet unavailable but with the relevant technology already presented in broader scientific disciplines. PMID- 25925653 TI - Certification renewal process of the American Board of Orthodontics. AB - The American Board of Orthodontics was established in 1929 and is the oldest specialty board in dentistry. Its goal is to protect the public by ensuring competency through the certification of eligible orthodontists. Originally, applicants for certification submitted a thesis, 5 case reports, and a set of casts with appliances. Once granted, the certification never expired. Requirements have changed over the years. In 1950, 15 cases were required, and then 10 in 1987. The Board has continued to refine and improve the certification process. In 1998, certification became time limited, and a renewal process was initiated. The Board continues to improve the recertification process. PMID- 25925654 TI - Litigation and legislation. Dento-legal and ethical observations on the last 100 years. PMID- 25925655 TI - Hydraulic lift as a determinant of tree-grass coexistence on savannas. AB - The coexistence of woody plants and grasses in savannas is determined by a complex set of interacting factors that determine access to resources and demographic dynamics, under the control of external drivers and vegetation feedbacks with the physical environment. Existing theories explain coexistence mainly as an effect of competitive relations and/or disturbances. However, theoretical studies on the way facilitative interactions resulting from hydraulic lift affect tree-grass coexistence and the range of environmental conditions in which savannas are stable are still lacking. We investigated the role of hydraulic lift in the stability of tree-grass coexistence in savannas. To that end, we developed a new mechanistic model that accounts for both competition for soil water in the shallow soil and fire-induced disturbance. We found that hydraulic lift favors grasses, which scavenge the water lifted by woody plants. Thus, hydraulic lift expands (at the expenses of woodlands) the range of environmental conditions in which savannas are stable. These results indicate that hydraulic lift can be an important mechanism responsible for the coexistence of woody plants and grasses in savannas. Grass facilitation by trees through the process of hydraulic lift could allow savannas to persist stably in mesic regions that would otherwise exhibit a forest cover. PMID- 25925656 TI - Accelerating health equity: the key role of universal health coverage in the Sustainable Development Goals. AB - The Sustainable Development Goals (SDGs), to be committed to by Heads of State at the upcoming 2015 United Nations General Assembly, have set much higher and more ambitious health-related goals and targets than did the Millennium Development Goals (MDGs). The main challenge among MDG off-track countries is the failure to provide and sustain financial access to quality services by communities, especially the poor. Universal health coverage (UHC), one of the SDG health targets indispensable to achieving an improved level and distribution of health, requires a significant increase in government investment in strengthening primary healthcare - the close-to-client service which can result in equitable access. Given the trend of increased fiscal capacity in most developing countries, aiming at long-term progress toward UHC is feasible, if there is political commitment and if focused, effective policies are in place. Trends in high income countries, including an aging population which increases demand for health workers, continue to trigger international migration of health personnel from low and middle income countries. The inspirational SDGs must be matched with redoubled government efforts to strengthen health delivery systems, produce and retain more and relevant health workers, and progressively realize UHC. PMID- 25925657 TI - C-H Activation of Benzene by a Photoactivated Ni(II)(azide): Formation of a Transient Nickel Nitrido Complex. AB - Photochemical activation of nickel-azido complex 2 [Ni(N3)(PNP)] (PN(H)P=2,2' di(isopropylphosphino)-4,4'-ditolylamine) in neat benzene produces diamagnetic complex 3 [Ni(Ph)(PN(P)N(H))], which is crystallographically characterized. DFT calculations support photoinitiated N2-loss of the azido complex to generate a rare, transient Ni(IV) nitrido species, which bears significant nitridyl radical character. Subsequent trapping of this nitrido through insertion into the Ni-P bond generates a coordinatively unsaturated Ni(II) imidophosphorane P=N donor. This species shows unprecedented reactivity toward 1,2-addition of a C-H bond of benzene to form 3. The structurally characterized chlorido complex 4 [Ni(Cl)(PN(P)N(H))] is generated by reaction of 3 with HCl or by direct photolysis of 2 in chlorobenzene. This is the first report of aromatic C-H bond activation by a trapped transient nitrido species of a late transition metal. PMID- 25925658 TI - Bicontinuous microemulsions for high yield, wet synthesis of ultrafine nanoparticles: a general approach. AB - The design of a synthesis strategy for metal nanoparticles by templating dense microemulsions is proposed. Particle size is controlled by surfactant size rather than by microemulsion composition. The strategy was demonstrated with various systems with different surfactant: cationic, anionic and non-ionic and of different sizes. Formulations were determined using the microemulsion phase diagrams. Synthesis was demonstrated for platinum nanoparticles with some examples for gold. The nanoparticles were subsequently extracted from the microemulsion by absorption onto a carbon support, after which the surfactant was recycled. PMID- 25925659 TI - Improvement of Energy Capacity with Vitamin C Treated Dual-Layered Graphene Sulfur Cathodes in Lithium-Sulfur Batteries. AB - A graphene-based cathode design for lithium-sulfur batteries (LSB) that shows excellent electrochemical performance is proposed. The dual-layered cathode is composed of a sulfur active layer and a polysulfide absorption layer, and both layers are based on vitamin C treated graphene oxide at various degrees of reduction. By controlling the degree of reduction of graphene, the dual-layered cathode can increase sulfur utilization dramatically owing to the uniform formation of nanosized sulfur particles, the chemical bonding of dissolved polysulfides on the oxygen-rich sulfur active layer, and the physisorption of free polysulfides on the absorption layer. This approach enables a LSB with a high specific capacity of over 600 mAh gsulfur (-1) after 100 cycles even under a high current rate of 1C (1675 mA gsulfur (-1) ). An intriguing aspect of our work is the synthesis of a high-performance dual-layered cathode by a green chemistry method, which could be a promising approach to LSBs with high energy and power densities. PMID- 25925660 TI - US babies born in withdrawal from opioids quadruples in nine years, study finds. PMID- 25925661 TI - Is There a Measurable Difference between the Left and Right Modified Myocardial Performance Indices, and Does This Change to Reflect Unilateral Myocardial Dysfunction in Pathology? AB - INTRODUCTION: Fetal cardiac dysfunction may manifest itself unilaterally as right and left ventricles differing in design, function and load, measurable as differing in myocardial performance indices (MPIs). We wished to define this difference ('delta-MPI' or DMPI), present its normal range and pilot its use in pathological pregnancy. MATERIAL AND METHODS: Prospective cross-sectional study of 324 normal singleton fetuses (16-38 weeks of gestation). Left and right modified MPI (LMPI and RMPI) were performed during a single examination using the 'peak' valve click technique. Thirty-seven pathological singleton and monochorionic diamniotic twin pregnancies were compared as pilot data. RESULTS: Modified MPIs (mean +/- SD) were 0.45 +/- 0.06 (LMPI) and 0.47 +/- 0.09 (RMPI), being similar at 18 weeks' gestation with DMPI increasing slightly throughout pregnancy (0.02 +/- 0.08). Both singleton intrauterine growth restriction (IUGR) and recipient twin-twin transfusion syndrome (TTTS) showed significantly elevated RMPI, LMPI and DMPI, most pronounced for DMPI (450 and 500% increase, respectively; p < 0.01). DMPI acquisition rates were 83.3% normal and 87.0% pathological. DISCUSSION: We demonstrate for the first time differing intrafetal LMPI and RMPI in a large gestational cohort, with this difference increasing with gestational age. Pilot data confirm the potential for DMPI as a tool to assess unilateral myocardial function in singleton IUGR and recipient twins in TTTS, and further studies are under way to evaluate its clinical utility. PMID- 25925662 TI - Is it time to switch to doxycycline from azithromycin for treating genital chlamydial infections in women? Modelling the impact of autoinoculation from the gastrointestinal tract to the genital tract. AB - BACKGROUND: Single-dose azithromycin is recommended over multi-dose doxycycline as treatment for chlamydial infection. However, even with imperfect adherence, doxycycline is more effective in treating genital and rectal infection. Recently, it has been suggested that autoinoculation from the rectum to the genitals may be a source of persistent chlamydial infection in women. We estimated the impact autoinoculation may have on azithromycin and doxycycline effectiveness. METHODS: We estimate treatment effectiveness using a simple mathematical model, incorporating data on azithromycin and doxycycline efficacy from recent meta analyses, and data on prevalence of rectal infection in women with genital chlamydial infection. RESULTS: When the possibility of autoinoculation is taken into account, we calculate that doxycycline effectiveness may be 97% compared to just 82% for azithromycin. CONCLUSIONS: Consideration should be given to re evaluating azithromycin as the standard treatment for genital chlamydia in women. PMID- 25925663 TI - Functional microbial diversity dynamics in common effluent treatment plants of South Gujarat and hydrocarbon degradation. AB - Common effluent treatment plants (CETPs) of South Gujarat region, India, process wastewater generated by more than 2500 industries because of the nonfeasibility of processing at the individual industrial unit. This study assessed functional microbial diversity in wastewater samples of CETPs over a geological belt using Ecoplate(r), isolation of the most abundant bacteria, and screening for hydrocarbon degradation. The high evenness (EPielou) values (0.9) in almost all samples indicated a highly even community structure. Principal component analysis of carbon source utilization showed a cluster of all inlet samples except E1 and another cluster of all outlet samples; aeration tank community samples were dispersed. In spite of the high richness found in microbial communities, 60 morphologically similar organisms were observed and isolated; 46 out of them were subjected to amplified ribosomal DNA restriction analysis with MboI, HaeIII, and TaqI enzyme, followed by UPGMA clustering. In screening the most abundant bacteria from each cluster, one of the cultures showed a high potential for hydrocarbon degradation and was identified as Pseudomonas citronellolis by 16S rDNA sequencing. Because of its highly adapted inherent nature, this bacterium may help augment the conventional procedure in wastewater treatment and efficiently decrease the organic load. PMID- 25925664 TI - Palliative care in South Asia: a systematic review of the evidence for care models, interventions, and outcomes. AB - BACKGROUND: The increasing incidence of cancer and chronic diseases in South Asia has created a growing public health and clinical need for palliative care in the region. As an emerging discipline with increasing coverage, palliative care must be guided by evidence. In order to appraise the state of the science and inform policy and best practice in South Asia this study aimed to systematically review the evidence for palliative care models, interventions, and outcomes. RESULTS: The search identified only 16 articles, reporting a small range of services. The 16 articles identified India as having greatest number of papers (n = 14) within South Asia, largely focused in the state of Kerala. Nepal and Pakistan reported a single study each, with nothing from Bhutan, Afghanistan, Maldives or Bangladesh. Despite the large population of South Asia, we found only 4 studies reporting intervention outcomes, with the remaining reporting service descriptions (n = 12). CONCLUSIONS: The dearth of evidence in terms of palliative care outcomes, and the lack of data from beyond India, highlight the urgent need for greater research investment and activity to guide the development of feasible, acceptable, appropriate and effective palliative care services. There is some evidence that suggests implementation of successful and well-developed community based models of palliative care may be replicated in other resource limited settings. Greater investigation to determine outcomes and costs are urgently needed, and require well-designed and validated tools to measure outcomes. Studies are also needed to better understand the cultural context of death and dying for patients and their families in South Asia, and to respond to the growing need for palliative and end-of-life care in the region. PMID- 25925665 TI - Vocal Loading in Speaking a Foreign Language. AB - AIMS: This study investigated whether speaking a foreign language affects the subjective notions of vocal fatigue, and whether acoustic measurements reveal a higher vocal loading. METHODS: The speech samples of 20 native Finnish-speaking and 23 native English-speaking subjects were recorded in Finnish and in English. From the speech samples, fundamental frequency, equivalent sound level, total duration of voiced speech, speech rate, alpha ratio and L1-L0 level difference were analyzed. Vocal doses were calculated. RESULTS: According to subjective notions, the voice gets tired more quickly when speaking a foreign language. The mean fundamental frequency increased but the speech rate and total duration of voiced speech decreased significantly when speaking a foreign language. Thus, the vocal doses decreased. CONCLUSIONS: The subjective sensations of increased vocal fatigue may be due to increased mental stress rather than to higher vocal loading. However, a trend that speaking a foreign language may involve more loading was found in L1-L0 level difference and in the doses normalized to time dose. Longer speech samples should be studied. Voice quality-based indicators of vocal loading are worth testing in addition to the measures based on the amount of voicing in speech. PMID- 25925666 TI - The prevalence of and major risk factors associated with diabetic retinopathy in Gegharkunik province of Armenia: cross-sectional study. AB - BACKGROUND: Diabetic retinopathy (DR) is one of the leading causes of blindness in adults in industrialized countries and the emerging cause of blindness in developing countries. The objective of this study was to describe the prevalence of DR and risk factors associated with it among diabetic patients. METHODS: The analytical cross-sectional survey and eye screenings were carried out among 625 diabetic patients from urban and rural areas of Gegharkunik region. DR was assessed by dilated ophthalmoscopy and defined based on the WHO International Classification of Diseases. The survey instrument, included questions about demographics, disease history, health status, medication use and healthy lifestyle. Descriptive statistics and logistic regression were used to analyze the data. RESULTS: The prevalence of DR in the sample was 36.2%. A total of 90.2% of patients with DR had non-proliferative, while 9.8% had proliferative DR. In bivariate analysis, age, diabetes duration, being under insulin treatment, blood glucose level, having non-communicable diseases were significantly associated with DR. In the adjusted analysis being under insulin treatment (OR = 3.24; 95% CI: 1.56-6.75), diabetes duration (OR = 1.23; 95% CI: 1.16-1.31) and age (OR = 1.05; 95% CI: 1.02-1.08) were independently associated with DR. CONCLUSION: Earlier diagnosis of diabetes and DR can help to control some of these factors and prevent further complications and vision loss. Population-based educational programs on diabetes and diabetic retinopathy and continuous medical education on diabetes management can improve diabetes care and self-management and prevent eye complications. PMID- 25925667 TI - A single nucleotide polymorphism in 3' untranslated region of epithelial growth factor receptor confers risk for pulmonary hypertension in chronic obstructive pulmonary disease. AB - OBJECTIVE: Polymorphisms located at microRNA (miRNA) binding sites may interfere with the miRNA/mRNA interaction. The objective of this study was to identify the association between a single nucleotide polymorphism (774 T>C) in 3'-untranslated region (3'-UTR) of Epithelial Growth Factor Receptor (EGFR) and development of pulmonary hypertension (PH) in chronic obstructive pulmonary disease (COPD) as well as to explore the molecular mechanism. METHODS AND RESULTS: In this study, we validated EGFR as a target of miR-214 in pulmonary artery smooth muscle cell (PASMC), which was further confirmed by the observation that exogenous overexpression of miR-214 significantly downregulated the expression of EGFR in the PASMCs genotyped as TT or TC, but not in CC group. Meanwhile, we found COPD patients with CC genotype had significantly higher risk for PH (OR = 1.965, p = 0.0095), compared with TT and TC genotypes,. Additionally, the PASMCs were isolated from 72 COPD patients, with which miR-214 and EGFR expression levels were determined, and we found that miR-214 level was comparable between each genotype group, the concentration of EGFR in CC genotype group was significantly higher than in TT or TC genotype group. CONCLUSION: Our study confirmed that EGFR 3'UTR 774 T>C polymorphism interfered with miRNA/mRNA interaction, and showed that the minor allele was associated with an elevated risk for development of PH in COPD. PMID- 25925668 TI - Phosphorylation of the exchange factor DENND3 by ULK in response to starvation activates Rab12 and induces autophagy. AB - Unc-51-like kinases (ULKs) are the most upstream kinases in the initiation of autophagy, yet the molecular mechanisms underlying their function are poorly understood. We report a new role for ULK in the induction of autophagy. ULK mediated phosphorylation of the guanine nucleotide exchange factor DENND3 at serines 554 and 572 upregulates its GEF activity toward the small GTPase Rab12. Through binding to LC3 and associating with LC3-positive autophagosomes, active Rab12 facilitates autophagosome trafficking, thus establishing a crucial role for the ULK/DENND3/Rab12 axis in starvation-induced autophagy. PMID- 25925669 TI - Paternal H3K4 methylation is required for minor zygotic gene activation and early mouse embryonic development. AB - Epigenetic modifications, such as DNA methylation and histone modifications, are dynamically altered predominantly in paternal pronuclei soon after fertilization. To identify which histone modifications are required for early embryonic development, we utilized histone K-M mutants, which prevent endogenous histone methylation at the mutated site. We prepared four single K-M mutants for histone H3.3, K4M, K9M, K27M, and K36M, and demonstrate that overexpression of H3.3 K4M in embryos before fertilization results in developmental arrest, whereas overexpression after fertilization does not affect the development. Furthermore, loss of H3K4 methylation decreases the level of minor zygotic gene activation (ZGA) predominantly in the paternal pronucleus, and we obtained similar results from knockdown of the H3K4 methyltransferase Mll3/4. We therefore conclude that H3K4 methylation, likely established by Mll3/4 at the early pronuclear stage, is essential for the onset of minor ZGA in the paternal pronucleus, which is necessary for subsequent preimplantation development in mice. PMID- 25925670 TI - A protocol of histone modification-based mechanistic study of acupuncture in patients with stable angina pectoris. AB - BACKGROUND: Angina pectoris (Angina) is a medical condition related to myocardial ischemia. Although acupuncture has been widely accepted as a clinical approach for angina, there is no sufficient evidence of its effectiveness against this syndrome, and its mechanisms have not yet been well elucidated. We develop this protocol to confirm the clinical efficacy of electro-acupuncture on stable angina pectoris by needling on acupoint Neiguan (PC6). Furthermore, we employ high throughput sequencing technology to investigate the gene expression profiling and determine involvement of histone modifications in the regulation of genes after electro-acupuncture treatment. METHODS/DESIGN: A randomized, controlled, double blinded (assessor and patients) trial will be carried out. Sixty participants will be randomly assigned to two acupuncture treatment groups and one control group in a 1:1:1 ratio. Participants in acupuncture groups will receive 12 sessions of electro-acupuncture treatment across 4 weeks, followed by a 12-week randomization period. The acupuncture groups are divided into Neiguan (PC6) on Pericardium Meridian of Hand-jueyin or a non-acupoint. The primary clinical measure of effect is the frequency of angina attacks between these groups for four weeks after randomization. RNAs are extracted from peripheral neutrophils collected from all participants on day 0, day 30, and week 16, and are processed to RNA-Seq. We then investigate profiles of histone modifications by ChIP-Seq, for H3 Lysine 4 (H3K4me) and acetylation of H3 Lysine 27 (H3K27ac), in the presence or absence of acupuncture treatment. DISCUSSION: This study determines the efficacy and mechanisms of electro-acupuncture on stable angina pectoris. We focus on effectiveness of acupuncture on alleviating symptoms of myocardial ischemia and the gene regulation and the chromatin remodeling marks, including H3K4me1, H3K4me2, and H3K27ac, which could be key factors for regulating gene expressions caused by electro-acupuncture treatment at Neiguan. This is the first genome-wide study of electro-acupuncture treatment in angina patients, and will provide valuable information for future studies in the fields of acupuncture and its underlying mechanisms. Fourteen patients have been recruited since recruitment opened in November of 2012. This study is scheduled to end in November of 2014. TRIALS REGISTRATION: ChiCTR-TRC-12002668. PMID- 25925671 TI - Regioselective synthesis of 2-chloroquinoline based ethyl 4-(3- hydroxyphenyl) 2,7,7-trimethyl-5-oxo-1,4,5,6,7,8-hexahydroquinoline-3- carboxylates and their in silico evaluation against P. falciparum lactate dehydrogenase. AB - The reaction of various substituted 2, 4-dichloroquinolines with ethyl 4-(3 hydroxyphenyl)- 2,7,7-trimethyl-5-oxo-1,4,5,6,7,8-hexahydroquinoline-3 carboxylate was carried out in the presence of K2CO3 as a mild and efficient base at controlled temperature leading to novel 2-chloroquinoline based polyhydroquinoline with high regioselectivity. All the synthesized compounds were characterized using IR, NMR, Mass spectral data and then subjected to an in silico analysis against P. falciparum lactate dehydrogenase. PMID- 25925673 TI - Statin-induced anti-proliferative effects via cyclin D1 and p27 in a window-of opportunity breast cancer trial. AB - PURPOSE: Cholesterol lowering statins have been demonstrated to exert anti tumoral effects on breast cancer by decreasing proliferation as measured by Ki67. The biological mechanisms behind the anti-proliferative effects remain elusive. The aim of this study was to investigate potential statin-induced effects on the central cell cycle regulators cyclin D1 and p27. EXPERIMENTAL DESIGN: This phase II window-of-opportunity trial (Trial registration: ClinicalTrials.gov NCT00816244 , NIH) included 50 patients with primary invasive breast cancer. High dose atorvastatin (80 mg/day) was prescribed to patients for two weeks prior to surgery. Paired paraffin embedded pre- and post-statin treatment tumor samples were analyzed using immunohistochemistry for the expression of estrogen receptor (ER), progesterone receptor (PR), human epidermal growth factor receptor 2 (HER2), and the cell cycle regulators cyclin D1 and p27. Corresponding frozen tumor sample pairs were analyzed for expression of the genes coding for cyclin D1 and p27, CCND1 and CDKN1B, respectively. RESULTS: Forty-two patients completed all study parts, and immunohistochemical evaluation of ER and PR was achievable in 30 tumor pairs, HER2 in 29 tumor pairs, cyclin D1 in 30 tumor pairs and p27 in 33 tumor pairs. The expression of ER, PR and HER2 did not change significantly following atorvastatin treatment. Cyclin D1 expression in terms of nuclear intensity was significantly decreased (P = 0.008) after statin treatment in paired tumor samples. The protein expression of the tumor suppressor p27, evaluated either as the fraction of stained tumor cells or as cytoplasmic intensity, increased significantly (P = 0.03 and P = 0.02, respectively). At the transcriptional level, no significant differences in mRNA expression were detected for cyclin D1 (CCND1) and p27 (CDKN1B). However, CCND1 expression was lower in tumors responding to atorvastatin treatment with a decrease in proliferation although not significantly (P = 0.08). CONCLUSIONS: We have previously reported statin-induced anti-proliferative effects in breast cancer. This study suggests that cell cycle regulatory effects may contribute to these anti-proliferative effects via cyclin D1 and p27. PMID- 25925672 TI - Translational toxicology in setting occupational exposure limits for dusts and hazard classification - a critical evaluation of a recent approach to translate dust overload findings from rats to humans. AB - BACKGROUND: We analyze the scientific basis and methodology used by the German MAK Commission in their recommendations for exposure limits and carcinogen classification of "granular biopersistent particles without known specific toxicity" (GBS). These recommendations are under review at the European Union level. We examine the scientific assumptions in an attempt to reproduce the results. MAK's human equivalent concentrations (HECs) are based on a particle mass and on a volumetric model in which results from rat inhalation studies are translated to derive occupational exposure limits (OELs) and a carcinogen classification. METHODS: We followed the methods as proposed by the MAK Commission and Pauluhn 2011. We also examined key assumptions in the metrics, such as surface area of the human lung, deposition fractions of inhaled dusts, human clearance rates; and risk of lung cancer among workers, presumed to have some potential for lung overload, the physiological condition in rats associated with an increase in lung cancer risk. RESULTS: The MAK recommendations on exposure limits for GBS have numerous incorrect assumptions that adversely affect the final results. The procedures to derive the respirable occupational exposure limit (OEL) could not be reproduced, a finding raising considerable scientific uncertainty about the reliability of the recommendations. Moreover, the scientific basis of using the rat model is confounded by the fact that rats and humans show different cellular responses to inhaled particles as demonstrated by bronchoalveolar lavage (BAL) studies in both species. CONCLUSION: Classifying all GBS as carcinogenic to humans based on rat inhalation studies in which lung overload leads to chronic inflammation and cancer is inappropriate. Studies of workers, who have been exposed to relevant levels of dust, have not indicated an increase in lung cancer risk. Using the methods proposed by the MAK, we were unable to reproduce the OEL for GBS recommended by the Commission, but identified substantial errors in the models. Considerable shortcomings in the use of lung surface area, clearance rates, deposition fractions; as well as using the mass and volumetric metrics as opposed to the particle surface area metric limit the scientific reliability of the proposed GBS OEL and carcinogen classification. PMID- 25925674 TI - Colchicine effectiveness in symptom and inflammation modification in knee osteoarthritis (COLKOA): study protocol for a randomized controlled trial. AB - BACKGROUND: Despite the high prevalence and global impact of knee osteoarthritis (KOA), current treatments are palliative. No disease modifying anti osteoarthritic drug (DMOAD) has been approved. We recently demonstrated significant involvement of uric acid and activation of the innate immune response in osteoarthritis (OA) pathology and progression, suggesting that traditional gout therapy may be beneficial for OA. We therefore assess colchicine, an existing commercially available agent for gout, for a new therapeutic application in KOA. METHODS/DESIGN: COLKOA is a double-blind, placebo-controlled, randomized trial comparing a 16-week treatment with standard daily dose oral colchicine to placebo for KOA. A total of 120 participants with symptomatic KOA will be recruited from a single center in Singapore. The primary end point is 30% improvement in total Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC) score at week 16. Secondary end points include improvement in pain, physical function, and quality of life and change in serum, urine and synovial fluid biomarkers of cartilage metabolism and inflammation. A magnetic resonance imaging (MRI) substudy will be conducted in 20 participants to evaluate change in synovitis. Logistic regression will be used to compare changes between groups in an intention-to-treat analysis. DISCUSSION: The COLKOA trial is designed to evaluate whether commercially available colchicine is effective for improving signs and symptoms of KOA, and reducing synovial fluid, serum and urine inflammatory and biochemical joint degradation biomarkers. These biomarkers should provide insights into the underlying mechanism of therapeutic response. This trial will potentially provide data to support a new treatment option for KOA. TRIAL REGISTRATION: The trial has been registered at clinicaltrials.gov as NCT02176460 . Date of registration: 26 June 2014. PMID- 25925675 TI - Coherence-Weighted Synthetic Focusing Applied to Photoacoustic Imaging Using a High-Frequency Annular-Array Transducer. AB - This paper presents an adaptive synthetic-focusing scheme that, when applied to photoacoustic (PA) data acquired using an annular array, improves focusing across a greater imaging depth and enhances spatial resolution. The imaging system was based on a 40-MHz, 5-element, annular-array transducer with a focal length of 12 mm and an 800-um diameter hole through its central element to facilitate coaxial delivery of 532-nm laser. The transducer was raster-scanned to facilitate 3D acquisition of co-registered ultrasound and PA image data. Three synthetic focusing schemes were compared for obtaining PA A-lines for each scan location: delay-and-sum (DAS), DAS weighted with a coherence factor (DAS + CF), and DAS weighted with a sign-coherence factor (DAS + SCF). Bench-top experiments that used an 80-um hair were performed to assess the enhancement provided by the two coherence-based schemes. Both coherence-based schemes increased the signal-to noise ratio by approximately 10 dB. When processed using the DAS-only scheme, the lateral dimension of the hair in a PA image with 20 dB dynamic range was between 300 um and 1 mm for imaging depth ranging from 8 to 20 mm. In comparison, the DAS + CF scheme resulted in a lateral dimension of 200 to 450 um over the same range. The DAS + SCF synthetic focusing further improved the smallest-resolvable dimension, which was between 150 and 400 um over the same range of imaging depth. When used on PA data obtained from a 12-day-old mouse embryo, the DAS + SCF processing improved visualization of neurovasculature. PMID- 25925676 TI - Advancing knowledge of rapid reviews: an analysis of results, conclusions and recommendations from published review articles examining rapid reviews. AB - BACKGROUND: Rapid review (RR) products are inherently appealing as they are intended to be less time-consuming and resource-intensive than traditional systematic reviews (SRs); however, there is concern about the rigor of methods and reliability of results. In 2013 to 2014, a workgroup comprising representatives from the Agency for Healthcare Research and Quality's Evidence based Practice Center Program conducted a formal evaluation of RRs. This paper summarizes results, conclusions, and recommendations from published review articles examining RRs. METHODS: A systematic literature search was conducted and publications were screened independently by two reviewers. Twelve review articles about RRs were identified. One investigator extracted data about RR methods and how they compared with standard SRs. A narrative summary is presented. RESULTS: A cross-comparison of review articles revealed the following: 1) ambiguous definitions of RRs, 2) varying timeframes to complete RRs ranging from 1 to 12 months, 3) limited scope of RR questions, and 4) significant heterogeneity between RR methods. CONCLUSIONS: RR definitions, methods, and applications vary substantially. Published review articles suggest that RRs should not be viewed as a substitute for a standard SR, although they have unique value for decision makers. Recommendations for RR producers include transparency of methods used and the development of reporting standards. PMID- 25925677 TI - Transforming training to reflect the workforce. PMID- 25925678 TI - American medical education at a crossroads. AB - New medical-education models in which research plays a modest role could engender a two-tiered educational system, cause a reduction in the physician-scientist pipeline, and diminish the translation of biomedical advances. PMID- 25925679 TI - Renal denervation: Not as easy as it looks. AB - Renal sympathetic denervation with intravascular radiofrequency catheters in hypertensive patients is less effective than anticipated, owing to radio frequency energy being applied to a part of the renal artery where the nerves are at the greatest distance from the aortic lumen and to distortion of energy distribution and temperature gradients by regional tissue anatomical variations (Tzafriri et al., this issue). PMID- 25925680 TI - Trauma in silico: Individual-specific mathematical models and virtual clinical populations. AB - Trauma-induced critical illness is driven by acute inflammation, and elevated systemic interleukin-6 (IL-6) after trauma is a biomarker of adverse outcomes. We constructed a multicompartment, ordinary differential equation model that represents a virtual trauma patient. Individual-specific variants of this model reproduced both systemic inflammation and outcomes of 33 blunt trauma survivors, from which a cohort of 10,000 virtual trauma patients was generated. Model predicted length of stay in the intensive care unit, degree of multiple organ dysfunction, and IL-6 area under the curve as a function of injury severity were in concordance with the results from a validation cohort of 147 blunt trauma patients. In a subcohort of 98 trauma patients, those with high-IL-6 single nucleotide polymorphisms (SNPs) exhibited higher plasma IL-6 levels than those with low IL-6 SNPs, matching model predictions. Although IL-6 could drive mortality in individual virtual patients, simulated outcomes in the overall cohort were independent of the propensity to produce IL-6, a prediction verified in the 98-patient subcohort. In silico randomized clinical trials suggested a small survival benefit of IL-6 inhibition, little benefit of IL-1beta inhibition, and worse survival after tumor necrosis factor-alpha inhibition. This study demonstrates the limitations of extrapolating from reductionist mechanisms to outcomes in individuals and populations and demonstrates the use of mechanistic simulation in complex diseases. PMID- 25925681 TI - Urinary metabolic signatures of human adiposity. AB - Obesity is a major public health problem worldwide. We used 24-hour urinary metabolic profiling by proton ((1)H) nuclear magnetic resonance (NMR) spectroscopy and ion exchange chromatography to characterize the metabolic signatures of adiposity in the U.S. (n = 1880) and UK (n = 444) cohorts of the INTERMAP (International Study of Macro- and Micronutrients and Blood Pressure) epidemiologic study. Metabolic profiling of urine samples collected over two 24 hour time periods 3 weeks apart showed reproducible patterns of metabolite excretion associated with adiposity. Exploratory analysis of the urinary metabolome using (1)H NMR spectroscopy of the U.S. samples identified 29 molecular species, clustered in interconnecting metabolic pathways, that were significantly associated (P = 1.5 * 10(-5) to 2.0 * 10(-36)) with body mass index (BMI); 25 of these species were also found in the UK validation cohort. We found multiple associations between urinary metabolites and BMI including urinary glycoproteins and N-acetyl neuraminate (related to renal function), trimethylamine, dimethylamine, 4-cresyl sulfate, phenylacetylglutamine and 2 hydroxyisobutyrate (gut microbial co-metabolites), succinate and citrate (tricarboxylic acid cycle intermediates), ketoleucine and the ketoleucine/leucine ratio (linked to skeletal muscle mitochondria and branched-chain amino acid metabolism), ethanolamine (skeletal muscle turnover), and 3-methylhistidine (skeletal muscle turnover and meat intake). We mapped the multiple BMI-metabolite relationships as part of an integrated systems network that describes the connectivities between the complex pathway and compartmental signatures of human adiposity. PMID- 25925682 TI - CMV-specific T cells generated from naive T cells recognize atypical epitopes and may be protective in vivo. AB - Adoptive transfer of cytomegalovirus (CMV)-specific T cells derived from adult seropositive donors can effectively restore antiviral immunity after transplantation. However, CMV-seronegative donors lack CMV-specific memory T cells, which restricts the availability of virus-specific T cells for immunoprophylaxis. We demonstrate the feasibility of deriving CMV-specific T cells from naive cells for T cell therapy. Naive T cells primed to recognize CMV were restricted to different, atypical epitopes than T cells derived from CMV seropositive individuals; however, these two cell populations had similar avidities. CMV-seropositive individuals also had T cells recognizing these atypical epitopes, but these cells had a lower avidity than those derived from the seronegative subjects, which suggests that high-avidity T cells to these epitopes may be lost over time. Indeed, recipients of cord blood (CB) grafts who did not develop CMV were found by clonotypic analysis to have T cells recognizing atypical CMVpp65 epitopes. Therefore, we examined unmanipulated CB units and found that T cells with T cell receptors restricted by atypical epitopes were the most common, which may explain why these T cells expanded. When infused to recipients, naive donor-derived virus-specific T cells that recognized atypical epitopes were associated with prolonged periods of CMV-free survival and complete remission. These data suggest that naive-derived T cells from seronegative patients may be an additional source of cells for CMV immunoprophylaxis. PMID- 25925683 TI - Mitigation of tracheobronchomalacia with 3D-printed personalized medical devices in pediatric patients. AB - Three-dimensional (3D) printing offers the potential for rapid customization of medical devices. The advent of 3D-printable biomaterials has created the potential for device control in the fourth dimension: 3D-printed objects that exhibit a designed shape change under tissue growth and resorption conditions over time. Tracheobronchomalacia (TBM) is a condition of excessive collapse of the airways during respiration that can lead to life-threatening cardiopulmonary arrests. We demonstrate the successful application of 3D printing technology to produce a personalized medical device for treatment of TBM, designed to accommodate airway growth while preventing external compression over a predetermined time period before bioresorption. We implanted patient-specific 3D printed external airway splints in three infants with severe TBM. At the time of publication, these infants no longer exhibited life-threatening airway disease and had demonstrated resolution of both pulmonary and extrapulmonary complications of their TBM. Long-term data show continued growth of the primary airways. This process has broad application for medical manufacturing of patient specific 3D-printed devices that adjust to tissue growth through designed mechanical and degradation behaviors over time. PMID- 25925684 TI - Arterial microanatomy determines the success of energy-based renal denervation in controlling hypertension. AB - Renal denervation (RDN) is a treatment option for patients with hypertension resistant to conventional therapy. Clinical trials have demonstrated variable benefit. To understand the determinants of successful clinical response to this treatment, we integrated porcine and computational models of intravascular radiofrequency RDN. Controlled single-electrode denervation resulted in ablation zone geometries that varied in arc, area, and depth, depending on the composition of the adjacent tissue substructure. Computational simulations predicted that delivered power density was influenced by tissue substructure, and peaked at the conductivity discontinuities between soft fatty adventitia and water-rich tissues (media, lymph nodes, etc.), not at the electrode-tissue interface. Electrode irrigation protected arterial wall tissue adjacent to the electrode by clearing heat that diffuses from within the tissue, without altering periarterial ablation. Seven days after multielectrode treatments, renal norepinephrine and blood pressure were reduced. Blood pressure reductions were correlated with the size-weighted number of degenerative nerves, implying that the effectiveness of the treatment in decreasing hypertension depends on the extent of nerve injury and ablation, which in turn are determined by the tissue microanatomy at the electrode site. These results may explain the variable patient response to RDN and suggest a path to more robust outcomes. PMID- 25925685 TI - Color stability and surface roughness of polished anterior restorative materials. AB - The purpose of this study was to investigate the effects of different finishing polishing techniques on the color stability and surface roughness of various anterior restorative materials after staining. A composite, a compomer, and a resin-modified glass ionomer were used to prepare 120 specimens. Specimens were divided into subgroups: polishing discs, liquid polishing material, aluminium oxidebonded discs, and control. The specimens were stained in a coffee solution. Color parameters (L*a*b*) and surface roughness before and after staining were measured. The color was affected by the material type (p<0.05) and finishing polishing systems (p<0.05). The composite showed the highest color stability; however, the color differences of all groups were visible even to the nonskilled operator. The Ra values did not significantly change after staining for any of the restorative groups (p>0.05). The finishing-polishing systems had an effect on color after storing in staining solution. PMID- 25925686 TI - Moving Beyond Minimization Trials in Kidney Transplantation. PMID- 25925687 TI - Adverse Outcomes of Tacrolimus Withdrawal in Immune-Quiescent Kidney Transplant Recipients. AB - Concerns about adverse effects of calcineurin inhibitors (CNIs) have prompted development of protocols that minimize their use. Whereas previous CNI withdrawal trials in heterogeneous cohorts showed unacceptable rates of acute rejection (AR), we hypothesized that we could identify individuals capable of tolerating CNI withdrawal by targeting immunologically quiescent kidney transplant recipients. The Clinical Trials in Organ Transplantation-09 Trial was a randomized, prospective study of nonsensitized primary recipients of living donor kidney transplants. Subjects received rabbit antithymocyte globulin, tacrolimus, mycophenolate mofetil, and prednisone. Six months post-transplantation, subjects without de novo donor-specific antibodies (DSAs), AR, or inflammation at protocol biopsy were randomized to wean off or remain on tacrolimus. The intended primary end point was the change in interstitial fibrosis/tubular atrophy score between implantation and 24-month protocol biopsies. Serially collected urine CXCL9 ELISA results were correlated with outcomes. The study was terminated prematurely because of unacceptable rates of AR (4 of 14) and/or de novo DSAs (5 of 14) in the tacrolimus withdrawal arm. Positive urinary CXCL9 predated clinical detection of AR by a median of 15 days. Analyses showed that >16 HLA-DQ epitope mismatches and pretransplant, peripheral blood, donor-reactive IFN-gamma ELISPOT assay results correlated with development of DSAs and/or AR on tacrolimus withdrawal. Although data indicate that urinary CXCL9 monitoring, epitope mismatches, and ELISPOT assays are potentially informative, complete CNI withdrawal must be strongly discouraged in kidney transplant recipients who are receiving standard of-care immunosuppression, including those who are deemed to be immunologically quiescent on the basis of current clinical and laboratory criteria. PMID- 25925688 TI - Calcification Propensity and Survival among Renal Transplant Recipients. AB - Calciprotein particle maturation time (T50) in serum is a novel measure of individual blood calcification propensity. To determine the clinical relevance of T50 in renal transplantation, baseline serum T50 was measured in a longitudinal cohort of 699 stable renal transplant recipients and the associations of T50 with mortality and graft failure were analyzed over a median follow-up of 3.1 years. Predictive value of T50 was assessed for patient survival with reference to traditional (Framingham) risk factors and the calcium-phosphate product. Serum magnesium, bicarbonate, albumin, and phosphate levels were the main determinants of T50, which was independent of renal function and dialysis vintage before transplant. During follow-up, 81 (12%) patients died, of which 38 (47%) died from cardiovascular causes. Furthermore, 45 (6%) patients developed graft failure. In fully adjusted models, lower T50 values were independently associated with increased all-cause mortality (hazard ratio, 1.43; 95% confidence interval, 1.11 to 1.85; P=0.006 per SD decrease) and increased cardiovascular mortality (hazard ratio, 1.55; 95% confidence interval, 1.04 to 2.29; P=0.03 per SD decrease). In addition to age, sex, and eGFR, T50 improved prognostication for all-cause mortality, whereas traditional risk factors or calcium-phosphate product did not. Lower T50 was also associated with increased graft failure risk. The associations of T50 with mortality and graft failure were confirmed in an independent replication cohort. In conclusion, reduced serum T50 was associated with increased risk of all-cause mortality, cardiovascular mortality, and graft failure and, of all tested parameters, displayed the strongest association with all-cause mortality in these transplant recipients. PMID- 25925689 TI - Time dynamics of protein complexes in the AD11 transgenic mouse model for Alzheimer's disease like pathology. AB - BACKGROUND: Many approaches exist to integrate protein-protein interaction data with other sources of information, most notably with gene co-expression data, to obtain information on network dynamics. It is of interest to look at groups of interacting gene products that form a protein complex. We were interested in applying new tools to the characterization of pathogenesis and dynamic events of an Alzheimer's-like neurodegenerative model, the AD11 mice, expressing an anti NGF monoclonal antibody. The goal was to quantify the impact of neurodegeneration on protein complexes, by measuring the correlation between gene expression data by different metrics. RESULTS: Data were extracted from the gene expression profile of AD11 brain, obtained by Agilent microarray, at 1, 3, 6, 15 months of age. For genes coding proteins in complexes, the correlation matrix of pairwise expression was computed. The dynamics between correlation matrices at different time points was evaluated: paired T-test between average correlation levels and a normalized Euclidean distance with z-score. We unveiled a differential wiring of interactions in a set of complexes, whose network structure discriminates between transgenic and control mice. Furthermore, we analyzed the dynamics of gene expression values, by looking at changes in gene-to-gene correlation over time and identified those complexes that exhibit a different timedependent behaviour between transgenic and controls. The most significant changes in correlation dynamics are concentrated in the early stage of disease, with higher correlation in AD11 mice compared to controls. Many complexes go through dynamic changes over time, showing the role of the dysfunctional immunoproteasome, as early neurodegenerative disease event. Furthermore, this analysis shows key events in the neurodegeneration process of the AD11 model, by identifying significant differences in co-expression values of other complexes, such as parvulin complex, with a role in protein misfolding and proteostasis, and of complexes involved in transcriptional mechanisms. CONCLUSIONS: We have proposed a novel approach to analyze the network structure of protein complexes, by two different measures to evaluate the dynamics of gene-gene correlation matrices from gene expression profiles. The methodology was able to investigate the re-organization of interactions within protein complexes in the AD11 model of neurodegeneration. PMID- 25925690 TI - Next-generation narrow band imaging system for colonic polyp detection: a prospective multicenter randomized trial. AB - PURPOSE: Previous studies have yielded conflicting results on the colonic polyp detection rate with narrow-band imaging (NBI) compared with white-light imaging (WLI). We compared the mean number of colonic polyps detected per patient for NBI versus WLI using a next-generation NBI system (EVIS LUCERA ELITE; Olympus Medical Systems) used with standard-definition (SD) colonoscopy and wide-angle (WA) colonoscopy. METHODS: DESIGN: this study is a 2 * 2 factorial, prospective, multicenter randomized controlled trial. SETTING: this study was conducted at five academic centers in Japan. INTERVENTIONS: patients were allocated to one of four groups: (1) WLI with SD colonoscopy (H260AZI), (2) NBI with SD colonoscopy (H260AZI), (3) WLI with WA colonoscopy (CF-HQ290), and (4) NBI with WA colonoscopy (CF-HQ290). MAIN OUTCOME: the mean numbers of polyps detected per patient were compared between the four groups: WLI with/without WA colonoscopy and NBI with/without WA colonoscopy. RESULTS: Of the 454 patients recruited, 431 patients were enrolled. The total numbers of polyps detected by WLI with SD, NBI with SD, WLI with WA, and NBI with WA were 164, 176, 188, and 241, respectively. The mean number of polyps detected per patient was significantly higher in the NBI group than in the WLI group (2.01 vs 1.56; P = 0.032). The rate was not higher in the WA group than in the SD group (1.97 vs 1.61; P = 0.089). CONCLUSIONS: Although WA colonoscopy did not improve the polyp detection, next generation NBI colonoscopy represents a significant improvement in the detection of colonic polyps. PMID- 25925691 TI - In situ formation of a MoS2 -based inorganic-organic nanocomposite by directed thermal decomposition. AB - Nanocomposites based on molybdenum disulfide (MoS2 ) and different carbon modifications are intensively investigated in several areas of applications due to their intriguing optical and electrical properties. Addition of a third element may enhance the functionality and application areas of such nanocomposites. Herein, we present a facile synthetic approach based on directed thermal decomposition of (Ph4 P)2 MoS4 generating MoS2 nanocomposites containing carbon and phosphorous. Decomposition at 250 degrees C yields a composite material with significantly enlarged MoS2 interlayer distances caused by in situ formation of Ph3 PS bonded to the MoS2 slabs through Mo?S bonds and (Ph4 P)2 S molecules in the van der Waals gap, as was evidenced by (31) P solid-state NMR spectroscopy. Visible-light-driven hydrogen generation demonstrates a high catalytic performance of the materials. PMID- 25925692 TI - Diagnosis of Cognitive Impairment Compatible with Early Diagnosis of Alzheimer's Disease. A Bayesian Network Model based on the Analysis of Oral Definitions of Semantic Categories. AB - BACKGROUND: Early detection of Alzheimer's disease (AD) has become one of the principal focuses of research in medicine, particularly when the disease is incipient or even prodromic, because treatments are more effective in these stages. Lexical-semantic-conceptual deficit (LSCD) in the oral definitions of semantic categories for basic objects is an important early indicator in the evaluation of the cognitive state of patients. OBJECTIVES: The objective of this research is to define an economic procedure for cognitive impairment (CI) diagnosis, which may be associated with early stages of AD, by analysing cognitive alterations affecting declarative semantic memory. Because of its low cost, it could be used for routine clinical evaluations or screenings, leading to more expensive and selective tests that confirm or rule out the disease accurately. It should necessarily be an explanatory procedure, which would allow us to study the evolution of the disease in relation to CI, the irregularities in different semantic categories, and other neurodegenerative diseases. On the basis of these requirements, we hypothesise that Bayesian networks (BNs) are the most appropriate tool for this purpose. METHODS: We have developed a BN for CI diagnosis in mild and moderate AD patients by analysing the oral production of semantic features. The BN causal model represents LSCD in certain semantic categories, both of living things (dog, pine, and apple) and non-living things (chair, car, and trousers), as symptoms of CI. The model structure, the qualitative part of the model, uses domain knowledge obtained from psychology experts and epidemiological studies. Further, the model parameters, the quantitative part of the model, are learnt automatically from epidemiological studies and Peraita and Grasso's linguistic corpus of oral definitions. This corpus was prepared with an incidental sampling and included the analysis of the oral linguistic production of 81 participants (42 cognitively healthy elderly people and 39 mild and moderate AD patients) from Madrid region's hospitals. Experienced neurologists diagnosed these cases following the National Institute of Neurological and Communicative Disorders and Stroke/Alzheimer's Disease and Related Disorders Association (NINCDS-ADRDA)'s Alzheimer's criteria, performing, among other explorations and tests, a minimum neuropsychological exploration that included the Mini-Mental State Examination test. RESULTS: BN's classification performance is remarkable compared with other machine learning methods, achieving 91% accuracy and 94% precision in mild and moderate AD patients. Apart from this, the BN model facilitates the explanation of the reasoning process and the validation of the conclusions and allows the study of uncommon declarative semantic memory impairments. CONCLUSIONS: Our method is able to analyse LSCD in a wide set of semantic categories throughout the progression of CI, being a valuable first screening method in AD diagnosis in its early stages. Because of its low cost, it can be used for routine clinical evaluations or screenings to detect AD in its early stages. Besides, due to its knowledge-based structure, it can be easily extended to provide an explanation of the diagnosis and to the study of other neurodegenerative diseases. Further, this is a key advantage of BNs over other machine learning methods with similar performance: it is a recognisable and explanatory model that allows one to study irregularities in different semantic categories. PMID- 25925693 TI - Fumonisin B1 induces autophagic cell death via activation of ERN1-MAPK8/9/10 pathway in monkey kidney MARC-145 cells. AB - Mycotoxins are secondary fungal metabolites that are capable of inducing a variety of toxic effects in animals and humans resulting from the consumption of the contaminated food. Understanding the mechanisms of the toxicities behind these mycotoxins is required to develop mechanism-based approach to counteract their toxic potential. Fumonisin B1 (FB1) is the most prevalent member of fumonisins that are a group of mycotoxins produced primarily by Fusarium verticillioides and Fusarium proliferatum. Kidney is one of the primary target organs for FB1 action. Using monkey kidney MARC-145 cells as an intro model, we found that FB1 induced caspase-independent programmed cell death accompanied with autophagy induction. Inhibition of autophagy by either chemical inhibitors or RNAi approach led to a significant reduction in cell death by FB1 exposure, indicating possible involvement of autophagy-mediated cell death in nephrotoxicity of FB1. Further mechanistic investigation revealed that activation of ERN1-MAPK8/9/10 axis played a critical role in autophagy induction and autophagy-mediated cell death by FB1 exposure. In addition, we demonstrated that disruption of sphingolipid metabolism was an apical event in FB1-induced ERN1 MAPK8/9/10-mediated autophagic cell death in MARC-145 cells. Lastly, we identified curcumin, a naturally occurring plant phenolic compound, as a possible anti-FB1 agent that can be used to protect kidney cells from FB1-induced cell death through inhibition of MAPK8/9/10 activation. PMID- 25925694 TI - Collagen VI Is Upregulated in COPD and Serves Both as an Adhesive Target and a Bactericidal Barrier for Moraxella catarrhalis. AB - Moraxella catarrhalis is a Gram-negative human mucosal commensal and pathogen. It is a common cause of exacerbation in chronic obstructive pulmonary disease (COPD). During the process of infection, host colonization correlates with recognition of host molecular patterns. Importantly, in COPD patients with compromised epithelial integrity the underlying extracellular matrix is exposed and provides potential adhesive targets. Collagen VI is a ubiquitous fibrillar component in the airway mucosa and has been attributed both adhesive and killing properties against Gram-positive bacteria. However, less is known regarding Gram negative microorganisms. Therefore, in the present study, the interaction of M. catarrhalis with collagen VI was characterized. We found that collagen VI is upregulated in the airways of COPD patients and exposed upon epithelial desquamation. Ex vivo, we inoculated airway biopsies and fibroblasts from COPD patients with M. catarrhalis. The bacteria specifically adhered to collagen VI containing matrix fibrils. In vitro, purified collagen VI microfibrils bound to bacterial surface structures. The primary adhesion target was mapped to the collagen VI alpha2-chain. Upon exposure to collagen VI, bacteria were killed by membrane destabilization in physiological conditions. These previously unknown properties of collagen VI provide novel insights into the extracellular matrix innate immunity by quickly entrapping and killing pathogen intruders. PMID- 25925695 TI - Outcome of Recipients of Hematopoietic Stem Cell Transplants Who Require Intensive Care Unit Support: A Single Institution Experience. AB - Admission to the intensive care unit (ICU) of a patient who has been grafted with hematopoietic stem cells is a serious event, but the role of the ICU in this setting remains controversial. Data were analyzed from patients who underwent autologous or allogeneic bone marrow transplantation at the Centro de Hematologia y Medicina Interna de Puebla, Mexico, between May 1993 and October 2014. In total, 339 patients were grafted: 150 autografts and 189 allografts; 68 of the grafted patients (20%) were admitted to the ICU after transplantation: 27% of the allografted and 11% of the autografted patients (p = 0.2). Two of 17 autografted patients (12%) and 5 of 51 allografted patients (10%) survived. All patients who required insertion of an endotracheal tube died, whereas 7 of 11 patients without invasive mechanical ventilation survived (p = 0.001). Only 10% of the grafted patients survived their stay in the ICU; this figure is lower than those reported from other centers and may reflect several facts, varying from the quality of the ICU support to ICU admission criteria to the initial management of all the grafts in an outpatient setting, which could somehow delay the arrival of patients to the hospital. PMID- 25925696 TI - Structural basis for binding of human IgG1 to its high-affinity human receptor FcgammaRI. AB - Cell-surface Fcgamma receptors mediate innate and adaptive immune responses. Human Fcgamma receptor I (hFcgammaRI) binds IgGs with high affinity and is the only Fcgamma receptor that can effectively capture monomeric IgGs. However, the molecular basis of hFcgammaRI's interaction with Fc has not been determined, limiting our understanding of this major immune receptor. Here we report the crystal structure of a complex between hFcgammaRI and human Fc, at 1.80 A resolution, revealing an unique hydrophobic pocket at the surface of hFcgammaRI perfectly suited for residue Leu235 of Fc, which explains the high affinity of this complex. Structural, kinetic and thermodynamic data demonstrate that the binding mechanism is governed by a combination of non-covalent interactions, bridging water molecules and the dynamic features of Fc. In addition, the hinge region of hFcgammaRI-bound Fc adopts a straight conformation, potentially orienting the Fab moiety. These findings will stimulate the development of novel therapeutic strategies involving hFcgammaRI. PMID- 25925697 TI - Clinical and laboratory profiles of primary Sjogren's syndrome in a Chinese population: A retrospective analysis of 315 patients. AB - AIM: To assess the clinical and laboratory features of primary Sjogren's syndrome (pSS) in a large teaching hospital in China. METHODS: Three hundred and fifteen pSS patients diagnosed according to American-European Classification Criteria and consecutively admitted to Anhui Provincial Hospital from 1 January 1999 to 30 September 2012 were retrospectively selected in this study. RESULTS: The median age was 46.8 +/- 14.4 years (range 13-83 years) and the majority of patients were female (96.5%). The common clinical features at initial presentations were dry mouth (50.2%), dry eyes (31.4%) and joint pain (24.8%); 92.6% of patients had positive anti-SSA antibody and 49.2% patients had positive anti-SSB antibody. One hundred and eighteen patients underwent labial salivary gland biopsy. According to Chisholm grading criteria, grade 3 to 4 was present in 58.5% of the patients. The frequency of interstitial lung disease (ILD) occurred (20.9%) in the patients with systemic extraglandular manifestations. The patients with ILD were frequently associated with positive anti-SSA (P = 0.005) and low levels of C3. The most common impairment of lung function was small airway function abnormalities. Sixty-six pSS patients with ILD (pSS-ILD) were diagnosed with high resolution computed tomography and treated with corticosteroids and/or immunosuppressants, in which 18 patients had improved pulmonary function. CONCLUSION: Labial salivary gland biopsy and anti-nuclear antibodies spectrum were important to the diagnosis of pSS. The pSS patients had high percentage of ILD, especially small airway function abnormalities. The combination of corticosteroids and immunosuppressants appears to be effective in treatment of pSS patients with ILD. PMID- 25925698 TI - Radical-induced metal-free alkynylation of aldehydes by direct C-H activation. AB - A direct C(sp(2) )?H alkynylation of aldehyde C(O)?H bonds with hypervalent iodine alkynylation reagents provides ynones under metal-free conditions. In this method, 1-[(triisopropylsilyl)ethynyl]-1,2-benziodoxol-3(1H)-one (TIPS-EBX) constitutes an efficient alkynylation reagent for the introduction of the triple bond. The substrate scope is extended to a variety of (hetero)aromatic, aliphatic, and alpha,beta-unsaturated aldehydes. PMID- 25925699 TI - The effects of repetitive transcranial magnetic stimulation on cognitive performance in treatment-resistant depression. A systematic review. AB - BACKGROUND: Major depressive disorder (MDD) is a disabling illness associated with significant functional and psychosocial impairment. Although many psychopharmacological agents are currently available for its treatment, many MDD patients suffer from treatment-resistant depression (TRD). METHODS: A systematic review of the current literature (Pubmed/Medline, Scopus and ScienceDirect search) has been conducted with the primary aim to investigate the role of repetitive transcranial magnetic stimulation (rTMS) in improving neurocognition in patients with TRD. Studies were included according to the following criteria: (a) being an original paper in a peer-reviewed journal and (b) having analyzed the effect of rTMS on neurocognitive functioning in TRD. RESULTS: The combined search strategy yielded a total of 91 articles, of which, after a complete analysis, 22 fulfilled our inclusion criteria. Based on the main findings, most of the selected studies suggested the existence of a trend towards improvements in the neurocognitive profile using rTMS. Negative findings have also been reported. However, most studies were limited by their small sample size or included mixed samples, or the adopted single-blind designs potentially biased the blinding of the study design. CONCLUSION: rTMS is a noninvasive brain stimulation that may be considered a valuable and promising technique for cognitive enhancement in TRD. PMID- 25925700 TI - Considerable variations in growth hormone policy and prescription in paediatric end-stage renal disease across European countries-a report from the ESPN/ERA-EDTA registry. AB - BACKGROUND: Growth retardation in paediatric end-stage renal disease (ESRD) has a serious impact on adult life. It is potentially treatable with recombinant growth hormone (rGH). In this study, we aimed to quantify the variation in rGH policies and actual provided care in these patients across Europe. METHODS: Renal registry representatives of 38 European countries received a structured questionnaire on rGH policy. Cross-sectional data on height and actual use of rGH on children with ESRD aged <18 years were retrieved from the ESPN/ERA-EDTA Registry. RESULTS: In 21 (75%) of 28 responding countries, rGH is reimbursed for children with ESRD. The specific conditions for reimbursement (minimum age, maximum age and chronic kidney disease stage) vary considerably. Mean height standard deviation scores (SDS) at renal replacement therapy (RRT) [95% confidence interval (CI)] were significantly higher in countries where rGH was reimbursed -1.80 (-2.06; -1.53) compared with countries in which it was not reimbursed [-2.34 (-2.49;-2.18), P < 0.001]. Comparison of the mean height SDS at onset of RRT and final height SDS yielded similar results. Among the 13 countries for which both data on actual rGH use between 2007 and 2011 and data from the questionnaire were available, 30.1% of dialysis and 42.3% of transplanted patients had a short stature, while only 24.1 and 7.6% of those short children used rGH, respectively. CONCLUSION: Reimbursement of rGH associates with a less compromised final stature of ESRD children. In many countries with full rGH reimbursement, the actual rGH prescription in growth-retarded ESRD children is low and obviously more determined by the doctor's and patients' attitude towards rGH therapy than by financial hurdles. PMID- 25925701 TI - A randomized, open-label trial of iron isomaltoside 1000 (Monofer(r)) compared with iron sucrose (Venofer(r)) as maintenance therapy in haemodialysis patients. AB - BACKGROUND: Iron deficiency anaemia is common in patients with chronic kidney disease, and intravenous iron is the preferred treatment for those on haemodialysis. The aim of this trial was to compare the efficacy and safety of iron isomaltoside 1000 (Monofer(r)) with iron sucrose (Venofer(r)) in haemodialysis patients. METHODS: This was an open-label, randomized, multicentre, non-inferiority trial conducted in 351 haemodialysis subjects randomized 2:1 to either iron isomaltoside 1000 (Group A) or iron sucrose (Group B). Subjects in Group A were equally divided into A1 (500 mg single bolus injection) and A2 (500 mg split dose). Group B were also treated with 500 mg split dose. The primary end point was the proportion of subjects with haemoglobin (Hb) in the target range 9.5-12.5 g/dL at 6 weeks. Secondary outcome measures included haematology parameters and safety parameters. RESULTS: A total of 351 subjects were enrolled. Both treatments showed similar efficacy with >82% of subjects with Hb in the target range (non-inferiority, P = 0.01). Similar results were found when comparing subgroups A1 and A2 with Group B. No statistical significant change in Hb concentration was found between any of the groups. There was a significant increase in ferritin from baseline to Weeks 1, 2 and 4 in Group A compared with Group B (Weeks 1 and 2: P < 0.001; Week 4: P = 0.002). There was a significant higher increase in reticulocyte count in Group A compared with Group B at Week 1 (P < 0.001). The frequency, type and severity of adverse events were similar. CONCLUSIONS: Iron isomaltoside 1000 and iron sucrose have comparative efficacy in maintaining Hb concentrations in haemodialysis subjects and both preparations were well tolerated with a similar short-term safety profile. PMID- 25925702 TI - Acute kidney injury-how does automated detection perform? AB - BACKGROUND: Early detection of acute kidney injury (AKI) is important for safe clinical practice. NHS England is implementing a nationwide automated AKI detection system based on changes in blood creatinine. Little has been reported on the similarities and differences of AKI patients detected by this algorithm and other definitions of AKI in the literature. METHODS: We assessed the NHS England AKI algorithm and other definitions using routine biochemistry in our own health authority in Scotland in 2003 (adult population 438 332). Linked hospital episode codes (ICD-10) were used to identify patients where AKI was a major clinical diagnosis. We compared how well the algorithm detected this subset of AKI patients in comparison to other definitions of AKI. We also evaluated the potential 'alert burden' from using the NHS England algorithm in comparison to other AKI definitions. RESULTS: Of 127 851 patients with at least one blood test in 2003, the NHS England AKI algorithm identified 5565 patients. The combined NHS England algorithm criteria detected 91.2% (87.6-94.0) of patients who had an ICD 10 AKI code and this was better than any individual AKI definition. Some of those not captured could be identified by algorithm modifications to identify AKI in retrospect after recovery, but this would not be practical in real-time. Any modifications also increased the number of alerted patients (2-fold in the most sensitive model). CONCLUSIONS: The NHS England AKI algorithm performs well as a diagnostic adjunct in clinical practice. In those without baseline data, AKI may only be seen in biochemistry in retrospect, therefore proactive clinical care remains essential. An alternative algorithm could increase the diagnostic sensitivity, but this would also produce a much greater burden of patient alerts. PMID- 25925703 TI - Professionalism and the role of medical colleges. AB - BACKGROUND: There has been substantial interest and emphasis on medical professionalism over the past twenty years. This speaks to the history of the medical profession, but increasingly to a broader understanding of the importance of socialisation and professional identity formation. METHOD: A literature review was undertaken of professionalism and the role of professions and medical professional organisations. RESULTS: A key outcome has been the recognition that medical professionalism must be actively taught and assessed. Substantial effort is required to improve the educational environment, so that it nurtures the development of professionalism within the work-place. Although medical colleges have been prominent in identifying and progressing the recent developments within professionalism there is still much to be done to deliver fully on the societal contract between the public and the profession. There are key gaps to address, particularly with regards to self-regulation, civil behaviour and effective leadership and advocacy. CONCLUSION: Medical colleges need to take direct responsibility for the professionalism of their members. The expectations of the community are increasingly clear in this regard. PMID- 25925704 TI - Autophagy inhibitors reduce avian-reovirus-mediated apoptosis in cultured cells and in chicken embryos. AB - Avian reovirus (ARV)-induced apoptosis contributes to the pathogenesis of reovirus in infected chickens. However, methods for effectively reducing ARV triggered apoptosis remain to be explored. Here, we show that pretreatment with chloroquine (CQ) or E64d plus pepstatin A decreases ARV-mediated apoptosis in chicken DF-1 cells. By acting as autophagy inhibitors, CQ and E64d plus pepstatin A increase microtubule-associated protein 1 light chain 3-II (LC3II) accumulation in ARV-infected cells, which results in decreased ARV protein synthesis and virus yield and thereby contributes to the reduction of apoptosis. Furthermore, ARV mediated apoptosis in the bursa, heart and intestines of chicken embryos is attenuated by CQ and E64d plus pepstatin A treatment. Importantly, treatment with these autophagy inhibitors increases the survival of infected chicken embryos. Together, our data suggest that pharmacological inhibition of autophagy might represent a novel strategy for reducing ARV-mediated apoptosis. PMID- 25925705 TI - Genetic diversity and recombination analysis of grapevine leafroll-associated virus 1 from China. AB - Grapevine leafroll-associated virus 1 (GLRaV-1) is one of the causal agents of grapevine leafroll disease (GLD). To investigate the prevalence and genetic variation of GLRaV-1 in China, 132 grapevine samples from 14 Chinese provinces and regions were tested using reverse transcription PCR (RT-PCR) and reverse transcription nested PCR (RT-nPCR). The samples included symptomatic and asymptomatic cultivars, and 36.4% of them tested positive for GLRaV-1. 'Beida' samples, previously identified as virus-free rootstocks, were also found to be infected with GLRaV-1 with an incidence of 40 . GLRaV-1 coat protein (CP) genes and heat-shock protein 70 (HSP70) genes from 43 GLRaV-1 isolates were selected and sequenced. Phylogenetic analysis of global CP and HSP70 gene sequences showed that all variants belonged to eight and seven groups, respectively. For CP gene sequence variants, group 4 was a new group that included only Chinese isolates. The results also showed that natural selection, rather than random processes, led to the evolution of variants belonging to CP gene sequence variants in group 2 and group 8. Furthermore, three new recombination events were identified in the GLRaV-1 CP gene population. This is the first report on the genetic variation of GLRaV-1 isolates in China, and this study will benefit grape clean-plant programs in China. PMID- 25925706 TI - Psychological support needs of patients with head and neck cancer and their caregivers: A qualitative study. AB - OBJECTIVE: The aim of this study was to explore the psychological support needs of patients with head and neck cancer (HNC) and their caregivers. The appropriate timing, length, format and content of sessions were also investigated. DESIGN: Eighty-three patients with HNC and 73 of their caregivers completed questionnaires at diagnosis. Follow-up questionnaires were mailed to patients six months later. MAIN OUTCOME MEASURES: Free text-comments to open-ended questions in the questionnaires were analysed using an inductive thematic approach with coding and theme development directed by the content of responses. This was used to determine psychological support needs both at diagnosis and at six month follow-up. RESULTS: Patients described 'just being there', empathy, maintaining normality and practical support as helpful from family/friends. They desired information, honesty, positivity and empathy from clinical staff. Formal psychological support was desired by approximately 40% of patients and caregivers, particularly early after diagnosis and during treatment. Most participants desired face to face sessions, providing individualised information and coping strategies. CONCLUSION: The results of this study suggest that psychological interventions for patients with HNC and their caregivers should be delivered early after diagnosis in face to face sessions, presenting honest and factual information about the disease and coping strategies. PMID- 25925707 TI - Continuous Microfluidic Self-Assembly of Hybrid Janus-Like Vesicular Motors: Autonomous Propulsion and Controlled Release. AB - A microfluidic strategy is developed for the continuous fabrication of hybrid Janus vesicular motors that uniquely combine the capability of autonomous propulsion and externally controlled delivery of encapsulated payload. PMID- 25925708 TI - Truncus arteriosus communis in combination with cor triatriatum sinsitrum. AB - Truncus arteriosus communis is a rare CHD, accounting for only 1% of all congenital cardiac abnormalities. It has been associated with other malformations of the heart, mainly truncal valve (bicuspid/quadricuspid) and aortic arch abnormalities such as right, interrupted, and hypoplastic aortic arch. Cor tratriatrum sinistrum is another rare CHD, and it has been associated with other cardiac defects such as anomalous pulmonary venous drainage, ventricular septal defect, coarctation of the aorta, and tetralogy of Fallot. The combination of truncus arteriosus communis and cor tratriatrum sinistrum has not been reported so far. This case study describes the diagnosis of a unique case, including these two very rare cardiac defects and the successful surgical treatment thereafter. PMID- 25925709 TI - Use and impact of intermittent versus continuous systemic treatment strategies in metastatic colorectal cancer in routine practice. AB - BACKGROUND: Randomized trials have shown that intermittent treatment may reduce toxicity without compromising survival in patients with metastatic colorectal cancer (mCRC). A population-based study examined patterns of use of chemotherapy free intervals (CFIs) in routine practice in Ontario and their impact on survival and toxicity. METHODS: Patients treated with first-line intravenous chemotherapy for mCRC in Ontario between 2007 and 2009 were identified from administrative data. A CFI was defined as more than 56 days between 2 chemotherapy doses. A propensity score analysis was used to compare the survival of patients with CFIs and patients without CFIs, stratified by the type of first-line treatment: irinotecan (IRI), irinotecan plus bevacizumab (IRI-B), and oxaliplatin (OX). Toxicity was estimated on the basis of the rate of emergency room visits and hospitalizations. RESULTS: There were 1989 patients who started first-line chemotherapy for mCRC in Ontario between 2007 and 2009, and 489 (25%) had at least 1 CFI. The median time to the first CFI was 155 days (interquartile range, 82-217 days). There was no difference in survival for the propensity score matched patients with or without CFIs in the IRI (hazard ratio [HR], 0.93; P = .70) and OX groups (HR, 0.73; P = .06). Survival was worse in the CFI group for patients treated with IRI-B (HR, 1.28; P = .03). Toxicity was lower for patients with at least 1 CFI (0.17 vs 0.25 acute visits per person-month of treatment, P = .007), although the magnitude varied with the treatment type. CONCLUSIONS: Intermittent treatment strategies are being used in routine practice for patients with mCRC. The impact on survival and toxicity varies with the type of first-line chemotherapy. PMID- 25925710 TI - Corrections to "Model Identification Using Stochastic Differential Equation Grey Box Models in Diabetes" (2013; vol. 7, no. 2: pp. 431-440). PMID- 25925711 TI - Age-Dependent Pharmacokinetics of Doxorubicin in Children with Cancer. AB - BACKGROUND AND OBJECTIVE: Knowledge on the pharmacokinetics of doxorubicin, especially in children, is very limited with conflicting evidence concerning a possible age dependency in the pharmacokinetics. The aim of the current investigation was to assess, by using population pharmacokinetics, whether an age dependency in the clearance (CL) of doxorubicin exists. METHODS: Pharmacokinetic data of doxorubicin and its main metabolite doxorubicinol from 94 children (aged 0-18 years) from the EPOC-MS-001-Doxo trial were available. A population pharmacokinetic model was developed in NONMEM((r)) 7.2.0. RESULTS: A linear three compartment model for doxorubicin, with one additional compartment for doxorubicinol, gave the best fit to the data. All model parameters were linearly scaled on body surface area. Including a power function of age as a covariate for CL led to a further improvement of the model. Variation in genes encoding for enzymes involved in the metabolism or active transport of doxorubicin had no influence on the pharmacokinetics. Estimates of CL were lower (26.6 L/h/m(2) in children aged >3 years and 21.1 L/h/m(2) in children aged <=3 years, p = 0.0004) in children aged <3 years, compared with older children. CONCLUSIONS: This is the first model to describe the pharmacokinetics of doxorubicin in children, with a specific focus on infants and children aged <3 years. The lower CL in younger children should be considered together with the pharmacodynamics, especially the cardiotoxicity, when selecting the dose for future protocols. PMID- 25925712 TI - Use of microdose phenotyping to individualise dosing of patients. AB - Administering the right amount of the right drug at the right time is a key mission of clinical medicine. This comprises dose adaptation according to a patient's intrinsic and extrinsic factors influencing drug disposition. Several biomarkers are available for dose adaptation; still, prediction of individual drug disposition may be improved. Phenotyping is the quantification of drug metabolism with probe substrates specific to drug-metabolising enzymes. This allows measurement of baseline metabolism and changes after modulation of drug metabolism. This article explores the concept of phenotyping using pharmacologically ineffective microdoses of probe substrates to obtain information on drug metabolism. Several probe drugs such as midazolam for cytochrome P450 3A have already been used, but validation of other microdosed probe drugs, analytical procedures and drug formulations still face some challenges that have to be overcome. Since microdosed probe drugs have no risk of adverse drug reactions or interference with therapy, more widespread use is possible. This allows drug-drug interaction data to be safely obtained during first-in-man studies, enhancing the clinical safety of human healthy volunteers and patients in clinical trials, and, most importantly, allows determination of the drug-metabolising phenotype in severely ill patients. With harmless probe drugs at hand quantifying drug metabolism and adapting the dose accordingly, a phenotyping-based dosing strategy could become reality, offering the possibility of individualised drug therapy with reduced adverse effects and fewer therapeutic failures. PMID- 25925713 TI - CHInese Medicine NeuroAiD Efficacy on Stroke Recovery - Extension Study (CHIMES E): A Multicenter Study of Long-Term Efficacy. AB - BACKGROUND: The CHInese Medicine NeuroAiD Efficacy on Stroke recovery (CHIMES) study was an international randomized double-blind placebo-controlled trial of MLC601 (NeuroAiD) in subjects with cerebral infarction of intermediate severity within 72 h. CHIMES-E (Extension) aimed at evaluating the effects of the initial 3-month treatment with MLC601 on long-term outcome for up to 2 years. METHODS: All subjects randomized in CHIMES were eligible for CHIMES-E. Inclusion criteria for CHIMES were age >=18, baseline National Institute of Health Stroke Scale of 6 14, and pre-stroke modified Rankin Scale (mRS) <=1. Initial CHIMES treatment allocation blinding was maintained, although no further study treatment was provided in CHIMES-E. Subjects received standard care and rehabilitation as prescribed by the treating physician. mRS, Barthel Index (BI), and occurrence of medical events were ascertained at months 6, 12, 18, and 24. The primary outcome was mRS at 24 months. Secondary outcomes were mRS and BI at other time points. RESULTS: CHIMES-E included 880 subjects (mean age 61.8 +/- 11.3; 36% women). Adjusted OR for mRS ordinal analysis was 1.08 (95% CI 0.85-1.37, p = 0.543) and mRS dichotomy <=1 was 1.29 (95% CI 0.96-1.74, p = 0.093) at 24 months. However, the treatment effect was significantly in favor of MLC601 for mRS dichotomy <=1 at 6 months (OR 1.49, 95% CI 1.11-2.01, p = 0.008), 12 months (OR 1.41, 95% CI 1.05-1.90, p = 0.023), and 18 months (OR 1.36, 95% CI 1.01-1.83, p = 0.045), and for BI dichotomy >=95 at 6 months (OR 1.55, 95% CI 1.14-2.10, p = 0.005) but not at other time points. Subgroup analyses showed no treatment heterogeneity. Rates of death and occurrence of vascular and other medical events were similar between groups. CONCLUSIONS: While the benefits of a 3-month treatment with MLC601 did not reach statistical significance for the primary endpoint at 2 years, the odds of functional independence defined as mRS <=1 was significantly increased at 6 months and persisted up to 18 months after a stroke. PMID- 25925714 TI - A novel protocol for antibiotic prophylaxis based on preoperative kidney function in patients undergoing open heart surgery under cardiopulmonary bypass. AB - OBJECTIVE: This study aimed to develop and assess the effectiveness of a protocol for antibiotic prophylaxis based on preoperative kidney function in patients undergoing open heart surgery. METHODS: We established a protocol for antibiotic prophylaxis based on preoperative kidney function in patients undergoing open heart surgery. This novel protocol was assessed by comparing patients undergoing open heart surgery before (control group; n = 30) and after its implementation (protocol group; n = 31) at Kyoto University Hospital between July 2012 and January 2013. RESULTS: Surgical site infections (SSIs) were observed in 4 control group patients (13.3 %), whereas no SSIs were observed in the protocol group patients (P < 0.05). The total duration of antibiotic use decreased significantly from 80.7 +/- 17.6 h (mean +/- SD) in the control group to 55.5 +/- 14.9 h in the protocol group (P < 0.05). Similarly, introduction of the protocol significantly decreased the total antibiotic dose used in the perioperative period (P < 0.05). Furthermore, antibiotic regimens were changed under suspicion of infection in 5 of 30 control group patients, whereas none of the protocol group patients required this additional change in the antibiotic regimen (P < 0.05). CONCLUSION: Our novel antibiotic prophylaxis protocol based on preoperative kidney function effectively prevents SSIs in patients undergoing open heart surgery. PMID- 25925715 TI - Complexities of the mu opioid receptor. PMID- 25925716 TI - Discounting of delayed rewards as an endophenotype. PMID- 25925717 TI - Unexpected results on the role of nucleus accumbens dopamine in stress-induced relapse. PMID- 25925718 TI - Smoking Behaviors Among Urban and Rural Pregnant Women Enrolled in the Kansas WIC Program. AB - Smoking during pregnancy is associated with poor birth outcomes. The Special Supplemental Nutrition Program for Women, Infants, and Children (WIC) is a public nutritional assistance program for low-income pregnant women and their children up to age five. This study examined differences in smoking behavior among women enrolled in the Kansas WIC program. A secondary analysis was conducted using the Pregnancy Nutrition Surveillance System dataset of enrolled women between 2005 and 2011. Geographic residency status was obtained through application of the Census tract-based rural-urban commuting area codes. Chi square tests of association were used to assess differences. Multi-variable binary logistic regression was used to assess maternal characteristics and smoking 3 months prior to pregnancy. Total sample size averaged 21,650 women for years 2005 through 2011. Low-income, rural pregnant women smoked at significantly higher rates before, during, and after pregnancy. High smoking rates have remained unchanged since 2008. The following characteristics were associated with reduced odds of smoking 3 months prior to pregnancy: being 17 years old or younger, Hispanic, a high school graduate, urban location, normal body mass index, no live births prior to current pregnancy, and using multi-vitamins. Results from this study indicate that the WIC population in rural areas may have different needs regarding smoking cessation programming than the urban WIC population. Findings help inform WIC program administrators and assist in enhancing current smoking cessation services to the Kansas WIC population. PMID- 25925719 TI - A School-Hospital Partnership Increases Knowledge of Pedestrian and Motor Vehicle Safety. AB - Pedestrian and motor vehicle-related injuries are leading causes of morbidity and mortality in children. Trauma centers have specialized resources to conduct interventions that improve the safety of whole communities. In the present study, we evaluated the effectiveness of a school-hospital partnership in increasing knowledge of pedestrian and motor vehicle safety among students and parents in a large, urban community. Staff from a Level I pediatric trauma center conducted educational interventions in an urban public school district. Elementary school students participated in a pedestrian safety program, middle school students completed a community safety program, and high school students learned about the dangers of drunk and distracted driving. Students completed pre- and post-tests. Parents in the neighboring community received child passenger safety education at two child restraint (CR) inspection events. A total of 2203 students participated at a total of nine schools. Post-test scores were significantly higher than pre test scores for students in all three age groups and within each grade level. At CR inspection events, 67 CRs were inspected, 49 (73 %) of which were replaced with new age- and weight- appropriate CRs. The most common instance of improper CR use was loose CR fit in vehicle seat (33 %). All 120 observed instances of misuse were corrected by a certified Child Passenger Safety Technician. Educational interventions effectively increased knowledge of pedestrian and motor vehicle safety among students and parents. We have demonstrated the utility of a school-hospital partnership for furthering knowledge of safety in an urban community. PMID- 25925720 TI - Understanding Cultural Beliefs in Families of Somali Children with Diabetes in the Twin Cities, Minnesota. AB - Describe cultural beliefs related to diabetes in Minnesota Somali children with type 1 diabetes (T1D), and compare their diabetes control to that of non-Somali children with diabetes. A cross-sectional study involving Somali children <= 19 years with T1D at the University of Minnesota Masonic Children's Hospital and Children's Hospitals and Clinics of Minnesota. A survey was administered to parents of all participants and to children aged >= 12 years. Data were collected by history and from the medical record. Twenty-five Somali children participated, with 24 parent-child pairs (2 siblings). Mean participant age was 12.2 +/- 5.2 (36% female). Seventy-one percent of parents indicated the child was "the same as before" other than having to do diabetes cares. Families were coping well, and the child was not treated differently than siblings. Performance of routine cares was described as the hardest part about having diabetes, but this was not related to traditional culture or religion. One notable exception was difficulty performing carbohydrate counting on Somali foods. Respondents were appreciative of the education provided by the diabetes team. Less than 10% used herbal supplements in addition to insulin. Mean HbA1c in Somali children was higher than the overall pediatric clinic average, 9.5 +/- 1.6 % versus 8.8 +/- 1.6 (p = 0.01). The difference was largely due to adolescent patients. The majority of Somali families cope well with diabetes and have a positive attitude towards the diabetes education. Glycemic control in adolescents is worse than in non-Somali peers. There is a need for culture-specific dietary instruction materials. PMID- 25925722 TI - Adapting the forms of yesterday to the functions of today and the needs of tomorrow: a genealogical case study of clinical teaching units in Canada. AB - Emergent discourses of social responsibility and accountability have in part fuelled the expansion of distributed medical education (DME). In addition to its potential for redressing physician maldistribution, DME has conferred multiple unexpected educational benefits. In several countries, its recent rise has occurred around the boundaries of traditional medical education practices. Canada has been no exception, with DME proliferating against a backdrop of its longstanding central node, the clinical teaching unit (CTU). The CTU first appeared just over 50 years ago with its position in Canadian health care largely taken-for-granted. Given the increasing prominence of DME, however, it is timely to reconsider what the place of tertiary centre-based practices such as the CTU might be in shifting medical education systems. From a genealogical perspective, it becomes clear that the CTU did not just "happen". Rather, its creation was made possible by multiple interrelated cultural, social, and political changes in Canadian society that, while subtle, are powerfully influential. Making them visible offers a better opportunity to harmonize the benefits of longstanding entities such as the CTU with novel practices such as DME. In so doing, the medical education field may sidestep the pitfalls of investing significant resources that may only produce superficial changes while unwittingly obstructing deeper transformations and improvements. Although this work is refracted through a Canadian prism, reconceptualizing the overall design of medical education systems to take advantage of both tradition and innovation is a persistent challenge across the international spectrum, resistant to tests of time and constraints of context. PMID- 25925721 TI - Epitope targeting of tertiary protein structure enables target-guided synthesis of a potent in-cell inhibitor of botulinum neurotoxin. AB - Botulinum neurotoxin (BoNT) serotype A is the most lethal known toxin and has an occluded structure, which prevents direct inhibition of its active site before it enters the cytosol. Target-guided synthesis by in situ click chemistry is combined with synthetic epitope targeting to exploit the tertiary structure of the BoNT protein as a landscape for assembling a competitive inhibitor. A substrate-mimicking peptide macrocycle is used as a direct inhibitor of BoNT. An epitope-targeting in situ click screen is utilized to identify a second peptide macrocycle ligand that binds to an epitope that, in the folded BoNT structure, is active-site-adjacent. A second in situ click screen identifies a molecular bridge between the two macrocycles. The resulting divalent inhibitor exhibits an in vitro inhibition constant of 165 pM against the BoNT/A catalytic chain. The inhibitor is carried into cells by the intact holotoxin, and demonstrates protection and rescue of BoNT intoxication in a human neuron model. PMID- 25925723 TI - Injectable and mechanically robust 4-arm PPO-PEO/graphene oxide composite hydrogels for biomedical applications. AB - Graphene-based nanomaterials with different oxidation degrees were incorporated into Tetronic-tyramine (Tet-TA) hydrogels via enzymatic cross-linking. The molecular oxidation of graphene in combination with amphiphilic Tet-TA significantly improved the water dispersibility of graphene oxide (GO), resulting in a significant reinforcement of Tet-TA/GO composite hydrogels that can be used as an injectable biomaterial platform. PMID- 25925724 TI - Assembly of selective biomimetic surface on an electrode surface: a design of nano-bio interface for biosensing. AB - In nature, cellular molecule sensing is usually achieved at the environment/membrane interface. In the meantime, rapid growth of nanotechnology is increasingly pushing engineered nanomaterials to interact with biological surfaces. Herein, inspired by trans-membrane signal transduction, a nano-bio interface has been constructed in this work for biosensing application. The interface is formed between a selective biomembrane mimetic surface (SBMMS) and a function-oriented 2D nanohybrid. Based on the design, target recognition can be performed in a biologically favorable environment, and the nano-bio interaction can be transduced into amplified electrochemical readouts. Furthermore, this sensing platform can be used to analyze various kinds of targets, including proteins, nucleic acids, and small molecules, just by changing the biorecognition element. Low detection limits and wide detection ranges can also be obtained. So, this nano-bio interface may provide a new platform for bioanalytical research in the future. PMID- 25925725 TI - The Role of p21 in Apoptosis, Proliferation, Cell Cycle Arrest, and Antioxidant Activity in UVB-Irradiated Human HaCaT Keratinocytes. AB - BACKGROUND: Skin cancer is the most common cancer in the United States, and ultraviolet B (UVB) radiation-induced DNA damage is the major environmental factor underlying skin cancer development. p21, a p53-inducible protein, plays a key role in the cellular response to UVB-induced DNA damage. MATERIAL AND METHODS: Through p21 silencing and overexpression, we investigated the role of p21 in apoptosis, proliferation, cell cycle arrest, and oxidative stress in UVB irradiated HaCaT keratinocytes. RESULTS: We found that UVB exposure induced significant p21 downregulation (p<0.05) and was associated with significantly increased apoptosis, significantly decreased proliferation, and significantly increased G2 phase arrest (p<0.05) in UVB-irradiated HaCaT keratinocytes. p21 silencing significantly promoted apoptosis, significantly inhibited G2 phase arrest, and significantly inhibited proliferation (p<0.05), but after UVB irradiation, p21 silencing demonstrated a less significant pro-apoptotic effect and a more significant inhibition of G2 phase arrest (p<0.05), which was reflected in significantly higher proliferative activity (p<0.05). p21 overexpression acted in an anti-apoptotic manner in the absence of UVB-induced DNA damage but acted in a pro-apoptotic manner in the presence of UVB-induced DNA damage, displaying an "antagonistic duality" similar to other growth-promoting oncoproteins. p53 expression mirrored p21 expression, suggesting a regulatory feedback mechanism between p21 and p53 expression. p21 overexpression significantly downregulated glutathione peroxidase and superoxide dismutase antioxidant activity (p<0.05) while significantly upregulating hydrogen peroxide and malondialdehyde content (p<0.05), suggesting a role in decreasing antioxidant defense capabilities in UVB-irradiated HaCaT keratinocytes. CONCLUSIONS: These findings reveal that p21 may play a key role in HaCaT keratinocytes' response to UVB exposure. PMID- 25925726 TI - Correcting Neuromuscular Deficits With Gene Therapy in Pompe Disease. AB - OBJECTIVE: We have recently reported on the pathology of the neuromuscular junction (NMJ) in Pompe disease, reflecting disruption of neuronal and muscle homeostasis as a result of glycogen accumulation. The aim of this study was to examine how the alteration of NMJ physiology contributes to Pompe disease pathology; we performed molecular, physiological, and histochemical analyses of NMJ-related measures of the tibialis anterior muscles of young-, mid-, and late stage alpha-glucosidase (GAA)-deficient mice. METHODS: We performed intramuscular injection of an adeno-associated virus (AAV)9 vector expressing GAA (AAV9-hGAA) into the tibialis anterior muscle of Gaa(-/-) mice at early, mid, and severe pathological time points. We analyzed expression of NMJ-related genes, in situ muscle force production, and clearance of glycogen in conjunction with histological assessment of the NMJ. RESULTS: Our data demonstrate that AAV9-hGAA is able to replace GAA to the affected tissue and modify AChR mRNA expression, muscle force production, motor endplate area, and innervation status. Importantly, the degree of restoration for these outcomes is limited by severity of disease. Early restoration of GAA activity was most effective, whereas late correction of GAA expression was not effective in modifying parameters reflecting NMJ structure and function nor in force restoration despite resolution of glycogen storage in muscle. INTERPRETATION: Our data provide new mechanistic insight into the pathology of Pompe disease and suggest that early systemic correction to both neural and muscle tissues may be essential for successful correction of neuromuscular function in Pompe disease. Ann Neurol 2015;78:222 234. PMID- 25925727 TI - A comparative ethno-botanical study of Cholistan (an arid area) and Pothwar (a semi-arid area) of Pakistan for traditional medicines. AB - BACKGROUND: The present study is intended to compare and document the therapeutic flora, their remedial use, and the traditional knowledge used frequently by the residents of the Cholistan desert and Pothwar (Potohar) Plateau of Punjab, Pakistan. The old endemic remedies of these areas are diminishing due to lack of qualitative and quantitative research. METHODS: The data was generated by unstructured-interviews, informal meetings, open-ended conversations and group discussions with local people and traditional health healers of the study area. Reported literature was also utilized. RESULTS: The study recorded a list of various medicinal plants used as traditional medicines by local people. Total 86 numbers of plant species belonging to 38 families and 67 plant species belonging to 29 families have been reported in the Pothwar and Cholistan respectively. Only 10.5% of similar plant species were present in the studied areas. CONCLUSION: The investigation revealed that the local people of study areas inherit a rich traditional knowledge but there is great danger of losing this wealth of knowledge in the near future. Documentation of the knowledge exclusively from desert area of Cholistan, Pakistan is unique information in its nature. The study presents the undocumented knowledge worth recognition that will not only help in conservation of medicinal plant species but will highlight the pharmacological capacity for improved human healthcare regarding many common ailments. PMID- 25925728 TI - Ghrelin promotes renal cell carcinoma metastasis via Snail activation and is associated with poor prognosis. AB - Ghrelin is an appetite-regulating molecule that promotes growth hormone (GH) release and food intake through growth hormone secretagogue receptor (GHS-R). Recently, high ghrelin levels have been detected in various types of human cancer. Ghrelin expression is observed in proximal and distal renal tubules, where renal cell carcinoma (RCC) arises. However, whether ghrelin is up-regulated and promotes renal cell carcinogenesis remains obscure. In this study, we observed that ghrelin was highly expressed in renal tumours, especially in metastatic RCC. In addition, high ghrelin levels correlated with poor outcome, lymph node and distant metastasis. The addition of ghrelin promoted the migration ability of RCC cell lines 786-0, ACHN and A-498. Furthermore, knockdown of ghrelin expression reduced in vitro migration and in vivo metastasis, suggesting a requirement for ghrelin accumulation in the microenvironment for RCC metastasis. Analysis of microarray signatures using Ingenuity Pathway Analysis (IPA) and MetaCore pointed to the potential regulation by ghrelin of Snail, a transcriptional repressor of E-cadherin. We further observed that Ghrelin increased the expression, nuclear translocation and promoter-binding activity of Snail. Snail silencing blocked the ghrelin-mediated effects on E-cadherin repression and cell migration. Snail-E-cadherin regulation was mediated by GHS-R triggered Akt phosphorylation at Ser473 and Thr308. Pretreatment with PI3K inhibitors, LY294002 and wortmannin, as well as Akt siRNA, decreased ghrelin induced Akt phosphorylation, Snail promoter binding activity and migration. Taken together, our findings indicate that ghrelin can activate Snail function via the GHS-R-PI3K-Akt axis, which may contribute to RCC metastasis. The microarray raw data were retrieved from the Cancer Genome Atlas (TCGA) [KIRC gene expression (IlluminaHiSeq) dataset]. PMID- 25925730 TI - Frequency modulated microrheology. AB - Coupling analog frequency modulation (FM) to the driving stimulus in active microrheology measurements conducted with optical tweezers effectively parallelizes numerous single-frequency experiments. Consequently, frequency modulated microrheology (FMMR) can efficiently characterize the dynamic stress response of complex fluids over several frequency decades in a single experiment. The time required to complete an FMMR measurement scales with the lowest frequency probed, improving throughput over the serial frequency sweep approach. The ease of implementation, straight-forward data analysis and rapidity of FMMR offer particular utility toward applications such as characterization of non equilibrium materials, automated microrheology instrumentation, high-throughput screening of biomaterials and (bio) pharmaceutical formulations, and in situ monitoring of chemical and biochemical reaction processes. PMID- 25925729 TI - The effects of topical application of metronidazole for treatment of chronic anal fissure: A randomized, controlled pilot study. AB - BACKGROUND: Chronic anal fissures (CAFs) rarely heal with conservative management. Because they are associated with strong anal sphincter tone, most treatment aim to reduce anal pressure. Although infections can cause fissures, as can traumatic injury to the anal canal, antimicrobial treatment is not recommended. In a previous study, we reported identifying a wide spectrum of pathogenic microorganisms in the bases of CAFs, anaerobic bacteria being present in half the cases. We postulated that microbial colonization delays healing of CAF and aimed to determine whether decreasing the bacterial load with topical antibacterial treatment accelerates fissure healing. METHODS: We cultured fecal samples and swabs from the bases of CAFs in 103 patients. Patients in whose samples anaerobic bacteria were identified (47 patients) were then invited to participate in a prospective randomized clinical trial comparing topical metronidazole with conventional treatment. The primary endpoint was fissure healing confirmed on anoscopy. Secondary endpoints of maximum pain on defecation assessed by visual analog scale, maximum anal resting pressure, and rectal pH were recorded on entry and at 10, 21, and 28 days. RESULTS: The CAFs were colonized by mixtures of gram-positive/gram-negative anaerobic bacteria or gram negative aerobic monocultures. Patients with anaerobic bacteria in their swabs who received topical metronidazole treatment experienced rapid relief of pain and anal sphincter spasm along with enhanced fissure healing (95.6 % healing rate compared with 70.8 % in the control group, p = 0.048). CONCLUSION: Topical antimicrobial treatment can be effective in patients with CAF provided the relevant microorganisms are correctly identified. PMID- 25925731 TI - When is an anti-D antibody not an anti-D antibody? PMID- 25925732 TI - The re-emergence of dengue in China. AB - The number of reports in the literature on dengue outbreaks in various parts of south China is increasing. This trend is likely contributed to by multiple factors, chief among which is the increase in trade and human movement in and out of China from the Southeast Asian region where dengue is firmly endemic. However, a holistic picture of dengue in China and how the public health authorities are responding to this global health challenge has been missing. In a research article published in BMC Medicine, Lai et al. have now filled this gap in knowledge by analysing statutorily mandated national dengue surveillance data from 1990 till 2014. They also conducted time series analyses to identify key drivers of dengue transmission in south China as well as from south China to the other parts of this vast and populous country. Their findings, as well as the description of surveillance and disease control activities in China, highlight urgent steps that need to be taken if China wishes to prevent itself from becoming another country that experiences large and frequent cycles of epidemic dengue. PMID- 25925733 TI - Complementarity in nutrient foraging strategies of absorptive fine roots and arbuscular mycorrhizal fungi across 14 coexisting subtropical tree species. AB - In most cases, both roots and mycorrhizal fungi are needed for plant nutrient foraging. Frequently, the colonization of roots by arbuscular mycorrhizal (AM) fungi seems to be greater in species with thick and sparsely branched roots than in species with thin and densely branched roots. Yet, whether a complementarity exists between roots and mycorrhizal fungi across these two types of root system remains unclear. We measured traits related to nutrient foraging (root morphology, architecture and proliferation, AM colonization and extramatrical hyphal length) across 14 coexisting AM subtropical tree species following root pruning and nutrient addition treatments. After root pruning, species with thinner roots showed more root growth, but lower mycorrhizal colonization, than species with thicker roots. Under multi-nutrient (NPK) addition, root growth increased, but mycorrhizal colonization decreased significantly, whereas no significant changes were found under nitrogen or phosphate additions. Moreover, root length proliferation was mainly achieved by altering root architecture, but not root morphology. Thin-root species seem to forage nutrients mainly via roots, whereas thick-root species rely more on mycorrhizal fungi. In addition, the reliance on mycorrhizal fungi was reduced by nutrient additions across all species. These findings highlight complementary strategies for nutrient foraging across coexisting species with contrasting root traits. PMID- 25925734 TI - Body weight gain and risk of colorectal cancer: a systematic review and meta analysis of observational studies. AB - While the relationship between body mass index as an indicator of excess body weight and the risk of colorectal cancer (CRC) is well established, the association between body weight gain in adulthood and risk of CRC remains unresolved. We quantified this association in a meta-analysis of 12 observational studies published until November 2014 with a total of 16,151 incident CRC cases. Random effect models were used to obtain summary relative risks (RR) and 95% confidence intervals (95% CIs). Between-study heterogeneity was assessed using I(2) statistics. Overall, the summary RR (95% CI) was 1.22 (1.14-1.30) for high body weight gain (midpoint: 15.2 kg) compared with stable weight (P for heterogeneity = 0.182; I(2) = 21.2%). In a dose-response analysis, each 5 kg weight gain was associated with a 4% (95% CI: 2%-5%) higher risk of CRC. The association persisted after adjustment for body weight at younger age and was present for both men and women, as well as for colon and rectal cancer. Differences by sex were detected for colon cancer (P for interaction = 0.003, with higher risk for men than women), but not for rectal cancer (P for interaction = 0.613). In conclusion, these data underscore the importance of body weight management from early adulthood onwards for the prevention of CRC development. PMID- 25925735 TI - Bright Fluorescence and Host-Guest Sensing with a Nanoscale M4L6 Tetrahedron Accessed by Self-Assembly of Zinc-Imine Chelate Vertices and Perylene Bisimide Edges. AB - A highly luminescent Zn4L6 tetrahedron is reported with 3.8 nm perylene bisimide edges and hexadentate Zn(II)-imine chelate vertices. Replacing Fe(II) and monoamines commonly utilized in subcomponent self-assembly with Zn(II) and tris(2 aminoethyl)amine provides access to a metallosupramolecular host with the rare combination of structural integrity at concentrations <10(-7) mol L(-1) and an exceptionally high fluorescence quantum yield of Phi(em) =0.67. Encapsulation of multiple perylene or coronene guest molecules is accompanied by strong luminescence quenching. We anticipate this self-assembly strategy may be generalized to improve access to brightly fluorescent coordination cages tailored for host-guest light-harvesting, photocatalysis, and sensing. PMID- 25925736 TI - Mild and Robust Redox-Neutral Pd/C-Catalyzed Lignol beta-O-4' Bond Cleavage Through a Low-Energy-Barrier Pathway. AB - A Pd/C catalyzed redox neutral CcO bond cleavage of 2-aryloxy-1-arylethanols has been developed. The reactions are carried out at 80 degrees C, in air, using a green solvent system to yield the aryl ketones in near quantitative yields. Addition of catalytic amounts of a hydrogen source to the reaction mixture activates the catalyst to proceed through a low energy barrier pathway. Initial studies support a transfer hydrogenolysis reaction mechanism that proceeds through an initial dehydrogenation followed by an enol adsorption to Pd/C and a reductive CcO bond cleavage. PMID- 25925737 TI - Interlaboratory Reproducibility of Blood Morphology Using the Digital Microscope. AB - Differential counting of peripheral blood cells is an important diagnostic tool. However, manual morphological analysis using the microscope is time-consuming and requires highly trained personnel. The digital microscope is capable of performing an automated peripheral blood cell differential, which is as reliable as manual classification by experienced laboratory technicians. To date, information concerning the interlaboratory variation and quality of cell classification by independently operated digital microscopy systems is limited. We compared four independently operated digital microscope systems for their ability in classifying the five main peripheral blood cell classes and detection of blast cells in 200 randomly selected samples. Set against the averaged results, the R(2) values for neutrophils ranged between 0.90 and 0.96, for lymphocytes between 0.83 and 0.94, for monocytes between 0.77 and 0.82, for eosinophils between 0.70 and 0.78, and for blast cells between 0.94 and 0.99. The R(2) values for the basophils were between 0.28 and 0.34. This study shows that independently operated digital microscopy systems yield reproducible preclassification results when determining the percentages of neutrophils, eosinophils, lymphocytes, monocytes, and blast cells in a peripheral blood smear. Detection of basophils was hampered by the low incidence of this cell class in the samples. PMID- 25925738 TI - Hybrid male sterility between Drosophila willistoni species is caused by male failure to transfer sperm during copulation. AB - BACKGROUND: The biological concept of species stresses the importance of understanding what mechanisms maintain species reproductively isolated from each other. Often such mechanisms are divided into premating and postmating, with the latest being the result of either prezygotic or postzygotic isolation barriers. Drosophila willistoni quechua and Drosophila willistoni willistoni are two subspecies that experience reproductive isolation. When a D. w. quechua female is crossed with a D. w. willistoni male, the hybrid males (F1QW) are unable to father progeny; however, the reciprocal cross produces fertile hybrids. Thus, the mechanism of isolation is unidirectional hybrid male sterility. However, the sterile F1QW males contain large amounts of motile sperm. Here we explore whether pre-copulatory or post-copulatory pre-zygotic mechanisms serve as major deterrents in the ability of F1QW males to father progeny. RESULTS: Comparisons of parental and hybrid males copulation durations showed no significant reduction in copulation duration of F1QW males. Interrupted copulations of the parental species confirmed that sperm transfer occurs before the minimum copulation duration registered for F1QW males. However, we found that when females mate with F1QW males, sperm is not present inside the female storage organs and that the lack of sperm in storage is due to failure to transfer sperm rather than spillage or active sperm dumping by females. CONCLUSIONS: Sterility of F1QW hybrid males is primarily driven by their inability to transfer sperm during copulation. PMID- 25925739 TI - Prevalence of glucose-6-phosphate dehydrogenase deficiency and diagnostic challenges in 1500 immigrants in Denmark examined for haemoglobinopathies. AB - Similar to the thalassaemia syndromes, glucose-6-phosphate dehydrogenase (G6PD) deficiency is highly prevalent in areas historically exposed to malaria. In the present study, we used quantitative and molecular methods to determine the prevalence of G6PD deficiency in a population of 1508 immigrants in Denmark. We found the allele frequency to be between 2.4 and 2.9% in the female immigrants. Furthermore, the mutation pattern in the studied population showed a high prevalence of the G6PD A-(202A) variant in African and African-American immigrants, a high prevalence of the G6PD Mediterranean variant in Mediterranean European and Western Asian immigrants, and substantial heterogeneity in the variants found in the Eastern Asian/Pacific immigrants. Inasmuch as many of the patients included in this investigation had various thalassaemic syndromes, we were able to evaluate the effects of the interaction between a low mean corpuscular haemoglobin (MCH) value and G6PD activity, particularly in heterozygous females. The activity level was markedly influenced by the MCH value in females with normal G6PD activity, but not in heterozygous and homozygous females. Comparison of patients with normal G6PD activity and heterozygous females indicated considerable overlap in activity levels. To help separating heterozygous females from females with wild-type genes, a DNA analysis is necessary when the female activity level is between 4.0 and 4.9 U/g hgb corresponding to 50-60% of the median activity of unaffected males. PMID- 25925740 TI - Comparability of Computer-Supported Concurrent Voice Analysis. AB - OBJECTIVE: The assessment of vocal ability parameters can be made easier and more objective by computer-supported analysis systems. For this, multiple commercially available systems exist. But how strongly do the measured results of one method differ from the results of another and is the evaluation result of one method replaceable by or directly comparable with another? PATIENTS AND METHODS: 15 women aged 20-55 years and 15 men aged 18-56 years took part in this prospective study. The programs lingWAVES and rpSzene(r) were compared for the results of jitter, shimmer and glottal-to-noise excitation ratio. Correlation coefficients, Youden plots and Bland-Altman plots were calculated to make the comparison. RESULTS: For both systems, none of the values were in accordance with a normal distribution. The results of the two programs did not produce satisfactory consistency. CONCLUSIONS: In this study, absolute equivalency in the recording was ensured by the simultaneous recording of the voice signal and subsequent analysis with two different voice analysis methods. Nevertheless, the results varied so much that they cannot be compared properly. To reach a comparability of voice analyses, it is necessary to develop perturbation measurements which guarantee good clinical applicability and comparability between different analysis systems. PMID- 25925741 TI - The long non-coding RNA, GAS5, enhances gefitinib-induced cell death in innate EGFR tyrosine kinase inhibitor-resistant lung adenocarcinoma cells with wide-type EGFR via downregulation of the IGF-1R expression. AB - BACKGROUND: Epidermal growth factor receptor-tyrosine kinase inhibitors (EGFR TKIs) are approved for patients with recurrent non-small cell lung cancer (NSCLC). However, the efficacy of EGFR-TKIs in NSCLC therapy is limited by primary and acquired resistance. Recent studies have revealed that long non coding RNAs (LncRNA) may be involved in EGFR-TKI resistance. Therefore, a better understanding of the interactive mechanisms underlying LncRNA-mediated EGFR-TKIs resistance may help us to improve clinical response rates. METHOD: To investigate the expression of growth arrest-specific 5 (GAS5) in lung adenocarcinoma, we performed real-time reverse-transcriptase polymerase chain reaction. The correlation between GAS5 expression levels and the samples' clinicopathological features was also analyzed. Primary resistance to EGFR-TKIs was identified in the human lung adenocarcinoma cell line A549. Plasmid vectors were used to overexpress GAS5 in A549 cells. MTT (3-(4,5-dimethylthiazol-2-Yl)-2,5 diphenyltetrazolium bromide) colony formation assays and EdU (5-ethynyl-2' deoxyuridine) assays were used to assess cell proliferation, and flow-cytometric analysis was used to evaluate the apoptosis rate. The expression levels of our target proteins, namely, EGFR, p-EGFR, ERK, p-ERK, Akt, p-Akt, IGF-1R (insulin like growth factor 1 receptor), and p-IGF-1R, were analyzed by western blotting. A549 cells transfected with pcDNA-GAS5 were injected into nude mice. The transplanted mice were treated with gefitinib to study the effect of GAS5 on the resistance to EGFR-TKIs in vivo. RESULTS: Our results showed that GAS5 was significantly downregulated in lung adenocarcinoma tissues compared with the paired adjacent non-tumorous tissue samples. Furthermore, lower GAS5 expression levels were associated with larger tumor sizes, poor tumor differentiation, and advanced pathological stages. However, GAS5 was almost equally expressed between benign tumors compared with the adjacent normal tissues. GAS5 was also overexpressed in EGFR-TKI sensitive cell lines compared with the resistant cell line. Using MTT, EdU incorporation, and colony formation assays, we showed that GAS5-expressing A549 cells displayed an elevated level of cell death. In addition to its pro-apoptotic effect in the A549 cell line, GAS5 overexpression also suppressed the growth of A549-derived tumors in nude mice treated with gefitinib. GAS5 overexpression was inversely correlated with the expression of the EGFR pathway and IGF-1R proteins. CONCLUSIONS: Collectively, our results indicated that GAS5 LncRNA may represent a potential biomarker for the diagnosis of lung adenocarcinoma and that GAS5 might play a novel role in the development of the resistance to gefitinib, which could be reversed by overexpressing GAS5. PMID- 25925743 TI - Employment, smoking, and health: the role of the hygienist. AB - The association between smoking and poverty is well established but the relationship between smoking and employment is less clear. Those in work are less likely to smoke, with recent data from Scotland suggesting the unemployed are nearly 2.5 times more likely to smoke than those in employment. This commentary looks at emerging evidence that work may have a positive role in reducing smoking prevalence. Occupational hygienists are uniquely placed to provide health-based information and risk communication that may help workers and those seeking employment to become smoke-free. The public health benefits of such intervention are likely to be substantial and are entirely in keeping with the health protection aims of the discipline of Occupational Hygiene. PMID- 25925742 TI - Patient education for alcohol cessation intervention at the time of acute fracture surgery: study protocol for a randomised clinical multi-centre trial on a gold standard programme (Scand-Ankle). AB - BACKGROUND: Patients with hazardous alcohol intake are overrepresented in emergency departments and surgical wards. These patients have an increased risk of postoperative complications with prolonged hospital stays and admissions to intensive care unit after surgery. In elective surgery, preoperative alcohol cessation interventions can reduce postoperative complications, but no studies have investigated the effect of alcohol cessation intervention at the time of acute fracture surgery. This protocol describes a randomised clinical trial that aims to evaluate the effect of a new gold standard programme for alcohol cessation intervention in the perioperative period regarding postoperative complications, alcohol intake and cost-effectiveness. METHODS/DESIGN: Patients with hazardous alcohol intake undergoing ankle fracture surgery will be recruited into the trial from multiple orthopaedic wards at university hospitals in Denmark, Sweden and Norway. Included patients will be randomly allocated to either standard care or the gold standard programme aimed at complete alcohol abstinence before, during and 6 weeks after surgery. It includes a structured patient education programme and weekly interventions meetings at the orthopaedic outpatient clinic. Furthermore, patients are provided with thiamine and B vitamins, alcohol withdrawal prophylaxis and treatment, and disulfiram to support abstinence. Alcohol intake is biochemically validated (blood, urine and breath tests) at the weekly intervention meetings and follow-up visits. Follow-up assessments will be conducted 6 weeks and 3, 6, 9 and 12 months after surgery for all patients. The effect of the gold standard programme will be assessed comparing the outcome measures between the intervention and control group at each follow-up point. DISCUSSION: The study will provide new knowledge about how to prevent alcohol-related postoperative complications at the time of acute fracture surgery. If effective, the results will be a benefit for the clinical course, patients and society alike. TRIAL REGISTRATION: The protocol is registered in ClinicalTrials.gov (Id: NCT00986791 ). PMID- 25925744 TI - Effect of Skin Protection and Skin Irritation on the Internal Exposure to Carbon Disulfide in Employees of the Viscose Industry. AB - INTRODUCTION: Occupational exposure to carbon disulfide (CS2) leads to inhalative and dermal uptake and thereby to internal exposure. In order to prevent occupational contact dermatitis, gloves and skin protection creams are used at the workplace. The aim of the study was the evaluation of the influence of personal skin protection and irritation on the internal exposure to CS2 of employees in the viscose industry. METHODS: One hundred and eighty-two male CS2 exposed employees were included in the study and were examined regarding working conditions, use of personal protective measures und skin status. Personal air monitoring and biological monitoring was performed and the 'relative internal exposure' (RIE, internal exposure in relation to external exposure) calculated. A multiple regression analysis calculated the influence of skin protection and irritation on CS2 uptake. RESULTS: Usage of skin protection creams and gloves (and both in combination) while working was associated with a significantly higher RIE indicating a higher dermal penetration of CS2. Equally, irritated skin and younger age was associated with a higher internal burden. CONCLUSIONS: Gloves and skin protection creams are useful for preventing occupational skin diseases. However, when handling skin-resorptive substances like CS2, they can increase internal exposure or skin irritation. Therefore, we recommend the careful consideration of benefits and risks of protective creams and gloves at the workplace. PMID- 25925745 TI - Characterization of Textiles Used in Chefs' Uniforms for Protection Against Thermal Hazards Encountered in the Kitchen Environment. AB - Within the kitchen the potential for burn injuries arising from contact with hot surfaces, flames, hot liquid, and steam hazards is high. The chef's uniform can potentially offer some protection against such burns by providing a protective barrier between the skin and the thermal hazard, although the extent to which can provide some protection is unknown. The purpose of this study was to examine whether fabrics used in chefs' uniforms were able to provide some protection against thermal hazards encountered in the kitchen. Fabrics from chefs' jackets and aprons were selected. Flammability of single- and multiple-layered fabrics was measured. Effect of jacket type, apron and number of layers on hot surface, hot water, and steam exposure was also measured. Findings showed that all of the jacket and apron fabrics rapidly ignited when exposed to a flame. Thermal protection against hot surfaces increased as layers increased due to more insulation. Protection against steam and hot water improved with an impermeable apron in the system. For wet thermal hazards increasing the number of permeable layers can decrease the level of protection due to stored thermal energy. As the hands and arms are most at risk of burn injury increased insulation and water impermeable barrier in the sleeves would improve thermal protection with minimal compromise to overall thermal comfort. PMID- 25925746 TI - Intestinal symptoms and psychological factors jointly affect quality of life of patients with irritable bowel syndrome with diarrhea. AB - BACKGROUND: Patients with irritable bowel syndrome (IBS) have significantly reduced quality of life (QOL). Although intestinal and extraintestinal symptoms, as well as comorbid psychological disorders, may reduce the QOL of IBS patients, the primary determinant of QOL in these patients remains unclear. This study aimed to identify the main factors affecting QOL in patients with IBS with diarrhea (IBS-D). METHODS: Consecutive patients meeting the Rome III Diagnostic Criteria for IBS-D were enrolled in this study. Patients with organic diseases were excluded. The intestinal symptoms, psychological states and QOL of these patients were evaluated using IBS-specific symptom questionnaires, the Hamilton Depression Scale (HAMD), the Hamilton Anxiety Scale (HAMA), and the Chinese version of the IBS-QOL instrument. Overall scores for intestinal symptoms were calculated by frequency and degree. RESULTS: This study enrolled 227 IBS-D patients, of mean age 44.68 +/- 10.81 years. Their mean overall IBS-QOL score was 71.68 +/- 18.54, with the lowest score being for food avoidance (53.71 +/- 26.92). Overall IBS-QOL score correlated negatively with overall scores of intestinal symptoms and HAMD and HAMA scores (p < 0.001 each). Overall intestinal symptoms scores correlated negatively with HAMD and HAMA scores (p < 0.001 each). Scores of HAMD, HAMA and structural factors (i.e., anxiety/somatization, cognitive disorder, psychomotor retardation, psychic anxiety, and somatic anxiety) were significantly higher in female than in male patients (p < 0.01). Food avoidance and social reaction scores of female patients were significantly lower than those of male patients (p < 0.05 each). The degree of defecation urgency, frequency of passing mucus and psychomotor retardation were independent factors predicting reduced QOL in IBS-D patients. CONCLUSION: Intestinal symptoms and psychological factors jointly reduce the QOL of IBS-D patients, with gender differences in the impact of both factors on QOL. PMID- 25925747 TI - Increasing prevalence of HIV infection among first time clients in Italian drug treatment services - is it sexual transmission? AB - BACKGROUND: Over the last two decades, the proportion of people who inject drugs among newly reported HIV cases in Italy has been continuously declining. This trend is reflected in the prevalence of HIV infection among problem drug users followed in drug treatment services. We report nationwide trends in the prevalence of HIV and HCV among tested clients in charge to drug addiction services from 2005 to 2011. METHODS: Data on the prevalence of HIV and HCV among drug users from public drug treatment services across Italy were collected and analyzed for the period from 2005 to 2011. Prevalence of HIV and HCV were compared between clients returning to treatment and those entering treatment for the first time, and by gender. Due to the high percentage of missing data, the "inverse probability weight" method was used. Trends in testing uptake were also analysed. RESULTS: A significant decrease of HIV and HCV prevalence is observed among all PDUs entering treatment (from 14.7% to 11.1% and from 61.6% to 50%, respectively, in 2005-2011). By contrast, among those entering the services for the first time, after an initial decline the prevalence of HIV infection steadily increased in both sexes, from 2.2% in 2009 to 5.3% in 2011. Self-reported injecting rates in this group decreased over time, and in 2011 the proportion reporting drug injecting was lower among new clients than in people returning to services (14.5 vs. 34.4%). We also observed a progressive and significant reduction in HIV and HCV testing in drug treatment services. CONCLUSIONS: Changes in injection practice and type of drugs used, coupled with a concurrent reduction in HCV prevalence, do not support drug injection as the main explanation for an increased HIV transmission in people entering drug treatment services for the first time. While reductions in testing rates raise concerns over data quality, the possibility of increased sexual transmission needs to be considered. PMID- 25925748 TI - Intravitreal aflibercept (Eylea) injection for cystoid macular edema secondary to retinitis pigmentosa - a first case report and short review of the literature. AB - BACKGROUND: Cystoid macular edema (CME) in retinitis pigmentosa (RP) has been managed in several ways as documented in the literature, with little success, though. The aim of our study was to report for the first time in literature the use of aflibercept in a patient with RP and CME. CASE PRESENTATION: A 52-year-old man presented for blurred vision in his right eye. Best-corrected visual acuity (BCVA) was 3/10 in his right eye and 7/10 in his left eye. Physical examination and appropriate laboratory tests lead to the diagnosis of bilateral RP with CME in the right eye. Retinal thickness in the foveal area of the right eye was 631 MUm. The patient was treated with a single intravitreal injection of 0.05 ml/0.5 mg aflibercept. One month later, BCVA of the right eye increased to 4/10, while BCVA of the left eye was unchanged. RT in the right eye decreased to 129 MUm. Multifocal electroretinogram response did not improve, yet peaks were better shaped and no areas of eccentral vision were present. Three and six months after injection, these improvements were maintained. CONCLUSION: This first-reported case indicates that intravitreal aflibercept injection for addressing CME in RP seems to be an effective treatment. PMID- 25925749 TI - Capecitabine and irinotecan with bevacizumab 2-weekly for metastatic colorectal cancer: the phase II AVAXIRI study. AB - BACKGROUND: The optimal sequence of chemotherapeutic agents is not firmly established for the treatment of metastatic colorectal cancer (mCRC). This phase II multi-centre study investigated the efficacy and tolerability of a standard capecitabine plus irinotecan (XELIRI) regimen with bevacizumab in previously untreated patients with mCRC. METHODS: Patients received intravenous irinotecan 175 mg/m(2) on day 1 and oral capecitabine 1000 mg/m(2) (800 mg/m(2) for patients >65 years of age) twice daily on days 2-8, followed by a 1-week rest, and bevacizumab 5 mg/kg as an intravenous infusion on day 1 every 2 weeks. RESULTS: Seventy-seven patients were included in the intention-to-treat and safety populations. Progression-free survival at 9 months was 61%. The overall response and disease control rates were 51% and 84%, respectively. Median progression-free and overall survival times were 11.9 and 24.8 months, respectively. 48 patients (62%) had at least one grade 3/4 adverse event, the most common being asthenia, diarrhoea and neutropenia. Quality of life varied little over the study period with mean visual analogue scale general health scores ranging from 71 to 76 over cycles 1-11. CONCLUSION: Our study found irinotecan and capecitabine administered fortnightly with bevacizumab in patients with mCRC to be an effective and tolerable regimen. TRIAL REGISTRATION: clinicaltrials.gov identifier NCT00875771. Trial registration date: 04/02/2009. PMID- 25925751 TI - Post-warmup strategies to maintain body temperature and physical performance in professional rugby union players. AB - We compared the effects of using passive-heat maintenance, explosive activity or a combination of both strategies during the post-warmup recovery time on physical performance. After a standardised warmup, 16 professional rugby union players, in a randomised design, completed a counter-movement jump (peak power output) before resting for 20 min and wearing normal-training attire (CON), wearing a passive heat maintenance (PHM) jacket, wearing normal attire and performing 3 * 5 CMJ (with a 20% body mass load) after 12 min of recovery (neuromuscular function, NMF), or combining PHM and NMF (COMB). After 20 min, participants completed further counter-movement jump and a repeated sprint protocol. Core temperature (Tcore) was measured at baseline, post-warmup and post-20 min. After 20 min of recovery, Tcore was significantly lower under CON and NMF, when compared with both PHM and COMB (P < 0.05); PHM and COMB were similar. Peak power output had declined from post-warmup under all conditions (P < 0.001); however, the drop was less in COMB versus all other conditions (P < 0.05). Repeated sprint performance was significantly better under COMB when compared to all other conditions. Combining PHM with NMF priming attenuates the post-warmup decline in Tcore and can positively influence physical performance in professional rugby union players. PMID- 25925752 TI - Epilepsy surgery: current status and ongoing challenges. AB - This article reviews the current status of surgical treatment of epilepsy and introduces the ongoing challenges. Seizure outcome of resective surgery for focal seizures associated with focal lesions is satisfactory. Particularly for mesial temporal lobe epilepsy, surgical treatment should be considered from the earlier stage of the disease. Meanwhile, surgical outcome in nonlesional extratemporal lobe epilepsy is still to be improved using various approaches. Disconnective surgeries reduce surgical complications of extensive resections while achieving equivalent or better seizure outcomes. Multiple subpial transection is still being modified expecting a better outcome by transection to the vertical cortices along the sulci- and multi-directional transection from a single entry point. Hippocampal transection is expected to preserve memory function while interrupting the abnormal epileptic synchronization. Proper selection or combination of subdural and depth electrodes and a wide-band analysis of electroencephalography may improve the accurate localization of epileptogenic region. Patients for whom curative resective surgery is not indicated because of generalized or bilateral multiple nature of their epilepsies, neuromodulation therapies are options of treatment which palliate their seizures. PMID- 25925753 TI - Intraoperative Motor Symptoms during Brain Tumor Resection in the Supplementary Motor Area (SMA) without Positive Mapping during Awake Surgery. AB - Awake surgery could be a useful modality for lesions locating in close proximity to the eloquent areas including primary motor cortex and pyramidal tract. In case with supplementary motor area (SMA) lesion, we often encounter with intraoperative motor symptoms during awake surgery even in area without positive mapping. Although the usual recovery of the SMA syndrome has been well documented, rare cases with permanent deficits could be encountered in the clinical setting. It has been difficult to evaluate during surgery whether the intraoperative motor symptoms lead to postoperative permanent deficits. The purpose of this study was to demonstrate the intraoperative motor symptoms could be reversible, further to provide useful information for making decision to continue surgical procedure of tumor resection. Eight consecutive patients (from July 2012 to June 2014, six men and two women, aged 33-63 years) with neoplastic lesions around the SMA underwent an awake surgery. Using a retrospective analysis of intraoperative video records, intraoperative motor symptoms during tumor resection were investigated. In continuous functional monitoring during resection of SMA tumor under awake conditions, the following motor symptoms were observed during resection of the region without positive mapping: delayed motor weakness, delay of movement initiation, slowness of movement, difficulty in dual task response, and coordination disturbance. In seven patients hemiparesis observed immediately after surgery recovered to preoperative level within 6 weeks. During awake surgery for SMA tumors, the above-mentioned motor symptoms could occur in area without positive mapping and might be predictors for reversible SMA syndrome. PMID- 25925754 TI - Epilepsy surgery for pediatric epilepsy: optimal timing of surgical intervention. AB - Pediatric epilepsy has a wide variety of etiology and severity. A recent epidemiological study suggested that surgery might be indicated in as many as 5% of the pediatric epilepsy population. Now, we know that effective epilepsy surgery can result in seizure freedom and improvement of psychomotor development. Seizure control is the most effective way to improve patients neurologically and psychologically. In this review, we look over the recent evidence related to pediatric epilepsy surgery, and try to establish the optimal surgical timing for patients with intractable epilepsy. Appropriate surgical timing depends on the etiology and natural history of the epilepsy to be treated. The most common etiology of pediatric intractable epilepsy patients is malformation of cortical development (MCD) and early surgery is recommended for them. Patients operated on earlier than 12 months of age tended to improve their psychomotor development compared to those operated on later. Recent progress in neuroimaging and electrophysiological studies provide the possibility of very early diagnosis and comprehensive surgical management even at an age before 12 months. Epilepsy surgery is the only solution for patients with MCD or other congenital diseases associated with intractable epilepsy, therefore physicians should aim at an early and precise diagnosis and predicting the future damage, consider a surgical solution within an optimal timing. PMID- 25925755 TI - New Approach for Exploring Cerebral Functional Connectivity: Review of Cortico cortical Evoked Potential. AB - There has been a paradigm shift in the understanding of brain function. The intrinsic architecture of neuronal connections forms a key component of the cortical organization in our brain. Many imaging studies, such as noninvasive magnetic resonance imaging (MRI) studies, have now enabled visualization of the white matter fiber tracts interconnecting the functional cortical areas in the living brain. Although such a structural connectome is essential for understanding of cortical function, the anatomical information alone is not sufficient. Practically, few techniques allow the investigation of the excitatory and inhibitory mechanisms of the cortex in vivo in humans. Several attempts have been made to track neuronal connectivity by applying direct electrical stimuli to the brain in order to stimulate subdural and/or depth electrodes and record responses from the functionally connected cortex. In vivo single-pulse electrical stimulation (SPES) and/or cortico-cortical evoked potential (CCEP) were recently introduced to track various brain networks. This article reviews the concepts, significance, methods, mechanisms, limitations, and clinical applications of CCEP in the analysis of these dynamic connections. PMID- 25925756 TI - Patterns and variations in microvascular decompression for trigeminal neuralgia. AB - Microvascular decompression (MVD) is a highly effective surgical treatment for trigeminal neuralgia (TN). Although there is little prospective clinical evidence, accumulated observational studies have demonstrated the benefits of MVD for refractory TN. In the current surgical practice of MVD for TN, there have been recognized patterns and variations in surgical anatomy and various decompression techniques. Here we provide a stepwise description of surgical procedures and relevant anatomical characteristics, as well as procedural options. PMID- 25925757 TI - The present indication and future of deep brain stimulation. AB - The use of electrical stimulation to treat pain in human disease dates back to ancient Rome or Greece. Modern deep brain stimulation (DBS) was initially applied for pain treatment in the 1960s, and was later used to treat movement disorders in the 1990s. After recognition of DBS as a therapy for central nervous system (CNS) circuit disorders, DBS use showed drastic increase in terms of adaptability to disease and the patient's population. More than 100,000 patients have received DBS therapy worldwide. The established indications for DBS are Parkinson's disease, tremor, and dystonia, whereas global indications of DBS expanded to other neuronal diseases or disorders such as neuropathic pain, epilepsy, and tinnitus. DBS is also experimentally used to manage cognitive disorders and psychiatric diseases such as major depression, obsessive-compulsive disorder (OCD), Tourette's syndrome, and eating disorders. The importance of ethics and conflicts surrounding the regulation and freedom of choice associated with the application of DBS therapy for new diseases or disorders is increasing. These debates are centered on the use of DBS to treat new diseases and disorders as well as its potential to enhance ability in normal healthy individuals. Here we present three issues that need to be addressed in the future: (1) elucidation of the mechanisms of DBS, (2) development of new DBS methods, and (3) miniaturization of the DBS system. With the use of DBS, functional neurosurgery entered into the new era that man can manage and control the brain circuit to treat intractable neuronal diseases and disorders. PMID- 25925750 TI - An original phylogenetic approach identified mitochondrial haplogroup T1a1 as inversely associated with breast cancer risk in BRCA2 mutation carriers. AB - INTRODUCTION: Individuals carrying pathogenic mutations in the BRCA1 and BRCA2 genes have a high lifetime risk of breast cancer. BRCA1 and BRCA2 are involved in DNA double-strand break repair, DNA alterations that can be caused by exposure to reactive oxygen species, a main source of which are mitochondria. Mitochondrial genome variations affect electron transport chain efficiency and reactive oxygen species production. Individuals with different mitochondrial haplogroups differ in their metabolism and sensitivity to oxidative stress. Variability in mitochondrial genetic background can alter reactive oxygen species production, leading to cancer risk. In the present study, we tested the hypothesis that mitochondrial haplogroups modify breast cancer risk in BRCA1/2 mutation carriers. METHODS: We genotyped 22,214 (11,421 affected, 10,793 unaffected) mutation carriers belonging to the Consortium of Investigators of Modifiers of BRCA1/2 for 129 mitochondrial polymorphisms using the iCOGS array. Haplogroup inference and association detection were performed using a phylogenetic approach. ALTree was applied to explore the reference mitochondrial evolutionary tree and detect subclades enriched in affected or unaffected individuals. RESULTS: We discovered that subclade T1a1 was depleted in affected BRCA2 mutation carriers compared with the rest of clade T (hazard ratio (HR) = 0.55; 95% confidence interval (CI), 0.34 to 0.88; P = 0.01). Compared with the most frequent haplogroup in the general population (that is, H and T clades), the T1a1 haplogroup has a HR of 0.62 (95% CI, 0.40 to 0.95; P = 0.03). We also identified three potential susceptibility loci, including G13708A/rs28359178, which has demonstrated an inverse association with familial breast cancer risk. CONCLUSIONS: This study illustrates how original approaches such as the phylogeny-based method we used can empower classical molecular epidemiological studies aimed at identifying association or risk modification effects. PMID- 25925758 TI - Evaluation of Language Function under Awake Craniotomy. AB - Awake craniotomy is the only established way to assess patients' language functions intraoperatively and to contribute to their preservation, if necessary. Recent guidelines have enabled the approach to be used widely, effectively, and safely. Non-invasive brain functional imaging techniques, including functional magnetic resonance imaging and diffusion tensor imaging, have been used preoperatively to identify brain functional regions corresponding to language, and their accuracy has increased year by year. In addition, the use of neuronavigation that incorporates this preoperative information has made it possible to identify the positional relationships between the lesion and functional regions involved in language, conduct functional brain mapping in the awake state with electrical stimulation, and intraoperatively assess nerve function in real time when resecting the lesion. This article outlines the history of awake craniotomy, the current state of pre- and intraoperative evaluation of language function, and the clinical usefulness of such functional evaluation. When evaluating patients' language functions during awake craniotomy, given the various intraoperative stresses involved, it is necessary to carefully select the tasks to be undertaken, quickly perform all examinations, and promptly evaluate the results. As language functions involve both input and output, they are strongly affected by patients' preoperative cognitive function, degree of intraoperative wakefulness and fatigue, the ability to produce verbal articulations and utterances, as well as perform synergic movement. Therefore, it is essential to appropriately assess the reproducibility of language function evaluation using awake craniotomy techniques. PMID- 25925759 TI - Vagus nerve stimulation therapy: indications, programing, and outcomes. AB - Vagus nerve stimulation (VNS) provides palliation of seizure reduction for patients with medically refractory epilepsy. VNS is indicated for symptomatic localization-related epilepsy with multiple and bilateral independent foci, symptomatic generalized epilepsy with diffuse epileptogenic abnormalities, refractory idiopathic generalized epilepsy, failed intracranial epilepsy surgery, and other several reasons of contraindications to epilepsy surgery. Programing of the parameters is a principal part in VNS. Output current and duty cycle should be adjusted to higher settings particularly when a patient does not respond to the initial setting, since the pivotal randomized trials performed in the United States demonstrated high stimulation made better responses in seizure frequency. These trials revealed that a >= 50% seizure reduction occurred in 36.8% of patients at 1 year, in 43.2% at 2 years, and in 42.7% at 3 years in 440 patients. Safety of VNS was also confirmed because side effects including hoarseness, throat discomfort, cough, paresthesia, and headache improved progressively during the period of 3 years. The largest retrospective study with 436 patients demonstrated the mean seizure reduction of 55.8% in nearly 5 years, and also found 75.5% at 10 years in 65 consecutive patients. The intermediate analysis report of the Japan VNS Registry showed that 60% of 164 cases got a >= 50% seizure reduction in 12 months. In addition to seizure reduction, VNS has positive effects in mood and improves energy level, memory difficulties, social aspects, and fear of seizures. VNS is an effective and safe option for patients who are not suitable candidates for intracranial epilepsy surgery. PMID- 25925761 TI - Deep brain stimulation for Parkinson's disease: recent trends and future direction. AB - To date, deep brain stimulation (DBS) has already been performed on more than 120,000 patients worldwide and in more than 7,000 patients in Japan. However, fundamental understanding of DBS effects on the pathological neural circuitry remains insufficient. Recent studies have specifically shown the importance of cortico-striato-thalamo-cortical (CSTC) loops, which were identified as functionally and anatomically discrete units. Three main circuits exist in the CSTC loops, namely, the motor, associative, and limbic circuits. From these theoretical backgrounds, it is determined that DBS sometimes influences not only motor functions but also the cognitive and affective functions of Parkinson's disease (PD) patients. The main targets of DBS for PD are subthalamic nucleus (STN) and globus pallidus interna (GPi). Ventralis intermedius (Vim)-DBS was found to be effective in improving tremor. However, Vim-DBS cannot sufficiently improve akinesia and rigidity. Therefore, Vim-DBS is seldom carried out for the treatment of PD. In this article, we review the present state of DBS, mainly STN DBS and GPi-DBS, for PD. In the first part of the article, appropriate indications and practical effects established in previous studies are discussed. The findings of previous investigations on the complications caused by the surgical procedure and on the adverse events induced by DBS itself are reviewed. In the second part, we discuss target selection (GPi vs. STN) and the effect of DBS on nonmotor symptoms. In the final part, as issues that should be resolved, the suitable timing of surgery, symptoms unresponsive to DBS such as on-period axial symptoms, and the related postoperative programing of stimulation parameters, are discussed. PMID- 25925762 TI - Paeonolum protects against MPP(+)-induced neurotoxicity in zebrafish and PC12 cells. AB - BACKGROUND: Parkinson's disease (PD) is the second most common neurodegenerative disease, affecting 2% of the population aged over 65 years old. Mitochondrial defects and oxidative stress actively participate in degeneration of dopaminergic (DA) neurons in PD. Paeonolum, a main component isolated from Moutan cortex, has potent antioxidant ability. Here, we have examined the effects of paeonolum against MPP(+)-induced neurotoxicity in zebrafish and PC12 cells. METHODS: The overall viability and neurodegeneration of DA neurons was assessed in ETvmat2:green fluorescent protein (GFP) transgenic zebrafish, in which most monoaminergic neurons are labeled by GFP. Damage to PC12 cells was measured using a cell viability assay and assessment of nuclear morphology. Intracellular reactive oxygen species (ROS) and the level of total GSH were assessed. The mitochondrial cell death pathway including mitochondrial membrane potential, cytochrome C release and caspase-3 activity were also examined in PC12 cells. RESULTS: Paeonolum protected against MPP(+)-induced DA neurodegeneration and locomotor dysfunction in zebrafish in a concentration-dependent manner. Similar neuroprotection was replicated in the PC12 cellular model of MPP(+) toxicity. Paeonolum attenuated MPP(+)-induced intracellular ROS accumulation and restored the level of total GSH in PC12 cells. Furthermore, paeonolum significantly inhibited the mitochondrial cell death pathway induced by MPP(+). CONCLUSIONS: Collectively, the present study demonstrates that paeonolum protects zebrafish and PC12 cells against MPP(+)-induced neurotoxicity. PMID- 25925763 TI - High expression of AFAP1-AS1 is associated with poor survival and short-term recurrence in pancreatic ductal adenocarcinoma. AB - BACKGROUND: Pancreatic ductal adenocarcinoma (PDAC) is still a lethal malignancy. Long noncoding RNAs (lncRNAs) have been shown to play a critical role in cancer development and progression. Here we identified overexpression of the lncRNA AFAP1-AS1 in PDAC patients and evaluated its prognostic and functional relevance. METHODS: The global lncRNA expression profile in PDAC was measured by lncRNA microarray. Expression of AFAP1-AS1 was evaluated by reverse-transcriptase quantitative polymerase chain reaction (RT-qPCR) in 90 PDAC tissue samples and adjacent normal tissues. The impact of AFAP1-AS1 expression on cell proliferation, migration, and invasion were evaluated in vitro using knockdown and ectopic expression strategies. RESULTS: Microarray analysis revealed that up regulation of AFAP1-AS1 expression in PDAC tissues compared with normal adjacent tissues, which was confirmed by RT-qPCR in 69/90 cases (76.7%). Its overexpression was associated with lymph node metastasis, perineural invasion, and poor survival. When using AFAP1-AS1 as a prognostic marker, the areas under ROC curves were 0.8669 and 0.9370 for predicting tumor progression within 6 months and 1 year, respectively. In vitro functional experiments involving knockdown of AFAP1-AS1 resulted in attenuated PDAC cell proliferation, migration, and invasion. Ectopic expression of AFAP1-AS1 promoted cell proliferation, migration, and invasion. CONCLUSIONS: AFAP1-AS1 is a potential novel prognostic marker to predict the clinical outcome of PDAC patients after surgery and may be a rational target for therapy. PMID- 25925764 TI - Serum S100B level may be correlated with carbon monoxide poisoning. AB - OBJECTIVE: To investigate the correlation between serum S100B level and carbon monoxide (CO) poisoning by meta-analysis. METHODS: By searching both English and Chinese language-based electronic databases (PubMed, EBSCO, Ovid, Springerlink, Wiley, Web of Science, Wanfang databases, China national knowledge infrastructure (CNKI), VIP database, etc.) thoroughly, we tabulated and analyzed the collected data with the use of Comprehensive Meta-analysis 2.0 (CMA 2.0). RESULTS: Totally 108 studies have been searched initially (92 studies in Chinese, 16 studies in English). Nine case-control studies (4 studies in English, 5 in Chinese) were chosen for an updated meta-analysis including 542 patients with CO poising and 236 healthy controls. Results identified that the serum S100B level were obviously higher than that in healthy controls (SMD=1.600, 95% CI=1.055-2.145, P<0.001). A subgroup based on the ethnicities revealed that the serum S100B level in Caucasian and Asian subgroups was clearly higher than serum S100B level in healthy controls (Asians: SMD=2.0624, 95% CI=1.736-3.511, P<0.001; Caucasians: SMD=0.447, 95% CI=0.197-0.697, P<0.001). CONCLUSION: Serum S100B level may be correlated with the CO poisoning and could be effective biomarker for early diagnosis and treatment monitoring in CO poisoning. PMID- 25925765 TI - [Elderly arrested people in correctional facilities Challenge for health care]. AB - BACKGROUND: At present there is no systematic, nationwide collection of data about the health status and health care of elderly persons imprisoned in Germany. The health status is highly significant with regard to the (re)socialization of elderly prisoners. From an ethical point of view a highly developed country should provide a good quality health care even in prisons. AIM: Using the example of male prisoners in the Federal State of Rhineland-Palatinate, a survey was carried out on the health status of elderly prisoners and the presence of functional handicaps. MATERIAL AND METHODS: A total of 222 elderly male prisoners in Rhineland-Palatinate who were at least 50 years old at the time of the quantitative analyses participated in the anonymous comprehensive survey by completing a questionnaire. RESULTS: The elderly prisoners in Rhineland Palatinate are concerned by age-related chronic diseases and functional handicaps significantly more often than the general extramural population. CONCLUSION: The data obtained in this survey are essential for the development and implementation of targeted strategies of prevention and health promotion and for improvement in the health care of elderly prisoners. PMID- 25925766 TI - Tetrakis(dimethoxyphenyl)adamantane (TDA) and its inclusion complexes in the crystalline state: a versatile carrier for small molecules. AB - Molecular storage solutions for incorporating small molecules in crystalline matrices are of interest in the context of structure elucidation, decontamination, and slow release of active ingredients. Here we report the syntheses of 1,3,5,7-tetrakis(2,4-dimethoxyphenyl)adamantane, 1,3,5,7-tetrakis(4 methoxyphenyl)adamantane, 1,3,5,7-tetrakis(4-methoxy-2-methylphenyl)adamantane, and 1,3,5,7-tetrakis(4-methoxy-2-ethylphenyl)adamantane, together with their X ray crystal structures. All four compounds crystallize readily. Only the octaether shows an unusual level of (pseudo)polymorphism in its crystalline state, combined with the ability to include a number of different small molecules in its crystal lattices. A total of 20 different inclusion complexes with guest molecules as different as ethanol or trifluorobenzene were found. For nitromethane and benzene, schemes for uptake and release are presented. PMID- 25925767 TI - The reliability of clinical decisions based on the cervical vertebrae maturation staging method. AB - OBJECTIVES: Of the various techniques used to determine the optimum timing for growth modification treatments, the cervical vertebrae maturation method has great advantages, including validity and no need for extra X-ray exposure. Recently, the reproducibility of this method has been questioned. The aim of this study was to investigate the cause of poor reproducibility of this method and to assess the reproducibility of the clinical decisions made based on it. MATERIALS/METHODS: Seventy lateral cephalograms of Iranian patients aged 9-15 years were observed twice by five experienced orthodontists. In addition to determining the developmental stage, each single parameter involved in this method was assessed in terms of inter- and intra-observer reproducibility. In order to evaluate the reproducibility of clinical decisions based on this method, cervical vertebrae maturation staging (CVMS) I and II were considered as phase 1 and CVMS IV and V were considered as phase 3. RESULTS: By considering the clinical approach of the CVMS method, inter-observer reproducibility of this method increased from 0.48 to 0.61 (moderate to substantial) and intra-observer reproducibility enhanced from 0.72 to 0.74. LIMITATIONS: 1. Complete visualization of the first four cervical vertebrae was an inclusion criterion, which also limits the clinical application of CVMS method. 2. These results can be generalized when determining growth modification treatments solely for Class II patients. CONCLUSIONS: Difficulty in determining the morphology of C3 and C4 leads to poor reproducibility of the CVMS method. Despite this, it has acceptable reproducibility in determining the timing of functional treatment for Class II patients. PMID- 25925768 TI - Low-level laser therapy and exercise for patients with shoulder disorders in physiotherapy practice (a systematic review protocol). AB - BACKGROUND: Low-level laser therapy is one of the adjunct treatments of choice with exercise therapy for shoulder rehabilitation in physiotherapy clinical practices. Although previous reviews have found little use of low-level laser therapy, there are recent trials whose findings are yet to be systematically reviewed. METHODS: We plan to do a systematic review to assess the effects of low level laser therapy with exercise and exercise alone in participants who are 18 years and above, with a clinical or radiological diagnosis of various shoulder pathologies. We will search CENTRAL, MEDLINE, CINAHL, PEDro, Science Direct, Scopus and Physiotherapy Choices regardless of publication status. We will hand search for subject-specific journals (PhotoMedicine and Laser Surgery, Lasers in Surgery and Medicine and Journals of Lasers in Medical Science) and conference proceedings of World Association for Laser Therapy. Two review authors will independently screen, select studies, extract data and assess the risk of bias based on a priori criteria. Disagreements between review authors will be resolved either through discussion or consultation with a third review author. If there are at least two clinically homogeneous studies, we will perform meta-analysis. DISCUSSION: The findings will shed more light on the benefit of low-level laser therapy as an adjunct treatment to exercise in the management of shoulder disorders. The findings may also inform decision makers in the review and development of guidelines for shoulder rehabilitation in physiotherapy practices. SYSTEMATIC REVIEW REGISTRATION: PROSPERO CRD42014013691. PMID- 25925769 TI - Efficient In Vitro Refolding and Characterization of Major Histocompatibility Complex Class I-Related Chain Molecules A (MICA) and Natural Killer Group 2 Member D (NKG2D) Expressed in E. coli. AB - Major Histocompatibility Complex class I-related chain molecules A (MICA) and receptor Natural killer group 2 member D (NKG2D) are important membrane proteins with immunosurveillance properties which could serve as therapeutic targets for immunotherapy. However, expression of MICA and NKG2D in E. coli often leads to the formation of inclusion bodies. Here, we present simple, inexpensive and convenient protocol for the solubilization and refolding of inclusion bodies of MICA and NKG2D expressed in E. coli. The inclusion bodies were firstly dissolved in strong chaotropic reagent (8M urea) and subsequently purified by immobilized metal affinity column. The denatured MICA/NKG2D was refolded by gradually removing both denaturant (8M urea) and imidazole via dialysis in dialysis buffer of pH 7.4. The appropriate pH of the dialysis buffer was selected based on the theoretical isoelectric points of MICA and NKG2D which were 5.0 and 5.2 respectively. The folded MICA and NKG2D demonstrated the capacity to bind to recombinant NKG2D and MICA respectively by ELISA, Western blot and Surface Plasmon Resonance (SPR) assays. Additionally, the folded MICA and NKG2D demonstrated significant binding to NKG2D-positive Human leukemic cell line U937 and MICA-positive Human pancreatic carcinoma, epithelial-like cell line (PANC-1) respectively, suggesting successful refolding. Successful refolding was further confirmed by Circular Dichroism spectroscopy (CD). We have successfully dissolved, refolded and characterized inclusion bodies of MICA/NKG2D expressed in E. coli using simple, inexpensive and convenient protocol which can be carried out in laboratories under-resourced. PMID- 25925770 TI - Heterogeneous Nuclear Ribonucleoprotein A2/B1 as a Target Antigen in Han Chinese for BD Patients. AB - Behcet's disease (BD) is a recurrent pathema with a typical symptom of inflammation involved in many organs. Previous report indicated that the serum of Korean patients with BD stimulates membrane expression of hnRNP A2/B1 in endothelial cells. In this study, the target 35 kDa recombinant human hnRNP A2/B1 were over-expressed and purified, then sequenced with MALDI-TOF- TOF mass spectrometry. Western blotting and ELISA were applied to detect serum reactivity against hnRNP A2/B1 respectively. The results demonstrate that hnRNP A2/B1 is an autoantigen of BD in Han Chinese population. PMID- 25925771 TI - Mechanism of Anti-HIV Activity of Ribosome Inactivating Protein, Saporin. AB - Ribosome inactivating proteins (RIPs) are a family of proteins produced by plants, bacteria and fungi. RIPs have specific N-glycosidase activity, and they cleave a specific glycosidic bond in a universally conserved stem and loop structure within the large ribosomal RNA of all organisms. Saporin, a cytotoxic RIP from the plant Saponaria officinalis has been earlier shown to manifest its cytotoxicity by a combination of its N-glycosidase and apoptosis inducing activities. Saporin, along with many other RIPs also has strong inhibitory activity towards HIV integrase. In the current study, using two in vitro model systems, it is established that saporin inhibits propagation of HIV-1 in host cells. Saporin also showed a potent anti-HIV-1 integrase activity in vitro. Using three active site mutants of saporin, which respectively lack N-glycosidase, apoptosis inducing or both activities, it is shown that saporin's in vitro anti HIV-1 integrase activity is independent of its N-glycosidase activity. However, for the anti-HIV activity of saporin, the apoptosis inducing activity is important. PMID- 25925772 TI - The Propeptide is Required for In Vivo Formation of Active Protealysin. AB - Two structurally distinct N-terminal propeptides are known in thermolysin-like proteases (TLPs). Propeptides of the first type are similar to the prosequence of thermolysin, while the second type propeptides resemble the protealysin propeptide. At the same time, the catalytic domains of all enzymes of the family are highly similar. The available data suggest that the propeptides determine the biological function of TLPs. It was shown that the thermolysin-type propeptides act as folding assistants, can inhibit cognate mature proteins, and influence their secretion. However, the functions of protealysin-like propeptides remain unclear. Here, we studied the effect of the propeptide on protealysin folding for the first time. After heterologous expression in E. coli cells, active enzyme is formed only in the presence of the propeptide either in cis or in trans. Thus, both types of TLP prosequences can function as folding assistants despite their structural dissimilarity and absolutely different interaction with the cognate catalytic domains as indicated by X-ray data. PMID- 25925773 TI - Cloning of a Novel Feruloyl Esterase from Rumen Microbial Metagenome for Substantial Yield of Mono- and Diferulic Acids from Natural Substrates. AB - A feruloyl esterase (FAE) gene was isolated from a rumen microbial metagenome, cloned into E. coli, and expressed in active form. The enzyme (RuFae4) was classified as a Type D feruloyl esterase based on its action on synthetic substrates and ability to release diferulates. The RuFae4 alone released ferulic acid (FA) and diferulic acid (diFA) from wheat insoluble arabinoxylan (WIA) and other natural substrates. The diFA released was confirmed by mass spectrometry. A maximum of 205+/-5.7 ug FA and 0.84+/-0.1 ug diFA were released (37 degrees C, pH 6.5, 2 hr) when a saturating amount of RuFae4 (23 nmole for 100 mg WIA) was used. These yields represent 48.3% of FA, and 6.6% of diFAs present in the WIA substrate. Addition of GH10 endoxylanase (EX) to RuFae4 both at 1 nmole concentrations increased the release of FA and diFAs by 17 and 10 fold, respectively. Addition of GH11 EX resulted in smaller increase in the amount of both FA and diFAs. Applying additive amount of the two enzymes did not lead to additive increase in the product yields, suggesting that it was primarily the GH10 enzyme contributing synergism to FA/diFA release in mixed reactions. PMID- 25925774 TI - Reference point detection for camera-based fingerprint image based on wavelet transformation. AB - BACKGROUND: Fingerprint recognition systems essentially require core-point detection prior to fingerprint matching. The core-point is used as a reference point to align the fingerprint with a template database. When processing a larger fingerprint database, it is necessary to consider the core-point during feature extraction. Numerous core-point detection methods are available and have been reported in the literature. However, these methods are generally applied to scanner-based images. Hence, this paper attempts to explore the feasibility of applying a core-point detection method to a fingerprint image obtained using a camera phone. METHOD: The proposed method utilizes a discrete wavelet transform to extract the ridge information from a color image. The performance of proposed method is evaluated in terms of accuracy and consistency. These two indicators are calculated automatically by comparing the method's output with the defined core points. RESULTS: The proposed method is tested on two data sets, controlled and uncontrolled environment, collected from 13 different subjects. In the controlled environment, the proposed method achieved a detection rate 82.98%. In uncontrolled environment, the proposed method yield a detection rate of 78.21%. CONCLUSION: The proposed method yields promising results in a collected-image database. Moreover, the proposed method outperformed compare to existing method. PMID- 25925776 TI - Quality Assurance of UMLS Semantic Type Assignments Using SNOMED CT Hierarchies. AB - BACKGROUND: The Unified Medical Language System (UMLS) is one of the largest biomedical terminological systems, with over 2.5 million concepts in its Metathesaurus repository. The UMLS's Semantic Network (SN) with its collection of 133 high-level semantic types serves as an abstraction layer on top of the Metathesaurus. In particular, the SN elaborates an aspect of the Metathesaurus's concepts via the assignment of one or more types to each concept. Due to the scope and complexity of the Metathesaurus, errors are all but inevitable in this semantic-type assignment process. OBJECTIVES: To develop a semi-automated methodology to help assure the quality of semantic-type assignments within the UMLS. METHODS: The methodology uses a cross-validation strategy involving SNOMED CT's hierarchies in combination with UMLS semantic types. Semantically uniform, disjoint concept groups are generated programmatically by partitioning the collection of all concepts in the same SNOMED CT hierarchy according to their respective semantic-type assignments in the UMLS. Domain experts are then called upon to review the concepts in any group having a small number of concepts. It is our hypothesis that a semantic-type assignment combination applicable only to a very small number of concepts in a SNOMED CT hierarchy is an indicator of potential problems. RESULTS: The methodology was applied to the UMLS 2013AA release along with the SNOMED CT from January 2013. An overall error rate of 33% was found for concepts proposed by the quality-assurance methodology. Supporting our hypothesis, that number was four times higher than the error rate found in control samples. CONCLUSION: The results show that the quality-assurance methodology can aid in effective and efficient identification of UMLS semantic type assignment errors. PMID- 25925775 TI - The evidence base of primary research in public health emergency preparedness: a scoping review and stakeholder consultation. AB - BACKGROUND: Effective public health emergency preparedness and response systems are important in mitigating the impact of all-hazards emergencies on population health. The evidence base for public health emergency preparedness (PHEP) is weak, however, and previous reviews have noted a substantial proportion of anecdotal event reports. To investigate the body of research excluding the anecdotal reports and better understand primary and analytical research for PHEP, a scoping review was conducted with two objectives: first, to develop a thematic map focused on primary research; and second, to use this map to inform and guide an understanding of knowledge gaps relevant to research and practice in PHEP. METHODS: A scoping review was conducted based on established methodology. Multiple databases of indexed and grey literature were searched based on concepts of public health, emergency, emergency management/preparedness and evaluation/evidence. Inclusion and exclusion criteria were applied iteratively. Primary research studies that were evidence-based or evaluative in nature were included in the final group of selected studies. Thematic analysis was conducted for this group. Stakeholder consultation was undertaken for the purpose of validating themes and identifying knowledge gaps. To accomplish this, a purposive sample of researchers and practicing professionals in PHEP or closely related fields was asked to complete an online survey and participate in an in-person meeting. Final themes and knowledge gaps were synthesized after stakeholder consultation. RESULTS: Database searching yielded 3015 citations and article selection resulted in a final group of 58 articles. A list of ten themes from this group of articles was disseminated to stakeholders with the survey questions. Survey findings resulted in four cross-cutting themes and twelve stand alone themes. Several key knowledge gaps were identified in the following themes: attitudes and beliefs; collaboration and system integration; communication; quality improvement and performance standards; and resilience. Resilience emerged as both a gap and a cross-cutting theme. Additional cross-cutting themes included equity, gender considerations, and high risk or at-risk populations. CONCLUSIONS: In this scoping review of the literature enhanced by stakeholder consultation, key themes and knowledge gaps in the PHEP evidence base were identified which can be used to inform future practice-oriented research in PHEP. PMID- 25925777 TI - Demographic, Hematologic, and Clinical Features of Myelodysplastic Syndrome Patients: Results from the First Polish Myelodysplastic Syndrome Registry. AB - Epidemiological studies on myelodysplastic syndromes (MDS) in Middle-Eastern Europe are scarce. No data about the demographic, clinical, and laboratory features of Polish MDS patients have been published. The aim of this study was to assess the epidemiological data and toxic exposure of Polish MDS patients and their association with hematological parameters and clinical outcomes. For 15 months, 966 living MDS patients were enrolled at 24 centers (12 university and 12 community hospitals). Follow-up was conducted for the next 55 months. The percentage of patients older than 80 years (16%) was between the values for Eastern and Western countries. In patients younger than 55 years, a female predominance was observed (male/female ratio 0.70:1 vs. 1.29:1; p < 0.001). Female patients had higher platelet counts (160 * 109/l vs. 111 * 109/l; p < 0.001). Patients exposed to chemicals were younger than patients without such exposure; their median age at MDS diagnosis was 66 vs. 70 years (p = 0.037). Smokers had significantly lower hemoglobin concentrations (8.6 vs. 9.1 g/dl; p = 0.032) and lower platelet counts (99 * 109/l vs. 137 * 109/l; p < 0.001) than nonsmokers. We provide the first description of the characteristics of Polish MDS patients. Females predominated in the group aged <60 years and they had higher platelet counts. The course of the disease is affected by toxic exposure and smoking. PMID- 25925778 TI - Retinoblastoma in Chinese Children Aged Five to Fourteen Years. AB - OBJECTIVE: To assess the characteristics of retinoblastomas enucleated from Chinese children aged 5-14 years. METHODS: This retrospective hospital-based study included all eyes with retinoblastomas consecutively enucleated in the Beijing Tongren Hospital between August 2003 and July 2013. RESULTS: Out of 1,205 patients, 47 (3.9%) were 5 years or older. All tumors in this age group occurred unilaterally, the patients had a negative family history, and the tumors were detected at an age of 6.9 +/- 1.8 years (range: 5-14). The main clinical features at the time of examining the as yet untreated children aged 5-7 years (n = 30) or >7-14 years (n = 10) were leukocoria, strabismus, pseudohypopyon, hypertension, vitreous seeds ('snowballs'), and calcifications. In 12 patients (26%), the retinoblastoma had not initially been diagnosed as a tumor. Histopathology revealed tumor invasion into nonretinal tissue in 19 eyes (40%). Therapy included enucleation only (n = 22; 47%), adjuvant systemic chemotherapy (n = 24; 51%), and additional orbital exenteration (n = 1). After a mean follow-up of 3.0 +/- 2.1 years (range: 0.2-9.8), which was done for 40 children, none of these children showed a tumor recurrence. CONCLUSIONS: Of the children undergoing enucleation for retinoblastoma in Beijing, 3.9% were aged 5 years or more. As in Western countries, the tumor occurrence was unilateral, their family history was negative, and the survival rate was relatively high in these children. In 1 out of 4 children, the tumor had initially been misdiagnosed due to a masquerade syndrome. Retinoblastoma should be considered in the differential diagnosis of any unclear intraocular situation in children. PMID- 25925779 TI - Persistent effects of chronic Delta9-THC exposure on motor impulsivity in rats. AB - RATIONALE: In humans, long-term marijuana use is associated with impaired impulse control and attentional capacity, though it has been difficult to distinguish pre existing cognitive deficits from possible consequences of prolonged marijuana exposure. OBJECTIVE: To evaluate the effects of long-term exposure to Delta9 Tetrahydrocannabinol (Delta9-THC), the primary psychoactive constituent in marijuana, on indices of impulse control and attentional capacity using the rat 5 Choice Serial Reaction Time Task (5-CSRTT). METHODS: Ten 14-day cycles of Delta9 THC dosing and 5-CSRTT testing were employed, each comprised of 5-day Delta9-THC dosing (0.3 or 3 mg/kg b.i.d.) and 5-CSRTT testing during the 9 days of drug abstinence. Subsequent 5-CSRTT testing continued during 5 weeks of protracted abstinence. RESULTS: Dose-dependent increases in motor impulsivity (premature responses) and behavioral disinhibition (perseverative responses) emerged following 5 cycles of Delta9-THC exposure that persisted for the remaining dosing and testing cycles. Delta9-THC-related disruptions in motor impulsivity and behavioral inhibition were most pronounced during cognitively challenging 5-CSRTT sessions incorporating varying novel inter-trial intervals (ITIs), and these disruptions persisted for at least 5 weeks of Delta9-THC abstinence. Delta9-THC related impairments in attentional capacity (response accuracy) were also evident during variable ITI challenge tests, though these attentional disruptions abated within 3 weeks of Delta9-THC abstinence. CONCLUSIONS: These observations demonstrate that long-term intermittent exposure to clinically meaningful Delta9 THC doses induces persistent impairments in impulse control and attentional function. If present in humans, these disruptions may impact academic and professional performance. PMID- 25925781 TI - Decreased right hippocampal volumes and neuroprogression markers in adolescents with bipolar disorder. AB - OBJECTIVES: The aim of the present study was to assess differences and correlations between the hippocampal volumes (HCVs), serum nerve growth factor (NGF), and brain-derived neurotrophic factor (BDNF) levels in adolescents with bipolar disorder (BP) compared to healthy controls. METHODS: Using structural magnetic resonance imaging, we compared HCVs of 30 patients with euthymic BP who were already enrolled in a naturalistic clinical follow-up. For comparison, we enrolled 23 healthy controls between the ages of 13 and 19. The boundaries of the hippocampus were outlined manually. The BDNF and NGF serum levels were measured with the sandwich ELISA. RESULTS: The groups did not differ in the right or left HCVs or in the NGF or BDNF serum levels. However, negative correlations were found between the right HCVs and the duration of the disorder and medication and positive correlations were found between the duration of the medications and the NGF and BDNF levels in the patient group. Additionally, positive correlations were found between the follow-up period and left normalized HCVs in both the BP and lithium-treated groups. CONCLUSIONS: The right HCVs may vary with illness duration and the medication used to treat BP; NGF and BDNF levels may be affected by long-term usage. Further research is needed to determine whether these variables and their structural correlates are associated with clinical or functional differences between adolescents with BP and healthy controls. PMID- 25925780 TI - In vivo potency and efficacy of the novel cathinone alpha pyrrolidinopentiophenone and 3,4-methylenedioxypyrovalerone: self-administration and locomotor stimulation in male rats. AB - RATIONALE: Numerous substituted cathinone drugs have appeared in recreational use. This variety is often a response to legal actions; the scheduling of 3,4 methylenedioxypyrovalerone (MDPV; "bath salts") in the USA was followed by the appearance of the closely related drug alpha-pyrrolidinopentiophenone (alpha-PVP; "flakka"). OBJECTIVES: This study aimed to directly compare the efficacy and potency of alpha-PVP with that of MDPV. METHODS: Groups of male Wistar rats were trained in the intravenous self-administration (IVSA) alpha-PVP or MDPV under a fixed-ratio 1 schedule of reinforcement. An additional group was examined for locomotor and body temperature responses to noncontingent administration of MDVP or alpha-PVP (1.0, 5.6, and 10.0 mg/kg, i.p.). RESULTS: Acquisition of alpha-PVP (0.1 mg/kg/infusion) IVSA resulted in low, yet consistent drug intake and excellent discrimination for the drug-paired lever. Dose substitution (0.05-0.25 mg/kg/infusion) under a fixed-ratio 1 schedule confirmed potency was similar to MDPV in prior studies. In direct comparison to MDPV (0.05 mg/kg/infusion), rats trained on alpha-PVP (0.05 mg/kg/infusion) responded for more infusions but demonstrated similar drug-lever discrimination by the end of acquisition. However, the dose-response (0.018-0.56 mg/kg/infusion) functions of these drugs under a progressive-ratio schedule of reinforcement reflected identical efficacy and potency. Peak locomotor responses to MDPV or alpha-PVP were observed after the 1.0 mg/kg, i.p. dose and lasted ~2 h. Modest body temperature decreases were of similar magnitude (~0.75 degrees C) for each compound. CONCLUSIONS: The potency and efficacy of MDPV and alpha-PVP were very similar across multiple assays, predicting that the abuse liability of alpha-PVP will be significant and similar to that of MDPV. PMID- 25925782 TI - Acetylation of MAT IIalpha represses tumour cell growth and is decreased in human hepatocellular cancer. AB - Metabolic alteration is a hallmark of cancer. Dysregulation of methionine metabolism is implicated in human liver cancer. Methionine adenosyltransferase IIalpha (MAT IIalpha) is a key enzyme in the methionine cycle, catalysing the production of S-adenosylmethionine (SAM), a key methyl donor in cellular processes, and is associated with uncontrolled cell proliferation in cancer. Here we show that P300 acetylates MAT IIalpha at lysine residue 81 and destabilizes MAT IIalpha by promoting its ubiquitylation and subsequent proteasomal degradation. Conversely, histone deacetylase-3 deacetylates and stabilizes MAT IIalpha by preventing its proteasomal degradation. Folate deprivation upregulates K81 acetylation and destabilizes MAT IIalpha to moderate cell proliferation, whereas a single mutation at K81 reverses the proliferative disadvantage of cancer cells upon folate deprivation. Moreover, MAT IIalpha K81 acetylation is decreased in human hepatocellular cancer. Collectively, our study reveals a novel mechanism of MAT IIalpha regulation by acetylation and ubiquitylation, and a direct functional link of this regulation to cancer development. PMID- 25925783 TI - Subjective ultrasound assessment, the ADNEX model and ultrasound-guided tru-cut biopsy to differentiate disseminated primary ovarian cancer from metastatic non ovarian cancer. AB - OBJECTIVES: To compare subjective ultrasound assessment and the ADNEX model with ultrasound-guided tru-cut biopsy to differentiate disseminated primary ovarian cancer from metastatic non-ovarian cancer. METHODS: This was a prospective study including 143 consecutive women with disseminated malignancy of unknown primary origin, with a pelvic tumor/carcinosis. Women underwent either transvaginal or transrectal ultrasound as well as transabdominal ultrasound examination followed by tru-cut biopsy. The ultrasound examiner assessed tumor morphology, spread in the pelvis and abdomen, and predicted tumor origin as primary ovarian or metastatic using both subjective assessment and the ADNEX model. Histology from tru-cut biopsy served as the gold standard for assessment of diagnostic accuracy. Biopsy adequacy and the complication rate were assessed. RESULTS: Tru-cut biopsy was performed transvaginally in 131/143 (92%) women. Two women needed inpatient care (one had abdominal wall hematoma, and one infection). Biopsy resulted in a conclusive diagnosis in 126/143 (88%) women, amongst whom cytoreductive surgery was performed in 30/126 confirming the diagnosis in all cases. Non-ovarian metastatic cancer was found in 37/126 (29%) women and primary ovarian cancer in 89/126 (71%) women. Subjective ultrasound evaluation had a sensitivity of 82% (73/89) and a specificity of 70% (26/37) in predicting primary ovarian cancer. The ADNEX model had an area under the receiver-operating characteristics curve of 0.891 (95% CI, 0.794-0.946) (in women with an ovarian lesion, n = 104). Tumor origin was associated with age, CA 125, previous neoplasia, presence of omental cake and tumor mobility. CONCLUSIONS: Subjective ultrasound assessment and the ADNEX model can both be used to predict whether a pelvic tumor is metastatic and of non-ovarian origin, indicating the need for tru-cut biopsy, which is associated with very few complications and will provide a conclusive diagnosis in nine out of 10 women. Copyright (c) 2015 ISUOG. PMID- 25925784 TI - Intervendor Variabilities of Left and Right Ventricular Myocardial Velocities among Three Tissue Doppler Echocardiography Systems. AB - BACKGROUND: Whether an intervendor discordance of myocardial velocities determined by tissue Doppler echocardiography (TDE) can be generalized remains unclear. We compared intervendor variabilities of left ventricular (LV) and right ventricular (RV) myocardial velocities among three TDE systems. METHODS: Examinations with TDE were performed in 41 healthy subjects and 11 patients with cardiovascular risk factors (CVR) using alpha-7 (V1, Hitachi Aloka Medical), Artida (V2, Toshiba Medical Systems), and Vivid E9 (V3, GE Healthcare) on the same day. Peak systolic (s'), early diastolic (e'), and late diastolic (a') myocardial velocities at medial and lateral sites of the mitral annulus and lateral site of the tricuspid annulus were measured using both pulsed-wave TDE and color TDE. Intra-observer and inter-observer variabilities were determined in 10 subjects and test-retest variability in 14 subjects. RESULTS: As for test retest variability, reproducibilities of LV and RV myocardial velocities determined by pulsed-wave TDE and color TDE were relatively low but comparable between V1, V2, and V3. Myocardial velocities in healthy subjects determined by both pulsed-wave TDE and color TDE were significantly different among the three TDE systems. Myocardial velocities by pulsed-wave TDE in V3 were 2-12% lower (P < 0.05) than those by V2 and 5-14% lower (P < 0.05) than those by V1. Similar differences in myocardial velocities determined by both pulsed-wave TDE and color TDE were found in patients with CVR. CONCLUSIONS: LV and RV myocardial velocities determined by both pulsed-wave TDE and color TDE are vendor dependent, and reproducibility of the myocardial velocities determined by both TDE systems is relatively low. PMID- 25925785 TI - A cross-sectional study to assess the prevalence of DSM-5 specific learning disorders in representative school samples from the second to sixth grade in Brazil. AB - Little is known about specific learning disorder (SLD) in low- and middle-income countries (LMICs), and even less from representative school samples in small size cities outside huge urban centers. Few studies addressed the new DSM-5 criteria for SLDs. We investigated the prevalence of DSM-5 SLDs, their comorbidities and correlates in school samples of students from the second to sixth grades living in median cities from four different geographic regions in Brazil. A national test for academic performance covering reading, writing and mathematical abilities was applied. Psychiatric diagnoses were assessed by the K-SADS-PL applied to the primary caregiver. A total of 1618 children and adolescents were included in the study. The following prevalence rates of SLDs were found: 7.6% for global impairment, 5.4% for writing, 6.0% for arithmetic, and 7.5% for reading impairment. Attention-deficit/hyperactivity disorder (ADHD) was the only comorbidity significantly associated with SLD with global impairment (p = 0.031). Anxiety disorders and ADHD were associated with SLD with arithmetic impairment. Significant differences were detected in prevalence rates among cities, and several socio-demographic correlates (age, gender, IQ, and socioeconomic status) were significantly associated with SLD with global impairment in our sample. Careful validation and normatization of instruments to assess academic performance is a major problem in LMICs. As expected, we found a significant heterogeneity in prevalence rates of SLD according to geographic regions considering that Brazil is a country with a robust diversity. SLD with global and arithmetic impairment was significantly associated with psychiatric comorbidities. PMID- 25925787 TI - Anomalous origin of the left pulmonary artery from the internal carotid artery. PMID- 25925786 TI - Identifying children and adolescents at ultra high risk of psychosis in Italian neuropsychiatry services: a feasibility study. AB - The past 20 years have seen the evolution of the construct of a clinical high risk (hereafter, HR) state for psychosis. This construct is designed to capture the pre-psychotic phase. Some aspects of this approach, such as its feasibility in children and adolescents, are still under investigation. In the present study, we address the feasibility of implementing prodrome clinics for HR individuals within the framework of Italy's national child and adolescent neuropsychiatry services and the clinical relevance of a HR diagnosis in this population. Using the Comprehensive Assessment of At-Risk Mental States (CAARMS) to identify help seeking patients meeting at least one HR criterion at baseline (HR+), we recruited 50 subjects for a feasibility study. The results obtained show that the Italian version of the CAARMS is easily administrable, causing patients no substantial discomfort. The prevalence of HR+ in our cohort was 44 %, which increased by an additional 18 % when negative symptoms were considered as an experimental inclusion criterion (HRNeg). The HR+ subjects were significantly more impaired in their social and occupational functioning than their HR- peers (subjects not at HR). The cumulative 1-year transition risk of psychosis of the HR+ group was 26.7 %. When the HRNeg group was added, the 1-year transition risk was 17.3 %. We suggest that administration of the CAARMS to children and adolescents with putative prodromal psychosis is feasible and that this assessment can easily be integrated into existing Italian neuropsychiatry services although clinicians should interpret results with caution as results in this age group still have to be replicated. PMID- 25925788 TI - Illness perceptions and self-care behaviours in the first years of living with type 2 diabetes; does the presence of complications matter? AB - OBJECTIVE: To assess illness perceptions, self-care behaviours and their relationship in recently diagnosed type 2 diabetes mellitus (T2DM) patients with and without diabetes-related complications. DESIGN: Cross-sectional survey among 192 recently diagnosed T2DM patients of whom 23% reported the presence of diabetes-related complications. Illness perceptions and self-care were assessed by the Revised Illness Perception Questionnaire (IPQ-R) and the revised Summary of Diabetes Self-Care Activities (SDSCA) measure. RESULTS: Generally, participating patients perceived T2DM as a chronic, but relatively controllable condition with minor consequences. In the presence of complications, however, T2DM was perceived as more unpredictable with more (serious) consequences and less controllable by self-care or medical treatment. Furthermore, engagement in exercise and foot care was reported more often by patients with complications. Self-care was related to certain illness perception dimensions, and interactions between perceptions and complications were found. CONCLUSION: T2DM patients in the first years of their illness are often recommended to make lifestyle changes in the absence of noticeable diabetes-related symptoms or complaints. As many T2DM patients do not seem to perceive their condition to be serious and postpone lifestyle changes until diabetes-related complications appear, a major challenge for professionals is to convince asymptomatic patients of the importance of self care. PMID- 25925789 TI - Androgen deprivation therapy and the risk of death from prostate cancer among men with favorable or unfavorable intermediate-risk disease. AB - BACKGROUND: Radiotherapy (RT), short-course androgen deprivation therapy (ADT), and brachytherapy in various combinations are treatment options for patients with intermediate-risk prostate cancer (PC), but the question of which combination if any is necessary to minimize PC-specific mortality (PCSM) risk in patients with favorable or unfavorable intermediate-risk PC is unknown. The authors assessed PCSM risk after commonly used treatments. METHODS: The cohort consisted of 2510 men with favorable (1902 men; 75.78%) or unfavorable (608 men; 24.22%) intermediate-risk PC who were treated from 1997 to 2013. Treatment included brachytherapy with or without neoadjuvant ADT among men with favorable disease and brachytherapy with neoadjuvant RT or ADT among men with unfavorable disease. Fine and Gray's competing-risks regression model was used to assess whether ADT among men with favorable disease or RT or ADT among men with unfavorable disease decreased PCSM risk after adjusting for treatment propensity score, year of brachytherapy, and PC prognostic factors. RESULTS: After a median follow-up of 7.78 years, 366 deaths (14.58%) were observed, 29 of which (7.92%) were from PC. There was a significant reduction in PCSM risk in men with unfavorable disease who were treated with ADT versus RT (adjusted hazard ratio, 0.34; 95% confidence interval, 0.13-0.91 [P = .03]), but no significant difference in PCSM risk in men with favorable disease who received ADT and brachytherapy versus brachytherapy (adjusted hazard ratio, 0.67; 95% confidence interval, 0.18-2.57 [P =.56]). CONCLUSIONS: Neoadjuvant ADT does not appear to reduce PCSM risk in men undergoing brachytherapy for favorable intermediate-risk PC and should not be considered a standard; however, it appears superior to neoadjuvant RT in men with unfavorable intermediate-risk PC undergoing brachytherapy, making neoadjuvant ADT and brachytherapy a preferred option in these men. PMID- 25925790 TI - Photosensitizer-Conjugated Albumin-Polypyrrole Nanoparticles for Imaging-Guided In Vivo Photodynamic/Photothermal Therapy. AB - Conjugated polymers with strong absorbance in the near-infrared (NIR) region have been widely explored as photothermal therapy agents due to their excellent photostability and high photothermal conversion efficiency. Herein, polypyrrole (PPy) nanoparticles are fabricated by using bovine serum albumin (BSA) as the stabilizing agent, which if preconjugated with photosensitizer chlorin e6 (Ce6) could offer additional functionalities in both imaging and therapy. The obtained PPy@BSA-Ce6 nanoparticles exhibit little dark toxicity to cells, and are able to trigger both photodynamic therapy (PDT) and photothermal therapy (PTT). As a fluorescent molecule that in the meantime could form chelate complex with Gd(3+), Ce6 in PPy@BSA-Ce6 nanoparticles after being labeled with Gd(3+) enables dual modal fluorescence and magnetic resonance (MR) imaging, which illustrate strong tumor uptake of those nanoparticles after intravenous injection into tumor bearing mice. In vivo combined PDT and PTT treatment is then carried out after systemic administration of PPy@BSA-Ce6, achieving a remarkably improved synergistic therapeutic effect compared to PDT or PTT alone. Hence, a rather simple one-step approach to fabricate multifunctional nanoparticles based on conjugated polymers, which appear to be promising in cancer imaging and combination therapy, is presented. PMID- 25925791 TI - MiR-31 Downregulation Protects Against Cardiac Ischemia/Reperfusion Injury by Targeting Protein Kinase C Epsilon (PKCepsilon) Directly. AB - BACKGROUND: Various miRNAs have been shown to participate in cardiac ischemia/reperfusion injury (I/R). miR-31 was identified as the most strikingly upregulated miRNA after acute myocardial infarction; therefore, the underlying role and mechanism of miR-31 in cardiac I/R was investigated. METHODS: miR-31 expression was detected after cardiac I/R in mice. The cardioprotective effect of miR-31 downregulation was assessed in vitro and in vivo. The functional target gene and its downstream molecule were determined. RESULTS: miR-31 expression increased after I/R. miR-31 downregulation increased cell viability and SOD activity and decreased LDH activity and MDA content in vitro. Additionally, miR 31 downregulation alleviated myocardial infarct size in vivo. PKCepsilon was identified as the functional target gene of miR-31, and NFkappaB was identified as its downstream molecule that was involved in the miR-31-mediated cardioprotective effect. CONCLUSION: miR-31 expression increased throughout the cardiac I/R process, and miR-31 downregulation induced a cardioprotective effect via a miR-31/PKCepsilon/NFkappaB-dependent pathway. PMID- 25925793 TI - Does the Hospital Predict Readmission? A Multi-level Survival Analysis Approach. AB - Time to psychiatric rehospitalization was predicted for a sample of 1473 Medicaid insured youth in Illinois in 2005 and 2006. A multi-level model statistical strategy was employed to account for the fact that youth days to rehospitalization were nested within hospital and to test the hypothesis that hospitals would vary significantly in return rates, controlling for individual level (e.g., symptom, demographic) variables. Hospitals did not vary significantly in days to rehospitalization. At the individual-level, level of externalizing behavior and residential treatment placement predicted a faster return to the hospital. These results support the perspective that hospital outcomes are best operationalized using variables tied more directly to the inpatient episode (e.g., LOS, reductions in acuity). PMID- 25925792 TI - The effect of thymoquinone treatment on the combined renal and pulmonary toxicity of cisplatin and diesel exhaust particles. AB - Particulate air pollution (PAP) exposure is associated with increased morbidity and mortality, particularly in patients with renal disease. However, there are only a few studies on the interaction between PAP and renal injury, and none on agents that may ameliorate it. We studied the interaction between cisplatin (CP) nephrotoxicity and a single exposure to diesel exhaust particle (DEP) in rats 24 h before sacrifice, and assessed the effect of co-treatment with the active ingredient in Nigella Sativa seed oil, thymoquinone (TQ) thereon. Rats were injected intraperitoneally with CP (6 mg/kg) and four days later, they were exposed intratracheally to DEP (0.5 mg/kg), and were sacrificed 24 h later. Oral TQ (20 mg/kg) was given daily throughout the experimental period. CP alone caused several physiological, biochemical, and histopathological changes that included reduced growth and creatinine clearance, and raised plasma neutrophil gelatinase associated lipocalin (NGAL), interleukin 6 (IL-6) and C-reactive protein (CRP), creatinine and urea concentrations, and urinary N-acetyl-b-D-glucosaminidase (NAG) activities. It adversely affected several indices of oxidative damage in the kidneys, and induced renal tubular necrosis. Most of these actions were significantly potentiated in rats given both CP and DEP. TQ significantly abrogated many of the effects of CP and DEP, given alone and in combination. These results provide experimental evidence that subjects with renal diseases can be at higher risk from PAP, and that TQ, pending further pharmacological and toxicological studies, can be considered a useful agent in patients with renal diseases and exposed to PAP. PMID- 25925794 TI - Heterostructure of Si and CoSe2: A Promising Photocathode Based on a Non-noble Metal Catalyst for Photoelectrochemical Hydrogen Evolution. AB - Development of a solar water splitting device requires design of a low-cost, efficient, and non-noble metal compound as alternative to noble metals. For the first time, we showed that CoSe2 can function as co-catalyst in phototoelectrochemical hydrogen production. We designed a heterostructure of p-Si and marcasite-type CoSe2 for solar-driven hydrogen production. CoSe2 successively coupled with p-Si can act as a superior photocathode in the solar-driven water splitting reaction. Photocurrents up to 9 mA cm(-2) were achieved at 0 V vs. reversible hydrogen electrode. Electrochemical impedance spectroscopy showed that the high photocurrents can be attributed to low charge transfer resistance between the Si and CoSe2 interfaces and that between the CoSe2 and electrolyte interfaces. Our results suggest that this CoSe2 is a promising alternative co catalyst for hydrogen evolution. PMID- 25925795 TI - First Report of NDM-1-Producing Acinetobacter guillouiae. AB - BACKGROUND: Acinetobacter spp. is an opportunistic pathogen that has demonstrated increasing relevance in nosocomial infections. Carbapenem-resistant strains have been reported worldwide. METHODS: Since 2014, screening for metallo-beta lactamases (MBLs) in all Acinetobacter spp. isolates using phenotypic methods and PCR has been implemented at the University Hospital Center Zagreb. RESULTS: The bacterial strain was isolated from the drain of a child hospitalized in a paediatric intensive care unit and identified as Acinetobacter guillouiae using a MALDI TOF automated system. The strain was resistant to meropenem, ceftazidime, cefotaxime, ceftriaxone, cefepime, sulbactam/ampicillin, gentamicin and ciprofloxacin, intermediately susceptible to piperacillin/tazobactam and imipenem, and susceptible to amikacin and colistin. The Hodge test and combined disk test with EDTA were positive. The MICs of meropenem and imipenem were not reduced by cloxacillin, but a small reduction of two dilutions was observed following the addition of sodium chloride, which indicated that OXA-58 was produced. PCR and sequencing of chromosomal DNA from boiled colonies revealed blaOXA-58 and blaNDM-1 genes. CONCLUSION: This is the first report of NDM-1 in Acinetobacter spp. in Croatia. The early detection of these genes will aid in the prevention and in the achievement of adequate infection control by limiting the spread of these organisms. PMID- 25925797 TI - Reporting guidelines for population pharmacokinetic analyses. AB - The purpose of this work was to develop a consolidated set of guiding principles for reporting of population pharmacokinetic (PK) analyses based on input from a survey of practitioners as well as discussions between industry, consulting and regulatory scientists. The survey found that identification of population covariate effects on drug exposure and support for dose selection (where population PK frequently serves as preparatory analysis to exposure-response modeling) are the main areas of influence for population PK analysis. The proposed guidelines consider two main purposes of population PK reports (1) to present key analysis findings and their impact on drug development decisions, and (2) as documentation of the analysis methods for the dual purpose of enabling review of the analysis and facilitating future use of the models. This work also identified two main audiences for the reports: (1) a technically competent group responsible for in-depth review of the data, methodology, and results, and (2) a scientifically literate, but not technically adept group, whose main interest is in the implications of the analysis for the broader drug development program. We recommend a generalized question-based approach with six questions that need to be addressed throughout the report. We recommend eight sections (Synopsis, Introduction, Data, Methods, Results, Discussion, Conclusions, Appendix) with suggestions for the target audience and level of detail for each section. A section providing general expectations regarding population PK reporting from a regulatory perspective is also included. We consider this an important step towards industrialization of the field of pharmacometrics such that non-technical audience also understands the role of pharmacometrics analyses in decision making. Population PK reports were chosen as representative reports to derive these recommendations; however, the guiding principles presented here are applicable for all pharmacometric reports including PKPD and simulation reports. PMID- 25925796 TI - Epidemiology and treatment of trichomoniasis. AB - Trichomonas vaginalis is the most common nonviral sexually transmitted infection (STI) in the world. It was once thought to be a nuisance STI, but it is now being recognized as an important source of reproductive morbidity and a facilitator of HIV transmission and acquisition, and thus it is an important public health problem. The prevalence of T. vaginalis varies greatly by geography and risk group, but is more common among persons of African descent and appears to increase with age, though this may be a screening phenomenon. Wet mount and culture are simple diagnostics, but have lower sensitivity than nucleic acid amplification techniques presently approved for women only. Single dose (2 g) metronidazole (MTZ) for both the index patient and their sexual partners is the preferred treatment. High rates of retest positivity are found after single-dose treatment which are likely due to clinical resistance rather than re-infection and/or drug resistance. PMID- 25925798 TI - Disease modification in epilepsy: from animal models to clinical applications. AB - Several relevant animal models of epileptogenesis and biomarkers have emerged for evaluating the antiepileptogenic potential of an investigational drug. Although several promising candidate compounds and approaches have been identified in these preclinical models, no treatment has yet successfully navigated the path from preclinical efficacy to clinical validation. Until such an agent can move from preclinical proof of concept to clinical success, the need remains to continually develop and optimize preclinical models and clinical trial design in an effort to guide potential clinical investigations. This review describes several available models of disease modification and/or epileptogenesis, preclinical studies in these models and potential biomarkers useful for evaluating the efficacy of a potential therapeutic agent in the preclinical setting. The results that emerge from such efforts may then guide the clinical evaluation of a candidate compound. This review discusses some of the known limitations and hurdles to moving compounds found effective in these models to clinical practice, in the hope that knowledge of this information will facilitate the design and conduct of clinical studies and effectively facilitate the identification of a first-in-class disease-modifying or antiepileptogenic agent. PMID- 25925799 TI - Human Milk MicroRNA and Total RNA Differ Depending on Milk Fractionation. AB - MicroRNA have been recently discovered in human milk signifying potentially important functions for both the lactating breast and the infant. Whilst human milk microRNA have started to be explored, little data exist on the evaluation of sample processing, and analysis to ensure that a full spectrum of microRNA can be obtained. Human milk comprises three main fractions: cells, skim milk, and lipids. Typically, the skim milk fraction has been measured in isolation despite evidence that the lipid fraction may contain more microRNA. This study aimed to standardize isolation of microRNA and total RNA from all three fractions of human milk to determine the most appropriate sampling and analysis procedure for future studies. Three different methods from eight commercially available kits were tested for their efficacy in extracting total RNA and microRNA from the lipid, skim, and cell fractions of human milk. Each fraction yielded different concentrations of RNA and microRNA, with the highest quantities found in the cell and lipid fractions, and the lowest in skim milk. The column-based phenol-free method was the most efficient extraction method for all three milk fractions. Two microRNAs were expressed and validated in the three milk fractions by qPCR using the three recommended extraction kits for each fraction. High expression levels were identified in the skim and lipid milk factions for these microRNAs. These results suggest that careful consideration of both the human milk sample preparation and extraction protocols should be made prior to embarking upon research in this area. PMID- 25925800 TI - Frailty among elderly adults in a rural area of Turkey. AB - BACKGROUND: The elderly population is growing in Turkey, as it is worldwide. The average age of residents in rural areas of Turkey is relatively high and is gradually increasing. The purpose of this study is to summarize the fitness and frailty of elderly adults living in a rural area of Turkey characterized by a relatively low level of socioeconomic development. MATERIAL/METHODS: This study was designed as a prospective, cross-sectional study, and was conducted in a rural area of Kars Province. A total of 168 elderly adults (>=65 years old) from 12 central villages were included in the study. The Fried Frailty Criteria was used to assess the frailty of the participants. In addition to frailty, the physical, social, and mental status of elderly adults was examined. RESULTS: The prevalence of frailty in this rural area of Turkey was 7.1%.The study group ranged in age from 65 to 96 years (mean 72.70+/-7.73 years), and 53.6% were female. Among the elderly adult group, 84.3% had not completed elementary school, and 43.29% had a monthly income of <=500 Turkish liras ($200). No significant relationship was identified between gender and frailty. There was a statistically significant relationship between frailty and older age, lower education level, lower economic level, co-morbidities, polypharmacy, diabetes, chronic obstructive pulmonary disease, gastric disease, arthritis, generalized pain, benign prostatic hyperplasia, urinary incontinence, auditory impairment, impaired oral care, caregiver burden, impaired cognitive function, depression, or a lack of social support (social isolation). CONCLUSIONS: It is believed that this study will contribute considerably to understanding the health status and needs of elderly adults in Turkey and the health problems of this population as well as to planning the development of public health and geriatric services based on regional needs. PMID- 25925802 TI - Doing good when times are bad: volunteering behaviour in economic hard times. AB - This paper examines how the 2008-9 recession has affected volunteering behaviours in the UK. Using a large survey dataset, we assess the recession effects on both formal volunteering and informal helping behaviours. Whilst both formal volunteering and informal helping have been in decline in the UK since 2008, the size of the decline is significantly larger for informal helping than for formal volunteering. The decline is more salient in regions that experienced a higher level of unemployment during the recession and also in socially and economically disadvantaged communities. However, we find that a growing number of people who personally experienced financial insecurity and hardship do not explain the decline. We argue that the decline has more to do with community-level factors such as civic organizational infrastructure and cultural norms of trust and engagement than personal experiences of economic hardship. PMID- 25925801 TI - Six-month outcomes of a Web-based intervention for users of amphetamine-type stimulants: randomized controlled trial. AB - BACKGROUND: The use of amphetamine-type stimulants (ATS) places a large burden on health services. OBJECTIVE: The aim was to evaluate the effectiveness of a self guided Web-based intervention ("breakingtheice") for ATS users over 6 months via a free-to-access site. METHODS: We conducted a randomized trial comparing a waitlist control with a fully automated intervention containing 3 modules derived from cognitive behavioral therapy and motivation enhancement. The main outcome was self-reported ATS use in the past 3 months assessed at 3- and 6-month follow ups using the Alcohol, Smoking, and Substance Involvement Screening Test (ASSIST). Secondary outcomes were help-seeking intentions (general help-seeking questionnaire), actual help seeking (actual help-seeking questionnaire), psychological distress (Kessler 10), polydrug use (ASSIST), quality of life (European Health Interview Survey), days out of role, and readiness to change. Follow-up data were evaluated using an intention-to-treat (ITT) analysis with a group by time interaction. RESULTS: We randomized 160 people (intervention: n=81; control: n=79). At 6 months, 38 of 81 (47%) intervention and 41 of 79 (52%) control participants provided data. ATS scores significantly declined for both groups, but the interaction effect was not significant. There were significant ITT time by group interactions for actual help seeking (rate ratio [RR] 2.16; d=0.45) and help-seeking intentions (RR 1.17; d=0.32), with help seeking increasing for the intervention group and declining for the control group. There were also significant interactions for days completely (RR 0.50) and partially (RR 0.74) out of role favoring the intervention group. However, 37% (30/81) of the intervention group did not complete even 1 module. CONCLUSIONS: This self guided Web-based intervention encouraged help seeking associated with ATS use and reduced days out of role, but it did not reduce ATS use. Thus, this program provides a means of engaging with some sections of a difficult-to-reach group to encourage treatment, but a substantial minority remained disengaged. TRIAL REGISTRATION: Australian and New Zealand Clinical Trials Registry: ACTRN12611000947909; https://www.anzctr.org.au/Trial/Registration/TrialReview.aspx?id=343307 (Archived by WebCite at http://www.webcitation.org/6Y0PGGp8q). PMID- 25925803 TI - Stereoselective synthesis of glycosides using (salen)Co catalysts as promoters. AB - The use of (salen)Co catalysts as a new class of bench-stable stereoselective glycosylation promoters of trichloroacetimidate glycosyl donors at room temperature is described. The conditions are practical and do not require the use of molecular sieves with products being isolated in good to high yields. PMID- 25925804 TI - A type I interferon signature characterizes chronic antibody-mediated rejection in kidney transplantation. AB - Chronic antibody-mediated rejection (CAMR) represents the main cause of kidney graft loss. To uncover the molecular mechanisms underlying this condition, we characterized the molecular signature of peripheral blood mononuclear cells (PBMCs) and, separately, of CD4(+) T lymphocytes isolated from CAMR patients, compared to kidney transplant recipients with normal graft function and histology. We enrolled 29 patients with biopsy-proven CAMR, 29 stable transplant recipients (controls), and 8 transplant recipients with clinical and histological evidence of interstitial fibrosis/tubular atrophy. Messenger RNA and microRNA profiling of PBMCs and CD4(+) T lymphocytes was performed using Agilent microarrays in eight randomly selected patients per group from CAMR and control subjects. Results were evaluated statistically and by functional pathway analysis (Ingenuity Pathway Analysis) and validated in the remaining subjects. In PBMCs, 45 genes were differentially expressed between the two groups, most of which were up-regulated in CAMR and were involved in type I interferon signalling. In the same patients, 16 microRNAs were down-regulated in CAMR subjects compared to controls: four were predicted modulators of six mRNAs identified in the transcriptional analysis. In silico functional analysis supported the involvement of type I interferon signalling. To further confirm this result, we investigated the transcriptomic profiles of CD4(+) T lymphocytes in an independent group of patients, observing that the activation of type I interferon signalling was a specific hallmark of CAMR. In addition, in CAMR patients, we detected a reduction of circulating BDCA2(+) dendritic cells, the natural type I interferon-producing cells, and their recruitment into the graft along with increased expression of MXA, a type I interferon-induced protein, at the tubulointerstitial and vascular level. Finally, interferon alpha mRNA expression was significantly increased in CAMR compared to control biopsies. We conclude that type I interferon signalling may represent the molecular signature of CAMR. PMID- 25925805 TI - [IgG responses to candidate malaria vaccine antigens in the urban area of Dakar (Senegal): evolution according to age and parasitemia in patients with mild symptoms]. AB - Malaria remains a major problem in African countries despite substantial decreases in morbidity and mortality due to sustained control programs. Studies for the evaluation of qualitative or quantitative Ab responses to key targets of anti-plasmodium immunity were mostly done in rural endemic setting compared to urban area. In a cohort of 200 patients with mild malaria and living in Dakar, we analyze total and subclasses IgG responses to a panel of P. falciparum blood stage antigens: MSP1p19, MSP3, EB200, GST-5 and R23. A mean age of 15 yrs (4 to 56 yrs) and parasitemia between 0.1 to 17% were found. Levels of IgG anti-MSP3 were higher in patients with low parasitemia (<=1%) and appear negatively correlated to parasite densities (Rho =. 0.54; p= 0.021). This correlation is more significant in children (<= 15 yrs). In addition, an increase of IgG responses against MSP1p19 is highly observed in adults having a parasitemia less than 1%. In those patients, we find that IgG1 subclasses were predominant (p <0.01). Our study shows an association between Ab responses and parasitemia. This association is dependant to IgG anti-MSP3 in children and IgG anti-MSP1p19 in adults living in urban area. PMID- 25925806 TI - [Severe hemorrhagic form of Rift Valley Fever in Mauritania]. AB - We report three severe cases of hemorrhagic form of Rift Valley Fever which have been observed in the Hospital of Aioun (two cases) and in the regional hospital of Tidjikdja (one case). The disease manifested itself by an infectious syndrome, an early infectious syndrome (on the second day) with onset of hemorrhagic complications and disorder of consciousness ranging from an agitation to deep coma. The biological examinations showed a severe anemia. Multiple organ failures were also observed. Of the three patients treated one died. Therefore, the management of both suspected and confirmed cases must be initiated as soon as possible in order to control organ damages and prevent fatality. There is no specific treatment. The importance of the epidemiological survey must be emphasized to avoid outbreaks and control any epidemic due to this virus. PMID- 25925807 TI - [Comparison of the effectiveness of artemether and quinine for treatment of severe malaria in children, Bangui, Central African Republic]. AB - The management of severe malaria is a major challenge in the health care services in sub-Saharan Africa. This study aimed to assess the efficacy and safety of artemether and quinine in severe malaria at Complexe pediatrique of Bangui, Central African Republic. A total of 212 children among 1125 hospital admissions (18.8%), and aged 6 to 59 months were randomly treated with artemether and quinine. Anemia (58.5%) and seizures (33.5%) were the major syndromes observed. On the third day of follow up, a regression of clinical signs and parasite clearance were observed in 98.1% of children treated with artemether and 97.1% of children treated with quinine. The death rate was 2.3% due to anemic and neurological forms. These findings show that the artemether and quinine have similar efficacy. Hence, associated with adequate intensive health care, the use of these antimalarial drugs can significantly reduce mortality from severe malaria in the Central African Republic. PMID- 25925808 TI - [Study of morbidity and Plasmodium species in the several geographic-climatic areas of Mauritania]. AB - We studied the proportion of malaria-infected patients among febrile outpatients in nine health centres selected in relation to their geo-climatic location and the level of malaria transmission in order to establish a reliable database on malaria-associated morbidity and Plasmodium species in three epidemiological strata in Mauritania. Blood samples were collected from a total of 7368 febrile individuals (1603 in sahelian zone, 3023 in sahelian-saharan transition zone, and 2742 in Saharan zone) to examine thin and thick blood smears between August 2010 and July 2011. The proportion of malaria-infected patients was 9.1% (672/7368). Depending on the season, the proportion varied from 16.3% (494/3021), 5.5% (157/2850), to 1.4% (21/1497) during the humid season (July-October), cool dry season (December-March), and hot dry season (April-June), respectively. Febrile patients in the sahelian-Saharan transition zone were most affected by malaria, with 65.6% (441/672) smear-positive cases. P. vivax occurred most frequently (61.6%, 414/672). P. falciparum, P. ovale, and P. malariae accounted for 32.4% (218/672), 5.2% (35/672), and 0.8% (5/672) of smear-positive cases, respectively. These data may contribute to improving our knowledge on malaria in Mauritania, which may in turn help develop control strategies and improved monitoring in each geo-climatic zone. PMID- 25925809 TI - [Retrospective study of cutaneous leishmaniasis in the district hospital of Am Timan, Chad]. AB - Cutaneous leishmaniasis is not included in the statistical yearbook of Health of the Ministry of Public Health. The aim of our study was to describe the epidemiological profile of cases of cutaneous leishmaniasis attended at the District Hospital of Am Timan in order to assess the importance and the prevalence of this neglected disease. This is a retrospective study of cases reported in the records of the Laboratory of the Hospital District of Am Timan between January 2008 and December 2012. It allowed the identification of 680 clinical cases. Direct microscopic diagnosis was positive in 580 cases (85%). The number of cases has been increasing from 2008 to 2010 (2008 = 80 cases, 123 cases in 2009; 2010 = 198 cases) before decreasing during the following year (2011 = 137 cases and in 2012 = 42 cases). The months of strong incidence of the cases were June, July, August and September. The M/F sex-ratio was 1.7. PMID- 25925810 TI - [Effect of a large scale community-based distribution of artemether-lumefantrine on its therapeutic efficacy among children living in a rural area of Burkina Faso]. AB - This study aimed to assess the effect of an integrated community case management of malaria and pneumonia programme (iCCMmp) on the efficacy of artemether lumefantrine (AL). Thus, we carried out two open label and unique centre clinical trials, before and after the iCCMmp, on the therapeutic efficacy of AL. A total of 210 children aged 6-59 months, were included in the study, 105 before and 105 after the iCCMmp. The adequate clinical and parasitological response was 90.5% and 86.7% respectively before and after the iCCMmp (p value = 0.516). Our findings reported no effect of iCCMmp on the therapeutic efficacy of the AL. PMID- 25925811 TI - [Histological aspect of urinary schistosomiasis in Togo: results of a cohort of 192 cases]. AB - The high prevalence of urinary schistosomiasis in Togo and its late management often lead to sequels. This study takes stock of these cancerous and non cancerous lesions observed on histological pieces in the pathology laboratory of the Teaching Hospital of Lome in 10 years. We find 28.1 % of malignant tumor lesions, dominated by urothelial carcinoma. PMID- 25925812 TI - A retrospective study on imported malaria in Jordan. 2. Malaria among non military Jordanians. AB - Cases of imported malaria among civilian Jordanians returning from Asian and African countries from 1991-2011 are documented. A total of 511 cases of imported malaria were diagnosed among civilian Jordanians travelling abroad. Majority of cases were reported among adults over 21 year old accounting for or 87,67% of the total number of cases. Eighteen different categories of occupation were identified, where as students studying abroad showed the highest infection rate (33.2%), especially those returning from India (n=70). Infection among males was as high as 91.78%, compared to 8.22% in females. Females were mostly housewives accompanying their spouses. Cases were reported from 34 Asian and African countries.Most cases were reported among Jordanians returning from Pakistan (23.68%), Yemen (18.6%), India (18.4%) and Sudan (5.1%). The majority of infections were due to Plasmodium vivax (n=370, 72.4%), followed by Plasmodium falciparum (n=138, 27%). Only one case of Plasmodium malariae was observed. Few cases (n=3, 0.65%) of mixed infection with P. vivax and P. falciparum were reported. Sudan was the main source of P. falciparum (25.4%) followed by Yemen (20.3%), while Pakistan was the main source of P. vivax (28.9%) followed by India (22.7%). Most mixed infection cases were acquired in Sudan (66.7%). PMID- 25925813 TI - [Study of phlebotomines sand fly wildlife suburban location of Bamako (Mali) presence of Phlebotomus (Phlebotomus) duboscqi]. AB - During three months of sampling, one thousand nine hundred and thirty five sand flies belonging to thirteen species of Phlebotomine sandflies were collected in suburban location of Bamako. Phlebotomus duboscqi, which is the common vector of cutaneous leishmaniasis in Mali, was found for the first time in Bamako mostly within human houses, which can confirm the possibility of a local transmission of Leishmania major. Sergentomyia freetownensis was found for the first time in Mali, which raises to 15 the number of sand flies species identified in Mali. PMID- 25925814 TI - [Socio-cultural aspects of epilepsy in a rural community in northern Benin in 2011]. AB - Despite the development of knowledge in diagnosis and therapeutic of epilepsy it remains to be cause of rejection and stigma. We aimed to study the knowledge, attitude and practice toward epilepsy and the stigma in a rural community. The cross-sectional study was carried out from 1st to 31st March 2011 in a rural community (Tourou) at Parakou in the northern Benin. It was a door-to-door survey and included 1 031 adults older than 15 years. The diagnosis of epilepsy was based on International League Against Epilepsy. The specific questionnaire was used and comprised 16 items which explored knowledge, attitude and practice toward epilepsy. Another questionnaire was developed to study stigma among epileptics. The associated factors to the misconception toward epilepsy have been studied. All adults have heard about epilepsy and knew the generalized tonic clonic form of epilepsy and knew someone with epilepsy. Hereditary (98%) and witchcraft (97.9%) and social problems (65.9%) were mentioned as the most cause of epilepsy. Epilepsy was cited as contagious disease by 90.6% of respondents and the associated factors were the sex (p=0.005) and occupational status (0.024). The saliva (98.1%) and witness of the place of seizure (97.8%) were the frequently mentioned modes of transmission. 65% of all mentioned that epileptics can not get marriage and the main associated factors to this belief were the advanced age (p=0.008) and occupational status (0.004). 64.4% believed that children with epilepsy shouldn't be attend to school, age (0.004), ethnicity (0.047) and occupational status were the associated factors with this misconception. Despite 99.4% considered epilepsy as treatable disease only 12.7% would have referred epileptics to the hospital. All the seven epileptics considered themselves as victims of stigma and rejected by their family and the community. The misconceptions associated to the epilepsy can explain the stigma and the therapeutic gap in this rural community. PMID- 25925815 TI - [Poisoning with Jatropha curcas: 24 cases reported to Paris and Marseille Poisons Centers]. AB - Jatropha curcas L. is an inedible plant belonging to the Euphorbiaceae family that is growing in subtropical zones of all continents. We report a series of 24 cases of poisoning with J. curcas seeds or fruits reported to poison centers in Paris and Marseille between December 2000 and June 2014. Fifteen adults and 9 children ingested J. curcas seeds or fruits. All patients experienced gastrointestinal disorders, within the first hours following ingestion: nausea, vomiting, diarrhea and abdominal pain. Laboratory investigations performed in 10 patients revealed minor abnormalities: CK elevation (8 cases), dehydration (5 cases) with moderate elevation of serum creatinine levels (3 cases), and mildly increased serum bilirubin (8 cases). Complete remission of all clinical signs was observed within 48 hours in the 20 cases for which the outcome was known. Previously published cases of J. curcas poisoning were very similar to ours: As in our series, gastrointestinal disorders were always present. They were sometimes associated with neurological or cardiovascular signs, and hepatic or renal disorders; these were generally interpreted as complications of severe gastroenteritis, although direct toxic effects could not be formally excluded. In most cases, simple supportive measures were sufficient to ensure complete recovery within 24-48 hours. J Curcas poisoning incidence is certainly increasing because the plant is cultivated to produce biodiesel and is now largely present in most subtropical countries. As a consequence, local health professionals should be informed of the toxic properties of this plant. PMID- 25925816 TI - Determination of enantiomeric excess in amine derivatives with molecular self assemblies. AB - We report the first fluorescence-based assay for the rapid determination of the ee value of amines, amino alcohols, and amino acid esters. The method uses the self-assembly of 2-formylphenylboronic acid with a chiral diol and a chiral amine or derivatives (of unknown chirality) to produce two diastereomeric iminoboronates that differ in their fluorescence intensity and polarization. The approach allows for the accurate determination of the ee value of chiral amines with errors of just 1-2%. We believe that this application of orthogonal dynamic covalent self-assembly in the determination of the enantioselectivity will lead to the development of high-throughput procedures for the determination of chirality. PMID- 25925817 TI - Improving the Thermochemical Energy Storage Performance of the Mn2 O3 /Mn3 O4 Redox Couple by the Incorporation of Iron. AB - Redox cycles of manganese oxides (Mn2 O3 /Mn3 O4 ) are a promising alternative for thermochemical heat storage systems coupled to concentrated solar power plants as manganese oxides are abundant and inexpensive materials. Although their cyclability for such a purpose has been proved, sintering processes, related to the high-temperature conditions at which charge-discharge cycles are performed, generally cause a cycle-to-cycle decrease in the oxidation rate of Mn3 O4 . To guarantee proper operation, both reactions should present stable reaction rates. In this study, it has been demonstrated that the incorporation of Fe, which is also an abundant material, into the manganese oxides improves the redox performance of this system by increasing the heat storage density, narrowing the redox thermal hysteresis, and, above all, stabilizing and enhancing the oxidation rate over long-term operation, which counteracts the negative effects caused by sintering, although its presence is not avoided. PMID- 25925818 TI - The Global Forum for Home Hemodialysis: a new open-source practical manual. AB - Encouraging clinical outcomes from observational and randomized controlled data in the forms of frequent hemodialysis (HD) has renewed interest in home HD. However, given its benefits, home HD is relatively underutilized throughout the world. The Global Forum for Home Hemodialysis, an independent panel comprised of internationally recognized nephrologists, home HD nurses, administrators, patient advocates, and a long-time home HD patient, has convened with the intention of creating an open-source, comprehensive, practical manual that provides useful information to clinicians who are interested in implementing home HD. PMID- 25925819 TI - Prescriptions for home hemodialysis. AB - Prescribing a regimen that provides "optimal dialysis" to patients who wish to dialyze at home is of major importance, yet there is substantial variation in how home hemodialysis (HD) is prescribed. Geographic location, patient health status and clinical goals, and patient lifestyle and preferences all influence the selection of a prescription for a particular patient-there is no single prescription that provides optimal therapy for all patients, and careful weighing of potential benefit and burden is required for long-term success. This article describes how home HD prescribing patterns have changed over time and provides examples of commonly used home HD prescriptions. In addition, associated clinical outcomes and adequacy parameters as well as criteria for identifying which patients may benefit most from these diverse prescriptions are also presented. PMID- 25925820 TI - Psychosocial aspects in home hemodialysis: a review. AB - Psychosocial aspects related to home hemodialysis (HD) play an important role in the success of home HD programs. Once patients commence HD at home, unique psychosocial issues related to patient and care partner burden can emerge. Proactive professional support, peer support, respite care, travel support, and financial support from the home HD health care team must be a priority for patient care. If the psychosocial aspects are not proactively addressed, patients receiving HD at home may return to in-center HD and the program may struggle as a result. This review provides a psychosocial guide for new start-up home HD programs. PMID- 25925821 TI - Funding and planning: what you need to know for starting or expanding a home hemodialysis program. AB - Planning and funding a home hemodialysis (HD) program requires a well-organized effort and close collaboration between clinicians and administrators. This resource provides guidance on the processes that are involved, including a thorough situational analysis of the dialysis landscape, emphasizing the opportunity for a home HD program; careful consideration of the clinical and operational characteristics of a proposed home HD program at your institution; the development of a compelling business case, highlighting the clinical and organizational benefits of a home HD program; and careful construction and evaluation of a request for proposal. PMID- 25925822 TI - Home hemodialysis needs you! AB - This special supplement of Hemodialysis International focuses on home hemodialysis (HD). It has been compiled by a group of international experts in home HD who were brought together throughout 2013-2014 to construct a home HD "manual." Drawing upon both the literature and their own extensive expertise, these experts have helped develop this supplement that now stands as an A-to-Z guide for any who may be unfamiliar or uncertain about how to establish and maintain a successful home HD program. PMID- 25925823 TI - Workforce development and models of care in home hemodialysis. AB - Creating and maintaining a successful home hemodialysis (HD) program is highly dependent on the workforce model and quality of staff. We describe the minimum staff required to start a home HD program (e.g., a clinical champion and lead nurse) and detail what additional workforce (e.g., renal technician, dietitian, psychologist, and others) may be necessary as the program evolves and expands. The goal of the program and allied staff should be to provide a seamless patient journey, a process that requires consideration of a patient recruitment strategy, a patient training pathway, thoughtful initiation of home HD, and development of support systems for routine care and emergencies at home. This module describes how care models are implemented at centers of excellence in various locations around the world, highlights the importance of an integrated care pathway, and describes workforce challenges that programs may encounter. PMID- 25925824 TI - Systems to cultivate suitable patients for home dialysis. AB - The key to developing, initiating, and maintaining a strong home dialysis program is a fundamental commitment by the entire team to identify and cultivate patients who are suitable candidates to perform home dialysis. This process must start as early as possible in the disease trajectory, and must include a passionate and daily focus by physicians, nurses, social workers, and other members of the multidisciplinary team. This effort must be constant and sustained over months, with active promotion of home dialysis for suitable patients at every opportunity. Cultivation of suitable patients must become a defining and overarching mission for the entire program. This article reviews some of the components involved in this worthwhile effort and provides practical tips and links to resources. PMID- 25925825 TI - Patient safety in home hemodialysis: quality assurance and serious adverse events in the home setting. AB - Interest in home hemodialysis (HD) is high because of the reported benefits and its excellent safety record. However, the potential for serious adverse events (AEs) exists when patients perform HD in their homes without supervision. We review the epidemiology of dialysis-related emergencies during home HD, and present a conceptual and practical framework for the prevention and management of serious AEs for those patients performing home HD. In addition, we describe a formal monitored and iterative quality assurance program, and make suggestions for the future development of safety strategies to mitigate the risk of AEs in home HD. PMID- 25925826 TI - Patient selection and training for home hemodialysis. AB - Patient selection and training is arguably the most important step toward building a successful home hemodialysis (HD) program. We present a step-by-step account of home HD training to guide providers who are developing home HD programs. Although home HD training is an important step in allowing patients to undergo dialysis in the home, there is a surprising lack of systematic research in this field. Innovations and research in this area will be pivotal in further promoting a higher acceptance rate of home HD as the renal replacement therapy of choice. PMID- 25925827 TI - The home hemodialysis hub: physical infrastructure and integrated governance structure. AB - An effective home hemodialysis program critically depends on adequate hub facilities and support functions and on transparent and accountable organizational processes. The likelihood of optimal service delivery and patient care will be enhanced by fit-for-purpose facilities and implementation of a well considered governance structure. In this article, we describe the required accommodation and infrastructure for a home hemodialysis program and a generic organizational structure that will support both patient-facing clinical activities and business processes. PMID- 25925828 TI - The care and keeping of vascular access for home hemodialysis patients. AB - Creating and maintaining a healthy vascular access is a critical factor in successful home hemodialysis (HD). This article aims to serve as a "how-to manual" regarding vascular access issues for both patients and health-care providers in a home HD program. This document outlines cannulation options for patients with arteriovenous access and describes troubleshooting techniques for potential complications; strategies are suggested to help patients overcome fear of cannulation and address problems associated with difficult cannulation. Technical aspects of central venous catheter care, as well as a guide to troubleshooting catheter complications, are covered in detail. Monitoring for access-related complications of stenosis, infection, and thrombosis is a key part of every home HD program. Key performance and quality indicators are important mechanisms to ensure patient safety in home HD and should be used during routine clinic visits. PMID- 25925829 TI - Home hemodialysis: infrastructure, water, and machines in the home. AB - We describe the infrastructure that is necessary for hemodialysis in the home focusing on physical requirements, the organization of plumbing and water, and the key features that should guide the selection of machines that are suitable for home use. PMID- 25925830 TI - Ethnobotanical study on medicinal plants used by Maonan people in China. AB - BACKGROUND: This paper is based on an ethnobotanical investigation that focused on the traditional medicinal plants used by local Maonan people to treat human diseases in Maonan concentration regions. The Maonan people have relied on traditional medicine since ancient times, especially medicinal plants. The aim of this study is to document medicinal plants used by the Maonans and to report the status of medicinal plants and associated traditional knowledge. METHODS: Ethnobotanical data were collected from June 2012 to September 2014 in Huanjiang Maonan Autonomous County, northern Guangxi, southwest China. In total, 118 knowledgeable informants were interviewed. Following statistically sampling method, eighteen villages from 5 townships were selected to conduct field investigations. Information was collected through the approache of participatory observation, semi-structured interviews, ranking exercises, key informant interviews, focus group discussions, and participatory rural appraisals. RESULTS: A total of 368 medicinal plant species were investigated and documented together with their medicinal uses by the Maonans, most of which were obtained from the wild ecosystems. The plants were used to treat 95 human diseases. Grinding was a widely used method to prepare traditional herbal medicines. There were significant relationships between gender and age, and between gender and informants' knowledge of medicinal plant use. Deforestation for agricultural purposes was identified as the most destructive factor of medicinal plants, followed by drought and over-harvest. CONCLUSIONS: The species diversity of medicinal plants used by the Maonans in the study area was very rich. Medicinal plants played a significant role in healing various human disorders in the Maonan communities. However, the conflicts between traditional inheriting system and recent socio-economic changes (and other factors) resulted in the reduction or loss of both medicinal plants and associated indigenous knowledge. Thus, conservation efforts and policies, and innovation of inheriting system are necessary for protecting the medicinal plants and associated indigenous knowledge. Awareness is also needed to be raised among local Maonans focusing on sustainable utilization and management of both medicinal plants and traditional knowledge. PMID- 25925831 TI - Recommendation to include a textile dye mix in the European baseline series. AB - BACKGROUND: Disperse dyes are common sensitizers, but are not currently included in the European baseline series. OBJECTIVES: To justify the inclusion of a textile dye mix in the European baseline patch test series. METHODS: A survey of the reported frequencies of contact allergy to textile dyes and textile dye mixes was performed by searching PubMed (http://www.ncbi.nlm.gov.ludwig.lub.lu.se/pubmed, last accessed 14 December 2014). The results from a multicentre study performed within the European Environmental Contact Dermatitis Research Group (EECDRG) and published in 2014 formed the final basis for the recommendation. RESULTS: The EECDRG study performed in Europe and the United States showed that 2.1-6.9% of consecutively tested dermatitis patients reacted to a 6.6% wt/wt textile dye mix consisting of eight disperse dyes. The clinical relevance was ascertained in >30% of the positive cases. A high frequency of simultaneous sensitivity to Disperse Orange 3 (DO 3) and p-phenylenediamine (PPD) was seen. Active sensitization to the mix was not noted. CONCLUSIONS: It is recommended to include a 6.6% textile dye mix consisting of eight disperse dyes in the European baseline series, even though one component, DO 3, may be superfluous, owing to its frequent cross-reactivity with PPD. Removal of DO 3 from the mix would need further study. PMID- 25925832 TI - Association of Pneumococcal Carriage and Expression of Foxp3+ Regulatory T Cells and Th17 Cells in the Adenoids of Children. AB - BACKGROUND: Pneumococcal carriage in the nasopharynx is a primary means of transmission and a necessary prerequisite for pneumococcal disease. OBJECTIVES: We analyzed the relationship between expressions of Foxp3+ regulatory T (Treg) cells and Th17 cells, and pneumococcal carriage in the adenoids of children who were either positive or negative for pneumococci. METHODS: We collected adenoidal tissue and nasopharyngeal swab samples from children undergoing an adenoidectomy. Adenoidal mononuclear cells were isolated, cultured and then stimulated with culture concentrated supernatant (CCS) obtained from a D39 bacterial strain. RESULTS: Foxp3+ Treg cells were upregulated and Th17 cells were downregulated in populations of adenoidal mononuclear cells obtained from the pneumococcus positive group. Following CCS stimulation, the increment in Foxp3+ Treg cells in the pneumococcus-positive group was significantly greater than that in the pneumococcus-negative group, while the increment in Th17 cells was less as compared to that in the pneumococcus-negative group. These results were consistent with variations in levels of Foxp3 mRNA and retinoic acid receptor related orphan receptor-gammat mRNA in adenoidal mononuclear cells. Levels of IL 17A and IL-6 in adenoid tissue were higher in the pneumococcus-negative group, and the levels of TGF-beta in adenoid tissue were lower in the pneumococcus negative group compared to the pneumococcus-positive group. Pneumococcal carriage in children was closely associated with the expressions of Foxp3+ Treg and Th17 cells in the adenoid. CONCLUSION: Upregulation of Foxp3+ Treg cells might downregulate the production of Th17 cells in the adenoid, resulting in decreased scavenging of Streptococcus pneumoniae and chronic pneumococcal carriage. PMID- 25925833 TI - The Effect of CAPE-V Sentences on Cepstral/Spectral Acoustic Measures in Dysphonic Speakers. AB - OBJECTIVE: To investigate the effect of connected speech stimuli from the Consensus Auditory-Perceptual Evaluation of Voice (CAPE-V) on cepstral/spectral acoustic measurements. PATIENTS AND METHODS: Recordings from 20 participants seeking treatment for dysphonia were analyzed in this study. The participants read the 6 sentence stimuli from the CAPE-V at a comfortable pitch and loudness. Acoustic measures of cepstral peak prominence (CPP) and its standard deviation, the low-to-high spectral ratio and its standard deviation (LH and LHsd) and the multiparametric measure Cepstral Spectral Index of Dysphonia were acquired from each sentence recording and applied to analyses. RESULTS: A significant main effect for sentence type was present on the measurements of CPP, LH and LHsd. Post hoc pairwise comparisons revealed the most robust effect on CPP from the all voiced sentence 'We were away a year ago'. For the measures of LH and LHsd, sentence effects were significant for the majority of comparisons. CONCLUSION: The connected speech stimuli from the CAPE-V affected cepstral/spectral acoustic measurements differentially. These findings support the rationale for using the various CAPE-V stimuli during clinical assessment, and indicate the need for further investigations to inform clinical practice. PMID- 25925834 TI - Cellulitis in Obesity: Adverse Outcomes Affected by Increases in Body Mass Index. AB - PURPOSE: Cellulitis in obese patients is associated with increased rates of treatment failure compared to those with normal body mass index (BMI); however, patients have not been extensively studied in the outpatient environment or stratified based on range of obesity and associated risk factors. This study looked at antibiotic dosing and treatment failure in the obese population from the primary care perspective and accounts for BMI range, weight, comorbid diabetes, and tobacco use. METHODS: This study was a retrospective chart review of 637 adult primary care patients designed to evaluate rates of treatment failure of outpatient cellulitis among patients of varying BMI. Treatment failure was defined as (a) hospital admission for intravenous antibiotics, (b) prolonged antibiotic course, or (c) requiring a different antibiotic after initial course. RESULTS: Adverse outcomes were not statistically significant between normal BMI and those with BMI >=40 kg/m(2). A subset of patients with a BMI >=50 kg/m(2) was noted to have approximately twice the rate of adverse outcomes as the normal BMI group. While controlling for age, gender, race, diagnosis of diabetes mellitus, and tobacco use, a BMI of >=50 kg/m(2) and a weight >=120 kg was associated with adverse outcomes with an odds ratio of 2.440 (95% CI, 1.260-4.724; P = .008) and 2.246 (95% CI, 1.154-4.369; P = .017), respectively. CONCLUSIONS: Patients with cellulitis weighing >120kg or with a BMI >=50 kg/m(2) were at greatest risk for treatment failure in the outpatient setting, even when controlling for comorbid diabetes and tobacco use. As morbid obesity continues to become more prevalent, it becomes imperative that primary care physicians have better antibiotic dosing guidelines to account for the physiologic effects of obesity to minimize the risk of increased morbidity, health care costs, and antibiotic resistance. PMID- 25925835 TI - Survival, differentiation, and neuroprotective mechanisms of human stem cells complexed with neurotrophin-3-releasing pharmacologically active microcarriers in an ex vivo model of Parkinson's disease. AB - Stem cell-based regenerative therapies hold great potential for the treatment of degenerative disorders such as Parkinson's disease (PD). We recently reported the repair and functional recovery after treatment with human marrow-isolated adult multilineage inducible (MIAMI) cells adhered to neurotrophin-3 (NT3) releasing pharmacologically active microcarriers (PAMs) in hemiparkinsonian rats. In order to comprehend this effect, the goal of the present work was to elucidate the survival, differentiation, and neuroprotective mechanisms of MIAMI cells and human neural stem cells (NSCs), both adhering to NT3-releasing PAMs in an ex vivo organotypic model of nigrostriatal degeneration made from brain sagittal slices. It was shown that PAMs led to a marked increase in MIAMI cell survival and neuronal differentiation when releasing NT3. A significant neuroprotective effect of MIAMI cells adhering to PAMs was also demonstrated. NSCs barely had a neuroprotective effect and differentiated mostly into dopaminergic neuronal cells when adhering to PAM-NT3. Moreover, those cells were able to release dopamine in a sufficient amount to induce a return to baseline levels. Reverse transcription quantitative polymerase chain reaction and enzyme-linked immunosorbent assay analyses identified vascular endothelial growth factor (VEGF) and stanniocalcin-1 as potential mediators of the neuroprotective effect of MIAMI cells and NSCs, respectively. It was also shown that VEGF locally stimulated tissue vascularization, which might improve graft survival, without excluding a direct neuroprotective effect of VEGF on dopaminergic neurons. These results indicate a prospective interest of human NSC/PAM and MIAMI cell/PAM complexes in tissue engineering for PD. SIGNIFICANCE: Stem cell-based regenerative therapies hold great potential for the treatment of degenerative disorders such as Parkinson's disease (PD). The present work elucidates and compares the survival, differentiation, and neuroprotective mechanisms of marrow-isolated adult multilineage inducible cells and human neural stem cells both adhered to neurotrophin-3-releasing pharmacologically active microcarriers in an ex vivo organotypic model of PD made from brain sagittal slices. PMID- 25925836 TI - Phosphodiesterase 7 inhibition induces dopaminergic neurogenesis in hemiparkinsonian rats. AB - Parkinson's disease is characterized by a loss of dopaminergic neurons in a specific brain region, the ventral midbrain. Parkinson's disease is diagnosed when approximately 50% of the dopaminergic neurons of the substantia nigra pars compacta (SNpc) have degenerated and the others are already affected by the disease. Thus, it is conceivable that all therapeutic strategies, aimed at neuroprotection, start too late. Therefore, an urgent medical need exists to discover new pharmacological targets and novel drugs with disease-modifying properties. In this regard, modulation of endogenous adult neurogenesis toward a dopaminergic phenotype might provide a new strategy to target Parkinson's disease by partially ameliorating the dopaminergic cell loss that occurs in this disorder. We have previously shown that a phosphodiesterase 7 (PDE7) inhibitor, S14, exerts potent neuroprotective and anti-inflammatory effects in different rodent models of Parkinson's disease, indicating that this compound could represent a novel therapeutic agent to stop the dopaminergic cell loss that occurs during the progression of the disease. In this report we show that, in addition to its neuroprotective effect, the PDE7 inhibitor S14 is also able to induce endogenous neuroregenerative processes toward a dopaminergic phenotype. We describe a population of actively dividing cells that give rise to new neurons in the SNpc of hemiparkinsonian rats after treatment with S14. In conclusion, our data identify S14 as a novel regulator of dopaminergic neuron generation. SIGNIFICANCE: Parkinson's disease is a neurodegenerative disorder characterized by the loss of dopaminergic neurons in the ventral midbrain. Currently, no cure and no effective disease-modifying therapy are available for Parkinson's disease; therefore, an urgent medical need exists to discover new pharmacological targets and novel drugs for the treatment of this disorder. The present study reports that an inhibitor of the enzyme phosphodiesterase 7 (S14) induces proliferation in vitro and in vivo of neural stem cells, promoting its differentiation toward a dopaminergic phenotype and therefore enhancing dopaminergic neuron generation. Because this drug is also able to confer neuroprotection of these cells in animal models of Parkinson's disease, S14 holds great promise as a therapeutic new strategy for this disorder. PMID- 25925837 TI - Freshly thawed and continuously cultured human bone marrow-derived mesenchymal stromal cells comparably ameliorate allergic airways inflammation in immunocompetent mice. AB - Recent data suggest that freshly thawed previously frozen mesenchymal stromal cells (MSCs) may not have the same effectiveness or breadth of anti-inflammatory activities as do continuously cultured MSCs. This has significant implications for clinical use, in which many infusion schemes use frozen cells thawed at the bedside for administration. The available data, however, predominantly evaluate in vitro MSC properties, and so far there has been limited in vivo analysis. To further assess this issue, we compared freshly thawed (thawed) versus continuously cultured (fresh) human bone marrow-derived MSC (hMSC) administration in a mouse model of mixed Th2/Th17 allergic airway inflammation induced by Aspergillus hyphal extract (AHE) exposures in immunocompetent C57Bl/6 mice. Control cell populations included fresh versus thawed murine bone marrow-derived MSCs (mMSCs) and human lung fibroblasts (HLFs). Systemic administration of both thawed and fresh hMSCs and mMSCs, but not HLFs, at the onset of antigen challenge in previously sensitized mice significantly ameliorated the AHE-provoked increases in airway hyper-reactivity, lung inflammation, and antigen-specific CD4 T-cell Th2 and Th17 phenotype. Notably, there was no difference in effects of fresh versus thawed hMSCs or mMSCs on any outcome measured except for some variability in the effects on the bronchoalveolar lavage fluid composition. These results demonstrated potent xenogeneic effects of human MSCs in an immunocompetent mouse model of allergic airways inflammation and that thawed MSCs are as effective as fresh MSCs. The question of fresh versus thawed MSC effectiveness needs to be investigated carefully and may differ in different in vivo disease-specific models. SIGNIFICANCE: This study addressed whether freshly thawed mesenchymal stromal cells (MSCs) are as effective in in vivo settings as those that have been continuously cultured. It also provided further data demonstrating that xenogeneic use of MSCs in immunocompetent mice is as effective as murine MSCs. This information provides further support and direction for potential clinical use of MSCs in patients with severe asthma. PMID- 25925838 TI - First-in-Human Case Study: Pregnancy in Women With Crohn's Perianal Fistula Treated With Adipose-Derived Stem Cells: A Safety Study. AB - The aim of this study was to determine whether treatment with adipose-derived stem cells (ASCs) had any influence on fertility, course of pregnancy, newborn weight, or physical condition of newborns. We performed a retrospective study of patients with a desire to become pregnant after having received intralesional injection of autologous ASCs for the treatment of perianal or rectovaginal fistula associated with Crohn's disease. We collected data on the resulting pregnancies, deliveries, and newborns of these patients. ASCs were expanded in vitro and characterized according to the international guidelines for cell surface markers (clusters of differentiation) and differentiated to adipocytes, chondrocytes, and osteocytes prior to implantation (except first implant in 2002). We analyzed five young women with Crohn's disease treated with ASCs: one for rectovaginal and perianal fistula, two for rectovaginal fistula only, and two for perianal fistula only. All patients received 2 doses of 20 million and 40 million cells at an interval of 3-4 months. Another patient received 2 doses of 6.6 million and 20 million ASCs with 9 months between each dose. Fertility and pregnancy outcomes were not affected by cell therapy treatment. No signs of treatment-related malformations were observed in the neonates by their respective pediatricians. In the patients studied, cell therapy with ASCs did not affect the course of pregnancy or newborn development. SIGNIFICANCE: Local treatment with mesenchymal stem cells derived from adipose tissue seems not to affect the ability to conceive, the course of pregnancy, pregnancy outcomes, or newborns' health in female patients. This is the first publication about pregnancy outcome in women with perianal fistula and Crohn's disease treated with stem cell therapy, and could be of interest for doctors working in cell therapy. This is a very important question for patients, and there was no answer for them until now. PMID- 25925839 TI - Extrinsic intestinal denervation modulates tumor development in the small intestine of Apc(Min/+) mice. AB - BACKGROUND: Innervation interacts with enteric immune responses. Chronic intestinal inflammation is associated with increased risk of colorectal cancer. We aimed to study potential extrinsic neuronal modulation of intestinal tumor development in a mouse model. METHODS: Experiments were performed with male Apc(Min/+) or wild type mice (4 weeks old, body weight approximately 20 g). Subgroups with subdiaphragmatic vagotomy (apcV/wtV), sympathetic denervation of the small intestine (apcS/wtS) or sham operated controls (apcC/wtC) were investigated (n = 6-14 per group). Three months after surgical manipulation, 10 cm of terminal ileum were excised, fixed for 48 h in 4% paraformaldehyde and all tumors were counted and their area determined in mm(2) (mean +/- standard error of the mean (SEM)). Whole mounts of the muscularis of terminal ileum and duodenum (internal positive control) were also stained for tyrosine hydroxylase to confirm successful sympathetic denervation. RESULTS: Tumor count in Apc(Min/+) mice was 62 +/- 8 (apcC), 46 +/- 11 (apcV) and 54 +/- 8 (apcS) which was increased compared to wildtype controls with 4 +/- 0.5 (wtC), 5 +/- 0.5 (wtV) and 5 +/- 0.6 (wtS; all p < 0.05). For Apc(Min/+) groups, vagotomized animals showed a trend towards decreased tumor counts compared to sham operated Apc(Min/+) controls while sympathetic denervation was similar to sham Apc(Min/+). Area covered by tumors in Apc(Min/+) mice was 55 +/- 10 (apcC), 31 +/- 8 (apcV) and 42 +/- 8 (apcS) mm(2), which was generally increased compared to wildtype controls with 7 +/- 0.6 (wtC), 7 +/- 0.4 (wtV) and 7 +/- 0.6 (wtS) mm(2) (all p < 0.05). In Apc(Min/+) groups, tumor area was decreased in vagotomized animals compared to sham operated controls (p < 0.05) while sympathetically denervated mice showed a minor trend to decreased tumor area compared to controls. CONCLUSIONS: Extrinsic innervation of the small bowel is likely to modulate tumor development in Apc(Min/+) mice. Interrupted vagal innervation, but not sympathetic denervation, seems to inhibit tumor growth. PMID- 25925840 TI - Ex Vivo Expansion and Differentiation of Human and Mouse Fetal Pancreatic Progenitors Are Modulated by Epidermal Growth Factor. AB - A comparative analysis of mouse and human pancreatic development may reveal common mechanisms that control key steps as organ morphogenesis and cell proliferation and differentiation. More specifically, understanding beta cell development remains an issue, despite recent progress related to their generation from human embryonic and induced pluripotent stem cells. In this study, we use an integrated approach, including prospective isolation, organ culture, and characterization of intermediate stages, and report that cells from human and mouse fetal pancreas can be expanded in the long term and give rise to hollow duct-like structures in 3D cultures. The expanded cells express a combination of markers (E-cadherin, PDX1, NKX6-1, SOX9, and HNF1beta) that reveals pancreatic progenitor identity. Proliferation of embryonic progenitors was stimulated by the Wnt agonist R-spondin1 (RSPO1), FGF10, and EGF. This combination of growth factors allowed maintaining human fetal pancreatic progenitors in culture for many passages, a finding not reported previously. Importantly, in the absence of EGF, proliferation was reduced, while endocrine differentiation was significantly enhanced. We conclude that modulation of EGF signaling affects in vitro expansion and differentiation of progenitors from embryonic pancreas of both mice and man. PMID- 25925841 TI - Vascular coil erosion into hepaticojejunostomy following hepatic arterial embolisation. AB - BACKGROUND: Right hepatic arterial injury (RHAI) is the most common vascular injury sustained during laparoscopic cholecystectomy, occurring in up to 7% of cholecystectomies. RHAI is also the most common vascular injury associated with a bile duct injury (BDI) and is reported to occur in up to 41 - 61% of cases when routine angiography is employed following a BDI. We present an unusual case of erosion of vascular coils from a previously embolised right hepatic artery into bilio-enteric anastomoses causing biliary obstruction. This is on a background of biliary reconstruction following a major BDI. CASE PRESENTATION: A 37-year old man underwent a bile duct reconstruction following a major BDI (Strasberg-Bismuth E4 injury) sustained at laparoscopic cholecystectomy. He had two separate bilio enteric anastomoses of the right and left hepatic ducts and had a modified Terblanche Roux-en-Y access limb formed. Approximately three weeks later he was admitted for significant gastrointestinal bleeding and was hypotensive and anaemic. Selective computed tomography angiography revealed a 2 x 2 centimetre right hepatic artery pseudoaneurysm, which was urgently embolised with radiological coils. Two months later he developed intermittent fevers, rigors, jaundice, and right upper quadrant pain with evidence of intrahepatic biliary dilatation on magnetic resonance cholangiopancreatography. The degree of intrahepatic biliary dilatation progressively increased on subsequent imaging over several months, suggesting stricturing of the bilio-enteric anastomoses. Several attempts to traverse these strictures with a percutaneous transhepatic approach had failed. Then, approximately ten months after the initial BDI repair, choledochoscopy through the Terblanche access limb revealed multiple radiological coils within the bilio-enteric anastomoses, which had eroded from the previously embolised right hepatic artery. A laparotomy was performed to remove the coils, take down the existing obstructed bilio-enteric anastomoses and revise this. Following this the patient recovered uneventfully. CONCLUSION: Obstructive jaundice and cholangitis secondary to erosion of angiographically placed embolisation coils is a rarely described complication. In view of the relative frequency of arterial injury and complications following major bile duct injury, we suggest that these patients be formally assessed for associated arterial injury following a major BDI. PMID- 25925842 TI - Short-Term Safety and Plasma Concentrations of Edoxaban in Japanese Patients With Non-Valvular Atrial Fibrillation and Severe Renal Impairment. AB - BACKGROUND: The short-term safety and plasma concentrations of edoxaban 15 mg once daily in Japanese patients with non-valvular atrial fibrillation (NVAF) and severe renal impairment (SRI; creatinine clearance [CLCR] >=15 to <30 ml/min) were compared with those in NVAF patients with normal renal function or mild renal impairment (normal/MiRI; CLCR>=50 ml/min) treated with edoxaban 30 or 60 mg. METHODS AND RESULTS: In this Phase 3 multicenter open-label 3 parallel-group study, SRI patients received once-daily edoxaban 15 mg (n=50), whereas normal/MiRI patients were randomized to receive either once-daily edoxaban 30 or 60 mg (n=22 and 21, respectively) for 12 weeks. Plasma edoxaban concentrations and biomarkers of blood coagulation and fibrinolysis were measured. Adverse events and thromboembolic events were recorded throughout the study. Rates of any bleeding were comparable between SRI patients receiving edoxaban 15 mg (20.0%) and normal/MiRI patients receiving edoxaban 30 or 60 mg (22.7% and 23.8%, respectively). No major bleeding or thromboembolic events occurred in any treatment group. Similar plasma concentrations and biomarker profiles were observed in SRI patients receiving edoxaban 15 mg and normal/MiRI patients receiving edoxaban 30 or 60 mg. CONCLUSIONS: In this 12-week short-term study in Japanese NVAF patients with SRI, edoxaban 15 mg once daily exhibited similar safety, plasma concentration, and biomarker profiles as did the 30-mg and 60-mg doses in patients with normal/MiRI. PMID- 25925843 TI - Poor Prognosis in Critical Limb Ischemia Without Pre-Onset Intermittent Claudication. AB - BACKGROUND: Some patients with critical limb ischemia (CLI) lack symptoms of intermittent claudication (IC) before the onset of CLI. We studied the outcome of such patients, because this is currently unknown. METHODS AND RESULTS: For retrospective exploratory analysis, we divided 225 patients (265 limbs) with CLI into 2 groups: 142 patients (172 limbs) without a history of IC (non-IC group) and 83 patients (93 limbs) with IC (IC group). We examined comorbid factors and found that a higher proportion of patients in the non-IC group failed to undergo arterial revascularization (49% vs. 20%, P<0.0001) due to progressed limb ischemia and infection. We then analyzed 140 patients (161 limbs) with revascularization. Patients in the non-IC group were more likely to have diabetes mellitus (P=0.03), hypoalbuminemia (P=0.02), advanced Rutherford's classification (P=0.0007), worse ambulatory function (P=0.009), and longer postoperative stay (P=0.04). Amputation-free survival was lower in the non-IC group (P=0.005). On Cox regression analysis, hemodialysis (P=0.002), coronary artery disease (P=0.04), cerebrovascular disease (P=0.02), non-ambulatory status (P=0.02), and non-IC (P=0.01) were independent risk factors for lower amputation-free survival. CONCLUSIONS: Patients without IC before CLI onset have several unique features, and non-IC is an independent risk factor for poor outcome. PMID- 25925844 TI - The first Malay database toward the ethnic-specific target molecular variation. AB - BACKGROUND: The Malaysian Node of the Human Variome Project (MyHVP) is one of the eighteen official Human Variome Project (HVP) country-specific nodes. Since its inception in 9(th) October 2010, MyHVP has attracted the significant number of Malaysian clinicians and researchers to participate and contribute their data to this project. MyHVP also act as the center of coordination for genotypic and phenotypic variation studies of the Malaysian population. A specialized database was developed to store and manage the data based on genetic variations which also associated with health and disease of Malaysian ethnic groups. This ethnic specific database is called the Malaysian Node of the Human Variome Project database (MyHVPDb). FINDINGS: Currently, MyHVPDb provides only information about the genetic variations and mutations found in the Malays. In the near future, it will expand for the other Malaysian ethnics as well. The data sets are specified based on diseases or genetic mutation types which have three main subcategories: Single Nucleotide Polymorphism (SNP), Copy Number Variation (CNV) followed by the mutations which code for the common diseases among Malaysians. MyHVPDb has been open to the local researchers, academicians and students through the registration at the portal of MyHVP ( http://hvpmalaysia.kk.usm.my/mhgvc/index.php?id=register ). CONCLUSIONS: This database would be useful for clinicians and researchers who are interested in doing a study on genomics population and genetic diseases in order to obtain up-to-date and accurate information regarding the population specific variations and also useful for those in countries with similar ethnic background. PMID- 25925845 TI - Germline TP53 mutational spectrum in French Canadians with breast cancer. AB - BACKGROUND: Specific germline mutations in the hereditary breast-ovarian cancer susceptibility (HBC/HBOC) genes, BRCA1, BRCA2 and PALB2, have been shown to recur in French Canadians of Quebec, Canada, and this has been attributed to common ancestors. Germline TP53 mutation carriers are known to segregate in Li-Fraumeni syndrome families, which feature young age of onset breast cancer. We have reported rare TP53 mutation carriers in French Canadian HBC families, though none recurred possibly due to the limited number of cancer families investigated. Here we describe TP53 germline mutations found in French Canadian cancer families provided from hereditary cancer clinics; investigate 37 new BRCA1 and BRCA2 mutation-negative HBC/HBOC families for the TP53 mutations; and assess the frequency of TP53 mutations in a 1235 French Canadian breast cancer cases not selected for family history of cancer. METHODS: TP53 mutation-positive pedigrees from French Canadian cancer families were provided from local hereditary cancer clinics. Bidirectional Sanger sequencing of all protein encoding exons of TP53 was performed using peripheral blood lymphocyte DNA from breast/ovarian cancer probands from 37 HBC/HBOC families of French Canadian descent. Targeted bidirectional Sanger sequencing assay of regions containing the identified TP53 mutations was performed on 1235 French Canadian breast cancer cases not selected for family history cancer. RESULTS: Five new TP53 mutations were identified in six pedigrees from hereditary cancer clinics. No deleterious mutations were identified in cancer probands from 37 HBC/HBOC families. A targeted mutation screen of the 1235 breast cancer cases identified a c.844C>T [p.Arg282Trp] mutation carrier. This mutation was also found among the six mutation-positive cancer families provided by the local hereditary cancer clinics. The targeted screen also uncovered a new TP53 mutation, c.685T>C [p.Cys229Arg] that was found in two breast cancer cases. All TP53 mutation carriers were among the 656 women with breast cancer diagnosed less than 50 years of age. CONCLUSIONS: In all six new TP53 mutations were identified in French Canadians, where two each occurred in independently ascertained cases/families. Although all newly identified breast cancer mutation carriers reported a family history of cancer, none were consistent with features of Li-Fraumeni syndrome families. PMID- 25925846 TI - Everolimus in metastatic renal cell carcinoma after failure of initial anti-VEGF therapy: final results of a noninterventional study. AB - BACKGROUND: Data are limited regarding routine use of everolimus after initial vascular endothelial growth factor (VEGF)-targeted therapy. The aim of this prospective, noninterventional, observational study was to assess efficacy and safety of everolimus after initial VEGF-targeted treatment in patients with metastatic renal cell carcinoma (mRCC) in routine clinical settings. METHODS: Everolimus was administered per routine clinical practice. Patients with mRCC of any histology from 116 active sites in Germany were included. The main objective was to determine everolimus efficacy in time to progression (TTP). Progression free survival (PFS), treatment duration, tumor response, adherence to everolimus regimen, treatment after everolimus, and safety were also assessed. RESULTS: In the total population (N = 334), median follow-up was 5.2 months (range, 0-32 months). Median treatment duration (safety population, n = 318) was 6.5 months (95% confidence interval [CI], 5-8 months). Median TTP and median PFS were similar in populations investigated. In patients who received everolimus as second-line treatment (n = 211), median (95% CI) TTP was 7.1 months (5-9 months) and median PFS was 6.9 months (5-9 months). Commonly reported adverse events (safety population, n = 318) were dyspnea (17%), anemia (15%), and fatigue (12%). Limitations of the noninterventional design should be considered. CONCLUSIONS: This study reflects routine clinical use of everolimus in a large sample of patients with mRCC. Favorable efficacy and safety were seen for everolimus after previous therapy with one VEGF-targeted agent. Results of this study confirm everolimus as one of the standard options in second-line therapy for patients with mRCC. Novartis study code, CRAD001LD27: VFA registry for noninterventional studies ( http://www.vfa.de/de/forschung/nisdb/). PMID- 25925848 TI - Tryptophan hydroxylase and serotonin receptor 1A expression in the retina of the sea lamprey. AB - The dual development of the retina of lampreys is exceptional among vertebrates and offers an interesting EvoDevo (evolutionary developmental biology) model for understanding the origin and evolution of the vertebrate retina. Only a single type of photoreceptor, ganglion cell and bipolar cell are present in the early differentiated central retina of lamprey prolarvae. A lateral retina appears later in medium-sized larvae (about 3 years after hatching in the sea lamprey), growing and remaining largely neuroblastic until metamorphosis. In this lateral retina, only ganglion cells and optic fibers differentiate in larvae, whereas differentiation of amacrine, horizontal, photoreceptor and bipolar cells mainly takes place during metamorphosis, which gives rise to the adult retina. Serotonin (5-hydroxytryptamine, 5-HT) is a neurotransmitter found in the retina of vertebrates whose synthesis is mediated by the rate-limiting enzyme tryptophan hydroxylase (TPH). TPH is also the first enzyme in the biosynthetic pathways of melatonin in photoreceptor cells. The serotonin 1A receptor (5-HT1A) is a major determinant of the activity of both serotonergic cells and their targets due to its pre- and post-synaptic location. Here, we report the developmental pattern of expression of tph and 5-ht1a transcripts in the sea lamprey retina by means of in situ hybridization. In larvae, strong tph mRNA signal was observed in photoreceptors and putative ganglion cells of the central retina, and in some neuroblasts of the lateral retina. In adults, strong tph expression was observed in bipolar, amacrine and ganglion cells and in photoreceptors. In the prolarval (central) retina, all the differentiated retinal cells expressed 5-ht1a transcripts, which were not observed in undifferentiated cells. In larvae, photoreceptors, bipolar cells and ganglion cells in the central retina, and neuroblasts in the lateral retina, showed 5-ht1a expression. In the adult retina, expression of 5-ht1a transcript was mainly observed in the myoid region of both short and long photoreceptors, and was also observed in bipolar, amacrine and ganglion cells. Some 5-HT-immunoreactive amacrine cells have already been reported in the adult lamprey retina. Our study supports the serotonergic phenotype of these amacrine cells of lampreys and also suggests that other retinal neurons could synthesize serotonin at levels not detectable by immunohistochemistry. The expression of the tph transcript in retinal photoreceptors of lampreys strongly suggests that they synthesize melatonin and that this pathway appeared early and has been conserved throughout evolution in vertebrates. The expression of tph and 5-ht1a in neuroblasts also indicates that serotonin might be playing developmental roles in the larval lamprey retina. PMID- 25925847 TI - A Dinuclear Ruthenium-Based Water Oxidation Catalyst: Use of Non-Innocent Ligand Frameworks for Promoting Multi-Electron Reactions. AB - Insight into how H2 O is oxidized to O2 is envisioned to facilitate the rational design of artificial water oxidation catalysts, which is a vital component in solar-to-fuel conversion schemes. Herein, we report on the mechanistic features associated with a dinuclear Ru-based water oxidation catalyst. The catalytic action of the designed Ru complex was studied by the combined use of high resolution mass spectrometry, electrochemistry, and quantum chemical calculations. Based on the obtained results, it is suggested that the designed ligand scaffold in Ru complex 1 has a non-innocent behavior, in which metal ligand cooperation is an important part during the four-electron oxidation of H2 O. This feature is vital for the observed catalytic efficiency and highlights that the preparation of catalysts housing non-innocent molecular frameworks could be a general strategy for accessing efficient catalysts for activation of H2 O. PMID- 25925849 TI - PTEN expression in endothelial cells is down-regulated by uPAR to promote angiogenesis. AB - The tumour suppressor phosphatase and tensin homologue (PTEN), mutated or lost in many human cancers, is a major regulator of angiogenesis. However, the cellular mechanism of PTEN regulation in endothelial cells so far remains elusive. Here, we characterise the urokinase receptor (uPAR, CD87) and its tumour-derived soluble form, suPAR, as a key molecule of regulating PTEN in endothelial cells. We observed uPAR-deficient endothelial cells to express enhanced PTEN mRNA- and protein levels. Consistently, uPAR expression in endogenous negative uPAR cells, down-regulated PTEN and activated the PI3K/Akt pathway. Additionally, we found that integrin adhesion receptors act as trans-membrane signaling partners for uPAR to repress PTEN transcription in a NF-kappaB-dependent manner. Functional in vitro assays with endothelial cells, derived from uPAR-deficient and PTEN heterozygous crossbred mice, demonstrated the impact of uPAR-dependent PTEN regulation on cell motility and survival. In an in vivo murine angiogenesis model uPAR-deficient PTEN heterozygous animals increased the impaired angiogenic phenotype of uPAR knockout mice and were able to reverse the high invasive potential of PTEN heterozygots. Our data provide first evidence that endogenous as well as exogenous soluble uPAR down-regulated PTEN in endothelial cells to support angiogenesis. The uPAR-induced PTEN regulation might represent a novel target for drug interference, and may lead to the development of new therapeutic strategies in anti-angiogenic treatment. PMID- 25925850 TI - Immunosuppressive Therapy in Myelodysplastic Syndromes Is Still Alive. PMID- 25925851 TI - Does BDNF Val66Met Polymorphism Confer Risk for Posttraumatic Stress Disorder? AB - BACKGROUND: Evidence has indicated that BDNF (brain-derived neurotrophic factor) Val66Met genetic variant could be linked to the development of posttraumatic stress disorder (PTSD). However, clinical observations studying the BDNF polymorphism and the risk of PTSD yielded contradictory results. In this meta analysis we evaluated the association between BDNF Val66Met and PTSD risk. METHOD: Systematic searches in online databases retrieved 6 relevant publications. Different inherited models were utilized to perform the pooled analysis. Subgroup analyses and sensitive analyses based on Hardy-Weinberg equilibrium (HWE) test results were also carried out. RESULTS: Our study did not found a significant overall effect of BDNF Val66Met on the susceptibility to PTSD under various genetic models. In contrast, subgroup analyses suggested that the stress status of the control group, but not ethnicity, may influence the relationship of BDNF Val66Met with PTSD risk. After the exclusion of a study that was not in HWE, our conclusions remained unchanged during the influence analyses. CONCLUSIONS: This meta-analysis suggested no genetic association of BDNF Val66Met with vulnerability to PTSD. Further research studies are warranted to clarify the impact of BDNF variants on the occurrence of PTSD. PMID- 25925852 TI - Development and evaluation of methods for starch dissolution using asymmetrical flow field-flow fractionation. Part I: Dissolution of amylopectin. AB - We have investigated methods of starch dissolution with the aim of finding an optimum method to completely dissolve starch granules to form a molecularly dissolved starch solution without degradation of the polymers. Glycogen was used as a model molecule for amylopectin, to identify the dissolution conditions under which the degradation of the polymers was limited or not present. Dissolution was performed in water with temperatures up to 200 degrees C, facilitated by the use of heating in an autoclave or a microwave oven, or in dimethyl sulfoxide (DMSO) at 100 degrees C. Waxy maize starch was chosen due to its high content of amylopectin and very low content of amylose. The degree of starch dissolution under different conditions was determined enzymatically. The effect of different dissolution conditions on the molar mass and root-mean-square radius of the polymers was determined with asymmetrical flow field-flow fractionation coupled to multi-angle light scattering and differential refractive index (AF4-MALS-dRI) detectors under aqueous conditions. The results suggest that reliable and accurate size separation and characterization of amylopectin can be obtained by dissolution of starch granules in an aqueous environment at 140 degrees C by autoclaving or in DMSO at 100 degrees C. The results also clearly show an upper limit for heat treatment of starch, above which degradation cannot be avoided. PMID- 25925853 TI - Automated direct-immersion solid-phase microextraction using crosslinked polymeric ionic liquid sorbent coatings for the determination of water pollutants by gas chromatography. AB - Four different crosslinked polymeric ionic liquid (PIL)-based sorbent coatings were evaluated in an automated direct-immersion solid-phase microextraction method (automated DI-SPME) in combination with gas chromatography (GC). The crosslinked PIL coatings were based on vinyl-alkylimidazolium- (ViCnIm-) or vinylbenzyl-alkylimidazolium- (ViBzCnIm-) IL monomers, and di (vinylimidazolium)dodecane ((ViIm)2C12-) or di-(vinylbenzylimidazolium)dodecane ((ViBzIm)2C12-) dicationic IL crosslinkers. In addition, a PIL-based hybrid coating containing multi-walled carbon nanotubes (MWCNTs) was also studied. The studied PIL coatings were covalently attached to derivatized nitinol wires and mounted onto the Supelco assembly to ensure automation when acting as SPME coatings. Their behavior was evaluated in the determination of a group of water pollutants, after proper optimization. A comparison was carried out with three common commercial SPME fibers. It was observed that those PILs containing a benzyl group in their structures, either in the IL monomer and crosslinker (PIL-1 1) or only in the crosslinker (PIL-0-1), were the most efficient sorbents for the selected analytes. The validation of the overall automated DI-SPME-GC-flame ionization detector (FID) method gave limits of detection down to 135 MUg . L(-1) for p-cresol when using the PIL-1-1 and down to 270 MUg . L(-1) when using the PIL-0-1; despite their coating thickness: ~2 and ~5 MUm, respectively. Average relative recoveries with waters were of 85 +/- 14 % and 87 +/- 15 % for PIL-1-1 and PIL-0-1, respectively. Precision values as relative standard deviation were always lower than 4.9 and 7.6 % (spiked level between 10 and 750 MUg . L(-1), as intra-day precision). Graphical Abstract Automated DI-SPME-GC-FID using crosslinked-PILs sorbent coatings for the determination of waterpollutants. PMID- 25925854 TI - Hydrodynamic and direct-current insulator-based dielectrophoresis (H-DC-iDEP) microfluidic blood plasma separation. AB - Evaluation and diagnosis of blood alterations is a common request for clinical laboratories, requiring a complex technological approach and dedication of health resources. In this paper, we present a microfluidic device that owing to a novel combination of hydrodynamic and dielectrophoretic techniques can separate plasma from fresh blood in a microfluidic channel and for the first time allows optical real-time monitoring of the components of plasma without pre- or post-processing. The microchannel is based on a set of dead-end branches at each side and is initially filled using capillary forces with a 2-MUL droplet of fresh blood. During this process, stagnation zones are generated at the dead-end branches and some red blood cells (RBCs) are trapped there. An electric field is then applied and dielectrophoretic trapping of RBCs is used to prevent more RBCs entering into the channel, which works like a sieve. Besides, an electroosmotic flow is generated to sweep the rest of the RBCs from the central part of the channel. Consequently, an RBC-free zone of plasma is formed in the middle of the channel, allowing real-time monitoring of the platelet behavior. To study the generation of stagnation zones and to ensure RBC trapping in the initial constrictions, two numerical models were solved. The proposed experimental design separates up to 0.1 MUL blood plasma from a 2-MUL fresh human blood droplet. In this study, a plasma purity of 99 % was achieved after 7 min, according to the measurements taken by image analysis. Graphical Abstract Schematics of a real-time plasma monitoring system based on a Hydrodynamic and direct-current insulator-based dielectrophoresis microfluidic channel. PMID- 25925855 TI - New environmentally friendly MSPD solid support based on golden mussel shell: characterization and application for extraction of organic contaminants from mussel tissue. AB - The use of golden mussel shells as a solid support in vortex-assisted matrix solid-phase dispersion (MSPD) was evaluated for the first time for extraction of residues of 11 pesticides and nine pharmaceutical and personal care products from mussel tissue samples. After they had been washed, dried, and milled, the mussel shells were characterized by scanning electron microscopy, energy-dispersive X ray spectroscopy, infrared spectroscopy, and Brunauer-Emmett-Teller analysis. The MSPD procedure with analysis by liquid chromatography-tandem mass spectrometry allowed the determination of target analytes at trace concentrations (nanograms per gram), with mean recoveries ranging from 61 to 107 % and relative standard deviations lower than 18 %. The optimized method consisted of dispersion of 0.5 g of mussel tissue, 0.5 g of NaSO4, and 0.5 g of golden mussel shell for 5 min, and subsequent extraction with 5 mL of ethyl acetate. The matrix effect was evaluated, and a low effect was found for all compounds. The results showed that mussel shell is an effective material and a less expensive material than materials that have traditionally been used, i.e., it may be used in the MSPD dispersion step during the extraction of pesticides and pharmaceutical and personal care products from golden mussel tissues. Graphical Abstract Vortex assited matrix solid-phase dispersion for extraction of 11 pesticides and 9 PPCPs care products from mussel tissue samples. PMID- 25925856 TI - Field and flow-based separations. PMID- 25925857 TI - Identification of known drugs targeting the endoplasmic reticulum stress response. AB - The endoplasmic reticulum (ER), a multifunctional organelle, plays a central role in cellular signaling, development, and stress response. Dysregulation of ER homeostasis has been associated with human diseases, such as cancer, inflammation, and diabetes. A broad spectrum of stressful stimuli including hypoxia as well as a variety of pharmacological agents can lead to the ER stress response. In this study, we have developed a stable ER stress reporter cell line that stably expresses a beta-lactamase reporter gene under the control of the ER stress response element (ESRE) present in the glucose-regulated protein, 78 kDa (GRP78) gene promoter. This assay has been optimized and miniaturized into a 1536 well plate format. In order to identify clinically used drugs that induce ER stress response, we screened approximately 2800 drugs from the NIH Chemical Genomics Center Pharmaceutical Collection (NPC library) using a quantitative high throughput screening (qHTS) platform. From this study, we have identified several known ER stress inducers, such as 17-AAG (via HSP90 inhibition), as well as several novel ER stress inducers such as AMI-193 and spiperone. The confirmed drugs were further studied for their effects on the phosphorylation of eukaryotic initiation factor 2alpha (eIF2alpha), the X-box-binding protein (XBP1) splicing, and GRP78 gene expression. These results suggest that the ER stress inducers identified from the NPC library using the qHTS approach could shed new lights on the potential therapeutic targets of these drugs. PMID- 25925858 TI - Improving FTIR imaging speciation of organic compound residues or their degradation products in wall painting samples, by introducing a new thin section preparation strategy based on cyclododecane pre-treatment. AB - Fourier transform infrared (FTIR) imaging in transmission mode, employing a bidimensional focal plane array (FPA) detector, was applied for the detection and spatially resolved chemical characterisation of organic compounds or their degradation products within the stratigraphy of a critical group of fragments, originating from prehistoric and roman wall paintings, containing a very low concentration of subsisted organic matter or its alteration products. Past analyses using attenuated total reflection (ATR) or reflection FTIR on polished cross sections failed to provide any evidence of any organic material assignable as binding medium of the original painting. In order to improve the method's performance, in the present study, a new method of sample preparation in thin section was developed. The procedure is based on the use of cyclododecane C12H24 as embedding material and a subsequent double-side polishing of the specimen. Such procedure provides samples to be studied in FTIR transmission mode without losing the information on the spatial distribution of the detected materials in the paint stratigraphy. For comparison purposes, the same samples were also studied after opening their stratigraphy with a diamond anvil cell. Both preparation techniques offered high-quality chemical imaging of the decay products of an organic substance, giving clues to the painting technique. In addition, the thin sections resulting from the cyclododecane pre-treatment offered more layer-specific data, as the layer thickness and order remained unaffected, whereas the samples resulting from compression within the diamond cell were slightly deformed; however, since thinner and more homogenous, they provided higher spectral quality in terms of S/N ratio. In summary, the present study illustrates the appropriateness of FTIR imaging in transmission mode associated with a new thin section preparation strategy to detect and localise very low-concentrated organic matter subjected to deterioration processes, when the application of FTIR in reflection mode or FTIR-ATR fails to give any relevant information. PMID- 25925859 TI - "Dilute-and-inject" multi-target screening assay for highly polar doping agents using hydrophilic interaction liquid chromatography high resolution/high accuracy mass spectrometry for sports drug testing. AB - In the field of LC-MS, reversed phase liquid chromatography is the predominant method of choice for the separation of prohibited substances from various classes in sports drug testing. However, highly polar and charged compounds still represent a challenging task in liquid chromatography due to their difficult chromatographic behavior using reversed phase materials. A very promising approach for the separation of hydrophilic compounds is hydrophilic interaction liquid chromatography (HILIC). Despite its great potential and versatile advantages for the separation of highly polar compounds, HILIC is up to now not very common in doping analysis, although most manufacturers offer a variety of HILIC columns in their portfolio. In this study, a novel multi-target approach based on HILIC high resolution/high accuracy mass spectrometry is presented to screen for various polar stimulants, stimulant sulfo-conjugates, glycerol, AICAR, ethyl glucuronide, morphine-3-glucuronide, and myo-inositol trispyrophosphate after direct injection of diluted urine specimens. The usage of an effective online sample cleanup and a zwitterionic HILIC analytical column in combination with a new generation Hybrid Quadrupol-Orbitrap(r) mass spectrometer enabled the detection of highly polar analytes without any time-consuming hydrolysis or further purification steps, far below the required detection limits. The methodology was fully validated for qualitative and quantitative (AICAR, glycerol) purposes considering the parameters specificity; robustness (rRT < 2.0%); linearity (R > 0.99); intra- and inter-day precision at low, medium, and high concentration levels (CV < 20%); limit of detection (stimulants and stimulant sulfo-conjugates < 10 ng/mL; norfenefrine; octopamine < 30 ng/mL; AICAR < 10 ng/mL; glycerol 100 MUg/mL; ETG < 100 ng/mL); accuracy (AICAR 103.8-105.5%, glycerol 85.1-98.3% at three concentration levels) and ion suppression/enhancement effects. PMID- 25925860 TI - An optimized method for the accurate determination of patulin in apple products by isotope dilution-liquid chromatography/mass spectrometry. AB - Patulin, a mycotoxin produced by several molds in fruits, has been frequently detected in apple products. Therefore, regulatory bodies have established recommended maximum permitted patulin concentrations for each type of apple product. Although several analytical methods have been adopted to determine patulin in food, quality control of patulin analysis is not easy, as reliable certified reference materials (CRMs) are not available. In this study, as a part of a project for developing CRMs for patulin analysis, we developed isotope dilution liquid chromatography-tandem mass spectrometry (ID-LC/MS/MS) as a higher order reference method for the accurate value-assignment of CRMs. (13)C7-patulin was used as internal standard. Samples were extracted with ethyl acetate to improve recovery. For further sample cleanup with solid-phase extraction (SPE), the HLB SPE cartridge was chosen after comparing with several other types of SPE cartridges. High-performance liquid chromatography was performed on a multimode column for proper retention and separation of highly polar and water-soluble patulin from sample interferences. Sample extracts were analyzed by LC/MS/MS with electrospray ionization in negative ion mode with selected reaction monitoring of patulin and (13)C7-patulin at m/z 153->m/z 109 and m/z 160->m/z 115, respectively. The validity of the method was tested by measuring gravimetrically fortified samples of various apple products. In addition, the repeatability and the reproducibility of the method were tested to evaluate the performance of the method. The method was shown to provide accurate measurements in the 3-40 MUg/kg range with a relative expanded uncertainty of around 1%. PMID- 25925861 TI - Bioluminescent detection probe for tick-borne encephalitis virus immunoassay. AB - To facilitate the detection of the tick-borne encephalitis virus (TBEV), the causative agent of one of the most severe human neuroinfections, we have developed an immunoassay based on bioluminescent hybrid protein 14D5a-Rm7 as a detection probe. The protein containing Renilla luciferase as a reporter and a single-chain variable fragment (scFv) of murine immunoglobulin to TBEV as a recognition element was constructed, produced by bacterial expression, purified, and tested. Both domains were shown to reveal their specific biological properties-affinity to the target antigen and bioluminescent activity. Hybrid protein was applied as a label for solid-phase immunoassay of the antigens, associated with the tick-borne encephalitis virus (native glycoprotein E or extracts of the infected strain of lab ticks). The assay demonstrates high sensitivity (0.056 ng of glycoprotein E; 10(4)-10(5) virus particles or 0.1 pg virions) and simplicity and is competitive with conventional methods for detection of TBEV. PMID- 25925862 TI - Molecular screening of cancer-derived exosomes by surface plasmon resonance spectroscopy. AB - We report on a generic method to detect and identify the molecular profile of exosomes either derived from cultured cell lines or isolated from biofluids. Exosomes are nanovesicles shed by cells into their microenvironment and carry the molecular identity of their mother cells. These vesicles are actively involved in intercellular communication under physiological conditions and ultimately in the spread of various diseases such as cancer. As they are accessible in most biofluids (e.g., blood, urine, or saliva), these biological entities are promising tools for cancer diagnostics, offering a non-invasive and remote access to the molecular state of the disease. The composition of exosomes derived from cancer cells depends on the sort and state of the tumor, requiring a screening of multiple antigens to fully characterize the disease. Here, we exploited the capacity of surface plasmon resonance biosensing to detect simultaneously multiple exosomal and cancer biomarkers on exosomes derived from breast cancer cells. We developed an immunosensor surface which provides efficient and specific capture of exosomes, together with their identification through their distinct molecular profiles. The successful analysis of blood samples demonstrated the suitability of our bioanalytical procedure for clinical use. PMID- 25925863 TI - Separation of monosaccharides hydrolyzed from glycoproteins without the need for derivatization. AB - Chromatographic separation of monosaccharides hydrolyzed from glycoconjugates or complex, aggregate biomaterials, can be achieved by classic analytical methods without a need for derivatizing the monosaccharide subunits. A simple and sensitive method is presented for characterizing underivatized monosaccharides following hydrolysis from N- and O-linked glycoproteins using high-performance liquid chromatography separation with mass spectrometry detection (LC-MS). This method is adaptable for characterizing anything from purified glycoproteins to mixtures of glycoforms, for relative or absolute quantification applications, and even for the analysis of complex biomaterials. Use of an amide stationary phase with HILIC chromatography is demonstrated to retain the highly polar, underivatized monosaccharides and to resolve stereoisomers and potentially interfering contaminants. This work illustrates an original approach for characterization of N- and O-linked glycoprotein standards, mixtures, and for complex biological materials such as a total yeast extract. PMID- 25925864 TI - Antidiabetic and antioxidant activities of ethanolic extract of Semecarpus anacardium (Linn.) bark. AB - BACKGROUND: Diabetes mellitus is a global health problem and constantly increasing day by day. The number of diabetic people in world is expected to rise to 366 million in 2030. The available drugs for diabetes, insulin or oral hypoglycemic agents have one or more side effects and search for new antidiabetic drugs with minimal or no side effects from medicinal plants is a challenging for us. The present study was undertaken to investigate the antidiabetic and antioxidant activity of Semecarpus anacardium (Linn.) (abbreviated as SF). METHODS: The antidiabetic activity was determined by using alloxan-induced diabetic rats. After 15 days of treatment, serum biochemical parameters such as TC, TG, LDL, HDL, SGOT and SGPT were estimated. The survival rate, body weight, organ weight, liver glycogen and blood parameters (RBC and Hb) were also measured. The antioxidant activity was measured by DPPH free radical scavenging assay. Phytochemical screening, total phenolic and total flavonoid content were determined by using standard methods. RESULTS: The results showed that the survival rate was 100% in rats of Group SA 400. The effect of extract on blood glucose level in Groups SA 100, SA 200 and SA 400 were dose-dependent throughout the treatment period. No significant changes in organ weight to body weight ratio were observed, liver weights significantly improved in Groups SA 200 and SA 400. The bark extract exhibited significant (p < 0.05) anti-diabetic activity with lowering TC, TG, LDL level dose-dependently and protected liver which may be partially explained by attenuation of SGOT and SGPT levels and increases liver glycogen. The percentage of Hb and RBC counts were negatively correlated with the doses of extracts. In DPPH scavenging assay, IC50 values of SA extract and ascorbic acid were found 72.24 MUg/ml and 17.81 MUg/ml, respectively. Phytochemical screening showed the presence of steroids, triterpenoids, flavonoids, glycosides, saponins, and tannins that were contribute to biological activity. CONCLUSIONS: These results indicated that stem barks of S. anacardium possess strong anti-diabetic and antioxidant potentials and support traditional medicinal use for the treatment of diabetes mellitus and good source for natural antioxidants. PMID- 25925865 TI - Different Patterns of Disease Spread between Advanced-Stage Type I and II Epithelial Ovarian Cancer. AB - BACKGROUND AND AIMS: Two types of epithelial ovarian carcinoma (EOC) have been recently distinguished. Type I comprises low-grade serous, endometrioid and clear cell tumors. High-grade endometrioid and serous tumors belong to type II. The aim of this study was to compare patterns of disease spread in advanced-stage type I and II EOCs at primary surgery. METHODS: Surgical and pathological data of 233 patients with advanced-stage EOCs were collected, 42 with type I and 191 with type II. The two groups were compared for tumor localization at primary surgery. Intraoperative mapping of ovarian cancer (IMO) was used to assess tumor dissemination. RESULTS: Tumor involvement was significantly higher in the type II group for the following: peritoneum (68.1 vs. 40.5%, p < 0.001), pouch of Douglas (60.2 vs. 40.5%, p = 0.06), vesicouterine ligament (40.8 vs. 19%, p = 0.027), diaphragm (45.0 vs. 11.9%, p < 0.001), serosa of liver (17.2 vs. 4.8%, p = 0.05), omentum (81.1 vs. 59.5%, p = 0.007), mesentery (42.9 vs. 16.7%, p = 0.005), pleural effusions (19.4 vs. 4.6%, p = 0.01) and ascites (60.7 vs. 21.4%, p < 0.001). IMO levels were different between the two groups (p = 0.001). CONCLUSIONS: This study provides clinical evidence in favor of the dualistic model of carcinogenesis, since types I and II are characterized by different findings at primary surgery. PMID- 25925866 TI - Extraction or adsorption? Voltammetric assessment of protamine transfer at ionophore-based polymeric membranes. AB - Cation-exchange extraction of polypeptide protamine from water into an ionophore based polymeric membrane has been hypothesized as the origin of a potentiometric sensor response to this important heparin antidote. Here, we apply ion-transfer voltammetry not only to confirm protamine extraction into ionophore-doped polymeric membranes but also to reveal protamine adsorption at the membrane/water interface. Protamine adsorption is thermodynamically more favorable than protamine extraction as shown by cyclic voltammetry at plasticized poly(vinyl chloride) membranes containing dinonylnaphthalenesulfonate as a protamine selective ionophore. Reversible adsorption of protamine at low concentrations down to 0.038 MUg/mL is demonstrated by stripping voltammetry. Adsorptive preconcentration of protamine at the membrane/water interface is quantitatively modeled by using the Frumkin adsorption isotherm. We apply this model to ensure that stripping voltammograms are based on desorption of all protamine molecules that are transferred across the interface during a preconcentration step. In comparison to adsorption, voltammetric extraction of protamine requires ~0.2 V more negative potentials, where a potentiometric super-Nernstian response to protamine is also observed. This agreement confirms that the potentiometric protamine response is based on protamine extraction. The voltammetrically reversible protamine extraction results in an apparently irreversible potentiometric response to protamine because back-extraction of protamine from the membrane extremely slows down at the mixed potential based on cation-exchange extraction of protamine. Significantly, this study demonstrates the advantages of ion-transfer voltammetry over potentiometry to quantitatively and mechanistically assess protamine transfer at ionophore-based polymeric membranes as foundation for reversible, selective, and sensitive detection of protamine. PMID- 25925867 TI - Tumour-derived SPARC drives vascular permeability and extravasation through endothelial VCAM1 signalling to promote metastasis. AB - Disruption of the endothelial barrier by tumour-derived secreted factors is a critical step in cancer cell extravasation and metastasis. Here, by comparative proteomic analysis of melanoma secretomes, we identify the matricellular protein SPARC as a novel tumour-derived vascular permeability factor. SPARC deficiency abrogates tumour-initiated permeability of lung capillaries and prevents extravasation, whereas SPARC overexpression enhances vascular leakiness, extravasation and lung metastasis. SPARC-induced paracellular permeability is dependent on the endothelial VCAM1 receptor and p38 MAPK signalling. Blocking VCAM1 impedes melanoma-induced endothelial permeability and extravasation. The clinical relevance of our findings is highlighted by high levels of SPARC detected in tumour from human pulmonary melanoma lesions. Our study establishes tumour-produced SPARC and VCAM1 as regulators of cancer extravasation, revealing a novel targetable interaction for prevention of metastasis. PMID- 25925869 TI - Meiotic recombination hotspots - a comparative view. AB - During meiosis homologous chromosomes pair and undergo reciprocal genetic exchange, termed crossover. Meiotic recombination has a profound effect on patterns of genetic variation and is an important tool during crop breeding. Crossovers initiate from programmed DNA double-stranded breaks that are processed to form single-stranded DNA, which can invade a homologous chromosome. Strand invasion events mature into double Holliday junctions that can be resolved as crossovers. Extensive variation in the frequency of meiotic recombination occurs along chromosomes and is typically focused in narrow hotspots, observed both at the level of DNA breaks and final crossovers. We review methodologies to profile hotspots at different steps of the meiotic recombination pathway that have been used in different eukaryote species. We then discuss what these studies have revealed concerning specification of hotspot locations and activity and the contributions of both genetic and epigenetic factors. Understanding hotspots is important for interpreting patterns of genetic variation in populations and how eukaryotic genomes evolve. In addition, manipulation of hotspots will allow us to accelerate crop breeding, where meiotic recombination distributions can be limiting. PMID- 25925868 TI - Defining novel parameters for the optimal priming and expansion of minor histocompatibility antigen-specific T cells in culture. AB - BACKGROUND: Adoptive transfer of minor histocompatibility antigen (MiHA)-specific T cells is a promising therapy for patients with hematological cancers. However, the efficacy of the transferred cells is hampered by the acquisition of terminal effector differentiation and exhaustion features during expansion in vitro thus preventing their function and persistence in vivo. Yet, the factors that induce T cell differentiation and functional impairment in culture remain poorly defined and are likely to vary depending on the method used for expansion. METHODS: Using the clinically relevant HLA-A0201-restricted MiHA HA-1 as well as reagents and procedures that are readily transferable to a clinical environment, we designed a novel culture protocol and defined how exhaustion features appeared in function of time. The optimal time points for the expansion of "fit" MiHA-specific T cells were delineated using phenotypic and functional assessments including KLRG-1 and PD-1 surface markers as well as Ki67 staining and cytokine secretion assays. RESULTS: Following a priming phase, an enrichment step and a rapid expansion stage, our method generates MiHA-specific T-cell lines. Evidence of phenotypic and functional dysfunction appear in function of culture duration, but display different characteristics following the extension of the priming or rapid expansion phases. While repeated antigen exposure during the priming phase induced the decline of the antigen-specific population and the expression of PD-1 and KLRG-1 on antigen-specific CD8+ T cells, the prolongation of an antigen-free expansion phase induced proliferation arrest and the relative loss of antigen specific cells without impairing polyfunctional cytokine secretion or inducing PD 1 and KLRG-1 expression. A similar pattern was also observed after stimulating a virus-specific memory repertoire, except for the more rapid acquisition of exhaustion features upon repeated antigen exposure. CONCLUSION: Our results offer novel insights on the impact of culture duration on the acquisition of T-cell exhaustion features. Using a new clinical-compliant protocol, we define critical parameters to monitor in order to optimally differentiate and expand MiHA specific T cells in culture prior to adoptive transfer. PMID- 25925870 TI - Effects of culture media on metabolic profiling of the human gastric cancer cell line SGC7901. AB - Cell culture metabolomics has demonstrated significant advantages in cancer research. However, its applications have been impeded by some influencing factors such as culture media, which could significantly affect cellular metabolic profiles and lead to inaccuracy and unreliability of comparative metabolomic analysis of cells. To evaluate the effects of different culture media on cellular metabolic profiling, we performed NMR-based metabolomic analysis of the human gastric cancer cell line SGC7901 cultured in both RPMI1640 and DMEM. We found that SGC7901 cultured in the two media exhibited distinct metabolic profiles with obviously different levels of discrepant metabolites, even though they showed almost the same cellular morphology and proliferation rates. When SGC7901 originally cultured in RPMI1640 was gradually acclimated in DMEM, both the metabolic profiles and most of the discrepant metabolite levels gradually converged toward those of the cells originally cultured in DMEM without significantly altered cell proliferation rates. However, several metabolite levels did not show the converging trends. Our results indicate that the effects of culture media on metabolic profiling must be carefully taken into account for comparative metabolomic analysis of cell lines. This work may be of benefit to the development of cell culture metabolomics. PMID- 25925872 TI - Changing filters. PMID- 25925871 TI - A study on quantitative structure-activity relationship and molecular docking of metalloproteinase inhibitors based on L-tyrosine scaffold. AB - BACKGROUND: MMP-2 enzyme is a kind of matrix metalloproteinases that digests the denatured collagens and gelatins. It is highly involved in the process of tumor invasion and has been considered as a promising target for cancer therapy. The structural requirements of an MMP-2 inhibitor are: (1) a functional group that binds the zinc ion, and (2) a functional group which interacts with the enzyme backbone and the side chains which undergo effective interactions with the enzyme subsites. METHODS: In the present study, a QSAR model was generated to screen new inhibitors of MMP-2 based on L-hydroxy tyrosine scaffold. Descriptors generation were done by Hyperchem 8, DRAGON and Gaussian98W programs. SPSS and MATLAB programs have been used for multiple linear regression (MLR) and genetic algorithm partial least squares (GA-PLS) analyses and for theoretical validation. Applicability domain of the model was performed to screen new compounds. The binding site potential of all inhibitors was verified by structure-based docking according to their binding energy and then the best inhibitors were selected. RESULTS: The best QSAR models in MLR and GA-PLS were reported, with the square correlation coefficient for leave-one-out cross-validation (Q(2) LOO) larger than 0.921 and 0.900 respectively. The created MLR and GA-PLS models indicated the importance of molecular size, degree of branching, flexibility, shape, three dimensional coordination of different atoms in a molecule in inhibitory activities against MMP-2. The docking study indicated that lipophilic and hydrogen bonding interactions among the inhibitors and the receptor are involved in a ligand-receptor interaction. The oxygen of carbonyl and sulfonyl groups is important for hydrogen bonds of ligand with Leu82 and Ala83. R2 and R3 substituents play a main role in hydrogen bonding interactions. R1 is sited in the hydrophobic pocket. Methylene group can help a ligand to be fitted in the lipophilic pocket, so two methylene groups are better than one. The Phenyl group can create a pi-pi interaction with Phe86. CONCLUSIONS: The QSAR and docking analyses demonstrated to be helpful tools in the prediction of anti-cancer activities and a guide to the synthesis of new metalloproteinase inhibitors based on L-tyrosine scaffold. PMID- 25925873 TI - Critical Ethnographic Analysis of "Doing Good" on Short-Term International Immersion Experiences. AB - Reciprocal partnerships are growing alongside the rise of international learning and "doing" experiences for students and clinicians. This paper questions how global citizenship, the acquisition of awareness and skills to sensitively navigate through a rapidly globalized social world, is cultivated amidst international partnerships focused on short-term immersion opportunities. Using an ethnographic methodology to examine the experiences of occupational therapy students abroad, this paper addresses the potential for competing agendas when the motivation to participate within these partnerships is driven in part by a desire to "do good." The empirical lens was directed towards the students' verbal, written and enacted narratives rather than the sociocultural realm of the sending institution, the host organization or the occupational realities of the local communities, therefore is limited in discursive scope. Nevertheless, the need is great for further critical appraisal of objectives and expectations by all parties to foster a partnership culture of reciprocity and equality and to diminish the neocolonial legacy of Western expertise dissemination. By examining how the stated and implied desire to do good exists alongside the risk to do harm to individuals and international networks, the conclusions can be extended locally to highlight the challenges to "partnering up" between clinicians and patients. PMID- 25925874 TI - Adherence to multiple micronutrient powder among young children in rural Bangladesh: a cross-sectional study. AB - BACKGROUND: Multiple micronutrient powder (MMNP) can be sprinkled onto any semisolid food and can be given to young children to address iron deficiency anemia. The female community health volunteers of BRAC (an NGO) known as Shasthya Shebikas (SS) sell MMNP sachets during their regular household visits. Currently there are no data on adherence or real uptake of MMNP by children. The objective of the study was to assess adherence to MMNP and associated factors among children aged 6-59 months in rural Bangladesh. METHODS: A cross sectional study was conducted in Saturia Sub-district among 78 children aged 6-59 months who were fed MMNP supplied by BRAC SS in the past 60 days. A one stage cluster sampling technique was used to select mothers with eligible children. Semi-structured questionnaire was used for interviews. A logistic regression model was developed to obtain adjusted odds ratios (AOR) with 95% CI. RESULTS: Sample mean adherence was calculated to be 70%. In multivariate analysis, age of mother in years (AOR = 0.74, 95% CI: 0.61-0.88), households belonging to poorer (AOR = 0.01, 95% CI: 0.00-0.68), middle (AOR = 0.04, 95% CI: 0.00-0.35) and richer (AOR = 0.11, 95% CI: 0.01-0.84) wealth quintiles and mothers who prefer to feed flexibly (AOR = 0.03, 95% CI: 0.00-0.26) were significantly associated with high adherence. Further, for every one unit increase in visit by BRAC SS in the past 60 days, the odds of having high adherence significantly increased by 55% (AOR = 1.55, 95% CI: 1.09-2.20). CONCLUSIONS: SS are the key to improving adherence through regular visits to households of MMNP users. However, expanding coverage beyond the vicinity of the SS's household is a challenge. Perception of families whose children have low adherence should be studied. PMID- 25925875 TI - Ginkgo biloba in the treatment of attention-deficit/hyperactivity disorder in children and adolescents. A randomized, placebo-controlled, trial. AB - OBJECTIVE: To evaluate the efficacy of Ginkgo biloba as a complementary therapy for attention-deficit/hyperactivity disorder (ADHD). METHODS: Children and adolescents with ADHD received methylphenidate (20-30 mg/day) plus either G. biloba (80-120 mg/day) or placebo for 6 weeks. Parent and teacher forms of the ADHD Rating Scale-IV (ADHD-RS-IV) were completed at baseline, week 2, and week 6. Treatment response was defined as 27% improvement from baseline in the ADHD-RS IV. RESULTS: Compared with placebo, more reduction was observed with G. biloba regarding ADHD-RS-IV parent rating inattention score (-7.74 +/- 1.94 vs. -5.34 +/ 1.85, P < 0.001) and total score (-13.1 +/- 3.36 vs. -10.2 +/- 3.01, P = 0.001) as well as teacher rating inattention score (-7.29 +/- 1.90 vs. -5.96 +/- 1.52, P = 0.004). Response rate was higher with G. biloba compared with placebo based on parent rating (93.5% vs. 58.6%, P = 0.002). CONCLUSIONS: The G. biloba is an effective complementary treatment for ADHD. Further studies with longer treatment duration are warranted in this regard. IRCT2014111519958N1. PMID- 25925876 TI - The microbial diversity, distribution, and ecology of permafrost in China: a review. AB - Permafrost in China mainly located in high-altitude areas. It represents a unique and suitable ecological niche that can be colonized by abundant microbes. Permafrost microbial community varies across geographically separated locations in China, and some lineages are novel and possible endemic. Besides, Chinese permafrost is a reservoir of functional microbial groups involved in key biogeochemical cycling processes. In future, more work is necessary to determine if these phylogenetic groups detected by DNA-based methods are part of the viable microbial community, and their functional roles and how they potentially respond to climate change. This review summaries recent studies describing microbial biodiversity found in permafrost and associated environments in China, and provides a framework for better understanding the microbial ecology of permafrost. PMID- 25925877 TI - Maternal body image dissatisfaction and BMI change in school-age children. AB - OBJECTIVE: Parental body image dissatisfaction (BID) is associated with children's weight in cross-sectional studies; however, it is unknown whether BID predicts development of adiposity. The objective of the present study was to investigate the associations between maternal dissatisfaction with her or her child's body and children's BMI trajectories. DESIGN: Longitudinal study. Maternal dissatisfaction (BID) with her and her child's body was calculated based on ratings of Stunkard scales obtained at recruitment, as current minus desired body image. Children's height and weight were measured at baseline and annually for a median of 2.5 years. Mixed-effects models with restricted cubic splines were used to construct sex- and weight-specific BMI-for-age curves according to maternal BID levels. SETTING: Public primary schools in Bogota, Colombia. SUBJECTS: Children (n 1523) aged 5-12 years and their mothers. RESULTS: After multivariable adjustment, heavy boys and thin girls whose mothers desired a thinner child gained an estimated 1.7 kg/m2 more BMI (P=0.04) and 2.4 kg/m2 less BMI (P=0.004), respectively, between the age 6 and 14 years, than children of mothers without BID. Normal-weight boys whose mothers desired a thinner child's body gained an estimated 1.8 kg/m2 less BMI than normal-weight boys of mothers without BID (P=0.02). Maternal BID with herself was positively related to children's BMI gain during follow-up. CONCLUSIONS: Maternal BID is associated with child's BMI trajectories in a sex- and weight-specific manner. PMID- 25925878 TI - Reply to age-related differences in quality of life among patients with diffuse large B-cell lymphoma. PMID- 25925879 TI - Profiles of dyadic adjustment for advanced prostate cancer to inform couple-based intervention. AB - OBJECTIVE: The purpose of the study is to describe from a relational perspective, partners' psychological adjustment, coping and support needs for advanced prostate cancer. DESIGN: A mixed methods design was adopted, employing triangulation of qualitative and quantitative data, to produce dyadic profiles of adjustment for six couples recruited from the urology clinics of local hospitals in Tasmania, Australia. METHODS: Dyads completed a video-taped communication task, semi-structured interview and standardised self-report questionnaires. RESULTS: Themes identified were associated with the dyadic challenges of the disease experience (e.g. relationship intimacy, disease progression and carer burden). Couples with poor psychological adjustment profiles had both clinical and global locus of distress, treatment side-effects, carer burden and poor general health. Resilient couples demonstrated relationship closeness and adaptive cognitive and behavioural coping strategies. The themes informed the adaption of an effective program for couples coping with women's cancers (CanCOPE, to create a program for couples facing advanced prostate cancer (ProCOPE-Adv). CONCLUSION: Mixed method results inform the development of psychological therapy components for couples coping with advanced prostate cancer. The concomitance of co-morbid health problems may have implications for access and engagement for older adult populations in face-to-face intervention. PMID- 25925880 TI - Empower: access to medicine - working towards early access. AB - Empower: Access to Medicine's contribution will document the founding of Empower: Access to Medicine and tactics used to create a lobbying campaign designed to facilitate the debate around barriers to medical innovation and patient access to medicines. The article will detail the evolution of the campaign's goals and the potential solutions to an expensive and slow system. Specifically the submission will look at the influence that Empower: Access to Medicine had on the Government's thinking and development of an early access scheme. PMID- 25925881 TI - Financial returns on R&D: looking back at history, looking forward to adaptive licensing. AB - Investment in R&D for drugs launched in the late 1970s to early 1990s generated good returns for investors. R&D was inexpensive. Clinical trial success rates were high. Consumption was increasing. Drug prices were outstripping inflation, which raised profit margins. Tax rates were falling. However, returns on R&D have been falling since the early 1990s given rising clinical trial costs, rising trial failure rates, and lower consumption growth in developed markets. Many investors believe that average financial returns on today's R&D will be below the cost of capital, particularly if US drug price inflation moderates. Thus R&D investment by major drug companies is flat or perhaps falling in real terms. Various regulatory initiatives have tried to streamline clinical development and approval. The latest is Adaptive Licensing (AL). The near-term effect of AL on industry-level financial returns will be modest. AL will, however, be salient for decisions to invest in specific trials and may make it easier for smaller companies to fund development. AL could become more important in the long run if it helps shift industry, regulators, and payers from what has been an increasingly linear model of innovation; predicated on the ideas that basic science predicts, trials test predictions, and trial results form a complete description of a drug's attributes. History shows that many drugs become important because doctors and patients discover utility that was not initially apparent to regulators, payers, or investors. One hope for AL, therefore, is that it will bring more acceptably safe chemical diversity into real world use at lower R&D cost. PMID- 25925882 TI - A more radical solution. AB - The current modifications to licensing procedures still leave a basically flawed system in place. A more radical solution is proposed that involves dispensing with Phase 3 trials and making medicines available at the end of Phase 2 to those who are fully informed of the potential risks and benefits and wish to take part in this novel procedure. The advantages include a shorter development time, lower development costs and allowing smaller companies to take medicines to the clinic. The principal obstacle is that medicines are subject to strict liability rather than the tort of negligence - and this will have to be amended in due course. PMID- 25925883 TI - Realising the potential of adaptive development of medicines. AB - The recent launch of a pilot scheme for 'adaptive licensing' by the European Medicines Agency could spell a new era in drug development. Rather than focusing on the purely regulatory aspect of the system, the proposals challenge several aspects of existing development processes, including the conventional roles of sponsor, regulatory and reimbursement agencies, payers and patients. They also exploit a number of scientific advances not available when the existing development path was laid out. Like all other innovations the new model of adaptive development also carries significant challenges, in areas as diverse as clinical management, economics, intellectual property, ethics and public communications. This paper outlines these changes to thinking, summarizes the benefits the model offers and proposes how some of the challenges should be met. The perspectives in the paper are drawn from the authors' own involvement with this European project and are informed by discussions at several workshops and conferences held over recent months. PMID- 25925884 TI - After thalidomide - do we have the right balance between public health and intellectual property. AB - The current European regulatory and consumer protection legal framework is the legacy of Thalidomide. The disaster led to the introduction of systematic biological and clinical data to endorse the safety and efficacy of new medicines. The European Medicines Directive outlined the pre-clinical, clinical data and product information to evaluate an appropriate benefit. Risk profile of new medicines and also allowed innovative companies to extend patent protection and data/marketing exclusivity periods to compensate for the cost for research and development. However in recent years it has become apparent that the costs and time for research and development are becoming increasingly burdensome, particularly for new drugs with recently discovered mechanisms of action for cancers and neurodegenerative disorders. The costs of development and the commercial uncertainty of such products is reducing commercialisation of these medicines. There is now considerable debate in the regulatory community as to how this regulatory burden may be eased by making earlier review of benefit risk and hence earlier access to authorised medicines. The Courts are moving away from the wide definition of medicinal product to a more nuanced view of the biological and clinical therapeutic mechanisms to satisfy the 'functional' limb definition in the Directive. This may be a move away from the rigorous scientific methodology generated after thalidomide. We discuss the ethical and public health implications of this shift in policy and the implications for intellectual property mechanisms currently available to protect the commercial needs of companies. PMID- 25925885 TI - Genesis of Changes to Legislation and Guidelines that Regulate Clinical Trials. AB - The genesis of changes to legislation and guidelines that regulate the development and licensing of medicines is complex and involves discussion and negotiation among a large number of people with different aims, interests and starting points. Those proposing a change to the way clinical trials are conducted need therefore to promote their proposal within the groups established for bringing forward changes to the guidance and legislation by participation in or responding to consultations. This paper reviews established European Union, United Kingdom and International procedures that would have to be used to introduce changes to clinical trials guidelines and legislation. PMID- 25925886 TI - Access to medicines and the safety of the people. AB - In this paper I will attempt to outline what I believe to be the most persuasive and acceptable (although not necessarily as yet accepted) theoretical justifications for the widest possible access to medicines and for prioritising measures to increase this access. This paper sets out the compelling arguments for state responsibility for these matters independently of any private or commercial arrangements that may be in place. PMID- 25925887 TI - Editorial: the urgent need to reform the present system of medicines' regulation. PMID- 25925888 TI - Flexible and Binder-Free Electrodes of Sb/rGO and Na3V2(PO4)3/rGO Nanocomposites for Sodium-Ion Batteries. AB - Flexible power sources have shown great promise in next-generation bendable, implantable, and wearable electronic systems. Here, flexible and binder-free electrodes of Na3V2(PO4)3/reduced graphene oxide (NVP/rGO) and Sb/rGO nanocomposites for sodium-ion batteries are reported. The Sb/rGO and NVP/rGO paper electrodes with high flexibility and tailorability can be easily fabricated. Sb and NVP nanoparticles are embedded homogenously in the interconnected framework of rGO nanosheets, which provides structurally stable hosts for Na-ion intercalation and deintercalation. The NVP/rGO paper-like cathode delivers a reversible capacity of 113 mAh g(-1) at 100 mA g(-1) and high capacity retention of ~96.6% after 120 cycles. The Sb/rGO paper-like anode gives a highly reversible capacity of 612 mAh g(-1) at 100 mA g(-1) , an excellent rate capacity up to 30 C, and a good cycle performance. Moreover, the sodium-ion full cell of NVP/rGO//Sb/rGO has been fabricated, delivering a highly reversible capacity of ~400 mAh g(-1) at a current density of 100 mA g(-1) after 100 charge/discharge cycles. This work may provide promising electrode candidates for developing next-generation energy-storage devices with high capacity and long cycle life. PMID- 25925889 TI - Hydrogen improves neurological function through attenuation of blood-brain barrier disruption in spontaneously hypertensive stroke-prone rats. AB - BACKGROUND: Enhanced oxidative stress occurs in spontaneously hypertensive stroke prone rats (SHRSP), and is important in blood-brain barrier (BBB) disruption. Hydrogen can exert potent protective cellular effects via reduction in oxidative stress in various diseases. The present study investigated whether long-term hydrogen treatment can improve neurological function outcome in the SHRSP model, and the effects of hydrogen on BBB function, especially the oxidative stress and the activity of matrix metalloproteinases (MMPs) in this model. Fifty-six animals were randomly assigned to 2 groups and treated as follows: SHRSP treated with hydrogen-rich water (HRW) (HRW group, n = 28); and SHRSP treated with regular water (control group, n = 28). The effect of HRW on overall survival and neurological function, and the effects of HRW on reactive oxygen species, BBB function, and MMP activities were examined. RESULTS: HRW treatment improved neurological function and tended to improve overall survival but without significant difference. The numbers of bleeds and infarcts were lower in the cortex and hippocampus in the HRW group. The HRW group exhibited a significantly lower number of 8-hydroxy-2'-deoxyguanosine-positive cells and vessels of extravasated albumin in the hippocampus compared with the control group. MMP-9 activity was reduced in the hippocampus in the HRW group compared with the control group. CONCLUSIONS: The present study suggests that ingestion of HRW can improve neurological function outcome in the SHRSP model. This beneficial effect may be due to attenuation of BBB disruption via reduction in reactive oxygen species and suppression of MMP-9 activity in the hippocampus. PMID- 25925890 TI - Cytoplasmic Accumulation of Sequestosome 1 (p62) Is a Predictor of Biochemical Recurrence, Rapid Tumor Cell Proliferation, and Genomic Instability in Prostate Cancer. AB - PURPOSE: Sequestosome 1 (p62) is a multifunctional adapter protein accumulating in autophagy-defective cells. EXPERIMENTAL DESIGN: To evaluate the clinical impact and relationship with key genomic alterations in prostate cancer, p62 protein levels were analyzed by immunohistochemistry on a tissue microarray containing 12,427 prostate cancers. Data on ERG status and deletions of PTEN, 3p13, 5q21, and 6q15 were available from earlier studies. RESULTS: p62 immunostaining was absent in benign prostatic glands but present in 73% of 7,822 interpretable prostate cancers. Strong cytoplasmic p62 staining was tightly linked to high Gleason grade, advanced pathologic tumor (pT) stage, positive nodal status, positive resection margin, and early PSA recurrence (P < 0.0001 each). Increased levels of p62 were significantly linked to TMPRSS2-ERG fusions, both by FISH and immunohistochemical analysis (P < 0.0001 each). For example, moderate or strong p62 immunostaining was seen in 28.5% of cancers with TMPRSS2 ERG fusion detected by FISH and in 23.1% of cancers without such rearrangements (P < 0.0001). Strong p62 staining was significantly linked to the presence of all tested deletions, including PTEN (P < 0.0001), 6q15 (P < 0.0001), 5q21 (P = 0.0002), 3p13 (P = 0.0088), and 6q15 (P < 0.0001), suggesting a link between p62 accumulation and loss of genomic stability. The prognostic role of p62 protein accumulation was striking and independent of Gleason grade, pT stage, pN stage, surgical margin status, and preoperative PSA, regardless of whether preoperative or postoperative parameters were used for modeling. CONCLUSIONS: Our study identifies cytoplasmic accumulation of p62 as a strong predictor of an adverse prognostic behavior of prostate cancer independently from established clinicopathologic findings. PMID- 25925891 TI - A Randomized Phase II Trial of Sipuleucel-T with Concurrent versus Sequential Abiraterone Acetate plus Prednisone in Metastatic Castration-Resistant Prostate Cancer. AB - PURPOSE: This phase II open-label study evaluated the effect of concurrent or sequential administration of abiraterone acetate plus prednisone (AA + P) on sipuleucel-T manufacture and immune responses in metastatic castration-resistant prostate cancer (mCRPC) patients. EXPERIMENTAL DESIGN: mCRPC patients received sipuleucel-T followed by AA + P 1 day (concurrent) or 10 weeks (sequential) after the first sipuleucel-T infusion. AA + P treatment continued for 26 weeks. The primary endpoint was cumulative antigen presenting cell (APC) activation, and secondary endpoints included cumulative APC number and total nucleated cell counts. Additional endpoints included in vivo peripheral immune responses to sipuleucel-T (T-cell responses, T-cell proliferation, humoral responses, and antigen spread) as well as safety. RESULTS: Sixty-nine mCRPC patients were enrolled, with 35 and 34 patients randomized to the concurrent and sequential arms, respectively. Ex vivo APC activation was significantly greater at the second and third infusions compared with baseline in both arms (P < 0.05), indicative of an immunologic prime-boost effect. In both arms, sipuleucel-T product parameter profiles and peripheral immune responses were consistent with previously conducted sipuleucel-T phase III trials. Antigen spread was similarly observed in both arms and consistent with the other immunologic endpoints. CONCLUSIONS: These data suggest that sipuleucel-T can be successfully manufactured during concurrent administration of AA + P without blunting immunologic effects or altering immune parameters that correlate with sipuleucel T's clinical benefit. Combination of these agents was well tolerated, with no new safety signals emerging. PMID- 25925893 TI - Spatial QT Dispersion Predicts Nonsustained Ventricular Tachycardia and Correlates with Confined Systodiastolic Dysfunction in Hypertrophic Cardiomyopathy. AB - OBJECTIVES: An increased dispersion of myocardial repolarization represents one of the mechanisms underlying the arrhythmic risk in hypertrophic cardiomyopathy (HCM). We investigated spatial myocardial repolarization dispersion indices in HCM patients with nonsustained ventricular tachycardia (NSVT) and, contextually, their main clinical determinants. METHODS: Fifty-two well-matched HCM outpatients were categorized into two groups according to the presence or the absence of NSVT at 24-hour Holter electrocardiogram (ECG) monitoring. Each patient underwent a clinical examination, including Doppler echocardiogram integrated with tissue Doppler imaging, cardiac magnetic resonance, and 12-lead surface ECG to calculate the dispersion for the following intervals: QRS, Q-Tend (QTe), Q-Tpeak, Tpeak Tend (TpTe), J-Tpeak, and J-Tend. RESULTS: The NSVT group showed only QTe dispersion and TpTe dispersion values to be significantly higher than their counterparts. NSVT occurrence was independently predicted by late gadolinium enhancement presence (p=0.021) and QTe Bazett dispersion (p=0.030), the latter strongly associated with the myocardial performance index (MPI) obtained at the basal segment of the interventricular septum (p=0.0004). CONCLUSION: Our data support QTe dispersion as an easy and noninvasive tool for identifying HCM patients with NSVT propensity. The strong relationship between QTe dispersion and MPI allows us to hypothesize an intriguing link between electrical instability and confined myocardial areas of systodiastolic dysfunction. PMID- 25925892 TI - Whole Exome Sequencing Reveals the Order of Genetic Changes during Malignant Transformation and Metastasis in a Single Patient with NF1-plexiform Neurofibroma. AB - PURPOSE: Malignant peripheral nerve sheath tumors (MPNST) occur at increased frequency in individuals with neurofibromatosis type 1 (NF1), where they likely arise from benign plexiform neurofibroma precursors. While previous studies have used a variety of discovery approaches to discover genes associated with MPNST pathogenesis, it is currently unclear what molecular events are associated with the evolution of MPNST from plexiform neurofibroma. EXPERIMENTAL DESIGN: Whole exome sequencing was performed on biopsy materials representing plexiform neurofibroma (n = 3), MPNST, and metastasis from a single individual with NF1 over a 14-year period. Additional validation cases were used to assess candidate genes involved in malignant progression, while a murine MPNST model was used for functional analysis. RESULTS: There was an increasing proportion of cells with a somatic NF1 gene mutation as the tumors progressed from benign to malignant, suggesting a clonal process in MPNST development. Copy number variations, including loss of one copy of the TP53 gene, were identified in the primary tumor and the metastatic lesion, but not in benign precursor lesions. A limited number of genes with nonsynonymous somatic mutations (betaIII-spectrin and ZNF208) were discovered, several of which were validated in additional primary and metastatic MPNST samples. Finally, increased betaIII-spectrin expression was observed in the majority of MPNSTs, and shRNA-mediated knockdown reduced murine MPNST growth in vivo. CONCLUSIONS: Collectively, the ability to track the molecular evolution of MPNST in a single individual with NF1 offers new insights into the sequence of genetic events important for disease pathogenesis and progression for future mechanistic study. PMID- 25925894 TI - Virulence and Antibiotic Resistance of Pseudomonas aeruginosa Isolated from Patients with Urinary Tract Infections in Southern Poland. AB - BACKGROUND: The aim of this study was to analyze the resistance and virulence of Pseudomonas aeruginosa strains causing urinary tract infections in in- and outpatients in Southern Poland. METHODS: The study included 83 inpatients and 66 outpatients; 36.9% were female. RESULTS: Monomicrobial infections accounted for 74.5%; polymicrobial infections occurred more frequently among inpatients (odds ratio, OR = 4.32, p = 0.0008). exoS and lasB were detected in 90 and 74% of isolates, respectively. aprA was present in 66%, pilB in 5% and pilA in 23% of isolates. Isolates from adults were more frequently resistant to fluoroquinolones (OR = 0.37, p = 0.029). Twenty-nine isolates were classified as multidrug resistant and 12 as extremely drug resistant, which occurred less frequently in patients <17 years (OR = 0.18, p = 0.024). Nine metallo-beta-lactamase-positive isolates were identified. blaSHV was present in 10, blaTEM in 6, blaOXA-10 in 3 and blaVIM-2 in 3 isolates. CONCLUSION: Antibiotic selection should be based on the knowledge of local antimicrobial susceptibilities to maximize the benefit for patients and minimize the risk of drug resistance. PMID- 25925895 TI - Low-threshold wavelength-switchable organic nanowire lasers based on excited state intramolecular proton transfer. AB - Coherent light signals generated at the nanoscale are crucial to the realization of photonic integrated circuits. Self-assembled nanowires from organic dyes can provide both a gain medium and an effective resonant cavity, which have been utilized for fulfilling miniaturized lasers. Excited-state intramolecular proton transfer (ESIPT), a classical molecular photoisomerization process, can be used to build a typical four-level system, which is more favorable for population inversion. Low-power driven lasing in proton-transfer molecular nanowires with an optimized ESIPT energy-level process has been achieved. With high gain and low loss from the ESIPT, the wires can be applied as effective FP-type resonators, which generated single-mode lasing with a very low threshold. The lasing wavelength can be reversibly switched based on a conformation conversion of the excited keto form in the ESIPT process. PMID- 25925896 TI - To have sex or not to have sex? An online focus group study of sexual decision making among sexually experienced and inexperienced gay and bisexual adolescent men. AB - Adolescent gay and bisexual men (AGBM) are at disproportionately high risk for HIV and other sexually transmitted infections, yet healthy sexuality and HIV prevention programs grounded in experiences unique to AGBM (e.g., coming out) are lacking, as is the formative work necessary to inform such programs. A richer understanding of factors informing AGBM's decisions to have or not have sex is needed. To fill this gap in the literature, we conducted qualitative and mixed methods analyses of data collected in online focus groups with 75 ethnically diverse 14-18-year-old AGBM across the United States. Findings suggest that many reasons why AGBM choose to have or abstain from sex mirror those noted in the previous literature as influential for heterosexual adolescents (e.g., temptation, "horniness"). AGBM conveyed additional experiences/concerns that appeared unique to their sexual identity, particularly fears about pain during anal sex, and difficulties safely and accurately identifying same-sex partners. Both sexually experienced and inexperienced youth voiced reasons to wait or stop having sex. Sexually inexperienced youth said their motivations centered on wanting to avoid STIs and HIV, a desire to wait for the right partner, and the specialness of sex. On the other hand, sexually experienced AGBM said they stopped having sex if there was not an available partner they had interest in, or to improve their romantic relationship. Thus, while our findings suggest that there may be common factors across sexual identities that impact youth's sexual decision making, healthy sexuality programs for AGBM also need to address issues specific to being gay and bisexual. PMID- 25925897 TI - A Comparison of Two Models of Risky Sexual Behavior During Late Adolescence. AB - Two models of risky sexual behavior (RSB) were compared in a community sample of late adolescents (N = 223). For the traumagenic model, early negative sexual experiences were posited to lead to an association between negative affect with sexual relationships. For the cognitive escape model, depressive affect was posited to lead to engagement in RSB as a way to avoid negative emotions. The current study examined whether depression explained the relationship between sexual trauma and RSB, supporting the cognitive escape model, or whether it was sexual trauma that led specifically to RSB, supporting the traumagenic model. Physical trauma experiences were also examined to disentangle the effects of sexual trauma compared to other emotionally distressing events. The study examined whether the results would be moderated by participant sex. For males, support was found for the cognitive escape model but not the traumagenic model. Among males, physical trauma and depression predicted engagement in RSB but sexual trauma did not. For females, support was found for the traumagenic and cognitive escape model. Among females, depression and sexual trauma both uniquely predicted RSB. There was an additional suppressor effect of socioeconomic status in predicting RSB among females. Results suggest that the association of trauma type with RSB depends on participant sex. Implications of the current study for RSB prevention efforts are discussed. PMID- 25925899 TI - The Nature and Meaning of Body Concepts in Everyday Language and Theoretical Discourse. AB - Within phenomenological philosophy four topics, (1) Body, (2) Time, (3) Others and the Social Order and (4) World serve as the major contexts in which human perception, action and reflection take place. At present only three of these domains have been studied from an empirical perspective, leaving Body as the one domain requiring further analysis. Given this state of affairs, the purpose of the present study is to determine the everyday and theoretical meanings of body. To accomplish this task participants coded randomly selected body- related words into groups on the basis of having similar meanings. Once these groupings were established they were then evaluated by statistical clustering and multidimensional scaling procedures. Results indicated that it was possible to define the everyday meaning of the human experience of the human body in terms of the following set of themes: (1) inside/outside, (2) visible/not visible, (3) vitality and activity, (4) instrument and object and (5) appearance and self expression. Concerns about the representativeness of the words studied led to the development and use of individual word pools from which a set of 50 partially different words was randomly selected for each participant. Results indicated little difference between themes produced in the present study when compared with those of an earlier study. The specific themes derived from the present study were then related to embodiment issues as reflected in the philosophical writings of Merleau-Ponty, the psycholinguistic analyses of Lakoff and Johnson and experimental psychology. PMID- 25925898 TI - Sociocognitive Predictors of Condom Use and Intentions Among Adolescents in Three Sub-Saharan Sites. AB - Many HIV intervention programs in sub-Saharan Africa have applied social cognitive theories such as the theory of planned behavior. However, a recent sub Saharan African review was unable to show increased effectiveness for theory based interventions. This study assessed whether the predictive value of attitudes, subjective norms, self-efficacy, and intention was similar to studies in Europe and the U.S., and whether there were differences between three sub Saharan sites. Longitudinal multigroup structural equation modeling was used to assess whether attitudes, subjective norms, and self-efficacy predicted condom use intentions and condom use (after 6 months) among adolescents in three sites, namely Cape Town (South Africa; N = 625), Dar es Salaam (Tanzania; N = 271), and Mankweng (South Africa; N = 404). Condom use intentions were predicted by subjective norms and self-efficacy in all three sites. Attitudes were not related to intentions in Dar es Salaam and were moderately related to intentions in Cape Town and Mankweng. The proportions of explained variance in intentions and behavior were decent (37-52 and 9-19%, respectively). Although significant differences in predictive value were found between sites and in comparison to European and U.S. studies, intentions could adequately be explained by attitudes, subjective norms, and self-efficacy. However, the limited proportions of variance in behavior explained by intentions could signify the importance of contextual and environmental factors. Future studies are recommended to use an integrative approach that takes into account both individual and contextual factors, as well as social and environmental differences. PMID- 25925900 TI - Is esophageal pressure monitoring essential for the most critically ill? PMID- 25925901 TI - An additional tip to facilitate glidescope intubation. PMID- 25925902 TI - Measuring (and interpreting) the esophageal pressure: a challenge for the intensivist. PMID- 25925903 TI - Anti-apoptotic effect of microRNA-30b in early phase of rat myocardial ischemia reperfusion injury model. AB - This study aimed to investigate the effect of microRNA-30b (miR-30b) in rat myocardial ischemic-reperfusion (I/R) injury model. We randomly divided Sprague Dawley (SD) rats (n = 80) into five groups: 1) control group; 2) miR-30b group; 3) sham-operated group; 4) I/R group, and 5) I/R+miR-30b group. Real-time quantitative polymerase chain reaction, immunohistochemical staining and Western blot analysis were conducted. TUNEL assay was employed for testing cardiomyocyte apoptosis. Our results showed that miR-30b levels were down-regulated in I/R group and I/R + miR-30b group compared with sham-operated group (both P < 0.05). However, miR-30b level in I/R + miR-30b group was higher than I/R group (P < 0.05). Markedly, the apoptotic rate in I/R group showed highest in I/R group (P < 0.05). Additionally, the results illustrated that protein levels of Bcl-2, Bax, and caspase-3 were at higher levels in ischemic regions in I/R group, comparing to sham-operated group (all P < 0.05), while Bcl-2/Bax was reduced (P < 0.05). Bcl-2 level and Bcl-2/Bax were obviously increased in I/R + miR-30b group by comparison with I/R group, and expression levels of Bax and caspase-3 were down regulated (all P < 0.05). We also found that in I/R + miR-30b group, KRAS level was apparently lower and p-AKT level was higher by comparing with I/R group (both P < 0.05). Our study indicated that miR-30b overexpression had anti-apoptotic effect on early phase of rat myocardial ischemia injury model through targeting KRAS and activating the Ras/Akt pathway. PMID- 25925904 TI - Renal artery stenting may not be appropriate for patients with atherosclerotic renal artery stenosis. AB - INTRODUCTION: This study compared aortorenal bypass to renal artery stenting to determine the most efficacious and financially sound method for treating patients with atherosclerotic renal artery stenosis (RAS). METHODS: A decision analysis using direct and indirect costs, and value of statistical life (VSL) was completed. Direct costs were obtained using the Nationwide Inpatient Sample (NIS), indirect costs from the National Institute of Diabetes and Digestive and Kidney Diseases, and VSL from the Department of Transportation. A variance-based sensitivity analysis was completed to assess the accuracy of the decision analysis. RESULTS: Aortorenal bypass has a 95% five-year patency, a 98% 30-day survival, a 26% rate of overall complications, and a 70% five-year dialysis-free survival. Renal artery stenting has a 56% five-year patency, a 99% 30-day survival, a 40% rate of complications, and a 65% five-year dialysis-free survival. Renal artery stenting has an overall cost of $305,370 and aortorenal bypass has an overall cost of $103,453 per patient. After accounting for VSL, renal artery stenting has a negative value of -$182,270 and aortorenal bypass has a value of $415,881. CONCLUSIONS: Lower five-year patency and higher rate of complications from renal artery stenting that ultimately lead to significantly lower five-year dialysis-free survival. PMID- 25925905 TI - Individual variations in ankle brachial index measurement among Turkish adults. AB - PURPOSE: Variability of ankle brachial index (ABI) measured by the same observer in the same individual on three different occasions was examined. BASIC METHODS: A single morning ABI was initially determined (measurement 1) with handheld Doppler device. One to four weeks apart, another morning (measurement 2) and afternoon (measurement 3) ABI was measured on the same day. PRINCIPAL FINDINGS: A total of 161 adults were enrolled. Mean ABI was similar among the three measurements. ABI differed more than >=0.15 in 15 individuals between measurement 1 and 3, in 10 subjects between measurement 1 and 2, and in 12 individuals between measurement 2 and 3. Intra-group correlation coefficients of reproducibility of ABI were 0.808 for single measurements (coefficient of the values lacking association with each other), and 0.927 for average measurements (coefficient of the values that were associated with each other). CONCLUSIONS: Although reproducibility of ABI values was found satisfactory, up to 12% of participants displayed more than 0.15 alternations between measurements, either on the same day or more than a week apart. PMID- 25925906 TI - Impaired aortic elastic properties in primary osteoarthritis. AB - Osteoarthritis is one of the most common chronic diseases and associated with increased cardiovascular comorbidity and deaths. Elastic properties of aorta are closely associated with cardiovascular mortality and morbidity. In our study, we aimed to evaluate aortic stiffness in primary osteoarthritis patients. A total of 160 patients including 80 patients with primary knee osteoarthritis and 80 controls without osteoarthritis were included in the study. Additionally, osteoarthritis patients were divided into four subgroups according to the severity of the disease. Aortic parameters were evaluated by using transthoracic echocardiography method. While measurements of aortic stiffness of osteoarthritis group were higher compared to the control group (p < 0.01), aortic strain and aortic distensibility measurements of osteoarthritis group are lower than the control group (p < 0.01). Additionally, it was determined that as the severity of osteoarthritis increased also aortic stiffness increased highly significantly (p = 0.001). Presence and severity of osteoarthritis are closely associated with elastic properties of aorta, which are correlated with cardiovascular mortality and morbidity. PMID- 25925907 TI - Emergent conversion of the Ovation Stent Graft System to aortouniiliac modification via occlusion of a unilateral internal iliac artery with a stentgraft as a bailout solution. AB - PURPOSE: To present a case of inadvertent collapse of the contralateral limb gate caused by misorientation during the deployment of the Ovation Abdominal Stent Graft System in a narrow aortic lumen and the bailout conversion to aortouniiliac modification, using a covered stent to exclude the orifice of the internal iliac artery (IIA). TECHNIQUE DESCRIPTION: Despite the repeated efforts from the femoral and brachial site, the collapsed/occluded contralateral limb gate could not be catheterized. In order to exclude successfully the orifice of the IIA, an oversized stentgraft was placed immediately at the common-to-external iliac artery (CIA-EIA) transition followed by peripheral ligation of the latter. The procedure was completed with crossover femorofemoral bypass. CONCLUSION: Occlusion the IIA orifice with an oversized stentgraft in the CIA-EIA transition can be considered as a safe, simple, fast, and efficient bailout maneuver, followed by EIA ligation and crossover bypass. PMID- 25925909 TI - NextGen nuclear DNA sequencing in cyclic vomiting syndrome reveals a significant association with the stress-induced calcium channel (RYR2). AB - BACKGROUND: Cyclic vomiting syndrome (CVS) is a common, frequently disabling, 'functional' condition characterized by recurring, stereotypical attacks of intense nausea, vomiting, and lethargy, with the essential absence of these symptoms between episodes. Although the pathogenesis of CVS is yet unexplained, evidence has accumulated which suggest pathogenic roles for stress-related, autonomic, neuroendocrine, and mitochondrial factors. The objective of this pilot study was to elucidate mechanism(s) by identifying genes involved in the presumed multifactorial pathogenesis of CVS. METHODS: In this pilot study, DNA from 75 unrelated CVS cases and 60 healthy controls were assayed by Courtagen Life Science's next-generation sequencing platform (nucSEEK(TM) ), including over 1100 nuclear-encoded genes involved with mitochondria, metabolism, or ion channels. Significant sequence variants were defined as evolutionary conservation at least to Xenopus (frog) per the UCSC Genome Browser. KEY RESULTS: The RYR2 gene, encoding a stress-induced calcium channel present in many neurons, was the only gene demonstrating a statistically significant difference in the proportion of conserved sequence variants among the groups (18/75 CVS, 24%, vs 3/60 controls, 5%; p = 0.0018, OR = 6.0, 95% CI = 1.7-22). CONCLUSIONS & INFERENCES: We propose a mechanism in which RYR2 sequence variants result in aberrant stress-induced calcium release into the mitochondria of autonomic neurons, resulting in an increased risk to develop autonomic/functional disease such as CVS, and related conditions such as migraine and gut dysmotility. This model incorporates the existing hypotheses regarding CVS pathogenesis into a cohesive mechanism, and might have treatment implications. PMID- 25925910 TI - Small bowel: from sideline to center stage in gastroenterology. PMID- 25925908 TI - Insight into the beneficial immunomodulatory mechanism of the sevoflurane metabolite hexafluoro-2-propanol in a rat model of endotoxaemia. AB - Volatile anaesthetics such as sevoflurane attenuate inflammatory processes, thereby impacting patient outcome significantly. Their inhalative administration is, however, strictly limited to controlled environments such as operating theatres, and thus an intravenously injectable immunomodulatory drug would offer distinct advantages. As protective effects of volatile anaesthetics have been associated with the presence of trifluorinated carbon groups in their basic structure, in this study we investigated the water-soluble sevoflurane metabolite hexafluoro-2-propanol (HFIP) as a potential immunomodulatory drug in a rat model of endotoxic shock. Male Wistar rats were subjected to intravenous lipopolysaccharide (LPS) and thereafter were treated with HFIP. Plasma and tissue inflammatory mediators, neutrophil invasion, tissue damage and haemodynamic stability were the dedicated end-points. In an endotoxin-induced endothelial cell injury model, underlying mechanisms were elucidated using gene expression and gene reporter analyses. HFIP reduced the systemic inflammatory response significantly and decreased endotoxin-induced tissue damage. Additionally, the LPS-provoked drop in blood pressure of animals was resolved by HFIP treatment. Pathway analysis revealed that the observed attenuation of the inflammatory process was associated with reduced nuclear factor kappa B (NF-kappaBeta) activation and suppression of its dependent transcripts. Taken together, intravenous administration of HFIP exerts promising immunomodulatory effects in endotoxaemic rats. The possibility of intravenous administration would overcome limitations of volatile anaesthetics, and thus HFIP might therefore represent an interesting future drug candidate for states of severe inflammation. PMID- 25925911 TI - Small bowel, celiac disease and adaptive immunity. AB - BACKGROUND: Celiac disease is a multifactorial and polygenic disease with autoimmune features. The disease is caused by an inappropriate immune response to gluten. Elimination of gluten from the diet leads to disease remission, which is the basis for today's treatment of the disease. There is an unmet need for new alternative treatments. KEY MESSAGES: Genetic findings point to adaptive immunity playing a key role in the pathogenesis of celiac disease. MHC is by far the single most important genetic factor in the disease. In addition, a number of non MHC genes, the majority of which have functions related to T cells and B cells, also contribute to the genetic predisposition, but each of them has modest effect. The primary MHC association is with HLA-DQ2 and HLA-DQ8. These HLA molecules present gluten epitopes to CD4+ T cells which can be considered to be the master regulators of the immune reactions that lead to the disease. The epitopes which the T cells recognize are usually deamidated, and this deamidation is mediated by the enzyme transglutaminase 2 (TG2). Celiac disease patients have disease-specific antibodies. In addition to antibodies to gluten, these include autoantibodies to TG2. Antibodies to deamidated gluten are nearly as specific for celiac disease as the anti-TG2 antibodies. Both types of antibodies appear only to be produced in subjects who are HLA-DQ2 or HLA-DQ8 when they are consuming gluten. CONCLUSION: It is hardly coincidental that TG2 is implicated in T-cell epitope formation and at the same time a target for autoantibodies. Understanding this connection is one of the major challenges for obtaining a complete understanding of how gluten causes tissue destruction and remodeling of the mucosa in the small bowel. PMID- 25925912 TI - Interleukin-15, a master piece in the immunological jigsaw of celiac disease. AB - BACKGROUND: The immune response causing celiac disease (CD) depends on the activation of intestinal CD4+ T cells by gluten-derived peptides presented by HLA DQ2 or HLA-DQ8 molecules, the main genetic risk factor. However, additional factors are necessary to impair immune tolerance to dietary gluten, to stimulate intraepithelial lymphocytes (IEL) and to induce intestinal damage. KEY MESSAGES: Current data point to a central role of interleukin-15 (IL-15). In situ and ex vivo studies indicate that IL-15 stimulates the accumulation and cytotoxic activation of CD8+ T IEL in active CD, and that of the malignant innate-like IEL in type II refractory CD (RCDII). Other studies show that IL-15 impairs the immunoregulatory control of effector T cells, notably CD8+. Recently, animal models have been designed to investigate the respective role of CD4+ T cells and IL-15 in CD. We discuss more particularly our results in such a model, which shows that IL-15 produced in excess in the intestine can cooperate with CD4+ T cells specific for a dietary antigen to trigger a celiac-like enteropathy. In this mouse model, CD4+ T cells activated by dietary ovalbumin secreted IL-2 which, along with IL-15, stimulated the expansion of noncognate intestinal cytotoxic CD8+ T cells containing large amounts of granzyme B. In the presence of IL-15, the latter cells did not respond to regulatory T cells, and accumulated in the intestine close to epithelial damage. CONCLUSION: On the basis of these data, we propose that, in CD, gluten-specific CD4+ T cells synthesize cytokines that synergize with IL-15 to license the expansion and activation of cytotoxic IEL, which drive tissue damage. We suggest that IL-15 is a meaningful therapeutic target, notably in patients with RCDII in which malignant IEL can respond to IL 15 independently of signals provided by CD4+ T cells. PMID- 25925913 TI - Host-microbiota interactions in the intestine. AB - The comprehensive collection of bacterial species, termed microbiota, within human and other mammalian hosts has profound effects on both innate and adaptive immunity. Multiple host innate mechanisms contribute to intestinal homeostasis, including epithelial production of protective mucin layers maintaining spatial segregation in the intestine as well as epithelial cell secretion of a broad range of antimicrobial peptides. Additionally, epithelial cells employ autophagy to contain and eliminate invading bacteria; interestingly, genetic variants in specific autophagy genes are linked to susceptibility to Crohn's disease. Innate lymphoid cells, which rapidly respond to cytokine and microbial signals, have emerged as important regulators of the intestinal immune response to the microbiota. With regard to adaptive immunity, specific microbial species stimulate induction of regulatory T cells while others induce effector T cells within the gut. Such stimulation is subject to dysregulation during inflammation and disease, contributing to 'dysbiosis' or an abnormal microbiota composition that has been associated with a variety of immune-mediated inflammatory disorders, including celiac disease. The microbiota communicates with the immune system and vice versa; thus, an abnormal microbiota composition likely translates into an altered host immune response, though the exact mechanisms of such are not yet clear. Immunoglobulin A plays a critical role in limiting bacterial access to the host and in maintaining mutualism with the microbiota. Perturbation of the mucosal barrier via infection or other means can induce effector T cells reactive to the intestinal microbiota, and these cells can persist as memory cells for extended periods of time and potentially serve as pathogenic effector cells upon re-encounter with antigen. Health is associated with a diverse microbiota that functions to maintain the balance between T effector and T regulatory cells in the intestine. Whether dysbiosis can be reversed in immune-mediated disease, thus restoring health, is a question of intense interest for this active area of research. PMID- 25925914 TI - Clinical manifestations of celiac disease. AB - Celiac disease (CD) is an immune-based condition affecting multiple organ systems. Clinical manifestations are manifold in form and number due to the multisystem nature of CD. There has been a progressive change in the clinical manifestations over the recent decades with fewer patients, both adults and children, presenting with a diarrheal, classical form. This, in children, is seen in only the youngest, while growth issues, screening at-risk groups and recurrent abdominal pain are the most common modes of presentation among children. Among adults, diarrhea is the most common presentation followed by anemia. Screening at risk groups, metabolic bone disease and incidental recognition at endoscopy performed for reflux are the other main modes of presentation. The bulk of those with CD remain undiagnosed. The symptoms are often common, and increased medical education should lead to greater awareness in the medical community and an increased rate of diagnosis. PMID- 25925915 TI - World perspective and celiac disease epidemiology. AB - In Europe and the USA, the mean frequency of celiac disease (CD) in the general population is approximately 1%, with some regional differences, the reasons for which remain elusive. A similar disease prevalence has been found in other countries mostly populated by individuals of European origin, e.g. Australia and Argentina. In Western countries, a true rise in overall CD prevalence of CD has been documented. CD is a common disorder in North Africa, the Middle East and India; however, the diagnostic rate is low in these countries due to low availability of diagnostic facilities and poor disease awareness. The highest CD prevalence in the world (5.6%) has been described in an African population originally living in Western Sahara, the Saharawi, of Arab-Berber origin. The reasons for this high CD frequency are unclear but could be primarily related to recent dietary changes and genetic factors, given the high level of consanguinity of this population. Further studies are needed to quantify the incidence of the celiac condition in apparently 'celiac-free' areas such as Sub-Saharan Africa and the Far East. In many developing countries, the frequency of CD is likely to increase in the near future given the diffuse tendency to adopt Western, gluten rich dietary patterns. As most cases currently escape diagnosis all over the world, an effort should be made to increase the awareness of CD polymorphism. A cost-effective case-finding policy and new strategies of mass CD screening could significantly reduce the morbidity and mortality associated with untreated disease. The current high prevalence of CD is just the last link in a chain of events started about 10,000 years ago after wheat domestication and diffusion from the Middle East. We hypothesize different mechanisms to explain the so called evolutionary celiac paradox of co-localization of gluten consumption and HLA CD-predisposing genotypes. PMID- 25925916 TI - Extraintestinal manifestations of celiac disease. AB - Case finding for celiac disease (CD) is becoming increasingly common practice and is conducted in a wide range of clinical situations ranging from the presence of gastrointestinal symptoms to failure to thrive in children, prolonged fatigue, unexpected weight loss and anemia. Case finding is also performed in associated conditions, such as autoimmune thyroid disease, dermatitis herpetiformis and type 1 diabetes, as well as in patients with irritable bowel syndrome, unexplained neuropsychiatric disorders and first-degree relatives of patients with diagnosed CD. This aggressive active case finding has dramatically changed the clinical characteristics of newly diagnosed patients. For instance, higher numbers of patients who present with extraintestinal symptoms are now being diagnosed with CD. Current recommendations state that due to a high risk for complications if the disease remains undiagnosed, patients with extraintestinal symptoms due to CD require appropriate diagnosis and treatment. Despite criticism regarding the cost effectiveness of case finding in CD, such an aggressive approach has been considered cost-effective for high-risk patients. The diagnosis of CD among patients with extraintestinal symptoms requires a high degree of awareness of the clinical conditions that carry a high risk for underlying CD. Also, understanding the correct use of specific serology and duodenal histology is key for an appropriate diagnostic approach. Both procedures combined are able to confirm diagnosis in the vast majority of cases. However, in certain circumstances, serology and even duodenal histology cannot confirm or rule out CD. A common cause of negative IgA serology is IgA deficiency. For such eventuality, IgG-based serological tests can help confirm the diagnosis. Importantly, some histologically diagnosed cases still remain seronegative despite exclusion of IgA deficiency. On the other hand, duodenal histology may be normal despite the presence of CD-specific antibodies and active CD. This has been clearly demonstrated in some cases of untreated dermatitis herpetiformis, but may also be due to the patchy condition of CD or lesions that are not adequately recognized by nonexpert endoscopists and/or pathologists. The effectiveness of agluten-free diet depends on the clinical end point addressed. A good example is the outcome of bone loss. While risk for fracture normalizes after the first year of dietary treatment, bone parameters measured by densitometry may not be normalized in the long-term follow-up. Moreover, it is still unclear how far an early gluten-free diet will positively affect associated autoimmune diseases like type 1 diabetes and autoimmune thyroiditis. PMID- 25925917 TI - Celiac disease and endocrine autoimmunity. AB - BACKGROUND: Celiac disease (CD) is a small-intestinal inflammatory disease that is triggered by the ingestion of the storage proteins (gluten) of wheat, barley and rye. KEY MESSAGES: Endocrine autoimmunity is prevalent in patients with CD and their relatives. The genes that predispose to endocrine autoimmune diseases, e.g. type 1 diabetes, autoimmune thyroid diseases, and Addison's disease, i.e. DR3-DQ2 and DR4-DQ8, are also the major genetic determinants of CD, which is the best understood HLA-linked disease. Thus, up to 30% of first-degree relatives both of patients with CD and/or endocrine autoimmunity are affected by the other disease. In CD, certain gluten proteins bind with high affinity to HLA-DQ2 or DQ8 in the small-intestinal mucosa, to activate gluten-specific T cells which are instrumental in the destruction of the resorptive villi. Here, the autoantigen tissue transglutaminase increases the T cell response by generating deamidated gluten peptides that bind more strongly to DQ2 or DQ8. Classical symptoms such as diarrhea and consequences of malabsorption like anemia and osteoporosis are often absent in patients with (screening-detected) CD, but this absence does not significantly affect these patients' incidence of endocrine autoimmunity. Moreover, once autoimmunity is established, a gluten-free diet is not able to induce remission. However, ongoing studies attempt to address how far a gluten free diet may prevent or retard the development of CD and endocrine autoimmunity in children at risk. CONCLUSIONS: The close relationship between CD and endocrine autoimmunity warrants a broader immune genetic and endocrine screening of CD patients and their relatives. PMID- 25925918 TI - Celiac disease: prevention in children. AB - Several studies have suggested a protective role of breastfeeding and/or the timing and quantity of gluten introduction in the subsequent development of celiac disease. Especially, prolonged breastfeeding during the introduction of gluten-containing feeding has been associated with a reduced risk of developing celiac disease in infancy. The mentioned results suggest the existence of a 'window of opportunity' between 4 and 6 months of age in which gluten can be introduced in small amounts. Therefore, the European Society for Pediatric Gastroenterology Hepatology and Nutrition recommends avoiding gluten introduction before the age of 4 months and after the age of 7 months and that gluten should be preferably introduced during ongoing breastfeeding. However, the influence of breastfeeding in the development of celiac disease is not clear, since some studies report prevention and others do not, and the studies reporting a protective effect of breastfeeding do not make clear if it concerns prevention of the disease or delays the onset of symptoms. In addition, most of the studies on this topic have been observational and retrospective. For these reasons, prospective studies are needed to understand the relationship between early nutrition in particular and environmental factors in general, concerning the development and possible prevention of celiac disease. Some of these studies are ongoing. One example is the European multicenter PreventCD project (www.preventcoeliacdisease.com) among infants with a first-degree family member with celiac disease carrying HLA-DQ2 and/or -DQ8, randomized to a double-blind dietary intervention with 100 mg of gluten daily or placebo between the age of 4 6 months. All included children are already 3 years old, and the first analyses are being prepared (http://www.trialregister.nl). PMID- 25925919 TI - Celiac disease screening in southern and East Asia. AB - Until 1970s, celiac disease (CD) was considered to be an uncommon disease except in Western Europe. The global epidemiology of CD continues to evolve with improvement in the diagnostic tests, simplification of the diagnostic criteria and increase in awareness about the disease. The Asian region is currently at the crossroads of the frontier of knowledge and awareness of CD. In many Asian nations, CD is still considered to be either nonexistent or very rare. A notable exception is India, where CD has been well recognized, especially in the northern part, and 2 population-based studies have revealed a prevalence of 0.3-1.04%. Initial reports from Malaysia, China, Japan and Singapore suggest the existence of CD in these countries. Furthermore, a meta-analysis of the predisposing factors predicts a high probability of occurrence of CD in fair numbers in China. There are no formal reports on CD from Malaysia, Indonesia, Korea, Taiwan and many other nations in this region. With the impending CD epidemic in Asia, there are many challenges. Some of the efforts which are required include determination of prevalence of CD across the region, spreading of awareness among physicians and patients, training of dieticians for proper counseling and supervision of patients, creation of gluten-free food infrastructure in the food supply and creation of patient advocacy organizations. Although the absolute number of patients with CD at present is not very large, this number is expected to increase over the next few years/decades. It is thus appropriate that the medical community across Asia define the extent of the problem and get prepared to handle the impending CD epidemic. PMID- 25925920 TI - Celiac disease and the gluten-free diet: consequences and recommendations for improvement. AB - BACKGROUND: Celiac disease (CD) is a chronic small intestinal immune-mediated enteropathy precipitated by exposure to dietary gluten in genetically susceptible individuals. CD-related enteropathy leads to multiple nutritional deficiencies involving macro- and micronutrients. Currently, medical nutrition therapy consisting of the gluten-free diet (GFD) is the only accepted treatment for CD. KEY MESSAGES: The GFD is the cornerstone of treatment for CD. Prior published studies have concluded that maintenance of the GFD results in improvement of the majority of nutritional deficiencies. In the past, counseling for CD focused mainly on the elimination of gluten in the diet. However, the GFD is not without its inadequacies; compliance to the GFD may result in certain deficiencies such as fiber, B vitamins, iron, and trace minerals. Paucity of fortified gluten-free foods may be responsible for certain deficiencies which develop on the GFD. Weight gain and obesity have been added to the list of nutritional consequences while on the GFD and have been partially attributed to hypercaloric content of commercially available gluten-free foods. Follow-up of patients diagnosed with CD after starting the GFD has been reported to be irregular and, hence, less than ideal. CONCLUSIONS: Monitoring of the nutritional status using blood tests and use of appropriate gluten-free supplementation are integral components in the management of CD. The ideal GFD should be nutrient-dense with naturally gluten free foods, balanced with macro- and micronutrients, reasonably priced, and easily accessible. Rotation of the pseudo-cereals provides a good source of complex carbohydrates, protein, fiber, fatty acids, vitamins and minerals. Fortification/enrichment of commonly consumed gluten-free commercial grain products should be encouraged. Dietitians specializing in CD play a critical role in the education and maintenance of the GFD for patients with CD. PMID- 25925921 TI - Eosinophilic enteritis. AB - BACKGROUND: Eosinophilic enteritis, also known as eosinophilic gastroenteritis, is a rare primary eosinophilic gastrointestinal disorder (EGID) of unknown etiology characterized by the presence of an intense eosinophilic infiltrate on histopathology of the intestinal mucosa. KEY MESSAGES: The etiology of eosinophilic enteritis remains obscure. There is growing evidence to support the role of aeroallergens and food allergens in the pathogenesis of this disorder as children and adults with EGIDs often have positive skin testing for food allergens and a familial history of allergic diseases. Moreover, significant progress has been made in elucidating that EGIDs involve mechanisms that fall between pure IgE-mediated and delayed Th2 type responses. Preclinical studies have identified a contributory role for the cytokine IL-5 and eotaxin chemokines, providing a rationale for specific disease therapy. Eosinophilic enteritis causes a wide array of gastrointestinal symptoms such as abdominal pain, diarrhea, nausea, vomiting, bloating or ascites, and its diagnosis requires a high degree of clinical likelihood given the nonspecific presentation and physical examination findings. The Klein classification arbitrarily divided patients with eosinophilic enteritis into those with predominantly mucosal, muscle layer or subserosal disease relying on the concept that clinical presentation is dependent on the predominant involved layer of the gastrointestinal tract. Main therapeutic options are represented by oral corticosteroids for a short period with good efficacy. Antihistaminic drugs and sodium cromoglycate have also been used to treat patients with eosinophilic enteritis. CONCLUSION: Eosinophilic enteritis is generally considered as a benign disease with no relapse, but half of the patients may present a more complex natural history characterized by unpredictable relapses and a chronic course. PMID- 25925922 TI - Tropheryma whipplei , Immunosuppression and Whipple's Disease: From a Low Pathogenic, Environmental Infectious Organism to a Rare, Multifaceted Inflammatory Complex. AB - BACKGROUND: The actinobacterium Tropheryma whipplei was detected 20 years ago by molecular techniques, and following its culture has been characterized as the cause of a systemic infection known as Whipple's disease (WD). T. whipplei occurs in the environment, is prevalent only in humans, is believed to be transmitted via oral routes and to be host dependent. KEY MESSAGES: The classical form of T. whipplei infection, i.e. classical WD (CWD), is rare. It is well defined as slowly progressing chronic infection with arthralgia, diarrhea and weight loss, mostly in middle-aged men. However, current research revealed a much broader spectrum of clinical features associated with T. whipplei infection. Thus, T. whipplei may cause acute and transient infections (observed primarily in children) and the bacterium, which is found in soil and water, occurs in asymptomatic carriers as well as in CWD patients in clinical remission. In addition, T. whipplei affects isolated and localized body compartments such as heart valves or the central nervous system. Subtle immune defects and HLA associations have been described. New findings indicate that the progression of asymptomatic T. whipplei infection to clinical WD may be associated with medical immunosuppression and with immunomodulatory conditions. This explains that there is a discrepancy between the widespread occurrence of T. whipplei and the rareness of WD, and that T. whipplei infection triggered by immunosuppression presents with protean clinical manifestations. CONCLUSIONS: This review highlights recent findings and the clinical spectrum of infection with T. whipplei and WD, focusing specifically on the role of host immunity and immunosuppression. Current concepts of the pathogenesis, diagnosis and therapy are discussed. PMID- 25925923 TI - Motility alterations in celiac disease and non-celiac gluten sensitivity. AB - Regulation of gut motility is complex and involves neuromuscular, immune and environmental mechanisms. It is well established that patients with celiac disease (CD) often display gut dysmotility. Studies have shown the presence of disturbed esophageal motility, altered gastric emptying, and dysmotility of the small intestine, gallbladder and colon in untreated CD. Most of these motor abnormalities resolve after a strict gluten-free diet, suggesting that mechanisms related to the inflammatory condition and disease process are responsible for the motor dysfunction. Motility abnormalities are also a hallmark of functional bowel disorders such as irritable bowel syndrome (IBS), where it has been proposed as underlying mechanism for symptom generation (diarrhea, constipation, bloating). Non-celiac gluten sensitivity (NCGS) is a poorly defined entity, mostly self diagnosed, that presents clinically with IBS symptoms in the absence of specific celiac markers. Patients with NCGS are believed to react symptomatically to wheat components, and some studies have proposed the presence of low-grade inflammation in these patients. There is little information regarding the functional characterization of these patients before and after a gluten-free diet. A study suggested the presence of altered gastrointestinal transit in NCGS patients who also have a high prevalence of nonspecific anti-gliadin antibodies. Results of an ongoing clinical study in NCGS patients with positive anti-gliadin antibodies before and after a gluten-free diet will be discussed. Elucidating the mechanisms for symptom generation in NCGS patients is important to find new therapeutic alternatives to the burden of imposing a strict gluten-free diet in patients who do not have CD. PMID- 25925924 TI - Microscopic colitis. AB - Microscopic colitis (MC) is the common denominator for lymphocytic and collagenous colitis (CC). It is now recognized as a relatively frequent cause of diarrhea that equals the prevalence of inflammatory bowel disease. Patients are typically middle-aged women, but disease may occur at every age. Patients with MC report watery, non-bloody diarrhea in the absence of endoscopic and radiologic abnormalities. Lymphocytic colitis is characterized by an increased number of intraepithelial lymphocytes, and CC by a thickened subepithelial collagen band, whereas in both an increased mononuclear infiltration of the lamina propria is found. The pathogenesis of MC is largely unknown, but may relate to autoimmunity, adverse reactions to drugs or (bacterial) toxins, and abnormal collagen metabolism in the case of CC. Budesonide is so far the only drug that has proven efficacy in randomized controlled trials both for the induction and maintenance of remission. Patients who are nonresponsive, dependent or who experience side effects on budesonide may benefit from thiopurine or anti-TNF treatment, but these options are still experimental. The long-term prognosis of MC is good; it does not appear to predispose to malignancies and can in some cases be self limiting. Further research and randomized clinical trials are required to expand our understanding of the natural course and the pathogenesis of MC. PMID- 25925925 TI - Drug-induced enteropathy. AB - BACKGROUND/AIMS: Many medications can cause diarrhea by increasing motility, inflammation or enteropathy. Olmesartan and mycophenolic acid (CellCept) are drugs that are capable of increasing inflammation and enteropathy in some individuals and, if not recognized, can lead to chronic diarrhea. It is this type of drug-induced diarrhea that is the focus of this review. METHODS: A summary of our findings (recent and earlier published) as well as a review of published works from other centers were conducted. RESULTS: There is increasing evidence that olmesartan use is associated with enteropathy in a small number of individuals who use angiotensin receptor II blockers, and that this enteropathy is characterized by severe diarrhea capable of inducing severe dehydration and, in some instances, failure of organs such as the kidney. Typical patient demographics are Caucasian individuals who are older (>50 years old) and obese or overweight prior to weight loss. Prolonged exposure to olmesartan use for 1-2 years is typical, although case reports of irbesartan and valsartan have been reported as well. Discontinuing olmesartan leads to improvement of symptoms; however, the period for healing is variable, with some patients requiring steroid therapy and even prolonged parental nutrition support. In addition, many histological features of olmesartan-associated enteropathy are also present in celiac disease, including villi shortening and lymphocyte infiltration. Other drug-associated enteropathies have also been reported with mycophenolate mofetil used in transplantation. CONCLUSIONS: Of the drug-associated enteropathies discussed in this review, olmesartan can generate the most severe symptoms, albeit quite rare. Therefore, with patients who present with severe diarrhea and weight loss, one should consider olmesartan-associated enteropathy. In addition, many of the features associated with olmesartan-associated enteropathy are also found in celiac disease enteropathy; as such, one should review any celiac disease diagnosis for any use of olmesartan at the time of diagnosis. PMID- 25925926 TI - Refractory celiac disease: epidemiology and clinical manifestations. AB - A small subset of celiac disease (CD) patients becomes refractory to a gluten free diet with persistent malabsorption and intestinal villous atrophy. This is a rare (probably less than 2% of adult CD patients), but serious disorder, with a high risk of progression to an overt T-cell lymphoma. Diagnosis of this condition defined as refractory CD (RCD) is made after exclusion of other small bowel diseases with villous atrophy. RCD has been subdivided into two subgroups according to the normal (RCDI) or abnormal phenotype of intraepithelial lymphocytes (RCDII). Whereas RCDI is hardly distinguishable from active noncompliant CD, RCDII has a severe clinical presentation and a very poor prognosis. We precisely describe below the different types of RCD and propose diagnostic and therapeutic guidelines for its clinical management. PMID- 25925927 TI - Therapy in RCDII: Rationale for Combination Strategies? AB - Refractory coeliac disease type II (RCDII) is characterized by a continuous gluten-independent duodenal immune activation with an extremely high risk of malignant transformation. It is therefore considered as an indolent lymphoma. RCDII is characterized by the presence of villous atrophy (Marsh III A-C) in combination with an aberrant intra- epithelial lymphocyte (IEL) population consisting of >20% sCD3-CD7+iCD3+ IELs. The sCD3-CD7+iCD3+ IELs are a heterogeneous lineage-negative cell population, consisting of cells that do or do not express CD127/IL7Ralpha. Experiments using IEL from non-RCDII patients have indicated that while the CD127- cells are IL-15 responsive, the CD127+ cells are not. Together with the observation that some patients express an aberrant (monoclonal) TCRgammadelta phenotype, this confirms the heterogeneity of the aberrant IEL population in RCDII and suggests that the aberrant cells are heterogeneous with respect to their response to common gamma-chain cytokines. Although cladribine with or without autologous stem cell transplantation is effective in the treatment of signs and symptoms of RCDII and improves survival as compared to symptomatic topical steroid therapy, cladribine failures still bear a high risk of malignant transformation, and the rate of enteropathy associated T-cell lymphoma (EATL) development in this subgroup is extremely high. It might be hypothesized that the heterogenous nature of aberrant IEL and the high risk of malignant transformation require a treatment strategy which is effective despite this heterogeneity. RCDII should be seen more in the light of a low-grade/no mass lymphoma or pre-EATL. We would suggest an upfront combination therapy approach integrating inhibition of downstream Jak-STAT signalling pathways with conventional therapy (2-CDA) to hopefully effectively treat signs and symptoms of RCDII and accomplish a more effective EATL prevention. PMID- 25925928 TI - Enteropathy-associated T-cell lymphoma: improving treatment strategies. AB - Enteropathy-associated T-cell lymphoma (EATL) is a rare and usually rapidly fatal intestinal T-cell non-Hodgkin lymphoma. It arises from intraepithelial lymphocytes and has a high association with coeliac disease. The high mortality of EATL is associated not only with the very aggressive and often chemotherapy refractory nature of the lymphoma. The poor condition of patients due to prolonged and severe malnutrition compromises the ability to deliver chemotherapy. There are no standardized treatment protocols, and the optimal therapy for EATL remains unclear. The primary step of treatment consists of local debulking, preferably as early as possible after EATL diagnosis. Morbidity and mortality seem to rise with advanced stages of disease due to tumour size progression, worse nutritional status and a higher risk of emergency surgery due to perforation. Standard induction therapy for EATL is anthracycline-based chemotherapy, preferably resumed between 2 and 5 weeks after surgery (depending on clinical condition). Intensification of therapy using high-dose chemotherapy followed by consolidation with BEAM and autologous stem cell transplantation is associated with better outcome. Notably, this treatment strategy has only been applied in patients eligible for this aggressive regimen which might reflect selection bias. Unfortunately, prognosis of EATL remains poor; 5-year survival varies from 8 to 60% depending on the eligibility to receive additional steps of therapy. New treatment strategies are urgently needed for a better prognosis of this lethal complication of coeliac disease. Brentuximab vedotin (anti-CD30) might be promising when added to conventional chemotherapy and is suggested as upfront treatment in EATL. PMID- 25925930 TI - Videocapsule endoscopy in celiac disease: indications and timing. AB - BACKGROUND: Because of its technical characteristics (i.e. 8-fold magnification, capability to inspect the entire small bowel) and minimal invasiveness, videocapsule endoscopy (VCE) has been proposed as a useful tool for managing patients with celiac disease (CD). KEY MESSAGES: Although VCE has been found to be highly sensitive and specific in identifying CD endoscopic markers, it is still inadequate to replace esophagogastroduodenoscopy (EGD) with biopsies in the diagnosis of CD. Nevertheless, it represents a reliable alternative in patients unable or unwilling to undergo EGD. Up to now, available studies have failed to identify any correlation between the length of small bowel involvement and the severity of symptoms. The available evidence on the use of VCE in diagnosing CD in equivocal cases (patients with positive serology and negative or nonspecific histology or those with negative serology and histologically proven villous atrophy) is limited, and its role is still under discussion. In CD patients not improving on gluten-free diet, a complete workup is necessary. In patients with nonresponsive (NRCD) or refractory CD (RCD), VCE has been shown to be able not only to detect significant findings, driving further management, but also to rule out major complications. Nevertheless, in this setting, the inability of VCE to take tissue samples and the risk of capsule retention can represent major limitations. CONCLUSIONS: At the present time, for diagnostic purposes, VCE can be proposed only in patients unable or unwilling to undergo EGD, whereas it could be useful in some equivocal cases. Conversely, there is no room for VCE either to estimate the length of the small bowel affected by villous atrophy or to follow up patients improving on gluten-free diet. In patients with NRCD or RCD, VCE can play a role, but it should be combined with other diagnostic techniques. PMID- 25925929 TI - Serum markers in the clinical management of celiac disease. AB - The advent of highly reliable noninvasive celiac diagnostic tests has transformed the field of celiac disease, from diagnosis, to evaluation of epidemiology, to clinical and translational research. Serologic tests in their modern forms are highly sensitive and specific for diagnosis, allowing for consideration of avoidance of diagnostic intestinal biopsy in some settings. On the other hand, as predictors of intestinal damage and for use in monitoring disease activity, currently available noninvasive tests have been disappointing. Serologic tests, while a measure of disease activity, do not correlate well with histology or symptomatology, and it is unclear if they predict long-term risk. Additionally, while the many clinically available tests have improved accessibility, they can have widely different cutoff levels and overall performance, making the comparison of levels in individual patients over time and across populations quite difficult. In the future, we can expect to see improvement in the currently available serologic tests including tissue transglutaminase and deamidated gliadin peptide with expansion of the dynamic range of the tests, and the celiac care community should push for a standardization of assays that would simplify research and patient care. Additionally, current serologic tests are measures of the adaptive immune response in celiac disease but do not directly measure intestinal inflammation. Promising work on intestinal fatty acid-binding protein and other assays which directly measure intestinal damage may complement traditional serologic tests and further improve our ability to noninvasively diagnose and monitor celiac disease. The coming years hold promise for the continuing evolution of serum-based tests in celiac disease with the possibility of substantial improvement of patient care and clinical research. PMID- 25925931 TI - Small bowel imaging in celiac disease. AB - BACKGROUND: Modern small bowel imaging techniques allow detailed depiction of small-intestinal abnormalities. The role of these techniques in the investigation of celiac disease is increasing, especially in patients with suspected complicated celiac disease. KEY MESSAGES: In general, there is no need for radiological small bowel imaging in uncomplicated celiac disease. It is however important that clinicians and radiologists are aware of certain specific radiological findings that may suggest celiac disease, especially since celiac disease is often not considered in adult patients, and small bowel radiology may be performed before specific tests for celiac disease. Radiological abnormalities can be observed with both conventional small bowel radiology studies, like small bowel follow-through or double-contrast small bowel enteroclysis, and newer modalities, like computed tomography or magnetic resonance enterography or enteroclysis. These signs include a decreased number of jejunal folds, an increased number of ileal folds, small bowel dilatation, wall thickening and intussusception. Extraintestinal abnormalities include mesenteric lymphadenopathy, vascular changes and splenic atrophy. Abnormalities congruent with refractory celiac disease type II include a severe decrease in jejunal folds, infiltration of the mesenteric fat and thickening of the small bowel wall. Additionally, a severely decreased splenic volume may indicate complicated celiac disease. Malignant complications of celiac disease, such as enteropathy associated T-cell lymphoma and small-intestinal adenocarcinoma, can be reliably investigated with cross-sectional enteroclysis techniques. CONCLUSIONS: Small bowel imaging and especially cross-sectional enteroclysis techniques are important extensions to the diagnostic workup of clinicians involved in the care of patients with celiac disease, especially those with suspected complicated disease. PMID- 25925932 TI - Wheat amylase trypsin inhibitors as nutritional activators of innate immunity. AB - While the central role of an adaptive, T cell-mediated immune response to certain gluten peptides in celiac disease is well established, the innate immune response to wheat proteins remains less well defined. We identified wheat amylase trypsin inhibitors (ATIs), but not gluten, as major stimulators of innate immune cells (dendritic cells>macrophages>monocytes), while intestinal epithelial cells were nonresponsive. ATIs bind to and activate the CD14-MD2 toll-like receptor 4 (TLR4) complex. This activation occurs both in vitro and in vivo after oral ingestion of purified ATIs or gluten, which is usually enriched in ATIs. Wheat ATIs represent a family of up to 17 proteins with molecular weights of around 15 kDa and a variable primary but conserved secondary structure characterized by 5 intrachain disulfide bonds and alpha helices. They mostly form di- and tetramers that appear to equally activate TLR4. Relevant biological activity is confined to ATIs in gluten-containing cereals, while gluten-free cereals display no or minimal activities. ATIs represent up to 4% of total wheat protein and are highly resistant to intestinal proteases. In line with their dose-dependent function as co-stimulatory molecules in adaptive immunity of celiac disease, they appear to play a role in promoting other immune-mediated diseases within and outside the GI tract. Thus, ATIs may be prime candidates of severe forms of non-celiac gluten (wheat) sensitivity. PMID- 25925933 TI - Gluten-related disorders: gluten ataxia. AB - The term gluten-related disorders (GRD) refers to a spectrum of diverse clinical manifestations triggered by the ingestion of gluten in genetically susceptible individuals. They include both intestinal and extraintestinal manifestations. Gluten ataxia (GA) is one of the commonest neurological manifestations of GRD. It was originally defined as otherwise idiopathic sporadic ataxia in the presence of circulating antigliadin antibodies of IgA and/or IgG type. Newer more specific serological markers have been identified but are not as yet readily available. GA has a prevalence of 15% amongst all ataxias and 40% of all idiopathic sporadic ataxias. It usually presents with gait and lower limb ataxia. It is of insidious onset with a mean age at onset of 53 years. Up to 40% of patients have evidence of enteropathy on duodenal biopsy. Gastrointestinal symptoms are seldom prominent and are not a reliable indicator for the presence of enteropathy. Furthermore, the presence of enteropathy does not influence the response to a gluten-free diet. Most patients will stabilise or improve with strict adherence to gluten free diet depending on the duration of the ataxia prior to the treatment. Up to 60% of patients with GA have evidence of cerebellar atrophy on MR imaging, but all patients have spectroscopic abnormalities primarily affecting the vermis. Recent evidence suggests that patients with newly diagnosed coeliac disease presenting to the gastroenterologists have abnormal MR spectroscopy at presentation associated with clinical evidence of subtle cerebellar dysfunction. The advantage of early diagnosis and treatment (mean age 42 years in patients presenting with gastrointestinal symptoms vs. 53 years in patients presenting with ataxia) may protect the first group from the development and/or progression of neurological dysfunction. PMID- 25925934 TI - Other Dietary Confounders: FODMAPS et al. AB - BACKGROUND: While it is well documented and widely appreciated that ingestion of wheat (and less so rye and barley) is associated with gastrointestinal symptoms such as bloating or abdominal pain, the component of wheat to which such an effect is attributed is less well established. KEY MESSAGES: Wheat is a complex of proteins (80% gluten, 20% metabolic proteins), carbohydrates (starch, non starch polysaccharides, fructans), lipids and other components. The majority of attention has focused on gluten as the culprit in triggering symptoms, but re challenge studies have nearly all used wheat flour-related products (such as bread) as the stimulus. When carbohydrate-deplete gluten was used as the challenge agent, gluten-specific feelings of depression and not gut symptoms were observed in those who fulfilled strict criteria of 'non-coeliac gluten sensitivity', thereby underlining the complexity of cereals and of undertaking research in this area. Candidate components other than gluten include poorly absorbed oligosaccharides (mainly fructans), non-gluten wheat proteins such as amylase-trypsin inhibitors or wheat germ agglutinin, and exorphins released during the digestion of gluten. Specific biological and/or clinical effects associated with gluten-free diets or wheat ingestion need to be carefully dissected before attribution to gluten can be claimed. CONCLUSIONS: Currently, coeliac disease is the only common condition that has been unequivocally linked to gluten. Inaccurate attribution will be associated with suboptimal therapeutic advice and at least partly underlies the current gluten-free epidemic gripping the Western world. PMID- 25925935 TI - Novel treatments for celiac disease: glutenases and beyond. AB - Currently, the only effective treatment for celiac disease is a strict lifelong gluten-free diet. However, gluten-free dieting is restrictive, difficult to maintain and nutritionally less than optimal. The improved knowledge on celiac disease pathogenesis has enabled researchers to suggest alternative strategies to treat the disorder. The drug development poses a challenge as any novel drug for celiac disease should be simultaneously effective and as safe as the gluten-free diet. The rationale behind enzyme supplementation therapy as a future treatment option for celiac patients lies in the fact that gluten is only poorly digested by gastrointestinal proteases. Due to incomplete degradation in the gastrointestinal tract, fairly long gluten peptides enter the small-intestinal lumen and come into contact with the mucosal epithelium, and in celiac disease patients this encounter launches deleterious downstream effects. Enzyme supplement therapy using either bacterial or fungal endopeptidases or proteases from germinating cereals has been proposed to promote complete digestion of prolamins and destroy disease-inducing gluten peptides. A major advantage of these glutenases is that they work in the lumen of the small intestine and do not themselves take part in the immunological cascade of events in the lamina propria, thus being unlikely to cause harmful side effects to the host. Studies to test this rationale, e.g. with Aspergillus niger prolyl endoprotease and a combination enzyme product ALV003, are already ongoing. The development of a novel medication for celiac disease is still in its early days, and thus the conventional dietary treatment will hold its place for the time being. PMID- 25925936 TI - Vaccination and other antigen-specific immunomodulatory strategies in celiac disease. AB - BACKGROUND: Celiac disease (CD) results from an alteration in the oral tolerance to dietary gluten. The response to gluten is normally tightly regulated and involves the secretion of TGF-beta and IL-10 from different subtypes of regulatory T cells (Tregs). Interestingly, in addition to proinflammatory cytokines, the inflamed CD mucosa also contains high levels of T cell-derived IL 10 compared with treated CD patients or normal donors. Furthermore, most studies describe an increase in the number of Foxp3+ Tregs in the small intestinal mucosa in CD patients compared to controls. This paradoxical condition suggests that regulatory mechanisms might operate to counterbalance the abnormal gliadin triggered immune activation in untreated mucosa. Indeed, addition of exogenous IL 10 to mucosal cultures from treated CD patients can suppress gliadin-induced T cell activation. Considering the central role of adaptive immunity in CD, the development of strategies to stimulate these mechanisms is a primary goal of efforts to restore gluten tolerance. Key Messages: Different immunomodulatory strategies have been explored. NexVax2, a desensitizing vaccine that uses three dominant gluten peptides administered subcutaneously to induce a tolerogenic response in CD patients, is under development. Alternatively, the potential of substituted, cyclic or dimeric peptide analogues as blockers to prevent HLA from binding to the immunodominant gliadin epitopes has been demonstrated in vitro. In line with these results, we recently found that modified (transamidated) gliadins influenced the immune response in intestinal biopsy samples from CD patients with overt disease by drastically reducing the production of IFN-gamma. Notably, in a mouse model, transamidated gliadins reverted the phenotype of the gliadin inducible immune response from an inflammatory phenotype to an anti-inflammatory phenotype. CONCLUSIONS: Various approaches are currently under investigation to recover gluten tolerance based on the use of both modified and native antigen molecules. More specific studies are now required to test the efficacy of such strategies for preventing CD. PMID- 25925939 TI - Arthroscopic Transplantation of Synovial Stem Cells Improves Clinical Outcomes in Knees With Cartilage Defects. AB - BACKGROUND: Transplantation of mesenchymal stem cells (MSCs) is one possible strategy to achieve articular cartilage repair. We previously reported that synovial MSCs were highly proliferative and able to undergo chondrogenesis. We also found that placing a suspension of synovial MSCs on a cartilage defect for 10 minutes promoted cartilage repair in rabbit and pig models. However, the in vivo efficacy of this approach has not been tested clinically. QUESTIONS/PURPOSES: We asked whether transplantation of synovial MSCs improves (1) MRI features, (2) histologic features, and (3) clinical evaluation scores in patients with cartilage defects in the knee? METHODS: Patients with a symptomatic single cartilage lesion of the femoral condyle were indicated for inclusion in our study, and between April 2008 and April 2011, 10 patients were enrolled in this study. All patients completed followups of 3 years or more. The average followup period was 52 months (range, 37-80 months). Synovial MSCs were expanded with 10% autologous human serum for 14 days after digestion. For transplantation, the patient was positioned so that the cartilage defect was facing upward, and synovial MSC suspension was placed on the cartilage defect with a syringe under arthroscopic control. The defect with the applied suspension then was held in the upward position for 10 minutes. Five patients underwent concomitant ACL reconstructions, among whom two had meniscus suturing performed simultaneously. For MRI quantification, the cartilage defect was scored from 0 to 5. Second-look arthroscopy was performed for four patients and biopsy specimens were evaluated histologically. Clinical outcome was assessed using the Lysholm score and Tegner Activity Level Scale at final followup. Comparisons of MRI and Lysholm scores before and after treatment for each patient were analyzed using the Wilcoxon signed-rank test. RESULTS: MRI score (median +/- 95% CI) was 1.0 +/- 0.3 before and 5.0 +/- 0.7 after, and increased after treatment in each patient (p = 0.005). Second-look arthroscopy in four patients showed that the cartilage defect appeared to be qualitatively better in all cases. Histologic analyses showed hyaline cartilage in three patients and fibrous cartilage in one at the deep zone. The Lysholm score (median +/- 95% CI) was 76 +/- 7 before and 95 +/- 3 after, and increased after treatment in each patient (p = 0.005). The Tegner Activity Level Scale did not decrease after treatment in each patient. CONCLUSIONS: For this small initial case series, transplantation of synovial MSCs was effective in terms of MRI score, qualitative histology, and Lysholm score. The use of synovial MSCs has an advantage in that the cells can be prepared at passage 0 in only 14 days. Transplantation of synovial MSCs may be less invasive than mosaicplasty and autologous chondrocyte implantation. To conclusively show the effectiveness of this treatment requires comparative studies, especially with more established arthroscopic procedures, such as marrow stimulation techniques. LEVEL OF EVIDENCE: Level IV, therapeutic study. PMID- 25925940 TI - Potentially inappropriate prescribing of renally cleared drugs in elderly patients in community and aged care settings. AB - BACKGROUND: Limited data are available on the prevalence of inappropriate prescribing of renally cleared drugs in elderly patients in Australia. OBJECTIVES: To quantify and compare the extent of inappropriate prescribing (defined as at least one drug prescribed in an excessive dose or when contraindicated with respect to renal function) of renally cleared drugs in elderly patients across the community and aged care settings, and to determine factors associated with patients being prescribed one or more potentially inappropriate renally cleared drugs. METHODS: This retrospective study examined de-identified Home Medicines Review (HMR) and Residential Medication Management Review (RMMR) cases pertaining to 30,898 patients aged 65 years and over. Only 25 % (n = 7625) of these patients had documented information on their renal function. Among them, 4035 patients were prescribed at least one of the 31 renally cleared drugs examined in this study. For these patients, details including demographics, medications, medical conditions and pathology test results were extracted. Creatinine clearance was estimated using the Cockcroft Gault formula, and the prevalence of inappropriate prescribing of the 31 drugs was examined on the basis of conformity with the recommendations in the Australian Medicines Handbook. Multivariate logistic regression was performed to determine the factors associated with patients being prescribed one or more potentially inappropriate renally cleared drugs. RESULTS: The mean (+/- standard deviation) ages of the HMR patients (n = 3315; 59 % female) and RMMR patients (n = 720; 68 % female) were 78.3 +/- 7.2 and 86 +/- 7.3 years, respectively. Over one quarter of the patients (n = 1135 out of 4035; 28.1 %) prescribed the renally cleared drugs examined in this study had evidence of inappropriate prescribing of at least one of the drugs, with respect to their renal function. The drugs/drug classes most commonly prescribed inappropriately were perindopril, fenofibrate, glibenclamide, gliptins, metformin, olmesartan, bisphosphonates and strontium. The factors independently associated with patients being prescribed one or more potentially inappropriate renally cleared drugs were advancing age [odds ratio (OR) 1.06 per year increase, 95 % confidence interval (CI) 1.05-1.07; P < 0.001], the total number of renally cleared drugs prescribed (OR 1.44 per unit increase, 95 % CI 1.29-1.61; P < 0.001), presence of diabetes (OR 1.51, 95 % CI 1.30-1.76; P < 0.001), presence of heart failure (OR 1.38, 95 % CI 1.13-1.69; P < 0.005) and living in aged care facilities (OR 1.28, 95 % CI 1.06-1.5; P < 0.05). CONCLUSION: Inappropriate prescribing of renally cleared drugs is common in older Australians. Intervention studies to improve prescribing of renally cleared drugs in the elderly appear to be warranted. PMID- 25925941 TI - Lenalidomide: a review of its continuous use in patients with newly diagnosed multiple myeloma not eligible for stem-cell transplantation. AB - Lenalidomide (Revlimid((r))) is a second-generation immunomodulatory drug structurally related to thalidomide, with improved efficacy and tolerability, for which the label in the EU was recently expanded to include continuous therapy in patients with previously untreated multiple myeloma not eligible for stem-cell transplantation. In randomized, controlled clinical trials, continuous lenalidomide therapy, either in combination with dexamethasone (FIRST trial) or as maintenance monotherapy following induction with melphalan/prednisone/lenalidomide (MM-015 trial), significantly improved progression-free survival (PFS) compared with induction therapy alone (with non lenalidomide- or lenalidomide-containing regimens) in patients with newly diagnosed multiple myeloma not eligible for stem-cell transplantation. The improvements in PFS with continuous lenalidomide were reflected in improved health-related quality-of-life measures. An overall survival benefit was observed in the FIRST trial, but not in the MM-015 trial. Continuous lenalidomide and continuous thalidomide regimens displayed similar efficacy, but lenalidomide was associated with significantly less toxicity than thalidomide. Continuous use of lenalidomide did not appear to negatively impact on the drug's tolerability and did not increase the incidence of neutropenia or second primary malignancy compared with shorter-term use. The incidence of most adverse events began to reduce after about 18 months of therapy. In conclusion, continuous lenalidomide regimens provide an effective longer-term treatment option in patients with newly diagnosed multiple myeloma ineligible for stem-cell transplantation. PMID- 25925942 TI - Prediction of Gestational Diabetes through NMR Metabolomics of Maternal Blood. AB - Metabolic biomarkers of pre- and postdiagnosis gestational diabetes mellitus (GDM) were sought, using nuclear magnetic resonance (NMR) metabolomics of maternal plasma and corresponding lipid extracts. Metabolite differences between controls and disease were identified through multivariate analysis of variable selected (1)H NMR spectra. For postdiagnosis GDM, partial least squares regression identified metabolites with higher dependence on normal gestational age evolution. Variable selection of NMR spectra produced good classification models for both pre- and postdiagnostic GDM. Prediagnosis GDM was accompanied by cholesterol increase and minor increases in lipoproteins (plasma), fatty acids, and triglycerides (extracts). Small metabolite changes comprised variations in glucose (up regulated), amino acids, betaine, urea, creatine, and metabolites related to gut microflora. Most changes were enhanced upon GDM diagnosis, in addition to newly observed changes in low-Mw compounds. GDM prediction seems possible exploiting multivariate profile changes rather than a set of univariate changes. Postdiagnosis GDM is successfully classified using a 26-resonance plasma biomarker. Plasma and extracts display comparable classification performance, the former enabling direct and more rapid analysis. Results and putative biochemical hypotheses require further confirmation in larger cohorts of distinct ethnicities. PMID- 25925943 TI - Access to care and use of the Internet to search for health information: results from the US National Health Interview Survey. AB - BACKGROUND: The insurance mandate of the Affordable Care Act has increased the number of people with health coverage in the United States. There is speculation that this increase in the number of insured could make accessing health care services more difficult. Those who are unable to access care in a timely manner may use the Internet to search for information needed to answer their health questions. OBJECTIVE: The aim was to determine whether difficulty accessing health care services for reasons unrelated to insurance coverage is associated with increased use of the Internet to obtain health information. METHODS: Survey data from 32,139 adults in the 2011 National Health Interview Study (NHIS) were used in this study. The exposure for this analysis was reporting difficulty accessing health care services or delaying getting care for a reason unrelated to insurance status. To define this exposure, we examined 8 questions that asked whether different access problems occurred during the previous 12 months. The outcome for this analysis, health information technology (HIT) use, was captured by examining 2 questions that asked survey respondents if they used an online health chat room or searched the Internet to obtain health information in the previous 12 months. Several multinomial logistic regressions estimating the odds of using HIT for each reported access difficulty were conducted to accomplish the study objective. RESULTS: Of a survey population of 32,139 adults, more than 15.90% (n=5109) reported experiencing at least one access to care barrier, whereas 3.63% (1168/32,139) reported using online health chat rooms and 43.55% (13,997/32,139) reported searching the Internet for health information. Adults who reported difficulty accessing health care services for reasons unrelated to their health insurance coverage had greater odds of using the Internet to obtain health information. Those who reported delaying getting care because they could not get an appointment soon enough (OR 2.2, 95% CI 1.9-2.5), were told the doctor would not accept them as a new patient or accept their insurance (OR 2.1, 95% CI 1.7-2.5 and OR 2.1, 95% CI 1.7-2.5, respectively), or because the doctor's office was not open when they could go (OR 2.2, 95% CI 1.9-2.7) had more than twice the odds of using the Internet to obtain health information compared to those who did not report such access difficulties. CONCLUSIONS: People experiencing trouble accessing health care services for reasons unrelated to their insurance status are more likely to report using the Internet to obtain health information. Improving the accuracy and reliability of health information resources that are publicly available online could help those who are searching for information due to trouble accessing health care services. PMID- 25925944 TI - Truncated HBx-dependent silencing of GAS2 promotes hepatocarcinogenesis through deregulation of cell cycle, senescence and p53-mediated apoptosis. AB - Hepatocellular carcinoma (HCC) is a worldwide threat to public health, especially in China, where chronic hepatitis B virus (HBV) infection is found in 80-90% of all HCCs. The HBV-encoded X antigen (HBx) is a trans-regulatory protein involved in virus-induced hepatocarcinogenesis. Although the carboxyl-terminus-truncated HBx, rather than the full-length counterpart, is frequently overexpressed in human HCCs, its functional mechanisms are not fully defined. We investigated the molecular function of a naturally occurring HBx variant which has 35 amino acids deleted at the C-terminus (HBxDelta35). Genome-wide scanning analysis and PCR validation identified growth arrest-specific 2 (GAS2) as a direct target of HBxDelta35 at transcriptional level in human immortalized liver cells. HBxDelta35 was found to bind the promoter region of GAS2 and attenuate its expression to promote hepatocellular proliferation and tumourigenicity. Further functional assays demonstrated that GAS2 induces p53-dependent apoptosis and senescence to counteract HBxDelta35-mediated tumourigenesis. Notably, GAS2 expression was significantly down-regulated in HCCs compared with the corresponding normal tissues. In conclusion, our integrated study uncovered a novel viral mechanism in hepatocarcinogenesis, wherein HBxDelta35 deregulates cell growth via direct silencing of GAS2 and thereby provides a survival advantage for pre-neoplastic hepatocytes to facilitate cancer development. PMID- 25925945 TI - Ponseti Casting and Achilles Release Versus Classic Casting and Soft Tissue Releases for the Initial Treatment of Arthrogrypotic Clubfeet. AB - BACKGROUND: Wide soft tissue releases (STRs) are considered the classic operative approach to the arthrogrypotic clubfoot, but recently the Ponseti method with Achilles tenotomy has been proposed as the initial treatment for those deformities. METHODS: A retrospective comparison of clinical results and treatment course after 5 to 10 years of follow-up (FU) in arthrogrypotic clubfeet treated initially with STRs or the Ponseti method was performed. Mann-Whitney and chi(2) tests were used to assess significant differences between variables. RESULTS: Twenty-nine children with 57 arthrogrypotic clubfeet were divided into 2 subgroups: the Ponseti subgroup (9 children, 18 clubfeet, mean FU: 7.3 years), which achieved 14 good and 4 satisfactory final results. The complication rate was 5.5%. Reoperation rate was 1.2 per foot, with 90.9% being STRs and 9.1% wedge osteotomies. The mean total anesthesia and surgery time equaled 116.6 and 77.4 minutes, respectively. The interval between primary and redo surgery was 27.3 months on average. The STR subgroup (20 children, 39 clubfeet, FU: 9.0 years on average) scored 20 good, 8 satisfactory, and 11 unsatisfactory results. Rate of complications was 23%. The mean total anesthesia and surgery times were 161.4 minutes and 102.8 minutes, respectively. The interval between the initial and secondary operations was 62.8 months on average. The revision rate was 1.0 per foot with 32.5% repeated STRs, while 67.5% were talectomies, osteotomies, or salvage procedures. CONCLUSIONS: The use of the Ponseti method as the initial treatment in arthrogrypotic clubfeet improved clinical outcomes, reduced invasiveness of revisions, and shortened overall time of anesthesia and surgery. LEVEL OF EVIDENCE: Level III, retrospective comparative series. PMID- 25925946 TI - Chronic Treatment with Naltrexone Prevents Memory Retention Deficits in Rats Poisoned with the Sarin Analog Diisopropylfluorophosphate (DFP) and Treated with Atropine and Pralidoxime. AB - Humans and rats poisoned with sarin develop chronic neurological disabilities that are not prevented with standardized antidotal therapy. We hypothesized that rats poisoned with the sarin analogue diisopropylfluorophosphate (DFP) and resuscitated with atropine and pralidoxime would have long-term memory deficits that were preventable with naltrexone treatment. Long Evans rats (250-275 g) were randomized to: DFP (N = 8): single subcutaneous (SC) injection of DFP (5 mg/kg). Treatment (N = 9): DFP (5 mg/kg) followed by chronic naltrexone (5 mg/kg/day * 12 weeks). Control (N = 12): single SC injection of isopropyl alcohol, (DFP vehicle) followed by chronic naltrexone (5 mg/kg/day). If toxicity developed after injection, antidotal therapy was initiated with atropine (2 mg/kg) and pralidoxime (25 mg/kg) and repeated as needed. After 12 weeks, rats underwent testing for place learning (acquisition) across 5 days of training using the Morris Water Maze. On day 6 a memory retention test was performed. Statistical analysis was performed using IBM SPSS Statistics. Rats receiving DFP rapidly developed toxicity requiring antidotal rescue. No differences in acquisition were seen between the DFP vs. DFP + naltrexone rats. During memory testing, DFP poisoned rats spent significantly less time (29.4 +/- 2.11 versus 38.5 +/- 2.5 s, p < 0.05) and traveled less distance (267 +/- 24.6 versus 370 +/- 27.5 cm, p < 0.05) in the target quadrant compared to the treatment group. Treatment rats performed as well as control rats (p > 0.05) on the test for memory retention. Poisoning with DFP induced impaired memory retention. Deficits were not prevented by acute rescue with atropine and pralidoxime. Chronic naltrexone treatment led to preserved memory after DFP poisoning. PMID- 25925947 TI - OlsG (Sinac_1600) Is an Ornithine Lipid N-Methyltransferase from the Planctomycete Singulisphaera acidiphila. AB - Ornithine lipids (OLs) are phosphorus-free membrane lipids widespread in bacteria but absent from archaea and eukaryotes. In addition to the unmodified OLs, a variety of OL derivatives hydroxylated in different structural positions has been reported. Recently, methylated derivatives of OLs were described in several planctomycetes isolated from a peat bog in Northern Russia, although the gene/enzyme responsible for the N-methylation of OL remained obscure. Here we identify and characterize the OL N-methyltransferase OlsG (Sinac_1600) from the planctomycete Singulisphaera acidiphila. When OlsG is co-expressed with the OL synthase OlsF in Escherichia coli, methylated OL derivatives are formed. An in vitro characterization shows that OlsG is responsible for the 3-fold methylation of the terminal delta-nitrogen of OL. Methylation is dependent on the presence of the detergent Triton X-100 and the methyldonor S-adenosylmethionine. PMID- 25925948 TI - Novel Role for gamma-Catenin in the Regulation of Cancer Cell Migration via the Induction of Hepatocyte Growth Factor Activator Inhibitor Type 1 (HAI-1). AB - gamma-Catenin (Plakoglobin), a well-described structural protein functioning at the adherens junctions and desmosomes, was shown to be either lost or weakly expressed in non-small cell lung cancer (NSCLC) cells and tumor tissues. However, the tumor suppressive affects of gamma-catenin were not fully understood. In this study, we have identified a novel role for the affects of gamma-catenin on non small cell lung cancer (NSCLC) cell migration. Expression of gamma-catenin in NSCLC cells resulted in reduced cell migration as determined by both scratch assays and trans-well cell migration assays. Moreover, the affects of gamma catenin on cell migration were observed to be p53-dependent. Mechanistically, the anti-migratory effects seen via gamma-catenin were driven by the expression of hepatocyte growth factor activator inhibitor Type I (HAI-1 or SPINT-1), an upstream inhibitor of the c-MET signaling pathway. Furthermore, the re-expression of gamma-catenin sensitized NSCLC cells to c-MET inhibitor-mediated growth inhibition. Taken together, we identify gamma-catenin as a novel regulator of HAI 1, which is a critical regulator of HGF/c-MET signaling. Therefore, targeting gamma-catenin-mediated HAI-1 expression might be a useful strategy to sensitize NSCLC to c-MET inhibitors. PMID- 25925949 TI - Pannexin-1 Up-regulation in the Dorsal Root Ganglion Contributes to Neuropathic Pain Development. AB - Pannexin-1 (Panx1) is a large-pore membrane channel involved in the release of ATP and other signaling mediators. Little is known about the expression and functional role of Panx1 in the dorsal root ganglion (DRG) in the development of chronic neuropathic pain. In this study, we determined the epigenetic mechanism involved in increased Panx1 expression in the DRG after nerve injury. Spinal nerve ligation in rats significantly increased the mRNA and protein levels of Panx1 in the DRG but not in the spinal cord. Immunocytochemical labeling showed that Panx1 was primarily expressed in a subset of medium and large DRG neurons in control rats and that nerve injury markedly increased the number of Panx1 immunoreactive DRG neurons. Nerve injury significantly increased the enrichment of two activating histone marks (H3K4me2 and H3K9ac) and decreased the occupancy of two repressive histone marks (H3K9me2 and H3K27me3) around the promoter region of Panx1 in the DRG. However, nerve injury had no effect on the DNA methylation level around the Panx1 promoter in the DRG. Furthermore, intrathecal injection of the Panx1 blockers or Panx1-specific siRNA significantly reduced pain hypersensitivity induced by nerve injury. In addition, siRNA knockdown of Panx1 expression in a DRG cell line significantly reduced caspase-1 release induced by neuronal depolarization. Our findings suggest that nerve injury increases Panx1 expression levels in the DRG through altered histone modifications. Panx1 up regulation contributes to the development of neuropathic pain and stimulation of inflammasome signaling. PMID- 25925950 TI - Coronin-1C Protein and Caveolin Protein Provide Constitutive and Inducible Mechanisms of Rac1 Protein Trafficking. AB - Sustained directional fibroblast migration requires both polarized activation of the protrusive signal, Rac1, and redistribution of inactive Rac1 from the rear of the cell so that it can be redistributed or degraded. In this work, we determine how alternative endocytic mechanisms dictate the fate of Rac1 in response to the extracellular matrix environment. We discover that both coronin-1C and caveolin retrieve Rac1 from similar locations at the rear and sides of the cell. We find that coronin-1C-mediated extraction, which is responsible for Rac1 recycling, is a constitutive process that maintains Rac1 protein levels within the cell. In the absence of coronin-1C, the effect of caveolin-mediated endocytosis, which targets Rac1 for proteasomal degradation, becomes apparent. Unlike constitutive coronin 1C-mediated trafficking, caveolin-mediated Rac1 endocytosis is induced by engagement of the fibronectin receptor syndecan-4. Such an inducible endocytic/degradation mechanism would predict that, in the presence of fibronectin, caveolin defines regions of the cell that are resistant to Rac1 activation but, in the absence of fibronectin leaves more of the membrane susceptible to Rac1 activation and protrusion. Indeed, we demonstrate that fibronectin-stimulated activation of Rac1 is accelerated in the absence of caveolin and that, when caveolin is knocked down, polarization of active Rac1 is lost in FRET experiments and culminates in shunting migration in a fibrous fibronectin matrix. Although the concept of polarized Rac1 activity in response to chemoattractants has always been apparent, our understanding of the balance between recycling and degradation explains how polarity can be maintained when the chemotactic gradient has faded. PMID- 25925951 TI - Structural Insights into the Neutralization Properties of the Fully Human, Anti interferon Monoclonal Antibody Sifalimumab. AB - We report the three-dimensional structure of human interferon alpha-2A (IFN alpha2A) bound to the Fab fragment of a therapeutic monoclonal antibody (sifalimumab; IgG1/kappa). The structure of the corresponding complex was solved at a resolution of 3.0 A using molecular replacement and constitutes the first reported structure of a human type I IFN bound to a therapeutic antibody. This study revealed the major contribution made by the first complementarity determining region in each of sifalimumab light and heavy chains. These data also provided the molecular basis for sifalimumab mechanism of action. We propose that its interferon-neutralizing properties are the result of direct competition for IFN-alpha2A binding to the IFN receptor subunit 1 (IFNAR1) and do not involve inhibiting IFN-alpha2A binding to the IFN receptor subunit 2 (IFNAR2). PMID- 25925952 TI - The Endoplasmic Reticulum Stress Sensor IRE1alpha in Intestinal Epithelial Cells Is Essential for Protecting against Colitis. AB - Intestinal epithelial cells (IECs) have critical roles in maintaining homeostasis of intestinal epithelium. Endoplasmic reticulum (ER) stress is implicated in intestinal epithelium homeostasis and inflammatory bowel disease; however, it remains elusive whether IRE1alpha, a major sensor of ER stress, is directly involved in these processes. We demonstrate here that genetic ablation of Ire1alpha in IECs leads to spontaneous colitis in mice. Deletion of IRE1alpha in IECs results in loss of goblet cells and failure of intestinal epithelial barrier function. IRE1alpha deficiency induces cell apoptosis through induction of CHOP, the pro-apoptotic protein, and sensitizes cells to lipopolysaccharide, an endotoxin from bacteria. IRE1alpha deficiency confers upon mice higher susceptibility to chemical-induced colitis. These results suggest that IRE1alpha functions to maintain the intestinal epithelial homeostasis and plays an important role in defending against inflammation bowel diseases. PMID- 25925953 TI - Inside-out Regulation of Ectodomain Cleavage of Cluster-of-Differentiation-44 (CD44) and of Neuregulin-1 Requires Substrate Dimerization. AB - Ectodomain shedding of transmembrane precursor proteins generates numerous life essential molecules, such as epidermal growth factor receptor ligands. This cleavage not only releases the regulatory growth factor, but it is also the required first step for the subsequent processing by gamma-secretase and the release of gene regulatory intracellular fragments. Signaling within the cell modifies the cytoplasmic tails of substrates, a step important in starting the specific and regulated cleavage of a large number of studied substrates. Ectodomain cleavage occurs, however, on the outside of the plasma membrane and is carried out by membrane-bound metalloproteases. How the intracellular domain modification communicates with the ectodomain of the substrate to allow for cleavage to occur is unknown. Here, we show that homodimerization of a cluster-of differentiation-44 or of pro-neuregulin-1 monomers represents an essential pre condition for their regulated ectodomain cleavage. Both substrates are associated with their respective metalloproteases under both basal or cleavage-stimulated conditions. These interactions only turn productive by specific intracellular signal-induced intracellular domain modifications of the substrates, which in turn regulate metalloprotease access to the substrates' ectodomain and cleavage. We propose that substrate intracellular domain modification induces a relative rotation or other positional change of the dimerization partners that allow metalloprotease cleavage in the extracellular space. Our findings fill an important gap in understanding substrate-specific inside-out signal transfer along cleaved transmembrane proteins and suggest that substrate dimerization (homo- or possibly heterodimerization) might represent a general principle in ectodomain shedding. PMID- 25925954 TI - Phosphoryl Transfer Reaction Snapshots in Crystals: INSIGHTS INTO THE MECHANISM OF PROTEIN KINASE A CATALYTIC SUBUNIT. AB - To study the catalytic mechanism of phosphorylation catalyzed by cAMP-dependent protein kinase (PKA) a structure of the enzyme-substrate complex representing the Michaelis complex is of specific interest as it can shed light on the structure of the transition state. However, all previous crystal structures of the Michaelis complex mimics of the PKA catalytic subunit (PKAc) were obtained with either peptide inhibitors or ATP analogs. Here we utilized Ca(2+) ions and sulfur in place of the nucleophilic oxygen in a 20-residue pseudo-substrate peptide (CP20) and ATP to produce a close mimic of the Michaelis complex. In the ternary reactant complex, the thiol group of Cys-21 of the peptide is facing Asp-166 and the sulfur atom is positioned for an in-line phosphoryl transfer. Replacement of Ca(2+) cations with Mg(2+) ions resulted in a complex with trapped products of ATP hydrolysis: phosphate ion and ADP. The present structural results in combination with the previously reported structures of the transition state mimic and phosphorylated product complexes complete the snapshots of the phosphoryl transfer reaction by PKAc, providing us with the most thorough picture of the catalytic mechanism to date. PMID- 25925955 TI - Design Principles of Perovskites for Thermochemical Oxygen Separation. AB - Separation and concentration of O2 from gas mixtures is central to several sustainable energy technologies, such as solar-driven synthesis of liquid hydrocarbon fuels from CO2 , H2 O, and concentrated sunlight. We introduce a rationale for designing metal oxide redox materials for oxygen separation through "thermochemical pumping" of O2 against a pO2 gradient with low-grade process heat. Electronic structure calculations show that the activity of O vacancies in metal oxides pinpoints the ideal oxygen exchange capacity of perovskites. Thermogravimetric analysis and high-temperature X-ray diffraction for SrCoO3 delta , BaCoO3-delta and BaMnO3-delta perovskites and Ag2 O and Cu2 O references confirm the predicted performance of SrCoO3-delta , which surpasses the performance of state-of-the-art Cu2 O at these conditions with an oxygen exchange capacity of 44 mmol O 2 mol SrCoO 3-delta(-1) exchanged at 12.1 MUmol O 2 min(-1) g(-1) at 600-900 K. The redox trends are understood due to lattice expansion and electronic charge transfer. PMID- 25925956 TI - Aplysiasecosterol A: A 9,11-Secosteroid with an Unprecedented Tricyclic gamma Diketone Structure from the Sea Hare Aplysia kurodai. AB - A new 9,11-secosteroid having an unprecedented tricyclic gamma-diketone structure, aplysiasecosterol A (1), was isolated from the sea hare Aplysia kurodai. The structure was determined by one- and two-dimensional NMR spectroscopic analysis, molecular modeling studies, a comparison of experimental and calculated ECD spectra, and a modified Mosher's method. Aplysiasecosterol A (1) exhibited cytotoxicity against human myelocytic leukemia HL-60 cells. A biosynthetic pathway for 1 from a known cholesterol was proposed and includes twice alpha-ketol rearrangements and an intramolecular acetalization. PMID- 25925957 TI - Herbal remedy knowledge acquisition and transmission among the Yucatec Maya in Tabi, Mexico: a cross-sectional study. AB - BACKGROUND: Ethnobotanical knowledge continues to be important for treating illness in many rural communities, despite access to health care clinics and pharmaceuticals. However, access to health care clinics and other modern services can have an impact on the distribution of medical ethnobotanical knowledge. Many factors have been shown to be associated with distributions in this type of knowledge. The goal of the sub-analyses reported in this paper was to better understand the relationship between herbal remedy knowledge, and two such factors, age and social network position, among the Yucatec Maya in Tabi, Yucatan. METHODS: The sample consisted of 116 Yucatec Maya adults. Cultural consensus analysis was used to measure variation in herbal remedy knowledge using competence scores, which is a measure of participant agreement within a domain. Social network analysis was used to measure individual position within a network using in-degree scores, based on the number of people who asked an individual about herbal remedies. Surveys were used to capture relevant personal attributes, including age. RESULTS: Analysis revealed a significant positive correlation between age and the herbal medicine competence score for individuals 45 and under, and no relationship for individuals over 45. There was an insignificant relationship between in-degree and competence scores for individuals 50 and under and a significant positive correlation for those over 50. CONCLUSIONS: There are two possible mechanisms that could account for the differences between cohorts: 1) knowledge accumulation over time; and/or 2) the stunting of knowledge acquisition through delayed acquisition, competing treatment options, and changes in values. Primary ethnographic evidence suggests that both mechanisms may be at play in Tabi. Future studies using longitudinal or cross-site comparisons are necessary to determine the whether and how the second mechanism is influencing the different cohorts. PMID- 25925958 TI - A sensitive colorimetric strategy for monitoring cerebral beta-amyloid peptides in AD based on dual-functionalized gold nanoplasmonic particles. AB - A sensitive and selective strategy for the colorimetric visualization of the total monomeric Abeta down to 40 pg mL(-1) based on dual-functionalized gold nanoplasmonic particles (GNPs) is developed and applied to evaluate Abeta levels in the AD cerebral system. PMID- 25925959 TI - Topical adenosine increases thick hair ratio in Japanese men with androgenetic alopecia. AB - OBJECTIVE: Hair thickness is more important than hair density in the appearance of baldness in male with androgenetic alopecia (AGA). Adenosine improves hair loss by stimulating hair growth and by thickening hair shafts in women. The objective of this study was to evaluate the hair growth efficacy and safety of topical adenosine in men with AGA. METHODS: A lotion containing either adenosine or niacinamide was administered to the scalps of 102 Japanese men twice daily for 6 months in a double-blind, randomized study. Efficacy was evaluated by dermatologists who assessed the quality of the hair and by calculating the percentages of vellus-like and thick hairs among the vertex hairs, as well as hair density. RESULTS: Adenosine was significantly (P < 0.05) superior to niacinamide in terms of global improvement of AGA, increase in the percentage of thick hairs (at least 60 MUm) and self-assessment of hair thickness by the study participants. No causal adverse event due to the adenosine lotion was observed. CONCLUSION: These data indicate that adenosine increases thick hair ratio in Japanese men with AGA, and this compound is useful for the improvement of AGA. PMID- 25925960 TI - A porcine model: surgical anatomy of the orbit for maxillofacial surgery. AB - Due to its similarity to humans, the pig has proven to be a suitable biomodel for both research purposes and for training medical professionals, particularly in surgical specializations. For example, new implant materials have been tested on pig jaws and pigs have also been used in the development of new surgical techniques. For optimizing the effectiveness of such research or training, detailed data on the anatomy of their particular features are needed. At present, however, only limited information related to surgical and imaging anatomy of the facial and orbital areas of the pig and its comparison to human structures from the experimental surgery point of view is available in the literature. The aim of this study was to obtain such data and to compare the morphological structures of the porcine and human orbital regions and to lay down the foundation for practical use in experimental surgery. Ten pig heads were examined using computed tomography (CT) and magnetic resonance imaging (MRI) and, subsequently, a dissection of the orbit was carried out. Attention was focused on the structure of the orbit (floor, rim and nerves) frequently affected by pathological processes in humans (such as trauma, infection or tumours) and which consequently are frequently the subject of maxillofacial surgery. The porcine orbit is suitable for use in experimental medicine. However, if used in experiments, its anatomical peculiarities must be taken into consideration. Our study presents a foundation of basic knowledge for researchers who plan to use the pig as a biomedical model to investigate alternative treatments in the head region. PMID- 25925961 TI - Immunolabelling of human metaphase chromosomes reveals the same banded distribution of histone H3 isoforms methylated at lysine 4 in primary lymphocytes and cultured cell lines. AB - BACKGROUND: Using metaphase spreads from human lymphoblastoid cell lines, we previously showed how immunofluorescence microscopy could define the distribution of histone modifications across metaphase chromosomes. We showed that different histone modifications gave consistent and clearly defined immunofluorescent banding patterns. However, it was not clear to what extent these higher level distributions were influenced by long-term growth in culture, or by the specific functional associations of individual histone modifications. RESULTS: Metaphase chromosome spreads from human lymphocytes stimulated to grow in short-term culture, were immunostained with antibodies to histone H3 mono- or tri-methylated at lysine 4 (H3K4me1, H3K4me3). Chromosomes were identified on the basis of morphology and reverse DAPI (rDAPI) banding. Both antisera gave the same distinctive immunofluorescent staining pattern, with unstained heterochromatic regions and a banded distribution along the chromosome arms. Karyotypes were prepared, showing the reproducibility of banding between sister chromatids, homologue pairs and from one metaphase spread to another. At the light microscope level, we detect no difference between the banding patterns along chromosomes from primary lymphocytes and lymphoblastoid cell lines adapted to long-term growth in culture. CONCLUSIONS: The distribution of H3K4me3 is the same across metaphase chromosomes from human primary lymphocytes and LCL, showing that higher level distribution is not altered by immortalization or long-term culture. The two modifications H3K4me1 (enriched in gene enhancer regions) and H3K4me3 (enriched in gene promoter regions) show the same distributions across human metaphase chromosomes, showing that functional differences do not necessarily cause modifications to differ in their higher-level distributions. PMID- 25925962 TI - Ultrasonic Vocalizations by the Spectral Tarsier, Tarsius spectrum. AB - Although the vocalizations of spectral tarsiers have been studied for over 3 decades by numerous primatologists, the data in this paper represent the first evidence that this species communicates in the ultrasonic range. In addition, this paper characterizes the types of ultrasonic vocalizations by spectral tarsiers, Tarsius spectrum. Data were collected at Tangkoko Nature Reserve in Sulawesi, Indonesia, from January through April 2013. Recordings were made on a Wildlife Acoustics Ultrasonic Song Meter BAT2 from 10 groups of varying sizes and compositions. The ultrasonic recorder was placed at the base of the group's sleeping tree and recorded from 5.00 to 7.00 h using an omnidirectional microphone. The ultrasonic vocalizations fell into 5 main categories: chirps, twitters, choruses, doubles and whistles. Chirps were the most frequent ultrasonic vocalizations, followed by twitters, choruses, doubles and then whistles. While chirps, twitters and choruses extended from the audible to the ultrasonic range, the doubles and whistles were pure ultrasound. Currently, the function of these ultrasonic vocalizations is not yet clear and requires additional research. PMID- 25925963 TI - Middle-aged rats orally supplemented with gel-encapsulated catechin favorably increases blood cytosolic NADPH levels. AB - Green tea catechins are primarily known to function as free radical scavengers and have several beneficial uses. Orally supplemented catechin (OSC) was previously shown to increase mitochondrial heme and catalase levels in rat heart blood, however, its effect in the cytosol has not been elucidated. Here, we determined the effects of OSC in the rat heart blood cytosol. We used middle-aged (40 week-old) and young (4 week-old) rats throughout the study. We isolated blood cytosol, verified its purity, and determined heme, hydrogen peroxide (H2O2) levels, catalase (CAT) activities, gp91(phox) amounts, NADP and NAD pools, sirtuin 1 (SIRT1) and glutathione reductase (GR) activities, and free fatty acids (FFA). We established that OSC is associated with decreased heme-dependent H2O2 amounts while increasing heme-independent CAT activity. Moreover, we found that OSC-related decrease in NAD(+) amounts among middle-aged rats is associated to increased NADPH levels and SIRT1 activity. In contrast, we associated OSC-related decrease in NAD(+) amounts among young rats to decreased NADPH levels and increased SIRT1 activity. This highlights a major difference between catechin treated middle-aged and young rats. Furthermore, we observed that cytosolic FFA and GR levels were significantly increased only among OSC-treated middle-aged rats which we hypothesize are related to increased NADPH levels. This insinuates that OSC treatment allows higher catechin amounts to enter the bloodstream of middle-aged rats. We propose that this would favorably increase NADPH amounts and lead to the simultaneous decrease in NADPH-related pro-oxidant activity and increase in NADPH-related biomolecules and anti-oxidant activities. PMID- 25925964 TI - Epigallocatechin-3-gallate inhibits VCAM-1 expression and apoptosis induction associated with LC3 expressions in TNFalpha-stimulated human endothelial cells. AB - Tumor necrosis factor alpha (TNF-alpha) promotes the expression of adhesion molecules and induces endothelial dysfunction, a process that can lead to atherosclerosis. Green tea consumption can inhibit endothelial dysfunction and attenuate the development of arteriosclerosis. The purpose of this study was to examine whether epigallocatechin-3-gallate (EGCG) prevents TNF-alpha-dependent endothelial dysfunction. Here, we compared the regulatory effects of the green tea components EGCG and L-theanine against TNF-alpha-induced stimulation of adhesion molecule expression and apoptosis induction, which is associated with autophagy. Monocytic cell adhesion to human endothelial cells was measured using a fluorescently-labeled cell line, U-937. Caspase 3/7 activity was examined with a fluorescent probe and fluorescence microscopy. In addition, we analyzed the expression of several genes by RT-PCR. TNF-alpha-modulation of LC3 and VCAM1 protein levels were investigated by Western blot (WB). TNF-alpha induced adhesion of U937 cells to endothelial cells, and gene expression associated with adhesion molecules and apoptosis. On the other hand, EGCG and L-theanine inhibited TNF alpha-induced adhesion of U937 cells to endothelial cells and inhibited increases in ICAM1, CCL2 and VCAM1 expression. Furthermore, EGCG and L-theanine inhibited TNF-alpha-induced apoptosis-related gene expression (e.g., CASP9), and caspase activity while inhibiting TNFalpha-induced VCAM1, LC3A and LC3B protein expression. Meanwhile, treatment of endothelial cells with autophagy inhibitor 3 methyladenine (3-MA) blocked EGCG-induced expression of CASP9. Together, these results indicate that EGCG can modulate TNF-alpha-induced monocytic cell adhesion, apoptosis and autophagy. We thus conclude that EGCG might be beneficial for inhibiting TNF-alpha-mediated human endothelial disorders by affecting LC3 expression-related processes. PMID- 25925965 TI - Cytotoxicity of natural products and derivatives toward MCF-7 cell monolayers and cancer stem-like mammospheres. AB - Although cancer stem-like cells (CSCs) are rare, they can enter a non proliferative or dormant state and resist therapy. Furthermore, quiescent CSCs are responsible for metastases that can appear after curative surgical treatment of a primary tumor. Because of drug resistance of CSCs, the development of novel therapies is urgently required that specifically target CSCs. PURPOSE: The aim of the present study was to investigate the potential of a panel of natural products and derivatives to inhibit CSC-enriched mammospheres of MCF-7 breast cancer cells. METHODS: CD44(high)/CD24(low) cells were identified by flow cytometry and maintained as mammospheres. As a control, we used two clinically established anticancer drugs (5-fluorouracil and docetaxel). A panel of natural products, shikonin, two cajanin stilbene acid (CSA) derivatives and artesunate were tested by resazurin assay on CSC-enriched mammospheres and MCF-7 monolayer cells. Besides, cellular shikonin uptake experiments were performed by flow cytometry. RESULTS: We found two CSA derivatives (Nos. 6 and 19) to be active cancer stem like MCF-7 mammospheres. Especially, CSA derivative No. 19 clearly showed collateral sensitivity in mammospheres compared to monolayer cells. CONCLUSION: Phytochemicals which provoke collateral sensitivity in cancer-stem like cells are worth more detailed investigations in the future, since there is a great potential for improved chemotherapy to eradicate tumors and prolong cancer patients' survival times. PMID- 25925966 TI - In vitro inhibitory effects of ethanol extract of Danshen (Salvia miltiorrhiza) and its components on the catalytic activity of soluble epoxide hydrolase. AB - BACKGROUND: Soluble epoxide hydrolase (sEH) has been demonstrated to be a key enzyme involved in the pathologic development of several cardiovascular diseases and inflammation, and inhibition of sEH is therefore very helpful or crucial for the treatment of ischemia-reperfusion injury, cardiac hypertrophy, hypertension and inflammation. Danshen, the dried root of Salvia miltiorrhiza (Fam. Labiatae), has been used for the treatment of cardiovascular and cerebrovascular diseases in China and other countries for hundreds of years. Recent studies indicated that Danshen and its preparations also have potential for the management of inflammation. However, little information is available about the possibility of Danshen and its components on sEH inhibition. PURPOSE AND METHODS: Danshen extracts and its constituents were tested for sEH inhibition using its physiological substrate, 8,9-EET, based on a LC-MS/MS assay in this study. RESULTS: Among the tested 15 compounds, tanshinone IIA and cryptotanshinone were found to be the potent (Ki = 0.87 MUM) and medium (Ki = 6.7 MUM) mixed-type inhibitors of sEH, respectively. Salvianolic acid C (Ki = 8.6 MUM) was proved to be a moderate noncompetitive sEH inhibitor. In consistent with the inhibition results of the pure compounds, the 75% ethanol extract of Danshen (EE, IC50 = 86.5 MUg/ml) which contained more tanshinone IIA and cryptotanshinone exhibited more potent inhibition on sEH than the water extract (WE, IC50 > 200 MUg/ml) or 1 M NaHCO3 (BE, IC50 > 200 MUg/ml) extract. CONCLUSION: These data indicated that using the ethanol fraction of Danshen and increasing the amounts of tanshinone IIA, cryptotanshinone and salvianolic acid C, especially the contents of tanshinone IIA in Danshen extract or preparations to enhance the inhibitory effects on sEH might be efficient ways to improve its cardiovascular protective and anti-inflammatory effects, and that herbal medicines could be an untapped reservoir for sEH-inhibition agents and developing sEH inhibitors from the cardiovascular protective and anti-inflammatory herbs is a promising approach. PMID- 25925967 TI - [6]-gingerol dampens hepatic steatosis and inflammation in experimental nonalcoholic steatohepatitis. AB - The aim of the study was to investigate the effects of [6]-gingerol ((S)-5 hydroxy-1-(4-hydroxy-3-methoxyphenyl)-3-decanone) in experimental models of non alcoholic steatohepatitis. HepG2 cells were exposed to 500 umol/l oleic acid (OA) for 24 h and preincubated for an additional 24 h with [6]-gingerol (25, 50 or 100 umol/l). [6]-Gingerol (100 umol/l) inhibited OA-induced triglyceride and inflammatory marker accumulation in HepG2 cells. After being fed a high-fat diet (HFD) for 2 weeks, male golden hamsters were dosed orally with [6]-gingerol (25, 50 or 100 mg/kg/day) once daily for 8 weeks while maintained on HFD. [6]-Gingerol (100 mg/kg/day) alleviated liver steatosis, inflammation, and reversed plasma markers of metabolic syndrome in HFD-fed hamsters. The expression of inflammatory cytokine genes and nuclear transcription factor-kappaB (NF-kappaB) were increased in the HFD group; these effects were attenuated by [6]-gingerol. The hepatic mRNA expression of lipogenic genes such as liver X receptor-alpha, sterol regulating element binding protein-1c and its target genes including acetyl-CoA carboxylase, fatty acid synthase, stearoyl-CoA desaturase 1, and acyl-CoA:diacylglycerol acyltransferase 2 in HFD-fed hamsters was also blocked by [6]-gingerol. [6] Gingerol may attenuate HFD-induced steatohepatitis by downregulating NF-kappaB mediated inflammatory responses and reducing hepatic lipogenic gene expression. PMID- 25925968 TI - Cell cycle arrest and induction of apoptosis by cajanin stilbene acid from Cajanus cajan in breast cancer cells. AB - BACKGROUND: The low abundant cajanin stilbene acid (CSA) from Pigeon Pea (Cajanus cajan) has been shown to kill estrogen receptor alpha positive cancer cells in vitro and in vivo. Downstream effects such as cell cycle and apoptosis-related mechanisms have not been analyzed yet. MATERIAL AND METHODS: We analyzed the activity of CSA by means of flow cytometry (cell cycle distribution, mitochondrial membrane potential, MMP), confocal laser scanning microscopy (MMP), DNA fragmentation assay (apoptosis), Western blotting (Bax and Bcl-2 expression, caspase-3 activation) as well as mRNA microarray hybridization and Ingenuity pathway analysis. RESULTS: CSA induced G2/M arrest and apoptosis in a concentration-dependent manner from 8.88 to 14.79 uM. The MMP broke down, Bax was upregulated, Bcl-2 downregulated and caspase-3 activated. Microarray profiling revealed that CSA affected BRCA-related DNA damage response and cell cycle regulated chromosomal replication pathways. CONCLUSION: CSA inhibited breast cancer cells by DNA damage and cell cycle-related signaling pathways leading to cell cycle arrest and apoptosis. PMID- 25925969 TI - Enhancing activity of antibiotics against Staphylococcus aureus: Zanthoxylum capense constituents and derivatives. AB - Six compounds (1-6), isolated from the methanol extract of the roots of the African medicinal plant Zanthoxylum capense Thunb. (Rutaceae), and seven ester derivatives (7-13) were evaluated for their antibacterial activities and modulatory effects on the MIC of antibiotics (erythromycin, oxacillin, and tetracycline) and ethidium bromide (EtBr) against a Staphylococcus aureus reference strain (ATCC 6538). Using the same model, compounds 1-13 were also assessed for their potential as efflux pump inhibitors by a fluorometric assay that measures the accumulation of the broad range efflux pump substrate EtBr. Compounds 8 and 11 were further evaluated for their antibacterial, modulatory and EtBr accumulation effects against four additional S. aureus strains, which included two clinical methicillin-resistant S. aureus (MRSA) strains. Compounds (1-13) have not shown antibacterial activity at the concentration ranges tested. When evaluated against S. aureus ATCC 6538, oxychelerythrine (1) a benzophenanthridine alkaloid, showed the highest modulatory activity enhancing the susceptibility of this strain to all the tested antibiotics from two to four fold. Ailanthoidiol diacetate (8) and ailanthoidiol di-2-ethylbutanoate (11) were also good modulators when combined with EtBr, increasing the bacteria susceptibility by four and two-fold, respectively. In the EtBr accumulation assay, using ATCC 6538 strain, the phenylpropanoid (+)-ailanthoidiol (6) and most of its ester derivatives (8-11) exhibited higher activity than the positive control verapamil. The highest effects were found for compounds 8 and 11 that also increased the accumulation of EtBr, using S. aureus ATCC 25923 as model. Furthermore, both compounds (8, 11) were able to enhance the ciprofloxacin activity against the MRSA clinical strains tested, causing a reduction of the antibiotic MIC values from two to four-fold. The EtBr accumulation assay revealed that this modulation activity was not due to an inhibition of efflux pumps mechanism. These results suggested that Z. capense constituents may be valuable as leads for restoring antibiotic activity against MRSA strains. PMID- 25925970 TI - Rhodiola crenulata extract suppresses hepatic gluconeogenesis via activation of the AMPK pathway. AB - BACKGROUND: Rhodiola, a popular herb, has been used for treating high altitude sicknesses, depression, fatigue, and diabetes. However, the detailed mechanisms by which Rhodiola crenulata functions in the liver need further clarification. PURPOSE: The current study was designed to examine the effects of Rhodiola crenulata root extract (RCE) on hepatic glucose production. METHODS: Human hepatoma HepG2 cells were treated with RCE for 6 h. Glucose production, the expression level of p-AMPK, and the expression of key gluconeogenic genes were measured. The effects of RCE were also studied in Sprague-Dawley (SD) rats. The efficacy and underlying mechanism of RCE in the liver were examined. RESULTS: RCE significantly suppressed glucose production and gluconeogenic gene expression in HepG2 cells while activating the AMPK signaling pathway. Interestingly, RCE suppressed hepatic gluconeogenesis was eliminated by an AMPK-specific inhibitor, but not by the PI3K/AKT-specific inhibitor. In addition, oral administration of RCE significantly increased phosphorylated AMPK levels and inhibited gluconeogenic gene expression in the rat liver. Furthermore, RCE treatment also decreased plasma glucose concentration in rats. CONCLUSION: We present in vitro and in vivo evidence that RCE might exert the glucose-lowering effect partly by inhibiting hepatic gluconeogenesis through activating the AMPK signaling pathway. These findings provide evidence that Rhodiola crenulata may be helpful for the management of type II diabetes. PMID- 25925971 TI - Systematic considerations for a multicomponent pharmacokinetic study of Epimedii wushanensis herba: From method establishment to pharmacokinetic marker selection. AB - BACKGROUND: Prenylflavonoids are major active components of Epimedii wushanensis herba (EWH). The global pharmacokinetics of prenylflavonoids are unclear, as these compounds yield multiple, often unidentified metabolites. PURPOSE: This study successfully elucidated the pharmacokinetic profiles of EWH extract and five EWH-derived prenylflavonoid monomers in rats. STUDY DESIGN: The study was a comprehensive analysis of metabolic pathways and pharmacokinetic markers. METHODS: Major plasma compounds identified after oral administration of EWH derived prototypes or extract included: (1) prenylflavonoid prototypes, (2) deglycosylated products, and (3) glucuronide conjugates. To select appropriate EWH-derived pharmacokinetic markers, a high performance liquid chromatography tandem mass spectrometry (HPLC-MS/MS) method was established to simultaneously monitor 14 major compounds in unhydrolyzed plasma and 10 potential pharmacokinetic markers in hydrolyzed plasma. RESULTS: The pharmacokinetic profiles indicated that the glucuronide conjugates of icaritin were the principle circulating metabolites and that total icaritin accounted for ~99% of prenylflavonoid exposure after administration of EWH-derived materials to rats. To further investigate icaritin as a prospective pharmacokinetic marker, correlation analysis was performed between total icaritin and its glucuronide conjugates, and a strong correlation (r > 0.5) was found, indicating that total icaritin content accurately reflected changes in the exposure levels of the glucuronide conjugates over time. Therefore, icaritin is a sufficient pharmacokinetic marker for evaluating dynamic prenylflavonoid exposure levels. Next, a mathematical model was developed based on the prenylflavonoid content of EWH and the exposure levels in rats, using icaritin as the pharmacokinetic marker. This model accurately predicted exposure levels in vivo, with similar predicted vs. experimental area under the curve (AUC)(0-96 h) values for total icaritin (24.1 vs. 32.0 mg/L h). CONCLUSION: Icaritin in hydrolyzed plasma can be used as a pharmacokinetic marker to reflect prenylflavonoid exposure levels, as well as the changes over time of its glucuronide conjugates. PMID- 25925972 TI - A structure-activity relationship study on antiosteoclastogenesis effect of triterpenoids from the leaves of loquat (Eriobotrya japonica). AB - Our previous results elucidated that the leaves of Eriobotrya japonica possessed the potential to suppress ovariectomy-induced bone mineral density deterioration, and ursolic acid, the major bioactive component in these leaves, suppressed the osteoclast differentiation. The aim of this study was to discover more candidates for development of novel antiosteoclastogenesis agents from the leaves of E. japonica. Phytochemical analysis following a cell-based osteoclastic tartrate resistant acid phosphatase (TRAP) activity assay revealed 11 more compounds with a potent antiosteoclastogenesis effect. The potency of ursane-type triterpenoids from the leaves of E. japonica prompted us to investigate the structure-activity relationships underlying their antiosteoclastogenesis. The results revealed that both the hydroxyl group at C-3 and the carboxylic group at C-17 played indispensable roles in the antiosteoclastogenesis activity of ursane-type triterpenoids. The configuration at C-3 (a beta-form of the hydroxyl group) was found to be important for this activity. While introducing a hydroxyl group at C 19 increased the inhibitory activity of ursane-type triterpenoids carrying an alpha-form hydroxyl group at C-3. The bioactivity analyses of ursolic acid and oleanolic acid demonstrated that the antiosteoclastogenesis effect of ursolic acid may be related to different positions of the C-29 and C-30 methyl groups on the E-ring, since oleanolic acid showed limited activity. The addition of a hydroxyl group at C-2 would dramatically improve the inhibition of oleanane-type triterpenoids. Collectively, these findings could provide important clues for the improvement of multi-targeted antiosteoclastogenesis agents from the leaves of E. japonica. PMID- 25925973 TI - Evaluation of pharmacodynamic activities of EPs(r) 7630, a special extract from roots of Pelargonium sidoides, in animals models of cough, secretolytic activity and acute bronchitis. AB - BACKGROUND: EPs((r)) 7630 is a proprietary aqueous-ethanolic extract from roots of Pelargonium sidoides DC and has been demonstrated to dispose among others of antibacterial, antiviral, immunomodulatory, antioxidant, and tissue-protective activity. It is an approved medicinal product in more than 50 countries for the treatment of airway infections such as acute bronchitis, common cold, and sinusitis. PURPOSE: While the pharmacological effects of EPs((r)) 7630 have extensively been evaluated in diverse in vitro test systems, the number of publications reporting results from in vivo models is limited. STUDY DESIGN: In the present study antitussive, secretolytic, and anti-inflammatory effects of EPs((r)) 7630 were assessed in animal experiments following oral administration at human equivalent doses. METHODS: Antitussive effects were evaluated using ammonia- and citric acid-induced models of cough in mice (20, 40, 120 mg/kg) and guinea pigs (10, 20, 45 mg/kg), respectively. For the determination of secretolytic activity tracheobronchial secretion of intraperitoneally injected phenol red was determined in mice, while antiinflammatory action was assessed in an acute bacterial bronchitis model in rats. RESULTS: A significant and dose dependent reduction of cough frequency was observed in both cough models, which was accompanied by a prolongation of cough latency time. Similarly, the extract exerted a marked secretolytic activity in mice. Induction of acute bacterial bronchitis caused characteristic histopathological changes in lung tissue adjacent to trachea and bronchi. The degree of these lesions was significantly reduced in rats treated with EPs((r)) 7630 at doses of 30 and 60 mg/kg. This protective effect at least partially seems to be mediated by an up-regulation of superoxide dismutase and a subsequent protective effect against oxidative stress as indicated by a reduced serum level of malondialdehyde. CONCLUSION: The present data further support the therapeutic use of EPs((r)) 7630 in respiratory tract infections and provide a basis for detailed studies on its bioactive constituents as well as their in vivo mode of action. PMID- 25925974 TI - Proanthocyanidins from the bark of Metasequoia glyptostroboides ameliorate allergic contact dermatitis through directly inhibiting T cells activation and Th1/Th17 responses. AB - OBJECTIVE: The leaves and bark of Metasequoia glyptostroboides are used as anti microbic, analgesic and anti-inflammatory drug for dermatic diseases in Chinese folk medicine. However, the pharmacological effects and material basis responsible for the therapeutic use of this herb have not yet been well studied. The objectives of this study were to evaluate the anti-inflammatory effects of the proanthocyanidin fraction from the bark of M. glyptostroboides (MGEB) and to elucidate its immunological mechanisms. MATERIALS AND METHODS: The anti inflammatory activity of MGEB was evaluated using 2,4-dinitrofluorobenzene (DNFB) induced allergic contact dermatitis (ACD) in mice. Its potential mechanisms were further investigated by determining its effects on Con A-induced T cell activation and Th1/Th17 responses in vitro. RESULTS: Both intraperitoneal injection and oral administration of MGEB significantly reduced the ear swelling in DNFB-induced ACD mice. MGEB inhibited Con A-induced proliferation and the expression levels of cell surface molecules CD69 and CD25 of T cells in vitro. MGEB also significantly decreased the production of Th1/Th17 specific cytokines (IL-2, IFN-gamma and IL-17) and down-regulated their mRNA expression levels in activated T-cells. CONCLUSIONS: MGEB could ameliorate ACD, at least in part, through directly inhibiting T cells activation and Th1/Th17 responses. PMID- 25925975 TI - The Identification of Stenotrophomonas maltophilia Contamination in Ultrasound Endoscopes and Reproduction of Decontamination Failure by Deliberate Soiling Tests. AB - BACKGROUND: An outbreak of Stenotrophomonas maltophilia was observed in the cultures of bronchial aspirations. After systematic culturing of the scopes and reprocessing the equipment, it turned out to be a pseudo-outbreak caused by a failure of the disinfector to sterilize ultrasound scopes, subsequently resulting in cross infection of the bronchoscopes via the connecting tubes in the dryer. OBJECTIVES: To support the above-mentioned findings and to show how different variables influence the decontamination process. METHODS: The ultrasound scopes were deliberately contaminated with test soil and subsequently disinfected with peracetic acid (PAA), glutaraldehyde (GA) and hot water. Cultures were taken immediately after disinfection and after 4 days in the drying cabinet. RESULTS: After disinfection with PAA, persistent contamination was observed in the endobronchial ultrasound scope, and after disinfection with PAA and prolonged storage in the drying cabinet, contamination of the endoscopic ultrasound scope persisted. All ultrasound scopes were effectively disinfected with GA. CONCLUSION: It is concluded that disinfection with PAA fails to decontaminate the small channels of the ultrasound scopes. Prolonged storage in humid conditions seems to enhance the outgrowth of microorganisms. By reassignment of all endoscopes to fixed locations in the drying cabinet, by using disposable connector tubes for the balloon channels, and by using GA instead of PAA, the reprocessing procedure in our hospital was corrected effectively. PMID- 25925976 TI - Omega 3 Polyunsaturated Fatty Acids Suppress the Development of Aortic Aneurysms Through the Inhibition of Macrophage-Mediated Inflammation. AB - BACKGROUND: Dietary intake of omega3 polyunsaturated fatty acids (omega3-PUFAs) reduces progression of atherosclerosis and prevents future cardiovascular events. Macrophages are key players in the pathogenesis of aortic aneurysm. The effects of omega3-PUFAs on abdominal aortic aneurysm (AAA) formation and macrophage mediated inflammation remain unclear. METHODS AND RESULTS: The AAA model was developed by angiotensin II infusion in apolipoprotein E-deficient mice. Mice were supplemented with eicosapentaenoic acid (EPA) or docosahexaenoic acid (DHA). The development of AAA lesions and macrophage infiltration in the aorta were analyzed. Gene expression of inflammatory markers in aortic tissues and peritoneal macrophages were measured by using quantitative polymerase chain reaction. AAA formation and macrophage infiltration were significantly suppressed after EPA and DHA administration. EPA administration and DHA administration significantly decreased the expression of tumor necrosis factor-alpha, monocyte chemoattractant protein-1, transforming growth factor-beta, matrix metalloproteinases (MMP)-2, MMP-9, and vascular cell adhesion molecule-1 in the aortas. The expression of arginase 2, which is a marker of pro-inflammatory macrophages, was significantly lower and that of Ym1, which is a marker of anti inflammatory macrophages, and was significantly higher after EPA and DHA administration. The same trends were observed in peritoneal macrophages after EPA and DHA administration. CONCLUSIONS: Dietary intake of EPA and DHA prevented AAA development through the inhibition of aortic and macrophage-mediated inflammation. PMID- 25925977 TI - Unveiling specific triggers and precipitating factors for fatal cardiac events in inherited arrhythmia syndromes. AB - Patients with inherited arrhythmia syndromes, such as long QT syndrome, Brugada syndrome, early repolarization syndrome, catecholaminergic polymorphic ventricular tachycardia, and their latent forms, are at risk for fatal arrhythmias. These diseases are typically associated with genetic mutations that perturb cardiac ionic currents. The analysis of cardiac events by genotype phenotype correlation studies has revealed that fatal arrhythmias in some genotypes are triggered by physical or emotional stress, and those in the others are more likely to occur during sleep or at rest. Thus, the risk stratification and management of affected patients differ strikingly according to the genetic variant of the inherited arrhythmia syndrome. Risk stratification may be further refined by considering the precipitating factors, such as drugs, bradycardia, electrolyte disturbances, fever, and cardiac memory. Moreover, an increasing number of studies imply that the susceptibility of fatal arrhythmias in patients with acute coronary syndrome or takotsubo cardiomyopathy is at least partly ascribed to the genetic variants causing inherited arrhythmia syndromes. In this article, we review the recent advances in the understanding of the molecular genetics and genotype-phenotype correlations in inherited arrhythmia syndromes and consider the triggers and precipitating factors for fatal arrhythmias in these disorders. Further studies to explore the triggers and precipitating factors specific to the genotypes and diseases are needed for better clinical management. PMID- 25925978 TI - Cardiopulmonary rehabilitation using adaptive servo-ventilation after cardiac surgery. PMID- 25925979 TI - Effects of the Rho-kinase inhibitor, fasudil, on pulmonary hypertension. PMID- 25925980 TI - Anti-obesity effect of Triticum aestivum sprout extract in high-fat-diet-induced obese mice. AB - Obesity is a common disease worldwide that often results in serious conditions including hypertension, diabetes, and hyperlipidemia. Many herbal medicines have been examined with regard to ameliorating obesity. We investigated the anti obesity effects of 50% EtOH extract of Triticum aestivum sprout (TAEE) in high fat-diet (HFD)-induced obese mice. TAEE administration (10, 50, or 200 mg/kg) for 6 weeks significantly decreased the body weights, serum total cholesterol (TC), and low-density lipoprotein cholesterol levels in HFD-fed mice. TAEE treatment reduced lipid accumulation in epididymal white adipose tissue (EWAT) and liver. Moreover, TC and lipid levels were decreased by TAEE treatment in liver. Serum leptin and adiponectin concentrations were reduced by TAEE treatment. TAEE treated mice showed decreases in peroxisome proliferator-activated receptor gamma (PPARgamma) and fatty acid synthase expression in EWAT. Furthermore, TAEE administration elevated levels of PPARalpha protein in the liver of HFD-induced obese mice. These results suggest that TAEE supplementation might be beneficial for the treatment and prevention of obesity and related diseases. PMID- 25925981 TI - Differential effects of enriched environment at work on cognitive decline in old age. AB - OBJECTIVES: The aim of the present study was to investigate how different mentally demanding work conditions during the professional life-i.e., enriched environments at work-might influence the rate of cognitive decline in old age. METHODS: Individuals (n = 1,054) of the Leipzig Longitudinal Study of the Aged, a representative population-based cohort study of individuals aged 75 years and older, underwent cognitive testing via the Mini-Mental State Examination (MMSE) in up to 6 measurement waves. Type and level of mentally demanding work conditions in the participants' former professional life were classified based on the O*NET job descriptor database. RESULTS: In multivariate mixed-model analyses (controlling for sociodemographic and health-related factors), a high level of mentally demanding work tasks stimulating verbal intelligence was significantly associated with a better cognitive functioning at baseline (on average 5 MMSE points higher) as well as a lower rate of cognitive decline (on average 2 MMSE points less) over the 8-year follow-up period compared with a low level. The rate of cognitive decline in old age was also significantly lower (on average 3 MMSE points less) in individuals who had a high level of mentally demanding work tasks stimulating executive functions than those who had a low level. CONCLUSIONS: The results suggest that a professional life enriched with work tasks stimulating verbal intelligence and executive functions may help to sustain a good cognitive functioning in old age (75+ years). The findings thus emphasize that today's challenging work conditions may also promote positive health effects. PMID- 25925982 TI - White matter disease and cognitive impairment in FMR1 premutation carriers. AB - OBJECTIVE: This cross-sectional, observational study examined the role of white matter involvement in the cognitive impairment of individuals with the fragile X mental retardation 1 (FMR1) premutation. METHODS: Eight asymptomatic premutation carriers, 5 participants with fragile X tremor/ataxia syndrome (FXTAS), and 7 noncarrier controls were studied. The mean age of the asymptomatic premutation carriers, participants with FXTAS, and noncarrier controls was 60, 71, and 67 years, respectively. Magnetic resonance spectroscopy (MRS) and diffusion tensor imaging (DTI) were used to examine the middle cerebellar peduncles (MCP) and the genu and splenium of the corpus callosum in relation to executive function and processing speed. MRS measures were N-acetyl aspartate/creatine (NAA/Cr) and choline/creatine, and fractional anisotropy (FA) was used for DTI. Executive function was assessed with the Behavioral Dyscontrol Scale and the Controlled Oral Word Association Test (COWAT), and processing speed with the Symbol Digit Modalities Test. RESULTS: Among all 13 FMR1 premutation carriers, significant correlations were found between N-acetyl aspartate/creatine and choline/creatine in the MCP and COWAT scores, and between FA in the genu and performance on the Behavioral Dyscontrol Scale, COWAT, and Symbol Digit Modalities Test; a correlation was also found between FA in the splenium and COWAT performance. In all regions studied, participants with FXTAS had the lowest mean FA. CONCLUSION: Microstructural white matter disease as determined by MRS and DTI correlated with executive dysfunction and slowed processing speed in these FMR1 premutation carriers. Neuroimaging abnormalities in the genu and MCP suggest that disruption of white matter within frontocerebellar networks has an important role in the cognitive impairment associated with the FMR1 premutation. PMID- 25925983 TI - Potential sex differences in nonmotor symptoms in early drug-naive Parkinson disease. AB - OBJECTIVE: To examine potential sex differences in nonmotor symptoms (NMS) among drug-naive patients with Parkinson disease (PD), and to identify NMS that can best differentiate patients with early PD from controls. METHODS: Our cross sectional analysis included 414 newly diagnosed, untreated patients with PD (269 men and 145 women) and 188 healthy controls (121 men and 67 women) in the Parkinson's Progression Markers Initiative Study. NMS were measured using well validated instruments covering sleep, olfactory, neurobehavioral, autonomic, and neuropsychological domains. RESULTS: Male and female patients with PD were fairly comparable on motor presentations but differed on several nonmotor features. Male patients with PD had significantly more pronounced deficits in olfaction (p = 0.02) and in certain cognitive measurements (all p < 0.01) than female patients, whereas female cases experienced higher trait anxiety (p = 0.02). Multiple stepwise logistic regression analysis showed that the combination of NMS measures University of Pennsylvania Smell Identification Test (UPSIT), Montreal Cognitive Assessment (MoCA), Scales for Outcomes in Parkinson's Disease-Autonomic (SCOPA AUT), and state anxiety from the State-Trait Anxiety Inventory-effectively differentiated patients with PD from controls with an area under the receiver operating characteristic curve (AUC) of 0.913 (95% confidence interval [CI]: 0.89 0.94). UPSIT, MoCA, and SCOPA-AUT were the most predictive NMS measurements in men (AUC = 0.919; 95% CI: 0.89-0.95) as compared to UPSIT, MoCA, and REM Sleep Behavior Disorder Screening Questionnaire in women (AUC = 0.903; 95% CI: 0.86 0.95). CONCLUSIONS: Our analysis revealed notable sex differences in several nonmotor features of patients with de novo PD. Furthermore, we found a parsimonious NMS combination that could effectively differentiate de novo cases from healthy controls. PMID- 25925984 TI - How much does sex matter in Parkinson disease? PMID- 25925985 TI - Impaired corticostriatal connectivity in impulse control disorders in Parkinson disease. AB - OBJECTIVES: To compare the striatum's resting-state functional connectivity in patients with Parkinson disease (PD) with and without impulse control disorders (ICDs). METHODS: Twenty patients with PD and ICDs, 19 patients with PD but no ICDs, and 19 healthy controls underwent fMRI in the resting state. The ventral striatum, dorsal caudate, and anterior and posterior putamen were segmented semiautomatically. For each region of interest, a seed-based connectivity analysis was performed on preprocessed fMRI data mapped on the ipsilateral cortical surface. An additional cortical thickness analysis was used to assess and compare gray matter atrophy in the 3 study subgroups. RESULTS: The presence of an ICD in patients with PD was associated with functional disconnection between the left anterior putamen and both the left inferior temporal gyrus and the left anterior cingulate gyrus, as well as a trend toward a functional disconnection between several motor and associative striatal regions and limbic, associative, and motor cortical regions. Patients without ICDs did not differ from healthy controls in corticostriatal connectivity. The cortical thickness analysis did not reveal any significant differences among the 3 study subgroups. CONCLUSIONS: In PD, ICDs are associated with altered connectivity between an associative striatal area (the left anterior putamen) and associative and limbic cortical regions (the left inferior temporal gyrus and the left anterior cingulate gyrus). PMID- 25925986 TI - Cystic leukoencephalopathy with cortical dysplasia related to LAMB1 mutations. PMID- 25925988 TI - Controllable galvanic synthesis of triangular Ag-Pd alloy nanoframes for efficient electrocatalytic methanol oxidation. AB - Triangular Ag-Pd alloy nanoframes were successfully synthesized through galvanic replacement by using Ag nanoprisms as sacrificial templates. The ridge thickness of the Ag-Pd alloy nanoframes could be readily tuned by adjusting the amount of the Pd source during the reaction. These obtained triangular Ag-Pd alloy nanoframes exhibit superior electrocatalytic activity for the methanol oxidation reaction as compared with the commercial Pd/C catalyst due to the alloyed Ag-Pd composition as well as the hollow-framed structures. This work would be highly impactful in the rational design of future bimetallic alloy nanostructures with high catalytic activity for fuel cell systems. PMID- 25925987 TI - A molecular systems approach to modelling human skin pigmentation: identifying underlying pathways and critical components. AB - BACKGROUND: Ultraviolet radiations (UV) serve as an environmental stress for human skin, and result in melanogenesis, with the pigment melanin having protective effects against UV induced damage. This involves a dynamic and complex regulation of various biological processes that results in the expression of melanin in the outer most layers of the epidermis, where it can exert its protective effect. A comprehensive understanding of the underlying cross talk among different signalling molecules and cell types is only possible through a systems perspective. Increasing incidences of both melanoma and non-melanoma skin cancers necessitate the need to better comprehend UV mediated effects on skin pigmentation at a systems level, so as to ultimately evolve knowledge-based strategies for efficient protection and prevention of skin diseases. METHODS: A network model for UV-mediated skin pigmentation in the epidermis was constructed and subjected to shortest path analysis. Virtual knock-outs were carried out to identify essential signalling components. RESULTS: We describe a network model for UV-mediated skin pigmentation in the epidermis. The model consists of 265 components (nodes) and 429 directed interactions among them, capturing the manner in which one component influences the other and channels information. Through shortest path analysis, we identify novel signalling pathways relevant to pigmentation. Virtual knock-outs or perturbations of specific nodes in the network have led to the identification of alternate modes of signalling as well as enabled determining essential nodes in the process. CONCLUSIONS: The model presented provides a comprehensive picture of UV mediated signalling manifesting in human skin pigmentation. A systems perspective helps provide a holistic purview of interconnections and complexity in the processes leading to pigmentation. The model described here is extensive yet amenable to expansion as new data is gathered. Through this study, we provide a list of important proteins essential for pigmentation which can be further explored to better understand normal pigmentation as well as its pathologies including vitiligo and melanoma, and enable therapeutic intervention. PMID- 25925989 TI - Transgenic systems for unequivocal identification of cardiac myocyte nuclei and analysis of cardiomyocyte cell cycle status. AB - Even though the mammalian heart has been investigated for many years, there are still uncertainties in the fields of cardiac cell biology and regeneration with regard to exact fractions of cardiomyocytes (CMs) at different developmental stages, their plasticity after cardiac lesion and also their basal turnover rate. A main shortcoming is the accurate identification of CM and the demonstration of CM division. Therefore, an in vivo model taking advantage of a live reporter based identification of CM nuclei and their cell cycle status is needed. In this technical report, we describe the generation and characterization of embryonic stem cells and transgenic mice expressing a fusion protein of human histone 2B and the red fluorescence protein mCherry under control of the CM specific alphaMHC promoter. This fluorescence label allows unequivocal identification and quantitation of CM nuclei and nuclearity in isolated cells and native tissue slices. In ventricles of adults, we determined a fraction of <20 % CMs and binucleation of 77-90 %, while in atria a CM fraction of 30 % and a binucleation index of 14 % were found. We combined this transgenic system with the CAG-eGFP anillin transgene, which identifies cell division and established a novel screening assay for cell cycle-modifying substances in isolated, postnatal CMs. Our transgenic live reporter-based system enables reliable identification of CM nuclei and determination of CM fractions and nuclearity in heart tissue. In combination with CAG-eGFP-anillin-mice, the cell cycle status of CMs can be monitored in detail enabling screening for proliferation-inducing substances in vitro and in vivo. PMID- 25925990 TI - Phase III randomized trial of second-line ixabepilone versus paclitaxel or doxorubicin in women with advanced endometrial cancer. AB - OBJECTIVE: The purpose of this multicenter, open label, randomized phase III study was to determine whether ixabepilone resulted in improved overall survival (OS) compared with commonly used single-agent chemotherapy (doxorubicin or paclitaxel) in women with locally advanced, recurrent, or metastatic endometrial cancer with at least one failed prior platinum-based chemotherapeutic regimen. METHODS: Patients were randomized 1:1 to ixabepilone (40mg/m(2)), or either paclitaxel (175mg/m(2)) or doxorubicin (60mg/m(2)), every 21days. Patients that had previously received an anthracycline were randomized to ixabepilone or paclitaxel; all other patients were randomized to ixabepilone or doxorubicin. An interim analysis of futility for OS was planned. RESULTS: At the time of database lock, 496 patients were randomized to receive ixabepilone (n=248) or control (n=248); nine patients in the control arm were not treated. The interim analysis of futility for OS (219 events) favored the control chemotherapy arm (hazard ratio=1.3 [95% confidence interval: 1.0-1.7], stratified log rank test P=0.0397), indicating that the study would not meet its primary objective. The study was discontinued based on the interim OS results. The frequency of adverse events was comparable between the treatment arms. CONCLUSIONS: The study did not meet its primary objective of improving OS in the ixabepilone arm compared to the control chemotherapy arm. A favorable risk/benefit ratio was not observed for ixabepilone versus control at the time of the interim analysis. The safety results were consistent with the known safety profiles of ixabepilone and control. PMID- 25925991 TI - A novel CCBE1 mutation leading to a mild form of hennekam syndrome: case report and review of the literature. AB - BACKGROUND: Mutations in CCBE1 have been found to be responsible for a subset of families with autosomal recessive Hennekam syndrome. Hennekam syndrome is defined as the combination of generalized lymphatic dysplasia (ie. lymphedema and lymphangiectasia), variable intellectual disability and characteristic dysmorphic features. The patient we describe here has a lymphatic dysplasia without intellectual disability or dysmorphism caused by mutation in CCBE1, highlighting the phenotypic variability that can be seen with abnormalities in this gene. CASE PRESENTATION: Our patient is a 5 week old child of Pakistani descent who presented to our center with generalized edema, ascites, and hypoalbuminemia. She was diagnosed with a protein losing enteropathy secondary to segmental primary intestinal lymphangiectasia. As the generalized edema resolved, it became clear that she had mild persistent lymphedema in her hands and feet. No other abnormalities were noted on examination and development was unremarkable at 27 months of age. Given the suspected genetic etiology and the consanguinity in the family, we used a combination of SNP genotyping and exome sequencing to identify the underlying cause of her disease. We identified several large stretches of homozygosity in the patient that allowed us to sort the variants found in the patient's exome to identify p.C98W in CCBE1 as the likely pathogenic variant. CONCLUSIONS: CCBE1 mutation analysis should be considered in all patients with unexplained lymphatic dysplasia even without the other features of classic Hennekam syndrome. PMID- 25925993 TI - Cyclosporine Combined with Levamisole for Lower-Risk Myelodysplastic Syndromes. AB - Clinical and experimental evidence suggests an immune-mediated pathophysiology in subjects with lower-risk myelodysplastic syndromes (MDS) in whom immunosuppressive therapy may be effective. The novel immunosuppressive strategy of cyclosporine A (CsA) alternately combined with levamisole (LMS; CsA + LMS regimen) can dramatically improve the response rate and survival in aplastic anemia from those of our previous study. Herein, we retrospectively analyzed the data of 89 lower-risk MDS patients who received the CsA + LMS regimen. A total of 63 patients (70.8%) achieved either complete remission or hematological improvement at 4 months. Overall, 51, 41 and 19 patients had erythroid, platelet and neutrophil responses, respectively. Following the CsA + LMS regimen, 6 patients progressed to more advanced MDS at a median interval of 5 months (range, 3-42 months). The estimated 24-month progression-free survival was 82.2% (95% CI, 72.84-91.56) for all patients. Within the median follow-up of 18.5 months (range, 7.0-61.0), 6 patients died. In conclusion, the CsA + LMS regimen alleviated cytopenias and improved survival and freedom from evolution, suggesting that it could be reserved as an alternative choice for lower-risk MDS. PMID- 25925992 TI - Peri-procedural use of rivaroxaban in elective percutaneous coronary intervention to treat stable coronary artery disease. The X-PLORER trial. AB - Patients on rivaroxaban requiring percutaneous coronary intervention (PCI) represent a clinical conundrum. We aimed to investigate whether rivaroxaban, with or without an additional bolus of unfractionated heparin (UFH), effectively inhibits coagulation activation during PCI. Stable patients (n=108) undergoing elective PCI and on stable dual antiplatelet therapy were randomised (2:2:2:1) to a short treatment course of rivaroxaban 10 mg (n=30), rivaroxaban 20 mg (n=32), rivaroxaban 10 mg plus UFH (n=30) or standard peri-procedural UFH (n=16). Blood samples for markers of thrombin generation and coagulation activation were drawn prior to and at 0, 0.5, 2, 6-8 and 48 hours (h) after start of PCI. In patients treated with rivaroxaban (10 or 20 mg) and patients treated with rivaroxaban plus heparin, the levels of prothrombin fragment 1 + 2 at 2 h post-PCI were 0.16 [0.1] nmol/l (median) [interquartile range, IQR] and 0.17 [0.2] nmol/l, respectively. Thrombin-antithrombin complex values at 2 h post-PCI were 3.90 [6.8]ug/l and 3.90 [10.1] ug/l, respectively, remaining below the upper reference limit (URL) after PCI and stenting. This was comparable to the control group of UFH treatment alone. However, median values for thrombin-antithrombin complex passed above the URL with increasing tendency, starting at 2 h post-PCI in the UFH-alone arm but not in rivaroxaban-treated patients. In this exploratory trial, rivaroxaban effectively suppressed coagulation activation after elective PCI and stenting. PMID- 25925994 TI - Nonallergic Rhinitis in the Elderly: A Reliable and Safe Therapeutic Approach. AB - OBJECTIVE: Nonallergic rhinitis (NAR) causes significant functional and emotional impairment, affecting the quality of life (QoL) of elderly patients often suffering from other chronic diseases that require additional therapies to be added to the numerous daily medications. This study aimed to evaluate the effectiveness of crenotherapy with sodium chloride sulfate hyperthermal water rich in mineral salts on the QoL of elderly patients with NAR. METHODS: Sixty elderly subjects with NAR were divided into 2 groups. Group I (n = 30) underwent crenotherapy with sodium chloride sulfate hyperthermal water rich in mineral salts, and group II (n = 30) underwent treatment with NaCl 0.9%. At baseline and after treatment, both groups underwent nasal endoscopy, and we determined their Visual Analogue Scale (VAS) scores for rhinorrhea, respiratory obstruction and sneezing. RESULTS: After treatment, the patients in both groups reported having no adverse reactions. Endoscopic and VAS score results were better in group I than in group II. All subjects showed a good degree of tolerability. CONCLUSIONS: Our data suggest that crenotherapy improves the QoL in elderly patients with NAR. Crenotherapy can prevent elderly patients with NAR from having to take additional medications, which can often cause relevant adverse reactions and considerable health care costs. PMID- 25925995 TI - Individual and contextual factors associated with verbal bullying among Brazilian adolescents. AB - BACKGROUND: Few studies have been carried out in low- middle-income countries assessing contextual characteristics associated with bullying. This study aimed to assess the relative importance of contextual (school and city) and individual level factors to explain the variance in verbal bullying among a nationally representative sample of Brazilian adolescents. METHODS: 59,348 students from 1,453 schools and 26 state capitals and the Federal District participated in the National Survey of School Health among 9th Grade Students (PeNSE, 2009). We performed multilevel logistic regression in a three level model (individual, school and city). RESULTS: The 30-day prevalence of verbal bullying among these students was 14.2%. We found that 1.8% and 0.3% of the total variance in bullying occurred at school-level and city-level, respectively, and 97.9% at individual level. At city-level, all factors included failed to demonstrate a significant association with bullying (p < 0.05) whereas at school-level, private schools presented more bullying than public schools (OR = 1.17, CI 1.04-1.31). At individual-level, male gender, younger age, not living with both parents, exposed to domestic violence, under or overweight were all associated with bullying. CONCLUSIONS: All socioeconomic indicators assessed contributed little to explain the variance in bullying at individual, school or city-level. Population subgroups at risk identified according to their individual profile could be targeted in future interventions in Brazil. PMID- 25925997 TI - Emerging land use practices rapidly increase soil organic matter. AB - The loss of organic matter from agricultural lands constrains our ability to sustainably feed a growing population and mitigate the impacts of climate change. Addressing these challenges requires land use activities that accumulate soil carbon (C) while contributing to food production. In a region of extensive soil degradation in the southeastern United States, we evaluated soil C accumulation for 3 years across a 7-year chronosequence of three farms converted to management intensive grazing. Here we show that these farms accumulated C at 8.0 Mg ha(-1) yr(-1), increasing cation exchange and water holding capacity by 95% and 34%, respectively. Thus, within a decade of management-intensive grazing practices soil C levels returned to those of native forest soils, and likely decreased fertilizer and irrigation demands. Emerging land uses, such as management intensive grazing, may offer a rare win-win strategy combining profitable food production with rapid improvement of soil quality and short-term climate mitigation through soil C-accumulation. PMID- 25925996 TI - Assessing the effects of tDCS over a delayed response inhibition task by targeting the right inferior frontal gyrus and right dorsolateral prefrontal cortex. AB - Many situations in our everyday life call for a mechanism deputed to outright stop an ongoing course of action. This behavioral inhibition ability, known as response stopping, is often impaired in psychiatric conditions characterized by impulsivity and poor inhibitory control. Transcranial direct current stimulation (tDCS) has recently been proposed as a tool for modulating response stopping in such clinical populations, and previous studies in healthy humans have already shown that this noninvasive brain stimulation technique is effectively able to improve response stopping, as measured in a stop-signal task (SST) administered immediately after the stimulation. So far, the right inferior frontal gyrus (rIFG) has been the main focus of these attempts to modulate response stopping by the means of noninvasive brain stimulation. However, other cortical areas such as the right dorsolateral prefrontal cortex (rDLPFC) have been implicated in inhibitory control with other paradigms. In order to provide new insight about the involvement of these areas in response stopping, in the present study, tDCS was delivered to 115 healthy subjects, using five stimulation setups that differed in terms of target area (rIFG or rDLPFC) and polarity of stimulation (anodal, cathodal, or sham). The SST was performed 15 min after the offset of the stimulation. Consistently with previous studies, only anodal stimulation over rIFG induced a reliable, although weak, improvement in the SST, which was specific for response stopping, as it was not mirrored in more general reaction time measures. PMID- 25925998 TI - A Novel Molecular Cytogenetic Finding of Leiomyomatosis Peritonealis Disseminata. AB - BACKGROUND: Leiomyomatosis peritonealis disseminata (LPD) is a rare disease characterised by the subperitoneal proliferation of smooth muscle cells that form benign nodules. A few studies have aimed to reveal the pathogenesis of LPD without reaching a clear explanation. METHODS: Karyotype analysis and array comparative genomic hybridization (aCGH) of a human LPD case were performed to evaluate the role of chromosomal abnormalities in LPD pathogenesis. RESULTS: The LPD nodules showed a 45, XX, del(7p), t(11; 17) (q23;q25),-22 de novo karyotype, and the aCGH analysis confirmed these deletions at 7p22.3-p12.1 (1,862,362 52,766,911 bp) and 22q11.23-q13.33 (21,973,915-49,265,116 bp) with lengths of 50.9 Mb and 27.3 Mb, respectively. CONCLUSION: In this study, we described two large novel aberrations - deletions in chromosome 7 and 22 - that might play an important role in LPD disease. These findings might contribute to new insights to unravel the pathogenesis of LPD and develop further clinical treatments. (c) 2015 S. Karger AG, Basel. PMID- 25925999 TI - Safety of adjunct pre-emptive intravenous tramadol with midazolam sedation for third molar surgery. AB - PURPOSE: The purpose of this study was to evaluate patient safety, in terms of adverse events, alterations in blood pressure or oxygen saturation (SpO2) in two routine sedation procedures, with and without intravenous analgesia. METHODS: Patients referred for surgical removal of mandibular third molars were treated in a randomized, controlled, single-blinded procedure. Eighty-seven men and women, aged 18 to 44 years, were allotted to either of two treatment groups, midazolam + tramadol (M + T) and midazolam + saline (M + S) or to a control group (C), given no sedation. RESULTS: Tramadol at 1 mg/kg body weight resulted in a higher frequency of oxygen desaturation (SpO2 < 90 %) than a placebo (p = 0.002) but had no effect on mean SpO2 at the end point or at the end of surgery. In both the test groups, there was a significant decrease in diastolic blood pressure (p < 0.001) from baseline to the end of surgery. CONCLUSION: The results confirm that pre-emptive intravenous tramadol, administered at 1 mg/kg body weight as an adjunct to midazolam sedation for third molar surgery, offers a safe method. But, it should be noted that our previous study shows that it is not a particularly effective analgesic. Further testing is therefore warranted, using other doses or other drugs, to find a better intravenous protocol for postoperative analgesia, with maximum effect and minimal risk, in outpatient oral and maxillofacial surgery procedures. PMID- 25926000 TI - Failure of eruption of permanent molars: a diagnostic dilemma. AB - BACKGROUND: Limited studies have proposed protocols for the management of failure of eruption (FOE) of permanent molars with no clear consensus or guidelines. Accurate diagnosis is challenging but key for successful management. AIMS: Confirm key diagnostic criteria that will aid diagnostic differentiation between primary failure of eruption (PFE) and mechanical failure of eruption (MFE) of permanent molars and identify successful management strategies. DESIGN: Retrospective descriptive study. Patients diagnosed with FOE of permanent molars (excluding impaction) between January 2003 and December 2013 were identified. Patient details and clinical and radiological features of FOE were recorded. Two examiners analysed the data. A diagnosis of PFE or MFE was made based on a combination of current protocols. Management strategies for each were identified and reported as satisfactory/unsatisfactory. RESULTS: Thirty-one patients met the inclusion criteria. Fifteen were classified as PFE and 14 as MFE. One patient was too young to confirm diagnosis, and one patient had delayed eruption. A total of 26% of cases were misdiagnosed which led to unsuccessful orthodontic management. CONCLUSION: We propose a protocol based on the results of this study coupled with existing protocols in the form of a simple flow diagram to aid accurate diagnosis and management of this rare and challenging clinical problem. PMID- 25926002 TI - Comparative membrane proteomics: a technical advancement in the search of renal cell carcinoma biomarkers. AB - Renal Cell Carcinoma (RCC) is the most common kidney cancer, accounting for 3% of adult malignancies, with high metastatic potential and radio-/chemo-resistance. To investigate the protein profile of membrane microdomains (MD), plasma membrane supramolecular structures involved in cell signaling, transport, and neoplastic transformation, we set up a proteomic bottom-up approach as a starting point for the identification of potential RCC biomarkers. We purified MD from RCC and adjacent normal kidney (ANK) tissues, through their resistance to non-ionic detergents followed by ultracentrifugation in sucrose density gradient. MD from 5 RCC/ANK tissues were then pooled and analysed by LC-ESI-MS/MS. In order to identify the highest number of proteins and increase the amount of membrane and hydrophobic ones, we first optimized an enzymatic digestion protocol based on Filter Aided Sample Preparation (FASP), coupled to MD delipidation. The MS analysis led to the identification of 742 ANK MD and 721 RCC MD proteins, of which, respectively, 53.1% and 52.6% were membrane- bound. Additionally, we evaluated RCC MD differential proteome by label-free quantification; 170 and 126 proteins were found to be, respectively, up-regulated and down-regulated in RCC MD. Some differential proteins, namely CA2, CD13, and ANXA2, were subjected to validation by immunodecoration. These results show the importance of setting up different protocols for the proteomic analysis of membrane proteins, specific to the different molecular features of the samples. Furthermore, the subcellular proteomic approach provided a list of differentially expressed proteins among which RCC biomarkers may be looked for. PMID- 25926003 TI - Age-related differences in quality of life among patients with diffuse large B cell lymphoma. PMID- 25926001 TI - A perspective on the structure and receptor binding properties of immunoglobulin G Fc. AB - Recombinant antibodies spurred a revolution in medicine that saw the introduction of powerful therapeutics for treating a wide range of diseases, from cancers to autoimmune disorders and transplant rejection, with more applications looming on the horizon. Many of these therapeutic monoclonal antibodies (mAbs) are based on human immunoglobulin G1 (IgG1) or contain at least a portion of the molecule. Most mAbs require interactions with cell surface receptors for efficacy, including the Fc gamma receptors. High-resolution structural models of antibodies and antibody fragments have been available for nearly 40 years; however, a thorough description of the structural features that determine the affinity with which antibodies interact with human receptors has not been published. In this review, we will cover the relevant history of IgG-related literature and how recent developments have changed our view of critical antibody-cell interactions at the atomic level with a nod to outstanding questions in the field and future prospects. PMID- 25926004 TI - Use of opportunistic sightings and expert knowledge to predict and compare Whooping Crane stopover habitat. AB - Predicting a species' distribution can be helpful for evaluating management actions such as critical habitat designations under the U.S. Endangered Species Act or habitat acquisition and rehabilitation. Whooping Cranes (Grus americana) are one of the rarest birds in the world, and conservation and management of habitat is required to ensure their survival. We developed a species distribution model (SDM) that could be used to inform habitat management actions for Whooping Cranes within the state of Nebraska (U.S.A.). We collated 407 opportunistic Whooping Crane group records reported from 1988 to 2012. Most records of Whooping Cranes were contributed by the public; therefore, developing an SDM that accounted for sampling bias was essential because observations at some migration stopover locations may be under represented. An auxiliary data set, required to explore the influence of sampling bias, was derived with expert elicitation. Using our SDM, we compared an intensively managed area in the Central Platte River Valley with the Niobrara National Scenic River in northern Nebraska. Our results suggest, during the peak of migration, Whooping Crane abundance was 262.2 (90% CI 40.2-3144.2) times higher per unit area in the Central Platte River Valley relative to the Niobrara National Scenic River. Although we compared only 2 areas, our model could be used to evaluate any region within the state of Nebraska. Furthermore, our expert-informed modeling approach could be applied to opportunistic presence-only data when sampling bias is a concern and expert knowledge is available. PMID- 25926005 TI - Novel partial duplication of EYA1 causes branchiootic syndrome in a large Brazilian family. AB - OBJECTIVE: To identify novel genetic causes of syndromic hearing loss in Brazil. DESIGN: To map a candidate chromosomal region through linkage studies in an extensive Brazilian family and identify novel pathogenic variants using sequencing and array-CGH. STUDY SAMPLE: Brazilian pedigree with individuals affected by BO syndrome characterized by deafness and malformations of outer, middle and inner ear, auricular and cervical fistulae, but no renal abnormalities. RESULTS: Whole genome microarray-SNP scanning on samples of 11 affected individuals detected a multipoint Lod score of 2.6 in the EYA1 gene region (chromosome 8). Sequencing of EYA1 in affected patients did not reveal pathogenic mutations. However, oligonucleotide-array-CGH detected a duplication of 71.8Kb involving exons 4 to 10 of EYA1 (heterozygous state). Real-time-PCR confirmed the duplication in fourteen of fifteen affected individuals and absence in 13 unaffected individuals. The exception involved a consanguineous parentage and was assumed to involve a different genetic mechanism. CONCLUSIONS: Our findings implicate this EYA1 partial duplication segregating with BO phenotype in a Brazilian pedigree and is the first description of a large duplication leading to the BOR/BO syndrome. PMID- 25926006 TI - Encouraging vegetable intake as a snack among children: the influence of portion and unit size. AB - OBJECTIVE: People eat more unhealthy foods when served more (portion size effect) and when the food is served in larger units (unit size effect). The present study aimed to examine whether these effects can be used for the good: to increase vegetable consumption among children. DESIGN: A 2*2 between-subjects experiment was conducted at two schools. Pupils were presented in class with cucumber that varied both in unit size (one piece v. pre-sliced) and portion size (one-third v. two-thirds of a cucumber). Children ate ad libitum during the morning break and filled in a survey. SETTING: Primary schools in the centre of the Netherlands. SUBJECTS: Primary-school pupils (n 255) aged 8-13 years. RESULTS: Children ate 54 % more cucumber when served a large compared with a smaller portion (difference of 49 g; P<0.001). Large units did not impact consumption (P=0.58), but were considered as less convenient to eat than small units (P=0.001). CONCLUSIONS: Findings suggest that children's vegetable intake can be improved by serving larger portions in smaller-sized pieces. PMID- 25926008 TI - Viability of dental implants in head and neck irradiated patients: A systematic review. AB - BACKGROUND: The purpose of this systematic review was to evaluate the safety of dental implants placed in irradiated bone and to discuss their viability when placed post-radiotherapy (RT). METHODS: A systematic review was performed to answer the questions: "Are dental implants in irradiated bone viable?" and "What are the main factors that influence the loss of implants in irradiated patients?" RESULTS: The search strategy resulted in 8 publications. A total of 331 patients received 1237 implants, with an overall failure rate of 9.53%. The osseointegration success rates ranged between 62.5% and 100%. The optimal time interval between irradiation and dental implantation varied from 6 to 15 months. CONCLUSION: The interval time between RT and implant placement and the radiation doses are not associated with significant implant failure rates. The placement of implants in irradiated bone is viable, and head and neck RT should not be considered as a contraindication for dental rehabilitation with implants. (c) 2015 Wiley Periodicals, Inc. Head Neck 38: E2229-E2240, 2016. PMID- 25926009 TI - The Open (Radial) Artery Hypothesis: How We Can Preserve a Better Arterial Access Site. PMID- 25926010 TI - Catalytic Conversion of Chitosan to 5-Hydroxymethylfurfural Under Low Temperature Hydrothermal Process. AB - In this work, the catalytic conversion of natural polymer chitosan to 5-HMF under low temperature hydrothermal condition was investigated. The highest 5-HMF yield of 12.1 wt% was obtained under the following conditions: 174 degrees C reaction temperature, 2.2 % catalyst amount, and 36.9 min reaction time. In the effect of combined severity, the 5-HMF production linearly increased to the combined severity factor of 3.07. By the way, higher combined severity factor can cause the over-degradation of 5-HMF. From this result, chitosan showed significant potential as a feedstock for the production of platform chemicals such as 5-HMF. PMID- 25926011 TI - Occurrence of Cellulose-Producing Gluconacetobacter spp. in Fruit Samples and Kombucha Tea, and Production of the Biopolymer. AB - Cellulose producing bacteria were isolated from fruit samples and kombucha tea (a fermented beverage) using CuSO4 solution in modified Watanabe and Yamanaka medium to inhibit yeasts and molds. Six bacterial strains showing cellulose production were isolated and identified by 16S rRNA gene sequencing as Gluconacetobacter xylinus strain DFBT, Ga. xylinus strain dfr-1, Gluconobacter oxydans strain dfr 2, G. oxydans strain dfr-3, Acetobacter orientalis strain dfr-4, and Gluconacetobacter intermedius strain dfr-5. All the cellulose-producing bacteria were checked for the cellulose yield. A potent cellulose-producing bacterium, i.e., Ga. xylinus strain DFBT based on yield (cellulose yield 5.6 g/L) was selected for further studies. Cellulose was also produced in non- conventional media such as pineapple juice medium and hydrolysed corn starch medium. A very high yield of 9.1 g/L cellulose was obtained in pineapple juice medium. Fourier transform infrared spectrometer (FT-IR) analysis of the bacterial cellulose showed the characteristic peaks. Soft cellulose with a very high water holding capacity was produced using limited aeration. Scanning electron microscopy (SEM) was used to analyze the surface characteristics of normal bacterial cellulose and soft cellulose. The structural analysis of the polymer was performed using (13)C solid-state nuclear magnetic resonance (NMR). More interfibrillar space was observed in the case of soft cellulose as compared to normal cellulose. This soft cellulose can find potential applications in the food industry as it can be swallowed easily without chewing. PMID- 25926012 TI - Isolation and Analysis of Cell Wall Proteome in Elsholtzia splendens Roots Using ITRAQ with LC-ESI-MS/MS. AB - Cell wall proteins (CWPs) are a prime site for signal perception and defense responses to environmental stresses. To gain further insights into CWPs and their molecular function, traditional techniques (e.g., two-dimensional gel electrophoresis) may be ineffective for special proteins. Elsholtzia splendens is a copper-tolerant plant species that grow on copper deposits. In this study, a fourplex isobaric tag was used for relative and absolute quantitation with liquid chromatography-tandem mass spectrometry approach to analyze the root CWPs of E. splendens. A total of 479 unique proteins were identified, including 121 novel proteins. Approximately 80.79 % of the proteins were extracted in the CaCl2 fraction, 16.08 % were detected in the NaCl fraction, and 3.13 % were identified in both fractions. The identified proteins have been involved in various processes, including cell wall remodeling, signal transduction, defense, and carbohydrate metabolism, thereby indicating a complex regulatory network in the apoplast of E. splendens roots. This study presents the first large-scale analysis of CWPs in metal-tolerant plants, which may be of paramount importance to understand the molecular functions and metabolic pathways in the root cell wall of copper-tolerant plants. PMID- 25926013 TI - Indigoids Biosynthesis from Indole by Two Phenol-Degrading Strains, Pseudomonas sp. PI1 and Acinetobacter sp. PI2. AB - In this study, two phenol-degrading bacterial strains, designated as PI1 and PI2, were isolated from activated sludge for the production of indigoids from indole. According to the 16S ribosomal RNA (rRNA) gene sequence analysis, strains PI1 and PI2 were identified as Pseudomonas sp. and Acinetobacter sp., respectively. Liquid chromatography/time-of-flight/mass spectrometry (LC/TOF/MS) was applied to analyze the metabolites during the biotransformation of indole by the phenol degrading strains. The results indicated that both strains could catalyze the formation of four indigoids with the same prominent molecular ion (M-H)(-) peak at m/z 261.067 and molecular formula of C16H10N2O2, including indigo and a purple product, 2-(7-oxo-1H-indol-6(7H)-ylidene) indolin-3-one. Isatin and 7 hydroxyindole were detected as the intermediates. Thus, the possible pathways for the production of indigoids from indole were proposed. Subsequently, the optimal conditions for the production of indigo from indole were determined using response surface methodology, and 11.82 +/- 0.30 and 17.19 +/- 0.49 mg/L indigo were produced by strains PI1 and PI2, respectively. The present study should provide potential candidates for microbial production of indigoids. PMID- 25926014 TI - Effects of CO2 Concentration and pH on Mixotrophic Growth of Nannochloropsis oculata. AB - This communication reports an experimental investigation of integrated CO2 bio conversion, wastewater treatment, and biomass production by microalgae cultivation. In this regard, the effects of CO2 concentrations on mixotrophic growth kinetics of a microalgae strain (Nannochloropsis oculata) are conducted in a semi-batch photobioreactor. The concentration of CO2 in the feed stream is varied from 4 to 12 mol% by adjusting CO2-to-air ratio. The variation of pH of the synthetic wastewater culture media and nutrient uptake by the microalgae are also monitored. The experimental evaluation shows that 8 % CO2 gives the highest growth rate of N. oculata with a productivity of 0.088 g L(-1) day(-1). Under the studied conditions, the pH value of the culture media between 5.5 and 6.5 is favorable for the growth of N. oculata in mixotrophic condition. Among the nutrients available in the culture media, percentage of ammonia removal is found to be the highest (98.9 %) as compared that of other compounds such as nitrate (88.2 %) and phosphate (18.9 %). The thermochemical characteristics of the cultivated microalgae are assessed by thermogravimetric analysis in presence of air. The produced microalgae is thermally stable up to 200 degrees C. Following that, the microalgae biomass is sharply decomposed within 600 degrees C. PMID- 25926015 TI - Image quality and radiation dose of a prospectively electrocardiography-triggered high-pitch data acquisition strategy for coronary CT angiography: The multicenter, randomized PROTECTION IV study. AB - BACKGROUND: Concerns have been raised about radiation dose of coronary CT angiography. Although high-pitch acquisition technique yields high potential for radiation dose savings, it is more vulnerable to artifacts, which impair diagnostic image quality. OBJECTIVE: The purpose of this study was to compare 2 scan strategies for coronary CT angiography: a high-pitch helical scan first or a conventional scan first strategy. METHODS: In this prospective, multicenter trial, we randomized 303 consecutive patients with a low and stable heart rate to either of the aforementioned mentioned strategies. Intravenous beta-blockers were administered to achieve target heart rates. All scans were performed on a second generation dual-source CT scanner. In case of nondiagnostic image quality, coronary CT angiography was allowed to be repeated. The primary end point was to demonstrate noninferior image quality in the high-pitch group. Image quality was assessed on a 4-point scale (1: nondiagnostic, 4: excellent). Secondary end point was total radiation dose. RESULTS: In the high-pitch helical first group, repeat scanning was necessary in 21 patients compared with 14 patients in the conventional first scan group (P = .25). Image quality in the high-pitch group was noninferior compared to the conventional scan group (3.81 +/- 0.35 vs. 3.83 +/- 0.37; P for noninferiority <.0001). The total effective radiation dose estimate was 58% lower in the high-pitch group (2.0 +/- 2.4 vs. 4.7 +/- 4.8 mSv; P < .0001). CONCLUSIONS: In patients with a low and stable heart rate diagnostic image quality can be maintained with a high-pitch helical scan first strategy while 58% of radiation dose can be saved. PMID- 25926016 TI - Variation in kinematic and spatiotemporal gait parameters by Gross Motor Function Classification System level in children and adolescents with cerebral palsy. AB - AIM: The aim of this study was to examine differences in gait kinematics and spatiotemporal parameters in ambulatory children and adolescents with bilateral spastic cerebral palsy (BSCP) among Gross Motor Function Classification System (GMFCS) levels I-III. METHOD: A retrospective review was conducted of individuals with BSCP who had three-dimensional motion analysis (3DGA) at one of seven pediatric hospitals. Means and standard deviations of each gait parameter were stratified by GMFCS levels (I-III) and for a typically developing comparison group. RESULTS: Data from 292 children and adolescents with BSCP (189 males, 103 females; mean age 13 y) were compared to a typically developing comparison group (24 male, 26 female; mean age 10 y 6 mo). Gait patterns differed from typically developing in all GMFCS levels, with increasing deviation as GMFCS level increased in 21 out of 28 parameters. Despite significant differences in selected mean kinematic parameters among GMFCS levels such as knee angle at initial contact of 24 degrees , 29 degrees , and 41 degrees in GMFCS levels I, II and III respectively, there was also substantial overlap among GMFCS levels. INTERPRETATION: GMFCS levels cannot be identified using specific gait kinematics. Treatment decisions should be guided by comprehensive 3DGA that allows measurement of gait impairments at the joint level for each individual. PMID- 25926017 TI - Detection of an amphiphilic biosample in a paper microchannel based on length. AB - We developed a simple method to achieve semiquantitative detection of an amphiphilic biosample through measuring the length of flow on a microfluidic analytical device (MUPAD) based on paper. When an amphiphilic sample was dripped into a straight microchannel defined with a printed wax barrier (hydrophobic) on filter paper (hydrophilic), the length of flow was affected by the reciprocal effect between the sample, the filter-paper channel and the wax barrier. The flow length decreased with increasing concentration of an amphiphilic sample because of adsorption of the sample on the hydrophobic barrier. Measurement of the flow length enabled a determination of the concentration of the amphiphilic sample. The several tested samples included surfactants (Tween 20 and Triton X-100), oligonucleotides (DNA), bovine serum albumin (BSA), human albumin, nitrite, glucose and low-density lipoprotein (LDL). The results show that the measurement of the flow length determined directly the concentration of an amphiphilic sample, whereas a non-amphiphilic sample was not amenable to this method. The proposed method features the advantages of small cost, simplicity, convenience, directness, rapidity (<5 min) and requirement of only a small volume (5 MUL) of sample, with prospective applications in developing areas and sites near patients for testing at a point of care (POCT). PMID- 25926018 TI - A scanometric antibody probe for facile and sensitive immunoassays. AB - We have developed a novel scanometric antibody probe for rapid, sensitive, and naked-eye-visible immunoassays. Using this probe, we clearly demonstrated the successful scanometric detection and identification of influenza A viruses on a microarray. In addition, the sensitivity of the scanometric immunoassay was comparable to that of the fluorescence-based method. PMID- 25926019 TI - Dietary Intake of Competitive Bodybuilders. AB - BACKGROUND: Competitive bodybuilders are well known for extreme physique traits and extremes in diet and training manipulation to optimize lean mass and achieve a low body fat. Although many of the dietary dogmas in bodybuilding lack scientific scrutiny, a number, including timing and dosing of high biological value proteins across the day, have more recently been confirmed as effective by empirical research studies. A more comprehensive understanding of the dietary intakes of bodybuilders has the potential to uncover other dietary approaches, deserving of scientific investigation, with application to the wider sporting, and potential health contexts, where manipulation of physique traits is desired. OBJECTIVE: Our objective was to conduct a systematic review of dietary intake practices of competitive bodybuilders, evaluate the quality and currency of the existing literature, and identify research gaps to inform future studies. METHODS: A systematic search of electronic databases was conducted from the earliest record until March 2014. The search combined permutations of the terms 'bodybuilding', 'dietary intake', and 'dietary supplement'. Included studies needed to report quantitative data (energy and macronutrients at a minimum) on habitual dietary intake of competitive bodybuilders. RESULTS: The 18 manuscripts meeting eligibility criteria reported on 385 participants (n = 62 women). Most studies were published in the 1980-1990s, with three published in the past 5 years. Study methodological quality was evaluated as poor. Energy intake ranged from 10 to 24 MJ/day for men and from 4 to 14 MJ/day for women. Protein intake ranged from 1.9 to 4.3 g/kg for men and from 0.8 to 2.8 g/kg for women. Intake of carbohydrate and fat was <6 g/kg/day and below 30% of energy, respectively. Carbohydrate intakes were below, and protein (in men) intakes were higher than, the current recommendations for strength athletes, with no consideration for exploration of macronutrient quality or distribution over the day. Energy intakes varied over different phases of preparation, typically being highest in the non competition (>6 months from competition) or immediate post-competition period and lowest during competition preparation (<=6 months from competition) or competition week. The most commonly reported dietary supplements were protein powders/liquids and amino acids. The studies failed to provide details on rationale for different dietary intakes. The contribution of diet supplements was also often not reported. When supplements were reported, intakes of some micronutrients were excessive (~1000% of US Recommended Dietary Allowance) and above the tolerable upper limit. CONCLUSION: This review demonstrates that literature describing the dietary intake practices of competitive bodybuilders is dated and often of poor quality. Intake reporting required better specificity and details of the rationale underpinning the use. The review suggests that high quality contemporary research is needed in this area, with the potential to uncover dietary strategies worthy of scientific exploration. PMID- 25926020 TI - Simulating Four Essential Conversations with Hematology/Oncology Trainees: a Qualitative Evaluation. AB - Hematologists/oncologists have a crucial responsibility to effectively communicate with patients. However, they have been criticized for ineffective communication with patients. To develop effective communication behaviors that meet the needs of patients and families, trainees need practice and feedback about their performance. Medical faculties frequently teach communication skills using simulation-based curricula; however, they often include only general communication skills, without tailored approaches for specialties. This study examined Hematology/Oncology trainees' qualitative perceptions about the value of and techniques used for simulations of specialty specific, essential conversations with patients and families, and debriefing sessions. Results demonstrate a highly effective curriculum and positive learner experiences. While most reports on this topic take place within major academic cancer centers, outcomes from a mid-sized Hematology/Oncology training program are unknown. The study confirms feasibility for implementing a simulation-based communications program in a mid-sized Hematology/Oncology program and describes simulation techniques that were effective. PMID- 25926021 TI - Potential use of Lentinus squarrosulus mushroom as fermenting agent and source of natural antioxidant additive in livestock feed. AB - BACKGROUND: Fermenting feed has gained a lot of popularity in recent years owing to its renowned benefits to the livestock and feed quality. In the current study, Lentinus squarrosulus mushroom mycelium was tested for its potential as a fermenting agent and source of natural antioxidant in the feed. RESULTS: Phenolic content of methanolic and hot water extracts of the mycelium culture and its fermented maize ranged from 94.01 to 386.59 mg gallic acid equivalents g(-1) extract while the DPPH radical scavenging, CUPRAC, reducing power (RPA) and beta carotene bleaching (BCB) antioxidant activity had EC50 values ranged from 15.30 to 120.3, 0.74 to 4.71, 1.86 to 13.5 and 0.01 to 0.21 mg mL(-1) , respectively. At 1.0-20.0 mg mL(-1) , the extracts retarded 21.02-55.35% of lipid deterioration. Pearson correlation analysis revealed the phenolic content of the extracts has moderate correlation with DPPH (r = 0.589) and RPA (r = 0.580), also a high correlation with BCB antioxidant activity (r = 0.872). In principal component analysis, DPPH, CUPRAC and RPA were seen to be clustered tightly together while BCB antioxidant activity was grouped with the phenolic content. CONCLUSION: Overall, L. squarrosulus mycelium functioned as antioxidants via several mechanisms, involving either electron transfer or hydrogen transfer-based reactions suggesting it as a promising fermentation agent to enhance feed nutrition and the fermented maize as a valuable feed resource. PMID- 25926022 TI - polyMOFs: A Class of Interconvertible Polymer-Metal-Organic-Framework Hybrid Materials. AB - Preparation of porous materials from one-dimensional polymers is challenging because the packing of polymer chains results in a dense, non-porous arrangement. Herein, we demonstrate the remarkable adaptation of an amorphous, linear, non porous, flexible organic polymer into a three-dimensional, highly porous, crystalline solid, as the organic component of a metal-organic framework (MOF). A polymer with aromatic dicarboxylic acids in the backbone functioned as a polymer ligand upon annealing with Zn(II), generating a polymer-metal-organic framework (polyMOF). These materials break the dogma that MOFs must be prepared from small, rigid ligands. Similarly, polyMOFs contradict conventional polymer chemistry by demonstrating that linear and amorphous polymers can be readily coaxed into a highly crystalline, porous, three-dimensional structure by coordination chemistry. PMID- 25926023 TI - Timing of High-Dose Rate Brachytherapy With External Beam Radiotherapy in Intermediate and High-Risk Localized Prostate CAncer (THEPCA) Patients and Its Effects on Toxicity and Quality of Life: Protocol of a Randomized Feasibility Trial. AB - BACKGROUND: Prostate cancer is the most common cancer in males in the UK and affects around 105 men for every 100,000. The role of radiotherapy in the management of prostate cancer significantly changed over the last few decades with developments in brachytherapy, external beam radiotherapy (EBRT), intensity modulated radiotherapy (IMRT), and image-guided radiotherapy (IGRT). One of the challenging factors of radiotherapy treatment of localized prostate cancer is the development of acute and late genitourinary and gastrointestinal toxicities. The recent European guidelines suggest that there is no consensus regarding the timing of high-dose rate (HDR) brachytherapy and EBRT. The schedules vary in different institutions where an HDR boost can be given either before or after EBRT. Few centers deliver HDR in between the fractions of EBRT. OBJECTIVE: Assessment of acute genitourinary and gastrointestinal toxicities at various time points to better understand if the order in which treatment modality is delivered (ie, HDR brachytherapy or EBRT first) has an effect on the toxicity profile. METHODS: Timing of HDR brachytherapy with EBRT in Prostate CAncer (THEPCA) is a single-center, open, randomized controlled feasibility trial in patients with intermediate and high-risk localized prostate cancer. A group of 50 patients aged 18 years old and over with histological diagnosis of prostate cancer (stages T1b T3BNOMO), will be randomized to one of two treatment arms (ratio 1:1), following explanation of the study and informed consent. Patients in both arms of the study will be treated with HDR brachytherapy and EBRT, however, the order in which they receive the treatments will vary. In Arm A, patients will receive HDR brachytherapy before EBRT. In Arm B (control arm), patients will receive EBRT before HDR brachytherapy. Study outcomes will look at prospective assessment of genitourinary and gastrointestinal toxicities. The primary endpoint will be grade 3 genitourinary toxicity and the secondary endpoints will be all other grades of genitourinary toxicities (grades 1 and 2), gastrointestinal toxicities (grades 1 to 4), prostate-specific antigen (PSA) recurrence-free survival, overall survival, and quality of life. RESULTS: Results from this feasibility trial will be available in mid-2016. CONCLUSIONS: If the results from this feasibility trial show evidence that the sequence of treatment modality does affect the patients' toxicity profiles, then funding would be sought to conduct a large, multicenter, randomized controlled trial. TRIAL REGISTRATION: International Standard Randomized Controlled Trial Number (ISRCTN): 15835424; http://www.isrctn.com/ISRCTN15835424 (Archived by WebCite at http://www.webcitation.org/6Xz7jfg1u). PMID- 25926024 TI - Conversion to complete resection with mFOLFOX6 with bevacizumab or cetuximab based on K-ras status for unresectable colorectal liver metastasis (BECK study). AB - BACKGROUND: Patients with colorectal liver metastasis (CRLM) might be down-staged by chemotherapy from an initially unresectable stage to a resectable stage. Because the tumor response to preoperative chemotherapy has been correlated with resection rate, the improved efficacy from the concept that only the patients without K-ras mutations receive an anti-EGFR antibody might be expected to increase the conversion rate. The purpose of this study is to evaluate the conversion rate from unresectable CRLM to complete resection. METHODS: We conducted a multi-institutional phase II trial for unresectable CRLM. Patients received mFOLFOX6 with either bevacizumab (bev) or cetuximab (cet) based on K-ras status (UMIN000004310). Planned treatment was for six cycles during which tumors were assessed for resectability every three cycles. Patients whose disease was unresectable after six cycles switched their chemotherapy regimen from mFOLFOX6 to FOLFIRI. The primary endpoint was R0 resection rate. RESULTS: Thirty-five patients with unresectable CRLM were enrolled. A total of 22/12 patients with K ras wild-type/mutant (wt/mt) were treated with mFOLFOX6 plus cet/bev, respectively. The overall response rate was 64.7% (wt/mt; 77.3%/41.7%, P = 0.04). In 20 patients (58.8%), hepatectomy was performed according to protocol treatment, and the conversion rate was 72.7%/33.3% in wt/mt patients, respectively (P = 0.03). Finally, 23 patients (67.6%) underwent hepatectomy, and the conversion rate was 77.2%/50.0% in wt/mt patients (P = 0.09). The overall R0 resection rate was 47.1% (wt/mt; 50.0%/41.7%, P = 0.36). CONCLUSIONS: This prospective study showed that combined chemotherapy based on K-ras status can facilitate conversion to resection in patients with unresectable CRLM. PMID- 25926026 TI - Regio- and enantioselective synthesis of N-substituted pyrazoles by rhodium catalyzed asymmetric addition to allenes. AB - The rhodium-catalyzed asymmetric N-selective coupling of pyrazole derivatives with terminal allenes gives access to enantioenriched secondary and tertiary allylic pyrazoles, which can be employed for the synthesis of medicinally important targets. The reaction tolerates a large variety of functional groups and labelling experiments gave insights into the reaction mechanism. This new methodology was further applied in a highly efficient synthesis of JAK 1/2 inhibitor (R)-ruxolitinib. PMID- 25926027 TI - Bonobos show limited social tolerance in a group setting: a comparison with chimpanzees and a test of the relational model. AB - Social tolerance is a core aspect of primate social relationships with implications for the evolution of cooperation, prosociality and social learning. We measured the social tolerance of bonobos in an experiment recently validated with chimpanzees to allow for a comparative assessment of group-level tolerance, and found that the bonobo group studied here exhibited lower social tolerance on average than chimpanzees in this paradigm. Furthermore, following the Relational Model of de Waal, we investigated whether bonobos responded to an increased potential for social conflict with tolerance, conflict avoidance or conflict escalation, and found that only behaviours indicative of conflict escalation differed across conditions. Taken together, these findings contribute to the current debate over the level of social tolerance of bonobos and lend support to the position that the social tolerance of bonobos may not be notably high compared with other primates. PMID- 25926025 TI - Phosphoproteome Analysis Links Protein Phosphorylation to Cellular Remodeling and Metabolic Adaptation during Magnaporthe oryzae Appressorium Development. AB - The rice pathogen, Magnaporthe oryzae, undergoes a complex developmental process leading to formation of an appressorium prior to plant infection. In an effort to better understand phosphoregulation during appressorium development, a mass spectrometry based phosphoproteomics study was undertaken. A total of 2924 class I phosphosites were identified from 1514 phosphoproteins from mycelia, conidia, germlings, and appressoria of the wild type and a protein kinase A (PKA) mutant. Phosphoregulation during appressorium development was observed for 448 phosphosites on 320 phosphoproteins. In addition, a set of candidate PKA targets was identified encompassing 253 phosphosites on 227 phosphoproteins. Network analysis incorporating regulation from transcriptomic, proteomic, and phosphoproteomic data revealed new insights into the regulation of the metabolism of conidial storage reserves and phospholipids, autophagy, actin dynamics, and cell wall metabolism during appressorium formation. In particular, protein phosphorylation appears to play a central role in the regulation of autophagic recycling and actin dynamics during appressorium formation. Changes in phosphorylation were observed in multiple components of the cell wall integrity pathway providing evidence that this pathway is highly active during appressorium development. Several transcription factors were phosphoregulated during appressorium formation including the bHLH domain transcription factor MGG_05709. Functional analysis of MGG_05709 provided further evidence for the role of protein phosphorylation in regulation of glycerol metabolism and the metabolic reprogramming characteristic of appressorium formation. The data presented here represent a comprehensive investigation of the M. oryzae phosphoproteome and provide key insights on the role of protein phosphorylation during infection related development. PMID- 25926028 TI - Ionic liquid phase microextraction combined with fluorescence spectrometry for preconcentration and quantitation of carvedilol in pharmaceutical preparations and biological media. AB - BACKGROUND: Carvedilol belongs to a group of medicines termed non-selective beta adrenergic blocking agents. In the presented approach, a practical and environmentally friendly microextraction method based on the application of ionic liquids (ILs) was followed by fluorescence spectrometry for trace determination of carvedilol in pharmaceutical and biological media. METHODS: A rapid and simple ionic liquid phase microextraction was utilized for preconcentration and extraction of carvedilol. A hydrophobic ionic liquid (IL) was applied as a microextraction solvent. In order to disperse the IL through the aqueous media and extract the analyte of interest, IL was injected into the sample solution and a proper temperature was applied and then for aggregating the IL-phase, the sample was cooled in an ice water-bath. The aqueous media was centrifuged and IL phase collected at the bottom of the test tube was introduced to the micro-cell of spectrofluorimeter, in order to determine the concentration of the enriched analyte. RESULTS: Main parameters affecting the accuracy and precision of the proposed approach were investigated and optimized values were obtained. A linear response range of 10-250 MUg I(-1) and a limit of detection (LOD) of 1.7 MUg I( 1) were obtained. CONCLUSION: Finally, the presented method was utilized for trace determination of carvedilol in commercial pharmaceutical preparations and biological media. PMID- 25926030 TI - The (Pulsed-Wave) Doppler Fetal Myocardial Performance Index: Technical Challenges, Clinical Applications and Future Research. AB - Functional cardiovascular assessment is becoming an increasingly important tool in the study of fetal pathology. The myocardial performance index (MPI) is a parameter measuring global myocardial function. Since its introduction, several studies have proposed methods to improve its reproducibility and have constructed normative reference ranges. Fetal heart evaluation using the MPI is technically challenging, requiring specific training and expertise, and a consensus has yet to be reached on the method of delineating the time periods used to calculate the index. Despite these limitations, it has been shown to be a useful and highly sensitive parameter of dysfunction in a number of fetal pathologies. Further research is warranted into the effect of pathology on MPI, parameters of unilateral cardiac strain that utilise MPI, and automation of the MPI to encourage incorporation of the MPI as a useful tool in clinical practice. PMID- 25926029 TI - Establishment of a patient-derived orthotopic osteosarcoma mouse model. AB - BACKGROUND: Osteosarcoma (OS) is the most common pediatric primary malignant bone tumor. As the prognosis for patients following standard treatment did not improve for almost three decades, functional preclinical models that closely reflect important clinical cancer characteristics are urgently needed to develop and evaluate new treatment strategies. The objective of this study was to establish an orthotopic xenotransplanted mouse model using patient-derived tumor tissue. METHODS: Fresh tumor tissue from an adolescent female patient with osteosarcoma after relapse was surgically xenografted into the right tibia of 6 immunodeficient BALB/c Nu/Nu mice as well as cultured into medium. Tumor growth was serially assessed by palpation and with magnetic resonance imaging (MRI). In parallel, a primary cell line of the same tumor was established. Histology and high-resolution array-based comparative genomic hybridization (aCGH) were used to investigate both phenotypic and genotypic characteristics of different passages of human xenografts and the cell line compared to the tissue of origin. RESULTS: A primary OS cell line and a primary patient-derived orthotopic xenotranplanted mouse model were established. MRI analyses and histopathology demonstrated an identical architecture in the primary tumor and in the xenografts. Array-CGH analyses of the cell line and all xenografts showed highly comparable patterns of genomic progression. So far, three further primary patient-derived orthotopic xenotranplanted mouse models could be established. CONCLUSION: We report the first orthotopic OS mouse model generated by transplantation of tumor fragments directly harvested from the patient. This model represents the morphologic and genomic identity of the primary tumor and provides a preclinical platform to evaluate new treatment strategies in OS. PMID- 25926031 TI - Ideological roadblocks to humanizing dentistry, an evaluative case study of a continuing education course on social determinants of health. AB - BACKGROUND: Front line providers of care are frequently lacking in knowledge on and sensitivity to social and structural determinants of underprivileged patients' health. Developing and evaluating approaches to raising health professional awareness and capacity to respond to social determinants is a crucial step in addressing this issue. McGill University, in partnership with Universite de Montreal, Quebec dental regulatory authorities, and the Quebec anti poverty coalition, co-developed a continuing education (CE) intervention that aims to transfer knowledge and improve the practices of oral health professionals with people living on welfare. Through the use of original educational tools integrating patient narratives and a short film, the onsite course aims to elicit affective learning and critical reflection on practices, as well as provide staff coaching. METHODS: A qualitative case study was conducted, in Montreal Canada, among members of a dental team who participated in this innovative CE course over a period of four months. Data collection consisted in a series of semi-structured individual interviews conducted with 15 members of the dental team throughout the training, digitally recorded group discussions linked to the CE activities, clinic administrative documents and researcher-trainer field notes and journal. In line with adult transformative learning theory, interpretive analysis aimed to reveal learning processes, perceived outcomes and collective perspectives that constrain individual and organizational change. RESULTS: The findings presented in this article consist in four interactive themes, reflective of clinic culture and context, that act as barriers to humanizing patient care: 1) belief in the "ineluctable" commoditization of dentistry; 2) "equal treatment", a belief constraining concern for equity and the recognition of discriminatory practices; 3) a predominantly biomedical orientation to care; and 4) stereotypical categorization of publically insured patients into "deserving" vs. "non deserving" poor. We discuss implications for oral health policy, orientations for dental education, as well as the role dental regulatory authorities should play in addressing discrimination and prejudice. CONCLUSION: Humanizing care and developing oral health practitioners' capacity to respond to social determinants of health, are challenged by significant ideological roadblocks. These require multi-level and multi-sectorial action if gains in social equity in oral health are to be made. PMID- 25926032 TI - Effects of heat treatment on oil-binding ability of rice flour. AB - Heat-treated (120 degrees C for 120 min) rice flour showed high affinity to oil (oil-binding ability). This oil-binding ability could be observed by shaking the heat-treated rice flour (2.0 g), oil (4.0 mL), and water (20 mL) vigorously in a test tube, and the oil bound to the rice flour sank into the water. To examine the time-dependent levels of the oil-binding ability, rice flour was heat-treated at 120 degrees C for 10, 20, 40, 60, and 120 min, and the precipitated volume of oil/rice flour complex increased with an increase of the heating time. The oil binding ability of the rice flour was not affected by the treatments with diethyl ether or boiled chloroform/methanol (2:1) solutions, which suggested no relationship to the oil in the rice flour, but was lost upon alkali (0.2% NaOH solution) or pepsin treatment, which suggested its relationship to the rice proteins. PMID- 25926033 TI - Clinical management of post-pyloric enteral feeding in children. AB - Post-pyloric feeding (PF) allows the administration of enteral nutrition beyond the pylorus, either into the duodenum or, ideally, into the jejunum. The main indications of PF are: upper gastrointestinal tract obstructions, pancreatic rest (e.g., acute pancreatitis), gastric dysmotility (e.g., critically ill patients and chronic intestinal pseudo-obstruction) or severe gastroesophageal reflux with risk of aspiration (e.g., neurological disability). Physiological and clinical evidence derives from adults, but can also be pertinent to children. This review will discuss the practical management and potential clinical applications of PF in pediatric patients. Some key studies pertaining to the physiological changes during PF will also be considered because they support the strategy of PF management. PMID- 25926034 TI - Comprehensive Analyses of White-Handed Gibbon Chromosomes Enables Access to 92 Evolutionary Conserved Breakpoints Compared to the Human Genome. AB - Gibbon species (Hylobatidae) impress with an unusually high number of numerical and structural chromosomal changes within the family itself as well as compared to other Hominoidea including humans. In former studies applying molecular cytogenetic methods, 86 evolutionary conserved breakpoints (ECBs) were reported in the white-handed gibbon (Hylobates lar, HLA) with respect to the human genome. To analyze those ECBs in more detail and also to achieve a better understanding of the fast karyotype evolution in Hylobatidae, molecular data for these regions are indispensably necessary. In the present study, we obtained whole chromosome specific probes by microdissection of all 21 HLA autosomes and prepared them for aCGH. Locus-specific DNA probes were also used for further molecular cytogenetic characterization of selected regions. Thus, we could map 6 yet unreported ECBs in HLA with respect to the human genome. Additionally, in 26 of the 86 previously reported ECBs, the present approach enabled a more precise breakpoint mapping. Interestingly, a preferred localization of ECBs within segmental duplications, copy number variant regions, and fragile sites was observed. PMID- 25926035 TI - Beyond resistance: social factors in the general public response to pandemic influenza. AB - BACKGROUND: Influencing the general public response to pandemics is a public health priority. There is a prevailing view, however, that the general public is resistant to communications on pandemic influenza and that behavioural responses to the 2009/10 H1N1 pandemic were not sufficient. Using qualitative methods, this paper investigates how members of the general public respond to pandemic influenza and the hygiene, social isolation and other measures proposed by public health. Going beyond the commonly deployed notion that the general public is resistant to public health communications, this paper examines how health individualism, gender and real world constraints enable and limit individual action. METHODS: In-depth interviews (n = 57) and focus groups (ten focus groups; 59 individuals) were conducted with community samples in Melbourne, Sydney and Glasgow. Participants were selected according to maximum variation sampling using purposive criteria, including: 1) pregnancy in 2009/2010; 2) chronic illness; 3) aged 70 years and over; 4) no disclosed health problems. Verbatim transcripts were subjected to inductive, thematic analysis. RESULTS: Respondents did not express resistance to public health communications, but gave insight into how they interpreted and implemented guidance. An individualistic approach to pandemic risk predominated. The uptake of hygiene, social isolation and vaccine strategies was constrained by seeing oneself 'at risk' but not 'a risk' to others. Gender norms shape how members of the general public enact hygiene and social isolation. Other challenges pertained to over-reliance on perceived remoteness from risk, expectation of recovery from infection and practical constraints on the uptake of vaccination. CONCLUSIONS: Overall, respondents were engaged with public health advice regarding pandemic influenza, indicating that the idea of public resistance has limited explanatory power. Public communications are endorsed, but challenges persist. Individualistic approaches to pandemic risk inhibit acting for the benefit of others and may deepen divisions in the community according to health status. Public communications on pandemics are mediated by gender norms that may overburden women and limit the action of men. Social research on the public response to pandemics needs to focus on the social structures and real world settings and relationships that shape the action of individuals. PMID- 25926036 TI - Functional connectivity alteration after real-time fMRI motor imagery training through self-regulation of activities of the right premotor cortex. AB - BACKGROUND: Real-time functional magnetic resonance imaging technology (real-time fMRI) is a novel method that can be used to investigate motor imagery training, it has attracted increasing attention in recent years, due to its ability to facilitate subjects in regulating the activities of specific brain regions to influence their behaviors. Lots of researchers have demonstrated that the right premotor area play critical roles during real-time fMRI motor imagery training. Thus, it has been hypothesized that modulating the activity of right premotor area may result in an alteration of the functional connectivity between the premotor area and other motor-related regions. RESULTS: The results indicated that the functional connectivity between the bilateral premotor area and right posterior parietal lobe significantly decreased during the imagination task. CONCLUSIONS: This finding is new evidence that real-time fMRI is effective and can provide a theoretical guidance for the alteration of the motor function of brain regions associated with motor imagery training. PMID- 25926037 TI - Molecular characterization and application of a novel cytoplasmic male sterility associated mitochondrial sequence in rice. AB - BACKGROUND: Cytoplasmic male sterility (CMS) is a maternally inherited inability to produce functional pollen found in numerous flowering plant species. CMS is associated with mitochondrial DNA mutation, novel chimeric open reading frames (ORFs), and rearrangement of coding and noncoding regions of the mitochondrial genome. RESULTS: BLAST (Basic Local Alignment Search Tool) analysis indicated that L-sp1, a new sequence-characterized amplified region, is non-homologous to atp6-orfH79 (or atp6-orf79) and WA352 cloned CMS-associated genes. L-sp1 was found in 11 of 102 wild rice accessions belonging to four AA genome species: Oryza rufipogon, Oryza nivara, Oryza glumaepatula, and Oryza meridionalis. Using L-sp1, two new CMS lines were developed, from either low natural fertility plants or sterile plants, by backcrossing BC1F1 with Yuetai B. Northern blot and RT-PCR revealed that L-sp1 was only expressed in the anthers of w1/YTB, w2/YTB, w1/YTB//YTB, and w2/YTB//YTB when in the same cytoplasm background. CONCLUSIONS: L-sp1 is a single-copy chimeric CMS-associated gene found in the mitochondrial genome. It can be expressed in anthers with the same specific cytoplasm background, and will be a useful molecular marker for the development and marker assisted selection of new CMS lines. PMID- 25926038 TI - MRI for differentiating ovarian endometrioid adenocarcinoma from high-grade serous adenocarcinoma. AB - PURPOSE: To investigate magnetic resonance imaging (MRI) features for differentiating ovarian endometrioid adenocarcinoma (OEC) from high-grade serous adenocarcinoma (HGSC). MATERIALS AND METHODS: Twenty-three patients with 25 OECs and 93 patients with 139 HGSCs confirmed by surgery and pathology underwent conventional MRI and diffusion-weighted imaging (DWI). The MRI features of the tumors, including laterality, size, shape, configuration, signal intensity, ADC value of solid component, enhancement, ascites, synchronous primary cancer (SPC) of the ovary and endometrium, and clinical stage, were evaluated and compared between two groups. RESULTS: The following characteristics were significantly more common for OECs than HGSCs: unilateral (91.3% vs 50.5%, P < 0.001), larger mass (80.0% vs 48.2%, P = 0.005), round or oval shape (64.0% vs 17.3%, P < 0.001), mainly cystic with mural nodules or papillary projections (72.0% vs 18.7%, P < 0.001), cystic component with homogeneous iso- or hyperintensity on T1WI (82.6% vs 4.3%, P < 0.001), moderate enhancement (52.0% vs 26.6%, P = 0.011), no or mild ascites (91.3% vs 57.0%, P = 0.002), and SPC (43.5% vs 4.3%, P < 0.001). The ADC value of the solid component was higher in OECs (0.979 +/- 0.197 * 10(-3) mm(2)/s) than in HGSCs (0.820 +/- 0.112 * 10(-3) mm(2)/s) (P = 0.002). When a mainly cystic mass with mural nodules or papillary projections was associated with any one of homogeneously iso- or hyperintense cystic component on TIWI, a relatively higher ADC value and SPC, the sensitivity, specificity, accuracy, and positive and negative predictive values for characterizing OEC were 87.0%, 93.5%, 92.2%, 76.9%, and 96.7%, respectively. CONCLUSIONS: Conventional MRI combining DWI is helpful for differentiating OECs from HGSCs. PMID- 25926039 TI - High PSA anxiety and low health literacy skills: drivers of early use of salvage ADT among men with biochemically recurrent prostate cancer after radiotherapy? AB - BACKGROUND: Although commonly used, early initiation of salvage androgen deprivation therapy (ADT) has not been proven to enhance survival. We evaluated whether prostate-specific antigen (PSA) anxiety or health literacy are associated with use of early salvage ADT among men with recurrent prostate cancer after radiotherapy. PATIENTS AND METHODS: The prospective Comprehensive, Observational, Multicenter, Prostate Adenocarcinoma Registry was used to study 375 men with biochemically recurrent prostate cancer after external beam radiation or brachytherapy. Multivariable logistic regression was used to determine whether PSA anxiety and health literacy are associated with salvage ADT as initial management after biochemical recurrence. RESULTS: Sixty-eight men (18.1%) received salvage ADT as initial management for PSA recurrence. Men with high PSA anxiety were twice as likely to receive salvage ADT compared with men who did not have high PSA anxiety on both univariable [28.8% versus 13.1%; odds ratio (OR) 2.15; 95% confidence interval (CI) 1.16-4.00; P = 0.015] and multivariable analysis [adjusted OR (AOR) 2.36; 95% CI 1.21-4.62; P = 0.012]. Furthermore, men who had higher levels of health literacy were nearly half as likely to undergo salvage ADT compared with men who had lower levels of health literacy on univariable analysis (15.2% versus 26.3%; OR 0.50; 95% CI 0.29-0.88; P = 0.016), with a trend toward this association on multivariable analysis (AOR 0.58; 95% CI 0.32-1.05; P = 0.07). CONCLUSIONS: Among men with PSA recurrence after radiotherapy, odds of use of salvage ADT were nearly twice as great among men with high PSA anxiety or low health literacy, suggesting that these men are receiving higher rates of unproven treatment. Given that early salvage ADT is costly, worsens quality of life, and has not been shown to improve survival, quality improvement strategies are needed for these individuals. PMID- 25926040 TI - Cobalt-catalyzed intermolecular C(sp(2))-O cross-coupling. AB - Cobalt(II)-catalyzed C(sp(2) )?O cross-coupling between aryl/heteroaryl alcohols and vinyl/aryl halides in the presence of Cu(I) has been achieved under ligand free conditions. In this reaction, copper plays a significant role in transmetalation rather than being directly involved in the C?O coupling. This unique Co/Cu-dual catalyst system provides an easy access to a library of aryl vinyl, heteroaryl-styryl, aryl-aryl, and heteroaryl-heteroaryl ethers in the absence of any ligand or additive. PMID- 25926041 TI - Are all RAS mutations the same? Coexisting KRAS and NRAS mutations in a caecal adenocarcinoma and contiguous tubulovillous adenoma. AB - Mutations of the human Kirsten rat sarcoma viral oncogene homologue (KRAS) and the highly homologous human neuroblastoma RAS viral oncogene homologue (NRAS) are associated with resistance to antiepidermal growth factor receptor therapies in patients with colorectal cancer. In this report, we describe a caecal adenocarcinoma that contains both KRAS c.35G>T (G12V) and NRAS c.34G>A (G12S) mutations. The adenocarcinoma arises from a contiguous high-grade tubulovillous adenoma, which also carries the identical KRAS and NRAS mutations, supporting their common origin. While KRAS mutations are common in colorectal cancers, NRAS mutations are relatively rare and the coexistence of multiple RAS mutations is not documented, presumably reflecting similar functions of wild-type and mutant forms of RAS. Recent experimental evidence has suggested that KRAS and NRAS may in fact mediate distinct biological processes in the colon, and this unusual case potentially illustrates the hypothesis clinically. Characterisation of the diverse and divergent functions of RAS family members and mutant forms of RAS in the colon form important considerations for the development of RAS-targeting therapeutics. PMID- 25926042 TI - Towards the development of specific antidotes: Idarucizumab for reversal of dabigatran effects. PMID- 25926044 TI - Redox regulation and pro-oxidant reactions in the physiology of circadian systems. AB - Rhythms of approximately 24 h are pervasive in most organisms and are known as circadian. There is a molecular circadian clock in each cell sustained by a feedback system of interconnected "clock" genes and transcription factors. In mammals, the timing system is formed by a central pacemaker, the suprachiasmatic nucleus, in coordination with a collection of peripheral oscillators. Recently, an extensive interconnection has been recognized between the molecular circadian clock and the set of biochemical pathways that underlie the bioenergetics of the cell. A principle regulator of metabolic networks is the flow of electrons between electron donors and acceptors. The concomitant reduction and oxidation (redox) reactions directly influence the balance between anabolic and catabolic processes. This review summarizes and discusses recent findings concerning the mutual and dynamic interactions between the molecular circadian clock, redox reactions, and redox signaling. The scope includes the regulatory role played by redox coenzymes (NAD(P)+/NAD(P)H, GSH/GSSG), reactive oxygen species (superoxide anion, hydrogen peroxide), antioxidants (melatonin), and physiological events that modulate the redox state (feeding condition, circadian rhythms) in determining the timing capacity of the molecular circadian clock. In addition, we discuss a purely metabolic circadian clock, which is based on the redox enzymes known as peroxiredoxins and is present in mammalian red blood cells and in other biological systems. Both the timing system and the metabolic network are key to a better understanding of widespread pathological conditions such as the metabolic syndrome, obesity, and diabetes. PMID- 25926043 TI - Overexpression of STARCH BRANCHING ENZYME II increases short-chain branching of amylopectin and alters the physicochemical properties of starch from potato tuber. AB - BACKGROUND: Starch is biosynthesised by a complex of enzymes including various starch synthases and starch branching and debranching enzymes, amongst others. The role of all these enzymes has been investigated using gene silencing or genetic knockouts, but there are few examples of overexpression due to the problems of either cloning large genomic fragments or the toxicity of functional cDNAs to bacteria during cloning. The aim of this study was to investigate the function of potato STARCH BRANCHING ENZYME II (SBEII) using overexpression in potato tubers. RESULTS: A hybrid SBEII intragene consisting of potato cDNA containing a fragment of potato genomic DNA that included a single intron was used in order to prevent bacterial translation during cloning. A population of 20 transgenic potato plants exhibiting SBEII overexpression was generated. Compared with wild-type, starch from these tubers possessed an increased degree of amylopectin branching, with more short chains of degree of polymerisation (DP) 6 12 and particularly of DP6. Transgenic lines expressing a GRANULE-BOUND STARCH SYNTHASE (GBSS) RNAi construct were also generated for comparison and exhibited post-transcriptional gene silencing of GBSS and reduced amylose content in the starch. Both transgenic modifications did not affect granule morphology but reduced starch peak viscosity. In starch from SBEII-overexpressing lines, the increased ratio of short to long amylopectin branches facilitated gelatinisation, which occurred at a reduced temperature (by up to 3 degrees C) or lower urea concentration. In contrast, silencing of GBSS increased the gelatinisation temperature by 4 degrees C, and starch required a higher urea concentration for gelatinisation. In lines with a range of SBEII overexpression, the magnitude of the increase in SBEII activity, reduction in onset of gelatinisation temperature and increase in starch swollen pellet volume were highly correlated, consistent with reports that starch swelling is greatly dependent upon the amylopectin branching pattern. CONCLUSION: This work reports the first time that overexpression of SBEII has been achieved in a non-cereal plant. The data show that overexpression of SBEII using a simple single-intron hybrid intragene is an effective way to modify potato starch physicochemical properties, and indicate that an increased ratio of short to long amylopectin branches produces commercially beneficial changes in starch properties such as reduced gelatinisation temperature, reduced viscosity and increased swelling volume. PMID- 25926045 TI - Hip Protectors: Are They Worth it? AB - Hip fractures are one of the most serious conditions in frail elderly subjects, greatly increasing morbidity and mortality, and decreasing healthy life years. Since their first introduction on the market, hip protectors have been revealed to be a potential preventive measure for hip fractures, in addition to other well known recognized medical interventions and rehabilitation procedures. However, randomized controlled trials have given contradictory results regarding their efficacy. Moreover, little data are available on the cost effectiveness of hip protectors. Adherence is a major problem in assessing the effectiveness of hip protectors in preventing fractures. Indeed, there is a lack of general consensus on a standard definition and quantitative objective estimation of adherence to hip protectors, along with still scarce evidence on specific interventions on how to ameliorate it. From what is known so far, it seems reasonable to advise the use of hip protectors in aged care facilities, since recent pooled analyses have suggested their efficacy in this setting. The introduction of sensors combined with hip protectors will probably address this issue, both for monitoring and optimizing compliance, especially in elderly people. In the meantime, new, well designed studies following specific guidelines are strongly encouraged and needed. In particular, studies in community-dwelling elderly individuals at high risk of first or further fragility fractures are required. The optimization of the tested devices in a preclinical setting according to international standard biomechanical testing is necessary. PMID- 25926046 TI - Effect of Combined Teriparatide and Monthly Risedronate Therapy on Cancellous Bone Mass in Orchidectomized Rats: A Bone Histomorphometry Study. AB - This study investigated the effects of combined teriparatide (an anabolic agent) and monthly risedronate (an anti-resorptive agent) therapy on cancellous bone mass in orchidectomized (ORX) rats. Fifty 14-week-old male Sprague-Dawley rats were randomized into five groups of ten animals each: sham-operation + vehicle; ORX + vehicle; ORX + risedronate (90 MUg/kg subcutaneous, every 4 weeks); ORX + teriparatide (30 MUg/kg subcutaneous, three times per week); and ORX + risedronate + teriparatide. After the 12-week experimental period, cancellous bone in the tibial proximal metaphysis was examined by static and dynamic histomorphometric analyses. ORX decreased bone volume per total volume (BV/TV) and trabecular number (Tb.N), and increased trabecular separation (Tb.Sp). Risedronate increased BV/TV and Tb.N above the sham control values, while teriparatide prevented the ORX-induced decrease in BV/TV and increased trabecular width (Tb.Wi) above sham control levels. Risedronate decreased Tb.Sp below control values, while teriparatide prevented the ORX-induced increase in Tb.Sp. The combination of teriparatide and risedronate further increased BV/TV and Tb.N and decreased Tb.Sp as a result of suppression of bone remodeling, compared with teriparatide alone. These results suggest that teriparatide and monthly risedronate exert different effects on cancellous bone structure and thus have additive effects on cancellous bone mass in ORX rats. PMID- 25926047 TI - Teriparatide Therapy Reduces Serum Phosphate and Intima-Media Thickness at the Carotid Wall Artery in Patients with Osteoporosis. AB - Although cross-sectional and longitudinal studies report a relationship between osteoporosis and cardiovascular disorders (known as the bone-cardiovascular axis), the benefits of osteoporosis treatment on atherosclerosis are largely unclear. Teriparatide is a bone-forming agent that increases urinary phosphate excretion. Because elevated serum phosphate is associated with the development of atherosclerosis, the purpose of our study was to examine the relationship among lumbar spine bone mineral density (LS-BMD), intima-media thickness at the carotid artery (CA-IMT), and phosphate metabolism in response to daily teriparatide therapy. Osteoporotic patients (n = 28) with low LS-BMD (T-score < -2.5) and/or at least one vertebral fracture were treated with teriparatide (20 MUg/day) for 12 months. Metabolic bone markers, LS-BMD, and CA-IMT were measured over the course of treatment. The LS-BMD significantly increased by 0.046 +/- 0.038 g/cm(2) over the 12-month period (P < 0.001). CA-IMT decreased from 0.701 mm (interquartile range: 0.655-0.774 mm) at baseline to 0.525 mm (0.477-0.670 mm) at 12 months (P < 0.05); however, CA-IMT change was not significantly associated with LS-BMD change. Serum phosphate decreased after 1 month of teriparatide administration, and the change in serum phosphate at 1 months was associated with the change in CA-IMT at 12 months (rho = 0.431, P = 0.025). Teriparatide improved LS-BMD and CA-IMT, suggesting the existence of the bone-cardiovascular axis. The association between serum phosphate and CA-IMT suggests that the teriparatide decreased CA-IMT in part by reducing serum phosphate, a well-known vascular toxin, in addition to the improvement of bone-cardiovascular axis. PMID- 25926048 TI - Detection of phylogenetically informative polymorphisms in the entire euchromatic portion of human Y chromosome from a Sardinian sample. AB - BACKGROUND: Next-Generation Sequencing methods have led to a great increase in phylogenetically useful markers within the male specific portion of the Y chromosome, but previous studies have limited themselves to the study of the X degenerate regions. METHODS: DNA was extracted from peripheral blood samples of adult males whose paternal grandfathers were born in Sardinia. The DNA samples were sequenced, genotyped and subsequently analysed for variant calling for approximately 23.1 Mbp of the Y chromosome. A phylogenetic tree was built using Network 4.6 software. RESULTS: From low coverage whole genome sequencing of 1,194 Sardinian males, we extracted 20,155 phylogenetically informative single nucleotide polymorphisms from the whole euchromatic region, including the X degenerate, X-transposed, and Ampliconic regions, along with variants in other unclassified chromosome intervals and in the readable sequences of the heterochromatic region. CONCLUSIONS: The non X-degenerate classes contain a significant portion of the phylogenetic variation of the whole chromosome and their inclusion in the analysis, almost doubling the number of informative polymorphisms, refining the known molecular phylogeny of the human Y chromosome. PMID- 25926049 TI - Does Functional Septorhinoplasty Provide Improvement of the Nasal Passage in Validated Patient-Reported Outcome Measures? AB - OBJECTIVE: The aim of this study was to determine whether functional septorhinoplasty provides improvement of the nasal passage in validated patient reported outcome measures (PROMs) for adults with an anatomical obstruction of the nasal valve. All patients with an anatomical obstruction of the nasal valve area due to nasal valve pathology and/or septal deviations in this area were included. METHODS: A systematic PubMed, Embase and Cochrane Library search was performed to identify relevant articles. The articles were critically appraised and ranked according to validity and relevance. RESULTS: Sixteen articles met our inclusion criteria, and after critical appraisal, 10 were eligible for further analysis. In 9 studies, the Nose Obstruction Symptom Evaluation (NOSE) score improved from 35 to 60 points. In 1 study, the Sino-Nasal Outcome Test (SNOT-22) improved 3.5 points. CONCLUSION: The results suggest that there is a significant improvement of the validated PROMs after functional septorhinoplasty in the first postoperative year. We recommend that adults with nasal breathing problems due to an anatomical problem of the nasal valve area should consider undergoing functional septorhinoplasty. PMID- 25926050 TI - High titer anti-basement membrane antibodies in a subset of patients with pediatric systemic lupus erythematosus. AB - BACKGROUND/AIMS: There is a critical need for more noninvasive biomarkers to identify nephritis in patients with systemic lupus erythematosus (SLE). Recent studies in a model mouse and an adult SLE patient cohort suggest that anti basement membrane antibody levels correlate well with lupus activity and kidney injury. The purpose of this study was to assess the anti-basement membrane reactivity in pediatric SLE (pSLE) patients with or without nephritis. METHODS: Auto-antibodies to basement membrane antigens were assessed using an anti matrigel ELISA. Endpoint titers were measured in pSLE patients and healthy children, as well as in autoimmune and non-immune mice, with good reproducing capabilities. Findings were also analyzed with respect to the presence or absence of nephritis, dsDNA antibodies, and other manifestations of pSLE. RESULTS: MRL/lpr mice developed high-titer anti-matrigel antibodies, whereas C57BL/6 mice did not. In a cohort of 21 pSLE patients and 22 pediatric controls, high-titer anti-matrigel IgG, IgM and IgA antibody levels were specific for pSLE. High-titer anti-matrigel IgG3 levels could distinguish with good sensitivity the 13 pSLE patients with a history of nephritis from the 8 non-renal pSLE patients. High titer anti-matrigel IgG, IgA, IgM or IgG3 did not correlate with positive anti double stranded DNA, but defined an overlapping subset of patients. CONCLUSION: The addition of anti-basement membrane antibody testing to serologic testing in pSLE may help to monitor disease activity or to define important subsets of patients with risks for specific disease manifestations. PMID- 25926051 TI - Validity and psychometric properties of the measure of psychologically abusive behaviors among young women and women in distressed relationships. AB - The Measure of Psychologically Abusive Behaviors (MPAB) was developed recently to improve on prior scales. Two nationally solicited samples of women were utilized to further validate the MPAB through the use of a criterion group, factor analysis, and designation of a threshold for accurate classification. MPAB scores were twice as high in the criterion group (M = 38.75 vs. M = 18.85; F = 22.17). Using a cutpoint of 1, the sensitivity and specificity for MPAB were .725 and .628, respectively. Cronbach's alpha was .97 for both samples. These data provide additional evidence for the MPAB as valid and internally consistent. PMID- 25926052 TI - Improving coordinated responses for victims of intimate partner violence: law enforcement compliance with state-mandated intimate partner violence documentation. AB - New York State law mandates specific intimate partner violence (IPV) documentation under all circumstances meeting the enumerated relationship and crime criteria at the scene of a domestic dispute. Law enforcement compliance with this mandate is unknown. We reviewed law enforcement completion rates of Domestic Violence Incident Reports (DVIRs) and assessed correlations with individual or legal factors. Law enforcement officers filed DVIRs in 54% of the cases (n = 191), more often when injury occurred (p < .01) and the defendant had prior court contact (p < .05). The discussion explores policy implications and potential means to rectify the gap between mandated processes and implementation. PMID- 25926053 TI - The molecular landscape of colorectal cancer cell lines unveils clinically actionable kinase targets. AB - The development of molecularly targeted anticancer agents relies on large panels of tumour-specific preclinical models closely recapitulating the molecular heterogeneity observed in patients. Here we describe the mutational and gene expression analyses of 151 colorectal cancer (CRC) cell lines. We find that the whole spectrum of CRC molecular and transcriptional subtypes, previously defined in patients, is represented in this cell line compendium. Transcriptional outlier analysis identifies RAS/BRAF wild-type cells, resistant to EGFR blockade, functionally and pharmacologically addicted to kinase genes including ALK, FGFR2, NTRK1/2 and RET. The same genes are present as expression outliers in CRC patient samples. Genomic rearrangements (translocations) involving the ALK and NTRK1 genes are associated with the overexpression of the corresponding proteins in CRC specimens. The approach described here can be used to pinpoint CRCs with exquisite dependencies to individual kinases for which clinically approved drugs are already available. PMID- 25926054 TI - Risk Factors for Haemorrhage during Suction Curettage after Uterine Artery Embolization for Treating Caesarean Scar Pregnancy: A Case-Control Study. AB - AIMS: To investigate the potential risk factors for haemorrhage during suction curettage after uterine artery embolization (UAE) in the treatment of caesarean scar pregnancy (CSP). METHODS: A case-control study was executed including 35 patients with CSP and haemorrhage during suction curettage after UAE and 140 controls without haemorrhage. The data collected included gestational age, the distance between the gestational mass and the bladder, and the volume of vaginal bleeding. RESULTS: Six patients with UAE needed blood transfusions and two had a hysterectomy, while no patient in the control group needed these interventions. Multivariate analysis showed that both gestational age and the distance between the gestational mass and the bladder were associated with haemorrhage in the CSP group. The odds ratio (OR) of gestational age between cases and controls was 1.579 (95% confidence interval [CI] 1.291-1.933), and the OR of the distance between the gestational mass and the bladder was 0.208 (95% CI 0.082-0.531). CONCLUSION: Increased gestational age might be an important risk factor for haemorrhage during suction curettage after UAE in the treatment of patients with CSP, and a distance of >0.2 cm between the gestational mass and the bladder was protective against haemorrhage. PMID- 25926055 TI - Childhood-onset systemic lupus erythematosus in Singapore: clinical phenotypes, disease activity, damage, and autoantibody profiles. AB - Childhood-onset systemic lupus erythematosus (cSLE) is a multisystem autoimmune disease characterized by immune dysregulation affecting patients less than 18 years old. One-fifth of SLE cases are diagnosed during childhood. cSLE presents differently from adults and has a more severe and aggressive course. We describe the clinical and antibody profiles in our cSLE Singapore cohort. All cSLE patients who satisfied the 1997 American College of Rheumatology diagnostic criteria were captured in our lupus registry from January 2009 to January 2014. Data including demographic, cumulative clinical, serologic data, and damage indices were collected. Adjusted mean SLEDAI-2K (AMS) was used to summarize disease activity over multiple visits. Cluster analysis using non-hierarchical K means procedure was performed on eight selected antibodies. The 64 patients (female:male ratio 5:1; Chinese 45.3%, Malay 28.1%, Indian 9.4%, and other races 17.2%) had a mean onset age of 11.5 years (range 2.1-16.7) and mean age at diagnosis was 11.9 years (range 2.6-18.0). Our study demonstrated differences in clinical manifestations for which hematologic involvement was the most common manifestation with less renal disease and uncommon neurologic manifestation as compared to other cSLE cohorts reported in our region. Antibody clusters were identified in our cohort but their clinical association/discrimination and outcome prediction required further validation study. Outcomes of our cohort in regard to disease activity after therapy and organ damages were comparable if not better to other cSLE cohorts elsewhere. Steroid-related damage, including symptomatic multifocal avascular necrosis and cataract, were not uncommon locally. Infection remains the major cause of death for the continent. Nevertheless, the five year survival rate of our cohort (98.4%) was high. PMID- 25926056 TI - Vitamin D levels and cytokine profiles in patients with systemic lupus erythematosus. AB - OBJECTIVES: To evaluate the expression of Th1, Th2, and Th17 cytokines in patients with systemic lupus erythematosus (SLE), and verify the association between serum cytokine levels and vitamin D concentration. METHODS: The sample consisted of 172 patients with SLE. 25-Hydroxyvitamin D (25(OH)D) levels were measured by chemiluminescence and 25(OH)D levels <20 ng/mL were considered to reflect vitamin D deficiency. Serum cytokine levels were measured in once-thawed samples, using a Th1/Th2/Th17 CBA (cytometric beads array) kit. RESULTS: One hundred and sixty-one (93.6%) patients were women and 128 (74.4%) were of European descent. Mean patient age was 40.5 +/- 13.8 years, and mean age at diagnosis was 31.5 +/- 13.4 years. At the time of study entry, patients had a median (IQR) SLEDAI of 2 (1-4) and SLICC of 0 (0-1). Mean 25(OH)D concentration was 25.4 +/- 11.04 ng/mL. Fifty-nine (34.3%) patients had a vitamin D deficiency. No statistically significant associations were identified between cytokine and vitamin D levels. The most significant finding was a positive correlation between INF-alpha levels and SLEDAI (r(s) = 0.22, p = 0.04). CONCLUSION: Although vitamin D deficiencies are highly prevalent in patients with SLE, vitamin D levels were not significantly associated with patient cytokine profiles. The positive correlation between IFN-alpha levels and SLEDAI showed in this study corroborates other findings in the literature. The present results did not replicate those of in vitro studies of the effect of vitamin D levels on cytokine profiles. Placebo controlled intervention trials of the effect of vitamin D on cytokine profiles are still required before any definitive conclusions can be drawn regarding the association between these variables. PMID- 25926057 TI - Copper(I) targeting in the Alzheimer's disease context: a first example using the biocompatible PTA ligand. AB - Copper(I) coordinating ligands in the Alzheimer's disease context have remained unexplored, despite the biological relevance of this redox state of the copper ion. Here, we show that the PTA ligand can remove copper from Abeta, prevent reactive oxygen species production and oligomer formation, two deleterious events in the disease's etiology. PMID- 25926058 TI - Framing the ecosystem concept through a longitudinal study of developments in science and policy. AB - This paper examines how scientific literature and policy documents frame the ecosystem concept and how these frames have shaped scientific dialogue and policy making over time. This was achieved by developing a frame typology, as a basis for organizing relevant value expressions, to assess how different frames have altered perspectives of the ecosystem concept. The frame typology and analysis is based on a semi-grounded and longitudinal document analysis of scientific literature and policy documents using the ecosystem concept. Despite changing discourses and public priorities (e.g., cultural constructs of biodiversity) both science and policy documents are characterized by stable value systems that have not changed substantially since the 1930s. These value systems were defined based on ethical principles that delineate 6 core frames: humans first, dual systems, eco-science, eco-holism, animals first, and multicentrism. Specific crises (e.g., climate change) and cross-disciplinary uptake and re-uptake of, for example, the ecosystem services concept, have brought new perspectives to the forefront of public discourse. These developments triggered changes in the core frames that, rather than being value based, are based on how the ecosystem is conceptualized under fixed value systems and over time. Fourteen subframes were developed to reflect these longitudinal changes. There are as such clear framing effects in both scientific literature and in policy. Ecosystem research is for instance often characterized by unstated value judgments even though the scientific community does not make these explicit. In contrast, policy documents are characterized by clear value expressions but are principally management driven and human centered. PMID- 25926059 TI - The graceful exit or reluctant demise of the older adult with acute myeloid leukemia. PMID- 25926060 TI - Bleeding diathesis associated with acquired von Willebrand Syndrome in three patients with chronic lymphocytic leukemia. PMID- 25926061 TI - Molecular and phenotypic heterogeneity of refractory anemia with ring sideroblasts associated with marked thrombocytosis. PMID- 25926062 TI - The glucocorticoid receptor A3669G SNP is not associated with polycythemia vera, essential thrombocythemia or primary myelofibrosis. PMID- 25926063 TI - The neutrophil-to-lymphocyte ratio is an independent prognostic factor in patients with peripheral T-cell lymphoma, unspecified. AB - Peripheral T-cell lymphoma (PTCL) encompasses a group of rare and aggressive lymphomas. PTCL, unspecified (PTCLU) is the most common subtype of PTCL, and carries a poor prognosis. The International Prognostic Index (IPI) and the Prognostic Index for PTCLU (PIT) scoring systems are powerful risk-stratification tools in patients with PTCL. The aim of this study was to evaluate whether the neutrophil-to-lymphocyte ratio (NLR) is a prognostic factor in PTCLU. We retrospectively studied 83 patients with diagnosis of PTCLU. In the univariate analysis, NLR >= 4 was associated with worse overall survival (HR 3.96, 95% CI 1.92-8.17; p < 0.001). In the multivariate analysis, NLR >= 4 was independently associated with worse overall survival after adjustment for the PIT score (HR 4.30, 95% CI 1.90-9.69; p < 0.001), and for the IPI score (HR 2.60, 95% CI 1. 12 6.04; p = 0.03). Our study suggests the NLR could be helpful in refining the survival prognostication in patients with PTCLU. PMID- 25926064 TI - Changing patterns of chemotherapy relative dose intensity and supportive care for aggressive B-cell non-Hodgkin lymphoma. AB - Maintaining high relative dose intensity (RDI) is associated with improved outcomes, especially in patients with aggressive B-cell non-Hodgkin lymphoma (NHL). To evaluate changes in practice, we examined RDI, chemotherapy treatment patterns, dose delays and reductions, neutropenia and related consequences, and supportive care in 500 patients with aggressive B-cell NHL treated between 2006 2009. We then compared the results to a previous study of patients treated between 1993-2001. Relative to the previous study, rituximab was a common addition to CHOP-21 (91% vs. 3%), more patients received an RDI >= 85% (68% vs. 52%), and fewer patients experienced dose reductions (21% vs. 35%), though incidences of dose delays were similar (26% vs. 23%). Incidences of febrile neutropenia (FN; 12% vs. 21%) and FN-related hospitalizations (10% vs. 16%) were lower. Finally, more patients received primary prophylaxis with colony stimulating factors (75% vs. 12%). Together, these results illustrate evolving practice patterns for patients with aggressive B-cell NHL. PMID- 25926065 TI - Jumping translocation involving 13q34 in chronic lymphocytic leukemia: report of the first case studied by fluorescent in situ hybridization. PMID- 25926066 TI - Second allogeneic transplantation using unrelated cord blood for relapsed hematological malignancies after allogeneic transplantation. AB - The efficacy of second allogeneic stem cell transplantation (SCT2) using cord blood (CB) for patients with relapsed hematological malignancies after initial allogeneic stem cell transplantation (SCT1) is unknown. We analyzed the results of SCT2 using single-unit unrelated CB in 34 adult patients with relapsed hematological malignancies after SCT1 in our institution. The patients had acute myeloid leukemia (n = 23), acute lymphoblastic leukemia (n = 7), chronic myelogenous leukemia (n = 2), and myelodysplastic syndrome (n = 2). The cumulative incidence of neutrophil and platelet engraftment was 81.6% at 30 days and 68.5% at 100 days, respectively. With a median follow-up of 40 months, the probability of overall survival at 3 years was 29.0%. The cumulative incidence of relapse and transplant-related mortality at 3 years were 60.7% and 27.2%, respectively. The use of CB could offer the opportunity to receive SCT2 for patients who experienced disease relapse after SCT1 without HLA-identical related or unrelated donors. PMID- 25926067 TI - In vitro and in vivo Anticancer Effects of a Novel 9-Phenyldibenzo[a,c]phenazin-9 ium Cation and Its Ligands. AB - BACKGROUND: Multidrug resistance (MDR) is a major problem in cancer treatment. Cu complexes possess the ability to overcome MDR in cancer. Therefore, the search for new Cu complexes is of great clinical significance and we address the anticancer effects of a previously synthesized novel 9-phenyldibenzo[a,c]phenazin 9-ium cation [1(+)] as [1] [CuCl2] and as [1] [I]. METHODS: The existence of the monovalent Cu(I) in [1] [CuCl2] was proven by electron paramagnetic resonance (EPR) studies and in vivo anticancer effects were studied in animals. RESULTS: The monovalent nature of the Cu ion in [1] [CuCl2] was determined through EPR. The mean survival time of mice bearing doxorubicin-resistant Ehrlich ascites carcinoma cells is longer when [1] [I] is injected intraperitoneally whereas [1] [CuCl2] does not significantly increase the median survival in tumor-bearing mice. Compounds do not follow the immunomodulatory route and only [1] [I] shows cytotoxic activity in both MDR and drug-sensitive leukemia cell lines. CONCLUSION: An organic iodide complex rather than a cupric complex possesses direct cytotoxic potential. PMID- 25926068 TI - Topography of primitive reflexes in dementia: an F-18 fluorodeoxyglucose positron emission tomography study. AB - BACKGROUND AND PURPOSE: Although primitive reflexes (PRs) are inhibited during the first years of childhood, they may reappear with brain injury. PRs have been linked to frontal lobe dysfunction, but their precise topography has not yet been defined. The purpose of this study was to map which regions of the brain display a reduced glucose metabolism in patients with cognitive impairment and PRs. METHODS: A prospective study was conducted to evaluate PRs in a group of patients assessed due to suspected cognitive decline. Neurological and neuropsychological examinations and (18) F-fluorodeoxyglucose positron emission tomography fused with computerized tomography were performed. Voxel-based brain mapping analysis by means of statistical parametric mapping was used to compare patients with and without PRs. RESULTS: The study included 99 patients (33 diagnosed with Alzheimer's disease, 33 on the frontotemporal dementia spectrum and 33 with other diagnoses). Mean age was 71 +/- 9.7 years; time since symptom onset was 3.6 +/- 2.9 years. At least one PR was observed in 43 cases (43.4% of the whole sample; 48.5% in the Alzheimer disease group, 63.6% in frontotemporal dementia and 18.2% in the group with other diagnoses). The group of patients with PRs exhibited a decreased cerebral metabolism in the bilateral superior frontal gyri (Brodmann area 6), bilateral putamina and thalami. CONCLUSIONS: The presence of PRs was associated with hypometabolism at the superior frontal gyrus and putamen. This suggests that dysfunction in the corticostriatal motor circuit (supplementary motor area-putamen-thalamus) may constitute the anatomical basis of the recurrence of PRs. PMID- 25926069 TI - Atorvastatin increases miR-124a expression: a mechanism of Gamt modulation in liver cells. AB - Atorvastatin is used to control cholesterol and lipid levels in hyperlipidaemic and hypercholesterolaemic patients. Myopathy and hepatotoxicity, however, have been reported as side effects in a small percentage of statin users. This study aimed to investigate the cytotoxicity and the effect of atorvastatin on microRNA expression in HepG2 cells. The methylthiazol tetrazolium assay was used to assess hepatocyte viability and at 20 MUM atorvastatin (24 h) treatment were 82 +/- 1.5% viable (P = 0.0002). Levels of intracellular ATP in cells treated with 20 MUM atorvastatin were reduced by 1.25-fold, P = 0.002. Cytotoxicity, measured by the release of intracellular lactate dehydrogenase, was increased from 0.95 +/- 0.29 units in control cells to 1.12 +/- 0.02 units (P = 0.002) in atorvastatin treated cells. A panel of 84-miRNA species was used to evaluate the effect of atorvastatin on miRNA expression. MiR-124a was significantly up-regulated by atorvastatin (12.94-fold). A significant decrease in GAMT expression (3.54-fold) was observed in atorvastatin treated cells following quantitative PCR analysis. In addition, western blotting data showed GAMT protein levels were significantly lower than the controls (3.02-fold) and analysis of creatine levels in treated cells showed a significant decrease in the atorvastatin treated culture supernatant compared to control culture supernatant (32.33 +/- 3.51 MUM/l vs. 59.67 +/- 1.52MUM/l, P = 0.0056). This is the first study to show that atorvastatin up-regulates miR-124a levels and consequently modulates GAMT expression in hepatocytes. PMID- 25926070 TI - Simulation in neurology. AB - Simulation is a frontier for disseminating knowledge in almost all the fields of medicine and it is attracting growing interest because it offers a means of developing new teaching and training models, as well as of verifying what has been learned in a critical setting that simulates clinical practice. The role of simulation in neurology, until now limited by the obvious physical limitations of the dummies used to train students and learners, is now increasing since, today, it allows anamnestic data to be related to the instrumental evidence necessary for diagnosis and therapeutic decision-making, i.e., to the findings of neurophysiological investigations (EEG, carotid and vertebral echography and transcranial Doppler, for example) and neuroradiological investigations (CT, MRI imaging), as well as vital parameter monitoring (ECG, saturimetry, blood pressure, respiratory frequency, etc.). Simulation, by providing learners with opportunities to discuss, with experts, different profiles of biological parameters (both during the simulation itself and in the subsequent debriefing session), is becoming an increasingly important tool for training those involved in evaluation of critical neurological patients (stroke, Guillan Barre syndrome, myasthenia, status epilepticus, headache, vertigo, confusional status, etc.) and complex cases. In this SIMMED (Italian Society for Simulation in Medicine) position paper, the applications (present and, possibly, future) of simulation in neurology are reported. PMID- 25926071 TI - Hospital admissions for seizure in Italy: a decennial retrospective analysis with a special focus on the burden in the pediatric age. AB - The aim of the study was to analyze the incidence of hospitalizations for different types of convulsions in Italy during the years 2001-2010, especially in the pediatric age, with a focus on febrile seizures. National hospital discharge records of admissions for any type of convulsion from 2001 to 2010 were analyzed. The incidence rates were calculated considering the pediatric resident population estimated by the Italian Institute of Statistics in the studied years. 675,189 Hospital discharge records were analyzed, 256,126 of which had at least one specific diagnosis code for convulsion. 77 % of seizures were concentrated in the age group 0-3 years (618/100,000 inhabitants). The admission regimen was mainly ordinary (92 %). 97.6 % of admissions were <7 days and 91 % of hospital discharges were ordinary discharges to home. The percentage distribution of seizures showed a constant trend over the considered period. The code "febrile seizures" represented 71.9 % of all seizures in the pediatric population. 94.5 % was concentrated in children aged 0-5 years. The obtained data could be useful to put into the right perspective issues arising from the reports of febrile seizures following the administration of pediatric vaccines. PMID- 25926072 TI - Validation of a simple method for atrial fibrillation screening in patients with stroke. AB - Atrial fibrillation (AF) is the most common cardiac arrhythmia in adult and old people and represents a risk factor for stroke. Correct AF individuation bears strong relevance in primary and secondary stroke prevention. Our goal was to evaluate the reliability of a low-cost, non-invasive technology in detecting AF in acute stroke patients. AFib model BP3MQ1-2D (Microlife USA, Dunedin, FL) showed good accuracy in diagnosing AF in a general cardiologic outpatient population. We carried out an observational study in patients with recent stroke. We studied 207 subjects, 103 men, 104 women, mean age (+/-SD) 77.7 +/- 11.34 years, who underwent a test by AFib device with indication of AF or lack of it. The golden standard was a 12-lead EKG done immediately and evaluated by a certified cardiologist. We computed estimates of Sensitivity and Specificity and their 95 % confidence intervals (CI). AF was present in 38 subjects from the sample of 207 (18.4 %). AFib correctly demonstrated AF in 34 and failed diagnosing AF in 4 cases; on the other hand, AFib correctly excluded AF in 167 and caused an erroneous diagnosis of AF in 2 cases. The Sensitivity was 0.895 (95 % CI 0.7597-0.958) and the Specificity was 0.988 (95 % CI 0.958-0.997). The AFib device global accuracy was 0.971 (95 % CI 0.938-0.987). This device was able to detect AF with high specificity and a good sensitivity. This device may be considered as an accurate tool in detecting AF in stroke patients. PMID- 25926073 TI - Transcript profiling distinguishes complete treatment responders with locally advanced cervical cancer. AB - Cervical cancer (CC) mortality is a major public health concern since it is the second cause of cancer-related deaths among women. Patients diagnosed with locally advanced CC (LACC) have an important rate of recurrence and treatment failure. Conventional treatment for LACC is based on chemotherapy and radiotherapy; however, up to 40% of patients will not respond to conventional treatment; hence, we searched for a prognostic gene signature able to discriminate patients who do not respond to the conventional treatment employed to treat LACC. Tumor biopsies were profiled with genome-wide high-density expression microarrays. Class prediction was performed in tumor tissues and the resultant gene signature was validated by quantitative reverse transcription polymerase chain reaction. A 27-predictive gene profile was identified through its association with pathologic response. The 27-gene profile was validated in an independent set of patients and was able to distinguish between patients diagnosed as no response versus complete response. Gene expression analysis revealed two distinct groups of tumors diagnosed as LACC. Our findings could provide a strategy to select patients who would benefit from neoadjuvant radiochemotherapy-based treatment. PMID- 25926074 TI - miR-888: A Novel Cancer-Testis Antigen that Targets the Progesterone Receptor in Endometrial Cancer. AB - Cancer-testis (CT) antigens are a large family of genes that are selectively expressed in human testis germ cells, overexpressed in a variety of tumors and predominantly located on the X chromosome. To date, all known CT antigens are protein-coding genes. Here, we identify miR-888 as the first miRNA with features characteristic of a CT antigen. In a panel of 21 normal human tissues, miR-888 expression was high in testes and minimal or absent in all other examined tissues. In situ hybridization localized miR-888 expression specifically to the early stages of sperm development within the testes. Using The Cancer Genome Atlas database, we discovered that miR-888 was predominately expressed in endometrial tumors, with a significant association to high-grade tumors and increased percent invasion. In a separate panel of endometrial tumor specimens, we validated overexpression of miR-888 by real-time polymerase chain reaction. In addition, miR-888 expression was highest in endometrial carcinosarcoma, a rare and aggressive type of endometrial tumor. Moreover, we identified the progesterone receptor (PR), a potent endometrial tumor suppressor, as a direct target of miR-888. These data define miR-888 as the first miRNA CT antigen and a potential mediator of an aggressive endometrial tumor phenotype through down regulation of PR. PMID- 25926075 TI - Lung Adenocarcinomas and Lung Cancer Cell Lines Show Association of MMP-1 Expression With STAT3 Activation. AB - Signal transducer and activator of transcription 3 (STAT3) is constitutively activated in the majority of lung cancer. This study aims at defining connections between STAT3 function and the malignant properties of non-small cell lung carcinoma (NSCLC) cells. To address possible mechanisms by which STAT3 influences invasiveness, the expression of matrix metalloproteinase-1 (MMP-1) was analyzed and correlated with the STAT3 activity status. Studies on both surgical biopsies and on lung cancer cell lines revealed a coincidence of STAT3 activation and strong expression of MMP-1. MMP-1 and tyrosine-phosphorylated activated STAT3 were found co-localized in cancer tissues, most pronounced in tumor fronts, and in particular in adenocarcinomas. STAT3 activity was constitutive, although to different degrees, in the lung cancer cell lines investigated. Three cell lines (BEN, KNS62, and A549) were identified in which STAT3 activitation was inducible by Interleukin-6 (IL-6). In A549 cells, STAT3 activity enhanced the level of MMP 1 mRNA and stimulated transcription from the MMP-1 promoter in IL-6-stimulated A549 cells. STAT3 specificity of this effect was confirmed by STAT3 knockdown through RNA interference. Our results link aberrant activity of STAT3 in lung cancer cells to malignant tumor progression through up-regulation of expression of invasiveness-associated MMPs. PMID- 25926076 TI - Novel prostate cancer biomarkers derived from autoantibody signatures. AB - BACKGROUND: Due to the low specificity of the prostate-specific antigen (PSA) assay and a high false positive rate, a large number of prostate cancer (PCA) biopsies are performed unnecessarily. Consequently, there is a need for new biomarkers that can identify PCA at any stage of progression while limiting the number of false positives. The use of autoantibody signature-developed biomarkers has proven to be an effective method to solve this problem. RESULTS: Using T7 phage-peptide detection, we identified a panel of eight biomarkers for PCA on a training set. The estimated receiver-operating characteristic (ROC) curve had an area under the ROC curve of 0.69 when applied to the validation set. Spearman correlations were high, within 0.7 to 0.9, indicating that the biomarkers have a degree of inter-relatedness. The identified biomarkers play a role in processes such as androgen response regulation and cellular structural integrity and are proteins that are thought to play a role in prostate tumorigenesis. CONCLUSIONS: Autoantibodies against PCA can be developed as biomarkers for detecting PCA. The scores from the algorithm developed here can be used to indicate a relative high or low risk of PCA, particularly for patients with intermediate (4.0 to 10 ng/ml) PSA levels. Since most commercially available assays test for PSA or have a PSA component, this novel approach has the potential to improve diagnosis of PCA using a biologic measure independent of PSA. PMID- 25926077 TI - Therapeutic Efficacy Assessment of CK6, a Monoclonal KIT Antibody, in a Panel of Gastrointestinal Stromal Tumor Xenograft Models. AB - We evaluated the efficacy of CK6, a KIT monoclonal antibody, in a panel of human gastrointestinal stromal tumor (GIST) xenograft models. Nude mice were bilaterally transplanted with human GIST xenografts (four patient derived and two cell line derived), treated for 3 weeks, and grouped as follows: control (untreated); CK6 (40 mg/kg, 3* weekly); imatinib (50 mg/kg, twice daily); sunitinib (40 mg/kg, once daily); imatinib + CK6; sunitinib + CK6 (same doses and schedules as in the single-agent treatments). Tumor volume assessment, Western blot analysis, and histopathology were used for evaluation of efficacy. Statistical analysis was performed using Mann-Whitney U (MWU) and Wilcoxon matched-pairs tests. CK6 as a single agent only reduced tumor growth rate in the UZLX-GIST3 model (P = .053, MWU compared to control), while in none of the other GIST models an effect on tumor growth rate was observed. CK6 did not result in significant anti-proliferative or pro-apoptotic effects in any of the GIST models, and moreover, CK6 did not induce a remarkable inhibition of KIT activation. Furthermore, no synergistic effect of combining CK6 with tyrosine kinase inhibitors (TKIs) was observed. Conversely, in certain GIST xenografts, anti-tumor effects seemed to be inferior under combination treatment compared to single-agent TKI treatment. In the GIST xenografts tested, the anti-tumor efficacy of CK6 was limited. No synergy was observed on combination of CK6 with TKIs in these GIST models. Our findings highlight the importance of using relevant in vivo human tumor xenograft models in the preclinical assessment of drug combination strategies. PMID- 25926078 TI - Significance of lymph node metastasis in cancer dissemination of head and neck cancer. AB - Lymph node metastasis (LNM) in many solid cancers is a well-known prognostic factor; however, it has been debated whether regional LNM simply reflects tumor aggressiveness or is a source for further tumor dissemination. Similarly, the metastatic process in head and neck cancer (HNC) has not been fully evaluated. Thus, we aimed to investigate the relative significance of LNM in metastatic cascade of HNC using functional imaging of HNC patients and molecular imaging in in vivo models. First, we analyzed (18)Fluorodeoxyglucose positron emission tomography (PET) parameters of 117 patients with oral cancer. The primary tumor and nodal PET parameters were measured separately, and survival analyses were conducted on the basis of clinical and PET variables to identify significant prognostic factors. In multivariate analyses, we found that only the metastatic node PET values were significant. Next, we compared the relative frequency of lung metastasis in primary ear tumors versus lymph node (LN) tumors, and we tested the rate of lung metastasis in another animal model, in which each animal had both primary and LN tumors that were expressing different colors. As a result, LN tumors showed higher frequencies of lung metastasis compared to orthotopic primary tumors. In color-matched comparisons, the relative contribution to lung metastasis was higher in LN tumors than in primary tumors, although both primary and LN tumors caused lung metastases. In summary, tumors growing in the LN microenvironment spread to systemic sites more commonly than primary tumors in HNC, suggesting that the adequate management of LNM can reduce further systemic metastasis. PMID- 25926079 TI - Quantification of Tumor Burden in a Genetically Engineered Mouse Model of Lung Cancer by Micro-CT and Automated Analysis. AB - Genetically engineered mouse models (GEMMs) of lung cancer closely recapitulate the human disease but suffer from the difficulty of evaluating tumor growth by conventional methods. Herein, a novel automated image analysis method for estimating the lung tumor burden from in vivo micro-computed tomography (micro CT) data is described. The proposed tumor burden metric is the segmented soft tissue volume contained within a chest space region of interest, excluding an estimate of the heart volume. The method was validated by comparison with previously published manual analysis methods and applied in two therapeutic studies in a mutant K-ras GEMM of non-small cell lung carcinoma. Mice were imaged by micro-CT pre-treatment and stratified into four treatment groups: an antibody inhibiting vascular endothelial growth factor (anti-VEGF), chemotherapy, combination of anti-VEGF and chemotherapy, or control antibody. In the first study, post-treatment imaging was performed 4 weeks later. In the second study, mice were scanned serially on a high-throughput scanner every 2 weeks for 8 weeks during treatment. In both studies, the automated tumor burden estimates were well correlated with manual metrics (r value range: 0.83-0.93, P < .0001) and showed a similar, significant reduction in tumor growth in mice treated with anti-VEGF alone or in combination with chemotherapy. Given the fully automated nature of this technique, the proposed analysis method can provide a valuable tool in preclinical drug research for screening and randomizing animals into treatment groups and evaluating treatment efficacy in mouse models of lung cancer in a highly robust and efficient manner. PMID- 25926080 TI - Current trends in palliative heart care. AB - Palliative care is an alternate therapeutic approach that involves specialised medical care of a patient diagnosed with serious life threatening illness like heart failure (HF). The prime aim of the palliative care is to provide patient with relief from the symptoms, pain, physical stress, and mental stress of the diagnosed disease. The palliative care helps in improving the quality of life for both the patient and the family. Advanced HF is a disease process that carries a high burden of symptoms, suffering, and death. Palliative care can complement traditional care to improve symptom amelioration, patient-caregiver communication, emotional support, and medical decision making. The present review summarized all the available on alternative palliative approaches provided to heart patient by a team of physicians, nurses and other healthcare professionals. PMID- 25926081 TI - New research at the 2015 National Abortion Federation Annual Meeting: putting research into practice. PMID- 25926083 TI - Practical Issues for Atom Probe Tomography Analysis of III-Nitride Semiconductor Materials. AB - Various practical issues affecting atom probe tomography (APT) analysis of III nitride semiconductors have been studied as part of an investigation using a c plane InAlN/GaN heterostructure. Specimen preparation was undertaken using a focused ion beam microscope with a mono-isotopic Ga source. This enabled the unambiguous observation of implantation damage induced by sample preparation. In the reconstructed InAlN layer Ga implantation was demonstrated for the standard "clean-up" voltage (5 kV), but this was significantly reduced by using a lower voltage (e.g., 1 kV). The characteristics of APT data from the desorption maps to the mass spectra and measured chemical compositions were examined within the GaN buffer layer underlying the InAlN layer in both pulsed laser and pulsed voltage modes. The measured Ga content increased monotonically with increasing laser pulse energy and voltage pulse fraction within the examined ranges. The best results were obtained at very low laser energy, with the Ga content close to the expected stoichiometric value for GaN and the associated desorption map showing a clear crystallographic pole structure. PMID- 25926082 TI - An automatically contamination-avoiding technique for intracorporeal esophagojejunostomy using a transorally inserted anvil during laparoscopic total gastrectomy for gastric cancer. AB - BACKGROUND: Intracorporeal Roux-en-Y esophagojejunostomy during laparoscopic total gastrectomy for gastric cancer remains a challenging manipulation due to the uncontrolled direction of the jejunal side or unintended embedded tissues, although several methods have been introduced. In this study, we simplified the procedure based on a surgical string fixing technique using a transorally inserted anvil (OrVilTM; Covidien Ltd., Mansfield, MA, USA). METHODS: From March 2012 to September 2013, 14 consecutive patients underwent simplified intracorporeal Roux-en-Y esophagojejunostomy using OrVilTM during laparoscopic total gastrectomy for gastric cancer at our hospital. Clinicopathologic characteristics and surgical outcomes of these patients were retrospectively analyzed. RESULTS: All of the procedures were successful completed with no complication or conversion to open surgery. The mean overall operative time was 193.8 +/- 41.8 min, whereas the mean reconstruction time was 32.6 +/- 4.6 min. The mean estimated blood loss was 105.7 +/- 65.4 ml. The mean diameter of anastomosis measured by upper gastrointestinal contrast X-ray test at 1 month after operation was 2.3 cm. During a median follow-up period of 12 months, neither local recurrence nor anastomosis-related morbidity was observed. CONCLUSIONS: Our preliminary results suggested that this automatically contamination-avoiding technique based on a surgical-string-fixing strategy using OrVilTM during laparoscopic total gastrectomy for gastric cancer might be feasible and safe and provide a simple solution for intracorporeal Roux-en-Y esophagojejunostomy. PMID- 25926084 TI - Hippocampus and two-way active avoidance conditioning: Contrasting effects of cytotoxic lesion and temporary inactivation. AB - Hippocampal lesions tend to facilitate two-way active avoidance (2WAA) conditioning, where rats learn to cross to the opposite side of a conditioning chamber to avoid a tone-signaled footshock. This classical finding has been suggested to reflect that hippocampus-dependent place/context memory inhibits 2WAA (a crossing response to the opposite side is inhibited by the memory that this is the place where a shock was received on the previous trial). However, more recent research suggests other aspects of hippocampal function that may support 2WAA learning. More specifically, the ventral hippocampus has been shown to contribute to behavioral responses to aversive stimuli and to positively modulate the meso-accumbens dopamine system, whose activation has been implicated in 2WAA learning. Permanent hippocampal lesions may not reveal these contributions because, following complete and permanent loss of hippocampal output, other brain regions may mediate these processes or because deficits could be masked by lesion-induced extra-hippocampal changes, including an upregulation of accumbal dopamine transmission. Here, we re-examined the hippocampal role in 2WAA learning in Wistar rats, using permanent NMDA-induced neurotoxic lesions and temporary functional inhibition by muscimol or tetrodotoxin (TTX) infusion. Complete hippocampal lesions tended to facilitate 2WAA learning, whereas ventral (VH) or dorsal hippocampal (DH) lesions had no effect. In contrast, VH or DH muscimol or TTX infusions impaired 2WAA learning. Ventral infusions caused an immediate impairment, whereas after dorsal infusions rats showed intact 2WAA learning for 40-50 min, before a marked deficit emerged. These data show that functional inhibition of ventral hippocampus disrupts 2WAA learning, while the delayed impairment following dorsal infusions may reflect the time required for drug diffusion to ventral hippocampus. Overall, using temporary functional inhibition, our study shows that the ventral hippocampus contributes to 2WAA learning. Permanent lesions may not reveal these contributions due to functional compensation and extra-hippocampal lesion effects. PMID- 25926085 TI - Blood Parameters and Toxicity of Chromium Picolinate Oral Supplementation in Lambs. AB - The effects of oral supplementation of chromium picolinate (CrPic) on various blood parameters and their possible toxicity on the liver, kidneys, lungs, heart, and testis were investigated. Twenty-four Santa Ines (SI) lambs were treated with four different concentrations of CrPic (six animals/treatment): placebo, 0.250, 0.375, and 0.500 mg CrPic/animal/day for 84 days. The basal diet consisted of hay Panicum maximum cv Massai and concentrate. Blood and serum were collected fortnightly for analysis. On day 84, the animals were euthanized, and histopathological analysis in the liver, kidney, heart, lung, and testis was made. The liver and kidney were also submitted to electronic microscopy analysis. Differences between treatments (P < 0.05) were observed for packed cell volume (day 84), hemoglobin (day 84), total plasm protein (day 56 and day 84), and triglycerides (day 70). There was no statistically significant relationship between Cr supplementation and histopathology findings, although some animals treated with supplementary Cr showed morphological changes in the liver, kidney, and testis. Thus, the effectiveness of supplementation with Cr remains in doubt as to its physiological action and toxicity in sheep. PMID- 25926086 TI - A novel null HLA allele, HLA-DRB1*15:115N, identified in a Chinese family. AB - The novel allele HLA-DRB1*15:115N differs from HLA-B*15:80N by a nucleotide substitution at position 227 T > A. PMID- 25926087 TI - Global access to surgical care: a modelling study. AB - BACKGROUND: More than 2 billion people are unable to receive surgical care based on operating theatre density alone. The vision of the Lancet Commission on Global Surgery is universal access to safe, affordable surgical and anaesthesia care when needed. We aimed to estimate the number of individuals worldwide without access to surgical services as defined by the Commission's vision. METHODS: We modelled access to surgical services in 196 countries with respect to four dimensions: timeliness, surgical capacity, safety, and affordability. We built a chance tree for each country to model the probability of surgical access with respect to each dimension, and from this we constructed a statistical model to estimate the proportion of the population in each country that does not have access to surgical services. We accounted for uncertainty with one-way sensitivity analyses, multiple imputation for missing data, and probabilistic sensitivity analysis. FINDINGS: At least 4.8 billion people (95% posterior credible interval 4.6-5.0 [67%, 64-70]) of the world's population do not have access to surgery. The proportion of the population without access varied widely when stratified by epidemiological region: greater than 95% of the population in south Asia and central, eastern, and western sub-Saharan Africa do not have access to care, whereas less than 5% of the population in Australasia, high income North America, and western Europe lack access. INTERPRETATION: Most of the world's population does not have access to surgical care, and access is inequitably distributed. The near absence of access in many low-income and middle income countries represents a crisis, and as the global health community continues to support the advancement of universal health coverage, increasing access to surgical services will play a central role in ensuring health care for all. FUNDING: None. PMID- 25926088 TI - Comparison of Effects of Low- versus High-Dose Heparin on Access-Site Complications during Transradial Coronary Angiography: A Double-Blind Randomized Study. AB - OBJECTIVES: Although heparin is highly effective in reducing the rate of radial artery occlusion after transradial catheterization, the optimal heparin dose is still controversial. The aim of this study was to evaluate the efficacy and safety of two different heparin doses during transradial coronary angiography. METHODS: 490 consecutive patients undergoing transradial coronary angiography were prospectively enrolled into this double-blind randomized trial. A total of 202 patients enrolled in the low-dose (LD; 2,500 U of heparin) group and 202 patients enrolled in the high-dose (HD; 5,000 U of heparin) group were included in the final analysis. The primary endpoint of the study was radial artery occlusion. Bleeding and hematomas were the secondary outcome measures. RESULTS: At day 7, radial artery occlusion occurred in 5.9% of the patients in the LD group and in 5.4% of the patients in the HD group (p = 0.83). Bleeding during deflation of the transradial band occurred in 6.4% of the patients in the LD group and in 18.3% of the patients in the HD group; the difference was statistically significant (p < 0.001). Higher-dose heparin was found to be an independent predictor of bleeding (p = 0.007). CONCLUSION: A lower dose of heparin (i.e. 2,500 U) decreases bleeding during transradial band deflation without an increase in radial artery occlusion. PMID- 25926089 TI - Neuropsychiatric manifestations of Sydenham's chorea: a systematic review. AB - AIM: Sydenham's chorea is a post-streptococcal, autoimmune, neuropsychiatric movement disorder. Sydenham's chorea is a major criterion for diagnosis of acute rheumatic fever with the implication of potential long-term sequelae including cardiac complications. It is well established that there is psychiatric comorbidity in Sydenham's chorea, but there are variations in the literature regarding the nature and prevalence of psychiatric diagnoses associated with Sydenham's chorea. The aim of this review was to systematically evaluate the evidence for psychiatric symptoms presenting with Sydenham's chorea. Knowledge of comorbid psychiatric symptomatology will support early diagnosis and treatment, leading to improved long-term outcomes for children with Sydenham's chorea. METHOD: The study used a systematic search strategy, using MEDLINE, MEDLINE in Process, EMBASE, and The Cochrane Library. Abstracts were screened to identify relevant papers which were then assessed further. Eligible papers were summarized. RESULTS: A total of 1429 abstracts of relevant studies were found, and 49 papers reporting neuropsychiatric symptoms in Sydenham's chorea were summarized. Obsessive-compulsive disorder was the most commonly studied, and hence reported, neuropsychiatric symptom in children with Sydenham's chorea. The studies analysed used a variety of tools to identify affected children and used different methods for analysing results. Attention-deficit-hyperactivity disorder, affective disorders, tic disorders, executive function disturbances, and psychotic features were also reported as comorbidities. INTERPRETATION: There is good evidence of neuropsychiatric comorbidities in Sydenham's chorea. In countries with a high prevalence of rheumatic fever, the early recognition of salient cognitive and psychiatric symptoms may aid in the management of Sydenham's chorea. PMID- 25926090 TI - Cost Effectiveness of Sequencing 34 Cancer-Associated Genes as an Aid for Treatment Selection in Patients with Metastatic Melanoma. AB - OBJECTIVE: To determine whether a next-generation sequencing (NGS) panel of 34 cancer-associated genes would cost-effectively aid in the treatment selection for patients with metastatic melanoma, compared with a single-site BRAF V600 mutation test. METHODS: A decision model was developed to estimate the costs and health outcomes of the two test strategies. The cost effectiveness of these two strategies was analyzed from a payer perspective over a 2-year time horizon with model parameters taken from the literature. RESULTS: In the base case, the gene sequencing panel strategy resulted in a cost of US$120,022 and 0.721 quality adjusted life years (QALYs) per patient, whereas the single-site mutation test strategy resulted in a cost of US$128,965 and 0.704 QALYs. Thus, the gene sequencing panel strategy cost US$8943 less per patient and increased QALYs by 0.0174 per patient. Sensitivity analyses showed that, compared with the single site mutation test strategy, the gene sequencing panel strategy had a 90.9% chance of having reduced costs and increased QALYs, with the cost of the gene sequencing panel test having minimal effect on the incremental cost. CONCLUSION: Compared with the single-site mutation test, the use of an NGS panel of 34 cancer associated genes as an aid in selecting therapy for patients with metastatic melanoma reduced costs and increased QALYs. If the base-case results were applied to the 8900 patients diagnosed with metastatic melanoma in the USA each year, the gene sequencing panel strategy could result in an annual savings of US$79.6 million and a gain of 155 QALYs. PMID- 25926091 TI - Next generation mitochondrial disease: change in diagnostics with eyes on therapy. PMID- 25926092 TI - Chemical Analysis of Drug Biocrystals: A Role for Counterion Transport Pathways in Intracellular Drug Disposition. AB - In mammals, highly lipophilic small molecule chemical agents can accumulate as inclusions within resident tissue macrophages. In this context, we characterized the biodistribution, chemical composition, and structure of crystal-like drug inclusions (CLDIs) formed by clofazimine (CFZ), a weakly basic lipophilic drug. With prolonged oral dosing, CFZ exhibited a significant partitioning with respect to serum and fat due to massive bioaccumulation and crystallization in the liver and spleen. The NMR, Raman, and powder X-ray diffraction (p-XRD) spectra of CLDIs isolated from the spleens of CFZ-treated mice matched the spectra of pure, CFZ hydrochloride crystals (CFZ-HCl). Elemental analysis revealed a 237-fold increase in chlorine content in CLDIs compared to untreated tissue samples and a 5-fold increase in chlorine content compared to CFZ-HCl, suggesting that the formation of CLDIs occurs through a chloride mediated crystallization mechanism. Single crystal analysis revealed that CFZ-HCl crystals had a densely packed orthorhombic lattice configuration. In vitro, CFZ-HCl formed at a pH of 4-5 only if chloride ions were present at sufficiently high concentrations (>50:1 Cl(-)/CFZ), indicating that intracellular chloride transport mechanisms play a key role in the formation of CLDIs. While microscopy and pharmacokinetic analyses clearly revealed crystallization and intracellular accumulation of the drug in vivo, the chemical and structural characterization of CLDIs implicates a concentrative, chloride transport mechanism, paralleling and thermodynamically stabilizing the massive bioaccumulation of a weakly basic drug. PMID- 25926093 TI - Human cytomegalovirus UL55, UL144, and US28 genotype distribution in infants infected congenitally or postnatally. AB - Cytomegalovirus (CMV) is the most common cause of congenital infection. This pathogen exhibits extensive genetic variability in the genes that encode structural envelope glycoproteins, regulatory proteins, and proteins that contribute to immune evasion. However, the role of specific viral strains in the outcome of congenital CMV infection is unclear. Variation in the UL55 gene encoding glycoprotein B (gB), the UL144 gene encoding TNF alpha-like receptor, and the US28 gene encoding beta-chemokine receptor was determined in 60 newborn infants with congenital CMV infection and 90 infants with postnatal or undefined CMV infection. CMV polymorphisms were studied in relation to disease outcome and viral load. Genotyping was performed by a sequencing analysis of PCR-amplified fragments, and the viral load was measured by quantitative real-time PCR. The results demonstrated that (1) the UL55 and US28 genotype distributions were similar among the group of congenital and postnatal CMV infection; (2) the UL144 B1 genotype was more prevalent in congenital than in postnatal infection and was detected in 70% of newborns with asymptomatic congenital infection; and (3) none of the examined genotype was significantly linked with symptomatic CMV infection. No relationship was observed between genotype and viral load. The results revealed that UL55, UL144, and US28 polymorphisms are not associated with the outcome of CMV infection in infants, but the presence of UL144 B1 genotype might be virological marker of asymptomatic infection at birth. PMID- 25926094 TI - SECULAR GROWTH AND MATURATION CHANGES IN HUNGARY IN RELATION TO SOCIOECONOMIC AND DEMOGRAPHIC CHANGES. AB - This paper analyses the secular changes in the body development patterns of Hungarian children between the 1910s and the beginning of the 2000s in relation to socioeconomic and demographic changes in the country. Individual growth data of children were available from two national growth studies (1983-86, 2003-06), while sample-size weighted means of children's body dimensions were collected through regional studies between the 1920s and 1970s. Gross domestic product, Gini index, life expectancy at birth and under-5 mortality rate were used to assess the changes in economic status, income inequalities of the society and the population's general health status, respectively. Secular changes in food consumption habits were also examined. The positive Hungarian secular changes in socioeconomic status were associated with a continuous increase in children's body dimensions. The negative socioeconomic changes reflected only in wartime and post-war periods of children's growth, and the considerable socioeconomic changes at the beginning of the 1990s did not appear to influence the positive trend in children's growth. The positive secular trend in stature and body mass did not level off at the beginning of the 2000s: the socioeconomic conditions that support optimal growth and maturation could improve in Hungary. PMID- 25926095 TI - Eczema in early childhood, sociodemographic factors and lifestyle habits are associated with food allergy: a nested case-control study. AB - BACKGROUND: Studies suggest an increase in food allergy prevalence over the last decade, but the contributing factors remain unknown. The aim of this study was to evaluate the association between the most common food allergies and atopic history, sociodemographic characteristics and lifestyle habits. METHODS: We conducted a case-control study nested within the SPAACE study (Surveying Prevalence of Food Allergy in All Canadian Environments) - a cross-Canada, random telephone survey. Cases consisted of individuals with probable food allergy (self report of convincing symptoms and/or physician diagnosis) to milk, egg, peanut, tree nut, shellfish, fish, wheat, soy, or sesame. Controls consisted of nonallergic individuals, matched for age. Cases and controls were queried on personal and family history of atopy, sociodemographic characteristics and lifestyle habits. Multivariate logistic regression was used to evaluate the association between atopy, sociodemographic characteristics and lifestyle habits with probable food allergy. RESULTS: Between September 2010 and September 2011, 480 cases and 4,950 controls completed the questionnaire. For all 9 allergens, factors associated with a higher risk of probable allergy were as follows: (1) personal history of eczema (in the first 2 years of life), asthma or hay fever (odds ratio, OR 2.3, 95% CI 1.6-3.5; OR 2.8, 95% CI 2.2-3.6, and OR 2.3, 95% CI 1.8-3.0, respectively), (2) maternal, paternal or sibling's food allergy (OR 3.7, 95% CI 2.5-5.6; OR 3.0, 95% CI 1.8-5.1, and OR 3.1, 95% CI 2.2-4.2), (3) high household income (top 20%; OR 1.5, 95% CI 1.2-2.0). Males and older individuals were less likely to have food allergy (OR 0.7, 95% CI 0.6-0.9, and OR 0.99, 95% CI 0.99-1.00). Eczema in the first 2 years of life was the strongest risk factor for egg, peanut, tree nut and fish allergy. CONCLUSIONS: This is the largest population-based nested case-control study exploring factors associated with food allergies. Our results reveal that, in addition to previously reported factors, eczema in the first 2 years of life is consistently associated with food allergies. PMID- 25926096 TI - Toxicity study of dibutyl phthalate of Rubia cordifolia fruits: in vivo and in silico analysis. AB - Natural toxins from plant sources with wide ranges of biological activities reflect the upswing of drug design in the pharmaceutical industry. Rubia cordifolia L. is one of the most important red dye yielding plants. Most of the former researches have focused on the bioactive compounds from the roots of R. cordifolia, while no attention was paid towards the fruits. For the first time, here we report the presence of dibutyl phthalate in the fruits of R. cordifolia. Structural characterization was carried out using Ultraviolet-Visible spectrophotometer (UV-Vis), Fourier transform infrared (FTIR), gas chromatography mass spectrophotometer (GC-MS), Nuclear magnetic resonance (NMR). Acute toxicity of the crude ethanolic extracts of the R. cordifolia fruits was examined in Swiss albino mice. No mortality was observed in all treated mice with 100, 500, 1000 mg/kg body weight of crude extract of R. cordifolia fruit and it indicates that the LD50 value is higher than 1000 mg/kg body weight. This study exhibited a significant change in the body weight. Alanine transaminase (ALT), total protein, triglycerides, glucose, and also the histopathological analysis of liver for all treated mice showed difference from the control group. The dibutyl phthalate was further evaluated for the toxicity study through in silico analysis. Together, the results highlighted that the toxic potential of R. cordifolia fruits extracts and also the toxicity profile of the fruit should be essential for the future studies dealing with the long term effect in animals. (c) 2015 Wiley Periodicals, Inc. Environ Toxicol 31: 1059-1067, 2016. PMID- 25926098 TI - Enteric neural differentiation in innervated, physiologically functional, smooth muscle constructs is modulated by bone morphogenic protein 2 secreted by sphincteric smooth muscle cells. AB - The enteric nervous system (ENS) controls gastrointestinal (GI) functions, including motility and digestion, which are impaired in ENS disorders. Differentiation of enteric neurons is mediated by factors released by the gut mesenchyme, including smooth muscle cells (SMCs). SMC-derived factors involved in adult enteric neural progenitor cells (NPCs) differentiation remain elusive. Furthermore, physiologically relevant in vitro models to investigate the innervations of various regions of the gut, such as the pylorus and lower oesophageal sphincter (LES), are not available. Here, neural differentiation in bioengineered innervated circular constructs composed of SMCs isolated from the internal anal sphincter (IAS), pylorus, LES and colon of rabbits was investigated. Additionally, SMC-derived factors that induce neural differentiation were identified to optimize bioengineered construct innervations. Sphincteric and non-sphincteric bioengineered constructs aligned circumferentially and SMCs maintained contractile phenotypes. Sphincteric constructs generated spontaneous basal tones. Higher levels of excitatory and inhibitory motor neuron differentiation and secretion of bone morphogenic protein 2 (BMP2) were observed in bioengineered, innervated, sphincteric constructs compared to non-sphincteric constructs. The addition of BMP2 to non-sphincteric colonic SMC constructs increased nitrergic innervations, and inhibition of BMP2 with noggin in sphincteric constructs decreased functional relaxation. These studies provide: (a) the first bioengineered innervated pylorus and LES constructs; (b) physiologically relevant models to investigate SMCs and adult NPCs interactions; and (c) evidence of the region-specific effects of SMCs on neural differentiation mediated by BMP2. Furthermore, this study paves the way for the development of innervated bioengineered GI tissue constructs tailored to specific disorders and locations within the gut. Copyright (c) 2015 John Wiley & Sons, Ltd. PMID- 25926099 TI - Assessment of Tamsulosin 0.2 mg for Symptomatic Bladder Outlet Obstruction Secondary to Benign Prostatic Enlargement: Data from a Korean Multicenter Cross Sectional Study. AB - AIMS: To estimate efficacy and treatment satisfaction with tamsulosin 0.2 mg in patients with symptomatic bladder outlet obstruction secondary to benign prostatic enlargement and lower urinary tract symptoms in relation to personal satisfaction. METHODS: The study was conducted in 1,260 subjects who were asked to fill in detailed questionnaires designed to evaluate their satisfaction with the treatment and symptom improvement 8 weeks after receiving tamsulosin 0.2 mg. RESULTS: After being treated with tamsulosin 0.2 mg for 8 weeks, the International Prostate Symptom Score (IPSS) score improved significantly. Among the 1,260 patients, 813 (64.52%) were satisfied, while 447 (35.48%) were dissatisfied with tamsulosin 0.2 mg. The reasons for patient dissatisfaction were efficacy problems (79.87%) and side effects (4.25%). Treatment satisfaction was affected by age, underlying medical disease and baseline IPSS severity (p = 0.020, 0.0427 and <0.001, respectively), but only age and baseline IPSS were risk factors for dissatisfaction. CONCLUSIONS: Tamsulosin 0.2 mg was effective in symptomatic improvement, but a relatively high proportion of patients were dissatisfied with the treatment. Efficacy problems were selected by patients as the main reason for dissatisfaction. It is also significant to note that the degree of satisfaction was related to age and baseline IPSS severity. PMID- 25926100 TI - How the [NiFe4S4] Cluster of CO Dehydrogenase Activates CO2 and NCO(-). AB - Ni,Fe-containing CO dehydrogenases (CODHs) use a [NiFe4S4] cluster, termed cluster C, to reversibly reduce CO2 to CO with high turnover number. Binding to Ni and Fe activates CO2, but current crystal structures have insufficient resolution to analyze the geometry of bound CO2 and reveal the extent and nature of its activation. The crystal structures of CODH in complex with CO2 and the isoelectronic inhibitor NCO(-) are reported at true atomic resolution (dmin <=1.1 A). Like CO2, NCO(-) is a MU2,eta(2) ligand of the cluster and acts as a mechanism-based inhibitor. While bound CO2 has the geometry of a carboxylate group, NCO(-) is transformed into a carbamoyl group, thus indicating that both molecules undergo a formal two-electron reduction after binding and are stabilized by substantial pi backbonding. The structures reveal the combination of stable MU2,eta(2) coordination by Ni and Fe2 with reductive activation as the basis for both the turnover of CO2 and inhibition by NCO(-). PMID- 25926102 TI - Conceptual framework of a simplified multi-dimensional model presenting the environmental and personal determinants of cardiometabolic risk behaviors in childhood. AB - Clinical manifestations of cardiometabolic risk (CMR) may be set early in childhood due to unfavorable behaviors or lifestyle patterns related to diet and physical activity. Several factors may determine the adoption of such lifestyle related behaviors, which researchers have tried to cluster under certain frameworks or models. In this context, the framework developed and proposed by this review gathers all the present knowledge regarding these determining factors to date and groups them into three main categories related to personal characteristics and the social and physical environment. Based on the proposed framework, a large variety of personal, social and physical environmental factors can positively or negatively influence CMR-related behaviors (either directly or indirectly via their interrelations), thus leading to decreased or increased risk, respectively. This framework could be of great value to public health policy makers and legislators for designing and implementing interventional programs tailored to the needs of susceptible population groups who are most in need for such initiatives. Targeting the correlates as potential determinants of CMR-related behaviors, and not just on the behaviors themselves, has been shown previously to be the most effective approach for tackling health issues related to CMR starting from early life stages. PMID- 25926101 TI - Differential beta3 Integrin Expression Regulates the Response of Human Lung and Cardiac Fibroblasts to Extracellular Matrix and Its Components. AB - Extracellular matrix (ECM) derived from whole organ decellularization has been successfully used in a variety of tissue engineering applications. ECM contains a complex mixture of functional and structural molecules that are ideally suited for the tissue from which the ECM is harvested. However, decellularization disrupts the structural properties and protein composition of the ECM, which may impact function when cells such as the fibroblast are reintroduced during recellularization. We hypothesized that the ECM structure and composition, fibroblast source, and integrin expression would influence the fibroblast phenotype. Human cardiac fibroblasts (HCFs) and normal human lung fibroblasts (NHLFs) were cultured on intact cardiac ECM, collagen gels, and coatings composed of cardiac ECM, lung ECM, and individual ECM components (collagen and fibronectin [FN]) for 48 h. COL1A expression of HCFs and NHLFs cultured on ECM and FN coatings decreased to <50% of that of untreated cells; COL1A expression for HCFs cultured on ECM coatings was one- to twofold higher than HCFs cultured on intact ECM. NHLFs cultured on ECM and FN coatings expressed 12- to 31-fold more alpha smooth muscle actin (alphaSMA) than HCFs; the alphaSMA expression for HCFs and NHLFs cultured on ECM coatings was ~2- to 5-fold higher than HCFs and NHLFs cultured on intact ECM. HCFs expressed significantly higher levels of beta3 and beta4 integrins when compared to NHLFs. Inhibition of the beta3 integrin, but not beta4, resulted in a 16- to 26-fold increase in alphaSMA expression in HCFs cultured on ECM coatings and FN. Our results demonstrate that beta3 integrin expression depends on the source of the fibroblast and that its expression inhibits alphaSMA expression (and thus the myofibroblast phenotype). We conclude that the fibroblast source and integrin expression play important roles in regulating the fibroblast phenotype. PMID- 25926103 TI - Predictive Markers of Tubo-Ovarian Abscess in Pelvic Inflammatory Disease. AB - BACKGROUND/AIMS: The purpose of this study was to identify predictive markers for tubo-ovarian abscess (TOA) through a comparison of clinical and laboratory data in patients diagnosed with pelvic inflammatory disease (PID). METHODS: We reviewed the medical charts of 499 females who were admitted to hospital with clinical, surgical, imaging-based diagnoses of PID between 2001 and 2011. The patients were divided into the following two groups: (1) PID with TOA and (2) PID without TOA. RESULTS: The TOA and non-TOA groups were comprised of 69 and 430 females, respectively. Mean age, history of intrauterine device (IUD) insertion and inflammatory markers, including erythrocyte sedimentation rate, C-reactive protein (CRP) and CA-125 levels, were higher in the TOA group than the non-TOA group. Independent factors that predicted TOA were older age, IUD insertion, increased CRP and CA-125, and chlamydia infection. CA-125 was found to have the highest predictive value for TOA. TOA size was associated with increased surgical therapy compared to patients with smaller abscesses. CONCLUSIONS: Increased age, IUD insertion, chlamydia infection, and increased CRP and CA-125 level were the independent factors predictive of TOA in acute PID. These predictive values will be expected to help decrease gynecological morbidity by early diagnosis and appropriate treatment of TOA. (c) 2015 S. Karger AG, Basel. PMID- 25926104 TI - Structural and solubility parameter correlations of gelation abilities for dihydroxylated derivatives of long-chain, naturally occurring fatty acids. AB - Creating structure-property correlations at different distance scales is one of the important challenges to the rational design of molecular gelators. Here, a series of dihydroxylated derivatives of long-chain fatty acids, derived from three naturally occurring molecules-oleic, erucic and ricinoleic acids-are investigated as gelators of a wide variety of liquids. Conclusions about what constitutes a more (or less!) efficient gelator are based upon analyses of a variety of thermal, structural, molecular modeling, and rheological results. Correlations between the manner of molecular packing in the neat solid or gel states of the gelators and Hansen solubility data from the liquids leads to the conclusion that diol stereochemistry, the number of carbon atoms separating the two hydroxyl groups, and the length of the alkanoic chains are the most important structural parameters controlling efficiency of gel formation for these gelators. Some of the diol gelators are as efficient or even more efficient than the well known, excellent gelator, (R)-12-hydroxystearic acid; others are much worse. The ability to form extensive intermolecular H-bonding networks along the alkyl chains appears to play a key role in promoting fiber growth and, thus, gelation. In toto, the results demonstrate how the efficiency of gelation can be modulated by very small structural changes and also suggest how other structural modifications may be exploited to create efficient gelators. PMID- 25926106 TI - Collaboration and learning. PMID- 25926105 TI - Down-regulation of NF kappa B activation is an effective therapeutic modality in acquired platinum-resistant bladder cancer. AB - BACKGROUND: No previous study has addressed the efficacy of NF-kappaB blockade when bladder tumors develop acquired resistance toward CDDP-treatments. We investigated the changes in NF-kappaB activation and therapeutic impact of NF kappaB blockade by the novel NF-kappaB inhibitor dehydroxymethyl derivative of epoxyquinomicin (DHMEQ) in CDDP-resistant bladder cancer cells. METHODS: Two human invasive bladder cancer cell lines, T24 and T24PR, were used. The T24PR cell line was newly established as an acquired platinum-resistant subline by culturing in CDDP-containing medium for 6 months. Expression of intranuclear p65 protein in the fractionated two cell lines was determined by Western blotting analysis. DNA-binding activity of NF-kappaB was detected by electrophoretic mobility shift assay. The cytotoxic effects and induction of apoptosis were analyzed in vivo and in vitro. RESULTS: Intranuclear expression and DNA-binding activity of p65 were strongly enhanced in T24PR cells compared with those of T24 cells, and both were significantly suppressed by DHMEQ. Lowered cell viability and strong induction of apoptosis were observed by treatment with DHMEQ alone in these chemo-resistant cells compared with parent cells. As T24PR cells did not show dramatic cross-resistance to paclitaxel in the in vitro study, we next examined whether the combination of DHMEQ with paclitaxel could enhance the therapeutic effect of the paclitaxel treatment in T24PR tumors. Using mouse xenograft models, the mean volume of tumors treated with the combination of DHMEQ (2 mg/kg) and paclitaxel (10 mg/kg) was significantly smaller than those treated with paclitaxel alone (p < 0.05), and the reduction of tumor volume in mice treated with DHMEQ in combination with paclitaxel and paclitaxel alone as compared to vehicle control was 66.9% and 17.0%, respectively. CONCLUSION: There was a distinct change in the activation level of NF-kappaB between T24 and T24PR cells, suggesting strong nuclear localization of NF-kappaB could be a promising target after developing acquired platinum-resistance in bladder cancer. PMID- 25926107 TI - The challenge of new directions. PMID- 25926108 TI - Toll-like receptor 3 (TLR3) and the development of type 1 diabetes mellitus. AB - Type 1 diabetes mellitus (T1DM) is a chronic, progressive autoimmune disease characterized by metabolic decompensation often leading to dehydration and ketoacidosis. Viral agents seem to play an important role in triggering the autoimmune destruction that leads to the development of T1DM. Among several viral strains investigated so far, the enterovirus family has been consistently associated with the onset of T1DM in humans. One of the mediators of viral damage is the double-stranded RNA (dsRNA) generated during replication and transcription of viral RNA and DNA. The Toll-like receptor 3 (TLR3) gene codes for an endoplasmic receptor of the pattern-recognition receptors (PRRs) family that recognizes dsRNA, plays an important role in the innate immune response triggered by viral infection. Binding of dsRNA to the TLR3 triggers the release of proinflammatory cytokines, such as interferons, which exhibit potent antiviral action; thus, protecting uninfected cells and inducing apoptosis of infected ones. Therefore, the TLR3 gene is a good candidate for the development of T1DM. Within this context, the objective of the present review was to address the role of the TLR3 gene in the development of T1DM. PMID- 25926110 TI - Evaluation of diabetic patients after three month use of continuous subcutaneous insulin infusion, dispensed by a protocolled form at outpatient reference clinic of Taguatinga Regional Hospital. AB - OBJECTIVE: To evaluate the data of continuous subcutaneous insulin infusion protocol (CSII) for diabetics waived by the Health State Secretariat of Distrito Federal (HSSDF) and therapeutic responses three months after the transfer of multiple daily injections regimen for CSII. SUBJECTS AND METHODS: Eighty patients (49 female) took part in this experimental study, mean age and disease duration were 27.9 years and 13 years, respectively; 96% patients had type 1 diabetes mellitus. RESULTS: The entire sample (ECO) and 3 subgroups (group 1 - A1c decrease, group 2 - A1c stable, and group 3 - A1c increase), stratified according to a >= 0.5% change in A1c, were analyzed. Group 1 involved 64% of the patients. The ECO showed a significant A1c decrease: MDI 8.1 +/- 1.4% vs. CSII 7.3 +/- 0.9%, p < 0.0001 (0.8% difference pro CSII therapy). Group 1 demonstrated an A1c decrease from 8.7% to 7.3% (1.4% difference). Group 2 mean A1c was 7.1%. Rate of hypoglycemia (< 50 mg/dL) decreased 61% in the ECO and 79% in Group 2. CONCLUSION: This study reinforces the safety and efficacy of CSII with a robust A1c reduction and hypoglycemia. The pioneer care HSSDF ambulatory attests to be achievable the free dispensing by Unified Health System (UHS) following a protocol, and this approach results in less wastage to the patient and represents a rational policy of therapy with CSII for UHS. PMID- 25926109 TI - Iodine nutritional status in Brazil: a meta-analysis of all studies performed in the country pinpoints to an insufficient evaluation and heterogeneity. AB - OBJECTIVES: Iodine deficiency disorder (IDD) is the result of an inadequate dietary intake of iodine, which physiological consequences are endemic goiter and thyroid dysfunction. The objective of this study was to a analyze studies that assessed the status of Brazil's population iodine nutrition and IDD prevalence. MATERIALS AND METHODS: Systematic review using PRISMA statement. Electronic database: PubMed, Medline, SciELO and Lilacs. Quality of studies: Newcastle Ottawa Scale. Meta-analysis was carried out with R Core Team Statistical Software, version 3.1.0 (2014). The summary measure (WMD) and its confidence interval (CI) of 95% were calculated. The "Funnel plot" graph assessed publication bias and heterogeneity. RESULTS: Seventeen papers were eligible: pregnant women (2), school children (9), adults/elderly (4) and preschool children/infants (2). Geographic distribution: North (1), Northeast (1), Midwest (2), Southeast (13), South (3). Twenty-three thousand two hundred seventy-two subjects were evaluated between 1997 and 2013 and all have use urinary iodine (UI) measurement. However, only 7 studies could be included in meta-analysis, all from Southeast region. The overall prevalence of IDD in school children in southeast region was 15.3% (95% CI, 13-35%), however this data had an important heterogeneity, expressed by the I2 Statistic of 99.5%. CONCLUSION: Only few studies have been performed and enrolled populations from south/southeast region of Brazil. The actual IDD prevalence analysis is complex because it was detected bias due influence of individual studies and very high heterogeneity. IDD might still be high in some areas but this remained unknown even after this meta analysis evaluation. The generation of a national program for analysis of iodine status in all regions is urgently required. PMID- 25926111 TI - The rs10885122 polymorphism of the adrenoceptor alpha 2A (ADRA2A) gene in Euro Brazilians with type 2 diabetes mellitus. AB - OBJECTIVE: To investigate the association of the rs10885122G>T polymorphism in the ADRA2A gene in a Euro-Brazilian sample of healthy (controls) and type 2 diabetic (T2D) subjects. SUBJECTS AND METHODS: We used fluorescent probes (TaqMan) to genotype 241 subjects, that is, 121 healthy and 120 T2D subjects, who were classified based on the Brazilian Diabetes Association (2013) and American Diabetes Association (2014) criteria. RESULTS: The genotype and allele frequencies showed no significant (P > 0.05) difference between the two studied groups. The minor allele (T) frequencies (95%CI) for rs10885122 were 19% (14-24%) and 20% (15-26%) for healthy and T2D groups, respectively. Carriers of the T allele (genotypes GT+TT) were significantly associated (P = 0.016) with approximately a 7-kg body weight reduction compared with the genotype GG, which was only found in the T2D group. CONCLUSION: The rs10885122G>T polymorphism of the ADRA2A gene was not associated with T2D in Euro-Brazilians, and carriers of the T allele had lower body weight in the presence of T2D. PMID- 25926112 TI - Risk factors associated with hypovitaminosis D in HIV/aids-infected adults. AB - OBJECTIVE: To investigate risk factors associated with hypovitaminosis D in adult patients infected with HIV/aids, at a referral hospital in Maceio, Brazil. SUBJECTS AND METHODS: This cross-sectional study involved 125 patients evaluated from April to September 2013 by means of interviews, review of medical records, physical examination, and laboratory tests. The data were analyzed using the SPSS(r) software, version 17.0; the prevalence of hypovitaminosis D and mean levels of vitamin D were determined. The association between hypovitaminosis D and the independent variables was assessed using the Chi-square or the Fisher's exact tests; mean vitamin D concentrations were analyzed using Kolmogorov Smirnov, Mann-Whitney, and Kruskal-Wallis tests. The level of significance was set at 5% across tests. RESULTS: The prevalence of hypovitaminosis D was 24%, with a significant association with higher household income (p < 0.05). Higher vitamin D levels were associated with female gender (p < 0.001), no use of sunscreen (p < 0.05), and previous opportunistic infections (p < 0.01). Lower values were associated with the use of antiretroviral medication (p < 0.05), overweight and obesity (p < 0.01). CONCLUSION: Lower vitamin D concentrations were significantly associated with well-known risk factors for hypovitaminosis D: use of sunscreen, antiretroviral medication, overweight, and obesity. The prevalence of hypovitaminosis D in this study, considering values > 20 ng/mL or > 30 ng/mL as vitamin D sufficiency, was lower to that of previous studies with HIV infected patients, a fact that might be related to the low latitude and high intensity of solar radiation of the location of the present study. PMID- 25926113 TI - The association of autoimmune thyroiditis and non-functional adrenal incidentalomas with insulin resistance. AB - OBJECTIVE: Patients with incidental nonfunctioning adrenal adenoma are associated with increased risk of obesity, impaired glucose tolerance and dyslipidemia. We aimed to investigate the relationship between thyroid function, serum lipids and insulin resistance in patients with nonfunctioning adrenal incidentaloma. SUBJECTS AND METHODS: Forty patients who had diagnosed as adrenal incidentaloma (AI) in our department were included in the study. Serum free triiodothyronine (fT3), free thyroxine (fT4), thyroid stimulating hormone (TSH), anti thyroperoxidase antibody (anti-TPO Ab) and anti-thyroglobulin antibody (anti-Tg Ab), lipid profile, hs-CRP, fasting insulin levels were measured and insulin resistance calculated by HOMA-IR. Thyroid volume (TV) was assessed. RESULTS: None of the patients showed specific signs and symptoms of hormone excess. TV, TSH and fT3 levels in the patient and control groups did not differ significantly (p > 0.05). The serum fT4, anti-TG Ab, anti-TPO Ab levels in the patient group were significantly higher than in the control group (p = 0.013, p < 0.0001, p = 0.016 respectively). The HOMA-IR, hs-CRP and HDL cholesterol levels in the AI patients were significantly higher than the control group (p = 0.034, p = 0.041, p = 0.002, respectively). Statistically significant relationship was found between HOMA-IR and thyroid volume (r = 0.373, p = 0.018), fT4 (r = 0.382, p = 0.015), hs CRP (r = 0.512, p = 0.001), HDL cholesterol (r = 0,351 p = 0.026) in AI patients. There were significant correlation between anti-TG Ab, anti-TPO Ab and TSH levels in AI patients (r = 0.431 p = 0.006, r = 0.402 p = 0.012). CONCLUSIONS: Patients with nonfunctioning adrenal incidentaloma have several metabolic disturbances. At the same time autoimmune thyroid disorders are more frequent in nonfunctioning adrenal incidentaloma patient so that thyroid functions must be evaluated in those patients. PMID- 25926114 TI - Propentofylline reverses delayed remyelination in streptozotocin-induced diabetic rats. AB - OBJECTIVE: The diabetic state induced by streptozotocin injection is known to impair oligodendroglial remyelination in the rat brainstem following intracisternal injection with the gliotoxic agent ethidium bromide (EB). In such experimental model, propentofylline (PPF) recently showed to improve myelin repair, probably due to its neuroprotective, antiinflammatory and antioxidant effects. The aim of this study was to evaluate the effect of PPF administration in diabetic rats submitted to the EB-demyelinating model. MATERIALS AND METHODS: Adult male rats, diabetic or not, received a single injection of 10 microlitres of 0.1% EB solution into the cisterna pontis. For induction of diabetes mellitus the streptozotocin-diabetogenic model was used (50 mg/kg, intraperitoneal route - IP). Some diabetic rats were treated with PPF (12.5 mg/kg/day, IP route) during the experimental period. The animals were anesthetized and perfused from 7 to 31 days after EB injection and brainstem sections were collected for analysis of the lesions by light and transmission electron microscopy. RESULTS: Diabetic rats injected with EB showed larger amounts of myelin-derived membranes in the central areas of the lesions and considerable delay in the remyelinating process played by surviving oligodendrocytes and invading Schwann cells after the 15th day. On the other hand, diabetic rats that received PPF presented lesions similar to those of non-diabetic animals, with rapid remyelination at the edges of the lesion site and fast clearance of myelin debris from the central area. CONCLUSION: The administration of PPF apparently reversed the impairment in remyelination induced by the diabetic state. PMID- 25926115 TI - Laboratory investigation of acromegaly: is basal or random GH > 0.4 ug/L in the presence of normal serum IGF-1 an important result? AB - OBJECTIVE: To determine the frequency of indication of the GH suppression test and pituitary magnetic resonance imaging (MRI) in patients with clinical suspicion of acromegaly with GH concentrations > 0.4 ug/L despite normal serum IGF-1. SUBJECTS AND METHODS: A total of 160 patients with clinical suspicion of acromegaly with normal IGF-1 were studied. RESULTS: Basal GH > 0.4 ug/L was observed in 70/88 women (79.5%). Nadir GH > 0.4 ug/L was found in 21/70 women (30%) and these patients were submitted to MRI, which revealed a microadenoma in 2/21 women (9.5%). In these two women, IGF-1 continued to be normal in subsequent measurements and no clinical progression has been observed so far (time of follow up until now 4 years). Basal GH > 0.4 ug/L was seen in 33/72 men (45.8%). Nadir GH was < 0.4 ug/L in all of them. CONCLUSIONS: In patients with clinical suspicion of acromegaly, concern over GH concentration in the presence of normal IGF-1 results in the unwarranted complementary investigation in many cases, and even in possible equivocal diagnoses. It is only in exceptional cases that normal IGF-1 should not rule out acromegaly. PMID- 25926116 TI - Relationship between pre-sarcopenia, sarcopenia and bone mineral density in elderly men. AB - OBJECTIVE: Analyze the influence of sarcopenia in bone health of elderly men. SUBJECTS AND METHODS: This cross-sectional study evaluated 198 men aged over 60 years. Body composition was measured by dual energy X-ray absorptiometry. The BMD was measured at the femoral neck, total hip, lumbar spine and 33% radius. The diagnosis of abnormal BMD was defined for men who presented densitometric diagnosis of osteopenia or osteoporosis defined by T-score of femoral neck, total hip and lumbar spine. The pre-sarcopenia and sarcopenia were defined according to the European Working Group on Sarcopenia in Older People. RESULTS: The group diagnosed with normal BMD, compared to the group of abnormal BMD, have significantly higher body weight, body mass index, grip strength, lean mass, fat mass, and relative appendicular skeletal muscle mass (RASM). However, after multiple linear regression analysis, we found that only the RASM, lean mass, and handgrip strength in the dominant hand influenced the variability of the BMD after adjustment for age and weight. Regression analyzes showed a positive association between greater appendicular lean mass and a smaller number of elderly patients with abnormal BMD diagnostic. The regression analyzes showed that elderly men diagnosed with pre-sarcopenia and sarcopenia had more abnormal BMD than non-sarcopenic elderly men. CONCLUSION: We concluded that pre-sarcopenia and sarcopenia were associated with abnormal BMD. The lean mass, compared to fat mass, has a greater positive influence on the BMD of elderly men. This result suggests the importance of the increase in lean mass for the bone health of elderly men. PMID- 25926117 TI - Melatonin prevents hyperglycemia in a model of sleep apnea. AB - OBJECTIVE: Obstructive sleep apnea is a common disorder associated with aging and obesity. Apneas cause repeated arousals, intermittent hypoxia, and oxidative stress. Changes in glucolipidic profile occur in apnea patients, independently of obesity. Animal models of sleep apnea induce hyperglycemia. This study aims to evaluate the effect of the antioxidants melatonin and N-acetylcysteine on glucose, triglyceride, and cholesterol levels in animals exposed to intermittent hypoxia. MATERIALS AND METHODS: Two groups of Balb/c mice were exposed to intermittent hypoxia (n = 36) or sham intermittent hypoxia (n = 36) for 35 days. The intermittent hypoxia group underwent a total of 480 cycles of 30 seconds reducing the inspired oxygen fraction from 21% to 7 +/- 1% followed by 30 seconds of normoxia, during 8 hours daily. Melatonin or N-acetylcysteine were injected intraperitonially daily from day 21 on. RESULTS: At day 35, glucose levels were significantly higher in the intermittent hypoxia group than in the control group. The intermittent hypoxia groups receiving N-acetylcysteine and vehicle showed higher glucose levels than the group receiving melatonin. The lipid profile was not affected by intermittent hypoxia or antioxidant administration. CONCLUSIONS: The present results suggest that melatonin prevents the well-recognized increase in glucose levels that usually follows exposure to intermittent hypoxia. Further exploration of the role of melatonin in sleep apnea is warranted. PMID- 25926118 TI - Sleep and glycemic control in type 1 diabetes. AB - OBJECTIVE: Our aim in the present study was to elucidate how type 1 diabetes mellitus (T1DM) and sleep parameters interact, which was rarely evaluated up to the moment. MATERIALS AND METHODS: Eighteen T1DM subjects without chronic complications, and 9 control subjects, matched for age and BMI, were studied. The following instruments used to evaluate sleep: the Epworth Sleepiness Scale, sleep diaries, actimeters, and polysomnography in a Sleep Lab. Glycemic control in T1DM individuals was evaluated through: A1C, home fingertip glucometer for 10 days (concomitant with the sleep diary and actimeter), and CGM or concomitant with continuous glucose monitoring (during the polysomnography night). RESULTS: Comparing with the control group, individuals with diabetes presented more pronounced sleep extension from weekdays to weekends than control subjects (p = 0.0303). Among T1DM, glycemic variability (SD) was positively correlated with sleep latency (r = 0.6525, p = 0.0033); full awakening index and arousal index were positively correlated with A1C (r = 0.6544, p = 0.0081; and r = 0.5680, p = 0.0272, respectively); and mean glycemia values were negatively correlated with sleep quality in T1DM individuals with better glycemic control (mean glycemia < 154 mg/dL). CONCLUSION: Our results support the hypothesis of an interaction between sleep parameters and T1DM, where the glycemic control plays an important role. More studies are needed to unveil the mechanisms behind this interaction, which may allow, in the future, clinicians and educators to consider sleep in the effort of regulating glycemic control. PMID- 25926119 TI - Is Doppler ultrasound of additional value to gray-scale ultrasound in differentiating malignant and benign thyroid nodules? AB - The objective of this study was to evaluate whether Doppler ultrasound (DUS) is of additional value to gray-scale ultrasound (GSUS) in predicting the benign or malignant nature of thyroid nodules. A total of 1,502 solid thyroid nodules >= 10 mm were evaluated. Suspicious vascularity (predominantly or exclusively central blood flow) was observed in only 5% of the nodules. This finding showed 96% specificity, but only 15% sensitivity. GSUS alone showed sensitivity and specificity of 88.7% and 68.2%, respectively, which did not improve with the addition of DUS (sensitivity of 89.4% and specificity of 66.4%). In non suspicious nodules on GSUS, the type of vascularity on DUS did not modify the risk of malignancy, which was low. In suspicious nodules on GSUS, suspicious vascularity on DUS increased the risk of malignancy, but non-suspicious vascularity did not reduce this risk. DUS provided no additional value to GSUS in predicting the benign or malignant nature of thyroid nodules. PMID- 25926120 TI - Association of primary hyperparathyroidism and humoral hypercalcemia of malignancy in a patient with clear cell renal carcinoma. AB - Hypercalcemia is found frequently in patients with cancer. Besides the etiology related to the malignancy, other causes should be considered in the differential diagnostic, as primary hyperparathyroidism, granulomatous diseases and the use of thiazide diuretics. We present a case report of a severe hypercalcemia due to a rare association and review the relevant literature. A female patient, 57 years old, sent to the Endocrinology Service of Hospital das Clinicas da Universidade do Parana (SEMPR) in order to investigate severe hypercalcemia with frequent need of hospitalization. The patient was in chemotherapy treatment for recurrence of clear cell renal cancer. During the investigation she presented high level of parathyroid hormone (PTH) and parathyroid scintigraphy suggestive of hyperplasia/ adenoma of parathyroid, histopathological diagnosis was confirmed after parathyroidectomy. After surgery the patient presented undetectable levels of PTH. However, she continued with progressive increase of serum calcium, with no signs of bone metastases or change in vitamin D metabolism. The investigation showed high levels of PTH-related protein (PTHrP), leading us to the diagnosis of hypercalcemia of malignancy. The patient presented severe hypercalcemia due to the rare association of primary hyperparathyroidism and humoral hypercalcemia of malignancy due to secretion of PTHrP by tumor cells. The presence of isolated primary hyperparathyroidism, as a cause of hypercalcemia in cancer patients, has been described in approximately 5-10% of the patients. However, the association of primary hyperparathyroidism and humoral hypercalcemia of malignancy (which means with concomitant elevation of PTH and PTHrP) is rare, only three cases have been described in the literature. PMID- 25926121 TI - Accelerated fracture healing with teriparatide. PMID- 25926122 TI - SNES makes sense? Single-cell exome sequencing evolves. AB - Technologies for single-cell sequencing are improving steadily. A recent study describes a new method for interrogating all coding sequences of the human genome at single-cell resolution. PMID- 25926123 TI - The association of long-term exposure to PM2.5 on all-cause mortality in the Nurses' Health Study and the impact of measurement-error correction. AB - BACKGROUND: Long-term exposure to particulate matter less than 2.5 MUm in diameter (PM2.5) has been consistently associated with risk of all-cause mortality. The methods used to assess exposure, such as area averages, nearest monitor values, land use regressions, and spatio-temporal models in these studies are subject to measurement error. However, to date, no study has attempted to incorporate adjustment for measurement error into a long-term study of the effects of air pollution on mortality. METHODS: We followed 108,767 members of the Nurses' Health Study (NHS) 2000-2006 and identified all deaths. Biennial mailed questionnaires provided a detailed residential address history and updated information on potential confounders. Time-varying average PM2.5 in the previous 12-months was assigned based on residential address and was predicted from either spatio-temporal prediction models or as concentrations measured at the nearest USEPA monitor. Information on the relationships of personal exposure to PM2.5 of ambient origin with spatio-temporal predicted and nearest monitor PM2.5 was available from five previous validation studies. Time-varying Cox proportional hazards models were used to estimate hazard ratios (HRs) and 95 percent confidence intervals (95%CI) for each 10 MUg/m(3) increase in PM2.5. Risk-set regression calibration was used to adjust estimates for measurement error. RESULTS: Increasing exposure to PM2.5 was associated with an increased risk of mortality, and results were similar regardless of the method chosen for exposure assessment. Specifically, the multivariable adjusted HRs for each 10 MUg/m(3) increase in 12-month average PM2.5 from spatio-temporal prediction models were 1.13 (95%CI:1.05, 1.22) and 1.12 (95%CI:1.05, 1.21) for concentrations at the nearest EPA monitoring location. Adjustment for measurement error increased the magnitude of the HRs 4-10% and led to wider CIs (HR = 1.18; 95%CI: 1.02, 1.36 for each 10 MUg/m(3) increase in PM2.5 from the spatio-temporal models and HR = 1.22; 95%CI: 1.02, 1.45 from the nearest monitor estimates). CONCLUSIONS: These findings support the large body of literature on the adverse effects of PM2.5, and suggest that adjustment for measurement error be considered in future studies where possible. PMID- 25926124 TI - Ameloblastoma: a clinical review and trends in management. AB - Ameloblastoma is a rare odontogenic neoplasm of the mandible and maxilla, with multiple histologic variants, and high recurrence rates if improperly treated. The current mainstay of treatment is wide local excision with appropriate margins and immediate reconstruction. Here we review the ameloblastoma literature, using the available evidence to highlight the change in management over the past several decades. In addition, we explore the recent molecular characterization of these tumors which may point towards new potential avenues of personalized treatment. PMID- 25926125 TI - Membrane Assays to Characterize Interaction of Drugs with ABCB1. AB - ATP-binding cassette sub-family B member 1 (ABCB1) [P-glycoprotein (P-gp), multidrug resistance protein 1 (MDR1)] can affect the pharmacokinetics, safety, and efficacy of drugs making it important to identify compounds that interact with ABCB1. The ATPase assay and vesicular transport (VT) assay are membrane based assays that can be used to measure the interaction of compounds with ABCB1 at a lower cost and higher throughput compared to cellular-based assays and therefore can be used earlier in the drug development process. To that end, we tested compounds previously identified as ABCB1 substrates and inhibitors for interaction with ABCB1 using the ATPase and VT assays. All compounds tested interacted with ABCB1 in both the ATPase and VT assays. All compounds previously identified as ABCB1 substrates activated ABCB1-mediated ATPase activity in the ATPase assay. All compounds previously identified as ABCB1 inhibitors inhibited the ABCB1-mediated transport in the VT assay. Interestingly, six of the ten compounds previously identified as ABCB1 inhibitors activated the basal ATPase activity in activation assays suggesting that the compounds are substrates of ABCB1 but can inhibit ABCB1 in inhibition assays. Importantly, for ATPase activators the EC50 of activation correlated with the IC50 values from the VT assay showing that interactions of compounds with ABCB1 can be measured with similar levels of potency in either assay. For ATPase nonactivators the IC50 values from the ATPase inhibition and VT inhibition assay showed correlation. These results demonstrate the utility of membrane assays as tools to detect and rank order drug-transporter interactions. PMID- 25926126 TI - Comparison of diffusion tensor imaging by cardiovascular magnetic resonance and gadolinium enhanced 3D image intensity approaches to investigation of structural anisotropy in explanted rat hearts. AB - BACKGROUND: Cardiovascular magnetic resonance (CMR) can through the two methods 3D FLASH and diffusion tensor imaging (DTI) give complementary information on the local orientations of cardiomyocytes and their laminar arrays. METHODS: Eight explanted rat hearts were perfused with Gd-DTPA contrast agent and fixative and imaged in a 9.4T magnet by two types of acquisition: 3D fast low angle shot (FLASH) imaging, voxels 50 * 50 * 50 MUm, and 3D spin echo DTI with monopolar diffusion gradients of 3.6 ms duration at 11.5 ms separation, voxels 200 * 200 * 200 MUm. The sensitivity of each approach to imaging parameters was explored. RESULTS: The FLASH data showed laminar alignments of voxels with high signal, in keeping with the presumed predominance of contrast in the interstices between sheetlets. It was analysed, using structure-tensor (ST) analysis, to determine the most (v1(ST)), intermediate (v2(ST)) and least (v3(ST)) extended orthogonal directions of signal continuity. The DTI data was analysed to determine the most (e1(DTI)), intermediate (e2(DTI)) and least (e3(DTI)) orthogonal eigenvectors of extent of diffusion. The correspondence between the FLASH and DTI methods was measured and appraised. The most extended direction of FLASH signal (v1(ST)) agreed well with that of diffusion (e1(DTI)) throughout the left ventricle (representative discrepancy in the septum of 13.3 +/- 6.7 degrees : median +/- absolute deviation) and both were in keeping with the expected local orientations of the long-axis of cardiomyocytes. However, the orientation of the least directions of FLASH signal continuity (v3(ST)) and diffusion (e3(ST)) showed greater discrepancies of up to 27.9 +/- 17.4 degrees . Both FLASH (v3(ST)) and DTI (e3(DTI)) where compared to directly measured laminar arrays in the FLASH images. For FLASH the discrepancy between the structure-tensor calculated v3(ST) and the directly measured FLASH laminar array normal was of 9 +/- 7 degrees for the lateral wall and 7 +/- 9 degrees for the septum (median +/- inter quartile range), and for DTI the discrepancy between the calculated v3(DTI) and the directly measured FLASH laminar array normal was 22 +/- 14 degrees and 61 +/- 53.4 degrees . DTI was relatively insensitive to the number of diffusion directions and to time up to 72 hours post fixation, but was moderately affected by b-value (which was scaled by modifying diffusion gradient pulse strength with fixed gradient pulse separation). Optimal DTI parameters were b = 1000 mm/s(2) and 12 diffusion directions. FLASH acquisitions were relatively insensitive to the image processing parameters explored. CONCLUSIONS: We show that ST analysis of FLASH is a useful and accurate tool in the measurement of cardiac microstructure. While both FLASH and the DTI approaches appear promising for mapping of the alignments of myocytes throughout myocardium, marked discrepancies between the cross myocyte anisotropies deduced from each method call for consideration of their respective limitations. PMID- 25926127 TI - Evaluating cognitive and motivational accounts of greater reinforcement effects among children with attention-deficit/hyperactivity disorder. AB - BACKGROUND: Attention Deficit/Hyperactivity Disorder is associated with cognitive deficits and dysregulated motivation. Reinforcement improves cognitive performance, often to a greater degree among children with ADHD compared to typically-developing controls. The current study tests the degree to which cognitive (individual differences in baseline cognition) and/or motivational (individual differences in Sensitivity to Reward; SR) processes can account for diagnostic group differences in reinforcement effects. METHODS: Participants were 58 children (25 ADHD, 33 control) ages 9-12. Children completed measures of inhibitory control (Stop Signal Task), working memory (n-back), and sustained attention (Continuous Performance Task) during a baseline week and again one week later under reinforcement and no-reinforcement conditions; composites were computed across cognitive domains. Parent-and child-reported trait SR (SPSRQ; BIS/BAS) were combined to index a child's response towards appetitive, rewarding stimuli. RESULTS: In separate analyses, diagnostic group, individual differences in baseline cognition, and individual differences in SR all moderated the impact of reinforcement on cognition. When considered together, the Diagnostic Group * Reinforcement and Baseline Cognition * Reinforcement interactions both remained robust. In contrast, neither the Diagnostic Group * Reinforcement nor the SR * Reinforcement interactions accounted for unique variance when evaluated together. CONCLUSIONS: Both baseline cognition and trait SR predict reinforcement effects on cognition, but only SR shares significant variance with diagnostic group. These results suggest that ADHD children's greater response to reinforcement on cognition is strongly related to their heightened trait sensitivity to rewarding stimuli, consistent with motivational models of ADHD. PMID- 25926128 TI - Cytoprotection of human endothelial cells from oxidant stress with CDDO derivatives: network analysis of genes responsible for cytoprotection. AB - AIM: To identify drugs that may reduce the impact of oxidant stress on cell viability. METHODS: Human umbilical vein endothelial cells were treated with 200 nmol/l CDDO-Im (imidazole) and CDDO-Me (methyl) after exposure to menadione and compared to vehicle-treated cells. Cell viability and cytotoxicity were assessed, and gene expression profiling was performed. RESULTS: CDDO-Im was significantly more cytoprotective and less cytotoxic (p < 0.001) than CDDO-Me. Although both provided cytoprotection by induction of gene transcription, CDDO-Im induced more genes. In addition to a higher induction of the key cytoprotective gene heme oxygenase-1 (38.9-fold increase for CDDO-Im and 26.5-fold increase for CDDO-Me), CDDO-Im also induced greater expression of heat shock proteins (5.5-fold increase compared to 2.8-fold for CDDO-Me). CONCLUSIONS: Both compounds showed good induction of heme oxygenase, which largely accounted for their cytoprotective effect. Differences were detected in cytotoxicity at higher doses, indicating that CDDO-Me was more cytotoxic than CDDO-Im. Significant differences were detected in the ability of CDDO-Im and CDDO-Me to affect differential gene transcription. CDDO-Im induced more genes than did CDDO-Me. The source of the differences in gene expression patterns between CDDO-Im and CDDO-Me was not determined but may be important in long-term use of this class of drugs. PMID- 25926129 TI - Urine and plasma osmolality in patients with autosomal dominant polycystic kidney disease: reliable indicators of vasopressin activity and disease prognosis? AB - BACKGROUND: Vasopressin plays an essential role in osmoregulation, but has deleterious effects in patients with ADPKD. Increased water intake to suppress vasopressin activity has been suggested as a potential renoprotective strategy. This study investigated whether urine and plasma osmolality can be used as reflection of vasopressin activity in ADPKD patients. METHODS: We measured urine and plasma osmolality, plasma copeptin concentration, total kidney volume (TKV, by MRI) and GFR ((125)I-iothalamate). In addition, change in estimated GFR (eGFR) during follow-up was assessed. RESULTS: Ninety-four patients with ADPKD were included (56 males, age 40 +/- 10, mGFR 77 +/- 32 ml/min/1.73 m(2), TKV 1.55 (0.99-2.40) l. Urine osmolality, plasma osmolality and copeptin concentration were 420 +/- 195, 289 +/- 7 mOsmol/l and 7.3 (3.2-14.6) pmol/l, respectively. Plasma osmolality was associated with copeptin concentration (R = 0.54, p < 0.001), whereas urine osmolality was not (p = 0.4). In addition, urine osmolality was not associated with TKV (p = 0.3), in contrast to plasma osmolality (R = 0.52, p < 0.001) and copeptin concentration (R = 0.61, p < 0.001). Fifty-five patients were followed for 2.8 +/- 0.8 years. Baseline plasma and urine osmolality were not associated with change in eGFR (p = 0.6 and p = 0.3, respectively), whereas baseline copeptin concentration did show an association with change in eGFR, in a crude analysis (St. beta = -0.41, p = 0.003) and also after adjustment for age, sex and TKV (St. beta = -0.23, p = 0.05). CONCLUSIONS: These data suggest that neither urine nor plasma osmolality are valid measures to identify ADPKD patients that may benefit from increasing water intake. Copeptin appears a better alternative for this purpose. PMID- 25926130 TI - A mechanistic model of tau amyloid aggregation based on direct observation of oligomers. AB - Protein aggregation plays a key role in neurodegenerative disease, giving rise to small oligomers that may become cytotoxic to cells. The fundamental microscopic reactions taking place during aggregation, and their rate constants, have been difficult to determine due to lack of suitable methods to identify and follow the low concentration of oligomers over time. Here we use single-molecule fluorescence to study the aggregation of the repeat domain of tau (K18), and two mutant forms linked with familial frontotemporal dementia, the deletion mutant DeltaK280 and the point mutant P301L. Our kinetic analysis reveals that aggregation proceeds via monomeric assembly into small oligomers, and a subsequent slow structural conversion step before fibril formation. Using this approach, we have been able to quantitatively determine how these mutations alter the aggregation energy landscape. PMID- 25926131 TI - Excellent response of intramedullary Erdheim-Chester disease to vemurafenib: a case report. AB - BACKGROUND: Erdheim-Chester disease is a rare histiocytosis characterized by multi-systemic organ involvement. Immune-modulating agents such as interferon alpha have limited success and the disorder is progressive and causes high morbidity and mortality. Treatment with the BRAF-inhibitor vemurafenib has recently produced substantial improvement in three patients with Erdheim-Chester disease expressing the p. V600E BRAF mutation. The disorder commonly affects the central nervous system and it is not yet known whether vemurafenib can reverse intra-axial infiltration and the resulting neurological impairment. CASE PRESENTATION: In this work, we report for the first time an excellent clinical response to vemurafenib in a Norwegian patient with debilitating progressive spastic paraparesis due to intra-axial infiltration of the thoracic spinal cord. The patient had been unresponsive to interferon-alpha. Low dose vemurafenib (720 mg daily) for a period of three months resulted in significant tumor shrinkage by >60% and regression of contrast enhancement and fluorodeoxyglucose uptake on positron-emission tomography. The patient's spastic paraparesis and gait function improved dramatically. She currently walks unaided and reports a substantially improved quality of life. CONCLUSION: Our findings show that vemurafenib therapy, even at low doses, can be effective for the treatment of intra-axial central nervous system involvement in BRAF-positive Erdheim-Chester disease. PMID- 25926132 TI - Exploring the role of practical nursing wisdom in the care of patients with urinary problems at the end of life: a qualitative interview study. AB - AIMS AND OBJECTIVES: This study examined how nurses understand urinary problems at the end of life, and identified sources of evidence upon which they base their practice through semi-structured qualitative interviews. The aim was to decide whether research or interventions (such as formulation of best practice guidelines) could improve continence care at the end of life. BACKGROUND: There is little evidence in nursing literature to indicate how nurses should manage urinary problems at the end of life. Evidence is particularly lacking regarding the insertion of indwelling urinary catheters. DESIGN: This was an applied qualitative interview study which used the 'guided interview' approach. METHODS: Twelve participants who worked in two hospital wards and one hospice were interviewed about management of patients with urinary problems approaching the end of life. The transcribed interviews were organised using the qualitative analysis software qsr NVivo version 10 (QSR International, Melbourne, Australia). Constant comparison was used to analyse the interviews. RESULTS: The patient and their family were a key concern of all interviewees. Participants focused on processes including: giving care, making decisions, managing uncertainty and assimilating knowledge. These processes are mediated by 'phronesis' or practical wisdom. CONCLUSIONS: Within each of the processes (giving care, making decisions, managing uncertainty and assimilating knowledge), participants approached each patient as an individual, using experience, patient wishes, available resources, clinical knowledge and advice from colleagues to provide care. A generalised set of guidelines on managing urinary problems at the end of life would probably not be useful. RELEVANCE TO CLINICAL PRACTICE: There is uncertainty about what constitutes best practice in specific areas of continence care at the end of life such as indwelling urinary catheter insertion. A careful approach is needed to ensure that the intellectual and moral knowledge that constitutes practical wisdom is shared and developed throughout teams. PMID- 25926133 TI - Chemistry and the Linkages between Air Quality and Climate Change. PMID- 25926134 TI - Metabolomics in chemical ecology. AB - Chemical ecology elucidates the nature and role of natural products as mediators of organismal interactions. The emerging techniques that can be summarized under the concept of metabolomics provide new opportunities to study such environmentally relevant signaling molecules. Especially comparative tools in metabolomics enable the identification of compounds that are regulated during interaction situations and that might play a role as e.g. pheromones, allelochemicals or in induced and activated defenses. This approach helps overcoming limitations of traditional bioassay-guided structure elucidation approaches. But the power of metabolomics is not limited to the comparison of metabolic profiles of interacting partners. Especially the link to other -omics techniques helps to unravel not only the compounds in question but the entire biosynthetic and genetic re-wiring, required for an ecological response. This review comprehensively highlights successful applications of metabolomics in chemical ecology and discusses existing limitations of these novel techniques. It focuses on recent developments in comparative metabolomics and discusses the use of metabolomics in the systems biology of organismal interactions. It also outlines the potential of large metabolomics initiatives for model organisms in the field of chemical ecology. PMID- 25926135 TI - Health care utilization and end-of-life care for older patients with acute myeloid leukemia. AB - BACKGROUND: Health care utilization in older adults (age >=60 years) with acute myeloid leukemia (AML) has not been well studied. METHODS: We conducted a retrospective analysis of 330 consecutive older patients who were diagnosed with AML between May 1, 2005 and December 23, 2011, at 2 hospitals in Boston to examine their health care utilization and end-of-life care. Using multivariable logistic and linear regression models adjusting for covariates, we also compared health care utilization between patients who received intensive induction chemotherapy (n = 197; cytarabine/ anthracycline combination) versus nonintensive chemotherapy (n = 133; single-agent therapy). RESULTS: The median number of hospitalizations for the entire cohort was 4.2 (range, 1-18 hospitalizations). Patients who died spent a mean of 28.3% of their life after diagnosis in the hospital and 13.8% of their life attending outpatient clinic appointments. Although the majority of patients (87.9%) died during the 2-year follow-up period, a minority received palliative care (16.2%) or hospice (23.1%) services. Within 30 days of death, 84.5% of patients were hospitalized, and 61% died in the hospital. Among the patients who died, those who received intensive induction therapy (vs nonintensive therapy) spent 30% more of their life after diagnosis in the hospital (P < .0001) and were less likely to receive hospice services (odds ratio, 0.45; P = .05). CONCLUSIONS: The current findings highlight the intensity of health care utilization among older patients with AML, regardless of treatment modality. Despite the poor prognosis, palliative care and hospice services are rarely used. Future work should study novel health care delivery models to optimize care throughout the course of illness and at the end of life. PMID- 25926136 TI - Gemcitabine plus vinorelbine as the second-line treatment and beyond in elderly patients with platinum-pretreated advanced non-small cell lung cancer. AB - BACKGROUND: The efficacy and tolerance of a gemcitabine and vinorelbine (GV) combination as salvage therapy have not been reported in elderly patients with advanced non-small cell lung cancer (NSCLC). METHODS: We reviewed elderly patients with advanced NSCLC who had disease progression after one or more chemotherapy regimens, at least one including platinum, and then who were treated with GV as the salvage therapy. RESULTS: In total 40 patients were analyzed. GV was at least the third-line chemotherapy in 24 patients (60.0%). Only 2 patients (5.0%) experienced grade 3 febrile neutropenia. Nonhematologic toxicities were generally mild and there was no treatment-related mortality. Among 29 patients evaluable for treatment response, 10 (34.5%) and 9 (31.0%) achieved a partial response and stable disease, respectively. The median overall survival was 10.3 months and the median progression-free survival was 3.1 months. CONCLUSIONS: GV in combination is an effective and tolerable salvage regimen in elderly and heavily pretreated patients with advanced NSCLC. PMID- 25926137 TI - Bendamustine and the immune system: a wolf in sheep's clothing? PMID- 25926138 TI - Psychological consequences associated with positive and negative responses to disclosure of sexual assault among college women: a prospective study. AB - A prospective design was utilized to explore the impact of social reactions to sexual assault disclosure among college women who experienced sexual victimization over a 4-month academic quarter. Women completed baseline, 4- and 7 month assessments of symptomatology, beliefs about why sexual assault occurs, victimization, and social reactions to sexual assault disclosure. Accounting for symptomatology or beliefs reported prior to the assault, positive social reactions were not associated with victims' subsequent symptomatology or beliefs. However, accounting for symptomatology or beliefs reported prior to the assault, higher negative social reactions were associated with victims' post-assault reports of hostility, fear, and beliefs about why sexual assault occurs. PMID- 25926139 TI - Mitofusin-2-mediated tethering of mitochondria and endoplasmic reticulum promotes cell cycle arrest of vascular smooth muscle cells in G0/G1 phase. AB - Mitofusin-2 (Mfn-2) is a hyperplasia suppressor. Changes in Mfn-2 expression are thought to reflect mitochondrial remodeling during cell proliferation. However, it is unclear how the participation of Mfn-2 in mitochondrial remodeling prevents cellular proliferation. Here we show that arresting vascular smooth muscle cells (VSMCs) in the G0/G1 phase by serum starvation up-regulates Mfn-2 expression and causes mitochondria to assemble into a tubular network and to attach to the endoplasmic reticulum (ER). In the S phase, short rod-shaped mitochondrial structures that were dissociated from the ER were observed. Levels of glucose, ATP, l-amino acid, and NADP(+) did not vary throughout the cell cycle. However, NAD(+) level was lower and NADH level was higher in the G0/G1 phase than in the S phase. Mitochondrial membrane potential was lower in the S phase than in the G0/G1 phase. Infecting VSMCs with an adenovirus encoding full-length Mfn-2 increased NADH level and reduced NAD(+) level, while infecting the cells with an adenovirus that silences the p21(ras) signature motif produced opposite effects. These results suggest that Mfn-2 up-regulation causes mitochondrial fusion into tubular networks and attachment to the ER, which in turn halts proliferation of VSMCs. PMID- 25926140 TI - Poly(ADP-ribose) polymerase 1 inhibition prevents interleukin-1beta-induced inflammation in human osteoarthritic chondrocytes. AB - Osteoarthritis (OA) is an age-related joint disease that is characterized by the degeneration of articular chondrocytes. Nuclear enzyme poly(ADP-ribose) polymerase 1 (PARP-1) is associated with inflammation response. We investigated the role of PARP-1 in interleukin-1beta (IL-1beta)-stimulated human articular chondrocytes and its underlying mechanism. Cell viability and apoptosis were evaluated by using 3-(4,5)-dimethylthiahiazo(-z-y1)-3,5-di-phenytetrazoliumromide assay and flow cytometry, respectively. Tumor necrosis factor-alpha (TNF-alpha) level was measured by enzyme-linked immunosorbent assay. The mRNA and protein expression levels of PARP-1, IL-1 receptor (IL-1R), inducible nitric oxide synthase (iNOS), matrix metalloproteinases (MMPs), and tissue inhibitor of metalloproteinases-1 (TIMP-1) were determined by real-time reverse transcriptase polymerase chain reaction and western blot analysis, respectively. The expression and phosphorylation of NF-kB p65 were measured by western blot analysis. Results showed that stimulation of chondrocytes with IL-1beta caused a significant up regulation of PARP-1 and IL-1R, resulting in NF-kB p65 nuclear translocation and phosphorylation associated with an increase of TNF-alpha secretion and iNOS expression. PARP-1 was inhibited by siRNA transfection. Results showed that PARP 1 inhibition suppressed IL-1beta-induced reduction of cell viability and up regulation of cell apoptosis, with a reduced IL-1R expression. PARP-1 inhibition also effectively reversed IL-1beta-induced inflammatory response through inhibiting the IL-1R/NF-kB pathway. These data suggested that PARP-1 inhibition prevents IL-1beta-induced inflammation response at least partly by inhibiting the IL-1R/NF-kB signaling pathway in human articular chondrocytes. Moreover, PARP-1 inhibition reduced MMPs expression and increased TIMP-1 expression, suggesting that PARP-1 inhibition could suppress cartilage destruction by modulating the balance between MMPs and TIMP-1. Inhibition of PARP-1 might be useful in the treatment of OA. PMID- 25926141 TI - Histamine reduces boron neutron capture therapy-induced mucositis in an oral precancer model. AB - OBJECTIVES: Searching for more effective and selective therapies for head and neck cancer, we demonstrated the therapeutic effect of boron neutron capture therapy (BNCT) to treat oral cancer and inhibit long-term tumor development from field-cancerized tissue in the hamster cheek pouch model. However, BNCT-induced mucositis in field-cancerized tissue was dose limiting. In a clinical scenario, oral mucositis affects patients' treatment and quality of life. Our aim was to evaluate different radioprotectors, seeking to reduce the incidence of BNCT induced severe mucositis in field-cancerized tissue. MATERIALS AND METHODS: Cancerized pouches treated with BNCT mediated by boronophenylalanine at 5 Gy were treated as follows: control: saline solution; Hishigh : histamine 5 mg kg(-1) ; Hislow : histamine 1 mg kg(-1) ; and JNJ7777120: 10 mg kg(-1). RESULTS: Hislow reduced the incidence of severe mucositis in field-cancerized tissue to 17% vs CONTROL: 55%; Hishigh : 67%; JNJ7777120: 57%. Hislow was non-toxic and did not compromise the long-term therapeutic effect of BNCT or alter gross boron concentration. CONCLUSION: Histamine reduces BNCT-induced mucositis in experimental oral precancer without jeopardizing therapeutic efficacy. The fact that both histamine and boronophenylalanine are approved for use in humans bridges the gap between experimental work and potential clinical application to reduce BNCT-induced radiotoxicity in patients with head and neck cancer. PMID- 25926142 TI - A novel measure of socioeconomic status using individual housing data to assess the association of SES with rheumatoid arthritis and its mortality: a population based case-control study. AB - OBJECTIVES: To assess whether HOUSES (HOUsing-based index of socioeconomic status (SES)) is associated with risk of and mortality after rheumatoid arthritis (RA). DESIGN: We conducted a population-based case-control study which enrolled population-based RA cases and their controls without RA. SETTING: The study was performed in Olmsted County, Minnesota. PARTICIPANTS: Study participants were all residents of Olmsted County, Minnesota, with RA identified using the 1987 American College of Rheumatology criteria for RA from 1 January 1988, to 31 December 2007, using the auspices of the Rochester Epidemiology Project. For each patient with RA, one control was randomly selected from Olmsted County residents of similar age and gender without RA. PRIMARY AND SECONDARY OUTCOME MEASURE: The disease status was RA cases and their matched controls in relation to HOUSES as an exposure. As a secondary aim, post-RA mortality among only RA cases was an outcome event. The associations of SES measured by HOUSES with the study outcomes were assessed using logistic regression and Cox models. HOUSES, as a composite index, was formulated based on a summed z-score for housing value, square footage and number of bedrooms and bathrooms. RESULTS: Of the eligible 604 participants, 418 (69%) were female; the mean age was 56+/-15.6 years. Lower SES, as measured by HOUSES, was associated with the risk of developing RA (0.5+/-3.8 for controls vs -0.2+/-3.1 for RA cases, p=0.003), adjusting for age, gender, calendar year of RA index date, smoking status and BMI. The lowest quartile of HOUSES was significantly associated with increased post-RA mortality compared to higher quartiles of HOUSES (HR 1.74; 95% CI 1.10 to 2.74; p=0.017) in multivariate analysis. CONCLUSIONS: Lower SES, as measured by HOUSES, is associated with increased risk of RA and mortality after RA. HOUSES may be a useful tool for health disparities research concerning rheumatological outcomes when conventional SES measures are unavailable. PMID- 25926143 TI - The burden of revision sinonasal surgery in the UK-data from the Chronic Rhinosinusitis Epidemiology Study (CRES): a cross-sectional study. AB - OBJECTIVES: The aim of this study was to investigate the surgical revision rate in patients with chronic rhinosinusitis (CRS) in the UK CRS Epidemiology Study (CRES). Previous evidence from National Sinonasal Audit showed that 1459 patients with CRS demonstrated a surgical revision rate 19.1% at 5 years, with highest rates seen in those with polyps (20.6%). SETTING: Thirty secondary care centres around the UK. PARTICIPANTS: A total of 221 controls and 1249 patients with CRS were recruited to the study including those with polyps (CRSwNPs), without polyps (CRSsNPs) and with allergic fungal rhinosinusitis (AFRS). INTERVENTIONS: Self administered questionnaire. PRIMARY OUTCOME MEASURE: The need for previous sinonasal surgery. RESULTS: A total of 651 patients with CRSwNPs, 553 with CRSsNPs and 45 with AFRS were included. A total of 396 (57%) patients with CRSwNPs/AFRS reported having undergone previous endoscopic nasal polypectomy (ENP), of which 182 of the 396 (46%) reported having received more than one operation. The mean number of previous surgeries per patient in the revision group was 3.3 (range 2-30) and a mean duration of time of 10 years since the last procedure. The average length of time since their first operation up to inclusion in the study was 15.5 years (range 0-74). Only 27.9% of all patients reporting a prior ENP had received concurrent endoscopic sinus surgery (ESS; n=102). For comparison, surgical rates in patients with CRSsNPs were significantly lower; 13% of cases specifically reported ESS, and of those only 30% reported multiple procedures (chi(2) p<0.001). CONCLUSIONS: This study demonstrated that there is a high burden of both primary and revision surgery in patients with CRS, worst in those with AFRS and least in those with CRSsNPs. The burden of revision surgery appears unchanged in the decade since the Sinonasal Audit. PMID- 25926144 TI - Methods and characteristics of published network meta-analyses using individual patient data: protocol for a scoping review. AB - INTRODUCTION: Individual patient data (IPD) meta-analysis (MA) offers advantages over aggregate MA of using standardised criteria for patient characteristics across trials, and allowing reliable investigation of subgroup effects of interventions. Network meta-analysis (NMA) allows for the comparison of multiple treatments in a comprehensive analysis and the determination of the best treatment among several competing treatments, including those that have never been compared in a head-to-head study. Including IPD in NMA may enable the prevention of misleading inferences due to several biases, such as aggregation bias. Application of IPD-NMA methods in healthcare have begun to appear in medical journals. Our objective is to conduct a scoping review of existing IPD NMA methods, and summarise their properties. We also aim to describe the characteristics of empirical IPD-NMAs, and examine how their results are reported. METHODS AND ANALYSIS: We will search relevant electronic databases from inception until October 2014 (eg, MEDLINE), grey literature, and Google. The scoping review will consider published and unpublished papers that report completion of an IPD-NMA, describe a method, or report the methodological quality of IPD-NMA. We will include IPD-NMA of any quantitative study (eg, experimental, quasiexperimental, observational studies). Two reviewers will independently screen titles, abstracts and full-text articles, and will complete data abstraction. The anticipated outcome will be a collection of all the IPD-NMAs completed to date, and a description of their methods and reporting of results. We will create summary tables providing the characteristics of the included studies, and the various methods. Quantitative data (eg, number of patients) will be summarised by medians and IQRs, and categorical data (eg, type of effect size) by frequencies and percentages. ETHICS AND DISSEMINATION: Ethical approval is not required as our study will not include confidential participant data and interventions. We will disseminate our results through an open access, peer reviewed publication. PMID- 25926145 TI - The cost-effectiveness of the MobileMums intervention to increase physical activity among mothers with young children: a Markov model informed by a randomised controlled trial. AB - OBJECTIVES: To determine the cost-effectiveness of the MobileMums intervention. MobileMums is a 12-week programme which assists mothers with young children to be more physically active, primarily through the use of personalised SMS text messages. DESIGN: A cost-effectiveness analysis using a Markov model to estimate and compare the costs and consequences of MobileMums and usual care. SETTING: This study considers the cost-effectiveness of MobileMums in Queensland, Australia. PARTICIPANTS: A hypothetical cohort of over 36 000 women with a child under 1 year old is considered. These women are expected to be eligible and willing to participate in the intervention in Queensland, Australia. DATA SOURCES: The model was informed by the effectiveness results from a 9-month two arm community-based randomised controlled trial undertaken in 2011 and registered retrospectively with the Australian Clinical Trials Registry (ACTRN12611000481976). Baseline characteristics for the model cohort, treatment effects and resource utilisation were all informed by this trial. MAIN OUTCOME MEASURES: The incremental cost per quality-adjusted life year (QALY) of MobileMums compared with usual care. RESULTS: The intervention is estimated to lead to an increase of 131 QALYs for an additional cost to the health system of 1.1 million Australian dollars (AUD). The expected incremental cost-effectiveness ratio for MobileMums is 8608 AUD per QALY gained. MobileMums has a 98% probability of being cost-effective at a cost-effectiveness threshold of 64 000 AUD. Varying modelling assumptions has little effect on this result. CONCLUSIONS: At a cost-effectiveness threshold of 64 000 AUD, MobileMums would likely be a cost-effective use of healthcare resources in Queensland, Australia. TRIAL REGISTRATION NUMBER: Australian Clinical Trials Registry; ACTRN12611000481976. PMID- 25926146 TI - Costs and quality of life associated with acute upper gastrointestinal bleeding in the UK: cohort analysis of patients in a cluster randomised trial. AB - OBJECTIVES: Data on costs associated with acute upper gastrointestinal bleeding (AUGIB) are scarce. We provide estimates of UK healthcare costs, indirect costs and health-related quality of life (HRQoL) for patients presenting to hospital with AUGIB. SETTING: Six UK university hospitals with >20 AUGIB admissions per month, >400 adult beds, 24 h endoscopy, and on-site access to intensive care and surgery. PARTICIPANTS: 936 patients aged >=18 years, admitted with AUGIB, and enrolled between August 2012 and March 2013 in the TRIGGER trial of AUGIB comparing restrictive versus liberal red blood cell (RBC) transfusion thresholds. PRIMARY AND SECONDARY OUTCOME MEASURES: Healthcare resource use during hospitalisation and postdischarge up to 28 days, unpaid informal care, time away from paid employment and HRQoL using the EuroQol EQ-5D at 28 days were measured prospectively. National unit costs were used to value resource use. Initial in hospital treatment costs were upscaled to a UK level. RESULTS: Mean initial in hospital costs were L2458 (SE=L216) per patient. Inpatient bed days, endoscopy and RBC transfusions were key cost drivers. Postdischarge healthcare costs were L391 (L44) per patient. One-third of patients received unpaid informal care and the quarter in paid employment required time away from work. Mean HRQoL for survivors was 0.74. Annual initial inhospital treatment cost for all AUGIB cases in the UK was estimated to be L155.5 million, with exploratory analyses of the incremental costs of treating hospitalised patients developing AUGIB generating figures of between L143 million and L168 million. CONCLUSIONS: AUGIB is a large burden for UK hospitals with inpatient stay, endoscopy and RBC transfusions as the main cost drivers. It is anticipated that this work will enable quantification of the impact of cost reduction strategies in AUGIB and will inform economic analyses of novel or existing interventions for AUGIB. TRIAL REGISTRATION NUMBER: ISRCTN85757829 and NCT02105532. PMID- 25926147 TI - Chemokine co-receptor usage in HIV-1-infected treatment-naive voluntary counselling and testing clients in Southern Taiwan. AB - OBJECTIVE: The goal of this present study was to determine the proportion of CCR5 tropic and CXCR4-tropic viruses and impact of tropism test on clinical presentation, CD4 cell counts, viral load and genotypic drug resistance from drug naive, voluntary counselling and testing (VCT) clients in southern Taiwan. DESIGN: This was a cross-sectional study. Plasma samples were collected from HIV 1-infected patients from January 2013 to December 2013; subjects were recruited from free VCT centres in southern Taiwan. SETTING: Taiwan. PARTICIPANTS: Plasma samples from 108 HIV-1-infected, treatment-naive, VCT clients were analysed. HIV 1 strains were sequenced, genotype resistance was determined by a commercial kit (Viro-seq) and co-receptor tropism (CRT) was predicted by an internet tool geno2pheno[coreceptor], with a 10% false-positive rate as the cut-off. Differences in progression markers, patient characteristics, VCT questionnaires and HIV subtype distribution were evaluated statistically. RESULTS: All the 108 VCT clients were male with 90% between the ages of 20 and 40 years. Eighty-eight per cent of the patients were men who have sex with men (MSM). The median (IQR) CD4 cell count was 342 cells/uL (221-454) and the viral load was 4.6 log (4.0 5.0). HIV-transmitted drug resistance was found in 9.3% (10/108) of the patients. CRT predictions indicated that 74% of the patients had only R5-tropic strains. CRT was not associated with CD4 cell counts, patient characteristics, VCT questionnaire and transmitted drug resistance. There was a significant difference with regard to viral load at the time of presentation, showing that patients with R5 more often had a higher viral load as compared with those with X4/DM strains (4.6+/-0.6 log vs 4.33+/-0.7 log, p=0.036). CONCLUSIONS: We found that 74% of the VCT clients were infected with R5-tropic virus strains. HIV-transmitted drug resistance was not associated with CRT predictions. Higher viral load at presentation was predictive of R5 co-receptor usage. PMID- 25926148 TI - OCD? Not Me! Protocol for the development and evaluation of a web-based self guided treatment for youth with obsessive-compulsive disorder. AB - BACKGROUND: OCD? Not Me! is a novel, web-based, self-guided intervention designed to treat obsessive-compulsive disorder (OCD) in young people aged 12-18, using the principles of exposure and response prevention. The current paper presents the protocol for the development of the programme and for an open trial that will evaluate the effectiveness of this programme for OCD in young people, and associated distress and symptom accommodation in their parents and caregivers. METHODS: We will measure the impact of the OCD? Not Me! programme on OCD symptoms using the Children's Florida Obsessive Compulsive Inventory (C-FOCI), and both the self-report and parent report of the Children's Obsessional Compulsive Inventory-Revised (ChOCI-R). The impact of the programme on OCD-related functional impairment will be measured using the parent report of the Child Obsessive-Compulsive Impact Scale-Revised (COIS-R). Secondary outcome measures include the Rosenberg Self-Esteem Scale and the Youth Quality of Life-Short Form (YQoL-SF). The 21-item Depression Anxiety Stress Scales (DASS-21) will be used to measure the impact of the programme on parent/caregiver distress, while the Family Accommodation Scale (FAS) will be used to measure change in family accommodation of OCD symptoms. Multilevel mixed effects linear regression will be used to analyse the impact of the intervention on the outcome measures. ETHICS AND DISSEMINATION: This study has been approved by the Curtin University Human Research Ethics Committee. The results of the study will be reported in international peer-reviewed journals. TRIAL REGISTRATION NUMBER: Australian New Zealand Clinical Trials Registry: ACTRN12613000152729. PMID- 25926149 TI - Electronic nicotine delivery devices, and their impact on health and patterns of tobacco use: a systematic review protocol. AB - INTRODUCTION: E-cigarettes or electronic nicotine delivery systems (ENDS) have recently attracted considerable attention. Among some individuals there is strong debate and a polarisation of views about the public health benefits versus harms of ENDS. With little regulation, the ENDS market is evolving, and new products are introduced and marketed constantly. Rapid developments in manufacturing, marketing and consumer domains related to ENDS will warrant frequent re evaluation, based on the state of the evolving science. The purpose of this article is to describe a protocol for an ongoing comprehensive review of the published scientific literature on ENDS. METHODS AND ANALYSIS: We will undertake a systematic review of published empirical research literature on ENDS using the National Library of Medicine's PubMed electronic database to search for relevant articles. Data from included studies will be extracted into a standardised form, tables with study details and key outcomes for each article will be created, and studies will be synthesised qualitatively. ETHICS AND DISSEMINATION: This review synthesises published literature and presents no primary data. Therefore, no ethical approval is required for this study. Subsequent papers will provide greater detail on results, within select categories, that represent gaps in the literature base. PMID- 25926150 TI - Survival in patients with breast cancer with bone metastasis: a Danish population based cohort study on the prognostic impact of initial stage of disease at breast cancer diagnosis and length of the bone metastasis-free interval. AB - OBJECTIVES: Since population-based data on prognostic factors affecting survival in patients with breast cancer with bone metastasis (BM) are currently limited, we conducted this nationwide retrospective cohort study to examine the prognostic role of disease stage at breast cancer diagnosis and length of BM-free interval (BMFI). SETTING: Denmark. PARTICIPANTS: 2427 women with a breast cancer diagnosis between 1997 and 2011 in the Danish Cancer Registry and a concurrent or subsequent BM diagnosis in the Danish National Registry of Patients. PRIMARY AND SECONDARY OUTCOME MEASURES: Survival (crude) based on Kaplan-Meier method and mortality risk (crude and adjusted for age, year of diagnosis, estrogen receptor status and comorbidity) based on Cox proportional hazards regression analyses by stage of disease at breast cancer diagnosis and by length of BMFI (time from breast cancer to BM diagnosis), following patients from BM diagnosis until death, emigration or until 31 December 2012, whichever came first. RESULTS: Survival decreased with more advanced stage of disease at the time of breast cancer diagnosis; risk of mortality during the first year following a BM diagnosis was over two times higher for those presenting with metastatic versus localised disease (adjusted HR=2.12 (95% CI 1.71 to 2.62)). With respect to length of BMFI, survival was highest in women with a BMFI <1 year (ie, in those who presented with BM at the time of breast cancer diagnosis or were diagnosed within 1 year). However, among patients with a BMFI >=1 year, survival increased with longer BMFI (1-year survival: 39.9% (95% CI 36.3% to 43.6%) for BMFI 1 to <3 years and 52.6% (95% CI 47.4% to 57.6%) for BMFI >=5 years). This pattern was also observed in multivariate analyses. CONCLUSIONS: Stage of disease at breast cancer diagnosis and length of BMFI appear to be important prognostic factors for survival following BM. PMID- 25926151 TI - Risk behaviours and prevalence of sexually transmitted infections and HIV in a group of Dominican gay men, other men who have sex with men and transgender women. AB - OBJECTIVES: The objectives of this study were to estimate the point prevalence of sexually transmitted infection (STI) and to investigate the sexual practices and behaviours associated with STIs in a group of gay men, other men who have sex with men and transgender women (GMT) in the province of La Romana, Dominican Republic. DESIGN: A cross-sectional study of a convenience sample of GMT persons. SETTING: The study was conducted in the province of La Romana, Dominican Republic, in June-July 2013. PARTICIPANTS: Out of 117 GMT persons screened, a total of 100 completed the study. Participants had to be at least 18 years of age, reside in La Romana and have had sex with another man in the preceding 12 months. All participants were interviewed and tested for STI. PRIMARY OUTCOME MEASURE: The main outcome of interest was the detection of any STI (HIV, herpes simplex virus type 2 (HSV-2), syphilis, hepatitis B or C) by serology. RESULTS: Among 100 participants, the median age was 22 years (range 18-65). One-third had consumed illicit drugs the preceding year and only 43% consistently used condoms. Prevalence was 38% for HSV-2, 5% for HIV and 13% for syphilis. There were no cases of hepatitis B or C. Factors associated with the odds of a STI were age >22 years (OR=11.1, 95% CI 3.6 to 34.5), receptive anal intercourse (OR=4.2, 95% CI 1.3 to 13.6) and having >=2 male sexual partners during the preceding month (OR=4, 95% CI 1.3 to 12.5). CONCLUSIONS: In this group of GMT persons, seroprevalence of STI was high, and a number of risk behaviours were associated with STI. These preliminary data will help inform policy and programmes to prevent HIV/STI in GMT persons in the region. PMID- 25926152 TI - A minimally invasive technique for decompression of Chiari malformation type I (DECMI study): study protocol for a randomised controlled trial. AB - INTRODUCTION: Chiari malformation type I (CM-I) is a congenital hindbrain anomaly that requires surgical decompression in symptomatic patients. Posterior fossa decompression with duraplasty (PFDD) has been widely practiced in Chiari decompression, but dural opening carries a high risk of surgical complications. A minimally invasive technique, dural splitting decompression (DSD), preserves the inner layer of the dura without dural opening and duraplasty, potentially reducing surgical complications, length of operative time and hospital stay, and cost. If DSD is non-inferior to PFDD in terms of clinical improvement, DSD could be an alternative treatment modality for CM-I. So far, no randomised study of surgical treatment of CM-I has been reported. This study aims to evaluate if DSD is an effective, safe and cost-saving treatment modality for adult CM-I patients, and may provide evidence for using the minimally invasive procedure extensively. METHODS AND ANALYSIS: DECMI is a randomised controlled, single-masked, non inferiority, single centre clinical trial. Participants meeting the criteria will be randomised to the DSD group and the PFDD group in a 1:1 ratio. The primary outcome is the rate of clinical improvement, which is defined as the complete resolution or partial improvement of the presenting symptoms/signs. The secondary outcomes consist of the incidence of syrinx reduction, postoperative morbidity rates, reoperation rate, quality of life (QoL) and healthcare resource utilisation. A total of 160 patients will be included and followed up at 3 and 12 months postoperatively. ETHICS AND DISSEMINATION: The study protocol was approved by the Biological and Medical Ethics Committee of West China Hospital. The findings of this trial will be published in a peer-reviewed scientific journal and presented at scientific conferences. TRIAL REGISTRATION NUMBER: ChiCTR-TRC 14004099. PMID- 25926153 TI - Re: Hilton P, Bryant A, Howel D, McColl E, Buckley BS, Lucas MG, et al. Assessing professional equipoise and views about a future clinical trial of invasive urodynamics prior to surgery for stress urinary incontinence in women: A survey within a mixed methods feasibility study. Neurourol Urodyn. 2012;31(8):1223-30. PMID- 25926154 TI - Autoantibodies to osteoprotegerin are associated with increased bone resorption in rheumatoid arthritis. PMID- 25926155 TI - Long-term safety of etanercept and adalimumab compared to methotrexate in patients with juvenile idiopathic arthritis (JIA). AB - IMPORTANCE: Published evidence on the long-term safety of etanercept (ETA) and adalimumab (ADA) in patients with polyarticular juvenile idiopathic arthritis (pJIA) is still limited. OBJECTIVES: To investigate the rates of serious adverse events (SAE) and of events of special interest (ESI) under ETA and ADA treatment. DESIGN, SETTING AND PARTICIPANTS: Patients with pJIA were prospectively observed in the national JIA biological register, Biologika in der Kinderrheumatologie, and its follow-up register, Juvenile arthritis Methotrexate/Biologics long-term Observation. MAIN OUTCOMES AND MEASURES: We calculated the relative risks of SAE and ESI for ETA and ADA compared with methotrexate (MTX). RESULTS: Among the 1414 patients treated with ETA (n=1414; 4461 exposure years (EY)) and ADA (n=320; 493 EY), significantly more SAE, infections and medically important infections were observed (ETA: 4.5, 5.7, 0.9; ADA: 4.7, 11.4, 0.4 per 100 EY) compared with those treated with MTX alone (n=1455; 2.907 EY; 2.6, 5.5, 0.5 per 100 EY). The risk for malignancies was not significantly increased for ETA and ADA compared with MTX (0.09, 0.27 and 0.07/100 person-years). Patients under ETA monotherapy developed more frequently incident inflammatory bowel disease (IBD) and incident uveitis (0.5 and 0.8/100 EY) than patients treated by ETA in combination with MTX (0.1 and 0.2/100 EY) or MTX alone (0.03 and 0.1/100 EY). CONCLUSIONS AND RELEVANCE: Our data confirm the acceptable long-term tolerability of ETA and ADA in pJIA. However, whether the onset of IBD and uveitis during ETA monotherapy is a paradoxical effect or an inadequate response to therapy remains unclear and requires further investigation in this growing cohort. PMID- 25926156 TI - Transcriptional and post-transcriptional regulation of transmembrane protein 132A. AB - Transmembrane protein 132A (TMEM132A) was first isolated from rat brain using PCR selected cDNA subtraction, and it was found to be predominantly expressed in the brain. However, the transcriptional regulation of the TMEM132A gene has not been fully characterized. In this study, we characterized the promoter activity of the 880-bp region upstream of the mouse TMEM132A, identifying several putative sites recognized by transcription factors, which are highly conserved between the mouse and human TMEM132A genes. Using four different mouse cell lines (Neuro2a, NSC-34, NIH3T3, and Raw264.7), we first evaluated the intrinsic levels of TMEM132A mRNA and protein expression. Interestingly, TMEM132A mRNA was expressed in all four cell lines, whereas the protein was negligible in Raw264.7 cells even by transfection of TMEM132A gene. Then, we analyzed the TMEM132A promoter activity using serial deleted constructs, finding it was nearly same pattern in all four cell lines. A mutational analysis of the TMEM132A promoter identified a critical region for its activation just upstream of the transcriptional start site. Finally, we investigated the levels of TMEM132A mRNA and protein after exposure to five different neurotoxic stimuli, including thapsigargin, tunicamycin, serum starvation, homocysteine, and hydrogen peroxide. Treatment with thapsigargin, a calcium modulating agent, markedly attenuated the levels of TMEM132A mRNA and protein in NSC-34 cells. These results give new insight into the mechanisms involved in regulating TMEM132A expression, and suggest that several transcriptional and post-transcriptional pathways regulate TMEM132A expression under developmental and pathophysiological conditions. PMID- 25926157 TI - Role of prebiotics and probiotics in pediatric diseases. AB - The increasing knowledge about the composition and activities of the microflora has shown the close link between the bacteria and the health of the human organism. For this reason it has focused attention on the possibility of modulating the gut flora. The use of probiotics and prebiotics has increased enormously in recent years, more for real beneficial effects demonstrated in patients than for their safety profiles. However, it is recorded an indiscriminate use also in conditions in which there are no scientific evidence to support. Their use in case of immunocompromised patients or with severe and debilitating chronic diseases should be very prudent, because of the risk of complications including sepsis. The use of a probiotic cannot ignore the knowledge of the genus and species of the strain and in pediatric patients has been demonstrated their role for treating acute viral gastroenteritis and preventing antibiotic-associated diarrhea in healthy children. Moreover probiotics are considered as an option for recurrent and relapsing antibiotic sensitive pouchitis and in select patients with mild ulcerative colitis. Further studies are needed to evaluate clinical conditions that may require their use and to define the optimal doses and intake durations. PMID- 25926158 TI - Association of clearance of middle- and large-molecular-weight substance with arterial stiffness and left ventricular mass in children receiving renal replacement therapy. AB - BACKGROUND: The prominent cause of mortality in children receiving dialysis treatment is cardiovascular diseases. Risk factors related to chronic renal disease, are effective in the development of cardiovascular diseases. The aim of study was to investigate cardiovascular system (CVS) involvement for functional and structural alterations in children receiving dialysis, and display any association between cardiovascular morbidity and uremic toxins. METHODS: 20 dialysis patients and 20 healthy controls were included to the study. Clearance of small, middle and large molecular-weight uremic toxins was evaluated in blood samples collected 30 minutes before (D0) and 2 hour after dialysis (D2), and change value was calculated as D0-D2/D0. Cardiovascular involvement was determined by comparing arterial stiffness, carotid intima-media thickness (CIMT) and Left Ventricular Mass Index (LVMI) with the control group. RESULTS: Four patients receiving hemodialysis and two patients in continuous ambulatory peritoneal dialysis (CAPD) group who have significant differences in all functional and structural parameters were detected. Four dialysis patients with detected cardiovascular disease have distinctively lower beta-2 microglobulin and homocysteine clearances compared to the patients with no CVS involvement. CONCLUSIONS: The clearance of middle and large molecular-weight substances should be closely monitored in children receiving dialysis. PMID- 25926159 TI - Focal hepatic lesions in Egyptian infants and children: the pediatric hepatologist perspective. AB - BACKGROUND: Hepatic focal lesions in the pediatric age group are diverse and can be broadly classified into congenital, neoplastic and infective. The aim of this paper was to describe the frequency, nature and clinical presentation of focal hepatic lesions from a pediatric hepatologist perspective. METHODS: Data were retrieved from files of all cases with focal hepatic lesions presenting to the Pediatric Hepatology Unit, Cairo University Pediatric Hospital, from January 2006 to December 2013, after the study protocol was approved by the department research committee and the institution ethical committee. RESULTS: Over an 8-year period, 38 cases had focal hepatic lesions. They constituted less than 1% of the 4475 new cases presenting to the unit over this period. The commonest lesion was hepatic hemangioma(s) (34%). Two-thirds were neoplastic lesions whether benign or malignant. Eighty percent were benign focal lesions. Infectious causes (fascioliasis and pyogenic liver abscess) accounted for 29% of cases. Hepatocellular carcinoma was the commonest malignant neoplasm; it occurred in 5 cases (13.2%) on top of a chronic liver disease. Hepatoblastoma was less common. CONCLUSIONS: From the hepatologist perspective, pediatric focal hepatic lesions are more likely to be benign. Hepatic hemangiomas are the commonest. Infectious causes are common in a developing country like Egypt. Hepatocellular carcinoma is the commoner malignant neoplasm and usually develops on a diseased liver. Screening infants and children with chronic liver disease for development of hepatocellular carcinoma is mandatory. Hepatoblastoma is less likely to present to the pediatric hepatologist as it is referred immediately to the oncologist or onco-surgeon. PMID- 25926160 TI - Severe psychosis due to Cushing's syndrome in a patient with a carcinoid tumour in the lung: a case report and review of the current management. AB - Severe psychosis in patients with Cushing's syndrome is a rare occurrence and can be extremely resistant to medical therapy. We describe a case of a 51-year-old Afro-Caribbean female patient, with refractory severe hypertension (initially resistant to polypharmacy) and gradual development of severe psychosis secondary to ectopic Cushing's syndrome, who was subsequently diagnosed to have a carcinoid tumour in her lung. Her psychotic episodes - secondary to hypercortisolism and initially refractory to the medical therapy - subsided only after the resection of the carcinoid tumour in her right lower pulmonary lobe. Early localization and appropriate surgical resection of the ectopic ACTH-secreting tumour can be of immense value to the successful alleviation of the psychotic episodes of the patients with ectopic Cushing's syndrome. PMID- 25926161 TI - Valuation of Child Health-Related Quality of Life in the United States. AB - Many economic analyses fail to incorporate evidence on child health-related quality of life because of a paucity of quality-adjusted life year (QALY) estimates. This health valuation study is the first to summarize the EQ-5D-Y on a QALY scale. Drawn from a nationally representative panel, 5207 adult respondents were asked to choose between two losses in child health-related quality of life. Based on their choices, a 1-year increase in child pain/discomfort from 'some' to 'a lot' equals a loss of 4 QALYs (95% CI, 3.8-4.4). Likewise, a 1-year increase in child anxiety/depression from 'a bit' to 'very worried, sad, or unhappy' equals a loss of 2 QALYs (95% CI, 1.9-2.2). These findings enable the integration of child-reported outcomes with adult preferences to inform economic analysis. Results inform both clinical practice and resource allocation decisions by enhancing understanding of difficult tradeoffs in child-reported outcomes. Copyright (c) 2015 John Wiley & Sons, Ltd. PMID- 25926162 TI - Genetic and environmental etiology of the relationship between childhood hyperactivity/inattention and conduct problems in a South Korean twin sample. AB - Recently, there has been increased research into the etiology of the comorbidity between hyperactivity/inattention problems (HIP) and conduct problems (CP). However, the nature of the etiology of the comorbidity has remained unclear. Mothers of 507 pairs of twins, comprised of 221 monozygotic (MZ) and 286 dizygotic (DZ) twin pairs aged from 6 to 13 years (mean = 9.6 years; SD = 2.0 years), completed the HIP and the CP scale of the Strengths and Difficulties Questionnaire (SDQ) via a telephone interview. The phenotypic correlation between HIP and CP was 0.43 (p < .01). MZ and DZ twin correlations were, respectively, 0.48 (95%CI: 0.37-0.58) and 0.06 (95% CI: -0.06-0.19) for HIP and 0.38 (95% CI: 0.26-0.49) and 0.35 (95% CI: 0.25-0.45) for CP. The bivariate model-fitting results revealed additive genetic correlation of 1.0 (95% CI: 0.72-1.00), a complete overlap of additive genetic variance component between HIP and CP, supporting the importance of correlated additive genetic risk factors for the comorbid condition of HIP and CP. HIP was additionally influenced by non-additive genetic factors that did not contribute to the relationship between HIP and CP. There was a significant but moderate child-specific environmental correlation (r e = 0.37) between HIP and CP. CP was additionally influenced by shared family environmental influences. While the results of the present study are generally consistent with the findings from Western twin studies of the relationship between HIP and CP, they add a new finding to the extant literature by showing that it is additive rather than non-additive genetic factors that are responsible for the co-occurrence of HIP and CP. PMID- 25926170 TI - Customized partially covered biodegradable stent for anastomotic leakage after esophagojejunostomy. PMID- 25926172 TI - Amebic colitis: colonoscopic appearance. PMID- 25926173 TI - Leishmaniasis presenting as small isolated mediastinal lymphadenopathy diagnosed by endoscopic ultrasound-guided fine-needle aspiration. PMID- 25926174 TI - Recurrent rectovaginal fistula: treatment with self-expanding metal stents. PMID- 25926175 TI - Esophageal stricture caused by a mediastinal hamartoma invading the esophageal wall. PMID- 25926176 TI - Endoscopic resection and enucleation of gastric submucosal tumor facilitated by subsequent closure of incision using over-the-scope clip. PMID- 25926177 TI - Endoscopic resection for esophageal high grade dysplasia in a patient with cervical esophageal stricture via the transgastric approach. PMID- 25926178 TI - Over-the-scope clip (OTSC)-induced colonic obstruction necessitating sigmoid resection. PMID- 25926179 TI - Computed tomography enterography as a tool for identifying pancreaticojejunal anastomoses in patients who have undergone Whipple's resection. PMID- 25926181 TI - Endoscopic ultrasound-guided pancreatic duct drainage using antegrade stenting. PMID- 25926182 TI - Feasibility of a thumb-controlled device in double-balloon enteroscopy-assisted ERCP. PMID- 25926183 TI - Overtube-assisted ERCP in a patient with a dilated atonic stomach. PMID- 25926184 TI - Subserosal recurrence without mucosal involvement diagnosed 5 years after endoscopic submucosal dissection for early rectal cancer. PMID- 25926185 TI - Specimen retrieval method using a sliding overtube for large colorectal neoplasm following endoscopic submucosal dissection. PMID- 25926186 TI - Gastric syphilis mimicking lymphoma. PMID- 25926205 TI - Endoscopic submucosal dissection of high grade intraepithelial neoplasia of the head and neck in a patient after surgical resection of esophageal cancer. PMID- 25926206 TI - Radical incision and cutting with an insulation-tipped knife: a new method to treat multiple diaphragmatic strictures of the small intestine. PMID- 25926207 TI - Tubercular lymph nodal mass mimicking pancreatic malignancy with extrahepatic biliary obstruction in a young woman. PMID- 25926208 TI - An unusual pancreatic lesion causing biliary obstruction and duodenal invasion. PMID- 25926209 TI - Obscure overt gastrointestinal bleeding due to Necator americanus diagnosed by double-balloon enteroscopy. PMID- 25926210 TI - Gastric outlet obstruction caused by intramural duodenal pseudocysts in a young man with acute pancreatitis. PMID- 25926211 TI - Combined stents for the treatment of large gastric fistulas or stenosis after sleeve gastrectomy. PMID- 25926213 TI - Cotton wool-like plaques due to Candida in ulcerative colitis. PMID- 25926214 TI - Argon plasma coagulation of a bleeding angioectasia in a jejunal diverticulum by single-balloon enteroscopy. PMID- 25926215 TI - Severe pancreatitis following hot-snare polypectomy of a distal biliary inflammatory polyp during ERCP in a heart transplant recipient. PMID- 25926216 TI - An alternative method of endoscopic retrieval of a proximally migrated biliary plastic stent using a "sphincterotome hooking the stent" technique. PMID- 25926217 TI - Aortic wall rupture from a mediastinal tumor invasion diagnosed by endoscopic ultrasound. PMID- 25926218 TI - Endoscopic ultrasound-guided drainage and necrosectomy of walled-off pancreatic necrosis using a metal stent with an electrocautery-enhanced delivery system and hydrogen peroxide. PMID- 25926219 TI - Huge hemothorax caused by endoscopic ultrasound-guided fine-needle aspiration of a submucosal tumor of the gastric fornix. PMID- 25926220 TI - Chronic diarrhea because of villous atrophy unrelated to celiac disease. PMID- 25926221 TI - Esophageal fully covered self-expanding metal stent for combined treatment of an aortoesophageal fistula. PMID- 25926222 TI - Gastric glomus tumor: a rare case of dyspepsia. PMID- 25926223 TI - Colonic plasmacytomas: a rare complication of plasma cell leukemia. PMID- 25926224 TI - A game theoretic approach to repeated foreign body ingestion. PMID- 25926226 TI - Primary malignant melanoma of the esophagus. PMID- 25926227 TI - Mid-gut bleeding due to a chronic splanchnic vascular stricture with secondary portal hypertension after gastric bypass. PMID- 25926228 TI - Colonoscopic finding of an unusual sigmoid colon fistula caused by ovarian teratoma. PMID- 25926229 TI - Fully covered self-expandable metal stent treatment of spurting bleeding into the biliary tract after endoscopic ultrasound-guided fine-needle aspiration of a solid lesion of the pancreatic head. PMID- 25926230 TI - Ileocutaneous fistula with distal ileal narrowing treated with an esophageal stent. PMID- 25926232 TI - Mantle cell lymphoma complicated by multiple widespread extranodal gastrointestinal lesions. PMID- 25926238 TI - Hyperactive mTORC1 signaling is unaffected by metformin treatment in aged skeletal muscle. AB - INTRODUCTION: Appropriate activation of growth signaling pathways, specifically mammalian target of rapamycin complex 1 (mTORC1), is central to muscle mass and metabolism. The goal of these studies was to examine the effects of metformin on mTORC1 signaling in aged skeletal muscle in an attempt to normalize growth signaling. METHODS: Aged (23m) and young (3m) male mice were fed a low fat diet without or with 0.5% metformin for up to 8 weeks, then mTORC1-related signaling was examined in the plantar flexor complex. RESULTS: Metformin had no significant effect on lowering body weight or muscle mass in aged animals, nor altered p70 S6 Kinase 1 (S6K1) and 4E-binding protein 1 (4E-BP1) phosphorylation. However, it significantly (P < 0.05) reduced body weight and lowered S6K1 and rpS6 phosphorylation in the young. CONCLUSIONS: Collectively, these data suggest metformin is ineffective at normalizing growth signaling in aged skeletal muscle. PMID- 25926239 TI - Fano Resonance and Spectrally Modified Photoluminescence Enhancement in Monolayer MoS2 Integrated with Plasmonic Nanoantenna Array. AB - The manipulation of light-matter interactions in two-dimensional atomically thin crystals is critical for obtaining new optoelectronic functionalities in these strongly confined materials. Here, by integrating chemically grown monolayers of MoS2 with a silver-bowtie nanoantenna array supporting narrow surface-lattice plasmonic resonances, a unique two-dimensional optical system has been achieved. The enhanced exciton-plasmon coupling enables profound changes in the emission and excitation processes leading to spectrally tunable, large photoluminescence enhancement as well as surface-enhanced Raman scattering at room temperature. Furthermore, due to the decreased damping of MoS2 excitons interacting with the plasmonic resonances of the bowtie array at low temperatures stronger exciton plasmon coupling is achieved resulting in a Fano line shape in the reflection spectrum. The Fano line shape, which is due to the interference between the pathways involving the excitation of the exciton and plasmon, can be tuned by altering the coupling strengths between the two systems via changing the design of the bowties lattice. The ability to manipulate the optical properties of two dimensional systems with tunable plasmonic resonators offers a new platform for the design of novel optical devices with precisely tailored responses. PMID- 25926241 TI - Tuberculosis in undiagnosed children: what are the criteria to start treatment in Portugal? PMID- 25926236 TI - The role of epidemic resistance plasmids and international high-risk clones in the spread of multidrug-resistant Enterobacteriaceae. AB - Escherichia coli sequence type 131 (ST131) and Klebsiella pneumoniae ST258 emerged in the 2000s as important human pathogens, have spread extensively throughout the world, and are responsible for the rapid increase in antimicrobial resistance among E. coli and K. pneumoniae strains, respectively. E. coli ST131 causes extraintestinal infections and is often fluoroquinolone resistant and associated with extended-spectrum beta-lactamase production, especially CTX-M-15. K. pneumoniae ST258 causes urinary and respiratory tract infections and is associated with carbapenemases, most often KPC-2 and KPC-3. The most prevalent lineage within ST131 is named fimH30 because it contains the H30 variant of the type 1 fimbrial adhesin gene, and recent molecular studies have demonstrated that this lineage emerged in the early 2000s and was then followed by the rapid expansion of its sublineages H30-R and H30-Rx. K. pneumoniae ST258 comprises 2 distinct lineages, namely clade I and clade II. Moreover, it seems that ST258 is a hybrid clone that was created by a large recombination event between ST11 and ST442. Epidemic plasmids with blaCTX-M and blaKPC belonging to incompatibility group F have contributed significantly to the success of these clones. E. coli ST131 and K. pneumoniae ST258 are the quintessential examples of international multidrug-resistant high-risk clones. PMID- 25926240 TI - Children's exposure to second hand smoke at home: a cross-sectional study in Portugal. AB - Second-hand tobacco smoke (SHS) is a major indoor pollutant that causes serious health problems for all exposed, especially children. Children are often exposed to SHS at home, due to parental or other households' or guests' smoking. This study describes Portuguese children's exposure to SHS at home (total and by Portuguese main regions). In 2010/2011, a questionnaire was applied to a sample of Portuguese children in the 4th grade (N=3187, mean age 9.05+/-0.7 years, 51.1% male). Descriptive analysis, chi-square tests and crude odds ratios were performed. Of the participants, 62.9% of those with smoking parents and 19.2% of those with non-smoking parents were exposed to SHS at their home. Parental smoking varied significantly among regions and was significantly associated with children's exposure to SHS at home. Children's exposure to SHS at home was high, especially if their parents smoke. Children living in Lisbon Region presented the highest SHS exposure rate. The association of SHS exposure with geographic regions suggests the influence of social and contextual factors on smoking behaviour and on tobacco control effectiveness. Our findings highlight the need to effectively prevent children's SHS exposure at their home and to develop tailored tobacco control measures by region. PMID- 25926242 TI - Immune influence of pregnancy on human H7N9 infection: a case report. AB - INTRODUCTION: H7N9 infection has raised serious concerns worldwide. Pregnant women were considered to be at a high risk of influenza infection. Normal pregnancy was dependent on T helper (Th) 2 deviation. However, whether pregnancy influences the immune status of influenza H7N9 patients has not been reported. CASE REPORT: Here, we reported a case of pregnant woman in the first trimester with H7N9 infection compared with the two non-pregnant female H7N9 patients for clinical features and relevant immunological changes. We found that there were no differences in plasma levels of Th1 and Th2 cytokines between the pregnant and non-pregnant patients, and there was no Th2 deviation in the acute phase. However, the Th2 deviation was recurrent along with the clearance of infection in the H7N9 pregnant patient. CONCLUSION: These cases highlighted that the pregnant patient infected with H7N9 could induce an effective Th1 immune response equal to that of non-pregnant patients with H7N9 virus infection, although the pregnancy itself could lead to a Th2 deviation. These data suggested that pregnant patients could acquire a similar antiviral response for H7N9 infection versus non-pregnant patients. PMID- 25926243 TI - Pulmonary function, functional capacity and quality of life in adults with cystic fibrosis. AB - BACKGROUND: As there are few studies on the impact of respiratory and functional status on the quality of life domains in adults with cystic fibrosis, this study aimed to evaluate the association between respiratory function, functional capacity and quality of life in these subjects. METHODS: This is a cross sectional study, where adults with clinical and laboratorial diagnoses of CF fibrosis underwent pulmonary function tests, the six-minute walk distance test (6MWT) and responded to the Cystic Fibrosis Questionnaire-Revised (CFQ-R). Descriptive statistics was used to summarize the findings. The associations were tested by means of Pearson's or Spearman tests, and the significance level was set at 5%. RESULTS: The 21 patients who completed the study presented with reduced quality of life in all CFQ-R domains, obstructive pulmonary disease and reduced 6MWT distance. The following associations were found between pulmonary function and CFQ-R domains: forced vital capacity - FVC (%) and treatment burden and digestive symptoms (r=-0.433, p<0.05; r=-0.443, p<0.05, respectively), forced expiratory volume in one second - FVC ratio - FEV1/FVC (%) and physical functioning, social and respiratory symptoms (r=0.5, p<0.05; r=0.58, p<0.01; r=0.45, p<0.05, respectively), residual volume (%) and physical functioning (r=0.49, p<0.05), airways' resistance - Raw and physical functioning and emotional functioning (r=-0.44, p<0.05; r=-0,46, p<0.05, respectively), carbon monoxide diffusing capacity (%pred) and physical functioning (r=-0,51; p<0.05). CONCLUSION: Adults with CF have reduced quality of life, which in part is associated with the severity of their lung function. PMID- 25926244 TI - Respiratory parameters in elite athletes--does sport have an influence? AB - INTRODUCTION: Unlike large population studies about cardiovascular components and how they adapt to intensive physical activity, there is less research into the causes of enlargement of the respiratory system in athletes (e.g. vital capacity, maximum flow rates and pulmonary diffusion capacity). The purpose of this research was to study and compare pulmonary function in different types of sports and compare them with controls in order to find out which sports improve lung function the most. MATERIALS AND METHOD: Pulmonary functional capacities, vital capacity (VC), forced vital capacity (FVC), forced expiratory volume in one second (FEV1) and maximum voluntary ventilation (MVV) of 493 top athletes belonging to 15 different sports disciplines and of 16 sedentary individuals were studied. Pulmonary function test was performed according to ATS/ERS guidelines. RESULTS: Basketball, water polo players and rowers had statistically higher vital capacity (VC), forced vital capacity (FVC), forced expiratory volume in one second (FEV1) than the healthy sedentary control individuals. Football and volleyball players had lower VC while FVC was higher in the football group compared to controls. Peak expiratory flow was lower in boxing, kayak, rugby, handball, taekwondo and tennis. The maximum voluntary ventilation (MVV) was significantly higher in water polo players and rowers. Boxers had statistically lower MVV than the controls. Players of other sports did not differ from the control group. CONCLUSION: The study suggests that specific type of training used in basketball, water polo or rowing could have potential for improving pulmonary function and rehabilitation. PMID- 25926245 TI - Pancreatopleural fistula contributing to a large volume recurrent pleural effusion. PMID- 25926247 TI - Bronchial-pulmonary adenocarcinoma subtyping relates with different molecular pathways. AB - Lung cancer is one of the most common cancers in the world with a high mortality rate. We analyzed 45 surgical samples of the adenocarcinoma, 13 with lymph node metastasis. APC, BCL2, chromogranin A, CK 5/6/18 (LP34), CK20, CK7, cyclin D1, EGFR, ERCC1, HER2, Ki67, LRP, MRP, P53, RB and TTF1 expressions were evaluated by immunohistochemistry (IHC). Higher Ki67, APC, ERCC1 expressions and lower TTF1 expression were identified in advanced stages (IIA and IIIA) of adenocarcinomas, which reflect a more aggressive, less differentiated, possibly a non-TRU adenocarcinoma. Acinar, micropapillary and BA/lepidic adenocarcinoma patterns were the most similar patterns and papillary was the most different pattern followed by solid pattern, according to expression of these markers. Different adenocarcinoma patterns are engaged with different molecular pathways for carcinogenesis, based on the differences of expression. Acinar, BA/lepidic and micropapillary showed higher TTF1 expression (type TRU), and papillary and solid patterns revealed less TTF1 expression, exhibiting a non-TRU/bronchial phenotype. Solid pattern revealed lower HER2 and higher EGFR and ERCC1 (this compared to papillary) expression; papillary higher HER2 and lower ERCC1 expressions; micropapillary higher RB expression; and acinar lower ERCC1 and higher EGFR expressions. Ciclin D1 seems to have more importance in acinar and BA/lepidic patterns than in micropapillary. ERCC1 protein expression in micropapillary, solid and BA/lepidic patterns may indicate DNA repair activation. Inhibition of apoptosis could be explained by BCL2 overexpression, present in all adenocarcinoma patterns. MRP-1 and LRP were overexpressed in all patterns, which may have implications for drug resistance. Further studies are needed to interpret these data regarding to therapy response in advanced staged bronchial pulmonary carcinomas. PMID- 25926248 TI - Respiratory functional evaluation and pulmonary hyperinflation in asymptomatic smokers: Preliminary study. AB - OBJECTIVES: To investigate the respiratory function and lung hyperinflation in asymptomatic smokers without previous pulmonary pathology and with normal chest radiography. To identify tobacco-related diseases and to correlate tobacco consumption, duration of exposure to tobacco smoke and urinary cotinine with the existence of tobacco-related disease. MATERIAL AND METHODS: Case-controlled study with pairing by sex, age, and body mass index. CASE DEFINITION: smokers who presented to the first appointment of smoking cessation at the Hospital Sousa Martins (HSM) without respiratory symptoms and with normal chest radiography. Definition of control: users without current and/or past tobacco exposition and with plethysmography and chest radiography at HSM within normal parameters. RESULTS: Reductions in FEV1/FVC, FEF 75%, FEF 25-75% and the cardiothoracic index were detected in smokers and showed a moderated inverse correlation of TLC (with statistical meaning) compared with the control group. Approximately 31.2% of the smokers showed extrapulmonary disease related to tobacco, and 9.38% of the smokers exhibited subclinical chronic obstructive pulmonary disease (COPD). Smokers with tobacco-related diseases presented a mean age and RV/TLC ratio superior to smokers without pathology. DISCUSSION: The reduction of the mean values of FEV1/FVC, FEF 75%, FEF 25-75% and the cardiothoracic index seems to indicate precocious pulmonary dysfunction. This work aims to reveal the importance of detecting premonitory anomalies of pulmonary disease during the subclinical phase in patients at risk. Smoking must be considered a factor of multisystemic repercussion; thus, intervention opportunities in this particular group must not be wasted. This preliminary study identifies potentially promising variables with the aim of testing the hypothesis that there can be premonitory alterations in COPD, according to its evolution versus reversibility after smoking cessation. This work will be concluded in a future study. PMID- 25926246 TI - Real-life efficacy and safety of omalizumab in Portuguese patients with persistent uncontrolled asthma. AB - INTRODUCTION: The real life effectiveness, safety and the use of omalizumab for Portuguese patients with uncontrolled persistent allergic asthma are not sufficiently well known. The objective of this report was to make an evaluation, in a post-marketing, non-interventional, observational registry, of the Portuguese population included in the eXpeRience study. METHODS: The methods used in this report are the same as the global eXpeRience ones, applied to a Portuguese sub-population. Patients with uncontrolled allergic asthma who had started omalizumab within the previous 15 weeks were enrolled and received omalizumab add-on therapy for 24 months. The physicians' global evaluation of treatment effectiveness (GETE), asthma symptoms and control (ACT score), quality of life (mini-AQLQ score), exacerbations, and serious adverse events (SAE) were reported. RESULTS: Of the 943 patients recruited in the eXpeRience registry, 62 patients were from Portugal. 62.1% of them were observed to be responders with good/excellent GETE assessment at Week 16. Clinically meaningful improvements in asthma control (ACT score) and quality of life (mini-AQLQ score) were observed with omalizumab therapy at Months 12 (mean change: +7.7 [n=35]; +2.1 [n=20], respectively) and 24 (mean change: +7.0 [n=26]; +2.7 [n=13], respectively). Asthma symptoms and rescue medication usage were reduced to <=1 day/week at Month 24 from a baseline of >=3.5 days/week. The proportion of patients with no clinically significant exacerbations increased from 6.5% during pre-treatment (n=62) to 50% at Month 12 (n=54) and 60% at Month 24 (n=45). CONCLUSION: The findings from the Portugal subpopulation of eXpeRience registry confirm that omalizumab add-on therapy is efficacious and well tolerated in the management of uncontrolled persistent allergic asthma. Another pertinent issue is the fact that the Portuguese subpopulation response is similar to the international population average of the study. PMID- 25926249 TI - Asthma control in the Portuguese National Asthma Survey. AB - INTRODUCTION: We aimed (1) to measure asthma control using a structure questionnaire and patient self-perception of asthma-control in the Portuguese National Asthma Survey (INAsma) and (2) to study the relationship between asthma control and asthma-related quality of life. METHODS: We analyze data of asthma patients from a cross-sectional, nationwide telephone interview study - INAsma. Controlled asthma was defined as CARAT global score >24 or CARAT lower airways score >=16. Mini-AQLQ was used to measure quality of life. RESULTS: Two hundred and seven (56.9% [95%CI: 51.8-62.0]) of the 364 patients had controlled asthma. Most patients with non-controlled asthma (88%) perceived their disease as controlled. Patients with controlled asthma presented higher mini-AQLQ scores (median, P25-P75; 6.6, 6.0-6.9) than those with non-controlled asthma (4.9, 3.7 5.7) (p<0.001) and a significant positive correlation between CARAT and mini-AQLQ scores was observed (r=0.706; p<0.001). CONCLUSION: More than half of the Portuguese patients presented controlled asthma and showed significantly better asthma-related quality of life. Almost 9 out of 10 patients with non-controlled disease have poor perception of their asthma control, which may hinder them from seeking better asthma control. PMID- 25926250 TI - Incidence and risk factors of major toxicity associated to first-line antituberculosis drugs for latent and active tuberculosis during a period of 10 years. AB - INTRODUCTION: Adverse drug reactions (ADR) to first-line antituberculosis drugs are frequent and have important implications that may affect the effectiveness of treatment and course of tuberculosis (TB). MATERIAL AND METHODS: Retrospective data analysis of clinical records and national registration forms from patients with ADR to first line antituberculosis that occurred between 2004 and 2013 at a Portuguese Pulmonology Diagnostic Centre, and from a case-control population matched by sex, age and year of initiation of treatment. RESULTS: Of the 764 patients treated with antituberculosis drugs, 55 (52.7% male, 92.7% European, mean age 50.8+/-19.5 years) had at least one severe ADR and six had a second ADR, for a total of 61 events. The most frequent ADR were hepatotoxicity (86.9%), rash (8.2%) and others, such as ocular toxicity, gastrointestinal intolerance and angioedema (4.9%). Isoniazid, alone or in combination, was the antituberculosis drug most associated to toxicity. Due to ADR, treatment time changed an average of 1.0+/-2.6 months (range -3.4 to 10.6). There was no correlation between age or gender and the overall incidence of ADR although we found a significant association between younger age and an increased risk of hepatotoxicity (P=0.035). There was also a statistically significant relationship between ADR and diabetes mellitus (P=0.042) but not for other comorbidities or multi resistant TB risk factors. CONCLUSIONS: This study found a high frequency of ADR with strong impact on subsequent therapeutic orientation. What seems to be of particular interest is the relationship between ADR and diabetes mellitus and the increased frequency of hepatotoxicity in younger patients. PMID- 25926251 TI - Clinical impact of adaptive servoventilation compared to other ventilatory modes in patients with treatment-emergent sleep apnea, central sleep apnea and Cheyne Stokes respiration. AB - INTRODUCTION: Adaptive servoventilation is a recent ventilatory mode initially designed to treat Cheyne-Stokes respiration (CSR). Recently, the efficacy of ASV has been discussed for the treatment of central sleep apnea (CSA) and treatment emergent central sleep apnea (treatment-emergent CSA) where other forms of traditional positive airway pressure (PAP) may be insufficient. OBJECTIVES: To compare the clinical impact of ASV with other forms of PAP in treating patients with treatment-emergent CSA, CSA and CSR. METHODS: Medical data of all the patients who underwent polysomnography (PSG) with ASV titration were evaluated. The patients were divided into two groups according to the mode of ventilation reimbursed: ASV and PAP (AutoCPAP/CPAP/BIPAP). All patients had a minimal follow up of 6 months. Both groups were compared in terms of symptoms, apnea hypopnea index, compliance, cardiac function and cardiovascular events. RESULTS: ASV titration was performed in 33 patients (30M/3F) with a mean age of 69+/-8 years. The majority (58%) present a treatment-emergent SA and 42% a CSA and or CSR. The median initial diagnostic AHI was 46+/-22events/h. After the initial diagnosis, 28 patients were treated with PAP and 5 with servoventilation. All of the patients treated with PAP were posteriorly submitted to PSG and ASV titration because of suboptimal response to PAP. Despite a clear indication for ASV, due to differences in reimbursement, 15 patients continued treatment with PAP (12 with AutoCPAP, 1 with BIPAP and 2 with CPAP) and 16 changed to ASV. Two patients were lost in follow-up. In both groups, most of patients present a treatment-emergent SA (53% in ASV group vs. 67% in PAP group) or a CSA/CSR (29.4% in ASV group vs. 20% in PAP). After ASV titration, the mean follow-up was 25+/-14 months. Both groups (ASV vs. PAP) were similar in terms of compliance (77+/-23% vs.88+/-14%) and in terms of Epworth sleepiness scale score (6+/-5 vs. 7+/-5). There was a statistical difference in terms of residual AHI: mean AHI was 4+/-3 in ASV group and 9+/-3 in PAP group (P=0.005). We found no differences in terms of left ventricular fractional shortening (ASV 33+/-10% vs. PAP 32+/-10%). Although no difference was observed between the 2 groups in terms of non-fatal cardiovascular events (3 events in each group), 2 fatal cardiovascular events occurred in the PAP group (sudden death). CONCLUSIONS: These data confirm that ASV is an efficient treatment in patients with treatment-emergent CSA, CSA/CSR significantly decreasing residual AHI. In both groups, compliance rate was high and sleepiness improved. It is relevant that the 2 patients who died of sudden death were treated with PAP. PMID- 25926252 TI - Long-term impact of pre-operative physical rehabilitation protocol on the 6-min walk test of patients with adolescent idiopathic scoliosis: A randomized clinical trial. AB - BACKGROUND: Monitored physical activities in patients with adolescent idiopathic scoliosis (AIS) have been shown to improve physical performance, endurance and cardiopulmonary function and may be assessed by the 6-min walk test (6MWT). We aimed to evaluate the long-term results of the 6MWT after a rehabilitation protocol employed before surgical correction for AIS. METHODS: This prospective randomized clinical trial studied the impact of a 4-month pre-operative physical rehabilitation protocol on post-operative cardiopulmonary function and physical endurance, by using the 6MWT, in patients with AIS submitted to surgical correction, comparing them to matched controls without physical rehabilitation. Studied variables were heart and respiratory rate, systolic and diastolic blood pressure, peripheral blood oxygen saturation, Borg score, and distance walked. Patients were assessed at baseline, after 4 months of rehabilitation, and 3, 6 and 12 months post-operatively. RESULTS: A total of 50 patients with AIS were included in the study and allocated blindly, by simple randomization, into either one of the two groups, with 25 patients each: study group (pre-operative physical rehabilitation) and control group. The physical rehabilitation protocol promoted significant progressive improvement in heart and respiratory rate, peripheral blood oxygen saturation, distance walked, and level of effort assessed by the Borg scale after surgery. CONCLUSIONS: Post-surgical recovery, evaluated by 6MWT, was significantly better in patients who underwent a 4-month pre-operative physical rehabilitation protocol. PMID- 25926253 TI - Lung adenocarcinoma: Sustained subtyping with immunohistochemistry and EGFR, HER2 and KRAS mutational status. AB - Pulmonary adenocarcinomas are still in the process of achieving morphological, immunohistochemical and genetic standardization. The ATS/ERS/IASLC proposed classification for lung adenocarcinomas supports the value of the identification of histological patterns, specifically in biopsies. Thirty pulmonary adenocarcinomas were subjected to immunohistochemical study (CK7, CK5, 6, 18, CK20, TTF1, CD56, HER2, EGFR and Ki-67), FISH and PCR followed by sequencing and fragment analysis for EGFR, HER2 and KRAS. Solid pattern showed lower TTF1 and higher Ki-67 expression. TTF1 expression was higher in non-mucinous lepidic and micropapillary patterns when compared to acinar and solid and acinar, solid and mucinous respectively. Higher Ki67 expression was present in lepidic and solid patterns compared to mucinous. EGFR membranous staining had increasing expression from non-mucinous lepidic/BA pattern to solid pattern and micropapillary until acinar pattern. EGFR mutations, mainly in exon 19, were more frequent in females, together with non-smoking status, while KRAS exon 2 mutations were statistically more frequent in males, especially in solid pattern. FISH EGFR copy was correlated gross, with mutations. HER2 copy number was raised in female tumours without mutations, in all cases. Although EGFR and KRAS mutations are generally considered mutually exclusive, in rare cases they can coexist as it happened in one of this series, and was represented in acinar pattern with rates of 42.9% and 17.9%, respectively. EGFR mutations were more frequent in lepidic/BA and acinar patterns. Some cases showed different EGFR mutations. The differences identified between the adenocarcinoma patterns reinforce the need to carefully identify the patterns present, with implications in diagnosis and in pathogenic understanding. EGFR and KRAS mutational status can be determined in biopsies representing bronchial pulmonary carcinomas because when a mutation is present it is generally present in all the histological patterns. PMID- 25926254 TI - Diagnostic yield of sputum microbiological analysis in the diagnosis of pulmonary tuberculosis in a period of 10 years. AB - INTRODUCTION: Pulmonary tuberculosis (TB) requires an early diagnosis for prompt introduction of treatment and prevention of transmission. Definitive diagnosis is obtained by microbiological culture and identification of Mycobacterium tuberculosis in respiratory specimens, mostly sputum samples. MATERIALS AND METHODS: Retrospective data analysis of all patients suspected of pulmonary TB that submitted three consecutive sputum samples to the Pulmonology Diagnostic Center (PDC) Laboratory between 2004 and 2013. Extrapulmonary TB cases were excluded. Four microbiological analyses were executed on each specimen: two smears with Ziehl-Neelsen staining, direct and concentrate; and two culture examinations, one in liquid and one in solid medium. Statistical analysis was performed by SPSS. RESULTS: A total of 694 patients were enrolled in this study (65% men, mean age 48.5+/-18.6 years, 97% Portuguese), most of them exhibiting TB related complaints. Pulmonary TB was diagnosed in 41% of the patients; 54% had non-specific radiological changes and 34% had pulmonary cavitation. The cumulative sensitivity rates of each of the three smears were 24.6%, 27.7% and 28.8% for concentrated samples and 19.3%, 20.4% and 22.5% for direct samples. The cumulative sensitivities of sputum culture were 33.3%, 37.9% and 41.8% for solid medium, and 43.9%, 51.6% and 55.4% for liquid medium. Pondering all forms of microbiological analysis, the cumulative sensitivities of each sample were 51.2%, 59.6% and 63.2%. There was an incremental yield of 8.4% for the second specimen and 3.5% for the third specimen. All sensitivity rates were higher among patients with pulmonary cavitation. CONCLUSIONS: This study showed an incremental yield with more than one sputum sample. However, overall sensitivity remained low, suggesting a need for new diagnostic strategies and novel and better diagnostic tools. PMID- 25926255 TI - Correlations between osteoprotegerin serum levels and body composition parameters in patients with sleep apnea syndrome and the possible influence on cardiovascular risk. AB - INTRODUCTION: Osteoprotegerin (OPG) is a member of the tumor necrosis factor family and a key regulator in bone turnover; it plays a role in the development of many cardiovascular diseases and may be treated as a marker of vascular damage. Bioelectrical impedance analysis (BIA) is a reliable, non-invasive and effective technique for measuring body composition. The aim of the study was to evaluate correlations between osteoprotegerin serum levels and body composition parameters in sleep apnea patients and their influence on cardiovascular risk. MATERIAL AND METHODS: A total of 125 patients with newly diagnosed OSA were enrolled in the study (including 34 females). The mean age was 54.48+/-8.81 years, mean AHI 33.16+/-20.44/h and mean BMI 33.76+/-7.18. A control group comprised 59 healthy subjects with mean age of 51.27+/-12.97 years and mean BMI 29.47+/-5.42. All subjects underwent a nocturnal respiratory polygraphy and body composition measurements were taken with bioelectrical impedance analysis. OPG serum levels were measured using the enzyme-linked immunosorbent assay (ELISA) method. RESULTS: In OSA patients OPG correlated negatively with muscle mass percentage (MM%), phase angle, fat free mass percentage (FFM%) and body cell mass percentage (BCM%), while there was a positive correlation between osteoprotegerin and fat mass percentage (FM%). We demonstrated higher OPG serum levels in OSA patients with cardiovascular diseases than in those without comorbidities (4.01 vs 3.46pmol/l, p<0.05). CONCLUSION: Our findings, combined with previous observations in other diseases, suggest that elevated OPG serum levels together with selected body composition parameters may be helpful in identifying OSA patients with increased cardiovascular risk. PMID- 25926256 TI - Constrictive bronchiolitis, two clinical reports. PMID- 25926257 TI - Tuberculosis retreatment in Northern Portugal. PMID- 25926258 TI - The value of rapid on-site evaluation during EBUS-TBNA. AB - BACKGROUND: Rapid on-site evaluation (ROSE) has the potential to increase endobronchial ultrasound-guided transbronchial needle aspiration (EBUS-TBNA) accuracy in the diagnosis of mediastinal lesions and lung cancer staging. However, studies have reported controversial results. The purpose of our study was to evaluate the influence of ROSE on sample adequacy and diagnostic accuracy of EBUS-TBNA. METHODS: Prospective observational study that enrolled 81 patients who underwent EBUS-TBNA for investigation of hilo-mediastinal lesions or lung cancer staging. The first 41 patients underwent EBUS-TBNA with ROSE (ROSE group) and the last 40 patients without ROSE (non-ROSE group). Sample adequacy and diagnostic accuracy of EBUS-TBNA in both groups were compared. RESULTS: Adequate samples were obtained in 93% of the patients in the ROSE group and 80% in non ROSE group (p=0.10). The diagnostic accuracy of EBUS-TBNA was 91% in ROSE group and 83% in non-ROSE group (p=0.08). Analyzing the EBUS-TBNA purpose, in the subgroup of patients who underwent EBUS-TBNA for investigation of hilo mediastinal lesions, these differences between ROSE and non-ROSE group were higher compared to lung cancer staging, 93% of patients with adequate samples in the ROSE group vs. 75% in the non-ROSE group (p=0.06) and 87% of diagnostic accuracy in ROSE group vs. 77% in non-ROSE group (p=0.10). CONCLUSIONS: Despite the lack of statistical significance, ROSE appears to be particularly useful in the diagnostic work-up of hilo-mediastinal lesions, increasing the diagnostic yield of EBUS-TBNA. PMID- 25926259 TI - Characterizing a population of smokers: An observational, transversal, non randomized pilot study based on smoking history and spirometry changes. PMID- 25926260 TI - A rare benign tumor of tracheobronchial tree: endobronchial fibroepithelial polyp. PMID- 25926261 TI - Lung transplant: complications and quality of life. PMID- 25926262 TI - Prognostic value of plasma D-dimer level in adults with community-acquired pneumonia: a prospective study. PMID- 25926263 TI - Asthma control and exacerbations in patients with severe asthma treated with omalizumab in Portugal. AB - The analysis of outcomes from patients with severe asthma treated with omalizumab, using real-life prospective data, should contribute to future informed decisions about this treatment in Portugal. The aim of this study was to assess the clinical effect of omalizumab in Portuguese patients with severe persistent allergic asthma, considering specifically asthma control and exacerbations. This was an observational, prospective, multicentre study. Data were collected at routine care over a 12-month period. Disease control was defined by Control of Allergic Rhinitis and Asthma Test (CARAT) global score >24. All asthma patients already under treatment with omalizumab in 7 departments from 6 Portuguese hospitals were included (n=48). Most (77%) patients were female and the mean (SD) age was 51.9 (10.2) years old. During the study period, asthma was controlled in 34% of the visits and the 12-month exacerbation rate was 1.7 per patient (0.6 with unscheduled medical care). One-third of the patients needed unscheduled medical care because of asthma and 29% had to start or increase oral corticosteroid. There was still a 41% reduction in the total sum of oral corticosteroids usage from the first to the last trimester of the study. During routine treatment with omalizumab, Portuguese patients with severe asthma achieved asthma control in 1/3 of the visits and only 1/3 needed unscheduled or Emergency Room care because of asthma exacerbations. These outcomes support the maintenance of the clinical effect during treatment with omalizumab in routine care in Portugal. PMID- 25926264 TI - Insomnia as an expression of obstructive sleep apnea syndrome--the effect of treatment with nocturnal ventilatory support. AB - INTRODUCTION: Obstructive sleep apnea syndrome (OSAS) and insomnia often coexist, and it is estimated that nearly half of those who suffer from the former report symptoms of the latter. The fact that these patients have no other causes of insomnia indicates that it is a sign of OSAS. OBJECTIVE: The aim of the study is to evaluate the effectiveness of nocturnal ventilatory support (NVS) in the treatment of insomnia secondary to OSAS. MATERIALS AND METHODS: In order to conduct the retrospective study, the authors reviewed the medical records of patients with insomnia and OSAS that had received NVS. Patients with psychiatric disorders, sleep movement disorders, psycho-physiological insomnia, circadian rhythm sleep disorders, inadequate sleep hygiene, use and abuse of hypnotic agents, stimulants, antidepressants, anxiolytics and alcohol, were excluded. For the selected patients, the effects of NVS in terms of clinical signs and symptoms of insomnia, apnea-hypopnea index (AHI), Epworth Sleepiness Scale (ESS) score, and number of sleep hours were analyzed, before and after treatment with NVS. RESULTS: After reviewing 1241 medical records, 56 patients were selected, with a mean age of 60.9+/-10.0 years. Twenty-two (39.3%) suffered from intermediate insomnia, 19 (33.9%) had initial insomnia, eight (14.3%) had the mixed type, and seven patients (12.5%) had terminal insomnia. The majority of patients (n=48; 85.7%) were treated with auto-titrating continuous positive airway pressure (APAP). Forty-four patients (78.6%) overcame insomnia; insomnia symptoms persisted in nine (16.1%), and three (5.4%) patients abandoned during the medical follow-up. There was an association between the type of insomnia and its resolution and, in percentage terms patients with the mixed type did not manage to overcome insomnia symptoms (75%). There was a statistically significant difference between patients that overcame insomnia and those who did not in terms of the average time which elapsed between the initiation of treatment with NVS and compliance with the adherence criteria: 161+/-61 days for the former, and 225+/-141 days for the latter (p=0.003). Before and after the NVS treatment, patients slept an average of 5.29+/-1.37 and 6.37+/-1.55h per night, respectively (p<0.001). Among the patients who overcame insomnia, six did not meet the treatment adherence criteria: five adhered more than 4h/night in less than 70% of all nights (60.6+/-3.2%), and one patient adhered less than 4h in all nights (3.5h/night). CONCLUSION: NVS has proved effective in treating insomnia secondary to OSAS, and favorable results could be observed even in patients that did not meet the criteria of NVS adherence. Results suggest that all insomnia subtypes, except the mixed subtype, may derive from OSAS. PMID- 25926265 TI - Questionable Validity of Peptide-Based ELISA Strategies in the Diagnostics of Cardiopathogenic Autoantibodies That Activate G-Protein-Coupled Receptors. PMID- 25926266 TI - Fibromuscular dysplasia: what the radiologist should know: a pictorial review. AB - Fibromuscular dysplasia (FMD) is an idiopathic, segmentary, non-inflammatory and non-atherosclerotic disease that can affect all layers of both small- and medium calibre arteries. The prevalence of FMD is estimated between 4 and 6 % in the renal arteries and between 0.3 and 3 % in the cervico-encephalic arteries. FMD most frequently affects the renal, carotid and vertebral arteries, but it can theoretically affect any artery. Radiologists play an important role in the diagnosis of FMD, and good knowledge of FMD's signs will certainly help reduce the delay between the first symptoms and diagnosis. The common string-of-beads aspect is well known, but less common presentations also have to be considered. These less common imaging findings include vascular loops, fusiform vascular ectasia, arterial dissection, aneurysm and subarachnoid haemorrhage. These radiologic presentations should be known by radiologists in order to diagnose possible FMD, particularly when present in young females or when associated with personal or familial hypertension, to reduce the delay between the onset of the first symptom and the final diagnosis. The patients have to be referred to specialised FMD centres for dedicated management. TEACHING POINTS: * Fibromuscular dysplasia is not a rare disease. * Radiologists should recognise less common presentations to orient specific management. * Vascular loops, fusiform vascular ectasia and a "string-of-beads" aspect are typical presentations. * Arterial dissection, aneurysm and subarachnoid haemorrhage are less typical radiologic presentations. PMID- 25926268 TI - Generators and Connectivity of the Early Auditory Evoked Gamma Band Response. AB - High frequency oscillations in the gamma range are known to be involved in early stages of auditory information processing in terms of synchronization of brain regions, e.g., in cognitive functions. It has been shown using EEG source localisation, as well as simultaneously recorded EEG-fMRI, that the auditory evoked gamma-band response (aeGBR) is modulated by attention. In addition to auditory cortex activity a dorsal anterior cingulate cortex (dACC) generator could be involved. In the present study we investigated aeGBR magnetic fields using magnetoencephalography (MEG). We aimed to localize the aeGBR sources and its connectivity features in relation to mental effort. We investigated the aeGBR magnetic fields in 13 healthy participants using a 275-channel CTF-MEG system. The experimental paradigms were two auditory choice reaction tasks with different difficulties and demands for mental effort. We performed source localization with eLORETA and calculated the aeGBR lagged phase synchronization between bilateral auditory cortices and frontal midline structures. The eLORETA analysis revealed sources of the aeGBR within bilateral auditory cortices and in frontal midline structures of the brain including the dACC. Compared to the control condition the dACC source activity was found to be significantly stronger during the performance of the cognitively demanding task. Moreover, this task involved a significantly stronger functional connectivity between auditory cortices and dACC. In accordance with previous EEG and EEG-fMRI investigations, our study confirms an aeGBR generator in the dACC by means of MEG and suggests its involvement in the effortful processing of auditory stimuli. PMID- 25926267 TI - Epithelial-specific ETS-1 (ESE1/ELF3) regulates apoptosis of intestinal epithelial cells in ulcerative colitis via accelerating NF-kappaB activation. AB - Epithelial-specific ETS-1 (ESE1), also named as ELF3, ERT and ESX, belonging to the ETS family of transcription factors, exerts multiple activities in inflammation, epithelial differentiation and cancer development. Previous data demonstrated that ESE1 synergizes with NF-kappaB to induce inflammation and drive tumor progress, and the nuclear translocation of ESE1 promotes colon cells apoptosis. However, the expression and biological functions of ESE1 in ulcerative colitis (UC) remain unclear. In this study, we reported for the first time that ESE1/ELF3 was over-expressed in intestinal epithelial cells (IECs) of patients with UC. In DSS-induced colitis mouse models, we observed the up-regulation of ESE1/ELF3 accompanied with the elevated levels of IEC apoptotic markers (active caspase-3 and cleaved PARP) and NF-kappaB activation indicators [phosphorylated NF-kappaB p65 subunit (p-p65) and p-IkappaB] in colitis IECs. Increased co localization of ESE1/ELF3 with active caspase-3 (and p-p65) in IECs of the DSS induced colitis group further indicated the possible involvement of ESE1/ELF3 in NF-kappaB-mediated IEC apoptosis in UC. Employing the TNF-alpha-treated HT-29 cells as an IEC apoptosis model, we confirmed the positive correlation of ESE1/ELF3 with NF-kappaB activation and caspase-dependent IEC apoptosis in vitro. Immunoprecipitation and immunofluorescence assay revealed the physical interaction and increased nuclear translocation of ESE1/ELF3 and the NF-kappaB p65 subunit in TNF-alpha-treated HT-29 cells. Knocking ESE1/ELF3 down by siRNA significantly alleviated TNF-alpha-induced NF-kappaB activation and cellular apoptosis in HT-29 cells. Taken together, our data suggested that ESE1/ELF3 may promote the UC progression via accelerating NF-kappaB activation and thus facilitating IEC apoptosis. PMID- 25926269 TI - Systematic review with meta-analysis: comparison between therapeutic regimens for paediatric chronic hepatitis C. AB - BACKGROUND: To decide when and how to treat children with chronic hepatitis C is an ongoing debate. AIM: To compare the outcomes of therapy for children with chronic hepatitis C. METHODS: An electronic database assessed clinical trials with sustained virological response rates specified by genotype. The data were extracted according to the therapeutic regimen; interferonalpha+/-ribavirin and pegylated interferonalpha+/-ribavirin. RESULTS: The search sourced 23 peer reviewed articles which enrolled 934 cases, aged 2-19 years. Sustained virological response rates were significantly higher with the addition of ribavirin to either interferonalpha or pegylated nterferonalpha vs. their monotherapies for genotypes 1,2&3 with crude and weighted estimates. The weighted estimate indicated higher sustained virological response rates for those treated with pegylated interferonalpha+ribavirin vs. interferonalpha+ribavirin for genotype 1 (50% vs. 40%) and genotypes 2&3 (90% vs. 84%), (odds ratio 1.5, 95% confidence interval 1.2-1.8, and 1.8, 1.2-2.9 respectively). Cases with genotype 4 treated with pegylated interferonalpha+ribavirin had a lower sustained virological response (41%) vs. genotype 1 (1.4, 1.2-1.8), and vs. genotypes 2&3 (13.5, 10.3-17.9). Some adverse events were significantly higher among cases treated with pegylated interferonalpha+ribavirin vs. interferonalpha+ribavirin. CONCLUSIONS: Despite the superiority of pegylated interferonalpha+ribavirin to interferonalpha+ribavirin for the treatment of chronic hepatitis C among children, the significant higher adverse events along with the modest outcome for genotypes 1&4 render that regimen a suboptimal therapy. These data indicated the need for the future comparison with clinical trials of direct anti-viral drugs for children with chronic hepatitis C. PMID- 25926270 TI - Islet Amyloid in Whole Pancreas Transplants for Type 1 Diabetes Mellitus (DM): Possible Role of Type 2 DM for Graft Failure. AB - Long-term results with whole pancreas (WPTx) and islet transplantation (IT) continue to be suboptimal. Graft failure with undetectable C-peptide level is attributed to graft sclerosis (chronic rejection), recurrence of Type 1 diabetes mellitus (DM), or insufficient islet mass. In contrast, graft failure with measurable C-peptide has overlapping clinical features with Type 2 DM (suggesting persistent but insufficient beta cell function), but is poorly understood. In general, the morphological substrate for islet failure is unclear because grafted islets are not routinely evaluated. We present two patients with graft failure at 5 and 8 years after successful WPTx for Type 1 DM, presenting with preserved C peptide levels. On histopathology, the islets had preserved both alpha and beta cell populations but also prominent accumulation of islet amyloid (IA), the morphological hallmark of Type 2 DM. IA previously reported in IT, represents fibrillary aggregates of islet amyloid polypeptide, a hormone normally cosecreted with insulin. Accumulation of IA correlates quantitatively with the development of hyperglycemia and is known to cause beta cell dysfunction and loss. Accumulation of IA and development of Type 2 DM should be considered and studied as a potential cause of long-term islet failure in IT and WPTx. PMID- 25926271 TI - Complete response and long-term survival (>20 years) of a child with tectal glioma: a case report. AB - Tectal glioma is a midbrain tumor. The patient generally presents with symptoms related to increased intracranial pressure and requires treatment for hydrocephalus. No effective pharmacological treatments have yet been introduced. This report discusses a case of a 13-year-old male diagnosed with tectal glioma who obtained a complete response and long-term survival after the treatment with antineoplastons (ANP) in phase II trial. Prior treatment consisted of placement of a ventriculoperitoneal shunt. After 6 years of stabilization there had been an increase in tumor size with signs of malignant transformation. The patient received treatment with ANP A10 and AS2-1 infusions for 20 months, obtained a complete response, and was switched to maintenance with ANP capsules. All treatments were discontinued in December 2003. Adverse events according to CTCAE v3.0 included: hypernatremia (two events of grade 3, one event of grade 2, four events of grade 1), one case of fatigue (grade 2), and one allergic reaction (grade 1). Currently, over 20 years from his diagnosis and over 13 years from treatment start he is symptom-free and leads a normal life. This report indicates that it is possible to obtain long-term survival of a child with tectal glioma with currently available investigational treatment. PMID- 25926272 TI - Magnetic assembly and field-tuning of ellipsoidal-nanoparticle-based colloidal photonic crystals. AB - Anisotropic nanostructures provide an additional degree of freedom for tailoring the collective properties of their ensembles. Using Fe@SiO2 nanoellipsoids as anisotropic building blocks, herein we demonstrate a new class of magnetically responsive photonic structures whose photonic properties can be dynamically tuned by controlling the direction of the magnetic fields they are exposed to. These novel photonic structures diffract at a minimum wavelength when the field direction is perpendicular to the incident angle, and a maximum wavelength when the field is switched to parallel direction; and the diffraction intensity reaches maximum values when the fields are either parallel or perpendicular to the incident light, and decreases when the field direction is moved off-angle. PMID- 25926273 TI - The acute and chronic toxic effect of cypermethrin, propetamphos, and their combinations in rats. AB - This study was aimed at determining the acute and chronic toxic effects of cypermethrin, propetamphos, and combined cypermethrin and propetamphos. Four groups, each comprising 10 animals, were established for the acute (a) and chronic (b) toxicity trials, and in total, 80 male Wistar albino rats were used. In the acute toxicity trial, the first group was maintained for control purposes, and groups 2a, 3a, and 4a were administered only once with 80 mg/kg.bw of cypermethrin, 25 mg/kg.bw of propetamphos and 80 mg/kg.bw of cypermethrin combined with 25 mg/kg.bw of propetamphos, respectively, by gavage directly into the stomach. In the chronic toxicity trial, the first group was also maintained for control purposes, while groups 2b, 3b, and 4b were administered daily with 12 mg/kg.bw of cypermethrin, 4 mg/kg.bw of propetamphos, and 12 mg/kg.bw of cypermethrin combined with 4 mg/kg.bw of propetamphos respectively, by gavage directly into the stomach for 60 days. Blood and tissue (liver, kidney, brain, spleen, and testis) samples were taken 24 h after pesticide administration in the acute toxicity trial and at the end of day 60 in the chronic toxicity trial. Oxidative stress (MDA, NO, SOD, CAT, GSH-Px, and G6PD) parameters, serum biochemical parameters (glucose, triglyceride, cholesterol, HDL, LDL, BUN, creatinine, AST, ALT, ALP, protein, and albumin) and hepatic drug-metabolizing parameters (CYP2E1, CYPB5, CYTC, GST, and GSH) were investigated in the samples. When administered either alone or in combination, both pesticides inhibited the antioxidant enzymes and increased MDA and NO levels. For the drug-metabolizing parameters investigated, particularly in the chronic period, either increase (CYP2E1, CYPB5, and CYTC) or decrease (GST and GSH) was observed. Furthermore, some negative changes were detected in the serum biochemical parameters. In result, cypermethrin and propetamphos combinations and long-term exposure to these combinations produced a greater toxic effect than the administration of these insecticides alone. (c) 2015 Wiley Periodicals, Inc. Environ Toxicol 31: 1415-1429, 2016. PMID- 25926274 TI - The Origin of the Variations of the Hyoid Apparatus in Human. AB - Currently, theories based on acquired calcification of the stylohyoid ligament are believed to be a pathogenesis of syndromes associated with the hyoid apparatus (HA) and its variations. We studied the development of the HA from Reichert's cartilage using serial sections of 25 human embryos and 45 fetuses. We ensured a fact that, at the initial stage, the HA appeared as two independent cartilage segments, that is, the cranial or styloid segment and the caudal or hyoid segment of Reichert's cartilage, those are connected by a mesenchymal structure. However, between 8 and 10 weeks of development, the mesenchymal connection was lost. We hypothesize that this disconnection is likely to be one of the major factors to make a descent of the hyoid bone in evolution. The stylohyoid ligament was not observed. The variations of the HA, should be considered variations of the development of Reicherts cartilage. If these variations are maintained in the adult, are likely to explain a major symptom associated with Eagle's syndrome. PMID- 25926275 TI - Performance comparison of sand and fine sawdust vermifilters in treating concentrated grey water for urban poor. AB - A comparative investigation was conducted for 10 months with sand and fine sawdust vermifilters and a control unit to treat concentrated grey water generated from a poor urban household in Ouagadougou, Burkina Faso. Each of the filters was made up of cylindrical DN200-PVC pipes and filled with 10 cm of gravel at the bottom. On top of the gravel layer, filter 1 (fully sand, F1) was completed with 40 cm of sand and 10 cm of fine sawdust, filter 2 (partially sand, F2) with 20 cm of sand and 30 cm of fine sawdust, respectively, and filter 3 (fully sawdust, F3) and 4 (control, F4) with 50 cm of fine sawdust only. Two hundred Eudrilus eugeniae earthworms were inoculated in each of the vermifilters. The vermifiltration system was supplied with grey water four times per day at a hydraulic loading rate of 64 L/m(2)/day on a batch basis. The removal efficiencies of biological oxygen demand, total chemical oxygen demand, and dissolved chemical oxygen demand (dCOD) by the vermifilters were 25-30% higher than the control, but little differences were observed in terms of total suspended solids and coliform removal efficiencies. Though there was no significant difference in the performance of the three vermifilters (p > 0.05), except for dCOD removal efficiency, the lifespan of F2 and F3 was longer than that of F1. Therefore, fine sawdust can substitute sand as a filter medium in vermifilters. PMID- 25926276 TI - A computationally efficient algorithm for genomic prediction using a Bayesian model. AB - BACKGROUND: Genomic prediction of breeding values from dense single nucleotide polymorphisms (SNP) genotypes is used for livestock and crop breeding, and can also be used to predict disease risk in humans. For some traits, the most accurate genomic predictions are achieved with non-linear estimates of SNP effects from Bayesian methods that treat SNP effects as random effects from a heavy tailed prior distribution. These Bayesian methods are usually implemented via Markov chain Monte Carlo (MCMC) schemes to sample from the posterior distribution of SNP effects, which is computationally expensive. Our aim was to develop an efficient expectation-maximisation algorithm (emBayesR) that gives similar estimates of SNP effects and accuracies of genomic prediction than the MCMC implementation of BayesR (a Bayesian method for genomic prediction), but with greatly reduced computation time. METHODS: emBayesR is an approximate EM algorithm that retains the BayesR model assumption with SNP effects sampled from a mixture of normal distributions with increasing variance. emBayesR differs from other proposed non-MCMC implementations of Bayesian methods for genomic prediction in that it estimates the effect of each SNP while allowing for the error associated with estimation of all other SNP effects. emBayesR was compared to BayesR using simulated data, and real dairy cattle data with 632 003 SNPs genotyped, to determine if the MCMC and the expectation-maximisation approaches give similar accuracies of genomic prediction. RESULTS: We were able to demonstrate that allowing for the error associated with estimation of other SNP effects when estimating the effect of each SNP in emBayesR improved the accuracy of genomic prediction over emBayesR without including this error correction, with both simulated and real data. When averaged over nine dairy traits, the accuracy of genomic prediction with emBayesR was only 0.5% lower than that from BayesR. However, emBayesR reduced computing time up to 8-fold compared to BayesR. CONCLUSIONS: The emBayesR algorithm described here achieved similar accuracies of genomic prediction to BayesR for a range of simulated and real 630 K dairy SNP data. emBayesR needs less computing time than BayesR, which will allow it to be applied to larger datasets. PMID- 25926277 TI - Assessing the components of adaptive capacity to improve conservation and management efforts under global change. AB - Natural-resource managers and other conservation practitioners are under unprecedented pressure to categorize and quantify the vulnerability of natural systems based on assessment of the exposure, sensitivity, and adaptive capacity of species to climate change. Despite the urgent need for these assessments, neither the theoretical basis of adaptive capacity nor the practical issues underlying its quantification has been articulated in a manner that is directly applicable to natural-resource management. Both are critical for researchers, managers, and other conservation practitioners to develop reliable strategies for assessing adaptive capacity. Drawing from principles of classical and contemporary research and examples from terrestrial, marine, plant, and animal systems, we examined broadly the theory behind the concept of adaptive capacity. We then considered how interdisciplinary, trait- and triage-based approaches encompassing the oft-overlooked interactions among components of adaptive capacity can be used to identify species and populations likely to have higher (or lower) adaptive capacity. We identified the challenges and value of such endeavors and argue for a concerted interdisciplinary research approach that combines ecology, ecological genetics, and eco-physiology to reflect the interacting components of adaptive capacity. We aimed to provide a basis for constructive discussion between natural-resource managers and researchers, discussions urgently needed to identify research directions that will deliver answers to real-world questions facing resource managers, other conservation practitioners, and policy makers. Directing research to both seek general patterns and identify ways to facilitate adaptive capacity of key species and populations within species, will enable conservation ecologists and resource managers to maximize returns on research and management investment and arrive at novel and dynamic management and policy decisions. PMID- 25926278 TI - Inflammatory myopathy: diagnosis and clinical course, specific clinical scenarios and new complementary tools. AB - Idiopathic inflammatory myopathies are a heterogeneous group of rare autoimmune diseases characterized by symmetric proximal muscle weakness and inflammatory infiltrates on muscle biopsy. A meticulously collected combination of clinical, serological, and pathological data is essential to correctly diagnose and classify myositis patients, often a considerable challenge for clinicians. This article provides a comprehensive overview of the most useful tools for the diagnosis and follow-up of patients with myositis. Capillaroscopy, serological biomarkers (particularly the autoantibody profile) and imaging techniques, such as muscle magnetic resonance and chest ultrasound, are of great aid in diagnosing, classifying and managing these patients. Relevant clinical scenarios, such as interstitial lung disease, associated cancer and pregnancy are also addressed in this review. Myositis registries, identification of new autoantibodies, and genetic studies will enhance our understanding of the pathogenesis of these conditions and help to define new diagnostic and therapeutic approaches. PMID- 25926279 TI - Hierarchical Assembly of Plasmonic Nanoparticles. AB - In this Minireview, we summarize recent advances in the ordering of plasmonic nanoparticles over extended areas on solid substrates. The spotlight is thus focused on examples showing one-, two-, and three-dimensional assemblies, with a particular attention on assemblies displaying hierarchical order. Throughout the manuscript we identify the main parameters and methods that can be tuned to achieve long range organization. PMID- 25926280 TI - The efficacy and safety of percutaneous nephrolithotomy under general versus regional anesthesia: a systematic review and meta-analysis. AB - This meta-analysis was performed to evaluate the efficacy and safety of percutaneous nephrolithotomy (PCNL) under regional anesthesia (RA) vs. general anesthesia (GA). A systematic literature search in the electronic databases (Cochrane CENTRAL, Medline and EMBASE) was performed up to April 2014. Twelve trials, including 1954 patients, met the inclusion criteria and were included in the final analysis. Our pooled analysis showed that PCNL under RA could reduce surgical duration (MD, -2.47; 95 % CI, -3.51 to -1.44), hospitalization period (MD, -0.48; 95 % CI -0.93 to -0.04), fluoroscopy time (MD, -0.48; 95 % CI, -0.83 to -0.14), blood transfusion (OR, 0.59; 95 % CI, 0.38-0.92), postoperative pain (MD, -1.99; 95 % CI, -2.2 to -1.78), and analgesic requirements (MD, -19.14; 95 % CI, -26.64 to -11.63). However, there was no difference between RA and GA groups with regard to stone-free rate (OR, 1.09; 95 % CI, 0.86-1.37) and postoperative complications associated with PCNL (OR, 0.95; 95 % CI 0.58-1.54). Our results show that PCNL under RA offers several potential advantages over GA in terms of surgical duration, hospitalization period, fluoroscopy time, blood transfusion, postoperative pain, and analgesic requirements, but both anesthetic techniques appear to be equivalent with regard to the stone-free rate and complication rate. Along with the suggested favorable hemodynamic profile and lower cost, RA may prove a better alternative than GA. PMID- 25926282 TI - An Efficient, Noniterative Method of Identifying the Cost-Effectiveness Frontier. AB - Cost-effectiveness analysis aims to identify treatments and policies that maximize benefits subject to resource constraints. However, the conventional process of identifying the efficient frontier (i.e., the set of potentially cost effective options) can be algorithmically inefficient, especially when considering a policy problem with many alternative options or when performing an extensive suite of sensitivity analyses for which the efficient frontier must be found for each. Here, we describe an alternative one-pass algorithm that is conceptually simple, easier to implement, and potentially faster for situations that challenge the conventional approach. Our algorithm accomplishes this by exploiting the relationship between the net monetary benefit and the cost effectiveness plane. To facilitate further evaluation and use of this approach, we also provide scripts in R and Matlab that implement our method and can be used to identify efficient frontiers for any decision problem. PMID- 25926281 TI - Evaluating Cost-effectiveness of Interventions That Affect Fertility and Childbearing: How Health Effects Are Measured Matters. AB - BACKGROUND: Current guidelines for economic evaluations of health interventions define relevant outcomes as those accruing to individuals receiving interventions. Little consensus exists on counting health impacts on current and future fertility and childbearing. Our objective was to characterize current practices for counting such health outcomes. METHODS: We developed a framework characterizing health interventions with direct and/or indirect effects on fertility and childbearing and how such outcomes are reported. We identified interventions spanning the framework and performed a targeted literature review for economic evaluations of these interventions. For each article, we characterized how the potential health outcomes from each intervention were considered, focusing on quality-adjusted life-years (QALYs) associated with fertility and childbearing. RESULTS: We reviewed 108 studies, identifying 7 themes: 1) Studies were heterogeneous in reporting outcomes. 2) Studies often selected outcomes for inclusion that tend to bias toward finding the intervention to be cost-effective. 3) Studies often avoided the challenges of assigning QALYs for pregnancy and fertility by instead considering cost per intermediate outcome. 4) Even for the same intervention, studies took heterogeneous approaches to outcome evaluation. 5) Studies used multiple, competing rationales for whether and how to include fertility-related QALYs and whose QALYs to include. 6) Studies examining interventions with indirect effects on fertility typically ignored such QALYs. 7) Even recent studies had these shortcomings. Limitations include that the review was targeted rather than systematic. CONCLUSIONS: Economic evaluations inconsistently consider QALYs from current and future fertility and childbearing in ways that frequently appear biased toward the interventions considered. As the Panel on Cost-Effectiveness in Health and Medicine updates its guidelines, making the practice of cost-effectiveness analysis more consistent is a priority. Our study contributes to harmonizing methods in this respect. PMID- 25926283 TI - Mapping from the Parkinson's Disease Questionnaire PDQ-39 to the Generic EuroQol EQ-5D-3L: The Value of Mixture Models. AB - OBJECTIVE: To compare a range of statistical models to enable the estimation of EQ-5D-3L utilities from responses to the Parkinson's Disease Questionnaire 39 (PDQ-39). METHODS: Linear regression, beta regression, mixtures of linear regressions and beta regressions, and multinomial logistic regression were compared in terms of their ability to accurately predict EQ-5D-3L utilities from responses to the PDQ-39 using mean error (ME), mean absolute error (MAE), and mean square error (MSE), overall and by Hoehn and Yahr stage. Models were estimated using data from the PD MED trial (n = 9123) and assessed on both the estimation data as well as external data from the PD SURG trial (n = 917). RESULTS: Overall, the differences in the metrics of fit between models were small in both data sets, with performance poorer for all models in PD SURG. The performance across Hoehn and Yahr stages 1 to 3 were also similar, but multinomial logistic regression was found to exhibit less bias and better individual-level predictive accuracy in PD MED for those in Hoehn and Yahr stages 4 or 5. Overall, the multinomial logistic regression reported an ME of 0.038 out of sample and MAEs of 0.128 and 0.164 and MSEs of 0.030 and 0.044 in the estimation and external data sets, respectively. Poorer levels of the mobility domain score of the PDQ-39 were associated with increased odds of reporting problems for all EQ-5D domains except anxiety/depression. CONCLUSIONS: Finite mixture models with only few components can approximate the distribution of EQ-5D 3L utilities well but did not demonstrate improvements in predictive accuracy compared with multinomial logistic regression in the present data set. PMID- 25926284 TI - Expansion of the National Salt Reduction Initiative: A Mathematical Model of Benefits and Risks of Population-Level Sodium Reduction. AB - BACKGROUND: The National Salt Reduction Initiative, in which food producers agree to lower sodium to levels deemed feasible for different foods, is expected to significantly reduce sodium intake if expanded to a large sector of food manufacturers. OBJECTIVE: Given recent data on the relationship between sodium intake, hypertension, and associated cardiovascular disease at a population level, we sought to examine risks and benefits of the program. DESIGN: To estimate the impact of further expanding the initiative on hypertension, myocardial infarction (MI) and stroke incidence, and related mortality, given food consumption patterns across the United States, we developed and validated a stochastic microsimulation model of hypertension, MI, and stroke morbidity and mortality, using data from food producers on sodium reduction among foods, linked to 24-hour dietary recalls, blood pressure, and cardiovascular histories from the National Health and Nutrition Examination Survey. RESULTS: Expansion of the initiative to ensure all restaurants and manufacturers reach agreed-upon sodium targets would be expected to avert from 0.9 to 3.0 MIs (a 1.6%-5.4% reduction) and 0.5 to 2.8 strokes (a 1.1%-6.2% reduction) per 10,000 Americans per year over the next decade, after incorporating consumption patterns and variations in the effect of sodium reduction on blood pressure among different demographic groups. Even high levels of consumer addition of table salt or substitution among food categories would be unlikely to neutralize this benefit. However, if recent epidemiological associations between very low sodium and increased mortality are causal, then older women may be at risk of increased mortality from excessively low sodium intake. CONCLUSIONS: An expanded National Salt Reduction Initiative is likely to significantly reduce hypertension and hypertension-related cardiovascular morbidity but may be accompanied by potential risks to older women. PMID- 25926285 TI - Medicinal effect and its JP2/RyR2-based mechanism of Smilax glabra flavonoids on angiotensin II-induced hypertrophy model of cardiomyocytes. AB - ETHNOPHARMACOLOGICAL RELEVANCE: Rhizome and root of Smilax glabra Roxb (Liliaceae family) is a widely used traditional Chinese medicine (TCM) named Tu-fu-ling (TFL) for cardiac disease therapy. The TFL flavonoids (TFLF) has been extracted and proven to possess the anti-cardiac hypertrophy effect in our previous reports. Such effect could be mediated by the modulation of intracellular Ca(2+) flux in myocardial cells, in which junctophilin-2 (JP2) and ryanodine receptor 2 (RyR2) play an important role. However, its mechanism of the anti-cardiac hypertrophy effect remains unclarified. MATERIALS AND METHODS: 2MUmol/L Ang II was applied to induce hypertrophy model of rat primary cardiomyocytes. After treatment of TFLF at 0.25, 0.5 and 1.0mg/ml, the cell size was microscopic measured, and the protein and mRNA expressions of JP2 and RyR2 in cardiomyocytes were estimated by immunofluorescence imaging, ELISA and real-time PCR assay. RESULTS: Obvious hypertrophy of cardiomyocytes was induced by Ang II but reversed by TFLF from 0.5 to 1.0mg/ml. The protein and mRNA expressions of JP2 and RyR2 in cardiomyocytes were also inhibited by Ang II but restored by TFLF at its dose range. Such effect of TFLF was exerted at a dose dependent manner, which was even better than that of verapamil. CONCLUSIONS: Our findings may evidence the correlation between JP2/RyR2 and myocardiac hypertrophy, and indicate the JP2/RyR2-mediated anti-hypertrophy mechanism of TFLF for the first time. It deserves to be developed as a promising TCM candidate of new drug for myocardial hypertrophy treatment. PMID- 25926286 TI - UPLC-Q-TOF/MS-based screening and identification of the main flavonoids and their metabolites in rat bile, urine and feces after oral administration of Scutellaria baicalensis extract. AB - ETHNOPHARMACOLOGICAL RELEVANCE: Traditional Chinese Medicines (TCMs) are increasingly used in combination with Western medicine. Scutellaria baicalensis Georgi (Lamiaceae) is a widely used TCM in treating various diseases. However, the in vivo metabolism of its main bioactive flavonoids, baicalin, baicalein, wogonoside and wogonin, needs further study. MATERIALS AND METHODS: A systematic method based on ultra-performance liquid chromatography/quadrupole-time-of-flight mass spectrometry (UPLC-Q-TOF/MS) technique combined with Metabolynx(TM) software was developed to speculate the metabolites and excretion profiles of the main flavonoids in S. baicalensis extract in rats bile, urine and feces samples after oral administration of the extract. RESULTS: Four parent components and a total of 15 metabolites were tentatively detected in vivo. All metabolites were detected including sulfate and glucuronide conjugates, hydroxylated, methylated, acetylated and deoxygenated products. Twelve metabolites were from the rat urine, five from the feces and two from the bile. Among them, several products were reported firstly. CONCLUSION: The research provided useful information for further study of the pharmacology and mechanism of action of S. baicalensis extract in vivo and a proposed method which could develop an integrated template approach to analyze screening and identification of biological samples after oral administration of TCMs. PMID- 25926288 TI - Significance of High Trough Concentration of Teicoplanin in the Treatment of Methicillin-Resistant Staphylococcus aureus Infection. AB - BACKGROUND: Teicoplanin (TEIC) is a glycopeptide currently used for the treatment of methicillin-resistant Staphylococcus aureus (MRSA). A plasma trough concentration (Cmin) of >20 mg/l should be used for severe infections. The aim of this study was to assess the efficacy, safety and use of Cmin >20 mg/l on day 4-6 in patients with complicated MRSA infections. METHODS: Blood samples were drawn from the 41 included patients just before TEIC administration between day 4 and 6. The patients were divided into three groups (group A: >20 mg/l, group B: 10-20 mg/l and group C: <10 mg/l) based on their Cmin on day 4-6. RESULTS: Differences in efficacy between the groups were significant, but differences in safety were not. The patients in group A required lower cumulative doses than those in either groups B or C. CONCLUSIONS: The optimal clinical efficacy and safety might be associated with TEIC Cmin on the fourth to sixth day. PMID- 25926287 TI - A canine-specific anti-nerve growth factor antibody alleviates pain and improves mobility and function in dogs with degenerative joint disease-associated pain. AB - BACKGROUND: There is a critical need for proven drugs other than non-steroidal anti-inflammatory drugs for treatment of degenerative joint disease (DJD) pain in dogs. Antibodies against nerve growth factor (NGF) are analgesic in rodent models and in humans with DJD. This pilot study aimed to evaluate the efficacy of a novel caninised anti-NGF antibody (NV-01) for the treatment of DJD pain in dogs. In a randomized, parallel group, stratified, double masked, placebo controlled, proof of principle clinical pilot study design, 26 dogs with DJD received NV-01 (200 mcg/kg IV) or placebo on day 0 (D0). In addition to objective accelerometry measures, owners completed clinical metrology instruments (Client-Specific Outcome Measures [CSOM], Canine Brief Pain Inventory [CBPI] and Liverpool Osteoarthritis in Dogs Index [LOAD]) on D0, D14 and D28. CBPI subscales (pain severity [PS] and pain interference [PI]), CSOM and LOAD scores were evaluated within and between groups for change over time. Recognized success/failure criteria were applied and success compared between groups. RESULTS: CBPI PS and PI scores significantly improved in the NV-01 group (PS: D0-14, P = 0.012 and D0 28, P = 0.019; PI: D0-14, P = 0.012 and D0-28, P = 0.032) but not in the placebo group. CSOM scores showed similar patterns with a significant difference between within-group changes at D14 and D28 (P = 0.038 and P = 0.009, respectively), and significantly more successes at D28 (P = 0.047). LOAD scores significantly improved in the NV-01 group (D0-14, P = 0.004 and D0-28, P = 0.002) but not in the placebo group. There were significant differences between the groups for change in LOAD score at D14 (P = 0.014) and D28 (P = 0.033). No side effects were noted. Activity in the NV-01 group increased over the study period compared to placebo (P = 0.063) and the difference between the groups for change in activity over the time period 9am-5pm (8 hours) was significant (P = 0.006). CONCLUSIONS: These pilot data demonstrate a positive analgesic effect of anti-NGF antibody in dogs suffering from chronic pain. The magnitude of the effect appeared identical to that expected with an NSAID. PMID- 25926289 TI - A meta-analysis examining the association between the MUC5B rs35705950 T/G polymorphism and susceptibility to idiopathic pulmonary fibrosis. AB - OBJECTIVE: To explore whether the mucin (MUC) 5B rs35705950 T/G polymorphism confers susceptibility to idiopathic pulmonary fibrosis (IPF). METHODS: A meta analysis was conducted to determine associations between the MUC5B rs35705950 T/G polymorphism and either IPF or connective tissue disease-associated interstitial lung disease (CTD-ILD). We used the allele contrast, recessive, dominant, and additive models. A total of 12 IPF studies comprising 2859 patients and 6901 controls and four CTD-ILD studies involving 903 patients and 3306 controls were included in the meta-analysis. RESULTS: There was a significant association between the Tallele of the MUC5B rs35705950 polymorphism and IPF in all subjects (OR 3.768, 95 % CI 2.935-4.836, p < 1.0 * 10(-8)). Analysis after stratification by ethnicity indicated that the Tallele was significantly associated with IPF in Europeans and Asians (OR 3.728, 95 % CI 2.858-4.863, p < 1.0 * 10(-8); OR 4.334, 95 % CI 2.186-8.594, p = 2.6 * 10(-6)). However, there was no association between the Tallele and CTD-ILD in all subjects (OR 1.130, 95 % CI 0.937-1.363, p = 0.200), and in Europeans and Asians. Subgroup analysis by CTD type revealed no association between the Tallele and systemic sclerosis-associated ILD (SSc-ILD) and other CTD-ILDs. CONCLUSIONS: The MUC5B rs35705950 T/G polymorphism confers susceptibility to IPF in Europeans and Asians, but is not associated with susceptibility to CTD-ILD. PMID- 25926290 TI - Urine osmolarity predicts the body weight-reduction response to tolvaptan in chronic kidney disease patients: a retrospective, observational study. AB - BACKGROUND/AIMS: Tolvaptan, a vasopressin V2 receptor antagonist, promotes the excretion of electrolyte-free water. Patients with heart failure or liver cirrhosis, whose urine osmolarity is high due to increased vasopressin, show a good response to tolvaptan; however, it remains dubious whether tolvaptan is also effective in patients with low urine osmolarity due to decreased renal function. The aim of this study was to investigate whether urine osmolarity predicts the effect of tolvaptan in patients with decreased renal function. METHODS: In this retrospective, observational study, 17 overhydrated chronic kidney disease patients with heart failure or liver cirrhosis who were admitted to Osaka University Hospital were included. They were treated with sodium-excreting diuretics first, and then tolvaptan was added. The clinically relevant parameters were evaluated before and after the use of tolvaptan, and they, including urine osmolarity before use of tolvaptan, were compared between the responder group and the non-responder group. The definition of responder was based on the decrease of body weight by >=5% in one week, which is a more rigorous indicator of the effectiveness of tolvaptan than the increase in urine output. RESULTS: The parameter that showed a significant difference between the responder and non responder groups was urine osmolarity before the use of tolvaptan. The cut-off point derived from the receiver operating characteristic (ROC) curve analysis was 279 mOsm/kg H2O, with sensitivity of 0.86 and specificity of 0.80. CONCLUSIONS: In patients with decreased renal function, urine osmolarity before the use of tolvaptan predicted the effectiveness of diuretics in terms of body weight reduction. PMID- 25926291 TI - Electronic grade and flexible semiconductor film employing oriented attachment of colloidal ligand-free PbS and PbSe nanocrystals at room temperature. AB - Electronic grade semiconductor films have been obtained via the sintering of solution processed PbS and PbSe nanocrystals at room temperature. Prior attempts to achieve similar films required the sintering of nanocrystals at higher temperatures (>350 degrees C), which inhibits the processing of such films on a flexible polymer substrate, and it is also expensive. We reduced the sintering temperature by employing two important strategies: (i) use of ligand-free nanocrystals and (ii) oriented attachment of nanocrystals. Colloidal ligand-free PbS and PbSe nanocrystals were synthesized at 70 degrees C with high yield (~70%). However, these nanocrystals start to agglomerate with time in formamide, and upon the removal of the solvation energy, nanocrystals undergo oriented attachment, forming larger elongated crystals. PbS and PbSe nanocrystal films made on both glass and flexible substrates at room temperature exhibit Ohmic behavior with optimum DC conductivities of 0.03 S m(-1) and 0.08 S m(-1), respectively. Mild annealing of the films at 150 degrees C increases the conductivity values to 1.1 S m(-1) and 137 S m(-1) for PbS and PbSe nanocrystal films, respectively. AC impedance was measured to distinguish the contributions from grain and grain boundaries to the charge transport mechanism. Charge transport properties remain similar after the repeated bending of the film on a flexible polymer substrate. Reasonably high thermoelectric Seebeck coefficients of 600 MUV K(-1) and 335 MUV K(-1) for PbS and PbSe nanocrystal pellets, respectively, were obtained at room temperature. PMID- 25926292 TI - Prognostic Indices and Mortality Prediction in COPD Caused by Biomass Smoke Exposure. AB - INTRODUCTION: Little is known about survival and prognostic factors in chronic obstructive pulmonary disease (COPD) due to biomass smoke exposure (BS-COPD). OBJECTIVES: (1) To determine the value of two indices of COPD severity: BODEx (body mass index, obstruction, dyspnea, and previous severe exacerbations) and Global Initiative for Chronic Obstructive Lung Disease (GOLD) categories system (ABCD) to predict all-cause mortality in BS-COPD, compared with COPD due to tobacco (T-COPD); (2) to verify the usefulness of 2 comorbidity indices, Charlson index and COTE (COPD comorbidity index); and (3) to put side by side the value of these indices. METHODS: 612 consecutive COPD patients were retrospectively studied. Prognostic factors were evaluated taking into account the exposure to biomass or tobacco smoke. The relative predictive values of the prognostic indices were compared using receiver-operating characteristic analysis. RESULTS: Mortality in the BS-COPD and T-COPD groups was not significantly different, when sex was taken into account. BODEx, Charlson and COTE indices-but not type of exposure-predicted mortality in multivariate analysis. The value of the C statistic for the BODEx index was not different than that of GOLD ABCD for BS COPD, but was higher for T-COPD. The discriminatory value of the Charlson index was higher than that of COTE for BS-COPD, but no significant differences were found for T-COPD. CONCLUSIONS: Multidimensional indices of COPD severity and comorbidity predict all-cause mortality in BS-COPD. The behavior of the different indices is different for BS-COPD and T-COPD. PMID- 25926293 TI - Intrinsic BMP Antagonist Gremlin-1 as a Novel Circulating Marker in Pulmonary Arterial Hypertension. AB - Gremlin-1, an intrinsic antagonist of bone morphogenetic protein (BMP) signaling, has been implicated in the pathophysiology of pulmonary arterial hypertension (PAH). However, it is unknown whether gremlin-1 can be detected in the circulation of PAH patients and whether it is associated with patients' functional status and outcome. With a mean level of 242 +/- 24 ng/ml, gremlin-1 levels of 31 PAH patients were significantly elevated compared to 151 +/- 18 ng/ml in 15 age- and gender-matched healthy subject (p = 0.016). In PAH patients, increasing gremlin-1 levels correlated with N-terminal prohormone of brain natriuretic peptide levels (r = 0.608, p < 0.001) and inversely with the 6-minute walking distance (r = -0.412, p = 0.029). Furthermore, gremlin-1 significantly stratified survival in PAH patients (p = 0.015). Gremlin-1 may represent a new biomarker for PAH which can be linked directly to the underlying pathomechanism. Elevated levels of gremlin-1 are associated with patients' functional status and survival, thus gremlin-1 neutralization could represent a potential therapeutic strategy to increase BMPR2 signaling. PMID- 25926294 TI - A qualitative investigation into nurses' perceptions of factors influencing staff injuries sustained during physical interventions employed in response to service user violence within one secure learning disability service. AB - AIMS AND OBJECTIVES: The aim of the study was to examine learning disability nurses' perceptions of incidents involving physical intervention, particularly factors contributing to injuries sustained by this group. BACKGROUND: This article reports on a qualitative study undertaken within one secure NHS Trust to respond to concerns about staff injuries sustained during physical interventions to prevent incidents of service user violence from escalating out of control. The context of the study relates to increasing debate about the most effective approaches to incidents of violence and agression. DESIGN: A qualitative research design was utilized for the study. METHODS: Semi-structured interviews were undertaken with 20 participants, two from each of the 10 incidents involving staff injury sustained during physical intervention. RESULTS: Four themes were produced by the analysis, the first, knowledge and understanding, contextualized the other three, which related to the physical intervention techniques employed, the interpretation of the incident and the impact on staff. CONCLUSION: Service user violence consistently poses nurses with the challenge of balancing the need to respond in order to maintain the safety of everyone whilst simultaneous supporting and caring for people with complex needs. This study highlights the need for further exploration of the contributory factors to the escalation of potentially violent situations. RELEVANCE TO CLINICAL PRACTICE: Services may have good systems in place for responding to and managing service user violence but appear less effective in understanding the reasons for and developing strategies to prevent violence occurring. PMID- 25926295 TI - Triplet pregnancy: is the mode of conception related to perinatal outcomes? AB - Many triplets are conceived as a consequence of assisted reproductive technology (ART). Concerns have been raised that triplet pregnancies conceived by ART are more complicated than those conceived spontaneously. The purpose of this study was to evaluate all triplet pregnancies managed over a 12-year period to determine if there were any differences in outcome based on the mode of conception. All triplet pregnancies between 1999 and 2011 that reached at least 20 weeks' gestation and that were managed at the Royal Women's Hospital (RWH), Melbourne, Victoria were identified. Maternal and neonatal outcomes were compared between ART conceived and spontaneously conceived triplets. In the study period, 53 sets of triplets managed in our institution met the eligibility criteria. Twenty-five triplet sets were conceived by ART and 28 were conceived spontaneously. More ART conceptions resulted in trichorionic triamniotic (TCTA) triplets than did spontaneous conceptions (p = .015). There were no differences between ART and spontaneously conceived triplets for any of the maternal or neonatal complications studied. Trichorionic (TC) triplets delivered at a later gestation than other triplets: 32.1 (SD 2.9) versus 30.4 (SD 3.9) weeks (p = .08). TC triplets were significantly less likely to die than monochorionic (MC) or dichorionic (DC) triplets: 3/93 (3%) versus 13/66 (20%) (p = .025). In conclusion, triplets conceived by ART are more likely to have TCTA placentation and TCTA triplet sets had lower mortality rates than other triplet combinations. Outcomes for triplets conceived by ART were similar to those of triplets conceived spontaneously. PMID- 25926296 TI - Less Than Total Excision of Infected Prosthetic PTFE Graft Does Not Increase the Risk of Reinfection. AB - BACKGROUND: Traditional treatment of infected polytetrafluoroethylene (PTFE) grafts consist of removal of the entire prosthesis. Closure of the native vessels may compromise vascular patency. We examined the outcomes for patients in whom a PTFE remnant of an infected graft was retained on the vessel. METHODS: We reviewed the operating room log from 2000 to 2011 and identified all patients who had partial removal of an infected PTFE graft used for hemodialysis or peripheral bypass. These patients were examined for subsequent complications. RESULTS: Twenty-seven patients underwent 30 partial graft excisions with mean follow-up of 27 months. A total of 17% (5 of 30) of the partial graft resection procedures resulted in complications. Of 48 total remnants left behind at the arterial or venous anastomoses, reinfection occurred in 15%. CONCLUSIONS: Leaving a well incorporated small 1-to 5-mm PTFE remnant at the arterial or venous anastomoses can be performed safely with a low risk of complications. PMID- 25926299 TI - (P007) Pooled Analysis of Locoregional Relapse After Minimally Invasive Surgery Alone for Intermediate- or High-Risk HPV+ Oropharyngeal Squamous Cell Carcinoma. PMID- 25926297 TI - Genetic similarity between cancers and comorbid Mendelian diseases identifies candidate driver genes. AB - Despite large-scale cancer genomics studies, key somatic mutations driving cancer, and their functional roles, remain elusive. Here, we propose that analysis of comorbidities of Mendelian diseases with cancers provides a novel, systematic way to discover new cancer genes. If germline genetic variation in Mendelian loci predisposes bearers to common cancers, the same loci may harbour cancer-associated somatic variation. Compilations of clinical records spanning over 100 million patients provide an unprecedented opportunity to assess clinical associations between Mendelian diseases and cancers. We systematically compare these comorbidities against recurrent somatic mutations from more than 5,000 patients across many cancers. Using multiple measures of genetic similarity, we show that a Mendelian disease and comorbid cancer indeed have genetic alterations of significant functional similarity. This result provides a basis to identify candidate drivers in cancers including melanoma and glioblastoma. Some Mendelian diseases demonstrate 'pan-cancer' comorbidity and shared genetics across cancers. PMID- 25926300 TI - (P014) absence of infection from injection of a rectal spacer into the anterior perirectal fat space. PMID- 25926298 TI - Intraoperative and postoperative anaesthetic and analgesic effect of multipoint transcutaneous electrical acupuncture stimulation combined with sufentanil anaesthesia in patients undergoing supratentorial craniotomy. AB - OBJECTIVES: To investigate the anaesthetic and analgesic effect of multipoint transcutaneous electrical acupuncture stimulation (TEAS) during supratentorial tumour resection for postoperative recovery and side effects. METHODS: In a blinded clinical trial, 92 patients scheduled for supratentorial craniotomy under general anaesthesia were randomly allocated into either a multipoint TEAS (n=46) or a sham TEAS group (n=46). All patients received total intravenous anaesthesia (TIVA) with propofol and sufentanil. The target concentration of sufentanil was adjusted and recorded according to mean arterial pressure (MAP), heart rate (HR) and bispectral index (BIS). Patients in the TEAS group received TEAS 30 min before anaesthesia induction and this was maintained throughout the operation at four pairs of acupuncture points. Postoperative pain, recovery and side effects were evaluated. RESULTS: Eighty-eight patients completed the study. Continuous monitoring of MAP, HR and BIS showed stable values with no significant differences between the two groups (p>0.05). Sufentanil target plasma concentration in TEAS patients was significantly lower at some time points during supratentorial craniotomy, and total sufentanil consumption was significantly higher in the sham group (p<0.05). Postoperative recovery and pain were significantly improved by TEAS (p<0.001), without the postoperative side effects. CONCLUSIONS: Multipoint TEAS at both proximal and distal points combined with TIVA can significantly decrease intraoperative sufentanil requirements, increase pain relief on postoperative day 1 and improve postoperative recovery of patients during supratentorial tumour resection, with no significant increase of side effects. These findings suggest that multipoint TEAS may be clinically effective as an adjunct to analgesia in intraoperative anaesthesia and postoperative pain treatment and may speed recovery. TRIAL REGISTRATION NUMBER: Chinese Clinical Trial Registry (registration number ChiCTR-TRC-10001078). PMID- 25926301 TI - Standardized pelvic floor exercises improve stress urinary incontinence in women with intrinsic sphincter deficiency. AB - OBJECTIVES: Pelvic floor rehabilitation is the conservative therapy of choice for women with stress urinary incontinence (SUI). The success rate of surgical procedures in SUI patients with intrinsic sphincter deficiency (ISD) is low. The aim of this study was to analyse the effect of a standardized physiotherapy on patients with SUI and normotonic urethra and ISD. METHODS: In this study, 64 patients with ISD and 69 patients with normotonic urethra were enrolled. Maximum urethral pressure (MUCP) >20 cm H2 O was considered as normotonic urethral pressure. Before and after physiotherapy MUCP was measured and cough testing was performed. Additionally, patient reported outcome was assessed using the King's Health Questionnaire (KHQ). For statistical analyses Excel 2010 (Microsoft Inc; Redmond, Washington) and SPSS 20 (SPSS Inc; Chicago, Illinois) for Windows were used. Power calculation was based on the primary endpoint incontinence impact and general health. For power calculation, GraphPad Statmate version 2.00 for Windows was used. RESULTS: Sixty-four patients with ISD and 69 patients with normotonic urethra were included in the study. In SUI patients with normotonic and hypotonic urethra KHQ-scores regarding the primary endpoins "general health" and "incontinence impact" significantly improved following standardized physiotherapy. In both groups MUCP increased after physiotherapy. In SUI patients with ISD standardized physiotherapy resulted in a decreased incidence of a positive cough test. CONCLUSIONS: Standardized physiotherapy should be offered to patients with SUI and ISD. Long-term results are subject to future studies. Neurourol. Urodynam. 35:711-716, 2016. (c) 2015 Wiley Periodicals, Inc. PMID- 25926302 TI - Co-infection as a confounder for the role of Clostridium difficile infection in children with diarrhoea: a summary of the literature. AB - Although Clostridium difficile is a major cause of antibiotic-associated diarrhoea in adults, the incidence and severity of C. difficile infection (CDI) in children is unclear. One complicating factor in assessing the role of CDI in children is the possibility of co-infection with other gastrointestinal pathogens. In this review, we summarise the literature concerning C. difficile co infections in young children, in an attempt to discuss the rate of co-infections and their potential role in the severity of CDI clinical presentation. We identified 31 studies where co-infections were analysed, comprising 1,718 patients with positive C. difficile tests. The pooled percentage of reported co infections was 20.7% (range 0-100%). Viral co-infections were most commonly reported (46%), with bacteria and parasites accounting for 14.9% and 0.01% of cases, respectively. However, the panel of co-infections tested for varied considerably among studies and 38% of stated co-infections did not have a pathogen reported. Substantial variation in how and when tests for gastrointestinal co-infections are carried out, small sample sizes and a lack of clear CDI case definitions preclude meaningful conclusions on the true rate of co infections in this patient population. This review suggests that co-infections may be common in children with diarrhoea who tested positive for C. difficile. Given a lack of CDI case definitions, especially in young children under the age of 5 years, a broad panel of pathogens should be tested for to exclude other microbiological causes. However, the summarised poor quality of the available literature on this subject highlights a need for further studies. PMID- 25926303 TI - Burkholderia gladioli infection isolated from the blood cultures of newborns in the neonatal intensive care unit. AB - Burkholderia gladioli was described as a plant pathogen, and it is a rare cause of infection in humans that is primarily associated with human pulmonary infections, such as chronic granulomatous disease and cystic fibrosis. The neonatal respiratory system is not fully developed and cannot expel bacterial aerosol properly. A total of 2,676 newborns in the neonatal intensive care unit were retrospectively analysed in Putian City, Fujian Province, China, from 2011 to 2014. All of the blood samples were tested for C-reactive protein (CRP), procalcitonin (PCT) and white blood cell (WBC). B. gladioli infections were determined and analysed using a blood culture system. Antibiotic susceptibility testing was performed using the K-B method. Of the 2,676 participants, 87 (3.25 %) had a positive B. gladioli blood culture that occurred >72 h after birth, including a premature group (54.0 %, asphyxia [vs. 9.20 %], fever [vs. 13.80 %], pneumonia [vs. 6.90 %] and hyperbilirubinaemia [vs. 8.05 %]) and newborns with necrotising enterocolitis (NEC) (vs. 5.75 %). The mean +/- standard deviation (SD) of the CRP level was 12.31 +/- 0.26 mg/L and that of the PCT level was 1.53 +/- 0.21 ng/ml in the 87 B. gladioli-infected newborns. Most of the B. gladioli isolates were sensitive to many antimicrobial agents and did not lead to serious consequences. All of the B. gladioli-infected newborns were unhealthy, especially the premature infants. B. gladioli might be a causative bacteraemia agent in neonates, it appears to have pathogenic potential in newborns and its sensitivity to antibiotics may be a beneficial factor. PMID- 25926304 TI - Is prosthesis retention effective for chronic infections in hip arthroplasties? A systematic literature review. AB - The success rate of prosthesis removal as the standard approach to manage chronic infection in hip arthroplasties (HA) is 80-90 %. The effectiveness of prosthesis retention, with or without surgical debridement, to treat patients with chronic HA infection (symptom duration of more than 4 weeks) has not been well established, whereas this strategy is sometimes used in clinical practice. This study aimed to explore the cumulative incidence of failure of chronic HA infections treated with prosthesis retention, with or without debridement. A systematic literature review was conducted in accordance with the methods described in the Preferred Reporting Items for Systematic Reviews and Meta Analyses (PRISMA). Studies concerning patients with chronically infected HA treated with prosthesis retention were included. The primary outcome was the cumulative risk of failure. We searched the MEDLINE, Embase, and Cochrane databases up to April 2014. The database searches provided a total of 1,213 studies for potential inclusion in the review. Six relevant studies were finally identified, corresponding to 29 patients included. Their treatments consisted of prosthesis retention with debridement. This strategy failed for 14 out of these 29 patients after a 1-year follow-up. The failure rate of the prosthesis retention approach associated to debridement for chronic infection in HA is 48.3 % in this review. Debridement and prosthesis retention in association with prolonged antimicrobial treatment may be an advantageous alternative to arthroplasty exchange for frail patients. The difficulty in finding relevant studies illustrates the challenges of interpreting the existing literature for the management of chronic prosthetic joint infection (PJI). PMID- 25926305 TI - The Uni-GoldTM Streptococcus pneumoniae urinary antigen test: an interassay comparison with the BinaxNOW(r) Streptococcus pneumoniae test on consecutive urine samples and evaluation on patients with bacteremia. AB - The performance of the recently commercialized Uni-GoldTM Streptococcus pneumoniae test for the detection of pneumococcal antigen in urine was studied in a multicenter study. First, we studied the interassay agreement between Uni GoldTM and the BinaxNOW(r) S. pneumoniae urinary antigen test on 337 consecutive urine samples sent to the laboratory for the detection of pneumococcal antigen. The two tests performed similarly (kappa = 0.82): both tests positive in 27 cases, both tests negative in 299 cases, and with divergent test results in 11 cases. Secondly, the tests were run on urine samples from 203 patients with bacteremia, including 51 patients with pneumococcal bacteremia. The sensitivities and specificities were 67 and 86 % for Uni-GoldTM, and 57 % and 94 % for BinaxNOW(r), respectively. The false-positivity rate was significantly higher for Uni-GoldTM compared with BinaxNOW(r) in patients with Escherichia coli bacteremia (15 vs. 2.1 %, p = 0.04), and tended to be higher in patients with bacteremia with alpha-hemolytic streptococci (32 vs. 11 %, p = 0.13). When cases with E. coli and alpha-hemolytic streptococci were excluded from the analysis, the overall false-positivity rate was 9/85 (11 %) for Uni-GoldTM and 6/85 (7.1 %) for BinaxNOW(r). In conclusion, the study showed that Uni-GoldTM was not inferior to BinaxNOW(r) for the detection of pneumococcal urinary antigen in patients with pneumococcal bacteremia. The specificity of Uni-GoldTM was suboptimal due to false-positive results in cases with E. coli and alpha-hemolytic streptococci bacteremia. However, in patient populations usually subjected to testing for pneumococcal urinary antigen, such as pneumonia and meningitis patients, bacteremia with these pathogens is uncommon. The diagnostic usefulness of the Uni GoldTM test should be further evaluated. PMID- 25926306 TI - MicroRNA-145 expression in the plasma of patients with benign and malignant bone tumors and its effects on osteosarcoma cell proliferation and migration. AB - BACKGROUND: The present study intends to investigate microRNA-145 expression level in the plasma and tissue of patients with benign and malignant bone tumors and its effects on the proliferation and migration of osteosarcoma cells. METHODS: Thirty-four cases of patients with bone tumors (malignant) and twenty cases with osteochondroma (benign) in the hospital were enrolled into the study. Meanwhile, thirty cases of healthy subjects admitted to the hospital for physical examination in the same period were selected as the control group. MicroRNA-145 expression levels in the plasma of patients in three groups were detected using real-time quantitative RT-PCR. The difference in microRNA-145 expression level in the tissue between patients with benign and malignant bone tumors were compared and analyzed. Human osteosarcoma cell line OS-732 was used for high and low expressions of microRNA-145. Its effect on osteosarcoma cell proliferation level was observed using CCK8 method, and its osteosarcoma cell invasion level was observed using Transwell method. RESULTS: MicroRNA-145 expression level in the plasma of patients with malignant bone tumors was significantly lower than that of patients with benign bone tumors; microRNA-145 expression level in the plasma of patients with benign bone tumors was significantly lower than that of healthy subjects; the differences were statistically significant (P<0.05). MicroRNA-145 expression level in the tissue of patients with malignant bone tumors was significantly lower than that of patients with benign bone tumors; the difference was statistically significant (P<0.05). Cell proliferation level of human osteosarcoma cell line OS-732 interfered with microRNA-145 was significantly increased, and its cell invasion capacity was also significantly increased; the differences were statistically significant (P < 0.05). However, cell proliferation level of OS-732 with microRNA-145 overexpression was significantly decreased, and OS-732 cell invasion capacity was also significantly decreased; the differences were statistically significant (P<0.05). CONCLUSIONS: Low expression of microRNA-145 in patients with malignant bone tumors may be involved in cell proliferation and invasion of malignant bone tumors like osteosarcoma as a tumor suppressor. PMID- 25926308 TI - "But-He'll Fall!": Children with Autism, Interspecies Intersubjectivity, and the Problem of 'Being Social'. AB - 'Being autistic' or 'having Autism Spectrum Disorder' implies a limited range of 'being social,' but the in situ organization of interaction, what Maynard and Marlaire (Qual Soc 15(2):177-202, 1992) call the 'interactional substrate,' within which this delimitation enfolds is usually hidden from sight. Analysis of processes constituting different 'interactional substrates' provides a view of how one comes to be known by and to self and others as a certain kind of being who is available (or not) for acting and feeling in certain ways. People diagnosed with Autism Spectrum Disorder (American Psychiatric Association, Diagnostic and statistical manual of mental disorders, 2013) are often described as 'being' impaired in intersubjective understanding of others. But the story of ASD as an impairment of sociality and intersubjectivity becomes more complicated when animals enter into the picture. I consider two interactional substrates: a psychological interview in a mental health clinic, and an animal-assisted activity in a child's neighborhood. I aim to elucidate the practical problems of 'being social' encountered by two children with ASD, both nine-year-old girls, within these two very differently organized interactional substrates. I consider ways in which 'being with' therapy animals provides a way of 'being social' through "sensory modalities of knowing" (Haraway, When species meet, 2008:371). PMID- 25926309 TI - A novel recursive algorithm for the calculation of the detailed identity coefficients. AB - BACKGROUND: A recursive algorithm to calculate the fifteen detailed coefficients of identity is introduced. Previous recursive procedures based on the generalized coefficients of kinship provided the detailed coefficients of identity under the assumption that the two individuals were not an ancestor of each other. FINDINGS: By using gametic relationships to include three, four or two pairs of gametes, we can obtain these coefficients for any pair of individuals. We have developed a novel linear transformation that allows for the calculation of pairwise detailed identity coefficients for any pedigree given the gametic relationships. We illustrate the procedure using the well-known pedigree of Julio and Mencha, which contains 20 Jicaque Indians of Honduras, to calculate their detailed coefficients. CONCLUSIONS: The proposed algorithm can be used to calculate the detailed identity coefficients of two or more individuals with any pedigree relationship. PMID- 25926311 TI - Prediction of fluid responsiveness using a non-invasive cardiac output monitor in children undergoing cardiac surgery. AB - BACKGROUND: This study evaluated the ability of a non-invasive cardiac output monitoring device (NICOM) to predict fluid responsiveness in paediatric patients undergoing cardiac surgery. METHODS: Children aged <5 yr undergoing congenital heart surgery were included. Once the sternum had been closed after repair of the congenital heart defect, 10 ml kg(-1) colloid solution was administered for volume expansion. Transoesophageal echocardiography (TOE) was performed to measure stroke volume (SV) and respiratory variation in aortic blood flow peak velocity (DeltaV(peak)) before and after volume expansion. Haemodynamic and NICOM variables, including SV(NICOM), stroke volume variance (SVV(NICOM)), cardiac index (CI(NICOM)), and percentage change in thoracic fluid content compared with baseline (TFCd0%), were also recorded. Patients in whom the stroke volume index (SVI), measured using TOE, increased by >15% were defined as fluid responders. RESULTS: Twenty-nine patients were included (13 responders and 16 non responders). Before volume expansion, only DeltaV(peak) differed between groups (P=0.036). The SVV(NICOM), HR, and central venous pressure did not predict fluid responsiveness, but DeltaV(peak) did. The CI(NICOM) was not correlated with CI(TOE) (r=0.107, P=0.43). Using Bland-Altman analysis, the mean bias between CI(TOE) and CI(NICOM) was 0.89 litre min(-1) m(-2), with a precision of 1.14 litre min(-1) m(-2). Trending ability of NICOM for SVI and CI was poor when TOE was a reference method. CONCLUSIONS: The SVV(NICOM) did not predict fluid responsiveness in paediatric patients during cardiac surgery. In addition, there was no correlation between CI(TOE) and CI(NICOM). Fluid management guided by NICOM should be performed carefully. CLINICAL TRIAL REGISTRATION: ClinicalTrials.gov NCT01996956. PMID- 25926310 TI - Building blocks of the cerebral cortex: from development to the dish. AB - Since Ramon y Cajal's examination of the cellular makeup of the cerebral cortex, it has been appreciated that this tissue exhibits some of the greatest degrees of cellular heterogeneity in the entire nervous system. This intricate structure emerges during a well-choreographed developmental process. Here, we review current classifications of the cellular constituents of the cerebral cortex and examine how these building blocks are forged during development. We also look at how basic developmental features underlying cortex formation in vivo have been applied to protocols aimed at generating cortical tissue in vitro. PMID- 25926313 TI - Global surgery as an equal partner in health: no longer the neglected stepchild. PMID- 25926312 TI - Enhanced recovery from surgery in the UK: an audit of the enhanced recovery partnership programme 2009-2012. AB - BACKGROUND: The UK Department of Health Enhanced Recovery Partnership Programme collected data on 24 513 surgical patients in the UK from 2009-2012. Enhanced Recovery is an approach to major elective surgery aimed at minimizing perioperative stress for the patient. Previous studies have shown Enhanced Recovery to be associated with reduced hospital length of stay and perioperative morbidity. METHODS: In this national clinical audit, National Health Service hospitals in the UK were invited to submit patient-level data. The data regarding length of stay and compliance with each element of Enhanced Recovery protocols for colorectal, orthopaedic, urological and gynaecological surgery patients were analysed. The relationship between Enhanced Recovery protocol compliance and length of stay was measured. RESULTS: From 16 267 patients from 61 hospital trusts, three out of four surgical specialties showed Enhanced Recovery, compliance being weakly associated with shorter length of stay (correlation coefficients -0.18, -0.14, -0.25 in colorectal, orthopaedics and gynaecology respectively). At a cut-off of 80% compliance, good compliance was associated with two, one and three day reductions in median length of stay respectively in colorectal, orthopaedic and urological surgeries, with no saving in gynaecology. CONCLUSIONS: This study is the largest assessment of the relationship between Enhanced Recovery protocol compliance and outcome in four surgical specialties. The data suggest that higher compliance with an Enhanced Recovery protocol has a weak association with shorter length of stay. This suggests that changes in process, resulting from highly protocolised pathways, may be as important in reducing perioperative length of stay as any individual element of Enhanced Recovery protocols in isolation. PMID- 25926314 TI - International migration of surgeons, anaesthesiologists, and obstetricians. PMID- 25926315 TI - Estimated need for surgery worldwide based on prevalence of diseases: a modelling strategy for the WHO Global Health Estimate. AB - BACKGROUND: Surgery is a foundational component of health-care systems. However, previous efforts to integrate surgical services into global health initiatives do not reflect the scope of surgical need and many health systems do not provide essential interventions. We estimate the minimum global volume of surgical need to address prevalent diseases in 21 epidemiological regions from the Global Burden of Disease Study 2010 (GBD). METHODS: Prevalence data were obtained from GBD 2010 and organised into 119 disease states according to the WHO's Global Health Estimate (GHE). These data, representing 187 countries, were then apportioned into the 21 GBD epidemiological regions. Using previously defined values for the incident need for surgery for each of the 119 GHE disease states, we calculate minimum global need for surgery based on the prevalence of each condition in each region. FINDINGS: We estimate that at least 321.5 million surgical procedures would be needed to address the burden of disease for a global population of 6.9 billion in 2010. Minimum rates of surgical need vary across regions, ranging from 3383 operations per 100 000 in central Latin America to 6495 operations per 100 000 in western sub-Saharan Africa. Global surgical need also varied across subcategories of disease, ranging from 131 412 procedures for nutritional deficiencies to 45.8 million procedures for unintentional injuries. INTERPRETATION: The estimated need for surgical procedures worldwide is large and addresses a broad spectrum of disease states. Surgical need varies between regions of the world according to disease prevalence and many countries do not meet the basic needs of their populations. These estimates could be useful for policy makers, funders, and ministries of health as they consider how to incorporate surgical capacity into health systems. FUNDING: US National Institutes of Health. PMID- 25926316 TI - Tracking global expenditures on surgery: gaps in knowledge hinder progress. PMID- 25926317 TI - Global economic consequences of selected surgical diseases: a modelling study. AB - BACKGROUND: The surgical burden of disease is substantial, but little is known about the associated economic consequences. We estimate the global macroeconomic impact of the surgical burden of disease due to injury, neoplasm, digestive diseases, and maternal and neonatal disorders from two distinct economic perspectives. METHODS: We obtained mortality rate estimates for each disease for the years 2000 and 2010 from the Institute of Health Metrics and Evaluation Global Burden of Disease 2010 study, and estimates of the proportion of the burden of the selected diseases that is surgical from a paper by Shrime and colleagues. We first used the value of lost output (VLO) approach, based on the WHO's Projecting the Economic Cost of Ill-Health (EPIC) model, to project annual market economy losses due to these surgical diseases during 2015-30. EPIC attempts to model how disease affects a country's projected labour force and capital stock, which in turn are related to losses in economic output, or gross domestic product (GDP). We then used the value of lost welfare (VLW) approach, which is conceptually based on the value of a statistical life and is inclusive of non-market losses, to estimate the present value of long-run welfare losses resulting from mortality and short-run welfare losses resulting from morbidity incurred during 2010. Sensitivity analyses were performed for both approaches. FINDINGS: During 2015-30, the VLO approach projected that surgical conditions would result in losses of 1.25% of potential GDP, or $20.7 trillion (2010 US$, purchasing power parity) in the 128 countries with data available. When expressed as a proportion of potential GDP, annual GDP losses were greatest in low-income and middle-income countries, with up to a 2.5% loss in output by 2030. When total welfare losses are assessed (VLW), the present value of economic losses is estimated to be equivalent to 17% of 2010 GDP, or $14.5 trillion in the 175 countries assessed with this approach. Neoplasm and injury account for greater than 95% of total economic losses with each approach, but maternal, digestive, and neonatal disorders, which represent only 4% of losses in high-income countries with the VLW approach, contribute to 26% of losses in low-income countries. INTERPRETATION: The macroeconomic impact of surgical disease is substantial and inequitably distributed. When paired with the growing number of favourable cost-effectiveness analyses of surgical interventions in low-income and middle-income countries, our results suggest that building surgical capacity should be a global health priority. FUNDING: US National Institutes of Health/National Cancer Institute. PMID- 25926318 TI - Timing and cost of scaling up surgical services in low-income and middle-income countries from 2012 to 2030: a modelling study. AB - BACKGROUND: Given the large burden of surgical conditions and the crosscutting nature of surgery, scale-up of basic surgical services is crucial to health system strengthening. The Lancet Commission on Global Surgery proposed that, to meet populations' needs, countries should achieve 5000 major operations per 100 000 population per year. We modelled the possible scale-up of surgical services in 88 low-income and middle-income countries with a population greater than 1 million from 2012 to 2030 at various rates and quantified the associated costs. METHODS: Major surgery includes any intervention within an operating room involving tissue manipulation and anaesthesia. We used estimates for the number of major operations achieved per country annually and the number of operating rooms per region, and data from Mongolia and Mexico for trends in the number of operations. Unit costs included a cost per operation, proxied by caesarean section cost estimates; hospital construction data were used to estimate cost per operating room construction. We determined the year by which each country would achieve the Commission's target. We modelled three scenarios for the scale-up rate: actual rates (5.1% per year) and two "aspirational" rates, the rates achieved by Mongolia (8.9% annual) and Mexico (22.5% annual). We subsequently estimated the associated costs. FINDINGS: About half of the 88 countries would achieve the target by 2030 at actual rates of improvements, with up to two-thirds if the rate were increased to Mongolian rates. We estimate the total costs of achieving scale-up at US$300-420 billion (95% UI 190-600 billion) over 2012-30, which represents 4-8% of total annual health expenditures among low-income and lower middle-income countries and 1% among upper middle-income countries. INTERPRETATION: Scale-up of surgical services will not reach the target of 5000 operations per 100 000 by 2030 in about half of low-income and middle-income countries without increased funding, which countries and the international community must seek to achieve expansion of quality surgical services. FUNDING: None. PMID- 25926319 TI - Catastrophic expenditure to pay for surgery worldwide: a modelling study. AB - BACKGROUND: Approximately 150 million individuals worldwide face catastrophic expenditure each year from medical costs alone, and the non-medical costs of accessing care increase that number. The proportion of this expenditure related to surgery is unknown. Because the World Bank has proposed elimination of medical impoverishment by 2030, the effect of surgical conditions on financial catastrophe should be quantified so that any financial risk protection mechanisms can appropriately incorporate surgery. METHODS: To estimate the global incidence of catastrophic expenditure due to surgery, we built a stochastic model. The income distribution of each country, the probability of requiring surgery, and the medical and non-medical costs faced for surgery were incorporated. Sensitivity analyses were run to test the robustness of the model. FINDINGS: 3.7 billion people (posterior credible interval 3.2-4.2 billion) risk catastrophic expenditure if they need surgery. Each year, 81.3 million people (80.8-81.7 million) worldwide are driven to financial catastrophe-32.8 million (32.4-33.1 million) from the costs of surgery alone and 48.5 million (47.7-49.3) from associated non-medical costs. The burden of catastrophic expenditure is highest in countries of low and middle income; within any country, it falls on the poor. Estimates were sensitive to the definition of catastrophic expenditure and the costs of care. The inequitable burden distribution was robust to model assumptions. INTERPRETATION: Half the global population is at risk of financial catastrophe from surgery. Each year, surgical conditions cause 81 million individuals to face catastrophic expenditure, of which less than half is attributable to medical costs. These findings highlight the need for financial risk protection for surgery in health-system design. FUNDING: MGS received partial funding from NIH/NCI R25CA92203. PMID- 25926320 TI - The blood drought in context. PMID- 25926321 TI - Strengthening emergency care: experience in central Haiti. PMID- 25926322 TI - Global burden of surgical disease: an estimation from the provider perspective. PMID- 25926323 TI - Global distribution of surgeons, anaesthesiologists, and obstetricians. PMID- 25926324 TI - Relationship of sharp force injuries to motivation. AB - Forensic pathologists are often expected to provide an opinion on the intention of the assailant in sharp force fatalities. A retrospective study was carried out on reports of post-mortems of victims of sharp force trauma over five years. The position and type of injuries were recorded and related to the known motivation for murder. Victims of different motives of killing had an almost similar injury pattern. There is no significant association of the pathology of sharp force injuries with the motive of killing. PMID- 25926326 TI - Effect of temperature and nutrients on the growth and development of seedlings of an invasive plant. AB - Plant species distributions are determined by the response of populations to regional climates; however, little is known about how alien plants that arrive in central Europe from climatically warmer regions cope with the temperature conditions at the early stage of population development. Ambrosia artemisiifolia (common ragweed) is an invasive annual plant causing considerable health and economic problems in Europe. Although climate-based models predict that the whole of the Czech Republic is climatically suitable for this species, it is confined to the warmest regions. To determine the factors possibly responsible for its restricted occurrence, we investigated the effects of temperature and nutrient availability on its seedlings. The plants were cultivated at one of seven temperature regimes ranging from 10 to 34 degrees C, combined with three nutrient levels. The data on the rate of leaf development were used to calculate the lower developmental threshold (LDT, the temperature, in degrees C, below which development ceases), the sum of effective temperatures (SET, the amount of heat needed to complete a developmental stage measured in degree days above LDT) and width of the thermal window. The rate of development decreased with decrease in temperature and nutrient supply. Besides this, the decrease in the availability of nutrients resulted in decreased LDT, increased SET and wider thermal window. The dependence of LDT and SET on the availability of nutrients contradicts the concept that thermal constants do not vary. Our results highlight temperature as the main determinant of common ragweed's distribution and identify nutrient availability as a factor that results in the realized niche being smaller than the fundamental niche; both of these need to be taken into account when predicting the future spread of A. artemisiifolia. PMID- 25926325 TI - DNA barcodes from four loci provide poor resolution of taxonomic groups in the genus Crataegus. AB - DNA barcodes can facilitate identification of organisms especially when morphological characters are limited or unobservable. To what extent this potential is realized in specific groups of plants remains to be determined. Libraries of barcode sequences from well-studied authoritatively identified plants represented by herbarium voucher specimens are needed in order for DNA barcodes to serve their intended purpose, where this is possible, and to understand the reasons behind their failure to do so, when this occurs. We evaluated four loci, widely regarded as universal DNA barcodes for plants, for their utility in hawthorn species identification. Three plastid regions, matK, rbcLa and psbA-trnH, and the internal transcribed spacer 2 (ITS2) of nuclear ribosomal DNA discriminate only some of the species of Crataegus that can be recognized on the basis of their morphology etc. This is, in part, because in Rosaceae tribe Maleae most individual plastid loci yield relatively little taxonomic resolution and, in part, because the effects of allopolyploidization have not been eliminated by concerted evolution of the ITS regions. Although individual plastid markers provided generally poor resolution of taxonomic groups in Crataegus, a few species were notable exceptions. In contrast, analyses of concatenated sequences of the 3 plastid barcode loci plus 11 additional plastid loci gave a well-resolved maternal phylogeny. In the ITS2 tree, different individuals of some species formed groups with taxonomically unrelated species. This is a sign of lineage sorting due to incomplete concerted evolution in ITS2. Incongruence between the ITS2 and plastid trees is best explained by hybridization between different lineages within the genus. In aggregate, limited between-species variation in plastid loci, hybridization and a lack of concerted evolution in ITS2 all combine to limit the utility of standard barcoding markers in Crataegus. These results have implications for authentication of hawthorn materials in natural health products. PMID- 25926327 TI - Large-Scale Arrays of Bowtie Nanoaperture Antennas for Nanoscale Dynamics in Living Cell Membranes. AB - We present a novel blurring-free stencil lithography patterning technique for high-throughput fabrication of large-scale arrays of nanoaperture optical antennas. The approach relies on dry etching through nanostencils to achieve reproducible and uniform control of nanoantenna geometries at the nanoscale, over millimeter-sizes in a thin aluminum film. We demonstrate the fabrication of over 400 000 bowtie nanoaperture (BNA) antennas on biocompatible substrates, having gap sizes ranging from (80 +/- 5) nm down to (20 +/- 10) nm. To validate their applicability on live cell research, we used the antenna substrates as hotspots of localized illumination to excite fluorescently labeled lipids on living cell membranes. The high signal-to-background afforded by the BNA arrays allowed the recording of single fluorescent bursts corresponding to the passage of freely diffusing individual lipids through hotspot excitation regions as small as 20 nm. Statistical analysis of burst length and intensity together with simulations demonstrate that the measured signals arise from the ultraconfined excitation region of the antennas. Because these inexpensive antenna arrays are fully biocompatible and amenable to their integration in most fluorescence microscopes, we foresee a large number of applications including the investigation of the plasma membrane of living cells with nanoscale resolution at endogenous expression levels. PMID- 25926328 TI - Health literacy and mortality: a cohort study of patients hospitalized for acute heart failure. AB - BACKGROUND: More than 30% of patients hospitalized for heart failure are rehospitalized or die within 90 days of discharge. Lower health literacy is associated with mortality among outpatients with chronic heart failure; little is known about this relationship after hospitalization for acute heart failure. METHODS AND RESULTS: Patients hospitalized for acute heart failure and discharged home between November 2010 and June 2013 were followed through December 31, 2013. Nurses administered the Brief Health Literacy Screen at admission; low health literacy was defined as Brief Health Literacy Screen <=9. The primary outcome was all-cause mortality. Secondary outcomes were time to first rehospitalization and, separately, time to first emergency department visit within 90 days of discharge. Cox proportional hazards models determined their relationships with health literacy, adjusting for age, gender, race, insurance, education, comorbidity, and hospital length of stay. For the 1379 patients, average age was 63.1 years, 566 (41.0%) were female, and 324 (23.5%) had low health literacy. Median follow-up was 20.7 months (interquartile range 12.8 to 29.6 months), and 403 (29.2%) patients died. Adjusted hazard ratio [aHR] for death among patients with LHL was 1.32 (95%confidence interval [CI] 1.05, 1.66, P=0.02) compared to BHLS>9 [corrected].Within 90 days of discharge, there were 415 (30.1%) rehospitalizations and 201 (14.6%) emergency department visits, with no evident association with health literacy. CONCLUSIONS: Lower health literacy was associated with increased risk of death after hospitalization for acute heart failure. There was no evident relationship between health literacy and 90-day rehospitalization or emergency department visits. PMID- 25926329 TI - Trifluoromethylchlorosulfonylation of alkenes: evidence for an inner-sphere mechanism by a copper phenanthroline photoredox catalyst. AB - A visible-light-mediated procedure for the unprecedented trifluoromethylchlorosulfonylation of unactivated alkenes is presented. It uses [Cu(dap)2]Cl as catalyst, and contrasts with [Ru(bpy)3]Cl2, [Ir(ppy)2(dtbbpy)]PF6, or eosin Y that exclusively give rise to trifluoromethylchlorination of the same alkenes. It is assumed that [Cu(dap)2]Cl plays a dual role, that is, acting both as an electron transfer reagent as well as coordinating the reactants in the bond forming processes. PMID- 25926330 TI - Proceedings: human leukocyte antigen haplo-homozygous induced pluripotent stem cell haplobank modeled after the california population: evaluating matching in a multiethnic and admixed population. AB - The development of a California-based induced pluripotent stem cell (iPSC) bank based on human leukocyte antigen (HLA) haplotype matching represents a significant challenge and a valuable opportunity for the advancement of regenerative medicine. However, previously published models of iPSC banks have neither addressed the admixed nature of populations like that of California nor evaluated the benefit to the population as a whole. We developed a new model for evaluating an iPSC haplobank based on demographic and immunogenetic characteristics reflecting California. The model evaluates haplolines or cell lines from donors homozygous for a single HLA-A, HLA-B, HLA-DRB1 haplotype. We generated estimates of the percentage of the population matched under various combinations of haplolines derived from six ancestries (black/African American, American Indian, Asian/Pacific Islander, Hispanic, and white/not Hispanic) and data available from the U.S. Census Bureau, the California Institute for Regenerative Medicine, and the National Marrow Donor Program. The model included both cis (haplotype-level) and trans (genotype-level) matching between a modeled iPSC haplobank and the recipient population following resampling simulations. We showed that serving a majority (>50%) of a simulated California population through cis matching would require the creation, redundant storage, and maintenance of almost 207 different haplolines representing the top 60 most frequent haplotypes from each ancestry group. Allowances for trans matching reduced the haplobank to fewer than 141 haplolines found among the top 40 most frequent haplotypes. Finally, we showed that a model optimized, custom haplobank was able to serve a majority of the California population with fewer than 80 haplolines. PMID- 25926331 TI - Human perivascular stem cell-based bone graft substitute induces rat spinal fusion. PMID- 25926332 TI - Proinflammatory Pathways: The Modulation by Flavonoids. AB - Inflammation is a natural, carefully orchestrated response of the organism to tissue damage, involving various signaling systems and the recruitment of inflammatory cells. These cells are stimulated to release a myriad of mediators that amplify the inflammatory response and recruit additional cells. These mediators present numerous redundancies of functions, allowing a broad and effective inflammatory response, but simultaneously make the understanding of inflammation pathways much difficult. The extent of the inflammatory response is usually self-limited, although it depends on the balance between the pro- and anti-inflammatory signals. When that equilibrium is dislocated, a more widespread inflammatory response may take place. Flavonoids have been shown to be possible alternatives to the traditionally molecules used as anti-inflammatory agents. In fact, the biological activities of flavonoids include the modulation of the diverse phases of inflammatory processes, from the gene transcription and expression to the inhibition of the enzymatic activities and the scavenging of the reactive species. In the present review, the inflammatory network is widely revised and the flavonoids' broad spectrum of action in many of the analyzed inflammatory pathways is revised. This kind of integrated revision is original in the field, providing the reader the simultaneous comprehension of the inflammatory process and the potential beneficial activities of flavonoids. PMID- 25926333 TI - Targeted inhibition of genome-wide DNA methylation analysis in epigenetically modulated phenotypes in lung cancer. AB - DNA methylation analysis, an epigenetic specification, has been explored for partial determination of cancer cell phenotypes. The development of metastasis in cancerogenesis has led its feasible association with the epigenetic modulations. We generated highly aggressive non-small cell lung cancer cell lines (HTB56 and A549) by using in vivo selection approach. These were, then, subjected to DNA methylation analysis (genome-wide). We also explored the therapeutic effects of azacytidine, an epigenetic agent, on DNA methylation patterns as well as the in vivo phenotypes. During the development of highly aggressive cell lines, we observed widespread modulations in DNA methylation. Reduced representation bisulfite sequencing was used and compared with the less aggressive parental cell lines to identify the differential methylation, which was achieved up to 2.7 % of CpG-rich region. Azacytidine inhibited DNA methyltransferase and reversed the prometastatic phenotype. We found its high association with the preferential loss of DNA methylation from hypermethylated sites. After persisted exposure of azacytidine, we observed that DNA methylation affected the polycomb-binding sites. We found close association of DNA methylome modifications with metastatic capability of non-small cell lung cancer. We also concluded that epigenetic modulation could be used as a potential therapeutic approach to prevent metastasis formation as prometastatic phenotype was reversed due to inhibition of DNA methyltransferase. PMID- 25926334 TI - Sympathetic activation and endothelial dysfunction in polycystic ovary syndrome are not explained by either obesity or insulin resistance. AB - OBJECTIVE: Polycystic ovary syndrome (PCOS) is a common endocrine condition underpinned by insulin resistance and associated with increased risk of obesity, type 2 diabetes and adverse cardiovascular risk profile. Previous data suggest autonomic imbalance [elevated sympathetic nervous system (SNS) activity and decreased heart rate variability (HRV)] as well as endothelial dysfunction in PCOS. However, it is not clear whether these abnormalities are driven by obesity and metabolic disturbance or whether they are independently related to PCOS. PARTICIPANTS AND METHODS: We examined multiunit and single-unit muscle SNS activity (by microneurography), HRV (time and frequency domain analysis) and endothelial function [ischaemic reactive hyperaemia index (RHI) using the EndoPAT device] in 19 overweight/obese women with PCOS (BMI: 31.3 +/- 1.5 kg/m(2), age: 31.3 +/- 1.6 years) and compared them with 21 control overweight/obese women (BMI: 33.0 +/- 1.4 kg/m(2), age: 28.2 +/- 1.6 years) presenting a similar metabolic profile (fasting total, HDL and LDL cholesterol, glucose, triglycerides, insulin sensitivity and blood pressure). RESULTS: Women with PCOS had elevated multiunit muscle SNS activity (41 +/- 2 vs 33 +/- 3 bursts per 100 heartbeats, P < 0.05). Single-unit analysis showed that vasoconstrictor neurons were characterized by elevated firing rate and probability and incidence of multiple spikes (P < 0.01 for all parameters). Women with PCOS also had impaired endothelial function (RHI: 1.77 +/- 0.14 vs 2.18 +/- 0.14, P < 0.05). HRV did not differ between the groups. CONCLUSION: Women with PCOS have increased sympathetic drive and impaired endothelial function independent of obesity and metabolic disturbances. Sympathetic activation and endothelial dysfunction may confer greater cardiovascular risk in women with PCOS. PMID- 25926335 TI - Genome-wide association study of footrot in Texel sheep. AB - BACKGROUND: This is the first study based on a genome-wide association approach that investigates the links between ovine footrot scores and molecular polymorphisms in Texel sheep using the ovine 50 K SNP array (42 883 SNPs (single nucleotide polymorphisms) after quality control). Our aim was to identify molecular predictors of footrot resistance. METHODS: This study used data from animals selected from a footrot-phenotyped Texel sheep population of 2229 sheep with an average of 1.60 scoring records per animal. From these, a subset of 336 animals with extreme trait values for footrot was selected for genotyping based on their phenotypic records. De-regressed estimated breeding values (EBV) for footrot were used as pseudo-phenotypes in the genome-wide association analysis. RESULTS: Seven SNPs were significant on a chromosome-wise level but the association analysis did not reveal any genome-wise significant SNPs associated with footrot. Based on the current state of knowledge of the ovine genome, it is difficult to clearly link the function of the genes that contain these significant SNPs with a potential role in resistance/susceptibility to footrot. Linkage disequilibrium (LD) was analysed as one of the factors that influence the power of detecting QTL (quantitative trait loci). A mean LD of 0.20 (r(2) at a distance of 50 kb between two SNPs) in the population analysed was estimated. LD declined from 0.15 to 0.07 and to 0.04 at distances between two SNPs of 100, 1000 and 2000 kb, respectively. CONCLUSIONS: Based on a relatively small number of genotyped animals, this study is a first step to search for genomic regions that are involved in resistance to footrot using the ovine 50 K SNP array. Seven SNPs were found to be significant on a chromosome-wise level. No major genome-wise significant QTL were identified. PMID- 25926336 TI - Ethics policies and procedures in imaging and interventional radiology. PMID- 25926337 TI - Uncovering the dynamic evolution of nucleotide-binding site-leucine-rich repeat (NBS-LRR) genes in Brassicaceae. AB - Plant genomes harbor dozens to hundreds of nucleotide-binding site-leucine-rich repeat (NBS-LRR) genes; however, the long-term evolutionary history of these resistance genes has not been fully understood. This study focuses on five Brassicaceae genomes and the Carica papaya genome to explore changes in NBS-LRR genes that have taken place in this Rosid II lineage during the past 72 million years. Various numbers of NBS-LRR genes were identified from Arabidopsis lyrata (198), A. thaliana (165), Brassica rapa (204), Capsella rubella (127), Thellungiella salsuginea (88), and C. papaya (51). In each genome, the identified NBS-LRR genes were found to be unevenly distributed among chromosomes and most of them were clustered together. Phylogenetic analysis revealed that, before and after Brassicaceae speciation events, both toll/interleukin-1 receptor-NBS-LRR (TNL) genes and non-toll/interleukin-1 receptor-NBS-LRR (nTNL) genes exhibited a pattern of first expansion and then contraction, suggesting that both subclasses of NBS-LRR genes were responding to pathogen pressures synchronically. Further, by examining the gain/loss of TNL and nTNL genes at different evolutionary nodes, this study revealed that both events often occurred more drastically in TNL genes. Finally, the phylogeny of nTNL genes suggested that this NBS-LRR subclass is composed of two separate ancient gene types: RPW8-NBS-LRR and Coiled-coil-NBS LRR. PMID- 25926338 TI - Moderate level of HER2 expression and its prognostic significance in breast cancer with intermediate grade. AB - Overexpression of human epidermal growth factor receptor 2 (HER2) is an important prognostic and predictive marker of response to anti-HER2 therapy in breast cancer. Our goal was to analyze the prognostic significance of moderate expression of HER2 in breast cancer with intermediate differentiation grade. We performed a multicenter retrospective register study of 8494 patients with primary non-metastatic breast cancer admitted between 2000 and 2011 to eight Clinics in Saxony-Anhalt, federal state of Germany. Patients were divided into three groups according to their HER2 score: 4073 were classified as HER2 negative (HER2 0 and 1+), 822 HER2 moderate (HER2 2+/HER2), and 1238 HER2 positive (HER2 3+ or HER2 2+/HER2+). HER2-positive cases were excluded from analysis. Tumors with moderate HER2 (HER2 2+) expression demonstrated an aggressive behavior and worse patient survival compared with HER2 0 and 1+ status. HER2 2+ status was associated with shorter median overall survival (OS) (P < 0.0001) in breast cancer patients with an intermediate grade of differentiation. Comparing low grade and high-grade tumors, HER2 moderate expression did not significantly influence patient survival. In multivariate analysis after adjustment for other prognostic factors HER2 2+ status remained an unfavorable prognostic factor for OS (HR 1.224, 95 % CI 1.059-1.415, P = 0.006) in breast cancer patients with an intermediate grade of differentiation. HER2 2+ status is an unfavorable prognostic factor regarding the OS of breast cancer patients with intermediate grade of differentiation and could be used to identify patients, who may benefit from adjuvant therapy. PMID- 25926339 TI - Lung cancer risk by years since quitting in 30+ pack year smokers. AB - OBJECTIVE: Current United States recommendations for low-dose computed tomography (LDCT) lung cancer screening limit eligibility to ever-smokers with 30+ pack years, with former smokers eligible only within 15 years of quitting. The 15 year limit is partly based on perceived decreases in lung cancer risk as years since quitting (YSQ) increase. We examine the relationship between lung cancer risk and YSQ among 30+ pack-year former smokers. METHODS: In the Prostate, Lung, Colorectal, and Ovarian trial, participants aged 55-74 were randomized to screening or usual care; screened subjects received annual chest-radiographs for lung cancer screening. Subjects completed a baseline questionnaire; smoking history included average cigarettes per day and age at starting and stopping smoking. Subjects were followed 13 years. Cox proportional hazards models were utilized to estimate hazard ratios (HRs) associated with YSQ, with YSQ treated as a time-varying covariate. The models adjusted for age and sex. RESULTS: Of 154899 subjects randomized, 27101 were former smokers with 30+ pack-years, and 69182 were never smokers. HRs relative to never smokers ranged from 30.8 (95% CI:23.4 40.5) for YSQ <= 5 to 6.4 (95% CI:5.1-8.0) for YSQ > 30. For YSQ of > 10-15, > 15 20, and > 20-25, HRs were 14.8 (95% CI:11.9-18.2), 13.5 (95% CI:11.3-16.2), and 9.9 (95% CI: 8.1-12.0), respectively. CONCLUSIONS: Lung cancer risk decreases gradually with YSQ in 30+ pack year former smokers. A range of upper limits on YSQ may be supportable for LDCT screening. PMID- 25926340 TI - Erratum to: Chediak-Higashi syndrome: brain MRI and MR spectroscopy manifestations. PMID- 25926341 TI - Governance and functionality of community water schemes in rural Ethiopia. AB - OBJECTIVES: A key challenge for achieving universal water access in Sub-Saharan Africa is poor sustainability of water schemes. Previous studies have posited factors that may lead to failed schemes; however, empirical data are lacking. METHODS: We conducted direct observations of water sources and interviewed water committee members about governance in two regions of Ethiopia. Based on direct observation at each water point, and harmonizing previous research in the sector, we developed an ordinal measure of functionality. Among functional systems, linear regression models were used to assess changes in score or level of functionality against governance characteristics. RESULTS: Of 89 water schemes over 5 years old, 82 had sufficient data to receive a score. Higher functionality scores were associated with having good records, meeting regularly, financial audits, higher monthly fees, a paid caretaker and water committees with capacity to perform minor repairs. CONCLUSIONS: Our continuous measure of functionality was simple to derive, objective and may be widely applicable for further studies assessing key indicators of sustainability. PMID- 25926342 TI - Physical inactivity and associated factors among university students in 23 low-, middle- and high-income countries. AB - OBJECTIVES: The aim of this study was to determine estimates of the prevalence and social correlates of physical inactivity among university students in 23 low , middle- and high-income countries. METHOD: The International Physical Activity Questionnaire was used to collect data from 17,928 undergraduate university students (mean age 20.8, SD = 2.8) from 24 universities in 23 countries. RESULTS: The prevalence of physical inactivity was 41.4 %, ranging from 21.9 % in Kyrgyzstan to 80.6 % in Pakistan. In multivariate logistic regression, older age (22-30 years), studying in a low- or lower middle-income country, skipping breakfast and lack of social support were associated with physical inactivity. In men, being underweight, being overweight or obese, not avoiding fat and cholesterol, not having severe depression symptoms, low beliefs in the health benefits of physical activity, low personal control and knowledge of exercise heart link, and in women, not trying to eat fibre, low personal mastery and medium personal control were additionally associated with physical inactivity. CONCLUSION: Four in each ten students are physically inactive, calling for strategic interventions by relevant professionals in higher educational institutions. PMID- 25926343 TI - Engineering application of activated alumina adsorption dams for emergency treatment of arsenic-contaminated rivers. AB - A batch of lab-based adsorption experiments were performed to investigate the arsenic (As) removal efficacy by activated alumina. Four factors including contact time, pH, initial As concentration and different coexisting ions were examined. The adsorbent made of activated alumina (AA) with particles of 2-4 mm diameter showed a high As removal efficiency and the As concentrations of the samples were below 0.05 mg/L when the hydraulic retention time (HRT) was operated above 5 min. The As concentrations of the samples could remain below 0.05 mg/L for 30 days. A series of AA adsorption dams coupled with several other supporting adsorption techniques were employed for As-contaminated river restoration. The engineering project functioned well, and the effluent As concentration was below 0.05 mg/L when the influent was between 0.2 and 0.7 mg/L, which met the discharge requirement of the Surface Water Quality Standards criteria III in China. The results demonstrated that AA adsorption dams could be applied for emergency treatments of small- or medium-sized rivers contaminated with As. PMID- 25926344 TI - Morphology and Topography of the Celiac Plexus in Degu (Octodon Degus). AB - Here, we investigate the morphology and topography of the celiac plexus components in degu (Octodon degus). The study was performed using six adult individuals of both sexes. Macromorphological observations were performed using a derivative of the thiocholine method specially adapted for this study type (Gienc, 1977). The classical H&E technique was used for analysis of the cytoarchitectonic of the ganglion, and the AChE (Karnovsky and Roots, 1964) and SPG (De la Torre, 1980) techniques to observe cholinergic and adrenergic activity. The celiac plexus of degu is located on the ventral and lateral surface of the abdominal aorta, at the level where the celiac artery separates from the aorta. This structure consists of two large and two smaller aggregations of neurocytes connected with postganglionic fibers. Histochemical investigations have demonstrated the mainly cholinergic characteristic of the intraganglionic and postganglionic fibers of the celiac plexus, while the adrenergic fibers accompanied only the blood vessels and neurocytes revealed differentiation of adrenergic activity. Histological analysis revealed that neurocytes occupied about half of the cross-section area, with the nerve fibers, connective tissue, and blood vessels forming the remaining part. Ganglionic cells were oval, and usually contained a single nucleus, although two nuclei were sometimes observed. PMID- 25926345 TI - Polyester: simulating RNA-seq datasets with differential transcript expression. AB - MOTIVATION: Statistical methods development for differential expression analysis of RNA sequencing (RNA-seq) requires software tools to assess accuracy and error rate control. Since true differential expression status is often unknown in experimental datasets, artificially constructed datasets must be utilized, either by generating costly spike-in experiments or by simulating RNA-seq data. RESULTS: Polyester is an R package designed to simulate RNA-seq data, beginning with an experimental design and ending with collections of RNA-seq reads. Its main advantage is the ability to simulate reads indicating isoform-level differential expression across biological replicates for a variety of experimental designs. Data generated by Polyester is a reasonable approximation to real RNA-seq data and standard differential expression workflows can recover differential expression set in the simulation by the user. AVAILABILITY AND IMPLEMENTATION: Polyester is freely available from Bioconductor (http://bioconductor.org/). CONTACT: jtleek@gmail.com SUPPLEMENTARY INFORMATION: Supplementary data are available at Bioinformatics online. PMID- 25926346 TI - PopIns: population-scale detection of novel sequence insertions. AB - MOTIVATION: The detection of genomic structural variation (SV) has advanced tremendously in recent years due to progress in high-throughput sequencing technologies. Novel sequence insertions, insertions without similarity to a human reference genome, have received less attention than other types of SVs due to the computational challenges in their detection from short read sequencing data, which inherently involves de novo assembly. De novo assembly is not only computationally challenging, but also requires high-quality data. Although the reads from a single individual may not always meet this requirement, using reads from multiple individuals can increase power to detect novel insertions. RESULTS: We have developed the program PopIns, which can discover and characterize non reference insertions of 100 bp or longer on a population scale. In this article, we describe the approach we implemented in PopIns. It takes as input a reads-to reference alignment, assembles unaligned reads using a standard assembly tool, merges the contigs of different individuals into high-confidence sequences, anchors the merged sequences into the reference genome, and finally genotypes all individuals for the discovered insertions. Our tests on simulated data indicate that the merging step greatly improves the quality and reliability of predicted insertions and that PopIns shows significantly better recall and precision than the recent tool MindTheGap. Preliminary results on a dataset of 305 Icelanders demonstrate the practicality of the new approach. AVAILABILITY AND IMPLEMENTATION: The source code of PopIns is available from http://github.com/bkehr/popins CONTACT: birte.kehr@decode.is SUPPLEMENTARY INFORMATION: Supplementary data are available at Bioinformatics online. PMID- 25926347 TI - Separate roles of different miRNA in the proliferation and migration of hepatocellular carcinoma. PMID- 25926349 TI - The role of type 2 diabetes in neurodegeneration. AB - A growing body of evidence links type-2 diabetes (T2D) with dementia and neurodegenerative diseases such as Alzheimer's disease (AD). AD is the most common form of dementia and is characterised neuropathologically by the accumulation of extracellular beta amyloid (Abeta) peptide aggregates and intracellular hyper-phosphorylated tau protein, which are thought to drive and/or accelerate inflammatory and oxidative stress processes leading to neurodegeneration. Although the precise mechanism remains unclear, T2D can exacerbate these neurodegenerative processes. Brain atrophy, reduced cerebral glucose metabolism and CNS insulin resistance are features of both AD and T2D. Cell culture and animal studies have indicated that the early accumulation of Abeta may play a role in CNS insulin resistance and impaired insulin signalling. From the viewpoint of insulin resistance and impaired insulin signalling in the brain, these are also believed to initiate other aspects of brain injury, including inflammatory and oxidative stress processes. Here we review the clinical and experimental pieces of evidence that link these two chronic diseases of ageing, and discuss underlying mechanisms. The evaluation of treatments for the management of diabetes in preclinical, and clinical studies and trials for AD will also be discussed. PMID- 25926348 TI - KCC2 function modulates in vitro ictogenesis. AB - GABAA receptor-mediated inhibition is active and may contribute to epileptiform synchronization. The efficacy of inhibition relies on low levels of intracellular Cl(-), which are controlled by KCC2 activity. This evidence has led us to analyze with field potential recordings the effects induced by the KCC2 blockers VU0240551 (10 MUM) or bumetanide (50 MUM) and by the KCC2 enhancer CLP257 (100 MUM) on the epileptiform discharges generated by piriform and entorhinal cortices (PC and EC, respectively) in an in vitro brain slice preparation. Ictal- and interictal-like discharges along with high-frequency oscillations (HFOs, ripples: 80-200 Hz, fast ripples: 250-500 Hz) were recorded from these two regions during application of 4-aminopyridine (4AP, 50 MUM). Blocking KCC2 activity with either VU024055 or high doses of bumetanide abolished ictal discharge in both PC and EC; in addition, these experimental procedures decreased the interval of occurrence and duration of interictal discharges. In contrast, enhancing KCC2 activity with CLP257 increased ictal discharge duration in both regions. Finally, blocking KCC2 activity decreased the duration and amplitude of pharmacologically isolated synchronous GABAergic events whereas enhancing KCC2 activity led to an increase in their duration. Our data demonstrate that in vitro ictogenesis is abolished or facilitated by inhibiting or enhancing KCC2 activity, respectively. We propose that these effects may result from the reduction of GABAA receptor-dependent increases in extracellular K(+) that are known to rest on KCC2 function. PMID- 25926350 TI - Phase II Study of Recombinant Antitumor and Antivirus Protein Injection Compared With Placebo in Metastatic Colorectal Cancer After Failure of Standard Treatment. AB - LESSONS LEARNED: Novaferon showed moderate efficacy and was well-tolerated in patients with metastatic colorectal cancer (mCRC), especially with the 20 MUg injected 3 times a week strategy.Although Novaferon did not provide a survival benefit for mCRC patients who have failed standard treatment, it may play a role in improvement of immune function. BACKGROUND: To observe the efficacy, safety, and optimal dosage of recombinant antitumor and antivirus protein (Novaferon) in treating patients with metastatic colorectal cancer (mCRC) who failed at least two prior palliative regimens. METHODS: We enrolled 108 patients from May 2011 to December 2012. According to different treatment modalities and therapeutic dosages, the participants were randomly divided into four cohorts at a 2:2:2:1 ratio: (a) 20 MUg Novaferon (Genova Biotech, Beijing, People's Republic of China, http://www.genovabiotech.net) injected twice per week, (b) 20 MUg Novaferon injected 3 times per week, (c) 40 MUg Novaferon injected 3 times per week, or (d) saline injected 3 times per week. The primary endpoint was overall survival. RESULTS: There was no significant difference in overall survival among the four cohorts. The 20-MUg dose of Novaferon injected 3 times per week had the highest disease control rate (44.0%) at 6 weeks but without significant differences when compared with placebo (p = .159). Major adverse events with Novaferon were influenza-like symptoms, bone marrow suppression, liver dysfunction, and gastrointestinal discomfort. The level of natural killer cells increased and regulatory T cells decreased significantly after treatment with Novaferon, whereas levels in the placebo group remained the same. CONCLUSION: Novaferon showed moderate efficacy and was well tolerated in patients with mCRC, especially with the 20-MUg dose injected 3 times per week. Furthermore, Novaferon might improve immune function of these patients. PMID- 25926351 TI - Expanding Cervical Cancer Screening and Treatment in Tanzania: Stakeholders' Perceptions of Structural Influences on Scale-Up. AB - Tanzania has the highest burden of cervical cancer in East Africa. This study aims to identify perceived barriers and facilitators that influence scale-up of regional and population-level cervical cancer screening and treatment programs in Tanzania. Convenience sampling was used to select participants for this qualitative study among 35 key informants. Twenty-eight stakeholders from public sector health facilities, academia, government, and nongovernmental organizations completed in-depth interviews, and a seven-member municipal health management team participated in a focus group discussion. The investigation identified themes related to the infrastructure of health services for cervical cancer prevention, service delivery, political will, and sociocultural influences on screening and treatment. Decentralizing service delivery, improving access to screening and treatment, increasing the number of trained health workers, and garnering political will were perceived as key facilitators for enhancing and initiating screening and treatment services. In conclusion, participants perceived that system-level structural factors should be addressed to expand regional and population-level service delivery of screening and treatment. IMPLICATIONS FOR PRACTICE: Tanzanian women have a high burden of cervical cancer. Understanding the perceived structural factors that may influence screening coverage for cervical cancer and availability of treatment may be beneficial for program scale-up. This study showed that multiple factors contribute to the challenge of cervical cancer screening and treatment in Tanzania. In addition, it highlighted systematic developments aimed at expanding services. This study is important because the themes that emerged from the results may help inform programs that plan to improve screening and treatment in Tanzania and potentially in other areas with high burdens of cervical cancer. PMID- 25926352 TI - Phase II Trial of Preoperative Radiation With Concurrent Capecitabine, Oxaliplatin, and Bevacizumab Followed by Surgery and Postoperative 5 Fluorouracil, Leucovorin, Oxaliplatin (FOLFOX), and Bevacizumab in Patients With Locally Advanced Rectal Cancer: 5-Year Clinical Outcomes ECOG-ACRIN Cancer Research Group E3204. AB - LESSONS LEARNED: The 5-year oncologic outcomes from the trial regimen were excellent. However, the neoadjuvant and surgical toxicity of this regimen was significant and was the primary reason for the low compliance with adjuvant systemic therapy.Due to the lack of an improvement in the pathologic complete response rate, the substantial associated toxicity, and the negative phase III trials of adjuvant bevacizumab in colon cancer, this regimen will not be pursued for further study. BACKGROUND: The addition of bevacizumab to chemotherapy improves overall survival for metastatic colorectal cancer. We initiated a phase II trial to evaluate preoperative capecitabine, oxaliplatin, and bevacizumab with radiation therapy (RT) followed by surgery and postoperative 5-fluorouracil, leucovorin, oxaliplatin (FOLFOX), and bevacizumab for locally advanced rectal cancer. The purpose of this report is to describe the 5-year oncologic outcomes of this regimen. METHODS: In a phase II Simon two-stage design study, we evaluated preoperative treatment with capecitabine (825 mg/m(2) b.i.d. Monday Friday), oxaliplatin (50 mg/m(2) weekly), bevacizumab (5 mg/kg on days 1, 15, and 29), and RT (50.4 Gy). Surgery was performed by 8 weeks after RT. Beginning 8-12 weeks after surgery, patients received FOLFOX plus bevacizumab (5 mg/kg) every 2 weeks for 12 cycles (oxaliplatin stopped after 9 cycles). The primary endpoint was a pathologic complete response (path-CR) rate of 30%. Fifty-seven patients with resectable T3/T4 rectal adenocarcinoma were enrolled between 2006 and 2010. RESULTS: Of 57 enrolled patients, 53 were eligible and included in the analysis. Forty-eight (91%) patients completed preoperative therapy, all of whom underwent curative surgical resection. Nine patients (17%) achieved path-CR. There were 29 worst grade 3 events, 8 worst grade 4 events, and 2 patient deaths, 1 of which was attributed to study therapy. Twenty-six patients (54%) began adjuvant chemotherapy. After a median follow-up period of 41 months, the 5-year overall survival (OS) rate for all patients was 80%. Only 2 patients experienced cancer recurrence: 1 distant (liver) and 1 loco-regional (pelvic lymph nodes), respectively. Both of these patients are still alive. The 5-year relapse-free survival rate was 81%. CONCLUSION: Despite the path-CR primary endpoint of this trial not being reached, the 5-year OS and recurrence-free survival rates were excellent. However, the neoadjuvant and surgical toxicity of this regimen was significant and was the primary reason for the low compliance with adjuvant systemic therapy. Because of the lack of an improvement in the path-CR rate, the substantial associated toxicity, and the negative phase III trials of adjuvant bevacizumab in colon cancer, this regimen will not be pursued for further study. PMID- 25926353 TI - Effects of landscape transformation on bird colonization and extinction patterns in a large-scale, long-term natural experiment. AB - Conversion of agricultural land to forest plantations is a major driver of global change. Studies on the impact of forest plantations on biodiversity in plantations and in the surrounding native vegetation have been inconclusive. Consequently, it is not known how to best manage the extensive areas of the planet currently covered by plantations. We used a novel, long-term (16 years) and large-scale (30,000 ha) landscape transformation natural experiment (the Nanangroe experiment, Australia) to test the effects of land conversion on population dynamics of 64 bird species associated with woodland and forest. A unique aspect of our study is that we focused on the effects of plantations on birds in habitat patches within plantations. Our study design included 56 treatment sites (Eucalyptus patches where the surrounding matrix was converted from grazed land to pine plantations), 55 control sites (Eucalyptus patches surrounded by grazed land), and 20 matrix sites (sites within the pine plantations and grazed land). Bird populations were studied through point counts, and colonization and extinction patterns were inferred through multiple season occupancy models. Large-scale pine plantation establishment affected the colonization or extinction patterns of 89% of studied species and thus led to a comprehensive turnover in bird communities inhabiting Eucalyptus patches embedded within the maturing plantations. Smaller bodied species appeared to respond positively to plantations (i.e., colonization increased and extirpation of these species decreased in patches surrounded by plantations) because they were able to use the newly created surrounding matrix. We found that the effects of forest plantations affected the majority of the bird community, and we believe these effects could lead to the artificial selection of one group of species at the expense of another. PMID- 25926354 TI - Roles of CYP2e1 in 1,2-dichloroethane-induced liver damage in mice. AB - The aim of this study was to explore the roles of cytochrome P450 2E1 (CYP2E1) in 1,2-dichloroethane (1,2-DCE)-induced liver damage. Two parts were included in this study: first, effect of 1,2-DCE on microsomal expression of CYP2E1, and second, potential of an inhibitor of CYP2E1 to reduce 1,2-DCE-induced liver damage. In part one, mice were exposed to 0, 0.225, 0.45, or 0.9 g/m3 1,2-DCE for 10 days, 3.5 h per day through static inhalation. In part two, mice were divided into blank control, solvent control, inhibitor control, 1,2-DCE-poisoned group, and low or high intervention group. In part one, compared to the control, serum alanine aminotransferase (ALT) activities and hepatic malondialdehyde (MDA) levels in 0.9 g/m3 1,2-DCE group, and microsomal CYP2E1 protein expression and activity in both 0.45 and 0.9 g/m3 1,2-DCE groups increased significantly; conversely, hepatic nonprotein sulfhydryl (NPSH) levels in both 0.45 and 0.9 g/m3 1,2-DCE groups and hepatic SOD activities in 0.9 g/m3 1,2-DCE group decreased significantly. In part two, microsomal CYP2E1 protein expression and activity decreased significantly in both low and high intervention groups compared to 1,2 DCE-poisoned group. Along with the changes of CYP2E1, hepatic MDA levels and serum ALT activities decreased; conversely, hepatic NPSH levels and SOD activities increased significantly in high intervention group. Taken together, our results suggested that 1,2-DCE could enhance CYP2E1 protein expression and enzymatic activity, which could cause oxidative damage in liver, serving as an important mechanism underlying 1,2-DCE-induced liver damage. (c) 2015 Wiley Periodicals, Inc. Environ Toxicol 31: 1430-1438, 2016. PMID- 25926355 TI - Metal nanocluster light-emitting devices with suppressed parasitic emission and improved efficiency: exploring the impact of photophysical properties. AB - Here we investigate the photophysical properties of Au(0)@Au(i)-thiolate nanoclusters by controlling the degree of aggregation, and measure electrochemical energy levels to design a metal nanocluster-based thin film LED (MNC-LED) structure. These efforts allow us to implement MNC-LEDs with luminance exceeding 40 cd m(-2) and external quantum efficiency exceeding 0.1% with clearly visible orange emission. It is also demonstrated that by varying the sizes of nanoclusters, the electroluminescence spectrum of the device can be tuned to the infrared emission, indicating the possibility of exploiting metal nanocluster emitters for use over a wide spectral range. PMID- 25926356 TI - Precipitation impacts on vegetation spring phenology on the Tibetan Plateau. AB - The ongoing changes in vegetation spring phenology in temperate/cold regions are widely attributed to temperature. However, in arid/semiarid ecosystems, the correlation between spring temperature and phenology is much less clear. We test the hypothesis that precipitation plays an important role in the temperature dependency of phenology in arid/semiarid regions. We therefore investigated the influence of preseason precipitation on satellite-derived estimates of starting date of vegetation growing season (SOS) across the Tibetan Plateau (TP). We observed two clear patterns linking precipitation to SOS. First, SOS is more sensitive to interannual variations in preseason precipitation in more arid than in wetter areas. Spatially, an increase in long-term averaged preseason precipitation of 10 mm corresponds to a decrease in the precipitation sensitivity of SOS by about 0.01 day mm(-1) . Second, SOS is more sensitive to variations in preseason temperature in wetter than in dryer areas of the plateau. A spatial increase in precipitation of 10 mm corresponds to an increase in temperature sensitivity of SOS of 0.25 day degrees C(-1) (0.25 day SOS advance per 1 degrees C temperature increase). Those two patterns indicate both direct and indirect impacts of precipitation on SOS on TP. This study suggests a balance between maximizing benefit from the limiting climatic resource and minimizing the risk imposed by other factors. In wetter areas, the lower risk of drought allows greater temperature sensitivity of SOS to maximize the thermal benefit, which is further supported by the weaker interannual partial correlation between growing degree days and preseason precipitation. In more arid areas, maximizing the benefit of water requires greater sensitivity of SOS to precipitation, with reduced sensitivity to temperature. This study highlights the impacts of precipitation on SOS in a large cold and arid/semiarid region and suggests that influences of water should be included in SOS module of terrestrial ecosystem models for drylands. PMID- 25926357 TI - Distinct sets of FGF receptors sculpt excitatory and inhibitory synaptogenesis. AB - Neurons in the brain must establish a balanced network of excitatory and inhibitory synapses during development for the brain to function properly. An imbalance between these synapses underlies various neurological and psychiatric disorders. The formation of excitatory and inhibitory synapses requires precise molecular control. In the hippocampus, the structure crucial for learning and memory, fibroblast growth factor 22 (FGF22) and FGF7 specifically promote excitatory or inhibitory synapse formation, respectively. Knockout of either Fgf gene leads to excitatory-inhibitory imbalance in the mouse hippocampus and manifests in an altered susceptibility to epileptic seizures, underscoring the importance of FGF-dependent synapse formation. However, the receptors and signaling mechanisms by which FGF22 and FGF7 induce excitatory and inhibitory synapse differentiation are unknown. Here, we show that distinct sets of overlapping FGF receptors (FGFRs), FGFR2b and FGFR1b, mediate excitatory or inhibitory presynaptic differentiation in response to FGF22 and FGF7. Excitatory presynaptic differentiation is impaired in Fgfr2b and Fgfr1b mutant mice; however, inhibitory presynaptic defects are only found in Fgfr2b mutants. FGFR2b and FGFR1b are required for an excitatory presynaptic response to FGF22, whereas only FGFR2b is required for an inhibitory presynaptic response to FGF7. We further find that FGFRs are required in the presynaptic neuron to respond to FGF22, and that FRS2 and PI3K, but not PLCgamma, mediate FGF22-dependent presynaptic differentiation. Our results reveal the specific receptors and signaling pathways that mediate FGF-dependent presynaptic differentiation, and thereby provide a mechanistic understanding of precise excitatory and inhibitory synapse formation in the mammalian brain. PMID- 25926358 TI - Control of brain patterning by Engrailed paracrine transfer: a new function of the Pbx interaction domain. AB - Homeoproteins of the Engrailed family are involved in the patterning of mesencephalic boundaries through a mechanism classically ascribed to their transcriptional functions. In light of recent reports on the paracrine activity of homeoproteins, including Engrailed, we asked whether Engrailed intercellular transfer was also involved in brain patterning and boundary formation. Using time controlled activation of Engrailed combined with tools that block its transfer, we show that the positioning of the diencephalic-mesencephalic boundary (DMB) requires Engrailed paracrine activity. Both zebrafish Eng2a and Eng2b are competent for intercellular transfer in vivo, but only extracellular endogenous Eng2b, and not Eng2a, participates in DMB positioning. In addition, disruption of the Pbx-interacting motif in Engrailed, known to strongly reduce the gain-of function phenotype, also downregulates Engrailed transfer, thus revealing an unsuspected participation of the Pbx interaction domain in this pathway. PMID- 25926359 TI - ATRX contributes to epigenetic asymmetry and silencing of major satellite transcripts in the maternal genome of the mouse embryo. AB - A striking proportion of human cleavage-stage embryos exhibit chromosome instability (CIN). Notably, until now, no experimental model has been described to determine the origin and mechanisms of complex chromosomal rearrangements. Here, we examined mouse embryos deficient for the chromatin remodeling protein ATRX to determine the cellular mechanisms activated in response to CIN. We demonstrate that ATRX is required for silencing of major satellite transcripts in the maternal genome, where it confers epigenetic asymmetry to pericentric heterochromatin during the transition to the first mitosis. This stage is also characterized by a striking kinetochore size asymmetry established by differences in CENP-C protein between the parental genomes. Loss of ATRX results in increased centromeric mitotic recombination, a high frequency of sister chromatid exchanges and double strand DNA breaks, indicating the formation of mitotic recombination break points. ATRX-deficient embryos exhibit a twofold increase in transcripts for aurora kinase B, the centromeric cohesin ESCO2, DNMT1, the ubiquitin-ligase (DZIP3) and the histone methyl transferase (EHMT1). Thus, loss of ATRX activates a pathway that integrates epigenetic modifications and DNA repair in response to chromosome breaks. These results reveal the cellular response of the cleavage stage embryo to CIN and uncover a mechanism by which centromeric fission induces the formation of large-scale chromosomal rearrangements. Our results have important implications to determine the epigenetic origins of CIN that lead to congenital birth defects and early pregnancy loss, as well as the mechanisms involved in the oocyte to embryo transition. PMID- 25926361 TI - On the development of the patella. AB - The current view of skeletal patterning fails to explain the formation of sesamoid bones. These small bones, which facilitate musculoskeletal function, are exceptionally embedded within tendons. Although their structural design has long puzzled researchers, only a limited model for sesamoid bone development has emerged. To date, sesamoids are thought to develop inside tendons in response to mechanical signals from the attaching muscles. However, this widely accepted model has lacked substantiation. Here, we show that, contrary to the current view, in the mouse embryo the patella initially develops as a bony process at the anteriodistal surface of the femur. Later, the patella is separated from the femur by a joint formation process that is regulated by mechanical load. Concurrently, the patella becomes superficially embedded within the quadriceps tendon. At the cellular level, we show that, similar to bone eminences, the patella is formed secondarily by a distinct pool of Sox9- and Scx-positive progenitor cells. Finally, we show that TGFbeta signaling is necessary for the specification of patella progenitors, whereas the BMP4 pathway is required for their differentiation. These findings establish an alternative model for patella development and provide the mechanical and molecular mechanisms that underlie this process. More broadly, our finding that activation of a joint formation program can be used to switch between the formation of bony processes and of new auxiliary bones provides a new perspective on plasticity during skeletal patterning and evolution. PMID- 25926360 TI - The transmembrane protein Crumbs displays complex dynamics during follicular morphogenesis and is regulated competitively by Moesin and aPKC. AB - The transmembrane protein Crumbs (Crb) functions in apical polarity and epithelial integrity. To better understand its role in epithelial morphogenesis, we examined Crb localization and dynamics in the late follicular epithelium of Drosophila. Crb was unexpectedly dynamic during middle-to-late stages of egg chamber development, being lost from the marginal zone (MZ) in stage 9 before abruptly returning at the end of stage 10b, then undergoing a pulse of endocytosis in stage 12. The reappearance of MZ Crb is necessary to maintain an intact adherens junction and MZ. Although Crb has been proposed to interact through its juxtamembrane domain with Moesin (Moe), a FERM domain protein that regulates the cortical actin cytoskeleton, the functional significance of this interaction is poorly understood. We found that whereas the Crb juxtamembrane domain was not required for adherens junction integrity, it was necessary for MZ localization of Moe, aPKC and F-actin. Furthermore, Moe and aPKC functioned antagonistically, suggesting that Moe limits Crb levels by reducing its interactions with the apical Par network. Additionally, Moe mutant cells lost Crb from the apical membrane and accumulated excess Crb at the MZ, suggesting that Moe regulates Crb distribution at the membrane. Together, these studies reveal reciprocal interactions between Crb, Moe and aPKC during cellular morphogenesis. PMID- 25926362 TI - Intramolecular Communication in Anionic Oxidized Phosphanes through a Chelated Proton. AB - Oxidation of the 1,2-(PR2 )2 -1,2-closo-C2 B10 H10 (R=Ph, iPr) platform with hydrogen peroxide in acetone is a two-step procedure in which partial deboronation of the closo cluster and oxidation of the phosphorus atoms occur. Based on NMR spectroscopic and kinetic data, we demonstrate that the phosphorus atoms are oxidized in the first step, followed by cluster deboronation. DFT calculations and natural-bond orbital (NBO) analysis were used to obtain insight into the electronic structures of diphosphane ortho-carborane derivatives. PMID- 25926363 TI - The mechanism of xylans removal during hydrothermal pretreatment of poplar fibers investigated by immunogold labeling. AB - MAIN CONCLUSION: Hydrothermal pretreatment initially removed the lignin-free xylan from the middle layer of secondary wall, followed by the lignin-bound xylan, but the cellulose-bound xylan was seldom removed by this pretreatment. An in-depth understanding of the mechanism of xylan removal during hydrothermal pretreatment (HTP) of wood is critical for cost-effective conversion of lignocellulosic biomass to biofuels. Several studies demonstrated the kinetics and mechanism of xylan removal during HTP on molecular scale, but the dissolution mechanism of xylan during HTP remains unclear at ultra-structural level. Our study investigated changes in the micro-distribution of xylan in poplar fiber cell walls during HTP by transmission electron microscopy (TEM) in combination with immunogold labeling. The study revealed that HTP caused greater decline in the density of xylan labeling in the S2 layer of fiber wall than in the S1 layer. There was a greater loss in the density of xylan labeling during HTP in the delignified and enzymatically treated fibers compared to untreated fibers. We propose that in the initial stages of HTP lignin-free xylan in the S2 layer was more readily hydrolyzed than in the S1 layer by hydronium ions. With increasing pretreatment time, the xylan covalently bound to lignin was also removed from the S2 layer due to the dissolution of lignin. The xylan tightly bound to cellulose was seldom removed during HTP, but was hydrolyzed in subsequent enzymatic treatment. This TEM-immunolabeling investigation reveals the manner in which different xylan fractions are removed from fiber cell wall during HTP, and we expect the information to be helpful in developing processes tailored for more effective conversion of cellulosic biomass into fermentable sugars. PMID- 25926366 TI - Type I diabetes: a new risk factor for obstructive sleep apnea. PMID- 25926364 TI - Self-Assembly of Disorazole C1 through a One-Pot Alkyne Metathesis Homodimerization Strategy. AB - Alkyne metathesis is increasingly explored as a reliable method to close macrocyclic rings, but there are no prior examples of an alkyne-metathesis-based homodimerization approach to natural products. In this approach to the cytotoxic C2-symmetric marine-derived bis(lactone) disorazole C1, a highly convergent, modular strategy is employed featuring cyclization through an ambitious one-pot alkyne cross-metathesis/ring-closing metathesis self-assembly process. PMID- 25926367 TI - Obstructive sleep apnea and diabetes mellitus. AB - BACKGROUND: There is convincing evidence that obstructive sleep apnea (OSA) is highly associated with impaired glucose metabolism. OBJECTIVES: Analyze the prevalence of OSA in type 1 and type 2 diabetes mellitus (DM) patients. Evaluate the influence of OSA on glycemic control. METHODS: The adult patients with diabetes mellitus (DM) followed in the department of internal medicine were referred to our Sleep Unit. A home respiratory polygraphy was then performed on all patients with body mass index (BMI) <40 kg/m(2). The glycemic control was assessed by the value of glycated hemoglobin (Hba1c) in the previous 3 months. RESULTS: A total of 46 patients were studied (20 men and 26 women), the mean age was 50+/-15 years and mean BMI was 28.6+/-4.9 kg/m(2). The mean Hba1c was 8.3+/ 1.2. Twenty three patients had type 2 DM and 23 patients had type 1 DM. Twenty nine patients (63.0%) had OSA and 8.7% had severe OSA (AHI>30/h). The mean CT90 was 5.3+/-12.5 and the mean AHI was 13.6+/-18.3. The mean AHI was similar between type 1 and type 2 DM (15.7+/-24.5 Vs 11.6+/-8.9; p=0.46). The AHI was not correlated with the BMI. Type 2 DM patients with poor glycemic control (HbA1c>7.5%) had a significantly higher mean AHI (14.3+/-9.0 vs 6.4+/-6.2; p=0.038). This difference did not remain significant after adjustment for BMI (p=0.151). CONCLUSIONS: The prevalence of OSA in type 1 DM is similar to that found in type 2 DM. We note the high prevalence of OSA in younger patients with type 1 DM. PMID- 25926368 TI - Validation of a Portuguese version of the STOP-Bang questionnaire as a screening tool for obstructive sleep apnea: Analysis in a sleep clinic. AB - INTRODUCTION: Screening methods have become increasingly important owing to the growing number of patients suspected of obstructive sleep apnea (OSA) being referred for sleep consultation. The STOP-Bang questionnaire has been validated as a screening tool for OSA in surgical patients. OBJECTIVES: To evaluate the performance of a Portuguese version of the STOP-Bang questionnaire for the diagnosis of OSA in a sleep clinic. METHODS: Prospectively, for 2 months, all patients referred to our clinic for clinical evaluation completed a translated version of the STOP-Bang questionnaire in Portuguese and underwent a sleep study. RESULTS: We observed 216 patients and 215 (99.5%) were included. Age was 53.63+/ 13.10 years, 63.3% were male patients, neck circumference was 40.4+/-44.11 cm and BMI was 29.41 [26.85; 33.06] kg/m(2). OSA was present in 78% of the patients, of whom, 33% had moderate and 37% had severe OSA. A STOP-Bang score >=3 had a sensitivity and positive predictive value (PPV) for OSA of 93.4% and 86.6%, respectively. Each increase in the STOP-Bang score was associated with an increase in the probability of OSA and severe OSA; reaching a 95% OSA probability, for a score of 6, and a 73% severe OSA probability, for a score of 8. A score of 3 and 2 had a negative predictive value for moderate/severe OSA of 85.3% and 91.7%, respectively. CONCLUSIONS: The STOP-Bang questionnaire showed high sensitivity and PPV for OSA with the probability of severe OSA steadily increasing, the higher the scores. Furthermore, a low score showed high predictive value for the exclusion of moderate/severe OSA. The STOP-Bang questionnaire can be a powerful tool for stratifying patients in the diagnosis of OSA. PMID- 25926369 TI - Alternative functional criteria to assess airflow-limitation reversibility in asthma. AB - INTRODUCTION: International guidelines define significant bronchodilator response as absolute and percentage change from baseline in forced expiratory volume (FEV1) in the first second and/or forced vital capacity (FVC) >=12% and 200 mL. However, bronchodilator effects on other lung function parameters have also been correlated to some degree of reversible airflow limitation. OBJECTIVES: To determine whether changes in other lung function parameters apart from FEV1 and FVC detect functional responses to bronchodilator in asthmatic patients. MATERIALS AND METHODS: Spirometry and body plethysmography were performed at baseline conditions and after administration of 400 MUg of salbutamol by metered dose inhaler through a space chamber device in asthmatic patients. Paired t-tests were used to compare lung function parameters between those with and without criteria for reversibility of airway obstruction according to ATS/ERS criteria. Cut-off values were obtained from the corresponding ROC curves. Measurements evaluated were FEV1, FVC, maximum mid-forced expiratory flow (FEF25-75%), residual volume (RV), inspiratory capacity (IC), airway resistance (Raw) and specific airway conductance (sGaw). RESULTS: From a total of 100 consecutive asthmatics patients (46% of them men; average age 58.7+/-14.1 years; 76% with mild to moderate obstruction), 50 patients had a significant bronchodilator response. All of these had noteworthy variations (p<0.004) in PEF, FEF25-75%, RV, Raw and sGaw. The most accurate in predicting a significant bronchodilator response were the absolute and percentage improvements in PEF (>=0.4 L/s and 8%), FEF25-75% (>=0.087 L/s and 27%) and the percentage of sGaw compared with that at baseline (>=25%). Based on these cut-off values, a sizeable number of the patients defined as non-responders had important changes in airway caliber. 17 patients had significant increments in the percentage of PEF and 10 had changes in absolute volume; 6 patients had increments in percentage and 16 in absolute change of FEF25-75%; 22 patients had increments in the percentage change of sGaw. CONCLUSIONS: Changes of FEV1 and/or FVC may underestimate significant functional response to bronchodilators in asthmatic patients with airway obstruction when considering the change in other lung function parameters. PMID- 25926370 TI - Inspiratory muscle training with threshold or incentive spirometry: Which is the most effective? AB - Inspiratory muscular training (IMT) increases the respiratory muscle strength, however, there is no data demonstrating its superiority over the incentive spirometry (IS) in doing so. Values of muscle strength after IMT (Threshold IMT((r))) and by the IS (Voldyne((r))) in healthy females was compared. Subjects (n=40) were randomly divided into control group (CG, n=14), IS group (ISG, n=13) and threshold group (TG, n=13). PImax was measured before (pre-IMT), at 15 and 30 days of IMT. There was an increase in PImax of the TG at 15 days (p<0.001) and 30 days of IMT (p<0.001). The same occurred with the ISG, which increased the PImax at 15 days (p<0.001) and 30 days of training (p<0.001). After 30 days of IMT, the TG presented a PImax which was significantly higher than ISG and the CG (p=0.045 and p<0.001, respectively). It can be concluded that IMT by threshold was more effective in increasing muscle strength than the Voldyne. PMID- 25926371 TI - Recurrent respiratory papillomatosis of the airway: The experience of an endoscopic unit. AB - INTRODUCTION: Recurrent respiratory papillomatosis (RPP) is a rare benign neoplasm caused by human papillomavirus (HPV). RPP is characterized by recurrent proliferation of the papillomata in the respiratory tract. OBJECTIVES AND METHODS: Retrospective analysis of all adult patients with diagnosis of recurrent respiratory papillomatosis admitted to our endoscopic unit between 2000 and 2013 with histological proved papillomatosis. RESULTS: Four patients were included (3 women) with an average age of 53+/-19 years (27-72). Before endoscopy unit admission, all the patients have been previously submitted to surgical removal of the papillomas with a median number of surgeries per patient of 6.5. These patients were submitted to therapeutic endoscopy and the most frequent endoscopic treatments were Laser YAG and local injection of cidofovir. All the patients treated with cidofovir presented complete remission of the disease. The median follow-up was 6 years: 2 presented malignant transformation to epidermoid carcinoma and 1 had severe dysplasia on the histological examination. We describe the four cases due to different forms of presentation. CONCLUSION: Papillomatosis of the airway is a rare condition predisposing to malignant transformation. RRP tends to recur and repeated surgeries are needed to remove papillomatas. Endoscopic treatment is important for the removal of the papillomas that are not accessible via laryngoscopy (YAG Laser, cryotherapy, etc.) and for resistant moderate/severe cases of RPP because it allows intralesional administration of adjuvant therapy like cidofovir. PMID- 25926372 TI - Who are the patients with extrapulmonary tuberculosis? AB - INTRODUCTION: Tuberculosis (TB) remains a major global public health problem and 20% of all cases are extrapulmonar. The purpose of this study was to identify risk factors associated with extrapulmonar tuberculosis. METHODS: We carried out a transversal study which included all patients with extrapulmonary tuberculosis registered in a TB reference center in northern Portugal, between January 2008 and January 2012. We evaluated demographic data, comorbidities, BCG vaccination and previous tuberculosis treatments. Multivariable logistic regression was used to identify independent risk factors (p<0.05). RESULTS: Among the 386 patients studied, 260 (67.4%) had pulmonary tuberculosis (PTB) and 126 (32.6%) extrapulmonary TB (EPTB). Age over 40 years old (OR=2.09; 95%CI: 1.29-3.38), female gender (OR=1.63; 95%CI=1.02-2.6) and HIV infection (OR=2.72, 95%CI=1.25 5.93) were independent risk factors for EPTB. Alcoholism (OR=2.22, 95%CI: 1.00 4.95) was associated with higher risk for PTB. Previous liver disease (OR=22.30; 95%IC: 1.89-263.57) was an independent risk factor for peritoneal TB. HIV co infection (OR=12.97; 95%IC: 1.71-48.42) and the presence of previous TB treatment (OR=7.62; 95%IC: 1.00-57.9) increase the risk of disseminated disease. CONCLUSION: We identified independent risk factors for EPTB. Recognizing risk factors associated with EPTB is essential for suspicion of disease and may help make an accurate diagnosis. PMID- 25926373 TI - The value of cough peak flow measurements in the assessment of extubation or decannulation readiness. AB - Insufficient cough strength has a major role in extubation and decannulation outcomes. Cough capacity can be easily evaluated by measuring flows during coughing. Values vary depending on whether cough flows are measured through the mouth or through a tracheostomy or endotracheal tube. It is important to standardize these measurements and start using them routinely in the extubation and decannulation processes. Values of cough peak flow >160 L/min measured at the mouth or a value of cough PEF >60 L/min measured at the endotracheal tube suggest successful decannulation or extubation. PMID- 25926374 TI - Tuberculosis screening and compliance rate with guidelines among northern Portuguese hospitals prescribers of anti-TNF therapy. PMID- 25926375 TI - Oxygen therapy: a clinical audit in an Internal Medicine Department. PMID- 25926376 TI - Solitary fibrous tumors of the pleura: not always a benign entity. PMID- 25926377 TI - Combined intrapleural therapy in infectious pleural effusion. PMID- 25926379 TI - ACTRIMS Symposium FOCIS Annual Meeting June 24, 2015 San Diego, California. PMID- 25926378 TI - mRNAs and miRNAs in whole blood associated with lung hyperplasia, fibrosis, and bronchiolo-alveolar adenoma and adenocarcinoma after multi-walled carbon nanotube inhalation exposure in mice. AB - Inhalation exposure to multi-walled carbon nanotubes (MWCNT) in mice results in inflammation, fibrosis and the promotion of lung adenocarcinoma; however, the molecular basis behind these pathologies is unknown. This study determined global mRNA and miRNA profiles in whole blood from mice exposed by inhalation to MWCNT that correlated with the presence of lung hyperplasia, fibrosis, and bronchiolo alveolar adenoma and adenocarcinoma. Six-week-old, male, B6C3F1 mice received a single intraperitoneal injection of either the DNA-damaging agent methylcholanthrene (MCA, 10 ug g(-1) body weight) or vehicle (corn oil). One week after injections, mice were exposed by inhalation to MWCNT (5 mg m(-3), 5 hours per day, 5 days per week) or filtered air (control) for a total of 15 days. At 17 months post-exposure, mice were euthanized and examined for the development of pathological changes in the lung, and whole blood was collected and analyzed using microarray analysis for global mRNA and miRNA expression. Numerous mRNAs and miRNAs in the blood were significantly up- or down-regulated in animals developing pathological changes in the lung after MCA/corn oil administration followed by MWCNT/air inhalation, including fcrl5 and miR-122-5p in the presence of hyperplasia, mthfd2 and miR-206-3p in the presence of fibrosis, fam178a and miR-130a-3p in the presence of bronchiolo-alveolar adenoma, and il7r and miR-210 3p in the presence of bronchiolo-alveolar adenocarcinoma, among others. The changes in miRNA and mRNA expression, and their respective regulatory networks, identified in this study may potentially serve as blood biomarkers for MWCNT induced lung pathological changes. PMID- 25926380 TI - A qualitative evaluation of capnography use in paediatric sedation: perceptions, practice and barriers. AB - AIMS AND OBJECTIVES: We explored perceptions about capnography for procedural sedation and barriers to use in a paediatric emergency department. BACKGROUND: Capnography is a sensitive monitor of ventilation and is increasingly being studied in procedural sedation. While benefits have been found, it has not gained wide acceptance for monitoring of children during sedation. DESIGN: A qualitative exploratory study was performed. METHODS: Using a grounded theory approach, physicians and nurses from the paediatric emergency department participated in one-on-one interviews about their experiences with and opinions of capnography. An iterative process of data collection and analysis was used to inductively generate theories and themes until theoretical saturation was achieved. RESULTS: Five physicians and 12 nurses were interviewed. Themes included: Experiences: Participants felt that procedural sedation is safe and adverse events are rare. Normal capnography readings reassured providers about the adequacy of ventilation. Knowledge: Despite experience with capnography, knowledge and comfort varied. Most participants requested additional education and training. Diffusion of Use: While participants expressed positive opinions about capnography, use for sedation was infrequent. Many participants felt that capnography use increased in other paediatric populations, such as patients with altered mental status, ingestions or head trauma. Barriers: Identified barriers to use included a lack of comfort with or knowledge about equipment, lack of availability of the monitor and cannulas, lack of inclusion of these supplies on a checklist for procedural sedation preparedness, and lack of a policy for use of capnography during sedation. CONCLUSION: Capnography use during sedation in the paediatric emergency department is limited despite positive experiences and opinions about this device. Addressing modifiable barriers such as instrument availability, continuing education, and inclusion on a checklist may increase use of capnography during sedation. RELEVANCE TO CLINICAL PRACTICE: Despite the perceived benefits, a broad implementation plan is required to introduce capnography successfully to the paediatric emergency department. PMID- 25926381 TI - Genetic and molecular analyses reveal G6PC as a key element connecting glucose metabolism and cell cycle control in ovarian cancer. AB - We aimed to evaluate the role of glucose-6-phosphatase, catalytic subunit (G6PC) in ovarian cancer and to exploit its therapeutic potential. With reproduction of The Cancer Genome Atlas (TCGA) database, we studied expressions of genes in the glucose metabolism pathways in silico. The cBioPortal For Cancer Genomics was used to study the clinical, pathological and molecular profiles of G6PC. In vitro studies were performed to validate the function of G6PC and the effect of genetic and pharmaceutical G6PC inhibition. In 158 ovarian cancer (OvCa) patients with complete RNA-seq data, G6PC expression was increased in 27 patients (17 %). Both overall survival (OS) and disease-free period were significantly shorter in cases with increased G6PC level. Significantly decreased total and phosphorylated CDKN1B level was noted in OvCa with increased G6PC expression. Silenced G6PC in OvCa cells induced decreased cell proliferation, viability, invasiveness and anchorage-independent cell growth. G6PC silencing also induced enhanced cell cycle control proteins and restoration of CDKN1B level. Pharmaceutical inhibition of G6PC with specific compound showed similar effects to genetic silencing. G6PC played dual roles both in glucose metabolism and cell cycle control in OvCa, which potentiated it a promising therapeutic target. PMID- 25926382 TI - Radioimmunotherapy--a potential novel tool for pancreatic cancer therapy? AB - Pancreatic cancer is one of the most severe cancers and is predicted to rise up to the number two cancer killer by 2030. The ineffective treatment options available and that the cancer is silent until very late in its course are the main reasons for the poor outcome of the disease. Surgery is the only curative option but only available for 10-15 % of the patients, but even then many relapse due to metastases. Many new treatments are under way, and one of the promising ones is radioimmunotherapy (RIT). This review includes clinical trials with RIT in pancreatic cancer as well as a review of adverse events observed during treatment of other solid tumors. Additionally, preclinical studies are reviewed with emphasis on effect, adverse events, the tumor targeting as well as isotope function. Four clinical trials with pancreatic cancer have been conducted with positive results, and one phase III trial is underway. The use of RIT in patients with solid tumors has proven to be well tolerated, and the adverse effects are almost exclusively hematological. Multiple targets and isotopes have been evaluated preclinically, alone, or in combination with existing drug options. Smaller tumors have in several studies completely regressed, while larger ones have stabilized or progressed more slowly. Pancreatic cancer is one of the solid tumors where RIT have reached the longest. The tumor heterogeneity will most likely leave room for more than one treatment option, and several aspiring therapies are under way. RIT may become part of multimodality tumor-directed therapy for pancreatic cancer. PMID- 25926384 TI - MiR-497 promotes metastasis of colorectal cancer cells through Nrdp1 inhibition. AB - We have recently shown that Nrdp1 inhibits phosphorylation of ErB3 in colorectal cancer (CRC) cells, to suppress epidermal growth factor receptor (EGFR) signaling stimulated MMP7 activation for CRC metastasis. In this study, we examined the control of Nrdp1 in CRC cells. We detected significant increases in miR-497 in CRC specimen, compared to paired normal colorectal tissue. Moreover, we detected a strong positive correlation between miR-497 levels and Nrdp1 levels, and a strong inverse correlation between miR-497 levels and MMP7 levels. In vitro, overexpression of miR-497 in human CRC cells significantly decreased Nrdp1 transcripts and protein, and vice versa. Moreover, overexpression of miR-497 in human CRC cells also significantly increased MMP7 transcripts, cellular protein, and secreted protein, resulting in increases in cell invasiveness in a transwell cell migration assay. Furthermore, we found that MiR-497 directly targeted 3'-UTR of Nrdp1 mRNA to inhibit its translation. Together, our data suggest that the regulation of MMP7 by Nrdp1 in CRC cells could be inhibited by miR-497 through suppressing Nrdp1 translation. Our work thus highlights a novel molecular regulatory machinery that regulates metastasis of CRC. PMID- 25926383 TI - Emerging role of silent information regulator 1 (SIRT1) in hepatocellular carcinoma: a potential therapeutic target. AB - Hepatocellular carcinoma (HCC) is one of the most prevalent neoplasms worldwide, ranking as the second leading cause of cancer-related death due to its high invasive and metastatic potential. SIRT1 (silent information regulator 1), a member of mammalian sirtuin family protein (SIRT1-SIRT7), functions as a conserved nicotinamide adenine dinucleotide (NAD)+-dependent deacetylase to implicate in the modulation of transcriptional silencing and cell survival. Recently, except for the regulatory role of SIRT1 in various biological processes, the carcinogenesis effect of SIRT1 was revealed in HCC. Importantly, SIRT1 was confirmed to be involved in tumorigenesis, metastasis, prognosis, and chemical resistant of HCC, as a result of its deacetylation of oncogenic or tumor suppressor factors. The focus of this review was to delineate the carcinogenesis effects of SIRT1 on HCC and present an overview of SIRT1 functions in normal liver followed by SIRT1 roles in HCC, with focus on the underlying molecular mechanism to promote SIRT1 as a new therapeutic target for HCC. PMID- 25926385 TI - Analysis of the downstream mediators of toll-like receptor 3-induced apoptosis in labial salivary glands in patients with Sjogren's syndrome. AB - OBJECTIVES: The aim of this study was to clarify the molecular mechanisms elicited by toll-like receptor (TLR)3 in salivary gland cell death in patients with SS. METHODS: Expression of TLR3 and its downstream molecules was examined by immunohistochemical analysis, immunofluorescence, Western blot (WB), and antibody dot-blot array in labial salivary glands (LSGs), and cultured primary salivary gland epithelial cells (SGECs) obtained from patients with SS. We also investigated the difference of expression between ducts/alveoli of LSGs and cultured SGECs. RESULTS: Phosphorylated Fas-associated protein with death domain (p-FADD) or caspase-8 was not found in ducts or alveoli of LSGs from SS patients and controls. Weak expression of receptor-interacting serine/threonine-protein kinase 3 (RIPK3) was found in SS patients, whereas no staining was observed in LSGs of controls. In contrast to LSGs, stimulation of SGECs with polyinosinic:cytidylic acid (poly I:C) significantly induced the expression of RIPK3, p-FADD, and cleaved caspase-8 by immunofluorescence and RIPK3, p-FADD, and cleaved caspase-3 by WB. However, it was counteracted by epidermal growth factor (EGF). Co-localization of anti-apoptotic molecules hemeoxygenase-2, heat shock protein 27, and p-protein kinase B or p-Akt was induced in EGF-stimulated SGECs. CONCLUSIONS: We observed that poly I:C induced apoptosis of SGECs in vitro compared with a relatively low prevalence of apoptosis found in the ducts and alveoli of LSGs in vivo. Thus, we speculate that other counter-regulatory mechanisms, including those induced by EGF, might exist to protect against TLR3 mediated apoptosis of ductal and acinar epithelial cells in vivo. PMID- 25926387 TI - Association between Serum Phospholipid Fatty Acids and Intraprostatic Inflammation in the Placebo Arm of the Prostate Cancer Prevention Trial. AB - Inflammation may play an etiologic role in prostate cancer. Several dietary factors influence inflammation; studies have shown that long-chain n-3 polyunsaturated fatty acids are anti-inflammatory, whereas n-6 and trans fatty acids are proinflammatory. We evaluated whether serum phospholipid n-3, n-6, and trans fatty acids were associated with intraprostatic inflammation, separately in 191 prostate cancer cases and 247 controls from the placebo arm of the Prostate Cancer Prevention Trial (PCPT). Men without a prostate cancer diagnosis underwent prostate biopsy at trial end, and benign prostate tissue inflammation was evaluated in approximately three biopsy cores per man; this was expressed as no, some, or all cores with inflammation. In controls, serum eicosapentaenoic acid [OR of all cores with inflammation versus none (95% CI), 0.35 (0.14-0.89)] and docosahexaenoic acid [OR (95% CI), 0.42 (0.17-1.02)] were inversely associated with, whereas linoleic acid [OR (95% CI), 3.85 (1.41-10.55)] was positively associated with intraprostatic inflammation. Serum trans fatty acids were not associated with intraprostatic inflammation. No significant associations were observed in cases; however, we could not rule out a positive association with linoleic acid and an inverse association with arachidonic acid. Thus, in the PCPT, we found that serum n-3 fatty acids were inversely, n-6 fatty acids were positively, and trans fatty acids were not associated with intraprostatic inflammation in controls. Although, in theory, inflammation could mediate associations of serum fatty acids with prostate cancer risk, our findings cannot explain the epidemiologic associations observed with n-3 and n-6 fatty acids. PMID- 25926389 TI - A direct access to heptasubstituted biguanides. AB - An efficient and experimentally simple copper-catalyzed carbon-nitrogen bond formation for the synthesis of [Formula: see text]-arylated biguanides starting from aryl halides, carbodiimides, and 1,1,3,3-tetramethylguanidine is reported. The potential diversity of this type of reaction, easily available starting materials, and commercially available low-cost catalysts are the incremental features of this methodology. PMID- 25926388 TI - Synthesis, reactivity, and biological activity of 5-aminouracil and its derivatives. AB - The synthesis and reactions of 5-aminouracil and its derivatives are comprehensively reviewed. A brief survey of biological activities, especially chemotherapeutic and pharmacological properties, is also reported. PMID- 25926390 TI - Somatostatin receptor 1-5; expression profiles during rat development. AB - BACKGROUND: Somatostatin acts through five receptor subtypes (SSTRs 1-5). We aimed to investigate SSTRs mRNA expression and protein distribution in whole rat embryos, with special emphasis on the pancreas. MATERIAL AND METHODS: Rat embryos were collected on embryonal days 10, 11, 12, 14, 15, 17, 19, 21, and at birth. Presence of SSTRs was investigated with RT-PCR techniques and immunohistochemistry. RESULTS: There was no SSTR5 mRNA expression in the whole rat embryos. All SSTR1-5 proteins were observed at embryonal day 10, but the localization varied between the different subtypes. From day 11 to birth SSTRs protein presence increased with time in major structures such as skin and cartilage. It remained similar over time in the heart and liver. In the fetal pancreas mRNA expression of SSTR2 and 4 was detected at day 14, and there was an increase up to birth. Only SSTR1 protein co-localized to a higher extent with the islet hormones studied. SSTR2 was present in all islet endocrine cells except for beta-cells. In contrast, the immunostaining for SSTR3-4 was co-localized with insulin and PP, and, finally, SSTR5 with glucagon and pancreatic polypeptide. In mRNA isolated from whole rat embryos SSTR1-2 and SSTR4 expression showed a peak at day 14, while SSTR3 mRNA was not present until day 15. CONCLUSION: The present data suggest a role for SSTRs during the development of the rat embryo. Subsequent functional studies may elucidate regulatory roles of specific SSTRs for the growth and differentiation of the pancreas as well as other organs. PMID- 25926391 TI - A root canal filling per se does not have a significant negative effect on the marginal periodontium. AB - AIM: To evaluate the periodontal status of single-rooted endodontically treated teeth (ET), correcting for patient- and tooth-related factors. METHODS: Clinical parameters (BoP,PD,CAL) of 240 ET and 240 contralateral vital teeth (VT), before and after non-surgical periodontal treatment, were extracted retrospectively from the journals of 175 patients. Possible patient-related (age, gender, smoking status) and tooth-related (interproximal restoration, root canal filling's extent, post, tooth type) confounders were tested. RESULTS: At baseline, frequency of BoP at an interproximal site at ET versus VT was 70.4% versus 65.0%, respectively. The frequency of teeth with interproximal PD >= 5 mm and CAL >= 5 mm was 47.9% versus 42.9% and 54.6% versus 49.6% at ET and VT, respectively. Interproximal PD and CAL at ET versus VT were 3.86 versus 3.61 mm and 4.11 versus 3.95 mm. After correcting for tooth-related factors, no significant differences were observed between ET and VT. An improper restoration had a significant (p < 0.001) negative effect on BoP [OR 3.49 (95%CI: 1.95-6.27)], PD [36.81% (95%CI: 18.52-57.92)] and CAL [27.01% (95%CI: 12.67-43.18)]. No significant differences between ET and VT were observed regarding clinical outcome of non-surgical periodontal therapy. CONCLUSIONS: Presence of a root canal filling per se does not have a significant negative influence on the marginal periodontium, when correcting for the quality of the interproximal restoration. PMID- 25926392 TI - Quantitation of biofilm and planktonic life forms of coexisting periodontal species. AB - BACKGROUND: Complexity of oral polymicrobial communities has prompted a need for developing in vitro models to study behavior of coexisting bacteria. Little knowledge is available of in vitro co-growth of several periodontitis-associated species without early colonizers of dental plaque. THE AIM: was to determine temporal changes in the quantities of six periodontal species in an in vitro biofilm model in comparison with parallel planktonic cultures. MATERIAL AND METHODS: Porphyromonas gingivalis, Aggregatibacter actinomycetemcomitans, Prevotella intermedia, Parvimonas micra, Campylobacter rectus and Fusobacterium nucleatum were anaerobically grown as multispecies and monospecies biofilms and parallel planktonic cultures using cell culture plates and microfuge tubes, respectively. After incubating 2, 4, 6, 8 days, biofilms and planktonic cultures were harvested, DNA extracted and the target species quantified using qPCR with species-specific 16S rDNA primers. Biofilm growth as monocultures was visualized at day 2 and 8 with confocal microscopy and crystal violet staining. RESULTS: The six species were found throughout the test period in all culture conditions, except that P. gingivalis and F. nucleatum were not detected in multispecies planktonic cultures at day 8. In multispecies biofilm, P. gingivalis qPCR counts (cells/ml) increased (P<0.05) from day 2-8 and were then higher (P<0.05) than those of A. actinomycetemcomitans and C. rectus, whereas in monospecies biofilm, P. gingivalis counts were lower (P<0.05) than those of the other species, except A. actinomycetemcomitans. When multi- and monospecies biofilm cultures were compared, P. gingivalis counts were higher (P<0.05) but those of the other species, except P. intermedia, lower (P<0.05) in multispecies biofilm. Comparison between planktonic and biofilm cultures showed that A. actinomycetemcomitans, P. micra and C. rectus had higher (P<0.05) counts in planktonic cultures no matter whether grown in mono- or multispecies environment. CONCLUSIONS: Six periodontal species were able to form multispecies biofilm up to 8 days in vitro without pioneer plaque bacteria. P. gingivalis seemed to prefer multispecies biofilm environment whereas P. micra and A. actinomycetemcomitans planktonic culture. PMID- 25926393 TI - Molecular analysis of residual ThinPrep material from thyroid FNAs increases diagnostic sensitivity. AB - BACKGROUND: Molecular testing for genetic alterations associated with malignancy is a potential triage approach for thyroid fine-needle aspiration (FNA) samples with indeterminate cytology. Because liquid-based FNA material allows for efficient RNA extraction, the authors analyzed residual material for common point mutations and rearrangements. METHODS: Thyroid FNAs were classified according to The Bethesda System for Reporting Thyroid Cytopathology after routine ThinPrep slide preparation. Residual samples from malignant and indeterminate cases were submitted for molecular analysis, along with a random cohort of nondiagnostic and benign aspirates. Blinded analysis of BRAF and RAS point mutations and RET/PTC and PAX8/PPARgamma rearrangements was correlated with subsequent follow-up. RESULTS: Adequate results were obtained in 402 of 597 cases (67%). Mutations or rearrangements were detected in 24 of 117 cytologically indeterminate specimens (21%) (17 RAS rearrangements, 6 BRAF rearrangements, and 1 PAX8/PPARgamma rearrangement). BRAF mutations were preferentially associated with malignant cytologic diagnoses (22 of 42 cases; 52%), with less frequent detection in the suspicious for malignancy category (4 of 27 cases; 15%) and very low detection in all other categories (1%-4%). Surgical follow-up confirmed malignancy in all 21 BRAF-mutated cases, 42% of RAS-mutated cases (10 of 24 cases), and 37% of cases with no detected mutation (39 of 105 cases). CONCLUSIONS: Molecular analysis is feasible on residual ThinPrep material with the advantage of not requiring additional FNA procedures. The majority of BRAF mutations are identified in cases classified cytologically as malignant, and, to a lesser extent, as suspicious for malignancy. The usefulness of BRAF testing is limited by the low rate of BRAF positive cases in other categories, thereby highlighting the need to identify other genetic drivers of clinically aggressive thyroid cancers. PMID- 25926394 TI - Fish Lice (Argulus japonicus) in Goldfish (Carassius auratus). AB - Fish lice (Argulus spp; family Argulidae) are branchiuran crustaceans that parasitize both marine and freshwater fishes. Argulus spp can be a major threat to fish health, because heavy infestations can cause significant morbidity and mortality. In addition, fish lice are known to be the vehicle for other fish diseases. During rounds at our facility, Argulus japonicus was collected from the caudal and anal fins of 3 goldfish (Carassius auratus). These goldfish were asymptomatic, and no additional cases were noted after manual removal of the lice. As soon as any Argulus organisms are identified, management and treatment are recommended because infections can escalate rapidly. Currently, there are no FDA-approved drugs for the control and treatment of this parasite, but several chemicals including organophosphates and diflubenzuron have been used with success. The screening and quarantine of incoming fish is the best way to avoid a facility-wide Argulus infestation. PMID- 25926397 TI - Abdominal Distension and Escherichia coli Peritonitis in Mice Lacking Myeloid Differentiation Factor 88. AB - Here we describe the gross and microscopic findings of naturally occurring, beta hemolytic Escherichia coli peritonitis in B6.129-Myd88(tm1Aki) male and female mice. Over approximately 5 mo, 10 homozygous mutant mice deficient in myeloid differentiation factor 88 (C57BL/6 strain; male and female) that had not been used in research protocols developed rapid-onset abdominal swelling associated with copious viscous ascites. Each mouse developed an anterior peritonitis, primarily involving the parietal peritoneum and the visceral surface of the spleen, liver, diaphragm, and stomach. Inflammation was confined to the organ surfaces, with no indication of septicemia or grossly apparent gastrointestinal perforation or other tissue compromise that would initiate peritonitis. Peritonitis was likely attributable to compromised antibacterial innate immunity; cohoused, similarly immunodeficient littermates did not develop similar clinical signs. An unusual finding in all cases was mesothelial cell hyperplasia and hypertrophy. Although the underlying innate immune deficiency accounts for much of the observed pathology, the remarkable mesothelial cell morphology and the episodic nature of the peritonitis in some littermates and not others remain unexplained. PMID- 25926396 TI - Effects of murine norovirus on atherosclerosis in ldlr(-/-) mice depends on the timing of infection. AB - We previously reported that murine norovirus (MNV), a virus prevalent in United States research institutions, increased atherosclerotic lesion size in Ldlr(-/-) mice when the mice were infected 8 wk after feeding an atherogenic diet. To determine whether the timing of MNV infection relative to atherosclerosis development altered the disease phenotype and to examine potential mechanisms by which MNV influences the disease process, we fed Ldlr(-/-) mice an atherogenic diet for 16 wk. Three days after initiating the atherogenic diet, half of the mice received MNV4 and the other half vehicle only (clarified cell-culture lysate; controls). Both groups of mice developed large aortic sinus lesions (control compared with MNV4: 133 +/- 8 * 103 MUm2 compared with 140 +/- 7 * 103 MUm2) that were not significantly different in size. Because the timing of MNV infection relative to atherosclerosis development and hypercholesterolemia differed between our previous and the current studies, we examined whether hypercholesterolemia altered MNV4-induced changes in bone-marrow-derived macrophages. MNV4 infection increased the potential of macrophages to take up and store cholesterol by increasing CD36 expression while suppressing the ABCA1 transporter. Thus, the effects of MNV4 infection on atherosclerotic lesion size appear to be dependent on the timing of the infection: MNV4 infection promotes only established lesions. This effect may be due to MNV4's ability to increase cholesterol uptake and decrease efflux by regulating CD36 and ABCA1 protein expression. PMID- 25926395 TI - Practical murine hematopathology: a comparative review and implications for research. AB - Hematologic parameters are important markers of disease in human and veterinary medicine. Biomedical research has benefited from mouse models that recapitulate such disease, thus expanding knowledge of pathogenetic mechanisms and investigative therapies that translate across species. Mice in health have many notable hematologic differences from humans and other veterinary species, including smaller erythrocytes, higher percentage of circulating reticulocytes or polychromasia, lower peripheral blood neutrophil and higher peripheral blood and bone marrow lymphocyte percentages, variable leukocyte morphologies, physiologic splenic hematopoiesis and iron storage, and more numerous and shorter-lived erythrocytes and platelets. For accurate and complete hematologic analyses of disease and response to investigative therapeutic interventions, these differences and the unique features of murine hematopathology must be understood. Here we review murine hematology and hematopathology for practical application to translational investigation. PMID- 25926398 TI - Histiocytic Sarcoma and Bilateral Facial Vein Thrombosis in a Siberian Hamster (Phodopus sungorus). AB - A 21-mo-old, male Siberian hamster (Phodopus sungorus) presented with left-sided facial swelling, proptosis of the left eye, and blepharospasm of the right eye. The hamster had been used only for breeding. Because of the poor prognosis, the hamster was euthanized without additional diagnostic assays or treatments. Routine gross pathologic evaluation demonstrated exophthalmos and presumptive hyphema of the left eye, bilateral facial edema, freely movable nodules within the mesentery, white foci within the liver, and a large mass effacing the cranial pole of the right kidney. On histologic evaluation, the mesenteric nodules and liver foci expressed histiocytic marker CD163 and thus were diagnosed as sites of histiocytic sarcoma, whereas the kidney mass was a well-differentiated renal cell carcinoma. The facial swelling resulted from bilateral, chronic, severe, branching thrombi in many facial veins. Additional age-related histopathologic findings were observed in other organs, including diffuse glomerulopathy, nesidioblastosis (pancreatic islet neoformation), and multiple foci of severe cartilage degeneration in the axial skeleton. To our knowledge, this report provides the first description of histiocytic sarcoma in a Siberian hamster. PMID- 25926399 TI - Hepatic Lipidosis in a Research Colony of Big Brown Bats (Eptesicus fuscus). AB - During a nearby construction project, a sudden decrease in food intake and guano production occurred in an outdoor colony of big brown bats (Eptesicus fuscus), and one animal was found dead. Investigation revealed that the project was generating a large amount of noise and vibration, which disturbed the bats' feeding. Consequently the bats were moved into an indoor enclosure away from the construction noises, and the colony resumed eating. Over the next 3 wk, additional animals presented with clinical signs of lethargy, weight loss, ecchymoses, and icterus and were necropsied. Gross necropsy of the affected bats revealed large, pale yellow to tan, friable livers with rounded edges that floated when placed in 10% neutral-buffered formalin. Some bats had ecchymoses on the webbing and skin and gross perirenal hemorrhage. Histologic examination showed hepatic and renal tubular lipidosis. The clinical and pathologic signs of hemorrhage and icterus were suggestive of hepatic failure. Hepatic lipidosis was attributed to stress and inappetence associated with environmental perturbations. Once the environmental stressor was removed, the colony morbidity and mortality decreased. However, 2 y later, a series of new environmental stressors triggered additional deaths associated with hepatic lipidosis. Over a 9-y period, 21 cases of hepatic lipidosis were diagnosed in this bat colony. PMID- 25926400 TI - Comparative Immunohistochemistry of Placental Corticotropin-Releasing Hormone and the Transcription Factor RelB-NFkappaB2 Between Humans and Nonhuman Primates. AB - The transcription factor RelB-NFkappaB2, activated by the noncanonical NFkappaB pathway, positively regulates corticotropin-releasing hormone (CRH) and prostaglandin production in the term human placenta and may play an important role in the timing of human parturition. Here we explored whether RelB-NFkappaB2 signaling plays a role in parturition in nonhuman anthropoid primates. We performed immunohistochemical staining to assess the correlation between CRH and nuclear activity of RelB-NFkappaB2 heterodimers in term placentas from humans, 3 catarrhine primate species, and a single platyrrhine primate species. Consistent with our previous studies, the human placenta showed cytoplasmic staining for CRH and nuclear staining for RelB-NFkappaB2. Similar staining patterns were noted in the 3 catarrhine primates (chimpanzee, baboon, and rhesus macaque). The platyrrhine (marmoset) placentas stained positively for CRH and RelB but not for NFkappaB2. Catarrhine (but not platyrrhine) nonhuman primate term placentas demonstrate the same CRH staining and nuclear localization patterns of RelB and NFkappaB2 as does human placenta. These results suggest that catarrhine primates, particularly rhesus macaques, may serve as useful animal models to study the biologic significance of the noncanonical NFkappaB pathway in human pregnancy. PMID- 25926401 TI - Osteosarcoma in Baboons (Papio spp). AB - Bone neoplasms in baboons (Papio spp) are rare, with only one confirmed case of osteosarcoma previously described in the literature. Over a 12-y period, 6 baboons at a national primate research center presented with naturally occurring osteosarcoma; 3 lesions affected the appendicular skeleton, and the remaining 3 were in the head (skull and mandible). The 6 cases presented were identified in members of a large outdoor-housed breeding colony. The subjects were not genetically related or exposed to the same research conditions. Diagnoses were made based on the presentation and radiographic findings, with histologic confirmation. PMID- 25926402 TI - Clinical and histological features of idiosyncratic liver injury: Dilemma in diagnosis of autoimmune hepatitis. AB - AIM: Drug-induced liver injury (DILI) is becoming a worldwide problem with its still unexplained properties. METHODS: The data of patients who were diagnosed with DILI between January 2008 and December 2013 were assessed. RESULTS: Five patients had been diagnosed with intrinsic and 82 patients with idiosyncratic DILI. The most common causative agents were antimicrobial drugs. The most common injury pattern was hepatocellular. When patients with bilirubin levels of more than 5 mg/dL were divided into two groups according to receiving steroid therapy (n = 11) or not (n = 40), there was not any significant difference according to their clinical results (P > 0.05). Five of the idiosyncratic DILI patients were diagnosed with drug-induced autoimmune hepatitis (DI-AIH). In histopathological examination, hepatic rosette formation and emperipolesis were observed to be more common among patients with DI-AIH when compared with ones without (P < 0.05). Interestingly, in the remaining patients with DILI (n = 77), three of them were diagnosed with classic autoimmune hepatitis during long-term follow up (range, 11 51 months). CONCLUSION: The most common causes were antimicrobials, but any agents that have not been defined to cause DILI can induce DILI. The efficacy of steroids in DILI has not been observed but all deaths were observed in the steroid-free group. The association of DILI and AIH was observed in two different types in terms of diagnosis in our study. The first association was DI-AIH. The second one is the classical AIH which developed in three patients after a few months following spontaneous recovery of DILI. PMID- 25926403 TI - Chronic toxicity of commercial chlorpyrifos to earthworm Pheretima peguana. AB - A chronic toxicity study was conducted in earthworms (Pheretima peguana) exposed to soil spiked with chlorpyrifos at concentrations of 0, 0.1, 1, 10, and 100 mg/kg soil dry matter for 7, 14, and 28 days. The integrity of the coelomocyte lysosomal membrane, nervous system, and male reproductive tissue was monitored using, respectively, the neutral-red retention assay, acetylcholinesterase (AChE) enzyme assay, and histomorphology of spermatogenic cells in the seminal vesicles and cocoon production (at 28 days after 28 days' exposure). Chlorpyrifos decreased the coelomocyte neutral-red retention time (NRRT) significantly (p < 0.05) at concentrations > 0.1 mg/kg soil as early as day 7 of exposure and was dose- and time-dependent. Chlorpyrifos inhibition of AChE activity was greater at day 7 than at day14 (p < 0.05) indicating possibly nerve recovery. Chlorpyrifos induced concentration-dependent damage to spermatogenic cells and cytophores in premature stages. The number and size of premature, maturing, and fully mature spermatogenic stages were increased at low concentrations (<1 mg/kg) but a number of these maturation stages declined at higher concentrations (10 and100 mg/kg) on day 28. The most severe effects were observed in the maturing and fully mature stages at the highest chlorpyrifos concentration, and this had an adverse impact on cocoon production and cocoon viability. Collectively, the results suggest induction of widespread effects on multiple organ systems in P. peguana exposed to chlorpyrifos. Although NRRT and AChE activity were the most sensitive of the biomarkers, cocoon production and cocoon viability could still be considered as diagnostic tools for monitoring effects from low-dose long-term chlorpyrifos toxicity and for evaluating population effects. (c) 2015 Wiley Periodicals, Inc. Environ Toxicol 31: 1450-1459, 2016. PMID- 25926404 TI - Targeting core groups for gonorrhoea control: feasibility and impact. AB - OBJECTIVE: We aimed to outline why core groups should be targeted in Neisseria gonorrhoeae control and suggest several important and timely interventions to target core groups while highly resistant strains are spreading. METHODS: Core group definition, feasibility and impact of gonorrhoea core group interventions as well as gonorrhoea resistance development have been reviewed in the paper. RESULTS: Core group interventions have proven effective in gonorrhoea control in the past but are compromised by the spread of highly resistant strains. CONCLUSIONS: Worldwide functional Gonorrhoea Antimicrobial Surveillance Program, better screening and better treatment programmes are needed. Prevention through condom promotion aimed at core groups remains essential. More specific treatment guidance for low-income and middle-income countries without resistance data is required in the meantime to achieve a better use of antibiotics. PMID- 25926405 TI - Will use of combination cephalosporin/azithromycin therapy forestall resistance to cephalosporins in Neisseria gonorrhoeae? PMID- 25926406 TI - Adiabatic burst evaporation from bicontinuous nanoporous membranes. AB - Evaporation of volatile liquids from nanoporous media with bicontinuous morphology and pore diameters of a few 10 nm is an ubiquitous process. For example, such drying processes occur during syntheses of nanoporous materials by sol-gel chemistry or by spinodal decomposition in the presence of solvents as well as during solution impregnation of nanoporous hosts with functional guests. It is commonly assumed that drying is endothermic and driven by non-equilibrium partial pressures of the evaporating species in the gas phase. We show that nearly half of the liquid evaporates in an adiabatic mode involving burst-like liquid-to-gas conversions. During single adiabatic burst evaporation events liquid volumes of up to 10(7) MUm(3) are converted to gas. The adiabatic liquid to-gas conversions occur if air invasion fronts get unstable because of the built up of high capillary pressures. Adiabatic evaporation bursts propagate avalanche like through the nanopore systems until the air invasion fronts have reached new stable configurations. Adiabatic cavitation bursts thus compete with Haines jumps involving air invasion front relaxation by local liquid flow without enhanced mass transport out of the nanoporous medium and prevail if the mean pore diameter is in the range of a few 10 nm. The results reported here may help optimize membrane preparation via solvent-based approaches, solution-loading of nanopore systems with guest materials as well as routine use of nanoporous membranes with bicontinuous morphology and may contribute to better understanding of adsorption/desorption processes in nanoporous media. PMID- 25926407 TI - Nitrogen absorbed from the large intestine increases whole-body nitrogen retention in pigs fed a diet deficient in dispensable amino acid nitrogen. AB - BACKGROUND: Nitrogen absorption from the large intestine is considered of limited value for supporting body protein synthesis in animals and humans, but it may be of benefit when the dietary supply of nitrogen for synthesis of dispensable amino acids (DAAs) is deficient. OBJECTIVE: A whole-body nitrogen balance study was conducted to evaluate the impact of nitrogen absorption from the large intestine of pigs fed a diet deficient in DAA nitrogen. METHODS: Nine cecally cannulated barrows were fed a cornstarch and casein-based diet with a high indispensable amino acid (IAA) nitrogen to total nitrogen ratio (IAA:TN; 0.75). Pigs were randomly assigned to saline or 1 of 2 urea nitrogen infusion rates into the cecum (low and high, 1.5 and 3.0 g/d, respectively) following a 3 * 3 Latin square design. At the high urea nitrogen infusion rate, IAA:TN was 0.55. At slaughter, liver samples were taken to measure activity of carbamoyl phosphate synthetase I (CPS-I), glutamate dehydrogenase (GDH), and Gln synthetase (Gln-S). RESULTS: Whole-body nitrogen retention improved with urea infusion (4.86 +/- 0.20 g/d, 6.40 +/- 0.21 g/d, and 7.75 +/- 0.19 g/d for saline and low and high infusion rates, respectively; P < 0.05), as well as body weight gain. The marginal efficiency of using nitrogen absorbed from the large intestine for improving nitrogen retention was not affected by urea nitrogen infusion rate (P > 0.10). Enzyme activity of CPS-I or Gln-S was not different between treatments (P > 0.10), but GDH showed a trend for a positive linear response with increasing urea nitrogen infusion rate (P = 0.06). CONCLUSION: These results indicate that urea nitrogen absorbed from the large intestine is efficiently used for increasing body protein deposition when feeding pigs a diet deficient in DAA nitrogen. PMID- 25926409 TI - Usual Dietary Energy Density Distribution Is Positively Associated with Excess Body Weight in Mexican Children. AB - BACKGROUND: Studies suggest a positive association between dietary energy density (DED) and body weight in adults, but evidence in children is inconclusive. OBJECTIVE: The objective of this study was to compare usual DED distributions of nonoverweight vs. overweight or obese (OW/O) Mexican children. METHODS: The study used 24-h recall (24HR) data from 2367 children aged 5-11 y from the 2012 Mexican National Health and Nutrition Survey (ENSANUT 2012). Repeated 24HR measures were obtained in a random sample (~10%) to estimate usual intake distributions by using the Iowa State University (PC-Side) method. Implausible dietary reports were identified. Multivariate linear regression models were used to evaluate the relation between DED and body mass index status and to compare results with and without PC-Side adjustment and restriction to plausible reporters. RESULTS: A total of 35.1% of the children in the sample were OW/O. The usual DED mean was ~175 kcal/100 g in both the complete sample and the plausible reporters subsample. Regression models adjusted by PC-Side and for potential confounders showed higher DED in OW/O relative to nonoverweight children for both plausible reporters (9.7 kcal/100 g; n = 1452, P < 0.0001) and the complete sample (7.9 kcal/100 g; n = 2367, P < 0.0001). The DED difference in plausible reporters translates into 88 additional kilocalories in daily energy intake of OW/O children. In the absence of PC-side adjustment, the difference was significant for plausible reporters (P < 0.05) but not for the complete sample (P > 0.10). CONCLUSIONS: A positive association between usual DED and OW/O was found in Mexican children. The association was stronger when only plausible reporters were considered. This suggests that there is a need for strategies to reduce energy density in the diet of Mexican children. PMID- 25926408 TI - Fat emulsion intragastric stability and droplet size modulate gastrointestinal responses and subsequent food intake in young adults. AB - BACKGROUND: Intragastric creaming and droplet size of fat emulsions may affect intragastric behavior and gastrointestinal and satiety responses. OBJECTIVES: We tested the hypotheses that gastrointestinal physiologic responses and satiety will be increased by an increase in intragastric stability and by a decrease in fat droplet size of a fat emulsion. METHODS: This was a double-blind, randomized crossover study in 11 healthy persons [8 men and 3 women, aged 24 +/- 1 y; body mass index (in kg/m(2)): 24.4 +/- 0.9] who consumed meals containing 300-g 20% oil and water emulsion (2220 kJ) with 1) larger, 6-MUm mean droplet size (Coarse treatment) expected to cream in the stomach; 2) larger, 6-MUm mean droplet size with 0.5% locust bean gum (LBG; Coarse+LBG treatment) to prevent creaming; or 3) smaller, 0.4-MUm mean droplet size with LBG (Fine+LBG treatment). The participants were imaged hourly by using MRI and food intake was assessed by using a meal that participants consumed ad libitum. RESULTS: The Coarse+LBG treatment (preventing creaming in the stomach) slowed gastric emptying, resulting in 12% higher gastric volume over time (P < 0.001), increased small bowel water content (SBWC) by 11% (P < 0.01), slowed appearance of the (13)C label in the breath by 17% (P < 0.01), and reduced food intake by 9% (P < 0.05) compared with the Coarse treatment. The Fine+LBG treatment (smaller droplet size) slowed gastric emptying, resulting in 18% higher gastric volume (P < 0.001), increased SBWC content by 15% (P < 0.01), and significantly reduced food intake by 11% (P < 0.05, equivalent to an average of 411 kJ less energy consumed) compared with the Coarse+LBG treatment. These high-fat meals stimulated substantial increases in SBWC, which increased to a peak at 4 h at 568 mL (range: 150-854 mL; P < 0.01) for the Fine+LBG treatment. CONCLUSION: Manipulating intragastric stability and fat emulsion droplet size can influence human gastrointestinal physiology and food intake. PMID- 25926410 TI - Dietary Fat Intake Modifies the Effect of a Common Variant in the LIPC Gene on Changes in Serum Lipid Concentrations during a Long-Term Weight-Loss Intervention Trial. AB - BACKGROUND: Hepatic lipase (HL) plays a pivotal role in the metabolism of HDL and LDL. Recent genome-wide association studies have identified common variants in the HL gene (LIPC) associated with HDL cholesterol. OBJECTIVE: We tested the effect of a common variant in LIPC on changes in blood lipids in response to weight-loss diets in the Preventing Overweight Using Novel Dietary Strategies Trial. METHODS: We genotyped LIPC rs2070895 in 743 overweight or obese adults aged 30-70 y (61% women) who were assigned to high-fat (40% energy) or low-fat (20% energy) diets for 2 y. We measured serum concentrations of total cholesterol (TC), triglycerides, LDL cholesterol, and HDL cholesterol at baseline and 2 y of intervention. RESULTS: At 2 y of intervention, dietary fat modified effects of the variant on changes in serum TC, LDL cholesterol, and HDL cholesterol (P interaction: 0.0008, 0.004, and 0.03, respectively). In the low-fat group, as compared to the G allele, the A allele tended to be related to the decrease in TC and LDL cholesterol concentrations [TC (beta +/- SE): -5.5 +/- 3.0, P = 0.07; LDL cholesterol: -4.8 +/- 2.5, P = 0.06] and a lower increase in HDL cholesterol concentrations (beta +/- SE: -1.37 +/- 0.69, P = 0.048), whereas an opposite effect in the high-fat diet group was evident [TC (beta +/- SE): 7.3 +/- 2.7, P = 0.008; LDL cholesterol: 4.1 +/- 2.3, P = 0.07], and there was no genetic effect on changes in HDL cholesterol concentrations (P = 0.54). CONCLUSION: Dietary fat intake modifies the effect of a common variant in LIPC on changes in serum lipids during a long-term weight-loss intervention in overweight or obese adults. This trial was registered at clinicaltrials.gov as NCT00072995. PMID- 25926411 TI - Preventive and therapeutic effects of Lactobacillus paracasei B21060-based synbiotic treatment on gut inflammation and barrier integrity in colitic mice. AB - BACKGROUND: Although gut microbiota perturbation is recognized as a main contributing factor to the pathogenesis of inflammatory bowel disease, synbiotic therapies, as prevention or treatment, have remained overlooked. OBJECTIVE: To verify whether Lactobacillus paracasei B21060-based synbiotic therapy could prevent or repair colon damage in a mouse model of colitis, we performed treatments before and after colitis induction. METHODS: The experimental study lasted 19 d. Experimental colitis was induced in BALB/c mice by giving them dextran sodium sulfate (DSS, 2.5%) in drinking water (days 7-12) followed by DSS free water (days 13-19) (DSS group). L. paracasei B21060 (2.5 * 10(7) bacteria/10 g body weight) was orally administered 7 d before DSS [synbiotic as preventive treatment (P-SYN) group] or 2 d after DSS [synbiotic as therapeutic treatment (T SYN) group] until day 19. Another group was not treated with DSS or synbiotic and was given tap water (control group), for a total of 4 groups. RESULTS: Compared with the DSS group, both synbiotic-treated groups had significantly less pronounced weight loss and colon damage. Consistently, mRNA levels of chemokine (C-C motif) ligand 5 in the colon were reduced in both P-SYN and T-SYN mice compared with the DSS group (51%, P < 0.05 and 72%, P < 0.001, respectively). In the P-SYN and T-SYN groups, neutrophil elastase transcription was also reduced (51%, P < 0.01 and 59%, P < 0.001, respectively). Accordingly, oxidative/nitrosative stress was lower in P-SYN and T-SYN mice than in the DSS group. In P-SYN and T-SYN mice, colonic gene expression of tumor necrosis factor (47%, P < 0.01 and 61%, P < 0.001, respectively) and prostaglandin-endoperoxide synthase 2 (45%, P < 0.01 and 35%, P < 0.05, respectively) was lower, whereas interleukin 10 mRNA was doubled compared with the DSS group (both P < 0.5). Remarkably, epithelial barrier integrity (zonulin and occludin) and gut protection (beta-defensin and mucin expression) were completely restored in P-SYN and T-SYN mice. CONCLUSIONS: Our data highlight the beneficial effects of this synbiotic formulation in acutely colitic mice, suggesting that it may have therapeutic and possibly preventive efficacy in human colitis. PMID- 25926412 TI - The Antiatherogenic Effect of Fish Oil in Male Mice Is Associated with a Diminished Release of Endothelial ADAM17 and ADAM10 Substrates. AB - BACKGROUND: Growing evidence suggests that disintegrin and metalloprotease (ADAM) 17 (ADAM17) and ADAM10 contribute to the pathogenesis of vascular diseases. ADAM17 promotes inflammatory processes by liberating tumor necrosis factor alpha, interleukin 6 receptor (IL-6R), and tumor necrosis factor receptor 1 (TNFR1). ADAM17 and ADAM10 modulate vascular permeability by cleaving endothelial adhesion molecules such as junctional adhesion molecule A (JAM-A) and vascular endothelial cadherin (VE-cadherin), respectively. OBJECTIVE: This study was designed to investigate whether a link might exist between the protective effects of fish oil (FO) supplementation against atherosclerosis and ADAM function. METHODS: Male LDL receptor knockout (LDLR(-/-)) mice and male wild-type (WT) mice were fed a Western diet (200 g/kg fat, 1.5 g/kg cholesterol) containing either 20% lard (LDLR(-/-)-lard and WT-lard groups) or 10% lard combined with 10% FO (LDLR(-/-) FO and WT-FO groups) for 12 wk. Atherosclerotic lesion development and fatty acid composition of liver microsomes were evaluated. ADAM10 and ADAM17 expression was determined by quantitative real-time polymerase chain reaction and immunoblot analyses. Concentrations of soluble ADAM substrates in plasma and liver extracts were measured by ELISA. RESULTS: Diets supplemented with FO markedly reduced development of early atherosclerotic lesions in LDLR(-/-) mice (LDLR(-/-)-lard group vs. LDLR(-/-)-FO group mean +/- SD: 29.6 +/- 6.1% vs. 22.5 +/- 4.2%, P < 0.05). This was not accompanied by changes in expression of ADAM17 or ADAM10 in the aorta or liver. No dietary effects on circulating TNFR1 (LDLR(-/-)-lard group vs. LDLR(-/-)-FO group mean +/- SD: 1.22 +/- 0.23 vs. 1.39 +/- 0.28, P > 0.2) or IL-6R (1.06 +/- 0.12 vs. 0.98 +/- 0.09 fold of WT-lard group, P > 0.1), classical substrates of ADAM17 on macrophages, and neutrophil granulocytes were observed. However, a reduction in atherosclerotic lesions in the LDLR(-/-)-FO group was accompanied by a significant reduction in the circulating endothelial cell adhesion molecules JAM-A (LDLR(-/-)-lard group vs. LDLR(-/-)-FO group mean +/- SD: 1.42 +/- 0.20 vs. 0.95 +/- 0.56 fold of WT-lard group, P < 0.05), intercellular adhesion molecule 1 (1.15 +/- 0.14 vs. 0.88 +/- 0.17 fold of WT lard group, P < 0.05), and VE-cadherin (0.88 +/- 0.12 vs. 0.72 +/- 0.15 fold of WT-lard group, P < 0.05), reflecting reduced ADAM activity in endothelial cells. CONCLUSION: FO exerted an antiatherogenic effect on male LDLR(-/-) mice that was accompanied by a reduced release of ADAM17 and ADAM10 substrates from endothelial cells. It is suggested that FO-decreased ADAM activity contributes to improved endothelial barrier function and thus counteracts intimal lipoprotein insudation and macrophage accumulation. PMID- 25926413 TI - Supplementation of Maternal Diets during Pregnancy and for 6 Months Postpartum and Infant Diets Thereafter with Small-Quantity Lipid-Based Nutrient Supplements Does Not Promote Child Growth by 18 Months of Age in Rural Malawi: A Randomized Controlled Trial. AB - BACKGROUND: Intrauterine growth restriction may be reduced by supplementing maternal diets during pregnancy, but few studies have assessed the impact of combined prenatal and postnatal interventions on child growth. OBJECTIVE: We tested a hypothesis that provision of small-quantity lipid-based nutrient supplements (SQ-LNSs) to mothers in pregnancy and 6 mo postpartum and to their infants from 6 to 18 mo of age would promote infant and child growth in the study area in rural Malawi. METHODS: We enrolled 869 pregnant women in a randomized trial in Malawi. During pregnancy and 6 mo thereafter, the women received daily 1 capsule of iron-folic acid (IFA), 1 capsule containing 18 micronutrients (MMN), or one 20-g sachet of SQ-LNS [lipid-based nutrient supplements (LNS), containing 21 MMN, protein, carbohydrates, essential fatty acids, and 118 kcal]. Children in the IFA and MMN groups received no supplementation; children in the LNS group received SQ-LNSs from 6 to 18 mo. Primary outcome was child length at 18 mo. RESULTS: At 18 mo, the mean length in the IFA, MMN, and LNS groups was 77.0, 76.9, and 76.8 cm (P = 0.90), respectively, and the prevalence of stunting was 32.7%, 35.6%, and 37.9% (P = 0.54), respectively. No intergroup differences were found in the mean weight, head circumference, or midupper arm circumference or the proportions with low z scores for these variables (P > 0.05). Covariate adjustment did not change the analysis results, and the associations between the intervention and child length were not modified by maternal parity, age, or nutritional status (P > 0.10). CONCLUSIONS: The findings do not support a hypothesis that provision of SQ-LNSs to women in pregnancy and postpartum and to children from 6 to 18 mo of age would promote child growth in this Malawian study area. This trial was registered at clinicaltrials.gov as NCT01239693. PMID- 25926415 TI - Protein Ingestion before Sleep Increases Muscle Mass and Strength Gains during Prolonged Resistance-Type Exercise Training in Healthy Young Men. AB - BACKGROUND: It has been demonstrated that protein ingestion before sleep increases muscle protein synthesis rates during overnight recovery from an exercise bout. However, it remains to be established whether dietary protein ingestion before sleep can effectively augment the muscle adaptive response to resistance-type exercise training. OBJECTIVE: Here we assessed the impact of dietary protein supplementation before sleep on muscle mass and strength gains during resistance-type exercise training. METHODS: Forty-four young men (22 +/- 1 y) were randomly assigned to a progressive, 12-wk resistance exercise training program. One group consumed a protein supplement containing 27.5 g of protein, 15 g of carbohydrate, and 0.1 g of fat every night before sleep. The other group received a noncaloric placebo. Muscle hypertrophy was assessed on a whole-body (dual-energy X-ray absorptiometry), limb (computed tomography scan), and muscle fiber (muscle biopsy specimen) level before and after exercise training. Strength was assessed regularly by 1-repetition maximum strength testing. RESULTS: Muscle strength increased after resistance exercise training to a significantly greater extent in the protein-supplemented (PRO) group than in the placebo-supplemented (PLA) group (+164 +/- 11 kg and +130 +/- 9 kg, respectively; P < 0.001). In addition, quadriceps muscle cross-sectional area increased in both groups over time (P < 0.001), with a greater increase in the PRO group than in the PLA group (+8.4 +/- 1.1 cm(2) vs. +4.8 +/- 0.8 cm(2), respectively; P < 0.05). Both type I and type II muscle fiber size increased after exercise training (P < 0.001), with a greater increase in type II muscle fiber size in the PRO group (+2319 +/- 368 MUm(2)) than in the PLA group (+1017 +/- 353 MUm(2); P < 0.05). CONCLUSION: Protein ingestion before sleep represents an effective dietary strategy to augment muscle mass and strength gains during resistance exercise training in young men. This trial was registered at clinicaltrials.gov as NCT02222415. PMID- 25926414 TI - Breastfeeding status at age 3 months is associated with adiposity and cardiometabolic markers at age 4 years in Mexican children. AB - BACKGROUND: The effect of breastfeeding (BF) on cardiometabolic risk factors is not well characterized. OBJECTIVE: The objective was to assess the association of BF status at 3 mo and duration with adiposity and cardiometabolic markers at 4 y. METHODS: We studied 727 children with prospectively collected BF information and anthropometric measurements at 4 y, of whom 524 provided a nonfasting blood sample. BF status at 3 mo was classified as exclusive or predominant (EBF-PreBF), partial (PaBF), or nonbreastfeeding (NBF). Total duration of any BF was classified as <3 mo, 3- 6 mo, >6 to 12 mo, and >12 mo. We modeled associations of BF with body mass index (BMI; in kg/m(2)), serum total cholesterol and low density lipoprotein (LDL) cholesterol, triglycerides (TGs), and insulin at 4 y. RESULTS: Children who were NBF or PaBF at 3 mo had higher BMI [0.46 (95% CI: 0.16, 0.76) and 0.31 (95% CI: 0.07, 0.54), respectively] than the EBF-PreBF group (P < 0.01). NBF children had higher total cholesterol (8.02 mg/dL; 95% CI: 1.39, 14.64; P = 0.02) than children who were EBF-PreBF. LDL cholesterol (5.04 mg/dL; 95% CI: -0.72, 10.81) and TGs (12% change; 95% CI: -0.01, 0.24) showed similar patterns. An inverse association between EBF-PreBF and insulin, mediated through abdominal circumference, was documented (P < 0.05). Children breastfed <3 mo had higher BMI (0.44; 95% CI: 0.11, 0.77) at 4 y than children breastfed for >12 mo. CONCLUSION: EBF and PreBF at 3 mo were associated with lower adiposity and serum total cholesterol in children at 4 y. In addition, BF >12 mo was associated with lower adiposity. These data confirm the importance of exclusive BF and prolonged BF for later cardiometabolic health. PMID- 25926416 TI - Prenatal Supplementation with Docosahexaenoic Acid Has No Effect on Growth through 60 Months of Age. AB - BACKGROUND: Prenatal supplementation with docosahexaenoic acid (DHA) has been shown to increase birth size, but it is unclear whether these differences translate into improved postnatal growth. OBJECTIVE: We assessed the effect of prenatal supplementation with DHA on offspring weight, length, and body mass index (BMI) through 60 mo of age. METHODS: We examined growth patterns (height, weight, and BMI) in a cohort of 802 Mexican children whose mothers participated in a randomized, controlled trial of daily supplementation with 400 mg/d of DHA or a placebo from week 18-22 of gestation through delivery, with the use of a longitudinal multilevel model of growth. RESULTS: Overall, means +/- SDs of height-, weight-, and BMI-for-age z scores relative to WHO growth standards at 60 mo were -0.49 +/- 0.91, -1.15 +/- 1.07 and 0.13 +/- 1.11, respectively. There were no significant differences by treatment group (all P > 0.05) for height, weight, or BMI at any age through 60 mo. Similarly, DHA did not affect the average growth or the trajectories for these measures through 60 mo. CONCLUSION: Prenatal DHA supplementation did not affect height, weight, or BMI through 60 mo of age. This trial was registered at clinicaltrials.gov as NCT00646360. PMID- 25926418 TI - The Patient Protection and Affordable Care Act - The Role of the School Nurse: Position Statement. AB - It is the position of the National Association of School Nurses that the registered professional school nurse (hereinafter referred to as the school nurse) serves a vital role in the delivery of health care to our nation's students within the health care system reshaped by the Patient Protection and Affordable Care Act of 2010, commonly known as the Affordable Care Act (ACA). This law presents an opportunity to transform the health care system through three primary goals: expanding access, improving quality, and reducing cost (U.S. Government Printing Office, 2010). School nurses stand at the forefront of this system change and continue to provide evidence-based, quality interventions and preventive care that, according to recent studies, actually save health care dollars (Wang et al., 2014). NASN supports the concept that school nursing services receive the same financial parity as other health care providers to improve overall health outcomes, including insurance reimbursement for services provided to students. PMID- 25926417 TI - Assessment of ToxCast Phase II for Mitochondrial Liabilities Using a High Throughput Respirometric Assay. AB - Previous high-throughput screens to identify mitochondrial toxicants used immortalized cell lines and focused on changes in mitochondrial membrane potential, which may not be sufficient and do not identify different types of mitochondrial dysfunction. Primary cultures of renal proximal tubule cells (RPTC) were examined with the Seahorse Extracellular Flux Analyzer to screen 676 compounds (5 MUM; 1 h) from the ToxCast Phase II library for mitochondrial toxicants. Of the 676 compounds, 19 were classified as cytotoxicants, 376 were electron transport chain (ETC) inhibitors, and 5 were uncouplers. The remaining 276 compounds were examined after a 5-h exposure to identify slower acting mitochondrial toxicants. This experiment identified 3 cytotoxicants, 110 ETC inhibitors, and 163 compounds with no effect. A subset of the ToxCast Phase II library was also examined in immortalized human renal cells (HK2) to determine differences in susceptibility to mitochondrial toxicity. Of the 131 RPTC ETC inhibitors tested, only 14 were ETC inhibitors in HK2 cells. Of the 5 RPTC uncouplers, 1 compound was an uncoupler in HK2 cells. These results demonstrate that 73% (491/676) of the compounds in the ToxCast Phase II library compounds exhibit RPTC mitochondrial toxicity, overwhelmingly ETC inhibition. In contrast, renal HK2 cells are markedly less sensitive and only identified 6% of the compounds as mitochondrial toxicants. We suggest caution is needed when studying mitochondrial toxicity in immortalized cell lines. This information will provide mechanisms and chemical-based criteria for assessing and predicting mitochondrial liabilities of new drugs, consumer products, and environmental agents. PMID- 25926419 TI - Evaluation of a workplace engagement project for people with younger onset dementia. AB - AIMS AND OBJECTIVES: In 2011, a workplace project was established to provide a small group of people who had younger onset dementia with the opportunity to return to the workplace. The project sought to explore the feasibility and safety of engaging these younger people in workplace activities if an appropriate framework of support was provided. BACKGROUND: Opportunities to engage in meaningful activities are quite limited for younger people with dementia because services are targeted at an older client population. DESIGN: A qualitative exploratory approach was used for the project evaluation. METHOD: Participants were people who were 65 years or younger and had a diagnosis of dementia. They attended a large metropolitan hardware store one day per week and worked beside a store employee for a four hour work shift. Evaluation of the project included observation of participant's engagement in the workplace, adverse events and a qualitative analysis that used participant-nominated good project outcomes. RESULTS: Nine people with a mean age of 58.8 years participated in the project. Six of these participants have been engaged at the workplace for more than two years. All participants were able to gain the skills needed to complete their respective work duties. Participants initially assisted with simple work tasks, but over time, they were able to expand their range of duties to include more complex activities such as customer sales. Participants achieved their nominated good outcomes of improved well-being, engaging in worthwhile activities, contributing to society and socialisation. CONCLUSION: The evaluation has shown that this workplace programme is a viable model of engagement for younger people with dementia. RELEVANCE TO CLINICAL PRACTICE: This evaluation offers a practical demonstration that it is feasible and safe to provide opportunities for younger people with dementia to engage in meaningful activities in the community if appropriate support is provided. PMID- 25926421 TI - Global transcriptional regulation in the immune system. Editorial. PMID- 25926422 TI - ADAM12 is a prognostic factor associated with an aggressive molecular subtype of high-grade serous ovarian carcinoma. AB - ADAM metallopeptidase domain 12 (ADAM12) is a promising biomarker because of its low expression in normal tissues and high expression in a variety of human cancers. However, ADAM12 levels in ovarian cancer have not been well characterized. We previously identified ADAM12 as one of the signature genes associated with poor survival in high-grade serous ovarian carcinoma (HGSOC). Here, we sought to determine if high levels of the ADAM12 protein and/or messenger RNA (mRNA) are associated with clinical variables in HGSOC. We show that high protein levels of ADAM12 in banked preoperative sera are associated with shorter progression-free and overall survival. Tumor levels of ADAM12 mRNA were also associated with shorter progression-free and overall survival as well as with lymphatic and vascular invasion, and residual tumor volume following cytoreductive surgery. The majority of genes co-expressed with ADAM12 in HGSOC were transforming growth factor (TGF)beta signaling targets that function in collagen remodeling and cell-matrix adhesion. In tumor sections, the ADAM12 protein and mRNA were expressed in epithelial cancer cells and surrounding stromal cells. In vitro data showed that ADAM12 mRNA levels can be increased by TGFbeta signaling and direct contact between epithelial and stromal cells. High tumor levels of ADAM12 mRNA were characteristic of the mesenchymal/desmoplastic molecular subtype of HGSOC, which is known to have the poorest prognosis. Thus, ADAM12 may be a useful biomarker of aggressive ovarian cancer for which standard treatment is not effective. PMID- 25926423 TI - The prevalence of noise-induced hearing loss among Tanzanian miners. AB - BACKGROUND: Tanzania has a young mining history with several operating open pit and underground mines. No prevalence studies of noise-induced hearing loss (NIHL) have been conducted among mine workers to provide an impetus for the development of comprehensive hearing protection programmes. AIMS: To determine the prevalence of NIHL and associated factors among miners in a major gold mining company operating in Tanzania. Associated risk factors such as age, sex and duration of exposure were examined. METHODS: Audiograms obtained from periodic medical examinations were categorized using the UK Health & Safety Executive system. RESULTS: A total of 246 audiograms were studied. The prevalence of NIHL was 47%, with 12% with poor hearing and 35% with mild hearing impairment. The proportion of NIHL increased with total years of exposure to noise. Underground miners were more affected (71%) than open pit miners (28%). These findings were statistically significant. The highest proportion of miners with NIHL (60%) was among the youngest age group (20-29 years). CONCLUSIONS: There was a high prevalence of NIHL in the company under study. There was a strong correlation with type of mining, age and years of exposure. The findings have been used to develop comprehensive hearing conservation programmes. PMID- 25926424 TI - Prediction of proximal femur strength by a quantitative computed tomography-based finite element method--Creation of predicted strength data of the proximal femur according to age range in a normal population. AB - OBJECTIVE: The objective of this study was to investigate the factors that affect the predicted bone strength of proximal femur in Japanese population. METHODS: Participants (552 men and 273 women) in a health checkup program with computed tomography (CT) at the University of Tokyo Hospital were enrolled in this study. Three-dimensional finite element models of the proximal femur were constructed from CT data of the participants with simultaneous scans of a calibration phantom containing hydroxyapatite rods. Multiple regression analysis was performed to analyze the relationship between the predicted bone strength and clinical factors. RESULTS: Average predicted strength of proximal femur was lower in women than in men in all age ranges. Predicted bone strength in women under both stance and fall configurations significantly decreased with age, and that in men had the tendency to decrease with age. Body weight positively affected the predicted bone strength in both men and women. CONCLUSIONS: This is the first cross-sectional analysis of the predicted bone strength of the proximal femur in Japanese population of wide age range. Age and body weight critically affected bone strength of proximal femur determined by quantitative CT-based finite element method, in particular in women, under both stance and fall configurations. PMID- 25926425 TI - Subclinical articular involvement in primary Sjogren's syndrome assessed by ultrasonography and its negative association with anti-centromere antibody. AB - OBJECTIVES: To evaluate the subclinical articular involvement in patients with primary Sjogren's syndrome (pSS) using musculoskeletal ultrasound (MSUS), and to correlate the findings with laboratory results and clinical manifestations. METHODS: Forty-eight consecutive patients with pSS were enrolled. The bilateral metacarpophalangeal, proximal interphalangeal, and interphalangeal joints were examined using MSUS, and the synovial hypertrophy and power Doppler signal were recorded for each joint using semi-quantitative scores (0 = normal, 1 = mild change compared with undamaged joint, 2 = moderate change, and 3 = severe change). RESULTS: Mild or moderate synovial hypertrophy was found in 151 (15.7%) and 2 (0.2%) out of 960 hand joints, respectively, and power Doppler signals were present in 19 (2.0%) of the 960 joints. While anti-centromere antibody (ACA) was found in 10 patients (20.8%), none of the patients with MSUS-confirmed synovitis was positive for ACA. No other autoantibodies, laboratory tests, or clinical manifestations correlated with MSUS-confirmed synovitis. CONCLUSION: MSUS is useful for detecting subclinical synovitis in pSS patients. MSUS showed that ACA positive pSS patients had a low prevalence of synovitis. PMID- 25926426 TI - Adequate Nutrition May Get You Home: Effect of Caloric/Protein Deficits on the Discharge Destination of Critically Ill Surgical Patients. AB - BACKGROUND: Macronutrient deficit in the surgical intensive care unit (ICU) is associated with worse in-hospital outcomes. We hypothesized that increased caloric and protein deficit is also associated with a lower likelihood of discharge to home vs transfer to a rehabilitation or skilled nursing facility. MATERIALS AND METHODS: Adult surgical ICU patients receiving >72 hours of enteral nutrition (EN) between March 2012 and May 2014 were included. Patients with absolute contraindications to EN, <72-hour ICU stay, moribund state, EN prior to surgical ICU admission, or previous ICU admission within the same hospital stay were excluded. Subjects were dichotomized by cumulative caloric (<6000 vs >= 6000 kcal) and protein deficit (<300 vs >= 300 g). Baseline characteristics and outcomes were compared using Wilcoxon rank and chi(2) tests. To test the association of macronutrient deficit with discharge destination (home vs other), we performed a logistic regression analysis, controlling for plausible confounders. RESULTS: In total, 213 individuals were included. Nineteen percent in the low-caloric deficit group were discharged home compared with 6% in the high-caloric deficit group (P = .02). Age, body mass index (BMI), Acute Physiology and Chronic Health Evaluation II (APACHE II), and initiation of EN were not significantly different between groups. On logistic regression, adjusting for BMI and APACHE II score, the high-caloric and protein-deficit groups were less likely to be discharged home (odds ratio [OR], 0.28; 95% confidence interval [CI], 0.08-0.96; P = .04 and OR, 0.29; 95% CI, 0.0-0.89, P = .03, respectively). CONCLUSIONS: In surgical ICU patients, inadequate macronutrient delivery is associated with lower rates of discharge to home. Improved nutrition delivery may lead to better clinical outcomes after critical illness. PMID- 25926427 TI - Remote His50 Acts as a Coordination Switch in the High-Affinity N-Terminal Centered Copper(II) Site of alpha-Synuclein. AB - Parkinson's disease (PD) etiology is closely linked to the aggregation of alpha synuclein (alphaS). Copper(II) ions can bind to alphaS and may impact its aggregation propensity. As a consequence, deciphering the exact mode of Cu(II) binding to alphaS is important in the PD context. Several previous reports have shown some discrepancies in the description of the main Cu(II) site in alphaS, which are resolved here by a new scenario. Three Cu(II) species can be encountered, depending on the pH and the Cu:alphaS ratio. At low pH, Cu(II) is bound to the N-terminal part of the protein by the N-terminal amine, the adjacent deprotonated amide group of the Asp2 residue, and the carboxylate group from the side chain of the same Asp2. At pH 7.4, the imidazole group of remote His50 occupies the fourth labile equatorial position of the previous site. At high Cu(II):alphaS ratio (>1), His50 leaves the coordination sphere of the first Cu site centered at the N-terminus, because a second weak affinity site centered on His50 is now filled with Cu(II). In this new scheme, the remote His plays the role of a molecular switch and it can be anticipated that the binding of the remote His to the Cu(II) ion can induce different folding of the alphaS protein, having various aggregation propensity. PMID- 25926428 TI - 17beta estradiol regulates adhesion molecule expression in mesangial cells during glomerulonephritis. AB - We showed previously that 17beta estradiol (E2) led to improved survival in nephrotoxic serum induced nephritis (NTN) in male mice. In this study we determined whether E2 regulates vascular cell adhesion molecule (VCAM)-1, an adhesion molecule that is upregulated in kidney during autoimmune nephritis, in mesangial cells (MC). We show that E2 inhibited VCAM-1 up-regulation in kidneys in vivo during NTN, and in MCs upon TNFalpha stimulation. VCAM-1 up-regulation in MCs was controlled by the transcription factor NFkappaB. E2 inhibited RNA polymerase II recruitment to the VCAM-1 promoter, but not p65 recruitment. Interestingly E2 inhibited TNFalpha stimulated interaction between poly (ADP ribose) polymerase-1 (PARP-1) and p65. As PARP-1 is required for VCAM-1 upregulation in MCs, our data suggest that E2 may inhibit pre-initiation complex formation at VCAM-1 promoter by inhibiting PARP-1 recruitment to p65. We propose that E2 plays an important role in regulating renal inflammation locally. PMID- 25926429 TI - Successful segmental thermal ablation of varicose saphenous veins in a patient with confirmed vascular Ehlers-Danlos syndrome. AB - We describe here the successful scheduled treatment of varicose veins by radiofrequency segmental thermal ablation in a 43-year-old patient with vascular Ehlers-Danlos syndrome. Her venous disease started at the age of 16 years, 1 year prior to her first major Ehlers-Danlos syndrome-related event which led to the diagnosis of her genetic condition. Surgical stripping was contra-indicated because of Ehlers-Danlos syndrome at the age of 18 years. More than 20 years later, her venous disease had become highly symptomatic despite daily compression and pain medication. Venous reassessment evidenced incompetent right and left great saphenous and left small saphenous veins, with increased diameters of both sapheno-femoral and sapheno-popliteal junctions. Radiofrequency endovenous ablation rather than surgery was considered because of its minimally invasive nature and because of standardized energy delivery.All intended-to-be-treated incompetent saphenous vein segments were occluded successfully, followed by an important improvement of clinical disease severity at day 30, persistent at 1 year post-treatment. Duplex ultrasound confirmed closure and fibrotic retraction of all treated venous segments at 1 year. This report shows that radiofrequency endovenous ablation may be a safe and effective therapy of varicose veins in patients with diagnosed vascular Ehlers-Danlos syndrome. PMID- 25926430 TI - Ethnic variability in the expression of hepatic drug transporters: absolute quantification by an optimized targeted quantitative proteomic approach. AB - Hepatic OATPs 1B1, 1B3 and 2B1, as well as P-gp, play important roles in regulating liver uptake and biliary excretion of drugs. The intrinsic ethnic variability in OATP1B1-mediated hepatic uptake of statins has been proposed to underlie the ethnic variability in plasma exposures of statins between Caucasians and Asians. Using a targeted quantitative proteomic approach, we determined hepatic protein concentrations of OATP1B1, OATP1B3, OATP2B1, P-gp, and PMCA4 (a housekeeping protein) in a panel of human livers (n = 141) and compared protein expression across Caucasian, Asian, African-American, and unidentified donors. Using an optimized protocol that included sodium deoxycholate as a membrane protein solubilizer, the hepatic protein expression levels (mean +/- S.D.) of these transporters across all livers were determined to be 15.0 +/- 6.0, 16.1 +/- 8.1, 4.1 +/- 1.3, 0.6 +/- 0.2, and 2.4 +/- 1.0 fmol/MUg of total membrane protein, respectively. The scaling factor was 3.5 mg of total membrane protein in 100 mg of wet liver tissue. OATP1B1 protein expression was significantly associated with the c.388A>G (rs2306283, N130D) single nucleotide polymorphism. When compared across ethnicity, the hepatic expression levels of OATP1B1 and OATP1B3 were unexpectedly higher in Asians relative to Caucasians, suggesting that hepatic OATP expression alone does not explain the increased systemic statin levels in Asians compared with Caucasians. These findings may help improve physiologically based pharmacokinetic modeling to predict statin pharmacokinetic profiles and enable extrapolation of pharmacokinetic data of OATP substrates across ethnic groups. PMID- 25926431 TI - Metabolite profiling and pharmacokinetic evaluation of hydrocortisone in a perfused three-dimensional human liver bioreactor. AB - Endotoxin lipopolysaccharide (LPS) is known to cause liver injury primarily involving inflammatory cells such as Kupffer cells, but few in vitro culture models are applicable for investigation of inflammatory effects on drug metabolism. We have developed a three-dimensional human microphysiological hepatocyte-Kupffer cell coculture system and evaluated the anti-inflammatory effect of glucocorticoids on liver cultures. LPS was introduced to the cultures to elicit an inflammatory response and was assessed by the release of proinflammatory cytokines, interleukin 6 and tumor necrosis factor alpha. A sensitive and specific reversed-phase-ultra high-performance liquid chromatography-quadrupole time of flight-mass spectrometry method was used to evaluate hydrocortisone disappearance and metabolism at near physiologic levels. For this, the systems were dosed with 100 nM hydrocortisone and circulated for 2 days; hydrocortisone was depleted to approximately 30 nM, with first-order kinetics. Phase I metabolites, including tetrahydrocortisone and dihydrocortisol, accounted for 8-10% of the loss, and 45-52% consisted of phase II metabolites, including glucuronides of tetrahydrocortisol and tetrahydrocortisone. Pharmacokinetic parameters, i.e., half-life, rate of elimination, clearance, and area under the curve, were 23.03 hours, 0.03 hour(-1), 6.6 * 10(-5) l?hour(-1), and 1.03 (mg/l)*h, respectively. The ability of the bioreactor to predict the in vivo clearance of hydrocortisone was characterized, and the obtained intrinsic clearance values correlated with human data. This system offers a physiologically relevant tool for investigating hepatic function in an inflamed liver. PMID- 25926432 TI - Gut Microbiota-Mediated Drug-Antibiotic Interactions. AB - Xenobiotic metabolism involves the biochemical modification of drugs and phytochemicals in living organisms, including humans and other animals. In the intestine, the gut microbiota catalyzes the conversion of hydrophilic drugs into absorbable, hydrophobic compounds through hydroxyzation and reduction. Drugs and phytochemicals are transformed into bioactive (sulfasalazine, lovastatin, and ginsenoside Rb1), bioinactive (chloramphenicol, ranitidine, and metronidazole), and toxic metabolites (nitrazepam), thus affecting the pharmacokinetics of the original compounds. Antibiotics suppress the activities of drug-metabolizing enzymes by inhibiting the proliferation of gut microbiota. Antibiotic treatment might influence xenobiotic metabolisms more extensively and potently than previously recognized and reduce gut microbiota-mediated transformation of orally administered drugs, thereby altering the systemic concentrations of intact drugs, their metabolites, or both. This review describes the effects of antibiotics on the metabolism of drugs and phytochemicals by the gut microbiota. PMID- 25926433 TI - Farnesoid X Receptor Agonist Represses Cytochrome P450 2D6 Expression by Upregulating Small Heterodimer Partner. AB - Cytochrome P450 2D6 (CYP2D6) is a major drug-metabolizing enzyme responsible for eliminating approximately 20% of marketed drugs. Studies have shown that differential transcriptional regulation of CYP2D6 may contribute to large interindividual variability in CYP2D6-mediated drug metabolism. However, the factors governing CYP2D6 transcription are largely unknown. We previously demonstrated small heterodimer partner (SHP) as a novel transcriptional repressor of CYP2D6 expression. SHP is a representative target gene of the farnesoid X receptor (FXR). The objective of this study is to investigate whether an agonist of FXR, 3-(2,6-dichlorophenyl)-4-(3'-carboxy-2-chlorostilben-4-yl)oxymethyl-5 isopropylisoxazole (GW4064), alters CYP2D6 expression and activity. In CYP2D6 humanized transgenic mice, GW4064 decreased hepatic CYP2D6 expression and activity (by 2-fold) while increasing SHP expression (by 2-fold) and SHP recruitment to the CYP2D6 promoter. CYP2D6 repression by GW4064 was abrogated in Shp(-/-);CYP2D6 mice, indicating a critical role of SHP in CYP2D6 regulation by GW4064. Also, GW4064 decreased CYP2D6 expression (by 2-fold) in primary human hepatocytes, suggesting that the results obtained in CYP2D6-humanized transgenic mice can be translated to humans. This proof of concept study provides evidence for CYP2D6 regulation by an inducer of SHP expression, namely, the FXR agonist GW4064. PMID- 25926434 TI - Genetic background of Brugada syndrome is more complex than what we would like it to be! PMID- 25926435 TI - Ethical Decisions in Palliative Care: Interprofessional Relations as a Burnout Protective Factor? Results From a Mixed-Methods Multicenter Study in Portugal. AB - BACKGROUND: Ethical decisions are part of contemporary practices in palliative care. The need of making such decisions is associated to higher burnout levels and other work related problems among healthcare professionals. AIMS: As part of the project entitled "Decisions in End-of-Life Care in Spain and Portugal" (DELiCaSP), this study aims to (i) identify the most common ethical decisions made by Portuguese palliative care teams and (ii) understand how the making of such decisions relates to burnout. METHODS: A mixed methods study was conducted with 9 palliative care teams, using (i) questionnaires of socio-demographic and professional variables, work-related experiences, (ii) the Maslach Burnout Inventory, (iii) interviews and (iv) observations. These teams were geographically dispersed across the country, covering the North, Centrum and South regions, and heterogeneous: Five palliative care units for inpatients; three home care teams; and one hospital support team. A total of 20 interviews and 240 hours of observations were completed until reaching saturation. RESULTS: The most common ethical decisions were related to communication issues (information disclosure of the diagnosis and prognosis), forgoing treatment and sedation. Although perceived as stressful, emotionally demanding and challenging, ethical decisions were not significantly associated with burnout. CONCLUSIONS: Making ethical decisions is not associated with higher burnout levels among professionals working in Portuguese palliative care teams. This can be explained by the interprofessional decision-making process followed by these teams, which promotes a sense of shared-decision and team-based empowerment; and by the advanced level of interdisciplinary education in palliative care that these professionals have. PMID- 25926436 TI - Uterine Contractility in the Nonpregnant Mouse: Changes During the Estrous Cycle and Effects of Chloride Channel Blockade. AB - Mechanisms involved in the generation of spontaneous uterine contractions are not fully understood. Kit-expressing interstitial cells of Cajal are pacemakers of contractile rhythm in other visceral organs, and recent studies describe a role for Ca(2+)-activated Cl(-) currents as the initiating conductance in these cells. The existence and role of similar specialized pacemaker cells in the nonpregnant uterus remains undetermined. Spontaneous contractility patterns were characterized throughout the estrous cycle in isolated, nonpregnant mouse uteri using spatiotemporal mapping and tension recordings. During proestrus, estrus, and diestrus, contraction origin predominated in the oviduct end of the uterus, suggesting the existence of a dominant pacemaker site. Propagation speed of contractions during estrus and diestrus were significantly slower than in proestrus and metestrus. Five major patterns of activity were predominantly exhibited in particular stages: quiescent (diestrus), high-frequency phasic (proestrus), low-frequency phasic (estrus), multivariant (metestrus), and complex. Kit-immunopositive cells reminiscent of pacemaking ICCs were not consistently observed within the uterus. Niflumic acid (10 MUM), anthracene-9 carboxylic acid (0.1-1 mM), and 5-nitro-2-(3-phenylpropylamino)benzoic acid (10 MUM) each reduced the frequency of spontaneous contractions, suggesting involvement of Cl(-) channels in generating spontaneous uterine motor activity. It is unlikely that this conductance is generated by the Ca(2+)-activated Cl(-) channels, anoctamin-1 and CLCA4, as immunohistochemical labeling did not reveal protein expression within muscle or pacemaker cell networks. In summary, these results suggest that spontaneous uterine contractions may be generated by a Kit negative pacemaker cell type or uterine myocytes, likely involving the activity of a yet-unidentified Cl(-) channel. PMID- 25926437 TI - Regulatory Role of Gonadotropins and Local Factors Produced by Ovarian Follicles on In Vitro Resistin Expression and Action on Porcine Follicular Steroidogenesis. AB - Resistin, a hormone secreted by adipocytes, is thought to be important in reproduction. Our previous study demonstrated resistin expression in porcine ovarian follicles and its direct effect on steroidogenesis. The aim of the current study was to evaluate the effect of gonadotropins and the local ovarian factors, such as insulin-like growth factor type 1 (IGF1) and steroids (progesterone, testosterone, and 17 beta-estradiol), on the expression and secretion of resistin, as well as its steroidogenic action. Porcine ovarian follicles were exposed to follicle-stimulating hormone (FSH) and luteinizing hormone (LH) at 50-150 ng/ml, IGF1 (10-100 ng/ml), and steroids at 10(-8) to 10( 6) M for 24 h. Then, mRNA, protein expression, and medium concentration of resistin were determined using real-time PCR, Western blot analysis, and ELISA, respectively. In the subsequent experiments, ovarian follicles were exposed to resistin and/or FSH, LH, IGF1, and steroids, and ovarian steroidogenesis was analyzed. Additionally, we examined the direct effect of resistin on the protein expression of receptors for gonadotropins and investigated local factors. The results showed that gonadotropins and steroids have stimulatory effects but that IGF1 has an inhibitory effect on resistin expression and secretion. Resistin decreased gonadotropins and local hormone-induced steroid secretion and inhibited 3beta-hydroxysteroid dehydrogenase, 17beta-hydroxysteroid dehydrogenase, and cytochrome P450 aromatase protein expression. Additionally, we demonstrated that resistin increased the expression of receptors for progesterone and testosterone. These findings all show that the expression and function of resistin are regulated by gonadotropins and local factors produced by ovarian follicles. PMID- 25926438 TI - Intrafollicular Oocyte Transfer (IFOT) of Abattoir-Derived and In Vitro-Matured Oocytes Results in Viable Blastocysts and Birth of Healthy Calves. AB - There are still major differences between in vitro production (IVP)-derived and in vivo-derived bovine blastocysts. Therefore, intrafollicular oocyte transfer (IFOT) was used in the present study to allow early embryonic development within the physiological oviductal environment, in order to avoid subsequent harmful effects of the in vitro culture environment. Using modified ovum pickup equipment, in vitro-matured oocytes were transferred into the preovulatory follicle of synchronized heifers (follicular recipients), enabling subsequent ovulation, in vivo fertilization, and in vivo development. When 1646 in vitro matured oocytes were transferred to 28 follicular recipients, a total of 583 embryos (35.2%) were recovered in excess after uterine flushing at Day 7. Although numbers of generated extra embryos were highly variable, preovulatory follicles with a diameter of 13-14 mm delivered significantly (P < 0.05) larger amounts of extra embryos (34.3 vs. 7.3), as well as extra morulae and blastocysts (8.3 vs. 0.8), compared with follicles with a diameter of 9-10 mm. Nevertheless, the developmental rate to the blastocyst stage was lower in IFOT compared with in vitro-derived control (Vitro) embryos at Day 7 (8.0% vs. 36.5%). Likewise, cumulative developmental rates to the morula or blastocyst stage until Day 7 were lower in IFOT-derived embryos when related to the number of transferred (8.4% vs. 51.7%) or flushed (22.8% vs. 51.7%) embryos. Of the latter, IFOT-derived embryos yielded significantly lower cleavage rates compared with the Vitro controls (63.2% vs. 88.8%), and developmental rate to the morula or blastocyst stage were lower even when related to the proportion of cleaved embryos (36.8% vs. 58.2%). In contrast, lipid content and cryotolerance did not differ between IFOT and fully IVP embryos; but IFOT-derived embryos showed significantly lower lipid content (P < 0.05) and significantly higher cryotolerance compared with IVP derived embryos cultured in CR1aa medium supplemented with estrus cow serum (ECS), but not when cultured in SOFaa medium supplemented with fatty acid-free BSA (BSA-FFA). Finally, transfer of 19 frozen-thawed IFOT-derived blastocysts to synchronized recipients (uterine recipients) resulted in pregnancy rates comparable with those obtained after transfer of fully in vivo-derived embryos or IVP-derived embryos cultured in SOFaa + BSA-FFA, whereas pregnancy rate following transfer of IVP-derived blastocysts was significantly lower when they were cultured in CR1aa + ECS (42.1% vs. 13.8%). All in all, seven pregnancies presumed to be IFOT derived went to term, and microsatellite analysis confirmed that five calves were indeed derived from IFOT. To our knowledge, these are the first calves born after IFOT in cattle. Interestingly, the average birth weight of IFOT derived calves was lower than that of IVP-derived calves, even when embryos were cultured in SOFaa + BSA-FFA, indicating that the environment during early embryo development might cause fetal overgrowth. Taken together, for the first time we were able to show that IFOT is a feasible technique to generate bovine blastocysts by transferring in vitro-matured oocytes derived from slaughterhouse ovaries. These IFOT-derived blastocysts closely resemble in vivo-derived blastocysts in terms of lipid content and freeze survival. Thus, the present study laid the groundwork for newly created scientific experiments enabling novel analytical possibilities. Nevertheless, IFOT-derived embryos still reached lower pregnancy rates by trend compared with in vivo-derived embryos, also implicating an important role for the maturational environment in further developmental characteristics. PMID- 25926439 TI - Heat Stress Alters Ovarian Insulin-Mediated Phosphatidylinositol-3 Kinase and Steroidogenic Signaling in Gilt Ovaries. AB - Heat stress (HS) compromises a variety of reproductive functions in several mammalian species. Inexplicably, HS animals are frequently hyperinsulinemic despite marked hyperthermia-induced hypophagia. Our objectives were to determine the effects of HS on insulin signaling and components essential to steroid biosynthesis in the pig ovary. Female pigs (35 +/- 4 kg) were exposed to constant thermoneutral (20 degrees C; 35%-50% humidity; n = 6) or HS conditions (35 degrees C; 20%-35% humidity; n = 6) for either 7 (n = 10) or 35 days (n = 12). After 7 days, HS increased (P < 0.05) ovarian mRNA abundance of the insulin receptor (INSR), insulin receptor substrate 1 (IRS1), protein kinase B subunit 1 (AKT1), low-density lipoprotein receptor (LDLR), luteinizing hormone receptor (LHCGR), and aromatase (CYP19a). After 35 days, HS increased INSR, IRS1, AKT1, LDLR, LHCGR, CYP19a, and steroidogenic acute regulatory protein (STAR) ovarian mRNA abundance. In addition, after 35 days, HS increased ovarian phosphorylated IRS1 (pIRS1), phosphorylated AKT (pAKT), STAR, and CYP19a protein abundance. Immunostaining analysis revealed similar localization of INSR and pAKT1 in the cytoplasmic membrane and oocyte cytoplasm, respectively, of all stage follicles, and in theca and granulosa cells. Collectively, these results demonstrate that HS alters ovarian insulin-mediated PI3K signaling pathway members, which likely impacts follicle activation and viability. In summary, environmentally induced HS is an endocrine-disrupting exposure that modifies ovarian physiology and potentially compromises production of ovarian hormones essential for fertility and pregnancy maintenance. PMID- 25926440 TI - Oviduct-Embryo Interactions in Cattle: Two-Way Traffic or a One-Way Street? AB - This study examined the effect of the presence of single or multiple embryos on the transcriptome of the bovine oviduct. In experiment 1, cyclic (nonbred, n = 6) and pregnant (artificially inseminated, n = 11) heifers were slaughtered on Day 3 after estrus, and the ampulla and isthmic regions of the oviduct ipsilateral to the corpus luteum were separately flushed. Oviductal epithelial cells from the isthmus region, in which all oocytes/embryos were located, were snap-frozen for microarray analysis. In experiment 2, heifers were divided into cyclic (nonbred, n = 6) or pregnant (multiple embryo transfer, n = 10) groups. In vitro-produced presumptive zygotes were transferred endoscopically to the ipsilateral oviduct on Day 1.5 postestrus (n = 50 zygotes/heifer). Heifers were slaughtered on Day 3, and oviductal isthmus epithelial cells were recovered for RNA sequencing. Microarray analysis in experiment 1 failed to detect any difference in the transcriptome of the oviductal isthmus induced by the presence of a single embryo. In experiment 2, following multiple embryo transfer, RNA sequencing revealed 278 differentially expressed genes, of which 123 were up-regulated and 155 were down-regulated in pregnant heifers. Most of the down-regulated genes were related to immune function. In conclusion, the presence of multiple embryos in the oviduct resulted in the detection of differentially expressed genes in the oviductal isthmus; failure to detect changes in the oviduct transcriptome in the presence of a single embryo may be due to the effect being local and undetectable under the conditions of this study. PMID- 25926441 TI - Inhibition of Endometrial Tiam1/Rac1 Signals Induced by miR-22 Up-Regulation Leads to the Failure of Embryo Implantation During the Implantation Window in Pregnant Mice. AB - This study assessed first the impact of endometrial Tiam1/Rac1 signals and microRNA-22 (miR-22) on embryo implantation in mice, and then the expression of the above three genes in the endometrium during the embryo implantation window in the natural menstrual cycle in women with repeated implantation failure (RIF) after in vitro fertilization treatment. Four hundred fifty-two Kun-ming female mice and 200 women (70 infertility patients with RIF, 130 women as controls) were entered into this study. Endometrial Tiam1/Rac1 signals and miR-22 expression were studied in clinical and mouse samples and serum estrogen (E2) and progesterone (P) were analyzed in clinical subjects. A pregnant mouse model based on an endometrial miR-22 and Tiam1 mRNA expression trend of patients with RIF was constructed and then the embryo implantation numbers were analyzed, and an ovariectomized mouse model was used to assess correlations of expression of these three genes with E2 and P. The results showed that during the embryo implantation window in the natural menstrual cycle, endometrial miR-22 was significantly higher whereas Tiam1/Rac1 signals were notably lower in patients with RIF than in controls, and the P:E2 ratio was statistically lower in the RIF group. Tiam1/Rac1 signal down-regulation and miR-22 up-regulation contributed to the inhibition of embryo implantation in mice. We also found a suppressive effect of miR-22 up regulation on Tiam1/Rac1 signal expression, and reciprocal regulation of E2 and P for these three genes' expression in mice. In conclusion, miR-22 up-regulation and Tiam1/Rac1 signal down-regulation inhibited embryo implantation in mice; this mechanism may be partially due to the suppressive effect of miR-22 on Tiam1 expression, and is regulated to some extent by serum E2 and P. Our findings provide evidence that endometrial Tiam1/Rac1 signal down-regulation along with miR-22 up-regulation during embryo implantation window in the natural menstrual cycle may be one of the reasons for the failure of embryo implantation in patients with RIF. PMID- 25926443 TI - Driving sleep slow oscillations by auditory closed-loop stimulation-a self limiting process. AB - The <1 Hz EEG slow oscillation (SO) is a hallmark of slow-wave sleep (SWS) and is critically involved in sleep-associated memory formation. Previous studies showed that SOs and associated memory function can be effectively enhanced by closed loop auditory stimulation, when clicks are presented in synchrony with upcoming SO up states. However, increasing SOs and synchronized excitability also bear the risk of emerging seizure activity, suggesting the presence of mechanisms in the healthy brain that counter developing hypersynchronicity during SOs. Here, we aimed to test the limits of driving SOs through closed-loop auditory stimulation in healthy humans. Study I tested a "Driving stimulation" protocol (vs "Sham") in which trains of clicks were presented in synchrony with SO up states basically as long as an ongoing SO train was identified on-line. Study II compared Driving stimulation with a "2-Click" protocol where the maximum of stimuli delivered in a train was limited to two clicks. Stimulation was applied during SWS in the first 210 min of nocturnal sleep. Before and after sleep declarative word-pair memories were tested. Compared with the Sham control, Driving stimulation prolonged SO trains and enhanced SO amplitudes, phase-locked spindle activity, and overnight retention of word pairs (all ps < 0.05). Importantly, effects of Driving stimulation did not exceed those of 2-Click stimulation (p > 0.180), indicating the presence of a mechanism preventing the development of hypersynchronicity during SO activity. Assessment of temporal dynamics revealed a rapidly fading phase-locked spindle activity during repetitive click stimulation, suggesting that spindle refractoriness contributes to this protective mechanism. PMID- 25926442 TI - Migraine: multiple processes, complex pathophysiology. AB - Migraine is a common, multifactorial, disabling, recurrent, hereditary neurovascular headache disorder. It usually strikes sufferers a few times per year in childhood and then progresses to a few times per week in adulthood, particularly in females. Attacks often begin with warning signs (prodromes) and aura (transient focal neurological symptoms) whose origin is thought to involve the hypothalamus, brainstem, and cortex. Once the headache develops, it typically throbs, intensifies with an increase in intracranial pressure, and presents itself in association with nausea, vomiting, and abnormal sensitivity to light, noise, and smell. It can also be accompanied by abnormal skin sensitivity (allodynia) and muscle tenderness. Collectively, the symptoms that accompany migraine from the prodromal stage through the headache phase suggest that multiple neuronal systems function abnormally. As a consequence of the disease itself or its genetic underpinnings, the migraine brain is altered structurally and functionally. These molecular, anatomical, and functional abnormalities provide a neuronal substrate for an extreme sensitivity to fluctuations in homeostasis, a decreased ability to adapt, and the recurrence of headache. Advances in understanding the genetic predisposition to migraine, and the discovery of multiple susceptible gene variants (many of which encode proteins that participate in the regulation of glutamate neurotransmission and proper formation of synaptic plasticity) define the most compelling hypothesis for the generalized neuronal hyperexcitability and the anatomical alterations seen in the migraine brain. Regarding the headache pain itself, attempts to understand its unique qualities point to activation of the trigeminovascular pathway as a prerequisite for explaining why the pain is restricted to the head, often affecting the periorbital area and the eye, and intensifies when intracranial pressure increases. PMID- 25926444 TI - Orexin-corticotropin-releasing factor receptor heteromers in the ventral tegmental area as targets for cocaine. AB - Release of the neuropeptides corticotropin-releasing factor (CRF) and orexin-A in the ventral tegmental area (VTA) play an important role in stress-induced cocaine seeking behavior. We provide evidence for pharmacologically significant interactions between CRF and orexin-A that depend on oligomerization of CRF1 receptor (CRF1R) and orexin OX1 receptors (OX1R). CRF1R-OX1R heteromers are the conduits of a negative crosstalk between orexin-A and CRF as demonstrated in transfected cells and rat VTA, in which they significantly modulate dendritic dopamine release. The cocaine target sigma1 receptor (sigma1R) also associates with the CRF1R-OX1R heteromer. Cocaine binding to the sigma1R-CRF1R-OX1R complex promotes a long-term disruption of the orexin-A-CRF negative crosstalk. Through this mechanism, cocaine sensitizes VTA cells to the excitatory effects of both CRF and orexin-A, thus providing a mechanism by which stress induces cocaine seeking. PMID- 25926445 TI - A network of visual motion-sensitive neurons for computing object position in an arthropod. AB - Highly active insects and crabs depend on visual motion information for detecting and tracking mates, prey, or predators, for which they require directional control systems containing internal maps of visual space. A neural map formed by large, motion-sensitive neurons implicated in processing panoramic flow is known to exist in an optic ganglion of the fly. However, an equivalent map for processing spatial positions of single objects has not been hitherto identified in any arthropod. Crabs can escape directly away from a visual threat wherever the stimulus is located in the 360 degrees field of view. When tested in a walking simulator, the crab Neohelice granulata immediately adjusts its running direction after changes in the position of the visual danger stimulus smaller than 1 degrees . Combining mass and single-cell staining with in vivo intracellular recording, we show that a particular class of motion-sensitive neurons of the crab's lobula that project to the midbrain, the monostratified lobula giants type 1 (MLG1), form a system of 16 retinotopically organized elements that map the 360 degrees azimuthal space. The preference of these neurons for horizontally moving objects conforms the visual ecology of the crab's mudflat world. With a mean receptive field of 118 degrees , MLG1s have a large superposition among neighboring elements. Our results suggest that the MLG1 system conveys information on object position as a population vector. Such computational code can enable the accurate directional control observed in the visually guided behaviors of crabs. PMID- 25926447 TI - Lateralized delay period activity marks the focus of spatial attention in working memory: evidence from somatosensory event-related brain potentials. AB - The short-term retention of sensory information in working memory (WM) is known to be associated with a sustained enhancement of neural activity. What remains controversial is whether this neural trace indicates the sustained storage of information or the allocation of attention. To evaluate the storage and attention accounts, we examined sustained tactile contralateral delay activity (tCDA component) of the event-related potential. The tCDA manifests over somatosensory cortex contralateral to task-relevant tactile information during stimulus retention. Two tactile sample sets (S1, S2) were presented sequentially, separated by 1.5 s. Each set comprised two stimuli, one per hand. Human participants memorized the location of one task-relevant stimulus per sample set and judged whether one of these locations was stimulated again at memory test. The two relevant pulses were unpredictably located on the same hand (stay trials) or on different hands (shift trials). Initially, tCDA components emerged contralateral to the relevant S1 pulse. Sequential loading of WM enhanced the tCDA after S2 was presented on stay trials. On shift trials, the tCDA's polarity reversed after S2 presentation, resulting in delay activity that was now contralateral to the task-relevant S2 pulse. The disappearance of a lateralized neural trace for the relevant S1 pulse did not impair memory accuracy for this stimulus on shift trials. These results contradict the storage account and suggest that delay period activity indicates the sustained engagement of an attention-based rehearsal mechanism. In conclusion, somatosensory delay period activity marks the current focus of attention in tactile WM. PMID- 25926446 TI - Prototypic and arkypallidal neurons in the dopamine-intact external globus pallidus. AB - Studies in dopamine-depleted rats indicate that the external globus pallidus (GPe) contains two main types of GABAergic projection cell; so-called "prototypic" and "arkypallidal" neurons. Here, we used correlative anatomical and electrophysiological approaches in rats to determine whether and how this dichotomous organization applies to the dopamine-intact GPe. Prototypic neurons coexpressed the transcription factors Nkx2-1 and Lhx6, comprised approximately two-thirds of all GPe neurons, and were the major GPe cell type innervating the subthalamic nucleus (STN). In contrast, arkypallidal neurons expressed the transcription factor FoxP2, constituted just over one-fourth of GPe neurons, and innervated the striatum but not STN. In anesthetized dopamine-intact rats, molecularly identified prototypic neurons fired at relatively high rates and with high regularity, regardless of brain state (slow-wave activity or spontaneous activation). On average, arkypallidal neurons fired at lower rates and regularities than prototypic neurons, and the two cell types could be further distinguished by the temporal coupling of their firing to ongoing cortical oscillations. Complementing the activity differences observed in vivo, the autonomous firing of identified arkypallidal neurons in vitro was slower and more variable than that of prototypic neurons, which tallied with arkypallidal neurons displaying lower amplitudes of a "persistent" sodium current important for such pacemaking. Arkypallidal neurons also exhibited weaker driven and rebound firing compared with prototypic neurons. In conclusion, our data support the concept that a dichotomous functional organization, as actioned by arkypallidal and prototypic neurons with specialized molecular, structural, and physiological properties, is fundamental to the operations of the dopamine-intact GPe. PMID- 25926448 TI - The role of sleep in motor sequence consolidation: stabilization rather than enhancement. AB - Sleep supports the consolidation of motor sequence memories, yet it remains unclear whether sleep stabilizes or actually enhances motor sequence performance. Here we assessed the time course of motor memory consolidation in humans, taking early boosts in performance into account and varying the time between training and sleep. Two groups of subjects, each participating in a short wake condition and a longer sleep condition, were trained on the sequential finger-tapping task in the evening and were tested (1) after wake intervals of either 30 min or 4 h and (2) after a night of sleep that ensued either 30 min or 4 h after training. The results show an early boost in performance 30 min after training and a subsequent decay across the 4 h wake interval. When sleep followed 30 min after training, post-sleep performance was stabilized at the early boost level. Sleep at 4 h after training restored performance to the early boost level, such that, 12 h after training, performance was comparable regardless of whether sleep occurred 30 min or 4 h after training. These findings indicate that sleep does not enhance but rather stabilizes motor sequence performance without producing additional gains. PMID- 25926449 TI - Callosal projections drive neuronal-specific responses in the mouse auditory cortex. AB - In the auditory cortex (AC), interhemispheric communication is involved in sound localization processes underlying spatial hearing. However, the neuronal microcircuits recruited by the callosal projections are unknown. We addressed this fundamental question by taking advantage of optogenetics and examining directly the functional effects of interhemispheric inputs to specific pyramidal neurons in layer 5 of the mouse AC, defined by their output as either corticocortical (CCort) or corticocollicular (CCol). We found that callosal projections suppress the activity of CCort pyramidal neurons, but facilitate firing of CCol pyramidal neurons. This difference is mechanistically explained by callosal activation of fast-spiking parvalbumin-expressing interneurons (FS PARV), which provide selective inhibition to CCort pyramidal neurons. Our results establish two distinct previously unknown cortical circuits underlying either callosal suppression (callosal projections -> FS-PARV -> CCort) or facilitation (callosal projections -> CCol) of projecting neurons in layer 5 of the AC and attribute a specific function to a genetically defined type of interneuron in interhemispheric communication. PMID- 25926450 TI - Schwann cells generated from neonatal skin-derived precursors or neonatal peripheral nerve improve functional recovery after acute transplantation into the partially injured cervical spinal cord of the rat. AB - The transplantation of Schwann cells (SCs) holds considerable promise as a therapy for spinal cord injury, but the optimal source of these cells and the best timing for intervention remains debatable. Previously, we demonstrated that delayed transplantation of SCs generated from neonatal mouse skin-derived precursors (SKP-SCs) promoted repair and functional recovery in rats with thoracic contusions. Here, we conducted two experiments using neonatal rat cells and an incomplete cervical injury model to examine the efficacy of acute SKP-SC transplantation versus media control (Experiment 1) and versus nerve-derived SC or dermal fibroblast (Fibro) transplantation (Experiment 2). Despite limited graft survival, by 10 weeks after injury, rats that received SCs from either source showed improved functional recovery compared with media- or fibroblast treated animals. Compared with media treatment, SKP-SC-transplanted rats showed enhanced rubrospinal tract (RST) sparing/plasticity in the gray matter (GM) rostral to injury, particularly in the absence of immunosuppression. The functional benefits of SC transplantations over fibroblast treatment correlated with the enhanced preservation of host tissue, reduced RST atrophy, and/or increased RST sparing/plasticity in the GM. In summary, our results indicate that: (1) early transplantation of neonatal SCs generated from skin or nerve promotes repair and functional recovery after incomplete cervical crush injury; (2) either of these cell types is preferable to Fibros for these purposes; and (3) age-matched SCs from these two sources do not differ in terms of their reparative effects or functional efficacy after transplantation into the injured cervical spinal cord. PMID- 25926451 TI - Striatal iron content predicts its shrinkage and changes in verbal working memory after two years in healthy adults. AB - The accumulation of non-heme iron in the brain has been proposed as a harbinger of neural and cognitive decline in aging and neurodegenerative disease, but support for this proposal has been drawn from cross-sectional studies, which do not provide valid estimates of change. Here, we present longitudinal evidence of subcortical iron accumulation in healthy human adults (age 19-77 at baseline). We used R2* relaxometry to estimate regional iron content twice within a 2 year period, measured volumes of the striatum and the hippocampus by manual segmentation, and assessed cognitive performance by working memory tasks. Two year change and individual differences in the change of regional volumes, regional iron content, and working memory were examined by latent change score models while taking into account the age at baseline and metabolic risk indicators. Over the examined period, volume reduction occurred in the caudate nucleus and hippocampus, but iron content increased only in the striatum, where it explained shrinkage. Higher iron content in the caudate nucleus at baseline predicted lesser improvement in working memory after repeat testing. Although advanced age and elevated metabolic syndrome risk were associated with greater iron content in the putamen at baseline, neither age nor metabolic risk influenced change in any variable. Thus, longitudinal evidence supports the notion that accumulation of subcortical iron is a risk factor for neural and cognitive decline in normal aging. PMID- 25926452 TI - Coinciding decreases in discharge rate suggest that spontaneous pauses in firing of external pallidum neurons are network driven. AB - The external segment of the globus pallidus (GPe) is one of the core nuclei of the basal ganglia, playing a major role in normal control of behavior and in the pathophysiology of basal ganglia-related disorders such as Parkinson's disease. In vivo, most neurons in the GPe are characterized by high firing rates (50-100 spikes/s), interspersed with long periods (~0.6 s) of complete silence, which are termed GPe pauses. Previous physiological studies of single and pairs of GPe neurons have failed to fully disclose the physiological process by which these pauses originate. We examined 1001 simultaneously recorded pairs of high frequency discharge GPe cells recorded from four monkeys during task-irrelevant periods, considering the activity in one cell while the other is pausing. We found that pauses (n = 137,278 pauses) coincide with a small yet significant reduction in firing rate (0.78 +/- 0.136 spikes/s) in other GPe cells. Additionally, we found an increase in the probability of the simultaneously recorded cell to pause during the pause period of the "trigger" cell. Importantly, this increase in the probability to pause at the same time does not account for the reduction in firing rate by itself. Modeling of GPe cells as class 2 excitability neurons (Hodgkin, 1948) with common external inputs can explain our results. We suggest that common inputs decrease the GPe discharge rate and lead to a bifurcation phenomenon (pause) in some of the GPe neurons. PMID- 25926453 TI - Intracellular FGF14 (iFGF14) Is Required for Spontaneous and Evoked Firing in Cerebellar Purkinje Neurons and for Motor Coordination and Balance. AB - Mutations in FGF14, which encodes intracellular fibroblast growth factor 14 (iFGF14), have been linked to spinocerebellar ataxia (SCA27). In addition, mice lacking Fgf14 (Fgf14(-/-)) exhibit an ataxia phenotype resembling SCA27, accompanied by marked changes in the excitability of cerebellar granule and Purkinje neurons. It is not known, however, whether these phenotypes result from defects in neuronal development or if they reflect a physiological requirement for iFGF14 in the adult cerebellum. Here, we demonstrate that the acute and selective Fgf14-targeted short hairpin RNA (shRNA)-mediated in vivo "knock-down" of iFGF14 in adult Purkinje neurons attenuates spontaneous and evoked action potential firing without measurably affecting the expression or localization of voltage-gated Na(+) (Nav) channels at Purkinje neuron axon initial segments. The selective shRNA-mediated in vivo "knock-down" of iFGF14 in adult Purkinje neurons also impairs motor coordination and balance. Repetitive firing can be restored in Fgf14-targeted shRNA-expressing Purkinje neurons, as well as in Fgf14(-/-) Purkinje neurons, by prior membrane hyperpolarization, suggesting that the iFGF14 mediated regulation of the excitability of mature Purkinje neurons depends on membrane potential. Further experiments revealed that the loss of iFGF14 results in a marked hyperpolarizing shift in the voltage dependence of steady-state inactivation of the Nav currents in adult Purkinje neurons. We also show here that expressing iFGF14 selectively in adult Fgf14(-/-) Purkinje neurons rescues spontaneous firing and improves motor performance. Together, these results demonstrate that iFGF14 is required for spontaneous and evoked action potential firing in adult Purkinje neurons, thereby controlling the output of these cells and the regulation of motor coordination and balance. PMID- 25926454 TI - Anti-Ganglioside Antibodies Induce Nodal and Axonal Injury via Fcgamma Receptor Mediated Inflammation. AB - Guillain-Barre syndrome (GBS) is a postinfectious autoimmune neuropathy and anti ganglioside antibodies (Abs) are strongly associated with this disorder. Several studies have implied that specific anti-ganglioside Abs induce neuropathy in patients with axonal forms of GBS. To study the mechanisms of anti-ganglioside Abs-induced neuropathy, we established a new passive transfer mouse model by L5 spinal nerve transection (L5SNT; modified Chung's model) and systemic administration of anti-ganglioside Abs. L5SNT causes degeneration of a small proportion of fibers that constitute sciatic nerve and its branches, but importantly breaks the blood-nerve barrier, which allows access to circulating Abs and inflammatory cells. Our studies indicate that, in this mouse model, anti ganglioside Abs induce sequential nodal and axonal injury of intact myelinated nerve fibers, recapitulating pathologic features of human disease. Notably, our results showed that immune complex formation and the activating Fc gamma receptors (FcgammaRs) were involved in the anti-ganglioside Abs-mediated nodal and axonal injury in this model. These studies provide new evidence that the activating FcgammaRs-mediated inflammation plays a critical role in anti ganglioside Abs-induced neuropathy (injury to intact nerve fibers) in GBS. PMID- 25926455 TI - Neuropeptide receptor transcript expression levels and magnitude of ionic current responses show cell type-specific differences in a small motor circuit. AB - We studied the relationship between neuropeptide receptor transcript expression and current responses in the stomatogastric ganglion (STG) of the crab, Cancer borealis. We identified a transcript with high sequence similarity to crustacean cardioactive peptide (CCAP) receptors in insects and mammalian neuropeptide S receptors. This transcript was expressed throughout the nervous system, consistent with the role of CCAP in a range of different behaviors. In the STG, single-cell qPCR showed expression in only a subset of neurons. This subset had previously been shown to respond to CCAP with the activation of a modulator activated inward current (IMI), with one exception. In the one cell type that showed expression but no IMI responses, we found CCAP modulation of synaptic currents. Expression levels within STG neuron types were fairly variable, but significantly different between some neuron types. We tested the magnitude and concentration dependence of IMI responses to CCAP application in two identified neurons, the lateral pyloric (LP) and the inferior cardiac (IC) neurons. LP had several-fold higher expression and showed larger current responses. It also was more sensitive to low CCAP concentrations and showed saturation at lower concentrations, as sigmoid fits showed smaller EC50 values and steeper slopes. In addition, occlusion experiments with proctolin, a different neuropeptide converging onto IMI, showed that saturating concentrations of CCAP activated all available IMI in LP, but only approximately two-thirds in IC, the neuron with lower receptor transcript expression. The implications of these findings for comodulation are discussed. PMID- 25926457 TI - Dissociating visual and motor directional selectivity using visuomotor adaptation. AB - Directional selectivity during visually guided hand movements is a fundamental characteristic of neural populations in multiple motor areas of the primate brain. In the current study, we assessed how directional selectivity changes when reaching movements are dissociated from their visual feedback by rotating the visual field. We recorded simultaneous movement kinematics and fMRI activity while human subjects performed out-and-back movements to four peripheral targets before and after adaptation to a 45 degrees visuomotor rotation. A classification algorithm was trained to identify movement direction according to voxel-by-voxel fMRI patterns in each of several brain areas. The direction of movements was successfully decoded with above-chance accuracy in multiple motor and visual areas when training and testing the classifier on trials within each condition, thereby demonstrating the existence of directionally selective fMRI patterns within each stage of the experiment. Most importantly, when training the classifier on baseline trials and decoding rotated trials, motor brain areas exhibited above-chance decoding according to the original movement direction and visual brain areas exhibited above-chance decoding according to the rotated visual target location, while posterior parietal cortex (PPC) exhibited chance level decoding according to both. These results reveal that directionally selective fMRI patterns in motor system areas faithfully represent movement direction regardless of visual feedback, while fMRI patterns in visual system areas faithfully represent target location regardless of movement direction. Directionally selective fMRI patterns in PPC, however, were altered following adaptation learning, thereby suggesting that the novel visuomotor mapping, which was learned during visuomotor adaptation, is stored in PPC. PMID- 25926456 TI - Reactivation of Lysosomal Ca2+ Efflux Rescues Abnormal Lysosomal Storage in FIG4 Deficient Cells. AB - Loss of function of FIG4 leads to Charcot-Marie-Tooth disease Type 4J, Yunis Varon syndrome, or an epilepsy syndrome. FIG4 is a phosphatase with its catalytic specificity toward 5'-phosphate of phosphatidylinositol-3,5-diphosphate (PI3,5P2). However, the loss of FIG4 decreases PI3,5P2 levels likely due to FIG4's dominant effect in scaffolding a PI3,5P2 synthetic protein complex. At the cellular level, all these diseases share similar pathology with abnormal lysosomal storage and neuronal degeneration. Mice with no FIG4 expression (Fig4( /-)) recapitulate the pathology in humans with FIG4 deficiency. Using a flow cytometry technique that rapidly quantifies lysosome sizes, we detected an impaired lysosomal fission, but normal fusion, in Fig4(-/-) cells. The fission defect was associated with a robust increase of intralysosomal Ca(2+) in Fig4(-/ ) cells, including FIG4-deficient neurons. This finding was consistent with a suppressed Ca(2+) efflux of lysosomes because the endogenous ligand of lysosomal Ca(2+) channel TRPML1 is PI3,5P2 that is deficient in Fig4(-/-) cells. We reactivated the TRPML1 channels by application of TRPML1 synthetic ligand, ML SA1. This treatment reduced the intralysosomal Ca(2+) level and rescued abnormal lysosomal storage in Fig4(-/-) culture cells and ex vivo DRGs. Furthermore, we found that the suppressed Ca(2+) efflux in Fig4(-/-) culture cells and Fig4(-/-) mouse brains profoundly downregulated the expression/activity of dynamin-1, a GTPase known to scissor organelle membranes during fission. This downregulation made dynamin-1 unavailable for lysosomal fission. Together, our study revealed a novel mechanism explaining abnormal lysosomal storage in FIG4 deficiency. Synthetic ligands of the TRPML1 may become a potential therapy against diseases with FIG4 deficiency. PMID- 25926458 TI - The white matter structural network underlying human tool use and tool understanding. AB - The ability to recognize, create, and use complex tools is a milestone in human evolution. Widely distributed brain regions in parietal, frontal, and temporal cortices have been implicated in using and understanding tools, but the roles of their anatomical connections in supporting tool use and tool conceptual behaviors are unclear. Using deterministic fiber tracking in healthy participants, we first examined how 14 cortical regions that are consistently activated by tool processing are connected by white matter (WM) tracts. The relationship between the integrity of each of the 33 obtained tracts and tool processing deficits across 86 brain-damaged patients was investigated. WM tract integrity was measured with both lesion percentage (structural imaging) and mean fractional anisotropy (FA) values (diffusion imaging). Behavioral abilities were assessed by a tool use task, a range of conceptual tasks, and control tasks. We found that three left hemisphere tracts connecting frontoparietal and intrafrontal areas overlapping with left superior longitudinal fasciculus are crucial for tool use such that larger lesion and lower mean FA values on these tracts were associated with more severe tool use deficits. These tracts and five additional left hemisphere tracts connecting frontal and temporal/parietal regions, mainly overlapping with left superior longitudinal fasciculus, inferior frontooccipital fasciculus, uncinate fasciculus, and anterior thalamic radiation, are crucial for tool concept processing. Largely consistent results were also obtained using voxel-based symptom mapping analyses. Our results revealed the WM structural networks that support the use and conceptual understanding of tools, providing evidence for the anatomical skeleton of the tool knowledge network. PMID- 25926460 TI - Tracking the Brain's Functional Coupling Dynamics over Development. AB - The transition from childhood to adulthood is marked by pronounced functional and structural brain transformations that impact cognition and behavior. Here, we use a functional imaging approach to reveal dynamic changes in coupling strength between networks and the expression of discrete brain configurations over human development during rest and a cognitive control task. Although the brain's repertoire of functional states was generally preserved across ages, state specific temporal features, such as the frequency of expression and the amount of time spent in select states, varied by age in ways that were dependent on condition. Increasing age was associated with greater variability of connection strengths across time at rest, while there was a selective inversion of this effect in higher-order networks during implementation of cognitive control. The results suggest that development is characterized by the modification of dynamic coupling to both maximize and constrain functional variability in response to ongoing cognitive and behavioral requirements. PMID- 25926459 TI - Dentate Gyrus Development Requires ERK Activity to Maintain Progenitor Population and MAPK Pathway Feedback Regulation. AB - The ERK/MAPK pathway is an important developmental signaling pathway. Mutations in upstream elements of this pathway result in neuro-cardio-facial cutaneous (NCFC) syndromes, which are typified by impaired neurocognitive abilities that are reliant upon hippocampal function. The role of ERK signaling during hippocampal development has not been examined and may provide critical insight into the cause of hippocampal dysfunction in NCFC syndromes. In this study, we have generated ERK1 and conditional ERK2 compound knock-out mice to determine the role of ERK signaling during development of the hippocampal dentate gyrus. We found that loss of both ERK1 and ERK2 resulted in 60% fewer granule cells and near complete absence of neural progenitor pools in the postnatal dentate gyrus. Loss of ERK1/2 impaired maintenance of neural progenitors as they migrate from the dentate ventricular zone to the dentate gyrus proper, resulting in premature depletion of neural progenitor cells beginning at E16.5, which prevented generation of granule cells later in development. Finally, loss of ERK2 alone does not impair development of the dentate gyrus as animals expressing only ERK1 developed a normal hippocampus. These findings establish that ERK signaling regulates maintenance of progenitor cells required for development of the dentate gyrus. PMID- 25926461 TI - Spike synchrony reveals emergence of proto-objects in visual cortex. AB - Neurons at early stages of the visual cortex signal elemental features, such as pieces of contour, but how these signals are organized into perceptual objects is unclear. Theories have proposed that spiking synchrony between these neurons encodes how features are grouped (binding-by-synchrony), but recent studies did not find the predicted increase in synchrony with binding. Here we propose that features are grouped to "proto-objects" by intrinsic feedback circuits that enhance the responses of the participating feature neurons. This hypothesis predicts synchrony exclusively between feature neurons that receive feedback from the same grouping circuit. We recorded from neurons in macaque visual cortex and used border-ownership selectivity, an intrinsic property of the neurons, to infer whether or not two neurons are part of the same grouping circuit. We found that binding produced synchrony between same-circuit neurons, but not between other pairs of neurons, as predicted by the grouping hypothesis. In a selective attention task, synchrony emerged with ignored as well as attended objects, and higher synchrony was associated with faster behavioral responses, as would be expected from early grouping mechanisms that provide the structure for object based processing. Thus, synchrony could be produced by automatic activation of intrinsic grouping circuits. However, the binding-related elevation of synchrony was weak compared with its random fluctuations, arguing against synchrony as a code for binding. In contrast, feedback grouping circuits encode binding by modulating the response strength of related feature neurons. Thus, our results suggest a novel coding mechanism that might underlie the proto-objects of perception. PMID- 25926463 TI - Estrogen permits vasopressin signaling in preoptic kisspeptin neurons in the female mouse. AB - The cellular mechanisms governing the impact of the central circadian clock on neuronal networks are incompletely understood. We examine here the influence of the suprachiasmatic nucleus output neuropeptide arginine-vasopressin (AVP) on the activity of preoptic area kisspeptin neurons. These cells integrate circadian and hormonal signals within the neuronal network that regulates fertility in females. Electrophysiological recordings in brain slices from kisspeptin-GFP mice showed that AVP dose-dependently increased the firing rate of most kisspeptin neurons. These actions were mediated directly at the kisspeptin neuron. Experiments in mice expressing the calcium indicator GCaMP3 in kisspeptin neurons enabled simultaneous monitoring of intracellular calcium concentrations ([Ca(2+)]i) in multiple cells and revealed that AVP increased [Ca(2+)]i in >80% of diestrous kisspeptin neurons via a mechanism involving voltage-gated calcium channels. We next examined whether AVP signaling in kisspeptin neurons was time and ovarian cycle dependent. AVP exerted the same effects on diestrous and proestrous days of the ovarian cycle, whether hours before [zeitgeber time 4 (ZT4)-ZT6] or just before (ZT10) the expected time of the proestrous preovulatory luteinizing hormone surge. Remarkably, however, AVP signaling was critically dependent on circulating ovarian steroids as AVP no longer excited preoptic kisspeptin neurons in ovariectomized mice, an effect that was fully restored by estradiol treatment. Together, these studies show that AVP exerts a potent and direct stimulatory influence upon the electrical activity and [Ca(2+)]i of most preoptic kisspeptin neurons. Unexpectedly, estrogen is found to permit circadian AVP signaling at preoptic kisspeptin neurons rather than dynamically modulate its activity throughout the estrous cycle. PMID- 25926462 TI - Intermittent Hypoxia-Induced Spinal Inflammation Impairs Respiratory Motor Plasticity by a Spinal p38 MAP Kinase-Dependent Mechanism. AB - Inflammation is characteristic of most clinical disorders that challenge the neural control of breathing. Since inflammation modulates neuroplasticity, we studied the impact of inflammation caused by prolonged intermittent hypoxia on an important form of respiratory plasticity, acute intermittent hypoxia (three, 5 min hypoxic episodes, 5 min normoxic intervals) induced phrenic long-term facilitation (pLTF). Because chronic intermittent hypoxia elicits neuroinflammation and pLTF is undermined by lipopolysaccharide-induced systemic inflammation, we hypothesized that one night of intermittent hypoxia (IH-1) elicits spinal inflammation, thereby impairing pLTF by a p38 MAP kinase-dependent mechanism. pLTF and spinal inflammation were assessed in anesthetized rats pretreated with IH-1 (2 min hypoxia, 2 min normoxia; 8 h) or sham normoxia and allowed 16 h for recovery. IH-1 (1) transiently increased IL-6 (1.5 +/- 0.2-fold; p = 0.02) and inducible nitric oxide synthase (iNOS) (2.4 +/- 0.4-fold; p = 0.01) mRNA in cervical spinal homogenates, (2) elicited a sustained increase in IL 1beta mRNA (2.4 +/- 0.2-fold; p < 0.001) in isolated cervical spinal microglia, and (3) abolished pLTF (-1 +/- 5% vs 56 +/- 10% in controls; p < 0.001). pLTF was restored after IH-1 by systemic NSAID administration (ketoprofen; 55 +/- 9%; p < 0.001) or spinal p38 MAP kinase inhibition (58 +/- 2%; p < 0.001). IH-1 increased phosphorylated (activated) p38 MAP kinase immunofluorescence in identified phrenic motoneurons and adjacent microglia. In conclusion, IH-1 elicits spinal inflammation and impairs pLTF by a spinal p38 MAP kinase-dependent mechanism. By targeting inflammation, we may develop strategies to manipulate respiratory motor plasticity for therapeutic advantage when the respiratory control system is compromised (e.g., sleep apnea, apnea of prematurity, spinal injury, or motor neuron disease). PMID- 25926465 TI - Enhanced Firing in NTS Induced by Short-Term Sustained Hypoxia Is Modulated by Glia-Neuron Interaction. AB - Humans ascending to high altitudes are submitted to sustained hypoxia (SH), activating peripheral chemoreflex with several autonomic and respiratory responses. Here we analyzed the effect of short-term SH (24 h, FIO210%) on the processing of cardiovascular and respiratory reflexes using an in situ preparation of rats. SH increased both the sympatho-inhibitory and bradycardiac components of baroreflex and the sympathetic and respiratory responses of peripheral chemoreflex. Electrophysiological properties and synaptic transmission in the nucleus tractus solitarius (NTS) neurons, the first synaptic station of afferents of baroreflexes and chemoreflexes, were evaluated using brainstem slices and whole-cell patch-clamp. The second-order NTS neurons were identified by previous application of fluorescent tracer onto carotid body for chemoreceptor afferents or onto aortic depressor nerve for baroreceptor afferents. SH increased the intrinsic excitability of NTS neurons. Delayed excitation, caused by A-type potassium current (IKA), was observed in most of NTS neurons from control rats. The IKA amplitude was higher in identified second-order NTS neurons from control than in SH rats. SH also blunted the astrocytic inhibition of IKA in NTS neurons and increased the synaptic transmission in response to afferent fibers stimulation. The frequency of spontaneous excitatory currents was also increased in neurons from SH rats, indicating that SH increased the neurotransmission by presynaptic mechanisms. Therefore, short-term SH changed the glia-neuron interaction, increasing the excitability and excitatory transmission of NTS neurons, which may contribute to the observed increase in the reflex sensitivity of baroreflex and chemoreflex in in situ preparation. PMID- 25926464 TI - Nitric oxide signaling is recruited as a compensatory mechanism for sustaining synaptic plasticity in Alzheimer's disease mice. AB - Synaptic plasticity deficits are increasingly recognized as causing the memory impairments which define Alzheimer's disease (AD). In AD mouse models, evidence of abnormal synaptic function is present before the onset of cognitive deficits, and presents as increased synaptic depression revealed only when synaptic homeostasis is challenged, such as with suppression of ryanodine receptor (RyR) evoked calcium signaling. Otherwise, at early disease stages, the synaptic physiology phenotype appears normal. This suggests compensatory mechanisms are recruited to maintain a functionally normal net output of the hippocampal circuit. A candidate calcium-regulated synaptic modulator is nitric oxide (NO), which acts presynaptically to boost vesicle release and glutamatergic transmission. Here we tested whether there is a feedforward cycle between the increased RyR calcium release seen in presymptomatic AD mice and aberrant NO signaling which augments synaptic plasticity. Using a combination of electrophysiological approaches, two-photon calcium imaging, and protein biochemistry in hippocampal tissue from presymptomatic 3xTg-AD and NonTg mice, we show that blocking NO synthesis results in markedly augmented synaptic depression mediated through presynaptic mechanisms in 3xTg-AD mice. Additionally, blocking NO reduces the augmented synaptically evoked dendritic calcium release mediated by enhanced RyR calcium release. This is accompanied by increased nNOS levels in the AD mice and is reversed upon normalization of RyR-evoked calcium release with chronic dantrolene treatment. Thus, recruitment of NO is serving a compensatory role to boost synaptic transmission and plasticity during early AD stages. However, NO's dual role in neuroprotection and neurodegeneration may convert to maladaptive functions as the disease progresses. PMID- 25926466 TI - Subthalamic nucleus activity in the awake hemiparkinsonian rat: relationships with motor and cognitive networks. AB - Oscillatory activity in both beta and gamma ranges has been recorded in the subthalamic nucleus (STN) of Parkinson's disease (PD) patients and linked to motor function, with beta activity considered antikinetic, and gamma activity, prokinetic. However, the extent to which nonmotor networks contribute to this activity is unclear. This study uses hemiparkinsonian rats performing a treadmill walking task to compare synchronized STN local field potential (LFP) activity with activity in motor cortex (MCx) and medial prefrontal cortex (mPFC), areas involved in motor and cognitive processes, respectively. Data show increases in STN and MCx 29-36 Hz LFP spectral power and coherence after dopamine depletion, which are reduced by apomorphine and levodopa treatments. In contrast, recordings from mPFC 3 weeks after dopamine depletion failed to show peaks in 29-36 Hz LFP power. However, mPFC and STN both showed peaks in the 45-55 Hz frequency range in LFP power and coherence during walking before and 21 days after dopamine depletion. Interestingly, power in this low gamma range was transiently reduced in both mPFC and STN after dopamine depletion but recovered by day 21. In contrast to the 45-55 Hz activity, the amplitude of the exaggerated 29-36 Hz rhythm in the STN was modulated by paw movement. Furthermore, as in PD patients, after dopamine treatment a third band (high gamma) emerged in the lesioned hemisphere. The results suggest that STN integrates activity from both motor and cognitive networks in a manner that varies with frequency, behavioral state, and the integrity of the dopamine system. PMID- 25926467 TI - Centrally Delivered BACE1 Inhibitor Activates Microglia, and Reverses Amyloid Pathology and Cognitive Deficit in Aged Tg2576 Mice. AB - Multiple small-molecule inhibitors of the beta-secretase enzyme (BACE1) are under preclinical or clinical investigation for Alzheimer's disease (AD). Prior work has illustrated robust lowering of central amyloid beta (Abeta) after acute administration of BACE1 inhibitors. However, very few studies have assessed the overall impact of chronically administered BACE1 inhibitors on brain amyloid burden, neuropathology, and behavioral function in aged preclinical models. We investigated the effects of a potent nonbrain-penetrant BACE1 inhibitor, delivered directly to the brain using intracerebroventricular infusion in an aged transgenic mouse model. Intracerebroventricular infusion of the BACE1 inhibitor (0.3-23.5 MUg/d) for 8 weeks, initiated in 17-month-old Tg2576 mice, produced dose-dependent increases in brain inhibitor concentrations (0.2-13 MUm). BACE1 inhibition significantly reversed the behavioral deficit in contextual fear conditioning, and reduced brain Abeta levels, plaque burden, and associated pathology (e.g., dystrophic neurites), with maximal effects attained with ~1 MUg/d dose. Strikingly, the BACE1 inhibitor also reversed amyloid pathology below baseline levels (amyloid burden at the start of treatment), without adversely affecting cerebral amyloid angiopathy, microhemorrhages, myelination, or neuromuscular function. Inhibitor-mediated decline in brain amyloid pathology was associated with an increase in microglial ramification. This is the first demonstration of chronically administered BACE1 inhibitor to activate microglia, reverse brain amyloid pathology, and elicit functional improvement in an aged transgenic mouse model. Thus, engagement of novel glial-mediated clearance mechanisms may drive disease-modifying therapeutic benefit with BACE1 inhibition in AD. PMID- 25926468 TI - Modulation of spinal motor output by initial arm postures in anesthetized monkeys. AB - Proper execution of voluntary movement requires a sensorimotor transformation based on the initial limb state. For example, successfully reaching to a stable target requires the recruitment of different muscle groups depending on limb position at movement initiation. To test whether this transformation could occur at the spinal level, we stimulated the cervical spinal cord of anesthetized monkeys while systematically changing initial posture and examined the modulation of the twitch response induced in the upper limb muscles. In three monkeys, a multichannel microelectrode array was implanted into the C6 segment of the spinal cord and electromyographic electrodes were implanted in 12 limb muscles (five hand, four elbow, and three shoulder muscles). The magnitude and onset latency of the evoked response in each electrode-muscle pair were examined by systematically changing the hand position through nine positions in a horizontal plane with the monkey prone. Among 330 electrode-muscle pairs examined, 61% of pairs exhibited significant modulation of either magnitude or latency of twitch responses across different hand/arm configurations (posture dependency). We found that posture dependency occurred preferentially in the distal rather than proximal muscles and was not affected by the location of the electrode within the stimulated spinal segment. Importantly, this posture dependency was not affected by spinalization at the C2 level. These results suggest that excitability in the cervical spinal cord is affected by initial arm posture through spinal reflex pathways. This posture dependency of spinal motor output could affect voluntary arm movement by adjusting descending motor commands relative to the initial arm posture. PMID- 25926469 TI - Age-Dependent Netrin-1 Signaling Regulates NG2+ Glial Cell Spatial Homeostasis in Normal Adult Gray Matter. AB - Neuron-glial antigen 2-positive (NG2(+)) glial cells are the most proliferative glia type in the adult CNS, and their tile-like arrangement in adult gray matter is under tight regulation. However, little is known about the cues that govern this unique distribution. To this end, using a NG2(+) glial cell ablation model in mice, we examined the repopulation dynamics of NG2(+) glial cells in the mature and aged mice gray matter. We found that some resident NG2(+) glial cells that escaped depletion rapidly enter the cell cycle to repopulate the cortex with altered spatial distribution. We reveal that netrin-1 signaling is involved in the NG2(+) glial cell early proliferative, late repopulation, and distribution response after ablation in the gray matter. However, ablation of NG2(+) glial cell in older animals failed to stimulate a similar repopulation response, possibly because of a decrease in the sensitivity to netrin-1. Our findings indicate that endogenous netrin-1 plays a role in NG2(+) glial cell homeostasis that is distinct from its role in myelination. PMID- 25926470 TI - Functional architecture for disparity in macaque inferior temporal cortex and its relationship to the architecture for faces, color, scenes, and visual field. AB - Binocular disparity is a powerful depth cue for object perception. The computations for object vision culminate in inferior temporal cortex (IT), but the functional organization for disparity in IT is unknown. Here we addressed this question by measuring fMRI responses in alert monkeys to stimuli that appeared in front of (near), behind (far), or at the fixation plane. We discovered three regions that showed preferential responses for near and far stimuli, relative to zero-disparity stimuli at the fixation plane. These "near/far" disparity-biased regions were located within dorsal IT, as predicted by microelectrode studies, and on the posterior inferotemporal gyrus. In a second analysis, we instead compared responses to near stimuli with responses to far stimuli and discovered a separate network of "near" disparity-biased regions that extended along the crest of the superior temporal sulcus. We also measured in the same animals fMRI responses to faces, scenes, color, and checkerboard annuli at different visual field eccentricities. Disparity-biased regions defined in either analysis did not show a color bias, suggesting that disparity and color contribute to different computations within IT. Scene-biased regions responded preferentially to near and far stimuli (compared with stimuli without disparity) and had a peripheral visual field bias, whereas face patches had a marked near bias and a central visual field bias. These results support the idea that IT is organized by a coarse eccentricity map, and show that disparity likely contributes to computations associated with both central (face processing) and peripheral (scene processing) visual field biases, but likely does not contribute much to computations within IT that are implicated in processing color. PMID- 25926471 TI - Persistent residual errors in motor adaptation tasks: reversion to baseline and exploratory escape. AB - When movements are perturbed in adaptation tasks, humans and other animals show incomplete compensation, tolerating small but sustained residual errors that persist despite repeated trials. State-space models explain this residual asymptotic error as interplay between learning from error and reversion to baseline, a form of forgetting. Previous work using zero-error-clamp trials has shown that reversion to baseline is not obligatory and can be overcome by manipulating feedback. We posited that novel error-clamp trials, in which feedback is constrained but has nonzero error and variance, might serve as a contextual cue for recruitment of other learning mechanisms that would then close the residual error. When error clamps were nonzero and had zero variance, human subjects changed their learning policy, using exploration in response to the residual error, despite their willingness to sustain such an error during the training block. In contrast, when the distribution of feedback in clamp trials was naturalistic, with persistent mean error but also with variance, a state space model accounted for behavior in clamps, even in the absence of task success. Therefore, when the distribution of errors matched those during training, state-space models captured behavior during both adaptation and error clamp trials because error-based learning dominated; when the distribution of feedback was altered, other forms of learning were triggered that did not follow the state-space model dynamics exhibited during training. The residual error during adaptation appears attributable to an error-dependent learning process that has the property of reversion toward baseline and that can suppress other forms of learning. PMID- 25926472 TI - Neutrophil-Lympocyte Ratio and Cardiovascular Diseases: An Update. PMID- 25926473 TI - Risk factors for cardiac implantable electronic device infection: a systematic review and meta-analysis. AB - Infectious complications after cardiac implantable electronic device (CIED) implantation are increasing over time and are associated with substantial mortality and healthcare costs. The aim of this study was to systematically summarize the literature on risk factors for infection after pacemaker, implantable cardioverter-defibrillator, and cardiac resynchronization therapy device implantation. Electronic searches (up to January 2014) were performed in PubMed, Scopus, and Web of Science databases. Sixty studies (21 prospective, 9 case-control, and 30 retrospective cohort studies) met the inclusion criteria. The average device infection rate was 1-1.3%. In the meta-analysis, significant host-related risk factors for infection included diabetes mellitus (odds ratio (OR) [95% confidence interval] = 2.08 [1.62-2.67]), end-stage renal disease (OR = 8.73 [3.42-22.31]), chronic obstructive pulmonary disease (OR = 2.95 [1.78 4.90]), corticosteroid use (OR = 3.44 [1.62-7.32]), history of the previous device infection (OR = 7.84 [1.94-31.60]), renal insufficiency (OR = 3.02 [1.38 6.64]), malignancy (OR = 2.23 [1.26-3.95]), heart failure (OR = 1.65 [1.14 2.39]), pre-procedural fever (OR = 4.27 [1.13-16.12]), anticoagulant drug use (OR = 1.59 [1.01-2.48]), and skin disorders (OR = 2.46 [1.04-5.80]). Regarding procedure-related factors, post-operative haematoma (OR = 8.46 [4.01-17.86]), reintervention for lead dislodgement (OR = 6.37 [2.93-13.82]), device replacement/revision (OR = 1.98 [1.46-2.70]), lack of antibiotic prophylaxis (OR = 0.32 [0.18-0.55]), temporary pacing (OR = 2.31 [1.36-3.92]), inexperienced operator (OR = 2.85 [1.23-6.58]), and procedure duration (weighted mean difference = 9.89 [0.52-19.25]) were all predictors of CIED infection. Among device-related characteristics, abdominal pocket (OR = 4.01 [2.48-6.49]), epicardial leads (OR = 8.09 [3.46-18.92]), positioning of two or more leads (OR = 2.02 [1.11-3.69]), and dual-chamber systems (OR = 1.45 [1.02-2.05]) predisposed to device infection. This systematic review on risk factors for CIED infection may contribute to developing better infection control strategies for high-risk patients and can also help risk assessment in the management of device revisions. PMID- 25926474 TI - A leadless solution. PMID- 25926475 TI - Electrophysiological studies in patients with paroxysmal supraventricular tachycardias but no electrocardiogram documentation: findings from a prospective registry. AB - AIMS: A significant proportion of patients presenting with paroxysmal supraventricular tachycardia (PSVT) has no electrocardiogram (ECG) documentation. In these patients an electrophysiological study (EPS) may be performed to facilitate the diagnosis. METHODS AND RESULTS: In a prospective registry we compared the prevalence of inducible arrhythmias and the clinical outcome in 525 patients with and without ECG documentation. Compared with patients with a documented PSVT a smaller but substantial proportion of patients (63.7%) without ECG documentation had inducible supraventricular tachycardias (SVT). Atrio ventricular nodal reentrant tachycardia was the most common type in both groups. Patients with an inducible SVT and no documentation were significantly younger, had a shorter episode duration and a lower hospitalization rate, which may be the cause for the lacking documentation. Similar to patients with documented PSVTs most of these patients (90.0%) were asymptomatic or clinically improved after the EPS. Even 43% of patients without an inducible tachycardia improved clinically, probably due to a placebo effect of the EPS. In particular, patients between 31 and 60 years of age seemed to benefit from an EPS because they were more likely to have inducible SVTs that could be cured by radiofrequency ablation. CONCLUSION: Our data show that a substantial proportion of patients with suspected paroxysmal tachycardia, but without ECG documentation, have inducible SVTs and obtain a clear clinical benefit from an EPS. Thus, our data provide justification for using EPS for patients in this category. To the best of our knowledge, ours is the first prospective registry that supports this approach. PMID- 25926476 TI - Preference for oral anticoagulation therapy for patients with atrial fibrillation in Europe in different clinical situations: results of the European Heart Rhythm Association Survey. AB - The purpose of this European Heart Rhythm Association Survey was to assess the clinical practice in relation to the use of oral anticoagulation therapy for patients with atrial fibrillation (AF) in Europe. Of special interest were patients undergoing percutaneous coronary intervention (PCI), cardioversion procedures, catheter ablation, surgery, and those suffering from anticoagulation related bleeding. Of 38 responding centres, non-vitamin K antagonist oral anticoagulants (NOACs) were used for stroke prophylaxis and were preferred (33.3%) or considered equal (48.5%) to vitamin K antagonists (VKAs). Only 3% did not use NOACs at all. There were some practice differences regarding the use of NOACs in combination with dual antiplatelet therapy in AF patients undergoing PCI, and only 12% preferred using NOACs in this setting. Bare metal stents were preferred rather than drug-eluting stents in AF patients at high bleeding risk. There were clear practice differences between centres regarding the use of triple therapy. Most of the major bleeding events would be handled using symptomatic and supportive measures (e.g. mechanical compression, fluid replacement, blood transfusion, prothrombin complex concentrate, or recombinant Factor VIIa). More than 80% of the centres offer either VKA or NOAC for at least 3 weeks before and after cardioversion and 70% offer either VKA or NOAC before and after AF catheter ablation. Patients treated with an NOAC were routinely re-assed in most centres. PMID- 25926477 TI - Dual-hormone changes are related to bargaining performance. AB - In the present research, we found that endogenous testosterone and cortisol changes were jointly related to bargaining outcomes. In a face-to-face competitive negotiation (Study 1) and a laboratory-based bargaining game (Study 2), testosterone rises were associated with high earnings and high relationship quality, but only if cortisol dropped. If cortisol rose, testosterone rises were associated with low earnings and poor relationship quality. Conflict between financial and social goals was related to the financially costly dual-hormone profile (testosterone increase and cortisol increase), whereas the absence of such conflict was related to the financially adaptive dual-hormone profile (testosterone increase and cortisol decrease) [corrected].The findings suggest that when cortisol decreases, rising testosterone is implicated in adaptive bargaining behavior that maximizes earnings and relationship quality. But when cortisol increases, rising testosterone is related to conflict between social and financial motives, weak earnings, and poor relationship quality. These results imply that there are both bright and dark sides to rising testosterone in economic social interactions that depend on fluctuations in cortisol. PMID- 25926478 TI - Modality and morphology: what we write may not be what we say. AB - Written language is an evolutionarily recent human invention; consequently, its neural substrates cannot be determined by the genetic code. How, then, does the brain incorporate skills of this type? One possibility is that written language is dependent on evolutionarily older skills, such as spoken language; another is that dedicated substrates develop with expertise. If written language does depend on spoken language, then acquired deficits of spoken and written language should necessarily co-occur. Alternatively, if at least some substrates are dedicated to written language, such deficits may doubly dissociate. We report on 5 individuals with aphasia, documenting a double dissociation in which the production of affixes (e.g., the -ing in jumping) is disrupted in writing but not speaking or vice versa. The findings reveal that written- and spoken-language systems are considerably independent from the standpoint of morpho-orthographic operations. Understanding this independence of the orthographic system in adults has implications for the education and rehabilitation of people with written-language deficits. PMID- 25926479 TI - The Sound of Intellect: Speech Reveals a Thoughtful Mind, Increasing a Job Candidate's Appeal. AB - A person's mental capacities, such as intellect, cannot be observed directly and so are instead inferred from indirect cues. We predicted that a person's intellect would be conveyed most strongly through a cue closely tied to actual thinking: his or her voice. Hypothetical employers (Experiments 1-3b) and professional recruiters (Experiment 4) watched, listened to, or read job candidates' pitches about why they should be hired. These evaluators rated a candidate as more competent, thoughtful, and intelligent when they heard a pitch rather than read it and, as a result, had a more favorable impression of the candidate and were more interested in hiring the candidate. Adding voice to written pitches, by having trained actors (Experiment 3a) or untrained adults (Experiment 3b) read them, produced the same results. Adding visual cues to audio pitches did not alter evaluations of the candidates. For conveying one's intellect, it is important that one's voice, quite literally, be heard. PMID- 25926480 TI - Bisphosphonate inhibitors reveal a large elasticity of plastidic isoprenoid synthesis pathway in isoprene-emitting hybrid aspen. AB - Recently, a feedback inhibition of the chloroplastic 1-deoxy-D-xylulose 5 phosphate (DXP)/2-C-methyl-D-erythritol 4-phosphate (MEP) pathway of isoprenoid synthesis by end products dimethylallyl diphosphate (DMADP) and isopentenyl diphosphate (IDP) was postulated, but the extent to which DMADP and IDP can build up is not known. We used bisphosphonate inhibitors, alendronate and zoledronate, that inhibit the consumption of DMADP and IDP by prenyltransferases to gain insight into the extent of end product accumulation and possible feedback inhibition in isoprene-emitting hybrid aspen (Populus tremula * Populus tremuloides). A kinetic method based on dark release of isoprene emission at the expense of substrate pools accumulated in light was used to estimate the in vivo pool sizes of DMADP and upstream metabolites. Feeding with fosmidomycin, an inhibitor of DXP reductoisomerase, alone or in combination with bisphosphonates was used to inhibit carbon input into DXP/MEP pathway or both input and output. We observed a major increase in pathway intermediates, 3- to 4-fold, upstream of DMADP in bisphosphonate-inhibited leaves, but the DMADP pool was enhanced much less, 1.3- to 1.5-fold. In combined fosmidomycin/bisphosphonate treatment, pathway intermediates accumulated, reflecting cytosolic flux of intermediates that can be important under strong metabolic pull in physiological conditions. The data suggested that metabolites accumulated upstream of DMADP consist of phosphorylated intermediates and IDP. Slow conversion of the huge pools of intermediates to DMADP was limited by reductive energy supply. These data indicate that the DXP/MEP pathway is extremely elastic, and the presence of a significant pool of phosphorylated intermediates provides an important valve for fine tuning the pathway flux. PMID- 25926481 TI - Unidirectional movement of cellulose synthase complexes in Arabidopsis seed coat epidermal cells deposit cellulose involved in mucilage extrusion, adherence, and ray formation. AB - Cellulose synthase5 (CESA5) synthesizes cellulose necessary for seed mucilage adherence to seed coat epidermal cells of Arabidopsis (Arabidopsis thaliana). The involvement of additional CESA proteins in this process and details concerning the manner in which cellulose is deposited in the mucilage pocket are unknown. Here, we show that both CESA3 and CESA10 are highly expressed in this cell type at the time of mucilage synthesis and localize to the plasma membrane adjacent to the mucilage pocket. The isoxaben resistant1-1 and isoxaben resistant1-2 mutants affecting CESA3 show defects consistent with altered mucilage cellulose biosynthesis. CESA3 can interact with CESA5 in vitro, and green fluorescent protein-tagged CESA5, CESA3, and CESA10 proteins move in a linear, unidirectional fashion around the cytoplasmic column of the cell, parallel with the surface of the seed, in a pattern similar to that of cortical microtubules. Consistent with this movement, cytological evidence suggests that the mucilage is coiled around the columella and unwinds during mucilage extrusion to form a linear ray. Mutations in CESA5 and CESA3 affect the speed of mucilage extrusion and mucilage adherence. These findings imply that cellulose fibrils are synthesized in an ordered helical array around the columella, providing a distinct structure to the mucilage that is important for both mucilage extrusion and adherence. PMID- 25926482 TI - TRANSPARENT TESTA GLABRA1 and GLABRA1 Compete for Binding to GLABRA3 in Arabidopsis. AB - The MBW (for R2R3MYB, basic helix-loop-helix [bHLH], and WD40) genes comprise an evolutionarily conserved gene cassette that regulates several traits such as (pro)anthocyanin and anthocyanin biosynthesis and epidermal cell differentiation in plants. Trichome differentiation in Arabidopsis (Arabidopsis thaliana) is governed by GLABRA1 (GL1; R2R3MYB), GL3 (bHLH), and transparent TESTA GLABRA1 (TTG1; WD40). They are thought to form a trimeric complex that acts as a transcriptional activation complex. We provide evidence that these three MBW proteins form either GL1 GL3 or GL3 TTG1 dimers. The formation of each dimer is counteracted by the respective third protein in yeast three-hybrid assays, pulldown experiments (luminescence-based mammalian interactome), and fluorescence lifetime imaging microscopy-fluorescence resonance energy transfer studies. We further show that two target promoters, Triptychon (TRY) and CAPRICE (CPC), are differentially regulated: GL1 represses the activation of the TRY promoter by GL3 and TTG1, and TTG1 suppresses the activation of the CPC promoter by GL1 and GL3. Our data suggest that the transcriptional activation by the MBW complex involves alternative complex formation and that the two dimers can differentially regulate downstream genes. PMID- 25926483 TI - DIR-visible grey matter lesions and atrophy in multiple sclerosis: partners in crime? AB - BACKGROUND: The extent and clinical relevance of grey matter (GM) pathology in multiple sclerosis (MS) are increasingly recognised. GM pathology may present as focal lesions, which can be visualised using double inversion recovery (DIR) MRI, or as diffuse pathology, which can manifest as atrophy. It is, however, unclear whether the diffuse atrophy centres on focal lesions. This study aimed to determine if GM lesions and GM atrophy colocalise, and to assess their independent relationship with motor and cognitive deficits in MS. METHODS: Eighty people with MS and 30 healthy controls underwent brain volumetric T1-weighted and DIR MRI at 3 T, and had a comprehensive neurological and cognitive assessment. Probability mapping of GM lesions marked on the DIR scans and voxel- based morphometry (assessing GM atrophy) were carried out. The associations of GM lesion load and GM volume with clinical scores were tested. RESULTS: DIR-visible GM lesions were most commonly found in the right cerebellum and most apparent in patients with primary progressive MS. Deep GM structures appeared largely free from lesions, but showed considerable atrophy, particularly in the thalamus, caudate, pallidum and putamen, and this was most apparent in secondary progressive patients with MS. Very little co-localisation of GM atrophy and lesions was seen, and this was generally confined to the cerebellum and postcentral gyrus. In both regions, GM lesions and volume independently correlated with physical disability and cognitive performance. CONCLUSIONS: DIR detectable GM lesions and GM atrophy do not significantly overlap in the brain but, when they do, they independently contribute to clinical disability. PMID- 25926484 TI - Direct Detection of Influenza A and B Viruses in Less Than 20 Minutes Using a Commercially Available Rapid PCR Assay. AB - We compared an FDA-cleared rapid (<20 min) PCR assay (Cobas Liat; Roche Diagnostics) to our routine influenza A and B real-time PCR assay (Simplexa Flu A/B & RSV Direct; Focus Diagnostics) using respiratory swabs (n = 197). The Cobas Liat influenza A and B assays demonstrated sensitivities of 99.2% (123/124) and 100% (23/23), respectively, while showing a specificity of 100% for each target. PMID- 25926485 TI - Efficient Detection of Carbapenemase Activity in Enterobacteriaceae by Matrix Assisted Laser Desorption Ionization-Time of Flight Mass Spectrometry in Less Than 30 Minutes. AB - The recognition of carbapenemase-producing Enterobacteriaceae (CPE) isolates is a major laboratory challenge, and their inappropriate or delayed detection may have negative impacts on patient management and on the implementation of infection control measures. We describe here a matrix-assisted laser desorption ionization time of flight (MALDI-TOF)-based method to detect carbapenemase activity in Enterobacteriaceae. After a 20-min incubation of the isolate with 0.5 mg/ml imipenem at 37 degrees C, supernatants were analyzed by MALDI-TOF in order to identify peaks corresponding to imipenem (300 Da) and an imipenem metabolite (254 Da). A total of 223 strains, 77 CPE (OXA-48 variants, KPC, NDM, VIM, IMI, IMP, and NMC-A) and 146 non-CPE (cephalosporinases, extended-spectrum beta-lactamases [ESBLs], and porin defects), were tested and used to calculate a ratio of imipenem hydrolysis: mass spectrometry [MS] ratio = metabolite/(imipenem + metabolite). An MS ratio cutoff was statistically determined to classify strains as carbapenemase producers (MS ratio of >=0.82). We validated this method first by testing 30 of our 223 isolates (15 CPE and 15 non-CPE) 10 times to calculate an intraclass correlation coefficient (ICC of 0.98), showing the excellent repeatability of the method. Second, 43 strains (25 CPE and 18 non-CPE) different from the 223 strains used to calculate the ratio cutoff were used as external controls and blind tested. They yielded sensitivity and specificity of 100%. The total cost per test is <0.10 U.S. dollars (USD). This easy-to-perform assay is time-saving, cost-efficient, and highly reliable and might be used in any routine laboratory, given the availability of mass spectrometry, to detect CPE. PMID- 25926486 TI - Assessment of Reproducibility of Matrix-Assisted Laser Desorption Ionization-Time of Flight Mass Spectrometry for Bacterial and Yeast Identification. AB - Matrix-assisted laser desorption ionization-time of flight (MALDI-TOF) mass spectrometry (MS) has revolutionized the identification of clinical bacterial and yeast isolates. However, data describing the reproducibility of MALDI-TOF MS for microbial identification are scarce. In this study, we show that MALDI-TOF MS based microbial identification is highly reproducible and can tolerate numerous variables, including differences in testing environments, instruments, operators, reagent lots, and sample positioning patterns. Finally, we reveal that samples of bacterial and yeast isolates prepared for MALDI-TOF MS identification can be repeatedly analyzed without compromising organism identification. PMID- 25926487 TI - Sepsis Due to a Novel Urease-Positive Helicobacter Species in a Young Man. AB - We report the first case of sepsis with enterocolitis that was caused by a novel urease-positive Helicobacter species in a young man. The isolate was characterized via 16S rRNA gene sequencing and their biochemical properties, and the patient was successfully treated with short-term antimicrobial therapy; no recurrence was observed. PMID- 25926488 TI - Escherichia coli O-Genotyping PCR: a Comprehensive and Practical Platform for Molecular O Serogrouping. AB - The O serogrouping of pathogenic Escherichia coli is a standard method for subtyping strains for epidemiological studies and enhancing phylogenetic studies. In particular, the identification of strains of the same O serogroup is essential in outbreak investigations and surveillance. In a previous study, we analyzed the O-antigen biosynthesis gene cluster in all known E. coli O serogroups (A. Iguchi et al., DNA Res, 22:101-107, 2015, http://dx.doi.org/10.1093/dnares/dsu043). Based on those results, we have arranged 162 PCR primer pairs for the identification or classification of O serogroups. Of these, 147 pairs were used to identify 147 individual O serogroups with unique O-antigen biosynthesis genes, and the other 15 pairs were used to identify 15 groups of strains (Gp1 to Gp15). Each of these groups consisted of strains with identical or very similar O antigen biosynthesis genes, and the groups represented a total of 35 individual O serogroups. We then used the 162 primer pairs to create 20 multiplex PCR sets. Each set contained six to nine primer pairs that amplify products of markedly different sizes. This genetic methodology (E. coli O-genotyping PCR) allowed for comprehensive, rapid, and low-cost typing. Validation of the PCR system using O serogroup references and wild strains showed that the correct O serogroups were specifically and accurately identified for 100% (182/182) and 90.8% (522/575) of references and wild strains, respectively. The PCR-based system reported here might be a promising tool for the subtyping of E. coli strains for epidemiological studies as well as for the surveillance of pathogenic E. coli during outbreaks. PMID- 25926489 TI - Genome-Based Characterization of Emergent Invasive Neisseria meningitidis Serogroup Y Isolates in Sweden from 1995 to 2012. AB - Invasive meningococcal disease (IMD) caused by Neisseria meningitidis serogroup Y has increased in Europe, especially in Scandinavia. In Sweden, serogroup Y is now the dominating serogroup, and in 2012, the serogroup Y disease incidence was 0.46/100,000 population. We previously showed that a strain type belonging to sequence type 23 was responsible for the increased prevalence of this serogroup in Sweden. The objective of this study was to investigate the serogroup Y emergence by whole-genome sequencing and compare the meningococcal population structure of Swedish invasive serogroup Y strains to those of other countries with different IMD incidence. Whole-genome sequencing was performed on invasive serogroup Y isolates from 1995 to 2012 in Sweden (n = 186). These isolates were compared to a collection of serogroup Y isolates from England, Wales, and Northern Ireland from 2010 to 2012 (n = 143), which had relatively low serogroup Y incidence, and two isolates obtained in 1999 in the United States, where serogroup Y remains one of the major causes of IMD. The meningococcal population structures were similar in the investigated regions; however, different strain types were prevalent in each geographic region. A number of genes known or hypothesized to have an impact on meningococcal virulence were shown to be associated with different strain types and subtypes. The reasons for the IMD increase are multifactorial and are influenced by increased virulence, host adaptive immunity, and transmission. Future genome-wide association studies are needed to reveal additional genes associated with serogroup Y meningococcal disease, and this work would benefit from a complete serogroup Y meningococcal reference genome. PMID- 25926490 TI - Two Rapidly Growing Mycobacterial Species Isolated from a Brain Abscess: First Whole-Genome Sequences of Mycobacterium immunogenum and Mycobacterium llatzerense. AB - Rapidly growing mycobacteria are rarely found in central nervous system infections. We describe a case of polymicrobial infection in a brain abscess including two rapidly growing Mycobacterium species, M. immunogenum and M. llatzerense. The Mycobacterium isolates were distinguishable by molecular methods, and whole-genome sequencing showed <60% pairwise nucleotide identity. PMID- 25926492 TI - Rapid Genotyping of Shigella sonnei by Use of Multiplex High-Resolution Melting. PMID- 25926491 TI - Real-Time PCR Assay for Detection and Differentiation of Shiga Toxin-Producing Escherichia coli from Clinical Samples. AB - Timely accurate diagnosis of Shiga toxin-producing Escherichia coli (STEC) infections is important. We evaluated a laboratory-developed real-time PCR (LD PCR) assay targeting stx1, stx2, and rfbEO157 with 2,386 qualifying stool samples submitted to the microbiology laboratory of a tertiary care pediatric center between July 2011 and December 2013. Broth cultures of PCR-positive samples were tested for Shiga toxins by enzyme immunoassay (EIA) (ImmunoCard STAT! enterohemorrhagic E. coli [EHEC]; Meridian Bioscience) and cultured in attempts to recover both O157 and non-O157 STEC. E. coli O157 and non-O157 STEC were detected in 35 and 18 cases, respectively. Hemolytic uremic syndrome (HUS) occurred in 12 patients (10 infected with STEC O157, one infected with STEC O125ac, and one with PCR evidence of STEC but no resulting isolate). Among the 59 PCR-positive STEC specimens from 53 patients, only 29 (54.7%) of the associated specimens were toxin positive by EIA. LD-PCR differentiated STEC O157 from non O157 using rfbEO157, and LD-PCR results prompted successful recovery of E. coli O157 (n = 25) and non-O157 STEC (n = 8) isolates, although the primary cultures and toxin assays were frequently negative. A rapid "mega"-multiplex PCR (FilmArray gastrointestinal panel; BioFire Diagnostics) was used retrospectively, and results correlated with LD-PCR findings in 25 (89%) of the 28 sorbitol MacConkey agar culture-negative STEC cases. These findings demonstrate that PCR is more sensitive than EIA and/or culture and distinguishes between O157 and non O157 STEC in clinical samples and that E. coli O157:H7 remains the predominant cause of HUS in our institution. PCR is highly recommended for rapid diagnosis of pediatric STEC infections. PMID- 25926493 TI - A Novel Reporter Phage To Detect Tuberculosis and Rifampin Resistance in a High HIV-Burden Population. AB - Improved diagnostics and drug susceptibility testing for Mycobacterium tuberculosis are urgently needed. We developed a more powerful mycobacteriophage (Phi(2)GFP10) with a fluorescent reporter. Fluorescence-activated cell sorting (FACS) allows for rapid enumeration of metabolically active bacilli after phage infection. We compared the reporter phage assay to GeneXpert MTB/RIF for detection of M. tuberculosis and rifampin (RIF) resistance in sputum. Patients suspected to have tuberculosis were prospectively enrolled in Durban, South Africa. Sputum was incubated with Phi(2)GFP10, in the presence and absence of RIF, and bacilli were enumerated using FACS. Sensitivity and specificity were compared to those of GeneXpert MTB/RIF with an M. tuberculosis culture as the reference standard. A total of 158 patients were prospectively enrolled. Overall sensitivity for M. tuberculosis was 95.90% (95% confidence interval (CI), 90.69% to 98.64%), and specificity was 83.33% (95% CI, 67.18% to 93.59%). In acid-fast bacillus (AFB)-negative sputum, sensitivity was 88.89% (95% CI, 73.92% to 96.82%), and specificity was 83.33% (95% CI, 67.18% to 93.59%). Sensitivity for RIF-resistant M. tuberculosis in AFB-negative sputum was 90.00% (95% CI, 55.46% to 98.34%), and specificity was 91.94% (95% CI, 82.16% to 97.30%). Compared to GeneXpert, the reporter phage was more sensitive in AFB smear-negative sputum, but specificity was lower. The Phi(2)GFP10 reporter phage showed high sensitivity for detection of M. tuberculosis and RIF resistance, including in AFB-negative sputum, and has the potential to improve phenotypic testing for complex drug resistance, paucibacillary sputum, response to treatment, and detection of mixed infection in clinical specimens. PMID- 25926494 TI - Microbiological and Clinical Studies of Legionellosis in 33 Patients with Cancer. AB - Legionella, a large group of environmental Gram-negative bacteria, represents an occasional cause of pneumonia. We analyzed the microbiological and clinical features of 33 consecutive cases of Legionella infections that occurred at the University of Texas MD Anderson Cancer Center, Houston, TX, from 2002 to 2014. The Legionella strains were isolated from bronchoscopy specimens (32 strains) and a blood culture (1 strain) and were identified by sequencing analysis of the full length 16S rRNA gene. The 33 strains involved 12 Legionella species or subspecies: 15 strains of L. pneumophila subsp. pneumophila, 3 strains of L. pneumophila subsp. fraseri or L. pneumophila subsp. pascullei, 4 strains of "L. donaldsonii," 3 strains of L. micdadei, and one each of L. bozemanae, L. feeleii, L. gormanii, L. longbeachae, L. maceachernii, L. parisiensis, L. sainthelensi, and Legionella sp. strain D5382. All patients except one asymptomatic carrier showed pneumonia, including one with concurrent bacteremia. Nine patients died, with this infection being the immediate cause of death in six. Twenty-seven patients had underlying hematologic malignancies. Twenty-three patients were leukopenic. Six patients were recipients of allogeneic hematopoietic stem cell transplant, with their infections caused by five Legionella species. Together, these results suggest that diverse Legionella species infect patients with cancer in the Houston area and its vicinity. The five cases of pneumonia due to L. donaldsonii and Legionella sp. D5382 are likely the first reports of human infection with these organisms. PMID- 25926495 TI - Characterization of Full-Length Genomes of Hepatitis B Virus Quasispecies in Sera of Patients at Different Phases of Infection. AB - Hepatitis B virus (HBV) infection results in different clinical presentation due to different levels of immune response. Our study aimed to characterize HBV full length genome quasispecies (QS) in patients with different phases of infection to better understand its pathogenesis. Forty treatment-naive HBV-infected patients were enrolled, including 10 cases of acute hepatitis B (AHB), 9 cases of immunotolerant (IT) HBV carriers, 11 cases of chronic hepatitis B (CHB), and 10 cases of acute-on-chronic liver failure (ACLF). The present study was conducted by clone-based sequencing. QS heterogeneity within each open reading frame was calculated. The mutation frequency index (MFI) and amino acid variations within the large HBsAg, HBcAg, and HBxAg regions were analyzed based on the different infection phases. In total, 606 HBV full-length sequences were obtained. HBV QS had higher heterogeneity in ACLF and CHB than that in IT among chronically infected individuals. AHB patients had the lower QS heterogeneity at onset than those with chronic infection. ACLF patients had the highest frequency of mutations in the core promoter and precore region. A triple mutation (A1762T/G1764A/G1896A) was observed more frequently in genotype C than in genotype B. The MFI indicated that specific peptides of the studied regions had more frequent mutations in ACLF. Furthermore, several amino acid variations, known as T- and B-cell epitopes, were potentially associated with the immunoactive phase of infection. More HBV genome mutations and deletions were observed in patients with more severe diseases, particularly in specific regions of the core and preS regions, the clinical significance and mechanism of which need to be further investigated. PMID- 25926496 TI - Contamination of Ambient Air with Acinetobacter baumannii on Consecutive Inpatient Days. AB - Acinetobacter-positive patients had their ambient air tested for up to 10 consecutive days. The air was Acinetobacter positive for an average of 21% of the days; the rate of contamination was higher among patients colonized in the rectum than in the airways (relative risk [RR], 2.35; P = 0.006). Of the 6 air/clinical isolate pairs available, 4 pairs were closely related according to rep-PCR results. PMID- 25926497 TI - Global Multilocus Sequence Type Analysis of Chlamydia trachomatis Strains from 16 Countries. AB - The Uppsala University Chlamydia trachomatis multilocus sequence type (MLST) database (http://mlstdb.bmc.uu.se) is based on five target regions (non housekeeping genes) and the ompA gene. Each target has various numbers of alleles hctB, 89; CT058, 51; CT144, 30; CT172, 38; and pbpB, 35-derived from 13 studies. Our aims were to perform an overall analysis of all C. trachomatis MLST sequence types (STs) in the database, examine STs with global spread, and evaluate the phylogenetic capability by using the five targets. A total of 415 STs were recognized from 2,089 specimens. The addition of 49 ompA gene variants created 459 profiles. ST variation and their geographical distribution were characterized using eBURST and minimum spanning tree analyses. There were 609 samples from men having sex with men (MSM), with 4 predominating STs detected in this group, comprising 63% of MSM cases. Four other STs predominated among 1,383 heterosexual cases comprising, 31% of this group. The diversity index in ocular trachoma cases was significantly lower than in sexually transmitted chlamydia infections. Predominating STs were identified in 12 available C. trachomatis whole genomes which were compared to 22 C. trachomatis full genomes without predominating STs. No specific gene in the 12 genomes with predominating STs could be linked to successful spread of certain STs. Phylogenetic analysis showed that MLST targets provide a tree similar to trees based on whole-genome analysis. The presented MLST scheme identified C. trachomatis strains with global spread. It provides a tool for epidemiological investigations and is useful for phylogenetic analyses. PMID- 25926498 TI - Effects of Frozen Storage on Detection of Intermediate Vancomycin Susceptibility and Heteroresistance in Methicillin-Resistant Staphylococcus aureus Blood Isolates. PMID- 25926500 TI - Identification of Haemophilus influenzae Type b Isolates by Use of Matrix Assisted Laser Desorption Ionization-Time of Flight Mass Spectrometry. AB - Haemophilus influenzae type b (Hib) is, in contrast to non-type b H. influenzae, associated with severe invasive disease, such as meningitis and epiglottitis, in small children. To date, accurate H. influenzae capsule typing requires PCR, a time-consuming and cumbersome method. Matrix-assisted laser desorption ionization time of flight mass spectrometry (MALDI-TOF MS) provides rapid bacterial diagnostics and is increasingly used in clinical microbiology laboratories. Here, MALDI-TOF MS was evaluated as a novel approach to separate Hib from other H. influenzae. PCR-verified Hib and non-Hib reference isolates were selected based on genetic and spectral characteristics. Mass spectra of reference isolates were acquired and used to generate different classification algorithms for Hib/non-Hib differentiation using both ClinProTools and the MALDI Biotyper software. A test series of mass spectra from 33 Hib and 77 non-Hib isolates, all characterized by PCR, was used to evaluate the algorithms. Several algorithms yielded good results, but the two best were a ClinProTools model based on 22 separating peaks and subtyping main spectra (MSPs) using MALDI Biotyper. The ClinProTools model had a sensitivity of 100% and a specificity of 99%, and the results were 98% reproducible using a different MALDI-TOF MS instrument. The Biotyper subtyping MSPs had a sensitivity of 97%, a specificity of 100%, and 93% reproducibility. Our results suggest that it is possible to use MALDI-TOF MS to differentiate Hib from other H. influenzae. This is a promising method for rapidly identifying Hib in unvaccinated populations and for the screening and surveillance of Hib carriage in vaccinated populations. PMID- 25926502 TI - Assessing Quality of Working Life Among Malaysian Workers. AB - The Work-Related Quality of Life Scale-2 (WRQLS-2) has been used to measure quality of working life (QOWL) in the United Kingdom. In this study, the scale was translated and normalized into Malay. The scale was translated using the back translation method, pretesting, and pilot testing. It was conducted among health care and office workers. It was tested in 3 stages; confirmatory factor analysis at stages 1 and 3 and exploratory factor analysis at stage 2. The Malaysian WRQLS 2 had 5 factors: "General Well-Being," "Job and Career Satisfaction," "Employee Engagement," "Home-Work Interface," and "Stress at Work." The scale showed good convergent and construct validity and also reliability. Perception of good QOWL may differ because of cultural influences and varying work environments. The validated Malaysian WRQLS-2 can be used to determine the QOWL of Malaysian office and health care workers. PMID- 25926499 TI - Naturally Occurring Resistance-Associated Variants of Hepatitis C Virus Protease Inhibitors in Poor Responders to Pegylated Interferon-Ribavirin. AB - The pretherapeutic presence of protease inhibitor (PI) resistance-associated variants (RAVs) has not been shown to be predictive of triple-therapy outcomes in treatment-naive patients. However, they may influence the outcome in patients with less effective pegylated interferon (pegIFN)-ribavirin (RBV) backbones. Using hepatitis C virus (HCV) population sequence analysis, we retrospectively investigated the prevalence of baseline nonstructural 3 (NS3) RAVs in a multicenter cohort of poor IFN-RBV responders (i.e., prior null responders or patients with a viral load decrease of <1 log IU/ml during the pegIFN-RBV lead-in phase). The impact of the presence of these RAVs on the outcome of triple therapy was studied. Among 282 patients, the prevalances (95% confidence intervals) of baseline RAVs ranged from 5.7% (3.3% to 9.0%) to 22.0% (17.3% to 27.3%), depending to the algorithm used. Among mutations conferring a >3-fold shift in 50% inhibitory concentration (IC50) for telaprevir or boceprevir, T54S was the most frequently detected mutation (3.9%), followed by A156T, R155K (0.7%), V36M, and V55A (0.35%). Mutations were more frequently found in patients infected with genotype 1a (7.5 to 23.6%) than 1b (3.3 to 19.8%) (P = 0.03). No other sociodemographic or viroclinical characteristic was significantly associated with a higher prevalence of RAVs. No obvious effect of baseline RAVs on viral load was observed. In this cohort of poor responders to IFN-RBV, no link was found with a sustained virological response to triple therapy, regardless of the algorithm used for the detection of mutations. Based on a cross-study comparison, baseline RAVs are not more frequent in poor IFN-RBV responders than in treatment-naive patients and, even in these difficult-to-treat patients, this study demonstrates no impact on treatment outcome, arguing against resistance analysis prior to treatment. PMID- 25926503 TI - What is the public's role in 'space' policymaking? Images of the public by practitioners of 'space' communication in the United Kingdom. AB - Studies on experts' understanding of the public have mainly focused on the views of scientists. We add to the literature on constructions of the public by analyzing the views of decision-makers, professional science communicators and scientists involved in 'space' communication on the public and public participation in policy. Findings show that contextual situations and roles determine the way the public is conceptualised: the public is sophisticated and knowledgeable to participate in space activities/citizen science, but in matters of policy, a gullible image of the public is brought up. Despite the democratic talk on participation, practitioners delimited public involvement in policy in some way or other to protect their own power and decision-making capabilities. This conception of the public competes with the stated aims of scientific and political institutions for public engagement and the substantive value of public participation, leaving a limited role for the public in space policymaking. PMID- 25926504 TI - Race, vitamin D-binding protein gene polymorphisms, 25-hydroxyvitamin D, and incident diabetes: the Atherosclerosis Risk in Communities (ARIC) Study. AB - BACKGROUND: Low 25-hydroxyvitamin D [25(OH)D] is associated with diabetes, but few studies have examined racially diverse populations while also accounting for key vitamin D-binding protein (DBP) gene polymorphisms. OBJECTIVE: We sought to evaluate whether the association between 25(OH)D and incident diabetes varied by race and important DBP single nucleotide polymorphisms (SNPs). DESIGN: We studied 10,222 adults (8120 whites, 2102 blacks) aged 46-70 y at baseline (1990-1992) from the ARIC (Atherosclerosis Risk in Communities) Study with follow-up for incident diabetes ascertained during study visits conducted in 1993-1995 and 1996 1998. Adjusted HRs and their 95% CIs for diabetes were estimated according to 25(OH)D status. RESULTS: During follow-up there were 750 incident cases of diabetes. The association of 25(OH)D with diabetes varied by race (P-interaction = 0.004). Among whites, the adjusted HR for diabetes corresponding to each additional SD higher 25(OH)D concentration (21.3 nmol/L) was 0.95 (95% CI: 0.91, 0.99). No significant association was observed among blacks (HR: 1.06; 95% CI: 0.99, 1.14). There was evidence that the A allele at rs4588 and the T allele at rs7041, which are reported to be associated with high and low DBP concentrations, respectively, modified the association between 25(OH)D and diabetes among whites (P-interaction < 0.05 for both) but not blacks (P-interaction > 0.50 for both). CONCLUSIONS: In this large, community-based study, low 25(OH)D concentrations were associated with diabetes among whites but not blacks. Interactions by key DBP SNPs varied between genotypes associated with either high or low DBP concentrations among whites but not blacks. Nevertheless, the findings from this prospective study suggest that there are important differences in the association of 25(OH)D with incident diabetes between white and black adults. PMID- 25926505 TI - Greater accordance with the Dietary Approaches to Stop Hypertension dietary pattern is associated with lower diet-related greenhouse gas production but higher dietary costs in the United Kingdom. AB - BACKGROUND: The Dietary Approaches to Stop Hypertension (DASH) diet is a proven way to prevent and control hypertension and other chronic disease. Because the DASH diet emphasizes plant-based foods, including vegetables and grains, adhering to this diet might also bring about environmental benefits, including lower associated production of greenhouse gases (GHGs). OBJECTIVE: The objective was to examine the interrelation between dietary accordance with the DASH diet and associated GHGs. A secondary aim was to examine the retail cost of diets by level of DASH accordance. DESIGN: In this cross-sectional study of adults aged 39-79 y from the European Prospective Investigation into Cancer and Nutrition-Norfolk, United Kingdom cohort (n = 24,293), dietary intakes estimated from food-frequency questionnaires were analyzed for their accordance with the 8 DASH food and nutrient-based targets. Associations between DASH accordance, GHGs, and dietary costs were evaluated in regression analyses. Dietary GHGs were estimated with United Kingdom-specific data on carbon dioxide equivalents associated with commodities and foods. Dietary costs were estimated by using national food prices from a United Kingdom-based supermarket comparison website. RESULTS: Greater accordance with the DASH dietary targets was associated with lower GHGs. Diets in the highest quintile of accordance had a GHG impact of 5.60 compared with 6.71 kg carbon dioxide equivalents/d for least-accordant diets (P < 0.0001). Among the DASH food groups, GHGs were most strongly and positively associated with meat consumption and negatively with whole-grain consumption. In addition, higher accordance with the DASH diet was associated with higher dietary costs, with the mean cost of diets in the top quintile of DASH scores 18% higher than that of diets in the lowest quintile (P < 0.0001). CONCLUSIONS: Promoting wider uptake of the DASH diet in the United Kingdom may improve population health and reduce diet related GHGs. However, to make the DASH diet more accessible, food affordability, particularly for lower income groups, will have to be addressed. PMID- 25926506 TI - Phenylalanine requirements of enterally fed term and preterm neonates. AB - BACKGROUND: Phenylalanine, which is an essential aromatic amino acid, is either used for protein synthesis or irreversibly hydroxylated to tyrosine. The provision of optimal amounts of dietary phenylalanine is not only important for growth and development but might also influence catecholamine synthesis and release rates. The current recommended aromatic amino acid requirement for infants aged 0-6 mo is based on the amino acid content of human milk. OBJECTIVE: We quantified the requirements for phenylalanine in the presence of excess tyrosine (166 or 177 mg/kg per day for term and preterm infants, respectively) for term and preterm neonates by using the indicator amino acid oxidation method with l-[1-(13)C]lysine 2HCl as an indicator. Hence, we determined the minimum obligatory phenylalanine requirement. DESIGN: Fully enterally fed term and preterm infants received randomly graded amounts of phenylalanine (5-177 mg/kg per day) as part of an elemental formula. Data are expressed as means +/- SDs. RESULTS: Twenty term (birth weight: 3.19 +/- 0.34 kg; gestational age: 38.9 +/- 1 wk) and 16 preterm (birth weight: 1.75 +/- 0.17 kg; gestational age: 32.5 +/- 0.6 wk) Asian infants participated at a postnatal age of 17 +/- 8 d. In total, 44 studies were performed. The minimum obligatory phenylalanine requirement was 58 mg/kg per day (95% CI: 38-78 mg/kg per day) and 80 mg/kg per day (95% CI: 40-119 mg/kg per day) for term and preterm infants, respectively. CONCLUSION: The determined mean phenylalanine-requirement estimates are lower than the contents of term and preterm formulas currently on the market. This trial was registered at www.trialregister.nl as NTR1610. PMID- 25926507 TI - Effect of Lactobacillus paracasei subsp. paracasei, L. casei 431 on immune response to influenza vaccination and upper respiratory tract infections in healthy adult volunteers: a randomized, double-blind, placebo-controlled, parallel-group study. AB - BACKGROUND: Probiotics can modulate the immune system in healthy individuals and may help reduce symptoms related to respiratory infections. OBJECTIVE: The objective of the study was to investigate the effect of the probiotic strain Lactobacillus paracasei subsp. paracasei, L. casei 431 (Chr. Hansen A/S) (hereafter, L. casei 431) on immune response to influenza vaccination and respiratory symptoms in healthy adults. DESIGN: A randomized double-blind, placebo-controlled trial was conducted in 1104 healthy subjects aged 18-60 y at 2 centers in Germany and Denmark. Subjects were randomly assigned to receive an acidified milk drink containing >=10(9) colony-forming units of L. casei 431 (n = 553) or placebo (n = 551) for 42 d. After 21 d, subjects received the seasonal influenza vaccination. The primary outcome was seroprotection rate (anti influenza antibody titers by hemagglutination inhibition) 21 d after vaccination. Other outcomes were seroconversion rate and mean titers, influenza A-specific antibodies and incidence, and duration and severity of upper respiratory symptoms. Antibiotic use and use of health care resources were recorded. RESULTS: There was no effect of L. casei 431 on immune responses to influenza vaccination. Generalized linear mixed modeling showed a shorter duration of upper respiratory symptoms in the probiotic group than in the placebo group (mean +/- SD: 6.4 +/- 6.1 vs. 7.3 +/- 9.7 d, P = 0.0059) in the last 3 wk of the intervention period. No statistically significant differences were found for incidence or severity. CONCLUSIONS: Daily consumption of L. casei 431 resulted in no observable effect on the components of the immune response to influenza vaccination but reduced the duration of upper respiratory symptoms. The trial was registered at www.isrctn.com as ISRCTN08280229. PMID- 25926508 TI - Effective translation of current dietary guidance: understanding and communicating the concepts of minimal and optimal levels of dietary protein. AB - Dietitians and health care providers have critical roles in the translation of the dietary guidance to practice. The protein content of diets for adults can be based on the Recommended Dietary Allowance (RDA) of 0.80 g/kg per day. Alternatively, the most recent Dietary Reference Intakes (DRIs) for macronutrients reflect expanded guidance for assessing protein needs and consider the relative relation of absolute amounts of protein, carbohydrate, and fat to total energy intake in the context of chronic disease prevention. The Acceptable Macronutrient Distribution Range (AMDR) reflects the interrelation between the macronutrients and affords dietitians and clinicians additional flexibility in diet planning. Accounting for the caloric value of RDAs for carbohydrate and fat, "flexible calories" emerge as an opportunity to create varied eating plans that provide for protein intakes in excess of the RDA but within the AMDR. Protein Summit 2.0 highlighted the growing body of scientific evidence documenting the benefits of higher protein intakes at amounts approximating twice the RDA, which include promotion of healthy body weight and preservation of lean body mass and functional ability with age. The essential amino acid (EAA) density of a food also emerged as a novel concept analogous to "nutrient density," which can enable the practitioner to calculate the caloric cost associated with a specific protein source to attain the daily requirement of EAAs to accomplish various health outcomes because these indispensable nutrients have a significant role in protein utilization and metabolic regulation. Tailoring recommendations unique to an individual's varying goals and needs remains a challenge. However, flexibility within the application of DRIs to include consideration of the AMDR provides a sound framework to guide practitioners in effective translation of current dietary guidance with a specific regard for the documented benefits of higher protein intakes. PMID- 25926509 TI - Commonly consumed protein foods contribute to nutrient intake, diet quality, and nutrient adequacy. AB - The amount of dietary protein needed to prevent deficiency in most individuals is defined in the United States and Canada by the Recommended Dietary Allowance and is currently set at 0.8 g protein . kg-1 . d-1 for adults. To meet this protein recommendation, the intake of a variety of protein food sources is advised. The goal of this article is to show that commonly consumed food sources of protein are more than just protein but also significant sources of essential nutrients. Commonly consumed sources of dietary protein frequently contribute substantially to intakes of nutrients such as calcium, vitamin D, potassium, dietary fiber, iron, and folate, which have been identified as nutrients of "concern" (i.e., intakes are often lower than recommended). Despite this, dietary recommendations to reduce intakes of saturated fat and solid fats may result in dietary guidance to reduce intakes of commonly consumed food sources of protein, in particular animal-based protein. We propose that following such dietary guidance would make it difficult to meet recommended intakes for a number of nutrients, at least without marked changes in dietary consumption patterns. These apparently conflicting pieces of dietary guidance are hard to reconcile; however, we view it as prudent to advise the intake of high-quality dietary protein to ensure adequate intakes of a number of nutrients, particularly nutrients of concern. PMID- 25926510 TI - Introduction to Protein Summit 2.0: continued exploration of the impact of high quality protein on optimal health. PMID- 25926511 TI - Protein and healthy aging. AB - Our understanding of the potential benefits and challenges of optimizing dietary protein intake in older adults continues to evolve. An overarching hypothesis generated during Protein Summit 2.0 was that consuming an adequate amount of high quality protein at each meal, in combination with physical activity, may delay the onset of sarcopenia, slow its progression, reduce the magnitude of its functional consequences, or all of these. The potential benefits of young and middle-aged adults adopting a diet pattern whereby adequate protein is consumed at each meal as a countermeasure to sarcopenia are presented and discussed. For example, meeting a protein threshold (~25-30 g/meal) represents a promising, yet still largely unexplored dietary strategy to help maintain muscle mass and function. For many older adults, breakfast is a carbohydrate-dominated lower protein meal and represents an opportunity to improve and more evenly distribute daily protein intake. Although both animal and plant-based proteins can provide the required essential amino acids for health, animal proteins generally have a higher proportion of the amino acid leucine. Leucine plays a key role in stimulating translation initiation and muscle protein anabolism and is the focus of ongoing research. Protein requirements should be assessed in the light of habitual physical activity. An evenly distributed protein diet provides a framework that allows older adults to benefit from the synergistic anabolic effect of protein and physical activity. To fully understand the role of dietary protein intake in healthy aging, greater efforts are needed to coordinate and integrate research design and data acquisition and interpretation from a variety of disciplines. PMID- 25926512 TI - The role of protein in weight loss and maintenance. AB - Over the past 20 y, higher-protein diets have been touted as a successful strategy to prevent or treat obesity through improvements in body weight management. These improvements are thought to be due, in part, to modulations in energy metabolism, appetite, and energy intake. Recent evidence also supports higher-protein diets for improvements in cardiometabolic risk factors. This article provides an overview of the literature that explores the mechanisms of action after acute protein consumption and the clinical health outcomes after consumption of long-term, higher-protein diets. Several meta-analyses of shorter term, tightly controlled feeding studies showed greater weight loss, fat mass loss, and preservation of lean mass after higher-protein energy-restriction diets than after lower-protein energy-restriction diets. Reductions in triglycerides, blood pressure, and waist circumference were also reported. In addition, a review of the acute feeding trials confirms a modest satiety effect, including greater perceived fullness and elevated satiety hormones after higher-protein meals but does not support an effect on energy intake at the next eating occasion. Although shorter-term, tightly controlled feeding studies consistently identified benefits with increased protein consumption, longer-term studies produced limited and conflicting findings; nevertheless, a recent meta-analysis showed persistent benefits of a higher-protein weight-loss diet on body weight and fat mass. Dietary compliance appears to be the primary contributor to the discrepant findings because improvements in weight management were detected in those who adhered to the prescribed higher-protein regimen, whereas those who did not adhere to the diet had no marked improvements. Collectively, these data suggest that higher-protein diets that contain between 1.2 and 1.6 g protein . kg-1 . d-1 and potentially include meal-specific protein quantities of at least ~25-30 g protein/meal provide improvements in appetite, body weight management, cardiometabolic risk factors, or all of these health outcomes; however, further strategies to increase dietary compliance with long-term dietary interventions are warranted. PMID- 25926513 TI - Defining meal requirements for protein to optimize metabolic roles of amino acids. AB - Dietary protein provides essential amino acids (EAAs) for the synthesis of new proteins plus an array of other metabolic functions; many of these functions are sensitive to postprandial plasma and intracellular amino acid concentrations. Recent research has focused on amino acids as metabolic signals that influence the rate of protein synthesis, inflammation responses, mitochondrial activity, and satiety, exerting their influence through signaling systems including mammalian/mechanistic target of rapamycin complex 1 (mTORC1), general control nonrepressed 2 (GCN2), glucagon-like peptide 1 (GLP-1), peptide YY (PYY), serotonin, and insulin. These signals represent meal-based responses to dietary protein. The best characterized of these signals is the leucine-induced activation of mTORC1, which leads to the stimulation of skeletal muscle protein synthesis after ingestion of a meal that contains protein. The response of this metabolic pathway to dietary protein (i.e., meal threshold) declines with advancing age or reduced physical activity. Current dietary recommendations for protein are focused on total daily intake of 0.8 g/kg body weight, but new research suggests daily needs for older adults of >=1.0 g/kg and identifies anabolic and metabolic benefits to consuming at least 20-30 g protein at a given meal. Resistance exercise appears to increase the efficiency of EAA use for muscle anabolism and to lower the meal threshold for stimulation of protein synthesis. Applying this information to a typical 3-meal-a-day dietary plan results in protein intakes that are well within the guidelines of the Dietary Reference Intakes for acceptable macronutrient intakes. The meal threshold concept for dietary protein emphasizes a need for redistribution of dietary protein for optimum metabolic health. PMID- 25926515 TI - 60 YEARS OF NEUROENDOCRINOLOGY: Biology of human craniopharyngioma: lessons from mouse models. AB - Adamantinomatous craniopharyngiomas (ACP) are clinically relevant tumours that are associated with high morbidity, poor quality of life and occasional mortality. Human and mouse studies have provided important insights into the biology of these aggressive tumours, and we are starting to understand why, how and when these tumours develop in humans. Mutations in beta-catenin that result in the over-activation of the WNT/beta-catenin signalling pathway are critical drivers of most, perhaps of all, human ACPs. Mouse studies have shown that only pituitary embryonic precursors or adult stem cells are able to generate tumours when targeted with oncogenic beta-catenin, which suggests that the cell context is critical in order for mutant beta-catenin to exert its oncogenic effect. Interestingly, mutant stem cells do not generate the bulk of the tumour cells; instead, they induce tumours in a paracrine manner. Combining basic studies in mice and humans will provide further insights into the biology of these neoplasms and will reveal pathogenic pathways that could be targeted with specific inhibitors for the benefit of patients. These benign tumours may additionally represent a unique model for investigating the early steps that lead to oncogenesis. PMID- 25926514 TI - Functional classification of 15 million SNPs detected from diverse chicken populations. AB - Next-generation sequencing has prompted a surge of discovery of millions of genetic variants from vertebrate genomes. Besides applications in genetic association and linkage studies, a fraction of these variants will have functional consequences. This study describes detection and characterization of 15 million SNPs from chicken genome with the goal to predict variants with potential functional implications (pfVars) from both coding and non-coding regions. The study reports: 183K amino acid-altering SNPs of which 48% predicted as evolutionary intolerant, 13K splicing variants, 51K likely to alter RNA secondary structures, 500K within most conserved elements and 3K from non-coding RNAs. Regions of local fixation within commercial broiler and layer lines were investigated as potential selective sweeps using genome-wide SNP data. Relationships with phenotypes, if any, of the pfVars were explored by overlaying the sweep regions with known QTLs. Based on this, the candidate genes and/or causal mutations for a number of important traits are discussed. Although the fixed variants within sweep regions were enriched with non-coding SNPs, some non synonymous-intolerant mutations reached fixation, suggesting their possible adaptive advantage. The results presented in this study are expected to have important implications for future genomic research to identify candidate causal mutations and in poultry breeding. PMID- 25926516 TI - Properties and clinical utility of topotecan fluorescence: uses for retinoblastoma. AB - Topotecan fluoresces when exposed to ultraviolet (UV) light. Our observations with UV light in retinoblastoma cases has allowed us to minimise and manage inadvertent skin contact, guide periocular injections and leakage from such injections and document conjunctival contact after periocular injection in addition to demonstrating the drug in the vitreous after intravitreal injection. The technique is safe, inexpensive and easy to perform. PMID- 25926517 TI - Preloaded donor corneal lenticules in a new validated 3D printed smart storage glide for Descemet stripping automated endothelial keratoplasty. AB - PURPOSE: To design and validate the efficacy of three-dimensional (3D) printed smart storage glide (SSG) which is capable of preserving and delivering posterior lenticules for Descemet stripping automated endothelial keratoplasty (DSAEK). METHODS: Laboratory investigation (A) was followed by clinical validation (B). Unsuitable corneas for transplantation (n=20) were used for study A. These tissues were cut using a standard microkeratome, punched and loaded into the SSG and preserved for 7 days in transport media. Endothelial cell density (ECD), Trypan blue and Alizarin red staining for endothelial morphology, thickness measurements and glucose uptake, cell apoptosis and immunostaining post preservation were analysed. For study B, clinical grade corneas (n=14) were preloaded in SSG and grafted in patients with indications of Fuchs' dystrophy (n=8), pseudophakic bullous keratopathy (n=3), posterior polymorphous dystrophy (n=2), and previous DSAEK failure (n=1). Standard DSAEK included descemetorhexis under air and bimanual delivery of the tissue under infusion of buffered saline solution through an anterior chamber maintainer placed at the 12 o'clock position. Main outcome measures for study B were less surgical time, best spectacle-corrected visual acuity (BSCVA), speed of visual recovery, and ECD. RESULTS: For study A, an average ECD loss was 2.30+/-3.21%, thickness increased by 30.80+/-20.85% and one-third of glucose was utilised during the preservation phase. Alizarin red showed hexagonality of the cells. Cell apoptosis was not observed and expression of ZO-1 was noted on the preserved tissues. In study B, 25% ECD loss was observed after 6 months. BSCVA improved to 20/25 or better within 3 months after DSAEK. Mean surgical time recorded was 21 min. CONCLUSIONS: This paper describes the development, design, laboratory and clinical validation of a 3D printed SSG which helps to store and deliver posterior lenticules, therefore allowing transportation of quality-controlled precut tissues. PMID- 25926518 TI - Retinal degeneration in autoimmune polyglandular syndrome type 1: a case series. AB - BACKGROUND: Autoimmune polyglandular syndrome type 1 (APS1) is a rare autosomal recessive disorder due to mutations in the AIRE gene. AIM: To report the ocular features and characterise the retinal phenotype in molecularly confirmed APS1. METHOD: This retrospective case series reviewed five molecularly confirmed cases with APS1 known to have ocular involvement (age range: 19 months-44 years; mean follow-up of 8 years). The medical history, ocular history and evaluation, visual field testing, full-field electroretinogram (ERG) and antiretinal antibody results were reviewed. RESULTS: All but one case had decreased vision at first presentation. All cases had peripheral pigmentary retinal changes; macular atrophy was noted in 80% of cases. The most common feature on spectral-domain optical coherence tomography was a disruption of the external limiting membrane and inner segment ellipsoid band (n=3). Fundus autofluorescence imaging demonstrated a parafoveal ring of hyper-autofluorescence (n=1) or a stippled and patchy autofluorescence pattern in the macula (n=1). The visual fields were constricted in all tested patients (n=3). The rod ERG was abnormal in all cases; the relative involvement of rods and cones differed. Four patients who were tested for antiretinal antibodies were found positive by immunohistochemistry (n=3) and/or western blot (n=2). CONCLUSIONS: Photoreceptor degeneration is part of APS1 phenotype and the presence of antiretinal antibodies strongly supports an aetiology similar to that of non-paraneoplastic autoimmune retinopathy. Periodic retinal evaluation and imaging, visual field testing and ERG would assist in monitoring the retinopathy in APS1-related disease. PMID- 25926519 TI - Cataract surgery outcomes at a UK independent sector treatment centre. AB - BACKGROUND/AIMS: The goal of this study was to review cataract surgery outcomes at three independent surgery treatment centres established by the UK Specialist Hospitals (UKSH) and to compare these outcomes with recognised benchmarks. METHODS: All patients who underwent cataract surgery at UKSH between July 2005 and March 2013 were included. Complication rates were obtained using annual quality reports, logbooks kept in operating theatres and outpatient departments, and electronic medical records. Refractive outcomes and biometry results between December 2010 and March 2013 were obtained from electronic medical records. Results were compared with previously published benchmarks. RESULTS: This study reviewed 20,070 cataract surgeries. UKSH had lower rates of several operative complications compared with the Cataract National Dataset benchmark study. These included choroidal haemorrhage, hyphaema, intraocular lens complications, iris damage from phacoemulsification, nuclear fragment into the vitreous, phacoemulsification wound burn, posterior capsule rupture or vitreous loss or both, vitreous in anterior chamber, and zonular dialysis. UKSH had lower rates of postoperative complications including corneal decompensation, cystoid macular oedema, iris to wound, posterior capsule opacification with yttrium aluminium garnet indicated, raised intraocular pressure, retained soft lens matter, uveitis, vitreous to section, and wound leak. Biometry outcomes at UKSH were significantly better than recently published benchmarks from the National Healthcare Service. CONCLUSIONS: This is the first large-scale retrospective study of cataract surgery outcomes in the UK independent sector. The results indicate comparable or lower rates for most complications as compared with data collected in a previously published study. PMID- 25926520 TI - Injury to the Posterior Tibial Tendon After Open Reduction Internal Fixation of the Medial Malleolus. AB - The management of ankle fractures with open reduction and internal fixation (ORIF) has been a proven method to help prevent deformity and posttraumatic arthritis. The incidence of continued ankle pain due to retained hardware after ORIF of ankle fractures has been documented. The goal of this study was to determine if the starting point for medial malleolus screw placement is associated with posterior tibial tendon (PTT) damage when performing ORIF of the medial malleolus. Patients that had ORIF of the medial malleolus and subsequent repair of the PTT with medial malleolar hardware removal were identified. Zones were established and labeled 1 through 3 as described in the literature. This template was used as an overlay on lateral ankle radiographs to analyze the position and assign zones to the medial malleolus screws. Fifteen patients met the inclusion criteria. Three screws were found in zone 1, 11 in zone 2, and 1 in zone 3. The middle and posterior zones (zones 2 and 3) contained 80% of the screws, which may potentially cause risk to the PTT. We conclude that there is an increased probability that medial malleolar hardware in zones 2 and 3 can compromise the PTT. LEVELS OF EVIDENCE: Therapeutic, Level IV: Case series. PMID- 25926521 TI - Glomus Tumors in the Foot: Case Series. AB - Glomus tumors are painful, benign neoplasms that frequently are associated with delayed diagnosis. Commonly in the hand, they rarely present in the foot. The purpose of this case series is to characterize the clinical presentation, radiology, pathology, and surgical outcomes associated with foot glomus tumors. We reviewed our pathology database for patients with foot glomus tumors diagnosed between 1995 and 2013. Medical records including physician notes, pathology, and radiology were reviewed. Eleven patients had foot glomus tumors excised at our institution during the study period. The mean age was 45.4 (range = 28-60) years. One patient was lost to follow-up. Mean follow-up for the remaining 10 patients was 44.7 (range = 3-142) months. Ten tumors were located in the subungual region, while 1 was located in the plantar pulp of the distal phalanx. All patients presented with pain. Point tenderness, cold hypersensitivity, and nail abnormalities were variably documented but frequently present. Four patients had had prior surgery for an ingrown toenail prior to presentation at our institution. Six patients had preoperative magnetic resonance imaging studies, which were diagnostic of glomus tumor in all cases except one. Radiographs failed to provide diagnosis in all 8 patients for whom they were obtained. Postoperatively, all patients had complete symptom relief with no recurrences.In conclusion, this case series demonstrates that foot glomus tumors frequently present with classic symptoms including pain, point tenderness, and cold hypersensitivity. When clinically suspected, magnetic resonance imaging should be obtained. Marginal excision results in symptom relief and cure. LEVEL OF EVIDENCE: Therapeutic, Level IV: Case series. PMID- 25926522 TI - Intestinal epithelium-specific knockout of the cytochrome P450 reductase gene exacerbates dextran sulfate sodium-induced colitis. AB - The potential involvement of intestinal microsomal cytochrome P450 (P450) enzymes in defending against colon inflammation and injury was studied in mice treated with dextran sulfate sodium (DSS) to induce colitis. Wild-type (WT) mice and mice with intestinal epithelium (IE)-specific deletion of the P450 reductase gene (IE Cpr-null) were compared. IE-Cpr-null mice have little microsomal P450 activity in IE cells. DSS treatment (2.5% in drinking water for 6 days) caused more severe colon inflammation, as evidenced by the presence of higher levels of myeloperoxidase and proinflammatory cytokines [tumor necrosis factor-alpha, interleukin (IL)-6, and IL-1beta], and greater weight loss, colonic tissue damage, and colon shortening, in IE-Cpr-null mice than in WT mice. The IE-Cpr null mice were deficient in colonic corticosterone (CC) synthesis, as indicated by the inability of ex vivo cultured colonic tissues from DSS-treated IE-Cpr-null mice (in contrast to DSS-treated WT mice) to show increased CC production, compared with vehicle-treated mice, and by the ability of added deoxycorticosterone (DOC), a precursor of CC biosynthesis via mitochondrial CYP11B1, to restore ex vivo CC production by colonic tissues from DSS-treated null mice. Intriguingly, null (but not WT) mice failed to show increased serum CC levels following DSS treatment. Nevertheless, cotreatment of DSS-exposed mice with DOC, which did not restore DSS-induced increase in serum CC, abolished the hypersensitivity of IE-Cpr-null mice to DSS-induced colon injury. Taken together, our results strongly support the notion that microsomal P450 enzymes in the intestine play an important role in protecting colon epithelium from DSS-induced inflammation and injury, possibly through increased local CC synthesis in response to DSS challenge. PMID- 25926523 TI - Four-month fluoroquinolone-containing regimens are inferior to standard 6-month tuberculosis treatment. PMID- 25926524 TI - Commissioning for COPD care: a new, recordable metric that supports the patient interest. AB - BACKGROUND: Healthcare metrics have been used to drive improvement in outcome and delivery in UK hospital stroke and cardiac care. This model is attractive for chronic obstructive pulmonary disease (COPD) care because of disease frequency and the burden it places on primary, secondary and integrated care services. METHODS: Using 'hospital episode statistics' (UK 'coding'), we examined hospital 'bed days/1000 population' in 150 UK Primary Care Trusts (PCTs) during 2006-07 and 2007-08. Data were adjusted for COPD prevalence. We looked at year-on-year consistency and factors which influenced variation. RESULTS: There were 248 996 COPD admissions during 2006-08. 'Bed days/1000 PCT population' was consistent between years (r = 0.87; P < 0.001). There was a >2-fold difference in bed days between the best and worst performing PCTs which was primarily a consequence of variation in emergency admission rate (P < 0.001) and proportion of emergency admissions due to COPD (P < 0.001) and to only a lesser extent length of hospital stay (P < 0.001). CONCLUSIONS: Bed days/1000 population appears a useful annual metric of COPD care quality. Good COPD care keeps patients active and out of hospital and requires co-ordinated action from both hospital and community services, with an important role for integrated care. This metric demonstrates that current care is highly variable and offers a measurable target to commission against. PMID- 25926525 TI - Analgesic use of inhaled methoxyflurane: Evaluation of its potential nephrotoxicity. AB - Methoxyflurane is a volatile, halogenated analgesic, self-administered in a controlled low dose from the Penthrox((r)) inhaler for short-term pain relief. It was formerly used in significantly higher doses to produce anaesthesia, when it caused a specific type of dose-related renal tubular damage. The pathogenesis of the renal damage and clinical use of methoxyflurane are discussed here with evidence that a low but effective analgesic dose is not associated with the risk of renal adverse effects. The maximum dose employed to produce analgesia is limited to methoxyflurane 6 mL/day and 15 mL/week, producing a minimum alveolar concentration (MAC) of 0.59 MAC-hours. Renal damage is due to the metabolism of methoxyflurane and release of fluoride ions. Exposure of humans to methoxyflurane <=2.0 MAC-hours, resulting in serum fluoride <=40 umol/L, has not been associated with renal tubular toxicity. The safety margin of analgesic use of methoxyflurane in the Penthrox (((r))) inhaler is at least 2.7- to 8-fold, based on methoxyflurane MAC-hours or serum fluoride level, with clinical experience suggesting it is higher. It is concluded from clinical experience in emergency medicine, surgical procedures and various experimental and laboratory investigations that the analgesic use of methoxyflurane in subanaesthetic doses in the Penthrox inhaler does not carry a risk of nephrotoxicity. PMID- 25926526 TI - Radioprotection of 1,2-dimethylhydrazine-initiated colon cancer in rats using low dose gamma rays by modulating multidrug resistance-1, cytokeratin 20, and beta catenin expression. AB - Ionizing radiation is a widely used therapy for solid tumors. However, high-dose ionizing radiation causes apoptosis, transforms normal cells into tumor cells, and impairs immune functions, leading to the defects in the removal of damaged or tumor cells. In contrast, low-dose radiation has been reported to exert various beneficial effects in cells. This experimental study investigated the effect of gamma rays at low dose on the development of colorectal tumor in a 1,2 dimethylhydrazine (DMH)-induced colon cancer. Colorectal tumor model was induced in Wistar rats by subcutaneous injection of DMH (20 mg/kg) once a week for 15 weeks. Starting from zero day of DMH injection, a single low dose of whole-body gamma irradiation of 0.5 Gy/week was applied to the rats. A significant reduction in lipid peroxidation, nitric oxide, and elevation in the glutathione content and antioxidant enzyme activity (superoxide dismutase and catalase) were observed after gamma irradiation comparing with DMH group. Moreover, gamma ray reduced the expressions of multidrug resistance 1 (MDR1), beta-catenin, and cytokeratin 20 (CK20) those increased in DMH-treated rats. However, survivin did not change with gamma ray treatment. A histopathological examination of the DMH-injected rats revealed ulcerative colitis, dysplasia, anaplasia, and hyperchromasia. An improvement in the histopathological picture was seen in the colon of rats exposed to gamma rays. In conclusion, the present results showed that low-dose gamma ray significantly inhibited DMH-induced colon carcinogenesis in rats by modulating CK20, MDR1, and beta-catenin expression but not survivin expression. PMID- 25926527 TI - Identification of riboflavin: revealing different metabolic characteristics between Escherichia coli BL21(DE3) and MG1655. AB - There are many physiological differences between Escherichia coli B and K-12 strains, owing to their different origins. Deeper insight into the metabolic and regulative mechanisms of these strains will inform improved usage of these industrial workhorses. In the present study, we observed that BL21 fermentation broth gradually turned yellow during cultivation. By spectral analysis and liquid chromatography-mass spectrometry identification, we confirmed for the first time that the yellow substance accumulated in the fermentation broth is riboflavin. Comparing the enzyme sequences involved in riboflavin metabolism between BL21 and MG1655, we identified a site mutation on the 115 residue of bifunctional riboflavin kinase/FMN adenylyltransferase (RibF) in BL21. This His115Leu mutation was found to reduce enzyme activity to 55% of that of MG1655, which is probably one reason for riboflavin accumulation in BL21. Quantitative PCR analysis showed that genes of the entire branch of the riboflavin and FAD biosynthesis pathways in BL21 were up-regulated. Several physiological and metabolic characteristics of BL21 and MG1655 were found to be different, and may also be related to the riboflavin accumulation. PMID- 25926528 TI - The effects of red ginseng saponin fraction-A (RGSF-A) on phagocytosis and intracellular signaling in Brucella abortus infected RAW 264.7 cells. AB - This study indicated that RGSF-A caused a marked reduction in the adherence, internalization and intracellular growth of Brucella abortus in RGSF-A-treated cells. Furthermore, a decline in the intensity of F-actin fluorescence was observed in RGSF-A-treated cells compared with untreated B. abortus-infected cells. In addition, an evaluation of phagocytic signaling proteins by Western blot analysis revealed an apparent reduction of ERK and p38alpha phosphorylation levels in B. abortus-infected RGSF-A-treated cells compared with the control. Upon intracellular trafficking of the pathogen, a higher number of B. abortus containing phagosomes colocalized with LAMP-1 in RGSF-A-treated cells compared with control cells. These results strongly suggest that inhibition of B. abortus uptake could be mediated by suppression in the activation of MAPKs signaling proteins phospho-ERK 1/2, and p38 levels. On the other hand, inhibition of intracellular replication results from the enhancement of phagolysosome fusion in host macrophages. This study highlights the phagocytic and intracellular modulating effect of RGSF-A and its potential as an alternative remedy to control B. abortus infection. PMID- 25926529 TI - Laccase-like enzyme activities from chlorophycean green algae with potential for bioconversion of phenolic pollutants. AB - In order to explore the abundance and potential environmental functions of green algal laccases, we screened various algae for extracellular laccase-like activities, characterized basic features of these activities in selected species and exemplarily studied the transformation of environmental pollutants and complex natural compounds by the laccase of Tetracystis aeria. Oxidation of the classical laccase substrate ABTS was found to be widespread in chlorophycean algae. The oxidation activity detected in members of the 'Scenedesmus' clade was caused by an unknown thermostable low-molecular-mass compound. In contrast, species of the Moewusinia, including Chlamydomonas moewusii and T. aeria, excreted putative 'true' laccases. Phenolic substrates were oxidized by these enzymes optimally at neutral to alkaline pH. The Tetracystis laccase efficiently transformed bisphenol A, 17alpha-ethinylestradiol, nonylphenol and triclosan in the presence of ABTS as redox mediator, while anthracene, veratrylalcohol and adlerol were not attacked. Lignosulfonate and humic acid underwent slight (de)polymerization reactions in the presence of the laccase and mediator(s), probably involving the oxidation of phenolic constituents. Possible natural functions of the enzymes, such as the synthesis of complex polymers or detoxification processes, may assist the survival of the algae in adverse environments. In contaminated surface waters, laccase-producing green algae might contribute to the environmental breakdown of phenolic pollutants. PMID- 25926530 TI - The Pseudomonas aeruginosa RhlR-controlled aegerolysin RahU is a low-affinity rhamnolipid-binding protein. AB - The opportunistic pathogen Pseudomonas aeruginosa uses quorum-sensing systems to regulate collective behaviour in response to the environment, by linking the expression of particular genes to population density. The quorum-sensing transcription factors LasR and RhlR and their cognate N-acyl-homoserine lactone (HSL) signals N-3-oxo-dodecanoyl-L-HSL (3OC12-HSL) and N-butanoyl-L-HSL (C4-HSL) control the expression of several hundred genes, which include those involved in virulence and biofilm formation. Here, we have focused on regulation of the expression of the putative virulence factor gene, rahU. We show that the intact las-rhl box immediately upstream of the -35 promoter element is needed for rahU expression in P. aeruginosa. Using beta-galactosidase assays and quantification of the mRNA levels for rahU, lasR and rhlR, we provide evidence that for rahU promoter activity, 3OC12-HSL-LasR is not sufficient, and instead C4-HSL-RhlR is the trigger. Furthermore, surface plasmon resonance analysis revealed that RahU binds the biosurfactant rhamnolipids. Thus, this is the first report of a bacterial molecule that interacts with RahU. PMID- 25926531 TI - Intestinal Cavernous Haemangioma and Ulcerative Colitis: Co-incidence or Association? PMID- 25926532 TI - Systematic versus Endoscopy-driven Treatment with Azathioprine to Prevent Postoperative Ileal Crohn's Disease Recurrence. AB - BACKGROUND AND AIMS: Prophylactic azathioprine (AZA) is efficacious in preventing postoperative Crohn's disease (CD) recurrence. However, it is unknown whether AZA should be started immediately after surgery. We compared the efficacy of systematic vs endoscopy-driven AZA in preventing CD recurrence at week 102. METHODS: This prospective, multicentre trial included CD patients undergoing curative resection with ileocolonic anastomosis and at higher risk of recurrence. Patients were randomized to systematic AZA initiated <=2 weeks from surgery, or endoscopy-driven AZA in which therapy was only initiated in case of endoscopic recurrence (Rutgeerts' score >=i2) at weeks 26 or 52 following surgery. The primary endpoint was endoscopic remission (i0-i1) at week 102. Secondary endpoints included complete endoscopic remission (i0) and clinical remission. RESULTS: The study was prematurely stopped due to slow recruitment. Between 2005 and 2011, 63 patients (28 male, median age 36 years) were randomized to systematic (n = 32) or endoscopy-driven AZA (n = 31). Twenty-one patients withdrew prematurely (8 clinical recurrence, 6 adverse reactions to AZA, 7 patient's preference). In the endoscopy-driven AZA group, 14 patients had to initiate AZA (11 at week 26, 3 at week 52). Endoscopic remission was achieved by 50% in the systematic and 42% in the endoscopy-driven AZA group (p = 0.521). No difference in secondary endpoints was found. CONCLUSIONS: Systematic AZA therapy in patients at higher risk of postoperative CD recurrence is not superior to endoscopy-driven treatment. Early postoperative endoscopic evaluation between weeks 26 and 52 seems most appropriate to guide further therapy, but larger studies are warranted. (ClinicalTrials.gov NCT02247258.). PMID- 25926533 TI - Cardioprotective Effect of Thiazide-Like Diuretics: A Meta-Analysis. AB - BACKGROUND AND PURPOSE: Thiazide diuretics (TD), including thiazide-type (chlorothiazide and hydrochlorothiazide) and thiazide-like diuretics (indapamide and chlorthalidone), have been used for the treatment of hypertension for more than 5 decades. This meta-analysis aimed to evaluate whether TD, including thiazide-type and thiazide-like diuretics have additional cardioprotective effects. EXPERIMENTAL APPROACH: We performed a pooled study of 19 randomized clinical trials (RCTs). PubMed and EMBASE databases were searched for RCTs assessing TD treatment in patients with hypertension. KEY RESULTS: Nineteen RCTs involving 112,113 patients (56,802 in TD; 55,311 in control) were included. The incidence ratio of cardiac events (CVs) was 34.3 vs. 37.8 per 1,000 patient-years in patients randomized to TD and controls, respectively. TD treatment was associated with reductions in the risks of CVs (odds ratio (OR): 0.86, P = 0.007) and heart failure (OR: 0.62, P < 0.001), but not different in stroke (OR: 0.92, P = 0.438) or CHD (OR: 0.95, P = 0.378) between diuretics and controls. Further analysis showed that the observed benefits were mainly confined to thiazide-like diuretic therapy rather than thiazide-type diuretics with a significant reduction in the risk of CVs (OR: 0.78, P < 0.001), heart failure (OR: 0.57, P < 0.001) and stroke (OR: 0.82, P = 0.016). CONCLUSIONS AND IMPLICATIONS: This study suggests that use of TD in hypertensive patients results in a reduction in the risk of CVs. Moreover, thiazide-like diuretics have greater protective effect against CVs than thiazide-type diuretics, especially on heart failure, suggesting that preferential use of thiazide-like diuretics over thiazide-type diuretics may result in greater cardiovascular benefits in hypertensive patients. PMID- 25926534 TI - Sap flow as a key trait in the understanding of plant hydraulic functioning. PMID- 25926535 TI - [Peripheral nerve entrapment neuropathy for neurosurgeon]. PMID- 25926536 TI - [Endoscopic endonasal skull base surgery using a four hands technique]. PMID- 25926537 TI - [Radiation Dose to Patients Undergoing X-ray Diagnosis, Treatment and Follow-up for Cerebral Aneurysms]. AB - This study aimed to evaluate radiation doses to patients undergoing X-ray diagnosis, treatment, and follow-up for cerebral aneurysms. Radiation doses were measured for computed tomography angiography (CTA), cerebral angiography (CAG), and interventional neuroradiology (IVNR) by using small-sized silicon-photodiode dosimeters, which were implanted at various tissue and organ positions within an anthropomorphic phantom. Lens doses, brain doses, and effective doses obtained in this study were 26mGy, 67mGy, and 4.6mSv for CAG;77mGy, 250mGy, and 8.7mSv for IVNR;and 56mGy, 53mGy, and 1.5mSv for CTA. Entrance skin dose associated with mean fluoroscopy time and digital subtraction angiography frame was 0.82Gy for IVNR, which was less than the threshold dose of 2Gy for the onset of skin injury. The lens doses obtained with CTA, including non-contrast CT, was 106mGy, which was a factor of 4 higher than the dose of 26mGy for CAG. Effective dose for CTA was 1.5mSv compared to 4.5mSv for CAG. Patients with cerebral aneurysms received a cumulative lens dose of 543mGy throughout 3 years follow-up, which was over the estimated threshold of 0.5Gy for cataracts. PMID- 25926538 TI - [Long-term Results Regarding the Instability of Decompressive Surgery without Fusion for Degenerative Spondylolisthesis]. AB - PURPOSE: The long-term results of decompressive surgery for degenerative spondylolisthesis (DS) were evaluated with reference to instability. MATERIALS AND METHODS: Patients (n=48) undergoing decompressive surgery without fusion were studied. The diagnosis of spondylolisthesis was made based on the presence of sagittal vertebral slippage greater than 3mm. Instability was defined as translation more than 2mm on lateral functional radiography. Surgical interventions were divided into two groups: bilateral laminotomy (n=25)and laminectomy (n=23). Clinical results were evaluated according to the McCulloch's classification and Japanese Orthopedic Association(JOA)score. RESULTS: Of 48 patients, 25 showed preoperative instability. Eleven patients showed both pre-and postoperative instability. The mean pre-and postoperative slippages were 7.5 and 7.6mm, respectively. Of 23 patients without preoperative instability, nine developed postoperative instability. In this group, slippage changed from 6.2 to 6.1mm. Instability was not related to slippage progression. Surgical results of patients undergoing laminotomy were superior to those undergoing laminectomy. The mean pre-and postoperative JOA scores and recovery rate were 14.5, 20.9, and 63.1 in instability group patients with laminotomy and 15.6, 23.2, and 59.0 in the non instability group, respectively. Surgical results were similar and not related to preoperative instability. Low back pain (LBP) showed no correlation to the degree of slippage, instability, and surgery type. LBP improved in each group. CONCLUSIONS: Instability, defined by vertebral translation on lateral functional radiography, did not affect the surgical results of patients with DS treated with laminotomy. PMID- 25926539 TI - [Dural cavernous angioma:a case report and review of the literature]. AB - Here, we report a case of dural cavernous angioma. A 54-year-old man presented with headache in his right frontal area for the previous few weeks. Computed tomography (CT) and magnetic resonance imaging revealed a well-demarcated extramedullary mass, 3 x 2.5cm in size, within the subdural space at the right frontal region. The mass was not enhanced on a contrast-enhanced CT scan, and heterogeneously enhanced after administration of Gd-DTPA on magnetic resonance images. Cerebral angiography revealed an avascular mass. Right frontal craniotomy was performed. On surgery, the mass was found to be mainly extramedullar, and partially intramedullar. No adhesion between the mass and the overlying dura was observed. It was removed in an en bloc fashion. The pathological diagnosis was cavernous angioma. The patient's headache was resolved soon after surgery. Cavernous angiomas are usually intramedullar in the subcortical white matter of the cerebral hemispheres;extramedullary cavernous angiomas are rare. Extramedullary dural cavernous angiomas located in the subdural space at the cerebral convexity are extremely rare. They usually present with headache or mass signs, and resemble meningioma radiologically. During surgery they are easily resected with minimal blood loss. Dural cavernous angiomas should be considered in the differential diagnosis of intradural extramedullary mass at the cerebral convexity. PMID- 25926540 TI - [Ruptured giant fusiform anterior cerebral artery aneurysm treated by proximal clipping with a3-a3 bypass:case report]. AB - Giant fusiform aneurysm of the anterior cerebral artery (ACA) involving the anterior communicating artery (AcomA) is difficult to treat, and its postoperative course is not well known. We treated a patient with subarachnoid hemorrhage (SAH) due to rupture of a giant fusiform aneurysm of the ACA involving the AcomA. Here we describe its treatment and postoperative course, and review the literature regarding ACA involving an AcomA aneurysm that was treated with bypass surgery. A 65-year-old man presented with sudden onset of headache and vomiting. Computed tomography (CT) revealed SAH due to rupture of a giant fusiform ACA involving an AcomA aneurysm. He was admitted to the local neurosurgical unit 5 days after symptom onset. After waiting for vasospasm to resolve, he was transferred to our hospital. Three-dimensional CT demonstrated giant fusiform dilatation (25mm in diameter) of the left ACA (A1-A2), and the AcomA was involved. The perforating branches around the aneurysm were not identified. We performed proximal clipping with A3-A3 bypass for protection of reversal flow to the perforating branches of the left ACA. Postoperative magnetic resonance imaging showed a small infarction in part of the left caudate nucleus and the fornix. Cerebral angiogram revealed complete obliteration of the aneurysm. The patient did not experience palsy or aphasia, but he suffered from transient disturbance of frontal lobe function. A few months later, his cognitive function had recovered, and he was able to resume his normal daily life. Although clinicians should monitor for the development of postoperative neurological symptoms, including cognitive dysfunction proximal clipping with A3-A3 bypass was an effective and reliable treatment for ruptured giant fusiform ACA involving an AcomA aneurysm. PMID- 25926541 TI - [Foramen magunum meningioma presented as subarachnoid haemorrhage]. AB - A 59-year-old woman was admitted with to our hospital with a sudden severe headache that had lasted for 5 days. Neck stiffness was present, but no other neurological deficits were present. Subarachnoid hemorrhage and intra-tumor hemorrhage were not noted on a head computed tomography (HCT). The patient's cerebrospinal fluid was xanthochromic. Magnetic resonance imaging (MRI) demonstrated a gadolinium-enhanced tumor with hemorrhagic changes around the foramen magnum. After conservative therapy, MRI showed a decrease in tumor size and a dural tail sign. This tumor was diagnosed as a hemorrhagic meningioma, and was resected with a posterior suboccipital approach. Histology confirmed that this tumor was a benign transitional meningioma with hemorrhagic change. This is a rare case involving benign meningioma onset by hemorrhagic change. Postoperative tumor recurrence was not present. PMID- 25926542 TI - [A Patient with Multiple Endocrine Neoplasia Type1(MEN1)Presenting with Hypoglycemic Attacks]. AB - Here, we report the case of a woman with multiple endocrine neoplasia type 1(MEN1) who experienced hypoglycemic attacks. At the age of 59, she underwent parathyroid tumor resection for hyperparathyroidism. At the age of 65, she presented with dizziness at our hospital. Magnetic resonance imaging (MRI) revealed a left cerebellopontine (CP) angle tumor and a pituitary tumor. The CP angle tumor (acoustic neurionoma) was removed;the pituitary adenoma (prolactinoma) was managed by using bromocriptine. At the age of 77, she lost consciousness and was transferred to a local hospital. Her blood sugar level was 24 mg/dL. Due to the frequent recurrence of hypoglycemic attacks, she was readmitted to our hospital. MRI revealed the almost complete removal of the acoustic tumor and that her pituitary gland was atrophied. Despite her baseline pituitary hormone levels being normal, we suspected panhypopituitarism and administered cortisol (15 mg/day). As her hypoglycemia failed to improve, we performed a 75-g oral glucose tolerance test, and its result was not indicative of diabetes mellitus. Her pretest immunoreactive insulin (IRI) level was 6.8MUU/mL;DeltaIRI/DeltaBS was 0.62, indicative of insulin hypersecretion. Contrast-enhanced abdominal computed tomography revealed multiple pancreatic tumors (insulinomas), and she underwent resection of the uncal tumor and pancreas body and tail. Her postoperative IRI level was normalized and she experienced no further hypoglycemic attacks. Based on her hyperparathyroidism, pancreatic tumor, and pituitary adenoma, we diagnosed her with MEN1. PMID- 25926543 TI - [Multiple and simultaneous intracranical hemorrhages with homocysteinemia]. AB - A decreased intake of brightly colored vegetables results in increased levels of serum homocysteine, and homocysteinemia is associated with the progression of arteriosclerosis. Moreover, homocysteinemia is a known risk factor for cerebral infarction. Here, we report three cases wherein multiple simultaneous intracranial hemorrhages developed in the presence of homocysteinemia. The dietary habits of the patients involved indicated that decreased intake of brightly colored vegetables and the consequent progression of arteriosclerosis caused intracranial hemorrhage. Thus, in daily medical care, the measurement of serum homocysteine levels is useful for managing dietary habits and progression of arteriosclerosis. PMID- 25926544 TI - [Required knowledge for stroke specialists(10)therapeutic strategy for brain artierovenous malformations]. PMID- 25926545 TI - The Effect of Pressure Glove Tightness on Forearm Muscle Activity and Psychophysical Responses. AB - OBJECTIVE: The impact of pressure glove tightness on maximum grip force, muscle activity, and psychophysical responses is investigated to facilitate the prescription of a suitable reduction factor (RF) for pressure treatment. BACKGROUND: The wearing of pressure therapy gloves is often considered to hinder hand performance and cause discomfort, resulting in unsatisfactory treatment adherence during burn rehabilitation. METHOD: A wear trial was carried out with 10 participants for three custom-made pressure gloves that consist of different RFs-10%, 15% and 20%-as well as for the bare hand. The surface electromyography of three forearm muscles was measured during tasks that involve moving marbles, buttoning a shirt, and typing. The psychophysical responses were also recorded. RESULTS: The use of pressure gloves results in a reduction in the maximum gripping force. Gloves with tighter pressure contribute to lower perceived comfort and ease of hand motion. Increased glove tightness (with RFs of 15% and 20%) decreases muscle activity as compared to the bare-hand condition when buttoning a shirt. In terms of typing, the forearm muscle activity increases with high glove pressure (RF of 20%). CONCLUSION: The forearm muscles are significantly affected by glove tightness in performing different daily tasks that required gripping, pinching, and typing. The increase of RF of pressure gloves causes negative impact on psychophysical response and handgrip strength. Glove tightness in relation to hand performance and comfort is important in prescribing an optimal pressure therapy glove for hypertrophic scar treatment. APPLICATION: The findings give insight into the impacts of pressure glove tightness on muscle activity, thus providing a reference for glove development. PMID- 25926546 TI - Using populations of human and microbial genomes for organism detection in metagenomes. AB - Identifying causative disease agents in human patients from shotgun metagenomic sequencing (SMS) presents a powerful tool to apply when other targeted diagnostics fail. Numerous technical challenges remain, however, before SMS can move beyond the role of research tool. Accurately separating the known and unknown organism content remains difficult, particularly when SMS is applied as a last resort. The true amount of human DNA that remains in a sample after screening against the human reference genome and filtering nonbiological components left from library preparation has previously been underreported. In this study, we create the most comprehensive collection of microbial and reference-free human genetic variation available in a database optimized for efficient metagenomic search by extracting sequences from GenBank and the 1000 Genomes Project. The results reveal new human sequences found in individual Human Microbiome Project (HMP) samples. Individual samples contain up to 95% human sequence, and 4% of the individual HMP samples contain 10% or more human reads. Left unidentified, human reads can complicate and slow down further analysis and lead to inaccurately labeled microbial taxa and ultimately lead to privacy concerns as more human genome data is collected. PMID- 25926547 TI - Thioredoxin system - a novel therapeutic target. AB - Nowadays there are numerous pathogens that have created a resistance to commonly used antibiotics and drugs. Therefore research is focused on finding new therapeutic targets and on determination of their 3D structures that could help in designing new effective substances and inhibitors. Thioredoxin system not only plays a crucial role as thiol/disulfide redox controller, it is also essential for certain organisms as the only system ensuring the redox homeostasis. It is the redox-regulating function, which makes thioredoxin and thioredoxin reductase attractive for scientific research, especially in many studies of diseases caused by redox instability. Thanks to these facts, the proteins of thioredoxin system are suitable candidates for new therapeutic purposes. In this review we summarized the basic features of the thioredoxin system, we justified why the proteins of thioredoxin system are appropriate therapeutical targets and we provided overview of the possibilities of their inhibition by several types of inhibitors. PMID- 25926548 TI - The interrelationship between cholinergic pathway in the magnocellular paraventricular nucleus and natriuresis. AB - The central nervous system is known to play important roles in the regulation of renal sodium excretion. The present study was designed to reveal the interrelationship between cholinergic pathway in the magnocellular paraventricular nucleus (PVN) and the natriuresis induced by brain cholinergic stimuli. The results indicated that urinary sodium excretion was significantly increased at 40 min after intracerebroventricular (ICV) injection of carbachol (CBC). Immunohistochemical studies showed that CBC increased choline acetyltransferase-immunoreactivity (ChAT-IR) in the magnocellular PVN and renal proximal convoluted tubule (PCT), respectively. After pretreatment with atropine, urinary sodium excretion was significantly reduced, and carbachol-increased ChAT IR in the magnocellular PVN and PCT was also significantly decreased. These results suggested that brain cholinergic stimuli induced the natriuresis and increased the activity of cholinergic neurons in the magnocellular PVN and cholinergic system in the PCT. The blockade of muscarinic receptor completely abolished the natriuresis and partially inhibited carbachol-exerted stimulatory effects in the magnocellular PVN and PCT. To summarize, brain cholinergic pathway and peripheral cholinergic system in kidney were found to contribute to the natriuresis following brain cholinergic stimulation. Our findings revealed novel evidence that PVN was involved in the natriuresis via humoral mechanisms. PMID- 25926549 TI - Agonistic effect of selected isoflavones on arylhydrocarbon receptor in a novel AZ-AhR transgenic gene reporter human cell line. AB - The aryl hydrocarbon receptor (AhR) is a ligand-activated transcription factor that controls the expression of a diverse set of genes. Structurally diverse compounds bind to AhR and act as AhR agonists. Well characterised family of natural AhR ligands are isoflavones, which are compounds found predominantly in soy beans or red clover. In this study we have examined agonistic effect of selected isoflavones (genistein, daidzein, biochanin A, formononetin and equol) on AhR in the novel transgenic gene reporter human cell line AZ-AhR, a stably transfected AhR-responsive cell line allowing rapid and sensitive assessment of AhR transcriptional activity. We demonstrated that biochanin A, formononetin and genistein at concentration 10(-4) mol/l exerted agonistic effects on AhR with fold activation of 309- fold, 108-fold and 27-fold, which is about 84.8%, 29.6% and 7.4%, respectively, of the value attained by 2,3,7,8-tetrachlorodibenzo-p dioxin. Daidzein and equol did not show any significant effects on AhR. PMID- 25926550 TI - Cellular and molecular mechanisms underlying the treatment of depression: focusing on hippocampal G-protein-coupled receptors and voltage-dependent calcium channels. AB - Depression is a brain disorder characterized by severe emotional, cognitive, neuroendocrine and somatic dysfunction. Although the latest generation of antidepressant drugs has improved clinical efficacy and safety, the onset of their clinical effect is significantly delayed after treatment commencement, and a large number of patients exhibit inadequate response to these drugs and/or depression relapse even following initially successful treatment. It is therefore essential to develop new antidepressant drugs and/or adjuncts to existing ones. Recent studies suggest that the beneficial effect of antidepressant drugs is mediated, at least in part, via stimulation of adult hippocampal neurogenesis and subsequent increase in hippocampal plasticity. Since the stimulatory effect of antidepressant drugs on hippocampal neurogenesis involves G-protein coupled receptors (GPCR) and voltage-dependent calcium channels (VDCC), greater efficacy may be available if future antidepressant drugs directly target these specific GPCR and VDCC. The potential advantages and limitations of these treatment strategies are discussed in the article. PMID- 25926551 TI - Association analysis of PDE4B polymorphisms with schizophrenia and smooth pursuit eye movement abnormality in a Korean population. AB - Schizophrenia is a debilitating mental disorder with a high heritability rate. Located on chromosome 1p31.3, the human cAMP-specific 3',5'-cyclic phosphodiesterase 4B (PDE4B) gene has been considered as an important candidate gene for the risk of schizophrenia. Several genetic association studies reported the association between PDE4B polymorphisms and the risk of schizophrenia in Caucasian, African American, Indian, and Japanese populations. The aim of this study is to examine the association of PDE4B variations with schizophrenia and smooth pursuit eye movement (SPEM) abnormality in a Korean population. A case control association analysis was carried out by comparing the genotype distribution of eight PDE4B polymorphisms between 457 schizophrenia patients and 386 normal healthy subjects. Differences in the frequency distribution of PDE4B single nucleotide polymorphisms (SNPs) and haplotypes were analyzed by logistic regression analyses controlling for age as a covariate. Statistical analyses revealed nominal significant associations of rs1040716, rs472952, rs1321177, and rs2144719 with the risk of schizophrenia (p = 0.02~0.05). The rs11208756 polymorphism showed a nominal significant association with SPEM abnormality (p = 0.05). In a meta-analysis with Japanese and Korean populations, three SNPs (rs472952, rs1040716, and rs2180335) revealed significant associations with schizophrenia (meta-p value = 0.0038~0.019). Our results support previously reported association of PDE4B variations with schizophrenia in other populations. The findings in this study add a new evidence for the involvement of PDE4B gene in schizophrenia etiology. PMID- 25926552 TI - Carbosulfan-induced oxidative damage following subchronic exposure and the protective effects of N-acetylcysteine in rats. AB - Carbosulfan (CB)-induced oxidative stress leads to the inevitable accumulation of free radicals and eventual alteration of antioxidant enzymes in various biological systems. The present study is designed to investigate the preventive effect of N-acetylcysteine (NAC) on carbosulfan-induced hepatic and renal dysfunction in rats. Rats exposed to CB and NAC were examined for toxicity by assessing various biochemical alteration and stress markers including in liver and kidney. Significant increases of blood alanine aminotransferase (ALT), alkaline phosphatase (ALP), gamma glutamyltransferase (GGT), creatinine and urea were detected in CB-treated rats. In addition, the levels of antioxidative enzymes such as catalase (CAT), superoxide dismutase (SOD) and reduced glutathione (GSH) also were assessed. According to the results, rats exposed to carbosulfan showed a significant increase in the accumulation of stress markers and an alteration in the antioxidative enzymes activity, when compared to their respective controls. Interestingly, administration of NAC to CB-treated rats attenuates the toxicity of this compound, objectified by biochemical and oxidative improvement of liver and kidney. Thus, the present study reports for the first time that NAC could be a promising therapeutic agent against CB induced oxidative stress. PMID- 25926553 TI - Willingness of Certified Health Education Specialists to Conduct Rapid HIV Testing: Results From the Promoting Research on Methods in Screening Expertise Study. AB - BACKGROUND: Approximately 16% of people living with HIV are not aware of their infection. Health education specialists, with their training in health program design, implementation, evaluation, and work with vulnerable communities, may have the necessary expertise to conduct rapid HIV testing (RHT). METHOD: A national, cross-sectional, online survey of Certified Health Education Specialists (CHES) and Master CHES (MCHES) was conducted from April to October 2013, with participants recruited through the National Commission on Health Education Credentialing. We surveyed CHES/MCHES on HIV knowledge and attitudes as well as willingness to conduct RHT. RESULTS: A total of 1,421 CHES/MCHES completed the survey, with a median age of 32 years and median level of 7 years of experience. The majority were White (70.3%), female (91.7%), and heterosexual (93.1%). The majority of respondents had high knowledge of HIV (69.7%), thought that CHES/MCHES should offer RHT (75.2%), and was willing to get trained/certified to conduct RHT (80.3%). Those willing to get trained/certified were more likely to feel comfortable educating clients about HIV prevention methods (p < .001) and planning health promotion programs for people living with HIV (p < .001). Perceived barriers to conducting RHT were related to lack of knowledge of RHT counseling (34.8%) and procedures (25%). CONCLUSIONS: CHES/MCHES have the potential to play a significant role in increasing the availability of HIV testing, and the majority of respondents expressed a willingness to become involved. However, training and implementation barriers were identified. Piloting such an approach should be considered to further evaluate the optimum ways in which expanding HIV testing can be achieved. PMID- 25926554 TI - Therapy of prostate cancer using a novel cancer terminator virus and a small molecule BH-3 mimetic. AB - Despite recent advances, treatment options for advanced prostate cancer (CaP) remain limited. We are pioneering approaches to treat advanced CaP that employ conditionally replication-competent oncolytic adenoviruses that simultaneously produce a systemically active cancer-specific therapeutic cytokine, mda-7/IL-24, Cancer Terminator Viruses (CTV). A truncated version of the CCN1/CYR61 gene promoter, tCCN1-Prom, was more active than progression elevated gene-3 promoter (PEG-Prom) in regulating transformation-selective transgene expression in CaP and oncogene-transformed rat embryo cells. Accordingly, we developed a new CTV, Ad.tCCN1-CTV-m7, which displayed dose-dependent killing of CaP without harming normal prostate epithelial cells in vitro with significant anti-cancer activity in vivo in both nude mouse CaP xenograft and transgenic Hi-Myc mice (using ultrasound-targeted microbubble (MB)-destruction, UTMD, with decorated MBs). Resistance to mda-7/IL-24-induced cell death correlated with overexpression of Bcl-2 family proteins. Inhibiting Mcl-1 using an enhanced BH3 mimetic, BI-97D6, sensitized CaP cell lines to mda-7/IL-24-induced apoptosis. Combining BI-97D6 with Ads expressing mda-7/IL-24 promoted ER stress, decreased anti-apoptotic Mcl 1 expression and enhanced mda-7/IL-24 expression through mRNA stabilization selectively in CaP cells. In Hi-myc mice, the combination induced enhanced apoptosis and tumor growth suppression. These studies highlight therapeutic efficacy of combining a BH3 mimetic with a novel CTV, supporting potential clinical applications for treating advanced CaP. PMID- 25926556 TI - A critical role of nicotinamide phosphoribosyltransferase in human telomerase reverse transcriptase induction by resveratrol in aortic smooth muscle cells. AB - Aging is the predominant risk factor for cardiovascular diseases and contributes to a considerably more severe outcome in patients with acute myocardial infarction. Resveratrol, a polyphenol found in red wine, is a caloric restriction mimetic with potential anti-aging properties which has emerged as a beneficial nutraceutical for patients with cardiovascular disease. Although resveratrol is widely consumed as a nutritional supplement, its mechanism of action remains to be elucidated fully. Here, we report that resveratrol activates human nicotinamide phosphoribosyltransferase (NAMPT), SIRT4 and telomerase reverse transcriptase (hTERT) in human aortic smooth muscle cells. Similar observations were obtained in resveratrol treated C57BL/6J mouse heart and liver tissues. Resverotrol can also augment telomerase activity in both human pulmonary microvascular endothelial cells and A549 cells. Blocking NAMPT and SIRT4 expression prevents induction of hTERT in human aortic smooth muscle cells while overexpression of NAMPT elevates the telomerase activity induced by resveratrol in A549 cells. Together, these results identify a NAMPT-SIRT4-hTERT axis as a novel mechanism by which resveratrol may affect the anti-aging process in human aortic smooth muscle cells, mouse hearts and other cells. These findings enrich our understanding of the positive effects of resveratrol in human cardiovascular diseases. PMID- 25926555 TI - Dysfunctional BLK in common variable immunodeficiency perturbs B-cell proliferation and ability to elicit antigen-specific CD4+ T-cell help. AB - Common Variable Immunodeficiency (CVID) is the most prevalent primary antibody deficiency, and characterized by defective generation of high-affinity antibodies. Patients have therefore increased risk to recurrent infections of the respiratory and intestinal tract. Development of high-affinity antigen-specific antibodies involves two key actions of B-cell receptors (BCR): transmembrane signaling through BCR-complexes to induce B-cell differentiation and proliferation, and BCR-mediated antigen internalization for class-II MHC-mediated presentation to acquire antigen-specific CD4(+) T-cell help.We identified a variant (L3P) in the B-lymphoid tyrosine kinase (BLK) gene of 2 related CVID patients, which was absent in healthy relatives. BLK belongs to the Src-kinases family and involved in BCR-signaling. Here, we sought to clarify BLK function in healthy human B-cells and its association to CVID.BLK expression was comparable in patient and healthy B-cells. Functional analysis of L3P-BLK showed reduced BCR crosslinking-induced Syk phosphorylation and proliferation, in both primary B cells and B-LCLs. B-cells expressing L3P-BLK showed accelerated destruction of BCR-internalized antigen and reduced ability to elicit CD40L-expression on antigen-specific CD4(+) T-cells.In conclusion, we found a novel BLK gene variant in CVID-patients that causes suppressed B-cell proliferation and reduced ability of B-cells to elicit antigen-specific CD4(+) T-cell responses. Both these mechanisms may contribute to hypogammaglobulinemia in CVID-patients. PMID- 25926557 TI - Organ-specific adaptive signaling pathway activation in metastatic breast cancer cells. AB - Breast cancer metastasizes to bone, visceral organs, and/or brain depending on the subtype, which may involve activation of a host organ-specific signaling network in metastatic cells. To test this possibility, we determined gene expression patterns in MDA-MB-231 cells and its mammary fat pad tumor (TMD-231), lung-metastasis (LMD-231), bone-metastasis (BMD-231), adrenal-metastasis (ADMD 231) and brain-metastasis (231-BR) variants. When gene expression between metastases was compared, 231-BR cells showed the highest gene expression difference followed by ADMD-231, LMD-231, and BMD-231 cells. Neuronal transmembrane proteins SLITRK2, TMEM47, and LYPD1 were specifically overexpressed in 231-BR cells. Pathway-analyses revealed activation of signaling networks that would enable cancer cells to adapt to organs of metastasis such as drug detoxification/oxidative stress response/semaphorin neuronal pathway in 231-BR, Notch/orphan nuclear receptor signals involved in steroidogenesis in ADMD-231, acute phase response in LMD-231, and cytokine/hematopoietic stem cell signaling in BMD-231 cells. Only NF-kappaB signaling pathway activation was common to all except BMD-231 cells. We confirmed NF-kappaB activation in 231-BR and in a brain metastatic variant of 4T1 cells (4T1-BR). Dimethylaminoparthenolide inhibited NF kappaB activity, LYPD1 expression, and proliferation of 231-BR and 4T1-BR cells. Thus, transcriptome change enabling adaptation to host organs is likely one of the mechanisms associated with organ-specific metastasis and could potentially be targeted therapeutically. PMID- 25926559 TI - Tri-leaflet mitral valve anatomy: a rare occurrence leading to severe mitral valve regurgitation. PMID- 25926558 TI - Reduction in gap junction intercellular communication promotes glioma migration. AB - Glioblastoma Multiforme (GBM), an aggressive form of adult brain tumor, is difficult to treat due to its invasive nature. One of the molecular changes observed in GBM is a decrease in the expression of the gap junction protein Connexin43 (Cx43); however, how a reduction in Cx43 expression contributes to glioma malignancy is still unclear. In this study we examine whether a decrease in Cx43 protein expression has a role in enhanced cell migration, a key feature associated with increased tumorigenicity. We used a 3D spheroid migration model that mimics the in vivo architecture of tumor cells to quantify migration changes. We found that down-regulation of Cx43 expression in the U118 human glioma cell line increased migration by reducing cell-ECM adhesion, and changed the migration pattern from collective to single cell. In addition gap junction intercellular communication (GJIC) played a more prominent role in mediating migration than the cytoplasmic interactions of the C-terminal tail. Live imaging revealed that reducing Cx43 expression enhanced relative migration by increasing the cell speed and affecting the direction of migration. Taken together our findings reveal an unexplored role of GJIC in facilitating collective migration. PMID- 25926560 TI - Contraception and cardiovascular disease. AB - Contraceptive counselling should begin early in females with heart disease, preferably directly after the start of menstruation. In coming to a decision about the method of contraception, the following issues should be considered: (i) the risk of pregnancy for the mother and the consequences of an unplanned pregnancy; (ii) the risks of the contraceptive method; (iii) failure rates; (iv) the non-contraceptive benefits; (v) the availability; (vi) the individual's preferences; (vii) protection against infection; and (viii) costs. In some women with heart disease, the issues may be complex and require the input of both a cardiologist and an obstetrician (or other feto-maternal expert) to identify the optimal approach. No studies have been performed in women with heart disease to investigate the relative risks and benefits of different contraceptive methods. PMID- 25926561 TI - Severe myocardial ischaemia after neonatal arterial switch operation. PMID- 25926562 TI - Bone marrow-derived mesenchymal stromal cell treatment in patients with severe ischaemic heart failure: a randomized placebo-controlled trial (MSC-HF trial). AB - AIMS: Regenerative treatment with mesenchymal stromal cells (MSCs) has been promising in patients with ischaemic heart failure but needs confirmation in larger randomized trials. We aimed to study effects of intra-myocardial autologous bone marrow-derived MSC treatment in patients with severe ischaemic heart failure. METHODS AND RESULTS: The MSC-HF trial is a randomized, double blind, placebo-controlled trial. Patients were randomized 2 : 1 to intra myocardial injections of MSC or placebo, respectively. The primary endpoint was change in left ventricular end-systolic volume (LVESV), measured by magnetic resonance imaging or computed tomography at 6 months follow-up. Sixty patients aged 30-80 years with severe ischaemic heart failure, New York Heart Association (NYHA) classes II-III, left ventricular ejection fraction (LVEF) <45% and no further treatment options were randomized. Fifty-five patients completed the 6 month follow-up (37 MSCs vs. 18 placebo). At 6 months, LVESV was reduced in the MSC group: -7.6 (95% CI -11.8 to -3.4) mL (P = 0.001), and increased in the placebo group: 5.4 (95% CI -0.4 to 11.2) mL (P = 0.07). The difference between groups was 13.0 (95% CI 5.9-20.1) mL (P = 0.001). Compared with placebo, there were also significant improvements in LVEF of 6.2% (P<0.0001), stroke volume of 18.4 mL (P < 0.0001), and myocardial mass of 5.7 g (P = 0.001). No differences were found in NYHA class, 6-min walking test and Kansas City cardiomyopathy questionnaire. No side effects were identified. CONCLUSION: Intra-myocardial injections of autologous culture expanded MSCs were safe and improved myocardial function in patients with severe ischaemic heart failure. STUDY REGISTRATION NUMBER: NCT00644410 (ClinicalTrials.gov). PMID- 25926563 TI - Structure of the K12 capsule containing 5,7-di-N-acetylacinetaminic acid from Acinetobacter baumannii isolate D36. AB - The repeat unit of the K12 capsular polysaccharide isolated from the Acinetobacter baumannii global clone 1 clinical isolate, D36, was elucidated by means of chemical and spectroscopical methods. The structure was shown to contain N-acetyl-D-galactosamine (D-GalpNAc), N-acetyl-D-fucosamine and N-acetyl-L fucosamine linked together in the main chain, with the novel sugar, 5,7 diacetamido-3,5,7,9-tetradeoxy-L-glycero-L-altro-non-2-ulosonic acid (5,7-di-N acetylacinetaminic acid or Aci5Ac7Ac), attached to D-GalpNAc as a side branch. This matched the sugar composition of the K12 capsule and the genetic content of the KL12 capsule gene cluster reported previously. D-FucpNAc was predicted to be the substrate for the initiating transferase, ItrB3, with the Wzy polymerase making a alpha-D-FucpNAc-(1 -> 3)-D-GalpNAc linkage between the repeat units. The three glycosyltransferases encoded by KL12 are all retaining glycosyltransferases and were predicted to form specific linkages between the sugars in the K12 repeat unit. PMID- 25926565 TI - Why and how inequality matters. AB - In this article, I share some thoughts about how we might extend the study of mental health inequalities by drawing from key insights in sociology and sociological social psychology about the nature of inequality and the processes through which it is produced, maintained, and resisted. I suggest several questions from sociological research on stratification that could help us understand unexpected patterns of mental health inequalities. I also advocate for the analysis of "generic" social psychological processes through which inequalities are produced, maintained, and resisted within proximate social environments. I consider the role of two such processes--status/devaluation processes and identity processes--in mental health inequalities. I then discuss how we can strengthen connections across subfields of the sociology of mental health by applying status and identity theories to two areas of research: (1) help-seeking and (2) the effects of mental health problems on social attainments. PMID- 25926564 TI - Cumulative inequality in child health and academic achievement. AB - Our understanding of health and social stratification can be enriched by testing tenets of cumulative inequality theory that emphasize how the accumulation of inequality is dependent on the developmental stage being considered, the duration and stability of poor health, and the family resources available to children. I analyze longitudinal data from the British National Child Development Study (N = 9,252) to ask: (1) if child health is a source of cumulative inequality in academic achievement, (2) whether this relationship depends on the timing and duration of poor health, and (3) whether trajectories are sensitive to levels of family capital. The results suggest that the relationship between health and academic achievement emerges very early in life and persists and that whether we observe shrinking or widening inequality as children age depends on when we measure their health and whether children have access to compensatory resources. PMID- 25926566 TI - [Vascular Calcification - Pathological Mechanism and Clinical Application - . Mechanisms of vascular calcification]. AB - Vascular calcification is an independent risk factor for the development of cardiovascular disease and is classified into two types based on the site of calcification : intimal atherosclerotic calcification and Monckeberg's medial calcification. Matrix vesicles released from macrophages and vascular smooth muscle cells (VSMC) during apoptosis play a pivotal role in formation of fine granular calcification, while osteogenic differentiation of VSMC contributes to progression of advanced calcification. Recent noninvasive imaging studies of atherosclerotic calcification provide robust evidence that inflammation precedes active calcification, leading to establish the inflammation-dependent calcification paradigm. On the other hand, elastin degradation by increased elastolytic activities and disturbance of regulatory systems of extracellular pyrophosphate metabolism play an important role in development of Monckeberg's medial calcification. PMID- 25926567 TI - [Vascular Calcification - Pathological Mechanism and Clinical Application - . Vascular calcification in chronic kidney disease-mineral and bone disorder (CKD MBD)]. AB - Chronic kidney disease-mineral and bone disorder (CKD-MBD), is sequential pathophysiology that starts in the very early stages of CKD. Three major aspects of CKD-MBD are laboratory abnormalities, bone abnormalities and vascular calcification. In dialysis patients, the prevalence of death due to cardiovascular disease accounts for more than 40% of all-cause mortality. Therefore, arteriosclerosis with vascular calcification may be an important pathophysiological mechanism in the development of cardiovascular disease. Vascular calcification is known to be an important risk factor influencing mortality in CKD patients. A number of studies have suggested a close association between serum FGF23 concentration and the risks of mortality, cardiovascular disease vascular calcification as well as CKD progression. Renal insufficiency leads to decline in klotho level and impaired phosphate excretion. However serum phosphate levels are maintained in the normal range by up regulation of FGF23 and PTH in early CKD stage. Early treatment intervention is necessary to improve the prognosis of the CKD patient. PMID- 25926568 TI - [Vascular Calcification - Pathological Mechanism and Clinical Application - . Vascular calcification as a clinical manifestation of bone-vascular axis]. AB - Several clinical studies has been shown the close relationship between osteoporosis and arteriosclerosis, and basic researches confirmed the reasonability of this association by the findings that organized molecular mechanism of bone formation in bone tissue was also observed in the lesion of vascular calcification, RANK/RANKL/OPG axis is one of potent and explainable molecular mechanism for bone-vascular association. However, one recent clinical intervetion study using RANKL antibody for post menopauisal women with primary osteoporosis could not validate that relationship. Further examinations are needed to improve understanding of the precise mechanism in this area. PMID- 25926569 TI - [Vascular Calcification - Pathological Mechanism and Clinical Application - . Role of vascular smooth muscle cells in vascular calcification]. AB - Vascular calcification is commonly seen with aging, chronic kidney disese (CKD), diabetes, and atherosclerosis, and is closely associated with cardiovascular morbidity and mortality. Vascular calcification has long been regarded as the final stage of degeneration and necrosis of arterial wall and a passive, unregulated process. However, it is now known to be an active and tightly regulated process involved with phenotypic transition of vascular smooth muscle cells (VSMC) that resembles bone mineralization. Briefly, calcium deposits of atherosclerotic plaque consist of hydroxyapatite and may appear identical to fully formed lamellar bone. By using a genetic fate mapping strategy, VSMC of the vascular media give rise to the majority of the osteochondrogenic precursor- and chondrocyte-like cells observed in the calcified arterial media of MGP (- / -) mice. Osteogenic differentiation of VSMC is characterized by the expression of bone-related molecules including bone morphogenetic protein (BMP) -2, Msx2 and osteopontin, which are produced by osteoblasts and chondrocytes. Our recent findings are that (i) Runx2 and Notch1 induce osteogenic differentiation, and (ii) advanced glycation end-product (AGE) /receptor for AGE (RAGE) and palmitic acid promote osteogenic differentiation of VSMC. To understand of the molecular mechanisms of vascular calcification is now under intensive research area. PMID- 25926570 TI - [Vascular Calcification - Pathological Mechanism and Clinical Application - . Vascular calcification in aged mice]. AB - Vascular calcification is a risk factor for cerebral and cardiovascular events and has a high prevalence among elderly. To finding ways of prevent or cure vascular calcification may leads to not only a healthy longevity but also medical expenditure reduction. However, the molecular mechanism underlying this pathogenic process is still obscure. To clarify the mechanism of vascular calcification, the development of animal models that exhibit extensive and robust vascular calcification is an important issue for research in vascular biology. PMID- 25926571 TI - [Vascular Calcification - Pathological Mechanism and Clinical Application - . The significance of arterial calcification in unstable plaques]. AB - Plaque rupture or erosion with subsequent thrombus formation is the principal mechanism underlying the sudden onset of acute coronary syndromes. Plaque inflammation and increased oxidative stress play important roles in the pathogenesis of plaque destabilization. Macrophages, T lymphocytes, and neutrophils are the dominant types of inflammatory cells at human coronary unstable plaques, such as ruptured plaques or eroded plaques. Calcification is a common finding in human atherosclerotic lesions, and arterial calcification is generally classified into calcification within an atherosclerotic plaque, and Monckeberg's medial calcific sclerosis characterized by calcific deposits within the media of small and medium-sized muscular arteries. It has been reported that a spotty pattern of calcification is associated with coronary unstable ruptured plaques in patients with acute myocardial infarction. Patients undergoing hemodialysis (HD) have a high prevalence of arterial calcification and cardiovascular events. We recently demonstrated that plasma oxidized low density lipoprotein (LDL) levels significantly increased after a single HD session. This HD session-related increase in plasma oxidized LDL levels could contribute to the progression and acceleration of atherosclerosis and arterial calcification, leading to the development of cardiovascular events in HD patients. PMID- 25926572 TI - [Vascular Calcification - Pathological Mechanism and Clinical Application - . Regulation of mineral metabolism and mineralization by FGF23]. AB - Fibroblast growth factor 23 (FGF23) decreases serum phosphate by inhibiting proximal tubular phosphate reabsorption and intestinal phosphate absorption through the reduction of serum 1,25-dihydroxyvitamin D [1,25 (OH) (2)D] levels. Excessive actions of FGF23 cause hypophosphatemic diseases with impaired mineralization of bone. On the other hand, impaired actions of FGF23 result in hyperphosphatemic familial tumoral calcinosis characterized by hyperphosphatemia and high 1,25 (OH) (2)D levels. Ectopic calcification around large joints and in blood vessels can be observed in patients with this disease. Therefore, FGF23 plays essential roles in the regulation of bone mineralization and prevention of ectopic calcification. PMID- 25926573 TI - [Vascular Calcification - Pathological Mechanism and Clinical Application - . Vascular calcification in klotho deficient environment]. AB - Klotho deficient (kl/kl) mice exhibit Moncheberg's vascular calcification in the tunica media due to hyperphosphatemia and hypercalcemia by mediating the disrupted signaling of FGF23/klotho axis. Recent studies have hypothesized the mechanism of medial vascular calcification : Vascular smooth muscle cells acquired excessive intake of phosphate ions undergo a phenotypic differentiation into osteoblasts and induce biological calcification in the tunica media. It is useful to clarify the underlying cellular mechanism of vascular calcification for the development of the treatment and preventive medicine. This review will introduce the histological and ultrastructual findings on medial vascular calcification in kl/kl mice. PMID- 25926574 TI - [Vascular Calcification - Pathological Mechanism and Clinical Application - . Extracellular matrix tenascin-X in calcific aortic valves]. AB - We previously disclosed a novel extracellular matrix tenascin-X (TNX) , the largest member of the tenascin family. So far, we have made efforts to elucidate the roles of TNX. TNX is involved in collagen deposition, collagen fibrillogenesis, and modulation of collagen stiffness. Homozygous mutations in TNXB, the gene encoding TNX, cause a classic-type Ehlers-Danlos syndrome (EDS) , a heritable connective tissue disorder, whereas haploinsufficiency of TNXB and heterozygous mutations in TNXB are associated with hypermobility-type EDS. Recently, we performed proteomic analyses of calcific aortic valves (CAVs) compared with relatively adjacent normal tissues to understand the underlying molecular mechanisms of dystrophic valvular calcification. Interestingly, we found that TNX was the protein with the greatest decrease in expression among the differentially expressed proteins and that expression levels of proteins modulating collagen structure and function, such as type I collagen and decorin, were also decreased in CAVs. In this review, I will discuss about the decreased level of collagen due to the reduction of expression levels of proteins that play regulatory roles in collagen functions such as fibril organization and fibrillogenesis in CAVs. PMID- 25926575 TI - [Vascular Calcification - Pathological Mechanism and Clinical Application - . The effect of phosphate binders on vascular calcification]. AB - Vascular calcification is the abnormality in chronic kidney disease-mineral bone disorder (CKD-MBD) that directly affects the prognosis in relation with cardiovascular diseases. Phosphate binders (PB) are widely used to prevent hyperphosphatemia that can lead to vascular calcification. Two types of PB are available ; calcium (Ca) -based PB and non-Ca-based PB. Non-Ca-based PB has been shown to retard the progression of vascular calcification, while there is a great concern that Ca overload can promote calcification. Moreover, the newer non-Ca based PBs have been developed including iron and magnesium. We must pay attention to select proper types of PB with costs, pill burdens and specific circumstances observed in Japan. PMID- 25926576 TI - [Vascular Calcification - Pathological Mechanism and Clinical Application - . Bisphosphonates for vascular calcification]. AB - In Japan, the number of diabetes mellitus and chronic kidney disease patients is increasing yearly. Vascular calcification is prevailing in patients suffering from diabetes mellitus and/or chronic kidney disease, and carries a poor prognosis. However, the effective treatment for suppressing the progression of vascular calcification has not been established. On the other hand, treatment of osteoporosis has advanced dramatically as the details of the mechanism become clearer. Bisphosphonates, which are inhibitors of bone resorption that are widely used to treat osteoporosis, also inhibit cholesterol biosynthesis, differentiation of macrophage to foam cell, differentiation of smooth muscle cells to osteoblast-like cells in certain stimuli during calcification processes of vessels. These findings extend the link between bone remodeling and vascular calcification, opening perspectives toward novel therapeutic strategies. We herein review recent findings about effectiveness of bisphosphonates for vascular calcification with our data. Here we will review recent advances in the researches of treatment of vascular calcification and present our findings that the bisphosphonate is useful in prevention of vascular calcification. PMID- 25926577 TI - [Vascular Calcification - Pathological Mechanism and Clinical Application - . The effect of cinacalcet on vascular calcification]. AB - Cinacalcet acts on calcium receptors (CaR) expressed on chief cells of the parathyroid gland to inhibit the secretion of parathyroid hormone (PTH) . This drug inhibits PTH secretion without causing an elevation of serum calcium and phosphorus, unlike active vitamin D. Several experimental studies demonstrated an inhibitory effect of calcimimetics on the progression of vascular calcification in animals with chronic kidney disease (CKD), in keeping with the expression of the calcium-sensing receptor (CaSR) in vascular tissue. The EVOLVE, evaluated in patients with CKD 5D the effects of the cinacalcet on the progression of vascular calcification and hard cardiovascular outcomes, respectively. The EVOLVE trials missed their respective primary end point by intent-to-treat analysis. However, recently, in order to define the frequency of fatal and nonfatal cardiovascular events attributable to atherosclerotic and nonatherosclerotic mechanisms, risk factors for these events, and the effects of cinacalcet, post hoc analysis using adjudicated data collected during the EVOLVE Trial were perfomed. In this trial, combining fatal and nonfatal cardiovascular events, randomization to cinacalcet reduced the rates of sudden death and heart failure. Patients randomized to cinacalcet experienced fewer nonatherosclerotic cardiovascular events, while the effect of cinacalcet on atherosclerotic events did not reach statistical significance. PMID- 25926578 TI - Ipsilateral supracondylar humerus fracture and Monteggia lesion with a 5-year follow-up: a rare injury in a young girl. AB - Although elbow injuries and fractures of the forearm are common in children, the combination of these injuries is rare. We present a case of a 5-year-old patient with a concomitant ipsilateral supracondylar humerus fracture and Monteggia lesion. After physical and radiographic examination of the injured extremity in the emergency department, closed reduction and percutaneous pinning were performed under image intensifier under general anaesthesia. A long-arm cast was applied for postoperative immobilisation. Excellent radiological and functional outcomes were obtained at the end of 1-year follow-up and no deformity was observed at 5-year follow-up. PMID- 25926580 TI - Dangerous misalignment of tracheostomy tube in a dystonic patient. PMID- 25926579 TI - Sino-nasal mucosal malignant melanoma. AB - A 49-year-old man with a history of left nasal discharge and nasal cavity blockage for 5 months was diagnosed with sino-nasal mucosal malignant melanoma on nasal biopsy. On CT scan, the tumour involved the nasal cavity, left maxillary sinus, ethmoid sinus and medial left orbit. The tumour was grossly excised and adjuvant radiation therapy was offered. The patient was planned for an Intensity Modulated Radiotherapy technique to keep tolerance doses of organs at risk within normal limits and at same time deliver the intended dose of radiation to the tumour site, using 66 Gy in 33 fractions. Owing to the anatomical complexity of the sino-nasal region, precision radiotherapy (RT) is mandatory to optimally irradiate the tumour area while sparing critical surrounding normal structures from late toxicity of RT. Established dose constraints for at-risk organs can only be accomplished through this novel technique of RT. However, despite advances in techniques, current treatment modalities have not significantly made an impact on survival of these patients. PMID- 25926581 TI - Cardiac tamponade as presenting symptom of tuberculosis. PMID- 25926582 TI - A giant prolactinoma with nasopharyngeal extension presenting with nasal blockage and epistaxis. PMID- 25926583 TI - Steroid unresponsive anti-NMDA receptor encephalitis during pregnancy successfully treated with plasmapheresis. AB - Anti-N-methyl-d-aspartate (NMDA) receptor encephalitis is an autoimmune disorder resulting in neurological and psychiatric symptoms. It is rare during pregnancy and treatment is extremely challenging as little data exist to guide management. A 26-year-old woman presented at 22 weeks of gestation with intermittent headache and an acute episode of bizarre behaviour and grandiose delusions resulting in hospitalisation. The patient was worked up for encephalitis and was found to have anti-NMDA receptor antibody in cerebrospinal fluid as well as in serum. She was initially treated with high-dose steroids but failed to improve clinically and serologically. She was then treated with plasmapheresis and showed clinical and serological response. She had a successful delivery at 37 weeks and the baby did not show serological evidence of disease. This case adds to the sparse literature of anti-NMDA receptor encephalitis during pregnancy and adds to the differential diagnosis of new onset psychiatric symptoms during pregnancy. PMID- 25926584 TI - Life-threatening opioid toxicity from a fentanyl patch applied to eczematous skin. AB - A 19-year-old man with a history of eczema was admitted to the emergency department following collapsing at home. The paramedics found him unresponsive with poor respiratory effort and a widespread erythematous rash. Anaphylaxis, thought to be secondary to flucloxacillin he had recently been prescribed, was diagnosed. Epinephrine, steroids and antihistamines were administered without clinical improvement. On arrival to hospital, constricted pupils were noted prompting the emergency physicians to consider opiate toxicity. Intravenous naloxone brought about an immediate recovery. His father subsequently disclosed that he had given his son one of his own fentanyl patches to alleviate the distressing symptoms of eczema. Although the patient had removed the patch prior to collapsing, he had suffered life-threatening opioid toxicity likely due to enhanced opiate absorption through eczematous skin. This case highlights the risks associated with fentanyl patches in patients with chronic skin conditions. PMID- 25926585 TI - Emergency reversal of dabigatran for emergency surgery. AB - An 80-year-old woman had the anticoagulant effect of dabigatran etexilate reversed using factor eight inhibitor bypassing activity (FEIBA) in order to facilitate emergency surgery for an incarcerated femoral hernia. She had atrial fibrillation was taking the anticoagulant for stroke prevention. That afternoon her international normalised ratio (INR) was 1.3 and activated partial thromboplastin time ratio (APPTr) was 2.17, having taken dabigatran that morning. 3000 units of FEIBA and 10 mg of vitamin K were administered and she was taken to theatre for emergency surgery. Surgery was successful, total blood loss was less than 100 mL and there were no complications. The following morning she had an INR of 1.1 and APPTr of 1.49. She made an uneventful postoperative recovery and was discharged home. There is a limited evidence base guiding practice in the clinical scenario described. The only controlled studies available are animal experiments. PMID- 25926586 TI - Endoscopic pedicled nasoseptal flap repair of spontaneous sphenoid sinus cerebrospinal fluid leaks. AB - Spontaneous cerebrospinal fluid (CSF) leaks in the sphenoid sinus are an uncommon but potentially significant condition associated with thin pneumatised bone, obesity and raised intracranial pressure. Despite advances in endoscopic sinus surgery, successful repair remains problematic due to limitations in visualisation, access and management of underlying aetiological factors. Utilisation of vascularised tissue in the primary repair process of sphenoid CSF leaks is yet to be well explored in the literature. In this series, we describe our surgical approach and explore related clinical, pathological and operative factors in three cases of spontaneous sphenoid sinus CSF leaks, successfully repaired on first attempt with the use of a vascularised nasoseptal flap. PMID- 25926587 TI - A suprasellar arachnoid cyst resulting from an intraventricular haemorrhage and showing complete resolution following endoscopic fenestration. AB - We present the case of a premature neonate who developed a large, acquired arachnoid cyst as a consequence of intraventricular haemorrhage. The child was managed with endoscopic fenestration and made an excellent recovery. PMID- 25926588 TI - Successful treatment of ulcerative bronchiolitis in a woman with refractory Mycobacterium intracellulare infection. AB - We present a case of a woman with medically refractory ulcerative colitis (UC) who developed severe bronchiectasis, bronchitis, bronchiolitis and Mycobacterium intracellulare (MAC) infection 2 years after total colectomy. Despite being on optimal therapy for her MAC and sterilising multiple consecutive sputum cultures, she remained highly symptomatic, and this led to further investigations that revealed the presence of UC-related airways disease. Addition of immunosuppressive therapy to her antimycobacterial treatment resulted in sustained and complete clinical remission of her disease. To our knowledge, this is the only case published in the literature that describes a case of successful treatment of concomitant UC-related pulmonary disease and symptomatic MAC. PMID- 25926589 TI - An object missed 10 years before. PMID- 25926590 TI - MRI features of a quadriceps tendon rupture. PMID- 25926591 TI - Immunohistochemical pattern of T lymphocytes population within bilharzial associated bladder neoplasm microenvironment. AB - The present work aimed to investigate the cellular and immunochemical pattern of T cells population in biopsy material from chronic schistosomiasis haematobium Egyptian patients complicated with bladder cancer. Digital real-time quantitative photocytometry was applied to auto-analyze 29 stained tissue sections from cases and 17 controls using STAT4, GATA3, FOXP3, and CD8 markers specific for Th1, Th2, T regulatory, and T cytotoxic cells, respectively. Area percentage showed significant high level of GATA, followed by FOXP3 and low level of both STAT and CD8 was reported. Tissue samples from five healthy bladder tissues showed significant lower optical density (OD) values. Tissue samples from 12 non bilharzial bladder cancers showed variable OD values, reflecting wide disparity in the control group.Our results hypothesized an exclusive pattern of T population in long standing complicated schistosomiasis haematobium. Our cases were poorly controlled by unbalanced Th1/Th2 in which Th2 was dominated. FOXP3 increased significantly, however, failed to downregulate Th2, instead, the relation between Th1 and T cytotoxic was forcibly limited by the high level of FOXP3, resulting in loss of their power in defending the host against both parasite and carcinogenic changes. These results provide more clarification for the immune evasion process played by the parasite and tumor cells under the supervision of T regulatory cells. Additionally a critical role of FOXP3 is suggested in manipulating STAT4 and CD8 in favor of malignant transformation in this life-threatening parasite. PMID- 25926592 TI - Millions of Americans may be eligible for Marketplace coverage outside open enrollment as a result of qualifying life events. AB - Federal regulations establish special enrollment periods--times outside of open enrollment periods--during which people may enroll in or change their health insurance plans offered through the federal and state-based exchanges, or Marketplaces. To be eligible, a person must experience a shift in income or another "qualifying life event," such as a change in marital status or the number of dependents, or the loss of minimum essential health coverage. We produced an upper-bound estimate that 3.7 million nonelderly adults with coverage through a federal or state Marketplace could have experienced a qualifying life event and become eligible for a special enrollment period because of income shifts. In addition, more than 8.4 million nonelderly adults who did not have Marketplace coverage--three-quarters of whom had no insurance--became eligible for a special enrollment period as a result of other qualifying life events. Many if not most of these people may be unaware of their eligibility. In states that did not expand Medicaid eligibility, we estimated that 1.9 million people experienced income shifts outside of the open enrollment period that would make them eligible for Marketplace subsidies. However, because they were uninsured or had nongroup coverage (instead of Medicaid) during the most recent open enrollment period, they had to wait until the next period to enroll in a Marketplace plan. PMID- 25926593 TI - If rollbacks go forward, up to 14 million children could become ineligible for public or subsidized coverage by 2019. AB - In spring 2015 Congress passed legislation to extend funding for the Children's Health Insurance Program (CHIP) through the end of fiscal year 2017. This two year extension pushes to 2017 the question of whether CHIP funding will end, allowing states to end their separate state CHIP programs. Also, when the Affordable Care Act's maintenance-of-effort requirements expire after 2019, states will be allowed to roll back Medicaid- and CHIP-eligibility thresholds to minimum levels allowed by federal law. This study investigated the potential health insurance options available to low-income children if these events happen. If all states roll back coverage to federal statutory minimums, then, among children in families with incomes up to 400 percent of the federal poverty guidelines, the share ineligible for public coverage or subsidized Marketplace coverage would increase from 22 percent in 2014 (12.5 million children) to 46 percent after 2019 (26.5 million children). While not all states are likely to reduce eligibility to federal statutory minimums, these estimates highlight the fact that many children who do lose public eligibility will not become eligible for subsidized Marketplace coverage. PMID- 25926594 TI - Treatment-resistant, five-year long, postpartum-onset Capgras episode resolving after electroconvulsive therapy. AB - Postpartum psychosis, which rarely presents with Capgras syndrome (delusional misidentification), requires rapid symptom resolution. First-line drugs have important drawbacks, such as delayed onset of clinical response and secretion in breast milk. In this report, we report successful treatment of a treatment resistant woman presenting with treatment-resistant Capgras syndrome, with onset during postpartum. A 36-year-old woman had presented with Capgras syndrome during postpartum. For more than five years, she believed her son and other family members were substituted by impostors. All adequately administrated treatments were unsuccessful. We suggested electroconvulsive therapy to overcome treatment resistance. After six electroconvulsive therapy sessions, delusions of doubles subsided and other symptoms improved. She was discharged two weeks later with a mood stabilizer and low-dose atypical antipychotic combination and is well at the one-and-a-half-year follow-up. Electroconvulsive therapy followed by a mood stabilizer-antipsychotic drug combination showed rapid, permanent, and effective control of long-standing Capgras syndrome in a young woman. PMID- 25926595 TI - The juxtaposition of science and medicine in sport. Can we all play together nicely? PMID- 25926596 TI - Treatment for acute anterior cruciate ligament tear: five year outcome of randomised trial. AB - STUDY QUESTION: In young active adults with an acute anterior cruciate ligament (ACL) rupture, do patient reported or radiographic outcomes after five years differ between those treated with rehabilitation plus early ACL reconstruction and those treated with rehabilitation and optional delayed ACL reconstruction? SUMMARY ANSWER: At five years, patients assigned to rehabilitation plus early ACL reconstruction did not differ significantly in patient reported or radiographic outcomes from those assigned to initial rehabilitation with the option of having a later reconstruction if needed. WHAT IS KNOWN AND WHAT THIS PAPER ADDS: The relative efficacy of surgical reconstruction and rehabilitation for short and long term outcomes of ACL rupture is debated. Clinicians and young active adult patients should consider rehabilitation as a primary treatment option following an acute ACL tear. PMID- 25926597 TI - Incidence and prognostic significance of new onset atrial fibrillation/flutter in acute pericarditis. AB - OBJECTIVE: Data on the incidence of new onset atrial fibrillation and flutter (AF/f) in patients with acute pericarditis are limited. We sought to determine the incidence and prognostic significance of AF/f in this setting. METHODS: Between January 2006 and June 2014, consecutive new cases of acute pericarditis were included in two urban referral centres for pericardial diseases. All new cases of AF/f defined as episodes lasting >=30 s were recorded. Events considered during follow-up consisted of AF/f and pericarditis recurrence, cardiac tamponade, pericardial constriction and death. RESULTS: 822 consecutive new cases of acute pericarditis (mean age 53+/-15 years, 444 men) were analysed. AF/f was detected in 35 patients (4.3%, mean age 66.5+/-11.3 years, 18 men). Patients with AF/f were significantly older (p=0.017) and presented more frequently with pericardial effusion (p<0.001). Arrhythmias developed within 24 h of pericarditis onset in 91.4% of cases, lasted >24 h in 25.7% and spontaneously converted in 74.3% of patients. Underlying structural heart disease was present in 17% of AF/f cases. In a 30-month follow-up, patients with history of AF/f at the initial episode had a higher rate of arrhythmia occurrence (34.3% vs 0.9%, p<0.001), mostly (75%) within 3 months. No other differences were detected in additional clinical events including haemorrhagic complications in patients receiving oral anticoagulation. CONCLUSIONS: The occurrence of AF/f in acute pericarditis identifies a predisposed population to AF/f with a high recurrence risk (about 35%): in these patients, pericarditis may act as an arrhythmic trigger and oral anticoagulation should be seriously considered according to guidelines. PMID- 25926598 TI - Cochrane corner: colchicine for pericarditis. PMID- 25926599 TI - Public knowledge and confidence in the use of public access defibrillation. AB - INTRODUCTION: Growing numbers of public access defibrillators aim to improve the effectiveness of bystander cardiopulmonary resuscitation prior to ambulance arrival. In the UK, however, public access defibrillators are only deployed successfully in 1.7% of out-of-hospital cardiac arrests. We aimed to understand whether this was due to a lack of devices, lack of awareness of their location or a reflection of lack of public knowledge and confidence to use a defibrillator. METHODS: Face-to-face semistructured open quantitative questionnaire delivered in a busy urban shopping centre, to identify public knowledge relating to public access defibrillation. RESULTS: 1004 members of the public aged 9-90 years completed the survey. 61.1% had been first aid trained to a basic life support level. 69.3% claimed to know what an automatic external defibrillator was and 26.1% reported knowing how to use one. Only 5.1% knew where or how to find their nearest public access defibrillator. Only 3.3% of people would attempt to locate a defibrillator in a cardiac arrest situation, and even fewer (2.1%) would actually retrieve and use the device. CONCLUSIONS: These findings suggest that a lack of public knowledge, confidence in using a defibrillator and the inability to locate a nearby device may be more important than a lack of defibrillators themselves. Underused public access defibrillation is a missed opportunity to save lives, and improving this link in the chain of survival may require these issues to be addressed ahead of investing more funds in actual defibrillator installation. PMID- 25926600 TI - Combination of 4Ts score and PF4/H-PaGIA for diagnosis and management of heparin induced thrombocytopenia: prospective cohort study. AB - Rapid exclusion of heparin-induced thrombocytopenia (HIT) is needed to determine which patients can continue to receive heparin. In this prospective management study, 526 participants had a 4Ts score, rapid particle gel immunoassay (platelet factor 4/heparin [PF4/H]-PaGIA), and serotonin-release assay (SRA) performed. While awaiting SRA results, participants with a low 4Ts score (irrespective of PF4/H-PaGIA result) or intermediate 4Ts score plus a negative PF4/H-PaGIA result received prophylactic doses of danaparoid or fondaparinux; all others received therapeutic doses of nonheparin anticoagulants. The primary outcome was the frequency of management failures defined as HIT-positive participants with a low 4Ts score (irrespective of PF4/H-PaGIA result) or intermediate 4Ts score plus negative PF4/H-PaGIA result. Six participants (1.1%; 95% confidence interval [CI], 0.2-2.1%) were management failures. A negative PF4/H-PaGIA result reduced the pretest probability of HIT from 1.9% to 0% (95% CI, 0-1.3%), 6.7% to 0% (95% CI, 0-2.7%), and 36.6% to 0% (95% CI, 0-14.3%) in the low, intermediate, and high score groups, respectively. A positive PF4/H-PaGIA result increased the probability of HIT in the low score group to 15.4% (95% CI, 5.9-30.5). Thus, a low or intermediate 4Ts score plus negative PaGIA result excluded HIT, whereas any other combination of results justified the use of alternative anticoagulants until HIT could be excluded. This trial was registered at www.clinicaltrials.gov as #NCT00489437. PMID- 25926602 TI - Role of C-type natriuretic peptide in the function of normal human sperm. AB - C-type natriuretic peptide (CNP) is a newly discovered type of local regulatory factor that mediates its biological effects through the specific, membrane-bound natriuretic peptide receptor-B (NPR-B). Recent studies have established that CNP is closely related to male reproductive function. The aims of this study were to determine the distribution of CNP/NPR-B in human ejaculated spermatozoa through different methods (such as immunolocalization, real time polymerase chain reaction and Western Blot), and then to evaluate the influence of CNP on sperm function i n vitro, such as motility and acrosome reaction. Human semen samples were collected from consenting donors who met the criteria of the World Health Organization for normozoospermia. Our results show that the specific receptor NPR B of CNP is localized in the acrosomal region of the head and the membrane of the front-end tail of the sperm, and there is no signal of CNP in human sperm. Compared with the control, CNP can induce a significant dose-dependent increase in spermatozoa motility and acrosome reaction. In summary, CNP/NPR-B can affect sperm motility and acrosome reaction, thus regulating the reproductive function of males. CNP may be a new key factor in regulating sperm function. PMID- 25926601 TI - Recruiting endogenous stem cells: a novel therapeutic approach for erectile dysfunction. AB - Transplanted stem cells (SCs), owing to their regenerative capacity, represent one of the most promising methods to restore erectile dysfunction (ED). However, insufficient source, invasive procedures, ethical and regulatory issues hamper their use in clinical applications. The endogenous SCs/progenitor cells resident in organ and tissues play critical roles for organogenesis during development and for tissue homeostasis in adulthood. Even without any therapeutic intervention, human body has a robust self-healing capability to repair the damaged tissues or organs. Therefore, SCs-for-ED therapy should not be limited to a supply-side approach. The resident endogenous SCs existing in patients could also be a potential target for ED therapy. The aim of this review was to summarize contemporary evidence regarding: (1) SC niche and SC biological features in vitro; (2) localization and mobilization of endogenous SCs; (3) existing evidence of penile endogenous SCs and their possible mode of mobilization. We performed a search on PubMed for articles related to these aspects in a wide range of basic studies. Together, numerous evidences hold the promise that endogenous SCs would be a novel therapeutic approach for the therapy of ED. PMID- 25926604 TI - Locally-advanced prostate cancer in the elderly: should we revisit our treatment paradigms? AB - Prostate cancer (PCa) represents the most common malignancy in adult males with an estimated number of 280 000 newly diagnosed cases only in the United States in 2015. [1] Due to the introduction of PSA in clinical practice, the majority of the patients are currently diagnosed with organ-confined and sometimes indolent disease. However, a nonnegligible proportion of individuals are still diagnosed with locally-advanced tumors. In their recently published article, Bekelman et al. [2] focused on elderly patients with locally-advanced PCa in the attempt to determine the best treatment approach in this patient category, and concluded that, even in these individuals, androgen deprivation therapy (ADT) plus radiotherapy (RT) may confer a survival benefit relative to ADT alone. The importance of the current article resides in the fact that it focuses on a patient population that has not been, or has been only scarcely, included in previous studies on the same topic. PMID- 25926603 TI - Percent free prostate-specific antigen is effective to predict prostate biopsy outcome in Chinese men with prostate-specific antigen between 10.1 and 20.0 ng ml(-1). AB - Percent free prostatic-specific antigen (%fPSA) has been introduced as a tool to avoid unnecessary biopsies in patients with a serum PSA level of 4.0-10.0 ng ml-1 , however, it remains controversial whether %fPSA is effective in PSA range of 10.1-20.0 ng ml-1 in both Chinese and Western population. In this study, the diagnostic performance of %fPSA and serum PSA in predicting prostate cancer (PCa) and high-grade PCa (HGPCa) was analyzed in a multi-center biopsy cohort of 5915 consecutive Chinese patients who underwent prostate biopsy in 22 hospitals across China from January 1, 2010 to December 31, 2013. The indication for biopsy was PSA>4.0 ng ml-1 or/and suspicious digital rectal examination. Total and free serum PSA determinations were performed by three types of electrochemiluminescence immunoassays with recalibration to the World Health Organization standards. The diagnostics accuracy of PSA, %fPSA and %fPSA in combination with PSA (%fPSA + PSA) was determined by the area under the receivers operating characteristic curve (AUC). %fPSA was more effective than PSA in men aged >=60 years old. The AUC was 0.584 and 0.635 in men aged >=60 years old with a PSA of 4.0-10.0 ng ml-1 and 10.1-20.0 ng ml-1 , respectively. The AUC of %fPSA was superior to that of PSA in predicting HGPCa in patients >=60 years old in these two PSA range. Our results indicated that %fPSA is both statistically effective and clinical applicable to predict prostate biopsy outcome in Chinese patients aged >=60 years old with a PSA of 4.0-10.0 ng ml-1 and 10.1-20.0 ng ml-1 . PMID- 25926605 TI - Evaluation of the expression of sperm proteins in normozoospermic and asthenozoospermic men using monoclonal antibodies. AB - Recent studies have shown that infertility affects estimated 15% of all couples. Male infertility is the primary or contributory cause in 60% of these cases. Consequently, the application of assisted reproduction is increasing. These methods could benefit from an extended evaluation of sperm quality. For this reason, we analyzed sperm proteins from 30 men with normal spermiograms and 30 men with asthenozoospermia. Ejaculates of both groups were tested by flow cytometry (FCM) and fluorescence with a set of well-characterized anti-human sperm Hs-monoclonal antibodies (MoAbs), which were generated in our laboratory. No statistically significant differences were found between normospermics and asthenospermics in the expression of the sperm surface protein clusterin, evaluated with Hs-3 MoAb, and semenogelin, evaluated with Hs-9 MoAb. However, FCM revealed quantitative differences in the acrosomal proteins between normozoospermic and asthenozoospermic men, namely, in glyceraldehyde-3-phosphate dehydrogenase, evaluated with Hs-8 MoAb, valosin-containing protein, evaluated with Hs-14 MoAb, and ATP synthase (cAMP-dependent protein kinase II, PRKAR2A), evaluated with MoAb Hs-36. Asthenozoospermic men displayed a highly reduced expression of intra-acrosomal proteins, with a likely decrease in sperm quality, and thus a negative impact on successful reproduction. Asthenozoospermia seems to be a complex disorder involving intra-acrosomal proteins. PMID- 25926606 TI - The paternal genome and the health of the assisted reproductive technology child. AB - As a number of children born by assisted reproductive technology (ART) are increasing each year across the developed world, the health of such offspring is a matter of public concern. Does the integrity of the paternal genome impact on offspring health? In societal terms, as birth rates fall, and the Western population become unsustainable, do the benefits outweigh the costs of creating and providing for this ART conceived subpopulation? There are little data to date to answer these questions. The long-term health of such children has largely been ignored, and success measured only by early (prebirth) outcomes such as embryo quality or pregnancy. However, there are powerful paradigms such as ageing and smoking that give vital clues as to the potential impact of unhealthy spermatozoa on disease risk, mental and physical health, fertility and mortality of these offspring. PMID- 25926607 TI - Human sperm chromatin epigenetic potential: genomics, proteomics, and male infertility. AB - The classical idea about the function of the mammalian sperm chromatin is that it serves to transmit a highly protected and transcriptionally inactive paternal genome, largely condensed by protamines, to the next generation. In addition, recent sperm chromatin genome-wide dissection studies indicate the presence of a differential distribution of the genes and repetitive sequences in the protamine condensed and histone-condensed sperm chromatin domains, which could be potentially involved in regulatory roles after fertilization. Interestingly, recent proteomic studies have shown that sperm chromatin contains many additional proteins, in addition to the abundant histones and protamines, with specific modifications and chromatin affinity features which are also delivered to the oocyte. Both gene and protein signatures seem to be altered in infertile patients and, as such, are consistent with the potential involvement of the sperm chromatin landscape in early embryo development. This present work reviews the available information on the composition of the human sperm chromatin and its epigenetic potential, with a particular focus on recent results derived from high throughput genomic and proteomic studies. As a complement, we provide experimental evidence for the detection of phosphorylations and acetylations in human protamine 1 using a mass spectrometry approach. The available data indicate that the sperm chromatin is much more complex than what it was previously thought, raising the possibility that it could also serve to transmit crucial paternal epigenetic information to the embryo. PMID- 25926608 TI - Redox regulation of mammalian sperm capacitation. AB - Capacitation is a series of morphological and metabolic changes necessary for the spermatozoon to achieve fertilizing ability. One of the earlier happenings during mammalian sperm capacitation is the production of reactive oxygen species (ROS) that will trigger and regulate a series of events including protein phosphorylation, in a time-dependent fashion. The identity of the sperm oxidase responsible for the production of ROS involved in capacitation is still elusive, and several candidates are discussed in this review. Interestingly, ROS-induced ROS formation has been described during human sperm capacitation. Redox signaling during capacitation is associated with changes in thiol groups of proteins located on the plasma membrane and subcellular compartments of the spermatozoon. Both, oxidation of thiols forming disulfide bridges and the increase on thiol content are necessary to regulate different sperm proteins associated with capacitation. Reducing equivalents such as NADH and NADPH are necessary to support capacitation in many species including humans. Lactate dehydrogenase, glucose-6-phospohate dehydrogenase, and isocitrate dehydrogenase are responsible in supplying NAD (P) H for sperm capacitation. Peroxiredoxins (PRDXs) are newly described enzymes with antioxidant properties that can protect mammalian spermatozoa; however, they are also candidates for assuring the regulation of redox signaling required for sperm capacitation. The dysregulation of PRDXs and of enzymes needed for their reactivation such as thioredoxin/thioredoxin reductase system and glutathione-S-transferases impairs sperm motility, capacitation, and promotes DNA damage in spermatozoa leading to male infertility. PMID- 25926609 TI - New insights into the regulation of cholesterol efflux from the sperm membrane. AB - Cholesterol is an essential component of the mammalian plasma membrane because it promotes membrane stability without comprising membrane fluidity. Given this important cellular role, cholesterol levels are tightly controlled at multiple levels. It has been clearly shown that cholesterol redistribution and depletion from the sperm membrane is a key part of the spermatozoon's preparation for fertilization. Some factors that regulate these events are described (e.g., bicarbonate, calcium) but the mechanisms underlying cholesterol export are poorly understood. How does a hydrophobic cholesterol molecule inserted in the sperm plasma membrane enter the energetically unfavorable aqueous surroundings? This review will provide an overview of knowledge in this area and highlight our gaps in understanding. The overall aim is to better understand cholesterol redistribution in the sperm plasma membrane, its relation to the possible activation of a cholesterol transporter and the role of cholesterol acceptors. Armed with such knowledge, sperm handling techniques can be adapted to better prepare spermatozoa for in vitro and in vivo fertilization. PMID- 25926611 TI - Odyssey of the spermatozoon. AB - This Opinion piece is offered as a cursory overview of sperm development, function, and transport through the eyes of an equine veterinarian. My professional background is predominantly clinical in nature, but my fascination with sperm function and preservation has led to a fairly sizeable review of the scientific literature over the years in hopes of extracting laboratory findings that have application to my daily activities in the clinical arena. Spermatozoa are quite unique among cellular types with regard to both form and function, and represent the only endogenously derived cell type that exerts its action in a separate being. This paper takes the reader on a voyage with a mammalian spermatozoon, from its formative stages through its transport in the male and female reproductive tracts, and culminating with its interaction with an ovulated oocyte at the time of fertilization. Specific emphasis is placed on equine spermatozoa when notable research findings have been unveiled. PMID- 25926610 TI - Varicocele and testicular function. AB - Testicular varicocele, a dilation of the veins of the pampiniform plexus thought to increase testicular temperature via venous congestion, is commonly associated with male infertility. Significant study has clarified the negative impact of varicocele on semen parameters and more recent work has shed light on its detrimental effects on the molecular and ultrastructural features of sperm and the testicular microenvironment, as well as more clearly defined the positive impacts of treatment on couples' fertility. The relationship between varicocele and testicular endocrine function, while known for some time based on histologic evaluation, has become more apparent in the clinical setting with a growing link between varicocele and hypogonadism. Finally, in the pediatric setting, while future study will clarify the impact of varicocele on fertility and testicular function, recent work supports a parallel effect of varicocele in adolescents and adults, suggesting a re-evaluation of current treatment approaches in light of the progressive nature of the condition and potential increased risk of future disease. PMID- 25926612 TI - The Ins and Outs of Spermatology. PMID- 25926613 TI - A model for the control of DNA integrity by the sperm nuclear matrix. AB - The highly condensed chromatin of mammalian spermatozoa is usually considered to be biologically inert before fertilization. However, we have demonstrated that even in this compacted state, sperm chromatin is subject to degradation at open configurations associated with the nuclear matrix through a process we have termed sperm chromatin fragmentation (SCF). This suggests that a mechanism exists to monitor the health of spermatozoa during transit through the male reproductive tract and to destroy the genome of defective sperm cells. The site of DNA damage in SCF, the matrix attachment sites, are the same that we hypothesize initiate DNA synthesis in the zygote. When sperm that have damaged DNA are injected into the oocyte, the newly created zygote responds by delaying DNA synthesis in the male pronucleus and, if the damage is severe enough, arresting the embryo's development. Here we present a model for paternal DNA regulation by the nuclear matrix that begins during sperm maturation and continues through early embryonic development. PMID- 25926614 TI - The future of computer-aided sperm analysis. AB - Computer-aided sperm analysis (CASA) technology was developed in the late 1980s for analyzing sperm movement characteristics or kinematics and has been highly successful in enabling this field of research. CASA has also been used with great success for measuring semen characteristics such as sperm concentration and proportions of progressive motility in many animal species, including wide application in domesticated animal production laboratories and reproductive toxicology. However, attempts to use CASA for human clinical semen analysis have largely met with poor success due to the inherent difficulties presented by many human semen samples caused by sperm clumping and heavy background debris that, until now, have precluded accurate digital image analysis. The authors review the improved capabilities of two modern CASA platforms (Hamilton Thorne CASA-II and Microptic SCA6) and consider their current and future applications with particular reference to directing our focus towards using this technology to assess functional rather than simple descriptive characteristics of spermatozoa. Specific requirements for validating CASA technology as a semi-automated system for human semen analysis are also provided, with particular reference to the accuracy and uncertainty of measurement expected of a robust medical laboratory test for implementation in clinical laboratories operating according to modern accreditation standards. PMID- 25926615 TI - A critical review of smoking, cessation, relapse and emerging research in pregnancy and post-partum. AB - INTRODUCTION: Smoking during pregnancy causes adverse health outcomes. Though the prevalence of smoking among pregnant women has declined, postpartum relapse rates remain high and smoking-related maternal, fetal and infant morbidity and mortality remains a public health burden. SOURCES OF DATA: A comprehensive literature search on smoking in pregnancy was conducted to provide a practical review for health professionals. AREAS OF AGREEMENT: Psychosocial support is an effective evidence-based treatment for pregnant women. Bio-psycho-socio factors that influence likelihood of quitting and remaining quit should be addressed. AREAS OF CONTROVERSY: Electronic cigarettes are marketed as a harm reduction tool, but research on safety and effectiveness are lacking for pregnant women. GROWING POINTS: The safety and efficacy of pharmacotherapy for use among pregnant women remains unclear. Clinicians should increase discussions regarding all resources for tobacco use treatment and secondhand smoke (SHS) exposure during pregnancy and postpartum and offer psychosocial support to all pregnant women. AREAS TIMELY FOR DEVELOPING RESEARCH: Research on developing stronger tobacco control policies in low- and middle-income countries, increasing cessation and relapse prevention among pregnant smokers with mental health conditions and increasing the impact of evidence-based supports, such as the quitline, among pregnant women can decrease consumption of tobacco in pregnancy. PMID- 25926617 TI - Put more paediatric knowledge into primary care to tackle UK's poor child health outcomes, says report. PMID- 25926616 TI - Characteristics of service users and provider organisations associated with experience of out of hours general practitioner care in England: population based cross sectional postal questionnaire survey. AB - OBJECTIVE: To investigate the experience of users of out of hours general practitioner services in England, UK. DESIGN: Population based cross sectional postal questionnaire survey. SETTING: General Practice Patient Survey 2012-13. MAIN OUTCOME MEASURES: Potential associations between sociodemographic factors (including ethnicity and ability to take time away from work during working hours to attend a healthcare consultation) and provider organisation type (not for profit, NHS, or commercial) and service users' experience of out of hours care (timeliness, confidence and trust in the out of hours clinician, and overall experience of the service), rated on a scale of 0-100. Which sociodemographic/provider characteristics were associated with service users' experience, the extent to which any observed differences could be because of clustering of service users of a particular sociodemographic group within poorer scoring providers, and the extent to which observed differences in experience varied across types of provider. RESULTS: The overall response rate was 35%; 971,232/2,750,000 patients returned surveys. Data from 902,170 individual service users were mapped through their registered practice to one of 86 providers of out of hours GP care with known organisation type. Commercial providers of out of hours GP care were associated with poorer reports of overall experience of care, with a mean difference of -3.13 (95% confidence interval -4.96 to -1.30) compared with not for profit providers. Asian service users reported lower scores for all three experience outcomes than white service users (mean difference for overall experience of care -3.62, -4.36 to -2.89), as did service users who were unable to take time away from work compared with service users who did not work (mean difference for overall experience of care -4.73, -5.29 to -4.17). CONCLUSIONS: Commercial providers of out of hours GP care were associated with poorer experience of care. Targeted interventions aimed at improving experience for patients from ethnic minorities and patients who are unable to take time away from work might be warranted. PMID- 25926618 TI - The experiential impact of hospitalisation: Parents' accounts of caring for young people with early psychosis. AB - This research examines the experiential impact of hospitalisation on the parents of young people with early psychosis. In-depth interviews were conducted with a small sample of parents, and the resulting transcripts were analysed using Interpretative Phenomenological Analysis. Five themes emerged from the data: Accepting and blaming, Feeling out of control, Hospitalisation as temporary containment, Feeling let down by services and Stigma. Aspects of the hospitalisation process were characterised by parents as generally negative, but a number of positive affirmations were also offered regarding the containing, supportive and crucial role of services. Parents' perceptions of hospitalisation as a difficult, and sometimes distressing, experience are exacerbated by the complexity of being the carer of a young person. Negotiating services and boundaries within the context of this relationship contributes to feelings of exclusion and disregard by professionals and services. The implications of this study resonate with the current government mental health strategy with regard to how services can engage and include carers in the mental health system, and equip and enable them to support their relatives with early psychosis. PMID- 25926619 TI - Increased interictal visual network connectivity in patients with migraine with aura. AB - OBJECTIVE: To evaluate the resting-state visual network functional connectivity in patients with migraine with aura and migraine without aura during the interictal period. POPULATION AND METHODS: Using resting-state functional magnetic resonance imaging, the resting-state visual network integrity was investigated in 20 patients with migraine with aura, 20 age- and sex-matched patients with migraine without aura and 20 healthy controls. Voxel-based morphometry and diffusion tensor imaging were used to assess whether between groups differences in functional connectivity were dependent on structural or microstructural changes. RESULTS: Resting-state functional magnetic resonance imaging data showed that patients with migraine with aura, compared to both patients with migraine without aura and healthy controls, had a significant increased functional connectivity in the right lingual gyrus within the resting state visual network (p < 0.05, cluster-level corrected). This abnormal resting state visual network functional connectivity was observed in the absence of structural or microstructural abnormalities and was not related to migraine severity. CONCLUSIONS: Our imaging data revealed that patients with migraine with aura exhibit an altered resting-state visual network connectivity. These results support the hypothesis of an extrastriate cortex involvement, centred in the lingual gyrus, a brain region related to mechanisms underlying the initiation and propagation of the migraine aura. This resting-state functional magnetic resonance imaging finding may represent a functional biomarker that could differentiate patients experiencing the aura phenomenon from patients with migraine without aura, even between migraine attacks. PMID- 25926620 TI - Randomized controlled trial of the CGRP receptor antagonist telcagepant for prevention of headache in women with perimenstrual migraine. AB - AIM: The aim of this article is to evaluate the safety and efficacy of perimenstrual telcagepant, a CGRP receptor antagonist, for headache prophylaxis. METHODS: We conducted a randomized, double-blind, placebo-controlled, six-month trial in women with migraine for >= 3 months who experienced perimenstrual headaches. Women were randomized to telcagepant 140 mg or placebo (2:1 ratio) for seven consecutive days perimenstrually. Safety was assessed by adverse events and laboratory tests. The primary efficacy endpoint was mean monthly headache days in the subset of women reporting perimenstrual migraine (-2 days to +3 days of menses onset) and >= 5 moderate or severe migraines per month prior to entering the trial. RESULTS: Telcagepant was generally well tolerated: 66/2660 (2.5%) on telcagepant and 36/1326 (2.7%) on placebo discontinued because of a clinical adverse event. The percentages of patients with clinical adverse events, laboratory adverse events, or discontinuation because of a laboratory adverse event were also similar between treatments. Alanine aminotransferase elevations >= 3x normal occurred in 0.6% of women on telcagepant and 0.4% on placebo. Three women on telcagepant vs none on placebo had alanine aminotransferase elevations >= 8* normal. In the efficacy subset there was no significant effect of telcagepant (n = 887) vs placebo (n = 447) in mean monthly headache days (treatment difference -0.5 day (95% CI: -1.1, 0.1)). However, telcagepant was associated with a reduction in on-drug headache days (treatment difference -0.4 day (95% CI: -0.5, -0.2), nominal p < 0.001). CONCLUSIONS: Telcagepant 140 mg taken perimenstrually for seven days was generally well tolerated, but was associated with transaminase elevations. Telcagepant did not reduce monthly headache frequency, but did reduce perimenstrual headaches. PMID- 25926621 TI - Non-melanoma Skin Cancer in Canada Chapter 3: Management of Actinic Keratoses. AB - BACKGROUND: Actinic keratosis (AK) and cheilitis (AC) are lesions that develop on photodamaged skin and may progress to form invasive squamous cell carcinomas (SCCs). OBJECTIVE: To provide guidance to Canadian health care practitioners regarding management of AKs and ACs. METHODS: Literature searches and development of graded recommendations were carried out as discussed in the accompanying introduction (chapter 1 of the NMSC guidelines). RESULTS: Treatment of AKs allows for secondary prevention of skin cancer in sun-damaged skin. Because it is impossible to predict whether a given AK will regress, persist, or progress, AKs should ideally be treated. This chapter discusses options for the management of AKs and ACs. CONCLUSIONS: Treatment options include surgical removal, topical treatment, and photodynamic therapy. Combined modalities may be used in case of inadequate response. AKs are particularly common following the long-term immunosuppression in organ transplant patients, who should be monitored frequently to identify emerging lesions that require surgery. PMID- 25926622 TI - Use of Complementary and Alternative Medicine Among Dermatology Outpatients: Results From a National Survey. AB - BACKGROUND: Little is known about the prevalence and practice of complementary and alternative medicine (CAM) among dermatology patients in the Arab world. The aim of this study was to determine knowledge and attitudes about CAM, prevalence of its use, reasons for its use, and types of CAM used in dermatology patients in Saudi Arabia. METHODS: This was a national survey of various regions of Saudi Arabia. In this cross-sectional study, dermatology outpatients were interviewed using a questionnaire. Sociodemographic characteristics, acceptability, utilization pattern, and reasons for CAM use were elicited. Dermatology life quality index (DLQI) was obtained. RESULTS: Overall, 1901 patients returned complete questionnaires out of 2500 distributed (76% response rate). Of these, 808 (40%) were CAM users, and the majority were woman (55.1%), with a mean age of 31.6+/-12 years. Most were literate (71.2%) and just over half were married (51.9%). Patients with acute skin diseases were found to be more likely to use CAM (P=.027). The mean DLQI score was higher (worse quality of life) among CAM users than among nonusers (P=.002). The results showed that 315 of 801 (40%) and 250 of 601 (30%) CAM users agreed that CAM methods are safer and more effective than modern medicine, respectively, and 83% will continue to use CAM in future. The most commonly used CAM modalities were vitamins, prayers, natural products, and herbs. Responses indicated that 379 of 803 (47.2%) CAM users did not consult their doctor before using CAM, and 219 of 743 (30%) did not obtain sufficient answers regarding CAM use from their dermatologists. CONCLUSIONS: There is a significant use of CAM among dermatology outpatients in Saudi Arabia. In view of the common belief that CAM has fewer side effects than conventional medicine, dermatologists need to increase their awareness of CAM. PMID- 25926624 TI - Progressive postnatal decline in leptin sensitivity of arcuate hypothalamic neurons in the Magel2-null mouse model of Prader-Willi syndrome. AB - Prader-Willi syndrome (PWS) is a multigene disorder associated with neonatal failure to thrive, developmental delay and endocrine abnormalities suggestive of hypothalamic dysfunction. Children with PWS typically develop overt hyperphagia and obesity ~8 years of age, later than children with other genetic forms of obesity. This suggests a postnatal developmental or degenerative component to PWS associated obesity. De novo inactivating mutations in one PWS candidate gene, MAGEL2, have been identified in children with features of PWS. Adult mice lacking Magel2 are insensitive to the anorexic effect of leptin treatment, and their hypothalamic pro-opiomelanocortin (POMC) neurons fail to depolarize in response to leptin. However, it is unclear whether this leptin insensitivity is congenital, or whether normal leptin sensitivity in neonatal Magel2-null mice is lost postnatally. We used in vitro cytosolic calcium imaging to follow the postnatal development of leptin responses in POMC neurons in these mice. Leptin caused an activation of POMC neurons in wild-type acute hypothalamic slice preparations at all ages, reflecting their normal leptin-invoked depolarization. Normal leptin responses were found in Magel2-null mice up to 4 weeks of age, but the proportion of leptin-responsive POMC neurons was reduced in 6-week-old Magel2 null mice. The number of alpha-melanocyte-stimulating hormone immunoreactive fibers in the paraventricular hypothalamic nucleus was also reduced in mutant mice at 6 weeks of age. A similar progressive loss of leptin sensitivity caused by loss of MAGEL2 in children with PWS could explain the delayed onset of increased appetite and weight gain in this complex disorder. PMID- 25926625 TI - BCM-95 and (2-hydroxypropyl)-beta-cyclodextrin reverse autophagy dysfunction and deplete stored lipids in Sap C-deficient fibroblasts. AB - Saposin (Sap) C deficiency is a rare variant form of Gaucher disease caused by impaired Sap C expression or accelerated degradation, and associated with accumulation of glucosylceramide and other lipids in the endo/lysosomal compartment. No effective therapies are currently available for the treatment of Sap C deficiency. We previously reported that a reduced amount and enzymatic activity of cathepsin (Cath) B and Cath D, and defective autophagy occur in Sap C deficient fibroblasts. Here, we explored the use of two compounds, BCM-95, a curcumin derivative, and (2-hydroxypropyl)-beta-cyclodextrin (HP-beta-CD), to improve lysosomal function of Sap C-deficient fibroblasts. Immunofluorescence and biochemical studies documented that each compound promotes an increase of the expression levels and activities of Cath B and Cath D, and efficient clearance of cholesterol (Chol) and ceramide (Cer) in lysosomes. We provide evidence that BCM 95 and HP-beta-CD enhance lysosomal function promoting autophagic clearance capacity and lysosome reformation. Our findings suggest a novel pharmacological approach to Sap C deficiency directed to treat major secondary pathological aspects in this disorder. PMID- 25926623 TI - The G2019S LRRK2 mutation increases myeloid cell chemotactic responses and enhances LRRK2 binding to actin-regulatory proteins. AB - The Leucine rich repeat kinase 2 (LRRK2) gene is genetically and biochemically linked to several diseases that involve innate immunity. LRRK2 protein is highly expressed in phagocytic cells of the innate immune system, most notably in myeloid cells capable of mounting potent pro-inflammatory responses. Knockdown of LRRK2 protein in these cells reduces pro-inflammatory responses. However, the effect of LRRK2 pathogenic mutations that cause Parkinson's disease on myeloid cell function is not clear but could provide insight into LRRK2-linked disease. Here, we find that rats expressing G2019S LRRK2 have exaggerated pro-inflammatory responses and subsequent neurodegeneration after lipopolysaccharide injections in the substantia nigra, with a marked increase in the recruitment of CD68 myeloid cells to the site of injection. While G2019S LRRK2 expression did not affect immunological homeostasis, myeloid cells expressing G2019S LRRK2 show enhanced chemotaxis both in vitro in two-chamber assays and in vivo in response to thioglycollate injections in the peritoneum. The G2019S mutation enhanced the association between LRRK2 and actin-regulatory proteins that control chemotaxis. The interaction between G2019S LRRK2 and actin-regulatory proteins can be blocked by LRRK2 kinase inhibitors, although we did not find evidence that LRRK2 phosphorylated these interacting proteins. These results suggest that the primary mechanism of G2019S LRRK2 with respect to myeloid cell function in disease may be related to exaggerated chemotactic responses. PMID- 25926626 TI - Errata. PMID- 25926628 TI - Problems and Cautions With Sequence Mismatch Analysis and Bayesian Skyline Plots to Infer Historical Demography. AB - Sequence mismatch analysis (MMA) and Bayesian skyline plots (BSP) are commonly used to reconstruct historical demography. A survey of 173 research articles (2009-2014), which included estimates of historical population sizes from mtDNA or cpDNA, shows a widespread genetic signature of demographic or spatial population expansion in species of all major taxonomic groups. Associating these expansions with climatic events can provide insights into the origins of lineage diversity, range expansions (or contractions), and speciation. However, several variables can introduce error into reconstructions of demographic history, including levels of sequence polymorphism, sampling scheme, sample size, natural selection, and estimates of mutation rate. Most researchers use substitution rates estimated from divergences in phylogenetic trees dated with fossils, or geological events. Recent studies show that molecular clocks calibrated with phylogenetic divergences can overestimate the timings of population-level events by an order of magnitude. Overestimates disconnect historical population reconstructions from climatic history and confound our understanding of the factors influencing genetic variability. If mismatch distributions and BSPs largely reflect demographic history, the widespread signature of population expansion in vertebrate, invertebrate, and plant populations appears to reflect responses to postglacial climate warming. PMID- 25926629 TI - Academic Skills Groups for Middle School Children With ADHD in the Outpatient Mental Health Setting: An Open Trial. AB - OBJECTIVE: To conduct an open trial assessing the initial efficacy of an intervention focusing on increasing skills related to academic performance (planning, organization, studying, and homework behaviors) for middle school children diagnosed with ADHD. The intervention is modeled on evidence-based interventions but designed for administration in the outpatient setting. METHOD: Parents and their children diagnosed with ADHD attended seven weekly group sessions targeting academic, organizational, and homework skills. Parents completed the Homework Problem Checklist and Impairment Rating Scale pre- and post-treatment. RESULTS: Following intervention, significant improvements in homework completion and management, as well as reductions in academic impairment and improvements in parent confidence and family relations, were reported. CONCLUSION: Despite limitations including small sample size and lack of a control group, our results demonstrate initial efficacy of an academic skills intervention designed for use in the outpatient setting with middle school children diagnosed with ADHD on clinically relevant outcome measures. PMID- 25926630 TI - Comorbidity and Behavior Characteristics of Russian Male Juvenile Delinquents With ADHD and Conduct Disorder. AB - OBJECTIVE: To test the previously suggested hypothesis that those with comorbid ADHD and Conduct Disorder (CD) diagnoses differ from other antisocially involved youth in terms of higher rates of violent behavior, impulsiveness, and psychopathic traits. METHOD: Three hundred eighty juvenile incarcerated delinquents from Northern Russia were assessed by means of semi-structured psychiatric interview and by student and teacher self-reports. RESULTS: The study has demonstrated higher rates of psychiatric disorders and of comorbidity, as well as more complicated substance abuse and disruptive behaviors in those with combined ADHD-CD diagnosis, as compared with CD only, ADHD only, and no CD no ADHD groups. The results regarding psychopathic traits were inconclusive. CONCLUSION: The group with combined ADHD-CD diagnosis is more severely disturbed, both as concerns psychiatric comorbidity and more severe aggressive and disruptive behaviors. However, there is only limited evidence supporting a higher prevalence of psychopathic traits in this group. PMID- 25926631 TI - Corrections. PMID- 25926632 TI - Corrections. PMID- 25926633 TI - Corrections. PMID- 25926634 TI - The Human Adenovirus Type 5 L4 Promoter Is Negatively Regulated by TFII-I and L4 33K. AB - The late phase of adenovirus gene expression is controlled by proteins made in the intermediate phase, including L4 proteins of 22,000- and 33,000-Da apparent molecular mass (L4-22K and -33K proteins) that are expressed initially from the L4 promoter (L4P). The L4P is activated by a combination of viral proteins and cellular p53 and is ultimately inhibited again by its own products. Here, we have examined the L4P of human adenovirus type 5 in detail and have defined its transcription start site, which our data suggest is positioned by a weak TATA box. Rather than contributing positively to promoter activity, a putative initiator element at the transcription start site acts as a target for negative regulation imposed on the L4P by cellular TFII-I. We show that this TFII-I inhibition is relieved by one of the previously defined viral activators of the L4P, the E4 Orf3 protein, which alters the pool of TFII-I in the cell. We also explore further the negative regulation of the L4P by its products and show that the L4-33K protein is more significant in this process than L4-22K. It is the combined actions of positive and negative factors that lead to the transient activation of the L4P at the onset of the late phase of adenovirus gene expression. IMPORTANCE: The adenovirus replication cycle proceeds through multiple phases of gene expression in which a key step is the activation of late phase gene expression to produce proteins from which progeny particles can be formed. Working with human adenovirus type 5, we showed previously that two proteins expressed from the L4 region of the viral genome perform essential roles in moving the infection on into the late phase; these two proteins are produced by the action of a dedicated promoter, the L4P, and without them the infection does not proceed successfully to progeny generation. In this new work, we delineate further aspects of L4P activity and regulation. Understanding how the L4P works, and how it contributes to activation of the late phase of infection, is important to our understanding of natural infections by the virus, in which late gene expression can fail to occur, allowing the virus to persist. PMID- 25926635 TI - Immediate and Ongoing Detection of Prions in the Blood of Hamsters and Deer following Oral, Nasal, or Blood Inoculations. AB - Infectious prions traverse epithelial barriers to gain access to the circulatory system, yet the temporal parameters of transepithelial transport and persistence in the blood over time remain unknown. We used whole-blood real-time quaking induced conversion (wbRT-QuIC) to analyze whole blood collected from transmissible spongiform encephalopathy (TSE)-inoculated deer and hamsters throughout the incubation period for the presence of common prion protein conversion competent amyloid (PrPCCCA). We observed PrPC-CCA in the blood of TSE inoculated hosts throughout the disease course from minutes postexposure to terminal disease. PMID- 25926636 TI - A Functional Interaction between Herpes Simplex Virus 1 Glycoprotein gH/gL Domains I and II and gD Is Defined by Using Alphaherpesvirus gH and gL Chimeras. AB - Whereas most viruses require only a single protein to bind to and fuse with cells, herpesviruses use multiple glycoproteins to mediate virus entry, and thus communication among these proteins is required. For most alphaherpesviruses, the minimal set of viral proteins required for fusion with the host cell includes glycoproteins gD, gB, and a gH/gL heterodimer. In the current model of entry, gD binds to a cellular receptor and transmits a signal to gH/gL. This signal then triggers gB, the conserved fusion protein, to insert into the target membrane and refold to merge the viral and cellular membranes. We previously demonstrated that gB homologs from two alphaherpesviruses, herpes simplex virus 1 (HSV-1) and saimiriine herpesvirus 1 (SaHV-1), were interchangeable. In contrast, neither gD nor gH/gL functioned with heterotypic entry glycoproteins, indicating that gD and gH/gL exhibit an essential type-specific functional interaction. To map this homotypic interaction site on gH/gL, we generated HSV-1/SaHV-1 gH and gL chimeras. The functional interaction with HSV-1 gD mapped to the N-terminal domains I and II of the HSV-1 gH ectodomain. The core of HSV-1 gL that interacts with gH also was required for functional homotypic interaction. The N-terminal gH/gL domains I and II are the least conserved and may have evolved to support species-specific glycoprotein interactions. IMPORTANCE: The first step of the herpesvirus life cycle is entry into a host cell. A coordinated interaction among multiple viral glycoproteins is required to mediate fusion of the viral envelope with the cell membrane. The details of how these glycoproteins interact to trigger fusion are unclear. By swapping the entry glycoproteins of two alphaherpesviruses (HSV-1 and SaHV-1), we previously demonstrated a functional homotypic interaction between gD and gH/gL. To define the gH and gL requirements for homotypic interaction, we evaluated the function of a panel of HSV-1/SaHV-1 gH and gL chimeras. We demonstrate that domains I and II of HSV-1 gH are sufficient to promote a functional, albeit reduced, interaction with HSV-1 gD. These findings contribute to our model of how the entry glycoproteins cooperate to mediate herpesvirus entry into the cell. PMID- 25926637 TI - Recombination Analysis of Herpes Simplex Virus 1 Reveals a Bias toward GC Content and the Inverted Repeat Regions. AB - Herpes simplex virus 1 (HSV-1) causes recurrent mucocutaneous ulcers and is the leading cause of infectious blindness and sporadic encephalitis in the United States. HSV-1 has been shown to be highly recombinogenic; however, to date, there has been no genome-wide analysis of recombination. To address this, we generated 40 HSV-1 recombinants derived from two parental strains, OD4 and CJ994. The 40 OD4-CJ994 HSV-1 recombinants were sequenced using the Illumina sequencing system, and recombination breakpoints were determined for each of the recombinants using the Bootscan program. Breakpoints occurring in the terminal inverted repeats were excluded from analysis to prevent double counting, resulting in a total of 272 breakpoints in the data set. By placing windows around the 272 breakpoints followed by Monte Carlo analysis comparing actual data to simulated data, we identified a recombination bias toward both high GC content and intergenic regions. A Monte Carlo analysis also suggested that recombination did not appear to be responsible for the generation of the spontaneous nucleotide mutations detected following sequencing. Additionally, kernel density estimation analysis across the genome found that the large, inverted repeats comprise a recombination hot spot. IMPORTANCE: Herpes simplex virus 1 (HSV-1) virus is the leading cause of sporadic encephalitis and blinding keratitis in developed countries. HSV-1 has been shown to be highly recombinogenic, and recombination itself appears to be a significant component of genome replication. To date, there has been no genome wide analysis of recombination. Here we present the findings of the first genome wide study of recombination performed by generating and sequencing 40 HSV-1 recombinants derived from the OD4 and CJ994 parental strains, followed by bioinformatics analysis. Recombination breakpoints were determined, yielding 272 breakpoints in the full data set. Kernel density analysis determined that the large inverted repeats constitute a recombination hot spot. Additionally, Monte Carlo analyses found biases toward high GC content and intergenic and repetitive regions. PMID- 25926638 TI - Lymph Node Macrophages Restrict Murine Cytomegalovirus Dissemination. AB - Cytomegaloviruses (CMVs) establish chronic infections that spread from a primary entry site to secondary vascular sites, such as the spleen, and then to tertiary shedding sites, such as the salivary glands. Human CMV (HCMV) is difficult to analyze, because its spread precedes clinical presentation. Murine CMV (MCMV) offers a tractable model. It is hypothesized to spread from peripheral sites via vascular endothelial cells and associated monocytes. However, viral luciferase imaging showed footpad-inoculated MCMV first reaching the popliteal lymph nodes (PLN). PLN colonization was rapid and further spread was slow, implying that LN infection can be a significant bottleneck. Most acutely infected PLN cells were CD169(+) subcapsular sinus macrophages (SSM). Replication-deficient MCMV also reached them, indicating direct infection. Many SSM expressed viral reporter genes, but few expressed lytic genes. SSM expressed CD11c, and MCMV with a cre sensitive fluorochrome switch showed switched infected cells in PLN of CD11c-cre mice but yielded little switched virus. SSM depletion with liposomal clodronate or via a CD169-diphtheria toxin receptor transgene shifted infection to ER-TR7(+) stromal cells, increased virus production, and accelerated its spread to the spleen. Therefore, MCMV disseminated via LN, and SSM slowed this spread by shielding permissive fibroblasts and poorly supporting viral lytic replication. IMPORTANCE: HCMV chronically infects most people, and it can cause congenital disability and harm the immunocompromised. A major goal of vaccination is to prevent systemic infection. How this is established is unclear. Restriction to humans makes HCMV difficult to analyze. We show that peripheral MCMV infection spreads via lymph nodes. Here, MCMV infected filtering macrophages, which supported virus replication poorly. When these macrophages were depleted, MCMV infected susceptible fibroblasts and spread faster. The capacity of filtering macrophages to limit MCMV spread argued that their infection is an important bottleneck in host colonization and might be a good vaccine target. PMID- 25926639 TI - Newcastle Disease Virus-Vectored H7 and H5 Live Vaccines Protect Chickens from Challenge with H7N9 or H5N1 Avian Influenza Viruses. AB - Sporadic human infections by a novel H7N9 virus occurred over a large geographic region in China. In this study, we show that Newcastle disease virus (NDV) vectored H7 (NDV-H7) and NDV-H5 vaccines are able to induce antibodies with high hemagglutination inhibition (HI) titers and completely protect chickens from challenge with the novel H7N9 or highly pathogenic H5N1 viruses, respectively. Notably, a baculovirus-expressed H7 protein failed to protect chickens from H7N9 virus infection. PMID- 25926640 TI - The Nectin-4/Afadin Protein Complex and Intercellular Membrane Pores Contribute to Rapid Spread of Measles Virus in Primary Human Airway Epithelia. AB - The discovery that measles virus (MV) uses the adherens junction protein nectin-4 as its epithelial receptor provides a new vantage point from which to characterize its rapid spread in the airway epithelium. We show here that in well differentiated primary cultures of airway epithelial cells from human donors (HAE), MV infectious centers form rapidly and become larger than those of other respiratory pathogens: human respiratory syncytial virus, parainfluenza virus 5, and Sendai virus. While visible syncytia do not form after MV infection of HAE, the cytoplasm of an infected cell suddenly flows into an adjacent cell, as visualized through wild-type MV-expressed cytoplasmic green fluorescent protein (GFP). High-resolution video microscopy documents that GFP flows through openings that form on the lateral surfaces between columnar epithelial cells. To assess the relevance of the protein afadin, which connects nectin-4 to the actin cytoskeleton, we knocked down its mRNA. This resulted in more-limited infectious center formation. We also generated a nectin-4 mutant without the afadin-binding site in its cytoplasmic tail. This mutant was less effective than wild-type human nectin-4 at promoting MV infection in primary cultures of porcine airway epithelia. Thus, in airway epithelial cells, MV spread requires the nectin 4/afadin complex and is based on cytoplasm transfer between columnar cells. Since the viral membrane fusion apparatus may open the passages that allow cytoplasm transfer, we refer to them as intercellular membrane pores. Virus-induced intercellular pores may contribute to extremely efficient measles contagion by promoting the rapid spread of the virus through the upper respiratory epithelium. IMPORTANCE: Measles virus (MV), while targeted for eradication, still causes about 120,000 deaths per year worldwide. The recent reemergence of measles in insufficiently vaccinated populations in Europe and North America reminds us that measles is extremely contagious, but the processes favoring its spread in the respiratory epithelium remain poorly defined. Here we characterize wild-type MV spread in well-differentiated primary cultures of human airway epithelial cells. We observed that viral infection promotes the flow of cytoplasmic contents from infected to proximal uninfected columnar epithelial cells. Cytoplasm flows through openings that form on the lateral surfaces. Infectious-center growth is facilitated by afadin, a protein connecting the adherens junction and the actin cytoskeleton. The viral fusion apparatus may open intercellular pores, and the cytoskeleton may stabilize them. Rapid homogenization of cytoplasmic contents in epithelial infectious centers may favor rapid spread and contribute to the extremely contagious nature of measles. PMID- 25926641 TI - A Combined Genetic-Proteomic Approach Identifies Residues within Dengue Virus NS4B Critical for Interaction with NS3 and Viral Replication. AB - Dengue virus (DENV) infection causes the most prevalent arthropod-borne viral disease worldwide. Approved vaccines are not available, and targets suitable for the development of antiviral drugs are lacking. One possible drug target is nonstructural protein 4B (NS4B), because it is absolutely required for virus replication; however, its exact role in the DENV replication cycle is largely unknown. With the aim of mapping NS4B determinants critical for DENV replication, we performed a reverse genetic screening of 33 NS4B mutants in the context of an infectious DENV genome. While the majority of these mutations were lethal, for several of them, we were able to select for second-site pseudoreversions, most often residing in NS4B and restoring replication competence. To identify all viral NS4B interaction partners, we engineered a fully viable DENV genome encoding an affinity-tagged NS4B. Mass spectrometry-based analysis of the NS4B complex isolated from infected cells identified the NS3 protease/helicase as a major interaction partner of NS4B. By combining the genetic complementation map of NS4B with a replication-independent expression system, we identified the NS4B cytosolic loop-more precisely, amino acid residue Q134-as a critical determinant for NS4B-NS3 interaction. An alanine substitution at this site completely abrogated the interaction and DENV RNA replication, and both were restored by pseudoreversions A69S and A137V. This strict correlation between the degree of NS4B-NS3 interaction and DENV replication provides strong evidence that this viral protein complex plays a pivotal role during the DENV replication cycle, hence representing a promising target for novel antiviral strategies. IMPORTANCE: With no approved therapy or vaccine against dengue virus infection, the viral nonstructural protein 4B (NS4B) represents a possible drug target, because it is indispensable for virus replication. However, little is known about its precise structure and function. Here, we established the first comprehensive genetic interaction map of NS4B, identifying amino acid residues that are essential for virus replication, as well as second-site mutations compensating for their defects. Additionally, we determined the NS4B viral interactome in infected cells and identified the NS3 protease/helicase as a major interaction partner of NS4B. We mapped residues in the cytosolic loop of NS4B as critical determinants for interaction with NS3, as well as RNA replication. The strong correlation between NS3-NS4B interaction and RNA replication provides strong evidence that this complex plays a pivotal role in the viral replication cycle, hence representing a promising antiviral drug target. PMID- 25926642 TI - Heterogeneous Nuclear Ribonucleoprotein M Facilitates Enterovirus Infection. AB - Picornavirus infection involves a dynamic interplay of host and viral protein interactions that modulates cellular processes to facilitate virus infection and evade host antiviral defenses. Here, using a proteomics-based approach known as TAILS to identify protease-generated neo-N-terminal peptides, we identify a novel target of the poliovirus 3C proteinase, the heterogeneous nuclear ribonucleoproteinM(hnRNP M), a nucleocytoplasmic shuttling RNA-binding protein that is primarily known for its role in pre-mRNA splicing. hnRNPMis cleaved in vitro by poliovirus and coxsackievirus B3 (CVB3) 3C proteinases and is targeted in poliovirus- and CVB3-infected HeLa cells and in the hearts of CVB3-infected mice. hnRNPMrelocalizes from the nucleus to the cytoplasm during poliovirus infection. Finally, depletion of hnRNPMusing small interfering RNA knockdown approaches decreases poliovirus and CVB3 infections in HeLa cells and does not affect poliovirus internal ribosome entry site translation and viral RNA stability. We propose that cleavage of and subverting the function of hnRNPMis a general strategy utilized by picornaviruses to facilitate viral infection. IMPORTANCE: Enteroviruses, a member of the picornavirus family, are RNA viruses that cause a range of diseases, including respiratory ailments, dilated cardiomyopathy, and paralysis. Although enteroviruses have been studied for several decades, the molecular basis of infection and the pathogenic mechanisms leading to disease are still poorly understood. Here, we identify hnRNPMas a novel target of a viral proteinase. We demonstrate that the virus subverts the function of hnRNPMand redirects it to a step in the viral life cycle. We propose that cleavage of hnRNPMis a general strategy that picornaviruses use to facilitate infection. PMID- 25926643 TI - Differential Expression of CX3CL1 in Hepatitis B Virus-Replicating Hepatoma Cells Can Affect the Migration Activity of CX3CR1+ Immune Cells. AB - In addition to stellate cells and immune cells, inflamed hepatocytes and hepatoma cells express various kinds of chemokines that attract various kinds of immune cells. Previously, we reported that hepatitis B virus (HBV) replication can induce physiological stress. The aim of this study was to analyze the effect of chemokines produced by HBV-infected hepatocytes and hepatoma cells. A real-time PCR array targeting genes related to chemokines and enzyme-linked immunosorbent assay (ELISA) were carried out to detect the specific chemokines produced by Huh7 cells and HepG2 cells infected with various HBV genotypes. A migration assay, flow cytometry analysis, and immunohistochemistry were carried out to analyze the candidate immune cells that can affect the immunopathogenesis of HBV infection. The expressions of CX3CL1 mRNA and protein were significantly different among HBV genotypes A, B, and C and control cells (mock) (P < 0.05). CD56(+) NK cells and CD8(+) T cells migrated to the hepatoma cells with HBV replication. Moreover, the migration activity of both immune cells was partially cancelled after the treatment of CX3CL1 neutralizing antibody. The expression level of NKG2D on CX3CR1(+) NK cells in HCC with HBV infection was significantly lower than that in hepatocellular carcinoma (HCC) with HCV infection and chronic hepatitis B and C patients (P < 0.05). On the other hand, the frequency of PD-1(high) CX3CR1(+) CD8(+) T cells in HCC with HBV infection was significantly higher than that in HCC with HCV infection and chronic hepatitis B and C (P < 0.05). The expression of CX3CL1 in HBV-replicating hepatocytes and hepatoma cells could contribute to the immunopathogenesis of HBV infection. IMPORTANCE: The progressions of the disease are significantly different among HBV genotypes. However, it has not been clear that how different HBV genotypes could induce different inflammatory responses. Here, we first report that the levels of expression of CX3CL1 mRNA and protein were significantly different among HBV genotypes A, B, and C and mock. Not only the differential expression of CX3CL1 among the genotypes but also the phenotype of CX3CR1(+) NK cells and T cells were gradually changed during the progression of the disease status. In addition to in vitro study, the analysis of immunohistochemistry with human samples and NOG mice with human lymphocytes and hepatoma cells supports this phenomenon. The quantification of CX3CL1 could contribute to better understanding of the disease status of HBV infection. Moreover, modifying CX3CL1 might induce an immune response appropriate to the disease status of HBV infection. PMID- 25926644 TI - Inefficient Codon Usage Impairs mRNA Accumulation: the Case of the v-FLIP Gene of Kaposi's Sarcoma-Associated Herpesvirus. AB - Latent Kaposi's sarcoma-associated herpesvirus (KSHV) genomes encode a homolog of cellular FLICE-inhibitory proteins (termed v-FLIP) that activates NF-kappaB and can trigger important proinflammatory and antiapoptotic changes in latently infected cells. The protein is present at very low levels in infection and has generally been difficult to efficiently express in recombinant vectors. Here we show that codon usage in the v-FLIP gene is strikingly suboptimal. Optimization of codon use in expression vectors, as expected, restores efficient protein expression. Surprisingly, however, it also dramatically increases the steady state level of v-FLIP mRNA, at least in part by increasing mRNA stability. When codon-optimized v-FLIP sequences are reintroduced into intact KSHV genomes, the resulting virus expresses readily detectable monocistronic v-FLIP mRNAs that are undetectable in wild-type (WT) infection by blot hybridization, suggesting that such RNAs are in fact transcribed in WT infection but fail to accumulate. The overexpression of v-FLIP by codon-optimized latent genomes results in a 5- to 7 fold decrement in virus production following lytic induction, indicating that maximizing NF-kappaB signaling is deleterious to induction. These studies provide a clear explanation for the evolution of inefficient codon usage in this gene and point to a strong connection between translational efficiency and RNA accumulation in mammalian cells. IMPORTANCE: This study reports that inefficient codon usage in a herpesviral gene is strikingly correlated with the inability of its mRNA to accumulate in cells; correction of efficient translatability restores RNA abundance. A similar correlation has been reported in yeast species, but the mechanisms operating in mammalian cells appear substantially different. PMID- 25926646 TI - Human Plasmacytoid Dendritic Cells Elicited Different Responses after Infection with Pathogenic and Nonpathogenic Junin Virus Strains. AB - The arenavirus Junin virus (JUNV) is the etiologic agent of Argentine hemorrhagic fever. We characterized the JUNV infection of human peripheral blood-derived plasmacytoid dendritic cells (hpDC), demonstrating that hpDC are susceptible to infection with the C#1 strain (attenuated) and even more susceptible to infection with the P (virulent) JUNV strain. However, hpDC elicited different responses in terms of viability, activation, maturation, and cytokine expression after infection with both JUNV strains. PMID- 25926645 TI - New Noncoding Lytic Transcripts Derived from the Epstein-Barr Virus Latency Origin of Replication, oriP, Are Hyperedited, Bind the Paraspeckle Protein, NONO/p54nrb, and Support Viral Lytic Transcription. AB - We have previously shown that the Epstein-Barr virus (EBV) likely encodes hundreds of viral long noncoding RNAs (vlncRNAs) that are expressed during reactivation. Here we show that the EBV latency origin of replication (oriP) is transcribed bi-directionally during reactivation and that both leftward (oriPtLs) and rightward (oriPtRs) transcripts are largely localized in the nucleus. While the oriPtLs are most likely noncoding, at least some of the oriPtRs contain the BCRF1/vIL10 open reading frame. Nonetheless, oriPtR transcripts with long 5' untranslated regions may partially serve noncoding functions. Both oriPtL and oriPtR transcripts are expressed with late kinetics, and their expression is inhibited by phosphonoacetic acid. RNA sequencing (RNA-seq) analysis showed that oriPtLs and oriPtRs exhibited extensive "hyperediting" at their Family of Repeat (FR) regions. RNA secondary structure prediction revealed that the FR region of both oriPtLs and oriPtRs may form large evolutionarily conserved and thermodynamically stable hairpins. The double-stranded RNA-binding protein and RNA-editing enzyme ADAR was found to bind to oriPtLs, likely facilitating editing of the FR hairpin. Further, the multifunctional paraspeckle protein, NONO, was found to bind to oriPt transcripts, suggesting that oriPts interact with the paraspeckle-based innate antiviral immune pathway. Knockdown and ectopic expression of oriPtLs showed that it contributes to global viral lytic gene expression and viral DNA replication. Together, these results show that these new vlncRNAs interact with cellular innate immune pathways and that they help facilitate progression of the viral lytic cascade. IMPORTANCE: Recent studies have revealed that the complexity of lytic herpesviral transcriptomes is significantly greater than previously appreciated with hundreds of viral long noncoding RNAs (vlncRNAs) being recently discovered. Work on cellular lncRNAs over the past several years has just begun to give us an initial appreciation for the array of functions they play in complex formation and regulatory processes in the cell. The newly identified herpesvirus lncRNAs are similarly likely to play a variety of different functions, although these functions are likely tailored to specific needs of the viral infection cycles. Here we describe novel transcripts derived from the EBV latency origin of replication. We show that they are hyperedited, that they interact with a relatively newly appreciated antiviral pathway, and that they play a role in facilitating viral lytic gene expression. These investigations are a starting point to unraveling the complex arena of vlncRNA function in herpesvirus lytic replication. PMID- 25926647 TI - SAMHD1 Limits HIV-1 Antigen Presentation by Monocyte-Derived Dendritic Cells. AB - Monocyte-derived dendritic cells (MDDC) stimulate CD8 cytotoxic T lymphocytes (CTL) by presenting endogenous and exogenous viral peptides via major histocompatibility complex class I (MHC-I) molecules. MDDC are poorly susceptible to HIV-1, in part due to the presence of SAMHD1, a cellular enzyme that depletes intracellular deoxynucleoside triphosphates (dNTPs) and degrades viral RNA. Vpx, an HIV-2/SIVsm protein absent from HIV-1, antagonizes SAMHD1 by inducing its degradation. The impact of SAMHD1 on the adaptive cellular immune response remains poorly characterized. Here, we asked whether SAMHD1 modulates MHC-I restricted HIV-1 antigen presentation. Untreated MDDC or MDDC pretreated with Vpx were exposed to HIV-1, and antigen presentation was examined by monitoring the activation of an HIV-1 Gag-specific CTL clone. SAMHD1 depletion strongly enhanced productive infection of MDDC as well as endogenous HIV-1 antigen presentation. Time-lapse microscopy analysis demonstrated that in the absence of SAMHD1, the CTL rapidly killed infected MDDC. We also report that various transmitted/founder (T/F) HIV-1 strains poorly infected MDDC and, as a consequence, did not stimulate CTL. Vesicular stomatitis virus glycoprotein (VSV-G) pseudotyping of T/F alleviated a block in viral entry and induced antigen presentation only in the absence of SAMHD1. Furthermore, by using another CTL clone that mostly recognizes incoming HIV-1 antigens, we demonstrate that SAMHD1 does not influence exogenous viral antigen presentation. Altogether, our results demonstrate that the antiviral activity of SAMHD1 impacts antigen presentation by DC, highlighting the link that exists between restriction factors and adaptive immune responses. IMPORTANCE: Upon viral infection, DC may present antigens derived from incoming viral material in the absence of productive infection of DC or from newly synthesized viral proteins. In the case of HIV, productive infection of DC is blocked at an early postentry step. This is due to the presence of SAMHD1, a cellular enzyme that depletes intracellular levels of dNTPs and inhibits viral reverse transcription. We show that the depletion of SAMHD1 in DCs strongly stimulates the presentation of viral antigens derived from newly produced viral proteins, leading to the activation of HIV-1-specific cytotoxic T lymphocytes (CTL). We further show in real time that the enhanced activation of CTL leads to killing of infected DCs. Our results indicate that the antiviral activity of SAMHD1 not only impacts HIV replication but also impacts antigen presentation by DC. They highlight the link that exists between restriction factors and adaptive immune responses. PMID- 25926648 TI - Recombination of Globally Circulating Varicella-Zoster Virus. AB - Varicella-zoster virus (VZV) is a human herpesvirus, which during primary infection typically causes varicella (chicken pox) and establishes lifelong latency in sensory and autonomic ganglia. Later in life, the virus may reactivate to cause herpes zoster (HZ; also known as shingles). To prevent these diseases, a live-attenuated heterogeneous vaccine preparation, vOka, is used routinely in many countries worldwide. Recent studies of another alphaherpes virus, infectious laryngotracheitis virus, demonstrate that live-attenuated vaccine strains can recombine in vivo, creating virulent progeny. These findings raised concerns about using attenuated herpesvirus vaccines under conditions that favor recombination. To investigate whether VZV may undergo recombination, which is a prerequisite for VZV vaccination to create such conditions, we here analyzed 115 complete VZV genomes. Our results demonstrate that recombination occurs frequently for VZV. It thus seems that VZV is fully capable of recombination if given the opportunity, which may have important implications for continued VZV vaccination. Although no interclade vaccine wild-type recombinant strains were found, intraclade recombinants were frequently detected in clade 2, which harbors the vaccine strains, suggesting that the vaccine strains have already been involved in recombination events, either in vivo or in vitro during passages in cell culture. Finally, previous partial and complete genomic studies have described strains that do not cluster phylogenetically to any of the five established clades. The additional VZV strains sequenced here, in combination with those previously published, have enabled us to formally define a novel sixth VZV clade. IMPORTANCE: Although genetic recombination has been demonstrated to frequently occur for other human alphaherpesviruses, herpes simplex viruses 1 and 2, only a few ancient and isolated recent recombination events have hitherto been demonstrated for VZV. In the present study, we demonstrate that VZV also frequently undergoes genetic recombination, including strains belonging to the clade containing the vOKA strain. PMID- 25926649 TI - Human Cytokinome Analysis for Interferon Response. AB - Cytokines are a group of small secreted proteins that mediate a diverse range of immune and nonimmune responses to inflammatory and microbial stimuli. Only a few of these cytokines mount an antiviral response, including type I, II, and III interferons (IFNs). During viral infections and under inflammatory conditions, a number of cytokines and chemokines are coproduced with IFN; however, no systematic study exists on the interactions of the cytokine repertoire with the IFN response. Here, we performed the largest cytokine and chemokine screen (the human cytokinome, with >240 members) to investigate their modulation of type I and type II IFN responses in a cell line model. We evaluated the cytokine activities in both IFN-stimulated response element (ISRE) and IFN-gamma activation sequence (GAS) reporter systems. Several cytokine clusters that augment either or both ISRE- and GAS-mediated responses to IFNs were derived from the screen. We identified novel modulators of IFN response-betacellulin (BTC), interleukin 11 (IL-11), and IL-17F-that caused time-dependent induction of the IFN response. The ability to induce endogenous IFN-beta and IFN-stimulated genes varies among these cytokines and was largely dependent on Stat1, as assessed by Stat1 mutant fibroblasts. Certain cytokines appear to augment the IFN-beta response through the NF-kappaB pathway. The novel IFN-like cytokines augmented the antiviral activity of IFN-alpha against several RNA viruses, including encephalomyocarditis virus, vesicular stomatitis virus, and influenza virus, in susceptible cell lines. Overall, the study represents a large-scale analysis of cytokines for enhancing the IFN response and identified cytokines capable of enhancing Stat1, IFN-induced gene expression, and antiviral activities. IMPORTANCE: Innate immunity to viruses is an early defense system to ward off viruses. One mediator is interferon (IFN), which activates a cascade of biochemical events that aim to control the virus life cycle. In our work, we examined more than 200 cytokines, soluble mediators produced within the body as a result of infection, for the ability to enhance IFN action. We identified enhanced interactions with specific IFNs and cytokines. We also revealed that betacellulin, IL-17, and IL-11 cytokines have the novel property of enhancing the antiviral action of IFN against several viruses. These results demonstrate that the human genome codes for previously unknown proteins with unrelated functions that can augment the innate immunity to viruses. Knowing these interactions not only helps our understanding of immunity to viruses and emerging diseases, but can also lead to devising possible new therapeutics by enhancing the mediator of antiviral action itself, IFN. PMID- 25926650 TI - Design and Structure of an Engineered Disulfide-Stabilized Influenza Virus Hemagglutinin Trimer. AB - We engineered a disulfide-stabilized influenza virus hemagglutinin (HA) trimer, termed HA3-SS, by introducing cysteine residues into the HA stem to covalently bridge the three protomers. HA3-SS has increased thermostability compared to wild type HA, and binding of head- and stem-targeted antibodies (Abs) is preserved; only minor structural changes are found in the vicinity of the additional disulfide. This platform has been applied to H1 and H3 HAs and provides prospects for design of intact, stabilized influenza virus HA immunogens. PMID- 25926651 TI - A Seminomadic Population in Bangladesh with Extensive Exposure to Macaques Does Not Exhibit High Levels of Zoonotic Simian Foamy Virus Infection. AB - Simian foamy viruses (SVF) are ubiquitous in nonhuman primates (NHP). SFV can be zoonotically transmitted to humans who either work with or live commensally with NHP. We analyzed the blood of 45 Bangladeshi performing monkey owners (an ethnic group called the Bedey) for SFV infection. Surprisingly, a PCR assay failed to detect SFV infection in any of these participants. This is in contrast to our previously reported infection rate of about 5% among Bangladeshi villagers. PMID- 25926652 TI - Identification of a Novel Hepacivirus in Domestic Cattle from Germany. AB - Hepatitis C virus (HCV) continues to represent one of the most significant threats to human health. In recent years, HCV-related sequences have been found in bats, rodents, horses, and dogs, indicating a widespread distribution of hepaciviruses among animals. By applying unbiased high-throughput sequencing, a novel virus of the genus Hepacivirus was discovered in a bovine serum sample. De novo assembly yielded a nearly full-length genome coding for a polyprotein of 2,779 amino acids. Phylogenetic analysis confirmed that the virus represents a novel species within the genus Hepacivirus. Viral RNA screening determined that 1.6% (n = 5) of 320 individual animals and 3.2% (n = 5) of 158 investigated cattle herds in Germany were positive for bovine hepacivirus. Repeated reverse transcription-PCR (RT-PCR) analyses of animals from one dairy herd proved that a substantial percentage of cows were infected, with some of them being viremic for over 6 months. Clinical and postmortem examination revealed no signs of disease, including liver damage. Interestingly, quantitative RT-PCR from different organs and tissues, together with the presence of an miR-122 binding site in the viral genome, strongly suggests a liver tropism for bovine hepacivirus, making this novel virus a promising animal model for HCV infections in humans. IMPORTANCE: Livestock animals act as important sources for emerging pathogens. In particular, their large herd size and the existence of multiple ways of direct and food-borne infection routes emphasize their role as virus reservoirs. Apart from the search for novel viruses, detailed characterization of these pathogens is indispensable in the context of risk analysis. Here, we describe the identification of a novel HCV-like virus in cattle. In addition, determination of the prevalence and of the course of infection in cattle herds provides valuable insights into the biology of this novel virus. The results presented here form a basis for future studies targeting viral pathogenesis of bovine hepaciviruses and their potential to establish zoonotic infections. PMID- 25926653 TI - Human Coronavirus HKU1 Spike Protein Uses O-Acetylated Sialic Acid as an Attachment Receptor Determinant and Employs Hemagglutinin-Esterase Protein as a Receptor-Destroying Enzyme. AB - Human coronavirus (hCoV) HKU1 is one of six hCoVs identified to date and the only one with an unidentified cellular receptor. hCoV-HKU1 encodes a hemagglutinin esterase (HE) protein that is unique to the group a betacoronaviruses (group 2a). The function of HKU1-HE remains largely undetermined. In this study, we examined binding of the S1 domain of hCoV-HKU1 spike to a panel of cells and found that the S1 could specifically bind on the cell surface of a human rhabdomyosarcoma cell line, RD. Pretreatment of RD cells with neuraminidase (NA) and trypsin greatly reduced the binding, suggesting that the binding was mediated by sialic acids on glycoproteins. However, unlike other group 2a CoVs, e.g., hCoV-OC43, for which 9-O-acetylated sialic acid (9-O-Ac-Sia) serves as a receptor determinant, HKU1-S1 bound with neither 9-O-Ac-Sia-containing glycoprotein(s) nor rat and mouse erythrocytes. Nonetheless, the HKU1-HE was similar to OC43-HE, also possessed sialate-O-acetylesterase activity, and acted as a receptor-destroying enzyme (RDE) capable of eliminating the binding of HKU1-S1 to RD cells, whereas the O-acetylesterase-inactive HKU1-HE mutant lost this capacity. Using primary human ciliated airway epithelial (HAE) cell cultures, the only in vitro replication model for hCoV-HKU1 infection, we confirmed that pretreatment of HAE cells with HE but not the enzymatically inactive mutant blocked hCoV-HKU1 infection. These results demonstrate that hCoV-HKU1 exploits O-Ac-Sia as a cellular attachment receptor determinant to initiate the infection of host cells and that its HE protein possesses the corresponding sialate-O-acetylesterase RDE activity. IMPORTANCE: Human coronaviruses (hCoV) are important human respiratory pathogens. Among the six hCoVs identified to date, only hCoV-HKU1 has no defined cellular receptor. It is also unclear whether hemagglutinin-esterase (HE) protein plays a role in viral entry. In this study, we found that, similarly to other members of the group 2a CoVs, sialic acid moieties on glycoproteins are critical receptor determinants for the hCoV-HKU1 infection. Interestingly, the virus seems to employ a type of sialic acid different from those employed by other group 2a CoVs. In addition, we determined that the HKU1-HE protein is an O-acetylesterase and acts as a receptor-destroying enzyme (RDE) for hCoV-HKU1. This is the first study to demonstrate that hCoV-HKU1 uses certain types of O-acetylated sialic acid residues on glycoproteins to initiate the infection of host cells and that the HKU1-HE protein possesses sialate-O-acetylesterase RDE activity. PMID- 25926654 TI - Human Endogenous Retrovirus Type K (HERV-K) Particles Package and Transmit HERV-K Related Sequences. AB - Human endogenous retroviruses (HERV) make up 8% of the human genome. While the youngest of these retroviruses, HERV-K(HML-2), termed HK2, is able to code for all viral proteins and produce virus-like particles, it is not known if these virus particles package and transmit HK2-related sequences. Here, we analyzed the capacity of HK2 for packaging and transmitting HK2 sequences. We created an HK2 probe, termed Bogota, which can be packaged into HK2 viruses, and transfected it into cells that make HK2 particles. Supernatants of the transfected cells, which contained HK2 viral particles, then were added to target cells, and the transmissibility of the HK2 Bogota reporter was tracked by G418 resistance. Our studies revealed that contemporary HK2 virions produced by some teratocarcinoma and breast cancer cell lines, as well as by peripheral blood lymphocytes from lymphoma patients, can package HK2 Bogota probes, and these viruses transmitted these probes to other cells. After transmission, HK2 Bogota transcripts undergo reverse transcription, a step impaired by antiretroviral agents or by introduction of mutations into the probe sequences required for reverse transcription. HK2 viruses were more efficiently transmitted in the presence of HK2 Rec or HIV-1 Tat and Vif. Transmitted Bogota probes formed episomes but did not integrate into the cellular genome. Resistance to integration might explain the relatively low number of HK2 insertions that were acquired during the last 25 million years of evolution. Whether transient transmission of modern HK2 sequences, which encode two putative oncoproteins, can lead to disease remains to be studied. IMPORTANCE: Retroviruses invaded the genome of human ancestors over the course of millions of years, yet these viruses generally have been inactivated during evolution, with only remnants of these infectious sequences remaining in the human genome. One of these viruses, termed HK2, still is capable of producing virus particles, although these particles have been regarded as being noninfectious. Using a genetic probe derived from HK2, we have discovered that HK2 viruses produced in modern humans can package HK2 sequences and transmit them to various other cells. Furthermore, the genetic sequences packaged in HK2 undergo reverse transcription. The transmitted probe circularized in the cell and failed to integrate into the cellular genome. These findings suggest that modern HK2 viruses can package viral RNA and transmit it to other cells. Contrary to previous views, we provide evidence of an extracellular viral phase of modern HK2 viruses. We have no evidence of sustained, spreading infection. PMID- 25926655 TI - Kallikrein-8 Proteolytically Processes Human Papillomaviruses in the Extracellular Space To Facilitate Entry into Host Cells. AB - The entry of human papillomaviruses into host cells is a complex process. It involves conformational changes at the cell surface, receptor switching, internalization by a novel endocytic mechanism, uncoating in endosomes, trafficking of a subviral complex to the Golgi complex, and nuclear entry during mitosis. Here, we addressed how the stabilizing contacts in the capsid of human papillomavirus 16 (HPV16) may be reversed to allow uncoating of the viral genome. Using biochemical and cell-biological analyses, we determined that the major capsid protein L1 underwent proteolytic cleavage during entry. In addition to a dispensable cathepsin-mediated proteolysis that occurred likely after removal of capsomers from the subviral complex in endosomes, at least two further proteolytic cleavages of L1 were observed, one of which was independent of the low-pH environment of endosomes. This cleavage occurred extracellularly. Further analysis showed that the responsible protease was the secreted trypsin-like serine protease kallikrein-8 (KLK8) involved in epidermal homeostasis and wound healing. Required for infection, the cleavage was facilitated by prior interaction of viral particles with heparan sulfate proteoglycans. KLK8-mediated cleavage was crucial for further conformational changes exposing an important epitope of the minor capsid protein L2. Occurring independently of cyclophilins and of furin that mediate L2 exposure, KLK8-mediated cleavage of L1 likely facilitated access to L2, located in the capsid lumen, and potentially uncoating. Since HPV6 and HPV18 also required KLK8 for entry, we propose that the KLK8 dependent entry step is conserved. IMPORTANCE: Our analysis of the proteolytic processing of incoming HPV16, an etiological agent of cervical cancer, demonstrated that the capsid is cleaved extracellularly by a serine protease active during wound healing and that this cleavage was crucial for infection. The cleavage of L1 is one of at least four structural alterations that prime the virus extracellularly for receptor switching, internalization, and possibly uncoating. This step was also important for HPV6 and HPV18, which may suggest that it is conserved among the papillomaviruses. This study advances the understanding of how HPV16 initially infects cells, strengthens the notion that wounding facilitates infection of epidermal tissue, and may help the development of antiviral measures. PMID- 25926656 TI - Highly Pathogenic New World and Old World Human Arenaviruses Induce Distinct Interferon Responses in Human Cells. AB - The arenavirus family includes several important pathogens that cause severe and sometimes fatal diseases in humans. The highly pathogenic Old World (OW) arenavirus Lassa fever virus (LASV) is the causative agent of Lassa fever (LF) disease in humans. LASV infections in severe cases are generally immunosuppressive without stimulating interferon (IFN) induction, a proinflammatory response, or T cell activation. However, the host innate immune responses to highly pathogenic New World (NW) arenaviruses are not well understood. We have previously shown that the highly pathogenic NW arenavirus, Junin virus (JUNV), induced an IFN response in human A549 cells. Here, we report that Machupo virus (MACV), another highly pathogenic NW arenavirus, also induces an IFN response. Importantly, both pathogenic NW arenaviruses, in contrast to the OW highly pathogenic arenavirus LASV, readily elicited an IFN response in human primary dendritic cells and A549 cells. Coinfection experiments revealed that LASV could potently inhibit MACV-activated IFN responses even at 6 h after MACV infection, while the replication levels of MACV and LASV were not affected by virus coinfection. Our results clearly demonstrated that although all viruses studied herein are highly pathogenic to humans, the host IFN responses toward infections with the NW arenaviruses JUNV and MACV are quite different from responses to infections with the OW arenavirus LASV, a discovery that needs to be further investigated in relevant animal models. This finding might help us better understand various interplays between the host immune system and highly pathogenic arenaviruses as well as distinct mechanisms underlying viral pathogenesis. IMPORTANCE: Infections of humans with the highly pathogenic OW LASV are accompanied by potent suppression of interferon or proinflammatory cytokine production. In contrast, infections with the highly pathogenic NW arenavirus JUNV are associated with high levels of IFNs and cytokines in severe and fatal cases. Arenaviruses initially target macrophages and dendritic cells, which are potent IFN/cytokine-producers. In human macrophages, JUNV reportedly does not trigger IFN responses. We here demonstrated that JUNV activated IFN responses in human dendritic cells. MACV, another highly pathogenic NW arenavirus, also activated IFN responses. LASV did not induce detectable IFN responses, in spite of higher replication levels, and blocked the MACV-triggered IFN response in a coinfection assay. Although these viruses are highly pathogenic to humans, our study highlights distinct innate immune responses to infections with the NW arenaviruses JUNV and MACV and to infection with the OW arenavirus LASV and provides important insights into the virus-host interaction and pathogenesis. PMID- 25926657 TI - Enterovirus 71 Proteins 2A and 3D Antagonize the Antiviral Activity of Gamma Interferon via Signaling Attenuation. AB - Enterovirus 71 (EV71) infection causes severe mortality involving multiple possible mechanisms, including cytokine storm, brain stem encephalitis, and fulminant pulmonary edema. Gamma interferon (IFN-gamma) may confer anti-EV71 activity; however, the claim that disease severity is highly correlated to an increase in IFN-gamma is controversial and would indicate an immune escape initiated by EV71. This study, investigating the role of IFN-gamma in EV71 infection using a murine model, showed that IFN-gamma was elevated. Moreover, IFN gamma receptor-deficient mice showed higher mortality rates and more severe disease progression with slower viral clearance than wild-type mice. In vitro results showed that IFN-gamma pretreatment reduced EV71 yield, whereas EV71 infection caused IFN-gamma resistance with attenuated IFN-gamma signaling in IFN regulatory factor 1 (IRF1) gene transactivation. To study the immunoediting ability of EV71 proteins in IFN-gamma signaling, 11 viral proteins were stably expressed in cells without cytotoxicity; however, viral proteins 2A and 3D blocked IFN-gamma-induced IRF1 transactivation following a loss of signal transducer and activator of transcription 1 (STAT1) nuclear translocation. Viral 3D attenuated IFN-gamma signaling accompanied by a STAT1 decrease without interfering with IFN-gamma receptor expression. Restoration of STAT1 or blocking 3D activity was able to rescue IFN-gamma signaling. Interestingly, viral 2A attenuated IFN-gamma signaling using another mechanism by reducing the serine phosphorylation of STAT1 following the inactivation of extracellular signal regulated kinase without affecting STAT1 expression. These results demonstrate the anti-EV71 ability of IFN-gamma and the immunoediting ability by EV71 2A and 3D, which attenuate IFN-gamma signaling through different mechanisms. IMPORTANCE: Immunosurveillance by gamma interferon (IFN-gamma) may confer anti-enterovirus 71 (anti-EV71) activity; however, the claim that disease severity is highly correlated to an increase in IFN-gamma is controversial and would indicate an immune escape initiated by EV71. IFN-gamma receptor-deficient mice showed higher mortality and more severe disease progression, indicating the anti-EV71 property of IFN-gamma. However, EV71 infection caused cellular insusceptibility in response to IFN-gamma stimulation. We used an in vitro system with viral protein expression to explore the novel IFN-gamma inhibitory properties of the EV71 2A and 3D proteins through the different mechanisms. According to this study, targeting either 2A or 3D pharmacologically and/or genetically may sustain a cellular susceptibility in response to IFN-gamma, particularly for IFN-gamma mediated anti-EV71 activity. PMID- 25926658 TI - Do Family Proxies Get It Right? Concordance in Reports of Nursing Home Residents' Everyday Preferences. AB - Limited work has examined how well family proxies understand nursing home residents' preferences. With 85 dyads of a nursing home resident and relative, we utilize descriptive statistics and multi-level modeling to examine the concordance in reports of importance ratings of 72 everyday preferences for residents. Results reveal significant mean differences at the p < .001 level between proxies and residents on 12 of 72 preferences; yet, perfect agreement in responses is poor and only increases when dichotomizing responses into an important versus not important outcome. Multi-level modeling further indicates that dyads are discrepant on reports of the importance of growth activities for residents, with residents reporting higher levels of importance than proxies. This discrepancy is associated with residents' hearing impairment and proxies' perception of resident openness. The findings highlight not only how proxies may be able to inform care for residents in nursing homes but also where further discussions are warranted. PMID- 25926659 TI - Therapeutic effects of cell-permeant peptides that activate G proteins downstream of growth factors. AB - In eukaryotes, receptor tyrosine kinases (RTKs) and trimeric G proteins are two major signaling hubs. Signal transduction via trimeric G proteins has long been believed to be triggered exclusively by G protein-coupled receptors (GPCRs). This paradigm has recently been challenged by several studies on a multimodular signal transducer, Galpha-Interacting Vesicle associated protein (GIV/Girdin). We recently demonstrated that GIV's C terminus (CT) serves as a platform for dynamic association of ligand-activated RTKs with Galphai, and for noncanonical transactivation of G proteins. However, exogenous manipulation of this platform has remained beyond reach. Here we developed cell-permeable GIV-CT peptides by fusing a TAT-peptide transduction domain (TAT-PTD) to the minimal modular elements of GIV that are necessary and sufficient for activation of Gi downstream of RTKs, and used them to engineer signaling networks and alter cell behavior. In the presence of an intact GEF motif, TAT-GIV-CT peptides enhanced diverse processes in which GIV's GEF function has previously been implicated, e.g., 2D cell migration after scratch-wounding, invasion of cancer cells, and finally, myofibroblast activation and collagen production. Furthermore, topical application of TAT-GIV-CT peptides enhanced the complex, multireceptor-driven process of wound repair in mice in a GEF-dependent manner. Thus, TAT-GIV peptides provide a novel and versatile tool to manipulate Galphai activation downstream of growth factors in a diverse array of pathophysiologic conditions. PMID- 25926662 TI - Prolonged Stridor and Epiglottitis With Concurrent Bacterial and Viral Etiologies. PMID- 25926660 TI - Understanding the Mechanism of Thermotolerance Distinct From Heat Shock Response Through Proteomic Analysis of Industrial Strains of Saccharomyces cerevisiae. AB - Saccharomyces cerevisiae has been intensively studied in responses to different environmental stresses such as heat shock through global omic analysis. However, the S. cerevisiae industrial strains with superior thermotolerance have not been explored in any proteomic studies for elucidating the tolerance mechanism. Recently a new diploid strain was obtained through evolutionary engineering of a parental industrial strain, and it exhibited even higher resistance to prolonged thermal stress. Herein, we performed iTRAQ-based quantitative proteomic analysis on both the parental and evolved industrial strains to further understand the mechanism of thermotolerant adaptation. Out of ~ 2600 quantifiable proteins from biological quadruplicates, 193 and 204 proteins were differentially regulated in the parental and evolved strains respectively during heat-stressed growth. The proteomic response of the industrial strains cultivated under prolonged thermal stress turned out to be substantially different from that of the laboratory strain exposed to sudden heat shock. Further analysis of transcription factors underlying the proteomic perturbation also indicated the distinct regulatory mechanism of thermotolerance. Finally, a cochaperone Mdj1 and a metabolic enzyme Adh1 were selected to investigate their roles in mediating heat-stressed growth and ethanol production of yeasts. Our proteomic characterization of the industrial strain led to comprehensive understanding of the molecular basis of thermotolerance, which would facilitate future improvement in the industrially important trait of S. cerevisiae by rational engineering. PMID- 25926663 TI - An Adolescent Boy With a Painless Enlarged Right Hemiscrotum. PMID- 25926664 TI - The Value of Comprehensive Thyroid Function Testing and Family History for Early Diagnosis of MCT8 Deficiency. PMID- 25926665 TI - Health Education Counseling During Pediatric Well-Child Visits in Physicians' Office Settings. AB - OBJECTIVE: The current study assessed factors associated with health education counseling during well-child visits. METHODS: Data from the 2007-2010 National Ambulatory Medical Care Survey (NAMCS) were used to examine well-child visits made to physicians' offices in the United States. Logistic regression models examined the relationship between the provision of health education counseling and selected covariates. Health education provisions measured included injury prevention, nutrition, exercise, tobacco use, and weight reduction. RESULTS: A total of 4837 well-child visits were identified during the study period, which is equivalent to a weighted estimate of 43.4 million well-child visits annually. Multivariate analyses indicated that the length of the well-child visit was the predominant factor associated with delivery of health education counseling. CONCLUSIONS: Provider education and counseling of patients concerning health behaviors were implemented at a low level. Time spent with the patient was associated with the majority of health education counseling. Implications for pediatric practice are discussed. PMID- 25926666 TI - A Child With Fever and Swelling of the Forehead. Pott's puffy tumor and epidural abscess complicating frontal sinusitis. PMID- 25926667 TI - After-Hours Versus Office-Hours Dental Injuries in Children: Does Timing Influence Outcome? AB - AIM: The aim of this study was to analyze the outcomes and factors associated with after-hours dental trauma. METHODS: Study sample consisted of 1762 permanent teeth injuries in children, gender and age matched with office-hours injuries. Epidemiological and clinical data were collected from 4 university dental trauma centers. RESULTS: During median follow-up time of 4.3 years, complications have occurred in 14.5% of injured teeth. Age, type, and degree of tissue injury and after-hours time of injury were significantly associated with complications. Unfavorable outcomes were 34% more likely in the after-hours group compared with office-hours. Urgent treatment was significantly delayed in after-hours group with a delay of more than 3 hours in 90.5% versus 38.9% in the office-hours group. Multivariate regression model showed that after-hours time of injury was significant predictor of complications. CONCLUSION: Delayed urgent treatment was one of the main factors associated with unfavorable outcome of after-hours injuries. PMID- 25926668 TI - Receipt of Pediatric Weight-Related Counseling and Screening in a National Sample After the Expert Committee Recommendations. AB - OBJECTIVE: It is uncertain whether children of all weight classifications receive the recommended screening and counseling and if these affect weight status in the subsequent year. METHODS: Data from the 2008-2011 Medical Expenditures Panel Survey were used to examine associations between weight classification and receipt of weight-related screening and counseling from the pediatric provider (n = 9835). Body mass index (BMI) z-score in the subsequent year was modeled as a function of the BMI z-score in year 1. RESULTS: Normal and overweight children have lower odds than obese children of receiving counseling regarding diet (adjusted odds ratio [AOR] = 0.58, 95% confidence interval [CI] = 0.50-0.68; AOR = 0.75, 95% CI = 0.63-0.89, respectively) and exercise (AOR = 0.56, 95% CI = 0.48 0.65; AOR = 0.75, 95% CI = 0.64-0.89, respectively). Counseling was associated with a small increase in BMI z-score in the subsequent year (beta = 0.06, 95% CI = 0.01-0.11), as was maternal weight class. CONCLUSIONS: Recommendations to focus prevention on the family unit may reduce childhood overweight and obesity. PMID- 25926669 TI - Pulse Oximetry: Could Wrist and Ankle Be Alternative Placement Sites? AB - OBJECTIVE: To compare the accuracy of pulse oximetry oxygen saturation (SpO2) measured on the right wrist and right ankle in relation to the ipsilateral palm and sole, respectively. STUDY DESIGN: A prospective observational study carried out on neonates and infants admitted to intensive care units. SpO2 was measured at the right palm and wrist and the right sole and ankle. Sensitivity and specificity tests were performed. RESULTS: Ninety-four patients, mean postnatal age of 29.9 days, were included in our study. Sensitivity and specificity tests for right wrist SpO2 in comparison to right palm SpO2 revealed sensitivity of 100% and specificity of 80.4%. Sensitivity and specificity tests for right ankle SpO2 in comparison to right sole SpO2 revealed sensitivity of 100% and specificity of 77.4%. CONCLUSION: The results of the current study revealed that the wrist and ankle can be alternative placement sites for the measurement of SpO2 in newborn and infants instead of the routinely used palm or sole. PMID- 25926670 TI - An Infant With Persistent Failure to Thrive. PMID- 25926671 TI - Thermosensitive tribrachia star-shaped s-P(NIPAM-co-DMAM) random copolymer micelle aggregates: Preparation, characterization, and drug release applications. AB - Tribrachia star-shaped random copolymers with tunable thermosensitive phase transition temperature were designed and synthesized via a simple one-pot ammonolysis reaction approach with trimesic acid as cores. The self-assembly micellization behavior of the copolymers in aqueous solution was examined by surface tension, UV-vis transmittance, transmission electron microscope, and dynamic light scattering measurements, etc. The results indicated that the resultant copolymers formed thermosensitive micelle aggregates through hydrophobic interactions among the isopropyl groups of poly(N isopropylacrylamide) PNIPAM chains and inter-star association at a polymer concentration above critical aggregation concentrations from 4.06 to 6.55 mg L( 1), with a cloud point range from 36.6C to 52.1C, and homogeneously distributed micelle size below 200 nm. The arm length and the compositional ratios of the two comonomers had effect on physicochemical properties of the polymer micelle aggregates. Particularly, the cloud point values were enhanced as the (N,N dimethylacrylamide) DMAM monomer was introduced and reached to 36.6C and 41.0C 44.7C when the mass ratio of NIPAM to DMAM was 90:10 and 80:20, respectively. The thermo-triggered drug release and cytotoxicity were evaluated to confirm the applicability of the random copolymer micelle aggregates as novel drug targeted release carriers. PMID- 25926672 TI - Re-engineering shared decision-making. AB - Shared decision-making is widely accepted as the gold standard of clinical care. Numerous obstacles to achieving shared decision-making have been identified, including patient factors, physician factors and systemic factors. Until now, the paradigm is seldom successfully implemented in clinical practice, raising questions about the practicality of the process recommended for its use. A re engineered model is proposed in which physicians elicit and prioritise patients' goals of care and then help translate those goals into treatment options, after clarifying the patient's underlying health status. Preliminary evidence suggests that each step of this revised process is feasible and that patients and physicians are comfortable with this strategy. Adoption of this model, after further testing, would allow the goal of shared decision-making to be realised. PMID- 25926673 TI - Invariant NKT cells require autophagy to coordinate proliferation and survival signals during differentiation. AB - Autophagy regulates cell differentiation, proliferation, and survival in multiple cell types, including cells of the immune system. In this study, we examined the effects of a disruption of autophagy on the differentiation of invariant NKT (iNKT) cells. Using mice with a T lymphocyte-specific deletion of Atg5 or Atg7, two members of the macroautophagic pathway, we observed a profound decrease in the iNKT cell population. The deficit is cell-autonomous, and it acts predominantly to reduce the number of mature cells, as well as the function of peripheral iNKT cells. In the absence of autophagy, there is reduced progression of iNKT cells in the thymus through the cell cycle, as well as increased apoptosis of these cells. Importantly, the reduction in Th1-biased iNKT cells is most pronounced, leading to a selective reduction in iNKT cell-derived IFN-gamma. Our findings highlight the unique metabolic and genetic requirements for the differentiation of iNKT cells. PMID- 25926674 TI - Mature cystic fibrosis airway neutrophils suppress T cell function: evidence for a role of arginase 1 but not programmed death-ligand 1. AB - Bacteria colonize cystic fibrosis (CF) airways, and although T cells with appropriate Ag specificity are present in draining lymph nodes, they are conspicuously absent from the lumen. To account for this absence, we hypothesized that polymorphonuclear neutrophils (PMNs), recruited massively into the CF airway lumen and actively exocytosing primary granules, also suppress T cell function therein. Programmed death-ligand 1 (PD-L1), which exerts T cell suppression at a late step, was expressed bimodally on CF airway PMNs, delineating PD-L1(hi) and PD-L1(lo) subsets, whereas healthy control (HC) airway PMNs were uniformly PD L1(hi). Blood PMNs incubated in CF airway fluid lost PD-L1 over time; in coculture, Ab blockade of PD-L1 failed to inhibit the suppression of T cell proliferation by CF airway PMNs. In contrast with PD-L1, arginase 1 (Arg1), which exerts T cell suppression at an early step, was uniformly high on CF and HC airway PMNs. However, arginase activity was high in CF airway fluid and minimal in HC airway fluid, consistent with the fact that Arg1 activation requires primary granule exocytosis, which occurs in CF, but not HC, airway PMNs. In addition, Arg1 expression on CF airway PMNs correlated negatively with lung function and positively with arginase activity in CF airway fluid. Finally, combined treatment with arginase inhibitor and arginine rescued the suppression of T cell proliferation by CF airway fluid. Thus, Arg1 and PD-L1 are dynamically modulated upon PMN migration into human airways, and, Arg1, but not PD-L1, contributes to early PMN-driven T cell suppression in CF, likely hampering resolution of infection and inflammation. PMID- 25926675 TI - The distal upstream promoter in Ly49 genes, Pro1, is active in mature NK cells and T cells, does not require TATA boxes, and displays enhancer activity. AB - Missing self recognition of MHC class I molecules is mediated in murine species primarily through the stochastic expression of CD94/NKG2 and Ly49 receptors on NK cells. Previous studies have suggested that the stochastic expression of Ly49 receptors is achieved through the use of an alternate upstream promoter, designated Pro1, that is active only in immature NK cells and operates via the mutually exclusive binding of transcription initiation complexes to closely opposed forward and reverse TATA boxes, with forward transcription being transiently required to activate the downstream promoters, Pro2/Pro3, that are subsequently responsible for transcription in mature NK cells. In this study, we report that Pro1 transcripts are not restricted to immature NK cells but are also found in mature NK cells and T cells, and that Pro1 fragments display strong promoter activity in mature NK cell and T cell lines as well as in immature NK cells. However, the strength of promoter activity in vitro does not correlate well with Ly49 expression in vivo and forward promoter activity is generally weak or undetectable, suggesting that components outside of Pro1 are required for efficient forward transcription. Indeed, conserved sequences immediately upstream and downstream of the core Pro1 region were found to inhibit or enhance promoter activity. Most surprisingly, promoter activity does not require either the forward or reverse TATA boxes, but is instead dependent on residues in the largely invariant central region of Pro1. Importantly, Pro1 displays strong enhancer activity, suggesting that this may be its principal function in vivo. PMID- 25926676 TI - DCIR maintains bone homeostasis by regulating IFN-gamma production in T cells. AB - Dendritic cell immunoreceptor (DCIR) is a C-type lectin receptor mainly expressed in DCs. Dcir (-/-) mice spontaneously develop autoimmune enthesitis and ankylosis accompanied by fibrocartilage proliferation and ectopic ossification. However, the mechanisms of new bone/cartilage formation in Dcir (-/-) mice remain to be elucidated. In this study, we show that DCIR maintains bone homeostasis by regulating IFN-gamma production under pathophysiological conditions. DCIR deficiency increased bone volume in femurs and caused aberrant ossification in joints, whereas these symptoms were abolished in Rag2(-/-)Dcir(-/-) mice. IFN gamma-producing T cells accumulated in lymph nodes and joints of Dcir(-/-) mice, and purified Dcir(-/-) DCs enhanced IFN-gamma(+) T cell differentiation. The ankylotic changes and bone volume increase were suppressed in the absence of IFN gamma. Thus, IFN-gamma is a positive chondrogenic and osteoblastogenic factor, and DCIR is a crucial regulator of bone metabolism; consequently, both factors are potential targets for therapies directed against bone metabolic diseases. PMID- 25926677 TI - IL-33 receptor ST2 amplifies the expansion of NK cells and enhances host defense during mouse cytomegalovirus infection. AB - NK cells provide important host defense against viruses and can differentiate into self-renewing memory NK cells after infection, alloantigen stimulation, and cytokine stimulation. In this study, we investigated the role of the IL-33 receptor ST2 in the differentiation of NK cells during mouse CMV (MCMV) infection. Although ST2-deficient (Il1rl1 (-/-)) Ly49H(+) NK cells develop normally and differentiate into memory cells after MCMV infection, naive and memory Il1rl1 (-/-) Ly49H(+) NK cells exhibited profound defects in MCMV-specific expansion, resulting in impaired protection against MCMV challenge. Additionally, IL-33 enhanced m157 Ag-specific proliferation of Ly49H(+) NK cells in vitro. Thus, an IL-33/ST2 signaling axis in NK cells contributes to host defense against MCMV. PMID- 25926678 TI - The Role of Ivabradine in Cardiac Rehabilitation in Patients With Recent Coronary Artery Bypass Graft. AB - BACKGROUND: Little is known about ivabradine in cardiac rehabilitation in patients with coronary artery bypass graft (CABG). METHODS: In this prospective, randomized study, suitable patients admitted for cardiac rehabilitation after recent CABG were randomized to ivabradine 5 mg twice a day + standard medical therapy including bisoprolol 1.25 mg once daily (group I-BB, n = 38) or standard medical therapy including bisoprolol 2.5 to 3.75 mg once daily (group BB, n = 43). Patients were evaluated at admission, discharge, and 3 months. The primary end point was improvement in functional status, and other end points were improvement in diastolic function and recovery of systolic function. End points were assessed by distance covered in 6-minute walking test (6MWT), percentage with normal diastolic function, and percentage increase in left ventricular ejection fraction (LVEF). RESULTS: Cardiac rehabilitation improved functional capacity in both groups. In group BB, distances covered in the 6MWT at admission, discharge, and 3 months were 215 +/- 53, 314 +/- 32, and 347 +/- 42 m, respectively. Corresponding distances in group I-BB were 180 +/- 91, 311 +/- 58, and 370 +/- 55 m. Normal diastolic function was restored in I-BB patients, increasing from 24% at admission to 50% and 79% at discharge and 3 months; in BB patients, it decreased from 23% to 19% and 16%. The LVEF improved in I-BB patients, from 57% +/- 3% at admission to 62% +/- 4% at discharge and 66% +/- 3% at 3 months, while remaining unchanged in BB patients (57% +/- 3%, 59% +/- 4%, and 59% +/- 3%). CONCLUSION: Adding ivabradine to low-dose bisoprolol during cardiac rehabilitation in patients with CABG improved functional capacity, enhanced recovery of systolic function, and reduced diastolic dysfunction. PMID- 25926679 TI - Added value of multi-pathogen probe-based real-time PCR SeptiFast in the rapid diagnosis of bloodstream infections in patients with bacteraemia. AB - The commercial multi-pathogen probe-based real-time PCR SeptiFast (SF) was evaluated as a rapid and complementing tool for the microbiological diagnosis of bloodstream infections (BSIs) in a series of 138 matched blood samples from 65 patients with bacteraemia, hospitalized in an intensive care unit, when antibiotics had already been administered. SF was positive in 32.6 % of the samples, whereas blood culture (BC) was positive in 21.7 % (P < 0.05). SF identified more pathogens (11 versus 5; specificity, 90.7 %) and reduced the time of aetiological diagnosis, with a mean of 16.3 versus 55.4 h needed for BC (P < 0.05). SF enabled appropriate pathogen-oriented therapy in 72 % (36/50) of the BSI group of patients on the basis of epidemiological data. According to our data, the use of SF provided important added value to BC, in terms of earlier aetiological diagnosis of BSIs, enabling pathogen-oriented therapy in patients receiving empirical antibiotic treatment. PMID- 25926680 TI - Clocks within the Master Gland: Hypophyseal Rhythms and Their Physiological Significance. AB - Various aspects of mammalian endocrine physiology show a time-of-day variation with a period of 24 h, which represents an adaptation to the daily environmental fluctuations resulting from the rotation of the earth. These 24-h rhythms in hormone abundance and consequently hormone function may rely on rhythmic signals produced by the master circadian clock, which resides in the suprachiasmatic nucleus and is thought to chiefly dictate the pattern of rest and activity in mammals in conjunction with the light/dark (LD) cycle. However, it is likely that clocks intrinsic to elements of the endocrine axes also contribute to the 24-h rhythms in hormone function. Here we review the evidence for rhythm generation in the endocrine master gland, the pituitary, and its physiological significance in the context of endocrine axes regulation and function. PMID- 25926681 TI - Adipose Clocks: Burning the Midnight Oil. AB - Circadian clocks optimize the timing of physiological processes in synchrony with daily recurring and therefore predictable changes in the environment. Until the late 1990s, circadian clocks were thought to exist only in the central nervous systems of animals; elegant studies in cultured fibroblasts and using genetically encoded reporters in Drosophila melanogaster and in mice showed that clocks are ubiquitous and cell autonomous. These findings inspired investigations of the advantages construed by enabling each organ to independently adjust its function to the time of day. Studies of rhythmic gene expression in several organs suggested that peripheral organ clocks might play an important role in optimizing metabolic physiology by synchronizing tissue-intrinsic metabolic processes to cycles of nutrient availability and energy requirements. The effects of clock disruption in liver, pancreas, muscle, and adipose tissues support that hypothesis. Adipose tissues coordinate energy storage and utilization and modulate behavior and the physiology of other organs by secreting hormones known as "adipokines." Due to behavior- and environment-driven diurnal variations in supply and demand for chemical and thermal energy, adipose tissues might represent an important peripheral location for coordinating circadian energy balance (intake, storage, and utilization) over the whole organism. Given the complexity of adipose cell types and depots, the sensitivity of adipose tissue biology to age and diet composition, and the plethora of known and yet-to-be discovered adipokines and lipokines, we have just begun to scratch the surface of understanding the role of circadian clocks in adipose tissues. PMID- 25926684 TI - A Luciferase Reporter Gene Assay to Measure Ebola Virus Viral Protein 35 Associated Inhibition of Double-Stranded RNA-Stimulated, Retinoic Acid-Inducible Gene 1-Mediated Induction of Interferon beta. AB - During Ebola virus (EBOV) infection, the type I interferon alpha/beta (IFN alpha/beta) innate immune response is suppressed by EBOV viral protein 35 (VP35), a validated drug target. Identification of EBOV VP35 inhibitors requires a cellular system able to assess the VP35-based inhibitory functions of viral double-stranded RNA (dsRNA) IFN-beta induction. We established a miniaturized luciferase gene reporter assay in A549 cells that measures IFN-beta induction by viral dsRNA and is dose-dependently inhibited by VP35 expression. When compared to influenza A virus NS1 protein, EBOV VP35 showed improved inhibition of viral dsRNA-based IFN-beta induction. This assay can be used to screen for EBOV VP35 inhibitors. PMID- 25926682 TI - Activation and regulation of DNA-driven immune responses. AB - The innate immune system provides early defense against infections and also plays a key role in monitoring alterations of homeostasis in the body. DNA is highly immunostimulatory, and recent advances in this field have led to the identification of the innate immune sensors responsible for the recognition of DNA as well as the downstream pathways that are activated. Moreover, information on how cells regulate DNA-driven immune responses to avoid excessive inflammation is now emerging. Finally, several reports have demonstrated how defects in DNA sensing, signaling, and regulation are associated with susceptibility to infections or inflammatory diseases in humans and model organisms. In this review, the current literature on DNA-stimulated innate immune activation is discussed, and important new questions facing this field are proposed. PMID- 25926683 TI - Redox-regulated dynamic interplay between Cox19 and the copper-binding protein Cox11 in the intermembrane space of mitochondria facilitates biogenesis of cytochrome c oxidase. AB - Members of the twin Cx9C protein family constitute the largest group of proteins in the intermembrane space (IMS) of mitochondria. Despite their conserved nature and their essential role in the biogenesis of the respiratory chain, the molecular function of twin Cx9C proteins is largely unknown. We performed a SILAC based quantitative proteomic analysis to identify interaction partners of the conserved twin Cx9C protein Cox19. We found that Cox19 interacts in a dynamic manner with Cox11, a copper transfer protein that facilitates metalation of the Cu(B) center of subunit 1 of cytochrome c oxidase. The interaction with Cox11 is critical for the stable accumulation of Cox19 in mitochondria. Cox19 consists of a helical hairpin structure that forms a hydrophobic surface characterized by two highly conserved tyrosine-leucine dipeptides. These residues are essential for Cox19 function and its specific binding to a cysteine-containing sequence in Cox11. Our observations suggest that an oxidative modification of this cysteine residue of Cox11 stimulates Cox19 binding, pointing to a redox-regulated interplay of Cox19 and Cox11 that is critical for copper transfer in the IMS and thus for biogenesis of cytochrome c oxidase. PMID- 25926685 TI - Amino Acid Residue at Position 79 of Marburg Virus VP40 Confers Interferon Antagonism in Mouse Cells. AB - Marburg viruses (MARVs) cause highly lethal infections in humans and nonhuman primates. Mice are not generally susceptible to MARV infection; however, if the strain is first adapted to mice through serial passaging, it becomes able to cause disease in this animal. A previous study correlated changes accrued during mouse adaptation in the VP40 gene of a MARV strain known as Ravn virus (RAVV) with an increased capacity to inhibit interferon (IFN) signaling in mouse cell lines. The MARV strain Ci67, which belongs to a different phylogenetic clade than RAVV, has also been adapted to mice and in the process the Ci67 VP40 acquired a different collection of genetic changes than did RAVV VP40. Here, we demonstrate that the mouse-adapted Ci67 VP40 more potently antagonizes IFN-alpha/beta-induced STAT1 and STAT2 tyrosine phosphorylation, gene expression, and antiviral activity in both mouse and human cell lines, compared with the parental Ci67 VP40. Ci67 VP40 is also demonstrated to target the activation of kinase Jak1. A single change at VP40 residue 79 was found to be sufficient for the increased VP40 IFN antagonism. These data argue that VP40 IFN-antagonist activity plays a key role in MARV pathogenesis in mice. PMID- 25926687 TI - Postegression Feeding Enhances Growth, Survival, and Nutrient Acquisition in the Endoparasitoid Toxoneuron nigriceps (Hymenoptera: Braconidae). AB - Toxoneuron nigriceps Viereck (Hymenoptera: Braconidae), a koinobiont endoparasitoid of the tobacco budworm, Heliothis virescens F. (Lepidoptera: Noctuidae), derives nutrition from the host hemolymph during the internal portion of its larval development but feeds destructively on host tissues externally after egression. To investigate the importance of this tissue-feeding phase, and to evaluate the behaviors associated with postegression feeding, T. nigriceps larvae were subjected to one of four treatments: 1) allowed to carry out normal tissue feeding, 2) deprived of tissue feeding, 3) presented with tissues scraped away from the host remains, and 4) fed tissues scraped from an unparasitized H. virescens larva. Additionally, total carbohydrates, lipids, and proteins were quantified from pre and posttissue feeding T. nigriceps larvae to examine the effect of postegression feeding on parasitoid nutritional physiology. Parasitoids that received no tissues after egression, or that received tissue from an unparasitized H. virescens larva, had significantly smaller body masses at all stages than those allowed to feed naturally or fed tissues scraped from a parasitized host. Parasitoids that underwent normal host feeding after egression also reached larger masses then those fed scraped host tissue. Parasitoids that received no tissue after egression survived to adulthood significantly less often than those that were presented with any H. virescens tissue. This suggests that postegression tissue feeding is a vital developmental step for T. nigriceps, and that T. nigriceps will not only feed when normal postegression behavior is disrupted, but will also feed on unparasitized tissue. The quantification of macronutrients in the tissues of pre and posttissue feeding T. nigriceps larvae showed significantly elevated proportions of proteins, lipids, and carbohydrates in the tissues of larvae that had completed feeding, with the greatest difference being in total lipids. PMID- 25926686 TI - Marburg Virus VP24 Protein Relieves Suppression of the NF-kappaB Pathway Through Interaction With Kelch-like ECH-Associated Protein 1. AB - BACKGROUND: Marburg virus (MARV) is an emerging zoonotic pathogen that causes hemorrhagic fever. MARV VP24 (mVP24) protein interacts with the host cell protein Kelch-like-ECH-associated protein 1 (Keap1). Keap1 interacts with and promotes the degradation of IkappaB kinase beta (IKKbeta), a component of the IkappaB kinase (IKK) complex that regulates nuclear factor-kappaB (NF-kappaB) activity. We studied whether mVP24 could relieve Keap1 repression of the NF-kappaB pathway. METHODS: Coimmunoprecipitation assays were used to examine the interaction between Keap1 and IKKbeta in the presence of wild-type mVP24 and mutants of mVP24 defective for binding to Keap1. Western blotting was used to determine levels of IKKbeta expression in the presence of Keap1 and mVP24. NF-kappaB promoter luciferase assays were used to determine the effect of mVP24 on Keap1-induced repression of activity. RESULTS: Expression of wild-type mVP24 disrupted the interaction of IKKbeta and Keap1, whereas weakly interacting and noninteracting mVP24 mutants did not disrupt the interaction between Keap1 and IKKbeta. The interaction of mVP24 with Keap1 enhanced IKKbeta levels in the presence of Keap1. The interaction of mVP24 with Keap1 also relieved Keap1 repression of NF-kappaB reporter activity. CONCLUSIONS: mVP24 can relieve Keap1 repression of the NF kappaB pathway through its interaction with Keap1. PMID- 25926688 TI - Proprotein convertase FURIN regulates T cell receptor-induced transactivation. AB - Antigen emergence rapidly stimulates T cells, which leads to changes in cytokine production, cell proliferation, and differentiation. Some of the key molecules involved in these events, such as TGF-beta1 and NOTCH1, are synthesized initially as inactive precursors and are proteolytically activated during T cell activation. PCSKs regulate proprotein maturation by catalyzing the proteolytic cleavage of their substrates. The prototype PCSK FURIN is induced upon TCR activation, and its expression in T cells is critical for the maintenance of peripheral immune tolerance. In this study, we tested the hypothesis that FURIN regulates T cell activation. Our data demonstrate that IL-2 is increased initially in FURIN-deficient mouse CD4(+) T cells, but the TCR-induced IL-2 mRNA expression is not sustained in the absence of FURIN. Accordingly, the inhibition of FURIN in human Jurkat T cell lines also results in a decrease in IL-2 production, whereas the overexpression of WT FURIN is associated with elevated IL 2 levels. In Jurkat cells, FURIN is dispensable for immediate TCR signaling steps, such as ERK, ZAP70, or LAT phosphorylation. However, with the use of gene reporter assays, we demonstrate that FURIN regulates the AP-1, NFAT, and NF kappaB transcription factors. Finally, by performing a transcription factor binding site enrichment analysis on FURIN-dependent transcriptomes, we identify the FURIN-regulated transcription factors in mouse CD4(+) T cell subsets. Collectively, our work confirms the hypothesis that the TCR-regulated protease FURIN plays an important role in T cell activation and that it can specifically modulate TCR-activated transactivation. PMID- 25926689 TI - Understanding the regulation of pituitary progesterone receptor expression and phosphorylation. AB - Administration of human FSH (hFSH) during the diestrus phase in cyclic rats is followed by a reduction in the preovulatory LH surge. This inhibitory action of FSH involves a decrease in the stimulatory effect of gonadotrope progesterone receptor (PR) activation, in a ligand-dependent (progesterone) and -independent (GNRH) manner. PR activation and action are mandatory for LH surge, and are dependent on the phosphorylation of serine (Ser) residues. Together with this post-translational modification, PR is marked for downregulation by proteasome machinery. These experiments used the western blotting technique to measure pituitary expression of PR-A and PR-B isoforms and phosphorylation levels of Ser294 and Ser400 PR-B in rats bearing i) hFSH treatment or ii) PR downregulation. Treatment with hFSH reduced LH secretion and increased that of estradiol in proestrus afternoon. hFSH injections, without altering PR-A and PR-B content or ratio, caused a reduction in phosphorylation of Ser294 and Ser400 but only when pituitaries were previously challenged with progesterone or GNRH for 2 h. However, while pSer294 levels increased after 2 h of pituitary incubation with progesterone or GNRH, those of pSer400 were not modified by these in vitro treatments. Finally, progesterone had a biphasic effect: in 2-h incubations increased pituitary PR-A and PR-B content, but after 8 h caused downregulation and altered PR-A:PR-B ratio. The results provide a potential mechanism through which LH levels are decreased by hFSH administration and better understanding of the control of PR expression and phosphorylation in rat pituitaries. PMID- 25926690 TI - Identification of target genes for a prolactin family paralog in mouse decidua. AB - Prolactin family 8, subfamily a, member 2 (PRL8A2; also called decidual prolactin related protein; dPRP) is a member of the expanded prolactin family. PRL8A2 is expressed in the uterine decidua and contributes to pregnancy-dependent adaptations to hypoxia. The purpose of this study was to identify gene targets for PRL8A2 action within the uteroplacental compartment. Affymetrix DNA microarray analysis was performed for RNA samples from WT and Prl8a2 null tissues. Validation of the DNA microarray was performed using quantitative RT PCR. Nine genes were confirmed with decreased expression in Prl8a2 null tissues (e.g., Klk7, Rimklb, Arhgef6, Calm4, Sprr2h, Prl4a1, Ccl27, Lipg, and Htra3). These include potential decidual, endothelial and trophoblast cell targets positively regulated by PRL8A2. A significant upregulation of Derl3, Herpud1, Creld2, Hsp90b1, Ddit3 and Hspa5 was identified in Prl8a2 null tissues, reflecting an increased endoplasmic reticulum (ER) stress response. ER stress genes were prominently expressed in the uterine decidua. We propose that PRL8A2 is a mediator of progesterone-dependent modulation of intrauterine responses to physiological stressors. PMID- 25926692 TI - High glucose concentrations per se do not adversely affect human sperm function in vitro. AB - Diabetes mellitus (DM) represents one of the greatest concerns to global health and it is associated with diverse clinical complications, including reproductive dysfunction. Given the multifactorial nature of DM, the mechanisms that underlie reproductive dysfunction remain unclear. Considering that hyperglycemia has been described as a major effector of the disease pathophysiology, we used an in vitro approach to address the isolated effect of high glucose conditions on human sperm function, thus avoiding other in vivo confounding players. We performed a complete and integrated analysis by measuring a variety of important indicators of spermatozoa functionality (such as motility, viability, capacitation status, acrosomal integrity, mitochondrial superoxide production and membrane potential) in human sperm samples after incubation with d- and l-glucose (5, 25, or 50 mM) for 24 and 48 h. No direct effects promoted by 25 or 50 mM d-glucose were found for any of the parameters assessed (P>0.05), except for the acrosome reaction, which was potentiated after 48 h of exposure to 50 mM d-glucose (P<0.05). Interestingly, non-metabolizable l-glucose drastically increased superoxide production (P<0.05) and suppressed sperm motility (P<0.05) and capacitation (P<0.05) after 24 h of treatment, whereas mitochondrial membrane potential (P<0.05), acrosomal integrity (P<0.01) and viability (P<0.05) were later decreased. The overall results suggest that high glucose levels per se do not influence human sperm function in vitro, which stresses the importance of other factors involved in DM pathology. Nevertheless, the absence of metabolizable glucose contributes to a severe impairment of sperm function and thus compromises male fertility. PMID- 25926691 TI - Physiological and pathophysiological roles for phospholipase D. AB - Individual members of the mammalian phospholipase D (PLD) superfamily undertake roles that extend from generating the second messenger signaling lipid, phosphatidic acid, through hydrolysis of the membrane phospholipid, phosphatidylcholine, to functioning as an endonuclease to generate small RNAs and facilitating membrane vesicle trafficking through seemingly nonenzymatic mechanisms. With recent advances in genome-wide association studies, RNA interference screens, next-generation sequencing approaches, and phenotypic analyses of knockout mice, roles for PLD family members are being uncovered in autoimmune, infectious neurodegenerative, and cardiovascular disease, as well as in cancer. Some of these disease settings pose opportunities for small molecule inhibitory therapeutics, which are currently in development. PMID- 25926693 TI - The polymorphism of rs6505162 in the MIR423 coding region and recurrent pregnancy loss. AB - Although the relationship between polymorphisms in microRNAs (miRNAs) and recurrent pregnancy loss (RPL) has been studied, there is very little data available in the literature. In the present study, we scanned 55 potentially functional polymorphisms in the miRNA coding region in Chinese women with unexplained RPL (URPL; no. 2011-10). The rs6505162 C>A in the MIR423 coding region was found to be significantly associated with the occurrence of human URPL. The rare A allele contributed to an increase in the expression of mature MIR423. C to A substitution in the polymorphism rs6505162 in pre-MIR423 repressed cell proliferation and migratory capacity. Further investigations showed that MIR423 could inversely regulate the expression of proliferation-associated 2 group 4 (PA2G4) by binding the 3'-UTR of PA2G4. Dual-luciferase assay indicated that the A allele in the polymorphism rs6505162 could more effectively suppress the expression of PA2G4 than the C allele could. Collectively, the present data suggest that rs6505162 C>A in pre-MIR423 may contribute to the genetic predisposition to RPL by disrupting the production of mature MIR423 and its target gene, which consequently interferes with MIR423 functioning. PMID- 25926694 TI - Night-time lighting alters the composition of marine epifaunal communities. AB - Marine benthic communities face multiple anthropogenic pressures that compromise the future of some of the most biodiverse and functionally important ecosystems in the world. Yet one of the pressures these ecosystems face, night-time lighting, remains unstudied. Light is an important cue in guiding the settlement of invertebrate larvae, and altering natural regimes of nocturnal illumination could modify patterns of recruitment among sessile epifauna. We present the first evidence of night-time lighting changing the composition of temperate epifaunal marine invertebrate communities. Illuminating settlement surfaces with white light-emitting diode lighting at night, to levels experienced by these communities locally, both inhibited and encouraged the colonization of 39% of the taxa analysed, including three sessile and two mobile species. Our results indicate that ecological light pollution from coastal development, shipping and offshore infrastructure could be changing the composition of marine epifaunal communities. PMID- 25926695 TI - Oxygen supply limits the heat tolerance of lizard embryos. AB - The mechanisms that set the thermal limits to life remain uncertain. Classically, researchers thought that heating kills by disrupting the structures of proteins or membranes, but an alternative hypothesis focuses on the demand for oxygen relative to its supply. We evaluated this alternative hypothesis by comparing the lethal temperature for lizard embryos developing at oxygen concentrations of 10 30%. Embryos exposed to normoxia and hyperoxia survived to higher temperatures than those exposed to hypoxia, suggesting that oxygen limitation sets the thermal maximum. As all animals pass through an embryonic stage where respiratory and cardiovascular systems must develop, oxygen limitation may limit the thermal niches of terrestrial animals as well as aquatic ones. PMID- 25926696 TI - The effects of sex-biased gene expression and X-linkage on rates of adaptive protein sequence evolution in Drosophila. AB - A faster rate of adaptive evolution of X-linked genes compared with autosomal genes may be caused by the fixation of new recessive or partially recessive advantageous mutations (the Faster-X effect). This effect is expected to be largest for mutations that affect only male fitness and absent for mutations that affect only female fitness. We tested these predictions in Drosophila melanogaster by using genes with different levels of sex-biased expression and by estimating the extent of adaptive evolution of non-synonymous mutations from polymorphism and divergence data. We detected both a Faster-X effect and an effect of male-biased gene expression. There was no evidence for a strong association between the two effects--modest levels of male-biased gene expression increased the rate of adaptive evolution on both the autosomes and the X chromosome, but a Faster-X effect occurred for both unbiased genes and female biased genes. The rate of genetic recombination did not influence the magnitude of the Faster-X effect, ruling out the possibility that it reflects less Hill Robertson interference for X-linked genes. PMID- 25926698 TI - A mechanism for cell motility by active polar gels. AB - We analyse a generic motility model, with the motility mechanism arising by contractile stress due to the interaction of myosin and actin. A hydrodynamic active polar gel theory is used to model the cytoplasm of a cell and is combined with a Helfrich-type model to account for membrane properties. The overall model allows consideration of the motility without the necessity for local adhesion. Besides a detailed numerical approach together with convergence studies for the highly nonlinear free boundary problem, we also compare the induced flow field of the motile cell with that of classical squirmer models and identify the motile cell as a puller or pusher, depending on the strength of the myosin-actin interactions. PMID- 25926697 TI - Rapid bursts and slow declines: on the possible evolutionary trajectories of enzymes. AB - The evolution of enzymes is often viewed as following a smooth and steady trajectory, from barely functional primordial catalysts to the highly active and specific enzymes that we observe today. In this review, we summarize experimental data that suggest a different reality. Modern examples, such as the emergence of enzymes that hydrolyse human-made pesticides, demonstrate that evolution can be extraordinarily rapid. Experiments to infer and resurrect ancient sequences suggest that some of the first organisms present on the Earth are likely to have possessed highly active enzymes. Reconciling these observations, we argue that rapid bursts of strong selection for increased catalytic efficiency are interspersed with much longer periods in which the catalytic power of an enzyme erodes, through neutral drift and selection for other properties such as cellular energy efficiency or regulation. Thus, many enzymes may have already passed their catalytic peaks. PMID- 25926699 TI - Interrogating protonated/deuterated fibronectin fragment layers adsorbed to titania by neutron reflectivity and their concomitant control over cell adhesion. AB - The fibronectin fragment, 9th-10th-type III domains (FIII9-10), mediates cell attachment and spreading and is commonly investigated as a bioadhesive interface for implant materials such as titania (TiO2). How the extent of the cell attachment-spreading response is related to the nature of the adsorbed protein layer is largely unknown. Here, the layer thickness and surface fraction of two FIII9-10 mutants (both protonated and deuterated) adsorbed to TiO2 were determined over concentrations used in cell adhesion assays. Unexpectedly, the isotopic forms had different adsorption behaviours. At solution concentrations of 10 mg l(-1), the surface fraction of the less conformationally stable mutant (FIII9'10) was 42% for the deuterated form and 19% for the protonated form (fitted to the same monolayer thickness). Similarly, the surface fraction of the more stable mutant (FIII9'10-H2P) was 34% and 18% for the deuterated and protonated forms, respectively. All proteins showed a transition from monolayer to bilayer between 30 and 100 mg l(-1), with the protein longitudinal orientation moving away from the plane of the TiO2 surface at high concentrations. Baby hamster kidney cells adherent to TiO2 surfaces coated with the proteins (100 mg l(-1)) showed a strong spreading response, irrespective of protein conformational stability. After surface washing, FIII9'10 and FIII9'10-H2P bilayer surface fractions were 30/25% and 42/39% for the lower/upper layers, respectively, implying that the cell spreading response requires only a partial protein surface fraction. Thus, we can use neutron reflectivity to inform the coating process for generating bioadhesive TiO2 surfaces. PMID- 25926700 TI - Fluid-flow-induced mesenchymal stem cell migration: role of focal adhesion kinase and RhoA kinase sensors. PMID- 25926701 TI - Game theory of pre-emptive vaccination before bioterrorism or accidental release of smallpox. AB - Smallpox was eradicated in the 1970s, but new outbreaks could be seeded by bioterrorism or accidental release. Substantial vaccine-induced morbidity and mortality make pre-emptive mass vaccination controversial, and if vaccination is voluntary, then there is a conflict between self- and group interests. This conflict can be framed as a tragedy of the commons, in which herd immunity plays the role of the commons, and free-riding (i.e. not vaccinating pre-emptively) is analogous to exploiting the commons. This game has been analysed previously for a particular post-outbreak vaccination scenario. We consider several post-outbreak vaccination scenarios and compare the expected increase in mortality that results from voluntary versus imposed vaccination. Below a threshold level of post outbreak vaccination effort, expected mortality is independent of the level of response effort. A lag between an outbreak starting and a response being initiated increases the post-outbreak vaccination effort necessary to reduce mortality. For some post-outbreak vaccination scenarios, even modest response lags make it impractical to reduce mortality by increasing post-outbreak vaccination effort. In such situations, if decreasing the response lag is impossible, the only practical way to reduce mortality is to make the vaccine safer (greater post-outbreak vaccination effort leads only to fewer people vaccinating pre-emptively). PMID- 25926702 TI - Anniversary of the discovery/isolation of the yeast centromere by Clarke and Carbon. AB - The first centromere was isolated 35 years ago by Louise Clarke and John Carbon from budding yeast. They embarked on their journey with rudimentary molecular tools (by today's standards) and little knowledge of the structure of a chromosome, much less the nature of a centromere. Their discovery opened up a new field, as centromeres have now been isolated from fungi and numerous plants and animals, including mammals. Budding yeast and several other fungi have small centromeres with short, well-defined sequences, known as point centromeres, whereas regional centromeres span several kilobases up to megabases and do not seem to have DNA sequence specificity. Centromeres are at the heart of artificial chromosomes, and we have seen the birth of synthetic centromeres in budding and fission yeast and mammals. The diversity in centromeres throughout phylogeny belie conserved functions that are only beginning to be understood. PMID- 25926704 TI - Correction. PMID- 25926703 TI - Maximizing the return on taxpayers' investments in fundamental biomedical research. AB - The National Institute of General Medical Sciences (NIGMS) at the U.S. National Institutes of Health has an annual budget of more than $2.3 billion. The institute uses these funds to support fundamental biomedical research and training at universities, medical schools, and other institutions across the country. My job as director of NIGMS is to work to maximize the scientific returns on the taxpayers' investments. I describe how we are optimizing our investment strategies and funding mechanisms, and how, in the process, we hope to create a more efficient and sustainable biomedical research enterprise. PMID- 25926705 TI - Investments, time preferences and public transfers paid to women. AB - The literature suggests men and women may have different preferences. This paper exploits a social experiment in which women in treatment households were given a large public cash transfer (PROGRESA). In an effort to disentangle the effect of additional income in the household from the effect of changing the distribution of income within the household, the impact of PROGRESA income on savings and investments decisions is compared with all other income sources (after taking into account participation in the program). Additional money in the hands of women is spent on small livestock (which are traditionally managed and cared for by women), improved nutrition and on child goods (particularly clothing). Among single headed households, PROGRESA income is not treated differently from other income. Direct evidence on inter-temporal preferences gathered in the Mexican Family Live Survey indicates that women are more patient than males when thinking about the future. Taken together, the results suggest that PROGRESA income results in a shift in the balance of power within households and women allocated more resources towards investments in the future. PMID- 25926706 TI - VULNERABILITY TO HURRICANE DAMAGE ON THE U.S. GULF COAST SINCE 1950. AB - We study hurricane risk on the U.S. Gulf Coast during 1950-2005, estimating the wind damage and storm surge from every hurricane in this extended period. Wind damage is estimated from the known path and wind speeds of individual storms and calibrated to fit actual damage reports for a sample of Gulf Coast storms. Storm surge is estimated using the SLOSH model developed by NOAA. These models provide the first comprehensive overview of the hurricane storm hazard as it has been experienced over a fifty-six-year period. We link the estimated damage with information on the population and specific socio-demographic components of the population (by age, race, and poverty status). Results show that white, young adult, and nonpoor populations have shifted over time away from zones with higher risk of wind damage, while more vulnerable population groups-the elderly, African Americans, and poor-have moved in the opposite direction. All groups have moved away from areas with high risk of storm surge since 1970. But in this case, perhaps because living near the water is still perceived as an amenity, those at highest risk are whites, elderly, and nonpoor households. Here exposure represents a trade-off between the risk and the amenity. PMID- 25926707 TI - Life-Course Transitions Among Adolescents With and Without Disabilities: A Longitudinal Examination of Expectations and Outcomes. AB - Research on adolescents suggests that young people are able to form reasonable expectations about future life-course transitions-and that these expectations are predictive of future outcomes. However, less is known about how these expectations might vary for adolescents with disabilities, who might face additional challenges when transitioning to adulthood. The present study addresses this gap in the literature by using nationally representative data from the National Longitudinal Survey of Youth (NLSY97) to suggest that young people's expectations about pregnancy, parenthood, education, and employment do vary according to disability status. Furthermore, disability status conditions the relationship between these expectations and their future outcomes. In general, adolescents with disabilities are more proficient in the prediction of educational outcomes than employment or pregnancy outcomes. However, their expectations about education are significantly lower-and expectations about teenage parenthood much higher-than those of adolescents without disabilities. PMID- 25926708 TI - Phosphorus balance and use efficiency on 21 intensive grass-based dairy farms in the South of Ireland. AB - Given the finite nature of global phosphorus (P) resources, there is an increasing concern about balancing agronomic and environmental impacts from P usage on dairy farms. Data from a 3-year (2009-2011) survey were used to assess farm-gate P balances and P use efficiency (PUE) on 21 intensive grass-based dairy farms operating under the good agricultural practice (GAP) regulations in Ireland. Mean stocking rate (SR) was 2.06 livestock units (LU)/ha, mean P surplus was 5.09 kg/ha, or 0.004 kg P/kg milk solids (MS), and mean PUE was 0.70. Phosphorus imports were dominated by inorganic fertilizer (7.61 kg P/ha) and feeds (7.62 kg P/ha), while exports were dominated by milk (6.66 kg P/ha) and livestock (5.10 kg P/ha). Comparison to similar studies carried out before the introduction of the GAP regulations in 2006 indicated that P surplus, both per ha and per kg MS, has significantly decreased (by 74 and 81%, respectively) and PUE increased (by 48%), mostly due to decreased inorganic fertilizer P import and improvements in P management. There has been a notable shift towards spring application of organic manures, indicating improved awareness of the fertilizer value of organic manures and good compliance with the GAP regulations regarding fertilizer application timing. These results suggested a positive impact of the GAP regulations on dairy farm P surplus and PUE, indicating an improvement in both environmental and economic sustainability of dairy production through improved resource use efficiencies. Such improvements will be necessary to achieve national targets of improved water quality and increased dairy production. Results suggest that optimizing fertilizer and feed P imports combined with improved on-farm P recycling are the most effective way to increase PUE. Equally, continued monitoring of soil test P (STP) and P management will be necessary to ensure that adequate soil P fertility is maintained. Mean P surplus was lower and PUE was much higher than the overall mean surplus (15.92 kg P/ha) and PUE (0.47) from three studies of continental and English dairy farms, largely due to the low import system that is more typical in Ireland, with seasonal milk production (compact spring calving), low use of imported feeds and high use of grazed grass. PMID- 25926709 TI - Interview-based sighting histories can inform regional conservation prioritization for highly threatened cryptic species. AB - The use of robust ecological data to make evidence-based management decisions is frequently prevented by limited data quantity or quality, and local ecological knowledge (LEK) is increasingly seen as an important source of information for conservation. However, there has been little assessment of LEK's usefulness for informing prioritization and management of landscapes for threatened species, or assessing comparative species status across landscapes.A large-scale interview survey in the Annamite Mountains (Vietnam and Lao PDR) compiled the first systematic LEK data set for saola Pseudoryx nghetinhensis, one of the world's rarest mammals, and eight other ungulates. Saola conservation is hindered by uncertainty over continued presence across much of its proposed distribution. We analysed comparative LEK-based last-sighting data across three landscapes to determine whether regional sighting histories support previous suggestions of landscape importance for saola conservation (Hue-Quang Nam: top-priority Vietnamese landscape; Pu Mat: lower priority Vietnamese landscape; Viengthong: high-priority Lao landscape) and whether they constitute an effective spatial prioritization tool for cryptic species management.Wild pig and red muntjac may be the only Annamite ungulates with stable populations; the regional status of all other species appears to be worse. Saola have declined more severely and/or are significantly rarer than most other ungulates and have been seen by relatively few respondents. Saola were also frequently considered locally rarest or declining, and never as species that had not declined.In contrast to other species, there are no regional differences in saola sighting histories, with continued persistence in all landscapes challenging suggestions that regional status differs greatly. Remnant populations persist in Vietnam despite heavy hunting, but even remote landscapes in Lao may be under intense pressure.Synthesis and applications. Our local ecological knowledge data suggest that intact saola populations probably no longer exist, but individuals persist in all three landscapes, making management activities to reduce hunting pressure on ungulates in each landscape a conservation priority. Analysis of last-sighting histories can constitute an important conservation tool when robust data are otherwise unavailable, and collection of last-sighting records should be incorporated more widely into field studies and management of other highly threatened, cryptic species. Our local ecological knowledge data suggest that intact saola populations probably no longer exist, but individuals persist in all three landscapes, making management activities to reduce hunting pressure on ungulates in each landscape a conservation priority. Analysis of last-sighting histories can constitute an important conservation tool when robust data are otherwise unavailable, and collection of last-sighting records should be incorporated more widely into field studies and management of other highly threatened, cryptic species. PMID- 25926710 TI - Spatially weighted functional clustering of river network data. AB - Incorporating spatial covariance into clustering has previously been considered for functional data to identify groups of functions which are similar across space. However, in the majority of situations that have been considered until now the most appropriate metric has been Euclidean distance. Directed networks present additional challenges in terms of estimating spatial covariance due to their complex structure. Although suitable river network covariance models have been proposed for use with stream distance, where distance is computed along the stream network, these models have not been extended for contexts where the data are functional, as is often the case with environmental data. The paper develops a method of calculating spatial covariance between functions from sites along a river network and applies the measure as a weight within functional hierarchical clustering. Levels of nitrate pollution on the River Tweed in Scotland are considered with the aim of identifying groups of monitoring stations which display similar spatiotemporal characteristics. PMID- 25926711 TI - An investigation of morphological awareness and processing in adults with low literacy. AB - Morphological awareness, which is an understanding of how words can be broken down into smaller units of meaning such as roots, prefixes, and suffixes, has emerged as an important contributor to word reading and comprehension skills. The first aim of the current study was to investigate the contribution of morphological awareness independent of phonological awareness and decoding to the reading comprehension abilities of adults with low literacy. Results indicated that morphological awareness was a significant unique predictor of reading comprehension. A second aim of the study was to investigate the processing of morphologically complex words of adults with low literacy in both an oral reading passage and a single-word naming task. Adults' accuracy and response times were measured on different types of morphologically complex words and compared with control words matched on frequency in both the passage and the naming tasks. Results revealed that adults were vulnerable to morphological complexity: they performed more accurately and faster on matched control words versus morphologically complex word types. The educational implications for Adult Basic Education programs are discussed. PMID- 25926712 TI - State-dependent foraging: lactating voles adjust their foraging behavior according to the presence of a potential nest predator and season. AB - Parental care often produces a trade-off between meeting nutritional demands of offspring and the duties of offspring protection, especially in altricial species. Parents have to leave their young unattended for foraging trips, during which nestlings are exposed to predators. We investigated how rodent mothers of altricial young respond to risk of nest predation in their foraging decisions. We studied foraging behavior of lactating bank voles (Myodes glareolus) exposed to a nest predator, the common shrew (Sorex araneus). We conducted the experiment in summer (high resource provisioning for both species) and autumn (less food available) in 12 replicates with fully crossed factors "shrew presence" and "season." We monitored use of feeding stations near and far from the nest as measurement of foraging activity and strategic foraging behavior. Vole mothers adapted their strategies to shrew presence and optimized their foraging behavior according to seasonal constraints, resulting in an interaction of treatment and season. In summer, shrew presence reduced food intake from feeding stations, while it enhanced intake in autumn. Shrew presence decreased the number of visited feeding stations in autumn and concentrated mother's foraging efforts to fewer stations. Independent of shrew presence or season, mothers foraged more in patches further away from the nest than near the nest. Results indicate that females are not investing in nest guarding but try to avoid the accumulation of olfactory cues near the nest leading a predator to the young. Additionally, our study shows how foraging strategies and nest attendance are influenced by seasonal food provision. PMID- 25926713 TI - Time is of the essence: an application of a relational event model for animal social networks. AB - Understanding how animal social relationships are created, maintained and severed has ecological and evolutionary significance. Animal social relationships are inferred from observations of interactions between animals; the pattern of interaction over time indicates the existence (or absence) of a social relationship. Autonomous behavioural recording technologies are increasingly being used to collect continuous interaction data on animal associations. However, continuous data sequences are typically aggregated to represent a relationship as part of one (or several) pictures of the network of relations among animals, in a way that parallels human social networks. This transformation entails loss of information about interaction timing and sequence, which are particularly important to understand the formation of relationships or their disruption. Here, we describe a new statistical model, termed the relational event model, that enables the analysis of fine-grained animal association data as a continuous time sequence without requiring aggregation of the data. We apply the model to a unique data set of interaction between familiar and unfamiliar steers during a series of 36 experiments to investigate the process of social disruption and relationship formation. We show how the model provides key insights into animal behaviour in terms of relationship building, the integration process of unfamiliar animals and group building dynamics. The relational event model is well suited to data structures that are common to animal behavioural studies and can therefore be applied to a range of social interaction data to understand animal social dynamics. PMID- 25926714 TI - Filamentous fungal endophthalmitis: results of combination therapy with intravitreal amphotericin B and voriconazole. AB - PURPOSE: To report outcomes of exogenous fungal endophthalmitis treated with combination of intravitreal antifungal agents. DESIGN: Retrospective, non randomized, interventional, consecutive case series. METHODS: Twelve eyes of twelve consecutive cases of filamentous fungal endophthalmitis were treated with a combination of intravitreal amphotericin-B and intravitreal voriconazole (AmB Vo Regime) along with pars plana vitrectomy at a single center. Clinical characteristics, microbiology results, treatment strategy, visual, and anatomical outcomes were analyzed. RESULTS: Ten cases out of the twelve were postoperative endophthalmitis of which nine were part of a post cataract surgery cluster. The remaining included endophthalmitis following keratitis post pterygium excision (1) and following open globe injury (2). The most common fungus was Aspergillus terreus, which was isolated in 8/12, followed by A. flavus in 2/12 and Fusarium solani in 1/12. The presenting visual acuity ranged from light perception (LP) to counting fingers. The visual acuity at final follow-up was 20/400 or better in 7/12 eyes (58.33%) and 20/60 in 2/12 eyes (range 20/60 to LP). All eyes with corneal involvement had final visual acuity 20/400 or worse. Globe salvage was achieved in all cases. CONCLUSION: Combining intravitreal amphotericin-B and voriconazole could be a novel treatment strategy in the management of endophthalmitis caused by filamentous fungus. Eyes with corneal involvement had poor visual outcome either with or without therapeutic penetrating keratoplasty. PMID- 25926715 TI - Role of biologics in intractable urticaria. AB - Chronic urticaria (CU) is a common condition faced by many clinicians. CU has been estimated to affect approximately 0.5%-1% of the population, with nearly 20% of sufferers remaining symptomatic 20 years after onset. Antihistamines are the first-line therapy for CU. Unfortunately, nearly half of these patients will fail this first-line therapy and require other medication, including immune response modifiers or biologics. Recent advances in our understanding of urticarial disorders have led to more targeted therapeutic options for CU and other urticarial diseases. The specific biologic agents most investigated for antihistamine-refractory CU are omalizumab, rituximab, and intravenous immunoglobulin (IVIG). Of these, the anti-IgE monoclonal antibody omalizumab is the best studied, and has recently been approved for the management of CU. Other agents, such as interleukin-1 inhibitors, have proved beneficial for Schnitzler syndrome and cryopyrin-associated periodic syndromes (CAPS), diseases associated with urticaria. This review summarizes the relevant data regarding the efficacy of biologics in antihistamine-refractory CU. PMID- 25926716 TI - Schisandrin B inhibits cell growth and induces cellular apoptosis and autophagy in mouse hepatocytes and macrophages: implications for its hepatotoxicity. AB - A number of drugs and herbal compounds have been documented to cause hepatoxicity. Schisandrin B (Sch B) is an active dibenzocyclooctadiene isolated from Schisandrae fructus, with a wide array of pharmacological activities. However, the potential hepatotoxicity of Sch B is a major safety concern, and the underlying mechanism for Sch B-induced liver toxic effects is not fully elucidated. In the present study, we aimed to investigate the liver toxic effects and the molecular mechanisms of Sch B in mouse liver and macrophage cells. The results have shown that Sch B exhibits potent grow inhibitory, proapoptotic, and proautophagic effects in AML-12 and RAW 264.7 cells. Sch B markedly arrested cells in G1 phase in both cell lines, accompanied by the down-regulation of cyclin dependent kinase 2 (CDK2) and cyclin D1 and up-regulation of p27 Kip1 and checkpoint kinase 1. Furthermore, Sch B markedly increased the apoptosis of AML 12 and RAW 264.7 cells with a decrease in the expression of B-cell lymphoma-extra large and (Bcl-xl) B-cell lymphoma 2 (Bcl-2), but an increase in the expression of B-cell lymphoma 2-associated X protein (Bax). Sch B promoted the cleavage of caspase 3 and poly-adenosine diphosphate-ribose polymerase (PARP) in both cell lines. Additionally, Sch B significantly induced autophagy of AML-12 and RAW 264.7 cells. Sch B inhibited the activation of phosphatidylinositol 3-kinase (PI3K)/protein kinase B (Akt)/mammalian target of rapamycin (mTOR) signaling pathway, as indicated by their altered phosphorylation, contributing to the proautophagic effect of Sch B. Taken together, our findings show that the inducing effects of Sch B on cell cycle arrest, apoptosis, and autophagy may contribute to its liver toxic effects, which might provide a clue for the investigation of the molecular toxic targets and underlying mechanisms for Sch B induced hepatotoxicity in herbal consumers. More studies are warranted to fully delineate the underlying mechanisms, efficacy, and safety of Sch B for clinical use. PMID- 25926717 TI - Impact of potential inappropriate NSAIDs use in chronic pain. AB - Pain remains one of the main reasons for medical consultation worldwide: moderate to severe-intensity pain occurs in 19% of adult Europeans, seriously affecting the quality of their social and working lives. Nonsteroidal anti-inflammatory drugs (NSAIDs) are not recommended for long-term use and a careful surveillance to monitor for toxicity and efficacy is critical. This study aims to assess: 1) the pattern of use of NSAIDs and opioids in a population covered by a cloud-based pharmacovigilance surveillance system; and 2) potential inappropriate use. A retrospective 18-months systematic analysis on patients' pain treatment was performed. The primary endpoint was evaluating the prevalence of NSAIDs and opioids use and the duration of therapy regimen. The secondary endpoint was to investigate the prevalence of NSAIDs taken for >21 consecutive days concomitant with drugs for peptic ulcer and gastroesophageal reflux disease (GORD) or antiplatelet drugs. The yearly cost for individual users of concomitant NSAIDs for more than 21 consecutive days and of GORD medications has been estimated. A total of 3,050 subjects with chronic pain were enrolled; 97% of them took NSAIDs for >21 consecutive days; about one-fourth of these users also received drugs for peptic ulcer and GORD (Anatomical Therapeutic Chemical code A02B). The yearly cost foran individual who uses NSAIDs for >21 consecutive days as well as concomitant GORD medications is 61.23 euros. In total, 238 subjects (8%) using NSAIDs for >21 days also received one antiplatelet agent. About 11% of subjects received opioids at least once and only 2% of them carried on the therapy for more than 90 consecutive days. In evaluating the escalation in dosage as a proxy of dependence risk, this study shows no dosage escalation in our cohort of chronic pain population - that is to say we show no risk of dependence. PMID- 25926718 TI - Management of severe sepsis: advances, challenges, and current status. AB - The complexity of treating severe sepsis and septic shock has been elucidated in myriad studies, particularly in the past 10 years. The development of clinical guidelines, insight into the effect of bundle elements, and results of clinical trials have brought to light further opportunities and questions in the approach to pharmaceutical interventions for the global challenge to save lives and reduce healthcare costs. Therapeutic interventions including fluid resuscitation, hemodynamic monitoring, glycemic control, corticosteroids, and antimicrobial therapy and stewardship inform outcomes. Research on biomarkers, use of mesenchymal stem cells, blood purification, immunoglobulins, and antioxidative treatments apropos the immune response may soon yield viable therapies. PMID- 25926720 TI - Roles of Ca(2+)/calmodulin-dependent protein kinase II in subcellular expression of striatal N-methyl-D-aspartate receptors in l-3, 4-dihydroxyphenylalanine induced dyskinetic rats. AB - BACKGROUND: The role of N-Methyl-D-aspartate (NMDA) receptors is critical to the development of L-3,4-dihydroxyphenylalanine (L-DOPA)-induced dyskinesia (LID) in Parkinson's disease (PD). Ca(2+)/calmodulin-dependent protein kinase II (CaMKII) is thought to regulate the expression and activation of NMDA receptors in LID, but the interaction between LID and CaMKII-modulated NMDA receptor activity is not clear so far. METHODS: We used 6-hydroxydopamine-lesioned rats to create PD rat model, and at least 21 days of L-DOPA was administrated followed with or without microinjection of CaMKII inhibitor KN-93 into the lesioned striatum of all the PD rats and sham rats. A surface receptor cross-linking assay was used to distinguish expression of striatal NMDA receptors in surface and intracellular compartments. RESULTS: L-DOPA treatment enhanced surface levels of GluN1 expression and reduced its intracellular expression, but did not change total levels of GluN1 protein in the lesioned striatum. In contrast, l-DOPA decreased GluN2A surface expression but increased its intracellular expression. L-DOPA increased GluN2B expression preferentially in the surface compartment. We also found that L-DOPA increased CaMKII autophosphorylation at T286 in striatal neurons. The inhibition of CaMKII by microinjecting CaMKII inhibitor KN-93 into the lesioned striatum largely reversed the L-DOPA-induced changes in three subunits. In addition, dyskinetic behaviors of animals were observed alleviated after treatment of KN-93. CONCLUSION: Our research indicates that long-term L DOPA administration activates CaMKII in striatal neurons. Activated CaMKII is involved at least in part in mediating L-DOPA-induced changes of NMDA receptors surface/intracellular expression. PMID- 25926719 TI - Drug delivery strategies to enhance the permeability of the blood-brain barrier for treatment of glioma. AB - Gliomas are amongst the most insidious and destructive types of brain cancer and are associated with a poor prognosis, frequent recurrences, and extremely high lethality despite combination treatment of surgery, radiotherapy, and chemotherapy. The existence of the blood-brain barrier (BBB) restricts the delivery of therapeutic molecules into the brain and offers the clinical efficacy of many pharmaceuticals that have been demonstrated to be effective for other kinds of tumors. This challenge emphasizes the need to be able to deliver drugs effectively across the BBB to reach the brain parenchyma. Enhancement of the permeability of the BBB and being able to transport drugs across it has been shown to be a promising strategy to improve drug absorption and treatment efficacy. This review highlights the innovative technologies that have been introduced to enhance the permeability of the BBB and to obtain an optimal distribution and concentration of drugs in the brain to treat gliomas, such as nanotechniques, hyperthermia techniques, receptor-mediated transport, cell penetrating peptides, and cell-mediated delivery. PMID- 25926721 TI - The clinicopathological significance of CDH1 in gastric cancer: a meta-analysis and systematic review. AB - BACKGROUND: CDH1 is a protein encoded by the CDH1 gene in humans. Loss of CDH1 function contributes to cancer progression by increasing proliferation, invasion, and/or metastasis. However, the association and clinicopathological significance between CDH1 hypermethylation and gastric cancer (GC) remains unclear. In this study, we systematically reviewed the studies of CDH1 hypermethylation and GC, and evaluated the association between CDH1 hypermethylation and GC using meta analysis methods. METHODS: A comprehensive search of the PubMed and Embase databases was performed for publications up to July 2014. Methodological quality of the studies was also evaluated. The data were extracted and assessed by two reviewers independently. Analyses of pooled data were performed. Odds ratios (ORs) were calculated and summarized. RESULTS: A final analysis of 1,079 GC patients from 14 eligible studies was performed. CDH1 hypermethylation level in the cancer group was significantly higher compared to the normal gastric mucosa (OR =8.55, 95% confidence interval [CI]: 2.39-33.51, Z=5.47, P<0.00001). CDH1 hypermethylation was not significantly higher in GC than in adjacent gastric mucosa (OR =3.68, 95% CI: 0.96-14.18, Z=1.90, P=0.06). However, CDH1 hypermethylation was higher in adjacent gastric mucosa compared to that in normal gastric mucosa (OR =2.55, 95% CI: 1.22-5.32, Z=2.49, P<0.01). In addition, CDH1 hypermethylation was correlated with Helicobacter pylori (HP) status in GC. The pooled OR from six studies including 280 HP-positive GCs and 193 HP-negative GCs is 1.72 (95% CI: 1.13-2.61, Z=2.55, P=0.01). CONCLUSION: The results of this meta analysis reveal that CDH1 hypermethylation levels in cancer and adjacent gastric mucosa are significantly higher compared to normal gastric mucosa. Thus, CDH1 hypermethylation is significantly correlated with GC risk. CDH1 hypermethylation is correlated with HP status, indicating that it plays a more important role in the pathogenesis of HP-positive GC and might be an interesting potential drug target for GC patients. PMID- 25926722 TI - Evaluation of combined famotidine with quercetin for the treatment of peptic ulcer: in vivo animal study. AB - The aim of this work was to prepare a combined drug dosage form of famotidine (FAM) and quercetin (QRT) to augment treatment of gastric ulcer. FAM was prepared as freeze-dried floating alginate beads using ion gelation method and then coated with Eudragit RL100 to sustain FAM release. QRT was prepared as solid dispersion with polyvinyl pyrrolidone K30 to improve its solubility. Photo images and scanning electron microscope images of the prepared beads were carried out to detect floating behavior and to reveal surface and core shape of the prepared beads. Anti-ulcerogenic effect and histopathological examination of gastric tissues were carried out to investigate the effect of the combined drug formulation compared with commercial FAM tablets and FAM beads. Gastric glutathione (GSH), superoxide dismutase, catalase, tissue myeloperoxidase, and lipid peroxidation enzyme activities and levels in rat stomach tissues were also determined. Results revealed that spherical beads were formed with an average diameter of 1.64+/-0.33 mm. They floated immediately with no lag time before floating, and remained buoyant throughout the test period. Treatment with a combination of FAM beads plus QRT showed the absence of any signs of inflammation or hemorrhage, and significantly prevented the indomethacin-induced decrease in GSH levels (P<0.05) with regain of normal GSH gastric tissue levels. Also, there was a significant difference in the decrease of malondialdehyde level compared to FAM commercial tablets or beads alone (P<0.05). The combined formula significantly improved the myeloperoxidase level compared to both the disease control group and commercial FAM tablet-treated group (P<0.05). Formulation of FAM as floating beads in combination with solid dispersion of QRT improved the anti-ulcer activity compared to commercially available tablets, which reveals a promising application for treatment of peptic ulcer. PMID- 25926723 TI - Identification of validated questionnaires to measure adherence to pharmacological antihypertensive treatments. AB - BACKGROUND: Low adherence to pharmacological treatments is one of the factors associated with poor blood pressure control. Questionnaires are an indirect measurement method that is both economic and easy to use. However, questionnaires should meet specific criteria, to minimize error and ensure reproducibility of results. Numerous studies have been conducted to design questionnaires that quantify adherence to pharmacological antihypertensive treatments. Nevertheless, it is unknown whether questionnaires fulfil the minimum requirements of validity and reliability. The aim of this study was to compile validated questionnaires measuring adherence to pharmacological antihypertensive treatments that had at least one measure of validity and one measure of reliability. METHODS: A literature search was undertaken in PubMed, the Excerpta Medica Database (EMBASE), and the Latin American and Caribbean Health Sciences Literature database (Literatura Latino-Americana e do Caribe em Ciencias da Saude [LILACS]). References from included articles were hand-searched. The included papers were all that were published in English, French, Portuguese, and Spanish from the beginning of the database's indexing until July 8, 2013, where a validation of a questionnaire (at least one demonstration of the validity and at least one of reliability) was performed to measure adherence to antihypertensive pharmacological treatments. RESULTS: A total of 234 potential papers were identified in the electronic database search; of these, 12 met the eligibility criteria. Within these 12 papers, six questionnaires were validated: the Morisky Green-Levine; Brief Medication Questionnaire; Hill-Bone Compliance to High Blood Pressure Therapy Scale; Morisky Medication Adherence Scale; Treatment Adherence Questionnaire for Patients with Hypertension (TAQPH); and Martin-Bayarre-Grau. Questionnaire length ranged from four to 28 items. Internal consistency, assessed by Cronbach's alpha, varied from 0.43 to 0.889. Additional statistical techniques utilized to assess the psychometric properties of the questionnaires varied greatly across studies. CONCLUSION: At this stage, none of the six questionnaires included could be considered a gold standard. However, this revision will assist health professionals in the selection of the most appropriate tool for their individual circumstances. PMID- 25926724 TI - Smoking cessation in Asians: focus on varenicline. AB - Smoking is a modifiable risk factor for morbidity and mortality caused by cancer, cardiovascular diseases, respiratory diseases, and many other diseases. Given the large population size and high prevalence of smoking in Asia, successful smoking cessation could potentially prevent the large number of premature deaths in Asians. However, most dependent smokers cannot successfully quit smoking due to nicotine addiction, and they need professional help and smoking cessation therapies. Varenicline is a highly selective partial agonist for the nicotinic acetylcholine receptor alpha4beta2 subtype, which is believed to be responsible for mediating the reinforcing properties of nicotine. This article is a narrative review, which summarizes the smoking cessation efficacy, side effects, and cost utilities of varenicline in Asians. From this review, we conclude that varenicline is an effective medication that could assist smoking cessation in the Asian populations. The adverse events of varenicline are tolerable, and the most common events were nausea and abnormal dreams. Both the efficacy and tolerance of varenicline in Asians are similar to that in Western populations. Considering the cost utilities, varenicline should be recommended for use in smoking cessation and be covered by medical insurance in most Asian countries. PMID- 25926725 TI - Effects of free leucine supplementation and resistance training on muscle strength and functional status in older adults: a randomized controlled trial. AB - OBJECTIVE: To assess the effect of free leucine supplementation combined with resistance training versus resistance training only on muscle strength and functional status in older adults. METHODS: This was a randomized, double-blind, placebo-controlled, parallel study with two intervention groups. Thirty older adults were randomly assigned to receive either 10 g leucine/day (leucine group [LG], n=15) or a placebo (control group [CG], n=15), plus resistance training over a 12-week period. Maximal overcoming isometric leg strength, functional status, nutritional status, body composition, health-related quality of life, depression, and dietary intake were assessed at 4 and 12 weeks. Missing data at 12 weeks were handled using mixed models for repeated measurements for data imputation. RESULTS: Twenty-four subjects completed the 4-week assessment and eleven completed the 12-week intervention. Clinically significant gains were found in isometric leg strength at both assessment time points. Analysis of the effect size also showed how participants in LG outperformed those in CG for chair stands and the timed up and go test. No significant changes were observed for the rest of the outcomes. CONCLUSION: Our combined analysis showed moderate changes in isometric leg muscle strength and certain components of functional status. The magnitude of changes found on these outcomes should be qualified as a positive effect of the concomitant intervention. PMID- 25926726 TI - Real-world comparative study of behavioral group therapy program vs education program implemented for smoking cessation in community-dwelling elderly smokers. AB - BACKGROUND: Tobacco smoking is known to be an important contributor to a wide variety of chronic diseases, especially in older adults. Information on health policy and practice, as well as evaluation of smoking cessation programs targeting older people, is almost nonexistent. PURPOSE: To compare the real-world implementation of behavioral group therapy in relation to education alone for elderly smokers. MATERIALS AND METHODS: Elderly smokers ready to quit smoking were identified from a cohort who completed a questionnaire at a smoking exhibition. They were allocated into two groups, behavioral therapy (3 days 9 hours) and education (2 hours), depending on their preferences. Demographic data, the Fagerstrom test for nicotine dependence (FTND) score, and exhaled carbon monoxide level were recorded at baseline. Smoking status of all subjects was followed at months 3, 6, and 12. Statistical differences in continuous abstinence rate (CAR) between the two groups were analyzed using chi-square tests. RESULTS: Two hundred and twenty-four out of 372 smoking exhibition attendants met the enrollment criteria; 120 and 104 elected to be in behavioral group therapy and education-alone therapy, respectively. Demographic characteristics and smoking history were similar between both groups, including age, age of onset of smoking, years of smoking, smoking pack-years, education level, and nicotine dependence as measured by the FTND scale. The CAR of the behavioral therapy group at the end of the study (month 12) was significantly higher than the education group (40.1% vs 33.3%, P=0.034). Similar results were also found throughout all follow-up visits at month 3 (57.3% vs 27.0%, P<0.001) and month 6 (51.7% vs 25%, P<0.001). CONCLUSION: Behavioral group therapy targeting elderly smokers could achieve higher short-and long-term CARs than education alone in real-world practice. PMID- 25926727 TI - Comparative study on health care utilization and hospital outcomes of severe acute exacerbation of chronic obstructive pulmonary disease managed by pulmonologists vs internists. AB - BACKGROUND: Care for many chronic health conditions is delivered by both specialists and generalists. Differences in patients' quality of care and management between generalists and specialists have been well documented for asthma, whereas a few studies for COPD reported no differences. OBJECTIVE: The objective of this study is to compare consistency with Global initiative for chronic Obstructive Lung Disease guidelines, as well as rate, health care utilization, and hospital outcomes of severe acute exacerbation (AE) of COPD patients managed by pulmonologists and internists. MATERIALS AND METHODS: This is a 12-month prospective, comparative observational study among 208 COPD patients who were regularly managed by pulmonologists (Group A) and internists (Group B). Clinical data, health care utilization, and hospital outcomes of the two groups were statistically compared. RESULTS: Out of 208 enrolled patients, 137 (Group A) and 71 (Group B) were managed by pulmonologists and internists, respectively. Pharmacological treatment corresponding to disease severity stages between the two groups was not statistically different. Group A received care consistent with guidelines in terms of annual influenza vaccination (31.4% vs 9.9%, P<0.001) and pulmonary rehabilitation (24.1% vs 0%, P<0.001) greater than Group B. Group A had reduced rates (12.4% vs 23.9%, P=0.033) and numbers of severe AE (0.20+/-0.63 person-years vs 0.41+/-0.80 person-years, P=0.029). Among patients with severe AE requiring mechanical ventilation, Group A had reduced mechanical ventilator duration (1.5 [1-7] days vs 5 [3-29] days, P=0.005), hospital length of stay (3.5 [1-20] days vs 16 [6-29] days, P=0.012), and total hospital cost ($863 [247 2,496] vs $2,095 [763-6,792], P=0.049) as compared with Group B. CONCLUSION: This study demonstrated that pulmonologists followed national COPD guidelines more closely than internists. The rates and frequencies of severe AE were significantly lower in patients managed by pulmonologists, and length of hospital stay and cost were significantly lower among the patients with severe AE who required mechanical ventilation. PMID- 25926728 TI - Procalcitonin and C-reactive protein cannot differentiate bacterial or viral infection in COPD exacerbation requiring emergency department visits. AB - BACKGROUND: Viral and bacterial infections are the most common causes of chronic obstructive pulmonary disease (COPD) exacerbations. Whether serum inflammatory markers can differentiate bacterial from virus infection in patients with COPD exacerbation requiring emergency department (ED) visits remains controversial. METHODS: Viral culture and polymerase chain reaction (PCR) were used to identify the viruses in the oropharynx of patients with COPD exacerbations. The bacteria were identified by the semiquantitative culture of the expectorated sputum. The peripheral blood white blood cell (WBC) counts, serum C-reactive protein (CRP), procalcitonin (PCT), and clinical symptoms were compared among patients with different types of infections. RESULTS: Viruses were isolated from 16 (22.2%) of the 72 patients enrolled. The most commonly identified viruses were parainfluenza type 3, influenza A, and rhinovirus. A total of 30 (41.7%) patients had positive bacterial cultures, with the most commonly found bacteria being Haemophilus influenzae and Haemophilus parainfluenzae. Five patients (6.9%) had both positive sputum cultures and virus identification. The WBC, CRP, and PCT levels of the bacteria-positive and bacteria-negative groups were not statistically different. Multivariate analysis showed that patients with increased sputum volumes during the COPD exacerbations had higher risks of recurrent exacerbations in the 1-year period following the first exacerbation. CONCLUSION: WBC, CRP, or PCT could not differentiate between bacterial and viral infections in patients with COPD exacerbation requiring ED visits. Those with increased sputum during a COPD exacerbation had higher risks for recurrent exacerbations. PMID- 25926729 TI - Role of the fixed combination of fluticasone and salmeterol in adult Chinese patients with asthma and COPD. AB - Chronic obstructive pulmonary disease (COPD) and asthma are common airway disorders characterized by chronic airway inflammation and airflow obstruction, and are a leading cause of morbidity and mortality in the People's Republic of China. These two diseases pose a high economic burden on the family and the whole of society. Despite evidence-based Global Initiative for Chronic Obstructive Lung Disease and Global Initiative for Asthma guidelines being available for the diagnosis and management of COPD and asthma, many of these patients are not properly diagnosed or managed in the People's Republic of China. The value of combination therapy with inhaled corticosteroids and long-acting beta2-agonists has been established in the management of asthma and COPD globally. Combinations of inhaled corticosteroids and long-acting beta2-agonists such as fluticasone and salmeterol, have been shown to be effective for improving symptoms, health status, and reducing exacerbations in both diseases. In this review, we discuss the efficacy and safety of this combination therapy from key studies, particularly in the People's Republic of China. PMID- 25926730 TI - Coadministration of doxorubicin and etoposide loaded in camel milk phospholipids liposomes showed increased antitumor activity in a murine model. AB - Small unilamellar vesicles from camel milk phospholipids (CML) mixture or from 1,2 dipalmitoyl-sn-glycero-3-phosphatidylcholine (DPPC) were prepared, and anticancer drugs doxorubicin (Dox) or etoposide (ETP) were loaded. Liposomal formulations were used against fibrosarcoma in a murine model. Results showed a very high percentage of Dox encapsulation (~98%) in liposomes (Lip) prepared from CML-Lip or DPPC-Lip, whereas the percentage of encapsulations of ETP was on the lower side, 22% of CML-Lip and 18% for DPPC-Lip. Differential scanning calorimetry curves show that Dox enhances the lamellar formation in CML-Lip, whereas ETP enhances the nonlamellar formation. Differential scanning calorimetry curves also showed that the presence of Dox and ETP together into DPPC-Lip produced the interdigitation effect. The in vivo anticancer activity of liposomal formulations of Dox or ETP or a combination of both was assessed against benzopyrene (BAP)-induced fibrosarcoma in a murine model. Tumor-bearing mice treated with a combination of Dox and ETP loaded into CML-Lip showed increased survival and reduced tumor growth compared to other groups, including the combination of Dox and ETP in DPPC-Lip. Fibrosarcoma-bearing mice treated with a combination of free (Dox + ETP) showed much higher tumor growth compared to those groups treated with CML-Lip-(Dox + ETP) or DPPC-Lip-(Dox + ETP). Immunohistochemical study was also performed to show the expression of tumor suppressor PTEN, and it was found that the tumor tissues from the group of mice treated with a combination of free (Dox + ETP) showed greater loss of cytoplasmic PTEN than tumor tissues obtained from the groups of mice treated with CML-Lip (Dox + ETP) or DPPC-Lip-(Dox + ETP). PMID- 25926731 TI - A novel nanobody specific for respiratory surfactant protein A has potential for lung targeting. AB - Lung-targeting drugs are thought to be potential therapies of refractory lung diseases by maximizing local drug concentrations in the lung to avoid systemic circulation. However, a major limitation in developing lung-targeted drugs is the acquirement of lung-specific ligands. Pulmonary surfactant protein A (SPA) is predominantly synthesized by type II alveolar epithelial cells, and may serve as a potential lung-targeting ligand. Here, we generated recombinant rat pulmonary SPA (rSPA) as an antigen and immunized an alpaca to produce two nanobodies (the smallest naturally occurring antibodies) specific for rSPA, designated Nb6 and Nb17. To assess these nanobodies' potential for lung targeting, we evaluated their specificity to lung tissue and toxicity in mice. Using immunohistochemistry, we demonstrated that these anti-rSPA nanobodies selectively bound to rat lungs with high affinity. Furthermore, we intravenously injected fluorescein isothiocyanate-Nb17 in nude mice and observed its preferential accumulation in the lung to other tissues, suggesting high affinity of the nanobody for the lung. Studying acute and chronic toxicity of Nb17 revealed its safety in rats without causing apparent histological alterations. Collectively, we have generated and characterized lung-specific nanobodies, which may be applicable for lung drug delivery. PMID- 25926733 TI - Inhibition of various gram-positive and gram-negative bacteria growth on selenium nanoparticle coated paper towels. AB - There are wide spread bacterial contamination issues on various paper products, such as paper towels hanging in sink splash zones or those used to clean surfaces, filter papers used in water and air purifying systems, and wrappings used in the food industry; such contamination may lead to the potential spread of bacteria and consequent severe health concerns. In this study, selenium nanoparticles were coated on normal paper towel surfaces through a quick precipitation method, introducing antibacterial properties to the paper towels in a healthy way. Their effectiveness at preventing biofilm formation was tested in bacterial assays involving Staphylococcus aureus, Pseudomonas aeruginosa, Escherichia coli, and Staphylococcus epidermidis. The results showed significant and continuous bacteria inhibition with about a 90% reduction from 24 to 72 hours for gram-positive bacteria including S. aureus and S. epidermidis. The selenium coated paper towels also showed significant inhibition of gram-negative bacteria like P. aeruginosa and E. coli growth at about 57% and 84%, respectively, after 72 hours of treatment. Therefore, this study established a promising selenium based antibacterial strategy to prevent bacterial growth on paper products, which may lead to the avoidance of bacteria spreading and consequent severe health concerns. PMID- 25926732 TI - Using inositol as a biocompatible ligand for efficient transgene expression. AB - Transgene transfection techniques using cationic polymers such as polyethylenimines (PEIs) and PEI derivatives as gene vectors have shown efficacy, although they also have shortcomings. PEIs have decent DNA-binding capability and good cell internalization performance, but they cannot deliver gene payloads very efficiently to cell nuclei. In this study, three hyperbranched polyglycerol polyethylenimine (PG6-PEI) polymers conjugated with myo-inositol (INO) molecules were developed. The three resulting PG6-PEI-INO polymers have an increased number of INO ligands per molecule. PG6-PEI-INO 1 had only 14 carboxymethyl INO (CMINO) units per molecule. PG6-PEI-INO 2 had approximately 130 CMINO units per molecule. PG6-PEI-INO 3 had as high as 415 CMINO units approximately. Mixing PG6-PEI-INO polymers with DNA produced compact nanocomposites. We then performed localization studies using fluorescent microscopy. As the number of conjugated inositol ligands increased in PG6-PEI-INO polymers, there was a corresponding increase in accumulation of the polymers within 293T cell nuclei. Transfection performed with spherical 293T cells yielded 82% of EGFP-positive cells when using PG6-PEI-INO 3 as the vehicle. Studies further revealed that extracellular adenosine triphosphate (eATP) can inhibit the transgene efficiency of PG6-PEI-INO polymers, as compared with PEI and PG6-PEI that were not conjugated with inositol. Our work unveiled the possibility of using inositol as an effective ligand for transgene expression. PMID- 25926735 TI - Catha edulis chewing effects on treatment of paranoid schizophrenic patients. AB - BACKGROUND: The current study's aim is to evaluate the possible interaction effects of khat chewing on treatment of paranoid schizophrenic patients. PATIENTS AND METHODS: In the study group, 42 male subjects suffered from paranoid schizophrenia and were classified according to their khat chewing habits into two subgroups: either khat-chewer subgroup (SKc; n=21; r=11, h=10) or non-khat-chewer subgroup (SNKc; n=21, r=11, h=10). Each subgroup was further subdivided according to type of treatment into r (risperidone) and h (haloperidol). Healthy male subjects (37) were subdivided into healthy khat-chewer as positive controls (HKc, n=17) and healthy non-khat-chewer as negative controls (HNKc, n=20). Plasma dopamine, 3,4-dihydroxyphenylacetic acid (DOPAC), homovanillic acid, 5 hydroxytryptamine (serotonin), 5-hydroxyindoleacetic acid, epinephrine, and norepinephrine were estimated. RESULTS: ANOVA and post hoc analysis showed that dopamine was illustrating significant elevation in all khat chewing groups. DOPAC was illustrating significant decrease in all khat chewing groups with an interesting outcome showing significant increase in DOPAC in SNKcr group due to risperidone effect. Homovanillic acid, serotonin, hydroxyindoleacetic acid, and norepinephrine were illustrating significant elevations in all khat chewing groups. Epinephrine was illustrating significant elevation in all chewers than non-chewers groups. Unexpected significant decrease in epinephrine in the SNKcr group indicated that risperidone drug is decreasing epinephrine through indirect mechanism involving calcium. CONCLUSION: Khat chewing in schizophrenic patients is contraindicated because it aggravates the disease symptoms, attenuates all used treatment medications, and deteriorates all biochemical markers of the patients. PMID- 25926734 TI - Synthesis, characterization, and immune efficacy of layered double hydroxide@SiO2 nanoparticles with shell-core structure as a delivery carrier for Newcastle disease virus DNA vaccine. AB - Layered double hydroxide (LDH)@SiO2 nanoparticles were developed as a delivery carrier for the plasmid DNA expressing the Newcastle disease virus F gene. The LDH was hydrotalcite-like materials. The plasmid DNA encapsulated in the LDH@SiO2 nanoparticles (pFDNA-LDH@SiO2-NPs) was prepared by the coprecipitation method, and the properties of pFDNA-LDH@SiO2-NPs were characterized by transmission electron microscopy, zeta potential analyzer, Fourier transform infrared spectroscopy, and X-ray diffraction analysis. The results demonstrated that the pFDNA-LDH@SiO2-NPs had a regular morphology and high stability with a mean diameter of 371.93 nm, loading capacity of 39.66%+/-0.45%, and a zeta potential of +31.63 mV. A release assay in vitro showed that up to 91.36% of the total plasmid DNA could be sustainably released from the pFDNA-LDH@SiO2-NPs within 288 hours. The LDH@SiO2 nanoparticles had very low toxicity. Additionally, their high transfection efficiency in vitro was detected by fluorescent microscopy. Intranasal immunization of specific pathogen-free chickens with pFDNA-LDH@SiO2 NPs induced stronger cellular, humoral, and mucosal immune responses and achieved a greater sustained release effect than intramuscular naked plasmid DNA, and the protective efficacy after challenge with the strain F48E9 with highly virulent (mean death time of chicken embryos <=60 hours, intracerebral pathogenicity index in 1 -day-old chickens >1.6) was 100%. Based on the results, LDH@SiO2 nanoparticles can be used as a delivery carrier for mucosal immunity of Newcastle disease DNA vaccine, and have great application potential in the future. PMID- 25926736 TI - A randomized crossover study comparing trehalose/hyaluronate eyedrops and standard treatment: patient satisfaction in the treatment of dry eye syndrome. AB - Dry eye is a common disorder in routine ophthalmological practice, and a better understanding of the complex pathophysiology is leading to improved treatment. Thealoz Duo((r)) is a novel artificial tear preparation containing two active ingredients: Trehalose, a naturally occurring disaccharide with anhydrobiotic functions in many organisms, and hyaluronate, a widely distributed anionic glycosaminoglycan polysaccharide with lubricative and water-retaining properties in biological systems. In a randomized, single center, open label, crossover study, 17 adult patients with moderate-to-severe dry eye syndrome were randomized to treatment with Thealoz Duo((r)) (combining trehalose and hyaluronic acid) or Systane((r)). Patients received 7 days of treatment. The primary efficacy variable was patient satisfaction evaluated by a 0-100 visual analog scale evaluated on days 0 and 7 of treatment. Secondary parameters included ocular surface disease index (OSDI), symptoms of dry eye, ocular staining scores (fluorescein and lissamine green), ocular clinical signs, Schirmer test, tear breakup time, and global efficacy assessed by the patient and the investigator. Seventeen patients were included. Patient satisfaction improved from 44.5+/-19.0 to 70.2+/-19.2 mm during Thealoz Duo((r)) treatment and from 47.2+/-23 to 57.1+/ 19.1 mm during Systane((r)) treatment (P=0.043, mixed-effects analysis of covariance). Two secondary efficacy parameters (dry eye symptoms and the impact of their symptoms on work) showed statistically significant advantages for Thealoz Duo((r)) over Systane((r)). There were no statistically significant advantages for Systane((r)) over Thealoz Duo((r)) for any measured parameter. No adverse events were reported. Thealoz Duo((r)) appears to be an effective combination of two active ingredients for the treatment of dry eye and is at least as effective as Systane((r)). PMID- 25926737 TI - Update on the emerging role of telavancin in hospital-acquired infections. AB - Telavancin is a lipoglycopeptide that has activity against Gram-positive aerobic and anaerobic bacteria. It has activity against methicillin-resistant Staphylococcus aureus, vancomycin-intermediate S. aureus and non-Van-A strains of vancomycin-resistant enterococci. It has been approved by the US Food and Drug Administration (FDA) for complicated skin and skin structure infections and hospital-acquired pneumonia. There is a need for more clinical studies to determine the role of telavancin in treating bacteremia and prosthetic device infections. In this review, we discuss the published data on the use of telavancin in treating hospital-acquired infections and provide an update on new research. PMID- 25926738 TI - Adalimumab in the management of Behcet's disease. AB - Behcet's disease (BD) is a relapsing, systemic, inflammatory disorder that affects various organ systems. Most of the manifestations of BD are self limiting, but ocular attacks are an exception. Gastrointestinal tract, central nervous system, and cardiovascular system manifestations are relatively infrequent but may be resistant to conventional immunosuppressive treatment and therefore life-threatening. Tumor necrosis factor alpha antagonists are increasingly being used in patients whose BD is inadequately controlled by standard immunosuppressive regimens. Most of the current experience regarding the treatment of refractory BD involves the use of infliximab; however, adalimumab has also been successfully used in cases of BD refractory to both conventional therapy and infliximab. Compared with infliximab, adalimumab offers several other advantages, such as the ability to self-administer at home, better patient compliance, and an improved side effect profile. Here, we review clinical experience of the use of adalimumab to treat the serious manifestations of BD. Adalimumab is a promising drug for the treatment of BD, and its randomized, prospective study in a large number of patients is warranted to fully determine its efficacy in the refractory BD setting. PMID- 25926739 TI - Comparison of the BPLab(r) sphygmomanometer for ambulatory blood pressure monitoring with mercury sphygmomanometry in pregnant women: validation study according to the British Hypertension Society protocol. AB - The purpose of this study was to validate the automated BPLab(r) sphygmomanometer for ambulatory blood pressure monitoring (ABPM) in pregnant women according to Part II of the 1993 British Hypertension Society protocol. Pregnant women attending the antenatal clinic were randomly asked to participate (n=30). The BPLab sphygmomanometer was tested on pregnant women in this study and achieved A/A ratings according to the BHS protocol when compared with the "gold" standard of mercury sphygmomanometry. The device can therefore be recommended for use in pregnancy. PMID- 25926740 TI - GSK1838705A, an insulin-like growth factor-1 receptor/insulin receptor inhibitor, induces apoptosis and reduces viability of docetaxel-resistant prostate cancer cells both in vitro and in vivo. AB - Prostate cancer is the leading malignancy and the second most common cause of cancer-related death in men. Despite high cure rates with surgery and/or radiation, 30%-40% of patients eventually develop advanced cancer. Docetaxel is one of the most effective and well established chemotherapeutic agents for prostate cancer. However, docetaxel resistance often develops within months. Combination therapies have been proposed to improve the therapeutic efficacy of docetaxel in prostate cancer, and there is an urgent need to identify agents that are effective for treatment of the disease, especially docetaxel-resistant prostate cancer. In this work, we investigated the activity of GSK1838705A, a potent insulin-like growth factor-1 receptor (IGF1R)/insulin receptor (IR) inhibitor, in prostate cancer, especially docetaxel-resistant prostate cancer. We found that GSK1838705A could effectively reduce the viability of both docetaxel sensitive and docetaxel-resistant prostate cancer cells. GSK1838705A induced marked apoptosis in docetaxel-resistant cells, and also dramatically inhibited migration of these cells. Further, GSK1838705A significantly inhibited phosphorylation of IGF1R/IR. Importantly, GSK1838705A significantly suppressed docetaxel-resistant PC-3R tumor growth in vivo. This is the first study of GSK1838705A in prostate cancer. Our results indicate that GSK1838705A is a promising compound for the treatment of prostate cancer, especially for those who develop resistance to docetaxel, and might shed new light on treatment for prostate cancer. PMID- 25926741 TI - Predictive value of plasma D-dimer levels in patients with advanced non-small cell lung cancer. AB - PURPOSE: The relationship between plasma D-dimer level and the prognosis of advanced non-small-cell lung cancer (NSCLC) is not well studied. This study investigated the role of plasma D-dimer as a prognostic factor in advanced NSCLC. METHODS: The plasma D-dimer was measured in 1,931 newly diagnosed advanced NSCLC patients by enzyme-linked immunosorbent assay. Correlations between plasma D dimer levels and other clinical parameters were analyzed. Survival curves were plotted using the Kaplan-Meier method. The Cox proportional hazard model was used for multivariate analysis. RESULTS: Plasma D-dimer concentrations were within the normal range in 1,393 patients (72.1%) and elevated in 538 patients (27.9%). The median overall survival was 11.5 and 8.8 months in the normal and high plasma D dimer group, respectively (P<0.001). The progression-free survival of first-line chemotherapy was 5.0 months and 4.4 months in the groups with normal and high levels of plasma D-dimer, respectively, (P<0.001). By multivariate analyses, the elevated plasma D-dimer level was found to be an independent prognostic factor for poor survival (hazard ratio =1.245; P<0.001). CONCLUSION: Plasma D-dimer is an independent determinant of poor prognosis in advanced NSCLC. PMID- 25926742 TI - Nimotuzumab enhances radiation sensitivity of NSCLC H292 cells in vitro by blocking epidermal growth factor receptor nuclear translocation and inhibiting radiation-induced DNA damage repair. AB - BACKGROUND: The epidermal growth factor receptor (EGFR) signaling pathway plays a significant role in radiation resistance. There is evidence that EGFR nuclear translocation is associated with DNA double-strand breaks (DSB) repair. Nimotuzumab has shown the effect of radiosensitization in various cancer cells, but little is known about the relationship between nimotuzumab and EGFR nuclear translocation in non-small cell lung cancer (NSCLC) cell lines. In this study, we selected two NSCLC cell lines, namely, H292 (with high EGFR expression) and H1975 (with low EGFR expression) and explored the mechanisms underlying radiation sensitivity. METHODS: MTT assay, clonogenic survival assay, and flow cytometry were performed separately to test cell viability, radiation sensitivity, cell cycle distribution, and apoptosis. Protein gamma-H2AX, DNA-PK/p-DNA-PK, and EGFR/p-EGFR expression were further compared both in the cytoplasm and the nucleus with the western blot. RESULTS: Nimotuzumab reduced the viability of H292 cells and sensitized H292 cells to ionizing radiation. The radiation sensitivity enhancement ratio (SER) was 1.304 and 1.092 for H292 and H1975 cells, respectively. H292 cells after nimotuzumab administration were arrested at the G0/G1 phase in response to radiation. Apoptosis was without statistical significance in both cell lines. gamma-H2AX formation in the combination group (nimotuzumab and radiation) increased both in the cytoplasm and the nucleus along with the decreased expression of nuclear EGFR/p-EGFR and p-DNA-PK in H292 cells (P<0.05) that was more significant than that in H1975 cells. CONCLUSION: Our research revealed a possible mechanism to explain the radiosensitivity in H292 cells. Nimotuzumab decreased the radiation-induced activation of DNA-PK by blocking EGFR nuclear translocation and impairing DNA DSB repair, thus enhancing radiosensitivity in H292 cells. Because these results represent early research, the matters of how gamma-H2AX and DNA-PK dynamically change simultaneously with nuclear EGFR and the best time to administer nimotuzumab will require further exploration. PMID- 25926743 TI - Profile of nimotuzumab in the treatment of high-grade glioma. AB - High-grade gliomas (HGG) are extremely aggressive lesions and represent the most common primary malignant brain tumors without an effective therapy. Standard treatment for HGG usually includes surgery followed by radiotherapy and chemotherapy. However, the prognosis of patients with HGG remains dismal. We review the humanized epidermal growth factor receptor (EGFR) and the major EGFR target drugs in HGG treatments, focusing on the EGFR antibody nimotuzumab as a new therapeutic strategy in HGG. We found that nimotuzumab with or without radiotherapy, chemotherapy in newly diagnosed or recurrent HGG, such as glioblastoma multiforme (GBM), anaplastic astrocytomas (AA), and diffuse intrinsic pontine glioma (DIPG), might improve the response rate or the survival time. In conclusion, nimotuzumab is a very well-tolerated drug with acceptable toxicity, and it may have promising value in the combination treatment. As a result, multiple center randomized controlled Phase III clinical trials need to be conducted to confirm the efficacy and toxicity for nimotuzumab in HGG. PMID- 25926744 TI - DNA ploidy of cervical epithelial cells should be a cure criterion of high-risk HPV infection in Xinjiang Uygur women. AB - BACKGROUND: The Uygur women have the highest incidence of cervical cancer in all Chinese ethnic groups. The research was conducted to explore whether DNA ploidy could be the prognostic indicator of human papillomavirus (HPV) infection in Xinjiang Uygur women. METHODS: Case data and cervical exfoliated cell samples from 326 Uygur women. The DNA ploidy was analyzed by flow cytometry. The flow through hybridization and gene chip (FHGC) for HPV type test then divided the cases into negative HPV group, non high-risk HPV infection group, single high risk HPV infection group, and multiple high-risk HPV infection group. Lastly, 113 cases from 273 HPV infection cases were followed up. RESULTS: The 16-type HPV had the highest rate in all genotypes infection; 16/18-type HPV mixed infection was the most common type in multiple high-risk HPV infection group. Abnormal DNA ploidy happened along with the seriousness of HPV infection. Compared with the HPV negative group, DNA heteroploid appeared 12.750 times and 22.705 times, respectively, in single high-risk HPV and multiple high-risk HPV infection groups. Followed up 1 year later, the DNA index, S-phase cells' peak percentage and heteroploid of cervical exfoliated cells significantly reduced in single and multiple high-risk HPV infection patients, but in nine patients negative HPV infection and DNA heteroploid still existed. CONCLUSION: The finally cure criterion of high-risk HPV infection should include the negative HPV test and normal DNA ploidy analysis. It was useful to prevent and cure cervical lesions in Xinjiang Uygur women through high-risk HPV test and DNA ploidy analysis. The transient infection and persistent infection in Xinjiang Uygur women should be taken as further research. PMID- 25926745 TI - The significance of combining VEGFA, FLT1, and KDR expressions in colon cancer patient prognosis and predicting response to bevacizumab. AB - Targeting angiogenesis through inhibition of the vascular endothelial growth factor (VEGF) pathway has been successful in the treatment of late stage colorectal cancer. However, not all patients benefit from inhibition of VEGF. Ras status is a powerful biomarker for response to anti-epidermal growth factor receptor therapy; however, an appropriate biomarker for response to anti-VEGF therapy is yet to be identified. VEGF and its receptors, FLT1 and KDR, play a crucial role in colon cancer progression; individually, these factors have been shown to be prognostic in colon cancer; however, expression of none of these factors alone was predictive of tumor response to anti-VEGF therapy. In the present study, we analyzed the expression levels of VEGFA, FLT1, and KDR in two independent colon cancer datasets and found that high expression levels of all three factors afforded a very poor prognosis. The observation was further confirmed in another independent colon cancer dataset, wherein high levels of expression of this three-gene signature was predictive of poor prognosis in patients with proficient mismatch repair a wild-type KRas status, or mutant p53 status. Most importantly, this signature also predicted tumor response to bevacizumab, an antibody targeting VEGFA, in a cohort of bevacizumab-treated patients. Since bevacizumab has been proven to be an important drug in the treatment of advanced stage colon cancer, our results suggest that the three-gene signature approach is valuable in terms of its prognostic value, and that it should be further evaluated in a prospective clinical trial to investigate its predictive value to anti-VEGF treatment. PMID- 25926746 TI - Regenerative medicine in the treatment of idiopathic pulmonary fibrosis: current position. AB - Idiopathic pulmonary fibrosis (IPF) is a progressive, irreversible disease of the lung that has no lasting option for therapy other than transplantation. It is characterized by replacement of the normal lung tissue by fibrotic scarring, honeycombing, and increased levels of myofibroblasts. The underlying causes of IPF are still largely unknown. The focus of the current review is the possible use of stem cell therapy, specifically mesenchymal stem cells (MSCs), a multipotent stromal cell population, which have demonstrated promising data in multiple animal models of pulmonary fibrosis (PF). The most studied source of MSCs is the bone marrow, although they can be found also in the adipose tissue and umbilical cord, as well as in the placenta. MSCs have immunomodulatory and tissue-protective properties that allow them to manipulate the local environment of the injured tissue, ameliorating the inflammation and promoting repair. Because IPF primarily affects older patients, the issue of aging is intrinsically linked to many aspects of the disease, including the age of the stem cells. Animal models have shown the success of MSC therapy in mitigating the fibrotic effects of bleomycin-induced PF. However, bleomycin, the most commonly used model for PF, is imperfect in mimicking IPF as it presents in humans, as the duration of the illness is not parallel or reversible, and honeycombing is not produced. Furthermore, the time of MSC dosage has proven to be critical in determining whether the cells will ultimately have a positive or negative effect on disease progression, since it has been demonstrated that the maximal beneficial effect of MSCs occurs during the early inflammatory phase of the disease and that there is no or negative effect during the late fibrotic phase. Therefore, all the current clinical trials of MSCs and IPF, though promising, should proceed with caution as we move toward true stem cell therapy for this disease. PMID- 25926747 TI - Inpatient cost of treating osteoporotic fractures in mainland China: a descriptive analysis. AB - PURPOSE: The objective of this study was to provide new estimates on the per admission inpatient hospital cost and per-admission length of stay (LOS) for osteoporosis-related fractures in mainland China. MATERIALS AND METHODS: Data for inpatient hospitalization associated with at least one osteoporosis-related fracture were obtained from the nationwide China Health Insurance Research Association and were analyzed post hoc. Patients' data were included if the patients were >=50 years old and diagnosed with osteoporosis and pathologic fracture, or osteoporosis therapy and fragility fracture by an International Statistical Classification of Diseases and Related Health Problems, 10th Revision (ICD-10) code designation, between 2008 and 2010. RESULTS: The analysis included 830 patients (female: 77.3%; mean age: 73.4+/-9.8 years). The medians of the per admission LOS and inpatient costs were 19 days and Y18,587, respectively. Longer LOS and higher costs per admission were associated with older patients (>=70 years) compared to younger patients (<70 years). Hip fracture had the longest median LOS (22 days) and highest median cost (Y32,594) among all fracture sites. The per-hospitalization episode and per-day costs of osteoporotic fracture increased rapidly (60% and 89%, respectively) between 2008 and 2010. CONCLUSION: The analysis showed that hospitalization cost increases were associated with increasing per-day hospitalization costs. The proportion of the costs reimbursed by health insurances increased, while the mean absolute patient copayment amounts decreased. The incidence and prevalence of osteoporosis and osteoporosis-related fractures may rise rapidly due to the projected growth of the aged population in mainland China. Therefore, the combination of greater anticipated total fractures and rising hospital costs may lead to a tremendously increased economic burden in the future. PMID- 25926748 TI - Saroglitazar for the treatment of hypertrig-lyceridemia in patients with type 2 diabetes: current evidence. AB - Diabetes mellitus (DM) is one of the most dreaded metabolic disorders in the world today. It is the leading cause of morbidity and mortality, and plays a cardinal role in quality of life and health economics. DM is associated with a high prevalence of microvascular and macrovascular complications. DM is a very important cardiovascular (CV) risk factor. Cardiovascular disease (CVD) has been implicated as the prime cause of mortality and morbidity in patients with DM. Hence, treatment of DM goes beyond glycemic control, and demands a multidisciplinary approach that comprehensively targets risk factors inherent in CV events. Lipid abnormalities are undoubtedly common in patients with DM, and they contribute to an increased risk of CVD. A high-risk lipid profile, termed atherogenic dyslipidemia of diabetes (ADD), is known to occur in patients with DM. The use of lipid-lowering agents, a quintessential part of the multifactorial risk factor approach, is a crucial intervention to minimize diabetes-related complications. In this article, we discuss the role of peroxisome proliferator activator receptor (PPAR) alpha/gamma (alpha/gamma) agonist, saroglitazar, in the management of ADD. While statins are irrefutably the first line of drugs for dyslipidemia management in patients with residual CV risk while on a statin, PPAR alpha/gamma agonists have been found to be of substantial benefit. Data from the PRESS I-VI clinical trials testify to the fact that saroglitazar and fibrates have similar efficacy in reducing triglycerides and improving high-density lipoprotein. The ancillary benefit of improved glycemic control, without the weight gain of PPAR gamma agonists, is an added advantage. Reduction in ADD, improved glycemic control, efficacy at par with fibrates, and an acceptable safety profile form the grounds on which this group of PPAR alpha/gamma agonists, with their novel mechanism, holds a promising future in the management of diabetic dyslipidemia. PMID- 25926749 TI - Diabetes mellitus and risk factors in human immunodeficiency virus-infected individuals at Jimma University Specialized Hospital, Southwest Ethiopia. AB - BACKGROUND: Globally, diabetes is rising dramatically causing high health burden in low- and middle-income countries. It is estimated that about 382 million people had diabetes in 2013. In 2013, diabetes caused 5.1 million deaths globally. Almost 80% of diabetes deaths occur in low- and middle-income countries. PURPOSE: To assess the magnitude of diabetes mellitus (DM) and associated risk factors in human immunodeficiency virus (HIV)-infected individuals. METHODS: An institution-based cross-sectional study was conducted from April to May 2014 at Jimma University Specialized Hospital. Convenient sampling technique was implemented. Sociodemographic and anthropometric data were collected by senior clinical nurses. Venous blood was collected from each study participant. Serum glucose and lipid profile of the study participants was measured using HumaStar 80 spectrophotometer. Data were analyzed using SPSS version 20. Bivariate and multivariate logistic regressions were utilized. RESULTS: A total of 393 HIV-infected individuals of age ranging from 21 years to 75 years had enrolled in this study. The overall prevalence of DM in this study was 6.4% (n=25). Two hundred and ninety-one (74%) and 77 (19.6%) of the study participants had normal (70-110 mg/dL) and impaired (111-125 mg/dL) fasting blood glucose values, respectively. After adjusting for the other variables, age (adjusted odds ratio [AOR] =4.812, 95% confidence interval [CI]: 1.668-13.881, P=0.004), duration of highly active antiretroviral therapy (HAART) (AOR =26.928, 95% CI: 3.722-194.822, P=0.001), hypertension (AOR =4.779, 95% CI: 1.646-13.874, P=0.004), and low-density lipoprotein cholesterol (AOR =5.669, 95% CI: 1.849 17.382, P=0.004) were significantly associated with DM. CONCLUSION: HAART may have an impact on the cause of diabetes. Hence, HIV-infected individuals should be screened for diabetes, both before and after initiation of HAART. PMID- 25926750 TI - Patient factors influencing dermal filler complications: prevention, assessment, and treatment. AB - While rare, complications do occur with the esthetic use of dermal fillers. Careful attention to patient factors and technique can do much to avoid these complications, and a well-informed practitioner can mitigate problems when they do occur. Since cosmetic surgery is usually an elective process, requested by the patient, clinical trials are complex to organize and run. For this reason, an international group of practicing physicians in the field of esthetics came together to share knowledge and to try and produce some informed guidance for their colleagues, considering the literature and also pooling their own extensive clinical experience. This manuscript aims to summarize the crucial aspects of patient selection, including absolute contraindications as well as situations that warrant caution, and also covers important considerations for the pre- and posttreatment periods as well as during the procedure itself. Guidance is given on both immediate and long-term management of adverse reactions. The majority of complications are related to accepting patients inappropriate for treatment or issues of sterility, placement, volume, and injection technique. It is clear that esthetic practitioners need an in-depth knowledge of all aspects of treatment with dermal fillers to achieve optimal outcomes for their patients. PMID- 25926751 TI - Degos disease - malignant atrophic papulosis or cutaneointestinal lethal syndrome: rarity of the disease. AB - BACKGROUND: Degos disease is a very rare syndrome with a rare type of multisystem vasculopathy of unknown cause that affects the skin, gastrointestinal tract, and central nervous system. Other organs such as the kidneys, lungs, pleura, liver, heart, and eyes, can also be involved. OBJECTIVE: To highlight the incidence of Degos disease with regard to age and sex, discuss the necessity of its accurate and early diagnosis, and demonstrate the most current techniques for its diagnosis; to discuss whether early therapeutic intervention can impact patient prognosis; and to present a literature review about this disease. DESIGN: With a retrospective, observational, nonrandomized trial, we described the evolution of the different forms of Degos disease and referenced the literature. DATA SOURCES: Research on rare documented cases in the literature, including two cases of potentially lethal form of the disease involving the skin and gastrointestinal system and, possibly, the lungs, kidneys, and central nervous system. A case of the benign form of the disease involving the skin was observed by the authors. MAIN OUTCOME MEASURES: Differences between outcomes in patients with the cutaneointestinal form and skin-only form of the disease. There was one fatal outcome. We reviewed possible new approaches to diagnosis and treatment. RESULTS: The study demonstrated the rapid evolution of the aggressive and malignant form of the disease. It also described newly accessible Phase I diagnostic tools being currently researched as well as new therapeutic approaches. LIMITATION: The rarity of the disease, with only eleven cases throughout the literature. CONCLUSION: The gastrointestinal form of Degos disease can be lethal. Its vascular etiology has finally been confirmed; however, new and more accurate early diagnostic modalities need to be developed. There are new therapeutic possibilities, but the studies of them are still in the early stages and have not yet shown the full effectiveness of these new therapies. PMID- 25926753 TI - Experiences of staff members participating in primary care research activities: a qualitative study. AB - BACKGROUND: The aim of this paper was to study primary care staff members' experiences and perceptions of participating in a randomized controlled trial concerning Internet therapy. METHODS: Data were collected via five focus groups, each containing four to eight nurses or general practitioners. The systematic text condensation method described by Malterud was used for thematic analysis of meaning and content of data across cases. RESULTS: The informants believed it was important to conduct research within the primary care setting, but it was difficult to combine clinical work and research. They stressed also that there was a need for continuous information and communication between primary care centers and researchers as well as internally at each primary care center. CONCLUSION: Staff members' experiences of participating in a research study were positive, although associated with various difficulties. It is important to include staff members when designing clinical studies; information should be given continuously during the study and communication facilitated between different occupational groups working at the primary care center. PMID- 25926754 TI - A cross-sectional study examining the psychometric properties of the painDETECT measure in neuropathic pain. AB - BACKGROUND: Similarities and differences on the nine-item and seven-item versions of painDETECT, a patient-reported screener to identify neuropathic pain (NeP), have not been psychometrically explored across NeP conditions. METHODS: Scores on the nine-item painDETECT (seven pain symptom items, one pain course pattern item, one pain radiation item) range from -1 to 38; scores >=19 indicate NeP is likely (>90% probability). The seven-item version (only pain symptoms) score range is 0 to 35. painDETECT was administered to subjects with confirmed diagnoses of human immunodeficiency virus-related peripheral NeP (HIVP) (n=103), spinal cord injury related NeP (SCI) (n=103), small fiber neuropathy (n=100), painful diabetic peripheral neuropathy (n=112), posttrauma/postsurgical NeP (n=100), and NeP in chronic low back pain (n=106) identified during office visits to US community based physicians. Analysis of covariance compared mean scores (adjusted for age, sex, race, ethnicity, time since NeP diagnosis, and number of comorbidities) on the nine-item and seven-item versions of painDETECT. Cronbach's alpha assessed internal consistency reliability, and corrected item-to-total correlations assessed item-level discrimination. RESULTS: The adjusted mean nine-item scores ranged from 21.0 (SCI) to 24.3 (small fiber neuropathy). Differences between conditions were either trivial or small-to-medium in magnitude. Cronbach's alpha gave overall internal consistency reliability of 0.76, with a range of 0.63 (SCI) to 0.82 (HIVP). Mean scores and Cronbach's alphas for the seven-item version were generally similar to the nine-item version. Corrected item-to-total correlations adequately discriminated all pain symptom items on both painDETECT versions for each condition (0.3-0.7), but the two nonsensory items on the nine-item version showed lackluster discrimination (<0.3). CONCLUSION: painDETECT scores were within the range indicating high probability of NeP. Differences between conditions were generally modest or not large. Both versions showed evidence of internal consistency reliability and item-level discrimination, suggesting that painDETECT is a useful screening measure for identifying NeP across NeP conditions. PMID- 25926752 TI - Inhibition of RAS in diabetic nephropathy. AB - Diabetic kidney disease (DKD) is a progressive proteinuric renal disorder in patients with type 1 or type 2 diabetes mellitus. It is a common cause of end stage kidney disease worldwide, particularly in developed countries. Therapeutic targeting of the renin-angiotensin system (RAS) is the most validated clinical strategy for slowing disease progression. DKD is paradoxically a low systematic renin state with an increased intrarenal RAS activity implicated in its pathogenesis. Angiotensin II (AngII), the main peptide of RAS, is not only a vasoactive peptide but functions as a growth factor, activating interstitial fibroblasts and mesangial and tubular cells, while promoting the synthesis of extracellular matrix proteins. AngII also promotes podocyte injury through increased calcium influx and the generation of reactive oxygen species. Blockade of the RAS using either angiotensin converting enzyme inhibitors, or angiotensin receptor blockers can attenuate progressive glomerulosclerosis in animal models, and slows disease progression in humans with DKD. In this review, we summarize the role of intrarenal RAS activation in the pathogenesis and progression of DKD and the rationale for RAS inhibition in this population. PMID- 25926755 TI - Multicenter, noninterventional, post-marketing surveillance study to evaluate dosing of recombinant human follicle-stimulating hormone using the redesigned follitropin alfa pen in women undergoing ovulation induction. AB - This prospective, noninterventional, post-marketing surveillance study evaluated doses of recombinant human follicle-stimulating hormone (r-hFSH) using the redesigned follitropin alfa pen in women who were anovulatory or oligomenorrheic and undergoing ovulation induction (OI) alone or OI with intrauterine insemination. The primary endpoint was the proportion of patients who achieved monofollicular or bifollicular development (defined as one or two follicles >=15 mm). Secondary endpoints included characteristics of ovulation stimulation treatment, such as mean total and mean daily r-hFSH doses. Data were analyzed for 3,193 patients from 30 German fertility centers. The proportion of patients with monofollicular or bifollicular development was 71.1% (n=2,270 of a total of 3,193 patients; intent-to-treat population). The mean+/-standard deviation total and daily doses of r-hFSH were 696.9+/-542.5 IU and 61.7+/-29.4 IU, respectively. The three doses prescribed most frequently were: 37.5 IU (n=703 from N=3,189; 22.0%), 50.0 IU (n=1,056 from N=3,189; 33.1%), and 75.0 IU (n=738 from N=3,189; 23.1%) on the first day of stimulation; and 37.5 IU (n=465 from N=3,189; 14.6%), 50.0 IU (n=922 from N=3,189; 28.9%), and 75.0 IU (n=895 from N=3,189; 28.1%) on the last day of stimulation. This noninterventional, post-marketing surveillance study found that monofollicular or bifollicular development was achieved in 71% of patients studied and the small dose increment (12.5 IU) of the redesigned follitropin alfa pen allowed individualized treatment of women undergoing OI. PMID- 25926756 TI - Individualized recombinant human follicle-stimulating hormone dosing using the CONSORT calculator in assisted reproductive technology: a large, multicenter, observational study of routine clinical practice. AB - PURPOSE: This postmarketing surveillance survey was conducted to investigate the utility of the CONsistency in r-FSH Starting dOses for individualized tReatmenT (CONSORT) calculator for individualizing recombinant human follicle-stimulating hormone (r-hFSH) starting doses for controlled ovarian stimulation (COS) in routine clinical practice. METHODS: This was a 3-year, open-label, observational study evaluating data from women undergoing COS for assisted reproductive technology at 31 German fertility centers. Physicians stated their recommended r hFSH starting dose, then generated a CONSORT-recommended r-hFSH starting dose. Physicians could prescribe any r-hFSH starting dose. The primary objective was to compare the r-hFSH starting dose recommended by the physician with the CONSORT calculated dose and that prescribed. Statistical analyses were conducted post hoc. RESULTS: Data were collected from 2,579 patients; the mean (standard deviation [SD]) age was 30.5 (2.93) years (range: 19-40 years). The mean (SD) CONSORT-calculated r-hFSH starting dose was significantly lower than the physician-recommended dose (134.5 [38.0] IU versus 164.6 [47.1] IU; P<0.0001); the mean (SD) starting dose prescribed was 162.2 (48.4) IU. CONSORT-calculated doses were prescribed for 27.3% (number [n] =677) of patients, and non-CONSORT calculated doses prescribed for 72.7% (n=1,800). The mean (SD) number of oocytes retrieved per patient was 10.6 (6.15) and 11.4 (6.66) in the CONSORT and non CONSORT groups, respectively; the mean (SD) number of embryos transferred per patient was 1.98 (0.41) and 2.03 (0.45), respectively. Clinical pregnancy rates per COS cycle were 38.8% (CONSORT) and 34.8% (non-CONSORT) (P=0.142); clinical pregnancy rates per embryos transferred were 45.0% and 39.5%, respectively (P=0.049). Miscarriage occurred in 14.8% of all clinical pregnancies ( CONSORT: 12.5%; non- CONSORT: 15.3%). The rate of grade 3 ovarian hyperstimulation syndrome (OHSS) was 0.3% (n=2) in the CONSORT group and 0.6% (n=11) in the non CONSORT group. OHSS led to hospitalization in 0.81% (n=21) of cases (CONSORT group: 0.74% [n=5]; non-CONSORT group: 0.83% [n=15]). CONCLUSION: Physician recommended r-hFSH starting doses were generally higher than those calculated by CONSORT; most patients were prescribed a higher starting dose than that recommended by CONSORT. PMID- 25926757 TI - Consistent condom use in HIV/AIDS patients receiving antiretroviral therapy in northwestern Ethiopia: implication to reduce transmission and multiple infections. AB - BACKGROUND: Human immunodeficiency virus (HIV)/acquired immune deficiency syndrome (AIDS) is one of the greatest public health problems of sub-Saharan African countries. Consistent condom use, among others, remains the most effective barrier method against HIV transmission. However, existing reports on frequency of consistent condom use have targeted the general public, rather than HIV/AIDS patients due, to the assumption that condom use is not important in HIV infected persons. Since consistent condom use among HIV/AIDS patients is vital, to prevent the virus transmission from the infected to noninfected as well as to prevent multiple infections among already infected persons, its frequency and determining factors need to be investigated. METHODS: A cross-sectional study was conducted from April 2013 to May 2013 among 317 randomly selected patients who were currently taking antiretroviral therapy (ART). Logistic regressions were performed to examine predictors of consistent condom use. RESULTS: A total of 317 HIV/AIDS patients who were currently receiving ART participated in the study, and the mean age of the study population was 31.4 (standard deviation [SD] 10.5) years. Overall, 250 (78.9%) participants reported consistent condom use in the past 6 months. Of these, 140 (88.6%) were males and 110 (69.1%) females. Multivariate analysis indicated that respondents with an advanced level of education were more likely to report regular use of condoms (odds ratio [OR] 8.98; 95% confidence interval [CI] 5.06-14.45) compared with illiterate participants. Being male (OR 6.87; 95% CI 3.84-11.22), living in or around a town (OR 4.65; 95% CI 3.09-9.11), and taking ART for longer time (OR 3.91; 95% CI 2.07 6.25) were also positively associated with consistent condom use. CONCLUSION: Females, patients living in rural areas, uneducated groups, and new ART users were less likely to use condoms consistently. The importance of consistent condom use should be well-addressed in HIV/AIDS patients, to prevent transmission and multiple infections of HIV. PMID- 25926758 TI - Utility of proteomics in obstetric disorders: a review. AB - The study of proteomics could explain many aspects of obstetric disorders. We undertook this review with the aim of assessing the utility of proteomics in the specialty of obstetrics. We searched the electronic databases of MEDLINE, EBSCOhost, BVS Bireme, and SciELO, using various search terms with the assistance of a librarian. We considered cohort studies, case-control studies, case series, and systematic review articles published until October 2014 in the English or Spanish language, and evaluated their quality and the internal validity of the evidence provided. Two reviewers extracted the data independently, then both researchers simultaneously revised the data later, to arrive at a consensus. The search retrieved 1,158 papers, of which 965 were excluded for being duplicates, not relevant, or unrelated studies. A further 86 papers were excluded for being guidelines, protocols, or case reports, along with another 64 that did not contain relevant information, leaving 43 studies for inclusion. Many of these studies showed the utility of proteomic techniques for prediction, pathophysiology, diagnosis, management, monitoring, and prognosis of pre eclampsia, perinatal infection, premature rupture of membranes, preterm birth, intrauterine growth restriction, and ectopic pregnancy. Proteomic techniques have enormous clinical significance and constitute an invaluable weapon in the management of obstetric disorders that increase maternal and perinatal morbidity and mortality. PMID- 25926759 TI - Safety and tolerability of dienogest in endometriosis: pooled analysis from the European clinical study program. AB - BACKGROUND: In four randomized, controlled, European trials, dienogest 2 mg once daily demonstrated significant efficacy for lesion reduction and reduction in pain intensity in endometriosis. We describe a pooled analysis of the safety and tolerability data from these trials to confirm and further characterize the safety profile of dienogest in the treatment of endometriosis. METHODS: All 332 women treated with dienogest 2 mg who participated in the four clinical trials were included in the pooled analyses for safety assessments, including adverse events, laboratory tests, vital signs, body weight, and bleeding patterns. Safety variables were analyzed using descriptive statistics. RESULTS: Pooled analyses of this large patient population confirmed that dienogest 2 mg is well tolerated, with a favorable safety profile extending over a period up to 65 weeks in women with endometriosis. The most common adverse drug reactions were headache, breast discomfort, depressed mood, and acne, each occurring in <10% of women. All these adverse events were generally of mild-to-moderate intensity and associated with low discontinuation rates. The bleeding pattern associated with dienogest 2 mg was well tolerated, and only two women (0.6%) reported bleeding events as the primary reason for premature discontinuation. Laboratory and vital sign assessments indicated no safety concerns for dienogest. Estradiol levels were maintained within the low-physiological range, in support of previous evidence indicating that dienogest 2 mg demonstrates therapeutic efficacy without inducing estradiol deficiency. CONCLUSION: In this pooled analysis of 332 women with endometriosis, dienogest was well tolerated with a favorable safety profile extending over a period of up to 65 weeks. There is a paucity of randomized trial evidence to support the use of many treatments in endometriosis. These pooled analyses from four clinical trials of dienogest 2 mg represent a contribution to evidence-based medicine in endometriosis, providing outcomes of potential relevance to daily practice. PMID- 25926760 TI - Biomarkers for hepatocellular carcinoma: diagnostic and therapeutic utility. AB - Because of the high prevalence and associated-mortality of hepatocellular carcinoma (HCC), early diagnosis of the disease is vital for patient survival. In this regard, tumor size is one of the two main prognostic factors for surgical resection, which constitutes the only curative treatment for HCC along with liver transplantation. However, techniques for HCC surveillance and diagnosis that are currently used in clinical practice have certain limitations that may be inherent to the tumor development. Thus, it is important to continue efforts in the search for biomarkers that increase diagnostic accuracy for HCC. In this review, we focus on different biological sources of candidate biomarkers for HCC diagnosis. Although those biomarkers identified from biological samples obtained by noninvasive methods have greater diagnostic value, we have also considered those obtained from liver tissue because of their potential therapeutic value. To date, sorafenib is the only US Food and Drug Administration-approved antineoplastic for HCC. However, this therapeutic agent shows very low tumor response rates and frequently causes acquired resistance in HCC patients. We discuss the use of HCC biomarkers as therapeutic targets themselves, or as targets to increase sensitivity to sorafenib treatment. PMID- 25926761 TI - Should NS5A inhibitors serve as the scaffold for all-oral anti-HCV combination therapies? AB - Chronic hepatitis C virus (HCV) infection represents a global health problem that affects up to 130-150 million people worldwide. The HCV treatment landscape has been transformed recently by the introduction of direct-acting antiviral (DAA) agents that target viral proteins, including the NS3 protease, the NS5B polymerase, and the NS5A protein. Treatment with multiple DAAs in combination has been shown to result in high rates of sustained virologic response, without the need for pegylated interferon, and a shorter duration of therapy compared with interferon-based regimens; however, the optimal combination of DAAs has yet to be determined. The class of NS5A inhibitors has picomolar potency with pangenotypic activity, and recent clinical studies have shown these inhibitors to be an important component of DAA combination regimens. This review discusses the rational design of an optimal anti-HCV DAA cocktail, with a focus on the role of NS5A in the HCV life cycle, the attributes of the NS5A class of inhibitors, and the potential for NS5A inhibitors to act as a scaffold for DAA-only treatment regimens. PMID- 25926762 TI - Manual accidents, biological risk control, and quality indicators at a children's hospital in north-east Italy. AB - BACKGROUND: Working in health care carries the risk of transmission of infected blood to patients by hospital workers and to other health personnel in the form of occupational infections. Conscientious application of the standard precautions is the main method used to avoid needle stick injuries, contamination of skin and mucous membranes, cuts with sharp tools, and inadequate disposal and recapping of needles. The aim of this work was to investigate in Friuli Venezia Giulia, a region in north-east Italy, the enhancement carried out to prevent situations of biologic risk for health care workers, and to verify the related laboratory analyses. METHODS: Biological accidents occurring during the years 2012-2013 in the departments of oncology and pediatric-obstetric surgery, and in the intensive care unit at Burlo Garofolo Children's Hospital in Trieste (a large town in Friuli Venezia Giulia) were reviewed, and a new panel of tests was introduced for patients and health care workers, to also detect human immunodeficiency virus (HIV), hepatitis C virus (HCV), hepatitis B virus (HBV), and aspartate transaminase and immunoglobulin G. All tests were submitted for external quality assessment. RESULTS: In total, 230 nosocomial events were reported by health care workers in the above-mentioned hospital departments in 2012-2013. There were 158 accidents in 2012, including 55 accidental needle stick injuries (34.81%), 59 blood splashes (37.34%), and 44 cuts with infected instruments (27.84%). The risk of sustaining a cut was related to movement error during surgery when the appropriate procedure was not followed or when devices were being assembled and passed between doctors and nurses. Most accidents happened among physicians compared to nurses; the high percentage of needle stick injuries (34.81%) versus nurses (25.94%) were due to incorrect recapping of needles after use. No cases of health care workers being infected with HCV, HBV, or HIV were identified. In 2013, the number of biological accidents decreased to 61, comprising two needle stick injuries (3.27%), 35 blood splashes (57.37%), and 25 cuts with contaminated instruments (40.98%). The number of subcutaneous abscesses with scarring resulting from cuts with sharp instruments decreased from three in 2012 (one of which was the subject of medicolegal proceedings) to none in 2013. Although our study population was relatively small, we did detect a statistically significant decrease in the number of needle stick injuries (P<0.05, chi(2) test). CONCLUSION: In this early experience at a maternal and child health institution in the Friuli Venezia Giulia region, application of a safety protocol, centralized organization of HIV tests, improved external quality assessment, and introduction of internal quality control for immunoglobulin G contributed to a decrease in the number of work-related biological accidents and their complications, which have the potential to result in medicolegal problems. PMID- 25926763 TI - Prevalence of HIV-related thrombocytopenia among clients at Mbarara Regional Referral Hospital, Mbarara, southwestern Uganda. AB - AIMS/OBJECTIVES: We aimed to determine the prevalence and correlates of thrombocytopenia among people living with human immunodeficiency virus (HIV)/acquired immune deficiency syndrome (AIDS) and to assess occurrence of antiplatelet antibodies, among thrombocytopenic HIV clients at Mbarara Regional Referral Hospital, southwestern Uganda. MATERIALS AND METHODS: This was a retrospective review of hematologic results at enrollment to HIV care from 2005 to 2013. The prevalence and correlates of thrombocytopenia were estimated based on the Immune Suppressed Syndrome (ISS) Clinic electronic database. A cross sectional study determined the occurrence of antiplatelet antibodies, using the monoclonal antibody-specific immobilization of platelet antigens (MAIPA) technique. RESULTS: We reviewed 15,030 client records. The median age was 35.0 (range 18-78; interquartile range [IQR] 28-42) years, and there were 63.2% (n=9,500) females. The overall prevalence of thrombocytopenia was 17.4% (95% confidence interval [CI]: 16.8%-18.0%). The prevalence of thrombocytopenia was 17.8% (95% CI: 17.1%-18.4%) among antiretroviral therapy (ART)-naive clients (n=2,675) and was 13.0% (95% CI: 0.3%-21.9%) for clients who were on ART (n=6). The study found a significant association between thrombocytopenia and other cytopenias, CD4 counts, ART, and deteriorating HIV stage (P<0.05). Two of the 40 participants (5.0%) had antiplatelet antibodies. CONCLUSION: This study has showed a high prevalence of HIV-related thrombocytopenia. Antiplatelet antibodies were found in 5.0% of HIV-infected thrombocytopenic participants. Our study shows a significant association of thrombocytopenia burden in a high-HIV study population (Southwest Uganda); therefore, there is need to monitor platelet counts and initiate platelet transfusion in our blood banking practices, to avert possible risks of bleeding. PMID- 25926764 TI - Not for industry only: medical students and office-based academic detailing the PIVOT (Pregnant women Influenza Vaccine Optimization Team) initiative. AB - Academic detailing is a method of educational outreach that utilizes individualized encounters with physicians to broach specific medical issues in an evidence-based and quality-driven manner. Medical students utilized the matter of influenza vaccination during pregnancy as a lens through which to explore the methods of academic detailing in a community setting. Structured and customized dialogues between North Shore-LIJ affiliated obstetricians and Hofstra North Shore-LIJ medical students were conducted regarding the disparity between the proportion of providers that recommend the vaccine and the percentage of pregnant women being vaccinated annually. Ultimately the project aimed to increase vaccine carrying rates throughout office based practices in the community, while establishing a viable method for up-to-date information exchange between practicing physicians and academic medicine. While the extent of affected change is currently being quantified, the project proved successful insofar as academic detailing allowed the students to gain access to physicians, and engage in compelling and educational conversations. Both the physicians and students felt these interactions were valuable and well worth continuing. The goal for the future is to expand these practices to other pressing public health issues while continuing to refine the technique. PMID- 25926765 TI - Gatekeepers of the academic world: a recipe for good peer review. PMID- 25926766 TI - On tests of activation map dimensionality for fMRI-based studies of learning. AB - A methodology for investigating learning is developed using activation distributions, as opposed to standard voxel-level interaction tests. The approach uses tests of dimensionality to consider the ensemble of paired changes in voxel activation. The developed method allows for the investigation of non-focal and non-localized changes due to learning. In exchange for increased power to detect learning-based changes, this procedure sacrifices the localization information gained via voxel-level interaction testing. The test is demonstrated on an arc pointing motor task for the study of motor learning, which served as the motivation for this methodological development. The proposed framework considers activation distribution, while the specific proposed test investigates linear tests of dimensionality. This paper includes: the development of the framework, a large scale simulation study, and the subsequent application to a study of motor learning in healthy adults. While the performance of the method was excellent when model assumptions held, complications arose in instances of massive numbers of null voxels or varying angles of principal dimension across subjects. Further analysis found that careful masking addressed the former concern, while an angle correction successfully resolved the latter. The simulation results demonstrated that the study of linear dimensionality is able to capture learning effects. The motivating data set used to illustrate the method evaluates two similar arc pointing tasks, each over two sessions, with training on only one of the tasks in between sessions. The results suggests different activation distribution dimensionality when considering the trained and untrained tasks separately. Specifically, the untrained task evidences greater activation distribution dimensionality than the trained task. However, the direct comparison between the two tasks did not yield a significant result. The nature of the indication for greater dimensionality in the untrained task is explored and found to be non linear variation in the data. PMID- 25926767 TI - Conjugating time and frequency: hemispheric specialization, acoustic uncertainty, and the mustached bat. AB - A prominent hypothesis of hemispheric specialization for human speech and music states that the left and right auditory cortices (ACs) are respectively specialized for precise calculation of two canonically-conjugate variables: time and frequency. This spectral-temporal asymmetry does not account for sex, brain volume, or handedness, and is in opposition to closed-system hypotheses that restrict this asymmetry to humans. Mustached bats have smaller brains, but greater ethological pressures to develop such a spectral-temporal asymmetry, than humans. Using the Heisenberg-Gabor Limit (i.e., the mathematical basis of the spectral-temporal asymmetry) to frame mustached bat literature, we show that recent findings in bat AC (1) support the notion that hemispheric specialization for speech and music is based on hemispheric differences in temporal and spectral resolution, (2) discredit closed-system, handedness, and brain-volume theories, (3) underscore the importance of sex differences, and (4) provide new avenues for phonological research. PMID- 25926768 TI - Imaging activity in astrocytes and neurons with genetically encoded calcium indicators following in utero electroporation. AB - Complex interactions between networks of astrocytes and neurons are beginning to be appreciated, but remain poorly understood. Transgenic mice expressing fluorescent protein reporters of cellular activity, such as the GCaMP family of genetically encoded calcium indicators (GECIs), have been used to explore network behavior. However, in some cases, it may be desirable to use long-established rat models that closely mimic particular aspects of human conditions such as Parkinson's disease and the development of epilepsy following status epilepticus. Methods for expressing reporter proteins in the rat brain are relatively limited. Transgenic rat technologies exist but are fairly immature. Viral-mediated expression is robust but unstable, requires invasive injections, and only works well for fairly small genes (<5 kb). In utero electroporation (IUE) offers a valuable alternative. IUE is a proven method for transfecting populations of astrocytes and neurons in the rat brain without the strict limitations on transgene size. We built a toolset of IUE plasmids carrying GCaMP variants 3, 6s, or 6f driven by CAG and targeted to the cytosol or the plasma membrane. Because low baseline fluorescence of GCaMP can hinder identification of transfected cells, we included the option of co-expressing a cytosolic tdTomato protein. A binary system consisting of a plasmid carrying a piggyBac inverted terminal repeat (ITR)-flanked CAG-GCaMP-IRES-tdTomato cassette and a separate plasmid encoding for expression of piggyBac transposase was employed to stably express GCaMP and tdTomato. The plasmids were co-electroporated on embryonic days 13.5 14.5 and astrocytic and neuronal activity was subsequently imaged in acute or cultured brain slices prepared from the cortex or hippocampus. Large spontaneous transients were detected in slices obtained from rats of varying ages up to 127 days. In this report, we demonstrate the utility of this toolset for interrogating astrocytic and neuronal activity in the rat brain. PMID- 25926770 TI - Local mechanisms for loud sound-enhanced aminoglycoside entry into outer hair cells. AB - Loud sound exposure exacerbates aminoglycoside ototoxicity, increasing the risk of permanent hearing loss and degrading the quality of life in affected individuals. We previously reported that loud sound exposure induces temporary threshold shifts (TTS) and enhances uptake of aminoglycosides, like gentamicin, by cochlear outer hair cells (OHCs). Here, we explore mechanisms by which loud sound exposure and TTS could increase aminoglycoside uptake by OHCs that may underlie this form of ototoxic synergy. Mice were exposed to loud sound levels to induce TTS, and received fluorescently-tagged gentamicin (GTTR) for 30 min prior to fixation. The degree of TTS was assessed by comparing auditory brainstem responses (ABRs) before and after loud sound exposure. The number of tip links, which gate the GTTR-permeant mechanoelectrical transducer (MET) channels, was determined in OHC bundles, with or without exposure to loud sound, using scanning electron microscopy. We found wide-band noise (WBN) levels that induce TTS also enhance OHC uptake of GTTR compared to OHCs in control cochleae. In cochlear regions with TTS, the increase in OHC uptake of GTTR was significantly greater than in adjacent pillar cells. In control mice, we identified stereociliary tip links at ~50% of potential positions in OHC bundles. However, the number of OHC tip links was significantly reduced in mice that received WBN at levels capable of inducing TTS. These data suggest that GTTR uptake by OHCs during TTS occurs by increased permeation of surviving, mechanically-gated MET channels, and/or non MET aminoglycoside-permeant channels activated following loud sound exposure. Loss of tip links would hyperpolarize hair cells and potentially increase drug uptake via aminoglycoside-permeant channels expressed by hair cells. The effect of TTS on aminoglycoside-permeant channel kinetics will shed new light on the mechanisms of loud sound-enhanced aminoglycoside uptake, and consequently on ototoxic synergy. PMID- 25926771 TI - Soluble Megalin is Reduced in Cerebrospinal Fluid Samples of Alzheimer's Disease Patients. AB - Megalin or low-density lipoprotein receptor-related protein-2 is a member of the low-density lipoprotein receptor family, which has been linked to Alzheimer's disease (AD) by clearing brain amyloid beta-peptide (Abeta) across the blood cerebrospinal fluid barrier at the choroid plexus. Here, we found a soluble form of megalin secreted from choroid plexus epithelial cells. Soluble megalin levels were also localized in the human cerebrospinal fluid (CSF), being reduced in AD patients. We have also shown that soluble megalin binding to Abeta is decreased in the CSF of AD patients, suggesting that decreased sequestration of Abeta in the CSF could be associated with defective clearance of Abeta and an increase of brain Abeta levels. Thus, therapies, which increase megalin expression, at the choroid plexus and/or enhance circulating soluble megalin hold potential to control brain Abeta-related pathologies in AD. PMID- 25926769 TI - Crosstalk between intracellular and extracellular signals regulating interneuron production, migration and integration into the cortex. AB - During embryogenesis, cortical interneurons are generated by ventral progenitors located in the ganglionic eminences of the telencephalon. They travel along multiple tangential paths to populate the cortical wall. As they reach this structure they undergo intracortical dispersion to settle in their final destination. At the cellular level, migrating interneurons are highly polarized cells that extend and retract processes using dynamic remodeling of microtubule and actin cytoskeleton. Different levels of molecular regulation contribute to interneuron migration. These include: (1) Extrinsic guidance cues distributed along migratory streams that are sensed and integrated by migrating interneurons; (2) Intrinsic genetic programs driven by specific transcription factors that grant specification and set the timing of migration for different subtypes of interneurons; (3) Adhesion molecules and cytoskeletal elements/regulators that transduce molecular signalings into coherent movement. These levels of molecular regulation must be properly integrated by interneurons to allow their migration in the cortex. The aim of this review is to summarize our current knowledge of the interplay between microenvironmental signals and cell autonomous programs that drive cortical interneuron porduction, tangential migration, and intergration in the developing cerebral cortex. PMID- 25926772 TI - Rapid modulation of synaptogenesis and spinogenesis by 17beta-estradiol in primary cortical neurons. AB - In the mammalian forebrain, the majority of excitatory synapses occur on dendritic spines. Changes in the number of these structures is important for brain development, plasticity and the refinement of neuronal circuits. The formation of excitatory synapses involves the coordinated formation of dendritic spines and targeting of multi-protein complexes to nascent connections. Recent studies have demonstrated that the estrogen 17beta-estradiol (E2) can rapidly increase the number of dendritic spines, an effect consistent with the ability of E2 to rapidly influence cognitive function. However, the molecular composition of E2-induced spines and whether these protrusions form synaptic connections has not been fully elucidated. Moreover, which estrogen receptor(s) (ER) mediate these spine-morphogenic responses are not clear. Here, we report that acute E2 treatment results in the recruitment of postsynaptic density protein 95 (PSD-95) to novel dendritic spines. In addition neuroligin 1 (Nlg-1) and the NMDA receptor subunit GluN1 are recruited to nascent synapses in cortical neurons. The presence of these synaptic proteins at nascent synapses suggests that the machinery to allow pre- and post-synapses to form connections are present in E2-induced spines. We further demonstrate that E2 treatment results in the rapid and transient activation of extracellular signal-regulated kinase 1/2 (ERK1/2), Akt and the mammalian target of rapamycin (mTOR) signaling pathways. However, only ERK1/2 and Akt are required for E2-mediated spinogenesis. Using synthetic receptor modulators, we further demonstrate that activation of the estrogen receptor beta (ERbeta) but not alpha (ERalpha) mimics rapid E2-induced spinogenesis and synaptogenesis. Taken together these findings suggest that in primary cortical neurons, E2 signaling via ERbeta, but not through ERalpha, is capable of remodeling neuronal circuits by increasing the number of excitatory synapses. PMID- 25926774 TI - A commentary on: "Cortical and thalamic excitation mediate the multiphasic responses of striatal cholinergic interneurons to motivationally salient stimuli". PMID- 25926773 TI - Detrimental role of prolonged sleep deprivation on adult neurogenesis. AB - Adult mammalian brains continuously generate new neurons, a phenomenon called adult neurogenesis. Both environmental stimuli and endogenous factors are important regulators of adult neurogenesis. Sleep has an important role in normal brain physiology and its disturbance causes very stressful conditions, which disrupt normal brain physiology. Recently, an influence of sleep in adult neurogenesis has been established, mainly based on sleep deprivation studies. This review provides an overview on how rhythms and sleep cycles regulate hippocampal and subventricular zone neurogenesis, discussing some potential underlying mechanisms. In addition, our review highlights some interacting points between sleep and adult neurogenesis in brain function, such as learning, memory, and mood states, and provides some insights on the effects of antidepressants and hypnotic drugs on adult neurogenesis. PMID- 25926775 TI - From the Cajal alumni Achucarro and Rio-Hortega to the rediscovery of never resting microglia. AB - Under the guidance of Ramon y Cajal, a plethora of students flourished and began to apply his silver impregnation methods to study brain cells other than neurons: the neuroglia. In the first decades of the twentieth century, Nicolas Achucarro was one of the first researchers to visualize the brain cells with phagocytic capacity that we know today as microglia. Later, his pupil Pio del Rio-Hortega developed modifications of Achucarro's methods and was able to specifically observe the fine morphological intricacies of microglia. These findings contradicted Cajal's own views on cells that he thought belonged to the same class as oligodendroglia (the so called "third element" of the nervous system), leading to a long-standing discussion. It was only in 1924 that Rio-Hortega's observations prevailed worldwide, thus recognizing microglia as a unique cell type. This late landing in the Neuroscience arena still has repercussions in the twenty first century, as microglia remain one of the least understood cell populations of the healthy brain. For decades, microglia in normal, physiological conditions in the adult brain were considered to be merely "resting," and their contribution as "activated" cells to the neuroinflammatory response in pathological conditions mostly detrimental. It was not until microglia were imaged in real time in the intact brain using two-photon in vivo imaging that the extreme motility of their fine processes was revealed. These findings led to a conceptual revolution in the field: "resting" microglia are constantly surveying the brain parenchyma in normal physiological conditions. Today, following Cajal's school of thought, structural and functional investigations of microglial morphology, dynamics, and relationships with neurons and other glial cells are experiencing a renaissance and we stand at the brink of discovering new roles for these unique immune cells in the healthy brain, an essential step to understand their causal relationship to diseases. PMID- 25926777 TI - As we may think and be: brain-computer interfaces to expand the substrate of mind. PMID- 25926776 TI - Differential organization of cortical inputs to striatal projection neurons of the matrix compartment in rats. AB - In prior studies, we described the differential organization of corticostriatal and thalamostriatal inputs to the spines of direct pathway (dSPNs) and indirect pathway striatal projection neurons (iSPNs) of the matrix compartment. In the present electron microscopic (EM) analysis, we have refined understanding of the relative amounts of cortical axospinous vs. axodendritic input to the two types of SPNs. Of note, we found that individual dSPNs receive about twice as many axospinous synaptic terminals from IT-type (intratelencephalically projecting) cortical neurons as they do from PT-type (pyramidal tract projecting) cortical neurons. We also found that PT-type axospinous synaptic terminals were about 1.5 times as common on individual iSPNs as IT-type axospinous synaptic terminals. Overall, a higher percentage of IT-type terminals contacted dSPN than iSPN spines, while a higher percentage of PT-type terminals contacted iSPN than dSPN spines. Notably, IT-type axospinous synaptic terminals were significantly larger on iSPN spines than on dSPN spines. By contrast to axospinous input, the axodendritic PT-type input to dSPNs was more substantial than that to iSPNs, and the axodendritic IT-type input appeared to be meager and comparable for both SPN types. The prominent axodendritic PT-type input to dSPNs may accentuate their PT type responsiveness, and the large size of axospinous IT-type terminals on iSPNs may accentuate their IT-type responsiveness. Using transneuronal labeling with rabies virus to selectively label the cortical neurons with direct input to the dSPNs projecting to the substantia nigra pars reticulata, we found that the input predominantly arose from neurons in the upper layers of motor cortices, in which IT-type perikarya predominate. The differential cortical input to SPNs is likely to play key roles in motor control and motor learning. PMID- 25926778 TI - Hearing colors: an example of brain plasticity. AB - Sensory substitution devices (SSDs) are providing new ways for improving or replacing sensory abilities that have been lost due to disease or injury, and at the same time offer unprecedented opportunities to address how the nervous system could lead to an augmentation of its capacities. In this work we have evaluated a color-blind subject using a new visual-to-auditory SSD device called "Eyeborg", that allows colors to be perceived as sounds. We used a combination of neuroimaging techniques including Functional Magnetic Resonance Imaging (fMRI), Diffusion Tensor Imaging (DTI) and proton Magnetic Resonance Spectroscopy ((1)H MRS) to study potential brain plasticity in this subject. Our results suggest that after 8 years of continuous use of this device there could be significant adaptive and compensatory changes within the brain. In particular, we found changes in functional neural patterns, structural connectivity and cortical topography at the visual and auditive cortex of the Eyeborg user in comparison with a control population. Although at the moment we cannot claim that the continuous use of the Eyeborg is the only reason for these findings, our results may shed further light on potential brain changes associated with the use of other SSDs. This could help to better understand how the brain adapts to several pathologies and uncover adaptive resources such as cross-modal representations. We expect that the precise understanding of these changes will have clear implications for rehabilitative training, device development and for more efficient programs for people with disabilities. PMID- 25926779 TI - A Commentary on: "Preserving cortico-striatal function: Deep Brain Stimulation in Huntington's disease". PMID- 25926781 TI - Actor-recipient role affects neural responses to self in emotional situations. AB - People often take either the role of an actor or that of recipient in positive and negative interpersonal events when they interact with others. The present study investigated how the actor-recipient role affected the neural responses to self in emotional situations. Twenty-five participants were scanned while they were presented with positive and negative interpersonal events and were asked to rate the degree to which the actor/the recipient was that kind of person who caused the interpersonal event. Half of the trials were self-relevant events and the other half were other-relevant events. Results showed that people were more likely to isolate self from negative events when they played the role of actor relative to recipient. Pregenual anterior cingulate cortex (pgACC) and posterior dorsal anterior cingulate cortex (pdACC) were more active for self than other only in negative events. More importantly, also in negative interpersonal events, dorsal medial prefrontal cortex (dmPFC) showed greater self-related activations (self-other) when participants played the role of recipient relative to actor, while activities in orbitofrontal cortex (OFC) were greater for self than other only when the evaluation target played the role of recipient. These results showed that the actor-recipient role affected neural responses to self in emotional situations, especially when a recipient role was played in negative situations. PMID- 25926782 TI - Long-lasting beneficial effects of central serotonin receptor 7 stimulation in female mice modeling Rett syndrome. AB - Rett syndrome (RTT) is a rare neurodevelopmental disorder, characterized by severe behavioral and physiological symptoms. Mutations in the methyl CpG binding protein 2 gene (MECP2) cause more than 95% of classic cases, and currently there is no cure for this devastating disorder. Recently we have demonstrated that specific behavioral and brain molecular alterations can be rescued in MeCP2-308 male mice, a RTT mouse model, by pharmacological stimulation of the brain serotonin receptor 7 (5-HT7R). This member of the serotonin receptor family crucially involved in the regulation of brain structural plasticity and cognitive processes-can be stimulated by systemic repeated treatment with LP-211, a brain penetrant selective 5-HT7R agonist. The present study extends previous findings by demonstrating that the LP-211 treatment (0.25 mg/kg, once per day for 7 days) rescues RTT-related phenotypic alterations, motor coordination (Dowel test), spatial reference memory (Barnes maze test) and synaptic plasticity (hippocampal long-term-potentiation) in MeCP2-308 heterozygous female mice, the genetic and hormonal milieu that resembles that of RTT patients. LP-211 also restores the activation of the ribosomal protein (rp) S6, the downstream target of mTOR and S6 kinase, in the hippocampus of RTT female mice. Notably, the beneficial effects on neurobehavioral and molecular parameters of a seven-day long treatment with LP 211 were evident up to 2 months after the last injection, thus suggesting long lasting effects on RTT-related impairments. Taken together with our previous study, these results provide compelling preclinical evidence of the potential therapeutic value for RTT of a pharmacological approach targeting the brain 5 HT7R. PMID- 25926783 TI - Prosocial behavior and gender. AB - This study revisits different experimental data sets that explore social behavior in economic games and uncovers that many treatment effects may be gender specific. In general, men and women do not differ in "neutral" baselines. However, we find that social framing tends to reinforce prosocial behavior in women but not men, whereas encouraging reflection decreases the prosociality of males but not females. The treatment effects are sometimes statistically different across genders and sometimes not but never go in the opposite direction. These findings suggest that (i) the social behavior of both sexes is malleable but each gender responds to different aspects of the social context; and (ii) gender differences observed in some studies might be the result of particular features of the experimental design. Our results contribute to the literature on prosocial behavior and may improve our understanding of the origins of human prosociality. We discuss the possible link between the observed differential treatment effects across genders and the differing male and female brain network connectivity, documented in recent neural studies. PMID- 25926780 TI - Systems approach to the study of brain damage in the very preterm newborn. AB - BACKGROUND: A systems approach to the study of brain damage in very preterm newborns has been lacking. METHODS: In this perspective piece, we offer encephalopathy of prematurity as an example of the complexity and interrelatedness of brain-damaging molecular processes that can be initiated inflammatory phenomena. RESULTS: Using three transcription factors, nuclear factor-kappa B (NF-kappaB), Notch-1, and nuclear factor erythroid 2 related factor 2 (NRF2), we show the inter-connectedness of signaling pathways activated by some antecedents of encephalopathy of prematurity. CONCLUSIONS: We hope that as biomarkers of exposures and processes leading to brain damage in the most immature newborns become more readily available, those who apply a systems approach to the study of neuroscience can be persuaded to study the pathogenesis of brain disorders in the very preterm newborn. PMID- 25926784 TI - Stage-independent, single lead EEG sleep spindle detection using the continuous wavelet transform and local weighted smoothing. AB - Sleep spindles are critical in characterizing sleep and have been associated with cognitive function and pathophysiological assessment. Typically, their detection relies on the subjective and time-consuming visual examination of electroencephalogram (EEG) signal(s) by experts, and has led to large inter-rater variability as a result of poor definition of sleep spindle characteristics. Hitherto, many algorithmic spindle detectors inherently make signal stationarity assumptions (e.g., Fourier transform-based approaches) which are inappropriate for EEG signals, and frequently rely on additional information which may not be readily available in many practical settings (e.g., more than one EEG channels, or prior hypnogram assessment). This study proposes a novel signal processing methodology relying solely on a single EEG channel, and provides objective, accurate means toward probabilistically assessing the presence of sleep spindles in EEG signals. We use the intuitively appealing continuous wavelet transform (CWT) with a Morlet basis function, identifying regions of interest where the power of the CWT coefficients corresponding to the frequencies of spindles (11-16 Hz) is large. The potential for assessing the signal segment as a spindle is refined using local weighted smoothing techniques. We evaluate our findings on two databases: the MASS database comprising 19 healthy controls and the DREAMS sleep spindle database comprising eight participants diagnosed with various sleep pathologies. We demonstrate that we can replicate the experts' sleep spindles assessment accurately in both databases (MASS database: sensitivity: 84%, specificity: 90%, false discovery rate 83%, DREAMS database: sensitivity: 76%, specificity: 92%, false discovery rate: 67%), outperforming six competing automatic sleep spindle detection algorithms in terms of correctly replicating the experts' assessment of detected spindles. PMID- 25926785 TI - Robot-aided assessment of wrist proprioception. AB - INTRODUCTION: Impaired proprioception severely affects the control of gross and fine motor function. However, clinical assessment of proprioceptive deficits and its impact on motor function has been difficult to elucidate. Recent advances in haptic robotic interfaces designed for sensorimotor rehabilitation enabled the use of such devices for the assessment of proprioceptive function. PURPOSE: This study evaluated the feasibility of a wrist robot system to determine proprioceptive discrimination thresholds for two different DoFs of the wrist. Specifically, we sought to accomplish three aims: first, to establish data validity; second, to show that the system is sensitive to detect small differences in acuity; third, to establish test-retest reliability over repeated testing. METHODOLOGY: Eleven healthy adult subjects experienced two passive wrist movements and had to verbally indicate which movement had the larger amplitude. Based on a subject's response data, a psychometric function was fitted and the wrist acuity threshold was established at the 75% correct response level. A subset of five subjects repeated the experimentation three times (T1, T2, and T3) to determine the test-retest reliability. RESULTS: Mean threshold for wrist flexion was 2.15 degrees +/- 0.43 degrees and 1.52 degrees +/- 0.36 degrees for abduction. Encoder resolutions were 0.0075 degrees (flexion-extension) and 0.0032 degrees (abduction-adduction). Motor resolutions were 0.2 degrees (flexion extension) and 0.3 degrees (abduction-adduction). Reliability coefficients were r T2-T1 = 0.986 and r T3-T2 = 0.971. CONCLUSION: We currently lack established norm data on the proprioceptive acuity of the wrist to establish direct validity. However, the magnitude of our reported thresholds is physiological, plausible, and well in line with available threshold data obtained at the elbow joint. Moreover, system has high resolution and is sensitive enough to detect small differences in acuity. Finally, the system produces reliable data over repeated testing. PMID- 25926786 TI - How can development and plasticity contribute to understanding evolution of the human brain? PMID- 25926787 TI - Slow dynamics in features of synchronized neural network responses. AB - In this report trial-to-trial variations in the synchronized responses of neural networks are explored over time scales of minutes, in ex-vivo large scale cortical networks. We show that sub-second measures of the individual synchronous response, namely-its latency and decay duration, are related to minutes-scale network response dynamics. Network responsiveness is reflected as residency in, or shifting amongst, areas of the latency-decay plane. The different sensitivities of latency and decay durations to synaptic blockers imply that these two measures reflect aspects of inhibitory and excitatory activities. Taken together, the data suggest that trial-to-trial variations in the synchronized responses of neural networks might be related to effective excitation-inhibition ratio being a dynamic variable over time scales of minutes. PMID- 25926788 TI - Python in neuroscience. PMID- 25926789 TI - Theta and alpha EEG frequency interplay in subjects with mild cognitive impairment: evidence from EEG, MRI, and SPECT brain modifications. AB - BACKGROUND: Temporo-parietal and medial temporal cortex atrophy are associated with mild cognitive impairment (MCI) due to Alzheimer disease (AD) as well as the reduction of regional cerebral blood perfusion in hippocampus. Moreover, the increase of EEG alpha3/alpha2 power ratio has been associated with MCI due to AD and with an increase in theta frequency power in a group of subjects with impaired cerebral perfusion in hippocampus. METHODS: Seventy four adult subjects with MCI underwent clinical and neuropsychological evaluation, electroencephalogram (EEG) recording and high resolution 3D magnetic resonance imaging (MRI). Among the patients, a subset of 27 subjects underwent also perfusion single-photon emission computed tomography and hippocampal atrophy evaluation. Alpha3/alpha2 power ratio as well as cortical thickness was computed for each subject. Three MCI groups were detected according to increasing tertile values of alpha3/alpha2 power ratio and difference of cortical thickness among the groups estimated. RESULTS: Higher alpha3/alpha2 power ratio group had wider cortical thinning than other groups, mapped to the Supramarginal and Precuneus bilaterally. Subjects with higher alpha3/alpha2 frequency power ratio showed a constant trend to a lower perfusion than lower alpha3/alpha2 group. Moreover, this group correlates with both a bigger hippocampal atrophy and an increase of theta frequency power. CONCLUSION: Higher EEG alpha3/alpha2 power ratio was associated with temporo-parietal cortical thinning, hippocampal atrophy and reduction of regional cerebral perfusion in medial temporal cortex. In this group an increase of theta frequency power was detected inMCI subjects. The combination of higher EEG alpha3/alpha2 power ratio, cortical thickness measure and regional cerebral perfusion reveals a complex interplay between EEG cerebral rhythms, structural and functional brain modifications. PMID- 25926790 TI - A randomized controlled trial of brain training with non-action video games in older adults: results of the 3-month follow-up. AB - This randomized controlled study (ClinicalTrials.gov NCT02007616) investigated the maintenance of training effects of 20 1-hr non-action video game training sessions with selected games from a commercial package on several age-declining cognitive functions and subjective wellbeing after a 3-month no-contact period. Two groups of cognitively normal older adults participated in both the post training (posttest) and the present follow-up study, the experimental group who received training and the control group who attended several meetings with the research team during the study but did not receive training. Groups were similar at baseline on demographics, vocabulary, global cognition, and depression status. Significant improvements in the trained group, and no variation in the control group had been previously found at posttest, in processing speed, attention and visual recognition memory, as well as in two dimensions of subjective wellbeing. In the current study, improvement from baseline to 3 months follow-up was found only in wellbeing (Affection and Assertivity dimensions) in the trained group whereas there was no change in the control group. Previous significant improvements in processing speed, attention and spatial memory become non significant after the 3-month interval. Training older adults with non-action video games enhanced aspects of cognition just after training but this effect disappeared after a 3-month no-contact follow-up period. Cognitive plasticity can be induced in older adults by training, but to maintain the benefits periodic boosting sessions would be necessary. PMID- 25926791 TI - Comparison of nine tractography algorithms for detecting abnormal structural brain networks in Alzheimer's disease. AB - Alzheimer's disease (AD) involves a gradual breakdown of brain connectivity, and network analyses offer a promising new approach to track and understand disease progression. Even so, our ability to detect degenerative changes in brain networks depends on the methods used. Here we compared several tractography and feature extraction methods to see which ones gave best diagnostic classification for 202 people with AD, mild cognitive impairment or normal cognition, scanned with 41-gradient diffusion-weighted magnetic resonance imaging as part of the Alzheimer's Disease Neuroimaging Initiative (ADNI) project. We computed brain networks based on whole brain tractography with nine different methods - four of them tensor-based deterministic (FACT, RK2, SL, and TL), two orientation distribution function (ODF)-based deterministic (FACT, RK2), two ODF-based probabilistic approaches (Hough and PICo), and one "ball-and-stick" approach (Probtrackx). Brain networks derived from different tractography algorithms did not differ in terms of classification performance on ADNI, but performing principal components analysis on networks helped classification in some cases. Small differences may still be detectable in a truly vast cohort, but these experiments help assess the relative advantages of different tractography algorithms, and different post-processing choices, when used for classification. PMID- 25926792 TI - Anodal transcranial direct current stimulation of parietal cortex enhances action naming in Corticobasal Syndrome. AB - BACKGROUND: Corticobasal Syndrome (CBS) is a neurodegenerative disorder that overlaps both clinically and neuropathologically with Frontotemporal dementia (FTD) and is characterized by apraxia, alien limb phenomena, cortical sensory loss, cognitive impairment, behavioral changes and aphasia. It has been recently demonstrated that transcranial direct current stimulation (tDCS) improves naming in healthy subjects and in subjects with language deficits. OBJECTIVE: The aim of the present study was to explore the extent to which anodal tDCS over the parietal cortex (PARC) could facilitate naming performance in CBS subjects. METHODS: Anodal tDCS was applied to the left and right PARC during object and action naming in seventeen patients with a diagnosis of possible CBS. Participants underwent two sessions of anodal tDCS (left and right) and one session of placebo tDCS. Vocal responses were recorded and analyzed for accuracy and vocal Reaction Times (vRTs). RESULTS: A shortening of naming latency for actions was observed only after active anodal stimulation over the left PARC, as compared to placebo and right stimulations. No effects have been reported for accuracy. CONCLUSIONS: Our preliminary finding demonstrated that tDCS decreased vocal reaction time during action naming in a sample of patients with CBS. A possible explanation of our results is that anodal tDCS over the left PARC effects the brain network implicated in action observation and representation. Further studies, based on larger patient samples, should be conducted to investigate the usefulness of tDCS as an additional treatment of linguistic deficits in CBS patients. PMID- 25926793 TI - Identifying genes that mediate anthracyline toxicity in immune cells. AB - The role of the immune system in response to chemotherapeutic agents remains elusive. The interpatient variability observed in immune and chemotherapeutic cytotoxic responses is likely, at least in part, due to complex genetic differences. Through the use of a panel of genetically diverse mouse inbred strains, we developed a drug screening platform aimed at identifying genes underlying these chemotherapeutic cytotoxic effects on immune cells. Using genome wide association studies (GWAS), we identified four genome-wide significant quantitative trait loci (QTL) that contributed to the sensitivity of doxorubicin and idarubicin in immune cells. Of particular interest, a locus on chromosome 16 was significantly associated with cell viability following idarubicin administration (p = 5.01 * 10(-8)). Within this QTL lies App, which encodes amyloid beta precursor protein. Comparison of dose-response curves verified that T-cells in App knockout mice were more sensitive to idarubicin than those of C57BL/6J control mice (p < 0.05). In conclusion, the cellular screening approach coupled with GWAS led to the identification and subsequent validation of a gene involved in T-cell viability after idarubicin treatment. Previous studies have suggested a role for App in in vitro and in vivo cytotoxicity to anticancer agents; the overexpression of App enhances resistance, while the knockdown of this gene is deleterious to cell viability. Further investigations should include performing mechanistic studies, validating additional genes from the GWAS, including Ppfia1 and Ppfibp1, and ultimately translating the findings to in vivo and human studies. PMID- 25926794 TI - Cost-effectiveness of prucalopride in the treatment of chronic constipation in the Netherlands. AB - OBJECTIVE: To assess the cost-effectiveness of prucalopride vs. continued laxative treatment for chronic constipation in patients in the Netherlands in whom laxatives have failed to provide adequate relief. METHODS: A Markov model was developed to estimate the cost-effectiveness of prucalopride in patients with chronic constipation receiving standard laxative treatment from the perspective of Dutch payers in 2011. Data sources included published prucalopride clinical trials, published Dutch price/tariff lists, and national population statistics. The model simulated the clinical and economic outcomes associated with prucalopride vs. standard treatment and had a cycle length of 1 month and a follow-up time of 1 year. Response to treatment was defined as the proportion of patients who achieved "normal bowel function". One-way and probabilistic sensitivity analyses were conducted to test the robustness of the base case. RESULTS: In the base case analysis, the cost of prucalopride relative to continued laxative treatment was ? 9015 per quality-adjusted life-year (QALY). Extensive sensitivity analyses and scenario analyses confirmed that the base case cost-effectiveness estimate was robust. One-way sensitivity analyses showed that the model was most sensitive in response to prucalopride; incremental cost effectiveness ratios ranged from ? 6475 to 15,380 per QALY. Probabilistic sensitivity analyses indicated that there is a greater than 80% probability that prucalopride would be cost-effective compared with continued standard treatment, assuming a willingness-to-pay threshold of ? 20,000 per QALY from a Dutch societal perspective. A scenario analysis was performed for women only, which resulted in a cost-effectiveness ratio of ? 7773 per QALY. CONCLUSION: Prucalopride was cost-effective in a Dutch patient population, as well as in a women-only subgroup, who had chronic constipation and who obtained inadequate relief from laxatives. PMID- 25926796 TI - Early pharmacological inhibition of angiotensin-I converting enzyme activity induces obesity in adulthood. AB - We have investigated early programming of body mass in order to understand the multifactorial etiology of obesity. Considering that the renin-angiotensin system (RAS) is expressed and functional in the white adipose tissue (WAT) and modulates its development, we reasoned whether early transitory inhibition of angiotensin-I converting enzyme activity after birth could modify late body mass development. Therefore, newborn Wistar rats were treated with enalapril (10 mg/kg of body mass) or saline, starting at the first day of life until the age of 16 days. Between days ninetieth and hundred and eightieth, a group of these animals received high fat diet (HFD). Molecular, biochemical, histological, and physiological data were collected. Enalapril treated animals presented hyperphagia, overweight, and increased serum level of triglycerides, total cholesterol and leptin, in adult life. Body composition analyses revealed higher fat mass with increased adipocyte size in these animals. Molecular analyses revealed that enalapril treatment increases neuropeptide Y (NPY) and cocaine- and amphetamine-regulated transcript (CART) gene expression in hypothalamus, fatty acid synthase (FAS), and hormone-sensitive lipase (HSL) gene expression in retroperitoneal WAT, and decreases peroxixome proliferators-activated receptor (PPAR)gamma, PPARalpha, uncoupling protein (UCP)2, and UCP3 gene expression in WAT. The results of the current study indicate that enalapril administration during early postnatal development increases body mass, adiposity and serum lipids in adulthood associated with enhanced food intake and decreased metabolic activity in WAT, predisposing to obesity in adulthood. PMID- 25926795 TI - The therapeutic potential of orphan GPCRs, GPR35 and GPR55. AB - The G protein-coupled receptor (GPCR) superfamily of integral proteins is the largest family of signal transducers, comprised of ~1000 members. Considering their prevalence and functional importance, it's not surprising that ~60% of drugs target GPCRs. Regardless, there exists a subset of the GPCR superfamily that is largely uncharacterized and poorly understood; specifically, more than 140 GPCRs have unknown endogenous ligands-the so-called orphan GPCRs. Orphan GPCRs offer tremendous promise, as they may provide novel therapeutic targets that may be more selective than currently known receptors, resulting in the potential reduction in side effects. In addition, they may provide access to signal transduction pathways currently unknown, allowing for new strategies in drug design. Regardless, orphan GPCRs are an important area of inquiry, as they represent a large gap in our understanding of signal transduction at the cellular level. Here, we focus on the therapeutic potential of two recently deorphanized GPCRs: GPR35/CXCR8 and GPR55. First, GPR35/CXCR8 has been observed in numerous tissues/organ systems, including the gastrointestinal tract, liver, immune system, central nervous system, and cardiovascular system. Not surprisingly, GPR35/CXCR8 has been implicated in numerous pathologies involving these tissues/systems. While several endogenous ligands have been identified, GPR35/CXCR8 has recently been observed to bind the chemokine CXCL17. Second, GPR55 has been observed to be expressed in the central nervous system, adrenal glands, gastrointestinal tract, lung, liver, uterus, bladder, kidney, and bone, as well as, other tissues/organ systems. Likewise, it is not surprising that GPR55 has been implicated in pathologies involving these tissues/systems. GPR55 was initially deorphanized as a cannabinoid receptor and this receptor does bind many cannabinoid compounds. However, the GPR55 endogenous ligand has been found to be a non-cannabinoid, lysophophatidylinositol (LPI) and subsequent high throughput assays have identified other GPR55 ligands that are not cannabinoids and do not bind to either the cannabinoid CB1 and CB2 receptors. Here, we review reports that suggest that GPR35/CXCR8 and GPR55 may be promising therapeutic targets, with diverse physiological roles. PMID- 25926797 TI - Obesity and inflammation: reduced cytokine expression due to resveratrol in a human in vitro model of inflamed adipose tissue. AB - Obesity is associated with an inflammatory status and linked with a number of pathophysiological complications among them cardiovascular disease, type 2 diabetes mellitus, or the metabolic syndrome. Resveratrol was proposed to improve obesity-related inflammatory problems, but the effect of resveratrol on cytokine expression in obesity is not completely understood. In this study, we used an in vitro model of human adipose tissue inflammation to examine the effects of resveratrol on the production of the inflammatory cytokines interleukin 6 (IL-6), IL-8, and monocyte chemoattractant protein 1 (MCP-1). We found that resveratrol reduced IL-6, IL-8, and MCP-1 levels in a concentration-dependent manner in adipocytes under inflammatory conditions. Further experiments showed that the action of resveratrol was mainly due to its NFkappaB inhibitory potential. Thus, our data support the concept that resveratrol can alleviate obesity-induced up regulation of inflammatory cytokines providing a new insight toward novel treatment options in obesity. PMID- 25926798 TI - Education and training for medicines development, regulation, and clinical research in emerging countries. AB - The aim of this satellite workshop held at the 17th World Congress of Basic and Clinical Pharmacology (WCP2014) was to discuss the needs, optimal methods and practical approaches for extending education and teaching of medicines development, regulation, and clinical research to Low and Middle Income Countries (LMICs). It was generally agreed that, for efficiently treating the rapidly growing number of patients suffering from non-communicable diseases, modern drug therapy has to become available more widely and with a shorter time lag in these countries. To achieve this goal many additional experts working in medicines development, regulation, and clinical research have to be trained in parallel. The competence-oriented educational programs designed within the framework of the European Innovative Medicine Initiative-PharmaTrain (IMI-PhT) project were developed with the purpose to cover these interconnected fields. In addition, the programs can be easily adapted to the various local needs, primarily due to their modular architecture and well defined learning outcomes. Furthermore, the program is accompanied by stringent quality assurance standards which are essential for providing internationally accepted certificates. Effective cooperation between international and local experts and organizations, the involvement of the industry, health care centers and governments is essential for successful education. The initiative should also support the development of professional networks able to manage complex health care strategies. In addition it should help establish cooperation between neighboring countries for jointly managing clinical trials, as well as complex regulatory and ethical issues. PMID- 25926800 TI - Implementing psychosocial evidence-based practices in mental health: are we moving in the right direction? PMID- 25926799 TI - Circulating levels of hormones, lipids, and immune mediators in post-traumatic stress disorder - a 3-month follow-up study. AB - A number of peripheral blood analytes have been proposed as potential biomarkers of post-traumatic stress disorder (PTSD). Few studies have investigated whether observed changes in biomarkers persist over time. The aim of this study was to investigate the association of combat-related chronic PTSD with a wide array of putative PTSD biomarkers and to determine reliability of the measurements, i.e., correlations over time. Croatian combat veterans with chronic PTSD (n = 69) and age-matched healthy controls (n = 32), all men, were assessed at two time points separated by 3 months. Serum levels of lipids, cortisol, dehydroepiandrosterone sulfate (DHEA-S), prolactin, and C-reactive protein were determined. Multiplex assay was used for the simultaneous assessment of 13 analytes in sera: cytokines [interferon-gamma, interleukin (IL)-1beta, IL-2, IL-4, IL-6, TNF-alpha], adhesion molecules (sPECAM-1, sICAM-1), chemokines (IL-8 and MIP-1alpha), sCD40L, nerve growth factor, and leptin. Group differences and changes over time were tested by parametric or non-parametric tests, including repeated measures analysis of covariance. Reliability estimates [intraclass correlation coefficient (ICC) and kappa] were also calculated. Robust associations of PTSD with higher levels of DHEA-S [F(1,75) = 8.14, p = 0.006)] and lower levels of prolactin [F(1,75) = 5.40, p = 0.023] were found. Measurements showed good to excellent reproducibility (DHEA-S, ICC = 0.50; prolactin, ICC = 0.79). Serum lipids did not differ between groups but significant increase of LDL-C after 3 months was observed in the PTSD group (t = 6.87, p < 0.001). IL-8 was lower in the PTSD group (t = 4.37, p < 0.001) but assessments showed poor reproducibility (ICC = 0.08). Stable DHEA-S and prolactin changes highlight their potential to be reliable markers of PTSD. Change in lipid profiles after 3 months suggests that PTSD patients may be more prone to hyperlipidemia. High intra-individual variability in some variables emphasizes the importance of longitudinal studies in investigations of PTSD biomarkers. PMID- 25926802 TI - The next step: mirror neurons, music, and mechanistic explanation. PMID- 25926801 TI - Managing chronic pathologies with a stepped mHealth-based approach in clinical psychology and medicine. AB - Chronic diseases and conditions typically require long-term monitoring and treatment protocols both in traditional settings and in out-patient frameworks. The economic burden of chronic conditions is a key challenge and new and mobile technologies could offer good solutions. mHealth could be considered an evolution of eHealth and could be defined as the practice of medicine and public health supported by mobile communication devices. mHealth approach could overcome limitations linked with the traditional, restricted, and highly expensive in patient treatment of many chronic pathologies. Possible applications include stepped mHealth approach, where patients can be monitored and treated in their everyday contexts. Unfortunately, many barriers for the spread of mHealth are still present. Due the significant impact of psychosocial factors on disease evolution, psychotherapies have to be included into the chronic disease protocols. Existing psychological theories of health behavior change have to be adapted to the new technological contexts and requirements. In conclusion, clinical psychology and medicine have to face the "chronic care management" challenge in both traditional and mHealth settings. PMID- 25926803 TI - Vision-based coaching: optimizing resources for leader development. AB - Leaders develop in the direction of their dreams, not in the direction of their deficits. Yet many coaching interactions intended to promote a leader's development fail to leverage the benefits of the individual's personal vision. Drawing on intentional change theory, this article postulates that coaching interactions that emphasize a leader's personal vision (future aspirations and core identity) evoke a psychophysiological state characterized by positive emotions, cognitive openness, and optimal neurobiological functioning for complex goal pursuit. Vision-based coaching, via this psychophysiological state, generates a host of relational and motivational resources critical to the developmental process. These resources include: formation of a positive coaching relationship, expansion of the leader's identity, increased vitality, activation of learning goals, and a promotion-orientation. Organizational outcomes as well as limitations to vision-based coaching are discussed. PMID- 25926804 TI - Corrigendum: Somatic Experiencing: using interoception and proprioception as core elements of trauma therapy. AB - [This corrects the article on p. 93 in vol. 6, PMID: 25699005.]. PMID- 25926805 TI - Eliciting mixed emotions: a meta-analysis comparing models, types, and measures. AB - The idea that people can experience two oppositely valenced emotions has been controversial ever since early attempts to investigate the construct of mixed emotions. This meta-analysis examined the robustness with which mixed emotions have been elicited experimentally. A systematic literature search identified 63 experimental studies that instigated the experience of mixed emotions. Studies were distinguished according to the structure of the underlying affect model dimensional or discrete-as well as according to the type of mixed emotions studied (e.g., happy-sad, fearful-happy, positive-negative). The meta-analysis using a random-effects model revealed a moderate to high effect size for the elicitation of mixed emotions (d IG+ = 0.77), which remained consistent regardless of the structure of the affect model, and across different types of mixed emotions. Several methodological and design moderators were tested. Studies using the minimum index (i.e., the minimum value between a pair of opposite valenced affects) resulted in smaller effect sizes, whereas subjective measures of mixed emotions increased the effect sizes. The presence of more women in the samples was also associated with larger effect sizes. The current study indicates that mixed emotions are a robust, measurable and non-artifactual experience. The results are discussed in terms of the implications for an affect system that has greater versatility and flexibility than previously thought. PMID- 25926806 TI - Victimization experiences and the stabilization of victim sensitivity. AB - People reliably differ in the extent to which they are sensitive to being victimized by others. Importantly, "victim sensitivity" predicts how people behave in social dilemma situations: Victim-sensitive individuals are less likely to trust others and more likely to behave uncooperatively-especially in socially uncertain situations. This pattern can be explained with the sensitivity to mean intentions (SeMI) model, according to which victim sensitivity entails a specific and asymmetric sensitivity to contextual cues that are associated with untrustworthiness. Recent research is largely in line with the model's prediction, but some issues have remained conceptually unresolved so far. For instance, it is unclear why and how victim sensitivity becomes a stable trait and which developmental and cognitive processes are involved in such stabilization. In the present article, we will discuss the psychological processes that contribute to a stabilization of victim sensitivity within persons, both across the life span ("ontogenetic stabilization") and across social situations ("actual genetic stabilization"). Our theoretical framework starts from the assumption that experiences of being exploited threaten a basic need, the need to trust. This need is so fundamental that experiences that threaten it receive a considerable amount of attention and trigger strong affective reactions. Associative learning processes can then explain (a) how certain contextual cues (e.g., facial expressions) become conditioned stimuli that elicit equally strong responses, (b) why these contextual untrustworthiness cues receive much more attention than, for instance, trustworthiness cues, and (c) how these cues shape spontaneous social expectations (regarding other people's intentions). Finally, avoidance learning can explain why these cognitive processes gradually stabilize and become a trait: the trait which is referred to as victim sensitivity. PMID- 25926807 TI - The reciprocal relationship between compounding awareness and vocabulary knowledge in Chinese: a latent growth model study. AB - The aim of this study is to examine the developmental relationship between compounding awareness and vocabulary knowledge from grades 1 to 2 in Chinese children. In this study, 149 Chinese children were tested on compounding awareness and vocabulary knowledge from Time 1 to Time 4, with non-verbal IQ, working memory, phonological awareness, orthographical awareness, and rapid automatized naming at Time 1 as control variables. Latent growth modeling was conducted to analyze the data. Univariate models separately calculated children's initial levels and growth rates in compounding awareness and vocabulary knowledge. Bivariate model was used to examine the direction of the developmental relationships between the two variables with other cognitive and linguistic variables and the autoregression controlled. The results demonstrated that the initial level of compounding awareness predicted the growth rate of vocabulary knowledge, and the reverse relation was also found, after controlling for other cognitive and linguistic variables and the autoregression. The results suggested a reciprocal developmental relationship between children's compounding awareness and vocabulary knowledge for Chinese children, a finding that informs current models of the relationship between morphological awareness and vocabulary knowledge. PMID- 25926808 TI - The role of personal purpose and personal goals in symbiotic visions. AB - It is believed that symbiotic visions can drive employees and organizations toward a common objective based on the premise that people have a high level of self-motivation and engagement when they are working toward something very personal. The field of organizational development has been aspiring to help organizations and people align their visions for decades without much, if any, empirical support for the role of personal purpose and goals in the symbiotic relationship with a company vision. This qualitative study examines the role personal purpose and goals play in how high performing leaders align to their company's vision. Whether and how senior managers articulate this alignment, and its correlation to their motivation and engagement, was examined. An observation was that most senior managers within organizations with a well-developed and widely known higher purpose vision are driven by something personal, identified as either personal goals or a personal purpose. One of the key findings is that personal purpose and goals, when aligned to a company vision, appear to impact motivation and engagement in different ways. When alignment is felt through the sense of the greater purpose, there is a deep, almost spiritual, commitment to making the world a better place and helping the organization contribute to that. This seems to motivate them to guide the organization toward its higher purpose vision. When alignment is felt through the organization's alignment to one's personal goals, there is a great sense of commitment to completing the steps or tasks necessary to move toward the vision, yet a clear delineation between work and life ambitions. PMID- 25926810 TI - Lexical decisions in adults with low and high susceptibility to pattern-related visual stress: a preliminary investigation. AB - Pattern-related visual stress (PRVS) is a form of sensory hypersensitivity that some people experience when viewing high contrast repeating patterns, notably alternating dark and light stripes. Those susceptible to PRVS typically have a strong aversion to such stimuli, and this is often accompanied by experiences of visual discomfort and disturbance. The patterns most likely to elicit symptoms of PRVS have a square-wave grating configuration of spatial frequency ~3 cycles/degree. Such stimuli are characteristic of printed text in which lines of words and the spaces between them present a high contrast grating-like stimulus. Consequently, much printed reading material has the potential to elicit PRVS that may impair reading performance, and this problem appears to be common in individuals with reading difficulties including dyslexia. However, the manner in which PRVS affects reading ability is unknown. One possibility is that the early sensory visual stress may interfere with the later cognitive word recognition stage of the reading process, resulting in reading performance that is slower and/or less accurate. To explore the association of PRVS with word recognition ability, lexical decision performance (speed and accuracy) to words and pronounceable non-words was measured in two groups of adults, having low and high susceptibility to PRVS. Results showed that lexical decisions were generally faster but less accurate in high-PRVS, and also that high-PRVS participants made decisions significantly faster for words than for non-words, revealing a strong lexicality effect that was not present in low-PRVS. These findings are novel and, as yet, unconfirmed by other studies. PMID- 25926811 TI - Experience sharing, emotional reciprocity, and turn-taking. AB - In this perspective article, we consider the relationship between experience sharing and turn-taking. There is much evidence suggesting that human social interaction is permeated by two temporal organizations: (1) the sequential framework of turn-taking and (2) the concurrent framework of emotional reciprocity. From this perspective, we introduce two alternative hypotheses about how the relationship between experience sharing and turn-taking could be viewed. According to the first hypothesis, the home environment of experience sharing is in the concurrent framework of emotional reciprocity, while the motivation to share experiences is in tension with the sequential framework of turn-taking. According to the second hypothesis, people's inclination to coordinate their actions in terms of turn-taking is motivated precisely by their propensity to share experiences. We consider theoretical and empirical ideas in favor of both of these hypotheses and discuss their implications for future research. PMID- 25926809 TI - The role of language in emotion: predictions from psychological constructionism. AB - Common sense suggests that emotions are physical types that have little to do with the words we use to label them. Yet recent psychological constructionist accounts reveal that language is a fundamental element in emotion that is constitutive of both emotion experiences and perceptions. According to the psychological constructionist Conceptual Act Theory (CAT), an instance of emotion occurs when information from one's body or other people's bodies is made meaningful in light of the present situation using concept knowledge about emotion. The CAT suggests that language plays a role in emotion because language supports the conceptual knowledge used to make meaning of sensations from the body and world in a given context. In the present paper, we review evidence from developmental and cognitive science to reveal that language scaffolds concept knowledge in humans, helping humans to acquire abstract concepts such as emotion categories across the lifespan. Critically, language later helps individuals use concepts to make meaning of on-going sensory perceptions. Building on this evidence, we outline predictions from a psychological constructionist model of emotion in which language serves as the "glue" for emotion concept knowledge, binding concepts to embodied experiences and in turn shaping the ongoing processing of sensory information from the body and world to create emotional experiences and perceptions. PMID- 25926812 TI - Brain circuitries involved in sleep disorders. PMID- 25926813 TI - Network collapse and cognitive impairment in multiple sclerosis. PMID- 25926814 TI - Neonatal Diabetes and Congenital Hyperinsulinism Caused by Mutations in ABCC8/SUR1 are Associated with Altered and Opposite Affinities for ATP and ADP. AB - ATP-sensitive K(+) (KATP) channels composed of potassium inward-rectifier type 6.2 and sulfonylurea receptor type 1 subunits (Kir6.2/SUR1)4 are expressed in various cells in the brain and endocrine pancreas where they couple metabolic status to membrane potential. In beta-cells, increases in cytosolic [ATP/ADP]c inhibit KATP channel activity, leading to membrane depolarization and exocytosis of insulin granules. Mutations in ABCC8 (SUR1) or KCNJ11 (Kir6.2) can result in gain or loss of channel activity and cause neonatal diabetes (ND) or congenital hyperinsulinism (CHI), respectively. SUR1 is reported to be a Mg(2+)-dependent ATPase. A prevailing model posits that ATP hydrolysis at SUR1 is required to stimulate openings of the pore. However, recent work shows nucleotide binding, without hydrolysis, is sufficient to switch SUR1 to stimulatory conformations. The actions of nucleotides, ATP and ADP, on ND (SUR1E1506D) and CHI (SUR1E1506K) mutants, without Kir6.2, were compared to assess both models. Both substitutions significantly impair hydrolysis in SUR1 homologs. SUR1E1506D has greater affinity for MgATP than wildtype; SUR1E1506K has reduced affinity. Without Mg(2+), SUR1E1506K has a greater affinity for ATP(4-) consistent with electrostatic attraction between ATP(4-), unshielded by Mg(2+), and the basic lysine. Further analysis of ND and CHI ABCC8 mutants in the second transmembrane and nucleotide binding domains (TMD2 and NBD2) found a relation between their affinities for ATP (+/-Mg(2+)) and their clinical phenotype. Increased affinity for ATP is associated with ND; decreased affinity with CHI. In contrast, MgADP showed a weaker relationship. Diazoxide, known to reduce insulin release in some CHI cases, potentiates switching of CHI mutants from non-stimulatory to stimulatory states consistent with diazoxide stabilizing a nucleotide-bound conformation. The results emphasize the greater importance of nucleotide binding vs. hydrolysis in the regulation of KATP channels in vivo. PMID- 25926815 TI - Farm management, not soil microbial diversity, controls nutrient loss from smallholder tropical agriculture. AB - Tropical smallholder agriculture is undergoing rapid transformation in nutrient cycling pathways as international development efforts strongly promote greater use of mineral fertilizers to increase crop yields. These changes in nutrient availability may alter the composition of microbial communities with consequences for rates of biogeochemical processes that control nutrient losses to the environment. Ecological theory suggests that altered microbial diversity will strongly influence processes performed by relatively few microbial taxa, such as denitrification and hence nitrogen losses as nitrous oxide, a powerful greenhouse gas. Whether this theory helps predict nutrient losses from agriculture depends on the relative effects of microbial community change and increased nutrient availability on ecosystem processes. We find that mineral and organic nutrient addition to smallholder farms in Kenya alters the taxonomic and functional diversity of soil microbes. However, we find that the direct effects of farm management on both denitrification and carbon mineralization are greater than indirect effects through changes in the taxonomic and functional diversity of microbial communities. Changes in functional diversity are strongly coupled to changes in specific functional genes involved in denitrification, suggesting that it is the expression, rather than abundance, of key functional genes that can serve as an indicator of ecosystem process rates. Our results thus suggest that widely used broad summary statistics of microbial diversity based on DNA may be inappropriate for linking microbial communities to ecosystem processes in certain applied settings. Our results also raise doubts about the relative control of microbial composition compared to direct effects of management on nutrient losses in applied settings such as tropical agriculture. PMID- 25926816 TI - Bacterial community structure across environmental gradients in permafrost thaw ponds: methanotroph-rich ecosystems. AB - Permafrost thawing leads to the formation of thermokarst ponds that potentially emit CO2 and CH4 to the atmosphere. In the Nunavik subarctic region (northern Quebec, Canada), these numerous, shallow ponds become well-stratified during summer. This creates a physico-chemical gradient of temperature and oxygen, with an upper oxic layer and a bottom low oxygen or anoxic layer. Our objective was to determine the influence of stratification and related limnological and landscape properties on the community structure of potentially active bacteria in these waters. Samples for RNA analysis were taken from ponds in three contrasting valleys across a gradient of permafrost degradation. A total of 1296 operational taxonomic units were identified by high throughput amplicon sequencing, targeting bacterial 16S rRNA that was reverse transcribed to cDNA. beta-proteobacteria were the dominant group in all ponds, with highest representation by the genera Variovorax and Polynucleobacter. Methanotrophs were also among the most abundant sequences at most sites. They accounted for up to 27% of the total sequences (median of 4.9% for all samples), indicating the importance of methane as a bacterial energy source in these waters. Both oxygenic (cyanobacteria) and anoxygenic (Chlorobi) phototrophs were also well-represented, the latter in the low oxygen bottom waters. Ordination analyses showed that the communities clustered according to valley and depth, with significant effects attributed to dissolved oxygen, pH, dissolved organic carbon, and total suspended solids. These results indicate that the bacterial assemblages of permafrost thaw ponds are filtered by environmental gradients, and are complex consortia of functionally diverse taxa that likely affect the composition as well as magnitude of greenhouse gas emissions from these abundant waters. PMID- 25926817 TI - Unravelling the genome of long chain N-acylhomoserine lactone-producing Acinetobacter sp. strain GG2 and identification of its quorum sensing synthase gene. AB - Myriad proteobacteria use N-acyl homoserine lactone (AHL) molecules as quorum sensing (QS) signals to regulate different physiological functions, including virulence, antibiotic production, and biofilm formation. Many of these proteobacteria possess LuxI/LuxR system as the QS mechanism. Recently, we reported the 3.89 Mb genome of Acinetobacter sp. strain GG2. In this work, the genome of this long chain AHL-producing bacterium was unravelled which led to the molecular characterization of luxI homologue, designated as aciI. This 552 bp gene was cloned and overexpressed in Escherichia coli BL21(DE3). The purified protein was ~20.5 kDa and is highly similar to several autoinducer proteins of LuxI family among Acinetobacter species. To verify the AHL synthesis activity of this protein, high-resolution liquid chromatography-mass spectrometry analysis revealed the production of 3-oxo-dodecanoyl-homoserine lactone and 3-hydroxy dodecanoyl-homoserine lactone from induced E. coli harboring the recombinant AciI. Our data show for the first time, the cloning and characterization of the luxI homologue from Acinetobacter sp. strain GG2, and confirmation of its AHLs production. These data are of great significance as the annotated genome of strain GG2 has provided a valuable insight in the study of autoinducer molecules and its roles in QS mechanism of the bacterium. PMID- 25926818 TI - Root-associated bacterial endophytes from Ralstonia solanacearum resistant and susceptible tomato cultivars and their pathogen antagonistic effects. AB - This study was undertaken to assess if the root-associated native bacterial endophytes in tomato have any bearing in governing the host resistance to the wilt pathogen Ralstonia solanacearum. Internal colonization of roots by bacterial endophytes was confirmed through confocal imaging after SYTO-9 staining. Endophytes were isolated from surface-sterilized roots of 4-weeks-old seedlings of known wilt resistant (R) tomato cultivar Arka Abha and susceptible (S) cv. Arka Vikas on nutrient agar after plating the tissue homogenate. Arka Abha displayed more diversity with nine distinct organisms while Arka Vikas showed five species with two common organisms (Pseudomonas oleovorans and Agrobacterium tumefaciens). Screening for general indicators of biocontrol potential showed more isolates from Arka Abha positive for siderophore, HCN and antibiotic biosynthesis than from Arka Vikas. Direct challenge against the pathogen indicated strong antagonism by three Arka Abha isolates (P. oleovorans, Pantoea ananatis, and Enterobacter cloacae) and moderate activity by three others, while just one isolate from Arka Vikas (P. oleovorans) showed strong antagonism. Validation for the presence of bacterial endophytes on three R cultivars (Arka Alok, Arka Ananya, Arka Samrat) showed 8-9 antagonistic bacteria in them in comparison with four species in the three S cultivars (Arka Ashish, Arka Meghali, Arka Saurabhav). Altogether 34 isolates belonging to five classes, 16 genera and 27 species with 23 of them exhibiting pathogen antagonism were isolated from the four R cultivars against 17 isolates under three classes, seven genera and 13 species from the four S cultivars with eight isolates displaying antagonistic effects. The prevalence of higher endophytic bacterial diversity and more antagonistic organisms associated with the seedling roots of resistant cultivars over susceptible genotypes suggest a possible role by the root-associated endophytes in natural defense against the pathogen. PMID- 25926820 TI - Species interactions differ in their genetic robustness. AB - Conflict and cooperation between bacterial species drive the composition and function of microbial communities. Stability of these emergent properties will be influenced by the degree to which species' interactions are robust to genetic perturbations. We use genome-scale metabolic modeling to computationally analyze the impact of genetic changes when Escherichia coli and Salmonella enterica compete, or cooperate. We systematically knocked out in silico each reaction in the metabolic network of E. coli to construct all 2583 mutant stoichiometric models. Then, using a recently developed multi-scale computational framework, we simulated the growth of each mutant E. coli in the presence of S. enterica. The type of interaction between species was set by modulating the initial metabolites present in the environment. We found that the community was most robust to genetic perturbations when the organisms were cooperating. Species ratios were more stable in the cooperative community, and community biomass had equal variance in the two contexts. Additionally, the number of mutations that have a substantial effect is lower when the species cooperate than when they are competing. In contrast, when mutations were added to the S. enterica network the system was more robust when the bacteria were competing. These results highlight the utility of connecting metabolic mechanisms and studies of ecological stability. Cooperation and conflict alter the connection between genetic changes and properties that emerge at higher levels of biological organization. PMID- 25926819 TI - The cognitive cell: bacterial behavior reconsidered. AB - Research on how bacteria adapt to changing environments underlies the contemporary biological understanding of signal transduction (ST), and ST provides the foundation of the information-processing approach that is the hallmark of the 'cognitive revolution,' which began in the mid-20th century. Yet cognitive scientists largely remain oblivious to research into microbial behavior that might provide insights into problems in their own domains, while microbiologists seem equally unaware of the potential importance of their work to understanding cognitive capacities in multicellular organisms, including vertebrates. Evidence in bacteria for capacities encompassed by the concept of cognition is reviewed. Parallels exist not only at the heuristic level of functional analogue, but also at the level of molecular mechanism, evolution and ecology, which is where fruitful cross-fertilization among disciplines might be found. PMID- 25926822 TI - Microbial growth and physiology: a call for better craftsmanship. AB - Virtually every microbiological experiment starts with the cultivation of microbes. Consequently, as originally pointed out by Monod (1949), handling microbial cultures is a fundamental methodology of microbiology and mastering different cultivation techniques should be part of every microbiologist's craftsmanship. This is particularly important for research in microbial physiology, as the composition and behavior of microbes is strongly dependent on their growth environment. It has been pointed out repeatedly by eminent microbiologists that we should give more attention to the media and culturing conditions. However, this is obviously not adhered to with sufficient rigor as mistakes in basic cultivation principles are frequently found in the published research literature. The most frequent mistakes are the use of inappropriate growth media and little or no control of the specific growth rate, and some examples will be discussed here in detail. Therefore, this is a call for better microbiological craftsmanship when cultivating microbial cultures for physiological experiments. This call is not only addressed to researchers but it is probably even more important for the teaching of our discipline. PMID- 25926821 TI - Isolation of a significant fraction of non-phototroph diversity from a desert Biological Soil Crust. AB - Biological Soil Crusts (BSCs) are organosedimentary assemblages comprised of microbes and minerals in topsoil of terrestrial environments. BSCs strongly impact soil quality in dryland ecosystems (e.g., soil structure and nutrient yields) due to pioneer species such as Microcoleus vaginatus; phototrophs that produce filaments that bind the soil together, and support an array of heterotrophic microorganisms. These microorganisms in turn contribute to soil stability and biogeochemistry of BSCs. Non-cyanobacterial populations of BSCs are less well known than cyanobacterial populations. Therefore, we attempted to isolate a broad range of numerically significant and phylogenetically representative BSC aerobic heterotrophs. Combining simple pre-treatments (hydration of BSCs under dark and light) and isolation strategies (media with varying nutrient availability and protection from oxidative stress) we recovered 402 bacterial and one fungal isolate in axenic culture, which comprised 116 phylotypes (at 97% 16S rRNA gene sequence homology), 115 bacterial and one fungal. Each medium enriched a mostly distinct subset of phylotypes, and cultivated phylotypes varied due to the BSC pre-treatment. The fraction of the total phylotype diversity isolated, weighted by relative abundance in the community, was determined by the overlap between isolate sequences and OTUs reconstructed from metagenome or metatranscriptome reads. Together, more than 8% of relative abundance of OTUs in the metagenome was represented by our isolates, a cultivation efficiency much larger than typically expected from most soils. We conclude that simple cultivation procedures combined with specific pre-treatment of samples afford a significant reduction in the culturability gap, enabling physiological and metabolic assays that rely on ecologically relevant axenic cultures. PMID- 25926823 TI - NDM-1 encoded by a pNDM-BJ01-like plasmid p3SP-NDM in clinical Enterobacter aerogenes. AB - A carbapenem-nonsusceptible Enterobacter aerogenes strain named 3-SP was isolated from a human case of pneumonia in a Chinese teaching hospital. NDM-1 carbapenemase is produced by a pNDM-BJ01-like conjugative plasmid designated p3SP NDM to account for carbapenem resistance of 3-SP. p3SP-NDM was fully sequenced and compared with all publically available pNDM-BJ01-like plasmids. The genetic differences between p3SP-NDM and pNDM-BJ01 include only 18 single nucleotide polymorphisms, a 1 bp deletion and a 706 bp deletion. p3SP-NDM and pNDM-BJ01 harbor an identical Tn125 element organized as ISAba125, bla NDM-1, ble MBL, DeltatrpF, dsbC, cutA, DeltagroES, groEL, ISCR27, and ISAba125. The bla NDM-1 surrounding regions in these pNDM-BJ01-like plasmids have a conserved linear organization ISAba14-aphA6-Tn125-unknown IS, with considerable genetic differences identified within or immediately downstream of Tn125. All reported pNDM-BJ01-like plasmids are exclusively found in Acinetobacter, whereas this is the first report of identification of a pNDM-BJ01-like plasmid in Enterobacteriaceae. PMID- 25926824 TI - The effect of imipenem and diffusible signaling factors on the secretion of outer membrane vesicles and associated Ax21 proteins in Stenotrophomonas maltophilia. AB - Outer membrane vesicles (OMVs) are small nanoscale structures that are secreted by bacteria and that can carry nucleic acids, proteins, and small metabolites. They can mediate intracellular communication and play a role in virulence. In this study, we show that treatment with the beta-lactam antibiotic imipenem leads to a dramatic increase in the secretion of outer membrane vesicles in the nosocomial pathogen Stenotrophomonas maltophilia. Proteomic analysis of their protein content demonstrated that the OMVs contain the chromosomal encoded L1 metallo-beta-lactamase and L2 serine-beta-lactamase. Moreover, the secreted OMVs contain large amounts of two Ax21 homologs, i.e., outer membrane proteins known to be involved in virulence and biofilm formation. We show that OMV secretion and the levels of Ax21 in the OMVs are dependent on the quorum sensing diffusible signal system (DSF). More specific, we demonstrate that the S. maltophilia DSF cis-Delta2-11-methyl-dodecenoic acid and, to a lesser extent, the Burkholderia cenocepacia DSF cis-Delta2-dodecenoic acid, stimulate OMV secretion. By a targeted proteomic analysis, we confirmed that DSF-induced OMVs contain large amounts of the Ax21 homologs, but not the beta-lactamases. This work illustrates that both quorum sensing and disturbance of the peptidoglycan biosynthesis provoke the release of OMVs and that OMV content is context dependent. PMID- 25926825 TI - Efflux pump-mediated drug resistance in Burkholderia. AB - Several members of the genus Burkholderia are prominent pathogens. Infections caused by these bacteria are difficult to treat because of significant antibiotic resistance. Virtually all Burkholderia species are also resistant to polymyxin, prohibiting use of drugs like colistin that are available for treatment of infections caused by most other drug resistant Gram-negative bacteria. Despite clinical significance and antibiotic resistance of Burkholderia species, characterization of efflux pumps lags behind other non-enteric Gram-negative pathogens such as Acinetobacter baumannii and Pseudomonas aeruginosa. Although efflux pumps have been described in several Burkholderia species, they have been best studied in Burkholderia cenocepacia and B. pseudomallei. As in other non enteric Gram-negatives, efflux pumps of the resistance nodulation cell division (RND) family are the clinically most significant efflux systems in these two species. Several efflux pumps were described in B. cenocepacia, which when expressed confer resistance to clinically significant antibiotics, including aminoglycosides, chloramphenicol, fluoroquinolones, and tetracyclines. Three RND pumps have been characterized in B. pseudomallei, two of which confer either intrinsic or acquired resistance to aminoglycosides, macrolides, chloramphenicol, fluoroquinolones, tetracyclines, trimethoprim, and in some instances trimethoprim+sulfamethoxazole. Several strains of the host-adapted B. mallei, a clone of B. pseudomallei, lack AmrAB-OprA, and are therefore aminoglycoside and macrolide susceptible. B. thailandensis is closely related to B. pseudomallei, but non-pathogenic to humans. Its pump repertoire and ensuing drug resistance profile parallels that of B. pseudomallei. An efflux pump in B. vietnamiensis plays a significant role in acquired aminoglycoside resistance. Summarily, efflux pumps are significant players in Burkholderia drug resistance. PMID- 25926826 TI - Spatial coordination between chromosomes and cell division proteins in Escherichia coli. AB - To successfully propagate, cells need to coordinate chromosomal replication and segregation with cell division to prevent formation of DNA-less cells and cells with damaged DNA. Here, we review molecular systems in Escherichia coli that are known to be involved in positioning the divisome and chromosome relative to each other. Interestingly, this well-studied micro-organism has several partially redundant mechanisms to achieve this task; none of which are essential. Some of these systems determine the localization of the divisome relative to chromosomes such as SlmA-dependent nucleoid occlusion, some localize the chromosome relative to the divisome such as DNA translocation by FtsK, and some are likely to act on both systems such as the Min system and newly described Ter linkage. Moreover, there is evidence that E. coli harbors other divisome-chromosome coordination systems in addition to those known. The review also discusses the minimal requirements of coordination between chromosomes and cell division proteins needed for cell viability. Arguments are presented that cells can propagate without any dedicated coordination between their chromosomes and cell division machinery at the expense of lowered fitness. PMID- 25926827 TI - Potential changes in bacterial metabolism associated with increased water temperature and nutrient inputs in tropical humic lagoons. AB - Temperature and nutrient concentrations regulate aquatic bacterial metabolism. However, few studies have focused on the effect of the interaction between these factors on bacterial processes, and none have been performed in tropical aquatic ecosystems. We analyzed the main and interactive effects of changes in water temperature and N and P concentrations on bacterioplankton production (BP), bacterioplankton respiration (BR) and bacterial growth efficiency (BGE) in tropical coastal lagoons. We used a factorial design with three levels of water temperature (25, 30, and 35 degrees C) and four levels of N and/or P additions (Control, N, P, and NP additions) in five tropical humic lagoons. When data for all lagoons were pooled together, a weak interaction was observed between the increase in water temperature and the addition of nutrients. Water temperature alone had the greatest impact on bacterial metabolism by increasing BR, decreasing BP, and decreasing BGE. An increase of 1 degrees C lead to an increase of ~4% in BR, a decrease of ~0.9% in BP, and a decrease of ~4% in BGE. When data were analyzed separately, lagoons responded differently to nutrient additions depending on Dissolved Organic Carbon (DOC) concentration. Lagoons with lowest DOC concentrations showed the strongest responses to nutrient additions: BP increased in response to N, P, and their interaction, BR increased in response to N and the interaction between N and P, and BGE was negatively affected, mainly by the interaction between N and P additions. Lagoons with the highest DOC concentrations showed almost no significant relationship with nutrient additions. Taken together, these results show that different environmental drivers impact bacterial processes at different scales. Changes of bacterial metabolism related to the increase of water temperature are consistent between lagoons, therefore their consequences can be predicted at a regional scale, while the effect of nutrient inputs is specific to different lagoons but seems to be related to the DOC concentration. PMID- 25926828 TI - Application of swine manure on agricultural fields contributes to extended spectrum beta-lactamase-producing Escherichia coli spread in Tai'an, China. AB - The prevalence of extended-spectrum beta-lactamase (ESBL)-producing Escherichia coli (E. coli) is increasing rapidly in both hospital environments and animal farms. A lot of animal manure has been directly applied into arable fields in developing countries. But the impact of ESBL-positive bacteria from animal manure on the agricultural fields is sparse, especially in the rural regions of Tai'an, China. Here, we collected 29, 3, and 10 ESBL-producing E. coli from pig manure, compost, and soil samples, respectively. To track ESBL-harboring E. coli from agricultural soil, these isolates of different sources were analyzed with regard to antibiotic resistance profiles, ESBL genes, plasmid replicons, and enterobacterial repetitive intergenic consensus (ERIC)-polymerase chain reaction (PCR) typing. The results showed that all the isolates exhibited multi-drug resistant (MDR). CTX-M gene was the predominant ESBL gene in the isolates from pig farm samples (30/32, 93.8%) and soil samples (7/10, 70.0%), but no SHV gene was detected. Twenty-five isolates contained the IncF-type replicon of plasmid, including 18 strains (18/32, 56.3%) from the pig farm and 7 (7/10, 70.0%) from the soil samples. ERIC-PCR demonstrated that 3 isolates from soil had above 90% genetic similarity with strains from pig farm samples. In conclusion, application of animal manure carrying drug-resistant bacteria on agricultural fields is a likely contributor to antibiotic resistance gene spread. PMID- 25926829 TI - Evaluation of the risk factors contributing to the African swine fever occurrence in Sardinia, Italy. AB - This study assesses the relation between hypothesized risk factors and African swine fever virus (ASFV) distribution in Sardinia (Italy) after the beginning of the eradication program in 1993, using a Bayesian multivariable logistic regression mixed model. Results indicate that the probability of ASFV occurrence in Sardinia was associated to particular socio-cultural, productive and economical factors found in the region, particularly to large number of confined (i.e., closed) farms (most of them backyard), high road density, high mean altitude, large number of open fattening farms, and large number of pigs per commune. Conversely, large proportion of open farms with at least one census and large proportion of open farms per commune, were found to be protective factors for ASFV. Results suggest that basic preventive and control strategies, such as yearly census or registration of the pigs per farm and better control of the public lands where pigs are usually raised, together with endanced effords of outreach and communication with pig producers should help in the success of the eradication program for ASF in the Island. Methods and results presented here will inform decision making to better control and eradicate ASF in Sardinia and in all those areas with similar management and epidemiological conditions. PMID- 25926830 TI - The where, when, how, and why of hyaluronan binding by immune cells. AB - Hyaluronan is made and extruded from cells to form a pericellular or extracellular matrix (ECM) and is present in virtually all tissues in the body. The size and form of hyaluronan present in tissues are indicative of a healthy or inflamed tissue, and the interactions of hyaluronan with immune cells can influence their response. Thus, in order to understand how inflammation is regulated, it is necessary to understand these interactions and their consequences. Although there is a large turnover of hyaluronan in our bodies, the large molecular mass form of hyaluronan predominates in healthy tissues. Upon tissue damage and/or infection, the ECM and hyaluronan are broken down and an inflammatory response ensues. As inflammation is resolved, the ECM is restored, and high molecular mass hyaluronan predominates again. Immune cells encounter hyaluronan in the tissues and lymphoid organs and respond differently to high and low molecular mass forms. Immune cells differ in their ability to bind hyaluronan and this can vary with the cell type and their activation state. For example, peritoneal macrophages do not bind soluble hyaluronan but can be induced to bind after exposure to inflammatory stimuli. Likewise, naive T cells, which typically express low levels of the hyaluronan receptor, CD44, do not bind hyaluronan until they undergo antigen-stimulated T cell proliferation and upregulate CD44. Despite substantial knowledge of where and when immune cells bind hyaluronan, why immune cells bind hyaluronan remains a major outstanding question. Here, we review what is currently known about the interactions of hyaluronan with immune cells in both healthy and inflamed tissues and discuss how hyaluronan binding by immune cells influences the inflammatory response. PMID- 25926831 TI - Negative Regulation of Humoral Immunity Due to Interplay between the SLAMF1, SLAMF5, and SLAMF6 Receptors. AB - Whereas the SLAMF-associated protein (SAP) is involved in differentiation of T follicular helper (Tfh) cells and antibody responses, the precise requirements of SLAMF receptors in humoral immune responses are incompletely understood. By analyzing mice with targeted disruptions of the Slamf1, Slamf5, and Slamf6 genes, we found that both T-dependent and T-independent antibody responses were twofold higher compared to those in single knockout mice. These data suggest a suppressive synergy of SLAMF1, SLAMF5, and SLAMF6 in humoral immunity, which contrasts the decreased antibody responses resulting from a defective GC reaction in the absence of the adapter SAP. In adoptive co-transfer assays, both [Slamf1 + 5 + 6] (-/-) B and T cells were capable of inducing enhanced antibody responses, but more pronounced enhancement was observed after adoptive transfer of [Slamf1 + 5 + 6] (-/-) B cells compared to that of [Slamf1 + 5 + 6] (-/-) T cells. In support of [Slamf1 + 5 + 6] (-/-) B cell intrinsic activity, [Slamf1 + 5 + 6] (-/ ) mice also mounted significantly higher antibody responses to T-independent type 2 antigen. Furthermore, treatment of mice with anti-SLAMF6 monoclonal antibody results in severe inhibition of the development of Tfh cells and GC B cells, confirming a suppressive effect of SLAMF6. Taken together, these results establish SLAMF1, SLAMF5, and SLAMF6 as important negative regulators of humoral immune response, consistent with the notion that SLAM family receptors have dual functions in immune responses. PMID- 25926832 TI - Heat Shock Protein 70 (Hsp70) Peptide Activated Natural Killer (NK) Cells for the Treatment of Patients with Non-Small Cell Lung Cancer (NSCLC) after Radiochemotherapy (RCTx) - From Preclinical Studies to a Clinical Phase II Trial. AB - Heat shock protein 70 (Hsp70) is frequently overexpressed in tumor cells. An unusual cell surface localization could be demonstrated on a large variety of solid tumors including lung, colorectal, breast, squamous cell carcinomas of the head and neck, prostate and pancreatic carcinomas, glioblastomas, sarcomas and hematological malignancies, but not on corresponding normal tissues. A membrane (m)Hsp70-positive phenotype can be determined either directly on single cell suspensions of tumor biopsies by flow cytometry using cmHsp70.1 monoclonal antibody or indirectly in the serum of patients using a novel lipHsp70 ELISA. A mHsp70-positive tumor phenotype has been associated with highly aggressive tumors, causing invasion and metastases and resistance to cell death. However, natural killer (NK), but not T cells were found to kill mHsp70-positive tumor cells after activation with a naturally occurring Hsp70 peptide (TKD) plus low dose IL-2 (TKD/IL-2). Safety and tolerability of ex vivo TKD/IL-2 stimulated, autologous NK cells has been demonstrated in patients with metastasized colorectal and non-small cell lung cancer (NSCLC) in a phase I clinical trial. Based on promising clinical results of the previous study, a phase II randomized clinical study was initiated in 2014. The primary objective of this multicenter proof-of-concept trial is to examine whether an adjuvant treatment of NSCLC patients after platinum-based radiochemotherapy (RCTx) with TKD/IL-2 activated, autologous NK cells is clinically effective. As a mHsp70-positive tumor phenotype is associated with poor clinical outcome only mHsp70-positive tumor patients will be recruited into the trial. The primary endpoint of this study will be the comparison of the progression-free survival of patients treated with ex vivo activated NK cells compared to patients who were treated with RCTx alone. As secondary endpoints overall survival, toxicity, quality-of-life, and biological responses will be determined in both study groups. PMID- 25926833 TI - Autoantibodies in systemic sclerosis: unanswered questions. AB - Systemic sclerosis (SSc) is an autoimmune disease characterized by vascular abnormalities, and cutaneous and visceral fibrosis. Serum autoantibodies directed to multiple intracellular antigens are present in more than 95% of patients and are considered a hallmark of SSc. They are helpful biomarkers for the early diagnosis of SSc and are associated with distinctive clinical manifestations. With the advent of more sensitive, multiplexed immunoassays, new and old questions about the relevance of autoantibodies in SSc are emerging. In this review, we discuss the clinical relevance of autoantibodies in SSc emphasizing the more recently published data. Moreover, we will summarize recent advances regarding the stability of SSc autoantibodies over the course of disease, whether they are mutually exclusive and their potential roles in the disease pathogenesis. PMID- 25926834 TI - Cancer microenvironment and inflammation: role of hyaluronan. AB - The role of inflammation in the development of cancer was described as early as the nineteenth century. Abundant evidence supports the preposition that various cancers are triggered by infection and chronic inflammatory disease whereas, evading immune destruction has been proposed as one of the new "hallmarks of cancer." Changes of the tumor microenvironment have been closely correlated to cancer-mediated inflammation. Hyaluronan (HA), an important extracellular matrices component, has become recognized as an active participant in inflammatory, angiogenic, fibrotic, and cancer promoting processes. This review discusses how HA and specific HA-binding proteins participate in and regulate cancer-related inflammatory processes. PMID- 25926835 TI - Human and Mouse CD8(+)CD25(+)FOXP3(+) Regulatory T Cells at Steady State and during Interleukin-2 Therapy. AB - In addition to CD4(+) regulatory T cells (Tregs), CD8(+) suppressor T cells are emerging as an important subset of regulatory T cells. Diverse populations of CD8(+) T cells with suppressive activities have been described. Among them, a small population of CD8(+)CD25(+)FOXP3(+) T cells is found both in mice and humans. In contrast to thymic-derived CD4(+)CD25(+)FOXP3(+) Tregs, their origin and their role in the pathophysiology of autoimmune diseases (AIDs) are less understood. We report here the number, phenotype, and function of CD8(+) Tregs cells in mice and humans, at the steady state and in response to low-dose interleukin-2 (IL-2). CD8(+) Tregs represent approximately 0.4 and 0.1% of peripheral blood T cells in healthy humans and mice, respectively. In mice, their frequencies are quite similar in lymph nodes (LNs) and the spleen, but two to threefold higher in Peyer patches and mesenteric LNs. CD8(+) Tregs express low levels of CD127. CD8(+) Tregs express more activation or proliferation markers such as CTLA-4, ICOS, and Ki-67 than other CD8(+) T cells. In vitro, they suppress effector T cell proliferation as well as or even better than CD4(+) Tregs. Owing to constitutive expression of CD25, CD8(+) Tregs are 20- to 40-fold more sensitive to in vitro IL-2 stimulation than CD8(+) effector T cells, but 2-4 times less than CD4(+) Tregs. Nevertheless, low-dose IL-2 dramatically expands and activates CD8(+) Tregs even more than CD4(+) Tregs, in mice and humans. Further studies are warranted to fully appreciate the clinical relevance of CD8(+) Tregs in AIDs and the efficacy of IL-2 treatment. PMID- 25926837 TI - Cold tolerance triggered by soluble sugars: a multifaceted countermeasure. PMID- 25926836 TI - Long Intergenic Non-Coding RNAs: Novel Drivers of Human Lymphocyte Differentiation. AB - Upon recognition of a foreign antigen, CD4(+) naive T lymphocytes proliferate and differentiate into subsets with distinct functions. This process is fundamental for the effective immune system function, as CD4(+) T cells orchestrate both the innate and adaptive immune response. Traditionally, this differentiation event has been regarded as the acquisition of an irreversible cell fate so that memory and effector CD4(+) T subsets were considered terminally differentiated cells or lineages. Consequently, these lineages are conventionally defined thanks to their prototypical set of cytokines and transcription factors. However, recent findings suggest that CD4(+) T lymphocytes possess a remarkable phenotypic plasticity, as they can often re-direct their functional program depending on the milieu they encounter. Therefore, new questions are now compelling such as which are the molecular determinants underlying plasticity and stability and how the balance between these two opposite forces drives the cell fate. As already mentioned, in some cases, the mere expression of cytokines and master regulators could not fully explain lymphocytes plasticity. We should consider other layers of regulation, including epigenetic factors such as the modulation of chromatin state or the transcription of non-coding RNAs, whose high cell-specificity give a hint on their involvement in cell fate determination. In this review, we will focus on the recent advances in understanding CD4(+) T lymphocytes subsets specification from an epigenetic point of view. In particular, we will emphasize the emerging importance of non-coding RNAs as key players in these differentiation events. We will also present here new data from our laboratory highlighting the contribution of long non-coding RNAs in driving human CD4(+) T lymphocytes differentiation. PMID- 25926838 TI - Advances in plant proteomics toward improvement of crop productivity and stress resistancex. AB - Abiotic and biotic stresses constrain plant growth and development negatively impacting crop production. Plants have developed stress-specific adaptations as well as simultaneous responses to a combination of various abiotic stresses with pathogen infection. The efficiency of stress-induced adaptive responses is dependent on activation of molecular signaling pathways and intracellular networks by modulating expression, or abundance, and/or post-translational modification (PTM) of proteins primarily associated with defense mechanisms. In this review, we summarize and evaluate the contribution of proteomic studies to our understanding of stress response mechanisms in different plant organs and tissues. Advanced quantitative proteomic techniques have improved the coverage of total proteomes and sub-proteomes from small amounts of starting material, and characterized PTMs as well as protein-protein interactions at the cellular level, providing detailed information on organ- and tissue-specific regulatory mechanisms responding to a variety of individual stresses or stress combinations during plant life cycle. In particular, we address the tissue-specific signaling networks localized to various organelles that participate in stress-related physiological plasticity and adaptive mechanisms, such as photosynthetic efficiency, symbiotic nitrogen fixation, plant growth, tolerance and common responses to environmental stresses. We also provide an update on the progress of proteomics with major crop species and discuss the current challenges and limitations inherent to proteomics techniques and data interpretation for non model organisms. Future directions in proteomics research toward crop improvement are further discussed. PMID- 25926840 TI - Two-dimensional phos-tag zymograms for tracing phosphoproteins by activity in-gel staining. AB - Protein phosphorylation is one of the most common post-translational modifications regulating many cellular processes. The phos-tag technology was combined with two-dimensional zymograms, which consisted of non-reducing IEF PAGE or NEPHGE in the first dimension and high resolution clear native electrophoresis (hrCNE) in the second dimension. The combination of these electrophoresis methods was mild enough to accomplish in-gel activity staining for Fe(III)-reductases by NADH/Fe(III)-citrate/ferrozine, 3,3'-Diaminobenzidine/H2O2 or TMB/H2O2 in the second dimension. The phos-tag zymograms can be used to investigate phosphorylation-dependent changes in enzyme activity. Phos-tag zymograms can be combined with further downstream analysis like mass spectrometry. Non-reducing IEF will resolve proteins with a pI of 3-10, whereas non-reducing NEPHGE finds application for alkaline proteins with a pI higher than eight. Advantages and disadvantages of these new methods will be discussed in detail. PMID- 25926841 TI - Characterization of a stearoyl-acyl carrier protein desaturase gene family from chocolate tree, Theobroma cacao L. AB - In plants, the conversion of stearoyl-ACP to oleoyol-ACP is catalyzed by a plastid-localized soluble stearoyl-acyl carrier protein (ACP) desaturase (SAD). The activity of SAD significantly impacts the ratio of saturated and unsaturated fatty acids, and is thus a major determinant of fatty acid composition. The cacao genome contains eight putative SAD isoforms with high amino acid sequence similarities and functional domain conservation with SAD genes from other species. Sequence variation in known functional domains between different SAD family members suggested that these eight SAD isoforms might have distinct functions in plant development, a hypothesis supported by their diverse expression patterns in various cacao tissues. Notably, TcSAD1 is universally expressed across all the tissues, and its expression pattern in seeds is highly correlated with the dramatic change in fatty acid composition during seed maturation. Interestingly, TcSAD3 and TcSAD4 appear to be exclusively and highly expressed in flowers, functions of which remain unknown. To test the function of TcSAD1 in vivo, transgenic complementation of the Arabidopsis ssi2 mutant was performed, demonstrating that TcSAD1 successfully rescued all AtSSI2 related phenotypes further supporting the functional orthology between these two genes. The identification of the major SAD gene responsible for cocoa butter biosynthesis provides new strategies for screening for novel genotypes with desirable fatty acid compositions, and for use in breeding programs to help pyramid genes for quality and other traits such as disease resistance. PMID- 25926839 TI - Strategies of seedlings to overcome their sessile nature: auxin in mobility control. AB - Plants are sessile organisms that are permanently restricted to their site of germination. To compensate for their lack of mobility, plants evolved unique mechanisms enabling them to rapidly react to ever changing environmental conditions and flexibly adapt their postembryonic developmental program. A prominent demonstration of this developmental plasticity is their ability to bend organs in order to reach the position most optimal for growth and utilization of light, nutrients, and other resources. Shortly after germination, dicotyledonous seedlings form a bended structure, the so-called apical hook, to protect the delicate shoot meristem and cotyledons from damage when penetrating through the soil. Upon perception of a light stimulus, the apical hook rapidly opens and the photomorphogenic developmental program is activated. After germination, plant organs are able to align their growth with the light source and adopt the most favorable orientation through bending, in a process named phototropism. On the other hand, when roots and shoots are diverted from their upright orientation, they immediately detect a change in the gravity vector and bend to maintain a vertical growth direction. Noteworthy, despite the diversity of external stimuli perceived by different plant organs, all plant tropic movements share a common mechanistic basis: differential cell growth. In our review, we will discuss the molecular principles underlying various tropic responses with the focus on mechanisms mediating the perception of external signals, transduction cascades and downstream responses that regulate differential cell growth and consequently, organ bending. In particular, we highlight common and specific features of regulatory pathways in control of the bending of organs and a role for the plant hormone auxin as a key regulatory component. PMID- 25926842 TI - Molecular phenotypes associated with anomalous stamen development in Alternanthera philoxeroides. AB - Alternanthera philoxeroides is a perennial amphibious weed native to South America but has now spread to diverse parts of the world. A. philoxeroides reproduces both sexually and asexually in its native range, but propagates solely through vegetative means in its introduced range. Traits associated with sexual reproduction become degraded for sexual dysfunction, with flowers possessing either pistillate stamens or male-sterile anthers. Degradations of sexual characters for loss of sexuality commonly take place in clonal plants. The underlying molecular-genetic processes remain largely unknown. We compared the gene expression profiles of abnormal stamens with that of normal stamens by RNA Seq analysis, and identified a large number of differentially expressed genes between abnormal and normal stamens. In accordance with flower morphology, the expression of B-class MADS-box genes (ApAP3, ApTM6, and ApPI) was markedly reduced in pistillate stamens. However, most of the genes involved in meiosis were expressed normally in stamens with male-sterile anthers. In addition to verifying the expression patterns of genes previously known to be related to stamen and pollen grain development, we also identified previously unknown molecular phenotypes associated with sexual dysfunction in A. philoxeroides, that is helpful for dissecting the molecular mechanisms underpinning various male sterile phenotypes and the molecular processes underlying the transition from sexuality to asexuality in clonal plants. PMID- 25926845 TI - Anti-aging dilemma: to restore the hardware or to reinstall the software? PMID- 25926843 TI - Recent progress in the use of 'omics technologies in brassicaceous vegetables. AB - Continuing advances in 'omics methodologies and instrumentation is enhancing the understanding of how plants cope with the dynamic nature of their growing environment. 'Omics platforms have been only recently extended to cover horticultural crop species. Many of the most widely cultivated vegetable crops belong to the genus Brassica: these include plants grown for their root (turnip, rutabaga/swede), their swollen stem base (kohlrabi), their leaves (cabbage, kale, pak choi) and their inflorescence (cauliflower, broccoli). Characterization at the genome, transcript, protein and metabolite levels has illustrated the complexity of the cellular response to a whole series of environmental stresses, including nutrient deficiency, pathogen attack, heavy metal toxicity, cold acclimation, and excessive and sub-optimal irradiation. This review covers recent applications of 'omics technologies to the brassicaceous vegetables, and discusses future scenarios in achieving improvements in crop end-use quality. PMID- 25926846 TI - Continental scale patterns and predictors of fern richness and phylogenetic diversity. AB - Because ferns have a wide range of habitat preferences and are widely distributed, they are an ideal group for understanding how diversity is distributed. Here we examine fern diversity on a broad-scale using standard and corrected richness measures as well as phylogenetic indices; in addition we determine the environmental predictors of each diversity metric. Using the combined records of Australian herbaria, a dataset of over 60,000 records was obtained for 89 genera to infer richness. A molecular phylogeny of all the genera was constructed and combined with the herbarium records to obtain phylogenetic diversity patterns. A hotspot of both taxic and phylogenetic diversity occurs in the Wet Tropics of northeastern Australia. Although considerable diversity is distributed along the eastern coast, some important regions of diversity are identified only after sample-standardization of richness and through the phylogenetic metric. Of all of the metrics, annual precipitation was identified as the most explanatory variable, in part, in agreement with global and regional fern studies. However, precipitation was combined with a different variable for each different metric. For corrected richness, precipitation was combined with temperature seasonality, while correlation of phylogenetic diversity to precipitation plus radiation indicated support for the species-energy hypothesis. Significantly high and significantly low phylogenetic diversity were found in geographically separate areas. These separate areas correlated with different climatic conditions such as seasonality in precipitation. The phylogenetic metrics identified additional areas of significant diversity, some of which have not been revealed using traditional taxonomic analyses, suggesting that different ecological and evolutionary processes have operated over the continent. Our study demonstrates that it is possible and vital to incorporate evolutionary metrics when inferring biodiversity hotspots from large compilations of data. PMID- 25926844 TI - Age-related vascular stiffening: causes and consequences. AB - Arterial stiffening occurs with age and is closely associated with the progression of cardiovascular disease. Stiffening is most often studied at the level of the whole vessel because increased stiffness of the large arteries can impose increased strain on the heart leading to heart failure. Interestingly, however, recent evidence suggests that the impact of increased vessel stiffening extends beyond the tissue scale and can also have deleterious microscale effects on cellular function. Altered extracellular matrix (ECM) architecture has been recognized as a key component of the pre-atherogenic state. Here, the underlying causes of age-related vessel stiffening are discussed, focusing on age-related crosslinking of the ECM proteins as well as through increased matrix deposition. Methods to measure vessel stiffening at both the macro- and microscale are described, spanning from the pulse wave velocity measurements performed clinically to microscale measurements performed largely in research laboratories. Additionally, recent work investigating how arterial stiffness and the changes in the ECM associated with stiffening contributed to endothelial dysfunction will be reviewed. We will highlight how changes in ECM protein composition contribute to atherosclerosis in the vessel wall. Lastly, we will discuss very recent work that demonstrates endothelial cells (ECs) are mechano-sensitive to arterial stiffening, where changes in stiffness can directly impact EC health. Overall, recent studies suggest that stiffening is an important clinical target not only because of potential deleterious effects on the heart but also because it promotes cellular level dysfunction in the vessel wall, contributing to a pathological atherosclerotic state. PMID- 25926847 TI - Hybrid incompatibilities are affected by dominance and dosage in the haplodiploid wasp Nasonia. AB - Study of genome incompatibilities in species hybrids is important for understanding the genetic basis of reproductive isolation and speciation. According to Haldane's rule hybridization affects the heterogametic sex more than the homogametic sex. Several theories have been proposed that attribute asymmetry in hybridization effects to either phenotype (sex) or genotype (heterogamety). Here we investigate the genetic basis of hybrid genome incompatibility in the haplodiploid wasp Nasonia using the powerful features of haploid males and sex reversal. We separately investigate the effects of heterozygosity (ploidy level) and sex by generating sex reversed diploid hybrid males and comparing them to genotypically similar haploid hybrid males and diploid hybrid females. Hybrid effects of sterility were more pronounced than of inviability, and were particularly strong in haploid males, but weak to absent in diploid males and females, indicating a strong ploidy level but no sex specific effect. Molecular markers identified a number of genomic regions associated with hybrid inviability in haploid males that disappeared under diploidy in both hybrid males and females. Hybrid inviability was rescued by dominance effects at some genomic regions, but aggravated or alleviated by dosage effects at other regions, consistent with cytonuclear incompatibilities. Dosage effects underlying Bateson Dobzhansky-Muller (BDM) incompatibilities need more consideration in explaining Haldane's rule in diploid systems. PMID- 25926848 TI - The interplay between DNA damage response and RNA processing: the unexpected role of splicing factors as gatekeepers of genome stability. AB - Genome integrity is constantly threatened by endogenous and exogenous factors. However, its preservation is ensured by a network of pathways that prevent and/or repair the lesion, which constitute the DNA damage response (DDR). Expression of the key proteins involved in the DDR is controlled by numerous post transcriptional mechanisms, among which pre-mRNA splicing stands out. Intriguingly, several splicing factors (SFs) have been recently shown to play direct functions in DNA damage prevention and repair, which go beyond their expected splicing activity. At the same time, evidence is emerging that DNA repair proteins (DRPs) can actively sustain the DDR by acting as post transcriptional regulator of gene expression, in addition to their well-known role in the mechanisms of signaling and repair of the lesion. Herein, we will review these non-canonical functions of both SFs and DRPs, which suggest the existence of a tight interplay between splicing regulation and canonical DNA safeguard mechanisms ensuring genome stability. PMID- 25926849 TI - Telomeric repeat-containing RNA TERRA: a noncoding RNA connecting telomere biology to genome integrity. AB - Telomeres are dynamic nucleoprotein structures that protect the ends of chromosomes from degradation and activation of DNA damage response. For this reason, telomeres are essential to genome integrity. Chromosome ends are enriched in heterochromatic marks and proper organization of telomeric chromatin is important to telomere stability. Despite their heterochromatic state, telomeres are transcribed giving rise to long noncoding RNAs (lncRNA) called TERRA (telomeric repeat-containing RNA). TERRA molecules play critical roles in telomere biology, including regulation of telomerase activity and heterochromatin formation at chromosome ends. Emerging evidence indicate that TERRA transcripts form DNA-RNA hybrids at chromosome ends which can promote homologous recombination among telomeres, delaying cellular senescence and sustaining genome instability. Intriguingly, TERRA RNA-telomeric DNA hybrids are involved in telomere length homeostasis of telomerase-negative cancer cells. Furthermore, TERRA transcripts play a role in the DNA damage response (DDR) triggered by dysfunctional telomeres. We discuss here recent developments on TERRA's role in telomere biology and genome integrity, and its implication in cancer. PMID- 25926850 TI - Gene function in schistosomes: recent advances toward a cure. PMID- 25926851 TI - Acromegaly with cardiomyopathy, cardiac thrombus and hemorrhagic cerebral infarct: a case report of therapeutic dilemma with review of literature. AB - INTRODUCTION: Cardiomyopathy with congestive heart failure (CHF) is a rare complication of growth hormone (GH)-secreting pituitary adenoma occurring in 3% of cases. We report a case of acromegaly complicated not only by CHF but also by the presence of intracardiac thrombus and cardioembolic stroke with hemorrhagic formation. CASE PRESENTATION: A 46-year-old Filipino female presented with amenorrhea, progressive coarsening of facial features, deepening of voice and enlargement of digits. She experienced easy fatigability, orthopnea and bipedal edema. The cardiac apex beat was sustained and displaced. Growth hormone was nonsuppressible. Cranial magnetic resonance imaging showed pituitary macroadenoma with hemorrhage. Incidentally, there was a left frontal lobe cortical infarct with hemorrhagic component. The echocardiogram demonstrated cardiomyopathic changes with a left ventricular thrombus. CONCLUSIONS: The primary treatment for GH-producing adenoma is surgery; however, this patient has high surgical risk from her severe cardiomyopathy. Radiotherapy poses a greater risk because of increased cerebrovascular mortality. Somatostatin receptor ligands are significantly associated with improvement of cardiovascular and hemodynamic parameters. Dopamine agonists must be considered regardless of prolactin level and immunostaining. The risks and benefits of any treatment must be emphasized in the presence of conflicting clinical features such as in the case reported. PMID- 25926852 TI - Prevalence of lipohypertrophy and associated risk factors in insulin-treated patients with type 2 diabetes mellitus. AB - BACKGROUND: Secondary failure of oral hypoglycemic agents is common in patients with type 2 diabetes mellitus (T2DM); thus, patients often need insulin therapy. The most common complication of insulin treatment is lipohypertrophy (LH). OBJECTIVES: This study was conducted to estimate the prevalence of LH among insulin-treated patients with Patients with T2DM, to identify the risk factors for the development of LH, and to examine the association between LH and glycemic control. PATIENTS AND METHODS: A total of 1090 patients with T2DM aged 20 to 89 years, who attended the diabetes clinics at the National Center for Diabetes, Endocrinology, and Genetics (NCDEG, Amman, Jordan) between October 2011 and January 2012, were enrolled. The presence of LH was examined by inspection and palpation of insulin injection sites at the time of the visit as relevant clinical and laboratory data were obtained. The LH was defined as a local tumor like swelling of subcutaneous fatty tissue at the site of repeated insulin injections. RESULTS: The overall prevalence of LH was 37.3% (27.4% grade 1, 9.7% grade 2, and 0.2% grade 3). The LH was significantly associated with the duration of diabetes, needle length, duration of insulin therapy, lack of systematic rotation of insulin injection sites, and poor glycemic control. CONCLUSIONS: The LH is a common problem in insulin-treated Jordanian patients with T2DM. More efforts are needed to educate patients and health workers on simple interventions such as using shorter needles and frequent rotation of the insulin injection sites to avoid LH and improve glycemic control. PMID- 25926853 TI - Cost-benefit analysis of internet therapeutic intervention on patients with diabetes. AB - BACKGROUND: With the emergence of IBGMS for allowing for patients to communicate their self-monitored blood glucose (SMBG) readings with their health care providers, their impact on the management of diabetes is becoming well-supported with regards to clinical benefits. Their impact on healthcare costs, however, has yet to be investigated. This study aims to determine the cost-benefits of such interventions in comparison to routine care. OBJECTIVES: To analyze the cost benefit of an Internet Blood Glucose Monitoring Service (IBGMS) in comparison to routine diabetes care. PATIENTS AND METHODS: 200 patients were surveyed to assess the cost associated with doctor appointments in the past 12 months. Annual number of visits to medical services for diabetes and costs of transportation, parking, and time taken off work for visits were surveyed. Self-reported frequency of SMBG and most recent A1C were also surveyed. We compared 100 patients who used the IBGMS with 100 patients who only used routine care. RESULTS: There is a trend of lowered total cost in the intervention group compared to the control group. The control group spent $210.89 per year on visits to physicians; the intervention group spent $131.26 (P = 0.128). Patients in control group visited their endocrinologist 1.76 times per year, those in intervention group visited their endocrinologist 1.36 times per year, significantly less frequently than the control group (P = 0.014). Number of visits to other medical services is similar between the groups. Average A1C in intervention group is 7.57%, in control group is 7.69% (P = 0.309). CONCLUSIONS: We have demonstrated that IBGMS, while not reaching statistical significance, may be associated with slightly reduced A1C and cost due to visiting physicians. PMID- 25926854 TI - In vivo and in vitro evidences of dehydroepiandrosterone protective role on the cardiovascular system. AB - CONTEXT: Dehydroepiandrosterone (DHEA) and its sulfate ester, Dehydroepiandrosterone Sulfate (DHEA-S) have been considered as putative anti aging hormones for many years. Indeed, while DHEAS is the most abundant circulating hormone, its concentration is markedly decreased upon aging and early epidemiologic trials have revealed a strong inverse correlation between the hormone concentrations and the occurrence of several dysfunctions frequently encountered in the elderly. Naturally, hormonal supplementation has been rapidly suggested to prevent DHEA (S) deficiency and therefore, age-related development of these pathologies, using the same strategy as estrogen replacement therapy proposed in postmenopausal women. EVIDENCE ACQUISITION: All references were searched using PubMed and the following strategy: our initial selection included all articles in English and we sorted them with the following keywords: "DHEA or DHEA-S" and "heart or vascular or endothelium or cardiovascular disease". The search was limited to neither the publication date nor specific journals. The final selection was made according to the relevance of the article content with the aims of the review. According to these criteria, fewer than 10% of the articles retrieved at the first step were discarded. RESULTS: In this short review, we have focused on the cardiovascular action of DHEA. We started by analyzing evidences in favor of a strong inverse association between DHEA (S) levels and the cardiovascular risk as demonstrated in multiple observational epidemiologic studies for several decades. Then we discussed the different trials aimed at supplementing DHEA (S), both in animals and human, for preventing cardiovascular diseases and we analyzed the possible reasons for the discrepancy observed among the results of some studies. Finally, we presented putative molecular mechanisms of action for DHEA (S), demonstrated in vitro in different models of vascular and cardiac cells, highlighting the complexity of the involved signaling pathways. CONCLUSIONS: The identification of the beneficial cardiovascular effects of DHEA (S) and a better understanding of the involved mechanisms should be helpful to develop new strategies or pharmacologic approaches for many lethal diseases in Western countries. PMID- 25926855 TI - An application of association rule mining to extract risk pattern for type 2 diabetes using tehran lipid and glucose study database. AB - BACKGROUND: Type 2 diabetes, common and serious global health concern, had an estimated worldwide prevalence of 366 million in 2011, which is expected to rise to 552 million people, by 2030, unless urgent action is taken. OBJECTIVES: The aim of this study was to identify risk patterns for type 2 diabetes incidence using association rule mining (ARM). PATIENTS AND METHODS: A population of 6647 individuals without diabetes, aged >= 20 years at inclusion, was followed for 10 12 years, to analyze risk patterns for diabetes occurrence. Study variables included demographic and anthropometric characteristics, smoking status, medical and drug history and laboratory measures. RESULTS: In the case of women, the results showed that impaired fasting glucose (IFG) and impaired glucose tolerance (IGT), in combination with body mass index (BMI) >= 30 kg/m(2), family history of diabetes, wrist circumference > 16.5 cm and waist to height >= 0.5 can increase the risk for developing diabetes. For men, a combination of IGT, IFG, length of stay in the city (> 40 years), central obesity, total cholesterol to high density lipoprotein ratio >= 5.3, low physical activity, chronic kidney disease and wrist circumference > 18.5 cm were identified as risk patterns for diabetes occurrence. CONCLUSIONS: Our study showed that ARM is a useful approach in determining which combinations of variables or predictors occur together frequently, in people who will develop diabetes. The ARM focuses on joint exposure to different combinations of risk factors, and not the predictors alone. PMID- 25926856 TI - Beneficial effect of troxerutin on diabetes-induced vascular damages in rat aorta: histopathological alterations and antioxidation mechanism. AB - BACKGROUND: Diabetes is associated with micro- and macro-vascular complications affecting several organs. Oxidative stress plays a crucial role in the etiology of vascular disease in diabetes. OBJECTIVES: The present study aimed to investigate the beneficial effect of troxerutin on diabetes-induced histopathological damages in rat aorta with focusing on its antioxidative actions. MATERIALS AND METHODS: Male Wistar rats were randomly divided into four groups (n = 8/each): control, control plus troxerutin, diabetic and diabetic plus troxerutin. Diabetes was induced in rats by a single intraperitoneal injection of streptozotocin (50 mg/kg) and lasted for 10 weeks. Troxerutin was administered orally in concentration of 150 mg/kg/daily for one month before killing rats. At the end of treatment period, thoracic aorta was isolated and divided into two parts; one part was immersed in 10% formalin for histopathological evaluations and the other was frozen by liquid nitrogen for assessment of malondialdehyde (MDA, the main product of lipid peroxidation), activity of antioxidant enzymes superoxide dismutase (SOD) and glutathione peroxidase (GPX). RESULTS: Lipid deposition in tunica intimae and media, thickening and structural deformity of vascular tissues as well as the level of plasma glucose and aortic tissue levels of lipid peroxidation were significantly increased in diabetic rats compared to control ones (P < 0.05). Troxerutin significantly reduced the severity of all vascular histopathological damages in treated versus untreated diabetic rats. In addition, treatment of diabetic rats with troxerutin significantly decreased the levels of MDA (5.1 +/- 0.3 vs. 9.3 +/- 1.2 nmol/mL) (P < 0.01) and increased the activity of antioxidant enzyme GPX compared to untreated-diabetic groups. CONCLUSIONS: Troxerutin may reduce the vascular complications and tissue injuries induced by chronic diabetes in rat aorta through increasing the activity of tissue antioxidant system and reducing the level of lipid peroxidation. PMID- 25926857 TI - The development of drug resistance mutations K103N Y181C and G190A in long term Nevirapine-containing antiviral therapy. AB - OBJECTIVE: We built a cohort study of HIV patients taking long-term first-line Antiretroviral Therapy in 2003. In this assay, we focused on the development of primary drug resistance mutations against Non-Nucleoside Reverse Transcriptase Inhibitor (NNRTI), K103N, Y181C and G190A. METHOD: The cohort study was built in Henan province, China. We used Single Genome Amplification (SGA) to analyze the frequency of K103N, Y181C and G190A in serial plasma samples of three individual patients. We also performed standard genotype HIV drug resistance assay in 204 patients of this cohort study to analyze the frequency of these mutations. RESULT: In the SGA sequences, the K103N decreased and vanished, while the frequency of Y181C and G190A increased in individual patient receiving long-term Antiretroviral Therapy (ART). In the sequences of standard genotype HIV drug resistance assay, the frequency of K103N, Y181C and G190A had the similar pattern with that in SGA sequences. Among these patients, the viral suppression were still sufficient after receiving ART for 72 months, and 78.6% (160/204) patients could have their CD4 count over than 200cells/ul. CONCLUSION: In some patients, first-line ART had the possibility to provide sufficient treatment effect for over than 72 months, but in long-term treatment, the dominant NNRTI drug resistance mutation K103N could reduced, while the proportion of variants with mutation Y181C or G190A may increased. This result was not similar with that in vitro study, which state that variant with K103N or Y181C had an equal viral fitness with wild type. PMID- 25926858 TI - Cobicistat-boosted darunavir in HIV-1-infected adults: week 48 results of a Phase IIIb, open-label single-arm trial. AB - BACKGROUND: Cobicistat is an alternative pharmacoenhancer to ritonavir. In healthy volunteers, darunavir exposure was comparable when darunavir 800 mg once daily was co-administered with cobicistat 150 mg once daily (as single agents or a fixed-dose combination) vs. with ritonavir 100 mg once daily. METHODS: This 48 week, Phase IIIb, single-arm, US multicenter study (NCT01440569) evaluated safety, efficacy and pharmacokinetics of darunavir/cobicistat 800/150 mg once daily (as single agents) plus two investigator-selected nucleoside/tide reverse transcriptase inhibitors (N[t]RTIs) in HIV-1-infected adults. Patients had no darunavir resistance-associated mutations (RAMs), plasma viral load (VL) >=1000 HIV-1 RNA copies/ml, eGFR >=80 ml/min and genotypic sensitivity to the two N[t]RTIs. The primary endpoint was any treatment-emergent grade 3 or 4 adverse events (AEs) through Week 24. RESULTS: The majority of the 313 intent-to-treat patients were treatment-naive (295/313; 94%), male (89%), White (60%) and received a tenofovir-based regimen (99%). Median baseline VL and CD4(+) count overall were 4.8 log10 HIV-1 RNA copies/ml and 361 cells/mm(3), respectively. Overall, 86% of patients (268/313) completed the study. The majority of discontinuations were for AEs (15/313; 5%). The incidence of treatment-emergent grade 3 or 4 AEs regardless of causality was 6% through Week 24 and 8% through Week 48. Most common AEs through Week 48 were diarrhea (27%) and nausea (23%), which were grade 1 or 2 in severity. Week 48 virologic response rates (% with VL <50 HIV-1 RNA copies/ml; Snapshot analysis) were 81% overall and 83% in treatment naive patients; median increases in CD4(+) count at 48 weeks were 167 and 169 cells/mm(3), respectively. Of 15/313 patients who met the criteria for resistance analysis, one developed a darunavir RAM as a mixture with wild-type (I84I/V), without phenotypic resistance to darunavir. The mean population pharmacokinetic derived darunavir areas under the plasma concentration-time curve were 102,000 overall and 100,620 ng*h/ml in treatment-naive patients. No clinically relevant relationships were seen between darunavir exposure and virologic response, AEs or laboratory parameters. CONCLUSION: Darunavir/cobicistat 800/150 mg once daily was generally well tolerated through Week 48, with no new safety concerns. Pharmacokinetics, virologic and immunologic responses for darunavir/cobicistat were similar to previous data for darunavir/ritonavir 800/100 mg once daily. PMID- 25926859 TI - Inflammation rapidly modulates the expression of ALDH1A1 (RALDH1) and vimentin in the liver and hepatic macrophages of rats in vivo. AB - BACKGROUND: Members of the ALDH1 protein family, known as retinal dehydrogenases (RALDH), produce retinoic acid (RA), a metabolite of vitamin A, and may also oxidize other lipid aldehydes. Of three related ALDH1 genes, ALDH1A1 is most highly expressed in liver. ALDH1A1 is also rapidly gaining importance as a stem cell marker. We hypothesized that ALDH1A1 may have a broad cellular distribution in the liver, and that its expression may be regulated by RA and perturbed by inflammation. METHODS: Studies were conducted in vitamin A-deficient and adequate rats that were further treated with all-trans-RA or lipopolysaccharide (LPS) to induce a state of moderate inflammation. RALDH1A1 expression was determined by quantitative PCR and RALDH1, as well as marker gene expression, was determined by immunocytochemical methods. RESULTS: Inflammation reduced ALDH1A1 mRNA in whole liver regardless of the level of vitamin A in the diet (P < 0.05), while treatment with RA reduced ALDH1A1 expression only in chow-fed rats. ALDH1A1 protein exhibited diffuse staining in hepatocytes, with greater intensity in the periportal region including surrounding bile ducts. Six h after administration of LPS, portal region macrophages were more numerous and some of these cells contained ALDH1A1. Vimentin, which was used as a marker for stellate cells and fibroblasts, was increased by LPS, P = 0.011 vs. without LPS, in both ED1 (CD68) positive macrophages and fibroblastic stellate-like cells in the parenchyma as well as portal regions. Alpha-smooth muscle actin staining was intense around blood vessels, but did not change after LPS or RA, nor overlap with staining for vimentin. CONCLUSIONS: Acute inflammation rapidly downregulates ALDH1A1 expression in whole liver while increasing its expression in periportal macrophages. Changes in ALDH1A1 expression appear to be part of the early acute phase inflammatory response, which has been shown to alter the expression of other retinoid homeostatic genes. In addition, the rapid strong response of vimentin expression after treatment with LPS suggests that increased vimentin may be a useful marker of early hepatic inflammation. PMID- 25926860 TI - High-cholesterol diet enriched with onion affects endothelium-dependent relaxation and NADPH oxidase activity in mesenteric microvessels from Wistar rats. AB - BACKGROUND: The aim of the present study was to examine the effects of onion as functional ingredient on the oxidative status, lipoprotein levels (total cholesterol-TC, HDL-C, LDL-C), triacylglycerides (TAG) and vascular reactivity of mesenteric arteries in hypercholesterolemic Wistar rats. METHODS: Twenty-four animals were fed with three different diets [control, high-cholesterol diet (HC) and high-cholesterol enriched with onion diet (HCO)]. After seven weeks of experimental feeding the rats were euthanized for blood and tissues collection. TC, HDL-C, LDL-C and TAG were measured, and 2,2'-azinobis-(3-ethylbenzothiazoline 6-sulfonic acid) radical cation (ABTS(*+)) scavenging capacity and ferric reducing antioxidant power (FRAP) were determined in plasma. Superoxide dismutase (SOD) and glutathione peroxidase (GPx) enzyme activities were assayed in erythrocyte lysates. Endothelium-dependent vasodilation to acetylcholine was evaluated in mesenteric arterial segments. NADPH oxidase (NOX) was also measured by lucigenin-derived chemiluminiscence. RESULTS: The dietary cholesterol content significantly affected plasma lipoprotein levels, increased superoxide generation from NOX, and caused impaired endothelium-dependent vasodilation in the rat mesenteric arteries. Onion ingredient improved antioxidant status in HCO group, as it was evidenced by ABTS(*+) and FRAP values and SOD and GPx enzyme activities compared to the HC-fed group, reduced the increment in NOX activity and reversed endothelial dysfunction promoted by the HC diet. Scavenging of superoxide with TEMPOL or inhibition of NOX with apocynin improved endothelium-dependent vasodilation only in HC-fed rats. CONCLUSIONS: Enrichment of diet with onion as functional ingredient could be proposed as a complementary approach to prevent or partially modulate vascular dysfunction, reducing some of the risk indexes linked to initial development of atherosclerosis. PMID- 25926861 TI - AFLPsim: an R package to simulate and detect dominant markers under selection in hybridizing populations. AB - BACKGROUND: In spite of a large diversity of approaches to investigate loci under selection from a population genetic perspective, very few programs have been specifically designed to date to test selection in hybrids using dominant markers. In addition, simulators of dominant markers are very scarce and they do not usually take into account hybridization. RESULTS: Here, we present a new, multifunctional, R package for dominant genetic markers, AFLPsim. This package can simulate dominant markers in hybridizing populations and implements genome scan methods for detecting outlier dominant loci in hybrids. In addition, it includes tools for further manipulating the results, plotting them and other tasks. We describe and tabulate the major functions implemented in AFLPsim. In addition, we provide some demonstration of its use and we perform a comparative study with other software. Finally, we conclude by briefly describing the input and output formats. CONCLUSIONS: The R package AFLPsim application provides several useful tools in the context of hybridization studies. It can simulate dominant markers in hybridizing populations and predict their demographic evolution. In addition, we implement a new genome scan method for detecting outlier dominant loci in hybrids, which shows a rather high sensitivity and is very conservative in comparison with Gagnaire et al.'s, Bayescan and introgress. The application is downloadable at http://cran.r project.org/web/packages/AFLPsim/. PMID- 25926862 TI - Increased of serum high-mobility group box chromosomal protein 1 correlated with intestinal mucosal barrier injury in patients with severe acute pancreatitis. AB - BACKGROUND: Secondary infections are the leading cause of death in patients with severe acute pancreatitis (SAP). The gut represents the main source of pancreatic contamination and related septic complications. High-mobility group box chromosomal protein 1 (HMGB1) was recently identified to play an important role in the SAP intestinal mucosal barrier dysfunction. OBJECTIVE: To investigate the correlation of high-mobility group box 1 (HMGB1) with intestinal barrier injury and infections in patients with severe acute pancreatitis (SAP). METHODS: The serum levels of HMGB1, amylase, lipase, and biochemical indicators were measured in 80 patients with SAP at the time of admission. Furthermore, relationship between their serum HMGB1 levels and intestinal barrier injury, infection and other clinical factors were analyzed. RESULTS: The mean value of serum HMGB1 levels was significantly higher in patients with SAP (6.02 +/- 2.42 ng/mL) than that in healthy volunteers (1.87 +/- 0.63 ng/mL). Serum HMGB1 levels were significantly positively correlated with the Ranson score. The HMGB1 levels were higher in patients with infection during the clinical course, the HMGB1 levels in non-survivors were higher than those in survivors, and positively correlated with DAO activity, L/M ratio, the concentration of endotoxin (R = 0.484, P <0.01). CONCLUSIONS: HMGBl level of patients with severe acute pancreatitis was significantly increased, and can be used as an important indicator to determine the intestinal barrier dysfunction and infection. PMID- 25926863 TI - Detection of MMTV-Like sequences in Moroccan breast cancer cases. AB - INTRODUCTION: The mouse mammary tumor virus (MMTV) like sequences have been reported to be present in some human breast cancers, but their association with breast cancer development is still controversial. METHODS: In this retrospective study, we investigated the status of MMTV-like in 42 tumor biopsies and 18 paired normal tissues from Moroccan patients with breast cancer. MMTV-like env sequences were identified by PCR and confirmed by direct DNA sequencing. RESULTS: Specific MMTV-like env sequences were found in 24 (57.14%) cases of breast carcinomas, and 6 (33.3%) cases of matched normal breast tissues. Comparison to sociologic and clinicopathological parameters showed no significant association between the presence of MMTV-like sequences and age, menopausal status, histological subtype, histological grade, tumor size and the expression of hormone receptors (estrogen ER and/or progesterone PgR) and Her 2. However, a significant correlation was found between MMTV-like presence and parity (p = 0.024). CONCLUSIONS: This present study confirms the presence of MMTV-like env sequences in breast cancer in Moroccan women, prompting further evaluation, on large sampling, to elucidate the probable causal roles of MMTV-like in breast cancer development. PMID- 25926864 TI - Prevalence and risk factors for High-Risk Human Papillomavirus (hrHPV) infection among HIV-infected and Uninfected Rwandan women: implications for hrHPV-based screening in Rwanda. AB - BACKGROUND: New World Health Organization guidelines recommend high-risk human papillomavirus (hrHPV) screen-and-treat strategies for cervical cancer prevention. We describe risk of, and risk factors for, testing hrHPV positive in a pilot study of hrHPV screen-and-treat conducted in Rwanda. METHODS: A total of 2,964 women, 1,289 HIV-infected (HIV [+]) and 1,675 HIV-uninfected (HIV [-]), aged 30-60 years and living in Rwanda were enrolled in 2010. Cervical specimens were collected and tested by careHPV, a DNA test for a pool of 14 hrHPV types. Prevalence with binomial 95% confidence intervals (95% CI) and determinants of testing hrHPV positive were calculated. RESULTS: hrHPV prevalence was higher in HIV [+] (31.8%, 95% CI = 29.2-34.4%) than HIV [-] women (8.2%, 95% CI = 6.7-9.8%; P < 0.0001). Among HIV [+] women, there was a significant trend (ptrend <0.001) of higher hrHPV prevalence with lower CD4 cell count, with the highest hrHPV prevalence among those with <200 CD4 cell counts (45.5%, 95% CI = 34.8-56.4%). In multivariate analysis of HIV [+] women, testing hrHPV positive was positively associated CD4 count of <200 cells/MUL, history of 3 or more sexual partners, and history of using hormonal contraception, and negatively associated with older age. In HIV [-] women, testing hrHPV positive was negatively associated only with older age groups of 45-49 and 50-60 years and surprisingly was not associated with lifetime number of sexual partners. CONCLUSION: hrHPV prevalence is high in HIV [+], especially in women with the lowest CD4 cell counts, which may have implications for utilizing hrHPV-based screening strategies such as screen-and treat in these high-risk subgroups. PMID- 25926865 TI - The changing pattern of ano-rectal cancer, squamous cell carcinoma of the eye, and Hodgkin's lymphoma as non-AIDS-defining cancers, by HIV status, in Tanzania over 11 years (2002-2012): a retrospective case-report study. AB - BACKGROUND: In Tanzania, 5.1% of adults aged 15-49 are infected with HIV. While rates of HIV-related malignancies have declined globally with antiretroviral therapy (ART), including Tanzania, rates of non-AIDS-defining cancers (NADCs) are believed to have increased. Therefore, we determined trends of three NADCs in Tanzania: ano-rectal cancer, squamous cell carcinoma of the eye, and Hodgkin's lymphoma. METHODS: This study was conducted at the Ocean Road Cancer Institute (ORCI) in Dar es Salaam. All medical records of patients diagnosed with ano rectal cancer, squamous cell carcinoma of the eye, and Hodgkin's lymphoma between 2002 and 2012 were reviewed regarding HIV status, cancer clinical characteristics and management. Analysis was conducted to determine trends and proportions in these three NADCs and patient characteristics. RESULTS: We identified 980 NADCs. The relative proportion of these three NADCs at ORCI out of all cancers treated increased from 2.37% in 2002 to a peak of 4.34% in 2009. The prevalence of HIV in patients diagnosed with these NADCs also increased-from 6.67% in 2002 to 20.87% in 2010-and 85% of squamous cell carcinoma of the eye cancer patients with a reported HIV status were HIV-positive. CONCLUSIONS: The frequency and proportions of these three NADCs in Tanzania have increased over the past 11 years, as has the prevalence of HIV positivity amongst these NADC patients. The current and possibly increasing burden of NADCs in Tanzania and other low- and middle-income countries with high HIV rates should be a focus for future cancer prevention and control and HIV therapy programs. PMID- 25926866 TI - Three algorithms and SAS macros for estimating power and sample size for logistic models with one or more independent variables of interest in the presence of covariates. AB - BACKGROUND: Commonly when designing studies, researchers propose to measure several independent variables in a regression model, a subset of which are identified as the main variables of interest while the rest are retained in a model as covariates or confounders. Power for linear regression in this setting can be calculated using SAS PROC POWER. There exists a void in estimating power for the logistic regression models in the same setting. METHODS: Currently, an approach that calculates power for only one variable of interest in the presence of other covariates for logistic regression is in common use and works well for this special case. In this paper we propose three related algorithms along with corresponding SAS macros that extend power estimation for one or more primary variables of interest in the presence of some confounders. RESULTS: The three proposed empirical algorithms employ likelihood ratio test to provide a user with either a power estimate for a given sample size, a quick sample size estimate for a given power, and an approximate power curve for a range of sample sizes. A user can specify odds ratios for a combination of binary, uniform and standard normal independent variables of interest, and or remaining covariates/confounders in the model, along with a correlation between variables. CONCLUSIONS: These user friendly algorithms and macro tools are a promising solution that can fill the void for estimation of power for logistic regression when multiple independent variables are of interest, in the presence of additional covariates in the model. PMID- 25926867 TI - Evaluating the use of locally-based health facility assessments in Afghanistan: a pilot study of a novel research method. AB - BACKGROUND: Through the Balanced Scorecard program there have been independent, annual and nationwide assessments of the Afghan health system from 2004 to 2013. During this period, Afghanistan remained in a dynamic state of conflict, requiring innovative approaches to health service evaluation in insecure areas. The primary objective of this pilot study was to evaluate the reliability of health facility assessments conducted by a novel, locally-based data collection method compared to a standard survey team. METHODS: In this cross-sectional study, one standard survey team of clinicians and multiple rapidly trained locally-based survey teams of teachers conducted health facility assessments in Badghis province, Afghanistan from March - August, 2010. Outpatient facilities covered under the country's Basic Package of Health Services were eligible for inclusion. Both approaches attempted to survey as many health facilities as safely possible, up to 25 total facilities per method. Each facility assessed was scored on 23 health services indicators used to evaluate performance in the annual Balanced Scorecard national assessment. For facilities assessed by both survey methods, the indicator scores produced by each method were compared using Spearman's correlation coefficients and linear regression analysis with generalized estimating equations. RESULTS: The standard survey team was able to assess 11 facilities; the locally-based approach was able to assess these 11 facilities, as well as 13 additional facilities in areas of greater insecurity. Among the 11 facilities assessed by both approaches, 19 of 23 indicators were statistically similar by survey method (p < .05). Spearman's coefficients varied widely from (-0.39) to (0.71). The differences were greatest for items requiring specialized data collector knowledge on reviewing patient records, patient examination and counseling, and health worker reported satisfaction. CONCLUSIONS: This pilot study of a novel method of data collection in health facility assessments showed that an approach using locally-based survey teams provided markedly increased access to areas of insecurity. Though analysis was limited by small sample size, indicator scores used for facility evaluation were relatively comparable overall, but less reliable for items requiring clinical knowledge or when asking health worker opinions, suggesting that alternative approaches may be needed to assess these parameters in insecure environments. PMID- 25926868 TI - Suitable classification of mortars from ancient Roman and Renaissance frescoes using thermal analysis and chemometrics. AB - BACKGROUND: Literature on mortars has mainly focused on the identification and characterization of their components in order to assign them to a specific historical period, after accurate classification. For this purpose, different analytical techniques have been proposed. Aim of the present study was to verify whether the combination of thermal analysis and chemometric methods could be used to obtain a fast but correct classification of ancient mortar samples of different ages (Roman era and Renaissance). RESULTS: Ancient Roman frescoes from Museo Nazionale Romano (Terme di Diocleziano, Rome, Italy) and Renaissance frescoes from Sistine Chapel and Old Vatican Rooms (Vatican City) were analyzed by thermogravimetry (TG) and differential thermal analysis (DTA). Principal Component analysis (PCA) on the main thermal data evidenced the presence of two clusters, ascribable to the two different ages. Inspection of the loadings allowed to interpret the observed differences in terms of the experimental variables. CONCLUSIONS: PCA allowed differentiating the two kinds of mortars (Roman and Renaissance frescoes), and evidenced how the ancient Roman samples are richer in binder (calcium carbonate) and contain less filler (aggregate) than the Renaissance ones. It was also demonstrated how the coupling of thermoanalytical techniques and chemometric processing proves to be particularly advantageous when a rapid and correct differentiation and classification of cultural heritage samples of various kinds or ages has to be carried out. Graphical abstractPCA analysis of TG data allows differentiating mortar samples from different ages (Roman era and Renaissance). PMID- 25926869 TI - Look away: arterial and venous intravascular embolisation following shotgun injury. AB - We describe two cases of intravascular embolization of shotgun pellets found distant to the entry site of penetrating firearm injury. The cases demonstrate antegrade embolization of a shotgun pellet from neck to right middle cerebral artery, and antegrade followed by retrograde venous embolization through the left lower limb to pelvis. Radiologists and Trauma Physicians should be aware that post shotgun injury, the likelihood of an embolised shot pellet is increased compared to other types of firearm missile injury, and should therefore search away from the site of injury to find such missiles. Shotgun pellets may travel in an antegrade or a retrograde intravascular direction - both were seen in these cases - and may not be clinically obvious. This underscores the importance of a meticuluous search through all images, including CT scout images, for evidence of their presence. PMID- 25926870 TI - Rates and predictors of mental stress in Rwanda: investigating the impact of gender, persecution, readiness to reconcile and religiosity via a structural equation model. AB - BACKGROUND: As a consequence of the 1994 Rwandan genocide, prevalences of mental disorders are elevated in Rwanda. More knowledge about determinants of mental stress can help to improve mental health services and treatment in the east central African country. The present study aimed to investigate actual rates of mental stress (posttraumatic stress disorder, syndromal depression and syndromal anxiety) in Rwanda and to examine if gender, persecution during the genocide, readiness to reconcile as well as importance given to religiosity and quality of religiosity are predictors of mental stress. METHODS: The study comprised a community sample of N = 200 Rwandans from Rwanda's capital Kigali, who experienced the Rwandan genocide. By conducting structured interviews, ten local Master level psychologists examined types of potentially lifetime traumatic events, symptoms of posttraumatic stress disorder (PTSD), depression and anxiety, readiness to reconcile and religiosity. Applying non-recursive structural equation modeling (SEM), the associations between gender, persecution, readiness to reconcile, religiosity and mental stress were investigated. RESULTS: Respondents had experienced an average number of 11.38 types of potentially lifetime traumatic events. Of the total sample, 11% met diagnostic criteria for PTSD, 19% presented with syndromal depression and 23% with syndromal anxiety. Female sex, persecution and readiness to reconcile were significant predictors of mental stress. Twofold association was found between centrality of religion (which captures the importance given to religiosity) and mental stress, showing, that higher mental stress provokes a higher centrality and that higher centrality reduces mental stress. The variables positive and negative religious functioning (which determine the quality of religiosity) respectively had an indirect negative and positive effect on mental stress. CONCLUSIONS: Study results provide evidence that rates of mental stress are still elevated in Rwanda and that female sex, persecution, readiness to reconcile, centrality and religious functioning are predictors of mental stress. Seventeen years after the genocide, there remains a large gap between the need for and provision of mental health services in Rwanda. Results underline the importance of improving the respective infrastructure, with a focus on the requirements of women and persons, who were persecuted during the genocide. They further highlight that the consideration of readiness to reconcile, centrality and religious functioning in therapeutic interventions can aid mental health in Rwanda. PMID- 25926871 TI - Factors associated with choice of high lethality methods in suicide attempters: a cross-sectional study. AB - BACKGROUND: Most attempted suicides have a low lethality, but hanging, drowning, and jumping from a great height have a high risk of completed suicide. The aim of this study was to assess the sociodemographic profiles of patients who attempted suicide using high lethality methods relative to all other methods of attempted suicide. METHODS: We retrospectively investigated all attempted suicides treated at a tertiary university hospital in Seoul between January 2008 and February 2012. The following variables were considered: the patients' attempted suicide methods, age, sex, history of attempted suicides, previous psychiatric history, occupation, and living conditions. The suicide methods were categorized into two groups: high lethality (e.g., hanging, falling, and drowning) and low lethality methods (e.g., self-poisoning and cutting). We investigated risk factors related to the choice of high lethality methods. RESULTS: A total of 560 patients were enrolled in this study. Deliberate self-poisoning was the most common method of attempted suicide (61.6%), followed by cutting (22.5%), hanging (10.4%), falling (4.1%), and drowning (1.4%). In logistic regression analyses, odds ratios for the choice of high lethality methods were 1.02 (95% CI = 1.01 to 1.03, p < .01), 7.22 (95% CI = 3.06 to 17.04, P < .01), and 0.59 (95% CI = 0.35 to 0.99, p = .04) for age, previous attempted suicide with a high lethality method, and alcohol co ingestion, respectively. CONCLUSIONS: Our findings indicated that age and past attempted suicide using a high lethality method are associated with the use of high lethality methods for attempting suicide. PMID- 25926872 TI - Associations between maternal stress during pregnancy and offspring internalizing and externalizing problems in childhood. AB - BACKGROUND: Maternal psychological health during pregnancy has been associated with offspring psychopathology. However, it is uncertain whether these associations are mediated by the postpartum depression and related child-rearing factors. Therefore, we examined the associations between prenatal and postnatal factors and internalizing and externalizing behavioral problems in childhood, focusing on maternal psychological health in school-aged children in Korea. FINDINGS: The current study included 1,003 children (580 boys, 423 girls, mean age 9.05 +/- 0.70 years, age range 8-11 years) recruited from schools in five Korean cities. Children's internalizing and externalizing problems were assessed by the Child Behavior Checklist (CBCL). The parents of the children completed structured questionnaires on perinatal factors. Among 1,003 children, 44 had internalizing problems (IP) and 30 had externalizing problems (EP). When comparing children with IP (n = 44) and without IP (n = 959), severe maternal stress during pregnancy (OR3.36, 95% CI 1.80-6.25) and postpartum depression (OR3.19, 95% CI 1.36-7.53) showed a significant association with the IP. When comparing children with EP (n = 30) and without EP (n = 973), low family income (OR2.19, 95% CI 1.05-4.56), unwanted pregnancy (OR2.76, 95% CI 1.28-5.95) and severe maternal stress during pregnancy (OR2.69, 95% CI 1.29-5.61) with the EP. Only maternal stress during pregnancy was significantly associated with the IP after controlling for postpartum depression and with the EP after controlling for family income and unwanted pregnancy. CONCLUSION: This study suggests the importance of maternal psychological health during perinatal period on children's mental health. Further prospective studies in a larger sample are required to confirm our findings. PMID- 25926873 TI - Properties of the Portuguese version of the empowerment scale with mental health organization users. AB - BACKGROUND: This study examines the reliability and validity of the Portuguese version of the Empowerment Scale (ES) to be used in the community/psychosocial mental health field. Authors also reviewed the properties of the development and cross-cultural adaptation of the ES. Because mental health services are required to encourage empowerment and recovery-oriented interventions, adequate empowerment-oriented outcome measures are needed to evaluate services and study interventions across countries. METHODS: The current research was part of a larger research project with 213 participants. A confirmatory factor analysis (CFA) was conducted to observe the ES's construct-related validity, and a reliability analysis for internal consistency. The ES concurrent validity with the recovery and psychiatric symptoms measures was also assessed using the Pearson's correlation coefficient. RESULTS: The CFA supported the five-factor configuration for the refined model of measure as satisfactory. The Portuguese version of the ES presented an overall satisfactory reliability (alpha = .79) and was positively correlated with personal recovery (r = .71) and inversely with psychiatric symptoms (r = -.22). CONCLUSIONS: The overall scale was considered reliable and valid to be used by Portuguese researchers and practitioners to evaluate empowering interventions in mental health services. Furthermore, in the effort to increase ES construct-related validity, this article suggests further improvements to enhance the empowerment measure. PMID- 25926874 TI - The impact of perception of discrimination and sense of belonging on the loneliness of the children of Chinese migrant workers: a structural equation modeling analysis. AB - BACKGROUND: The children of migrant workers can experience several mental health problems after they enter the cities, among which, loneliness is the most prominent and the most common psychological problem. The current study aimed to examine the impact of discrimination perception on loneliness of migrant children, mainly focused on confirmation of the mediator role of sense of belonging. METHOD: 357 children of Chinese migrant workers were as participants involving in this research. Data were collected by using the Perception of Discrimination Scale, Sense of Belonging Instrument, and the Social and Emotional Loneliness Scale. RESULTS: The results revealed that both perception of discrimination and sense of belonging were significantly correlated with loneliness of the children of migrant workers. Structural equation modeling indicated that sense of belonging partially mediated perception of discrimination to job loneliness. CONCLUSIONS: Sense of belonging played a significant role in the relation between perception of discrimination and loneliness of the children of migrant workers. PMID- 25926876 TI - Research highlights for issue 4: applied evolution in fisheries science. PMID- 25926875 TI - Different effects of rumination on depression: key role of hope. AB - BACKGROUND: Both rumination and hope have significant impacts on depression. However, few studies concern their trilateral relationship. This study examined the moderator effect of hope on the relationship between rumination on depression in Chinese university students. METHODS: 517 college students completed the measures of rumination, hope and depression. RESULTS: Hierarchical regression analysis showed that hope moderated the association between rumination and depression. When students reported a low level of hope, those with high rumination reported higher scores in depression than those with low rumination. However, in high hope group, the effect of rumination on depression became not significant. CONCLUSIONS: Hope can significantly moderate the effect of rumination on depression. The significance and limitations of the results are discussed. PMID- 25926879 TI - Polylysogeny magnifies competitiveness of a bacterial pathogen in vivo. AB - The rise of next generation sequencing is revealing a hidden diversity of temperate phages within the microbial community. While a handful of these phages have been well characterized, for the vast majority, the role of phage carriage, and especially multiple phage carriage, is poorly understood. The Liverpool epidemic strain of Pseudomonas aeruginosa is an aggressive pathogen in cystic fibrosis lung infections that has recently been found to contain several unique prophages within its genome. Here, we experimentally investigate the role of two of these phages in vivo, using an insect model of infection. We find that while no benefit is conferred by phage carriage in single bacterial infections, phages confer a large fitness advantage during mixed infections by mediating bacteria bacteria competition. Differences between the two phages appeared to be associated with the rate at which the competitor acquired the phage, and therefore resistance. However, the advantage was greatest in the polylysogen, carrying both phages. These findings suggest that the LES phages may play an important role in host invasions and more generally show that the carriage of multiple phages may itself be beneficial by hindering the spread of resistance in rival bacterial populations. PMID- 25926877 TI - Genomic conflicts and sexual antagonism in human health: insights from oxytocin and testosterone. AB - We review the hypothesized and observed effects of two of the major forms of genomic conflicts, genomic imprinting and sexual antagonism, on human health. We focus on phenotypes mediated by peptide and steroid hormones (especially oxytocin and testosterone) because such hormones centrally mediate patterns of physical and behavioral resource allocation that underlie both forms of conflict. In early development, a suite of imprinted genes modulates the human oxytocinergic system as predicted from theory, with paternally inherited gene expression associated with higher oxytocin production, and increased solicitation to mothers by infants. This system is predicted to impact health through the incompatibility of paternal-gene and maternal-gene optima and increased vulnerability of imprinted gene systems to genetic and epigenetic changes. Early alterations to oxytocinergic systems have long-term negative impacts on human psychological health, especially through their effects on attachment and social behavior. In contrast to genomic imprinting, which generates maladaptation along an axis of mother-infant attachment, sexual antagonism is predicted from theory to generate maladaptation along an axis of sexual dimorphism, modulated by steroid and peptide hormones. We describe evidence of sexual antagonism from studies of humans and other animals, demonstrating that sexually antagonistic effects on sex dimorphic phenotypes, including aspects of immunity, life history, psychology, and behavior, are commonly observed and lead to forms of maladaptation that are demonstrated, or expected, to impact human health. Recent epidemiological and psychiatric studies of schizophrenia in particular indicate that it is mediated, in part, by sexually antagonistic alleles. The primary implication of this review is that data collection focused on (i) effects of imprinted genes that modulate the oxytocin system, and (ii) effects of sexually antagonistic alleles on sex dimorphic, disease-related phenotypes will lead to novel insights into both human health and the evolutionary dynamics of genomic conflicts. PMID- 25926878 TI - Habitat segregation and ecological character displacement in cryptic African malaria mosquitoes. AB - Understanding how divergent selection generates adaptive phenotypic and population diversification provides a mechanistic explanation of speciation in recently separated species pairs. Towards this goal, we sought ecological gradients of divergence between the cryptic malaria vectors Anopheles coluzzii and An. gambiae and then looked for a physiological trait that may underlie such divergence. Using a large set of occurrence records and eco-geographic information, we built a distribution model to predict the predominance of the two species across their range of sympatry. Our model predicts two novel gradients along which the species segregate: distance from the coastline and altitude. Anopheles coluzzii showed a 'bimodal' distribution, predominating in xeric West African savannas and along the western coastal fringe of Africa. To test whether differences in salinity tolerance underlie this habitat segregation, we assessed the acute dose-mortality response to salinity of thirty-two larval populations from Central Africa. In agreement with its coastal predominance, Anopheles coluzzii was overall more tolerant than An. gambiae. Salinity tolerance of both species, however, converged in urban localities, presumably reflecting an adaptive response to osmotic stress from anthropogenic pollutants. When comparing degree of tolerance in conjunction with levels of syntopy, we found evidence of character displacement in this trait. PMID- 25926880 TI - A quantitative genetic approach to assess the evolutionary potential of a coastal marine fish to ocean acidification. AB - Assessing the potential of marine organisms to adapt genetically to increasing oceanic CO2 levels requires proxies such as heritability of fitness-related traits under ocean acidification (OA). We applied a quantitative genetic method to derive the first heritability estimate of survival under elevated CO2 conditions in a metazoan. Specifically, we reared offspring, selected from a wild coastal fish population (Atlantic silverside, Menidia menidia), at high CO2 conditions (~2300 MUatm) from fertilization to 15 days posthatch, which significantly reduced survival compared to controls. Perished and surviving offspring were quantitatively sampled and genotyped along with their parents, using eight polymorphic microsatellite loci, to reconstruct a parent-offspring pedigree and estimate variance components. Genetically related individuals were phenotypically more similar (i.e., survived similarly long at elevated CO2 conditions) than unrelated individuals, which translated into a significantly nonzero heritability (0.20 +/- 0.07). The contribution of maternal effects was surprisingly small (0.05 +/- 0.04) and nonsignificant. Survival among replicates was positively correlated with genetic diversity, particularly with observed heterozygosity. We conclude that early life survival of M. menidia under high CO2 levels has a significant additive genetic component that could elicit an evolutionary response to OA, depending on the strength and direction of future selection. PMID- 25926881 TI - Anthropogenic host plant expansion leads a nettle-feeding butterfly out of the forest: consequences for larval survival and developmental plasticity in adult morphology. AB - Recent anthropogenic eutrophication has meant that host plants of nettle-feeding insects became quasi-omnipresent in fertile regions of Western Europe. However, host plant resource quality - in terms of microclimate and nutritional value - may vary considerably between the 'original' forest habitat and 'recent' agricultural habitat. Here, we compared development in both environmental settings using a split-brood design, so as to explore to what extent larval survival and adult morphology in the nettle-feeding butterfly Aglais urticae are influenced by the anthropogenic environment. Nettles along field margins had higher C/N ratios and provided warmer microclimates to larvae. Larvae developed 20% faster and tended to improve their survival rates, on the agricultural land compared to woodland. Our split-brood approach indicated plastic responses within families, but also family effects in the phenotypic responses. Adult males and females had darker wing pigmentation in the drier and warmer agricultural environment, which contrasts with the thermal melanism hypothesis. Developmental plasticity in response to this microclimatically different and more variable habitat was associated with a broader phenotypic parameter space for the species. Both habitat expansion and developmental plasticity are likely contributors to the ecological and evolutionary success of these nettle-feeding insects in anthropogenic environments under high nitrogen load. PMID- 25926882 TI - Anthropogenic and natural drivers of gene flow in a temperate wild fruit tree: a basis for conservation and breeding programs in apples. AB - Gene flow is an essential component of population adaptation and species evolution. Understanding of the natural and anthropogenic factors affecting gene flow is also critical for the development of appropriate management, breeding, and conservation programs. Here, we explored the natural and anthropogenic factors impacting crop-to-wild and within wild gene flow in apples in Europe using an unprecedented dense sampling of 1889 wild apple (Malus sylvestris) from European forests and 339 apple cultivars (Malus domestica). We made use of genetic, environmental, and ecological data (microsatellite markers, apple production across landscapes and records of apple flower visitors, respectively). We provide the first evidence that both human activities, through apple production, and human disturbance, through modifications of apple flower visitor diversity, have had a significant impact on crop-to-wild interspecific introgression rates. Our analysis also revealed the impact of previous natural climate change on historical gene flow in the nonintrogressed wild apple M. sylvestris, by identifying five distinct genetic groups in Europe and a north south gradient of genetic diversity. These findings identify human activities and climate as key drivers of gene flow in a wild temperate fruit tree and provide a practical basis for conservation, agroforestry, and breeding programs for apples in Europe. PMID- 25926883 TI - Crop pathogen emergence and evolution in agro-ecological landscapes. AB - Remnant areas hosting natural vegetation in agricultural landscapes can impact the disease epidemiology and evolutionary dynamics of crop pathogens. However, the potential consequences for crop diseases of the composition, the spatial configuration and the persistence time of the agro-ecological interface - the area where crops and remnant vegetation are in contact - have been poorly studied. Here, we develop a demographic-genetic simulation model to study how the spatial and temporal distribution of remnant wild vegetation patches embedded in an agricultural landscape can drive the emergence of a crop pathogen and its subsequent specialization on the crop host. We found that landscape structures that promoted larger pathogen populations on the wild host facilitated the emergence of a crop pathogen, but such landscape structures also reduced the potential for the pathogen population to adapt to the crop. In addition, the evolutionary trajectory of the pathogen population was determined by interactions between the factors describing the landscape structure and those describing the pathogen life histories. Our study contributes to a better understanding of how the shift of land-use patterns in agricultural landscapes might influence crop diseases to provide predictive tools to evaluate management practices. PMID- 25926884 TI - Correlated genetic effects on reproduction define a domestication syndrome in a forest tree. AB - Compared to natural selection, domestication implies a dramatic change in traits linked to fitness. A number of traits conferring fitness in the wild might be detrimental under domestication, and domesticated species typically differ from their ancestors in a set of traits known as the domestication syndrome. Specifically, trade-offs between growth and reproduction are well established across the tree of life. According to allocation theory, selection for growth rate is expected to indirectly alter life-history reproductive traits, diverting resources from reproduction to growth. Here we tested this hypothesis by examining the genetic change and correlated responses of reproductive traits as a result of selection for timber yield in the tree Pinus pinaster. Phenotypic selection was carried out in a natural population, and progenies from selected trees were compared with those of control trees in a common garden experiment. According to expectations, we detected a genetic change in important life-history traits due to selection. Specifically, threshold sizes for reproduction were much higher and reproductive investment relative to size significantly lower in the selected progenies just after a single artificial selection event. Our study helps to define the domestication syndrome in exploited forest trees and shows that changes affecting developmental pathways are relevant in domestication processes of long-lived plants. PMID- 25926886 TI - Blue and UV LED-induced fluorescence in cotton foreign matter. AB - BACKGROUND: Cotton is an important domesticated fiber used to manufacture a variety of products and industrial goods. During harvesting with cotton strippers and cotton pickers, it is contaminated with foreign matter from botanical and non botanical sources which adversely affect the quality and consistency of cotton, and therefore reduces its market value. To improve the current grading done by the High Volume Instrument (HVI) and human inspectors, it was explored whether fluorescence imaging can be used for cotton foreign matter detection. RESULTS: Eight types of botanical foreign matter (bark, bract, brown leaf, green leaf, hull, seed coat, seed, stem), and four types of non-botanical foreign matter (paper, twine, plastic bale packaging, plastic bag) were subjected to a fluorescence spectroscopy analysis to determine their optimal excitation and emission wavelength range. Matrix 3D scans were performed in the excitation range from 300 nm to 500 nm, and emission range from 320 nm to 700 nm, and the results indicated the photo-excitable fluorescence in the aforementioned excitation range for all the selected foreign matter categories. Consequently, the blue and the UV LEDs were selected as the excitation sources. The blue LED light provided optimal excitation light for bark, brown leaf, bract, green leaf, hull, and stem, while the UV LED light provided optimal excitation light for paper, plastic bag, plastic packaging, seed, seed coat, and twine. CONCLUSIONS: UV and blue light induces fluorescence in 12 types of botanical and non-botanical cotton foreign matter. An imaging apparatus with blue and UV light excitation sources, and a consumer grade SLR camera was successfully developed to capture and characterize fluorescent images of cotton foreign matter. Based on the results, fluorescent imaging could be a promising method for cotton foreign matter detection. Future studies will focus on the classification of cotton foreign matter categories and to further refine the image processing sequence. PMID- 25926887 TI - Electrospun nanofibers as versatile interfaces for efficient gene delivery. AB - The integration of gene delivery technologies with electrospun nanofibers is a versatile strategy to increase the potential of gene therapy as a key platform technology that can be readily utilized for numerous biomedical applications, including cancer therapy, stem cell therapy, and tissue engineering. As a spatial template for gene delivery, electrospun nanofibers possess highly advantageous characteristics, such as their ease of production, their ECM-analogue nature, the broad range of choices for materials, the feasibility of producing structures with varied physical and chemical properties, and their large surface-to-volume ratios. Thus, electrospun fiber-mediated gene delivery exhibits a great capacity to modulate the spatial and temporal release kinetics of gene vectors and enhance gene delivery efficiency. This review discusses the powerful characteristics of electrospun nanofibers, which can function as spatial interfaces capable of promoting controlled and efficient gene delivery. PMID- 25926888 TI - Characterization of a copper responsive promoter and its mediated overexpression of the xylanase regulator 1 results in an induction-independent production of cellulases in Trichoderma reesei. AB - BACKGROUND: Trichoderma reesei represents an important workhorse for industrial production of cellulases as well as other proteins. The large-scale production is usually performed in a substrate-inducing manner achieved by a fine-tuned cooperation of a suite of transcription factors. Their production and subsequent analysis are, however, often either difficult to manipulate or complicated by the concomitant production of other inducible proteins. Alternatives to control gene expression independent of the nutritional state are thus preferred in some cases to facilitate not only biochemical studies of proteins but also genetic engineering of the producer. RESULTS: We identified a copper transporter encoding gene tcu1 (jgi:Trire2:52315) in T. reesei, the transcription of which was highly responsive to copper availability. Whereas excess copper repressed the expression of tcu1 from T. reesei, eliminating copper addition in the medium resulted in a high-level transcription of tcu1. The usefulness of the system was further illustrated by the high-level expression of specific cellulases driven by the tcu1 promoter in T. reesei when cultivated on D-glucose or glycerol as the sole carbon source. A recombinant T. reesei strain, which overexpressed the main transcription activator of hydrolases (xylanase regulator 1) under the control of tcu1 promoter, was found to be relieved from the carbon catabolite repression and thus displayed a constitutive cellulase expression. Moreover, the amount and activities of cellulases produced by this strain on glycerol or glucose fully recapitulated those of the parental strain produced on Avicel. CONCLUSION: Expression of T. reesei tcu1 gene was tightly controlled by copper availability, and a homologous protein expression system was developed based on this promoter. Deregulation of XYR1 (xylanase regulator 1) mediated by the tcu1 promoter not only overcame the carbon catabolite repression of cellulases but also resulted in their full expression even on the non-inducing carbon sources. PMID- 25926889 TI - Vitamin D status and surgical outcomes: a systematic review. AB - The importance of vitamin D for musculoskeletal health has long been recognized, and awareness of significant extra-skeletal effects in health and disease is rapidly emerging. Although it has been possible for many decades to quantify serum markers of vitamin D deficiency, and to correct deficiency at low cost and with high safety, the influence of vitamin D status on post-surgical outcomes has only recently been identified as a research topic of interest. To the present, these data have not been the subject matter of formal review. Accordingly, we conducted a systematic review to assess the association between perioperative vitamin D status and outcomes after surgery. The databases of PubMed, Ovid MEDLINE, EMBASE, AMED, CINAHL (EBSCOHost), The Cochrane Databases of Systematic Review, and PROSPERO were searched through December, 2014 for studies relating to vitamin D and surgery. The initial search yielded 90 manuscripts. After applying exclusion criteria, 31 studies were eligible for inclusion. Fifteen studies employed prospective observational designs, 3 used prospective randomized protocols, and 13 report retrospective database interrogations. The main finding of the present review is that 26 of 31 studies (84%) report at least one statistically significant worse outcome in patients with low vitamin D status. Five of 31 studies (16%) found no association. In conclusion, this review supports the hypothesis that hypovitaminosis D is associated with adverse outcomes after diverse surgical procedures. Future studies should focus on additional surgeries and outcomes, and on the role of vitamin D supplementation in the improvement of patient safety in participants with low vitamin D status at the time of surgery. PMID- 25926890 TI - Defining functional signatures of dysbiosis in periodontitis progression. AB - Periodontitis is a common inflammatory disease that leads to tooth loss and has been linked to cardiovascular disease and diabetes mellitus. The periodontal microbiome is highly diverse, and metatranscriptomic studies have indicated that the genes that are expressed by the microbiota are more relevant than the microbial composition in the pathogenesis of periodontitis. A recent study of early metabolic activities in the dysbiotic microbiome reveals a functional signature that distinguishes periodontal sites that will become inflamed, supporting the idea that microbial communities as a whole drive disease progression. PMID- 25926891 TI - Worldwide productivity in the field of foot and ankle research from 2009-2013: a bibliometric analysis of highly cited journals. AB - BACKGROUND: Significant growth has been observed in the field of foot and ankle research in recent years. However, bibliometric studies concerning the quantity and quality of articles published in foot and ankle journals are scarce. This study aimed to reveal the characteristics of national productivity in the field of foot and ankle research and to provide a general picture of foot and ankle research for surgeons and researchers. METHODS: Web of Science was searched for foot and ankle articles in 4 highly cited journals from 2009 to 2013. The number of total articles and citations were collected to evaluate the contribution of different countries. Publication activity was adjusted for the countries by population size and gross domestic product (GDP). RESULTS: A total number of 2083 articles were published worldwide. North America, West Europe, Australia and East Asia were the most productive world regions. High income countries published 90.35% of articles, middle-income 9.60%, and low-income just 0.05%. The United States published the largest number of articles (1025/2083, 49.2%), followed by the United Kingdom (221/2083, 10.6%), Australia (92/2083, 4.4%), and had the highest total citations (3631). However, Canada had the highest average citations per article (5.0), followed by Australia (4.6) and Switzerland (4.2). There were positive correlations between the total number of publications and population/GDP (p < 0.01). When normalized to population size, Switzerland ranked the highest, followed by Australia, and the United Kingdom. When adjusted for GDP, Switzerland ranked the highest, followed by United Kingdom, and South Korea. CONCLUSIONS: The United States is the most productive country in the field of foot and ankle research. However, Australia, some smaller European and Asian countries may be more productive relative to their size. PMID- 25926892 TI - Proteochemometric modelling coupled to in silico target prediction: an integrated approach for the simultaneous prediction of polypharmacology and binding affinity/potency of small molecules. AB - The rampant increase of public bioactivity databases has fostered the development of computational chemogenomics methodologies to evaluate potential ligand-target interactions (polypharmacology) both in a qualitative and quantitative way. Bayesian target prediction algorithms predict the probability of an interaction between a compound and a panel of targets, thus assessing compound polypharmacology qualitatively, whereas structure-activity relationship techniques are able to provide quantitative bioactivity predictions. We propose an integrated drug discovery pipeline combining in silico target prediction and proteochemometric modelling (PCM) for the respective prediction of compound polypharmacology and potency/affinity. The proposed pipeline was evaluated on the retrospective discovery of Plasmodium falciparum DHFR inhibitors. The qualitative in silico target prediction model comprised 553,084 ligand-target associations (a total of 262,174 compounds), covering 3,481 protein targets and used protein domain annotations to extrapolate predictions across species. The prediction of bioactivities for plasmodial DHFR led to a recall value of 79% and a precision of 100%, where the latter high value arises from the structural similarity of plasmodial DHFR inhibitors and T. gondii DHFR inhibitors in the training set. Quantitative PCM models were then trained on a dataset comprising 20 eukaryotic, protozoan and bacterial DHFR sequences, and 1,505 distinct compounds (in total 3,099 data points). The most predictive PCM model exhibited R (2) 0 test and RMSEtest values of 0.79 and 0.59 pIC50 units respectively, which was shown to outperform models based exclusively on compound (R (2) 0 test/RMSEtest = 0.63/0.78) and target information (R (2) 0 test/RMSEtest = 0.09/1.22), as well as inductive transfer knowledge between targets, with respective R (2) 0 test and RMSEtest values of 0.76 and 0.63 pIC50 units. Finally, both methods were integrated to predict the protein targets and the potency on plasmodial DHFR for the GSK TCAMS dataset, which comprises 13,533 compounds displaying strong anti malarial activity. 534 of those compounds were identified as DHFR inhibitors by the target prediction algorithm, while the PCM algorithm identified 25 compounds, and 23 compounds (predicted pIC50 > 7) were identified by both methods. Overall, this integrated approach simultaneously provides target and potency/affinity predictions for small molecules. Graphical abstractProteochemometric modelling coupled to in silico target prediction. PMID- 25926893 TI - Inflammation triggers specific microRNA profiles in human adipocytes and macrophages and in their supernatants. AB - BACKGROUND: The relevance of microRNAs (miRNAs) in adipose tissue is increasingly recognized, being intrinsically linked to different pathways, including obesity related inflammation. In this study, we aimed to characterize the changes induced by inflammation on the miRNA pattern of human adipocytes and macrophages. Therefore, an extensive profile of 754 common miRNAs was assessed in cells (human primary mature adipocytes, and the macrophage-like cell line THP-1) and in their supernatants (SN) using TaqMan low-density arrays. These profiles were evaluated at the baseline and after administration of lipopolysaccharide (LPS, 10 ng/ml) and LPS-conditioned medium from M1 macrophages (MCM, 5%). The miRNAs that experienced the most dramatic changes were studied in subcutaneous human adipose tissue before and approximately 2 years after bariatric surgery-induced weight loss. RESULTS: Differentiated adipocytes expressed 169 miRNAs, being 85 detectable in the SN. In M1 macrophages, 183 miRNAs were detected, being 106 also present in the SN. Inflammation led to an increased number of miRNAs detectable in cells and in their SNs in both adipocytes (+8.3% and +24.7%) and M1 macrophages (+1.4% and +5%, respectively). Indeed, under inflammatory conditions, adipocytes and M1 macrophages shared the expression of 147 (+9%) miRNAs, and 100 (+41%) common miRNAs were found in their SNs. Twelve of these factors were also linked to inflammation in whole adipose tissue from obese subjects. Interestingly, miR-221 (2-fold, P = 0.002), miR-222 (2.5-fold, P = 0.04), and miR 155 (5-fold, P = 0.015) were increased in inflamed adipocytes and in their SNs (15-, 6-, and 4-fold, respectively, all P < 0.001). Furthermore, their expressions in human adipose tissue concordantly decreased after weight loss ( 51%, P = 0.003, -49%, P = 0.03, and -54.4%, P = 0.005, respectively). CONCLUSIONS: Inflammation induces a specific miRNA pattern in adipocytes and M1 macrophages, with impact on the physiopathology of obesity-induced inflammation of adipose tissue. The crosstalk between cells should be investigated further. PMID- 25926894 TI - Biochemical and In-silico Studies on Pectin Methylesterase from G9 Variety of Musa acuminata for Delayed Ripening. AB - Ripening of fruit is a very important process but in some fruits early ripening leads to a great damage during long distance transportation. There are various biochemical changes taking place during the phase of ripening of fruit such as changes in respiration, aroma, flavor, ethylene production and activity of cell wall degrading enzymes. Some important cell wall degrading enzymes are Polygalacturonase (PG), Pectin methylesterase (PME), Pectin lyase, RGase. PME is known to act as a cell wall hydrolyzing enzyme, responsible for demethyl esterification of cell wall polygalacturonan. The present study includes the biochemical and molecular characterization of PME from Grand naine variety of Musa acuminata (banana). This study also deals with the in-silico study reflecting inhibition of PME activity in context to delayed ripening in banana. It mainly deals with the identification of a PME1 gene from Grand naine variety of banana. The expression of this gene is related with the process of ripening. The expression of PME1 gene was observed to be peaked on 3(rd) day in ethylene treated samples of banana but the activity in untreated samples called control was rather slow and then there was a sudden decrease in their activity in both treated as well as untreated samples. With the help of in-silico study, we observed that banana has maximum homology with carrot by using cross species analysis.The designed model has been reported to be of good quality on the basis of its verification and validation. The designed model was observed to be appropriate for docking. The information of binding sites of ligand provides new insights into the predictable functioning of relevant protein. PMID- 25926895 TI - Development of In Vitro Denture Biofilm Models for Halitosis Related Bacteria and their Application in Testing the Efficacy of Antimicrobial Agents. AB - OBJECTIVE: Since dentures can serve as a reservoir for halitosis-causing oral bacteria, halitosis development is a concern for denture wearers. In this study, we surveyed the prevalence of four selected halitosis-related species (Fusobacterium nucleatum, Tannerella forsythia, Veillonella atypica and Klebsiella pneumoniae) in clinical denture plaque samples, and developed denture biofilm models for these species in vitro to facilitate assessment of antimicrobial treatment efficacy. Design : Denture plaque from ten healthy and ten denture stomatitis patients was screened for the presence of aforementioned four species by PCR. Biofilm formation by these halitosis-associated species on the surfaces of denture base resin (DBR) discs was evaluated by crystal violet staining and confocal laser scanning microscopy. The efficacy of denture cleanser treatment on these mono-species biofilms was evaluated by colony counting. Results : 80% of the subjects in the denture stomatitis group and 60% in the healthy group contained at least one of the targeted halitosis-related species in their denture plaque. All halitosis species tested were able to form biofilms on DBR disc surfaces to varying degrees. These in vitro mono-species resin biofilm models were used to evaluate the efficacy of denture cleansers, which exhibited differential efficacies. When forming biofilms on resin surfaces, the halitosis related species displayed enhanced resistance to denture cleansers compared with their planktonic counterparts. Conclusion : The four selected halitosis-related bacterial species examined in this study are present on the majority of dentures. The mono-species biofilm models established on DBR discs for these species are an efficient screening tool for dental product evaluation. PMID- 25926896 TI - Clinical evaluation of removable partial dentures on the periodontal health of abutment teeth: a retrospective study. AB - The aim of this retrospective study was to evaluate the effect of removable partial dentures in periodontal abutment teeth in relation to the type of denture support and design of RPD in a five-year worn period. Methods : A total of 64 patients with removable partial dentures (RPDs), participated in this study. It were examined ninety-one RPDs. There were seventy-five RPDs with clasp-retained and sixteenth were RPDs with attachments. There were 28 females and 36 males, aged between 40-64 years, 41 maxillary and 50 mandible RPDs. For each subjects the following data were collected: denture design, denture support, and Kennedy classification. Abutment teeth were assessed for plaque index (PI), calculus index (CI), blending on probing (BOP), probing depth (PD), gingival recession (GR), tooth mobility (TM). Level of significance was set at p<0.05. Results : According to denture support of RPD, BOP, PD, PI, GR, CI and TM-index showed no statistically significant difference. Based on the denture design of RPD's, BOP, PD, PI, CI, and TM-index proved no statistically significant difference. Except GR-index according to denture design confirmed statistically significant difference in RPD with clasp p<0.01. The higher values of all periodontal parameter as BOP, PD, PI, CI and TM were in patients with RPD's with claps comparing with RPD's with attachment. Conclusion : RPD's with clasp increased level of gingival inflammation in regions covered by the dentures and below the clasp arms in abutment teeth. PMID- 25926897 TI - The Temperature Dependence of Micro-Leakage between Restorative and Pulp Capping Materials by Cu Diffusion. AB - We used the Cu ions for the leakage analysis between pulp capping and restorative materials. Theoretically, Cu has more advantages than Ag ions due to their smaller radii (rCu (2+)=73 pm and rAg (2+)=94 pm), lower mass density (dCu=8.96 g/cm(3) and dAg=10.49 g/cm(3)) and higher radio opacity which can be more useful by X-ray or EDX detectors, cheaper price and more abundance in planet when compared with Ag element which is generally used in the leakage studies. The micro leakage between dental restorations and pulp capping materials has been determined by using Micro Computed Tomography, Scanning Electron Microscopy and EDX analysis. It is found that the leakage has temperature dependent mechanism which increases with the increasing temperature. As a result, using Cu solution for leakage studies in dentine is an effective and easy method which can be used in dental science. PMID- 25926898 TI - Independent factors affecting recovery time after sedation in patients with intellectual disabilities. AB - Purpose : The purpose of this study was to identify independent factors associated with prolonged recovery time after intravenous sedation for dental treatment in patients with intellectual disabilities. Methods : This study was designed as a prospective cohort study. Participants were patients with intellectual disabilities, for whom sedation for dental treatment was planned in Okayama University Hospital. The outcome variable was recovery time. The predictor variables were patient background, antiepileptic and psychotropic drugs, and anesthesia-related variables. Factors affecting the outcome were examined with multiple regression analysis. Results : We enrolled 260 cases in this study. Oral midazolam was a strong independent determinant in prolonged recovery time. Teeth extraction, short treatment time and lower body mass index were significant independent predictors of prolonged recovery time. Conclusion : Oral midazolam is a clear independent determinant of prolonged recovery time after sedation, while psychotropic drugs and antiepileptic drugs were not independent determinants in this study. PMID- 25926899 TI - Plant-microbe Cross-talk in the Rhizosphere: Insight and Biotechnological Potential. AB - Rhizosphere, the interface between soil and plant roots, is a chemically complex environment which supports the development and growth of diverse microbial communities. The composition of the rhizosphere microbiome is dynamic and controlled by multiple biotic and abiotic factors that include environmental parameters, physiochemical properties of the soil, biological activities of the plants and chemical signals from the plants and bacteria which inhabit the soil adherent to root-system. Recent advancement in molecular and microbiological techniques has unravelled the interactions among rhizosphere residents at different levels. In this review, we elaborate on various factors that determine plant-microbe and microbe-microbe interactions in the rhizosphere, with an emphasis on the impact of host genotype and developmental stages which together play pivotal role in shaping the nature and diversity of root exudations. We also discuss about the coherent functional groups of microorganisms that colonize rhizosphere and enhance plant growth and development by several direct and indirect mechanisms. Insights into the underlying structural principles of indigenous microbial population and the key determinants governing rhizosphere ecology will provide directions for developing techniques for profitable applicability of beneficial microorganisms in sustainable agriculture and nature restoration. PMID- 25926900 TI - Angiotensin(1-7) and ACE2, "The Hot Spots" of Renin-Angiotensin System, Detected in the Human Aqueous Humor. AB - BACKGROUND: The main purpose of the study was to establish whether essential components of the renin-angiotensin system (RAS) exist in the human aqueous humor. METHODS: Forty-five patients >= 60 (74+/-7) years of age undergoing cataract surgery at Tampere University Hospital were randomly selected for the prospective study. The exclusion criterion was the use of oral antihypertensive medicine acting via renin-angiotensin system. Aqueous humor samples were taken at the beginning of normal cataract extraction. The samples were frozen and stored at -80 degrees C. The concentrations of intraocular endogenous RAS components Ang(1-7), ACE2, and ACE1 were measured using ELISA. RESULTS: Concentration medians of Ang(1-7), ACE2, and ACE1 in the aqueous humor were: Ang(1-7) 4.08 ng/ml, ACE2 2.32 ng/ml and ACE1 0.35 ng/ml. The concentrations were significantly higher in glaucomatous than in non-glaucomatous eyes, ACE1 (p=0.014) and Ang(1-7) (p=0.026) vs non-glaucomatous eyes. CONCLUSIONS: Ang(1-7), ACE2 and ACE1 are found in the human aqueous humor. The observations are consistent with the conception that local tissue-RAS exists in the human eye and it might have a role in the control of intraocular pressure. PMID- 25926901 TI - LETTER TO THE EDITOR Excision of Congenital Bilateral Persistent Pupillary Membrane in a Child with Exotropia. AB - PURPOSE: To report the clinical and histopathological findings of a patient who had bilateral persistent pupillary membrane with exotropia and high hyperopia. METHODS: CASE REPORT: A 7-year-old boy presented with a persistent pupillary membrane in both eyes. His best corrected visual acuity (BCVA) was 20/20 in the right eye and 20/32 in the left eye with exotropia of 18 prism diopters. He underwent surgical resection of both membranes. At 5 months postoperatively, BCVA was 20/20 with final bilateral refraction of +6.5 D in both eyes. Exotropia and photophobia showed improvement immediately after surgery. Histopathological examination revealed typical features of normal iris tissue in the excised membranes. CONCLUSION: Bilateral persistent pupillary membranes were excised successfully without injury to other ocular tissues, including the crystalline lens. Surgical treatment may be required for the management of persistent pupillary membrane associated with visual impairment such as exotropia or photophobia. PMID- 25926902 TI - The causes of hyperreflective dots in optical coherence tomography excluding diabetic macular edema and retinal venous occlusionS. AB - PURPOSE: To investigate the causes of hyperreflective dots (HRDs) in spectral domain optical coherence tomography (OCT) excluding diabetic macular edema (DME) and RVO (retinal vein occlusion). PATIENTS AND METHODS: The medical records of 56 patients with HRDs documented by OCT were reviewed retrospectively. The patients with DME and RVO were excluded from the study in order to prevent misdiagnosing hard exudates or HRDs. The causes, unilaterality or bilaterality of HRD and demographic properties of the patients with HRD were evaluated. RESULTS: Sixty four eyes of 56 patients having HRDs were included in this study. Of the patients with HRD, 17 (30.36%) were women and 39 (69.64%) were men. The ages of patients were between 13 to 84 years (median 60.18 years). The causes of HRD were as follows: papilledema in 4 eyes (6.25%), active neovascular age related macular degeneration (AMD) in 33 eyes (51.56%), familial dominant drusen in 2 eyes (3.13%), central serous chorioretinopathy in 19 eyes (29.69%) and commotio retina in 2 eyes (3.13%), choroidal folds in one eye (1.56%), branch retinal artery occlusion in one eye (1.56%), central retinal artery occlusion in one patient (1.56%) and Best vitelliform macular dystrophy in one eye (1.56%). The most common cause of HRD was AMD. The causes of HRDs in both eyes were AMD and papilledema. CONCLUSION: The most common causes of HRDs excluding DME and RVO seem as active exudative AMD. The presence of HRDs in retinal diseases might affect the decisions and the results of the treatment and the prognosis of diseases. PMID- 25926903 TI - Optical coherence tomography, scanning laser polarimetry and confocal scanning laser ophthalmoscopy in retinal nerve fiber layer measurements of glaucoma patients. AB - PURPOSE: To determine the correlations and strength of association between different imaging systems in analyzing the retinal nerve fiber layer (RNFL) of glaucoma patients: optical coherence tomography (OCT), scanning laser polarimetry (SLP) and confocal scanning laser ophthalmoscopy (CSLO). MATERIALS AND METHODOLOGY: 114 eyes of patients with moderate open angle glaucoma underwent spectral domain OCT (Topcon SD-OCT 2000 and Zeiss Cirrus HD-OCT), SLP (GDx VCC and GDx Pro) and CSLO (Heidelberg Retina Tomograph, HRT 3). Correlation coefficients were calculated between the structural parameters yielded by these examinations. The quantitative relationship between the measured RNFL thickness globally and for the four regions (superior, inferior, nasal, temporal) were evaluated with different regression models for all used imaging systems. RESULTS: The strongest correlation of RNFL measurements was found between devices using the same technology like GDx VCC and GDx Pro as well as Topcon OCT and Cirrus OCT. In glaucoma patients, the strongest associations (R2) were found between RNFL measurements of the two optical coherence tomography devices Topcon OCT and Cirrus OCT (R2 = 0.513) and between GDx VCC and GDx Pro (R2 = 0.451). The results of the OCTs and GDX Pro also had a strong quantitative relationship (Topcon OCT R2 = 0.339 and Cirrus OCT R2 = 0.347). GDx VCC and the OCTs showed a mild to moderate association (Topcon OCT R2 = 0.207 and Cirrus OCT R2 = 0.258). The confocal scanning laser ophthalmoscopy (HRT 3) had the lowest association to all other devices (Topcon OCT R2 = 0.254, Cirrus OCT R2 = 0.158, GDx Pro R2 = 0.086 and GDx VCC R2 = 0.1). CONCLUSION: The measurements of the RNFL in glaucoma patients reveal a high correlation of OCT and GDx devices because OCTs can measure all major retinal layers and SLP can detect nerve fibers allowing a comparison between the results of this devices. However, CSLO by means of HRT topography can only measure height values of the retinal surface but it cannot distinguish between different retinal layers. This may explain the rather poor correlations and associations between CSLO measurements and those of all other imaging devices which makes it difficult to compare HRT 3 nerve fiber data. These correlations are important in clinical routine especially when different techniques are used in the follow-up of glaucoma patients. PMID- 25926904 TI - Future Monetary Costs of Dementia in the United States under Alternative Dementia Prevalence Scenarios. AB - Population aging will likely lead to increases is health care spending and the ability of governments to support entitlement programs such as Medicare and Medicaid. Dementia is a chronic condition that is especially pertinent because of its strong association with old age and because care for dementia is labor intensive and expensive. Indeed, prior research has found that if current dementia prevalence rates persist population aging will generate very large increases in health care spending for dementia. In this study we considered two alternative assumptions or scenarios about future prevalence. The first adjusts the prevalence projections using recent research that suggests dementia prevalence may be declining. The second uses growth hypertension, obesity and diabetes, and the relationship between dementia and these conditions to adjust future prevalence rates. We find under the first scenario that if the rates of decline in age-specific dementia rates persist, future costs will be much less than previous estimates, about 40% lower. Under the second scenario, the growth in those conditions makes only small differences in costs. PMID- 25926905 TI - Retinal venous pressure in chronic smokers. AB - BACKGROUND: The overall aim of this study was to determine retinal venous pressure (RVP) in healthy chronic smokers and compare values to those of healthy non-smokers. METHODS: Both eyes of 25 healthy chronic smokers and 41 healthy non smokers were included. Measurements of RVP were performed by means of contact lens ophthalmodynamometry. Ophthalmodynamometry is done by applying increasing force on the eye via a contact lens. If a spontaneous venous pulsation was present, it was noted. If not, the compressive force was increased until the first venous pulsation was detected, and the measurement value was fixed and read. RVP was calculated as the sum of pressure increase induced by the instrument and intraocular pressure. RESULTS: Smokers had a significantly higher frequency of spontaneous venous pulsations than non-smokers (p < 0.001). Mean values of RVP were slightly lower in smokers than in non-smokers: 15.3 and 15.5 (smokers) versus 15.9 and 16.2 (non-smokers) for the right and left eye, respectively; however, the difference in RVP between the two groups did not reach significance. There was no significant difference in blood pressure between the two groups, but heart rate was significantly higher in smokers (p = 0.043). CONCLUSIONS: RVP values may differ in healthy smokers than in non-smokers. Therefore, smoking habits should be considered when interpreting RVP results. PMID- 25926906 TI - Atypical imaging features of tuberculous spondylitis: case report with literature review. AB - Spinal tuberculosis in its typical form that shows destruction of two adjacent vertebral bodies and opposing end plates, destruction of the intervening intervertebral disc and a paravertebral or psoas abscess, is easily recognized and readily treated. Atypical tuberculous spondylitis without the above mentioned imaging features, although seen infrequently, has been well documented. We present, in this report, a case of atypical tuberculous spondylitis showing involvement of contiguous lower dorsal vertebral bodies and posterior elements with paravertebral and epidural abscess but with preserved intervertebral discs. The patient presented in advanced stage with progressive severe neurological symptoms due to spinal cord compression. Non-enhanced magnetic resonance imaging led to misdiagnosis of the lesion as a neoplastic process. It was followed by contrast enhanced computed tomography of the chest and abdomen that raised the possibility of an infectious process and, post-operatively, histopathological examination of the operative specimen confirmed tuberculosis. This case indicates the difficulty in differentiating atypical spinal tuberculosis from other diseases causing spinal cord compression. The different forms of atypical tuberculous spondylitis reported in the literature are reviewed. The role of the radiologist in tuberculous spondylitis is not only to recognize the imaging characteristics of the disease by best imaging modality, which is contrast enhanced magnetic resonance imaging, but also to be alert to the more atypical presentations to ensure early diagnosis and prompt treatment to prevent complications. However, when neither clinical examination nor magnetic resonance imaging findings are reliable in differentiating spinal infection from one another and from neoplasm, adequate biopsy, either imaging guided or surgical biopsy is essential for early diagnosis. PMID- 25926907 TI - Apical Pneumocystis jiroveci as an AIDS defining illness: A case report illustrating a change in the paradigm. AB - Pneumocystis jiroveci pneumonia is a common acquired immune deficiency syndrome defining illness. Pneumocystis jiroveci pneumonia is classically described as having symmetrical bilateral perihilar ground-glass opacities on chest radiographs. We present an "atypical" case of Pneumocystis jiroveci pneumonia presenting as symmetric biapical cystic spaces with relative sparing of the remainder of the lungs in a 22 year-old male, previously undiagnosed with acquired immune deficiency syndrome. Our case illustrates that formerly unusual presentations of Pneumocystis jiroveci pneumonia are becoming more common as acquired immune deficiency syndrome defining illnesses as more patients are being imaged with further imaging such as high resolution computed tomography. PMID- 25926908 TI - The quadricuspid aortic valve. AB - The quadricuspid aortic valve is a very rare congenital defect that may be an isolated entity or associated with a multitude of cardiovascular abnormalities. Isolated cases usually manifest late in life with the complication of aortic regurgitation, which can be delayed by early valve replacement. We present a case of quadricuspid aortic valve associated with truncus arteriosus, ventricular septal defect, and interrupted aortic arch. PMID- 25926909 TI - Ovarian Sertoli-Leydig cell tumor with heterologous elements of gastrointestinal type associated with elevated serum alpha-fetoprotein level: an unusual case and literature review. AB - Here we describe the case of a 19-year-old woman with a poorly differentiated ovarian Sertoli-Leydig cell tumor and an elevated serum alpha-fetoprotein level. The patient presented with diffuse abdominal pain and bloating. Physical examination, ultrasound, and magnetic resonance imaging revealed a right ovarian tumor that was histopathologically diagnosed as a poorly differentiated Sertoli Leydig cell tumor with heterologous elements. Her alpha-fetoprotein serum level was undetectable after tumor resection. Sertoli-Leydig cell tumors are rare sex cord-stromal tumors that account for 0.5% of all ovarian neoplasms. Sertoli Leydig cell tumors tend to be unilateral and occur in women under 30 years of age. Although they are the most common virilizing tumor of the ovary, about 60% are endocrine-inactive tumors. Elevated serum levels of alpha-fetoprotein are rarely associated with Sertoli-Leydig cell tumors, with only approximately 30 such cases previously reported in the literature. The differential diagnosis should include common alpha-fetoprotein-producing ovarian entities such as germ cell tumors, as well as other non-germ cell tumors that have been rarely reported to produce this tumor marker. PMID- 25926910 TI - FDG Positron Emission Tomography and Computed Tomography Demonstration of Carcinoma Arising in an Epiphrenic Diverticulum. AB - Esophageal carcinoma arising within an epiphrenic diverticulum is rare. We describe a case of a carcinoma in a long-standing epiphrenic diverticulum in a 62 year-old patient. Fluorine-18-2-Fluoro-2-Deoxy-D-Glucose Positron Emission Tomography and Computed Tomography, and endoscopic ultrasound revealed a hypermetabolic mass within the diverticulum. A preoperative diagnosis was made via endoscopic biopsy. The patient underwent Ivor-Lewis esophagectomy. He remains well and free of recurrence 18 months after surgery. PMID- 25926911 TI - Solitary fibrous tumor of the infratemporal fossa. AB - Solitary fibrous tumors represent fewer than 2% of all soft tissue tumors, and only about 12-15% of them occur in the head and neck. We report a case of a 38 year-old male who presented with a six-month history of increasing right cheek swelling. Computed tomography of the paranasal sinuses with contrast demonstrated a well-circumscribed avidly enhancing mass in the right retroantral fat. On magnetic resonance imaging the lesion was homogenously slightly hyperintense to muscle on T1 weighted and T2 weighted images and enhanced avidly with contrast. Surgical resection was performed and pathology was consistent with solitary fibrous tumor. There have been very few reported cases of solitary fibrous tumors in the infratemporal fossa and none described as originating in the retroantral fat. PMID- 25926912 TI - Ischemic colitis due to a mesenteric arteriovenous malformation in a patient with a connective tissue disorder. AB - Ischemic colitis is a rare, life-threatening, consequence of mesenteric arteriovenous malformations. Ischemia ensues from a steal phenomenon through shunting, and may be compounded by the resulting portal hypertension. Computed tomographic angiography is the most common first-line test because it is quick, non-invasive, and allows for accurate anatomic characterization. Also, high resolution three-dimensional images can be created for treatment planning. Magnetic resonance angiography is similarly sensitive for vascular mapping. Conventional angiography remains the gold standard for diagnosis and also allows for therapeutic endovascular embolization. Our patient underwent testing using all three of these modalities. We present the first reported case of this entity in a patient with a vascular connective tissue disorder. PMID- 25926913 TI - Inadvertent intravesicular placement of a vaginal contraceptive ring: a case report and review of literature. AB - The NuvaRing(r) is a deformable, ring-shaped hormonal contraceptive device which is typically vaginally self-inserted by the patient. While there are several potential side effects of usage, essentially all of them result from hormone delivery. Complications from incorrect placement are rare. We present the case of a 31 year old female who presented to our emergency department after being unable to retrieve a NuvaRing(r) for its scheduled removal. CT scan showed a hypodense intravesicular NuvaRing(r) which the patient had inadvertently placed transurethrally 3 weeks prior. Cystoscopy was performed and retrieval using a 3 pronged grasper was eventually successful after several failed attempts with an alligator grasper. Our purpose in presenting this case is to introduce the reader to a rare complication of incorrect NuvaRing(r) placement, explain how this complication may occur as a result of NuvaRing(r) construction/functionality, describe how alternative cystoscopic instruments may aid in cystoscopic retrieval, and review the 3 other case reports of intravesicular NuvaRing(r) placement to discuss the utility of various imaging modalities when clinical suspicion of the complication is high. PMID- 25926914 TI - Pentalogy of Cantrell with Ectopia Cordis: CT Findings. AB - A 14-month-old girl with pentalogy of Cantrell, a very rare congenital syndrome characterized by an epigastric omphalocele and malformations of the heart, sternum, pericardium, and diaphragm, underwent echocardiography and multidetector computed tomography before surgical repair of these deformities was attempted. These tests revealed multiple cardiovascular and noncardiovascular abnormalities. After surgery, the patient's cardiovascular status was stable. Although studies have shown that echocardiography, multidetector computed tomography, and magnetic resonance imaging may each play a role in the diagnosis and management of this condition, there are few data available to support the use of one imaging modality over another. PMID- 25926915 TI - Lumbar discal cyst: Diagnostic discography followed by therapeutic computed tomography-guided aspiration and injection. AB - Discal cysts are extradural masses that communicate with the intervertebral disk and are a rare cause of lower back pain and lumbar radiculopathy. This case report describes a lumbar discal cyst, the diagnosis of which was confirmed on conventional discography, and which was treated with computed tomography-guided aspiration and steroid injection. Several reports have described this procedure, but only one in the radiology literature, and thus the purpose of this report is to remind the radiology community of the existence of this entity and propose a minimally invasive means of treatment. PMID- 25926916 TI - Coronary periarteritis in a patient with multi-organ IgG4-related disease. AB - Immunoglobulin G4-related disease is a recently described systemic clinicopathological entity characterized by immunoglobulin G4-producing plasmacytic infiltration of tissue and frequently by elevated serum immunoglobulin G4 concentration. Manifestations of this disease have been documented in nearly all organs and locations, but coronary artery involvement is not widely recognized. We report the coronary findings of a patient with multi organ immunoglobulin G4-related disease. Non-electrocardiogram-gated computed tomography of the chest demonstrated nodular and rind-like periarterial soft tissue thickening along the proximal coronary artery segments with improvement following steroid therapy. PMID- 25926917 TI - Seeding of the rectus sheath with hepatocellular carcinoma after image guided percutaneous liver biopsy using coaxial biopsy needle system. AB - Needle track seeding following image guided needle biopsy is a known but uncommon complication in the workup of hepatocellular carcinoma. We present the case of a 55 year-old male who was found to have a recurrent hepatocellular carcinoma in the rectus sheath five years following a CT guided biopsy with the biopsy needle passing through the anterior abdominal wall muscles. PMID- 25926918 TI - Soft tissue aneurysmal bone cyst: a rare case in a middle aged patient. AB - Soft tissue aneurysmal bone cyst is a rare entity, with about 20 cases reported in literature, only 3 of which are in patients over 40 years of age. We present a case of a 41 year old Latin American female who presented for evaluation of atraumatic chest pain with radiation to the left shoulder. Her initial workup was negative, including radiographic imaging of the chest and left shoulder. 4 months later, she presented to her orthopedic surgeon with a palpable mass and mild left shoulder pain. Radiographs acquired at that time demonstrated a 7.0 * 5.5 * 6.7 cm mass with rim calcification in the region of the upper triceps muscle. Subsequent CT imaging showed central areas of hypodensity and thin septations, a few of which were calcified. MR evaluation showed hemorrhagic cystic spaces with multiple fluid-fluid levels and enhancing septations. Surgical biopsy was performed and pathology was preliminarily interpreted as cystic myositis ossificans, however on final review the diagnosis of soft tissue aneurysmal bone cyst was made. The lesion was then surgically excised and no evidence of recurrence was seen on a 3 year post-op radiograph. Following description of our case, we conduct a literature review of the imaging characteristics, diagnosis, and treatment of soft tissue aneurysmal bone cyst. PMID- 25926919 TI - Inflammatory pseudotumor of the urinary bladder. AB - We report a case of an inflammatory pseudotumor of the urinary bladder in a 31 year-old woman. She presented at the emergency room with low abdominal pain and urinary symptoms. Abdominal ultrasound, computed tomography and magnetic resonance imaging were performed and revealed asymmetric thickening of the urinary bladder wall. Cystoscopy with urinary cytology revealed a benign nature of the process. The patient underwent partial cystectomy and the pathologic examination of the specimen revealed an inflammatory pseudotumor. We reviewed the clinical, imaging and pathological features of the inflammatory pseudotumor of the urinary bladder and discussed its differential diagnosis. PMID- 25926920 TI - Transduodenal migration of a retained surgical swab causing small bowel obstruction--imaging findings in the acute setting and prior to onset of symptoms. AB - Transmural migration of a retained surgical sponge causing small bowel obstruction is a rare occurrence. We report a case which demonstrates both the associated foreign body reaction seen on computed tomography months in advance of the onset of symptoms and confirms the subsequent fistulous decompression into the duodenum on both computed tomography and barium meal studies. To the best of the author's knowledge, a retained surgical swab causing small bowel obstruction has not been previously described with imaging both pre and post transluminal decompression. PMID- 25926922 TI - IgG4-Related Disease Presenting as a Solitary Neck Mass. AB - IgG4-related disease is a newly recognized entity associated with autoimmune conditions involving almost every organ system. It is characterized by elevated serum IgG4 as well as mass like tissue infiltration by IgG4-positive plasma cells. Imaging findings are nonspecific, vary depending on the site of disease, and include mass like enlargement of the salivary or lacrimal glands and enlarged lymph nodes. Radiographic findings often mimic malignancy, necessitating tissue sampling to confirm the diagnosis. Distinguishing IgG4-related disease from malignancy is important as IgG4 responds well to steroids and conservative management. PMID- 25926923 TI - Pulmonary imaging abnormalities in an adult case of congenital lobar emphysema. AB - Congenital lobar emphysema is mainly diagnosed in infants, although rare cases are reported in adults. A 20-yr-old female with acute dyspnea, chest pain and left upper lobe (LUL) chest x-ray hyperlucency underwent 3He magnetic resonance imaging (MRI) for ventilation and apparent diffusion coefficient (ADC) measurements, as well as CT for emphysema and airway wall measurements. Forced expiratory volume in 1s, residual volume, and airways-resistance were abnormal, but there was normal carbon-monoxide-diffusing-capacity. The LUL relative area of the density histogram <-950 HU and airway morphology were highly abnormal compared with the other lobes and coincident with highly abnormal MRI-derived acinar duct dimensions. CT also identified bronchial atresia and congenital lobar emphysema as the source of symptoms in this case where there was also functional imaging evidence of collateral ventilation from the fissure (and not the abnormally terminated airway) into the emphysematous LUL. PMID- 25926924 TI - Situs ambiguous, levocardia, right sided stomach, obstructing duodenal web, and intestinal nonrotation: a case report. AB - When approaching a case with a situs abnormality, using the proper terminology, making a specific diagnosis, and understanding the other often associated abnormalities that need to be excluded are of great importance. We present a case of situs ambiguous in the presence of intestinal nonrotation and an obstructing duodenal web. Our patient initially presented at two days old with bilious emesis and failure to pass meconium after birth. An abdominal radiograph demonstrated an unusual bowel gas pattern, a reversed "double bubble" sign. A subsequent thorough imaging survey was crucial to further characterize our patient's unique anatomy. Overall, our case demonstrates many of the unusual plain radiographic and sonographic findings associated with our patient's situs abnormality and allows for review of situs abnormalities and their significance. PMID- 25926925 TI - Synovial sarcoma of the abdominal wall: Imaging findings and review of the literature. AB - Synovial sarcoma is the fourth most common type of soft-tissue sarcoma (following undifferentiated pleomorphic sarcoma, liposarcoma, and rhabdomyosarcoma), and should be considered a high-grade neoplasm with a high number of local recurrences and late metastases. Synovial sarcoma predominantly occurs in adolescents and young adults, and typically arises near the joints of the lower extremity. However, this tumor can also occur at uncommon sites such as the abdominal wall, which is illustrated in this article. Furthermore, we reviewed the available literatures on the clinical, pathological and radiological appearances, as well as the current knowledge concerning treatment options and prognosis. PMID- 25926926 TI - Systemic mastocytosis: a rare cause of single vertebral body uptake on bone scan. AB - Systemic Mastocytosis is a rare condition characterized by the abnormal proliferation of Mast Cells. Presentation as a solitary vertebral body lesion is extremely uncommon and may be confused with more ominous conditions such as metastasis. Familiarity with the condition can heighten clinical suspicion, direct tissue diagnosis, guide management and indicate appropriate follow up. We present a case of a 64-year-old woman undergoing staging for recently diagnosed breast cancer who was found to have Systemic Mastocytosis of a single vertebral body. PMID- 25926927 TI - A case of neurocutaneous melanosis and neuroimaging findings. AB - Neurocutaneous melanosis is a rare congenital disorder which presents with congenital cutaneous nevi and involvement of the central nervous system. We herein present a rare case of a 2-year-old girl who had central nervous system melanosis and giant congenital melanocytic nevi. Magnetic resonance imaging, especially precontrast T1 images play a crucial role in making the diagnosis combined with the skin findings of physical examination. PMID- 25926928 TI - Congenital midline cervical cleft. AB - Congenital midline cervical cleft is a rare anomaly that typically presents in the neonatal period as a thin suprasternal vertical band of erythematous skin with a nipple-like projection superiorly, which may exude fluid. We present the clinical and pathophysiologic features and the imaging findings of this uncommon, and rarely described entity in a newborn girl. PMID- 25926929 TI - Amniotic band syndrome with sacral agenesis and umbilical cord entrapment: A case report emphasizing the value of evaluation of umbilical cord. AB - Amniotic band syndrome is a rare congenital disorder caused by entrapment of fetal parts by fibrous amniotic bands in utero. The congenital anomalies seen in this syndrome vary widely and defects may be isolated or multiple and do not follow a specific pattern. Asymmetric distribution of defects is the hallmark of this syndrome. The diagnosis is difficult to make on ultrasound and relies on identification of amniotic bands. We report a case of amniotic band syndrome with sacral agenesis diagnosed on routine antenatal ultrasound scan in the second offspring of a recently diagnosed diabetic mother. The associated features were entrapment of umbilical cord, caudal adhesions and lower limb anomalies. Medical termination of pregnancy was done and all the fetal anomalies as well as umbilical cord abnormalities were confirmed. The importance of meticulous scanning to evaluate for amniotic bands and the umbilical cord in addition to the fetal structures is emphasized. PMID- 25926930 TI - Posterior Hoffa's fat pad impingement secondary to a thickened infrapatellar plica: a case report and review of the literature. AB - We report a case of posterior hoffitis in a middle-aged woman with no prior history of significant major trauma. Her symptoms of anterior knee pain and limited extension failed conservative measures. Preoperative magnetic resonance imaging demonstrated a significantly thickened infrapatellar plica tethering Hoffa's fat pad in the anterior interval of the knee. Arthroscopic resection of the infrapatellar plica resulted in complete resolution of symptoms within six months following the surgery. PMID- 25926931 TI - Chronic innominate artery occlusion with hyperacute intracranial thromboembolism: Revascularization with simultaneous local thromboaspiration and mechanical thrombectomy. AB - Chronic innominate artery occlusion with acute right internal carotid terminus thromboembolism and successful revascularization using simultaneous local thromboaspiration and mechanical thrombectomy has not been previously described. A 51-year-old male presented with transient left hemiparesis. A CT angiogram of the head and neck demonstrated chronic occlusion of the right innominate artery with no intracranial thromboembolism. More profound symptoms recurred twelve hours after admission. A diagnostic catheter-based angiogram confirmed occlusion of the innominate artery and identified hyper-acute right carotid terminus thromboembolism. Angioplasty of the innominate artery was followed by simultaneous mechanical and aspiration thrombectomy of the right internal carotid artery terminus. Combination local thromboaspiration and mechanical thrombectomy was shown in this case to be effective in achieving a favorable clinical outcome. PMID- 25926932 TI - Gluten free diet is a cure not a poison! PMID- 25926933 TI - Innate immune system: the no man's land where discover new biomarkers for gluten related-disorders. PMID- 25926934 TI - Mucosal histopathology in celiac disease: a rebuttal of Oberhuber's sub-division of Marsh III. AB - Individuals with particular genetic backgrounds develop immune responses to wheat proteins and become 'gluten-sensitised'. Mucosal pathology arises through activated mucosal T lymphocytes, resulting in a graded, adverse reaction between particular genes and wheat proteins. Given these varied influences, the Marsh Classification broadly itemises those stages through which a normal mucosa (Marsh 0) evolves in becoming 'flat' (Marsh I, II, III). Recently, Oberhuber and colleagues suggested that Marsh III lesions required subdividing into a, b, c categories. We critically examined these subdivisions by means of correlative light and scanning electron microscopy (SEM). Our results demonstrate that Oberhuber's classification is untenable. In our view deriving from our observations, the artificial subdivisions proposed by those authors actually reflect misinterpretations of the true architectural contours of flat mucosae. Although these workers refer to "villous projections", SEM demonstrates that no such structures are present on flat - or immediately recovering - mucosae. Our data revealed on the surfaces of flat (Marsh III) mucosae, large open "basins", surrounded by raised collars - the latter, when viewed in histological section, being easily misconstrued as "villi". It seems that with subsequent upward growth, these collars coalesce into low ridges, thence becoming broader and higher convolutions. It is noticeable that there are more open spaces on the surfaces of flat mucosae than was appreciated hitherto. We conclude that Oberhuber's revisions of Marsh III into three subcategories (a, b, c), are misinterpretations of the histological appearances of flattened mucosae. Therefore, histopathologists when classifying celiac mucosae, since they add nothing either of diagnostic, nor prognostic, value should resist these subcategories. PMID- 25926935 TI - Seronegative celiac disease: where is the specific setting? AB - The diagnosis of Celiac Disease (CD) relies on the concordance of pathological, serological, genetic and clinical features. For this reason, the diagnosis of CD is often a challenge. Seronegative celiac disease (SNCD) is defined by the negativity of anti-tissue transglutaminase antibodies in the presence of a positive histology on duodenal biopsy samples, i.e. inflammatory infiltrate of intra-epithelial lymphocytes (IELs > 25/100 enterocytes), mild villous atrophy and uneven brush border associated to human leukocyte antigen (HLA) haplotype DQ2 and/or DQ8. SNCD is characterized by mucosal deposits of tissue transglutaminase (tTG)/anti-tTG immuno-complexes. These may counteract the passage of anti-tTG into the bloodstream, thus explaining seronegativity. Another reason for seronegativity may be found in an incomplete maturation of plasma cells with a consequent failure of antibodies production. This condition often characterizes immunoglobulin deficiencies, and, indeed, SNCD is common in subjects with immunoglobulin deficiencies. The management of SNCD still remains debated. The treatment option for SNCD may be represented by gluten free diet (GFD), but the usefulness and appropriateness of prescribing GFD are controversial. Some evidences support its use only in SNCD subjects showing CD clear clinical picture and compatible HLA status. The choice of GFD administration could be linked to an investigation able to diagnose SNCD in no doubt even if a reliable test is not currently available. On these bases, a test helping the diagnosis of SNCD is justifiable and desirable. PMID- 25926936 TI - Th17, intestinal microbiota and the abnormal immune response in the pathogenesis of celiac disease. AB - Celiac disease (CD) is an autoimmune enteropathy induced by the ingestion of gluten in genetically predisposed individuals who carry the HLA-DQ2 or -DQ8 alleles. The immune response is abnormal in celiac disease with small intestinal epithelial damage via CD8+CD4- intraepithelial lymphocytes. The etiology is multifactorial involving genetic and environmental factors, an abnormal immune response, and intestinal dysbiosis. The innate and acquired T-cell mediated immunity play important roles in the pathogenesis of this disease, particularly CD4+ Th17 cells, which have been shown to have critical functions in host defense against bacterial pathogens and in the inflammatory responses to deamidated gluten peptides. We review what is known about the interaction between immune system and intestinal microbiota in the pathogenesis of celiac disease. PMID- 25926937 TI - The relationship between intestinal parasites and some immune-mediated intestinal conditions. AB - Over the last decades, the incidence of infestation by minor parasites has decreased in developed countries. Infectious agents can also suppress autoimmune and allergic disorders. Some investigations show that various protozoa and helminthes are connected with the main immune-mediated intestinal conditions including celiac disease (CD), inflammatory bowel diseases (IBD) and irritable bowel syndrome (IBS). Celiac disease is a digestive and autoimmune disorder that can damage the small intestine and characterized by a multitude gastrointestinal (GI) and extra GI symptoms. IBD (including ulcerative colitis and Crohn's disease) is a group of inflammatory conditions of the small intestine and colon. The etiology of IBD is unknown, but it may be related to instability in the intestinal microflora that leading to an immoderate inflammatory response to commensal microbiota. Irritable bowel syndrome (IBS) is a common, long-term condition of the digestive system. Bloating, diarrhoea and/or constipation are nonspecific symptoms of IBS. Various studies have shown that some intestinal parasites can effect on immune system of infected hosts and in some cases, they are able to modify and change the host's immune responses, particularly in autoimmune disorders like celiac disease and IBD. The main objective of this review is to investigate the relationship between intestinal parasites and different inflammatory bowel disorders. PMID- 25926938 TI - Phenotypical characterization of the peripheral blood T cells in patients with celiac disease: does it differentiate suspicious celiac disease cases? AB - AIM: The present study aimed to study the immunological changes seen in the intestinal epithelium of the celiac patients could also be detected in the peripheral blood lymphocyte populations. BACKGROUND: Celiac disease (CD) is a small bowel enteropathy caused by permanent wheat gluten intolerance. One of the earliest signs of CD is an increase in the numbers of the intestinal intraepithelial lymphocytes (iIEL). PATIENTS AND METHODS: In this case-control study, totally 13 untreated subjects with acceptable criteria for CD without any complication and 16 healthy subjects without any positive criteria for CD were selected. Peripheral blood T cells were analyzed by two-color flow cytometry in both groups. RESULTS: The mean age of patients was 33.6 +/- 3.4 years and two patients had Marsh IIIB, five patients had Marsh IIIA and six patients had Marsh II histology class. The mean percentages of the TCR(+) T cells in the patients were significantly higher than the controls (p=0.015). However, the mean percentages of the alphabetaTCR(+) T cells were significantly lower in the untreated patients than the controls (p=0.025). There were no significant difference between the mean percentages of lymphocytes expressing the CD3, CD4 and CD8 molecules in the patients and the controls. CONCLUSION: The change in the percentages of the peripheral blood T cells expressing the gammadeltaTCR and alphabetaTCR in the celiac patients could be used in conjunction with the other serological markers to identify new CD cases. PMID- 25926939 TI - Is it necessary to screen for celiac disease in adult idiopathic osteoporosis? AB - AIM: the aim of this study was to investigate the necessity of screening for celiac disease in idiopathic osteoporotic patients. BACKGROUND: Osteopenia and osteoporosis are well-known and prevalent complications of celiac disease. However, the relative prevalence of celiac disease among osteoporotic populations is not known, and the benefit of screening for celiac disease among the osteoporotic population remains controversial. PATIENTS AND METHODS: We evaluated a total of 560 individuals, 460 with osteoporosis and 100 healthy subjects, from the rheumatology clinic in Imam Khomeini and Shariati hospital by IgA anti-tissue transglutaminase (anti-tTG) for celiac disease. Then individuals with positive serologic test underwent upper GI Endoscopy & 2nd part duodenum biopsies. The clinical findings were evaluated in both groups and were compared with each other. RESULTS: Five (1.08%) of 460 patients with osteoporosis and 1 (1%) of 100 subjects without osteoporosis had celiac disease by positive serologic & pathology results. Three patients with positive serology & pathology results were female. All patients in osteoporotic group had at least one other symptom of celiac disease. Two of them had anemia and others had chronic abdominal pain, recurrent oral aphtous lesion & chronic bloating. CONCLUSION: In the present study, the prevalence of celiac disease in osteoporotic patients is not high enough to justify recommendation for serologic screening of celiac disease in all patients with idiopathic osteoporosis; but in osteoporotic patients with other celiac or gastrointestinal symptoms and signs, for example iron deficiency anemia, chronic dyspepsia and bloating, constipation or diarrhea and recurrent aphtous lesions, it is necessary to evaluate for celiac disease. PMID- 25926940 TI - Clinical and immunological relevance of anti-neuronal antibodies in celiac disease with neurological manifestations. AB - AIM: To assess anti-neuronal antibodies (NA) prevalence and their correlation with neurological disorders and bowel habits in celiac disease (CD) patients. BACKGROUND: Neurological manifestations are estimated to occur in about 10% of celiac disease patients and NA to central nervous system (CNS) and enteric nervous system (ENS) are found in a significant proportion of them. Little is known about the clinical and immunological features in CD patients with neurological manifestations. PATIENTS AND METHODS: NA to CNS and ENS were investigated in 106 CD patients and in 60 controls with autoimmune disorders by indirect immunofluorescence on rat / primate cerebellar cortex and intestinal (small and large bowel) sections. RESULTS: IgG NA to CNS (titer 1:50 - 1:400) were positive in 23 celiacs (21%), being more frequently detected in those with neurological disorders that in those without neurological dysfunction (49% vs. 8%, P< 0.0001). Of the 26 celiacs (24%) with IgG NA to ENS, 11 out of 12 with an antibody titer > 1:200 had severe constipation. Only one patient with cerebellar ataxia and intestinal sub-occlusion was positive for NA to CNS and ENS. NA to CNS and ENS were found in 7% and 5% of controls, respectively. CONCLUSION: In CD the positivity of NA to CNS can be regarded as a marker of neurological manifestations. High titer NA to ENS are associated with severe constipation. The demonstration of NA to CNS and ENS suggests an immune-mediated pathogenesis leading to central neural impairment as well as gut dysfunction (hence constipation), respectively. PMID- 25926941 TI - Serologic evaluation of celiac disease in patients with beta thalassemia major and control. AB - AIM: This study reports evaluated prevalence of CD in patients with Beta thalassemia major. BACKGROUND: Celiac Disease (CD) is an autoimmune disorder triggered by ingestion of gluten in genetically predisposed individuals. PATIENTS AND METHODS: In this case-control study in a period of 3 years, which was performed on 620 children in two groups of Beta-thalassemia major patients (n=200) and control (n=420), serum tissue transglutamianse (tTG) IgA levels were measured. The two groups were compared together in terms of tTG IgA levels, and p<0.05 was considered significant. RESULTS: The means of serum tTG IgA levels in patients with Beta-thalassemia major and control groups were 28.81+/-68.44 and 6.94+/-6.68 U/mL, respectively. There was a significant difference in favor of the case group (p=0.000). Body mass index in the two case and control groups had a significant difference (t=3.859, p=0.001). Belonging to each group will change the probability of having less than 20 in tTG IgA (odds=0.285) and it means that belonging to the control group has a protective role. There is only a significant association in the case of all population (r=0.102, p=0.011). Body mass index in the two case and control groups had a significant difference (t=3.859, p=0.001). CONCLUSION: Probability of CD should be considered since the prevalence of CD is high in patients with and Beta-thalassemia major. Patients with thalassemia major are recommended for screening for CD. PMID- 25926942 TI - Does gluten free diet have more implications than treatment of celiac disease? AB - AIM: This study was aimed to evaluate symptomatic as well as histopathologic response to GFD in patients with gluten-sensitive enteropathies including celiac disease, lymphocytic duodenosis and non-specific duodenitis. BACKGROUND: Gluten free diet (GFD) is the main treatment of celiac disease. However, its impact on other disorders of gluten sensitivity spectrum is less clear. PATIENTS AND METHODS: In a prospective observational study in Modarres hospital Tehran, Iran, 35 patients with chronic manifestations including low BMI, diarrhea, greasy stool and bloating were evaluated using serology for anti-tTG, endoscopy and histopathology. Patients were categorized in three diagnostic groups accordingly including celiac disease (CD), lymphocytic doudenosis (LD) and non-specific duodenitis (NSD). All patients were put on a GFD for 6 months, and subjective symptomatic response, serology, endoscopy and histopathologic tests were repeated and compared with baselines and among groups. RESULTS: Of the total 35 patients, 5 had CD (14.3%), 9 had LD (25.7%) and 21 (60%) had NSD. Bloating was the most common symptom followed by diarrhea. Majority of patients (80%) had low BMI. All symptoms alleviated following a GFD but bloating was the only significant one. A significant increase was found in total mean BMI (17.3+/-0.7 v.s. 17.9+/-0.9). Histopathologic examination showed a complete resolution in 48.5% (n=17) patients, 10 in NSD group, 4 in LD group and 3 in CD group. Final prevalence of gluten-sensitive enteropathy (LD and NSD cases that responded to GFD) was 46.6%. CONCLUSION: GFD may have more implications other than celiac disease. Other gluten-sensitive enteropathies, like LD and NSD, might also respond to this treatment particularly in patients with low BMI. PMID- 25926943 TI - An unusual cause of constipation in a patient without any underlying disorders. AB - Constipation is the most common digestive complaint in the general population. It is associated with considerable adverse effect on quality of life and substantial economic costs and often has no underlying pathology. Non-Celiac Gluten Sensitivity (NCGS) has been described as a cause of constipation in a few studies. We present a 62-year-old male with long standing constipation without any underlying cause during extensive surveys and not responding to any conservative treatment but significant response with gluten free diet (GFD). PMID- 25926944 TI - Histology of gluten related disorders. PMID- 25926945 TI - Autistic disorders and medical biotechnology. PMID- 25926946 TI - Production and Characterization of Monoclonal Antibodies against Human Prostate Specific Antigen. AB - BACKGROUND: Prostate Specific Antigen (PSA) is an important laboratory marker for diagnosis of prostatic cancer. Thus, development of diagnostic tools specific for PSA plays an important role in screening, monitoring and early diagnosis of prostate cancer. In this paper, the production and characterization of a panel of murine monoclonal antibodies (mAbs) against PSA have been presented. METHODS: Balb/c mice were immunized with PSA, which was purified from seminal plasma. Splenocytes of hyperimmunized mice were extracted and fused with Sp2/0 cells. By adding selective HAT medium, hybridoma cells were established and positive clones were selected by ELISA after four times of cloning. The isotypes of produced mAbs were determined by ELISA and then purified from ascitic fluids using Hi-Trap protein G column. The reactivities of the mAbs were examined with the purified PSA and seminal plasma by ELISA and western blot techniques. Furthermore, the reactivities of the mAbs were assessed in Prostate Cancer (PCa), Benign Prostatic Hyperplasia (BPH) and brain cancer tissues by Immunohistochemistry (IHC). RESULTS: Five anti-PSA mAbs (clones: 2G2-B2, 2F9-F4, 2D6-E8, IgG1/K) and clones (2C8-E9, 2G3-E2, IgG2a/K) were produced and characterized. All mAbs, except 2F9 F4 detected the expression of PSA in PCa and BPH tissues and none of them reacted with PSA in brain cancer tissue in IHC. Besides, all mAbs could detect a protein band around 33 kDa in human seminal plasma in western blot. CONCLUSION: These mAbs can specifically recognize PSA and may serve as a component of PSA diagnostic kit in various biological fluids. PMID- 25926947 TI - Comparative Analysis of Prostate Cancer Gene Regulatory Networks via Hub Type Variation. AB - BACKGROUND: Prostate cancer is one of the most widespread cancers in men and is fundamentally a genetic disease. Identifying regulators in cancer using novel systems biology approaches will potentially lead to new insight into this disease. It was sought to address this by inferring gene regulatory networks (GRNs). Moreover, dynamical analysis of GRNs can explain how regulators change among different conditions, such as cancer subtypes. METHODS: In our approach, independent gene regulatory networks from each prostate state were reconstructed using one of the current state-of-art reverse engineering approaches. Next, crucial genes involved in this cancer were highlighted by analyzing each network individually and also in comparison with each other. RESULTS: In this paper, a novel network-based approach was introduced to find critical transcription factors involved in prostate cancer. The results led to detection of 38 essential transcription factors based on hub type variation. Additionally, experimental evidence was found for 29 of them as well as 9 new transcription factors. CONCLUSION: The results showed that dynamical analysis of biological networks may provide useful information to gain better understanding of the cell. PMID- 25926948 TI - Effects of Combined Soy Isoflavone Extract and Docetaxel Treatment on Murine 4T1 Breast Tumor Model. AB - BACKGROUND: Emergence of drug resistance has brought major problems in chemotherapy. Using nutrients in combination with chemotherapy could be beneficial for improvement of sensitivity of tumors to drug resistance. Soybean derived isoflavones have been suggested as chemopreventive agents for certain types of cancer, particularly breast cancer. In this study, the synergistic effects of soy isoflavone extract in combination with docetaxel in murine 4T1 breast tumor model were investigated. METHODS: In this study, mice were divided into 4 groups (15 mice per group) of control, the dietary Soy Isoflavone Extract (SIE, 100 mg/kg diet), the Docetaxel (DOCE, 10 mg/kg) injection and the combination of dietary soy isoflavone extract and intravenous docetaxel injection (DOCE+SIE). After 3 injections of docetaxel (once a week), 7 mice were sacrificed to analyze MKI67 gene and protein expressions and the rest were monitored for diet consumption, tumor growth and survival rates. RESULTS: In DOCE+SIE group, diet consumption was significantly higher than DOCE group. While lifespan showed a trend towards improvement in DOCE+SIE group, no significant difference was observed among the 4 studied groups. Tumor volume was not significantly affected in treated groups. A lower but not significant MKI67 protein expression was detected in western blot in DOCE+SIE group. The mRNA expression was not significantly different among groups. CONCLUSION: The results suggest that the combination of soy isoflavone as an adjunct to docetaxel chemotherapy can be effective in improving diet consumption in breast cancer. PMID- 25926949 TI - Intravenous transplantation of very small embryonic like stem cells in treatment of diabetes mellitus. AB - BACKGROUND: Diabetes Mellitus (DM), simply known as diabetes, refers to a group of metabolic diseases in which there are high blood sugar levels over a prolonged period. In this study, the feasibility and safety of intravenous transplantation of Very Small Embryonic Like stem cells (VSELs) were investigated for diabetes repair, and finally the migration and distribution of these cells in hosts were observed. METHODS: Mouse bone marrow VSELs were isolated by Fluorescent Activating Cell Sorting (FACS) method by using fluorescent antibodies against CD45, CXCR4 and Sca1 markers. Sorted cells were analyzed for expression of oct4 and SSEA1 markers with immunocytochemistry staining method. To determine multilineage differentiation, sorted cells were differentiated to Schwann, osteocyte and beta cells. Ten days after the establishment of a mouse model of pancreas necrosis, DiI-labeled VSELs were injected into these mice via tail vein. Pancreases were harvested 4 weeks after transplantation and the sections of these tissues were observed under fluorescent microscope. RESULTS: It was proved that CD45-, CXCR4+, and Sca1+ sorted cells express oct4 and SSEA1. Our results revealed that intravenously implanted VSELs could migrate into the pancreas of hosts and survive in the diabetic pancreas. In treated groups, blood glucose decreased significantly for at least two month and the weights of mice increased gradually. CONCLUSION: This study provides a strategy for using VSELs for curing diabetes and other regenerative diseases, and the strategy is considered an alternative for other stem cell types. PMID- 25926950 TI - ADSCs on PLLA/PCL Hybrid Nanoscaffold and Gelatin Modification: Cytocompatibility and Mechanical Properties. AB - BACKGROUND: Development of tissue engineering and regenerative medicine has led to designing scaffolds and their modification to provide a better microenvironment which mimics the natural niche of the cells. Gelatin surface modification was applied to improve scaffold flexibility and cytocompatibility. METHODS: PLLA/PCL aligned fibrous scaffold was fabricated using electrospinning method. ADSCs were seeded after O2 plasma treatment and gelatin coating of the scaffolds. The morphological and mechanical properties of blends were assessed by Scanning Electron Microscopy (SEM), tensile test and ATR-FTIR. The cells proliferation was evaluated by MTT assay. RESULTS: Based on the results, it is supposed that gelatin coating is a brilliant method of surface modification which significantly increases the mechanical properties of scaffold without any changes on the construction or on the direction of nanofibers which conducts cell's elongation. MTT analysis exhibited that ADSCs attachment, viability and proliferation significantly (p < 0.05) increased after gelatin treatment. CONCLUSION: Gelatin surface modification is a highly beneficial method to improve cytocompatibility, flexibility and mechanical features of the scaffolds which doesn't affect the nanofibers construction. Proliferation of Adipose Derived Stem Cells (ADSCs) as a remarkable source of stem cells was investigated for the first time on PLLA/PCL hybrid scaffold. PMID- 25926951 TI - Cloning and Expression of CD19, a Human B-Cell Marker in NIH-3T3 Cell Line. AB - BACKGROUND: CD19 is a pan B cell marker that is recognized as an attractive target for antibody-based therapy of B-cell disorders including autoimmune disease and hematological malignancies. The object of this study was to stably express the human CD19 antigen in the murine NIH-3T3 cell line aimed to be used as an immunogen in our future study. METHODS: Total RNA was extracted from Raji cells in which high expression of CD19 was confirmed by flow cytometry. Synthesized cDNA was used for CD19 gene amplification by conventional PCR method using Pfu DNA polymerase. PCR product was ligated to pGEM-T Easy vector and ligation mixture was transformed to DH5alpha competent bacteria. After blue/white selection, one positive white colony was subjected to plasmid extraction and direct sequencing. Then, CD19 cDNA was sub-cloned into pCMV6-Neo expression vector by double digestion using KpnI and HindIII enzymes. NIH-3T3 mouse fibroblast cell line was subsequently transfected by the construct using Jet-PEI transfection reagent. After 48 hours, surface expression of CD19 was confirmed by flow cytometry and stably transfected cells were selected by G418 antibiotic. RESULTS: Amplification of CD19 cDNA gave rise to 1701 bp amplicon confirmed by alignment to reference sequence in NCBI database. Flow cytometric analysis showed successful transient and stable expression of CD19 on NIH-3T3 cells (29 and 93%, respectively). CONCLUSION: Stable cell surface expression of human CD19 antigen in a murine NIH-3T3 cell line may develop a proper immunogene which raises specific anti-CD19 antibody production in the mice immunized sera. PMID- 25926952 TI - Use of Raman spectroscopy to decrease time for identifying the species of Candida growth in cultures. AB - BACKGROUND: The objective of this study is to establish Raman signatures from pure cultures of different Candida species using Raman Spectroscopy (RS) and use these signatures for rapid identification of unknown Candida species. METHODS: Pure cultures of five Candida species were evaluated using RS to build a limited signature library. 'Raman Processing' (RP) software was used for Principal Component Analysis (PCA) and Differential Functional Analysis (DFA). RESULTS: Eleven principal components described at least 95% variance in the spectra. Raman signatures from these known Candida species were able to identify the species of unknown Candida cultures with 100% accuracy. CONCLUSION: Raman spectroscopy can improve early identification of Candida species and may facilitate early optimal antifungal therapy. PMID- 25926953 TI - Varicella immunity in Iran: an age-stratified systematic review and meta analysis. AB - OBJECTIVES: To generate synthesized information on the epidemiology of VZV infection, as well as an estimation of prevalence of age-specific antibody in Iranian less than 40. MATERIAL AND METHODS: After exclusion of irrelevant and overlapping reports, 15 papers were included (from nine major cities). Studies were pooled according to the heterogeneity test results. Random effect model methods were used for meta-analysis where significant heterogeneity was observed (age 1-16years).For other age groups, fixed model were used. RESULTS: Significant heterogeneity was observed in prevalence rates of all childhood age-groups. The seropositivity prevalence increased steeply from the age of 1-5 to 6-10 [from 21.9% (95% CI; 10.8-33.1) to 42.1 %(95% CI; 33.6-50.6)]. At the age of 11 15, 59.4% (95% CI; 46.1-72.8) of children showed to be infected. The rate of seropositivity was more than 87% in individuals of 40 and older. CONCLUSION: The varicella seroeprevalence in Iran is in accordance with average tropical and temperate areas. Comparison of conducted studies during 2003 to 2011 didn't show any alteration in VZV seroprovalence in Iran. PMID- 25926954 TI - Antimicrobial susceptibility trends among Streptococcus pneumoniae over an 11 year period in an Iranian referral children Hospital. AB - BACKGROUND AND OBJECTIVES: The appearance of antibiotic resistance in Streptococcus pneumoniae has raised a global concern over the past three decades. This study was conducted to determine the antimicrobial susceptibility of S. pneumoniae isolated from patients in Children's Medical Center (CMC) Hospital during 2001 to 2011. MATERIALS AND METHODS: During the 11 years period, a total of 194 S. pneumoniae isolates were collected in CMC Hospital. Antimicrobial susceptibility testing was performed by the Kirby-Bauer disk diffusion method and time-series analysis was used to evaluate the antimicrobial susceptibility changes over the time. RESULTS AND CONCLUSION: Antimicrobial susceptibility of S. pneumoniae to different antibiotics decreased from 2001 to 2011 as: penicillin from 78% to 32%, erythromycin from 75% to 35%, chloramphenicol from 94% to 55%, ampicillin from 70% to 62%, ceftriaxone from 100% to 87%, sulfametoxazole from 57% to 40%. We did not find any significant difference between the susceptibility of isolates from sterile and non-sterile sources. It would be an important key to consider antimicrobial stewardship as an essential factor to prevent the development of antimicrobial resistance. PMID- 25926955 TI - Choosing the correct empirical antibiotic for urinary tract infection in pediatric: Surveillance of antimicrobial susceptibility pattern of Escherichia coli by E-Test method. AB - BACKGROUND AND OBJECTIVES: Urinary Tract Infections (UTIs) are of the most common bacterial diseases worldwide. We investigate the antibiotic susceptibility patterns of Escherichia coli (E. coli) strains isolated from pediatric patients with community acquired urinary tract infection (UTI) to find a clinical guidance for choosing a right empirical antibiotic in these patients. MATERIALS AND METHODS: In this cross sectional study, 100 urine specimens which were positive for E. coli had been investigated for antibiotics susceptibility pattern. The susceptibility to Co-trimoxazol (25MUg), Amikacin (30MUg), Ceftriaxone (30MUg), Nalidixic Acid (30MUg), Cefixime (5MUg), and Nitrofurantoin (300MUg) tested with Disk diffusion agar and MIC determined with the E-test. RESULTS: Mean age of patients was 38 Months. Girls had greater proportion than boys (74 versus 26%). In Disk diffusion method, 26% of the isolates were susceptible to cotrimoxazole. Susceptibility to amikacin, ceftriaxone, nitrofurantoin, nalidixic acid and cefixime was 94%, 66%, 97%, 62% and 52%, respectively. By E-Test method and according to CLSI criteria susceptibility for co-trimoxazol, amikacin, ceftriaxone and nalidixic acid was 37%, 97%, 67% and 50%, respectively. The highest percentage of agreement between Disk diffusion and E-Test method was found for amikacin (96%) and the lowest percentage for co-trimoxazole (89%). CONCLUSIONS: Treatment failure, prolonged or repeated hospitalization, increased costs of care, and increased mortality are some consequence of bacterial resistance in UTIs. Misuse of antibiotics in each geographic location directly affects antibiotic resistance pattern. In the treatment of UTI, proper selection of antimicrobial agents should be relevant to the bacterial susceptibility testing surveillance. According to our results, amikacin as an injectable drug and nitrofurantoin as an oral agent could be used as a drug of choice in our region for children with UTIs. PMID- 25926956 TI - Association between Ureaplasma urealyticum endocervical infection and spontaneous abortion. AB - BACKGROUND AND OBJECTIVES: Ureaplasma urealyticum can colonize women genital tract and be isolated from the amniotic fluid of women with adverse pregnancy outcomes. The association of U. urealyticum with spontaneous abortion remains controversial. The aim of this study was to evaluate the frequency of U. urealyticum infection among pregnant women and its association with spontaneous abortion. MATERIALS AND METHODS: In this case-control study we included 109 women with spontaneous abortion with gestation age between 10-20 weeks (Cases), and 109 women with normal pregnancy with gestation age between 20-30 weeks (Controls) in Sanandaj, Iran. Using specific primers and extracted DNA from endocervical swabs, a PCR test was conducted for detection of U. urealyticum in both women groups. RESULTS: Total prevalence of U. urealyticum infection in women was 26 out of 218 cases (11.92%). The prevalence of U. urealyticum infection was 18 out of 109 (16.5%) and 8 out of 109 (7.3%) in case (spontaneous abortion) and control groups, respectively. Using chi-square test, association between U. urealyticum infection and spontaneous abortion was statistically significant (P<0.05). CONCLUSIONS: Colonization of U. urealyticum in genital tract of women, and its asymptomatic feature in combination with other factors such as other microorganisms or cervical incompetence may induce spontaneous abortion. Further studies are needed to confirm this possibility. PMID- 25926957 TI - Detection of genital mycoplasmal infections among infertile females by multiplex PCR. AB - BACKGROUND AND OBJECTIVES: Women reproductive system is a suitable environment for growth of various pathogen and nonpathogenic microorganisms. Mycoplasmataceae is a family of bacteria which cause oligosymptomatic genital infections. The complications caused by these bacteria may lead to infertility in women. The aim of this study was detection of genital Mycoplasma hominis, Ureaplasmaurealyticum and Mycoplasma genitalium among infertile females who referred to the infertility clinics. MATERIALS AND METHODS: A total of 104 infertile women (in reproductive age) who referred to infertility clinics in the city of Sanandaj, Kurdistan, Iran, from February to May 2013 were selected for this study. Cervical swabs were collected from all patients. The presence of genital Mycoplasmas was detected by multiplex-PCR. All data were analyzed statistically. RESULTS: Out of 104 patients, 39 cases (37.5%) were infected with U. urealyticum. Mycuplasma. genitalium and M. homimis were detected in 3 (2.9%) of the infertile women. Co infection was seen in 3.8% of the patients. There was no statistically the infections and patient age, educational levels, literacy, situation of employment, age of first significant sexual intercourse, history of abortion, type of infertility and infertility duration (p value > 0.05). CONCLUSIONS: The data showed a low percentage of infection for M. genitalium and M. hominis in the studied women while the prevalence of U. urealyticum was high. Despite having no symptoms of an ongoing acute inflammation of the reproductive tract, many women may have genital mycoplasmas in the cervix. We concluded that multiplex PCR using a pair of primers is a useful and cost-effective method for diagnosis of female genital infections. PMID- 25926958 TI - Assessing the prevalence of bacterial vaginosis among infertile women of Qom city. AB - BACKGROUND AND OBJECTIVES: Bacterial vaginosis (BV) is a common disorder which happens when the balance of bacterial flora in vagina is disrupted by a shift in concentration of lactobacillus and pathogenic bacteria.It has significant sequelae including increased rates of late miscarriage when diagnosed in early pregnancy, premature rupture of the membranes, endometritis, preterm labour and delivery and tubal factor infertility. So it seems to be necessary to evaluate the prevalence of BV among women with primary infertility. MATERIAL AND METHODS: All specimens were collected during vagina examination by use of a speculum and swabbing. A sampling swab was introduced into vaginal canal and rotated for at least 8 seconds before withdrawal. The vaginal swabs were examined in standard microbiological analysis including of microscopy, culture and sensitivity examination. RESULTS AND CONCLUSION: Totally identified Gram positive bacteria were significantly higher in number than the Gram negative bacteria. We found that the prevalence of bacterial vaginosis as 70.34% among infertile women of Qom city. Staphylococcus aureus was the most prevalent vaginal pathogen (57.33%) followed by E. coli (25.33%). S. aureus showed maximum sensitivity to penicillin and gentamicin. It means that fortunately in Qom, this bacterium has not acquired resistance against penicillin yet. So, all physicians must have a high index of suspicion and use readily available screening methods to recognize and treat the patients with infectious vaginitis adequately. PMID- 25926959 TI - Role of Gardnerella vaginalis as an etiological agent of bacterial vaginosis. AB - BACKGROUND AND OBJECTIVES: Bacterial vaginosis is a risk factor for obstetric infections, various adverse outcomes of pregnancy and pelvic inflammatory disease. The objectives of this study were to assess the prevalence of bacterial vaginosis in women attending Gynaecology Outpatient Department (O.P.D) and sexually transmitted disease (S.T.D.) clinic and to assess the role of Gardnerella vaginalis as an etiological agent of bacterial vaginosis. MATERIALS AND METHODS: Two hundred women attending Gynaecology O.P.D and S.T.D. clinic with symptoms suggesting lower genital tract infection were included in the study. pH of the vaginal discharge was measured and three high vaginal swabs were collected. Bacterial vaginosis was diagnosed using Amsel's criteria and Nugent's method. Gardnerella vaginalis was isolated and identified by standard methods. RESULTS: Prevalence of bacterial vaginosis using Amsel's criteria and Gram stain scoring method was found to be 51.5% and 49% respectively. Gardnerella vaginalis was isolated in only 8.7% cases of bacterial vaginosis. CONCLUSION: Our study showed a relatively high prevalence of bacterial vaginosis in the population under study. Women attending various healthcare facilities should be screened and treated properly to prevent recurrence. Low isolation rate of Gardnerella vaginalis may be attributed to factors like poor viability and fastidiousness of the organism to grow in various media. PMID- 25926960 TI - Design of PCR-based method for detection of a gene-encoding Mycoplasma arthritidis mitogen superantigen in synovial fluid of rheumatoid arthritis patients. AB - BACKGROUND AND OBJECTIVES: Mycoplasma arthritidis mitogen (MAM) superantigen has been shown to induce chronic arthritis, which resembles human rheumatoid arthritis (RA) in a rodent model. However, its role as a causative agent in human RA is not well understood yet. The aim of this study was to investigate the presence of MAM superantigen gene in the synovial fluid (SF) of RA patients. MATERIALS AND METHODS: The MAM superantigen gene a reference was synthesized based on GenBank Data base (Gene ID: 6418105). Specific primer pairs were designed and PCR amplification was performed for MAM superantigen gene detection. A total of 133 SF samples of RA patients were assayed. The PCR products were subjected to sequencing and were descriptively analyzed. RESULTS: The results of the PCR product sequencing showed the method has objective applicability and accuracy. The sensitivity of the PCR reaction for the reference DNA template was 1ng/ml. The PCR results assay of the 133 SF samples raveled that, 9.7% and 22.5% of them were positive for the MAM superantigen gene and Mycoplasma pneumoniae (M. pneumoniae), respectively. CONCLUSION: In this study, two Mycoplasma genomes were detected with increased frequency in RA SF patients' samples. This finding appears to be a promising instrument in the etiological diagnostic of RA patients and could also lead to improved treatment selection. Further research on the other Mycoplasma species present in the SF of RA patients is essential. PMID- 25926961 TI - Inducible clindamycin resistance in clinical isolates of Staphylococcus aureus due to erm genes, Iran. AB - BACKGROUND AND OBJECTIVES: Resistance to macrolide can be mediated by erm and msrA genes in Staphylococcus aureus. There are the evidences that show erm genes may be causative agent of inducible or constitutive resistance. The aim of this study was to investigate the incidence of inducible clindamycin resistance and determine the most frequency of erm and msrA genes among S. aureus isolates. MATERIALS AND METHODS: In this study a total of 124 non duplicated clinical isolates of S. aureus were tested with disk diffusion method. All isolates were tested by PCR for mecA, ermA, ermB, ermC and msrA genes. RESULTS: According to PCR results, 48.4% had mecA gene and 51.6% were mecA negative. By phenotypic D test method, 32.3% revealed inducible resistance and recorded as D and D(+). Sensitive and constitutive phenotypes were found in 54.8% and 12.9% of isolates respectively. Inducible clindamycin resistance was more prevalent in MRSA (29%) than MSSA isolates (2.4%). Among studied erm genes, the most frequency genes were ermA and ermC with 41.1% and 17.7% respectively. Three isolates of them had D phenotype, while the PCR results of erm genes were negative. All isolates were negative for ermB or msrA genes. CONCLUSION: Since S. aureus isolates with inducible resistance may mutate and change to constitutive resistance, to prevent treatment failure, we suggest that inducible resistance test be performed on erythromycin resistant/clindamycin sensitive isolates. PMID- 25926962 TI - Use of Taguchi methodology to enhance the yield of caffeine removal with growing cultures of Pseudomonas pseudoalcaligenes. AB - BACKGROUND AND OBJECTIVES: Microbial caffeine removal is a green solution for treatment of caffeinated products and agro-industrial effluents. We directed this investigation to optimizing a bio-decaffeination process with growing cultures of Pseudomonas pseudoalcaligenes through Taguchi methodology which is a structured statistical approach that can be lowered variations in a process through Design of Experiments (DOE). MATERIAL AND METHODS: Five parameters, i.e. initial fructose, tryptone, Zn(+2) ion and caffeine concentrations and also incubation time selected and an L16 orthogonal array was applied to design experiments with four 4-level factors and one 3-level factor (4(4) * 1(3)). Data analysis was performed using the statistical analysis of variance (ANOVA) method. Furthermore, the optimal conditions were determined by combining the optimal levels of the significant factors and verified by a confirming experiment. Measurement of residual caffeine concentration in the reaction mixture was performed using high performance liquid chromatography (HPLC). RESULTS: Use of Taguchi methodology for optimization of design parameters resulted in about 86.14% reduction of caffeine in 48 h incubation when 5g/l fructose, 3 mM Zn(+2) ion and 4.5 g/l of caffeine are present in the designed media. Under the optimized conditions, the yield of degradation of caffeine (4.5 g/l) by the native strain of Pseudomonas pseudoalcaligenes TPS8 has been increased from 15.8% to 86.14% which is 5.4 fold higher than the normal yield. CONCLUSION: According to the experimental results, Taguchi methodology provides a powerful methodology for identifying the favorable parameters on caffeine removal using strain TPS8 which suggests that the approach also has potential application with similar strains to improve the yield of caffeine removal from caffeine containing solutions. PMID- 25926963 TI - Identification of Chlorophyceae based on 18S rDNA sequences from Persian Gulf. AB - BACKGROUND AND OBJECTIVES: Chlorophyceae are important constituents of marine phytoplankton. The taxonomy of Chlorophyceae was traditionally based solely on morphological characteristics. In the present research project, genetic diversity was investigated to analyze five species of Chlorophyceae from waters of the Persian Gulf. MATERIALS AND METHODS: A clone library of the ribosomal small subunit RNA gene (18S rDNA) in the nuclear genome was constructed by PCR, and then, after examining the clones, selected clones were sequenced. The determined clone sequences were analyzed by a similarity search of the NCBI GenBank database using BLAST. RESULTS AND CONCLUSION: Eleven sequences were identified correctly and used for phylogenetic analysis. We identified species of Chlorophyta (Chlorella sorokiniana, Chlamydomonas sp., Neochloris aquatic, Picochlorum sp. and Nannochloris atomus) without the need to conduct extensive colony isolation techniques. Therefore, this improved molecular method can be used to generate a robust database describing the species diversity of environmental samples. PMID- 25926964 TI - Capturing domain knowledge from multiple sources: the rare bone disorders use case. AB - BACKGROUND: Lately, ontologies have become a fundamental building block in the process of formalising and storing complex biomedical information. The community driven ontology curation process, however, ignores the possibility of multiple communities building, in parallel, conceptualisations of the same domain, and thus providing slightly different perspectives on the same knowledge. The individual nature of this effort leads to the need of a mechanism to enable us to create an overarching and comprehensive overview of the different perspectives on the domain knowledge. RESULTS: We introduce an approach that enables the loose integration of knowledge emerging from diverse sources under a single coherent interoperable resource. To accurately track the original knowledge statements, we record the provenance at very granular levels. We exemplify the approach in the rare bone disorders domain by proposing the Rare Bone Disorders Ontology (RBDO). Using RBDO, researchers are able to answer queries, such as: "What phenotypes describe a particular disorder and are common to all sources?" or to understand similarities between disorders based on divergent groupings (classifications) provided by the underlying sources. AVAILABILITY: RBDO is available at http://purl.org/skeletome/rbdo. In order to support lightweight query and integration, the knowledge captured by RBDO has also been made available as a SPARQL Endpoint at http://bio-lark.org/se_skeldys.html. PMID- 25926965 TI - Do we know others' visual liking? AB - Although personal liking varies considerably, there is a general trend of liking shared by many people (public favour). Visual liking in particular may be largely shared by people, as it is strongly influenced by relatively low-level perceptual factors. If so, it is likely that people have correct knowledge of public favour. We examined the human ability to predict public favour. In three experiments, participants rated the subjective likability of various visual objects (e.g. car, chair), and predicted the mean liking rating by other participants. Irrespective of the object's category, the correlation between individual prediction and actual mean liking of others (prediction validity) was not higher than the correlation between the predictor's own liking and the mean liking of others. Further, individual prediction correlated more with the predictor's own liking than it was with others' liking. Namely, predictions were biased towards the predictor's subjective liking (a variation of the false consensus effect). The results suggest that humans do not have (or cannot access) correct knowledge of public favour. It was suggested that increasing the number of predictors is the appropriate strategy for making a good prediction of public favour. PMID- 25926966 TI - Illusory drifting within a window that moves across a flickering background. AB - When a striped disk moves across a flickering background, the stripes paradoxically seem to move faster than the disk itself. We attribute this new illusion to reverse-phi motion, which slows down the disk rim but does not affect the stripes. PMID- 25926967 TI - Generalization across view in face memory and face matching. AB - While a change in view is considered to be one of the most damaging manipulations for facial identification, this phenomenon has been measured traditionally with tasks that confound perceptual processes with recognition memory. This study explored facial identification with a pairwise matching task to determine whether view generalization is possible when memory factors are minimised. Experiment 1 showed that the detrimental view effect in recognition memory is attenuated in face matching. Moreover, analysis of individual differences revealed that some observers can identify faces across view with perfect accuracy. This was replicated in Experiment 2, which also showed that view generalization is unaffected when only the internal facial features are shown. These results indicate that the view effect in recognition memory does not arise from data limits, whereby faces contain insufficient visual information to allow identification across views. Instead, these findings point to resource limits, within observers, that hamper such person identification in recognition memory. PMID- 25926968 TI - Is this a "Fettecke" or just a "greasy corner"? About the capability of laypersons to differentiate between art and non-art via object's originality. AB - Which components are needed to identify an object as an artwork, particularly if it is contemporary art? A variety of factors determining aesthetic judgements have been identified, among them stimulus-related properties such as symmetry, complexity and style, but also person-centred as well as context-dependent variables. We were particularly interested in finding out whether laypersons are at all able to distinguish between pieces of fine art endorsed by museums and works not displayed by galleries and museums. We were also interested in analysing the variables responsible for distinguishing between different levels of artistic quality. We ask untrained (Exp.1) as well as art-trained (Exp.2) people to rate a pool of images comprising contemporary art plus unaccredited objects with regard to preference, originality, ambiguity, understanding and artistic quality. Originality and ambiguity proved to be the best predictor for artistic quality. As the concept of originality is tightly linked with innovativeness, a property known to be appreciated only by further, and deep, elaboration (Carbon, 2011i-Perception, 2, 708-719), it makes sense that modern artworks might be cognitively qualified as being of high artistic quality but are meanwhile affectively devaluated or even rejected by typical laypersons-at least at first glance. PMID- 25926969 TI - Troxler fading, eye movements, and retinal ganglion cell properties. AB - We present four movies demonstrating the effect of flicker and blur on the magnitude and speed of adaptation for foveal and peripheral vision along the three color axes that isolate retinal ganglion cells projecting to magno, parvo, and konio layers of the LGN. The demonstrations support the eye movement hypothesis for Troxler fading for brightness and color, and demonstrate the effects of flicker and blur on adaptation of each class of retinal ganglion cells. PMID- 25926970 TI - The visual light field in real scenes. AB - Human observers' ability to infer the light field in empty space is known as the "visual light field." While most relevant studies were performed using images on computer screens, we investigate the visual light field in a real scene by using a novel experimental setup. A "probe" and a scene were mixed optically using a semitransparent mirror. Twenty participants were asked to judge whether the probe fitted the scene with regard to the illumination intensity, direction, and diffuseness. Both smooth and rough probes were used to test whether observers use the additional cues for the illumination direction and diffuseness provided by the 3D texture over the rough probe. The results confirmed that observers are sensitive to the intensity, direction, and diffuseness of the illumination also in real scenes. For some lighting combinations on scene and probe, the awareness of a mismatch between the probe and scene was found to depend on which lighting condition was on the scene and which on the probe, which we called the "swap effect." For these cases, the observers judged the fit to be better if the average luminance of the visible parts of the probe was closer to the average luminance of the visible parts of the scene objects. The use of a rough instead of smooth probe was found to significantly improve observers' abilities to detect mismatches in lighting diffuseness and directions. PMID- 25926971 TI - Effect of depth order on linear vection with optical flows. AB - In the present study, the effects of depth order on forward and backward vection were examined using optical flows simulating motion in depth (i.e., approaching or receding). In an experiment, space extending 10 or 20 m in depth was simulated, and the space was divided into foreground and background spaces. In each space, a random-dot pattern was presented and the binocular disparity, size, and velocity of each dot were continuously manipulated in a way consistent with the depth being simulated. Participants reported whether they perceived vection. Latency, total duration (i.e., the amount of time that participants reported perceiving vection during a 60-s presentation), and strong-vection duration (i.e., the amount of time that participants reported perceiving strong vection) were measured. The results indicated that, even though the dots making up the optical flow were much smaller and slower moving in the background space than in the foreground space, vection was strongly dependent on flow motion in the background space. This supports the idea that the perceptual system uses background stimulus motion as a reliable cue for self-motion perception. PMID- 25926972 TI - Hyperbaric oxygen therapy ameliorates TNBS-induced acute distal colitis in rats. AB - BACKGROUND: This study investigated the therapeutic effects of hyperbaric oxygen in experimental acute distal colitis focusing on its effect on the production of pro-inflammatory cytokines, nitric oxide and hypoxia-inducible factor 1alpha. METHODS: Colitis was induced with a rectal infusion of 150 mg/kg of TNBS under anesthesia with Ketamine (50 mg/kg) and Xylazine (10 mg/kg). Control animals received only rectal saline. After colitis induction, animals were subjected to two sessions of hyperbaric oxygen and were then euthanized. The distal intestine was resected for macroscopic analysis, determination of myeloperoxidase activity, western-blotting analyses of inducible nitric oxide synthase and cyclooxygenase-2 expression and immunohistochemical analysis of hypoxia-inducible factor 1alpha and cyclooxygenase-2. Cytokines levels in the distal intestine were measured using an enzyme-linked immunosorbent assay. RESULTS: Hyperbaric oxygen therapy attenuated the severity of acute distal colitis, with reduced macroscopic damage score. This effect was associated with prevention in the increase of pro inflammatory cytokine production; myeloperoxidase activity, in the expression of inducible nitric oxide synthase and cyclooxygenase-2. Finally, hyperbaric oxygen inhibited the acute distal colitis-induced up-regulation of hypoxia-inducible factor 1alpha. CONCLUSIONS: The results indicate that hyperbaric oxygen attenuates the severity of acute distal colitis through the down-regulation of pro-inflammatory events. PMID- 25926973 TI - An epitope tag alters phosphoglycerate dehydrogenase structure and impairs ability to support cell proliferation. AB - BACKGROUND: The gene encoding the serine biosynthesis pathway enzyme PHGDH is located in a region of focal genomic copy number gain in human cancers. Cells with PHGDH amplification are dependent on enzyme expression for proliferation. However, dependence on increased PHGDH expression extends beyond production of serine alone, and further studies of PHGDH function are necessary to elucidate its role in cancer cells. These studies will require a physiologically relevant form of the enzyme for experiments using engineered cell lines and recombinant protein. RESULTS: The addition of an N-terminal epitope tag to PHGDH abolished the ability to support proliferation of PHGDH-amplified cells despite retention of some activity to convert 3-PG to PHP. Introducing an R236E mutation into PHGDH eliminates enzyme activity, and this catalytically inactive enzyme cannot support proliferation of PHGDH-dependent cells, arguing that canonical enzyme activity is required. Tagged and untagged PHGDH exhibit the same intracellular localization and ability to produce D-2-hydroxyglutarate (D-2HG), an error product of PHGDH, arguing that neither mislocalization nor loss of D-2HG production explains the inability of epitope-tagged PHGDH to support proliferation. To enable studies of PHGDH function, we report a method to purify recombinant PHGDH and found that untagged enzyme activity was greater than N-terminally tagged enzyme. Analysis of tagged and untagged PHGDH using size exclusion chromatography and electron microscopy found that an N-terminal epitope tag alters enzyme structure. CONCLUSIONS: Purification of untagged recombinant PHGDH eliminates the need to use an epitope tag for enzyme studies. Furthermore, while tagged PHGDH retains some ability to convert 3PG to PHP, the structural alterations caused by including an epitope tag disrupts the ability of PHGDH to sustain cancer cell proliferation. PMID- 25926974 TI - Adult attachment style as a risk factor for maternal postnatal depression: a systematic review. AB - BACKGROUND: Postnatal depression (PND) is an important health problem of global relevance for maternal health and impacts on the health and wellbeing of the child over the life-course. Multinational data is hard to locate, the economic burden of PND on health care systems have been calculated in several countries, including Canada and in the UK. In Canada, health and social care costs for a mother with PND were found to be just over twice that of mothers with no mental illness. The extra community care cost for women with PND living in the UK was found to be L35.7 million per year. METHOD: We carried out a systematic search to the literature to investigate the associations between attachment style and PND, using meta-narrative analysis methods, reporting statistical data and life narratives. The following databases were searched: PsycInfo, PsycExtra Web of Science, The Cochrane Library and Pubmed. We focused on research papers that examined adult attachment styles and PND, and published between 1991 and 2013. We included any papers showing relationship between maternal adult attachment and PND. Out of 353 papers, 20 met the study inclusion criteria, representing a total of 2306 participants. Data from these 20 studies was extracted by means of a data extraction table. RESULTS: We found that attachment and PND share a common aetiology and that 'insecure adult attachment style' is an additional risk factor for PND. Of the insecure adult attachment styles, anxious styles were found to be associated with PND symptoms more frequently than avoidant or dismissing styles of attachment. CONCLUSION: More comprehensive longitudinal research would be crucial to examine possible cause-effect associations between adult attachment style (as an intergenerational construct and risk factor) and PND (as an important maternal mental health), with new screening and interventions being essential for alleviating the suffering and consequences of PND. If more is understood about the risk profile of a new or prospective mother, more can be done to prevent the illness trajectory (PND); as well as making existing screening measures and treatment options more widely available. PMID- 25926975 TI - Does it matter how you ask? Self-reported emotions to depictions of need-of-help and social context. AB - BACKGROUND: When humans observe other people's emotions they not only can relate but also experience similar affective states. This capability is seen as a precondition for helping and other prosocial behaviors. Our study aims to quantify the influence of help-related picture content on subjectively experienced affect. It also assesses the impact of different scales on the way people rate their emotional state. METHODS: The participants (N=242) of this study were shown stimuli with help-related content. In the first subset, half the drawings depicted a child or a bird needing help to reach a simple goal. The other drawings depicted situations where the goal was achieved. The second subset showed adults either actively helping a child or as passive bystanders. We created control conditions by including pictures of the adults on their own. Participants were asked to report their affective responses to the stimuli using two types of 9-point scales. For one half of the pictures, scales of arousal (calm to excited) and of bipolar valence (unhappy to happy) were employed; for the other half, unipolar scales of pleasantness and unpleasantness (strong to absent) were used. RESULTS: Even non-dramatic depictions of simple need-of-help situations were rated systematically lower in valence, higher in arousal, less pleasant and more unpleasant than corresponding pictures with the child or bird not needing help. The presence of a child and adult together increased pleasantness ratings compared to pictures in which they were depicted alone. Arousal was lower for pictures showing only an adult than for those including a child. Depictions of active helping were rated similarly to pictures showing a passive adult bystander, when the need-of-help was resolved. Aggregated unipolar pleasantness and unpleasantness ratings accounted well for arousal and even better for bipolar valence ratings and for content effects on them. CONCLUSION: This is the first study to report upon the meaningful impact of harmless need-of help content on self-reported emotional experience. It provides the basis for further investigating the links between subjective emotional experience and active prosocial behavior. It also builds upon recent findings on the correspondence between emotional ratings on bipolar and unipolar scales. PMID- 25926976 TI - Plasmodesmata spread their influence. AB - Plasmodesmata (PDs) are microscopic channels that connect virtually every plant cell to its neighbors. They also provide a route for molecules to access the phloem for systemic movement throughout the plant. In this report, I review recent findings that broaden the potential impact of these channels, by revealing their contribution to auxin movement and as potential sites of receptor signaling. These discoveries should prompt a reassessment of symplasmic connectivity and its importance to plant development, defense, and physiology. PMID- 25926977 TI - Angiogenesis versus arteriogenesis: neuropilin 1 modulation of VEGF signaling. AB - In development and disease, vascular endothelial growth factor (VEGF) regulates the expansion of the vascular tree. In response to hypoxia, VEGF promotes new capillary formation through the process of angiogenesis by inducing endothelial cell sprouting, proliferation, and migration. Wound healing, tissue regeneration, and tumor growth depend on angiogenesis for adequate nutrient and oxygen delivery. Under different conditions, VEGF promotes arterial growth, modulates lumen expansion, and induces collateral vessel formation, events collectively referred to as arteriogenesis. Induction of arteriogenesis after cardiac or cerebral arterial occlusion can reduce ischemia and improve disease outcome. Endothelial VEGF receptor 2 (VEGFR2) signaling governs both processes. However, modulation of downstream VEGF signaling effectors, such as extracellular-signal regulated kinase (ERK) activation, differs in order to achieve angiogenic versus arteriogenic outcomes. Recent reports show that neuropilin 1 (NRP1), a VEGF receptor, can instill VEGF signaling outcomes that specifically regulate either angiogenesis or arteriogenesis. Here, we discuss how NRP1 functions as a VEGFR2 co-receptor in angiogenesis and a modulator of VEGFR2 trafficking in arteriogenesis. The unique role played by neuropilin in different endothelial processes makes it an exciting therapeutic target to specifically enhance angiogenesis or arteriogenesis in disease settings. PMID- 25926978 TI - Evolutionary models of in-group favoritism. AB - In-group favoritism is the tendency for individuals to cooperate with in-group members more strongly than with out-group members. Similar concepts have been described across different domains, including in-group bias, tag-based cooperation, parochial altruism, and ethnocentrism. Both humans and other animals show this behavior. Here, we review evolutionary mechanisms for explaining this phenomenon by covering recently developed mathematical models. In fact, in-group favoritism is not easily realized on its own in theory, although it can evolve under some conditions. We also discuss the implications of these modeling results in future empirical and theoretical research. PMID- 25926979 TI - Recent advances in understanding/management of non-alcoholic steatohepatitis. AB - Non-alcoholic steatohepatitis (NASH) can lead to advanced fibrosis, hepatocellular carcinoma, and end-stage liver disease requiring liver transplantation. A myriad of pathways and genetic influence contribute to NASH pathogenesis and liver disease progression. Diagnosing patients with NASH and advanced fibrosis is critical prior to treatment and prognostication. There has been ongoing interest in developing non-invasive biomarkers and tools for identifying NASH and advanced fibrosis. To date, there has been no approved therapy for NASH. Recently, the FLINT (Farnesoid X Receptor [FXR] Ligand Obeticholic Acid in NASH Treatment) trial provided promising results of the efficacy of obeticholic acid, a farnesoid X receptor agonist, in improving histological features of NASH and fibrosis. Long-term studies are needed to assess the safety of obeticholic acid and its effects on liver- and cardiovascular-related outcomes. PMID- 25926980 TI - Duality of lipid mediators in host response against Mycobacterium tuberculosis: good cop, bad cop. AB - Lipid mediators play an important role in infection- and tissue injury-driven inflammatory responses and in the subsequent inhibition and resolution of the response. Here, we discuss recent findings that substantiate how Mycobacterium tuberculosis promotes its survival in the host by dysregulation of lipid mediator balance. By inhibiting prostaglandin E2 (PGE2) and enhancing lipoxin production, M. tuberculosis induces necrotic death of the macrophage, an environment that favors its growth. These new findings provide opportunities for developing and repurposing therapeutics to modulate lipid mediator balance and enhance M. tuberculosis growth restriction. PMID- 25926982 TI - Post-transcriptional regulation of early embryogenesis. AB - Gene expression is controlled by diverse mechanisms before, during, and after transcription. Chromatin modification factors as well as transcriptional repressors, silencers, and enhancers all feed into how eukaryotes transcribe RNA in the nucleus. However, there is increasing evidence that post-transcriptional regulation of gene expression is as widespread as transcriptional control if not more so. Studies of specific transcripts in oocytes and embryos are at the core of our mechanistic understanding of many post-transcriptional events. Coupled with genome-wide and large-scale experimental approaches, research is bringing to light how these regulatory events function independently and in concert to regulate protein expression. PMID- 25926981 TI - The hunt for origins of DNA replication in multicellular eukaryotes. AB - Origins of DNA replication (ORIs) occur at defined regions in the genome. Although DNA sequence defines the position of ORIs in budding yeast, the factors for ORI specification remain elusive in metazoa. Several methods have been used recently to map ORIs in metazoan genomes with the hope that features for ORI specification might emerge. These methods are reviewed here with analysis of their advantages and shortcomings. The various factors that may influence ORI selection for initiation of DNA replication are discussed. PMID- 25926983 TI - Lateral root initiation in Arabidopsis thaliana: a force awakens. AB - Osmotically driven turgor pressure of plant cells can be higher than that of a car tire. It puts tremendous forces onto cell walls and drives cell growth and changes in cell shape. This has given rise to unique mechanisms to control organ formation compared to metazoans. The fascinating interplay between forces and local cellular reorganization is still poorly understood. Growth of lateral roots is a prominent example of a developmental process in which mechanical forces between neighboring cells are generated and must be dealt with. Lateral roots initiate from a single cell layer that resides deep within the primary root. On their way out, lateral roots grow through the overlying endodermal, cortical, and epidermal cell layers. It was recently demonstrated that endodermal cells actively accommodate lateral root formation. Interfering genetically with these accommodating responses in the endodermis completely blocks cell proliferation in the pericycle. The lateral root system provides a unique opportunity to elucidate the molecular and cellular mechanisms whereby mechanical forces and intercellular communication regulate spatial accommodation during plant development. PMID- 25926984 TI - Recent advances in managing and understanding menstrual disorders. AB - Menstrual disorders are a major reason for gynaecological consultations worldwide and, unfortunately there are many different definitions and classifications of this condition. Clear definitions and terminology are necessary for scientific literature, particularly for clinicians, and for clinical trials comparing two treatments. The International Federation of Gynaecology and Obstetrics (FIGO) Menstrual Disorders Working Group has proposed abandoning the use of one common term, dysfunctional uterine bleeding (DUB), while continuing to use the terms abnormal uterine bleeding (AUB) and heavy menstrual bleeding (HMB). Furthermore, the group issued the PALM-COEIN classification system for menstrual disorders, which has quickly been adopted around the world. The PALM-COEIN system allows clinicians and researchers to identify and classify women with both AUB and HMB in a systematic manner, provides reliable information for research purposes and for epidemiological and prevalence studies in different settings, and supports accurate diagnoses and treatment. Additionally, this classification system is useful for selecting treatments appropriate for different stages of women's reproductive years and for different patterns of menstrual bleeding. Among the proposed treatments are the use of combined oral contraceptives, the levonorgestrel-releasing intrauterine system, tranexamic acid, mefenamic acid, and other nonsteroidal anti-inflammatory drugs (NSAIDs). PMID- 25926985 TI - Drug-induced liver injury: the dawn of biomarkers? AB - Drug-induced liver injury (DILI) is a potentially fatal adverse event with significant medical and economic impact. Many drugs, especially anti-infective, neurologic or pain-modifying substances, act as hepatotoxins. With cardiovascular toxicity, liver toxicity is one of the two leading causes for drug withdrawal from the market. The liver can be affected directly, in a predictable and dose dependent manner, or idiosyncratically, independent of the dose and therefore unpredictable. Currently DILI is a diagnosis of exclusion that physicians have to bear in mind in patients with an unexplained increase of liver enzymes. The type of injury is categorized into hepatocellular, cholestatic, or mixed by the respective enzyme pattern of injury. Symptoms of affected patients can mimic any other liver disease. Therefore, new diagnostic and prognostic biomarkers for early liver injury are currently being evaluated in multi-centre clinical trials that are conducted by international consortia and other initiatives. Pharmacogenetic testing, next-generation sequencing, proteomics, metabolomics and mechanistic markers can help to preselect susceptible patient populations and tailor drug therapy to individual patients. Proposed DILI indicators that are under investigation include microRNAs, cytokeratin-18 (CK18), high mobility group box protein 1 (HMGB-1), and several other biomarkers. These developments can change clinical practice, and improve patients' safety and management. However, they have not been translated into clinical practice or approved for routine use yet. Management of DILI usually consists of initial withdrawal of the suspected drug and-if applicable-administration of specific antidotes, such as N acetylcysteine. However, the overall management of DILI could change in the near future with the advent of novel diagnostic and prognostic DILI markers. PMID- 25926986 TI - The rapidly changing world of food allergy in children. AB - Food allergy is a common problem in childhood. The term is used to include both immunoglobulin E (IgE)-mediated and non-IgE-mediated food allergies, which have a significant effect on the quality of life of patients and their families. In this report, we aim to discuss recent advances in the diagnosis, management, and treatment modalities of food allergy in children. PMID- 25926987 TI - Unique among ciliopathies: primary ciliary dyskinesia, a motile cilia disorder. AB - Primary ciliary dyskinesia (PCD) is a ciliopathy, but represents the sole entity from this class of disorders that results from the dysfunction of motile cilia. Characterized by respiratory problems appearing in childhood, infertility, and situs defects in ~50% of individuals, PCD has an estimated prevalence of approximately 1 in 10,000 live births. The diagnosis of PCD can be prolonged due to a lack of disease awareness, coupled with the fact that symptoms can be confused with other more common genetic disorders, such as cystic fibrosis, or environmental insults that result in frequent respiratory infections. A primarily autosomal recessive disorder, PCD is genetically heterogeneous with >30 causal genes identified, posing significant challenges to genetic diagnosis. Here, we provide an overview of PCD as a disorder underscored by impaired ciliary motility; we discuss the recent advances towards uncovering the genetic basis of PCD; we discuss the molecular knowledge gained from PCD gene discovery, which has improved our understanding of motile ciliary assembly; and we speculate on how accelerated diagnosis, together with detailed phenotypic data, will shape the genetic and functional architecture of this disorder. PMID- 25926988 TI - Associations between poor oral health and reinjuries in male elite soccer players: a cross-sectional self-report study. AB - BACKGROUND: Although it is well known that oral pathogens can enter the systemic circulation and cause disease, it is largely unknown if poor oral health increases the risk of sports injuries. The purpose of this study is to investigate the association between poor oral health and reinjuries in male elite soccer players, adjusted for psychosocial problems and player characteristics. METHODS: 184 Players in premier league soccer clubs and 31 elite, junior soccer players in the Netherlands, Belgium and England, were enrolled in a retrospective cross-sectional study. The Sports Injury Risk Indicator, a self assessed questionnaire, was used to obtain information on reinjuries, age and player position, oral health and psychosocial problems. The number of different types of oral health problems was used as an indicator of poor oral health. (SumDental, range 0-2: 0 = no oral health problems, 1 = one type of oral health problem and 2 = two or more types of oral health problems). Multivariable logistic regression was used to investigate whether SumDental was associated with reinjuries, after adjustment for psychosocial problems and player characteristics. RESULTS: 37% of the players reported no oral health problems, 43% reported one type of oral health problem and 20% reported two or more types of oral health problems. After full adjustment for age, player position and psychosocial problems (i.e. injury anxiety, psychophysical stress, unhealthy eating habits and dissatisfaction with trainer/team), poor oral health (SumDental) was positively associated with all kind of reinjuries whether analyzed as a continuous variable or as a categorical variable. The fully adjusted odds ratios for SumDental analyzed as a continuous variable were: in relation to repeated exercise-associated muscle cramps: 1.82 (95% confidence interval (CI): 1.07, 3.12), in relation to muscle or tendon reinjury 1.57 (95% CI: 1.01, 2.45) and in relation to multiple types of reinjury 1.88 (95% CI: 1.19, 2.97). CONCLUSION: The results from this study justify a thorough examination of the effects of oral health problems on the injury risk of playing elite soccer. PMID- 25926989 TI - Treatment of Febrile illness with artemisinin combination therapy: prevalence and predictors in five African household surveys. AB - OBJECTIVES: To evaluate the determinants of compliance with national policies recommending Artemisinin Combination Therapy (ACT) for the treatment of uncomplicated malaria in the community. METHODS: We used data from Gambia, Ghana, Kenya, Nigeria, and Uganda national household surveys that were conducted with a standardized World Health Organization (WHO) methodology to measure access to and use of medicines. We analyzed all episodes of acute fever reported in the five surveys. We used logistic regression models accounting for the clustered design of the surveys to identify determinants of seeking care in public healthcare facilities, of being treated with antimalarials, and of receiving ACT. RESULTS: Overall, 92% of individuals with a febrile episode sought care outside the home, 96% received medicines, 67% were treated with antimalarials, and 16% received ACT. The choice of provider was influenced by perceptions about medicines availability and affordability. In addition, seeking care in a public healthcare facility was the single most important predictor of treatment with ACT [odds ratio (OR): 4.64, 95% confidence intervals (CI): 2.98-7.22, P < 0.001]. Children under 5 years old were more likely than adults to be treated with antimalarials [OR: 1.28, CI: 0.91-1.79, not significant (NS)] but less likely to receive ACT (OR: 0.80, CI: 0.57-1.13, NS). CONCLUSIONS: Our results confirm the high prevalence of presumptive antimalarial treatment for acute fever, especially in public healthcare facilities where poor people seek care. They show that perceptions about access to medicines shape behaviors by directing patients and caregivers to sources of care where they believe medicines are accessible. The success of national policies recommending ACT for the treatment of uncomplicated malaria depends not only on restricting ACT to confirmed malaria cases, but also on ensuring that ACT is available and affordable for those who need it. PMID- 25926990 TI - Farmacia Popular Program: changes in geographic accessibility of medicines during ten years of a medicine subsidy policy in Brazil. AB - OBJECTIVES: The Brazilian constitution guarantees the right to health, including access to medicines. In May 2004, Brazil's government announced the "Farmacia Popular" Program (FPP) as a new mechanism to improve the Brazilian population's access to medicines. Under FPP, a selected list of medicines is subsidized by the government and provided in public and private pharmacies. The aim of this study is to describe the historical stages of the FPP and to identify associated changes in the geographical accessibility of medicines through the FPP over time. METHODS: It was performed documentary review and an ecological study assessing program coverage in terms of number of facilities and a FPP Pharmacy Facilities Density (PFD) index at national and regional levels from 2004 to 2013, using the FPP database. We used geographic information system mapping to depict a pharmaceutical facilities density (PFD) index at the municipality level on thematic maps. RESULTS: A growth of the PFD index coincident with the phases of the FPP was noticed. In the public sector, the program started in 2004; by 2006, there was a sharp increase in the numbers of participating pharmacies, stabilizing in 2009. In the private sector, the program started in 2006; by 2009 the PFD ratio had increased substantially and it continued to grow through 2011. There was an increase in FPP coverage in most regions between 2006, when the private pharmacy component started, and 2013, but participating pharmacies remain unequally distributed across geographical regions. Specifically, the wealthy areas in the South and Southeast have higher coverage, with lower coverage mostly in the North and Northeast, relatively poorer areas with greater need for access to medicines, health care, and other basic services such as potable water and sanitization. CONCLUSIONS: There has been a substantial increase in the number of pharmacies participating in the FPP over time. This has led to greater program coverage and has potentially improved access to FPP medicines in the country. Nevertheless, disparities in pharmacy coverage remain among the regions. PMID- 25926991 TI - High lead exposure in two leaded bronze ingot foundry workers. AB - BACKGROUND: Awareness about lead poisoning in South Korea has increased; however, occupational exposures occurring in small-scale businesses have not been thoroughly investigated. We report two cases of high lead exposure in a leaded bronze ingot foundry. CASE PRESENTATION: Two employees, a 54-year-old primary operator and a 46-year-old assistant, at a small-scale metalworking company who had been employed for 18 years and 1 month, respectively, showed elevated blood lead levels (61.1 MUg/dL and 51.7 MUg/dL, respectively) at an occupational health checkup. Neither worker complained of abnormal symptoms nor signs related to lead poisoning. Health assessment follow-ups were conducted and biological exposure indices of lead were calculated every four weeks. After the initial follow-up assessment, both workers were relocated from the foundry process to the metalworking process. In addition, a localized exhaust system was installed after the second follow-up. CONCLUSIONS: Foundry workers in a small-scale businesses might be at high risk of lead exposure because these businesses might be vulnerable to poor industrial hygiene. Therefore, regular occupational health checkups are required. PMID- 25926992 TI - American-Indian diabetes mortality in the Great Plains Region 2002-2010. AB - OBJECTIVE: To compare American-Indian and Caucasian mortality rates from diabetes among tribal Contract Health Service Delivery Areas (CHSDAs) in the Great Plains Region (GPR) and describe the disparities observed. RESEARCH DESIGN AND METHODS: Mortality data from the National Center for Vital Statistics and Seer*STAT were used to identify diabetes as the underlying cause of death for each decedent in the GPR from 2002 to 2010. Mortality data were abstracted and aggregated for American-Indians and Caucasians for 25 reservation CHSDAs in the GPR. Rate ratios (RR) with 95% CIs were used and SEER*Stat V.8.0.4 software calculated age adjusted diabetes mortality rates. RESULTS: Age-adjusted mortality rates for American-Indians were significantly higher than those for Caucasians during the 8 year period. In the GPR, American-Indians were 3.44 times more likely to die from diabetes than Caucasians. South Dakota had the highest RR (5.47 times that of Caucasians), and Iowa had the lowest RR, (1.1). Reservation CHSDA RR ranged from 1.78 to 10.25. CONCLUSIONS: American-Indians in the GPR have higher diabetes mortality rates than Caucasians in the GPR. Mortality rates among American Indians persist despite special programs and initiatives aimed at reducing diabetes in these populations. Effective and immediate efforts are needed to address premature diabetes mortality among American-Indians in the GPR. PMID- 25926993 TI - Phytochelatin synthase is required for tolerating metal toxicity in a basidiomycete yeast and is a conserved factor involved in metal homeostasis in fungi. AB - BACKGROUND: Phytochelatin synthase (PCS) is an enzyme that catalyzes the biosynthesis of phytochelatin from glutathione. Phytochelatins protect cells against the toxic effects of non-essential heavy metals, such as cadmium, and hence growth is restricted in the presence of these metals in mutants in PCS encoding genes. PCS genes from fungi have been characterized in only two species in the Ascomycota, and these genes are considered sparsely distributed in the fungal kingdom. RESULTS: A gene encoding a putative PCS was identified in Sporobolomyces sp. strain IAM 13481, a fungus that is a member of the Pucciniomycotina subphylum of the Basidiomycota. The function of this PCS1 gene was assessed by heterologous expression in the Ascomycota yeasts Saccharomyces cerevisiae and Schizosaccharomyces pombe, and by mutating the gene in Sporobolomyces. The gene is required for tolerance to toxic concentrations of non essential cadmium as well as the essential metal copper. Pcs1 homologs in fungi and other eukaryotes have putative targeting sequences for mitochondrial localization: the S. pombe homolog was fused to green fluorescent protein and it co-localized with a mitochondrial dye. Evaluation of the presence or absence of PCS and PCS-like homologs in the genome sequences of fungi indicates that they have a wide distribution, and the absence in most Ascomycota and Basidiomycota (the Dikarya) species can be explained by a small number of gene losses. CONCLUSIONS: The ecology of the species within the fungi carrying putative PCS genes, the phenotypes of phytochelatin synthase mutants in two major fungal lineages, and the presence of homologs in many non-Dikarya lineages parallel what is seen in the plant and animal kingdoms. That is, PCS is a protein present early during the evolution of the fungi and whose role is not solely dedicated to combating toxic concentrations of non-essential metals. PMID- 25926994 TI - A population-based study of prevalence and risk factors of chronic kidney disease in Leon, Nicaragua. AB - BACKGROUND: Recent studies have shown an excess of chronic kidney disease (CKD) among younger adult males in the Pacific coastal region of Nicaragua and suggest a non-conventional CKD etiology in this region. These studies have been conducted in small, non-representative populations. OBJECTIVES: We conducted a large population-based cross-sectional study to estimate CKD prevalence in Leon, Nicaragua, and to evaluate the association between previously investigated risk factors and CKD. METHODS: Estimated glomerular filtration rate, derived using the MDRD equation, was assessed to determine CKD status of 2275 Leon residents. Multivariable logistic regression was used to estimate adjusted prevalence odds ratios. Leon CKD prevalence was also standardized to the demographic distributions of the Leon Health and Demographic Surveillance System and the Leon 2005 Census. RESULTS: CKD prevalence was 9.1%; twice as high for males (13.8%) than females (5.8%). In addition to gender, older age, rural zone, lower education level, and self-reported high blood pressure, more years of agricultural work, lija (unregulated alcohol) consumption, and higher levels of daily water consumption were significantly associated with CKD. Notably, self reported diabetes was associated with CKD in adjusted models for females but not males. CONCLUSIONS: Our findings are comparable to those found in regional studies and further support the hypothesis of a Mesoamerican Nephropathy. PMID- 25926995 TI - Benefits and harms of citrate locking solutions for hemodialysis catheters: a systematic review and meta-analysis. AB - BACKGROUND: Citrate has theoretical advantages over heparin for locking hemodialysis central venous catheters (CVCs), but the comparative effectiveness of these agents is not clear. OBJECTIVES: 1) To compare the benefits and harms of citrate versus heparin locking solutions among patients undergoing hemodialysis through CVCs; 2) to appraise methodological quality of the supporting evidence. DATA SOURCES: CENTRAL, MEDLINE, EMBASE, CINAHL, ISI Web of Science, and nephrology conference abstracts. STUDY ELIGIBILITY PARTICIPANTS AND INTERVENTIONS: We included randomized, parallel arm clinical trials that enrolled adult patients (>18 years) receiving chronic hemodialysis through CVCs using a citrate locking solution. We excluded studies in which citrate was combined with other agents, such as antibiotics. APPRAISAL AND SYNTHESIS METHODS: We used the GRADE approach to systematic reviews and quality appraisal. Two reviewers performed data extraction independently and in duplicate. We pooled count data using generic inverse variance with random-effects models, and used fixed-effect models when only two studies were available for pooling. Subgroups included low (<=5%) vs. higher (>=30%) citrate. RESULTS: We screened 600 citations. Forty-one proceeded to full-text screen; 5 met inclusion criteria. Studies included between 19 and 291 participants (Median N = 61) followed for a total of 174.6 catheter years; 2 were multi-centred trials. Three studies assessed all-cause mortality; the pooled relative risk for death was 0.71 (95% CI = 0.42-1.24; p = 0.21; I(2) = 0%). The rate ratio for bacteremic episodes was 0.54 (95% CI = 0.23-1.29; p = 0.16; I(2) = 65%) while the rate ratio for bleeding was 0.48 (95% CI = 0.3-0.75; p = 0.001;I I(2) = 5%). Rates of catheter exchange/replacement, all-cause hospitalization and in-situ thrombolysis were not significantly different between groups in any of the pooled analyses. Risk of bias within pooled studies was low. LIMITATIONS: Outcome definitions varied across studies. Imprecision due to small sample sizes and low event rates reduce our overall confidence in the pooled effect estimates. IMPLICATIONS: Benefits and harms of citrate vs. heparin locking solutions remain unclear; larger studies and standardization of outcome measurement and reporting are warranted. TRIAL REGISTRATION: Protocol Registration Number: CRD42013004781. PMID- 25926996 TI - Acute kidney injury: an acceptable risk of treatment with renin-angiotensin system blockade in primary care? AB - BACKGROUND: Use of renin-angiotensin system (RAS) blockade has become increasingly widespread driven by evidence-based guidance. There is concern about the role of these agents in the genesis of avoidable acute kidney injury (AKI). OBJECTIVES: To investigate the association between AKI and use of RAS blockade. DESIGN: Multilevel hierarchical analysis of a large cohort of patients registered with UK general practitioners. SETTING: Primary care practices in East and West Kent, United Kingdom. PATIENTS: 244,715 patients from 27 practices. MEASUREMENTS: Demographic, clinical, biochemical and prescription data. METHODS: Analyses of data acquired between 02/3/2004 and 17/04/2012 using multilevel logistic regression to determine the relationship between AKI and use of RAS blockade; further analysed by indication for treatment with RAS blockade. RESULTS: Sufficient serum creatinine data were available to define AKI in 63,735 patients with 208,275 blood test instances. In 95,569 instances the patient was prescribed a RAS antagonist of which 5.4% fulfilled criteria for AKI. The unadjusted odds ratio (OR) for AKI in those prescribed RAS blockade was 1.93 (1.81-2.06, 95%CI) falling to 1.11 (1.02-1.20, 95%CI) when adjusted for age, gender, co-morbidity, GFR category, proteinuria, systolic blood pressure and diuretic therapy. In patients with an evidence-based indication there was no difference in absolute risk of AKI. However, prescription of RAS blockade in the absence of indication appeared to be associated with greater risk of AKI. When analysis was repeated with AKIN2/AKIN3 as the outcome, although risk of AKI remained significant when unadjusted (OR 1.73, 95%CI 1.42-2.11, p<0.001), after full adjustment there was no increased risk (OR 0.83, 95%CI 0.63-1.09) in those taking RAS antagonists. However, when analysed by indication AKIN2/AKIN3 was significantly more likely in those prescribed RAS antagonists without indication (OR 2.04, 95%CI 1.41-2.94, p<0.001). LIMITATIONS: Observational database study. No information concerning hospitalisation. Prescribing assumptions and potential inaccurate coding. Potential survival bias; patients surviving longer will contribute more data. CONCLUSIONS: Use of RAS antagonists increased the risk of AKI, independent of common confounding variables. After correction for confounders the risk fell away and became non-significant for moderate and severe AKI. However, where there was no evidence-based indication for RAS antagonists the risk of AKI, whether mild, moderate or severe, remained greater. PMID- 25926997 TI - Strategies to increase living kidney donation: a retrospective cohort study. AB - BACKGROUND: Living kidney transplantation (LKT) offers the best medical outcomes for organ recipients. Historically, our centre had a low rate of LKT. In 2009, in an effort to increase living organ donation (LOD), a dedicated team was created. Its mandate was to promote LOD at our centre and at referring centres, to coordinate assessments of living organ donors, to facilitate the process, and to ensure long-term follow-up after the donation. In November 2010, our centre joined the national living donor paired exchange registry (LDPE). OBJECTIVE: To document the impact of the LOD team and LDPE registry on LOD rates at our centre. DESIGN: Retrospective cohort study. SETTING: Single center study in a university hospital with an adult kidney transplant program. PATIENTS: Using our electronic database, we included all potential living organ donors who contacted our centre from 01/01/2005 to 31/12/2008 and from 01/01/2009 to 31/12/2012. Follow-up was conducted until 31/12/2013. MEASUREMENTS: Number of transplantations from living donors, number of potential donors who contacted the centre, donor and recipient characteristics. METHODS: We compared the number of transplantations from living donors performed and the number of potential donors who contacted the centre before and after the creation of the LOD team and participation in the LDPE. RESULTS: A total of 50 renal transplantations were performed using organs from living donors during the first time period, whereas this increased to 73 in the 2009-2012 cohort (incidence rate difference (IRD): 0.030, 95% confidence interval (CI) 0.003-0.056). We also observed a significant increase in the number of individuals who contacted our centre to donate a kidney. During the 2005-2008 period (cohort 1), 191 individuals interested in donating a kidney contacted our centre, whereas this figure was 304 during the 2009-2012 period (cohort 2) (IRD: 0.143, 95% CI 0.091-0.196). LIMITATIONS: Single center study, relatively low sample size. CONCLUSION: The implementation of a LOD team, combined with our participation in the LDPE registry, was associated with a significant increase in the actual number of living kidney transplantations performed. These data support initiatives such as the creation of dedicated LOD teams and LDPE registry to increase LKT. PMID- 25926998 TI - Theories of aging: an ever-evolving field. AB - Senescence has been the focus of research for many centuries. Despite significant progress in extending average human life expectancy, the process of aging remains largely elusive and, unfortunately, inevitable. In this review, we attempted to summarize the current theories of aging and the approaches to understanding it. PMID- 25927000 TI - Structure and Biological Functions of beta-Hairpin Antimicrobial Peptides. AB - Antimicrobial peptides (AMPs) are evolutionarily ancient factors of the innate immune system that serve as a crucial first line of defense for humans, animals, and plants against infection. This review focuses on the structural organization, biosynthesis, and biological functions of AMPs that possess a beta-hairpin spatial structure. Representatives of this class of AMPs are among the most active antibiotic molecules of animal origin. Due to their wide spectrum of activity and resistance to internal environmental factors, natural beta-hairpin AMPbased compounds might become the most promising drug candidates. PMID- 25926999 TI - Model systems of motor neuron diseases as a platform for studying pathogenic mechanisms and searching for therapeutic agents. AB - Over the past 30 years, many molecular genetic mechanisms underlying motor neuron diseases (MNDs) have been discovered and studied. Among these diseases, amyotrophic lateral sclerosis (ALS), which causes the progressive degeneration and death of central and peripheral motor neurons, and spinal muscular atrophy (SMA), which is one of the inherited diseases that prevail among hereditary diseases in the pattern of child mortality, hold a special place. These diseases, like most nerve, neurodegenerative, and psychiatric diseases, cannot be treated appropriately at present. Artificial model systems, especially those that are based on the use of embryonic stem cells (ESCs) and induced pluripotent stem cells (iPSCs), are of paramount importance in searching for adequate therapeutic agents, as well as for a deep understanding of the MND pathogenesis. This review is mainly focused on the recent advance in the development of and research into cell and animal models of ALS and SMA. The main issues concerning the use of cellular technologies in biomedical applications are also described. PMID- 25927001 TI - Regulation of PGC-1alpha Isoform Expression in Skeletal Muscles. AB - The coactivator PGC-1alpha is the key regulator of mitochondrial biogenesis in skeletal muscle. Skeletal muscle expresses several PGC-1alpha isoforms. This review covers the functional role of PGC-1alpha isoforms and the regulation of their exercise-associated expression in skeletal muscle. The patterns of PGC 1alpha mRNA expression may markedly differ at rest and after muscle activity. Different signaling pathways are activated by different physiological stimuli, which regulate the expression of the PGC-1alpha gene from the canonical and alternative promoters: expression from a canonical (proximal) promoter is regulated by activation of the AMPK; expression from an alternative promoter, via a beta2-adrenergic receptor. All transcripts from both promoters are subject to alternative splicing. As a result, truncated isoforms that possess different properties are translated: truncated isoforms are more stable and predominantly activate angiogenesis, whereas full-length isoforms manly regulate mitochondrial biogenesis. The existence of several isoforms partially explains the broad spectrum function of this protein and allows the organism to adapt to different physiological stimuli. Regulation of the PGC-1alpha gene expression by different signaling pathways provides ample opportunity for pharmacological influence on the expression of this gene. Those opportunities might be important for the treatment and prevention of various diseases, such as metabolic syndrome and diabetes mellitus. Elucidation of the regulatory mechanisms of the PGC-1alpha gene expression and their functional role may provide an opportunity to control the expression of different isoforms through exercise and/or pharmacological intervention. PMID- 25927002 TI - The role of ala198 in the stability and coenzyme specificity of bacterial formate dehydrogenases. AB - It has been shown by an X-ray structural analysis that the amino acid residues Ala198, which are located in the coenzyme-binding domain of NAD(+)-dependent formate dehydrogenases (EC 1.2.1.2., FDH) from bacteria Pseudomonas sp.101 and Moraxella sp. C-1 (PseFDH and MorFDH, respectively), have non-optimal values of the angles psi and phi. These residues were replaced with Gly by site-directed mutagenesis. The mutants PseFDH A198G and MorFDH A198G were expressed in E.coli cells and obtained in active and soluble forms with more than 95% purity. The study of thermal inactivation kinetics showed that the mutation A198G results in a 2.5- fold increase in stability compared to one for the wild-type enzymes. Kinetic experiments indicate that A198G replacement reduces the KM (NAD+) value from 60 to 35 and from 80 to 45 MUM for PseFDH and MorFDH, respectively, while the KM (HCOO-) value remains practically unchanged. Amino acid replacement A198G was also added to the mutant PseFDH D221S with the coenzyme specificity changed from NAD(+) to NADP(+). In this case, an increase in thermal stability was also observed, but the influence of the mutation on the kinetic parameters was opposite: KM increased from 190 to 280 MUM and from 43 to 89 mM for NADP(+) and formate, respectively. According to the data obtained, inference could be drawn that earlier formate dehydrogenase from bacterium Pseudomonas sp. 101 was specific to NADP(+), but not to NAD(+). PMID- 25927003 TI - Reconstruction of rabbit urethral epithelium with skin keratinocytes. AB - We have investigated the living skin equivalent (LSE) as an alternative source of plastic material for closing full-thickness epithelial-stromal urethral injuries. The possibility of transdifferentiation of epidermal keratinocytes, a component of 3D tissue constructs, was investigated in vivo in a model of the recovery of urethral injuries in laboratory rabbits. Autologous grafting of LSE in de epithelialized urethra showed that skin keratinocytes placed in a specific in vivo microenvironment can be incorporated into the damaged area and function as urothelium. The use of EGFP transfected keratinocytes allowed us to identify transplanted cells. The reconstructed urethral tubes did not develop strictures or fistulas at the site of the grafted LSE. Immunohistochemical studies of neo urothelium revealed EGFP-positive cells expressing the urothelial markers K7 and UP3. PMID- 25927004 TI - Influence of Drug Resistance Mutations on the Activity of HIV-1 Subtypes A and B Integrases: a Comparative Study. AB - Integration of human immunodeficiency virus (HIV-1) DNA into the genome of an infected cell is one of the key steps in the viral replication cycle. The viral enzyme integrase (IN), which catalyzes the integration, is an attractive target for the development of new antiviral drugs. However, the HIV-1 therapy often results in the IN gene mutations inducing viral resistance to integration inhibitors. To assess the impact of drug resistance mutations on the activity of IN of HIV-1 subtype A strain FSU-A, which is dominant in Russia, variants of the consensus IN of this subtype containing the primary resistance mutations G118R and Q148K and secondary compensatory substitutions E138K and G140S were prepared and characterized. Comparative study of these enzymes with the corresponding mutants of IN of HIV-1 subtype B strains HXB-2 was performed. The mutation Q148K almost equally reduced the activity of integrases of both subtypes. Its negative effect was partially compensated by the secondary mutations E138K and G140S. Primary substitution G118R had different influence on the activity of proteins of the subtypes A and B, and the compensatory effect of the secondary substitution E138K also depended on the viral subtype. Comparison of the mutants resistance to the known strand transfer inhibitors raltegravir and elvitegravir, and a new inhibitor XZ-259 (a dihydro-1H-isoindol derivative), showed that integrases of both subtypes with the Q148K mutation were insensitive to raltegravir and elvitegravir but were effectively inhibited by XZ-259. The substitution G118R slightly reduced the efficiency of IN inhibition by raltegravir and elvitegravir and caused no resistance to XZ_259. PMID- 25927005 TI - The role of HCV e2 protein glycosylation in functioning of virus envelope proteins in insect and Mammalian cells. AB - The hepatitis C virus (HCV) envelope proteins E1 and E2, being virion components, are involved in the formation of infectious particles in infected cells. The detailed structure of the infectious particle of HCV remains poorly understood. Moreover, the virion assembly and release of virions by the cell are the least understood processes. It is believed that virion properties depend on glycosylation of the virus envelope proteins in a cell, while glycansat several glycosylation sites of these proteins play a pivotal role in protein functioning and the HCV life cycle. N-glycans of glycoproteins can influence viral particle formation, virus binding to cell surface, and HCV pathogenesis. We studied the effect of glycans on the folding ofthe E2 glycoprotein, formation of functional glycoprotein complexes and virus particles in insect and mammalian cells. In order to investigate these processes, point mutations of the N-glycosylation sites of HCV protein E2 (genotype 1b strain 274933RU) were generated and the mutant proteins were further analyzed in the baculovirus expression system. Elimination of the single glycosylation sites of the E2 glycoprotein, except for the N6 site, did not affect its synthesis efficiency in Sf9 insect cells, while the electrophoretic mobility of mutant proteins increased in proportion to the decrease in the number of glycosylation sites. The level of synthesis of HCV glycoprotein E2 in human HEK293T cells depended on the presence of glycans at the N1 and N8 glycosylation sites in contrast to Sf9 cells. At the same time, elimination of glycans at the N1, N2, and N10 sites led to the accumulation of unproductive E1E2 dimers as aggregates and productive assembly suppression of virus-like particles both in insect and mammalian cells. In addition, elimination of single glycosylation sites of HCV E2 had no impact on the RNA synthesis of structural proteins and formation of virus-like particles in insect and mammalian cells. PMID- 25927006 TI - New nanobiocomposite materials for bioelectronic devices. AB - We have developed and synthesized nanobiocomposite materials based on graphene, poly(3,4-ethylenedioxythiophene), and glucose oxidase immobilized on the surface of various nanomaterials (gold nanoparticles and multi-walled carbon nanotubes) of different sizes (carbon nanotubes of different diameters). Comparative studies of the possible influence of the nanomaterial's nature on the bioelectrocatalytic characteristics of glucose- oxidizing bioanodes in a neutral phosphate buffer solution demonstrated that the bioelectrocatalytic current densities of nanocomposite-based bioanodes are only weakly dependent on the size of the nanomaterial and are primarily defined by its nature. The developed nanobiocomposites are promising materials for new bioelectronic devices due to the ease in adjusting their capacitive and bioelectrocatalytic characteristics, which allows one to use them for the production of dual-function electrodes: i.e., electrodes which are capable of generating and storing electric power simultaneously. PMID- 25927007 TI - Selective Protective Potency of Yersinia pestis DeltanlpD Mutants. AB - It has recently been shown that the NlpD lipoprotein is essential to Yersinia pestis virulence and that subcutaneous administration of the nlpD mutant could protect mice against bubonic and pneumonic plague better than the EV vaccine strain [PLoS One 2009. V. 4. No 9. e7023]. In this study, similar DeltanlpD mutants were generated on the basis of other Y. pestis parent strains, including strains from the subspecies microtus, which is avirulent to guinea pigs and humans. Comparative testing confirmed that immunization of mice with DeltanlpD mutants induces immunity 105 times more potent than the one induced by the administration of the EV vaccine strain. At the same time, NlpD- bacteria failed to protect guinea pigs in the case of a subcutaneous challenge with Y. pestis, inducing a 106 times less potent protection compared with that conferred by immunization with the EV vaccine strain. The possible causes of the observed phenomena are discussed. PMID- 25927008 TI - Interaction with serum albumin as a factor of the photodynamic efficacy of novel bacteriopurpurinimide derivatives. AB - Optimization of the chemical structure of antitumor photosensitizers (PSs) is aimed at increasing their affinity to a transport protein, albumin and irreversible light-induced tumor cell damage. Bacteriopurpurinimide derivatives are promising PSs thanks to their ability to absorb light in the near infrared spectral region. Using spectrophotometry, we show that two new bacteriopurpurinimide derivatives with different substituents at the N atoms of the imide exocycle and the pyrrole ring A are capable of forming non-covalent complexes with human serum albumin (HSA). The association constant (calculated with the Benesi-Hildebrand equation) for N-ethoxybacteriopurpurinimide ethyloxime (compound 1) is higher than that for the methyl ether of methoxybacteriopurpurinimide (compound 2) (1.18*10(5) M-1 vs. 1.26*10(4) M(-1), respectively). Molecular modeling provides details of the atomic interactions between 1 and 2 and amino acid residues in the FA1 binding site of HSA. The ethoxy group stabilizes the position of 1 within this site due to hydrophobic interaction with the protein. The higher affinity of 1 for HSA makes this compound more potent than 2 in photodynamic therapy for cultured human colon carcinoma cells. Photoactivation of 1 and 2 in cells induces rapid (within a few minutes of irradiation) necrosis. This mechanism of cell death may be efficient for eliminating tumors resistant to other therapies. PMID- 25927009 TI - Recombinant alpha-NAcetylgalactosaminidase from Marine Bacterium-Modifying A Erythrocyte Antigens. AB - A plasmid based on pET-40b was constructed to synthesize recombinant alpha-N acetylgalactosaminidase of the marine bacterium Arenibacter latericius KMM 426T (alpha-AlNaGal) in Escherichia coli cells. The yield of alpha-Al- NaGal attains 10 mg/ml with activity of 49.7 +/- 1.3 U at 16 degrees C, concentration of inductor 2 mM, and cultivation for 12 h. Techniques such as anion exchange, metal affinity and gel filtration chromatography to purify alpha-AlNaGal were applied. alpha-AlNaGal is a homodimer with a molecular weight of 164 kDa. This enzyme is stable at up to 50 degrees C with a temperature range optimum activity of 20-37 degrees C. Furthermore, its activity is independent of the presence of metal ions in the incubation medium. 1H NMR spectroscopy revealed that alpha-AlNaGal catalyzes the hydrolysis of the O-glycosidic bond with retention of anomeric stereochemistry and possesses a mechanism of action identical to that of other glycoside hydrolases of the 109 family. alpha-AlNaGal reduces the serological activity of A erythrocytes at pH 7.3. This property of alpha-AlNaGal can potentially be used for enzymatic conversion of A and AB erythrocytes to blood group O erythrocytes. PMID- 25927011 TI - A Mixtures-of-Trees Framework for Multi-Label Classification. AB - We propose a new probabilistic approach for multi-label classification that aims to represent the class posterior distribution P(Y|X). Our approach uses a mixture of tree-structured Bayesian networks, which can leverage the computational advantages of conditional tree-structured models and the abilities of mixtures to compensate for tree-structured restrictions. We develop algorithms for learning the model from data and for performing multi-label predictions using the learned model. Experiments on multiple datasets demonstrate that our approach outperforms several state-of-the-art multi-label classification methods. PMID- 25927010 TI - Mechanisms of Antimicrobial Peptide Resistance in Gram-Negative Bacteria. AB - Cationic antimicrobial peptides (CAMPs) are important innate immune defenses that inhibit colonization by pathogens and contribute to clearance of infections. Gram negative bacterial pathogens are a major target, yet many of them have evolved mechanisms to resist these antimicrobials. These resistance mechanisms can be critical contributors to bacterial virulence and are often crucial for survival within the host. Here, we summarize methods used by Gram-negative bacteria to resist CAMPs. Understanding these mechanisms may lead to new therapeutic strategies against pathogens with extensive CAMP resistance. PMID- 25927012 TI - Quantitative Electroencephalography Analysis (qEEG) of Neuro-Electro-Adaptive Therapy 12TM [NEAT12] Up-Regulates Cortical Potentials in an Alcoholic during Protracted Abstinence: Putative Anti-Craving Implications. AB - INTRODUCTION: Cranial electrotherapy stimulation (CES) is a noninvasive therapy that has been used for decades in the United States to treat anxiety, depression, and insomnia in the general population. The effectiveness of CES has been questioned by many and its use is considered controversial. In this study we are presenting data on one alcoholic patient using a newly engineered device we call Neuro-Electro-Adaptive Therapy 12TM [NEAT12]. This hybrid device utilizes TENS current characteristics yielding CES effects. This device has been found to primarily target the excitation of the Cingulate Gyrus region of the brain. CASE PRESENTATION: This is a 42 year old male who has been abstinent from alcohol for approximately two months. The data presented herein represents the pre to post qEEG differences of an alcoholic in protracted abstinence. This subject was evaluated both before and after using the NEAT-12 device. The pre to post comparisons suggest that the cortical potentials especially at the Cingulate Gyrus are up regulated after using the device. The absolute power changes obtained shows a decrease of more than 2 SD as noted in the delta wave spectrum. Also noted is an overall cortical increase in the alpha spectrum. The resting alert state of a neuro typical population is most prominently marked by a regulation of 7.5-11 Hz alpha throughout the cortex. The decreased in delta and theta suggests an up regulation of the prefrontal cortex and the anterior Cingulate Gyrus a site involved in substance use disorder (SUD). CONCLUSION: A presence of dominant slow waves through the prefrontal cortex and the anterior Cingulate Gyrus is often associated with OCD, anxiety, impulsivity and cravings in addicted populations. It is conceivable that our initial finding of altered electrical activity of the brain using qEEG analysis suggests the NEAT-12 may induce a "normalization" of aberrant electrical activity of the cortical region of the brain known to occur during protracted abstinence of alcoholics. It may have utility as a putative anti-craving CES device and therefore warrants intensive investigation. PMID- 25927013 TI - Obtaining Well Calibrated Probabilities Using Bayesian Binning. AB - Learning probabilistic predictive models that are well calibrated is critical for many prediction and decision-making tasks in artificial intelligence. In this paper we present a new non-parametric calibration method called Bayesian Binning into Quantiles (BBQ) which addresses key limitations of existing calibration methods. The method post processes the output of a binary classification algorithm; thus, it can be readily combined with many existing classification algorithms. The method is computationally tractable, and empirically accurate, as evidenced by the set of experiments reported here on both real and simulated datasets. PMID- 25927014 TI - DuSK: A Dual Structure-preserving Kernel for Supervised Tensor Learning with Applications to Neuroimages. AB - With advances in data collection technologies, tensor data is assuming increasing prominence in many applications and the problem of supervised tensor learning has emerged as a topic of critical significance in the data mining and machine learning community. Conventional methods for supervised tensor learning mainly focus on learning kernels by flattening the tensor into vectors or matrices, however structural information within the tensors will be lost. In this paper, we introduce a new scheme to design structure-preserving kernels for supervised tensor learning. Specifically, we demonstrate how to leverage the naturally available structure within the tensorial representation to encode prior knowledge in the kernel. We proposed a tensor kernel that can preserve tensor structures based upon dual-tensorial mapping. The dual-tensorial mapping function can map each tensor instance in the input space to another tensor in the feature space while preserving the tensorial structure. Theoretically, our approach is an extension of the conventional kernels in the vector space to tensor space. We applied our novel kernel in conjunction with SVM to real-world tensor classification problems including brain fMRI classification for three different diseases (i.e., Alzheimer's disease, ADHD and brain damage by HIV). Extensive empirical studies demonstrate that our proposed approach can effectively boost tensor classification performances, particularly with small sample sizes. PMID- 25927015 TI - An Optimization-based Framework to Learn Conditional Random Fields for Multi label Classification. AB - This paper studies multi-label classification problem in which data instances are associated with multiple, possibly high-dimensional, label vectors. This problem is especially challenging when labels are dependent and one cannot decompose the problem into a set of independent classification problems. To address the problem and properly represent label dependencies we propose and study a pairwise conditional random Field (CRF) model. We develop a new approach for learning the structure and parameters of the CRF from data. The approach maximizes the pseudo likelihood of observed labels and relies on the fast proximal gradient descend for learning the structure and limited memory BFGS for learning the parameters of the model. Empirical results on several datasets show that our approach outperforms several multi-label classification baselines, including recently published state-of-the-art methods. PMID- 25927017 TI - Introduction for the special issue on "Tissue Barriers in Inflammation". AB - This issue of Tissue Barriers contains the inaugural special issue devoted to recent advances in barrier function of endothelial and epithelial cells. We used this opportunity to invite experts in vascular endothelial cell biology and epithelial cell biology to comment on critical questions and problems in permeability of organ and tissue barriers, and to provide insight into common areas in these fields, namely how these cells maintain homeostasis and response to injury and infection. To complement these reviews, this issue also contains four research articles that explore specific questions related respiratory and intestinal epithelial cell function. PMID- 25927016 TI - The role of intestinal epithelial barrier function in the development of NEC. AB - The intestinal epithelial barrier plays an important role in maintaining host health. Breakdown of intestinal barrier function is known to play a role in many diseases such as infectious enteritis, idiopathic inflammatory bowel disease, and neonatal inflammatory bowel diseases. Recently, increasing research has demonstrated the importance of understanding how intestinal epithelial barrier function develops in the premature neonate in order to develop strategies to promote its maturation. Optimizing intestinal barrier function is thought to be key to preventing neonatal inflammatory bowel diseases such as necrotizing enterocolitis. In this review, we will first summarize the key components of the intestinal epithelial barrier, what is known about its development, and how this may explain NEC pathogenesis. Finally, we will review what therapeutic strategies may be used to promote optimal development of neonatal intestinal barrier function in order to reduce the incidence and severity of NEC. PMID- 25927018 TI - In-vivo singlet oxygen threshold doses for PDT. AB - OBJECTIVE: Dosimetry of singlet oxygen (1O2) is of particular interest because it is the major cytotoxic agent causing biological effects for type-II photosensitizers during photodynamic therapy (PDT). An in-vivo model to determine the singlet oxygen threshold dose, [1O2]rx,sh, for PDT was developed. MATERIAL AND METHODS: An in-vivo radiation-induced fibrosarcoma (RIF) tumor mouse model was used to correlate the radius of necrosis to the calculation based on explicit PDT dosimetry of light fluence distribution, tissue optical properties, and photosensitizer concentrations. Inputs to the model include five photosensitizer specific photochemical parameters along with [1O2]rx,sh. Photosensitizer-specific model parameters were determined for benzoporphyrin derivative monoacid ring A (BPD) and compared with two other type-II photosensitizers, Photofrin(r) and m tetrahydroxyphenylchlorin (mTHPC) from the literature. RESULTS: The mean values (standard deviation) of the in-vivo [1O2]rx,sh are approximately 0.56 (0.26) and 0.72 (0.21) mM (or 3.6*107 and 4.6*107 singlet oxygen per cell to reduce the cell survival to 1/e) for Photofrin(r) and BPD, respectively, assuming that the fraction of generated singlet oxygen that interacts with the cell is 1. While the values for the photochemical parameters (xi, sigma, g, beta) used for BPD were preliminary and may need further refinement, there is reasonable confidence for the values of the singlet oxygen threshold doses. DISCUSSION: In comparison, the [1O2]rx,sh value derived from in-vivo mouse study was reported to be 0.4 mM for mTHPC-PDT. However, the singlet oxygen required per cell is reported to be 9*108 per cell per 1/e fractional kill in an in-vitro mTHPC-PDT study on a rat prostate cancer cell line (MLL cells) and is reported to be 7.9 mM for a multicell in vitro EMT6/Ro spheroid model for mTHPC-PDT. A theoretical analysis is provided to relate the number of in-vitro singlet oxygen required per cell to reach cell killing of 1/e to in-vivo singlet oxygen threshold dose (in mM). The sensitivity of threshold singlet oxygen dose for our experiment is examined. The possible influence of vascular vs. apoptotic cell killing mechanisms on the singlet oxygen threshold dose is discussed by comparing [1O2]rx,sh for BPD with 3 hr and 15 min drug-light-intervals, with the later being known to have a dominantly vascular effect. CONCLUSIONS: The experimental results of threshold singlet oxygen concentration in an in-vivo RIF tumor model for Photofrin(r), BPD, and mTHPC are about 20 times smaller than those observed in vitro. These results are consistent with knowledge that factors other than singlet oxygen-mediated tumor cell killing can contribute to PDT damage in-vivo. PMID- 25927019 TI - T Follicular Helper Cells in Transplantation: The Target to Attenuate Antibody Mediated Allogeneic Responses? AB - Antibody-mediated, humoral rejection has been recognized as a common cause of transplant dysfunction and is responsible for 30-50 % of failed allografts. The production of antibody is dependent on instructions from memory CD4+ T helper cells that interact with antigen-specific B cells. Recently, a specialized T-cell subset has been identified-T follicular helper (Tfh) cells-which support activated B cells via interleukin (IL)-21 after binding to the IL-21 receptor expressed by these B cells. Therefore, neutralizing the IL-21 pathway will selectively inhibit the allogeneic IL-21-driven Tfh- and B-cell functions. However, little is known of the role of Tfh cells in alloreactivity. In this review, we debate the role of Tfh cells in B-cell-mediated allogeneic responses by discussing their mechanisms of actions. In addition, we speculate about the use of agents that intervene in Tfh-B-cell interaction and consequently prevent or treat antibody-mediated rejection in patients after transplantation. PMID- 25927021 TI - Recurrent Pregnancy Loss through the Lens of Immunology. PMID- 25927020 TI - Vascularized Composite Allografts: Procurement, Allocation, and Implementation. AB - Vascularized composite allotransplantation is a continuously evolving area of modern transplant medicine. Recently, vascularized composite allografts (VCAs) have been formally classified as 'organs'. In this review, key aspects of VCA procurement are discussed, with a special focus on interaction with the procurement of classical solid organs. In addition, options for a matching and allocation system that ensures VCA donor organs are allocated to the best-suited recipients are looked at. Finally, the different steps needed to promote VCA transplantation in society in general and in the medical community in particular are highlighted. PMID- 25927022 TI - Exploring the human seminal plasma proteome: an unexplored gold mine of biomarker for male infertility and male reproduction disorder. AB - BACKGROUND: The human seminal fluid is a complex body fluid. It is not known how many proteins are expressed in the seminal plasma; however in analog with the blood it is possible up to 10,000 proteins are expressed in the seminal plasma. The human seminal fluid is a rich source of potential biomarkers for male infertility and reproduction disorder. METHODS: In this review, the ongoing list of proteins identified from the human seminal fluid was collected. To date, 4188 redundant proteins of the seminal fluid are identified using different proteomics technology, including 2-DE, SDS-PAGE-LC-MS/MS, MudPIT. However, this was reduced to a database of 2168 non-redundant protein using UniProtKB/Swiss-Prot reviewed database. RESULTS: The core concept of proteome were analyzed including pI, MW, Amino Acids, Chromosome and PTM distribution in the human seminal plasma proteome. Additionally, the biological process, molecular function and KEGG pathway were investigated using DAVID software. Finally, the biomarker identified in different male reproductive system disorder was investigated using proteomics platforms so far. CONCLUSION: In this study, an attempt was made to update the human seminal plasma proteome database. Our finding showed that human seminal plasma studies used to date seem to have converged on a set of proteins that are repeatedly identified in many studies and that represent only a small fraction of the entire human seminal plasma proteome. PMID- 25927023 TI - Lipopolysaccharide- and Lipoteichoic Acid-mediated Pro-inflammatory Cytokine Production and Modulation of TLR2, TLR4 and MyD88 Expression in Human Endometrial Cells. AB - BACKGROUND: Toll-like receptor (TLR)-mediated inflammatory processes are supposed to be involved in pathophysiology of spontaneous abortion and preterm labor. Here, we investigated functional responses of human endometrial stromal cells (ESCs) and whole endometrial cells (WECs) to lipopolysaccharide (LPS) and lipoteichoic acid (LTA). METHODS: Endometrial tissues were obtained from 15 cycling women who underwent laparoscopic tubal ligation. Modulation of TLR2, TLR4 and MyD88 expression and production of pro-inflammatory cytokines by WECs and ESCs in response to LPS and LTA were assessed. RESULTS: WECs and ESCs expressed significant levels of TLR4 and MyD88 transcripts but, unlike WECs, ESCs failed to express TLR2 gene. Regardless of positive results of Western blotting, ESCs did not express TLR4 at their surface as judged by flow cytometry. Immunofluorescent staining revealed intracellular localization of TLR4 with predominant perinuclear pattern. LPS stimulation marginally increased TLR4 gene expression in both cell types, whereas such treatment significantly upregulated MyD88 gene expression after 8 hr (p < 0.05). At the protein level, however, LPS activation significantly increased TLR4 expression by ESCs (p < 0.05). LTA stimulation of WECs was accompanied with non-significant increase of TLR2 and MyD88 transcripts. LPS and LTA stimulation of WECs caused significant production of IL-6 and IL-8 in a dose-dependent manner (p < 0.05). Similarly, ESCs produced significant amounts of IL-6, IL-8 and also TNF-alpha in response to LPS activation (p < 0.05). CONCLUSION: Our results provided further evidence of initiation of inflammatory processes following endometrial TLR activation by bacterial components which could potentially be harmful to developing fetus. PMID- 25927024 TI - Female reproductive hormones and biomarkers of oxidative stress in genital Chlamydia infection in tubal factor infertility. AB - BACKGROUND: Genital Chlamydia infection (GCI) and the associated pathologies have been implicated in tubal infertility. Though the actual pathologic mechanisms are still uncertain, oxidative stress and other factors have been implicated. The purpose of the study was to determine the possible contribution of female reproductive hormones and biomarkers of oxidative stress in genital Chlamydial infection to tubal occlusion. METHODS: This prospective case control study was carried out by recruiting 150 age matched women grouped into infertile Chlamydia positive women (n = 50), fertile Chlamydia positive women (n = 50) and fertile Chlamydia negative women as controls (n = 50). High vaginal swabs and endocervical swabs were collected for screening Neisseria gonorrhoeae, Chlamydia trachomatis, Trichomonas vaginalis, Treponema pallidum, Staphylococcus aureus, and Candida albicans. Sera were collected for estimation of Chlamydia trachomatis antibody, female reproductive hormones [Follicle Stimulating Hormone (FSH), Luteinizing Hormone (LH), Oestradiol (E2), Progesterone (P4), Prolactin (PRL)] and biomarkers of oxidative stress [Total Antioxidant Capacity (TAC) and 8 hydroxyl-2-deoxyguanosine (8-OHdG)] by enzyme immunoassay (EIA). Data were analyzed using chi square, analysis of variance and LSD Post hoc to determine mean differences at p = 0.05. RESULTS: Among women with GCI, higher levels of LH and 8-OHdG were observed in infertile Chlamydia positive women compared to fertile Chlamydia positive women (p < 0.05). Higher levels of LH and 8-OHdG and lower TAC levels were observed in infertile Chlamydia positive women compared to fertile Chlamydia negative controls (p < 0.05). CONCLUSION: Mechanisms including oxidative DNA damage and reduced antioxidant capacity may be involved in the pathology of Chlamydia induced tubal damage. PMID- 25927025 TI - Stereological analysis of human placenta in cases of placenta previa in comparison with normally implanted controls. AB - BACKGROUND: Placenta previa (PP) is an obstetric complication that can affect maternal and fetal morbidity and mortality. Its prevalence is rising due to cesarean sections. There is no quantitative data of placenta in PP. In this study, quantitative parameters of placenta in cases with PP in comparison with normally implanted controls were investigated. METHODS: In this quasi experimental study, placentas from pregnancies with PP and normally implanted controls (n = 10) were obtained from women who underwent cesarean section. Three full-thickness columns of each placenta were sampled using systematic uniform random sampling (SURS). Columns were cut into slices and slices were sectioned with 4 um thickness. SURS selected sections were stained by Masson's trichrome. Stereological analysis was done on 8-10 SURS microscopic fields of each section. Absolute volume and volume density of chorionic villi, intervillous space, syncytiotrophoblast, fibrin and blood vessels in chorionic villi were estimated in both groups. Statistical analysis was done using Mann Whitney-U test and significant level was set at p < 0.05. RESULTS: There was a significant reduction in total volume and volume density of fibrin deposits on the surface of chorionic villi (p < 0.05), and a significant increment in total volume and volume density of chorionic villous blood vessels in PP group in comparison with C group (p < 0.05). CONCLUSION: Results showed that impairment in situation of implantation in PP can cause significant changes in the structure of placenta. These changes probably can be influential on the evolution and survival of fetus. PMID- 25927026 TI - Effect of Administration of Single Dose GnRH Agonist in Luteal Phase on Outcome of ICSI-ET Cycles in Women with Previous History of IVF/ICSI Failure: A Randomized Controlled Trial. AB - BACKGROUND: GnRH agonist administration in the luteal phase has been suggested to beneficially affect the outcome of intracytoplasmic sperm injection (ICSI) and embryo transfer (ET) cycles. This blind randomized controlled study evaluates the effect of GnRH (Gonadotropine Releasing Hormone) agonist administration on ICSI outcome in GnRH antagonist ovarian stimulation protocol in women with 2 or more previous IVF/ICSI-ET failures. METHODS: One hundred IVF failure women who underwent ICSI cycles and stimulated with GnRH antagonist ovarian stimulation protocol, were included in the study. Women were randomly assigned to intervention (received a single dose injection of GnRH agonist (0.1 mg of Decapeptil) subcutaneously 6 days after oocyte retrieval) and control (did not receive GnRH agonist) groups. Implantation and clinical pregnancy rates were the primary outcome measures. RESULTS: Although the age of women, the number of embryos transferred in the current cycle and the quality of the transferred embryos were similar in the two groups, there was a significantly higher rate of implantation (Mann Whitney test, p = 0.041) and pregnancy (32.6% vs. 12.5%, p = 0.030, OR = 3.3, 95%CI, 1.08 to 10.4) in the intervention group. CONCLUSION: Our results suggested that, in addition to routine luteal phase support using progesterone, administration of 0.1 mg of Decapeptil 6 days after oocyte retrieval in women with previous history of 2 or more IVF/ICSI failures led to a significant improvement in implantation and pregnancy rates after ICSI following ovarian stimulation with GnRH antagonist protocol. PMID- 25927027 TI - Comparison of Sexual Dysfunction in Women Using Depo-Medroxyprogesterone Acetate (DMPA) and Cyclofem. AB - BACKGROUND: Sexual affairs are one of the physiological needs affecting human health. Sexual functioning disorders can reduce individual's capabilities and creativities. Sexual relations are in the center of women's quality of life. The most important family planning is to prevent unintended pregnancies. Injectable contraceptives protect women exposed to many complications and mortality due to unintended pregnancies, with tolerable effects on other aspects of women's life. An important aspect of women's life is sexual health. This study aimed to compare sexual function of women using DMPA with women using Cyclofem presented to health centers affiliated to Shahid Beheshti University of Medical Sciences in Tehran, Iran in 2013. METHODS: This descriptive-comparative study was conducted on 240 women in health centers in Tehran, Iran. They were selected by multistage sampling. The data was collected using a questionnaire completed by interviewing. The questionnaire had 2 parts, demographic characteristic section and Female Sexual Function Index (FSFI). Data was analyzed by descriptive statistics, independent T-test, U-test, Chi-square, Fisher exact test. The p-value less than 0.05 were applied for all statistical tests as significance level. RESULTS: The difference in sexual function between Cyclofem and DMPA groups was insignificant, but in terms of sexual desire in DMPA users better than and sexual pain them less than in Cyclofem users, the difference between the groups was significant (p < 0.05). CONCLUSION: In introducing hormonal contraceptive methods, health workers should emphasize their adverse effects on sexual function. Women who use Cyclofem and DMPA should be aware that they may experience some changes in libido and sexual pain. PMID- 25927028 TI - An Association Study between INSR/NsiI (rs2059806) and INSR/PmlI (rs1799817) SNPs in Women with Polycystic Ovary Syndrome from West Azerbaijan Province, Iran. AB - BACKGROUND: It has been demonstrated that insulin signaling pathway related genes have important roles in polycystic ovary syndrome (PCOS) risk. The goal of present investigation was to assess the potential association between INSR/NsiI (rs2059806) and INSR/PmlI (rs1799817) SNPs and PCOS. METHODS: 50 women with PCOS and 47 normal controls entered the study. NsiI and PmlI SNPs in the INSR gene were determined by RFLP-PCR. RESULTS: INSR/NsiI (rs2059806) SNP GG, GA, AA, G and A genotypic and allelic frequencies were 45(90%), 5(10%), 0(0%), 95(95%) and 5(5%) in cases and 41 (87.2%), 6(12.8%), 0(0%), 88(93.6%) and 6(6.38%) in controls, respectively. INSR/ PmlI (rs1799817) SNPs resulted in three genotypes of CC, CT, and TT with C and T alleles. The frequencies of PmlI (rs1799817) SNPs in the INSR gene were 37(37%) and 63(63%) in cases, also 39(41.49%) and 55 (58.51%) in controls regarding T and C alleles. The frequencies of PmlI (rs1799817) SNPs in the INSR gene were 4(8%), 29(58%), and 17(34%) in cases, also 5(10.64%), 29(61.7%), and 13(27.66%) in controls regarding TT, TC, and CC genotypes, respectively. CONCLUSION: The present study as the first investigation of its own kind in Iranian Azeri Turkish women, reported no association between NsiI (rs2059806) and PmlI (rs1799817) SNPs in the INSR gene and PCOS risk. PMID- 25927029 TI - Posterior urethral valve: an unusual cause of primary male infertility. AB - BACKGROUND: Posterior urethral valve presenting in adulthood is uncommon. This can be an unusual cause of primary male infertility as a result of abnormalities in sexual function. CASE PRESENTATION: This report describes a 40 year old man who presented to us on account of inability to impregnate his wife after 2 years of marriage. History revealed poor stream of urine since childhood and passage of scanty ejaculate during intercourse. A micturating cystourethrogram revealed dilated posterior urethra in keeping with posterior urethral valves. Endoscopic valve ablation was done with subsequent improvement in ejaculate volume and urine stream. His spouse achieved pregnancy thereafter. CONCLUSION: In this report, it was found that adult posterior urethral valve though uncommon may be a cause of male infertility. Restoration of fertility potential can be achieved following valve ablation. PMID- 25927030 TI - A successful healthy childbirth in a case of total globozoospermia with oocyte activation by calcium ionophore. AB - BACKGROUND: Globozoospermia is a rare (incidence of 0.1% among andrological patients) and poorly understood condition, but a severe disorder in male infertility. This case report detailed the course of treatment and protocol of a patient with type 1 globozoospermia using Intracytoplasmic Sperm Injection (ICSI) and oocyte activation by calcium ionophore, which yielded conception and birth of a healthy baby after six previous unsuccessful attempts, using ICSI alone. CASE PRESENTATION: A 39-year-old male with normal findings on routine examination presented to TDV 29 Mayis Hospital, Assisted Reproduction Unit (ART) with his 37 year-old wife. Her examination was also within normal limits and ovulatory cycle was regular. The male's diagnostic screening revealed normal karyotype (46, XY) and no Y-microdeletion. However, the spermogram was abnormal; sperm count of 14 million/ml with 35% active motility and 100% morphologically abnormal sperm, indicating globozoospermia. Ovarian stimulation was provided using classic long down-regulation protocol and 13 MII oocytes were collected. Next, calcium ionophore was applied following the ICSI procedure to improve the chances for fertilization. The case report compared quantitative procedural and diagnostic screening data, and fertilization rates. On day 5, two grade 1 blastocysts out of 5 embryos were transferred, yielding positive beta-human chorionic gonadotropin (beta hCG), and ultimately a healthy delivery. CONCLUSION: ICSI with assisted oocyte activation by calcium ionophore may overcome male infertility where there is total globozoospermia. PMID- 25927033 TI - Individual and environmental factors determining sedentary lifestyle of the polish population. AB - BACKGROUND: The aim of the current investigation was to evaluate the sedentary lifestyle of the Polish population and its link with prolonged sitting in light of individual and environmental factors. METHODS: The sample consisted of 1505 Polish people between 18 and 64 years old. The Computer-Assisted Telephone Interview (CATI) survey was conducted with the Polish version of International Physical Activity Questionnaire (IPAQ-LF) and the survey of the determinants of a sport activity among the Polish population. The relationships between the time spent sitting and the individual and environmental factors among Polish citizens were investigated through log-linear analysis. RESULTS: The total time Polish people spent sitting was 2812.4+/-1593.9 min/week. During the weekend, men (Chi(2)=45.0; P=0.04) spent significantly more time sitting than women (251.1+/ 170.1min/week, 230.9+/-155.0 min/week, respectively). Despite the relatively high proportion of people declaring participation in the Sport for All initiative (67.8%), only 9.6% of Polish people undertake a physical activity on a daily basis. The odds ratios above the median (>2545 min/week) are higher (OR=1.33; 95% CI=1.03-1.72) for those who are not physically active (54.5% vs. 45.5%). There was no relationship between prolonged sitting time and the environmental factors. CONCLUSION: It is necessary to increase consistent efforts to create an environment that would successfully promote anactive lifestyle among Polish citizens in their place of residence and prevent sedentary behaviours within this population. The recommendations for physical activity should include the guidelines intervening in the time people spend sitting. PMID- 25927034 TI - Development of Welding Fumes Health Index (WFHI) for Welding Workplace's Safety and Health Assessment. AB - BACKGROUND: This study aimed to develop an index that can rank welding workplace that associate well with possible health risk of welders. METHODS: Welding Fumes Health Index (WFHI) were developed based on data from case studies conducted in Plant 1 and Plant 2. Personal sampling of welding fumes to assess the concentration of metal constituents along with series of lung function tests was conducted. Fifteen metal constituents were investigated in each case study. Index values were derived from aggregation analysis of metal constituent concentration while significant lung functions were recognized through statistical analysis in each plant. RESULTS: The results showed none of the metal constituent concentration was exceeding the permissible exposure limit (PEL) for all plants. However, statistical analysis showed significant mean differences of lung functions between welders and non-welders. The index was then applied to one of the welding industry (Plant 3) for verification purpose. The developed index showed its promising ability to rank welding workplace, according to the multiple constituent concentrations of welding fumes that associates well with lung functions of the investigated welders. CONCLUSION: There was possibility that some of the metal constituents were below the detection limit leading to '0' value of sub index, thus the multiplicative form of aggregation model was not suitable for analysis. On the other hand, maximum or minimum operator forms suffer from compensation issues and were not considered in this study. PMID- 25927031 TI - Neuroendocrine differentiation in prostate cancer: a mechanism of radioresistance and treatment failure. AB - Neuroendocrine differentiation (NED) in prostate cancer is a well-recognized phenotypic change by which prostate cancer cells transdifferentiate into neuroendocrine-like (NE-like) cells. NE-like cells lack the expression of androgen receptor and prostate specific antigen, and are resistant to treatments. In addition, NE-like cells secrete peptide hormones and growth factors to support the growth of surrounding tumor cells in a paracrine manner. Accumulated evidence has suggested that NED is associated with disease progression and poor prognosis. The importance of NED in prostate cancer progression and therapeutic response is further supported by the fact that therapeutic agents, including androgen deprivation therapy, chemotherapeutic agents, and radiotherapy, also induce NED. We will review the work supporting the overall hypothesis that therapy-induced NED is a mechanism of resistance to treatments, as well as discuss the relationship between therapy-induced NED and therapy-induced senescence, epithelial-to-mesenchymal transition, and cancer stem cells. Furthermore, we will use radiation-induced NED as a model to explore several NED-based targeting strategies for development of novel therapeutics. Finally, we propose future studies that will specifically address therapy-induced NED in the hope that a better treatment regimen for prostate cancer can be developed. PMID- 25927032 TI - Burden and nutritional deficiencies in opiate addiction- systematic review article. AB - Addiction to the illicit and prescribed use of opiate is an alarming public health issue. Studies on addictive disorders have demonstrated severe nutritional deficiencies in opiate abusers with behavioral, physiological and cognitive symptoms. Opiate addiction is also link with a significant number of diseases including Human Immunodeficiency Virus (HIV), Hepatitis C Virus (HCV) and other blood borne diseases generally stem from the use of needles to inject heroin. The use of medication assisted treatment for opioid addicts in combination with behavioural therapies has been considered as a highly effective treatment. Methadone is a long-lasting MU-opioid agonist and a pharmacological tool which attenuates withdrawal symptoms effectively replacement therapies. This review article aims to explain opiate addiction mechanisms, epidemiology and disease burden with emphasis on dietary and nutritional status of opiate dependent patients in methadone maintenance therapy. PMID- 25927035 TI - Relationship between CATSPERB, NR5A2 gene polymorphisms and Peak Bone Mineral Density in College Students in China. AB - BACKGROUND: Peak bone mineral density (PBMD) is influenced by both genetic and environmental factors, genes explains most of variation. As the novel candidate genes CATSPERB and NR5A2 may have been associated with spinal PBMD in adult. This study was to investigate the relationship among these two genes^ PBMD and the life style factors in young female. METHODS: The rs1298989 single nucleotide polymorphism (SNP) of the CATSPERB gene and the rs3762397 SNP of the NR5A2 gene were genotyped using SNaPshot(r) in 359 students from Xinjiang. The prospective study included 203 Han and 156 Uyghur subjects. PBMD was measured using quantitative computed tomography (QCT). Calcium, phosphate and alkaline phosphatase were measured by ELISA method. Physical activity, dietary calcium and life styles were assessed by questionnaire. RESULTS: Both SNPs showed differences in genotype and allele frequencies (P < 0.05) between the Han and Uyghur subjects. Total calcium intake, energy intake, tea and milk intake were also significantly different between two groups (P < 0.05). Multiple regression analysis showed an association between PBMD and vitamin D intake (P = 0.000), milk (P = 0.000), exercise (P = 0.029), rs1298989 (P = 0.028), energy intake (P = 0.043). CONCLUSION: This study demonstrated the polymorphisms of the rs1298989 and rs3762397 are associated with PBMD both in Han and Uyghur subjects. PBMD, in Xinjiang, appears to be associated with several known factors that are well described in the literature. While the genotypes of rs1298989 and rs3762397 do not appear have a strong effect on the PBMD. PMID- 25927036 TI - Aerobic steps as measured by pedometry and their relation to central obesity. AB - BACKGROUND: The purpose of this study was to examine the relation between daily steps and aerobic steps, and anthropometric variables, using the waist-to-hip ratio (WHR) and waist-to-height ratio (WHtR). METHODS: The participants in this cross-sectional study were taken the measurements of by a trained anthropologist and then instructed to wear an Omron pedometer for seven consecutive days. A series of statistical tests (Mann-Whitney U test, Kruskal-Wallis ANOVA, multiple comparisons of z' values and contingency tables) was performed in order to assess the relation between daily steps and aerobic steps, and anthropometric variables. RESULTS: A total of 507 individuals (380 females and 127 males) participated in the study. The average daily number of steps and aerobic steps was significantly lower in the individuals with risky WHR and WHtR as compared to the individuals with normal WHR (P=0.005) and WHtR (P=0.000). A comparison of age and anthropometric variables across aerobic steps activity categories was statistically significant for all the studied parameters. According to the contingency tables for normal steps, there is a 5.75x higher risk in the low activity category of having WHtR>0.50 as compared to the high-activity category. CONCLUSIONS: Both normal and aerobic steps are significantly associated with central obesity and other body composition variables. This result is important for older people, who are more likely to perform low-intensity activities rather than moderate- or high-intensity activities. Our results also indicate that risk of having WHtR>0.50 can be reduced by almost 6x by increasing daily steps over 8985 steps per day. PMID- 25927037 TI - Social network size estimation and determinants in tehran province residents. AB - BACKGROUND: Network scale-up is an indirect method for estimating the size of hidden, hard-to-count or high risk populations. Social network size estimation is the first step in this method. The present study was conducted with the purpose of estimating the social network size of the Tehran Province residents and its determinants. METHODS: Maximum Likelihood Estimation was applied to estimate people's network sizes by using populations of known sizes and the scale-up method. Respondents were selected from Tehran province through convenience sampling in 2012. Out of thirteen selected subpopulations with known size, ten had minimum accuracy which used in our analysis. RESULTS: Of the 1029 respondents in this study, 46.7% were male. The social network size of Tehran Province residents was estimated to be 259.1 (CI95%: 242.2, 276) based on the ten known populations remained in this study. This size was 291.8 in men and 230.4 in women. Younger people (18-25 years old) had larger network sizes compared to the other age groups (P<0.001). CONCLUSION: Our estimation for social network size of Tehran inhabitants was smaller than that previously estimated size for the whole country (c=380). In addition, we found that the social network of subpopulations was different. This difference means that we need local estimations for sub populations to improve the accuracy of population size estimation using network scale up method. PMID- 25927038 TI - A Gene Selection Method for Survival Prediction in Diffuse Large B-Cell Lymphomas Patients using 1D Discrete Wavelet Transform. AB - BACKGROUND: An important aspect of microarray studies includes the prediction of patient survival based on their gene expression profile. To deal with the high dimensionality of this data, use of a dimension reduction procedure along with the survival prediction model is necessary. This study aimed to present a new method based on wavelet transform for survival relevant gene selection. METHODS: The data included 2042 gene expression measurements from 40 patients with Diffuse Large B-Cell Lymphomas (DLBCL). The pre-processing gene expression data is decomposed using third level of the 1D discrete wavelet transform. The detail coefficients at levels 1 and 2 are filtered out and expression data reconstructed using the approximation and detailed coefficients at the third level. All the genes are then scored based on the t score. Then genes with the highest scores are selected. By using forward selection method in Cox regression model, significant genes were identified. RESULTS: The results showed wavelet-based gene selection method presents acceptable survival prediction. Using this method, six significant genes were selected. It was indicated the expression of GENE3359X and GENE3968X decreased the survival time, whereas the expression of GENE967X, GENE3980X, GENE3405X and GENE1813X increased the survival time. CONCLUSION: Wavelet-based gene selection method is a potentially useful tool for the gene selection from microarray data in the context of survival analysis. PMID- 25927039 TI - Structural modeling of safety performance in construction industry. AB - BACKGROUND: With rapid economic development and industrialization, the construction industry continues to rank among the most hazardous industries in the world. Therefore, construction safety is always a significant concern for both practitioners and researchers. The objective of this study was to create a structural modeling of components that influence the safety performance in construction projects. METHODS: We followed a two-stage Structural Equation Model based on a questionnaire study (n=230). In the first stage, we applied the Structural Equation Model to the proposed model to test the validity of the observed variables of each latent variable. In the next stage, we modified the proposed model. The LISREL 8.8 software was used to conduct the analysis of the structural model. RESULTS: A good-fit structural model (Goodness of Fit Index=0.92; Root Mean Square Residual=0.04; Root Mean Square Error of Approximation=0.04; Comparative Fit Index=0.98; Normalized Fit Index=0.96) indicated that social and organizational constructs influence safety performance via the general component of the safety climate. CONCLUSION: The new structural model can be used to provide better understanding of the links between safety performance indicators and contributing components, and make stronger recommendations for effective intervention in construction projects. PMID- 25927040 TI - Is the polymorphism at position -1082 of IL-10 gene associated with visceral leishmaniasis? AB - BACKGROUND: Immune responses play critical roles in the leishmaniasis eradication. IL-10 is a key regulator of immune responses, and the polymorphisms within its promoter region are associated with alteration in its expression. Therefore, this study was designed to examine the correlation between polymorphism at the -1082 position of the IL-10 gene and visceral leishmaniasis (VL). METHODS: The IL-10 -1082 polymorphism and anti-Leishmania antibody titration were examined in 110 patients with clinical presentation of VL and seropositive for the Leishmania (group 1), 74 seropositive patients but without clinical presentation (group 2) and 113 healthy controls (group 3) using the PCR RFLP and immunofluorescence techniques, respectively. RESULTS: The polymorphism at IL-10 -1082 (A/G) position was significantly associated with VL and A/G genotype was significantly higher in VL patients when compared to the groups 2 and 3 (P< 0.001). However, the results demonstrated that the A and G alleles were not associated with VL (P= 0.263). CONCLUSIONS: Previous investigations have shown that the polymorphism at the -1082 position of the IL-10 gene can influence its expression and also it has been proved that IL-10 level was increased during VL. Our results suggest that the A/G genotype may be considered as a risk factor for VL. PMID- 25927041 TI - Normative data of grip and pinch strengths in healthy adults of Iranian population. AB - BACKGROUND: Measuring and comparing grip and pinch strengths with their normative data is a valid method to detect intensity of the numerous damages of hand. This research was carried out with the aim of establishing normative data of grip strength and three types of pinch strengths (Tip, Key and Palmar) in healthy Iranian adults. METHODS: In this cross-sectional study, the study population was formed of 1008 people (526 men and 482 women) from healthy Fars race adults of over 20 years old in five cities of Iran. American Society of Hand Therapists (ASHT) recommendations were followed to establish normative data of grip and pinch strengths. Normative data of grip and pinch strengths were developed based on sex, 12 different age groups and dominant and non-dominant hands. Jamar dynamometer and Seahan pinch gauge were used to measure grip and pinch strengths, respectively. RESULTS: Normative data of grip and pinch strengths were provided. Grip and pinch strengths of men were significantly stronger than women. The maximum grip strength of men was obtained in the group of 20-24 years and among women it was in the age group 35-39 years. Regardless of gender, grip and pinch strengths were declined with aging. CONCLUSION: Normative data of grip and pinch strengths were developed for Iranian population. PMID- 25927042 TI - Maintenance Treatment with Opium Tincture: A Preliminary Qualitative Study of the Factors Related to Treatment entry. AB - BACKGROUND: The current preliminary study aimed to explore the reasons that a group of opiate-dependent patients reported for entry into opium tincture treatment (OTT). METHODS: Through examinations of 52 qualitative focus group interviews with patients from six OTT centers and 10 health providers (in key informant interviews) in Tehran, this study highlights the factors that participants reported as the reasons associated with entry into OTT. Quantitative data including demographic data and details of drug use were analyzed by using SPSS.v.18.0. Qualitative data was analyzed by using Atlas-ti software. RESULTS: 86.5% of patients were male and 13.5% were female. The median age of patients was 39 yr. The most frequently reasons associated with entry into OTT included methadone misconceptions including dissatisfaction with taking methadone as a chemical medication, methadone dependence, and long duration of MMT. The other reasons included the recommendation of other people in treatment and OT-related characteristics and expectations including the herbal compound of OT, treating opiate craving and withdrawal symptoms, and improving general health. CONCLUSION: The study findings preliminarily showed the reasons associated with entry into OTT in a sample of treatment seekers. Longitudinal studies with more representative samples and follow-up stages are required to evaluate the clinical effectiveness of OTT as a maintenance treatment in comparison with methadone and buprenorphine. Patient-centered program and policy implications are discussed. PMID- 25927043 TI - Shortcomings in dealing with psychological effects of natural disasters in iran. AB - BACKGROUND: Natural disasters result in numerous economic, social, psychological and cultural consequences. Of them, psychological consequences of disasters will affect the lives of people long after the critical conditions finish. Thus, concerning the importance of psychological support in disasters, this study has identified problems and weaknesses in dealing with the psychological effects of the disasters occurred in Iran. METHODS: This qualitative study was carried out using semi-structured in-depth interviews and focus groups. Sample volume consisted of 26 experts in the field of disaster management. Content analysis was used to analyze data. RESULTS: Nine major problems were identified as weaknesses in handling the psychological effects of the disaster. These weaknesses include: rescuers' unfamiliarity with the basic principles of psychosocial support, shortage of relevant experts and inadequate training, paying no attention to the needs of specific groups, weaknesses in organizational communications, discontinuation of psychological support after disaster, unfamiliarity with native language and culture of the disaster area, little attention paid by media to psychological principles in broadcasting news, people's long-term dependence on governmental aid. CONCLUSIONS: Disaster management has various aspects; in Iran, less attention has been paid to psychological support in disasters. Increasing education at all levels, establishing responsible structures and programming seem necessary in dealing with the psychological effects of disasters. PMID- 25927044 TI - Aflatoxin M1 Concentration in Various Dairy Products: Evidence for Biologically Reduced Amount of AFM1 in Yoghurt. AB - BACKGROUND: Aflatoxin M1 (AFM1), a carcinogenic substance is found in milk and dairy products. The effect of season and type of dairy products on AFMi level in northern Iran was investigated in this study. METHODS: Three hundred samples (each season 75 samples) including raw and pasteurized milk, yoghurt, cheese, and cream samples were collected from three distinct milk producing farms. The samples were subjected to chemical and solid phase extractions and were analyzed by using HPLC technique. Recovery percentages, limit of detection and limit of quantification values were determined. RESULTS: Seventy percent and 98% were the minimum and maximum recoveries for cheese and raw milk, respectively and 0.021 and 0.063 ppb were the limit of detection and limit of quantification values for AFM1. We found that in autumn and winter the highest level (0.121 ppb) of AFM1 in cheese and cream samples and failed to detect any AFM1 in spring samples. Interestingly, our data showed that the yoghurt samples had the lowest level of AFM1 in all seasons. CONCLUSION: There are significant differences between the AFM1 levels in dairy products in various seasons and also various types of products, suggesting spring and summer yoghurt samples as the safest products from AFM1 level point of view. PMID- 25927045 TI - Multiple warty dyskeratomas: case report. AB - Warty dyskeratoma is a rare tumor that presents mainly as an isolated papule or nodule on the scalp, face or neck in the adults. Warty dyskeratoma frequently arises as a single lesion with a central keratotic plug on the skin of middle aged or elderly people. Multiple warty dyskeratomas are very rare cutaneous lesions which are mostly seen on the scalp. We herein report a multiple warty dyskeratoma in a female patient. PMID- 25927046 TI - Understanding determinants of inequality in sanitation improvement in rural china. PMID- 25927047 TI - Social security: offering welfare opportunities for the vulnerable people. PMID- 25927048 TI - Dentistry's Cardinal Role in Forensic Odontology. PMID- 25927049 TI - Know your blood pressure; the theme of world hypertension day 2014. PMID- 25927050 TI - Tragedy of rostam and sohrab: first example introducing the science of mytho pathology. PMID- 25927051 TI - Distribution of Human Papillomavirus Genotypes in Liquid-based Samples; Abundance of HPV-53 in Tehran, Iran. PMID- 25927052 TI - Haly abbas and the early description of obstructive jaundice. PMID- 25927053 TI - Elders' General Self-efficacy and Its Affecting Factors in Iran. PMID- 25927054 TI - Is HbA1c an Accurate Predictor for Diabetes Risk in Patients with Chronic Periodontitis? PMID- 25927055 TI - Women presented with breast involvement of tuberculosis. PMID- 25927056 TI - Sperm DNA fragmentation and standard semen parameters in algerian infertile male partners. AB - PURPOSE: To date, standard semen parameters have been the only parameters investigated in sperm samples of infertile men in Algeria. We investigated, for the first time, semen parameters according to sperm DNA fragmentation (SDF) in these subjects. MATERIALS AND METHODS: SDF was determined by a validated sperm chromatin dispersion test in 26 infertile men. Patients were split into two groups according to the SDF level estimated by the DNA fragmentation index (DFI): the low fragmentation group (LFG; LFG with DFI <=18%) and high fragmentation group (HFG; HFG with DFI >18%). The standard semen parameters were measured in both groups. RESULTS: We found that semen concentration and motility were negatively correlated with DFI (r=-0.65, r=-0.45, respectively; p<0.05), while morphology and semen volume were not correlated with it (r=0.24, r=-0.18, respectively; p>0.05). Comparison of the sperm concentration revealed that it was significantly higher in LFG than in HFG (37.57%+/-13.16% vs. 7.32%+/-3.59%, respectively; p<0.05), whereas no significant difference was observed regarding sperm motility and morphology. CONCLUSIONS: Our findings suggest that SDF correlates well with both sperm motility and concentration but not with morphology. Thus, we conclude that SDF evaluation provides additional information regarding sperm quality, and should be used as a complementary test for assessing semen characteristics in infertile males. PMID- 25927057 TI - Semen Analysis in Cancer Patients Referred for Sperm Cryopreservation before Chemotherapy over a 15-Year Period in Korea. AB - PURPOSE: This study evaluated the demographics and semen parameters of males with cancer who banked their sperm prior to chemotherapy. MATERIALS AND METHODS: This is a retrospective study of 66 cases referred for sperm banking prior to initiation of chemotherapy over a 15-year period (1999~2014). Patients who had previously received cancer treatment including chemotherapy or radiotherapy were not included in this study. RESULTS: We studied a total of 66 cancer patients referred for cryopreservation of sperm prior to chemotherapy. The mean age of the patients at the time of banking was 32.0+/-7.9 years (range, 19~58 years). The types of cancer were testicular cancer (31 cases, 47.0%), non-Hodgkin's disease (10 cases, 15.1%), Hodgkin's disease (5 cases, 7.6%), leukemia (8 cases, 12.1%), gastrointestinal malignancy (5 cases, 7.6%), and musculoskeletal malignancy (5 cases, 7.6%). There were significant differences in sperm concentration and viability among the various types of cancer, but no significant difference in semen volume or sperm motility and morphology. CONCLUSIONS: In this study we found that sperm quality could decrease even before chemotherapy. Because chemotherapy can also negatively affect spermatogenesis, sperm cryopreservation prior to treatment should be strongly recommended for cancer patients of reproductive age. PMID- 25927058 TI - The effect of two weeks of treatment with dutasteride on bleeding after transurethral resection of the prostate. AB - PURPOSE: Dutasteride affects the prostate by reducing intraprostatic dihydrotestosterone and prostate tissue vascularity. We evaluated the effect of pretreatment with dutasteride for two weeks on perioperative and postoperative bleeding during transurethral resection of the prostate (TURP). MATERIALS AND METHODS: Eighty-three patients who had benign prostatic hyperplasia together with the criteria for eligibility for TURP were included. The dutasteride group consisted of 40 patients who were treated with dutasteride (0.5 mg/d) for two weeks before surgery, and the control group consisted of 43 patients who did not receive dutasteride. Blood loss was evaluated in terms of reduction in serum hemoglobin (Hb) and hematocrit (Hct) levels, which were measured before, immediately after, and 24 hours after surgery. We also measured the durations of indwelling urethral catheter use, continuous saline bladder irrigation, and hospitalization. RESULTS: Lower mean blood loss was observed in the dutasteride group than the control group immediately after and 24 hours after surgery (DeltaHb=0.65+/-1.27 g/dL vs. 1.16+/-0.73 g/dL, 1.30+/-1.00 g/dL vs. 1.86+/-1.05 g/dL respectively, p=0.019, p=0.011; DeltaHct=1.89%+/-3.83% vs. 3.47%+/-2.09%, 3.69%+/-2.95% vs. 5.39%+/-3.23% respectively, p=0.016, p=0.011). In addition, there were fewer days of indwelling urethral catheter use (2.95+/-1.02 d vs. 3.92+/-1.14 d, p=0.000), continuous saline bladder irrigation (1.81+/-1.08 d vs. 2.36+/-1.06 d, p=0.016), and hospitalization after TURP (3.95+/-1.09 d vs. 4.76+/ 1.19 d, p=0.001) in the dutasteride group. CONCLUSIONS: Preoperative treatment with dutasteride for two weeks before TURP reduces surgical bleeding and length of hospitalization after TURP. This pretreatment can be used to decrease surgical bleeding associated with TURP. PMID- 25927059 TI - Protective Effect of Administered Rolipram against Radiation-Induced Testicular Injury in Mice. AB - PURPOSE: Pelvic irradiation for the treatment of cancer can affect normal cells, such as the rapidly proliferating spermatogenic cells of the testis, leading to infertility, a common post-irradiation problem. The present study investigated the radioprotective effect of rolipram, a specific phosphodiesterase type-IV inhibitor known to increase the expression and phosphorylation of the cyclic adenosine monophosphate response element-binding protein (CREB), a key factor for spermatogenesis, with the testicular system against pelvic irradiation. MATERIALS AND METHODS: Male C57BL/6 mice were treated with pelvic irradiation (2 Gy) and rolipram, alone or in combination, and were sacrificed at 12 hours and 35 days after irradiation. RESULTS: Rolipram protected germ cells from radiation-induced apoptosis at 12 hours after irradiation and significantly increased testis weight compared with irradiation controls at 35 days. Rolipram also ameliorated radiation-induced testicular morphological changes, such as changes in seminiferous tubular diameter and epithelial height. Additionally, seminiferous tubule repopulation and stem cell survival indices were higher in the rolipram treated group than in the radiation group. Moreover, rolipram treatment counteracted the radiation-mediated decrease in the sperm count and mobility in the epididymis. CONCLUSIONS: These protective effects of rolipram treatment prior to irradiation may be mediated by the increase in pCREB levels at 12 hours post irradiation and the attenuated decrease in pCREB levels in the testis at 35 days post-irradiation in the rolipram-treated group. These findings suggest that activation of CREB signaling by rolipram treatment ameliorates the detrimental effects of acute irradiation on testicular dysfunction and the related male reproductive functions in mice. PMID- 25927060 TI - Learning curve of robot-assisted laparoscopic radical prostatectomy for a single experienced surgeon: comparison with simultaneous laparoscopic radical prostatectomy. AB - PURPOSE: Despite the large number of analytical reports regarding the learning curve in the transition from open to robot-assisted radical prostatectomy (RARP), few comparative results with laparoscopic radical prostatectomy (LRP) have been reported. Thus, we evaluated operative and postoperative outcomes in RARP versus 100 simultaneously performed LRPs. MATERIALS AND METHODS: A single surgeon had performed more than 1,000 laparoscopic operations, including 415 cases of radical nephrectomy, 85 radical cystectomies, 369 radical prostatectomies, and treatment of 212 other urological tumors, since 2009. We evaluated operative (operation time, intraoperative transfusion, complications, hospital stay, margin status, pathological stage, Gleason score) and postoperative (continence and erectile function) parameters in initial cases of RARP without tutoring compared with 100 recently performed LRPs. RESULTS: Mean operation time and length of hospital stay for RARP and LRP were 145.5+/-43.6 minutes and 118.1+/-39.1 minutes, and 6.4+/ 0.9 days and 6.6+/-1.1 days, respectively (p=0.003 and p=0.721). After 17 cases, the mean operation time for RARP was similar to LRP (less than 2 hours). Positive surgical margins in localized cancer were seen in 11.1% and 8.9% of cases in RARP and LRP, respectively (p=0.733). At postoperative 3 months, sexual intercourse was reported in 14.0% and 12.0%, and pad-free continence in 96.0% and 81.0% in patients with RARP and LRP, respectively (p=0.796 and p=0.012). CONCLUSIONS: Previous large-volume experience of LRPs may shorten the learning curve for RARP in terms of oncological outcome. Additionally, previous experience with laparoscopy may improve the functional outcomes of RARP. PMID- 25927061 TI - Spontaneous corpus cavernosum abscess in a healthy man using long-term androgenic anabolic steroids. AB - Abscess formation of the corpus cavernosum is very rare. Here, we report a case of long-term anabolic androgenic steroid (AAS) abuse that is suspected to have facilitated the development of a corpus cavernosum abscess in a healthy bodybuilder. Cultures obtained from the abscess contained Staphylococcus epidermidis, a microorganism that almost exclusively affects immunocompromised patients. Therefore, prompt drainage of pus from cavernosal bodies should be the primary aim of the treatment. This case illustrates the potential danger of AAS suppressing the immune system and causing a serious infection. PMID- 25927062 TI - Electrocautery resection, shaving with a scalpel, and podophyllin: a combination therapy for giant condyloma acuminatum. AB - Giant condyloma acuminatum (also known as Buschke-Lowenstein tumor) is a rare disease, for which the treatment of choice is still controversial. In the case described in this report, we used a combination of electrocautery and a surgical scalpel to resect a huge genital wart, followed by long-term local treatment with podophyllin. This procedure was relatively fast, easy to perform, involved minimal bleeding, and did not result in any complications. Moreover, combination therapy enabled us to avoid deep resection of the lesion and consequently, sexual function was preserved completely. PMID- 25927063 TI - Time to act: lessons learnt from the first pilot school-based intervention study from Lebanon to prevent and reduce childhood obesity. AB - Today, childhood overweight and obesity are serious public health problems that the world faces. Obese children suffer from both short-term and long-term health consequences, and poorer adult health. Despite the rising prevalence of childhood obesity in the Eastern Mediterranean Region, including Lebanon, no intervention research studies have been undertaken. This paper summarizes the main challenges and lessons learned emanating from the first evidence-based multicomponent school intervention aimed at promoting Healthy Eating and Physical Activity in Lebanese School children (Health-E-PALS). Health-E-PALS, which includes three components (class curriculum, family involvement, and food service) and relies on interactive fun learning activities, achieved an increase in students' nutritional knowledge and self-efficacy, and a decrease in their purchase and consumption of high energy dense snacks and beverages. Recommendations for future school-based programs are also highlighted. PMID- 25927064 TI - Fractal, multifractal, and lacunarity analysis of microglia in tissue engineering. PMID- 25927065 TI - Long Non-Coding RNAs: New Players in Hematopoiesis and Leukemia. AB - Long non-coding RNAs (lncRNAs) are important regulators of gene expression that influence almost every step in the life cycle of genes, from transcription to mRNA splicing, RNA decay, and translation. Besides their participation to normal physiology, lncRNA expression and function have been already associated to cancer development and progression. Here, we review the functional role and mechanisms of action of lncRNAs in normal hematopoiesis and how their misregulation may be implicated in the development of blood cell cancer, such as leukemia. PMID- 25927066 TI - The effectiveness of cognitive behavior stress management on functional dyspepsia symptoms. AB - INTRODUCTION: Functional dyspepsia and digestive disorders are common, debilitating and costly. Little information is available about the role of stress management in terms of cognitive-behavioral treatment of dyspepsia. The purpose of this study was to investigate the effectiveness of cognitive-behavioral stress management on functional dyspepsia symptoms in patients who referred to digestion clinics in Ahvaz. METHODS: This was a quasi-experimental study, using pre-test, post-test and follow-up with control group. The sample size was decided according to availability. For this purpose, 30 patients were selected using Rome-III diagnostic criteria with diagnosis of functional dyspepsia. They were divided with block randomization into two experimental and control groups (Each with 15 subjects). The experimental group received 10 sessions of cognitive behavioral stress management. But, the control group did not receive any intervention. Two groups were assessed at post-test and follow-up after the intervention. Data collection in this study was based on the NDI index. All subjects completed the NDI index for evaluating dyspeptic symptoms in the pre-test phase. At the end of interventions and post-test phase, both groups completed the NDI index. Also, all subjects completed a month after the end of the the NDI index in order to follow the effects of treatment. After the follow-up, the data were analyzed using the SPSS 14 and univariate analysis of variance. The significance level was considered p<0.05. RESULTS: The result of this study showed that there were significant differences between the experimental and control groups in terms of functional dyspepsia in the post-test (p=0.000). Also, there were significant differences between the experimental and control groups in terms of functional dyspepsia in the follow-up (p =0.000). CONCLUSION: The results of the present study suggest that cognitive-behavioral stress management strategies are effective in reducing symptoms in patients with functional dyspepsia. So, cooperation among gastroenterologists, psychologists and psychiatrists can have positive effects on these patients. PMID- 25927067 TI - Emotional intelligence as a predictor of self-efficacy among students with different levels of academic achievement at Kermanshah University of Medical Sciences. AB - INTRODUCTION: studies have indicated that emotional intelligence is positively related to self-efficacy and can predict the academic achievement. The present study aimed to investigate the role of emotional intelligence in identifying self efficacy among the students of Public Health School with different levels of academic achievement. METHODS: This correlational study was conducted on all the students of Public Health School. 129 students were included in the study through census method. Data were collected using Emotional Intelligence and self-efficacy questionnaires and analyzed using descriptive statistics and regression analysis by SPSS 14. RESULTS: The average score of students with high academic achievement was higher in self-efficacy (39.78+/-5.82) and emotional intelligence (117.07+/ 10.33) variables and their components than that of students with low academic achievement (39.17+/-5.91, 112.07+/-13.23). The overall emotional intelligence score to predict self-efficacy explanation was different among students with different levels of academic achievement (p<0.001). Self-efficacy structure was explained through self-awareness and self-motivation components in students with low academic achievement (r=0.571). In students with high academic achievement, self-awareness, self-motivation and social consciousness played an effective role in explaining self-efficacy (r=0.677, p<0.001). CONCLUSION: Emotional intelligence and self-efficacy play an important role in achieving academic success and emotional intelligence can explain self-efficacy. Therefore, it is recommended to teach emotional intelligence skills to students with low academic achievement through training workshops. PMID- 25927068 TI - The effects of educational program on health volunteers' knowledge regarding their approach to earthquake in health centers in Tehran. AB - INTRODUCTION: The people's mental, intellectual and physical non-readiness to confront earthquake may result in disastrous outcomes. This research aimed to study of effects of a training intervention on health connector's knowledge regarding their approach to earthquake in health-training centers in East of Tehran. METHODS: This research which is a semi-experimental study was designed and executed in 2011, using a questionnaire with items based on the information of Crisis Management Org. After a pilot study and making the questionnaire valid and reliable, we determined the sample size. Then, the questionnaires were completed before and after the training program by 82 health connectors at health treatment centers in the East of Tehran. Finally, the collected data were analyzed by SPSS 14, using paired sample t-test and Pearson's correlation coefficient. RESULTS: Health connectors were women with the mean age of 43.43+/ 8.51 years. In this research, the mean score of connectors' knowledge before and after the training was 35.15+/-4.3 and 43.73+/-2.91 out of 48, respectively. The difference was statistically significant (p=0.001). The classes were the most important source of information for the health connectors. CONCLUSION: The people's knowledge to confront earthquake can be increased by holding training courses and workshops. Such training courses and workshops have an important role in data transfer and readiness of health connectors. PMID- 25927069 TI - An evaluation of the elements of internal medicine physiopathology curriculum in general practice based on the perspectives of faculty members of Shiraz University of Medical Sciences. AB - INTRODUCTION: An evaluation of the curriculum elements can be recognized as a necessity in curriculum dynamic and improvement. This study aimed at evaluating five main elements of a physiopathology curriculum in internal medicine (objectives, content, methods, evaluation, and management). METHOD: The present study is of a descriptive-analytical type, and the studypopulation consisted of a total of 48 faculty members of internal medicine physiopathology departmentat Shiraz University of Medical Sciences. Participants wereselected using Cochran's sample size formula andthrough simple random sampling.Thedatawere collected using a 58-item questionnaire devised by the researcher, usingcurriculum planning experts. Face and content validity of the scale were obtained throughexpert views and modifications provided by 10 professors and experts in medical curriculum evaluation. Also, research reliability was calculated using Alpha Cronbachto be 0.99. Reliability value and coefficient was acceptable.Moreover, One-sample t test, Independent t-test and one-way ANOVA were used for data analysis. RESULTS: Based on the faculty members' views, of the five curriculum elements, objectives and content were in relatively good conditions (at an average level) while other elements including method, evaluation and management were in poor conditions (lower than average). According to results oftwo-way ANOVA, there wasa significant relationship between faculty members with various work experiencein terms of curriculum evaluation. CONCLUSION: According to research findings, a comparative examination of the curriculum elements and their characteristics in physiopathology course can be conducted, resulting in identification of curriculum weaknesses and their pitfalls. Also, with regard to teaching, evaluation, management methods, weak and strong pointsof the course,efficiency, and effectiveness of the elements were identified. PMID- 25927070 TI - A comparative study of teaching clinical guideline for prevention of ventilator associated pneumonia in two ways: face-to-face and workshop training on the knowledge and practice of nurses in the intensive care unit. AB - INTRODUCTION: Ventilator-associated pneumonia (VAP) is one of the most popular nosocomial infections in the intensive care units and the nurse's role in preventing it is very important. The aim of this study was to compare the effect of two methods of face to face training and work- shop clinical guidelines in prevention of VAP. METHODS: In this experimental randomized clinical trial, the knowledge and practice of nurses in ICUs were studied in two groups: face to face training (35 nurses) and workshops (40 nurses) by using clinical guidelines in prevention of VAP in one of the hospitals of Shiraz University of Medical Sciences. The level of knowledge and practice in each group was assessed by self report questionnaire, knowledge questionnaire and also direct observation of practice, before and after training. Data were analyzed with descriptive statistics, paired t-test, independent t-test, McNemar test, Fisher's exact, sign and Chi-square test, using SPSS 14. RESULTS: This study demonstrated that both methods of face to face training and workshop were very effective. The incidence of inappropriate pressure of cuff in the tracheal tubes and tracheostomy tubes was significantly reduced after training (p=0.001). But, by comparison of these two methods and the relationship between the variables revealed that no significant difference was found between the two groups of face to face training and workshop. CONCLUSION: Training the nurses is highly effective in preventing VAP, particularly for appropriate cuff pressure, suctioning and disinfecting hands. PMID- 25927071 TI - Using video-taped examples of standardized patient to teach medical students taking informed consent. AB - INTRODUCTION: Medical student should be trained in medical ethics and one of the most essential issues in this field is taking informed consents. In this research, we compared the effect of effectiveness of teaching methods on students' ability intaking informed consent from patients. METHODS: This semi experimental study was carried out on fifty eight subjects from the 4th-year students of Shiraz University of Medical Sciences who attended in medical ethics coursebefore their 'clinical clerkship'training.Method of sampling was census and students were randomly allocated into two groups of control group(n=28) was trained in traditional lecture-based class and the case groupnamed as A1(n=22) were taught by video-taped examples of standardized patient.Then A1 group attended in traditional lecture-based classes named as A2. The groups were evaluated in terms the ability of recognition of ethical issuesthrough the scenario based ethical examination before and after each training. Scenarios were related to the topics ofinformed consent. Data were analyzed by SPSS 14 software using descriptive statistics and anovatest.P-Value less than 0.05 was considered as significant. RESULTS: The mean scores results of A2, A1and B groupwere found to be7.21 , 5.91 and 5.73 out of 8,respectively. Comparison between the groups demonstrated that the ability of taking informed consent was significantly higher in A2 group (p<0.001), followed by A1group (p<0.05),while was the leastin the B group (p=0.875). CONCLUSION: According to this research, lecture-based teaching is still of great value in teaching medical ethics, but when combined with standardized patient, the outcome will be much better.it should be considered that mixed methodsof teaching should be used together for better result. PMID- 25927072 TI - Inservice trainings for Shiraz University of Medical Sciences employees: Effectiveness assessment by using the CIPP model. AB - INTRODUCTION: Nowadays, the employees' in-service training has become one of the core components in survival and success of any organization. Unfortunately, despite the importance of training evaluation, a small portion of resources are allocated to this matter. Among many evaluation models, the CIPP model or Context, Input, Process, Product model is a very useful approach to educational evaluation. So far, the evaluation of the training courses mostly provided information for learners but this investigation aims at evaluating the effectiveness of the experts' training programs in SUMS and identifying its pros and cons based on the 4 stages of the CIPP model. METHOD: In this descriptive analytical study, done in 2013, 250 employees of SUMS participated in in-service training courses were randomly selected. The evaluated variables were designed using CIPP model and a researcher-made questionnaire was used for data collection; the questionnaire was validated using expert opinion and its reliability was confirmed by Cronbach's alpha (0.89). Quantitative data were analyzed using SPSS 14 and statistical tests was done as needed. RESULTS: In the context phase, the mean score was highest in solving work problems (4.07+/-0.88) and lowest in focusing on learners' learning style training courses (2.68+/ 0.91). There is a statistically significant difference between the employees' education level and the product phase evaluation (p<0.001). The necessary effectiveness was not statistically significant in context and input level (p>0.001), in contrast with the process and product phase which showed a significant deference (p<0.001). CONCLUSION: Considering our results, although the in-service trainings given to sums employees has been effective in many ways, it has some weaknesses as well. Therefore improving these weaknesses and reinforcing strong points within the identified fields in this study should be taken into account by decision makers and administrators. PMID- 25927073 TI - Educational needs of family physicians in the domains of health and conformity with continuing education in Fasa University of Medical Sciences. AB - INTRODUCTION: Assessment and prioritization are the first steps of planning. According to the family physician's idea, evaluating programs in order to improve them is one of the necessities of promoting quality and increases the efficiency and effectiveness of continuing education. This study aimed to determine family physicians' educational needs regarding health and its applicability in continuous medical education in Fasa University of Medical Sciences. METHODS: In this cross-sectional study, viewpoints of 45 general physicians working at Fasa University of Medical Sciences in 2013 were studied. Samples were selected through census. Data collection was done using a researcher-made questionnaire using 10-point Likert scale and a checklist with Delphi technique. Content validity of the questionnaire and its reliability were confirmed by the experts' opinion and Cronbach's alpha of 80%. The data were analyzed through SPSS software version 16, using both descriptive and inferential statistics (mean and standard deviation, standard score (SQ), t-test, ANOVAs). A significance level of <0.05 was considered. RESULTS: The highest educational priority was in the field of mental health (SQ= 0.38), and environmental and professional health was the lowest priority (SQ= _0.24). Additionally, within each of the areas above specific priorities were determined. Based on the results of this study, gender, graduation date, cooperation time, and university they were educated in did not affect expressing educational needs (p>0.05). The most educational conformity with continuing education was in the diseases area (topic 27%, content 37%). In the areas of environmental and professional health and health education, compliance was zero. CONCLUSIONS: The physicians stated that mental health was the first educational need and environmental and professional health was the last one. According to the results, proper continuing medical programs should be coordinated with educational needs. PMID- 25927074 TI - Preparation of Candida albicans Biofilms for Transmission Electron Microscopy. AB - Transmission Electron Microscopy is a form of microscopy that allows for imaging of distinct portions of an individual cell. For Candida albicans biofilms, it is often used to visualize the cell walls of fixed samples of yeast and hyphae. This protocol describes how to grow, harvest, and fix Candida albicans biofilms in preparation for Transmission Electron Microscopy. PMID- 25927075 TI - Preparation of Candida albicans Biofilms Using an in vivo Rat Central Venous Catheter Model. AB - In vivo biofilms grown on medical devices are necessary to understand the interactions of the fungal biofilm and the host environment in which it is most commonly found. This protocol describes a way to grow Candida albicans biofilms on the interior lumen of central venous catheters surgically implanted into rats, which mimics quite well the clinical cases of biofilms found on human central venous catheters. These infected catheters can then be studied via a multitude of different experiments, including cell counting by plating, imaging the catheters under light or electron microscopy, or comparing the relative content of in vivo biofilms to in vitro biofilms and planktonic cultures. These biofilms also provide enough high quality RNA for transcriptional profiling. PMID- 25927076 TI - Integrating COPD into Patient-Centered Hospital Readmissions Reduction Programs. AB - About 1 in 5 patients hospitalized for exacerbations of chronic obstructive pulmonary disease (COPD) in the United States are readmitted within 30 days. The U.S. Centers for Medicare and Medicaid Services has recently expanded its Hospital Readmissions Reduction Program to financially penalize hospitals with higher than expected all-cause 30-day readmission rates following a hospitalization for COPD exacerbation. In October 2013, the COPD Foundation convened a multi-stakeholder National COPD Readmissions Summit to summarize our understanding of how to reduce hospital readmissions in patients hospitalized for COPD exacerbations. Over 225 individuals participated in the Summit, including patients, clinicians, health service researchers, policy makers and representatives of academic health care centers, industry, and payers. Summit participants recommend that programs to reduce hospital readmissions: 1) Include specific recommendations about how to promote COPD self-management skills training for patients and their caregivers; 2) Adequately address co-existing disorders common to COPD in care plans during and after hospitalizations; 3) Include an evaluation of adverse events when implementing strategies to reduce hospital readmissions; and 4) Develop a strategy (e.g., a learning collaboratory) to connect groups who are engaged in developing, testing, and implementing programs to reduce hospital readmissions for COPD and other conditions. PMID- 25927077 TI - A unique chromatin complex occupies young alpha-satellite arrays of human centromeres. AB - The intractability of homogeneous alpha-satellite arrays has impeded understanding of human centromeres. Artificial centromeres are produced from higher-order repeats (HORs) present at centromere edges, although the exact sequences and chromatin conformations of centromere cores remain unknown. We use high-resolution chromatin immunoprecipitation (ChIP) of centromere components followed by clustering of sequence data as an unbiased approach to identify functional centromere sequences. We find that specific dimeric alpha-satellite units shared by multiple individuals dominate functional human centromeres. We identify two recently homogenized alpha-satellite dimers that are occupied by precisely positioned CENP-A (cenH3) nucleosomes with two ~100-base pair (bp) DNA wraps in tandem separated by a CENP-B/CENP-C-containing linker, whereas pericentromeric HORs show diffuse positioning. Precise positioning is largely maintained, whereas abundance decreases exponentially with divergence, which suggests that young alpha-satellite dimers with paired ~100-bp particles mediate evolution of functional human centromeres. Our unbiased strategy for identifying functional centromeric sequences should be generally applicable to tandem repeat arrays that dominate the centromeres of most eukaryotes. PMID- 25927078 TI - Network-Guided Sparse Learning for Predicting Cognitive Outcomes from MRI Measures. AB - Alzheimer's disease (AD) is characterized by gradual neurodegeneration and loss of brain function, especially for memory during early stages. Regression analysis has been widely applied to AD research to relate clinical and biomarker data such as predicting cognitive outcomes from MRI measures. In particular, sparse models have been proposed to identify the optimal imaging markers with high prediction power. However, the complex relationship among imaging markers are often overlooked or simplified in the existing methods. To address this issue, we present a new sparse learning method by introducing a novel network term to more flexibly model the relationship among imaging markers. The proposed algorithm is applied to the ADNI study for predicting cognitive outcomes using MRI scans. The effectiveness of our method is demonstrated by its improved prediction performance over several state-of-the-art competing methods and accurate identification of cognition-relevant imaging markers that are biologically meaningful. PMID- 25927079 TI - The corrosion protection of AA2024-T3 aluminium alloy by leaching of lithium containing salts from organic coatings. AB - Lithium carbonate and lithium oxalate were incorporated as leachable corrosion inhibitors in model organic coatings for the protection of AA2024-T3. The coated samples were artificially damaged with a scribe. It was found that the lithium salts are able to leach from the organic coating and form a protective layer in the scribe on AA2024-T3 under neutral salt spray conditions. The present paper shows the first observation and analysis of these corrosion protective layers, generated from lithium-salt loaded organic coatings. The scribed areas were examined by scanning and transmission electron microscopy before and after neutral salt spray exposure (ASTM-B117). The protective layers typically consist of three different layered regions, including a relatively dense layer near the alloy substrate, a porous middle layer and a flake-shaped outer layer, with lithium uniformly distributed throughout all three layers. Scanning electron microscopy and white light interferometry surface roughness measurements demonstrate that the formation of the layer occurs rapidly and, therefore provides an effective inhibition mechanism. Based on the observation of this work, a mechanism is proposed for the formation of these protective layers. PMID- 25927080 TI - Determination of a localized surface plasmon resonance mode of Cu7S4 nanodisks by plasmon coupling. AB - Plasmon properties such as peak position, extinction cross-section and local electric field intensity are strongly dependent on excited, localized surface plasmon resonance (LSPR) modes. In non-spherical copper chalcogenide nanoparticles, assignment of the LSPR peaks to the corresponding oscillation modes has been controversial and requires experimental verification. We determined the in-plane LSPR mode of roxbyite Cu7S4 nanodisks from the plasmon coupling effect of nanodisks in solution. Compared with individual Cu7S4 nanodisks, self-assembled Cu7S4 nanodisk arrays in chloroform exhibited a blue shifted LSPR peak with weaker optical density. This strongly suggests that the singular LSPR peak in the near-infrared region mainly originates from the in plane oscillation mode. In addition, we demonstrate that the same LSPR peak can be readily tuned by controlling the number of disks in the array. PMID- 25927081 TI - Temperature effects on nanostructure and mechanical properties of single nanoparticle thick membranes. AB - The properties of mechanically stable single-nanoparticle (NP)-thick membranes have largely been studied at room temperature. How these membranes soften as nanoparticle ligands disorder with increasing temperature is unknown. Molecular dynamics simulations are used to probe the temperature dependence of the mechanical and nanostructural properties of nanoparticle membranes made of 6 nm diameter Au nanoparticles coated with dodecanethiol ligands and terminated with either methyl (CH3) or carboxyl (COOH) terminal groups. For methyl-terminated ligands, interactions along the alkane chain provide mechanical stiffness, with a Young's modulus of 1.7 GPa at 300 K. For carboxyl-terminated chains, end-group interactions are significant, producing stiffer membranes at all temperatures, with a Young's modulus of 3.8 GPa at 300 K. For both end-group types, membrane stiffness is reduced to zero at about 400 K. Ligand structure and mechanical properties of membranes at 300 K that have been annealed at 400 K are comparable to samples that do not undergo thermal annealing. PMID- 25927082 TI - A sequential enriched design for target patient population in psychiatric clinical trials. AB - High placebo response is widely believed to be one major reason why many psychiatric clinical trials fail to demonstrate drug efficacy. In order to alleviate this problem, research has developed several enrichment designs, including the parallel design with a placebo lead-in phase, the sequential parallel design, and a recently proposed two-way enriched design. While these designs have been evaluated and discussed individually, their effectiveness against each other has not been rigorously compared. The current study examines the various enrichment designs simultaneously. Building on their strengths, we introduce a new improved design named' sequential enriched design' (SED) aimed at removing not only patients with high placebo response but also patients who do not respond to any treatment from the study. The SED begins with a double-blind placebo lead-in phase followed by a traditional parallel design in the first stage. Only patients who respond to the drug in the first stage are re-randomized to the drug or placebo at the second stage. We simulate data for a mixed population composed of four subgroups of patients who are predetermined as to whether they respond to drug or not as well as to placebo or not. By focusing on the target patients whose responses reflect the drug's efficacy,we evaluate the bias, mean squared error, and power for different designs. We demonstrate that the SED produces a less biased estimate for the target treatment effect and yields reasonably high power in general compared with the other designs. PMID- 25927083 TI - The Cambridge Otology Quality of Life Questionnaire: an otology-specific patient recorded outcome measure. A paper describing the instrument design and a report of preliminary reliability and validity. AB - OBJECTIVE: The Cambridge Otology Quality of Life Questionnaire (COQOL) is a patient-recorded outcome measurement (PROM) designed to quantify the quality of life of patients attending otology clinics. DESIGN: Item-reduction model. A systematically designed long-form version (74 items) was tested with patient focus groups before being presented to adult otology patients (n. 137). Preliminary item analysis tested reliability, reducing the COQOL to 24 questions. This was then presented in conjunction with the SF-36 (V1) questionnaire to a total of 203 patients. Subsequently, these were re-presented at T + 3 months, and patients recorded whether they felt their condition had improved, deteriorated or remained the same. Non-responders were contacted by post. A correlation between COQOL scores and patient perception of change was examined to analyse content validity. SETTING: Teaching hospital and university psychology department. PARTICIPANTS: Adult patients attending otology clinics with a wide range of otological conditions. MAIN OUTCOME MEASUREMENTS: Item reliability measured by item-total correlation, internal consistency and test- retest reliability. Validity measured by correlation between COQOL scores and patient-reported symptom change. RESULTS: Reliability: the COQOL showed excellent internal consistency at both initial presentation (a = 0.90) and 3 months later (a = 0.93). Validity: One-way analysis of variance showed a significant difference between groups reporting change and those reporting no change in quality of life (F(2, 80) = 5.866, P < 0.01). CONCLUSIONS: The COQOL is the first otology specific PROM. Initial studies demonstrate excellent reliability and encouraging preliminary criterion validity: further studies will allow a deeper validation of the instrument. PMID- 25927084 TI - Pancytopenia in a patient with methylmalonic acidemia. PMID- 25927085 TI - Dehydrated hereditary stomatocytosis masquerading as MDS. PMID- 25927086 TI - Erratum. AB - Syed, M. I., Rutka, J. A. & Pothier, D. D.(2015) Clin. Otolaryngol. 40, 69. Application of phenol as topical anaesthesia using the Derlacki elevator for myringotomy. In the title of this article, the word 'myringotomy' was incorrectly spelt as 'miringotomy'. We apologise for this typographical error. Lachanas, V.A., Tsea, M., Tsiouvaka, S., Exarchos, S.T., Skoulakis, C.E. & Bizakis, J.G.(2015) Clin. Otolaryngol. 40, 56. The effect of active cigarette smoking on Sino-Nasal Outcome Test in 127 subjects without rhinologic disease. A prospective study. In the Results section, paragraph 2, line 3, the result "SNOT-20 +/- SD was 15.75 +/- 1.68 and 8.65 +/- 0.95" should have read "SNOT-22 +/- SD was 17.59 +/- 1.79 and 9.76 +/- 1.06". We apologise for this error. PMID- 25927087 TI - Covering life science. PMID- 25927088 TI - Designing a microscale lab. PMID- 25927089 TI - Inositol in preterm infants at risk for or having respiratory distress syndrome. AB - BACKGROUND: Inositol is an essential nutrient required by human cells in culture for growth and survival. Inositol promotes maturation of several components of surfactant and may play a critical role in fetal and early neonatal life. OBJECTIVES: To assess the effectiveness and safety of supplementary inositol in preterm infants with or without respiratory distress syndrome (RDS) in reducing adverse neonatal outcomes. SEARCH METHODS: The Cochrane Central Register of Controlled Trials (CENTRAL) in The Cochrane Library, MEDLINE, EMBASE, CINAHL, Clinicaltrials.gov and Controlled-trials.com were searched in September 2014. The reference lists of identified randomised controlled trials (RCTs), personal files and Web of Science were searched. SELECTION CRITERIA: All RCTs of inositol supplementation of preterm infants compared with a control group that received a placebo or no intervention were included. Outcomes of interest were neonatal death, infant death, bronchopulmonary dysplasia (BPD), retinopathy of prematurity (ROP), intraventricular haemorrhage (IVH), necrotizing enterocolitis (NEC) and sepsis. DATA COLLECTION AND ANALYSIS: Data on neonatal outcomes were abstracted independently by the three review authors and any discrepancy was resolved through consensus. Outcomes were reported as relative risk (RR), risk difference (RD) and number needed to treat to benefit (NNTB) or to harm (NNTH). MAIN RESULTS: Four published RCTs and one ongoing RCT were identified. Study quality varied and interim analyses had occurred in all trials of repeat doses of inositol that provided data for the outcomes of interest in this review. In these trials neonatal death was found to be significantly reduced (3 trials, 355 neonates; typical RR 0.53, 95% CI 0.31 to 0.91; typical RD -0.09, 95% CI -0.17 to -0.03; NNTB 11, 95% CI 6 to 33). Infant deaths were reduced (3 trials, 355 infants; typical RR 0.55, 95% CI 0.40 to 0.77; typical RD -0.18, 95% CI -0.27 to 0.08; NNTB 6, 95% CI 4 to 13). ROP stage >= 3 was significantly reduced (2 trials, 262 infants; typical RR 0.09, 95% CI 0.01 to 0.67; typical RD -0.08, 95% CI -0.13 to -0.03; NNTB 13, 95% CI 8 to 33) and IVH grade > II was significantly decreased (3 trials, 355 infants; typical RR 0.53, 95% CI 0.31 to 0.90; typical RD -0.09, 95% CI -0.16 to -0.02; NNTB 11, 95% CI 6 to 50). Neither sepsis nor NEC differed significantly between groups. One study (74 infants) that administered a single dose of inositol (60 or 120 mg/kg) found no significant differences in adverse outcomes using RR, but an increased RD for BPD at 36 weeks postmenstrual age (RD 0.23, 95% CI 0.03 to 0.43; NNTH 4, 95% CI 2 to 33). This result should be interpreted with caution as only one dose of inositol was given and only the RD, but not the RR, was significant. One ongoing large study of repeat doses of inositol in preterm infants was identified. AUTHORS' CONCLUSIONS: Inositol supplementation results in statistically significant and clinically important reductions in important short-term adverse neonatal outcomes. A large size multi centre randomised controlled trial is currently ongoing and the trial will likely confirm or refute the findings from this systematic review. PMID- 25927090 TI - Proceedings of the 17th International Congress of Comparative Endocrinology, (ICCE 2013), July 15-19, 2013, Barcelona, Spain. PMID- 25927091 TI - Interventions for the eradication of meticillin-resistant Staphylococcus aureus (MRSA) in people with cystic fibrosis. AB - BACKGROUND: Cystic fibrosis is an inherited recessive disorder of chloride transport that is characterised by recurrent and persistent pulmonary infections from resistant organisms that result in lung function deterioration and early mortality in sufferers.Meticillin-resistant Staphylococcus aureus (MRSA) has emerged as, not only an important infection in long-term hospitalised patients, but also as a potentially harmful pathogen in cystic fibrosis, and has been increasing steadily in prevalence internationally. Chronic pulmonary infection with MRSA is thought to confer cystic fibrosis patients with a worse overall clinical outcome and, in particular, result in an increased rate of decline in lung function. Clear guidance for the eradication of MRSA in cystic fibrosis, supported by robust evidence from good quality trials, is urgently needed. OBJECTIVES: To evaluate the effectiveness of treatment regimens designed to eradicate MRSA and to determine whether the eradication of MRSA confers better clinical and microbiological outcomes for people with cystic fibrosis. SEARCH METHODS: Randomised and quasi-randomised controlled trials were identified by searching the Cochrane Cystic Fibrosis and Genetic Disorders Group's Cystic Fibrosis Trials Register, PUBMED, MEDLINE, Embase, handsearching article reference lists and through contact with local and international experts in the field.Date of the last search of the Group's Cystic Fibrosis Trials Register: 04 September 2014. SELECTION CRITERIA: Randomised or quasi-randomised controlled trials comparing any combinations of topical, inhaled, oral or intravenous antimicrobials with the primary aim of eradicating MRSA compared with placebo, standard treatment or no treatment. DATA COLLECTION AND ANALYSIS: The authors independently assessed all search results for eligibility. No eligible trials were identified for inclusion. MAIN RESULTS: No current published eligible trials were identified, although three ongoing clinical trials are likely to be eligible for inclusion in future updates of this review. AUTHORS' CONCLUSIONS: We did not identify any randomised trials which would allow us to make any evidence-based recommendations. Although the results of several non-randomised studies would suggest that, once isolated, the eradication of MRSA is possible; whether this has a significant impact on clinical outcome is still unclear. Further research is required to guide clinical decision making in the management of MRSA infection in cystic fibrosis. PMID- 25927092 TI - Nitric oxide donors for cervical ripening in first-trimester surgical abortion. AB - BACKGROUND: Cervical priming before first-trimester surgical abortion is recommended in certain groups of women. Nitric oxide (NO) donors induce cervical ripening without uterine contractions, but the efficacy and side effects are of concern. OBJECTIVES: To evaluate NO donors for cervical ripening before first trimester surgical abortion, in terms of efficacy, side effects, and reduction of complications. SEARCH METHODS: We searched the Cochrane Central Register of Controlled Trials (CENTRAL), MEDLINE, EMBASE, and POPLINE. We also searched reference lists of retrieved papers. We contacted experts in the field for information on both published and unpublished trials. SELECTION CRITERIA: Randomised controlled trials comparing NO donors alone or in combination with other methods for cervical ripening in first-trimester surgical abortion. DATA COLLECTION AND ANALYSIS: Two review authors independently selected and extracted the data onto a data extraction form. We processed the data using Review Manager (RevMan 5) software. MAIN RESULTS: We included 9 studies involving 766 participants. There were no serious complications (infection requiring antibiotic treatment, blood transfusion, complications requiring unintended operation, cervical injury, uterine perforation, death or serious morbidity) in the included trials.NO donors were more effective in cervical ripening when compared with placebo or no treatment. Baseline cervical dilatation before the procedure was higher in NO donors group (mean difference (MD) 0.30, 95% confidence interval (CI) 0.01 to 0.58) The cumulative force required to dilate the cervix to 8 mm (MD -4.29, 95% CI -9.92 to 1.35), headache (risk ratio (RR) 1.73, 95% CI 0.86 to 3.46), abdominal pain (RR 0.87, 95% CI 0.50 to 1.50), or patient satisfaction (RR 0.95, 95% CI 0.84 to 1.07) were not different. More nausea and vomiting occurred in the women who received a NO donor (RR 2.62, 95% CI 1.07 to 6.45).NO donors were inferior to prostaglandins for cervical ripening. The cumulative force required to dilate the cervix to 8 mm to 9 mm was higher (MD 13.12, 95% CI 9.72 to 16.52), and baseline cervical dilatation was less (MD -0.73, 95% CI -1.01 to 0.45) in the NO donor group. However, the probability of dilation greater than 8 mm at three hours was higher in the NO donor group (RR 6.67, 95% CI 2.21 to 20.09). Side effects including headache (RR 5.13, 95% CI 3.29 to 8.00), palpitation (RR 3.43, 95% CI 1.64 to 7.15), dizziness (RR 3.29, 95% CI 1.46 to 7.41), and intraoperative blood loss (MD 33.59 ml, 95% CI 24.50 to 42.67) were also higher. However, abdominal pain (RR 0.33, 95% CI 0.25 to 0.44) and vaginal bleeding (RR 0.14, 95% CI 0.07 to 0.27) were less in the NO donor group. No difference for nausea/vomiting in both groups(RR 1.17, 95% CI 0.94 to 1.46). Patient satisfaction was not different.One trial compared a NO donor with a NO donor plus prostaglandin. The cumulative force required to dilate the cervix to 8 mm was higher (MD 14.50, 95% CI 0.50 to 28.50) in the NO donor group. There was no difference in headache (RR 0.88, 95% CI 0.38 to 2.00), abdominal pain (RR 0.14, 95% CI 0.02 to 1.07), or intraoperative blood loss (MD -50, 95% CI -164.19 to 64.19). AUTHORS' CONCLUSIONS: NO donors are superior to placebo or no treatment, but inferior to prostaglandins for first-trimester cervical ripening, and associated with more side effects. PMID- 25927093 TI - Preoperative bathing or showering with skin antiseptics to prevent surgical site infection. AB - BACKGROUND: Surgical site infections (SSIs) are wound infections that occur after invasive (surgical) procedures. Preoperative bathing or showering with an antiseptic skin wash product is a well-accepted procedure for reducing skin bacteria (microflora). It is less clear whether reducing skin microflora leads to a lower incidence of surgical site infection. OBJECTIVES: To review the evidence for preoperative bathing or showering with antiseptics for preventing hospital acquired (nosocomial) surgical site infections. SEARCH METHODS: For this fifth update we searched the Cochrane Wounds Group Specialised Register (searched 18 December 2014); the Cochrane Central Register of Controlled Trials (The Cochrane Library 2014 Issue 11); Ovid MEDLINE (2012 to December Week 4 2014), Ovid MEDLINE (In-Process & Other Non-Indexed Citations December 18, 2014); Ovid EMBASE (2012 to 2014 Week 51), EBSCO CINAHL (2012 to December 18 2014) and reference lists of articles. SELECTION CRITERIA: Randomised controlled trials comparing any antiseptic preparation used for preoperative full-body bathing or showering with non-antiseptic preparations in people undergoing surgery. DATA COLLECTION AND ANALYSIS: Two review authors independently assessed studies for selection, risk of bias and extracted data. Study authors were contacted for additional information. MAIN RESULTS: We did not identify any new trials for inclusion in this fifth update. Seven trials involving a total of 10,157 participants were included. Four of the included trials had three comparison groups. The antiseptic used in all trials was 4% chlorhexidine gluconate (Hibiscrub/Riohex). Three trials involving 7791 participants compared chlorhexidine with a placebo. Bathing with chlorhexidine compared with placebo did not result in a statistically significant reduction in SSIs; the relative risk of SSI (RR) was 0.91 (95% confidence interval (CI) 0.80 to 1.04). When only trials of high quality were included in this comparison, the RR of SSI was 0.95 (95%CI 0.82 to 1.10). Three trials of 1443 participants compared bar soap with chlorhexidine; when combined there was no difference in the risk of SSIs (RR 1.02, 95% CI 0.57 to 1.84). Three trials of 1192 patients compared bathing with chlorhexidine with no washing, one large study found a statistically significant difference in favour of bathing with chlorhexidine (RR 0.36, 95%CI 0.17 to 0.79). The smaller studies found no difference between patients who washed with chlorhexidine and those who did not wash preoperatively. AUTHORS' CONCLUSIONS: This review provides no clear evidence of benefit for preoperative showering or bathing with chlorhexidine over other wash products, to reduce surgical site infection. Efforts to reduce the incidence of nosocomial surgical site infection should focus on interventions where effect has been demonstrated. PMID- 25927094 TI - Corrigendum. AB - Corrigendum to "Rationale and design of the NAGOYA HEART Study: Comparison between valsartan and amlodipine regarding morbidity and mortality in patients with hypertension and glucose intolerance" [J. Cardiol. 56 (2010) 111-117] The authors of the manuscript would like to correct affiliation of Mr. Nobuo Shirahashi, who was mentioned in the Appendix section of this article. The correct affiliation of Mr. Shirahashi was Novartis Pharma KK and Department of Preventive Medicine and Environmental Health, Osaka City University Medical School, Osaka, Japan. PMID- 25927095 TI - Abstracts of the Thirteenth Annual UT- KBRIN Bioinformatics Summit 2014, April 11 13, 2014, Cadiz, Kentucky. PMID- 25927096 TI - Probiotics for preventing acute upper respiratory tract infections. AB - BACKGROUND: Probiotics may improve a person's health by regulating their immune function. Some trials have shown that probiotic strains can prevent respiratory infections. Even though the previous version of our review showed benefits of probiotics for acute upper respiratory tract infections (URTIs), several new studies have been published. OBJECTIVES: To assess the effectiveness and safety of probiotics (any specified strain or dose), compared with placebo, in the prevention of acute URTIs in people of all ages, at risk of acute URTIs. SEARCH METHODS: We searched CENTRAL (2014, Issue 6), MEDLINE (1950 to July week 3, 2014), EMBASE (1974 to July 2014), Web of Science (1900 to July 2014), the Chinese Biomedical Literature Database, which includes the China Biological Medicine Database (from 1978 to July 2014), the Chinese Medicine Popular Science Literature Database (from 2000 to July 2014) and the Masters Degree Dissertation of Beijing Union Medical College Database (from 1981 to July 2014). We also searched the World Health Organization (WHO) International Clinical Trials Registry Platform (ICTRP) and ClinicalTrials.gov for completed and ongoing trials on 31 July 2014. SELECTION CRITERIA: Randomised controlled trials (RCTs) comparing probiotics with placebo to prevent acute URTIs. DATA COLLECTION AND ANALYSIS: Two review authors independently assessed the eligibility and quality of trials, and extracted data using the standard methodological procedures expected by The Cochrane Collaboration. MAIN RESULTS: We included 13 RCTs, although we could only extract data to meta-analyse 12 trials, which involved 3720 participants including children, adults (aged around 40 years) and older people. We found that probiotics were better than placebo when measuring the number of participants experiencing episodes of acute URTI (at least one episode: odds ratio (OR) 0.53; 95% confidence interval (CI) 0.37 to 0.76, P value < 0.001, low quality evidence; at least three episodes: OR 0.53; 95% CI 0.36 to 0.80, P value = 0.002, low quality evidence); the mean duration of an episode of acute URTI (mean difference (MD) -1.89; 95% CI -2.03 to -1.75, P value < 0.001, low quality evidence); reduced antibiotic prescription rates for acute URTIs (OR 0.65; 95% CI 0.45 to 0.94, moderate quality evidence) and cold-related school absence (OR 0.10; 95% CI 0.02 to 0.47, very low quality evidence). Probiotics and placebo were similar when measuring the rate ratio of episodes of acute URTI (rate ratio 0.83; 95% CI 0.66 to 1.05, P value = 0.12, very low quality evidence) and adverse events (OR 0.88; 95% CI 0.65 to 1.19, P value = 0.40, low quality evidence). Side effects of probiotics were minor and gastrointestinal symptoms were the most common. We found that some subgroups had a high level of heterogeneity when we conducted pooled analyses and the evidence level was low or very low quality. AUTHORS' CONCLUSIONS: Probiotics were better than placebo in reducing the number of participants experiencing episodes of acute URTI, the mean duration of an episode of acute URTI, antibiotic use and cold-related school absence. This indicates that probiotics may be more beneficial than placebo for preventing acute URTIs. However, the quality of the evidence was low or very low. PMID- 25927097 TI - Single dose oral ibuprofen plus codeine for acute postoperative pain in adults. AB - BACKGROUND: This is an update of the original Cochrane review published in Issue 3, 2013. There is good evidence that combining two different analgesics in fixed doses in a single tablet can provide better pain relief in acute pain and headache than either drug alone, and that the drug-specific effects are essentially additive. This appears to be broadly true in postoperative pain and migraine headache across a range of different drug combinations and when tested in the same and different trials. Some combinations of ibuprofen and codeine are available without prescription (but usually only from a pharmacy) where the dose of codeine is lower, and with a prescription when the dose of codeine is higher.Use of combination analgesics that contain codeine has been a source of some concern because of misuse from over-the-counter preparations. OBJECTIVES: To assess the analgesic efficacy and adverse effects of a single oral dose of ibuprofen plus codeine for acute moderate-to-severe postoperative pain using methods that permit comparison with other analgesics evaluated in standardised trials using almost identical methods and outcomes. SEARCH METHODS: We searched the Cochrane Central Register of Controlled Trials (CENTRAL), MEDLINE, EMBASE, the Oxford Pain Relief Database, ClinicalTrials.gov, and the reference lists of articles. The date of the most recent search was 1 December 2014. SELECTION CRITERIA: Randomised, double-blind, placebo- or active-controlled clinical trials of single dose oral ibuprofen plus codeine for acute postoperative pain in adults. DATA COLLECTION AND ANALYSIS: Two review authors independently considered trials for inclusion in the review, assessed risk of bias, and extracted data. We used the area under the pain relief versus time curve to derive the proportion of participants prescribed ibuprofen plus codeine, placebo, or the same dose of ibuprofen alone with at least 50% pain relief over six hours, using validated equations. We calculated the risk ratio (RR) and number needed to treat to benefit (NNT). We used information on the use of rescue medication to calculate the proportion of participants requiring rescue medication and the weighted mean of the median time to use. We also collected information on adverse effects. Analyses were planned for different doses of ibuprofen and codeine, but especially for codeine where we set criteria for low (< 10 mg), medium (10 to 20 mg), and high (> 20 mg) doses. MAIN RESULTS: Since the last version of this review no new studies were found. Information was available from six studies with 1342 participants, using a variety of doses of ibuprofen and codeine. In four studies (443 participants) using ibuprofen 400 mg plus codeine 25.6 mg to 60 mg (high dose codeine) 64% of participants had at least 50% maximum pain relief with the combination compared to 18% with placebo. The NNT was 2.2 (95% confidence interval 1.8 to 2.6) (high quality evidence). In three studies (204 participants) ibuprofen plus codeine (any dose) was better than the same dose of ibuprofen (69% versus 55%) but the result was barely significant with a relative benefit of 1.3 (1.01 to 1.6) (moderate quality evidence). In two studies (159 participants) ibuprofen plus codeine appeared to be better than the same dose of codeine alone (69% versus 33%), but no analysis was done. There was no difference between the combination and placebo in the reporting of adverse events in these acute studies (moderate quality evidence). AUTHORS' CONCLUSIONS: The combination of ibuprofen 400 mg plus codeine 25.6 mg to 60 mg demonstrates good analgesic efficacy. Very limited data suggest that the combination is better than the same dose of either drug alone, and that similar numbers of people experience adverse events with the combination as with placebo. PMID- 25927098 TI - Surgery for small asymptomatic abdominal aortic aneurysms. AB - BACKGROUND: An abdominal aortic aneurysm (AAA) is an abnormal ballooning of the major abdominal artery. Some AAAs present as emergencies and require surgery; others remain asymptomatic. Treatment of asymptomatic AAAs depends on many factors, but an important one is the size of the aneurysm, as risk of rupture increases with aneurysm size. Large asymptomatic AAAs (greater than 5.5 cm in diameter) are usually repaired surgically; very small AAAs (less than 4.0 cm diameter) are monitored with ultrasonography. Debate continues over the appropriate roles of immediate repair and surveillance with repair on subsequent enlargement in people presenting with asymptomatic AAAs of 4.0 cm to 5.5 cm diameter. This is the third update of the review first published in 1999. OBJECTIVES: To compare mortality, quality of life, and cost effectiveness of immediate surgical repair versus routine ultrasound surveillance in people with asymptomatic AAAs between 4.0 cm and 5.5 cm in diameter. SEARCH METHODS: For this update, the Cochrane Peripheral Vascular Diseases Group Trials Search Co ordinator searched the Specialised Register (February 2014) and the Cochrane Central Register of Controlled Trials (CENTRAL; 2014, Issue 1). We checked reference lists of relevant articles for additional studies. SELECTION CRITERIA: Randomised controlled trials in which men and women with asymptomatic AAAs of diameter 4.0 cm to 5.5 cm were randomly allocated to immediate repair or imaging based surveillance at least every six months. Outcomes had to include mortality or survival. DATA COLLECTION AND ANALYSIS: Three members of the review team independently extracted the data, which were cross-checked by other team members. Risk ratios (RR) (endovascular aneurysm repair only), hazard ratios (HR) (open repair only), and 95% confidence intervals based on Mantel-Haenszel Chi(2) statistic were estimated at one and six years (open repair only) following randomisation. We included all relevant published studies in this review. MAIN RESULTS: For this update, four trials with a combined total of 3314 participants fulfilled the inclusion criteria. Two trials compared surveillance with immediate open repair; two trials compared surveillance with immediate endovascular repair. Overall, the risk of bias within the included studies was low and the quality of the evidence high. The four trials showed an early survival benefit in the surveillance group (due to 30-day operative mortality with surgery) but no significant differences in long-term survival (adjusted HR 0.88, 95% confidence interval (CI) 0.75 to 1.02, mean follow-up 10 years; HR 1.21, 95% CI 0.95 to 1.54, mean follow-up 4.9 years; HR 0.76, 95% CI 0.30 to 1.93, median follow-up 32.4 months; HR 1.01, 95% CI 0.49 to 2.07, mean follow-up 20 months). A pooled analysis of participant-level data from two trials (with a maximum follow-up of seven to eight years) showed no statistically significant difference in survival between immediate open repair and surveillance (propensity score-adjusted HR 0.99; 95% CI 0.83 to 1.18), and that this lack of treatment effect did not vary by AAA diameter (P = 0.39) or participant age (P = 0.61). The meta-analysis of mortality at one year for the endovascular trials likewise showed no significant association (RR at one year 1.15, 95% CI 0.60 to 2.17). Quality-of-life results among trials were conflicting. AUTHORS' CONCLUSIONS: The results from the four trials to date demonstrate no advantage to immediate repair for small AAA (4.0 cm to 5.5 cm), regardless of whether open or endovascular repair is used and, at least for open repair, regardless of patient age and AAA diameter. Thus, neither immediate open nor immediate endovascular repair of small AAAs is supported by currently available evidence. PMID- 25927100 TI - Proceedings of the Sixth International Congress on Vegetarian Nutrition, February 24-26. 2013, Loma Linda, CA. PMID- 25927099 TI - Virtual reality for stroke rehabilitation. AB - BACKGROUND: Virtual reality and interactive video gaming have emerged as recent treatment approaches in stroke rehabilitation. In particular, commercial gaming consoles have been rapidly adopted in clinical settings. This is an update of a Cochrane Review published in 2011. OBJECTIVES: PRIMARY OBJECTIVE: To determine the efficacy of virtual reality compared with an alternative intervention or no intervention on upper limb function and activity. SECONDARY OBJECTIVE: To determine the efficacy of virtual reality compared with an alternative intervention or no intervention on: gait and balance activity, global motor function, cognitive function, activity limitation, participation restriction and quality of life, voxels or regions of interest identified via imaging, and adverse events. Additionally, we aimed to comment on the feasibility of virtual reality for use with stroke patients by reporting on patient eligibility criteria and recruitment. SEARCH METHODS: We searched the Cochrane Stroke Group Trials Register (October 2013), the Cochrane Central Register of Controlled Trials (The Cochrane Library 2013, Issue 11), MEDLINE (1950 to November 2013), EMBASE (1980 to November 2013) and seven additional databases. We also searched trials registries and reference lists. SELECTION CRITERIA: Randomised and quasi randomised trials of virtual reality ("an advanced form of human-computer interface that allows the user to 'interact' with and become 'immersed' in a computer-generated environment in a naturalistic fashion") in adults after stroke. The primary outcome of interest was upper limb function and activity. Secondary outcomes included gait and balance function and activity, and global motor function. DATA COLLECTION AND ANALYSIS: Two review authors independently selected trials based on pre-defined inclusion criteria, extracted data and assessed risk of bias. A third review author moderated disagreements when required. The authors contacted investigators to obtain missing information. MAIN RESULTS: We included 37 trials that involved 1019 participants. Study sample sizes were generally small and interventions varied. The risk of bias present in many studies was unclear due to poor reporting. Thus, while there are a large number of randomised controlled trials, the evidence remains 'low' or 'very low' quality when rated using the GRADE system. Control groups received no intervention or therapy based on a standard care approach. Intervention approaches in the included studies were predominantly designed to improve motor function rather than cognitive function or activity performance. The majority of participants were relatively young and more than one year post stroke. PRIMARY OUTCOME: results were statistically significant for upper limb function (standardised mean difference (SMD) 0.28, 95% confidence intervals (CI) 0.08 to 0.49 based on 12 studies with 397 participants). SECONDARY OUTCOMES: there were no statistically significant effects for grip strength, gait speed or global motor function. Results were statistically significant for the activities of daily living (ADL) outcome (SMD 0.43, 95% CI 0.18 to 0.69 based on eight studies with 253 participants); however, we were unable to pool results for cognitive function, participation restriction, quality of life or imaging studies. There were few adverse events reported across studies and those reported were relatively mild. Studies that reported on eligibility rates showed that only 26% of participants screened were recruited. AUTHORS' CONCLUSIONS: We found evidence that the use of virtual reality and interactive video gaming may be beneficial in improving upper limb function and ADL function when used as an adjunct to usual care (to increase overall therapy time) or when compared with the same dose of conventional therapy. There was insufficient evidence to reach conclusions about the effect of virtual reality and interactive video gaming on grip strength, gait speed or global motor function. It is unclear at present which characteristics of virtual reality are most important and it is unknown whether effects are sustained in the longer term. PMID- 25927101 TI - Zinc supplementation for improving pregnancy and infant outcome. AB - BACKGROUND: It has been suggested that low serum zinc levels may be associated with suboptimal outcomes of pregnancy such as prolonged labour, atonic postpartum haemorrhage, pregnancy-induced hypertension, preterm labour and post-term pregnancies, although many of these associations have not yet been established. OBJECTIVES: To assess the effects of zinc supplementation in pregnancy on maternal, fetal, neonatal and infant outcomes. SEARCH METHODS: We searched the Cochrane Pregnancy and Childbirth Group's Trials Register (31 October 2014) and reference lists of retrieved studies. SELECTION CRITERIA: Randomised trials of zinc supplementation in pregnancy. We excluded quasi-randomised controlled trials. DATA COLLECTION AND ANALYSIS: Three review authors applied the study selection criteria, assessed trial quality and extracted data. When necessary, we contacted study authors for additional information. The quality of the evidence was assessed using GRADE. MAIN RESULTS: We included 21 randomised controlled trials (RCTs) reported in 54 papers involving over 17,000 women and their babies. One trial did not contribute data. Trials were generally at low risk of bias. Zinc supplementation resulted in a small reduction in preterm birth (risk ratio (RR) 0.86, 95% confidence interval (CI) 0.76 to 0.97 in 16 RCTs; 16 trials of 7637 women). This was not accompanied by a similar reduction in numbers of babies with low birthweight (RR 0.93, 95% CI 0.78 to 1.12; 14 trials of 5643 women). No clear differences were seen between the zinc and no zinc groups for any of the other primary maternal or neonatal outcomes, except for induction of labour in a single trial. No differing patterns were evident in the subgroups of women with low versus normal zinc and nutrition levels or in women who complied with their treatment versus those who did not. The GRADE quality of the evidence was moderate for preterm birth, small-for-gestational age, and low birthweight, and low for stillbirth or neonatal death and birthweight. AUTHORS' CONCLUSIONS: The evidence for a 14% relative reduction in preterm birth for zinc compared with placebo was primarily represented by trials involving women of low income and this has some relevance in areas of high perinatal mortality. There was no convincing evidence that zinc supplementation during pregnancy results in other useful and important benefits. Since the preterm association could well reflect poor nutrition, studies to address ways of improving the overall nutritional status of populations in impoverished areas, rather than focusing on micronutrient and or zinc supplementation in isolation, should be an urgent priority. PMID- 25927102 TI - A quantitative analysis of the behavior maintained by delayed reinforcers. AB - Random-interval reinforcement was arranged for a sequence of pigeon first-key pecks followed by second-key pecks. First-key pecks, separated from reinforcers by delays that included number of second-key pecks and time, decreased in rate as delays increased. Delay functions, or gradients, were obtained in one experiment with reinforced sequences consisting of M first-key pecks followed by N second key pecks (M + N = 16), in a second where required first-key pecks were held constant (M = 8), and in a third where minimum delay between most recent first key pecks and reinforcers varied. In each, gradients were equally well fitted by exponential, hyperbolic and logarithmic functions. Performances were insensitive to reinforcer duration and functions were consistent across varied random interval values. In one more experiment, time and number delays were independently varied using differential reinforcement of rate of second-key pecks. Delay gradients depended primarily on time rather than on number of second key pecks. Thus, reinforcers have effects based on earlier responses, not just the ones that produced them, with the contribution of each response weighted by the time separating it from the reinforcer rather than by intervening behavior. Situations where unwanted responses (e.g., errors) often precede reinforced corrects can maintain them unless designed to avoid such effects of delay. PMID- 25927103 TI - WITHDRAWN: Rehabilitation interventions for foot drop in neuromuscular disease. PMID- 25927105 TI - [Not Available]. PMID- 25927104 TI - Special issue dedicated to Nicki R Crick. PMID- 25927106 TI - [In Process Citation]. PMID- 25927107 TI - Retraction notice to "Methylation of apoptosis related genes in the pathogenesis and prognosis of prostate cancer" [Cancer Lett. 242 (2) (2006) 222-230]. Makoto Suzuki, Hisayuki Shigematsu, Narayan Shivapurkar, Jyotsna Reddy, Kuniharu Miyajima, Takao Takahashi, Adi F. Gazdar, Eugene P. Frenke. AB - Available online <2nd December 2008>. This article has been retracted: please see Elsevier Policy on Article Withdrawal (http://www.elsevier.com/locate/withdrawalpolicy). This article has been retracted at the request of the first author, who accepts responsibility. Following an internal review at the UT Southwestern Medical Center in Dallas, evidence has been found of improper manipulation and duplication of Figure 1 in this article. PMID- 25927108 TI - Evidence for exercise training in the management of hypertension in adults. AB - OBJECTIVE To provide recommendations on exercise training as part of the management of hypertension in adults.Quality of evidence Evidence was found through a systematic search of PubMed, MEDLINE, EMBASE, Agency for Healthcare Research and Quality evidence-based reports, Bandolier, Clinical Evidence, the Institute for Clinical Systems Improvement guidelines, the National Guideline Clearinghouse database, UpToDate,and the Cochrane Database of Systematic Reviews (part of Ovid Evidence Based Medicine Reviews) for articles published from January 1973 to September 2013. Study types were limited to meta-analyses, randomized controlled trials, clinical trials, and reviews. MAIN MESSAGE: Exercise exerts an antiinflammatoryaction through the sympathetic nervous system and the hypothalamic-pituitary adrenal axis, and has direct effects on blood pressure. The resulting physiologic effects are classified as acute, postexercise, and chronic. Current treatment guidelines emphasize the role of nonpharmacologic interventions, including physical activity, in the management of mild to moderate hypertension. CONCLUSION: Moderate intensity aerobic exercise has been proven to prevent hypertension and to help in the management of stage 1 hypertension. Dynamic resistance exercises, if done properly, contribute to lowering both systolic and diastolic blood pressures. There is insufficient evidence about the safety and efficacy of isometric resistance training to recommend it. PMID- 25927109 TI - Sedating drugs and breastfeeding. AB - QUESTION: If a mother takes a sedating drug during breastfeeding, will it cause central nervous system (CNS) depression in her breastfed baby? ANSWER: In some cases (eg, with the use of codeine or oxycodone) sedating drugs will likely cause CNS depression in breastfed infants and in other cases (eg, with the use of benzodiazepines) they will likely not. Mothers using sedating drugs should monitor their breastfed infants for signs of CNS depression (eg, drowsiness; difficulty breathing, feeding, or latching; or cyanosis), paradoxical effects (eg, unusual excitement,irritability), or inadequate weight gain. PMID- 25927110 TI - Care by design: New model of coordinated on-site primary and acute care in long term care facilities. AB - PROBLEM ADDRESSED: A recently implemented model of care in long-term care facilities (LTCFs) called Care by Design addresses concerns about a previously uncoordinated care system, a reduction in family physician services, and high rates of ambulance transports to emergency departments. OBJECTIVE OF PROGRAM: Care by Design is designed to increase access to care and continuity and quality of care by family physicians, reduce unwanted and unnecessary transfers to the emergency department, and lessen the burden on care teams including physicians and nurses in LTCFs. PROGRAM DESCRIPTION: The core of Care by Design is a dedicated family physician for each LTCF floor, with regular on-site visits; physician on-call coverage, 24 hours a day, 7 days a week; and standing orders and protocols. Care by Design also includes a comprehensive geriatric assessment tool, an interdisciplinary team approach, access to a dedicated extended care paramedic program to respond to urgent care needs, and ongoing performance measurement. CONCLUSION: Care by Design aims to improve on-site care for LTCF residents and family physicians' experiences with providing care in several ways, including increased clinical efficiency, communication, and continuity, and appropriate support within the interdisciplinary team model. PMID- 25927111 TI - Five-weekend care of the elderly certificate course: continuing professional development activity for family physicians. AB - PROBLEM ADDRESSED: Primary care practitioners have unique clinical challenges in caring for elderly patients and require educational courses that are specifically designed for their needs in caring for this patient population. OBJECTIVE OF PROGRAM: To improve family physicians' knowledge of and confidence in managing common geriatric problems. PROGRAM DESCRIPTION: The accredited course curriculum is delivered on 5 weekends over approximately 6 months.Each weekend focuses on a different theme including cognitive impairment, gait disorders, mental health and pain management, geriatric medical problems, and failure to thrive. Participants complete written assignments between weekend sessions, which involve self reflection on how the new knowledge and skills gained through the course will be incorporated in the management of elderly patients in their practices. CONCLUSION: The 5-Weekend Care of the Elderly Certificate Course is an accredited continuing professional development program for primary care practitioners. Preliminary evaluation suggests improvement in participants' self-rated knowledge of and confidence in managing geriatric problems. Qualitative data show positive changes in clinical practice. PMID- 25927112 TI - An evaluation of video modeling with embedded instructions to teach implementation of stimulus preference assessments. AB - A multiple baseline design across participants was used to evaluate the effects of video modeling with embedded instructions on training teachers to implement 3 preference assessments. Each assessment was conducted with a confederate learner or a child with autism during generalization probes. All teachers met the predetermined mastery criterion, and 2 of the 3 demonstrated skill maintenance at 1-month follow-up. PMID- 25927113 TI - CardioPulse: Andreas Gruntzig's beginnings started in peripheral arteries. PMID- 25927114 TI - CardioPulse: developments in the treatment of aortic aneurysms in 2014. PMID- 25927115 TI - CardioPulse: interventional treatment of venous thromboembolism: a review and update of treatments in 2014. PMID- 25927116 TI - CardioPulse: working in industry requires wanting to make medicines. PMID- 25927117 TI - CardioPulse: STEMI and stroke: distant cousins at best. PMID- 25927140 TI - Erratum. PMID- 25927139 TI - Inhibition of Plk1 represses androgen signaling pathway in castration-resistant prostate cancer. AB - Prostate cancer (PCa) is the second leading cause of cancer-related death in males in the United States. Majority of prostate cancers are originally androgen dependent and sensitive to androgen-deprivation therapy (ADT), however, most of them eventually relapse and progress into incurable castration-resistant prostate cancer (CRPC). Of note, the activity of androgen receptor (AR) is still required in CRPC stage. The mitotic kinase polo-like kinase 1 (Plk1) is significantly elevated in PCa and its expression correlates with tumor grade. In this study, we assess the effects of Plk1 on AR signaling in both androgen-dependent and androgen-independent PCa cells. We demonstrate that the expression level of Plk1 correlated with tumorigenicity and that inhibition of Plk1 caused reduction of AR expression and AR activity. Furthermore, Plk1 inhibitor BI2536 down-regulated SREBP-dependent expression of enzymes involved in androgen biosynthesis. Of interest, Plk1 level was also reduced when AR activity was inhibited by the antagonist MDV3100. Finally, we show that BI2536 treatment significantly inhibited tumor growth in LNCaP CRPC xenografts. Overall, our data support the concept that Plk1 inhibitor such as BI2536 prevents AR signaling pathway and might have therapeutic potential for CRPC patients. PMID- 25927141 TI - Sudden Cardiac Death Due To IgG4-Related Disease. PMID- 25927142 TI - In reply. PMID- 25927143 TI - beta-Catenin as a Morpho-immunohistochemical Marker for the Diagnosis of Papillary Thyroid Carcinoma. PMID- 25927144 TI - Who will do my autopsy? PMID- 25927145 TI - Cancer biomarker testing in the everyday practice of pathology. PMID- 25927146 TI - Timeliness and accuracy of reporting preliminary blood culture results: a College of American Pathologists Q-probes study of 65 institutions. AB - CONTEXT: The speed and accuracy of preliminary blood culture reports impacts patient management and outcomes. OBJECTIVE: To evaluate the accuracy and timeliness of preliminary blood culture results among multiple laboratories. DESIGN: Q-Probes participants collected turnaround time (TAT) data on preliminary Gram stains, compared accuracy of up to 100 preliminary to final culture Gram stain results, and described blood culture laboratory practices. RESULTS: Sixty four laboratories and 5031 blood cultures were evaluated. All participants used continuously monitoring blood culture systems. Median TAT from initial growth detection to notification of results was 45 minutes, with the longest component being preparation of Gram stains (median time = 25 minutes). Participants (N = 40) reporting a continuous schedule for processing blood cultures had significantly lower overall TAT (median= 37 minutes) compared with 15 participants with intermittent processing schedules (median= 124 minutes), P= .003. Time to complete Gram stain processing was lower (median time = 21 minutes) for 39 participants using continuous processing schedule compared with 14 others (median time= 67 minutes), P= .03. Goals for total TAT were used by 27 of 56 participants (48.2%). Having goals did not significantly affect TAT. A total of 4962 of 5021 Gram stain results (98.8%) agreed with final culture results. The highest discrepancy rates occurred among gram-positive bacilli (20 of 335; 6.0%) and mixed cultures (22 of 106; 20.8%). CONCLUSIONS: This study provides benchmarks for assessing blood culture quality performance. Timeliness and accuracy of preliminary blood culture reports were excellent. However, nearly one third of laboratories did not process blood cultures continuously. This significantly prolonged reporting results, which could affect patient outcomes. PMID- 25927147 TI - Genomic profiling of advanced-stage, metaplastic breast carcinoma by next generation sequencing reveals frequent, targetable genomic abnormalities and potential new treatment options. AB - CONTEXT: Metastatic metaplastic breast carcinoma (MPBC) is an uncommon, but aggressive, tumor resistant to conventional chemotherapy. OBJECTIVE: To learn whether next-generation sequencing could identify potential targets of therapy for patients with relapsed and metastatic MPBC. DESIGN: Hybridization capture of 3769 exons from 236 cancer-related genes and 47 introns of 19 genes commonly rearranged in cancer was applied to a minimum of 50 ng of DNA extracted from 20 MPBC formalin-fixed, paraffin-embedded specimens and sequenced to high uniform coverage. RESULTS: The 20 patients with MPBC had a median age of 62 years (range, 42-86 years). There were 9 squamous (45%), 9 chondroid (45%), and 2 spindle cell (10%) MPBCs, all of which were high grade. Ninety-three genomic alterations were identified, (range, 1-11) with 19 of the 20 cases (95%) harboring an alteration that could potentially lead to a targeted treatment option. The most-common alterations were in TP53 (n = 69; 75%), PIK3CA (n = 37; 40%), MYC (n = 28; 30%), MLL2 (n = 28; 30%), PTEN (n = 23; 25%), CDKN2A/B (n = 19; 20%), CCND3 (n = 14; 15%), CCNE1 (n = 9; 10%), EGFR (n = 9; 10%), and KDM6A (n = 9; 10%); AKT3, CCND1, CCND2, CDK4, FBXW7, FGFR1, HRAS, NF1, PIK3R1, and SRC were each altered in a single case. All 16 MPBCs (100%) that were negative for ERBB2 (HER2) overexpression by immunohistochemistry and/or ERBB2 (HER2) amplification by fluorescence in situ hybridization were also uniformly (100%) negative for ERBB2 amplification by next-generation sequencing-based copy-number assessment. CONCLUSIONS: Our results indicate that genomic profiling using next-generation sequencing can identify clinically meaningful alterations that have the potential to guide targeted treatment decisions in most patients with metastatic MPBC. PMID- 25927148 TI - An assessment of gynecological cytology screening practices among health care providers nationwide. AB - CONTEXT: The Michigan Public Health Institute and the Michigan Cancer Consortium's Cervical Cancer Committee conducted a national survey of health care providers, thanks to funding from the Centers for Disease Control Cooperative Agreement 5U47CI000743-02. Papanicolaou test screening practices were examined, emphasizing the relationship between clinical and laboratory practices. This survey found differing screening practices among providers of women's health care. OBJECTIVES: To collect information from family medicine practitioners, women's nurse practitioners, obstetricians and gynecologists, and certified nurse midwives on Papanicolaou and human papillomavirus testing; to discuss how those practices align with current cytology screening and follow-up recommendations from professional organizations (US Preventive Services Task Force, American Cancer Society, American College of Obstetricians and Gynecologists, and American Society for Colposcopy, and Cervical Pathology); and ultimately, to make recommendations aimed at standardizing practice performance. DESIGN: This survey was conducted in part to examine clinicians' practices and their perceptions of laboratory performance, to evaluate items that are known to enhance quality of care, and to examine factors that may prohibit universal implementation of best standards of care. The survey used a self-administered questionnaire, distributed to 9366 clinicians, with 1601 (17.1%) completed surveys. RESULTS: This assessment shows a clear lack of consensus among practitioners in performing Papanicolaou testing. It demonstrates how differently patients are tested, based on the providers' screening practices, and demonstrates specific cervical cancer screening practice disparities between and among the 4 provider groups, both in Papanicolaou testing and in the use of human papillomavirus testing. CONCLUSION: A unified mandate for screening is needed to standardize screening practices. PMID- 25927149 TI - Validation of multiple whole slide imaging scanners based on the guideline from the College of American Pathologists Pathology and Laboratory Quality Center. AB - CONTEXT: Whole slide imaging (WSI) produces a virtual image that can be transmitted electronically. This technology has clinical applications in situations in which glass slides are not readily available. OBJECTIVE: To examine the results of a validation study performed using the draft version of the WSI clinical validation guideline recently released by the College of American Pathologists. DESIGN: Ten iScan Coreo Au scanners (Ventana Medical Systems, Tucson, Arizona) were validated, 6 with one set of 100 cases and 4 with a different set of 100 cases, for 1000 case examinations. The cases were selected consecutively from the following case types: internal consultations and malignancies and cases with frozen sections, special stains, and/or immunohistochemistry. Only key slides were scanned from each case. The slides were scanned at *20 magnification. Pathologists reviewed the cases as both glass slides and WSI, with at least a 3-week washout period between viewings. RESULTS: Intraobserver agreement between glass slides and WSI was present for 786 (79%) of the 1000 cases. Major discrepancies occurred in 18 cases (1.8%). kappa statistics compiled for the subset of cases (n = 504; 50%) with concern for neoplasia showed excellent agreement (kappa = 0.8782). Individual scanners performed similarly to one another. Analysis of the results revealed an area of concern: small focal findings. CONCLUSIONS: The results were felt to validate the use of WSI for the intended applications in our multiinstitutional laboratory system, although scans at *20 magnification may be insufficient for cases hinging on small focal findings, such as microorganisms and inflammatory processes. PMID- 25927152 TI - Angiolymphoid hyperplasia with eosinophilia. AB - Angiolymphoid hyperplasia with eosinophilia (ALHE), also named epithelioid hemangioma (EH), is an inflamed vascular tumefaction of uncertain pathogenesis, characterized by proliferation of histiocytoid endothelial cells with prominent lymphocytic and eosinophilic infiltration. Although considered a benign condition, it may recur in up to one-third of cases in the absence of complete surgical excision. The pathogenesis of ALHE/EH is still controversial. However, reaction to trauma and arteriovenous shunting are considered relevant. Histologically, ALHE/EH may be differentiated from other vascular neoplasms by its several unique characteristics including prominent proliferation of plump endothelial cells, and accompanying eosinophilic and lymphocytic inflammation, often with formation of lymphoid follicles. Surgery is the mainstay of treatment and various other treatment strategies have been used with varying results. PMID- 25927150 TI - Use of Thromboelastography (TEG) for Detection of New Oral Anticoagulants. AB - CONTEXT: The clinical introduction of new oral anticoagulants (NOACs) has stimulated the development of tests to quantify the effects of these drugs and manage complications associated with their use. Until recently, the only treatment choices for the prevention of venous thromboembolism in orthopedic surgical patients, as well as for stroke and systemic embolism in patients with atrial fibrillation, were vitamin K antagonists, antiplatelet drugs, and unfractionated and low-molecular-weight heparins. With the approval of NOACs, treatment options and consequent diagnostic challenges have expanded. OBJECTIVE: To study the utility of thromboelastography (TEG) in monitoring and differentiating between 2 currently approved classes of NOACs, direct thrombin inhibitors (dabigatran) and factor Xa inhibitors (rivaroxaban and apixaban). DESIGN: Blood samples from healthy volunteers were spiked with each NOAC in both the presence and absence of ecarin, and the effects on TEG were evaluated. RESULTS: Both the kaolin test reaction time (R time) and the time to maximum rate of thrombus generation were prolonged versus control samples and demonstrated a dose response for apixaban (R time within the normal range) and dabigatran. The RapidTEG activated clotting time test allowed the creation of a dose-response curve for all 3 NOACs. In the presence of anti-Xa inhibitors, the ecarin test promoted significant shortening of kaolin R times to the hypercoagulable range, while in the presence of the direct thrombin inhibitor only small and dose proportional R time shortening was observed. CONCLUSIONS: The RapidTEG activated clotting time test and the kaolin test appear to be capable of detecting and monitoring NOACs. The ecarin test may be used to differentiate between Xa inhibitors and direct thrombin inhibitors. Therefore, TEG may be a valuable tool to investigate hemostasis and the effectiveness of reversal strategies for patients receiving NOACs. PMID- 25927151 TI - Angiomatoid fibrous histiocytoma: the current status of pathology and genetics. AB - CONTEXT: Angiomatoid fibrous histiocytoma (AFH) is a rare soft tissue neoplasm of intermediate biologic potential and uncertain differentiation, most often arising in the superficial extremities of children and young adults. While it has characteristic histologic features of nodular distributions of ovoid and spindle cells with blood-filled cystic cavities and a surrounding dense lymphoplasmacytic infiltrate, there is a significant morphologic spectrum, which coupled with its rarity and lack of specific immunoprofile can make diagnosis challenging. Angiomatoid fibrous histiocytoma is associated with 3 characteristic gene fusions, EWSR1-CREB1 and EWSR1-ATF1, which are also described in other neoplasms, and rarely FUS-ATF1. Angiomatoid fibrous histiocytoma is now recognized at an increasing number of sites and is known to display a variety of unusual histologic features. OBJECTIVE: To review the current status of AFH, discussing putative etiology, histopathology with variant morphology and differential diagnosis, and current genetics, including overlap with other tumors harboring EWSR1-CREB1 and EWSR1-ATF1 fusions. DATA SOURCES: Review of published literature, including case series, case reports, and review articles, in online medical databases. CONCLUSIONS: The occurrence of AFH at several unusual anatomic sites and its spectrum of morphologic patterns can result in significant diagnostic difficulty, and correct diagnosis is particularly important because of its small risk of metastasis and death. This highlights the importance of diagnostic recognition, ancillary molecular genetic confirmation, and close clinical follow up of patients with AFH. Further insight into the genetic and epigenetic changes arising secondary to the characteristic gene fusions of AFH will be integral to understanding its tumorigenic mechanisms. PMID- 25927153 TI - Novel oral anticoagulants: efficacy, laboratory measurement, and approaches to emergent reversal. AB - Warfarin, the most commonly used of the vitamin K antagonists, has been a mainstay of oral anticoagulation for decades. However, its usage is limited by morbidity and mortality secondary to bleeding as well as a cumbersome therapeutic monitoring process. In the past several years, a number of competing novel oral anticoagulants (NOACs) have been developed, each of which aspires to match or exceed warfarin's effectiveness while mitigating bleeding risk and eliminating therapeutic monitoring requirements. At present, 1 oral direct thrombin inhibitor and 2 direct factor Xa inhibitors are approved by the US Food and Drug Administration. Here, we compare the clinical efficacy and safety profiles of these new drugs. In addition, we discuss various laboratory assays that may be useful to measure these drugs in certain clinical circumstances. Finally, we discuss emerging strategies to reverse these agents in an emergency. The purpose of this article is to provide a framework for practicing pathologists to advise clinicians on NOAC laboratory measurement and management of NOAC-associated bleeding. PMID- 25927154 TI - Conjunctival myxoma: a synopsis of a rare ocular tumor. AB - Conjunctival myxoma is an exceptionally rare, slow-growing, benign neoplasm of primitive mesenchyme origin. Forty-one cases of conjunctival myxoma from a literature review, including the authors' case, are listed. The usual clinical history is a painless mass appearing during months to years. Grossly, the tumor is a well-circumscribed, cystlike, gelatinous, yellow-to-pink, translucent-to solid mass. Microscopically, the hypocellular tumor contains stellate- and spindle-shaped cells in a mucoid stroma with abundant hyaluronic acid mucopolysaccharides. Vimentin and alpha-smooth muscle actin highlight the spindle and stellate cells. S100 protein and desmin are negative for the tumor cells. Treatment is complete surgical excision, with no recurrence reported in the follow-up period. Notably, conjunctival myxoma may be associated with Carney complex, an autosomal-dominant disorder associated with skin pigmentation, endocrine abnormalities, and myxoma of the heart and eye. Physicians should appreciate this unique ocular tumor because of its potential association with Carney complex. PMID- 25927156 TI - Azulenylcarbene and naphthylcarbene isomerizations. Falling solid flash vacuum pyrolysis. AB - 1-Azulenylcarbene 18 has been generated from 5-(1-azulenyl)tetrazole and the sodium salt of azulene-1-carbaldehyde tosylhydrazone using the falling solid flash vacuum pyrolysis (FS-FVP) method. The principal products, which are also formed from both 1- and 2-naphthylcarbenes, cyclobuta[de]naphthalene 6, cyclopenta[cd]indene 16, and benzofulvenallene 17, are explained in terms of two reaction paths, (a) a rearrangement to benzofulvenyl-7-carbene 13 and (b) a rearrangement to 1-naphthylcarbene 1. Moreover, 16 is also formed from 2 azulenylcarbene 30, thereby indicating the occurrence of a 2-azulenylcarbene-1 azulenylcarbene rearrangement. The reaction mechanisms are supported by density functional theory calculations at the B3LYP/6-31G** level, which indicate that all the rearrangements have activation barriers of <35 kcal/mol, thus making them readily achievable under FVP conditions. PMID- 25927157 TI - Therapeutic Germ Line Alteration: Has CRISPR/Cas9 Technology Forced the Question? PMID- 25927158 TI - Challenges of biomolecular detection at the nanoscale: nanopores and microelectrodes. AB - The interest in analytical devices, which typically rely on the reactivity of a biological component for specificity, is growing rapidly. In this Perspective, we highlight current challenges in all-electrical biosensing as these systems shrink toward the nanoscale and enable the detection of analytes at the single-molecule level. We focus on two sensing principles: nanopores and amperometric microelectrode devices. PMID- 25927159 TI - Introduction. These two issues contain a selected subset of the papers presented at RECOMB 2014. PMID- 25927160 TI - Smaller is Plastic: Polymorphic Structures and Mechanism of Deformation in Nanoscale hcp Metals. AB - Using first-principles calculations, we establish the existence of highly stable polymorphs of hcp metals (Ti, Mg, Be, La and Y) with nanoscale structural periodicity. They arise from heterogeneous deformation of the hcp structure occurring in response to large shear stresses localized at the basal planes separated by a few nanometers. Through Landau theoretical analysis, we show that their stability derives from nonlinear coupling between strains at different length scales. Such multiscale hyperelasticity and long-period structures constitute a new mechanism of size-dependent plasticity and its enhancement in nanoscale hcp metals. PMID- 25927161 TI - Growth of Highly Conductive Ga-Doped ZnO Nanoneedles. AB - The molecular beam epitaxy growth of highly degenerate Ga-doped ZnO (GaZnO) nanoneedles (NNs) based on the vapor-liquid-solid (VLS) growth mode using Ag nanoparticles (NPs) as the growth catalyst is demonstrated. It is shown that when the growth substrate temperature is sufficiently high, a portion of a Ag NP can be melted for serving as the catalyst to precipitate GaZnO on the residual Ag NP and form a GaZnO NN. Record-low turn-on and threshold electric fields in the field emission test of the grown GaZnO NNs are observed. Also, a record-high field enhancement factor in field emission is calibrated. Such superior field emission performances are attributed to a few factors, including (1) the low work function and high conductivity of the grown GaZnO NNs due to highly degenerate Ga doping, (2) the sharp-pointed geometry of the vertically aligned GaZnO NNs, (3) the Ag doping in VLS precipitation of GaZnO for further reducing NN resistivity, and (4) the residual small Ag NP at the NN tip for making the tip even sharper and tip conductivity even higher. PMID- 25927162 TI - Rational design of coaxial structured carbon nanotube-manganese oxide (CNT-MnO2) for energy storage application. AB - Recently, there has been great research interest in the development of composites (core-shell structures) of carbon nanotubes (CNTs) with metal oxides for improved electrochemical energy storage, photonics, electronics, catalysis, etc. Currently, the synthetic strategies for metal oxides/hydroxides are well established, but the development of core-shell structures by robust, cost effective chemical methods is still a challenge. The main drawbacks for obtaining such electrodes are the very complex synthesis methods which ultimately result in high production costs. Alternatively, the solution based method offers the advantages of simple and cost effective synthesis, as well as being easy to scale up. Here, we report on the development of multi-walled carbon nanotube-manganese oxide (CNT-MnO2) core-shell structures. These samples were directly utilized for asymmetric supercapacitor (ASC) applications, where the CNT-MnO2 composite was used as the positive electrode and ZIF-8 (zeolitic imidazolate framework, ZIF) derived nanoporous carbon was used as the negative electrode. This unconventional ASC shows a high energy density of 20.44 W h kg(-1) and high power density of 16 kW kg(-1). The results demonstrate that these are efficient electrodes for supercapacitor application. PMID- 25927163 TI - Self-assembled polymer/inorganic hybrid nanovesicles for multiple drug delivery to overcome drug resistance in cancer chemotherapy. AB - With the aim to develop a facile strategy to prepare functional drug carriers to overcome multidrug resistance (MDR), we prepared heparin/protamine/calcium carbonate (HP/PS/CaCO3) hybrid nanovesicles with enhanced cell internalization, good serum stability, and pH sensitivity for drug delivery. All the functional components including protamine to improve the cell uptake, heparin to enhance the stability, and CaCO3 to improve drug loading and endow the system with pH sensitivity were introduced to the nanovesicles by self-assembly in an aqueous medium. An antitumor drug (doxorubicin, DOX) and a drug resistance inhibitor (tariquidar, TQR) were coloaded in the nanovesicles during self-assembly preparation of the nanovesicles. The drug loaded nanovesicles, which had a mean size less than 200 nm, exhibited a pH-sensitive drug release behavior. In vitro study was carried out in both nonresistant cells (HeLa and MCF-7) and drug resistant cancer cells (MCF-7/ADR). Because of the enhanced intracellular and nuclear drug accumulation through effective inhibition of the P-gp efflux transporter, DOX/TQR coloaded nanovesicles showed significantly improved tumor cell inhibitory efficiency, especially for drug-resistant cells. These results suggest the self-assembled nanovesicles have promising applications in multidrug delivery to overcome drug resistance in tumor treatments. PMID- 25927165 TI - Synthesis of multiply substituted 1,6-dihydropyridines through Cu(I)-catalyzed 6 endo cyclization. AB - Copper-catalyzed 6-endo cyclization of N-propargylic beta-enaminocarbonyls was developed for the synthesis of oxidation-labile 1,6-dihydropyridines. This synthetic method allows flexible and regio-defined assembly of various substituents at the N1, C2, C3, C4, and C6 positions of 1,6-dihydropyridines under mild conditions. PMID- 25927166 TI - Ocular Complications in Laparoscopic Surgery: Review of Existing Literature and Possible Prevention and Treatment. AB - During laparoscopic surgery, ocular complications are possible, sometimes leading to devastating visual losses, hardly susceptible to recovery, although rare. Principal ocular adverse events are represented by corneal abrasions and the perioperative visual loss (POVL). POVL onset is related to intraocular pressure elevations (particularly after patient positioning in Trendelenburg or prone decubitus, depending on the surgical procedure), anesthesiologic factors and patients' characteristics. In the light of evidence from the existing literature, the authors suggest surgical and anesthesiologic measures to prevent and manage ocular complications in laparoscopic surgery. Apart from general recommendations, this article indicates practical guidelines specific for robot-assisted laparoscopic interventions and spinal surgery, as well as laparoscopic colorectal resection, radical prostatectomy, and gynecologic surgery. In conclusion, in order to better manage these complications, it is advisable to develop an interdisciplinary collaboration between surgeons, anesthesiologists, and ophthalmologists, on a procedural and medico-legal level, with the intent of mutual training. PMID- 25927167 TI - Noninvasive method of DNA isolation from fecal epithelial tissue of dairy animals. AB - A novel noninvasive genomic DNA isolation protocol from fecal tissue, by the proteinase K digestion and guanidine hydrochloride extraction method, was assessed for the genotyping of cattle and buffalo. The epithelial tissues present on the surface of the feces were used as source for isolation of genomic DNA. The DNA isolated from fecal tissue was found to be similar as those obtained from other body tissues such as skin, brain, liver, kidney, and muscle. The quality of DNA was checked by agarose gel electrophoresis and polymerase chain reaction (PCR). We successfully amplified a 320 bp MHC class II DRB gene and a 125 bp mt DNA D-loop region from isolated genomic DNA of cattle. Thus, the DNA isolated using this method was suitable for common molecular biology methods, such as restriction enzyme digestion and genotyping of dairy animals through PCR. PMID- 25927164 TI - MMP-10 Regulates Collagenolytic Activity of Alternatively Activated Resident Macrophages. AB - Matrix metalloproteinase-10 (MMP-10) is expressed by macrophages and epithelium in response to injury, but its functions in wound repair are unknown. We observed increased collagen deposition and skin stiffness in Mmp10(-/-) wounds, with no difference in collagen expression or reepithelialization. Increased collagen deposition in Mmp10(-/-) wounds was accompanied by less collagenolytic activity and reduced expression of specific metallocollagenases, particularly MMP-8 and MMP-13, where MMP-13 was the key collagenase. Ablation and adoptive transfer approaches and cell-based models demonstrated that the MMP-10-dependent collagenolytic activity was a product of alternatively activated (M2) resident macrophages. These data demonstrate a critical role for macrophage MMP-10 in controlling the tissue remodeling activity of macrophages and moderating scar formation during wound repair. PMID- 25927168 TI - Comparative Study on the Genetic Diversity of GHR Gene in Tibetan Cattle and Holstein Cows. AB - Due to the phenotype-based artificial selection in domestic cattle, the underlying functional genes may be indirectly selected and show decreasing diversity in theory. The growth hormone receptor (GHR) gene has been widely proposed to significantly associate with critical economic traits in cattle. In the present study, we comparatively studied the genetic diversity of GHR in Tibetan cattle (a traditional unselected breed, n = 93) and Chinese Holstein cow (the intensively selected breed, n = 94). The Tibetan yak (n = 38) was also included as an outgroup breed. A total of 21 variants were detected by sequencing 1279 bp genomic fragments encompassing the largest exon 9. Twelve haplotypes (H1~H12) constructed by 15 coding SNPs were presented as a star-like network profile, in which haplotype H2 was located at the central position and almost occupied by Tibetan yaks. Furthermore, H2 was also identical to the formerly reported sequence specific to African cattle. Only haplotype H5 was simultaneously shared by all three breeds. Tibetan cattle showed higher nucleotide diversity (0.00215 +/- 0.00015) and haplotype diversity (0.678 +/- 0.026) than Holstein cow. Conclusively, we found Tibetan cattle have retained relatively high genetic variation of GHR. The predominant presence of African cattle specific H2 in the outgroup yak breed would highlight its ancestral relationship, which may be used as one informative molecular marker in the phylogenetic studies. PMID- 25927169 TI - Yak response to high-altitude hypoxic stress by altering mRNA expression and DNA methylation of hypoxia-inducible factors. AB - Hypoxia-inducible factors (HIFs) are oxygen-dependent transcriptional activators, which play crucial roles in tumor angiogenesis and mammalian development, and regulate the transcription of genes involved in oxygen homeostasis in response to hypoxia. However, information on HIF-1alpha and HIF-2alpha in yak (Bos grunniens) is scarce. The complete coding region of yak HIF-2alpha was cloned, its mRNA expression in several tissues were determined, and the expression levels were compared with those of closely related low-altitude cattle (Bos taurus), and the methylation status of promoter regions were analyzed to better understand the roles of HIF-1alpha and HIF-2alpha in domesticated yak. The yak HIF-2alpha cDNA was cloned and sequenced in the present work reveals the evolutionary conservation through multiple sequence alignment, although 15 bases changed, resulting in 8 amino acid substitutions in the translated proteins in cattle. The tissue-specific expression results showed that HIF-1alpha is ubiquitously expressed, whereas HIF-2alpha expression is limited to endothelial tissues (kidney, heart, lung, spleen, and liver) and blood in yak. Both HIF-1alpha and HIF-2alpha expressions were higher in yak tissues than in cattle. The HIF-1alpha expression level is much higher in yak than cattle in these organs, except for the lung (P < 0.05), but the HIF-2alpha gene is significantly different in the heart, spleen, and kidney (P < 0.05). Furthermore, the methylation levels in the 5' flanking regulatory regions of HIF-1alpha and HIF-2alpha in yak kidney were significantly decreased than cattle counterparts (P < 0.05). Identifying these genes and the comparison of different expressions facilitates the understanding of the biological high-altitude hypoxic stress response mechanism and may assist current medical research to understand hypoxia-related diseases. PMID- 25927170 TI - Molecular Characterization, Polymorphism, and Association of Porcine GADD45G Gene. AB - Growth arrest and DNA-damage-inducible gamma (GADD45G) is a reproduction related gene. In this study, the full-length cDNA sequence of porcine GADD45G gene was cloned through rapid amplification of cDNA ends (RACE) method. The porcine GADD45G gene encodes a protein of 159 amino acids that shares high homology with the GADD45G of nine species: chimpanzee (97%), sumatran orangutan (97%), white tufted-ear marmoset (97%), northern white-cheeked gibbon (97%), cattle (97%), human (97%), rhesus monkey (97%), rat (96%), and mouse (95%). This novel porcine gene was assigned to GeneID: 100152997. Phylogenetic analysis revealed that the porcine GADD45G gene has a closer genetic relationship with the GADD45G gene of cattle. Computer-assisted analysis indicated that porcine GADD45G gene is structured in four exons and three introns. PCR-Rsa I-RFLP was established to detect an A/G mutation on the position of 294-bp of coding sequence and eight pig breeds display obvious genotype and allele frequency differences at this mutation locus. Association of this SNP with litter size traits was assessed in Large White (n = 100) and Landrace (n = 100) pig populations, and result demonstrated that this polymorphic locus was significantly associated with the litter size of all parities in Large White and Landrace sows (P < 0.01). Therefore, porcine GADD45G gene could be a useful candidate gene in selection for increasing the litter size. These data serve as a foundation for further insight into this novel porcine gene. PMID- 25927171 TI - Single-Nucleotide Polymorphisms in Pig EPHX1 Gene are Associated with Pork Quality Traits. AB - Epoxide hydrolase 1 (EPHX1) plays an important role in both the activation and detoxification of exogenous chemicals. Reverse transcription-polymerase chain reaction (RT-PCR) analysis showed that the highest level of EPHX1 expression occurred in Berkshire liver, which is an organ that plays a key role in detoxification. We examined EPHX1 SNPs to analyze effect on increased expression of EPHX1 gene in Berkshire liver by total of 192 pigs of a pure Berkshire line (males = 97; females = 95). As a result, two nonsynonymous SNPs (nsSNPs) of EPHX1 were found from c.685T>G and c.776C > T, and located in 5th and 6th exons, respectively, which constitute the A/b hydrolase 1 domain of epoxide hydrolase. The nsSNP c.685T > G was significant differences in meat color, protein content, collagen content, and pH24 hr. Especially, T and G alleles of the nsSNP c.685T > G were significantly associated with CIE a*/CIE b* and protein content/pH24 hr, respectively. The nsSNP c.776C > T was significant differences in drip loss and protein content. Among meat quality traits to associate with SNPs, the protein content was only significantly associated with sex. Therefore, it is suggested that nsSNP c.685T > G in EPHX1 gene is a potential to apply as appropriate DNA markers for improvement of porcine economic traits. PMID- 25927172 TI - The effect of triamcinolone acetonide on laser-induced choroidal neovascularization in mice using a hypoxia visualization bio-imaging probe. AB - Hypoxic stress is a risk factor of ocular neovascularization. Hypoxia visualization may provide clues regarding the underlying cause of angiogenesis. Recently, we developed a hypoxia-specific probe, protein transduction domain oxygen-dependent degradation domain-HaloTag-Rhodamine (POH-Rhodamine). In this study, we observed the localization of HIF-1alpha proteins by immunohistochemistry and the fluorescence of POH-Rhodamine on RPE-choroid flat mounts. Moreover, we compared the localization of POH-Rhodamine with pimonidazole which is a standard reagent for detecting hypoxia. Next, we investigated the effects of triamcinolone acetonide (TAAC) against visual function that was evaluated by recording electroretinogram (ERG) and choroidal neovascularization (CNV) development. Mice were given laser-induced CNV using a diode laser and treated with intravitreal injection of TAAC. Finally, we investigated POH Rhodamine on CNV treated with TAAC. In this study, the fluorescence of POH Rhodamine and HIF-1alpha were co-localized in laser-irradiated sites, and both the POH-Rhodamine and pimonidazole fluorescent areas were almost the same. Intravitreal injection of TAAC restored the reduced ERG b-wave but not the a-wave and decreased the mean CNV area. Furthermore, the area of the POH-Rhodamine positive cells decreased. These findings indicate that POH-Rhodamine is useful for evaluating tissue hypoxia in a laser-induced CNV model, suggesting that TAAC suppressed CNV through tissue hypoxia improvement. PMID- 25927173 TI - [Effect of Photodynamic Inactivation (PDI) using Riboflavin-Conjugated Antibody against Staphylococcus aureus]. AB - PURPOSE: Crosslinking/riboflavin-UVA photodynamic therapy is a potential treatment alternative in antibiotic resistant infectious keratitis. For photodynamic therapy a specific (against bacteria) conjugated antibody may be used in order to increase the effect of the treatment. In our present study we analysed the impact of photodynamic inactivation using riboflavin-conjugated antibody or riboflavin alone on Staphylococcus aureus, in vitro. METHODS: Staphylococcus aureus (S. aureus) was incubated in 1 : 100 diluted riboflavin conjugated antibody (R-AB) for 30 minutes in darkness. Following UVA-light illumination (375 nm) with an energy dose of 2, 3, 4 and 8 J/cm(2), bacteria were brought to blood agar Plates for 24 hours before colony-forming unit (CFU) counting. In an additional group, we incubated bacteria to 0, 0.05 or 0.1 % riboflavin 5-phosphate as described above followed by illumination using UVA light (375 nm) with an energy dose of 2 J/cm(2), before CFU counting. RESULTS: The number of CFU decreased significantly (inactivation of 36 %, p = 0.022) using 1 : 100 diluted riboflavin-conjugated antibody and 2 J/cm(2) UVA-light illumination, compared to untreated controls. The use of 3, 4 und 8 J/cm(2) energy dose and R-AB in 1 : 100 dilution did not further change the decrease of CFU (inactivation of 39, 39 and 40 %; p = 0.016; p = 0.016; p = 0.015). The use of 0.05 % or 0.1 % riboflavin 5-phosphate alone and UVA-light illumination reduced the CFU count significantly (inactivation of 73 and 55 %; p = 0.002; p = 0.005), compared to untreated controls. CONCLUSIONS: The use of riboflavin conjugated antibody or 0.05 % or 0.1 % riboflavin 5-phosphate and UVA-light illumination reduces the number of CFU of S. aureus. However, none of these photodynamic therapies reached the necessary 99 % killing rate of these bacteria. Further work is needed to increase the efficacy of riboflavin-conjugated antibodies against antibiotic resistant bacteria. PMID- 25927174 TI - [Sensitivity and Specificity of the Nerve Fibre Imaging Using Scanning Laser Ophthalmoscopy and of Optic Nerve Analysis Using Heidelberg Retina Tomography in Glaucoma]. AB - PURPOSE: Imaging of the optic nerve head and the nerve fibre layer are used in the diagnosis of glaucoma. We have investigated the diagnostic precision of nerve fibre layer imaging using a manually operated scanning laser ophthalmoscope and analysis of the optic nerve head using the Heidelberg Retina Tomograph II (HRT). PATIENTS AND METHODS: 42 patients with glaucoma, 16 patients with ocular hypertension (OHT) and 24 healthy control subjects were included in a clinical study. Nerve fibre layer imaging was performed using a scanning laser ophthalmoscope (SLO, Rodenstock Instr. argon laser 488 nm). Nerve fibre layer defects were analysed peripapillarily for every single degree (defect or no defect) at 1.7 mm (near) and at 3.4 mm (far) distance to the optic nerve head. Specificity and sensitivity of the HRT II were calculated using the Moorfields regression analysis (MRA). RESULTS: Patients with glaucoma were found to have 109 +/- 92 degrees (near) and 109 +/- 92 degrees (far) defects of the nerve fibre layer. Patients with OHT (8 +/- 14 degrees [far] and 6 +/- 11 degrees [near]) and control subjects (0 +/- 0 degrees [far] and 0 +/- 1 degrees [near]) showed significantly smaller defects (p < 0.0001). Sensitivity at > 90 % specificity for POAG and controls was 85.7 % (far) and 82.9 % (near). Sensitivity at > 90 % specifity for OHT and POAG was 85.7 % (far) und 82.9 % (near). Specificity of controls for the MRA was 83.3 % (borderline classified as normal). Specificity of OHT patients was 93.8 % (borderline classified normal). Sensitivity of the MRA for POAG was 80.9 % (borderline classified normal) and 90.5 % (borderline classified glaucoma). CONCLUSIONS: Nerve fiber layer imaging using a manually operated scanning laser ophthalmoscope was found to achieve a higher diagnostic precision as compared to optic disc evaluation using the HRT II. PMID- 25927175 TI - [Level of Binocular Pseudoaccommodation in Patients Implanted with an Apodised, Diffractive and Trifocal Multifocal Intraocular Lens]. AB - PURPOSE: The aim of this study was to make an evaluation of the pseudoaccommodation span and clinical results after implantation of a diffractive, apodised and trifocal multifocal intraocular lens (MIOL). METHODS: In a prospective, single-centre study 28 eyes of 14 patients were evaluated after in the bag implantation of the Micro-F MIOL (PhysIOL, Belgium) during routine microsurgical cataract surgery. Two to four months postoperatively the final examinations were performed. Refraction, visual acuity monocular and binocular (near in 40 cm, intermediate in 80 cm and distance) as well as binocular defocus curves were evaluated. RESULTS: Mean monocular UDVA (uncorrected distance visual acuity) increased significantly (p < 0.0001) from 0.471 +/- 0.22 logMAR to 0.144 +/- 0.14 logMAR. For the monocular UNVA (uncorrected near visual acuity) and UIVA (uncorrected intermediate visual acuity) postoperative values of 0.127 +/- 0.117 and 0.158 +/- 0.20 logMAR compared to binocular results of 0.057 +/- 0.137 and 0.094 +/- 0.181 logMAR were found. In the analysis of the binocular defocus curve two peaks could be found between 0.0 and - 0.5 D with a visual acuity of 0.0 logMAR and at - 3.0 D with a visual acuity of 0.068 logMAR. In the intermediate range a constant pseudoaccommodation of 0.2 logMAR could be found. CONCLUSIONS: The trifocal, diffractive MIOL shows good functional results in all distances with a span of pseudoaccommodation of 3D and a mean visual acuity of 0.2 logMAR and better. Indeed it is offering a high level of spectacle independency without the typical intermediate gap of bifocal diffractive MIOLs. PMID- 25927176 TI - [Surgeon's Impact on Graft Endothelial Cell Density and Corneal Thickness after Penetrating Keratoplasty for Keratoconus and Fuchs' Dystrophy]. AB - PURPOSE: The aim of this study was to examine the short- and long-term variability of graft endothelial cell density (ECD) and central corneal thickness (CCT) after penetrating keratoplasty (PKP) between different surgeons. PATIENTS AND METHODS: 370 eyes with keratoconus (KC) or Fuchs' dystrophy (FUCHS) after standardised primary excimer laser PKP (four experienced surgeons) were analysed. ECD and CCT were determined at 12 months after PKP before suture removal, and at two years after final suture removal. RESULTS: 12 months after PKP, ECD was significantly higher for surgeon 1 in FUCHS as compared to surgeons 3 (p = 0.05) and 4 (p = 0.04), in KC it was significantly higher for surgeon 1 as compared to surgeon 2 (p = 0.001) and for surgeon 1 as compared to surgeon 4 (p = 0.006). However, in FUCHS this difference was no longer significant two years after suture removal (p > 0.5), and in KK only in comparison of surgeons 1 and 2 (p = 0.04). RESULTS concerning CCT were inhomogeneous. CONCLUSIONS: The surgeon's individual handwriting seems to have an impact on the ECD in the short-term after PKP. However, differences between surgeons tend to become insignificant in the long run after suture removal. PMID- 25927177 TI - [Refraction after Implantation of Multifocal and Presbyopia-Correcting Intraocular Lenses]. AB - Nowadays, further developments in the field of intraocular lenses offer a higher level of spectacle independence for our patients. As light gets scattered on different focal points a wider range of defocus is created. This greater defocus area makes it more difficult for us to determine the objective or subjective refraction. This contribution is concerned with the difficulties of measuring visual acuity in different intraocular lens designs and different measurement distances. Measuring refraction after implantation of a multifocal intraocular lens is a complex procedure and the experience of the examiner plays a crucial role. Retinoscopy, keratometry and the defocus curve are reliable methods for testing, while the auto refractometer, bichromatic testing and the cross-cylinder have limitations. PMID- 25927178 TI - Nanoplasmonics: Concluding remarks. PMID- 25927179 TI - Requiem for the Night Shift: In Memory Of.... PMID- 25927180 TI - Model to Estimate Threshold Mechanical Stability of Lower Lateral Cartilage. AB - IMPORTANCE: In rhinoplasty, techniques used to alter the shape of the nasal tip often compromise the structural stability of the cartilage framework in the nose. Determining the minimum threshold level of cartilage stiffness required to maintain long-term structural stability is a critical aspect in performing these surgical maneuvers. OBJECTIVE: To quantify the minimum threshold mechanical stability (elastic modulus) of lower lateral cartilage (LLC) according to expert opinion. METHODS: Five anatomically correct LLC phantoms were made from urethane via a 3-dimensional computer modeling and injection molding process. All 5 had identical geometry but varied in stiffness along the intermediate crural region (0.63-30.6 MPa). DESIGN, SETTING, AND PARTICIPANTS: A focus group of experienced rhinoplasty surgeons (n = 33) was surveyed at a regional professional meeting on October 25, 2013. Each survey participant was presented the 5 phantoms in a random order and asked to arrange the phantoms in order of increasing stiffness based on their sense of touch. Then, they were asked to select a single phantom out of the set that they believed to have the minimum acceptable mechanical stability for LLC to maintain proper form and function. MAIN OUTCOMES AND MEASURES: A binary logistic regression was performed to calculate the probability of mechanical acceptability as a function of the elastic modulus of the LLC based on survey data. A Hosmer-Lemeshow test was performed to measure the goodness of fit between the logistic regression and survey data. The minimum threshold mechanical stability for LLC was taken at a 50% acceptability rating. RESULTS: Phantom 4 was selected most frequently by the participants as having the minimum acceptable stiffness for LLC intermediate care. The minimum threshold mechanical stability for LLC was determined to be 3.65 MPa. The Hosmer-Lemeshow test revealed good fit between the logistic regression and survey data (chi23 = 0.92, P = .82). CONCLUSIONS AND RELEVANCE: This study presents a novel method of modeling anatomical structures and quantifying the mechanical properties of nasal cartilage. Quantifying these parameters is an important step in guiding surgical maneuvers performed in rhinoplasty. LEVEL OF EVIDENCE: 5. PMID- 25927181 TI - Progesterone metabolites regulate induction, growth, and suppression of estrogen- and progesterone receptor-negative human breast cell tumors. AB - INTRODUCTION: Of the nearly 1.4 million new cases of breast cancer diagnosed each year, a large proportion is characterized as hormone receptor negative, lacking estrogen receptors (ER) and/or progesterone receptors (PR). Patients with receptor-negative tumors do not respond to current steroid hormone-based therapies and generally have significantly higher risk of recurrence and mortality compared with patients with tumors that are ER- and/or PR-positive. Previous in vitro studies had shown that the progesterone metabolites, 5alpha dihydroprogesterone (5alphaP) and 3alpha-dihydroprogesterone (3alphaHP), respectively, exhibit procancer and anticancer effects on receptor-negative human breast cell lines. Here in vivo studies were conducted to investigate the ability of 5alphaP and 3alphaHP to control initiation, growth, and regression of ER/PR negative human breast cell tumors. METHODS: ER/PR-negative human breast cells (MDA-MB-231) were implanted into mammary fat pads of immunosuppressed mice, and the effects of 5alphaP and 3alphaHP treatments on tumor initiation, growth, suppression/regression, and histopathology were assessed in five separate experiments. Specific radioimmunoassays and gas chromatography-mass spectrometry were used to measure 5alphaP, 3alphaHP, and progesterone in mouse serum and tumors. RESULTS: Onset and growth of ER/PR-negative human breast cell tumors were significantly stimulated by 5alphaP and inhibited by 3alphaHP. When both hormones were applied simultaneously, the stimulatory effects of 5alphaP were abrogated by the inhibitory effects of 3alphaHP and vice versa. Treatment with 3alphaHP subsequent to 5alphaP-induced tumor initiation resulted in suppression of further tumorigenesis and regression of existing tumors. The levels of 5alphaP in tumors, regardless of treatment, were about 10-fold higher than the levels of 3alphaHP, and the 5alphaP:3alphaHP ratios were about fivefold higher than in serum, indicating significant changes in endogenous synthesis of these hormones in tumorous breast tissues. CONCLUSIONS: The studies showed that estrogen/progesterone-insensitive breast tumors are sensitive to, and controlled by, the progesterone metabolites 5alphaP and 3alphaHP. Tumorigenesis of ER/PR negative breast cells is significantly enhanced by 5alphaP and suppressed by 3alphaHP, the outcome depending on the relative concentrations of these two hormones in the microenvironment in the breast regions. The findings show that the production of 5alphaP greatly exceeds that of 3alphaHP in ER/PR-negative tumors and that treatment with 3alphaHP can effectively block tumorigenesis and cause existing tumors to regress. The results provide the first hormonal theory to explain tumorigenesis of ER/PR-negative breast tissues and support the hypothesis that a high 3alphaHP-to-5alphaP concentration ratio in the microenvironment may foster normalcy in noncancerous breast regions. The findings suggest new diagnostics based on the relative levels of these hormones and new approaches to prevention and treatment of breast cancers based on regulating the levels and action mechanisms of anti- and pro-cancer progesterone metabolites. PMID- 25927182 TI - Antibiotic-resistance Staphylococcus aureus isolated from cow's milk in the Hawassa area, South Ethiopia. AB - BACKGROUND: Quarter milk samples from cows were examined to determine the prevalence of Staphylococcus aureus (SA) and different antibiotic resistant pattern were determined in a cross-sectional study design. OBJECTIVE: The objective of this study was to isolate Staphylococcus aureus from samples of cow's milk obtained from Hawassa area and to determine their antibiotic susceptibility patterns. METHOD: A total of 160 milk (CCP1-CCP5) samples were collected and screened for the presence of S. aureus. Gram staining, oxidase, catalase, DNase, haemolysis and coagulase tests were employed for bacterial identification. RESULTS: All the samples were contaminated with S. aureus. A total of 78 S. aureus isolates were obtained during this study. The levels of contamination with S. aureus were higher in milk obtained from CCP1, CCP2, CCP3, CCP4 and CCP5 at Hawassa area farms (18.0%, 25.6%, 27.0%, 21.8% and 7.7%) respectively. A large percentage of the S. aureus isolates (25.6% and 27.0%) were from CCP2 and CCP3. All strains were resistant to Penicillin G (PG) (10 MUg), Ampicillin (AP) (10 MUg), Amoxicillin-Clavulanic acid (AC) (30 MUg), Ciprofloxacin (CIP) (5 MUg), Erythromycin (E) (15 MUg), Ceftriaxone (CRO) (30 MUg), Trimethoprime-Sulfamethoxazole (TMP-SMZ) (25 MUg) Oxacillin (Ox) (1 MUg) and Vancomycin (V) (30 MUg), 67.9%, 70.9%, 30.9%, 0%, 32.1%, 23.1%, 7.7%, 60.3% and 38.5% respectively. CONCLUSION: The proportion of isolates resistant to CIP, TMP-SMZ, CRO, AC, E and V were low compared to AP, PG and Ox. S. aureus is normally resident in humans; therefore, the S. aureus present in the cow's milk may have resulted from transmission between the two species, emphasizing the need to improve sanitary conditions in the milking environment. PMID- 25927187 TI - Clinical and cost effectiveness of staff training in Positive Behaviour Support (PBS) for treating challenging behaviour in adults with intellectual disability: a cluster randomised controlled trial. AB - BACKGROUND: Many people with intellectual disability present with challenging behaviour which often has serious consequences such as the prescription of long term medication, in-patient admissions and disruption of normal daily activities. Small scale studies of Positive Behaviour Support (PBS) delivered by paid carers suggest that it reduces challenging behaviour and costs of care and improves quality of life. This study aims to investigate whether professionals training in the delivery of PBS as part of routine practice is clinically and cost effective compared to treatment as usual in community intellectual disability services. METHOD: The study is a multi-centre cluster randomised controlled trial involving community intellectual disability services in England and service users with mild to severe intellectual disability and challenging behaviour. The teams will be randomly allocated into one of two conditions, either training and support to deliver PBS or treatment as usual. We will carry out assessments of challenging behaviour, use of services, quality of life, mental health, and family and paid carer burden at six and 12 months. We will monitor treatment fidelity and we will interview a sample of paid and family carers, service users, staff and managers about what they think of the treatment and how best we can deliver it in routine care. The main outcome is reduction in challenging behaviour at one year after randomisation. We will also carry out a health economic evaluation to examine the costs and consequences of staff training in PBS. DISCUSSION: The study findings will have significant implications for the delivery of PBS in community based services with the potential for reducing inpatient admissions and out-of-area placements for adults with intellectual disability and challenging behaviour. TRIAL REGISTRATION: This trial is registered with Clinical Trials.gov (Ref NCT01680276 ). Clinical Trials Unit: PRIMENT https://www.ucl.ac.uk/priment/ . PMID- 25927192 TI - Usefulness scale for patient information material (USE) - development and psychometric properties. AB - BACKGROUND: One economical way to inform patients about their illness and medical procedures is to provide written health information material. So far, a generic and psychometrically sound scale to evaluate cognitive, emotional, and behavioral aspects of the subjectively experienced usefulness of patient information material from the patient's perspective is lacking. The aim of our study was to develop and psychometrically test such a scale. METHODS: The Usefulness Scale for Patient Information Material (USE) was developed using a multistep approach. Ultimately, three items for each subscale (cognitive, emotional, and behavioral) were selected under consideration of face validity, discrimination, difficulty, and item content. The final version of the USE was subjected to reliability analysis. Structural validity was tested using confirmatory factor analysis, and convergent and divergent validity were tested using correlation analysis. The criterion validity of the USE was tested in an experimental design. To this aim, patients were randomly allocated to one of two groups. One group received a full version of an information brochure on depression or chronic low back pain depending on the respective primary diagnosis. Patients in the second group received a reduced version with a lower design quality, smaller font size and less information. Patients were recruited in six hospitals in Germany. After reading the brochure, they were asked to fill in a questionnaire. RESULTS: Analyzable data were obtained from 120 questionnaires. The confirmatory factor analysis supported the structural validity of the scale. Reliability analysis of the total scale and its subscales showed Cronbach's alpha values between .84 and .94. Convergent and divergent validity were supported. Criterion validity was confirmed in the experimental condition. Significant differences between the groups receiving full and reduced information were found for the total score (p<.001) and its three subscales (cognitive p<.001, emotional p=.001, and behavioral p<.001), supporting criterion validity. CONCLUSIONS: We developed a generic scale to measure the subjective usefulness of written patient information material from a patient perspective. Our construct is defined in line with current theoretical models for the evaluation of written patient information material. The USE was shown to be a short, reliable and valid psychometric scale. PMID- 25927191 TI - Protocol of a randomized controlled trial of hearing protection interventions for farm operators. AB - BACKGROUND: Hearing loss and tinnitus are prevalent in America, and noise-induced hearing loss is a leading cause of hearing loss. Noise-induced hearing loss has negative impact on quality of life, physical and emotional functioning, social life, and employment. In addition, noise-induced hearing loss results in heavy social and economic burdens on families and communities from all ethnic and socioeconomic groups. Farmers are a group that is particularly high risk for noise-induced hearing loss, and is underserved by programs designed to limit that risk. They are among the most noise-exposed group of workers, and experience the second highest prevalence of noise-induced hearing loss among all occupational categories. In agriculture, 1.5 million workers (43.3%) report exposure to hazardous noise. Although use of hearing protection devices (HPDs) would protect them from noise-induced hearing loss, use among farmers is low. METHODS/DESIGN: The purpose of this project is to compare the effectiveness of several approaches to influencing hearing protector use. Approaches include: a) an interactive, predictors-based intervention delivered via the Internet; b) a static informational web site; and c) a mailed sampler of hearing protectors. The goals are to further develop an intervention to promote farmers' use of HPDs, and compare the effectiveness of the interventions delivered in various combinations. Participants will include 701 farmers. Sites will be affiliates of a major farmer organization. Data will be collected at baseline, 6, and 12 months. A random intercept mixed model will be used to explore the fixed effects of the three NIHL prevention interventions over time while adjusting for age and gender. This project will involve a partnership between the University of Michigan and a major farmer organization to accomplish project aims. DISCUSSION: Results of this study will be used to inform future research-to-practice studies to increase hearing protector use. Increased use of hearing protectors is expected to reduce rates of noise-induced hearing loss and other negative effects of high noise exposure, and improve quality of life in this high-risk and underserved group. TRIAL REGISTRATION: Clinicaltrials.gov NCT01454895 Registered 14 October, 2011. PMID- 25927193 TI - In memoriam: Herbert Benzer. PMID- 25927195 TI - Prevalence of Toxoplasma gondii in common moles (Talpa europaea). AB - BACKGROUND: The prevalence of Toxoplasma gondii in common moles, Talpa europaea, was investigated in order to determine whether moles can serve as an indicator species for T. gondii infections in livestock. FINDINGS: In total, 86 moles were caught from 25 different sites in the Netherlands. Five different trapping habitats were distinguished: pasture, garden, forest, roadside, and recreation area. No positive samples (brain cysts) were found during microscopic detection (n = 70). Using the Latex Agglutination Test (LAT), sera of 70 moles were examined, whereby no sample reacted with T. gondii antigen. Real Time-PCR tests on brain tissue showed 2 positive samples (2.3%). CONCLUSIONS: Because of the low number of positives in our study, the use of the common mole as an indicator species for livestock infections is currently not recommended. PMID- 25927183 TI - Rationale and study design for an individualized perioperative open lung ventilatory strategy (iPROVE): study protocol for a randomized controlled trial. AB - BACKGROUND: Postoperative pulmonary and non-pulmonary complications are common problems that increase morbidity and mortality in surgical patients, even though the incidence has decreased with the increased use of protective lung ventilation strategies. Previous trials have focused on standard strategies in the intraoperative or postoperative period, but without personalizing these strategies to suit the needs of each individual patient and without considering both these periods as a global perioperative lung-protective approach. The trial presented here aims at comparing postoperative complications when using an individualized ventilatory management strategy in the intraoperative and immediate postoperative periods with those when using a standard protective ventilation strategy in patients scheduled for major abdominal surgery. METHODS: This is a comparative, prospective, multicenter, randomized, and controlled, four arm trial that will include 1012 patients with an intermediate or high risk for postoperative pulmonary complications. The patients will be divided into four groups: (1) individualized perioperative group: intra- and postoperative individualized strategy; (2) intraoperative individualized strategy + postoperative continuous positive airway pressure (CPAP); (3) intraoperative standard ventilation + postoperative CPAP; (4) intra- and postoperative standard strategy (conventional strategy). The primary outcome is a composite analysis of postoperative complications. DISCUSSION: The Individualized Perioperative Open lung Ventilatory Strategy (iPROVE) is the first multicenter, randomized, and controlled trial to investigate whether an individualized perioperative approach prevents postoperative pulmonary complications. TRIAL REGISTRATION: Registered on 5 June 2014 with identification no. NCT02158923 . PMID- 25927199 TI - Optimally choosing PWM motif databases and sequence scanning approaches based on ChIP-seq data. AB - BACKGROUND: For many years now, binding preferences of Transcription Factors have been described by so called motifs, usually mathematically defined by position weight matrices or similar models, for the purpose of predicting potential binding sites. However, despite the availability of thousands of motif models in public and commercial databases, a researcher who wants to use them is left with many competing methods of identifying potential binding sites in a genome of interest and there is little published information regarding the optimality of different choices. Thanks to the availability of large number of different motif models as well as a number of experimental datasets describing actual binding of TFs in hundreds of TF-ChIP-seq pairs, we set out to perform a comprehensive analysis of this matter. RESULTS: We focus on the task of identifying potential transcription factor binding sites in the human genome. Firstly, we provide a comprehensive comparison of the coverage and quality of models available in different databases, showing that the public databases have comparable TFs coverage and better motif performance than commercial databases. Secondly, we compare different motif scanners showing that, regardless of the database used, the tools developed by the scientific community outperform the commercial tools. Thirdly, we calculate for each motif a detection threshold optimizing the accuracy of prediction. Finally, we provide an in-depth comparison of different methods of choosing thresholds for all motifs a priori. Surprisingly, we show that selecting a common false-positive rate gives results that are the least biased by the information content of the motif and therefore most uniformly accurate. CONCLUSION: We provide a guide for researchers working with transcription factor motifs. It is supplemented with detailed results of the analysis and the benchmark datasets at http://bioputer.mimuw.edu.pl/papers/motifs/ . PMID- 25927201 TI - Erratum to: Using text mining for study identification in systematic reviews: a systematic review of current approaches. PMID- 25927202 TI - Targeted Next Generation Sequencing reveals previously unidentified TSC1 and TSC2 mutations. AB - BACKGROUND: Tuberous sclerosis complex (TSC) is an autosomal dominant disorder caused by mutations in TSC1 and TSC2. Conventional DNA diagnostic screens identify a TSC1 or TSC2 mutation in 75 - 90% of individuals categorised with definite TSC. The remaining individuals either have a mutation that is undetectable using conventional methods, or possibly a mutation in another as yet unidentified gene. METHODS: Here we apply a targeted Next Generation Sequencing (NGS) approach to screen the complete TSC1 and TSC2 genomic loci in 7 individuals fulfilling the clinical diagnostic criteria for definite TSC in whom no TSC1 or TSC2 mutations were identified using conventional screening methods. RESULTS: We identified and confirmed pathogenic mutations in 3 individuals. In the remaining individuals we identified variants of uncertain clinical significance. The identified variants included mosaic changes, changes located deep in intronic sequences and changes affecting promoter regions that would not have been identified using exon-only based analyses. CONCLUSIONS: Targeted NGS of the TSC1 and TSC2 loci is a suitable method to increase the yield of mutations identified in the TSC patient population. PMID- 25927203 TI - Homozygous haplotype deficiency reveals deleterious mutations compromising reproductive and rearing success in cattle. AB - BACKGROUND: Cattle breeding populations are susceptible to the propagation of recessive diseases. Individual sires generate tens of thousands of progeny via artificial insemination. The frequency of deleterious alleles carried by such sires may increase considerably within few generations. Deleterious alleles manifest themselves often by missing homozygosity resulting from embryonic/fetal, perinatal or juvenile lethality of homozygotes. RESULTS: A scan for homozygous haplotype deficiency in 25,544 Fleckvieh cattle uncovered four haplotypes affecting reproductive and rearing success. Exploiting whole-genome resequencing data from 263 animals facilitated to pinpoint putatively causal mutations in two of these haplotypes. A mutation causing an evolutionarily unlikely substitution in SUGT1 was perfectly associated with a haplotype compromising insemination success. The mutation was not found in homozygous state in 10,363 animals (P=1.79*10(-5)) and is thus likely to cause lethality of homozygous embryos. A frameshift mutation in SLC2A2 encoding glucose transporter 2 (GLUT2) compromises calf survival. The mutation leads to premature termination of translation and activates cryptic splice sites resulting in multiple exon variants also with premature translation termination. The affected calves exhibit stunted growth, resembling the phenotypic appearance of Fanconi-Bickel syndrome in humans (OMIM 227810), which is also caused by mutations in SLC2A2. CONCLUSIONS: Exploiting comprehensive genotype and sequence data enabled us to reveal two deleterious alleles in SLC2A2 and SUGT1 that compromise pre- and postnatal survival in homozygous state. Our results provide the basis for genome-assisted approaches to avoiding inadvertent carrier matings and to improving reproductive and rearing success in Fleckvieh cattle. PMID- 25927207 TI - Transcending differences to study the transcendent: an exploratory study of researchers' and chaplains' reflections on interdisciplinary spiritual care research collaboration. AB - BACKGROUND: Despite recognition of the centrality of professional board-certified chaplains (BCC) in palliative care, the discipline has little research to guide its practices. To help address this limitation, HealthCare Chaplaincy Network funded six proposals in which BCCs worked collaboratively with established researchers. Recognizing the importance of interdisciplinary collaboration in the development of a new field, this paper reports on an exploratory study of project members' reflections over time on the benefits and challenges of conducting inter disciplinary spiritual care research. METHODS: Data collection occurred in two stages. Stage 1 entailed two independent, self-reflective focus groups, organized by professional discipline, mid-way through the site projects. Stage 2 entailed end-of-project site reports and a conference questionnaire. RESULTS: Eighteen professionals participated in the group discussions. Stage 1: researchers perceived chaplains as eager workers passionately committed to their patients and to research, and identified challenges faced by chaplains in learning to conduct research. Chaplains perceived researchers as passionate about their work, were concerned research might uncover negative findings for their profession, and sensed they used a dissimilar paradigm from their research colleagues regarding the 'ways of relating' to knowledge and understanding. Stage 2: researchers and chaplains noted important changes they ascribed to the interdisciplinary collaboration that were classified into six domains of cultural and philosophical understanding: respect; learning; discovery; creativity; fruitful partnerships; and learning needs. CONCLUSIONS: Chaplains and researchers initially expressed divergent perspectives on the research collaborations. During the projects' lifespans, these differences were acknowledged and addressed. Mutual appreciation for each discipline's strengths and contributions to inter-professional dialogue emerged. PMID- 25927209 TI - Detection of laurel wilt disease in avocado using low altitude aerial imaging. AB - Laurel wilt is a lethal disease of plants in the Lauraceae plant family, including avocado (Persea americana). This devastating disease has spread rapidly along the southeastern seaboard of the United States and has begun to affect commercial avocado production in Florida. The main objective of this study was to evaluate the potential to discriminate laurel wilt-affected avocado trees using aerial images taken with a modified camera during helicopter surveys at low altitude in the commercial avocado production area. The ability to distinguish laurel wilt-affected trees from other factors that produce similar external symptoms was also studied. RmodGB digital values of healthy trees and laurel wilt affected trees, as well as fruit stress and vines covering trees were used to calculate several vegetation indices (VIs), band ratios, and VI combinations. These indices were subjected to analysis of variance (ANOVA) and an M-statistic was performed in order to quantify the separability of those classes. Significant differences in spectral values among laurel wilt affected and healthy trees were observed in all vegetation indices calculated, although the best results were achieved with Excess Red (ExR), (Red-Green) and Combination 1 (COMB1) in all locations. B/G showed a very good potential for separate the other factors with symptoms similar to laurel wilt-affected trees, such as fruit stress and vines covering trees, from laurel wilt-affected trees. These consistent results prove the usefulness of using a modified camera (RmodGB) to discriminate laurel wilt affected avocado trees from healthy trees, as well as from other factors that cause the same symptoms and suggest performing the classification in further research. According to our results, ExR and B/G should be utilized to develop an algorithm or decision rules to classify aerial images, since they showed the highest capacity to discriminate laurel wilt-affected trees. This methodology may allow the rapid detection of laurel wilt-affected trees using low altitude aerial images and be a valuable tool in mitigating this important threat to Florida avocado production. PMID- 25927212 TI - Differential expression of transforming growth factor-beta in benign vs. papillary thyroid cancer nodules; a potential diagnostic tool? AB - BACKGROUND: Thyroid nodules are common, but only 5% of nodules are found to be malignant. In North America, the incidence of thyroid cancer is increasing. Fine needle aspirate (FNA) biopsy is the diagnostic test of choice. Unfortunately, up to 20% of FNAs are non-diagnostic. A specific molecular marker for thyroid cancer is desirable. Evidence suggests that cell signaling through transforming growth factor beta (TGF-beta) is important in the development of thyroid cancer. We sought to compare the expression of TGF-beta in malignant and benign thyroid nodules. METHODS: From 2008-present, thyroid nodule tissue from thyroidectomy specimens was prospectively collected and stored at -80 degrees C. RNA extraction and reverse transcription was performed on 47 samples (24 papillary thyroid cancer and 23 benign nodules). Quantitative PCR using SYBR green was performed to detect TGF-beta-1 and -2. Resulting CT values were normalized against beta-actin. Gene expression was calculated using the 2(-DeltaC)T method. RESULTS: A significantly greater expression of TGF-beta1 (p < 0.0001) was detected in the group of malignant thyroid nodules compared to benign nodules. There was no difference in the expression of TGF-beta2 (p = 0.4735) between the two groups. CONCLUSIONS: In this study, we demonstrated that expression of TGF-beta1 but not TGF-beta2 is significantly increased in papillary thyroid cancer compared to benign thyroid nodules. This may serve as a potential diagnostic marker for papillary thyroid cancer. PMID- 25927213 TI - Monoacylglycerol lipase inhibitor JZL184 reduces neuroinflammatory response in APdE9 mice and in adult mouse glial cells. AB - BACKGROUND: Recently, the role of monoacylglycerol lipase (MAGL) as the principal regulator of simultaneous prostaglandin synthesis and endocannabinoid receptor activation in the CNS was demonstrated. To expand upon previously published research in the field, we observed the effect of the MAGL inhibitor JZL184 during the early-stage proinflammatory response and formation of beta-amyloid (Abeta) in the Alzheimer's disease mouse model APdE9. We also investigated its effects in proinflammatory agent - induced astrocytes and microglia isolated from adult mice. FINDINGS: Transgenic APdE9 mice (5 months old) were treated with JZL184 (40 mg/kg) or vehicle every day for 1 month. In vivo binding of the neuroinflammation related, microglia-specific translocator protein (TSPO) targeting radioligand [(18) F]GE-180 decreased slightly but statistically non-significantly in multiple brain areas compared to vehicle-treated mice. JZL184 treatment induced a significant decrease in expression levels of inflammation-induced, Iba1 immunoreactive microglia in the hippocampus (P < 0.01) and temporal and parietal (P < 0.05) cortices. JZL184 also induced a marked decrease in total Abeta burden in the temporal (P < 0.001) and parietal (P < 0.01) cortices and, to some extent, in the hippocampus. Adult microglial and astrocyte cultures pre-treated with JZL184 and then exposed to the neuroinflammation-inducing agents lipopolysaccharide (LPS), interferon-gamma (IFN-gamma), and Abeta42 had significantly reduced proinflammatory responses compared to cells without JZL184 treatment. CONCLUSIONS: JZL184 decreased the proinflammatory reactions of microglia and reduced the total Abeta burden and its precursors in the APdE9 mouse model. It also reduced the proinflammatory responses of microglia and astrocytes isolated from adult mice. PMID- 25927214 TI - Histological antiphospholipid-associated nephropathy versus lupus nephritis in patients with systemic lupus erythematosus: an observational cross-sectional study with longitudinal follow-up. AB - INTRODUCTION: Renal involvement is a severe complication in systemic lupus erythematosus (SLE). Moreover, a subset of SLE patients develop the anti phospholipid syndrome (APS), characterised by the occurrence of anti-phospholipid antibodies in combination with macro- and microvascular thrombotic manifestations, including acute and chronic antiphospholipid-associated nephropathy (APLN). Clinical presentations of lupus nephritis and APLN are similar and a renal biopsy is necessary to differentiate between the conditions. Our aim with this study was to investigate the occurrence of histopathological findings consistent with APLN (hAPLN) in renal biopsies from SLE patients and to investigate associations with anti-phospholipid antibody specificities, clinical manifestations, HLA-DRB1 alleles, and long-term renal outcome. METHOD: Consecutive renal biopsies from 112 SLE patients with renal involvement were investigated and evaluated for findings of hAPLN; in all there were 236 renal biopsies. Data from biopsy reports and clinical information were collected. Autoantibodies against cardiolipin and beta2-glycoprotein-1 were measured by enzyme-linked immunosorbent assay. A lupus anticoagulant test was determined with a modified Dilute Russel Viper Venom method. HLA genotyping was performed by sequence-specific primer PCR. Renal outcome was determined at study end. RESULTS: The prevalence of hAPLN was 14.3% among SLE patients with renal involvement. Compared to patients with pure lupus nephritis, occurrence of hAPLN was associated with intima changes (odds ratio (OR) = 24; 95% confidence interval (CI), 3.0 to 189.8; P < 0.0001), hypertensive vascular changes (OR = 7.8; 95% CI, 1.6 to 39.4; P = 0.01), inflammatory infiltrates (OR = 6.5; 95% CI, 1.7 to 25.1; P = 0.007) and tubular atrophy (OR = 13.1; 95% CI, 1.7 to 103.6; P = 0.002). hAPLN was associated with the presence of cardiolipin antibodies (OR = 3.3; 95% CI, 1.0 to 10.8; P = 0.05) and triple anti-phospholipid antibody positivity (OR = 4.2; 95% CI, 1.3 to 13.7; P = 0.02). Patients with hAPLN were more hypertensive (OR = 3.8; 95% CI, 1.2 to 12.3; P = 0.03) and had higher levels of creatinine as compared to lupus nephritis patients (median 116 versus 75 MUmol/L; P < 0.0001). We found significantly higher frequency of HLA-DRB1*13 (OR = 5.1; 95% CI, 1.7 to 15.4; P = 0.03) and development of end-stage renal disease (OR = 5.8; 95% CI, 1.7 to 19.7; P = 0.008) in hAPLN compared with lupus nephritis. CONCLUSION: hAPLN is a severe and often unrecognized condition in SLE patients with renal involvement. We have demonstrated an increased risk for development of renal impairment and a genetic predisposition in hAPLN patients compared to lupus nephritis patients. PMID- 25927216 TI - Web-based tool for dynamic functional outcome after acute ischemic stroke and comparison with existing models. AB - BACKGROUND: Acute ischemic stroke (AIS) is one of the leading causes of death and adult disability worldwide. In the present study, we aimed to develop a web-based risk model for predicting dynamic functional status at discharge, 3-month, 6 month, and 1-year after acute ischemic stroke (Dynamic Functional Status after Acute Ischemic Stroke, DFS-AIS). METHODS: The DFS-AIS was developed based on the China National Stroke Registry (CNSR), in which eligible patients were randomly divided into derivation (60%) and validation (40%) cohorts. Good functional outcome was defined as modified Rankin Scale (mRS) score <= 2 at discharge, 3 month, 6-month, and 1-year after AIS, respectively. Independent predictors of each outcome measure were obtained using multivariable logistic regression. The area under the receiver operating characteristic curve (AUROC) and plot of observed and predicted risk were used to assess model discrimination and calibration. RESULTS: A total of 12,026 patients were included and the median age was 67 (interquartile range: 57-75). The proportion of patients with good functional outcome at discharge, 3-month, 6-month, and 1-year after AIS was 67.9%, 66.5%, 66.9% and 66.9%, respectively. Age, gender, medical history of diabetes mellitus, stroke or transient ischemic attack, current smoking and atrial fibrillation, pre-stroke dependence, pre-stroke statins using, admission National Institutes of Health Stroke Scale score, admission blood glucose were identified as independent predictors of functional outcome at different time points after AIS. The DFS-AIS was developed from sets of predictors of mRS <= 2 at different time points following AIS. The DFS-AIS demonstrated good discrimination in the derivation and validation cohorts (AUROC range: 0.837 0.845). Plots of observed versus predicted likelihood showed excellent calibration in the derivation and validation cohorts (all r = 0.99, P < 0.001). When compared to 8 existing models, the DFS-AIS showed significantly better discrimination for good functional outcome and mortality at discharge, 3-month, 6 month, and 1-year after AIS (all P < 0.0001). CONCLUSION: The DFS-AIS is a valid risk model to predict functional outcome at discharge, 3-month, 6-month, and 1 year after AIS. PMID- 25927219 TI - Genomic prediction based on data from three layer lines: a comparison between linear methods. AB - BACKGROUND: The prediction accuracy of several linear genomic prediction models, which have previously been used for within-line genomic prediction, was evaluated for multi-line genomic prediction. METHODS: Compared to a conventional BLUP (best linear unbiased prediction) model using pedigree data, we evaluated the following genomic prediction models: genome-enabled BLUP (GBLUP), ridge regression BLUP (RRBLUP), principal component analysis followed by ridge regression (RRPCA), BayesC and Bayesian stochastic search variable selection. Prediction accuracy was measured as the correlation between predicted breeding values and observed phenotypes divided by the square root of the heritability. The data used concerned laying hens with phenotypes for number of eggs in the first production period and known genotypes. The hens were from two closely-related brown layer lines (B1 and B2), and a third distantly-related white layer line (W1). Lines had 1004 to 1023 training animals and 238 to 240 validation animals. Training datasets consisted of animals of either single lines, or a combination of two or all three lines, and had 30 508 to 45 974 segregating single nucleotide polymorphisms. RESULTS: Genomic prediction models yielded 0.13 to 0.16 higher accuracies than pedigree-based BLUP. When excluding the line itself from the training dataset, genomic predictions were generally inaccurate. Use of multiple lines marginally improved prediction accuracy for B2 but did not affect or slightly decreased prediction accuracy for B1 and W1. Differences between models were generally small except for RRPCA which gave considerably higher accuracies for B2. Correlations between genomic predictions from different methods were higher than 0.96 for W1 and higher than 0.88 for B1 and B2. The greater differences between methods for B1 and B2 were probably due to the lower accuracy of predictions for B1 (~0.45) and B2 (~0.40) compared to W1 (~0.76). CONCLUSIONS: Multi-line genomic prediction did not affect or slightly improved prediction accuracy for closely-related lines. For distantly-related lines, multi-line genomic prediction yielded similar or slightly lower accuracies than single-line genomic prediction. Bayesian variable selection and GBLUP generally gave similar accuracies. Overall, RRPCA yielded the greatest accuracies for two lines, suggesting that using PCA helps to alleviate the "n ? p" problem in genomic prediction. PMID- 25927222 TI - Veno-venous extracorporeal CO2 removal for the treatment of severe respiratory acidosis. PMID- 25927221 TI - Stepwise tapering of remifentanil at the end of surgery decreased postoperative pain and the need of rescue analgesics after thyroidectomy. AB - BACKGROUND: This study was designed to investigate whether stepwise tapering of remifentanil at the end of surgery could decrease postoperative pain scores and requirements of rescue analgesics after remifentanil-desflurane anesthesia in patients with thyroidectomy. METHODS: Sixty two patients undergoing thyroidectomy under general anesthesia were randomly allocated into two groups. All patients were anesthetised with desflurane and high-dose remifentanil. Remifentnail was infused at the rate of 0.3 MUg/kg/min until the end of surgery in patients of the control group (group A) whereas remifentanil was tapered gradually from 0.3 to 0.1 MUg/kg/min until the end of surgery for at least 30 minutes in patients with group B. Pain scores (0-100 numerical rating scale, NRS), rescue analgesic requirements and adverse events were assessed at 30 min, 2 h, 6 h, 12 h, and 24 h after operation. RESULTS: There was a significant decrease in pain scores at 30 min (20 [0-80] vs. 50 [0-100], P = 0.002) and 2 h (30 [10-60] vs. 40 [20-80], P = 0.018) after surgery in group B compared with group A. In addition, rescue analgesics are less required in group B than in group A postoperatively (2 [1-3] vs. 3 [2,3], P = 0.039). There were no significant differences in adverse events between the two groups. CONCLUSIONS: Tapering of remifentanil at the end of surgery decreased postoperative pain scores immediately after thyroidectomy with desflurane and high-dose remifentanil anesthesia. TRIAL REGISTRATION: Clinical Research information Service (CRiS, registration number KCT0000589). PMID- 25927223 TI - Lung particle overload: old school -new insights? PMID- 25927225 TI - Comparing new treatments for idiopathic pulmonary fibrosis--a network meta analysis. AB - BACKGROUND: The treatment landscape for idiopathic pulmonary fibrosis, a devastating lung disease, is changing. To investigate the effectiveness of treatments for idiopathic pulmonary fibrosis we undertook a systematic review, network meta-analysis and indirect comparison. METHODS: We searched MEDLINE, EMBASE and The Cochrane library for relevant studies. Randomised controlled trials of pirfenidone, nintedanib or N-acetylcysteine were eligible. Predefined processes for selecting references, extracting data and assessing study quality were applied. Our network meta-analysis of published data used a fixed effect model. For forced vital capacity measures a standardised mean difference approach was used and converted to odds ratios for interpretation. RESULTS: Of 1076 references, 67 were retrieved and 11 studies included. Studies were of reasonable size, populations were similar, and the overall quality was good. Only two treatments, pirfenidone (odds ratio 0.62, 95% credible interval 0.52, 0.74) and nintedanib (0.41, 95% credible interval 0.34, 0.51) produced a statistically significant slowing in the rate of forced vital capacity decline compared with placebo. In an indirect comparison, results indicate that nintedanib is statistically significantly better than pirfenidone in slowing forced vital capacity decline (odds ratio 0.67, 95% credible interval 0.51, 0.88). Results were stable in scenario analysis and random effects models. Indirect comparisons of mortality were not statistically significant between nintedanib and pirfenidone. CONCLUSIONS: Two treatments show beneficial effects and when compared indirectly nintedanib appears to have superior benefit on forced vital capacity. Limitations to indirect comparisons should be considered when interpreting these results, however, our findings can be useful to inform treatment decisions. PMID- 25927226 TI - Facilitating health and wellbeing is "everybody's role": youth perspectives from Vanuatu on health and the post-2015 sustainable development goal agenda. AB - BACKGROUND: Progress towards achievement of the Millennium Development Goals (MDGs) amongst Pacific island countries (PICs) has seen mixed results. As focus shifts to formulation of new health-related development goals beyond 2015, there is a need for bringing community consultation into this process. For this purpose, Go4Health is a global consortium examining the development of these goals, with Work Package 2 capturing viewpoints of marginalised populations regarding health. This paper examines the perspectives of youth in Vanuatu on essential health needs in the context of the post-2015 development agenda, to make these concerns more visible for their communities, stakeholders and health policy decision makers. METHODS: As part of a larger investigation undertaken in Vanuatu involving 100 residents from various rural and urban communities, this paper explores the perspectives of twenty 17-year old secondary school students gathered through two focus group discussions during September 2013. Questions sought viewpoints across areas including health ideals, essential needs, responsibility for health services and their governance. Focus group discussions were conducted in English and digitally recorded, with resulting transcripts subjected to thematic analysis. RESULTS: This youth cohort from Vanuatu had a strong understanding of the social determinants of health. They placed value on all aspects of health, indicating the need for youth to have access to positive lifestyle opportunities (sport, community participation) and also increased protection from the impact of harmful substances and causes of chronic illness. Participants identified barriers to health due to unevenly distributed health services throughout Vanuatu, with members at all levels of society ultimately perceived as responsible for improving health throughout the nation. CONCLUSION: Against a background of a weak health system and significant challenges to public health, young people are acutely aware that improving Vanuatu's health status requires a communal effort. While contributing factors to health depend on actions taken at individual, local, national and global levels, no single actor currently provides enough support to cover all essential health needs. As a consequence, they see health in the Pacific as "everybody's role", of importance for the post-2015 sustainable development goal agenda and health policy makers in general. PMID- 25927227 TI - Safety assessment of chronic oral exposure to iron oxide nanoparticles. AB - Iron oxide nanoparticles with engineered physical and biochemical properties are finding a rapidly increasing number of biomedical applications. However, a wide variety of safety concerns, especially those related to oral exposure, still need to be addressed for iron oxide nanoparticles in order to reach clinical practice. Here, we report on the effects of chronic oral exposure to low doses of gamma Fe2O3 nanoparticles in growing chickens. Animal observation, weight, and diet intake reveal no adverse signs, symptoms, or mortality. No nanoparticle accumulation was observed in liver, spleen, and duodenum, with feces as the main excretion route. Liver iron level and duodenal villi morphology reflect the bioavailability of the iron released from the partial transformation of gamma Fe2O3 nanoparticles in the acid gastric environment. Duodenal gene expression studies related to the absorption of iron from gamma-Fe2O3 nanoparticles indicate the enhancement of a ferric over ferrous pathway supporting the role of mucins. Our findings reveal that oral administration of iron oxide nanoparticles is a safe route for drug delivery at low nanoparticle doses. PMID- 25927224 TI - Risk of first cervical HPV infection and pre-cancerous lesions after onset of sexual activity: analysis of women in the control arm of the randomized, controlled PATRICIA trial. AB - BACKGROUND: More information is needed about time between sexual initiation and human papillomavirus (HPV) infection and development of cervical precancer. METHODS: The objectives were to investigate the time between first sexual activity and detection of first cervical HPV infection or development of first cervical intraepithelial neoplasia (CIN), and associated factors in women from the double-blind, multinational, 4-year PATRICIA trial. PATRICIA enroled women aged 15-25 years with no more than 6 lifetime sexual partners. Women were randomized 1:1 to the HPV-16/18 AS04-adjuvanted vaccine or to control, but only women from the control arm who began sexual intercourse during the study or within 6 months before enrolment, and had no HPV infection detected before the recorded date of their first sexual intercourse, were included in the present analysis. The time between onset of sexual activity and detection of the first cervical HPV infection or development of the first CIN lesion was analyzed using Kaplan-Meier and univariate and multivariable Cox proportional-hazards models. RESULTS: A total of 9337 women were enroled in the control arm of PATRICIA of whom 982 fulfilled the required inclusion criteria for analysis. A cumulative total of 28%, 44%, and 62% of the subjects had HPV infection within 12, 24, and 48 months, respectively. The overall incidence rate was 27.08 per 100 person years. The most common oncogenic types associated with 6-month persistent infection were HPV-16 (incidence rate: 2.74 per 100 person-years), HPV-51 (2.70), HPV-52 (1.66), HPV-66 (1.14), and HPV-18 (1.09). Increased infection risk was associated with more lifetime sexual partners, being single, Chlamydia trachomatis history, and duration of hormone use. CIN1+ and CIN2+ lesions were most commonly associated with HPV-16, with an overall incidence rate of 1.87 and 1.07 per 100 person-years, respectively. Previous cervical HPV infection was most strongly associated with CIN development. CONCLUSIONS: More than 25% of women were infected with HPV within 1 year of beginning sexual activity. Without underestimating the value of vaccination at older ages, our findings emphasize its importance before sexual initiation. TRIAL REGISTRATION: clinicaltrials.gov: NCT00122681 . PMID- 25927228 TI - Temperament type specific metabolite profiles of the prefrontal cortex and serum in cattle. AB - In the past decade the number of studies investigating temperament in farm animals has increased greatly because temperament has been shown not only to affect handling but also reproduction, health and economically important production traits. However, molecular pathways underlying temperament and molecular pathways linking temperament to production traits, health and reproduction have yet to be studied in full detail. Here we report the results of metabolite profiling of the prefrontal cortex and serum of cattle with distinct temperament types that were performed to further explore their molecular divergence in the response to the slaughter procedure and to identify new targets for further research of cattle temperament. By performing an untargeted comprehensive metabolite profiling, 627 and 1097 metabolite features comprising 235 and 328 metabolites could be detected in the prefrontal cortex and serum, respectively. In total, 54 prefrontal cortex and 51 serum metabolite features were indicated to have a high relevance in the classification of temperament types by a sparse partial least square discriminant analysis. A clear discrimination between fearful/neophobic-alert, interested-stressed, subdued/uninterested-calm and outgoing/neophilic-alert temperament types could be observed based on the abundance of the identified relevant prefrontal cortex and serum metabolites. Metabolites with high relevance in the classification of temperament types revealed that the main differences between temperament types in the response to the slaughter procedure were related to the abundance of glycerophospholipids, fatty acyls and sterol lipids. Differences in the abundance of metabolites related to C21 steroid metabolism and oxidative stress indicated that the differences in the metabolite profiles of the four extreme temperament types could be the result of a temperament type specific regulation of molecular pathways that are known to be involved in the stress and fear response. PMID- 25927229 TI - Activation and enhancement of Fredericamycin A production in deepsea-derived Streptomyces somaliensis SCSIO ZH66 by using ribosome engineering and response surface methodology. AB - BACKGROUND: Marine microorganisms are an important source of new drug leads. However, the discovery and sustainable production of these compounds are often hampered due to the unavailable expression of cryptic biosynthetic gene clusters or limited titer. Ribosome engineering and response surface methodology (RSM) integrated strategy was developed in this study to activate cryptic gene cluster in the deepsea-derived Streptomyces somaliensis SCSIO ZH66, and subsequently isolation, structural analysis, and the yield enhancement of the activated compound, anticancer drug lead Fredericamycin A (FDM A), were performed. RESULTS: In order to discover novel natural products from marine Streptomyces strains by genome mining strategy, the deepsea-derived S. somaliensis SCSIO ZH66 was subject to ribosome engineering to activate the expression of cryptic gene clusters. A resistant strain ZH66-RIF1 was thereby obtained with 300 MUg/mL rifampicin, which accumulated a brown pigment with cytotoxicity on MS plate while absent in the wild type strain. After screening of fermentation conditions, the compound with pigment was purified and identified to be FDM A, indicating that the activation of a cryptic FDM A biosynthetic gene cluster was taken place in strain ZH66-RIF1, and then it was identified to be ascribed to the mutation of R444H in the beta subunit of RNA polymerase. To further improve the yield efficiently, nine fermentation medium components were examined for their significance on FDM A production by Plackett-Burman design and Box-Behnken design. The optimum medium composition was achieved by RSM strategy, under which the titer of FDM A reached 679.5 +/- 15.8 mg/L after 7 days of fermentation, representing a 3-fold increase compared to the original medium. In terms of short fermentation time and low-cost fermentation medium, strain ZH66-RIF1 would be an ideal alternative source for FDM A production. CONCLUSIONS: Our results would hasten the efforts for further development of FDM A as a drug candidate. Moreover, this ribosome engineering and RSM integrated methodology is effective, fast and efficient; it would be applicable to genome mining for novel natural products from other strains. PMID- 25927230 TI - Characterization of Hydrogen Metabolism in the Multicellular Green Alga Volvox carteri. AB - Hydrogen gas functions as a key component in the metabolism of a wide variety of microorganisms, often acting as either a fermentative end-product or an energy source. The number of organisms reported to utilize hydrogen continues to grow, contributing to and expanding our knowledge of biological hydrogen processes. Here we demonstrate that Volvox carteri f. nagariensis, a multicellular green alga with differentiated cells, evolves H2 both when supplied with an abiotic electron donor and under physiological conditions. The genome of Volvox carteri contains two genes encoding putative [FeFe]-hydrogenases (HYDA1 and HYDA2), and the transcripts for these genes accumulate under anaerobic conditions. The HYDA1 and HYDA2 gene products were cloned, expressed, and purified, and both are functional [FeFe]-hydrogenases. Additionally, within the genome the HYDA1 and HYDA2 genes cluster with two putative genes which encode hydrogenase maturation proteins. This gene cluster resembles operon-like structures found within bacterial genomes and may provide further insight into evolutionary relationships between bacterial and algal [FeFe]-hydrogenase genes. PMID- 25927232 TI - Role of Hypoxia Inducible Factor-1alpha (HIF-1alpha) in Innate Defense against Uropathogenic Escherichia coli Infection. AB - Uropathogenic E. coli (UPEC) is the primary cause of urinary tract infections (UTI) affecting approximately 150 million people worldwide. Here, we revealed the importance of transcriptional regulator hypoxia-inducible factor-1 alpha subunit (HIF-1alpha) in innate defense against UPEC-mediated UTI. The effects of AKB 4924, a HIF-1alpha stabilizing agent, were studied using human uroepithelial cells (5637) and a murine UTI model. UPEC adherence and invasion were significantly reduced in 5637 cells when HIF-1alpha protein was allowed to accumulate. Uroepithelial cells treated with AKB-4924 also experienced reduced cell death and exfoliation upon UPEC challenge. In vivo, fewer UPEC were recovered from the urine, bladders and kidneys of mice treated transurethrally with AKB-4924, whereas increased bacteria were recovered from bladders of mice with a HIF-1alpha deletion. Bladders and kidneys of AKB-4924 treated mice developed less inflammation as evidenced by decreased pro-inflammatory cytokine release and neutrophil activity. AKB-4924 impairs infection in uroepithelial cells and bladders, and could be correlated with enhanced production of nitric oxide and antimicrobial peptides cathelicidin and beta-defensin-2. We conclude that HIF-1alpha transcriptional regulation plays a key role in defense of the urinary tract against UPEC infection, and that pharmacological HIF-1alpha boosting could be explored further as an adjunctive therapy strategy for serious or recurrent UTI. PMID- 25927233 TI - Extremely sparse olfactory inputs are sufficient to mediate innate aversion in Drosophila. AB - Innate attraction and aversion to odorants are observed throughout the animal kingdom, but how olfactory circuits encode such valences is not well understood, despite extensive anatomical and functional knowledge. In Drosophila melanogaster, ~50 types of olfactory receptor neurons (ORNs) each express a unique receptor gene, and relay information to a cognate type of projection neurons (PNs). To examine the extent to which the population activity of ORNs is required for olfactory behavior, we developed a genetic strategy to block all ORN outputs, and then to restore output in specific types. Unlike attraction, aversion was unaffected by simultaneous silencing of many ORNs, and even single ORN types previously shown to convey neutral valence sufficed to mediate aversion. Thus, aversion may rely on specific activity patterns in individual ORNs rather than the number or identity of activated ORNs. ORN activity is relayed into the brain by downstream circuits, with excitatory PNs (ePN) representing a major output. We found that silencing the majority of ePNs did not affect aversion, even when ePNs directly downstream of single restored ORN types were silenced. Our data demonstrate the robustness of olfactory aversion, and suggest that its circuit mechanism is qualitatively different from attraction. PMID- 25927235 TI - Spillover effects of a community-managed marine reserve. AB - The value of no-take marine reserves as fisheries-management tools is controversial, particularly in high-poverty areas where human populations depend heavily on fish as a source of protein. Spillover, the net export of adult fish, is one mechanism by which no-take marine reserves may have a positive influence on adjacent fisheries. Spillover can contribute to poverty alleviation, although its effect is modulated by the number of fishermen and fishing intensity. In this study, we quantify the effects of a community-managed marine reserve in a high poverty area of Northern Mozambique. For this purpose, underwater visual censuses of reef fish were undertaken at three different times: 3 years before (2003), at the time of establishment (2006) and 6 years after the marine reserve establishment (2012). The survey locations were chosen inside, outside and on the border of the marine reserve. Benthic cover composition was quantified at the same sites in 2006 and 2012. After the reserve establishment, fish sizes were also estimated. Regression tree models show that the distance from the border and the time after reserve establishment were the variables with the strongest effect on fish abundance. The extent and direction of the spillover depends on trophic group and fish size. Poisson Generalized Linear Models show that, prior to the reserve establishment, the survey sites did not differ but, after 6 years, the abundance of all fish inside the reserve has increased and caused spillover of herbivorous fish. Spillover was detected 1 km beyond the limit of the reserve for small herbivorous fishes. Six years after the establishment of a community managed reserve, the fish assemblages have changed dramatically inside the reserve, and spillover is benefitting fish assemblages outside the reserve. PMID- 25927237 TI - Effects of age and acute ethanol on glutamatergic neurotransmission in the medial prefrontal cortex of freely moving rats using enzyme-based microelectrode amperometry. AB - Ethanol abuse during adolescence may significantly alter development of the prefrontal cortex which continues to undergo structural remodeling into adulthood. Glutamatergic neurotransmission plays an important role during these brain maturation processes and is modulated by ethanol. In this study, we investigated glutamate dynamics in the medial prefrontal cortex of freely moving rats, using enzyme-based microelectrode amperometry. We analyzed the effects of an intraperitoneal ethanol injection (1 g/kg) on cortical glutamate levels in adolescent and adult rats. Notably, basal glutamate levels decreased with age and these levels were found to be significantly different between postnatal day (PND) 28-38 vs PND 44-55 (p<0.05) and PND 28-38 vs adult animals (p<0.001). We also observed spontaneous glutamate release (transients) throughout the recordings. The frequency of transients (per hour) was significantly higher in adolescent rats (PND 28-38 and PND 44-55) compared to those of adults. In adolescent rats, post-ethanol injection, the frequency of glutamate transients decreased within the first hour (p<0.05), it recovered slowly and in the third hour there was a significant rebound increase of the frequency (p<0.05). Our data demonstrate age dependent differences in extracellular glutamate levels in the medial prefrontal cortex and suggest that acute ethanol injections have both inhibitory and excitatory effects in adolescent rats. These effects of ethanol on the prefrontal cortex may disturb its maturation and possibly limiting individuals' control over addictive behaviors. PMID- 25927238 TI - 5Z-7-Oxozeanol Inhibits the Effects of TGFbeta1 on Human Gingival Fibroblasts. AB - Transforming growth factor (TGF)beta acts on fibroblasts to promote the production and remodeling of extracellular matrix (ECM). In adult humans, excessive action of TGFbeta is associated with fibrotic disease and fibroproliferative conditions, including gingival hyperplasia. Understanding how the TGFbeta1 signals in fibroblasts is therefore likely to result in valuable insights into the fundamental mechanisms underlying fibroproliferative disorders. Previously, we used the TAK1 inhibitor (5Z)-7-Oxozeaenol to show that, in dermal fibroblasts, the non-canonical TAK1 pathway mediates the ability of TGFbeta1 to induce genes promoting tissue remodeling and repair. However, the extent to which TAK1 mediates fibroproliferative responses in fibroblasts in response to TGFbeta1 remains unclear. Herein, we show that, in gingival fibroblasts, (5Z)-7-Oxozeaenol blocks the ability of TGFbeta1 to induce expression of the pro-fibrotic mediator CCN2 (connective tissue growth factor, CTGF) and type I collagen protein. Moreover, genome-wide expression profiling revealed that, in gingival fibroblasts, (5Z)-7-Oxozeaenol reduces the ability of TGFbeta1 to induce mRNA expression of essentially all TGFbeta1-responsive genes (139/147), including those involved with a hyperproliferative response. Results from microarray analysis were confirmed using real time polymerase chain reaction analysis and a functional cell proliferation assay. Our results are consistent with the hypothesis that TAK1 inhibitors might be useful in treating fibroproliferative disorders, including that in the oral cavity. PMID- 25927239 TI - [Day-clinic and Inpatient Psychotherapy of Depression (DIP-D)--Secondary Outcomes and Follow-up Results of a Randomized-Controlled Pilot Trial]. AB - Depressions are frequent disorders in psychosomatic medicine and psychotherapy. However, there are only few controlled studies comparing different levels of care for depressed patients. Especially the efficacy of day-clinic psychotherapy for depression remains understudied. The pilot study aims to close this gap by examining the feasibility of a randomized-controlled trial comparing day-clinic and inpatient psychotherapy for depression in a routine hospital setting. The current paper adds the secondary outcome measures on patient self-reported symptoms and interpersonal problems. In addition, findings of a 6-month follow-up are analyzed. Overall, 44 patients were recruited and randomly allocated to either day clinic or inpatient psychotherapy for 8 weeks. Depressive symptoms and interpersonal problems decreased during treatment, and follow-up scores stayed below intake scores. There were no differences between the treatment groups in this pilot study. For the future, it is desirable to compare randomized patients with those patients who received their preferred treatment option. Although the findings need to be replicated in larger samples, they appear promising for day clinic psychotherapy. The better understanding of differential effectiveness of different levels of care of patient subgroups remains an important goal. PMID- 25927241 TI - Safeguarding genome stability: RASSF1A tumor suppressor regulates BRCA2 at stalled forks. AB - While it has been widely established that defective fork restart after exposure to stress results in increased genomic instability, the importance of fork protection during stalling for safeguarding genomic integrity has recently been fully appreciated. BRCA2, Breast tumor suppressor, has dual functionality promoting not only DNA repair but also preventing DNA lesions at stalled forks. In response to replication stress, BRCA2 recruits RAD51 onto nascent DNA at stalled forks, protecting nascent DNA from nucleolitic cleavage. Phosphorylation of the BRCA2 C-terminal RAD51 binding site by CDK2 promotes RAD51 filament disassembly, leading to nucleolitic cleavage of newly synthesized DNA and compromised fork integrity. Recently we uncovered how the core Hippo pathway components RASSF1A, MST2 and LATS1 regulate CDK2 activity towards BRCA2, in response to fork stalling. In complex with LATS1, CDK2 exhibits reduced kinase activity which results in low levels of pBRCA2-S3291 and stable RAD51 filaments protecting nascent DNA from MRE11 cleavage. In the absence of the RASSF1A/MST2/LATS1/CDK2 pathway increased resection of newly synthesized DNA leads to chromosomal instability and malignant transformation. This function of RASSF1A in stalled replication fork protection adds to the role of RASSF1A as a tumor suppressor and builds up evidence for RASSF1A status and its prognostic and predictive value in cancer. PMID- 25927242 TI - 46,XY Gonadal Dysgenesis due to a Homozygous Mutation in Desert Hedgehog (DHH) Identified by Exome Sequencing. AB - BACKGROUND: 46,XY disorders of sex development (DSD) comprise a heterogeneous group of congenital conditions. Mutations in a variety of genes can affect gonadal development or androgen biosynthesis/action and thereby influence the development of the internal and external genital organs. OBJECTIVE: The objective of the study was to identify the genetic cause in two 46,XY sisters of a consanguineous family with DSD and gonadal tumor formation. METHODS: We used a next-generation sequencing approach by exome sequencing. Electrophysiological and high-resolution ultrasound examination of peripheral nerves as well as histopathological examination of the gonads were performed. RESULTS: We identified a novel homozygous R124Q mutation in the desert hedgehog gene (DHH), which alters a conserved residue among the three mammalian Hedgehog ligands sonic hedgehog, Indian hedgehog, and desert hedgehog. No other relevant mutations in DSD-related genes were encountered. The gonads of one patient showed partial gonadal dysgenesis with loss of Leydig cells in tubular areas with seminoma in situ and a hyperplasia of Leydig cell-like cells expressing CYP17A1 in more dysgenetic parts of the gonad. In addition, both patients suffer from a polyneuropathy. High-resolution ultrasound revealed a structural change of peripheral nerve structure that fits well to a minifascicle formation of peripheral nerves. CONCLUSION: Mutations in DHH play a role in 46,XY gonadal dysgenesis and are associated with seminoma formation and a neuropathy with minifascicle formation. Gonadal dysgenesis in these cases may be due to impairment of Sertoli cell-Leydig cell interaction during gonadal development. PMID- 25927243 TI - Outcomes of Patients Initially Treated with Intravitreal Bevacizumab for Central Retinal Vein Occlusion: Long-Term Follow-Up. AB - BACKGROUND AND OBJECTIVE: To assess outcomes of visual acuity (VA) and central retinal thickness (RT) in patients with macular edema (ME) secondary to central retinal vein occlusion (CRVO) who were initially treated with bevacizumab and followed for up to four years. STUDY DESIGN/MATERIALS AND METHODS: In this observational case series, 51 patients with non-ischemic and ischemic CRVO who had initial treatment with bevacizumab were included. Main outcome measures were VA and RT at one year, with follow-up of up to four years. RESULTS: Mean VA improved from 20/214 at baseline to 20/107 at one year (p = 0.0009) and this improvement was maintained clinically at four years. RT decreased from 595 MUm to 339 MUm at one year (p = 0.0027) and this was maintained at four years. CONCLUSION: Patients who received bevacizumab as initial therapy for ME from CRVO maintained VA and RT improvement for up to four years. PMID- 25927244 TI - Molecular pathology of myelodysplastic syndromes: new developments and implications for diagnosis and treatment. AB - The diagnosis of myelodysplastic syndromes (MDS) has been based on clinical presentations, laboratory and morphological findings, and molecular and cytogenetic profiles. With the advent of single nucleotide polymorphism (SNP) microarrays and high throughput sequencing technologies, a tremendous amount of progress has been made toward better understanding of MDS genetic and molecular changes. Recurring genetic abnormalities have been revealed in up to 80-90% of MDS patients. We herein review clinical and pathological basis of MDS, the most up-to-date advances in molecular diagnostics of MDS, including current understanding of cytogenetic and molecular markers of MDS, and their implications for MDS diagnosis and therapy selection. PMID- 25927245 TI - A new NPM1 gene mutation. PMID- 25927246 TI - Features of cell death, mitochondrial activation and caspase dependence of rabbit anti-T-lymphocyte globulin signaling in lymphoblastic Jurkat cells are distinct from classical apoptosis signaling of CD95. AB - Rabbit anti-T-lymphocyte-globulin (ATG) is used for immunosuppression in organ and stem cell transplantation. The aim of this study was to investigate ATG induced cell death compared to CD95-signaling of apoptosis. We measured features of cell death at the cell membrane, mitochondria, nuclei and caspase-3 cleavage. We used the following inhibitors: the caspase inhibitor N-benzyloxycarbonyl-Val Ala-Asp (O-Me)-fluoromethyl ketone (zVAD-fmk), the serine protease inhibitors 3,4 dichloroisocoumarin (DCI) and N-alpha-tosyl-L-lysinyl-chloromethylketone (TLCK) and the reducing agent N-acetycysteine (NAC). ATG-induced cellular changes were rapid, included mitochondrial membrane permeability (MMP) induction and annexin V/propidium iodide (PI) positivity but little caspase-3 activation and nuclear morphology changes. MMP was not sensitive to caspase inhibition, serine protease inhibition with DCI moderately reduced MMP. These findings were in contrast to CD95-signaling. Interestingly, TLCK massively augmented CD95-induced MMP which could be abrogated by NAC. In conclusion, ATG-signaling differs in features and kinetics from CD95-induced apoptosis with caspase-independent mechanisms involved in MMP. PMID- 25927247 TI - Perception of Object Length Via Manual Wielding in Children With and Without Developmental Coordination Disorder. AB - The authors compared haptic perception via active manual wielding in children with and without developmental coordination disorder (DCD). Forty-eight children, 11-12 years old, participated as volunteers. Twenty-four were typically developing children (TDC), and 24 had been diagnosed with DCD. Individually, children held and wielded unseen rods of five lengths (20, 45, 60, 75, or 90 cm). Based on this wielding, children judged the length of each rod. Judgments of rod length were shorter in the DCD group than in the TDC group. In addition, significant interactions revealed that the difference between the 2 groups was progressively greater for longer rods. The results provide support for the hypothesis that DCD includes deficits in the ability to use manual wielding in the perception of object length. In addition, the results suggest that the deficit is not general, but is greater for longer objects. PMID- 25927248 TI - Synthesis and photophysics of a 2,7-disubstituted donor-acceptor pyrene derivative: an example of the application of sequential Ir-catalyzed C-H borylation and substitution chemistry. AB - We report a general and selective method to synthesize 2,7-disubstituted pyrene derivatives containing two different substituents by sequential Ir-catalyzed borylation and substitution chemistry. To demonstrate the utility of our approach, we synthesized 2-cyano-7-(N,N-diethylamino)pyrene (3), a pyrene analogue of the widely studied chromophore 4-(N,N-dimethylamino)benzonitrile (DMABN). Compound 3 and the monosubstituted compounds 2-(N,N-diethylamino)pyrene (1) and 2-cyanopyrene (2) have been structurally characterized. Their electronic and optical properties have been studied by a combination of absorption and emission spectroscopies, lifetime and quantum yield measurements, and modeling by DFT and TD-DFT. The photophysical properties of 3 are compared to those of DMABN and 2-cyano-7-(N,N-dimethylamino)-4,5,9,10-tetrahydropyrene, and we show that 2,7 disubstituted pyrene is a moderately effective pi-bridge for the construction of donor-acceptor compounds. It is also shown that donor or acceptor groups are only effective at the 2,7-positions of pyrene if they are suitably strong, leading to a switch in the energetic ordering of the HOMO-1 and HOMO or the LUMO and LUMO+1 of pyrene, respectively. PMID- 25927249 TI - Scanning Tunneling Spectroscopy on InAs-GaSb Esaki Diode Nanowire Devices during Operation. AB - Using a scanning tunneling and atomic force microscope combined with in-vacuum atomic hydrogen cleaning we demonstrate stable scanning tunneling spectroscopy (STS) with nanoscale resolution on electrically active nanowire devices in the common lateral configuration. We use this method to map out the surface density of states on both the GaSb and InAs segments of GaSb-InAs Esaki diodes as well as the transition region between the two segments. Generally the surface shows small bandgaps centered around the Fermi level, which is attributed to a thin multielement surface layer, except in the diode transition region where we observe a sudden broadening of the bandgap. By applying a bias to the nanowire we find that the STS spectra shift according to the local nanoscale potential drop inside the wire. Importantly, this shows that we have a nanoscale probe with which we can infer both surface electronic structure and the local potential inside the nanowire and we can connect this information directly to the performance of the imaged device. PMID- 25927250 TI - Low-Temperature Conformal Atomic Layer Deposition of SiNx Films Using Si2Cl6 and NH3 Plasma. AB - A plasma-enhanced atomic layer deposition (ALD) process was developed for the growth of SiNx thin films using Si2Cl6 and NH3 plasma. At substrate temperatures <=400 degrees C, we show that this ALD process leads to films with >95% conformality over high aspect ratio nanostructures with a growth per cycle of ~1.2 A. The film growth mechanism was studied using in situ attenuated total reflection Fourier transform infrared spectroscopy. Our data show that on the SiNx growth surface, Si2Cl6 reacts with surface -NH2 groups to form surface -NH species, which are incorporated into the growing film. In the subsequent half cycle, radicals generated in the NH3 plasma abstract surface Cl atoms, and restore an NHx (x = 1,2)-terminated surface. Surface Si-N-Si bonds are also primarily formed during the NH3 plasma half-cycle. The infrared data and Rutherford backscattering combined with hydrogen forward scattering shows that the films contain ~23% H atoms primarily incorporated as -NH groups. PMID- 25927251 TI - beta-Relaxation of PMMA: Tip Size and Stress Effects in Friction Force Microscopy. AB - The kinetic signature of the beta-relaxation of poly(methyl methacrylate) (PMMA) is investigated by friction force microscopy. The variation in friction force was measured as a function of scan velocity, temperature (300 K-410 K), and applied load using both sharp and blunt probe tips. The friction data show distinct maxima, which can be ascribed to the beta-relaxation of PMMA. The contact area was varied over the ranges of approximately 20 to 70 nm(2) and 12,000 to 43,000 nm(2) through the use of probe tips with radii of approximately 15, 18, 1350, and 2650 nm. Kinetic analysis shows that the apparent activation energy of the beta relaxation decreases with the tip radius. Accompanying finite element simulations indicate that for the sharp tips a substantial subvolume of the polymer underneath the tip exceeds the yield stress of PMMA. This suggests that for small contact sizes and high stresses the activation barrier of the beta-process decreases through the activation of the alpha-process by material yielding. PMID- 25927252 TI - Trans-cis isomerization of lipophilic dyes probing membrane microviscosity in biological membranes and in live cells. AB - Membrane environment and fluidity can modulate the dynamics and interactions of membrane proteins and can thereby strongly influence the function of cells and organisms in general. In this work, we demonstrate that trans-cis isomerization of lipophilic dyes is a useful parameter to monitor packaging and fluidity of biomembranes. Fluorescence fluctuations, generated by trans-cis isomerization of the thiocarbocyanine dye Merocyanine 540 (MC540), were first analyzed by fluorescence correlation spectroscopy (FCS) in different alcohol solutions. Similar isomerization kinetics of MC540 in lipid vesicles could then also be monitored, and the influence of lipid polarity, membrane curvature, and cholesterol content was investigated. While no influence of membrane curvature and lipid polarity could be observed, a clear decrease in the isomerization rates could be observed with increasing cholesterol contents in the vesicle membranes. Finally, procedures to spatially map photoinduced and thermal isomerization rates on live cells by transient state (TRAST) imaging were established. On the basis of these procedures, MC540 isomerization was studied on live MCF7 cells, and TRAST images of the cells at different temperatures were found to reliably detect differences in the isomerization parameters. Our studies indicate that trans-cis isomerization is a useful parameter for probing membrane dynamics and that the TRAST imaging technique can provide spatial maps of photoinduced isomerization as well as both photoinduced and thermal back-isomerization, resolving differences in local membrane microviscosity in live cells. PMID- 25927253 TI - The use of free online educational resources by Canadian emergency medicine residents and program directors. AB - Introduction Online educational resources (OERs) are increasingly available for emergency medicine (EM) education. This study describes and compares the use of free OERs by the Royal College of Physicians and Surgeons of Canada (RCPSC) EM residents and program directors (PDs) and investigates the relationship between the use of OERs and peer-reviewed literature. METHODS: A bilingual, online survey was distributed to RCPSC-EM residents and PDs using a modified Dillman method. The chi-square test and Fisher's exact test were used to compare the responses of residents and PDs. RESULTS: The survey was completed by 214/350 (61%) residents and 11/14 (79%) PDs. Free OERs were used by residents most frequently for general EM education (99.5%), procedural skills training (96%), and learning to interpret diagnostic tests (92%). OER modalities used most frequently included wikis (95%), file-sharing websites (95%), e-textbooks (94%), and podcasts (91%). Residents used wikis, podcasts, vodcasts, and file-sharing websites significantly more frequently than PDs. Relative to PDs, residents found entertainment value to be more important for choosing OERs (p<0.01). Some residents (23%) did not feel that literature references were important, whereas all PDs did. Both groups reported that OERs increased the amount of peer-reviewed literature (75% and 60%, respectively) that they read. CONCLUSIONS: EM residents make extensive use of OERs and differ from their PDs in the importance that they place on their entertainment value and incorporation of peer-reviewed references. OERs may increase the use of peer-reviewed literature in both groups. Given the prevalence of OER use for core educational goals among RCPSC-EM trainees, future efforts to facilitate critical appraisal and appropriate resource selection are warranted. PMID- 25927254 TI - Administration and leadership competencies: establishment of a national consensus for emergency medicine. AB - INTRODUCTION: The Royal College of Physicians and Surgeons of Canada requires emergency medicine (EM) residency programs to meet training objectives relating to administration and leadership. The purpose of this study was to establish a national consensus on the competencies for inclusion in an EM administration and leadership curriculum. METHODS: A modified Delphi process involving two iterative rounds of an electronic survey was used to achieve consensus on competencies for inclusion in an EM administration and leadership curriculum. An initial list of competencies was compiled using peer-reviewed and grey literature. The participants included 14 EM residency program directors and 43 leadership and administration experts from across Canada who were recruited using a snowball technique. The proposed competencies were organized using the CanMEDS Physician Competency Framework and presented in English or French. Consensus was defined a priori as >70% agreement. RESULTS: Nearly all (13 of 14) of the institutions with an FRCPC EM program had at least one participant complete both surveys. Thirty five of 57 (61%) participants completed round 1, and 30 (53%) participants completed both rounds. Participants suggested an additional 16 competencies in round 1. The results of round 1 informed the decisions in round 2. Fifty-nine of 109 (54.1%) competencies achieved consensus for inclusion. CONCLUSIONS: Based on a national modified Delphi process, we describe 59 competencies for inclusion in an EM administration and leadership curriculum that was arranged by CanMEDS Role. EM educators may consider these competencies when designing local curricula. PMID- 25927255 TI - Canadian pediatric emergency physician knowledge of concussion diagnosis and initial management. AB - Introduction The diagnosis of concussion is a critical step in the appropriate management of patients following minor head trauma. The authors hypothesized that wide practice variation exists among pediatric emergency medicine physicians in the application of physical and cognitive rest recommendations following an acute concussion. METHODS: The authors developed a 35-item questionnaire incorporating case vignettes to examine pediatric emergency physician knowledge of concussion diagnosis, understanding of initial management using return-to-play/school/work guidelines, use of existing concussion protocols, and perceived barriers to protocol use. Using a modified Dillman technique, the authors distributed an online survey to members of Pediatric Emergency Research Canada, a national association of pediatric emergency physicians. RESULTS: Of 176 potential participants, 115 (65%) responded to the questionnaire, 89% (95% confidence interval [CI]: 0.81, 0.93) of whom reported having diagnosed 20 or more concussions annually. Although 90% (95% CI: 0.83, 0.94) of respondents adequately diagnosed concussion, only 64% (95% CI: 0.54, 0.72) correctly applied graduated return-to-play guidelines. Cognitive rest recommendations were also frequently limited: 40% (95% CI: 0.31, 0.49) did not recommend school absence, 30% (95% CI: 0.22, 0.39) did not recommend schoolwork reduction, and 35% (95% CI: 0.27, 0.45) did not recommend limiting screen time. Eighty percent (95% CI: 0.72, 0.87) of respondents reported having used guidelines frequently or always to guide clinical decisions regarding concussion. CONCLUSION: Despite a proficiency in the diagnosis of concussion, pediatric emergency physicians exhibit wide variation in recommending the graduated return to play and cognitive rest following concussion. PMID- 25927256 TI - Closing the circle of care: implementation of a web-based communication tool to improve emergency department discharge communication with family physicians. AB - OBJECTIVE: Postdischarge emergency department (ED) communication with family physicians is often suboptimal and negatively impacts patient care. We designed and piloted an online notification system that electronically alerts family physicians of patient ED visits and provides access to visitspecific laboratory and diagnostic information. METHODS: Nine (of 10 invited) high-referring family physicians participated in this single ED pilot. A prepilot chart audit (30 patients from each family physician) determined the baseline rate of paper-based record transmission. A webbased communication portal was designed and piloted by the nine family physicians over 1 year. Participants provided usability feedback via focus groups and written surveys. RESULTS: Review of 270 patient charts in the prepilot phase revealed a 13% baseline rate of handwritten chart and a 44% rate of any information transfer between the ED and family physician offices following discharge. During the pilot, participant family physicians accrued 880 patient visits. Seven and two family physicians accessed online records for 74% and 12% of visits, respectively, an overall 60.7% of visits, corresponding to an overall absolute increase in receipt of patient ED visit information of 17%. The postpilot survey found that 100% of family physicians reported that they were ''often'' or ''always'' aware of patient ED visits, used the portal ''always'' or ''regularly'' to access patients' health records online, and felt that the web portal contributed to improved actual and perceived continuity of patient care. CONCLUSION: Introduction of a web-based ED visit communication tool improved ED family physician communication. The impact of this system on improved continuity of care, timeliness of follow-up, and reduced duplication of investigations and referrals requires additional study. PMID- 25927257 TI - An exploration of Canadian emergency physicians' and residents' knowledge of computed tomography radiation dosing and risk. AB - OBJECTIVE: The objective of this study was to measure the current knowledge of Canadian emergency physicians and emergency medicine residents regarding computed tomography (CT) radiation dosing and its associated risks. METHODS: Three focus groups were conducted as the qualitative element of this study. Cognitive debriefing was carried out to ensure the validity and reliability of the focus group findings and to aid with survey development. A 26-item electronic survey was developed and pilot tested for distribution to the membership of the Canadian Association of Emergency Physicians. RESULTS: Eighteen emergency medicine physicians and three emergency medicine residents participated in the focus groups. Four major themes emerged: 1) physician knowledge of risks associated with CT, 2) risk management strategies, 3) communication, and 4) knowledge translation. The survey response rate was 49.8% (638 of 1,281). The mean respondent age was 40.9+/-9.9 years, and 70.7% were male. Of all respondents, 82.5% were actively practicing attending physicians, 56.4% of all respondents practiced in urban academic emergency departments, and the average time practicing was 10.7+/-9.6 years. Radiography and CT were correctly identified by 92.2% and 95.1% of respondents, respectively, as sources of ionizing radiation, whereas magnetic resonance imaging and ultrasonography were selected by 1.0% and 0.5%, respectively. With respect to the lifetime attributable risk (LAR) of malignancy due to CT, 82.2% of participants correctly identified that abdominal CT increases the risk of cancer by 0.2 to 2%, whereas 51.3% correctly identified that the LAR increases twofold in a 7- year-old boy. When asked to identify populations at risk for potential harm due to ionizing radiation, 92.2% of respondents identified children, 80.3% identified pregnant women, and 71.4% identified women of reproductive age. A minority (37.2%) reported communicating the potential risks of CT to a majority of their patients. Electronic platforms were identified by 74.8% of respondents as their preferred method of knowledge translation on this topic. CONCLUSIONS: Canadian emergency medicine physicians and emergency medicine residents demonstrated identifiable gaps in knowledge surrounding CT radiation dose and risk. PMID- 25927258 TI - The TACTIC: development and validation of the Tool for Assessing Chest Tube Insertion Competency. AB - OBJECTIVES: Pediatric emergency medicine (PEM) physicians receive little opportunity to practice and perform chest tube insertion. We sought to develop and validate a scoring tool to assess chest tube insertion competency and identify areas where training is required for PEM physicians. METHODS: We developed a 40-point, 20-item (scored 0, 1, or 2) assessment tool entitled the Tool for Assessing Chest Tube Insertion Competency (TACTIC) and studied how PEM physicians and fellows scored when inserting a chest tube into a pork rib model. Participants were scored at baseline and compared to themselves after receiving targeted training using Web-based animations and presentations followed by expert instruction and practice on chest tube insertion task trainers. All insertions were video recorded and reviewed by two blinded reviewers. Eight common videos were reviewed to assess interrater reliability. RESULTS: The TACTIC demonstrated good interrater reliability with an r 2 =0.86. Our cohort demonstrated a significant improvement in TACTIC scores by taking part in targeted training (precourse TACTIC=65%, 95% CI 54-76 v. postcourse TACTIC=84%, 95% CI 80-88), highlighting the construct validity of the TACTIC. Individual participants increased their TACTIC scores by an average of 17%. CONCLUSIONS: The TACTIC demonstrates good interrater reliability, content validity, and construct validity in assessing a PEM practitioner's skill inserting chest tubes in a simulated setting. PMID- 25927259 TI - Investigating the necessity of computed tomographic scans in children with headaches: a retrospective review. AB - OBJECTIVE: Headaches are a common problem in the pediatric population. In 2002, the American Academy of Neurology (AAN) developed guidelines on neuroimaging for patients presenting with headache. Our objective was to determine the frequency of computed tomographic (CT) scanning ordered by a range of medical practitioners for pediatric patients presenting with primary headache. METHODS: A retrospective chart review was conducted at the Children's Hospital of Eastern Ontario (CHEO), a tertiary care centre in Ontario. One hundred fifty-one records of patients referred to the outpatient neurology clinic at CHEO with ''headache'' or ''migraine'' as the primary complaint from 2004 to 2009 were randomly selected. Ninety-nine patients with normal neurologic examinations were ultimately included. RESULTS: Thirty-four patients (34%; 95% CI 25-45) had undergone CT scanning. None of the 34 CT scans (0%; 95% CI 0-10) showed significant findings, and none changed the headache diagnosis or management. Eleven (32%) of the CT scans were ordered by CHEO neurologists, 15 (44%) by community physicians, and 8 (24%) by CHEO emergency physicians. CONCLUSION: A high proportion of children presenting with primary headaches and a normal neurologic examination undergo CT scanning, despite well-established AAN guidelines regarding neuroimaging. Most of these CT scans do not appear to alter diagnosis and management. A variety of non evidencebased factors may be encouraging physicians to overinvestigate this population and, as a result, increasing the risk of adverse events due to radiation exposure. Implementing initiatives at a site-based level that promote the use of established guidelines before performing CT scanning in this population may be beneficial. PMID- 25927260 TI - What are emergency-sensitive conditions? A survey of Canadian emergency physicians and nurses. AB - OBJECTIVE: In a previous study, we assembled a multidisciplinary Canadian panel and identified 37 International Classification of Diseases-10-Canada Diagnosis Groups (DGs) for which emergency department (ED) management may potentially reduce mortality (emergency-sensitive conditions). Before using these 37 DGs to calculate a hospital standardized mortality ratio (HSMR) specific to emergency care, we aimed to test their face validity with ED care providers. METHODS: We conducted a self-administered web survey among Canadian emergency physicians and nurses between November 22 and December 31, 2012. All members (N=2,507) of the Canadian Association of Emergency Physicians and the National Emergency Nurses Association were surveyed. They were asked to agree or disagree (binary response) with the panel classification for each of the 37 DG emergency-sensitive conditions identified and provide free text responses to identify missing entities. RESULTS: A total of 719 ED providers (719 of 2,507, 29%) completed the survey, of whom 470 were physicians (470 of 1,407, 33%) and 232 were nurses (232 of 1,100, 21%). Information on professional status was not provided for 17 respondents. Of 37 DGs, 32 (e.g., A41 sepsis) were rated by more than 80% of respondents to be emergency-sensitive conditions. The remaining five DGs (e.g., E11 type 2 diabetes mellitus) were rated by 68.5 to 79.7% of the respondents to be emergency-sensitive conditions. Respondents suggested an additional 31 emergency-sensitive diagnoses. CONCLUSION: We identified 37 emergency-sensitive DGs that had high face validity with emergency physicians and nurses, which will enable the calculation of an ED-HSMR. PMID- 25927261 TI - Sorry--we're full! Access block and accountability failure in the health care system. PMID- 25927262 TI - Implementing peer review at an emergency medicine blog: bridging the gap between educators and clinical experts. AB - Emergency physicians are leaders in the ''free open-access meducation'' (FOAM) movement. The mandate of FOAM is to create open-access education and knowledge translation resources for trainees and practicing physicians (e.g., blogs, podcasts, and vodcasts). Critics of FOAM have suggested that because such resources can be easily published online without quality control mechanisms, unreviewed FOAM resources may be erroneous or biased. We present a new initiative to incorporate open, expert, peer review into an established academic medical blog. Experts provided either pre- or postpublication reviews that were visible to blog readers. This article outlines the details of this initiative and discusses the potentially transformative impact of this educational innovation. PMID- 25927263 TI - Studying with the cloud: the use of online Web-based resources to augment a traditional study group format. AB - Cloud-based applications such as Google Docs, Skype, Dropbox, and SugarSync are revolutionizing the way that we interact with the world. Members of the millennial generation (those born after 1980) are now becoming senior residents and junior attending physicians. We describe a novel technique combining Internet and cloud-based methods to digitally augment the classic study group used by final-year residents studying for the Royal College of Physicians and Surgeons of Canada examination. This material was developed by residents and improved over the course of 18 months. This is an innovation report about a process for enhanced communication and collaboration as there has been little research to date regarding the augmentation of learner-driven initiatives with virtual resources. PMID- 25927264 TI - Point-of-care ultrasonography for the diagnosis of small bowel obstruction in the emergency department. AB - Small bowel obstruction (SBO) is a common cause of acute abdominal pain presenting to the emergency department (ED). Although the literature is limited, point-of-care ultrasonography (POCUS) has been found to have superior diagnostic accuracy for SBO compared to plain radiography; however, it is rarely used in North America for this. We present the case of a middle-aged man who presented with abdominal pain where POCUS by the emergency physician early in the hospital course expedited the diagnosis of SBO and led to earlier surgical consultation. The application of POCUS for SBO is easily learned and applied in the ED. POCUS for SBO may obviate the need for plain radiography and expedite patient care. PMID- 25927265 TI - Extracorporeal membrane oxygenation after protracted ventricular fibrillation cardiac arrest: case report and discussion. AB - Extracorporeal membrane oxygenation (ECMO) is a method to provide temporary cardiac and respiratory support to critically ill patients. In recent years, the role of ECMO in emergency departments (EDs) for select adults has increased. We present the dramatic case of a 29-year-old man who was placed on venoarterial ECMO for cardiogenic shock and respiratory failure following collapse and protracted ventricular fibrillation cardiac arrest in our ED. Resuscitation efforts prior to ECMO commencement included 49 minutes of virtually continuous cardiopulmonary resuscitation (CPR), 11 defibrillations, administration of numerous medications, including a thrombolytic agent, while CPR was ongoing, percutaneous coronary intervention and stenting for a mid-left anterior descending coronary artery dissection and thrombotic occlusion, inotropic support, and intra-aortic balloon pump counterpulsation. Over the next 48 hours following ECMO commencement, the patient's cardiorespiratory function rapidly improved, and he was discharged home 9 days after admission with no neurologic sequelae. The history, indications, and increasing role of ECMO in a range of conditions, including cardiac arrest, are reviewed. PMID- 25927266 TI - A mechanistic investigation of anti-elimination in (Z)-1,2-bis(arylseleno)-1 alkenes and their sulfur analogs. AB - The oxidation of (Z)-1,2-bis(arylseleno)-1-alkenes is known to afford alkynyl selenoxides via a unique selenoxide anti-elimination mechanism; however, to date, there have been no mechanistic studies of this reaction. During our studies of this transformation, monoselenoxides 6 and 7 were unexpectedly isolated as stable reaction intermediates. In addition, (77)Se NMR studies of the reaction mixture revealed the presence of an intramolecular Se...O interaction and the formation of alkynyl selenoxides. Meanwhile, even at higher temperatures, the reaction of a (Z)-1,2-bis(arylsulfinyl)-1-alkene, the sulfur analog of (Z)-1,2 bis(arylseleninyl)-1-alkenes, did not proceed via sulfoxide elimination but proceeded via isomerization and disproportionation. Therefore, the intramolecular Se...O interaction can be concluded to play a pivotal role in the anti elimination reaction. PMID- 25927267 TI - Green synthesis of multifunctional carbon dots from coriander leaves and their potential application as antioxidants, sensors and bioimaging agents. AB - In the present study, a facile one-step hydrothermal treatment of coriander leaves for preparing carbon dots (CDs) has been reported. Optical and structural properties of the CDs have been extensively studied by UV-visible and fluorescence spectroscopic, microscopic (transmission electron microscopy, scanning electron microscopy) and X-ray diffraction techniques. Surface functionality and composition of the CDs have been illustrated by elemental analysis and Fourier transform infrared spectroscopy (FTIR). Quenching of the fluorescence of the CDs in the presence of metal ions is of prime significance, hence CDs have been used as a fluorescence probe for sensitive and selective detection of Fe(3+) ions. Eventually, biocompatibility and bioimaging aspects of CDs have been evaluated on lung normal (L-132) and cancer (A549) cell lines. Qualitative analysis of cellular uptake of CDs has been pursued through fluorescence microscopy, while quantitative analysis using a flow cytometer provided an insight into the concentration and cell-type dependent uptake of CDs. The article further investigates the antioxidant activity of CDs. Therefore, we have validated the practicality of CDs obtained from a herbal carbon source for versatile applications. PMID- 25927268 TI - Hydrophobicity and antioxidant activity acting together for the beneficial health properties of nordihydroguaiaretic acid. AB - Nordihydroguaiaretic acid (NDGA) and rosmarinic acid (RA), phenolic compounds found in various plants and functional foods, have known antioxidant and anti inflammatory properties. In the present study, we comparatively investigated the importance of hydrophobicity and oxidisability of NDGA and RA, regarding their antioxidant and pharmacological activities. Using a panel of cell-free antioxidant protocols, including electrochemical measurements, we demonstrated that the anti-radical capacities of RA and NDGA were similar. However, the relative capacity of NDGA as an inhibitor of NADPH oxidase (ex vivo assays) was significantly higher compared to RA. The inhibitory effect on NADPH oxidase was not related to simple scavengers of superoxide anions, as confirmed by oxygen consumption by the activated neutrophils. The higher hydrophobicity of NDGA was also a determinant for the higher efficacy of NDGA regarding the inhibition of the release of hypochlorous acid by PMA-activated neutrophil and cytokine (TNF alpha and IL-10) production by Staphylococcus aureus-stimulated peripheral blood mononuclear cells. In conclusion, although there have been extensive studies about the pharmacological properties of NDGA, our study showed, for the first time, the importance not only of its antioxidant activity, but also its hydrophobicity as a crucial factor for pharmacological action. PMID- 25927269 TI - Offering induction of labor for 22-week premature rupture of membranes: a survey of obstetricians. AB - OBJECTIVE: To describe obstetricians' induction counseling practices for 22-week preterm premature rupture of membranes (PPROM) and identify provider characteristics associated with offering induction. METHODS: Surveyed 295 obstetricians on their likelihood (0-10) of offering induction for periviable PPROM across 10 vignettes. Twenty-two-week vignettes were analyzed, stratified by parental resuscitation preference. Bivariate analyses identified physician characteristics associated with reported likelihood ratings. RESULTS: Obstetricians (N=205) were not likely to offer induction. Median ratings by preference were as follows: resuscitation 1.0, uncertain 1.0 and comfort care 3.0. Only 41% of obstetricians were likely to offer induction to patients desiring comfort care. In addition, several provider-level factors, including practice region, parenting status and years in practice, were significantly associated with offering induction. CONCLUSIONS: Obstetricians do not readily offer induction when counseling patients with 22-week ruptured membranes, even when patients prefer palliation. This may place women at risk for infectious complications without accruing a neonatal benefit from prolonged latency. PMID- 25927270 TI - Maternal serum markers, characteristics and morbidly adherent placenta in women with previa. AB - OBJECTIVE: To examine associations with morbidly adherent placenta (MAP) among women with placenta previa. STUDY DESIGN: Women with MAP (cases) and previa alone (controls) were identified from a cohort of 236,714 singleton pregnancies with both first and second trimester prenatal screening, and live birth and hospital discharge records; pregnancies with aneuploidies and neural tube or abdominal wall defects were excluded. Logistic binomial regression was used to compare cases with controls. RESULT: In all, 37 cases with MAP and 699 controls with previa alone were included. Risk for MAP was increased among multiparous women with pregnancy-associated plasma protein-A (PAPP-A) ?95th percentile (?2.63 multiple of the median (MoM); adjusted OR (aOR) 8.7, 95% confidence interval (CI) 2.8 to 27.4), maternal-serum alpha fetoprotein (MS-AFP) ?95th percentile (?1.79 MoM; aOR 2.8, 95% CI 1.0 to 8.0), and 1 and ?2 prior cesarean deliveries (CDs; aORs 4.4, 95% CI 1.5 to 13.6 and 18.4, 95% CI 5.9 to 57.5, respectively). CONCLUSION: Elevated PAPP-A, elevated MS-AFP and prior CDs are associated with MAP among women with previa. PMID- 25927271 TI - Intestinal perforation in very preterm neonates: risk factors and outcomes. AB - OBJECTIVE: To compare neonatal outcomes of preterm infants (born at <32 weeks' gestation) with focal/spontaneous intestinal perforation (SIP), necrotizing enterocolitis (NEC)-related perforation, NEC without perforation or no NEC/perforation. STUDY DESIGN: Retrospective cohort study of 17,426 infants admitted to Canadian neonatal intensive care units during 2010 to 2013. The primary outcome was a composite of mortality or morbidity (bronchopulmonary dysplasia, severe retinopathy, periventricular leukomalacia or nosocomial infection). Association of intestinal perforation with neonatal outcome was evaluated using multivariate logistic regression. RESULT: SIP was present in 178 (1.0%) infants, NEC-related perforation in 246 (1.4%) and NEC without perforation in 538 (3.1%). Any intestinal perforation was associated with higher odds of the composite outcome (adjusted odds ratio (AOR): 8.21, 95% confidence interval (95% CI) 6.26 to 10.8); however, the odds were significantly lower for focal/SIP compared with NEC-related perforation (AOR: 0.29, 95% CI 0.17 to 0.51). CONCLUSION: Of the two types of intestinal perforation, NEC-related perforation was associated with the highest risk of an adverse neonatal outcome. PMID- 25927272 TI - Increasing incidence and geographic distribution of neonatal abstinence syndrome: United States 2009 to 2012. AB - OBJECTIVE: Neonatal abstinence syndrome (NAS), a postnatal opioid withdrawal syndrome, increased threefold from 2000 to 2009. Since 2009, opioid pain reliever prescriptions and complications increased markedly throughout the United States. Understanding recent changes in NAS and its geographic variability would inform state and local governments in targeting public health responses. STUDY DESIGN: We utilized diagnostic and demographic data for hospital discharges from 2009 to 2012 from the Kids' Inpatient Database and the Nationwide Inpatient Sample. NAS associated diagnoses were identified utilizing International Classification of Diseases, Ninth Revision, Clinical Modification codes. All analyses were conducted with nationally weighted data. Expenditure data were adjusted to 2012 US dollars. Between-year differences were determined utilizing least squares regression. RESULTS: From 2009 to 2012, NAS incidence increased nationally from 3.4 (95% confidence interval (CI): 3.2 to 3.6) to 5.8 (95% CI 5.5 to 6.1) per 1000 hospital births, reaching a total of 21,732 infants with the diagnosis. Aggregate hospital charges for NAS increased from $732 million to $1.5 billion (P<0.001), with 81% attributed to state Medicaid programs in 2012. NAS incidence varied by geographic census division, with the highest incidence rate (per 1000 hospital births) of 16.2 (95% CI 12.4 to 18.9) in the East South Central Division (Kentucky, Tennessee, Mississippi and Alabama) and the lowest in West South Central Division Oklahoma, Texas, Arkansas and Louisiana 2.6 (95% CI 2.3 to 2.9). CONCLUSION: NAS incidence and hospital charges grew substantially during our study period. This costly public health problem merits a public health approach to alleviate harm to women and children. States, particularly, in areas of the country most affected by the syndrome must continue to pursue primary prevention strategies to limit the effects of opioid pain reliever misuse. PMID- 25927273 TI - Effects of sodium bicarbonate correction of metabolic acidosis on regional tissue oxygenation in very low birth weight neonates. AB - OBJECTIVE: To determine the effects of sodium bicarbonate (NaHCO3) correction of metabolic acidosis on cardiopulmonary, laboratory, and cerebral, renal and splanchnic regional oxygen saturation (rSO2) and fractional tissue oxygen extraction (FTOE) in extremely premature neonates during the first postnatal week. STUDY DESIGN: Observational cohort data were collected from 500 to 1250 g neonates who received NaHCO3 'half' corrections (0.3 * Weight (kg) * Base Deficit (mmol l(-1))) for presumed renal losses. RESULT: Twelve subjects with normal blood pressure and heart rate received 17 NaHCO3 corrections. Mean (+/-s.d.) gestational age was 27+/-2 week and birth weight was 912+/-157 g. NaHCO3 corrections provided a mean (+/-s.d.) 4.5+/-1.0 ml kg(-1) fluid bolus, shifted mean (+/-s.d.) base deficit from 7.6+/-1.8 to 3.4+/-2.1 mmol l(-1) (P<0.05), and increased median (+/-s.d.) pH from 7.23+/-0.06 to 7.31+/-0.05 (P<0.05). No significant changes in blood pressure, pulse oximetry, PCO2, lactate, sodium, blood urea nitrogen, creatinine or hematocrit were observed. Cerebral, renal and splanchnic rSO2 (74%, 66% and 44%, respectively, at baseline) and FTOE (0.21, 0.29 and 0.52, respectively, at baseline) were unchanged following NaHCO3 correction. CONCLUSION: NaHCO3 infusions decreased base deficits and increased pH though produced no discernible effects or benefits on cardiopulmonary parameters including rSO2 and FTOE. These findings warrant further prospective evaluation in larger populations with more significant metabolic acidosis to determine the utility of tissue oxygenation monitoring in differentiating metabolic acidosis due to oxygen delivery/consumption imbalance versus renal bicarbonate losses. PMID- 25927274 TI - Standardization of amniotic fluid leptin levels and utility in maternal overweight and fetal undergrowth. AB - OBJECTIVE: Leptin is an adipokine that regulates energy homeostasis. The objective of this study was to establish a gestational age-specific standard for amniotic fluid leptin (AFL) levels and examine the relationship between AFL, maternal overweight and fetal growth restriction. STUDY DESIGN: Amniotic fluid was obtained at mid-gestation from singleton gravidas, and leptin was quantified using enzyme-linked immunosorbent assay. Amniotic fluid samples from 321 term pregnancies were analyzed. Clinical data, including fetal ultrasound measurements and maternal and infant characteristics, were available for a subset of patients (n=45). RESULTS: The median interquartile range AFL level was significantly higher at 14 weeks' gestation (2133 pg ml(-1) (1703 to 4347)) than after 33 weeks' gestation (519 pg ml(-1) (380 to 761), P trend<0.0001), an average difference of 102 pg ml(-1) per week. AFL levels were positively correlated with maternal pre-pregnancy body mass index (BMI) (r=0.36, P=0.03) adjusting for gestational age at measurement, but were not associated with fetal growth. CONCLUSIONS: AFL levels are higher at mid-gestation than at late gestation, and are associated with maternal pre-pregnancy BMI. PMID- 25927276 TI - Charge transport and ac response under light illumination in gate-modulated DNA molecular junctions. AB - Using a two-strand tight-binding model and within nonequilibrium Green's function approach, we study charge transport through DNA sequences (GC)NGC and (GC)1(TA)NTA (GC)3 sandwiched between two Pt electrodes. We show that at low temperature DNA sequence (GC)NGC exhibits coherent charge carrier transport at very small bias, since the highest occupied molecular orbital in the GC base pair can be aligned with the Fermi energy of the metallic electrodes by a gate voltage. A weak distance dependent conductance is found in DNA sequence (GC)1(TA)NTA (GC)3 with large NTA. Different from the mechanism of thermally induced hopping of charges proposed by the previous experiments, we find that this phenomenon is dominated by quantum tunnelling through discrete quantum well states in the TA base pairs. In addition, ac response of this DNA junction under light illumination is also investigated. The suppression of ac conductances of the left and right lead of DNA sequences at some particular frequencies is attributed to the excitation of electrons in the DNA to the lead Fermi surface by ac potential, or the excitation of electrons in deep DNA energy levels to partially occupied energy levels in the transport window. Therefore, measuring ac response of DNA junctions can reveal a wealth of information about the intrinsic dynamics of DNA molecules. PMID- 25927275 TI - Meta-Analysis of the Relationship between XRCC1-Arg399Gln and Arg280His Polymorphisms and the Risk of Prostate Cancer. AB - Prostate cancer is one of the most common noncutaneous malignancies in Western countries. Because there has been a debate regarding the relationship between the XRCC1-Arg399Gln and Arg280His polymorphisms and prostate cancer risk, we therefore performed this meta-analysis. The electronic databases PubMed, EMBASE, and Medline were searched prior to October 1, 2014. An odds ratio and 95% confidence interval were used to calculate association. Heterogeneity was tested by both a chi-square test and I statistic. Funnel plots and Egger's test were used to assess publication bias. All statistical analyses were performed using STATA 12.0 software. A significant association between the XRCC1-Arg399Gln polymorphism and prostate cancer risk was found under a homozygote model and a recessive model. A significant association between XRCC1-Arg280His and prostate cancer risk was found under a heterozygote model and a dominant model [corrected]. Overall, the results of this meta-analysis show that the XRCC1 Arg399Gln polymorphism may be associated with an increased risk for prostate cancer under the homozygote model and the recessive model. And XRCC1-Arg280His polymorphism is likely to be related with prostate cancer risk under the heterozygote model and the dominant model. Additional larger well-designed studies are needed to validate our results. PMID- 25927277 TI - Update in general internal medicine: evidence published in 2014. PMID- 25927278 TI - [A Problematic Case: Removal of a Broken Cannulated Tibial Nail]. AB - We present a case illustrating a simple and safe technique for the removal of a broken cannulated tibial nail after a pseudarthrosis of a lower leg shaft fracture. A 3 mm Ball-Tip guide wire was inserted into the proximal and the distal segment of the nail. A 2.5 mm tip-flattened second wire was forwarded into the distal segment pushing the Ball-Tip guide wire out of the axis and blocking it. This way the Ball-Tip could act as a hook and consecutively could be knocked back with an impactor forceps removing the complete nail. An exchange nailing was performed with a reamed AO standard nail and the further course was uneventful with a healed fracture after 12 months. PMID- 25927279 TI - [Influence of Parkinson's Disease on the Perioperative Course of Patients after Lumbar Fusion Surgery]. AB - BACKGROUND: The incidence of Morbus Parkinson (MP) increases with age. An increasing number of patients with MP in the orthopaedic patient population is expected. In the case of general surgery and trauma surgery MP in patients was identified as an important factor for perioperative morbidity. This study investigates the influence of MP on the perioperative course of patients after elective lumbar fusion. PATIENTS AND METHODS: A retrospective matched-pairs analysis with 17 patients in each group was conducted with patients treated in the department of spinal surgery in an orthopaedic university hospital for symptomatic degenerative lumbar spine disease without improvement after conservative therapy. The analysis compared the perioperative courses of patients with MP (MP) and patients without MP (no MP) concerning duration of hospital and intensive care treatment, duration for mobilisation, rehabilitation and occurrence of complications. RESULTS: The mean duration of inpatient treatment (MP 18.4 +/- 11.6 d; no MP 14.7 +/- 5.4 d), duration of intensive care (MP 1.7 +/ 4.2 d; no MP 1,0 +/- 1,9 d) and duration for mobilisation (MP 8.8 +/- 12.46 d; no MP 5.0 +/- 4.2 d) tend to be longer for MP patients. There was no statistically significant difference between both patient groups. A rehabilitative inpatient follow-up treatment was more frequent in patients with MP (MP n = 4; no MP n = 2). None of the two groups showed an increased occurrence of complications. CONCLUSION: While general surgery and trauma surgery patients show significant differences regarding duration of inpatient treatment, more frequent falls and more frequent rehabilitative inpatient follow-up treatments, patients after elective lumbar fusion show only a trend. Possibly the result is due to the underlying degenerative disease of the lumbar spine with spinal stenosis and gait disturbance in the MP group and as well in the control group. Therefore both groups suffered from impaired mobility. Additionally there was a high incidence of other comorbidities in the control group, which could have affected the results of this study. Another limitation is the number of the included patients. Although, this study showed no increased occurrence of complications, typical risk factors, like increased risk for airway complications, urinary tract infection and falls, should be considered for the treatment of MP patients. PMID- 25927280 TI - [Significance of Helicopter Emergency Medical Service in Prehospital Trauma Care]. AB - BACKGROUND: In the late 1960s, the helicopter emergency medical service (HEMS) was established in Germany because of an increasing number of severe injuries in traffic accidents. To get a doctor quickly on scene was the initial intention, rather than transporting the patient. Today, rescue helicopters cover the entire field of emergency medicine and are an important transportation device for polytrauma patients. MATERIAL AND METHODS: The importance of the HEMS for the treatment of severely injured patients was examined by an analysis of the databases of the leading air rescue organisations ADAC and DRF Luftrettung (2005 2011). RESULTS: Traumatological cases, albeit with large regional differences, make up 35 % of all uses of the helicopter emergency services. CONCLUSIONS: For the multiply injured patient in particular, in over 40 % of the cases there is a joint patient care involving both helicopter- and ambulance-based emergency services. The HEMS undertakes especially the rapid, if necessary, even transregional transport to specialised trauma centres. PMID- 25927281 TI - [Historical Changes in Meniscus Surgery--The Changing Appreciation of Disease, Surgical Techniques and Complications]. AB - The menisci play an important role in normal function of the knee joint. Meniscal injuries are associated with pain, swelling, impairment in function and activity level as well as early arthrosis of the knee joint. Patients with meniscal tears have to undergo surgery frequently. The pathway from the beginning of meniscal surgery to the modern arthroscopic meniscal surgery was not straightforward. The clinical picture of meniscal injuries, which caused articular trouble, was controversial for a long time. Meniscal surgery developed from knee joint surgery of the loose articular bodies. The first meniscal tear was not described until 1731. More than 100 years later, in 1866 the first planned meniscal surgery was performed. The importance of surgical techniques of meniscal resection and meniscal repair was emphasised in 1885. The beginning of knee joint arthroscopy took place in the 2nd decade of the 20th century. However, arthroscopy did not start its triumphal phase not until the 1960s coursing from Japan over North America to Europe. Approximately 150 years had passed from the risky arthrotomy surgeries of the past to the modern arthroscopic meniscal surgeries with low complication rates. Today, arthroscopic knee surgeries and especially arthroscopic meniscal surgeries are one of the most frequently performed orthopaedic procedures. PMID- 25927282 TI - [Is there Sense in Having a Certified Centre for Geriatric Trauma Surgery?]. AB - INTRODUCTION: By 2030, 30 % of German residents will be over 70 years of age. In 2009, we conceptualised a TUV (German Technical Inspection Authority) certified interdisciplinary centre for geriatric trauma care. All treatment pathways were agreed upon by all disciplines. Complex geriatric therapy was established, and patients were seen by trauma surgeons, geriatricians, therapists, and a pharmacist. Cases were discussed in team meetings. Morbidity and mortality conferences were conducted. In 2014, supplementary DGU (German Society for Trauma Surgery) certification was achieved. QUESTION: Have these measures led to improved quality of care and have the increased costs been covered? Is the formation of such a centre worthwhile for patients and hospitals? METHODS: This interdisciplinary treatment was implemented for all patients over 70 admitted with proximal femur, proximal humerus, and vertebral fractures. In 2012, there were 208 proximal femur, 171 vertebral, and 69 humeral fractures. The following parameters were defined for quality control: admission and diagnosis completed within 90 minutes, over 80 % of operations performed within 24 hours, reoperation rate under 12 %, decubitus rate under 5 %, mobilisation within 24 hours of surgery in 75 %, discharge to the previous environment in over 80 % of cases, and minimal mortality rates. RESULTS: Surgery performed within 24 hours fell just short of target in 2012 with 78 %, and 2013 with 81 %. The target time for diagnosis was reached in only 30 % of patients in 2012 and in 42 % in 2013; thus, more outpatient personnel was added. Mobilisation within 24 hours of surgery was completed in 79 % of patients in 2012. Implementation of decubitus standards reduced the rate of decubitus formation from 8 to 3.2 %. Reoperation rate was 5.2 % in 2012 and 3.1 % in 2013. In 2012, 6.4 % and in 2013, 9.3 % of discharged patients required short- and long-term care facilities for the first time, and the rest were discharged to rehabilitation or directly back home. Mortality rates for proximal femur fractures were 5.7 % in 2010, 5.1 % in 2011, 2.9 % in 2012, and 3.0 % in 2013. The implementation of complex geriatric therapy generated 103 treatments in 2012 with revenue of 912,000 ?, and 160 treatments in 2013 with revenue of 1.35 million ?. CONCLUSION: Interdisciplinary geriatric-trauma therapy for older patients resulted in improved measurable outcomes. Interdisciplinary geriatric trauma care with implementation of complex therapy benefits both patients and hospitals. PMID- 25927283 TI - "Clip-strasse": A novel complication following partial nephrectomy. AB - This report presents the case of a 63-year-old man who presented with recurrent visible haematuria and loin pain 18 months after open partial nephrectomy for renal cell carcinoma. A computed tomography urogram revealed three obstructing calculi in the mid- to distal ureter with hydronephrosis. Rigid ureteroscopy revealed three calcified objects in the pelvic ureter. These had the appearance of calcified Weck(r) clips. A laser was used to remove the calcification, confirming the presence of three Weck clips, which had been used for haemostasis during the partial nephrectomy. These were removed with graspers after balloon dilatation of the distal ureter. This phenomenon of multiple clips migrating with stone formation and obstruction of the ureter was named "clip-strasse". PMID- 25927285 TI - Pharmacologic therapy for Peyronie's disease: what should we prescribe? AB - INTRODUCTION: Peyronie's disease (PD) is a wound healing disorder of the penis with a myriad of proposed treatment options reported in the literature. Evaluating the available data and therapeutic management of PD can be challenging and confusing, even for the most experienced treating physician. This review provides a comprehensive overview of pharmacologic treatment options for PD, focusing on the best available evidence. AREAS COVERED: A comprehensive literature search for published articles evaluating oral, topical, and injectable pharmacologic agents for PD was completed. Prospective, controlled trials were given precedence for inclusion. EXPERT OPINION: Although a multitude of oral agents have been proposed and evaluated in PD patients, results vary widely and a reproducible objective benefit has not yet been strongly established for any single oral agent. Well-designed, large-scale, randomized controlled trials evaluating oral agents in PD patients are lacking. Consistent objective benefit from injectable agents has been supported for years by various non-controlled trials. Recently, injectable collagenase Clostridium histolyticum became the first pharmacologic agent to obtain FDA approval for use in PD patients, supported by data from a large-scale, Phase III randomized controlled trial. Further elucidation of the genetic and mechanistic pathways involved in the development and progression of PD will help define future therapeutic targets. PMID- 25927284 TI - BRCA1 deficiency in ovarian cancer is associated with alteration in expression of several key regulators of cell motility - A proteomics study. AB - Functional loss of expression of breast cancer susceptibility gene 1(BRCA1) has been implicated in genomic instability and cancer progression. There is emerging evidence that BRCA1 gene product (BRCA1) also plays a role in cancer cell migration. We performed a quantitative proteomics study of EOC patient tumor tissues and identified changes in expression of several key regulators of actin cytoskeleton/cell adhesion and cell migration (CAPN1, 14-3-3, CAPG, PFN1, SPTBN1, CFN1) associated with loss of BRCA1 function. Gene expression analyses demonstrate that several of these proteomic hits are differentially expressed between early and advanced stage EOC thus suggesting clinical relevance of these proteins to disease progression. By immunohistochemistry of ovarian tumors with BRCA1(+/+) and BRCA1(null) status, we further verified our proteomic-based finding of elevated PFN1 expression associated with BRCA1 deficiency. Finally, we established a causal link between PFN1 and BRCA1-induced changes in cell migration thus uncovering a novel mechanistic basis for BRCA1-dependent regulation of ovarian cancer cell migration. Overall, findings of this study open up multiple avenues by which BRCA1 can potentially regulate migration and metastatic phenotype of EOC cells. PMID- 25927286 TI - Continuous Glucose Monitoring in Type 1 Diabetes Pregnancy Shows that Fetal Heart Rate Correlates with Maternal Glycemia. AB - BACKGROUND: Much evidence has shown that pregnancies in women with preexisting diabetes are affected by an increased risk of maternal and fetal adverse outcomes, probably linked to poor glycemic control. Despite great progress in medical care, the rate of stillbirths remains much higher in diabetes patients than in the general population. Recent technological advances in the field of glucose monitoring and noninvasive fetal heart rate monitoring made it possible to observe the fetal-maternal dependencies in a continuous manner. SUBJECTS AND METHODS: Fourteen type 1 diabetes patients were involved into the study and fitted with a blinded continuous glucose monitoring (CGM) recorder. Fetal electrocardiogram data were recorded using the Monica AN24TM device (Monica Healthcare Ltd., Nottingham, United Kingdom), the recordings of which were matched with CGM data. Statistical analysis was performed using a generalized mixed-effect logistic regression to account for individual factors. RESULTS: The mean number of paired data points per patient was 254+/-106, representing an observation period of 21.2+/-8.8 h. Mean glycemia equaled 5.64+/-0.68 mmol/L, and mean fetal heart rate was 135+/-6 beats/min. Higher glycemia correlated with fetal heart rate (R=0.32; P<0.0001) and was associated with higher odds of the fetus developing small accelerations (odds ratio=1.05; 95% confidence interval, 1.00-1.10; P=0.04). CONCLUSIONS: Elevated maternal glycemia of mothers with diabetes is associated with accelerations of fetal heart rate. PMID- 25927290 TI - Correction to new anticancer agents mimicking protein recognition motifs. PMID- 25927288 TI - Muscular and functional effects of partitioning exercising muscle mass in patients with chronic obstructive pulmonary disease - a study protocol for a randomized controlled trial. AB - BACKGROUND: Low-load, high-repetitive single-limb resistance training may increase limb muscle function and functional exercise capacity in patients with chronic obstructive pulmonary disease (COPD) while minimizing the occurrence of limiting exertional symptoms. Whether high-repetitive single-limb resistance training would perform better than high-repetitive two-limb resistance training is unknown. In addition, the mechanisms underlying possible benefits of high repetitive resistance training has not been investigated. The aims of this study are to compare single versus two-limb high-repetitive resistance training in patients with COPD and to investigate mechanisms of action of these training modalities. METHODS/DESIGN: This trial is a prospective, assessor-blind, randomized controlled trial. The participants are patients with stable severe to very severe COPD who are older than 40 years of age and healthy controls. The intervention is single-limb, high-repetitive, resistance training with elastic bands, three times/week for 8 weeks. The control is two-limb high-repetitive resistance training with elastic bands, three times/week for 8 weeks. The primary outcomes is change in the 6-min walking distance after 8 weeks of single-limb or two-limb high-repetitive resistance training. The secondary outcomes are changes in limb muscle strength and endurance capacity, key protein involved in quadriceps anabolic/catabolic signalization, fiber-type distribution and capillarization, subjective dyspnea and muscle fatigue, muscle oxygenation, cardiorespiratory demand and health-related quality-of-life after 8 weeks of single-limb or two-limb high-repetitive resistance training. The acute effects of single-limb versus two-limb high-repetitive resistance training on contractile fatigue, exercise stimulus (the product of number of repetition and load), subjective dyspnea and muscle fatigue, muscle oxygenation, and cardiorespiratory demand during upper and lower limb exercises will also be investigated in patients with COPD and healthy controls. Randomization will be performed using a random number generator by a person independent of the recruitment process, using 1:1 allocation to the intervention and the control group using random block sizes. BLINDING: All outcome assessors will be blinded to group assignment. DISCUSSION: The results of this project will provide important information to help developing and implementing customized exercise training programs for patients with COPD. TRIAL REGISTRATION: ClinicalTrials.gov Identifier NCT02283580 Registration date: 4 November 2014. First participant randomized: 10 November 2014. PMID- 25927293 TI - Sociodemographic, behavioural and health factors associated with changes in older adults' TV viewing over 2 years. AB - BACKGROUND: Of all age groups, older adults spend the most time watching TV, which is one of the most common sedentary behaviours. Such sedentary activity in older adulthood is thought to risk deterioration of physical and mental functioning, health and wellbeing. Identifying the characteristics of older adults whose TV viewing increases over time may help to target sedentary behaviour reduction interventions to those in most urgent need. Yet, studies of the factors associated with TV viewing have predominantly been cross-sectional. This study used a prospective design to describe changes in TV viewing over a two year follow-up period, and to model socio-demographic, behavioural and health factors associated with observed changes in viewing time. METHODS: A two-year follow-up of 6,090 male and female older adults (mean age 64.9 +/- 8.9 years) was conducted in the English Longitudinal Study of Ageing, a cohort of community dwelling older adults. TV viewing time was self-reported at baseline and at follow-up. The sample was categorised according to baseline TV viewing duration (<2 hrs/d, 2 < 4 hrs/d, 4 < 6 hrs/d, >=6 hrs/d), and the observed direction and extent of changes in viewing duration were described for each category. Socio demographic, behavioural and health variables (socioeconomic status, depressive symptoms, disability, chronic illness, body mass index, physical activity, smoking), as measured at baseline, were entered into regression models as predictors of changes in TV viewing time between baseline and follow-up. RESULTS: Mean self-reported TV viewing time increased from 5.32 +/- 4.08 hrs/d at baseline to 5.53 +/- 4.19 hrs/d at follow-up (p < 0.001). Forty-nine per cent of participants increased their TV viewing (23% of all participants by 60 minutes or more), 41% decreased their viewing, and 10% reported no change in viewing duration. Increases in TV viewing at follow-up were associated with lower socioeconomic status, presence of depressive symptoms, higher BMI, physical inactivity, and being a smoker at baseline. CONCLUSIONS: Findings call for the development of effective behaviour change interventions to counter increases in inactive TV viewing among older adults, and point to subgroups who may need to be prioritised for such interventions. PMID- 25927294 TI - Establishing confidence in the output of qualitative research synthesis: the ConQual approach. AB - BACKGROUND: The importance of findings derived from syntheses of qualitative research has been increasingly acknowledged. Findings that arise from qualitative syntheses inform questions of practice and policy in their own right and are commonly used to complement findings from quantitative research syntheses. The GRADE approach has been widely adopted by international organisations to rate the quality and confidence of the findings of quantitative systematic reviews. To date, there has been no widely accepted corresponding approach to assist health care professionals and policy makers in establishing confidence in the synthesised findings of qualitative systematic reviews. METHODS: A methodological group was formed develop a process to assess the confidence in synthesised qualitative research findings and develop a Summary of Findings tables for meta aggregative qualitative systematic reviews. RESULTS: Dependability and credibility are two elements considered by the methodological group to influence the confidence of qualitative synthesised findings. A set of critical appraisal questions are proposed to establish dependability, whilst credibility can be ranked according to the goodness of fit between the author's interpretation and the original data. By following the processes outlined in this article, an overall ranking can be assigned to rate the confidence of synthesised qualitative findings, a system we have labelled ConQual. CONCLUSIONS: The development and use of the ConQual approach will assist users of qualitative systematic reviews to establish confidence in the evidence produced in these types of reviews and can serve as a practical tool to assist in decision making. PMID- 25927296 TI - A potential mechanism for extracellular matrix induction of breast cancer cell normality. AB - Extracellular matrix proteins from embryonic mesenchyme have a normalizing effect on cancer cells in vitro and slow tumor growth in vivo. This concept is suggestive of a new method for controlling the growth and spread of existing cancer cells in situ and indicates the possibility that extracellular proteins and/or embryonic mesenchymal fibroblasts may represent a fertile subject for study of new anti-cancer treatments. PMID- 25927297 TI - Adapting narrative exposure therapy for Chinese earthquake survivors: a pilot randomised controlled feasibility study. AB - BACKGROUND: Narrative exposure therapy (NET) is a brief, manualised treatment for Posttraumatic Stress Disorder (PTSD). It has been shown to have therapeutic benefits for a wide range of individuals and settings. This study, following our previous work applying the original NET in earthquake survivors, aimed to revise NET to be adaptable for treating PTSD after a natural disaster. METHODS: A randomised waiting-list controlled study was conducted with 30 adult participants with PTSD who were randomly allocated to NET (n = 10), revised NET (NET-R; n = 10) or a waiting list condition (WL; n = 10). Participants in NET and NET-R received treatment immediately; those in the WL condition received NET-R treatment after a waiting period. All groups were assessed on PTSD, general distress, anxiety, depression, social support, coping and posttraumatic change before and after treatment and three-month follow-up. RESULTS: Compared with WL, both NET and NET-R groups showed significant reductions in PTSD and related symptoms. Significant increases were found in posttraumatic growth, active coping and perceived social support. The WL group showed similar improvements after treatment. Further reductions on PTSD symptoms were found at three months, showing that NET-R is as effective as the original NET in treating post earthquake traumatic symptoms in adult Chinese earthquake survivors. CONCLUSIONS: NET-R is a feasible and cost-effective intervention for Chinese earthquake survivors. Further studies are needed to replicate these findings in other survivor populations, and with larger samples and over longer periods. This study highlighted the value of oral narrative approach, which is well-accepted and useful in the context of single natural disaster and lower- income area. TRIAL REGISTRATION: Chinese Clinical Trial Registry: ChiCTR-TRC-12002931. PMID- 25927298 TI - Increased health and well-being in preschools (DAGIS): rationale and design for a randomized controlled trial. AB - BACKGROUND: Effective interventions that target socioeconomic status (SES) differences to avoid the potential widening of inequalities in health are needed. Children at preschool age is a valuable intervention target since sedentary behaviors, physical activity (PA), dietary behaviors, and sleep habits, jointly called the energy balance-related behaviors (EBRBs), are established in early childhood and tend to persist later in life. The interventions are most effective, when they focus on evidence-based factors. One potential factor associated with EBRBs and SES is children's stress regulation, which receives special attention in this study. Based on the socioecological approach, the combinations of multiple levels (e.g. individual, environmental, societal) of analysis and diverse methodologies (e.g. surveys, observations, biological measurements) are used to assess the healthfulness of environments (e.g. social, physical, learning, policy) in preschool and family settings. The intervention aimed to diminish SES differences in EBRBs is then conducted in the preschool setting. METHODS/DESIGN: The DAGIS study is divided into two phases. The first phase comprises focus group interviews and a cross-sectional survey. Parents and preschool personnel in low SES neighborhoods participated in interviews about children's sedentary behaviors, dietary behaviors, and PA in 2014. In the cross sectional survey beginning in autumn 2015, preschools will be recruited from a random sample of preschools in 3-5 municipalities in Southern Finland. A total of 800 children will wear an accelerometer for seven days. Children's hair and saliva samples will be taken. Parents and preschool personnel will complete questionnaires on EBRBs, social and physical environments and SES factors. The quality of preschool environment is also observed. In the second phase, an intervention targeting to narrowing SES differences in EBRBs is conducted. The effects of the intervention will be evaluated in randomised controlled trial. The implementation of the intervention will also be evaluated. CONCLUSION: If effective, this unique preschool-based study will be able to narrow the SES differences in preschool children's EBRBs. This study is anticipated to identify the most important modifiable factors in preschool and family environmental settings associated with children's EBRBs, especially in children from low SES backgrounds. TRIAL REGISTRATION: ISRCTN57165350 (January, 8th, 2015). PMID- 25927300 TI - Mixed reality temporal bone surgical dissector: mechanical design. AB - OBJECTIVE: The Development of a Novel Mixed Reality (MR) Simulation. An evolving training environment emphasizes the importance of simulation. Current haptic temporal bone simulators have difficulty representing realistic contact forces and while 3D printed models convincingly represent vibrational properties of bone, they cannot reproduce soft tissue. This paper introduces a mixed reality model, where the effective elements of both simulations are combined; haptic rendering of soft tissue directly interacts with a printed bone model. This paper addresses one aspect in a series of challenges, specifically the mechanical merger of a haptic device with an otic drill. This further necessitates gravity cancelation of the work assembly gripper mechanism. In this system, the haptic end-effector is replaced by a high-speed drill and the virtual contact forces need to be repositioned to the drill tip from the mid wand. Previous publications detail generation of both the requisite printed and haptic simulations. METHOD: Custom software was developed to reposition the haptic interaction point to the drill tip. A custom fitting, to hold the otic drill, was developed and its weight was offset using the haptic device. The robustness of the system to disturbances and its stable performance during drilling were tested. The experiments were performed on a mixed reality model consisting of two drillable rapid-prototyped layers separated by a free-space. Within the free-space, a linear virtual force model is applied to simulate drill contact with soft tissue. RESULTS: Testing illustrated the effectiveness of gravity cancellation. Additionally, the system exhibited excellent performance given random inputs and during the drill's passage between real and virtual components of the model. No issues with registration at model boundaries were encountered. CONCLUSION: These tests provide a proof of concept for the initial stages in the development of a novel mixed-reality temporal bone simulator. PMID- 25927309 TI - The protein phosphatase activity of PTEN is essential for regulating neural stem cell differentiation. AB - BACKGROUND: The tumor suppressor gene Phosphatase and tensin homolog (PTEN) is highly expressed in neural progenitor cells (NPCs) and plays an important role in development of the central nervous system. As a dual-specificity phosphatase, the loss of PTEN phosphatase activity has been linked to various diseases. RESULTS: Here we report that the protein phosphatase activity of Pten is critical for regulating differentiation of neural progenitor cells. First we found that deletion of Pten promotes neuronal differentiation. To determine whether the protein or lipid phosphatase activity is required for regulating neuronal differentiation, we generated phosphatase domain-specific Pten mutations. Interestingly, only expression of protein phosphatase-deficient mutant Y138L could mimic the effect of knocking down Pten, suggesting the protein phosphatase of Pten is critical for regulating NPC differentiation. Importantly, we showed that the wild-type and lipid phosphatase mutant (G129E) forms of Pten are able to rescue neuronal differentiation in Pten knockout NPCs, but mutants containing protein phosphatase mutant cannot. We further found that Pten-dependent dephosphorylation of CREB is critical for neuronal differentiation. CONCLUSION: Our data indicate that the protein phosphatase activity of PTEN is critical for regulating differentiation of NSCs during cortical development. PMID- 25927305 TI - Independent and combined effects of environmental factors and CYP2C19 polymorphisms on the risk of esophageal squamous cell carcinoma in Fujian Province of China. AB - BACKGROUND: The purpose of this study was to explore the effects of CYP2C19 gene polymorphisms and various environmental factors and their interactions on the risk of esophageal squamous cell carcinoma (ESCC) in a Chinese Han population. METHODS: A 1:2 frequency-matched case control study of 285 patients and 570 controls was conducted from June 2010 to May 2011 in AnXi of Fujian province, China. Environmental factors were investigated using a self-administered questionnaire and genotypes were determined using polymerase chain reaction restriction fragment length polymorphism based methods. Unconditional logistic regression models were used for statistical evaluation. RESULTS: Current or former smoking, consumption of pickled vegetables or hot beverages/food, having a first degree relative with ESCC and history of reflux esophagitis were significantly associated with increased ESCC risk, whereas tea drinking and consumption of fresh vegetables and fruits were significantly associated with decreased risk. The CYP2C19*2 GA/AA genotype was significantly more prevalent in ESCC patients and individuals with at least one copy of the CYP2C19*2 A allele had a 3.19-fold increased risk (adjusted 95% confidence interval (CI): 2.21-4.61, P < 0.001) of ESCC compared with those without this allele. We found no significant associations between CYP2C19*3 genotypes and ESCC. The Cyp2C19*2 polymorphism appeared to have a multiplicative joint effect with tea drinking and hot beverage/food consumption (gene-tea drinking: P(interaction) = 0.042; hot beverage/food consumption: P(interaction) = 6.98 * 10(-6)) and an additive joint effect with pickled vegetable consumption (interaction contrast ratio = 1.96, 95% CI: 0.12-3.80). CONCLUSIONS: Our findings suggest that the CYP2C19*2 polymorphism plays an important role in the development of ESCC in the Chinese population, modified by tea drinking and consumption of pickled vegetables or hot beverages/food. Further studies are warranted to confirm our results. PMID- 25927310 TI - Determinants of care outcomes for patients who die in hospital in Ireland: a retrospective study. AB - BACKGROUND: More people die in hospital than in any other setting which is why it is important to study the outcomes of hospital care at end of life. This study analyses what influenced outcomes in a sample of patients who died in hospital in Ireland in 2008/9. The study was undertaken as part of the Irish Hospice Foundation's Hospice Friendly Hospitals Programme (2007-2012). METHODS: Outcomes of care were assessed by nurses, doctors and relatives who cared for the patient during the last week of life. Multi-level modelling was used to analyse how care outcomes were influenced by care inputs. RESULTS: The sample of 999 patients represents 10% of acute hospital deaths and 29% of community hospital deaths in Ireland in 2008/9. Five care outcomes were assessed for each patient: symptom experience, symptom management, patient care, acceptability of the way patient died, family support. Care outcomes during the last week of life tended to be better when: the patient had cancer; admission to hospital was planned rather than emergency; death occurred in a single room or where privacy, dignity and environment of the ward was better; team meetings were held; there was good communication with patients and relatives; relatives were facilitated to stay overnight and were present at the time of death; nursing staff were experienced and had training in end-of-life care; the hospital had specific objectives for developing end-of-life care in its service plan. CONCLUSIONS: The study shows significant differences in how care outcomes, including pain, were assessed by nurses, doctors and relatives. Care inputs operate in a mutually reinforcing manner to generate care outcomes which implies that improvements in one area are likely to have spill-over effects in others. Building on these findings, the Irish Hospice Foundation has developed an audit and review system to support quality improvement in all care settings where people die. PMID- 25927312 TI - A cross-sectional study assessing determinants of the attitude to the introduction of eHealth services among patients suffering from chronic conditions. AB - BACKGROUND: Provision of care to patients with chronic diseases remains a great challenge for modern health care systems. eHealth is indicated as one of the strategies which could improve care delivery to this group of patients. The main objective of this study was to assess determinants of the acceptance of the Internet use for provision of chosen health care services remaining in the scope of current nationwide eHealth initiative in Poland. METHODS: The survey was carried out among patients with diagnosed chronic conditions who were treated in three health care facilities in Krakow, Poland. Survey data was used to develop univariate and multivariate logistic regression models for six outcome variables originating from the items assessing the acceptance of specific types of eHealth applications. The variables used as predictors were related to the sociodemographic characteristics of respondents, burden related to chronic disease, and the use of the Internet and its perceived usefulness in making personal health-related decisions. RESULTS: Among 395 respondents, there were 60.3% of Internet users. Univariate logistic regression models developed for six types of eHealth solutions demonstrated their higher acceptance among younger respondents, living in urban areas, who have attained a higher level of education, used the Internet on their own, and were more confident about its usefulness in making health-related decisions. Furthermore, the duration of chronic disease and hospitalization due to chronic disease predicted the acceptance of some of eHealth applications. However, when combined in multivariate models, only the belief in the usefulness of the Internet (five of six models), level of education (four of six models), and previous hospitalization due to chronic disease (three of six models) maintained the effect on the independent variables. CONCLUSIONS: The perception of the usefulness of the Internet in making health-related decision is a key determinant of the acceptance of provision of health care services online among patients with chronic diseases. Among sociodemographic factors, only the level of education demonstrates a consistent impact on the level of acceptance. Interestingly, a greater burden of chronic disease related to previous hospitalizations leads to lower acceptance of eHealth solutions. PMID- 25927313 TI - Dual 3'Seq using deepSuperSAGE uncovers transcriptomes of interacting Salmonella enterica Typhimurium and human host cells. AB - BACKGROUND: The interaction of eukaryotic host and prokaryotic pathogen cells is linked to specific changes in the cellular proteome, and consequently to infection-related gene expression patterns of the involved cells. To simultaneously assess the transcriptomes of both organisms during their interaction we developed dual 3'Seq, a tag-based sequencing protocol that allows for exact quantification of differentially expressed transcripts in interacting pro- and eukaryotic cells without prior fixation or physical disruption of the interaction. RESULTS: Human epithelial cells were infected with Salmonella enterica Typhimurium as a model system for invasion of the intestinal epithelium, and the transcriptional response of the infected host cells together with the differential expression of invading and intracellular pathogen cells was determined by dual 3'Seq coupled with the next-generation sequencing-based transcriptome profiling technique deepSuperSAGE (deep Serial Analysis of Gene Expression). Annotation to reference transcriptomes comprising the operon structure of the employed S. enterica Typhimurium strain allowed for in silico separation of the interacting cells including quantification of polycistronic RNAs. Eighty-nine percent of the known loci are found to be transcribed in prokaryotic cells prior or subsequent to infection of the host, while 75% of all protein-coding loci are represented in the polyadenylated transcriptomes of human host cells. CONCLUSIONS: Dual 3'Seq was alternatively coupled to MACE (Massive Analysis of cDNA ends) to assess the advantages and drawbacks of a library preparation procedure that allows for sequencing of longer fragments. Additionally, the identified expression patterns of both organisms were validated by qRT-PCR using three independent biological replicates, which confirmed that RELB along with NFKB1 and NFKB2 are involved in the initial immune response of epithelial cells after infection with S. enterica Typhimurium. PMID- 25927315 TI - Comparing genomic prediction accuracy from purebred, crossbred and combined purebred and crossbred reference populations in sheep. AB - BACKGROUND: The accuracy of genomic prediction depends largely on the number of animals with phenotypes and genotypes. In some industries, such as sheep and beef cattle, data are often available from a mixture of breeds, multiple strains within a breed or from crossbred animals. The objective of this study was to compare the accuracy of genomic prediction for several economically important traits in sheep when using data from purebreds, crossbreds or a combination of those in a reference population. METHODS: The reference populations were purebred Merinos, crossbreds of Border Leicester (BL), Poll Dorset (PD) or White Suffolk (WS) with Merinos and combinations of purebred and crossbred animals. Genomic breeding values (GBV) were calculated based on genomic best linear unbiased prediction (GBLUP), using a genomic relationship matrix calculated based on 48 599 Ovine SNP (single nucleotide polymorphisms) genotypes. The accuracy of GBV was assessed in a group of purebred industry sires based on the correlation coefficient between GBV and accurate estimated breeding values based on progeny records. RESULTS: The accuracy of GBV for Merino sires increased with a larger purebred Merino reference population, but decreased when a large purebred Merino reference population was augmented with records from crossbred animals. The GBV accuracy for BL, PD and WS breeds based on crossbred data was the same or tended to decrease when more purebred Merinos were added to the crossbred reference population. The prediction accuracy for a particular breed was close to zero when the reference population did not contain any haplotypes of the target breed, except for some low accuracies that were obtained when predicting PD from WS and vice versa. CONCLUSIONS: This study demonstrates that crossbred animals can be used for genomic prediction of purebred animals using 50 k SNP marker density and GBLUP, but crossbred data provided lower accuracy than purebred data. Including data from distant breeds in a reference population had a neutral to slightly negative effect on the accuracy of genomic prediction. Accounting for differences in marker allele frequencies between breeds had only a small effect on the accuracy of genomic prediction from crossbred or combined crossbred and purebred reference populations. PMID- 25927318 TI - Post-stroke memory impairment among patients with vascular mild cognitive impairment. AB - BACKGROUND: The American Stroke Association/American Heart Association recommended the criteria for diagnosis of vascular cognitive impairment and memory impairment (MI) is a feature in the classification of vascular mild cognitive impairment (VaMCI). VaMCI patients with MI may differ in terms of infarct location or demographic features, so we evaluated the clinical characteristics associated with MI in patients with VaMCI. METHODS: A prospective multicenter study enrolled 353 acute ischemic stroke patients who underwent evaluation using the Korean Vascular Cognitive Impairment Harmonization Standard Neuropsychological Protocol at three months after onset. The association between MI and demographic features, stroke risk factors, and infarct location was assessed. RESULTS: VaMCI was diagnosed in 141 patients, and 58 (41.1%) exhibited MI. Proportions of men and of left side infarcts were higher in VaMCI with MI than those without (75.9 vs. 57.8%, P = 0.03, 66.7 vs. 47%, P = 0.02). Multiple logistic analyses revealed that male sex (odds ratio [OR] 3.07, 95% confidence interval [95% CI] 1.12-8.42), left-side infarcts (OR 3.14, 95% CI 1.37-7.20), and basal ganglia/internal capsule infarcts (OR 4.53, 95% CI 1.55-13.22) were associated with MI after adjusting other demographic variables, vascular risk factors, and subtypes of stroke. CONCLUSIONS: MI is associated with sex and infarct location in VaMCI patients. PMID- 25927321 TI - Preference, satisfaction and critical errors with Genuair and Breezhaler inhalers in patients with COPD: a randomised, cross-over, multicentre study. AB - BACKGROUND: The specific attributes of inhaler devices can influence patient use, satisfaction and treatment compliance, and may ultimately impact on clinical outcomes in patients with chronic obstructive pulmonary disease (COPD). AIMS: To assess patient preference, satisfaction and critical inhaler technique errors with Genuair (a multidose inhaler) and Breezhaler (a single-dose inhaler) after 2 weeks of daily use. METHODS: Patients with COPD and moderate to severe airflow obstruction were randomised in a cross-over, open-label, multicentre study to consecutive once-daily inhalations of placebo via Genuair and Breezhaler, in addition to current COPD medication. The primary end point was the proportion of patients who preferred Genuair versus Breezhaler after 2 weeks (Patient Satisfaction and Preference Questionnaire). Other end points included overall satisfaction and correct use of the inhalers after 2 weeks, and willingness to continue with each device. RESULTS: Of the 128 patients enrolled, 127 were included in the safety population (male n=91; mean age 67.6 years). Of the 110 of the 123 patients in the intent-to-treat population who indicated an inhaler preference, statistically significantly more patients preferred Genuair than Breezhaler (72.7 vs. 27.3%; P<0.001). Mean overall satisfaction scores were also greater for Genuair than for Breezhaler (5.9 vs. 5.3, respectively; P<0.001). After 2 weeks, there was no statistically significant difference in the number of patients who made ?1 critical inhaler technique error with Breezhaler than with Genuair (7.3 vs. 3.3%, respectively). CONCLUSIONS: Patient overall preference and satisfaction was significantly higher with Genuair compared with Breezhaler. The proportion of patients making critical inhaler technique errors was low with Genuair and Breezhaler. PMID- 25927324 TI - Platycodin D isolated from the aerial parts of Platycodon grandiflorum protects alcohol-induced liver injury in mice. AB - Platycodin D (PD) is the main active saponin of Platycodon grandiflorum (PG) and is reported to exhibit multiple biological effects, including anti-tumor, anti inflammation, and anti-obesity properties. Although recently there have been many research reports on the chemical constituents of the plant's roots, only few works have been reported on the aerial parts of PG. In the present study, we report the first isolation of PD from the aerial parts of PG and its protective effect against acute alcohol-induced liver oxidative injury and inflammatory response in mice. In brief, the protective effect was evaluated by tracking biochemical markers, enzymatic antioxidants and proinflammatory cytokines in serum and liver tissue. The results indicated that PD pretreatment significantly decreased the levels of triglyceride (TG), total cholesterol (TC), low density lipoprotein cholesterol (L-DLC) in serum and malondialdehyde (MDA) in liver. PD was also found to increase the activities of catalase (CAT), superoxide dismutase (SOD), and glutathione peroxidase (GSH-Px) in the liver (p < 0.05). In addition, PD markedly decreased the levels of proinflammatory cytokines, including tumor necrosis factor-alpha (TNF-alpha), interleukin (IL)-1beta, and IL-6, which was caused by alcohol exposure (p < 0.05). In contrast, histopathological examinations revealed that PD pretreatment noticeably prevented alcohol-induced hepatocyte apoptosis and steatosis. Collectively, the present study clearly suggests that the protective effect exhibited by PD on alcohol-induced liver oxidative injury may occur via the alleviation of oxidative stress and inflammatory response. PMID- 25927327 TI - Base flipping in open complex formation at bacterial promoters. AB - In the process of transcription initiation, the bacterial RNA polymerase binds double-stranded (ds) promoter DNA and subsequently effects strand separation of 12 to 14 base pairs (bp), including the start site of transcription, to form the so-called "open complex" (also referred to as RP(o)). This complex is competent to initiate RNA synthesis. Here we will review the role of sigma70 and its homologs in the strand separation process, and evidence that strand separation is initiated at the -11A (the A of the non-template strand that is 11 bp upstream from the transcription start site) of the promoter. By using the fluorescent adenine analog, 2-aminopurine, it was demonstrated that the -11A on the non template strand flips out of the DNA helix and into a hydrophobic pocket where it stacks with tyrosine 430 of sigma70. Open complexes are remarkably stable, even though in vivo, and under most experimental conditions in vitro, dsDNA is much more stable than its strand-separated form. Subsequent structural studies of other researchers have confirmed that in the open complex the -11A has flipped into a hydrophobic pocket of sigma70. It was also revealed that RPo was stabilized by three additional bases of the non-template strand being flipped out of the helix and into hydrophobic pockets, further preventing re-annealing of the two complementary DNA strands. PMID- 25927328 TI - Nanofilament Formation and Regeneration During Cu/Al2O3 Resistive Memory Switching. AB - Conductive bridge random access memory (CBRAM) is a leading candidate to supersede flash memory, but poor understanding of its switching process impedes widespread implementation. The underlying physics and basic, unresolved issues such as the connecting filament's growth direction can be revealed with direct imaging, but the nanoscale target region is completely encased and thus difficult to access with real-time, high-resolution probes. In Pt/Al2O3/Cu CBRAM devices with a realistic topology, we find that the filament grows backward toward the source metal electrode. This observation, consistent over many cycles in different devices, corroborates the standard electrochemical metallization model of CBRAM operation. Time-resolved scanning transmission electron microscopy (STEM) reveals distinct nucleation-limited and potential-limited no-growth periods occurring before and after a connection is made, respectively. The subfemtoampere ionic currents visualized move some thousands of atoms during a switch and lag the nanoampere electronic currents. PMID- 25927329 TI - Adherence to treatment in children and adolescents with cystic fibrosis: a cross sectional, multi-method study investigating the influence of beliefs about treatment and parental depressive symptoms. AB - BACKGROUND: Adherence to treatment is often reported to be low in children with cystic fibrosis. Adherence in cystic fibrosis is an important research area and more research is needed to better understand family barriers to adherence in order for clinicians to provide appropriate intervention. The aim of this study was to evaluate adherence to enzyme supplements, vitamins and chest physiotherapy in children with cystic fibrosis and to determine if any modifiable risk factors are associated with adherence. METHODS: A sample of 100 children (<=18 years) with cystic fibrosis (44 male; median [range] 10.1 [0.2-18.6] years) and their parents were recruited to the study from the Northern Ireland Paediatric Cystic Fibrosis Centre. Adherence to enzyme supplements, vitamins and chest physiotherapy was assessed using a multi-method approach including; Medication Adherence Report Scale, pharmacy prescription refill data and general practitioner prescription issue data. Beliefs about treatments were assessed using refined versions of the Beliefs about Medicines Questionnaire-specific. Parental depressive symptoms were assessed using the Center for Epidemiologic Studies Depression Scale. RESULTS: Using the multi-method approach 72% of children were classified as low-adherers to enzyme supplements, 59% low-adherers to vitamins and 49% low-adherers to chest physiotherapy. Variations in adherence were observed between measurement methods, treatments and respondents. Parental necessity beliefs and child age were significant independent predictors of child adherence to enzyme supplements and chest physiotherapy, but parental depressive symptoms were not found to be predictive of adherence. CONCLUSIONS: Child age and parental beliefs about treatments should be taken into account by clinicians when addressing adherence at routine clinic appointments. Low adherence is more likely to occur in older children, whereas, better adherence to cystic fibrosis therapies is more likely in children whose parents strongly believe the treatments are necessary. The necessity of treatments should be reinforced regularly to both parents and children. PMID- 25927331 TI - Raman spectroscopic sensing of carbonate intercalation in breast microcalcifications at stereotactic biopsy. AB - Microcalcifications are an early mammographic sign of breast cancer and frequent target for stereotactic biopsy. Despite their indisputable value, microcalcifications, particularly of the type II variety that are comprised of calcium hydroxyapatite deposits, remain one of the least understood disease markers. Here we employed Raman spectroscopy to elucidate the relationship between pathogenicity of breast lesions in fresh biopsy cores and composition of type II microcalcifications. Using a chemometric model of chemical-morphological constituents, acquired Raman spectra were translated to characterize chemical makeup of the lesions. We find that increase in carbonate intercalation in the hydroxyapatite lattice can be reliably employed to differentiate benign from malignant lesions, with algorithms based only on carbonate and cytoplasmic protein content exhibiting excellent negative predictive value (93-98%). Our findings highlight the importance of calcium carbonate, an underrated constituent of microcalcifications, as a spectroscopic marker in breast pathology evaluation and pave the way for improved biopsy guidance. PMID- 25927332 TI - Change in serum sodium level predicts clinical manifestations of transurethral resection syndrome: a retrospective review. AB - BACKGROUND: Patients undergoing transurethral resection (TUR) of the prostate are at risk of TUR syndrome, generally defined as having cardiovascular and/or neurological manifestations, along with serum sodium concentrations less than or equal to 125 mmol/l. As these symptoms can also occur in patients with serum sodium greater than 125 mmol/l, this study aimed to investigate the relationship between serum sodium concentrations and neurological manifestations of TUR syndrome. METHODS: Data on patients who underwent TUR of the prostate under local anesthesia over an 8-year period were retrospectively reviewed. Based on their cardiovascular and neurological manifestations, patients were divided into two groups: a symptomatic and an asymptomatic group. Logistic regression analysis was used to detect the risk factors for being symptomatic. Receiver operator characteristic (ROC) curve analysis was used to determine the optimal cutoff value of estimated change in serum sodium level that could predict the development of clinical manifestation of TUR syndrome. RESULTS: Of the 229 patients, 60 showed symptoms. Serum sodium level correlated with neurological score (Spearman's correlation coefficient > 0.5). Logistic regression detected that the risk factors for being symptomatic were serum sodium level variables, operation time longer than or equal 90 min, and presence of continuous drainage from the bladder. ROC curve analysis showed that a change in serum sodium level of 7.4 mmol/l was the optimal cutoff value, with a sensitivity of 0.72, a specificity of 0.87, and an area under the curve (AUC) of 0.87. ROC curve analysis also showed that a 7.0% change in serum sodium level was optimal for this parameter, with a sensitivity of 0.70, a specificity of 0.89, and an AUC of 0.87. CONCLUSIONS: Changes in serum sodium concentration of > 7 mmol/l and of > 7% could predict the development of cardiovascular and neurological manifestations, which were assumed to be symptoms of TUR syndrome. PMID- 25927334 TI - Comparison of radiation regimens in the treatment of Glioblastoma multiforme: results from a single institution. AB - BACKGROUND: The optimal fractionation schedule of radiotherapy (RT) for Glioblastoma multiforme (GBM) is yet to be determined. We aim to compare different fractionation regimens and identify prognostic factors to better tailor RT for newly diagnosed GBM patients. METHODS: All data for patients who underwent surgery for GBM between January 2005 and December 2012 were compiled. Clinical information was collected using patient charts and government registry. Cox analysis was used to identify variables affecting survival and treatment outcome. RESULTS: The median follow-up time was 13.2 months. Two hundred and seventy-six patients met the inclusion criteria, including 147 patients in the 60 Gy in 30 fractions (ConvRT) group, 86 patients in the 60 Gy in 20 fractions (HF60) group, and 43 patients in the 40 Gy in 15 fractions (HF40) group. Median survival (MS) was 16.0 months with a median progression-free survival (PFS) of 9.23 months in the ConvRT group. This was comparable to outcome in the HF60 group with MS 15.0 months and a median PFS of 9.1 months. Patients in the HF40 group had MS of 8 months, with a median PFS 5.4 months. Cox analysis showed no significant difference in OS between the ConvRT and HF60 groups but worse outcome in the HF40 group (HR 2.22, P=0.04). MGMT methylation, extent of resection, use of chemotherapy, and repeat surgery were found to be significant independent prognostic factors for survival. CONCLUSIONS: HF60 constitutes a safe RT approach that shows survival comparable to standard RT while allowing for a shorter treatment time. PMID- 25927335 TI - The tuberculin skin test in school going adolescents in South India: associations of socio-demographic and clinical characteristics with TST positivity and non response. AB - BACKGROUND: India has generally used 1 TU purified protein derivative (PPD) as opposed to 2 TU PPD globally, limiting comparisons. It is important to assess latent TB infection in adolescents given that they may be a target group for new post-exposure TB vaccines. The aim of this study is to describe the pattern and associations of tuberculin skin test (TST) responses (0.1 ml 2 TU) in adolescents in South India. METHODS: 6643 school-going adolescents (11 to <18 years) underwent TST. Trained tuberculin reader made the reading visit between 48 and 96 hours after the skin test RESULTS: Of 6608 available TST results, 9% had 0 mm, and 12% >=10 mm responses. The proportion of TST positive (>=10 mm) was higher among older children, boys, those with a history of TB contact and reported BCG immunization Those with no TST response (0 mm) included younger participants (<14 years), those whose mothers were illiterate and those with a recent history of weight loss. Those of a higher socio-economic status (houses with brick walls, LPG gas as cooking fuel) and those with a visible BCG scar were less likely to be non-responders. CONCLUSION: Proportion of non-responders was lower than elsewhere in the world. Proportion of TST positivity was higher in those already exposed to TB and in children who had been BCG immunized, with a zero response more likely in younger adolescents and those with recent weight loss. PMID- 25927336 TI - Update in cardiology: evidence published in 2014. PMID- 25927338 TI - Response to 'interspinous bursitis is common in polymyalgia rheumatica, but is not associated with spinal pain'. PMID- 25927337 TI - Dissolution and biodurability: Important parameters needed for risk assessment of nanomaterials. AB - Biopersistence and biodurability have the potential to influence the long-term toxicity and hence pathogenicity of particles that deposit in the body. Therefore, biopersistence and biodurability are considered to be important parameters needed for the risk assessment of particles and fibres. Dissolution, as a measure of biodurability, is dependent on the chemical and physical properties (size, surface area, etc.) of particles and fibres and also of the suspension medium including its ionic strength, pH, and temperature. In vitro dissolution tests can provide useful insights as to how particles and fibres may react in biological environments; particles and fibres that release ions at a higher rate when suspended in vitro in a specific simulated biological fluid will be expected to do so when they exist in a similar biological environment in vivo. Dissolution of particles and fibres can follow different reaction kinetics. For example, the majority of micro-sized particles and fibres follow zero-order reaction kinetics. In this case, although it is possible to calculate the half time of a particle or fibre, such calculation will be dependent on the initial concentration of the investigated particle or fibre. Such dependence was eliminated in the shrinking sphere and fibre models where it was possible to estimate the lifetimes of particles and fibres as a measure of their biodurability. The latter models can be adapted for the dissolution studies of nanomaterials. However, the models may apply only to nanomaterials where their dissolution follows zero-order kinetics. The dissolution of most nanomaterials follows first-order kinetics where dependence on their initial concentration of the investigated nanomaterials is not required and therefore it is possible to estimate their half-times as a measure of their biodurability. In dissolution kinetics for micro-sized and nano-sized particles and fibres, knowledge of dissolution rate constants is necessary to understand biodurability. Unfortunately, many studies on dissolution of nanoparticles and nanofibres do not determine the dissolution rates and dissolution rate constants. The recommendation is that these parameters should be considered as part of the important descriptors of particle and fibre physicochemical properties, which in turn, will enable the determination of their biodurability. PMID- 25927339 TI - Chemical State Analysis of Phosphorus Performed by X-ray Emission Spectroscopy. AB - An experimental and theoretical study of phosphorus electronic structure based on high energy resolution X-ray emission spectroscopy was performed. The Kalpha and Kbeta emission spectra of several phosphorus compounds were recorded using monochromatic synchrotron radiation and megaelectronvolt (MeV) proton beam for target excitation. Measured spectra are compared to the results of ab initio quantum chemical calculations based on density functional theory (DFT). Clear correlation between energy position of the Kalpha emission line and the phosphorus formal oxidation state as well as DFT-calculated number of valence electrons is obtained; measured energy shifts are reproduced by the calculations. Chemical sensitivity is increased further by looking at the Kbeta emission spectra probing directly the structure of occupied molecular orbitals. Energies and relative intensities of main components are given together with the calculated average atomic character of the corresponding molecular orbitals involved in transitions. PMID- 25927340 TI - Synthesis, Photochemical Properties, and Cytotoxicities of 2H-Naphtho[1,2-b]pyran and Its Photodimers. AB - A 2H-naphtho[1,2-b]pyran, prepared by dimerization of 2-bromo-3-methyl-1,4 naphthoquinone and O-methylation, readily undergoes solid-state [2 + 2] photodimerization to give a photodimer in excellent yield and with excellent selectivity. Retro [2 + 2] cycloaddition can be achieved by irradiation of a solution of the photodimer in chloroform. Interestingly, the 2H-naphtho[1,2 b]pyran dimerizes with a skeletal rearrangement to afford 2,5-dihydro-1 benzoxepin dimers upon irradiation in methanol or via irradiation with hexamethylditin. Furthermore, treatment of the resulting dimers with triethylamine regenerates the 2H-naphtho[1,2-b]pyran monomer. Significant differences in the color, fluorescence, and cytotoxic properties of the monomer and dimers were observed. PMID- 25927341 TI - Methyl-CpG-binding domain proteins: readers of the epigenome. AB - How DNA methylation is interpreted and influences genome regulation remains largely unknown. Proteins of the methyl-CpG-binding domain (MBD) family are primary candidates for the readout of DNA methylation as they recruit chromatin remodelers, histone deacetylases and methylases to methylated DNA associated with gene repression. MBD protein binding requires both functional MBD domains and methyl-CpGs; however, some MBD proteins also bind unmethylated DNA and active regulatory regions via alternative regulatory domains or interaction with the nucleosome remodeling deacetylase (NuRD/Mi-2) complex members. Mutations within MBD domains occur in many diseases, including neurological disorders and cancers, leading to loss of MBD binding specificity to methylated sites and gene deregulation. Here, we summarize the current state of knowledge about MBD proteins and their role as readers of the epigenome. PMID- 25927342 TI - Noncircular stable displacement patterns in a meshed porous layer. AB - We report noncircular, stable liquid propagation patterns in a displacement process in a confined thin patterned porous layer. For constant fluid injection rates, the average front location of the interface r(t) exhibits a power-law behavior r ? t(1/2); however, when surface tension effects become important, the interface displays noncircular shapes, e.g., square, rectangular, or octagonal, and maintains the same shape during most of the injection process. The interface shape is controlled by the value of a dimensionless group representing the strength of surface tension stresses relative to stresses accompanying injection. Furthermore, we show that the propagation patterns of the interface can be controlled by the relative orientation of the different porous layers. PMID- 25927343 TI - A brief patient-reported outcome instrument for primary care: German translation and validation of the Measure Yourself Medical Outcome Profile (MYMOP). AB - BACKGROUND: Measure Yourself Medical Outcome Profile (MYMOP) is a patient generated outcome instrument capable of measuring effects from a wide range of health care interventions. This paper reports the translation of this instrument into German (MYMOP-D) and the assessment of validity and sensitivity to change for the MYMOP-D. The instrument was piloted in a German primary care context. METHODS: The translation process was conducted according to international guidelines. Recruited patients of both general practitioners and non-medical Complementary and Alternative Medicine (CAM) practitioners ("Heilpraktiker") in the German state of Baden-Wuerttemberg completed a questionnaire comprised of the MYMOP-D and the EQ-5D. Responses were analysed to assess construct validity. For assessing the instrument's sensitivity to change, patients received the MYMOP-D again after four weeks at which point they were also asked for their subjective views on change of symptoms. Correlation between MYMOP-D and EQ-5D and sensitivity to change as gradient in score change and as standardized response mean (SRM) were calculated. RESULTS: 476 patients from general practices and 91 patients of CAM practitioners were included. Construct validity of the MYMOP-D was given with a correlation of r = .47 with the EQ-5D. Sensitivity to change for subjective change of symptoms could only be analysed for improvement or no change of symptoms, as only 12 patients reported deterioration of symptoms. Results showed the expected smooth gradient with 2.2, 1.3, and 0.5 points of change for large, little improvement and no change, respectively. SRM for MYMOP-D Profile Score was 0.88. CONCLUSIONS: The MYMOP-D shows excellent construct validity. It is able to detect changes when symptoms in patients improve or remain unchanged. Deterioration of symptoms could not be evaluated due to too few data. With its brevity and simplicity, it might be an important tool for enhancing patient centred care in the German health care context. PMID- 25927344 TI - Controlling the magnetic structure of Co/Pd thin films by direct laser interference patterning. AB - Nanosecond pulsed two-beam laser interference is used to generate two-dimensional temperature patterns on a magnetic thin film sample. We show that the original domain structure of a [Co/Pd] multilayer thin film changes drastically upon exceeding the Curie temperature by thermal demagnetization. At even higher temperatures the multilayer system is irreversibly changed. In this area no out of-plane magnetization can be found before and after a subsequent ac demagnetization. These findings are supported by numerical simulations using the Landau-Lifshitz-Bloch formalism which shows the importance of defect sites and anisotropy changes to model the experiments. Thus, a one-dimensional temperature pattern can be transferred into a magnetic stripe pattern. In this way one can produce magnetic nanowire arrays with lateral dimensions of the order of 100 nm. Typical patterned areas are in the range of several square millimeters. Hence, the parallel direct laser interference patterning method of magnetic thin films is an attractive alternative to the conventional serial electron beam writing of magnetic nanostructures. PMID- 25927345 TI - Divergent synthesis of 4,6-diarylated pyridin-2(1H)-ones from chalcones: novel access to 2,4,6-triaryl pyridines. AB - A wide range of 4,6-diarylated/heterylated pyridin-2(1H)-one derivatives were synthesized in good to excellent yields from 1,3-diarylated/heterylated-2-propen 1-ones (chalcones) in one pot under metal and base-free conditions. This domino reaction suggests a novel mechanism comprising of Michael addition followed by amination, subsequent intramolecular amidation and finally dehydronitrosation. The usefulness of the designed 4,6-diarylated/heterylated pyridin-2(1H)-one derivatives has further been demonstrated by synthesizing medicinally important 2,4,6-triaryl/heteryl pyridines via Pd-catalyzed cross-coupling reaction. PMID- 25927346 TI - PRMT5- mediated symmetric arginine dimethylation is attenuated by mutant huntingtin and is impaired in Huntington's disease (HD). AB - Abnormal protein interactions of mutant huntingtin (Htt) triggered by polyglutamine expansion are thought to mediate Huntington's disease (HD) pathogenesis. Here, we explored a functional interaction of Htt with protein arginine methyltransferase 5 (PRMT5), an enzyme mediating symmetrical dimethylation of arginine (sDMA) of key cellular proteins, including histones, and spliceosomal Sm proteins. Gene transcription and RNA splicing are impaired in HD. We demonstrated PRMT5 and Htt interaction and their co-localization in transfected neurons and in HD brain. As a result of this interaction, normal (but to a lesser extend mutant) Htt stimulated PRMT5 activity in vitro. SDMA of histones H2A and H4 was reduced in the presence of mutant Htt in primary cultured neurons and in HD brain, consistent with a demonstrated reduction in R3Me2s occupancy at the transcriptionally repressed promoters in HD brain. SDMA of another PRMT5 substrate, Cajal body marker coilin, was also reduced in the HD mouse model and in human HD brain. Finally, compensation of PRMT5 deficiency by ectopic expression of PRMT5/MEP50 complexes, or by the knock-down of H4R3Me2 demethylase JMJD6, reversed the toxic effects of mutant Htt in primary cortical neurons, suggesting that PRMT5 deficiency may mediate, at least in part, HD pathogenesis. These studies revealed a potential new mechanism for disruption of gene expression and RNA processing in HD, involving a loss of normal function of Htt in facilitation of PRMT5, supporting the idea that epigenetic regulation of gene transcription may be involved in HD and highlighting symmetric dimethylation of arginine as potential new therapeutic target. PMID- 25927347 TI - Is immune checkpoint modulation a potential therapeutic option in triple negative breast cancer? PMID- 25927348 TI - Red blood cell transfusion and mortality effect in aneurysmal subarachnoid hemorrhage: a systematic review and meta-analysis protocol. AB - BACKGROUND: Aneurysmal subarachnoid hemorrhage (aSAH) is a devastating disease that leads to important morbidity and mortality in a young patient population. Anemia following aSAH is common and may be exacerbated by the treatments instituted by clinicians as part of standard care. The role and optimal thresholds for red blood cell (RBC) transfusion in this patient population remains unknown. METHODS/DESIGN: We will conduct a systematic review of the literature using MEDLINE, EMBASE, and EBM Reviews (including Cochrane Central databases) using a comprehensive search strategy for observational and interventional studies of RBC transfusion in aSAH. Our primary objective is to evaluate the association of RBC transfusion with mortality in aSAH patients. Secondary objectives include a) determining associations between RBC transfusion and poor neurologic outcome, b) defining an optimal RBC transfusion threshold in aSAH patients, and c) describing complications associated with RBC transfusion in aSAH patients. We plan a descriptive reporting of all included citations including study characteristics, methodological quality, and reported outcomes. Clinical and statistical heterogeneity observed between studies will be described. If appropriate, meta-analyses of suitable studies and interpretation of their results will be performed. Effect measures will be converted to obtain relative risks and odds ratios (RR and ORs) with 95% confidence intervals and pooled according to study design (randomized trials and observational studies respectively) using a random effects model. DISCUSSION: This review will summarize the existing observational and trial evidence regarding RBC transfusion in aSAH patients. The analytical plan has made considerations for different study designs, both observational and interventional in nature, and will summarize the best available evidence to inform the end user and policy and guideline producers and to highlight areas in need of further study. SYSTEMATIC REVIEW REGISTRATION: PROSPERO CRD42014014806. PMID- 25927349 TI - Biological synthesis of coumarins in Escherichia coli. AB - BACKGROUND: Coumarins are a major group of plant secondary metabolites that serves as defense compounds against pathogens. Although coumarins can be obtained from diverse plant sources, the use of microorganisms to synthesize them could be an alternative way to supply building blocks for the synthesis of diverse coumarin derivatives. RESULTS: Constructs harboring two genes, F6'H (encoding feruloyl CoA 6' hydroxylase) and 4CL (encoding 4-coumarate CoA:ligase), were manipulated to increase the productivity of coumarins. Escherichia coli expressing the two genes was cultured in medium supplemented with hydroxycinnamic acids (HCs) including p-coumaric acid, caffeic acid, and ferulic acid, resulting in the synthesis of the corresponding coumarins, umbelliferone, esculetin, and scopoletin. Cell concentration and initial substrate feeding concentration were optimized. In addition, umbelliferone, and esculetin were synthesized from glucose by using a ybgC deletion mutant and co-expressing tyrosine ammonia lyase and other genes involved in the tyrosine biosynthesis pathway. CONCLUSIONS: To produce coumarin derivatives (umbelliferone, scopoletin, and esculetin) in E. coli, several constructs containing F6'H and 4CL were made, and their ability to synthesize coumarin derivatives was tested. The solubility of F6'H was critical for the final yield. After optimization, 82.9 mg/L of umbelliferone, 79.5 mg/L of scopoletin, and 52.3 mg/L of esculetin were biosynthesized from the corresponding HCs, respectively in E. coli. Umbelliferone and esculetin were also synthesized from glucose using engineered E. coli strains. The final yields of umbelliferone and esculetin were 66.1 and 61.4 mg/L, respectively. PMID- 25927350 TI - Early mobilization on continuous renal replacement therapy is safe and may improve filter life. PMID- 25927351 TI - Pre-emptive steroids for a severe oedematous Buruli ulcer lesion: a case report. AB - INTRODUCTION: Severe oedematous forms of Buruli ulcer (BU) often result in extensive tissue destruction, even with the institution of appropriate antibiotic treatment, leading to reconstructive surgery and long-term disability. We report a case of a patient with severe oedematous BU, which describes for the first time the pre-emptive use of prednisolone therapy commenced at the time of antibiotic initiation aimed at limiting the ongoing tissue destruction and its secondary sequelae. CASE PRESENTATION: A 91-year-old Australian-born Caucasian woman presented with a WHO category 3 oedematous BU lesion on the anterior aspect of her right ankle that she had first noticed three weeks earlier. Treatment was commenced with an antibiotic combination of rifampicin and ciprofloxacin. At the same time, pre-emptive prednisolone was commenced (a dose of 0.5mg/kg daily). Treatment resulted in rapid and significant reduction in the size of the induration associated with the lesion, and no significant increase in the size of the skin ulceration. Antibiotics were continued for 56 days and prednisolone therapy ceased 130 days after antibiotics commenced. No surgery was required. The wound healed completely after 10 months and there was no long-term limitation of movement at the ankle joint. CONCLUSIONS: Pre-emptive corticosteroid therapy may prevent further progressive tissue necrosis and the need for secondary reconstructive surgery that commonly occurs during the antibiotic treatment of severe odematous forms of BU. PMID- 25927352 TI - "Post-Gay" Yet? The Relevance of the Lesbian and Gay Scene to Same-Sex Attracted Young People in Contemporary Australia. AB - In recent years, the lesbian and gay "scene" of bars, nightclubs, and dance parties has been undergoing a structural decline in many Western cities. This article aimed to examine the relevance of the scene to same-sex attracted young adults amid these changes. An online survey was conducted with 572 same-sex attracted young women and men in Sydney. Only a minority of respondents participated in the scene at least weekly (16%), and the majority did not regard the scene as important to their leisure time (60%). However, respondents valued the scene as a space to connect with other same-sex attracted people and display same-sex affection without fear of hostility. Lesbian and gay identified respondents tended to be more socially engaged with the scene compared to other same-sex attracted respondents. The findings suggest that while the scene continues to be valued by many same-sex attracted young people, improved social attitudes have made participating in the scene less of an imperative. PMID- 25927353 TI - A New Regulatory Framework for Platelet-Rich Plasma in Spain. PMID- 25927354 TI - Identification of Synovial Fluid Biomarkers for Knee Osteoarthritis and Correlation with Radiographic Assessment. AB - Osteoarthritis (OA) is a costly and debilitating condition that is typically not diagnosed early enough to prevent progression of disease. The purpose of this study was to evaluate synovial fluid from knees with and without OA for potential markers of joint inflammation and degradation and to correlate these findings with radiographic severity of disease. With Institutional Review Board approval, synovial fluid samples were collected before the patient undergoing total knee arthroplasty. Control knees (n = 3) were patients younger than 30 years of age with no history of anterior cruciate ligament, posterior cruciate ligament, or meniscal injury, and no surgical history for either knee. Weight-bearing, anterior-posterior radiographic views were used to determine radiographic OA severity using the modified Kellgren and Lawrence scale. Synovial fluid samples from 18 patients (21 knees) were analyzed using a multiplex assay. Matrix metalloproteinase (MMP)-1 (p < 0.001), interleukin (IL)-6 (p < 0.013), IL-8 (p < 0.024), and Chemokine (C-C motif) ligand 5 (CCL5) (p < 0.006) were significantly higher in the synovial fluid of OA patients compared with normal patients. The radiographic score was significantly higher in patients with OA compared with normal knees (p < 0.002). MMP-1 had a moderate positive correlation with MMP-2, IL-6, IL-8, and CCL5. IL-6 had a strong positive correlation with IL-8 and a moderate positive correlation with MMP-2. Monocyte chemotactic protein 1 had a moderate positive correlation with IL-6 and a strong positive correlation with IL 8. Radiographic scores had a strong positive correlation with IL-6 and IL-8 and a moderate positive correlation with MCP-1. These data provide novel and clinically relevant information for the investigation of synovial fluid biomarkers for knee OA. PMID- 25927355 TI - Stable Meniscal Tears Left In Situ at the Time of Arthroscopic Anterior Cruciate Ligament Reconstruction: A Systematic Review. AB - Meniscal tears can be incidentally encountered at the time of anterior cruciate ligament (ACL) reconstruction. In these cases, the surgeon has several treatment options that include benign neglect, debridement, trephination, and repair. The authors performed a systematic review of the literature studying the various treatment options for meniscal tears discovered at the time of ACL reconstruction. This systematic review included eight articles that had relevant data regarding benign neglect compared with debridement, trephination, or repair of incidentally encountered meniscal tears. Combined data from these studies resulted in a total of 646 meniscal tears treated with benign neglect with follow up information available. Importantly, there were differences in reoperation rates between medial and lateral meniscal tears left in situ. However, stable medial and lateral meniscal tears treated with benign neglect did not have different subjective or objective outcomes than those treated with surgical intervention. This systematic review concludes that when stable meniscal tears are encountered at the time of arthroscopic ACL reconstruction, benign neglect can be used for a successful outcome. PMID- 25927357 TI - Taking a Closer Look--Continuous Glucose Monitoring in Non-Critically Ill Hospitalized Patients with Type 2 Diabetes Mellitus Under Basal-Bolus Insulin Therapy. AB - BACKGROUND: Inpatient glucose management is based on four daily capillary blood glucose (BG) measurements. The aim was to test the capability of continuous glucose monitoring (CGM) for assessing the clinical impact and safety of basal bolus insulin therapy in non-critically ill hospitalized patients with type 2 diabetes mellitus (T2DM). MATERIALS AND METHODS: Eighty-four patients with T2DM (age, 68+/-10 years; glycosylated hemoglobin, 72+/-28 mmol/mol; body mass index, 31+/-7 kg/m(2)) were treated with basal-bolus insulin. CGM was performed with the iPro((r))2 system (Medtronic MiniMed, Northridge, CA) and calibrated retrospectively. RESULTS: A remarkable consistency between CGM and BG measurements and therapy improvement was shown over the study period of 501 patient-days. The number of CGM and BG measurements (CGM/BG) in the range from 3.9-10 mmol/L increased from 67.7%/67.2% (on Day 1) to 77.5%/78.6% (on the last day) (P<0.04). The number of low glycemic episodes (3.3 to <3.9 mmol/L) during nighttime detected by CGM was 15-fold higher, and the number of episodes >13.9 mmol/L detected by CGM during night was 12.5-fold higher than the values from the BG measurements. Ninety-nine percent of data points were in the clinically accurate or acceptable Clarke Error Grid Zones A+B, and the relative numbers of correctly identified episodes of <3.9 and >13.9 mmol/L detected by CGM (sensitivity) were 47.3% and 81.5%, respectively. CONCLUSIONS: Our data exhibit a good agreement between overall CGM and BG measurements, but there were a high number of missed hypo- and hyperglycemic episodes with BG measurements, particularly during nighttime. Overall assessment of glycemic control using CGM is feasible, whereas the use of CGM for individualized therapy decisions needs further improvement. PMID- 25927356 TI - Identification of a comprehensive spectrum of genetic factors for hereditary breast cancer in a Chinese population by next-generation sequencing. AB - The genetic etiology of hereditary breast cancer has not been fully elucidated. Although germline mutations of high-penetrance genes such as BRCA1/2 are implicated in development of hereditary breast cancers, at least half of all breast cancer families are not linked to these genes. To identify a comprehensive spectrum of genetic factors for hereditary breast cancer in a Chinese population, we performed an analysis of germline mutations in 2,165 coding exons of 152 genes associated with hereditary cancer using next-generation sequencing (NGS) in 99 breast cancer patients from families of cancer patients regardless of cancer types. Forty-two deleterious germline mutations were identified in 21 genes of 34 patients, including 18 (18.2%) BRCA1 or BRCA2 mutations, 3 (3%) TP53 mutations, 5 (5.1%) DNA mismatch repair gene mutations, 1 (1%) CDH1 mutation, 6 (6.1%) Fanconi anemia pathway gene mutations, and 9 (9.1%) mutations in other genes. Of seven patients who carried mutations in more than one gene, 4 were BRCA1/2 mutation carriers, and their average onset age was much younger than patients with only BRCA1/2 mutations. Almost all identified high-penetrance gene mutations in those families fulfill the typical phenotypes of hereditary cancer syndromes listed in the National Comprehensive Cancer Network (NCCN) guidelines, except two TP53 and three mismatch repair gene mutations. Furthermore, functional studies of MSH3 germline mutations confirmed the association between MSH3 mutation and tumorigenesis, and segregation analysis suggested antagonism between BRCA1 and MSH3. We also identified a lot of low-penetrance gene mutations. Although the clinical significance of those newly identified low-penetrance gene mutations has not been fully appreciated yet, these new findings do provide valuable epidemiological information for the future studies. Together, these findings highlight the importance of genetic testing based on NCCN guidelines and a multi gene analysis using NGS may be a supplement to traditional genetic counseling. PMID- 25927358 TI - Taxonomic review of the orders Mysida and Stygiomysida (crustacea, peracarida). AB - The order Mysida (2 families, 178 genera, 1132 species) contains species across a broad range of habitats, such as subterranean, fresh, brackish, coastal, and surface to deep-sea habitats. The Stygiomysida (2 families, 2 genera, 16 species), however, are found primarily in subterranean waters, but always in waters with a marine influence. The Mysida and Stygiomysida body is divided into three main regions: cephalon, thorax, and abdomen. They are shrimp-like in appearance, containing morphological features earlier referred to as defining a "caridoid facies". The shrimp-like morphology was to some extent diagnostic for the historic Decapod taxon Schizopoda, containing the Nebalia, Mysida, Lophogastrida, and Euphausiacea. In 1904 the concept of Schizopoda was abandoned, and the Mysidacea (Mysida and Lophogastrida) along with Cumacea, Amphipoda, Isopoda, and Tanaidacea were placed in a new taxon, the Peracarida. Later discoveries of groundwater mysids led to the establishment of Stygiomysida, but placement to either Lophogastrida or Mysida remained unclear. The presence of oostegites and absence of podobranchiae, coupled with non-statocyst bearing uropods have been used to classify the Stygiomysida as a primitive Mysida family, comparable to Petalophthalmidae. On the other hand, equally suggestive characters, but for a Lophogastrida affiliation, was suggested for the archaic foregut characters and again, non-statocyst bearing uropods. With the inclusion of DNA sequence data of ribosomal genes, sister group relationships between Stygiomysida, Lophogastrida, and Mictacea within the Peracarida are observed, which supports a classification of the Stygiomysida as a separate order removed from the Mysida. PMID- 25927359 TI - IFIT1 Differentially Interferes with Translation and Replication of Alphavirus Genomes and Promotes Induction of Type I Interferon. AB - Alphaviruses are a group of widely distributed human and animal pathogens. It is well established that their replication is sensitive to type I IFN treatment, but the mechanism of IFN inhibitory function remains poorly understood. Using a new experimental system, we demonstrate that in the presence of IFN-beta, activation of interferon-stimulated genes (ISGs) does not interfere with either attachment of alphavirus virions to the cells, or their entry and nucleocapsid disassembly. However, it strongly affects translation of the virion-delivered virus-specific RNAs. One of the ISG products, IFIT1 protein, plays a major role in this translation block, although an IFIT1-independent mechanism is also involved. The 5'UTRs of the alphavirus genomes were found to differ significantly in their ability to drive translation in the presence of increased concentration of IFIT1. Prior studies have shown that adaptation of naturally circulating alphaviruses to replication in tissue culture results in accumulation of mutations in the 5'UTR, which increase the efficiency of the promoter located in the 5'end of the genome. Here, we show that these mutations also decrease resistance of viral RNA to IFIT1 induced translation inhibition. In the presence of higher levels of IFIT1, alphaviruses with wt 5'UTRs became potent inducers of type I IFN, suggesting a new mechanism of type I IFN induction. We applied this knowledge of IFIT1 interaction with alphaviruses to develop new attenuated variants of Venezuelan equine encephalitis and chikungunya viruses that are more sensitive to the antiviral effects of IFIT1, and thus could serve as novel vaccine candidates. PMID- 25927360 TI - Phase I Clinical Trial of a Recombinant Blood Stage Vaccine Candidate for Plasmodium falciparum Malaria Based on MSP1 and EBA175. AB - BACKGROUND: A phase I randomised, controlled, single blind, dose escalation trial was conducted to evaluate safety and immunogenicity of JAIVAC-1, a recombinant blood stage vaccine candidate against Plasmodium falciparum malaria, composed of a physical mixture of two recombinant proteins, PfMSP-1(19), the 19 kD conserved, C-terminal region of PfMSP-1 and PfF2 the receptor-binding F2 domain of EBA175. METHOD: Healthy malaria naive Indian male subjects aged 18-45 years were recruited from the volunteer database of study site. Fifteen subjects in each cohort, randomised in a ratio of 2:1 and meeting the protocol specific eligibility criteria, were vaccinated either with three doses (10 MUg, 25 MUg and 50 MUg of each antigen) of JAIVAC-1 formulated with adjuvant Montanide ISA 720 or with standard dosage of Hepatitis B vaccine. Each subject received the assigned vaccine in the deltoid muscle of the upper arms on Day 0, Day 28 and Day 180. RESULTS: JAIVAC-1 was well tolerated and no serious adverse event was observed. All JAIVAC-1 subjects sero-converted for PfF2 but elicited poor immune response to PfMSP-1(19). Dose-response relationship was observed between vaccine dose of PfF2 and antibody response. The antibodies against PfF2 were predominantly of IgG1 and IgG3 isotype. Sera from JAIVAC-1 subjects reacted with late schizonts in a punctate pattern in immunofluorescence assays. Purified IgG from JAIVAC-1 sera displayed significant growth inhibitory activity against Plasmodium falciparum CAMP strain. CONCLUSION: Antigen PfF2 should be retained as a component of a recombinant malaria vaccine but PfMSP-1(19) construct needs to be optimised to improve its immunogenicity. TRIAL REGISTRATION: Clinical Trial Registry, India CTRI/2010/091/000301. PMID- 25927361 TI - Multi-Level Effects of Low Dose Rate Ionizing Radiation on Southern Toad, Anaxyrus [Bufo] terrestris. AB - Despite their potential vulnerability to contaminants from exposure at multiple life stages, amphibians are one of the least studied groups of vertebrates in ecotoxicology, and research on radiation effects in amphibians is scarce. We used multiple endpoints to assess the radiosensitivity of the southern toad (Anaxyrus [Bufo] terrestris) during its pre-terrestrial stages of development -embryonic, larval, and metamorphic. Toads were exposed, from several hours after oviposition through metamorphosis (up to 77 days later), to four low dose rates of 137Cs at 0.13, 2.4, 21, and 222 mGy d-1, resulting in total doses up to 15.8 Gy. Radiation treatments did not affect hatching success of embryos, larval survival, or the length of the larval period. The individual family variation in hatching success of embryos was larger than the radiation response. In contrast, newly metamorphosed individuals from the higher dose-rate treatments had higher mass and mass/length body indices, a measure which may relate to higher post metamorphic survival. The increased mass and index at higher dose rates may indicate that the chronic, low dose rate radiation exposures triggered secondary responses. Additionally, the increases in growth were linked to a decrease in DNA damage (as measured by the Comet Assay) in red blood cells at a dose rate of 21 mGy d-1 and a total dose of 1.1 Gy. In conclusion, the complex effects of low dose rates of ionizing radiation may trigger growth and cellular repair mechanisms in amphibian larvae. PMID- 25927362 TI - Antimetastatic Therapies of the Polysulfide Diallyl Trisulfide against Triple Negative Breast Cancer (TNBC) via Suppressing MMP2/9 by Blocking NF-kappaB and ERK/MAPK Signaling Pathways. AB - BACKGROUND: Migration and invasion are two crucial steps of tumor metastasis. Blockage of these steps may be an effective strategy to reduce the risk. The objective of the present study was to investigate the effects of diallyl trisulfide (DATS), a natural organosulfuric compound with most sulfur atoms found in garlic, on migration and invasion in triple negative breast cancer (TNBC) cells. Molecular mechanisms underlying the anticancer effects of DATS were further investigated. METHODS AND RESULTS: MDA-MB-231 cells and HS 578t breast cancer cells were treated with different concentrations of DATS. DATS obviously suppressed the migration and invasion of two cell lines and changed the morphological. Moreover, DATS inhibited the mRNA/protein/ enzymes activities of MMP2/9 via attenuating the NF-kappaB pathway. DATS also inhibited ERK/MAPK rather than p38 and JNK. CONCLUSION: DATS inhibits MMP2/9 activity and the metastasis of TNBC cells, and emerges as a potential anti-cancer agent. The inhibitory effects are associated with down-regulation of the transcriptional activities of NF kappaB and ERK/MAPK signaling pathways. PMID- 25927363 TI - Does presentation format influence visual size discrimination in tufted capuchin monkeys (Sapajus spp.)? AB - Most experimental paradigms to study visual cognition in humans and non-human species are based on discrimination tasks involving the choice between two or more visual stimuli. To this end, different types of stimuli and procedures for stimuli presentation are used, which highlights the necessity to compare data obtained with different methods. The present study assessed whether, and to what extent, capuchin monkeys' ability to solve a size discrimination problem is influenced by the type of procedure used to present the problem. Capuchins' ability to generalise knowledge across different tasks was also evaluated. We trained eight adult tufted capuchin monkeys to select the larger of two stimuli of the same shape and different sizes by using pairs of food items (Experiment 1), computer images (Experiment 1) and objects (Experiment 2). Our results indicated that monkeys achieved the learning criterion faster with food stimuli compared to both images and objects. They also required consistently fewer trials with objects than with images. Moreover, female capuchins had higher levels of acquisition accuracy with food stimuli than with images. Finally, capuchins did not immediately transfer the solution of the problem acquired in one task condition to the other conditions. Overall, these findings suggest that--even in relatively simple visual discrimination problems where a single perceptual dimension (i.e., size) has to be judged--learning speed strongly depends on the mode of presentation. PMID- 25927365 TI - Correction to Monolithically integrated micro- and nanostructured glass surface with antiglare, antireflection, and superhydrophobic properties. PMID- 25927364 TI - Phytohormonal networks promote differentiation of fiber initials on pre-anthesis cotton ovules grown in vitro and in planta. AB - The number of cotton (Gossypium sp.) ovule epidermal cells differentiating into fiber initials is an important factor affecting cotton yield and fiber quality. Despite extensive efforts in determining the molecular mechanisms regulating fiber initial differentiation, only a few genes responsible for fiber initial differentiation have been discovered. To identify putative genes directly involved in the fiber initiation process, we used a cotton ovule culture technique that controls the timing of fiber initial differentiation by exogenous phytohormone application in combination with comparative expression analyses between wild type and three fiberless mutants. The addition of exogenous auxin and gibberellins to pre-anthesis wild type ovules that did not have visible fiber initials increased the expression of genes affecting auxin, ethylene, ABA and jasmonic acid signaling pathways within 1 h after treatment. Most transcripts expressed differentially by the phytohormone treatment in vitro were also differentially expressed in the ovules of wild type and fiberless mutants that were grown in planta. In addition to MYB25-like, a gene that was previously shown to be associated with the differentiation of fiber initials, several other differentially expressed genes, including auxin/indole-3-acetic acid (AUX/IAA) involved in auxin signaling, ACC oxidase involved in ethylene biosynthesis, and abscisic acid (ABA) 8'-hydroxylase an enzyme that controls the rate of ABA catabolism, were co-regulated in the pre-anthesis ovules of both wild type and fiberless mutants. These results support the hypothesis that phytohormonal signaling networks regulate the temporal expression of genes responsible for differentiation of cotton fiber initials in vitro and in planta. PMID- 25927366 TI - A randomized controlled trial of the efficacy of orally administered fluralaner (BravectoTM) against induced Ixodes holocyclus (Australian paralysis tick) infestations on dogs. AB - BACKGROUND: Ixodes holocyclus ticks are a frequently fatal threat to dogs in eastern Australia. These ticks secrete a neurotoxin that can produce an ascending paralysis after 72 h attachment that can lead to death in affected animals. Fluralaner is a potent systemic acaricide with immediate and persistent efficacy for tick control including evidence of 100% efficacy against Ixodes ricinus ticks within 72 h. This study investigated the potential for oral fluralaner administration to control I. holocyclus infestation and the subsequent risk of host paralysis. METHODS: Healthy Foxhound and Foxhound cross dogs immunized against holocyclotoxin were randomly allocated to receive either a single fluralaner (at least 25 mg/kg) dose or no treatment. All dogs were penned individually and infested with 30 adult unfed female I. holocyclus 1 day before treatment and 14, 28, 42, 56, 70, 84, 112 and 140 days following treatment. Ticks were counted and assessed at 24, 48 and 72 h after the initial fluralaner treatment and after each subsequent infestation. Ticks were not removed at the 24 and 48 h assessments, but were removed after the 72 h assessments. On 112 and 140 days post treatment a new group of untreated control dogs was used. RESULTS: Fluralaner treatment efficacy against I. holocyclus was 100% at 72 h post treatment. Following re-infestations the efficacy remained at 100% at the 72 h assessments for 115 days and reached 95.7% at 143 days. The differences between mean live tick counts on treatment and control groups were significant (P < 0.00l) at all assessment time points for 143 days following treatment. CONCLUSIONS: Oral fluralaner treatment can prevent Australian paralysis tick infestations for at least 115 days. PMID- 25927369 TI - Economic analysis of participation in physical activity in England: implications for health policy. AB - BACKGROUND: Changing the relative price of (in) activity is an important tool for health policies. Nonetheless, to date, analyses of correlates of physical activity (PA) have excluded the notion of price. Using the first nationwide dataset on prices of PA for England, we explore for the first time how money and time prices are associated with PA (in general) and specific activities. METHODS: A nationally representative telephone follow-up survey to Health Survey for England (HSE) 2008 was undertaken in 2010. The sample covered individuals who reported to have undertaken some PA in the HSE 2008. Questions focussed on: ex post money and time prices; type and quantity of PA; perceived benefits of PA and socio-economic details. Count regression models (all activities together, and swimming, workout, walking separately) were fitted to investigate the variation in quantity of PA. RESULTS: Of 1683 respondents, 83% participated in PA (one or more activities), and spent an average of L2.40 per occasion of participation in PA and 23 minutes travelling. Participation in PA was negatively associated with money prices per occasion (i.e. family member/child care fees, parking fees, and facility charges) and travel time price. Participation in PA was more sensitive to travel time price than money price. Among the specific activities, the money price effect was highest for swimming with a 10% higher price associated with 29% fewer occasions of swimming; followed by workout (3% fewer occasions) and walking (2% fewer occasions). Only swimming and workout were sensitive to travel time price. People who felt doing PA could help them 'get outdoors', 'have fun', or 'lose weight' were likely to do more PA. CONCLUSIONS: Two main policy implications emerge from the findings. First, the results support the notion that positive financial incentives, e.g. subsidising price of participation, could generally lead to an increase in quantity of PA among those already exercising. Second, such policies could lead to desired policy goals if implemented at an individual activity level (e.g. 50% subsidy on swimming entrance charges) rather than a blanket implementation (e.g. subsidising average entrance charges across all activities by 50%). PMID- 25927371 TI - Moderate-to-vigorous physically active academic lessons and academic engagement in children with and without a social disadvantage: a within subject experimental design. AB - BACKGROUND: Integration of physical active academic lessons in the school curriculum may be an innovative way to improve academic outcomes. This study examined the effect of physically active academic lessons (Fit en Vaardig op school) on academic engagement of socially disadvantaged children and children without this disadvantage. In addition, the relationship between lesson time spent in moderate to vigorous physical activity and academic engagement was examined. METHODS: From four elementary schools, 86 children who participated in the 22-weeks intervention were recruited (23 socially disadvantaged children). Academic engagement was determined by observing time-on-task during three classroom observation moments (start, midway and end observation). Every moment consisted of lesson observations after intervention lessons (post-intervention) and after regular classroom lessons (post-control). Differences in time-on-task between socially disadvantaged children and children without this disadvantage were analyzed using independent samples t-test. Differences between post intervention and post-control observations were analyzed using multilevel analysis. Heart rate monitors measured the lesson time spent in moderate to vigorous physical activity. The relationship between percentage of moderate to vigorous physical activity during the intervention lessons and time-on-task was analyzed by calculation of partial correlations. RESULTS: Time-on-task of socially disadvantaged children was lower than that of children without this disadvantage, differences were significant at the start post-control (t(65) = 2.39, p < 0.05) and post-intervention (t(71) = 2.75, p < 0.05) observation and at the midway post-control (t(68) = 2.45, p < 0.05) observation. Multilevel analysis showed that the time-on-task of all children was significantly higher during post intervention in comparison with post-control lessons (ES = 0.41). No significant difference was found at the start observation, but there were significant differences at the midway (ES = 0.60) and end (ES = 0.59) observation. On average, the children were exercising in moderate to vigorous physical activity during 60% of de lesson time (14 minutes of an average lesson of 23 minutes). No significant relationships were found between percentage of moderate to vigorous physical activity during the intervention and time-on-task in the post intervention lessons. CONCLUSIONS: Physically active academic lessons may positively influence time-on-task in children, which can contribute to academic success in the long term. PMID- 25927377 TI - A tertiary approach to improving equity in health: quantitative analysis of the Maori and Pacific Admission Scheme (MAPAS) process, 2008-2012. AB - INTRODUCTION: Achieving health equity for indigenous and ethnic minority populations requires the development of an ethnically diverse health workforce. This study explores a tertiary admission programme targeting Maori and Pacific applicants to nursing, pharmacy and health sciences (a precursor to medicine) at the University of Auckland (UoA), Aotearoa New Zealand (NZ). Application of cognitive and non-cognitive selection tools, including a Multiple Mini Interview (MMI), are examined. METHODS: Indigenous Kaupapa Maori methodology guided analysis of the Maori and Pacific Admission Scheme (MAPAS) for the years 2008 2012. Multiple logistic regression models were used to identify the predicted effect of admission variables on the final MAPAS recommendation of best starting point for success in health professional study i.e. 'CertHSc' (Certificate in Health Sciences, bridging/foundation), 'Bachelor' (degree-level) or 'Not FMHS' (Faculty of Medical and Health Sciences). Regression analyses controlled for interview year, gender and ancestry. RESULTS: Of the 918 MAPAS interviewees: 35% (319) were Maori, 58% (530) Pacific, 7% (68) Maori/Pacific; 71% (653) school leavers; 72% (662) females. The average rank score was 167/320, 40-80 credits below guaranteed FMHS degree offers. Just under half of all interviewees were recommended 'CertHSc' 47% (428), 13% (117) 'Bachelor' and 38% (332) 'Not FMHS' as the best starting point. Strong associations were identified between Bachelor recommendation and exposure to Any 2 Sciences (OR:7.897, CI:3.855-16.175; p < 0.0001), higher rank score (OR:1.043, CI:1.034-1.052; p < 0.0001) and higher scores on MAPAS mathematics test (OR:1.043, CI:1.028-1.059; p < 0.0001). MMI stations had mixed associations, with academic preparation and career aspirations more consistently associated with recommendations. CONCLUSIONS: Our findings raise concerns about the ability of the secondary education sector to prepare Maori and Pacific students adequately for health professional study. A comprehensive tertiary admissions process using multiple tools for selection (cognitive and non-cognitive) and the provision of alternative entry pathways are recommended for indigenous and ethnic minority health workforce development. The application of the MMI within an equity and indigenous cultural context can support a holistic assessment of an applicant's potential to succeed within tertiary study. The new MAPAS admissions process may provide an exemplar for other tertiary institutions looking to widen participation via equity-targeted admission processes. PMID- 25927378 TI - To assess whether addition of pyriproxyfen to long-lasting insecticidal mosquito nets increases their durability compared to standard long-lasting insecticidal mosquito nets: study protocol for a randomised controlled trial. AB - BACKGROUND: The effectiveness of pyrethroid-treated bednets for malaria control in sub-Saharan Africa is under threat because of high levels of resistance to pyrethroid insecticides in the vectors. Here we assess the durability of polyethylene nets with a novel combination of permethrin, a pyrethroid, with pyriproxyfen, an insect juvenile mimic (PPF-LLIN), in comparison with a typical permethrin-treated long-lasting insecticidal net (LLIN). METHODS: This is a cluster randomised controlled trial of net durability in Burkina Faso, with clustering at the level of the compound and includes entomological outcome measurements. Half the compounds in each village will be randomly allocated PPF LLIN and half the LLIN. All sleeping places in a compound will be provided with one type of net. We will distribute the nets at the start of the first transmission season and follow net use at the start and end of each transmission season for 3 years. In one village, bio-efficacy and chemical content will be recorded immediately after net distribution and then at 6, 12, 18, 24, 30 and 36 months. In the other village net survivorship and fabric integrity will be recorded immediately after distribution, and then at 6, 12, 18, 24, 30 and 36 months. Routine measurements of indoor temperature and relative humidity will be made in both villages during the study. Residents will be followed for possible side effects of the PPF-LLIN by surveillance of known asthmatic subjects during the first month post-distribution and pregnancy outcomes will be monitored from antenatal clinic records. DISCUSSION: The protocol is novel on two accounts. Firstly, it is the first to describe the procedure for measuring net durability following recent World Health Organisation (WHO) guidelines. Meeting the minimum requirements set in the guidelines is essential before a new type of net can be recommended by WHO's Pesticide Evaluation Scheme (WHOPES). Secondly, it describes methods to monitor the persistence of an active ingredient that reduces vector fertility and fecundity. If the PPF-LLIN is both effective and persistent it will provide an alternative vector control strategy where pyrethroid-resistant vectors are present. TRIAL REGISTRATION: ISRCTN30634670 assigned 13 August 2014. PMID- 25927380 TI - Clinical characterization of int22h1/int22h2-mediated Xq28 duplication/deletion: new cases and literature review. AB - BACKGROUND: Int22h1/int22h2-mediated Xq28 duplication syndrome is caused by ~0.5 Mb chromosomal duplications mediated by nonallelic homologous recombination between intron 22 homologous region 1 (int22h1) and 2 (int22h2), which, in addition to int22h3, are also responsible for inversions disrupting the F8 gene in hemophilia A. This syndrome has recently been described in 9 males with cognitive impairment, behavioral problems, and distinctive facial features; and 6 females with milder phenotypes. The reciprocal deletion was previously reported in a mother and daughter. It was suggested that this deletion may not have phenotypic effects in females because of skewed chromosome X inactivation, but may be embryonic lethal in males. METHODS: Array comparative genomic hybridization analyses were performed using oligonucleotide-based chromosomal microarray. Chromosome X inactivation studies were performed at the AR (androgen receptor) and FMR1 (fragile X mental retardation 1) loci. RESULTS: We present here 5 males and 6 females with int22h1/int22h2-mediated Xq28 duplication syndrome. The males manifested cognitive impairment, behavioral problems, and distinctive facial features. Two of the six females manifested mild cognitive impairment. This duplication was maternally inherited, and skewed chromosome X inactivation was observed in the majority of females carrying the duplication. We also report the reciprocal deletion in a mother and daughter with overweight, but normal cognition. In addition, we present the first case of a prenatally diagnosed de novo int22h1/int22h2-mediated deletion in a healthy female infant. We reviewed individuals previously reported with similar or overlapping rearrangements and evaluated the potential roles of genes in the rearrangement region. CONCLUSIONS: The similarity of clinical features among individuals with the int22h1/int22h2-mediated Xq28 duplication supports the notion that this duplication causes a recognizable syndrome that affects males with females exhibiting milder phenotypes. It is suggested that the observed cognitive impairment in this syndrome results from increased dosage of RAB39B gene located within the duplicated region. Increased dosage of CLIC2 may also contribute to the phenotype. The reciprocal deletion results in skewed chromosome X inactivation and no clinical phenotype in females. Review of overlapping deletions suggests that hemizygous loss of VBP1 may be the cause for the proposed male lethality associated with this deletion. PMID- 25927384 TI - Conditions potentially sensitive to a personal health record (PHR) intervention, a systematic review. AB - BACKGROUND: Personal Health Records (PHRs) are electronic health records controlled, shared or maintained by patients to support patient centered care. The potential for PHRs to transform health care is significant; however, PHRs do not always achieve their potential. One reason for this may be that not all health conditions are sensitive to the PHR as an intervention. The goal of this review was to discover which conditions were potentially sensitive to the PHR as an intervention, that is, what conditions have empirical evidence of benefit from PHR-enabled management. METHODS: A systematic review of Medline and CINAHL was completed to find articles assessing PHR use and benefit from 2008 to 2014 in specific health conditions. Two researchers independently screened and coded articles. Health conditions with evidence of benefit from PHR use were identified from the included studies. RESULTS: 23 papers were included. Seven papers were RCTs. Ten health conditions were identified, seven of which had documented benefit associated with PHR use: asthma, diabetes, fertility, glaucoma, HIV, hyperlipidemia, and hypertension. Reported benefits were seen in terms of care quality, access, and productivity, although many benefits were measured by self report through quasi-experimental studies. No study examined morbidity/mortality. No study reported harm from the PHR. CONCLUSION: There is a small body of condition specific evidence that has been published. Conditions with evidence of benefit when using PHRs tended to be chronic conditions with a feedback loop between monitoring in the PHR and direct behaviours that could be self-managed. These findings can point to other potentially PHR sensitive health conditions and guide PHR designers, implementers, and researchers. More research is needed to link PHR design, features, adoption and health outcomes to better understand how and if PHRs are making a difference to health outcomes. PMID- 25927386 TI - Unified method to integrate and blend several, potentially related, sources of information for genetic evaluation. AB - BACKGROUND: A condition to predict unbiased estimated breeding values by best linear unbiased prediction is to use simultaneously all available data. However, this condition is not often fully met. For example, in dairy cattle, internal (i.e. local) populations lead to evaluations based only on internal records while widely used foreign sires have been selected using internally unavailable external records. In such cases, internal genetic evaluations may be less accurate and biased. Because external records are unavailable, methods were developed to combine external information that summarizes these records, i.e. external estimated breeding values and associated reliabilities, with internal records to improve accuracy of internal genetic evaluations. Two issues of these methods concern double-counting of contributions due to relationships and due to records. These issues could be worse if external information came from several evaluations, at least partially based on the same records, and combined into a single internal evaluation. Based on a Bayesian approach, the aim of this research was to develop a unified method to integrate and blend simultaneously several sources of information into an internal genetic evaluation by avoiding double-counting of contributions due to relationships and due to records. RESULTS: This research resulted in equations that integrate and blend simultaneously several sources of information and avoid double-counting of contributions due to relationships and due to records. The performance of the developed equations was evaluated using simulated and real datasets. The results showed that the developed equations integrated and blended several sources of information well into a genetic evaluation. The developed equations also avoided double-counting of contributions due to relationships and due to records. Furthermore, because all available external sources of information were correctly propagated, relatives of external animals benefited from the integrated information and, therefore, more reliable estimated breeding values were obtained. CONCLUSIONS: The proposed unified method integrated and blended several sources of information well into a genetic evaluation by avoiding double-counting of contributions due to relationships and due to records. The unified method can also be extended to other types of situations such as single-step genomic or multi-trait evaluations, combining information across different traits. PMID- 25927389 TI - Isolation and analysis of group 2 innate lymphoid cells in mice. AB - Recent studies have identified distinct subsets of innate lymphocytes, collectively called innate lymphoid cells (ILCs), which lack antigen receptor expression but produce various effector cytokines. Group 2 ILCs (ILC2s) respond to epithelial cell-derived cytokines such as interleukin (IL)-25, IL-33 and thymic stromal lymphopoietin (TSLP), produce large amounts of type 2 cytokines, and have a key role in anti-helminth innate immunity and in the pathophysiology of allergic inflammation. The reported phenotypic characteristics of mouse ILC2s vary, depending on the tissue source and preparation method. This protocol describes improved methods for tissue-specific isolation and analysis of mouse ILC2s of high purity and yield from fat tissue, lung, bronchoalveolar lavage fluid (BALF) and small intestine. These improved methods are the result of our thorough investigation of enzymes used for tissue digestion, methods for the elimination of undesired cells, and a combination of antibodies for the detection and isolation of ILC2s. In addition, this new protocol now enables the isolation of ILC2s of high yield, even from inflamed tissues. Depending on the tissue being analyzed, it takes ~2-4 h for isolation and flow cytometric analysis of ILC2s from the various tissues of a single mouse and ~4-8 h to sort purified ILC2s from pooled tissues of multiple mice. PMID- 25927392 TI - Transparent, broadband, flexible, and bifacial-operable photodetectors containing a large-area graphene-gold oxide heterojunction. AB - In this study, we combine graphene with gold oxide (AuOx), a transparent and high work-function electrode material, to achieve a high-efficient, low-bias, large area, flexible, transparent, broadband, and bifacial-operable photodetector. The photodetector operates through hot electrons being generated in the graphene and charge separation occurring at the AuOx-graphene heterojunction. The large-area graphene covering the AuOx electrode efficiently prevented reduction of its surface; it also acted as a square-centimeter-scale active area for light harvesting and photodetection. Our graphene/AuOx photodetector displays high responsivity under low-intensity light illumination, demonstrating picowatt sensitivity in the ultraviolet regime and nanowatt sensitivity in the infrared regime for optical telecommunication. In addition, this photodetector not only exhibited broadband (from UV to IR) high responsivity-3300 A W(-1) at 310 nm (UV), 58 A W(-1) at 500 nm (visible), and 9 A W(-1) at 1550 nm (IR)-but also required only a low applied bias (0.1 V). The hot-carrier-assisted photoresponse was excellent, especially in the short-wavelength regime. In addition, the graphene/AuOx photodetector exhibited great flexibility and stability. Moreover, such vertical heterojunction-based graphene/AuOx photodetectors should be compatible with other transparent optoelectronic devices, suggesting applications in flexible and wearable optoelectronic technologies. PMID- 25927390 TI - Design of a functional cyclic HSV1-TK reporter and its application to PET imaging of apoptosis. AB - Positron emission tomography (PET) is a sensitive and noninvasive imaging method that is widely used to explore molecular events in living subjects. PET can precisely and quantitatively evaluate cellular apoptosis, which has a crucial role in various physiological and pathological processes. In this protocol, we describe the design and use of an engineered cyclic herpes simplex virus 1 thymidine kinase (HSV1-TK) PET reporter whose kinase activity is specifically switched on by apoptosis. The expression of cyclic TK (cTK) in healthy cells leads to inactive product, whereas the activation of apoptosis through the caspase-3 pathway cleaves cTK, thus restoring its activity and enabling PET imaging. In addition to detailing the design and construction of the cTK plasmid in this protocol, we include assays for evaluating the function and specificity of the cTK reporter in apoptotic cells, such as assays for measuring the cell uptake of PET tracer in apoptotic cells, correlating doxorubicin (Dox)-induced cell apoptosis to cTK function recovery, and in vivo PET imaging of cancer cell apoptosis, and we also include corresponding data acquisition methods. The time to build the entire cTK reporter is ~2-3 weeks. The selection of a stable cancer cell line takes ~4-6 weeks. The time to implement assays regarding cTK function in apoptotic cells and the in vivo imaging varies depending on the experiment. The cyclization strategy described in this protocol can also be adapted to create other reporter systems for broad biomedical applications. PMID- 25927395 TI - Unification of catalytic oxygen reduction and hydrogen evolution reactions: highly dispersive Co nanoparticles encapsulated inside Co and nitrogen co-doped carbon. AB - The Co nanoparticles encapsulated inside Co and nitrogen co-doped carbon catalysts with small particle size and homogenous distribution of Co NPs were elaborately synthesized, which exhibit evidently outstanding activity and stability toward ORR/HER. PMID- 25927398 TI - Chemical components from the haulm of Artemisia selengensis and the inhibitory effect on glycation of beta-lactoglobulin. AB - Artemisia selengensis (AS) has been traditionally used as both food and medicine for thousands of years in China. In our studies, l-tryptophan was first isolated from the haulm of AS together with luteolin, rutin, and kaempferol-3-O glucuronide. Their structures were elucidated by spectroscopic methods including HRMS, 1D and 2D NMR. Three flavonoid compounds showed satisfactory suppression effects on the formation of advanced glycation end products (AGEs) in beta lactoglobulin-lactose/MGO/GO model systems, and their anti-glycation activities exhibited a dose-dependent manner. Among these compounds, kaempferol-3-O glucuronide was demonstrated to be the strongest inhibitor against the formation of AGEs. PMID- 25927399 TI - Faceted Gold Nanorods: Nanocuboids, Convex Nanocuboids, and Concave Nanocuboids. AB - Au nanorods are optically tunable anisotropic nanoparticles with built-in catalytic activities. The state-of-the-art seed-mediated nanorod synthesis offers excellent control over the aspect ratios of cylindrical Au nanorods, which enables fine-tuning of plasmon resonances over a broad spectral range. However, facet control of Au nanorods with atomic-level precision remains significantly more challenging. The coexistence of various types of low-index and high-index facets on the highly curved nanorod surfaces makes it extremely challenging to quantitatively elucidate the atomic-level structure-property relationships that underpin the catalytic competence of Au nanorods. Here we demonstrate that cylindrical Au nanorods undergo controlled facet evolution during their overgrowth in the presence of Cu(2+) and cationic surfactants, resulting in the formation of anisotropic nanostructures enclosed by well-defined facets, such as low-index faceting nanocuboids and high-index faceting convex nanocuboids and concave nanocuboids. These faceted Au nanorods exhibit enriched optical extinction spectral features, broader plasmonic tuning range, and enhanced catalytic tunability in comparison to the conventional cylindrical Au nanorods. The capabilities to both fine-tailor the facets and fine-tune the plasmon resonances of anisotropic Au nanoparticles open up unique opportunities for us to study, in great detail, the facet-dependent interfacial molecular transformations on Au nanocatalysts using surface-enhanced Raman scattering as a time-resolved spectroscopic tool. PMID- 25927401 TI - Vasectomy and prostate cancer risk: a meta-analysis of cohort studies. AB - Some studies have suggested that vasectomy is associated with the increased risk of prostate cancer, however, this conclusion is not supported by all the published studies. In order to examine the relationship between vasectomy and prostate cancer risk, we conducted a meta-analysis of cohort studies to clarify this controversial association. PubMed and Medline were used to identify the cohort studies that reported the association of vasectomy with prostate cancer risk from 1980 to January 2015. Based on a random effects model, the RR and 95% CI were used to assess the combined risk. In total, 10 cohort studies involving more than 7027 cases and 429914 participants were included. There was no significant relationship between vasectomy and prostate cancer risk, the pooled RR (95%CI) was 1.11[0.98, 1.27] (P = 0.109). In subgroup-analysis, the relationship between vasectomy and prostate cancer risk was not significantly modified by the length of follow-up and population distribution except Americans. Omission of any single study had little effect on the pooled risk estimate. Little evidence of publication bias was found. In conclusion, our meta-analysis suggests that vasectomy is not associated with the increased risk of prostate cancer. More studies based on other populations including the Chinese are needed. PMID- 25927403 TI - Update in endocrinology: evidence published in 2014. PMID- 25927402 TI - Dosimetric Comparison and Potential for Improved Clinical Outcomes of Paediatric CNS Patients Treated with Protons or IMRT. AB - BACKGROUND: We compare clinical outcomes of paediatric patients with CNS tumours treated with protons or IMRT. CNS tumours form the second most common group of cancers in children. Radiotherapy plays a major role in the treatment of many of these patients but also contributes to late side effects in long term survivors. Radiation dose inevitably deposited in healthy tissues outside the clinical target has been linked to detrimental late effects such as neurocognitive, behavioural and vascular effects in addition to endocrine abnormalities and second tumours. METHODS: A literature search was performed using keywords: protons, IMRT, CNS and paediatric. Of 189 papers retrieved, 10 were deemed relevant based on title and abstract screening. All papers directly compared outcomes from protons with photons, five papers included medulloblastoma, four papers each included craniopharyngioma and low grade gliomas and three papers included ependymoma. RESULTS: This review found that while proton beam therapy offered similar clinical target coverage, there was a demonstrable reduction in integral dose to normal structures. CONCLUSIONS: This in turn suggests the potential for superior long term outcomes for paediatric patients with CNS tumours both in terms of radiogenic second cancers and out-of-field adverse effects. PMID- 25927404 TI - Is generalization of exhaled CO assessment in primary care helpful for early diagnosis of COPD? AB - BACKGROUND: COPD is largely under-diagnosed and once diagnosed usually at a late stage. Early diagnosis is thoroughly recommended but most attempts failed as the disease is marginally known and screening marginally accepted. It is a rare cause of concern in primary care and spirometry is not very common. Exhaled carbon monoxide (eCO) is a 5-seconds easy-to-use device dedicated to monitor cigarette smoke consumption. We aimed to assess whether systematic eCO measurement in primary care is a useful tool to improve acceptance for early COPD diagnosis. METHODS: This was a two-center randomized controlled trial enrolling 410 patients between March and May, 2013. Whatever was the reason of attendance to the clinic, all adults were proposed to measure eCO during randomly chosen days and outcomes were compared between the two different groups of patients (performing and not performing eCO). Primary outcome was the rates of acceptance for COPD screening. RESULTS: Rate of acceptance for COPD screening was 28% in the eCO group and 26% in the other (P = 0.575). These rates increased to 48 and 51% in smokers (current and former). eCO significantly increased the rate of clinics during which a debate on smoking was initiated (42 vs. 24%, P = 0.001). eCO at 2.5 ppm was the discriminative concentration for identifying active smokers (ROC curve AUC: 0.935). Smoking was the only independent risk factor associated with acceptance for early COPD screening (OR = 364.6 (82.5-901.5) and OR = 78.5 (18.7-330.0) in current and former smokers, respectively) while eCO measurement was not. CONCLUSIONS: Early COPD diagnosis is a minor cause of concern in primary care. Systematic eCO assessment failed to improve acceptance for early COPD screening. PMID- 25927406 TI - Design, Synthesis, and Biological Evaluation of Hexacyclic Tetracyclines as Potent, Broad Spectrum Antibacterial Agents. AB - A series of novel hexacyclic tetracycline analogues ("hexacyclines") was designed, synthesized, and evaluated for antibacterial activity against a wide range of clinically important bacteria isolates, including multidrug-resistant, Gram-negative pathogens. Valuable structure-activity relationships were identified, and several hexacyclines displayed potent, broad spectrum antibacterial activity, including promising anti-Pseudomonas aeruginosa activity in vitro and in vivo. PMID- 25927407 TI - Sudden hypoxemia after uneventful laparoscopic cholecystectomy: another form of SAM presentation. AB - BACKGROUND: Perioperative dynamic left ventricular outflow obstruction associated with systolic anterior motion of the mitral valve is well recognized as a cause for unexplained sudden hypotension in perioperative settings, even without underlying heart diseases such as hypertrophic obstructive cardiomyopathy. We treated a patient who experienced sudden hypoxemia without severe hypotension during emergence from anesthesia after an uneventful laparoscopic cholecystectomy. CASE PRESENTATION: A 65-year-old female patient with a history of hypertension presented a sudden decrease in oxygen saturation to 80% after an uneventful cholecystectomy. Although a portable chest radiograph showed bilateral hilar pulmonary infiltrates consistent with pulmonary edema, we explored the underlying cause, i.e., systolic anterior motion of the mitral valve and left ventricular outflow tract obstruction with bedside transthoracic echocardiography. We speculate that dynamic mitral regurgitation resulted in pulmonary edema and, thereby, hypoxemia in this case without severe hypotension. CONCLUSIONS: Careful bedside examination with transthoracic echocardiography was useful in making diagnosis and in guiding appropriate therapy for this patient. Clinicians should be aware that systolic anterior motion of the mitral valve may present as unexplained sudden hypoxemia in the perioperative setting. PMID- 25927408 TI - Targeting IAP proteins in combination with radiotherapy. AB - The efficacy of radiotherapy critically depends on the activation of intrinsic cell death programs in cancer cells. This implies that evasion of cell death, a hallmark of human cancers, can contribute to radioresistance. Therefore, novel strategies to reactivate cell death programs in cancer cells are required in order to overcome resistance to radiotherapy. Since Inhibitor of Apoptosis (IAP) proteins are expressed at high levels in multiple cancers and block cell death induction at a central point, therapeutic targeting of IAP proteins represents a promising approach to potentiate the efficacy of radiotherapy. The current review discusses the concept of targeting IAP proteins in combination with radiotherapy. PMID- 25927411 TI - Molecular Beacon-Based Fluorescent Assay for Specific Detection of Oversulfated Chondroitin Sulfate Contaminants in Heparin without Enzyme Treatment. AB - Oversulfated chondroitin sulfate (OSCS) is a harmful contaminant in the pharmaceutical heparin. The development of a rapid, convenient, sensitive, and selective method is required for routine analysis of OSCS in pharmaceutical heparin. Here we report a simple, rapid, sensitive, and enzyme-free method for detecting OSCS in heparin based on the competitive binding between OSCS and the adenosine-repeated molecular beacon (MB) stem to coralyne in the presence of Ca(2+) ions. The MB (A8-MB-A8) contains a 22-mer loop, a stem of a pair of 8-mer adenosine (A) bases, a fluorophore unit at the 5'-end, and a quencher at the 3' end. The presence of coralyne promotes these A-A mismatches to form a hairpin shaped MB. However, this kind of MB is incapable of differentiating between heparin and OSCS because they both exhibit strong electrostatic attraction with coralyne. This study found that while Ca(2+) ions can efficiently suppress the negative charges of heparin, they do not neutralize the negative charge of OSCS. Thus, in the presence of Ca(2+) ions, OSCS can remove coralyne from the MB stem, initiating fluorescence of the MB. Under optimal conditions (10 nM A8-MB-A8, 800 nM coralyne, and 0.5 mM Ca(2+) ions), the proposed system can detect 0.01% w/w OSCS in heparin in under 5 min without enzyme treatment. This study also validates the practicality of the proposed system to determine 0.01% w/w OSCS in the pharmaceutical heparin. PMID- 25927410 TI - Multicenter case-control study protocol of pneumonia etiology in children: Global Approach to Biological Research, Infectious diseases and Epidemics in Low-income countries (GABRIEL network). AB - BACKGROUND: Data on the etiologies of pneumonia among children are inadequate, especially in developing countries. The principal objective is to undertake a multicenter incident case-control study of <5-year-old children hospitalized with pneumonia in developing and emerging countries, aiming to identify the causative agents involved in pneumonia while assessing individual and microbial factors associated with the risk of severe pneumonia. METHODS/DESIGN: A multicenter case control study, based on the GABRIEL network, is ongoing. Ten study sites are located in 9 countries over 3 continents: Brazil, Cambodia, China, Haiti, India, Madagascar, Mali, Mongolia, and Paraguay. At least 1,000 incident cases and 1,000 controls will be enrolled and matched for age and date. Cases are hospitalized children <5 years with radiologically confirmed pneumonia, and the controls are children without any features suggestive of pneumonia. Respiratory specimens are collected from all enrolled subjects to identify 19 viruses and 5 bacteria. Whole blood from pneumonia cases is being tested for 3 major bacteria. S. pneumoniae positive specimens are serotyped. Urine samples from cases only are tested for detection of antimicrobial activity. The association between procalcitonin, C reactive protein and pathogens is being evaluated. A discovery platform will enable pathogen identification in undiagnosed samples. DISCUSSION: This multicenter study will provide descriptive results for better understanding of pathogens responsible for pneumonia among children in developing countries. The identification of determinants related to microorganisms associated with pneumonia and its severity should facilitate treatment and prevention. PMID- 25927412 TI - Association between epidermal growth factor gene +61A/G polymorphism and the risk of hepatocellular carcinoma: a meta-analysis based on 16 studies. AB - BACKGROUND: The association between epidermal growth factor (EGF) gene +61A/G polymorphism (rs4444903) and hepatocellular carcinoma (HCC) susceptibility has been widely reported, but the results were inconsistent. To clarify the effect of this polymorphism on HCC risk, a meta-analysis was performed. METHODS: The PubMed, Embase, Cochrane Library, Web of Science, Chinese BioMedical Literature (CBM), Wanfang and Chinese National Knowledge Infrastructure (CNKI) databases were systematically searched to identify relevant studies published up to December 2013. Data were extracted independently by two authors. Odds ratios (ORs) and 95% confidence intervals (95% CIs) were calculated to assess the strength of association. RESULTS: A total of 16 studies including 2475 HCC cases and 5381 controls were included in this meta-analysis. Overall, a significantly increased HCC risk was observed under all genetic models (G vs. A: OR = 1.383, P < 0.001, 95% CI: 1.174-1.629; GG vs. GA + AA: OR = 1.484, P < 0.001, 95% CI: 1.198-1.838; GG + GA vs. AA: OR = 1.530, P < 0.001, 95% CI: 1.217-1.924; GG vs. AA: OR = 1.958, P < 0.001, 95% CI: 1.433-2.675; GA vs. AA: OR = 1.215, P = 0.013, 95% CI: 1.041-1.418). In the subgroup analyses by ethnicity, a significant association with HCC risk was found in Asian populations (G vs. A: OR = 1.151, P = 0.001, 95% CI: 1.056-1.255), European populations (G vs. A: OR = 1.594, P = 0.027, 95% CI: 1.053-2.413, and African populations (G vs. A: OR = 3.599, P < 0.001, 95% CI: 2.550-5.080), respectively. CONCLUSIONS: Our study shows that EGF +61A/G polymorphism is significantly associated with the increased HCC risk, especially in Asian populations. Further large-scale and well-designed studies are required to confirm this conclusion. PMID- 25927415 TI - Combination multinitrogen with good oxygen balance: molecule and synthesis design of polynitro-substituted tetrazolotriazine-based energetic compounds. AB - We investigated 5,8-dinitro-5,6,7,8-tetrahydrotetrazolo[1,5-b][1,2,4]triazine (short for DNTzTr (1)) using various ab initio quantum chemistry methods. We proposed an additional three novel polynitro-substituted tetrazolotriazine-based compounds with exceptional performance, including 5,8-dinitro-5,6 dioxotetrazolo[1,5-b][1,2,4]triazine, DNOTzTr (2), 4,5,9,10 tetranitro[1,2,4,5]tetrazolo[3,4-b][1,2,4,5]tetrazolo[3',4':5,6]triazino[2,3 e]triazine, TNTzTr (3), and 4,5,6,10,11,12-hexanitro bis[1,2,4,5]tetrazolo[3',4':5,6]triazino[2,3-b:2',3'-e]triazine, HNBTzTr (4). The optimized structure, electronic density, natural bond orbital (NBO) charges and HOMO-LUMO orbitals, electrostatic potential on surface of molecule, IR- and NMR predicted spectra, as well as thermochemical parameters were calculated with the B3LYP/6-311+G(2d) level of theory. Critical parameters such as density, enthalpy of formation (EOF), and detonation performance have also been predicted. Characters with positive EOF (1386.00 and 1625.31 kJ/mol), high density (over 2.00 g/cm(3)), outstanding detonation properties (D = 9.82 km/s, P = 45.45 GPa; D = 9.94 km/s, P = 47.30 GPa), the perfect oxygen balance set to zero, and acceptable impact sensitivity led novel compounds 3 and 4 to be very promising energetic materials. This work provides the theoretical molecule design and a reasonable synthesis path for further experimental synthesis and testing. PMID- 25927414 TI - Comparison and evaluation of lupus nephritis response criteria in lupus activity indices and clinical trials. AB - Systemic lupus erythematosus (SLE) is a systemic autoimmune disease with diverse manifestations. Although the approval of new therapies includes only one agent in 50 years, a number of promising new drugs are in development. Lupus nephritis is a dreaded complication of SLE as it is associated with significant morbidity and mortality. Advancing the treatment of lupus nephritis requires well-designed clinical trials and this can be challenging in SLE. The major obstacles involve identifying the correct population of patients to enroll and ensuring that a clinically appropriate and patient-centered endpoint is being measured. In this review, we will first discuss the clinical utility of endpoints chosen to represent lupus nephritis in global disease activity scales. Second, we will review completed and active trials focused on lupus nephritis and discuss the endpoints chosen. There are many important lessons to be learned from existing assessment tools and clinical trials. Reviewing these points will help ensure that future efforts will yield meaningful disease activity measures and well designed clinical trials to advance our understanding of lupus management. PMID- 25927416 TI - Local level inequalities in the use of hospital-based maternal delivery in rural South Africa. AB - BACKGROUND: There is global concern with geographical and socio-economic inequalities in access to and use of maternal delivery services. Little is known, however, on how local-level socio-economic inequalities are related to the uptake of needed maternal health care. We conducted a study of relative socio-economic inequalities in use of hospital-based maternal delivery services within two rural sub-districts of South Africa. METHODS: We used both population-based surveillance and facility-based clinical record data to examine differences in the relative distribution of socio-economic status (SES), using a household assets index to measure wealth, among those needing maternal delivery services and those using them in the Bushbuckridge sub-district, Mpumalanga, and Hlabisa sub-district, Kwa-Zulu Natal. We compared the SES distributions in households with a birth in the previous year with the household SES distributions of representative samples of women who had delivered in hospitals in these two sub districts. RESULTS: In both sub-districts, women in the lowest SES quintile were significantly under-represented in the hospital user population, relative to need for delivery services (8% in user population vs 21% in population in need; p < 0.001 in each sub-district). Exit interviews provided additional evidence on potential barriers to access, in particular the affordability constraints associated with hospital delivery. CONCLUSIONS: The findings highlight the need for alternative strategies to make maternal delivery services accessible to the poorest women within overall poor communities and, in doing so, decrease socioeconomic inequalities in utilisation of maternal delivery services. PMID- 25927418 TI - Rhodium-catalyzed denitrogenative thioacetalization of N-sulfonyl-1,2,3-triazoles with disulfides: an entry to diverse transformation of terminal alkynes. AB - An efficient and useful rhodium-catalyzed denitrogenative thioacetalization of N sulfonyl-1,2,3-triazoles has been developed for the first time. The protocol uses readily available N-sulfonyl-1,2,3-triazoles and diaryl disulfides as the starting materials. The corresponding hydrolytic and reductive products with thioacetals were obtained in good to excellent yields, and the reactions were carried out easily under mild conditions with tolerance of some functional groups. Furthermore, the generated thioacetals could be transformed into some useful compounds. Therefore, the present method provides a novel and valuable strategy for the diverse transformation of alkynes. PMID- 25927419 TI - Investigation into the Formation and Adhesion of Cyclopentane Hydrates on Mechanically Robust Vapor-Deposited Polymeric Coatings. AB - Blockage of pipelines by formation and accumulation of clathrate hydrates of natural gases (also called gas hydrates) can compromise project safety and economics in oil and gas operations, particularly at high pressures and low temperatures such as those found in subsea or arctic environments. Cyclopentane (CyC5) hydrate has attracted interest as a model system for studying natural gas hydrates, because CyC5, like typical natural gas hydrate formers, is almost fully immiscible in water; and thus CyC5 hydrate formation is governed not only by thermodynamic phase considerations but also kinetic factors such as the hydrocarbon/water interfacial area, as well as mass and heat transfer constraints, as for natural gas hydrates. We present a macroscale investigation of the formation and adhesion strength of CyC5 hydrate deposits on bilayer polymer coatings with a range of wettabilities. The polymeric bilayer coatings are developed using initiated chemical vapor deposition (iCVD) of a mechanically robust and densely cross-linked polymeric base layer (polydivinylbenzene or pDVB) that is capped with a covalently attached thin hydrate-phobic fluorine-rich top layer (poly(perfluorodecyl acrylate) or pPFDA). The CyC5 hydrates are formed from CyC5-in-water emulsions, and differential scanning calorimetry (DSC) is used to confirm the thermal dissociation properties of the solid hydrate deposits. We also investigate the adhesion of the CyC5 hydrate deposits on bare and bilayer polymer-coated silicon and steel substrates. Goniometric measurements with drops of CyC5-in-water emulsions on the coated steel substrates exhibit advancing contact angles of 148.3 +/- 4.5 degrees and receding contact angles of 142.5 +/- 9.8 degrees , indicating the strongly emulsion-repelling nature of the iCVD coatings. The adhesion strength of the CyC5 hydrate deposits is reduced from 220 +/- 45 kPa on rough steel substrates to 20 +/- 17 kPa on the polymer-coated steel substrates. The measured strength of CyC5 hydrate adhesion is found to correlate very well with the work of adhesion between the emulsion droplets used to form the CyC5 hydrate and the underlying substrates. PMID- 25927420 TI - In(x)Ga(1-x)As nanowires with uniform composition, pure wurtzite crystal phase and taper-free morphology. AB - Obtaining compositional homogeneity without compromising morphological or structural quality is one of the biggest challenges in growing ternary alloy compound semiconductor nanowires. Here we report growth of Au-seeded InxGa1-xAs nanowires via metal-organic vapour phase epitaxy with uniform composition, morphology and pure wurtzite (WZ) crystal phase by carefully optimizing growth temperature and V/III ratio. We find that high growth temperatures allow the InxGa1-xAs composition to be more uniform by suppressing the formation of typically observed spontaneous In-rich shells. A low V/III ratio results in the growth of pure WZ phase InxGa1-xAs nanowires with uniform composition and morphology while a high V/III ratio allows pure zinc-blende (ZB) phase to form. Ga incorporation is found to be dependent on the crystal phase favouring higher Ga concentration in ZB phase compared to the WZ phase. Tapering is also found to be more prominent in defective nanowires hence it is critical to maintain the highest crystal structure purity in order to minimize tapering and inhomogeneity. The InP capped pure WZ In0.65Ga0.35As core-shell nanowire heterostructures show 1.54 MUm photoluminescence, close to the technologically important optical fibre telecommunication wavelength, which is promising for application in photodetectors and nanoscale lasers. PMID- 25927421 TI - Neutrophil and vaccine. PMID- 25927423 TI - Interleukin-6 Family of Cytokines in Crevicular Fluid of Renal Transplant Recipients With and Without Cyclosporine A-Induced Gingival Overgrowth. AB - BACKGROUND: Interleukin (IL)-6 family of cytokines, including IL-6, oncostatin M (OSM), leukemia inhibitory factor (LIF), and IL-11, have fibrogenic features. The current study determines gingival crevicular fluid (GCF) levels of fibrosis related IL-6-type cytokines in cyclosporine A (CsA)-induced gingival overgrowth (GO). METHODS: Eighty non-smokers were included (40 CsA-medicated renal transplant patients with GO [GO+; n = 20] or without GO [GO-; n = 20], 20 individuals with gingivitis, and 20 healthy participants). Probing depth and plaque, papilla bleeding, and hyperplastic index scores were recorded. GCF samples were obtained from the mesio-buccal aspects of two teeth. GCF IL-6, IL 1beta, OSM, LIF, and IL-11 levels were analyzed by enzyme-linked immunosorbent assay. RESULTS: The GO+ and GO- groups had higher IL-6 total amounts than the healthy group (P <0.008). IL-1beta total amounts in the GO+ group were significantly higher than in both the healthy and GO- groups (P <0.008). OSM total amount was elevated in the GO+ and GO- groups compared with both the gingivitis and healthy groups (P <0.008). All groups had similar LIF and IL-11 total amounts (P >0.008). Moderate positive correlations were detected among IL 6, IL-1beta, OSM, and IL-11 total amount in GCF and clinical parameters (P <0.05). CONCLUSIONS: IL-6 and OSM increases in GCF as a result of CsA usage or an immunosuppressed state irrespective of the severity of inflammation and the presence of GO. The IL-6 family of cytokines might not be directly involved in biologic mechanisms associated with CsA-induced GO. Lack of an association between assessed IL-6 cytokines and CsA-induced GO might indicate distinct effects of these cytokines on fibrotic changes of different tissues. PMID- 25927424 TI - Change in the Gingival Margin Profile After the Single Flap Approach in Periodontal Intraosseous Defects. AB - BACKGROUND: The aim of the present study is to evaluate the association of patient-related and site-specific factors, as well as the adopted treatment modality, with the change in buccal (bREC) and interdental (iREC) gingival recession observed at 6 months after treatment of periodontal intraosseous defects with the single flap approach (SFA). METHODS: Sixty-six patients contributing 74 intraosseous defects accessed with a buccal SFA and treated with different modalities were selected retrospectively. A two-level (patient and site) model was constructed, with the 6-month changes in bREC and iREC as the dependent variables. RESULTS: (1) Significant 6-month increases in bREC (-0.6 +/- 0.7 mm) and iREC (-0.9 +/- 1.1 mm) were observed. (2) bREC change was significantly predicted by presurgery interproximal probing depth (PD) and depth of osseous dehiscence at the buccal aspect. (3) iREC change was significantly predicted by presurgery interproximal PD and the treatment modality, with defects treated with SFA in combination with a graft material and a bioactive agent being less prone to iREC increase compared to defects treated with SFA alone. CONCLUSIONS: After buccal SFA, greater post-surgery increase in bREC must be expected for deep intraosseous defects associated with a buccal dehiscence. The combination of a graft material and a bioactive agent in adjunct to the SFA may limit the postoperative increase in iREC. PMID- 25927425 TI - Exploring meanings of illness causation among those severely affected by multiple sclerosis: a comparative qualitative study of Black Caribbean and White British people. AB - BACKGROUND: Illness attributions, particularly for those living with life limiting illnesses, are associated with emotional adjustment or psychological distress. Few studies have examined attributions among people severely affected by multiple sclerosis (PwMS), and specifically among from diverse communities. This study aimed to explore and compare the presence and construction of meanings among Black Caribbean and White British PwMS. METHODS: Cross sectional qualitative interviews were conducted among Black Caribbean (BC) and White British (WB) PwMS with an EDSS of >=6.0 (severe disease). Data were analysed using the framework approach. RESULTS: 15 BC and 15 WB PwMS were interviewed. Attributions were complex with most PwMS reporting multiple explanations. Uncertainty, represents the first theme surrounding the aetiology of MS where participants constantly rehearsed the "why me?" question in relation to their illness, a number expressing considerable frustration. The second theme, 'logical and scientific', was voiced more often by WB PwMS and accounts for a range of genetic/viral influences, stress, environmental and lifestyle factors. Third, the 'supernatural' illness attribution theme departs from a biomedical perspective and was reported often among BC PwMS. This theme included the sub-categories of tests of faith and divine punishment, a view although exclusive to BC participants but was sometimes in conflict with notions of modernity. CONCLUSION: Our findings identify evidence of cross-cultural and intra-group diversity in relation to MS causation. A greater professional awareness of the processes used by PwMS from diverse communities to make sense of their situation will enable health care professionals to facilitate effective support for those in their care and channel relevant psychosocial resources to them. This requires heightened skills in communication and cultural competency. PMID- 25927426 TI - Recognizing and managing sepsis: what needs to be done? AB - Sepsis is associated with significant morbidity and mortality if not promptly recognized and treated. Since the development of early goal-directed therapy, mortality rates have decreased, but sepsis remains a major cause of death in patients arriving at the emergency department or staying in hospital. In this forum article, we asked clinicians and researchers with expertise in sepsis care to discuss the importance of rapid detection and treatment of the condition, as well as special considerations in different patient groups. PMID- 25927428 TI - Propensity matching cannot substitute for randomization in albumin studies. PMID- 25927427 TI - The Epstein-Barr virus latent membrane protein-1 (LMP1) 30-bp deletion and XhoI polymorphism in nasopharyngeal carcinoma: a meta-analysis of observational studies. AB - BACKGROUND: Epstein-Barr virus (EBV) is considered to be closely associated with nasopharyngeal carcinoma (NPC), in which EBV-encoded latent membrane protein 1 (LMP1) was found to have an oncogenic role. However, the results published on the LMP1 polymorphism are inconsistent. In the present study, we performed a meta analysis to determine the frequency of the associations and a more precise association between NPC and EBV LMP1 gene variants (30-bp deletion (del)/XhoI loss). METHODS: Eligible articles met the inclusion/exclusion criteria and were identified in the following electronic databases: PubMed, ScienceDirect, and SciELO. Consequently, the data of interest were extracted and plotted in a table to calculate the frequency and odds ratio (OR) of the outcomes of interest (30-bp del-LMP1/XhoI-loss) in patients with NPC. Study quality (Newcastle-Ottawa Scale (NOS)), publication bias, and heterogeneity were assessed. RESULTS: Thirty-one observational studies were included with a total of 2,846 individuals (NPC, n = 1,855; control, n = 991). The risk of bias in relation to study quality evaluated by NOS was considered low. The pooled estimate of the frequency of 30-bp del-LMP1 and XhoI-loss in patients with NPC was 77% (95% confidence interval (CI): 72 to 82) and 82% (95% CI: 71 to 92), respectively. There was an association between 30 bp del-LMP1 and NPC susceptibility (OR = 2.86, 95% CI: 1.35 to 6.07, P = 0.00). Similarly, there was an association between XhoI-loss and NPC (OR = 8.5, 95% CI: 1.7 to 41, P = 0.00). However, when we analyze the co-existence of the 30-bp del LMP1 and XhoI-loss in patients with NPC, there was no association (OR = 1.09, 95% CI: 0.06 to 18.79, P = 0.002). CONCLUSIONS: Our results suggest an association between the 30-bp del-LMP1 and XhoI-loss with NPC susceptibility. However, our data should be interpreted with caution because the sample size was small, and there was heterogeneity between the studies. Thus, future studies are needed with adjusted estimates to simultaneously evaluate multiple factors involved in the development of NPC. SYSTEMATIC REVIEW REGISTRATION: PROSPERO CRD42014013496 . PMID- 25927429 TI - Underestimation of foraging behaviour by standard field methods in malaria vector mosquitoes in southern Africa. AB - BACKGROUND: Defining the anopheline mosquito vectors and their foraging behaviour in malaria endemic areas is crucial for disease control and surveillance. The standard protocol for molecular identification of host blood meals in mosquitoes is to morphologically identify fed mosquitoes and then perform polymerase chain reaction (PCR), precipitin tests, or ELISA assays. The purpose of this study was to determine the extent to which the feeding rate and human blood indices (HBIs) of malaria vectors were underestimated when molecular confirmation by PCR was performed on both visually fed and unfed mosquitoes. METHODS: In association with the Southern Africa International Centers of Excellence in Malaria Research (ICEMR), mosquito collections were performed at three sites: Choma district in southern Zambia, Nchelenge district in northern Zambia, and Mutasa district in eastern Zimbabwe. All anophelines were classified visually as fed or unfed, and tested for blood meal species using PCR methods. The HBIs of visually fed mosquitoes were compared to the HBIs of overall PCR confirmed fed mosquitoes by Pearson's Chi-Square Test of Independence. RESULTS: The mosquito collections consisted of Anopheles arabiensis from Choma, Anopheles funestus s.s., Anopheles gambiae s.s. and Anopheles leesoni from Nchelenge, and An. funestus s.s. and An. leesoni from Mutasa. The malaria vectors at all three sites had large human blood indices (HBI) suggesting high anthropophily. When only visually fed mosquitoes tested by PCR for blood meal species were compared to testing those classified as both visually fed and unfed mosquitoes, it was found that the proportion blooded was underestimated by up to 18.7%. For most Anopheles species at each site, there was a statistically significant relationship (P < 0.05) between the HBIs of visually fed mosquitoes and that of the overall PCR confirmed fed mosquitoes. CONCLUSION: The impact on HBI of analysing both visually fed and unfed mosquitoes varied from site to site. This discrepancy may be due to partial blood feeding behaviour by mosquitoes, digestion of blood meals, sample condition, and/or expertise of entomology field staff. It is important to perform molecular testing on all mosquitoes to accurately characterize vector feeding behaviour and develop interventions in malaria endemic areas. PMID- 25927430 TI - Association of DRD3, COMT, and SLC6A4 Gene Polymorphisms with Type 2 Diabetes in Southern Chinese: A Hospital-Based Case-Control Study. AB - AIM: The aim of this study was to assess the associations of six single nucleotide polymorphisms (SNPs) of three genes (DRD3, COMT, and SCL6A4) with type 2 diabetes mellitus (T2DM) in Southern Chinese. SUBJECTS AND METHODS: Five hundred ninety-five cases with T2DM and 725 healthy controls of Han origin were recruited from six hospitals in Guangdong Province, Southern China. Fasting serum concentrations of markers of interest (total cholesterol, triglyceride, plasma glucose, etc.) were measured in hospitals. SNP genotyping was performed using a custom-by-design 2-*48-Plex SNPscanTM kit (Genesky Biotechnologies Inc., Shanghai, China). Single-point SNP analysis, haplotype analysis, and SNP-SNP interactions were carried out. RESULTS: SNP rs4646312 in COMT achieved statistical significance in both allelic association and genotypic association and even after adjusting covariates (odds ratio [OR]=1.26; 95% confidence interval [CI], 1.04-1.53; P=0.021). Two haplotypes consisting of rs4646312 and rs4680 were also significantly associated with T2DM, of which C-G was a protective haplotype for T2DM (OR=0.83; 95% CI, 0.70-0.98; P=0.029), whereas T-A was a risk one (OR=1.23, 95% CI, 1.03-1.46; P=0.022). Interaction analysis identified a significant epistatic effect between rs4680 in COMT and rs2066713 in SCL6A4 after adjusting for covariates (OR=3.59, 95% CI, 1.72-7.48; P=0.001 for dominant-dominant model). However, only the interaction between rs4680 and rs2066713 was significant, and haplotype T-A showed a marginally increased risk after Bonferroni correction. CONCLUSIONS: The genetic polymorphisms in COMT and SCL6A4 confer significant effects in joint actions to T2DM in Southern Chinese. PMID- 25927434 TI - Discovery of new biomarkers for malignant mesothelioma. AB - Malignant mesothelioma is an asbestos-induced, aggressive tumour with limited treatment options and very poor outcome. Currently, there are no tumour biomarkers in widespread clinical use for this disease. Soluble mesothelin is the most intensively investigated mesothelioma biomarker and has been approved by the US FDA primarily as a tool for monitoring patient response and progression. Mesothelin is elevated in the blood and effusions of patients with mesothelioma, and is rarely elevated in people with benign disease with normal renal function. However, the sensitivity of mesothelin limits its use as a stand-alone tool for the screening of the asymptomatic asbestos-exposed population-one of the primary aims of mesothelioma biomarker studies. Thus, there is an intense research effort focused on the identification of new and/or novel biomarkers for mesothelioma. Some of the challenges associated with biomarker discovery in mesothelioma are discussed. PMID- 25927435 TI - A modularity-based method reveals mixed modules from chemical-gene heterogeneous network. AB - For a multicomponent therapy, molecular network is essential to uncover its specific mode of action from a holistic perspective. The molecular system of a Traditional Chinese Medicine (TCM) formula can be represented by a 2-class heterogeneous network (2-HN), which typically includes chemical similarities, chemical-target interactions and gene interactions. An important premise of uncovering the molecular mechanism is to identify mixed modules from complex chemical-gene heterogeneous network of a TCM formula. We thus proposed a novel method (MixMod) based on mixed modularity to detect accurate mixed modules from 2 HNs. At first, we compared MixMod with Clauset-Newman-Moore algorithm (CNM), Markov Cluster algorithm (MCL), Infomap and Louvain on benchmark 2-HNs with known module structure. Results showed that MixMod was superior to other methods when 2 HNs had promiscuous module structure. Then these methods were tested on a real drug-target network, in which 88 disease clusters were regarded as real modules. MixMod could identify the most accurate mixed modules from the drug-target 2-HN (normalized mutual information 0.62 and classification accuracy 0.4524). In the end, MixMod was applied to the 2-HN of Buchang naoxintong capsule (BNC) and detected 49 mixed modules. By using enrichment analysis, we investigated five mixed modules that contained primary constituents of BNC intestinal absorption liquid. As a matter of fact, the findings of in vitro experiments using BNC intestinal absorption liquid were found to highly accord with previous analysis. Therefore, MixMod is an effective method to detect accurate mixed modules from chemical-gene heterogeneous networks and further uncover the molecular mechanism of multicomponent therapies, especially TCM formulae. PMID- 25927436 TI - The shh signaling pathway is upregulated in multiple cell types in cortical ischemia and influences the outcome of stroke in an animal model. AB - Recently the sonic hedgehog (shh) signaling pathway has been shown to play an important role in regulating repair and regenerative responses after brain injury, including ischemia. However, the precise cellular components that express and upregulate the shh gene and the cellular components that respond to shh signaling remain to be identified. In this study, using a distal MCA occlusion model, our data show that the shh signal is upregulated both at the cortical area near the injury site and in the adjacent striatum. Multiple cell types upregulate shh signaling in ischemic brain, including neurons, reactive astrocytes and nestin-expressing cells. The shh signaling pathway genes are also expressed in the neural stem cells (NSCs) niche in the subventricular zone (SVZ). Conditional deletion of the shh gene in nestin-expressing cells both at the SVZ niche and at the ischemic site lead to significantly more severe behavioral deficits in these shh iKO mice after cortical stroke, measured using an automated open field locomotion apparatus (Student's t-test, p<0.05). In contrast, animals given post stroke treatment with the shh signaling agonist (SAG) demonstrated less deficits in behavioral function, compared to vehicle-treated mice. At 7 days after stroke, SAG-treated mice showed higher values in multiple horizontal movement parameters compared to vehicle treated mice (Student's t-test, p<0.05) whereas there were no differences in pre-stroke measurements, (Student's t-test, p>0.05). In summary, our data demonstrate that shh signaling plays critical and ongoing roles in response to ischemic injury and modulation of shh signaling in vivo alters the functional outcome after cortical ischemic injury. PMID- 25927438 TI - Locational determinants of emissions from pollution-intensive firms in urban areas. AB - Industrial pollution has remained as one of the most daunting challenges for many regions around the world. Characterizing the determinants of industrial pollution should provide important management implications. Unfortunately, due to the absence of high-quality data, rather few studies have systematically examined the locational determinants using a geographical approach. This paper aimed to fill the gap by accessing the pollution source census dataset, which recorded the quantity of discharged wastes (waste water and solid waste) from 717 pollution intensive firms within Huzhou City, China. Spatial exploratory analysis was applied to analyze the spatial dependency and local clusters of waste emissions. Results demonstrated that waste emissions presented significantly positive autocorrelation in space. The high-high hotspots generally concentrated towards the city boundary, while the low-low clusters approached the Taihu Lake. Their locational determinants were identified by spatial regression. In particular, firms near the city boundary and county road were prone to discharge more wastes. Lower waste emissions were more likely to be observed from firms with high proximity to freight transfer stations or the Taihu Lake. Dense populous districts saw more likelihood of solid waste emissions. Firms in the neighborhood of rivers exhibited higher waste water emissions. Besides, the control variables (firm size, ownership, operation time and industrial type) also exerted significant influence. The present methodology can be applicable to other areas, and further inform the industrial pollution control practices. Our study advanced the knowledge of determinants of emissions from pollution-intensive firms in urban areas. PMID- 25927437 TI - Deficiency for the cysteine protease cathepsin L impairs Myc-induced tumorigenesis in a mouse model of pancreatic neuroendocrine cancer. AB - Motivated by the recent implication of cysteine protease cathepsin L as a potential target for anti-cancer drug development, we used a conditional MycERTAM;Bcl-xL model of pancreatic neuroendocrine tumorigenesis (PNET) to assess the role of cathepsin L in Myc-induced tumor progression. By employing a cysteine cathepsin activity probe in vivo and in vitro, we first established that cathepsin activity increases during the initial stages of MycERTAM;Bcl-xL tumor development. Among the cathepsin family members investigated, only cathepsin L was predominately produced by beta-tumor cells in neoplastic pancreata and, consistent with this, cathepsin L mRNA expression was rapidly upregulated following Myc activation in the beta cell compartment. By contrast, cathepsins B, S and C were highly enriched in tumor-infiltrating leukocytes. Genetic deletion of cathepsin L had no discernible effect on the initiation of neoplastic growth or concordant angiogenesis. However, the tumors that developed in the cathepsin L deficient background were markedly reduced in size relative to their typical wild type counterparts, indicative of a role for cathepsin L in enabling expansive tumor growth. Thus, genetic blockade of cathepsin L activity is inferred to retard Myc-driven tumor growth, encouraging the potential utility of pharmacological inhibitors of cysteine cathepsins in treating late stage tumors. PMID- 25927439 TI - Neuronal Networks during Burst Suppression as Revealed by Source Analysis. AB - INTRODUCTION: Burst-suppression (BS) is an electroencephalography (EEG) pattern consisting of alternant periods of slow waves of high amplitude (burst) and periods of so called flat EEG (suppression). It is generally associated with coma of various etiologies (hypoxia, drug-related intoxication, hypothermia, and childhood encephalopathies, but also anesthesia). Animal studies suggest that both the cortex and the thalamus are involved in the generation of BS. However, very little is known about mechanisms of BS in humans. The aim of this study was to identify the neuronal network underlying both burst and suppression phases using source reconstruction and analysis of functional and effective connectivity in EEG. MATERIAL/METHODS: Dynamic imaging of coherent sources (DICS) was applied to EEG segments of 13 neonates and infants with burst and suppression EEG pattern. The brain area with the strongest power in the analyzed frequency (1-4 Hz) range was defined as the reference region. DICS was used to compute the coherence between this reference region and the entire brain. The renormalized partial directed coherence (RPDC) was used to describe the informational flow between the identified sources. RESULTS/CONCLUSION: Delta activity during the burst phases was associated with coherent sources in the thalamus and brainstem as well as bilateral sources in cortical regions mainly frontal and parietal, whereas suppression phases were associated with coherent sources only in cortical regions. Results of the RPDC analyses showed an upwards informational flow from the brainstem towards the thalamus and from the thalamus to cortical regions, which was absent during the suppression phases. These findings may support the theory that a "cortical deafferentiation" between the cortex and sub-cortical structures exists especially in suppression phases compared to burst phases in burst suppression EEGs. Such a deafferentiation may play a role in the poor neurological outcome of children with these encephalopathies. PMID- 25927440 TI - Attenuated XPC expression is not associated with impaired DNA repair in bladder cancer. AB - Bladder cancer has a high incidence with significant morbidity and mortality. Attenuated expression of the DNA damage response protein Xeroderma Pigmentosum complementation group C (XPC) has been described in bladder cancer. XPC plays an essential role as the main initiator and damage-detector in global genome nucleotide excision repair (NER) of UV-induced lesions, bulky DNA adducts and intrastrand crosslinks, such as those made by the chemotherapeutic agent Cisplatin. Hence, XPC protein might be an informative biomarker to guide personalized therapy strategies in a subset of bladder cancer cases. Therefore, we measured the XPC protein expression level and functional NER activity of 36 bladder tumors in a standardized manner. We optimized conditions for dissociation and in vitro culture of primary bladder cancer cells and confirmed attenuated XPC expression in approximately 40% of the tumors. However, NER activity was similar to co-cultured wild type cells in all but one of 36 bladder tumors. We conclude, that (i) functional NER deficiency is a relatively rare phenomenon in bladder cancer and (ii) XPC protein levels are not useful as biomarker for NER activity in these tumors. PMID- 25927441 TI - Critical evaluation of particle size distribution models using soil data obtained with a laser diffraction method. AB - Mathematical descriptions of classical particle size distribution (PSD) data are often used to estimate soil hydraulic properties. Laser diffraction methods (LDM) now provide more detailed PSD measurements, but deriving a function to characterize the entire range of particle sizes is a major challenge. The aim of this study was to compare the performance of eighteen PSD functions for fitting LDM data sets from a wide range of soil textures. These models include five lognormal models, five logistic models, four van Genuchten models, two Fredlund models, a logarithmic model, and an Andersson model. The fits were evaluated using Akaike's information criterion (AIC), adjusted R2, and root-mean-square error (RMSE). The results indicated that the Fredlund models (FRED3 and FRED4) had the best performance for most of the soils studied, followed by one logistic growth function extension model (MLOG3) and three lognormal models (ONLG3, ORLG3, and SHCA3). The performance of most PSD models was better for soils with higher silt content and poorer for soils with higher clay and sand content. The FRED4 model best described the PSD of clay, silty clay, clay loam, silty clay loam, silty loam, loam, and sandy loam, whereas FRED3, MLOG3, ONLG3, ORLG3, and SHCA3 showed better performance for most soils studied. PMID- 25927442 TI - Modelling the spatial distribution of the nuisance mosquito species Anopheles plumbeus (Diptera: Culicidae) in the Netherlands. AB - BACKGROUND: Landscape modifications, urbanization or changes of use of rural agricultural areas can create more favourable conditions for certain mosquito species and therefore indirectly cause nuisance problems for humans. This could potentially result in mosquito-borne disease outbreaks when the nuisance is caused by mosquito species that can transmit pathogens. Anopheles plumbeus is a nuisance mosquito species and a potential malaria vector. It is one of the most frequently observed species in the Netherlands. Information on the distribution of this species is essential for risk assessments. The purpose of the study was to investigate the potential spatial distribution of An. plumbeus in the Netherlands. METHODS: Random forest models were used to link the occurrence and the abundance of An. plumbeus with environmental features and to produce distribution maps in the Netherlands. Mosquito data were collected using a cross sectional study design in the Netherlands, from April to October 2010-2013. The environmental data were obtained from satellite imagery and weather stations. Statistical measures (accuracy for the occurrence model and mean squared error for the abundance model) were used to evaluate the models performance. The models were externally validated. RESULTS: The maps show that forested areas (centre of the Netherlands) and the east of the country were predicted as suitable for An. plumbeus. In particular high suitability and high abundance was predicted in the south-eastern provinces Limburg and North Brabant. Elevation, precipitation, day and night temperature and vegetation indices were important predictors for calculating the probability of occurrence for An. plumbeus. The probability of occurrence, vegetation indices and precipitation were important for predicting its abundance. The AUC value was 0.73 and the error in the validation was 0.29; the mean squared error value was 0.12. CONCLUSIONS: The areas identified by the model as suitable and with high abundance of An. plumbeus, are consistent with the areas from which nuisance was reported. Our results can be helpful in the assessment of vector-borne disease risk. PMID- 25927447 TI - Erratum: A randomized, double-blind, placebo-controlled study of rapid-acting intramuscular olanzapine in Japanese patients for schizophrenia with acute agitation. PMID- 25927449 TI - The implications of a Silurian and other thylacocephalan crustaceans for the functional morphology and systematic affinities of the group. AB - BACKGROUND: Thylacocephala is a group of enigmatic extinct arthropods. Here we provide a full description of the oldest unequivocal thylacocephalan, a new genus and species Thylacares brandonensis, which is present in the Silurian Waukesha fauna from Wisconsin, USA. We also present details of younger, Jurassic specimens, from the Solnhofen lithographic limestones, which are crucial to our interpretation of the systematic position of Thylacocephala. In the past, Thylacocephala has been interpreted as a crustacean ingroup and as closely related to various groups such as cirripeds, decapods or remipeds. RESULTS: The Waukesha thylacocephalan, Thylacares brandonensis n. gen. n. sp., bears compound eyes and raptorial appendages that are relatively small compared to those of other representatives of the group. As in other thylacocephalans the large bivalved shield encloses much of the entire body. The shield lacks a marked optical notch. The eyes, which project just beyond the shield margin, appear to be stalked. Head appendages, which may represent antennulae, antennae and mandibles, appear to be present. The trunk is comprised of up to 22 segments. New details observed on thylacocephalans from the Jurassic Solnhofen lithographic limestones include antennulae and antennae of Mayrocaris bucculata, and endites on the raptorial appendages and an elongate last trunk appendage in Clausocaris lithographica. Preserved features of the internal morphology in C. lithographica include the muscles of the raptorial appendage and trunk. CONCLUSIONS: Our results indicate that some 'typical' thylacocephalan characters are unique to the group; these autapomorphies contribute to the difficulty of determining thylacocephalan affinities. While the new features reported here are consistent with a eucrustacean affinity, most previous hypotheses for the position of Thylacocephala within Eucrustacea (as Stomatopoda, Thecostraca or Decapoda) are shown to be unlikely. A sister group relationship to Remipedia appears compatible with the observed features of Thylacocephala but more fossil evidence is required to test this assertion. The raptorial appendages of Thylacocephala most likely projected 45 degrees abaxially instead of directly forward as previously reconstructed. The overall morphology of thylacocephalans supports a predatory mode of life. PMID- 25927454 TI - Capital interplays and the self-rated health of young men: results from a cross sectional study in Switzerland. AB - INTRODUCTION: We apply capital interplay theory to health inequalities in Switzerland by investigating the interconnected effects of parental cultural, economic and social capitals and personal educational stream on the self-rated health of young Swiss men who live with their parents. METHODS: We apply logistic regression modelling to self-rated health in original cross-sectional survey data collected during mandatory conscription of Swiss male citizens in 2010 and 2011 (n = 23,975). RESULTS: In comparison with sons whose parents completed mandatory schooling only, sons with parents who completed technical college or university were significantly more likely to report very good or excellent self-rated health. Parental economic capital was an important mediating factor in this regard. Number of books in the home (parental cultural capital), family economic circumstances (parental economic capital) and parental ties to influential people (parental social capital) were also independently associated with the self-rated health of the sons. Although sons in the highest educational stream tended to report better health than those in the lowest, we found little evidence for a health-producing intergenerational transmission of capitals via the education stream of the sons. Finally, the positive association between personal education and self-rated health was stronger among sons with relatively poorly educated parents and stronger among sons with parents who were relatively low in social capital. CONCLUSIONS: Our study provides empirical support for the role of capital interplays, social processes in which capitals interpenetrate or co constitute one another, in the intergenerational production of the health of young men in Switzerland. PMID- 25927452 TI - Tailored approaches to stroke health education (TASHE): study protocol for a randomized controlled trial. AB - BACKGROUND: Stroke is a leading cause of adult disability and mortality. Intravenous thrombolysis can minimize disability when patients present to the emergency department for treatment within the 3 - 41/2 h of symptom onset. Blacks and Hispanics are more likely to die and suffer disability from stroke than whites, due in part to delayed hospital arrival and ineligibility for intravenous thrombolysis for acute stroke. Low stroke literacy (poor knowledge of stroke symptoms and when to call 911) among Blacks and Hispanics compared to whites may contribute to disparities in acute stroke treatment and outcomes. Improving stroke literacy may be a critical step along the pathway to reducing stroke disparities. The aim of the current study is to test a novel intervention to increase stroke literacy in minority populations in New York City. DESIGN AND METHODS: In a two-arm cluster randomized trial, we will evaluate the effectiveness of two culturally tailored stroke education films - one in English and one in Spanish - on changing behavioral intent to call 911 for suspected stroke, compared to usual care. These films will target knowledge of stroke symptoms, the range of severity of symptoms and the therapeutic benefit of calling 911, as well as address barriers to timely presentation to the hospital. Given the success of previous church-based programs targeting behavior change in minority populations, this trial will be conducted with 250 congregants across 14 churches (125 intervention; 125 control). Our proposed outcomes are (1) recognition of stroke symptoms and (2) behavioral intent to call 911 for suspected stroke, measured using the Stroke Action Test at the 6-month and 1-year follow-up. DISCUSSION: This is the first randomized trial of a church-placed narrative intervention to improve stroke outcomes in urban Black and Hispanic populations. A film intervention has the potential to make a significant public health impact, as film is a highly scalable and disseminable medium. Since there is at least one church in almost every neighborhood in the USA, churches have the ability and reach to play an important role in the dissemination and translation of stroke prevention programs in minority communities. TRIAL REGISTRATION: NCT01909271 ; July 22, 2013. PMID- 25927456 TI - Validation study of candidate single nucleotide polymorphisms associated with left ventricular hypertrophy in the Korean population. AB - BACKGROUND: Left ventricular hypertrophy (LVH) is a valid predictor for cardiovascular mortality and morbidity regardless of age, gender, and race. The HyperGEN study conducted a genome-wide association study and identified twelve single nucleotide polymorphisms (SNPs) associated with LVH. The aim of this study was to validate these candidate SNPs in the Korean population. METHODS: Among 1637 individuals from the Korean Multi-Rural Communities Cohort Study (MRCohort) of the Korean Genome Epidemiology Study (KoGES), we carried out a linear regression analysis with left ventricular mass index (LVMI) and a logistic regression analysis for LVH status. RESULTS: The rs4129218 on chromosome 12 tended to be associated with LVM/body surface area (adjusted beta = -0.023; p = 0.036) and LVM/height(2.7) (adjusted beta = -0.027; p = 0.016), and was marginally protective against LVH after adjustment for age, sex, body mass index, serum creatinine, systolic blood pressure, heart rate and antihypertensive medication (adjusted odds ratio = 0.766 and 0.731; p = 0.027 and 0.007 according to indexation by BSA and height(2.7), respectively). CONCLUSIONS: In the Korean population, the minor allele of rs4129218 had borderline association with lower LVM. This study suggests that rs4129218 on chromosome 12 showed consistent tendency of possibly related loci for LVH independent of ethnic background. PMID- 25927460 TI - Safety and effectiveness of a Patient Blood Management (PBM) program in surgical patients--the study design for a multi-centre prospective epidemiologic non inferiority trial. AB - BACKGROUND: Preoperative and hospital-acquired anaemia is common among surgical patients. It is associated with an increased risk of morbidity and mortality and a strong risk factor for allogeneic blood transfusions with their own inherent risks. Patient Blood Management (PBM) concepts aim to increase and preserve autologous erythrocyte volume and to optimise haemotherapy. They thus have great potential to benefit patients. METHODS/DESIGN: This prospective, multi-centre clinical trial tests the hypothesis that PBM programs are safe and effective in the care of adult surgical patients. Primary outcome is a composite endpoint of adverse events and in-hospital mortality. DISCUSSION: This trial will determine whether the implementation of a PBM program is safe and effective in terms of clinical outcome compared to a pre-implementation cohort. This trial is registered at www.clinicaltrials.gov (NCT01820949). PMID- 25927461 TI - Copper-triggered three-component reaction of CF3CHN2, nitriles, and aldehydes: highly diastereoselective synthesis of CF3-substituted oxazolines and vicinal amino alcohols. AB - A novel, three-component C-C, C-N and C-O bond forming reaction is described. In the presence of 20 mol% CuO, this condensation reaction of CF3CHN2, nitriles, and aldehydes proceeds to afford CF3-substituted oxazolines in moderate to high yields with excellent diastereoselectivities. Subsequent ring-opening of oxazolines gives rise to the corresponding vicinal amino alcohols. PMID- 25927463 TI - The McGill simulator for endoscopic sinus surgery (MSESS): a validation study. AB - BACKGROUND: Endoscopic sinus surgery (ESS) is a technically challenging procedure, associated with a significant risk of complications. Virtual reality simulation has demonstrated benefit in many disciplines as an important educational tool for surgical training. Within the field of rhinology, there is a lack of ESS simulators with appropriate validity evidence supporting their integration into residency education. The objectives of this study are to evaluate the acceptability, perceived realism and benefit of the McGill Simulator for Endoscopic Sinus Surgery (MSESS) among medical students, otolaryngology residents and faculty, and to present evidence supporting its ability to differentiate users based on their level of training through the performance metrics. METHODS: 10 medical students, 10 junior residents, 10 senior residents and 3 expert sinus surgeons performed anterior ethmoidectomies, posterior ethmoidectomies and wide sphenoidotomies on the MSESS. Performance metrics related to quality (e.g. percentage of tissue removed), efficiency (e.g. time, path length, bimanual dexterity, etc.) and safety (e.g. contact with no-go zones, maximum applied force, etc.) were calculated. All users completed a post simulation questionnaire related to realism, usefulness and perceived benefits of training on the MSESS. RESULTS: The MSESS was found to be realistic and useful for training surgical skills with scores of 7.97 +/- 0.29 and 8.57 +/- 0.69, respectively on a 10-point rating scale. Most students and residents (29/30) believed that it should be incorporated into their curriculum. There were significant differences between novice surgeons (10 medical students and 10 junior residents) and senior surgeons (10 senior residents and 3 sinus surgeons) in performance metrics related to quality (p < 0.05), efficiency (p < 0.01) and safety (p < 0.05). CONCLUSION: The MSESS demonstrated initial evidence supporting its use for residency education. This simulator may be a potential resource to help fill the void in endoscopic sinus surgery training. PMID- 25927465 TI - Design of catalytic substrates for uniform graphene films: from solid-metal to liquid-metal. AB - The controllable synthesis of uniform graphene with a specific layer number is crucial for both fundamental research and emerging applications due to the high sensitivity of the various extraordinary physicochemical properties of graphene to its layer numbers. However, the excessive segregation of extra C, the inactivation of the self-limiting of Cu and the superabundant nucleation at grain boundaries and defect sites render that the controllable synthesis of uniform graphene is still a challenge. By the employment of various solid and liquid metals with quasi-atomically smooth surfaces to avoid defects or grain boundaries, a series of studies have been performed and significant improvements have been achieved in the controllable synthesis of uniform graphene films. In this review, the representative strategies of designing catalytic substrates, including polycrystalline metals, single-crystalline metals, binary metal alloys and liquid metals, are highlighted. The future of the controllable synthesis of uniform graphene is also discussed. PMID- 25927464 TI - Genome assembly using Nanopore-guided long and error-free DNA reads. AB - BACKGROUND: Long-read sequencing technologies were launched a few years ago, and in contrast with short-read sequencing technologies, they offered a promise of solving assembly problems for large and complex genomes. Moreover by providing long-range information, it could also solve haplotype phasing. However, existing long-read technologies still have several limitations that complicate their use for most research laboratories, as well as in large and/or complex genome projects. In 2014, Oxford Nanopore released the MinION(r) device, a small and low cost single-molecule nanopore sequencer, which offers the possibility of sequencing long DNA fragments. RESULTS: The assembly of long reads generated using the Oxford Nanopore MinION(r) instrument is challenging as existing assemblers were not implemented to deal with long reads exhibiting close to 30% of errors. Here, we presented a hybrid approach developed to take advantage of data generated using MinION(r) device. We sequenced a well-known bacterium, Acinetobacter baylyi ADP1 and applied our method to obtain a highly contiguous (one single contig) and accurate genome assembly even in repetitive regions, in contrast to an Illumina-only assembly. Our hybrid strategy was able to generate NaS (Nanopore Synthetic-long) reads up to 60 kb that aligned entirely and with no error to the reference genome and that spanned highly conserved repetitive regions. The average accuracy of NaS reads reached 99.99% without losing the initial size of the input MinION(r) reads. CONCLUSIONS: We described NaS tool, a hybrid approach allowing the sequencing of microbial genomes using the MinION(r) device. Our method, based ideally on 20x and 50x of NaS and Illumina reads respectively, provides an efficient and cost-effective way of sequencing microbial or small eukaryotic genomes in a very short time even in small facilities. Moreover, we demonstrated that although the Oxford Nanopore technology is a relatively new sequencing technology, currently with a high error rate, it is already useful in the generation of high-quality genome assemblies. PMID- 25927467 TI - Three-year survival and recurrence after first-ever stroke: the Joinville stroke registry. AB - BACKGROUND: Data estimating the recurrence and risk of death are lacking in low and middle income countries, where two thirds of the stroke burden occurs. Previously we had shown that the incidence and mortality have been decreasing over the last 18 years in Joinville, Southern Brazil. In this study, we aim to determine the recurrence rates, survival rates and the cause of death in 3 years after their first-ever incident in a urban population-based setting. METHODS: From the Joinville Stroke Registry, we identified all the cases of first-ever stroke that occurred from October 2009 to September 2010. Multiple overlapping sources of information were used to ensure the completeness of case identification. Patients were followed up prospectively at regular intervals from 30-days to 3 years after the index event. Kaplan-Meir and Cox proportional hazards were used to assess the cumulative risk of death and recurrence. RESULTS: We registered 407 first-ever stroke patients. After 3 years, 136 (33%) had died. In the first year of stroke the risk of death was 28% (95% CI, 25 to 32). Beyond the first year, approximately 3 to 5% of survivors died each year. The cumulative risk of death in ischemic stroke (IS) subtypes was 3.6 higher for cardioembolic (CE) IS (hazard ratio 3.6, 95% CI, 2.1 to 6.4; p = 0.001) and 3.3 times higher for undetermined IS (HR 3.3, 95% CI 1.9 to 5.8; p = 0.001) compared to small artery occlusion IS. Over 3 years, the overall stroke recurrence risk was 9% (35/407). We found no difference in stroke recurrence risk between IS subtypes. Cardiovascular disease was the main cause of death all follow up time. CONCLUSIONS: Compared to other cohort studies conducted between 10 and 20 years ago in high-income countries, our recurrence rates and 3-year risk of death were similar. Among IS subtypes, we confirmed that CE has highest risk of death. The most common cause of death after a first-ever stroke is cardiovascular disease. This has implications for the uptake of current secondary preventive strategies and the development of new strategies. PMID- 25927468 TI - Accuracies of genomically estimated breeding values from pure-breed and across breed predictions in Australian beef cattle. AB - BACKGROUND: The major obstacles for the implementation of genomic selection in Australian beef cattle are the variety of breeds and in general, small numbers of genotyped and phenotyped individuals per breed. The Australian Beef Cooperative Research Center (Beef CRC) investigated these issues by deriving genomic prediction equations (PE) from a training set of animals that covers a range of breeds and crosses including Angus, Murray Grey, Shorthorn, Hereford, Brahman, Belmont Red, Santa Gertrudis and Tropical Composite. This paper presents accuracies of genomically estimated breeding values (GEBV) that were calculated from these PE in the commercial pure-breed beef cattle seed stock sector. METHODS: PE derived by the Beef CRC from multi-breed and pure-breed training populations were applied to genotyped Angus, Limousin and Brahman sires and young animals, but with no pure-breed Limousin in the training population. The accuracy of the resulting GEBV was assessed by their genetic correlation to their phenotypic target trait in a bi-variate REML approach that models GEBV as trait observations. RESULTS: Accuracies of most GEBV for Angus and Brahman were between 0.1 and 0.4, with accuracies for abattoir carcass traits generally greater than for live animal body composition traits and reproduction traits. Estimated accuracies greater than 0.5 were only observed for Brahman abattoir carcass traits and for Angus carcass rib fat. Averaged across traits within breeds, accuracies of GEBV were highest when PE from the pooled across-breed training population were used. However, for the Angus and Brahman breeds the difference in accuracy from using pure-breed PE was small. For the Limousin breed no reasonable results could be achieved for any trait. CONCLUSION: Although accuracies were generally low compared to published accuracies estimated within breeds, they are in line with those derived in other multi-breed populations. Thus PE developed by the Beef CRC can contribute to the implementation of genomic selection in Australian beef cattle breeding. PMID- 25927469 TI - Protective effect of theaflavin-enriched black tea extracts against dimethylnitrosamine-induced liver fibrosis in rats. AB - Liver cirrhosis is responsible for hepatic fibrosis resulting in high mortality and is also a risk factor for developing hepatocellular carcinoma (HCC), which is the fifth most common cancer in men and the seventh in women globally. Several studies have found effective anti-cancer activities of theaflavins, the major black tea polyphenols. The objective of this study was to investigate the protective effects of theaflavin-enriched black tea extracts (TF-BTE) on hepatic fibrosis induced by dimethylnitrosamine (DMN) administration in Sprague-Dawley (SD) rats. Treatment of SD rats with DMN (10 mg per kg bw) for 4 weeks produced inflammation and remarkable liver fibrosis assessed by serum biochemistry and histopathological examination. Fibrotic status and the activation of hepatic stellate cells were improved by oral administration of 40% theaflavins in black tea extracts (40% TF-BTE) as evidenced by histopathological examination. Oral administration of 40% TF-BTE at a low dose of 50 mg per kg bw per day and a high dose of 100 mg per kg bw per day attenuated the DMN-induced elevation of serum GOT (glutamate oxaloacetate transaminase) and GPT (glutamic pyruvic transaminase) levels and reduced necrosis, bile duct proliferation, and inflammation. Western blot analyses revealed that TF-BTE inhibited the expression of liver alpha-smooth muscle actin (alpha-SMA) and transforming growth factor-beta1 (TGF-beta1) protein. The histochemical examination showed the inhibitory effect of TF-BTE on the p-Smad3 expression. Overall, these data demonstrated that TF-BTE exhibited hepatoprotective effects on experimental fibrosis, potentially by inhibiting the TGF-beta1/Smad signaling. PMID- 25927475 TI - Zone-Folded Phonons and the Commensurate-Incommensurate Charge-Density-Wave Transition in 1T-TaSe2 Thin Films. AB - Bulk 1T-TaSe2 exhibits unusually high charge density wave (CDW) transition temperatures of 600 and 473 K below which the material exists in the incommensurate (I-CDW) and the commensurate (C-CDW) charge-density-wave phases, respectively. The (13)(1/2) * (13)(1/2) C-CDW reconstruction of the lattice coincides with new Raman peaks resulting from zone-folding of phonon modes from middle regions of the original Brillouin zone back to Gamma. The C-CDW transition temperatures as a function of film thickness are determined from the evolution of these new Raman peaks, and they are found to decrease from 473 to 413 K as the film thicknesses decrease from 150 to 35 nm. A comparison of the Raman data with ab initio calculations of both the normal and C-CDW phases gives a consistent picture of the zone-folding of the phonon modes following lattice reconstruction. The Raman peak at ~154 cm(-1) originates from the zone-folded phonons in the C CDW phase. In the I-CDW phase, the loss of translational symmetry coincides with a strong suppression and broadening of the Raman peaks. The observed change in the C-CDW transition temperature is consistent with total energy calculations of bulk and monolayer 1T-TaSe2. PMID- 25927476 TI - Mechanism of the defect formation in supported graphene by energetic heavy ion irradiation: the substrate effect. AB - Although ion beam technology has frequently been used for introducing defects in graphene, the associated key mechanism of the defect formation under ion irradiation is still largely unclear. We report a systematic study of the ion irradiation experiments on SiO2-supported graphene, and quantitatively compare the experimental results with molecular dynamic simulations. We find that the substrate is, in fact, of great importance in the defect formation process, as the defects in graphene are mostly generated through an indirect process by the sputtered atoms from the substrate. PMID- 25927477 TI - Do people with disabilities have difficulty finding a family physician? AB - Primary care has been ideally characterized as the medical home for all citizens, and yet recent data shows that approximately 6% do not have a family physician, and only 17.5% of family practices are open to new patients. Given acknowledged shortages of family physicians, this research asks the question: Do people with disabilities have particular difficulty finding a family physician? Health Care Connect (HCC) is a government-funded agency in Ontario Canada, designed to "help Ontarians who are without a family health care provider to find one". Using data from HCC, supplemented by interviews with HCC staff, the study explores the average wait time for patients with disabilities to be linked with a primary care physician, and the challenges faced by agency staff in doing so. The study found that disabled registrants with the program are only slightly disadvantaged in terms of wait times to find a family physician, and success rates are ultimately comparable; however, agency staff report that there are a number of significant challenges associated with placing disabled patients. PMID- 25927479 TI - Update in gastroenterology and hepatology: evidence published in 2014. PMID- 25927478 TI - A Method for the Preparation of Chicken Liver Pate that Reliably Destroys Campylobacters. AB - This study devised a protocol for the manufacture of commercial quantities of chicken liver pate that reliably destroyed campylobacters. A literature search identified 40 pate manufacture recipes. Recipes stages with a potential to be antimicrobial were assembled to form a new protocol that included washing with organic acid, freeze-thaw and flambe in alcohol. Naturally-contaminated, high risk livers were obtained from clearance flocks at slaughter and the effect of each stage of the protocol on Campylobacter populations was determined. Organic acid washing changed the color of the liver surfaces. However, there were no significant differences between liver surface color changes when a range of concentrations of lactic acid and ethanoic acid washes were compared by reflective spectrophotometry. A 5% (w/v) acid wash reduced numbers of indigenous campylobacters by around 1.5 log10 CFU/g for both acids. The use of a Bain Marie was found to more reproducibly apply heat compared with pan-frying. Antimicrobial recipe stages reduced the numbers of campylobacters, but not significantly if thermal processing was ineffective. Cooking to 63 degrees C was confirmed to be a critical control point for campylobacters cooked in a Bain Marie. Organoleptic and sensory assessment of pate determined an overall preference for pate made from frozen livers. PMID- 25927480 TI - Voltage-Gated Sodium Channels: Structure, Function, Pharmacology, and Clinical Indications. AB - The tremendous therapeutic potential of voltage-gated sodium channels (Na(v)s) has been the subject of many studies in the past and is of intense interest today. Na(v)1.7 channels in particular have received much attention recently because of strong genetic validation of their involvement in nociception. Here we summarize the current status of research in the Na(v) field and present the most relevant recent developments with respect to the molecular structure, general physiology, and pharmacology of distinct Na(v) channel subtypes. We discuss Na(v) channel ligands such as small molecules, toxins isolated from animal venoms, and the recently identified Na(v)1.7-selective antibody. Furthermore, we review eight characterized ligand binding sites on the Na(v) channel alpha subunit. Finally, we examine possible therapeutic applications of Na(v) ligands and provide an update on current clinical studies. PMID- 25927482 TI - Fast Comparative Structural Characterization of Intact Therapeutic Antibodies Using Hydrogen-Deuterium Exchange and Electron Transfer Dissociation. AB - Higher-order structural characterization plays an important role in many stages of therapeutic antibody production. Herein, we report a new top-down mass spectrometry approach for characterizing the higher-order structure of intact antibodies, by combining hydrogen/deuterium exchange (HDX), subzero temperature chromatography, and electron transfer dissociation on the Orbitrap mass spectrometer. Individual IgG domain-level deuteration information was obtained for 6 IgG domains on Herceptin (HER), which included the antigen binding sites. This is the first time that top-down HDX has been applied to an intact protein as large as 150 kDa, which has never been done before on any instrument. Ligand binding induced structural differences in HER were determined to be located only on the variable region of the light chain. Global glycosylation profile of antibodies and HDX property of the glycoforms were also determined by accurate intact mass measurements. Although the presence of disulfide bonds prevent the current approach from being able to obtain amino acid level structural information within the disulfide-linked regions, the advantages such as minimal sample manipulation, fast workflow, very low level of back exchange, and simple data analysis, make it well-suited for fast comparative structural evaluation of intact antibodies. PMID- 25927484 TI - Comparison of 2-Arylnaphtho[2,3-b]phospholes and 2-Arylbenzo[b]phospholes: Effects of 2-Aryl Groups and Fused Arene Moieties on Their Optical and Photophysical Properties. AB - Suzuki-Miyaura cross-coupling reactions were used in the divergent synthesis of a series of 2-arylnaphtho[2,3-b]phosphole P-oxides and their benzo[b]phosphole counterparts. We elucidated the electronic and steric effects of the 2-aryl groups and fused arene moieties on the optical and photophysical properties of these two types of phosphole-based pi-systems. PMID- 25927483 TI - Inhalation characteristics of asthma patients, COPD patients and healthy volunteers with the Spiromax(r) and Turbuhaler(r) devices: a randomised, cross over study. AB - BACKGROUND: Spiromax(r) is a novel dry-powder inhaler containing formulations of budesonide plus formoterol (BF). The device is intended to provide dose equivalence with enhanced user-friendliness compared to BF Turbuhaler(r) in asthma and chronic obstructive pulmonary disease (COPD). The present study was performed to compare inhalation parameters with empty versions of the two devices, and to investigate the effects of enhanced training designed to encourage faster inhalation. METHODS: This randomised, open-label, cross-over study included children with asthma (n = 23), adolescents with asthma (n = 27), adults with asthma (n = 50), adults with COPD (n = 50) and healthy adult volunteers (n = 50). Inhalation manoeuvres were recorded with each device after training with the patient information leaflet (PIL) and after enhanced training using an In-Check Dial device. RESULTS: After PIL training, peak inspiratory flow (PIF), maximum change in pressure (?P) and the inhalation volume (IV) were significantly higher with Spiromax than with the Turbuhaler device (p values were at least <0.05 in all patient groups). After enhanced training, numerically or significantly higher values for PIF, ?P, IV and acceleration remained with Spiromax versus Turbuhaler, except for ?P in COPD patients. After PIL training, one adult asthma patient and one COPD patient inhaled <30 L/min through the Spiromax compared to one adult asthma patient and five COPD patients with the Turbuhaler. All patients achieved PIF values of at least 30 L/min after enhanced training. CONCLUSIONS: The two inhalers have similar resistance so inhalation flows and pressure changes would be expected to be similar. The higher flow related values noted for Spiromax versus Turbuhaler after PIL training suggest that Spiromax might have human factor advantages in real-world use. After enhanced training, the flow-related differences between devices persisted; increased flow rates were achieved with both devices, and all patients achieved the minimal flow required for adequate drug delivery. Enhanced training could be useful, especially in COPD patients. PMID- 25927485 TI - Nonthermal fluctuations of the mitotic spindle. AB - We present direct measurements of fluctuations in the nucleus of yeast cells. While prior work has shown these fluctuations to be active and non-thermal in character, their origin and time dependence are not understood. We show that the nuclear fluctuations we observe are quantitatively consistent with uncorrelated, active force fluctuations driving a nuclear medium that is dominated by an uncondensed DNA solution, for which we perform rheological measurements on an in vitro model system under similar conditions to what is expected in the nucleus. PMID- 25927487 TI - Time impact on non-activated and kaolin-activated blood samples in thromboelastography. AB - BACKGROUND: The correct methodology of thrombelastography might be influenced by elapsing time. In our study we investigated kaolin activated citrated samples together with non-activated citrated samples in relation to the elapsed times of 0, 15 and 30 minutes to compare both methods and to find out if there is an impact of time on results of thrombelastography. METHODS: Blood samples obtained from 10 healthy volunteers were analyzed after 0, 15 and 30 minutes from sampling with kaolin activation and without activation. Then the results were analysed and compared between the non-activated and the kaolin-activated method. RESULTS: All blood samples became more hypercoagulable with the time elapsing, both in non activated and kaolin-activated samples and differences between both groups were found statistically and clinically significant after only 0 minutes. CONCLUSIONS: The non-activated citrated method seems to be reliable and suitable for thrombelastography in non-emergency cases (planned surgical procedures) when we have time to wait 15-30 minutes to get results. In urgent situations a rapid thrombelastography test should be preferred. Although the kaolin-activated method can also be used, results must be interpreted with caution. PMID- 25927488 TI - Magnetic field aligned assembly of nonmagnetic composite dumbbells in nanoparticle-based aqueous ferrofluid. AB - Monodisperse, nonmagnetic, asymmetrical composite dumbbells in a suspension of magnetic nanoparticles (ferrofluid) were aligned by application of an external magnetic field to the ferrofluid. The asymmetrical composite dumbbells were prepared by two-step soap-free emulsion polymerization consisting of the first polymerization to coat spherical silica cores with cross-linked poly(methyl methacrylate) (PMMA) shell and the second polymerization to protrude a polystyrene (PSt) lobe from the core-shell particles. A chain structure of nonmagnetic dumbbells oriented to the applied magnetic field was observed at nanoparticle content of 2.0 vol % and field strengths higher than 1.0 mT. A similar chain structure of the dumbbells was observed under application of alternating electric field at strengths higher than 50 V/mm. Parallel and orthogonally combined applications of the electric and magnetic fields were also conducted to examine independence of the electric and magnetic applications as operational factors in the dumbbell assembling. Dumbbell chains stiffer than those in a single application of external field were formed in the parallel combined application of electric and magnetic fields. The orthogonal combination of the different applied fields could form a magnetically aligned chain structure of the nonmagnetic dumbbells oriented to the electric field. The present work experimentally indicated that the employment of inverse magnetorheological effect for nonmagnetic, anisotropic particles can be a useful method for the simultaneous controls over the orientation and the positon of anisotropic particles in their assembling. PMID- 25927489 TI - Transport spectroscopy of low disorder silicon tunnel barriers with and without Sb implants. AB - We present transport measurements of silicon MOS split gate structures with and without Sb implants. We observe classical point contact (PC) behavior that is free of any pronounced unintentional resonances at liquid He temperatures. The implanted device has resonances superposed on the PC transport indicative of transport through the Sb donors. We fit the differential conductance to a rectangular tunnel barrier model with a linear barrier height dependence on source-drain voltage and non-linear dependence on gate bias. Effects such as Fowler-Nordheim (FN) tunneling and image charge barrier lowering (ICBL) are considered. Barrier heights and widths are estimated for the entire range of relevant biases. The barrier heights at the locations of some of the resonances for the implanted tunnel barrier are between 15-20 meV, which are consistent with transport through shallow partially hybridized Sb donors. The dependence of width and barrier height on gate voltage is found to be linear over a wide range of gate bias in the split gate geometry but deviates considerably when the barrier becomes large and is not described completely by standard 1D models such as FN or ICBL effects. PMID- 25927491 TI - OverAKT3: tumor progression and chemoresistance. PMID- 25927490 TI - Visualization of risk of radiogenic second cancer in the organs and tissues of the human body. AB - BACKGROUND: Radiogenic second cancer is a common late effect in long term cancer survivors. Currently there are few methods or tools available to visually evaluate the spatial distribution of risks of radiogenic late effects in the human body. We developed a risk visualization method and demonstrated it for radiogenic second cancers in tissues and organs of one patient treated with photon volumetric modulated arc therapy and one patient treated with proton craniospinal irradiation. METHODS: Treatment plans were generated using radiotherapy treatment planning systems (TPS) and dose information was obtained from TPS. Linear non-threshold risk coefficients for organs at risk of second cancer incidence were taken from the Biological Effects of Ionization Radiation VII report. Alternative risk models including linear exponential model and linear plateau model were also examined. The predicted absolute lifetime risk distributions were visualized together with images of the patient anatomy. RESULTS: The risk distributions of second cancer for the two patients were visually presented. The risk distributions varied with tissue, dose, dose-risk model used, and the risk distribution could be similar to or very different from the dose distribution. CONCLUSIONS: Our method provides a convenient way to directly visualize and evaluate the risks of radiogenic second cancer in organs and tissues of the human body. In the future, visual assessment of risk distribution could be an influential determinant for treatment plan scoring. PMID- 25927492 TI - Improving outcomes in peripartum cardiomyopathy. AB - Peripartum cardiomyopathy (PPCM) is a rare condition with a diverse spectrum of potential outcomes, ranging from frequent complete recovery to fulminant heart failure and death. The pathogenesis of PPCM is not well understood, and relatively little is known about its incidence and prevalence. PPCM is often under-recognised in the clinical setting. Early investigation and diagnosis with subsequent expert management may improve outcomes. The development of registries will allow this condition to be better characterised and may help answer crucial questions regarding its optimal medical and surgical management. This paper reviews the potential approaches to improve outcomes in patients with PPCM. PMID- 25927494 TI - Erratum: Enhanced surveillance of invasive listeriosis in the Lombardy region, Italy, in the years 2006-2010 reveals major clones and an increase in serotype 1/2a. PMID- 25927495 TI - Internet-based cognitive behavioral therapy for sexual dysfunctions in women treated for breast cancer: design of a multicenter, randomized controlled trial. AB - BACKGROUND: Sexual dysfunction is a prevalent, long-term complication of breast cancer and its treatment and can be treated effectively with face-to-face sexual counselling. However, relatively few women actually opt for face-to-face sex therapy, with many women indicating that it is too confronting. Internet-based interventions might be a less threatening and more acceptable approach, because of the convenience, accessibility and privacy it provides. Recent studies have demonstrated the efficacy of internet-based programs for improving sexual functioning in the general population. The objective of the current study is to investigate the efficacy of an internet-based cognitive behavioral therapy (CBT) program in alleviating problems with sexuality and intimacy in women who have been treated for breast cancer. METHODS/DESIGN: In a multicenter, randomized controlled trial we are evaluating the efficacy of an internet-based CBT program in reducing problems with sexuality and intimacy in breast cancer survivors. Secondary outcomes include body image, marital functioning, psychological distress, menopausal symptoms, and health-related quality of life. We will recruit 160 breast cancer survivors (aged 18-65 years) with a formal DSM-IV diagnosis of sexual dysfunction from general and academic hospitals in the Netherlands. Women are randomized to either an intervention or waiting-list control group. Self-report questionnaires are completed by the intervention group at baseline (T0), ten weeks after start of therapy (T1), post-treatment (T2), 3 months post-treatment (T3), and 9 months post-treatment (T4). The control group completes questionnaires at T0, T1 and T2. DISCUSSION: There is a need for accessible and effective interventions for the treatment of sexual dysfunctions in breast cancer survivors. This study will provide evidence about the efficacy of an internet-based approach to delivering a CBT intervention targeted specifically at these sexual health issues. If proven to be effective, internet based CBT for problems with sexuality and intimacy will be a welcome addition to the care offered to breast cancer survivors. Hopefully this therapy will lower the barrier to seeking help for these problems, resulting in improved quality of life after breast cancer. TRIAL REGISTRATION: The study is registered at ClinicalTrials.gov (NCT02091765). PMID- 25927498 TI - Accreditation as a path to achieving universal quality health coverage. AB - As many low- and middle-income countries (LMICs) pursue health care reforms in order to achieve universal health coverage (UHC), development of national accreditation systems has become an increasingly common quality-enhancing strategy endorsed by payers, including Ministries of Health. This article describes the major considerations for health system leaders in developing and implementing a sustainable and successful national accreditation program, using the 20-year evolution of the Thai health care accreditation system as a model. The authors illustrate the interface between accreditation as a continuous quality improvement strategy, health insurance and other health financing schemes, and the overall goal of achieving universal health coverage. PMID- 25927499 TI - Cross-cultural Adaptation and Validation of the Exercise-Induced Leg Pain Questionnaire for English- and Greek-Speaking Individuals. AB - STUDY DESIGN: Clinical measurement. OBJECTIVES: To translate the German version of the Exercise-Induced Leg Pain Questionnaire (EILP-G) to Greek and English and evaluate the psychometric properties of the Greek version. BACKGROUND: The EILP-G was developed to evaluate the severity of symptoms and sports ability in individuals with exercise-induced leg pain (EILP). Translation of the questionnaire to other languages will provide a standard outcome measure across populations. METHODS: The EILP-G questionnaire was cross-culturally adapted to Greek and English, according to established guidelines. The validity and reliability of the Greek version were assessed in 40 patients with EILP, 40 patients with other lower extremity injuries, 40 track-and-field athletes with no history of EILP, and 40 young adults without pathology. Participants completed the questionnaire at baseline and again after 7 to 10 days. RESULTS: The expert committee and the participants considered the questionnaire to have good face and content validity. Concurrent validity as assessed using the Schepsis score was almost perfect (rho = 0.947, P<.001). Dimensionality analysis revealed a 1-factor solution, explaining 83.8% of the total variance. Known group validity was demonstrated by significant differences between patients compared with the asymptomatic groups (P<.001). The Greek version exhibited excellent test-retest reliability (intraclass correlation coefficient = 0.995 for the EILP group) and internal consistency (Cronbach alpha = .942 for the EILP group). Finally, no ceiling or floor effects were found, as none of the individuals with EILP scored the maximum or minimum possible values on the questionnaire. CONCLUSION: The Greek version, adapted from the original EILP-G, is a valid and reliable questionnaire, and its psychometric properties are comparable with the original version. PMID- 25927497 TI - Anti-citrullinated peptide/protein antibody (ACPA)-negative RA shares a large proportion of susceptibility loci with ACPA-positive RA: a meta-analysis of genome-wide association study in a Japanese population. AB - INTRODUCTION: Although susceptibility genes for anti-citrullinated peptide/protein antibodies (ACPA)-positive rheumatoid arthritis (RA) have been successfully discovered by genome-wide association studies (GWAS), little is known about the genetic background of ACPA-negative RA. We intended to elucidate genetic background of ACPA-negative RA. METHOD: We performed a meta-analysis of GWAS comprising 670 ACPA-negative RA and 16,891 controls for 1,948,138 markers, followed by a replication study of the top 35 single nucleotide polymorphisms (SNPs) using 916 cases and 3,764 controls. Inverse-variance method was applied to assess overall effects. To assess overlap of susceptibility loci between ACPA positive and -negative RA, odds ratios (ORs) of the 21 susceptibility markers to RA in Japanese were compared between the two subsets. In addition, SNPs were stratified by the p-values in GWAS meta-analysis for either ACPA-positive RA or ACPA-negative RA to address the question whether weakly-associated genes were also shared. The correlations between ACPA-positive RA and the subpopulations of ACPA-negative RA (rheumatoid factor (RF)-positive and RF-negative subsets) were also addressed. RESULTS: Rs6904716 in LEMD2 of the human leukocyte antigen (HLA) locus showed a borderline association with ACPA-negative RA (overall p = 5.7 * 10(-8)), followed by rs6986423 in CSMD1 (p = 2.4 * 10(-6)) and rs17727339 in FCRL3 (p = 1.4 * 10(-5)). ACPA-negative RA showed significant correlations of ORs with ACPA-positive RA for the 21 susceptibility SNPs and non-HLA SNPs with p values far from significance. These significant correlations with ACPA-positive RA were true for ACPA-negative RF-positive and ACPA-negative RF-negative RA. On the contrary, positive correlations were not observed between the ACPA-negative two subpopulations. CONCLUSION: Many of the susceptibility loci were shared between ACPA-positive and -negative RA. PMID- 25927500 TI - Orthopaedic manual physical therapy for shoulder pain and impaired movement in a patient with glenohumeral joint osteoarthritis: a case report. AB - STUDY DESIGN: Case report. BACKGROUND: Comprehensive treatment strategies are needed for individuals with glenohumeral joint osteoarthritis (OA), especially when they are young and active. Prior dislocation, with or without subsequent shoulder stabilization surgery, complicates the clinical presentation and increases the risk of OA progression. The purpose of this case report was to describe an orthopaedic manual physical therapy approach used in a patient with glenohumeral joint OA who presented with shoulder pain and impaired movement. CASE DESCRIPTION A 38-year-old male military officer presented with left-shoulder pain of 2 months in duration that was unrelieved with a subacromial injection. He reported a history of anterior-inferior dislocation with subsequent stabilization surgery 15 years prior and arthroscopic subacromial decompression 2 years prior. Physical examination demonstrated painful limitations in shoulder elevation and internal/external rotation movements, stiffness with testing using accessory glides, and rotator cuff and scapular musculature weakness associated with pain. OUTCOMES: Treatment consisted of 5 sessions provided over 4 weeks. The plan of care included manual physical therapy, exercises, and progressive functional activities specifically tailored to the patient's clinical presentation. Shoulder Pain and Disability Index scores decreased from 43% to 17%, and the Patient Specific Functional Scale average score improved from 3.0 to 7.3 out of 10. After 4 additional weeks of a home exercise program, the Shoulder Pain and Disability Index score was 4% and Patient-Specific Functional Scale average score was 9.0. Improvements in self-reported function were maintained at 6 months. Four "booster" treatment sessions were administered at 9 months, contributing to sustained outcomes through 1 year. DISCUSSION: In a young, active patient with glenohumeral joint OA, clinically meaningful short-term improvements in self reported function and pain, maintained at 1 year, were observed with manual physical therapy and exercise. LEVEL OF EVIDENCE: Therapy, level 4. PMID- 25927503 TI - Quantitative analysis of receptor allosterism and its implication for drug discovery. AB - INTRODUCTION: G protein-coupled receptors represent the largest class of druggable targets and are known to be modulated by both orthosteric agonists and positive/negative allosteric modulators (PAMs/NAMs). Proper experimental design and data analysis for the dose matrix between an agonist and PAM or NAM are critical to elucidate the key parameters for understanding molecular mechanism and structure-activity relationship (SAR) in drug discovery. AREAS COVERED: The authors provide an overview and best practice recommendations on the quantitative analysis of receptor allosterism. The authors propose a simple classification system for receptor modulators on the basis of their efficacy and affinity modifiers. The authors also outline the optimal assay designs for both fixed dose screening and dose matrix study of receptor modulators. EXPERT OPINION: The authors recommend the global curve fitting approach to reliably yield system- and modulator-specific parameters for SAR ranking. Furthermore, the authors suggest that the uncertainty in maximal system response has insignificant impact on SAR ranking. The authors anticipate that systems pharmacology models integrating both binding kinetics and functional allosterism will be needed to address the inherent limitations of current allosterism models. PMID- 25927504 TI - Effects of strength training on body composition, physical functioning, and quality of life in prostate cancer patients during androgen deprivation therapy. AB - BACKGROUND: Androgen deprivation therapy (ADT) increases survival rates in prostate cancer (PCa) patients with locally advanced disease, but is associated with side effects that may impair daily function. Strength training may counteract several side effects of ADT, such as changes in body composition and physical functioning, which in turn may affect health-related quality of life (HRQOL). However, additional randomised controlled trials are needed to expand this knowledge. MATERIAL AND METHODS: Fifty-eight PCa patients on ADT were randomised to either 16 weeks of high-load strength training (n = 28) or usual care (n = 30). The primary outcome was change in total lean body mass (LBM) assessed by dual x-ray absorptiometry (DXA). Secondary outcomes were changes in regional LBM, fat mass, and areal bone mineral density (aBMD) measured by DXA; physical functioning assessed by 1-repetition maximum (1RM) tests, sit-to-stand test, stair climbing test and Shuttle walk test; and HRQOL as measured by the European Organization for the Research and Treatment of Cancer Quality of Life Questionnaire Core 30. RESULTS AND CONCLUSION: No statistically significant effect of high-load strength training was demonstrated on total LBM (p = 0.16), but significant effects were found on LBM in the lower and upper extremities (0.49 kg, p < 0.01 and 0.15 kg, p < 0.05, respectively). Compared to usual care, high-load strength training showed no effect on fat mass, aBMD or HRQOL, but beneficial effects were observed in all 1RM tests, sit-to-stand test and stair climbing tests. Adherence to the training program was 88% for lower body exercises and 84% for upper body exercises. In summary, high-load strength training improved LBM in extremities and physical functioning, but had no effect on fat mass, aBMD, or HRQOL in PCa patients on ADT. PMID- 25927507 TI - Smartphone use to answer clinical questions: a descriptive study of APNs. AB - This study examines the use of smartphones by Alabama Advanced Practice Nurses to find information to address clinical questions and seeks to describe the types of questions answered using smartphones; barriers to information seeking; apps and online resources perceived as most helpful; and training/resource needs. Information collected in this study can be used by libraries that serve nursing students to develop training and resources to assist both nursing students and practicing nurses to become more efficient and effective information seekers. PMID- 25927506 TI - Association between body mass index and suicidal behaviors: a systematic review protocol. AB - BACKGROUND: Suicide is among the leading causes of death worldwide. Suicide attempts and suicidal ideation are more common than completed suicide and are associated with psychological distress. These behaviors are considered risk factors of completed suicide. Considering the psychosocial stigma and medical comorbidities associated with obesity, an accumulating body of studies have investigated body mass index (BMI) as a potential risk factor of suicide. However, several cohort studies have demonstrated an inverse relationship between BMI and completed suicide, suggesting a protective effect of increasing BMI against completed suicide. The association between BMI and attempted suicide is more equivocal, with several studies reporting both positive and negative relationships between BMI and attempted suicide. The primary objective of this study is to systematically review the literature to determine the association between BMI and suicidal behavior (including completed suicide, attempted suicide, suicidal ideation) in an adult population (18 years and older). The secondary objective is to explore whether sex, age, and the method used in suicide modify the relationship between BMI and suicidal behavior. METHODS/DESIGN: An electronic search will be conducted using PubMed/MEDLINE, PsycINFO, CINAHL, and EMBASE using a predefined search strategy; databases will be searched from their inception. Two authors (SP and RE) will independently screen articles using predefined inclusion and exclusion criteria and will extract pertinent data using a pilot tested extraction form. At all levels of screening, discrepancies between the two authors will be resolved by consensus, and in the case of disagreement, by consulting a third author (ZS). The primary outcomes include the association between BMI and completed suicide, attempted suicide, and suicidal ideation. If appropriate, a meta-analysis will be conducted. Risk of bias and quality of evidence will be assessed. DISCUSSION: The results of this systematic review will inform health care professionals and researchers about whether BMI has a significant role in suicidal behavior and psychological well-being. SYSTEMATIC REVIEW REGISTRATION: PROSPERO CRD42014014739 . PMID- 25927508 TI - Evaluating nursing collections with the ICIRN's Essential Nursing Resources list. AB - This study examines libraries' nursing collections using the Interagency Council on Information Resources in Nursing's Essential Nursing Resources' (ENR) 26th edition. An inventory of the online collections of 235 libraries was assembled and compared to free, government, or National Library of Medicine resources and licensed resources from the ENR. The top five resources listed on library websites in descending order were MEDLINE, CINAHL, ERIC, PsycINFO, and Google Scholar. The availability of specialized resources varied, based on factors such as the level of nursing degree at each institution or the libraries' National Network of Libraries of Medicine membership statuses. PMID- 25927509 TI - Developing a library systematic review service: a case study. AB - Systematic review searching is a standard job responsibility for many health sciences librarians. The strategies a library uses to market its expertise may affect the number of researchers requesting librarian assistance as well as how researchers perceive librarians as systematic review collaborators. This article describes how one health sciences library developed, launched, and promoted its systematic review service to researchers on campus. PMID- 25927510 TI - Personal branding: building your pathway to professional success. AB - Personal branding is an introspective process by which you define yourself professionally, and it can serve as your pathway to professional success. There are six steps to building your personal brand: (1) taking an introspective look, (2) understanding the brand that may already exist, (3) developing your personal brand mantra, (4) crafting your physical footprint, (5) creating your digital footprint, and (6) communicating your message. Your personal brand is a promise of value and performance, and it is necessary to meet the expectations of your audience. Effective brand management is a key component to maintaining a positive brand reputation. PMID- 25927511 TI - Capturing citation activity in three health sciences departments: a comparison study of Scopus and Web of Science. AB - Scopus and Web of Science are the two major citation databases that collect and disseminate bibliometric statistics about research articles, journals, institutions, and individual authors. Liaison librarians are now regularly called upon to utilize these databases to assist faculty in finding citation activity on their published works for tenure and promotion, grant applications, and more. But questions about the accuracy, scope, and coverage of these tools deserve closer scrutiny. Discrepancies in citation capture led to a systematic study on how Scopus and Web of Science compared in a real-life situation encountered by liaisons: comparing three different disciplines at a medical school and nursing program. How many articles would each database retrieve for each faculty member using the author-searching tools provided? How many cited references for each faculty member would each tool generate? Results demonstrated troubling differences in publication and citation activity capture between Scopus and Web of Science. Implications for librarians are discussed. PMID- 25927512 TI - Clinical librarian support for rapid review of clinical utility of cancer molecular biomarkers. AB - The clinical librarian used a restricted literature searching and quality filtering approach to provide relevant clinical evidence for the use of cancer molecular biomarkers by institutional policy makers and clinicians in the rapid review process. The librarian-provided evidence was compared with the cited references in the institutional molecular biomarker algorithm. The overall incorporation rate of the librarian-provided references into the algorithm was above 80%. This study suggests the usefulness of clinical librarian expertise for clinical practice. The searching and filtering methods for high-level evidence can be adopted by information professionals who are involved in the rapid literature review. PMID- 25927513 TI - ClinicalAccess: a clinical decision support tool. AB - ClinicalAccess is a new clinical decision support tool that uses a question-and answer format to mirror clinical decision-making strategies. The unique format of ClinicalAccess delivers concise, authoritative answers to more than 120,000 clinical questions. This column presents a review of the product, a sample search, and a comparison with other point-of-care search engines. PMID- 25927514 TI - Presenting your best: web-based applications for library instruction. AB - Library instruction in academic, health sciences, and hospital libraries is an evolving concept. Content, the intended learner, and various teaching models influence the creation of library instructional tutorials and presentations. Standard programs such as PowerPoint and Keynote are often used to generate these instructional materials. However, new and dynamic web-based presentation applications have the potential to improve the learning experience for patients and health care professionals. This column will briefly touch on library instruction and standard presentation creators, but will mainly concentrate on six web-based applications that can be used for the creation of library instructional presentations. PMID- 25927515 TI - A solo hospital librarian's experience in clinical informatics. AB - This column reviews some of a solo librarian's experiences that led to involvement with the hospital Clinical Informatics Team. This included work on the electronic health record (EHR), computerized physician order entry (CPOE) system, development of order sets, and participation in the Physician Technology Committee. PMID- 25927516 TI - Library tutorials in an allied health evidence-based practice class. AB - This column describes a collaboration between faculty members in an Allied Health program and academic librarians to provide information literacy instruction to students enrolled in an evidence-based practice course. The process of collaboration is described beginning with the inception of the idea to collaborate, which grew out of an informal conversation between librarians and Allied Health faculty. Implementation of the project is described as well as future plans for the collaboration. The column also discusses initial impressions of student outcomes as well as plans for a more rigorous study of those outcomes. PMID- 25927522 TI - Lessons learnt from the first controlled human malaria infection study conducted in Nairobi, Kenya. AB - BACKGROUND: Controlled human malaria infection (CHMI) studies, in which healthy volunteers are infected with Plasmodium falciparum to assess the efficacy of novel malaria vaccines and drugs, have become a vital tool to accelerate vaccine and drug development. CHMI studies provide a cost-effective and expeditious way to circumvent the use of large-scale field efficacy studies to deselect intervention candidates. However, to date few modern CHMI studies have been performed in malaria-endemic countries. METHODS: An open-label, randomized pilot CHMI study was conducted using aseptic, purified, cryopreserved, infectious P. falciparum sporozoites (SPZ) (Sanaria(r) PfSPZ Challenge) administered intramuscularly (IM) to healthy Kenyan adults (n = 28) with varying degrees of prior exposure to P. falciparum. The purpose of the study was to establish the PfSPZ Challenge CHMI model in a Kenyan setting with the aim of increasing the international capacity for efficacy testing of malaria vaccines and drugs, and allowing earlier assessment of efficacy in a population for which interventions are being developed. This was part of the EDCTP-funded capacity development of the CHMI platform in Africa. DISCUSSION: This paper discusses in detail lessons learnt from conducting the first CHMI study in Kenya. Issues pertinent to the African setting, including community sensitization, consent and recruitment are considered. Detailed reasoning regarding the study design (for example, dose and route of administration of PfSPZ Challenge, criteria for grouping volunteers according to prior exposure to malaria and duration of follow-up post CHMI) are given and changes other centres may want to consider for future studies are suggested. CONCLUSIONS: Performing CHMI studies in an African setting presents unique but surmountable challenges and offers great opportunity for acceleration of malaria vaccine and drug development. The reflections in this paper aim to aid other centres and partners intending to use the CHMI model in Africa. PMID- 25927523 TI - Molecular differences between stromal cell populations from deciduous and permanent human teeth. AB - INTRODUCTION: Deciduous and permanent human teeth represent an excellent model system to study aging of stromal populations. Aging is tightly connected to self renewal and proliferation and thus, mapping potential molecular differences in these characteristics between populations constitutes an important task. METHODS: Using specifically designed microarray panels, Real-Time Quantitative Polymerase Chain Reaction (RT q-PCR), Western blot, immunohistochemistry and siRNA-mediated knock down experiments, we have detected a number of molecules that were differentially expressed in dental pulp from deciduous and permanent teeth extracted from young children and adults, respectively. RESULTS: Among the differentially regulated genes, high-mobility group AT-hook 2 (HMGA2), a stem cell-associated marker, stood out as a remarkable example with a robust expression in deciduous pulp cells. siRNA-mediated knock down of HMGA2 expression in cultured deciduous pulp cells caused a down-regulated expression of the pluripotency marker NANOG. This finding indicates that HMGA2 is a pulpal stem cell regulatory factor. In addition to this, we discovered that several proliferation-related genes, including CDC2A and CDK4, were up-regulated in deciduous pulp cells, while matrix genes COL1A1, fibronectin and several signaling molecules, such as VEGF, FGFr-1 and IGFr-1 were up-regulated in the pulp cells from permanent teeth. CONCLUSIONS: Taken together, our data suggest that deciduous pulp cells are more robust in self- renewal and proliferation, whereas adult dental pulp cells are more capable of signaling and matrix synthesis. PMID- 25927524 TI - Regulation of HbPIP2;3, a Latex-Abundant Water Transporter, Is Associated with Latex Dilution and Yield in the Rubber Tree (Hevea brasiliensis Muell. Arg.). AB - Rubber tree (Hevea brasiliensis) latex, the source of natural rubber, is synthesised in the cytoplasm of laticifers. Efficient water inflow into laticifers is crucial for latex flow and production since it is the determinant of the total solid content of latex and its fluidity after tapping. As the mature laticifer vessel rings are devoid of plasmodesmata, water exchange between laticifers and surrounding cells is believed to be governed by plasma membrane intrinsic proteins (PIPs). To identify the most important PIP aquaporin in the water balance of laticifers, the transcriptional profiles of ten-latex-expressed PIPs were analysed. One of the most abundant transcripts, designated HbPIP2;3, was characterised in this study. When tested in Xenopus laevis oocytes HbPIP2;3 showed a high efficiency in increasing plasmalemma water conductance. Expression analysis indicated that the HbPIP2;3 gene was preferentially expressed in latex, and the transcripts were up-regulated by both wounding and exogenously applied Ethrel (a commonly-used ethylene releaser). Although regular tapping up-regulated the expression of HbPIP2;3 during the first few tappings of the virginal rubber trees, the transcriptional kinetics of HbPIP2;3 to Ethrel stimulation in the regularly tapped tree exhibited a similar pattern to that of the previously reported HbPIP2;1 in the virginal rubber trees. Furthermore, the mRNA level of HbPIP2;3 was associated with clonal yield potential and the Ethrel stimulation response. Together, these results have revealed the central regulatory role of HbPIP2;3 in laticifer water balance and ethylene stimulation of latex production in Hevea. PMID- 25927525 TI - Frequency dependent topological patterns of resting-state brain networks. AB - The topological organization underlying brain networks has been extensively investigated using resting-state fMRI, focusing on the low frequency band from 0.01 to 0.1 Hz. However, the frequency specificities regarding the corresponding brain networks remain largely unclear. In the current study, a data-driven method named complementary ensemble empirical mode decomposition (CEEMD) was introduced to separate the time series of each voxel into several intrinsic oscillation rhythms with distinct frequency bands. Our data indicated that the whole brain BOLD signals could be automatically divided into five specific frequency bands. After applying the CEEMD method, the topological patterns of these five temporally correlated networks were analyzed. The results showed that global topological properties, including the network weighted degree, network efficiency, mean characteristic path length and clustering coefficient, were observed to be most prominent in the ultra-low frequency bands from 0 to 0.015 Hz. Moreover, the saliency of small-world architecture demonstrated frequency density dependency. Compared to the empirical mode decomposition method (EMD), CEEMD could effectively eliminate the mode-mixing effects. Additionally, the robustness of CEEMD was validated by the similar results derived from a split half analysis and a conventional frequency division method using the rectangular window band-pass filter. Our findings suggest that CEEMD is a more effective method for extracting the intrinsic oscillation rhythms embedded in the BOLD signals than EMD. The application of CEEMD in fMRI data analysis will provide in depth insight in investigations of frequency specific topological patterns of the dynamic brain networks. PMID- 25927526 TI - A Controlled Study of Tuberculosis Diagnosis in HIV-Infected and Uninfected Children in Peru. AB - BACKGROUND: Diagnosing tuberculosis in children is challenging because specimens are difficult to obtain and contain low tuberculosis concentrations, especially with HIV-coinfection. Few studies included well-controls so test specificities are poorly defined. We studied tuberculosis diagnosis in 525 children with and without HIV-infection. METHODS AND FINDINGS: 'Cases' were children with suspected pulmonary tuberculosis (n = 209 HIV-negative; n = 81 HIV-positive) and asymptomatic 'well-control' children (n = 200 HIV-negative; n = 35 HIV-positive). Specimens (n = 2422) were gastric aspirates, nasopharyngeal aspirates and stools analyzed by a total of 9688 tests. All specimens were tested with an in-house hemi-nested IS6110 PCR that took <24 hours. False-positive PCR in well-controls were more frequent in HIV-infection (P<=0.01): 17% (6/35) HIV-positive well controls versus 5.5% (11/200) HIV-negative well-controls; caused by 6.7% (7/104) versus 1.8% (11/599) of their specimens, respectively. 6.7% (116/1719) specimens from 25% (72/290) cases were PCR-positive, similar (P>0.2) for HIV-positive versus HIV-negative cases. All specimens were also tested with auramine acid-fast microscopy, microscopic-observation drug-susceptibility (MODS) liquid culture, and Lowenstein-Jensen solid culture that took <=6 weeks and had 100% specificity (all 2112 tests on 704 specimens from 235 well-controls were negative). Microscopy-positivity was rare (0.21%, 5/2422 specimens) and all microscopy positive specimens were culture-positive. Culture-positivity was less frequent (P<=0.01) in HIV-infection: 1.2% (1/81) HIV-positive cases versus 11% (22/209) HIV-negative cases; caused by 0.42% (2/481) versus 4.7% (58/1235) of their specimens, respectively. CONCLUSIONS: In HIV-positive children with suspected tuberculosis, diagnostic yield was so low that 1458 microscopy and culture tests were done per case confirmed and even in children with culture-proven tuberculosis most tests and specimens were false-negative; whereas PCR was so prone to false-positives that PCR-positivity was as likely in specimens from well controls as suspected-tuberculosis cases. This demonstrates the importance of control participants in diagnostic test evaluation and that even extensive laboratory testing only rarely contributed to the care of children with suspected TB. TRIAL REGISTRATION: This study did not meet Peruvian and some other international criteria for a clinical trial but was registered with the ClinicalTrials.gov registry: ClinicalTrials.gov NCT00054769. PMID- 25927527 TI - Prognostic significance of tumor volume in locally recurrent nasopharyngeal carcinoma treated with salvage intensity-modulated radiotherapy. AB - INTRODUCTION: To evaluate the prognostic value of gross tumor volume (TV) in patients with locally recurrent, nonmetastatic nasopharyngeal carcinoma. METHODS: Between 2001 and 2012, 291 consecutive patients with locally recurrent, nonmetastatic nasopharyngeal carcinoma underwent salvage IMRT were retrospectively reviewed. The correlations between TV and recurrent T classification were analyzed. Survival analyses were performed. Receiver operating characteristic (ROC) curves were calculated to identify cut-off point of TV. The Akaike information criterion and Harrell's concordance index (c-index) were utilized to test the prognostic value. RESULTS: The median TV significantly increased with advancing recurrent T classification (P<0.001). The 5-year overall survival rate was 33.2% for the entire cohort. On multivariate analysis, TV was an independent negative prognostic factor for distant metastasis-free survival (hazard ratio =1.013, P =0.003), overall survival (hazard ratio = 1.015, P<0.001) and toxicity-related death (hazard ratio = 1.014, P<0.001). The 5-year overall survival rates were 63.1% and 20.8% for patients with a TV < 22 cm3 and TV >=22 cm3, respectively (P < 0.001). In patient with TV <22 cm3, locoregional failure is the leading cause of death. In patients with TV>=22 cm3, distant metastasis rate is higher and occurred within short term after local recurrence; meanwhile, radiation-induced injuries became more common and led to half of deaths in this group. The Akaike information criterion and c-index analyses indicated that the predictive ability of recurrent T classification improved when combined with TV. CONCLUSIONS: Our data suggests TV is a significant prognostic factor for predicting the distant metastasis, overall survival and toxicity-related death of patients with locally recurrent, nonmetastatic nasopharyngeal carcinoma after salvage IMRT. TV should be considered when designing personalized salvage treatments for these patients. For patients with bulky local recurrent tumor, radiation may need to be de-emphasized in favor of systemic treatment or best supportive care. PMID- 25927528 TI - Genomic and clinical effects associated with a relaxation response mind-body intervention in patients with irritable bowel syndrome and inflammatory bowel disease. AB - INTRODUCTION: Irritable Bowel Syndrome (IBS) and Inflammatory Bowel Disease (IBD) can profoundly affect quality of life and are influenced by stress and resiliency. The impact of mind-body interventions (MBIs) on IBS and IBD patients has not previously been examined. METHODS: Nineteen IBS and 29 IBD patients were enrolled in a 9-week relaxation response based mind-body group intervention (RR MBI), focusing on elicitation of the RR and cognitive skill building. Symptom questionnaires and inflammatory markers were assessed pre- and post-intervention, and at short-term follow-up. Peripheral blood transcriptome analysis was performed to identify genomic correlates of the RR-MBI. RESULTS: Pain Catastrophizing Scale scores improved significantly post-intervention for IBD and at short-term follow-up for IBS and IBD. Trait Anxiety scores, IBS Quality of Life, IBS Symptom Severity Index, and IBD Questionnaire scores improved significantly post-intervention and at short-term follow-up for IBS and IBD, respectively. RR-MBI altered expression of more genes in IBD (1059 genes) than in IBS (119 genes). In IBD, reduced expression of RR-MBI response genes was most significantly linked to inflammatory response, cell growth, proliferation, and oxidative stress-related pathways. In IBS, cell cycle regulation and DNA damage related gene sets were significantly upregulated after RR-MBI. Interactive network analysis of RR-affected pathways identified TNF, AKT and NF-kappaB as top focus molecules in IBS, while in IBD kinases (e.g. MAPK, P38 MAPK), inflammation (e.g. VEGF-C, NF-kappaB) and cell cycle and proliferation (e.g. UBC, APP) related genes emerged as top focus molecules. CONCLUSIONS: In this uncontrolled pilot study, participation in an RR-MBI was associated with improvements in disease specific measures, trait anxiety, and pain catastrophizing in IBS and IBD patients. Moreover, observed gene expression changes suggest that NF-kappaB is a target focus molecule in both IBS and IBD-and that its regulation may contribute to counteracting the harmful effects of stress in both diseases. Larger, controlled studies are needed to confirm this preliminary finding. TRIAL REGISTRATION: ClinicalTrials.Gov NCT02136745. PMID- 25927529 TI - Infants' preference for native audiovisual speech dissociated from congruency preference. AB - Although infant speech perception in often studied in isolated modalities, infants' experience with speech is largely multimodal (i.e., speech sounds they hear are accompanied by articulating faces). Across two experiments, we tested infants' sensitivity to the relationship between the auditory and visual components of audiovisual speech in their native (English) and non-native (Spanish) language. In Experiment 1, infants' looking times were measured during a preferential looking task in which they saw two simultaneous visual speech streams articulating a story, one in English and the other in Spanish, while they heard either the English or the Spanish version of the story. In Experiment 2, looking times from another group of infants were measured as they watched single displays of congruent and incongruent combinations of English and Spanish audio and visual speech streams. Findings demonstrated an age-related increase in looking towards the native relative to non-native visual speech stream when accompanied by the corresponding (native) auditory speech. This increase in native language preference did not appear to be driven by a difference in preference for native vs. non-native audiovisual congruence as we observed no difference in looking times at the audiovisual streams in Experiment 2. PMID- 25927530 TI - Energy-Related Indicators and Breast Cancer Risk among White and Black Women. AB - Energy-related indicators, including physical activity, energy intake, body mass index (BMI) and adult weight change, have been linked to breast cancer risk. Very few studies of these associations have been conducted among black women, therefore we used the Nashville Breast Health Study (NBHS) to determine whether similar effects were seen in black and white women. The NBHS is a population based case-control study of breast cancer among women age 25 to 75 years conducted between 2001 and 2010 in and around the Nashville Metropolitan area. Telephone interviews and self-administered food frequency questionnaires were completed with 2,614 incident breast cancer cases ascertained through hospitals and the statewide cancer registry, and 2,306 controls selected using random digit dialing. Among premenopausal white and black women, there was little effect of adult exercise or other energy-related indicators on breast cancer risk, regardless of tumor estrogen receptor (ER) status. The beneficial effect of adult exercise on postmenopausal breast cancer appeared to be comparable between white and black women (highest tertile relative to none - white odds ratio [OR] 0.8, 95% confidence interval [CI] 0.6-1.0, p for trend=0.05; black OR 0.7, 95% CI 0.4 1.1, p for trend=0.07); however, among black women the reduction was limited to those with ER-positive disease. White and black women should be encouraged to engage in more physical activity to reduce their risk of postmenopausal breast cancer. PMID- 25927535 TI - The feasibility of epidemiological research on prostate cancer in African men in Ibadan, Nigeria. AB - BACKGROUND: Men of African descent have the highest incidence and mortality rates of prostate cancer (PrCa) worldwide. Notably, PrCa is increasing in Africa with Nigerian men being mostly affected. Thus, it is important to understand risk factors for PrCa in Nigeria and build capacity for cancer research. The goals of this study were to determine the feasibility of conducting an epidemiological study of PrCa and to obtain preliminary data on risk factors for PrCa in Nigeria. METHODS: A case-control study (50 cases/50 controls) was conducted at the University College Hospital (UCH) in Ibadan, Nigeria, between October 2011 and December 2012. Men aged 40 to 80 years were approached for the study and asked to provide informed consent and complete the research protocol. Logistic regression models were used to examine associations between demographic, social and lifestyle characteristics and risk of PrCa. RESULTS: The participation rate among cases and controls was 98% and 93%, respectively. All participants completed a questionnaire and 99% (50 cases/49 controls) provided blood samples. Cases had a median serum diagnostic PSA of 73 ng/ml, and 38% had a Gleason score 8-10 tumor. Family history of PrCa was associated with a 4.9-fold increased risk of PrCa (95% CI 1.0 - 24.8). There were statistically significant inverse associations between PrCa and height, weight and waist circumference, but there was no association with body mass index (kg/m(2)). There were no associations between other socio demographic and lifestyle characteristics and PrCa risk. CONCLUSION: This feasibility study demonstrated the ability to ascertain and recruit participants at UCH and collect epidemiological, clinical and biospecimen data. Our results highlighted the advanced clinical characteristics of PrCa in Nigerian men, and that family history of PrCa and some anthropometric factors were associated with PrCa risk in this population. However, larger studies are needed to better understand the epidemiological risk factors of PrCa in Nigeria. PMID- 25927536 TI - The images of psychiatry scale: development, factor structure, and reliability. AB - BACKGROUND: This analysis is based on a survey questionnaire designed to describe medical educators' views of psychiatry and psychiatrists. Our goals in this paper were to assess the psychometric properties of the survey questions by (a) using exploratory factor analysis to identify the basic factor structure underlying 37 survey items; (b) testing the resulting factor structure using confirmatory factor analysis; and (c) assessing the internal reliability of each identified factor. To our knowledge, this is the first attempt to use these techniques to psychometrically assess a scale measuring the strength of stigma that medical educators attached to psychiatry. METHODS: Survey data were collected from a random sample of 1,059 teaching faculty in 23 academic teaching sites in 15 countries. We conducted exploratory and confirmatory factor analysis to identify the scale structure and Cronbach's alpha to assess internal consistency of the resulting scales. RESULTS: Results showed that a two-factor solution was the best fit for the data. Following exploratory factor analysis, we conducted confirmatory factor analysis on a split half of the sample. Results highlighted several items with low loadings. Excluding factors with low correlations and allowing for several correlated variances resulted in a good fitting model explaining 95% of the variance in the data. CONCLUSIONS: We identified two unidimensional scales. The Images Scale contained 11 items measuring stereotypic content concerning psychiatry and psychiatrists. The Efficacy of Psychiatry Scale contained 5 items addressing perceptions of the challenges and effectiveness of psychiatry as a discipline. PMID- 25927537 TI - Impact of thermal stress on evolutionary trajectories of pathogen resistance in three-spined stickleback (Gasterosteus aculeatus). AB - BACKGROUND: Pathogens are a major regulatory force for host populations, especially under stressful conditions. Elevated temperatures may enhance the development of pathogens, increase the number of transmission stages, and can negatively influence host susceptibility depending on host thermal tolerance. As a net result, this can lead to a higher prevalence of epidemics during summer months. These conditions also apply to marine ecosystems, where possible ecological impacts and the population-specific potential for evolutionary responses to changing environments and increasing disease prevalence are, however, less known. Therefore, we investigated the influence of thermal stress on the evolutionary trajectories of disease resistance in three marine populations of three-spined sticklebacks Gasterosteus aculeatus by combining the effects of elevated temperature and infection with a bacterial strain of Vibrio sp. using a common garden experiment. RESULTS: We found that thermal stress had an impact on fish weight and especially on survival after infection after only short periods of thermal acclimation. Environmental stress reduced genetic differentiation (QST) between populations by releasing cryptic within-population variation. While life history traits displayed positive genetic correlations across environments with relatively weak genotype by environment interactions (GxE), environmental stress led to negative genetic correlations across environments in pathogen resistance. This reversal of genetic effects governing resistance is probably attributable to changing environment-dependent virulence mechanisms of the pathogen interacting differently with host genotypes, i.e. GPathogenxGHostxE or (GPathogenxE)x(GHostxE) interactions, rather than to pure host genetic effects, i.e. GHostxE interactions. CONCLUSION: To cope with climatic changes and the associated increase in pathogen virulence, host species require wide thermal tolerances and pathogen-resistant genotypes. The higher resistance we found for some families at elevated temperatures showed that there is evolutionary potential for resistance to Vibrio sp. in both thermal environments. The negative genetic correlation of pathogen resistance between thermal environments, on the other hand, indicates that adaptation to current conditions can be a weak predictor for performance in changing environments. The observed feedback on selective gradients exerted on life history traits may exacerbate this effect, as it can also modify the response to selection for other vital components of fitness. PMID- 25927541 TI - Using surface enhanced Raman scattering to analyze the interactions of protein receptors with bacterial quorum sensing modulators. AB - Many members of the LuxR family of quorum sensing (QS) transcriptional activators, including LasR of Pseudomonas aeruginosa, are believed to require appropriate acyl-homoserine lactone (acyl-HSL) ligands to fold into an active conformation. The failure to purify ligand-free LuxR homologues in nonaggregated form at the high concentrations required for their structural characterization has limited the understanding of the mechanisms by which QS receptors are activated. Surface-enhanced Raman scattering (SERS) is a vibrational spectroscopy technique that can be applied to study proteins at extremely low concentrations in their active state. The high sensitivity of SERS has allowed us to detect molecular interactions between the ligand-binding domain of LasR (LasRLBD) as a soluble apoprotein and modulators of P. aeruginosa QS. We found that QS activators and inhibitors produce differential SERS fingerprints in LasRLBD, and in combination with molecular docking analysis provide insight into the relevant interaction mechanism. This study reveals signal-specific structural changes in LasR upon ligand binding, thereby confirming the applicability of SERS to analyze ligand-induced conformational changes in proteins. PMID- 25927539 TI - An internet-based adolescent depression preventive intervention: study protocol for a randomized control trial. AB - BACKGROUND: The high prevalence of major depressive disorder in adolescents and the low rate of successful treatment highlight a pressing need for accessible, affordable adolescent depression prevention programs. The Internet offers opportunities to provide adolescents with high quality, evidence-based programs without burdening or creating new care delivery systems. Internet-based interventions hold promise, but further research is needed to explore the efficacy of these approaches and ways of integrating emerging technologies for behavioral health into the primary care system. METHODS/DESIGN: We developed a primary care Internet-based depression prevention intervention, Competent Adulthood Transition with Cognitive Behavioral Humanistic and Interpersonal Training (CATCH-IT), to evaluate a self-guided, online approach to depression prevention and are conducting a randomized clinical trial comparing CATCH-IT to a general health education Internet intervention. This article documents the research framework and randomized clinical trial design used to evaluate CATCH-IT for adolescents, in order to inform future work in Internet-based adolescent prevention programs. The rationale for this trial is introduced, the current status of the study is reviewed, and potential implications and future directions are discussed. DISCUSSION: The current protocol represents the only current, systematic approach to connecting at-risk youth with self-directed depression prevention programs in a medical setting. This trial undertakes the complex public health task of identifying at-risk individuals through mass screening of the general primary care population, rather than solely relying on volunteers recruited over the Internet, and the trial design provides measures of both symptomatic and diagnostic clinical outcomes. At the present time, we have enrolled N = 234 adolescents/expected 400 and N = 186 parents/expected 400 in this trial, from N = 6 major health systems. The protocol described here provides a model for a new generation of interventions that blend substantial computer based instruction with human contact to intervene to prevent mental disorders such as depression. Because of the potential for broad generalizability of this model, the results of this study are important, as they will help develop the guidelines for preventive interventions with youth at-risk for the development of depressive and other mental disorders. TRIAL REGISTRATION: CLINICAL TRIAL REGISTRY: NCT01893749 date 6 May 2012. PMID- 25927542 TI - Risk of idiopathic nephrotic syndrome among children with asthma: a nationwide, population-based cohort study. AB - BACKGROUND: Although clinical and immunological studies have shown a possible link between allergy and idiopathic nephrotic syndrome (INS), the nature of the relationship remains unclear. Asthma is the most common chronic allergic airway inflammation. However, no study has used a longitudinal design with a population cohort to investigate INS in children with asthma. METHODS: Using nationwide claims data from 2000 through 2007, we randomly selected 251,698 asthma cases and 1,006,791 frequency-matched controls. Incidence rates of INS and hazard ratios (HRs) were calculated. RESULTS: The INS incidence was 3.36-fold greater in the asthma cohort than in the nonasthma control (9.26 vs. 2.76 per 100,000 person years; 95% confidence interval (CI): 2.65-4.26). The HR for INS increased for those with more asthma-related medical visits per year, from 1.49 (95% CI: 1.06 2.11) for <3 visits to 15.7 (95% CI: 11.5-21.5) for >=6 visits (trend test, P < 0.0001). The HR for INS slightly decreased during the follow-up period, from 3.41 (95% CI: 2.66-4.38) for <=5.5 y to 2.90 (95% CI: 1.33-6.30) for >5.5 y. CONCLUSION: We conclude that children with asthma had an increased incidence rate of INS, and increased incidence rate correlated with asthma-related medical visits. PMID- 25927543 TI - Potential effects of reward and loss avoidance in overweight adolescents. AB - BACKGROUND: Reward system and inhibitory control are brain functions that exert an influence on eating behavior regulation. We studied the differences in inhibitory control and sensitivity to reward and loss avoidance between overweight/obese and normal-weight adolescents. METHODS: We assessed 51 overweight/obese and 52 normal-weight 15-y-old Chilean adolescents. The groups were similar regarding sex and intelligence quotient. Using Antisaccade and Incentive tasks, we evaluated inhibitory control and the effect of incentive trials (neutral, loss avoidance, and reward) on generating correct and incorrect responses (latency and error rate). RESULTS: Compared to normal-weight group participants, overweight/obese adolescents showed shorter latency for incorrect antisaccade responses (186.0 (95% CI: 176.8-195.2) vs. 201.3 ms (95% CI: 191.2 211.5), P < 0.05) and better performance reflected by lower error rate in incentive trials (43.6 (95% CI: 37.8-49.4) vs. 53.4% (95% CI: 46.8-60.0), P < 0.05). Overweight/obese adolescents were more accurate on loss avoidance (40.9 (95% CI: 33.5-47.7) vs. 49.8% (95% CI: 43.0-55.1), P < 0.05) and reward (41.0 (95% CI: 34.5-47.5) vs. 49.8% (95% CI: 43.0-55.1), P < 0.05) compared to neutral trials. CONCLUSION: Overweight/obese adolescents showed shorter latency for incorrect responses and greater accuracy in reward and loss avoidance trials. These findings could suggest that an imbalance of inhibition and reward systems influence their eating behavior. PMID- 25927544 TI - A functional approach to cerebral visual impairments in very preterm/very-low birth-weight children. AB - BACKGROUND: Cerebral visual impairment (CVI) is a major cause of visual impairment, with very preterm birth/very low birth weight (VP/VLBW) being a major risk factor. There is no generally accepted definition of CVI. This study aims to investigate the usefulness of an empirically-based functional definition of CVI. METHODS: One-hundred-five VP/VLBW children and 67 controls participated. CVI was defined after comprehensive oculomotor, visual sensory and perceptive assessment, and validated against vision problems in daily life and in terms of intellectual, behavioral, emotional and social functioning, as well as use of therapeutic services. RESULTS: Twenty-four per cent of the VP/VLBW children met criteria for CVI, compared to 7% of controls (P = 0.006, OR: 3.86, 95% CI: 1.40-10.70). VP/VLBW children with CVI had lower performance IQ, but not verbal IQ, than those without CVI. Visual problems in daily life were confirmed in VP/VLBW children classified with CVI. Additionally, difficulties in behavioral and social functioning were most prominent among VP/VLBW children with CVI. CONCLUSION: In VP/VLBW children, CVI defined in terms of visual function deficits is accompanied by intellectual, behavioral, and social impairments, validating our operational definition of CVI. CVI might act as a marker for developmental problems in VP/VLBW children. PMID- 25927545 TI - A model for predicting the thermal conductivity of SiO2-Ge nanoparticle composites. AB - We present a simple theoretical model that predicts the thermal conductivity of SiO2 layers with embedded Ge quantum dots (QDs). Overall, the resulting nanoscale architecture comprising the structural relaxation in the SiO2 matrix, deviation in mass density of the QDs compared to the surrounding matrix and local strains associated with the dots are all likely to enhance phonon scattering and thus reduce the thermal conductivity in these systems. We have found that the conductivity reduction can be predicted by the dot-induced local elastic perturbations in SiO2. Our model is able to explain not only this large reduction but also the magnitude and temperature variation of the thermal conductivity with size and density of the dots. Within the error range, the theoretical calculations of the temperature-dependent thermal conductivity in different samples are in close agreement with the experimental measurements. Including the details of the strain fields in oxidized Si nanostructured layers is therefore essential for a better prediction of the heat pathways in on-chip thermoelectric devices and circuits. PMID- 25927546 TI - The role of social support and social networks in health information-seeking behavior among Korean Americans: a qualitative study. AB - INTRODUCTION: This study used social network theory to explore the role of social support and social networks in health information-seeking behavior among Korean American (KA) adults. METHODS: A descriptive qualitative study using a web-based online survey was conducted from January 2013 to April 2013 in the U.S. The survey included open-ended questions about health information-seeking experiences in personal social networks and their importance in KA adults. Themes emerging from a constant comparative analysis of the narrative comments by 129 of the 202 respondents were analyzed. RESULTS: The sample consisted of 129 KA adults, 64.7% female, with a mean age of 33.2 (SD = 7.7). Friends, church members, and family members were the important network connections for KAs to obtain health information. KAs looked for a broad range of health information from social network members, from recommendations and reviews of hospitals/doctors to specific diseases or health conditions. These social networks were regarded as important for KAs because there were no language barriers, social network members had experiences similar to those of other KAs, they felt a sense of belonging with those in their networks, the network connections promoted increased understanding of different health care systems of the U.S. system, and communication with these network connections helped enhance feelings of being physically and mentally healthy. CONCLUSIONS: This study demonstrates the important role that social support and personal social networks perform in the dissemination of health information for a large ethnic population, KAs, who confront distinct cultural challenges when seeking health information in the U.S. Data from this study also illustrate the cultural factors that influence health information acquisition and access to social support for ethnic minorities. This study provides practical insights for professionals in health information services, namely, that social networks can be employed as a channel for disseminating health information to immigrants. PMID- 25927549 TI - An organic approach for nanostructured multiferroics. AB - Multiferroics are materials that simultaneously exhibit more than one ferroic order parameters, such as ferroelectricity, ferroelasticity and ferromagnetism. Recently, multiferroicity has received a significant revival of interest due to the colossal magnetoelectric coupling effect for the development of nano ferronics. In this mini-review, we focus on a recent study of ferroelectricity, magnetism and magnetoelectric coupling within the newly discovered organic charge transfer complexes. A systemic understanding of the origin of organic ferroelectricity and magnetism is provided. Furthermore, based on the recent mechanism of the magnetoelectric coupling effect: spin-ordering-induced electric polarization and ferroelectricity-induced spin alignment, we further present the recent progress in organic charge-transfer multiferroics and metal-organic framework multiferroics. The coexistence of polarization and magnetism at room temperature of organic charge-transfer complexes will be critical for the development of all-organic multiferroics. PMID- 25927548 TI - An atypical form of AOA2 with myoclonus associated with mutations in SETX and AFG3L2. AB - BACKGROUND: Hereditary ataxias are a heterogeneous group of neurodegenerative disorders, where exome sequencing may become an important diagnostic tool to solve clinically or genetically complex cases. METHODS: We describe an Italian family in which three sisters were affected by ataxia with postural/intentional myoclonus and involuntary movements at onset, which persisted during the disease. Oculomotor apraxia was absent. Clinical and genetic data did not allow us to exclude autosomal dominant or recessive inheritance and suggest a disease gene. RESULTS: Exome sequencing identified a homozygous c.6292C > T (p.Arg2098*) mutation in SETX and a heterozygous c.346G > A (p.Gly116Arg) mutation in AFG3L2 shared by all three affected individuals. A fourth sister (II.7) had subclinical myoclonic jerks at proximal upper limbs and perioral district, confirmed by electrophysiology, and carried the p.Gly116Arg change. Three siblings were healthy. Pathogenicity prediction and a yeast-functional assay suggested p.Gly116Arg impaired m-AAA (ATPases associated with various cellular activities) complex function. CONCLUSIONS: Exome sequencing is a powerful tool in identifying disease genes. We identified an atypical form of Ataxia with Oculoapraxia type 2 (AOA2) with myoclonus at onset associated with the c.6292C > T (p.Arg2098*) homozygous mutation. Because the same genotype was described in six cases from a Tunisian family with a typical AOA2 without myoclonus, we speculate this latter feature is associated with a second mutated gene, namely AFG3L2 (p.Gly116Arg variant). We suggest that variant phenotypes may be due to the combined effect of different mutated genes associated to ataxia or related disorders, that will become more apparent as the costs of exome sequencing progressively will reduce, amplifying its diagnostics use, and meanwhile proposing significant challenges in the interpretation of the data. PMID- 25927551 TI - Marigold flower-powder exhibits significant potential to inhibit lipid oxidation in rice bran tea. AB - We supplemented marigold flower-powder (MFP) in rice bran tea at different proportions as a source of natural antioxidant compounds. Changes of phenolic compounds, antioxidant activity, fatty acid composition and lipid oxidation in the rice bran tea with MFP after 30 days of storage were investigated, comparing results with the initial data. Adding MFP in rice bran tea resulted in an increased content and composition of phenolics and flavonoids along with enhanced antioxidant activities, which were increased in a dose-dependent manner. As a result, MFP supplementation of rice bran tea was able to retard the lipid oxidation as determined by the peroxide value (PV), due to the protection of essential fatty acids during 30 days of storage. The PVs were strongly negatively correlated (p < 0.01) with phenolic compounds, total phenolic content (TPC) and total flavonoid content (TFC), but were positively correlated with tocopherols and gamma-oryzanol contents. We also found that the PV was positively correlated with the PUFA (poly unsaturated fatty acid) content but adverse results were found for SFA (saturated fatty acid) and MUFA (mono unsaturated fatty acid) contents. These findings suggest that MFP could be used as a natural antioxidant in foods for preventing lipid oxidation as well as extending the shelf-life of food products. PMID- 25927555 TI - Assessing cost and technical efficiency of HIV prevention interventions in sub Saharan Africa: the ORPHEA study design and methods. AB - BACKGROUND: Scaling up services to achieve HIV targets will require that countries optimize the use of available funding. Robust unit cost estimates are essential for the better use of resources, and information on the heterogeneity in the unit cost of delivering HIV services across facilities - both within and across countries - is critical to identifying and addressing inefficiencies. There is limited information on the unit cost of HIV prevention services in sub Saharan Africa and information on the heterogeneity within and across countries and determinants of this variation is even more scarce. The "Optimizing the Response in Prevention: HIV Efficiency in Africa" (ORPHEA) study aims to add to the empirical body of knowledge on the cost and technical efficiency of HIV prevention services that decision makers can use to inform policy and planning. METHODS/DESIGN: ORPHEA is a cross-sectional observational study conducted in 304 service delivery sites in Kenya, Rwanda, South Africa, and Zambia to assess the cost, cost structure, cost variability, and the determinants of efficiency for four HIV interventions: HIV testing and counselling (HTC), prevention of mother to-child transmission (PMTCT), voluntary medical male circumcision (VMMC), and HIV prevention for sex workers. ORPHEA collected information at three levels (district, facility, and individual) on inputs to HIV prevention service production and their prices, outputs produced along the cascade of services, facility-level characteristics and contextual factors, district-level factors likely to influence the performance of facilities as well as the demand for HIV prevention services, and information on process quality for HTC, PMTCT, and VMMC services. DISCUSSION: ORPHEA is one of the most comprehensive studies on the cost and technical efficiency of HIV prevention interventions to date. The study applied a robust methodological design to collect comparable information to estimate the cost of HTC, PMTCT, VMMC, and sex worker prevention services in Kenya, Rwanda, South Africa, and Zambia, the level of efficiency in the current delivery of these services, and the key determinants of efficiency. The results of the study will be important to decision makers in the study countries as well as those in countries facing similar circumstances and contexts. PMID- 25927558 TI - Erratum to: On estimation of genetic variance within families using genome-wide identity-by-descent sharing. PMID- 25927556 TI - Microarray: a global analysis of biomineralization-related gene expression profiles during larval development in the pearl oyster, Pinctada fucata. AB - BACKGROUND: The molluscan Pinctada fucata is an important pearl-culturing organism to study biomineralization mechanisms. Several biomineralization-related genes play important roles regulating shell formation, but most previous work has focused only on their functions in adult oysters. Few studies have investigated biomineralization during larval development, when the shell is initially constructed and formed until the juvenile stage in dissoconch shells. Here, we report, for the first time, a global gene analysis during larval development of P. fucata based on a microarray and reveal the relationships between biomineralization-related genes and the shell formation process. RESULTS: Based on the P. fucata mantle transcriptome, 58,940 probes (60 nt), representing 58,623 transcripts, were synthesized. The gene expression profiles of the fertilized egg, trochophore, D-shaped, and umbonal stage larvae, as well as juveniles were analyzed by microarray performance. The expression patterns of the biomineralization-related genes changed corresponding to their regulatory function during shell formation. Matrix proteins chitin synthase and PFMG2 were highly expressed at the D-shaped stage, whereas PFMG6, PFMG8 and PfN23 were significantly up-regulated at the umbonal stage, indicating different roles regulating the formation of either periostracum, Prodissoconch I or Prodissoconch II shells. However, the majority of matrix proteins were expressed at high levels at the juvenile stage, and the shells comprised both an aragonitic nacreous layer and a calcitic prismatic layer as adults. We also identified five new genes that were significantly up-regulated in juveniles. These genes were expressed particularly in the mantle and coded for secreted proteins with tandem-arranged repeat units, as most matrix proteins. RNAi knockdown resulted in disrupted nacreous and prismatic shell layers, indicating their potential roles in shell formation. CONCLUSIONS: Our results add a global perspective on larval expression patterns of P. fucata genes and propose a mechanism of how biomineralization related genes regulate the larval shell formation process. These results increase knowledge about biomineralization-related genes and highlight new aspects of shell formation mechanisms. PMID- 25927561 TI - In tribute to Joep Lange. PMID- 25927564 TI - Update in geriatric medicine: evidence published in 2014. PMID- 25927567 TI - Total synthesis of proanthocyanidin A1, A2, and their stereoisomers. AB - The first novel stereoselective synthesis of naturally occurring A1 (1) and A2 proanthocyanidins (2) has been achieved. The key synthetic steps involved (a) the formation of a coupled product (13 or 14) between an open chain C-ring C-4 hydroxyethoxy analogue of either (+)-catechin or (-)-epicatechin with 5,7,3',3' tetra-O-benzyl-(+)-catechin/-(-)-epicatechin in the presence of bentonite clay K 10, (b) removal of benzyl protecting groups under mild catalytic hydrogenation conditions to form the desired A-type compound in situ as a mixture of diastereomers via ketal/oxonium ion/carbonium ion formation, and (c) separation of the diasteromers via silica gel column chromatography. The structures of A1 and A2 proanthocyanidins were unequivocally established by analytical comparison to the natural products. Following this methodology, an additional six diastereomers of proanthocyanidins A1 and A2 have been synthesized. A plausible mechanism for the formation of the A-type linkage in proanthocyanidins has been proposed. PMID- 25927562 TI - The effectiveness of critical time intervention for abused women and homeless people leaving Dutch shelters: study protocol of two randomised controlled trials. AB - BACKGROUND: One of the main priorities of Dutch organisations providing shelter services is to develop evidence-based interventions in the care for abused women and homeless people. To date, most of these organisations have not used specific intervention models and the interventions which have been implemented rarely have an empirical and theoretical foundation. The present studies aim to examine the effectiveness of critical time intervention (CTI) for abused women and homeless people. METHODS: In two multi-centre randomised controlled trials we investigate whether CTI, a time-limited (nine month) outreach intervention, is more effective than care-as-usual for abused women and homeless people making the transition from shelter facilities to supported or independent housing. Participants were recruited in 19 women's shelter facilities and 22 homeless shelter facilities across The Netherlands and randomly allocated to the intervention group (CTI) or the control group (care-as-usual). They were interviewed four times in nine months: once before leaving the shelter, and then at three, six and nine months after leaving the shelter. Quality of life (primary outcome for abused women) and recurrent loss of housing (primary outcome for homeless people) as well as secondary outcomes (e.g. care needs, self-esteem, loneliness, social support, substance use, psychological distress and service use) were assessed during the interviews. In addition, the model integrity of CTI was investigated during the data collection period. DISCUSSION: Based on international research CTI is expected to be an appropriate intervention for clients making the transition from institutional to community living. If CTI proves to be effective for abused women and homeless people, shelter services could include this case management model in their professional standards and improve the (quality of) services for clients. TRIAL REGISTRATION: NTR3463 and NTR3425. PMID- 25927569 TI - Preoperative smoking cessation counseling activities of anesthesiologists: a cross-sectional study. AB - BACKGROUND: Smokers undergoing surgery are at a higher risk of complications than non-smokers. Preoperative evaluation by an anesthesiologist could provide an excellent opportunity to promote smoking cessation. Previous surveys of anesthesiologists have found that self-reported smoking cessation counseling rates have room for improvement, but no study has surveyed patients to obtain more accurate estimates. METHODS: A single-center study was conducted from January 2010 to June 2010 in a tertiary teaching hospital. A telephone survey was conducted, which included all adult cigarette smokers who visited the preoperative anesthesia clinic. The survey recorded anesthesiologist-delivered interventions to help patients quit smoking before surgery. At the end of the study period, the self-reported smoking cessation counseling of the anesthesiologist was evaluated by questionnaire. RESULTS: One thousand one hundred and sixty-five patients were evaluated, of which 217 were current smokers with a median pack-year of 15 (interquartile range 5.25-30.00) and 34% were scheduled to undergo major surgery. With regard to preoperative interventions, most anesthesiologists (85%) asked about smoking status, although only 31% advised patients about the health risks of smoking and 23% advised patients to quit before surgery. Provision of assistance to help patients quit was provided in 3% of cases. By contrast, 75% of anesthesiologists stated that they frequently or almost always advised patients about the health risks of smoking. CONCLUSIONS: This study shows significant discrepancies between direct patient surveys of preoperative smoking cessation counseling activities by anesthesiologists and the self-reported perceptions of the anesthesiologists. Future studies are urgently needed to evaluate the provision of educational materials and other interventions to improve smoking cessation counseling rates among anesthesiologists and to narrow these discrepancies. PMID- 25927570 TI - K-space polarimetry of bullseye plasmon antennas. AB - Surface plasmon resonators can drastically redistribute incident light over different output wave vectors and polarizations. This can lead for instance to sub-diffraction sized nanoapertures in metal films that beam and to nanoparticle antennas that enable efficient conversion of photons between spatial modes, or helicity channels. We present a polarimetric Fourier microscope as a new experimental tool to completely characterize the angle-dependent polarization resolved scattering of single nanostructures. Polarimetry allows determining the full Stokes parameters from just six Fourier images. The degree of polarization and the polarization ellipse are measured for each scattering direction collected by a high NA objective. We showcase the method on plasmonic bullseye antennas in a metal film, which are known to beam light efficiently. We find rich results for the polarization state of the beamed light, including complete conversion of input polarization from linear to circular and from one helicity to another. In addition to uncovering new physics for plasmonic groove antennas, the described technique projects to have a large impact in nanophotonics, in particular towards the investigation of a broad range of phenomena ranging from photon spin Hall effects, polarization to orbital angular momentum transfer and design of plasmon antennas. PMID- 25927572 TI - Brachial plexus dose tolerance in head and neck cancer patients treated with sequential intensity modulated radiation therapy. AB - PURPOSE: We aimed to study the radiation induced brachial plexopathy in patients with head and neck squamous cell carcinoma (HNSCC) treated with Sequential Intensity Modulated Radiation Therapy (S-IMRT). METHODS AND MATERIALS: This IRB approved study included 68 patients with HNSCC treated consecutively. Detailed dose volume histogram data was generated for ipsilateral and contralateral brachial plexus (BP) volumes receiving a specified dose (Vds) i.e. V50-V75 and dose in Gray covering specified percent of BP volume (Dvs) i.e. D5-D30 and maximum point doses (Dmax). To assess BP injury all patients' charts were reviewed in detail for sign and symptoms of BP damage. Post-hoc comparisons were done using Tukey-Kramer method to account for multiple significance testing. RESULTS: The mean and maximum doses to BP were significantly different (p < .05) based on tumor site, nodal status and tumor stage. The mean volume to the ipsilateral BP for V50, V60, V70, and V75 were 7.01 cc, 4.37 cc, 1.47 cc and 0.24 cc, respectively. The mean dose delivered to <=5% of ipsilateral BP was 68.70 Gy (median 69.5Gy). None of the patients had acute or late brachial plexopathy or any other significant neurological complications, with a minimum follow up of two years (mean 54 months). CONCLUSIONS: In this study cohort, at a minimum of two years follow up, the mean dose of 68.7Gy, a median dose to 69.5Gy to <=5% of ipsilateral BP, and a median Dmax of 72.96Gy did not result in BP injury when patients were treated with S-IMRT technique. However, longer follow up is needed. PMID- 25927573 TI - Drug use patterns associated with risk of non-adherence to antiretroviral therapy among HIV-positive illicit drug users in a Canadian setting: a longitudinal analysis. AB - BACKGROUND: Among people living with HIV/AIDS, illicit drug use is a risk for sub optimal treatment outcomes. However, few studies have examined the relative contributions of different patterns of drug use on adherence to antiretroviral therapy (ART). We sought to estimate the effect of different types of illicit drug use on adherence in a setting of universal free HIV/AIDS treatment and care. METHODS: Using data from ongoing prospective cohorts of HIV-positive illicit drug users linked to comprehensive pharmacy dispensation records in Vancouver, Canada, we examined factors associated with >=95% prescription refill adherence using generalized estimating equations (GEE) logistic regression. RESULTS: Between 1996 and 2013, 692 ART-exposed individuals were followed for a median of 42.7 months (Interquartile Range: 29.1-71.7). In multivariable GEE analyses, heroin injection (Adjusted Odds Ratio [AOR] = 0.75, 95% Confidence Interval [CI]: 0.66-0.85) as well as cocaine injection (AOR = 0.80, 95% CI: 0.72-0.90) were associated with lower likelihoods of optimal adherence. Methadone maintenance therapy (AOR = 1.88, 95% CI: 1.68-2.11) was associated with a greater likelihood of adherence. CONCLUSIONS: Periods of heroin and cocaine injection appeared to have the most deleterious impact upon antiretroviral adherence. The findings point to the need for improved access to treatment for heroin use disorder, particularly methadone, and highlight the need to identify strategies to support ART adherence among cocaine injectors. PMID- 25927574 TI - Economic analyses of venous thromboembolism prevention strategies in hospitalized patients: a systematic review. AB - INTRODUCTION: Despite evidence-based guidelines for venous thromboembolism prevention, substantial variability is found in practice. Many economic evaluations of new drugs for thromboembolism prevention do not occur prospectively with efficacy studies and are sponsored by the manufacturers, raising the possibility of bias. We performed a systematic review of economic analyses of venous thromboembolism prevention in hospitalized patients to inform clinicians and policy makers about cost-effectiveness and the potential influence of sponsorship. METHODS: We searched MEDLINE, EMBASE, Cochrane Databases, ACP Journal Club, and Database of Abstracts of Reviews of Effects, from 1946 to September 2011. We extracted data on study characteristics, quality, costs, and efficacy. RESULTS: From 5,180 identified studies, 39 met eligibility and quality criteria. Each addressed pharmacologic prevention: low-molecular-weight heparins versus placebo (five), unfractionated heparin (12), warfarin (eight), one or another agents (five); fondaparinux versus enoxaparin (11); and rivaroxaban and dabigatran versus enoxaparin (two). Low-molecular-weight heparins were most economically attractive among most medical and surgical patients, whereas fondaparinux was favored for orthopedic patients. Fondaparinux was associated with increased bleeding events. Newer agents rivaroxaban and dabigatran may offer additional value. Of all economic evaluations, 64% were supported by manufacturers of a "new" agent. The new agent had a favorable outcome in 38 (97.4%) of 39 evaluations [95% confidence interval [CI] (86.5 to 99.9)]. Among studies supported by a pharmaceutical company, the sponsored medication was economically attractive in 24 (96.0%) of 25 [95% CI, 80.0 to 99.9)]. We could not detect a consistent bias in outcome based on sponsorship; however, only a minority of studies were unsponsored. CONCLUSION: Low-molecular-weight heparins and fondaparinux are the most economically attractive drugs for venous thromboembolism prevention in hospitalized patients. Approximately two thirds of evaluations were supported by the manufacturer of the new agent; such drugs were likely to be reported as economically favorable. PMID- 25927576 TI - Structural, magnetic and luminescent properties of lanthanide complexes with N salicylideneglycine. AB - A series of anionic heavy lanthanide complexes, involving the N salicylideneglycinato(2-) Schiff base ligand (salgly) and having the general formula K[Ln(salgly)2(H2O)2]?H2O (1-6), where Ln stands for Gd, Tb, Dy, Ho, Er and Tm, was prepared using the one-pot template synthesis. The complexes were thoroughly characterized by elemental and Thermogravimetric/Differential Thermal Analyses (TG/DTA), Fourier Transform Infrared Spectroscopy (FT-IR), and photoluminescence spectroscopies, electrospray-ionization mass spectrometry, and their magnetic properties were studied by temperature-dependent dc magnetic measurements using the superconducting quantum interference device (SQUID). The X ray structure of the terbium(III) complex (2), representing the unique structure between the lanthanide complexes of N-salicylideneamino acids, was determined. The results of spectral and structural studies revealed the isostructural nature of the prepared complexes, in which the lanthanide ion is octacoordinated by two O,N,O-donor salgly ligands and two aqua ligands. The analysis of magnetic data confirmed that the complexes behave as paramagnets obeying the Curie law. The results of photoluminescence spectral studies of the complexes showed the different origin in their luminescent properties between the solid state and solution. An antenna effect of the Schiff base ligand was observed in a powder form of the complex only, while it acts as a fluorophore in a solution. PMID- 25927577 TI - Single-Stage Operation of Hybrid Dark-Photo Fermentation to Enhance Biohydrogen Production through Regulation of System Redox Condition: Evaluation with Real Field Wastewater. AB - Harnessing hydrogen competently through wastewater treatment using a particular class of biocatalyst is indeed a challenging issue. Therefore, biohydrogen potential of real-field wastewater was evaluated by hybrid fermentative process in a single-stage process. The cumulative hydrogen production (CHP) was observed to be higher with distillery wastewater (271 mL) than with dairy wastewater (248 mL). Besides H2 production, the hybrid process was found to be effective in wastewater treatment. The chemical oxygen demand (COD) removal efficiency was found higher in distillery wastewater (56%) than in dairy wastewater (45%). Co culturing photo-bacterial flora assisted in removal of volatile fatty acids (VFA) wherein 63% in distillery wastewater and 68% in case of dairy wastewater. Voltammograms illustrated dominant reduction current and low cathodic Tafel slopes supported H2 production. Overall, the augmented dark-photo fermentation system (ADPFS) showed better performance than the control dark fermentation system (DFS). This kind of holistic approach is explicitly viable for practical scale-up operation. PMID- 25927578 TI - miRNAs in the Pathogenesis of Systemic Lupus Erythematosus. AB - MicroRNAs (miRNAs) were first discovered as regulatory RNAs that controlled the timing of the larval development of Caenorhabditis elegans. Since then, nearly 30,000 mature miRNA products have been found in many species, including plants, warms, flies and mammals. Currently, miRNAs are well established as endogenous small (~22 nt) noncoding RNAs, which have functions in regulating mRNA stability and translation. Owing to intensive investigations during the last decade, miRNAs were found to play essential roles in regulating many physiological and pathological processes. Systemic lupus erythematosus (SLE) is a chronic autoimmune disease characterized by elevated autoantibodies against nuclear antigens and excessive inflammatory responses affecting multiple organs. Although efforts were taken and theories were produced to elucidate the pathogenesis of SLE, we still lack sufficient knowledge about the disease for developing effective therapies for lupus patients. Recent advances indicate that miRNAs are involved in the development of SLE, which gives us new insights into the pathogenesis of SLE and might lead to the finding of new therapeutic targets. Here, we will review recent discoveries about how miRNAs are involved in the pathogenesis of SLE and how it can promote the development of new therapy. PMID- 25927579 TI - In Vivo Molecular MRI Imaging of Prostate Cancer by Targeting PSMA with Polypeptide-Labeled Superparamagnetic Iron Oxide Nanoparticles. AB - The prostate specific membrane antigen (PSMA) is broadly overexpressed on prostate cancer (PCa) cell surfaces. In this study, we report the synthesis, characterization, in vitro binding assay, and in vivo magnetic resonance imaging (MRI) evaluation of PSMA targeting superparamagnetic iron oxide nanoparticles (SPIONs). PSMA-targeting polypeptide CQKHHNYLC was conjugated to SPIONs to form PSMA-targeting molecular MRI contrast agents. In vitro studies demonstrated specific uptake of polypeptide-SPIONs by PSMA expressing cells. In vivo MRI studies found that MRI signals in PSMA-expressing tumors could be specifically enhanced with polypeptide-SPION, and further Prussian blue staining showed heterogeneous deposition of SPIONs in the tumor tissues. Taken altogether, we have developed PSMA-targeting polypeptide-SPIONs that could specifically enhance MRI signal in tumor-bearing mice, which might provide a new strategy for the molecular imaging of PCa. PMID- 25927580 TI - Carotenoid profile of tomato sauces: effect of cooking time and content of extra virgin olive oil. AB - The consumption of carotenoid-rich vegetables such as tomatoes and tomato sauces is associated with reduced risk of several chronic diseases. The predominant carotenoids in tomato products are in the (all-E) configuration, but (Z) isomers can be formed during thermal processing. The effect of cooking time (15, 30, 45 and 60 min) and the addition of extra virgin olive oil (5% and 10%) on the carotenoid extractability of tomato sauces was monitored using liquid chromatography-tandem mass spectrometry (LC-ESI-MS/MS) and LC-ultraviolet detection (LC-UV). The thermal treatment and the addition of extra virgin olive oil increased the levels of antioxidant activity, total carotenoids, Z-lycopene isomers, alpha-carotene and beta-carotene. These results are of particular nutritional benefit since higher lycopene intake has been associated with a reduced risk of lethal prostate and a reduction of prostate-specific antigen (PSA) levels. Moreover, beta-carotene has been reported to suppress the up regulation of heme oxygenase-1 gene expression in a dose dependent manner and to suppress UVA-induced HO-1 gene expression in cultured FEK4. PMID- 25927581 TI - High density infill in cracks and protrusions from the articular calcified cartilage in osteoarthritis in standardbred horse carpal bones. AB - We studied changes in articular calcified cartilage (ACC) and subchondral bone (SCB) in the third carpal bones (C3) of Standardbred racehorses with naturally occurring repetitive loading-induced osteoarthritis (OA). Two osteochondral cores were harvested from dorsal sites from each of 15 post-mortem C3 and classified as control or as showing early or advanced OA changes from visual inspection. We re examined X-ray micro-computed tomography (uCT) image sets for the presence of high-density mineral infill (HDMI) in ACC cracks and possible high-density mineralized protrusions (HDMP) from the ACC mineralizing (tidemark) front (MF) into hyaline articular cartilage (HAC). We hypothesized and we show that 20-um uCT resolution in 10-mm diameter samples is sufficient to detect HDMI and HDMP: these are lost upon tissue decalcification for routine paraffin wax histology owing to their predominant mineral content. The findings show that uCT is sufficient to discover HDMI and HDMP, which were seen in 2/10 controls, 6/9 early OA and 8/10 advanced OA cases. This is the first report of HDMI and HDMP in the equine carpus and in the Standardbred breed and the first to rely solely on uCT. HDMP are a candidate cause for mechanical tissue destruction in OA. PMID- 25927582 TI - Skeletal muscle depletion predicts the prognosis of patients with hepatocellular carcinoma treated with sorafenib. AB - The aim of this study was to determine whether skeletal muscle depletion predicts the prognosis of patients with hepatocellular carcinoma (HCC) that is being treated with sorafenib. We evaluated 40 consecutive HCC patients who received sorafenib treatment. The skeletal muscle cross-sectional area was measured by computed tomography at the third lumbar vertebra (L3), from which the L3 skeletal muscle index (L3 SMI) was obtained. The factors contributing to overall survival, sorafenib dose reduction, and discontinuation of sorafenib were analyzed using the Cox proportional hazards model. L3 SMI (p = 0.020) and log (alpha-fetoprotein (AFP)) (p = 0.010) were identified as independent prognostic factors in HCC patients treated with sorafenib. The initial dose of sorafenib (p = 0.008) was an independent risk factor for sorafenib dose reduction, and log (AFP) (p = 0.008) was the only significant risk factor for the discontinuation of this drug. L3 SMI was not a risk factor for either dose reduction (p = 0.423) or the discontinuation (p = 0.132) of sorafenib. A multiple linear regression analysis determined the following relationship between skeletal muscle mass (assessed as L3 SMI) and the explanatory factors: L3 SMI = -0.1896 * (Age) - 10.3441 * (Child Pugh score) - 9.3922 * (log (AFP)) + 1.6139 * (log (AFP)) * (Child-Pugh score) + 112.9166. Skeletal muscle depletion is inversely associated with age, Child-Pugh score, and log (AFP). Moreover, it is an independent prognostic factor for HCC patients treated with sorafenib. PMID- 25927583 TI - A Fusion Protein of RGD4C and beta-Lactamase Has a Favorable Targeting Effect in Its Use in Antibody Directed Enzyme Prodrug Therapy. AB - Antibody directed enzyme prodrug therapy (ADEPT) utilizing beta-lactamase is a promising treatment strategy to enhance the therapeutic effect and safety of cytotoxic agents. In this method, a conjugate (antibody-beta-lactamase fusion protein) is employed to precisely activate nontoxic cephalosporin prodrugs at the tumor site. A major obstacle to the clinical translation of this method, however, is the low catalytic activity and high immunogenicity of the wild-type enzymes. To overcome this challenge, we fused a cyclic decapeptide (RGD4C) targeting to the integrin with a beta-lactamase variant with reduced immunogenicity which retains acceptable catalytic activity for prodrug hydrolysis. Here, we made a further investigation on its targeting effect and pharmacokinetic properties, the results demonstrated that the fusion protein retains a targeting effect on integrin positive cells and has acceptable pharmacokinetic characteristics, which benefits its use in ADEPT. PMID- 25927585 TI - Association between serum vitamin D status and health-related quality of life (HRQOL) in an older Korean population with radiographic knee osteoarthritis: data from the Korean national health and nutrition examination survey (2010-2011). AB - BACKGROUND: Vitamin D is important in bone health and its relationship with osteoarthritis has recently been reported. Both vitamin D deficiency and knee osteoarthritis are age dependent and are known to affect quality of life (QOL) in older populations. In this study, we aimed to determine the association between vitamin D status and health-related quality of life (HRQOL) in an older Korean population with knee osteoarthritis. METHODS: A total of 2,165 participants aged >=50 years with radiographic knee osteoarthritis defined as Kellgren-Lawrence (KL) grade >=2 were selected from data from the 5th Korean National Health and Nutrition Examination Survey (KNHANES V), a representative cross-sectional nationwide survey conducted in 2010-2011. They stratified into two levels by vitamin D status (deficiency <10 ng/dL and normal >=10 ng/dL). HRQOL was measured using the EuroQOL visual analogue scale (EQ-VAS) and the five dimensions and summary index of the EuroQOL-5 dimension (EQ-5D). RESULTS: The vitamin D deficiency group was more likely to report problems with mobility, self-care, and usual activities. Vitamin D deficiency was significantly associated with poor HRQOL indicated by the lowest quartile of EQ-VAS (unadjusted odds ratio [OR] =1.832, p = 0.006) and the lowest quartile of the EQ-5D index (unadjusted OR = 1.992, p = 0.003). Theses associations of vitamin D status with EQ-VAS and EQ-5D index were maintained after adjustment for age and sex (Model 1: OR = 1.677, p = 0.022 and OR = 1.701, p = 0.021, respectively). The significant associations of vitamin D status with EQ-VAS were maintained after adjustment for other possible covariates (Model 3: OR = 1.562, p = 0.044). Also, a trend of associations between vitamin D status and EQ-5D index were shown after adjustment for other covariates (Model3: OR = 1.681, p = 0.056). CONCLUSION: This is the first study to reveal that vitamin D status is independently associated with HRQOL in an older Korean population with knee osteoarthritis. Our results suggest that the maintenance of sufficient vitamin D status may be important to prevent QOL decline in older populations with knee osteoarthritis. PMID- 25927586 TI - Isolation, Structural Modification, and HIV Inhibition of Pentacyclic Lupane-Type Triterpenoids from Cassine xylocarpa and Maytenus cuzcoina. AB - As a part of our investigation into new anti-HIV agents, we report herein the isolation, structure elucidation, and biological activity of six new (1-6) and 20 known (7-26) pentacyclic lupane-type triterpenoids from the stem of Cassine xylocarpa and root bark of Maytenus cuzcoina. Their stereostructures were elucidated on the basis of spectroscopic and spectrometric methods, including 1D and 2D NMR techniques. To gain a more complete understanding of the structural requirements for anti-HIV activity, derivatives 27-48 were prepared by chemical modification of the main secondary metabolites. Sixteen compounds from this series displayed inhibitory effects of human immunodeficiency virus type 1 replication with IC50 values in the micromolar range, highlighting compounds 12, 38, and 42 (IC50 4.08, 4.18, and 1.70 MUM, respectively) as the most promising anti-HIV agents. PMID- 25927587 TI - Reproductive health of women with and without disabilities in South India, the SIDE study (South India Disability Evidence) study: a case control study. AB - BACKGROUND: Evidence shows that women with disability have adverse pregnancy outcomes compared to those without a disability. There is a lack of published data on reproductive health of women with disability in India till date. The objective of the South India Disability Evidence (SIDE) Study was to compare reproductive health parameters including pregnancy experience, health access during pregnancy and type of delivery among women with disability compared to women with no disability. METHODS: The study was conducted in one district each in two States (Andhra Pradesh and Karnataka) in 2012. A case-control design was used to identify appropriate age and sex-matched controls for women with disability identified through a population-based survey. Trained key informants first listed women with disabilities who were then examined by a medical team to confirm the diagnosis. Trained research investigators administered questionnaire schedules to both groups of women to collect information on reproductive health and outcomes of any pregnancy experienced in the past two years. RESULTS: A total of 247 women with disability and 324 age-matched controls aged 15-45 years were recruited for the study. 87% of the women with disability had a physical disability. The mean age of women with disability was 29.86 against 29.71 years among women without a disability. A significantly lower proportion of women with disability experienced pregnancy (36.8%) compared to women without a disability (X (2) -16.02 P <0.001). The odds ratio for suffering from diabetes among women with disability compared to women without a disability was 19.3(95% CI: 1.2- 313.9), while it was 9.5 (95% CI: 2.2-40.8) for depression. A higher proportion of women without a disability (7.7%) compared to women with a disability (5.3%) reported a successful pregnancy in the past two years. There were no statistically significant differences between women with and without a disability with regard to utilization of antenatal care and pregnancy outcomes. CONCLUSIONS: The study provides evidence on some reproductive health parameters of women with disability in India for the first time ever. The findings will help in formulating policy and to develop specific interventions to improve pregnancy outcomes for women with disability in India. PMID- 25927588 TI - Place of Death among Hospitalized Patients with Cancer at the End of Life. AB - BACKGROUND: The majority of hospital deaths in the United States occur after ICU admission. The characteristics associated with the place of death within the hospital are not known for patients with cancer. OBJECTIVE: The study objective was to identify patient characteristics associated with place of death among hospitalized patients with cancer who were at the end of life. METHODS: A retrospective cohort study design was implemented. Subjects were consecutive patients hospitalized between 2003 and 2007 at a large comprehensive cancer center in the United States. Multinomial logistic regression analysis was used to identify patient characteristics associated with place of death (ICU, hospital following ICU, hospital without ICU) among hospital decedents. RESULTS: Among 105,157 hospital discharges, 3860 (3.7%) died in the hospital: 42% in the ICU, 14% in the hospital following an ICU stay, and 44% in the hospital without ICU services. Individuals with the following characteristics had an increased risk of dying in the ICU: nonlocal residence, newly diagnosed hematologic or nonmetastatic solid tumor malignancies, elective admission, surgical or pediatric services. A palliative care consultation on admission was associated with dying in the hospital without ICU services. CONCLUSIONS: Understanding existing patterns of care at the end of life will help guide decisions about resource allocation and palliative care programs. Patients who seek care at dedicated cancer centers may elect more aggressive care; thus the generalizability of this study is limited. Although dying in a hospital may be unavoidable for patients who have uncontrolled symptoms that cannot be managed at home, palliative care consultations with patients and their families in advance regarding end-of-life preferences may prevent unwanted admission to the ICU. PMID- 25927589 TI - Clinical significance of protocadherin 8 (PCDH8) promoter methylation in non muscle invasive bladder cancer. AB - BACKGROUND: PCDH8 is a novel tumor suppressor gene, and frequently inactivated by promoter methylation in human cancers. However, there is little information regarding PCDH8 methylation in non-muscle invasive bladder cancer (NMIBC). The aim of this study was to investigate the methylation status of PCDH8 in NMIBC and its clinical significance. METHODS: The methylation status of PCDH8 in 233 NMIBC tissues and 43 normal bladder epithelial tissues was examined by methylation specific PCR (MSP), and then analyzed the correlations between PCDH8 methylation and clinicopatholocial features. Subsequently, Kaplan-Meier survival analysis and Multivariate Cox proportional hazard model analysis was used to investigate the correlation between PCDH8 methylation and prognosis of patients with NMIBC. RESULTS: PCDH8 methylation occurred frequently in NMIBC tissues than those in normal bladder epithelial tissues. In addition, PCDH8 methylation significantly correlated with advanced stage, high grade, larger tumor size, tumor recurrence and progression in NMIBC. Kaplan-Meier survival analysis revealed that patients with PCDH8 methylated have shorter recurrence-free survival, progression-free survival and five-year overall survival than patients with PCDH8 unmethylated. Multivariate analysis suggested that PCDH8 methylation was an independent prognostic biomarker for recurrence-free survival, progression-free survival and five-year overall survival simultaneously. CONCLUSIONS: PCDH8 methylation may be associated with tumor progression and poor prognosis in NMIBC and may be used as a potential biomarker to predict the prognosis of patients with NMIBC. PMID- 25927590 TI - Erratum: Consumption of whole grains and cereal fiber and total and cause specific mortality: prospective analysis of 367,442 individuals. AB - This is an Erratum to BMC Medicine 2015, 13:59, highlighting previously undeclared competing interests and including more information in the acknowledgements section.Please see related article: http://www.biomedcentral.com/1741-7015/13/59. The statement in the competing interests should read as follows: This study is funded by unrestricted research fund from NutraSource. Susan Cho is founder and owner of NutraSource and Albert Lee is an employee of NutraSource. The other authors declare that they have no competing interests. The following information should be included in the acknowledgements section: The authors also thank Dr. Yi K Park at National Cancer Institute for her guidance in the study design. PMID- 25927591 TI - A systematic review of the efficacy of self-management programs for increasing physical activity in community-dwelling adults with acquired brain injury (ABI). AB - BACKGROUND: Individuals living with acquired brain injury, typically caused by stroke or trauma, are far less likely to achieve recommended levels of physical activity for optimal health and well-being. With a growing number of people living with chronic disease and disability globally, self-management programs are seen as integral to the management of these conditions and the prevention of secondary health conditions. However, to date, there has been no systematic review of the literature examining the efficacy of self-management programs specifically on physical activity in individuals with acquired brain injury, whether delivered face-to-face or remotely. Therefore, the purpose of this review is to evaluate the efficacy of self-management programs in increasing physical activity levels in adults living in the community following acquired brain injury. The efficacy of remote versus face-to-face delivery was also examined. METHODS: A systematic review of the literature was conducted. Electronic databases were searched. Two independent reviewers screened all studies for eligibility, assessed risk of bias, and extracted relevant data. RESULTS: Five studies met the inclusion criteria for this review. Studies were widely heterogeneous with respect to program content and delivery characteristics and outcomes, although all programs utilized behavioral change principles. Four of the five studies examined interventions in which physical activity was a component of a multifaceted intervention, where the depth to which physical activity specific content was covered, and the extent to which skills were taught and practiced, could not be clearly established. Three studies showed favorable physical activity outcomes following self-management interventions for stroke; however, risk of bias was high, and overall efficacy remains unclear. Although not used in isolation from face-to-face delivery, remote delivery via telephone was the predominant form of delivery in two studies with support for its inclusion in self-management programs for individuals following stroke. CONCLUSIONS: The efficacy of self-management programs in increasing physical activity levels in community-dwelling adults following acquired brain injury (ABI) is still unknown. Research into the efficacy of self-management programs specifically aimed at improving physical activity in adults living in the community following acquired brain injury is needed. The efficacy of remote delivery methods also warrants further investigation. SYSTEMATIC REVIEW REGISTRATION: PROSPERO CRD42013006748. PMID- 25927592 TI - Prevalence of K13-propeller polymorphisms in Plasmodium falciparum from China Myanmar border in 2007-2012. AB - BACKGROUND: The recent emergence and spread of artemisinin resistance in the Greater Mekong Subregion poses a great threat to malaria control and elimination. A K13-propeller gene (K13), PF3D7_1343700, has been associated lately with artemisinin resistance both in vitro and in vivo. This study aimed to investigate the K13 polymorphisms in Plasmodium falciparum parasites from the China-Myanmar border area where artemisinin use has the longest history. METHODS: A total of 180 archived P. falciparum isolates containing 191 parasite clones, mainly collected in 2007-2012 from the China-Myanmar area, were used to obtain the full length K13 gene sequences. RESULTS: Seventeen point mutations were identified in 46.1% (88/191) parasite clones, of which seven were new. The F446I mutation predominated in 27.2% of the parasite clones. The C580Y mutation that is correlated with artemisinin resistance was detected at a low frequency of 1.6%. Collectively, 43.1% of the parasite clones contained point mutations in the kelch domain of the K13 gene. Moreover, there was a trend of increase in the frequency of parasites carrying kelch domain mutations through the years of sample collection. In addition, a microsatellite variation in the N-terminus of the K13 protein was found to have reached a high frequency (69.1%). CONCLUSIONS: This study documented the presence of mutations in the K13 gene in parasite populations from the China-Myanmar border. Mutations present in the kelch domain have become prevalent (>40%). A predominant mutation F446I and a prevalent microsatellite variation in the N-terminus were identified, but their importance in artemisinin resistance remains to be elucidated. PMID- 25927593 TI - The Volume-Outcome Relationship in Critical Care: A Systematic Review and Meta analysis. AB - OBJECTIVE: The purpose of this study was to systematically review the research on volume and outcome relationships in critical care. METHODS: From January 1, 2001, to April 30, 2014, MEDLINE and EMBASE were searched for studies assessing the relationship between admission volume and clinical outcomes in critical illness. Bibliographies were reviewed to identify other articles of interest, and experts were contacted about missing or unpublished studies. Of 127 studies reviewed, 46 met inclusion criteria, covering seven clinical conditions. Two investigators independently reviewed each article using a standardized form to abstract information on key study characteristics and results. RESULTS: Overall, 29 of the studies (63%) reported a statistically significant association between higher admission volume and improved outcomes. The magnitude of the association (mortality OR between the lowest vs highest stratum of volume centers), as well as the thresholds used to characterize high volume, varied across clinical conditions. Critically ill patients with cardiovascular (n = 7, OR = 1.49 [1.11 2.00]), respiratory (n = 12, OR = 1.20 [1.04-1.38]), severe sepsis (n = 4, OR = 1.17 [1.03-1.33]), hepato-GI (n = 3, OR = 1.30 [1.08-1.78]), neurologic (n = 3, OR = 1.38 [1.22-1.57]), and postoperative admission diagnoses (n = 3, OR = 2.95 [1.05-8.30]) were more likely to benefit from admission to higher-volume centers compared with lower-volume centers. Studies that controlled for ICU or hospital organizational factors were less likely to find a significant volume-outcome relationship than studies that did not control for these factors. CONCLUSIONS: Critically ill patients generally benefit from care in high-volume centers, with more substantial benefits in selected high-risk conditions. This relationship may in part be mediated by specific ICU and hospital organizational factors. PMID- 25927594 TI - Recombinant B domain deleted porcine factor VIII for the treatment of bleeding episodes in adults with acquired hemophilia A. AB - Hemophilia A is an inherited deficiency of clotting factor VIII (FVIII) often complicated by inhibitor development (CHAWI) in which neutralizing antibodies block the therapeutic benefit of replacement therapy. Inhibitors to FVIII can also be seen in an auto-immune disease known as acquired hemophilia A (AHA). 'Bypassing' therapies have been shown to provide hemostasis but dosing must be done empirically because current assays cannot measure objective markers of treatment efficacy and safety. A recombinant porcine sequence factor VIII (r pFVIII) has been developed for the management of AHA. Preclinical, Phase I and Phase II clinical research studies in CHAWI subjects showed therapeutic potential and safety of this agent. A Phase II/III study in AHA with serious bleeding episodes shows a positive response in all subjects after administration. Based on current preclinical and clinical trial data, r-pFVIII should become the first line of treatment in the management of hemorrhage in patients with AHA. PMID- 25927595 TI - Mechanistic study of silver-catalyzed decarboxylative fluorination. AB - The silver-catalyzed fluorination of aliphatic carboxylic acids by Selectfluor in acetone/water provides access to fluorinated compounds under mild and straightforward reaction conditions. Although this reaction provides efficient access to fluorinated alkanes from a pool of starting materials that are ubiquitous in nature, little is known about the details of the reaction mechanism. We report spectroscopic and kinetic studies on the role of the individual reaction components in decarboxylative fluorination. The studies presented herein provide evidence that Ag(II) is the intermediate oxidant in the reaction. In the rate-limiting step of the reaction, Ag(I)-carboxylate is oxidized to Ag(II) by Selectfluor. Substrate inhibition of the process occurs through the formation of a silver-carboxylate. Water is critical for solubilizing reaction components and ligates to Ag(I) under the reaction conditions. The use of donor ligands on Ag(I) provides evidence of oxidation to Ag(II) by Selectfluor. The use of sodium persulfate as an additive in the reaction as well as NFSI as a fluorine source further supports the generation of a Ag(II) intermediate; this data will enable the development of a more efficient set of reaction conditions for the fluorination. PMID- 25927596 TI - Rapid Preparation of Released N-Glycans for HILIC Analysis Using a Labeling Reagent that Facilitates Sensitive Fluorescence and ESI-MS Detection. AB - N-glycosylation of proteins is now routinely characterized and monitored because of its significance to the detection of disease states and the manufacturing of biopharmaceuticals. At the same time, hydrophilic interaction chromatography (HILIC) has emerged as a powerful technology for N-glycan profiling. Sample preparation techniques for N-glycan HILIC analyses have however tended to be laborious or require compromises in sensitivity. To address these shortcomings, we have developed an N-glycan labeling reagent that provides enhanced fluorescence response and MS sensitivity for glycan detection and have also simplified the process of preparing a sample for analysis. The developed labeling reagent rapidly reacts with glycosylamines upon their release from glycoproteins. Within a 5 min reaction, enzymatically released N-glycans are labeled with this reagent comprised of an NHS-carbamate reactive group, a quinoline fluorophore, and a tertiary amine for enhancing ESI+ MS ionization. To further expedite the released N-glycan sample preparation, rapid tagging has been integrated with a fast PNGase F deglycosylation procedure that achieves complete deglycosylation of a diverse set of glycoproteins in approximately 10 min. Moreover, a technique for HILIC-SPE of the labeled glycans has been developed to provide quantitative recovery and facilitate immediate HILIC analysis of the prepared samples. The described approach makes it possible to quickly prepare N-glycan samples and to incorporate the use of a fluorescence and MS sensitivity enhancing labeling reagent. In demonstration of these new capabilities, we have combined the developed sample preparation techniques with UHPLC HILIC chromatography and high sensitivity mass spectrometry to thoroughly detail the N-glycan profile of a monoclonal antibody. PMID- 25927597 TI - Effect of Sodium-Glucose Cotransport Inhibition on Polycystic Kidney Disease Progression in PCK Rats. AB - The sodium-glucose-cotransporter-2 (SGLT2) inhibitor dapagliflozin (DAPA) induces glucosuria and osmotic diuresis via inhibition of renal glucose reabsorption. Since increased diuresis retards the progression of polycystic kidney disease (PKD), we investigated the effect of DAPA in the PCK rat model of PKD. DAPA (10 mg/kg/d) or vehicle was administered by gavage to 6 week old male PCK rats (n=9 per group). Renal function, albuminuria, kidney weight and cyst volume were assessed after 6 weeks of treatment. Treatment with DAPA markedly increased glucose excretion (23.6 +/- 4.3 vs 0.3 +/- 0.1 mmol/d) and urine output (57.3 +/- 6.8 vs 19.3 +/- 0.8 ml/d). DAPA-treated PCK rats had higher clearances for creatinine (3.1 +/- 0.1 vs 2.6 +/- 0.2 ml/min) and BUN (1.7 +/- 0.1 vs 1.2 +/- 0.1 ml/min) after 3 weeks, and developed a 4-fold increase in albuminuria. Ultrasound imaging and histological analysis revealed a higher cyst volume and a 23% higher total kidney weight after 6 weeks of DAPA treatment. At week 6 the renal cAMP content was similar between DAPA and vehicle, and staining for Ki67 did not reveal an increase in cell proliferation. In conclusion, the inhibition of glucose reabsorption with the SGLT2-specific inhibitor DAPA caused osmotic diuresis, hyperfiltration, albuminuria and an increase in cyst volume in PCK rats. The mechanisms which link glucosuria to hyperfiltration, albuminuria and enhanced cyst volume in PCK rats remain to be elucidated. PMID- 25927599 TI - SOD3 Variant, R213G, Altered SOD3 Function, Leading to ROS-Mediated Inflammation and Damage in Multiple Organs of Premature Aging Mice. AB - AIMS: Among the isoforms of superoxide dismutase, SOD3 is uniquely associated with the extracellular matrix (ECM) by virtue of its heparin-binding domain (HBD). Substitution of arginine by glycine at amino acid 213 (R213G) of its HBD was first identified in patients with heart failure, followed by many studies that focused on the role of this variant (SOD3(R213G)) in ischemic heart disease and cardiovascular disease. However, the biological significance of this mutation in a physiological context is largely unknown. RESULTS: As a first step, we generated SOD3(R213G) transgenic mice, in which the variant gene was driven by the beta-actin promoter allowing expression in all tissues. Unexpectedly, we found that SOD3(R213G) transgenic mice exhibited premature aging, including hair graying, abnormal gait, and a shortened life span. Specifically, the aged mice showed systemic inflammation and organ degeneration. In addition, aged SOD3(R213G) mice are susceptible to neutrophil-mediated inflammation. Among other functions, the neutrophils of SOD3(R213G) mice produce high amounts of reactive oxygen species, which would normally be controlled by SOD3 in ECM. INNOVATION: These findings showed for the first time that arginine 213 in the HBD of SOD3 is critical for maintaining proper organ function through moderating the normal innate immune response, which would otherwise lead to chronic inflammation and degenerative diseases in aged mice. CONCLUSION: Therefore, patients with this variant may be treated with SOD3 as a therapeutic strategy to prevent or cure these diseases. PMID- 25927598 TI - Autophagy and apoptosis in liver injury. AB - Apoptosis is a primary characteristic in the pathogenesis of liver disease. Hepatic apoptosis is regulated by autophagic activity. However, mechanisms mediating their interaction remain to be determined. Basal level of autophagy ensures the physiological turnover of old and damaged organelles. Autophagy also is an adaptive response under stressful conditions. Autophagy can control cell fate through different cross-talk signals. A complex interplay between hepatic autophagy and apoptosis determines the degree of hepatic apoptosis and the progression of liver disease as demonstrated by pre-clinical models and clinical trials. This review summarizes recent advances on roles of autophagy that plays in pathophysiology of liver. The autophagic pathway can be a novel therapeutic target for liver disease. PMID- 25927600 TI - Lipophilic triphenylphosphonium cations inhibit mitochondrial electron transport chain and induce mitochondrial proton leak. AB - BACKGROUND: The lipophilic positively charged moiety of triphenylphosphonium (TPP+) has been used to target a range of biologically active compounds including antioxidants, spin-traps and other probes into mitochondria. The moiety itself, while often considered biologically inert, appears to influence mitochondrial metabolism. METHODOLOGY/PRINCIPAL FINDINGS: We used the Seahorse XF flux analyzer to measure the effect of a range of alkylTPP+ on cellular respiration and further analyzed their effect on mitochondrial membrane potential and the activity of respiratory complexes. We found that the ability of alkylTPP+ to inhibit the respiratory chain and decrease the mitochondrial membrane potential increases with the length of the alkyl chain suggesting that hydrophobicity is an important determinant of toxicity. CONCLUSIONS/SIGNIFICANCE: More hydrophobic TPP+ derivatives can be expected to have a negative impact on mitochondrial membrane potential and respiratory chain activity in addition to the effect of the biologically active moiety attached to them. Using shorter linker chains or adding hydrophilic functional groups may provide a means to decrease this negative effect. PMID- 25927601 TI - Preclinical discovery and development of maraviroc for the treatment of HIV. AB - INTRODUCTION: Maraviroc is a first-in-class antiretroviral (ARV) drug acting on a host cell target (CCR5), which blocks the entry of the HIV virus into the cell. Maraviroc is currently indicated for combination ARV treatment in adults infected only with CCR5-tropic HIV-1. AREAS COVERED: This drug discovery case history focuses on the key studies that led to the discovery and approval of maraviroc, as well as on post-launch clinical reports. The article is based on the data reported in published preclinical and clinical studies, conference posters and on drug package data. EXPERT OPINION: The profound understanding of HIV's entry mechanisms has provided a strong biological rationale for targeting the chemokine receptor CCR5. The CCR5-antagonist mariviroc, with its unique mode of action and excellent safety profile, is an important therapeutic option for HIV patients. In general, the authors believe that targeting host factors is a useful approach for combating new and re-emerging transmissible diseases, as well as pathogens that easily become resistant to common antiviral drugs. Maraviroc, offering a potent and safe cellular receptor-mediated pharmacological response to HIV, has paved the way for the development of a new generation of host-targeting antivirals. PMID- 25927602 TI - A case of Norman-Roberts syndrome identified from postnatal diagnosis of microlissencephaly. AB - Lissencephaly is a rare brain malformation. What differentiates microlissencephaly from classical lissencephaly and other variants is the presence of severe microcephaly. Very few postnatal cases of Norman-Roberts syndrome are described in the literature. We report a case of microlissencephaly with a polymalformative syndrome that prompted postnatal diagnosis of Norman Roberts syndrome. PMID- 25927603 TI - The Receptor CMRF35-Like Molecule-1 (CLM-1) Enhances the Production of LPS Induced Pro-Inflammatory Mediators during Microglial Activation. AB - CMRF35-like molecule-1 (CLM-1) belongs to a receptor family mainly expressed in myeloid cells that include activating and inhibitory receptors. CLM-1 contains two ITIMs and a single immunoreceptor tyrosine-based switch motif (ITSM), although also displays a binding site for p85alpha regulatory subunit of PI3K. By using murine primary microglial cultures, we show the presence of all CLM members in microglial cells and characterize the expression of CLM-1 both in basal conditions and during microglial activation. The TLR4 agonist lipopolysaccharide (LPS) and the TLR3 agonist polyinosinic-polycytidylic acid (Poly I:C) induce an increase in microglial CLM-1 mRNA levels in vitro, whereas the TLR2/6 heterodimer agonist peptidoglycan (PGN) produces a marked decrease. In this study we also describe a new soluble isoform of CLM-1 that is detected at mRNA and protein levels in basal conditions in primary microglial cultures. Interestingly, CLM-1 engagement enhances the transcription of the pro-inflammatory mediators TNFalpha, COX-2 and NOS-2 in microglial cells challenged with LPS. These results reveal that CLM-1 can acts as a co-activating receptor and suggest that this receptor could play a key role in the regulation of microglial activation. PMID- 25927604 TI - Getting research to the policy table: a qualitative study with public health researchers on engaging with policy makers. AB - INTRODUCTION: Little attention has been given to how researchers can best provide evidence to policy makers so that it informs policy making. The objectives of this study were to increase understanding about the current state of public health nutrition and obesity researcher practices, beliefs, barriers, and facilitators to communicating and engaging with policy makers, and to identify best practices and suggest improvements. METHODS: Eighteen semistructured interviews were conducted from 2011 to 2013 with public health nutrition and obesity researchers who were highly involved in communicating research to policy makers. Interviews were transcribed verbatim, coded, and analyzed to identify common themes. RESULTS: Study participants described wide variation in practices for communicating and engaging with policy makers and had mixed beliefs about whether and when researchers should engage. Besides a lack of formal policy communication training, barriers noted were promotion and tenure processes and a professional culture that does not value communicating and engaging with policy makers. Study participants cited facilitators to engaging with policy makers as ranging from the individual level (eg, desire to make a difference, relationships with collaborators) to the institutional level (eg, training/mentorship support, institutional recognition). Other facilitators identified were research- and funding-driven. Promising strategies suggested to improve policy engagement were more formal training, better use of intermediaries, and learning how to cultivate relationships with policy makers. CONCLUSION: Study findings provide insights into the challenges that will need to be overcome and the strategies that might be tried to improve communication and engagement between public health researchers and policy makers. PMID- 25927605 TI - Nutrition-related policy and environmental strategies to prevent obesity in rural communities: a systematic review of the literature, 2002-2013. AB - INTRODUCTION: Residents of rural communities in the United States are at higher risk for obesity than their urban and suburban counterparts. Policy and environmental-change strategies supporting healthier dietary intake can prevent obesity and promote health equity. Evidence in support of these strategies is based largely on urban and suburban studies; little is known about use of these strategies in rural communities. The purpose of this review was to synthesize available evidence on the adaptation, implementation, and effectiveness of policy and environmental obesity-prevention strategies in rural settings. METHODS: The review was guided by a list of Centers for Disease Control and Prevention Recommended Community Strategies and Measurements to Prevent Obesity in the United States, commonly known as the "COCOMO" strategies. We searched PubMed, Cumulative Index of Nursing and Allied Health Literature, Public Affairs Information Service, and Cochrane databases for articles published from 2002 through 2013 that reported findings from research on nutrition-related policy and environmental strategies in rural communities in the United States and Canada. Two researchers independently abstracted data from each article, and resolved discrepancies by consensus. RESULTS: Of the 663 articles retrieved, 33 met inclusion criteria. The interventions most commonly focused on increasing access to more nutritious foods and beverages or decreasing access to less nutritious options. Rural adaptations included accommodating distance to food sources, tailoring to local food cultures, and building community partnerships. CONCLUSIONS: Findings from this literature review provide guidance on adapting and implementing policy and environmental strategies in rural communities. PMID- 25927606 TI - Developing local board of health guidelines to promote healthy food access - King County, Washington, 2010-2012. AB - Policies that change environments are important tools for preventing chronic diseases, including obesity. Boards of health often have authority to adopt such policies, but few do so. This study assesses 1) how one local board of health developed a policy approach for healthy food access through vending machine guidelines (rather than regulations) and 2) the impact of the approach. Using a case study design guided by "three streams" policy theory and RE-AIM, we analyzed data from a focus group, interviews, and policy documents. The guidelines effectively supported institutional policy development in several settings. Recognition of the problem of chronic disease and the policy solution of vending machine guidelines created an opening for the board to influence nutrition environments. Institutions identified a need for support in adopting vending machine policies. Communities could benefit from the study board's approach to using nonregulatory evidence-based guidelines as a policy tool. PMID- 25927607 TI - Elevating the impact of nutrition and obesity policy research and evaluation. PMID- 25927608 TI - Streptococcus pneumoniae GAPDH Is Released by Cell Lysis and Interacts with Peptidoglycan. AB - Release of conserved cytoplasmic proteins is widely spread among Gram-positive and Gram-negative bacteria. Because these proteins display additional functions when located at the bacterial surface, they have been qualified as moonlighting proteins. The GAPDH is a glycolytic enzyme which plays an important role in the virulence processes of pathogenic microorganisms like bacterial invasion and host immune system modulation. However, GAPDH, like other moonlighting proteins, cannot be secreted through active secretion systems since they do not contain an N-terminal predicted signal peptide. In this work, we investigated the mechanism of GAPDH export and surface retention in Streptococcus pneumoniae, a major human pathogen. We addressed the role of the major autolysin LytA in the delivery process of GAPDH to the cell surface. Pneumococcal lysis is abolished in the DeltalytA mutant strain or when 1% choline chloride is added in the culture media. We showed that these conditions induce a marked reduction in the amount of surface-associated GAPDH. These data suggest that the presence of GAPDH at the surface of pneumococcal cells depends on the LytA-mediated lysis of a fraction of the cell population. Moreover, we demonstrated that pneumococcal GAPDH binds to the bacterial cell wall independently of the presence of the teichoic acids component, supporting peptidoglycan as a ligand to surface GAPDH. Finally, we showed that peptidoglycan-associated GAPDH recruits C1q from human serum but does not activate the complement pathway. PMID- 25927609 TI - Temperature Impacts the Development and Survival of Common Cutworm (Spodoptera litura): Simulation and Visualization of Potential Population Growth in India under Warmer Temperatures through Life Cycle Modelling and Spatial Mapping. AB - The common cutworm, Spodoptera litura, has become a major pest of soybean (Glycine max) throughout its Indian range. With a changing climate, there is the potential for this insect to become an increasingly severe pest in certain regions due to increased habitat suitability. To examine this possibility, we developed temperature-based phenology model for S. litura, by constructing thermal reaction norms for cohorts of single life stages, at both constant and fluctuating temperatures within the ecologically relevant range (15-38 degrees C) for its development. Life table parameters were estimated stochastically using cohort updating and rate summation approach. The model was implemented in the geographic information system to examine the potential future pest status of S. litura using temperature change projections from SRES A1B climate change scenario for the year 2050. The changes were visualized by means of three spatial indices demonstrating the risks for establishment, number of generations per year and pest abundance according to the temperature conditions. The results revealed that the development rate as a function of temperature increased linearly for all the immature stages of S. litura until approximately 34-36 degrees C, after which it became non-linear. The extreme temperature of 38 degrees C was found lethal to larval and pupal stages of S. litura wherein no development to the next stage occurred. Females could lay no eggs at the extreme low (15 degrees C) and high (> 35 degrees C) test temperatures, demonstrating the importance of optimum temperature in determining the suitability of climate for the mating and reproduction in S. litura. The risk mapping predicts that due to temperature increase under future climate change, much of the soybean areas in Indian states like Madhya Pradesh, Maharashtra and Rajasthan, will become suitable for S. litura establishment and increased pest activity, indicating the expansion of the suitable and favourable areas over time. This has serious implication in terms of soybean production since these areas produce approximately 95% of the total soybeans in India. As the present model results are based on temperature only, and the effects of other abiotic and biotic factors determining the pest population dynamics were excluded, it presents only the potential population growth parameters for S. litura. However, if combined with the field observations, the model results could certainly contribute to gaining insight into the field dynamics of S. litura. PMID- 25927610 TI - Long distance transport of irradiated male Glossina palpalis gambiensis pupae and its impact on sterile male yield. AB - BACKGROUND: The application of the sterile insect technique (SIT) requires mass production of sterile males of good biological quality. The size of the project area will in most cases determine whether it is more cost effective to produce the sterile flies locally (and invest in a mass-rearing facility) or import the sterile flies from a mass-rearing facility that is located in another country. This study aimed at assessing the effect of long distance transport of sterile male Glossina palpalis gambiensis pupae on adult male fly yield. METHODS: The male pupae were produced at the Centre International de Recherche-Developpement sur l'Elevage en zone Subhumide (CIRDES), Bobo-Dioulasso, Burkina Faso, and shipped with a commercial courier service in insulated transport boxes at a temperature of +/-10 degrees C to Senegal (+/-36 h of transport). Upon arrival in the insectary in Dakar, the pupae were transferred to an emergence room and the flies monitored for 3-6 days. RESULTS: The results showed that the used system of isothermal boxes that contained phase change material packs (S8) managed to keep the temperature at around 10 degrees C which prevented male fly emergence during transport. The emergence rate was significantly higher for pupae from batch 2 (chilled at 4 degrees C for one day in the source insectary before transport) than those from batch 1 (chilled at 4 degrees C for two days in the source insectary before transport) i.e. an average (+/-sd) of 76.1 +/- 13.2% and 72.2 +/ 14.3%, respectively with a small proportion emerging during transport (0.7 +/- 1.7% and 0.9 +/- 2.9%, respectively). Among the emerged flies, the percentage with deformed (not fully expanded) wings was significantly higher for flies from batch 1 (12.0 +/- 6.3%) than from batch 2 (10.7 +/- 7.5%). The amount of sterile males available for release as a proportion of the total pupae shipped was 65.8 +/- 13.3% and 61.7 +/- 14.7% for batch 1 and 2 pupae, respectively. CONCLUSIONS: The results also showed that the temperature inside the parcel must be controlled around 10 degrees C with a maximal deviation of 3 degrees C to maximize the male yield. PMID- 25927611 TI - Modulation of bleomycin-induced lung fibrosis by pegylated hyaluronidase and dopamine receptor antagonist in mice. AB - Hyaluronidases are groups of enzymes that degrade hyaluronic acid (HA). To stop enzymatic hydrolysis we modified testicular hyaluronidase (HYAL) by activated polyethylene oxide with the help of electron-beam synthesis. As a result we received pegylated hyaluronidase (pegHYAL). Spiperone is a selective D2 dopamine receptor antagonist. It was demonstrated on the model of a single bleomycin damage of alveolar epithelium that during the inflammatory phase monotherapy by pegHYAL or spiperone reduced the populations of hematopoietic stem /progenitor cells in the lung parenchyma. PegHYAL also reduced the levels of transforming growth factor (TGF)-beta, interleukin (IL)-1beta, tumor necrosis factor (TNF) alpha in the serum and lungs, while spiperone reduced the level of the serum IL 1beta. Polytherapy by spiperone and pegHYAL caused the increase of the quantity of hematopoietic stem/ progenitor cells in the lungs. Such an influx of blood cell precursors was observed on the background of considerable fall level of TGF beta and the increase level of TNF-alpha in the serum and lungs. These results show pegHYAL reduced the bleomycin-induced fibrosis reaction (production and accumulation of collagen) in the lung parenchyma. This effect was observed at a single and repetitive bleomycin damage of alveolar epithelium, the antifibrotic activity of pegHYAL surpassing the activity of testicular HYAL. The antifibrotic effect of pegHYAL is enhanced by an additional instillation of spiperone. Therapy by pegHYAL causes the flow of CD31- CD34- CD45- CD44+ CD73+ CD90+ CD106+-cells into the fibrous lungs. These cells are incapable of differentiating into fibroblast cells. Spiperone instillation separately or together with pegHYAL reduced the MSC-like cells considerably. These data enable us to assume, that pegHYAL is a new and promising instrument both for preventive and therapy of toxic pneumofibrosis. The blockage of D2 dopamine receptors with the following change of hyaluronan matrix can be considered as a new strategy in treatment of pneumofibrosis. PMID- 25927612 TI - Typing of Mycobacterium avium subspecies paratuberculosis isolates from Newfoundland using fragment analysis. AB - Short Sequence Repeat (SSR) typing of Mycobacterium avium subspecies paratuberculosis (Map) isolates is one of the most commonly used method for genotyping this pathogen. Currently used techniques have challenges in analyzing mononucleotide repeats >15 bp, which include some of the Map SSRs. Fragment analysis is a relatively simple technique, which can accurately measure the size of DNA fragments and can be used to calculate the repeat length of the target SSR loci. In the present study, fragment analysis was used to analyze 4 Map SSR loci known to provide sufficient discriminatory power to determine the relationship between Map isolates. Eighty-five Map isolates from 18 animals from the island of Newfoundland were successfully genotyped using fragment analysis. To the best of our knowledge, this is the first report on Map SSR diversity from Newfoundland dairy farms. Previously unreported Map SSR-types or combinations were also identified during the course of the described work. In addition, multiple Map SSR types were isolated from a single animal in many cases, which is not a common finding. PMID- 25927620 TI - Comparative phylogeography of the plateau zokor (Eospalax baileyi) and its host associated flea (Neopsylla paranoma) in the Qinghai-Tibet Plateau. AB - BACKGROUND: Specific host-parasite systems often embody a particular co distribution phenomenon, in which the parasite's phylogeographic pattern is dependent on its host. In practice, however, both congruent and incongruent phylogeographic patterns between the host and the parasite have been reported. Here, we compared the population genetics of the plateau zokor (Eospalax baileyi), a subterranean rodent, and its host-associated flea species, Neopsylla paranoma, with an aim to determine whether the two animals share a similar phylogeographic pattern. RESULTS: We sampled 130 host-parasite pairs from 17 localities in the Qinghai-Tibet Plateau (QTP), China, and sequenced a mitochondrial DNA (mtDNA) segment (~2,500 bp), including the complete COI and COII genes. We also detected 55 zokor and 75 flea haplotypes. AMOVA showed that the percentage of variation among the populations of zokors constituted 97.10%, while the within population variation was only 2.90%; for fleas, the values were 85.68% and 14.32%, respectively. Moreover, the flea Fst (fixation index) values were significantly smaller than in zokor. Although the Fst values between zokors and fleas were significantly and positively correlated (N=105, R=0.439, p=0.000), only a small amount (R2=0.19) of the flea Fst variations could be explained by the zokor Fst variations. The two animals showed very distinct haplotype network structures from each other while co-phylogenetic analyses were unable to reject the hypothesis of an independence of speciation events. CONCLUSIONS: Zokors and fleas have very distinct population genetic patterns from each other, likely due to the influence of other sympatrically-distributed vertebrates on the transmission of fleas. PMID- 25927621 TI - Photoemission study of the electronic structure and charge density waves of Na2Ti2Sb2O. AB - The electronic structure of Na2Ti2Sb2O single crystal is studied by photon energy and polarization dependent angle-resolved photoemission spectroscopy (ARPES). The obtained band structure and Fermi surface agree well with the band structure calculation of Na2Ti2Sb2O in the non-magnetic state, which indicates that there is no magnetic order in Na2Ti2Sb2O and the electronic correlation is weak. Polarization dependent ARPES results suggest the multi-band and multi-orbital nature of Na2Ti2Sb2O. Photon energy dependent ARPES results suggest that the electronic structure of Na2Ti2Sb2O is rather two-dimensional. Moreover, we find a density wave energy gap forms below the transition temperature and reaches 65 meV at 7 K, indicating that Na2Ti2Sb2O is likely a weakly correlated CDW material in the strong electron-phonon interaction regime. PMID- 25927623 TI - The low coordination number of nitrogen in hard tungsten nitrides: a first principles study. AB - Tungsten-nitrogen (W-N) compounds are studied via a combination of first principles calculations and variable-composition evolutionary structure searches. New candidate ground states and high-pressure phases at 3 : 2, 1 : 1, and 5 : 6 compositions are uncovered and established for possible synthesis. We found that the structures in 4/5-fold N coordination (i.e., NbO-WN and W5N6) are more favoured for the W-N system at low-pressures compared with the conventional 6 fold phases (rs-WN and delta-WN). We attribute the low N coordination feature of W-N ground states to the enhanced W 5d-N 2p orbital hybridization and strong covalent W-N bonding, which involves the full-filling of W-N bonding and antibonding states and can remarkably improve the mechanical strength and hardness. These findings not only clarify the phase diagram of the W-N system, but also shed light on the correlations of hardness with microscopic crystal and electronic structures. PMID- 25927615 TI - A model for presenting accelerometer paradata in large studies: ISCOLE. AB - BACKGROUND: We present a model for reporting accelerometer paradata (process related data produced from survey administration) collected in the International Study of Childhood Obesity Lifestyle and the Environment (ISCOLE), a multi national investigation of >7000 children (averaging 10.5 years of age) sampled from 12 different developed and developing countries and five continents. METHODS: ISCOLE employed a 24-hr waist worn 7-day protocol using the ActiGraph GT3X+. Checklists, flow charts, and systematic data queries documented accelerometer paradata from enrollment to data collection and treatment. Paradata included counts of consented and eligible participants, accelerometers distributed for initial and additional monitoring (site specific decisions in the face of initial monitoring failure), inadequate data (e.g., lost/malfunction, insufficient wear time), and averages for waking wear time, valid days of data, participants with valid data (>=4 valid days of data, including 1 weekend day), and minutes with implausibly high values (>=20,000 activity counts/min). RESULTS: Of 7806 consented participants, 7372 were deemed eligible to participate, 7314 accelerometers were distributed for initial monitoring and another 106 for additional monitoring. 414 accelerometer data files were inadequate (primarily due to insufficient wear time). Only 29 accelerometers were lost during the implementation of ISCOLE worldwide. The final locked data file consisted of 6553 participant files (90.0% relative to number of participants who completed monitoring) with valid waking wear time, averaging 6.5 valid days and 888.4 minutes/day (14.8 hours). We documented 4762 minutes with implausibly high activity count values from 695 unique participants (9.4% of eligible participants and <0.01% of all minutes). CONCLUSIONS: Detailed accelerometer paradata is useful for standardizing communication, facilitating study management, improving the representative qualities of surveys, tracking study endpoint attainment, comparing studies, and ultimately anticipating and controlling costs. TRIAL REGISTRATION: ClinicalTrials.gov: NCT01722500. PMID- 25927622 TI - Baclofen as relapse prevention in the treatment of Gamma- Hydroxybutyrate (GHB) dependence: an open label study. AB - BACKGROUND: GHB dependence is a growing health problem in several western countries, especially the Netherlands. Attempts to stop using GHB are often followed by relapse shortly after successful detoxification. Craving for GHB use and co-morbid psychiatric symptom levels are thought to be the major factors contributing to the high relapse rates. Given its pharmacological profile, baclofen might prove an effective anti-craving agent for patients with GHB dependence. The aim of the current study is to assess the potential of baclofen as an anti-craving agent relapse prevention intervention in GHB dependent patients. METHODS/DESIGN: In an open label non-randomized trial treatment with baclofen to a maximum of 60 mg/day will be compared with treatment as usual (TAU) in recently detoxified GHB dependent patients (n = 80). The primary outcome measure will be the level of GHB use. Secondary outcome measures are craving levels, psychiatric symptom levels and quality of life. Questionnaires will be administered during 12 weeks of baclofen treatment and at follow-up (six months after the start of treatment). DISCUSSION: It is hypothesized that baclofen treatment compared to TAU will be associated with significantly reduced GHB use. In addition, we hypothesize that baclofen treatment will be associated with decreased craving and anxiety levels, and higher quality of life. If results are in line with our hypotheses, further studies on the efficacy of baclofen using placebo controlled designs and long term follow-up are warranted. TRIAL REGISTRATION: The Netherlands Trial Register with number NTR4528 . Registered 19 April 2014. PMID- 25927625 TI - Comparative studies on the inhibitory activities of selected benzoic acid derivatives against secretory phospholipase A2, a key enzyme involved in the inflammatory pathway. AB - Inflammation is considered to be a key factor in major diseases like cancer, Alzheimer's disease, Parkinson's disease, etc. For the past few decades, pharmaceutical companies have explored new effective medications against inflammation. As a part of their detailed studies, many drug targets and drugs have been introduced against inflammation. In the present study, the inhibiting capacities of selected benzoic acid derivatives like gallic acid, vannilic acid, syringic acid and protocatechuic acid against secretory phospholipase A2 (sPLA2), a major enzyme involved in the inflammatory pathway, have been investigated. The detailed in vitro, biophysical and in silico studies carried out on these benzoic acid derivatives revealed that all the selected compounds have a uniform mode of binding in the active site of sPLA2 and are inhibitory in micromolar concentrations. The study also focuses on the non-selective inhibitory activity of an NSAID, aspirin, against sPLA2. PMID- 25927626 TI - Weight bearing or non-weight bearing after surgically fixed ankle fractures, the WOW! Study: study protocol for a randomized controlled trial. AB - BACKGROUND: The optimal post-operative care regimen after surgically fixed Lauge Hansen supination exorotation injuries remains to be established. This study compares whether unprotected weight bearing as tolerated is superior to protected weight bearing and unprotected non-weight bearing in terms of functional outcome and safety. METHODS/DESIGN: The WOW! Study is a prospective multicenter clinical trial. Patients between 18 and 65 years of age with a Lauge Hansen supination exorotation type 2, 3 or 4 ankle fractures requiring surgical treatment are eligible for inclusion. An expert panel validates the classification and inclusion eligibility. After surgery, patients are randomized to either the 1) unprotected non-weight-bearing, 2) protected weight-bearing, or 3) unprotected weight-bearing group. The primary outcome measure is ankle-specific disability measured by the Olerud-Molander ankle score. Secondary outcomes are 1) quality of life (e.g., return to work and resumption of sport), 2) complications, 3) range of motion, 4) calf wasting, and 5) maximum pressure load after 3 months and 1 year. DISCUSSION: This trial is designed to compare the effectiveness and safety of unprotected weight bearing with two commonly used post-operative treatment regimens after internal fixation of specified, intrinsically stable but displaced ankle fractures. An expert panel has been established to evaluate every potential subject, which ensures that every patient is strictly screened according to the inclusion and exclusion criteria and that there is a clear indication for surgical fixation. TRIAL REGISTRATION: The WOW! Study is registered in the Dutch Trial Register ( NTR3727 ). Date of registration: 28-11-2012. PMID- 25927631 TI - Update in hematology: evidence published in 2014. PMID- 25927630 TI - Impact of PTBP1 rs11085226 on glucose-stimulated insulin release in adult Danes. AB - BACKGROUND: The variant rs11085226 (G) within the gene encoding polypyrimidine tract binding protein 1 (PTBP1) was reported to associate with reduced insulin release determined by an oral glucose tolerance test (OGTT) as well as an intravenous glucose tolerance test (IVGTT). The aim of the present study was to validate the association of the rs11085226 G-allele of PTBP1 with previously investigated OGTT- and IVGTT-derived diabetes-related metabolic quantitative phenotypes, to conduct exploratory analyses of additional measures of beta-cell function, and to further investigate a potential association with type 2 diabetes. METHODS: PTBP1 rs11085226 was genotyped in 20,911 individuals of Danish Caucasian ethnicity ascertained from 9 study samples. Case control analysis was performed on 5,634 type 2 diabetic patients and 11,319 individuals having a normal fasting glucose level as well as 4,641 glucose tolerant controls, respectively. Quantitative trait analyses were performed in up to 13,605 individuals subjected to an OGTT or blood samples obtained after an overnight fast, as well as in 596 individuals subjected to an IVGTT. RESULTS: Analyses of fasting and OGTT-derived quantitative traits did not show any significant associations with the PTBP1 rs11085226 variant. Meta-analysis of IVGTT-derived quantitative traits showed a nominally significant association between the variant and reduced beta-cell responsiveness to glucose (beta = -0.1 mmol . kg( 1) . min(-1); 95% CI: -0.200.20 - -0.024; P = 0.01) assuming a dominant model of inheritance, but failed to replicate a previously reported association with area under the curve (AUC) for insulin. Case control analysis did not show an association of the PTBP1 rs11085226 variant with type 2 diabetes. CONCLUSIONS: Despite failure to replicate the previously reported associations of PTBP1 rs11085226 with OGTT- and IVGTT-derived measures of beta-cell function, we did find a nominally significant association with reduced beta-cell responsiveness to glucose during an IVGTT, a trait not previously investigated, leaving the potential influence of this variant in PTBP1 on glucose stimulated insulin release open for further investigation. However, the present study does not support the hypothesis that the variant confers risk of type 2 diabetes. PMID- 25927636 TI - 'Real-world' health care priority setting using explicit decision criteria: a systematic review of the literature. AB - BACKGROUND: Health care decision making requires making resource allocation decisions among programs, services, and technologies that all compete for a finite resource pool. Methods of priority setting that use explicitly defined criteria can aid health care decision makers in arriving at funding decisions in a transparent and systematic way. The purpose of this paper is to review the published literature and examine the use of criteria-based methods in 'real world' health care allocation decisions. METHODS: A systematic review of the published literature was conducted to find examples of 'real-world' priority setting exercises that used explicit criteria to guide decision-making. RESULTS: We found thirty-three examples in the peer-reviewed and grey literature, using a variety of methods and criteria. Program effectiveness, equity, affordability, cost-effectiveness, and the number of beneficiaries emerged as the most frequently-used decision criteria. The relative importance of criteria in the 'real-world' trials differed from the frequency in preference elicitation exercises. Neither the decision-making method used, nor the relative economic strength of the country in which the exercise took place, appeared to have a strong effect on the type of criteria chosen. CONCLUSIONS: Health care decisions are made based on criteria related both to the health need of the population and the organizational context of the decision. Following issues related to effectiveness and affordability, ethical issues such as equity and accessibility are commonly identified as important criteria in health care resource allocation decisions. PMID- 25927638 TI - Imputation of sequence level genotypes in the Franches-Montagnes horse breed. AB - BACKGROUND: A cost-effective strategy to increase the density of available markers within a population is to sequence a small proportion of the population and impute whole-genome sequence data for the remaining population. Increased densities of typed markers are advantageous for genome-wide association studies (GWAS) and genomic predictions. METHODS: We obtained genotypes for 54 602 SNPs (single nucleotide polymorphisms) in 1077 Franches-Montagnes (FM) horses and Illumina paired-end whole-genome sequencing data for 30 FM horses and 14 Warmblood horses. After variant calling, the sequence-derived SNP genotypes (~13 million SNPs) were used for genotype imputation with the software programs Beagle, Impute2 and FImpute. RESULTS: The mean imputation accuracy of FM horses using Impute2 was 92.0%. Imputation accuracy using Beagle and FImpute was 74.3% and 77.2%, respectively. In addition, for Impute2 we determined the imputation accuracy of all individual horses in the validation population, which ranged from 85.7% to 99.8%. The subsequent inclusion of Warmblood sequence data further increased the correlation between true and imputed genotypes for most horses, especially for horses with a high level of admixture. The final imputation accuracy of the horses ranged from 91.2% to 99.5%. CONCLUSIONS: Using Impute2, the imputation accuracy was higher than 91% for all horses in the validation population, which indicates that direct imputation of 50k SNP-chip data to sequence level genotypes is feasible in the FM population. The individual imputation accuracy depended mainly on the applied software and the level of admixture. PMID- 25927639 TI - Identifiable biomarker and treatment development using HIV-1 long term non progressor sera. AB - BACKGROUND: HIV-infected long-term non-progressor (LTNP) subjects can prevent viral replication and may harbor useful information for the development of both antibody and active vaccination treatments. In this study we used LTNP sera to examine the epitopes presented to the gp160 protein, and from this procedure we hope to elucidate potential biomarkers pertaining to the level of resistance a patient may have in developing AIDS after infection with HIV. We used five clinical sera samples from LTNP patients to identify common epitopes by ELISA; peptides with high binding to sera were selected and analyzed for conservation among HIV clades. Antibodies were generated against one identified epitope using a chimeric peptide in BALB/c mice, and both the sera from these mice and LTNP sera were tested for viral inhibition capabilities. RESULTS: A monoclonal antibody, CL3, against one identified epitope was used to compare these epitopes neutralizing capability. LTNP sera was also studied to determine chemokine/cytokine changes in these patients. The sera from LTNP patients 2, 3, 4, and 5 were identified as having the highest titers, and also significantly inhibited syncytia formation in vitro. Finally, the protein cytokine array demonstrated that I-309 and IGFBP-1 decreased in LTNPs, but levels of TIMP-1 and NAP-2 increased significantly. CONCLUSIONS: Our results indicate that the use of LTNP samples may be a useful for identifying further anti-viral epitopes, and may be a possible predictor for determining if patients show higher resistances of converting the HIV infection to AIDS. PMID- 25927641 TI - The influence of cholinesterase inhibitor therapy for dementia on risk of cardiac pacemaker insertion: a retrospective, population-based, health administrative databases study in Ontario, Canada. AB - BACKGROUND: Cholinesterase inhibitors are used to treat the symptoms of dementia and can theoretically cause bradycardia. Previous studies suggest that patients taking these medications have an increased risk of undergoing pacemaker insertion. Since these drugs have a marginal impact on patient outcomes, it might be preferable to change drug treatment rather than implant a pacemaker. This population-based study determined the association of people with dementia exposed to cholinesterase inhibitor medication and pacemaker insertion. METHODS: We used data from the Ontario health administrative databases from January 1, 1993 to June 30, 2012. We included all community-dwelling seniors who had a code for dementia and were exposed to cholinesterase inhibitors (donezepil, galantamine, and rivastigmine) and/or drugs used to treat co-morbidities of hypertension, diabetes, depression and hypothyroidism. We controlled for exposure to anti arrhythmic drugs. Observation started at first exposure to any medication and continued until the earliest of pacemaker insertion, death, or end of study. RESULTS: 2,353,909 people were included with 96,000 (4.1%) undergoing pacemaker insertion during the observation period. Case-control analysis showed that pacemaker patients were less likely to be coded with dementia (unadjusted OR 0.42 [95%CI 0.41-0.42]) or exposed to cholinesterase inhibitors (unadjusted OR 0.39 [95%CI 0.37-0.41]). That Cohort analysis showed patients with dementia taking cholinesterase inhibitors had a decreased risk of pacemaker insertion (unadj-HR 0.58 [0.55-0.61]). Adjustment for patient age, sex, and other medications did not notably change results, as did restricting the analysis to incident users. CONCLUSIONS: Patients taking cholinesterase inhibitors rarely undergo, and have a significantly reduced risk of, cardiac pacemaker insertion. PMID- 25927647 TI - [Adverse effects of public health interventions]. PMID- 25927648 TI - [Vocational training in public health during medical school: a pilot study]. AB - The need to integrate clinical and public health training of medical students is increasingly important. Future physicians need to be able to deal with new, complex and growing public health challenges. MATERIALS AND METHODS: A literature search was performed through Pubmed to identify the conceptual reference framework. Meetings were carried out to identify the most appropriate modalities and priorities required for drafting the project, to identify the skills to be acquired by students, to decide on teaching formats and methods to assess student learning, to draw up the teaching schedule, to define the statistical methods to be used to assess student satisfaction, and to perform the statistical analysis of results. Training in hospital hygiene and environmental safety was carried out through presentation of a relevant case. After being divided into groups the students attended the three units (Environmental Microbiology, Environmental Xenobiotics, Genetic Epidemiology and Molecular Biology) of the Hygiene Section of a Public Health Institute. Training in Organization and Health Programming involved presentation of a set of indicators for the definition of objectives and assessment of health systems or services. RESULTS: The literature search led to the identification of the relevant literature. With regard to student satisfaction, 96% of those who replied to the questionnaire gave an overall positive review of the training course (at least 3 on a scale from 1 to 5). CONCLUSIONS: the overall high level of student satisfaction suggests that the proposed model may be exportable. Further developments will be the assessment of trends regarding functioning of the organizational model and perceived teaching quality. PMID- 25927649 TI - Water supply, sanitation and health risks in Douala 5 municipality, Cameroon. AB - BACKGROUND: In the poor zones of sub-Saharan Africa, the conventional drinking water network is very weak. The populations use alternative groundwater sources which are wells and springs. However, because of urbanization, the groundwater sources are degrading gradually making pure, safe, healthy and odourless drinking water a matter of deep concern. There are many pollutants in groundwater due to seepage of organic and inorganic pollutants, heavy metals as well as microbiological contamination. This study was carried out in October 2012 and aimed to analyze the practices and behaviors of populations related to water supply that may constitute potential risks of microbiological contamination and emergence of waterborne diseases. METHOD: This study was carried out on a sample of 285 households, distributed in twelve principal quarters of the Douala V municipality in Cameroon. After data collection through the questionnaires, the selection of vulnerable quarters was done by the tabulation of some specific results on the questionnaire. The microbiological analysis was carried out using an innovative rapid test called "Micro Biological Survey (MBS)" that has been developed and patented by MBS srl, a recent spin-off of the University of Roma Tre. RESULT: We found out that 42.30% of households used water from drilled wells (forages), 33.80% from Cameroon National Water Company (CDE) distribution network, 9.50% from spring, and 9.40% used other source of water such as buying industrial mineral water. However, it should be noted that, as dangerous as it may be, wells ("puits" in French) water is used as permanent source of drinking water by 5% of households. In general, 63.2% of households affirmed not to have benefited the fitting of public water point. Moreover, among the quarters were the households affirmed to have benefited from the development of a public water point, 52.5% of these water point were no longer functional. From the obtained data we have assessed that 83% of wells analyzed are faecally contaminated and all the forages analyzed (100%) are not contaminated. The most affected people by water-related diseases are children under 5 years (43%). CONCLUSION: We highly recommend the City Council of Douala V to restrict the use of the contaminated wells and provide alternative water sources such as forages for public use and to ensure that microbiological quality of the new and already existing water sources is controlled regularly by the Technical Service. PMID- 25927650 TI - [Quality of life and level of satisfaction of elderly persons receiving home health care: a cross-sectional study]. AB - This study evaluated quality of life and level of satisfaction of elderly persons receiving home health care. Data was collected through a questionnaire and by examining medical records of 500 elderly patients. The mean age of study participants was 81 years. Results shows a high level of satisfaction with the quality of care received, the training of doctors and relationships with staff. Healthcare services requested by patients and supplied almost completely match; however, social services offered need to be intensified. PMID- 25927651 TI - [An example of a hub and spoke network system in Plastic Surgery: the Regional reference center for non-healing wounds in Ancona (Italy)]. AB - Chronic wounds cause morbidity due to local infections, sepsis, osteomyelitis, but also increase mortality in the most severe cases and in patients with multiple comorbidities. Their increasing prevalence, associated disabilities and relevant health costs make chronic wounds a real social disease. At a time in which we hear more and more about spending reviews and reduction of health care costs, the natural evolution of Medicine and Health Care is increasingly directed towards the achievement of high quality standards while at the same time, reducing costs. It is in this framework that a hub and spoke model was used for organizing Plastic Surgery services in Ancona (Italy). In order to ensure appropriate clinical and organizational management of services, the activities of reference centres need to be widely integrated, by functional interconnections with activities of peripheral hospitals and local centres. Through a careful analysis of the Regional Reference Center for non - healing wounds in Ancona, the authors make some considerations regarding appropriate diagnostic-therapeutic healthcare pathways and the correct use of human, material and technological resources in the area of wound healing. PMID- 25927652 TI - [Cost analysis of sterilization facilities in the Rizzoli Hospital (Bologna, Italy): a study of different organizational models]. AB - Preventing healthcare-associated infections requires a number of actions, including adequate disinfection and sterilization of medical devices. A cost analysis of hospital sterilization processes is fundamental to increase quality and safety, reduce costs and to make a decision about outsourcing. The aim of this analysis was to determine the cost of sterilization and the average cost of surgical procedures at the Rizzoli hospital in Bologna (Italy), a largesurgical hospital that performs more than 11,000 surgical procedures per year. PMID- 25927653 TI - [Ebola Virus Disease (EVD): proposed guideline for hospital triage of suspect and probable cases]. AB - The magnitude of the present Ebola epidemic and the resonance in the media has led to the need to draw clear guidelines for the health personnel potentially involved, since the fears raised by the high lethality of the disease may create inefficiencies Here we present the guidelines for a medium-sized hospital, where, at present, the chance to confront a case of Ebola virus disease is rare, but not impossible. The role and activities of each professional involved and the procedures have been set out. We think that this exercise will be useful for all structureswith characteristics similar to ours. PMID- 25927654 TI - [Universal vaccination against varicella in Italy: the same opportunity for all children]. AB - Varicella is an infectious disease still frequent in Italy, where 8 out 20 Regions have adopted universal vaccination programs starting from 2003. Accordingly to National Vaccination Plan, all Regions should introduce universal varicella vaccination in 2015. An independent multidisciplinary group of experts met to discuss some debated questions. The available evidence of varicella vaccine efficacy in the 8 Regions was evaluated and the evidence of safety of monovalent and combined varicella vaccines are presented. The strategy for introducing universal varicella vaccine in the pediatric immunization schedule is discussed. The expert group concludes that available evidence supports the active offer of varicella vaccine in all Italian Regions and that catch up programs for susceptible cohorts should be encouraged. PMID- 25927655 TI - The Synthesis of Cyclic Poly(ethylene imine) and Exact Linear Analogues: An Evaluation of Gene Delivery Comparing Polymer Architectures. AB - The delivery of genetic material to cells offers the potential to treat many genetic diseases. Cationic polymers, specifically poly(ethylene imine) (PEI), are promising gene delivery vectors due to their inherent ability to condense genetic material and successfully affect its transfection. However, PEI and many other cationic polymers also exhibit high cytotoxicity. To systematically study the effect of polymer architecture on gene delivery efficiency and cell cytotoxicity, a set of cyclic PEIs were prepared for the first time and compared to a set of linear PEIs of the exact same molecular weight. Subsequent in vitro transfection studies determined a higher transfection efficiency for each cyclic PEI sample when compared to its linear PEI analogue in addition to reduced toxicity relative to the branched PEI "gold standard" control. These results highlight the critical role that the architecture of PEI can play in both optimizing transfection and reducing cell toxicity. PMID- 25927657 TI - Comparison of the Airtraq laryngoscope and the GlideScope for double-lumen tube intubation in patients with predicted normal airways: a prospective randomized trial. AB - BACKGROUND: The Airtraq laryngoscope and the GlideScope are commonly used in many airway scenarios. However, their features have not been fully described for double-lumen tube intubation. A prospective randomized study was designed to compare their intubation performances in thoracic surgery patients. METHODS: Seventy ASA physical status I and II patients with predicted normal airway were scheduled for thoracic surgeries with double-lumen tube intubation. They were randomly assigned to one of two groups and intubated with either the Airtraq laryngoscope (group A, n = 35) or the GlideScope (group G, n = 35). Airway assessments were performed prior to anesthesia, and all patients were induced with a standard anesthetic regimen. The Cormack-Lehane grades were initially evaluated with a Macintosh laryngoscope and subsequently with the group-specific laryngoscope before intubation. Intubation time was recorded as the primary outcome. The Cormack-Lehane grade, the success of the first intubation attempt, the intubation difficulty scales and ease of tube advancement were noted. Hemodynamic variables during intubation and incidence of post-operative sore throat were documented as well. RESULTS: The intubation time of group A was shorter than that of group G (36.6 +/- 20.2 s vs. 54.6 +/- 25.7 s, p = 0.002). The Cormack-Lehane grade (I/II/III/IV) was significantly better in group A (33/2/0/0 vs. 28/7/0/0, p = 0.042). The mean arterial pressure and heart rate rose to higher levels during intubation with the GlideScope than with the Airtraq laryngoscope. The success of the first intubation attempt and the intubation difficulty scales were comparable between the two groups. The numbers of patients who experienced postoperative sore throat were similar (6 vs. 8) in the two groups. CONCLUSIONS: Compared with the GlideScope, the specially designed Airtraq laryngoscope might be more suitable for double-lumen tube intubations in patients with predicted normal airway. TRIAL REGISTRATION: www.chictr.org Identifier: ChiCTR-TRC-11001628. PMID- 25927659 TI - Positioning accuracy during VMAT of gynecologic malignancies and the resulting dosimetric impact by a 6-degree-of-freedom couch in combination with daily kilovoltage cone beam computed tomography. AB - BACKGROUND: To improve the delivery of radiotherapy in gynecologic malignancies and to minimize the irradiation of unaffected tissues by using daily kilovoltage cone beam computed tomography (kV-CBCT) to reduce setup errors. METHODS: Thirteen patients with gynecologic cancers were treated with postoperative volumetric modulated arc therapy (VMAT). All patients had a planning CT scan and daily CBCT during treatment. Automatic bone anatomy matching was used to determine initial inter-fraction positioning error. Positional correction on a six-degrees-of freedom (6DoF) couch was followed by a second scan to calculate the residual inter-fraction error, and a post-treatment scan assessed intra-fraction motion. The margins of the planning target volume (MPTV) were calculated from these setup variations and the effect of margin size on normal tissue sparing was evaluated. RESULTS: In total, 573 CBCT scans were acquired. Mean absolute pre-/post correction errors were obtained in all six planes. With 6DoF couch correction, the MPTV accounting for intra-fraction errors was reduced by 3.8-5.6 mm. This permitted a reduction in the maximum dose to the small intestine, bladder and femoral head (P=0.001, 0.035 and 0.032, respectively), the average dose to the rectum, small intestine, bladder and pelvic marrow (P=0.003, 0.000, 0.001 and 0.000, respectively) and markedly reduced irradiated normal tissue volumes. CONCLUSIONS: A 6DoF couch in combination with daily kV-CBCT can considerably improve positioning accuracy during VMAT treatment in gynecologic malignancies, reducing the MPTV. The reduced margin size permits improved normal tissue sparing and a smaller total irradiated volume. PMID- 25927660 TI - Management and prognosis of patients with brain metastasis from gestational trophoblastic neoplasia: a 24-year experience in Peking union medical college hospital. AB - BACKGROUND: The optimal treatment for patients with brain metastasis from gestational trophoblastic neoplasia (GTN) has not been established. This study aims to investigate the clinical characteristics and the management of brain metastasis from GTN in relation to patients' outcomes. METHODS: We retrospectively investigated 109 GTN patients with brain metastasis treated at Peking Union Medical College Hospital from January 1990 to December 2013. Patients mainly received multiagent chemotherapy with florouracil or floxuridine, dactinomycin, etoposide, and vincristine (FAEV) combined with intrathecal methotrexate with or without surgery. RESULTS: In the 109 patients, sixty-two (56.1%) patients presented for primary therapy and 47 patients had failed chemotherapy elsewhere. Eight early demise patients who died before or during first cycle of chemotherapy were excluded from analysis. The median follow-up time was 47 months (range 9-180 months). The overall 5-year survival rate (OS) was 71.1%, while the OS rate for patients receiving primary chemotherapy in our hospital was 85.5%, and this fell to 51.9% in patients with failure multidrug chemotherapy elsewhere. Multivariate analysis demonstrated that International Federation of Gynecology and Obstetrics (FIGO) scores over 12 (Hazard ratio-HR 1.279, 95% CI 1.061-1.541, P = 0.010), failure of previous multidrug chemotherapy (HR 3.177, 95% CI 1.277-7.908, P = 0.013), and concurrent renal metastasis (HR 2.654, 95% CI 1.125-6.261, P = 0.026) were the risk factors of overall survival in patients with brain metastases from GTN. CONCLUSIONS: Patients with brain metastasis from GTN have favorable outcome by multidrug chemotherapy and adjuvant therapies. Nevertheless, the prognosis is poor if the patients had previous multidrug failure chemotherapy history, concomitant with renal metastasis, or FIGO score over 12. Initial treatment with FAEV combined with intrathecal methotrexate chemotherapy can bring bright prospect to patients with brain metastases from GTN. PMID- 25927661 TI - Novel Adociaquinone Derivatives from the Indonesian Sponge Xestospongia sp. AB - Seven new adociaquinone derivatives, xestoadociaquinones A (1a), B (1b), 14 carboxy-xestoquinol sulfate (2) and xestoadociaminals A-D (3a, 3c, 4a, 4c), together with seven known compounds (5-11) were isolated from an Indonesian marine sponge Xestospongia sp. Their structures were elucidated by extensive 1D and 2D NMR and mass spectrometric data. All the compounds were evaluated for their potential inhibitory activity against eight different protein kinases involved in cell proliferation, cancer, diabetes and neurodegenerative disorders as well as for their antioxidant and antibacterial activities. PMID- 25927662 TI - Correction: Argatroban therapy for heparin-induced thrombocytopenia in ICU patients with multiple organ dysfunction syndrome: a retrospective study. PMID- 25927664 TI - Flavonoids from Matteuccia struthiopteris and Their Anti-influenza Virus (H1N1) Activity. AB - Seven new flavonoid glycosides (1-7), matteflavosides A-G, together with 12 known flavonoids (8-19) were isolated from the rhizomes of Matteuccia struthiopteris (L.) Todar. Their structures were established via the analyses of extensive spectroscopic data. All compounds were evaluated for their anti-influenza virus (H1N1) activity using the neuraminidase inhibition assay. The results showed that compound 7 exhibited significant inhibitory activity against the H1N1 influenza virus neuraminidase with an EC50 value of 6.8 +/- 1.1 MUM and an SI value of 34.4, and compounds 8 and 17 showed moderate inhibitory activity. PMID- 25927665 TI - Methylnaltrexone for Opioid-Induced Constipation in Children and Adolescents and Young Adults with Progressive Incurable Cancer at the End of Life. AB - BACKGROUND: Opioid-induced constipation (OIC) is common among children and adolescents and young adults (AYA) with progressive incurable cancer. Although methylnaltrexone is a successful treatment for OIC in adult cancer patients, no case series has established its safety and efficacy in pediatric cancer patients. OBJECTIVES: The aim of the study was to describe the safety and efficacy of methylnaltrexone use for OIC in children and AYA with progressive incurable cancer at the end of life in the inpatient and outpatient settings. METHODS: We conducted a retrospective review of medical records of children and AYA with progressive incurable cancer who received methylnaltrexone at our institution from May 2008 to June 2013. Pharmacy data were reviewed for each patient and a chart review was performed for documentation of laxation and side effects. RESULTS: Of the 9 patients (age range: 17 months to 21 years) with progressive incurable cancer who developed OIC, 7 (78%) had laxation after methylnaltrexone administration (0.15 mg/kg/dose). Of these 7 patients, 5 (71%) had laxation with the first dose, and 5 (71%) who responded had a continued response to repeated doses. The longest a patient regularly received methylnaltrexone was 9 months. Of 5 patients with intraabdominal disease, 4 (80%) had laxation. There were no negative side effects in any of the patients. Also, there was no increase in pain either qualitatively or by pain score. CONCLUSIONS: Methylnaltrexone appears to be safe and efficacious in treating OIC in children and AYA with progressive incurable cancer. Methylnaltrexone was tolerated in both the inpatient and outpatient settings and with repeated dosing. PMID- 25927667 TI - Transarterial chemoembolization is ineffective for neuroendocrine tumors metastatic to the caudate lobe: a single institution review. AB - BACKGROUND: Caudate lobe liver metastases occur commonly in patients with neuroendocrine tumors. It is unknown, however, how these lesions respond to regional therapy and how their presence impacts outcomes. We reviewed our experience treating these lesions using transarterial chemoembolization (TACE). METHODS: We reviewed radiographic response to TACE in 86 patients with metastatic neuroendocrine tumors to the liver. We determined the impact of caudate lesions on outcomes in comparison to the cohort of patients without caudate lesions, as well as response of caudate lesions to TACE versus lesions elsewhere in the liver. RESULTS: Caudate lesions were identified in 45 (52%) patients. All patients had disease in other liver segments. Only seven caudate lesions (12.3%) had a radiographic response to TACE, whereas 82% of lesions elsewhere in the liver demonstrated a response. The presence or absence of a caudate lesion did not impact the overall radiographic (82.2% vs. 82.9%), symptomatic (64.4% vs. 56.1%), or biochemical (97.6% vs. 88.9%) response to TACE (P > 0.1 for all). However, median overall survival was reduced in those presenting with caudate lesions (87.1 vs. 45.6 months, P = 0.031). CONCLUSIONS: Metastatic neuroendocrine tumors to the caudate lobe respond poorly to TACE. Symptomatic or threatening caudate lobe lesions should be considered for palliative resection in spite of additional inoperable liver metastases. PMID- 25927668 TI - Macromolecular crowding gives rise to microviscosity, anomalous diffusion and accelerated actin polymerization. AB - Macromolecular crowding (MMC) has been used in various in vitro experimental systems to mimic in vivo physiology. This is because the crowded cytoplasm of cells contains many different types of solutes dissolved in an aqueous medium. MMC in the extracellular microenvironment is involved in maintaining stem cells in their undifferentiated state (niche) as well as in aiding their differentiation after they have travelled to new locations outside the niche. MMC at physiologically relevant fractional volume occupancies (FVOs) significantly enhances the adipogenic differentiation of human bone marrow-derived mesenchymal stem cells during chemically induced adipogenesis. The mechanism by which MMC produces this enhancement is not entirely known. In the context of extracellular collagen deposition, we have recently reported the importance of optimizing the FVO while minimizing the bulk viscosity. Two opposing properties will determine the net rate of a biochemical reaction: the negative effect of bulk viscosity and the positive effect of the excluded volume, the latter being expressed by the FVO. In this study we have looked more closely at the effect of viscosity on reaction rates. We have used fluorimetry to measure the rate of actin polymerization and fluorescence correlation spectroscopy (FCS) to measure diffusion of various probes in solutions containing the crowder Ficoll at physiological concentrations. Similar to its effect on collagen, Ficoll enhanced the actin polymerization rate despite increasing the bulk viscosity. Our FCS measurements reveal a relatively minor component of anomalous diffusion. In addition, our measurements do suggest that microviscosity becomes relevant in a crowded environment. We ruled out bulk viscosity as a cause of the rate enhancement by performing the actin polymerization assay in glycerol. These opposite effects of Ficoll and glycerol led us to conclude that microviscosity becomes relevant at the length scale of the reacting molecules within a crowded microenvironment. The excluded volume effect (arising from crowding) increases the effective concentration of actin, which increases the reaction rate, while the microviscosity does not increase sufficiently to lower the reaction rate. This study reveals finer details about the mechanism of MMC. PMID- 25927669 TI - A novel mechanism of regulation of the anti-metastatic miR-31 by EMSY in breast cancer. AB - miR-31 is well known as an anti-metastatic microRNA (miRNA) in the context of breast cancer. However, to date the mechanism of regulation of this miRNA has yet to be elucidated. The recent publication by Vire et al. in Molecular Cell demonstrates for the first time that one mechanism of regulation of miR-31 is through the putative oncogene EMSY, whose amplification in breast cancer patients correlates with reduced expression of the miRNA. This regulation is dependent on the DNA-binding transcription factor ETS-1 which recruits EMSY and the histone demethylase KDM5B to the miR-31 promoter, thus repressing its transcription. PMID- 25927670 TI - MicroRNA-144 inhibits the metastasis of gastric cancer by targeting MET expression. AB - Gastric cancer (GC) remains one of the most common types of malignant cancer, and the molecular mechanism underlying its metastasis is still largely unclear. MicroRNAs have emerged as important regulators of metastasis because of their ability to act on multiple signaling pathways. In our study, we found that miR 144 is significantly downregulated in both highly metastatic GC cell lines and tissues. Results from both gain-of-function and loss-of-function experiments demonstrate that increased miR-144 expression significantly reduced GC cell migration, whereas decreased miR-144 expression dramatically enhanced GC cell migration. The met proto-oncogene (MET), which is often amplified in human cancers and functions as an important regulator of cell growth and tumor invasion, was identified as a direct target of miR-144. Moreover, silencing of MET using small interfering RNA (siRNA) recapitulated the anti-metastatic function of miR-144, whereas restoring MET expression attenuated the function of miR-144 in GC cells. Furthermore, we found that miR-144, by targeting MET, suppresses phosphorylation of Akt. Finally, we observed an inverse correlation between the expression of miR-144 and MET mRNA in GC metastatic tissues. In summary, miR-144 suppresses GC progression by directly downregulating MET expression, which subsequently prevents activation of the pro-oncogenic Akt pathway. Reintroduction of miR-144 expression in GC cells presents an attractive therapeutic approach to block the metastasis of gastric cancer. PMID- 25927671 TI - Pressure-Controlled vs Volume-Controlled Ventilation in Acute Respiratory Failure: A Physiology-Based Narrative and Systematic Review. AB - BACKGROUND: Mechanical ventilation is a cornerstone in the management of acute respiratory failure. Both volume-targeted and pressure-targeted ventilations are used, the latter modes being increasingly used. We provide a narrative review of the physiologic principles of these two types of breath delivery, performed a literature search, and analyzed published comparisons between modes. METHODS: We performed a systematic review and meta-analysis to determine whether pressure control-continuous mandatory ventilation (PC-CMV) or pressure control-inverse ratio ventilation (PC-IRV) has demonstrated advantages over volume control continuous mandatory ventilation (VC-CMV). The Cochrane tool for risk of bias was used for methodologic quality. We also introduced physiologic criteria as quality indicators for selecting the studies. Outcomes included compliance, gas exchange, hemodynamics, work of breathing, and clinical outcomes. Analyses were completed with RevMan5 using random effects models. RESULTS: Thirty-four studies met inclusion criteria, many being at high risk of bias. Comparisons of PC-CMV/PC-IRV and VC-CMV did not show any difference for compliance or gas exchange, even when looking at PC-IRV. Calculating the oxygenation index suggested a poorer effect for PC-IRV. There was no difference between modes in terms of hemodynamics, work of breathing, or clinical outcomes. CONCLUSIONS: The two modes have different working principles but clinical available data do not suggest any difference in the outcomes. We included all identified trials, enhancing generalizability, and attempted to include only sufficient quality physiologic studies. However, included trials were small and varied considerably in quality. These data should help to open the choice of ventilation of patients with acute respiratory failure. PMID- 25927672 TI - Addressing the needs of colorectal cancer survivors: current strategies and future directions. AB - Colorectal cancer (CRC) is one of the three topmost common cancers in men and the second most common cancer in women worldwide. With current advances in the medical and surgical treatment of CRC, care has slowly transformed to curative treatment. With these advances, CRC survivors are increasing in numbers and these patients have a unique range of medical, physical and psychological needs that require regular follow-up. In 2006, the Institute of Medicine recommended that cancer survivors who are completing primary treatment receive a survivorship care plan. There are many different programs of different complexity that are implemented for CRC survivors. This review outlines the needs of CRC survivors, the current surveillance techniques used in the continuing care of patients with CRC after curative treatment and the evidence behind these strategies. PMID- 25927673 TI - Resuscitation strategies with different arterial pressure targets after surgical management of traumatic shock. AB - INTRODUCTION: Hypotensive fluid resuscitation has a better effect before and during surgical intervention for multiple trauma patients with haemorrhagic shock. However, it is questionable whether hypotensive fluid resuscitation is suitable after surgical intervention for these patients, and whether resuscitation with different mean arterial pressure (MAP) targets after surgical intervention can obtain different results. The aim of this study was to investigate these questions and to explore the underlying mechanisms. METHODS: A total of 30 anesthetized piglets were randomly divided into 3 groups (n = 10 per group): low MAP, middle MAP, and high MAP, which had MAP targets of 60, 80, and 100 mmHg, respectively. All animals underwent femur fracture, intestine and liver injury, haemorrhagic shock, early hypotensive resuscitation, and surgical intervention. Then, the animals received fluid resuscitation with different MAP targets as mentioned above for 24 hours. Hemodynamic parameters and vital organ functions were evaluated. RESULTS: Fluid resuscitation in the 80 mmHg MAP group maintained haemodynamic stability, tissue perfusion, and organ function better than that in the other groups. The 60 mmHg MAP group presented with profound metabolic acidosis and organ histopathologic damage. In addition, animals in the 100 mmHg MAP group exhibited severe tissue oedema, organ function failure, and histopathologic damage. CONCLUSIONS: In our porcine model of resuscitation, targeting high MAP by fluid administration alone resulted in a huge increase in the infusion volume, severe tissue oedema, and organ dysfunction. Meanwhile, targeting low MAP resulted in persistent tissue hypoperfusion and metabolic stress. Hence, a resuscitation strategy of targeting appropriate MAP might be compatible with maintaining haemodynamic stability, tissue perfusion, and organ function. PMID- 25927674 TI - [3 + 2] Cycloadditions of Azides with Arynes via Photolysis of Phthaloyl Peroxide Derivatives. AB - Photolysis of phthaloyl peroxides yields arynes, which undergo [3 + 2] cycloadditions with azides. This reaction tolerates a variety of organic azides and phthaloyl peroxides and affords the corresponding benzotriazoles in moderate to good yields at room temperature. PMID- 25927675 TI - Novel pantothenate derivatives for anti-malarial chemotherapy. AB - BACKGROUND: A number of synthetic pantothenate derivatives, such as pantothenamides, are known to inhibit the growth of the human malaria parasite Plasmodium falciparum, by interfering with the parasite Coenzyme A (CoA) biosynthetic pathway. The clinical use of pantothenamides is limited by their sensitivity to breakdown by ubiquitous human pantetheinases of the vanin family. METHODS: A number of pantothenate derivatives (pantothenones) with potent and specific inhibitory activity against mammalian vanins were tested in a proliferation assay of asexual P. falciparum blood stages alone, and in combination with pantothenamides. RESULTS: The vanin inhibitors were found to protect pantothenamides against breakdown by plasma vanins, thereby preserving the in vitro anti-malarial activity. Moreover, some of the vanin inhibitors showed in vitro anti-malarial activity in the low micromolar range. The most potent antimalarial in this series of compounds (RR8), was found to compete with pantothenate in a combination proliferation assay. No correlation, however, was found between anti-vanin and anti-malarial activity, nor was pantetheinase activity detected in P. falciparum extracts. CONCLUSIONS: Growth inhibition is most likely due to competition with pantothenate, rather than pantetheinase inhibition. As vanin inhibitors of the pantothenone class are stable in biological fluids and are non-toxic to mammalian cells, they may represent novel pantothenate-based anti-malarials, either on their own or in combination with pantothenamides. PMID- 25927676 TI - A new 3'RR regulatory role during lymphomagenesis. PMID- 25927678 TI - Long-term results of microcoil embolization for colonic haemorrhage: how common is rebleeding? AB - OBJECTIVE: To determine the long-term results of patients undergoing transcatheter coil embolization for the treatment of acute colonic haemorrhage. METHODS: Patients undergoing angiography for suspected colonic bleeding between January 2002 and December 2012 were reviewed (average age, 60 years; 38.4% male). Baseline, procedural and outcome parameters were recorded following the Society of Interventional Radiology guidelines. Primary outcome measures included early (<30 days) and delayed (>30 days) rebleeding events and adverse procedure-related complication. Average follow-up time was 996 days (median, 232 days; range, 30 3663 days). RESULTS: One or multiple sites of bleeding were identified in 40 cases. Coil embolization was performed in 39 patients, 26 (66.7%, 26/39) of whom were treated successfully without technical/clinical failure (n = 12) or loss to follow-up (n = 1). Three patients (11.5%, 3/26) rebled in the early period within 30 days; one patient went on to hemicolectomy. Four patients (15.3%, 4/26) experienced delayed rebleeding after 30 days; two of whom also underwent hemicolectomy. No major complication occurred. One minor complication of short segment arterial dissection was seen in the clinical failure group. One case of asymptomatic ischaemia was identified on a patient undergoing pre-operative colonoscopy for elective bowel resection. No instances of ischaemic stricture were seen. All-cause mortality of successfully treated and all patients at 1 year was 31% (8/26) and 30% (12/40), respectively. CONCLUSION: Transcatheter coil embolization is a durable treatment option with a technical and clinical success rate of 67% in the setting of acute colonic haemorrhage. A modest level of rebleeding was seen among successfully treated patients in both the early and delayed periods; in the majority of patients, embolization proved to be definitive therapy. ADVANCES IN KNOWLEDGE: Transcatheter coil embolization is a durable and potentially definitive therapy in the management of acute colonic haemorrhage. PMID- 25927677 TI - Rodent models for Alzheimer's disease drug discovery. AB - INTRODUCTION: Alzheimer's disease (AD) is a neurodegenerative disorder characterized by memory loss and personality changes, leading to dementia. Histopathological hallmarks are represented by aggregates of beta-amyloid peptide (Abeta) in senile plaques and deposition of hyperphosphorylated tau protein in neurofibrillary tangles in the brain. Rare forms of early onset familial Alzheimer's disease are due to gene mutations. This has prompted researchers to develop genetically modified animals that could recapitulate the main features of the disease. The use of these models is complemented by non-genetically modified animals. AREAS COVERED: This review summarizes the characteristics of the most used transgenic (Tg) and non-Tg models of AD. The authors have focused on models mainly used in their laboratories including amyloid precursor protein (APP) Tg2576, APP/presenilin 1, 3xAD, single h-Tau, non-Tg mice treated with acute injections of Abeta or tau, and models of physiological aging. EXPERT OPINION: Animal models of disease might be very useful for studying the pathophysiology of the disease and for testing new therapeutics in preclinical studies but they do not reproduce the entire clinical features of human AD. When selecting a model, researchers should consider the various factors that might influence the phenotype. They should also consider the timing of testing/treating animals since the age at which each model develops certain aspects of the AD pathology varies. PMID- 25927679 TI - Cellular and molecular mechanisms of statins: an update on pleiotropic effects. AB - Coronary artery disease (CAD) is the leading cause of death worldwide. The efficacy and safety of statins (3-hydroxy-3-methylglutaryl-coenzyme A reductase inhibitors) in primary and secondary prevention of CAD are confirmed in several large studies. It is well known that statins have some pleiotropic, anti atherosclerotic effects. We review the molecular mechanisms underlying the beneficial effects of statins revealed in recently published studies. Endothelial cell injury is regarded as the classic stimulus for the development of atherosclerotic lesions. In addition, the inflammatory process plays an important role in the aetiology of atherosclerosis. In particular, chronic inflammation plays a key role in coronary artery plaque instability and subsequent occlusive thrombosis. Our previous reports and others have demonstrated beneficial effects of statins on endothelial dysfunction and chronic inflammation in CAD. A better understanding of the molecular mechanism underlying the effectiveness of statins against atherosclerosis may provide a novel therapeutic agent for the treatment of coronary atherosclerosis. The present review summarizes the cellular and molecular mechanism of statins against coronary atherosclerosis. PMID- 25927680 TI - Are reactive oxygen species still the basis for diabetic complications? AB - Despite the wealth of pre-clinical support for a role for reactive oxygen and nitrogen species (ROS/RNS) in the aetiology of diabetic complications, enthusiasm for antioxidant therapeutic approaches has been dampened by less favourable outcomes in large clinical trials. This has necessitated a re-evaluation of pre clinical evidence and a more rational approach to antioxidant therapy. The present review considers current evidence, from both pre-clinical and clinical studies, to address the benefits of antioxidant therapy. The main focus of the present review is on the effects of direct targeting of ROS-producing enzymes, the bolstering of antioxidant defences and mechanisms to improve nitric oxide availability. Current evidence suggests that a more nuanced approach to antioxidant therapy is more likely to yield positive reductions in end-organ injury, with considerations required for the types of ROS/RNS involved, the timing and dosage of antioxidant therapy, and the selective targeting of cell populations. This is likely to influence future strategies to lessen the burden of diabetic complications such as diabetes-associated atherosclerosis, diabetic nephropathy and diabetic retinopathy. PMID- 25927681 TI - Streptococcus pneumoniae: the forgotten microorganism in neonatal sepsis. AB - Streptococcus pneumoniae is a rarely cause of neonatal sepsis. Its prevalence is low but with a mortality of 50%. Measures to prevent Streptococcus agalactiae transmission could help to increase Invasive Pneumococcal Disease (IPD) in newborns. Transmission could be from mother intrapartum; or in those cases of late onset sepsis, the community carriers. Systematic vaccination with PCV-7 and PCV-13 has reduced IPD rates. We present a case of a newborn with no perinatal risk factors for infection. In the first 24 hours after surgery of an ovarian cyst, the patient started with bad general condition with fever and regular perfusion. Empiric antibiotic treatment was started. Streptococcus pneumoniae was isolated in blood culture. CONCLUSION: In neonatal sepsis, we always think in Streptococcus agalactiae. Streptococcus pneumoniae is rare but with a high morbidity and mortality. Systematic vaccination is a measure that has demonstrated a reduction in the incidence of Invasive pneumococcal disease. PMID- 25927682 TI - Explicit correlated exciton-vibrational dynamics of the FMO complex. AB - The coupled exciton-vibrational dynamics of a three-site model of the Fenna Matthews-Olson complex is investigated using the numerically exact multilayer multiconfiguration time-dependent Hartree approach. Thereby the specific coupling of the vibrational modes to local electronic transitions is adapted from a discretized experimental spectral density. The solution of the resulting time dependent Schrodinger equation including three electronic and 450 vibrational degrees of freedom is analyzed in terms of excitonic populations and coherences. Emphasis is put onto the role of specific ranges of vibrational frequencies. It is observed that modes between 160 and 300 cm(-1) are responsible for the sub picosecond population and coherence decay. Further, it is found that a mean-field approach with respect to the vibrational degrees of freedom is not applicable. PMID- 25927683 TI - Prevalence and characterization of murine leukemia virus contamination in human cell lines. AB - Contaminations of cell cultures with microbiological organisms are well documented and can be managed in cell culture laboratories applying reliable detection, elimination and prevention strategies. However, the presence of viral contaminations in cell cultures is still a matter of debate and cannot be determined with general detection methods. In the present study we screened 577 human cell lines for the presence of murine leukemia viruses (MLV). Nineteen cell lines were found to be contaminated with MLV, including 22RV1 which is contaminated with the xenotropic murine leukemia virus-related virus variant of MLV. Of these, 17 cell lines were shown to produce active retroviruses determined by product enhanced reverse transcriptase PCR assay for reverse transcriptase activity. The contaminated cell lines derive from various solid tumor types as well as from leukemia and lymphoma types. A contamination of primary human cells from healthy volunteers could not be substantiated. Sequence analyses of 17 MLV PCR products and five complete MLV genomes of different infected cell lines revealed at least three groups of related MLV genotypes. The viruses harvested from the supernatants of infected cell cultures were infectious to uninfected cell cultures. In the course of the study we found that contamination of human genomic DNA preparations with murine DNA can lead to false-positive results. Presumably, xenotransplantations of the human tumor cells into immune-deficient mice to determine the tumorigenicity of the cells are mainly responsible for the MLV contaminations. Furthermore, the use of murine feeder layer cells during the establishment of human cell lines and a cross-contamination with MLV from infected cultures might be sources of infection. A screening of cell cultures for MLV contamination is recommended given a contamination rate of 3.3%. PMID- 25927686 TI - Synthesis, characterization and insights into stable and well organized hexagonal mesoporous zinc-doped alumina as promising metathesis catalysts carrier. AB - A series of highly ordered hexagonal mesoporous alumina and zinc-modified mesoporous alumina samples are synthesized via a sol-gel method through an evaporation-induced self-assembly process using Pluronic F127 as nonionic templating agent and several aluminum precursors. The process was mediated using several carboxylic acids along with hydrochloric acid in ethanol. Successful impregnation of ZnCl2 was achieved while maintaining the ordered structure. The surface and textural properties of the materials were investigated. N2 physisorption analysis revealed a BET surface area of 394 m(2) g(-1) and a pore volume around 0.55 cm(3) g(-1). Moreover, small-angle XRD diffraction patterns highlighted the well-organized hexagonal structure even upon the incorporation of zinc chloride. The organized-structure arrangement was further confirmed by transmission electron microscopy (TEM) analysis. The Zn/Al composition of the final materials was confirmed by EDX and XPS analysis, and the zinc amount incorporated was analyzed by ICP. Furthermore, the surface modification with zinc chloride impregnation was analyzed by XPS, (1)H and (27)Al MAS-NMR and FTIR spectroscopic techniques. In addition, the effects of synthesis conditions and the mechanism of the mesostructure formation were explored. The catalytic activity of several methyltrioxorhenium (MTO)-based catalysts supported on these hexagonal mesoporous alumina materials was tested for methyl oleate self metathesis. The results showed improved kinetics using hexagonal alumina in comparison to those using wormhole-like alumina counterparts. This behavior could be attributed to better mass transfer features of hexagonal mesoporous alumina. The prepared materials with desirable pore size and structure are suitable candidates as catalyst supports for metathesis of bulky functionalized olefins and other catalytic transformations due to their enhanced Lewis acidity and more uniform pore networks favoring enhanced and selective mass transfer phenomena. PMID- 25927685 TI - Dopaminergic lesions of the dorsolateral striatum in rats increase delay discounting in an impulsive choice task. AB - Dysregulated dopamine transmission in striatal circuitry is associated with impulsivity. The current study evaluated the influence of dopaminergic inputs to the dorsolateral striatum on impulsive choice, one aspect of impulsive behavior. We implemented an operant task that measures impulsive choice in rats via delay discounting wherein intracranial self-stimulation (ICSS) was used as the positive reinforcer. To do so, rats were anesthetized to allow implanting of a stimulating electrode within the lateral hypothalamus of one hemisphere and bilateral dorsal striatal injections of the dopaminergic toxin, 6-OHDA (lesioned) or its vehicle (sham). Following recovery, rats were trained in a delay discounting task wherein they selected between a small ICSS current presented immediately after lever pressing, and a large ICSS current presented following a 0 to 15 s delay upon pressing the alternate lever. Task acquisition and reinforcer discrimination were similar for lesioned and sham rats. All rats exhibited an initial preference for the large reinforcer, and as the delay was increased, preference for the large reinforcer was decreased indicating that the subjective value of the large reinforcer was discounted as a function of delay time. However, this discounting effect was significantly enhanced in lesioned rats for the longer delays. These data reveal a contribution of dopaminergic inputs to the dorsolateral striatum on impulsive choice behavior, and provide new insights into neural substrates underlying discounting behaviors. PMID- 25927687 TI - Verbal forward digit span in Spanish population. AB - BACKGROUND: Older people complain of difficulties in recalling telephone numbers and being able to dial them in the correct order. This study examined the developmental trend of verbal forward digit span across adulthood and aging in a Spanish population, as an index of one of the components of Baddeley’s working memory model—the phonological loop—, which illustrates these two aspects. METHOD: A verbal digit span was administered to an incidental sample of 987 participants ranging from 35 to 90 years old. The maximum length was defined that participants could recall of at least two out of three series in the same order as presented with no errors. Demographic variables of gender and educational level were also examined. RESULTS: The ANOVA showed that the three main factors (age group, gender and educational level) were significant, but none of the interactions was. Verbal forward digit span decreases during the lifespan, but gender and educational level affect it slightly. CONCLUSION: Phonological loop is affected by age. The verbal forward digit span in this study is generally lower than the one reported in other studies. PMID- 25927688 TI - Verbal interaction patterns in the clinical context: a model of how people change in therapy. AB - BACKGROUND: The paper "Why do people change in therapy? A preliminary study" (2006), published in this journal, led to the beginning of a line of research based on observational methodology and aimed at the clarification of the therapeutic process. Throughout these years, significant progress has been made towards an explanation of clinical change. In this paper, a synthesis of this line of research is presented, along with a series of conclusions that can, to some extent, provide an answer to the questions we posed in the aforementioned first paper. METHOD: Verbal behavior both of therapist and client was coded for 92 clinical sessions using the Verbal Behavior Interaction Category System (SISC INTER-CVT). Descriptive and sequential analyses of the observations were then performed. RESULTS: The data show the existence of certain patterns of verbal interaction that are related to the clinically relevant activities undertaken by the therapist, from which a model for verbal interaction in the clinical context was developed. CONCLUSIONS: The functional analysis of the therapist-client verbal interaction is essential for the comprehension of the processes that explain clinical change as well as for the improvement of the quality of psychological therapy. PMID- 25927689 TI - Factors associated with prolonging psychological treatment for anxiety disorders. AB - BACKGROUND: Anxiety disorders are one of the disorders most frequently requested for psychological attention. The purpose of this study is to identify the factors that can explain a longer duration of psychological treatment for anxiety disorders. METHOD: 202 patients from the University Psychology Clinic of the Complutense University of Madrid were analyzed. RESULTS: Multivariate regression analysis showed that the presence of obsessive-compulsive disorder and the application of arousal control techniques followed by modeling and other specific techniques were the best predictors of treatment duration. CONCLUSION: Reducing as much as possible the number of techniques applied without reducing intervention efficacy is suggested. In some disorders that produce a greater life disorganization, it may be useful to try to organize the patient´s life either as a first goal or at the same time as the intervention program, so as to increase its effectiveness and reduce the number of sessions. PMID- 25927690 TI - Application of a relational frame theory account of psychological flexibility in young children. AB - BACKGROUND: Acceptance and commitment therapy (ACT) is a contextual behavior therapy based on relational frame theory (RFT), a functional-contextual approach to human language and cognition. The main aim of ACT is to promote psychological flexibility, which has been defined in middle-level terms. The current study proposes that a recently developed RFT account of psychological flexibility might facilitate the adaptation of ACT to the work with young children. METHOD: A case study with a 5-year-old boy presenting problematic anger is presented to illustrate the previous suggestion. The intervention consisted of a brief ACT protocol applied in four, 20-min sessions and a token economy at the service of promoting psychological flexibility. The ACT protocol involved a multiple exemplar training in framing own ongoing experiences through deictic and hierarchical relations and transforming the discriminative functions of those experiences by relating them to rules that progressively specified longer term and symbolic, positive consequences. RESULTS: The intervention was shown to be highly effective in reducing the anger episodes, and the results were maintained during the one year of follow-up. CONCLUSIONS: This study supports the feasibility of the RFT account of psychological flexibility to adapt ACT to the work with young children. PMID- 25927691 TI - The effect of relational training on intelligence quotient: a case study. AB - BACKGROUND: Relational training protocols based on Relational Frame Theory (RFT) are showing promising results in increasing intelligence quotient. This case study aimed at analyzing the effect of a training protocol in fluency and flexibility in relational responding on intelligence quotient with a 4-year-old child. METHOD: The child’s cognitive and psychomotor development was evaluated before and after the implementation of the training protocol using the McCarthy’s Aptitudes and Psychomotricity Scale (MSCA). The training protocol consisted of a multiple-exemplar-training (MET) in relational framing in accordance with COORDINATION (Phases 1 and 2), OPPOSITION (Phase 3 and 4), and COMPARISON (Phases 5 and 6). The MET protocol was implemented in approximately 12 hours throughout five and one half months. RESULTS: The training was effective in establishing relational responding in OPPOSITION and COMPARISON frames as well as in promoting fluency and flexibility in all the three types of trained relations. After this training, the child showed an increase above 1.5 SD in the General Cognitive Index of the MSCA (from 106 to 131). CONCLUSIONS: This case study adds further empirical evidence of the potential of RFT training to improve cognitive abilities and intelligence. PMID- 25927692 TI - A brief nursing intervention reduces anxiety before breast cancer screening mammography. AB - BACKGROUND: Anxiety experienced by women during their participation in breast cancer screening programs can condition their adherence to the program. The aim was to determine whether a brief nursing intervention could reduce anxiety before screening mammography. METHOD: A randomized controlled trial carried out with 436 Spanish women aged between 50-69 years, who attended a population breast cancer screening program. The experimental group received an ad-hoc tailored intervention, which consisted of offering information about the screening program and the mammography exam, as well as of providing personal emotional support. Anxiety was assessed using the State-Trait Anxiety Inventory (STAI). Fear of screening outcome and fear of breast cancer were also assessed. RESULTS: Women of the experimental group had 60% less probability of having a high anxiety state (OR = 0.40; 95%: CI [0.25, 0.65]), after adjusting for sociodemographic and clinical variables. Regarding trait anxiety, no differences were observed between groups. The stratified analysis showed that this positive impact was greater in women who did not fear the screening outcome (OR = 0.24; 95% CI [0.11, 0.52]) or breast cancer (OR = 0.07; 95% CI [0.01, 0.41]). CONCLUSIONS: A protocolized nursing intervention reduced the probability of being anxious when undergoing a screening mammography. PMID- 25927693 TI - The Spanish adaptation of the Interpersonal Sexual Objectification Scale (ISOS). AB - BACKGROUND: Sexual objectification of women is a subtle manifestation of gender violence. The aim of this study was to adapt the 15-item Interpersonal Sexual Objectification Scale (ISOS) to Spanish to obtain a valid instrument to evaluate this construct. METHOD: After its adaptation, the questionnaire was administered to 771 women from the general population. Subsequently, the psychometric properties of the questionnaire were evaluated from both the classical perspective and item response theory. RESULTS: The data obtained were very similar to those of the original version. The ISOS showed good internal consistency and a two-factor structure: body evaluation and unwanted explicit sexual advances. In addition, the ISOS showed correlations with benevolent sexism, state-anxiety and self-esteem. CONCLUSIONS: The Spanish version of the ISOS is a reliable and valid measure of sexual objectification of women in the interpersonal context. PMID- 25927694 TI - Factor structure and psychometric properties of the TFEQ in morbid obese patients, candidates to bariatric surgery. AB - BACKGROUND: To analyze the factor structure and psychometric properties of the TFEQ in a morbid obese Spanish sample of bariatric surgery candidates. METHOD: Multi-trait/ multi-item analyses and alpha coefficients were conducted to test the convergent /discriminant validity and the internal consistency reliability. Principal components analyses (varimax) were used to explore the factor structure. Sub-group factor analyses by gender, age and body mass index (BMI) were conducted to identify unstable items. RESULTS: The internal structure of the original TFEQ factors was unsatisfactory, especially the Disinhibition Scale. Most Disinhibition and Hunger items were grouped on one factor labeled “Dysregulation Eating”. Cognitive Restraint was split into two factors. The first one, related to the behavioral component of Restraint, labeled “Restrained Behaviour” and the second one related to weight and eating concerns called “Predisposition to Restraint”. CONCLUSIONS: The original factor structure of the TFEQ was not replicated. A revised 23-item instrument, representing the three new derived factors is offered as a valid screening instrument for severely obese patients. PMID- 25927695 TI - Construction and psychometric characteristics of the self-concept scale of interaction in the classroom. AB - BACKGROUND: Both construction and psychometric characteristics of a self-concept scale associated with observable behaviors by students and teacher, useful to guide a pedagogic intervention in the classroom are presented. METHOD: A total of 1,385 primary school students, aged between 8 and 12 years, from 24 high-social vulnerability schools of the Province of Concepcion, Chile, participated in the study. The scale was constructed, including a theoretical review of the construct, pilot application with students and interjudge reliability. For the study of psychometric characteristics, exploratory factorial analysis (EFA), confirmatory factorial analysis (CFA), factorial invariance and recurrent validity were performed. RESULTS: A self-report instrument with 22 items shows a three-factor structure, with an explained variance of 44.71% and a high level of fi t for the model. CFA in two different samples showed fi t indicators for configural invariance. It also has concurrent validity. CONCLUSIONS: The scale has good psychometric properties to assess the academic self-concept in the dimensions of Capacity, Work Procedure, and Participation in class. This can be useful to guide an educational intervention in the context of the teacher-student interaction in the classroom, in primary schools with high socio-economic vulnerability. PMID- 25927696 TI - Parents' conceptions of their homework involvement in elementary school. AB - BACKGROUND: Homework is a universal practice used in schools, and is commonly related to academic achievement. According to literature, parental homework involvement has positive and negative aspects, depending on parents’ behaviors. METHOD: Assuming a phenomenographic perspective, this study examined 4th graders’ parents’ conceptions of their involvement in homework. With the purpose of mapping the parents’ various conceptions of homework involvement, 32 semi-structured interviews were conducted and analyzed. RESULTS: The results show that parents’ conceptions of homework involvement have a positive meaning, and focus primarily on the role played in the promotion of academic learning by (a) fostering their children’s autonomy, (b) exerting control over their learning, and (c) providing them with emotional encouragement (when children struggle with difficulties). CONCLUSIONS: Given that parents perceive their involvement in their children’s homework as important, it is necessary to promote parent-teacher collaboration and parent-training workshops to improve the quality of parental homework involvement. PMID- 25927697 TI - Evaluation of satisfaction in an extracurricular enrichment program for high intellectual ability participants. AB - BACKGROUND: The objective of this study was to evaluate the satisfaction of an extracurricular enrichment program of the cognitive and personal management of participants with high intellectual ability. METHOD: At the first time point, the sample consisted of n= 38 participants, and n= 20 parents; n= 48 participants at the second time point; and n= 60 participants at the third time point. The Satisfaction Questionnaire (CSA in Spanish), both for students (CSA-S) and for parents (CSA-P), was constructed. RESULTS: The CSA-S scores showed adequate psychometric properties. Exploratory factor analysis yielded a unidimensional structure. Cronbach’s alpha ranged between 85 and .86. Test-retest reliability was 0.45 (p<.05). The generalizability coefficient was .98. A high percentage of the sample was satisfied with the program, perceived improvements in cognitive and emotional management, motivation and interest in learning, and in the frequency and quality of their interpersonal relationships. CONCLUSIONS: The evaluation of educational programs is necessary in order to determine the efficacy and the effects of their implementation on the participants’ personal and intellectual management. PMID- 25927698 TI - Exploring the factorial structure of the Sport Anxiety Scale-2: invariance across language, gender, age and type of sport. AB - BACKGROUND: This study evaluates the metric and scalar invariance of the Sport Anxiety Scale-2 (SAS-2), which is considered one of the best sport performance anxiety assessment tools for child and adolescent athletes, across four sampling variables: language, gender, age and type of sport. METHOD: The participants were 842 athletes (Mage = 11.73, SD = 2.20) from Spain, Belgium and Portugal, each of whom completed the language-adapted version of the SAS-2. Confirmatory factor analysis was used to test the invariance of the measurement model, and the relative importance of the sampling variables was assessed using a multiple indicator multiple causes model (MIMIC). RESULTS: The results revealed metric and scalar invariance across all sampling variables and null to modest effects of gender, age and type of sport as covariates for the factors of the SAS-2. However, there was a marked effect (ß = -.56) of language on worry, which reflected lower scores on this factor for the Flemish sample. CONCLUSIONS: The results of this study provide evidence of the invariance of the SAS-2 across samples, thereby endorsing the reliability of its factorial structure for future multi-group research. PMID- 25927699 TI - Analyzing data from a fuzzy rating scale-based questionnaire. A case study. AB - BACKGROUND: The fuzzy rating scale was introduced to cope with the imprecision of human thought and experience in measuring attitudes in many fields of Psychology. The flexibility and expressiveness of this scale allow us to properly describe the answers to many questions involving psychological measurement. METHOD: Analyzing the responses to a fuzzy rating scale-based questionnaire is indeed a critical problem. Nevertheless, over the last years, a methodology is being developed to analyze statistically fuzzy data in such a way that the information they contain is fully exploited. In this paper, a summary review of the main procedures is given. RESULTS: The methods are illustrated by their application on the dataset obtained from a case study with nine-year-old children. In this study, children replied to some questions from the well-known TIMSS/PIRLS questionnaire by using a fuzzy rating scale. The form could be filled in either on the computer or by hand. CONCLUSIONS: The study indicates that the requirements of background and training underlying the fuzzy rating scale are not too demanding. Moreover, it is clearly shown that statistical conclusions substantially often differ depending on the responses being given in accordance with either a Likert scale or a fuzzy rating scale. PMID- 25927700 TI - The dilemma of combining positive and negative items in scales. AB - BACKGROUND: This study analyzed the advantages and disadvantages of combining negative and positive items in scales in a Spanish-speaking context. METHOD: Three telephone surveys of 233 people each were carried out. In one survey, 15 items from the Keyes Social Well-Being Scale were worded in a positive fashion; another survey presented 8 items in a positive fashion and 7 items in terms of direct denial; and in the third survey, 7 items were worded positively, 5 were worded in negative terms using polar opposites, and 3 terms were presented in terms of direct denial. RESULTS: The results show a greater tendency for the items in the Positive questionnaire to show results associated with the directionality of the items. However, this questionnaire shows higher values of the Cronbach’s alpha coefficient, and better fit of the theoretical factor structure. CONCLUSIONS: In the survey that included only positive items, findings indicated the existence of acquiescence bias. However, a remedy to this situation only made matters worse, as the combination of positive and negative items seriously affected the internal consistency of the scales. PMID- 25927701 TI - Determination of Zygosity in Adult Chinese Twins Using the 450K Methylation Array versus Questionnaire Data. AB - Previous studies have shown that both single nucleotide polymorphisms (SNPs) and questionnaires-based method can be used for twin zygosity determination, but few validation studies have been conducted using Chinese populations. In the current study, we recruited 192 same sex Chinese adult twin pairs to evaluate the validity of using genetic markers-based method and questionnaire-based method in zygosity determination. We considered the relatedness analysis based on more than 0.6 million SNPs genotyping as the golden standards for zygosity determination. After quality control, qualified twins were left for relatedness analysis based on identical by descent calculation. Then those same sex twin pairs were included in the zygosity questionnaire validation analysis. Logistic regression model was applied to assess the discriminant ability of age, sex and the three questions in zygosity determination. Leave one out cross-validation was used as a measurement of internal validation. The results of zygosity determination based on 65 SNPs in 450k methylation array were all consistent with genotyping. Age, gender, questions of appearance confused by strangers and previously perceived zygosity consisted of the most predictable model with a consistency rate of 0.8698, cross validation predictive error of 0.1347. For twin studies with genotyping and?or 450k methylation array, there would be no need to conduct other zygosity testing for the sake of costs consideration. PMID- 25927702 TI - Characterization of the apoptotic response induced by the cyanine dye D112: a potentially selective anti-cancer compound. AB - Chemotherapeutic drugs that are used in anti-cancer treatments often cause the death of both cancerous and noncancerous cells. This non-selective toxicity is the root cause of untoward side effects that limits the effectiveness of therapy. In order to improve chemotherapeutic options for cancer patients, there is a need to identify novel compounds with higher discrimination for cancer cells. In the past, methine dyes that increase the sensitivity of photographic emulsions have been investigated for anti-cancer properties. In the 1970's, Kodak Laboratories initiated a screen of approximately 7000 dye structural variants for selective toxicity. Among these, D112 was identified as a promising compound with elevated toxicity against a colon cancer cell line in comparison to a non-transformed cell line. Despite these results changing industry priorities led to a halt in further studies on D112. We decided to revive investigations on D112 and have further characterized D112-induced cellular toxicity. We identified that in response to D112 treatment, the T-cell leukemia cell line Jurkat showed caspase activation, mitochondrial depolarization, and phosphatidylserine externalization, all of which are hallmarks of apoptosis. Chemical inhibition of caspase enzymatic activity and blockade of the mitochondrial pathway through Bcl-2 expression inhibited D112-induced apoptosis. At lower concentrations, D112 induced growth arrest. To gain insight into the molecular mechanism of D112 induced mitochondrial dysfunction, we analyzed the intracellular localization of D112, and found that D112 associated with mitochondria. Interestingly, in the cell lines that we tested, D112 showed increased toxicity toward transformed versus non-transformed cells. Results from this work identify D112 as a potentially interesting molecule warranting further investigation. PMID- 25927703 TI - Sonication, Vacuum Infiltration and Thiol Compounds Enhance the Agrobacterium Mediated Transformation Frequency of Withania somnifera (L.) Dunal. AB - In the present study, we have established a stable transformation protocol via Agrobacterium tumafacines for the pharmaceutically important Withania somnifera. Six day-old nodal explants were used for 3 day co-cultivation with Agrobacterium tumefaciens strain LBA4404 harbouring the vector pCAMIBA2301. Among the different injury treatments, sonication, vacuum infiltration and their combination treatments tested, a vacuum infiltration for 10 min followed by sonication for 10 sec with A. tumefaciens led to a higher transient GUS expression (84% explants expressing GUS at regenerating sites). In order to improve gene integration, thiol compounds were added to co-cultivation medium. A combined treatment of L Cys at 100 mg/l, STS at 125 mg/l, DTT at 75 mg/l resulted in a higher GUS expression (90%) in the nodal explants. After 3 days of co-cultivation, the explants were subjected to three selection cycles with increasing concentrations of kanamycin [100 to 115 mg/l]. The integration and expression of gusA gene in T0 and T1 transgenic plants were confirmed by polymerase chain reaction (PCR), and Southern blott analysis. These transformed plants (T0 and T1) were fertile and morphologically normal. From the present investigation, we have achieved a higher transformation efficiency of (10%). Withanolides (withanolide A, withanolide B, withanone and withaferin A) contents of transformed plants (T0 and T1) were marginally higher than control plants. PMID- 25927705 TI - A comparison of aggregate p-value methods and multivariate statistics for self contained tests of metabolic pathway analysis. AB - For pathway analysis of genomic data, the most common methods involve combining p values from individual statistical tests. However, there are several multivariate statistical methods that can be used to test whether a pathway has changed. Because of the large number of variables and pathway sizes in genomics data, some of these statistics cannot be computed. However, in metabolomics data, the number of variables and pathway sizes are typically much smaller, making such computations feasible. Of particular interest is being able to detect changes in pathways that may not be detected for the individual variables. We compare the performance of both the p-value methods and multivariate statistics for self contained tests with an extensive simulation study and a human metabolomics study. Permutation tests, rather than asymptotic results are used to assess the statistical significance of the pathways. Furthermore, both one and two-sided alternatives hypotheses are examined. From the human metabolomic study, many pathways were statistically significant, although the majority of the individual variables in the pathway were not. Overall, the p-value methods perform at least as well as the multivariate statistics for these scenarios. PMID- 25927706 TI - Preferential feeding and occupation of sunlit leaves favors defense response and development in the flea beetle, Altica brevicollis coryletorum--a pest of Corylus avellana. AB - The monophagous beetle, Altica brevicollis coryletorum, is a major leaf pest of Corylus avellana (common hazel). In contrast to majority of the other studied species of shrubs, sunlit leaves are grazed to a much greater extent than shaded leaves. Since the observation of a link between leaf irradiance level and A. brevicollis feeding is unique, we hypothesized that feeding preference of this beetle species is related to the speed needed to escape threats i.e. faster jumping. We also hypothesized that sunlit leaves are more nutritious and easier to consume than the leaves of shaded shrubs. Results indicated that beetle mass was greater in beetles occupying sunlit leaves, which is consistent with our second hypothesis. The study also confirmed under laboratory conditions, that larvae, pupae and beetles that were fed full-light (100% of full light) leaves were significantly heavier than those fed with shaded leaves (15% of full light). In the high irradiance conditions (higher temperature) duration of larval development is also reduced. Further results indicated that neither the concentration of soluble phenols, leaf toughness, or the number of trichomes could explain the insect's preference for sunlit leaves. Notably, measurements of jump length of beetles of this species, both in the field and under laboratory conditions, indicated that the defense pattern related to jumping was associated with light conditions. The jump length of beetles in the sun was significantly higher than in the shade. Additionally, in laboratory tests, beetle defense (jumping) was more strongly affected by temperature (15, 25, or 35 degrees C for 24 h) than by leaf type. The effect of sunlit, higher nutrient leaves (greater level of non-structural carbohydrates) on defense (jumping) appears to be indirect, having a positive effect on insect mass in all developmental stages. PMID- 25927714 TI - Activation helix orientation of the estrogen receptor is mediated by receptor dimerization: evidence from molecular dynamics simulations. AB - In recent years, the nuclear receptors (NR) dynamics have been studied extensively by various approaches. However, the transition path of helix 12 (H12) to an agonist or an antagonist conformation and the exchange pathway between these states is not clear yet. A number of accelerated molecular dynamics (aMD) runs were performed on both an ERalpha monomer and a homodimer with a total length of 2.2 MUs. We have been able to sample reasonably well the H12 conformational landscape to reproduce precisely both the agonist and the antagonist conformations, starting from an unfolded position, and to describe the transition path between them, even in the presence of an agonist ligand. These conformations were the most prevalent, suggesting that the extended H12 state is not likely to exist and that the natural ERalpha H12 position might exist in both the agonist and antagonist states. Remarkably, the H12 transition occurs and is regulated only in a dimer form and the proper agonist or antagonist H12 conformation can be achieved solely in one of the dimer subunits. These results clearly demonstrate that clusters of the two well-known H12 states exist by themselves in the protein free energy landscape, i.e. they are not constituted directly by the ligands, and dimerization favors the switch between them. Conversely, in a monomer, no transitions have been observed. Thus, the dimer formation helps the constitution of populations of discrete H12 conformational states and reshapes the conformational landscape. Further analyses have shown that these observations can be explained by specific interface and long range protein-protein interactions, resulting in conformational fluctuations in helices 5 and 11. Based on these results, a new ERalpha activation/deactivation mechanism and a sequence of binding events during receptor activity modulation have been suggested according to which ligands control the H12 conformation via alterations of the inter-dimer interactions. These findings agree with the HDX and fluorescence experiments and provide an explanation on a structural basis of these data, demonstrating that the dynamics of H12 are not altered greatly upon ligand binding and large fluctuations at the end of H11 are present. PMID- 25927708 TI - Differential Natural Selection of Human Zinc Transporter Genes between African and Non-African Populations. AB - Zinc transporters play important roles in all eukaryotes by maintaining the rational zinc concentration in cells. However, the diversity of zinc transporter genes (ZTGs) remains poorly studied. Here, we investigated the genetic diversity of 24 human ZTGs based on the 1000 Genomes data. Some ZTGs show small population differences, such as SLC30A6 with a weighted-average FST (WA-FST = 0.015), while other ZTGs exhibit considerably large population differences, such as SLC30A9 (WA FST = 0.284). Overall, ZTGs harbor many more highly population-differentiated variants compared with random genes. Intriguingly, we found that SLC30A9 was underlying natural selection in both East Asians (EAS) and Africans (AFR) but in different directions. Notably, a non-synonymous variant (rs1047626) in SLC30A9 is almost fixed with 96.4% A in EAS and 92% G in AFR, respectively. Consequently, there are two different functional haplotypes exhibiting dominant abundance in AFR and EAS, respectively. Furthermore, a strong correlation was observed between the haplotype frequencies of SLC30A9 and distributions of zinc contents in soils or crops. We speculate that the genetic differentiation of ZTGs could directly contribute to population heterogeneity in zinc transporting capabilities and local adaptations of human populations in regard to the local zinc state or diets, which have both evolutionary and medical implications. PMID- 25927715 TI - Knowledge and attitude towards rape and child sexual abuse--a community-based cross-sectional study in rural Tanzania. AB - BACKGROUND: Violence against women and children is globally recognized as a social and human rights concern. In Tanzania, sexual violence towards women and children is a public health problem. The aim of this study was to determine community knowledge of and attitudes towards rape and child sexual abuse, and assess associations between knowledge and attitudes and socio-demographic characteristics. METHODS: A cross-sectional study was undertaken between May and June 2012. The study was conducted in the Kilombero and Ulanga rural districts in the Morogoro Region of Tanzania. Men and women aged 18-49 years were eligible for the study. Through a three-stage cluster sampling strategy, a household survey was conducted using a structured questionnaire. The questionnaire included socio demographic characteristics, attitudes about gender roles and violence, and knowledge on health consequences of rape. Data were analyzed using the Statistical Package for Social Sciences (SPSS) software, version 21. Main outcome measures were knowledge of and attitudes towards sexual violence. Multivariate analyses were used to assess associations between socio-demographic characteristics and knowledge of and attitudes towards sexual violence. RESULTS: A total of 1,568 participants were interviewed. The majority (58.4%) of participants were women. Most (58.3%) of the women respondents had poor knowledge on sexual violence and 63.8% had accepting attitudes towards sexual violence. Those who were married were significantly more likely to have good knowledge on sexual violence compared to the divorced/separated group (AOR = 1.6 (95% CI: 1.1 2.2)) but less likely to have non-accepting attitudes towards sexual violence compared to the single group (AOR = 1.8 (95%CI: 1.4-2.3)). Sex of respondents, age, marital status and level of education were associated with knowledge and attitudes towards sexual violence. CONCLUSIONS: Our study showed that these rural communities have poor knowledge on sexual violence and have accepting attitudes towards sexual violence. Increasing age and higher education were associated with better knowledge and less accepting attitudes towards sexual violence. The findings have potentially important implications for interventions aimed at preventing violence. The results highlight the challenges associated with changing attitudes towards sexual violence, particularly as the highest levels of support for such violence were found among women. PMID- 25927716 TI - Effects of ECT in treatment of depression: study protocol for a prospective neuroradiological study of acute and longitudinal effects on brain structure and function. AB - BACKGROUND: Major depression can be a serious and debilitating condition. For some patients in a treatment resistant depressive episode, electroconvulsive treatment (ECT) is the only treatment that is effective. Although ECT has shown efficacy in randomized controlled trials, the treatment is still controversial and stigmatized. This can in part be attributed to our lack of knowledge of the mechanisms of action. Some reports also suggest potential harmful effects of ECT treatment and memory related side effects have been documented. METHODS/DESIGN: The present study will apply state of the art radiology through advanced magnetic resonance imaging (MRI) techniques to investigate structural and functional brain effects of ECT. As a multi-disciplinary collaboration, imaging findings will be correlated to psychiatric response parameters, neuropsychological functioning as well as neurochemical and genetic biomarkers that can elucidate the underlying mechanisms. The aim is to document both treatment effects and potential harmful effects of ECT. SAMPLE: n = 40 patients in a major depressive episode (bipolar and major depressive disorder). Two control groups with n = 15 in each group: age and gender matched healthy volunteers not receiving ECT and patients undergoing electrical cardioversion (ECV) for atrial fibrillation (AF). Observation time: six months. DISCUSSION: The study will contribute to our understanding of the pathophysiology of major depression as well as mechanisms of action for the most effective treatment for the disorder; ECT. PMID- 25927718 TI - PROspective MEmory Training to improve HEart failUre Self-care (PROMETHEUS): study protocol for a randomised controlled trial. AB - BACKGROUND: Cognitive impairment is seen in up to three quarters of heart failure (HF) patients and has a significant negative impact on patients' health outcomes. Prospective memory, which is defined as memory to carry out future intentions, is important for functional independence in older adults and involves application of multiple cognitive processes that are often impaired in HF patients. The objective of this study is to examine the effects of prospective memory training on patients' engagement in HF self-care and health outcomes, carer strain and quality of life. METHODS/DESIGN: The proposed study is a randomised, controlled trial in which 200 patients diagnosed with HF, and their carers will be recruited from 3 major hospitals across Melbourne. Eligible patients with HF will be randomised to receive either: 1) The Virtual Week Training Program - a computerised prospective memory (PM) training program (intervention) or 2) non adaptive computer-based word puzzles (active control). HF patients' baseline cognitive function will be compared to a healthy control group (n = 60) living independently in the community. Patients will undergo a comprehensive assessment of PM, neuropsychological functioning, self-care, physical, and emotional functioning. Assessments will take place at baseline, 4 weeks and 12 months following intervention. Carers will complete measures assessing quality of life, strain, perceived control in the management of the patients' HF symptoms, and ratings of the patients' level of engagement in HF self-care behaviours. DISCUSSION: If the Virtual Week Training Program is effective in improving: 1) prospective memory; 2) self-care behaviours, and 3) wellbeing in HF patients, this study will enhance our understanding of impaired cognitive processes in HF and potentially is a mechanism to reduce healthcare costs. TRIAL REGISTRATION: Australian New Zealand Clinical Trials Registry #366376; 27 May 2014. https://www.anzctr.org.au/Trial/Registration/TrialReview.aspx?id=366376&isClinica Trial=False . PMID- 25927722 TI - Erratum: OTUB1 de-ubiquitinating enzyme promotes prostate cancer cell invasion in vitro and tumorigenesis in vivo. PMID- 25927719 TI - Molecular species delimitation of a symbiotic fig-pollinating wasp species complex reveals extreme deviation from reciprocal partner specificity. AB - BACKGROUND: Symbiotic relationships have contributed to major evolutionary innovations, the maintenance of fundamental ecosystem functions, and the generation and maintenance of biodiversity. However, the exact nature of host/symbiont associations, which has important consequences for their dynamics, is often poorly known due to limited understanding of symbiont taxonomy and species diversity. Among classical symbioses, figs and their pollinating wasps constitute a highly diverse keystone resource in tropical forest and savannah environments. Historically, they were considered to exemplify extreme reciprocal partner specificity (one-to-one host-symbiont species relationships), but recent work has revealed several more complex cases. However, there is a striking lack of studies with the specific aims of assessing symbiont diversity and how this varies across the geographic range of the host. RESULTS: Here, we use molecular methods to investigate cryptic diversity in the pollinating wasps of a widespread Australian fig species. Standard barcoding genes and methods were not conclusive, but incorporation of phylogenetic analyses and a recently developed nuclear barcoding gene (ITS2), gave strong support for five pollinator species. Each pollinator species was most common in a different geographic region, emphasising the importance of wide geographic sampling to uncover diversity, and the scope for divergence in coevolutionary trajectories across the host plant range. In addition, most regions had multiple coexisting pollinators, raising the question of how they coexist in apparently similar or identical resource niches. CONCLUSION: Our study offers a striking example of extreme deviation from reciprocal partner specificity over the full geographical range of a fig-wasp system. It also suggests that superficially identical species may be able to co exist in a mutualistic setting albeit at different frequencies in relation to their fig host's range. We show that comprehensive sampling and molecular taxonomic techniques may be required to uncover the true structure of cryptic biodiversity underpinning intimate ecological interactions. PMID- 25927726 TI - Target specific proteochemometric model development for BACE1 - protein flexibility and structural water are critical in virtual screening. AB - BACE1 is an attractive target in Alzheimer's disease (AD) treatment. A rational drug design effort for the inhibition of BACE1 is actively pursued by researchers in both academic and pharmaceutical industries. This continued effort led to the steady accumulation of BACE1 crystal structures, co-complexed with different classes of inhibitors. This wealth of information is used in this study to develop target specific proteochemometric models and these models are exploited for predicting the prospective BACE1 inhibitors. The models developed in this study have performed excellently in predicting the computationally generated poses, separately obtained from single and ensemble docking approaches. The simple protein-ligand contact (SPLC) model outperforms other sophisticated high end models, in virtual screening performance, developed during this study. In an attempt to account for BACE1 protein active site flexibility information in predictive models, we included the change in the area of solvent accessible surface and the change in the volume of solvent accessible surface in our models. The ensemble and single receptor docking results obtained from this study indicate that the structural water mediated interactions improve the virtual screening results. Also, these waters are essential for recapitulating bioactive conformation during docking study. The proteochemometric models developed in this study can be used for the prediction of BACE1 inhibitors, during the early stage of AD drug discovery. PMID- 25927723 TI - Tissue-specific patterns of gene expression in the epithelium and stroma of normal colon in healthy individuals in an aspirin intervention trial. AB - BACKGROUND: Regular aspirin use reduces colon adenoma and carcinoma incidence. UDP-glucuronosyltransferases (UGT) are involved in aspirin metabolism and clearance, and variant alleles in UGT1A6 have been shown to alter salicylic acid metabolism and risk of colon neoplasia. METHODS: In a randomized, cross-over, placebo-controlled trial of 44 healthy men and women, homozygous for UGT1A6*1 or UGT1A6*2, we explored differences between global epithelial and stromal expression, using Affymetrix U133 + 2.0 microarrays and tested effects of 60-day aspirin supplementation (325 mg/d) on epithelial and stromal gene expression and colon prostaglandin E2 (PGE2) levels. RESULTS: No statistically significant differences in gene expression were observed in response to aspirin or UGT1A6 genotype, but tissue PGE2 levels were lower with aspirin compared to placebo (p <0.001). Transcripts differentially expressed between epithelium and stroma (N = 4916, P <0.01, false discovery rate <0.001), included a high proportion of genes involved in cell signaling, cellular movement, and cancer. Genes preferentially expressed in epithelium were involved in drug and xenobiotic metabolism, fatty acid and lipid metabolism, apoptosis signaling, and ion transport. Genes preferentially expressed in stroma included those involved in inflammation, cellular adhesion, and extracellular matrix production. Wnt-Tcf4 pathway genes were expressed in both epithelium and stroma but differed by subcellular location. CONCLUSIONS: These results suggest that, in healthy individuals, subtle effects of aspirin on gene expression in normal colon tissue are likely overwhelmed by inter-individual variability in microarray analyses. Differential expression of critical genes between colonic epithelium and stroma suggest that these tissue types need to be considered separately. PMID- 25927729 TI - Quantification and characterization of Salmonella spp. isolates in sewage sludge with potential usage in agriculture. AB - BACKGROUND: This study aims to scrutinize Salmonella spp. and its serotypes in sewage sludge samples from wastewater treatment plants, and assesses the presence of virulence genes and antibiotics resistant to the profile. Samples (n = 54) were collected and analyzed in accordance with the EPA Method 1682/2006. For positive serological reaction, 40 strains were selected for PCR analyses and detection of spvC, invA and sseL virulence genes, plasmid presence and resistance to antibiotics. RESULTS: Salmonella spp. was detected in 38.9% of the samples collected (<0.006473 to 12.19 MPN/gTS). The most prevalent serotype was Salmonella Infantis. All Salmonella spp. (n = 35) presented at least one of the three virulence genes mentioned above and 40% harboured plasmids. Salmonella Typhimurium strains were isolated harbouring at least one of the following virulence genes: spvC, invA or sseL. Four Salmonella spp. isolates were resistant to tetracycline; three were resistant to trimethoprim-sulfamethoxazole, and one isolate was resistant to ciprofloxacin. Two Salmonella spp. strains presented multi resistance to antimicrobial agents. CONCLUSIONS: The results obtained demonstrated that Salmonella spp. have been found in sewage sludge, thus it is essential to set measures to mitigate human health risks when it is intended to be applied on agricultural soils. PMID- 25927731 TI - Two recessive mutations in FGF5 are associated with the long-hair phenotype in donkeys. AB - BACKGROUND: Seven donkey breeds are recognized by the French studbook. Individuals from the Pyrenean, Provence, Berry Black, Normand, Cotentin and Bourbonnais breeds are characterized by a short coat, while those from the Poitou breed (Baudet du Poitou) are characterized by a long-hair phenotype. We hypothesized that loss-of-function mutations in the FGF5 (fibroblast growth factor 5) gene, which are associated with a long-hair phenotype in several mammalian species, may account for the special coat feature of Poitou donkeys. To the best of our knowledge, mutations in FGF5 have never been described in Equidae. METHODS: We sequenced the FGF5 gene from 35 long-haired Poitou donkeys, as well as from a panel of 67 short-haired donkeys from the six other French breeds and 131 short-haired ponies and horses. RESULTS: We identified a recessive c.433_434delAT frameshift deletion in FGF5, present in Poitou and three other donkey breeds and a recessive nonsense c.245G > A substitution, present in Poitou and four other donkey breeds. The frameshift deletion was associated with the long-hair phenotype in Poitou donkeys when present in two copies (n = 31) or combined with the nonsense mutation (n = 4). The frameshift deletion led to a stop codon at position 159 whereas the nonsense mutation led to a stop codon at position 82 in the FGF5 protein. In silico, the two truncated FGF5 proteins were predicted to lack the critical beta strands involved in the interaction between FGF5 and its receptor, a mandatory step to inhibit hair growth. CONCLUSIONS: Our results highlight the allelic heterogeneity of the long-hair phenotype in donkeys and enlarge the panel of recessive FGF5 loss-of-function alleles described in mammals. Thanks to the DNA test developed in this study, breeders of non-Poitou breeds will have the opportunity to identify long-hair carriers in their breeding stocks. PMID- 25927736 TI - Update in perioperative medicine: evidence published in 2014. PMID- 25927734 TI - Workforce interventions to improve access to emergency contraception pills: a systematic review of current evidence in low- and middle-income countries and recommendations for improving performance. AB - BACKGROUND: Emergency contraceptive pills (ECP) are one of the 13 essential commodities addressed by the UN Commission on Life-Saving Commodities for Women and Children. Although ECP have been available for 20 years, a number of barriers still limit women's access ECP in low and middle-income countries (LMIC). The workforce who prescribe or dispense ECP are diverse reflecting the varied contexts where ECP are available across the health, commercial and justice sectors and in the community. No reviews currently exist that examine the roles and experiences of the workforce that provide ECP in LMIC. METHOD: We present a narrative synthesis of research to: identify provider factors that facilitate and constraint access to ECP; assess the effectiveness of associated interventions and; explore associated health system issues in LMIC. A search of bibliographic databases, meta-indexes and websites was undertaken to retrieve peer reviewed and grey literature. Literature was screened and identified documents examined to appraise quality. RESULTS: Thirty-seven documents were included in the review. Studies focused on formal health workers revealing knowledge gaps concerning the role of private sector and non-health providers who increasingly provide ECP. Data from the findings section in the documents were coded under 4 themes: provider knowledge; provider attitudes and beliefs; provider practice and provider training. The analysis revealed provider knowledge gaps, less than favourable attitudes and practice issues. The findings provide limited insight into products prescribed and/or dispensed, the frequency of provision, and information and advice offered to consumers. Pre and in-service training needs were noted. CONCLUSION: As the provision of ECPs shifts from the clinic-based health sector to increasing provision by the private sector, the limited understanding of provider performance and the practice gaps revealed in this review highlight the need to further examine provider performance to inform the development of appropriate workforce interventions. A standardized approach to assessing performance using agreed outcomes measures may serve to ensure a systematic way forward that is inclusive of the diverse workforce that deliver ECP. Recommendations are outlined to enhance the performance of providers to improve access to ECP. A framework is offered to help guide this process with indicators. PMID- 25927737 TI - Extensive retroviral diversity in shark. AB - BACKGROUND: Retroviruses infect a wide range of vertebrates. However, little is known about the diversity of retroviruses in basal vertebrates. Endogenous retrovirus (ERV) provides a valuable resource to study the ecology and evolution of retrovirus. FINDINGS: I performed a genome-scale screening for ERVs in the elephant shark (Callorhinchus milii) and identified three complete or nearly complete ERVs and many short ERV fragments. I designate these retroviral elements "C. milli ERVs" (CmiERVs). Phylogenetic analysis shows that the CmiERVs form three distinct lineages. The genome invasions by these retroviruses are estimated to take place more than 50 million years ago. CONCLUSIONS: My results reveal the extensive retroviral diversity in the elephant shark. Diverse retroviruses appear to have been associated with cartilaginous fishes for millions of years. These findings have important implications in understanding the diversity and evolution of retroviruses. PMID- 25927739 TI - Compact polarization splitter based on silicon grating-assisted couplers. AB - Compact polarization beam splitter (PBS) based on grating-assisted couplers is proposed by utilizing contra-directional coupling between two corrugated strip waveguides. The co-directional coupling in the device is greatly suppressed by the designed asymmetric structure. The phase matching condition is only satisfied for TE polarization at the central wavelength of 1550 nm by a spatially periodic refractive-index perturbation. Due to the contra-directional coupling, the device breaks the limit of the precise control of the coupling strength and length. The simulation results show that the presented PBS, with a coupling length of only 19 MUm, has a broad working bandwidth (~40 nm) for a crosstalk below -12 dB. A large fabrication tolerance (+/-40 nm) for the waveguide width is also achieved. PMID- 25927740 TI - Improved performance of thermal-optic switch using polymer/silica hybrid and air trench waveguide structures. AB - By exploiting the polymer/silica hybrid and the air trench waveguide structures, we demonstrate a new type of low-power consuming and high-speed thermal-optic (TO) switch. Such a design provides an effective means to shorten the switching time of the TO switches, as well as to reduce the power consumption at the same time. This TO switch operated with less than 150 MUs of switching time via a polymer/silica hybrid waveguide structure. Meanwhile, the power consumption was reduced to be 3.4 mW by introducing the air trench structure. PMID- 25927741 TI - Ultrahigh-Q silicon resonators in a planarized local oxidation of silicon platform. AB - We describe a platform for the fabrication of smooth waveguides and ultrahigh quality-factor (Q factor) silicon resonators using a modified local oxidation of silicon (LOCOS) technique. Unlike the conventional LOCOS process, our approach allows the fabrication of nearly planarized structures, supporting a multilayer silicon photonics configuration. Using this approach we demonstrate the fabrication and the characterization of a microdisk resonator with an intrinsic Q factor that is one of the highest Q factors achieved with a compact silicon-on insulator platform. PMID- 25927742 TI - Mapping transverse velocity of particles in capillary vessels by time-varying laser speckle through perturbation analyses. AB - We propose a cross-correlation method to map the transverse velocities of particles moving in capillary vessels using full-field time-varying laser speckle technique. The mapping is achieved by a semi-random perturbation model that describes the intensity fluctuation of time-varying laser speckle signals. When passing through probing volume, moving particles encode a random perturbation into the observed laser speckle pattern. We calculate the transverse flow velocity by cross-correlating the temporal envelopes of the perturbation signals. The proposed method is experimentally verified by the use of polymer microsphere suspension in a glass capillary. PMID- 25927743 TI - Cancellation of non-conservative scattering forces in optical traps by counter propagating beams. AB - Non-conservative forces in optical tweezers generate undesirable behavior, such as particle loss due to radiation pressure and the preclusion of the thermodynamic equilibrium. Here, we rigorously derive criteria for the elimination of non-conservative forces, and describe how these criteria can be met by a large class of counter-propagating, focused optical beams. PMID- 25927744 TI - InAsSb/InAsPSb multiple quantum well disk cavities with pedestal structures on a GaSb substrate for mid-infrared whispering-gallery-mode emission beyond 4 MUm. AB - The mid-infrared whispering-gallery-mode disk cavities with InAs0.85Sb0.15/InAs0.53P0.23Sb0.24 multiple quantum wells active medium on a GaSb substrate were fabricated. For this material system in the mid-infrared range, fabrication techniques were developed to form the disk cavity structure. The smooth sidewalls of the disk cavities were achieved by appropriate gas mixture flow ratio of BCl3/Ar in the inductively coupled plasma-reactive ion etching. In addition, selective wet etching technique was used to form the pedestal of the disk cavity using dilute hydrofluoric acid with good selectivity. For efficient confinement of the whispering gallery modes along the radial direction, the extent of the lateral etching was carefully controlled. The processed 30-MUm diameter disk cavities were optically pumped, and the whispering gallery modes with wavelengths around 4.1 MUm can be observed up to 90 K. PMID- 25927745 TI - Power transfer mechanism of metallic grating coupled whispering gallery microsphere resonator. AB - The power transfer mechanism of the Fano resonance in a metallic grating coupled whispering gallery microsphere resonator is both theoretically investigated and experimentally verified. Based on temporal coupled mode theory, a two-stage cascaded scattering model is formulated to account for the power interaction of multiple resonances in the system. The modeled results show agreement with experimental measurements and are able to explain several counter-intuitive observations in the spectra. The coupling efficiency of the grating coupler is evaluated at critical coupling by approximating symmetric resonance line-shape with grating design. Based on the modeled results, it is found that the coupling efficiency can be further improved by enhancing diffraction efficiency of the first-order diffractions. PMID- 25927746 TI - 456-mW graphene Q-switched Yb:yttria waveguide laser by evanescent-field interaction. AB - In this Letter, we present a passively Q-switched Yb:Y2O3 waveguide laser using evanescent-field interaction with an atmospheric-pressure-chemical-vapor deposited graphene saturable absorber. The waveguide, pumped by a broad area diode laser, produced an average output power of 456 mW at an absorbed power of 4.1 W. The corresponding pulse energy and peak power were 330 nJ and 2 W, respectively. No graphene damage was observed, demonstrating the suitability of top-deposited graphene for high-power operation. PMID- 25927747 TI - Switchable multi-wavelength Tm-doped mode-locked fiber laser. AB - We propose and demonstrate for the first time a switchable tri-wavelength Tm doped ultra-fast fiber laser based on nonlinear polarization evolution (NPE) technique. The NPE effect induces wavelength-dependent loss in the cavity that changes the homogeneous broadening of the effective gain to become inhomogeneous. This inhomogeneous effective gain spectral profile enables the multi-wavelength mode locking. Binary control of three bits can be realized by controlling the polarization in the compact fiber ring cavity. Such switchable laser has potential applications in optical signal processing and communication. PMID- 25927748 TI - Random Fabry-Perot resonator-based sub-kHz Brillouin fiber laser to improve spectral resolution in linewidth measurement. AB - For the first time, we propose a novel Brillouin random fiber laser with a narrow linewidth of ~860 Hz based on the bi-directionally pumped stimulated Brillouin scattering (SBS) in a 10-km-long optical fiber. A random fiber Fabry-Perot (FP) resonator is built up through the pump depletion effects of SBS at both ends of the fiber. A theoretical model is developed to reveal the physics behind the unique random FP resonator that enables narrow random lasing emission. The novel laser is successfully applied for linewidth characterization beyond 860 Hz of light source under test. PMID- 25927749 TI - Differential phase-detecting localized surface plasmon resonance sensor with self assembly gold nano-islands. AB - Self-assembly (SAM) gold nano-islands are fabricated by two-step thin-film deposition-annealing method. Despite random distribution of the SAM, the p polarized light after total internal reflection shows significant phase transition at the extinction wavelengths upon refractive index variation due to localized surface plasmon resonance (LSPR) effect. It resembles the sharp phase transition observed in conventional surface plasmon resonance (SPR) biosensors, so that the bulk sensitivity of the SAM-LSPR sensor is improved via the phase interrogation method. In this Letter, we present both computational and experimental investigations to the SAM-LSPR sensor and the results show excellent agreement with each other. With bulk refractive index resolution to 9.75*10(-8) RIU, we believe the phase-detecting SAM-LSPR sensor would be an essential step toward low-cost label-free sensing applications. PMID- 25927750 TI - Fabrication of large-area concave microlens array on silicon by femtosecond laser micromachining. AB - In this Letter, a novel fabrication of large-area concave microlens array (MLA) on silicon is demonstrated by combination of high-speed laser scanning, which would result in single femtosecond laser pulse ablation on surface of silicon, and subsequent wet etching. Microscale concave microlenses with tunable dimensions and accessional aspherical profile are readily obtained on the 1 cm * 1 cm silicon film, which are useful as optical elements for infrared (IR) applications. The aperture diameter and height of the microlens were characterized and the results reveal that they are both proportional to the laser scanning speed. Moreover, the optical property of high-performance silicon MLAs as a reflective homogenizer was investigated for the visible wavelength, and it can be easily extended to IR light. PMID- 25927751 TI - Second-harmonic generation of light at 245 nm in a lithium tetraborate whispering gallery resonator. AB - A millimeter-sized, monolithic whispering gallery resonator made of a lithium tetraborate, Li2B4O7, crystal was employed for doubly resonant second-harmonic generation with a continuous-wave laser source at 490 nm. An intrinsic quality factor of 2*10(8) was observed at the pump wavelength. A conversion efficiency of 2.2% was attained with 5.9 mW of mode-matched pump power. In the lithium tetraborate resonator, it is feasible to achieve phase-matching of second harmonic generation for pump wavelengths between 486 and 506 nm. PMID- 25927752 TI - Definition of the waist plane for general astigmatic Gaussian beams. AB - We propose a possible generalization of the waist plane for a two-dimensional astigmatic Gaussian beam as a plane of minimal spot area of the beam during propagation. It is shown that the defocusing component of the beam phase vanishes in this plane. Some examples of astigmatic Gaussian beams and corresponding area waist planes are presented and discussed. PMID- 25927753 TI - BREN: body reflection essence-neuter model for separation of reflection components. AB - We propose a novel reflection color model consisting of body essence and (mixed) neuter, and present an effective method for separating dichromatic reflection components using a single image. Body essence is an entity invariant to interface reflection, and has two degrees of freedom unlike hue and maximum chromaticity. As a result, the proposed method is insensitive to noise and proper for colors around CMY (cyan, magenta, and yellow) as well as RGB (red, green, and blue), contrary to the maximum chromaticity-based methods. Interface reflection is separated by using a Gaussian function, which removes a critical thresholding problem. Furthermore, the method does not require any region segmentation. Experimental results show the efficacy of the proposed model and method. PMID- 25927754 TI - Dynamic control of light beams in second harmonic generation. AB - In this Letter, we report the dynamic control of the spatial shape of the second harmonic (SH) beam generated in a nonlinear crystal, by controlling the phase of the input fundamental beam before entering the crystal. This method enables 2D beam shaping and does not require any special fabrication beforehand. We have shown in simulation and experiment that this is possible for both short and long crystals: for short crystals, we assume the transverse phase of the SH beam is doubled relative to the input phase of the fundamental beam; for longer crystals, genetic algorithms were used in order to solve the inverse phase problem, which generally does not have an analytical solution. The method we present enables us to dynamically shape a beam in a nonlinear process, using standard crystals and optical equipment, and without the need to use any optical element after the nonlinear crystal. PMID- 25927755 TI - Wavelength-division multiplexing of nano-optomechanical doubly clamped beam systems. AB - Wavelength-division multiplexing is demonstrated for a set of two doubly clamped beams. Using a single input/output waveguide in a nanophotonic detection system, the two mechanical beams are independently addressable using different wavelength channels as determined by their respective racetrack resonator detection cavities. The two cavities slightly overlap, which also enables the mechanical frequency of both beams to be detected simultaneously with a single wavelength. Finally, to physically map which wavelength channel corresponds to which specific device, a heating laser is targeted individually on each beam to create a reversible mechanical frequency shift. This multiplexing method would allow for the simpler detection of large arrays of nanomechanical devices in a sensor system. PMID- 25927756 TI - Post-process wavelength tuning of silicon photonic crystal slow-light waveguides. AB - Silicon photonic crystal waveguides have enabled a range of technologies, yet their fabrication continues to present challenges. Here, we report on a post processing method that allows us to tune the operational wavelength of slow-light photonic crystal waveguides in concert with optical characterization, offsetting the effects of hole-radii and slab thickness variations. Our method consist of wet chemical surface oxidation, followed by oxide stripping. Theoretical modelling shows that the changes in optical behavior were predictable, and hence controlled tuning can be achieved by changing the number of processing cycles, where each cycle removes approximately 0.25 nm from all exposed surfaces, producing a blueshift of 1.6+/-0.1 nm in operating wavelength. PMID- 25927757 TI - Broadband and fabrication-tolerant on-chip scalable mode-division multiplexing based on mode-evolution counter-tapered couplers. AB - A broadband and fabrication-tolerant on-chip scalable mode-division multiplexing (MDM) scheme based on mode-evolution counter-tapered couplers is designed and experimentally demonstrated on a silicon-on-insulator (SOI) platform. Due to the broadband advantage offered by mode evolution, the two-mode MDM link exhibits a very large, -1 dB bandwidth of >180 nm, which is considerably larger than most of the previously reported MDM links whether they are based on mode-interference or evolution. In addition, the performance metrics remain stable for large-device width deviations from the designed valued by -60 nm to 40 nm, and for temperature variations from -25 degrees C to 75 degrees C. This MDM scheme can be readily extended to higher-order mode multiplexing and a three-mode MDM link is measured with less than -10 dB crosstalk from 1.46 to 1.64 MUm wavelength range. PMID- 25927758 TI - Condition for unity absorption in an ultrathin and highly lossy film in a Gires Tournois interferometer configuration. AB - We present a condition for unity absorption for a Gires-Tournois interferometer configuration constructed from an ultrathin and highly lossy film on top of metallic mirror. From the impedance matching condition in the transmission line theory, we identify a solution space for the required complex refractive index of the lossy film in various film thickness and dielectric constants of the metallic mirror. It is shown that strong absorption requires the imaginary part of the refractive index of the ultrathin lossy film be larger than 0.64, and the physical origin of this condition is elucidated. The proposed method is useful in identifying candidate semiconductor materials that can be used as the lossy film in a unity-absorption Gires-Tournois interferometer configuration and designing the thickness of this film to maximize absorption. PMID- 25927759 TI - All-optical frequency and intensity noise suppression of single-frequency fiber laser. AB - An all-optical frequency and intensity noise suppression technique of a single frequency fiber laser is demonstrated. By exploiting the recursive noise reduction effect of a semiconductor optical amplifier (SOA) in a self-injection locked fiber laser, the frequency and intensity noise of the laser are remarkably suppressed in a significantly wide frequency range. In addition to the linewidth suppression from 3.5 kHz to 700 Hz, the frequency noise has been reduced by ~25 dB. After suppression, the relative intensity noise (RIN) is within 5 dB of the shot noise limit at frequencies from 1.5 to 3 MHz, and the frequency range of the suppression reaches about 30 MHz. The relaxation oscillation peak is observed to shift to lower frequencies and is reduced by about 35 dB from -90 dB/Hz to -125 dB/Hz. It is believed that the achieved low noise makes the fiber laser a promising candidate in applications such as ultra-long haul coherent optical communication and LIDAR. PMID- 25927760 TI - Annular folded electrowetting liquid lens. AB - We report an annular folded electrowetting liquid lens. The front surface of the lens is coated with a circular reflection film, while the back surface of the lens is coated with a ring-shaped reflection film. This approach allows the lens to get optical power from the liquid-liquid interface three times so that the optical power is tripled. An analysis of the properties of the annular folded electrowetting liquid lens is presented along with the design, fabrication, and testing of a prototype. Our results show that the optical power of the proposed liquid lens can be enhanced from ~20.1 to ~50.2 m(-1) in comparison with that of the conventional liquid lens (aperture ~3.9 mm). It can reduce the operating voltage by ~10 V to reach the same diopter as a conventional liquid lens. Our liquid lens has the advantages of compact structure, light weight, and improved optical resolution. PMID- 25927761 TI - Radio-frequency spectroscopy of the active fiber heating under condition of high power lasing generation. AB - A novel method for the precise temperature measurement of active fibers in high power fiber lasers and amplifiers is introduced. This method allows the determination of active fiber longitudinal temperature distribution at different optical pump powers. PMID- 25927762 TI - Phase retrieval with the transport-of-intensity equation in an arbitrarily shaped aperture by iterative discrete cosine transforms. AB - A transport-of-intensity equation (TIE)-based phase retrieval method is proposed with putting an arbitrarily shaped aperture into the optical wavefield. In this arbitrarily shaped aperture, the TIE can be solved under nonuniform illuminations and even nonhomogeneous boundary conditions by iterative discrete cosine transforms with a phase compensation mechanism. Simulation with arbitrary phase, arbitrary aperture shape, and nonuniform intensity distribution verifies the effective compensation and high accuracy of the proposed method. Experiment is also carried out to check the feasibility of the proposed method in real measurement. Comparing to the existing methods, the proposed method is applicable for any types of phase distribution under nonuniform illumination and nonhomogeneous boundary conditions within an arbitrarily shaped aperture, which enables the technique of TIE with hard aperture to become a more flexible phase retrieval tool in practical measurements. PMID- 25927763 TI - 4 * 20 Gbit/s mode division multiplexing over free space using vector modes and a q-plate mode (de)multiplexer. AB - Vector modes are spatial modes that have spatially inhomogeneous states of polarization, such as, radial and azimuthal polarization. In this work, the spatially inhomogeneous states of polarization of vector modes are used to increase the transmission data rate of free-space optical communication via mode division multiplexing. A mode (de)multiplexer for vector modes based on a liquid crystal q-plate is introduced. As a proof of principle, four vector modes each carrying a 20-Gbit/s quadrature phase shift keying signal (aggregate 80 Gbit/s) on a single wavelength channel (lambda~1550 nm) were transmitted ~1 m over the lab table with <-16.4 dB mode crosstalk. Bit error rates for all vector modes were measured at the 7% forward error correction threshold with power penalties <3.41 dB. PMID- 25927764 TI - Graphene-enabled electrically controlled terahertz spatial light modulators. AB - In this Letter, we demonstrate a broadband terahertz (THz) spatial light modulator using 5*5 arrays of large area graphene supercapacitors. Our approach relies on controlling spatial charge distribution on a passive matrix array of patterned graphene electrodes. By changing the voltage bias applied to the rows and columns, we were able to pattern the THz transmittance through the device with high modulation depth and low operation voltage. We anticipate that the simplicity of the device architecture with high contrast THz modulation over a broad spectral range could provide new tools for THz imaging and communication systems. PMID- 25927765 TI - Polarization-independent Talbot effect. AB - We report the first observation of polarization-independent Talbot effect with a high-density grating for TE and TM polarizations, which is attributed to the identical phases and diffraction efficiencies of the diffraction orders for both polarizations. We introduce the simplified modal method that provides an insightful physical description for explanation of the diffraction efficiency and phase of the polarization-independent Talbot effect. Only two even grating modes can be excited, which determines the diffraction properties of the near-field image. We expect that this theoretical work will be helpful for the tremendous potential applications of the Talbot effect. PMID- 25927766 TI - Deep red diode-pumped Pr3+:KY3F10 continuous-wave laser. AB - We report the first observation of continuous-wave laser emission at 720 nm, in the deep red region, of a Pr3+:KY3F10 (Pr:KYF) single crystal, pumped with a blue InGaN-based laser diode at 446 nm. We employed a hemispherical cavity with three different output coupling mirrors transmitting 0.7%, 1.4%, and 2.7% of laser radiation. We obtained a maximum output power of 207 mW with a slope efficiency of 24.3%, comparable for the first time to what has been reported for other praseodymium-doped fluoride crystals. The round-trip cavity losses for our sample were estimated to be between 0.3% and 0.6%, a remarkably small value for this material. PMID- 25927767 TI - Cryogenically monolithic self-Raman lasers: observation of single-longitudinal mode operation. AB - A cryogenically monolithic Nd:YVO4 self-Raman laser is experimentally explored and theoretically analyzed. The variation of the stimulated Raman scattering (SRS) threshold on the temperature is found to be nonlinear because the reduction of thermal lensing enlarges the cavity mode size. In spite of the nonlinear variation of the SRS threshold on the temperature, the overall SRS output power can be efficiently increased from 0.78 to 1.36 W for temperature decreasing from 285 to 80 K at an absorbed power of 17.2 W. More interestingly, the single longitudinal-mode operation is experimentally achieved when temperature is lower than 125 K. PMID- 25927768 TI - Atomic Faraday filter with equivalent noise bandwidth less than 1 GHz. AB - We demonstrate an atomic bandpass optical filter with an equivalent noise bandwidth less than 1 GHz using the D1 line in a cesium vapor. We use the ElecSus computer program to find optimal experimental parameters and find that, for important quantities, the cesium D1 line clearly outperforms other alkali metals on either D-lines. The filter simultaneously achieves a peak transmission of 77%, a passband of 310 MHz, and an equivalent noise bandwidth of 0.96 GHz, for a magnetic field of 45.3 G and a temperature of 68.0 degrees C. Experimentally, the prediction from the model is verified. The experiment and theoretical predictions show excellent agreement. PMID- 25927769 TI - Doppler-broadened noise-immune cavity-enhanced optical heterodyne molecular spectrometry down to 4 * 10-13 cm-1 Hz(-1/2): implementation of a 50,000 finesse cavity. AB - We report on the realization of a Doppler-broadened noise-immune cavity-enhanced optical heterodyne molecular spectrometry (NICE-OHMS) instrumentation based on a high-finesse (50,000) cavity with a detection sensitivity of 4*10(-13) cm(-1) Hz(-1/2). For the P(e)(11) transition targeted at 1.5316 MUm, this corresponds to a C(2)H(2) concentration of 240 ppq (parts-per-quadrillion) detected at 100 Torr. The setup was originally affected by recurrent dips in the cavity transmission, which were attributed to excitation of high-order transverse mode by scattering from the mirrors. The effect of these was reduced by insertion of a small pinhole in the cavity. PMID- 25927770 TI - Highly birefringent phase-shifted fiber Bragg gratings inscribed with femtosecond laser. AB - We demonstrate a highly birefringent phase-shifted fiber Bragg grating (PS-FBG) inscribed in H2-free fiber with a near-infrared femtosecond Gaussian laser beam and uniform phase mask. The PS-FBG was fabricated from an ordinary fiber Bragg grating (FBG) in a case in which overexposure was applied. The spectral evolution from FBG to FS-FBG was observed experimentally with a decrease in transmission loss at dip wavelength, blueshift of the dip wavelength, decrease in the cladding mode loss, and an increase in the insertion loss. A high birefringence was demonstrated experimentally with the existence of PS-FBG only in TM polarization. The formation of the PS-FBG may be due to a negative index change induced by the higher intensity in the center of the Gaussian laser beam. PMID- 25927771 TI - Experimental demonstration of robustness and accuracy of a DLI-based OSNR monitor under changes in the transmitter and link for different modulation formats and baud rates. AB - We experimentally studied the performance of a delay-line interferometer-based optical signal-to-noise ratio (OSNR) monitor that is pre-calibrated in optimal conditions for 25-Gbaud pol-muxed quadrature-amplitude-modulation (QAM) signals, when unpredicted changes outside the monitor occurred either in the transmitter or the link. PMID- 25927772 TI - Fabrication and characterization of high-contrast mid-infrared GeTe4 channel waveguides. AB - We report the fabrication and characterization of high index contrast (Deltan~0.9) GeTe4 channel waveguides on ZnSe substrate for evanescent-field based biosensing applications in the mid-IR spectral region. GeTe4 films were deposited by RF sputtering and characterized for their structure, composition, transparency, and dispersion. The lift-off technique was used to pattern the waveguide channels. Waveguiding from 2.5-3.7 and 6.4-7.5 MUm was demonstrated, and mode intensity profile and estimated propagation losses are given for the 3.5 MUm wavelength. PMID- 25927773 TI - Forward-peaked scattering of polarized light: erratum. AB - We intend to correct the typographical errors that occurred in our recent Letter [Opt. Lett.39, 6422 (2014)]. PMID- 25927774 TI - Continuously tunable and fast-response terahertz metamaterials using in-plane switching dual-frequency liquid crystal cells. AB - A metamaterial that is embedded in an in-plane-switching dual-frequency liquid crystal cell is used to develop an electrically controllable terahertz (THz) metamaterial. The resonance peak of the metamaterial can be redshifted and blueshifted as the frequency of an external voltage is switched, and the response times for the redshift and blueshift are 1.044 and 1.376 ms, respectively. A simulation confirms the spectral redshift and blueshift. The variation in peak frequency as a function of applied frequency at the external voltage is presented. Experimental results show that the resonance peak of the metamaterial can be continuously tuned within a frequency range of 15 GHz as the applied frequency is switched between 19 and 22 kHz. Therefore, this metamaterial is a continuously tunable and fast-response THz filter and could be used for THz imaging and THz telecommunications. PMID- 25927775 TI - Single input state, single-mode fiber-based polarization-sensitive optical frequency domain imaging by eigenpolarization referencing. AB - Fiber-based polarization-sensitive optical frequency domain imaging is more challenging than free-space implementations. Using multiple input states, fiber based systems provide sample birefringence information with the benefit of a flexible sample arm but come at the cost of increased system and acquisition complexity, and either reduce acquisition speed or require increased acquisition bandwidth. Here we show that with the calibration of a single polarization state, fiber-based configurations can approach the conceptual simplicity of traditional free-space configurations. We remotely control the polarization state of the light incident at the sample using the eigenpolarization states of a wave plate as a reference, and determine the Jones matrix of the output fiber. We demonstrate this method for polarization-sensitive imaging of biological samples. PMID- 25927776 TI - Quantitative time-averaged gas and liquid distributions using x-ray fluorescence and radiography in atomizing sprays. AB - A method for quantitative measurements of gas and liquid distributions is demonstrated using simultaneous x-ray fluorescence and radiography of both phases in an atomizing coaxial spray. Synchrotron radiation at 10.1 keV from the Advanced Photon Source at Argonne National Laboratory is used for x-ray fluorescence of argon gas and two tracer elements seeded into the liquid stream. Simultaneous time-resolved x-ray radiography combined with time-averaged dual tracer fluorescence measurements enabled corrections for reabsorption of x-ray fluorescence photons for accurate, line-of-sight averaged measurements of the distribution of the gas and liquid phases originating from the atomizing nozzle. PMID- 25927777 TI - All-fiber bidirectional optical parametric oscillator for precision sensing. AB - We present the design and operation of an all-fiber, synchronously pumped, bidirectional optical parametric oscillator (OPO) for precision sensing applications. The fiber-based OPO (FOPO) generates two frequency combs with identical repetition rates but different carrier offset frequencies. A narrow beatnote was observed with full-width at half-maximum (FWHM) linewidth of <10 Hz when the two frequency combs were overlapped on a photodetector. The all-fiber design removes the need for free-space alignment and adjustment. In addition, an external delay line to overlap the two pulse trains in time on the detector is not needed since our unique design provides automatic delay compensation. We expect the novel FOPO to find important applications in precision measurements including rotation sensing with ultra-large sensing area and sensitivity. PMID- 25927778 TI - Spatio-temporal light springs: extended encoding of orbital angular momentum in ultrashort pulses. AB - We introduce a new class of spatio-temporally coupled ultrashort laser beams, which are obtained by superimposing Laguerre-Gauss beams whose azimuthal mode index is correlated to their frequency. These beams are characterized by helical structures for their phase and intensity profiles, which both encode the orbital angular momentum carried by the light. They can easily be engineered in the optical range, and are naturally produced at shorter wavelengths when attosecond pulses are generated by intense femtosecond Laguerre-Gauss laser beams. These spatio-temporal "light springs" will allow for the transfer of the orbital angular momentum to matter by stimulated Raman scattering. PMID- 25927779 TI - Temperature dependence of sapphire fiber Raman scattering. AB - Anti-Stokes Raman scattering in sapphire fiber has been observed for the first time. Temperature dependence of Raman peaks' intensity, frequency shift, and linewidth were also measured. Three anti-Stokes Raman peaks were observed at temperatures higher than 300 degrees C in a 0.72-m-long sapphire fiber excited by a second-harmonic Nd YAG laser. The intensity of anti-Stokes peaks are comparable to that of Stokes peaks when the temperature increases to 1033 degrees C. We foresee the combination of sapphire fiber Stokes and anti-Stokes measurement in use as a mechanism for ultrahigh temperature sensing. PMID- 25927780 TI - Nanopillar arrays with nanoparticles fabricated by a femtosecond laser pulse train for highly sensitive SERRS. AB - This work presents a novel method for fabricating repeatable, uniform, large area, highly sensitive, surface-enhanced resonance Raman scattering (SERRS) substrates combined with silicon nanopillar arrays and silver nanoparticles. The proposed method consists of two steps: (1) induce periodic ripples in deionized water using a linearly polarized femtosecond laser; and (2) generate dense 80-nm diameter nanopillar arrays with silver nanoparticles in silver nitrate solution with a 90 degrees rotated polarization, femtosecond double-pulse train. As the pulse delay increases from 0 to 1000 fs, the mean size of the silver nanoparticles reduces, and the average number of nanoparticles increases, which, in turn, increases the enhancement factor of SERRS signals up to 1.1*10(9). Furthermore, melamine (down to 125 ppb) was detected by the fabricated SERRS substrates. PMID- 25927781 TI - On the rewriting of ultrashort pulse-induced nanogratings. AB - In this study, we report on the erasure and rewriting of nanogratings by femtosecond laser pulses in the bulk of fused silica. To map the structural processes during rewriting, a combination of optical retardance measurement, small angle X-ray scattering, and scanning electron microscopy was used. The results reveal that already few pulses lead to erasure and formation of anisotropic structures. Repetitive rewriting favors the formation of nanoscopic pores, which increases the optical retardance of nanogratings for large pulse numbers. PMID- 25927782 TI - Cancellation of lateral displacement noise of three-port gratings for coupling light to cavities. AB - Reflection gratings enable light coupling to optical cavities without transmission through substrates. Gratings that have three ports and are mounted in a second-order Littrow configuration even allow the coupling to high-finesse cavities using low diffraction efficiencies. In contrast to conventional transmissive cavity couplers, however, the phase of the diffracted light depends on the lateral position of the grating, which introduces an additional noise coupling. Here, we experimentally demonstrate that this kind of noise cancels out once both diffracted output ports of the grating are combined. We achieve the same signal-to-shot-noise ratio as for a conventional coupler. From this perspective, three-port grating couplers in a second-order Littrow configuration remain a valuable approach to reducing optical absorption of cavity coupler substrates in future gravitational-wave detectors. PMID- 25927783 TI - Superattraction mediated by quantum fluctuations of plasmon quasi-continuum. AB - We investigate the force between a plasmonic nanoparticle and a highly excited two-level system (molecule). Usually van der Waals' force between nanoscale electrically neutral systems is monotonic and attractive at moderate and larger distances and repulsive at small distances. In our system, the van der Waals' force acting on a molecule has a quantum-optical nature. At moderate distances it is attractive as usual but its strength highly increases in narrow distance ranges (lacunas). We show that quantum fluctuations of quasi-continuum of multipole plasmons of high, nearly infinite degree, altogether form an effective environment and determine the interaction force while their spectral peculiarities stand behind the large and narrow lacunas in force. We exactly solve the Hamiltonian problem and discuss the role of the dissipation. PMID- 25927784 TI - Multiple plasmonic-photonic couplings in the Au nanobeaker arrays: enhanced robustness and wavelength tunability. AB - Diffractive coupling in the plasmonic nanoparticle arrays introduces the collective plasmon resonances with high scattering efficiency and narrow linewidth. However, the collective plasmon resonances can be suppressed when the arrays are supported on the solid-state substrates with different superstrates because of the different dispersion relations between the substrate and the superstrate. Herein, we develop a general concept which seeks to synergize the subnanoparticle engineering of "hot spots" with the far-field coupling behavior, for the versatile control of plasmonic-photonic couplings in an asymmetric environment. To demonstrate our concept, we choose as an example the Au nanobeaker arrays (NBAs), which are the conformally coated Au thin layers on the interior sidewalls and bottoms of nanohole arrays in SiO2 substrates. Using the finite-difference time-domain simulations, we show that engineering the plasmonic "hot spots" in the NBAs by simply controlling the depth-to-diameter aspect ratio of individual units enables multiple plasmonic-photonic couplings in an asymmetric environment. These couplings are robust with a wide range of resonance wavelengths from visible to infrared. Furthermore, the angle-dependent transmission spectra of the arrays reveal a transition from band-edge to propagating state for the orthogonal coupling and a splitting of diffraction waves in the parallel coupling. The proposed NBAs will find enhanced applications in plasmonic lasers and biosensing. PMID- 25927785 TI - Burst train generator of high energy femtosecond laser pulses for driving heat accumulation effect during micromachining. AB - A new method for generating high-repetition-rate (12.7-38.2 MHz) burst trains of femtosecond laser pulses has been demonstrated for the purpose of tailoring ultrashort laser interactions in material processing that can harness the heat accumulation effect among pulses separated by a short interval (i.e., 26 ns). Computer-controlled time delays were applied to synchronously trigger the high frequency switching of a high voltage Pockels cell to specify distinctive values of polarization rotation for each round-trip of a laser pulse cycling within a passive resonator. Polarization dependent output coupling facilitated the flexible shaping of the burst envelope profile to provide burst trains of up to ~1 mJ of burst energy divided over a selectable number (1 to 25) of pulses. Individual pulses of variable energy up to 150 MUJ and with pulse duration tunable over 70 fs to 2 ps, were applied in burst trains to generate deep and high aspect ratio holes that could not form with low-repetition-rate laser pulses. PMID- 25927786 TI - Mid-infrared-to-mid-ultraviolet supercontinuum enhanced by third-to-fifteenth odd harmonics. AB - A high-energy supercontinuum spanning 4.7 octaves, from 250 to 6500 nm, is generated using a 0.3-TW, 3.9-MUm output of a mid-infrared optical parametric chirped-pulse amplifier as a driver inducing a laser filament in the air. The high-frequency wing of the supercontinuum spectrum is enhanced by odd-order optical harmonics of the mid-infrared driver. Optical harmonics up to the 15th order are observed in supercontinuum spectra as overlapping, yet well-resolved peaks broadened, as verified by numerical modeling, due to spatially nonuniform ionization-induced blue shift. PMID- 25927787 TI - Surface second harmonic generation from silicon pillar arrays with strong geometrical dependence. AB - We present experimental demonstration and analysis of enhanced surface second harmonic generation (SHG) from hexagonal arrays of silicon pillars. Three sets of Si pillar samples with truncated cone-shaped pillar arrays having periods of 500, 1000, and 2000 nm, and corresponding average diameters of 200, 585 and 1550 nm, respectively, are fabricated by colloidal lithography and plasma dry etching. We have observed strong dependence of SHG intensity on the pillar geometry. Pillar arrays with a 1000 nm period and a 585 nm average diameter give more than a one order of magnitude higher SHG signal compared to the other two samples. We theoretically verified the dependence of SHG intensity on pillar geometry by finite difference time domain simulations in terms of the surface normal E-field component. The enhanced surface SHG light can be useful for nonlinear silicon photonics, surface/interface characterization, and optical biosensing. PMID- 25927788 TI - TE-polarized graphene modes sustained by photonic crystal structures. AB - We present the design of a supporting photonic crystal structure that would allow for the excitation of the predicted transverse electric (TE) polarized excitation in a single layer of graphene. We show that it is possible to measure this excitation at room temperature, and that adding an extra layer of dielectric material on top of the structure would further facilitate the experimental observation of the graphene mode. PMID- 25927789 TI - Concept for a transmissive, large angle, light steering device with high efficiency. AB - A device concept is presented to allow very large angle deflection of light passing through a transmissive device. Deflection of light, switchable between angles larger than +/-60 deg, is shown to be possible with efficiencies approaching 100%. PMID- 25927790 TI - Ground-plane-less bidirectional terahertz absorber based on omega resonators. AB - We present a new ultrathin metamaterial that acts as a frequency-selective absorber of terahertz radiation. The absorber is a square array of pairs of omega shaped micro-resonators made of high-ohmic-loss metal. The metamaterial provides significant suppression of transmitted and reflected radiation in a bidirectional regime (that is, for both forward and backward propagating radiation). The absorber is efficient in a wide range of angles of incidence. The absence of a ground plane makes the absorber unique in comparison with numerous analogs with a ground plane that operate in a unidirectional regime. The novel metamaterial potentially enables controllable transmission of terahertz radiation in imaging systems. Analytical calculations as well as finite-element electromagnetic modeling are presented for an exemplary case with peak absorption at ~3 THz. PMID- 25927791 TI - Fabrication and characterization of an all-solid tellurite-phosphate photonic bandgap fiber. AB - We present an all-solid tellurite-phosphate photonic bandgap fiber (PBGF) with two layers of high-index rods (TeO2-Li2O-WO3-MoO3-Nb2O5, TLWMN) in the cladding (TeO2-ZnO-Li2O-K2O-Al2O3-P2O5, TZLKAP). TLWMN and TZLKAP glasses have good compatibility for fabricating the all-solid PBGF. Photonic bandgap (PBG) properties are calculated by the plane wave expansion method (PWM), and the results agree well with the measured transmission spectrum. Furthermore, the modal field patterns are measured at ~1300 and 1520 nm, respectively. The light is confined to the core at ~1300 nm and lost in the cladding at ~1520 nm, which match well with the calculated modal field intensities. PMID- 25927792 TI - Laser damage density measurement of optical components in the sub-picosecond regime. AB - A rasterscan procedure adapted to the sub-picosecond regime is set to determine laser-induced damage densities as function of fluences. Density measurement is carried out on dielectric high-reflective coatings operating at 1053 nm. Whereas laser-induced damage is usually considered deterministic in this regime, damage events occur on these structures for fluences significantly lower than their intrinsic damage threshold. Scanning electron microscope observations of these "under-threshold" damage sites evidence ejections of defects, embedded in the dielectric stack. This method brings a new viewpoint for the qualification of optical components and their optimization for a high resistance in the sub picosecond regime. PMID- 25927793 TI - Background-free 3D chemical imaging based on polarization coherent Raman holography. AB - We report on a holographic coherent anti-Stokes Raman scattering imaging by using polarization discrimination for nonresonant background suppression. With reduced polarization scrambling effect under weakly focused excitation, nonresonant background-free coherent Raman imaging is demonstrated. A fast chemically selective imaging is achieved in a three-dimensional volume of 70 MUm *70 MUm *100 MUm in 2 s. PMID- 25927795 TI - Flexible compensation of dispersion-induced power fading for multi-service RoF links based on a phase-coherent orthogonal lightwave generator. AB - A novel technique to simultaneously compensate dispersion-induced power fading for multi-service radio-over-fiber (RoF) links is proposed. At the central office (CO), a phase-coherent orthogonal lightwave generator (POLG) consisting of a polarization rotator (PR) and a single-driver Mach-Zehnder modulator (MZM) is used. By adjusting a polarization controller (PC) in the base station (BS), the phase difference between the orthogonal polarization carrier and two sidebands can be controlled, and the frequency response can be flexibly shifted for individual radio frequency (RF) service. We experimentally shift the destructive interference to the constructive interference at various frequencies for 25 km and 30 km fiber links. The performances of two services carrying 1 Gb/s on-off keying (OOK) data at 9 GHz and 16.6 GHz over a 30 km fiber in the proposed system show receiver sensitivity improvement of ~12 dB at the bit error rate (BER) of 10(-3) compared with the conventional double sideband (DSB) modulation case. PMID- 25927794 TI - Imaging and characterizing shear wave and shear modulus under orthogonal acoustic radiation force excitation using OCT Doppler variance method. AB - We report on a novel acoustic radiation force orthogonal excitation optical coherence elastography (ARFOE-OCE) technique for imaging shear wave and quantifying shear modulus under orthogonal acoustic radiation force (ARF) excitation using the optical coherence tomography (OCT) Doppler variance method. The ARF perpendicular to the OCT beam is produced by a remote ultrasonic transducer. A shear wave induced by ARF excitation propagates parallel to the OCT beam. The OCT Doppler variance method, which is sensitive to the transverse vibration, is used to measure the ARF-induced vibration. For analysis of the shear modulus, the Doppler variance method is utilized to visualize shear wave propagation instead of Doppler OCT method, and the propagation velocity of the shear wave is measured at different depths of one location with the M scan. In order to quantify shear modulus beyond the OCT imaging depth, we move ARF to a deeper layer at a known step and measure the time delay of the shear wave propagating to the same OCT imaging depth. We also quantitatively map the shear modulus of a cross-section in a tissue-equivalent phantom after employing the B scan. PMID- 25927796 TI - Plastic fiber design for THz generation through wavelength translation. AB - We report on an all-fiber terahertz (THz) radiation source by exploiting nonlinear parametric process in a theoretically designed microstructured-core double-clad plastic fiber (MC-DCPF). The required phase-matching condition is satisfied through suitable tailoring of the fiber dispersion and nonlinear properties at the pump wavelength of a high-power CO2 laser, with a CO laser of much lower power acting as a seed concomitantly. Our simulated results reveal that a THz radiation source at the frequency of ~3 THz could be realized with a 3-dB phase-matching band width of 2.13 GHz in a 65-m-long optimized MC-DCPF. Maximum power conversion efficiency >1% is realizable even after including the material loss. PMID- 25927798 TI - 8 * 10-17 fractional laser frequency instability with a long room-temperature cavity. AB - We present a laser system based on a 48 cm long optical glass resonator. The large size requires a sophisticated thermal control and optimized mounting design. A self-balancing mounting was essential to reliably reach sensitivities to acceleration of below Deltanu/nu<2*10(-10)/g in all directions. Furthermore, fiber noise cancellations from a common reference point near the laser diode to the cavity mirror and to additional user points (Sr clock and frequency comb) are implemented. Through comparison with other cavity-stabilized lasers and with a strontium lattice clock, instability of below 1*10(-16) at averaging times from 1 to 1000 s is revealed. PMID- 25927797 TI - Measurement of the absolute energy level and hyperfine structure of the 87Rb 4D5/2 state: erratum. AB - In our previous Letter [Opt. Lett.32, 2810 (2007)] an error was made regarding the polarization configuration for the L1 and L2 lasers. That error is corrected here. PMID- 25927799 TI - Molecular decay rate near nonlocal plasmonic particles. AB - When the size of metal nanoparticles is smaller than typically 10 nm, their optical response becomes sensitive to both spatial dispersion and quantum size effects associated with the confinement of the conduction electrons inside the particle. In this Letter, we propose a nonlocal scheme to compute molecular decay rates near spherical nanoparticles which includes the electron-electron interactions through a simple model of electronic polarizabilities. The plasmonic particle is schematized by a dynamic dipolar polarizability alpha(NL)(omega), and the quantum system is characterized by a two-level system. In this scheme, the light matter interaction is described in terms of classical field susceptibilities. This theoretical framework could be extended to address the influence of nonlocality on the dynamics of quantum systems placed in the vicinity of nano-objects of arbitrary morphologies. PMID- 25927800 TI - Four-wave mixing in silicon coupled-cavity resonators with port-selective, orthogonal supermode excitation. AB - We propose coupled-cavity triply-resonant systems for degenerate-pump four-wave mixing (FWM) applications that support strong nonlinear interaction between distributed pump, signal and idler modes, and allow independent coupling of the pump mode and signal/idler modes to separate ports based on nonuniform supermode profile. We demonstrate seeded FWM with wavelength conversion efficiency of -54 dB at input pump power of 3.5 dBm, and discuss applications of such orthogonal supermode coupling. PMID- 25927801 TI - Enhanced spectral response of pi-phase shifted fiber Bragg gratings in closed loop configuration. AB - The transmission spectrum of a ring resonator enclosing a pi-phase shifted fiber Bragg grating (pi-FBG) shows a spectral feature at the Bragg wavelength that is much sharper than resonance of the pi-FBG alone, and that can be detected with a simple integrated cavity output technique. Hence, the resolution of any sensor based on the fitting of the pi-FBG spectral profile can be largely improved by the proposed configuration at no additional fabrication costs and without altering the sensor robustness. A theoretical model shows that the resolution enhancement attainable in the proposed closed-loop geometry depends on the quality factor of the ring resonator. With a commercial grating in a medium finesse ring, a spectral feature 12 times sharper than the pi-FBG resonance is experimentally demonstrated. A larger enhancement is expected in a low-loss, polarization maintaining setup. PMID- 25927802 TI - Single-pass UV generation at 222.5 nm based on high-power GaN external cavity diode laser. AB - We demonstrate a compact system for single-pass frequency doubling of high-power GaN diode laser radiation. The deep UV laser light at 222.5 nm is generated in a beta-BaB2O4 (BBO) crystal. A high-power GaN external cavity diode laser (ECDL) system in Littrow configuration with narrowband emission at 445 nm is used as pump source. At a pump power of 680 mW, a maximum UV power of 16 MUW in continuous-wave operation at 222.5 nm is achieved. This concept enables a compact diode laser-based system emitting in the deep ultraviolet spectral range. PMID- 25927803 TI - Prescribed intensity design for extended sources in three-dimensional rotational geometry. AB - Regulating the intensity distribution of an extended source to produce a prescribed illumination in three-dimensional (3D) rotationally symmetric geometry remains a challenging issue in illumination design. In this Letter, we present an effective method focusing on creating prescribed intensity designs for extended sources. By this method, a prescribed 3D intensity design is first converted into a two-dimensional intensity design for the extended source, a new approach is used to calculate the initial patch to generate a more stable design, and then a feedback strategy is employed to improve the performance of the aspherical lens in 3D rotational geometry. Three examples are presented to demonstrate the effectiveness of the proposed method in terms of performance and capacity for tackling complex designs. PMID- 25927804 TI - Ultracompact and broadband polarization beam splitter based on polarization dependent critical guiding condition. AB - An ultracompact and broadband polarization beam splitter (PBS) based on the polarization-dependent critical guiding condition of an asymmetrical directional coupler is proposed. The device consists of a pair of silicon waveguides with different height and width. Due to the different cutoff conditions for the TE and TM polarization modes, it is possible to have the TM mode guided in one waveguide while the TE mode is supported in both. Therefore, only the phase-matching condition for the cross-coupling of the TE mode needs to be considered. This approach not only simplifies the design procedures but also significantly improves device performance with smaller total length and larger bandwidth. Finally, regardless of the contribution of S-bend waveguides, our proposed PBS has a coupling region as short as 0.2 MUm, which is the shortest reported until now. The simulation result shows that the extinction ratios for the TE and TM polarization are 13.5 and 16.6 dB at their respective output ports, and their insertion losses are 0.29 and 0.13 dB, respectively. Numerical simulations also show that the device offers a very large bandwidth (~140 nm) with large extinction ratio (>10 dB) and low insertion loss (<1 dB). PMID- 25927805 TI - Engineering wavefront caustics trajectories in PT-symmetric lattices. AB - We utilize caustic theory in PT-symmetric lattices to design focusing and curved beam dynamics. We show that the gain and loss parameter in these systems provides an additional degree of freedom that allows for the design of the same caustics trajectories with different intensity distribution in the individual waveguides. Moreover we can create aberration-free focal points at any paraxial distance z(f), with anomalously large focal intensity. PMID- 25927806 TI - Soliton annihilation into a polychromatic dispersive wave. AB - We investigate the propagation of a soliton in an axially varying optical fiber with a progressive change from anomalous to normal dispersion regimes. Spectral and temporal measurements provide evidence for a complete annihilation of the soliton, which explodes into a polychromatic dispersive wave. This interpretation is confirmed by numerical solution of the generalized nonlinear Schrodinger equation. PMID- 25927807 TI - Self-induced transparency and coherent population trapping of 87Rb vapor in a mode-locked laser. AB - Simultaneous self-induced transparency and a dark line resonance are observed inside a mode-locked laser. The circulating pulse, tuned to the 795-nm optical resonance of rubidium, has sufficient intensity to create at each passage a population inversion-return to ground state, typical of self-induced transparency. A drop in fluorescence (dark line resonance), is observed as the repetition rate is tuned to a submultiple of the hyperfine ground-state splitting. PMID- 25927808 TI - Transverse single-mode edge-emitting lasers based on coupled waveguides. AB - We report on the transverse single-mode emission from InGaAs/GaAs quantum well edge-emitting lasers with broadened waveguide. The lasers are based on coupled large optical cavity (CLOC) structures where high-order vertical modes of the broad active waveguide are suppressed due to their resonant tunneling into a coupled single-mode passive waveguide. The CLOC lasers have shown stable Gaussian shaped vertical far-field profiles with a reduced divergence of ~22 degrees FWHM (full width at half-maximum) in CW (continuous-wave) operation. PMID- 25927809 TI - In-plane and out-of-plane tissue micro-displacement measurement by correlation coefficients of optical coherence tomography. AB - We propose a method to measure the in-plane and out-of-plane displacements of tissue using the correlation coefficients of optical coherence tomography (OCT) signals. The displacements are determined by the local correlation coefficients between digitally shifted reference OCT images and a target image. The method achieves sub-micron displacement measurement with an accuracy better than 0.32 MUm and repeatability better than 0.36 MUm. The feasibility of the method was examined by measuring the displacement field of a laser irradiated porcine retina. This method successfully visualized the dynamic change of the displacement field during laser irradiation. PMID- 25927810 TI - Efficient Large Scale Syntheses of 3-Deoxy-D-manno-2-octulosonic acid (Kdo) and Its Derivatives. AB - An efficient method to rapidly synthesize 3-deoxy-D-manno-2-octulosonic acid (Kdo) and its derivatives in large scale has been developed. Starting from D mannose, the di-O-isopropylidene derivative of Kdo ethyl ester was prepared in three steps on a scale of more than 40 g in one batch in an overall yield of 75 80% without any intermediate purification. Kdo, Kdo glycal, and 2-acetylated Kdo ester were synthesized quickly in high yield from a di-O-isopropylidene derivative of Kdo ethyl ester. 2-Deoxy-beta-Kdo ester was obtained with high stereoselectivity via the epimerization of the alpha-isomer using t-BuOH as a proton source. PMID- 25927811 TI - Dual Vacancies: An Effective Strategy Realizing Synergistic Optimization of Thermoelectric Property in BiCuSeO. AB - Vacancy is a very important class of phonon scattering center to reduce thermal conductivity for the development of high efficient thermoelectric materials. However, conventional monovacancy may also act as an electron or hole acceptor, thereby modifying the electrical transport properties and even worsening the thermoelectric performance. This issue urges us to create new types of vacancies that scatter phonons effectively while not deteriorating the electrical transport. Herein, taking BiCuSeO as an example, we first reported the successful synergistic optimization of electrical and thermal parameters through Bi/Cu dual vacancies. As expected, as compared to its pristine and monovacancy samples, these dual vacancies further increase the phonon scattering, which results in an ultra low thermal conductivity of 0.37 W m(-1) K(-1) at 750 K. Most importantly, the clear-cut evidence in positron annihilation unambiguously confirms the interlayer charge transfer between these Bi/Cu dual vacancies, which results in the significant increase of electrical conductivity with relatively high Seebeck coefficient. As a result, BiCuSeO with Bi/Cu dual vacancies shows a high ZT value of 0.84 at 750 K, which is superior to that of its native sample and monovacancies-dominant counterparts. These findings undoubtedly elucidate a new strategy and direction for rational design of high performance thermoelectric materials. PMID- 25927813 TI - Can bone apposition predict the retention force of a femoral stem? An experimental weight-bearing hip-implant model in goats. AB - BACKGROUND: The increasing incidence of prosthesis revision surgery in the Western world has led to an increased focus on the capacity for stem removal. We previously reported on a femoral stem implanted in goats with an approximate 15% reduction in retention force by drilling longitudinally orientated grooves on the side of the stem. In this current study, we aimed to histologically evaluate the bony apposition towards this stem and correlate this apposition with the pullout force. METHODS: We analyzed the femora of 22 goats after stem removal. All stems remained in place for 6 months, and the goats were allowed regular loading of the hip during this time. For histological evaluation, all femora were immersed in EDTA and decalcified until sufficiently soft for standard technique preparation. We evaluated bone apposition, the presence of foreign particle debris and other factors. The apposition was evaluated with a scoring system based on semi quantitative bone apposition in four quadrants. Kappa statistics were calculated for the score. We correlated the retention force with the amount of bone apposition. RESULTS: The stem drilling was the only significant factor influencing the retention force (p = 0.020). The bone apposition Kappa score comparing poor and good apposition scores was fair (kappa = 0.4, 95% CI 0.00 0.88). Signs of foreign body reaction were noted in 5 of 22 goats. CONCLUSIONS: Based on the current findings in an experimental goat model, it appears that the effect of drilling tissue/bone out of the longitudinal grooves has a more significant impact on the retention force required to remove the stem than the amount of bone apposition outside the stem grooves. This observation may be further explored in the research of stem designs that are potentially easier to remove. PMID- 25927816 TI - Footprints of optimal protein assembly strategies in the operonic structure of prokaryotes. AB - In this work, we investigate optimality principles behind synthesis strategies for protein complexes using a dynamic optimization approach. We show that the cellular capacity of protein synthesis has a strong influence on optimal synthesis strategies reaching from a simultaneous to a sequential synthesis of the subunits of a protein complex. Sequential synthesis is preferred if protein synthesis is strongly limited, whereas a simultaneous synthesis is optimal in situations with a high protein synthesis capacity. We confirm the predictions of our optimization approach through the analysis of the operonic organization of protein complexes in several hundred prokaryotes. Thereby, we are able to show that cellular protein synthesis capacity is a driving force in the dissolution of operons comprising the subunits of a protein complex. Thus, we also provide a tested hypothesis explaining why the subunits of many prokaryotic protein complexes are distributed across several operons despite the presumably less precise co-regulation. PMID- 25927817 TI - Antibacterial Balsacones J-M, Hydroxycinnamoylated Dihydrochalcones from Populus balsamifera Buds. AB - A phytochemical investigation of buds from the hardwood tree Populus balsamifera led to the isolation of six new cinnamoylated dihydrochalcones as pairs of racemates and one as a racemic mixture along with the known compound iryantherin D (2), the absolute configuration of which was determined for the first time. The structures of balsacones J (1), K (3), L (4), and M (5) were elucidated on the basis of spectroscopic data (1D and 2D NMR, IR, and MS). Chiral HPLC separations were carried out, and the absolute configuration of the isolated enantiomers unambiguously established via X-ray diffraction analyses and electron circular dichroism spectroscopic data. Each of the purified enantiomers exhibited potent in vitro antibacterial activity against Staphylococcus aureus with IC50 values ranging from 0.61 to 6 MUM. PMID- 25927818 TI - Patient Preferences versus Family Physicians' Perceptions Regarding the Place of End-of-Life Care and Death: A Nationwide Study in Taiwan. AB - BACKGROUND: Enabling people to die in their preferred place is important for providing high-quality end-of-life care. OBJECTIVE: The study objective was to explore patients' preferences regarding the place of end-of-life care and death and to compare these preferences with the perceptions of their family physicians. METHODS: This cross-sectional study used stratified random sampling, surveying 400 registered patients and 200 of their family physicians nationwide, with a five-part, structured, self-report questionnaire. RESULTS: Of the selected population, 310 patients (response rate 77.5%) and 169 physicians (response rate 84.5%) responded. Regarding the preferred place for end-of-life care, most of the patients would choose to receive care at home (60.6%) if home care services were available. Additionally, home was the most frequently preferred (66.5%) place of death. The family physicians' survey showed that a higher proportion of physicians selected home as the preferred place for end-of-life care and death (71.6% and 87.2%, respectively). The results of logistic regression analysis showed that patients younger than 50 years of age who believed in Chinese folk religion and who resided in a rural area were more likely to prefer to die at home. CONCLUSIONS: The most commonly preferred place for end-of-life care and death is the patient's home. Establishing a community-based palliative care system should be encouraged to allow more individuals to die in their preferred locations. There were discrepancies in the preferred place of end-of-life care and death between the patients' preferences and their family physicians' perceptions. More effective physician-patient communication regarding end-of-life care is needed. PMID- 25927819 TI - Conservative management of a perianal rhabdomyosarcoma in a 2-year old child by Papillon's technique. AB - Rhabdomyosarcoma (RMS) is the most common sarcoma in paediatric patients. A perianal site is unusual and is associated with a low cure rate. The few cases of reported perianal RMS have been associated with sequelae. Here, we report the case of a 29-month-old male child who received sequential treatment by surgery, chemotherapy and radiotherapy inspired by Papillon's irradiation of adult anal/low-rectum cancers (including external beam radiotherapy in the gynecological exam position followed by brachytherapy) and who remains in complete remission 49 months post treatment with no sphincter or other anorectal disorders. PMID- 25927821 TI - Determinants of gastric cancer screening attendance in Korea: a multi-level analysis. AB - BACKGROUND: We aimed to assess individual and area-level determinants of gastric cancer screening participation. METHOD: Data on gastric cancer screening and individual-level characteristics were obtained from the 2007-2009 Fourth Korea National Health and Nutrition Examination Survey. The area-level variables were collected from the 2005 National Population Census, 2008 Korea Medical Association, and 2010 National Health Insurance Corporation. The data were analyzed using multilevel logistic regression models. RESULTS: The estimated participation rate in gastric cancer screening adhered to the Korea National Cancer Screening Program guidelines was 44.0% among 10,658 individuals aged over 40 years who were included in the analysis. Among the individual-level variables, the highest income quartile, a college or higher education level, living with spouse, having a private health insurance, limited general activity, previous history of gastric or duodenal ulcer, and not currently smoking were associated with a higher participation rate in gastric cancer screening. Urbanization showed a significant negative association with gastric cancer screening attendance among the area-level factors (odds ratio (OR) = 0.73; 95% confidence interval (CI) = 0.57-0.93 for the most urbanized quartile vs. least urbanized quartile). CONCLUSION: There are differences in gastric cancer screening attendance according to both individual and regional area characteristics. PMID- 25927823 TI - Universal distribution of mutational effects on protein stability, uncoupling of protein robustness from sequence evolution and distinct evolutionary modes of prokaryotic and eukaryotic proteins. AB - Robustness to destabilizing effects of mutations is thought of as a key factor of protein evolution. The connections between two measures of robustness, the relative core size and the computationally estimated effect of mutations on protein stability (DeltaDeltaG), protein abundance and the selection pressure on protein-coding genes (dN/dS) were analyzed for the organisms with a large number of available protein structures including four eukaryotes, two bacteria and one archaeon. The distribution of the effects of mutations in the core on protein stability is universal and indistinguishable in eukaryotes and bacteria, centered at slightly destabilizing amino acid replacements, and with a heavy tail of more strongly destabilizing replacements. The distribution of mutational effects in the hyperthermophilic archaeon Thermococcus gammatolerans is significantly shifted toward strongly destabilizing replacements which is indicative of stronger constraints that are imposed on proteins in hyperthermophiles. The median effect of mutations is strongly, positively correlated with the relative core size, in evidence of the congruence between the two measures of protein robustness. However, both measures show only limited correlations to the expression level and selection pressure on protein-coding genes. Thus, the degree of robustness reflected in the universal distribution of mutational effects appears to be a fundamental, ancient feature of globular protein folds whereas the observed variations are largely neutral and uncoupled from short term protein evolution. A weak anticorrelation between protein core size and selection pressure is observed only for surface residues in prokaryotes but a stronger anticorrelation is observed for all residues in eukaryotic proteins. This substantial difference between proteins of prokaryotes and eukaryotes is likely to stem from the demonstrable higher compactness of prokaryotic proteins. PMID- 25927824 TI - The use of fluorescence microscopy and image analysis for rapid detection of non producing revertant cells of Synechocystis sp. PCC6803 and Synechococcus sp. PCC7002. AB - BACKGROUND: Ethanol production via genetically engineered cyanobacteria is a promising solution for the production of biofuels. Through the introduction of a pyruvate decarboxylase and alcohol dehydrogenase direct ethanol production becomes possible within the cells. However, during cultivation genetic instability can lead to mutations and thus loss of ethanol production. Cells then revert back to the wild type phenotype. A method for a rapid and simple detection of these non-producing revertant cells in an ethanol producing cell population is an important quality control measure in order to predict genetic stability and the longevity of a producing culture. Several comparable cultivation experiments revealed a difference in the pigmentation for non-producing and producing cells: the accessory pigment phycocyanin (PC) is reduced in case of the ethanol producer, resulting in a yellowish appearance of the culture. Microarray and western blot studies of Synechocystis sp. PCC6803 and Synechococcus sp. PCC7002 confirmed this PC reduction on the level of RNA and protein. METHODS: Based on these findings we developed a method for fluorescence microscopy in order to distinguish producing and non-producing cells with respect to their pigmentation phenotype. By applying a specific filter set the emitted fluorescence of a producer cell with a reduced PC content appeared orange. The emitted fluorescence of a non-producing cell with a wt pigmentation phenotype was detected in red, and dead cells in green. In an automated process multiple images of each sample were taken and analyzed with a plugin for the image analysis software ImageJ to identify dead (green), non-producing (red) and producing (orange) cells. RESULTS: The results of the presented validation experiments revealed a good identification with 98 % red cells in the wt sample and 90 % orange cells in the producer sample. The detected wt pigmentation phenotype (red cells) in the producer sample were either not fully induced yet (in 48 h induced cultures) or already reverted to a non-producing cells (in long-term photobioreactor cultivations), emphasizing the sensitivity and resolution of the method. CONCLUSIONS: The fluorescence microscopy method displays a useful technique for a rapid detection of non-producing single cells in an ethanol producing cell population. PMID- 25927825 TI - Erratum: Dual HER2 blockade: preclinical and clinical data. PMID- 25927826 TI - Standpoints of Roma women regarding reproductive health. AB - BACKGROUND: Little is known about the reproductive health of Roma women in Slovenia. The aim of this study is to present the standpoints of Roma women regarding reproductive health, the degree to which primary healthcare services are available to Roma women and the reproductive health circumstances which lead most Roma women to decide to visit a gynaecologist. METHODS: A qualitative research study was carried out. Forty-four adult Roma women from the Hudeje/Vejar settlement in the Dolenjska region, Slovenia, took part in the research. The collected material was processed by means of inductive (qualitative) content analysis. The coding procedure was supported by the QDA software Atlas.ti. RESULTS: Eighteen categories and six themes were identified that enable with the relevant codes an understanding of the standpoints of Roma women regarding reproductive health. The research results showed that the cultural needs of Roma women should be taken into account in their comprehensive healthcare treatment. Roma women wish for equal treatment when health is in question, drawing attention to better communication and the problem of ethnic discrimination in medical facilities. Roma women also feel a need to be educated and to receive professional advice, such as appropriate lectures and/or workshops dealing with reproductive health that would ensure them a higher quality of life over time. CONCLUSIONS: The research results call attention to the necessity of recognising both the need to educate Roma women as well as the need for different approaches to the provision of healthcare services in the field of reproductive health with such a sensitive group of female inhabitants. It will be necessary to familiarise them with preventive programmes and to implement such programmes, to inform them of possible diseases and to encourage them in a friendly and easy-to-understand manner to regularly visit their gynaecologist. PMID- 25927827 TI - Administration of trimethoprim-sulphadimidine does not improve healing of glandular gastric ulceration in horses receiving omeprazole: a randomised, blinded, clinical study. AB - BACKGROUND: Interest in Equine Gastric Ulcer Syndrome (EGUS) has recently increased in part due to a growing awareness of the differences between squamous and glandular disease. The pathophysiology and epidemiology of squamous and glandular disease are different and recently it has been shown that the response of glandular gastric ulceration to monotherapy with omeprazole is poor. Given these differences it has been recommended that specific treatment guidelines be formulated for equine glandular disease and that adjunctive therapies be investigated. Along these lines it has been suggested that the addition of antimicrobials may enhance healing. The objective of this study was to investigate whether the addition of trimethoprim-sulphadimidine to omeprazole therapy would result in superior healing of naturally occurring equine glandular ulceration compared with omeprazole monotherapy. RESULTS: Combination therapy of omeprazole plus trimethoprim-sulphadimidine could not be demonstrated to be superior to omeprazole monotherapy. Healing of the glandular mucosa was observed in 7/15 (47%; 95% CI 24 to 71%) and 3/13 (23%; 95% CI 7% to 50%) of horses in the TMPS and OMEP groups, respectively (OR = 1.8; 95% CI 0.32 to 10.0; p = 0.67). Improvement of the glandular mucosa was observed in 12/15 (80%; 95% CI 56 to 94%) and 9/13 (69%; 95% CI 42 to 89%) of horses in the TMPS and OMEP groups, respectively (OR = 2.9; 95% CI 0.6 to 15.0; p = 0.25). CONCLUSIONS: The results of the present study do not support the addition of trimethoprim-sulphadimidine to therapeutic protocols for equine glandular ulceration. Several limitations were present in the study and the use of antimicrobials as an adjunctive treatment warrants further investigation. However, given the potential deleterious consequences associated with the indiscriminate use of antimicrobials, the inclusion of antimicrobials in treatment regimes for EGUS is not justified until their efficacy is further validated. PMID- 25927828 TI - Measurement properties of adult quality-of-life measurement instruments for eczema: protocol for a systematic review. AB - BACKGROUND: Eczema is a common chronic or chronically relapsing skin disease that has a substantial impact on quality of life (QoL). By means of a consensus-based process, the Harmonising Outcome Measures in Eczema (HOME) initiative has identified QoL as one of the four core outcome domains to be assessed in all eczema trials (Allergy 67(9):1111-7, 2012). Various measurement instruments exist to measure QoL in adults with eczema, but there is a great variability in both content and quality (for example, reliability and validity) of the instruments used, and it is not always clear if the best instrument is being used. Therefore, the aim of the proposed research is a comprehensive systematic assessment of the measurement properties of the existing measurement instruments that were developed and/or validated for the measurement of patient-reported QoL in adults with eczema. METHODS/DESIGN: This study is a systematic review of the measurement properties of patient-reported measures of QoL developed and/or validated for adults with eczema. Medline via PubMed and EMBASE will be searched using a selection of relevant search terms. Eligible studies will be primary empirical studies evaluating, describing, or comparing measurement properties of QoL instruments for adult patients with eczema. Eligibility assessment and data abstraction will be performed independently by two reviewers. Evidence tables will be generated for study characteristics, instrument characteristics, measurement properties, and interpretability. The quality of the measurement properties will be assessed using predefined criteria. Methodological quality of studies will be assessed using the COnsensus-based Standards for the selection of health Measurement INstruments (COSMIN) checklist. A best evidence synthesis will be undertaken if more than one study has investigated a particular measurement property. DISCUSSION: The proposed systematic review will produce a comprehensive assessment of measurement properties of existing QoL instruments in adult patients with eczema. We aim to identify one best currently available instrument to measure QoL in eczema patients. SYSTEMATIC REVIEW REGISTRATION: PROSPERO CRD42015017138. PMID- 25927829 TI - Effect of initial calorie intake via enteral nutrition in critical illness: a meta-analysis of randomised controlled trials. AB - INTRODUCTION: Guidelines support the use of enteral nutrition to improve clinical outcomes in critical illness; however, the optimal calorie and protein intake remains unclear. The purpose of this meta-analysis was to quantitatively analyze randomised controlled trials with regard to clinical outcomes related to varying calorie and protein administration in critically ill adult patients. METHOD: We searched Medline, EMBASE, and Cochrane databases to identify randomised controlled trials that compared the effects of initially different calorie and protein intake in critical illness. The risk ratio (RR) and weighted mean difference with 95% confidence intervals (CI) were calculated using random effects models. The primary endpoint was mortality; secondary endpoints included infection, pneumonia, gastrointestinal intolerance, hospital and intensive care unit lengths of stay, and mechanical ventilation days. RESULTS: In the eight randomised controlled trials that enrolled 1,895 patients there was no statistical difference between the low-energy and high-energy groups in mortality (RR, 0.90; 95% CI, 0.71 to 1.15; P = 0.40), infection (RR, 1.09; 95% CI, 0.92 to 1.29; P = 0.32), or the risk of gastrointestinal intolerance (RR, 0.84; 95% CI, 0.59 to 1.19; P = 0.33). In subgroup analysis, the low-energy subgroup, fed 33.3 to 66.6% of goal energy, showed a lower mortality than the high-energy group (RR, 0.68; 95% CI, 0.51 to 0.92; P = 0.01). The improvements in mortality and gastrointestinal intolerance were absent when calorie intake was >66.6% of goal energy in the low-energy group. High-energy intake combined with high-protein intake reduced the infections (RR, 1.25; 95% CI, 1.04 to 1.52; P = 0.02); however, when the daily protein intake was similar in both groups, a high-energy intake did not decrease the infections. No statistical differences were observed in other secondary outcomes. CONCLUSION: This meta-analysis indicates that high energy intake does not improve outcomes and may increase complications in critically ill patients who are not malnourished. Initial moderate nutrient intake (33.3 to 66.6% of goal energy), compared to high energy, may reduce mortality, and a higher protein intake combined with high energy (>= 0.85 g/kg per day) may decrease the infection rate. However, the contribution of energy versus protein intake to outcomes remains unknown. PMID- 25927831 TI - Are we filling the data void? An assessment of the amount and extent of plant collection records and census data available for tropical South America. AB - Large-scale studies are needed to increase our understanding of how large-scale conservation threats, such as climate change and deforestation, are impacting diverse tropical ecosystems. These types of studies rely fundamentally on access to extensive and representative datasets (i.e., "big data"). In this study, I asses the availability of plant species occurrence records through the Global Biodiversity Information Facility (GBIF) and the distribution of networked vegetation census plots in tropical South America. I analyze how the amount of available data has changed through time and the consequent changes in taxonomic, spatial, habitat, and climatic representativeness. I show that there are large and growing amounts of data available for tropical South America. Specifically, there are almost 2,000,000 unique geo-referenced collection records representing more than 50,000 species of plants in tropical South America and over 1,500 census plots. However, there is still a gaping "data void" such that many species and many habitats remain so poorly represented in either of the databases as to be functionally invisible for most studies. It is important that we support efforts to increase the availability of data, and the representativeness of these data, so that we can better predict and mitigate the impacts of anthropogenic disturbances. PMID- 25927832 TI - Heterogeneity of synovial molecular patterns in patients with arthritis. AB - OBJECTIVES: Early diagnosis of rheumatoid arthritis (RA) is an unmet medical need in the field of rheumatology. Previously, we performed high-density transcriptomic studies on synovial biopsies from patients with arthritis, and found that synovial gene expression profiles were significantly different according to the underlying disorder. Here, we wanted to further explore the consistency of the gene expression signals in synovial biopsies of patients with arthritis, using low-density platforms. METHODS: Low-density assays (cDNA microarray and microfluidics qPCR) were designed, based on the results of the high-density microarray data. Knee synovial biopsies were obtained from patients with RA, spondyloarthropathies (SA) or osteoarthritis (OA) (n = 39), and also from patients with initial undifferentiated arthritis (UA) (n = 49). RESULTS: According to high-density microarray data, several molecular pathways are differentially expressed in patients with RA, SA and OA: T and B cell activation, chromatin remodelling, RAS GTPase activation and extracellular matrix regulation. Strikingly, disease activity (DAS28-CRP) has a significant influence on gene expression patterns in RA samples. Using the low-density assays, samples from patients with OA are easily discriminated from RA and SA samples. However, overlapping molecular patterns are found, in particular between RA and SA biopsies. Therefore, prediction of the clinical diagnosis based on gene expression data results in a diagnostic accuracy of 56.8%, which is increased up to 98.6% by the addition of specific clinical symptoms in the prediction algorithm. Similar observations are made in initial UA samples, in which overlapping molecular patterns also impact the accuracy of the diagnostic algorithm. When clinical symptoms are added, the diagnostic accuracy is strongly improved. CONCLUSIONS: Gene expression signatures are overall different in patients with OA, RA and SA, but overlapping molecular signatures are found in patients with these conditions. Therefore, an accurate diagnosis in patients with UA requires a combination of gene expression and clinical data. PMID- 25927833 TI - Patterns in Abundance, Cell Size and Pigment Content of Aerobic Anoxygenic Phototrophic Bacteria along Environmental Gradients in Northern Lakes. AB - There is now evidence that aerobic anoxygenic phototrophic (AAP) bacteria are widespread across aquatic systems, yet the factors that determine their abundance and activity are still not well understood, particularly in freshwaters. Here we describe the patterns in AAP abundance, cell size and pigment content across wide environmental gradients in 43 temperate and boreal lakes of Quebec. AAP bacterial abundance varied from 1.51 to 5.49 x 105 cells mL-1, representing <1 to 37% of total bacterial abundance. AAP bacteria were present year-round, including the ice-cover period, but their abundance relative to total bacterial abundance was significantly lower in winter than in summer (2.6% and 7.7%, respectively). AAP bacterial cells were on average two-fold larger than the average bacterial cell size, thus AAP cells made a greater relative contribution to biomass than to abundance. Bacteriochlorophyll a (BChla) concentration varied widely across lakes, and was not related to AAP bacterial abundance, suggesting a large intrinsic variability in the cellular pigment content. Absolute and relative AAP bacterial abundance increased with dissolved organic carbon (DOC), whereas cell specific BChla content was negatively related to chlorophyll a (Chla). As a result, both the contribution of AAP bacteria to total prokaryotic abundance, and the cell-specific BChla pigment content were positively correlated with the DOC:Chla ratio, both peaking in highly colored, low-chlorophyll lakes. Our results suggest that photoheterotrophy might represent a significant ecological advantage in highly colored, low-chlorophyll lakes, where DOC pool is chemically and structurally more complex. PMID- 25927834 TI - Molecular and immunological tools for the evaluation of the cellular immune response in the neotropical monkey Saimiri sciureus, a non-human primate model for malaria research. AB - BACKGROUND: The neotropical, non-human primates (NHP) of the genus Saimiri and Aotus are recommended by the World Health Organization as experimental models for the study of human malaria because these animals can be infected with the same Plasmodium that cause malaria in humans. However, one limitation is the lack of immunological tools to assess the immune response in these models. The present study focuses on the development and comparative use of molecular and immunological methods to evaluate the cellular immune response in Saimiri sciureus. METHODS: Blood samples were obtained from nineteen uninfected Saimiri. Peripheral blood mononuclear cells (PBMC) from these animals and splenocytes from one splenectomized animal were cultured for 6, 12, 18, 24, 48, 72 and 96 hrs in the presence of phorbol-12-myristate-13-acetate and ionomycin. The cytokine levels in the supernatant were detected using human and NHP cytometric bead array Th1/Th2 cytokine kits, the Bio-Plex Pro Human Cytokine Th1/Th2 Assay, enzyme linked immunosorbent assay, enzyme-linked immunospot assays and intracellular cytokine secretion assays. Cytokine gene expression was examined through TaqMan(r) Gene Expression Real-Time PCR using predesigned human gene-specific primers and probes or primers and probes designed based on published S. sciureus cytokine sequences. RESULTS: The use of five assays based on monoclonal antibodies specific for human cytokines facilitated the detection of IL-2, IL-4 and/or IFN-gamma. TaqMan array plates facilitated the detection of 12 of the 28 cytokines assayed. However, only seven cytokines (IL-1A, IL-2, IL-10, IL-12B, IL 17, IFN-beta, and TNF) presented relative expression levels of at least 70% of the gene expression observed in human PBMC. The use of primers and probes specific for S. sciureus cytokines facilitated the detection of transcripts that showed relative expression below the threshold of 70%. The most efficient evaluation of cytokine gene expression, in PBMC and splenocytes, was observed after 6-12 hrs of culture, except for LTA in PBMC, whose expression was best analysed after 24 hrs of culture. CONCLUSIONS: Real-time PCR facilitates the analysis of a large number of cytokines altered during malaria infection, and this technique is considered the best tool for the evaluation of the cellular immune response in S. sciureus. PMID- 25927835 TI - Terrestrial Dispersal and Potential Environmental Transmission of the Amphibian Chytrid Fungus (Batrachochytrium dendrobatidis). AB - Dispersal and exposure to amphibian chytrid fungus (Batrachochytrium dendrobatidis, Bd) is not confined to the aquatic habitat, but little is known about pathways that facilitate exposure to wild terrestrial amphibians that do not typically enter bodies of water. We explored the possible spread of Bd from an aquatic reservoir to terrestrial substrates by the emergence of recently metamorphosed infected amphibians and potential deposition of Bd-positive residue on riparian vegetation in Cusuco National Park, Honduras (CNP). Amphibians and their respective leaf perches were both sampled for Bd presence and the pathogen was detected on 76.1% (35/46) of leaves where a Bd-positive frog had rested. Although the viability of Bd detected on these leaves cannot be discerned from our quantitative PCR results, the cool air temperature, closed canopy, and high humidity of this cloud forest environment in CNP is expected to encourage pathogen persistence. High prevalence of infection (88.5%) detected in the recently metamorphosed amphibians and frequent shedding of Bd-positive residue on foliage demonstrates a pathway of Bd dispersal between aquatic and terrestrial habitats. This pathway provides the opportunity for environmental transmission of Bd among and between amphibian species without direct physical contact or exposure to an aquatic habitat. PMID- 25927836 TI - Associations between Parental Feeding Styles and Childhood Eating Habits: A Survey of Hong Kong Pre-School Children. AB - Childhood obesity is a global public health issue, including in the Chinese setting, and its prevalence has increased dramatically throughout the last decade. Since the origins of childhood obesity may lie in the pre-school period, factors relating to very young children's food consumption should be investigated. Parental influence, including feeding style, is the major determinant of childhood dietary behaviour through altering food provision and social environment. However, the applicability of previous research on parental feeding styles was limited by small sample size. To evaluate the influence of parental feeding styles on children's dietary patterns, a cross-sectional study was conducted among 4553 pre-schoolers in Hong Kong. Information was obtained about dietary intake and how regularly they had breakfast, using previous health surveillance surveys taken among primary school students. Parental feeding styles were assessed by a validated Parental Feeding Style Questionnaire and categorized into 'instrumental feeding', 'emotional feeding', 'prompting and encouragement to eat' and 'control over eating'. Multivariable analysis was performed, adjusted for demographic information. Instrumental and/or emotional feeding was found to relate to inadequate consumption of fruit, vegetables and breakfast, and positively correlated with intake of high-energy-density food. Encouragement on eating was associated with more frequent consumption of fruits, vegetables, dairy products and breakfast. Control over eating correlated with more frequent consumption of fruits, vegetables and breakfast, and less consumption of dairy products and high-energy-density food. The present study has provided evidence on the associations between parental feeding styles and dietary patterns of Hong Kong pre-school children from a reasonably large population. Parents should avoid instrumental and emotional feeding, and implement control and encouragement to promote healthy food intake. Longitudinal studies and interventions on parental feeding style are required to confirm the research findings. PMID- 25927838 TI - Behavioral Plasticity in Response to Environmental Manipulation among Zebrafish (Danio rerio) Populations. AB - Plastic responses can have adaptive significance for organisms occurring in unpredictable environments, migratory species and organisms occupying novel environments. Zebrafish (Danio rerio) occur in a wide range of habitats and environments that fluctuate frequently across seasons and habitats. We expect wild populations of fish to be behaviorally more flexible than fish reared in conventional laboratory and hatchery environments. We measured three behavioral traits among 2 wild (U and PN) and 1 laboratory bred (SH) zebrafish populations in four environments differing in water flow and vegetation regimes. We found that the degree of plasticity varied with the type of behavior and also among populations. In general, vegetation increased aggression and water flow decreased latency to feed after a disturbance, but the patterns were population dependent. For example, while wild U fish fed more readily after a disturbance in vegetated and/or flowing habitats, fish from the wild PN population and lab-reared SH strain showed little variation in foraging across different environmental conditions. Zebrafish from all the three populations were more aggressive when tested in an arena with vegetation. In contrast, while there was an inter population difference in shoaling distances, variation in shoaling distance across environmental conditions within populations was not significant. These results suggest that both foraging and aggression in zebrafish are more plastic and influenced by immediate context than is shoaling distance, which may have a stronger genetic basis. Our findings point to different underlying mechanisms influencing the expression of these traits and warrants further investigations. PMID- 25927839 TI - Response of spring wheat (Triticum aestivum L.) quality traits and yield to sowing date. AB - The unpredictability and large fluctuation of the climatic conditions in rainfed regions do affect spring wheat yield and grain quality. These variations offer the opportunity for the production of better quality wheat. The effect of variable years, locations and sowing managements on wheat grain yield and quality was studied through field experiments using three genotypes, three locations for two years under rainfed conditions. The two studied years as contrasting years at three locations and sowing dates depicted variability in temperature and water stress during grain filling which resulted considerable change in grain yield and quality. Delayed sowing, years (2009-10) and location (Talagang) with high temperature and water stress resulted increased proline, and grain quality traits i.e. grain protein (GP) and grain ash (GA) than optimum conditions (during 2008 09, at Islamabad and early sowing). However, opposite trend was observed for dry gluten (DG), sodium dodecyl sulphate (SDS), SPAD content and grain yield irrespective of genotypes. The influence of variable climatic conditions was dominant in determining the quality traits and inverse relationship was observed among some quality traits and grain yield. It may be concluded that by selecting suitable locations and different sowing managements for subjecting the crop to desirable environmental conditions (temperature and water) quality traits of wheat crop could be modified. PMID- 25927841 TI - Proteomic database mining opens up avenues utilizing extracellular protein phosphorylation for novel therapeutic applications. AB - Recent advances in extracellular signaling suggest that extracellular protein phosphorylation is a regulatory mechanism outside the cell. The list of reported active extracellular protein kinases and phosphatases is growing, and phosphorylation of an increasing number of extracellular matrix molecules and extracellular domains of trans-membrane proteins is being documented. Here, we use public proteomic databases, collagens - the major components of the extracellular matrix, extracellular signaling molecules and proteolytic enzymes as examples to assess what the roles of extracellular protein phosphorylation may be in health and disease. We propose that novel tools be developed to help assess the role of extracellular protein phosphorylation and translate the findings for biomedical applications. Furthermore, we suggest that the phosphorylation state of extracellular matrix components as well as the presence of extracellular kinases be taken into account when designing translational medical applications. PMID- 25927843 TI - Graves' disease presenting as bi-ventricular heart failure with severe pulmonary hypertension and pre-eclampsia in pregnancy--a case report and review of the literature. AB - BACKGROUND: Graves' disease, a well-known cause of hyperthyroidism, is an autoimmune disease with multi-system involvement. More prevalent among young women, it appears as an uncommon cardiovascular complication during pregnancy, posing a diagnostic challenge, largely owing to difficulty in detecting the complication, as a result of a low index of suspicion of Graves' disease presenting during pregnancy. Globally, cardiovascular disease is an important factor for pregnancy-related morbidity and mortality. Here, we report a case of Graves' disease detected for the first time in pregnancy, in a patient presenting with bi- ventricular heart failure, severe pulmonary hypertension and pre- eclampsia. Emphasis is placed on the spectrum of clinical presentations of Graves' disease, and the importance of considering this thyroid disorder as a possible aetiological factor for such a presentation in pregnancy. CASE PRESENTATION: A 30-year-old Bangladeshi-Bengali woman, in her 28th week of pregnancy presented with severe systemic hypertension, bi-ventricular heart failure and severe pulmonary hypertension with a moderately enlarged thyroid gland. She improved following the administration of high dose intravenous diuretics, and delivered a premature female baby of low birth weight per vaginally, twenty four hours later. Pre-eclampsia was diagnosed on the basis of hypertension first detected in the third trimester, 3+ oedema and mild proteinuria. Electrocardiography revealed sinus tachycardia with incomplete right bundle branch block and echocardiography showed severe pulmonary hypertension with an estimated pulmonary arterial systolic pressure of 73 mm Hg, septal and anterior wall hypokinesia with an ejection fraction of 51%, grade I mitral and tricuspid regurgitation. Thyroid function tests revealed a biochemically hyperthyroid state and positive anti- thyroid peroxidase antibodies was found. (99m)Technetium pertechnetate thyroid scans demonstrated diffuse toxic goiter as evidenced by an enlarged thyroid gland with intense radiotracer concentration all over the gland. The clinical and biochemical findings confirmed the diagnosis of Graves' disease. CONCLUSIONS: Graves' disease is an uncommon cause of bi ventricular heart failure and severe pulmonary hypertension in pregnancy, and a high index of clinical suspicion is paramount to its effective diagnosis and treatment. PMID- 25927844 TI - New insights into the role of ID proteins in breast cancer metastasis: a MET affair. AB - The establishment of lethal metastases depends on the capacity of a small number of cancer cells to regenerate a tumor after entering a target organ. Stankic and colleagues have identified a role for the inhibitor of differentiation protein, ID1, as a critical regulator of breast cancer stem-like properties and metastatic colonization. Under the control of tumor growth factor-beta signaling, ID1 induces mesenchymal-epithelial transition at the metastatic site by antagonizing the activity of the basic helix-loop-helix transcription factor Twist1. This study sheds light on mechanisms that initiate metastatic outgrowth, and strengthens the concept that epithelial-mesenchymal plasticity is crucial at different stages of metastasis. PMID- 25927848 TI - Developing models for cachexia and their implications in drug discovery. AB - INTRODUCTION: Cachexia is a complex metabolic syndrome associated with underlying illness and characterized by loss of muscle with or without loss of fat mass. Systemic inflammation plays a central role in its pathophysiology. As millions of patients are in a cachectic state of chronic disease, cachexia is one of the major causes of death worldwide. Difficulties in the recruitment and follow-up of clinical trials mean that well-characterized animal models are of great importance in developing cachexia therapies. However, some of the widely used animal models have limitations in procedural reproducibility or in recapitulating in the cachectic phenotype, which has warranted the development of novel models for cachexia. AREAS COVERED: This review focuses on some of the currently developing rodent models designed to mimic each co-morbidity in cachexia. EXPERT OPINION: Through developing cancer models, researchers have been seeking more targets for intervention. In cardiac cachexia, technical issues have been overcome by transgenic models. Furthermore, the development of new animal models has enabled the elucidation of the roles of inflammation, anabolism/catabolism in muscle/fat tissue and anorexia on cachexia. As metabolic and inflammatory pathways in cachexia may compromise cardiac muscle, the analysis of cardiac function/tissue in non-cardiac cachexia may be a useful component of cachexia assessment common to different underlying diseases and pave the way for novel drug discovery. PMID- 25927845 TI - Experiences of adolescents and young adults with ADHD in Hong Kong: treatment services and clinical management. AB - BACKGROUND: Specialist services for the treatment of attention deficit hyperactivity disorder (ADHD) in adulthood in Hong Kong are yet to be developed. This study aims to explore the experiences of adolescents and young adults with ADHD in accessing treatment and services, coping with ADHD-related impairment, and their expectations of future treatment in Hong Kong. METHOD: Qualitative interviews were conducted with a semi-structured guide. Forty young adult patients aged between 16 and 23 were included in the study. The interview recordings were transcribed verbatim and anonymised. Data were analysed with a thematic approach based on key principles of Grounded Theory. RESULTS: Four meta themes were developed: Accessing ADHD diagnosis and treatment services; ADHD related impairment; Experience of ADHD treatments; and Attitudes and expectations of future ADHD treatment. The role of parents and schools were highly significant in accessing services for patients diagnosed with ADHD in childhood. In general, ADHD affected every aspect of patients' lives including academic outcome, employment, family and social relationships. Medications were the principal treatment for ADHD amongst the interviewees and were reported to be generally effective. Half of the patients received non-pharmacological treatments in childhood but these effects were reported to be temporary. There was general consensus that the needs of patients with ADHD could not be met by the current service. In particular, there is a lack of specialist service for adults with ADHD, follow-up by different clinicians, and insufficient provision of non pharmacological treatments. CONCLUSION: The findings suggest that further development of specialist ADHD services and non-pharmacological options for young adults are essential to meet their diverse needs with a holistic approach. PMID- 25927846 TI - Factors associated with HIV counseling and testing behavior among undergraduates of universities and vocational technical training schools in Tbilisi, Georgia. AB - BACKGROUND: Stigmatizing attitude towards HIV/AIDS alongside other factors such as HIV knowledge, substance use, sexual behavior, and involvement in various social activities (e.g., internet use, exposure to media) may be related to likelihood of having HIV counseling and testing (HCT). Thus, we examined these associations among 18-24 year old post-secondary school students in Tbilisi, Georgia. METHODS: We conducted a secondary data analysis of a 2010 cross sectional survey of 1,879 secondary and post-secondary school students aged 15 to 24 years in Tbilisi, Georgia examining sociodemographics, substance use, sexual behavior, HIV-related knowledge and stigmatizing attitudes, and recreational activities in relation to lifetime HCT. A stratified two-stage cluster sample design was used by the parent study with universities selected with probabilities proportional to their size at the first stage, and with a random selection of students stratified by gender in each of the participating university at the second stage. RESULTS: The vast majority (95.6%) of participants never received HCT. In the multivariate regression model, significant predictors of lifetime receipt of HCT included being married (p = 0.03), not having HIV stigmatized attitude (p = 0.03), more often reading fiction literature (p = 0.02), more often going out in the evenings (p = 0.03), and more often passing time with friends (p = 0.05). CONCLUSIONS: Intervening on HIV stigmatizing attitudes may be a critical prevention or HCT promotion strategy among youth in Georgia. In order to better inform policy and programs, future research should examine contextual factors in secondary and post-secondary schools that impact HCT among Georgian youth. Specifically, factors impacting differential rates of HCT among males and females, the social stigma and knowledge related to HCT and HIV, and the impact of leisure time activity involvement on HCT should be examined further. In addition, interventions and policies that might impact attitudes toward HIV and HCT should be investigated and considered. PMID- 25927849 TI - Effects of traditional Chinese medicine Shu Gan Jian Pi granules on patients with breast cancer and cancer-related fatigue: study protocol for a randomized controlled trial. AB - BACKGROUND: Cancer-related fatigue (CRF) is a common and often long-lasting symptom for many breast cancer survivors. Evidence for its management is scarce. However, the Traditional Chinese Medicine (TCM) Shu Gan Jian Pi (SGJP) granules is an effective and practical therapy for CRF. METHODS/DESIGN: We will conduct a multicenter, randomized, double-blind, placebo-controlled clinical trial to determine whether the SGJP granules can effectively manage CRF. Breast cancer survivors experiencing fatigue within 5 years of primary treatment completion will be enrolled and randomly assigned to Group S (SGJP) or Group P (placebo). The primary outcome measures will include Revised Piper Fatigue Scale score. Outcome measures will be collected at baseline and at weeks 2, 4, and 8. DISCUSSION: This study's findings may contribute to the development of an effective intervention for CRF. TRIAL REGISTRATION: Current controlled trials ISRCTN12702489 , 14 August, 2013. PMID- 25927852 TI - Variation in DNAH1 may contribute to primary ciliary dyskinesia. AB - BACKGROUND: Primary Ciliary Dyskinesia (PCD) is a genetically heterogeneous ciliopathy caused by ultrastructural defects in ciliary or flagellar structure and is characterized by a number of clinical symptoms including recurrent respiratory infections progressing to permanent lung damage and infertility. CASE PRESENTATION: Here we describe our search to delineate the molecular basis in two affected sisters with clinically diagnosed PCD from a consanguineous Saudi Arabian family, in which all known genes have been excluded. A homozygosity mapping-based approach was utilized that ultimately identified one single affected-shared region of homozygosity using 10 additional unaffected family members. A plausible candidate gene was directly sequenced and analyzed for mutations. A novel homozygous missense aberration (p.Lys1154Gln) was identified in both sisters in the DNAH1 gene that segregated completely with the disease phenotype. Further confirmation of this interesting variant was provided by exome wide analysis in the proband. CONCLUSION: Molecular variation in DNAH1 may play a role in PCD and its potential contribution should be considered in patients where all known genes are excluded. PMID- 25927851 TI - Mitochondrial sequences reveal a clear separation between Angolan and South African giraffe along a cryptic rift valley. AB - BACKGROUND: The current taxonomy of the African giraffe (Giraffa camelopardalis) is primarily based on pelage pattern and geographic distribution, and nine subspecies are currently recognized. Although genetic studies have been conducted, their resolution is low, mainly due to limited sampling. Detailed knowledge about the genetic variation and phylogeography of the South African giraffe (G. c. giraffa) and the Angolan giraffe (G. c. angolensis) is lacking. We investigate genetic variation among giraffe matrilines by increased sampling, with a focus on giraffe key areas in southern Africa. RESULTS: The 1,562 nucleotides long mitochondrial DNA dataset (cytochrome b and partial control region) comprises 138 parsimony informative sites among 161 giraffe individuals from eight populations. We additionally included two okapis as an outgroup. The analyses of the maternally inherited sequences reveal a deep divergence between northern and southern giraffe populations in Africa, and a general pattern of distinct matrilineal clades corresponding to their geographic distribution. Divergence time estimates among giraffe populations place the deepest splits at several hundred thousand years ago. CONCLUSIONS: Our increased sampling in southern Africa suggests that the distribution ranges of the Angolan and South African giraffe need to be redefined. Knowledge about the phylogeography and genetic variation of these two maternal lineages is crucial for the development of appropriate management strategies. PMID- 25927854 TI - Casein kinase 1 (alpha, delta and epsilon) localize at the spindle poles, but may not be essential for mammalian oocyte meiotic progression. AB - CK1 (casein kinase 1) is a family of serine/threonine protein kinase that is ubiquitously expressed in eukaryotic organism. CK1 members are involved in the regulation of many cellular processes. Particularly, CK1 was reported to phosphorylate Rec8 subunits of cohesin complex and regulate chromosome segregation in meiosis in budding yeast and fission yeast. (1-3) Here we investigated the expression, subcellular localization and potential functions of CK1alpha, CK1delta and CK1epsilon during mouse oocyte meiotic maturation. We found that CK1alpha, CK1delta and CK1epsilon all concentrated at the spindle poles and co-localized with gamma-tubulin in oocytes at both metaphase I (MI) and metaphase II (MII) stages. However, depletion of CK1 by RNAi or overexpression of wild type or kinase-dead CK1 showed no effects on either spindle organization or chromosome segregation during oocyte meiotic maturation. Thus, CK1 is not the kinase that phosphorylates Rec8 cohesin in mammalian oocytes, and CK1 may not be essential for spindle organization and meiotic progression although they localize at spindle poles. PMID- 25927855 TI - Identification of TRAIL-inducing compounds highlights small molecule ONC201/TIC10 as a unique anti-cancer agent that activates the TRAIL pathway. AB - BACKGROUND: We previously reported the identification of ONC201/TIC10, a novel small molecule inducer of the human TRAIL gene that improves efficacy-limiting properties of recombinant TRAIL and is in clinical trials in advanced cancers based on its promising safety and antitumor efficacy in several preclinical models. METHODS: We performed a high throughput luciferase reporter screen using the NCI Diversity Set II to identify TRAIL-inducing compounds. RESULTS: Small molecule-mediated induction of TRAIL reporter activity was relatively modest and the majority of the hit compounds induced low levels of TRAIL upregulation. Among the candidate TRAIL-inducing compounds, TIC9 and ONC201/TIC10 induced sustained TRAIL upregulation and apoptosis in tumor cells in vitro and in vivo. However, ONC201/TIC10 potentiated tumor cell death while sparing normal cells, unlike TIC9, and lacked genotoxicity in normal fibroblasts. Investigating the effects of TRAIL-inducing compounds on cell signaling pathways revealed that TIC9 and ONC201/TIC10, which are the most potent inducers of cell death, exclusively activate Foxo3a through inactivation of Akt/ERK to upregulate TRAIL and its pro apoptotic death receptor DR5. CONCLUSION: These studies reveal the selective activity of ONC201/TIC10 that led to its selection as a lead compound for this novel class of antitumor agents and suggest that ONC201/TIC10 is a unique inducer of the TRAIL pathway through its concomitant regulation of the TRAIL ligand and its death receptor DR5. PMID- 25927862 TI - Atorvastatin counteracts high glucose-induced Kruppel-like factor 2 suppression in human umbilical vein endothelial cells. AB - OBJECTIVE: Kruppel-like factor 2 (KLF2) is a transcription factor that regulates endothelial function and atorvastatin can stabilize atherosclerotic plaque and inhibit inflammation on endothelial cells by attenuating the role of cytokines. The aim of this study is to investigate the effect of high glucose (HG) on KLF2 expression in human umbilical vein endothelial cells (HUVECs) and the underlying mechanisms. METHODS: HUVECs were isolated from the human umbilical cords from normal pregnancies and exposed to medium containing 25.5 mM D-glucose for 24 hours as the HG induction model (HG group). In the HG plus atorvastatin groups or KLF2 gene transduction, the medium then was collected for the nitric oxide (NO) assay and the cells were harvested for Western blot and for the real-time polymerase chain reaction to observe the expression of KLF2, vascular cell adhesion molecule (VCAM)-1, intercellular adhesion molecule (ICAM)-1, total and phosphorylated endothelial NO synthase (eNOS), p38 mitogen-activated protein kinase (MAPK), extracellular signal-regulated kinase (ERK)1/2, caspase-3 and cleaved caspase-3 and the role of the p38MAPK and ERK1/2 intracellular signal pathway. The cells' apoptosis was analyzed by flow cytometry. RESULTS: HG dose dependently increased apoptosis. The presence of HG inhibited the expression of KLF2 mRNA and protein in HUVECs and atorvastatin treatment increased KLF2 expression, thus counteracted HG-induced suppression of KLF2 expression, and overexpression of KLF2 might protect the cells from apoptosis. HG increased the expression of VCAM-1, ICAM-1, but decreased the nitric oxide release and the expression of p-eNOs/eNos in HUVECs. However, atorvastatin reversed these changes and also attenuated high-glucose induced p38 MAPK and ERK1/2 phosphorylation. CONCLUSIONS: HG suppressed the KLF2 expression in HUVECs. The suppression was counteracted by atorvastatin treatment, probably via attenuating the activation of the signal pathyway p38 MAPK and ERK1/2. PMID- 25927861 TI - Microbiological diagnostic procedures for respiratory cystic fibrosis samples in Spain: towards standard of care practices. AB - BACKGROUND: The microbiological procedures for cystic fibrosis (CF) samples of 17 participating Spanish centers were examined to verify their compliance with current international and national guidelines and to implement the best standards of care for microbiology practices. A 47-item questionnaire covering different CF microbiology aspects was sent to participant laboratories. Telephone interviews were performed when necessary. Data about samples processing for bacteria, mycobacteria and fungi were collected. RESULTS: Gene sequencing (71%), MALDI-TOF (59%) or both (94%) were available for most laboratories. Susceptibility testing was performed by automated microdilution systems (94%) and manual diffusion methods (59%). However, a low use of selective media for Staphylococcus aureus (59%) and Burkholderia cepacia complex (71%), and of epidemiological typing methods (41%) was reported. CONCLUSIONS: Most Spanish laboratories are in agreement with consensus guidelines for the processing of CF respiratory samples, but need to improve in the use of specific selective media and typing methods for epidemiologic studies. PMID- 25927864 TI - The interactive effect of diabetes and central obesity on stroke: a prospective cohort study of inner Mongolians. AB - BACKGROUND: The relationship between central obesity and stroke is inconsistent in diabetic and non-diabetic populations. This indicates an interaction between diabetes and central obesity on stroke risk. The present study aimed to examine the interaction in a cohort of Inner Mongolians. METHODS: In this prospective cohort study, we assessed the interaction between diabetes and central obesity on stroke incidence between June 2003 and July 2012. At baseline, 2,589 adults were recruited and examined from Inner Mongolia, China. Participants were categorized into four subgroups according to presence of diabetes and/or central obesity. Both additive and multiplicative interactions were evaluated using Cox proportional-hazard models. RESULTS: 121 stroke events were recorded during the follow-up period. The cumulative incidence of stroke was highest for participants with both diabetes and central obesity (log-rank test, P = 0.042). The multivariable-adjusted risk for stroke was significantly higher in participants with both conditions (HR = 3.02, 95% CI 1.24-7.33, P = 0.015) compared to those with neither diabetes nor central obesity. Attributable proportion due to the interaction between diabetes and central obesity was 0.571 (95% CI 0.017-1.125). The multiplicative interactive effect between diabetes and central obesity on stroke was also statistically significant (HR = 2.67, 95% CI 1.14-6.26, P = 0.024). CONCLUSIONS: The participants who were both diabetic and centrally obese had significantly higher risk for incident stroke than the combination of individuals who individually had either condition among Mongolian population. This study suggests that central obesity and diabetes act synergistically to increase the risk of stroke. PMID- 25927866 TI - Comparison of joint versus purebred genomic evaluation in the French multi-breed dairy goat population. AB - BACKGROUND: All progeny-tested bucks from the two main French dairy goat breeds (Alpine and Saanen) were genotyped with the Illumina goat SNP50 BeadChip. The reference population consisted of 677 bucks and 148 selection candidates. With the two-step approach based on genomic best linear unbiased prediction (GBLUP), prediction accuracy of candidates did not outperform that of the parental average. We investigated a GBLUP method based on a single-step approach, with or without blending of the two breeds in the reference population. METHODS: Three models were used: (1) a multi-breed model, in which Alpine and Saanen breeds were considered as a single breed; (2) a within-breed model, with separate genomic evaluation per breed; and (3) a multiple-trait model, in which a trait in the Alpine was assumed to be correlated to the same trait in the Saanen breed, using three levels of between-breed genetic correlations (rho): rho = 0, rho = 0.99, or estimated rho. Quality of genomic predictions was assessed on progeny-tested bucks, by cross-validation of the Pearson correlation coefficients for validation accuracy and the regression coefficients of daughter yield deviations (DYD) on genomic breeding values (GEBV). Model-based estimates of average accuracy were calculated on the 148 candidates. RESULTS: The genetic correlations between Alpine and Saanen breeds were highest for udder type traits, ranging from 0.45 to 0.76. Pearson correlations with the single-step approach were higher than previously reported with a two-step approach. Correlations between GEBV and DYD were similar for the three models (within-breed, multi-breed and multiple traits). Regression coefficients of DYD on GEBV were greater with the within breed model and multiple-trait model with rho = 0.99 than with the other models. The single-step approach improved prediction accuracy of candidates from 22 to 37% for both breeds compared to the two-step method. CONCLUSIONS: Using a single step approach with GBLUP, prediction accuracy of candidates was greater than that based on parent average of official evaluations and accuracies obtained with a two-step approach. Except for regression coefficients of DYD on GEBV, there were no significant differences between the three models. PMID- 25927868 TI - Immune-related strategies driving immunotherapy in breast cancer treatment: a real clinical opportunity. AB - Because its original use as a treatment for hematologic disease, more recently immunotherapy has emerged as a novel effective therapeutic strategy for solid malignancies, such as melanoma and prostate carcinoma. For breast carcinoma, an immunologic therapeutic approach has not been well evaluated, even though there is evidence to suggest it would be a successful novel strategy, especially taking into account the high mortality rate of the most aggressive variants of this heterogeneous disease. Here, we briefly describe the most recently awarded immune based therapies with a consolidated or potential implication for the treatment of solid malignancies. We focus on immune checkpoints and on the clinical potential of their abrogation, with a further overview of novel vaccine-based approaches and the most relevant immunotherapeutic techniques. We aim to provide an exhaustive review of the most promising immune-therapeutic agents that may have implications for breast cancer treatment. PMID- 25927870 TI - Is cost effectiveness sustained after weekend inpatient rehabilitation? 12 month follow up from a randomized controlled trial. AB - BACKGROUND: Our previous work showed that providing additional rehabilitation on a Saturday was cost effective in the short term from the perspective of the health service provider. This study aimed to evaluate if providing additional rehabilitation on a Saturday was cost effective at 12 months, from a health system perspective inclusive of private costs. METHODS: Cost effectiveness analyses alongside a single-blinded randomized controlled trial with 12 months follow up inclusive of informal care. Participants were adults admitted to two publicly funded inpatient rehabilitation facilities. The control group received usual care rehabilitation services from Monday to Friday and the intervention group received usual care plus additional Saturday rehabilitation. Incremental cost effectiveness ratios were reported as cost per quality adjusted life year (QALY) gained and for a minimal clinical important difference (MCID) in functional independence. RESULTS: A total of 996 patients [mean age 74 years (SD 13)] were randomly assigned to the intervention (n = 496) or control group (n = 500). The intervention was associated with improvements in QALY and MCID in function, as well as a non-significant reduction in cost from admission to 12 months (mean difference (MD) AUD$6,325; 95% CI -4,081 to 16,730; t test p = 0.23 and MWU p = 0.06), and a significant reduction in cost from admission to 6 months (MD AUD$6,445; 95% CI 3,368 to 9,522; t test p = 0.04 and MWU p = 0.01). There is a high degree of certainty that providing additional rehabilitation services on Saturday is cost effective. Sensitivity analyses varying the cost of informal carers and self-reported health service utilization, favored the intervention. CONCLUSIONS: From a health system perspective inclusive of private costs the provision of additional Saturday rehabilitation for inpatients is likely to have sustained cost savings per QALY gained and for a MCID in functional independence, for the inpatient stay and 12 months following discharge, without a cost shift into the community. TRIAL REGISTRATION: Australian and New Zealand Clinical Trials Registry November 2009 ACTRN12609000973213. PMID- 25927871 TI - Open-circuit voltage deficit, radiative sub-bandgap states, and prospects in quantum dot solar cells. AB - Quantum dot photovoltaics (QDPV) offer the potential for low-cost solar cells. To develop strategies for continued improvement in QDPVs, a better understanding of the factors that limit their performance is essential. Here, we study carrier recombination processes that limit the power conversion efficiency of PbS QDPVs. We demonstrate the presence of radiative sub-bandgap states and sub-bandgap state filling in operating devices by using photoluminescence (PL) and electroluminescence (EL) spectroscopy. These sub-bandgap states are most likely the origin of the high open-circuit-voltage (VOC) deficit and relatively limited carrier collection that have thus far been observed in QDPVs. Combining these results with our perspectives on recent progress in QDPV, we conclude that eliminating sub-bandgap states in PbS QD films has the potential to show a greater gain than may be attainable by optimization of interfaces between QDs and other materials. We suggest possible future directions that could guide the design of high-performance QDPVs. PMID- 25927872 TI - Severity of OSA is an independent predictor of incident atrial fibrillation hospitalization in a large sleep-clinic cohort. AB - BACKGROUND: OSA is a common condition that has been associated with atrial fibrillation (AF), but there is a paucity of data from large longitudinal cohorts to establish whether OSA is a risk factor for AF independent of obesity and other established risk factors. METHODS: We studied patients attending a sleep clinic referred for in-laboratory polysomnography for possible OSA between 1989 and 2001. Whole-population hospital data in Western Australia for 1970 to 2009 were linked to sleep study cases to determine incident AF hospitalization to 2009. Cox regression analyses were used to assess the independent association of OSA with incident AF. RESULTS: Study case subjects (6,841) were predominantly middle aged (48.3 +/- 12.5 years old) and men (77%), and 455 developed AF during a median 11.9 years of follow-up. Univariate predictors of AF included age, BMI, hypertension, diabetes, valvular heart disease, coronary or peripheral artery disease, heart failure, and COPD (all P < .001). After multivariable adjustment, independent predictors of incident AF were an apnea/hypopnea index (AHI) > 5/h (hazard ratio [HR], 1.55; 95% CI, 1.21-2.00), log (AHI + 1) (HR, 1.15; 95% CI, 1.06-1.26), and log (time with oxygen saturation < 90% + 1) (HR, 1.12; 95% CI, 1.06-1.19). There were no interactions between age, sex, or BMI and AHI for AF development. CONCLUSIONS: OSA diagnosis and severity are independently associated with incident AF. Clinical trials are required to determine if treatment of OSA will reduce the burden of AF. PMID- 25927873 TI - Update in pulmonary medicine: evidence published in 2014. PMID- 25927874 TI - Perspectives on the energy landscape of Au-Cl binary systems from the structural phase diagram of AuxCly (x + y = 20). AB - Ligand-protected gold (Au-L) nanoclusters have attracted much attention, where the reported electronic and geometric structures show great diversity. To give a direct and overall view of the energy landscape of Au-L binary systems, the AuxCly (x + y = 20) system is taken as a test case. By intensive global search of the potential energy surface at the level of density functional theory, a diverse set of global minima and low-lying isomers are found at each composition, and the structural phase diagram is obtained. The unbiased global search is carried out using the method combining the genetic algorithm with the TPSS functional. At x = 10 with the stoichiometric ratio of Au and Cl (1 : 1), the cluster presents a catenane structure. When x is in the range of 11-20, the clusters are Au-rich, and the Au-Cl system can be viewed as Cl-protected gold nanoclusters, where the gold cores consist of superatoms, superatom networks, or superatomic molecules in electronic structures. At x = 11-15, the gold cores consist of Au3, Au4 and Au5 2e-superatoms protected by staple motifs. At x = 16-20, the clusters are pyramidal superatomic molecules with one Au16 superatom core bonding with the four vertical atoms (Au or Cl). When x is in the scope of 9-5, the clusters are Cl-rich, and the 5d electrons of Au participate in bonding, resulting in high multiplicities. The Au-Cl binary system shows great diversity and flexibility in electronic and geometric structures, and there are corresponding structures to most of the experimentally produced Au-L nanoclusters in our structural phase diagram. We believe that the structural phase diagram gives an overall perspective on the universe of Au-L nanoclusters. PMID- 25927875 TI - Calcium bioaccessibility and uptake by human intestinal like cells following in vitro digestion of casein phosphopeptide-calcium aggregates. AB - Casein phosphopeptides (CPPs), derived by casein proteolysis, can bind calcium ions and keep them in solution. In vitro studies have demonstrated CPP-induced cell calcium uptake, depending on the formation of (CPP + calcium) complexes and on the degree of differentiation of the intestinal cells. With the present study, we address the persistence of the complexes and of the CPP-induced calcium uptake in intestinal like cells after the digestion process, thus examining their eligibility to serve as nutraceuticals. A calcium-preloaded CPP preparation of commercial origin (Ca-CPPs) was subjected to in vitro digestion. The evolution of the supramolecular structure of the Ca-CPP complexes was studied using laser light and X-ray scattering. The bioactivity of the pre- and post-digestion Ca CPPs was determined in differentiated Caco2 and HT-29 cells by video imaging experiments using Fura-2. We found that Ca-CPP aggregates keep a complex supramolecular organization upon digestion, despite getting smaller in size and increasing internal calcium dispersion. Concomitantly and most interestingly, digested Ca-CPPs clearly enhance the uptake of calcium ions, especially in Caco2 cells. In contrast, digestion depletes the ability of post-loaded decalcified CPPs (Ca-dekCPPs), with a weaker internal structure, to induce calcium uptake. The enhanced bioactivity reached upon digestion strongly suggests a recognized role of Ca-CPPs, in the form used here, as nutraceuticals. PMID- 25927876 TI - Intracavitary moderator balloon combined with (252)Cf brachytherapy and boron neutron capture therapy, improving dosimetry in brain tumour and infiltrations. AB - OBJECTIVE: This article proposes a combination of californium-252 ((252)Cf) brachytherapy, boron neutron capture therapy (BNCT) and an intracavitary moderator balloon catheter applied to brain tumour and infiltrations. METHODS: Dosimetric evaluations were performed on three protocol set-ups: (252)Cf brachytherapy combined with BNCT (Cf-BNCT); Cf-BNCT with a balloon catheter filled with light water (LWB) and the same set-up with heavy water (HWB). RESULTS: Cf-BNCT-HWB has presented dosimetric advantages to Cf-BNCT-LWB and Cf BNCT in infiltrations at 2.0-5.0 cm from the balloon surface. However, Cf-BNCT LWB has shown superior dosimetry up to 2.0 cm from the balloon surface. CONCLUSION: Cf-BNCT-HWB and Cf-BNCT-LWB protocols provide a selective dose distribution for brain tumour and infiltrations, mainly further from the (252)Cf source, sparing the normal brain tissue. ADVANCES IN KNOWLEDGE: Malignant brain tumours grow rapidly and often spread to adjacent brain tissues, leading to death. Improvements in brain radiation protocols have been continuously achieved; however, brain tumour recurrence is observed in most cases. Cf-BNCT-LWB and Cf BNCT-HWB represent new modalities for selectively combating brain tumour infiltrations and metastasis. PMID- 25927879 TI - [Epidemiological studies about cancer and herbicides]. PMID- 25927878 TI - Twin tubular pinch effect in curving confined flows. AB - Colloidal suspensions of buoyancy neutral particles flowing in circular pipes focus into narrow distributions near the wall due to lateral migration effects associated with fluid inertia. In curving flows, these distributions are altered by Dean currents and the interplay between Reynolds and Dean numbers is used to predict equilibrium positions. Here, we propose a new description of inertial lateral migration in curving flows that expands current understanding of both focusing dynamics and equilibrium distributions. We find that at low Reynolds numbers, the ratio delta between lateral inertial migration and Dean forces scales simply with the particle radius, coil curvature and pipe radius as (Rp(3)R)/a(4). A critical value deltac = 0.148 of this parameter is identified along with two related inertial focusing mechanisms. In the regime below deltac, coined subcritical, Dean forces generate permanently circulating, twinned annuli, each with intricate equilibrium particle distributions including eyes and trailing arms. At delta > deltac (supercritical regime) inertial lateral migration forces are dominant and particles focus to a single stable equilibrium position. PMID- 25927880 TI - [Eating Disorders: a systemic disorder]. PMID- 25927881 TI - Association of systolic dysfunction with left ventricular hypertrophy and diastolic dysfunction in hypertensive patients. AB - BACKGROUND: the presence of systolic dysfunction has not been well recognized in hypertensive patients (p). OBJECTIVES: The aim of this study is to demonstrate that hypertensive p with left ventricular hypertrophy (LVH) have systolic dysfunction, and that this functional alteration increases when it is associated to diastolic dysfunction (DD). METHODS: descriptivecross-sectional studywith aprospectivelycollected sample according to specified inclusion and exclusion criteria. Left ventricular function was evaluated with conventional echocardiography, mitral valvular orifice Doppler and tissue Doppler following international guidelines. The p were divided in four groups by the presence or absence of LVH and DD. STATISTICAL ANALYSIS: students t tests and ANOVA test, statistical significance <0,05. RESULTS: 292 p were included, 130 p (51 %) LVH- DD-; 36 p (5,9 %) LVH- DD+; 87 p (37,6 %) LVH+ DD-; and 39 p (5,5 %) LVH+ DD+. Patients with diastolic dysfunction were older and more frequently of female sex, had greater systolic blood pressure and central aortic systolic blood pressure. The shortening rate of longitudinal myocardial fibers measured by tissue Doppler (s wave) were 6,3 +1,1 cm/sec in LVH+ DD+ p, 7,2+1,3 cm/sec in LVH+ DD- p, 6,8+1,2 cm/sec in LVH- DD+ p, and 7,8+0,6 cm/seg in LVH- DD- p (<0,005). CONCLUSIONS: hypertensives p had systolic dysfunction when LVH is present and it is greater when it is associated to DD. PMID- 25927882 TI - [The repeated biopsy in patients with lupus nephritis]. AB - We retrospectively studied patients with SLE according to ACR criteria, with NL who underwent a repeat renal biopsy from 2005 to 2012. We analyzed the main indications of renal biopsies, the histopathological Class and activity and chronicity changes. RESULTS The total number of patients with NL was 120, of which 18 (15%) patients underwent repeat renal biopsy, 18 had 2 renal biopsies and 6 had 3 biopsies. 3 (16.7%) patients were smokers; 1 (5.6%) had a history of previous DBT, 2 (11.1%) had a history of hypertension; and 3 (16.7%) patients had previous obesity. The duration of SLE was 15 +/- 96 months; the time between the 1st and the 2nd biopsy was 45 +/- 11 months and the time between the 2nd and 3rd biopsy was 56 +/- 12 months. Indications for repeat biopsy were proteinuria in 10 biopsies (41.6%); proteinuria with impaired renal function in 2 biopsies (8.3%); proteinuria with pathological urine sediment in 8 (33.3%); . and pathological proteinuria with pathological urine sediment and impaired renal function in 4 biopsies (16.6%) The most frequent histological changes found between first and repeat biopsies were class IV to class III: 2 (8.2%) ; Class IV to Class IV: 8 (33.3%), class IV to class III + V: 2 (8.2%); class IV to class IV + V 3 (12.5%); class IV to class V: 2 (8.2%). Changes in NL biopsies with proliferative activity and chronicity indices (A / C) were: A to A / C: 7 (29.1%), A / C to A / C: 7 (29.1%). The immunosuppressive therapy was increased in 79.1% and 16.6% remained without changes. 20% patients received cyclophosphamide 1 g every 30 days, 26% Cyclophosphamide 500 mg every 15 days, 23% induction therapy with mycophenolate mofetil; 23% with Rituximab; 8% Cyclosporin A. Maintenance therapy with mycophenolate mofetil was performed in 87.5%; azathioprine in 1 case. Hydroxychloroquine was used in all cases. PMID- 25927883 TI - [Morning rise in home blood pressure and target organ damage in hypertensive patients]. AB - The morning blood pressure (BP) rise entails a higher cardiovascular risk. Studies evaluating the association between home BP morning rise and target organ damage are scarce and almost exclusively based on Asians. The aim of our study was to characterize hypertensive patients with morning rise in home BP and to establish a possible association with left ventricular hypertrophy (LVH). METHODS: treated hypertensive patients >= 18 years underwent home BP measurements (duplicate measurements for 4 days in the morning, afternoon and evening), and completed a questionnaire regarding risk factors and history of cardiovascular disease. Medical records were reviewed to extract data from grams. A morning rise in systolic home BP was defined as a difference between morning and evening systolic BP averages >=15 mmHg. Subjects were considered to have LVH if the left ventricular mass index was >95 g/m2 in women and >115 g/m2 in men. Variables identified as relevant predictors of home BP morning rise were entered into a multivariable logistic regression analysis model. RESULTS: 216 patients were included, mean age 68 (+13.3), 69.4% women and 99.1% Caucasians. The prevalence of BP morning rise was 13.4% and independently associated factors were LVH (OR 3.5; 95%CI 1.1-11.4), age (OR 1.05; 95%CI 1.003-1.1) and a history of cerebrovascular disease (OR 3.9; 95%CI 1.1-14.2). In conclusion, a morning rise in systolic BP detected through home BP monitoring is independently associated with LVH, age and a history of cerebrovascular disease. The therapeutic implications of this observation need to be clarified in large-scale prospective studies. PMID- 25927884 TI - [Evaluation of general health status by SF-36 tool in Hip Osteoarthritis]. AB - OBJECTIVE: To determine the general health status perceived by patients undergoing total hip arthroplasty with mini-stem. MATERIAL AND METHODS: Health questionnaire SF-36 has been used to assess health perceived by 13 male patients with a mean age of 46.62 (34-53) years after the implantation of an uncemented, MiniHip(r) (CorinMedical) total hip arthroplasty, after a mean follow up of 23.2 (12-47) months. Results were compared with the reference values of Spanish men population from 45 to 54 years. RESULTS: Differences were found in areas such as physical and emotional role, physical function, social function and pain; while scores of the remaining items were similar to the population of reference. DISCUSSION: It is important to know how our surgical actions affect the quality of life of patients and how it is perceived by them to complement the results of our surgeries. PMID- 25927885 TI - [Restless Legs Syndrome : A Threat to the quality of life]. AB - Restless legs syndrome is a disorder associated with the imperative need to move the legs, starting at different times of day and it gets worse at night, relieved by activity, affecting the quality of life and sleep who sufferers it. Despite being a common disorder at any age, in adults with a prevalence of up to 10%, is not diagnosed by doctors and first level specialists that is why diagnostic and therapeutic interventions get delayed contributing to the perpetuation of symptoms and worsening quality of life. Since its diagnosis is purely clinical, getting familiar with this disorder is essential to ensure proper focus and thus rule out other diseases commonly confused with this one. Restless legs syndrome has a multi-factorial etiology that ranges from a genetic and hereditary, which are called primary restless legs syndrome, to its association with multiple pathologies, known as secondary restless legs syndrome. As for its management, drug therapy and non-drug therapy is aimed at symptom control, as its cure is not possible, although occasionally the condition can refer to later repeat in months or years. PMID- 25927886 TI - [Mucormycosis. Clinical cases and update]. AB - Mucormycosis is an emerging mycotic infection with high mortality. We described the clinical presentation, evolution and treatment of 5 patients with diagnosis of mucormycosis. PMID- 25927887 TI - [Congenital diaphragmatic hernia]. PMID- 25927890 TI - Understanding the spatial and temporal patterns of copper in-use stocks in China. AB - Two approaches are adopted to characterize the comprehensive pattern of the copper in-use stocks in China. The top-down results indicate that both the total amount and the per capita quantity of the stocks have exhibited a significant and increasing trend for the past 60 years, especially since 2000. The top-down results show that the copper stocks increased from a negligible level of less than 1 kg/capita in 1952 to 44 kg/capita in 2012. The total stocks in 2012 are estimated to be 60 Mt by a top-down approach or 48 Mt by a bottom-up calculation. The bottom-up method determines that the largest reservoir is the infrastructure sector, which accounts for approximately 58% of the total stocks. The spatial pattern indicates that the copper in-use stocks are predominately spatially distributed in the eastern regions of China, a feature that is obviously different from the geographical distribution of the primary resources. Analysis on the prospects of stocks shows both the total magnitude and per capita value will continuously increase in the following decade, and enter a relatively stable stage in around 2030, with a maximum value of 106 kg/capita. The results improve the knowledge about closing copper cycles. PMID- 25927889 TI - Human endogenous retroviruses sustain complex and cooperative regulation of gene containing loci and unannotated megabase-sized regions. AB - BACKGROUND: Evidence suggests that some human endogenous retroviruses and endogenous retrovirus-like repeats (here collectively ERVs) regulate the expression of neighboring genes in normal and disease states; e.g. the human globin locus is regulated by an ERV9 that coordinates long-range gene switching during hematopoiesis and activates also intergenic transcripts. While complex transcription regulation is associated with integration of certain exogenous retroviruses, comparable regulation sustained by ERVs is less understood. FINDINGS: We analyzed ERV transcription using ERV9 consensus sequences and publically available RNA-sequencing, chromatin immunoprecipitation with sequencing (ChIP-seq) and cap analysis gene expression (CAGE) data from ENCODE. We discovered previously undescribed and advanced transcription regulation mechanisms in several human reference cell lines. We show that regulation by ERVs involves long-ranging activations including complex RNA splicing patterns, and transcription of large unannotated regions ranging in size from several hundred kb to around 1 Mb. Moreover, regulation was found to be cooperatively sustained in some loci by multiple ERVs and also non-LTR repeats. CONCLUSION: Our analyses show that endogenous retroviruses sustain advanced transcription regulation in human cell lines, which shows similarities to complex insertional mutagenesis effects exerted by exogenous retroviruses. By exposing previously undescribed regulation effects, this study should prove useful for understanding fundamental transcription mechanisms resulting from evolutionary acquisition of retroviral sequence in the human genome. PMID- 25927891 TI - A novel branched TAT(47-57) peptide for selective Ni(2+) introduction into the human fibrosarcoma cell nucleus. AB - A TAT47-57 peptide was modified on the N-terminus by elongation with a 2,3 diaminopropionic acid residue and then by coupling of two histidine residues on its N-atoms. This branched peptide could bind to Ni under physiological conditions as a 1 : 1 complex. We demonstrated that the complex was quantitatively taken up by human fibrosarcoma cells, in contrast to Ni(2+) ions. Ni localization (especially at the nuclei) was confirmed by imaging using both scanning X-ray fluorescence microscopy and Newport Green fluorescence. A competitive assay with Newport Green showed that the latter displaced the peptide ligand from the Ni-complex. Ni(2+) delivered as a complex with the designed peptide induced substantially more DNA damage than when introduced as a free ion. The availability of such a construct opens up the way to investigate the importance of the nucleus as a target for the cytotoxicity, genotoxicity or carcinogenicity of Ni(2+). PMID- 25927895 TI - Binary and ternary superlattices self-assembled from colloidal nanodisks and nanorods. AB - Self-assembly of multicomponent anisotropic nanocrystals with controlled orientation and spatial distribution allows the design of novel metamaterials with unique shape- and orientation-dependent collective properties. Although many phases of binary structures are theoretically proposed, the examples of multicomponent assemblies, which are experimentally realized with colloidal anisotropic nanocrystals, are still limited. In this report, we demonstrate the formation of binary and ternary superlattices from colloidal two-dimensional LaF3 nanodisks and one-dimensional CdSe/CdS nanorods via liquid interfacial assembly. The colloidal nanodisks and nanorods are coassembled into AB-, AB2-, and AB6-type binary arrays determined by their relative size ratio and concentration to maximize their packing density. The position and orientation of anisotropic nanocrystal building blocks are tightly controlled in the self-assembled binary and ternary lattices. The macroscopic orientation of the superlattices is further tuned by changing the liquid subphase used for self-assembly, resulting in the formation of lamellar-type binary liquid crystalline superlattices. In addition, we demonstrate a novel ternary superlattice self-assembled from two different sizes of nanodisks and a nanorod, which offers the unique opportunity to design multifunctional metamaterials. PMID- 25927892 TI - A Bayesian ensemble approach for epidemiological projections. AB - Mathematical models are powerful tools for epidemiology and can be used to compare control actions. However, different models and model parameterizations may provide different prediction of outcomes. In other fields of research, ensemble modeling has been used to combine multiple projections. We explore the possibility of applying such methods to epidemiology by adapting Bayesian techniques developed for climate forecasting. We exemplify the implementation with single model ensembles based on different parameterizations of the Warwick model run for the 2001 United Kingdom foot and mouth disease outbreak and compare the efficacy of different control actions. This allows us to investigate the effect that discrepancy among projections based on different modeling assumptions has on the ensemble prediction. A sensitivity analysis showed that the choice of prior can have a pronounced effect on the posterior estimates of quantities of interest, in particular for ensembles with large discrepancy among projections. However, by using a hierarchical extension of the method we show that prior sensitivity can be circumvented. We further extend the method to include a priori beliefs about different modeling assumptions and demonstrate that the effect of this can have different consequences depending on the discrepancy among projections. We propose that the method is a promising analytical tool for ensemble modeling of disease outbreaks. PMID- 25927893 TI - Hepatic Sclerosed Hemangioma: a case report and review of the literature. AB - BACKGROUND: Although cavernous hemangioma is one of the most frequently encountered benign hepatic neoplasms, hepatic sclerosed hemangioma is very rare. We report a case of hepatic sclerosed hemangioma that was difficult to distinguish from an intrahepatic cholangiocarcinoma by imaging studies. CASE PRESENTATION: A 76-year-old male patient with right hypochondralgia was referred to our hospital. Abdominal ultrasonography revealed a heterogeneously hyperechoic tumor that was 59 mm in diameter in segment 7 of the liver. Dynamic computed tomography showed a low-density tumor with delayed ring enhancement. Gadolinium ethoxybenzyl-diethylenetriamine pentaacetic acid-enhanced magnetic resonance imaging (EOB-MRI) demonstrated a low-signal intensity mass with ring enhancement on T1-weighted images. The mass had several high-signal intensity lesions on T2 weighted images. EOB-MRI revealed a hypointense nodule on the hepatobiliary phase. From these imaging studies, the tumor was diagnosed as intrahepatic cholangiocarcinoma, and we performed laparoscopy-assisted posterior sectionectomy of the liver with lymph node dissection in the hepatoduodenal ligament. Histopathological examination revealed a hepatic sclerosed hemangioma with hyalinized tissue and collagen fibers. CONCLUSION: Hepatic sclerosed hemangioma is difficult to diagnose preoperatively because of its various imaging findings. We report a case of hepatic sclerosed hemangioma and review the literatures, especially those concerning imaging findings. PMID- 25927897 TI - Estimation of creatinine clearance using plasma creatinine or cystatin C: a secondary analysis of two pharmacokinetic studies in surgical ICU patients. AB - BACKGROUND: In ICU patients, glomerular filtration is often impaired, but also supraphysiological values are observed ("augmented renal clearance", >130 mL/min/1.73 m(2)). Renally eliminated drugs (e.g. many antibiotics) must be adjusted accordingly, which requires a quantitative measure of renal function throughout all the range of clinically encountered values. Estimation from plasma creatinine is standard, but cystatin C may be a valuable alternative. METHODS: This was a secondary analysis of renal function parameters in 100 ICU patients from two pharmacokinetic studies on vancomycin and betalactam antibiotics. Estimated clearance values obtained by the Cockcroft-Gault formula (eCLCG), the CKD-EPI formula (eCLCKD-EPI) or the cystatin C based Hoek formula (eCLHoek) were compared with the measured endogenous creatinine clearance (CLCR). Agreement of values was assessed by modified Bland-Altman plots and by calculating bias (median error) and precision (median absolute error). Sensitivity and specificity of estimates to identify patients with reduced (<60 mL/min/1.73 m(2)) or augmented (>130 mL/min/1.73 m(2)) CLCR were calculated. RESULTS: The CLCR was well distributed from highly compromised to supraphysiological values (median 73.2, range 16.8-234 mL/min/1.73 m(2)), even when plasma creatinine was not elevated (<=0.8 mg/dL for women, <=1.1 mg/dL for men). Bias and precision were +13.5 mL/min/1.73 m(2) and +/-18.5 mL/min/1.73 m(2) for eCLCG, +7.59 and +/-16.8 mL/min/1.73 m(2) for eCLCKD-EPI, and -4.15 and +/-12.9 mL/min/1.73 m(2) for eCLHoek, respectively, with eCLHoek being more precise than the other two (p < 0.05). The central 95% of observed errors fell between -59.8 and +250 mL/min/1.73 m(2) for eCLCG, -83.9 and +79.8 mL/min/1.73 m(2) for eCLCKD-EPI, and -103 and +27.9 mL/min/1.73 m(2) for eCLHoek. Augmented renal clearance was underestimated by eCLCKD-EPI and eCLHoek. Patients with reduced CLCR were identified with good specificity by eCLCG, eCLCKD-EPI and eCLHoek (0.95, 0.97 and 0.91, respectively), but with less sensitivity (0.55, 0.55 and 0.83). For augmented renal clearance, specificity was 0.81, 0.96 and 0.96, but sensitivity only 0.69, 0.25 and 0.38. CONCLUSIONS: Normal plasma creatinine concentrations can be highly misleading in ICU patients. Agreement of the cystatin C based eCLHoek with CLCR is better than that of the creatinine based eCLCG or eCLCKD-EPI. Detection and quantification of augmented renal clearance by estimates is problematic, and should rather rely on CLCR. PMID- 25927899 TI - Special Effect of Ionic Liquids on the Extraction of Flavonoid Glycosides from Chrysanthemum morifolium Ramat by Microwave Assistance. AB - A microwave-assisted extraction approach based on ionic liquids of different chain lengths was successfully applied to the extraction of ten flavonoid glycosides from the flowering heads of Chrysanthemum morifolium Ramat. The pretreated sample was quantified by HPLC-ESI-MSn. The main components were identified as flavonoid glycosides, including three luteolin glycosides, three apigenin glycosides, three kaempferide glycosides, and one acacetin glycoside according to the characteristics of the corresponding CID mass spectrometric patterns. Eight ionic liquids from the imidazolium family with different chain lengths, namely, 1-alkyl-3-methylimidazolium bromide, [Cnmim]Br, (n=2-16) were studied as extraction medium in water. Results indicated that alkyl chain length had an irregular impact on the extraction efficiency. Moreover, the best extraction efficiency was achieved by 1-dodecyl-3-methylimidazolium bromide aqueous solution ([C12mim]Br). Besides the alkyl chain length of the cations, other factors influencing extraction efficiency were systematically investigated, including concentration of the IL solutions, extraction time, matrix-to-solvent ratio and irradiation power. PMID- 25927900 TI - Investigation of Carbohydrate Recognition via Computer Simulation. AB - Carbohydrate recognition by proteins, such as lectins and other (bio)molecules, can be essential for many biological functions. Recently, interest has arisen due to potential protein and drug design and future bioengineering applications. A quantitative measurement of carbohydrate-protein interaction is thus important for the full characterization of sugar recognition. We focus on the aspect of utilizing computer simulations and biophysical models to evaluate the strength and specificity of carbohydrate recognition in this review. With increasing computational resources, better algorithms and refined modeling parameters, using state-of-the-art supercomputers to calculate the strength of the interaction between molecules has become increasingly mainstream. We review the current state of this technique and its successful applications for studying protein-sugar interactions in recent years. PMID- 25927901 TI - Pharmacokinetics, tissue distribution and excretion of isoalantolactone and alantolactone in rats after oral administration of Radix Inulae extract. AB - Radix Inulae is endemic to China and has been used in traditional medicine to treat upper body pain, emesis and diarrhoea, and to eliminate parasites. Here, an UPLC-MS/MS method was developed and applied to study the pharmacokinetics, distribution and excretion of isoalantolactone and alantolactone, which are two main active sesquiterpene lactones in Radix Inulae, in Sprague-Dawley rats following oral administration of total Radix Inulae extract. Isoalantolactone, alantolactone and osthole (internal standard) were prepared using acetonitrile precipitation, and the separation of isoalantolactone and alantolactone was achieved by isocratic elution using water (containing 0.1% formic acid) and acetonitrile as the mobile phase using a ZORBAX Eclipse Plus C18 column. The total run time was 6.4 min. The present study showed poor absorption of isoalantolactone and alantolactone in vivo. The apparent Cmax, Tmax, T1/2 and total exposure (AUC0-12h) in rat plasma were 37.8 ng/mL, 120 min, 351.7 min and 6112.3 ng-min/mL for isoalantolactone and 25.9 ng/mL, 90 min, 321.0 min and 4918.9 ng-min/mL for alantolactone, respectively. It was shown that the highest concentration was achieved in the small intestine and feces clearance was shown to be the dominant elimination pathway of the lactones. PMID- 25927902 TI - Proteomic analysis of polysaccharide-milk protein interactions induced by chitosan. AB - The chitosan-induced coacervation of milk proteins was investigated using a proteomic approach. The addition of 0.8% chitosan to milk caused the milk proteins to coacervate after a 1 h incubation period. Approximately 86% of the milk proteins were present in the milk pellet fraction (MPF), and the protein concentration of the milk supernatant fraction (MSF) decreased from 29.4+/-0.2 to 4.2+/-0.6 mg/mL. SDS-PAGE analysis showed that the total intensities of serum albumin (BSA), alphaS-casein (alphaS-CN), beta-casein (beta-CN), kappa-casein (kappa-CN) and beta-lactoglobulin (beta-LG) in the MSF decreased to 8.5%+/-0.2%, 0.9%+/-0.3%, 0.7%+/-0.3%, 0.5%+/-0.2% and 15.0%+/-0.5%, respectively. Two dimensional electrophoresis analysis indicated that alphaS1-, alphaS2-, beta- and kappa-CN and a fraction of the beta-LG and BSA were found in the MSF following incubation with 0.8% chitosan. Isothermal titration calorimetry analysis indicated that binding of chitosan to milk proteins is an exothermic reaction based on binding titration curves of milk proteins dispersions with chitosan, and the enthalpy of binding (DeltaH) and binding constant (Ka) were -7.85*10(4) cal/mol and 1.06*10(5)/mol, respectively. These results suggested that the addition of 0.8% chitosan causes milk proteins to coacervate due to polysaccharide-protein interactions. PMID- 25927903 TI - Anti-trypanosomal activity of nigerian plants and their constituents. AB - African trypanosomiasis is a vector-borne parasitic disease causing serious risks to the lives of about 60 million people and 48 million cattle globally. Nigerian medicinal plants are known to contain a large variety of chemical structures and some of the plant extracts have been screened for antitrypanosomal activity, in the search for potential new drugs against the illness. We surveyed the literatures on plants and plant-derived products with antitrypanosomal activity from Nigerian flora published from 1990 to 2014. About 90 plants were identified, with 54 compounds as potential active agents and presented by plant families in alphabetical order. This review indicates that the Nigerian flora may be suitable as a starting point in searching for new and more efficient trypanocidal molecules. PMID- 25927906 TI - Facile Synthesis of Isoindolinones via Rh(III)-Catalyzed One-Pot Reaction of Benzamides, Ketones, and Hydrazines. AB - A Rh(III)-catalyzed one-pot reaction of benzamides, ketones, and hydrazines for facile access to isoindolinones is reported. In this method, various ketones are transformed into donor-donor diazo compounds, which sequentially engage in insertion with benzamides under Rh(III) catalysis to generate N-substituted quaternary isoindolinones. PMID- 25927905 TI - Immunolocalization of the 29 kDa Schistosoma haematobium species-specific antigen: a potential diagnostic marker for urinary schistosomiasis. AB - BACKGROUND: The 29 kDa Schistosoma haematobium species-specific antigen (ShSSA) is of remarkable interest in the diagnosis of urinary schistosomiasis although it had not been fully characterized. METHOD: To determine the biological importance of ShSSA in S. haematobium and pathogenesis of the disease, we immunolocalized ShSSA in schistosome eggshells, miracidia and adult worm sections using indirect fluorescent antibody test (IFAT). RESULTS: ShSSA was strongly immunolocalized in the schistosome eggshells, selective regions of the miracidia body and walls of internal organs such as oviduct, ovary, vitelline duct and gut of the adult worm. CONCLUSION: The strong immunolocalization of ShSSA in schistosome eggshells and adult worm internal organs suggests that the antigens involved in the pathogenesis of urinary schistosomiasis could have originated from the eggs and adult worms of the parasite. The findings also indicate that ShSSA may play a mechanical protective role in the survival of the parasite. PMID- 25927907 TI - Can early introduction of specialized palliative care limit intensive care, emergency and hospital admissions in patients with severe and very severe COPD? a randomized study. AB - BACKGROUND: COPD is a progressive lung disorder with rates of mortality between 36-50%, within 2 years after admission for an acute exacerbation. While treatment with inhaled bronchodilators and steroids may partially relieve symptoms and oxygen therapy may prolong life, for many patients the course of the disease is one of inexorable decline. Very few palliative care intervention studies are available for this population. This trial seeks to determine the effectiveness of the introduction of specialized palliative care on hospital, intensive care unit and emergency admissions of patients with severe and very severe COPD. METHODS/DESIGN: The study is a three year single centre, randomized controlled trial using a 2 arms parallel groups design conducted in a tertiary center (University Hospitals; Geneva). For the intervention group, an early palliative care consultation is added to standard care; the control group benefits from standard care only. Patients with COPD defined according to GOLD criteria with a stage III or IV disease and/or long term treatment with domiciliary oxygen and/or home mechanical ventilation and/or one or more hospital admissions in the previous year for an acute exacerbation are eligible to participate. Allocation concealment is achieved using randomisation by sealed envelopes. Our sample size of 90 patients/group gives the study a 80% power to detect a 20% decrease in intensive care unit and emergency admissions--the primary endpoint. All data regarding participants will be analysed by a researcher blinded to treatment allocation, according to the "Intention to treat" principle. DISCUSSION: Given the trends toward aggressive and costly care near end-of-life among patients with COPD, a timely introduction of palliative care may limit unnecessary and burdensome personal and societal costs, and invasive approaches. The results of this study may provide directions for future palliative care interventions in this particular population. TRIAL REGISTRATION: This trial has been registered at clinicaltrials.gov under NCT02223780. PMID- 25927909 TI - Predictors of Physical Restraint Use in Hospitalized Veterans at End of Life: An Analysis of Data from the BEACON Trial. AB - BACKGROUND: The use of physical restraints in dying patients may be a source of suffering and loss of dignity. Little is known about the prevalence or predictors for restraint use at end of life in the hospital setting. OBJECTIVE: The objective was to determine the prevalence and predictors of physical restraint use at the time of death in hospitalized adults. METHODS: Secondary analysis was performed on data from the "Best Practices for End-of-Life Care for Our Nation's Veterans" (BEACON) trial conducted between 2005 and 2011. Medical record data were abstracted from six Veterans Administration Medical Centers (VAMCs). Data on processes of care in the last seven days of life were abstracted from the medical records of 5476 who died in the six VAMCs. We prospectively identified potential risk factors for restraint use at the time of death from among the variables measured in the parent trial, including location of death, medications administered, nasogastric tube, intravenous (IV) fluids, family presence, and receipt of a palliative care consultation. RESULTS: Physical restraint use at time of death was documented in 890 decedents (16.3%). Restraint use varied by location of death, with patients in intensive settings being at higher risk. Restraint use was significantly more likely in patients with a nasogastric tube and those receiving IV fluids, benzodiazepines, or antipsychotics. CONCLUSIONS: This is the first study to document that one in six hospitalized veterans were restrained at the time of death and to identify predictors of restraint use. Further research is needed to identify intervention opportunities. PMID- 25927910 TI - Full-field speckle interferometry for non-contact photoacoustic tomography. AB - A full-field speckle interferometry method for non-contact and prospectively high speed Photoacoustic Tomography is introduced and evaluated as proof of concept. Thermoelastic pressure induced changes of the objects topography are acquired in a repetitive mode without any physical contact to the object. In order to obtain high acquisition speed, the object surface is illuminated by laser pulses and imaged onto a high speed camera chip. In a repetitive triple pulse mode, surface displacements can be acquired with nanometre sensitivity and an adjustable sampling rate of e.g. 20 MHz with a total acquisition time far below one second using kHz repetition rate lasers. Due to recurring interferometric referencing, the method is insensitive to thermal drift of the object due to previous pulses or other motion. The size of the investigated area and the spatial and temporal resolution of the detection are scalable. In this study, the approach is validated by measuring a silicone phantom and a porcine skin phantom with embedded silicone absorbers. The reconstruction of the absorbers is presented in 2D and 3D. The sensitivity of the measurement with respect to the photoacoustic detection is discussed. Potentially, Photoacoustic Imaging can be brought a step closer towards non-anaesthetized in vivo imaging and new medical applications not allowing acoustic contact, such as neurosurgical monitoring or burnt skin investigation. PMID- 25927911 TI - An unexpected alliance between stress responses to drive oncogenesis. AB - XBP1 is a well-characterized regulator of the unfolding protein response that is activated in response to unfolded or misfolded proteins or nutrient deprivation. The conventional wisdom is that XBP1 is activated to coordinate the unfolded protein response and promote cellular survival under stresses. A recent study provides intriguing evidence that, in triple-negative breast cancer, XBP1 plays a major role in promoting oncogenesis and cancer stem cell properties. Unexpectedly, XBP1 accomplishes this by recruiting hypoxia-inducible factor 1alpha and activating oncogenic transcriptional programs. This study reveals a surprising hierarchy and alliance between two stress regulators with distinct transcriptional outputs to promote an aggressive oncogenic state. PMID- 25927913 TI - Alkaline phosphatase in nasal secretion of cattle: biochemical and molecular characterisation. AB - BACKGROUND: Nasal secretion (NS) was investigated as a source of information regarding the mucosal and systemic immune status of cattle challenged by respiratory disease. A method for the collection of substantial volumes (~12 ml) of NS from cattle was developed to establish a reference range of analytes that are present in the NS of healthy cattle. Biochemical profiles of NS from a group of 38 healthy Holstein-Friesian cows revealed high alkaline phosphatase (AP) activity of up to 2392 IU/L. The character and source of the high activity of AP in bovine NS was investigated. RESULTS: Histochemical analysis confirmed the localization of the AP enzyme activity to epithelial cells and serous glands of the nasal respiratory mucosa. Analysis of mRNA levels from nasal mucosa by end point RT-PCR and PCR product sequencing confirmed that the AP was locally produced and is identical at the nucleotide level to the non-specific AP splice variant found in bovine liver, bone and kidney. Analysis by isoelectric focussing confirmed that AP was produced locally at a high level in nasal epithelium demonstrating that AP from nasal secretion and nasal mucosa had similar pI bands, though differing from those of the liver, kidney, bone and intestine, suggesting different post-translational modification (PTM) of AP in these tissues. CONCLUSIONS: A nasal isozyme of AP has been identified that is present at a high activity in NS, resulting from local production and showing distinctive PTM and may be active in NS as an anti-endotoxin mediator. PMID- 25927914 TI - The impact of chronic pain on opioid addiction treatment: a systematic review protocol. AB - BACKGROUND: The consequences of opioid relapse among patients being treated with opioid substitution treatment (OST) are serious and can result in abnormal cardiovascular function, overdose, and mortality. Chronic pain is a major risk factor for opioid relapse within the addiction treatment setting. There exist a number of opioid maintenance therapies including methadone, buprenorphine, naltrexone, and levomethadyl acetate (LAAM), of which the mediating effects of pain on treatment attrition, substance use behavior, and social functioning may differ across therapies. We aim to 1) evaluate the impact of pain on the treatment outcomes of addiction patients being managed with OST and 2) identify the most recently published opioid maintenance treatment guidelines from the United States, Canada, and the UK to determine how the evidence is being translated into clinical practice. METHODS/DESIGN: The authors will search Medline, EMBASE, PubMed, PsycINFO, Web of Science, Cochrane Database of Systematic Reviews, ProQuest Dissertations and theses Database, Cochrane Central Register of Controlled Trials (CENTRAL), World Health Organization International Clinical Trials Registry Platform Search Portal, and the National Institutes for Health Clinical Trials Registry. We will search www. GUIDELINES: gov and the National Institute for Care and Excellence (NICE) databases to identify the most recently published OST guidelines. All screening and data extraction will be completed in duplicate. Provided the data are suitable, we will perform a multiple treatment comparison using Bayesian meta-analytic methods to produce summary statistics estimating the effect of chronic pain on all OSTs. Our primary outcome is substance use behavior, which includes opioid and non-opioid substance use. We will also evaluate secondary endpoints such as treatment retention, general physical health, intervention adherence, personal and social functioning, as well as psychiatric symptoms. DISCUSSION: This review will capture the experience of treatment outcomes for a sub-population of opioid addiction patients and provide an opportunity to distinguish the best quality guidelines for OST. If chronic pain truly does result in negative consequences for opioid addiction patients, it is important we identify which OSTs are most appropriate for chronic pain patients as well as ensure the treatment guidelines incorporate this information. SYSTEMATIC REVIEW REGISTRATION: PROSPERO CRD42014014015 http://www.crd.york.ac.uk/PROSPERO/display_record.asp?ID=CRD42014014015#.VS1Qw1wk GM. PMID- 25927915 TI - Multicenter evaluation of a lateral-flow device test for diagnosing invasive pulmonary aspergillosis in ICU patients. AB - INTRODUCTION: The incidence of invasive pulmonary aspergillosis (IPA) in intensive care unit (ICU) patients is increasing, and early diagnosis of the disease and treatment with antifungal drugs is critical for patient survival. Serum biomarker tests for IPA typically give false-negative results in non neutropenic patients, and galactomannan (GM) detection, the preferred diagnostic test for IPA using bronchoalveolar lavage (BAL), is often not readily available. Novel approaches to IPA detection in ICU patients are needed. In this multicenter study, we evaluated the performance of an Aspergillus lateral-flow device (LFD) test for BAL IPA detection in critically ill patients. METHODS: A total of 149 BAL samples from 133 ICU patients were included in this semiprospective study. Participating centers were the medical university hospitals of Graz, Vienna and Innsbruck in Austria and the University Hospital of Mannheim, Germany. Fungal infections were classified according to modified European Organization for Research and Treatment of Cancer/Mycoses Study Group criteria. RESULTS: Two patients (four BALs) had proven IPA, fourteen patients (sixteen BALs) had probable IPA, twenty patients (twenty-one BALs) had possible IPA and ninety-seven patients (one hundred eight BALs) did not fulfill IPA criteria. Sensitivity, specificity, negative predictive value, positive predictive value and diagnostic odds ratios for diagnosing proven and probable IPA using LFD tests of BAL were 80%, 81%, 96%, 44% and 17.6, respectively. Fungal BAL culture exhibited a sensitivity of 50% and a specificity of 85%. CONCLUSION: LFD tests of BAL showed promising results for IPA diagnosis in ICU patients. Furthermore, the LFD test can be performed easily and provides rapid results. Therefore, it may be a reliable alternative for IPA diagnosis in ICU patients if GM results are not rapidly available. TRIAL REGISTRATION: ClinicalTrials.gov NCT02058316. Registered 20 January 2014. PMID- 25927917 TI - Emerging, Non-PCV13 Serotypes 11A and 35B of Streptococcus pneumoniae Show High Potential for Biofilm Formation In Vitro. AB - BACKGROUND: Since the use of pneumococcal conjugate vaccines PCV7 and PCV13 in children became widespread, invasive pneumococcal disease (IPD) has dramatically decreased. Nevertheless, there has been a rise in incidence of Streptococcus pneumoniae non-vaccine serotypes (NVT) colonising the human nasopharynx. Nasopharyngeal colonisation, an essential step in the development of S. pneumoniae-induced IPD, is associated with biofilm formation. Although the capsule is the main pneumococcal virulence factor, the formation of pneumococcal biofilms might, in fact, be limited by the presence of capsular polysaccharide (CPS). METHODOLOGY/PRINCIPAL FINDINGS: We used clinical isolates of 16 emerging, non-PCV13 serotypes as well as isogenic transformants of the same serotypes. The biofilm formation capacity of isogenic transformants expressing CPSs from NVT was evaluated in vitro to ascertain whether this trait can be used to predict the emergence of NVT. Fourteen out of 16 NVT analysed were not good biofilm formers, presumably because of the presence of CPS. In contrast, serotypes 11A and 35B formed >=45% of the biofilm produced by the non-encapsulated M11 strain. CONCLUSIONS/SIGNIFICANCE: This study suggest that emerging, NVT serotypes 11A and 35B deserve a close surveillance. PMID- 25927918 TI - The GLP-1 Receptor Agonist Exendin-4 and Diazepam Differentially Regulate GABAA Receptor-Mediated Tonic Currents in Rat Hippocampal CA3 Pyramidal Neurons. AB - Glucagon-like peptide-1 (GLP-1) is a metabolic hormone that is secreted in a glucose-dependent manner and enhances insulin secretion. GLP-1 receptors are also found in the brain where their signalling affects neuronal activity. We have previously shown that the GLP-1 receptor agonists, GLP-1 and exendin-4 enhanced GABA-activated synaptic and tonic currents in rat hippocampal CA3 pyramidal neurons. The hippocampus is the centre for memory and learning and is important for cognition. Here we examined if exendin-4 similarly enhanced the GABA activated currents in the presence of the benzodiazepine diazepam. In whole-cell recordings in rat brain slices, diazepam (1 MUM), an allosteric positive modulator of GABAA receptors, alone enhanced the spontaneous inhibitory postsynaptic current (sIPSC) amplitude and frequency by a factor of 1.3 and 1.6, respectively, and doubled the tonic GABAA current normally recorded in the CA3 pyramidal cells. Importantly, in the presence of exendin-4 (10 nM) plus diazepam (1 MUM), only the tonic but not the sIPSC currents transiently increased as compared to currents recorded in the presence of diazepam alone. The results suggest that exendin-4 potentiates a subpopulation of extrasynaptic GABAA receptors in the CA3 pyramidal neurons. PMID- 25927919 TI - Paradoxical sleep deprivation impairs mouse survival after infection with malaria parasites. AB - BACKGROUND: Parasitic diseases like malaria are a major public health problem in many countries and disrupted sleep patterns are an increasingly common part of modern life. The aim of this study was to assess the effects of paradoxical sleep deprivation (PSD) and sleep rebound (RB) on malarial parasite infection in mice. METHODS: After PSD, one group was immediately infected with parasites (PSD). The two other PSD rebound groups were allowed to sleep normally for either 24 h (24 h RB) or 48 h (48 h RB). After the recovery periods, mice were inoculated with parasites. RESULTS: The PSD group was the most affected by parasites presenting the higher death rate (0.02), higher number of infected cells (p < 0.01), and decrease in body weight (p < 0.04) compared to control and 48 h RB groups. The 24 h RB group was also different from control group in survival (p < 0.03), number of infected cells (p < 0.05) and body weight (p < 0.04). After 48 hours of sleep rebound animals were allowed to restore their response to parasitic infection similar to normal sleep animals. CONCLUSIONS: These results suggest that PSD is damaging to the immune system and leads to an increased infection severity of malaria parasites; only 48 hours of recovery sleep was sufficient to return the mice infection response to baseline values. PMID- 25927920 TI - IDOL N342S Variant, Atherosclerosis Progression and Cardiovascular Disorders in the Italian General Population. AB - Inducible degrader of the low density lipoprotein receptor (IDOL), is an E3 ubiquitin ligase that negatively modulates low density lipoprotein receptor (LDL R) expression. Genome-wide association studies (GWAS) indicated that genetic variants in IDOL gene contributes to variation in LDL-C plasma levels and the detailed analysis of a specific locus resulted in the identification of the functional common single nucleotide polymorphism (SNP) rs9370867 (c.G1025A, p.N342S) associates with increased LDL-R degradation and increased LDL-C levels. These findings, however, were not confirmed in two other independent cohorts and no data about the impact of this variant on atherosclerosis progression and cardiovascular risk are available. Aim of this study was to investigate the association between a functional variant in IDOL and atherosclerosis progression in an Italian general population. 1384 subjects enrolled in the PLIC study (Progression of Lesions in the Intima of Carotid) were genotyped by Q-PCR allelic discrimination and the association with anthropometric parameters, plasma lipids and the carotid intima media thickness (cIMT) and the impact on cardiovascular disease (CVD) incidence were investigated. The N342S variant was not associated with changes of the plasma lipid profile among GG, AG or AA carriers, including total cholesterol (249+/-21, 249+/-19 and 248+/-21 mg/dl respectively), LDL-C (158+/-25, 161+/-22 and 160+/-23 mg/dL), cIMT (0.74+/-0.14, 0.75+/-0.17 and 0.77+/-0.15 mm) and CVD incidence. In agreement, the expression of LDLR and the uptake of LDL was similar in macrophages derived from GG and AA carriers. Taken together our findings indicate that the N342S variant does not impact plasma lipid profile and is not associated with atherosclerosis progression and CVD in the general population, suggesting that other variants in the IDOL gene might be functionally linked with cholesterol metabolism. PMID- 25927921 TI - Children's Attentional Processing of Mother and Proximity Seeking. AB - Attachment expectations regarding the availability of mother as a source for support are supposed to influence distressed children's support seeking behavior. Because research is needed to better understand the mechanisms related to support seeking behavior, this study tested the hypothesis that the cognitive processing of mother-related information is linked to proximity and support seeking behavior. Uncertainty in maternal support has been shown to be characterized by a biased attentional encoding of mother, reducing the breadth of children's attentional field around her. We investigated whether this attentional bias is related to how long distressed children wait before seeking their mother's proximity. Thirty-three children (9-11 years) participated in this study that consisted of experimental tasks to measure attentional breadth and to observe proximity seeking behavior and of questionnaires to measure confidence in maternal support and experienced distress. Results suggested that distressed children with a more narrow attentional field around their mother wait longer to seek her proximity. Key Message: These findings provide a first support for the hypothesis that the attentional processing of mother is related to children's attachment behavior. PMID- 25927922 TI - EGCG Enhances Cisplatin Sensitivity by Regulating Expression of the Copper and Cisplatin Influx Transporter CTR1 in Ovary Cancer. AB - Cisplatin is one of the first-line platinum-based chemotherapeutic agents for treatment of many types of cancer, including ovary cancer. CTR1 (copper transporter 1), a transmembrane solute carrier transporter, has previously been shown to increase the cellular uptake and sensitivity of cisplatin. It is hypothesized that increased CTR1 expression would enhance the sensitivity of cancer cells to cisplatin (cDDP). The present study demonstrates for the first time that (-)-epigallocatechin-3-gallate (EGCG), a major polyphenol from green tea, can enhance CTR1 mRNA and protein expression in ovarian cancer cells and xenograft mice. EGCG inhibits the rapid degradation of CTR1 induced by cDDP. The combination of EGCG and cDDP increases the accumulation of cDDP and DNA-Pt adducts, and subsequently enhances the sensitivity of ovarian cancer SKOV3 and OVCAR3 cells to the chemotherapeutic agent. In the OVCAR3 ovarian cancer xenograft nude mice model, the combination of the lower concentration of cDDP and EGCG strongly repressed the tumor growth and exhibited protective effect on the nephrotoxicity induced by cisplatin. Overall, these findings uncover a novel chemotherapy mechanism of EGCG as an adjuvant for the treatment of ovarian cancer. PMID- 25927927 TI - Gender differences in predictors of left ventricular myocardial relaxation in non obese, healthy individuals. AB - BACKGROUND: Previous studies indicate that individuals with metabolic syndrome (MetS) might be at risk for left ventricular (LV) diastolic dysfunction. However, little is known about which metabolic factors contribute to the development of LV dysfunction in individuals who are not obese or overweight and who do not have diabetes mellitus and/or cardiovascular disease. METHODS: Participants without diabetes mellitus, systolic dysfunction, or other heart diseases underwent a thorough physical examination, including tissue Doppler echocardiography. A peak early mitral annular velocity (e') of <5.0 was designated as indicating abnormal LV myocardial relaxation (LVMR). We performed single and multiple logistic regression analyses of e' and cardiovascular risk factors, including MetS factors and indicators of major organ dysfunction. Normal-weight subjects (body mass index <25 kg/m2) were also analyzed. RESULTS: A total of 1055 individuals (mean age, 63 +/- 13 years) participated, of which 307 (29.1%) had MetS and 199 (18.9%) had abnormal LVMR. Multiple logistic regression analysis revealed waist circumference (WC) (odds ratio [OR] 1.04, P < 0.05) and age (OR 1.10, P < 0.05) to be predictors of abnormal LVMR. In normal-weight subjects (n = 806), aging (OR 1.08, P < 0.01), abnormal WC (OR 3.80, P < 0.01), and renal dysfunction (OR 2.14, P < 0.01) were predictors of abnormal LVMR. Among MetS factors, abnormal WC in men (OR 3.70, P < 0.01) and high diastolic blood pressure (DBP) in women (OR 4.00, P = 0.01) were related to abnormal LVMR. PMID- 25927923 TI - Circadian metabolism in the light of evolution. AB - Circadian rhythm, or daily oscillation, of behaviors and biological processes is a fundamental feature of mammalian physiology that has developed over hundreds of thousands of years under the continuous evolutionary pressure of energy conservation and efficiency. Evolution has fine-tuned the body's clock to anticipate and respond to numerous environmental cues in order to maintain homeostatic balance and promote survival. However, we now live in a society in which these classic circadian entrainment stimuli have been dramatically altered from the conditions under which the clock machinery was originally set. A bombardment of artificial lighting, heating, and cooling systems that maintain constant ambient temperature; sedentary lifestyle; and the availability of inexpensive, high-calorie foods has threatened even the most powerful and ancient circadian programming mechanisms. Such environmental changes have contributed to the recent staggering elevation in lifestyle-influenced pathologies, including cancer, cardiovascular disease, depression, obesity, and diabetes. This review scrutinizes the role of the body's internal clocks in the hard-wiring of circadian networks that have evolved to achieve energetic balance and adaptability, and it discusses potential therapeutic strategies to reset clock metabolic control to modern time for the benefit of human health. PMID- 25927925 TI - Swine is a possible source of hepatitis E virus infection by comparative study of hepatitis A and E seroprevalence in Thailand. AB - Hepatitis A virus (HAV) and hepatitis E virus (HEV) infection in developing countries are associated with contaminated food or water. Although Thailand is non-endemic for HEV, sporadic infections may occur from zoonotic transmission. Individuals between 7 months to 69 years (mean age = 32.8) from predominantly Islamic Narathiwat (n = 305) and swine farm-dense Lop Buri (n = 416) provinces were screened for anti-HEV and anti-HAV antibodies by commercial enzyme-linked immunosorbent assay and automated chemiluminescent microparticle immunoassay, respectively. Seroprevalence and relative antibody titers were analyzed according to age groups. HAV IgG antibody positive rates in Lop Buri and Narathiwat residents were 39.9% and 58%, respectively (p < 0.001). Greater than 90% of individuals >50 years old in both provinces possessed anti-HAV IgG. In contrast, seroprevalence for anti-HEV IgG was much higher in Lop Buri (37.3%) than in Narathiwat (8.9%) (p < 0.001). Highest anti-HEV IgG prevalence was found among 21 30 year-olds (50%) in Lop Buri and 41-50 year-olds (14.1%) in Narathiwat. In summary, fewer individuals possessed anti-HEV IgG in Narathiwat where most residents abstained from pork and fewer swine farms are present. Therefore, an increased anti-HEV IgG seroprevalence was associated with the density of swine farm and possibly pork consumption. Adults were more likely than children to have antibodies to both HEV and HAV. PMID- 25927928 TI - miR-148b reverses cisplatin-resistance in non-small cell cancer cells via negatively regulating DNA (cytosine-5)-methyltransferase 1(DNMT1) expression. AB - BACKGROUND: The emergence of drug resistance in cancer patients limits the success rate of clinical chemotherapy. MicroRNAs (miRNAs) may play a role in chemoresistance and may be involved in modulating of some drug resistance-related pathways in cancer cells. In this study, the involvement of microRNA-148b (miR 148b) and its roles in the development of chemoresistance in lung cancer are determined. METHODS: This study was performed in two lung cancer cell lines (A549 and SPC-A1). The levels of miR-148b and DNMT1 mRNA expression were determined by using Quantitative Real-Time PCR. Proteins of DNMTs are represented by western blot assay. Cell viability was assessed by MTT assay. Cell apoptosis was evaluated using flow cytometry. RESULTS: The data showed a down-regulated of miR 148b expression and evaluated methyltransferases (DNMTs) expression in cisplatin resisted human non-small cell lung cancer (NSCLC) cell line-A549/DDP and SPC A1/DDP compared with their parental A549 and SPC-A1 cell line. In transfection experiments, miR-148b mimics reduced the DNMT1 expression, as well as enhanced the sensitivity of cells to cisplatin and cisplatin-induced apoptosis in A549/DDP or SPC-A1/DDP cells. While miR-148b inhibitor increased DNMT1 expression, as well as attenuated the sensitivity of cells to cisplatin in A549 and SPC-A1 cells. miR 148b was showed to exert negative effect on DNMT1 expression by targeting its 3'UTR in A549/DDP and A549 cells. Importantly, silenced DNMT1 increases cisplatin sensitivity of A549/DDP cells and over-expressed DNMT1 reverses pro-apoptosis effect of miR-148b mimic. CONCLUSIONS: miR-148b reverses cisplatin-resistance in non-small cell cancer cells via negatively regulating DNMT1 expression. PMID- 25927931 TI - Nutritional and lifestyle risk behaviors and their association with mental health and violence among Pakistani adolescents: results from the National Survey of 4583 individuals. AB - BACKGROUND: Unhealthy behaviors are associated with mental health problems and violence in adolescents, yet their combined association has been understudied. Using the Global School Health Survey, this study examined the association between combined unhealthy behaviors (including fast food, soft drink, smoking, other tobacco products and physical inactivity) and anxiety, suicidal ideation and involvement in physical fight among Pakistani adolescents. METHODS: Data were obtained from the Global School Health Survey conducted in Pakistan (2009). The study population consisted of school going adolescents aged 13 to 15 years. Association of combined unhealthy behaviors with anxiety, suicidal ideation and involvement in physical fight were studied through secondary analysis. We used univariate and multivariate logistic regression analysis by complex sample method, accounting for cluster sampling technique used for data collection. RESULTS: Of the total 4583 students, weighted percentage and unweighted count for one, two, three and four or more unhealthy behaviors was 39.4% (n = 1770), 22.1% (n = 963), 5.9% (n = 274) and 1.2% (n = 62) respectively. The weighted prevalence for anxiety, suicidal ideation and involvement in physical fight were 8.4%, 7.3% and 37.4% respectively. The results of multivariate logistic regression analysis after adjustment showed that students who had four or more unhealthy behaviors had higher odds of; being anxious (OR 2.45, 95%CI 1.31-4.59, p value 0.004), suicide ideation (OR 4.56, 95%CI 2.58-8.07, p value <0.001) and being involved in physical fight (OR 3.15, 95% CI 1.63-6.08, p value <0.001) as compared to those who had not adopted any unhealthy behaviors. CONCLUSIONS: This study suggests that the co-occurrence of unhealthy behaviors is associated with anxiety, suicidal ideation and physical fight among adolescents. These findings should be considered when developing interventions to combat detrimental outcomes of unhealthy behaviors during adolescence. PMID- 25927932 TI - Cyclin D3-dependent control of the dNTP pool and HIV-1 replication in human macrophages. AB - Cyclins control the activation of cyclin-dependent kinases (CDK), which in turn, control the cell cycle and cell division. Intracellular availability of deoxynucleotides (dNTP) plays a fundamental role in cell cycle progression. SAM domain and HD domain-containing protein 1 (SAMHD1) degrades nucleotide triphosphates and controls the size of the dNTP pool. SAMHD1 activity appears to be controlled by CDK. Here, we show that knockdown of cyclin D3 a partner of CDK6 and E2 a partner of CDK2 had a major impact in SAMHD1 phosphorylation and inactivation and led to decreased dNTP levels and inhibition of HIV-1 at the reverse transcription step in primary human macrophages. The effect of cyclin D3 RNA interference was lost after degradation of SAMHD1 by HIV-2 Vpx, demonstrating the specificity of the mechanism. Cyclin D3 inhibition correlated with decreased activation of CDK2. Our results confirm the fundamental role of the CDK6-cyclin D3 pair in controlling CDK2-dependent SAMHD1 phosphorylation and dNTP pool in primary macrophages. PMID- 25927933 TI - Combining the strength of genomics, nanoparticle technology, and direct intraductal delivery for breast cancer treatment. AB - A large number of genes are altered in cancer cells. Often, reversal or inhibition of just one of these alterations leads to death of the cancer cells. Technological advances in multiple areas are necessary to potentiate clinical translation of these findings. In a recent article, Brock and colleagues reported that overexpressed HOXA1 is a critical event in tumor progression in a mouse mammary tumor model. They developed HOXA1-small interfering RNA nanoparticles and achieved effective therapeutic doses by delivering them intraductally through the nipple to the site of the tumor and at the same time circumvented the systemic immune response. This study strengthens the concept of targeting overexpressed genes by using small interfering RNA and bypassing systemic immunity through local intraductal delivery. PMID- 25927934 TI - The ancestral shape hypothesis: an evolutionary explanation for the occurrence of intervertebral disc herniation in humans. AB - BACKGROUND: Recent studies suggest there is a relationship between intervertebral disc herniation and vertebral shape. The nature of this relationship is unclear, however. Humans are more commonly afflicted with spinal disease than are non human primates and one suggested explanation for this is the stress placed on the spine by bipedalism. With this in mind, we carried out a study of human, chimpanzee, and orangutan vertebrae to examine the links between vertebral shape, locomotion, and Schmorl's nodes, which are bony indicators of vertical intervertebral disc herniation. We tested the hypothesis that vertical disc herniation preferentially affects individuals with vertebrae that are towards the ancestral end of the range of shape variation within Homo sapiens and therefore are less well adapted for bipedalism. RESULTS: The study employed geometric morphometric techniques. Two-dimensional landmarks were used to capture the shapes of the superior aspect of the body and posterior elements of the last thoracic and first lumbar vertebrae of chimpanzees, orangutans, and humans with and without Schmorl's nodes. These data were subjected to multivariate statistical analyses. Canonical Variates Analysis indicated that the last thoracic and first lumbar vertebrae of healthy humans, chimpanzees, and orangutans can be distinguished from each other (p<0.028), but vertebrae of pathological humans and chimpanzees cannot (p>0.4590). The Procrustes distance between pathological humans and chimpanzees was found to be smaller than the one between pathological and healthy humans. This was the case for both vertebrae. Pair-wise MANOVAs of Principal Component scores for both the thoracic and lumbar vertebrae found significant differences between all pairs of taxa (p<0.029), except pathological humans vs chimpanzees (p>0.367). Together, these results suggest that human vertebrae with Schmorl's nodes are closer in shape to chimpanzee vertebrae than are healthy human vertebrae. CONCLUSIONS: The results support the hypothesis that intervertebral disc herniation preferentially affects individuals with vertebrae that are towards the ancestral end of the range of shape variation within H. sapiens and therefore are less well adapted for bipedalism. This finding not only has clinical implications but also illustrates the benefits of bringing the tools of evolutionary biology to bear on problems in medicine and public health. PMID- 25927936 TI - Impact of withholding early parenteral nutrition completing enteral nutrition in pediatric critically ill patients (PEPaNIC trial): study protocol for a randomized controlled trial. AB - BACKGROUND: The state-of-the-art nutrition used for critically ill children is based essentially on expert opinion and extrapolations from adult studies or on studies in non-critically ill children. In critically ill adults, withholding parenteral nutrition (PN) during the first week in ICU improved outcome, as compared with early supplementation of insufficient enteral nutrition (EN) with PN. We hypothesized that withholding PN in children early during critical illness reduces the incidence of new infections and accelerates recovery. METHODS/DESIGN: The Pediatric Early versus Late Parenteral Nutrition in Intensive Care Unit (PEPaNIC) study is an investigator-initiated, international, multicenter, randomized controlled trial (RCT) in three tertiary referral pediatric intensive care units (PICUs) in three countries on two continents. This study compares early versus late initiation of PN when EN fails to reach preset caloric targets in critically ill children. In the early-PN (control, standard of care) group, PN comprising glucose, lipids and amino acids is administered within the first days to reach the caloric target. In the late-PN (intervention) group, PN completing EN is only initiated beyond PICU-day 7, when EN fails. For both study groups, an early EN protocol is applied and micronutrients are administered intravenously. The primary assessor-blinded outcome measures are the incidence of new infections during PICU-stay and the duration of intensive care dependency. The sample size (n = 1,440, 720 per arm) was determined in order to detect a 5% absolute reduction in PICU infections, with at least 80% 1-tailed power (70% 2-tailed) and an alpha error rate of 5%. Based on the actual incidence of new PICU infections in the control group, the required sample size was confirmed at the time of an a priori- planned interim-analysis focusing on the incidence of new infections in the control group only. DISCUSSION: Clinical evidence in favor of early administration of PN in critically ill children is currently lacking, despite potential benefit but also known side effects. This large international RCT will help physicians to gain more insight in the clinical effects of omitting PN during the first week of critical illness in children. TRIAL REGISTRATION: ClinicalTrials.gov: NCT01536275 on 16 February 2012. PMID- 25927942 TI - Carrier transport at the metal-MoS2 interface. AB - This study illustrates the nature of electronic transport and its transition from one mechanism to another between a metal electrode and MoS2 channel interface in a field effect transistor (FET) device. Interestingly, measurements of the contact resistance (Rc) as a function of temperature indicate a transition in the carrier transport across the energy barrier from thermionic emission at a high temperature to tunneling at a low temperature. Furthermore, at a low temperature, the nature of the tunneling behavior is ascertained by the current-voltage dependency that helps us feature direct tunneling at a low bias and Fowler Nordheim tunneling at a high bias for a Pd-MoS2 contact due to the effective barrier shape modulation by biasing. In contrast, only direct tunneling is observed for a Cr-MoS2 contact over the entire applied bias range. In addition, simple analytical calculations were carried out to extract Rc at the gating range, and the results are consistent with the experimental data. Our results describe the transition in carrier transport mechanisms across a metal-MoS2 interface, and this information provides guidance for the design of future flexible, transparent electronic devices based on 2-dimensional materials. PMID- 25927938 TI - Deletion of REXO1L1 locus in a patient with malabsorption syndrome, growth retardation, and dysmorphic features: a novel recognizable microdeletion syndrome? AB - BACKGROUND: Copy number variations (CNVs) can contribute to genetic variation among individuals and/or have a significant influence in causing diseases. Many studies consider new CNVs' effects on protein family evolution giving rise to gene duplicates or losses. "Unsuccessful" duplicates that remain in the genome as pseudogenes often exhibit functional roles. So, changes in gene and pseudogene number may contribute to development or act as susceptibility alleles of diseases. CASE PRESENTATION: We report a de novo heterozygous 271 Kb microdeletion at 8q21.2 region which includes the family of REXO1L genes and pseudogenes in a young man affected by global development delay, progeroid signs, and gastrointestinal anomalies. Molecular and cellular analysis showed that the REXO1L1 gene hemizygosity in a patient's fibroblasts induces genetic instability and increased apoptosis after treatment with different DNA damage-induced agents. CONCLUSIONS: The present results support the hypothesis that low copy gene number within REXO1L1 cluster could play a significant role in this complex clinical and cellular phenotype. PMID- 25927939 TI - High expression of protein phosphatase 4 is associated with the aggressive malignant behavior of colorectal carcinoma. AB - BACKGROUND: Recent evidence suggests an important role of protein phosphatase 4 (PP4C) in the progression of several cancers, including breast cancer, lung cancer and pancreatic ductal adenocarcinoma. However, the contribution of PP4C to colorectal carcinoma (CRC) remains elusive. METHODS: The expression of PP4C in CRC tissues compared with matched non-tumor tissues and CRC cells was detected using quantitative RT-PCR, immunohistochemistry and western blotting assays. Through univariate and Kaplan-Meier analysis, we correlated the PP4C expression with clinicopathological features and patient survival. A series of experiments, including cell proliferation, lentiviral infection, cell invasion and MMP gelatinase activity assays, were performed to investigate the underlying mechanisms. Through further experiments, tumor growth and metastasis were evaluated in vivo using a xenogenous subcutaneously implant model and a tail vein metastasis model. RESULTS: In the present study, we found that PP4C expression is frequently increased in human CRC and that the upregulation of PP4C correlates with a more invasive tumor phenotype and poor prognosis. The ectopic expression of PP4C promoted CRC cell proliferation, migration and invasion in vitro and tumor growth and lung metastasis in vivo. Silencing the expression of PP4C resulted in the inhibition of cell proliferation and invasion. Further investigations showed that phosphorylated Akt (p-AKT) is required for the PP4C mediated upregulation of MMP-2 and MMP-9, which promotes cell invasion. CONCLUSIONS: Our data suggested a potential role of PP4C in tumor progression and provided novel insights into the mechanism of how this factor positively regulated cell proliferation and invasion in CRC cells. PMID- 25927944 TI - Traditional clinical risk factors predict clopidogrel hypo-responsiveness in unselected patients undergoing non-emergent percutaneous coronary intervention. AB - High and low platelet reactivity, HPR and LPR respectively, to clopidogrel and aspirin have previously been associated with adverse events following percutaneous coronary intervention (PCI). The aim is to test the ability of a previously developed clinical risk-score, the PREDICT score, to identify patients with HPR and LPR. Nine hundred and twenty-three consecutive patients undergoing non-emergent PCI were enrolled. Platelet reactivity (PR) was determined using Multiplate assays. Patients were grouped into quintiles based on their PR values. Upper and lower quintiles defined HPR and LPR, respectively, whereas quintiles 2 4 defined normal responders. All patients were assigned PREDICT score points in clinical categories (age > 65, reduced left ventricular function, reduced kidney function, acute coronary syndrome (ACS) and diabetes). We found an association between the cumulative number of PREDICT score variables and the incidence of HPR for clopidogrel (HPR (ADP)) (p < 0.001) and aspirin (HPR (AA)) (p = 0.007). In addition, the higher the PREDICT score, the higher the risk of HPR (ADP) (1-3 points, odds ratio (OR) 3.82 (95% CI 1.5-9.73, p = 0.005); 4-6 points OR 4.11 (95% CI 1.61-10.52, p = 0.003); 7-9 points OR 9.84 (95% CI 3.49-27.7, p < 0.001); patients with 0 PREDICT points defined the reference population). The relation was reversed with regards to clopidogrel LPR (LPR (ADP)). On the other hand, there was no clear association between PREDICT score and AA response. The PREDICT score was able to identify patients with a high risk of HPR (ADP) but did not correlate well with PR to AA. In order to assure an optimal tailoring of antiplatelet therapy, costly platelet function tests (PFTs) could be reserved for patients with high clinical likelihood for HPR. PMID- 25927945 TI - The importance of patents to innovation: updated cross-industry comparisons with biopharmaceuticals. AB - Patents have long been considered essential incentives to foster innovation, particularly the development of new prescription drugs, due to the lengthy, costly, and risky nature of the research and development (R&D) process as compared to the lower levels of investment and risk associated with generic drug entry. Compared with other forms of intellectual property protection (such as trade secrets, trademarks, and copyrights) and strategic complementary assets (such as lead time, sales and service, and manufacturing advantages), researchers focused on the US since the 1980s consistently have found patents to be relatively more important to R&D in pharmaceuticals than in other industries. Despite many changes in the market and patent landscape, the most recent data from government surveys and annual surveys of licensing professionals continue to find differential and high importance of patents to biopharmaceutical innovation. PMID- 25927946 TI - Development of a serological assay to predict antibody bactericidal activity against non-typeable Haemophilus influenzae. AB - BACKGROUND: Non-typeable Haemophilus influenzae (NTHi) is a Gram negative microorganism residing in the human nasopharyngeal mucosa and occasionally causing infections of both middle ear and lower respiratory airways. A broadly protective vaccine against NTHi has been a long-unmet medical need, as the high genetic variability of this bacterium has posed great challenges. RESULTS: In this study, we developed a robust serum bactericidal assay (SBA) to optimize the selection of protective antigens against NTHi. SBA takes advantage of the complement-mediated lysis of bacterial cells and is a key in vitro method for measuring the functional activity of antibodies. As a proof of concept, we assessed the bactericidal activity of antibodies directed against antigens known to elicit a protective response, including protein D used as carrier protein in the Synflorix pneumococcal polysaccharide conjugate vaccine. Prior to SBA screening, the accessibility of antigens to antibodies and the capacity of the latter to induce C3 complement deposition was verified by flow cytometry. Using baby rabbit serum as a source of complement, the proposed assay not only confirmed the bactericidal activity of the antibodies against the selected vaccine candidates, but also showed a significant reproducibility. CONCLUSIONS: Considering the rapidity and cost-effectiveness of this novel SBA protocol, we conclude that it is likely to become an important tool to prove the capability of antibodies directed against recombinant antigens to induce NTHi in vitro killing and to both select new protective vaccine candidates, and predict vaccine efficacy. PMID- 25927949 TI - The use of balloons for uterine cervical ripening is associated with an increased risk of umbilical cord prolapse: population based questionnaire survey in Japan. AB - BACKGROUND: To clarify whether the use of balloons for cervical ripening is associated with the incidence of umbilical cord prolapse. METHODS: A postal questionnaire survey was distributed in Japan. Cases of umbilical cord prolapse occurring during labor in association with the use of balloons for cervical ripening between 2007 and 2011 in Japan were analyzed. RESULTS: Answers from 942 institutions were obtained. The subjects included 369 patients with fore-lying or prolapse of the umbilical cord among a total of 2,037,460 deliveries. Among the singleton vertex cases, fore-lying or prolapse of the umbilical cord during labor were observed in 88 (0.005%) of 1,891,189 deliveries not associated with the use of balloons for cervical ripening and in 93 (0.064%) of 146,271 deliveries associated with the use of balloons for cervical ripening (Odds ratio 13.67, 95% confidence interval 10.21, 18.30). All types of balloons were significantly associated with the occurrence of fore-lying or prolapse of the umbilical cord. A total of 39% of cases of umbilical cord prolapse occurred during manual or spontaneous balloon removal, while 53% of cases occurred after a while not directly associated with balloon removal. CONCLUSION: The risk of umbilical cord prolapse was significantly increased during the use of balloons for cervical ripening, especially in cases involving the use of disk-type and ball-type balloons filled with large amounts of water. PMID- 25927950 TI - Accuracy of genotype imputation in Nelore cattle. AB - BACKGROUND: Genotype imputation from low-density (LD) to high-density single nucleotide polymorphism (SNP) chips is an important step before applying genomic selection, since denser chips tend to provide more reliable genomic predictions. Imputation methods rely partially on linkage disequilibrium between markers to infer unobserved genotypes. Bos indicus cattle (e.g. Nelore breed) are characterized, in general, by lower levels of linkage disequilibrium between genetic markers at short distances, compared to taurine breeds. Thus, it is important to evaluate the accuracy of imputation to better define which imputation method and chip are most appropriate for genomic applications in indicine breeds. METHODS: Accuracy of genotype imputation in Nelore cattle was evaluated using different LD chips, imputation software and sets of animals. Twelve commercial and customized LD chips with densities ranging from 7 K to 75 K were tested. Customized LD chips were virtually designed taking into account minor allele frequency, linkage disequilibrium and distance between markers. Software programs FImpute and BEAGLE were applied to impute genotypes. From 995 bulls and 1247 cows that were genotyped with the Illumina(r) BovineHD chip (HD), 793 sires composed the reference set, and the remaining 202 younger sires and all the cows composed two separate validation sets for which genotypes were masked except for the SNPs of the LD chip that were to be tested. RESULTS: Imputation accuracy increased with the SNP density of the LD chip. However, the gain in accuracy with LD chips with more than 15 K SNPs was relatively small because accuracy was already high at this density. Commercial and customized LD chips with equivalent densities presented similar results. FImpute outperformed BEAGLE for all LD chips and validation sets. Regardless of the imputation software used, accuracy tended to increase as the relatedness between imputed and reference animals increased, especially for the 7 K chip. CONCLUSIONS: If the Illumina(r) BovineHD is considered as the target chip for genomic applications in the Nelore breed, cost-effectiveness can be improved by genotyping part of the animals with a chip containing around 15 K useful SNPs and imputing their high-density missing genotypes with FImpute. PMID- 25927951 TI - Timing the First Postoperative Dose of Anticoagulants: Lessons Learned From Clinical Trials. AB - The non-vitamin K antagonist oral anticoagulants (NOACs), rivaroxaban, apixaban, and dabigatran, have been shown in phase 3 trials to be effective for thromboprophylaxis in patients undergoing elective hip or knee arthroplasty. Results from prior studies suggested that the safety of anticoagulants in such patients was improved if the first postoperative dose was delayed for at least 6 h after surgery. The timing of the first postoperative dose of the NOACs tested in phase 2 studies differed among the three NOACs: dabigatran was started 1 to 4 h postoperatively, whereas rivaroxaban and apixaban were started at least 6 and 12 h, postoperatively, respectively. Our review of the timing of initiation of thromboprophylaxis in randomized trials provides three related lessons. First, clinical trials performed before the NOACs were evaluated demonstrated that delaying the first dose of prophylactic anticoagulation until after major surgery is effective and safe. Second, the optimal timing of the first dose of prophylactic anticoagulation after surgery depends on the dose that is selected. Third, the results of the phase 3 trials with NOACs for thromboprophylaxis support the concept that acceptable efficacy and safety can be achieved when the appropriate first postoperative dose of anticoagulant is delayed for at least 6 h after surgery. PMID- 25927953 TI - Can shared decision-making reduce medical malpractice litigation? A systematic review. AB - BACKGROUND: To explore the likely influence and impact of shared decision-making on medical malpractice litigation and patients' intentions to initiate litigation. METHODS: We included all observational, interventional and qualitative studies published in all languages, which assessed the effect or likely influence of shared decision-making or shared decision-making interventions on medical malpractice litigation or on patients' intentions to litigate. The following databases were searched from inception until January 2014: CINAHL, Cochrane Register of Controlled Trials, Cochrane Database of Systematic Reviews, EMBASE, HMIC, Lexis library, MEDLINE, NHS Economic Evaluation Database, Open SIGLE, PsycINFO and Web of Knowledge. We also hand searched reference lists of included studies and contacted experts in the field. Downs & Black quality assessment checklist, the Critical Appraisal Skill Programme qualitative tool, and the Critical Appraisal Guidelines for single case study research were used to assess the quality of included studies. RESULTS: 6562 records were screened and 19 articles were retrieved for full-text review. Five studies wee included in the review. Due to the number and heterogeneity of included studies, we conducted a narrative synthesis adapted from the ESRC guidance for narrative synthesis. Four themes emerged. The analysis confirms the absence of empirical data necessary to determine whether or not shared decision making promoted in the clinical encounter can reduce litigation. Three out of five included studies provide retrospective and simulated data suggesting that ignoring or failing to diagnose patient preferences, particularly when no effort has been made to inform and support understanding of possible harms and benefits, puts clinicians at a higher risk of litigation. Simulated scenarios suggest that documenting the use of decision support interventions in patients' notes could offer some level of medico-legal protection. Our analysis also indicated that a sizeable proportion of clinicians prefer ordering more tests and procedures, irrespective of patient informed preferences, as protection against litigation. CONCLUSIONS: Given the lack of empirical data, there is insufficient evidence to determine whether or not shared decision-making and the use of decision support interventions can reduce medical malpractice litigation. Further investigation is required. TRIAL REGISTRATION: This review was registered on PROSPERO. REGISTRATION NUMBER: CRD42012002367 . PMID- 25927954 TI - Mass-spectrometry-based molecular characterization of extracellular vesicles: lipidomics and proteomics. AB - This review discusses extracellular vesicles (EVs), which are submicron-scale, anuclear, phospholipid bilayer membrane enclosed vesicles that contain lipids, metabolites, proteins, and RNA (micro and messenger). They are shed from many, if not all, cell types and are present in biological fluids and conditioned cell culture media. The term EV, as coined by the International Society of Extracellular Vesicles (ISEV), encompasses exosomes (30-100 nm in diameter), microparticles (100-1000 nm), apoptotic blebs, and other EV subsets. EVs have been implicated in cell-cell communication, coagulation, inflammation, immune response modulation, and disease progression. Multiple studies report that EV secretion from disease-affected cells contributes to disease progression, e.g., tumor niche formation and cancer metastasis. EVs are attractive sources of biomarkers due to their biological relevance and relatively noninvasive accessibility from a range of physiological fluids. This review is focused on the molecular profiling of the protein and lipid constituents of EVs, with emphasis on mass-spectrometry-based "omic" analytical techniques. The challenges in the purification and molecular characterization of EVs, including contamination of isolates and limitations in sample quantities, are discussed along with possible solutions. Finally, the review discusses the limited but growing investigation of post-translational modifications of EV proteins and potential strategies for future in-depth molecular characterization of EVs. PMID- 25927955 TI - Optical control of fluorescence through plasmonic eigenmode extinction. AB - We introduce the concept of optical control of the fluorescence yield of CdSe quantum dots through plasmon-induced structural changes in random semicontinuous nanostructured gold films. We demonstrate that the wavelength- and polarization dependent coupling between quantum dots and the semicontinuous films, and thus the fluorescent emission spectrum, can be controlled and significantly increased through the optical extinction of a selective band of eigenmodes in the films. This optical method of effecting controlled changes in the metal nanostructure allows for versatile functionality in a single sample and opens a pathway to in situ control over the fluorescence spectrum. PMID- 25927957 TI - Differential accumulation and elimination behavior of perfluoroalkyl Acid isomers in occupational workers in a manufactory in China. AB - In this study, serum and urine samples were collected from 36 occupational workers in a fluorochemical manufacturing plant in China from 2008 to 2012 to evaluate the body burden and possible elimination of linear and branched perfluoroalkyl acids (PFAAs). Indoor dust, total suspended particles (TSP), diet, and drinking water samples were also collected to trace the occupational exposure pathway to PFAA isomers. The geometric mean concentrations of perfluorooctanesulfonate (PFOS), perfluorooctanoate (PFOA), and perfluorohexanesulfonate (PFHxS) isomers in the serum were 1386, 371, and 863 ng mL(-1), respectively. The linear isomer of PFOS, PFOA, and PFHxS was the most predominant PFAA in the serum, with mean proportions of 63.3, 91.1, and 92.7% respectively, which were higher than the proportions in urine. The most important exposure routes to PFAA isomers in the occupational workers were considered to be the intake of indoor dust and TSP. A renal clearance estimation indicated that branched PFAA isomers had a higher renal clearance rate than did the corresponding linear isomers. Molecular docking modeling implied that linear PFOS (n-PFOS) had a stronger interaction with human serum albumin (HSA) than branched isomers did, which could decrease the proportion of n-PFOS in the blood of humans via the transport of HSA. PMID- 25927960 TI - A New Core/Shell NiAu/Au Nanoparticle Catalyst with Pt-like Activity for Hydrogen Evolution Reaction. AB - We report a general approach to NiAu alloy nanoparticles (NPs) by co-reduction of Ni(acac)2 (acac = acetylacetonate) and HAuCl4.3H2O at 220 degrees C in the presence of oleylamine and oleic acid. Subject to potential cycling between 0.6 and 1.0 V (vs reversible hydrogen electrode) in 0.5 M H2SO4, the NiAu NPs are transformed into core/shell NiAu/Au NPs that show much enhanced catalysis for hydrogen evolution reaction (HER) with Pt-like activity and much robust durability. The first-principles calculations suggest that the high activity arises from the formation of Au sites with low coordination numbers around the shell. Our synthesis is not limited to NiAu but can be extended to FeAu and CoAu as well, providing a general approach to MAu/Au NPs as a class of new catalyst superior to Pt for water splitting and hydrogen generation. PMID- 25927959 TI - Disruption of endothelial adherens junctions by high glucose is mediated by protein kinase C-beta-dependent vascular endothelial cadherin tyrosine phosphorylation. AB - BACKGROUND: Hyperglycemia has been recognized as a primary factor in endothelial barrier dysfunction and in the development of micro- and macrovascular diseases associated with diabetes, but the underlying biochemical mechanisms remain elusive. Tyrosine phosphorylation of vascular endothelial cadherin (VE-cad) leads to the disruption of endothelial adherens junctions and increases the transendothelial migration (TEM) of leukocytes. METHODS: VE-cad tyrosine phosphorylation, adherens junction integrity and TEM of monocytes in human umbilical vein endothelial cells (HUVECs) treated with high-concentration glucose were evaluated. The role of protein kinase C (PKC) in induction of endothelial cells adherence junction disruption by exposure of HUVECs to high concentration of glucose was explored. RESULTS: The treatment of HUVEC with high-concentration glucose increased VE-cad tyrosine phosphorylation, whereas mannitol or 3-O-methyl D-glucose had no effect. In addition, high-concentration glucose increased the dissociation of the VE-cad-beta-catenin complex, activation of the Wnt/beta catenin pathway, and the TEM of monocytes. These alterations were accompanied by the activation of endothelial PKC and increased phosphorylation of ERK and myosin light chain (MLC). High-concentration glucose-induced tyrosine phosphorylation of VE-cad was attenuated by: 1- the inhibition of PKC-beta by overexpression of dominant-negative PKC-beta 2- inhibition of MLC phosphorylation by overexpression of a nonphosphorylatable dominant-negative form of MLC, 3- the inhibition of actin polymerization by cytochalasin D and 4- the treatment of HUVECs with forskolin (an activator of adenylate cyclase). CONCLUSIONS: Our findings show that the high-concentration glucose-induced disruption of endothelial adherens junctions is mediated by tyrosine phosphorylation of VE-cad through PKC-beta and MLC phosphorylation. PMID- 25927961 TI - Staphylococcus aureus is More Prevalent in Retail Beef Livers than in Pork and other Beef Cuts. AB - Staphylococcus aureus is one of the top five pathogens contributing to acquired foodborne illnesses causing an estimated quarter million cases every year in the US. The objectives of this study were to determine the prevalence of Methicillin Susceptible S. aureus (MSSA) and Methicillin Resistant S. aureus (MRSA) in retail beef livers, beef, and pork meats sold in Tulsa, Oklahoma and to characterize the recovered strains for their virulence and antimicrobial resistance. Ninety six chilled retail beef (50 beef livers and 46 beef other cuts), and 99 pork meat samples were collected. The prevalence in beef livers was 40/50 (80%) followed by other beef cuts 23/46 (50%) then pork 43/99 (43.3%). No isolates were positive for MRSA since none harbored the mecA or mecC gene. A total of 334 recovered S. aureus isolates (143 beef livers, 76 beef, and 115 pork isolates) were screened for their antimicrobial susceptibility against 16 different antimicrobials and their possession of 18 different toxin genes. Multidrug resistance was more prevalent in the pork isolates followed by beef then beef livers. The prevalence of enterotoxin genes such as seg, seh, and sei and the toxic shock syndrome gene tst was higher in the pork isolates than in the beef ones. The hemolysin genes, particularly hlb, were more prevalent in isolates from beef livers. Molecular typing of a subset of the recovered isolates showed that they are highly diverse where spa typing was more discriminatory than PFGE. The alarmingly high incidence of S. aureus in retail beef livers in this study should raise awareness about the food safety of such meat products. PMID- 25927962 TI - Genome-wide amplification of proviral sequences reveals new polymorphic HERV K(HML-2) proviruses in humans and chimpanzees that are absent from genome assemblies. AB - BACKGROUND: To date, the human population census of proviruses of the Betaretrovirus-like human endogenous retroviral (HERV-K) (HML-2) family has been compiled from a limited number of complete genomes, making it certain that rare polymorphic loci are under-represented and are yet to be described. RESULTS: Here we describe a suppression PCR-based method called genome-wide amplification of proviral sequences (GAPS) that selectively amplifies DNA fragments containing the termini of HERV-K(HML-2) proviral sequences and their flanking genomic sequences. We analysed the HERV-K(HML-2) proviral content of 101 unrelated humans, 4 common chimpanzees and three centre d'etude du polymorphisme humain (CEPH) pedigrees (44 individuals). The technique isolated HERV-K(HML-2) proviruses that had integrated in the genomes of the great apes throughout their divergence and included evolutionarily young elements still unfixed for presence/absence. CONCLUSIONS: By examining the HERV-K(HML-2) proviral content of 145 humans we detected a new insertionally polymorphic Type I HERV-K(HML-2) provirus. We also observed provirus versus solo long terminal repeat (LTR) polymorphism within humans at a previously unreported, but ancient, locus. Finally, we report two novel chimpanzee specific proviruses, one of which is dimorphic for a provirus versus solo LTR. Thus GAPS enables the isolation of uncharacterised HERV-K(HML-2) proviral sequences and provides a direct means to assess inter-individual genetic variation associated with HERV-K(HML-2) proviruses. PMID- 25927963 TI - Nonfunctional adrenocortical carcinoma initially presenting as retroperitoneal hemorrhage. AB - BACKGROUND: Acute adrenal hemorrhage is an uncommon entity. Although trauma is the most common cause of adrenal hemorrhage, non-traumatic etiologies have also been reported. We report an unusual case of a spontaneously ruptured adrenocortical carcinoma that initially presented as a critical massive retroperitoneal hemorrhage. The case was treated successfully using a combination of emergency interventional radiology and elective surgery. CASE PRESENTATION: A 47-year-old woman was transported to our hospital because of the sudden onset of severe pain in her left lower back. The shadow of a tumor-like soft mass accompanied by bleeding was observed in the upper pole of the left kidney, together with vascular leakage from the middle suprarenal artery on computed tomography. Transcatheter embolization of the left middle adrenal artery was administered based on a diagnosis of acute adrenal hemorrhage. Further observation indicated that the bleeding was caused by rupture of an adrenocortical carcinoma. Left adrenalectomy was subsequently carried out via laparotomy. CONCLUSIONS: We experienced an unusual case of acute massive adrenal hemorrhage caused by the rupture of a non-functional adrenocortical carcinoma, which was treated successfully by ambulatory transcatheter embolization therapy and elective surgery. PMID- 25927964 TI - Optimal Treatment Strategies in the Context of 'Treatment for Prevention' against HIV-1 in Resource-Poor Settings. AB - An estimated 2.7 million new HIV-1 infections occurred in 2010. 'Treatment-for prevention' may strongly prevent HIV-1 transmission. The basic idea is that immediate treatment initiation rapidly decreases virus burden, which reduces the number of transmittable viruses and thereby the probability of infection. However, HIV inevitably develops drug resistance, which leads to virus rebound and nullifies the effect of 'treatment-for-prevention' for the time it remains unrecognized. While timely conducted treatment changes may avert periods of viral rebound, necessary treatment options and diagnostics may be lacking in resource constrained settings. Within this work, we provide a mathematical platform for comparing different treatment paradigms that can be applied to many medical phenomena. We use this platform to optimize two distinct approaches for the treatment of HIV-1: (i) a diagnostic-guided treatment strategy, based on infrequent and patient-specific diagnostic schedules and (ii) a pro-active strategy that allows treatment adaptation prior to diagnostic ascertainment. Both strategies are compared to current clinical protocols (standard of care and the HPTN052 protocol) in terms of patient health, economic means and reduction in HIV 1 onward transmission exemplarily for South Africa. All therapeutic strategies are assessed using a coarse-grained stochastic model of within-host HIV dynamics and pseudo-codes for solving the respective optimal control problems are provided. Our mathematical model suggests that both optimal strategies (i)-(ii) perform better than the current clinical protocols and no treatment in terms of economic means, life prolongation and reduction of HIV-transmission. The optimal diagnostic-guided strategy suggests rare diagnostics and performs similar to the optimal pro-active strategy. Our results suggest that 'treatment-for-prevention' may be further improved using either of the two analyzed treatment paradigms. PMID- 25927965 TI - Facile synthesis of 2,5-disubstituted thiazoles from terminal alkynes, sulfonyl azides, and thionoesters. AB - A sequential procedure for the synthesis of 2,5-disubstituted thiazoles from terminal alkynes, sulfonyl azides, and thionoesters is reported. A copper(I) catalyzed 1,3-dipolar cycloaddition of terminal alkynes with sulfonyl azides affords 1-sulfonyl-1,2,3-triazoles, which then react with thionoesters in the presence of a rhodium(II) catalyst. The resulting 3-sulfonyl-4-thiazolines subsequently aromatize into the corresponding 2,5-disubstituted thiazoles by elimination of the sulfonyl group. PMID- 25927970 TI - Description and validation of a spectrum score method to measure antimicrobial de escalation in healthcare associated pneumonia from electronic medical records data. AB - BACKGROUND: Comparison of antimicrobial de-escalation rates between healthcare settings is problematic. To objectively and electronically measure de-escalation a method based upon the spectrum of antimicrobial regimens administered (i.e., spectrum score) was developed. METHODS: A Delphi process was used to develop applicable concepts. Spectrum scores were created for 27 antimicrobials based upon susceptibility for 19 organisms. National VA susceptibility data was used to estimate microbial spectrum. Susceptibility estimates were converted to ordinal scores, and values for organisms with multi-drug resistance potential were weighted more heavily. Organism scores were summed to create antibiotic-specific spectrum scores and extended mathematically to score multi-antimicrobial regimens. Vignettes were created from antimicrobial regimens administered to 300 patients hospitalized with pneumonia. Daily spectrum scores were calculated for each case. Hospitalization day 4 scores were subtracted from day 2 scores (i.e., spectrum score ?). A positive spectrum score ? defined de-escalation. Experts ranked each pneumonia case on a 7-point Likert scale (Likert >4 indicated de escalation). Spectrum score ?s were compared to expert review. Findings were used to identify score deficiencies. Next, 40 pairs of cases were modified to include antimicrobial administration routes. Each pair contained almost similar regimens; however, one contained oral (PO) the other only intravenous (IV) antimicrobials on day 4 of therapy. Experts reviewed cases as described. Spectrum score ? credits to account for PO conversion were derived from the mean paired differences in Likert Score. De-escalation status was evaluated in 100 vignettes containing antimicrobial route by different experts and compared to the modified method. RESULTS: Initial sensitivity and specificity of the spectrum score ? to detect expert classified de-escalation events was 86.3 and 96.0%, respectively. In paired cases, the mean (+/- SD) Likert score was 5.0 (1.5) and 4.6 (1.5) for PO and IV (P = 0.002), respectively. To improve de-escalation event detection, two credits were added to spectrum score ?s based upon the percentage of antimicrobials administered PO on day 4. The final method, exhibited sensitivity and specificity to detect expert classified de-escalation events of 96.2 and 93.6%, respectively. CONCLUSIONS: The final spectrum score method exhibited excellent agreement with expert judgments of de-escalation events in pneumonia. PMID- 25927971 TI - Monte Carlo modelling of daylight activated photodynamic therapy. AB - The treatment of superficial skin lesions via daylight activated photodynamic therapy (PDT) has been explored theoretically with three dimensional (3D) Monte Carlo radiation transfer simulations. For similar parameters and conditions, daylight activated PDT was compared to conventional PDT using a commercially available light source. Under reasonable assumptions for the optical properties of the tissue, protoporphyrin IX (PpIX) concentration and a treatment dose of 75 J cm(-2), it was found that during a clear summer day an effective treatment depth of over 2 mm can be achieved after 30 min of daylight illumination at a latitude of 56 degrees North. The same light dose would require 2.5 h of daylight illumination during an overcast summer day where a treatment depth of about 2 mm can be achieved. For conventional PDT the developed model suggests that 15 min of illumination is required to deliver a light dose of 75 J cm(-2), which would result in an effective treatment depth of about 3 mm. The model developed here allows for the determination of photo-toxicity in skin tissue as a function of depth for different weather conditions as well as for conventional light sources. Our theoretical investigation supports clinical studies and shows that daylight activated PDT has the potential for treating superficial skin lesions during different weather conditions. PMID- 25927972 TI - Choosing care homes as the least preferred place to die: a cross-national survey of public preferences in seven European countries. AB - BACKGROUND: Care homes are increasingly becoming places where people spend the final stages of their lives and eventually die. This trend is expected to continue due to population ageing, yet little is known about public preferences regarding this setting. As part of a larger study examining preferences and priorities for end of life care, we investigated the extent to which care homes are chosen as the least preferred place of death, and the factors associated with this negative preference. METHODS: We conducted a cross-sectional telephone survey among 9,344 adults from random private households in England, Flanders, Germany, Italy, the Netherlands, Portugal and Spain. We asked participants where they would least prefer to die in a situation of serious illness with less than one year to live. Multivariate binary logistic regressions were used to identify factors associated with choosing care homes as the least preferred place of death in each country. RESULTS: Care homes were the most frequently mentioned least preferred place of death in the Netherlands (41.5%), Italy and Spain (both 36.7%) and the second most frequent in England (28.0%), Portugal (25.8%), Germany (23.7%) and Flanders (18.9%). Only two factors had a similar and significant effect on the least preferred place of death in more than one country. In Germany and the Netherlands those doing housework were less likely to choose care homes as their least preferred place (AOR 0.72; 95% CI:0.54-0.96 and AOR 0.68; 95% CI:0.52-0.90 respectively), while those born in the country where the survey took place were more likely to choose care homes (AOR 1.77; 95% CI:1.05-2.99 and AOR 1.74; 95% CI:1.03-2.95 respectively). Experiences of serious illness, death and dying were not associated with the preference. CONCLUSIONS: Our results suggest it might be difficult to promote care homes as a good place to die. This is an urgent research area in order to meet needs and preferences of a growing number of older people with chronic, debilitating conditions across Europe. From a research perspective and in order to allow people to be cared for and die where they wish, our findings highlight the need to build more in depth evidence on reasons underlying this negative preference. PMID- 25927973 TI - Focal non granulomatous orchitis in a patient with Crohn's disease. AB - Crohn's disease is a systemic disease and sometimes involves the testicle, usually leading to granulomatous lesions. We report herein a case of focal non granulomatous orchitis in a 21-year-old patient with active Crohn's disease treated by an anti-tumor necrosis factor monoclonal antibody. This circumscribed testicular lesion mimicked a tumor, leading to orchiectomy. Pre-operative blood tests (i.e. alpha-fetoprotein, lactate dehydrogenase and human chorionic gonadotrophin) were strictly normal Pathological examination of the testicle revealed a focal inflammatory infiltrate predominantly composed of lymphocytes accompanied by few plasma cells, lacking giant cells or granulomas. Importantly, intratubular germ cell neoplasia, atrophy or lithiasis were not observed.After discussing and excluding other plausible causes (burnt-out /regressed germ cell tumor, infection, vascular or traumatic lesions, iatrogenic effects), we concluded that this particular case of orchitis was most likely an extra digestive manifestation of inflammatory bowel disease. To our knowledge, this is the first described case of focal non-granulomatous orchitis associated with Crohn's disease. Virtual Slides: The virtual slide(s) for this article can be found here: http://www.diagnosticpathology.diagnomx.eu/vs/2117747284160112. PMID- 25927974 TI - Transcriptional implications of intragenic DNA methylation in the oestrogen receptor alpha gene in breast cancer cells and tissues. AB - BACKGROUND: DNA methylation variability regions (MVRs) across the oestrogen receptor alpha (ESR1) gene have been identified in peripheral blood cells from breast cancer patients and healthy individuals. In contrast to promoter methylation, gene body methylation may be important in maintaining active transcription. This study aimed to assess MVRs in ESR1 in breast cancer cell lines, tumour biopsies and exfoliated epithelial cells from expressed breast milk (EBM), to determine their significance for ESR1 transcription. METHODS: DNA methylation levels in eight MVRs across ESR1 were assessed by pyrosequencing bisulphite-converted DNA from three oestrogen receptor (ER)-positive and three ER negative breast cancer cell lines. DNA methylation and expression were assessed following treatment with DAC (1 MUM), or DMSO (controls). ESR1 methylation levels were also assayed in DNA from 155 invasive ductal carcinoma biopsies provided by the Breast Cancer Campaign Tissue Bank, and validated with DNA methylation profiles from the TCGA breast tumours (n = 356 ER-pos, n = 109 ER-neg). DNA methylation was profiled in exfoliated breast epithelial cells from EBM using the Illumina 450 K (n = 36) and pyrosequencing in a further 53 donor samples. ESR1 mRNA levels were measured by qRT-PCR. RESULTS: We show that ER-positive cell lines had unmethylated ESR1 promoter regions and highly methylated intragenic regions (median, 80.45%) while ER-negative cells had methylated promoters and lower intragenic methylation levels (median, 38.62%). DAC treatment increased ESR1 expression in ER-negative cells, but significantly reduced methylation and expression of ESR1 in ER-positive cells. The ESR1 promoter was unmethylated in breast tumour biopsies with high levels of intragenic methylation, independent of ER status. However, ESR1 methylation in the strongly ER-positive EBM DNA samples were very similar to ER-positive tumour cell lines. CONCLUSION: DAC treatment inhibited ESR1 transcription in cells with an unmethylated ESR1 promoter and reduced intragenic DNA methylation. Intragenic methylation levels correlated with ESR1 expression in homogenous cell populations (cell lines and exfoliated primary breast epithelial cells), but not in heterogeneous tumour biopsies, highlighting the significant differences between the in vivo tumour microenvironment and individual homogenous cell types. These findings emphasise the need for care when choosing material for epigenetic research and highlights the presence of aberrant intragenic methylation levels in tumour tissue. PMID- 25927976 TI - Bipotent mammary stem cells: now in amazing 3D. AB - For many decades, developmental biologists and cancer researchers alike have been trying to understand the relationship between the basal and luminal cell compartments in the mouse mammary epithelium. Delineating the mammary stem and progenitor cell hierarchy will provide fundamental knowledge of how cell proliferation and differentiation are orchestrated to build, maintain and regenerate a complex mammalian tissue. Moreover, it is expected to offer insight into the cells of origin for human breast cancer. A new lineage-tracing study has fuelled the discussion as to the existence of bipotent stem cells in the basal layer of the mouse mammary epithelium. PMID- 25927975 TI - Well-differentiated abdominal liposarcoma: experience of a tertiary care center. AB - BACKGROUND: We presented abdominal liposarcoma cases diagnosed and managed in a tertiary care center and also conducted a literature review on main features of this tumor. METHODS: Chart reviews of eight cases were conducted, and clinical, surgical, histopathological, and follow-up data were recorded. RESULTS: Overall, complete surgical resection was performed with adjacent organ resection in 25% of cases, and radiotherapy was not administered. Recurrence was developed in only one case and died after 2 years and 3 months, and other cases are under follow-up without recurrence. Histopatological examinations revealed findings of well differentiated liposarcoma. CONCLUSIONS: According to our surgical experience, the surgical margin positivity may not be a determining factor for the survival of patients with well-differentiated liposarcoma, and in the absence of macroscopic invasion, adjacent organ resection may not be required. Radiotherapy may not be preferred when complete resection of abdominal mass was achieved. PMID- 25927977 TI - Update in rheumatology: evidence published in 2014. PMID- 25927979 TI - Safety of pembrolizumab for the treatment of melanoma. AB - INTRODUCTION: The immune checkpoint inhibitor pembrolizumab is the first anti programmed-death-1 (PD-1) drug licensed by the FDA. It has been approved for the treatment of advanced melanoma, thanks to its positive results in terms of efficacy and its favorable toxicity profile. However, it is not exempt from side effects. In general, these are usually mild and easily manageable but there are pembrolizumab-induced immune-related adverse events (irAEs) that can be severe. Therefore, the understanding, diagnosis and management of those side effects are essential for the optimal care of patients treated with pembrolizumab. AREAS COVERED: In this article, the safety and efficacy of pembrolizumab in melanoma are extensively reviewed as well as its mechanism of action and the role of the PD-1 pathway in cancer. Also, its profile of side effects is compared with other immune checkpoint inhibitors such as ipilimumab and nivolumab. EXPERT OPINION: Pembrolizumab is generally a well-tolerated drug but irAEs are not infrequent. However, these are usually mild and easily manageable in most cases. Early diagnosis and correct management of side effects induced by immune checkpoint inhibitors such as pembrolizumab should be areas of further work in forthcoming years. PMID- 25927978 TI - A clickable and photocleavable lipid analogue for cell membrane delivery and release. AB - For drug delivery purposes, the ability to conveniently attach a targeting moiety that will deliver drugs to cells and then enable controlled release of the active molecule after localization is desirable. Toward this end, we designed and synthesized clickable and photocleavable lipid analogue 1 to maximize the efficiency of bioconjugation and triggered release. This compound contains a dibenzocyclooctyne group for bioorthogonal derivatization linked via a photocleavable 2-nitrobenzyl moiety at the headgroup of a synthetic lipid backbone for targeting to cell membranes. To assess delivery and release using this system, we report fluorescence-based assays for liposomal modification and photocleavage in solution as well as through surface immobilization to demonstrate successful liposome functionalization and photoinduced release. In addition, fluorophore delivery to and release from live cells was confirmed and characterized using fluorescence microscopy and flow cytometry analysis in which 1 was delivered to cells, derivatized, and photocleaved. Finally, drug delivery studies were performed using an azide-tagged analogue of camptothecin, a potent anticancer drug that is challenging to deliver due to poor solubility. In this case, the ester attachment of the azide tag acted as a caging group for release by intracellular esterases rather than through photocleavage. This resulted in a dose-dependent response in the presence of liposomes containing delivery agent 1, confirming the ability of this compound to stimulate delivery to the cytoplasm of cells. PMID- 25927980 TI - EuReCa ONE - 27 Nations, ONE Europe, ONE Registry: a prospective observational analysis over one month in 27 resuscitation registries in Europe - the EuReCa ONE study protocol. AB - BACKGROUND: There is substantial variation in the incidence, likelihood of attempted resuscitation and outcomes from out-of-hospital cardiac arrest (OHCA) across Europe. A European, multi-centre study provides the opportunity to uncover differences throughout Europe and may help find explanations for these differences. Results may also have potential to support the development of quality benchmarking between European Emergency Medical Services (EMS). METHODS/DESIGN: This prospective European study involves 27 different countries. It provides a common Utstein-based dataset, data collection tool and a common data collection period for all participants. Study research questions will address the following: OHCA incidence in different European regions; incidence of cardiopulmonary resuscitation (CPR); initial presenting rhythm in patients where bystanders or EMS start CPR or any other resuscitation intervention; proportion of patients with any return of spontaneous circulation (ROSC); patient status at the end of pre-hospital treatment i.e. ROSC at handover to hospital, ongoing CPR, dead; proportion of patients still alive 30 days after OHCA; proportion of patients discharged alive from hospital. All patients who suffered an OHCA during October 2014 and were attended and/or treated by an EMS and documented in one of the participating registries will be included in the study. Each National Coordinator is responsible for data collection and quality control in his/her country and will transfer unprocessed anonymised data via secure electronic transfer. Descriptive analysis will be performed at European, national and registry level. For endpoints like ROSC, admission or survival, multivariate logistic regression analysis will be performed. DISCUSSION: Documenting differences in epidemiology, treatment and outcome in out-of-hospital cardiac arrest throughout Europe is a first step in finding explanations for these differences. Study results might also support the development of quality benchmarking between Emergency Medical Services (EMS) which in turn will facilitate initiatives to improve OHCA outcome in Europe. TRIAL REGISTRATION: The EuReCa ONE Study is registered by ClinicalTrials.gov National Coordinator T02236819 ). PMID- 25927981 TI - Biventricular thrombi in dilated cardiomyopathy in a patient with human immunodeficiency virus infection: a case report. AB - BACKGROUND: Sub-Saharan Africa is undergoing epidemiological transition with an increase in the prevalence of cardiovascular diseases that will add to the already devastating burden of infectious diseases such as human immunodeficiency virus infection. Human immunodeficiency virus infection is increasingly being recognized as an important etiological factor for dilated cardiomyopathy with the potential complication of intraventricular thrombus. However, biventricular thrombi are extremely rare. We report on a rare finding of biventricular thrombi in dilated cardiomyopathy in a patient with human immunodeficiency virus infection in Cameroon. CASE PRESENTATION: A 52-year old Cameroonian male patient with human immunodeficiency virus infection since 4 years, longstanding heavy alcohol consumption and cigarette smoking presented with gradually worsening shortness of breath, fatigue, persistent dry cough and lower extremity swelling of about two weeks duration. Congestive heart failure was diagnosed. Echocardiography showed left ventricular chamber enlargement with severe left ventricular systolic dysfunction and biventricular thrombi. The thrombi were immobile and regular in configuration, suggesting they were old. He was treated with a conventional heart failure treatment including loop diuretics and angiotensin converting enzyme inhibitors and anticoagulants for the biventricular thrombi. Six months later, a control echocardiography showed a significant decrease in the size of the thrombi. There was no evidence of systemic or pulmonary embolization during follow up. CONCLUSION: Dilated cardiomyopathy may be seen in patients with human immunodeficiency virus infection, although other mechanisms needs to be assessed, but the occurrence of biventricular thrombi is rare. PMID- 25927982 TI - Mechanisms of gastroprotection of methanol extract of Melastoma malabathricum leaves. AB - BACKGROUND: Melastoma malabathricum L. (Melastomaceae) is a small shrub with various medicinal uses. The present study was carried out to determine the gastroprotective mechanisms of methanol extract of M. malabathricum leaves (MEMM) in rats. METHODS: The extract's mechanisms of gastroprotection (50, 250, 500 mg/kg) were studied using the pylorus-ligation in rat model wherein volume, pH, free and total acidity of gastric juice, and gastric wall mucus content were determined. The involvement of endogenous nitric oxide (NO) and sulfhydryl (SH) compounds in the gastroprotective effect of MEMM were also measured. MEMM was subjected to the antioxidant, anti-inflammatory and phytochemical analysis and HPLC profiling. RESULTS: MEMM contained various phyto-constituents with quercitrin being identified as part of them. MEMM and quercitrin: i) significantly (p < 0.05) reduced the volume and acidity of gastric juice while increasing the pH and gastric wall mucus content.; ii) significantly (p < 0.05) increased the level of SOD, GTP and GTR while significantly (p < 0.05) reduced the level of CAT, MPO and TBARS activities.; iii) exerted gastroprotective activity when assessed using the ethanol-induced gastric ulcer assay, which was reversed by N(G)-nitro-L-arginine methyl esters (L-NAME; an inhibitor of NO synthase) and N-ethylmaleimide (NEM; a sulfhydryl (SH) blocker). MEMM inhibited the lipoxygenase (LOX) and xanthine oxidase (XO) activities with the highest affinity for the former while quercitrin showed high affinity for XO activity. CONCLUSIONS: MEMM exhibited a gastroprotective activity due partly to the presence of quercitrin, its antioxidant and anti-inflammatory activities, and via the modulation of NO and SH groups. PMID- 25927983 TI - Monitoring HIV Testing in the United States: Consequences of Methodology Changes to National Surveys. AB - OBJECTIVE: In 2011, the National Health Interview Survey (NHIS), an in-person household interview, revised the human immunodeficiency virus (HIV) section of the survey and the Behavioral Risk Factor Surveillance System (BRFSS), a telephone-based survey, added cellphone numbers to its sampling frame. We sought to determine how these changes might affect assessment of HIV testing trends. METHODS: We used linear regression with pairwise contrasts with 2003-2013 data from NHIS and BRFSS to compare percentages of persons aged 18-64 years who reported HIV testing in landline versus cellphone-only households before and after 2011, when NHIS revised its in-person questionnaire and BRFSS added cellphone numbers to its telephone-based sample. RESULTS: In NHIS, the percentage of persons in cellphone-only households increased 13-fold from 2003 to 2013. The percentage ever tested for HIV was 6%-10% higher among persons in cellphone-only than landline households. The percentage ever tested for HIV increased significantly from 40.2% in 2003 to 45.0% in 2010, but was significantly lower in 2011 (40.6%) and 2012 (39.7%). In BRFSS, the percentage ever tested decreased significantly from 45.9% in 2003 to 40.2% in 2010, but increased to 42.9% in 2011 and 43.5% in 2013. CONCLUSIONS: HIV testing estimates were lower after NHIS questionnaire changes but higher after BRFSS methodology changes. Data before and after 2011 are not comparable, complicating assessment of trends. PMID- 25927984 TI - Clinical investigation on Theileria equi and Babesia caballi infections in Italian donkeys. AB - BACKGROUND: Interest in the welfare and diseases of donkeys is constantly increasing in several countries. Despite this, clinical research into donkeys needs to be in continual development since they show different reactions compared to horses in many conditions, including infectious diseases, and need specific clinical and therapeutic approaches. No reports are currently available on clinical and clinical pathology data regarding donkeys with natural piroplasms infection. RESULTS: Venous blood samples were taken from one hundred and thirty eight donkeys and underwent indirect fluorescent antibody test (IFAT) to detect IgG antibodies against Theileria equi and Babesia caballi and real-time polimerase chain reaction (PCR) to detect Babesia spp. and Theileria spp. Clinical examinations, haematological analyses and serum bilirubin evaluation were also performed and compared with positive or negative status. A seroprevalence of 40.6% and 47.8% was found for T. equi and B. caballi, respectively; double positivity was detected in 19.6% of the animals. PCR results showed that 17.4% of the animals tested positive for T.equi and 3.6% for B. caballi with no double positivity. Twelve donkeys (8.7%) had clinical signs consistent with chronic forms of the disease and no acute forms were detected. Fifty-eight donkeys had haematological and serum bilirubin alterations and 56 (96.6%) of them were IFAT and/or PCR positive. Changes in erythrocyte number, packed cell volume, hemoglobin concentration, mean corpuscular hemoglobin, platelets number and total bilirubin were significantly associated with positive and symptomatic animals. CONCLUSION: Nonspecific clinical presentation seems to be very common in donkeys and several clinical pathology alterations persist after natural infection. Therefore, apparently healthy donkeys can have masked but severe clinical pathology alterations. Acute forms are very seldom observed in donkeys. Clinical monitoring of chronically infected donkeys is recommended since such animals represent a risk both for transmission to other animals and for their own health; furthermore, their production performances could be reduced. The study should also be intended as a contribution for veterinary practitioners because it describes the most usual clinical presentations and laboratory findings of equine piroplasmosis in naturally infected donkeys in endemic areas. PMID- 25927985 TI - Picroside II Inhibits Neuronal Apoptosis and Improves the Morphology and Structure of Brain Tissue following Cerebral Ischemic Injury in Rats. AB - This paper aimed to explore the protective effects of picroside II against the neuronal apoptosis and changes in morphology and structure that follow cerebral ischemic injury in rats. A focal cerebral ischemic model was established by inserting a monofilament thread to achieve middle cerebral artery occlusion (MCAO) in 60 Wistar rats, and intraperitoneal injections of picroside II (20 mg/kg) were administered. The neurobehavioral functions were evaluated with the modified neurological severity score (mNSS) test. The cerebral infarct volumes were measured with tetrazolium chloride (TTC) staining. The morphology and ultrastructure of the cortical brain tissues were observed with hematoxylin-eosin staining and transmission electron microscopy, respectively. The apoptotic cells were counted with terminal deoxynucleotidyl transferase dUTP nick-end labeling and flow cytometry, and pERK1/2 expression was determined by immunohistochemical assay and Western blot. The results indicated that neurological behavioral malfunctions and cerebral infarcts were present in the MCAO rats. In the model group, the damage to the structures of the neurons and the blood brain barrier (BBB) in the cortex was more severe, and the numbers of apoptotic cells, the early apoptotic ratio (EAR) and pERK1/2 expression were significantly increased in this group compared to the control group (P<0.05). In the treatment group, the neurological behavioral function and the morphology and ultrastructure of the neurons and the BBB were improved including the number of Mi increased and relative area of condensed chromosome and basement (BM) thickness descreased, and the cerebral infarct volume, the number of apoptotic cells, the EAR and pERK1/2 expression were significantly decreased compared to the model group (P<0.05). These results suggest that picroside II reduced apoptosis and improved the morphology and ultrastructure of the neurons and the BBB and that these effects resulted in the recovery of the neurobehavioral function of rats with cerebral ischemia. PMID- 25927986 TI - Time in blood glucose range 70 to 140 mg/dl >80% is strongly associated with increased survival in non-diabetic critically ill adults. AB - INTRODUCTION: Hyperglycemia, hypoglycemia and increased glucose variability are independently associated with increased risk of death in critically ill adults. The relationship between time in targeted blood glucose range (TIR) and mortality is not well described and may be a factor that has confounded the results of the major interventional trials of intensive insulin therapy. METHODS: We conducted a retrospective analysis of prospectively collected data involving 3,297 patients with intensive care unit (ICU) lengths of stay (LOS) of >= 1.0 day who were admitted between 1 January 2009 and 31 December 2013 to a single mixed medical surgical ICU. We investigated the relationship between TIR 70 to 140 mg/dl with mortality and compared outcomes of non-diabetics (NON) and individuals with diabetes mellitus (DM), including stratifying by TIR above (TIR-hi) and below (TIR-lo) the median value for the NON and DM groups. RESULTS: There were 85,799 blood glucose (BG) values for the NON group and 32,651 for the DM group, and we found that 75.5% and 54.8%, respectively, were between 70 and 140 (P < 0.0001). The median (interquartile range) TIR (%) values for the NON and DM groups were 80.6% (61.4% to 94.0%) and 55.0% (35.5% to 71.1%), respectively (P < 0.0001). For the NON group, mortality was 8.47% and 15.71% for TIR-hi and TIR-lo, respectively (P < 0.0001). For the DM group, mortality was 16.09% and 14.44% for TIR-hi and TIR-lo, respectively (P = NS). We observed similar relationships for the NON group when we stratified by ICU LOS or severity of illness, especially in the most severely ill patients. There was a cumulative interaction of indices of hypoglycemia, hyperglycemia or glucose variability with TIR. Multivariable analysis demonstrated, for the NON group, that TIR-hi was independently associated with increased survival (P = 0.0019). For the NON group, the observed to-expected mortality ratios for TIR-hi and TIR-lo, based on Acute Physiology and Chronic Health Evaluation IV methodology, were 0.53 and 0.78, respectively. In contrast, among those in the DM group, there was no clear relationship between TIR 70 to 140 mg/dl and survival. CONCLUSIONS: Independently of ICU LOS and severity of illness, TIR 70 to 140 mg/dl > 80% is strongly associated with survival in critically ill patients without diabetes. These findings have implications for the design of clinical protocols for glycemic control in critically ill patients as well for the design of future interventional trials of intensive insulin therapy. PMID- 25927987 TI - Control of Morphological Differentiation of Streptomyces coelicolor A3(2) by Phosphorylation of MreC and PBP2. AB - During morphological differentiation of Streptomyces coelicolor A3(2), the sporogenic aerial hyphae are transformed into a chain of more than fifty spores in a highly coordinated manner. Synthesis of the thickened spore envelope is directed by the Streptomyces spore wall synthesizing complex SSSC which resembles the elongasome of rod-shaped bacteria. The SSSC includes the eukaryotic type serine/threonine protein kinase (eSTPK) PkaI, encoded within a cluster of five independently transcribed eSTPK genes (SCO4775-4779). To understand the role of PkaI in spore wall synthesis, we screened a S. coelicolor genomic library for PkaI interaction partners by bacterial two-hybrid analyses and identified several proteins with a documented role in sporulation. We inactivated pkaI and deleted the complete SCO4775-4779 cluster. Deletion of pkaI alone delayed sporulation and produced some aberrant spores. The five-fold mutant NLDelta4775-4779 had a more severe defect and produced 18% aberrant spores affected in the integrity of the spore envelope. Moreover, overbalancing phosphorylation activity by expressing a second copy of any of these kinases caused a similar defect. Following co expression of pkaI with either mreC or pbp2 in E. coli, phosphorylation of MreC and PBP2 was demonstrated and multiple phosphosites were identified by LC-MS/MS. Our data suggest that elaborate protein phosphorylation controls activity of the SSSC to ensure proper sporulation by suppressing premature cross-wall synthesis. PMID- 25927990 TI - The ubiquitin proteasome system plays a role in venezuelan equine encephalitis virus infection. AB - Many viruses have been implicated in utilizing or modulating the Ubiquitin Proteasome System (UPS) to enhance viral multiplication and/or to sustain a persistent infection. The mosquito-borne Venezuelan equine encephalitis virus (VEEV) belongs to the Togaviridae family and is an important biodefense pathogen and select agent. There are currently no approved vaccines or therapies for VEEV infections; therefore, it is imperative to identify novel targets for therapeutic development. We hypothesized that a functional UPS is required for efficient VEEV multiplication. We have shown that at non-toxic concentrations Bortezomib, a FDA approved inhibitor of the proteasome, proved to be a potent inhibitor of VEEV multiplication in the human astrocytoma cell line U87MG. Bortezomib inhibited the virulent Trinidad donkey (TrD) strain and the attenuated TC-83 strain of VEEV. Additional studies with virulent strains of Eastern equine encephalitis virus (EEEV) and Western equine encephalitis virus (WEEV) demonstrated that Bortezomib is a broad spectrum inhibitor of the New World alphaviruses. Time-of-addition assays showed that Bortezomib was an effective inhibitor of viral multiplication even when the drug was introduced many hours post exposure to the virus. Mass spectrometry analyses indicated that the VEEV capsid protein is ubiquitinated in infected cells, which was validated by confocal microscopy and immunoprecipitation assays. Subsequent studies revealed that capsid is ubiquitinated on K48 during early stages of infection which was affected by Bortezomib treatment. This study will aid future investigations in identifying host proteins as potential broad spectrum therapeutic targets for treating alphavirus infections. PMID- 25927991 TI - Temperature-Dependent Fecundity and Life Table of the Fennel Aphid Hyadaphis foeniculi (Passerini) (Hemiptera: Aphididae). AB - Hyadaphis foeniculi (Passerini) (Hemiptera: Aphididae) is a cosmopolitan species and the main pest of fennel in northeastern Brazil. Understanding the relationship between temperature variations and the population growth rates of H. foeniculi is essential to predict the population dynamics of this aphid in the fennel crop. The aim of this study was to measure the effect of constant temperature on the adult prereproductive period and the life table fertility parameters (infinitesimal increase ratio (rm), gross reproduction rate (GRR), net reproduction rate (R0), finite increase ratio (lambda), generation time (GT), the time required for the population to double in the number of individuals (DT), and the reproduction value (RVx)) of the fennel pest H. foeniculi. The values of lx (survival of nymphs at age x) increased as the temperature rose from 15 to 28 degrees C and fell at 30 degrees C, whereas mx (number of nymphs produced by each nymph of age x) increased from 15 to 25 degrees C and fell at 28 and 30 degrees C. The net reproduction rates (R0) of populations of H. foeniculi increased with temperature and ranged from 1.9 at 15 degrees C to 12.23 at 28 degrees C for each generation. The highest population increase occurred with the apterous aphids at 28 degrees C. The rate of population increase per unit time (rm) (day) ranged from 0.0033 (15 degrees C) to 0.1995 (28 degrees C). The highest values of rm were recorded at temperatures of 28 degrees C and 30 degrees C. The rm values were a good fit to the models tested, with R2 > 0.91 and R2adj > 0.88. The models tested (Davidson, Sharpe and DeMichele modified by Schoolfield et al., Logan et al., Lamb, and Briere et al.) were very good fits for the rm values observed, with R2 > 0.91 and R2adj > 0.88. The only exception was the Davidson model. Of the parameters studied, the reproductive capacity was higher in the apterous aphids, with the unique exception of daily fecundity at 28 degrees C, which was higher in the alate aphids of H. foeniculi. Parameters relating to the age specific fertility table for H. foeniculi were heavily influenced by temperature, with the highest biotic potential and population growth capacity found at 34 degrees C. Therefore, the results obtained in this study could be of practical significance for predicting outbreaks of fennel aphids and improving the management of this aphid in fennel crops. PMID- 25927993 TI - Interventions targeted at primary care practitioners to improve the identification and referral of patients with co-morbid obesity: a realist review protocol. AB - BACKGROUND: Obesity is one of the most significant public health challenges in the developed world. Recent policy has suggested that more can be done in primary care to support adults with obesity. In particular, general practitioners (GPs) and practice nurses (PNs) could improve the identification and referral of adults with obesity to appropriate weight management services. Previous interventions targeted at primary care practitioners in this area have had mixed results, suggesting a more complex interplay between patients, practitioners, and systems. The objectives of this review are (i) to identify the underlying 'programme theory' of interventions targeted at primary care practitioners to improve the identification and referral of adults with obesity and (ii) to explore how and why GPs and PNs identify and refer individuals with obesity, particularly in the context of weight-related co-morbidity. This protocol will explain the rationale for using a realist review approach and outline the key steps in this process. METHODS: Realist review is a theory-led approach to knowledge synthesis that provides an explanatory analysis aimed at discerning what works, for whom, in what circumstances, how, and why. In this review, scoping interviews with key stakeholders involved in the planning and delivery of adult weight management services in Scotland helped to inform the identification of formal theories - from psychology, sociology, and implementation science - that will be tested as the review progresses. A comprehensive search strategy is described, including scope for iterative searching. Data analysis is outlined in three stages (describing context-mechanism-outcome configurations, exploring patterns in these configurations, and developing and testing middle-range theories, informed by the formal theories previously identified), culminating in the production of explanatory programme theory that considers individual, interpersonal, and institutional/systems-level components. DISCUSSION: This is the first realist review that we are aware of looking at interventions targeted at primary care practitioners to improve the weight management of adults with obesity. Engagement with stakeholders at an early stage is a unique feature of realist review. This shapes the scope of the review, identification of candidate theories and dissemination strategies. The findings of this review will inform policy and future interventions. SYSTEMATIC REVIEW REGISTRATION: PROSPERO CRD42014009391. PMID- 25927994 TI - CARM1 and BAF155: an example of how chromatin remodeling factors can be relocalized and contribute to cancer. AB - In a recent article, Wang and colleagues reported the discovery of a mechanism by which CARM1 regulates the genomic localization of BAF155 (a SWI/SNF subunit involved in chromatin remodeling) through post-translational methylation at R1064 arginine residues. This modification leads to the relocalization of BAF155 containing SWI/SNF complexes to regions containing genes involved in the Myc oncogenic pathway. The results presented are evidence that these interactions constitute a mechanism by which the BAF155 chromatin remodeling factor contributes to cancer. PMID- 25927995 TI - The dynamic consequences of cooperation and competition in small-world networks. AB - We present a study of the social dynamics among cooperative and competitive actors interacting on a complex network that has a small-world topology. In this model, the state of each actor depends on its previous state in time, its inertia to change, and the influence of its neighboring actors. Using numerical simulations, we determine how the distribution of final states of the actors and measures of the distances between the values of the actors at local and global levels, depend on the number of cooperative to competitive actors and the connectivity of the actors in the network. We find that similar numbers of cooperative and competitive actors yield the lowest values for the local and global measures of the distances between the values of the actors. On the other hand, when the number of either cooperative or competitive actors dominate the system, then the divergence is largest between the values of the actors. Our findings make new testable predictions on how the dynamics of a conflict depends on the strategies chosen by groups of actors and also have implications for the evolution of behaviors. PMID- 25927997 TI - Identification and analysis of unitary loss of long-established protein-coding genes in Poaceae shows evidences for biased gene loss and putatively functional transcription of relics. AB - BACKGROUND: Long-established protein-coding genes may lose their coding potential during evolution ("unitary gene loss"). Members of the Poaceae family are a major food source and represent an ideal model clade for plant evolution research. However, the global pattern of unitary gene loss in Poaceae genomes as well as the evolutionary fate of lost genes are still less-investigated and remain largely elusive. RESULTS: Using a locally developed pipeline, we identified 129 unitary gene loss events for long-established protein-coding genes from four representative species of Poaceae, i.e. brachypodium, rice, sorghum and maize. Functional annotation suggested that the lost genes in all or most of Poaceae species are enriched for genes involved in development and response to endogenous stimulus. We also found that 44 mutated genomic loci of lost genes, which we referred as relics, were still actively transcribed, and of which 84% (37 of 44) showed significantly differential expression across different tissues. More interestingly, we found that there were totally five expressed relics may function as competitive endogenous RNA in brachypodium, rice and sorghum genome. CONCLUSIONS: Based on comparative genomics and transcriptome data, we firstly compiled a comprehensive catalogue of unitary gene loss events in Poaceae species and characterized a statistically significant functional preference for these lost genes as well showed the potential of relics functioning as competitive endogenous RNAs in Poaceae genomes. PMID- 25927996 TI - Genetic chimeras reveal the autonomy requirements for Vsx2 in embryonic retinal progenitor cells. AB - BACKGROUND: Vertebrate retinal development is a complex process, requiring the specification and maintenance of retinal identity, proliferative expansion of retinal progenitor cells (RPCs), and their differentiation into retinal neurons and glia. The homeobox gene Vsx2 is expressed in RPCs and required for the proper execution of this retinal program. However, our understanding of the mechanisms by which Vsx2 does this is still rudimentary. To define the autonomy requirements for Vsx2 in the regulation of RPC properties, we generated chimeric mouse embryos comprised of wild-type and Vsx2-deficient cells. RESULTS: We show that Vsx2 maintains retinal identity in part through the cell-autonomous repression of the retinal pigment epithelium determinant Mitf, and that Lhx2 is required cell autonomously for the ectopic Mitf expression in Vsx2-deficient cells. We also found significant cell-nonautonomous contributions to Vsx2-mediated regulation of RPC proliferation, pointing to an important role for Vsx2 in establishing a growth-promoting extracellular environment. Additionally, we report a cell autonomous requirement for Vsx2 in controlling when neurogenesis is initiated, indicating that Vsx2 is an important mediator of neurogenic competence. Finally, the distribution of wild-type cells shifted away from RPCs and toward retinal ganglion cell precursors in patches of high Vsx2-deficient cell density to potentially compensate for the lack of fated precursors in these areas. CONCLUSIONS: Through the generation and analysis of genetic chimeras, we demonstrate that Vsx2 utilizes both cell-autonomous and cell-nonautonomous mechanisms to regulate progenitor properties in the embryonic retina. Importantly, Vsx2's role in regulating Mitf is in part separable from its role in promoting proliferation, and proliferation is excluded as the intrinsic timer that determines when neurogenesis is initiated. These findings highlight the complexity of Vsx2 function during retinal development and provide a framework for identifying the molecular mechanisms mediating these functions. PMID- 25927998 TI - Female family caregivers face a higher risk of hypertension and lowered estimated glomerular filtration rates: a cross-sectional, comparative study. AB - BACKGROUND: Despite societal efforts to alleviate the challenges, caregiving seems to constitute a substantial burden and source of stress for many families of older adults in Japan. However, precise information on the physical health of caregivers, based on objective data, is not available. The purpose of this study was to improve the understanding of the physical health of Japanese family caregivers using objective indicators and a comparative research design. METHODS: A cross-sectional, comparative study was conducted among family caregivers and their non-caregiver counterparts. Surveyors visited caregivers in their homes to administer a questionnaire survey, measure their blood pressure, and collect blood samples using a kit. Blood samples were tested for LDL-Cholesterol, HDL Cholesterol, AST, ALT, gamma-GTP, uric acid, creatinine and HbA1c. Non-caregiver data were collected at a university-based health checkup center. We compared 149 caregivers with 149 sex- and age-matched non-caregivers using conditional logistic regression analyses to examine the impact of caregiving, adjusting for multiple control variables. Analyses were conducted separately for men and female. RESULTS: The prevalence of high blood pressure was significantly higher among caregivers than non-caregivers (male: 72.7% among caregivers vs. 40.9% among non-caregivers, female: 57.1% vs. 27.6%, respectively). After adjusting for related sociodemographic and health factors, high blood pressure remained significantly more prevalent among caregivers than non-caregivers, only among female (adjusted OR=2.16, 95% CI [1.14, 4.08]). Female caregivers showed lower eGFR than their non-caregiver counterparts (adjusted OR=6.54, 95% CI [2.38, 17.91]). No significant differences were observed between the two groups on any other indicators. CONCLUSIONS: Results suggest that female caregivers are at a higher risk of conditions such as cerebral, cardiovascular or kidney diseases than non-caregivers. Steps must be taken to identify caregivers with high blood pressure and lowered eGFR and provide them with the support they need before these risk factors develop into serious diseases. PMID- 25927999 TI - Fast and Efficient XML Data Access for Next-Generation Mass Spectrometry. AB - MOTIVATION: In mass spectrometry-based proteomics, XML formats such as mzML and mzXML provide an open and standardized way to store and exchange the raw data (spectra and chromatograms) of mass spectrometric experiments. These file formats are being used by a multitude of open-source and cross-platform tools which allow the proteomics community to access algorithms in a vendor-independent fashion and perform transparent and reproducible data analysis. Recent improvements in mass spectrometry instrumentation have increased the data size produced in a single LC MS/MS measurement and put substantial strain on open-source tools, particularly those that are not equipped to deal with XML data files that reach dozens of gigabytes in size. RESULTS: Here we present a fast and versatile parsing library for mass spectrometric XML formats available in C++ and Python, based on the mature OpenMS software framework. Our library implements an API for obtaining spectra and chromatograms under memory constraints using random access or sequential access functions, allowing users to process datasets that are much larger than system memory. For fast access to the raw data structures, small XML files can also be completely loaded into memory. In addition, we have improved the parsing speed of the core mzML module by over 4-fold (compared to OpenMS 1.11), making our library suitable for a wide variety of algorithms that need fast access to dozens of gigabytes of raw mass spectrometric data. AVAILABILITY: Our C++ and Python implementations are available for the Linux, Mac, and Windows operating systems. All proposed modifications to the OpenMS code have been merged into the OpenMS mainline codebase and are available to the community at https://github.com/OpenMS/OpenMS. PMID- 25928000 TI - EPHA4 haploinsufficiency is responsible for the short stature of a patient with 2q35-q36.2 deletion and Waardenburg syndrome. AB - BACKGROUND: Waardenburg syndrome type I (WS1), an auditory-pigmentary genetic disorder, is caused by heterozygous loss-of-function mutations in PAX3. Abnormal physical signs such as dystopia canthorum, patchy hypopigmentation and sensorineural hearing loss are common, but short stature is not associated with WS1. CASE PRESENTATION: We reported a 4-year and 6 month-old boy with a rare combination of WS1 and severe short stature (83.5 cm (-5.8SD)). His facial features include dystopia canthorum, mild synophrys, slightly up-slanted palpebral fissure, posteriorly rotated ears, alae nasi hypoplasia and micrognathia. No heterochromia was noticed. He had a normal intelligence quotient and hearing. Insulin-like growth factor-1 (IGF-1) was 52.7 ng/ml, lower than the normal range (55 ~ 452 ng/ml) and the peak growth hormone level was 7.57 ng/ml at 90 minutes after taking moderate levodopa and pyridostigmine bromide. The patient exhibited a good response to human growth hormone (rhGH) replacement therapy, showing a 9.2 cm/year growth rate and an improvement of 1 standard deviation (SD) of height after one year treatment. CMA test of patient's DNA revealed a 4.46 Mb de novo deletion at 2q35-q36.2 (hg19; chr2:221,234,146-225,697,363). CONCLUSIONS: PAX3 haploinsufficiency is known to cause Waardenburg syndrome. Examining overlapping deletions in patients led to the conclusion that EPHA4 is a novel short stature gene. The finding is supported by the splotch-retarded and epha4 knockout mouse models which both showed growth retardation. We believe this rare condition is caused by the haploinsufficiency of both PAX3 and EPH4 genes. We further reported a growth response to recombinant human growth hormone treatment in this patient. PMID- 25928001 TI - Young adult's own and parental social characteristics predict injury morbidity: a register-based follow-up of 135,000 men and women. AB - BACKGROUND: Sociodemographic differences in injury mortality are well established, but population-level studies on social patterns of injury morbidity remain few in numbers, particularly among young adults. Yet injuries are the leading cause of mortality, morbidity and disability among young people. Studies among children have shown steep social gradients in severe injuries, but less is known on the social patterning of injuries in late adolescence and early adulthood, when young people are in the process of becoming independent adults. This study examines how young adults' current living arrangements, education, main economic activity, and parental social background are associated with hospital-treated injuries in late adolescence and early adulthood. METHODS: The study uses prospective, individual-level data gathered from several administrative sources. From a representative 11% sample of the total Finnish population, we included young people between ages 17-29 years during the follow up (N = 134,938). We used incidence rates and Cox proportional hazards models to study hospital-treated injuries and poisonings in 1998-2008. RESULTS: Higher rates of injury were found among young adults living alone, single mothers, the lower educated and the non-employed, as well as those with lower parental social background, experience of childhood family changes or living with a single parent, and those who had left the parental home at a young age. Injury risks were consistently higher among young adults with lower education, but current living arrangements and main economic activity showed some age-related nuances in the associations: both earlier and later than average transitions in education, employment, and family formation associated with increased injury risks. The social differentials were strongest in poisonings, intentional self-harm, and assaults, but social patterns were also found in falls, traffic-related injuries and other unintentional injuries, underlining the existence of multiple distinct mechanisms and pathways behind the differentials. CONCLUSIONS: The transition to adulthood is a life period of heightened risk of injury, during which both parental social background and the young people's own social position are important determinants of serious injuries that require inpatient care. PMID- 25928008 TI - Estradiol induces HOTAIR levels via GPER-mediated miR-148a inhibition in breast cancer. AB - HOTAIR plays an important role in the regulation of cancer cell proliferation and cancer invasion in breast cancer. The up-regulation of HOTAIR has been reported in both estrogen receptor (ER) positive and triple-negative (TN) breast cancer. It has been reported that HOTAIR is regulated by estrogen (E2) via ERs in ER positive breast cancer. However, it is unknown how HOTAIR is regulated in TN breast cancer. In this study, we found that HOTAIR was increased in the peripheral blood mononuclear cells and cancer tissues from breast cancer patients, and was especially higher in patients with metastatic breast cancer. In addition, we found that estrogen promoted HOTAIR through its receptor GPER and estrogen-induced breast cancer cell migration was reversed by deleting HOTAIR in TN breast cancer cells MDA-MB-231and BT549. Furthermore, we identified that E2 GPER induces the level of HOTAIR through the suppression of miR-148a. miR-148a level was negatively correlated with HOTAIR level in breast cancer patients. After the mutation of the predicted miR-148a binding sites in HOTAIR, miR-148a had no effect on HOTAIR. In conclusion, our findings offer important new insights into the ability of estrogenic GPER signaling to increase the HOTAIR level by inhibiting miR-148a in breast cancer. PMID- 25928009 TI - Effect of an integrated maternal health intervention on skilled provider's care for maternal health in remote rural areas of Bangladesh: a pre and post study. AB - BACKGROUND: An integrated maternal health intervention in a rural sub district of Bangladesh focused on the training and deployment of a required number of Community Based Skilled Birth Attendants (CSBAs). The aim of the study was to assess the effect of the intervention on use of skilled provider care during pregnancy, delivery and after delivery. METHODS: The effect compared the skilled providers care in low performing areas with high and medium performing areas through pre-and post-intervention surveys. The post-intervention survey was conducted two years after the completion of the intervention. Village clusters, with populations of approximately 3000, were randomly assigned to the surveys. Mothers who had delivered within the 6 months prior to the surveys, were recruited for the structured interviews. Logistic regression was conducted to compare the effect. RESULTS: Majority of mothers in the low performing areas belonged to a poor economic quintile. The level of skilled attendance for 4+ Antenatal Care (ANC) and delivery increased sharply from baseline to endline survey in low performing areas (ANC: 1.6% to 15.3%, p < 0.0001; skilled birth attendant at delivery: 12.6% to 38.3%, p < 0.0001). Less than 1% of the women received Post Natal Care (PNC) from a skilled provider prior to the intervention, and this proportion increased to 20% at the end of the intervention. Adjusted odds showed that the intervention had an effect on the individual performing area on use of skilled provider care during ANC, delivery and PNC. The increase of 4+ ANC from skilled providers and skilled birth attendants during delivery in the low performing areas due to the integrated maternal health intervention was significant relative to the increase in the high performing areas [4+ ANC from skilled providers - OR: 3.8 (1.9-7.6); skilled birth attendants - OR: 2.8 (2.1 3.8)]. CONCLUSION: An integrated maternal health care intervention focused on deployment of a required number of CSBAs increased the opportunity for underprivileged women to benefit from skilled providers care during their pregnancy. This integrated intervention might improve the maternal health in developing countries where home delivery with unskilled attendants is common. PMID- 25928011 TI - Raman spectroscopy for grading of live osteosarcoma cells. AB - INTRODUCTION: Osteosarcoma is the most common primary malignant bone tumor, and the grading of osteosarcoma cells relies on traditional histopathology and molecular biology methods, which require RNA extraction, protein isolation and immunohistological staining. All these methods require cell isolation, lysis or fixation, which is time-consuming and requires certain amount of tumor specimen. In this study, we report the use of Raman spectroscopy for grading of malignant osteosarcoma cells. METHODS: We demonstrate that, based on the detection of differential production of mineral species, Raman spectroscopy can be used as a live cell analyzer to accurately assess the grades of osteosarcoma cells by evaluating their mineralization levels. Mineralization level was assessed by measuring amount of hydroxyapatite (HA), which is highly expressed in mature osteoblasts, but not in poorly differentiated osteosarcoma cell or mesenchymal stem cells, the putative cell-of-origin of osteosarcoma. RESULTS: We found that under Raman spectroscopy, the level of HA production was high in MG-63 cells, which are low-grade. Moreover, hydroxyapatite production was low in high-grade osteosarcoma cells such as 143B and SaOS2 cells (p < 0.05). Matrix metalloproteinase MMP2, MMP9 were highly expressed in SaOS2, 143B and MSCs and decreased in human fetal osteoblast (FOB) and MG-63 cells as expected (p < 0.05). These results may highlight the inverse correlation between HA level and prognosis of osteosarcoma. CONCLUSIONS: The use of Raman spectroscopy for the measurement of HA production by the protocol reported in this study may serve as a useful tool to rapidly and accurately assess the degree of malignancy in osteosarcoma cells in a label-free manner. Such application may shorten the period of pathological diagnosis and may benefit patients who are inflicted with osteosarcoma. PMID- 25928015 TI - FL118, a novel camptothecin derivative, is insensitive to ABCG2 expression and shows improved efficacy in comparison with irinotecan in colon and lung cancer models with ABCG2-induced resistance. AB - BACKGROUND: Irinotecan is a camptothecin analogue currently used in clinical practice to treat advanced colorectal cancer. However, acquired resistance mediated by the drug efflux pump ABCG2 is a recognized problem. We reported on a novel camptothecin analogue, FL118, which shows anticancer activity superior to irinotecan. In this study, we sought to investigate the potency of FL118 versus irinotecan or its active metabolite, SN-38, in both in vitro and in vivo models of human cancer with high ABCG2 activity. We also sought to assess the potency and ABCG2 affinity of several FL118 analogues with B-ring substitutions. METHODS: Colon and lung cancer cells with and without ABCG2 overexpression were treated with FL118 in the presence and absence of Ko143, an ABCG2-selective inhibitor, or alternatively by genetically modulating ABCG2 expression. Using two distinct in vivo human tumor animal models, we further assessed whether FL118 could extend time to progression in comparison with irinotecan. Lastly, we investigated a series of FL118 analogues with B-ring substitutions for ABCG2 sensitivity. RESULTS: Both pharmacological inhibition and genetic modulation of ABCG2 demonstrated that, in contrast to SN-38, FL118 was able to bypass ABCG2-mediated drug resistance. FL118 also extended time to progression in both in vivo models by more than 50% compared with irinotecan. Lastly, we observed that FL118 analogues with polar substitutions had higher affinity for ABCG2, suggesting that the nonpolar nature of FL118 plays a role in bypassing ABCG2-mediated resistance. CONCLUSIONS: Our results suggest that in contrast to SN-38 and topotecan, FL118 is a poor substrate for ABCG2 and can effectively overcome ABCG2-mediated drug resistance. Our findings expand the uniqueness of FL118 and support continued development of FL118 as an attractive therapeutic option for patients with drug refractory cancers resulting from high expression of ABCG2. PMID- 25928016 TI - Role of community health outreach program "living for health" in improving access to federally qualified health centers in Miami-dade county, Florida: a cross sectional study. AB - BACKGROUND: Care of the underserved remains one of the most compelling challenges to American healthcare. Federally Qualified Health Centers (FQHCs) address uninsurance and underinsurance by providing primary and preventive care to vulnerable populations with fees charged based on ability to pay. Our goal is to study the effectiveness of FQHCs system in engaging patients and the barriers to utilization, which have not been well defined. METHODS: Retrospective analysis was performed on data from "Living for Health" (L4H) program participants from 2008 to 2012. Univariate and multivariate logistic regression analysis were performed to determine factors associated with FQHC utilization. RESULTS: Among 9453 subjects screened, 1889 were referred to a FQHC, but only 201(11%) actually sought treatment. Public insurance, non-Hispanic ethnicity, and hypertension were associated with higher rates of FQHC utilization. Inability to afford costs, cultural factors and inflexible appointment times were the most common reasons for FQHC underutilization. CONCLUSION: The current status of FQHC utilization is sub-optimal. Community outreach programs like L4H can improve the access and utilization of FQHCs. PMID- 25928018 TI - Erratum to: indirect genetic effects contribute substantially to heritable variation in aggression-related traits in group-housed mink (Neovison vison). PMID- 25928019 TI - Standards of resuscitation during inter-hospital transportation: the effects of structured team briefing or guideline review - a randomised, controlled simulation study of two micro-interventions. AB - BACKGROUND: Junior physicians are sometimes sent in ambulances with critically ill patients who require urgent transfer to another hospital. Unfamiliar surroundings and personnel, time pressure, and lack of experience may imply a risk of insufficient treatment during transportation as this can cause the physician to loose the expected overview of the situation. While health care professionals are expected to follow complex algorithms when resuscitating, stress can compromise both solo-performance and teamwork. AIM: To examine whether inter-hospital resuscitation improved with a structured team briefing between physician and ambulance crew in preparation for transfer vs. review of resuscitation guidelines. The effect parameters were physician team leadership (requesting help, delegating tasks), time to resuscitation key elements (chest compressions, defibrillation, ventilations, medication, or a combination of these termed "the first meaningful action"), and hands-off ratio. METHODS: PARTICIPANTS: 46 physicians graduated within 5 years. DESIGN: A simulation intervention study with a control group and two interventions (structured team briefing or review of guidelines). Scenario: Cardiac arrest during simulated inter-hospital transfer. RESULTS: Forty-six candidates participated: 16 (control), 13 (review), and 17 (team briefing). Reviewing guidelines delayed requesting help to 162 seconds, compared to 21 seconds in control and team briefing groups (p = 0.021). Help was not requested in 15% of cases; never requesting help was associated with an increased hands-off ratio, from 39% if the driver's assistance was requested to 54% if not (p < 0.01). No statistically significant differences were found between groups regarding time to first chest compression, defibrillation, ventilation, drug administration, or the combined "time to first meaningful action". CONCLUSION: Neither review nor team briefing improved the time to resuscitation key elements. Review led to an eight-fold increase in the delay to requesting help. The association between never requesting help and an increased hands-off ratio underpins the importance of prioritising available resources. Other medical and non-medical domains have benefited from the use of guidelines reviews and structured team briefings. Reviewing guidelines may compromise the ability to focus on aspects such as team leading and delegating tasks and warrants the need for further studies focusing on how to avoid this cognitive impairment. PMID- 25928024 TI - Combat exposure, social relationships, and subjective well-being among middle aged and older Veterans. AB - OBJECTIVES: This study described the association of subjective well-being with combat exposure and social relationships among middle-aged and older Veteran men in the USA. The stress-buffering hypothesis, which predicts social relationships may moderate the association between combat exposure and subjective well-being, was also examined. METHOD: Data from the 2008 Health and Retirement Study (N = 2961) were used to estimate logistic regression models, focusing on three measures of subjective well-being: depression, life satisfaction, and self reported health. RESULTS: In the fully adjusted models, there were no statistically significant relationships between combat exposure and the three indicators of subjective well-being. However, compared to Veterans who had lower scores on the social relationship index, Veterans who had higher scores were less likely to be depressed and less likely to report poor or fair health. Veterans who had higher scores on the social relationships index reported higher levels of life satisfaction than those Veterans who had lower scores. There was no evidence for a social relationships buffering effect. CONCLUSION: The results of this study demonstrated that combat exposure did not have a long-term relationship with subjective well-being. Longitudinal research designs with more comprehensive indicators of combat exposure may help researchers better understand some of the underlying complexity of this relationship. Complementary research with samples of women Veterans, as well as samples of Hispanic, and non-Black, non-White Veterans, is also needed. PMID- 25928025 TI - Neuroendocrine tumors of the pancreas: a retrospective single-center analysis using the ENETS TNM-classification and immunohistochemical markers for risk stratification. AB - BACKGROUND: This study was performed to assess the 2006 introduced ENETS TNM classification with respect to patient survival and surgical approach for patients who underwent surgery for a neuroendocrine tumor of the pancreas (PNET). METHODS: Between 2001 and 2010 38 patients after resection of a PNET were investigated regarding tumor localization and size. Further, patient survival with regards to the new TNM-classification, the operation methods and immunohistochemical markers was analyzed. RESULTS: The estimated mean survival time of the 38 patients was 91 +/- 10 months (female 116 +/- 9, male 56 +/- 14 months; p = 0.008). The 5-year survival rate was 63.9%. Patient survival differed significantly depending on tumor size (pT1 107 +/- 13, pT2 94 +/- 16, pT3 44 +/- 7 and pT4 18 +/- 14 months; P = 0.006). Patients without lymph node metastasis survived significantly longer compared to patients with positive lymph node status (108 +/- 9 vs. 19 +/- 5 months; P < 0.001). However, survival in patients with and without distant metastasis did not differ significantly (92 +/- 11 vs. 80 +/- 23 months; P = 0.876). Further, the tumor grading significantly influenced patient survival (G1 111 +/- 12, G2 68 +/- 12 and G3 21 +/- 14 months; P = 0.037). CONCLUSIONS: As part of the TNM-classification especially lymph node status and also tumor size and grading were identified as important factors determining patient survival. Further, gender was demonstrated to significantly influence survival time. If an R0 resection was achieved in patients with distant metastases patient survival was comparable to patients without metastasis. PMID- 25928026 TI - The exploits of cancer's greedy sweet-tooth. PMID- 25928030 TI - Platelets: 25 years under the editorship of Stan Heptinstall. PMID- 25928027 TI - Mice transgenic for equine cyclin T1 and ELR1 are susceptible to equine infectious anemia virus infection. AB - BACKGROUND: As a member of the tumor necrosis factor receptor (TNFR) protein superfamily, equine lentivirus receptor 1 (ELR1) has been shown to be expressed in various equine cells that are permissive for equine infectious anemia virus (EIAV) replication. The EIAV Tat protein (eTat) activates transcription initiated at the viral long terminal repeat (LTR) promoter through a unique mechanism that requires the recruitment of the equine cyclin T1 (eCT1) cofactor into the viral TAR RNA target element. In vitro studies have demonstrated that mouse fibroblast cell lines (e.g., NIH 3T3 cells) that express the EIAV receptor ELR1 and eCT1 support the productive replication of EIAV. Therefore, we constructed transgenic eCT1- and ELR1-expressing mice to examine whether they support in vivo EIAV replication. FINDINGS: For the first time, we constructed mice transgenic for ELR1 and eCT1. Real-time reverse transcription polymerase chain reaction (RT-PCR) and Western blot analysis confirmed that ELR1 and eCT1 were expressed in the transgenic mouse tissues, particularly in the intestines, spleen and lymph nodes. Consistent with the results of EIAV infection in NIH 3T3 cells expressing ELR1 and eCT1, mouse embryonic fibroblasts (MEFs) from the transgenic mice could support EIAV replication. More importantly, this virus could infect and replicate in mouse blood monocyte-derived macrophages (mMDMs). Macrophages are the principle target cell of EIAV in its natural hosts. Furthermore, after the transgenic mice were inoculated with EIAV, the virus could be detected not only in the plasma of the circulating blood but also in multiple organs, among which, the spleen and lymph nodes were the predominant sites of EIAV replication. Finally, we found that consistent with high viral replication levels, the relevant pathological changes occurred in the spleen and lymph nodes. CONCLUSIONS: Our results show that mice transgenic for ELR1 and eCT1 are susceptible to EIAV infection and replication. Further, EIAV infection can cause lesions on the spleen and lymph nodes, similar to those frequently observed in horses, the natural hosts. Therefore, ELR1 and eCT1 are essential in vivo for EIAV invasion and replication. PMID- 25928031 TI - Ten simple (empirical) rules for writing science. PMID- 25928033 TI - Ideological meaning making after the loss of a child: the case of Israeli bereaved parents. AB - The study provides a view of ideological meaning-making processes of 10 Israelis who lost a child examining the parents' perspectives and written public documents. The texts and interviews were analyzed using Gadamer's hermeneutic philosophy. Findings indicate that bereaved parents construct conflicting ideologically oriented viewpoints: doubting and affirming the Zionist ideology; ascribing sense and senselessness to the loss; and joining the ethos but keeping personal meanings. Our conclusion is consistent with theorists who reject the notion that the human narrative should be coherently unified. We point to potential links between relational dialectics and meaning-making theory and outline implications for practice. PMID- 25928035 TI - Bactericidal Mechanism of Bio-oil Obtained from Fast Pyrolysis of Pinus densiflora Against Two Foodborne Pathogens, Bacillus cereus and Listeria monocytogenes. AB - Foodborne bacteria are the leading cause of food spoilage and other related diseases. In the present study, the antibacterial activity of bio-oil (BO) manufactured by fast pyrolysis of pinewood sawdust (Pinus densiflora Siebold and Zucc.) against two disease-causing foodborne pathogens (Bacillus cereus and Listeria monocytogenes) was evaluated. BO at a concentration of 1000 MUg/disc was highly active against both B. cereus (10.0-10.6 mm-inhibition zone) and L. monocytogenes (10.6-12.0-mm inhibition zone). The minimum inhibitory concentration (MIC) and minimum bactericidal concentration values of BO were 500 and 1000 MUg/mL, respectively, for both pathogens. At the MIC concentration, BO exhibited an inhibitory effect on the viability of the bacterial pathogens. The mechanism of action of BO revealed its strong impairing effect on the membrane integrity of bacterial cells, which was confirmed by a marked release of 260-nm absorbing material, leakage of electrolytes and K(+) ions, and reduced capacity for osmoregulation under high salt concentration. Scanning electron microscopy clearly showed morphological alteration of the cell membrane due to the effect of BO. Overall, the results of this study suggest that BO exerts effective antibacterial potential against foodborne pathogens and can therefore potentially be used in food processing and preservation. PMID- 25928034 TI - The histone methyltransferase SDG8 mediates the epigenetic modification of light and carbon responsive genes in plants. AB - BACKGROUND: Histone methylation modifies the epigenetic state of target genes to regulate gene expression in the context of developmental and environmental changes. Previously, we used a positive genetic screen to identify an Arabidopsis mutant, cli186, which was impaired in carbon and light signaling. Here, we report a deletion of the Arabidopsis histone methyltransferase SDG8 in this mutant (renamed sdg8-5), which provides a unique opportunity to study the global function of a specific histone methyltransferase within a multicellular organism. RESULTS: To assess the specific role of SDG8, we examine how the global histone methylation patterns and transcriptome were altered in the sdg8-5 deletion mutant compared to wild type, within the context of transient light and carbon treatments. Our results reveal that the sdg8 deletion is associated with a significant reduction of H3K36me3, preferentially towards the 3' end of the gene body, accompanied by a reduction in gene expression. We uncover 728 direct targets of SDG8 that have altered methylation in the sdg8-5 mutant and are also bound by SDG8. As a group, this set of SDG8 targets is enriched in specific biological processes including defense, photosynthesis, nutrient metabolism and energy metabolism. Importantly, 64% of these SDG8 targets are responsive to light and/or carbon signals. CONCLUSIONS: The histone methyltransferase SDG8 functions to regulate the H3K36 methylation of histones associated with gene bodies in Arabidopsis. The H3K36me3 mark in turn is associated with high-level expression of a specific set of light and/or carbon responsive genes involved in photosynthesis, metabolism and energy production. PMID- 25928036 TI - Proteomic Profiling of Paclitaxel Treated Cells Identifies a Novel Mechanism of Drug Resistance Mediated by PDCD4. AB - Paclitaxel (PTX) is a widely used chemotherapeutic drug effective against numerous cancers. To elucidate cellular pathways targeted by PTX and identify novel mechanisms of PTX resistance, we used a SILAC based quantitative proteomic approach to evaluate global changes of cellular protein abundance in HeLa cells. We identified 347 proteins involved in a number of biological processes including spindle assembly, mitotic exit, and extracellular adhesion whose abundance changes upon PTX treatment. Notably, the tumor suppressor PDCD4 involved in translation suppression was down-regulated by PTX. We demonstrated that PDCD4 is a cell-cycle regulated protein and that changes in its abundance are sufficient to alter PTX sensitivity in multiple human cancer cell lines. Immunoprecipitation of PDCD4-RNA complexes and RT-PCR revealed that PDCD4 mediated PTX sensitivity acts through its interaction with mRNA of UBE2S, a ubiquitin K11 linkage conjugating enzyme critical for mitotic exit. Lastly, high levels of PDCD4 in lung cancer tissues are positively correlated with the longer overall survival time of the examined lung cancer patients with PTX involved adjuvant therapy. Therefore, our proteomic screen for paclitaxel targets not only provided novel insight into the cellular resistance to paclitaxel via the PDCD4-mitotic exit regulation axis, but also offered a predictive biomarker for paclitaxel-based personalized chemotherapy in the treatment of lung cancer. PMID- 25928039 TI - Immunohistochemical evaluation of a sarcomatoid hepatocellular carcinoma with osteoclastlike giant cells. AB - BACKGROUND: Malignant liver tumors with osteoclast-like giant cells are rare. A literature search showed 17 previously reported cases that included the following: (1) 8 undifferentiated hepatocellular carcinomas, (2) 5 sarcomatous tumors with osteoclast-like giant cells associated with intrahepatic cholangiocarcinoma or liver cystadenocarcinoma, and (3) 4 sarcomatoid tumors with osteoclast-like giant cells associated with areas of a conventional hepatocellular carcinoma. CASE PRESENTATION: A 68-year-old man presented with a tumor of the right lobe of the liver on ultrasonography and computed tomography. Laparoscopy showed a tumor (diameter, 4 cm) in segments 7 and 8 of the right liver lobe that adhered to the retroperitoneum. The tumor recurred 3 months after liver segmentectomy. Repeat laparoscopy showed diffuse and nodular metastases to the omentum and peritoneum. RESULT: Light microscopy showed that part of the tumor had features of classic hepatocellular carcinoma. Another part of the tumor had a solid sarcomatous pattern with osteoclast-like giant cells that were irregularly distributed between the smaller undifferentiated tumor cells; cells of this part of the tumor were positive for heppar-1. CONCLUSION: Light microscopic findings including osteoclast-like giant cells, and the strong reaction of heppar-1 antibody with cells of the sarcomatous part of the tumor, confirmed that this sarcomatous element was a metaplastic or transformed portion of hepatocellular carcinoma. VIRTUAL SLIDES: The virtual slide(s) for this article can be found here: http://www.diagnosticpathology.diagnomx.eu/vs/6000512901462616. PMID- 25928041 TI - Therapeutic effect of intravesical administration of paclitaxel solubilized with poly(2-methacryloyloxyethyl phosphorylcholine-co-n-butyl methacrylate) in an orthotopic bladder cancer model. AB - BACKGROUND: To evaluate the effects of intravesical administration of paclitaxel (PTX-30W), which was prepared by solubilization with a water-soluble amphiphilic polymer composed of PMB30W, a copolymer of 2-methacryloyloxyethyl phosphorylcholine and n-butyl methacrylate, in an orthotopic bladder cancer model. METHODS: The cytotoxicities of PMB30W were examined in MBT-2 cell cultures and the results were compared with those of the conventional paclitaxel solubilizer Cremophor. In an orthotopic MBT-2 bladder cancer model, the effect of intravesical administration of PTX-30W was compared with that of paclitaxel solubilized with Cremophor (PTX-CrEL). The paclitaxel concentration in bladder tumors after the intravesical treatment was also evaluated using liquid chromatography tandem mass spectrometry (LC-MS/MS) system. RESULTS: In vitro, Cremophor exhibited dose-dependent cytotoxicity towards MBT-2 cells, whereas no cytotoxicity was observed with PMB30W. In the orthotopic bladder cancer model, intravesical administration of PTX-30W resulted in a significant reduction of bladder wet weight compared with that of PTX-CrEL. The paclitaxel concentration in bladder tumors after the intravesical treatment was significantly higher in PTX-30W treated mice than in PTX-CrEL treated mice. CONCLUSIONS: Intravesically administered PTX-30W can elicit stronger antitumor effects on bladder tumors than conventional paclitaxel formulated in Cremophor, presumably because of its better penetration into tumor cells. PTX-30W might be a promising antitumor agent for intravesical treatment of non-muscle invasive bladder cancer. PMID- 25928042 TI - Comparative proteomic analysis of spermatozoa isolated by swim-up or density gradient centrifugation. AB - BACKGROUND: Reports about the morphologic and functional characteristics of spermatozoa prepared by density gradient centrifugation (DC) or swim-up (SU) have produced discordant results. We have performed a proteomic comparison of cells prepared by DC and SU providing a molecular insight into the differences between these two methods of sperm cell isolation. METHODS: Protein maps were obtained by 2-dimensional (2-D) separations consisting of isoelectrofocusing (IEF) from pI 3 to 11 followed by SDS-polyacrylamide gel electrophoresis. 2-D gels were stained with Sypro Ruby. Map images of DC and SU spermatozoa were compared using dedicated software. Intensities of a given spot were considered different between DC and SU when their group mean differed by >1.5-fold (p<0.05, Anova). RESULTS: No differences were observed for 853 spots, indicating a 98.7% similarity between DC and SU. Five spots were DC>SU and 1 was SU>DC. Proteins present in 3 of the differential spots could be identified. One DC>SU spot contained lactate dehydrogenase C and gamma-glutamylhydrolase, a second DC>SU spot contained fumarate hydratase and glyceraldehyde-3-phosphate dehydrogenase-2, and a SU>DC spot contained pyruvate kinase M1/M2. CONCLUSIONS: The differences in protein levels found on comparison of DC with SU spermatozoa indicate possible dissimilarities in their glycolytic metabolism and DNA methylation and suggest that DC cells may have a better capacitation potential. PMID- 25928044 TI - Complexation of uranium(VI) with glutarimidoxioxime: thermodynamic and computational studies. AB - The complex formation between a cyclic ligand glutarimidoxioxime (denoted as HL(III) in this paper) and UO2(2+) is studied by potentiometry and microcalorimetry. Glutarimidoxioxime (HL(III)), together with glutarimidedioxime (H2L(I)) and glutardiamidoxime (H2L(II)), belongs to a family of amidoxime derivatives with prospective applications as binding agents for the recovery of uranium from seawater. An optimized procedure of synthesis that leads to the preparation of glutarimidoxioxime in the absence of other amidoxime byproducts is described in this paper. Speciation models based on the thermodynamic results from this study indicate that, compared with H2L(I) and H2L(II), HL(III) forms a much weaker complex with UO2(2+), UO2(L(III))(+), and cannot effectively compete with the hydrolysis equilibria of UO2(2+) under neutral or alkaline conditions. DFT computations, taking into account the solvation by including discrete hydration water molecules and bulk solvent effects, were performed to evaluate the structures and energies of the possible isomers of UO2(L(III))(+). Differing from the tridentate or eta(2)-coordination modes previously found in the U(vi) complexes with amidoxime-related ligands, a bidentate mode, involving the oxygen of the oxime group and the nitrogen of the imino group, is found to be the most probable mode in UO2(L(III))(+). The bidentate coordination mode seems to be stabilized by the formation of a hydrogen bond between the carbonyl group of HL(III) and a water molecule in the hydration sphere of UO2(2+). PMID- 25928043 TI - Association between hepatitis B vaccine antibody response and CD4 reconstitution after initiation of combination antiretroviral therapy in HIV-infected persons. AB - BACKGROUND: Hepatitis B virus (HBV) vaccine antibody response has been associated with reduced risk of AIDS or death. However, it is unknown whether HBV vaccine responsiveness is associated with improved immune reconstitution during treatment with combination antiretroviral therapy (cART). We evaluated the relationship between HBV vaccine response status and CD4 reconstitution on cART in the U.S Military HIV Natural History Study. METHODS: Participants with viral load <400 copies/mL within 1 year on initial cART and documented HBV vaccination and surface antibody (anti-HBs) prior to cART were included. Participants were characterized as HBV vaccine responders (anti-HBs >=10 IU/L) or non-responders (<10 IU/L) and further divided into 2 groups based on vaccine administration before or after HIV diagnosis. Linear mixed regression was used to model CD4 reconstitution during the first year of cART. RESULTS: Of the 307 and 169 participants vaccinated before or after HIV diagnosis, HBV vaccine response occurred in 288 (94%) and 74 (44%), respectively. For those vaccinated before HIV diagnosis, CD4 counts increased by a median 190 [IQR 99-310] cells/mm(3) for responders and 186 [IQR 116-366] cells/mm(3) for non-responders during the first year (P = 0.684). Participants vaccinated after HIV diagnosis had median increases of 185 [IQR 76-270] and 143 [IQR 47-238] cells/mm(3) for responders and non-responders, respectively (P = 0.134). In contrast to those with CD4 > 350 cells/mm(3) at cART initiation, participants with CD4 < 200 and 200-350 cells/mm(3) had significantly reduced CD4 gains in both groups by longitudinal mixed models, but there was no difference in CD4 recovery according to HBV vaccine seroresponse. CONCLUSIONS: Although HBV vaccine responsiveness is associated with a reduction in HIV disease progression, HBV vaccine responders do not achieve greater CD4 gains during the first year of cART. Additional clinical markers are needed to predict the magnitude of post-cART immune recovery. PMID- 25928045 TI - Trapping and assembling of particles and live cells on large-scale random gold nano-island substrates. AB - We experimentally demonstrated the use of random plasmonic nano-islands for optical trapping and assembling of particles and live cells into highly organized pattern with low power density. The observed trapping effect is attributed to the net contribution due to near-field optical trapping force and long-range thermophoretic force, which overcomes the axial convective drag force, while the lateral convection pushes the target objects into the trapping zone. Our work provides a simple platform for on-chip optical manipulation of nano- and micro sized objects, and may find applications in physical and life sciences. PMID- 25928047 TI - Sexual health literacy of the student population of the University of Tasmania: results of the RUSSL Study. AB - Background Evidence suggests a varied level of sexual health literacy (SHL) among university student populations, so we evaluated the SHL among students at the University of Tasmania. METHODS: Students were invited to complete an anonymous online questionnaire during August/September 2013. SHL was assessed using the ARCSHS National Survey of Australian Secondary Students & Sexual Health (ARC) and the Sexual Health Questionnaire (SHS). Predictors of literacy scores were evaluated by linear regression. RESULTS: The study recruited 1786 participants (8.2% of 2013 student population), of similar composition to the general university population. Female sex, older age, sexual education, and sexual experience were significant predictors of SHL. As hypothesised, students in medical/nursing disciplines had the highest SHL. Less expected were the significant differences by birthplace and religious affiliation, many of which persisted on adjustment for confounders. Compared with Australian/New Zealander students, overseas-born students had significantly lower ARC (-3.6%, P<0.001) & SHS (-4.2%, P<0.001); this was driven by Malaysian, Indian, and Chinese students. Compared with agnostic/atheist-identifying students, those of Buddhist (ARC: 5.4%, P=0.014; SHS: -6.7%, P=0.002), Hindu (ARC: -8.8%, P=0.098; SHS: -12.2%, P=0.027), Muslim (ARC: -16.5%, P<0.001; SHS: -13.4%, P=0.001) and Protestant (ARC: -2.3%, P=0.023; SHS: -4.4%, P<0.001) identifications had markedly lower SHL. CONCLUSIONS: This study, one of the first among university students in Australia, found a varied SHL by sex, age, sexual education and sexual experience, as well as by birthplace and religious affiliation. These findings have applications in orientation and education programs at Australian universities. PMID- 25928049 TI - Workplace Blame and Related Concepts: An Analysis of Three Case Studies. AB - Blame has been thought to affect quality by decreasing error reporting. Very little is known about the incidence, characteristics, or consequences of the distress caused by being blamed. Blame-related distress (B-RD) may be related to moral distress, but may also be a factor in burnout, compassion fatigue, lateral violence, and second-victim syndrome. The purpose of this article is to explore these related concepts through a literature review applied to three index critical care clinician cases. PMID- 25928046 TI - The role of androgens in experimental rodent mammary carcinogenesis. AB - Breast cancer is currently the most frequent, fatal cancer of women in western countries. While estrogens have a widely understood involvement in breast cancer, a significant but not yet fully understood role for androgens has also been suggested. The principal androgen, testosterone, is the obligate steroidal precursor of estradiol, but can equally be metabolized into dihydrotestosterone, a more potent, pure androgen. Both androgens exert their distinctive biological effects via the androgen receptor, which is coexpressed with estrogen receptor alpha in 80 to 90% of breast cancers. The hormonal control of breast development and pathology has been examined experimentally through the use of animal models, notably mice and rats. This review summarizes the data from experimental rodent models on the effects of androgens in experimental breast cancer, aiming to address the importance of androgens and the androgen receptor in the origins and pathogenesis of breast cancers, as well as to discuss potential biomarker and therapeutic opportunities arising from novel insights based on the experimental research. PMID- 25928050 TI - Synthesis of 2-bromoimidazoles from alkynes, N-sulfonylazides, and bromocyanides. AB - A synthetic method for 2-bromoimidazoles is developed from Rh-catalyzed cyclization of N-sulfonyl-1,2,3-triazoles with bromocyanides. Cu-catalyzed [3 + 2] cycloaddition followed by Rh-catalyzed cyclization starting from alkynes, N sulfonylazides, and bromocyanides is also demonstrated for de novo synthesis of 2 bromoimidazoles in one pot. Moreover, this work was successfully employed to introduce diverse functional groups to the 2-position of imidazoles via cross coupling reaction. PMID- 25928052 TI - Te(II)/Te(IV) Mediated C-N Bond Formation on 2,5-Diphenyltellurophene and a Reassignment of the Product from the Reaction of PhI(OAc)2 with 2 TMS-OTf. AB - We report a novel C-H to C-N bond metathesis at the 3-position of 1,2 diphenyltellurophene via oxidation of the Te(II) center to Te(IV) using the I(III) oxidant [PhI(4-DMAP)2](2+). Spontaneous reduction of a transient Te(IV) coordination compound to Te(II) generates an electrophilic equivalent of 4-DMAP that substitutes at a C-H bond at the 3-position of the tellurophene. Theoretical and synthetic reaction pathway studies confirm that a Te(IV) coordination complex with 4-DMAP is an intermediate. In the course of these pathway studies, it was also found that the identity of the I(III) oxidant generated from PhI(OAc)2 and 2 TMS-OTf is PhI(OAc)(OTf) and not PhI(OTf)2, as had been previously thought. PMID- 25928051 TI - The number of prehospital defibrillation shocks and 1-month survival in patients with out-of-hospital cardiac arrest. AB - BACKGROUND: The relationship between the number of pre-hospital defibrillation shocks and treatment outcome in patients with out-of-hospital cardiac arrest (OHCA) presenting with ventricular fibrillation (VF) is unknown currently. We examined the association between the number of pre-hospitalization defibrillation shocks and 1-month survival in OHCA patients. METHODS: We conducted a prospective observational study using national registry data obtained from patients with OHCA between January 1, 2009 and December 31, 2012 in Japan. The study subjects were >= 18-110 years of age, had suffered from an OHCA before arrival of EMS personnel, had a witnessed collapse, had an initial rhythm that was shockable [VF/ventricular tachycardia (pulseless VT)], were not delivered a shock using a public automated external defibrillator (AED), received one or more shocks using a biphasic defibrillator by EMS personnel, and were transported to a medical institution between January 1, 2009 and December 31, 2012. There were 20,851 OHCA cases which met the inclusion criteria during the study period. Signal detection analysis was used to identify the cutoff point in the number of prehospital defibrillation shocks most closely related to one-month survival. Variables related to the number of defibrillations or one-month survival in OHCA were identified using multiple logistic regression analysis. RESULTS: A cutoff point in the number of pre-hospital defibrillation shocks most closely associated with 1-month OHCA survival was between two and three (chi(2) = 209.61, p < 0.0001). Among those patients who received two shocks or less, 34.48% survived for at least 1 month, compared with 24.75% of those who received three shocks or more. The number of defibrillations (odds ratio [OR] = 1.19, 95% CI: 1.03, 1.38), OHCA origin (OR = 2.81, 95% CI: 2.26, 3.49), use of ALS devices (OR = 0.68, 95% CI: 0.59, 0.79), use of epinephrine (OR = 0.33, 95% C: 0.28, 0.39), interval between first defibrillation and first ROSC (OR = 1.45, 95% CI: 1.18, 1.78), and chest compression (OR = 1.21, 95% CI: 1.06, 1.38) were associated significantly with 1 month OCHA survival. CONCLUSIONS: The cutoff point in the number of defibrillations of patients with OHCA most closely related to one-month survival was between 2 and 3, and the likelihood of non-survival 1 month after an OHCA was increased when >=3 shocks were needed. Further studies are needed to verify this finding. PMID- 25928053 TI - Primigravida with Bernard-Soulier Syndrome: a case report. AB - BACKGROUND: Bernard-Soulier Syndrome is a rare congenital bleeding disorder, mainly inherited in an autosomal recessive pattern. It is characterized by a genetic defect on one of the four genes encoding the subunits of the transmembrane protein complex GPIb-V-IX, physiologically expressed only in platelets. The exact phenotype varies widely from individual to individual depending on the particular mutation presented. Currently, there is no consensus about ideal management of affected pregnant women, in face of the scarcity of cases. CASE PRESENTATION: We report on a 28-year-old Black Brazilian primigravida who was referred to our maternity hospital, a tertiary care center, for decision about the most adequate mode of delivery. She was admitted with a platelet count of 43.000 plt/MUL, and hemoglobin of 13.6 g/dL. Platelet transfusion was regarded as a necessary prophylactic measure prior to delivery. Ten units of random donor platelets were administered on the course of three days, after which the patient was submitted to an elective cesarean section delivery under general anesthesia at 40 weeks of gestational age. A healthy male baby with a normal birthweight of 3.615 kg was delivered. After the delivery, the mother's state continued being assessed daily, with special attention taken to lochia and surgical wound healing. At one week postpartum, a complete blood count revealed a platelet count of 41.000 plt/MUL, and hemoglobin of 13.3 g/dL. As there were no signs of neither evident nor occult hemorrhage, and surgical wound was healing accordingly, the patient was discharged, after being oriented about bleeding preventive measures. CONCLUSION: The peripartum period is regarded as the most crucial moment of pregnancy in women with Bernard-Soulier Syndrome, hence the importance of a judiciously planned mode of delivery, and of careful prophylaxis against bleeding beforehand. Furthermore, absence of complications during the peripartum period does not predict how the woman will do subsequently. Strict vigilance is warranted at least until six weeks postpartum, due to the virtual risk of secondary postpartum hemorrhage. PMID- 25928054 TI - Field inhomogeneity correction using partial differential phases in magnetic resonance imaging. AB - Correction of an inhomogeneous magnetic field is proposed using partial differential phases in magnetic resonance imaging. Estimation of the inhomogeneous magnetic field from a measured phase is not an easy task due to phase wrapping and chemical-dependent phase shifts. Using the proposed partial differential phase technique, such problems are resolved. The proposed technique uses most of the 3D pixel data regardless of chemical compounds for the estimation of the inhomogeneous magnetic field. A large number of partial difference data compared to the number of expansion terms for the model of inhomogeneous magnetic field provides a very stable estimation, robust to noise. The technique is applicable to in vivo shimming, water-fat imaging, eddy current compensation, and most phase-related measurements and imaging. The efficacy of the proposed technique is demonstrated with in vivo water-fat imaging. PMID- 25928055 TI - Unusual intermolecular "through-space" j couplings in p-se heterocycles. AB - Solid-state NMR spectra of new P-Se heterocycles based on peri-substituted naphthalene motifs show the presence of unusual J couplings between Se and P. These couplings are between atoms in adjacent molecules and occur "through space", rather than through conventional covalent bonds. Experimental measurements are supported by relativistic DFT calculations, which confirm the presence of couplings between nonbonded atoms, and provide information on the pathway of the interaction. This observation improves the understanding of J couplings and offers insight into the factors that affect crystal packing in solids, for future synthetic exploitation. PMID- 25928056 TI - Serum substance P levels are associated with severity and mortality in patients with severe traumatic brain injury. AB - INTRODUCTION: Substance P (SP) is a member of the tachykinin family of neuropeptides, which are widely distributed throughout the central nervous system (CNS) and actively involved in inflammatory processes. SP is released early following acute injury to the CNS, promoting a neurogenic inflammatory response characterized by an increase in the permeability of the blood-brain barrier and the development of vasogenic edema. High levels of SP could lead to an exacerbated inflammatory response that could be fatal for patients with traumatic brain injury (TBI). Thus, the main goal of the present study was to determine whether serum SP levels are associated with injury severity and mortality in patients with severe TBI. METHODS: This multicenter, observational, prospective study was carried out in six Spanish intensive care units and included patients with Glasgow Coma Scale (GCS) scores <= 8. Patients with an Injury Severity Score >= 10 in non-cranial aspects were excluded. Blood samples were collected on day 1 of TBI to measure serum SP levels. The endpoint was 30-day mortality. RESULTS: We found higher serum SP levels (P = 0.002) in non-surviving patients (n = 27) than in surviving patients (n = 73). The area under the curve for serum SP levels with regard to predicting 30-day mortality was 0.70 (95% confidence interval (CI), 0.60 to 0.79; P < 0.001). Survival analysis showed that patients with serum SP levels >299 pg/ml had higher 30-day mortality than patients with lower levels (hazard ratio = 3.7; 95% CI, 1.75 to 7.94; P < 0.001). Multiple binomial logistic regression analysis showed that serum SP levels >299 pg/ml were associated with 30-day mortality when we controlled for APACHE II score and Marshall computed tomography lesion classification (odds ratio (OR) = 5.97; 95% CI, 1.432 to 24.851; P = 0.01) and for GCS score and age (OR = 5.71; 95% CI, 1.461 to 22.280; P = 0.01). We found a negative association between serum SP levels and GCS score (Spearman's rho = -0.22; P = 0.03). CONCLUSIONS: We report, for the first time to our knowledge, that serum SP levels were associated with injury severity and mortality in patients with severe TBI. These results open the possibility that SP antagonists may be useful in the treatment of patients with severe TBI. PMID- 25928057 TI - Genomic Characterizations of Six Pigeon Paramyxovirus Type 1 Viruses Isolated from Live Bird Markets in China during 2011 to 2013. AB - The genomes of six pigeon paramyxovirus type 1 (PPMV-1) isolated from symptomless pigeons in live poultry markets during the national active surveillance from 2011 to 2013 were sequenced and analyzed in this study. The complete genome lengths of all isolates were 15,192 nucleotides with the gene order of 3'-NP-P-M-F-HN-L-5'. All isolates had the same motif of 112RRQKRF117 at the cleavage site of the fusion protein, which was typical of velogenic Newcastle disease virus (NDV). Several mutations were identified in the functional domains of F and HN proteins, including fusion peptide, heptad repeat region, transmembrane domains and neutralizing epitopes. Phylogenetic analysis based on sequences of complete genomes and six genes revealed that all isolates belonged to genotype VI in class II, but at least 2 sub-genotypes were identified. Most isolates were placed into sub-genotype VIb with the exception of pi/GX/1015/13, which was classified in sub genotype VIa. The obvious antigenic difference between PPMV-1 isolates and La Sota strain was found based on the R-value calculated by cross hemagglutination inhibition (HI) assay. These results provided the evidence that PPMV-1 could be detected from healthy pigeons, and our study may be useful in designing vaccines used in pigeon, and developing molecular diagnostic tools to monitor and prevent future PPMV-1 outbreaks. PMID- 25928058 TI - Berberine Suppresses Adipocyte Differentiation via Decreasing CREB Transcriptional Activity. AB - Berberine, one of the major constituents of Chinese herb Rhizoma coptidis, has been demonstrated to lower blood glucose, blood lipid, and body weight in patients with type 2 diabetes mellitus. The anti-obesity effect of berberine has been attributed to its anti-adipogenic activity. However, the underlying molecular mechanism remains largely unknown. In the present study, we found that berberine significantly suppressed the expressions of CCAAT/enhancer-binding protein (C/EBP)alpha, peroxisome proliferators-activated receptor gamma2 (PPARgamma2), and other adipogenic genes in the process of adipogenesis. Berberine decreased cAMP-response element-binding protein (CREB) phosphorylation and C/EBPbeta expression at the early stage of 3T3-L1 preadipocyte differentiation. In addition, CREB phosphorylation and C/EBPbeta expression induced by 3-isobutyl-1-methylxanthine (IBMX) and forskolin were also attenuated by berberine. The binding activities of cAMP responsive element (CRE) stimulated by IBMX and forskolin were inhibited by berberine. The binding of phosphorylated CREB to the promoter of C/EBPbeta was abrogated by berberine after the induction of preadipocyte differentiation. These results suggest that berberine blocks adipogenesis mainly via suppressing CREB activity, which leads to a decrease in C/EBPbeta-triggered transcriptional cascades. PMID- 25928059 TI - Daytime Land Surface Temperature Extraction from MODIS Thermal Infrared Data under Cirrus Clouds. AB - Simulated data showed that cirrus clouds could lead to a maximum land surface temperature (LST) retrieval error of 11.0 K when using the generalized split window (GSW) algorithm with a cirrus optical depth (COD) at 0.55 MUm of 0.4 and in nadir view. A correction term in the COD linear function was added to the GSW algorithm to extend the GSW algorithm to cirrus cloudy conditions. The COD was acquired by a look up table of the isolated cirrus bidirectional reflectance at 0.55 MUm. Additionally, the slope k of the linear function was expressed as a multiple linear model of the top of the atmospheric brightness temperatures of MODIS channels 31-34 and as the difference between split-window channel emissivities. The simulated data showed that the LST error could be reduced from 11.0 to 2.2 K. The sensitivity analysis indicated that the total errors from all the uncertainties of input parameters, extension algorithm accuracy, and GSW algorithm accuracy were less than 2.5 K in nadir view. Finally, the Great Lakes surface water temperatures measured by buoys showed that the retrieval accuracy of the GSW algorithm was improved by at least 1.5 K using the proposed extension algorithm for cirrus skies. PMID- 25928060 TI - Beyond where to how: a machine learning approach for sensing mobility contexts using smartphone sensors. AB - This paper presents the results of research on the use of smartphone sensors (namely, GPS and accelerometers), geospatial information (points of interest, such as bus stops and train stations) and machine learning (ML) to sense mobility contexts. Our goal is to develop techniques to continuously and automatically detect a smartphone user's mobility activities, including walking, running, driving and using a bus or train, in real-time or near-real-time (<5 s). We investigated a wide range of supervised learning techniques for classification, including decision trees (DT), support vector machines (SVM), naive Bayes classifiers (NB), Bayesian networks (BN), logistic regression (LR), artificial neural networks (ANN) and several instance-based classifiers (KStar, LWLand IBk). Applying ten-fold cross-validation, the best performers in terms of correct classification rate (i.e., recall) were DT (96.5%), BN (90.9%), LWL (95.5%) and KStar (95.6%). In particular, the DT-algorithm RandomForest exhibited the best overall performance. After a feature selection process for a subset of algorithms, the performance was improved slightly. Furthermore, after tuning the parameters of RandomForest, performance improved to above 97.5%. Lastly, we measured the computational complexity of the classifiers, in terms of central processing unit (CPU) time needed for classification, to provide a rough comparison between the algorithms in terms of battery usage requirements. As a result, the classifiers can be ranked from lowest to highest complexity (i.e., computational cost) as follows: SVM, ANN, LR, BN, DT, NB, IBk, LWL and KStar. The instance-based classifiers take considerably more computational time than the non instance-based classifiers, whereas the slowest non-instance-based classifier (NB) required about five-times the amount of CPU time as the fastest classifier (SVM). The above results suggest that DT algorithms are excellent candidates for detecting mobility contexts in smartphones, both in terms of performance and computational complexity. PMID- 25928061 TI - A Sensorless Predictive Current Controlled Boost Converter by Using an EKF with Load Variation Effect Elimination Function. AB - To realize accurate current control for a boost converter, a precise measurement of the inductor current is required to achieve high resolution current regulating. Current sensors are widely used to measure the inductor current. However, the current sensors and their processing circuits significantly contribute extra hardware cost, delay and noise to the system. They can also harm the system reliability. Therefore, current sensorless control techniques can bring cost effective and reliable solutions for various boost converter applications. According to the derived accurate model, which contains a number of parasitics, the boost converter is a nonlinear system. An Extended Kalman Filter (EKF) is proposed for inductor current estimation and output voltage filtering. With this approach, the system can have the same advantages as sensored current control mode. To implement EKF, the load value is necessary. However, the load may vary from time to time. This can lead to errors of current estimation and filtered output voltage. To solve this issue, a load variation elimination effect elimination (LVEE) module is added. In addition, a predictive average current controller is used to regulate the current. Compared with conventional voltage controlled system, the transient response is greatly improved since it only takes two switching cycles for the current to reach its reference. Finally, experimental results are presented to verify the stable operation and output tracking capability for large-signal transients of the proposed algorithm. PMID- 25928062 TI - MEMS Flow Sensors Based on Self-Heated aGe-Thermistors in a Wheatstone Bridge. AB - A thermal flow transduction method combining the advantages of calorimetric and hot-film transduction principles is developed and analyzed by Finite Element Method (FEM) simulations and confirmed experimentally. The analyses include electrothermal feedback effects of current driven NTC thermistors. Four thin-film germanium thermistors acting simultaneously as heat sources and as temperature sensors are embedded in a micromachined silicon-nitride membrane. These devices form a self-heated Wheatstone bridge that is unbalanced by convective cooling. The voltage across the bridge and the total dissipated power are exploited as output quantities. The used thin-film thermistors feature an extremely high temperature sensitivity. Combined with properly designed resistance values, a power demand in sub-1mW range enables efficient gas-flow transduction, as confirmed by measurements. Two sensor configurations with different arrangements of the membrane thermistors were examined experimentally. Moreover, we investigated the influence of different layouts on the rise time, the sensitivity, and the usable flow range by means of two-dimensional finite element simulations. The simulation results are in reasonable agreement with corresponding measurement data confirming the basic assumptions and modeling approach. PMID- 25928063 TI - A multi-agent framework for packet routing in wireless sensor networks. AB - Wireless sensor networks (WSNs) have been widely investigated in recent years. One of the fundamental issues in WSNs is packet routing, because in many application domains, packets have to be routed from source nodes to destination nodes as soon and as energy efficiently as possible. To address this issue, a large number of routing approaches have been proposed. Although every existing routing approach has advantages, they also have some disadvantages. In this paper, a multi-agent framework is proposed that can assist existing routing approaches to improve their routing performance. This framework enables each sensor node to build a cooperative neighbour set based on past routing experience. Such cooperative neighbours, in turn, can help the sensor to effectively relay packets in the future. This framework is independent of existing routing approaches and can be used to assist many existing routing approaches. Simulation results demonstrate the good performance of this framework in terms of four metrics: average delivery latency, successful delivery ratio, number of live nodes and total sensing coverage. PMID- 25928064 TI - Predictors for physical activity in adolescent girls using statistical shrinkage techniques for hierarchical longitudinal mixed effects models. AB - We examined associations among longitudinal, multilevel variables and girls' physical activity to determine the important predictors for physical activity change at different adolescent ages. The Trial of Activity for Adolescent Girls 2 study (Maryland) contributed participants from 8th (2009) to 11th grade (2011) (n=561). Questionnaires were used to obtain demographic, and psychosocial information (individual- and social-level variables); height, weight, and triceps skinfold to assess body composition; interviews and surveys for school-level data; and self-report for neighborhood-level variables. Moderate to vigorous physical activity minutes were assessed from accelerometers. A doubly regularized linear mixed effects model was used for the longitudinal multilevel data to identify the most important covariates for physical activity. Three fixed effects at the individual level and one random effect at the school level were chosen from an initial total of 66 variables, consisting of 47 fixed effects and 19 random effects variables, in additional to the time effect. Self-management strategies, perceived barriers, and social support from friends were the three selected fixed effects, and whether intramural or interscholastic programs were offered in middle school was the selected random effect. Psychosocial factors and friend support, plus a school's physical activity environment, affect adolescent girl's moderate to vigorous physical activity longitudinally. PMID- 25928067 TI - Downregulated Long Noncoding RNA BANCR Promotes the Proliferation of Colorectal Cancer Cells via Downregualtion of p21 Expression. AB - BRAF activated non-coding RNA (BANCR), a long non-coding RNA (lncRNA), is crucial for cell migration in melanoma cells and non-small cell lung cancer (NSCLC) cells. However, little is known regarding the role of this gene in the proliferation of colorectal cancer. Therefore, we investigated the involvement of BANCR in the proliferation of colorectal cancer cells. In this study, we show that BANCR expression was significantly down-regulated in colorectal cancer tissues compared with normal tissues, and overexpression of BANCR suppressed colorectal cancer cell growth in vitro and in vivo. We also determined that pCDNA BANCR-mediated colorectal cancer cell proliferation was associated with induction of G0/G1 cell-cycle arrest and apoptosis enhancement through regulation of p21, and its effects were most likely posttranscriptional. Taken together, our findings suggest that down-regulation of BANCR contributes to the proliferation of colorectal cancer cells, at least in part, through the regulation of p21 protein. PMID- 25928068 TI - Oxaliplatin-Induced Peripheral Neuropathy via TRPA1 Stimulation in Mice Dorsal Root Ganglion Is Correlated with Aluminum Accumulation. AB - Oxaliplatin is a platinum-based anticancer drug used to treat metastatic colorectal, breast, and lung cancers. While oxaliplatin kills cancer cells effectively, it exhibits several side effects of varying severity. Neuropathic pain is commonly experienced during treatment with oxaliplatin. Patients describe symptoms of paresthesias or dysesthesias that are triggered by cold (acute neuropathy), or as abnormal sensory or motor function (chronic neuropathy). In particular, we found that aluminum levels were relatively high in some cancer patients suffering from neuropathic pain based on clinical observations. Based on these findings, we hypothesized that aluminum accumulation in the dorsal root ganglion (DRG) in the course of oxaliplatin treatment exacerbates neuropathic pain. In mice injected with oxaliplatin (three cycles of 3 mg/kg i.p. daily for 5 days, followed by 5 days of rest), we detected cold allodynia using the acetone test, but not heat hyperalgesia using a hot plate. However, co-treatment with aluminum chloride (AlCl3?6H2O; 7 mg/kg i.p. for 14 days: equivalent 0.78 mg/kg of elemental Al) and oxaliplatin (1 cycle of 3 mg/kg i.p. daily for 5 days, followed by 5 days of rest) synergistically induced cold allodynia as well as increased TRPAl mRNA and protein expression. Inductively Coupled Plasma Mass Spectrometry (ICP-MS) analysis showed a significant increase in aluminum concentrations in the DRG of mice treated with aluminum chloride and oxaliplatin compared to aluminum chloride alone. Similarly, in a mouse induced-tumor model, aluminum concentrations were increased in DRG tissue and tumor cells after oxaliplatin treatment. Taken together, these findings suggest that aluminum accumulation in the DRG may exacerbate neuropathic pain in oxaliplatin-treated mice. PMID- 25928070 TI - Breast cancer intra-tumor heterogeneity. AB - In recent years it has become clear that cancer cells within a single tumor can display striking morphological, genetic and behavioral variability. Burgeoning genetic, epigenetic and phenomenological data support the existence of intra tumor genetic heterogeneity in breast cancers; however, its basis is yet to be fully defined. Two of the most widely evoked concepts to explain the origin of heterogeneity within tumors are the cancer stem cell hypothesis and the clonal evolution model. Although the cancer stem cell model appeared to provide an explanation for the variability among the neoplastic cells within a given cancer, advances in massively parallel sequencing have provided several lines of evidence to suggest that intra-tumor genetic heterogeneity likely plays a fundamental role in the phenotypic heterogeneity observed in cancers. Many challenges remain, however, in the interpretation of the next generation sequencing results obtained so far. Here we review the models that explain tumor heterogeneity, the causes of intra-tumor genetic diversity and their impact on our understanding and management of breast cancer, methods to study intra-tumor heterogeneity and the assessment of intra-tumor genetic heterogeneity in the clinic. PMID- 25928069 TI - Designer drugs 2015: assessment and management. AB - Recent designer drugs, also known as "legal highs," include substituted cathinones (e.g., mephedrone, methylone, and methylenedioxypyrovalerone, often referred to as "bath salts"); synthetic cannabinoids (SCs; e.g., Spice); and synthetic hallucinogens (25I-NBOMe, or N-bomb). Compound availability has evolved rapidly to evade legal regulation and detection by routine drug testing. Young adults are the primary users, but trends are changing rapidly; use has become popular among members of the military. Acute toxicity is common and often manifests with a constellation of psychiatric and medical effects, which may be severe (e.g., anxiety, agitation, psychosis, and tachycardia), and multiple deaths have been reported with each of these types of designer drugs. Clinicians should keep designer drugs in mind when evaluating substance use in young adults or in anyone presenting with acute neuropsychiatric complaints. Treatment of acute intoxication involves supportive care targeting manifesting signs and symptoms. Long-term treatment of designer drug use disorder can be challenging and is complicated by a lack of evidence to guide treatment. PMID- 25928071 TI - Control of rural house infestation by Triatoma infestans in the Bolivian Chaco using a microencapsulated insecticide formulation. AB - BACKGROUND: Triatoma infestans, the main vector of Trypanosoma cruzi (causative agent of Chagas disease) has been successfully eliminated over much of its original geographic distribution over the southern cone countries of South America. However, populations of the species are still infesting houses of rural communities of the Gran Chaco region of Argentina and Bolivia. This study reports for the first time a large-scale effect of a vector control intervention using a microencapsulated formulation of organophosphates and insect growth regulator on house infestation by T. infestans, in the southwestern region of Santa Cruz de la Sierra Department, within the Bolivian chaco. METHODS: The vector control intervention included the treatment and entomological evaluation of 1626 individually coded and georeferenced houses with the microencapsulated formulation. House infestation by T. infestans was evaluated by active searches with fixed capture effort carried out before and after two, 16 and 32 months of the treatment application. RESULTS: House infestation prevalence was 30.5% before the intervention, spatially aggregated in two clusters of 38 and 25 localities that showed 41% and 38% house infestation by T. infestans. Infestation prevalence was reduced to 2.4% two months after the intervention and remained very low (1.7%) until the end of the study after 32 months of the control intervention, without any other additional vector control intervention. CONCLUSIONS: The obtained results show an important long lasting effect on house protection against triatomine infestation in a region of known pyrethroid resistant populations of T. infestans, as the result of the slow release of the active ingredients, protected by the formulation microcapsule. PMID- 25928072 TI - Long-term-stable near-infrared polymer dots with ultrasmall size and narrow-band emission for imaging tumor vasculature in vivo. AB - Fluorescent nanoprobes have become one of the most promising classes of materials for cancer imaging. However, there remain many unresolved issues with respect to the understanding of their long-term colloidal stability and photostability in both biological systems and the environment. In this study, we report long-term stable near-infrared (NIR) polymer dots for in vivo tumor vasculature imaging. NIR-emitting polymer dots were prepared by encapsulating an NIR dye, silicon 2,3 naphthalocyanine bis(trihexylsilyloxide) (NIR775), into a matrix of polymer dots, poly[2-methoxy-5-(2-ethylhexyloxy)-1,4-phenylenevinylene] (MEH-PPV), using a nanoscale precipitation method. The prepared NIR polymer dots were sub-5 nm in diameter, exhibited narrow-band NIR emission at 778 nm with a full width at half maximum of 20 nm, and displayed a large Stokes shift (>300 nm) between the excitation and emission maxima. In addition, no significant uptake of the prepared NIR polymer dots by either human glioblastoma U87MG cells or human non small cell lung carcinoma H1299 cells was detected. Moreover, these NIR polymer dots showed long-term colloidal stability and photostability in water at 4 degrees C for at least 9 months, and were able to image vasculature of xenografted U87MG tumors in living mice after intravenous injection. These results thus open new opportunities for the development of whole-body imaging of mice based on NIR polymer dots as fluorescent nanoprobes. PMID- 25928073 TI - Probing mechanical properties of Jurkat cells under the effect of ART using oscillating optical tweezers. AB - Acute lymphoid leukemia is a common type of blood cancer and chemotherapy is the initial treatment of choice. Quantifying the effect of a chemotherapeutic drug at the cellular level plays an important role in the process of the treatment. In this study, an oscillating optical tweezer was employed to characterize the frequency-dependent mechanical properties of Jurkat cells exposed to the chemotherapeutic agent, artesunate (ART). A motion equation for a bead bound to a cell was applied to describe the mechanical characteristics of the cell cytoskeleton. By comparing between the modeling results and experimental results from the optical tweezer, the stiffness and viscosity of the Jurkat cells before and after the ART treatment were obtained. The results demonstrate a weak power law dependency of cell stiffness with frequency. Furthermore, the stiffness and viscosity were increased after the treatment. Therefore, the cytoskeleton cell stiffness as the well as power-law coefficient can provide a useful insight into the chemo-mechanical relationship of drug treated cancer cells and may serve as another tool for evaluating therapeutic performance quantitatively. PMID- 25928075 TI - Cervical Cancer Screening in Average-Risk Women: Best Practice Advice From the Clinical Guidelines Committee of the American College of Physicians. AB - DESCRIPTION: The purpose of this best practice advice article is to describe the indications for screening for cervical cancer in asymptomatic, average-risk women aged 21 years or older. METHODS: The evidence reviewed in this work is a distillation of relevant publications (including systematic reviews) used to support current guidelines. BEST PRACTICE ADVICE 1: Clinicians should not screen average-risk women younger than 21 years for cervical cancer. BEST PRACTICE ADVICE 2: Clinicians should start screening average-risk women for cervical cancer at age 21 years once every 3 years with cytology (cytologic tests without human papillomavirus [HPV] tests). BEST PRACTICE ADVICE 3: Clinicians should not screen average-risk women for cervical cancer with cytology more often than once every 3 years. BEST PRACTICE ADVICE 4: Clinicians may use a combination of cytology and HPV testing once every 5 years in average-risk women aged 30 years or older who prefer screening less often than every 3 years. BEST PRACTICE ADVICE 5: Clinicians should not perform HPV testing in average-risk women younger than 30 years. BEST PRACTICE ADVICE 6: Clinicians should stop screening average-risk women older than 65 years for cervical cancer if they have had 3 consecutive negative cytology results or 2 consecutive negative cytology plus HPV test results within 10 years, with the most recent test performed within 5 years. BEST PRACTICE ADVICE 7: Clinicians should not screen average-risk women of any age for cervical cancer if they have had a hysterectomy with removal of the cervix. PMID- 25928076 TI - Oligomerization of Cu,Zn-Superoxide Dismutase (SOD1) by Docosahexaenoic Acid and Its Hydroperoxides In Vitro: Aggregation Dependence on Fatty Acid Unsaturation and Thiols. AB - Docosahexaenoic acid (C22:6, n-3, DHA) is a polyunsaturated fatty acid highly enriched in the brain. This fatty acid can be easily oxidized yielding hydroperoxides as primary products. Cu, Zn-Superoxide dismutase (SOD1) aggregation is a common hallmark of Amyotrophic Lateral Sclerosis (ALS) and the molecular mechanisms behind their formation are not completely understood. Here we investigated the effect of DHA and its hydroperoxides (DHAOOH) on human SOD1 oligomerization in vitro. DHA induced the formation of high-molecular-weight (HMW) SOD1 species (>700 kDa). Aggregation was dependent on free thiols and occurred primarily with the protein in its apo-form. SOD1 incubation with DHA was accompanied by changes in protein structure leading to exposure of protein hydrophobic patches and formation of non-amyloid aggregates. Site-directed mutagenesis studies demonstrated that Cys 6 and Cys 111 in wild-type and Cys 6 in ALS-linked G93A mutant are required for aggregation. In contrast, DHAOOH did not induce HMW species formation but promoted abnormal covalent dimerization of apo SOD1 that was resistant to SDS and thiol reductants. Overall, our data demonstrate that DHA and DHAOOH induce distinct types of apo-SOD1 oligomerization leading to the formation of HMW and low-molecular-weight species, respectively. PMID- 25928077 TI - Screening toll-like receptor markers to predict latent tuberculosis infection and subsequent tuberculosis disease in a Chinese population. AB - BACKGROUND: We investigated whether polymorphisms in the toll-like receptor genes or gene-gene interactions are associated with susceptibility to latent tuberculosis infection (LTBI) or subsequent pulmonary tuberculosis (PTB) in a Chinese population. METHODS: Two matched case-control studies were undertaken. Previously reported polymorphisms in the toll-like receptors (TLRs) were compared between 422 healthy controls (HC) and 205 LTBI patients and between 205 LTBI patients and 109 PTB patients, to assess whether these polymorphisms and their interactions are associated with LTBI or PTB. A PCR-based restriction fragment length polymorphism analysis was used to detect genetic polymorphisms in the TLR genes. Nonparametric multifactor dimensionality reduction (MDR) was used to analyze the effects of interactions between complex disease genes and other genes or environmental factors. RESULTS: Sixteen markers in TLR1, TLR2, TLR4, TLR6, TLR8, TLR9, and TIRAP were detected. In TLR2, the frequencies of the CC genotype (OR = 2.262; 95% CI: 1.433-3.570) and C allele (OR = 1.566; 95% CI: 1.223-1.900) in single-nucleotide polymorphism (SNP) rs3804100 were significantly higher in the LTBI group than in the HC group, whereas the GA genotype of SNP rs5743708 was associated with PTB (OR = 6.087; 95% CI: 1.687-21.968). The frequencies of the GG genotype of SNP rs7873784 in TLR4 (OR = 2.136; 95% CI: 1.312-3.478) and the CC genotype of rs3764879 in TLR8 (OR = 1.982; 95% CI: 1.292-3.042) were also significantly higher in the PTB group than in the HC group. The TC genotype frequency of SNP rs5743836 in TLR9 was significantly higher in the LTBI group than in the HC group (OR = 1.664; 95% CI: 1.201-2.306). An MDR analysis of gene gene and gene-environment interactions identified three SNPs (rs10759932, rs7873784, and rs10759931) that predicted LTBI with 84% accuracy (p = 0.0004) and three SNPs (rs3804100, rs1898830, and rs10759931) that predicted PTB with 80% accuracy (p = 0.0001). CONCLUSIONS: Our results suggest that genetic variation in TLR2, 4, 8 and 9, implicating TLR-related pathways affecting the innate immunity response, modulate LTBI and PTB susceptibility in Chinese. PMID- 25928079 TI - Modelling the contribution of walking between home and school to daily physical activity in primary age children. AB - BACKGROUND: The purpose of this study was to identify the independent association of frequency of walking trips between home and school with daily physical activity in a sample of school-aged children. METHODS: Participants were 109 children (mean age = 12.05 years [+/- 0.71]) attending nine primary schools in Adelaide, South Australia. Physical activity was derived from accelerometers with total counts as the outcome variable. Transport patterns were self-reported for each of the previous five school days. Walking trips were summed for each day and across the school week. The relationship between the number of active transport journeys and individual school day and school week physical activity was modelled separately in boys and girls using multiple linear regression. RESULTS: Frequency of walking was positively associated with school day and school week accelerometer counts in boys, accounting for 6% and 12% of the explained variance in total counts, respectively. There were no significant associations among girls. CONCLUSION: Despite sex-specific differences in associations between active transport to school and total physical activity, active transport is likely to have important ancillary benefits for development of independence and physical activity habits, and should continue to be promoted. PMID- 25928080 TI - Multiple genetic lineages challenge the monospecific status of the West African endemic frog family Odontobatrachidae. AB - BACKGROUND: Correct species identification is crucial in different fields of biology, and in conservation. The endemic West African frog family Odontobatrachidae currently contains a single described species, Odontobatrachus natator. From western Guinea to western Cote d'Ivoire it inhabits forests around waterfalls or cascades. Based on more than 130 specimens from 78 localities, covering the entire distribution, we investigated the molecular diversity of these frogs. RESULTS: Our analyses included mitochondrial and nuclear genes, with a concatenated alignment of 3527 base pairs. We detected high level of genetic differentiation with five distinct lineages or operational taxonomic units (OTUs). These OTUs were also identified by two different species delimitation approaches, Generalized Mixed Yule Coalescent (GMYC) and cluster algorithm. All OTUs occur in parapatry in the Upper Guinean forests. One OTU, assigned to the "true" Odontobatrachus natator, covers the largest distribution, ranging from the border region of western Sierra Leone-Guinea to eastern Liberia. Two OTUs are restricted to western Guinea (Fouta Djallon and foothills), while two others occur in eastern Guinea and the border region of Guinea-Liberia-Cote d'Ivoire. The OTU representing O. natator consists of two divergent subclades: one restricted to the Freetown Peninsula (Sierra Leone) and the other covering all populations further inland. Environmental niche models indicated that the restricted Freetown Peninsula population is separated by unsuitable habitat from remaining populations. CONCLUSION: Geographic isolation of OTUs and molecular differences comparable to species level differentiation in other frog families indicate that O. natator contains cryptic species diversity. Respective distribution patterns most probably resulted from repeated changes of forest cover (contraction and expansion) over evolutionary timescales. The survival within forest refugia that have persisted through multiple drier periods and subsequent dispersal during wetter times may best explain the observed geographic distributions of OTUs. According to the IUCN Red List range criteria each OTU should be classified as "Endangered." If the Freetown Peninsula "natator" population is recognized as a distinct species it would warrant recognition as "Critically Endangered." The identification of cryptic lineages highlights the urgent need to protect these frogs, all of which are endemic to small areas within the Upper Guinean biodiversity hotspot. PMID- 25928082 TI - "Like a lots happened with my whole childhood": violence, trauma, and addiction in pregnant and postpartum women from Vancouver's Downtown Eastside. AB - BACKGROUND: Women living in poor and vulnerable neighbourhoods like Vancouver's Downtown Eastside (DTES) face multiple burdens related to the social determinants of health. Many of them struggle with addiction, are involved in the sex trade and experience homelessness and gender-based violence. Such evidence suggests that psychological trauma is also a common experience for these women. METHODS: The purpose of this qualitative study was to explore themes and subjective perspectives of trauma and gender-based violence in women who lived in an impoverished neighbourhood and struggled with substance use during pregnancy and early motherhood. We interviewed 27 individuals accessing harm reduction services for pregnant and postpartum women in Vancouver, Canada. RESULTS: Key themes that emerged from these women's narratives highlighted the ubiquity of multiple and continuing forms of adversities and trauma from childhood to adulthood, in a variety of contexts, through a variety of offenders and on multiple levels. Both individual and environmental/structural conditions mutually intensified each other, interfering with a natural resolution of trauma-related symptoms and substance use. Women were also concerned that trauma could be passed on from one generation to the next, yet expressed hesitation when asked about their interest in trauma-specific counselling. CONCLUSIONS: In offering harm reduction services for poor and marginalized women, it is clear that an understanding of trauma must be integrated. It is recommended that service providers integrate trauma-informed care into their programme in order to offer this service in a trusted environment. However, it is also necessary to shift the focus from the individual to include environmental, social, economic and policy interventions on multiple levels and from issues of drug use and reduction of drug-related harms to include issues of gendered vulnerabilities and human rights. PMID- 25928084 TI - Systems biology analysis reveals NFAT5 as a novel biomarker and master regulator of inflammatory breast cancer. AB - BACKGROUND: Inflammatory breast cancer (IBC) is the most rare and aggressive variant of breast cancer (BC); however, only a limited number of specific gene signatures with low generalization abilities are available and few reliable biomarkers are helpful to improve IBC classification into a molecularly distinct phenotype. We applied a network-based strategy to gain insight into master regulators (MRs) linked to IBC pathogenesis. METHODS: In-silico modeling and Algorithm for the Reconstruction of Accurate Cellular Networks (ARACNe) on IBC/non-IBC (nIBC) gene expression data (n = 197) was employed to identify novel master regulators connected to the IBC phenotype. Pathway enrichment analysis was used to characterize predicted targets of candidate genes. The expression pattern of the most significant MRs was then evaluated by immunohistochemistry (IHC) in two independent cohorts of IBCs (n = 39) and nIBCs (n = 82) and normal breast tissues (n = 15) spotted on tissue microarrays. The staining pattern of non neoplastic mammary epithelial cells was used as a normal control. RESULTS: Using in-silico modeling of network-based strategy, we identified three top enriched MRs (NFAT5, CTNNB1 or beta-catenin, and MGA) strongly linked to the IBC phenotype. By IHC assays, we found that IBC patients displayed a higher number of NFAT5-positive cases than nIBC (69.2% vs. 19.5%; p-value = 2.79 10(-7)). Accordingly, the majority of NFAT5-positive IBC samples revealed an aberrant nuclear expression in comparison with nIBC samples (70% vs. 12.5%; p-value = 0.000797). NFAT5 nuclear accumulation occurs regardless of WNT/beta-catenin activated signaling in a substantial portion of IBCs, suggesting that NFAT5 pathway activation may have a relevant role in IBC pathogenesis. Accordingly, cytoplasmic NFAT5 and membranous beta-catenin expression were preferentially linked to nIBC, accounting for the better prognosis of this phenotype. CONCLUSIONS: We provide evidence that NFAT-signaling pathway activation could help to identify aggressive forms of BC and potentially be a guide to assignment of phenotype-specific therapeutic agents. The NFAT5 transcription factor might be developed into routine clinical practice as a putative biomarker of IBC phenotype. PMID- 25928087 TI - Phosphorylation propels p31(comet) for mitotic exit. PMID- 25928085 TI - Determinants of women's satisfaction with maternal health care: a review of literature from developing countries. AB - BACKGROUND: Developing countries account for 99 percent of maternal deaths annually. While increasing service availability and maintaining acceptable quality standards, it is important to assess maternal satisfaction with care in order to make it more responsive and culturally acceptable, ultimately leading to enhanced utilization and improved outcomes. At a time when global efforts to reduce maternal mortality have been stepped up, maternal satisfaction and its determinants also need to be addressed by developing country governments. This review seeks to identify determinants of women's satisfaction with maternity care in developing countries. METHODS: The review followed the methodology of systematic reviews. Public health and social science databases were searched. English articles covering antenatal, intrapartum or postpartum care, for either home or institutional deliveries, reporting maternal satisfaction from developing countries (World Bank list) were included, with no year limit. Out of 154 shortlisted abstracts, 54 were included and 100 excluded. Studies were extracted onto structured formats and analyzed using the narrative synthesis approach. RESULTS: Determinants of maternal satisfaction covered all dimensions of care across structure, process and outcome. Structural elements included good physical environment, cleanliness, and availability of adequate human resources, medicines and supplies. Process determinants included interpersonal behavior, privacy, promptness, cognitive care, perceived provider competency and emotional support. Outcome related determinants were health status of the mother and newborn. Access, cost, socio-economic status and reproductive history also influenced perceived maternal satisfaction. Process of care dominated the determinants of maternal satisfaction in developing countries. Interpersonal behavior was the most widely reported determinant, with the largest body of evidence generated around provider behavior in terms of courtesy and non-abuse. Other aspects of interpersonal behavior included therapeutic communication, staff confidence and competence and encouragement to laboring women. CONCLUSIONS: Quality improvement efforts in developing countries could focus on strengthening the process of care. Special attention is needed to improve interpersonal behavior, as evidence from the review points to the importance women attach to being treated respectfully, irrespective of socio-cultural or economic context. Further research on maternal satisfaction is required on home deliveries and relative strength of various determinants in influencing maternal satisfaction. PMID- 25928088 TI - Maternal obesity disrupts circadian rhythms of clock and metabolic genes in the offspring heart and liver. AB - Early life nutritional adversity is tightly associated with the development of long-term metabolic disorders. Particularly, maternal obesity and high-fat diets cause high risk of obesity in the offspring. Those offspring are also prone to develop hyperinsulinemia, hepatic steatosis and cardiovascular diseases. However, the precise underlying mechanisms leading to these metabolic dysregulation in the offspring remain unclear. On the other hand, disruptions of diurnal circadian rhythms are known to impair metabolic homeostasis in various tissues including the heart and liver. Therefore, we investigated that whether maternal obesity perturbs the circadian expression rhythms of clock, metabolic and inflammatory genes in offspring heart and liver by using RT-qPCR and Western blotting analysis. Offspring from lean and obese dams were examined on postnatal day 17 and 35, when pups were nursed by their mothers or took food independently. On P17, genes examined in the heart either showed anti-phase oscillations (Cpt1b, Pparalpha, Per2) or had greater oscillation amplitudes (Bmal1, Tnf-alpha, Il-6). Such phase abnormalities of these genes were improved on P35, while defects in amplitudes still existed. In the liver of 17-day-old pups exposed to maternal obesity, the oscillation amplitudes of most rhythmic genes examined (except Bmal1) were strongly suppressed. On P35, the oscillations of circadian and inflammatory genes became more robust in the liver, while metabolic genes were still kept non-rhythmic. Maternal obesity also had a profound influence in the protein expression levels of examined genes in offspring heart and liver. Our observations indicate that the circadian clock undergoes nutritional programing, which may contribute to the alternations in energy metabolism associated with the development of metabolic disorders in early life and adulthood. PMID- 25928091 TI - A comparative study of caregivers' perceptions of health-care needs and burden of patients with bipolar affective disorder and schizophrenia. AB - BACKGROUND: Although many studies in schizophrenia have evaluated health-care needs, there is a lack of data on the needs of patients with bipolar affective disorder (BPAD), with only occasional studies evaluating them, and no study has evaluated the relationship of health-care needs of patients with caregiver's burden. AIM: To study the relationship of caregiver's burden and needs of patients as perceived by caregivers of patients with BPAD and schizophrenia. METHOD: Caregivers of patients with BPAD and schizophrenia were assessed using the Camberwell Assessment of Needs - Research version (CAN-R) and Supplementary Needs Assessment Scale (SNAS), the Family Burden Interview schedule (FBI) and the Involvement Evaluation Questionnaire (IEQ). RESULTS: Mean total needs of patients on CAN-R were 7.54 (SD 3.59) and 7.58 (SD 4.24) for BPAD and schizophrenia respectively. Mean total needs for SNAS were 7.24 (SD 3.67) and 7.68 (SD 5.02) for BPAD and schizophrenia groups, respectively. Total objective and subjective burden as assessed on FBI was significantly more for the schizophrenia group. Caregivers of patients with BPAD perceived significantly less disruption of routine family activities and lower impact on the mental health of others. On IEQ, the mean score on the domain of supervision was significantly higher for the BPAD group. In the schizophrenia group, positive correlations were seen between the total number of unmet and total (met and unmet) needs and certain aspects of burden, but no such correlations emerged in the BPAD group. CONCLUSION: There is no correlation between number of needs and burden in the BPAD group; however, in the schizophrenia group the number of needs correlated with the perceived burden. Accordingly, orienting services to address needs of patients with schizophrenia can lead to reduction in burden among caregivers. PMID- 25928092 TI - Alcohol use in young indigenous Sami in Sweden. AB - BACKGROUND: Evidence suggests socially disadvantaged people or those who live in socially disadvantaged areas experience more harm per gram of alcohol consumed than people with greater social advantages. In the Sami group, probable associations between alcohol use and several areas of health have been explored, but there are no studies regarding the drinking habits of young Sami in Sweden. AIMS: To investigate alcohol use in young Sami in Sweden, and in a reference group from the general young Swedish population in the same area; to evaluate likely associations between gender, education, family situation and alcohol use. METHODS: The Alcohol Use Disorder Identification Test was used in a cross sectional study comprising 516 Sami (18-28 years), and a reference group (18-29 years, n = 218). RESULTS: No significant differences in hazardous/harmful alcohol drinking in young Sami and Swedes were found. Nearly half the men and ~35% of the women reported risky alcohol use. Gender differences were reported only in the Sami. Sami men had 1.6 times higher odds of hazardous/harmful drinking compared to Sami women. Only in the Sami were lower education levels associated with higher odds of hazardous/harmful drinking. Experiences of "often forgetting important things", seldom "looking forward with joy", and self-perceived ethnicity-related negative treatment were associated with hazardous/harmful drinking. CONCLUSIONS: Although alcohol use in young Sami appears to be similar to alcohol use in young non-Sami Swedes, important risk factors for hazardous/harmful drinking are identified, e.g. ethnicity-related negative treatment. These should be taken into account when planning for preventive interventions. PMID- 25928089 TI - Regulation of the inflammatory profile of stromal cells in human breast cancer: prominent roles for TNF-alpha and the NF-kappaB pathway. AB - INTRODUCTION: Breast cancer progression is promoted by stromal cells that populate the tumors, including cancer-associated fibroblasts (CAFs) and mesenchymal stem/stromal cells (MSCs). The activities of CAFs and MSCs in breast cancer are integrated within an intimate inflammatory tumor microenvironment (TME) that includes high levels of tumor necrosis factor alpha (TNF-alpha) and interleukin 1beta (IL-1beta). Here, we identified the impact of TNF-alpha and IL 1beta on the inflammatory phenotype of CAFs and MSCs by determining the expression of inflammatory chemokines that are well-characterized as pro tumorigenic in breast cancer: CCL2 (MCP-1), CXCL8 (IL-8) and CCL5 (RANTES). METHODS: Chemokine expression was determined in breast cancer patient-derived CAFs by ELISA and in patient biopsies by immunohistochemistry. Chemokine levels were determined by ELISA in (1) human bone marrow-derived MSCs stimulated by tumor conditioned media (Tumor CM) of breast tumor cells (MDA-MB-231 and MCF-7) at the end of MSC-to-CAF-conversion process; (2) Tumor CM-derived CAFs, patient CAFs and MSCs stimulated by TNF-alpha (and IL-1beta). The roles of AP-1 and NF kappaB in chemokine secretion were analyzed by Western blotting and by siRNAs to c-Jun and p65, respectively. Migration of monocytic cells was determined in modified Boyden chambers. RESULTS: TNF-alpha (and IL-1beta) induced the release of CCL2, CXCL8 and CCL5 by MSCs and CAFs generated by prolonged stimulation of MSCs with Tumor CM of MDA-MB-231 and MCF-7 cells. Patient-derived CAFs expressed CCL2 and CXCL8, and secreted CCL5 following TNF-alpha (and IL-1beta) stimulation. CCL2 was expressed in CAFs residing in proximity to breast tumor cells in biopsies of patients diagnosed with invasive ductal carcinoma. CCL2 release by TNF-alpha-stimulated MSCs was mediated by TNF-RI and TNF-RII, through the NF kappaB but not via the AP-1 pathway. Exposure of MSCs to TNF-alpha led to potent CCL2-induced migration of monocytic cells, a process that may yield pro-cancerous myeloid infiltrates in breast tumors. CONCLUSIONS: Our novel results emphasize the important roles of inflammation-stroma interactions in breast cancer, and suggest that NF-kappaB may be a potential target for inhibition in tumor-adjacent stromal cells, enabling improved tumor control in inflammation-driven malignancies. PMID- 25928095 TI - 3D intra-stacked CoO/carbon nanocomposites welded by Ag nanoparticles for high capacity, reversible lithium storage. AB - A wet-chemical, facile strategy is proposed for forming three-dimensional intra structured nanocomposites to facilitate the development of high performance anodes for lithium ion batteries. The nanocomposites are composed of cobalt oxide nanoparticles, reduced graphene oxides, and Ag nanoparticles, and all the constituent materials are incorporated homogenously in a layer-by-layer structured geometry by a simple sono-chemical hybridizing process in a single, one-pot batch. Herein, it is revealed that the homogenously intra-stacked oxide, carbon, and metallic phases play critical roles in determining electrochemical performance (i.e. high capacity, rate capability, and cycling stability) of nanocomposite-based anodes, owing to the characteristic chemical/physical nature of constituent materials welded by partial melting of the metallic nanoparticles. In particular, by virtue of a characteristic role of a nano-Ag phase in suppressing the irreversible capacity, a critical drawback for metal oxide-based anodes, excellent capacities are demonstrated (983 and 770 mA h g(-1) at current densities of 100 and 2000 mA g(-1), respectively). PMID- 25928094 TI - Simulation of alcohol action upon a detailed Purkinje neuron model and a simpler surrogate model that runs >400 times faster. AB - BACKGROUND: An approach to investigate brain function/dysfunction is to simulate neuron circuits on a computer. A problem, however, is that detailed neuron descriptions are computationally expensive and this handicaps the pursuit of realistic network investigations, where many neurons need to be simulated. RESULTS: We confront this issue; we employ a novel reduction algorithm to produce a 2 compartment model of the cerebellar Purkinje neuron from a previously published, 1089 compartment model. It runs more than 400 times faster and retains the electrical behavior of the full model. So, it is more suitable for inclusion in large network models, where computational power is a limiting issue. We show the utility of this reduced model by demonstrating that it can replicate the full model's response to alcohol, which can in turn reproduce experimental recordings from Purkinje neurons following alcohol application. CONCLUSIONS: We show that alcohol may modulate Purkinje neuron firing by an inhibition of their sodium potassium pumps. We suggest that this action, upon cerebellar Purkinje neurons, is how alcohol ingestion can corrupt motor co-ordination. In this way, we relate events on the molecular scale to the level of behavior. PMID- 25928096 TI - Characterization of 46 patient-specific BCR-ABL1 fusions and detection of SNPs upstream and downstream the breakpoints in chronic myeloid leukemia using next generation sequencing. AB - In chronic myeloid leukemia, the identification of individual BCR-ABL1 fusions is required for the development of personalized medicine approach for minimal residual disease monitoring at the DNA level. Next generation sequencing (NGS) of amplicons larger than 1000 bp simplified and accelerated a process of characterization of patient-specific BCR-ABL1 genomic fusions. NGS of large regions upstream and downstream the individual breakpoints in BCR and ABL1 genes, respectively, also provided information about the sequence variants such are single nucleotide polymorphisms. PMID- 25928097 TI - Economic consequences of ill-health for households in northern rural India. AB - BACKGROUND: As compared to other countries in South East Asia, India's health care system is characterized by very high out of pocket payments, and consequently low financial protection and access to care. This paper describes the relative importance of ill-health compared to other adverse events, the conduits through which ill-health affects household welfare and the coping strategies used to finance these expenses. METHODS: Cross-sectional data are used from a survey conducted with 5241 households in Uttar Pradesh and Bihar in 2010 that included a household shocks module and detailed information about health care use and spending. RESULTS: Health-related adverse events were the second most common adverse events (34%), after natural disasters (51%). Crop and livestock disease and weddings each affected about 8% of households. Only a fourth of households reported to have recovered from illness and/or death in the family (by the time of the survey). Most of the households' economic burden related to ill-health was depending on direct medical costs, but indirect costs (such as lost earnings and transportation or food costs) were also not negligible. Close to half of the health expenditures were made for chronic conditions. Households tried to cope with health-related expenditures mostly by dissaving, borrowing and selling assets. Few households reported having to reduce (food) consumption in response to ill-health. CONCLUSIONS: In the absence of pre financing schemes, ill-health events pose a substantial threat to household welfare in rural India. While most households seem to be able to smooth consumption in the short term, coping strategies like selling assets and borrowing from moneylenders are likely to have severe long term consequences. As most of the households' economic risk related to ill-health appears to depend on out of pocket spending, introducing health insurance may contribute significantly to alleviate economic hardship for families in rural India. The importance of care for chronic diseases, however, represents a big challenge for the sustainability of community based health insurance schemes, since it is necessary to ensure a sufficient degree of risk pooling. PMID- 25928098 TI - Genomic best linear unbiased prediction method including imprinting effects for genomic evaluation. AB - BACKGROUND: Genomic best linear unbiased prediction (GBLUP) is a statistical method used to predict breeding values using single nucleotide polymorphisms for selection in animal and plant breeding. Genetic effects are often modeled as additively acting marker allele effects. However, the actual mode of biological action can differ from this assumption. Many livestock traits exhibit genomic imprinting, which may substantially contribute to the total genetic variation of quantitative traits. Here, we present two statistical models of GBLUP including imprinting effects (GBLUP-I) on the basis of genotypic values (GBLUP-I1) and gametic values (GBLUP-I2). The performance of these models for the estimation of variance components and prediction of genetic values across a range of genetic variations was evaluated in simulations. RESULTS: Estimates of total genetic variances and residual variances with GBLUP-I1 and GBLUP-I2 were close to the true values and the regression coefficients of total genetic values on their estimates were close to 1. Accuracies of estimated total genetic values in both GBLUP-I methods increased with increasing degree of imprinting and broad-sense heritability. When the imprinting variances were equal to 1.4% to 6.0% of the phenotypic variances, the accuracies of estimated total genetic values with GBLUP I1 exceeded those with GBLUP by 1.4% to 7.8%. In comparison with GBLUP-I1, the superiority of GBLUP-I2 over GBLUP depended strongly on degree of imprinting and difference in genetic values between paternal and maternal alleles. When paternal and maternal alleles were predicted (phasing accuracy was equal to 0.979), accuracies of the estimated total genetic values in GBLUP-I1 and GBLUP-I2 were 1.7% and 1.2% lower than when paternal and maternal alleles were known. CONCLUSIONS: This simulation study shows that GBLUP-I1 and GBLUP-I2 can accurately estimate total genetic variance and perform well for the prediction of total genetic values. GBLUP-I1 is preferred for genomic evaluation, while GBLUP I2 is preferred when the imprinting effects are large, and the genetic effects differ substantially between sexes. PMID- 25928099 TI - Cover Lines Using Positive, Urgent, Unique Language Entice Moms to Read Health Communications. AB - Crafting messages that capture consumer interest is a frequent challenge of health communicators. A better understanding of the techniques magazine editors use to create cover lines may aid health communicators in their efforts to arouse interest in their communiques. This study (a) content-analyzed magazine cover lines, (b) used content analysis findings to create health-related cover lines, and (c) assessed the degree to which the health-related cover lines fostered motivation to read the health communication. Cover lines (N = 867) from 11 magazines published in 2012 frequently read by mothers of young children used a variety of themes, with those focusing on informative/how-to, control/improve, and unique/special being most common. Health communication experts used key descriptor terms corresponding to each theme and wrote 310 cover lines for topics focusing on childhood obesity prevention strategies. Unpaired t tests revealed that mothers of young children (N = 77) reported they were significantly (p < .05) more motivated to read a short, health-related magazine article when cover lines had a happiness/fun, unique/special, or quick/urgency theme and were significantly less motivated to read when cover lines used a control/improve theme. Study findings may help health communicators create cover lines that better attract reader attention. PMID- 25928106 TI - Kikuchi-Fujimoto lymphadenitis imitating metastatic melanoma on positron emission tomography: a case report. AB - BACKGROUND: Accurate staging is critical for decision-making for the treatment of malignant conditions. Fluoro-deoxy-glucose positron emission tomography-computed tomography (FDG PET-CT) is a highly sensitive imaging modality for the assessment of distant metastases; however false positive results are possible due to its lower specificity with detection of other hypermetabolic pathologies. CASE PRESENTATION: A patient with high-risk thigh melanoma was staged with FDG PET-CT. Four ipsilateral inguinal nodes (three superficial, one deep) demonstrated intense hypermetabolic activity. Metastatic melanoma was confirmed in the largest superficial inguinal node with ultrasound-guided fine needle aspiration. Histopathology demonstrated metastatic melanoma in one superficial node and histiocytic necrotizing lymphadenitis, also known as Kikuchi-Fujimoto disease in five deep inguinal nodes. CONCLUSION: This case illustrates a false positive FDG PET-CT due to coincidental, synchronous melanoma and Kikuchi-Fujimoto disease in the same draining lymph node basin. PMID- 25928107 TI - Cost analysis of youth clinic network in Estonia. AB - BACKGROUND: Youth-friendly sexual and reproductive health (YFSRH) services for young people have high priority in many countries. Yet, little is known about the actual cost of delivering YFSRH services. This article analyses costs of a fully scaled up national youth clinic network (YCN) in Estonia. It reports; 1) total budget of the YCN during the period 2002-2012, and 2) annual clinic level costs of three youth clinics (YCs) in 2012. METHODS: The retrospective cost analysis is based on financial and medical records of Estonian Health Insurance Fund (EHIF), Estonian Sexual Health Association (ESHA), National Institute for Health Development and the YCs. The programme level costs are analysed per year, financing source and a portion spent on coordination in 2002-2012. Costs of three YCs are analysed per clinic, expense category, patient and healthcare service in 2012. RESULTS: The total budget of the YCN was ?8.38 million and it served 304,000 young patients in 2002-2012. 95% of the total budget was financed by the EHIF. 3.6% was spent on coordination. The YCs in Tallinn, Tartu and Ida-Virumaa had annual budgets of ?247,000, ?267,000 and ?42,000 respectively. In 2012 the three YCs provided YFSRH services to 19,700 patients, excluding sexuality education lessons and internet counselling. The YFSRH services cost ?543,000. Consequently, the average cost per patient was ?27.76. The largest expense categories were personnel salaries 35% and medical supplies 33%. Cost of the YFSRH services were; STI consultation ?54.80, SRH counselling ?13.13, contraception consultation ?9.32, internet counselling ?8.21 and sexuality education lesson ?1.52. CONCLUSIONS: The Estonian YCN is a positive example for other countries considering or already implementing similar programmes. The cost analyses highlighted the following: Sustainable funding is particularly important, without it the YFSRH services would not have been scaled up and sustained on the national level in Estonia. Investment in professional coordination of the YFSRH services is recommended, and it does not necessarily have to be expensive. Only 3.6% of the total budget of YCN was used for ESHA coordination, which is a small portion especially when taking into account ESHA's substantial contributions to development, training, quality improvements and representation of the YCN. PMID- 25928108 TI - Flipped polyelectrolyte multilayer films: accessing the buried interface. AB - Little is known concerning the interface between a polyelectrolyte multilayer, PEMU, and its substrate. Recent models suggest that excess polymer charge, compensated by counterions, remains buried within the PEMU, especially for thicker films having a nonlinear component to their growth. We report a novel approach for making free-standing multilayers of poly(diallyldimethylammonium) (PDADMA) and poly(styrenesulfonate) (PSS): after assembly on aluminum substrates, films were released by brief immersion in aqueous alkali. The multilayers were then flipped, allowing access to the initially buried substrate/PEMU interface. Experiments were performed to show that this method of release, one of many established for PEMUs, perturbed the surface and bulk of the film minimally. Film/solution and film/substrate interfaces were compared using atomic force microscopy (AFM) and X-ray photoelectron spectroscopy (XPS). AFM was used to record topography and perform nanoindentation, while XPS provided surface elemental composition. All three methods revealed data consistent with an excess of PDADMA at the buried interface. This excess PDADMA was then complexed with additional PSS to yield "nanosandwiches" of nonstoichiometric PEMU between layers of stoichiometric PEMU. PMID- 25928110 TI - A novel albumin nanocomplex containing both small interfering RNA and gold nanorods for synergetic anticancer therapy. AB - Therapeutic nanocomplexes have been extensively developed for the effective treatment of aggressive cancers because of their outstanding versatility, easy manipulation, and low cytotoxicity. In this study, we describe the synthesis of a novel bovine serum albumin (BSA)-based nanocomplex harboring both Bcl-2-specific small interfering RNA (siRNA) and gold (Au) nanorods (siRNA and rods encapsulated in BSA; SREB) with the aim of developing a targeted breast cancer therapeutic. The SREB complexes contained 2 * 10(5) siRNA molecules and eight Au nanorods per BSA complex and were successively functionalized with polyethylene glycol (PEG) and anti-ErbB-2 antibodies to facilitate active targeting. The synergetic therapeutic activity originating from the two components effectively induced cell death (~80% reduction in viability compared with control cells) in target breast cancer cells after a single dose of laser irradiation. Intracellular SREB nanocomplex decomposition by proteolytic enzymes resulted in simultaneous RNA interference and thermal ablation, thus leading to apoptosis in the targeted cancer cells. Moreover, these therapeutic effects were sustained for approximately 72 hours. The intrinsic biocompatibility, multifunctionality, and potent in vitro anticancer properties of these SREB nanocomplexes indicate that they have great therapeutic potential for in vivo targeted cancer therapy, in addition to other areas of nanomedicine. PMID- 25928112 TI - Short-range guiding can result in the formation of circular aggregates in myxobacteria populations. AB - Myxobacteria are social bacteria that upon starvation form multicellular fruiting bodies whose shape in different species can range from simple mounds to elaborate tree-like structures. The formation of fruiting bodies is a result of collective cell movement on a solid surface. In the course of development, groups of flexible rod-shaped cells form streams and move in circular or spiral patterns to form aggregation centers that can become sites of fruiting body formation. The mechanisms of such cell movement patterns are not well understood. It has been suggested that myxobacterial development depends on short-range contact-mediated interactions between individual cells, i.e. cell aggregation does not require long-range signaling in the population. In this study, by means of a computational mass-spring model, we investigate what types of short-range interactions between cells can result in the formation of streams and circular aggregates during myxobacterial development. We consider short-range head-to-tail guiding between individual cells, whereby movement direction of the head of one cell is affected by the nearby presence of the tail of another cell. We demonstrate that stable streams and circular aggregates can arise only when the trailing cell, in addition to being steered by the tail of the leading cell, is able to speed up to catch up with it. It is suggested that necessary head-to-tail interactions between cells can arise from physical adhesion, response to a diffusible substance or slime extruded by cells, or pulling by motility engine pili. Finally, we consider a case of long-range guiding between cells and show that circular aggregates are able to form without cells increasing speed. These findings present a possibility to discriminate between short-range and long-range guiding mechanisms in myxobacteria by experimentally measuring distribution of cell speeds in circular aggregates. PMID- 25928113 TI - Case report: Anesthesia management for emergency cesarean section in a patient with dwarfism. AB - BACKGROUND: Dwarfism is characterized by short stature. Pregnancy in women with dwarfism is uncommon and cesarean section is generally indicated for delivery. Patients with dwarfism are high-risk population for both general and regional anesthesia, let alone in an emergency surgery. CASE PRESENTATION: In this case report we present a 27-year-old Chinese puerpera with dwarfism who underwent emergency cesarean section under combined spinal and epidural anesthesia. CONCLUSION: It is an original case report, which provides instructive significance for anesthesia management especially combined spinal and epidural anesthesia in this rare condition. There was only one former article that reported a puerpera who underwent combined spinal and epidural anesthesia for a selective cesarean section. PMID- 25928115 TI - Retinal vessels change in primary angle-closure glaucoma: the Handan Eye Study. AB - Glaucoma is the second leading cause of blindness worldwide. To examine the relationship between angle closure and the retinal vessel diameter in Chinese adults, we conducted Handan Eye Study (HES), a large population-based cross sectional study, which enrolled 6830 participants >30 year-old living in 13 randomly selected villages of Yongnian County. After adjusting for age, gender, spherical equivalent (SE), diabetes, and hypertension, the mean central retinal artery equivalent (CRAE, MUm) was 127.1 +/- 7.0 and 145.6 +/- 4.4 in primary open angle glaucoma (POAG) and primary angle closure glaucoma (PACG), respectively; narrower than that in normal control (156.1 +/- 0.4), primary angle-closure suspect (PACS) (156.3 +/- 1.1) or primary angle closure (PAC) (156.0 +/- 3.4) (P = 0.001). The mean central retinal vein equivalent (CRVE, MUm) was 229.0 +/- 5.9 and 215.8 +/- 9.5 in POAG and PACG, respectively; narrower than that in normal control (238.3 +/- 0.5), PACS (241.2 +/- 1.4) or PAC (242.2 +/- 4.6) (P = 0.001). There was no significant difference in the mean CRAE or CRVE between PACG and POAG. Compared to the normal control (0.66), the mean arterio-venous ratio (AVR) was smaller in POAG (0.64) and PACG (0.59), whereas larger in PACS (0.65) and PAC (0.67) (P = 0.003). To conclude, PACG and POAG individuals have narrower retinal arteries and veins. PMID- 25928117 TI - Persistence of chloroquine-resistant haplotypes of Plasmodium falciparum in children with uncomplicated Malaria in Lagos, Nigeria, four years after change of chloroquine as first-line antimalarial medicine. AB - BACKGROUND: In Nigeria, despite the change in National malaria drug policy to artemisinin combination therapy (ACT) in 2005 due to widespread chloroquine resistance, chloroquine (CQ) is still widely used in the treatment of malaria because it is cheap, affordable and accessible. The use of ACT for the management of uncomplicated malaria is currently being promoted. The employment of genetic markers to track circulating chloroquine-resistant parasites are useful in elucidating likely poor efficacy of chloroquine, especially in settings where it is not recommended for the treatment of uncomplicated falciparum malaria. This study determined the prevalence of pfcrt haplotypes and point mutations in pfmdr1 genes four years after the change in antimalarial treatment policy from CQ to the ACTs in Lagos, a commercial city in South-West, Nigeria. METHODS: This was a cross sectional study on uncomplicated malaria in children less than 12 years that presented with fever and other symptoms suggestive of malaria. Parasite DNA was extracted from 119 patients out of 251 children who were positive for Plasmodium falciparum by microscopy and amplified. The occurrence of haplotypes was investigated in pfcrt gene using probe-based qPCR and single nucleotide polymorphisms in pfmdr1 gene using nested PCR. RESULTS: One hundred and nine (109) of the 119 children with P falciparum infection (91.6%) harbourd parasites with the mutant pfcrt haplotype (CVIET). Out of this, 4.2% comprised a mixture of genotypes encoding CVMNK and CVIET, while 4.2% had the wild type (CVMNK). Furthermore, the frequency of point mutations in pfmdr1 was 62.2% and 69.0% for codons Y86 and F184 respectively. There were no mutations at codons 1034, 1042 and 1246 of the Pfmdr1 genes. CONCLUSION: The high frequency of the CQ-resistant haplotypes (CVIET) and mutations in Pfmdr1 associated with CQ resistance in P. falciparum among these children suggest that CQ-resistant parasites are still in circulation. Continuous use of chloroquine may continue to increase the level of mutations in pfcrt and pfmdr1genes. There is need to strengthen current case management efforts at promoting ACT use as well as urgently restricting access to chloroquine by the National drug regulatory agency, National Agency for Food Drug Administration and Control (NAFDAC). VIRTUAL SLIDES: The virtual slide(s) for this article can be found here: http://www.diagnosticpathology.diagnomx.eu/vs/2069472010142303. PMID- 25928118 TI - A phase II clinical trial of weekly paclitaxel and carboplatin in combination with panitumumab in metastatic triple negative breast cancer. AB - PURPOSE: Women with metastatic triple negative breast cancer (TNBC) can have a poor prognosis with treatment limited to cytotoxic chemotherapy. The identification of effective therapies that may limit exposure to cytotoxic chemotherapy and lead to prolonged survival is an unmet medical need. We tested an inhibitor of the epidermal growth factor receptor, panitumumab in combination with chemotherapy. METHODS: We conducted a single arm clinical trial in women with metastatic or locally advanced TNBC to paclitaxel 80 mg/m2 and carboplatin AUC of 2 on days 1, 8, and 15 and panitumumab 6 mg/kg on days 1 and 15 for a cycle length of 28 days. The objectives were to evaluate the response rate and safety of the combination in comparison to historical controls. RESULTS: Fourteen patients with TNBC were enrolled with a median age of 53 years. The majority of women were African American (64.3%) with visceral metastasis (64.2%). Hematologic toxicities, particularly neutropenia and thrombocytopenia, were a major cause of missed chemotherapy and delayed treatment in this study. The overall response rate (complete and partial response) of the 13 evaluable patients was 46%. The median time to best response was 2.4 months and the median time to disease progression was 3.6 months. We were able to perform the PAM50 analysis on tumors from 7 of our subjects. All the samples tested clustered within the basal-like subtype. CONCLUSIONS: In our experience the response rate of carboplatin, paclitaxel and panitumumab was consistent with other reports of response for cytotoxic chemotherapy in metastatic TNBC. PMID- 25928119 TI - Percutaneous ethanol injection vs reoperation for locally recurrent papillary thyroid cancer: a systematic review and pooled analysis. AB - IMPORTANCE: Reoperation for recurrent papillary thyroid cancer (PTC) can be associated with a high rate of complications and failure to provide lasting remission. Percutaneous ethanol injection (PEI) may be an effective nonsurgical management option for locally recurrent PTC. OBJECTIVE: This systematic analysis of the current literature compares the efficacy and complications related to PEI vs reoperative surgical intervention for treatment of locally recurrent PTC. DATA SOURCES: Original studies were identified using the keywords "thyroid/ethanol" and "recurrent thyroid cancer/repeat surgery." STUDY SELECTION: Studies evaluating reoperation or PEI for lymph node metastases in patients with primary surgery of total thyroidectomy with appropriate lymph node dissection where indicated were included in the analysis for both reoperation and PEI. Animal studies, single case reports, and studies with fewer than 10 lesions were excluded. DATA EXTRACTION AND SYNTHESIS: Outcomes included interval to detection of recurrence, success and failure rates, recurrence rates, complication rates, and follow-up duration. Between-group outcome differences were calculated using random-effects models, and pooled data cross-tabulation and logistic regression analysis were used. RESULTS: In all, 945 publications were identified, and 27 studies met the inclusion criteria. There were no studies that directly compared the 2 treatment techniques. A total of 1617 patients were included in this analysis; 168 (11.4%) were treated with PEI, and 1449 (88.6%) were treated with reoperation. Reoperation was successful in 94.8% of cases compared with an 87.5% success rate for PEI (odds ratio [OR], 2.58; 95% CI, 1.55-4.31; P < .001). The recurrence rates for PEI and reoperation at the site of the treated lesion or elsewhere in the neck were also similar (OR, 1.07; 95% CI, 0.65-1.77; P = .78). Reoperation was associated with a 3.5% pooled risk of complications, while PEI incurred a pooled risk of 1.2% (OR, 2.9; 95% CI, 0.72-12.3; P = .08). However, most studies did not report routine preoperative and postoperative laryngoscopies, an evaluation needed for accurate neural complication analysis associated with each procedure. CONCLUSIONS AND RELEVANCE: High-quality, well designed studies are needed to evaluate the feasibility of incorporating PEI into the treatment protocol of PTC. Although presently inferior to reoperation, PEI has the potential to be a widely accepted and effective nonsurgical treatment option for limited recurrent PTC in poor surgical candidates or patients seeking to avoid multiple reoperations. PMID- 25928122 TI - Clinical evaluation of commercial nucleic acid amplification tests in patients with suspected sepsis. AB - BACKGROUND: Sepsis is a serious medical condition requiring timely administered, appropriate antibiotic therapy. Blood culture is regarded as the gold standard for aetiological diagnosis of sepsis, but it suffers from low sensitivity and long turnaround time. Thus, nucleic acid amplification tests (NAATs) have emerged to shorten the time to identification of causative microbes. The aim of the present study was to evaluate the clinical utility in everyday practice in the emergency department of two commercial NAATs in patients suspected with sepsis. METHODS: During a six-week period, blood samples were collected consecutively from all adult patients admitted to the general emergency department for suspicion of a community-onset sepsis and treated with intravenous antibiotics. Along with conventional blood cultures, multiplex PCR (MagicplexTM) was performed on whole blood specimens whereas portions from blood culture bottles were used for analysis by microarray-based assay (Prove-itTM). The aetiological significance of identified organisms was determined by two infectious disease physicians based on clinical presentation and expected pathogenicity. RESULTS: Among 382 episodes of suspected sepsis, clinically relevant microbes were detected by blood culture in 42 episodes (11%), by multiplex PCR in 37 episodes (9.7%), and by microarray in 32 episodes (8.4%). Although moderate agreement with blood culture (kappa 0.50), the multiplex PCR added diagnostic value by timely detection of 15 clinically relevant findings in blood culture-negative specimens. Results of the microarray corresponded very well to those of blood culture (kappa 0.90), but were available just marginally prior to blood culture results. CONCLUSIONS: The use of NAATs on whole blood specimens in adjunct to current culture-based methods provides a clinical add-on value by allowing for detection of organisms missed by blood culture. However, the aetiological significance of findings detected by NAATs should be interpreted with caution as the high analytical sensitivity may add findings that do not necessarily corroborate with the clinical diagnosis. PMID- 25928124 TI - A Concise Synthesis of the Repeating Unit of Capsular Polysaccharide Staphylococcus aureus Type 8. AB - The first synthesis of the repeating unit of S. aureus capsular polysaccharide type 8 is described. The repeating unit is an unusual trisaccharide sequence of three uncommon sugars, all connected via 1,2-cis linkages. The synthetic trisaccharide was equipped with capping methyl groups at the points of propagation of the polysaccharide sequence. PMID- 25928126 TI - Molecular and Electronic Structures of Mononuclear and Dinuclear Titanium Complexes Containing pi-Radical Anions of 2,2'-Bipyridine and 1,10 Phenanthroline: An Experimental and DFT Computational Study. AB - Whereas reaction of [(eta(5)-Cp*)Ti(IV)Cl3](0) (1) with 2 equiv of neutral 2,2' bipyridine (bpy) and 1.5 equiv of magnesium in tetrahydrofuran affords the mononuclear complex [(eta(5)-Cp*)Ti(III)(bpy(*))2](0) (2), performing the same reaction with only 1 equiv each of magnesium and bpy provides the dinuclear complex [{(eta(5)-Cp*)Ti(MU-Cl)(bpy(*))}2](0) (3). Conducting the latter reaction using 1,10-phenanthroline (phen) in place of bpy resulted in formation of dinuclear [{(eta(5)-Cp*)Ti(MU-Cl)(phen(*))}2](0) (4). The structures of 2, 3, and 4 have all been determined by high-resolution X-ray crystallography at 153 K; the Cpy-Cpy distances of 1.420(3) and 1.431(4) A in the N,N'-coordinated bpy ligands of 2 and 3, respectively, are indicative of the presence of (bpy(*))(1-) ligands, rather than neutral (bpy(0)). The electronic spectra (300-1600 nm) of these two complexes are similar in form, and contain intense pi -> pi* transitions associated with the (bpy(*))(1-) radical anion. Temperature dependent magnetic susceptibility measurements (4-300 K) show that mononuclear 2 possesses a temperature independent magnetic moment of 1.73 MUB, which is indicative of an S = (1)/2 ground state. Broken symmetry density functional theory (BS-DFT) calculations yield a picture consistent with the experimental findings, in which the central Ti atom possesses a +3 oxidation state and is coordinated by a eta(5) Cp* ligand and two (bpy(*))(1-). Strong intramolecular antiferromagnetic coupling of these three unpaired spins, one each on the Ti(III) center and on the two (bpy(*))(1-) ligands, affords the experimentally observed doublet ground state. The magnetic susceptibility measurements for dinuclear 3 and 4 display weak but significant ferromagnetic coupling, and indicate that these complexes possess S = 1 ground states. The mechanism of the spin coupling phenomenon that yields the observed behavior was analyzed using BS-DFT calculations, and it was discovered that the tight pi-stacking of the N,N'-coordinated (bpy(*))(1-)/(phen(*))(1-) ligands in these two complexes results from direct overlap of their SOMOs and formation of a two-electron multicentered bond. This yields a diamagnetic {(bpy)2}(2-)/{(phen)2}(2-) bridging unit whose doubly occupied HOMO is spread equally over both ligands. The two remaining unpaired electrons, one at each Ti(III) center, couple weakly in a ferromagnetic fashion to yield the experimentally observed S = 1 ground states. PMID- 25928127 TI - Iridium-Catalyzed Branch-Selective Hydroarylation of Vinyl Ethers via C-H Bond Activation. AB - Iridium-catalyzed hydroarylation of vinyl ethers via a directed C-H bond activation of aromatic compounds gave high yields of the corresponding addition products with high branch selectivity. PMID- 25928128 TI - Model selection for radiochromic film dosimetry. AB - The purpose of this study was to find the most accurate model for radiochromic film dosimetry by comparing different channel independent perturbation models. A model selection approach based on (algorithmic) information theory was followed, and the results were validated using gamma-index analysis on a set of benchmark test cases. Several questions were addressed: (a) whether incorporating the information of the non-irradiated film, by scanning prior to irradiation, improves the results; (b) whether lateral corrections are necessary when using multichannel models; (c) whether multichannel dosimetry produces better results than single-channel dosimetry; (d) which multichannel perturbation model provides more accurate film doses. It was found that scanning prior to irradiation and applying lateral corrections improved the accuracy of the results. For some perturbation models, increasing the number of color channels did not result in more accurate film doses. Employing Truncated Normal perturbations was found to provide better results than using Micke-Mayer perturbation models. Among the models being compared, the triple-channel model with Truncated Normal perturbations, net optical density as the response and subject to the application of lateral corrections was found to be the most accurate model. The scope of this study was circumscribed by the limits under which the models were tested. In this study, the films were irradiated with megavoltage radiotherapy beams, with doses from about 20-600 cGy, entire (8 inch * 10 inch) films were scanned, the functional form of the sensitometric curves was a polynomial and the different lots were calibrated using the plane-based method. PMID- 25928123 TI - Effects of increased paternal age on sperm quality, reproductive outcome and associated epigenetic risks to offspring. AB - Over the last decade, there has been a significant increase in average paternal age when the first child is conceived, either due to increased life expectancy, widespread use of contraception, late marriages and other factors. While the effect of maternal ageing on fertilization and reproduction is well known and several studies have shown that women over 35 years have a higher risk of infertility, pregnancy complications, spontaneous abortion, congenital anomalies, and perinatal complications. The effect of paternal age on semen quality and reproductive function is controversial for several reasons. First, there is no universal definition for advanced paternal ageing. Secondly, the literature is full of studies with conflicting results, especially for the most common parameters tested. Advancing paternal age also has been associated with increased risk of genetic disease. Our exhaustive literature review has demonstrated negative effects on sperm quality and testicular functions with increasing paternal age. Epigenetics changes, DNA mutations along with chromosomal aneuploidies have been associated with increasing paternal age. In addition to increased risk of male infertility, paternal age has also been demonstrated to impact reproductive and fertility outcomes including a decrease in IVF/ICSI success rate and increasing rate of preterm birth. Increasing paternal age has shown to increase the incidence of different types of disorders like autism, schizophrenia, bipolar disorders, and childhood leukemia in the progeny. It is thereby essential to educate the infertile couples on the disturbing links between increased paternal age and rising disorders in their offspring, to better counsel them during their reproductive years. PMID- 25928129 TI - Pediatric migraine and episodic syndromes that may be associated with migraine. AB - IMPORTANCE: Migraine is a common disorder and a frequent cause of medical consultation in children. Many childhood episodic syndromes have been described as common precursors of migraine. OBJECTIVE: To review current knowledge on migraine and childhood episodic syndromes, and to discuss future directions for research and clinical practice. FINDINGS: For most children it is difficult to describe a headache and fully verbalize symptoms such as photophobia and phonophobia that must be inferred from behaviour. Classical migraine features are rare before the age of 6 years, but some migraine-related syndromes have been described. Benign paroxysmal torticollis of infancy, benign paroxysmal vertigo of childhood, cyclic vomiting syndrome and abdominal migraine are currently classified as childhood episodic syndromes, and therefore common precursors of migraine. A strong association between infantile colic and migraine has recently been reported. There are similarities between children with episodic syndromes and children with migraine, regarding social and demographic factors, precipitating and relieving factors, and accompanying gastrointestinal, neurologic, and vasomotor features. The real pathophysiological mechanisms of migraine are not fully understood. Current data obtained through molecular and functional studies provide a complex model in which vascular and neurologic events cooperate in the pathogenesis of migraine attacks. Genetic factors causing disturbances in neuronal ion channels, make a migraineur more sensitive to multiple trigger factors that activate the nociception cascade. The expanding knowledge on migraine genetics and pathophysiology may be applicable to childhood episodic syndromes. Migraine preventive strategies are particularly important in children, and could be beneficial in childhood episodic syndromes. Nonspecific analgesics like ibuprofen and acetaminophen are widely used in pediatrics to control pain and have been found to be effective also in the treatment of acute migraine attacks. Triptans are the specific fist-line drugs for acute migraine treatment. CONCLUSIONS AND RELEVANCE: Migraine phenotype differs somewhat in the developing brain, and childhood episodic syndromes may arise before typical migraine headache. Diagnosing pediatric migraine may be difficult because of children's language and cognitive abilities. The risk of underestimating migraine in pediatric age is high. An adequate diagnosis is important to maintain a good quality of life and to avoid inappropriate therapy. PMID- 25928130 TI - Uptake of influenza vaccination in pregnancy amongst Australian Aboriginal and Torres Strait Islander women: a mixed-methods pilot study. AB - BACKGROUND: Influenza infection during pregnancy causes significant morbidity and mortality. Immunisation against influenza is recommended during pregnancy in several countries however, there are limited data on vaccine uptake, and the determinants of vaccination, in pregnant Australian Aboriginal and/or Torres Islander women. This study aimed to collect pilot data on vaccine uptake and attitudes towards, and perceptions of, maternal influenza vaccination in this population in order to inform the development of larger studies. METHODS: A mixed methods study comprised of a cross-sectional survey and yarning circles (focus groups) amongst Aboriginal and Torres Strait Islander women attending two primary health care services. The women were between 28 weeks gestation and less than 16 weeks post-birth. These data were supplemented by data collected in an ongoing national Australian study of maternal influenza vaccination. Aboriginal research officers collected community data and data from the yarning circles which were based on a narrative enquiry framework. Descriptive statistics were used to analyse quantitative data and thematic analyses were applied to qualitative data. RESULTS: Quantitative data were available for 53 women and seven of these women participated in the yarning circles. The proportion of women who reported receipt of an influenza vaccine during their pregnancy was 9/53. Less than half of the participants (21/53) reported they had been offered the vaccine in pregnancy. Forty-three percent reported they would get a vaccine if they became pregnant again. Qualitative data suggested perceived benefits to themselves and their infants were important factors in the decision to be vaccinated but there was insufficient information available to women to make that choice. CONCLUSIONS: The rates of influenza immunisation may continue to remain low for Aboriginal and/or Torres Strait Islander women during pregnancy. Access to services and recommendations by a health care worker may be factors in the lower rates. Our findings support the need for larger studies directed at monitoring and understanding the determinants of maternal influenza vaccine uptake during pregnancy in Australian Aboriginal and Torres Strait Islander women. This research will best be achieved using methods that account for the social and cultural contexts of Aboriginal and Torres Strait Islander communities in Australia. PMID- 25928131 TI - Quality of life, sense of coherence and experiences with three different treatments in patients with psychological distress in primary care: a mixed methods study. AB - BACKGROUND: Psychological distress is associated with impaired health-related quality of life (HRQL) and poor sense of coherence (SOC). In a previous study, we found that therapeutic acupuncture (TA) and an integrative treatment that combined TA with person-centred approach in a salutogenic dialogue (IT) alleviated anxiety and depression significantly more than conventional treatment (CT) in primary care patients. Here, we report on secondary analyses regarding the HRQL and SOC from that previous pragmatic randomised controlled trial (RCT). METHOD: Quantitative and qualitative design. One hundred twenty patients were referred for psychological distress. Quantitative analyses were performed at baseline and after 8 weeks of treatment using the SF-36 mental component summary (MCS), physical component summary (PCS) and the Sense of Coherence-13 (SOC) questionnaires. Qualitative manifest content analyses were based on open-ended questions-"Have you experienced any changes since the start of the treatment? Will you describe these changes?" RESULTS: No baseline differences were found. At 8 weeks, both the IT and TA groups had statistically better scores and greater improvement from baseline on the MCS and SOC than the CT group. The effect sizes were large. No significant differences were found between the IT and TA groups or in relation to the PCS. SOC was highly correlated with the MCS but not with the PCS. Dropout rates were low. The experiences of the intervention resulted in four categories: Being heading back; Status quo; Feeling confirmed; and Feeling abandoned, with 13 related subcategories. CONCLUSION: IT and TA seem to improve sense of coherence and mental health status in primary care patients with psychological distress, whereas CT appears to be less beneficial. IT and TA appear to be well-accepted and may serve as useful adjunct treatment modalities to standard primary care. Our results are consistent with much of the previous research in highlighting a strong relationship between SOC and mental health status. The written qualitative data described feeling confirmed and feeling increased self-efficacy, self-care and faith in the future. Those in the CT group, however, described feeling abandoned, missing treatment and experiencing increased emotional and physical problems. More research is needed. TRIAL REGISTRATION: ISRCTN trial number NCT01631500. PMID- 25928132 TI - Erratum: New GOLD classification: longitudinal data on group assignment. PMID- 25928133 TI - Aflatoxin biosynthesis is a novel source of reactive oxygen species--a potential redox signal to initiate resistance to oxidative stress? AB - Aflatoxin biosynthesis in the filamentous fungus Aspergillus parasiticus involves a minimum of 21 enzymes, encoded by genes located in a 70 kb gene cluster. For aflatoxin biosynthesis to be completed, the required enzymes must be transported to specialized early and late endosomes called aflatoxisomes. Of particular significance, seven aflatoxin biosynthetic enzymes are P450/monooxygenases which catalyze reactions that can produce reactive oxygen species (ROS) as byproducts. Thus, oxidative reactions in the aflatoxin biosynthetic pathway could potentially be an additional source of intracellular ROS. The present work explores the hypothesis that the aflatoxin biosynthetic pathway generates ROS (designated as "secondary" ROS) in endosomes and that secondary ROS possess a signaling function. We used specific dyes that stain ROS in live cells and demonstrated that intracellular ROS levels correlate with the levels of aflatoxin synthesized. Moreover, feeding protoplasts with precursors of aflatoxin resulted in the increase in ROS generation. These data support the hypothesis. Our findings also suggest that secondary ROS may fulfill, at least in part, an important mechanistic role in increased tolerance to oxidative stress in germinating spores (seven-hour germlings) and in regulation of fungal development. PMID- 25928134 TI - Links between Genetic Groups, Indole Alkaloid Profiles and Ecology within the Grass-Parasitic Claviceps purpurea Species Complex. AB - The grass parasitic fungus Claviceps purpurea sensu lato produces sclerotia with toxic indole alkaloids. It constitutes several genetic groups with divergent habitat preferences that recently were delimited into separate proposed species. We aimed to 1) analyze genetic variation of C. purpurea sensu lato in Norway, 2) characterize the associated indole alkaloid profiles, and 3) explore relationships between genetics, alkaloid chemistry and ecology. Approximately 600 sclerotia from 14 different grass species were subjected to various analyses including DNA sequencing and HPLC-MS. Molecular results, supported by chemical and ecological data, revealed one new genetic group (G4) in addition to two of the three known; G1 (C. purpurea sensu stricto) and G2 (C. humidiphila). G3 (C. spartinae) was not found. G4, which was apparently con-specific with the recently described C. arundinis sp. nov, was predominantly found in very wet habitats on Molinia caerulea and infrequently in saline habitats on Leymus arenarius. Its indole-diterpene profile resembled G2, while its ergot alkaloid profile differed from G2 in high amounts of ergosedmam. In contrast to G1, indole-diterpenes were consistently present in G2 and G4. Our study supports and complements the newly proposed species delimitation of the C. purpurea complex, but challenges some species characteristics including host spectrum, habitat preferences and sclerotial floating ability. PMID- 25928135 TI - Disulfiram attenuates osteoclast differentiation in vitro: a potential antiresorptive agent. AB - Disulfiram (DSF), a cysteine modifying compound, has long been clinically employed for the treatment of alcohol addiction. Mechanistically, DSF acts as a modulator of MAPK and NF-kappaB pathways signaling pathways. While these pathways are crucial for osteoclast (OC) differentiation, the potential influence of DSF on OC formation and function has not been directly assessed. Here, we explore the pharmacological effects of DSF on OC differentiation, activity and the modulation of osteoclastogenic signaling cascades. We first analyzed cytotoxicity of DSF on bone marrow monocytes isolated from C57BL/6J mice. Upon the establishment of optimal dosage, we conducted osteoclastogenesis and bone resorption assays in the presence or absence of DSF treatment. Luciferase assays in RAW264.7 cells were used to examine the effects of DSF on major transcription factors activation. Western blot, reverse transcription polymerase chain reaction, intracellular acidification and proton influx assays were employed to further dissect the underlying mechanism. DSF treatment dose-dependently inhibited both mouse and human osteoclastogenesis, especially at early stages of differentiation. This inhibition correlated with a decrease in the expression of key osteoclastic marker genes including CtsK, TRAP, DC-STAMP and Atp6v0d2 as well as a reduction in bone resorption in vitro. Suppression of OC differentiation was found to be due, at least in part, to the blockade of several key receptor activators of nuclear factor kappa-B ligand (RANKL)-signaling pathways including ERK, NF-kappaB and NFATc1. On the other hand, DSF failed to suppress intracellular acidification and proton influx in mouse and human osteoclasts using acridine orange quenching and microsome-based proton transport assays. Our findings indicate that DSF attenuates OC differentiation via the collective suppression of several key RANKL mediated signaling cascades, thus making it an attractive agent for the treatment of OC-mediated disorders. PMID- 25928137 TI - Summaries for Patients. Cervical Cancer Screening in Average-Risk Women. PMID- 25928138 TI - Ensemble learning for spatial interpolation of soil potassium content based on environmental information. AB - One important method to obtain the continuous surfaces of soil properties from point samples is spatial interpolation. In this paper, we propose a method that combines ensemble learning with ancillary environmental information for improved interpolation of soil properties (hereafter, EL-SP). First, we calculated the trend value for soil potassium contents at the Qinghai Lake region in China based on measured values. Then, based on soil types, geology types, land use types, and slope data, the remaining residual was simulated with the ensemble learning model. Next, the EL-SP method was applied to interpolate soil potassium contents at the study site. To evaluate the utility of the EL-SP method, we compared its performance with other interpolation methods including universal kriging, inverse distance weighting, ordinary kriging, and ordinary kriging combined geographic information. Results show that EL-SP had a lower mean absolute error and root mean square error than the data produced by the other models tested in this paper. Notably, the EL-SP maps can describe more locally detailed information and more accurate spatial patterns for soil potassium content than the other methods because of the combined use of different types of environmental information; these maps are capable of showing abrupt boundary information for soil potassium content. Furthermore, the EL-SP method not only reduces prediction errors, but it also compliments other environmental information, which makes the spatial interpolation of soil potassium content more reasonable and useful. PMID- 25928139 TI - CO2 and H2O: Understanding Different Stakeholder Perspectives on the Use of Carbon Credits to Finance Household Water Treatment Projects. AB - BACKGROUND: Carbon credits are an increasingly prevalent market-based mechanism used to subsidize household water treatment technologies (HWT). This involves generating credits through the reduction of carbon emissions from boiling water by providing a technology that reduces greenhouse gas emissions linked to climate change. Proponents claim this process delivers health and environmental benefits by providing clean drinking water and reducing greenhouse gases. Selling carbon credits associated with HWT projects requires rigorous monitoring to ensure households are using the HWT and achieving the desired benefits of the device. Critics have suggested that the technologies provide neither the benefits of clean water nor reduced emissions. This study explores the perspectives of carbon credit and water, sanitation and hygiene (WASH) experts on HWT carbon credit projects. METHODS: Thirteen semi-structured, in-depth interviews were conducted with key informants from the WASH and carbon credit development sectors. The interviews explored perceptions of the two groups with respect to the procedures applied in the Gold Standard methodology for trading Voluntary Emission Reduction (VER) credits. RESULTS: Agreement among the WASH and carbon credit experts existed for the concept of suppressed demand and parameters in the baseline water boiling test. Key differences, however, existed. WASH experts' responses highlighted a focus on objectively verifiable data for monitoring carbon projects while carbon credit experts called for contextualizing observed data with the need for flexibility and balancing financial viability with quality assurance. CONCLUSIONS: Carbon credit projects have the potential to become an important financing mechanism for clean energy in low- and middle-income countries. Based on this research we recommend that more effort be placed on building consensus on the underlying assumptions for obtaining carbon credits from HWT projects, as well as the approved methods for monitoring correct and consistent use of the HWT technologies in order to support public health impacts. PMID- 25928142 TI - Sodium thiosulfate ameliorates oxidative stress and preserves renal function in hyperoxaluric rats. AB - BACKGROUND: Hyperoxaluria causes crystal deposition in the kidney, which leads to oxidative stress and to injury and damage of the renal epithelium. Sodium thiosulfate (STS, Na2S2O3) is an anti-oxidant, which has been used in human medicine for decades. The effect of STS on hyperoxaluria-induced renal damage is not known. METHODS: Hyperoxaluria and renal injury were induced in healthy male Wistar rats by chronic exposure to ethylene glycol (EG, 0.75%) in the drinking water for 4 weeks. The treatment effects of STS, NaCl or Na2SO4 were compared. Furthermore, the effects of STS on oxalate-induced oxidative stress were investigated in vitro in renal LLC-PK1 cells. RESULTS: Chronic EG exposure led to hyperoxaluria, oxidative stress, calcium oxalate crystalluria and crystal deposition in the kidneys. Whereas all tested compounds significantly reduced crystal load, only STS-treatment maintained tissue superoxide dismutase activity and urine 8-isoprostaglandin levels in vivo and preserved renal function. In in vitro studies, STS showed the ability to scavenge oxalate-induced ROS accumulation dose dependently, reduced cell-released hydrogen peroxide and preserved superoxide dismutase activity. As a mechanism explaining this finding, STS was able to directly inactivate hydrogen peroxide in cell-free experiments. CONCLUSIONS: STS is an antioxidant, which preserves renal function in a chronic EG rat model. Its therapeutic use in oxidative-stress induced renal-failure should be considered. PMID- 25928140 TI - Identification and Characterization of Cyprinid Herpesvirus-3 (CyHV-3) Encoded MicroRNAs. AB - MicroRNAs (miRNAs) are a class of small non-coding RNAs involved in post transcriptional gene regulation. Some viruses encode their own miRNAs and these are increasingly being recognized as important modulators of viral and host gene expression. Cyprinid herpesvirus 3 (CyHV-3) is a highly pathogenic agent that causes acute mass mortalities in carp (Cyprinus carpio carpio) and koi (Cyprinus carpio koi) worldwide. Here, bioinformatic analyses of the CyHV-3 genome suggested the presence of non-conserved precursor miRNA (pre-miRNA) genes. Deep sequencing of small RNA fractions prepared from in vitro CyHV-3 infections led to the identification of potential miRNAs and miRNA-offset RNAs (moRNAs) derived from some bioinformatically predicted pre-miRNAs. DNA microarray hybridization analysis, Northern blotting and stem-loop RT-qPCR were then used to definitively confirm that CyHV-3 expresses two pre-miRNAs during infection in vitro. The evidence also suggested the presence of an additional four high-probability and two putative viral pre-miRNAs. MiRNAs from the two confirmed pre-miRNAs were also detected in gill tissue from CyHV-3-infected carp. We also present evidence that one confirmed miRNA can regulate the expression of a putative CyHV-3-encoded dUTPase. Candidate homologues of some CyHV-3 pre-miRNAs were identified in CyHV-1 and CyHV-2. This is the first report of miRNA and moRNA genes encoded by members of the Alloherpesviridae family, a group distantly related to the Herpesviridae family. The discovery of these novel CyHV-3 genes may help further our understanding of the biology of this economically important virus and their encoded miRNAs may have potential as biomarkers for the diagnosis of latent CyHV 3. PMID- 25928145 TI - Endocrine therapy: defining the path of least resistance. AB - One of the best-characterized oncogenic mechanisms in breast cancer is the aberrant activation of phosphatidylinositol-3-kinase, protein kinase B, and mammalian target of rapamycin signaling. In both endocrine-resistant disease and breast cancer stem cells, this is commonly caused by specific genetic lesions or amplification of key pathway components or both. These observations have generated two interesting hypotheses. Firstly, do these genetic anomalies provide clinically significant biomarkers predictive of endocrine resistance? Secondly, do tamoxifen-resistant breast cancer cells emerge from a stem-like cell population? New studies, published in Breast Cancer Research, raise the possibility that these hypotheses are intrinsically linked. PMID- 25928147 TI - State-dependent changes in auditory sensory gating in different cortical areas in rats. AB - Sensory gating is a process in which the brain's response to a repetitive stimulus is attenuated; it is thought to contribute to information processing by enabling organisms to filter extraneous sensory inputs from the environment. To date, sensory gating has typically been used to determine whether brain function is impaired, such as in individuals with schizophrenia or addiction. In healthy subjects, sensory gating is sensitive to a subject's behavioral state, such as acute stress and attention. The cortical response to sensory stimulation significantly decreases during sleep; however, information processing continues throughout sleep, and an auditory evoked potential (AEP) can be elicited by sound. It is not known whether sensory gating changes during sleep. Sleep is a non-uniform process in the whole brain with regional differences in neural activities. Thus, another question arises concerning whether sensory gating changes are uniform in different brain areas from waking to sleep. To address these questions, we used the sound stimuli of a Conditioning-testing paradigm to examine sensory gating during waking, rapid eye movement (REM) sleep and Non-REM (NREM) sleep in different cortical areas in rats. We demonstrated the following: 1. Auditory sensory gating was affected by vigilant states in the frontal and parietal areas but not in the occipital areas. 2. Auditory sensory gating decreased in NREM sleep but not REM sleep from waking in the frontal and parietal areas. 3. The decreased sensory gating in the frontal and parietal areas during NREM sleep was the result of a significant increase in the test sound amplitude. PMID- 25928148 TI - A systems biology approach identifies a regulatory network in parotid acinar cell terminal differentiation. AB - OBJECTIVE: The transcription factor networks that drive parotid salivary gland progenitor cells to terminally differentiate, remain largely unknown and are vital to understanding the regeneration process. METHODOLOGY: A systems biology approach was taken to measure mRNA and microRNA expression in vivo across acinar cell terminal differentiation in the rat parotid salivary gland. Laser capture microdissection (LCM) was used to specifically isolate acinar cell RNA at times spanning the month-long period of parotid differentiation. RESULTS: Clustering of microarray measurements suggests that expression occurs in four stages. mRNA expression patterns suggest a novel role for Pparg which is transiently increased during mid postnatal differentiation in concert with several target gene mRNAs. 79 microRNAs are significantly differentially expressed across time. Profiles of statistically significant changes of mRNA expression, combined with reciprocal correlations of microRNAs and their target mRNAs, suggest a putative network involving Klf4, a differentiation inhibiting transcription factor, which decreases as several targeting microRNAs increase late in differentiation. The network suggests a molecular switch (involving Prdm1, Sox11, Pax5, miR-200a, and miR-30a) progressively decreases repression of Xbp1 gene transcription, in concert with decreased translational repression by miR-214. The transcription factor Xbp1 mRNA is initially low, increases progressively, and may be maintained by a positive feedback loop with Atf6. Transfection studies show that Xbp1 activates the Mist1 promoter [corrected]. In addition, Xbp1 and Mist1 each activate the parotid secretory protein (Psp) gene, which encodes an abundant salivary protein, and is a marker of terminal differentiation. CONCLUSION: This study identifies novel expression patterns of Pparg, Klf4, and Sox11 during parotid acinar cell differentiation, as well as numerous differentially expressed microRNAs. Network analysis identifies a novel stemness arm, a genetic switch involving transcription factors and microRNAs, and transition to an Xbp1 driven differentiation network. This proposed network suggests key regulatory interactions in parotid gland terminal differentiation. PMID- 25928149 TI - A study in Polish patients with cardiomyopathy emphasizes pathogenicity of phospholamban (PLN) mutations at amino acid position 9 and low penetrance of heterozygous null PLN mutations. AB - BACKGROUND: In humans mutations in the PLN gene, encoding phospholamban - a regulator of sarcoplasmic reticulum calcium ATPase (SERCA), cause cardiomyopathy with prevalence depending on the population. Our purpose was to identify PLN mutations in Polish cardiomyopathy patients. METHODS: We studied 161 unrelated subjects referred for genetic testing for cardiomyopathies: 135 with dilated cardiomyopathy, 22 with hypertrophic cardiomyopathy and 4 with other cardiomyopathies. In 23 subjects multiple genes were sequenced by next generation sequencing and in all subjects PLN exons were analyzed by Sanger sequencing. Control group included 200 healthy subjects matched with patients for ethnicity, sex and age. Large deletions/insertions were screened by real time polymerase chain reaction. RESULTS: We detected three different heterozygous mutations in the PLN gene: a novel null c.9_10insA:(p.Val4Serfs*15) variant and two missense variants: c.25C > T:(p.Arg9Cys) and c.26G > T:(p.Arg9Leu). The (p.Val4Serfs*15) variant occurred in the patient with Wolff-Parkinson-White syndrome in whom the diagnosis of cardiomyopathy was not confirmed and his mother who had concentric left ventricular remodeling but normal left ventricular mass and function. We did not detect large deletions/insertions in PLN in cohort studied. CONCLUSIONS: In Poland, similar to most populations, PLN mutations rarely cause cardiomyopathy. The 9(th) PLN residue is apparently a mutation hot spot whereas a single dose of c.9_10insA, and likely other null PLN mutations, cause the disease only with low penetrance or are not pathogenic. PMID- 25928151 TI - Selection towards different adaptive optima drove the early diversification of locomotor phenotypes in the radiation of Neotropical geophagine cichlids. AB - BACKGROUND: Simpson envisaged a conceptual model of adaptive radiation in which lineages diversify into "adaptive zones" within a macroevolutionary adaptive landscape. However, only a handful of studies have empirically investigated this adaptive landscape and its consequences for our interpretation of the underlying mechanisms of phenotypic evolution. In fish radiations the evolution of locomotor phenotypes may represent an important dimension of ecomorphological diversification given the implications of locomotion for feeding and habitat use. Neotropical geophagine cichlids represent a newly identified adaptive radiation and provide a useful system for studying patterns of locomotor diversification and the implications of selective constraints on phenotypic divergence in general. RESULTS: We use multivariate ordination, models of phenotypic evolution and posterior predictive approaches to investigate the macroevolutionary adaptive landscape and test for evidence of early divergence of locomotor phenotypes in Geophagini. The evolution of locomotor phenotypes was characterized by selection towards at least two distinct adaptive peaks and the early divergence of modern morphological disparity. One adaptive peak included the benthic and epibenthic invertivores and was characterized by fishes with deep, laterally compressed bodies that optimize precise, slow-swimming manoeuvres. The second adaptive peak resulted from a shift in adaptive optima in the species-rich ram feeding/rheophilic Crenicichla-Teleocichla clade and was characterized by species with streamlined bodies that optimize fast starts and rapid manoeuvres. Evolutionary models and posterior predictive approaches favoured an early shift to a new adaptive peak over decreasing rates of evolution as the underlying process driving the early divergence of locomotor phenotypes. CONCLUSIONS: The influence of multiple adaptive peaks on the divergence of locomotor phenotypes in Geophagini is compatible with the expectations of an ecologically driven adaptive radiation. This study confirms that the diversification of locomotor phenotypes represents an important dimension of phenotypic evolution in the geophagine adaptive radiation. It also suggests that the commonly observed early burst of phenotypic evolution during adaptive radiations may be better explained by the concentration of shifts to new adaptive peaks deep in the phylogeny rather than overall decreasing rates of evolution. PMID- 25928154 TI - LED light between Nobel Prize and cancer risk factor. PMID- 25928152 TI - The role of vaccination coverage, individual behaviors, and the public health response in the control of measles epidemics: an agent-based simulation for California. AB - BACKGROUND: Measles cases continue to occur among susceptible individuals despite the elimination of endemic measles transmission in the United States. Clustering of disease susceptibility can threaten herd immunity and impact the likelihood of disease outbreaks in a highly vaccinated population. Previous studies have examined the role of contact tracing to control infectious diseases among clustered populations, but have not explicitly modeled the public health response using an agent-based model. METHODS: We developed an agent-based simulation model of measles transmission using the Framework for Reconstructing Epidemiological Dynamics (FRED) and the Synthetic Population Database maintained by RTI International. The simulation of measles transmission was based on interactions among individuals in different places: households, schools, daycares, workplaces, and neighborhoods. The model simulated different levels of immunity clustering, vaccination coverage, and contact investigations with delays caused by individuals' behaviors and/or the delay in a health department's response. We examined the effects of these characteristics on the probability of uncontrolled measles outbreaks and the outbreak size in 365 days after the introduction of one index case into a synthetic population. RESULTS: We found that large measles outbreaks can be prevented with contact investigations and moderate contact rates by having (1) a very high vaccination coverage (>= 95%) with a moderate to low level of immunity clustering (<= 0.5) for individuals aged less than or equal to 18 years, or (2) a moderate vaccination coverage (85% or 90%) with no immunity clustering for individuals (<= 18 years of age), a short intervention delay, and a high probability that a contact can be traced. Without contact investigations, measles outbreaks may be prevented by the highest vaccination coverage with no immunity clustering for individuals (<= 18 years of age) with moderate contact rates; but for the highest contact rates, even the highest coverage with no immunity clustering for individuals (<= 18 years of age) cannot completely prevent measles outbreaks. CONCLUSIONS: The simulation results demonstrated the importance of vaccination coverage, clustering of immunity, and contact investigations in preventing uncontrolled measles outbreaks. PMID- 25928155 TI - Co-expressed Cyclin D variants cooperate to regulate proliferation of germline nuclei in a syncytium. AB - The role of the G1-phase Cyclin D-CDK 4/6 regulatory module in linking germline stem cell (GSC) proliferation to nutrition is evolutionarily variable. In invertebrate Drosophila and C. elegans GSC models, G1 is nearly absent and Cyclin E is expressed throughout the cell cycle, whereas vertebrate spermatogonial stem cells have a distinct G1 and Cyclin D1 plays an important role in GSC renewal. In the invertebrate, chordate, Oikopleura, where germline nuclei proliferate asynchronously in a syncytium, we show a distinct G1-phase in which 2 Cyclin D variants are co-expressed. Cyclin Dd, present in both somatic endocycling cells and the germline, localized to germline nuclei during G1 before declining at G1/S. Cyclin Db, restricted to the germline, remained cytoplasmic, co-localizing in foci with the Cyclin-dependent Kinase Inhibitor, CKIa. These foci showed a preferential spatial distribution adjacent to syncytial germline nuclei at G1/S. During nutrient-restricted growth arrest, upregulated CKIa accumulated in arrested somatic endoreduplicative nuclei but did not do so in germline nuclei. In the latter context, Cyclin Dd levels gradually decreased. In contrast, the Cyclin Dbbeta splice variant, lacking the Rb-interaction domain and phosphodegron, was specifically upregulated and the number of cytoplasmic foci containing this variant increased. This upregulation was dependent on stress response MAPK p38 signaling. We conclude that under favorable conditions, Cyclin Dbbeta-CDK6 sequesters CKIa in the cytoplasm to cooperate with Cyclin Dd-CDK6 in promoting germline nuclear proliferation. Under nutrient-restriction, this sequestration function is enhanced to permit continued, though reduced, cycling of the germline during somatic growth arrest. PMID- 25928157 TI - Endometrial Cancer: Combined MR Volumetry and Diffusion-weighted Imaging for Assessment of Myometrial and Lymphovascular Invasion and Tumor Grade. AB - PURPOSE: To investigate magnetic resonance (MR) volumetry of endometrial tumors and its association with deep myometrial invasion, tumor grade, and lymphovascular invasion and to assess the value of apparent diffusion coefficient (ADC) histographic analysis of the whole tumor volume for prediction of tumor grade and lymphovascular invasion. MATERIALS AND METHODS: The institutional review board approved this retrospective study; patient consent was not required. Between May 2010 and May 2012, 70 women (mean age, 64 years; range, 24-91 years) with endometrial cancer underwent preoperative MR imaging, including axial oblique and sagittal T2-weighted, dynamic contrast material-enhanced, and diffusion-weighted imaging. Volumetry of the tumor and uterus was performed during the six sequences, with manual tracing of each section, and the tumor volume ratio (TVR) was calculated. ADC histograms were generated from pixel ADCs from the whole tumor volume. The threshold of TVR associated with myometrial invasion was assessed by using receiver operating characteristic curves. An independent sample Mann Whitney U test was used to compare differences in ADCs, skewness, and kurtosis between tumor grade and the presence of lymphovascular invasion. RESULTS: No significant difference in tumor volume and TVR was found among the six MR imaging sequences (P = .95 and .86, respectively). A TVR greater than or equal to 25% allowed prediction of deep myometrial invasion with sensitivity of 100% and specificity of 93% (area under the curve, 0.96; 95% confidence interval: 0.86, 0.99) at axial oblique diffusion-weighted imaging. A TVR of greater than or equal to 25% was associated with grade 3 tumors (P = .0007) and with lymphovascular invasion (P < .0001). There was no significant difference in the ADCs between grades 1 and 2 tumors (P > .05). The minimum, 10th, 25th, 50th, 75th, and 90th percentile ADCs were significantly lower in grade 3 tumors than in grades 1 and 2 tumors (P < .02). CONCLUSION: The combination of whole tumor volume and ADC can be used for prediction of tumor grade, lymphovascular invasion, and depth of myometrial invasion. PMID- 25928159 TI - Quality of websites of obstetrics and gynecology departments: a cross-sectional study. AB - BACKGROUND: The internet has become an easily accessible and widely used source of healthcare information. There are, however, no standardized or commonly accepted criteria for the quality of Obstetrics and Gynecology websites. In this study, we aimed to evaluate the quality of websites of Obstetrics and Gynecology departments in German-speaking countries and to compare websites nationally and internationally. METHODS: We scored 672 websites from Germany (n = 566), Austria (n = 57), and Switzerland (n = 49) using the objective criteria: Google search rank (2 items), technical aspects (11 items), navigation (8 items), and content (6 items) for a 26 point score. Scores were compared nationally and internationally. Multivariable regression models assessed good quality scores (>=50% of maximum) as the dependent variables and country, academic affiliation, being member of a healthcare consortium, confessional affiliation, and content management system (CMS) use as independent variables. RESULTS: The mean score of websites was 13.8 +/- 3.3. 4.2% were rated as good (>=75% of maximum), 61.8% as fair (>=50% of maximum). German (14.0 +/- 3.2) and Swiss (13.8 +/- 4.0) websites scored significantly higher compared to Austrian websites (11.6 +/- 2.5) (P < 0.001 and P = 0.005, respectively). Within Germany, academic had higher scores than non-academic departments (14.9 +/- 3.2 vs. 13.7 +/- 3.1, P < 0.001). Single institutions had higher scores compared to healthcare consortium institutions (14.1 +/- 3.2 vs. 13.2 +/- 2.6, P = 0.003). Departments in Northern and Southern states had higher scores compared to Eastern states (14.4 +/- 3.2 and 14.2 +/- 3.2 vs. 13.0 +/- 3.0, P < 0.001). In multivariate regression models, all subscores (all: P < 0.001) independently predicted a website's reaching a good quality score, with navigation subscore as strongest predictor. Affiliations were predictors for some good individual subscores, but not for others. High content subscore was associated with good Google search rank, technical aspects, and navigation subscores. CONCLUSIONS: The quality of websites of Obstetrics and Gynecology departments varies widely. We found marked differences depending on country, affiliation, and region. PMID- 25928161 TI - Tailored eHealth Lifestyle Promotion: Which Behavioral Modules Do Users Prefer? AB - Health risk behaviors are widespread among adults and often co-occur. eHealth computer-tailored technology provides individuals with personalized feedback regarding multiple lifestyle behaviors. First, the authors investigated individuals' preferences for particular lifestyle modules and hypothesised that health preventive behavior modules would be preferred over addictive behavior modules. Second, characteristics associated with these choices were examined. A web-based questionnaire assessed demographics, health status, and five lifestyle behaviors (i.e., physical activity, fruit consumption, vegetable consumption, alcohol intake and tobacco use) among adults (N = 1,828). Responses were translated into a health risk appraisal outlining whether respondents adhered to the national guidelines for these behaviors. Next, respondents could select one of the lifestyle modules providing personalized advice. More than 60% of the participants failed to meet the guidelines for more than one lifestyle behavior. The physical activity module was the most popular, followed by the smoking and fruit modules. Young adults tended to prefer the physical activity and fruit modules, whereas the vegetable module was more popular among older adults. No consistent pattern was identified for the alcohol and smoking modules. The results support the authors' hypothesis that health preventive behaviors-in particular, physical activity-would be preferred. Although this could imply that physical activity could serve as a gateway behavior when aiming at multiple behavior changes, it is also conceivable that other mechanisms, such as the actual success of behavior change, or the fact that people can choose, may increase chances of multiple behavior change. Hence, mechanisms leading to multiple behavior change need to be further explored. PMID- 25928165 TI - Long noncoding RNA, CCDC26, controls myeloid leukemia cell growth through regulation of KIT expression. AB - BACKGROUND: Accumulating evidence suggests that some long noncoding RNAs (lncRNAs) are involved in certain diseases, such as cancer. The lncRNA, CCDC26, is related to childhood acute myeloid leukemia (AML) because its copy number is altered in AML patients. RESULTS: We found that CCDC26 transcripts were abundant in the nuclear fraction of K562 human myeloid leukemia cells. To examine the function of CCDC26, gene knockdown (KD) was performed using short hairpin RNAs (shRNAs), and four KD clones, in which CCDC26 expression was suppressed to 1% of its normal level, were isolated. This down-regulation included suppression of CCDC26 intron-containing transcripts (the CCDC26 precursor mRNA), indicating that transcriptional gene suppression (TGS), not post-transcriptional suppression, was occurring. The shRNA targeting one of the two CCDC26 splice variants also suppressed the other splice variant, which is further evidence for TGS. Growth rates of KD clones were reduced compared with non-KD control cells in media containing normal or high serum concentrations. In contrast, enhanced growth rates in media containing much lower serum concentrations and increased survival periods after serum withdrawal were observed for KD clones. DNA microarray and quantitative polymerase chain reaction screening for differentially expressed genes between KD clones and non-KD control cells revealed significant up regulation of the tyrosine kinase receptor, KIT, hyperactive mutations of which are often found in AML. Treatment of KD clones with ISCK03, a KIT-specific inhibitor, eliminated the increased survival of KD clones in the absence of serum. CONCLUSIONS: We suggest that CCDC26 controls growth of myeloid leukemia cells through regulation of KIT expression. A KIT inhibitor might be an effective treatment against the forms of AML in which CCDC26 is altered. PMID- 25928166 TI - An evaluation on the effect of the copayment waiver policy for Korean hospitalized children under the age of six. AB - BACKGROUND: In January 2006, the Korean government implemented a copayment waiver policy for hospitalized children under the age of 6 years to reduce the economic burden on patients. This policy was implemented from 2006 to 2007 in Korea and involved hospitalized children under the age of 6 years. The goal of this study is to evaluate the effect of the copayment waiver policy on health insurance beneficiaries. METHODS: The change in medical service utilization before and after the policy implementation was analyzed using data from the national health insurance corporation (NHIC) and compared with medical aid beneficiaries who were already exempt from copayment. The "difference in difference" method was applied to determine the net effect of the copayment waiver policy. RESULTS: The net effect of policy implementation on NHIC beneficiaries was unclear by the "difference in difference" method because the number of inpatient days and hospital expenditure after policy implementation showed opposite results. The copayment waiver policy did not decrease the intensity of health care utilization when compared with the medical aid beneficiaries group. Among the NHIC beneficiaries, patients who utilized medical services for fatal disease and those with the low premiums group were more affected by the policy. CONCLUSIONS: The net effect of copayment waiver policy remains unclear. Therefore, further studies are needed to determine the effects of policies implemented to reduce the economic burden on patients, such as the herein-described copayment waiver policy. PMID- 25928167 TI - Defining window-boundaries for genomic analyses using smoothing spline techniques. AB - BACKGROUND: High-density genomic data is often analyzed by combining information over windows of adjacent markers. Interpretation of data grouped in windows versus at individual locations may increase statistical power, simplify computation, reduce sampling noise, and reduce the total number of tests performed. However, use of adjacent marker information can result in over- or under-smoothing, undesirable window boundary specifications, or highly correlated test statistics. We introduce a method for defining windows based on statistically guided breakpoints in the data, as a foundation for the analysis of multiple adjacent data points. This method involves first fitting a cubic smoothing spline to the data and then identifying the inflection points of the fitted spline, which serve as the boundaries of adjacent windows. This technique does not require prior knowledge of linkage disequilibrium, and therefore can be applied to data collected from individual or pooled sequencing experiments. Moreover, in contrast to existing methods, an arbitrary choice of window size is not necessary, since these are determined empirically and allowed to vary along the genome. RESULTS: Simulations applying this method were performed to identify selection signatures from pooled sequencing FST data, for which allele frequencies were estimated from a pool of individuals. The relative ratio of true to false positives was twice that generated by existing techniques. A comparison of the approach to a previous study that involved pooled sequencing FST data from maize suggested that outlying windows were more clearly separated from their neighbors than when using a standard sliding window approach. CONCLUSIONS: We have developed a novel technique to identify window boundaries for subsequent analysis protocols. When applied to selection studies based on F ST data, this method provides a high discovery rate and minimizes false positives. The method is implemented in the R package GenWin, which is publicly available from CRAN. PMID- 25928173 TI - Frequency and severity of globus pharyngeus symptoms in patients undergoing thyroidectomy: a pre-post short term cross-sectional study. AB - BACKGROUND: Globus pharyngeus is a sensation of a lump or foreign body in the throat, sometimes associated with thyroid diseases and surgery. Previous studies investigated this condition with contradictory results, mainly because not standardized instruments of measure were used. The aim of this study was to evaluate the prevalence and severity of globus pattern symptoms in a population of patients three months after a thyroidectomy, and the reduction or increase of pre-existing symptoms or the onset of new symptoms. METHODS: Ninety-five patients (65 women, 30 men, mean age 56.03 +/- 12.45) were assessed for globus pattern symptoms before and three months after thyroid surgery (72 patients: benign goiter, 23 patients: papillary cancer). The Glasgow-Edinburgh Throat Scale (GETS) was translated into Italian and used as a validated instrument of measure of the severity of globus pattern symptoms. RESULTS: The Italian version of the GETS was reliable (Cronbach alpha = 0.85) and valid. Normative data were used to classify patients into 4 groups of severity. A significant decrease of the mean GETS score was observed at the postoperative assessment (13.02 +/- 11.84 vs 8.00 +/- 11.26; p < 0.01), but beside symptomatic patients who improved we could observe also two other significant groups of patients: asymptomatic patients who developed symptoms and symptomatic patients who remained symptomatic. CONCLUSIONS: The significant decrease of the mean GETS postoperative score was mainly due to the improvement of strongly symptomatic patients. Two other significant outcomes exist and further studies are needed to understand their pathophysiological mechanism. PMID- 25928175 TI - Well-oriented epitaxial gold nanotriangles and bowties on MoS2 for surface enhanced Raman scattering. AB - We report on epitaxial growth of Au nanotriangles (AuNTs) and bowties consisting of opposing tip-to-tip AuNTs with a few-nanometer gap on n-layer MoS2. These AuNTs exhibit well-defined crystallographic orientations with the average size determined by the MoS2 thickness. Monolayer (1L) MoS2 shows the weakest coalescence, corroborating the layer-dependent interactions among Au and n-layer MoS2. High-resolution transmission electron microscopy characterization confirms the lattice directing of thin MoS2 sheets on the AuNT formation with [111]Au||[001]MoS2 and <211>Au||<210>MoS(2). By introducing misfit dislocation arrays, the system with an 8.8% lattice misfit is stress-free. In particular, subwavelength-sized gold bowtie nanoantennas can be easily found on the MoS2 surface with a spacing gap down to 3 nm and a density up to 1.6 * 10(13) m(-2). This technique is low cost, time-saving and free of impurities compared to the conventional lithography technologies. Meanwhile, the equilateral AuNTs can enhance Raman signals of thin MoS2 sheets far stronger than that by ordinary gold films, indicating the potential use of AuNTs as SERS substrates for SERS applications. PMID- 25928177 TI - An international study of research misconduct policies. AB - Research misconduct is an international concern. Misconduct policies can play a crucial role in preventing and policing research misconduct, and many institutions have developed their own policies. While institutional policies play a key role in preventing and policing misconduct, national policies are also important to ensure consistent promulgation and enforcement of ethical standards. The purpose of this study was to obtain more information about research misconduct policies across the globe. We found that twenty-two of the top forty research and development funding countries (55%) had a national misconduct policy. Four countries (18.2%) are in the process of developing a policy, and four (18.2%) have a national research ethics code but no misconduct policy. All twenty-two countries (100%) with national policies included fabrication, falsification, and plagiarism in the definition of misconduct, but beyond that there was considerable diversity. Unethical authorship was mentioned in 54.6% of the misconduct definitions, followed by unethical publication practices (36.4%), conflict of interest mismanagement (36.4%), unethical peer review (31.8%), misconduct related to misconduct investigations (27.3%), poor record keeping (27.3%), other deception (27.3%), serious deviations (22.7%), violating confidentiality (22.7%), and human or animal research violations (22.7%). Having a national policy was positively associated with research and development funding ranking and intensiveness. To promote integrity in international research collaborations, countries should seek to harmonize and clarify misconduct definitions and develop procedures for adjudicating conflicts when harmonization does not occur. PMID- 25928176 TI - Once-per-step control of ankle-foot prosthesis push-off work reduces effort associated with balance during walking. AB - BACKGROUND: Individuals with below-knee amputation have more difficulty balancing during walking, yet few studies have explored balance enhancement through active prosthesis control. We previously used a dynamical model to show that prosthetic ankle push-off work affects both sagittal and frontal plane dynamics, and that appropriate step-by-step control of push-off work can improve stability. We hypothesized that this approach could be applied to a robotic prosthesis to partially fulfill the active balance requirements of human walking, thereby reducing balance-related activity and associated effort for the person using the device. METHODS: We conducted experiments on human participants (N = 10) with simulated amputation. Prosthetic ankle push-off work was varied on each step in ways expected to either stabilize, destabilize or have no effect on balance. Average ankle push-off work, known to affect effort, was kept constant across conditions. Stabilizing controllers commanded more push-off work on steps when the mediolateral velocity of the center of mass was lower than usual at the moment of contralateral heel strike. Destabilizing controllers enforced the opposite relationship, while a neutral controller maintained constant push-off work regardless of body state. A random disturbance to landing foot angle and a cognitive distraction task were applied, further challenging participants' balance. We measured metabolic rate, foot placement kinematics, center of pressure kinematics, distraction task performance, and user preference in each condition. We expected the stabilizing controller to reduce active control of balance and balance-related effort for the user, improving user preference. RESULTS: The best stabilizing controller lowered metabolic rate by 5.5% (p = 0.003) and 8.5% (p = 0.02), and step width variability by 10.0% (p = 0.009) and 10.7% (p = 0.03) compared to conditions with no control and destabilizing control, respectively. Participants tended to prefer stabilizing controllers. These effects were not due to differences in average push-off work, which was unchanged across conditions, or to average gait mechanics, which were also unchanged. Instead, benefits were derived from step-by-step adjustments to prosthesis behavior in response to variations in mediolateral velocity at heel strike. CONCLUSIONS: Once-per-step control of prosthetic ankle push-off work can reduce both active control of foot placement and balance-related metabolic energy use during walking. PMID- 25928178 TI - Rethinking authorship in the era of collaborative research. AB - The size and complexity of research teams continues to grow, especially within the realms of science and engineering. This has intensified already existing concerns about relying on traditional authorship schemes as the way to allocate credit for a contribution to a research project. In this paper, we examine current authorship problems plaguing research communities and provide suggestions for how those problems could potentially be mitigated. We recommend that research communities, especially those involved in large scale collaborations, revisit the contributor model and embrace it as means for allocating credit more authentically and transparently. PMID- 25928179 TI - Playing, sitting out, and observing the game: an investigation of faculty members' perspectives on political behavior in ethical decision making. AB - Ethical dilemmas are inherently ambiguous, complex, and ill-defined. Additionally, these dilemmas involve multiple stakeholders. These characteristics may induce political behavior as a resolution tactic. Thus, the goal of the present effort was to investigate perspectives on politics among researchers in an ethical decision-making context. A qualitative analysis of interviews with university faculty members revealed that faculty members' perspectives on political behavior in an ethical decision-making context fall into a number of categories, including positive, negative, and realistic views of political activity. The implications of these varying perspectives on ethical decision making are discussed. PMID- 25928180 TI - Research ethics committee: dominance and accountability. PMID- 25928181 TI - Synthesis of mixed-valence hexanuclear Mn(II/III) clusters from its Mn(II) precursor: variations of catecholase-like activity and magnetic coupling. AB - One Mn(II) coordination polymer, [Mn(o-(NO2)C6H4COO)2(pyz)(H2O)]n (1), has been synthesized and oxidized with n-Bu4NMnO4 in non-aqueous media to two mixed valence hexanuclear Mn(II/III) complexes [MnIII2MnII4O2(pyz)0.61/(MeOH)0.39(o (NO2)C6H4COO)10.(H2O).{(CH3)2CO}2].(CH3)2CO (2) and [MnIII2MnII4O2(pyz)0.28/(MeCN)3.72(o-(NO2)C6H4COO)10.(H2O)] (3) (where pyz = pyrazine). All three complexes were characterized by elemental analyses, IR spectroscopy, single-crystal X-ray diffraction analyses, and variable-temperature magnetic measurements. The structural analyses reveal that complex 1 is comprised of linear chains of pyz bridged Mn(II), which are further linked to one another by syn-anti carboxylate bridges, giving rise to a two-dimensional (2D) net. Complexes 2 and 3 feature mixed valence [MnIII2MnII4] units in which each of the six manganese centres reside in an octahedral environment. Apart from the variations in terminal ligands (acetone for 2 and acetonitrile for 3), the complexes are very similar. Using 3,5-di-tert-butyl catechol (3,5-DTBC) as the substrate, the catecholase-like activity of the complexes has been studied and it is found that the mixed valent Mn6 complexes (2 and 3) are much more active towards aerial oxidation of catechol compared to the Mn(II) complex (1). Variable temperature (1.8-300 K) magnetic susceptibility measurements showed the presence of antiferromagnetic coupling in all three complexes. The magnetic data have been fitted with a 2D quadratic model derived by Lines, giving the exchange constant J/kB = -0.0788(5) K for 1. For 2 and 3, antiferromagnetic interactions within the Mn6 cluster have been fitted with models containing three exchange constants: JA/kB = -70 K, JB/kB = -0.5 K, JC/kB = -2.9 K for 2 and JA/kB = -60 K, JB/kB = 0.3 K, JC/kB = -2.8 K for 3. PMID- 25928182 TI - Argininosuccinate synthetase 1 suppression and arginine restriction inhibit cell migration in gastric cancer cell lines. AB - Gastric cancer metastasis remains a major cause of cancer-related deaths. There is an urgent need to develop new therapeutic approaches targeting metastatic gastric cancer. Argininosuccinate synthetase 1 (ASS1) expression is increased in gastric cancer. We detected the protein expression of ASS1 in human gastric cancer cell lines (AGS, NCI-N87, and MKN45) and in murine gastric cancer cell lines (3I and 3IB2). We used vector-mediated short hairpin RNA (shRNA) expression to silence ASS1 expression in the MKN45 and 3IB2 cell lines, and analyzed the effects of this protein on cell migration and metastasis. We demonstrated that ASS1 silencing suppressed cell migration in the MKN45 and 3IB2 cell lines. ASS1 knockdown significantly reduced liver metastasis in mice after the intrasplenic implantation of 3IB2 cancer cell clones. To determine whether arginine restriction may represent a therapeutic approach to treat gastric cancer, the sensitivity of tumor cells to arginine depletion was determined in gastric cancer cells. Arginine depletion significantly inhibited cell migration in the gastric cancer cell line. The silencing of ASS1 expression in MKN45 and 3IB2 gastric cancer cells markedly decreased STAT3 protein expression. In conclusion, our results indicate that the ASS1 protein is required for cell migration in gastric cancer cell lines. PMID- 25928184 TI - Ten simple rules for a successful cross-disciplinary collaboration. PMID- 25928185 TI - Chromosome differentiation patterns during cichlid fish evolution. PMID- 25928186 TI - Automatic discovery of cell types and microcircuitry from neural connectomics. AB - Neural connectomics has begun producing massive amounts of data, necessitating new analysis methods to discover the biological and computational structure. It has long been assumed that discovering neuron types and their relation to microcircuitry is crucial to understanding neural function. Here we developed a non-parametric Bayesian technique that identifies neuron types and microcircuitry patterns in connectomics data. It combines the information traditionally used by biologists in a principled and probabilistically coherent manner, including connectivity, cell body location, and the spatial distribution of synapses. We show that the approach recovers known neuron types in the retina and enables predictions of connectivity, better than simpler algorithms. It also can reveal interesting structure in the nervous system of Caenorhabditis elegans and an old man-made microprocessor. Our approach extracts structural meaning from connectomics, enabling new approaches of automatically deriving anatomical insights from these emerging datasets. PMID- 25928187 TI - A PreSTIGEous use of LncRNAs to predict enhancers. PMID- 25928189 TI - Intraoperative burst suppression is associated with postoperative delirium following cardiac surgery: a prospective, observational study. AB - BACKGROUND: Postoperative delirium (POD) occurs frequently after cardiac surgery and is associated with increased morbidity and mortality. We analysed whether perioperative bilateral BIS monitoring may detect abnormalities before the onset of POD in cardiac surgery patients. METHODS: In a prospective observational study, 81 patients undergoing cardiac surgery were included. Bilateral Bispectral Index (BIS)-monitoring was applied during the pre-, intra- and postoperative period, and BIS, EEG Asymmetry (ASYM), and Burst Suppression Ratio (BSR) were recorded. POD was diagnosed according to the Confusion Assessment Method for the Intensive Care Unit, and patients were divided into a delirium and non-delirium group. RESULTS: POD was detected in 26 patients (32%). A trend towards a lower ASYM was observed in the delirium group as compared to the non-delirium group on the preoperative day (ASYM = 48.2 +/- 3.6% versus 50.0 +/- 4.7%, mean +/- sd, p = 0.087) as well as before induction of anaesthesia, with oral midazolam anxiolysis (median ASYM = 49.5%, IQR [47.4;51.5] versus 50.6%, IQR [49.1;54.2], p = 0.081). Delirious patients remained significantly (p = 0.018) longer in a burst suppression state intraoperatively (107 minutes, IQR [47;170] versus 44 minutes, IQR [11;120]) than non-delirious patients. Receiver operating analysis revealed burst suppression duration (area under the curve = 0.73, p = 0.001) and BSR (AUC = 0.68, p = 0.009) as predictors of POD. CONCLUSIONS: Intraoperative assessment of BSR may identify patients at risk of POD and should be investigated in further studies. So far it remains unknown whether there is a causal relationship or rather an association between intraoperative burst suppression and the development of POD. TRIAL REGISTRATION: clinicaltrials.gov NCT01048775. PMID- 25928190 TI - Endoscopic type 1 tympanoplasty in pediatric patients using tragal cartilage. AB - IMPORTANCE: The main objective in the treatment of chronic otitis media is to relieve drainage and to rehabilitate hearing. Various materials can be used to repair the tympanic membrane (TM) through different tympanoplasty techniques. OBJECTIVE: To assess the results of endoscopic type I tympanoplasty in pediatric patients using tragal cartilage as a grafting material. DESIGN, SETTING, AND PARTICIPANTS: In this prospective study, we studied 80 ears in 80 pediatric patients (ages, 5-17 years) who had undergone type I tympanoplasty from January 2011 to December 2013 at a tertiary referral hospital. We classified our patients into a younger group (<=10 years; n = 40) and an older group (>10 years; n = 40). Patients were followed for up to 6 months. INTERVENTIONS: Endoscopic type I tympanoplasty using split-thickness tragal cartilage. MAIN OUTCOMES AND MEASURES: We identified the following criteria for success: (1) healing of the TM (anatomical success) and (2) improvement in hearing by assessing the change in the air-bone gap (ABG). We also assessed the mean operation duration and the different prognostic factors. RESULTS: Healing of the TM healing occurred in 34 patients (85%) in the younger group vs 36 patients (90%) in the older group. Both groups had notable improvement compared with the preoperative measurements, with no significant differences between the 2 groups. Thirty patients (75%) in the younger group had improvement in their ABG vs 32 patients (80%) in the older group, with a mean ABG of 8.0 dB and 10.5 dB in the younger and older groups, respectively. Both groups had significant functional success with no significant differences between the 2 groups. Sixty patients (75%) displayed a type A tympanogram at their 6-month postoperative audiometric testing (28 patients in the younger group vs 32 patients in the older group). There were no statistically significant differences regarding the anatomical and functional success between the patients who had previously undergone adenotonsillectomy and the other patients. The mean (SD) operation duration was 55.03 (2.50) minutes. CONCLUSIONS AND RELEVANCE: In pediatric patients undergoing type I tympanoplasty, the endoscopic approach using the tragal cartilage as a grafting material resulted in successful anatomical and functional outcomes that are in comparable to other techniques but with a shorter operation duration. Age of the patient, auditory tube dysfunction, and previous adenotonsillectomy were not prognostic factors for this procedure. PMID- 25928191 TI - Michael Addition of Soft Carbon Nucleophiles to Alkylidene Isoxazol-5-ones: A Divergent Entry to beta-Branched Carbonyl Compounds. AB - A novel, divergent strategy toward the synthesis of beta-branched (and linear) carbonyl compounds is developed by taking advantage of alkylidene isoxazol-5-ones as key building blocks. The yields obtained range from good to excellent, therefore making the described methods attractive options for building such molecules. PMID- 25928193 TI - On Why the Two Polymorphs of NaFePO4 Exhibit Widely Different Magnetic Structures: Density Functional Analysis. AB - Triphylite-NaFePO4 is a cathode material for Na(+)-ion batteries, whereas its alternative polymorph maricite-NaFePO4 is not. These two different polymorphs exhibit widely different magnetic structures; the ordered magnetic structure of triphylite-NaFePO4 below ~50 K is described by the propagation vector q1 = (0, 0, 0) with collinear spins, and that of maricite-NaFePO4 below ~13 K is described by q2 = (1/2, 0, 1/2) with noncollinear spins. We probed the causes for these differences by calculating the spin exchange interactions of the two polymorphs and determining the preferred orientations of their high-spin Fe(2+) (d(6), S = 2) ions on the basis of density functional calculations. Our study shows that maricite-NaFePO4 is not spin-frustrated, which is also the case for triphylite NaFePO4, that the ordered magnetic structure of triphylite-NaFePO4 is determined mainly by spin exchange, whereas that of maricite-NaFePO4 is determined by both spin exchange and magnetic anisotropy, and that the preferred spin orientations in the two polymorphs can be explained by perturbation theory using spin-orbit coupling as the perturbation. PMID- 25928192 TI - Primary cardiac tumors on the verge of oblivion: a European experience over 15 years. AB - BACKGROUND: Primary tumors of the heart represent an exceedingly rare entity in cardiac surgery and literature regarding management and outcome is rare. The aim of this study was to translate 15 years of experience in both multimodal diagnosis and surgical treatment of one of the largest collective of patients in literature into a detailed analysis of patient prognosis, mean survival and best treatment approach. METHODS AND RESULTS: All patients who underwent open-heart surgery at the Hospital of the Medical University of Vienna for primary cardiac tumor excision between 1999 and 2014 were analyzed retrospectively. Mean follow up was 76.8 months. Descriptive statistical measurements were applied. 113 patients were identified, 71 (62.8%) female and 42 (37.2%) male patients with a mean age of 57.9 +/- 16.8 years. 90.3% (n = 102) masses were benign, 9.7% (n = 11) were malignant. Complete resection was possible for 99% and for 18.2% of benign and malignant masses, respectively. 2.9% of benign tumors and 45.5% of malignant tumors relapsed. The 30-day mortality was 1.8% (n = 2). Mean survival was 187.2 +/- 2.7 months and 26.2 +/- 9.8 months for benign and malignant pathologies, respectively. Sarcoma patients who underwent adjuvant combination chemotherapy or adjuvant mono-chemotherapy and radiation had a statistically significant survival advantage of 41.5 months. CONCLUSION: Primary cardiac tumors remain challenging in the clinical setting. A multimodality treatment approach especially for sarcoma patients prolongs mean survival and should be regarded as the standard of care. PMID- 25928194 TI - An Ultimate Stereocontrol in Asymmetric Synthesis of Optically Pure Fully Aromatic Helicenes. AB - The role of the helicity of small molecules in enantioselective catalysis, molecular recognition, self-assembly, material science, biology, and nanoscience is much less understood than that of point-, axial-, or planar-chiral molecules. To uncover the envisaged potential of helically chiral polyaromatics represented by iconic helicenes, their availability in an optically pure form through asymmetric synthesis is urgently needed. We provide a solution to this problem present since the birth of helicene chemistry in 1956 by developing a general synthetic methodology for the preparation of uniformly enantiopure fully aromatic [5]-, [6]-, and [7]helicenes and their functionalized derivatives. [2 + 2 + 2] Cycloisomerization of chiral triynes combined with asymmetric transformation of the first kind (ultimately controlled by the 1,3-allylic-type strain) is central to this endeavor. The point-to-helical chirality transfer utilizing a traceless chiral auxiliary features a remarkable resistance to diverse structural perturbations. PMID- 25928197 TI - A unique view on male infertility around the globe. AB - BACKGROUND: Infertility affects an estimated 15% of couples globally, amounting to 48.5 million couples. Males are found to be solely responsible for 20-30% of infertility cases and contribute to 50% of cases overall. However, this number does not accurately represent all regions of the world. Indeed, on a global level, there is a lack of accurate statistics on rates of male infertility. Our report examines major regions of the world and reports rates of male infertility based on data on female infertility. METHODS: Our search consisted of systematic reviews, meta-analyses, and population-based studies by searching the terms "epidemiology, male infertility, and prevalence." We identified 16 articles for detailed study. We typically used the assumption that 50% of all cases of infertility are due to female factors alone, 20-30% are due to male factors alone, and the remaining 20-30% are due to a combination of male and female factors. Therefore, in regions of the world where male factor or rates of male infertility were not reported, we used this assumption to calculate general rates of male factor infertility. RESULTS: Our calculated data showed that the distribution of infertility due to male factor ranged from 20% to 70% and that the percentage of infertile men ranged from 2.5% to 12%. Infertility rates were highest in Africa and Central/Eastern Europe. Additionally, according to a variety of sources, rates of male infertility in North America, Australia, and Central and Eastern Europe varied from 4 5-6%, 9%, and 8-12%, respectively. CONCLUSION: This study demonstrates a novel and unique way to calculate the distribution of male infertility around the world. According to our results, at least 30 million men worldwide are infertile with the highest rates in Africa and Eastern Europe. Results indicate further research is needed regarding etiology and treatment, reduce stigma & cultural barriers, and establish a more precise calculation. PMID- 25928198 TI - Kimura disease accompanied with nephrotic syndrome in a 45-year-old male. AB - Kimura disease (KD) is an uncommon chronic inflammatory disorder of unknown etiology, occurs mainly in Asian young males, presenting as subcutaneous growing masses, with a predilection for head and neck, with or without satellite lymphadenopathy. Herein, we report a case of an atypical manifestation of KD accompanied with NS in a middle-aged man, though the patient was clinically misdiagnosed previously. The diagnosis of KD can be difficult and misleading, so we must explore the main points of KD so as to prevent misdiagnosis. PMID- 25928199 TI - Fully automatic evaluation of the corneal endothelium from in vivo confocal microscopy. AB - BACKGROUND: Manual and semi-automatic analyses of images, acquired in vivo by confocal microscopy, are often used to determine the quality of corneal endothelium in the human eye. These procedures are highly time consuming. Here, we present two fully automatic methods to analyze and quantify corneal endothelium imaged by in vivo white light slit-scanning confocal microscopy. METHODS: In the first approach, endothelial cell density is estimated with the help of spatial frequency analysis. We evaluate published methods, and propose a new, parameter-free method. In the second approach, based on the stochastic watershed, cells are automatically segmented and the result is used to estimate cell density, polymegathism (cell size variability) and pleomorphism (cell shape variation). We show how to determine optimal values for the three parameters of this algorithm, and compare its results to a semi-automatic delineation by a trained observer. RESULTS: The frequency analysis method proposed here is more precise than any published method. The segmentation method outperforms the fully automatic method in the NAVIS software (Nidek Technologies Srl, Padova, Italy), which significantly overestimates the number of cells for cell densities below approximately 1200 mm(-2), as well as previously published methods. CONCLUSIONS: The methods presented here provide a significant improvement over the state of the art, and make in vivo, automated assessment of corneal endothelium more accessible. The segmentation method proposed paves the way to many possible new morphometric parameters, which can quickly and precisely be determined from the segmented image. PMID- 25928201 TI - Targeted next generation sequencing of RB1 gene for the molecular diagnosis of Retinoblastoma. AB - BACKGROUND: The spectrum of RB1gene mutations in Retinoblastoma (RB) patients and the necessity of multiple traditional methods for complete variant analysis make the molecular diagnosis a cumbersome, labor-intensive and time-consuming process. Here, we have used targeted next generation sequencing (NGS) approach with in house analysis pipeline to explore its potential for the molecular diagnosis of RB. METHODS: Thirty-three patients with RB and their family members were selected randomly. DNA from patient blood and/or tumor was used for RB1 gene targeted sequencing. The raw reads were obtained from Illumina Miseq. An in-house bioinformatics pipeline was developed to detect both single nucleotide variants (SNVs) and small insertions/deletions (InDels) and to distinguish between somatic and germline mutations. In addition, ExomeCNV and Cn. MOPS were used to detect copy number variations (CNVs). The pathogenic variants were identified with stringent criteria, and were further confirmed by conventional methods and cosegregation in families. RESULTS: Using our approach, an array of pathogenic variants including SNVs, InDels and CNVs were detected in 85% of patients. Among the variants detected, 63% were germline and 37% were somatic. Interestingly, nine novel pathogenic variants (33%) were also detected in our study. CONCLUSIONS: We demonstrated for the first time that targeted NGS is an efficient approach for the identification of wide spectrum of pathogenic variants in RB patients. This study is helpful for the molecular diagnosis of RB in a comprehensive and time-efficient manner. PMID- 25928202 TI - Superior Properties of Energetically Stable La(2/3)Sr(1/3)MnO(3)/Tetragonal BiFeO3 Multiferroic Superlattices. AB - The superlattice of energetically stable La2/3Sr1/3MnO3 and tetragonal BiFeO3 is investigated by means of density functional theory. The superlattice as a whole exhibits a half-metallic character, as is desired for spintronic devices. The interfacial electronic states and exchange coupling are analyzed in details. We demonstrate that the interfacial O atoms play a key role in controlling the coupling. The higher ferroelectricity of tetragonal BiFeO3 and stronger response to the magnetic moments in the La2/3Sr1/3MnO3/BiFeO3 superlattice show a strongly enhanced electric control of the magnetism as compared to the rhombohedral one. Therefore, it is particularly practical interest in the magnetoelectrically controlled spintronic devices. PMID- 25928203 TI - Genetic characterization of the tick-borne orbiviruses. AB - The International Committee for Taxonomy of Viruses (ICTV) recognizes four species of tick-borne orbiviruses (TBOs): Chenuda virus, Chobar Gorge virus, Wad Medani virus and Great Island virus (genus Orbivirus, family Reoviridae). Nucleotide (nt) and amino acid (aa) sequence comparisons provide a basis for orbivirus detection and classification, however full genome sequence data were only available for the Great Island virus species. We report representative genome-sequences for the three other TBO species (virus isolates: Chenuda virus (CNUV); Chobar Gorge virus (CGV) and Wad Medani virus (WMV)). Phylogenetic comparisons show that TBOs cluster separately from insect-borne orbiviruses (IBOs). CNUV, CGV, WMV and GIV share low level aa/nt identities with other orbiviruses, in 'conserved' Pol, T2 and T13 proteins/genes, identifying them as four distinct virus-species. The TBO genome segment encoding cell attachment, outer capsid protein 1 (OC1), is approximately half the size of the equivalent segment from insect-borne orbiviruses, helping to explain why tick-borne orbiviruses have a ~1 kb smaller genome. PMID- 25928204 TI - Estrogen receptor mutations and their role in breast cancer progression. AB - Endocrine therapy is the mainstay of treatment in estrogen receptor-positive breast cancers and significantly reduces disease recurrence and breast cancer related mortality. However, acquired resistance to therapy has been noted in nearly one-third of women treated with tamoxifen and other endocrine therapies. Mutations in the estrogen receptor have long been speculated to play a role in endocrine therapy resistance but have been rarely detected. However, recent studies utilizing next-generation sequencing on estrogen receptor-positive, metastatic clinical samples have revealed that recurrent ESR1 mutations are far more frequent than previously thought and may play an important role in acquired endocrine therapy resistance. Here we review recent advances in detection and characterization of ESR1 mutations in advanced, endocrine therapy-resistant breast cancers. PMID- 25928205 TI - Recommendations on complementary feeding for healthy, full-term infants. AB - Weaning (or introduction of complementary feeding) is a special and important moment in the growth of a child, both for the family and the infant itself, and it can play a major role in the child's future health. Throughout the years, various weaning modes have come in succession, the latest being baby-led weaning; the timing for introducing foods and the requirements of which sort of nutrient for weaning have also changed over time. Furthermore, the role played by nutrition, especially in the early stages of life, for the onset of later non communicable disorders, such as diabetes, obesity or coeliac disease has also been increasingly highlighted.Members of Italian Society of Gastroenterology, Hepathology and Pediatric Nutrition (SIGENP) and the Italian Society of Allergology and Pediatric Immunology (SIAIP) Emilia Romagna here propose a practical approach for pediatricians to deal with daily practice. The four main areas for discussion were weaning in relation with the onset of allergic diseases, coeliac disease, diabetes and metabolic syndrome, the nutrition requirements to take into account for assessing the diet of infants under one year of age and about the practice of baby-led weaning focusing on limits and benefits, respectively. PMID- 25928206 TI - Acupuncture attenuates cognitive deficits and increases pyramidal neuron number in hippocampal CA1 area of vascular dementia rats. AB - BACKGROUND: Decreased cognition is recognized as one of the most severe and consistent behavioral impairments in dementia. Experimental studies have reported that acupuncture may improve cognitive deficits, relieve vascular dementia (VD) symptoms, and increase cerebral perfusion and electrical activity. METHODS: Multi infarction dementia was modeled in rats with 3% microemboli saline suspension. Two weeks after acupuncture at Zusanli (ST36), all rats were subjected to a hidden platform trial to test their 3-day spatial memory using the Morris water maze test. To estimate the numbers of pyramidal neuron, astrocytes, and synaptic boutons in hippocampal CA1 area, we adopted an unbiased stereology method to accurately sample and measure the size of cells. RESULTS: We found that acupuncture at ST36 significantly decreased the escape latency of VD rats. In addition, acupuncture significantly increased the pyramidal neuron number in hippocampal CA1 area (P < 0.05) and tended to decrease the number of astrocytes (P = 0.063). However, there was no significant change in the synaptic bouton number of hippocampal CA1 area in any of the groups (P > 0.05). CONCLUSIONS: These findings suggest that acupuncture may improve cognitive deficits and increase pyramidal neuron number of hippocampal CA1 area in VD rats. PMID- 25928207 TI - Giant congenital lower lip nevus restored by local advanced skin flap: a case report. AB - INTRODUCTION: A congenital lower lip nevus is common, but a lower lip length lesion of more than 40% is hard to excise simply, without any distortion. We designed a lower lip bilateral advanced skin flap to restore the wound surface after completely and successfully removing the nevus. CASE PRESENTATION: A 13 year-old Mongolian girl was referred to us with a giant congenital lower lip nevus. The lesion covered nearly half of her lower lip. We designed a lower lip bilateral advanced skin flap to restore the wound surface, after completely removing the nevus without advanced repair. CONCLUSIONS: This case report demonstrates a case of a lower lip length defect of more than 40%, repaired by direct closure without dysfunction. It was a successful attempt that minimized the subsequent scar and dysfunction. PMID- 25928208 TI - Derivation and validation of clinical phenotypes for COPD: a systematic review. AB - BACKGROUND: The traditional classification of COPD, which relies solely on spirometry, fails to account for the complexity and heterogeneity of the disease. Phenotyping is a method that attempts to derive a single or combination of disease attributes that are associated with clinically meaningful outcomes. Deriving phenotypes entails the use of cluster analyses, and helps individualize patient management by identifying groups of individuals with similar characteristics. We aimed to systematically review the literature for studies that had derived such phenotypes using unsupervised methods. METHODS: Two independent reviewers systematically searched multiple databases for studies that performed validated statistical analyses, free of definitive pre-determined hypotheses, to derive phenotypes among patients with COPD. Data were extracted independently. RESULTS: 9156 citations were retrieved, of which, 8 studies were included. The number of subjects ranged from 213 to 1543. Most studies appeared to be biased: patients were more likely males, with severe disease, and recruited in tertiary care settings. Statistical methods used to derive phenotypes varied by study. The number of phenotypes identified ranged from 2 to 5. Two phenotypes, with poor longitudinal health outcomes, were common across multiple studies: young patients with severe respiratory disease, few cardiovascular co morbidities, poor nutritional status and poor health status, and a phenotype of older patients with moderate respiratory disease, obesity, cardiovascular and metabolic co-morbidities. CONCLUSIONS: The recognition that two phenotypes of COPD were often reported may have clinical implications for altering the course of the disease. This review also provided important information on limitations of phenotype studies in COPD and the need for improvement in future studies. PMID- 25928209 TI - The precision medicine initiative: a new national effort. PMID- 25928210 TI - Biochemical and structural analysis of an Eis family aminoglycoside acetyltransferase from bacillus anthracis. AB - Proteins from the enhanced intracellular survival (Eis) family are versatile acetyltransferases that acetylate amines at multiple positions of several aminoglycosides (AGs). Their upregulation confers drug resistance. Homologues of Eis are present in diverse bacteria, including many pathogens. Eis from Mycobacterium tuberculosis (Eis_Mtb) has been well characterized. In this study, we explored the AG specificity and catalytic efficiency of the Eis family protein from Bacillus anthracis (Eis_Ban). Kinetic analysis of specificity and catalytic efficiency of acetylation of six AGs indicates that Eis_Ban displays significant differences from Eis_Mtb in both substrate binding and catalytic efficiency. The number of acetylated amines was also different for several AGs, indicating a distinct regiospecificity of Eis_Ban. Furthermore, most recently identified inhibitors of Eis_Mtb did not inhibit Eis_Ban, underscoring the differences between these two enzymes. To explain these differences, we determined an Eis_Ban crystal structure. The comparison of the crystal structures of Eis_Ban and Eis_Mtb demonstrates that critical residues lining their respective substrate binding pockets differ substantially, explaining their distinct specificities. Our results suggest that acetyltransferases of the Eis family evolved divergently to garner distinct specificities while conserving catalytic efficiency, possibly to counter distinct chemical challenges. The unique specificity features of these enzymes can be utilized as tools for developing AGs with novel modifications and help guide specific AG treatments to avoid Eis-mediated resistance. PMID- 25928214 TI - Clinical impact of stress dose steroids in patients with septic shock: insights from the PROWESS-Shock trial. AB - INTRODUCTION: The aim of our study was to evaluate the clinical impact of the administration of intravenous steroids, alone or in conjunction with drotrecogin alfa (activated) (DrotAA), on the outcomes in septic shock patients. METHODS: We performed a sub-study of the PROWESS-Shock trial (septic shock patients who received fluids and vasopressors above a predefined threshold for at least 4 hours were randomized to receive either DrotAA or placebo for 96 hours). A propensity score for the administration of intravenous steroids for septic shock at baseline was constructed using multivariable logistic regression. Cox proportional hazards model using inverse probability of treatment weighting of the propensity score was used to estimate the effect of intravenous steroids, alone or in conjunction with DrotAA, on 28-day and 90-day all-cause mortality. RESULTS: A total of 1695 patients were enrolled of which 49.5% received intravenous steroids for treatment of septic shock at baseline (DrotAA + steroids N = 436; DrotAA + no steroids N = 414; placebo + steroids N = 403; placebo + no steroids N = 442). The propensity weighted risk of 28-day as well as 90-day mortality in those treated vs. those not treated with steroids did not differ among those randomized to DrotAA vs. placebo (interaction p-value = 0.38 and p = 0.27, respectively) nor was a difference detected within each randomized treatment. Similarly, the course of vasopressor use and cardiovascular SOFA did not appear to be influenced by steroid therapy. In patients with lung infection (N = 744), abdominal infection (N = 510), Gram-positive sepsis (N = 420) and Gram negative sepsis (N = 461), the propensity weighted risk of 28-day as well as 90 day mortality in those treated vs. those not treated with steroids did not differ among those randomized to DrotAA vs. placebo nor was a difference detected within each randomized treatment. CONCLUSIONS: In the present study of septic shock patients, after adjustment for treatment selection bias, we were unable to find noticeable positive impact from intravenous steroids for treatment of septic shock at baseline either in patients randomized for DrotAA or placebo. TRIAL REGISTRATION: Clinicaltrials.gov NCT00604214 . Registered 24 January 2008. PMID- 25928215 TI - RNA-Seq Uncovers SNPs and Alternative Splicing Events in Asian Lotus (Nelumbo nucifera). AB - RNA-Seq is an efficient way to comprehensively identify single nucleotide polymorphisms (SNPs) and alternative splicing (AS) events from the expressed genes. In this study, we conducted transcriptome sequencing of four Asian lotus (Nelumbo nucifera) cultivars using Illumina HiSeq2000 platform to identify SNPs and AS events in lotus. A total of 505 million pair-end RNA-Seq reads were generated from four cultivars, of which 86% were mapped to the lotus reference genome. Using the four sets of data together, a total of 357,689 putative SNPs were identified with an average density of one SNP per 2.2 kb. These SNPs were located in 1,253 scaffolds and 15,016 expressed genes. A/G and C/T were the two major types of SNPs in the Asian lotus transcriptome. In parallel, a total of 177,540 AS events were detected in the four cultivars and were distributed in 64% of the expressed genes of lotus. The predominant type of AS events was alternative 5' first exon, which accounted for 41.2% of all the observed AS events, and exon skipping only accounted for 4.3% of all AS. Gene Ontology analysis was conducted to analyze the function of the genes containing SNPs and AS events. Validation of selected SNPs and AS events revealed that 74% of SNPs and 80% of AS events were reliable, which indicates that RNA-Seq is an efficient approach to uncover gene-associated SNPs and AS events. A large number of SNPs and AS events identified in our study will facilitate further genetic and functional genomics research in lotus. PMID- 25928216 TI - Functional Characterization of D9, a Novel Deazaneplanocin A (DZNep) Analog, in Targeting Acute Myeloid Leukemia (AML). AB - Aberrant epigenetic events contribute to tumorigenesis of all human cancers. Significant efforts are underway in developing new generation of epigenetic cancer therapeutics. Although clinical trials for agents targeting DNA hypermethylation and histone deacetylation have yielded promising results, developing agents that target histone methylation remains to be in the early stage. We and others have previously reported that 3-Deazaneplanocin A (DZNep) is a histone methylation inhibitor that has a wide range of anticancer effects in various human cancers. Here, focusing on acute myeloid leukemia (AML) as a model, we reported a less toxic analog of DZNep, named D9, which is shown to be efficacious in AML cell lines and patient-derived samples in vitro, as well as AML tumorigenesis in vivo. Gene expression analysis in a panel of AML cell lines treated with D9 identified a set of genes that is associated with D9 sensitivity and implicated in multiple oncogenic signaling pathways. Moreover, we show that D9 is able to deplete the leukemia stem cells (LSC) and abolish chemotherapy induced LSC enrichment, leading to dramatic elimination of AML cell survival. Thus, D9 appears to be a robust epigenetic compound that may constitute a potential for AML therapy. PMID- 25928217 TI - Impact of the 2009 H1N1 Pandemic on Age-Specific Epidemic Curves of Other Respiratory Viruses: A Comparison of Pre-Pandemic, Pandemic and Post-Pandemic Periods in a Subtropical City. AB - BACKGROUND: The 2009 H1N1 influenza pandemic caused offseason peaks in temperate regions but coincided with the summer epidemic of seasonal influenza and other common respiratory viruses in subtropical Hong Kong. This study was aimed to investigate the impact of the pandemic on age-specific epidemic curves of other respiratory viruses. METHODS: Weekly laboratory-confirmed cases of influenza A (subtypes seasonal A(H1N1), A(H3N2), pandemic virus A(H1N1)pdm09), influenza B, respiratory syncytial virus (RSV), adenovirus and parainfluenza were obtained from 2004 to 2013. Age-specific epidemic curves of viruses other than A(H1N1)pdm09 were compared between the pre-pandemic (May 2004-April 2009), pandemic (May 2009-April 2010) and post-pandemic periods (May 2010-April 2013). RESULTS: There were two peaks of A(H1N1)pdm09 in Hong Kong, the first in September 2009 and the second in February 2011. The infection rate was found highest in young children in both waves, but markedly fewer cases in school children were recorded in the second wave than in the first wave. Positive proportions of viruses other than A(H1N1)pdm09 markedly decreased in all age groups during the first pandemic wave. After the first wave of the pandemic, the positive proportion of A(H3N2) increased, but those of B and RSV remained slightly lower than their pre-pandemic proportions. Changes in seasonal pattern and epidemic peak time were also observed, but inconsistent across virus-age groups. CONCLUSION: Our findings provide some evidence that age distribution, seasonal pattern and peak time of other respiratory viruses have changed since the pandemic. These changes could be the result of immune interference and changing health seeking behavior, but the mechanism behind still needs further investigations. PMID- 25928218 TI - HIV Malaria Co-Infection Is Associated with Atypical Memory B Cell Expansion and a Reduced Antibody Response to a Broad Array of Plasmodium falciparum Antigens in Rwandan Adults. AB - HIV infected individuals in malaria endemic areas experience more frequent and severe malaria episodes compared to non HIV infected. This clinical observation has been linked to a deficiency in antibody responses to Plasmodium falciparum antigens; however, prior studies have only focused on the antibody response to <0.5% of P. falciparum proteins. To obtain a broader and less-biased view of the effect of HIV on antibody responses to malaria we compared antibody profiles of HIV positive (HIV+) and negative (HIV-) Rwandan adults with symptomatic malaria using a microarray containing 824 P. falciparum proteins. We also investigated the cellular basis of the antibody response in the two groups by analyzing B and T cell subsets by flow cytometry. Although HIV malaria co-infected individuals generated antibodies to a large number of P. falciparum antigens, including potential vaccine candidates, the breadth and magnitude of their response was reduced compared to HIV- individuals. HIV malaria co-infection was also associated with a higher percentage of atypical memory B cells (MBC) (CD19+CD10 CD21-CD27-) compared to malaria infection alone. Among HIV+ individuals the CD4+ T cell count and HIV viral load only partially explained variability in the breadth of P. falciparum-specific antibody responses. Taken together, these data indicate that HIV malaria co-infection is associated with an expansion of atypical MBCs and a diminished antibody response to a diverse array of P. falciparum antigens, thus offering mechanistic insight into the higher risk of malaria in HIV+ individuals. PMID- 25928219 TI - Cytosolic BolA Plays a Repressive Role in the Tolerance against Excess Iron and MV-Induced Oxidative Stress in Plants. AB - The BolA-like protein is present in all eukaryotes, and it is able to form complex with monothiol glutaredoxin of the same subcellular compartments, suggesting that the BolA-like protein has essential function in eukaryotes, and that the function is associated with its partner glutaredoxin. Some studies have indicated a role for BolA proteins in Fe-S cluster synthesis or in redox homeostasis. However, the physiological function of BolA proteins remains to be elucidated. Here, we report the characterization of an insertion mutant of BolA3 in Arabidopsis. Among the four AtBolA proteins found in Arabidopsis, the AtBolA3 was the only BolA located in the cytosol of plant cells. It was highly expressed in roots. AtBolA3 was able to interact with the cytosolic monothiol glutaredoxin, AtGRXS17. The bola3 mutant did not show any notable phenotype under normal growth condition, but rather grew better than wild type under some stresses. The bola3 mutant was more tolerant to excess iron and the MV-induced oxidative stress than wild type. It displayed no necrosis in leaves, developed longer roots, accumulated more iron and higher Fe-S protein activities in roots. In addition, the mutant possessed a more potent antioxidant defense to scavenge ROS species. Taken together, our data indicated that the cytosolic AtBolA3 has a suppressive role in the tolerance to excess iron and the MV-induced oxidative stress in plants. AtBolA3 seems to be a repressor under some stress conditions. PMID- 25928220 TI - Effect of coffee intake on hip fracture: a meta-analysis of prospective cohort studies. AB - Several observational studies suggest an association between coffee intake and hip fracture risk. However, the results among them are inconsistent. We aimed to evaluate the association between coffee consumption and risk of hip fracture by performing a meta-analysis of prospective cohort studies. PubMed, Embase, and Web of Science were searched through July 2014 to identify studies that met pre stated inclusion criterion and reference lists of retrieved articles were reviewed. Information on the characteristics of the included study, risk estimates, and control for possible confounding factors were extracted independently by two authors. A random effects model of meta-analysis was used to calculate the pooled risk estimate. Ten prospective cohort studies involving 5408 patients with hip fracture and 205,930 participants were included in this systematic review. Compared with individuals who did not or seldom drink coffee, the pooled relative risks of hip fracture was 1.13 (95% confidence interval: 0.86 to 1.48) for individuals with the highest coffee consumption. Exception of any single study did not materially alter the combined risk estimate. Visual inspection of funnel plot and Begg's and Egger's tests did not indicate evidence of publication bias. In summary, integrated evidence from prospective cohort studies does not suggest a statistically significant association between coffee consumption and risk of hip fracture in developed countries. PMID- 25928223 TI - Adjusting the incidence increase when screening for statistical lead time will always give estimates of overdiagnosis close to zero. PMID- 25928221 TI - Technology-based interventions for tobacco and other drug use in university and college students: a systematic review and meta-analysis. AB - BACKGROUND: University students have high levels of tobacco and other drug use, yet they are unlikely to seek traditional care. Technology-based interventions are highly relevant to this population. This paper comprises a systematic review and meta-analysis of published randomized trials of technology-based interventions evaluated in a tertiary (university/college) setting for tobacco and other drug use (excluding alcohol). It extends previous reviews by using a broad definition of technology. METHODS: PubMed, PsycInfo, and the Cochrane databases were searched using keywords, phrases, and MeSH terms. Retrieved abstracts (n = 627) were double screened and coded. Included studies met the following criteria: (1) the study was a randomized trial or a randomized controlled trial (RCT); (2) the sample was composed of students attending a tertiary (e.g., university, college) institution; (3) the intervention was either delivered by or accessed using a technological device or process (e.g., computer/internet, telephone, mobile short message services [SMS]); (4) the age range or mean of the sample was between 18 and 25 years; and (5) the intervention was designed to alter a drug use outcome relating to tobacco or other drugs (excluding alcohol). RESULTS: A total of 12 papers met inclusion criteria for the current review. The majority of included papers examined tobacco use (n = 9; 75%), two studies targeted marijuana use (17%); and one targeted stress, marijuana, alcohol, and tobacco use. A quantitative meta-analysis was conducted on the tobacco use studies using an abstinence outcome measure (n = 6), demonstrating that the interventions increased the rate of abstinence by 1.5 times that of controls (Risk Ratio [RR] = 1.54; 95% Confidence Interval [CI] = 1.20-1.98). Across all 12 studies, a total of 20 technology-based interventions were reviewed. A range of technology was employed in the interventions, including stand-alone computer programs (n = 10), internet (n = 5), telephone (n = 3), and mobile SMS (n = 2). CONCLUSIONS: Although technological interventions have the potential to reduce drug use in tertiary students, very few trials have been conducted, particularly for substances other than tobacco. However, the improvement shown in abstinence from tobacco use has the potential to impact substantially on morbidity and mortality. PMID- 25928224 TI - Larvicidal activity and possible mode of action of four flavonoids and two fatty acids identified in Millettia pinnata seed toward three mosquito species. AB - BACKGROUND: Aedes aegypti and Aedes albopictus and Culex pipiens pallens mosquitoes transmit dengue fever and West Nile virus diseases, respectively. This study was conducted to determine the toxicity and mechanism of action of four flavonoids and two fatty acids from Millettia pinnata (Fabaceae) seed as well as six pure fatty acids and four fatty acid esters toward third instar larvae from insecticide-susceptible C. pipiens pallens and A. aegypti as well as wild A. albopictus. Efficacy of 12 experimental liquid formulations containing M. pinnata seed methanol extract and hydrodistillate (0.5-10.0% liquids) was also assessed. METHODS: The contact toxicities of all compounds and 12 formulations were compared with those of two larvicides, temephos and fenthion and the commercial temephos 200 g/L emulsifiable concentrate (EC). The possible mode of larvicidal action of the constituents was elucidated using biochemical methods. Larval mortality and cAMP level were analyzed by the Bonferroni multiple-comparison method. RESULTS: Potent toxicity was produced by karanjin, oleic acid, karanjachromene, linoleic acid, linolenic acid, pongamol, pongarotene, and elaidic acid toward C. pipiens pallens larvae (24 h LC50, 14.61-28.22 mg/L) and A. aegypti larvae (16.13-37.61 mg/L). Against wild A. albopictus larvae, oleic acid (LC50, 18.79 mg/L) and karanjin (35.26 mg/L) exhibited potent toxicity. All constituents were less toxic than either temephos or fenthion. Structure-activity relationship indicates that the degree of saturation, the side chain length, and the geometric isomerism of fatty acids appear to play a role in determining the fatty acid toxicity. Acetylcholinesterase (AChE) is the main site of action of the flavonoids, oleic acid, and palmitic acid. The mechanism of larvicidal action of elaidic acid, arachidic acid, and behenic acid might be due to interference with the octopaminergic system. Linoleic acid and linolenic acid might act on both AChE and octopaminergic receptor. M. pinnata seed extract or hydrodistillate applied as 10% liquid provided 100% mortality toward the three mosquito species larvae and the efficacy of the liquids was comparable to that of temephos 200 g/L EC. CONCLUSION: Further studies will warrant possible applications of M. pinnata seed-derived products as potential larvicides for the control of mosquito populations. PMID- 25928226 TI - Magnetic resonance imaging cooling-reheating protocol indicates decreased fat fraction via lipid consumption in suspected brown adipose tissue. AB - OBJECTIVES: To evaluate whether a water-fat magnetic resonance imaging (MRI) cooling-reheating protocol could be used to detect changes in lipid content and perfusion in the main human brown adipose tissue (BAT) depot after a three-hour long mild cold exposure. MATERIALS AND METHODS: Nine volunteers were investigated with chemical-shift-encoded water-fat MRI at baseline, after a three-hour long cold exposure and after subsequent short reheating. Changes in fat fraction (FF) and R2*, related to ambient temperature, were quantified within cervical supraclavicular adipose tissue (considered as suspected BAT, denoted sBAT) after semi-automatic segmentation. In addition, FF and R2* were quantified fully automatically in subcutaneous adipose tissue (not considered as suspected BAT, denoted SAT) for comparison. By assuming different time scales for the regulation of lipid turnover and perfusion in BAT, the changes were determined as resulting from either altered absolute fat content (lipid-related) or altered absolute water content (perfusion-related). RESULTS: sBAT-FF decreased after cold exposure (mean change in percentage points = -1.94 pp, P = 0.021) whereas no change was observed in SAT-FF (mean = 0.23 pp, P = 0.314). sBAT-R2* tended to increase (mean = 0.65 s-1, P = 0.051) and SAT-R2* increased (mean = 0.40 s-1, P = 0.038) after cold exposure. sBAT-FF remained decreased after reheating (mean = -1.92 pp, P = 0.008, compared to baseline) whereas SAT-FF decreased (mean = -0.79 pp, P = 0.008, compared to after cold exposure). CONCLUSIONS: The sustained low sBAT-FF after reheating suggests lipid consumption, rather than altered perfusion, as the main cause to the decreased sBAT-FF. The results obtained demonstrate the use of the cooling-reheating protocol for detecting changes in the cervical supraclavicular fat depot, being the main human brown adipose tissue depot, in terms of lipid content and perfusion. PMID- 25928227 TI - Urban-rural differences in childhood and adolescent obesity in the United States: a systematic review and meta-analysis. AB - BACKGROUND: A systematic literature review and subsequent meta-analysis were performed to investigate differences in childhood obesity between urban and rural areas in the United States. METHODS: A search of published studies comparing childhood obesity in urban and rural settings was undertaken by probing PubMed and Cumulative Index to Nursing and Allied Health Literature (CINAHL) for articles that met predetermined inclusion criteria. A subsequent meta-analysis was conducted to determine the combined effect size and significance of differences in childhood obesity between urban and rural areas. RESULTS: Ten studies were identified for systematic review, five of which contributed to the meta-analysis. All but one study suggested that residence in rural areas was associated with higher prevalence or increased odds of childhood obesity, compared to children living in urban areas. A meta-analysis of 74,168 pooled participants ages 2-19 found that rural children have 26% greater odds of obesity, compared to urban children (odds ratio=1.26; 95% confidence interval, 1.21-1.32). CONCLUSIONS: Obesity rates are higher among rural children than urban children in the United States. To ensure successful targeted interventions and effective resource allocation, practitioners and policy makers alike should be cognizant of this disparity in childhood obesity. PMID- 25928228 TI - Role of mTOR-Chk1 in enhancing DNA-damaging therapy. PMID- 25928230 TI - Evidence for a clinical association between body mass index and malabsorption in patients with systemic sclerosis. PMID- 25928229 TI - Central presynaptic terminals are enriched in ATP but the majority lack mitochondria. AB - Synaptic neurotransmission is known to be an energy demanding process. At the presynapse, ATP is required for loading neurotransmitters into synaptic vesicles, for priming synaptic vesicles before release, and as a substrate for various kinases and ATPases. Although it is assumed that presynaptic sites usually harbor local mitochondria, which may serve as energy powerhouse to generate ATP as well as a presynaptic calcium depot, a clear role of presynaptic mitochondria in biochemical functioning of the presynapse is not well-defined. Besides a few synaptic subtypes like the mossy fibers and the Calyx of Held, most central presynaptic sites are either en passant or tiny axonal terminals that have little space to accommodate a large mitochondrion. Here, we have used imaging studies to demonstrate that mitochondrial antigens poorly co-localize with the synaptic vesicle clusters and active zone marker in the cerebral cortex, hippocampus and the cerebellum. Confocal imaging analysis on neuronal cultures revealed that most neuronal mitochondria are either somatic or distributed in the proximal part of major dendrites. A large number of synapses in culture are devoid of any mitochondria. Electron micrographs from neuronal cultures further confirm our finding that the majority of presynapses may not harbor resident mitochondria. We corroborated our ultrastructural findings using serial block face scanning electron microscopy (SBFSEM) and found that more than 60% of the presynaptic terminals lacked discernible mitochondria in the wild-type mice hippocampus. Biochemical fractionation of crude synaptosomes into mitochondria and pure synaptosomes also revealed a sparse presence of mitochondrial antigen at the presynaptic boutons. Despite a low abundance of mitochondria, the synaptosomal membranes were found to be highly enriched in ATP suggesting that the presynapse may possess alternative mechanism/s for concentrating ATP for its function. The potential mechanisms including local glycolysis and the possible roles of ATP binding synaptic proteins such as synapsins, are discussed. PMID- 25928231 TI - Association of 42 SNPs with genetic risk for cervical cancer: an extensive meta analysis. AB - BACKGROUND: A large number of single nucleotide polymorphisms (SNPs) associated with cervical cancer have been identified through candidate gene association studies and genome-wide association studies (GWAs). However, some studies have yielded different results for the same SNP. To obtain a more comprehensive understanding, we performed a meta-analysis on previously published case-control studies involving the SNPs associated with cervical cancer. METHODS: Electronic searches of PubMed and Embase were conducted for all publications about the association between gene polymorphisms and cervical cancer. One-hundred and sixty seven association studies were included in our research. For each SNP, three models (the allele, dominant and recessive effect models) were adopted in the meta-analysis. For each model, the effect summary odds ratio (OR) and 95% CI were calculated. Heterogeneity between studies was evaluated by Cochran's Q test. If the p value of Q test was less than 0.01, a random effect model was used; otherwise, a fixed effect model was used. RESULTS: The results of our meta analysis showed that: (1) There were 8, 2 and 8 SNPs that were significantly associated with cervical cancer (P < 0.01) in the allele, dominant and recessive effect models, respectively. (2) rs1048943 (CYP1A1 A4889G) showed the strongest association with cervical cancer in the allele effect model (1.83[1.57, 2.13]); in addition, rs1048943 (CYP1A1 A4889G) had a very strong association in the dominant and recessive effect model. (3) 15, 11 and 10 SNPs had high heterogeneity (P < 0.01) in the three models, respectively. (4) There was no published bias for most of the SNPs according to Egger's test (P < 0.01) and Funnel plot analysis. For some SNPs, their association with cervical cancer was only tested in a few studies and, therefore, might have been subjected to published bias. More studies on these loci are required. CONCLUSION: Our meta analysis provides a comprehensive evaluation of cervical cancer association studies. PMID- 25928232 TI - Plain water consumption is associated with lower intake of caloric beverage: cross-sectional study in Mexican adults with low socioeconomic status. AB - BACKGROUND: Plain water (PW) should be the main beverage consumed by the population. However, consumption of caloric beverages (CB) has increased considerably worldwide. The purpose of this paper is to analyze the association between CB and PW intake in Mexican adults with a low socioeconomic status (SES). METHODS: In a cross-sectional design, beverage consumption was evaluated with a 24-h beverages recall using the five-step multiple-pass method recommended by the U.S. Department of Agriculture. Physical activity, anthropometric and sociodemographic information were obtained. CB was defined as those beverages that provide energy, with the exception of low-fat milk and beverages with noncaloric sweeteners. Participants were classified into five groups according to their PW consumption (nondrinkers and four quartiles). Differences between groups were evaluated with ANOVA and Bonferroni tests for multiple comparisons among quartiles. A two-stage Heckman regression model was designed with robust standard errors, adjusting for potential confounders. RESULTS: A total of 1108 adults between 21 and 59 years of age were evaluated. A negative association was noted between PW intake and CB consumption (p <0.001) with the exception of natural juice, which was positive (p <0.01) and sodas that no differences were found between quartiles. Specifically, for every milliliter of PW, the intake of CB was 3.4, 1.3, 0.68 and 0.38 mL in each quartile, respectively (p <0.001). In Heckman's model, PW consumers were 0.5 times less likely to consume CB (p = 0.029). This probability increased to 0.9 for low-fat milk, skim milk and beverages without added sugar (LFM-BWAS) consumers (p <0.001). Also, for every 100 mL of PW consumption, CB intake diminished by 20 mL (p <0.001). In turn, for every 100 mL of LFM-BWAS consumption, a reduction of 47 mL in CB was observed (p <0.001). CONCLUSIONS: Higher PW consumption was associated with lower CB consumption. This association suggests that future studies are warranted to determine if increasing PW intake in a low SES Mexican population can reduce intake of CB. PMID- 25928234 TI - Darwin and Fisher meet at biotech: on the potential of computational molecular evolution in industry. AB - BACKGROUND: Today computational molecular evolution is a vibrant research field that benefits from the availability of large and complex new generation sequencing data - ranging from full genomes and proteomes to microbiomes, metabolomes and epigenomes. The grounds for this progress were established long before the discovery of the DNA structure. Specifically, Darwin's theory of evolution by means of natural selection not only remains relevant today, but also provides a solid basis for computational research with a variety of applications. But a long-term progress in biology was ensured by the mathematical sciences, as exemplified by Sir R. Fisher in early 20th century. Now this is true more than ever: The data size and its complexity require biologists to work in close collaboration with experts in computational sciences, modeling and statistics. RESULTS: Natural selection drives function conservation and adaptation to emerging pathogens or new environments; selection plays key role in immune and resistance systems. Here I focus on computational methods for evaluating selection in molecular sequences, and argue that they have a high potential for applications. Pharma and biotech industries can successfully use this potential, and should take the initiative to enhance their research and development with state of the art bioinformatics approaches. CONCLUSIONS: This review provides a quick guide to the current computational approaches that apply the evolutionary principles of natural selection to real life problems - from drug target validation, vaccine design and protein engineering to applications in agriculture, ecology and conservation. PMID- 25928236 TI - Mistrust surrounding vaccination recommendations by the Japanese government: results from a national survey of working-age individuals. AB - BACKGROUND: Considering that public attitudes on vaccine safety and effectiveness are known to influence the success of vaccination campaigns, an increased understanding of socio-demographic characteristics might help improve future communication strategies and lead to greater rates of vaccination uptake. This study investigated associations between mistrust for governmental vaccine recommendations and the socio-demographic characteristics of working-age individuals in Japan. METHODS: A web-based, cross-sectional survey of vaccination attitudes was conducted among 3140 Japanese people aged 20 to 69 years. Multiple logistic regression analysis was used to examine statistical associations between vaccination attitudes and socio-demographic characteristics, including the participant's most trusted information resources, demographic factors and general health conditions. RESULTS: A total of 893 (28.4%) individuals reported a general mistrust towards the Japanese government's recommendations for vaccination. Respondents who did not trust official government sources were more likely to consider friends, the internet and books (for both genders); family members and newspapers (among women only); and television (among men only), as the most trusted resources for vaccination-related information. Relatively poor health in men was associated with a general mistrust of vaccination recommendations (adjusted Odds Ratio (aOR): 1.37, 95% Confidence Interval (95% CI): 1.07-1.69). A trend towards worsening general health was also associated with decreasing trust in vaccination recommendations by female respondents as follows: those reporting relatively good health (aOR: 1.24, 95% CI: 1.02-1.47); relatively poor health (aOR: 1.55, 95% CI: 1.22-1.90); and poor health (aOR: 2.10, 95% CI: 1.41-2.63) (p for trend < 0.05). CONCLUSIONS: Overall, this study suggests that communication strategies for rebuilding public trust in vaccination safety need to be urgently addressed in Japan. Such protocols must consider the information sources that working-age populations are most likely to utilize in this country, as well as their general health conditions, especially among females. PMID- 25928238 TI - Hegemonic structure of basic, clinical and patented knowledge on Ebola research: a US army reductionist initiative. AB - BACKGROUND: Ebola hemorrhagic fever (Ebola) is still a highly lethal infectious disease long affecting mainly neglected populations in sub-Saharan Africa. Moreover, this disease is now considered a potential worldwide threat. In this paper, we present an approach to understand how the basic, clinical and patent knowledge on Ebola is organized and intercommunicated and what leading factor could be shaping the evolution of the knowledge translation process for this disease. METHODOLOGY: A combination of citation network analysis; analysis of Medical heading Subject (MeSH) and Gene Ontology (GO) terms, and quantitative content analysis for patents and scientific literature, aimed to map the organization of Ebola research was carried out. RESULTS: We found six putative research fronts (i.e. clusters of high interconnected papers). Three research fronts are basic research on Ebola virus structural proteins: glycoprotein, VP40 and VP35, respectively. There is a fourth research front of basic research papers on pathogenesis, which is the organizing hub of Ebola research. A fifth research front is pre-clinical research focused on vaccines and glycoproteins. Finally, a clinical-epidemiology research front related to the disease outbreaks was identified. The network structure of patent families shows that the dominant design is the use of Ebola virus proteins as targets of vaccines and other immunological treatments. Therefore, patents network organization resembles the organization of the scientific literature. Specifically, the knowledge on Ebola would flow from higher (clinical-epidemiology) to intermediated (cellular tissular pathogenesis) to lower (molecular interactions) levels of organization. CONCLUSION: Our results suggest a strong reductionist approach for Ebola research probably influenced by the lethality of the disease. On the other hand, the ownership profile of the patent families network and the main researches relationship with the United State Army suggest a strong involvement of this military institution in Ebola research. PMID- 25928241 TI - Diels-Alder functionalized carbon nanotubes for bone tissue engineering: in vitro/in vivo biocompatibility and biodegradability. AB - The risk-benefit balance for carbon nanotubes (CNTs) dictates their clinical fate. To take a step forward at this crossroad it is compulsory to modulate the CNT in vivo biocompatibility and biodegradability via e.g. chemical functionalization. CNT membranes were functionalised combining a Diels-Alder cycloaddition reaction to generate cyclohexene (-C6H10) followed by a mild oxidisation to yield carboxylic acid groups (-COOH). In vitro proliferation and osteogenic differentiation of human osteoblastic cells were maximized on functionalized CNT membranes (p,f-CNTs). The in vivo subcutaneously implanted materials showed a higher biological reactivity, thus inducing a slighter intense inflammatory response compared to non-functionalized CNT membranes (p-CNTs), but still showing a reduced cytotoxicity profile. Moreover, the in vivo biodegradation of CNTs was superior for p,f-CNT membranes, likely mediated by the oxidation-induced myeloperoxidase (MPO) in neutrophil and macrophage inflammatory milieus. This proves the biodegradability faculty of functionalized CNTs, which potentially avoids long-term tissue accumulation and triggering of acute toxicity. On the whole, the proposed Diels-Alder functionalization accounts for the improved CNT biological response in terms of the biocompatibility and biodegradability profiles. Therefore, CNTs can be considered for use in bone tissue engineering without notable toxicological threats. PMID- 25928242 TI - Communication resources for obesity prevention among African American and Latino residents in an urban neighborhood. AB - African Americans and Latinos are at disproportionately high risk for obesity and for the chronic conditions and diseases associated with it. This study uses communication infrastructure theory to explore how connections to neighborhood communication resources and communication with family members can affect residents' regular exercise and healthy eating behaviors-two of the most direct strategies for achieving or maintaining a healthy weight. Regression analyses revealed that connections to the neighborhood storytelling network and family interaction predicted residents' regular exercise and that family interaction had the strongest effect on the likelihood of exercising regularly. Family interaction was the only independent variable that predicted residents' daily intake of fruits and vegetables. Implications of these findings for community health programs and theory development are discussed. PMID- 25928246 TI - Synergistic anti-tumor effect of combined inhibition of EGFR and JAK/STAT3 pathways in human ovarian cancer. AB - BACKGROUND: The EGFR signaling pathway is frequently activated in human ovarian cancer and associated with poor prognosis. However, inhibition of EGFR signaling in patients with recurrent ovarian cancer has been disappointing. It remains to be addressed whether ovarian cancer patients could benefit from targeting EGFR signaling. Here we investigated the mechanisms underlying the resistance to EGFR inhibition in ovarian cancer and developed a strategy to overcome it. RESULTS: We found that treatment of human ovarian cancer cells with an EGFR inhibitor, gefitinib, resulted in increased STAT3 phosphorylation in a dose- and time dependent manner. Inhibiting STAT3 activation with a small molecule inhibitor of JAK, an upstream kinase that phosphorylates and activates STAT3, synergistically increased the anti-tumor activity of gefitinib in vitro. Similar results were obtained when STAT3 or JAK1 expression was knocked down. In contrast, inhibiting other signaling pathways, such as AKT/mTOR, MEK or SRC, was relatively less effective. The combined treatment resulted in simultaneous attenuation of multiple survival pathways and increased inhibition of ERK pathway. In addition, the dual inhibition showed a stronger suppression of xenograft tumor growth than either single inhibition. CONCLUSIONS: Our findings demonstrate that feedback activation of STAT3 pathway might contribute to the resistance to EGFR inhibition. Combined blockade of both pathways appears to be more effective against human ovarian cancer than inhibition of each pathway alone both in vitro and in vivo. This study may provide a strategy to improve clinical benefit of targeting EGFR pathway in ovarian cancer patients. PMID- 25928247 TI - MiR171h restricts root symbioses and shows like its target NSP2 a complex transcriptional regulation in Medicago truncatula. AB - BACKGROUND: Legumes have the unique capability to undergo root nodule and arbuscular mycorrhizal symbiosis. Both types of root endosymbiosis are regulated by NSP2, which is a target of microRNA171h (miR171h). Although, recent data implies that miR171h specifically restricts arbuscular mycorrhizal symbiosis in the root elongation zone of Medicago truncatula roots, there is limited knowledge available about the spatio-temporal regulation of miR171h expression at different physiological and symbiotic conditions. RESULTS: We show that miR171h is functionally expressed from an unusual long primary transcript, previously predicted to encode two identical miR171h strands. Both miR171h and NSP2 transcripts display a complex regulation pattern, which involves the symbiotic status and the fertilization regime of the plant. Quantitative Real-time PCR revealed that miR171h and NSP2 transcript levels show a clear anti-correlation in all tested conditions except in mycorrhizal roots, where NSP2 transcript levels were induced despite of an increased miR171h expression. This was also supported by a clear correlation of transcript levels of NSP2 and MtPt4, a phosphate transporter specifically expressed in a functional AM symbiosis. MiR171h is strongly induced in plants growing in sufficient phosphate conditions, which we demonstrate to be independent of the CRE1 signaling pathway and which is also not required for transcriptional induction of NSP2 in mycorrhizal roots. In situ hybridization and promoter activity analysis of both genes confirmed the complex regulation involving the symbiotic status, P and N nutrition, where both genes show a mainly mutual exclusive expression pattern. Overexpression of miR171h in M. truncatula roots led to a reduction in mycorrhizal colonization and to a reduced nodulation by Sinorhizobium meliloti. CONCLUSION: The spatio-temporal expression of miR171h and NSP2 is tightly linked to the nutritional status of the plant and, together with the results from the overexpression analysis, points to an important function of miR171h to integrate the nutrient homeostasis in order to safeguard the expression domain of NSP2 during both, arbuscular mycorrhizal and root nodule symbiosis. PMID- 25928248 TI - Aromatic-turmerone induces neural stem cell proliferation in vitro and in vivo. AB - INTRODUCTION: Aromatic (ar-) turmerone is a major bioactive compound of the herb Curcuma longa. It has been suggested that ar-turmerone inhibits microglia activation, a property that may be useful in treating neurodegenerative disease. Furthermore, the effects of ar-turmerone on neural stem cells (NSCs) remain to be investigated. METHODS: We exposed primary fetal rat NSCs to various concentrations of ar-turmerone. Thereafter, cell proliferation and differentiation potential were assessed. In vivo, naive rats were treated with a single intracerebroventricular (i.c.v.) injection of ar-turmerone. Proliferative activity of endogenous NSCs was assessed in vivo, by using noninvasive positron emission tomography (PET) imaging and the tracer [(18)F]-fluoro-L-thymidine ([(18)F]FLT), as well as ex vivo. RESULTS: In vitro, ar-turmerone increased dose dependently the number of cultured NSCs, because of an increase in NSC proliferation (P < 0.01). Proliferation data were supported by qPCR-data for Ki 67 mRNA. In vitro as well as in vivo, ar-turmerone promoted neuronal differentiation of NSCs. In vivo, after i.c.v. injection of ar-turmerone, proliferating NSCs were mobilized from the subventricular zone (SVZ) and the hippocampus of adult rats, as demonstrated by both [(18)F]FLT-PET and histology (P < 0.05). CONCLUSIONS: Both in vitro and in vivo data suggest that ar-turmerone induces NSC proliferation. Ar-turmerone thus constitutes a promising candidate to support regeneration in neurologic disease. PMID- 25928250 TI - Low levels of taurine introgression in the current Brazilian Nelore and Gir indicine cattle populations. AB - BACKGROUND: Nelore and Gir are the two most important indicine cattle breeds for production of beef and milk in Brazil. Historical records state that these breeds were introduced in Brazil from the Indian subcontinent, crossed to local taurine cattle in order to quickly increase the population size, and then backcrossed to the original breeds to recover indicine adaptive and productive traits. Previous investigations based on sparse DNA markers detected taurine admixture in these breeds. High-density genome-wide analyses can provide high-resolution information on the genetic composition of current Nelore and Gir populations, estimate more precisely the levels and nature of taurine introgression, and shed light on their history and the strategies that were used to expand these breeds. RESULTS: We used the high-density Illumina BovineHD BeadChip with more than 777 K single nucleotide polymorphisms (SNPs) that were reduced to 697 115 after quality control filtering to investigate the structure of Nelore and Gir populations and seven other worldwide populations for comparison. Multidimensional scaling and model-based ancestry estimation clearly separated the indicine, European taurine and African taurine ancestries. The average level of taurine introgression in the autosomal genome of Nelore and Gir breeds was less than 1% but was 9% for the Brahman breed. Analyses based on the mitochondrial SNPs present in the Illumina BovineHD BeadChip did not clearly differentiate taurine and indicine haplotype groupings. CONCLUSIONS: The low level of taurine ancestry observed for both Nelore and Gir breeds confirms the historical records of crossbreeding and supports a strong directional selection against taurine haplotypes via backcrossing. Random sampling in production herds across the country and subsequent genotyping would be useful for a more complete view of the admixture levels in the commercial Nelore and Gir populations. PMID- 25928251 TI - On the Basicity of 8-Phenylsulfanyl Quipazine Derivatives: New Potential Serotonergic Agents. AB - A protonation state of serotonergic ligands plays a crucial role in their pharmacological activity. In this research, the basicity of 8-phenylsulfanyl quipazine derivatives as new potential serotonergic agents was studied. The most favorable protonation sites were determined in the gas and aqueous phases. In water, a solvation effect promoting the protonation of the N3 atom overcomes a positive charge delocalization phenomenon favoring a N1 atom protonation. The most stable conformations of neutral and protonated molecules in gas and water were found. It was demonstrated that a diprotonation reaction may occur. The most favorable among the diprotonated structures is the molecule with the N1 and N3 atoms protonated. A calculation of the pKa and pKa2 in water of a set of monosubstituted 8-phenylsulfanyl quipazine derivatives was performed using B3LYP/6-31G(d) and the SMD continuum solvation model. Enthalpic and entropic contributions to the pKa and pKa2 in gas and water were separated for a rationalization of a substituent effect on values of the pKa and pKa2. The relationship of the proton affinity and the solvation enthalpy in water with some reactivity descriptors, such as the Fukui function, the molecular electrostatic potential (MEP), and the global softness, was investigated. The order of the pKa values is the most controlled by the entropy. The diprotonation reaction, despite having an unfavorable enthalpy in water, is driven entropically. Final state effects in the diprotonated species were analyzed with the triadic formula. Results of a calculation of the theoretical basicity of the 8-phenylsulfanyl quipazines indicate that they should be monoprotonated on the N3 atom in the CNS environment. Diprotonation of the studied compounds may occur in very acidic body fluids such as the gastric juice. PMID- 25928252 TI - Rapid assessment of infrastructure of primary health care facilities - a relevant instrument for health care systems management. AB - BACKGROUND: Health care infrastructure constitutes a major component of the structural quality of a health system. Infrastructural deficiencies of health services are reported in literature and research. A number of instruments exist for the assessment of infrastructure. However, no easy-to-use instruments to assess health facility infrastructure in developing countries are available. Present tools are not applicable for a rapid assessment by health facility staff. Therefore, health information systems lack data on facility infrastructure. METHODS: A rapid assessment tool for the infrastructure of primary health care facilities was developed by the authors and pilot-tested in Tanzania. The tool measures the quality of all infrastructural components comprehensively and with high standardization. Ratings use a 2-1-0 scheme which is frequently used in Tanzanian health care services. Infrastructural indicators and indices are obtained from the assessment and serve for reporting and tracing of interventions. The tool was pilot-tested in Tanga Region (Tanzania). RESULTS: The pilot test covered seven primary care facilities in the range between dispensary and district hospital. The assessment encompassed the facilities as entities as well as 42 facility buildings and 80 pieces of technical medical equipment. A full assessment of facility infrastructure was undertaken by health care professionals while the rapid assessment was performed by facility staff. Serious infrastructural deficiencies were revealed. The rapid assessment tool proved a reliable instrument of routine data collection by health facility staff. CONCLUSIONS: The authors recommend integrating the rapid assessment tool in the health information systems of developing countries. Health authorities in a decentralized health system are thus enabled to detect infrastructural deficiencies and trace the effects of interventions. The tool can lay the data foundation for district facility infrastructure management. PMID- 25928254 TI - Zinc(II)-methimazole complexes: synthesis and reactivity. AB - The tetrahedral S-coordinated complex [Zn(MeImHS)4](ClO4)2, synthesised from the reaction of [Zn(ClO4)2] with methimazole (1-methyl-3H-imidazole-2-thione, MeImHS), reacts with triethylamine to yield the homoleptic complex [Zn(MeImS)2] (MeImS = anion methimazole). ESI-MS and MAS (13)C-NMR experiments supported MeImS acting as a (N,S)-chelating ligand. The DFT-optimised structure of [Zn(MeImS)2] is also reported and the main bond lengths compared to those of related Zn methimazole complexes. The complex [Zn(MeImS)2] reacts under mild conditions with methyl iodide and separates the novel complex [Zn(MeImSMe)2I2] (MeImSMe = S methylmethimazole). X-ray diffraction analysis of the complex shows a ZnI2N2 core, with the methyl thioethers uncoordinated to zinc. Conversely, the reaction of [Zn(MeImS)2] with hydroiodic acid led to the formation of the complex [Zn(MeImHS)2I2] having a ZnI2S2 core with the neutral methimazole units S coordinating the metal centre. The Zn-coordinated methimazole can markedly modify the coordination environment when changing from its thione to thionate form and vice versa. The study of the interaction of the drug methimazole with the complex [Zn(MeIm)4](2+) (MeIm = 1-methylimidazole) - as a model for Zn-enzymes containing a N4 donor set from histidine residues - shows that methimazole displaces only one of the coordinated MeIm molecules; the formation constant of the mixed complex [Zn(MeIm)3(MeImHS)](2+) was determined. PMID- 25928255 TI - Clinical translation section: accelerating the pace from bench to bedside. PMID- 25928256 TI - New insights into the causes of human illness due to consumption of azaspiracid contaminated shellfish. AB - Azaspiracid (AZA) poisoning was unknown until 1995 when shellfish harvested in Ireland caused illness manifesting by vomiting and diarrhoea. Further in vivo/vitro studies showed neurotoxicity linked with AZA exposure. However, the biological target of the toxin which will help explain such potent neurological activity is still unknown. A region of Irish coastline was selected and shellfish were sampled and tested for AZA using mass spectrometry. An outbreak was identified in 2010 and samples collected before and after the contamination episode were compared for their metabolite profile using high resolution mass spectrometry. Twenty eight ions were identified at higher concentration in the contaminated samples. Stringent bioinformatic analysis revealed putative identifications for seven compounds including, glutarylcarnitine, a glutaric acid metabolite. Glutaric acid, the parent compound linked with human neurological manifestations was subjected to toxicological investigations but was found to have no specific effect on the sodium channel (as was the case with AZA). However in combination, glutaric acid (1 mM) and azaspiracid (50 nM) inhibited the activity of the sodium channel by over 50%. Glutaric acid was subsequently detected in all shellfish employed in the study. For the first time a viable mechanism for how AZA manifests itself as a toxin is presented. PMID- 25928257 TI - miR-221 facilitates the TGFbeta1-induced epithelial-mesenchymal transition in human bladder cancer cells by targeting STMN1. AB - BACKGROUND: Distant metastasis is the major cause of cancer-related death, and epithelial-to-mesenchymal transition (EMT) has a critical role in this process. Accumulating evidence indicates that EMT can be regulated by microRNAs (miRNAs). miR-221, as oncogenes in several human cancers, was significantly up-regulated in bladder cancers. However, the role of miR-221 in the progression of bladder cancer metastasis remains largely unknown. METHODS: We used qRT-PCR and western blot to accurately measure the levels of miR-221, STMN1 and EMT markers in TGFbeta1 induced EMT of bladder cancer cells. miR-221 inhibitors were re introduced into bladder cancer cells to investigate its role on tumor metastasis which was measured by MTT, wound healing, transwell invasion and adherent assays. Luciferase reporter assay was used to reveal the target gene of miR-221. RESULTS: miR-221 expression was greatly increased by TGFbeta1 in bladder cancer cell. miR 221 inhibition reversed TGFbeta1 induced EMT by sharply increasing the expression of the epithelial marker E-cadherin and decreasing the expression of the mesenchymal markers vimentin, Fibroactin and N-cadherin. Furthermore, miR-221 expression is positively correlated with malignant potential of bladder cancer cell through promoting loss of cell adhesion and prometastatic behavior. Luciferase reporter assay revealed that miR-221 negatively regulates STMN1 expression by direct targeting to the 3'UTR region of STMN1. CONCLUSIONS: Our study demonstrated that miR-221 facilitated TGFbeta1-induced EMT in human bladder cancer cells by targeting STMN1 and represented a promising therapeutic target in the process of metastasis. PMID- 25928261 TI - Isolation of an individual already treated for Ebola: has India gone too far? AB - A 26-year-old Indian male travelling from Liberia to India after being treated for Ebola Virus Disease (EVD) was isolated at Delhi airport, even though he was symptom-free, because his semen was positive for Ebola virus. His blood, saliva and urine samples had tested negative for Ebola. There is no conclusive evidence of sexual transmission of EVD and the World Health Organisation does not recommend the isolation of convalescent patients whose blood is negative for Ebola virus. The decision of the Indian health authorities to isolate this individual is not only unscientific and excessively precautionary, but also raises various ethical and legal issues related to the potential violation of individual rights. The decision to impose individual restrictions during public health emergencies should be a transparent one that is guided by science, and should follow consultations among the various stakeholders. Further, such restrictions should be imposed only when alternative approaches are not sufficient or effective. PMID- 25928263 TI - Pancreatic oncogenic signaling cascades converge at Protein Kinase D1. PMID- 25928266 TI - The B chromosome of the cichlid fish Haplochromis obliquidens harbors 18S rRNA genes. PMID- 25928264 TI - Muscle synergies and spinal maps are sensitive to the asymmetry induced by a unilateral stroke. AB - BACKGROUND: Previous studies have shown that a cerebrovascular accident disrupts the coordinated control of leg muscles during locomotion inducing asymmetric gait patterns. However, the ability of muscle synergies and spinal maps to reflect the redistribution of the workload between legs after the trauma has not been investigated so far. METHODS: To investigate this issue, twelve post-stroke and ten healthy participants were asked to walk on a treadmill at controlled speeds (0.5, 0.7, 0.9, 1.1 km/h), while the EMG activity of twelve leg muscles was recorded on both legs. The synergies underlying muscle activation and the estimated motoneuronal activity in the lumbosacral enlargement (L2-S2) were computed and compared between groups. RESULTS: Results showed that muscle synergies in the unaffected limb were significantly more comparable to those of the healthy control group than the ones in the affected side. Spinal maps were dissimilar between the affected and unaffected sides highlighting a significant shift of the foci of the activity toward the upper levels of the spinal cord in the unaffected leg. CONCLUSIONS: Muscle synergies and spinal maps reflect the asymmetry as a motor deficit after stroke. However, further investigations are required to support or reject the hypothesis that the altered muscular organization highlighted by muscle synergies and spinal maps may be due to the concomitant contribution of the altered information coming from the upper part of the CNS, as resulting from the stroke, and to the abnormal sensory feedback due to the neuromuscular adaptation of the patients. PMID- 25928268 TI - Cell-specific cardiac electrophysiology models. AB - The traditional cardiac model-building paradigm involves constructing a composite model using data collected from many cells. Equations are derived for each relevant cellular component (e.g., ion channel, exchanger) independently. After the equations for all components are combined to form the composite model, a subset of parameters is tuned, often arbitrarily and by hand, until the model output matches a target objective, such as an action potential. Unfortunately, such models often fail to accurately simulate behavior that is dynamically dissimilar (e.g., arrhythmia) to the simple target objective to which the model was fit. In this study, we develop a new approach in which data are collected via a series of complex electrophysiology protocols from single cardiac myocytes and then used to tune model parameters via a parallel fitting method known as a genetic algorithm (GA). The dynamical complexity of the electrophysiological data, which can only be fit by an automated method such as a GA, leads to more accurately parameterized models that can simulate rich cardiac dynamics. The feasibility of the method is first validated computationally, after which it is used to develop models of isolated guinea pig ventricular myocytes that simulate the electrophysiological dynamics significantly better than does a standard guinea pig model. In addition to improving model fidelity generally, this approach can be used to generate a cell-specific model. By so doing, the approach may be useful in applications ranging from studying the implications of cell-to cell variability to the prediction of intersubject differences in response to pharmacological treatment. PMID- 25928269 TI - Efficiency and effectiveness evaluation of an automated multi-country patient count cohort system. AB - BACKGROUND: With the increase of clinical trial costs during the last decades, the design of feasibility studies has become an essential process to reduce avoidable and costly protocol amendments. This design includes timelines, targeted sites and budget, together with a list of eligibility criteria that potential participants need to match. The present work was designed to assess the value of obtaining potential study participant counts using an automated patient count cohort system for large multi-country and multi-site trials: the Electronic Health Records for Clinical Research (EHR4CR) system. METHODS: The evaluation focuses on the accuracy of the patient counts and the time invested to obtain these using the EHR4CR platform compared to the current questionnaire based process. This evaluation will assess the patient counts from ten clinical trials at two different sites. In order to assess the accuracy of the results, the numbers obtained following the two processes need to be compared to a baseline number, the "alloyed" gold standard, which was produced by a manual check of patient records. RESULTS: The patient counts obtained using the EHR4CR system were in three evaluated trials more accurate than the ones obtained following the current process whereas in six other trials the current process counts were more accurate. In two of the trials both of the processes had counts within the gold standard's confidence interval. In terms of efficiency the EHR4CR protocol feasibility system proved to save approximately seven calendar days in the process of obtaining patient counts compared to the current manual process. CONCLUSIONS: At the current stage, electronic health record data sources need to be enhanced with better structured data so that these can be re-used for research purposes. With this kind of data, systems such as the EHR4CR are able to provide accurate objective patient counts in a more efficient way than the current methods. Additional research using both structured and unstructured data search technology is needed to assess the value of unstructured data and to compare the amount of efforts needed for data preparation. PMID- 25928270 TI - Using the maxillary-nasal angle to evaluate congenital nasal pyriform aperture stenosis. AB - IMPORTANCE: Congenital nasal pyriform aperture stenosis (CNPAS) is a rare cause of nasal airway obstruction in newborns. The decision to operate is made clinically. Although pyriform aperture width is used for diagnosing CNPAS, it does not fully characterize stenosis of the nasal cavity. OBJECTIVE: To determine the utility of additional metrics for evaluating CNPAS. DESIGN, SETTING, AND PARTICIPANTS: The medical records of 13 patients with CNPAS treated from 2007 through 2012 at a single tertiary pediatric facility were retrospectively examined. Data on patient demographic characteristics, known genetic abnormalities, and hospital courses were extracted. Computed tomographic images were evaluated for pyriform aperture width; maxillary-nasal angle (MNA), defined as the angle between the anterior maxilla and anterior-posterior nasal axis; and choanal width. INTERVENTIONS: Medical management and surgical management. MAIN OUTCOMES AND MEASURES: Pyriform aperture width, MNA, and choanal width. RESULTS: Six of 13 patients underwent medical management, and 7 patients underwent surgical treatment. For patients who were managed medically as compared with those managed surgically, the evaluation revealed a larger pyriform aperture width (median [interquartile range {IQR}], 5.6 [5.4-6.1] vs 4.6 [4.5-4.7] mm; P = .03) and MNA (median [IQR], 70 degrees [63 degrees -73 degrees ] vs 59 degrees [59 degrees -64 degrees ]; P = .048) but no significant difference in choanal width (median [IQR], 11.0 [9.6-12.2] vs 11.9 [10.3-11.9] mm; P = .76). CONCLUSIONS AND RELEVANCE: The MNA, when used in conjunction with pyriform aperture width, provides additional pertinent information to supplement clinical decision making in the evaluation of patients with CNPAS. These measurements may be helpful in identifying patients who should undergo surgical intervention, although additional studies would be required to allow predictive use of the MNA. PMID- 25928271 TI - Nickel-Catalyzed Addition-Type Alkenylation of Unactivated, Aliphatic C-H Bonds with Alkynes: A Concise Route to Polysubstituted gamma-Butyrolactones. AB - Through the nickel-catalyzed chelation-assisted C-H bond activation strategy, the addition-type alkenylation of unreactive beta-C(sp(3))-H bonds of aliphatic amides with internal alkynes is developed for the first time to produce gamma,delta-unsaturated carboxylic amide derivatives. The resulting alkenylated products can further be transformed into polysubstituted gamma-butyrolactones with pyridinium chlorochromate (PCC). PMID- 25928272 TI - Tunable Electrochemical and Catalytic Features of BIAN- and BIAO-Derived Ruthenium Complexes. AB - This article deals with a class of ruthenium-BIAN-derived complexes, [Ru(II)(tpm)(R-BIAN)Cl]ClO4 (tpm = tris(1-pyrazolyl)methane, R-BIAN = bis(arylimino)acenaphthene, R = 4-OMe ([1a]ClO4), 4-F ([1b]ClO4), 4-Cl ([1c]ClO4), 4-NO2 ([1d]ClO4)) and [Ru(II)(tpm)(OMe-BIAN)H2O](2+) ([3a](ClO4)2). The R-BIAN framework with R = H, however, leads to the selective formation of partially hydrolyzed BIAO ([N-(phenyl)imino]acenapthenone)-derived complex [Ru(II)(tpm)(BIAO)Cl]ClO4 ([2]ClO4). The redox-sensitive bond parameters involving -N?C-C?N- or -N?C-C?O of BIAN or BIAO in the crystals of representative [1a]ClO4, [3a](PF6)2, or [2]ClO4 establish its unreduced form. The chloro derivatives 1a(+)-1d(+) and 2(+) exhibit one oxidation and successive reduction processes in CH3CN within the potential limit of +/-2.0 V versus SCE, and the redox potentials follow the order 1a(+) < 1b(+) < 1c(+) < 1d(+) ~ 2(+). The electronic structural aspects of 1a(n)-1d(n) and 2(n) (n = +2, +1, 0, -1, -2, -3) have been assessed by UV-vis and EPR spectroelectrochemistry, DFT-calculated MO compositions, and Mulliken spin density distributions in paramagnetic intermediate states which reveal metal-based (Ru(II) -> Ru(III)) oxidation and primarily BIAN- or BIAO-based successive reduction processes. The aqua complex 3a(2+) undergoes two proton-coupled redox processes at 0.56 and 0.85 V versus SCE in phosphate buffer (pH 7) corresponding to {Ru(II)-H2O}/{Ru(III)-OH} and {Ru(III)-OH}/{Ru(IV)?O}, respectively. The chloro (1a(+)-1d(+)) and aqua (3a(2+)) derivatives are found to be equally active in functioning as efficient precatalysts toward the epoxidation of a wide variety of alkenes in the presence of PhI(OAc)2 as oxidant in CH2Cl2 at 298 K, though the analogous 2(+) remains virtually inactive. The detailed experimental analysis with the representative precatalyst 1a(+) suggests the involvement of the active {Ru(IV)?O} species in the catalytic cycle, and the reaction proceeds through the radical mechanism, as also supported by the DFT calculations. PMID- 25928273 TI - Synthesis, characterization, and alkyne trimerization catalysis of a heteroleptic two-coordinate fe(i) complex. AB - The synthesis of the first heteroleptic, two-coordinate Fe(I) complex IPr-Fe N(SiMe3)DIPP (1) (IPr = 1,3-bis(2,6-diisopropylphenyl)imidazol-2-ylidene; DIPP = 2,6-(i)Pr2-C6H3) is reported. Protonation of the Fe(II) bis(amido) complex Fe[N(SiMe3)DIPP]2 followed by addition of IPr and reduction by potassium graphite in a one-pot reaction results in good yields of 1. The redox activity of 1 and comparison between 1 and its reduction product by (57)Fe Mossbauer spectroscopy are discussed, and the reduction was found to be metal-based rather than ligand based. The activity of 1 toward the catalytic cyclotrimerization of terminal and internal alkynes is described. PMID- 25928275 TI - Synchrotron-based rotationally resolved high-resolution FTIR spectroscopy of azulene and the unidentified infrared bands of astronomy. AB - Chasing the unidentified IR bands: The first rotationally resolved high resolution infrared spectrum of azulene is reported using synchrotron Fourier transform infrared spectroscopy including a rovibrational analysis of the out-of plane fundamental nu44. Comparison of azulene, naphthalene, indole, and biphenyl infrared bands leads to coincidences with UIR bands at 12.8 MUm with naphthalene and at 13.55 and 14.6 MUm with biphenyl bands, but excluding azulene as a strong absorber. PMID- 25928274 TI - Correcting thrombin generation ex vivo using different haemostatic agents following cardiac surgery requiring the use of cardiopulmonary bypass. AB - Recently, lower thrombin generation has been associated with excess bleeding post cardiopulmonary bypass (CPB). Therefore, treatment to correct thrombin generation is a potentially important aspect of management of bleeding in this group of patients. The objective of the present study was to investigate the effects of fresh frozen plasma (FFP), recombinant factor VIIa (rFVIIa), prothrombin complex concentrate (PCC) and tissue factor pathway inhibitor (TFPI) inhibition on thrombin generation when added ex vivo to the plasma of patients who had undergone cardiac surgery requiring CPB. Patients undergoing elective cardiac surgery were recruited. Blood samples were collected before administration of heparin and 30 min after its reversal. Thrombin generation was measured in the presence and absence of different concentrations of FFP, rFVIIa, PCC and an anti TFPI antibody. A total of 102 patients were recruited. Thrombin generation following CPB was lower compared with pre-CPB (median endogenous thrombin potential pre-CPB 339 nmol/l per min, post-CPB 155 nmol/l per min, P < 0.0001; median peak thrombin pre-CPB 35 nmol/l, post-CPB 11 nmol/l, P < 0.0001). Coagulation factors and anticoagulants decreased, apart from total TFPI, which increased (55-111 ng/ml, P < 0.0001), and VWF (144-170 IU/dl, P < 0.0001). Thrombin generation was corrected to pre-CPB levels by the equivalent of 15 ml/kg FFP, 45 MUg/kg rFVIIa and 25 U/kg of PCC. Inhibition of TFPI resulted in an enhancement of thrombin generation significantly beyond pre-CPB levels. This study shows that FFP, rFVIIa, PCC and inhibition of TFPI correct thrombin generation in the plasma of patients who have undergone surgery requiring CPB. Inhibition of TFPI may be a further potential therapeutic strategy for managing bleeding in this group of patients. PMID- 25928276 TI - Hybrid coronary revascularization versus coronary artery bypass grafting for multivessel coronary artery disease: systematic review and meta-analysis. AB - BACKGROUND: The concept of hybrid coronary revascularization (HCR) combines the left internal mammary artery (LIMA)-left anterior descending (LAD) graft and percutaneous coronary intervention (PCI) to non-LAD vessels. Multiple comparative studies have evaluated the safety and feasibility of HCR and coronary artery bypass grafting (CABG) for multivessel coronary artery disease (MCAD). However, the sample size of each study was small, and evidences based on single institutional experience. The purpose of this meta-analysis was to compare the short-term outcomes of HCR with those of CABG for MCAD. METHOD: PubMed, EMBASE and Cochrane Library databases, as well as conference proceedings, were searched for eligible studies published up to March 2014. We calculated summary odds ratios (OR) for primary endpoints (death, stroke; myocardial infarction (MI); target vessel revascularization (TVR); major adverse cardiac or cerebrovascular events (MACCEs)) and secondary endpoints (atrial fibrillation (AF); renal failure; length of stay in the intensive care unit (LoS in ICU); length of stay in hospital (LoS in hospital); red blood cell (RBC) transfusion). Data from 6176 participants were derived from ten cohort studies. RESULTS: HCR was non-inferior to CABG in terms of MACCEs during hospitalization (odds ratio (OR), 0.68, 95% confidence interval (CI), 0.34-1.33)and at one-year follow-up(0.32, 0.05-1.89) , and no significant difference was found between HCR and CABG groups in in hospital and one-year follow-up outcomes of death, MI, stroke, the prevalence of AF and renal failure, whereas HCR was associated with a lower requirement of RBC transfusion and shorter LoS in ICU and LoS in hospital than CABG (weighted mean difference (WMD) -1.25, 95% CI, -1.62 to -0.88; -17.47, -31.01 to -3.93; -1.77, 3.07 to -0.46; respectively). CONCLUSION: Our meta-analysis indicates that HCR is feasible, safe and effective for the treatment of MCAD, with similar in-hospital and one-year follow-up outcome, significantly lower requirement of RBC transfusion, and faster recovery compared with CABG. PMID- 25928277 TI - Hydrogenated TiO2 Branches Coated Mn3O4 Nanorods as an Advanced Anode Material for Lithium Ion Batteries. AB - Rational design and delicate control on the component, structure, and surface of electrodes in lithium ion batteries are highly important to their performances in practical applications. Compared with various components and structures for electrodes, the choices for their surface are quite limited. The most widespread surface for numerous electrodes, a carbon shell, has its own issues, which stimulates the desire to find another alternative surface. Here, hydrogenated TiO2 is exemplified as an appealing surface for advanced anodes by the growth of ultrathin hydrogenated TiO2 branches on Mn3O4 nanorods. High theoretical capacity of Mn3O4 is well matched with low volume variation (~4%), enhanced electrical conductivity, good cycling stability, and rate capability of hydrogenated TiO2, as demonstrated in their electrochemical performances. The proof-of-concept reveals the promising potential of hydrogenated TiO2 as a next-generation material for the surface in high-performance hybrid electrodes. PMID- 25928278 TI - Unicentric Castleman's disease presenting as a pulmonary mass: a diagnostic dilemma. AB - BACKGROUND: Castleman's disease, or angiofollicular lymphoid hyperplasia, is a rare disorder and can be easily misdiagnosed as lymphoma, neoplasm, or infection. The diagnosis is challenging due to the nonspecific signs and symptoms as well as the rarity of the disease. We present an unusual case of a young girl presenting with an enlarging pulmonary mass that was believed to be infectious in origin. CASE REPORT: A 16-year-old Native American female from Arizona initially presented with occasional non-productive cough and chest pain. Imaging revealed a 3-cm left upper lobe lobulated mass. This mass was thought to be due to coccidioidomycosis and was treated with fluconazole. Follow-up imaging demonstrated growth of the mass to 4.8 cm. The patient underwent a left video assisted thoracoscopic left upper lobectomy and mediastinal lymphadenectomy. Histopathological examination revealed Castleman's disease. CONCLUSIONS: Pulmonary masses in young patients can be easily misdiagnosed as infections or cancer. We present the case of a 16-year-old female misdiagnosed as having a fungal infection of the lung, which was later revealed to be Castleman's disease of the left upper lobe. PMID- 25928281 TI - Role of domain swapping in the hetero-oligomeric cytochrome b6f lipoprotein complex. AB - Domain swapping that contributes to the stability of biologically crucial multisubunit complexes has been implicated in protein oligomerization. In the case of membrane protein assemblies, domain swapping of the iron-sulfur protein (ISP) subunit occurs in the hetero-oligomeric cytochrome b6f and bc1 complexes, which are organized as symmetric dimers that generate the transmembrane proton electrochemical gradient utilized for ATP synthesis. In these complexes, the ISP C-terminal predominantly beta-sheet extrinsic domain containing the redox-active [2Fe-2S] cluster resides on the electrochemically positive side of each monomer in the dimeric complex. This domain is bound to the membrane sector of the complex through an N-terminal transmembrane alpha-helix that is "swapped' to the other monomer of the complex where it spans the complex and the membrane. Detailed analysis of the function and structure of the b6f complex isolated from the cyanobacterium Fremyella diplosiphon SF33 shows that the domain-swapped ISP structure is necessary for function but is not necessarily essential for maintenance of the dimeric structure of the complex. On the basis of crystal structures of the cytochrome complex, the stability of the cytochrome dimer is attributed to specific intermonomer protein-protein and protein-lipid hydrophobic interactions. The geometry of the domain-swapped ISP structure is proposed to be a consequence of the requirement that the anchoring helix of the ISP not perturb the heme organization or quinone channel in the conserved core of each monomer. PMID- 25928282 TI - Diagnostic and prognostic potential of miR-21, miR-29c, miR-148 and miR-203 in adenocarcinoma and squamous cell carcinoma of esophagus. AB - BACKGROUND: Esophageal cancer is the malignant tumor with very poor prognosis and increasing incidence often diagnosed at very late stage, so the prognosis of affected patients is unsatisfactory, despite the development of therapeutic option such as surgery, chemotherapy and radiotherapy. Consequently, there is a great need for biomarkers to allow a tailored multimodality approach with increased efficiency. Altered expression of microRNAs has been reported in wide range of malignancies, including esophageal cancer. The aim of this study was to examine the expression levels of candidate microRNAs in esophageal cancer and evaluate their diagnostic and prognostic potential. FINDINGS: Using quantitative real-time PCR, expression levels of 9 candidate microRNAs were examined in 62 tissue samples, 23 esophageal adenocarcinomas, 22 esophageal squamous cell carcinomas and 17 adjacent esophageal mucosa samples. MicroRNA expression levels were further analyzed in regards to clinico-pathological features of esophageal cancer patients. We observed significantly decreased levels of miR-203 and increased levels of miR-21 in adenocarcinoma tissues when compared to normal mucosa. MiR-29c and miR-148 indicated good ability to distinguish between histological subtypes of esophageal cancer. MiR-203 and miR-148 were linked to disease-free survival and overall survival in esophageal adenocarcinoma patients, and miR-148 also in esophageal squamous cell carcinoma patients. CONCLUSIONS: Our data suggest that altered expression of miR-21, miR-29c, miR-148 and miR-203 are related to neoplastic transformation and progression of the disease and these microRNAs could serve as a potential diagnostic and prognostic biomarkers in esophageal cancer. VIRTUAL SLIDES: The virtual slide(s) for this article can be found here: http://www.diagnosticpathology.diagnomx.eu/vs/4646922201567057. PMID- 25928283 TI - Incidence Estimate of Nonmelanoma Skin Cancer (Keratinocyte Carcinomas) in the U.S. Population, 2012. AB - IMPORTANCE: Understanding skin cancer incidence is critical for planning prevention and treatment strategies and allocating medical resources. However, owing to lack of national reporting and previously nonspecific diagnosis classification, accurate measurement of the US incidence of nonmelanoma skin cancer (NMSC) has been difficult. OBJECTIVE: To estimate the incidence of NMSC (keratinocyte carcinomas) in the US population in 2012 and the incidence of basal cell carcinoma (BCC) and squamous cell carcinoma (SCC) in the 2012 Medicare fee for-service population. DESIGN, SETTING, AND PARTICIPANTS: This study analyzes US government administrative data including the Centers for Medicare & Medicaid Services Physicians Claims databases to calculate totals of skin cancer procedures performed for Medicare beneficiaries from 2006 through 2012 and related parameters. The population-based National Ambulatory Medical Care Survey database was used to estimate NMSC-related office visits for 2012. We combined these analyses to estimate totals of new skin cancer diagnoses and affected individuals in the overall US population. MAIN OUTCOMES AND MEASURES: Incidence of NMSC in the US population in 2012 and BCC and SCC in the 2012 Medicare fee-for service population. RESULTS: The total number of procedures for skin cancer in the Medicare fee-for-service population increased by 13% from 2,048,517 in 2006 to 2,321,058 in 2012. The age-adjusted skin cancer procedure rate per 100,000 beneficiaries increased from 6075 in 2006 to 7320 in 2012. The number of procedures in Medicare beneficiaries specific for NMSC increased by 14% from 1,918,340 in 2006 to 2,191,100 in 2012. The number of persons with at least 1 procedure for NMSC increased by 14% (from 1,177,618 to 1,336,800) from 2006 through 2012. In the 2012 Medicare fee-for-service population, the age-adjusted procedure rate for BCC and SCC were 3280 and 3278 per 100,000 beneficiaries, respectively. The ratio of BCC to SCC treated in Medicare beneficiaries was 1.0. We estimate the total number of NMSCs in the US population in 2012 at 5,434,193 and the total number of persons in the United States treated for NMSC at 3,315,554. CONCLUSIONS AND RELEVANCE: This study is a thorough nationwide estimate of the incidence of NMSC and provides evidence of continued increases in numbers of skin cancer diagnoses and affected patients in the United States. This study also demonstrates equal incidence rates for BCC and SCC in the Medicare population. PMID- 25928284 TI - Erratum to: High-resolution SNP array analysis of patients with developmental disorder and normal array CGH result. PMID- 25928286 TI - Neoadjuvant chemoradiation therapy for resectable esophago-gastric adenocarcinoma: a meta-analysis of randomized clinical trials. AB - BACKGROUND: The efficacy and safety of preoperative chemoradiation therapy (CRT) for advanced esophago-gastric adenocarcinoma are still in question, and the prognosis of these patients is poor. METHODS: We systematically searched electronic databases from January 1990 to July 2014. The primary outcome was overall survival. The secondary outcomes were a R0 resection rate, positive rate of lymph node metastasis, postoperative recurrence rate, pathological complete response (pCR) rate and perioperative mortality. Overall survival was measured with a hazard ratio (HR), while other secondary outcomes were measured with an odds ratio (OR). RESULTS: Seven randomized controlled trials (RCTs) including 1085 patients were searched and, of these, 869 had adenocarcinoma. Patients receiving preoperative CRT had a longer overall survival (HR 0.74; 95% confidence interval (CI) 0.63-0.88), higher likelihood of R0 resection and greater chance of pCR, while they had a lower likelihood of lymph node metastasis and postoperative recurrence. The difference of perioperative mortality was non-significant. In addition, the result of the comparison between preoperative CRT and preoperative chemotherapy (CT) in two RCTs was non-significant. CONCLUSION: Patients with resectable esophago-gastric adenocarcinoma can gain a survival advantage from preoperative CRT. However, limited to the number of RCTs, the effect of adding radiotherapy to preoperative CT separately is still uncertain and more high quality prospective trials are needed. PMID- 25928287 TI - Benefits and harms of mammography screening. AB - Mammography screening for breast cancer is widely available in many countries. Initially praised as a universal achievement to improve women's health and to reduce the burden of breast cancer, the benefits and harms of mammography screening have been debated heatedly in the past years. This review discusses the benefits and harms of mammography screening in light of findings from randomized trials and from more recent observational studies performed in the era of modern diagnostics and treatment. The main benefit of mammography screening is reduction of breast-cancer related death. Relative reductions vary from about 15 to 25% in randomized trials to more recent estimates of 13 to 17% in meta-analyses of observational studies. Using UK population data of 2007, for 1,000 women invited to biennial mammography screening for 20 years from age 50, 2 to 3 women are prevented from dying of breast cancer. All-cause mortality is unchanged. Overdiagnosis of breast cancer is the main harm of mammography screening. Based on recent estimates from the United States, the relative amount of overdiagnosis (including ductal carcinoma in situ and invasive cancer) is 31%. This results in 15 women overdiagnosed for every 1,000 women invited to biennial mammography screening for 20 years from age 50. Women should be unpassionately informed about the benefits and harms of mammography screening using absolute effect sizes in a comprehensible fashion. In an era of limited health care resources, screening services need to be scrutinized and compared with each other with regard to effectiveness, cost-effectiveness and harms. PMID- 25928288 TI - Antipyretic, anti-inflammatory and analgesic activity of Acacia hydaspica R. Parker and its phytochemical analysis. AB - BACKGROUND: Inflammation and pain underlies several pathological conditions. Synthetic drugs used for the management of these conditions carry severe toxic effects. Globally efforts are ongoing to introduce novel medicinal plants to develop effective, economic and innocuous drugs. The current study was aimed at investigating the antipyretic, anti-inflammatory and analgesic activity of methanol extract of A. hydaspica aerial parts (AHM) and its active fraction. Furthermore identification and isolation of polyphenolic compounds was carried out to identify the active principles. METHODS: Yeast induced pyrexia, Paw edema, acetic acid-induced writhing and hot plate test were carried out in vivo. HPLC DAD analysis and combination of different chromatographic techniques, involving vacuum liquid chromatography (VLC) and flash chromatography (FC) were carried out for chemical characterization. The structural heterogeneity of flavanols was characterized by ESI- MS, (1)H NMR, (13)C NMR and (2)D NMR spectroscopic analyses, and also by comparison with reported literature. RESULTS: Oral administration of A. hydaspica methanol extract (AHM) and A. hydaspica ethyl acetate fraction (AHE), showed dose and time dependent decrease in body temperature in yeast induced pyrexia, comparable to standard, Paracetamol. AHM and AHE (150 mg/kg) significantly (p < 0.001) inhibit pain sensation in various pain models, i.e. acetic acid induced writhing and hot plate test. Similarly AHM and AHE demonstrated an anti-inflammatory effect in carrageenan-induced paw edema in rats and 150 mg/kg dose being distinctly more effective (91.92% inhibition). When studied on prostaglandin E2 (PGE2) induced edema in rats, AHM and AHE showed maximum inhibition of edema at 150 mg/kg after 4 h. HPLC chromatogram of AHM revealed the presence of gallic acid, catechin, rutin and caffeic acid. Chromatographic separation and structure characterization of AHE, has led to the identification of three flavan-3-ol derivative including 7-O-galloyl catechin, +catechin and methyl gallate, which have been reported for the first time in A. hydaspica. CONCLUSION: These results revealed that the presence of bioactive compounds in A. hydaspica might be responsible for the pharmacological activities, confirming the indigenous utility of A. hydaspica against inflammatory disorders. PMID- 25928289 TI - A fatal case of acute progression of generalized edema and simultaneous flash pulmonary edema in a patient with idiopathic systemic capillary leak syndrome: a case report. AB - INTRODUCTION: Idiopathic systemic capillary leak syndrome is a rare and fatal disease due to the unexplained episodic attacks of capillary leakage of plasma from the intravascular into the interstitial space. The attack consists of three phases, a prodromal phase, peripheral leak phase and recruitment phase. During the peripheral leak phase, generalized edema, mainly in the trunk and extremities, with hemoconcentration and hypoalbuminemia occurs, while usually the visceral organs like lungs, brain, heart and kidneys seem not to be involved. Treatment of the acute phase is supportive, focusing on adequate but not overzealous fluid resuscitation, because pulmonary edema usually occurs in the recruitment phase. CASE PRESENTATION: A 65-year-old Japanese woman was admitted to our hospital because of severe hypovolemic shock with metabolic acidosis and hemoconcentration and hypoalbuminemia. Although she was considered to be in the peripheral leak phase of idiopathic systemic capillary leak syndrome, which could not be diagnosed during the treatment, the generalized edema worsened further, severe flash pulmonary edema progressed rapidly after fluid resuscitation and she died. The autopsy showed generalized edema, especially alveolar pulmonary edema without endothelial apoptosis. CONCLUSIONS: Because hypovolemic shock and fatal pulmonary edema may progress rapidly together even in the peripheral leak phase of idiopathic systemic capillary leak syndrome, we should keep in mind this rare and fatal disease and recognize the pathophysiology to treat it effectively when the patient has hypovolemia with metabolic acidosis. PMID- 25928290 TI - Gene susceptibility identification in a longitudinal study confirms new loci in the development of chronic obstructive pulmonary disease and influences lung function decline. AB - BACKGROUND: To identify COPD associated gene susceptibility and lung function in a longitudinal cohort including COPD and subjects who were at risk for developing COPD, and to replicate this in two cross-sectional and longitudinal populations in Chinese Han population. METHODS: Three cohorts were recruited in this study, including an 18-year follow-up population (306 COPD and 743 control subjects) in one village in 1992 and it changed to 409 COPD and 611 controls in 2010, a 2 year follow-up study in another village (374 COPD and 377 controls) and another 2 year follow-up one in a city (541 COPD and 560 controls) in 2010. Sixteen candidate single nucleotide polymorphisms (SNPs) were selected for genotyping. Among them, 5SNPs in or near HHIP, 1SNP in IREB2 and 1SNP in FAM13A were previously reported to be associated with COPD susceptibility or lung function decline. And another 9SNPs were selected from HapMap website as HHIP tags. In 2010, totaling 1,324 COPD patients and 1,548 healthy controls were finally included in our genetic susceptibility analyses. RESULTS: We identified two new regions showing an association with COPD susceptibility in the Human Hedgehog interacting protein (HHIP) rs11100865 and rs7654947, and we confirmed that the family with sequence similarity 13 member A gene (FAM13A) rs7671167 was associated with the development of COPD in Chinese Han population. And the HHIP rs7654947 and FAM13A rs7671167 were associated with lung function decline, and this result was replicated in other two populations. CONCLUSIONS: These results suggest an important role of the HHIP and FAM13A regions as genetic risk factors for COPD development and lung function decline in Chinese Han population. Future research on these genes should focus on the molecular mechanisms of these genes on developing COPD and creating therapies to alleviate reduced lung function. PMID- 25928292 TI - Survey of Argentine health researchers on the use of evidence in policymaking. AB - OBJECTIVE: In this study, Argentine health researchers were surveyed regarding their perceptions of facilitators and barriers to evidence-based policymaking in Argentina, as well as their publication activities, and research environment satisfaction. METHODS: A self-administered online survey was sent to health researchers in Argentina. The survey questions were based on a preceding qualitative study of Argentine health researchers, as well as the scientific literature. RESULTS: Of the 647 researchers that were reached, 226 accessed the survey, for a response rate of 34.9%. Over 80% of researchers surveyed had never been involved in or contributed to decision-making, while over 90% of researchers indicated they would like to be involved in the decision-making process. Decision maker self-interest was perceived to be the driving factor in the development of health and healthcare policies. Research conducted by a research leader was seen to be the most influential factor in influencing health policy, followed by policy relevance of the research. With respect to their occupational environment, researchers rated highest and most favourably the opportunities available to present, discuss and publish research results and their ability to further their education and training. Argentine researchers surveyed demonstrated a strong interest and willingness to contribute their work and expertise to inform Argentine health policy development. CONCLUSION: Despite Argentina's long scientific tradition, there are relatively few institutionalized linkages between health research results and health policymaking. Based on the results of this study, the disconnect between political decision-making and the health research system, coupled with fewer opportunities for formalized or informal researcher/decision-maker interaction, contribute to the challenges in evidence informing health policymaking in Argentina. Improving personal contact and the building of relationships between researchers and policymakers in Argentina will require taking into account researcher perceptions of policymakers, as highlighted in this study. PMID- 25928293 TI - Regioselective Sequential Modification of Chitosan via Azide-Alkyne Click Reaction: Synthesis, Characterization, and Antimicrobial Activity of Chitosan Derivatives and Nanoparticles. AB - Recently, the attention of researchers has been drawn toward the synthesis of chitosan derivatives and their nanoparticles with enhanced antimicrobial activities. In this study, chitosan derivatives with different azides and alkyne groups were synthesized using click chemistry, and these were further transformed into nanoparticles by using the ionotropic gelation method. A series of chitosan derivatives was successfully synthesized by regioselective modification of chitosan via an azide-alkyne click reaction. The amino moieties of chitosan were protected during derivatization by pthaloylation and subsequently unblocked at the end to restore their functionality. Nanoparticles of synthesized derivatives were fabricated by ionic gelation to form complexes of polyanionic penta-sodium tripolyphosphate (TPP) and cationic chitosan derivatives. Particle size analysis showed that nanoparticle size ranged from 181.03 +/- 12.73 nm to 236.50 +/- 14.32 nm and had narrow polydispersity index and positive surface charge. The derivatives and corresponding nanoparticles were evaluated in vitro for antibacterial and antifungal activities against three gram-positive and gram negative bacteria and three fungal strains, respectively. The minimum inhibitory concentration (MIC) of all derivatives ranged from 31.3 to 250 ug/mL for bacteria and 188 to1500 ug/mL for fungi and was lower than that of native chitosan. The nanoparticles with MIC ranging from 1.56 to 25 ug/mLfor bacteria and 94 to 750 ug/mL for fungi exhibited higher activity than the chitosan derivatives. Chitosan O-(1-methylbenzene) triazolyl carbamate and chitosan O-(1-methyl phenyl sulfide) triazolyl carbamate were the most active against the tested bacterial and fungal strains. The hemolytic assay on erythrocytes and cell viability test on two different cell lines (Chinese hamster lung fibroblast cells V79 and Human hepatic cell line WRL68) demonstrated the safety; suggesting that these derivatives could be used in future medical applications. Chitosan derivatives with triazole functionality, synthesized by Huisgen 1,3-dipolar cycloaddition, and their nanoparticles showed significant enhancement in antibacterial and antifungal activities in comparison to those associated with native, non-altered chitosan. PMID- 25928294 TI - TB Treatment Delays in Odisha, India: Is It Expected Even after These Many Years of RNTCP Implementation? AB - BACKGROUND: In India, the Revised National TB Control Programme (RNTCP) envisages initiation of TB treatment within seven days of diagnosis among smear-positive patients. After nearly two decades of RNTCP implementation, treatment delays are usually not expected. OBJECTIVES: To determine the proportion of sputum smear positive TB patients who were initiated on treatment after seven days and their associated risk factors. METHODS: The study was conducted in Cuttack and Rayagada districts of Odisha. It was a retrospective cohort study that involves review of TB treatment registers and laboratory registers for 2013. RESULTS: Among 1,800 pulmonary TB (PTB) patients, 1,074 (60%) had been initiated on treatment within seven days of diagnosis, 721 (40%) had been initiated on treatment more than seven days, and 354 (20%) had delays of more than 15 days. The mean duration between TB diagnosis and treatment initiation was 21 days with a range of 8-207 days (median = 14 days). Odds of treatment delay of more than seven days were 4.9 times (95% confidence interval [CI] 3.3-6.6) among those who had been previously treated, 6.2 times (95% CI 1.3-29.7) among those infected with HIV, and 1.8 times (95% CI 1.1-2.9) among those diagnosed outside district DMC. CONCLUSION: Delay in initiation of TB treatment occurred in majority of the smear-positive patients. The RNTCP should focus on core areas of providing quality TB services with time tested strategies. To have real-time monitoring mechanisms for diagnosed smear positive TB patients is expected to be the way forward. PMID- 25928295 TI - Physiological Strategies to Improve the Performance of Spring Maize (Zea mays L.) Planted under Early and Optimum Sowing Conditions. AB - Low temperature at stand establishment and high temperature at reproductive stage are involved in reduction of grain yield of spring maize. A field study was therefore conducted to evaluate different physiological strategies for improving performance of spring maize under temperature extremes. Seed priming and foliar spray with 3% moringa leaf extract (MLE) and 100 mg L-1 kinetin solution alone or in all possible combinations with each other at three growth stages (knee height, tasseling and grain filling stage) and hydropriming was compared with control. Seed priming plus foliar spray of MLE and kinetin significantly improved stand establishment especially under early sown crop as indicated by reduced mean emergence time (MET), improved emergence index (EI) and final emergence percentage (FEP). Similarly increased chlorophyll contents, crop growth rate, leaf area index, photosynthetic rate, transpiration rate, relative water content and decreased membrane permeability were recorded in both early and optimum sowing conditions in MLE priming plus foliar spray treatment. All these improvements were harvested in the form of increased yield and harvest index compared with control treatment. Overall crop sown at optimum time performed best but exogenous application of MLE through seed priming and foliar spray maximally improved the performance of early sown maize crop which is attributed more likely due to improved stand establishment, chlorophyll and phenolic contents, increased leaf area duration and grain filling period. It can be concluded that seed priming with MLE along with its foliar spray could increase production of maize under temperature extremes. PMID- 25928296 TI - Granzyme A Is Required for Regulatory T-Cell Mediated Prevention of Gastrointestinal Graft-versus-Host Disease. AB - In our previous work we could identify defects in human regulatory T cells (Tregs) likely favoring the development of graft-versus-host disease (GvHD) following allogeneic stem cell transplantation (SCT). Treg transcriptome analyses comparing GvHD and immune tolerant patients uncovered regulated gene transcripts highly relevant for Treg cell function. Moreover, granzyme A (GZMA) also showed a significant lower expression at the protein level in Tregs of GvHD patients. GZMA induces cytolysis in a perforin-dependent, FAS-FASL independent manner and represents a cell-contact dependent mechanism for Tregs to control immune responses. We therefore analyzed the functional role of GZMA in a murine standard model for GvHD. For this purpose, adoptively transferred CD4+CD25+ Tregs from gzmA-/- mice were analyzed in comparison to their wild type counterparts for their capability to prevent murine GvHD. GzmA-/- Tregs home efficiently to secondary lymphoid organs and do not show phenotypic alterations with respect to activation and migration properties to inflammatory sites. Whereas gzmA-/- Tregs are highly suppressive in vitro, Tregs require GZMA to rescue hosts from murine GvHD, especially regarding gastrointestinal target organ damage. We herewith identify GZMA as critical effector molecule of human Treg function for gastrointestinal immune response in an experimental GvHD model. PMID- 25928298 TI - Evaluating whether direct-to-consumer marketing can increase demand for evidence based practice among parents of adolescents with substance use disorders: rationale and protocol. AB - BACKGROUND: Fewer than one in 10 adolescents with substance use disorders (ASUDs) will receive specialty treatment, and even fewer will receive treatment designated as evidence-based practice (EBP). Traditional efforts to increase the utilization of EBP by ASUDs typically focus on practitioners-either in substance use clinics or allied health settings. Direct-to-consumer (DTC) marketing that directly targets parents of ASUDs represents a potentially complementary paradigm that has yet to be evaluated. The current study is the first to evaluate the relevance of a well-established marketing framework (the Marketing Mix) and measurement approach (measurement of perceived service quality [PSQ]) with parents of ASUDs in need of treatment. METHODS/DESIGN: A mixed-methods design is employed across three study phases, consistent with well-established methods used in the field of marketing science. Phase 1 consists of formative qualitative research with parents (and a supplementary sample of adolescents) in order to evaluate and potentially adapt a conceptual framework (Marketing Mix) and measure of PSQ. Phase 2 is a targeted survey of ASUD parents to elucidate their marketing preferences, using the adapted Marketing Mix framework, and to establish the psychometric properties of the PSQ measure. The survey will also gather data on parents' preferences for different targeted marketing messages. Phase 3 is a two group randomized controlled trial comparing the effectiveness of targeted marketing messages versus standard clinical information. Key outcomes will include parents' ratings of PSQ (using the new measure), behavioral intentions to seek out information about EBP, and actual information-seeking behavior. DISCUSSION: The current study will inform the field whether a well-established marketing framework and measurement approach can be used to increase demand for EBP among parents of ASUDs. Results of this study will have the potential to immediately inform DTC marketing efforts by professional organizations, federal agencies, clinicians, and clinical researchers. PMID- 25928297 TI - Three-dimensional cardiac computational modelling: methods, features and applications. AB - The combination of computational models and biophysical simulations can help to interpret an array of experimental data and contribute to the understanding, diagnosis and treatment of complex diseases such as cardiac arrhythmias. For this reason, three-dimensional (3D) cardiac computational modelling is currently a rising field of research. The advance of medical imaging technology over the last decades has allowed the evolution from generic to patient-specific 3D cardiac models that faithfully represent the anatomy and different cardiac features of a given alive subject. Here we analyse sixty representative 3D cardiac computational models developed and published during the last fifty years, describing their information sources, features, development methods and online availability. This paper also reviews the necessary components to build a 3D computational model of the heart aimed at biophysical simulation, paying especial attention to cardiac electrophysiology (EP), and the existing approaches to incorporate those components. We assess the challenges associated to the different steps of the building process, from the processing of raw clinical or biological data to the final application, including image segmentation, inclusion of substructures and meshing among others. We briefly outline the personalisation approaches that are currently available in 3D cardiac computational modelling. Finally, we present examples of several specific applications, mainly related to cardiac EP simulation and model-based image analysis, showing the potential usefulness of 3D cardiac computational modelling into clinical environments as a tool to aid in the prevention, diagnosis and treatment of cardiac diseases. PMID- 25928299 TI - Breast-related effects of selective estrogen receptor modulators and tissue selective estrogen complexes. AB - A number of available treatments provide relief of menopausal symptoms and prevention of postmenopausal osteoporosis. However, as breast safety is a major concern, new options are needed, particularly agents with an improved mammary safety profile. Results from several large randomized and observational studies have shown an association between hormone therapy, particularly combined estrogen progestin therapy, and a small increased risk of breast cancer and breast pain or tenderness. In addition, progestin-containing hormone therapy has been shown to increase mammographic breast density, which is an important risk factor for breast cancer. Selective estrogen receptor modulators (SERMs) provide bone protection, are generally well tolerated, and have demonstrated reductions in breast cancer risk, but do not relieve menopausal symptoms (that is, vasomotor symptoms). Tissue-selective estrogen complexes (TSECs) pair a SERM with one or more estrogens and aim to blend the positive effects of the components to provide relief of menopausal symptoms and prevention of postmenopausal osteoporosis without stimulating the breast or endometrium. One TSEC combination pairing conjugated estrogens (CEs) with the SERM bazedoxifene (BZA) has completed clinical development and is now available as an alternative option for menopausal therapy. Preclinical evidence suggests that CE/BZA induces inhibitory effects on breast tissue, and phase 3 clinical studies suggest breast neutrality, with no increases seen in breast tenderness, breast density, or cancer. In non hysterectomized postmenopausal women, CE/BZA was associated with increased bone mineral density and relief of menopausal symptoms, along with endometrial safety. Taken together, these results support the potential of CE/BZA for the relief of menopausal symptoms and prevention of postmenopausal osteoporosis combined with breast and endometrial safety. PMID- 25928301 TI - Change in Misperception of Child's Body Weight among Parents of American Preschool Children. AB - BACKGROUND: Little is known about parental recognition of their child's overweight status over time. The aim of this study was to examine the prevalence of parental misperceptions related to preschool children's weight in the last two decades. METHODS: Data come from the National Health and Nutrition Examination Survey from 1988 to 1994 (early survey; n=3839) and 2007 to 2012 (recent survey; n=3153). Parents were asked whether they considered their child, ages 2-5 years, to be overweight, underweight, or just about the right weight. We estimated the probability ratio (PR) between the two surveys for parents perceiving their overweight child as overweight. RESULTS: Percentages of parents who inappropriately perceived their overweight child as just about the right weight was 96.6% and 94.9% for the early and recent survey, respectively. As high as 78.4% of parents perceived their obese child as just about the right weight in the recent survey. The probability of overweight/obese children being perceived as overweight in the early survey was 0.18 (95% confidence interval [CI]=0.14 0.22) and further lowered to 0.14 (95% CI=0.11-0.17) in the recent survey. After adjustment for sociodemographics and BMI z-scores of directly measured body weight, probability of being appropriately perceived by the parents declined by 30% between surveys (PR=0.70 [0.63, 0.78]). CONCLUSIONS: There was a declining tendency among parents to perceive overweight children appropriately. Strategies are needed to explore how to encourage clinician discussions with parents about appropriate weight for their child and strengthen capacity for childhood obesity prevention. PMID- 25928302 TI - EcSTAT3ic about K63-Linked Ubiquitylation of IKKbeta. PMID- 25928303 TI - Assessment of systemic and pulmonary arterial remodelling in women with systemic sclerosis. AB - OBJECTIVES: Systemic sclerosis (SSc) leads to pulmonary circulation dysfunctionand there are some indications of systemic circulation impairment. We evaluated the influence of SSc on the elastic properties of large systemic arterial walls and potential correlations between systemic and pulmonary circulation involvement. METHOD: We examined 75 consecutive women (mean age 53.13+/-10.1 years) with confirmed SSc [mean disease duration (DD) 7.1+/-9.1 years] and 21 age-matched female volunteers (mean age 52.6+/-8.3 years, ns). Pulse wave velocity (PWV) and transthoracic echocardiography were performed. SSc patients were divided into two groups according to the median of DD: <=3 years (39 patients) and >3 years (36 patients). RESULTS: Patients with DD>3 years had higher PWV than those with DD<=3 years and controls (log PWV: 2.23+/-0.23 vs. 2.13+/-0.16 and vs. 2.11+/-0.16 m/s; p=0.028 and 0.029, respectively). In addition, echocardiographic indices showed impaired right ventricular (RV) function in the patients with DD>3 years. Also in these SSc patients, PWV correlated with clinical and echocardiographic parameters of pulmonary circulation: age (r=0.64, p<0.0001), acceleration time of pulmonary ejection (AcT; r=-0.38, p=0.021), and tricuspid regurgitation peak gradient (TRPG; r=0.34, p=0.04). Multiple linear regression analysis showed that PWV was independently associated with DD (beta=0.22, p==0.02), AcT (beta=-0.215, p=0.03), and age (beta=0.44, p<0.001). CONCLUSIONS: In patients with SSc lasting more than 3 years, the disease is characterized by increased stiffness of the large systemic arteries. Longer duration of SSc leads simultaneously to the increased stiffness of the large systemic arteries and to the progressive impairment of RV function and its coupling to the pulmonary arterial bed. PMID- 25928305 TI - Correction: Folate receptor-alpha (FOLR1) expression and function in triple negative tumors. PMID- 25928306 TI - Receipt of Glucose Testing and Performance of Two US Diabetes Screening Guidelines, 2007-2012. AB - BACKGROUND: Screening guidelines are used to help identify prediabetes and diabetes before implementing evidence-based prevention and treatment interventions. We examined screening practices benchmarking against two US guidelines, and the capacity of each guideline to identify dysglycemia. METHODS: Using 2007-2012 National Health and Nutrition Examination Surveys, we analyzed nationally-representative, cross-sectional data from 5,813 fasting non-pregnant adults aged >=20 years without self-reported diabetes. We examined proportions of adults eligible for diagnostic glucose testing and those who self-reported receiving testing in the past three years, as recommended by the American Diabetes Association (ADA) and the US Preventive Services Task Force (USPSTF 2008) guidelines. For each screening guideline, we also assessed sensitivity, specificity, and positive (PPV) and negative predictive values in identifying dysglycemia (defined as fasting plasma glucose >=100 mg/dl or hemoglobin A1c >=5.7%). RESULTS: In 2007-2012, 73.0% and 23.7% of US adults without diagnosed diabetes met ADA and USPSTF-2008 criteria for screening, respectively; and 91.5% had at least one major risk factor for diabetes. Of those ADA- or USPSTF-eligible adults, about 51% reported being tested within the past three years. Eligible individuals not tested were more likely to be lower educated, poorer, uninsured, or have no usual place of care compared to tested eligible adults. Among adults with >=1 major risk factor, 45.7% reported being tested, and dysglycemia yields (i.e., PPV) ranged from 45.8% (high-risk ethnicity) to 72.6% (self-reported prediabetes). ADA criteria and having any risk factor were more sensitive than the USPSTF-2008 guideline (88.8-97.7% vs. 31.0%) but less specific (13.5-39.7% vs. 82.1%) in recommending glucose testing, resulting in lower PPVs (47.7-54.4% vs. 58.4%). CONCLUSION: Diverging recommendations and variable performance of different guidelines may be impeding national diabetes prevention and treatment efforts. Efforts to align screening recommendations may result in earlier identification of adults at high risk for prediabetes and diabetes. PMID- 25928307 TI - Awareness of moderate-to-vigorous physical activity: can information on guidelines prevent overestimation? AB - BACKGROUND: Mass-media campaigns such as Change4Life use messaging to promote physical activity guidelines. Raising knowledge of MVPA guidelines within UK adults is a main goal of current mass media campaigns aimed at increasing engagement in MVPA. As this may help to inform accurate perceptions of adults' own MVPA level it is an important area of investigation. Subjective norms, health status and normal walking intensity may also influence adult's awareness of their own MVPA behaviour. The aim of this study was to examine the hypothesis that greater knowledge of MVPA guidelines, supportive subjective norms, lower self reported health status and intensity of typical walking pace are associated with accurate awareness of MVPA engagement within a sample of UK adults. METHODS: A cross-sectional study of UK adults was conducted. UK adults who subscribed to the National Academic Mailing List Service (JISCMail) were sent an invitation to complete an online survey. 1,724 UK adults completed the online survey which included items on minutes spent in MVPA, awareness of MVPA using constructs highlighted by the precaution adoption process model, subjective norms, knowledge of guidelines, health status and demographics. RESULTS: The sample was 70% female, 57% aged under 45, 93% White and 69% in full-time employment. 62% reported their health to be above average, while 62% demonstrated accurate awareness of their own physical activity level, only 18% correctly reported the MVPA guidelines and 51% reported high subjective norms towards MVPA. Logistic regression analyses identified high subjective norms (OR = 1.84, CI: 1.29, 2.63, p = .001), average or below average health status (OR = .71, CI: .53 .97, p = .001), and a self-reported regular walking pace of moderate-to-vigorous (OR = 1.31, CI: 1.05, 1.63, p = .02) to be associated with accurate MVPA awareness. Knowledge of MVPA guidelines was not associated with MVPA awareness. CONCLUSIONS: Mass media campaigns, such as Change4Life, inform the general public of MVPA guidelines. Campaign messages may be more influential targeting subjective norms instead of knowledge of guidelines, thereby raising awareness of personal MVPA behaviour amongst inactive adults and increasing motivation to engage in more MVPA. PMID- 25928309 TI - Sperm quality but not relatedness predicts sperm competition success in threespine sticklebacks (Gasterosteus aculeatus). AB - BACKGROUND: Mating between close relatives often leads to a reduction of an individual's fitness, due to an increased expression of deleterious alleles. Thus, in many animal taxa pre- as well as postcopulatory inbreeding avoidance mechanisms have evolved. An increased risk of inbreeding and hence a loss of genetic variation may occur during founder events as in most cases only few individuals establish a new population. The threespine stickleback (Gasterosteus aculeatus) is a small externally fertilizing fish species subject to strong sperm competition. Sticklebacks inhabit both marine and freshwater environments and anadromous populations have repeatedly established new genetically less diverse freshwater populations. Previous studies showed that anadromous sticklebacks strongly suffer from inbreeding depression and when given the choice females prefer to mate with unrelated males. RESULTS: The present study aimed to address whether there exists a postcopulatory inbreeding avoidance mechanism solely based on sperm-egg interactions in sperm competition experiments. We used F1 individuals that originated either from a large, genetically heterogeneous anadromous population or from a small, genetically less diverse freshwater population. For each population, eggs of two different females were in vitro fertilized by the same two males' sperm in a paired study design. In the main experiment one male was the female's full-sib brother and in the control experiment all individuals were unrelated. The results revealed that fertilization success was independent of relatedness in both populations suggesting a general lack of a postcopulatory inbreeding avoidance mechanism. Instead, male quality (i.e. sperm morphology) predicted paternity success during competitive fertilization trials. CONCLUSION: In sticklebacks, there is no evidence for postcopulatory inbreeding avoidance. Sperm morphology predicted paternity instead, thus sperm quality traits are under strong sexual selection, presumably driven by the high risk of sperm competition under natural conditions. PMID- 25928311 TI - Injection practice in Kaski district, Western Nepal: a community perspective. AB - BACKGROUND: Previous studies have shown that unsafe injection practice is a major public health problem in Nepal but did not quantify the problem. The present community-based study was planned to: 1) quantify injection usage, 2) identify injection providers, 3) explore differences, if any, in injection usage and injection providers, and 4) study and compare people's knowledge and perception about injections between the urban and rural areas of Kaski district. METHODS: A descriptive, cross-sectional mixed-methods study was conducted from July to November 2012, using a questionnaire based survey and focus group discussions (FGDs). A semi-structured questionnaire advocated by the World Health Organization was modified and administered to household heads and injection receivers in selected households and the FGDs were conducted using a topic guide. The district was divided into urban and rural areas and 300 households from each area were selected. Twenty FGDs were held. RESULTS: In 218 households (36.33%) [99 in urban and 119 in rural] one or more members received at least one injection. During the three month recall period, 258 subjects (10.44%) reported receiving injection(s) with a median of two injections. The average number of injections per person per year was calculated to be 2.37. Health care workers (34.8%), staff of medical dispensaries (37.7%), physicians (25.2%), and traditional healers (2.3%) were consulted by the respondents for their basic health care needs and for injections. Compared to urban respondents, more rural respondents preferred injections for fever (p < 0.001). People preferred injections due to injections being perceived by them as being powerful, fast acting, and longer lasting than oral pills. More than 82% of respondents were aware of, and named, at least one disease transmitted by using unsterile syringes during injection administration or when syringes are shared between people. CONCLUSIONS: Less preference for injections and high awareness about the association between injections and injection-borne infections among the general population is encouraging for safe injection practice. However, respondents were not aware of the importance of having qualified injection providers for safe injections and were receiving injections from unqualified personnel. PMID- 25928315 TI - The effects of tailoring knowledge acquisition on colorectal cancer screening self-efficacy. AB - Interventions tailored to psychological factors such as personal and vicarious behavioral experiences can enhance behavioral self-efficacy but are complex to develop and implement. Information seeking theory suggests tailoring acquisition of health knowledge (without concurrent psychological factor tailoring) could enhance self-efficacy, simplifying the design of tailored behavior change interventions. To begin to examine this issue, the authors conducted exploratory analyses of data from a randomized controlled trial, comparing the effects of an experimental colorectal cancer screening intervention tailoring knowledge acquisition with the effects of a nontailored control on colorectal cancer screening knowledge and self-efficacy in 1159 patients comprising three ethnicity/language strata (Hispanic/Spanish, 23.4%, Hispanic/English, 27.2%, non Hispanic/English, 49.3%) and 5 recruitment center strata. Adjusted for study strata, the mean postintervention knowledge score was significantly higher in the experimental group than in the control group. Adjusted experimental intervention exposure (B = 0.22, 95% CI [0.14, 0.30]), preintervention knowledge (B = 0.11, 95% CI [0.05, 0.16]), and postintervention knowledge (B = 0.03, 95% CI [0.01, 0.05]) were independently associated with subsequent colorectal cancer screening self-efficacy (p < .001 all associations). These exploratory findings suggest that tailoring knowledge acquisition may enhance self-efficacy, with potential implications for tailored intervention design, but this implication requires confirmation in studies specifically designed to examine this issue. PMID- 25928314 TI - Normal values for cardiovascular magnetic resonance in adults and children. AB - Morphological and functional parameters such as chamber size and function, aortic diameters and distensibility, flow and T1 and T2* relaxation time can be assessed and quantified by cardiovascular magnetic resonance (CMR). Knowledge of normal values for quantitative CMR is crucial to interpretation of results and to distinguish normal from disease. In this review, we present normal reference values for morphological and functional CMR parameters of the cardiovascular system based on the peer-reviewed literature and current CMR techniques and sequences. PMID- 25928320 TI - High levels of gene flow and genetic diversity in Irish populations of Salix caprea L. inferred from chloroplast and nuclear SSR markers. AB - BACKGROUND: Salix caprea is a cold-tolerant pioneer species that is ecologically important in Europe and western and central Asia. However, little data is available on its population genetic structure and molecular ecology. We describe the levels of geographic population genetic structure in natural Irish populations of S. caprea and determine the extent of gene flow and sexual reproduction using both chloroplast and nuclear simple sequence repeats (SSRs). RESULTS: A total of 183 individuals from 21 semi-natural woodlands were collected and genotyped. Gene diversity across populations was high for the chloroplast SSRs (H T = 0.21-0.58) and 79 different haplotypes were discovered, among them 48% were unique to a single individual. Genetic differentiation of populations was found to be between moderate and high (mean G ST = 0.38). For the nuclear SSRs, G ST was low at 0.07 and observed heterozygosity across populations was high (H O = 0.32-0.51); only 9.8% of the genotypes discovered were present in two or more individuals. For both types of markers, AMOVA showed that most of the variation was within populations. Minor geographic pattern was confirmed by a Bayesian clustering analysis. Gene flow via pollen was found to be approximately 7 times more important than via seeds. CONCLUSIONS: The data are consistent with outbreeding and indicate that there are no significant barriers for gene flow within Ireland over large geographic distances. Both pollen-mediated and seed mediated gene flow were found to be high, with some of the populations being more than 200 km apart from each other. These findings could simply be due to human intervention through seed trade or accidental transportation of both seeds and pollen. These results are of value to breeders wishing to exploit natural genetic variation and foresters having to choose planting material. PMID- 25928321 TI - The photoinduced E -> Z isomerization of bisazobenzenes: a surface hopping molecular dynamics study. AB - The photoinduced E -> Z isomerization of azobenzene is a prototypical example of molecular switching. On the way toward rigid molecular rods such as those for opto-mechanical applications, multiazobenzene structures have been suggested in which several switching units are linked together within the same molecule (Bleger et al., J. Phys. Chem. B 2011, 115, 9930-9940). Large differences in the switching efficiency of multiazobenzenes have been observed, depending on whether the switching units are electronically decoupled or not. In this paper we study, on a time-resolved molecular level, the E-> Z isomerization of the simplest multiazobenzene, bisazobenzene (BAB). Two isomers (ortho- and para-BAB), differing only in the connectivity of two azo groups on a shared phenyl ring will be considered.To do so, nonadiabatic semiclassical dynamics after photoexcitation of the isomers are studied by employing an "on-the-fly", fewest switches surface hopping approach. States and couplings are calculated by Configuration Interaction (CI) based on a semiempirical (AM1) Hamiltonian (Persico and co workers, Chem. Eur. J. 2004, 10, 2327-2341). In the case of para-BAB, computed quantum yields for photoswitching are drastically reduced compared to pristine azobenzene, due to electronic coupling of both switching units. A reason for this (apart from altered absorption spectra and reduced photochromicity) is the drastically reduced lifetimes of electronically excited states which are transiently populated. In contrast for meta-connected species, electronic subsystems are largely decoupled, and computed quantum yields are slightly higher than that for pristine azobenzene because of new isomerization channels. In this case we can also distinguish between single- and double-switch events and we find a cooperative effect: The isomerization of a single azo group is facilitated if the other azo group is already in the Z-configuration. PMID- 25928322 TI - miR-21 and miR-145 cooperation in regulation of colon cancer stem cells. AB - BACKGROUND: Acquired drug resistance is one of the major reasons for failing cancer therapies. Although the reasons are not fully understood, they may be related to the presence of cancer stem cells (CSCs). We have reported that chemo resistant (CR) colon cancer cells, highly enriched in CSCs, exhibit a marked up regulation of miR-21 and that down-regulation of this miR renders the CR cells more susceptible to therapeutic regimens. However, the underlying molecular mechanism is poorly understood. The aim of this investigation is to unravel this mechanism. METHODS: The levels of miR-145 and miR-21 were manipulated by transfection of mature, antago-miRs or pCMV/miR-145 expression plasmid. Quantitative RT-PCR or/and Western blots were performed to examine the expression of CD44, beta-catenin, Sox-2, PDCD4, CK-20 and k-Ras. Colonosphere formation and SCID mice xenograft studies were performed to evaluate the tumorigenic properties of CSC-enriched colon CR cells. RESULTS: We investigated the role that microRNAs (miRs), specifically miR-21 and miR-145 play in regulating colon CSCs. We found the expression of miR-21 to be greatly increased and miR-145 decreased in CR colon cancer cells that are highly enriched in CSC, indicating a role for these miRNAs in regulating CSCs. In support of this, we found that whereas forced expression of miR-145 in colon cancer cells greatly inhibits CSCs and tumor growth, up-regulation of miR-21 causes an opposite phenomenon. In addition, administration of mature miR-145 or antagomir-21 (anti-sense miR-21) greatly suppresses the growth of colon cancer cell xenografts in SCID mice. This was associated with decreased expression of CD44, beta-catenin, Sox-2 and induction of CK-20 indicating that administration of miR-145 or antagomir-21 decreases CSC proliferation and induces differentiation. In vitro studies further demonstrate that miR-21 negatively regulates miR-145 and vice versa. k-Ras appears to play critical role in regulation of this process, as evidenced by the fact that the absence of k-Ras in CR colon cancer cells increases miR-145 expression, suppresses miR-21, and interrupts the negative cooperation between miR-21 and miR 145. CONCLUSIONS: Our current observations suggest that miR-21, miR-145, and their networks play critical roles in regulating CSCs growth and/or differentiation in the colon cancer and progression of chemo-resistance. PMID- 25928325 TI - The mechanism of hydrogen evolution in Cu(bztpen)-catalysed water reduction: a DFT study. AB - The mechanism of water reduction catalysed by a mononuclear copper complex Cu(bztpen) (bztpen = N-benzyl-N,N',N'-tris(pyridine-2-ylmethyl)ethylenediamine) has been elucidated by DFT calculations, revealing that hydrogen evolution proceeds via coupling of a Cu(ii)-hydride and a pendant pyridinium, and providing important implications for the future design of new catalytic systems for water reduction. PMID- 25928324 TI - Secondary structural entropy in RNA switch (Riboswitch) identification. AB - BACKGROUND: RNA regulatory elements play a significant role in gene regulation. Riboswitches, a widespread group of regulatory RNAs, are vital components of many bacterial genomes. These regulatory elements generally function by forming a ligand-induced alternative fold that controls access to ribosome binding sites or other regulatory sites in RNA. Riboswitch-mediated mechanisms are ubiquitous across bacterial genomes. A typical class of riboswitch has its own unique structural and biological complexity, making de novo riboswitch identification a formidable task. Traditionally, riboswitches have been identified through comparative genomics based on sequence and structural homology. The limitations of structural-homology-based approaches, coupled with the assumption that there is a great diversity of undiscovered riboswitches, suggests the need for alternative methods for riboswitch identification, possibly based on features intrinsic to their structure. As of yet, no such reliable method has been proposed. RESULTS: We used structural entropy of riboswitch sequences as a measure of their secondary structural dynamics. Entropy values of a diverse set of riboswitches were compared to that of their mutants, their dinucleotide shuffles, and their reverse complement sequences under different stochastic context-free grammar folding models. Significance of our results was evaluated by comparison to other approaches, such as the base-pairing entropy and energy landscapes dynamics. Classifiers based on structural entropy optimized via sequence and structural features were devised as riboswitch identifiers and tested on Bacillus subtilis, Escherichia coli, and Synechococcus elongatus as an exploration of structural entropy based approaches. The unusually long untranslated region of the cotH in Bacillus subtilis, as well as upstream regions of certain genes, such as the sucC genes were associated with significant structural entropy values in genome-wide examinations. CONCLUSIONS: Various tests show that there is in fact a relationship between higher structural entropy and the potential for the RNA sequence to have alternative structures, within the limitations of our methodology. This relationship, though modest, is consistent across various tests. Understanding the behavior of structural entropy as a fairly new feature for RNA conformational dynamics, however, may require extensive exploratory investigation both across RNA sequences and folding models. PMID- 25928326 TI - Why Muslim women in Northern Ghana do not use skilled maternal healthcare services at health facilities: a qualitative study. AB - BACKGROUND: Muslim women are one sub-population in Ghana among whom the rate of skilled maternal health services accessibility and utilisation is very low. However, there are no studies in Ghana that explore the maternity needs and care experiences of Muslim women, and why they do not utilise maternal healthcare services at health facilities. The purpose of this paper is to explore the maternity healthcare needs and care experiences of Muslim women and the barriers to accessing and using maternal health services. METHODS: Qualitative research was conducted with 94 Muslim women in three communities in northern Ghana between November 2011 and May 2012. Data were analysed using the Attride-Stirling's thematic network analysis framework. RESULTS: Findings suggest that although Muslim women do want to receive skilled care in a health facility, they often experience difficulties with accessing and using such services. These difficulties were often conditioned by a religious obligation to maintain bodily sanctity through modest dressing and the avoidance of unlawful bodily exposure or contact with certain people including male or alien caregivers. Other related access barriers include lack of privacy, healthcare providers' insensitivity and lack of knowledge about Muslim women's religious and cultural practices, and health information that lacked the cultural and religious specificity to meet Muslim women's maternity care needs. CONCLUSION: Maternal healthcare services designed to meet the needs of mainstream non-Muslim Ghanaian women might lack the flexibility and responsiveness to meet the unique maternity care needs of Muslim women. Recommendations for change include cultural competence training for healthcare providers and cultural/religious matching to meet Muslim women's care needs and to enhance their care experience. PMID- 25928330 TI - Manipulating senescence in health and disease: emerging tools. PMID- 25928327 TI - Preclinical Study of Locoregional Therapy of Hepatocellular Carcinoma by Bioelectric Ablation with Microsecond Pulsed Electric Fields (MUsPEFs). AB - Unresectable hepatocellular carcinoma (HCC) needs locoregional ablation as a curative or downstage therapy. Microsecond Pulsed Electric Fields (MUsPEFs) is an option. A xenograft tumor model was set up on 48 nude mice by injecting human hepatocellular carcinoma Hep3B cells subcutaneously. The tumor-bearing mice were randomly divided into 3 groups: MUsPEFs treated, sham and control group. MUsPEFs group was treated by MUsPEFs twice in 5 days. Tumor volume, survival, pathology, mitochondria function and cytokines were followed up. MUsPEFs was also conducted on 3 swine to determine impact on organ functions. The tumors treated by MUsPEFs were completely eradicated while tumors in control and sham groups grew up to 2 cm(3) in 3 weeks. The MUsPEFs-treated group indicated mitochondrial damage and tumor necrosis as shown in JC-1 test, flow cytometry, H&E staining and TEM. MUsPEFs activates CD56+ and CD68+ cells and inhibits tumor proliferating cell nuclear antigen. MUsPEFs inhibits HCC growth in the nude mice by causing mitochondria damage, tumor necrosis and non-specific inflammation. MUsPEFs treats porcine livers without damaging vital organs. MUsPEFs is a feasible minimally invasive locoregional ablation option. PMID- 25928331 TI - Characterization of competitive interactions in the coexistence of Bt-transgenic and conventional rice. AB - BACKGROUND: Transgene flow through pollen and seeds leads to transgenic volunteers and feral populations in the nature, and consumer choice and economic incentives determine whether transgenic crops will be cultivated in the field. Transgenic and non-transgenic plants are likely to coexist in the field and natural habitats, but their competitive interactions are not well understood. METHODS: Field experiments were conducted in an agricultural ecosystem with insecticide spraying and a natural ecosystem, using Bt-transgenic rice (Oryza sativa) and its non-transgenic counterpart in pure and mixed stands with a replacement series. RESULTS: Insect damage and competition significantly decreased plant growth and reproduction under the coexistence of transgenic and conventional rice. Insect-resistant transgenic rice was not competitively superior to its counterpart under different densities in both agricultural and natural ecosystems, irrespective of insect infection. Fitness cost due to Bt transgene expression occurred only in an agroecosystem, where the population yield decreased with increasing percentage of transgenic rice. The population yield fluctuated in a natural ecosystem, with slight differences among pure and mixed stands under plant competition or insect pressure. The presence of Chilo suppressalis infection increased the number of non-target insects. CONCLUSIONS: Plant growth and reproduction patterns, relative competition ability and population yield indicate that Bt-transgenic and non-transgenic rice can coexist in agroecosystems, whereas in more natural habitats, transgenic rice is likely to outcompete non-transgenic rice. PMID- 25928337 TI - Should patients with CKD stage 5D and biochemical evidence of secondary hyperparathyroidism be prescribed calcimimetic therapy? An ERA-EDTA position statement. AB - This paper reflects the position of the CKD-MBD workgroup, an official working group of ERA-EDTA and of the ERBP advisory board, the official guideline producing body of ERA-EDTA, on the topic of the use of calcimimetics in patients with CKD stage 5D, as based on two recent meta-analysis. PMID- 25928341 TI - Synergistic and independent actions of multiple terminal nucleotidyl transferases in the 3' tailing of small RNAs in Arabidopsis. AB - All types of small RNAs in plants, piwi-interacting RNAs (piRNAs) in animals and a subset of siRNAs in Drosophila and C. elegans are subject to HEN1 mediated 3' terminal 2'-O-methylation. This modification plays a pivotal role in protecting small RNAs from 3' uridylation, trimming and degradation. In Arabidopsis, HESO1 is a major enzyme that uridylates small RNAs to trigger their degradation. However, U-tail is still present in null hen1 heso1 mutants, suggesting the existence of (an) enzymatic activities redundant with HESO1. Here, we report that UTP: RNA uridylyltransferase (URT1) is a functional paralog of HESO1. URT1 interacts with AGO1 and plays a predominant role in miRNA uridylation when HESO1 is absent. Uridylation of miRNA is globally abolished in a hen1 heso1 urt1 triple mutant, accompanied by an extensive increase of 3'-to-5' trimming. In contrast, disruption of URT1 appears not to affect the heterochromatic siRNA uridylation. This indicates the involvement of additional nucleotidyl transferases in the siRNA pathway. Analysis of miRNA tailings in the hen1 heso1 urt1 triple mutant also reveals the existence of previously unknown enzymatic activities that can add non-uridine nucleotides. Importantly, we show HESO1 may also act redundantly with URT1 in miRNA uridylation when HEN1 is fully competent. Taken together, our data not only reveal a synergistic action of HESO1 and URT1 in the 3' uridylation of miRNAs, but also independent activities of multiple terminal nucleotidyl transferases in the 3' tailing of small RNAs and an antagonistic relationship between uridylation and trimming. Our results may provide further insight into the mechanisms of small RNA 3' end modification and stability control. PMID- 25928342 TI - Does health literacy affect patients' receipt of preventative primary care? A multilevel analysis. AB - BACKGROUND: People with limited health literacy are more likely to be socioeconomically disadvantaged and have risk factors for preventable chronic diseases. General practice is the ideal setting to address these inequalities however these patients engage less in preventive activities and experience difficulties navigating health services. This study aimed to compare primary care patients with and without sufficient health literacy in terms of their lifestyle risk factors, and explore factors associated with receiving advice and referral for these risk factors from their GPs. METHODS: A mailed survey of 739 patients from 30 general practices across four Australian states was conducted in 2012. Health literacy was measured using the Health Literacy Management Scale. Patients with a mean score of <4 within any domain were defined as having insufficient health literacy. Multilevel logistic regression was used to adjust for clustering of patients within practices. RESULTS: Patients with insufficient health literacy (n = 351; 48%) were more likely to report being overweight or obese, and less likely to exercise adequately. Having insufficient health literacy increased a patient's chance of receiving advice on diet, physical activity or weight management, and referral to and attendance at lifestyle modification programs. Not speaking English at home; being overweight or obese; and attending a small sized practice also increased patients' chances of receiving advice on these lifestyle risks. Few (5%, n = 37) of all patients reported being referred to lifestyle modification program and of those around three-quarters had insufficient health literacy. Overweight or obese patients were more likely to be referred to lifestyle modification programs and patients not in paid employment were more likely to be referred to and attend lifestyle programs. CONCLUSION: Patients with insufficient health literacy were more likely to report receiving advice and being referred by GPs to attend lifestyle modification. Although the number of patients referred from this sample was very low, these findings are positive in that they indicate that GPs are identifying patients with low health literacy and appropriately referring them for assistance with lifestyle modification. Future research should measure the effectiveness of these lifestyle programs for patients with low health literacy. PMID- 25928343 TI - Scarf pin inhalation: clinical characteristics and surgical treatment. AB - OBJECTIVE: Scarf pin inhalation is becoming a frequent accident among young Moroccan woman who wears islamic veil. The aim of the study is to highlight indications, principles and challenges of surgical removal of that particular foreign body. METHODS: Twenty-eight patients were hospitalized in Thoracic Surgery department of Ibn Sina Hospital at Rabat between January 2008 and June 2013 for surgical removal of a pin scarf after unsuccessful endoscopy. RESULTS: Mean age was 20 years. Inhalation was accidental in all cases. Average interval between inhalation and surgery was 10 days. Penetration syndrome was found in 82% of patients. Pin was located at the left tracheo-bronchial tree in 53.5% of cases and at the right one in 46.4%. All were operated by thoracotomy. Surgery was conservative in all cases, and postoperative course was uneventful. CONCLUSION: In case of failure endoscopic treatment, surgery remains the only alternative. It must be as conservative as possible. Short interval between inhalation accident and surgery prevents parenchymal resection. PMID- 25928346 TI - Assessment of human resources for health programme implementation in 15 Latin American and Caribbean countries. AB - BACKGROUND: The health systems in the Americas region are characterized by fragmentation and segmentation, which constitute an important barrier to expanding coverage, achieving integrated primary health care, and reducing inefficiency and discontinuity of care. An assessment of the human resources for health (HRH) programmes that have been implemented at the country level was developed as part of the measurement of the 20 HRH regional goals for 2007-2015, adopted in 2007 by the Pan American Sanitary Conference (CSPA). METHODS: The exercise was a combination of academic research and the development/application of an advocacy tool involving policy makers and stakeholders to influence the decision-making in the development, implementation, or change of HRH programmes while building evidence through a structured approach based on qualitative and quantitative information and the exchange and dissemination of best practices. RESULTS: This paper covers the methodological challenges, as well as a summary of the main findings of the study, which included 15 countries: Belize, Costa Rica, El Salvador, Guatemala, Honduras, Nicaragua and Panama in the Central America, Dominican Republic in the Caribbean, Chile, Colombia, Ecuador and Peru in the Andean sub region, and Argentina, Paraguay, and Uruguay in the South Cone. Despite the different contexts, the results showed that the programmes evaluated faced common challenges, such as lack of political support and financial unsustainability. CONCLUSIONS: The evaluation process allowed the exchange and dissemination of practices, interventions, and programmes currently running in the region. A shared lesson was the importance of careful planning of the implementation of programmes and interventions. The similarities in the problems and challenges of HRH among the participating countries highlighted the need for a cooperation programme on the evaluation and assessment of implementation strategies in the Americas region. PMID- 25928347 TI - Keratinocytic epidermal nevus syndrome with Schwann cell proliferation, lipomatous tumour and mosaic KRAS mutation. AB - BACKGROUND: Keratinocytic epidermal nevus syndrome (KENS) is a complex disorder not only characterized by the presence of epidermal nevi but also by abnormalities in the internal organ systems. A small number of cases with KENS are molecularly characterized and reported in the literature with somatic activating RAS, FGFR3 and PIK3CA mutations. CASE PRESENTATION: In this study we present a patient with hyper- and hypopigmented regions, verrucous pigmented skin lesions and a paravertebral conglomerate tumour at the level of the cervical and thoracic spine. A large lipomatous dumbbell tumour caused atrophy of the spinal cord with progressive paraparesis. We identified a mosaic c.35G > A (p.Gly12Asp) KRAS mutation in the pigmented verrucous epidermal nevus tissue, the intraneural schwann cells and the lipoma. The c.35G > A (p.Gly12Asp) KRAS mutation was absent in the peripheral blood leukocytes. CONCLUSION: We conclude that KENS, the intraneural Schwann cell proliferation and the lipoma in this individual were caused by a postzygotic and mosaic activating c.35G > A (p.Gly12Asp) KRAS mutation. PMID- 25928348 TI - Local pelvic irradiation modulates Pharmacokinetics of 5-Fluorouracil in the plasma but not in the Lymphatic System. AB - BACKGROUND: 5-fluorouracil (5-FU) is employed to enhance radiotherapy (RT) effect. Here, we evaluated the influence of whole-pelvic irradiation on the pharmacokinetics (PK) of 5-FU in plasma and lymphatic system of rats as the experimental model. METHODS: RT with 2 Gy was delivered to the whole pelvis of Sprague-Dawley rats. 5-FU at 100 mg/kg was intravenously infused 24 hours after radiation. The pharmacokinetics of 5-FU in plasma and lymphatic system were calculated. RESULTS: RT at 2 Gy reduced the area under the plasma concentration vs. time curve and mean residence time of 5-FU by 21.5% and 31.5%, respectively compared with those of non-RT controls. By contrast, RT at 2 Gy increased drug clearances of 5-FU by 28.2% when compared with those of non-RT controls. There was no significant difference in T1/2, Cmax and Vss in plasma between both groups. Intriguingly, 5-Fu could be detected in the lymphatic system. In addition, the AUC in 5-FU without and with RT was 3.3-fold and 4.9-fold greater for lymph than for plasma, respectively. Compared with the non-RT group, the RT group showed increase in distribution of 5-FU in the lymphatic system (p = 0.001). CONCLUSIONS: The local whole pelvic RT at 2 Gy could modulate systemic PK of 5-FU in plasma of rats and intravenous 5-FU passing into the lymphatic system was proved. The metabolism of 5-FU might be modulated by RT but the distribution of 5-FU from blood circulation to the lymphatic system might not be changed. The RT-PK phenomena in plasma provide references for adjustment of drug administration. Chemotherapy drugs entering the lymphatic system is worthy of further investigation. PMID- 25928349 TI - Implementation of multidimensional knowledge translation strategies to improve procedural pain in hospitalized children. AB - BACKGROUND: Despite extensive research, institutional policies, and practice guidelines, procedural pain remains undertreated in hospitalized children. Knowledge translation (KT) strategies have been employed to bridge the research to practice gap with varying success. The most effective single or combination of KT strategies has not been found. A multifaceted KT intervention, Evidence-based Practice for Improving Quality (EPIQ), that included tailored KT strategies was effective in improving pain practices and clinical outcomes at the unit level in a prospective comparative cohort study in 32 hospital units (16 EPIQ intervention and 16 Standard Care), in eight pediatric hospitals in Canada. In a study of the 16 EPIQ units (two at each hospital) only, the objectives were to: determine the effectiveness of evidence-based KT strategies implemented to achieve unit aims; describe the KT strategies implemented and their influence on pain assessment and management across unit types; and identify facilitators and barriers to their implementation. METHODS: Data were collected from each EPIQ intervention unit on targeted pain practices and KT strategies implemented, through chart review and a process evaluation checklist, following four intervention cycles over a 15-month period. RESULTS: Following the completion of the four cycle intervention, 78% of 23 targeted pain practice aims across units were achieved within 80% of the stated aims. A statistically significant improvement was found in the proportion of children receiving pain assessment and management, regardless of pre determined aims (p < 0.001). The median number of KT strategies implemented was 35 and included reminders, educational outreach and materials, and audit and feedback. Units successful in achieving their aims implemented more KT strategies than units that did not. No specific type of single or combination of KT strategies was more effective in improving pain assessment and management outcomes. Tailoring KT strategies to unit context, support from unit leadership, staff engagement, and dedicated time and resources were identified as facilitating effective implementation of the strategies. CONCLUSIONS: Further research is required to better understand implementation outcomes, such as feasibility and fidelity, how context influences the effectiveness of multifaceted KT strategies, and the sustainability of improved pain practices and outcomes over time. PMID- 25928351 TI - Total synthesis and structural revision of (+)-muironolide a. AB - Muironolide A is a fascinating tetrachlorinated marine polyketide isolated from the sponge of Phorbas sp. Only 90 MUg had been isolated, and the structure was established by nanoscale NMR techniques. Herein we report the total synthesis of the substance with the assigned structure of muironolide A, propose a revised structure based on NMR data, and complete the enantioselective total synthesis of muironolide A. PMID- 25928352 TI - Antimicrobial and antioxidant flavonoids from the leaves of Oncoba spinosa Forssk. (Salicaceae). AB - BACKGROUND: Naturally occurring flavonoids have been reported to possess various pharmacological properties. The aim of this study was to evaluate the antimicrobial and antioxidant activities of the MeOH extract and flavonoids from the leaves of Oncoba spinosa, a plant used for the treatment of syphilis, wounds and sexual impotence. METHODS: The plant extract was prepared by maceration in methanol and sequentially fractionated by column chromatography. The structures of isolated compounds were elucidated on the basis of spectral studies and comparison with published data. The MeOH extract and its isolated compounds were evaluated for their antibacterial and antifungal activities by broth microdilution method. The 1,1-diphenyl-2-picrylhydrazyl (DPPH) and trolox equivalent antioxidant capacity (TEAC) assays were used to detect the antioxidant activity. The samples were tested spectrophotometrically for their hemolytic properties against human red blood cells. RESULTS: The fractionation of the MeOH extract afforded five known flavonoids including kaempferol (1), quercetin (2), apigenin-7-O-beta-D-glucuronopyranoside (3), quercetin 3-O-beta-D galactopyranoside (4) and quercetin 3-O-alpha-L-rhamnopyranosyl (1 -> 6) beta-D glucopyranoside (5). The MeOH extract displayed weak to moderate antimicrobial activities (MIC = 256-2048 MUg/ml). Quercetin 3-O-alpha-L-rhamnopyranosyl (1 -> 6) beta-D-glucopyranoside (5) and quercetin (2) were respectively the most active compounds against bacteria (MIC = 8-64 MUg/ml) and fungi (MIC = 64 - 128 MUg/ml). These tested samples also showed high radical-scavenging activities (EC50 = 5.08 70.56 MUg/ml) and gallic acid equivalent antioxidant capacities (TEAC = 53.76 - 89.86 MUg/ml) when compared with vitamin C (EC50 = 4.72 MUg/ml). The MeOH extract and compounds 2-5 were non-toxic to human red blood cells indicating their high selectivity to be used as antimicrobial and antioxidant drugs. CONCLUSION: The MeOH extract of O. spinosa as well as compounds 2 - 5 could be a potential source of natural antimicrobial and antioxidant products. PMID- 25928353 TI - Incidental thyroid nodules and thyroid cancer: considerations before determining management. AB - The worldwide incidence of thyroid cancer is increasing substantially, almost exclusively attributable to small papillary thyroid cancers. Increased use of diagnostic imaging is considered the most likely explanation for this reported rise, but other factors may also be contributing. The increase in health care expenditures related to managing these presumably low-risk cancers, without a clear patient benefit, has resulted in a backlash against the early detection of thyroid cancer. Currently, there is no way to confidently predict which incidentally detected thyroid nodule may be the precursor to a more aggressive process. Predictions such as these would require more accurate characterization of the biology of individual thyroid cancers than is currently possible. With time, we might prove our ability to confidently differentiate low-risk from high risk thyroid cancers, but until that happens, routine screening for thyroid cancer by imaging billed as a "health checkup" should not be performed. However, incidentally detected thyroid nodules should be reported, and a clear medical team management plan should be developed. Our ethical responsibility is to provide patients with objective, evidence-based information about their disease status, not to assume that we know what is best for them by selectively withholding information. In addition, providing patients with psychosocial assistance will help them process the information necessary to make informed decisions that will provide them with the most value when a small thyroid nodule or cancer is incidentally identified. Herein, we summarize the epidemiological data for disease incidence, discuss some controversies in disease management, and outline the key elements and ethical considerations of informed decision making as they apply to managing incidentally detected thyroid nodules and thyroid cancer. PMID- 25928354 TI - Polymeric Perturbation to the Magnetic Relaxations of the C2v-Symmetric [Er(Cp)2(OBu)2](-) Anion. AB - To test the coordination symmetry effect on the magnetization-reversal barrier trend of Er(III)-based single-ion magnets, the C2v-symmetric organolanthanide anion [Er(Cp)2(O(t)Bu)2](-) has been incorporated with different countercations, resulting in two structures, namely, the discrete [K2(Cp)(18-C 6)2][Er(Cp)2(O(t)Bu)2] (1) and the polymeric [ErK2(Cp)3(O(t)Bu)2(THF)2]n (2), where 18-C-6 = 18-crown-6 ether and Cp = cyclopentadienide. Surprisingly, the polymeric 2 exhibits much stronger field-induced magnetization relaxing behavior compared to the monomeric 1. Such disparate dynamic magnetism is attributable to the subtle coordination environmental perturbations of the central Er(III) ions. PMID- 25928355 TI - Obesity attenuates gender differences in cardiovascular mortality. AB - BACKGROUND: To estimate cardiovascular disease (CVD) mortality in relation to obesity and gender. METHODS: Data from 11 prospective cohorts from four European countries including 23 629 men and 21 965 women, aged 24 to 99 years, with a median follow-up of 7.9 years were analyzed. Hazards ratios (HR) for CVD mortality in relation to baseline body mass index (BMI), waist circumference (WC), waist-to-hip ratio (WHR) and waist-to-height ratio (WHtR) were estimated using Cox proportional hazards models with age as the timescale. RESULTS: Men had higher CVD mortality than women in all four BMI categories (<25.0, 25.0-29.9, 30.0-34.9 and >=35.0 kg/m(2)). Compared with the lowest BMI category in women, multivariable adjusted HRs (95% confidence intervals) for higher BMI categories are 1.0 (0.8-1.4), 1.6 (1.1-2.1) and 2.8 (2.0-3.8) in women and 2.8 (2.2-3.6), 3.1 (2.5-3.9), 3.8 (2.9-4.9) and 5.4 (3.8-7.7) in men, respectively. Similar findings were observed for abdominal obesity defined by WC, WHR or WHtR. The gender difference was slightly smaller in obese than in non-obese individuals; but the interaction was statistically significant only between gender and WC (p = 0.02), and WHtR (p = 0.01). None of the interaction terms was significant among non-diabetic individuals. CONCLUSIONS: Men had higher CVD mortality than women across categories of anthropometric measures of obesity. The gender difference was attenuated in obese individuals, which warrants further investigation. PMID- 25928356 TI - Angiogenesis is induced and wound size is reduced by electrical stimulation in an acute wound healing model in human skin. AB - Angiogenesis is critical for wound healing. Insufficient angiogenesis can result in impaired wound healing and chronic wound formation. Electrical stimulation (ES) has been shown to enhance angiogenesis. We previously showed that ES enhanced angiogenesis in acute wounds at one time point (day 14). The aim of this study was to further evaluate the role of ES in affecting angiogenesis during the acute phase of cutaneous wound healing over multiple time points. We compared the angiogenic response to wounding in 40 healthy volunteers (divided into two groups and randomised), treated with ES (post-ES) and compared them to secondary intention wound healing (control). Biopsy time points monitored were days 0, 3, 7, 10, 14. Objective non-invasive measures and H&E analysis were performed in addition to immunohistochemistry (IHC) and Western blotting (WB). Wound volume was significantly reduced on D7, 10 and 14 post-ES (p = 0.003, p = 0.002, p<0.001 respectively), surface area was reduced on days 10 (p = 0.001) and 14 (p<0.001) and wound diameter reduced on days 10 (p = 0.009) and 14 (p = 0.002). Blood flow increased significantly post-ES on D10 (p = 0.002) and 14 (p = 0.001). Angiogenic markers were up-regulated following ES application; protein analysis by IHC showed an increase (p<0.05) in VEGF-A expression by ES treatment on days 7, 10 and 14 (39%, 27% and 35% respectively) and PLGF expression on days 3 and 7 (40% on both days), compared to normal healing. Similarly, WB demonstrated an increase (p<0.05) in PLGF on days 7 and 14 (51% and 35% respectively). WB studies showed a significant increase of 30% (p>0.05) on day 14 in VEGF-A expression post-ES compared to controls. Furthermore, organisation of granulation tissue was improved on day 14 post-ES. This randomised controlled trial has shown that ES enhanced wound healing by reduced wound dimensions and increased VEGF-A and PLGF expression in acute cutaneous wounds, which further substantiates the role of ES in up-regulating angiogenesis as observed over multiple time points. This therapeutic approach may have potential application for clinical management of delayed and chronic wounds. PMID- 25928358 TI - A systematic composite service design modeling method using graph-based theory. AB - The composite service design modeling is an essential process of the service oriented software development life cycle, where the candidate services, composite services, operations and their dependencies are required to be identified and specified before their design. However, a systematic service-oriented design modeling method for composite services is still in its infancy as most of the existing approaches provide the modeling of atomic services only. For these reasons, a new method (ComSDM) is proposed in this work for modeling the concept of service-oriented design to increase the reusability and decrease the complexity of system while keeping the service composition considerations in mind. Furthermore, the ComSDM method provides the mathematical representation of the components of service-oriented design using the graph-based theoryto facilitate the design quality measurement. To demonstrate that the ComSDM method is also suitable for composite service design modeling of distributed embedded real-time systems along with enterprise software development, it is implemented in the case study of a smart home. The results of the case study not only check the applicability of ComSDM, but can also be used to validate the complexity and reusability of ComSDM. This also guides the future research towards the design quality measurement such as using the ComSDM method to measure the quality of composite service design in service-oriented software system. PMID- 25928357 TI - Pre-Training Reversible Inactivation of the Basal Amygdala (BA) Disrupts Contextual, but Not Auditory, Fear Conditioning, in Rats. AB - The basolateral amygdala complex (BLA), including the lateral (LA), basal (BA) and accessory basal (AB) nuclei, is involved in acquisition of contextual and auditory fear conditioning. The BA is one of the main targets for hippocampal information, a brain structure critical for contextual learning, which integrates several discrete stimuli into a single configural representation. Congruent with the hodology, selective neurotoxic damage to the BA results in impairments in contextual, but not auditory, fear conditioning, similarly to the behavioral impairments found after hippocampal damage. This study evaluated the effects of muscimol-induced reversible inactivation of the BA during a simultaneous contextual and auditory fear conditioning training on later fear responses to both the context and the tone, tested separately, without muscimol administration. As compared to control rats micro-infused with vehicle, subjects micro-infused with muscimol before training exhibited, during testing without muscimol, significant reduction of freezing responses to the conditioned context, but not to the conditioned tone. Therefore, reversible inactivation of the BA during training impaired contextual, but not auditory fear conditioning, thus confirming and extending similar behavioral observations following selective neurotoxic damage to the BA and, in addition, revealing that this effect is not related to the lack of a functional BA during testing. PMID- 25928359 TI - Impact of income inequality and other social determinants on suicide rate in Brazil. AB - PURPOSE: To analyze whether income inequality and other social determinants are associated with suicide rate in Brazil. METHOD: This study used panel data from all 5,507 Brazilian municipalities from 2000 to 2011. Suicide rates were calculated by sex and standardized by age for each municipality and year. The independent variables of the regression model included the Gini Index, per capita income, percentage of individuals with up to eight years of education, urbanization, average number of residents per household, percentage of divorced people, of Catholics, Pentecostals, and Evangelicals. A multivariable negative binomial regression for panel data with fixed-effects specification was performed. RESULTS: The Gini index was positively associated with suicide rates; the rate ratio (RR) was 1.055 (95% CI: 1.011-1.101). Of the other social determinants, income had a significant negative association with suicide rates (RR: 0.968, 95% CI: 0.948-0.988), whereas a low-level education had a positive association (RR: 1.015, 95% CI: 1.010-1.021). CONCLUSIONS: Income inequality represents a community-level risk factor for suicide rates in Brazil. The decrease in income inequality, increase in income per capita, and decrease in the percentage of individuals who did not complete basic studies may have counteracted the increase in suicides in the last decade. Other changes, such as the decrease in the mean residents per household, may have contributed to their increase. Therefore, the implementation of social policies that may improve the population's socioeconomic conditions and reduce income inequality in Brazil, and in other low and middle-income countries, can help to reduce suicide rates. PMID- 25928360 TI - A Titanium(III)-Catalyzed Reductive Umpolung Reaction for the Synthesis of 1,1 Disubstituted Tetrahydroisoquinolines. AB - A catalytic reductive C1-acylation of 3,4-dihydroisoquinolines is presented that gives direct access to 1,1-disubstituted tetrahydroisoquinolines. The reaction is a titanium(III)-catalyzed reductive umpolung process in which nitriles act as effective acylation agents. The method is highly chemo- and regioselective and is demonstrated in 20 examples. It is well-suited for the large-scale synthesis of functionalized tetrahydroisoquinoline products, which is exemplified in the form of a six-step synthesis of (+/-)-3-demethoxyerythratidinone. PMID- 25928362 TI - Systematic review of the pharmacological treatment of alcohol use disorders in individuals infected with hepatitis C. AB - Treating alcohol use disorders (AUD) is critical in individuals suffering from hepatitis C infection (HCV). Aside from psychosocial interventions, pharmacological treatment is effective for decreasing alcohol consumption and promoting abstinence. However, unique factors belonging to HCV-infected individuals, such as baseline hepatic vulnerability and possible ongoing hepatitis C treatment, complicate AUD drug therapy. The goal of this review is to systematically identify, summarize, and evaluate the existing evidence on the pharmacological management of AUD in HCV-infected individuals. MEDLINE, Embase, PsycINFO, and the Cochrane Central Register of Controlled Trials were searched for English- and French-language articles published from 1993 to December 2013. The search criteria focused on clinical trials and observational studies assessing the efficacy and/or safety of pharmacological management of AUD in patients infected with HCV. Of 421 identified studies, three were included for analysis. Two were observational studies assessing the safety of disulfiram. One was a randomized controlled trial assessing the efficacy and safety of baclofen. There is paucity of data regarding the efficacy and safety of pharmacological treatment of AUD in HCV-infected individuals, with studies being small series and showing significant heterogeneity. No strong recommendations can be made based on the current studies as to which pharmacological option should be preferred in this sub-population. PMID- 25928363 TI - Using Graph Components Derived from an Associative Concept Dictionary to Predict fMRI Neural Activation Patterns that Represent the Meaning of Nouns. AB - In this study, we introduce an original distance definition for graphs, called the Markov-inverse-F measure (MiF). This measure enables the integration of classical graph theory indices with new knowledge pertaining to structural feature extraction from semantic networks. MiF improves the conventional Jaccard and/or Simpson indices, and reconciles both the geodesic information (random walk) and co-occurrence adjustment (degree balance and distribution). We measure the effectiveness of graph-based coefficients through the application of linguistic graph information for a neural activity recorded during conceptual processing in the human brain. Specifically, the MiF distance is computed between each of the nouns used in a previous neural experiment and each of the in-between words in a subgraph derived from the Edinburgh Word Association Thesaurus of English. From the MiF-based information matrix, a machine learning model can accurately obtain a scalar parameter that specifies the degree to which each voxel in (the MRI image of) the brain is activated by each word or each principal component of the intermediate semantic features. Furthermore, correlating the voxel information with the MiF-based principal components, a new computational neurolinguistics model with a network connectivity paradigm is created. This allows two dimensions of context space to be incorporated with both semantic and neural distributional representations. PMID- 25928365 TI - The molecular landscape of the normal human breast--defining normal. AB - A key approach in understanding how breast cancer can occur is to determine the regulatory pathways at play in the normal breast and to identify precisely the normal developmental mechanisms subverted during early breast cancer progression. Using normal human breast tissue samples, Pardo and colleagues have identified the gene targets and pathways displaying fluctuating expression as a consequence of the menstrual cycle. Detailed characterization of how the human breast functions in its normal state, and how this may be perturbed at its earliest point, will provide a critical step toward the prevention of breast cancer. PMID- 25928366 TI - Baited-boats: an innovative way to control riverine tsetse, vectors of sleeping sickness in West Africa. AB - BACKGROUND: Human African Trypanosomiasis (HAT) is an important neglected tropical disease caused by Trypanosoma spp. parasites transmitted by species of tsetse fly (Glossina spp). The most important vectors of HAT are riverine tsetse and these can be controlled by attracting them to stationary baits such as insecticide-impregnated traps or targets deployed along the banks of rivers. However, the geographical nature of some riverine habitats, particularly mangroves but also extensive lake and river networks, makes deployment of baits difficult and limits their efficacy. It is known that tsetse are attracted by the movement of their hosts. Our hypothesis was that mounting a target on canoes typically used in Africa ('pirogues') would produce an effective means of attracting-and-killing riverine tsetse in extensive wetland habitats. METHODS: In Folonzo, southern Burkina Faso, studies were made of the numbers of tsetse attracted to a target (75 * 50 cm) of blue cloth and netting mounted on a pirogue moving along a river, versus the same target placed on the riverbank. The targets were covered with a sticky film which caught tsetse as they contacted the target. RESULTS: The pirogue-mounted target caught twice as many G. tachinoides and G. p. gambiensis, and 8 times more G. morsitans submorsitans than the stationary one (P < 0.001). CONCLUSION: Pirogues are common vehicle for navigating the rivers, lakes and swamps of West Africa. The demonstration that tsetse can be attracted to targets mounted on such boats suggests that pirogues might provide a cost effective and convenient platform for deploying targets to control tsetse in the mangrove systems of West Africa where HAT persists. Further studies to assess the impact of pirogue-mounted targets on tsetse populations in HAT foci and the protective value of targets for pirogue passengers are recommended. PMID- 25928368 TI - TGFbeta-1 and TGFBR2 polymorphisms, cooking oil fume exposure and risk of lung adenocarcinoma in Chinese nonsmoking females: a case control study. AB - BACKGROUND: Transforming growth factor-beta (TGF-beta) plays an important role in regulating cellular functions, and many studies have demonstrated important roles for TGF-beta in various cancers. Single nucleotide polymorphisms (SNPs) of TGF beta may influence lung carcinogenesis. The aim of this study was to test whether TGF-beta1 C509T and TGF-beta receptor II (TGFBR2) G-875A polymorphisms were associated with lung adenocarcinoma in nonsmoking females. METHODS: A hospital based case-control study was performed in Chinese nonsmoking females. Genotyping was performed using TaqMan SNP genotyping assay, and demographic data and environmental exposure were collected by trained interviewers after informed consents were obtained. RESULTS: A total of 272 (95.4%) cases and 313 (99.4%) controls were successfully genotyped, and the results showed that the polymorphic allele frequencies of C509T and G875A were similar among lung adenocarcinoma patients and controls (P=0.589 and 0.643, respectively). However, when the data were stratified for cooking oil fume exposure, the TT genotype of the TGFB1 C509T polymorphism showed a significantly decreased risk for lung adenocarcinoma compared with the CC genotype (adjusted OR=0.362, 95% CI=0.149-0.878, P=0.025). CONCLUSIONS: TGF-beta1 gene C509T polymorphism might be associated with decreased risk of lung adenocarcinoma in Chinese females exposed to cooking oil fumes, but no association was observed TGFBR2 gene G875A polymorphism. PMID- 25928370 TI - Sestamibi scanning and outcomes in minimally invasive parathyroidectomy. AB - OBJECTIVE: To determine whether preoperative sestamibi scanning facilitates the desired outcome of successful completion of minimally invasive parathyroidectomy (MIP) and also to analyze the results in patients with underlying concurrent thyroid disease. METHODS: We undertook a retrospective analysis by review of medical records of 133 parathyroidectomies for sporadic primary hyperparathyroidism with preoperative sestamibi scanning during a 26-month period at our medical center. RESULTS: Of the 133 patients with preoperative sestamibi scanning, 106 were candidates for MIP, and 86 had positive scans showing a localized focus of uptake. MIP, with use of intraoperative parathyroid hormone level monitoring, was successfully completed in 70 patients; the other 16 patients required conversion to bilateral neck exploration. Another 20 patients with negative sestamibi scans (no localized focus of uptake) also underwent MIP. The surgeon used ultrasonography or subtle, nondiscrete sestamibi scan findings to decide on this approach. In this group, 65% of patients had successful completion of MIP, in comparison with 81% (95% confidence interval, 72% to 89%) in the group with positive scans (P = 0.13). Subgroup analysis of patients with underlying concomitant thyroid abnormalities showed successful completion of MIP in 39 of 51 (76%), in comparison with 31 of 35 patients (89%) without thyroid abnormalities (P = 0.16). CONCLUSION: In patients with sporadic primary hyperparathyroidism, finding a localized focus of uptake on a preoperative sestamibi scan facilitates successful completion of MIP. In patients with underlying thyroid disease, positive sestamibi scans are still useful in completing MIP, but more patients in this group require conversion to bilateral neck dissection. PMID- 25928369 TI - Probing Mechanistic Similarities between Response Regulator Signaling Proteins and Haloacid Dehalogenase Phosphatases. AB - Response regulator signaling proteins and phosphatases of the haloacid dehalogenase (HAD) superfamily share strikingly similar folds, active site geometries, and reaction chemistry. Proteins from both families catalyze the transfer of a phosphoryl group from a substrate to one of their own aspartyl residues, and subsequent hydrolysis of the phosphoprotein. Notable differences include an additional Asp that functions as an acid/base catalyst and an active site well-structured prior to phosphorylation in HAD phosphatases. Both features contribute to reactions substantially faster than those for response regulators. To investigate mechanisms underlying the functional differences between response regulators and HAD phosphatases, we characterized five double mutants of the response regulator CheY designed to mimic HAD phosphatases. Each mutant contained the extra Asp paired with a phosphatase-inspired substitution to potentially position the Asp properly. Only CheY DR (Arg as the anchor) exhibited enhanced rates of both autophosphorylation with phosphoramidate and autodephosphorylation compared to those of wild-type CheY. Crystal structures of CheY DR complexed with MoO4(2-) or WO4(2-) revealed active site hydrogen bonding networks similar to those in HAD.substrate complexes, with the extra Asp positioned for direct interaction with the leaving group (phosphorylation) or nucleophile (dephosphorylation). However, CheY DR reaction kinetics did not exhibit the pH sensitivities expected for acid/base catalysis. Biochemical analysis indicated CheY DR had an enhanced propensity to adopt the active conformation without phosphorylation, but a crystal structure revealed unphosphorylated CheY DR was not locked in the active conformation. Thus, the enhanced reactivity of CheY DR reflected partial acquisition of catalytic and structural features of HAD phosphatases. PMID- 25928371 TI - Correction: De novo sequencing, assembly and characterization of antennal transcriptome of Anomala corpulenta Motschulsky (Coleoptera: Rutelidae). PMID- 25928374 TI - Genome wide linkage disequilibrium and genetic structure in Sicilian dairy sheep breeds. AB - BACKGROUND: The recent availability of sheep genome-wide SNP panels allows providing background information concerning genome structure in domestic animals. The aim of this work was to investigate the patterns of linkage disequilibrium (LD), the genetic diversity and population structure in Valle del Belice, Comisana, and Pinzirita dairy sheep breeds using the Illumina Ovine SNP50K Genotyping array. RESULTS: Average r (2) between adjacent SNPs across all chromosomes was 0.155 +/- 0.204 for Valle del Belice, 0.156 +/- 0.208 for Comisana, and 0.128 +/- 0.188 for Pinzirita breeds, and some variations in LD value across chromosomes were observed, in particular for Valle del Belice and Comisana breeds. Average values of r (2) estimated for all pairwise combinations of SNPs pooled over all autosomes were 0.058 +/- 0.023 for Valle del Belice, 0.056 +/- 0.021 for Comisana, and 0.037 +/- 0.017 for Pinzirita breeds. The LD declined as a function of distance and average r (2) was lower than the values observed in other sheep breeds. Consistency of results among the several used approaches (Principal component analysis, Bayesian clustering, F ST, Neighbor networks) showed that while Valle del Belice and Pinzirita breeds formed a unique cluster, Comisana breed showed the presence of substructure. In Valle del Belice breed, the high level of genetic differentiation within breed, the heterogeneous cluster in Admixture analysis, but at the same time the highest inbreeding coefficient, suggested that the breed had a wide genetic base with inbred individuals belonging to the same flock. The Sicilian breeds were characterized by low genetic differentiation and high level of admixture. Pinzirita breed displayed the highest genetic diversity (He, Ne) whereas the lowest value was found in Valle del Belice breed. CONCLUSIONS: This study has reported for the first time estimates of LD and genetic diversity from a genome-wide perspective in Sicilian dairy sheep breeds. Our results indicate that breeds formed non overlapping clusters and are clearly separated populations and that Comisana sheep breed does not constitute a homogenous population. The information generated from this study has important implications for the design and applications of association studies as well as for development of conservation and/or selection breeding programs. PMID- 25928375 TI - Under the banyan tree--exclusion and inclusion of people with mental disorders in rural North India. AB - BACKGROUND: Social exclusion is both cause and consequence of mental disorders. People with mental disorders (PWMD) are among the most socially excluded in all societies yet little is known about their experiences in North India. This qualitative study aims to describe experiences of exclusion and inclusion of PWMD in two rural communities in Uttar Pradesh, India. METHODS: In-depth interviews with 20 PWMD and eight caregivers were carried out in May 2013. Interviews probed experiences of help-seeking, stigma, discrimination, exclusion, participation, agency and inclusion in their households and communities. Qualitative content analysis was used to generate codes, categories and finally 12 key themes. RESULTS: A continuum of exclusion was the dominant experience for participants, ranging from nuanced distancing, negative judgements and social isolation, and self-stigma to overt acts of exclusion such as ridicule, disinheritance and physical violence. Mixed in with this however, some participants described a sense of belonging, opportunity for participation and support from both family and community members. CONCLUSIONS: These findings underline the urgent need for initiatives that increase mental health literacy, access to services and social inclusion of PWMD in North India, and highlight the possibilities of using human rights frameworks in situations of physical and economic violence. The findings also highlight the urgent need to reduce stigma and take actions in policy and at all levels in society to increase inclusion of people with mental distress and disorders. PMID- 25928376 TI - Nanoscale Synaptic Membrane Mimetic Allows Unbiased High Throughput Screen That Targets Binding Sites for Alzheimer's-Associated Abeta Oligomers. AB - Despite their value as sources of therapeutic drug targets, membrane proteomes are largely inaccessible to high-throughput screening (HTS) tools designed for soluble proteins. An important example comprises the membrane proteins that bind amyloid beta oligomers (AbetaOs). AbetaOs are neurotoxic ligands thought to instigate the synapse damage that leads to Alzheimer's dementia. At present, the identities of initial AbetaO binding sites are highly uncertain, largely because of extensive protein-protein interactions that occur following attachment of AbetaOs to surface membranes. Here, we show that AbetaO binding sites can be obtained in a state suitable for unbiased HTS by encapsulating the solubilized synaptic membrane proteome into nanoscale lipid bilayers (Nanodiscs). This method gives a soluble membrane protein library (SMPL)--a collection of individualized synaptic proteins in a soluble state. Proteins within SMPL Nanodiscs showed enzymatic and ligand binding activity consistent with conformational integrity. AbetaOs were found to bind SMPL Nanodiscs with high affinity and specificity, with binding dependent on intact synaptic membrane proteins, and selective for the higher molecular weight oligomers known to accumulate at synapses. Combining SMPL Nanodiscs with a mix-incubate-read chemiluminescence assay provided a solution-based HTS platform to discover antagonists of AbetaO binding. Screening a library of 2700 drug-like compounds and natural products yielded one compound that potently reduced AbetaO binding to SMPL Nanodiscs, synaptosomes, and synapses in nerve cell cultures. Although not a therapeutic candidate, this small molecule inhibitor of synaptic AbetaO binding will provide a useful experimental antagonist for future mechanistic studies of AbetaOs in Alzheimer's model systems. Overall, results provide proof of concept for using SMPLs in high throughput screening for AbetaO binding antagonists, and illustrate in general how a SMPL Nanodisc system can facilitate drug discovery for membrane protein targets. PMID- 25928379 TI - Identification of sample-specific regulations using integrative network level analysis. AB - BACKGROUND: Histologically similar tumors even from the same anatomical position may still show high variability at molecular level hindering analysis of genome wide data. Leveling the analysis to a gene regulatory network instead of focusing on single genes has been suggested to overcome the heterogeneity issue although the majority of the network methods require large datasets. Network methods that are able to function at a single sample level are needed to overcome the heterogeneity and sample size issues. METHODS: We present a novel network method, Differentially Expressed Regulation Analysis (DERA) that integrates expression data to biological network information at a single sample level. The sample specific networks are subsequently used to discover samples with similar molecular functions by identification of regulations that are shared between samples or are specific for a subgroup. RESULTS: We applied DERA to identify key regulations in triple negative breast cancer (TNBC), which is characterized by lack of estrogen receptor, progesterone receptor and HER2 expression and has poorer prognosis than the other breast cancer subtypes. DERA identified 110 core regulations consisting of 28 disconnected subnetworks for TNBC. These subnetworks are related to oncogenic activity, proliferation, cancer survival, invasiveness and metastasis. Our analysis further revealed 31 regulations specific for TNBC as compared to the other breast cancer subtypes and thus form a basis for understanding TNBC. We also applied DERA to high-grade serous ovarian cancer (HGS OvCa) data and identified several common regulations between HGS-OvCa and TNBC. The performance of DERA was compared to two pathway analysis methods GSEA and SPIA and our results shows better reproducibility and higher sensitivity in a small sample set. CONCLUSIONS: We present a novel method called DERA to identify subnetworks that are similarly active for a group of samples. DERA was applied to breast cancer and ovarian cancer data showing our method is able to identify reliable and potentially important regulations with high reproducibility. R package is available at http://csbi.ltdk.helsinki.fi/pub/czliu/DERA/. PMID- 25928382 TI - Characterization of proanthocyanidin metabolism in pea (Pisum sativum) seeds. AB - BACKGROUND: Proanthocyanidins (PAs) accumulate in the seeds, fruits and leaves of various plant species including the seed coats of pea (Pisum sativum), an important food crop. PAs have been implicated in human health, but molecular and biochemical characterization of pea PA biosynthesis has not been established to date, and detailed pea PA chemical composition has not been extensively studied. RESULTS: PAs were localized to the ground parenchyma and epidermal cells of pea seed coats. Chemical analyses of PAs from seeds of three pea cultivars demonstrated cultivar variation in PA composition. 'Courier' and 'Solido' PAs were primarily prodelphinidin-types, whereas the PAs from 'LAN3017' were mainly the procyanidin-type. The mean degree of polymerization of 'LAN3017' PAs was also higher than those from 'Courier' and 'Solido'. Next-generation sequencing of 'Courier' seed coat cDNA produced a seed coat-specific transcriptome. Three cDNAs encoding anthocyanidin reductase (PsANR), leucoanthocyanidin reductase (PsLAR), and dihydroflavonol reductase (PsDFR) were isolated. PsANR and PsLAR transcripts were most abundant earlier in seed coat development. This was followed by maximum PA accumulation in the seed coat. Recombinant PsANR enzyme efficiently synthesized all three cis-flavan-3-ols (gallocatechin, catechin, and afzalechin) with satisfactory kinetic properties. The synthesis rate of trans-flavan-3-ol by co-incubation of PsLAR and PsDFR was comparable to cis-flavan-3-ol synthesis rate by PsANR. Despite the competent PsLAR activity in vitro, expression of PsLAR driven by the Arabidopsis ANR promoter in wild-type and anr knock-out Arabidopsis backgrounds did not result in PA synthesis. CONCLUSION: Significant variation in seed coat PA composition was found within the pea cultivars, making pea an ideal system to explore PA biosynthesis. PsANR and PsLAR transcript profiles, PA localization, and PA accumulation patterns suggest that a pool of PA subunits are produced in specific seed coat cells early in development to be used as substrates for polymerization into PAs. Biochemically competent recombinant PsANR and PsLAR activities were consistent with the pea seed coat PA profile composed of both cis- and trans-flavan-3-ols. Since the expression of PsLAR in Arabidopsis did not alter the PA subunit profile (which is only comprised of cis-flavan-3 ols), it necessitates further investigation of in planta metabolic flux through PsLAR. PMID- 25928384 TI - A coronary artery disease-associated SNP rs6903956 contributed to asymptomatic hyperuricemia susceptibility in Han Chinese. AB - BACKGROUND: To investigate the association of a coronary artery disease (CAD) risk SNP rs6903956 with asymptomatic hyperuricemia (aHU) susceptibility in Han Chinese. METHODS: Two hundred and twenty one patients with aHU and 447 healthy controls were recruited for this study. SNP rs6903956 were genotyped using TaqMan probe. RESULTS: The overall genotype and allele frequency distribution of the rs6903956 showed significant difference between aHU cases and controls (p<0.001 for genotype and allele, respectively). AA genotype of rs6903956 was significantly associated with aHU (OR=8.672, 95% CI 2.811-26.753, p<0.001) in our Han Chinese aHU cohort. Multivariate logistic regression analysis indicated that rs6903956 might be an independent risk factor for aHU susceptibility (OR=10.642 [2.671-42.400], p=0.001 for codominant model and OR=9.205 [2.336-36.280], p=0.002 for recessive model) after adjustment for some well- known CAD risk factors including age, gender, body mass index, smoking, hypertension, diabetes mellitus, abnormal glycometabolism, lipid abnormality and alcohol intake. No significant genotype-specific difference in uric acid levels was observed in aHU patients and controls. CONCLUSIONS: Our findings are the first to establish a genetic link of a CAD-associated rs6903956 with aHU in a Han Chinese population, providing the genetic evidence to support the close relationship between hyperuricemia and CAD. PMID- 25928385 TI - Encapsulation of Hemin in Metal-Organic Frameworks for Catalyzing the Chemiluminescence Reaction of the H2O2-Luminol System and Detecting Glucose in the Neutral Condition. AB - Novel metal-organic frameworks (MOFs) based solid catalysts have been synthesized by encapsulating Hemin into the HKUST-1 MOF materials. These have been first applied in the chemiluminescence field with outstanding performance. The functionalized MOFs not only maintain an excellent catalytic activity inheriting from Hemin but also can be cyclically utilized as solid mimic peroxidases in the neutral condition. The synthesized Hemin@HKUST-1 composites have been used to develop practical sensors for H2O2 and glucose with wide response ranges and low detection limits. It was envisioned that catalyst-functionalized MOFs for chemiluminescence sensing would have promising applications in green, selective, and sensitive detection of target analytes in the future. PMID- 25928386 TI - Raman spectroscopic study on the excystation process in a single unicellular organism amoeba (Acanthamoeba polyphaga). AB - An in vivo Raman spectroscopic study of amoeba (Acanthamoeba polyphaga) is presented. The changes of the spectra during the amoeba cyst activation and excystation are analyzed. The spectra show the changes of the relative intensities of bands corresponding to protein, lipid, and carotenoid components during cyst activation. The presence of carotenoids in the amoeba is observed via characteristic Raman bands. These signals in the Raman spectra are intense in cysts but decrease in intensity with cyst activation and exhibit a correlation with the life cycle of amoeba. This work demonstrates the feasibility of using Raman spectroscopy for the detection of single amoeba microorganisms in vivo and for the analysis of the amoeba life activity. The information obtained may have implications for the estimation of epidemiological situations and for the diagnostics and prognosis of the development of amoebic inflammations. PMID- 25928388 TI - The role of Nrf2 in pathology of pleomorphic adenoma in parotid gland. AB - BACKGROUND: Pleomorphic adenoma (benign mixed tumor) is one of the most common salivary gland tumors. However, the processes involved in its carcinogenesis are not well defined. This study aimed to define the contribution of Nfr2 (nuclear factor (erythroid-derived 2)-like 2) to pleomorphic adenoma pathology. The Nrf2 controlled gene system is one of the most critical cytoprotective mechanisms, providing antioxidant responses. MATERIAL AND METHODS: The study was carried out in pleomorphic adenoma and control parotid gland tissues, investigating gene expression of NFE2L2, as well as KEAP1 (Kelch-like ECH-associated protein 1) and NQO1 (quinone oxidoreductase), at mRNA and protein (immunohistochemistry) levels. Functional evaluation of Nrf2 system in the parotid gland was evaluated in HSY cells (human parotid gland adenocarcinoma cells). RESULTS: Pleomorphic adenoma specimens showed cytoplasmic and nuclear Nfr2 expression in epithelial cells, as well as more variable lower Nrf2 level in mesenchymal cells. In the parotid gland, Nrf2 was expressed in cytoplasm of serous, mucous, and duct cells. Nuclear Nrf2 expression was predominantly seen in serous cells, whereas mucous and duct cells were mostly negative. Comparable mRNA levels of NFE2L2 and NQO1 genes and significantly higher expression of KEAP1 in pleomorphic adenoma were seen. HSY cell incubation with oltipraz demonstrated significant elevation of NFE2L2 after 24 and 48 hours of stimulation, whereas NQO1 was elevated, but significantly only after 24 hours, and KEAP1 expression remained unchanged. CONCLUSIONS: Summarizing both in vitro and in vivo observations, it can be stated that Nrf2 may play a role in the pathology of pleomorphic adenoma. PMID- 25928391 TI - Cytosolic calcium changes affect the incidence of early afterdepolarizations in canine ventricular myocytes. AB - This study was designed to investigate the influence of cytosolic Ca(2+) levels ([Ca(2+)]i) on action potential duration (APD) and on the incidence of early afterdepolarizations (EADs) in canine ventricular cardiomyocytes. Action potentials (AP) of isolated cells were recorded using conventional sharp microelectrodes, and the concomitant [Ca(2+)]i was monitored with the fluorescent dye Fura-2. EADs were evoked at a 0.2 Hz pacing rate by inhibiting the rapid delayed rectifier K(+) current with dofetilide, by activating the late sodium current with veratridine, or by activating the L-type calcium current with BAY K8644. These interventions progressively prolonged the AP and resulted in initiation of EADs. Reducing [Ca(2+)]i by application of the cell-permeant Ca(2+) chelator BAPTA-AM lengthened the AP at 1.0 Hz if it was applied alone, in the presence of veratridine, or in the presence of BAY K8644. However, BAPTA-AM shortened the AP if the cells were pretreated with dofetilide. The incidence of the evoked EADs was strongly reduced by BAPTA-AM in dofetilide, moderately reduced in veratridine, whereas EAD incidence was increased by BAPTA-AM in the presence of BAY K8644. Based on these experimental data, changes in [Ca(2+)]i have marked effects on APD as well as on the incidence of EADs; however, the underlying mechanisms may be different, depending on the mechanism of EAD generation. As a consequence, reduction of [Ca(2+)]i may eliminate EADs under some, but not all, experimental conditions. PMID- 25928393 TI - Buried chloride stereochemistry in the Protein Data Bank. AB - BACKGROUND: Despite the chloride anion is involved in fundamental biological processes, its interactions with proteins are little known. In particular, we lack a systematic survey of its coordination spheres. RESULTS: The analysis of a non-redundant set (pairwise sequence identity < 30%) of 1739 high resolution (<2 A) crystal structures that contain at least one chloride anion shows that the first coordination spheres of the chlorides are essentially constituted by hydrogen bond donors. Amongst the side-chains positively charged, arginine interacts with chlorides much more frequently than lysine. Although the most common coordination number is 4, the coordination stereochemistry is closer to the expected geometry when the coordination number is 5, suggesting that this is the coordination number towards which the chlorides tend when they interact with proteins. CONCLUSIONS: The results of these analyses are useful in interpreting, describing, and validating new protein crystal structures that contain chloride anions. PMID- 25928394 TI - MRI assessment of the effects of acetazolamide and external lumbar drainage in idiopathic normal pressure hydrocephalus. AB - BACKGROUND: The objective was to identify changes in quantitative MRI measures in patients with idiopathic normal pressure hydrocephalus (iNPH) occurring in common after oral acetazolamide (ACZ) and external lumbar drainage (ELD) interventions. METHODS: A total of 25 iNPH patients from two clinical sites underwent serial MRIs and clinical assessments. Eight received ACZ (125-375 mg/day) over 3 months and 12 underwent ELD for up to 72 hours. Five clinically-stable iNPH patients who were scanned serially without interventions served as controls for the MRI component of the study. Subjects were divided into responders and non-responders to the intervention based on gait and cognition assessments made by clinicians blinded to MRI results. The MRI modalities analyzed included T1-weighted images, diffusion tensor Imaging (DTI) and arterial spin labelling (ASL) perfusion studies. Automated threshold techniques were used to define regions of T1 hypo intensities. RESULTS: Decreased volume of T1-hypointensities and decreased mean diffusivity (MD) within remaining hypointensities was observed after ACZ and ELD but not in controls. Patients responding positively to these interventions had more extensive decreases in T1-hypointensites than non-responders: ACZ-responders (4,651 +/- 2,909 mm(3)), ELD responders (2,338 +/- 1,140 mm(3)), ELD non responders (44 +/- 1,188 mm(3)). Changes in DTI MD within T1-hypointensities were greater in ACZ-responders (7.9% +/- 2%) and ELD-responders (8.2% +/- 3.1%) compared to ELD non-responders (2.1% +/- 3%). All the acetazolamide-responders showed increases in whole-brain-average cerebral blood flow (wbCBF) estimated by ASL (18.8% +/- 8.7%). The only observed decrease in wbCBF (9.6%) occurred in an acetazolamide-non-responder. A possible association between cerebral atrophy and response was observed, with subjects having the least cortical atrophy (as indicated by a positive z-score on cortical thickness measurements) showing greater clinical improvement after ACZ and ELD. CONCLUSIONS: T1-hypointensity volume and DTI MD measures decreased in the brains of iNPH patients following oral ACZ and ELD. The magnitude of the decrease was greater in treatment responders than non-responders. Despite having different mechanisms of action, both ELD and ACZ may decrease interstitial brain water and increase cerebral blood flow in patients with iNPH. Quantitative MRI measurements appear useful for objectively monitoring response to acetazolamide, ELD and potentially other therapeutic interventions in patients with iNPH. PMID- 25928398 TI - IQGAP1 is associated with nuclear envelope reformation and completion of abscission. AB - The final stage of mitosis is cytokinesis, which results in 2 independent daughter cells. Cytokinesis has 2 phases: membrane ingression followed by membrane abscission. IQGAP1 is a scaffold protein that interacts with proteins implicated in mitosis, including F-actin, myosin and CaM. IQGAP1 in yeast recruits actin and myosin II filaments to the contractile ring for membrane ingression. In contrast, we show that mammalian IQGAP1 is not required for ingression, but coordinates nuclear pore complex (NPC) reassembly and completion of abscission. Depletion of IQGAP1 disrupts Nup98 and mAb414 nuclear envelope localization and delays abscission timing. IQGAP1 phosphorylation increases 15 fold upon mitotic entry at S86, S330 and T1434, with the latter site being targeted by CDK2/Cyclin A and CDK1/Cyclin A/B in vitro. Expressing the phospho deficient mutant IQGAP1-S330A impairs NPC reassembly in cells undergoing abscission. Thus, mammalian IQGAP1 functions later in mitosis than its yeast counterpart to regulate nuclear pore assembly in a S330 phosphorylation-dependent manner during the abscission phase of cytokinesis. PMID- 25928399 TI - Mitotic activity of survivin is regulated by acetylation at K129. AB - Survivin is a cancer-associated protein regulated by multiple factors, including acetylation at K129 within its C-terminal alpha-helical tail. Acetylation of survivin is being pursued as a potential prognostic marker in breast cancer. This modification at K129 may cause nuclear accumulation of survivin in interphase cells; however, whether this affects its essential role during mitosis has not been addressed. We posited whether mimicking acetylation of survivin at K129 alters its activity during mitosis. Fluorescence microscopy and time-lapse imaging showed that, mutating this site to an alanine to act as a constitutive acetyl mimetic, K129A, causes defects in chromosome segregation and cytokinesis. As a non-acetylatable version, K129R, also has difficulty during mitotic exit, we conclude that cyclical acetylation and deacetylation is required for fully functional survivin during mitosis. PMID- 25928400 TI - Designation and Exploration of Halide-Anion Recognition Based on Cooperative Noncovalent Interactions Including Hydrogen Bonds and Anion-pi. AB - A novel urea-based anion receptor with an electron-deficient aromatic structural unit, N-p-nitrophenyl-N-(4-vinyl-2-five-fluoro-benzoic acid benzyl ester)-phenyl urea (FUR), was designed to probe the potential for halide-anion recognition through the cooperation of two distinct noncovalent interactions including hydrogen bonds and anion-pi in this work. The nature of the recognition interactions between halide-anion and the designed receptor was theoretically investigated at the molecular level. The geometric features of the hydrogen bond and anion-pi of the FUR@X(-) (X = F, Cl, Br, and I) systems were thoroughly investigated. The binding energies and thermodynamic information on the halide anion recognitions show that the presently designed FUR might selectively recognize anion F(-) based on the cooperation of the N-H...F(-) hydrogen bond and anion-pi interactions both in vacuum and in solvents. IR and UV-visible spectra of free FUR and FUR@F(-) have been simulated and discussed qualitatively, which may be helpful for further experimental investigations in the future. Additionally, the electronic properties and behaviors of the FUR@X(-) systems were discussed according to the calculations on the natural bond orbital (NBO) data, molecular electrostatic potential (MEP), and weak interaction regions. PMID- 25928401 TI - Reaching the global community during disasters: findings from a content analysis of the organizational use of Twitter after the 2010 Haiti earthquake. AB - Social networking sites provide virtual environments in which individuals and organizations exchange real-time information on a multitude of topics, including health promotion and disease prevention. The January 2010 earthquake in Haiti has been posited as a turning point in the way in which organizations use social media, such as Twitter, for crisis communication. The purpose of this content analysis was to explore whether organizations' use of Twitter changed after the 2010 Haiti earthquake. A team of 13 coders analyzed all English-language tweets (N = 2,616) during the 3 months before and post earthquake from 6 leading organizations in the Haiti disaster relief efforts. Study findings indicate that the ways in which organizations used Twitter changed over time. Chi-square analyses demonstrated that organizations decreased in their use of certain strategies to disseminate information through Twitter, such as the use of links. Organizations did not change in their use of techniques to involve users (e.g., retweet, call to action), with the exception of using tweets as a fundraising mechanism. Study findings highlight missed opportunities among organizations to maximize Twitter in order to encourage more interactive and immediate communication with the global community. PMID- 25928402 TI - In situ analysis of interleukin-6 expression at different sites of zygapophyseal joints from patients with ankylosing spondylitis in comparison to controls. AB - OBJECTIVES: Analysis of interleukin (IL)-6 serum levels in patients with ankylosing spondylitis (AS) has indicated that IL-6 might be a pro-inflammatory cytokine involved in AS. However, two placebo-controlled trials with monoclonal antibodies directed against the IL-6 receptor have failed to demonstrate the efficacy of the monoclonal humanized anti-human IL-6 receptor antibody over placebo for the treatment of symptoms of AS. In this study we conducted an in situ analysis of IL-6 expression at different sites of inflammation in zygapophyseal joints of patients with AS in comparison to osteoarthritis autopsy controls (CO). METHOD: Our immunohistochemical analysis involved 14 patients with AS, 12 autopsy controls (CO), and 11 patients with osteoarthritis (OA). Immunohistochemistry was performed to detect IL-6+ cells at five different sites: within subchondral bone marrow, fibrous tissue replacing subchondral bone marrow, hyaline cartilage, and the subchondral bone plate, and at entheseal sites. RESULTS: Apart from changes in subchondral bone marrow, no significant differences were observed at the sites analysed when comparing AS patients and controls. A significantly lower frequency of IL-6+ cells was evident in AS patients compared to controls (p = 0.0043). In addition, AS patients tended to have even lower percentages of IL-6+ cells than controls at subchondral bone plates and entheseal sites. A significantly lower number of IL-6 expressing cells was also seen within the fibrous tissue of AS compared to OA patients (p = 0.0237). CONCLUSIONS: This in situ analysis confirms that IL-6 is not a key player in the pathogenesis of inflammatory processes in spondyloarthritides (SpA). The relevance of pro-inflammatory agents in axial SpA might be studied better in situ in bony specimens at the primary site of inflammation. PMID- 25928403 TI - Synthesis of chelating diamido Sn(IV) compounds from oxidation of Sn(II) and directly from Sn(IV) precursors. AB - Three dimethyltindiamides containing chelating diamide ligands were synthesised from the reaction of the dilithiated diamine and Me2SnCl2; [SnMe2(L1)] 1 (L1 = kappa(2)-N(Dipp)C2H4N(Dipp)), [SnMe2(L2)] 2 (L2 = kappa(2)-N(Dipp)C3H6N(Dipp)) and [SnMe2(L3)] 3 (L3 = kappa(2)-N(Dipp)SiPh2N(Dipp)), Dipp = 2,6-(i)Pr2C6H3. Reaction of (L2)H2 with SnCl4 and NEt3 led to the formation of the diamidotin dichloride [SnCl2(L2)] 4 whereas reaction of (L1)H2 with SnCl4 and NEt3, or [Sn(L1)] with SnCl4, led to the exclusive formation of the amidotin trichloride [SnCl3{kappa(2)-DippN(H)C2H4N(Dipp)}] 5. Reactions of [Sn(L1)] with sulfur and selenium formed [{Sn(L1)(MU-E)}2] (E = S 10 and Se )11. MeI reacted with N heterocyclic stannylenes to generate the Sn(iv) addition products [Sn(Me)I(L1)] 12, [Sn(Me)I(L2)] 13, [Sn(Me)I(L3)] 14 and [Sn(Me)I(L4)] 15 (L4 = kappa(3) N(Dipp)C2H4OC2H4N(Dipp)), and subsequent reaction with AgOTf (OTf = OSO2CF3) generated the corresponding Sn(iv) triflates [Sn(Me)OTf(L1)] 16, [Sn(Me)OTf(L2)] 17 and [Sn(Me)OTf(L4)] 19 with [Sn(Me)OTf(L3)] 18 formed only as a mixture with unidentified by-products. All of the compounds were characterised by single crystal X-ray diffraction. PMID- 25928405 TI - Distinct and cooperative activities of HESO1 and URT1 nucleotidyl transferases in microRNA turnover in Arabidopsis. AB - 3' uridylation is increasingly recognized as a conserved RNA modification process associated with RNA turnover in eukaryotes. 2'-O-methylation on the 3' terminal ribose protects micro(mi)RNAs from 3' truncation and 3' uridylation in Arabidopsis. Previously, we identified HESO1 as the nucleotidyl transferase that uridylates most unmethylated miRNAs in vivo, but substantial 3' tailing of miRNAs still remains in heso1 loss-of-function mutants. In this study, we found that among nine other potential nucleotidyl transferases, UTP:RNA uridylyltransferase 1 (URT1) is the single most predominant nucleotidyl transferase that tails miRNAs. URT1 and HESO1 prefer substrates with different 3' end nucleotides in vitro and act cooperatively to tail different forms of the same miRNAs in vivo. Moreover, both HESO1 and URT1 exhibit nucleotidyl transferase activity on AGO1 bound miRNAs. Although these enzymes are able to add long tails to AGO1-bound miRNAs, the tailed miRNAs remain associated with AGO1. Moreover, tailing of AGO1 bound miRNA165/6 drastically reduces the slicing activity of AGO1-miR165/6, suggesting that tailing reduces miRNA activity. However, monouridylation of miR171a by URT1 endows the miRNA the ability to trigger the biogenesis of secondary siRNAs. Therefore, 3' tailing could affect the activities of miRNAs in addition to leading to miRNA degradation. PMID- 25928408 TI - Influences of laparoscopic-assisted gastrectomy and open gastrectomy on serum interleukin-6 levels in patients with gastric cancer among Asian populations: a systematic review. AB - BACKGROUND: To compare the effects of laparoscopic-assisted gastrectomy (LAG) and open gastrectomy (OG) on serum interleukin-6 (IL-6) levels in gastric cancer (GC) patients from Asia. METHODS: The following scientific literature databases were searched for relevant clinical studies: PubMed, EBSCO, Ovid, Wiley, Web of Science, Cochrane library, EMBASE, WANFANG and VIP databases. The studies retrieved from database searches were screened based on stringent inclusion and exclusion criteria to select high quality cohort studies for the present meta analysis. The data extracted from final selected studies were analyzed using STATA 12.0 software. RESULTS: A total of 54 studies were initially retrieved from database searches, and 11 clinical cohort studies were eventually enrolled in this meta-analysis. The 11 selected studies contained a combined total of 767 GC patients (427 patients in LAG group and 340 patients in OG group). Meta-analysis results demonstrated that postoperative serum IL-6 levels in GC patients in LAG group was significantly lower than the OG group (SMD = -2.16, 95% CI = -3.19 ~ 1.14, P < 0.001). The difference in serum IL-6 levels between the preoperative and postoperative GC patients was significantly lower in the LAG group compared to the difference found in the OG group (SMD = -3.44, 95% CI = -4.87 ~ -2.01, P < 0.001). Subgroup analysis based on country showed that, in both Chinese and Japanese GC patients, the postoperative increase in serum IL-6 levels in LAG group were significantly lower than the increase observed in the OG group (all P < 0.05). In Korean GC patients, the postoperative increase in serum IL-6 levels was not significantly different between the LAG group and OG group (all P > 0.05). CONCLUSION: Our results provide strong evidence that LAG is associated with significantly lower serum IL-6 levels, compared to OG. Thus, LAG carries markedly lower risk of adverse inflammatory reactions in GC patients among Asian population. PMID- 25928409 TI - Evolution of the RAG1-RAG2 locus: both proteins came from the same transposon. AB - The RAG1 and RAG2 proteins are essential subunits of the V(D)J recombinase that is required for the generation of the enormous variability of antibodies and T cell receptors in jawed vertebrates. It was demonstrated previously that the 600 aa catalytic core of RAG1 evolved from the transposase of the Transib superfamily transposons. However, although homologs of RAG1 and RAG2 genes are adjacent in the purple sea urchin genome, a transposon encoding both proteins so far has not been reported. Here we describe such transposons in the genomes of green sea urchin, a starfish and an oyster. Comparison of the domain architectures of the RAG1 homologs in these transposons, denoted TransibSU, and other Transib superfamily transposases provides for reconstruction of the structure of the hypothetical TransibVDJ transposon that gave rise to the VDJ recombinases at the onset of vertebrate evolution some 500 million years ago. PMID- 25928414 TI - Assessing the implementation and influence of policies that support research and innovation systems for health: the cases of Mozambique, Senegal, and Tanzania. AB - BACKGROUND: Without good policies it will be difficult to provide guidance to research and innovation systems. However, policies need to be followed through and implemented to have the desired effect. We studied the policies and strategies in place to support research and innovation systems for health in Mozambique, Senegal, and Tanzania, and looked at the extent to which these policies and strategies have been implemented. METHODS: We reviewed documents and reports and conducted in-depth interviews with 16 key informants representing various actors of the national research for health systems. RESULTS: The results illustrate that there are various policies and strategies governing research and innovation for health in the three countries. However, implementation of these policies and strategies is generally rated as being poor. The reasons highlighted for this include lack of policy coherence, lack of enforcement and accountability mechanisms, and a lack of financing for implementing the policies. These contextual factors seem to be of such importance that even the increased stakeholder involvement and political leadership, as mentioned by the interviewees, cannot guarantee policy implementation. CONCLUSIONS: We conclude that due to the contextual realities of the study countries, there is need for greater focus on policy implementation than on developing additional policies. Government institutions should play a central role in all stages of the policy process, and should ensure implementation of defined policies. Strong mechanisms, including financing, that strengthen the position and role of government in policy coordination and the oversight of the policy process will help increase efficient and impactful implementation of research and innovation for health policies. PMID- 25928412 TI - Genetic association of fetal-hemoglobin levels in individuals with sickle cell disease in Tanzania maps to conserved regulatory elements within the MYB core enhancer. AB - BACKGROUND: Common genetic variants residing near upstream regulatory elements for MYB, the gene encoding transcription factor cMYB, promote the persistence of fetal hemoglobin (HbF) into adulthood. While they have no consequences in healthy individuals, high HbF levels have major clinical benefits in patients with sickle cell disease (SCD) or beta thalassemia. Here, we present our detailed investigation of HBS1L-MYB intergenic polymorphism block 2 (HMIP-2), the central component of the complex quantitative-trait locus upstream of MYB, in 1,022 individuals with SCD in Tanzania. METHODS: We have looked at 1022 individuals with HbSS or HbS/beta(0) in Tanzania. In order to achieve a detailed analysis of HMIP-2, we performed targeted genotyping for a total of 10 SNPs and extracted additional 528 SNPs information from a genome wide scan involving the same population. Using MACH, we utilized the existing YRI data from 1000 genomes to impute 54 SNPs situated within HIMP-2. RESULTS: Seven HbF-increasing, low frequency variants (beta > 0.3, p < 10(-5), f <= 0.05) were located in two partially-independent sub-loci, HMIP-2A and HMIP-2B. The spectrum of haplotypes carrying such alleles was diverse when compared to European and West African reference populations: we detected one such haplotype at sub-locus HMIP-2A, two at HMIP-2B, and a fourth including high-HbF alleles at both sub-loci ('Eurasian' haplotype clade). In the region of HMIP-2A a putative functional variant (a 3-bp indel) has been described previously, but no such candidate causative variant exists at HMIP-2B. Extending our dataset through imputation with 1000 Genomes, whole-genome-sequence data, we have mapped peak association at HMIP-2B to an 11 kb region around rs9494145 and rs9483788, flanked by two conserved regulatory elements for MYB. CONCLUSIONS: Studies in populations from the African continent provide distinct opportunities for mapping disease-modifying genetic loci, especially for conditions that are highly prevalent there, such as SCD. Population-genetic characteristics of our cohort, such as ethnic diversity and the predominance of shorter, African-type haplotypes, can add to the power of such studies. PMID- 25928416 TI - Organized breast screening improves reattendance compared to physician referral: a case control study. AB - BACKGROUND: The Ontario Breast Screening Program (OBSP) is a population-based breast screening programme, not requiring physician referral. OBSP invites women by mail to book their next screens. However, women who do not participate in the OBSP, may be referred by physicians to non-OBSP mammography facilities, which do not remind women to book their next screen. METHODS: We identified women without breast cancer prior to June 30, 2011, having bilateral mammography (M) during a baseline period at age 50 - 69 at OBSP or non-OBSP facilities, and during a re exposure period, at the same facility type. We used a case-control design to study the association of facility type and having M during an outcome period. Cases were women failing to receive the outcome M. Controls were matched by age, census tract, and socioeconomic status. Exposure was baseline facility type. Covariates were comorbidity, residential mobility, and primary care physician (PCP) characteristics. Conditional logistic regression analysis was performed. RESULTS: Cases were less likely to have been screened at OBSP facilities. Failure to receive the outcome M was associated with having moved after re-exposure M (OR = 1.61, 95% confidence interval (CI) 1.52, 1.71), having a male PCP (OR = 1.05, 95% CI 1.02, 1.05), or a higher Charlson score (OR = 1.06 per unit increase, 95% CI 1.03, 1.09). Having re-exposure M at an OBSP facility (OR = 0.18, 95% CI 0.18, 0.19)., having a Canadian trained PCP (OR = 0.83, 95% CI 0.8, 0.87), and having a PCP one year after the re-exposure M (OR = 0.81, 95% CI 0.68, 0.97) were protective against failure to receive the outcome M. CONCLUSIONS: The OBSP, not requiring physician referral, and inviting women by mail to book their next screen, is associated with a lower probability of failure to reattend for subsequent screening than screening by PCP referral to non-OBSP facilities. PMID- 25928417 TI - Early deep sedation is associated with decreased in-hospital and two-year follow up survival. AB - INTRODUCTION: There is increasing evidence that deep sedation is detrimental to critically ill patients. The aim of this study was to examine effects of deep sedation during the early period after ICU admission on short- and long-term survival. METHODS: In this observational, matched-pair analysis, patients receiving mechanical ventilation that were admitted to ICUs of a tertiary university hospital in six consecutive years were grouped as either lightly or deeply sedated within the first 48 hours after ICU admission. The Richmond Agitation-Sedation Score (RASS) was used to assess sedation depth (light sedation: -2 to 0; deep: -3 or below). Multivariate Cox regression was conducted to investigate the impact of early deep sedation within the first 48 hours of admission on in-hospital and two-year follow-up survival. RESULTS: In total, 1,884 patients met inclusion criteria out of which 27.2% (n = 513) were deeply sedated. Deeply sedated patients had longer ventilation times, increased length of stay and higher rates of mortality. Early deep sedation was associated with a hazard ratio of 1.661 (95% CI: 1.074 to 2.567; P = 0.022) for in-hospital survival and 1.866 (95% CI: 1.351 to 2.576; P < 0.001) for two-year follow-up survival. CONCLUSIONS: Early deep sedation during the first 48 hours of intensive care treatment was associated with decreased in-hospital and two-year follow-up survival. Since early deep sedation is a modifiable risk factor, this data shows an urgent need for prospective clinical trials focusing on light sedation in the early phase of ICU treatment. PMID- 25928418 TI - Travellers' diarrhoea. AB - INTRODUCTION: It is estimated that approximately 30% to 70% of international travellers will develop diarrhoea during their travels or after returning home. METHODS AND OUTCOMES: We conducted a systematic review and aimed to answer the following clinical question: What are the effects of treatments for acute mild-to moderate diarrhoea in adults from resource-rich countries travelling to resource poor countries? We searched: Medline, Embase, The Cochrane Library, and other important databases up to September 2014 (Clinical Evidence reviews are updated periodically; please check our website for the most up-to-date version of this review). We included harms alerts from relevant organisations such as the US Food and Drug Administration (FDA) and the UK Medicines and Healthcare products Regulatory Agency (MHRA). RESULTS: We found 24 studies that met our inclusion criteria. We performed a GRADE evaluation of the quality of evidence for interventions. CONCLUSIONS: In this systematic review we present information relating to the effectiveness and safety of the following interventions: antibiotics (empirical), antibiotics plus antimotility agents, antimotility agents, bismuth subsalicylate, diet, oral rehydration solutions, and racecadotril for travellers' diarrhoea. PMID- 25928419 TI - Polymorphisms of the peroxisome proliferator-activated receptor-gamma (rs1801282) and its coactivator-1 (rs8192673) are associated with obesity indexes in subjects with type 2 diabetes mellitus. AB - The aim of this study was to clarify whether common single nucleotide polymorphisms (SNPs) of the Peroxisome Proliferator-Activated Receptor-gamma (PPAR-gamma) gene (rs1801282) and the Peroxisome Proliferator-Activated Receptor gamma Coactivator-1 (PGC-1alpha) gene (rs8192673) are associated with obesity indexes (BMI, waist circumference) in subjects with type 2 diabetes mellitus (T2DM) in Caucasian population. The second aim was to find an association of both polymorphisms with T2DM. METHODS: Two exonic SNPs of both genes rs1801282 of the PPAR-gamma gene and rs8192673 of the PGC-1alpha gene) were genotyped in 881 unrelated Slovene subjects (Caucasians) with T2DM and in 348 subjects without T2DM (control subjects). RESULTS: Female homozygotes with the CC genotype of the rs8192673 had higher waist circumference in comparison with subjects with other genotypes. Homozygotes (females, males) with wild allele (Pro) of the rs1801282 (Pro12Ala polymorphism) had higher waist circumference in comparison with subjects with other genotypes. In the study, there were no differences in the distributions of the rs8192673 and the rs1801282 genotypes between patients with T2DM and controls. Linear regression analyses for both polymorphisms were performed and demonstrated an independent effect of the rs1801282 of the PPAR gamma on waist circumference in subjects with T2DM, whereas an independent effect on waist circumference was not demonstrated for the rs8192673 of the PGC-1alpha gene. CONCLUSIONS: In a large sample of the Caucasians the rs8192673 of the PGC 1alpha gene and the rs1801282 of the PPAR-gamma gene were associated with waist circumference in subjects with T2DM. PMID- 25928420 TI - Transcriptional modulation of intestinal innate defense/inflammation genes by preterm infant microbiota in a humanized gnotobiotic mouse model. AB - BACKGROUND AND AIMS: It is known that postnatal functional maturation of the small intestine is facilitated by microbial colonization of the gut. Preterm infants exhibit defects in gut maturation, weak innate immunity against intestinal infection and increased susceptibility to inflammatory disorders, all of which may be related to the inappropriate microbial colonization of their immature intestines. The earliest microbes to colonize the preterm infant gut encounter a naive, immature intestine. Thus this earliest microbiota potentially has the greatest opportunity to fundamentally influence intestinal development and immune function. The aim of this study was to characterize the effect of early microbial colonization on global gene expression in the distal small intestine during postnatal gut development. METHODS: Gnotobiotic mouse models with experimental colonization by early (prior to two weeks of life) intestinal microbiota from preterm human infants were utilized. Microarray analysis was used to assess global gene expression in the intestinal epithelium. RESULTS AND CONCLUSION: Multiple intestinal genes involved in metabolism, cell cycle regulation, cell-cell or cell-extracellular matrix communication, and immune function are developmental- and intestinal microbiota- regulated. Using a humanized gnotobiotic mouse model, we demonstrate that certain early preterm infant microbiota from prior to 2 weeks of life specifically induce increased NF kappaB activation and a phenotype of increased inflammation whereas other preterm microbiota specifically induce decreased NF-kappaB activation. These fundamental differences correlate with altered clinical outcomes and suggest the existence of optimal early microbial communities to improve health outcomes. PMID- 25928421 TI - Cycling promotion and non-communicable disease prevention: health impact assessment and economic evaluation of cycling to work or school in Florence. AB - OBJECTIVE: To estimate the effects of cycling promotion on major non-communicable diseases (NCDs) and costs from the public healthcare payer's perspective. DESIGN: Health impact assessment and economic evaluation using a dynamic model over a ten year period and according to two cycling promotion scenarios. SETTING: Cycling to work or school in Florence, Italy. POPULATION: All individuals aged 15 and older commuting to work or school in Florence. MAIN OUTCOME MEASURES: The primary outcome measures were changes in NCD incidence and healthcare direct costs for the Tuscany Regional Health Service (SST) due to increased cycling. The secondary outcome was change in road traffic accidents. RESULTS: Increasing cycling modal share in Florence from 7.5% to about 17% (Scenario 1) or 27% (Scenario 2) could decrease the incidence of type 2 diabetes by 1.2% or 2.5%, and the incidence of acute myocardial infarction (AMI) and stroke by 0.6% or 1.2%. Within 10 years, the number of cases that can be prevented is 280 or 549 for type 2 diabetes, 51 or 100 for AMI, and 51 or 99 for stroke in Scenario 1 or Scenario 2, respectively. Average annual discounted savings for the SST are estimated to amount to ?400,804 or ?771,201 in Scenario 1 or Scenario 2, respectively. In Florence, due to the high use of vulnerable motorized vehicles (such as scooters, mopeds, and motorcycles), road traffic accidents are expected to decline in both our scenarios. Sensitivity analyses showed that health benefits and savings for the SST are substantial, the most sensitive parameters being the relative risk estimates of NCDs and active commuting. CONCLUSIONS: Effective policies and programs to promote a modal shift towards cycling among students and workers in Florence will contribute to reducing the NCD burden and helping long-term economic sustainability of the SST. PMID- 25928422 TI - Adipocyte secreted factors enhance aggressiveness of prostate carcinoma cells. AB - Obesity has been associated with increased incidence and risk of mortality of prostate cancer. One of the proposed mechanisms underlying this risk association is the change in adipokines expression that could promote the development and progression of the prostate tumor cells. The main goal of this study was to evaluate the effect of preadipocyte and adipocyte secretome in the proliferation, migration and invasion of androgen independent prostate carcinoma cells (RM1) and to assess cell proliferation in the presence of the adiposity signals leptin and insulin. RM1 cells were co-cultured in with preadipocytes, adipocytes or cultured in their respective conditioned medium. Cell proliferation was assessed by flow cytometry and XTT viability test. Cell migration was evaluated using a wound healing injury assay of RM1 cells cultured with conditioned media. Cellular invasion of RM1 cells co-cultured with adipocytes and preadipocytes was assessed using matrigel membranes. Preadipocyte conditioned medium was associated with a small increase in RM1 proliferation, while adipocytes conditioned media significantly increased RM1 cell proliferation (p<0.01). Adipocytes also significantly increased the RM1 cells proliferation in co-culture (p <0.01). Cell migration was higher in RM1 cells cultured with preadipocyte and adipocyte conditioned medium. RM1 cell invasion was significantly increased after co culture with preadipocytes and adipocytes (p <0.05). Insulin also increased significantly the cell proliferation in contrast to leptin, which showed no effect. In conclusion, prostate carcinoma cells seem to be influenced by factors secreted by adipocytes that are able to increase their ability to proliferate, migrate and invade. PMID- 25928423 TI - Enhancing anti-tumor efficacy of Doxorubicin by non-covalent conjugation to gold nanoparticles - in vitro studies on feline fibrosarcoma cell lines. AB - BACKGROUND: Feline injection-site sarcomas are malignant skin tumors of mesenchymal origin, the treatment of which is a challenge for veterinary practitioners. Methods of treatment include radical surgery, radiotherapy and chemotherapy. The most commonly used cytostatic drugs are cyclophosphamide, doxorubicin and vincristine. However, the use of cytostatics as adjunctive treatment is limited due to their adverse side-effects, low biodistribution after intravenous administration and multidrug resistance. Colloid gold nanoparticles are promising drug delivery systems to overcome multidrug resistance, which is a main cause of ineffective chemotherapy treatment. The use of colloid gold nanoparticles as building blocks for drug delivery systems is preferred due to ease of surface functionalization with various molecules, chemical stability and their low toxicity. METHODS: Stability and structure of the glutathione stabilized gold nanoparticles non-covalently modified with doxorubicin (Au-GSH Dox) was confirmed using XPS, TEM, FT-IR, SAXRD and SAXS analyses. MTT assay, Annexin V and Propidium Iodide Apoptosis assay and Rhodamine 123 and Verapamil assay were performed on 4 feline fibrosarcoma cell lines (FFS1WAW, FFS1, FFS3, FFS5). Statistical analyses were performed using Graph Pad Prism 5.0 (USA). RESULTS: A novel approach, glutathione-stabilized gold nanoparticles (4.3 +/- 1.1 nm in diameter) non-covalently modified with doxorubicin (Au-GSH-Dox) was designed and synthesized. A higher cytotoxic effect (p<0.01) of Au-GSH-Dox than that of free doxorubicin has been observed in 3 (FFS1, FFS3, FFS1WAW) out of 4 feline fibrosarcoma cell lines. The effect has been correlated to the activity of glycoprotein P (main efflux pump responsible for multidrug resistance). CONCLUSIONS: The results indicate that Au-GSH-Dox may be a potent new therapeutic agent to increase the efficacy of the drug by overcoming the resistance to doxorubicin in feline fibrosarcoma cell lines. Moreover, as doxorubicin is non covalently attached to glutathione coated nanoparticles the synthesized system is potentially suitable to a wealth of different drug molecules. PMID- 25928424 TI - Illumina MiSeq Sequencing Reveals Diverse Microbial Communities of Activated Sludge Systems Stimulated by Different Aromatics for Indigo Biosynthesis from Indole. AB - Indole, as a typical N-heteroaromatic compound existed in coking wastewater, can be used for bio-indigo production. The microbial production of indigo from indole has been widely reported during the last decades using culture-dependent methods, but few studies have been carried out by microbial communities. Herein, three activated sludge systems stimulated by different aromatics, i.e. naphthalene plus indole (G1), phenol plus indole (G2) and indole only (G3), were constructed for indigo production from indole. During the operation, G1 produced the highest indigo yield in the early stage, but it switched to G3 in the late stage. Based on LC-MS analysis, indigo was the major product in G1 and G3, while the purple product 2-(7-oxo-1H-indol-6(7H)-ylidene) indolin-3-one was dominant in G2. Illumina MiSeq sequencing of 16S rRNA gene amplicons was applied to analyze the microbial community structure and composition. Detrended correspondence analysis (DCA) and dissimilarity tests showed that the overall community structures of three groups changed significantly during the operation (P<0.05). Nevertheless, the bacteria assigned to phylum Proteobacteria, family Comamonadaceae, and genera Diaphorobacter, Comamonas and Aquamicrobium were commonly shared dominant populations. Pearson correlations were calculated to discern the relationship between microbial communities and indigo yields. The typical indigo-producing populations Comamonas and Pseudomonas showed no positive correlations with indigo yields, while there emerged many other genera that exhibited positive relationships, such as Aquamicrobium, Truepera and Pusillimonas, which had not been reported for indigo production previously. The present study should provide new insights into indigo bio-production by microbial communities from indole. PMID- 25928427 TI - Patient-centered feedback on the results of personality testing increases early engagement in residential substance use disorder treatment: a pilot randomized controlled trial. AB - BACKGROUND: Patient-centered models of assessment have shown considerable promise for increasing patients' readiness for mental health treatment in general, but have not been used to facilitate patients' engagement in substance use disorder (SUD) treatment. We developed a brief patient-centered intervention using assessment and feedback of personality data and examined its acceptability and efficacy to increase early engagement in residential SUD treatment. METHODS: Thirty patients entering a 90-day residential SUD treatment program were randomly assigned to a feedback (n = 17) or control (n = 13; assessment-only) condition. Normal-range personality was assessed with the NEO Personality Inventory-Revised (NEO PI-R). Patients were re-interviewed one month after treatment entry to obtain information on their satisfaction with the intervention, as well as their adjustment to the residential milieu. Electronic medical records were reviewed to obtain information on patients' length of stay in the program and discharge status. Univariate ANOVAs and chi-square tests were conducted to examine group differences on outcomes. RESULTS: Patients' ratings indicated strong satisfaction with the feedback intervention and expectations that it would have a positive impact on their treatment experiences. Among patients who had not previously been treated in the residential program, the feedback intervention was associated with more positive relationships with other residents in treatment and a stronger alliance with the treatment program one month after treatment entry. The feedback intervention was also associated with a longer length of stay in treatment, although this effect did not reach statistical significance. CONCLUSIONS: The findings highlight the clinical utility of providing SUD patients with patient centered feedback based on the results of personality testing, and provide preliminary support for the acceptability and efficacy of this intervention to facilitate early engagement in residential SUD treatment. PMID- 25928428 TI - Oxo Transfer from Nitrogen Dioxide to Nitrito Group in a Copper(II) Complex. AB - Reaction of Cu(II) complex [Cu(II)(LH)(O2CCH3)2] (1) [LH = 4,6-ditert-butyl-2-((2 picolyl(isopropyl)amino)methyl)phenol] with equivalent amount of NO2 leads to the reduction of Cu(II) to Cu(I) with concomitant nitration at the phenol ring of the ligand. This resulted in the in situ formation of intermediate Cu(I) complex of the nitrated ligand (L'H). Additional equivalent of NO2 coordinates to the Cu(I) complex to form corresponding O-nitrito Cu(II) complex [Cu(II)(L'(eta(1)-ONO)] (2). Subsequent addition of NO2 led to the corresponding O-nitrato complex, [Cu(II)(L')(eta(1)-ONO2)] (3) with concomitant formation of NO. Complexes 2 and 3 were isolated and structurally characterized. The formation of NO in the reaction was established by spin-trapping experiment. Isotopic labeling experiment revealed that the oxo transfer takes place from NO2 to the coordinated eta(1)-ONO group. PMID- 25928431 TI - Developing a new generation of breast cancer clinical gene expression tests. AB - When treatment decisions are based purely on clinicopathological factors, many women with estrogen receptor-positive/human epidermal growth factor receptor 2 negative cancers are overtreated. Gene expression profiles are valuable clinical tools that stratify the recurrence risk to identify patients most likely to benefit from adjuvant systemic therapies. Building upon greater understanding of tumor biology and more rigorous approaches to validation (including independent studies with a high level of evidence), several second-generation multigene tests have been developed. In the previous issue, Martin and colleagues report the third clinical validation study for EndoPredict, a distributed assay to assess risk of distant recurrences in estrogen receptor-positive/human epidermal growth factor receptor 2-negative women. The authors confirm the assay's independent prognostic value in premenopausal and postmenopausal, node-positive women treated with contemporary chemotherapy followed by endocrine therapy. EndoPredict did not, however, predict benefit from adding paclitaxel. Predictive signatures for selecting among chemotherapy regimens remain an area needing further development. PMID- 25928432 TI - Spatial-sequential and spatial-simultaneous working memory in individuals with Williams syndrome. AB - The aim of the present study was to compare visuospatial working memory performance in 18 individuals with Williams syndrome (WS) and 18 typically developing (TD) children matched for nonverbal mental age. Two aspects were considered: task presentation format (i.e., spatial-sequential or spatial simultaneous), and level of attentional control (i.e., passive or active tasks). Our results showed that individuals with WS performed less well than TD children in passive spatial-simultaneous tasks, but not in passive spatial-sequential tasks. The former's performance was also worse in both active tasks. These findings suggest an impairment in the spatial-simultaneous working memory of individuals with WS, together with a more generalized difficulty in tasks requiring information storage and concurrent processing, as seen in other etiologies of intellectual disability. PMID- 25928429 TI - TIGAR regulates DNA damage and repair through pentosephosphate pathway and Cdk5 ATM pathway. AB - Previous study revealed that the protective effect of TIGAR in cell survival is mediated through the increase in PPP (pentose phosphate pathway) flux. However, it remains unexplored if TIGAR plays an important role in DNA damage and repair. This study investigated the role of TIGAR in DNA damage response (DDR) induced by genotoxic drugs and hypoxia in tumor cells. Results showed that TIGAR was increased and relocated to the nucleus after epirubicin or hypoxia treatment in cancer cells. Knockdown of TIGAR exacerbated DNA damage and the effects were partly reversed by the supplementation of PPP products NADPH, ribose, or the ROS scavenger NAC. Further studies with pharmacological and genetic approaches revealed that TIGAR regulated the phosphorylation of ATM, a key protein in DDR, through Cdk5. The Cdk5-AMT signal pathway involved in regulation of DDR by TIGAR defines a new role of TIGAR in cancer cell survival and it suggests that TIGAR may be a therapeutic target for cancers. PMID- 25928433 TI - Validity of the social communication questionnaire in adults with intellectual disabilities and suspected autism spectrum disorder. AB - This study examined the validity of the Social Communication Questionnaire (SCQ) to identify autism spectrum disorder (ASD) in 151 adults with intellectual disabilities (ID) in Germany. Sensitivities and specificities for ASD were 98/47% for the SCQ-current version and 92/22% for the SCQ-lifetime version. Sensitivities and specificities were increased to 89/66% and 78/48% by adjusting the recommended cut-points. The SCQ-current score correlated with the Scale for Pervasive Developmental Disorders in Mentally Retarded Persons and the Autism Diagnostic Observation Schedule, whereas the SCQ-lifetime score correlated with the Autism Diagnostic Interview-Revised. Our findings support the use of the SCQ current version for ASD screening in adults with ID, although the SCQ-lifetime version should be used with caution in this population. PMID- 25928434 TI - Executive functions and Prader-Willi syndrome: global deficit linked with intellectual level and syndrome-specific associations. AB - The aim of this study was to support the growing evidence suggesting that Prader Willi Syndrome (PWS) might present with an impairment of executive functions (EFs) and to investigate whether this impairment is specific to patients with PWS or due to their intellectual disability (ID). Six tasks were administered to assess EFs (inhibition, switching, updating, cognitive estimation, and planning) to 17 patients with PWS and 17 age-matched healthy individuals. Performance was significantly impaired in the PWS group on all EFs and after controlling for IQ level, intergroup differences remained only for switching and cognitive estimation. In conclusion, PWS seems to be associated with a global impairment of EFs that appears to be closely linked with intellectual impairment but also with the PWS itself. PMID- 25928435 TI - Emergency department and inpatient hospitalizations for young people with fragile X syndrome. AB - We compared hospital encounters between adolescents and young adults with fragile X syndrome (FXS) to peers with intellectual disability (ID) from other causes, autism spectrum disorder (ASD), and a comparison group without these conditions matched by gender, age, and insurance coverage. Those with FXS, ASD, or ID were more likely to have had hospital encounters. In terms of age groups, we found mental illness hospitalizations decreased during adulthood as compared to adolescence for those with FXS, and we found that for conditions unrelated to FXS (e.g., respiratory, genitourinary, gastroenteritis, and pneumonia) adolescents had higher rates of hospitalization compared to their peers with FXS, ID, or ASD. We analyzed epilepsy, common among people with FXS and designated as an ambulatory care sensitive condition that can be treated outside the hospital, and found that people with FXS, ID, and ASD had higher odds of hospitalization due to epilepsy in both age groups than did the comparison group. PMID- 25928436 TI - Association Between Low IQ Scores and Early Mortality in Men and Women: Evidence From a Population-Based Cohort Study. AB - Lower (versus higher) IQ scores have been shown to increase the risk of early mortality, however, the underlying mechanisms are poorly understood and previous studies underrepresent individuals with intellectual disability (ID) and women. This study followed one third of all senior-year students (approximately aged 17) attending public high school in Wisconsin, U.S. in 1957 (n = 10,317) until 2011. Men and women with the lowest IQ test scores (i.e., IQ scores <= 85) had increased rates of mortality compared to people with the highest IQ test scores, particularly for cardiovascular disease. Importantly, when educational attainment was held constant, people with lower IQ test scores did not have higher mortality by age 70 than people with higher IQ test scores. Individuals with lower IQ test scores likely experience multiple disadvantages throughout life that contribute to increased risk of early mortality. PMID- 25928437 TI - Coping with criticism and praise. AB - Through experiencing stigma and discrimination, people with intellectual disability may become more sensitive to criticism from others and be less likely to believe praise. This study compared how people with and without intellectual disability viewed praise and criticism, using a vignette task developed for the study. Participants were asked to imagine someone saying something praiseworthy or critical and were then asked about their emotions, beliefs, and thoughts. People with intellectual disability were more likely to believe and be distressed by criticism. Contrary to predictions, this group were also more likely to believe praise and experience positive affect. The results suggest that the self perceptions of people with intellectual disabilities is more dynamic and reliant on the views of others. PMID- 25928441 TI - Transmission efficiency of the plague pathogen (Y. pestis) by the flea, Xenopsylla skrjabini, to mice and great gerbils. AB - BACKGROUND: Plague, a zoonotic disease caused by Yersinia pestis, is characterized by its ability to persist in the plague natural foci. Junggar Basin plague focus was recently identified in China, with Rhombomys opimus (great gerbils) and Xenopsylla skrjabini as the main reservoir and vector for plague. No transmission efficiency data of X. skrjabini for Y. pestis is available till now. METHODS: In this study, we estimated the median infectious dose (ID50) and the blockage rates of X. skrjabini with Y. pestis, by using artificial feeders. We then evaluated the flea transmission ability of Y. pestis to the mice and great gerbils via artificial bloodmeal feeding. Finally, we investigated the transmission of Y. pestis to mice with fleas fed by infected great gerbils. RESULTS: ID50 of Y. pestis to X. skrjabini was estimated as 2.04 * 10(5) CFU (95% CI, 1.45 * 10(5) - 3.18 * 10(5) CFU), around 40 times higher than that of X. cheopis. Although fleas fed by higher bacteremia bloodmeal had higher infection rates for Y. pestis, they lived significantly shorter than their counterparts. X. skrjabini could get fully blocked as early as day 3 post of infection (7.1%, 3/42 fleas), and the overall blockage rate of X. cheopis was estimated as 14.9% (82/550 fleas) during the 14 days of investigation. For the fleas infected by artificial feeders, they seemed to transmit plague more efficiently to great gerbils than mice. Our single flea transmission experiments also revealed that, the transmission capacity of naturally infected fleas (fed by infected great gerbils) was significantly higher than that of artificially infected ones (fed by artificial feeders). CONCLUSION: Our results indicated that ID50 of Y. pestis to X. skrjabini was higher than other fleas like X. cheopis, and its transmission efficiency to mice might be lower than other flea vectors in the artificial feeding modes. We also found different transmission potentials in the artificially infected fleas and the naturally infected ones. Further studies are needed to figure out the role of X. skrjabini in the plague epidemiological cycles in Junggar Basin plague focus. PMID- 25928442 TI - Postoperative Visual Acuity Should Be Reported in Studies of Binocular Summation. PMID- 25928443 TI - Individual and school level correlates of moderate to vigorous physical activity among school-children in Germany--a multi-level analysis. AB - BACKGROUND: Young people spend half of their days in school, but evidence concerning the influence of school environment on the physical activity (PA) of pupils is still inconsistent. A better understanding of potential correlates of PA on the school-level and their possible interaction with individual aspects is needed to improve the development of more effective interventions. METHODS: We used data from the 2009/10 German Health Behaviour in School-aged Children study (HBSC)-sample (n=5,005 students aged 11-15 years) including self-reported moderate to vigorous intensity PA as well as a variety of biological, demographic and behavioral correlates and matched them with school-level data from the national school principals' HBSC questionnaire. We analyzed the associations of individual- and school-level correlates with MVPA by gender-specific multi-level regression. RESULTS: Only a small share of the overall variation in student's PA was attributable to the school-level. Consequently, the associations of individual-level correlates with PA were stronger than those of the school-level. Our analysis revealed significant associations of individual-level (i.e. age, consumption of softdrinks, overweight) as well as school-level correlates (i.e. the availability of a football ground and a swimming pool) with MVPA. We also observed some gender-specific findings especially for the school level correlates. Cross-level interactions between individual- and school-level were not apparent. CONCLUSIONS: Our findings indicate the usefulness of applying an ecological framework to understand and explain complex health behaviors like PA. As we found gender-specific association it might be important to acknowledge that boys and girls have specific needs to be more physically active. Further research should also take other features/elements of the school environment and neighborhood as well as socio-cognitive correlates into account to advance the field. PMID- 25928444 TI - Stress Transfer Quantification in Gelatin-Matrix Natural Composites with Tunable Optical Properties. AB - This work reports on the preparation and characterization of natural composite materials prepared from bacterial cellulose (BC) incorporated into a gelatin matrix. Composite morphology was studied using scanning electron microscopy and 2D Raman imaging revealing an inhomogeneous dispersion of BC within the gelatin matrix. The composite materials showed controllable degrees of transparency to visible light and opacity to UV light depending on BC weight fraction. By adding a 10 wt % fraction of BC in gelatin, visible (lambda = 550 nm) and UV (lambda = 350 nm) transmittances were found to decrease by ~35 and 40%, respectively. Additionally, stress transfer occurring between the gelatin and BC fibrils was quantified using Raman spectroscopy. This is the first report for a gelatin matrix composite containing cellulose. As a function of strain, two distinct domains, both showing linear relationships, were observed for which an average initial shift rate with respect to strain of -0.63 +/- 0.2 cm(-1)%(-1) was observed, followed by an average shift rate of -0.25 +/- 0.03 cm(-1)%(-1). The average initial Raman band shift rate value corresponds to an average effective Young's modulus of 39 +/- 13 GPa and 73 +/- 25 GPa, respectively, for either a 2D and 3D network of BC fibrils embedded in the gelatin matrix. As a function of stress, a linear relationship was observed with a Raman band shift rate of -27 +/ 3 cm(-1)GPa(-1). The potential use of these composite materials as a UV blocking food coating is discussed. PMID- 25928445 TI - Correction: Substrate selection for fundamental studies of electrocatalysts and photoelectrodes: inert potential windows in acidic, neutral, and basic electrolyte. PMID- 25928450 TI - Foetal blood flow measured using phase contrast cardiovascular magnetic resonance -preliminary data comparing 1.5 T with 3.0 T. AB - BACKGROUND: Phase contrast cardiovascular magnetic resonance (PC CMR) has emerged as a clinical tool for blood flow quantification but its use in the foetus has been hampered by the need for gating with the foetal heart beat. The previously described metric optimized gating (MOG) technique has been successfully used to measure foetal blood flow in late gestation foetuses on a 1.5 T CMR magnet. However, there is increasing interest in performing foetal cardiac imaging using 3.0 T CMR. We describe our pilot investigation of foetal blood flow measured using 3.0 T CMR. METHODS: Foetal blood flows were quantified in 5 subjects at late gestational age (35-38 weeks). Three were normal pregnancies and two were pregnancies with ventricular size discrepancy. Data were obtained at 1.5 T and 3.0 T using a previously described PC CMR protocol. After reconstruction using MOG, blood flow was quantified independently by two observers. Intra- and inter observer reproducibility of flow measurements at the two field strengths was assessed by Pearson correlation coefficient (R(2)), linear regression and Bland Altman analysis. RESULTS: PC CMR flow measurements were obtained in 36 of 40 target vessels. Strong intra-observer agreement was obtained between measurements at each field strength (R(2) = 0.78, slope = 0.83 +/- 0.11), with a mean bias of 1 ml/min/kg and 95% confidence limits of +/-71 ml/min/kg. Inter-observer agreement was similarly high for measurements at both 1.5 T (R(2) = 0.86, slope = 0.95 +/- 0.13, bias = 6 +/- 52 ml/min/kg) and 3.0 T (R(2) = 0.88, slope = 0.94 +/ 0.13, bias = 4 +/- 47 ml/min/kg). Across all PC CMR measurements, SNR per pixel was expectedly higher at 3.0 T relative to 1.5 T (165 +/- 50%). The relative differences in flow measurements between observers were low (range: 4-16%) except for pulmonary blood flow which showed much higher variability at 1.5 T (34%) versus that at 3.0 T (11%). This was attributed to the poorly visualized, small pulmonary vessels at 1.5 T, which made delineation inconsistent between observers. CONCLUSIONS: This is the first pilot study to measure foetal blood flow using PC CMR at 3.0 T. The flow data obtained were in good correlation with those measured at 1.5 T, both within and between observers. With increased SNR at 3.0 T, smaller pulmonary vessels were better visualized which improved inter observer agreement of associated flows. PMID- 25928451 TI - The feasibility of community mobilisation for child injury prevention in rural Nepal: a programme for female community health volunteers. AB - BACKGROUND: Injuries accounted for 23% of all deaths in children and adolescents in Nepal during 2010 (n = 3,700). Despite this, there is no national death registration or injury surveillance system. Non-fatal injuries are many times more common than fatal injuries and may leave the injured person with lifelong consequences. Children in low-income settings are exposed to widespread risks of injuries but there is little awareness of how they can be prevented. Community mobilisation has been shown to be effective to reduce maternal and neonatal morbidity. This study aimed to develop a child safety programme and assess the feasibility of delivering the programme through a community mobilisation approach. METHODS: We developed a culturally appropriate, educational programme for Female Community Health Volunteers that included both primary and secondary prevention materials for unintentional child injuries. We determined the feasibility of evaluating its effectiveness through the mobilisation of women's groups in rural Nepal. Ten women's groups across 9 wards in one village development committee area completed the programme during 6 monthly meetings. Parent-reported injuries were collected through a notification system established for this study. Experience of the programme by women's group participants and leaders was assessed through a structured questionnaire and process measures assessed the delivery and reach of the programme. RESULTS: Programme resources were developed for this setting and adapted following feedback from users. Nine FCHVs received first-aid training and shown how to use the facilitation manual and injury prevention resources. The FCHVs convened 10 women's groups to run over 6 months with 24-29 mothers attending each meeting (290 mothers participated in total). Each group presented their views on child injury risks and proposed prevention activities at local public meetings. Women reported 155 injuries to children under 18 years during 7 months of follow up using the notification system. CONCLUSIONS: It is feasible to develop and implement a community mobilisation intervention where women's groups work together with local FCHVs to prevent injuries in children. The intervention was well received by the women's groups and by community members. The effectiveness and cost effectiveness of the intervention should now be evaluated through an experimental study. PMID- 25928452 TI - Roles of climate, vegetation and soil in regulating the spatial variations in ecosystem carbon dioxide fluxes in the Northern Hemisphere. AB - Climate, vegetation, and soil characteristics play important roles in regulating the spatial variation in carbon dioxide fluxes, but their relative influence is still uncertain. In this study, we compiled data from 241 eddy covariance flux sites in the Northern Hemisphere and used Classification and Regression Trees and Redundancy Analysis to assess how climate, vegetation, and soil affect the spatial variations in three carbon dioxide fluxes (annual gross primary production (AGPP), annual ecosystem respiration (ARE), and annual net ecosystem production (ANEP)). Our results showed that the spatial variations in AGPP, ARE, and ANEP were significantly related to the climate and vegetation factors (correlation coefficients, R = 0.22 to 0.69, P < 0.01) while they were not related to the soil factors (R = -0.11 to 0.14, P > 0.05) in the Northern Hemisphere. The climate and vegetation together explained 60% and 58% of the spatial variations in AGPP and ARE, respectively. Climate factors (mean annual temperature and precipitation) could account for 45-47% of the spatial variations in AGPP and ARE, but the climate constraint on the vegetation index explained approximately 75%. Our findings suggest that climate factors affect the spatial variations in AGPP and ARE mainly by regulating vegetation properties, while soil factors exert a minor effect. To more accurately assess global carbon balance and predict ecosystem responses to climate change, these discrepant roles of climate, vegetation, and soil are required to be fully considered in the future land surface models. Moreover, our results showed that climate and vegetation factors failed to capture the spatial variation in ANEP and suggest that to reveal the underlying mechanism for variation in ANEP, taking into account the effects of other factors (such as climate change and disturbances) is necessary. PMID- 25928457 TI - A pilot study of bevacizumab combined with etoposide and cisplatin in breast cancer patients with leptomeningeal carcinomatosis. AB - BACKGROUND: Elevated vascular endothelial growth factor (VEGF) was associated with poor prognosis in leptomeningeal carcinomatosis and anti-angiogenic therapy was found to prolong the survival of mice in preclinical studies. This prospective pilot study investigated the efficacy of anti-VEGF therapy plus chemotherapy in patients with leptomeningeal carcinomatosis originating from breast cancer. METHODS: Eligible patients were scheduled to receive bevacizumab combined with etoposide and cisplatin (BEEP) every 3 weeks for a maximum of 6 cycles or until unacceptable toxicity. The primary objective was the central nervous system (CNS)-specific response rate, which was defined as disappearance of cancer cells in the cerebrospinal fluid (CSF) and an improved or stabilized neurologic status. The impact of VEGF inhibition on etoposide penetration into the CSF was analyzed. RESULTS: Eight patients were enrolled. The CNS-specific response rate was 60% in 5 evaluable patients. According to intent-to-treat analysis, the median overall survival of the eight patients was 4.7 months (95% confidence interval, CI, 0.3-9.0) and the neurologic progression-free survival was 4.7 months (95% CI 0-10.5). The most common grade 3/4 adverse events were neutropenia (23.1%), leukopenia (23.1%), and hyponatremia (23.1%). The etoposide concentrations in the CSF were much lower than those in plasma, and bevacizumab did not increase etoposide delivery to the CSF. CONCLUSIONS: BEEP exhibited promising efficacy in breast cancer patients with leptomeningeal carcinomatosis. Additional studies are warranted to verify its efficacy and clarify the role of anti-angiogenic therapy in this disease. TRIAL REGISTRATION: ClinicalTrials.gov identifying number NCT01281696 . PMID- 25928459 TI - The plasticity of NBS resistance genes in sorghum is driven by multiple evolutionary processes. AB - BACKGROUND: Increased disease resistance is a key target of cereal breeding programs, with disease outbreaks continuing to threaten global food production, particularly in Africa. Of the disease resistance gene families, the nucleotide binding site plus leucine-rich repeat (NBS-LRR) family is the most prevalent and ancient and is also one of the largest gene families known in plants. The sequence diversity in NBS-encoding genes was explored in sorghum, a critical food staple in Africa, with comparisons to rice and maize and with comparisons to fungal pathogen resistance QTL. RESULTS: In sorghum, NBS-encoding genes had significantly higher diversity in comparison to non NBS-encoding genes and were significantly enriched in regions of the genome under purifying and balancing selection, both through domestication and improvement. Ancestral genes, pre dating species divergence, were more abundant in regions with signatures of selection than in regions not under selection. Sorghum NBS-encoding genes were also significantly enriched in the regions of the genome containing fungal pathogen disease resistance QTL; with the diversity of the NBS-encoding genes influenced by the type of co-locating biotic stress resistance QTL. CONCLUSIONS: NBS-encoding genes are under strong selection pressure in sorghum, through the contrasting evolutionary processes of purifying and balancing selection. Such contrasting evolutionary processes have impacted ancestral genes more than species-specific genes. Fungal disease resistance hot-spots in the genome, with resistance against multiple pathogens, provides further insight into the mechanisms that cereals use in the "arms race" with rapidly evolving pathogens in addition to providing plant breeders with selection targets for fast-tracking the development of high performing varieties with more durable pathogen resistance. PMID- 25928462 TI - Diabetes, patient-centered medical homes, and accountable care organizations, oh my! PMID- 25928461 TI - Associations of the APOC3 rs5128 polymorphism with plasma APOC3 and lipid levels: a meta-analysis. AB - BACKGROUND: Studies of the association between the apolipoprotein C3 gene (APOC3) rs5128 polymorphism and plasma levels of apolipoprotein C3 (APOC3) and lipids have reported apparently conflicting findings. This meta-analysis aimed to investigate the associations of the rs5128 polymorphism with fasting APOC3 and lipid levels. METHODS: The following information was abstracted for each study: ethnicity, age, sex, health condition, sample size, genotyping and lipid assay methods, mean and standard deviation or standard error by genotypes for APOC3 and lipid variables. There were 42 eligible studies with 23846 subjects included in this meta-analysis. A dominant model was used for this meta-analysis. RESULTS: The results showed that the carriers of the variant allele G had higher levels of APOC3 [standardized mean difference (SMD): 0.22, 95% confidence interval (CI): 0.12-0.31, P<0.00001], triglycerides (TG) (SMD: 0.33, 95% CI: 0.23-0.44, P<0.00001), total cholesterol (TC) (SMD: 0.15, 95% CI: 0.09-0.22, P<0.00001), and low-density lipoprotein cholesterol (LDL-C) (SMD: 0.11, 95% CI: 0.04-0.17, P=0.001) than the non-carriers. No significant association between the APOC3 rs5128 polymorphism and lower levels of high-density lipoprotein cholesterol (HDL C) was detected under the dominant model (SMD: -0.03, 95% CI: -0.06-0.01, P=0.156). CONCLUSIONS: The results from the present meta-analysis demonstrate a significant association between the APOC3 rs5128 polymorphism and higher levels of APOC3, TG, TC and LDL-C, but further studies are needed to elucidate the underlying mechanisms. PMID- 25928463 TI - Diabetes management within evolving health care delivery models: the osteopathic perspective. PMID- 25928464 TI - Leveraging the principles of osteopathic medicine to improve diabetes outcomes within a new era of health care reform. AB - First introduced conceptually decades before the passage of the Patient Protection and Affordable Care Act, the patient-centered medical home (PCMH) has evolved as a foundational element within the larger health care system or medical neighborhood, highlighting a coordinated and comprehensive disease management approach centered on intensive primary care interventions. More recently, in the wake of health care reform, accountable care organizations (ACOs) have been established to help health plans, physicians, hospitals, home health care practitioners, and other health care providers better coordinate care through an incentive-based payment arrangement. Osteopathic medicine is poised to proactively capitalize on these emerging health care models, with the anticipated end result of improved quality of care and reduced health care costs. As such, osteopathic physicians involved in the prevention and care of patients with type 2 diabetes mellitus need to identify models, best practices, and solutions to advance the medical neighborhood. PMID- 25928466 TI - Gene-specific selective sweeps in bacteria and archaea caused by negative frequency-dependent selection. AB - BACKGROUND: Fixation of beneficial genes in bacteria and archaea (collectively, prokaryotes) is often believed to erase pre-existing genomic diversity through the hitchhiking effect, a phenomenon known as genome-wide selective sweep. Recent studies, however, indicate that beneficial genes spread through a prokaryotic population via recombination without causing genome-wide selective sweeps. These gene-specific selective sweeps seem to be at odds with the existing estimates of recombination rates in prokaryotes, which appear far too low to explain such phenomena. RESULTS: We use mathematical modeling to investigate potential solutions to this apparent paradox. Most microbes in nature evolve in heterogeneous, dynamic communities, in which ecological interactions can substantially impact evolution. Here, we focus on the effect of negative frequency-dependent selection (NFDS) such as caused by viral predation (kill-the winner dynamics). The NFDS maintains multiple genotypes within a population, so that a gene beneficial to every individual would have to spread via recombination, hence a gene-specific selective sweep. However, gene loci affected by NFDS often are located in variable regions of microbial genomes that contain genes involved in the mobility of selfish genetic elements, such as integrases or transposases. Thus, the NFDS-affected loci are likely to experience elevated rates of recombination compared with the other loci. Consequently, these loci might be effectively unlinked from the rest of the genome, so that NFDS would be unable to prevent genome-wide selective sweeps. To address this problem, we analyzed population genetic models of selective sweeps in prokaryotes under NFDS. The results indicate that NFDS can cause gene-specific selective sweeps despite the effect of locally elevated recombination rates, provided NFDS affects more than one locus and the basal rate of recombination is sufficiently low. Although these conditions might seem to contradict the intuition that gene-specific selective sweeps require high recombination rates, they actually decrease the effective rate of recombination at loci affected by NFDS relative to the per locus basal level, so that NFDS can cause gene-specific selective sweeps. CONCLUSION: Because many free-living prokaryotes are likely to evolve under NFDS caused by ubiquitous viruses, gene-specific selective sweeps driven by NFDS are expected to be a major, general phenomenon in prokaryotic populations. PMID- 25928467 TI - Outbreak of Human Pneumonic Plague with Dog-to-Human and Possible Human-to-Human Transmission--Colorado, June-July 2014. AB - On July 8, 2014, the Colorado Department of Public Health and Environment (CDPHE) laboratory identified Yersinia pestis, the bacterium that causes plague, in a blood specimen collected from a man (patient A) hospitalized with pneumonia. The organism had been previously misidentified as Pseudomonas luteola by an automated system in the hospital laboratory. An investigation led by Tri-County Health Department (TCHD) revealed that patient A's dog had died recently with hemoptysis. Three other persons who had contact with the dog, one of whom also had contact with patient A, were ill with fever and respiratory symptoms, including two with radiographic evidence of pneumonia. Specimens from the dog and all three human contacts yielded evidence of acute Y. pestis infection. One of the pneumonia cases might have resulted through human-to-human transmission from patient A, which would be the first such event reported in the United States since 1924. This outbreak highlights 1) the need to consider plague in the differential diagnosis of ill domestic animals, including dogs, in areas where plague is endemic; 2) the limitations of automated diagnostic systems for identifying rare bacteria such as Y. pestis; and 3) the potential for milder plague illness in patients taking antimicrobial agents. Hospital laboratorians should be aware of the limitations of automated identification systems, and clinicians should suspect plague in patients with clinically compatible symptoms from whom P. luteola is isolated. PMID- 25928468 TI - Laboratory-acquired vaccinia virus infection in a recently immunized person- Massachusetts, 2013. AB - On November 26, 2013, the CDC poxvirus laboratory was notified by the Boston Public Health Commission (BPHC) of an inadvertent inoculation of a recently vaccinated (ACAM2000 smallpox vaccine) laboratory worker with wild type vaccinia virus (VACV) Western Reserve. A joint investigation by CDC and BPHC confirmed orthopoxvirus infection in the worker, who had reported a needle stick in his thumb while inoculating a mouse with VACV. He experienced a non-tender, red rash on his arm, diagnosed at a local emergency department as cellulitis. He subsequently developed a necrotic lesion on his thumb, diagnosed as VACV infection. Three weeks after the injury, the thumb lesion was surgically debrided and at 2 months post-injury, the skin lesion had resolved. The investigation confirmed that the infection was the first reported VACV infection in the United States in a laboratory worker vaccinated according to the Advisory Committee on Immunization Practices (ACIP) recommendations. The incident prompted the academic institution to outline biosafety measures for working with biologic agents, such as biosafety training of laboratory personnel, vaccination (if appropriate), and steps in incident reporting. Though vaccination has been shown to be an effective measure in protecting personnel in the laboratory setting, this case report underscores the importance of proper safety measures and incident reporting. PMID- 25928469 TI - Using electronic clinical quality measure reporting for public health surveillance. AB - By June 2013, three fourths of office-based practicing physicians in the United States had adopted some form of electronic health record (EHR) system. With greater EHR use, more health data are linked with available patient demographic information in a format that is easily retrievable and collected at the point of care. This highlights the potential of electronic clinical quality measure (CQM) reporting data for use in monitoring population health for those receiving health care services. To assess this possibility, electronic CQM data that were submitted to the Medicare EHR Incentive Program were analyzed to assess provider progress toward achieving blood pressure control among their patients with hypertension. Approximately 63,000 health care providers reported at least 1 time over 3 years, representing approximately 17 million patients with hypertension. On average, 62% of patients with hypertension had controlled blood pressure. Use of EHR data for public health surveillance could streamline reporting, facilitating more timely and possibly more complete data collection in key areas of public health concern. PMID- 25928470 TI - Community Outbreak of HIV Infection Linked to Injection Drug Use of Oxymorphone- Indiana, 2015. AB - On January 23, 2015, the Indiana State Department of Health (ISDH) began an ongoing investigation of an outbreak of human immunodeficiency virus (HIV) infection, after Indiana disease intervention specialists reported 11 confirmed HIV cases traced to a rural county in southeastern Indiana. Historically, fewer than five cases of HIV infection have been reported annually in this county. The majority of cases were in residents of the same community and were linked to syringe-sharing partners injecting the prescription opioid oxymorphone (a powerful oral semi-synthetic opioid analgesic). As of April 21, ISDH had diagnosed HIV infection in 135 persons (129 with confirmed HIV infection and six with preliminarily positive results from rapid HIV testing that were pending confirmatory testing) in a community of 4,200 persons. PMID- 25928471 TI - Carbon-Coated Mesoporous TiO2 Nanocrystals Grown on Graphene for Lithium-Ion Batteries. AB - Graphene-based hybrids have been well studied as advanced catalysts and high performance electrode materials. In this Article, we have fabricated a novel graphene@mesoporous TiO2 nanocrystals@carbon nanosheet by a simple one-step solvothermal method. We have found that titanocene dichloride can act as an extraordinary source with multiple roles for forming TiO2 nanocrystals, ultrathin carbon outer shells, and cross-linkers to binding TiO2 nanocrystals on graphene surface. Moreover, it also serves as a controlling agent to produce mesoporous structure on TiO2 nanocrystals. The loading-concentration of mesoporous TiO2 nanocrystals on graphene sheets can be well controlled by adjusting the initial content of titanocene dichloride. The as-obtained graphene@mTiO2@carbon nanosheets possess a uniform sandwich-like structure, highly crystalline mesoporous TiO2 nanocrystals, a high surface area of ~209 m(2)/g, and a large pore volume of ~0.68 cm(3) g(-1). When used as anodes for LIBs, the resultant nanosheets show a high reversible capacity (~145 mAh/g), good rate capability, and long cycling life (capacity remains 110 mAh/g after 100 cycles at a current density of 0.2 A/g). We believe that our method represents a new path way to synthesize novel nanostructured graphene-based hybrids for future applications. PMID- 25928472 TI - Combined inhibition of key potassium currents has different effects on cardiac repolarization reserve and arrhythmia susceptibility in dogs and rabbits. AB - A reliable assessment of the pro-arrhythmic potential for drugs in the development phase remains elusive. Rabbits and dogs are commonly used to create models of pro-arrhythmia, but the differences between them with respect to repolarizing potassium currents are poorly understood. We investigated the incidence of drug-induced torsades de pointes (TdP) and measured conventional ECG parameters and the short-term variability of the QT interval (STVQT) following combined pharmacological inhibition of IK1+IKs and IK1+IKr in conscious dogs and anesthetized rabbits. A high incidence of TdP was observed following the combined inhibition of IK1+IKs in dogs (67% vs. 14% in rabbits). Rabbits exhibited higher TdP incidence after inhibition of IK1+IKr (72% vs. 14% in dogs). Increased TdP incidence was associated with significantly larger STVQT in both models. The relatively different roles of IK1 and IKs in dog and rabbit repolarization reserve should be taken into account when extrapolating the results from animal models of pro-arrhythmia to humans. A stronger repolarization reserve in dogs (likely due to stronger IK1 and IKs), and the more human-like susceptibility to arrhythmia of rabbits argues for the preferred use of rabbits in the evaluation of adverse pro-arrhythmic effects. PMID- 25928475 TI - Destabilization of pluripotency in the absence of Mad2l2. AB - The induction and maintenance of pluripotency requires the expression of several core factors at appropriate levels (Oct4, Sox2, Klf4, Prdm14). A subset of these proteins (Oct4, Sox2, Prdm14) also plays crucial roles for the establishment of primordial germ cells (PGCs). Here we demonstrate that the Mad2l2 (MAD2B, Rev7) gene product is not only required by PGCs, but also by pluripotent embryonic stem cells (ESCs), depending on the growth conditions. Mad2l2(-/-) ESCs were unstable in LIF/serum medium, and differentiated into primitive endoderm. However, they could be stably propagated using small molecule inhibitors of MAPK signaling. Several components of the MAPK cascade were up- or downregulated even in undifferentiated Mad2l2(-/-) ESCs. Global levels of repressive histone H3 variants were increased in mutant ESCs, and the epigenetic signatures on pluripotency-, primitive endoderm-, and MAPK-related loci differed. Thus, H3K9me2 repressed the Nanog promoter, while the promoter of Gata4 lost H3K27me3 and became de-repressed in LIF/serum condition. Promoters associated with genes involved in MAPK signaling also showed misregulation of these histone marks. Such epigenetic modifications could be indirect consequences of mutating Mad2l2. However, our previous observations suggested the histone methyltransferases as direct (G9a) or indirect (Ezh2) targets of Mad2l2. In effect, the intricate balance necessary for pluripotency becomes perturbed in the absence of Mad2l2. PMID- 25928476 TI - Next generation sequencing demonstrates association between tumor suppressor gene aberrations and poor outcome in patients with cancer. AB - Next generation sequencing is transforming patient care by allowing physicians to customize and match treatment to their patients' tumor alterations. Our goal was to study the association between key molecular alterations and outcome parameters. We evaluated the characteristics and outcomes (overall survival (OS), time to metastasis/recurrence, and best progression-free survival (PFS)) of 392 patients for whom next generation sequencing (182 or 236 genes) had been performed. The Kaplan-Meier method and Cox regression models were used for our analysis, and results were subjected to internal validation using a resampling method (bootstrap analysis). In a multivariable analysis (Cox regression model), the parameters that were statistically associated with a poorer overall survival were the presence of metastases at diagnosis (P = 0.014), gastrointestinal histology (P < 0.0001), PTEN (P < 0.0001), and CDKN2A alterations (P = 0.0001). The variables associated with a shorter time to metastases/recurrence were gastrointestinal histology (P = 0.004), APC (P = 0.008), PTEN (P = 0.026) and TP53 (P = 0.044) alterations. TP53 (P = 0.003) and PTEN (P = 0.034) alterations were independent predictors of a shorter best PFS. A personalized treatment approach (matching the molecular aberration with a cognate targeted drug) also correlated with a longer best PFS (P = 0.046). Our study demonstrated that, across diverse cancers, anomalies in specific tumor suppressor genes (PTEN, CDKN2A, APC, and/or TP53) were independently associated with a worse outcome, as reflected by time to metastases/recurrence, best PFS on treatment, and/or overall survival. These observations suggest that molecular diagnostic tests may provide important prognostic information in patients with cancer. PMID- 25928477 TI - PaPI: pseudo amino acid composition to score human protein-coding variants. AB - BACKGROUND: High throughput sequencing technologies are able to identify the whole genomic variation of an individual. Gene-targeted and whole-exome experiments are mainly focused on coding sequence variants related to a single or multiple nucleotides. The analysis of the biological significance of this multitude of genomic variant is challenging and computational demanding. RESULTS: We present PaPI, a new machine-learning approach to classify and score human coding variants by estimating the probability to damage their protein-related function. The novelty of this approach consists in using pseudo amino acid composition through which wild and mutated protein sequences are represented in a discrete model. A machine learning classifier has been trained on a set of known deleterious and benign coding variants with the aim to score unobserved variants by taking into account hidden sequence patterns in human genome potentially leading to diseases. We show how the combination of amphiphilic pseudo amino acid composition, evolutionary conservation and homologous proteins based methods outperforms several prediction algorithms and it is also able to score complex variants such as deletions, insertions and indels. CONCLUSIONS: This paper describes a machine-learning approach to predict the deleteriousness of human coding variants. A freely available web application (http://papi.unipv.it) has been developed with the presented method, able to score up to thousands variants in a single run. PMID- 25928479 TI - Pristine Graphene-Based Catalysis: Significant Reduction of the Inversion Barriers of Adsorbed and Confined Corannulene, Sumanene, and Dibenzo[a,g]corannulene. AB - Herein, we investigated the inversion of corannulene, sumanene, and dibenzo[a,g]corannulene when they are adsorbed onto graphene or intercalated in bilayer graphene. The results obtained with the M06-L, M06-2X, TPPS-D3, TPSS D3BJ, B3LYP-D3, and B3LYP-D3BJ methods supported a significant reduction of the inversion barriers. In the case of corannulene adsorbed onto graphene, nonbonded interactions reduce the inversion barrier by at least a 50% with respect to the gas phase, whereas for adsorbed sumanene and dibenzo[a,g]corannulene the reductions are at least 39 and 67%, respectively. When the molecules are intercalated in bilayer graphene the lowering of the activation energy is more significant. In the particular case of dibenzo[a,g]corannulene the molecule is expected to display an almost planar structure, with its 0.83 A bowl depth almost completely quenched. For intercalated corannulene and sumanene, the inversion barriers are at least 66 and 60% lower, respectively. It is our hope that these results can help to improve the design of receptors that can catalyze the inversion of buckybowls. PMID- 25928480 TI - Human coronavirus OC43 3CL protease and the potential of ML188 as a broad spectrum lead compound: homology modelling and molecular dynamic studies. AB - BACKGROUND: The coronavirus 3 chymotrypsin-like protease (3CL(pro)) is a validated target in the design of potential anticoronavirus inhibitors. The high degree of homology within the protease's active site and substrate conservation supports the identification of broad spectrum lead compounds. A previous study identified the compound ML188, also termed 16R, as an inhibitor of the Severe Acute Respiratory Syndrome coronavirus (SARS-CoV) 3CL(pro). This study will detail the generation of a homology model of the 3CL(pro) of the human coronavirus OC43 and determine the potential of 16R to form a broad-spectrum lead compound. MODELLER was used to generate a suitable three-dimensional model of the OC43 3CL(pro) and the Prime module of Schrodinger predicted the binding conformation and free energy of binding of 16R within the 3CL(pro) active site. Molecular dynamics further confirmed ligand stability and hydrogen bonding networks. RESULTS: A high quality homology model of the OC43 3CL(pro) was successfully generated in an active conformation. Further studies reproduced the binding pose of 16R within the active site of the generated model, where its free energy of binding was shown to equal that of the 3CL(pro) of SARS-CoV, a receptor it is experimentally proven to inhibit. The stability of the ligand was subsequently confirmed by molecular dynamics. CONCLUSION: The lead compound 16R may represent a broad-spectrum inhibitor of the 3CL(pro) of OC43 and potentially other coronaviruses. This study provides an atomistic structure of the 3CL(pro) of OC43 and supports further experimental validation of the inhibitory effects of 16R. These findings further confirm that the 3CL(pro) of coronaviruses can be inhibited by broad spectrum lead compounds. PMID- 25928481 TI - Bicycle rider control skills: expertise and assessment. AB - Research on how human balance and control bicycles are inconclusive, largely due to the small number of participants in the previous studies. Therefore, the aim of this study was to test the hypotheses that 1) cycling lateral deviation amplitude will reliably show differences between more and less experienced cyclists and 2) more experienced will exhibit slower and smaller steering motions compared to the less experienced cyclists. Twenty-eight experienced and inexperienced cyclists rode a bicycle in a straight line. Lateral deviation, steering and roll were measured. Intersession reliability of the deviation was high with Cronbach's alpha values higher than 0.75. The amplitude, variability and rate of steering and roll parameters showed statistically significant differences between the groups. The test used in this study is sensitive to detect differences between more and less experienced cyclists and can be used for further research that aims to test the effect of a specific intervention addressing rider control. We also showed that steering and roll angle, which were described before as two of the main motor control actions in bicycle control, differ in the variability, amplitude and rate between more and less experienced cyclists. The results of the present study have practical implications for improving bicycle rider control and increasing the safety of cyclists. PMID- 25928482 TI - Editorial. PMID- 25928483 TI - Tossing the baby with the (magnetized) bathwater: commentary on jacobson and colleagues. AB - This article critiques two studies conducted by Jacobson and colleagues whose findings indicated that hypnosis hinders encoding and might not be useful in education. While their findings provide important information about hypnosis and its possible uses in teaching and learning, there are several important methodological and interpretive shortcomings that limit the applicability of the study. It is argued that the authors conflated some components of hypnotic phenomenology, as measured by the Phenomenology of Consciousness Inventory, and consequently failed to assess the hypnotic experience properly. This article argues that the encoding deficits produced by hypnosis may have resulted from the way hypnosis was used and other contextual factors, and highlights some additional concerns with the statistical analyses. This article suggests some more effective uses of hypnosis and suggestion in improving the learning process in light of prior research, and offers some ideas for future research. PMID- 25928484 TI - Hypnotizability, personality style, and attachment: an exploratory study, part 1 general results. AB - This article is an exploratory study investigating the relationship between hypnotizability, personality style, and attachment. Data were collected from 99 students by means of the Harvard Group Scale of Hypnotic Susceptibility, Form A; Personality Styles and Disorders Inventory; and Relationship Scale Questionnaire. Results suggest that individual personality styles accounted for a significant amount of variance in hypnotizability in: (a) the whole sample, (b) the securely attached, and (c) the insecurely attached. High hypnotizables among both the whole sample and securely attached individuals shared the unselfish/self sacrificing personality style as a main predictor of hypnotizability and displayed elevated scores for the charming/histrionic and the optimistic/rhapsodic personality style. Furthermore, two groups were identified among the high hypnotizables that differed mainly according to attachment style: one consists of securely attached, charming/histrionic, and optimistic/rhapsodic people, who are best described by socio-cognitive theories. The other is composed of insecurely attached intuitive/schizotypal people, who are better depicted by dissociation theories. PMID- 25928485 TI - Hypnotizability, personality style, and attachment: an exploratory study, part 2 results with particular focus on sex. AB - The relationship between hypnotizability, personality style, and attachment was examined according to sex in 99 student participants. No specific differences for personality and hypnotizability were found in the highly hypnotizable participants according to sex. Similarly, no differences were found between high, medium, and low hypnotizable females, though differences were found among males. For males, the best predictor of hypnotizability was the unselfish/self sacrificing personality style, which explained 40% of variance. This was in contrast to low hypnotizable males, who were less spontaneous/borderline, self critical/avoidant, unselfish/self-sacrificing, but more assertive/antisocial. In comparison with females, low hypnotizable males were less intuitive/schizotypal and less loyal/dependent. Within the whole sample and among securely attached high hypnotizables, two peaks were observed for charming/histrionic and optimistic/rhapsodic styles, which suggests a "prone to hypnosis" personality style. Such people are optimistic and charming, and tend to be securely attached. This may suggest a high self-selection bias in hypnosis experiments and potentially creates confounds for the majority of such studies. PMID- 25928486 TI - Automatic word processing hypnosis and cognitive therapy for psychosis: a case report. AB - Hallucinations are often perceived as auditory and visual experiences emanating from outside the mind and it is this belief by patients that is a powerfully convincing factor in maintaining psychotic symptoms and accompanying distress. One of the main tasks of cognitive therapy for psychosis is to help the person recognize that the hallucinations emerge from within their own mind for some meaningful reason. A change in meaning can change a person's affective and behavioral responses to hallucinatory phenomena. Automatic Word Processing (AWP) hypnosis is a novel way to help a person realize that the hallucinations they perceive as external and distressful are really internally generated phenomena often based upon his or her life experiences. The case presented here illustrates how AWP hypnosis helped a 13-year-old girl access the internal material that shaped the form and content of visual and auditory hallucinations and interfered with her social and academic functioning. PMID- 25928487 TI - The illness/non-illness model: hypnotherapy for physically ill patients. AB - This article proposes a focused, novel sub-set of the cognitive behavioral therapy approach to hypnotherapy for physically ill patients, based upon the illness/non-illness psychotherapeutic model for physically ill patients. The model is based on three logical rules used in differentiating illness from non illness: duality, contradiction, and complementarity. The article discusses the use of hypnotic interventions to help physically ill and/or disabled patients distinguish between illness and non-illness in their psychotherapeutic themes and attitudes. Two case studies illustrate that patients in this special population group can be taught to learn the language of change and to use this language to overcome difficult situations. The model suggests a new clinical mode of treatment in which individuals who are physically ill and/or disabled are helped in coping with actual motifs and thoughts related to non-illness or non disability. PMID- 25928488 TI - Hypnotic relaxation therapy: principles and applications by gary elkins. PMID- 25928489 TI - Creative therapeutic technique: skills for the art of bringing forth change by hillary keeney and bradford keeney. PMID- 25928490 TI - Neuroscience for clinicians: evidence, models, and practice by C. Alexander simpkins and m. Annellen simpkins. PMID- 25928492 TI - Review of the international literature. PMID- 25928491 TI - Therapeutic Hypnosis with Children and Adolescents by Laurence I. Sugarman and William C. Wester II (Eds.). PMID- 25928495 TI - Nano-sized Mn oxides as true catalysts for alcohol oxidation by a mononuclear manganese(II) complex. AB - Herein new findings on the alcohol-oxidizing activity of a mononuclear manganese(II) complex are reported. We propose that nano-sized Mn oxides are true catalysts for the oxidation of some alcohols to aldehydes in the presence of Oxone (2KHSO5.KHSO4.K2SO4) as an oxidant. PMID- 25928499 TI - Imputation-based population genetics analysis of Plasmodium falciparum malaria parasites. AB - Whole-genome sequencing technologies are being increasingly applied to Plasmodium falciparum clinical isolates to identify genetic determinants of malaria pathogenesis. However, genome-wide discovery methods, such as haplotype scans for signatures of natural selection, are hindered by missing genotypes in sequence data. Poor correlation between single nucleotide polymorphisms (SNPs) in the P. falciparum genome complicates efforts to apply established missing-genotype imputation methods that leverage off patterns of linkage disequilibrium (LD). The accuracy of state-of-the-art, LD-based imputation methods (IMPUTE, Beagle) was assessed by measuring allelic r2 for 459 P. falciparum samples from malaria patients in 4 countries: Thailand, Cambodia, Gambia, and Malawi. In restricting our analysis to 86 k high-quality SNPs across the populations, we found that the complete-case analysis was restricted to 21k SNPs (24.5%), despite no single SNP having more than 10% missing genotypes. The accuracy of Beagle in filling in missing genotypes was consistently high across all populations (allelic r2, 0.87 0.96), but the performance of IMPUTE was mixed (allelic r2, 0.34-0.99) depending on reference haplotypes and population. Positive selection analysis using Beagle imputed haplotypes identified loci involved in resistance to chloroquine (crt) in Thailand, Cambodia, and Gambia, sulfadoxine-pyrimethamine (dhfr, dhps) in Cambodia, and artemisinin (kelch13) in Cambodia. Tajima's D-based analysis identified genes under balancing selection that encode well-characterized vaccine candidates: apical merozoite antigen 1 (ama1) and merozoite surface protein 1 (msp1). In contrast, the complete-case analysis failed to identify any well validated drug resistance or candidate vaccine loci, except kelch13. In a setting of low LD and modest levels of missing genotypes, using Beagle to impute P. falciparum genotypes is a viable strategy for conducting accurate large-scale population genetics and association analyses, and supporting global surveillance for drug resistance markers and candidate vaccine antigens. PMID- 25928502 TI - Specifying the target difference in the primary outcome for a randomised controlled trial: guidance for researchers. AB - BACKGROUND: Central to the design of a randomised controlled trial is the calculation of the number of participants needed. This is typically achieved by specifying a target difference and calculating the corresponding sample size, which provides reassurance that the trial will have the required statistical power (at the planned statistical significance level) to identify whether a difference of a particular magnitude exists. Beyond pure statistical or scientific concerns, it is ethically imperative that an appropriate number of participants should be recruited. Despite the critical role of the target difference for the primary outcome in the design of randomised controlled trials, its determination has received surprisingly little attention. This article provides guidance on the specification of the target difference for the primary outcome in a sample size calculation for a two parallel group randomised controlled trial with a superiority question. METHODS: This work was part of the DELTA (Difference ELicitation in TriAls) project. Draft guidance was developed by the project steering and advisory groups utilising the results of the systematic review and surveys. Findings were circulated and presented to members of the combined group at a face-to-face meeting, along with a proposed outline of the guidance document structure, containing recommendations and reporting items for a trial protocol and report. The guidance and was subsequently drafted and circulated for further comment before finalisation. RESULTS: Guidance on specification of a target difference in the primary outcome for a two group parallel randomised controlled trial was produced. Additionally, a list of reporting items for protocols and trial reports was generated. CONCLUSIONS: Specification of the target difference for the primary outcome is a key component of a randomized controlled trial sample size calculation. There is a need for better justification of the target difference and reporting of its specification. PMID- 25928503 TI - Global evaluation of men - check-up and follow-up. PMID- 25928504 TI - Focal Cryotherapy in Low-Risk Prostate Cancer: Are We Treating the Cancer or the Mind? - The Cancer. PMID- 25928505 TI - The Mind: Focal Cryotherapy in Low-Risk Prostate Cancer: Are We Treating the Cancer or the Mind? PMID- 25928506 TI - Accuracy of Percutaneous Core Biopsy in the Diagnosis of Small Renal Masses (<= 4.0 cm): A Meta-analysis. AB - OBJECTIVE: To use meta-analysis to determine the accuracy of percutaneous core needle biopsy in the diagnosis of small renal masses (SMRs <= 4.0 cm). MATERIALS AND METHODS: Studies were identified by searching PubMed, Embase, and the Cochrane Library database up to March 2013. Two of the authors independently assessed the study quality using QUADAS-2 tool and extracted data that met the inclusion criteria. The sensitivity, specificity, likelihood ratios, diagnostic odds ratio (DOR) and also summary receiver operating characteristic (SROC) curve were investigated and draw. Deek's funnel plot was used to evaluate the publication bias. RESULT: A total of 9 studies with 788 patients (803 biopsies) were included. Failed biopsies without repeated or aborted from follow-up/surgery result were excluded (232 patients and 353 biopsies). For all cases, the pooled sensitivity was 94.0% (95% CI: 91.0%, 95.0%), the pooled positive likelihood was 22.57 (95 % CI: 9.20-55.34), the pooled negative likelihood was 0.09 (95 % CI: 0.06-0.13), the pooled DOR was 296.52(95 % CI: 99. 42-884.38). The area under the curve of SROC analysis was 0.959 +/- 0.0254. CONCLUSION: Imaging-guided percutaneous core needle biopsy of small renal masses (SMRs <= 4.0 cm) is highly accurate to malignant tumor diagnosis with unknown metastatic status and could be offered to some patients after clinic judgment prior to surgical intervention consideration. PMID- 25928507 TI - "I will not cut, even for the stone": origins of urology in the Hippocratic Collection. AB - The Hippocratic Collection, including the most of ancient Greek medicine, remains still interesting, despite the recent advances that transformed definitely the urological healing methods. Considering the patient as a unique psycho-somatic entity and avoiding high risk surgical manipulations were the leading principles dictating the everyday practice. Contemporary physicians can still learn from the clinical observations in times of complete absence of laboratory or imaging aid, from the prognostic thoughts, the ethics, and the philosophical concepts, represented by the Hippocratic writings, tracing into them the roots of Rational Medicine in general and Urology in particular. PMID- 25928508 TI - Risk groups in bladder cancer patients treated with radical cystectomy. AB - OBJECTIVE: To stratify patients with bladder cancer into homogeneous risk groups according to statistically significant differences found in PFS (progression-free survival). To identify those patients at increased risk of progression and to provide oncological follow-up according to patient risk group. MATERIALS AND METHODS: A retrospective study of 563 patients treated with radical cystectomy (RC). In order to determine which factors might predict bladder tumour progression and death, uni- and multivariate analyses were performed. The risk groups were identified according to "inter-category" differences found in PFS and lack of differences, thus revealing intra-category homogeneity. RESULTS: Median follow up time was 37.8 months. Recurrence occurred in a total of 219 patients (38, 9 %). In 63 % of cases this was distant recurrence. Only two variables retained independent prognostic value in the multivariate analysis for PFS: pathological organ confinement and lymph node involvement. By combining these two variables, we created a new "risk group " variable. In this second model it was found that the new variable behaved as an independent predictor associated with PFS. Four risk groups were identified: very low, low, intermediate and high risk: * Very low risk: pT0 N0 * Low risk: pTa, pTis, pT1, pT2 and pN0 * Intermediate risk: pT3 and pN0 * High risk: pT4 N0 or pN1-3. CONCLUSIONS: We retrospectively identified 4 risk groups with an independent prognostic value for progression free survival following RC. Differences in recurrence patterns after RC between risk groups have led us to set different intervals in monitoring for cancer. PMID- 25928509 TI - Quality of life after high-dose-rate brachytherapy monotherapy for prostate cancer. AB - PURPOSE: There is little information in the literature on health-related quality of life (HRQOL) changes due to high-dose-rate (HDR) brachytherapy monotherapy for prostate cancer. MATERIALS AND METHODS: We conducted a prospective study of HRQOL changes due to HDR brachytherapy monotherapy for low risk or favorable intermediate risk prostate cancer. Sixty-four of 84 (76 %) patients who were treated between February 2011 and April 2013 completed 50 questions comprising the Expanded Prostate Cancer Index Composite (EPIC) before treatment and 6 and/or 12 months after treatment. RESULTS: Six months after treatment, there was a significant decrease (p <0.05) in EPIC urinary, bowel, and sexual scores, including urinary overall, urinary function, urinary bother, urinary irritative, bowel overall, bowel bother, sexual overall, and sexual bother scores. By one year after treatment, EPIC urinary, bowel, and sexual scores had increased and only the bowel overall and bowel bother scores remained significantly below baseline values. CONCLUSIONS: HDR brachytherapy monotherapy is well-tolerated in patients with low and favorable intermediate risk prostate cancer. EPIC urinary and sexual domain scores returned to close to baseline 12 months after HDR brachytherapy. PMID- 25928510 TI - Short-term prophylaxis with ciprofloxacin in extended 16-core prostate biopsy. AB - OBJECTIVE: To evaluate the safety, efficacy and possible complications of 16-core transrectal prostate biopsies using two doses of ciprofloxacin for prophylaxis of infectious complications. MATERIALS AND METHODS: Sixteen-core prostate biopsies were performed on a number of patients with different signs of potential prostate cancer. Complications were assessed both during the procedure and one week later. After the procedure, urine samples were collected for culture. The rate of post biopsy complications, hospital visits and hospitalizations were also analyzed. Ciprofloxacin (500 mg) was administered two hours before, and eight hours after the procedure. RESULTS: The overall rate of post-biopsy complications was 87.32%, being 5.4% of those considered major complications due to hemorrhage, or to urinary retention. Eight patients required hospital treatment post-biopsy. Fever occurred in just one patient (0.29%). There was no incidence of orchitis, epididymitis, prostatitis, septicemia, hospitalization, or death. The urine culture showed positive results in five patients (2.15%). CONCLUSION: One-day prophylaxis with ciprofloxacin proved to be safe and effective in the prevention of infectious complications following 16-core prostate biopsies. PMID- 25928511 TI - The efficacy of immediate versus delayed antibiotic administration on bacterial growth and biofilm production of selected strains of uropathogenic Escherichia coli and Pseudomonas aeruginosa. AB - PURPOSE: The treatment of urinary tract infections (UTI) with antibiotics is commonly used, but recurrence and antibiotic resistance have been growing and concerning clinicians. We studied whether the rapid onset of a protective biofilm may be responsible for the lack of effectiveness of antibiotics against selected bacteria. MATERIALS AND METHODS: Two established uropathogenic Escherichia coli strains, UTI89 and CFT073, and two Pseudomonas aeruginosa strains, PA01 and Boston-41501, were studied to establish a reliable biofilm formation process. Bacterial growth (BG) was determined by optical density at 600 nm (OD 600) using a spectrophotometer, while biofilm formation (BF) using crystal violet staining was measured at OD 550. Next, these bacterial strains were treated with clinically relevant antibiotics, ciprofloxacin HCl (200 ng/mL and 2 MUg/mL), nitrofurantoin (20 ug/mL and 40 ug/mL) and ampicillin (50 ug/mL) at time points of 0 (T0) or after 6 hours of culture (T6). All measurements, including controls (bacteria -1% DMSO), were done in triplicates and repeated three times for consistency. RESULTS: The tested antibiotics effectively inhibited both BG and BF when administered at T0 for UPEC strains, but not when the antibiotic administration started 6 hours later. For Pseudomonas strains, only Ciprofloxacin was able to significantly inhibit bacterial growth at T0 but only at the higher concentration of 2 ug/mL for T6. CONCLUSION: When established UPEC and Pseudomonas bacteria were allowed to culture for 6 hours before initialization of treatment, the therapeutic effect of selected antibiotics was greatly suppressed when compared to immediate treatment, probably as a result of the protective nature of the biofilm. PMID- 25928512 TI - Stage IIA and IIB testicular seminoma treated postorchiectomy with radiation therapy versus other approaches: a population-based analysis of 241 patients. AB - OBJECTIVES: To evaluate post-orchiectomy utilization of radiation therapy (RT) versus other management approaches in stage IIA and IIB testicular seminoma patients. MATERIALS AND METHODS: Two hundred and forty-one patients with stage IIA and IIB testicular seminoma were identified between 1988 and 2003 using the Surveillance, Epidemiology, and End Results (SEER) database. RESULTS: Median follow-up was 10 years. Patients with stage IIA disease underwent RT more frequently than those with stage IIB disease (72 % vs. 46 %, respectively; P < 0.001). There was no significant change in RT utilization for stage IIA or IIB disease between 1988 and 2003 (P = 0.89). CONCLUSIONS: Between 1988 and 2003, stage IIA patients underwent RT more often than stage IIB patients in the United States. There was no significant change in RT utilization for stage IIA or IIB disease during this time period. Based on reports describing excellent progression-free survival with cisplatin-based chemotherapy, this approach has increased in popularity since 2003 and may eventually become the most popular treatment approach for both stage IIA and IIB testicular seminoma. PMID- 25928513 TI - Comparison of imaging modalities for detection of residual fragments and prediction of stone related events following percutaneous nephrolitotomy. AB - INTRODUCTION: Achieving stone free status (SFS) is the goal of stone surgery. In this study it is aimed to compare effectiveness of unenhanced helical computerized tomography (UHCT), KUB and ultrasonography (US) for detection of residual RFs and predicition of stone releated events following percutaneous nephrolitotomy (PNL). MATERIALS AND METHODS: Patients underwent PNL for radiopaque stones between November 2007 and February 2010 were followed. Patients were examined within 24-48 hours after the procedure by KUB, US and UHCT. For stone size 4 mm was accepted as cut off level of significance.Sensitivity and specificity of KUB and US for detection of RFs and value of them for prediction of stone related events were calculated. RESULTS: SFS was achieved in 95 patients (54.9%) and when cut off value of 4 mm for RFs was employed, SFS was achieved in 131 patients (75.7%). Sensitivity was 70.5% for KUB, and 52.5% for US. UHCT was shown to be significantly more efficient for detection of RFs compared to both KUB (p=0.01) and US (p=0.001). When cut off level of 4 mm employed, sensitivity of KUB and US increased to 85.7% and 57.1%. Statistical significant superiority of UHCT still remained (p value vs. KUB: 0.03 and p value vs. US: 0.008). CONCLUSION: UHCT is the most sensitive diagnostic tool for detecting RFs after PNL. It has higher sensitivity regardless of stone size compared to KUB and US. Additionally UHCT has higher capability of predicting occurrence of stone related events. PMID- 25928514 TI - Perineostomy: the last oportunity. AB - OBJECTIVE: To review the technique and outcome of perineal urethrostomy or urethral perineostomy and to identify factors related to the procedure failure. MATERIAL AND METHODS: We studied 17 patients who underwent perineal urethrostomy between 2009-2013 in a single hospital. Success was defined as no need for additional surgical treatment or urethral dilatation. We reviewed the clinical data related to age, weight, previous urethral surgery, diabetes, hypertension, ischemic cardiopathy, lichen sclerosus and other causes and studied their association with the procedure failure (univariate analysis). We completed the analysis with a multivariate test based on binary regression. RESULTS: The average follow-up was 39.41 months. From all the causes, we found Lichen Sclerosus in 35 %, idiopathic etiology in 29 % and prior hypospadia repair in 18 %. Postoperative failure occurred in 3 patients, with a final success of 82.4 %. The binary regression model showed as independent risk factors ischemic cardiopathy (OR: 2.34), and the presence of Lichen Sclerosis (OR: 3.21). CONCLUSIONS: The success rate with the perineal urethrostomy technique shows it to be a valid option above all when we preserve the urethral blood supply and plate. Lichen sclerosus and ischemic vascular problems are risk factors to re stenosis. PMID- 25928515 TI - Intrarectal ice application prior to transrectal prostate biopsy: a prospective randomised trial accessing pain and collateral effects. AB - OBJECTIVES: To analyze the efficacy of intrarectal ice application as an anesthetic method prior to transrectal ultrasound (TRUS) guided prostate biopsy. MATERIALS AND METHODS: A total of 120 consecutive men were included into the study prospectively. Patients were equally randomized as group 1 and 2 with 60 patients each. Ice was applied as an anesthetic method 5 minutes before procedure to the patients in group 1. Patients in group 2 were applied 10 mL of 2% lidocaine gel 10 minutes before procedure. Twelve core biopsy procedure was performed for all patients. The pain level was evaluated using a visual analogue scale (VAS). RESULTS: Median pain score was 3.5 (1-8) in group 1 and 5 (1-8) in group 2. There is significantly difference between groups regarding the mean sense of pain level during the procedure. (p=0.007) There was also no difference in complications between two groups about presence and duration of macroscopic hematuria and rectal bleeding. CONCLUSIONS: Intrarectal ice application prior to TRUS prostate biopsy has an effect on reducing pain. Development of new techniques about cold effect or ice can make this method more useful and decrease complication rates. PMID- 25928516 TI - Insulin-like growth factor (IGF)-I, IGF binding protein-3, and prostate cancer: correlation with Gleason score. AB - INTRODUCTION: Non-androgenic growth factors are involved in the growth regulation of prostate cancer (PCa). OBJECTIVE: This is the first Brazilian study to correlate, in a population of patients operated for PCa, PSA, total testosterone, insulin-like growth factor-I (IGF-I) and insulin-like growth factor-binding protein-3 (IGFBP-3) with Gleason score and to compare with a control group with benign prostate hyperplasia (BPH). MATERIALS AND METHODS: This retrospective single-center study included 49 men with previously diagnosed PCa and 45 with previously diagnosed BPH. PSA, testosterone, IGF-I, IGFBP-3 were determined in both groups. RESULTS: PSA and IGFBP-3 levels were significantly higher in the PCa group as compared to the BPH group (p < 0.001 and p=0.004, respectively). There was a significant difference when we compared the PSA before surgery (p < 0.001) and at the inclusion in the study (p < 0.001) and IGFBP3 (0.016) among patients with Gleason < 7, >=7 and BPH. In the PCa group, PSA, testosterone, IGF-I and IGFBP-3 levels were comparable between Gleason < 7 and >=7. CONCLUSIONS: Our data suggest that in localized PCa, the quantification of PSA and, not of IGF-1, may provide independent significant information in the aggressiveness. IGFBP-3 could be a biochemical marker of disease control in PCa patients. PMID- 25928517 TI - Continued administration of antithrombotic agents during transperineal prostate biopsy. AB - PURPOSE: To determine the safety of continued administration of antithrombotic agents during transperineal (TP) prostate biopsy. PATIENTS AND METHODS: A total of 811 men who underwent transrectal ultrasound (TRUS)-guided TP biopsy from January 2008 to June 2012 at our two institutions were retrospectively analyzed. Among these 811 men, 672 received no antithrombotic agents (group I), 103 received and continued administration of antithrombotic agents (group II), and 36 interrupted administration of antithrombotic agents (group III). Overall complications were graded and hemorrhagic complications were compared (group I with group II) using propensity score matching (PSM) analysis. RESULTS: An overall complication rate of 4.6% was recorded. Hemorrhagic complications occurred in 1.8% and they were virtually identical in all the three groups, and no severe hemorrhagic complications occurred. One patient in group III required intensive care unit admission for cerebral infarction. PSM analysis revealed no statistical difference between groups I and II with regard to the incidence of gross hematuria, perineal hematoma, and rectal bleeding. Multiple regression analysis revealed that hemorrhagic complications were associated with lower body mass index (<21 kg/m2, P=0.0058), but not with administration of antithrombotic agents. CONCLUSIONS: Continued administration of antithrombotic agents does not increase the risk of hemorrhagic complications; these agents are well tolerated during TP biopsy. PMID- 25928518 TI - Preoperative prostate biopsy and multiparametric magnetic resonance imaging: reliability in detecting prostate cancer. AB - PURPOSE: The aim of the study was to analyse and compare the ability of multiparametric magnetic resonance imaging (mp-MRI) and prostate biopsy (PB) to correctly identify tumor foci in patients undergoing radical prostatectomy (RP) for prostate cancer (PCa). MATERIALS AND METHODS: 157 patients with clinically localised PCa with a PSA <10 ng/ mL and a negative DRE diagnosed on the first (12 samples, Group A) or second (18 samples, Group B) PB were enrolled at our institution. All patients underwent mp-MRI with T2-weighted images, diffusion weighted imaging, dynamic contrast enhanced-MRI prior to RP. A map of comparison describing each positive biopsy sample was created for each patient, with each tumor focus shown on the MRI and each lesion present on the definitive histological examination in order to compare tumor detection and location. The sensitivity of mp-MRI and PB for diagnosis was compared using Student's t-test. The ability of the two exams to detect the prevalence of Gleason pattern 4 in the identified lesions was compared using a chi-square test. RESULTS: Overall sensitivity of PB and mp-MRI to identify tumor lesion was 59.4% and 78.9%, respectively (p<0.0001). PB missed 144/355 lesions, 59 of which (16.6%) were significant. mp-MRI missed 75/355 lesions, 12 of which (3.4%) were significant. No lesions with a GS>=8 were missed. Sensitivity of PB and mp-MRI to detect the prevalence of Gleason pattern 4 was 88.2% and 97.4%, respectively. CONCLUSIONS: mp-MRI seems to identify more tumor lesions than PB and to provide more information concerning tumor characteristics. PMID- 25928519 TI - Concurrent stone stabilization improves ultrasonic and pneumatic efficacy during cystolithopaxy: an in vitro analysis. AB - OBJECTIVE: To identify whether stabilization of larger bladder stones would improve the efficacy of combination (ultrasonic/pneumatic) lithotripsy in a phantom bladder stone model for percutaneous cystolithopaxy. MATERIALS AND METHODS: Using 1cm phantom Bego stones, a spherical model bladder was used to simulate percutaneous bladder access. A UroNet (US Endoscopy, USA) was placed alongside a Swiss Lithoclast probe through the working channel of a Storz 26Fr rigid nephroscope. Using a 30Fr working sheath, the stone was captured, and fragmented for 60 seconds. Resulting fragments and irrigation were filtered through a 1mm strainer, and recorded. Five trials were performed with and without the UN. Durability was then assessed by measuring net defects, and residual grasp strength of each instrument. Descriptive statistics (mean, standard deviations) were used to summarize the data, and Student's t-tests (alpha < 0.05) were used to compare trials. RESULTS: The mean time to stone capture was 12s (8-45s). After fragmentation with UN stabilization, there were significant improvements in the amount of residual stone (22% dry weight reduction vs 8.1% without UN, p < 0.001), number of fragments (17.5 vs 5.0 frag/stone, p=0.0029), and fragment size (3.6mm vs. 7.05 mm, p=0.035). Mesh defects were noted in all nets, ranging from 2 14 mm, though all but one net retained their original grip strength (36.8N). CONCLUSIONS: Bladder stone stabilization improved fragmentation when used in conjunction with ultrasonic/pneumatic lithotripsy. However, due to limitations in maneuverability and durability of the UN, other tools need to identified for this indication. PMID- 25928520 TI - Is quantitative diffusion-weighted MRI a valuable technique for the detection of changes in kidneys after extracorporeal shock wave lithotripsy? AB - OBJECTIVE: The aim of this study was to evaluate the capability and the reliability of diffusion-weighted imaging (DWI) in the changes of kidneys occurring after extracorporeal shock wave lithotripsy (ESWL) treatment for renal stones. MATERIALS AND METHODS: A total of 32 patients who underwent ESWL treatment for renal stone disease between June and December 2011 were enrolled in this prospective study. Color Doppler ultrasonography (CDUS) and DWI were performed before and within 24 hours after ESWL. DWI was obtained with b factors of 0, 500 and 1000 s/ mm2 at 1.5 T MRI. Each of Resistive index (RI) and ADC values were calculated from the three regions of renal upper, middle and lower zones for both of the affected and contralateral kidneys. Paired sample t test was used for statistical analyses. RESULTS: After ESWL, the treated kidneys had statistically significant lower ADC values in all different regions compared with previous renal images. The best discriminative parameter was signal intensity with a b value of 1000 s/mm2. The changes of DWI after ESWL were noteworthy in the middle of the treated kidney (p < 0.01). There were no significant difference between RI values in all regions of treated and contralateral kidneys before and after treatment with ESWL (p>0.05). CONCLUSION: DWI is a valuable technique enables the detection of changes in DWI after ESWL treatment that may provide useful information in prediction of renal damage by shock waves, even CDUS is normal. PMID- 25928521 TI - Oncological and functional outcomes of salvage renal surgery following failed primary intervention for renal cell carcinoma. AB - PURPOSE: To assess the oncologic and functional outcomes of salvage renal surgery following failed primary intervention for RCC. MATERIALS AND METHODS: We performed a retrospective review of patients who underwent surgery for suspected RCC during 2004-2012. We identified 839 patients, 13 of whom required salvage renal surgery. Demographic data was collected for all patients. Intraoperative and postoperative data included ischemic duration, blood loss and perioperative complications. Preoperative and postoperative assessments included abdominal CT or magnetic resonance imaging, chest CT and routine laboratory work. Estimated glomerular filtration rate (eGFR) was calculated according to the Modification of Diet in Renal Disease equation. RESULTS: The majority (85%) of the patients were male, with an average age of 64 years. Ten patients underwent salvage partial nephrectomy while 3 underwent salvage radical nephrectomy. Cryotherapy was the predominant primary failed treatment modality, with 31% of patients undergoing primary open surgery. Pre-operatively, three patients were projected to require permanent post-operative dialysis. In the remaining 10 patients, mean pre- and postoperative serum creatinine and eGFR levels were 1.35 mg/dL and 53.8 mL/min/1.73 m2 compared to 1.43 mg/dL and 46.6 mL/min/1.73 m2, respectively. Mean warm ischemia time in 10 patients was 17.4 min and for all patients, the mean blood loss was 647 mL. The predominant pathological stage was pT1a (8/13; 62%). Negative surgical margins were achieved in all cases. The mean follow-up was 32.9 months (3.5-88 months). CONCLUSION: While salvage renal surgery can be challenging, it is feasible and has adequate surgical, functional and oncological outcomes. PMID- 25928522 TI - Validation of Portuguese version of Quality of Erection Questionnaire (QEQ) and comparison to International Index of Erectile Function (IIEF) and RAND 36-Item Health Survey. AB - PURPOSE: To validate the Quality of Erection Questionnaire (QEQ) considering Brazilian social-cultural aspects. MATERIALS AND METHODS: To determine equivalence between the Portuguese and the English QEQ versions, the Portuguese version was back-translated by two professors who are native English speakers. After language equivalence had been determined, urologists considered the QEQ Portuguese version suitable. Men with self-reported erectile dysfunction (ED) and infertile men who had a stable sexual relationship for at least 6 months were invited to answer the QEQ, the International Index of Erectile Function (IIEF) and the RAND 36-Item Health Survey (RAND-36). The questionnaires were presented together and answered without help in a private room. Internal consistency (Cronbach's alpha), test-retest reliability (Spearman), convergent validity (Spearman correlation) coefficients and known-groups validity (the ability of the QEQ Portuguese version to differentiate erectile dysfunction severity groups) were assessed. RESULTS: We recruited 197 men (167 ED patients and 30 non-ED patients), mean age of 53.3 and median of 55.5 years (23-82 years). The Portuguese version of the QEQ had high internal consistency (Cronbach alpha=0.93), high stability between test and retest (ICC 0.83, with IC 95%: 0.76 0.88, p<0.001) and Spearman correlation coefficient r=0.82 (p<0.001), which demonstrated the high correlation between the QEQ and IIEF results. The correlations between the QEQ and RAND-36 were significantly low in ED (r=0.20, p=0.01) and non-ED patients (r=0.37, p=0.04). CONCLUSION: The QEQ Portuguese version presented good psychometric properties and high convergent validity in relation to IIEF. The low correlations between the QEQ and the RAND-36, as well as between the IIEF and the RAND-36 indicated IIEF and QEQ specificity, which may have resulted from the patients' psychological adaptations that minimized the impact of ED on Quality of Life (QoL) and reestablished the well-being feeling. PMID- 25928523 TI - Single-port retroperitoneal renal biopsy using standard urological instruments. AB - OBJECTIVE: To describe the surgical technique and initial experience with a single-port retroperitoneal renal biopsy (SPRRB). MATERIALS AND METHODS: Between January and April 2013, five children underwent SPRRB in our hospital. A single 1.5 cm incision was performed under the 12th rib at mid-axillary line, and an 11 mm trocar was inserted. A nephroscope was used to identify the kidney and dissect the perirenal fat. After lower pole exposure, a laparoscopic biopsy forceps was introduced through the nephroscope working channel to collect a renal tissue sample. RESULTS: SPRRB was successfully performed in five children. The mean operative time was 32 minutes, and mean estimated blood loss was less than 10 mL. The hospital stay of all patients was two days because they were discharged in the second postoperative day, after remaining at strict bed rest for 24 hours after the procedure. The average number of glomeruli present in the specimen was 31. CONCLUSION: SPRRB is a simple, safe and reliable alternative to open and videolaparoscopic approaches to surgical renal biopsy. PMID- 25928524 TI - Nephron-sparing surgery for treatment of reninoma: a rare renin secreting tumor causing secondary hypertension. AB - MAIN FINDINGS: A 25-year-old hypertensive female patient was referred to our institution. Initial workup exams demonstrated a 2.8 cm cortical lower pole tumor in the right kidney. She underwent laparoscopic partial nephrectomy without complications. Histopathologic examination revealed a rare juxtaglomerular cell tumor known as reninoma. After surgery, she recovered uneventfully and all medications were withdrawn. Case hypothesis: Secondary arterial hypertension is a matter of great interest to urologists and nephrologists. Renovascular hypertension, primary hyperadosteronism and pheocromocytoma are potential diagnosis that must not be forgotten and should be excluded. Although rare, chronic pyelonephritis and renal tumors as rennin-producing tumors, nephroblastoma, hypernephroma, and renal cell carcinoma might also induce hypertension and should be in the diagnostic list of clinicians. Promising future implications: Approximately 5% of patients with high blood pressure have specific causes and medical investigation may usually identify such patients. Furthermore, these patients can be successfully treated and cured, most times by minimally invasive techniques. This interesting case might expand knowledge of physicians and aid better diagnostic care in future medical practice. PMID- 25928525 TI - Peripyelitis: A risk factor for urinary fistula after tubeless PCNL. AB - A 43 years-old man presented to our stone clinic complaining of back pain for the last 3 months. He had significant past medical history for nephrolithiasis: he had undergone unsuccessful SWL for left renal calculi five years ago and also presented with several episodes of pyelonephritis in the last months, requiring hospitalization for intravenous antibiotics. Initial laboratory work-up revealed normal serum creatinine (0.92 mg/dL) and hemoglobin levels (15.3 g/dL); urine culture was negative. Abdominal computed tomography (CT) revealed a 140 mm2 stone in the left renal pelvis with 1500 Hounsfield Units (Figure-1a); thickening of the urothelium surrounding the stone was suspected after contrast infusion (Figure-1b) and confirmed in the excretory phase (Figure-1c). PMID- 25928526 TI - Robotic transmesocolonic Pyelolithotomy of horseshoe kidney. AB - INTRODUCTION: The purpose of this video is to demonstrate the use of the robot to perform a transmesocolonic pyelolithotomy of a horseshoe kidney. MATERIALS AND METHODS: A 35-year old female presented with vague abdominal pain. CT scan imaging revealed the presence of a left horseshoe kidney with multiple pelvicalyceal stones. The patient was positioned in the supine position. A total of 4 ports were introduced. A 3-arm da Vinci robotic surgical system was docked, and the arms were connected. First, the dilated renal pelvis was identified behind the thin mesocolon. The mesocolon was entered and renal pelvis was dissected completely from the surrounding fat. Then, the renal pelvis was opened after adequate dissection and stones were visualized inside the calyces. By Prograsp forceps, stones were removed from all the calyces under vision and were extracted from the assistant trocar. Finally, the pylotomy incision was closed using 4 0 Maxon in a continuous fashion and the mesocolon was closed using 3 0 PDS interrupted sutures. A JP drain was placed. RESULT: Operative time was forty five minutes, blood loss was 100 ml. The patient was discharged after 48 hours with no immediate complications. CONCLUSION: The utilization of minimal invasive surgery using the robot to extract multiple pelvicalyceal stones from a horseshoe kidney without reflecting the mesocolon proved to be a feasible and novel way in the management of complex stone disease improving the outcome with minimal morbidity. PMID- 25928527 TI - RE: Clinical relevance of routine semen analysis and controversies surrounding the 2010 World Health Organization criteria for semen examination. PMID- 25928528 TI - RE: Minimal Hydrocelectomy with the aid of scrotoscope: a ten-year experience. PMID- 25928529 TI - RE: Proximal bulbar periurethral abscess. PMID- 25928530 TI - A cross-sectional study of cryptorchidism in children: testicular volume and hormonal function at 18 years of age. AB - PURPOSE: To evaluate the relationship between unilateral or bilateral criptorchidism, patient age, primary location of the gonad and modality of treatment with testicular volume and hormonal status at 18 years in patients diagnosed and treated for cryptorchidism during childhood. MATERIALS AND METHODS: Testicular volume, LH, FSH, and testosterone were evaluated in 143 young men at 18 years treated in childhood for unilateral (n=103) or bilateral (n=40) cryptorchidism. RESULTS: Unilateral cryptorchidism: Location of testis was prescrotal in 36 patients, inguinal in 52 and non-palpable in 15. The mean volume was 9.7 mL compared to 16.2 L. for the spontaneously descended testicle in unilateral cryptorchidism. However, 22 patients who received HCG had a significantly bigger testis (11.8 mL.) than those treated with primary surgery (9.2 mL). The results showed a significant positive correlation between testicular volume and patient age at treatment. Bilateral cryptorchidism: Location of testis was prescrotal in 34 cases, inguinal in 40 and 6 patients with non-palpable testicles. Mean volume at 18 years was 12.9 mL, greater than unilateral cryptorchid testis (9.7 mL) but smaller than healthy contralateral in unilateral cases (16.2 mL). There were significant differences in the testicular growth for bilateral patients with testicular descent after being treated with HCG (14.4 mL) in respect with those untreated (11.1 mL) or those who underwent primary surgery (11.4 mL). There was a significant positive correlation between the testicular volume and palpable (12.4 mL) or non-palpable testis (10.4 mL). There was a correlation between unilateral or bilateral cryptorchidism and levels of FSH. CONCLUSIONS: Testicular volume and hormonal function at 18 years for patients diagnosed and treated for cryptorchidism during childhood are strongly influenced by whether the undescended testis was unilateral or bilateral. Location of the testes at diagnosis or age of initial treatment exerts no definite effect on testicular volume improvement r hormonal levels at 18 years of age. PMID- 25928531 TI - Molecular characterization of subcutaneous panniculitis-like T-cell lymphoma reveals upregulation of immunosuppression- and autoimmunity-associated genes. AB - BACKGROUND: Subcutaneous panniculitis-like T cell lymphomas represent a rare and difficult to diagnose entity of cutaneous T cell lymphomas. SPTL affects predominantly young adults and presents with multifocal subcutaneous nodules and frequently associated autoimmune features. The pathogenesis of SPTL is not completely understood. METHODS: The aim of this study was to unravel molecular pathways critical to the SPTL pathogenesis. Therefore, we analyzed 23 skin samples from 20 newly diagnosed SPTL patients and relevant control samples of adipose and non-malignant panniculitis tissue by using gene expression microarray, quantitative PCR, and two-colour immunohistochemistry. RESULTS: Interestingly, indoleamine 2,3-dioxygenase (IDO-1), an immunotolerance-inducing enzyme, was among the most highly overexpressed genes in all comparisons. The expression of Th1-specific cytokines, known to be associated with autoimmune inflammation (i.e. IFNG, CXCR3, CXCL9, CXCL10, CXCL11, and CCL5), were also significantly increased. Confirmed using immunohistochemistry, the morphologically malignant lymphocytes expressed CXCR3 and CXCL9. IDO-1 expression was found both in some morphologically malignant lymphocytes rimming the adipocytes and in surrounding CD11c(-) CD68(-) cells but not in CD11c(+) dendritic cells in the microenvironment. The proportion of FoxP3+ cells in SPTL exceeded that in the benign panniculitis samples. CONCLUSIONS: Our results indicate that the up regulation of the tolerogenic IDO-1 together with the up regulation of IFNG, CXCR3 ligands, and CCL5 are features of SPTL lesions. We anticipate that the IFNG-inducible IDO-1 expression contributes to the formation of an immunosuppressive microenvironment, favorable for the malignant T cells. This study provides a relevant molecular basis for further studies exploring novel therapeutic means for subcutaneous T cell lymphoma. PMID- 25928534 TI - Novel domain-specific POU3F4 mutations are associated with X-linked deafness: examples from different populations. AB - BACKGROUND: Mutations in the POU3F4 gene cause X-linked deafness type 3 (DFN3), which is characterized by inner ear anomalies. METHODS: Three Turkish, one Ecuadorian, and one Nigerian families were included based on either inner ear anomalies detected in probands or X-linked family histories. Exome sequencing and/or Sanger sequencing were performed in order to identify the causative DNA variants in these families. RESULTS: Four novel, c.707A>C (p.(Glu236Ala)), c.772delG (p.(Glu258ArgfsX30)), c.902C>T (p.(Pro301Leu)), c.987T>C (p.(Ile308Thr)), and one previously reported mutation c.346delG (p.(Ala116ProfsX26)) in POU3F4, were identified. All mutations identified are predicted to affect the POU-specific or POU homeo domains of the protein and co segregated with deafness in all families. CONCLUSIONS: Expanding the spectrum of POU3F4 mutations in different populations along with their associated phenotypes provides better understanding of their clinical importance and will be helpful in clinical evaluation and counseling of the affected individuals. PMID- 25928535 TI - Exploring the perspectives and preferences for HTA across German healthcare stakeholders using a multi-criteria assessment of a pulmonary heart sensor as a case study. AB - BACKGROUND: Health technology assessment and healthcare decision-making are based on multiple criteria and evidence, and heterogeneous opinions of participating stakeholders. Multi-criteria decision analysis (MCDA) offers a potential framework to systematize this process and take different perspectives into account. The objectives of this study were to explore perspectives and preferences across German stakeholders when appraising healthcare interventions, using multi-criteria assessment of a heart pulmonary sensor as a case study. METHODS: An online survey of 100 German healthcare stakeholders was conducted using a comprehensive MCDA framework (EVIDEM V2.2). Participants were asked to provide i) relative weights for each criterion of the framework; ii) performance scores for a health pulmonary sensor, based on available data synthesized for each criterion; and iii) qualitative feedback on the consideration of contextual criteria. Normalized weights and scores were combined using a linear model to calculate a value estimate across different stakeholders. Differences across types of stakeholders were explored. RESULTS: The survey was completed by 54 participants. The most important criteria were efficacy, patient reported outcomes, disease severity, safety, and quality of evidence (relative weight >0.075 each). Compared to all participants, policymakers gave more weight to budget impact and quality of evidence. The quantitative appraisal of a pulmonary heart sensor revealed differences in scoring performance of this intervention at the criteria level between stakeholder groups. The highest value estimate of the sensor reached 0.68 (on a scale of 0 to 1, 1 representing maximum value) for industry representatives and the lowest value of 0.40 was reported for policymakers, compared to 0.48 for all participants. Participants indicated that most qualitative criteria should be considered and their impact on the quantitative appraisal was captured transparently. CONCLUSIONS: The study identified important variations in perspectives across German stakeholders when appraising a healthcare intervention and revealed that MCDA can demonstrate the value of a specified technology for all participating stakeholders. Better understanding of these differences at the criteria level, in particular between policymakers and industry representatives, is important to focus innovation aligned with patient health and healthcare system values and constraints. PMID- 25928536 TI - Is there a role for music in the ICU? PMID- 25928538 TI - Mapping barriers and intervention activities to behaviour change theory for Mobilization of Vulnerable Elders in Ontario (MOVE ON), a multi-site implementation intervention in acute care hospitals. AB - BACKGROUND: As evidence-informed implementation interventions spread, they need to be tailored to address the unique needs of each setting, and this process should be well documented to facilitate replication. To facilitate the spread of the Mobilization of Vulnerable Elders in Ontario (MOVE ON) intervention, the aim of the current study is to develop a mapping guide that links identified barriers and intervention activities to behaviour change theory. METHODS: Focus groups were conducted with front line health-care professionals to identify perceived barriers to implementation of an early mobilization intervention targeted to hospitalized older adults. Participating units then used or adapted intervention activities from an existing menu or developed new activities to facilitate early mobilization. A thematic analysis was performed on the focus group data, emphasizing concepts related to barriers to behaviour change. A behaviour change theory, the 'capability, opportunity, motivation-behaviour (COM-B) system', was used as a taxonomy to map the identified barriers to their root causes. We also mapped the behaviour constructs and intervention activities to overcome these. RESULTS: A total of 46 focus groups were conducted across 26 hospital inpatient units in Ontario, Canada, with 261 participants. The barriers were conceptualized at three levels: health-care provider (HCP), patient, and unit. Commonly mentioned barriers were time constraints and workload (HCP), patient clinical acuity and their perceived 'sick role' (patient), and lack of proper equipment and human resources (unit level). Thirty intervention activities to facilitate early mobilization of older adults were implemented across hospitals; examples of unit-developed intervention activities include the 'mobility clock' communication tool and the use of staff champions. A mapping guide was created with barriers and intervention activities matched though the lens of the COM-B system. CONCLUSIONS: We used a systematic approach to develop a guide, which maps barriers, intervention activities, and behaviour change constructs in order to tailor an implementation intervention to the local context. This approach allows implementers to identify potential strategies to overcome local-level barriers and to document adaptations. PMID- 25928539 TI - Elevation of soluble guanylate cyclase suppresses proliferation and survival of human breast cancer cells. AB - Nitric oxide (NO) is an essential signaling molecule in biological systems. Soluble guanylate cyclase (sGC), composing of alpha1 and beta1 subunit, is the receptor for NO. Using radioimmunoassay, we discovered that activation of sGC by treatment with bradykinin or sodium nitroprusside (SNP) is impaired in MCF-7 and MDA-MB-231 breast cancer cells as compared to normal breast epithelial 184A1 cells. The 184A1 cells expressed both sGC alpha1 and sGCbeta1 mRNAs. However, levels of sGCbeta1 mRNAs were relatively lower in MCF-7 cells while both mRNA of sGC subunits were absent in MDA-MB-231 cells. Treatment with DNA methyltransferase inhibitor 5-aza-2'-deoxycytidine (5-aza-dC) increased mRNA levels of both sGCalpha1 and sGCbeta1 in MDA-MB-231 cells but only sGCbeta1 mRNAs in MCF-7 cells. The 5-aza-dC treatment increased the SNP-induced cGMP production in MCF-7 and MDA-MB-231, but not in 184A1 cells. Bisulfite sequencing revealed that the promoter of sGCalpha1 in MDA-MB-231 cells and promoter of sGCbeta1 in MCF-7 cells were methylated. Promoter hypermethylation of sGCalpha1 and sGCbeta1 was found in 1 out of 10 breast cancer patients. Over-expression of both sGC subunits in MDA-MB-231 cells induced apoptosis and growth inhibition in vitro as well as reduced tumor incidence and tumor growth rate of MDA-MB-231 xenografts in nude mice. Elevation of sGC reduced protein abundance of Bcl-2, Bcl-xL, Cdc2, Cdc25A, Cyclin B1, Cyclin D1, Cdk6, c-Myc, and Skp2 while increased protein expression of p53. Our study demonstrated that down-regulation of sGC, partially due to promoter methylation, provides growth and survival advantage in human breast cancer cells. PMID- 25928540 TI - A Novobiocin Derivative, XN4, Inhibits the Proliferation of Chronic Myeloid Leukemia Cells by Inducing Oxidative DNA Damage. AB - XN4 might induce DNA damage and apoptotic cell death through reactive oxygen species (ROS). The inhibition of proliferation of K562 and K562/G01 cells was measured by MTT (3-(4,5-Dimethylthiazol-2-yl)-2,5-Diphenyltetrazolium Bromide). The mRNA levels of NADPH oxidase 1-5 (Nox1-5) genes were evaluated by qRT-PCR. The levels of extracellular reactive oxygen species (ROS), DNA damage, apoptosis, and cell cycle progression were examined by flow cytometry (FCM). Protein levels were analyzed by immunoblotting. XN4 significantly inhibited the proliferation of K562 and K562/G01 cells, with IC50 values of 3.75+/-0.07 uM and 2.63+/-0.43 uM, respectively. XN4 significantly increased the levels of Nox4 and Nox5 mRNA, stimulating the generation of intracellular ROS, inducing DNA damage and activating ATM-gamma-H2AX signaling, which increased the number of cells in the S and G2/M phase of the cell cycle. Subsequently, XN4 induced apoptotic cell death by activating caspase-3 and PARP. Moreover, the above effects were all reversed by the ROS scavenger N-acetylcysteine (NAC). Additionally, XN4 can induce apoptosis in progenitor/stem cells isolated from CML patients' bone marrow. In conclusion, XN4-induced DNA damage and cell apoptosis in CML cells is mediated by the generation of ROS. PMID- 25928541 TI - Interplay between Organic-Organometallic Electrophores within Bis(cyclopentadienyl)Molybdenum Dithiolene Tetrathiafulvalene Complexes. AB - Tetrathiafulvalenes (TTF) and bis(cyclopentadienyl) molybdenum dithiolene complexes, Cp2Mo(dithiolene) complexes, are known separately to act as good electron donor molecules. For an investigation of the interaction between both electrophores, two types of complexes were synthesized and characterized. The first type has one Cp2Mo fragment coordinated to one TTF dithiolate ligand, and the second type has one TTF bis(dithiolate) bridging two Cp2Mo fragments. Comparisons of the electrochemical properties of these complexes with those of models of each separate electrophore provide evidence for their mutual influence. All of these complexes act as very good electron donors with a first oxidation potential 430 mV lower than the tetrakis(methylthio)TTF. DFT calculations suggest that the HOMO of the neutral complex and the SOMO of the cation are delocalized across the whole TTF dithiolate ligand. The X-ray crystal structure analyses of the neutral and the mono-oxidized Cp2Mo(dithiolene)(bismethylthio)TTF complexes are consistent with the delocalized assignment of the highest occupied frontier molecular orbitals. UV-vis-NIR spectroelectrochemical investigations confirm this electronic delocalization within the TTF dithiolate ligand. PMID- 25928542 TI - Pharmacological postconditioning with lactic acid and hydrogen rich saline alleviates myocardial reperfusion injury in rats. AB - This study investigated whether pharmacological postconditioning with lactic acid and hydrogen rich saline can provide benefits similar to that of mechanical postconditioning. To our knowledge, this is the first therapeutic study to investigate the co-administration of lactic acid and hydrogen. SD rats were randomly divided into 6 groups: Sham, R/I, M-Post, Lac, Hyd, and Lac + Hyd. The left coronary artery was occluded for 45 min. Blood was withdrawn from the right atrium to measure pH. The rats were sacrificed at different time points to measure mitochondrial absorbance, infarct size, serum markers and apoptotic index. Rats in Lac + Hyd group had similar blood pH and ROS levels when compared to the M-Post group. Additionally, the infarct area was reduced to the same extent in Lac + Hyd and M-Post groups with a similar trends observed for serum markers of myocardial injury and apoptotic index. Although the level of P-ERK in Lac + Hyd group was lower, P-p38/JNK, TNFalpha, Caspase-8, mitochondrial absorbance and Cyt-c were all similar in Lac + Hyd and M-Post groups. The Lac and Hyd groups were able to partially mimic this protective role. These data suggested that pharmacological postconditioning with lactic acid and hydrogen rich saline nearly replicates the benefits of mechanical postconditioning. PMID- 25928543 TI - Specific RNA Interference in Caenorhabditis elegans by Ingested dsRNA Expressed in Bacillus subtilis. AB - In nematodes, genome-wide RNAi-screening has been widely used as a rapid and efficient method to identify genes involved in the aging processes. By far the easiest way of inducing RNA interference (RNAi) in Caenorhabditis elegans is by feeding Escherichia coli that expresses specific double stranded RNA (dsRNA) to knockdown translation of targeted mRNAs. However, it has been shown that E. coli is mildly pathogenic to C. elegans and this pathogenicity might influence aging and the accuracy of the RNAi-screening during aging may as well be affected. Here, we describe a novel system that utilizes the non-pathogenic bacterium Bacillus subtilis, to express dsRNA and therefore eliminates the effects of bacterial pathogenicity from the genetic analysis of aging. PMID- 25928544 TI - Quantitative Trait Loci for Light Sensitivity, Body Weight, Body Size, and Morphological Eye Parameters in the Bumblebee, Bombus terrestris. AB - Bumblebees such as Bombus terrestris are essential pollinators in natural and managed ecosystems. In addition, this species is intensively used in agriculture for its pollination services, for instance in tomato and pepper greenhouses. Here we performed a quantitative trait loci (QTL) analysis on B. terrestris using 136 microsatellite DNA markers to identify genes linked with 20 traits including light sensitivity, body size and mass, and eye and hind leg measures. By composite interval mapping (IM), we found 83 and 34 suggestive QTLs for 19 of the 20 traits at the linkage group wide significance levels of p = 0.05 and 0.01, respectively. Furthermore, we also found five significant QTLs at the genome wide significant level of p = 0.05. Individual QTLs accounted for 7.5-53.3% of the phenotypic variation. For 15 traits, at least one QTL was confirmed with multiple QTL model mapping. Multivariate principal components analysis confirmed 11 univariate suggestive QTLs but revealed three suggestive QTLs not identified by the individual traits. We also identified several candidate genes linked with light sensitivity, in particular the Phosrestin-1-like gene is a primary candidate for its phototransduction function. In conclusion, we believe that the suggestive and significant QTLs, and markers identified here, can be of use in marker-assisted breeding to improve selection towards light sensitive bumblebees, and thus also the pollination service of bumblebees. PMID- 25928545 TI - Antenatal Iron Supplementation Regimens for Pregnant Women in Rural Vietnam and Subsequent Haemoglobin Concentration and Anaemia among Their Infants. AB - BACKGROUND: Little evidence about the effects of antenatal iron supplementation on infant anaemia is available. The aim was to compare effects on six-month-old infants' Haemoglobin (Hb) concentration and anaemia of daily iron-folic acid (IFA), twice-weekly IFA with or without other micronutrients (MMN) and usual antenatal care in rural Vietnam. METHODS AND FINDINGS: Secondary data analysis from: a prospective population-based observational study (OS) which examined effects of antenatal psychosocial factors, anaemia and iron deficiency on infant development and health; and a three-arm cluster randomised trial (CRT) of different antenatal iron supplementation regimens. In the OS 497 women (<20 weeks gestation) from 50 randomly-selected communes participated, and in the CRT 1,258 pregnant women (<16 weeks gestation) in 104 communes were allocated randomly to trial arms. The main outcome was six-month-old infant Hb concentration. Baseline data included women's socio-demographic characteristics, reproductive health, Hb and serum ferritin. Mean differences in infant Hb and odds ratios of infant anaemia between CRT arms and OS were calculated by multivariable regression models, controlling for baseline differences and clustering, using robust standard errors. Infant anaemia prevalence was 68.6% in the OS, 47.2% daily IFA, 53.5% weekly IFA, and 50.3% MMN conditions. After adjustment, mean infant haemoglobin levels in daily IFA (mean difference = 0.95 g/dL; 95%CI 0.7-11.18); weekly IFA (0.91; 95%CI 0.69-1.12) and MMN (1.04; 95%CI 0.8-1.27) were higher than in the OS. After adjustment there were lower odds ratios of anaemia among infants in the daily IFA (OR = 0.31; 95% CI 0.22-0.43), weekly IFA (0.38; 95%CI 0.26-0.54) and MMN (0.33; 95%CI 0.23-0.48) groups than in the OS. CONCLUSIONS: Infant anaemia is a public health problem in Vietnam and other resource constrained countries. All supplementation regimens could have clinically significant benefits for Hb and reduce anaemia risk among six-month-old infants. Universal provision of free intermittent iron supplements is warranted. PMID- 25928547 TI - Institutional Tuberculosis Transmission. Controlled Trial of Upper Room Ultraviolet Air Disinfection: A Basis for New Dosing Guidelines. AB - RATIONALE: Transmission is driving the global tuberculosis epidemic, especially in congregate settings. Worldwide, natural ventilation is the most common means of air disinfection, but it is inherently unreliable and of limited use in cold climates. Upper room germicidal ultraviolet (UV) air disinfection with air mixing has been shown to be highly effective, but improved evidence-based dosing guidelines are needed. OBJECTIVES: To test the efficacy of upper room germicidal air disinfection with air mixing to reduce tuberculosis transmission under real hospital conditions, and to define the application parameters responsible as a basis for proposed new dosing guidelines. METHODS: Over an exposure period of 7 months, 90 guinea pigs breathed only untreated exhaust ward air, and another 90 guinea pigs breathed only air from the same six-bed tuberculosis ward on alternate days when upper room germicidal air disinfection was turned on throughout the ward. MEASUREMENTS AND MAIN RESULTS: The tuberculin skin test conversion rates (>6 mm) of the two chambers were compared. The hazard ratio for guinea pigs in the control chamber converting their skin test to positive was 4.9 (95% confidence interval, 2.8-8.6), with an efficacy of approximately 80%. CONCLUSIONS: Upper room germicidal UV air disinfection with air mixing was highly effective in reducing tuberculosis transmission under hospital conditions. These data support using either a total fixture output (rather than electrical or UV lamp wattage) of 15-20 mW/m(3) total room volume, or an average whole-room UV irradiance (fluence rate) of 5-7 MUW/cm(2), calculated by a lighting computer assisted design program modified for UV use. PMID- 25928549 TI - Severe Conjunctival Reaction Following Attempted Corneal Tattooing. PMID- 25928550 TI - Implementation of a clinical pathway may improve alcohol treatment outcome. AB - This article describes the design, implementation, and evaluation of a clinical pathway system in a two-cohort quasi-experimental study before and after implementation, controlling for confounders. The main outcome measures were retention in care and sensible alcohol use (defined as abstinent or drinking no more than 21 standard drinks per week). Patients with harmful alcohol use or dependence as their primary problem who were seeking psychosocial treatment at one of four alcohol clinics in Denmark participated in the study. After implementation of the clinical pathway system, which incorporated a structured intake, a referral and independent follow-up system, checklists, audit, and feedback, there was no change in length of stay, but significantly more patients had a good clinical outcome (stopped or moderated their consumption) at the end of treatment (OR = 1.9; 1.2-3.1). The study documents the feasibility of using a clinical pathway framework, incorporating a local monitoring system, checklists, audit, and feedback to enhance treatment quality and improve outcomes for alcohol use disorders. PMID- 25928551 TI - Corrections to Redox proteomics: chemical principles, methodological approaches and biological/biomedical promises. PMID- 25928553 TI - European economic crisis and health inequities: research challenges in an uncertain scenario. PMID- 25928556 TI - Urate lowering therapy to improve renal outcomes in patients with chronic kidney disease: systematic review and meta-analysis. AB - BACKGROUND: Hyperuricemia may contribute to renal injury. We do not know whether use of treatments that lower urate reduce the progression of chronic kidney disease (CKD) and cardiovascular disease. We performed a systematic review and meta-analysis of randomized controlled trials to assess the benefits and risks of treatments that lower urate in patients with stages 3-5 CKD. METHODS: We searched MEDLINE, EMBASE, CENTRAL, Web of Science and trial registers for randomized controlled trials (RCTs) without language restriction. Two authors independently screened articles, assessed risk of bias and extracted data. Data obtained included serum uric acid, serum creatinine or other estimates of glomerular filtration rate, incidence of end-stage renal disease (ESRD), systolic and diastolic blood pressure, proteinuria, cardiovascular disease and adverse events. RESULTS: From the 5497 citations screened, 19 RCTs enrolling 992 participants met our inclusion criteria. Given significant heterogeneity in duration of follow-up and study comparators, only trials greater than 3 months comparing allopurinol and inactive control were meta-analyzed using random effects models. Pooled estimate for eGFR was in favour of allopurinol with a mean difference (MD) of 3.2 ml/min/1.73 m(2), 95% CI 0.16-6.2 ml/min/1.73 m(2), p = 0.039 and this was consistent with results for serum creatinine. Statistically significant reductions in serum uric acid, systolic and diastolic blood pressure were found, favouring allopurinol. There were insufficient data on adverse events, incidence of ESRD and cardiovascular disease for analysis. CONCLUSIONS: Adequately powered RCTs are needed to establish whether treatments that lower urate have beneficial renal and cardiovascular effects. PMID- 25928557 TI - Lyme disease bacterium does not affect attraction to rodent odour in the tick vector. AB - BACKGROUND: Vector-borne pathogens experience a conflict of interest when the arthropod vector chooses a vertebrate host that is incompetent for pathogen transmission. The qualitative manipulation hypothesis suggests that vector-borne pathogens can resolve this conflict in their favour by manipulating the host choice behaviour of the arthropod vector. METHODS: European Lyme disease is a model system for studying this conflict because Ixodes ricinus is a generalist tick species that vectors Borrelia pathogens that are specialized on different classes of vertebrate hosts. Avian specialists like B. garinii cannot survive in rodent reservoir hosts and vice versa for rodent specialists like B. afzelii. The present study tested whether Borrelia genospecies influenced the attraction of field-collected I. ricinus nymphs to rodent odours. RESULTS: Nymphs were significantly attracted to questing perches that had been scented with mouse odours. However, there was no difference in questing behaviour between nymphs infected with rodent- versus bird-specialized Borrelia genospecies. CONCLUSION: Our study suggests that the tick, and not the pathogen, controls the early stages of host choice behaviour. PMID- 25928559 TI - Correction: Host glycan sugar-specific pathways in Streptococcus pneumonia: galactose as a key sugar in colonisation and infection. PMID- 25928558 TI - Relationship between alcohol-attributable disease and socioeconomic status, and the role of alcohol consumption in this relationship: a systematic review and meta-analysis. AB - BACKGROUND: Studies show that alcohol consumption appears to have a disproportionate impact on people of low socioeconomic status. Further exploration of the relationship between alcohol consumption, socioeconomic status and the development of chronic alcohol-attributable diseases is therefore important to inform the development of effective public health programmes. METHODS: We used systematic review methodology to identify published studies of the association between socioeconomic factors and mortality and morbidity for alcohol-attributable conditions. To attempt to quantify differences in the impact of alcohol consumption for each condition, stratified by SES, we (i) investigated the relationship between SES and risk of mortality or morbidity for each alcohol attributable condition, and (ii) where, feasible explored alcohol consumption as a mediating or interacting variable in this relationship. RESULTS: We identified differing relationships between a range of alcohol-attributable conditions and socioeconomic indicators. Pooled analyses showed that low, relative to high socioeconomic status, was associated with an increased risk of head and neck cancer and stroke, and in individual studies, with hypertension and liver disease. Conversely, risk of female breast cancer tended to be associated with higher socioeconomic status. These findings were attenuated but held when adjusted for a number of known risk factors and other potential confounding factors. A key finding was the lack of studies that have explored the interaction between alcohol-attributable disease, socioeconomic status and alcohol use. CONCLUSIONS: Despite some limitations to our review, we have described relationships between socioeconomic status and a range of alcohol-attributable conditions, and explored the mediating and interacting effects of alcohol consumption where feasible. However, further research is needed to better characterise the relationship between socioeconomic status alcohol consumption and alcohol-attributable disease risk so as to gain a greater understanding of the mechanisms and pathways that influence the differential risk in harm between people of low and high socioeconomic status. PMID- 25928560 TI - Pulmonary vascular permeability index and global end-diastolic volume: are the data consistent in patients with femoral venous access for transpulmonary thermodilution: a prospective observational study. AB - BACKGROUND: Transpulmonary thermodilution (TPTD) derived parameters are used to direct fluid management in ICU-patients. Extravascular lung water EVLW and its ratio to pulmonary blood volume (pulmonary vascular permeability index PVPI) have been associated with mortality. In single indicator TPTD pulmonary blood volume (PBV) is estimated to be 25% of global end-diastolic volume (GEDV). A recent study demonstrated marked overestimation of GEDV indexed to body-surface area (BSA; GEDVI) when using a femoral central venous catheter (CVC) for indicator injection due to the additional volume measured in the vena cava inferior. Therefore, a correction formula derived from femoral TPTD and biometric data has been suggested. Consequence, one of the commercially available TPTD-devices (PiCCO; Pulsion Medical Systems, Germany) requires information about CVC site. Correction of GEDVI for femoral CVC can be assumed. However, there is no data if correction also pertains to unindexed GEDV, which is used for calculation of PBV and PVPI. Therefore, we investigated, if also GEDV, PBV and PVPI are corrected by the new PiCCO-algorithm. METHODS: In this prospective study 110 triplicate TPTDs were performed within 30 hours in 11 adult ICU-patients with PiCCO-monitoring and femoral CVC. We analyzed if the femoral TPTD correction formula for GEDVI was also applied to correct GEDV. Furthermore, we compared PVPIdisplayed to PVPIcalculated which was calculated as EVLWdisplayed/(0.25*GEDVdisplayed). RESULTS: Multiplication of GEDVIdisplayed by BSA resulted in GEDVcalculated which was not significantly different to GEDVdisplayed (1459 +/- 365 mL vs. 1459 +/- 366 mL) suggesting that correction for femoral indicator injection also pertains to GEDVdisplayed. However, PVPIdisplayed was significantly lower than PVPIcalculated (1.64 +/- 0.57 vs. 2.27 +/- 0.72; p < 0.001). In addition to a bias of -0.64 +/- 0.22 there was a percentage error of 22%. Application of the correction formula suggested for GEDVI to PVPIdisplayed reduced the bias of PVPIdisplayed compared to EVLW/PBV from -0.64 +/- 0.22 to -0.10 +/- 0.05 and the percentage error from 22% to 4%. CONCLUSIONS: Correction for femoral CVC in the PiCCO-device pertains to both GEDVIdisplayed and GEDVdisplayed, but not to PVPIdisplayed. To provide consistent information, PVPI should be calculated based on GEDVcorrected in case of femoral CVC. PMID- 25928561 TI - Assessment of physical activity in older Belgian adults: validity and reliability of an adapted interview version of the long International Physical Activity Questionnaire (IPAQ-L). AB - BACKGROUND: Adequate monitoring of older adults' physical activity (PA) is essential to develop effective health promotion programs. The present study examined criterion validity and test-retest reliability of the long International Physical Activity Questionnaire (IPAQ-L), adapted for Belgian, community-dwelling older adults (65 y and older). METHODS: Participants (n = 434) completed the last seven days version of IPAQ-L, modified for the Belgian population of community dwelling older adults. This elderly-adapted version of IPAQ-L combined vigorous and moderate activities, and questions on gait speed and recreational cycling were added. Furthermore, participants wore an ActiGraph GT3X(+) accelerometer for at least five days. Criterion validity was determined by comparing self-reported weekly minutes of moderate-to-vigorous physical activity (MVPA) and weekly minutes of total PA with accelerometer data, defined by two different cut points (Freedson vs. Copeland). To examine test-retest reliability, a subsample of 29 participants completed IPAQ-L for a second time within a ten day interval. RESULTS: IPAQ-L showed moderate criterion validity for measuring weekly minutes of MVPA and total PA (Spearman's rho range 0.33-0.40). However, plots on agreement between self-reported and accelerometer PA showed a systematic over reporting of IPAQ-L for MVPA. In contrast, plots indicated that IPAQ-L under estimated levels of total PA, however, this under-estimation of total PA was substantially lower than the observed over-reporting of MVPA. Test-retest reliability was moderate-to-good for work-related PA, domestic PA, MVPA and total PA (ICC range 0.52-0.81), but poorer for transportation and recreational PA (ICC 0.44 and 0.43, respectively). CONCLUSIONS: Criterion validity results suggest that IPAQ-L is more valid to measure older adults' weekly minutes of total PA than weekly MVPA minutes. Moreover, results might imply that content validity of IPAQ-L can be improved if specific light-intensity PA items are incorporated into IPAQ-L. Test-retest reliability of IPAQ-L was moderate to good, except for weekly minutes of transportation and recreational PA, probably due to week-to-week variability of these behaviors. PMID- 25928562 TI - Effects of an adolescent sexual and reproductive health intervention on health service usage by young people in northern Ghana: a community-randomised trial. AB - BACKGROUND: While many Ghanaian adolescents encounter sexual and reproductive health problems, their usage of services remains low. A social learning intervention, incorporating environment, motivation, education, and self-efficacy to change behaviour, was implemented in a low-income district of northern Ghana to increase adolescent services usage. This study aimed to assess the impact of this intervention on usage of sexual and reproductive health services by young people. METHODS: Twenty-six communities were randomly allocated to (i) an intervention consisting of school-based curriculum, out-of-school outreach, community mobilisation, and health-worker training in youth-friendly health services, or (ii) comparison consisting of community mobilisation and youth friendly health services training only. Outcome measures were usage of sexually transmitted infections (STIs) management, HIV counselling and testing, antenatal care or perinatal services in the past year and reported service satisfaction. Data was collected, at baseline and three years after, from a cohort of 2,664 adolescents aged 15-17 at baseline. RESULTS: Exposure was associated with over twice the odds of using STI services (AOR 2.47; 95%CI 1.78-3.42), 89% greater odds of using perinatal services (AOR 1.89; 95%CI 1.37-2.60) and 56% greater odds of using antenatal services (AOR 1.56; 95%CI 1.10-2.20) among participants in intervention versus comparison communities, after adjustment for baseline differences. CONCLUSIONS: The addition of targeted school-based and outreach activities increased service usage by young people more than community mobilisation and training providers in youth-friendly services provision alone. PMID- 25928565 TI - Hepatic steatosis in HIV-HCV coinfected patients receiving antiretroviral therapy is associated with HCV-related factors but not antiretrovirals. AB - In this paper we evaluate the economic gains of a joint deployment of femtocells and macrocells for the provision of Long Term Evolution (LTE) mobile broadband services in urban environments. Frequency bands of 2.6 GHz and 900 MHz are analyzed and different parameters related to the business model are considered for a 30% market share operator. Results show important benefits for the base case where the service is offered to fixed-broadband clients, up to 75%, for small bandwidths. It results feasible to attribute subscriber loop costs to the radio access network (RAN) costs, so that the service could be offered to non fixed-broadband clients, in both cases of closed access and open access femtocells. However, initial savings result notably reduced, up to 50% less than in the base case if closed access is adopted and up to 13% less for open access. Site reuse reduces the initial savings only in 3%. PMID- 25928563 TI - Transcriptome changes in rice (Oryza sativa L.) in response to high night temperature stress at the early milky stage. AB - BACKGROUND: Rice yield and quality are adversely affected by high temperatures, especially at night; high nighttime temperatures are more harmful to grain weight than high daytime temperatures. Unfortunately, global temperatures are consistently increasing at an alarming rate and the minimum nighttime temperature has increased three times as much as the corresponding maximum daytime temperature over the past few decades. RESULTS: We analyzed the transcriptome profiles for rice grain from heat-tolerant and -sensitive lines in response to high night temperatures at the early milky stage using the Illumina Sequencing method. The analysis results for the sequencing data indicated that 35 transcripts showed different expressions between heat-tolerant and -sensitive rice, and RT-qPCR analyses confirmed the expression patterns of selected transcripts. Functional analysis of the differentially expressed transcripts indicated that 21 genes have functional annotation and their functions are mainly involved in oxidation-reduction (6 genes), metabolic (7 genes), transport (4 genes), transcript regulation (2 genes), defense response (1 gene) and photosynthetic (1 gene) processes. Based on the functional annotation of the differentially expressed genes, the possible process that regulates these differentially expressed transcripts in rice grain responding to high night temperature stress at the early milky stage was further analyzed. This analysis indicated that high night temperature stress disrupts electron transport in the mitochondria, which leads to changes in the concentration of hydrogen ions in the mitochondrial and cellular matrix and influences the activity of enzymes involved in TCA and its secondary metabolism in plant cells. CONCLUSIONS: Using Illumina sequencing technology, the differences between the transcriptomes of heat tolerant and -sensitive rice lines in response to high night temperature stress at the early milky stage was described here for the first time. The candidate transcripts may provide genetic resources that may be useful in the improvement of heat-tolerant characters of rice. The model proposed here is based on differences in expression and transcription between two rice lines. In addition, the model may support future studies on the molecular mechanisms underlying plant responses to high night temperatures. PMID- 25928566 TI - Activated microglia/macrophage whey acidic protein (AMWAP) inhibits NFkappaB signaling and induces a neuroprotective phenotype in microglia. AB - BACKGROUND: Microglia reactivity is a hallmark of neurodegenerative diseases. We have previously identified activated microglia/macrophage whey acidic protein (AMWAP) as a counter-regulator of pro-inflammatory response. Here, we studied its mechanisms of action with a focus on toll-like receptor (TLR) and nuclear factor kappaB (NFkappaB) signaling. METHODS: Recombinant AMWAP was produced in Escherichia coli and HEK293 EBNA cells and purified by affinity chromatography. AMWAP uptake was identified by fluorescent labeling, and pro-inflammatory microglia markers were measured by qRT-PCR after stimulation with TLR ligands. NFkappaB pathway proteins were assessed by immunocytochemistry, Western blot, and immunoprecipitation. A 20S proteasome activity assay was used to investigate the anti-peptidase activity of AMWAP. Microglial neurotoxicity was estimated by nitrite measurement and quantification of caspase 3/7 levels in 661W photoreceptors cultured in the presence of microglia-conditioned medium. Microglial proliferation was investigated using flow cytometry, and their phagocytosis was monitored by the uptake of 661W photoreceptor debris. RESULTS: AMWAP was secreted from lipopolysaccharide (LPS)-activated microglia and recombinant AMWAP reduced gene transcription of IL6, iNOS, CCL2, CASP11, and TNFalpha in BV-2 microglia treated with LPS as TLR4 ligand. This effect was replicated with murine embryonic stem cell-derived microglia (ESdM) and primary brain microglia. AMWAP also diminished pro-inflammatory markers in microglia activated with the TLR2 ligand zymosan but had no effects on IL6, iNOS, and CCL2 transcription in cells treated with CpG oligodeoxynucleotides as TLR9 ligand. Microglial uptake of AMWAP effectively inhibited TLR4-dependent NFkappaB activation by preventing IRAK-1 and IkappaBalpha proteolysis. No inhibition of IkappaBalpha phosphorylation or ubiquitination and no influence on overall 20S proteasome activity were observed. Functionally, both microglial nitric oxide (NO) secretion and 661W photoreceptor apoptosis were significantly reduced after AMWAP treatment. AMWAP promoted the filopodia formation of microglia and increased the phagocytic uptake of apoptotic 661W photoreceptor cells. CONCLUSIONS: AMWAP is secreted from reactive microglia and acts in a paracrine fashion to counter-balance TLR2/TLR4-induced reactivity through NFkappaB inhibition. AMWAP also induces a neuroprotective microglial phenotype with reduced neurotoxicity and increased phagocytosis. We therefore hypothesize that anti-inflammatory whey acidic proteins could have a therapeutic potential in neurodegenerative diseases of the brain and the retina. PMID- 25928569 TI - Application of next-generation sequencing technology to study genetic diversity and identify unique SNP markers in bread wheat from Kazakhstan. AB - BACKGROUND: New SNP marker platforms offer the opportunity to investigate the relationships between wheat cultivars from different regions and assess the mechanism and processes that have led to adaptation to particular production environments. Wheat breeding has a long history in Kazakhstan and the aim of this study was to explore the relationship between key varieties from Kazakhstan and germplasm from breeding programs for other regions. RESULTS: The study revealed 5,898 polymorphic markers amongst ten cultivars, of which 2,730 were mapped in the consensus genetic map. Mapped SNP markers were distributed almost equally across the A and B genomes, with between 279 and 484 markers assigned to each chromosome. Marker coverage was approximately 10-fold lower in the D genome. There were 863 SNP markers identified as unique to specific cultivars, and clusters of these markers (regions containing more than three closely mapped unique SNPs) showed specific patterns on the consensus genetic map for each cultivar. Significant intra-varietal genetic polymorphism was identified in three cultivars (Tzelinnaya 3C, Kazakhstanskaya rannespelaya and Kazakhstanskaya 15). Phylogenetic analysis based on inter-varietal polymorphism showed that the very old cultivar Erythrospermum 841 was the most genetically distinct from the other nine cultivars from Kazakhstan, falling in a clade together with the American cultivar Sonora and genotypes from Central and South Asia. The modern cultivar Kazakhstanskaya 19 also fell into a separate clade, together with the American cultivar Thatcher. The remaining eight cultivars shared a single sub-clade but were categorised into four clusters. CONCLUSION: The accumulated data for SNP marker polymorphisms amongst bread wheat genotypes from Kazakhstan may be used for studying genetic diversity in bread wheat, with potential application for marker-assisted selection and the preparation of a set of genotype-specific markers. PMID- 25928572 TI - Effect of the beta-3 adrenergic receptor Trp64Arg and uncoupling protein 1-3826 A>G genotypes on lipid and apolipoprotein levels in overweight/obese and non obese Chinese subjects. AB - BACKGROUND: The beta-3 adrenergic receptor (beta3-AR) Trp64Arg and uncoupling protein 1 (UCP1) -3826 A>G polymorphisms have been reported to be associated with obesity and/or lipid metabolism in some populations. This study examined the possible association of the beta3-AR and UCP1 polymorphisms with overweight/obesity or lipid variation in a Southwest Chinese population. METHODS: A total of 418 Han Chinese (249 overweight/obese and 169 healthy control subjects) in the Chengdu area were studied using PCR-RFLP analysis. Total serum cholesterol (TC) and triglycerides (TGs) were measured using an enzymatic method. High density lipoprotein cholesterol (HDL-C) was determined after sodium phosphotungstate/magnesium chloride precipitation of low-density lipoproteins by polyvinyl sulfate. Serum apolipoproteins were quantified by radial immunodiffusion. RESULTS: The genotype and allele frequencies of the beta3-AR Trp64Arg and UCP1 -3826 A>G polymorphisms in overweight/obese subjects exhibited no significant differences compared to the controls. However, subjects carrying the beta3-AR TrpTrp genotype and UCP1 AG genotype had higher TG levels than those carrying the Arg allele and AA genotype, respectively (P<0.05), while controls carrying the beta3-AR Arg allele had significantly higher TC and apo AII concentrations than those carrying the TrpTrp genotype (P<0.05). Additionally, subjects carrying the UCP1 AG genotype exhibited elevated apo C-II and apo C-III levels compared to those carrying the AA genotype (P<0.05). We were unable to find an association of the UCP1 and beta3-AR polymorphisms with low HDL cholesterolemia in the overweight/obese subjects. CONCLUSIONS: The present study provides evidence that the beta3-AR Trp64Arg and UCP1 -3826 A>G polymorphisms are associated with TG levels in overweight/obese Chinese subjects and that the two polymorphisms are also associated with certain lipid and apolipoprotein variations, depending on BMI. However, these polymorphisms are not associated with overweight/obesity or low HDL-cholesterolemia in a Chinese population from the Chengdu area. PMID- 25928579 TI - Nuclear matrix revisited? PMID- 25928577 TI - Amino acid substitutions in the neuraminidase protein of an H9N2 avian influenza virus affect its airborne transmission in chickens. AB - Cases of H9N2 avian influenza virus (AIV) in poultry are increasing throughout many Eurasian countries, and co-infections with other pathogens have resulted in high morbidity and mortality in poultry. Few studies have investigated the genetic factors of virus airborne transmission which determine the scope of this epidemic. In this study, we used specific-pathogen-free chickens housed in isolators to investigate the airborne transmissibility of five recombinant H9N2 AIV rescued by reverse genetic technology. The results show that airborne transmission of A/Chicken/Shandong/01/2008 (SD01) virus was related to the neuraminidase (NA) gene, and four amino acid mutations (D368E, S370L, E313K and G381D) within the head region of the SD01 NA, reduced virus replication in the respiratory tract of chickens, reduced virus NA activity, and resulted in a loss of airborne transmission ability in chickens. Similarly, reverse mutations of these four amino acids in the NA protein of r01/NASS virus, conferred an airborne transmission ability to the recombinant virus. We conclude that these four NA residues may be significant genetic markers for evaluating potential disease outbreak of H9N2 AIV, and propose that immediate attention should be paid to the airborne transmission of this virus. PMID- 25928580 TI - Explaining educational differences in sickness absence: a population-based follow up study. AB - OBJECTS: There is a marked socioeconomic gradient in sickness absences, but the causes of this gradient are poorly understood. This study examined the role of health and work-related factors as determinants of educational differences in long-term sickness absence in an 8-year follow-up. METHODS: The study comprised a population-based sample of 5835 Finns aged 30-64 years (participation 89%, N=3946) in a register-based 8-year follow-up. This is a novel method to predict the population average of sickness absence days per working year (DWY) based on the expected outcome values using Poisson and gamma regression models. RESULTS: The difference in the DWY between the lowest and highest educational level was clear among both men (3.2 days/year versus 8.0 days/year) and women (women 4.4 days/year versus 10.1 days/year). Adjusting for physical working conditions, health status and health behavior, and obesity attenuated the differences. Psychosocial working conditions had only a minor effect on the association. After adjusting for health and work-related factors, the difference attenuated by 1.8 days and 2.6 days among men and women, respectively. CONCLUSIONS: Our results suggest that improvements in physical working conditions and reducing smoking, particularly among employees with a low level of education, may markedly reduce educational differences in sickness absence. PMID- 25928581 TI - Cryptosporidiosis surveillance -- United States, 2011-2012. AB - PROBLEM/CONDITION: Cryptosporidiosis is a nationally notifiable gastrointestinal illness caused by extremely chlorine-tolerant protozoa of the genus Cryptosporidium. REPORTING PERIOD: 2011-2012. DESCRIPTION OF SYSTEM: Fifty state and two metropolitan public health agencies voluntarily report cases of cryptosporidiosis through CDC's National Notifiable Diseases Surveillance System. RESULTS: For 2011, a total of 9,313 cryptosporidiosis cases (confirmed and nonconfirmed) were reported; for 2012, a total of 8,008 cases were reported; 5.8% and 5.3%, respectively, were associated with a detected outbreak. The rates of reported nonconfirmed cases were 1.0 and 0.9 per 100,000 population in 2011 and 2012, respectively, compared with an average of 0.0 during 1995-2004, and 0.3 during 2005-2010. The highest overall reporting rates were observed in the Midwest; 10 states reported >3.5 cases per 100,000 population in 2011 and in 2012. During 2011-2012, reported cases were highest among children aged 1-4 years (6.6 per 100,000 population), followed for the first time by elderly adults aged >=80 years (3.4), and 75-79 years (3.3). Overall, cryptosporidiosis rates were higher among females than males during both years. For specific age groups, rates were higher among males than females aged <15 years and higher among females than males aged >=15 years. Cryptosporidiosis symptom onset increased 4.4 fold during late summer. INTERPRETATION: Cryptosporidiosis incidence rates remain elevated nationally, and rates of nonconfirmed cases have increased. Rates remain highest in young children, although rates among elderly adults are increasing. Transmission of Cryptosporidium occurs throughout the United States, with increased reporting occurring in Midwestern states. Seasonal onset peaks coincide with the summer recreational water season and might reflect increased use of communal swimming venues. PUBLIC HEALTH ACTION: Future research is needed to address the evolving epidemiology of cryptosporidiosis cases, with a specific focus on the increase in nonconfirmed cases and increasing incidence rates among elderly adults. National systematic genotyping and subtyping of Cryptosporidium isolates could also help elucidate Cryptosporidium transmission and thus cryptosporidiosis epidemiology in the United States. PMID- 25928582 TI - Giardiasis surveillance -- United States, 2011-2012. AB - PROBLEM/CONDITION: Giardiasis is a nationally notifiable gastrointestinal illness caused by the protozoan parasite Giardia intestinalis. REPORTING PERIOD: 2011 2012. DESCRIPTION OF SYSTEM: Forty-four states, the District of Columbia, New York City, the Commonwealth of Puerto Rico, and Guam voluntarily reported cases of giardiasis to CDC through the National Notifiable Diseases Surveillance System (NNDSS). RESULTS: For 2011, a total of 16,868 giardiasis cases (98.8% confirmed and 1.2% nonconfirmed) were reported; for 2012, a total of 15,223 cases (98.8% confirmed and 1.3% nonconfirmed) were reported. In 2011 and 2012, 1.5% and 1.3% of cases, respectively, were associated with a detected outbreak. The incidence rates of all reported cases were 6.4 per 100,000 population in 2011 and 5.8 per 100,000 population in 2012. This represents a slight decline from the relatively steady rates observed during 2005-2010 (range: 7.1-7.9 cases per 100,000 population). In both 2011 and 2012, cases were most frequently reported in children aged 1-4 years, followed by those aged 5-9 years and adults aged 45-49 years. Incidence of giardiasis was highest in Northwest states. Peak onset of illness occurred annually during early summer through early fall. INTERPRETATION: For the first time since 2002, giardiasis rates appear to be decreasing. Possible reasons for the decrease in rates during 2011-2012 could include changes in transmission patterns, a recent change in surveillance case definition, increased uptake of strategies to reduce waterborne transmission, or a combination of these factors. Transmission of giardiasis occurs throughout the United States, with more frequent diagnosis or reporting occurring in northern states. Geographical differences might suggest actual regional differences in giardiasis transmission or variation in surveillance capacity across states. Six states did not report giardiasis cases in 2011-2012, representing the largest number of nonreporting states since giardiasis became nationally notifiable in 2002. Giardiasis is reported more frequently in young children, which might reflect increased contact with contaminated water or ill persons, or a lack of immunity. PUBLIC HEALTH ACTION: Educational efforts to decrease exposure to unsafe drinking and recreational water and prevent person-to-person transmission have the potential to reduce giardiasis transmission. The continual decrease in jurisdictions opting to report giardiasis cases could negatively impact the ability to interpret national surveillance data; thus, further investigation is needed to identify barriers to and facilitators of giardiasis case reporting. Existing state and local public health infrastructure supported through CDC (e.g., Epidemiology and Laboratory Capacity grants and CDC-sponsored Council of State and Territorial Epidemiologists Applied Epidemiology Fellows) could provide resources to enhance understanding of giardiasis epidemiology. PMID- 25928584 TI - Stereoselective Syntheses of the Conjugation-Ready, Downstream Disaccharide and Phosphorylated Upstream, Branched Trisaccharide Fragments of the O-PS of Vibrio cholerae O139. AB - N-Bromosuccinimide-mediated 4,6-O-benzylidene ring opening in 8-azido-3,6 dioxaoctyl 4,6-O-benzylidene-2-deoxy-2-trichloroacetamido-beta-D-glucopyranoside afforded the corresponding 4-O-benzoyl-6-bromo-6-deoxy analogue, which was coupled with 3,4,6-tri-O-acetyl-2-O-benzyl-alpha-D-galactopyranosyl chloride to give the 1,2-cis alpha-linked disaccharide as the major product. Conventional hydroxyl group manipulation in the latter and products of further conversions gave the desired, functionalized disaccharide alpha-D-GalpA-(1->3)-beta-D QuipNAc. The rare, foregoing sequence forms the downstream end in the O-specific polysaccharide of both Vibrio cholerae O22 and O139. Halide-assisted glycosylation at 4(I)-OH in 8-azido-3,6-dioxaoctyl 6-O-benzyl-2-deoxy-3-O (2,3,4,6-tetra-O-acetyl-beta-D-galactopyranosyl)-2-trichloroacetamido-beta-D glucopyranoside, obtained by regioselective reductive opening of the acetal ring in the parent 4(I),6(I)-O-benzylidene derivative, with 2,4-di-O-benzyl-alpha colitosyl bromide, gave exclusively the alpha-linked trisaccharide. The latter was sequentially deacetylated and selectively benzylated to give 8-azido-3,6 dioxaoctyl 2,4-di-O-benzyl-3,6-dideoxy-alpha-L-xylo-hexopyranosyl-(1->4)-[3-O benzyl-beta-D-galactopyranosyl-(1->3)]-6-O-benzyl-2-deoxy-2-trichloroacetamido beta-D-glucopyranoside. Subsequent selective phosphorylation of the triol, thus obtained, with 2,2,2-trichloroethyl phosphorodichloridate afforded isomeric (R,S) (P)-4(II),6(II)-cyclic phosphates, which were both obtained in crystalline form and fully characterized. Each of the latter was globally deprotected by catalytic (Pd/C) hydrogenation/hydrogenolysis to give the desired, amino-functionalized, spacer-equipped, phosphorylated upstream trisaccharide fragment of the O-PS of V. cholerae O139. PMID- 25928583 TI - A dynein independent role of Tctex-1 at the kinetochore. AB - Dynein light chains are accessory subunits of the cytoplasmic dynein complex, a minus-end directed microtubule motor. Here, we demonstrate that the dynein light chain Tctex-1 associates with unattached kinetochores and is essential for accurate chromosome segregation. Tctex-1 knockdown in cells does not affect the localization and function of dynein at the kinetochore, but produces a prolonged mitotic arrest with a few misaligned chromosomes, which are subsequently missegregated during anaphase. This function is independent of Tctex-1's association with dynein. The kinetochore localization of Tctex-1 is independent of the ZW10-dynein pathway, but requires the Ndc80 complex. Thus, our findings reveal a dynein independent role of Tctex-1 at the kinetochore to enhance the stability of kinetochore-microtubule attachment. PMID- 25928585 TI - Low-dose carvedilol protects against acute septic renal injury in rats during the early and late phases. AB - Recent findings from septic acute renal injury studies have implicated the mitochondrion as an important factor in kidney injury, and that increased sympathetic nerve activity may contribute to the induction of organ failure. This study investigated the impact of a nondepressor dose of carvedilol, which is a beta-adrenoreceptor antagonist with antioxidant activity, on septic renal injury induced in rats with cecal ligation and puncture (CLP). Three groups of rats were studied. The first group was the sham-operated control. The other 2 groups of rats underwent CLP, and were administered either the vehicle or carvedilol (2.0 mg/kg body mass, by intraperitoneal (i.p.) injection, daily for 2 days as well as 30 min prior to CLP). Kidney function, inflammatory parameters, mitochondrial function, and renal perfusion pressure (RPP) were investigated at 6 and 18 h after CLP. Carvedilol did not significantly induce hypotension, and it significantly improved RPP and renal dysfunction induced with CLP, together with significant reductions in serum levels of interleukin 6 and tumor necrosis factor alpha. Septic kidney injury mediated increased levels of malondialdehyde and protein carbonyls. Carvedilol also attenuated the decrease in kidney mitochondrial glutathione and nicotinamide adenine dinucleotide phosphate dehydrogenase. Further, intracellular renal edema and inflammation induced with CLP were reduced with carvedilol. These findings suggest renoprotective effects of carvedilol in sepsis. PMID- 25928587 TI - Direct Low-Temperature Growth of Single-Crystalline Anatase TiO2 Nanorod Arrays on Transparent Conducting Oxide Substrates for Use in PbS Quantum-Dot Solar Cells. AB - We report on the direct growth of anatase TiO2 nanorod arrays (A-NRs) on transparent conducting oxide (TCO) substrates that can be directly applied to various photovoltaic devices via a seed layer mediated epitaxial growth using a facile low-temperature hydrothermal method. We found that the crystallinity of the seed layer and the addition of an amine functional group play crucial roles in the A-NR growth process. The A-NRs exhibit a pure anatase phase with a high crystallinity and preferred growth orientation in the [001] direction. Importantly, for depleted heterojunction solar cells (TiO2/PbS), the A-NRs improve both electron transport and injection properties, thereby largely increasing the short-circuit current density and doubling their efficiency compared to TiO2 nanoparticle-based solar cells. PMID- 25928588 TI - Noble-Gas-Inserted Fluoro(sulphido)boron (FNgBS, Ng = Ar, Kr, and Xe): A Theoretical Prediction. AB - The possibility of the existence of a new series of neutral noble gas compound, FNgBS (where Ng = Ar, Kr, Xe), is explored theoretically through the insertion of a Ng atom into the fluoroborosulfide molecule (FBS). Second-order Moller-Plesset perturbation theory, density functional theory, and coupled cluster theory based methods have been employed to predict the structure, stability, harmonic vibrational frequencies, and charge distribution of FNgBS molecules. Through energetics study, it has been found that the molecules could dissociate into global minima products (Ng + FBS) on the respective singlet potential energy surface via a unimolecular dissociation channel; however, the sufficiently large activation energy barriers provide enough kinetic stability to the predicted molecules, which, in turn, prevent them from dissociating into the global minima products. Moreover, the FNgBS species are thermodynamically stable, owing to very high positive energies with respect to other two two-body dissociation channels, leading to FNg + BS and F(-) + NgBS(+), and two three-body dissociation channels, corresponding to the dissociation into F + Ng + BS and F(-) + Ng + BS(+). Furthermore, the Mulliken and NBO charge analysis together with the AIM results reveal that the Ng-B bond is more of covalent in nature, whereas the F-Ng bond is predominantly ionic in character. Thus, these compounds can be better represented as F(-)[NgBS](+). This fact is also supported by the detail analysis of bond length, bond dissociation energy, and stretching force constant values. All of the calculated results reported in this work clearly indicate that it might be possible to prepare and characterize the FNgBS molecules in cryogenic environment through matrix isolation technique by using a mixture of OCS/BF3 in the presence of large quantity of noble gas under suitable experimental conditions. PMID- 25928589 TI - ContextMap 2: fast and accurate context-based RNA-seq mapping. AB - BACKGROUND: Mapping of short sequencing reads is a crucial step in the analysis of RNA sequencing (RNA-seq) data. ContextMap is an RNA-seq mapping algorithm that uses a context-based approach to identify the best alignment for each read and allows parallel mapping against several reference genomes. RESULTS: In this article, we present ContextMap 2, a new and improved version of ContextMap. Its key novel features are: (i) a plug-in structure that allows easily integrating novel short read alignment programs with improved accuracy and runtime; (ii) context-based identification of insertions and deletions (indels); (iii) mapping of reads spanning an arbitrary number of exons and indels. ContextMap 2 using Bowtie, Bowtie 2 or BWA was evaluated on both simulated and real-life data from the recently published RGASP study. CONCLUSIONS: We show that ContextMap 2 generally combines similar or higher recall compared to other state-of-the-art approaches with significantly higher precision in read placement and junction and indel prediction. Furthermore, runtime was significantly lower than for the best competing approaches. ContextMap 2 is freely available at http://www.bio.ifi.lmu.de/ContextMap . PMID- 25928590 TI - Detection of Individual Proteins Bound along DNA Using Solid-State Nanopores. AB - DNA in cells is heavily covered with all types of proteins that regulate its genetic activity. Detection of DNA-bound proteins is a challenge that is well suited to solid-state nanopores as they provide a linear readout of the DNA and DNA-protein volume in the pore constriction along the entire length of a molecule. Here, we demonstrate that we can realize the detection of even individual DNA-bound proteins at the single-DNA-molecule level using solid-state nanopores. We introduce and use a new model system of anti-DNA antibodies bound to lambda phage DNA. This system provides several advantages since the antibodies bind individually, tolerate high salt concentrations, and will, because of their positive charge, not translocate through the pore unless bound to the DNA. Translocation of DNA-antibody samples reveals the presence of short 12 MUs current spikes within the DNA traces, with amplitudes that are about 4.5 times larger than that of dsDNA, which are associated with individual antibodies. We conclude that transient interactions between the pore and the antibodies are the primary mechanism by which bound antibodies are observed. This work provides a proof-of-concept for how nanopores could be used for future sensing applications. PMID- 25928593 TI - Editorial. PMID- 25928594 TI - Tribute to edward j. Frischholz (1956-2014). PMID- 25928592 TI - Living with type 1 diabetes is challenging for Zambian adolescents: qualitative data on stress, coping with stress and quality of care and life. AB - BACKGROUND: Psychosocial problems are common in patients with diabetes. However, data on psychosocial issues affecting patients with diabetes in Zambia are scarce. The present study explored sources of stress, stress coping strategies, stigma and perceived quality of life and care as experienced by adolescents living with Type 1 Diabetes in Zambia. METHODS: Semi-structured interviews were carried out. Three groups of participants involving adolescents with Type 1 Diabetes (n = 10), caregivers (n = 8) and health practitioners (n = 4) were interviewed. Transcripts were analyzed using a thematic approach. RESULTS: Stress was commonly reported by adolescents mainly stemming from social, psychological and physical sources. To deal with stress, adolescents often employed different coping strategies such as adapting, accepting and avoiding among others. Both internal factors (those relating to the patients themselves) and external factors (those related to the context of the patients') influenced the patients' quality of health care. In addition, low quality of life was an issue among adolescents and their families. Poor diet, low socioeconomic status and lack of medicine were factors affecting quality of health care. CONCLUSION: Stress was an issue affecting adolescents; the coping strategies employed were sometimes maladaptive such as avoiding injecting themselves to escape stress. Several aspects of quality of life were suboptimal in both adolescents and their families, such as stigmatization, short life expectancy, low socioeconomic status and poor social participation. Findings show that there is an urgent need for a strong response from all stakeholders (governments, patients, organizations and companies) to improve diabetes care and living conditions for young people with type 1 diabetes living in Zambia. PMID- 25928595 TI - Construct Validity of the Dissociative Experiences Scale: II. Its Relationship to Hypnotizability. AB - Undergraduates (n = 311) who volunteered to participate in an experiment on "Hypnotizability and Personality" filled out several personality questionnaires (including the Dissociative Experiences Scale; DES), were administered the Harvard Group Scale of Hypnotic Susceptibility (HGSHS), and completed a self rating of hypnotizability. The DES overall score correlated significantly with the HGSHS summary score (r(309) = .12, p < .05, two-tailed) and with subject's self-rating of hypnotizability (r(309) = .13, p < .05, two-tailed). The magnitude of these correlations was similar to that observed in a previous study (.14 & .18) and is also similar in magnitude to the correlations typically observed between the HGSHS and the Tellegen Absorption Scale. The potential clinical implications of these findings are discussed. PMID- 25928596 TI - Suggested posthypnotic amnesia in psychiatric patients and normals. AB - The present study examined both quantitative and qualitative hypnotizability differences among four psychiatric patient groups (dissociative disorder (n = 17), schizophrenic (n = 13), mood disorder (n = 14), and anxiety disorder (n = 14) patients), and normals (college students (n = 63)). Dissociative disorder patients earned significantly higher corrected total scores on the Stanford Hypnotic Susceptibility Scale, Form C (mean = 7.94), than all other groups. Likewise, dissociative disorder patients initially recalled significantly fewer items when the posthypnotic amnesia suggestion was in effect (mean = .41) and reversed significantly more items when the suggestion was canceled (mean = 3.82) than all other groups. In contrast, schizophrenic patients recalled significantly fewer items when the amnesia suggestion was in effect (mean = 1.85) and reversed significantly fewer items when it was canceled (mean = .77) than the remaining groups. This qualitative difference between schizophrenic patients and the other groups on the suggested posthypnotic amnesia item was observed even though there were no significant quantitative differences between groups in overall hypnotic responsivity. PMID- 25928597 TI - The hypnotic induction profile and absorption. AB - This study examined the relationship between scores on the Hypnotic Induction Profile (HIP) and the trait of absorption in three different clinical groups: Smokers (n = 226), Phobics (n = 95), and patients with Chronic Pain (n = 65). Two hypotheses were investigated. The first predicted that both the Eye-Roll sign (ERS) and Induction Score (IND) of the HIP would correlate similarly (r = .30) with scores on the Tellegen Absorption Scale (TAS), as has been previously reported with other measures of hypnotic responsivity in student samples. The second was that using a combination of both ERS and IND scores to predict TAS scores would result in a significant increase in forecasting accuracy over using either HIP measure alone. Both hypotheses were supported in all three clinical groups. Correlations between HIP and Absorption scores ranged from .33 to .53. Clinical and theoretical implications of the findings are discussed. PMID- 25928598 TI - The relationship between the hypnotic induction profile and the stanford hypnotic susceptibility scale, form C: revisited. AB - Hilgard's comment raises some important issues, although many of these have little to do with the primary purpose of the study under discussion. This purpose was to objectively examine the relationship between three conceptually and operationally different procedures for measuring hypnotic responsivity. Hilgard's concern over the magnitude of the correlation between the HIP and SHSS:C is unfounded. A cross-validated correlation of .66 was found between the HIP and SHSS:C in a new sample of 44 student volunteers. This demonstrates that the HIP correlates about the same with SHSS:C as the Harvard Group Scale of Hypnotic Susceptibility. Hilgard's conception of the Eye-Roll (ER) hypothesis is clarified. Evidence which utilizes all cases in the correlational analysis is presented in support of the ER hypothesis. Happily, we all agree on a new methodology which will be definitive in testing the validity of the ER hypothesis. PMID- 25928599 TI - The future of professional hypnosis: comment on kirsch, mazzoni, and montgomery. AB - I believe the paper by Kirsch, Mazzoni, and Montgomery (this issue) should surprise about 95% of ASCH members (maybe only 93% of SCEH members) because the three facts espoused in their paper speciously seem to be 100% true. To paraphrase from their abstract: 1) nothing that can be produced by hypnotic induction plus suggestion cannot also be produced by suggestion alone; 2) administration of a hypnotic induction does not produce a meaningful increase in response to suggestion relative to suggestion alone; and 3) responsivity to suggestions are highly correlated to responsivity on the same measure when preceded by a hypnotic induction ceremony. In order to persuade that these propositions are true, several objections to them must be addressed. However, just because one's facts are true does not mean that one's interpretation of the facts and their interrelationships are also true. The ramifications of the above facts and their interrelationships for the future of professional hypnosis (experimental, clinical and forensic) are identified and discussed. PMID- 25928600 TI - Medicare procedure code 90880 (medical hypnotherapy): use the code (not the word). PMID- 25928601 TI - Different perspectives on informed consent and clinical hypnosis. PMID- 25928602 TI - Hypnotic responsivity and the treatment of flying phobia. AB - Systematic follow-up data are reported for 178 consecutive flying phobia patients treated with a single 45-minute session involving hypnosis and a problem restructuring strategy. One hundred fifty-eight (89%) of the patients completed follow-up questionnaires between six months and ten and one half years after treatment. Results showed that hypnotizable patients were over two and one half times more likely to report some positive treatment impact than those who were found to be nonhypnotizable on the Hypnotic Induction Profile. In addition, the patients' previous experiences with psychotherapy were found to be significantly associated with treatment outcome. The clinical implications of these findings are discussed. PMID- 25928603 TI - Hypnosis, hypnotizability, and placebo. AB - Dr. Raz's speculations about the relation between placebo responsivity and hypnotizability are critically examined. While there is no generally accepted theoretical definition of hypnosis, there is a general consensus that hypnotizability can be reliably measured. In contrast, there seems to be a general consensus about a theoretical definition of placebo (including placebo effect, placebo response, and nocebo). There is no widely accepted measure of individual differences in placebo responsivity. Various methodological considerations about how to examine the relation between placebo responsivity and hypnotizability are identified. Studies are identified which indicate that response to treatments which utilize adjunctive hypnosis are superior to placebo treatments. The only study which examined whether placebo responsivity was correlated with hypnotizability seems to indicate that they are only slightly related at best. The possibility that there may be such thing as a "good placebo responder (GPR)" is questioned, while the known clinical value of hypnotizability assessment is reaffirmed. Future directions for empirical research on the relation between placebo responsivity and hypnotizability are identified. PMID- 25928604 TI - A historical context for understanding "an eye roll test for hypnotizability" by herbert spiegel, m.d. AB - Herb Spiegel was known for many professional and scientific achievements. He may be best remembered for his discovery of the Eye Roll Sign (ERS) and its relation to innate trance capacity and the parallel creation and development of the Hypnotic Induction Profile (HIP). The present paper provides a historical context for understanding Herb's 1972 publication of "An Eye Roll Test for Hypnotizability" which originally appeared in the American Journal of Clinical Hypnosis 38 years ago and is reprinted in this journal issue. PMID- 25928605 TI - Kenneth s. Bowers, interactionism and hypnosis. AB - Like most seminal thinkers in hypnosis, Kenneth Bowers' interests and contributions have ranged beyond that particular domain. The list of his published works is impressive by anyone's standards, and includes important contributions in the areas of health, psychotherapy, and hypnosis. This paper will focus on his major contribution to personality theory, "Situationism in Psychology: An Analysis and Critique," published in 1973 in the Psychological Review. PMID- 25928606 TI - The examined life: how we lose and find ourselves by stephen grosz. PMID- 25928607 TI - The philosophy of animal magnetism: together with the system of manipulating adapted to produce ecstasy and somnambulism-the effects and the rationale by a gentleman from Philadelphia. PMID- 25928608 TI - Shelter from the storm by richard kluft. PMID- 25928609 TI - Review of the international literature. PMID- 25928610 TI - Age-Related Performance on the Brixton Spatial Anticipation Test in Healthy Child and Adolescent Girls: A Preliminary Evaluation. AB - The Brixton Spatial Anticipation Test assesses individuals' cognitive flexibility in terms of rule detection and attainment. It has been used to assess executive functioning in both clinical and nonclinical adult samples. However, little is currently known about the suitability of this task for younger populations. The current study therefore aimed to provide an initial exploration of this task's suitability for young people. Brixton responses from a healthy sample of children and adolescents were presented to investigate performance in both rule detection and rule attainment, respectively. A convenience sample of 72 female participants (Mage = 14.95 years, SD = 1.53 years, range = 11-17 years; MIQ = 103.76, SD = 10.81) was studied. The sample was divided according to age into four groups (11 12 years, 13-14 years, 15 years, and 16-17 years) to allow for developmental trajectory. No significant age performance differences were found. Small effect sizes between age groups lend support to the null findings. The current study suggests that the Brixton task norms are suitable for use with individuals aged 11 to 17 years old. However, normative work is still needed in this area, incorporating an adult sample for comparison, to comment upon the developmental trajectory specific to this task. PMID- 25928611 TI - Mixed-metal metallocavitands: a new approach to tune their electrostatic potentials for controllable selectivity towards substituted benzene derivatives. AB - We have successfully developed a new synthetic approach to modulate the electrostatic potentials of metallocavitands and thus their selective recognition towards substituted benzene derivatives via integrating two metal cations of different electronegativity into a self-assembled system. PMID- 25928617 TI - Helminth elimination in the pursuit of sustainable development goals: a "worm index" for human development. PMID- 25928620 TI - Effects of adaptive servo-ventilation therapy on cardiac function and remodeling in patients with chronic heart failure (SAVIOR-C): study protocol for a randomized controlled trial. AB - BACKGROUND: Adaptive servo-ventilation (ASV) therapy, which is a form of noninvasive positive pressure ventilation therapy and uses an innovative ventilator that has simple operability and provides good patient adherence, potentially has therapeutic benefits-suppression of the deterioration and progression of chronic heart failure (CHF) and a reduction in the number of repeated hospitalizations. Therefore, ASV therapy draws attention as a novel, noninvasive nonpharmacotherapy for patients with CHF owing to its hemodynamics improving effect, and it is currently being accepted in real-world clinical settings in Japan. However, clinical evidence sufficient for treatment recommendation is lacking because a multicenter, randomized, controlled study of ASV therapy has never been conducted. METHODS/DESIGN: The present study is a confirmatory, prospective, multicenter, collaborative, open-label, blinded endpoint, parallel-group, randomized, controlled study. At 40 medical institutions in Japan, 200 Japanese outpatients with mild to severe CHF (age: >= 20 years; New York Heart Association classification: greater than or equal to class II) will be randomly assigned to either of the following two study groups: the ASV group, in which 100 outpatients undergo guideline-directed medical therapy and ASV therapy for 24 weeks; and the control group, in which 100 outpatients undergo only guideline-directed medical therapy for 24 weeks. The objective of the present study is to confirm whether the ASV group is superior to the control group concerning the improvement of left ventricular contractility and remodeling, both assessed by two-dimensional echocardiography. Furthermore, the present study will also secondarily examine the effects of ASV therapy on the prognosis and quality of life of patients with CHF. DISCUSSION: ASV therapy using the device has the potential to provide therapeutic benefits based on its simple operability and good patient adherence and possesses the potential to improve left ventricular contractility and remodeling. Therefore, the present study is expected to afford more solid scientific evidence regarding ASV therapy as a novel, noninvasive, nonpharmacological, in-home, long-term ventilation therapy for patients with mild to severe CHF. TRIAL REGISTRATION: UMIN identifier: UMIN000006549 , registered on 17 October, 2011. PMID- 25928621 TI - Association between pain, neuropsychiatric symptoms, and physical function in dementia: a systematic review and meta-analysis. AB - BACKGROUND: Pain, neuropsychiatric symptoms (NPS) and functional impairment are prevalent in patients with dementia and pain is hypothesized to be causal in both neuropsychiatric symptoms (NPS) and functional impairment. As the exact nature of the associations is unknown, this review examines the strength of associations between pain and NPS, and pain and physical function in patients with dementia. Special attention is paid to the description of measurement instruments and the methods used to detect pain, NPS and physical function. METHODS: A systematic search was made in the databases of PubMed (Medline), Embase, Cochrane, Cinahl, PsychINFO, and Web of Science. Studies were included that described associations between pain and NPS and/or physical function in patients with moderate to severe dementia. RESULTS: The search yielded 22 articles describing 18 studies, including two longitudinal studies. Most evidence was found for the association between pain and depression, followed by the association between pain and agitation/aggression. The longitudinal studies reported no direct effects between pain and NPS but some indirect effects, e.g. pain through depression. Although some association was established between pain and NPS, and pain and physical function, the strength of associations was relatively weak. Interestingly, only three studies used an observer rating scale for pain-related behaviour. CONCLUSIONS: Available evidence does not support strong associations between pain, NPS and physical function. This might be due to inadequate use or lack of rating scales to detect pain-related behaviour. These results show that the relationship between pain and NPS, as well as with physical function, is complicated and warrants additional longitudinal evaluation. PMID- 25928625 TI - Capacity for conducting systematic reviews in low- and middle-income countries: a rapid appraisal. AB - BACKGROUND: Systematic reviews of research are increasingly recognised as important for informing decisions across policy sectors and for setting priorities for research. Although reviews draw on international research, the host institutions and countries can focus attention on their own priorities. The uneven capacity for conducting research around the world raises questions about the capacity for conducting systematic reviews. METHODS: A rapid appraisal was conducted of current capacity and capacity strengthening activities for conducting systematic reviews in low- and middle-income countries (LMICs). A systems approach to analysis considered the capacity of individuals nested within the larger units of research teams, institutions that fund, support, and/or conduct systematic reviews, and systems that support systematic reviewing internationally. RESULTS: International systematic review networks, and their support organisations, are dominated by members from high-income countries. The largest network comprising a skilled workforce and established centres is the Cochrane Collaboration. Other networks, although smaller, provide support for systematic reviews addressing questions beyond effective clinical practice which require a broader range of methods. Capacity constraints were apparent at the levels of individuals, review teams, organisations, and system wide. Constraints at each level limited the capacity at levels nested within them. Skills training for individuals had limited utility if not allied to opportunities for review teams to practice the skills. Skills development was further constrained by language barriers, lack of support from academic organisations, and the limitations of wider systems for communication and knowledge management. All networks hosted some activities for strengthening the capacities of individuals and teams, although these were usually independent of core academic programmes and traditional career progression. Even rarer were efforts to increase demand for systematic reviews and to strengthen links between producers and potential users of systematic reviews. CONCLUSIONS: Limited capacity for conducting systematic reviews within LMICs presents a major technical and social challenge to advancing their health systems. Effective capacity in LMICs can be spread through investing effort at multiple levels simultaneously, supported by countries (predominantly high-income countries) with established skills and experience. PMID- 25928624 TI - Consensus clinical management guidelines for Friedreich ataxia. AB - Friedreich ataxia (FRDA), a multisystem autosomal recessive condition, is the most common inherited ataxia in Caucasians, affecting approximately 1 in 29,000 individuals. The hallmark clinical features of FRDA include progressive afferent and cerebellar ataxia, dysarthria, impaired vibration sense and proprioception, absent tendon reflexes in lower limbs, pyramidal weakness, scoliosis, foot deformity and cardiomyopathy. Despite significant progress in the search for disease modifying agents, the chronic progressive nature of FRDA continues to have a profound impact on the health and well-being of people with FRDA. At present there is no proven treatment that can slow the progression or eventual outcome of this life-shortening condition. Thirty-nine expert clinicians located in Europe, Australia, Canada and USA critically appraised the published evidence related to FRDA clinical care and provided this evidence in a concise manner. Where no published data specific to FRDA existed, recommendations were based on data related to similar conditions and/or expert consensus. There were 146 recommendations developed to ensure best practice in the delivery of health services to people with FRDA. Sixty-two percent of recommendations are based on expert opinion or good practice indicating the paucity of high-level quality clinical studies in this area. Whilst the development of these guidelines provides a critical first step in the provision of appropriate clinical care for people with FRDA, it also highlights the urgency of undertaking high-quality clinical studies that will ensure the delivery of optimum clinical management and intervention for people with FRDA. PMID- 25928628 TI - Low fasting glucose is associated with enhanced thrombin generation and unfavorable fibrin clot properties in type 2 diabetic patients with high cardiovascular risk. AB - OBJECTIVE: To investigate the effect of low blood glucose on thrombin generation and fibrin clot properties in type 2 diabetes (T2DM). METHODS: In 165 patients with T2DM and high cardiovascular risk, we measured ex vivo plasma fibrin clot permeation [Ks], turbidity and efficiency of fibrinolysis including clot lysis time [t50%], together with thrombin generation and platelet activation markers in relation to fasting blood glucose. RESULTS: As compared to patients in medium (4.5-6.0 mmol/l, n = 52) and higher (>6.0 mmol/l, n = 75) glucose group, subjects with low glycemia (<4.5 mmol/l, n = 38) had lower Ks by 11% (p < 0.001) and 8% (p = 0.01), respectively, prolonged t50% by 10% (p < 0.001) and 7% (p = 0.016), respectively, and higher peak thrombin generation by 21% and 16%, respectively (p < 0.001 for both). There were no significant differences in Ks and t50% between patients in medium and higher glucose group. In the whole group, a J-shape relationship was observed between glycemia and the following factors: peak thrombin generation, Ks and t50%. Only in patients with HbA1c < 6.0% (42 mmol/mol) (n = 26) fasting glucose positively correlated with Ks (r = 0.53, P = 0.006) and inversely with t50% (r = -0.46, P = 0.02). By multiple regression analysis, after adjustment for age, fibrinogen, HbA1c, insulin treatment and T2DM duration, fasting glycemia was the independent predictor of Ks (F = 6.6, df = 2, P = 0.002), t50% (F = 8.0, df = 2, P < 0.001) and peak thrombin generation (F = 13.5, df = 2, P < 0.0001). CONCLUSIONS: In T2DM patients fasting glycemia <4.5 mmol/l is associated with enhanced thrombin formation and formation of denser fibrin clots displaying lower lysability, especially when strict glycemia control was achieved (HbA1c<6.0%). PMID- 25928629 TI - RNASET2 tag SNP but not CCR6 polymorphisms is associated with autoimmune thyroid diseases in the Chinese Han population. AB - BACKGROUND: Polymorphisms of the CC chemokine receptor 6 (CCR6) and RNASET2 tag SNP have been shown to be associated with the susceptibility to several immune related diseases. This study was conducted to identify the association of CCR6 and RNASET2 tag SNP with autoimmune thyroid diseases (AITDs) in the Chinese Han population. METHODS: We enrolled 1061 patients with AITDs, including 701 patients with Graves' disease (GD) and 360 patients with Hashimoto's thyroiditis (HT), and 938 healthy individuals for a case-control genetic association study. Three CCR6 single nucleotides polymorphisms (SNPs) (rs3093023/rs3093024/rs6902119) and one tagging SNP (rs9355610) within RNASET2 gene were selected for genotyping by multiplex polymerase chain reaction (PCR) and ligase detection reaction (LDR). RESULTS: The frequency of rs9355610 genotypes in the patients with GD differed significantly from that in the controls (p = 0.017). The frequency of the minor G allele of rs9355610 was significantly higher in the GD patients than in the healthy controls (p = 0.005, OR = 1.225, 95% CI:1.063-1.412). However, we could not find significant differences in the genotype or allele frequencies of HT patients compared with healthy controls. After gender stratification, the frequency of the minor G allele in both male and female GD patients was significantly higher than that in the healthy controls (p = 0.036, OR = 1.308, 95% CI:1.017-1.684 ; p = 0.048, OR = 1.19, 95% CI:1.001-1.413; respectively);. Furthermore, the frequency of haplotype AT in GD patients was significantly lower than that in their control groups (p = 0.003) and showed a protective effect against GD (OR = 0.806, 95% CI: 0.699-0.929). The frequency of haplotype GT in GD patients was significantly higher than that in their control groups (p = 0.048), indicating that GT was the risk haplotype to GD (OR = 1.267, 95% CI: 1.001 1.603). There were no significant differences in the allele or genotype frequencies of three SNPs of CCR6 (rs3093023/rs3093024/ rs6902119) gene between GD patients, HT patients and controls. CONCLUSIONS: Our results suggest that the rs9355610 tag SNP of RNASET2 gene is positively associated with susceptibility to GD in the Chinese Han population. No association was found for the tested CCR6 SNPs. PMID- 25928630 TI - A systematic review and meta-analysis to compare the efficacy of acyclovir 3% ophthalmic ointment to idoxuridine in curing herpetic keratitis by Day 7 of treatment. AB - BACKGROUND: This objective of the review and analysis is to demonstrate that acyclovir (ACV) 3% ophthalmic ointment is superior to idoxuridine (IDU) in treating herpetic keratitis (HK) presenting as dendritic and geographic ulcer sub types. METHODS: DATA SOURCES: Publications in human subjects were identified by searching the Ovid MEDLINE database through April 2011, combining medical subject headings (MESH) "Keratitis, Herpetic/" AND "Acyclovir/" limiting by the key words "topical" OR "ointment" and also restricted to MESH "Administration, Topical/" OR "Ointments/". The results were cross checked with the references used in the Cochrane Database Syst Rev. 1:1-134, 2009 and GlaxoSmithKline clinical documents related to acyclovir. STUDY SELECTION: Randomized, double-masked studies in subjects diagnosed with HK with head to head comparator arms of ACV ophthalmic ointment and topical IDU that had actual or calculable healing rates at Day seven. DATA EXTRACTION: Data independently extracted from identified articles by two authors of this manuscript. DATA SYNTHESIS: Data from seven randomized, controlled trials (RCT) evaluating 432 subjects that met inclusion criteria (214 were treated with ACV and 218 were treated with IDU) and had Day seven healing rates calculable. All sub-classified lesions were identified as either dendritic ulcers (n = 185) or geographic ulcers (n = 35). The Cochran-Mantel-Haenszel (CMH) method in Biometrics 10:417-51, 1954 and JNCI 22:719-48, 1959, controlling for study, was performed as the primary analysis using SAS v9. Homogeneity was assessed using Breslow-Day-Tarone (BDT) test in IARC 1:1-32, 1980 and Biometrika 72:91-5, 1985. The analysis was performed with outliers removed to assess their impact. RESULTS: ACV showed statistically significant greater odds of healing HK at Day seven in all subjects (Odds Ratio 3.95, 95% CI2.60, 6.00, p < 0.0001), in dendritic ulcers (Odds Ratio 4.22, 95% CI: 2.14, 8.32; p < 0.0001) and geographic ulcers (Odds Ratio 5.31, 95% CI: 1.09, 25.93; p = 0.0244). CONCLUSION: ACV 3% ophthalmic ointment is a valuable intervention for dendritic and geographic corneal ulcers. ACV and IDU were generally well tolerated in the studies reviewed. PMID- 25928631 TI - Native Variants of the MRB1 Complex Exhibit Specialized Functions in Kinetoplastid RNA Editing. AB - Adaptation and survival of Trypanosoma brucei requires editing of mitochondrial mRNA by uridylate (U) insertion and deletion. Hundreds of small guide RNAs (gRNAs) direct the mRNA editing at over 3,000 sites. RNA editing is controlled during the life cycle but the regulation of substrate and stage specificity remains unknown. Editing progresses in the 3' to 5' direction along the pre-mRNA in blocks, each targeted by a unique gRNA. A critical editing factor is the mitochondrial RNA binding complex 1 (MRB1) that binds gRNA and transiently interacts with the catalytic RNA editing core complex (RECC). MRB1 is a large and dynamic complex that appears to be comprised of distinct but related subcomplexes (termed here MRBs). MRBs seem to share a 'core' complex of proteins but differ in the composition of the 'variable' proteins. Since some proteins associate transiently the MRBs remain imprecisely defined. MRB1 controls editing by unknown mechanisms, and the functional relevance of the different MRBs is unclear. We previously identified two distinct MRBs, and showed that they carry mRNAs that undergo editing. We proposed that editing takes place in the MRBs because MRBs stably associate with mRNA and gRNA but only transiently interact with RECC, which is RNA free. Here, we identify the first specialized functions in MRBs: 1) 3010-MRB is a major scaffold for RNA editing, and 2) REH2-MRB contains a critical trans-acting RNA helicase (REH2) that affects multiple steps of editing function in 3010-MRB. These trans effects of the REH2 include loading of unedited mRNA and editing in the first block and in subsequent blocks as editing progresses. REH2 binds its own MRB via RNA, and conserved domains in REH2 were critical for REH2 to associate with the RNA and protein components of its MRB. Importantly, REH2 associates with a ~30 kDa RNA-binding protein in a novel ~15S subcomplex in RNA depleted mitochondria. We use these new results to update our model of MRB function and organization. PMID- 25928632 TI - An isolated left common carotid artery from the main pulmonary artery in a neonate with aortic valve atresia. AB - A 20-day-old girl was referred to our clinic for systolic murmur, cyanosis, and dyspnoea with feeding. Echocardiography revealed an atretic aortic valve. CT angiography scan revealed that the left common carotid artery originated from the distal main pulmonary artery. The plan was patent ductus artriosus stenting and bilateral pulmonary artery banding and then follow-up for any possible future intervention. PMID- 25928627 TI - A cluster randomized trial of a multifaceted quality improvement intervention in Brazilian intensive care units: study protocol. AB - BACKGROUND: The uptake of evidence-based therapies in the intensive care environment is suboptimal, particularly in limited-resource countries. Checklists, daily goal assessments, and clinician prompts may improve compliance with best practice processes of care and, in turn, improve clinical outcomes. However, the available evidence on the effectiveness of checklists is unreliable and inconclusive, and the mechanisms are poorly understood. We aim to evaluate whether the use of a multifaceted quality improvement intervention, including the use of a checklist and the definition of daily care goals during multidisciplinary daily rounds and clinician prompts, can improve the in-hospital mortality of patients admitted to intensive care units (ICUs). Our secondary objectives are to assess the effects of the study intervention on specific processes of care, clinical outcomes, and the safety culture and to determine which factors (the processes of care and/or safety culture) mediate the effect of the study intervention on mortality. METHODS/DESIGN: This is a cluster randomized trial involving 118 ICUs in Brazil conducted in two phases. In the observational preparatory phase, we collect baseline data on processes of care and clinical outcomes from 60 consecutive patients with lengths of ICU stay longer than 48 h and apply the Safety Attitudes Questionnaire (SAQ) to 75% or more of the health care staff in each ICU. In the randomized phase, we assign ICUs to the experimental or control arm and repeat data collection. Experimental arm ICUs receive the multifaceted quality improvement intervention, including a checklist and definition of daily care goals during daily multidisciplinary rounds, clinician prompting, and feedback on rates of adherence to selected care processes. Control arm ICUs maintain usual care. The primary outcome is in hospital mortality, truncated at 60 days. Secondary outcomes include the rates of adherence to appropriate care processes, rates of other clinical outcomes, and scores on the SAQ domains. Analysis follows the intention-to-treat principle, and the primary outcome is analyzed using mixed effects logistic regression. DISCUSSION: This is a large scale, pragmatic cluster-randomized trial evaluating whether a multifaceted quality improvement intervention, including checklists applied during the multidisciplinary daily rounds and clinician prompting, can improve the adoption of proven therapies and decrease the mortality of critically ill patients. If this study finds that the intervention reduces mortality, it may be widely adopted in intensive care units, even those in limited-resource settings. TRIAL REGISTRATION: ClinicalTrials.gov NCT01785966. PMID- 25928633 TI - When the waves of European Neolithization met: first paleogenetic evidence from early farmers in the southern Paris Basin. AB - An intense debate concerning the nature and mode of Neolithic transition in Europe has long received much attention. Recent publications of paleogenetic analyses focusing on ancient European farmers from Central Europe or the Iberian Peninsula have greatly contributed to this debate, providing arguments in favor of major migrations accompanying European Neolithization and highlighting noticeable genetic differentiation between farmers associated with two archaeologically defined migration routes: the Danube valley and the Mediterranean Sea. The aim of the present study was to fill a gap with the first paleogenetic data of Neolithic settlers from a region (France) where the two great currents came into both direct and indirect contact with each other. To this end, we analyzed the Gurgy 'Les Noisats' group, an Early/Middle Neolithic necropolis in the southern part of the Paris Basin. Interestingly, the archaeological record from this region highlighted a clear cultural influence from the Danubian cultural sphere but also notes exchanges with the Mediterranean cultural area. To unravel the processes implied in these cultural exchanges, we analyzed 102 individuals and obtained the largest Neolithic mitochondrial gene pool so far (39 HVS-I mitochondrial sequences and haplogroups for 55 individuals) from a single archaeological site from the Early/Middle Neolithic period. Pairwise FST values, haplogroup frequencies and shared informative haplotypes were calculated and compared with ancient and modern European and Near Eastern populations. These descriptive analyses provided patterns resulting from different evolutionary scenarios; however, the archaeological data available for the region suggest that the Gurgy group was formed through equivalent genetic contributions of farmer descendants from the Danubian and Mediterranean Neolithization waves. However, these results, that would constitute the most ancient genetic evidence of admixture between farmers from both Central and Mediterranean migration routes in the European Neolithization debate, are subject to confirmation through appropriate model-based approaches. PMID- 25928634 TI - An objective fluctuation score for Parkinson's disease. AB - INTRODUCTION: Establishing the presence and severity of fluctuations is important in managing Parkinson's Disease yet there is no reliable, objective means of doing this. In this study we have evaluated a Fluctuation Score derived from variations in dyskinesia and bradykinesia scores produced by an accelerometry based system. METHODS: The Fluctuation Score was produced by summing the interquartile range of bradykinesia scores and dyskinesia scores produced every 2 minutes between 0900-1800 for at least 6 days by the accelerometry based system and expressing it as an algorithm. RESULTS: This Score could distinguish between fluctuating and non-fluctuating patients with high sensitivity and selectivity and was significant lower following activation of deep brain stimulators. The scores following deep brain stimulation lay in a band just above the score separating fluctuators from non-fluctuators, suggesting a range representing adequate motor control. When compared with control subjects the score of newly diagnosed patients show a loss of fluctuation with onset of PD. The score was calculated in subjects whose duration of disease was known and this showed that newly diagnosed patients soon develop higher scores which either fall under or within the range representing adequate motor control or instead go on to develop more severe fluctuations. CONCLUSION: The Fluctuation Score described here promises to be a useful tool for identifying patients whose fluctuations are progressing and may require therapeutic changes. It also shows promise as a useful research tool. Further studies are required to more accurately identify therapeutic targets and ranges. PMID- 25928635 TI - Characterization of differentially expressed genes involved in pathways associated with gastric cancer. AB - To explore the patterns of gene expression in gastric cancer, a total of 26 paired gastric cancer and noncancerous tissues from patients were enrolled for gene expression microarray analyses. Limma methods were applied to analyze the data, and genes were considered to be significantly differentially expressed if the False Discovery Rate (FDR) value was < 0.01, P-value was <0.01 and the fold change (FC) was >2. Subsequently, Gene Ontology (GO) categories were used to analyze the main functions of the differentially expressed genes. According to the Kyoto Encyclopedia of Genes and Genomes (KEGG) database, we found pathways significantly associated with the differential genes. Gene-Act network and co expression network were built respectively based on the relationships among the genes, proteins and compounds in the database. 2371 mRNAs and 350 lncRNAs considered as significantly differentially expressed genes were selected for the further analysis. The GO categories, pathway analyses and the Gene-Act network showed a consistent result that up-regulated genes were responsible for tumorigenesis, migration, angiogenesis and microenvironment formation, while down regulated genes were involved in metabolism. These results of this study provide some novel findings on coding RNAs, lncRNAs, pathways and the co-expression network in gastric cancer which will be useful to guide further investigation and target therapy for this disease. PMID- 25928636 TI - A critical role for the transient receptor potential channel type 6 in human platelet activation. AB - While calcium signaling is known to play vital roles in platelet function, the mechanisms underlying its receptor-operated calcium entry component (ROCE) remain poorly understood. It has been proposed, but never proven in platelets, that the canonical transient receptor potential channel-6 (TRPC6) mediates ROCE. Nonetheless, we have previously shown that the mouse TRPC6 regulates hemostasis, thrombogenesis by regulating platelet aggregation. In the present studies, we used a pharmacological approach to characterize the role of TRPC6 in human platelet biology. Thus, interestingly, we observed that a TRPC6 inhibitor exerted significant inhibitory effects on human platelet aggregation in a thromboxane receptor (TPR)-selective manner; no additional inhibition was observed in the presence of the calcium chelator BAPTA. This inhibitor also significantly inhibited human platelet secretion (dense and alpha granules), integrin IIb-IIIa, Akt and ERK phosphorylation, again, in a TPR-selective manner; no effects were observed in response to ADP receptor stimulation. Furthermore, there was a causal relationship between these inhibitory effects, and the capacity of the TRPC6 inhibitor to abrogate elevation in intracellular calcium, that was again found to be TPR-specific. This effect was not found to be due to antagonism of TPR, as the TRPC6 inhibitor did not displace the radiolabeled antagonist [3H]SQ29,548 from its binding sites. Finally, our studies also revealed that TRPC6 regulates human clot retraction, as well as physiological hemostasis and thrombus formation, in mice. Taken together, our findings demonstrate, for the first time, that TRPC6 directly regulates TPR-dependent ROCE and platelet function. Moreover, these data highlight TRPC6 as a novel promising therapeutic strategy for managing thrombotic disorders. PMID- 25928639 TI - Interaction with indoor plants may reduce psychological and physiological stress by suppressing autonomic nervous system activity in young adults: a randomized crossover study. AB - BACKGROUND: Developments in information technology cause a great deal of stress to modern people, and controlling this stress now becomes an important issue. The aim of this study was to examine psychological and physiological benefits of interaction with indoor plants. METHODS: The study subjects were 24 young male adults at the age of 24.9 +/- 2.1 (mean +/- SD). The crossover experimental design was used to compare the differences in physiological responses to a computer task and a plant-related task. Subjects were randomly distributed into two groups. The first group (12 subjects) carried out transplanting of an indoor plant, whereas the second group (12 subjects) worked on a computer task. Then, each subject switched activities. The psychological evaluation was carried out using the semantic differential method (SDM) and physiological evaluation using heart rate variability (low-frequency (LF) and high-frequency (HF) components) and blood pressure. RESULTS: Analysis of the SDM data showed that the feelings during the transplanting task were different from that during the computer task: the subjects felt more comfortable, soothed, and natural after the transplanting task than after the computer task. The mean value of total log[LF/(LF + HF)] (sympathetic activity) increased over time during the computer task but decreased at the end of the transplanting task, and the differences were significant. Furthermore, diastolic blood pressure was significantly lower after the transplanting task. CONCLUSIONS: Our results suggest that active interaction with indoor plants can reduce physiological and psychological stress compared with mental work. This is accomplished through suppression of sympathetic nervous system activity and diastolic blood pressure and promotion of comfortable, soothed, and natural feelings. PMID- 25928642 TI - Community participation in formulating the post-2015 health and development goal agenda: reflections of a multi-country research collaboration. AB - Global discussion on the post-2015 development goals, to replace the Millennium Development Goals when they expire on 31 December 2015, is well underway. While the Millennium Development Goals focused on redressing extreme poverty and its antecedents for people living in developing countries, the post-2015 agenda seeks to redress inequity worldwide, regardless of a country's development status. Furthermore, to rectify the UN's top-down approach toward the Millennium Development Goals' formulation, widespread negotiations are underway that seek to include the voices of people and communities from around the globe to ground each post-2015 development goal. This reflexive commentary, therefore, reports on the early methodological challenges the Go4Health research project experienced in its engagement with communities in nine countries in 2013. Led by four research hubs in Uganda, Bangladesh, Australia and Guatemala, the purpose of this engagement has been to ascertain a 'snapshot' of the health needs and priorities of socially excluded populations particularly from the Global South. This is to inform Go4Health's advice to the European Commission on the post-2015 global goals for health and new governance frameworks. Five methodological challenges were subsequently identified from reflecting on the multidisciplinary, multiregional team's research practices so far: meanings and parameters around qualitative participatory research; representation of marginalization; generalizability of research findings; ethical research in project time frames; and issues related to informed consent. Strategies to overcome these methodological hurdles are also examined. The findings from the consultations represent the extraordinary diversity of marginal human experience requiring contextual analysis for universal framing of the post-2015 agenda. Unsurprisingly, methodological challenges will, and did, arise. We conclude by advocating for a discourse to emerge not only critically examining how and whose voices are being obtained at the community-level to inform the post-2015 health and development goal agenda, but also how these voices are being translated and integrated into post-2015 decision-making at national and global levels. PMID- 25928643 TI - Demographic factors associated with smoking cessation during pregnancy in New South Wales, Australia, 2000-2011. AB - BACKGROUND: Smoking during pregnancy increases the risk of adverse health outcomes for both the mother and the child. Rates of smoking during pregnancy, and rates of smoking cessation during pregnancy, vary between demographic groups. This study describes demographic factors associated with smoking cessation during pregnancy in New South Wales, Australia, and describes trends in smoking cessation in demographic subgroups over the period 2000 - 2011. METHODS: Data were obtained from the New South Wales Perinatal Data Collection, a population based surveillance system covering all births in New South Wales. Multivariate logistic regression was used to explore associations between smoking cessation during pregnancy and demographic factors. RESULTS: Between 2000 and 2011, rates of smoking cessation in pregnancy increased from 4.0% to 25.2%. Demographic characteristics associated with lower rates of smoking cessation during pregnancy included being a teenage mother, being an Aboriginal person, and having a higher number of previous pregnancies. CONCLUSIONS: Between 2000 and 2011, rates of smoking cessation during pregnancy increased dramatically across all demographic groups. However, specific demographic groups remain significantly less likely to quit smoking, suggesting a need for targeted efforts to promote smoking cessation in these groups. PMID- 25928645 TI - Surveillance systems evaluation: a systematic review of the existing approaches. AB - BACKGROUND: Regular and relevant evaluations of surveillance systems are essential to improve their performance and cost-effectiveness. With this in mind several organizations have developed evaluation approaches to facilitate the design and implementation of these evaluations. METHODS: In order to identify and to compare the advantages and limitations of these approaches, we implemented a systematic review using the PRISMA guidelines (Preferred Reporting Items for Systematic Reviews and Meta-Analyses). RESULTS: After applying exclusion criteria and identifying other additional documents via citations, 15 documents were retained. These were analysed to assess the field (public or animal health) and the type of surveillance systems targeted; the development process; the objectives; the evaluation process and its outputs; and the attributes covered. Most of the approaches identified were general and provided broad recommendations for evaluation. Several common steps in the evaluation process were identified: (i) defining the surveillance system under evaluation, (ii) designing the evaluation process, (iii) implementing the evaluation, and (iv) drawing conclusions and recommendations. CONCLUSIONS: A lack of information regarding the identification and selection of methods and tools to assess the evaluation attributes was highlighted; as well as a lack of consideration of economic attributes and sociological aspects. PMID- 25928646 TI - Evaluation of the PaO2/FiO2 ratio after cardiac surgery as a predictor of outcome during hospital stay. AB - BACKGROUND: The arterial partial pressure of O2 and the fraction of inspired oxygen (PaO2/FiO2) ratio is widely used in ICUs as an indicator of oxygenation status. Although cardiac surgery and ICU scores can predict mortality, during the first hours after cardiac surgery few instruments are available to assess outcome. The aim of this study was to evaluate the usefulness of PaO2/FIO2 ratio to predict mortality in patients immediately after cardiac surgery. METHODS: We prospectively studied 2725 consecutive cardiac surgery patients between 2004 and 2009. PaO2/FiO2 ratio was measured on admission and at 3 h, 6 h, 12 h and 24 h after ICU admission, together with clinical data and outcomes. RESULTS: All PaO2/FIO2 ratio measurements differed between survivors and non-survivors (p < 0.001). The PaO2/FIO2 at 3 h after ICU admission was the best predictor of mortality based on area under the curve (p < 0.001) and the optimum threshold estimation gave an optimal cut-off of 222 (95% Confidence interval (CI): 202 242), yielding three groups of patients: Group 1, with PaO2/FIO2 > 242; Group 2, with PaO2/FIO2 from 202 to 242; and Group 3, with PaO2/FIO2 < 202. Group 3 showed higher in-ICU mortality and ICU length of stay and Groups 2 and 3 also showed higher respiratory complication rates. The presence of a PaO2/FIO2 ratio < 202 at 3 h after admission was shown to be a predictor of in-ICU mortality (OR:1.364; 95% CI:1.212-1.625, p < 0.001) and of worse long-term survival (88.8% vs. 95.8%; Log rank p = 0.002. Adjusted Hazard ratio: 1.48; 95% CI:1.293-1.786; p = 0.004). CONCLUSIONS: A simple determination of PaO2/FIO2 at 3 h after ICU admission may be useful to identify patients at risk immediately after cardiac surgery. PMID- 25928647 TI - Altered resting-state functional connectivity of the frontal-striatal reward system in social anxiety disorder. AB - We investigated differences in the intrinsic functional brain organization (functional connectivity) of the human reward system between healthy control participants and patients with social anxiety disorder. Functional connectivity was measured in the resting-state via functional magnetic resonance imaging (fMRI). 53 patients with social anxiety disorder and 33 healthy control participants underwent a 6-minute resting-state fMRI scan. Functional connectivity of the reward system was analyzed by calculating whole-brain temporal correlations with a bilateral nucleus accumbens seed and a ventromedial prefrontal cortex seed. Patients with social anxiety disorder, relative to the control group, had (1) decreased functional connectivity between the nucleus accumbens seed and other regions associated with reward, including ventromedial prefrontal cortex; (2) decreased functional connectivity between the ventromedial prefrontal cortex seed and lateral prefrontal regions, including the anterior and dorsolateral prefrontal cortices; and (3) increased functional connectivity between both the nucleus accumbens seed and the ventromedial prefrontal cortex seed with more posterior brain regions, including anterior cingulate cortex. Social anxiety disorder appears to be associated with widespread differences in the functional connectivity of the reward system, including markedly decreased functional connectivity between reward regions and between reward regions and lateral prefrontal cortices, and markedly increased functional connectivity between reward regions and posterior brain regions. PMID- 25928649 TI - Racial Differences in Outcomes within the National Lung Screening Trial. Implications for Widespread Implementation. AB - RATIONALE: Black individuals with lung cancer (LC) experience higher mortality because they present with more advanced disease and are less likely to undergo curative resection for early-stage disease. The National Lung Screening Trial (NLST) demonstrated improved LC mortality by screening high-risk patients with low-dose computed tomography (LDCT). The benefit of LDCT screening in black individuals is unknown. OBJECTIVES: Examine results of the NLST by race. METHODS: This was a secondary analysis of a randomized trial (NCT00047385) performed in 33 U.S. centers. MEASUREMENTS AND MAIN RESULTS: Overall and lung cancer-specific mortality were measured. Screening with LDCT reduced LC mortality in all racial groups but more so in black individuals (hazard ratio [HR], 0.61 vs. 0.86). Smoking increased the likelihood of death from LC, and when stratified by race black smokers were twice as likely to die as white smokers (HR, 4.10 vs. 2.25). Adjusting for sociodemographic and behavioral characteristics, black individuals experienced higher all-cause mortality than white individuals (HR, 1.35; 95% confidence interval, 1.22-1.49); however, black individuals screened with LDCT had a reduction in all-cause mortality. Black individuals were younger, were more likely to be current smokers, had more comorbidities, and had fewer years of formal education than white individuals (P < 0.05). CONCLUSIONS: Black individuals screened with LDCT had decreased mortality from lung cancer. However, the demographics associated with improved LC survival were less commonly found in black individuals. The overall mortality in the NLST was higher for black individuals than white individuals, but improved in black individuals screened, suggesting that this subgroup may have had improved access to care. To realize the reductions in mortality from LC screening, dissemination efforts need to be tailored to meet the needs of this community. PMID- 25928650 TI - Erratum: Secretome weaponries of Cochliobolus lunatus interacting with potato leaf at different temperature regimes reveal a CL[xxxx]LHM - motif. PMID- 25928652 TI - Repetitive sequence analysis and karyotyping reveals centromere-associated DNA sequences in radish (Raphanus sativus L.). AB - BACKGROUND: Radish (Raphanus sativus L., 2n = 2x = 18) is a major root vegetable crop especially in eastern Asia. Radish root contains various nutritions which play an important role in strengthening immunity. Repetitive elements are primary components of the genomic sequence and the most important factors in genome size variations in higher eukaryotes. To date, studies about repetitive elements of radish are still limited. To better understand genome structure of radish, we undertook a study to evaluate the proportion of repetitive elements and their distribution in radish. RESULTS: We conducted genome-wide characterization of repetitive elements in radish with low coverage genome sequencing followed by similarity-based cluster analysis. Results showed that about 31% of the genome was composed of repetitive sequences. Satellite repeats were the most dominating elements of the genome. The distribution pattern of three satellite repeat sequences (CL1, CL25, and CL43) on radish chromosomes was characterized using fluorescence in situ hybridization (FISH). CL1 was predominantly located at the centromeric region of all chromosomes, CL25 located at the subtelomeric region, and CL43 was a telomeric satellite. FISH signals of two satellite repeats, CL1 and CL25, together with 5S rDNA and 45S rDNA, provide useful cytogenetic markers to identify each individual somatic metaphase chromosome. The centromere-specific histone H3 (CENH3) has been used as a marker to identify centromere DNA sequences. One putative CENH3 (RsCENH3) was characterized and cloned from radish. Its deduced amino acid sequence shares high similarities to those of the CENH3s in Brassica species. An antibody against B. rapa CENH3, specifically stained radish centromeres. Immunostaining and chromatin immunoprecipitation (ChIP) tests with anti-BrCENH3 antibody demonstrated that both the centromere-specific retrotransposon (CR-Radish) and satellite repeat (CL1) are directly associated with RsCENH3 in radish. CONCLUSIONS: Proportions of repetitive elements in radish were estimated and satellite repeats were the most dominating elements. Fine karyotyping analysis was established which allow us to easily identify each individual somatic metaphase chromosome. Immunofluorescence- and ChIP-based assays demonstrated the functional significance of satellite and centromere specific retrotransposon at centromeres. Our study provides a valuable basis for future genomic studies in radish. PMID- 25928653 TI - Current situation of scrub typhus in South Korea from 2001-2013. AB - BACKGROUND: The bacteria Orientia tsutsugamushi is the causative agent of scrub typhus, mite-borne disease, which causes an acute febrile illness in patients. An epidemiologic study was conducted to understand the characteristics of scrub typhus in South Korea. FINDINGS: Reporting of tsutsugamushi disease is mandatory in South Korea since 1994. To investigate the prevalence of tsutsugamushi disease from 2001 to 2013, medical records from the Korea Center for Disease Control and Prevention were reviewed. In total, 70,914 cases were reported during 2001-2013. Of these, 37.16% (26,349) were male and 62.84% (44,565) were female. The highest number of cases was in the 60-69-year-old age group (19,484; 27.48%), and 72.22% (51,212) were in the 50-79-year-old age group. There were 65,100 cases (91.80%) reported during October (24,964; 35.20%) and November (40,136; 56.60%). An almost four-fold increase in the number of patients was observed in 2013 (10,485 cases) compared to 2001 (2,637 cases). The highest number of patients was reported in the Jeonbuk (9,425; 13.29%) and lowest in the Jeju (362; 0.51%). CONCLUSIONS: A rapid increase in the incidence of patients with tsutsugamushi disease was observed in most areas from 2001 to 2013, with the majority of cases reported in the western and southern coast. PMID- 25928654 TI - Correction: Access to tuberculosis services for individuals with disability in rural Malawi, a qualitative study. PMID- 25928661 TI - Heterometallic complexes with cube-type [MTi3N4] cores containing Group 10 metals in a variety of oxidation states. AB - Treatment of [{Ti(eta5-C5Me5)(MU-NH)}3(MU3-N)] (1) with one equivalent of [Ni(cod)2] (cod = 1,5-cyclooctadiene) in toluene at 60-80 degrees C and subsequent addition of diphenylacetylene, trans-stilbene or triphenylphosphane afforded the nickel(0) complexes [LNi{(MU3-NH)3Ti3(eta5-C5Me5)3(MU3-N)}] (L = PhCCPh (2), PhCH=CHPh (3), PPh3 (4)). The nickel(II) complex [I2Ni{(MU3 NH)3Ti3(eta5-C5Me5)3(MU3-N)}] (5) was prepared by analogous addition of iodine to the solution obtained from the heating of 1 and [Ni(cod)2]. Treatment of 1 with one equivalent of [Pd(dba)2] (dba = dibenzylideneacetone) in toluene at room temperature led to the palladium(0) complex [(dba)Pd{(MU3-NH)3Ti3(eta5 C5Me5)3(MU3-N)}] (6). Compound 6 reacted immediately with chloroform-d1 to give the palladium dichloride derivative [Cl2Pd{(MU3-NH)2Ti3(eta5-C5Me5)3(MU-NH)(MU3 N)}] (7), which was prepared by treatment of 1 with [PdCl2(cod)] at room temperature. Addition of iodine to a toluene solution of 6 afforded the analogous palladium(II) derivative [I2Pd{(MU3-NH)2Ti3(eta5-C5Me5)3(MU-NH)(MU3-N)}] (8). Complex 6 reacted with two equivalents of dimethylacetylenedicarboxylate (dmad) to give the metallacyclopentadiene palladium(II) complex [{(MeOOC)4C4}Pd{(MU3 NH)2Ti3(eta5-C5Me5)3(MU-NH)(MU3-N)}] (9) via oxidative coupling. The treatment of 1 with [Pt(nbe)3] (nbe = norbornene) in toluene at room temperature gave the platinum(0) complex [(nbe)Pt{(MU3-NH)3Ti3(eta5-C5Me5)3(MU3-N)}] (10). Compound 10 reacted with excess iodine to afford the platinum(IV) ionic derivative [I3Pt{(MU3 NH)3Ti3(eta5-C5Me5)3(MU3-N)}]2(I3)(I5) (11) via an intermediate platinum(II) complex [I2Pt{(MU3-NH)2Ti3(eta5-C5Me5)3(MU-NH)(MU3-N)}] (12). The X-ray crystal structures of 5, 8, 9 and 11 have been determined. PMID- 25928658 TI - Quantification of transmission of foot-and-mouth disease virus caused by an environment contaminated with secretions and excretions from infected calves. AB - Foot-and-mouth disease virus (FMDV) infected animals can contaminate the environment with their secretions and excretions. To quantify the contribution of a contaminated environment to the transmission of FMDV, this study used calves that were not vaccinated and calves that were vaccinated 1 week prior to inoculation with the virus in direct and indirect contact experiments. In direct contact experiments, contact calves were exposed to inoculated calves in the same room. In indirect contact experiments, contact calves were housed in rooms that previously had held inoculated calves for three days (either from 0 to 3 or from 3 to 6 days post inoculation). Secretions and excretions from all calves were tested for the presence of FMDV by virus isolation; the results were used to quantify FMDV transmission. This was done using a generalized linear model based on a 2 route (2R, i.e. direct contact and environment) SIR model that included information on FMDV survival in the environment. The study shows that roughly 44% of transmission occurs via the environment, as indicated by the reproduction ratio R0(2R)environment that equalled 2.0, whereas the sum of R0(2R)contact and R0(2R)environment equalled 4.6. Because vaccination 1 week prior to inoculation of the calves conferred protective immunity against FMDV infection, no transmission rate parameters could be estimated from the experiments with vaccinated calves. We conclude that a contaminated environment contributes considerably to the transmission of FMDV therefore that hygiene measures can play a crucial role in FMD control. PMID- 25928662 TI - Understanding the role of hyponitrite in nitric oxide reduction. AB - Herein, we review the preparation and coordination chemistry of cis and trans isomers of hyponitrite, [N2O2](2-). Hyponitrite is known to bind to metals via a variety of bonding modes. In fact, at least eight different bonding modes have been observed, which is remarkable for such a simple ligand. More importantly, it is apparent that the cis isomer of hyponitrite is more reactive than the trans isomer because the barrier of N2O elimination from cis-hyponitrite is lower than that of trans-hyponitrite. This observation may have important mechanistic implications for both heterogeneous NOx reduction catalysts and NO reductase. However, our understanding of the hyponitrite ligand has been limited by the lack of a general route to this fragment, and most instances of its formation have been serendipitous. PMID- 25928663 TI - Elviz - exploration of metagenome assemblies with an interactive visualization tool. AB - BACKGROUND: Metagenomics, the sequencing of DNA collected from an entire microbial community, enables the study of natural microbial consortia in their native habitats. Metagenomics studies produce huge volumes of data, including both the sequences themselves and metadata describing their abundance, assembly, predicted functional characteristics and environmental parameters. The ability to explore these data visually is critically important to meaningful biological interpretation. Current genomics applications cannot effectively integrate sequence data, assembly metadata, and annotation to support both genome and community-level inquiry. RESULTS: Elviz (Environmental Laboratory Visualization) is an interactive web-based tool for the visual exploration of assembled metagenomes and their complex metadata. Elviz allows scientists to navigate metagenome assemblies across multiple dimensions and scales, plotting parameters such as GC content, relative abundance, phylogenetic affiliation and assembled contig length. Furthermore Elviz enables interactive exploration using real-time plot navigation, search, filters, axis selection, and the ability to drill from a whole-community profile down to individual gene annotations. Thus scientists engage in a rapid feedback loop of visual pattern identification, hypothesis generation, and hypothesis testing. CONCLUSIONS: Compared to the current alternative of generating a succession of static figures, Elviz can greatly accelerate the speed of metagenome analysis. Elviz can be used to explore both user-submitted datasets and numerous metagenome studies publicly available at the Joint Genome Institute (JGI). Elviz is freely available at http://genome.jgi.doe.gov/viz and runs on most current web-browsers. PMID- 25928664 TI - Thermal invisibility based on scattering cancellation and mantle cloaking. AB - We theoretically and numerically analyze thermal invisibility based on the concept of scattering cancellation and mantle cloaking. We show that a small object can be made completely invisible to heat diffusion waves, by tailoring the heat conductivity of the spherical shell enclosing the object. This means that the thermal scattering from the object is suppressed, and the heat flow outside the object and the cloak made of these spherical shells behaves as if the object is not present. Thermal invisibility may open new vistas in hiding hot spots in infrared thermography, military furtivity, and electronics heating reduction. PMID- 25928665 TI - STAT3 is involved in miR-124-mediated suppressive effects on esophageal cancer cells. AB - BACKGROUND: Esophageal cancer (EC) is one of the most common cancers worldwide. The cancer-related inflammation pathway- signal transducer and activator of transition 3 (STAT3) signaling pathway has been reported to play critical role in its initiation and progression, while the way mediated its hyperactivation remains elusive so far. Accumulating studies reported the important role of microRNAs (miRNAs) in the regulation of gene expression, among of which, the miR 124/STAT3 interaction has been widely reported in various cancers, while its role in EC has not been investigated yet. METHODS: Firstly, we identified the target role of STAT3 in esophageal cancers using Dual-luciferase reporter assays. Next, we explored the expression of miR-124 in EC tissues. To further investigate its effects on the malignant phenotype of EC cells, we completed a series of experiments. Through transfection with miR-124 mimic, the expression of miR-124 in esophageal cancer cell lines, Eca109 and TE-1, were restored. Next, we detected the effects of ectopic miR-124 expression on the proliferation, cell cycle distribution, apoptosis, migration and invasion of EC cells in vitro, and the tumor growth in vivo. RESULTS: Dual-luciferase assays identified that STAT3 is a target gene of miR-124 in esophageal cancer cells. Over-expression of miR 124 significantly down-regulated the mRNA and protein levels of STAT3. Moreover, we found that the expression of miR-124 was consistently suppressed in esophageal cancer tissues and cell lines. Next, functional experiments showed that ectopic expression of miR-124 in EC cells induced a complex phenotype, namely an inhibition of cell proliferation, block of G1/S phase transition, induction of cell apoptosis, and suppression of cell invasion in vitro, as well as inhibition of tumor growth in vivo. Moreover, restored the expression of STAT3 in esophageal cancer cells transfected with miR-124 before, could partially abolished the suppressive effects of miR-124 on the proliferation and invasion of Eca109 cells. CONCLUSION: Collectively, these data suggest that miR-124 functions as a tumor suppressor in esophageal cancer through, at least partially, targeting STAT3 signaling pathway. PMID- 25928675 TI - The American Journal of Clinical Hypnosis. Introduction. PMID- 25928673 TI - Reviewing dengue: still a neglected tropical disease? AB - Dengue is currently listed as a "neglected tropical disease" (NTD). But is dengue still an NTD or not? Classifying dengue as an NTD may carry advantages, but is it justified? This review considers the criteria for the definition of an NTD, the current diverse lists of NTDs by different stakeholders, and the commonalities and differences of dengue with other NTDs. We also review the current research gaps and research activities and the adequacy of funding for dengue research and development (R&D) (2003-2013). NTD definitions have been developed to a higher precision since the early 2000s, with the following main features: NTDs are characterised as a) poverty related, b) endemic to the tropics and subtropics, c) lacking public health attention, d) having poor research funding and shortcomings in R&D, e) usually associated with high morbidity but low mortality, and f) often having no specific treatment available. Dengue meets most of these criteria, but not all. Although dengue predominantly affects resource-limited countries, it does not necessarily only target the poor and marginalised in those countries. Dengue increasingly attracts public health attention, and in some affected countries it is now a high profile disease. Research funding for dengue has increased exponentially in the past two decades, in particular in the area of dengue vaccine development. However, despite advances in dengue research, dengue epidemics are increasing in frequency and magnitude, and dengue is expanding to new areas. Specific treatment and a highly effective vaccine remain elusive. Major research gaps exist in the area of integrated surveillance and vector control. Hence, although dengue differs from many of the NTDs, it still meets important criteria commonly used for NTDs. The current need for increased R&D spending, shared by dengue and other NTDs, is perhaps the key reason why dengue should continue to be considered an NTD. PMID- 25928666 TI - Size dependent translocation and fetal accumulation of gold nanoparticles from maternal blood in the rat. AB - BACKGROUND: There is evidence that nanoparticles (NP) cross epithelial and endothelial body barriers. We hypothesized that gold (Au) NP, once in the blood circulation of pregnant rats, will cross the placental barrier during pregnancy size-dependently and accumulate in the fetal organism by 1. transcellular transport across the hemochorial placenta, 2. transcellular transport across amniotic membranes 3. transport through ~20 nm wide transtrophoblastic channels in a size dependent manner. The three AuNP sizes used to test this hypothesis are either well below, or of similar size or well above the diameters of the transtrophoblastic channels. METHODS: We intravenously injected monodisperse, negatively charged, radio-labelled 1.4 nm, 18 nm and 80 nm 198AuNP at a mass dose of 5, 3 and 27 MUg/rat, respectively, into pregnant rats on day 18 of gestation and in non-pregnant control rats and studied the biodistribution in a quantitative manner based on the radio-analysis of the stably labelled 198AuNP after 24 hours. RESULTS: We observed significant biokinetic differences between pregnant and non-pregnant rats. AuNP fractions in the uterus of pregnant rats were at least one order of magnitude higher for each particle size roughly proportional to the enlarged size and weight of the pregnant uterus. All three sizes of 198AuNP were found in the placentas and amniotic fluids with 1.4 nm AuNP fractions being two orders of magnitude higher than those of the larger AuNP on a mass base. In the fetuses, only fractions of 0.0006 (30 ng) and 0.00004 (0.1 ng) of 1.4 nm and 18 nm AuNP, respectively, were detected, but no 80 nm AuNP (<0.000004 (<0.1 ng)). These data show that no AuNP entered the fetuses from amniotic fluids within 24 hours but indicate that AuNP translocation occurs across the placental tissues either through transtrophoblastic channels and/or via transcellular processes. CONCLUSION: Our data suggest that the translocation of AuNP from maternal blood into the fetus is NP-size dependent which is due to mechanisms involving (1) transport through transtrophoblastic channels - also present in the human placenta - and/or (2) endocytotic and diffusive processes across the placental barrier. PMID- 25928676 TI - Mapping the domain of hypnosis. PMID- 25928677 TI - Orienting hypnosis. AB - This article presents a new frame for understanding hypnosis and its clinical applications. Despite great potential to transform health and care, hypnosis research and clinical integration is impaired in part by centuries of misrepresentation and ignorance about its demonstrated efficacy. The authors contend that advances in the field are primarily encumbered by the lack of distinct boundaries and definitions. Here, hypnosis, trance, and mind are all redefined and grounded in biological, neurological, and psychological phenomena. Solutions are proposed for boundary and language problems associated with hypnosis. The biological role of novelty stimulating an orienting response that, in turn, potentiates systemic plasticity forms the basis for trance. Hypnosis is merely the skill set that perpetuates and influences trance. This formulation meshes with many aspects of Milton Erickson's legacy and Ernest Rossi's recent theory of mind and health. Implications of this hypothesis for clinical skills, professional training, and research are discussed. PMID- 25928678 TI - Traditional and alert hypnotic phenomena: development through anteriorization. AB - Modern research techniques show that hypnotic induction involves behavioral and cognitive inhibition as components of many hypnotic phenomena. One standard laboratory technique for measuring cognitive inhibition is the Go/NoGo procedure. The procedure moves the average, or centroid, of electroencephalography signals toward the frontal, or anterior, part of the brain. This process, called anteriorization, produces a shift in the emotional and cognitive signals from the anterior cingulate cortex. This has implications for both the scientific understanding and clinical use of hypnosis. PMID- 25928679 TI - Placebo and nocebo effects: a complex interplay between psychological factors and neurochemical networks. AB - Placebo and nocebo effects have recently emerged as an interesting model to understand some of the intricate underpinnings of the mind-body interaction. A variety of psychological mechanisms, such as expectation, conditioning, anxiety modulation, and reward, have been identified, and a number of neurochemical networks have been characterized across different conditions, such as pain and motor disorders. What has emerged from the recent insights into the neurobiology of placebo and nocebo effects is that the psychosocial context around the patient and the therapy, which represents the ritual of the therapeutic act, may change the biochemistry and the neuronal circuitry of the patient's brain. Furthermore, the mechanisms activated by placebos and nocebos have been found to be the same as those activated by drugs, which suggests a cognitive/affective interference with drug action. Overall, these findings highlight the important role of therapeutic rituals in the overall therapeutic outcome, including hypnosis, which may have profound implications both in routine medical practice and in the clinical trials setting. PMID- 25928680 TI - Hypnosis and imaging of the living human brain. AB - Over more than two decades, studies using imaging techniques of the living human brain have begun to explore the neural correlates of hypnosis. The collective findings provide a gripping, albeit preliminary, account of the underlying neurobiological mechanisms involved in hypnotic phenomena. While substantial advances lend support to different hypotheses pertaining to hypnotic modulation of attention, control, and monitoring processes, the complex interactions among the many mediating variables largely hinder our ability to isolate robust commonalities across studies. The present account presents a critical integrative synthesis of neuroimaging studies targeting hypnosis as a function of suggestion. Specifically, hypnotic induction without task-specific suggestion is examined, as well as suggestions concerning sensation and perception, memory, and ideomotor response. The importance of carefully designed experiments is highlighted to better tease apart the neural correlates that subserve hypnotic phenomena. Moreover, converging findings intimate that hypnotic suggestions seem to induce specific neural patterns. These observations propose that suggestions may have the ability to target focal brain networks. Drawing on evidence spanning several technological modalities, neuroimaging studies of hypnosis pave the road to a more scientific understanding of a dramatic, yet largely evasive, domain of human behavior. PMID- 25928681 TI - Hypnosis, suggestion, and suggestibility: an integrative model. AB - This article elucidates an integrative model of hypnosis that integrates social, cultural, cognitive, and neurophysiological variables at play both in and out of hypnosis and considers their dynamic interaction as determinants of the multifaceted experience of hypnosis. The roles of these variables are examined in the induction and suggestion stages of hypnosis, including how they are related to the experience of involuntariness, one of the hallmarks of hypnosis. It is suggested that studies of the modification of hypnotic suggestibility; cognitive flexibility; response sets and expectancies; the default-mode network; and the search for the neurophysiological correlates of hypnosis, more broadly, in conjunction with research on social psychological variables, hold much promise to further understanding of hypnosis. PMID- 25928682 TI - Mysteries of hypnosis and the self are revealed by the psychology and neuroscience of empathy. AB - This article reviews a growing body of research and theory in hypnosis and neuroscience that supports the empathic involvement theory (EIT) of hypnosis (Wickramasekera II, 2001; Wickramasekera II & Szlyk, 2003; Wickramasekera II, 2007c). The EIT is a unified transpersonal theory of hypnosis and the self, which weaves together empathic elements of Dzogchen, neodissociative, neuroscience, psychoanalytic, sociocognitive, and other theories by proposing that hypnotic phenomena are inherently characterized by their deep involvement with processes of empathy and the self. The EIT proposes that the experience of hypnosis is embodied in a system of neural networks in the brain that utilizes empathy related processes, adaptive resonance between perceptual input and top-down expectancies, and connectionist learning algorithms to (a) empathically enact the affect, cognition, body language, response expectancies, social roles, sensations, etc. that are presented to them during hypnosis in accordance with socio-cognitive theories of hypnosis; (b) engage in a convergent psychophysiological relationship with another person in accordance with psychoanalytic, Ericksonian, and polyvagal/social engagement system theories; (c) alter the empathic self/other (theory of mind) coding of phenomenological experiences during hypnosis in accordance with aspects of the neo-dissociative and socio-cognitive traditions; and (d) develop an experiential understanding of the illusion of self that may lead, in some people, to its transcendence in accordance with Bon-Buddhist, Dzogchen, and transpersonal scholars. A unified definition of hypnosis is proposed based on findings in the empathic neuroscience of hypnosis as well as a working model of the neuromatrix of the self. PMID- 25928683 TI - Hypnosis, neuroplasticity, and the plastic paradox. PMID- 25928684 TI - Brain Oscillations, Hypnosis, and Hypnotizability. AB - This article summarizes the state-of-science knowledge regarding the associations between hypnosis and brain oscillations. Brain oscillations represent the combined electrical activity of neuronal assemblies, usually measured as specific frequencies representing slower (delta, theta, alpha) and faster (beta, gamma) oscillations. Hypnosis has been most closely linked to power in the theta band and changes in gamma activity. These oscillations are thought to play a critical role in both the recording and recall of declarative memory and emotional limbic circuits. The authors propose that this role may be the mechanistic link between theta (and perhaps gamma) oscillations and hypnosis, specifically, that the increases in theta oscillations and changes in gamma activity observed with hypnosis may underlie some hypnotic responses. If these hypotheses are supported, they have important implications for both understanding the effects of hypnosis and for enhancing response to hypnotic treatments. PMID- 25928689 TI - A little more conversation please? Qualitative study of researchers' and patients' interview accounts of training for patient and public involvement in clinical trials. AB - BACKGROUND: Training in patient and public involvement (PPI) is recommended, yet little is known about what training is needed. We explored researchers' and PPI contributors' accounts of PPI activity and training to inform the design of PPI training for both parties. METHODS: We used semi-structured qualitative interviews with researchers (chief investigators and trial managers) and PPI contributors, accessed through a cohort of clinical trials, which had been funded between 2006 and 2010. An analysis of transcripts of audio-recorded interviews drew on the constant comparative method. RESULTS: We interviewed 31 researchers and 17 PPI contributors from 28 trials. Most researchers could see some value in PPI training for researchers, although just under half had received such training themselves, and some had concerns about the purpose and evidence base for PPI training. PPI contributors were evenly split in their perceptions of whether researchers needed training in PPI. Few PPI contributors had themselves received training for their roles. Many informants across all groups felt that training PPI contributors was unnecessary because they already possessed the skills needed. Informants were also concerned that training would professionalise PPI contributors, limiting their ability to provide an authentic patient perspective. However, informants welcomed informal induction 'conversations' to help contributors understand their roles and support them in voicing their opinions. Informants believed that PPI contributors should be confident, motivated, intelligent, focussed on helping others and have relevant experience. Researchers looked for these qualities when selecting contributors, and spoke of how finding 'the right' contributor was more important than accessing 'the right' training. CONCLUSIONS: While informants were broadly receptive to PPI training for researchers, they expressed considerable reluctance to training PPI contributors. Providers of training will need to address these reservations. Our findings point to the importance of reconsidering how training is conceptualised, designed and promoted and of providing flexible, learning opportunities in ways that flow from researchers' and contributors' needs and preferences. We also identify some areas of training content and the need for further consideration to be given to the selection of PPI contributors and models for implementing PPI to ensure clinical trials benefit from a diversity of patient perspectives. PMID- 25928690 TI - Mercury physicochemical and biogeochemical transformation in the atmosphere and at atmospheric interfaces: a review and future directions. PMID- 25928693 TI - Using conjoint analysis to develop a system to score research engagement actions by health decision makers. AB - BACKGROUND: Effective use of research to inform policymaking can be strengthened by policymakers undertaking various research engagement actions (e.g., accessing, appraising, and applying research). Consequently, we developed a thorough measurement and scoring tool to assess whether and how policymakers undertook research engagement actions in the development of a policy document. This scoring tool breaks down each research engagement action into its key 'subactions' like a checklist. The primary aim was to develop the scoring tool further so that it assigned appropriate scores to each subaction based on its effectiveness for achieving evidence-informed policymaking. To establish the relative effectiveness of these subactions, we conducted a conjoint analysis, which was used to elicit the opinions and preferences of knowledge translation experts. METHOD: Fifty-four knowledge translation experts were recruited to undertake six choice surveys. Respondents were exposed to combinations of research engagement subactions called 'profiles', and rated on a 1-9 scale whether each profile represented a limited (1-3), moderate (4-6), or extensive (7-9) example of each research engagement action. Generalised estimating equations were used to analyse respondents' choice data, where a utility coefficient was calculated for each subaction. A large utility coefficient indicates that a subaction was influential in guiding experts' ratings of extensive engagement with research. RESULTS: The calculated utilities were used as the points assigned to the subactions in the scoring system. The following subactions yielded the largest utilities and were regarded as the most important components of engaging with research: searching academic literature databases, obtaining systematic reviews and peer-reviewed research, appraising relevance by verifying its applicability to the policy context, appraising quality by evaluating the validity of the method and conclusions, engaging in thorough collaborations with researchers, and undertaking formal research projects to inform the policy in question. CONCLUSIONS: We have generated an empirically-derived and context-sensitive method of measuring and scoring the extent to which policymakers engaged with research to inform policy development. The scoring system can be used by organisations to quantify staff research engagement actions and thus provide them with insights into what types of training, systems, and tools might improve their staff's research use capacity. PMID- 25928695 TI - Implementation science: a reappraisal of our journal mission and scope. AB - The implementation of research findings into healthcare practice has become increasingly recognised as a major priority for researchers, service providers, research funders and policymakers over the past decade. Nine years after its establishment, Implementation Science, an international online open access journal, currently publishes over 150 articles each year. This is fewer than 30% of those submitted for publication. The majority of manuscript rejections occur at the point of initial editorial screening, frequently because we judge them to fall outside of journal scope. There are a number of common reasons as to why manuscripts are rejected on grounds of scope. Furthermore, as the field of implementation research has evolved and our journal submissions have risen, we have, out of necessity, had to become more selective in what we publish. We have also expanded our scope, particularly around patient-mediated and population health interventions, and will monitor the impact of such changes. We hope this editorial on our evolving priorities and common reasons for rejection without peer review will help authors to better judge the relevance of their papers to Implementation Science. PMID- 25928694 TI - Epidemiology of invasive aspergillosis in critically ill patients: clinical presentation, underlying conditions, and outcomes. AB - INTRODUCTION: Invasive aspergillosis (IA) is a fungal infection that particularly affects immunocompromised hosts. Recently, several studies have indicated a high incidence of IA in intensive care unit (ICU) patients. However, few data are available on the epidemiology and outcome of patients with IA in this setting. METHODS: An observational study including all patients with a positive Aspergillus culture during ICU stay was performed in 30 ICUs in 8 countries. Cases were classified as proven IA, putative IA or Aspergillus colonization according to recently validated criteria. Demographic, microbiologic and diagnostic data were collected. Outcome was recorded 12 weeks after Aspergillus isolation. RESULTS: A total of 563 patients were included, of whom 266 were colonized (47%), 203 had putative IA (36%) and 94 had proven IA (17%). The lung was the most frequent site of infection (94%), and Aspergillus fumigatus the most commonly isolated species (92%). Patients with IA had higher incidences of cancer and organ transplantation than those with colonization. Compared with other patients, they were more frequently diagnosed with sepsis on ICU admission and more frequently received vasopressors and renal replacement therapy (RRT) during the ICU stay. Mortality was 38% among colonized patients, 67% in those with putative IA and 79% in those with proven IA (P < 0.001). Independent risk factors for death among patients with IA included older age, history of bone marrow transplantation, and mechanical ventilation, RRT and higher Sequential Organ Failure Assessment score at diagnosis. CONCLUSIONS: IA among critically ill patients is associated with high mortality. Patients diagnosed with proven or putative IA had greater severity of illness and more frequently needed organ support than those with Aspergillus spp colonization. PMID- 25928696 TI - A randomised controlled intervention trial evaluating the efficacy of a Mediterranean dietary pattern on cognitive function and psychological wellbeing in healthy older adults: the MedLey study. AB - BACKGROUND: The incidence of age-related cognitive decline is rising considerably around the world. There is evidence from a number of recent cross-sectional and prospective studies indicating positive associations between the Mediterranean dietary pattern (MedDiet) and improved cognitive outcomes among the elderly including, reduced age-related cognitive decline and enhanced age-related cognitive performance. However, to date no study has validated these associations in healthy older adult populations (>=65 years and above) with randomised evidence. The main aim of the present study is to provide justified evidence regarding the efficacy of a MedDiet approach to safely reduce the onset of cognitive decline, and promote optimal cognitive performance among healthy older adults using rigorous, randomised intervention methodology. METHODS/DESIGN: MedLey is a 6-month, randomised controlled 2-cohort parallel group intervention trial, with initial assessment at baseline and repeated every three months. A sample of 166 healthy Australian men and women aged 65 years and above, with normal cognitive function and proficient in English language were recruited from metropolitan Adelaide, South Australia for the study. Participants randomly allocated to the experimental group are required to maintain an intervention dietary pattern based from the traditional Cretan MedDiet (i.e. vegetables, fruits, olive oil, legumes, fish, whole grain cereals, nuts and seeds and low consumption of processed foods, dairy products, red meat and vegetable oils) for six months, while those participants allocated to the control group are asked to maintain their customary lifestyle and diet. The primary outcome of interest is the quantitative difference in age-related cognitive performance, as measured by latent variables (cognitive constructs) sensitive to normal ageing and diet (i.e. speed of processing, memory, attention, executive functions, visual spatial and visuomotor ability). Secondary outcomes include change in biomarkers of inflammation, oxidative stress, lipid metabolism, glucose, insulin, blood flow velocity, and psychological well-being factors (i.e. stress, sleep, anxiety, depression). DISCUSSION: To our knowledge this will be one of the first randomised clinical trials worldwide to provide evidence for the cause-effect relationship between the MedDiet and age-related cognitive function in a healthy older adult population (>=65 years and over). TRIAL REGISTRATION: Australia and New Zealand Clinical Trials Register (ANZCTR): ACTRN12613000602729. PMID- 25928697 TI - Skeletal muscle insulin resistance in salt-sensitive hypertension: role of angiotensin II activation of NFkappaB. AB - BACKGROUND: We have previously shown that in hypertensive Dahl salt-sensitive (DS) rats, impaired endothelium-dependent relaxation to acetylcholine and to insulin is mechanistically linked to up-regulation of angiotensin (Ang) II actions and the production of reactive oxygen species (ROS) and to activation of the proinflammatory transcription factor (NF)kappaB. Here we investigated whether Ang II activation of NFkappaB contributed to insulin resistance in the skeletal muscle of this animal model. METHODS: DS rats were fed either a normal (NS, 0.5% NaCl) or high (HS, 4% NaCl) salt diet for 6 weeks. In addition, 3 separate groups of HS rats were given angiotensin receptor 1 blocker candesartan (ARB, 10 mg/kg/day in drinking water), antioxidant tempol (1 mmol/L in drinking water) or NFkappaB inhibitor PDTC (150 mg/kg in drinking water). RESULTS: DS rats manifested an increase in soleus muscle Ang II content, ROS production and phosopho-IkappaBalpha/IkappaBalpha ratio, ARB or tempol reduced ROS and phospho IkappaBalpha/IkappaBalpha ratio. Hypertensive DS rats also manifested a reduction in glucose infusion rate, impaired insulin-induced Akt phosphorylation and Glut-4 translocation in the soleus muscle, which were prevented with treatment of either ARB, tempol, or PDTC. Data from the rat diabetes signaling pathway PCR array showed that 8 genes among 84 target genes were altered in the muscle of hypertensive rats with the increase in gene expression of ACE1 and 5 proinflammatory genes, and decrease of 2 glucose metabolic genes. Incubation of the muscle with NFkappaB SN50 (a specific peptide inhibitor of NFkappaB) ex vivo reversed changes in hypertension-induced gene expression. CONCLUSION: The current findings strongly suggest that the activation of NFkappaB inflammatory pathway by Ang II play a critical role in skeletal muscle insulin resistance in salt sensitive hypertension. PMID- 25928698 TI - Whole exome sequencing in an Indian family links Coats plus syndrome and dextrocardia with a homozygous novel CTC1 and a rare HES7 variation. AB - BACKGROUND: Coats plus syndrome is an autosomal recessive, pleiotropic, multisystem disorder characterized by retinal telangiectasia and exudates, intracranial calcification with leukoencephalopathy and brain cysts, osteopenia with predisposition to fractures, bone marrow suppression, gastrointestinal bleeding and portal hypertension. It is caused by compound heterozygous mutations in the CTC1 gene. CASE PRESENTATION: We encountered a case of an eight-year old boy from an Indian family with manifestations of Coats plus syndrome along with an unusual occurrence of dextrocardia and situs inversus. Targeted resequencing of the CTC1 gene as well as whole exome sequencing (WES) were conducted in this family to identify the causal variations. The identified candidate variations were screened in ethnicity matched healthy controls. The effect of CTC1 variation on telomere length was assessed using Southern blot. A novel homozygous missense mutation c.1451A > C (p.H484P) in exon 9 of the CTC1 gene and a rare 3'UTR known dbSNP variation (c.*556 T > C) in HES7 were identified as the plausible candidates associated with this complex phenotype of Coats plus and dextrocardia. This CTC1 variation was absent in the controls and we also observed a reduced telomere length in the affected individual's DNA, suggesting its likely pathogenic nature. The reported p.H484P mutation is located in the N-terminal 700 amino acid regionthat is important for the binding of CTC1 to ssDNA through its two OB domains. WES data also showed a rare homozygous missense variation in the TEK gene in the affected individual. Both HES7 and TEK are targets of the Notch signaling pathway. CONCLUSIONS: This is the first report of a genetically confirmed case of Coats plus syndrome from India. By means of WES, the genetic variations in this family with unique and rare complex phenotype could be traced effectively. We speculate the important role of Notch signaling in this complex phenotypic presentation of Coats plus syndrome and dextrocardia. The present finding will be useful for genetic diagnosis and carrier detection in the family and for other patients with similar disease manifestations. PMID- 25928699 TI - Use of Remifentanil in a Novel Clinical Paradigm to Characterize Onset and Duration of Opioid Blockade by Samidorphan, a Potent MU-Receptor Antagonist. AB - A novel clinical study design was used to evaluate the blockade of a selective short-acting MU-opioid agonist (remifentanil) in 24 opioid-experienced subjects. Samidorphan (3-carboxamido-4-hydroxynaltrexone) is a novel opioid modulator with MU-antagonist properties. Objective (pupil diameter) and subjective (visual analog scale) responses to repeated remifentanil and saline infusion challenges were assessed after single oral administration of placebo (day 1) and samidorphan (day 2). Complete blockade persisted with samidorphan for 24 hours for pupil miosis and 48 hours for the drug liking visual analog scale. Samidorphan effects persisted beyond measurable samidorphan exposure (t1/2 = 7 hours). Samidorphan was associated with complete blockade of remifentanil, and the duration supports daily administration. This study used a novel approach with multiple administrations of remifentanil to successfully demonstrate a durable effect with samidorphan and a rapid and potent blockade of physiological and subjective MU opioid effects. PMID- 25928700 TI - Interrater reliability of the modified Monitoring of Side Effects Scale for assessment of adverse effects of psychiatric medication in clinical and research settings. AB - The assessment of adverse effects of psychiatric medications is important in clinical and research settings because they are often associated with medication discontinuation, symptom exacerbation, and reduced quality of life. Currently available assessment tools are either limited with regard to the number and variety of included adverse effects or are not practical for use in most clinical or research settings owing to specialized rater training required and administration length. This report describes a modification of the Monitoring of Side Effects Scale (MOSES), an established adverse effect rating scale, by adding severity anchors to improve its reliability and ease of use. Interrater reliability was good for 7 of the 8 bodily adverse effects assessed, with intraclass correlation coefficients ranging from 0.76 to 0.91 in a sample of patients with severe mental illness. This modified version of the Monitoring of Side Effects Scale holds promise as a useful tool for assessing medication adverse effects in clinical and research settings. PMID- 25928701 TI - Concomitant benzodiazepine use attenuates ketamine response: implications for large scale study design and clinical development. PMID- 25928702 TI - Exacerbation of tics after combining aripiprazole with pimozide: a case with Tourette Syndrome. PMID- 25928703 TI - Persistent genital arousal disorder following selective serotonin reuptake inhibitor cessation. PMID- 25928704 TI - Treatment of binge eating disorder with high-dose baclofen: a case series. PMID- 25928705 TI - Disappearance of soft drusen and subsequent development of choroidal neovascularization following macular hole surgery: a case report. AB - BACKGROUND: Drusen are important risk factor for neovascular age-related macular degeneration (AMD) and have a dynamic nature as they can enlarge, newly form, or disappear over time. There have been few reports on drusen regression or choroidal neovascularization (CNV) development after macular hole surgery. We report, to our knowledge, the first case of both drusen regression and subsequent CNV development within 7 months of successful macular hole surgery. CASE PRESENTATION: A 73-year-old woman presented with a stage 3 full-thickness macular hole and large, confluent soft macular drusen in the right eye and a neovascular age-related macular degeneration (AMD) in the fellow eye. Four months after the successful macular hole surgery, significant regression of drusen was seen, especially in the temporal area to the fovea. Three months later, the patient developed CNV and her best-corrected visual acuity decreased to 20/100, despite further regression of macular drusen. CONCLUSIONS: Macular hole patients with macular soft drusen need to be carefully followed up after surgery for possible drusen regression and CNV development. PMID- 25928706 TI - Stomach cancer and occupational exposure to asbestos: a meta-analysis of occupational cohort studies. AB - BACKGROUND: A recent Monographs Working Group of the International Agency for Research on Cancer concluded that there is limited evidence for a causal association between exposure to asbestos and stomach cancer. METHODS: We performed a meta-analysis to quantitatively evaluate this association. Random effects models were used to summarise the relative risks across studies. Sources of heterogeneity were explored through subgroup analyses and meta-regression. RESULTS: We identified 40 mortality cohort studies from 37 separate papers, and cancer incidence data were extracted for 15 separate cohorts from 14 papers. The overall meta-SMR for stomach cancer for total cohort was 1.15 (95% confidence interval 1.03-1.27), with heterogeneous results across studies. Statistically significant excesses were observed in North America and Australia but not in Europe, and for generic asbestos workers and insulators. Meta-SMRs were larger for cohorts reporting a SMR for lung cancer above 2 and cohort sizes below 1000. CONCLUSIONS: Our results support the conclusion by IARC that exposure to asbestos is associated with a moderate increased risk of stomach cancer. PMID- 25928707 TI - Cancer risk in the relatives of patients with nasopharyngeal carcinoma-a register based cohort study in Sweden. AB - BACKGROUND: Little is known about cancer susceptibility among relatives of nasopharyngeal carcinoma (NPC) patients in non-endemic areas. We conducted a register-based cohort study to assess the relative risks (RRs) of cancer in families of NPC probands in Sweden. METHODS: By linking 11,602,616 Swedish-born individuals (defined as 'general population') identified from national censuses to the Swedish Cancer Register and Multi-Generation Register, we identified 9157 relatives (3645 first-degree and 5512 second-degree) of 1211 NPC probands. Cancer incidence during 1961-2009 was ascertained through the Cancer Register. Relative risks of cancer in the relatives of NPC probands, compared with the rest of the general population, were calculated from Poisson regression models. RESULTS: First-degree relatives had higher risks of NPC (N=2, RR=4.29, 95% confidence interval (CI)=1.07 to 17.17) and cancers of the larynx (N=5, RR=2.53, 95% CI=1.05 to 6.09), prostate (N=76, RR=1.35, 95% CI=1.07 to 1.68), and thyroid (N=10, RR=2.44, 95% CI=1.31 to 4.53) than the rest of the general population. In addition, a raised risk of cancer of the salivary glands was observed among first degree relatives of probands with undifferentiated NPC (N=2, RR=6.64, 95% CI=1.66 to 26.57). In contrast, a decreased risk of colorectal cancer was observed in first- and second-degree relatives (N=43, RR=0.71, 95% CI=0.53 to 0.96). CONCLUSION: The increased risk of NPC and certain other cancers among first degree relatives may be explained by shared genetic and environmental risk factors, the latter including Epstein-Barr virus infection and smoking or by increased diagnostic intensity. PMID- 25928708 TI - Physiological ER Stress Mediates the Differentiation of Fibroblasts. AB - Recently, accumulating reports have suggested the importance of endoplasmic reticulum (ER) stress signaling in the differentiation of several tissues and cells, including myoblasts and osteoblasts. Secretory cells are easily subjected to ER stress during maturation of their secreted proteins. Skin fibroblasts produce and release several proteins, such as collagens, matrix metalloproteinases (MMPs), the tissue inhibitors of metalloproteinases (TIMPs) and glycosaminoglycans (GAGs), and the production of these proteins is increased at wound sites. Differentiation of fibroblasts into myofibroblasts is one of the key factors for wound healing and that TGF-beta can induce fibroblast differentiation into myofibroblasts, which express alpha-smooth muscle actin. Well-differentiated myofibroblasts show increased production of collagen and TGF beta, and bring about wound healing. In this study, we examined the effects of ER stress signaling on the differentiation of fibroblasts, which is required for wound healing, using constitutively ER stress-activated primary cultured fibroblasts. The cells expressed positive alpha-smooth muscle actin signals without TGF-beta stimulation compared with control fibroblasts. Gel-contraction assays suggested that ER stress-treated primary fibroblasts caused stronger shrinkage of collagen gels than control cells. These results suggest that ER stress signaling could accelerate the differentiation of fibroblasts to myofibroblasts at injured sites. The present findings may provide important insights for developing therapies to improve wound healing. PMID- 25928709 TI - Impact of ICU-acquired weakness on post-ICU physical functioning: a follow-up study. AB - INTRODUCTION: ICU-acquired weakness is thought to mediate physical impairments in survivors of critical illness, but few studies have investigated this thoroughly. The purpose was to investigate differences in post-ICU mortality and physical functioning between patients with and without ICU-acquired weakness at 6 months after ICU discharge. METHOD: ICU patients, mechanically ventilated >= 2 days, were included in a single-center prospective observational cohort study. ICU acquired weakness was diagnosed when the average Medical Research Council score was <4 in awake and attentive patients. Post-ICU mortality was recorded until 6 months after ICU discharge; in surviving patients, physical functioning was assessed using the Short-Form Health Survey physical functioning domain. The independent effect of ICU-acquired weakness on post-ICU mortality was analyzed using a multivariable Cox proportional hazards model. The independent effect of ICU-acquired weakness on the physical functioning domain score was analyzed using a multivariable linear regression model. RESULTS: Of the 156 patients included, 80 had ICU-acquired weakness. Twenty-three patients died in the ICU (20 with ICU acquired weakness); during 6 months follow-up after ICU discharge another 25 patients died (17 with ICU-acquired weakness). Physical functioning domain scores were available for 96 survivors (39 patients with ICU-acquired weakness). ICU acquired weakness was independently associated with an increase in post-ICU mortality (hazard ratio 3.6, 95% confidence interval, 1.3 to 9.8; P = 0.01) and with a decrease in physical functioning (beta: -16.7 points; 95% confidence interval, -30.2 to -3.1; P = 0.02). CONCLUSION: ICU-acquired weakness is independently associated with higher post-ICU mortality and with clinically relevant lower physical functioning in survivors at 6 months after ICU discharge. PMID- 25928711 TI - The Lipoxygenase Gene Family in Poplar: Identification, Classification, and Expression in Response to MeJA Treatment. AB - BACKGROUND: Lipoxygenases (LOXs) are important dioxygenases in cellular organisms. LOXs contribute to plant developmental processes and environmental responses. However, a systematic and comprehensive analysis has not been focused on the LOX gene family in poplar. Therefore, in the present study, we performed a comprehensive analysis of the LOX gene family in poplar. RESULTS: Using bioinformatics methods, we identified a total of 20 LOX genes. These LOX genes were clustered into two subfamilies. The gene structure and motif composition of each subfamily were relatively conserved. These genes are distributed unevenly across nine chromosomes. The PtLOX gene family appears to have expanded due to high tandem and low segmental duplication events. Microarray analysis showed that a number of PtLOX genes have different expression pattern across disparate tissues and under various stress treatments. Quantitative real-time PCR (qRT-PCR) analysis was further performed to confirm the responses to MeJA treatment of the 20 poplar LOX genes. The results show that the PtLOX genes are regulated by MeJA (Methyl jasmonate) treatment. CONCLUSIONS: This study provides a systematic analysis of LOX genes in poplar. The gene family analysis reported here will be useful for conducting future functional genomics studies to uncover the roles of LOX genes in poplar growth and development. PMID- 25928712 TI - Severity score for hereditary hemorrhagic telangiectasia. AB - BACKGROUND: A disease severity score in hereditary hemorrhagic telangiectasia (HHT) would be a useful tool for assessing burden of disease and for designing clinical trials. Here, we propose the first known HHT severity score, the HHT score. METHODS: Demographics and disease characteristics were collected for the first 525 HHT patients recruited to the HHT Project of the Brain Vascular Malformation Consortium (BVMC). HHT-score was calculated based on presence of: organ arteriovenous malformations (maximum 3 points); chronic bleeding (maximum 2 points); and severe organ involvement (maximum 2 points). Points were summed and patients categorized as having mild (0-2), moderate (3-4) or severe (5-7) disease. The occurrence of "any adverse outcome" was evaluated for association with HHT-score categories. RESULTS: The frequency of "any adverse outcome" was significantly different across the three groups (49.6% in mild, 65.8% in moderate and 89.5% in severe, p<0.001). Adjusting for age and gender, the risk of "any adverse outcome" was higher in the moderate (OR=1.84, 95% CI: 1.15-2.95, p=0.011) and severe groups (OR=9.16, 95% CI: 1.99-42.09, p=0.004) compared to the mild. CONCLUSIONS: We have taken the first steps toward creating a global measure of disease severity in HHT. While the initial results are promising, further validation of the HHT-score is still required. PMID- 25928713 TI - Increasing trends of herpes zoster in Australia. AB - BACKGROUND: Increasing trends in incidence of herpes zoster (HZ) have been reported in Australia and internationally. This may reflect the impact of childhood VZV vaccination programs introduced universally in Australia in late 2005. The objective of this study was to evaluate changes in incidence of HZ and PHN in Australia over time, and associated healthcare resource utilisation. METHODS: Australian data on general practice (GP) encounters for HZ, specific antiviral prescribing data from the pharmaceutical benefits scheme, emergency department presentations from the states of NSW and Victoria and national hospitalisation data for HZ were analysed for time trends using regression models. Two time periods (2000-2006 and 2006-2013) were compared which correspond broadly with the pre- and post- universal VZV vaccination period. RESULTS: All data sources showed increasing rates of HZ with age and over time. The GP database showed a significant annual increase in encounters for HZ of 2.5 per 100,000 between 1998 and 2013, and the rates of prescriptions for HZ increased by 4.2% per year between 2002 and 2012. In the 60+ population HZ incidence was estimated to increase from 11.9 to 15.4 per 1,000 persons using GP data or from 12.8 to 14.2 per 1,000 persons using prescription data (p<0.05, between the two periods). Hospitalisation data did not show the same increasing trend over time, except for the age group >=80 years. Most emergency visits for HZ were not admitted, and showed significant increases over time. DISCUSSION: The burden of HZ in Australia is substantial, and continues to increase over time. This increase is seen both pre- and post-universal VZV vaccination in 2005, and is most prominent in the older population. The substantial burden of HZ, along with ageing of the Australian population and the importance of healthy ageing, warrants consideration of HZ vaccination for the elderly. PMID- 25928714 TI - Efficacy of aerobic physical retraining in a case of combined pulmonary fibrosis and emphysema syndrome: a case report. AB - INTRODUCTION: Combined pulmonary fibrosis and emphysema has recently been recognized as a syndrome but remains under-diagnosed. Neither clinical management nor therapeutic approaches have been clearly defined. Pulmonary rehabilitation has not been considered within the therapeutic options for combined pulmonary fibrosis and emphysema. In this case we explored the potential benefits of a specific aerobic physical retraining program in the management of combined pulmonary fibrosis and emphysema. CASE PRESENTATION: We describe the case of a 65 year-old Caucasian man with combined pulmonary fibrosis and emphysema and respiratory failure who was receiving long-term oxygen therapy. Our patient underwent physical retraining with moderate intensity aerobic and breathing exercises for four weeks. Clinical and motor tests, as well as questionnaires assessing quality of life and depression levels, were performed prior to and following the retraining. At the end of the retraining program a relevant reduction of long-term oxygen therapy requirement was registered; improvements in terms of physical performance, quality of life, and mood were observed in our patient but no change in respiratory parameters. CONCLUSIONS: A program of aerobic physical retraining appears to be beneficial to patients with combined pulmonary fibrosis and emphysema and may be considered as an additional therapeutic option. PMID- 25928715 TI - Target values of cardiovascular risk factors are not associated with all-cause mortality in patients with type 2 diabetes mellitus. AB - BACKGROUND: To investigate prospectively the relationship between target values of glycated hemoglobin, blood pressure and LDL-cholesterol, as considered in a combined fashion, and all-cause mortality in patients with type 2 diabetes mellitus. METHODS: Two cohorts of patients with type 2 diabetes mellitus, the Gargano Mortality Study (n=810) and the Foggia Mortality Study (n=929), were investigated. A weighted target risk score was built as a weight linear combination of the recommended targets reached by each patient. RESULTS: In the Gargano Mortality Study and in the Foggia Mortality Study (mean follow up=7.4 and 5.5 years, respectively), 161 (19.9%) and 220 (23.7%) patients died, with an age and sex adjusted annual incidence rate of 2.1 and 2.8 per 100 person-years, respectively. In both study samples the weighted target risk score tended to be linearly associated with all-cause mortality (HR for one point increment=1.30, 95% CI: 1.11-1.53, p=0.001, and HR=1.08, 95% CI: 0.95-1.24, p=0.243, respectively). When the two cohorts were pooled and analyzed together, a clear association between weighted target risk score and all-cause mortality was observed (HR for one point increment=1.17, 95% CI:1.05-1.30, p=0.004). This counterintuitive association was no longer observable in a model including age, sex, body mass index, smoking habit, estimated glomerular filtration rate, albuminuria and anti-diabetic, anti-hypertensive and anti-dyslipidemic treatment as covariates (HR for one point increment=0.99, 95% CI: 0.87-1.12, p=0.852). CONCLUSIONS: In a real life clinical set of patients with type 2 diabetes mellitus, the combination of recommended target values of established cardiovascular risk factors is not associated with all-cause mortality. PMID- 25928718 TI - Flow regulation in coronary vascular tree: a model study. AB - BACKGROUND: Coronary blood flow can always be matched to the metabolic demand of the myocardium due to the regulation of vasoactive segments. Myocardial compressive forces play an important role in determining coronary blood flow but its impact on flow regulation is still unknown. The purpose of this study was to develop a coronary specified flow regulation model, which can integrate myocardial compressive forces and other identified regulation factors, to further investigate the coronary blood flow regulation behavior. METHOD: A theoretical coronary flow regulation model including the myogenic, shear-dependent and metabolic responses was developed. Myocardial compressive forces were included in the modified wall tension model. Shear-dependent response was estimated by using the experimental data from coronary circulation. Capillary density and basal oxygen consumption were specified to corresponding to those in coronary circulation. Zero flow pressure was also modeled by using a simplified capillary model. RESULT: Pressure-flow relations predicted by the proposed model are consistent with previous experimental data. The predicted diameter changes in small arteries are in good agreement with experiment observations in adenosine infusion and inhibition of NO synthesis conditions. Results demonstrate that the myocardial compressive forces acting on the vessel wall would extend the auto regulatory range by decreasing the myogenic tone at the given perfusion pressure. CONCLUSIONS: Myocardial compressive forces had great impact on coronary auto regulation effect. The proposed model was proved to be consistent with experiment observations and can be employed to investigate the coronary blood flow regulation effect in physiological and pathophysiological conditions. PMID- 25928716 TI - Associations between prenatal physical activity, birth weight, and DNA methylation at genomically imprinted domains in a multiethnic newborn cohort. AB - Birth weight is a commonly used indicator of the fetal environment and a predictor of future health outcomes. While the etiology of birth weight extremes is likely multifactorial, epidemiologic data suggest that prenatal physical activity (PA) may play an important role. The mechanisms underlying this association remain unresolved, although epigenetics has been proposed. This study aimed to estimate associations between prenatal PA, birth weight, and newborn DNA methylation levels at differentially methylated regions (DMRs) regulating 4 imprinted genes known to be important in fetal development. Study participants (N = 1281) were enrolled as part of the Newborn Epigenetics Study. Prenatal PA was ascertained using the Pregnancy Physical Activity Questionnaire, and birth weight data obtained from hospital records. Among 484 term mother-infant pairs, imprinted gene methylation levels were measured at DMRs using bisulfite pyrosequencing. Generalized linear and logistic regression models were used to estimate associations. After adjusting for preterm birth and race/ethnicity, we found that infants born to mothers in the highest quartile of total non-sedentary time had lower birth weight compared to infants of mothers in the lowest quartile (beta = -81.16, SE = 42.02, P = 0.05). These associations appeared strongest among male infants (beta = -125.40, SE = 58.10, P = 0.03). Methylation at the PLAGL1 DMR was related to total non-sedentary time (P < 0.05). Our findings confirm that prenatal PA is associated with reduced birth weight, and is the first study to support a role for imprinted gene plasticity in these associations. Larger studies are required. PMID- 25928719 TI - Top ten reasons to read behavioral sleep medicine. PMID- 25928724 TI - Postoperative Visual Acuity Should Be Reported in Studies of Binocular Summation Reply. PMID- 25928721 TI - MicroRNA-124 Targets Tip110 Expression and Regulates Hematopoiesis. AB - MicroRNA (miR) regulates hematopoiesis through targeting different genes post transcriptionally. We have recently shown that Tip110 expression is downregulated during hematopoietic stem cell differentiation. However, the underlying mechanisms are not known. In this study, we identified a conserved miR-124 binding site on the Tip110 3'-untranslated region (3'-UTR) and showed that Tip110 was downregulated by miR-124 through its 3'-UTR. We then examined the relationship among miR-124 and Tip110 expression and differentiation of human cord blood CD34(+) cells. We found that miR-124 was expressed in a low level in human cord blood CD34(+) cells, but it was considerably upregulated during culturing and differentiation of these cells. Moreover, we demonstrated that miR 124 expression decreased Tip110 expression and promoted differentiation of human cord blood CD34(+) cells, while miR-124 knockdown increased Tip110 expression, slowed down differentiation of human cord blood CD34(+) cells, and caused an expansion of hematopoietic progenitor cells in vitro. Finally, we used mouse embryonic fibroblasts derived from Tip110 transgenic mice, performed the exon array analysis, and found that Tip110 altered a number of genes in the hematopoiesis pathways. Dnmt3a as de novo methyltransferase was also significantly upregulated. That miR-124 was markedly upregulated during human cord blood CD34(+) cell differentiation could be the result of direct loss of its promoter methylation from Dnmt3a. Taken together, our study demonstrates that miR 124 regulates Tip110 expression and differentiation of human cord blood CD34(+) cells and suggests important roles of miR-124/Tip110 in hematopoiesis. PMID- 25928727 TI - Hypertension-Management of Hypertensive Disorders of Pregnancy According to International Guidelines: A Panel Discussion (Case 2: Severe Gestational Hypertension). PMID- 25928726 TI - Si- and C-Functional Organosilicon Building Blocks for Synthesis Based on 4 Silacyclohexan-1-ones Containing the Silicon Protecting Groups MOP (4 Methoxyphenyl), DMOP (2,6-Dimethoxyphenyl), or TMOP (2,4,6-Trimethoxyphenyl). AB - 4-Silacyclohexan-1-ones 1a-1c, 4-silacyclohexan-1-one oximes 2a-2c, 1,4 azasilepan-7-ones 3a-3c, 1,4-azasilepanes 4a-4c, and 2-bromo-4-silacyclohexan-1 ones 5a and 5b were prepared in multistep syntheses, starting from trimethoxypropylsilane. All of these compounds represent C-functional (R2C?O, R2C?N-OH, R-NH(C?O)-R, R2NH, or R3C-Br) silicon-containing heterocycles that contain Si-MOP, Si-DMOP, or Si-TMOP moieties (MOP = 4-methoxyphenyl; DMOP = 2,6 dimethoxyphenyl; TMOP = 2,4,6-trimethoxyphenyl), which can be cleaved under mild conditions by protodesilylation. As a proof of principle, compounds 3a-3c were transformed quantitatively and selectively into the chlorosilane 6 (treatment with hydrogen chloride in dichloromethane). Thus, the C- and Si-functional compounds 1a-1c, 2a-2c, 3a-3c, 4a-4c, 5a, and 5b represent versatile building blocks for synthesis. PMID- 25928728 TI - Theoretical Study on the Dynamics of the Reaction of HNO((1)A') with HO2((2)A"). AB - We used stochastic one-dimensional chemical master equation (CME) simulation to gain insight into the dynamics of the reaction of HNO((1)A') with HO2((2)A"). The reaction takes place over a multiwell, multichannel potential energy surface that is based on the computations at the CBS-QB3 level of theory. The calculated multipath potential energy surface consists of three potential wells and three van der Waals complexes. In solving the master equation, the Lennard-Jones potential is used to model the collision between the collider gases. The fractional population of different intermediates and products in the early stages of the reaction is examined to determine the role of the energized intermediates and van der Waals complexes on the kinetics of the title reaction. The major products of the title reaction at lower temperatures are OH, HNO2, HNOH, and O2(X(3)Sigmag(-)). The temperature- and pressure-dependence of the reaction over a wide range of temperature (300-3000 K) and pressure (0.1-2000 Torr) are studied. No sign of pressure dependence was being observed for the title reaction over the stated range of pressure. The calculated rate constants from the CME simulation are compared with those obtained from the RRKM-SSA method that is based on strong collision assumption. Our results indicate that the strong collision assumption increases the calculated rate constant for the formation of the main products (HNO2 + OH) by a factor of 2 at 300 K and 1 atm pressure, compared to the results of CME simulation, although the results are in good agreement at higher temperatures. PMID- 25928729 TI - Saffron as an antidote or a protective agent against natural or chemical toxicities. AB - Saffron (Crocus sativus) is an extensively used food additive for its color and taste. Since ancient times this plant has been introduced as a marvelous medicine throughout the world. The wide spectrum of saffron pharmacological activities is related to its major constituents including crocin, crocetin and safranal. Based on several studies, saffron and its active ingredients have been used as an antioxidant, antiinflammatory and antinociceptive, antidepressant, antitussive, anticonvulsant, memory enhancer, hypotensive and anticancer. According to the literatures, saffron has remarkable therapeutic effects. The protective effects of saffron and its main constituents in different tissues including brain, heart, liver, kidney and lung have been reported against some toxic materials either natural or chemical toxins in animal studies.In this review article, we have summarized different in vitro and animal studies in scientific databases which investigate the antidotal and protective effects of saffron and its major components against natural toxins and chemical-induced toxicities. Due to the lake of human studies, further investigations are required to ascertain the efficacy of saffron as an antidote or a protective agent in human intoxication. PMID- 25928730 TI - Human artificial chromosomes for future biomedicine. PMID- 25928731 TI - Global constitutionalism, responsibility to protect, and extra-territorial obligations to realize the right to health: time to overcome the double standard (once again). AB - If human rights are "inalienable rights of all members of the human family", as is enshrined in the Universal Declaration of Human Rights, then no government should be allowed to deny people of them. When some governments fail to realize them for the people under their jurisdiction, the international community has a responsibility to step in. This extra-territorial effect of human rights was not included in the original conception of human rights. It is of recent date, and, in practice, limited to interventions to end severe violations of civil and political human rights. For economic, social and cultural human rights, extra territorial obligations are still contested. In this paper, we elaborate three contentions: first, that the realization of social human rights requires the acceptance of and compliance with extra-territorial obligations; second, that compliance with extra-territorial obligations would help transform the international assistance paradigm from charity into legal obligation; and third, that for global constitutionalism to succeed in improving the fairness of the international legal order requires acceptance of the indivisibility of human rights. PMID- 25928732 TI - Photo-cross-linkable methacrylated gelatin and hydroxyapatite hybrid hydrogel for modularly engineering biomimetic osteon. AB - Modular tissue engineering holds great potential in regenerating natural complex tissues by engineering three-dimensional modular scaffolds with predefined geometry and biological characters. In modular tissue-like construction, a scaffold with an appropriate mechanical rigidity for assembling fabrication and high biocompatibility for cell survival is the key to the successful bioconstruction. In this work, a series of composite hydrogels (GH0, GH1, GH2, and GH3) based on a combination of methacrylated gelatin (GelMA) and hydroxyapatite (HA) was exploited to enhance hydrogel mechanical rigidity and promote cell functional expression for osteon biofabrication. These composite hydrogels presented a lower swelling ratio, higher mechanical moduli, and better biocompatibility when compared to the pure GelMA hydrogel. Furthermore, on the basis of the composite hydrogel and photolithograph technology, we successfully constructed an osteon-like concentric double-ring structure in which the inner ring encapsulating human umbilical vascular endothelial cells (HUVECs) was designed to imitate blood vessel tubule while the outer ring encapsulating human osteoblast-like cells (MG63s) acts as part of bone. During the coculture period, MG63s and HUVECs exhibited not only satisfying growth status but also the enhanced genic expression of osteogenesis-related and angiogenesis-related differentiations. These results demonstrate this GelMA-HA composite hydrogel system is promising for modular tissue engineering. PMID- 25928733 TI - New technologies in the management of risk and violence in forensic settings. AB - Novel technological interventions are increasingly used in mental health settings. In this article, we describe 3 novel technological strategies in use for management of risk and violence in 2 forensic psychiatry settings in the United Kingdom: electronic monitoring by GPS-based tracking devices of patients on leave from a medium secure service in London, and closed circuit television (CCTV) monitoring and motion sensor technology at Broadmoor high secure hospital. A common theme is the use of these technologies to improve the completeness and accuracy of data used by clinicians to make clinical decisions. Another common thread is that each of these strategies supports and improves current clinical approaches rather than drastically changing them. The technologies offer a broad range of benefits. These include less restrictive options for patients, improved accountability of both staff and patients, less invasive testing, improved automated record-keeping, and better assurance reporting. Services utilizing technologies need also be aware of limitations. Technologies may be seen as unduly restrictive by patients and advocates, and technical issues may reduce effectiveness. It is vital that the types of technological innovations described in this article should be subject to thorough evaluation that addresses cost effectiveness, qualitative analysis of patients' attitudes, safety, and ethical considerations. PMID- 25928734 TI - Comparative changes in treatment practices and clinical outcomes following implementation of a prospective payment system: the STEPPS study. AB - BACKGROUND: The aim of the US dialysis Prospective Payment System bundle, launched in January 2011, was reduction and more accurate prediction of costs of services, whilst maintaining or improving patient care. Dialysis facilities could either adopt the bundle completely (100%) in the first year of launch, or phase in (25%) over four years. Differences in practice patterns and patient outcomes were hypothesized to occur in facilities that phased-in 25% compared to those that did not. METHODS: Data are from STEPPS, a study of 51 small dialysis organization facilities designed to describe trends in dialytic treatment before and after bundle implementation. Baseline was defined as October-December 2010; follow-up as January-December 2011. Facility- and patient-level data were collected at enrollment and regularly thereafter. Cox proportional hazards and linear multi-level models were used to estimate the effect of opting-in 25% (vs. 100%) on practice patterns and clinical outcomes. RESULTS: 12 facilities (patient n = 346) opted-in 25% and 37 facilities (patient n = 1296) opted-in 100% to the dialysis bundle. At baseline, patients at 25% facilities were primarily covered by Medicare, were more likely to be black, and were receiving higher monthly epoetin alfa (EPO) doses. Throughout 2011, patients in 100% facilities received lower monthly EPO doses, and had lower mean hemoglobin concentrations; hospitalization and mortality rates were numerically lower in 25% facilities but not statistically different. CONCLUSIONS: The economic pressure for dialysis providers to work within an expanded composite rate bundle whilst maintaining patient care may be a driver of practice indicator outcomes. Additional investigations are warranted to more precisely estimate clinical outcomes in patients attending facilities enrolling into the bundle 100% relative to the previous fee-for-service framework. PMID- 25928736 TI - Fast Water Thermo-pumping Flow Across Nanotube Membranes for Desalination. AB - Development of high-efficiency and low-cost seawater desalination technologies is critical to meet global water crisis. Here we report a fast water pumping method in which the water molecules in seawater are continuously pumped across nanotube membranes driven by a small temperature difference, opening the possibility of high-throughput small-scale desalination devices driven by low-grade thermal energy. Using molecular dynamics simulations, we show that an equivalent driving pressure of 5.3 MPa is achieved with a temperature difference of only 15 K. The remarkable water pumping ability is attributed to the asymmetric thermal fluctuation of water molecules. With this method, a 10 cm(2) nanotube membrane with 1.5 * 10(13) pores per cm(2) will produce freshwater with a flow rate of 7.77 L/h under a small temperature difference of 15 K. PMID- 25928739 TI - The MOVE study: a study protocol for a randomised controlled trial assessing interventions to maximise attendance at physical activity facilities. AB - BACKGROUND: Physical activity is associated with a host of health benefits, yet many individuals do not perform sufficient physical activity to realise these benefits. One approach to rectifying this situation is through modifying the built environment to make it more conducive to physical activity, such as by building walking tracks or recreational physical activity facilities. Often, however, modifications to the built environment are not connected to efforts aimed at encouraging their use. The purpose of the Monitoring and Observing the Value of Exercise (MOVE) study is to evaluate the effectiveness of two interventions designed to encourage the ongoing use of a new, multi-purpose, community-based physical activity facility. METHODS/DESIGN: A two-year, randomised controlled trial with yearly survey points (baseline, 12 months follow up, 24 months follow-up) will be conducted among 1,300 physically inactive adult participants aged 18-70 years. Participants will be randomly assigned to one of three groups: control, intervention 1 (attendance incentives), or intervention 2 (attendance incentives and tailored support following a model based on customer relationship management). Primary outcome measures will include facility usage, physical activity participation, mental and physical wellbeing, community connectedness, social capital, friendship, and social support. Secondary outcome measures will include stages of change for facility usage and social cognitive decision-making variables. DISCUSSION: This study will assess whether customer relationship management systems, a tool commonly used in commercial marketing settings, can encourage the ongoing use of a physical activity facility. Findings may also indicate the population segments among which the use of such systems are most effective, as well as their cost-effectiveness. TRIAL REGISTRATION: Australian New Zealand Clinical Trials Registry: ACTRN12615000012572 (registered 9 January 2015). PMID- 25928741 TI - Perceptions of risk from nanotechnologies and trust in stakeholders: a cross sectional study of public, academic, government and business attitudes. AB - BACKGROUND: Policy makers and regulators are constantly required to make decisions despite the existence of substantial uncertainty regarding the outcomes of their proposed decisions. Understanding stakeholder views is an essential part of addressing this uncertainty, which provides insight into the possible social reactions and tolerance of unpredictable risks. In the field of nanotechnology, large uncertainties exist regarding the real and perceived risks this technology may have on society. Better evidence is needed to confront this issue. METHODS: We undertook a computer assisted telephone interviewing (CATI) survey of the Australian public and a parallel survey of those involved in nanotechnology from the academic, business and government sectors. Analysis included comparisons of proportions and logistic regression techniques. We explored perceptions of nanotechnology risks both to health and in a range of products. We examined views on four trust actors. RESULTS: The general public's perception of risk was significantly higher than that expressed by other stakeholders. The public bestows less trust in certain trust actors than do academics or government officers, giving its greatest trust to scientists. Higher levels of public trust were generally associated with lower perceptions of risk. Nanotechnology in food and cosmetics/sunscreens were considered riskier applications irrespective of stakeholder, while familiarity with nanotechnology was associated with a reduced risk perception. CONCLUSIONS: Policy makers should consider the disparities in risk and trust perceptions between the public and influential stakeholders, placing greater emphasis on risk communication and the uncertainties of risk assessment in these areas of higher concern. Scientists being the highest trusted group are well placed to communicate the risks of nanotechnologies to the public. PMID- 25928743 TI - Parasites and vectors of malaria on Rusinga Island, Western Kenya. AB - BACKGROUND: There is a dearth of information on malaria endemicity in the islands of Lake Victoria in western Kenya. In this study malaria prevalence and Plasmodium sporozoite rates on Rusinga Island were investigated. The contribution of different Anopheles species to indoor and outdoor transmission of malaria was also determined. METHODS: Active case detection through microscopy was used to diagnose malaria in a 10% random sample of the human population on Rusinga Island and a longitudinal entomological survey conducted in Gunda village in 2012. Nocturnally active host-seeking mosquitoes were captured indoors and outdoors using odour-baited traps. Anopheles species were tested for the presence of Plasmodium parasites using an enzyme linked immunosorbent assay. All data were analyzed using generalized linear models. RESULTS: Single infections of Plasmodium falciparum (88.1%), P. malariae (3.96%) and P. ovale (0.79%) as well as multiple infections (7.14%) of these parasites were found on Rusinga Island. The overall malaria prevalence was 10.9%. The risk of contracting malaria was higher among dwellers of Rusinga West than Rusinga East locations (Odds Ratio [OR] = 1.5, 95% Confidence Interval [CI] 1.14 - 1.97, P = 0.003). Parasite positivity was significantly associated with individuals who did not use malaria protective measures (OR = 2.65, 95% CI 1.76 - 3.91, p < 0.001). A total of 1,684 mosquitoes, including 74 anophelines, were captured. Unlike Culex species, more of which were collected indoors than outdoors (P < 0.001), the females of An. gambiae s.l. (P = 0.477), An. funestus s.l. (P = 0.153) and Mansonia species captured indoors versus outdoors were not different. The 46 An. gambiae s.l. collected were mainly An. arabiensis (92.3%). Of the 62 malaria mosquitoes tested, 4, including 2 indoor and 2 outdoor-collected individuals had Plasmodium. CONCLUSION: The rather significant and unexpected contribution of P. malariae and P. ovale to the overall malaria prevalence on Rusinga Island underscores the epidemiological importance of these species in the big push towards eliminating malaria. Although current entomological interventions mainly target indoor environments, additional strategies should be considered to prevent outdoor transmission of malaria. PMID- 25928744 TI - Task type affects location of language-positive cortical regions by repetitive navigated transcranial magnetic stimulation mapping. AB - OBJECTIVES: Recent repetitive TMS (rTMS) mapping protocols for language mapping revealed deficits of this method, mainly in posterior brain regions. Therefore this study analyzed the impact of different language tasks on the localization of language-positive brain regions and compared their effectiveness, especially with regard to posterior brain regions. METHODS: Nineteen healthy, right-handed subjects performed object naming, pseudoword reading, verb generation, and action naming during rTMS language mapping of the left hemisphere. Synchronically, 5 Hz/10 pulses were applied with a 0 ms delay. RESULTS: The object naming task evoked the highest error rate (14%), followed by verb generation (13%) and action naming (11%). The latter revealed more errors in posterior than in anterior areas. Pseudoword reading barely generated errors, except for phonological paraphasias. CONCLUSIONS: In general, among the evaluated language tasks, object naming is the most discriminative task to detect language-positive regions via rTMS. However, other tasks might be used for more specific questions. PMID- 25928745 TI - Comparative transcriptome analysis of latex from rubber tree clone CATAS8-79 and PR107 reveals new cues for the regulation of latex regeneration and duration of latex flow. AB - BACKGROUND: Rubber tree (Hevea brasiliensis Muell. Arg.) is the primarily commercial source of natural rubber in the world. Latex regeneration and duration of latex flow after tapping are the two factors that determine rubber yield of rubber tree, and exhibit a huge variation between rubber tree clones CATAS8-79 and PR107. RESULTS: To dissect the molecular mechanism for the regulation of latex regeneration and duration of latex flow, we sequenced and comparatively analyzed latex of rubber tree clone CATAS8-79 and PR107 at transriptome level. More than 26 million clean reads were generated in each pool and 51,829 all unigenes were totally assembled. A total of 6,726 unigenes with differential expression patterns were detected between CATAS8-79 and PR107. Functional analysis showed that genes related to mass of categories were differentially enriched between the two clones. Expression pattern of genes which were involved in latex regeneration and duration of latex flow upon successive tapping was analyzed by quantitative PCR. Several genes related to rubber biosynthesis, cellulose and lignin biosynthesis and rubber particle aggregation were differentially expressed between CATAS8-79 and PR107. CONCLUSIONS: This is the first report about probing latex regeneration and duration of latex flow by comparative transcriptome analysis. Among all the suggested factors, it is more important that the level of endogenous jasmonates, carbohydrate metabolism, hydroxymethylglutaryl-CoA reductase (HMGR) and Hevea rubber transferase (HRT) in mevalonate (MVA) parthway for latex regeneration while the level of endogenous ethylene (ETH), lignin content of laticifer cell wall, antioxidants and glucanases for the duration of latex flow. These data will provide new cues for understanding the molecular mechanism for the regulation of latex regeneration and duration of latex flow in rubber tree. PMID- 25928746 TI - Correction: Soil bacterial community structure responses to precipitation reduction and forest management in forest ecosystems across Germany. PMID- 25928751 TI - The brief report: a multitasking, concise feature of high-quality. PMID- 25928752 TI - Factors affecting match running performance of elite soccer players: shedding some light on the complexity. AB - Time-motion analysis is a valuable data-collection technique used to quantify the match running performance of elite soccer players. However, interpreting the reductions in running performance in the second half or temporarily after the most intense period of games is highly complex, as it could be attributed to physical or mental fatigue, pacing strategies, contextual factors or a combination of mutually inclusive factors. Given that research in this domain typically uses a reductionist approach whereby match-running performance is examined in isolation without integrating other factors this ultimately leads to a 1-dimensional insight into match performance. Subsequently, a cohesive review of influencing factors does not yet exist. The aim of this commentary is to provide a detailed insight into the complexity of match running performance and the most influential factors. PMID- 25928750 TI - Function and mechanism of toll-like receptors in cerebral ischemic tolerance: from preconditioning to treatment. AB - Increasing evidence suggests that toll-like receptors (TLRs) play an important role in cerebral ischemia-reperfusion injury. The endogenous ligands released from ischemic neurons activate the TLR signaling pathway, resulting in the production of a large number of inflammatory cytokines, thereby causing secondary inflammation damage following cerebral ischemia. However, the preconditioning for minor cerebral ischemia or the preconditioning with TLR ligands can reduce cerebral ischemic injury by regulating the TLR signaling pathway following ischemia in brain tissue (mainly, the inhibition of the TLR4/NF-kappaB signaling pathway and the enhancement of the interferon regulatory factor-dependent signaling), resulting in TLR ischemic tolerance. Additionally, recent studies found that postconditioning with TLR ligands after cerebral ischemia can also reduce ischemic damage through the regulation of the TLR signaling pathway, showing a significant therapeutic effect against cerebral ischemia. These studies suggest that the ischemic tolerance mediated by TLRs can serve as an important target for the prevention and treatment of cerebral ischemia. On the basis of describing the function and mechanism of TLRs in mediating cerebral ischemic damage, this review focuses on the mechanisms of cerebral ischemic tolerance induced by the preconditioning and postconditioning of TLRs and discusses the clinical application of TLRs for ischemic tolerance. PMID- 25928753 TI - Childhood obesity at the crossroads. PMID- 25928754 TI - Obesogenic environments: environmental approaches to obesity prevention. AB - Childhood obesity is a major concern for public health. There are multiple factors (e.g., genetic, social, and environmental) that contribute to unhealthy weight gain. Drawing from findings on "obesogenic environments" and core principles of preventive strategies to reduce health inequalities, this paper gives an overview of recent childhood prevention programs that target aspects of the physical environment ("environmental changes"). Out of the ten reviews we screened (including more than 300 studies), we identified very few that addressed aspects of the environment. We focus here on 14 programs that follow different approaches to environmental changes (e.g., access to/quality of playgrounds, changes in school cafeterias). Altering the environment offers opportunities for healthier behaviors and seems to be an effective strategy to prevent childhood obesity. However, the evaluation of those (mostly) multidimensional interventions does not allow drawing firm conclusions about the single effect of environmental changes. We conclude that obesity prevention programs should combine person-based and environmental approaches. PMID- 25928755 TI - Vitamin D status and its associations with components of metabolic syndrome in healthy children. AB - AIM: High prevalence of vitamin D insufficiency/deficiency has been reported in populations of different countries. The aim of this cross-sectional study was to determine the prevalence and association of vitamin D status with components of metabolic syndrome. METHODS: Lipid profile indices, anthropometric indices [body mass index and waist circumference (WC)], insulin resistance index (HOMA-IR), systolic blood pressure (SBP), diastolic blood pressure (DBP), C-reactive protein, intact parathyroid hormone (iPTH), and serum 25-hydroxyvitamin D [25(OH)D] concentration were evaluated in 297 healthy schoolchildren aged 7-11 years. Multivariate linear regression was used to determine independent predictors associated with low serum 25(OH)D concentrations. RESULTS: The mean serum 25(OH)D concentration was 14.12+/-8.20 ng/mL (35.3+/-20.5 nmol/L); 96% of children had low serum 25(OH)D levels, 31.0% were deficient, and 65.0% had insufficient levels of 25(OH)D. Vitamin D deficiency was higher in girls (chi2=13.66; p=0.00); 25(OH)D level was negatively associated with WC, HOMA-IR, SBP, DBP, and iPTH. In the multivariate model, WC, DBP, and HOMA-IR were significant independent predictor of low 25(OH)D concentrations. CONCLUSION: The prevalence of low vitamin D level in the studied healthy children was high and it is correlated with some components of metabolic syndrome. Outdoor activity for optimum sun exposure and additional studies are needed to evaluate the underlying metabolic syndrome components and hypovitaminosis D complications. PMID- 25928756 TI - Hypothyroidism caused by the combination of two heterozygous mutations: one in the TSH receptor gene the other in the DUOX2 gene. AB - Subjects who are heterozygous for thyroid stimulating hormone receptor (TSHR) gene mutations present various phenotypes that range from euthyroid to hyperthyrotropinemia. Similarly, heterozygous dual oxidase 2 (DUOX2) gene mutations result in variable phenotypes, such as transient congenital hypothyroidism, subclinical hyperthyrotropinemia, and euthyroid in children. Here, we describe an 8-year-old boy who had normal newborn screening results, but who developed nonautoimmune hypothyroidism at the age of 1 year and 8 months of age. He was heterozygous for previously reported R450H-TSHR mutation and heterozygous for a novel double mutant allele A1323T-DUOX2 and L1343F-DUOX2. He needed levothyroxine (l-T4) replacement therapy to keep serum TSH levels within normal limits; l-T4 dose of 2.01-2.65 MUg/kg/day corresponded to the dose taken by children homozygous for R450H-TSHR and by children with permanent congenital hypothyroidism. Therefore, the coexistence of a heterozygous TSHR mutation and a heterozygous DUOX2 mutation may have affected the severity of his hypothyroid condition. PMID- 25928757 TI - Rationale for using data on biological variation. AB - The aims of this study are: 1) to use the data included in the biological variation (BV) database to address the usability of BV estimates; and 2) to use different examples from the authors' laboratories to illustrate the use and the usefulness of BV data in laboratory medicine. The BV database is an essential tool for laboratory management. Examples of application of data derived from BV are given in this paper, such as analytical performance specifications that have been included in various quality control software designed to optimize operative rules; also they have been incorporated as acceptability limits in external quality assurance reports. BV data from pathological status are of utmost interest for monitoring patients and differences between the intra-individual coefficients of variation (CVI) estimated from healthy and patients are shown. However, for a number of analytes there are limited data available and for many there are no data, consequently new studies should be encouraged at an international level. In addition, developing international criteria to evaluate publications dealing with the estimation of BV components would be of the utmost interest. We are ready and willing to collaborate with such worthy initiatives. The first EFLM strategic conference on analytical performance specifications is an excellent opportunity for debating these ideas. PMID- 25928758 TI - Teaching Nursing Leadership: Comparison of Simulation versus Traditional Inpatient Clinical. AB - Nurse educators claim accountability to ensure their students are prepared to assume leadership responsibilities upon graduation. Although front-line nurse leaders and nurse executives feel new graduates are not adequately prepared to take on basic leadership roles, professional nursing organizations such as the American Nurses Association (ANA) and the Association of Colleges of Nursing (AACN) deem leadership skills are core competencies of new graduate nurses. This study includes comparison of a leadership-focused multi-patient simulation and the traditional leadership clinical experiences in a baccalaureate nursing leadership course. The results of this research show both environments contribute to student learning. There was no statistical difference in the overall score. Students perceived a statistically significant difference in communication with patients in the traditional inpatient environment. However, the students perceived a statistical significant difference in teaching-learning dyad toward simulation. PMID- 25928761 TI - The immunoglobulin M-degrading enzyme of Streptococcus suis, IdeSsuis, is involved in complement evasion. AB - Streptococcus (S.) suis is one of the most important pathogens in pigs causing meningitis, arthritis, endocarditis and serositis. Furthermore, it is also an emerging zoonotic agent. In our previous work we identified a highly specific IgM protease in S. suis, designated Ide(Ssuis) . The objective of this study was to characterize the function of Ide(Ssuis) in the host-pathogen interaction. Edman sequencing revealed that Ide(Ssuis) cleaves the heavy chain of the IgM molecule between constant domain 2 and 3. As the C1q binding motif is located in the C3 domain, we hypothesized that Ide(Ssuis) is involved in complement evasion. Complement-mediated hemolysis induced by porcine hyperimmune sera containing erythrocyte-specific IgM was abrogated by treatment of these sera with recombinant Ide(Ssuis) . Furthermore, expression of Ide(Ssuis) reduced IgM triggered complement deposition on the bacterial surface. An infection experiment of prime-vaccinated growing piglets suggested attenuation in the virulence of the mutant 10Deltaide(Ssuis). Bactericidal assays confirmed a positive effect of Ide(Ssuis) expression on bacterial survival in porcine blood in the presence of high titers of specific IgM. In conclusion, this study demonstrates that Ide(Ssuis) is a novel complement evasion factor, which is important for bacterial survival in porcine blood during the early adaptive (IgM-dominated) immune response. PMID- 25928762 TI - Preventative effects of prostaglandin E1 in combination with iodized olive oil on liver fibrosis after transcatheter arterial chemoembolization in a rabbit model of CCl4-induced liver fibrosis. AB - To explore the preventative effects of prostaglandin E1 (PGE1) on a rabbit model of CCl4-induced liver fibrosis after transcatheter arterial chemoembolization (TACE), we generated a rabbit model of CCl4-induced liver fibrosis by treatment with 40% CCl4 in iodized olive oil for 16 weeks. Body mass and serum levels of alanine aminotransferase (ALT), aspartate aminotransferase (AST), total protein (TP), albumin (ALB), albumin:globulin ratio (A:G), total bilirubin (TBIL), and direct bilirubin (DBIL) were measured. After TACE, the levels of hyaluronic acid (HA), procollagen III (PC III), laminin (LN), and collagen IV (IV-C) were measured, and the severity of liver fibrosis as well as the morphology of liver tissues were determined. Body mass in the model group was significantly decreased from 10 to 16 weeks, and the serum levels of ALT, AST, TP, TBIL, and DBIL levels were significantly increased while the model was being generated; the levels of ALB and A:G were significantly decreased. After TACE, serum levels of HA, PC III, and LN in the group injected with 1.0 mL iodized olive oil (Group B) were higher than in the group that were injected with 1.0 mL iodized olive oil + 0.2 mL PGE1 (Group C), whereas the serum levels of IV-C were lower. The severity of liver fibrosis was ameliorated in Group C. The combination of PGE1 and iodized olive oil prevented the development of liver fibrosis following TACE. PMID- 25928765 TI - coMET: visualisation of regional epigenome-wide association scan results and DNA co-methylation patterns. AB - BACKGROUND: Epigenome-wide association scans (EWAS) are an increasingly powerful and widely-used approach to assess the role of epigenetic variation in human complex traits. However, this rapidly emerging field lacks dedicated visualisation tools that can display features specific to epigenetic datasets. RESULT: We developed coMET, an R package and online tool for visualisation of EWAS results in a genomic region of interest. coMET generates a regional plot of epigenetic-phenotype association results and the estimated DNA methylation correlation between CpG sites (co-methylation), with further options to visualise genomic annotations based on ENCODE data, gene tracks, reference CpG-sites, and user-defined features. The tool can be used to display phenotype association signals and correlation patterns of microarray or sequencing-based DNA methylation data, such as Illumina Infinium 450k, WGBS, or MeDIP-seq, as well as other types of genomic data, such as gene expression profiles. The software is available as a user-friendly online tool from http://epigen.kcl.ac.uk/comet and as an R Bioconductor package. Source code, examples, and full documentation are also available from GitHub. CONCLUSION: Our new software allows visualisation of EWAS results with functional genomic annotations and with estimation of co methylation patterns. coMET is available to a wide audience as an online tool and R package, and can be a valuable resource to interpret results in the fast growing field of epigenetics. The software is designed for epigenetic data, but can also be applied to genomic and functional genomic datasets in any species. PMID- 25928763 TI - The left ventricle in aortic stenosis--imaging assessment and clinical implications. AB - Aortic stenosis has an increasing prevalence in the context of aging population. In these patients non-invasive imaging allows not only the grading of valve stenosis severity, but also the assessment of left ventricular function. These two goals play a key role in clinical decision-making. Although left ventricular ejection fraction is currently the only left ventricular function parameter that guides intervention, current imaging techniques are able to detect early changes in LV structure and function even in asymptomatic patients with significant aortic stenosis and preserved ejection fraction. Moreover, new imaging parameters emerged as predictors of disease progression in patients with aortic stenosis. Although proper standardization and confirmatory data from large prospective studies are needed, these novel parameters have the potential of becoming useful tools in guiding intervention in asymptomatic patients with aortic stenosis and stratify risk in symptomatic patients undergoing aortic valve replacement.This review focuses on the mechanisms of transition from compensatory left ventricular hypertrophy to left ventricular dysfunction and heart failure in aortic stenosis and the role of non-invasive imaging assessment of the left ventricular geometry and function in these patients. PMID- 25928769 TI - Auto-inhibitory Mechanism of the Human Mitochondrial RNase P Protein Complex. AB - It is known that tRNAs play an essential role in genetic information transfer from DNA to protein. The maturation of tRNA precursors is performed by the endoribonuclease RNase P, which classically consists of a main RNA segment and accessory proteins. However, the newly identified human mitochondrial RNase P like protein (MRPP123) complex is unique in that it is composed of three proteins without RNA. Here, we determined the crystal structure of MRPP123 complex subunit 3 (MRPP3), which is thought to carry out the catalytic reaction. A detailed structural analysis in combination with biochemical assays suggests that MRPP3 is in an auto-inhibitory conformation in which metal ions that are essential for catalysis are excluded from the active site. Our results indicate that further regulation is necessary to rearrange the conformation of the active site of MRPP3 and trigger it, thus providing important information to understand the activation of MRPP123. PMID- 25928775 TI - A SoC Model of Hypnosis and Induction. PMID- 25928772 TI - Acceptability and Feasibility of a Cell Phone Support Intervention for Youth Living with HIV with Nonadherence to Antiretroviral Therapy. AB - A pilot randomized clinical trial of youth ages 15-24 nonadherent to antiretroviral therapy (ART) utilizing daily cell phone support was found to have significant improvement in self-reported adherence and HIV RNA. Understanding acceptability and feasibility is critical for future implementation in clinic settings. Exit interviews were obtained from participants and adherence facilitators (AF). Acceptability was assessed from content analysis of exit interviews. Feasibility was assessed via intervention retention and study retention rates. Thirty-seven eligible youth were enrolled with 19 assigned to the intervention. Seven (37%) discontinued the intervention either due to missing over 20% of calls for two consecutive months (N=5) or missing 10 consecutive calls (N=2). Sixteen participants completed exit interviews, 15 reported the call length was just right, 13 reported they would have liked to continue calls after the 24-week intervention, and all participants reported they would recommend the intervention to friends. Scheduling and making calls required less than 1 h per week per participant. Providing cell phone support to youth nonadherent to ART was acceptable and feasible. While the cost is low compared to the price of ART, healthcare systems will need to explore how to cover the cost of providing cell phones (incentive). PMID- 25928774 TI - The association between nutritional status and malaria in children from a rural community in the Amazonian region: a longitudinal study. AB - BACKGROUND: The relationship between malaria and undernutrition is controversial and complex. Synergistic associations between malnutrition and malaria morbidity and mortality have been suggested, as well as undernutrition being protective against infection, while other studies found no association. We sought to evaluate the relationship between the number of malaria episodes and nutritional statuses in a cohort of children below 15 years of age living in a rural community in the Brazilian Amazon. METHODOLOGY/PRINCIPAL FINDINGS: Following a baseline survey of clinical, malaria and nutritional assessment including anthropometry measurements and hemoglobin concentration, 202 children ranging from 1 month to 14 years of age were followed for one year through passive case detection for malaria episodes. After follow-up, all children were assessed again in order to detect changes in nutritional indicators associated with malaria infection. We also examined the risk of presenting malaria episodes during follow up according to presence of stunting at baseline. Children who suffered malaria episodes during follow-up presented worse anthropometric parameters values during this period. The main change was a reduction of the linear growth velocity, associated with both the number of episodes and how close the last or only malaria episode and the second anthropometric assessment were. Changes were also observed for indices associated with chronic changes, such as weight-for-age and BMI-for-age, which conversely, were more frequently observed in children with the last or only episode occurring between 6 and 12 months preceding the second nutritional assessment survey. Children with inadequate height-for-age at baseline (Z-score < -2) presented lower risk of suffering malaria episodes during follow-up as assessed by both the log-rank test (p =0.057) and the multivariable Cox-proportional hazards regression (Hazard Ratio = 0.31, 95%CI [0.10; 0.99] p=0.049). CONCLUSIONS: Malaria was associated with impaired nutritional status amongst children in an endemic area of the Western Brazilian Amazon where P. vivax predominates. Our data all supports that the association presents differential effects for each age group, suggesting distinct pathophysiology pathways. We were also able to demonstrate that undernourishment at baseline was protective to malaria during follow-up. These findings support an intriguing interaction between these conditions in the rural Amazon and the need for a more integrative approach by health systems in endemic areas. PMID- 25928776 TI - Advancing Research and Practice: The Revised APA Division 30 Definition of Hypnosis. AB - This article describes the history, rationale, and guidelines for developing a new definition of hypnosis by the Society of Psychological Hypnosis, Division 30 of the American Psychological Association. The definition was developed with the aim of being concise, being heuristic, and allowing for alternative theories of the mechanisms (to be determined in empirical scientific study). The definition of hypnosis is presented as well as definitions of the following related terms: hypnotic induction, hypnotizability, and hypnotherapy. The implications for advancing research and practice are discussed. The definitions are presented within the article. PMID- 25928777 TI - Words, words, words: some final thoughts. PMID- 25928778 TI - Grounding Hypnosis in Science: The "New" APA Division 30 Definition of Hypnosis as a Step Backward. PMID- 25928779 TI - Hypnosis as a "state of consciousness": how quantifying the mind can help us better understand hypnosis. PMID- 25928780 TI - The new division 30 definitions regarding hypnosis: is "concise" better? PMID- 25928781 TI - The Revised APA Division 30 Definition of Hypnosis: An Appreciation, a Commentary, and a Wish List. PMID- 25928782 TI - Defining hypnosis: an integrative, multi-factor conceptualization. PMID- 25928783 TI - A Defining Moment: Commentary on the Revised APA Division 30 Definition of Hypnosis. PMID- 25928784 TI - Revision of the APA Division 30 Definition of Hypnosis. PMID- 25928785 TI - The elephant, the blind men, and hypnosis. PMID- 25928786 TI - Hypnosis: statehood at last. PMID- 25928787 TI - The New APA Definition of Hypnosis: Spontaneous Hypnosis MIA. PMID- 25928788 TI - On embracing plurality and tolerating ambiguity in the definitions of hypnosis. PMID- 25928791 TI - Correction: Two types of nitrito support for MU4-oxido-bridged [Cu4] complexes: synthesis, crystal structures, magnetic properties and DFT analysis. AB - Correction for 'Two types of nitrito support for MU4-oxido-bridged [Cu4] complexes: synthesis, crystal structures, magnetic properties and DFT analysis' by Moumita Pait, et al., Dalton Trans., 2015, 44, 6107-6117. PMID- 25928792 TI - DEFENS - Drug Exposure Feedback and Education for Nurses' Safety: study protocol for a randomized controlled trial. AB - BACKGROUND: Three decades of research findings have documented the health effects of handling hazardous drugs. Oncology nurses are vulnerable due to frequent administration of antineoplastics, low adherence to equipment use, reported barriers to use, and perceived low risk of health effects. No interventions have been tested in a controlled, multi-site trial to increase nurses' use of protective equipment when handling hazardous drugs. The Drug Exposure Feedback and Education for Nurses' Safety (DEFENS) study will compare the efficacy of education (control) versus an audit and feedback intervention (treatment) on nurses' self-reported use of personal protective equipment when handling hazardous drugs. The treatment intervention will include tailored messages based on nurses' reported barriers to protective equipment use. METHODS/DESIGN: The DEFENS Study is a cluster randomized controlled trial. We are enrolling cancer centers and will recruit nurse participants in April 2015. Eligible cancer centers employ at least 20 eligible registered nurses in the chemotherapy infusion setting and have on-site phlebotomy resources. Eligible participants are nurses who work at least 0.40 full-time equivalent hours in the chemotherapy infusion setting and have not received an antineoplastic drug for a health problem in the past year. An encrypted, user-authenticated website will administer surveys and deliver control and treatment interventions. The primary endpoint is the change in score on nurses' reports of the Revised Hazardous Drug Handling Questionnaire between baseline and approximately 18 months later. A baseline survey is completed after informed consent and is repeated 18 months later. Nurses in all sites who experience a drug spill will also report incidents as they occur; these reports inform the treatment intervention. Plasma will be obtained at baseline, approximately 18 months later (the primary endpoint), and with drug spill occurrences to measure hazardous drugs levels and to inform the treatment intervention. Potential mediators include knowledge of hazardous drug handling and perceived risk of drug exposure. We will examine whether personal factors and organizational factors moderate the intervention effects. TRIAL REGISTRATION: Clinicaltrials.gov NCT02283164 , registered 31 October 2014. PMID- 25928795 TI - Structural Determination of (Al2O3)(n) (n = 1-15) Clusters Based on Graphic Processing Unit. AB - Global optimization algorithms have been widely used in the field of chemistry to search the global minimum structures of molecular and atomic clusters, which is a nondeterministic polynomial problem with the increasing sizes of clusters. Considering that the computational ability of a graphic processing unit (GPU) is much better than that of a central processing unit (CPU), we developed a GPU based genetic algorithm for structural prediction of clusters and achieved a high acceleration ratio compared to a CPU. On the one-dimensional (1D) operation of a GPU, taking (Al2O3)n clusters as test cases, the peak acceleration ratio in the GPU is about 220 times that in a CPU in single precision and the value is 103 for double precision in calculation of the analytical interatomic potential. The peak acceleration ratio is about 240 and 107 on the block operation, and it is about 77 and 35 on the 2D operation compared to a CPU in single precision and double precision, respectively. And the peak acceleration ratio of the whole genetic algorithm program is about 35 compared to CPU at double precision. Structures of (Al2O3)n clusters at n = 1-10 reported in previous works are successfully located, and their low-lying structures at n = 11-15 are predicted. PMID- 25928796 TI - Integration of metabolic and inflammatory mediator profiles as a potential prognostic approach for septic shock in the intensive care unit. AB - INTRODUCTION: Septic shock is a major life-threatening condition in critically ill patients and it is well known that early recognition of septic shock and expedient initiation of appropriate treatment improves patient outcome. Unfortunately, to date no single compound has shown sufficient sensitivity and specificity to be used as a routine biomarker for early diagnosis and prognosis of septic shock in the intensive care unit (ICU). Therefore, the identification of new diagnostic tools remains a priority for increasing the survival rate of ICU patients. In this study, we have evaluated whether a combined nuclear magnetic resonance spectroscopy-based metabolomics and a multiplex cytokine/chemokine profiling approach could be used for diagnosis and prognostic evaluation of septic shock patients in the ICU. METHODS: Serum and plasma samples were collected from septic shock patients and ICU controls (ICU patients with the systemic inflammatory response syndrome but not suspected of having an infection). (1)H Nuclear magnetic resonance spectra were analyzed and quantified using the targeted profiling methodology. The analysis of the inflammatory mediators was performed using human cytokine and chemokine assay kits. RESULTS: By using multivariate statistical analysis we were able to distinguish patient groups and detect specific metabolic and cytokine/chemokine patterns associated with septic shock and its mortality. These metabolites and cytokines/chemokines represent candidate biomarkers of the human response to septic shock and have the potential to improve early diagnosis and prognosis of septic shock. CONCLUSIONS: Our findings show that integration of quantitative metabolic and inflammatory mediator data can be utilized for the diagnosis and prognosis of septic shock in the ICU. PMID- 25928798 TI - Use of alcohol vinegar in the inhibition of Candida spp. and its effect on the physical properties of acrylic resins. AB - BACKGROUND: Given the high prevalence of oral candidiasis and the restricted number of antifungal agents available to control infection, this study investigated the in vitro antifungal activity of alcohol vinegar on Candida spp. and its effect on the physical properties of acrylic resins. METHODS: Tests to determine the Minimum Inhibitory Concentration (MIC) and Minimum Fungicidal Concentration (MFC) of vinegar alcohol (0.04 g/ml of acetic acid) and nystatin (control) were performed. The antifungal activity of alcohol vinegar was assessed through microbial growth kinetic assays and inhibition of Candida albicans adhesion to acrylic resin at different intervals of time. Surface roughness and color of the acrylic resin were analyzed using a roughness meter and color analyzer device. RESULTS: Alcohol vinegar showed MIC75% and MFC62.5% of 2.5 mg/ml, with fungicidal effect from 120 min, differing from nystatin (p < 0.0001), which showed fungistatic effect. Alcohol vinegar caused greater inhibition of C. albicans adhesion to the acrylic resin (p <= 0.001) compared to nystatin and did not change the roughness and color parameters of the material. CONCLUSION: Alcohol vinegar showed antifungal properties against Candida strains and caused no physical changes to the acrylic resin. PMID- 25928799 TI - Characteristics of older adults admitted to the emergency department (ED) and their risk factors for ED readmission based on comprehensive geriatric assessment: a prospective cohort study. AB - BACKGROUND: Patients aged 75 years and older represent 12% of the overall emergency department (ED) population, and this proportion will increase over the next decades. Many of the discharged patients suffer an unplanned readmission in the immediate and midterm post-discharge period, suggesting under recognition of psychosocial, cognitive and medical problems. The aim of this study was to compare the characteristics of older patients admitted and discharged from the ED and to determine independent predictors for ED readmission 1 month and 3 months after ED discharge based on comprehensive geriatric assessment (CGA). METHODS: Cohort study in a Belgian university hospital. A CGA, including demographic and medical data (e.g. reason for admission, comorbidity, number of medications), functional (e.g. activities of daily living, falls), mental (i.e. cognition, dementia, delirium), and nutritional status, and pain, was performed in 442 ED patients aged 75 years or older. RESULTS: Patients discharged from the ED (n = 117, 26.5%) were significantly less dependent for ADL, mobility, shopping and finances compared with hospitalised patients. Hospitalised patients (n = 325, 73.5%) were significantly more at risk for having nutritional problems, had a higher comorbidity index, and a lower cognitive status compared with those discharged. Ninety-seven patients (82.9%) were discharged home from the ED. Of the latter, 18 (18.6%) and 28 patients (28.9%) suffered an ED readmission within 1 and 3 months, respectively. At one month post-discharge, nursing care at home, meals on wheels, and risk for depression; and at 3 months post-discharge previous hospitalisation in the last 3 months, physiotherapy and meals on wheels were found to be independent predictors for ED readmission, respectively. CONCLUSIONS: This study observed a geriatric risk profile in older adults at the ED and a high readmission rate of those discharged, and suggests the potential value of CGA in identifying older patients at high risk for ED readmission. PMID- 25928800 TI - Nitroimidazole-Containing H2dedpa and H2CHXdedpa Derivatives as Potential PET Imaging Agents of Hypoxia with (68)Ga. AB - (68)Ga is an attractive radiometal for use in positron emission tomography (PET) imaging. The success of (68)Ga-based agents is dependent on a chelator that exhibits rapid radiometal incorporation, and strong kinetic inertness to prevent transchelation of (68)Ga in vivo. The linear chelating agents H2dedpa (1,2-[[6 carboxypyridin-2-yl]methylamino]ethane) and H2CHXdedpa (CHX = cyclohexyl/cyclohexane) (N4O2) have recently been developed that bind Ga(3+) quickly and under mild conditions, ideal properties to be incorporated into a (68)Ga PET imaging agent. Herein, nitroimidazole (NI) derivatives of H2dedpa and H2CHXdedpa to investigate specific targeting of hypoxic tumor cells are investigated, given that NI can be reduced and retained exclusively in hypoxic cells. Nine N,N'-bis-alkylated derivatives of H2dedpa and H2CHXdedpa have been synthesized; they have been screened for their ability to bind gallium, and cyclic voltammetry of nonradioactive complexes was performed to probe the redox cycling mechanism of NI. The compounds were radiolabeled with (67)Ga and (68)Ga and show promising radiolabeling efficiencies (>99%) when labeled at 10(-5) M for 10 min at room temperature. Moreover, stability studies (via apo-transferrin challenge, 37 degrees C) show that the (67)Ga complexes exhibit exceptional stability (86-99% intact) after 2 h. In vitro uptake studies under hypoxic (0.5% O2) and normoxic (21% O2) conditions in three cancerous cell lines [HT-29 (colon), LCC6(HER-2) (breast), and CHO (Chinese hamster ovarian)] were performed. Of the four H2dedpa or H2CHXdedpa NI derivatives tested, all showed preferential uptake in hypoxic cells compared to normoxic cells with hypoxic/normoxic ratios as high as 7.9 +/- 2.7 after 120 min. The results suggest that these novel bis alkylated NI-containing H2dedpa and H2CHXdedpa ligands would be ideal candidates for further testing in vivo for PET imaging of hypoxia with (68)Ga. PMID- 25928801 TI - c.620C>T mutation in GATA4 is associated with congenital heart disease in South India. AB - BACKGROUND: Congenital heart diseases (CHDs) usually refer to abnormalities in the structure and/or function of the heart that arise before birth. GATA4 plays an important role in embryonic heart development, hence the aim of this study was to find the association of GATA4 mutations with CHD among the south Indian CHD patients. METHOD: GATA4 gene was sequenced in 100 CHD patients (ASD, VSD, TOF and SV) and 200 controls. Functional significance of the observed GATA4 mutations was analyzed using PolyPhen, SIFT, PMut, Plink, Haploview, ESE finder 3.0 and CONSITE. RESULTS: We observed a total of 19 mutations, of which, one was in 5' UTR, 10 in intronic regions, 3 in coding regions and 5 in 3' UTR. Of the above mutations, one was associated with Atrial Septal Defect (ASD), two were found to be associated with Tetralogy of Fallot (TOF) and three (rs804280, rs4841587 and rs4841588) were strongly associated with Ventricular Septal Defect (VSD). Interestingly, one promoter mutation (-490 to 100 bp) i.e., 620 C>T (rs61277615, p-value = 0.008514), one splice junction mutation (G>A rs73203482; p-value = 9.6e 3, OR = 6.508) and one intronic mutation rs4841587 (p-value = 4.6e-3, OR = 4.758) were the most significant findings of this study. In silico analysis also proves that some of the mutations reported above are pathogenic. CONCLUSION: The present study found that GATA4 genetic variations are associated with ASD, TOF and VSD in South Indian patients. In silico analysis provides further evidence that some of the observed mutations are pathogenic. PMID- 25928802 TI - Role of oxidative stress mediated by glutathione-s-transferase in thiopurines' toxic effects. AB - Azathioprine (AZA), 6-mercaptopurine (6-MP), and 6-thioguanine (6-TG) are antimetabolite drugs, widely used as immunosuppressants and anticancer agents. Despite their proven efficacy, a high incidence of toxic effects in patients during standard-dose therapy is recorded. The aim of this study is to explain, from a mechanistic point of view, the clinical evidence showing a significant role of glutathione-S-transferase (GST)-M1 genotype on AZA toxicity in inflammatory bowel disease patients. To this aim, the human nontumor IHH and HCEC cell lines were chosen as predictive models of the hepatic and intestinal tissues, respectively. AZA, but not 6-MP and 6-TG, induced a concentration dependent superoxide anion production that seemed dependent on GSH depletion. N Acetylcysteine reduced the AZA antiproliferative effect in both cell lines, and GST-M1 overexpression increased both superoxide anion production and cytotoxicity, especially in transfected HCEC cells. In this study, an in vitro model to study thiopurines' metabolism has been set up and helped us to demonstrate, for the first time, a clear role of GST-M1 in modulating AZA cytotoxicity, with a close dependency on superoxide anion production. These results provide the molecular basis to shed light on the clinical evidence suggesting a role of GST-M1 genotype in influencing the toxic effects of AZA treatment. PMID- 25928803 TI - Exploring sources of variability in adherence to guidelines across hospitals in low-income settings: a multi-level analysis of a cross-sectional survey of 22 hospitals. AB - BACKGROUND: Variability in processes of care and outcomes has been reported widely in high-income settings (at geographic, hospital, physician group and individual physician levels); however, such variability and the factors driving it are rarely examined in low-income settings. METHODS: Using data from a cross sectional survey undertaken in 22 hospitals (60 case records from each hospital) across Kenya that aimed at evaluating the quality of routine hospital services, we sought to explore variability in four binary inpatient paediatric process indicators. These included three prescribing tasks and use of one diagnostic. To examine for sources of variability, we examined intra-class correlation coefficients (ICC) and their changes using multi-level mixed models with random intercepts for hospital and clinician levels and adjusting for patient and clinician level covariates. RESULTS: Levels of performance varied substantially across indicators and hospitals. The absolute values for ICCs also varied markedly ranging from a maximum of 0.48 to a minimum of 0.09 across the models for HIV testing and prescription of zinc, respectively. More variation was attributable at the hospital level than clinician level after allowing for nesting of clinicians within hospitals for prescription of quinine loading dose for malaria (ICC = 0.30), prescription of zinc for diarrhoea patients (ICC = 0.11) and HIV testing for all children (ICC = 0.43). However, for prescription of correct dose of crystalline penicillin, more of the variability was explained by the clinician level (ICC = 0.21). Adjusting for clinician and patient level covariates only altered, marginally, the ICCs observed in models for the zinc prescription indicator. CONCLUSIONS: Performance varied greatly across place and indicator. The variability that could be explained suggests interventions to improve performance might be best targeted at hospital level factors for three indicators and clinician factors for one. Our data suggest that better understanding of performance and sources of variation might help tailor improvement interventions although further data across a larger set of indicators and sites would help substantiate these findings. PMID- 25928804 TI - Validation of the foot length measure as an alternative tool to identify low birth weight and preterm babies in a low-resource setting like Nepal: a cross sectional study. AB - BACKGROUND: The majority of infants who die in the neonatal period are born with a low birth weight (LBW, <2500 grams), or prematurely (before 37 weeks). Most deaths among these infants could be prevented with simple, low-cost interventions like kangaroo mother care (KMC) or prevention and early identification of infection. It is difficult, however, to determine birth weight and gestational age in community settings, and therefore necessary to find an appropriate alternative screening tool that can identify LBW and preterm infants. METHODS: This cross-sectional study was conducted at a tertiary hospital in Nepal to compare the validity of using three different foot length measurement methods (plastic ruler, measuring tape, and paper footprint) as screening tools for identifying babies with birth weights <2000 grams or infants born preterm (<37 weeks). LBW was defined as less than 2000 grams because of the implication for use of KMC for these infants. Non-parametric receiver operating characteristics (ROC) analysis was completed to determine which measurement method best predicted LBW and preterm birth. For the method that was the best predictor for each outcome (i.e. highest area under the curve), further analyses were completed to determine sensitivity, specificity, likelihood ratios and predictive values of an operational screening cutoff to predict LBW or preterm birth in this setting. RESULTS: Of the 811 infants included in this study, 30 infants had LBW and 54 were born preterm. The plastic ruler was the measurement method with the highest area under the curve, and thus predictive score for estimating both outcomes, so operational cutoffs were identified based on this method. An operational cutoff of 7.2 cm was identified to screen for infants weighing <2000 grams at birth (sensitivity: 75.9%, specificity: 90.3%), and 7.8 cm was determined as the operational cutoff to identify preterm infants (sensitivity: 76.9%, specificity: 53.9%). CONCLUSIONS: In Nepal, at least in community settings, foot length measurement with a hard ruler may be a valid proxy to identify at-risk infants when birth weight or gestational age is unavailable. Further studies and piloting should be conducted to identify exact cutoffs that can be used within community settings. PMID- 25928805 TI - On-chip immunoelectrophoresis of extracellular vesicles released from human breast cancer cells. AB - Extracellular vesicles (EVs) including exosomes and microvesicles have attracted considerable attention in the fields of cell biology and medicine. For a better understanding of EVs and further exploration of their applications, the development of analytical methods for biological nanovesicles has been required. In particular, considering the heterogeneity of EVs, methods capable of measuring individual vesicles are desired. Here, we report that on-chip immunoelectrophoresis can provide a useful method for the differential protein expression profiling of individual EVs. Electrophoresis experiments were performed on EVs collected from the culture supernatant of MDA-MB-231 human breast cancer cells using a measurement platform comprising a microcapillary electrophoresis chip and a laser dark-field microimaging system. The zeta potential distribution of EVs that reacted with an anti-human CD63 (exosome and microvesicle marker) antibody showed a marked positive shift as compared with that for the normal immunoglobulin G (IgG) isotype control. Thus, on-chip immunoelectrophoresis could sensitively detect the over-expression of CD63 glycoproteins on EVs. Moreover, to explore the applicability of on-chip immunoelectrophoresis to cancer diagnosis, EVs collected from the blood of a mouse tumor model were analyzed by this method. By comparing the zeta potential distributions of EVs after their immunochemical reaction with normal IgG, and the anti-human CD63 and anti-human CD44 (cancer stem cell marker) antibodies, EVs of tumor origin circulating in blood were differentially detected in the real sample. The result indicates that the present method is potentially applicable to liquid biopsy, a promising approach to the low-invasive diagnosis of cancer. PMID- 25928807 TI - Development and Validation of the Keele Musculoskeletal Patient Reported Outcome Measure (MSK-PROM). AB - OBJECTIVE: To develop and validate a patient report outcome measure (PROM) for clinical practice that can monitor health status of patients with a range of musculoskeletal (MSK) disorders. METHODS: Constructs for inclusion in the MSK PROM were identified from a consensus process involving patients with musculoskeletal conditions, clinicians, purchasers of healthcare services, and primary care researchers. Psychometric properties of the brief tool, including face and construct validity, repeatability and responsiveness were assessed in a sample of patients with musculoskeletal pain consulting physiotherapy services in the United Kingdom (n=425). RESULTS: The consensus process identified 10 prioritised domains for monitoring musculoskeletal health status: pain intensity, quality of life, physical capacity, interference with social/leisure activities, emotional well-being, severity of most difficult thing, activities and roles, understanding independence, and overall impact. As the EuroQol (EQ-5D-5L) is a widely adopted PROMs tool and covers the first four domains listed, to reduce patient burden to a minimum the MSK-PROM was designed to capture the remaining six prioritised domains which are not measured by the EQ-5D-5L. The tool demonstrated excellent reliability, construct validity, responsiveness and acceptability to patients and clinicians for use in clinical practice. CONCLUSION: We have validated a brief patient reported outcome measure (MSK-PROM) for use in clinical practice to measure musculoskeletal health status and monitor outcomes over time using domains that are meaningful to patients and sensitive to change. Further work will establish whether the MSK-PROM is useful in other musculoskeletal healthcare settings. PMID- 25928806 TI - Proceedings of the fourth international conference on central hypoventilation. AB - Central hypoventilation syndromes (CHS) are rare diseases of central autonomic respiratory control associated with autonomous nervous dysfunction. Severe central hypoventilation is the hallmark and the most life-threatening feature. CHS is a group of not-fully defined disorders. Congenital CHS (CCHS) (ORPHA661) is clinically and genetically well-characterized, with the disease-causing gene identified in 2003. CCHS presents at birth in most cases, and associated with Hirschsprung's disease (ORPHA99803) and neural crest tumours in 20% and 5% of cases, respectively. The incidence of CCHS is estimated to be 1 of 200,000 live births in France, yet remains unknown for the rest of the world. In contrast, late-onset CHS includes a group of not yet fully delineated diseases. Overlap with CCHS is likely, as a subset of patients harbours PHOX2B mutations. Another subset of patients present with associated hypothalamic dysfunction. The number of these patients is unknown (less than 60 cases reported worldwide). Treatment of CHS is palliative using advanced techniques of ventilation support during lifetime. Research is ongoing to better understand physiopathological mechanisms and identify potential treatment pathways.The Fourth International Conference on Central Hypoventilation was organised in Warsaw, Poland, April 13-15, 2012, under the patronage of the European Agency for Health and Consumers and Public Health European Agency of European Community. The conference provided a state-of-the-art update of knowledge on all the genetic, molecular, cellular, and clinical aspects of these rare diseases. PMID- 25928808 TI - Somatic DNA Hypomethylation in H. pylori-Associated High-Risk Gastritis and Gastric Cancer: Enhanced Somatic Hypomethylation Associates with Advanced Stage Cancer. AB - OBJECTIVES: Helicobacter pylori-related high-risk gastritis (HRG) is a severe risk factor for gastric cancer (GC). The link between HRG and long-term risk for GC may involve genetic and epigenetic alterations underlying a field defect, i.e. a region of the mucosa prone to cancer development. Global DNA hypomethylation is a pervasive alteration in GC that associates with chromosomal instability and poor prognosis. The aim of this study was to determine the chronology of this alteration along the progression of HRG to GC, to test the hypothesis that it occurs early in the chronology of this pathway and plays a mechanistic role in the long-term cancer risk. METHODS: We comparatively measured the genomic methylation level in gastric biopsies from 94 GC patients and 16 of their cancer free relatives, 38 HRG patients, and 17 GERD patients, using a quantitative enzymatic method. RESULTS: GC biopsies were hypomethylated compared to their matching non-tumor mucosa (P=9.4 * 10(-12)), irrespective of the tumor location or patients' country of origin. Genome-wide hypomethylation was also found in gastric mucosa of GC (P=1.5 * 10(-5)) and HRG (P=0.004) patients compared with healthy donors and GC relatives, regardless of the biopsy location within the stomach or previous H. pylori eradication therapy. An enhanced hypomethylation, distinguished by a bi-slope distribution of the differences in methylation between tumor and normal tissues, associated with a more invasive (P=0.005) and advanced stage (P=0.017) type of GC. CONCLUSIONS: Universal DNA demethylation in normal gastric mucosa in GC patients appears sporadic rather than familial. Genomic hypomethylation in HRG possibly contributes to a field defect for cancerization that is not reversed by bacterial eradication. Enhanced somatic hypomethylation may stratify GC for prognostic purposes. PMID- 25928809 TI - Albumin gains immune boosting credibility. PMID- 25928810 TI - A two-gene blood test for methylated DNA sensitive for colorectal cancer. AB - BACKGROUND: Specific genes are methylated with high frequency in colorectal neoplasia, and may leak into blood. Detection of multiple methylated DNA biomarkers in blood may improve assay sensitivity for colorectal cancer (CRC) relative to a single marker. We undertook a case-control study evaluating the presence of two methylation DNA markers, BCAT1 and IKZF1, in circulation to determine if they were complementary for detection of CRC. METHODS: Methylation specific PCR assays were developed to measure the level of methylated BCAT1 and IKZF1 in DNA extracted from plasma obtained from colonoscopy-confirmed 144 healthy controls and 74 CRC cases. RESULTS: DNA yields ranged from 2 to 730 ng/mL plasma (mean 18.6ng/mL; 95% CI 11-26 ng/mL) and did not correlate with gender, age or CRC status. Methylated BCAT1 and IKZF1 DNA were detected in respectively 48 (65%) and 50 (68%) of the 74 cancers. In contrast, only 5 (4%) and 7 (5%) controls were positive for BCAT1 and IKZF1 DNA methylation, respectively. A two gene classifier model ("either or" rule) improved segregation of CRC from controls, with 57 of 74 cancers (77%) compared to only 11 of 144 (7.6%) controls being positive for BCAT1 and/or IKZF1 DNA methylation. Increasing levels of methylated DNA were observed as CRC stage progressed. CONCLUSIONS: Detection of methylated BCAT1 and/or IKZF1 DNA in plasma may have clinical application as a novel blood test for CRC. Combining the results from the two methylation-specific PCR assays improved CRC detection with minimal change in specificity. Further validation of this two-gene blood test with a view to application in screening is now indicated. PMID- 25928811 TI - Switching patients with non-dialysis chronic kidney disease from oral iron to intravenous ferric carboxymaltose: effects on erythropoiesis-stimulating agent requirements, costs, hemoglobin and iron status. AB - BACKGROUND: Patients with non-dialysis-dependent chronic kidney disease (ND-CKD) often receive an erythropoiesis-stimulating agent (ESA) and oral iron treatment. This study evaluated whether a switch from oral iron to intravenous ferric carboxymaltose can reduce ESA requirements and improve iron status and hemoglobin in patients with ND-CKD. METHODS: This prospective, single arm and single-center study included adult patients with ND-CKD (creatinine clearance <=40 mL/min), hemoglobin 11-12 g/dL and iron deficiency (ferritin <100 MUg/L or transferrin saturation <20%), who were regularly treated with oral iron and ESA during 6 months prior to inclusion. Study patients received an intravenous ferric carboxymaltose dose of 1,000 mg iron, followed by a 6-months ESA/ ferric carboxymaltose maintenance regimen (target: hemoglobin 12 g/dL, transferrin saturation >20%). Outcome measures were ESA dose requirements during the observation period after initial ferric carboxymaltose treatment (primary endpoint); number of hospitalizations and transfusions, renal function before and after ferric carboxymaltose administration, number of adverse reactions (secondary endpoints). Hemoglobin, mean corpuscular volume, ferritin and transferrin saturation were measured monthly from baseline until end of study. Creatinine clearance, proteinuria, C-reactive protein, aspartate aminotransferase, alanine aminotransferase and alkaline phosphatase bimonthly from baseline until end of study. RESULTS: Thirty patients were enrolled (age 70.1+/-11.4 years; mean+/-SD). Mean ESA consumption was significantly reduced by 83.2+/-10.9% (from 41,839+/-3,668 IU/patient to 6,879+/-4,271 IU/patient; p<0.01). Hemoglobin increased by 0.7+/-0.3 g/dL, ferritin by 196.0+/-38.7 MUg/L and transferrin saturation by 5.3+/-2.9% (month 6 vs. baseline; all p<0.01). No ferric carboxymaltose-related adverse events were reported and no patient withdrew or required transfusions during the study. CONCLUSION: Among patients with ND-CKD and stable normal or borderline hemoglobin, switching from oral iron to intravenous ferric carboxymaltose was associated with significant improvements in hematological and iron parameters and a significant reduction in ESA dose requirements in this single-center pilot study. TRIAL REGISTRATION: ClinicalTrials.gov NCT02232906. PMID- 25928813 TI - Tumor homologous recombination deficiency assays: another step closer to clinical application? AB - Inherited and acquired defects in homologous recombination, a phenotype termed 'BRCAness', may lend to therapeutic exploitation in breast cancer. To this end, development and clinical evaluation of platforms to identify signatures of BRCAness are of immense interest. In this issue of Breast Cancer Research, Vollebergh and colleagues report that a BRCA-like array comparative genomic hybridization (aCGH) genomic instability signature is associated with benefit from high-dose cyclophosphamide-thiotepa-carboplatin chemotherapy. We discuss the strengths and weaknesses of this study and consider the clinical significance and applicability of this aCGH BRCAness signature in the context of other existing homologous recombination deficiency detection platforms. PMID- 25928816 TI - The role of behavioral economic incentive design and demographic characteristics in financial incentive-based approaches to changing health behaviors: a meta analysis. AB - OBJECTIVE: To evaluate the use of behavioral economics to design financial incentives to promote health behavior change and to explore associations with demographic characteristics. DATA SOURCE: Studies performed by the Center for Health Incentives and Behavioral Economics at the University of Pennsylvania published between January 2006 and March 2014. STUDY INCLUSION AND EXCLUSION CRITERIA: Randomized, controlled trials with available participant-level data. Studies that did not use financial incentives to promote health behavior change were excluded. DATA EXTRACTION: Participant-level data from seven studies were pooled. DATA SYNTHESIS: Meta-analysis on the pooled sample using a random-effects model with interaction terms to examine treatment effects and whether they varied by incentive structure or demographic characteristics. RESULTS: The pooled study sample comprised 1403 participants, of whom 35% were female, 70% were white, 24% were black, and the mean age was 48 years (standard deviation 11.2 years). In the fully adjusted model, participants offered financial incentives had higher odds of behavior change (odds ratio [OR]: 3.96; p < .01) when compared to control. There were no significant interactions between financial incentives and gender, age, race, income, or education. When further adjusting for incentive structure, blacks had higher odds than whites of achieving behavior change (OR: 1.67; p < .05) with a conditional payment. Compared to lower-income participants, higher income participants had lower odds of behavior change (OR: 0.46; p = .01) with a regret lottery. CONCLUSION: Financial incentives designed using concepts from behavioral economics were effective for promoting health behavior change. There were no large and consistent relationships between the effectiveness of financial incentives and observable demographic characteristics. Second-order examinations of incentive structure suggest potential relationships among the effectiveness of financial incentives, incentive structure, and the demographic characteristics of race and income. PMID- 25928819 TI - Editor's Desk: The Wellness Movement. PMID- 25928815 TI - Neonatal isoflurane exposure induces neurocognitive impairment and abnormal hippocampal histone acetylation in mice. AB - BACKGROUND: Neonatal exposure to isoflurane may induce long-term memory impairment in mice. Histone acetylation is an important form of chromatin modification that regulates the transcription of genes required for memory formation. This study investigated whether neonatal isoflurane exposure-induced neurocognitive impairment is related to dysregulated histone acetylation in the hippocampus and whether it can be attenuated by the histone deacetylase (HDAC) inhibitor trichostatin A (TSA). METHODS: C57BL/6 mice were exposed to 0.75% isoflurane three times (each for 4 h) at postnatal days 7, 8, and 9. Contextual fear conditioning (CFC) was tested at 3 months after anesthesia administration. TSA was intraperitoneally injected 2 h before CFC training. Hippocampal histone acetylation levels were analyzed following CFC training. Levels of the neuronal activation and synaptic plasticity marker c-Fos were investigated at the same time point. RESULTS: Mice that were neonatally exposed to isoflurane showed significant memory impairment on CFC testing. These mice also exhibited dysregulated hippocampal H4K12 acetylation and decreased c-Fos expression following CFC training. TSA attenuated isoflurane-induced memory impairment and simultaneously increased histone acetylation and c-Fos levels in the hippocampal cornu ammonis (CA)1 area 1 h after CFC training. CONCLUSIONS: Memory impairment induced by repeated neonatal exposure to isoflurane is associated with dysregulated histone H4K12 acetylation in the hippocampus, which probably affects downstream c-Fos gene expression following CFC training. The HDAC inhibitor TSA successfully rescued impaired contextual fear memory, presumably by promoting histone acetylation and histone acetylation-mediated gene expression. PMID- 25928820 TI - Why do we wait until people die to ask about our roots? PMID- 25928822 TI - Altered resting-state frontoparietal control network in children with attention deficit/hyperactivity disorder. AB - The frontoparietal control network, anatomically and functionally interposed between the dorsal attention network and default mode network, underpins executive control functions. Individuals with attention-deficit/hyperactivity disorder (ADHD) commonly exhibit deficits in executive functions, which are mainly mediated by the frontoparietal control network. Involvement of the frontoparietal control network based on the anterior prefrontal cortex in neurobiological mechanisms of ADHD has yet to be tested. We used resting-state functional MRI and seed-based correlation analyses to investigate functional connectivity of the frontoparietal control network in a sample of 25 children with ADHD (7-14 years; mean 9.94 +/- 1.77 years; 20 males), and 25 age-, sex-, and performance IQ-matched typically developing (TD) children. All participants had limited in-scanner head motion. Spearman's rank correlations were used to test the associations between altered patterns of functional connectivity with clinical symptoms and executive functions, measured by the Conners' Continuous Performance Test and Spatial Span in the Cambridge Neuropsychological Test Automated Battery. Compared with TD children, children with ADHD demonstrated weaker connectivity between the right anterior prefrontal cortex (PFC) and the right ventrolateral PFC, and between the left anterior PFC and the right inferior parietal lobule. Furthermore, this aberrant connectivity of the frontoparietal control network in ADHD was associated with symptoms of impulsivity and opposition-defiance, as well as impaired response inhibition and attentional control. The findings support potential integration of the disconnection model and the executive dysfunction model for ADHD. Atypical frontoparietal control network may play a pivotal role in the pathophysiology of ADHD. PMID- 25928824 TI - An unusual case of pneumoperitoneum, pneumomediastinum, and subcutaneous emphysema following colorectal stent placement. PMID- 25928825 TI - Common bile duct stones: if you can't sweep them, vacuum them! PMID- 25928826 TI - Hidden duodenal gastrointestinal stromal tumor. PMID- 25928827 TI - Early gastric adenocarcinoma of the fundic gland type. PMID- 25928828 TI - Abdominal angiostrongyliasis mimicking acute appendicitis. PMID- 25928829 TI - Myeloid sarcoma of the duodenum: a rare cause of bowel obstruction and gastrointestinal bleeding. PMID- 25928830 TI - Gastrointestinal manifestations of common variable immunodeficiency disease. PMID- 25928831 TI - A stinging wasp in the stomach: accidental endoscopic diagnosis of a systemic anaphylactic reaction. PMID- 25928832 TI - Metal-Free Oxidative Spirocyclization of Alkynes with Sulfonylhydrazides Leading to 3-Sulfonated Azaspiro[4,5]trienones. AB - A novel and direct oxidative spirocyclization of arylpropiolamides with sulfonylhydrazides leading to 3-sulfonated azaspiro[4,5]trienones has been developed under metal-free conditions. The reaction is performed in a tandem manner constituted by the sequential sulfonylation of alkynes, ipso carbocyclization, dearomatization, hydration, and oxidation processes, providing a convenient and efficient approach to various sulfonated azaspiro[4,5] trienones of biological importance. PMID- 25928833 TI - On-the-Fly ab Initio Semiclassical Dynamics of Floppy Molecules: Absorption and Photoelectron Spectra of Ammonia. AB - We investigate the performance of on-the-fly ab initio (OTF-AI) semiclassical dynamics combined with the thawed Gaussian approximation (TGA) for computing vibrationally resolved absorption and photoelectron spectra. Ammonia is used as a prototype of floppy molecules, whose potential energy surfaces display strong anharmonicity. We show that despite complications due to the presence of large amplitude motion, the main features of the spectra are captured by the OTF-AI TGA, which-by definition-does not require any a priori knowledge of the potential energy surface. Moreover, the computed spectra are significantly better than those based on the popular global harmonic approximation. Finally, we probe the limit of the TGA to describe higher-resolution spectra, where long time dynamics is required. PMID- 25928834 TI - Correction. PMID- 25928835 TI - Association of Nonarteritic Ischemic Optic Neuropathy With Obstructive Sleep Apnea Syndrome: Consequences for Obstructive Sleep Apnea Screening and Treatment. AB - IMPORTANCE: The prevalence of obstructive sleep apnea syndrome (OSAS) in patients with nonarteritic anterior ischemic optic neuropathy (NAION) and its influence on second eye involvement is not well known. OBJECTIVE: To evaluate the prevalence of OSAS in patients with NAION and risk factors of second eye involvement. DESIGN, SETTING, AND PARTICIPANTS: In this cohort study, we examined 118 patients with anterior ischemic optic neuropathy referred to a tertiary care center from January 1, 2003, through December 31, 2010. EXPOSURES: Patients underwent polysomnography to detect OSAS and were prospectively followed up to assess the risk of second eye involvement. MAIN OUTCOMES AND MEASURES: The prevalence of OSAS in patients with NAION and the risk of second eye involvement using survival analysis based on the presence of OSAS, indication for ventilation treatment with continuous positive airway pressure, and other potential ocular and systemic confounders. RESULTS: In 89 patients with NAION who underwent polysomnography, 67 (75%) had OSAS. Second eye involvement was found in 10 (13.7%) of 73 patients at 3 years: 8 (15.4%) of 52 patients with OSAS at 3 years and 2 (9.5%) of 21 patients without OSAS at 3 years; P = .04. In multivariate analysis, nonadherence to ventilation treatment with continuous positive airway pressure in patients with severe OSAS increased the risk of second eye involvement (hazard ratio, 5.54; 95% CI, 1.13-27.11; P = .04). CONCLUSIONS AND RELEVANCE: These results suggest that OSAS is common in patients with NAION and that polysomnography should be considered in these patients. These findings also suggest that patients with severe OSAS who are nonadherent to ventilation treatment with continuous positive airway pressure have an increased risk of second eye involvement. PMID- 25928836 TI - Step-flow kinetics model for the vapor-solid-solid Si nanowires growth. AB - Vapor-solid-solid (VSS) process has recently received continued attention as an alternative to grow Si nanowire. In comparison with common vapor-liquid-solid (VLS) growth with liquid catalyst, VSS growth can prevent the catalyst species from incorporating into nanowires with deep-level impurity, and achieve the compositionally abrupt interfaces by restraining the so-called "reservoir effect". However, despite the huge advances in experimental observations with in situ electron microscopy, VSS growth still remains much less understood in theory. Here, we developed a general mass-transport-limited kinetic model to describe the VSS growth process of Si nanowires by considering three surface diffusion processes and a slow interface diffusion process, where the former determines the atoms supplies way, while the latter dominates the growth of nanowires. The present model is not only well consistent with the available experimental data of Si nanowire, but also gives a clear physical image for the successive side-to-side ledge flow VSS growth. PMID- 25928837 TI - Aggregated silver nanoparticles based surface-enhanced Raman scattering enzyme linked immunosorbent assay for ultrasensitive detection of protein biomarkers and small molecules. AB - Lowering the detection limit is critical to the design of bioassays required for medical diagnostics, environmental monitoring, and food safety regulations. The current sensitivity of standard color-based analyte detection limits the further use of enzyme-linked immunosorbent assays (ELISAs) in research and clinical diagnoses. Here, we demonstrate a novel method that uses the Raman signal as the signal-generating system of an ELISA and combines surface-enhanced Raman scattering (SERS) with silver nanoparticles aggregation for ultrasensitive analyte detection. The enzyme label of the ELISA controls the dissolution of Raman reporter-labeled silver nanoparticles through hydrogen peroxide and generates a strong Raman signal when the analyte is present. Using this assay, prostate-specific antigen (PSA) and the adrenal stimulant ractopamine (Rac) were detected in whole serum and urine at the ultralow concentrations of 10(-9) and 10(-6) ng/mL, respectively. The methodology proposed here could potentially be applied to other molecules detection as well as PSA and Rac. PMID- 25928838 TI - Grafted carbazole-assisted electrodeposition of graphene oxide. AB - The electrodeposition of graphene oxide (GO) by covalently linked electroactive monomer, carbazole (Cbz) is first demonstrated herein. This is based on the electropolymerization and electrodeposition of covalently linked Cbz units when a potential is applied. During the electrochemical process, the Cbz groups electropolymerize and carry the GO nanosheets as it electrodeposits on the substrate. Moreover, the GO-Cbz sheets selectively deposit onto the conducting regions of the substrate, which demonstrates its promise for the fabrication of electropatterned graphene-based devices. In addition, GO-Cbz is a promising material for the fabrication of nanocomposite coatings for anticorrosion application. In as little as 1 wt % GO-Cbz loading, a protection efficiency as high as 95.4% was achieved. PMID- 25928839 TI - Comparative sequence- and structure-inspired drug design for PilF protein of Neisseria meningitidis. AB - Serogroup A of Neisseria meningitidis is the organism responsible for causing epidemic diseases in developing countries by a pilus-mediated adhesion to human brain endothelial cells. Type IV pilus assembly protein (PilF) associated with bacterial adhesion, aggregation, invasion, host cell signaling, surface motility, and natural transformation can be considered as a candidate for effective anti meningococcal drug development. Since the crystal structure of PilF was not available, in the present study, it was modeled after the Z2491 strain (CAM09255.1) using crystal structure of chain A of Vibrio cholerae putative Ntpase EpsE (Protein Data Bank (PDB) ID: 1P9R) and then we based this analysis on sequence comparisons and structural similarity using in silico methods and docking processes, to design a suitable inhibitor molecule. The ligand 3-{(4S)-5 {[(1R)-1-cyclohexylethyl]amino}-4-[(5S)-5-(prop-2-en-1-yl) cyclopent-1-en-1-yl] 1,4-dihydro-7H-pyrrolo[2,3-d] pyrimidin-7-yl}-1,2-dideoxy-b-L-erythro-hex-1-en-3 ulofuranosyl binds to the protein with a binding energy of -8.10 kcal and showed a drug likeness of 0.952 with no predicted health hazard. It can be utilized as a potent inhibitor of N. meningitidis pilus-mediated adhesion to human brain endothelial cells preventing meningeal colonization. PMID- 25928840 TI - Achieving equity within universal health coverage: a narrative review of progress and resources for measuring success. AB - INTRODUCTION: Equity should be implicit within universal health coverage (UHC) however, emerging evidence is showing that without adequate focus on measurement of equity, vulnerable populations may continue to receive inadequate or inferior health care. This study undertakes a narrative review which aims to: (i) elucidate how equity is contextualised and measured within UHC, and (ii) describe tools, resources and lessons which will assist decision makers to plan and implement UHC programmes which ensure equity for all. METHODS: A narrative review of peer-reviewed literature published in English between 2005 and 2013, retrieved from PubMed via the search words, 'universal health coverage/care' and 'equity/inequity' was performed. Websites of key global health organizations were also searched for relevant grey literature. Papers were excluded if they failed to focus on equity (of access, financial risk protection or health outcomes) as well as focusing on one of the following: (i) the impact of UHC programmes, policies or interventions on equity (ii) indicators, measurement, monitoring and/or evaluation of equity within UHC, or (iii) tools or resources to assist with measurement. RESULTS: Eighteen journal articles consisting mostly of secondary analysis of country data and qualitative case studies in the form of commentaries/reviews, and 13 items of grey literature, consisting largely of reports from working groups and expert meetings focusing on defining, understanding and measuring inequity in UHC (including recent drafts of global/country monitoring frameworks) were included. DISCUSSION: The literature advocates for progressive universalism addressing monetary and non-monetary barriers to access and strengthening existing health systems. This however relies on countries being effectively able to identify and reach disadvantaged populations and estimate unmet need. Countries should assess the new WHO/WB proposed framework for its ability to adequately track the progress of disadvantaged populations in terms of achieving equitable access, effective coverage and financial risk protection within their own settings. CONCLUSIONS: Recently published resources contextualise equity as a measurable component of UHC and propose several useful indicators and frameworks. Country case-studies also provide useful lessons and recommendations for planning and implementing equitable UHC which will assist other countries to consider their own requirements for UHC monitoring and evaluation. PMID- 25928841 TI - Correction: Involvement in emergency situations by primary care doctors on-call in Norway--a prospective population-based observational study. PMID- 25928843 TI - The perceptions and experiences of people injured in motor vehicle crashes in a compensation scheme setting: a qualitative study. AB - BACKGROUND: The evidence that compensation related factors are associated with poor recovery is substantial but these measures are generic and do not consider the complexity of scheme design. The objectives of this study were to understand people's perceptions and experiences of the claims process after sustaining a compensable injury in a motor vehicle crash (including why people seek legal representation); and to explore ways to assist people following a compensable injury and improve their experience with the claims process. METHODS: A qualitative study in a Compulsory Third Party (CTP) personal injury scheme covering the state of New South Wales (NSW), Australia. A series of five focus groups, with a total of 32 participants who had sustained mild to moderate injuries in a motor vehicle crash, were conducted from May to June 2011 with four to eight attendees in each group. These were audio-recorded and transcribed. The methodology was based on a grounded theory approach using thematic analysis and constant comparison to generate coding categories for themes. Data saturation was reached. Analyst triangulation was used to ensure credibility of the results. RESULTS: Five primary themes were identified: complexity of the claims process; requirement of legal representation; injury recovery expectations; importance of timely healthcare decision making; and improvements for injury recovery. Some participants struggled, finding the claims process stressful and subsequently sought legal advice; whilst others reported a straight forward recovery, helpful insurer interactions and no legal representation. Most participants were influenced by injury recovery expectations, and timely healthcare decision making. To assist with injury recovery, access to objective information about the claims process using online technology and social media was considered paramount. CONCLUSIONS: Participants had contrasting injury recovery experiences and their perceptions of the claims process differed and were influenced by injury recovery expectations, and timeliness of healthcare decision making. Improvements to the claims process are required, including: simplification or streamlining (possibly using online technology and/or social media to reduce paperwork); and providing access to objective information. There is a need to trial early interventions and new claims management policies that could improve injury recovery and satisfaction with the claims process. PMID- 25928845 TI - Community Structure and Survival of Tertiary Relict Thuja sutchuenensis (Cupressaceae) in the Subtropical Daba Mountains, Southwestern China. AB - A rare coniferous Tertiary relict tree species, Thuja sutchuenensis Franch, has survived in the Daba Mountains of southwestern China. It was almost eliminated by logging during the past century. We measured size and age structures and interpreted regeneration dynamics of stands of the species in a variety of topographic contexts and community associations. Forest communities containing T. sutchuenensis were of three types: (1) the Thuja community dominated by T. sutchuenensis, growing on cliffs; (2) the Thuja-Quercus-Cyclobalanopsis community dominated by T. sutchuenensis, Quercus engleriana and Cyclobalanopsis oxyodon, along with Fagus engleriana and Carpinus fargesiana, on steep slopes; (3) the Thuja-Tsuga-Quercus community dominated by T. sutchuenensis, Tsuga chinensis, and Quercus spinosa, on crest ridges. The established seedlings/saplings were found in limestone crevices, on scarred cliff-faces, cliff-edges, fallen logs, canopy gaps and forest margins. The radial growth rate was 0.5-1.1 mm per year. Its growth forms were distorted. It had strong sprouting ability after disturbances. The T. sutchuenensis population thrives on cliffs where there is little competition from other species because of harsh conditions and rockslide disturbances. It is shade-intolerant but stress-tolerant. Its regeneration has depended on natural disturbances. PMID- 25928846 TI - Genome-wide co-occupancy of AML1-ETO and N-CoR defines the t(8;21) AML signature in leukemic cells. AB - BACKGROUND: Many leukemias result from chromosomal rearrangements. The t(8;21) chromosomal translocation produces AML1-ETO, an oncogenic fusion protein that compromises the function of AML1, a transcription factor critical for myeloid cell differentiation. Because of the pressing need for new therapies in the treatment of acute myleoid leukemia, we investigated the genome-wide occupancy of AML1-ETO in leukemic cells to discover novel regulatory mechanisms involving AML ETO bound genes. RESULTS: We report the co-localization of AML1-ETO with the N CoR co-repressor to be primarily on genomic regions distal to transcriptional start sites (TSSs). These regions exhibit over-representation of the motif for PU.1, a key hematopoietic regulator and member of the ETS family of transcription factors. A significant discovery of our study is that genes co-occupied by AML1 ETO and N-CoR (e.g., TYROBP and LAPTM5) are associated with the leukemic phenotype, as determined by analyses of gene ontology and by the observation that these genes are predominantly up-regulated upon AML1-ETO depletion. In contrast, the AML1-ETO/p300 gene network is less responsive to AML1-ETO depletion and less associated with the differentiation block characteristic of leukemic cells. Furthermore, a substantial fraction of AML1-ETO/p300 co-localization occurs near TSSs in promoter regions associated with transcriptionally active loci. CONCLUSIONS: Our findings establish a novel and dominant t(8;21) AML leukemia signature characterized by occupancy of AML1-ETO/N-CoR at promoter-distal genomic regions enriched in motifs for myeloid differentiation factors, thus providing mechanistic insight into the leukemic phenotype. PMID- 25928848 TI - Participation in sport and physical activity: associations with socio-economic status and geographical remoteness. AB - BACKGROUND: Many factors influence participation in sport and Physical Activity (PA). It is well established that socio-economic status (SES) is a critical factor. There is also growing evidence that there are differences in participation patterns according to residential location. However, little is known more specifically about the relationship of PA participation and frequency of participation in particular contexts, to SES and residential location. This study investigated the relationship of participation, and frequency and context of participation, to SES and location. METHODS: Three aspects of participation were investigated from data collected in the Exercise, Recreation and Sport Survey (ERASS) 2010 of persons aged 15+ years: any participation (yes, no), regular participation (<12 times per year, >= 12 times per year) and level of organisation of participation setting (non-organised, organised non-club setting, club setting). RESULTS: The rates of both any and regular PA participation increased as SES increased and decreased as remoteness increased. However, participation in PA was SES- or remoteness-prohibitive for only a few types of PA. As remoteness increased and SES decreased, participation in many team sports actually increased. For both SES and remoteness, there were more significant associations with overall participation, than with regular participation or participation in more organised contexts. CONCLUSIONS: This study demonstrates the complexity of the associations between SES and location across different contexts of participation. Nevertheless, it seems that once initial engagement in PA is established, SES and remoteness are not critical determinants of the depth of engagement. PMID- 25928847 TI - Serological evidence of vector and parasite exposure in Southern Ghana: the dynamics of malaria transmission intensity. AB - BACKGROUND: Seroepidemiology provides robust estimates for tracking malaria transmission when intensity is low and useful when there is no baseline entomological data. Serological evidence of exposure to malaria vectors and parasite contribute to our understanding of the risk of pathogen transmission, and facilitates implementation of targeted interventions. Ab to Anopheles gambiae salivary peptide (gSG6-P1) and merozoite surface protein one (MSP-1(19)) reflect human exposure to malaria vectors and parasites. This study estimated malaria transmission dynamics using serological evidence of vector and parasite exposure in southern Ghana. METHODS: Total IgG responses to both antigens in an age stratified cohort (<5, 5-14, >14) were measured from South-eastern Ghana. 295 randomly selected sera were analyzed from archived samples belonging to a cohort study that were followed at 3 consecutive survey months (n = 885); February, May and August 2009. Temporal variations in seroprevalence of both antigens as well as differences between the age-stratified cohorts were determined by chi (2) test with p < 0.05 statistically significant. Non-parametric repeated ANOVA - Friedman's test was used to test differences in antibody levels. Seroprevalence data were fitted to reversible catalytic model to estimate sero-conversion rates. RESULTS: Whereas parasite prevalence was generally low 2.4%, 2.7% and 2.4% with no apparent trends with season, seroprevalence to both gSG6-P1 and MSP1(19) were high (59%, 50.9%, 52.2%) and 57.6%, 52.3% and 43.6% in respective order from Feb. to August. Repeated measures ANOVA showed differences in median antibody levels across surveys with specific significant differences between February and May but not August by post hoc Dunn's multiple comparison tests for gSG6-P1. For MSP1(19), no differences were observed in antibody levels between February and May but a significant decline was observed from May to August. Seroconversion rates for gSG6-P1 increased by 1.5 folds from February to August and 3 folds for MSP1(19). CONCLUSION: Data suggests exposure to infectious bites may be declining whereas mosquito bites remains high. Sustained malaria control efforts and surveillance are needed to drive malaria further down and to prevent catastrophic rebound. Operational factors for scaling up have been discussed. PMID- 25928849 TI - Ebola virus entry: a curious and complex series of events. PMID- 25928853 TI - Transcriptional regulation of the paper mulberry under cold stress as revealed by a comprehensive analysis of transcription factors. AB - BACKGROUND: Several studies have focused on cold tolerance in multiple regulated levels. However, a genome-scale molecular analysis of the regulated network under the control of transcription factors (TFs) is still lacking, especially for trees. To comprehensively identify the TFs that regulate cold stress response in the paper mulberry and understand their regulatory interactions, transcriptomic data was used to assess changes in gene expression induced by exposure to cold. RESULTS: Results indicated that 794 TFs, belonging to 47 families and comprising more than 59% of the total TFs of this plant, were involved in the cold stress response. They were clustered into three groups, namely early, intermediate and late responsive groups which contained 95, 550 and 149 TFs, respectively. Among of these differentially expressed TFs, one bHLH, two ERFs and three CAMTAs were considered to be the key TFs functioning in the primary signal transduction. After that, at the intermediate stage of cold stress, there were mainly two biological processes that were regulated by TFs, namely cold stress resistance (including 5 bHLH, 14 ERFs, one HSF, 4 MYBs, 3 NACs, 11 WRKYs and so on) and growth and development of lateral organ or apical meristem (including ARR-B, B3, 5 bHLHs, 2 C2H2, 4 CO-like, 2 ERF, 3 HD-ZIP, 3 YABBYs, G2-like, GATA, GRAS and TCP). In late responsive group, 3 ARR-B, C3H, 6 CO-like, 2 G2-like, 2 HSFs, 2 NACs and TCP. Most of them presented the up-regulated expression at 12 or 24 hours after cold stress implied their important roles for the new growth homeostasis under cold stress. CONCLUSIONS: Our study identified the key TFs that function in the regulatory cascades mediating the activation of downstream genes during cold tress tolerance in the paper mulberry. Based on the analysis, we found that the AP2/ERF, bHLH, MYB, NAC and WRKY families might play the central and significant roles during cold stress response in the paper mulberry just as in other species. Meanwhile, many other TF families previously reported as involving in regulation of growth and development, including ARF, DBB, G2-like, GRF, GRAS, LBD, WOX and YAABY exhibited their important potential function in growth regulation under cold stress. PMID- 25928856 TI - Vaccination of pigs with the S48 strain of Toxoplasma gondii--safer meat for human consumption. AB - As clinical toxoplasmosis is not considered a problem in pigs, the main reason to implement a control strategy against Toxoplasma gondii (T. gondii) in this species is to reduce the establishment of T. gondii tissue cysts in pork, consequently reducing the risk of the parasite entering the human food chain. Consumption of T. gondii tissue cysts from raw or undercooked meat is one of the main sources of human infection, with infected pork being considered a high risk. This study incorporates a mouse bioassay with molecular detection of T. gondii DNA to study the effectiveness of vaccination (incomplete S48 strain) in its ability to reduce tissue cyst burden in pigs, following oocyst (M4 strain) challenge. Results from the mouse bioassay show that 100% of mice which had received porcine tissues from vaccinated and challenged pigs survived compared with 51.1% of mice which received tissues from non-vaccinated and challenged pigs. The presence (or absence) of T. gondii DNA from individual mouse brains also confirmed these results. This indicates a reduction in viable T. gondii tissue cysts within tissues from pigs which have been previously vaccinated with the S48 strain. In addition, the study demonstrated that the main predilection sites for the parasite were found to be brain and highly vascular muscles (such as tongue, diaphragm, heart and masseter) of pigs, while meat cuts used as human food such as chop, loin, left tricep and left semitendinosus, had a lower burden of T. gondii tissue cysts. These promising results highlight the potential of S48 strain tachyzoites for reducing the number of T. gondii tissues cysts in pork and thus improving food safety. PMID- 25928857 TI - Fluid retention index predicts the 30-day mortality in geriatric care. AB - The incidence and medical consequences of dehydration and fluid retention in senior citizens are unclear. The present study used urine sampling to detect renal conservation of water, which is an early sign of dehydration, and assessed its relationship to mortality in elderly patients admitted for acute hospital care. A urine sample was collected from 256 patients (mean age 82 years) and analyzed for color, specific gravity and osmolality. These markers were used to calculate a composite index of fluid retention, which was indicated by urine color >= 4, specific gravity >= 1.020 and osmolality >= 600 mOsmol/kg as suggested from eight previous studies of exercise-induced dehydration, of which one extends to age 69. Concentrated urine consistent with dehydration was present in 39 (16%) of the patients. This finding was relatively more common among those with confusion and/or dementia, but less common in patients with medical disease, and in those taking diuretics daily. Patients with such fluid retention had a higher 30-day mortality when compared to those who were euhydrated (21% versus 8%; p < 0.03). A difference of 10% remained at three months and one year after the admission to hospital. Concentrated urine consistent with fluid retention was found in 16% of the geriatric patients admitted to hospital for acute care. In these patients the mortality within 30 days was almost tripled compared to those who were euhydrated. PMID- 25928859 TI - SNAI2/SLUG and estrogen receptor mRNA expression are inversely correlated and prognostic of patient outcome in metastatic non-small cell lung cancer. AB - BACKGROUND: Epithelial-mesenchymal transition (EMT) is involved in important malignant features of cancer cells, like invasion, metastatic potential, anti apoptotic and stem-cell like phenotypes. Among several transcription factors, SNAI2/SLUG is supposed to play an essential role for EMT. METHODS: Paraffin embedded tumor samples from 63 patients with metastatic non-small cell lung cancer, enrolled in a randomized phase II trial, were prospectively collected, 53 samples qualified for further analysis. Automated RNA extraction from paraffin and RT-quantitative PCR was used for evaluation of SNAI2/SLUG, estrogen receptor 1 (ESR1) and matrix-metalloproteinases (MMP) mRNA expression. RESULTS: Clinical features like age, gender, performance status, histological subtype and stage were similarly distributed among SNAI2/SLUG positive and negative patients. SNAI2/SLUG was significantly, inversely correlated with ESR1 mRNA expression (p < 0.0001). In contrast, MMP2 (p = 0.387), MMP7 (p = 0.396) and MMP9 mRNA expression (p = 0.366) did not correlate with SNAI2/SLUG. Patients with high SNAI2/SLUG expression (grouped by median expression) had a worse outcome. Median overall survival in patients with high SNAI2/SLUG expression was 5.7 months versus 11.6 months with low SNAI2/SLUG expression (p = .038). Inversely, patients with high ESR1 expression (grouped by median expression) had an improved median OS with 10.9 months vs. 5.0 months in the low expression group (p = .032). In multivariate analysis, SNAI2/SLUG2 (p = .022) and ESR1 (p = .017) separately were independent prognostic factors for survival. CONCLUSION: SNAI2/SLUG is prognostic of patients' outcome. The strong inverse correlation with ESR1 indicates a significant impact of estrogen receptor pathway regarding these malignant features. PMID- 25928860 TI - Self-organized alternating chimera states in oscillatory media. AB - Oscillatory media can exhibit the coexistence of synchronized and desynchronized regions, so-called chimera states, for uniform parameters and symmetrical coupling. In a phase-balanced chimera state, where the totals of synchronized and desynchronized regions, respectively, are of the same size, the symmetry of the system predicts that interchanging both phases still gives a solution to the underlying equations. We observe this kind of interchange as a self-emerging phenomenon in an oscillatory medium with nonlinear global coupling. An interplay between local and global couplings renders the formation of these alternating chimeras possible. PMID- 25928861 TI - Moment based gene set tests. AB - BACKGROUND: Permutation-based gene set tests are standard approaches for testing relationships between collections of related genes and an outcome of interest in high throughput expression analyses. Using M random permutations, one can attain p-values as small as 1/(M+1). When many gene sets are tested, we need smaller p values, hence larger M, to achieve significance while accounting for the number of simultaneous tests being made. As a result, the number of permutations to be done rises along with the cost per permutation. To reduce this cost, we seek parametric approximations to the permutation distributions for gene set tests. RESULTS: We study two gene set methods based on sums and sums of squared correlations. The statistics we study are among the best performers in the extensive simulation of 261 gene set methods by Ackermann and Strimmer in 2009. Our approach calculates exact relevant moments of these statistics and uses them to fit parametric distributions. The computational cost of our algorithm for the linear case is on the order of doing |G| permutations, where |G| is the number of genes in set G. For the quadratic statistics, the cost is on the order of |G|(2) permutations which can still be orders of magnitude faster than plain permutation sampling. We applied the permutation approximation method to three public Parkinson's Disease expression datasets and discovered enriched gene sets not previously discussed. We found that the moment-based gene set enrichment p-values closely approximate the permutation method p-values at a tiny fraction of their cost. They also gave nearly identical rankings to the gene sets being compared. CONCLUSIONS: We have developed a moment based approximation to linear and quadratic gene set test statistics' permutation distribution. This allows approximate testing to be done orders of magnitude faster than one could do by sampling permutations. We have implemented our method as a publicly available Bioconductor package, npGSEA (www.bioconductor.org) . PMID- 25928866 TI - Shifting Patterns of the HIV Epidemic in Southwest China: A Case Study Based on Sentinel Surveillance, 1995-2012. AB - The HIV epidemic is experiencing a rapid shift in transmission profile in China. This study aims to examine the changes in magnitude, transmission pattern, and trend of the HIV epidemic in a typical Southwest Chinese prefecture over the period of 1995-2012. HIV surveillance data from the web-based reporting system were analyzed during this period. We investigated the temporal trends in the changing characteristics of HIV transmission, the HIV disease burden in key affected populations, and assessed the impacts on HIV disease progression due to scale-up of antiretroviral treatment. A total of 3556 HIV/AIDS cases were reported in Yuxi prefecture, Yunnan, over the study period. The number of HIV tests conducted has dramatically increased from 1041 in 1995 to 247,859 in 2012, resulting in a substantial increase in HIV diagnoses from 11 cases to 327 cases over the same period. Since 2005, cumulatively 1250 eligible people living with HIV (PLHIV) have received combination antiretroviral therapy which reduced AIDS disease progression from 9.0% (95% CI: 6.7-11.4%) in 1995 to 0.1% (0-0.3%) in 2012 (ptrend=0.0002). The primary mode of HIV transmission has been shifted from injection sharing (71.9% diagnoses in 1995-2004) to unsafe sexual contacts (82.6% diagnoses in 2012). Yuxi prefecture is experiencing a concentrated but shifting HIV epidemic. Scale-up of HIV testing is essential to effective sentinel surveillance and enhancing early diagnosis and treatment in PLHIV. PMID- 25928874 TI - Relationship between reduced albumin and inflammation in the critically ill. PMID- 25928870 TI - Neurofeedback as a nonpharmacological treatment for adults with attention deficit/hyperactivity disorder (ADHD): study protocol for a randomized controlled trial. AB - BACKGROUND: Neurofeedback has been applied effectively in various areas, especially in the treatment of children with attention-deficit/hyperactivity disorder (ADHD). This study protocol is designed to investigate the effect of slow cortical potential (SCP) feedback and a new form of neurofeedback using near infrared spectroscopy (NIRS) on symptomatology and neurophysiological parameters in an adult ADHD population. A comparison of SCP and NIRS feedback therapy methods has not been previously conducted and may yield valuable findings about alternative treatments for adult ADHD. METHODS/DESIGN: The outcome of both neurofeedback techniques will be assessed over 30 treatment sessions and after a 6-month follow-up period, and then will be compared to a nonspecific biofeedback treatment. Furthermore, to investigate if treatment effects in this proof-of principle study can be predicted by specific neurophysiological baseline parameters, regression models will be applied. Finally, a comparison with healthy controls will be conducted to evaluate deviant pretraining neurophysiological parameters, stability of assessment measures, and treatment outcome. DISCUSSION: To date, an investigation and comparison of SCP and NIRS feedback training to an active control has not been conducted; therefore, we hope to gain valuable insights in effects and differences of these types of treatment for ADHD in adults. TRIAL REGISTRATION: This study is registered with the German Registry of Clinical Trials: DRKS00006767 , date of registration: 8 October 2014. PMID- 25928875 TI - Genomic prediction of breeding values using previously estimated SNP variances. AB - BACKGROUND: Genomic prediction requires estimation of variances of effects of single nucleotide polymorphisms (SNPs), which is computationally demanding, and uses these variances for prediction. We have developed models with separate estimation of SNP variances, which can be applied infrequently, and genomic prediction, which can be applied routinely. METHODS: SNP variances were estimated with Bayes Stochastic Search Variable Selection (BSSVS) and BayesC. Genome enhanced breeding values (GEBV) were estimated with RR-BLUP (ridge regression best linear unbiased prediction), using either variances obtained from BSSVS (BLUP-SSVS) or BayesC (BLUP-C), or assuming equal variances for each SNP. Datasets used to estimate SNP variances comprised (1) all animals, (2) 50% random animals (RAN50), (3) 50% best animals (TOP50), or (4) 50% worst animals (BOT50). Traits analysed were protein yield, udder depth, somatic cell score, interval between first and last insemination, direct longevity, and longevity including information from predictors. RESULTS: BLUP-SSVS and BLUP-C yielded similar GEBV as the equivalent Bayesian models that simultaneously estimated SNP variances. Reliabilities of these GEBV were consistently higher than from RR-BLUP, although only significantly for direct longevity. Across scenarios that used data subsets to estimate GEBV, observed reliabilities were generally higher for TOP50 than for RAN50, and much higher than for BOT50. Reliabilities of TOP50 were higher because the training data contained more ancestors of selection candidates. Using estimated SNP variances based on random or non-random subsets of the data, while using all data to estimate GEBV, did not affect reliabilities of the BLUP models. A convergence criterion of 10(-8) instead of 10(-10) for BLUP models yielded similar GEBV, while the required number of iterations decreased by 71 to 90%. Including a separate polygenic effect consistently improved reliabilities of the GEBV, but also substantially increased the required number of iterations to reach convergence with RR-BLUP. SNP variances converged faster for BayesC than for BSSVS. CONCLUSIONS: Combining Bayesian variable selection models to re-estimate SNP variances and BLUP models that use those SNP variances, yields GEBV that are similar to those from full Bayesian models. Moreover, these combined models yield predictions with higher reliability and less bias than the commonly used RR-BLUP model. PMID- 25928876 TI - Expert opinion on the management of pain in hospitalised older patients with cognitive impairment: a mixed methods analysis of a national survey. AB - BACKGROUND: Hospitalised older patients are complex. Comorbidity and polypharmacy complicate frailty. Significant numbers have dementia and/or cognitive impairment. Pain is highly prevalent. The evidence base for pain management in cognitively impaired individuals is sparse due to methodological issues. A wealth of expert opinion is recognised potentially providing a useful evidence base for guiding clinical practice. The study aimed to gather expert opinion on pain management in cognitively impaired hospitalised older people. METHODS: Consultant Geriatricians listed as dementia leads in the National Dementia Audit were contacted electronically and invited to respond. The questionnaire sought information on their role, confidence and approach to pain management in cognitively impaired hospitalised patients. Responses were analysed using a mixed methods approach. RESULTS: Respondents considered themselves very confident in the clinical field. Awareness of potential to do harm was highly evident. Unequivocally responses suggested paracetamol is safe and should be first choice analgesic, newer opiates should be used preferentially in renal impairment and nefopam is unsafe. A grading of the safety profile of specific medications became apparent, prompting requirement for further evaluation and holistic assessment. CONCLUSION: The lack of consensus reached highlights the complexity of this clinical field. The use of paracetamol first line, newer opiates in renal impairment and avoidance of nefopam are immediately transferrable to clinical practice. Further review, evaluation and comparison of the risks associated with other specific analgesics are necessary before a comprehensive clinical guideline can be produced. PMID- 25928877 TI - Variability of systemic and oro-dental phenotype in two families with non-lethal Raine syndrome with FAM20C mutations. AB - BACKGROUND: Raine syndrome (RS) is a rare autosomal recessive bone dysplasia typified by osteosclerosis and dysmorphic facies due to FAM20C mutations. Initially reported as lethal in infancy, survival is possible into adulthood. We describe the molecular analysis and clinical phenotypes of five individuals from two consanguineous Brazilian families with attenuated Raine Syndrome with previously unreported features. METHODS: The medical and dental clinical records were reviewed. Extracted deciduous and permanent teeth as well as oral soft tissues were analysed. Whole exome sequencing was undertaken and FAM20C cDNA sequenced in family 1. RESULTS: Family 1 included 3 siblings with hypoplastic Amelogenesis Imperfecta (AI) (inherited abnormal dental enamel formation). Mild facial dysmorphism was noted in the absence of other obvious skeletal or growth abnormalities. A mild hypophosphataemia and soft tissue ectopic mineralization were present. A homozygous FAM20C donor splice site mutation (c.784 + 5 g > c) was identified which led to abnormal cDNA sequence. Family 2 included 2 siblings with hypoplastic AI and tooth dentine abnormalities as part of a more obvious syndrome with facial dysmorphism. There was hypophosphataemia, soft tissue ectopic mineralization, but no osteosclerosis. A homozygous missense mutation in FAM20C (c.1487C > T; p.P496L) was identified. CONCLUSIONS: The clinical phenotype of non-lethal Raine Syndrome is more variable, including between affected siblings, than previously described and an adverse impact on bone growth and health may not be a prominent feature. By contrast, a profound failure of dental enamel formation leading to a distinctive hypoplastic AI in all teeth should alert clinicians to the possibility of FAM20C mutations. PMID- 25928878 TI - Engineering Saccharomyces pastorianus for the co-utilisation of xylose and cellulose from biomass. AB - BACKGROUND: Lignocellulosic biomass is a viable source of renewable energy for bioethanol production. For the efficient conversion of biomass into bioethanol, it is essential that sugars from both the cellulose and hemicellulose fractions of lignocellulose be utilised. RESULTS: We describe the development of a recombinant yeast system for the fermentation of cellulose and xylose, the most abundant pentose sugar in the hemicellulose fraction of biomass. The brewer's yeast Saccharomyces pastorianus was chosen as a host as significantly higher recombinant enzyme activities are achieved, when compared to the more commonly used S. cerevisiae. When expressed in S. pastorianus, the Trichoderma reesei xylose oxidoreductase pathway was more efficient at alcohol production from xylose than the xylose isomerase pathway. The alcohol yield was influenced by the concentration of xylose in the medium and was significantly improved by the additional expression of a gene encoding for xylulose kinase. The xylose reductase, xylitol dehydrogenase and xylulose kinase genes were co-expressed with genes encoding for the three classes of T. reesei cellulases, namely endoglucanase (EG2), cellobiohydrolysase (CBH2) and beta-glucosidase (BGL1). The initial metabolism of xylose by the engineered strains facilitated production of cellulases at fermentation temperatures. The sequential metabolism of xylose and cellulose generated an alcohol yield of 82% from the available sugars. Several different types of biomass, such as the energy crop Miscanthus sinensis and the industrial waste, brewer's spent grains, were examined as biomass sources for fermentation using the developed yeast strains. Xylose metabolism and cell growth were inhibited in fermentations carried out with acid-treated spent grain liquor, resulting in a 30% reduction in alcohol yield compared to fermentations carried out with mixed sugar substrates. CONCLUSIONS: Reconstitution of complete enzymatic pathways for cellulose hydrolysis and xylose utilisation in S. pastorianus facilitates the co-fermentation of cellulose and xylose without the need for added exogenous cellulases and provides a basis for the development of a consolidated process for co-utilisation of hemicellulose and cellulose sugars. PMID- 25928879 TI - The nitric oxide donor pentaerythritol tetranitrate reduces platelet activation in congestive heart failure. AB - BACKGROUND: Platelet activation associated with endothelial dysfunction and impaired endogenous platelet inhibition is part of the cardiovascular phenotype of congestive heart failure (CHF) and contributes to the increased risk for thromboembolic complications. Pentaerythritol tetranitrate (PETN) has been shown to release nitric oxide without development of nitrate tolerance. We investigated the effect of chronic PETN treatment on platelet activation and aggregation in an experimental CHF model. METHODS AND RESULTS: Chronic ischemic heart failure was induced in male Wistar rats by coronary artery ligation. Starting 7 days thereafter, rats were randomised to placebo or PETN (80 mg/kg twice daily). After 9 weeks, activation of circulating platelets was determined measuring platelet bound fibrinogen, which requires activated glycoprotein IIb/IIIa on the platelet surface. Binding was quantified by flow-cytometry using a FITC-labelled anti fibrinogen antibody. Platelet-bound fibrinogen was significantly increased in CHF Placebo (mean fluorescence intensity: Sham 88+/-4, CHF-Placebo 104+/-6, p<0.05) and reduced following treatment with PETN (89+/-7, p<0.05 vs. CHF-Placebo). Maximal and final ADP-induced aggregation was significantly enhanced in CHF Placebo vs. Sham-operated animals and normalized / decreased following chronic PETN treatment. Moreover, platelet adhesion was significantly reduced (number of adherent platelets: control: 85.6+/-5.5, PETN: 40+/-3.3; p<0.001) and VASP phosphorylation significantly enhanced following in vitro PETN treatment. CONCLUSION: Chronic NO supplementation using PETN reduces platelet activation in CHF rats. Thus, PETN may constitute a useful approach to prevent thromboembolic complications in CHF. PMID- 25928880 TI - Still births, neonatal deaths and neonatal near miss cases attributable to severe obstetric complications: a prospective cohort study in two referral hospitals in Uganda. AB - BACKGROUND: Neonatal near miss cases occur more often than neonatal deaths and could enable a more comprehensive analysis of risk factors, short-term outcomes and prognostic factors in neonates born to mothers with severe obstetric complications. The objective was to assess the incidence, presentation and perinatal outcomes of severe obstetric morbidity in two referral hospitals in Central Uganda. METHODS: A prospective cohort study was conducted between March 1, 2013 and February 28, 2014, in which all newborns from cases of severe pregnancy and childbirth complications were eligible for inclusion. The obstetric conditions included obstetric haemorrhage, hypertensive disorders, obstructed labour, chorioamnionitis and pregnancy-specific complications such as malaria, anemia and premature rupture of membranes. Still births, neonatal deaths and neonatal near miss cases (defined using criteria that employed clinical features, presence of organ-system dysfunction and management provided to the newborns were compiled). Stratified and multivariate logistic regression analysis was conducted to identify risk factors for perinatal death. RESULTS: Of the 3100 mothers, 192 (6.2%) had abortion complications. Of the remainder, there were 2142 (73.1%) deliveries, from whom the fetal outcomes were 257 (12.0%) still births, 369 (17.2%) neonatal deaths, 786 (36.7%) neonatal near misses and 730 (34.1%) were newborns with no or minimal life threatening complications. Of the 235 babies admitted to the neonatal intensive care unit (NICU), the main reasons for admission were prematurity for 64 (26.8%), birth asphyxia for 59 (23.7%), and grunting respiration for 26 (11.1%). Of the 235 babies, 38 (16.2%) died in the neonatal period, and of these, 16 died in the first 24 hours after admission. Ruptured uterus caused the highest case-specific mortality of 76.8%, and led to 16.9% of all newborn deaths. Across the four groups, there were significant differences in mean birth weight, p = 0.003. CONCLUSIONS: Antepartum hemorrhage, ruptured uterus, severe preeclampsia, eclampsia, and the syndrome of Hemolysis, Elevated Liver Enzymes, Low Platelets (HELLP syndrome), led to statistically significant attributable risk of newborn deaths (still birth or neonatal deaths). Development of severe maternal outcomes, the mothers having been referred, and gravidity of 5 or more were significantly associated with newborn deaths. PMID- 25928881 TI - Toll-like receptor gene variants and bacterial vaginosis among HIV-1 infected and uninfected African women. AB - Bacterial vaginosis (BV) is a common vaginal syndrome associated with altered microflora that increases the risk of preterm delivery and acquisition of sexually transmitted diseases. The cause of BV is unknown although toll-like receptors (TLRs), that are central to innate immune responses, may be important. We evaluated associations between TLR SNPs and BV among HIV-1 infected and uninfected African women. Logistic regression was used to assess associations between SNPs (N=99) in TLRs 2-4, 7-9 and BV (as classified by Nugent's criteria). Among HIV-1 uninfected women, TLR7 rs5743737 and TLR7 rs1634323 were associated with a decreased risk of BV, whereas TLR7 rs179012 was associated with an increased risk. TLR2 SNP rs3804099 was associated with a decreased risk of BV among HIV-1 infected women. Our findings indicate that there may be differences in TLR association with BV among HIV-1 infected and HIV-1 uninfected women. PMID- 25928882 TI - Fine-mapping butyrophilin family genes revealed several polymorphisms influencing viral genotype selection in hepatitis C infection. AB - Host-viral genetic interaction has a key role in hepatitis C infection (HCV) and maybe in the viral selection. In a preliminary GWAS analysis, we identified BTN3A2 rs9104 to be associated with HCV genotype 1. Therefore, our aim was to determine the influence of BTN family on the selection of HCV genotype. We performed a fine-mapping analysis of BTN gene region in a cohort of chronic HCV infection (N=841), validating significant results in another independent chronic HCV infection cohort (N=637), according to selection of viral genotype. BTN3A2 rs9104, BTN3A2 rs733528, BTN2A1 rs6929846, BTN2A1 rs7763910 and BTN3A3 rs13220495 were associated with viral genotype selection. Interestingly, BTN3A2 rs9104 GG genotype was closely related to genotype 1 infection (80.7% (394/488) compared with genotype 3 infection (53.5% (23/43); P=0.0001) in patients harboring IL28B CT/TT genotype, although this effect was not observed in IL28B-CC genotype. Similarly, BTN3A3 rs13220495 CC genotype was linked to genotype 3 infection (100% (32/32)) compared to genotype 1 (87.3% (137/157); P=0.028) in patients harboring IL28B-CC genotype, but did not in IL28B-CT/TT genotype. Genetic variants in the butyrophilin family genes may alter susceptibility to infection, selecting HCV genotype and influencing disease progression. BTN3A2 rs9104 was strongly associated with genotype 1 infection and the haplotype BTN3A3 rs13220495 CC+IL28B genotype CC was universal in patients with hepatitis C genotype 3a. PMID- 25928883 TI - Genome-wide association study of IgG1 responses to the choline-binding protein PspC of Streptococcus pneumoniae. AB - Streptococcus pneumoniae causes invasive pneumococcal disease. Delayed development of antibodies to S. pneumoniae in infancy is associated with the development of atopy and asthma. Pneumococcal surface protein C (PspC) is a vaccine candidate and variation in its choline-binding region is associated with invasive disease. This study examined 523 060 single-nucleotide polymorphisms in The Western Australian Pregnancy Cohort (Raine) Study to find loci influencing immunoglobulin G1 (IgG1) responses to PspC measured at age 14 years (n=1152). Genome-wide significance (top SNP rs9275596; P=3.1 * 10(-14)) was only observed at human leucocyte antigen (HLA). Imputed HLA amino-acid polymorphisms showed the strongest associations at positions DRB1 47 (P=3.2 * 10(-11)), 13SRG (P=9.8 * 10( 10)) and 11SP (P=9.8 * 10(-10)), and at DQA1 34 (P=6.4 * 10(-10)), DQB1 167R (P=9.3 * 10(-6)) and HLA-B 95 W (P=1.2 * 10(-9)). Conditional analyses showed independent contributions from DRB1 47 and DQB1 167R to the signal at rs9275596, supported by an omnibus test showing a strong signal for the haplotype DRB1_47_DQB1_167 (P=9.02 * 10(-15)). In silico analysis showed that DRB1 four digit allele groups defined by DRB1 47F bind to a greater complexity of core 9 mer epitopes compared with DRB1 47Y, especially across repeats in the C-term choline-binding region. Consequent differences in CD4 T-cell help for IgG1 to PspC could have implications for vaccine design. Further analysis in other cohorts is merited. PMID- 25928884 TI - Making (anti-) sense out of huntingtin levels in Huntington disease. AB - BACKGROUND: Huntington disease (HD) is an autosomal dominant neurodegenerative disorder, characterized by motor, psychiatric and cognitive symptoms. HD is caused by a CAG repeat expansion in the first exon of the HTT gene, resulting in an expanded polyglutamine tract at the N-terminus of the huntingtin protein. Typical disease onset is around mid-life (adult-onset HD) whereas onset below 21 years is classified as juvenile HD. While much research has been done on the underlying HD disease mechanisms, little is known about regulation and expression levels of huntingtin RNA and protein. RESULTS: In this study we used 15 human post-mortem HD brain samples to investigate the expression of wild-type and mutant huntingtin mRNA and protein. In adult-onset HD brain samples, there was a small but significantly lower expression of mutant huntingtin mRNA compared to wild-type huntingtin mRNA, while wild-type and mutant huntingtin protein expression levels did not differ significantly. Juvenile HD subjects did show a lower expression of mutant huntingtin protein compared to wild-type huntingtin protein. Our results in HD brain and fibroblasts suggest that protein aggregation does not affect levels of huntingtin RNA and protein. Additionally, we did not find any evidence for a reduced expression of huntingtin antisense in fibroblasts derived from a homozygous HD patient. CONCLUSIONS: We found small differences in allelic huntingtin mRNA levels in adult-onset HD brain, with significantly lower mutant huntingtin mRNA levels. Wild-type and mutant huntingtin protein were not significantly different in adult-onset HD brain samples. Conversely, in juvenile HD brain samples mutant huntingtin protein levels were lower compared with wild type huntingtin, showing subtle differences between juvenile HD and adult-onset HD. Since most HD model systems harbor juvenile repeat expansions, our results suggest caution with the interpretation of huntingtin mRNA and protein studies using HD cell and animal models with such long repeats. Furthermore, our huntingtin antisense results in homozygous HD cells do not support reduced huntingtin antisense expression due to an expanded CAG repeat. PMID- 25928885 TI - MLViS: A Web Tool for Machine Learning-Based Virtual Screening in Early-Phase of Drug Discovery and Development. AB - Virtual screening is an important step in early-phase of drug discovery process. Since there are thousands of compounds, this step should be both fast and effective in order to distinguish drug-like and nondrug-like molecules. Statistical machine learning methods are widely used in drug discovery studies for classification purpose. Here, we aim to develop a new tool, which can classify molecules as drug-like and nondrug-like based on various machine learning methods, including discriminant, tree-based, kernel-based, ensemble and other algorithms. To construct this tool, first, performances of twenty-three different machine learning algorithms are compared by ten different measures, then, ten best performing algorithms have been selected based on principal component and hierarchical cluster analysis results. Besides classification, this application has also ability to create heat map and dendrogram for visual inspection of the molecules through hierarchical cluster analysis. Moreover, users can connect the PubChem database to download molecular information and to create two-dimensional structures of compounds. This application is freely available through www.biosoft.hacettepe.edu.tr/MLViS/. PMID- 25928886 TI - Lake Tanganyika--a 'melting pot' of ancient and young cichlid lineages (Teleostei: Cichlidae)? AB - A long history of research focused on the East Africa cichlid radiations (EAR) revealed discrepancies between mtDNA and nuclear phylogenies, suggesting that interspecific hybridisation may have been significant during the radiation of these fishes. The approximately 250 cichlid species of Lake Tanganyika have their roots in a monophyletic African cichlid assemblage, but controversies remain about the precise phylogenetic origin and placement of different lineages and consequently about L. Tanganyika colonization scenarios. 3312 AFLP loci and the mitochondrial ND2 gene were genotyped for 91 species representing almost all major lacustrine and riverine haplotilapiine east African cichlid lineages with a focus on L. Tanganyika endemics. Explicitly testing for the possibility of ancient hybridisation events, a comprehensive phylogenetic network hypothesis is proposed for the origin and diversification of L. Tanganyika cichlids. Inference of discordant phylogenetic signal strongly suggests that the genomes of two endemic L. Tanganyika tribes, Eretmodini and Tropheini, are composed of an ancient mixture of riverine and lacustrine lineages. For the first time a strong monophyly signal of all non-haplochromine mouthbrooding species endemic to L. Tanganyika ("ancient mouthbrooders") was detected. Further, in the genomes of early diverging L. Tanganyika endemics Trematocarini, Bathybatini, Hemibatini and Boulengerochromis genetic components of other lineages belonging to the East African Radiation appear to be present. In combination with recent palaeo geological results showing that tectonic activity in the L. Tanganyika region resulted in highly dynamic and heterogeneous landscape evolution over the Neogene and Pleistocene, the novel phylogenetic data render a single lacustrine basin as the geographical cradle of the endemic L. Tanganyika cichlid lineages unlikely. Instead a scenario of a pre-rift origin of several independent L. Tanganyika precursor lineages which diversified in ancient rivers and precursor lakes and then amalgamated in the extant L. Tanganyika basin is put forward as an alternative: the 'melting pot Tanganyika' hypothesis. PMID- 25928887 TI - Murine left atrium and left atrial appendage structure and function: echocardiographic and morphologic evaluation. AB - Aim of this study was to provide an echocardiographic protocol for the description of the normal murine venous reservoir (atrium, appendage and pulmonary veins) and to investigate the possibility to use this approach to discriminate changes on left atrium (LA) and left atrial appendage (LAA) in a stress-induced model such us myocardial infarction. Global left ventricular function and the venous reservoir were assessed by a Vevo2100 in 20 female C57BL/6N. LA and LAA were also studied in 10 CD-1 and 10 FVB mice, whereas modifications investigated in 15 C57BL/6N subjected to coronary artery ligation. Left ventricle function was evaluated as well as pulsed Doppler mitral valve, pulmonary vein, and LAA velocities. From 2D view monoplane LA volumes were obtained and LAA long axis measured. Macroscopic inspection with casts and immunohistochemistry were performed. Results show that compared to humans, in C57BL/6N mice left atrium was disproportionately smaller (5.2+/-1.4 MUL) than the left ventricle (53+/-8 MUL) and connected through a duct by a large LAA and posteriorly to three pulmonary veins. The LA volume increased 2-fold during reservoir with two distinct phases, early and late divided by a short pause. LAA long axis (4.1+/-0.5 mm) was almost 2 times longer than the LA. LAA flow volume together with LA volume reservoir account for about 36% of stroke volume and the rest was provided by conduit flow. Linear regressions showed that stroke volume was strongly influenced by LAA flow, LA early filling volume and left ventricle base descent. Moreover, we also report the ability to assess LA and LAA in other mice strains and discriminate size increase following myocardial infarction. In conclusion, we performed a complete characterization of murine left venous reservoir establishing an optimized protocol that can be used in both investigative and pharmacological studies requiring rapid and serial determination of cardiac structure and function. PMID- 25928891 TI - A "ticklish" belly button.... PMID- 25928889 TI - Dual HER2 blockade: preclinical and clinical data. AB - The estrogen receptor and human epidermal growth factor receptor (HER) signaling pathways are the dominant drivers of cell proliferation and survival in the majority of human breast cancers. Not surprisingly, targeting these pathways provides the most effective therapies in appropriately selected patients. However, de novo and acquired resistance remain major obstacles to successful treatment. By increasing the understanding of the molecular mechanisms of combined HER2-targeted therapies, we aim to be better able to select patients who would respond to these treatments and understand some of the mechanisms of resistance to HER2-targeted treatments. Recent studies have demonstrated an increased effectiveness of dual targeted HER2 therapies against HER2-amplified breast cancer as compared with single blockade. These studies have resulted in the recent US Food and Drug Administration approval of the combination of taxane chemotherapy with pertuzumab and trastuzumab in the first-line metastatic setting as well as an accelerated approval in the neoadjuvant setting. Another mechanism for overcoming resistance to HER2 targeted therapies is the antibody-drug conjugate trastuzumab-emtansine, which targets the HER2 receptor conjugated to the potent antimicrotubule agent mertansine, allowing for intracellular release of the cytotoxic drug. Studies evaluating the efficacy of dual blockade with antibody-drug conjugate are currently ongoing. This article reviews recent data on different combinations of anti-HER2 treatments as well as ongoing and future research in this area. PMID- 25928892 TI - Dissociation of learned helplessness and fear conditioning in mice: a mouse model of depression. AB - The state of being helpless is regarded as a central aspect of depression, and therefore the learned helplessness paradigm in rodents is commonly used as an animal model of depression. The term 'learned helplessness' refers to a deficit in escaping from an aversive situation after an animal is exposed to uncontrollable stress specifically, with a control/comparison group having been exposed to an equivalent amount of controllable stress. A key feature of learned helplessness is the transferability of helplessness to different situations, a phenomenon called 'trans-situationality'. However, most studies in mice use learned helplessness protocols in which training and testing occur in the same environment and with the same type of stressor. Consequently, failures to escape may reflect conditioned fear of a particular environment, not a general change of the helpless state of an animal. For mice, there is no established learned helplessness protocol that includes the trans-situationality feature. Here we describe a simple and reliable learned helplessness protocol for mice, in which training and testing are carried out in different environments and with different types of stressors. We show that with our protocol approximately 50% of mice develop learned helplessness that is not attributable to fear conditioning. PMID- 25928893 TI - Association of Cone-Rod Homeobox Transcription Factor Messenger RNA With Pediatric Metastatic Retinoblastoma. AB - IMPORTANCE: Disseminated retinoblastoma is usually fatal. Identification of small amounts (minimal dissemination [MD]) of tumor cells in extraocular sites might be a tool for designing appropriate treatments. OBJECTIVE: To test cone-rod homeobox (CRX) transcription factor as a lineage-specific molecular marker for metastatic retinoblastoma and for evaluation of MD. DESIGN, SETTING, AND PARTICIPANTS: In a prospective cohort design study, we evaluated CRX messenger RNA (mRNA) by retrotranscription followed by real-time polymerase chain reaction as a diagnostic test in samples obtained from bone marrow, peripheral blood, and cerebrospinal fluid (CSF) at diagnosis, after induction chemotherapy, and during follow-up. The study was conducted from June 30, 2008, to June 30, 2014. Seventeen retinoblastoma primary tumors, 2 retinoblastoma cell lines, and 47 samples of bone marrow from other cancers (controls) were studied. Seventeen patients with metastatic retinoblastoma (9 at diagnosis, 8 at relapse; age range: 18-41 months) were included. MAIN OUTCOMES AND MEASURES: Detection of CRX mRNA as a marker for metastatic retinoblastoma and MD in bone marrow and CSF and its correlation with clinical findings. RESULTS: Cone-rod homeobox mRNA was expressed in all tumors (relative expression levels range, 8.1 * 10-5 to 5.6) and cell lines. In control samples, there was no amplification of CRX; only the housekeeping gene (GAPDH) demonstrated amplification. Bone marrow metastatic cells showed expression of CRX mRNA in all 9 children presenting with metastasis at the diagnosis (relative expression levels, 6.0 * 10-5 to 0.67). After induction chemotherapy, no evidence of MD of tumor cells was seen in any of the 8 responding children since only GAPDH showed amplification. In the CSF of children who had a metastatic relapse, CRX mRNA detection was positive in 2 patients in whom no conclusive results were reached by immunocytology for disialoganglioside GD2. Minimal dissemination in the CSF was associated with a clinical relapse in 2 cases. No concomitant MD was evident in the bone marrow in any case. CONCLUSIONS AND RELEVANCE: These data suggest that CRX mRNA is a novel marker for retinoblastoma at extraocular sites. In this study among patients with bone marrow metastasis, there was a quick, complete, and sustained molecular response after induction chemotherapy. In all patients with secondary metastasis, CSF relapse occurred independently from the bone marrow, suggesting a sanctuary site. PMID- 25928894 TI - Electrochemical Reaction in Single Layer MoS2: Nanopores Opened Atom by Atom. AB - Ultrathin nanopore membranes based on 2D materials have demonstrated ultimate resolution toward DNA sequencing. Among them, molybdenum disulfide (MoS2) shows long-term stability as well as superior sensitivity enabling high throughput performance. The traditional method of fabricating nanopores with nanometer precision is based on the use of focused electron beams in transmission electron microscope (TEM). This nanopore fabrication process is time-consuming, expensive, not scalable, and hard to control below 1 nm. Here, we exploited the electrochemical activity of MoS2 and developed a convenient and scalable method to controllably make nanopores in single-layer MoS2 with subnanometer precision using electrochemical reaction (ECR). The electrochemical reaction on the surface of single-layer MoS2 is initiated at the location of defects or single atom vacancy, followed by the successive removals of individual atoms or unit cells from single-layer MoS2 lattice and finally formation of a nanopore. Step-like features in the ionic current through the growing nanopore provide direct feedback on the nanopore size inferred from a widely used conductance vs pore size model. Furthermore, DNA translocations can be detected in situ when as fabricated MoS2 nanopores are used. The atomic resolution and accessibility of this approach paves the way for mass production of nanopores in 2D membranes for potential solid-state nanopore sequencing. PMID- 25928895 TI - Valence state control and third-order nonlinear optical properties of copper embedded in sodium borosilicate glass. AB - The integrated and transparent sodium borosilicate glasses that contain copper exhibiting different colors, that is, red, green, and blue were synthesized by combining the sol-gel process and heat treatment in H2 gas. To reveal substantially the cause of different colors in the glass, X-ray diffraction (XRD), transmission electron microscopy (TEM) and high resolution TEM (HRTEM) were systematically applied to investigate and determine the microstructure of the doped matter. The results showed three different crystals had formed in the red, green and blue glass, and the sizes of these crystals were range from 9 to 34, 1 to 6, and 1 to 5 nm, respectively. The valence state of copper was further analyzed by X-ray photoelectron spectroscopy (XPS) and electron energy loss spectroscopy (EELS). The third-order nonlinear optical properties of the glasses were investigated by using Z-scan technique at the wavelength of 800 nm. Interestingly, the third-order nonlinear absorption of the red, green, and blue glass can be successfully controlled from reverse saturable absorption, no absorption to saturable absorption and the optical nonlinear susceptibility chi((3)) of the red, green and blue glass were estimated to be 6.4 * 10(-14), 1.6 * 10(-14), and 2.6 * 10(-14) esu in the single-pulse energy of 0.36 MUJ, respectively. PMID- 25928896 TI - Perceptions and experiences of access to public healthcare by people with disabilities and older people in Uganda. AB - INTRODUCTION: In the year 2000, a set of eight Millennium Development Goals (MDGs) were presented as a way to channel global efforts into the reduction of poverty and the promotion of social development. A global discussion regarding how to renew these goals is underway and it is in this context that the Goals and Governance for Global Health (Go4Health) research consortium conducted consultations with marginalized communities in Asia, Latin America, the Pacific and Africa as a way to include their voices in world's new development agenda. The goal of this paper is to present the findings of the consultations carried out in Uganda with two groups within low-resource settings: older people and people living with disabilities. METHODS: This qualitative study used focus group discussions and key informant interviews with older people in Uganda's Kamwenge district, and with persons with disabilities from the Gulu region. Thematic analysis was performed and emerging categories and themes identified and presented in the findings. FINDINGS: Our findings show that a sense of community marginalization is present within both older persons and persons living with disabilities. These groups report experiencing political sidelining, discrimination and inequitable access to health services. This is seen as the key reason for their poor health. Clinical services were found to be of low quality with little or no access to facilities, trained personnel, and drugs and there are no rehabilitative or mental health services available. CONCLUSION: Uganda must fulfil its international obligations and take progressive measures to meet the right to health for all its peoples, but especially allocate its limited resources to proactively support its most marginalized citizens. The growing impetus within post-2015 development negotiations to redress in-country health and other inequalities through a comprehensive systems approach is of importance in the Ugandan development context. This approach reflects the participant's perspectives, which also calls for a more equitable approach to health and development as opposed to a narrow, vertical focus on specific population groups, as was the case with the MDGs. PMID- 25928897 TI - Comparing antibiotic self-medication in two socio-economic groups in Guatemala City: a descriptive cross-sectional study. AB - BACKGROUND: Self-medication with antibiotics may result in antimicrobial resistance and its high prevalence is of particular concern in Low to Middle Income Countries (LMIC) like Guatemala. A better understanding of self-medication with antibiotics may represent an opportunity to develop interventions guiding the rational use of antibiotics. We aimed to compare the magnitude of antibiotic self-medication and the characteristics of those who self-medicate in two pharmacies serving disparate socio-economic communities in Guatemala City. METHODS: We conducted a descriptive, cross-sectional study in one Suburban pharmacy and one City Center pharmacy in Guatemala City. We used a questionnaire to gather information about frequency of self-medication, income and education of those who self-medicate. We compared proportions between the two pharmacies, using two-sample z-test as appropriate. RESULTS: Four hundred and eighteen respondents completed the survey (221 in the Suburban pharmacy and 197 in the City Center pharmacy). Most respondents in both pharmacies were female (70%). The reported monthly income in the suburban pharmacy was between $1,250.00-$2,500.00, the city-center pharmacy reported a monthly income between $125.00- $625.00 (p < 0.01). Twenty three percent of Suburban pharmacy respondents and 3% in the City Center pharmacy completed high school (p < 0.01). Proportion of self-medication was 79% in the Suburban pharmacy and 77% in City Center pharmacy. In both settings, amoxicillin was reported as the antibiotic most commonly used. CONCLUSIONS: High proportions of self-medication with antibiotics were reported in two pharmacies serving disparate socio-economic groups in Guatemala City. Additionally, self-medicating respondents were most often women and most commonly self-medicated with amoxicillin. Our findings support future public health interventions centered on the regulation of antibiotic sales and on the potential role of the pharmacist in guiding prescription with antibiotics in Guatemala. PMID- 25928898 TI - Assessing Posidonia oceanica seedling substrate preference: an experimental determination of seedling anchorage success in rocky vs. sandy substrates. AB - In the last decades the growing awareness of the ecological importance of seagrass meadows has prompted increasing efforts to protect existing beds and restore degraded habitats. An in-depth knowledge of factors acting as major drivers of propagule settlement and recruitment is required in order to understand patterns of seagrass colonization and recovery and to inform appropriate management and conservation strategies. In this work Posidonia oceanica seedlings were reared for five months in a land-based culture facility under simulated natural hydrodynamic conditions to identify suitable substrates for seedling anchorage. Two main substrate features were investigated: firmness (i.e., sand vs. rock) and complexity (i.e., size of interstitial spaces between rocks). Seedlings were successfully grown in culture tanks, obtaining overall seedling survival of 93%. Anchorage was strongly influenced by substrate firmness and took place only on rocks, where it was as high as 89%. Anchorage occurred through adhesion by sticky root hairs. The minimum force required to dislodge plantlets attached to rocky substrates reached 23.830 N (equivalent to 2.43 kg), which would potentially allow many plantlets to overcome winter storms in the field. The ability of rocky substrates to retain seedlings increased with their complexity. The interstitial spaces between rocks provided appropriate microsites for seedling settlement, as seeds were successfully retained, and a suitable substrate for anchorage was available. In conclusion P. oceanica juveniles showed a clear-cut preference for hard substrates over the sandy one, due to the root system adhesive properties. In particular, firm and complex substrates allowed for propagule early and strong anchorage, enhancing persistence and establishment probabilities. Seedling substrate preference documented here leads to expect a more successful sexual recruitment on hard bottoms compared with soft ones. This feature could have influenced P. oceanica patterns of colonization in past and present time. PMID- 25928900 TI - Evaluation of uncertainties in in situ and ex situ gamma measurements on land areas with low contamination levels. AB - Previous work on the characterisation of land areas with moderate contamination levels showed that in situ measurements made with a gamma detector can achieve lower levels of the random component of uncertainty than laboratory measurements of extracted samples. This was found when the variance caused by small-scale lateral heterogeneity of contaminants was included in the uncertainty estimation. The present paper documents the results of applying the same techniques of uncertainty estimation to an area with contamination levels that were lower by a factor of 10. If the same counting times were used, it would be expected that both measurement types would be affected by higher levels of random uncertainty in the individual measurements because of increased uncertainty from counting statistics and other factors such as interpretation of gamma spectra. However, when uncertainty due to sampling was included, it was found that both measurements methods were subject to similar combined uncertainties at individual locations. Using an assumption of the depth distributions of radionuclides that was supported by ex situ measurements, in situ measurements were able to produce averaging estimates with an approximate reduction of 50% in the standard error on the mean at ~50% of the cost of the ex situ measurements. PMID- 25928899 TI - Heterologous Expression in Remodeled C. elegans: A Platform for Monoaminergic Agonist Identification and Anthelmintic Screening. AB - Monoamines, such as 5-HT and tyramine (TA), paralyze both free-living and parasitic nematodes when applied exogenously and serotonergic agonists have been used to clear Haemonchus contortus infections in vivo. Since nematode cell lines are not available and animal screening options are limited, we have developed a screening platform to identify monoamine receptor agonists. Key receptors were expressed heterologously in chimeric, genetically-engineered Caenorhabditis elegans, at sites likely to yield robust phenotypes upon agonist stimulation. This approach potentially preserves the unique pharmacologies of the receptors, while including nematode-specific accessory proteins and the nematode cuticle. Importantly, the sensitivity of monoamine-dependent paralysis could be increased dramatically by hypotonic incubation or the use of bus mutants with increased cuticular permeabilities. We have demonstrated that the monoamine-dependent inhibition of key interneurons, cholinergic motor neurons or body wall muscle inhibited locomotion and caused paralysis. Specifically, 5-HT paralyzed C. elegans 5-HT receptor null animals expressing either nematode, insect or human orthologues of a key Galphao-coupled 5-HT1-like receptor in the cholinergic motor neurons. Importantly, 8-OH-DPAT and PAPP, 5-HT receptor agonists, differentially paralyzed the transgenic animals, with 8-OH-DPAT paralyzing mutant animals expressing the human receptor at concentrations well below those affecting its C. elegans or insect orthologues. Similarly, 5-HT and TA paralyzed C. elegans 5-HT or TA receptor null animals, respectively, expressing either C. elegans or H. contortus 5-HT or TA-gated Cl- channels in either C. elegans cholinergic motor neurons or body wall muscles. Together, these data suggest that this heterologous, ectopic expression screening approach will be useful for the identification of agonists for key monoamine receptors from parasites and could have broad application for the identification of ligands for a host of potential anthelmintic targets. PMID- 25928901 TI - Involvement of RORgammat-overexpressing T cells in the development of autoimmune arthritis in mice. AB - INTRODUCTION: Differentiation of T helper 17 cells is dependent on the expression of transcription retinoid-related orphan receptor gamma t (RORgammat). The purpose of our study is to determine the role of RORgammat expression in T cells on the development of collagen-induced arthritis (CIA). METHODS: CIA was induced in C57BL/6 and T cell-specific RORgammat transgenic (RORgammat Tg) mice. At day 10 post-1st-immunization, lymph node (LN) cells were cultured with type II collagen (CII), and the expression levels of various cytokines and transcription factors on CD4+ T cells were measured. Total cells or CD4+ cells of draining LN were harvested from each mouse group after CII-immunization and transferred into C57BL/6 mice, and then CIA was induced in recipient mice. The expression levels of RORgammat and other surface antigens, and the production of cytokines were analyzed in forkhead box P3 (Foxp3)+ regulatory T (Treg) cells. Foxp3+ Treg cells were analyzed for suppressive activity against proliferation of effector CD4+ T cells. Interlukin (IL)-10 neutralizing antibody was administrated in the course of CIA. RESULTS: CIA was significantly suppressed in RORgammat Tg mice compared with C57BL/6 mice. RORgammat expression and IL-17 production were significantly higher in CII-reactive CD4+ T cells from RORgammat Tg mice. Arthritis was significantly attenuated in C57BL/6 mice recipient of cells from RORgammat Tg mice. Most of Foxp3+ Treg cells expressed RORgammat, produced IL-10 but not IL 17, and overexpressed CC chemokine receptor 6 (CCR6) and surface antigens related to the suppressive activity of Foxp3+ Treg cells in RORgammat Tg mice. In vitro suppression assay demonstrated significant augmentation of the suppressive capacity of Foxp3+ Treg cells in RORgammat Tg mice. CIA was exacerbated in both C57BL/6 mice and RORgammat Tg mice by the treatment of anti-IL-10 antibody. CONCLUSION: Our results indicated that RORgammat overexpression in T cells protected against the development of CIA. The protective effects were mediated, at least in part, through the anti-inflammatory effects including high production of IL-10 of RORgammat+Foxp3+ Treg cells. PMID- 25928902 TI - Incubation of ovine scrapie with environmental matrix results in biological and biochemical changes of PrP(Sc) over time. AB - Ovine scrapie can be transmitted via environmental reservoirs. A pool of ovine scrapie isolates were incubated on soil for one day or thirteen months and eluted prion was used to challenge tg338 mice transgenic for ovine PrP. After one-day incubation on soil, two PrP(Sc) phenotypes were present: G338 or Apl338ii. Thirteen months later some divergent PrP(Sc) phenotypes were seen: a mixture of Apl338ii with either G338 or P338, and a completely novel PrP(Sc) deposition, designated Cag338. The data show that prolonged ageing of scrapie prions within an environmental matrix may result in changes in the dominant PrP(Sc) biological/biochemical properties. PMID- 25928903 TI - Descemet Membrane Endothelial Keratoplasty for Graft Failure After Descemet Stripping Endothelial Keratoplasty: Clinical Results and Histopathologic Findings. AB - IMPORTANCE: The management of graft failure is increasingly relevant with the spread and growing acceptance of endothelial keratoplasty. OBJECTIVES: To investigate the functional and anatomical results of secondary Descemet membrane endothelial keratoplasty (DMEK) for graft failure after Descemet stripping endothelial keratoplasty (DSEK) and to histologically analyze the stroma-to stroma interface with respect to clinical implications. DESIGN, SETTING, AND PARTICIPANTS: In a single-surgeon prospective comparative case series at the Department of Ophthalmology, Charite-University Medicine Berlin, Berlin, Germany, 8 eyes (3.8%) of 210 consecutively performed DMEK procedures underwent a secondary DMEK for graft failure after DSEK from March 1, 2012, through February 28, 2013. Those cases were compared with the eyes of a reference collective (n = 30) and matched-pairs group (n = 8) after primary DMEK for Fuchs endothelial dystrophy. INTERVENTION: Descemet membrane endothelial keratoplasty. MAIN OUTCOMES AND MEASURES: Postoperative best-corrected visual acuity (BCVA) and central corneal thickness at 1, 3, 6, and 12 months. Intraoperatively obtained DSEK graft lenticels were investigated immunohistochemically. RESULTS: Patients with graft failure after DSEK had a mean (SD) age of 79.4 (7.2) years (range, 70 90 years). Preoperatively, the mean (SD) BCVA was 1.13 (0.50) logMAR (20/250 Snellen equivalents), and the mean (SD) central corneal thickness measured 704 (161) um. Twelve months postoperatively, the mean (SD) corneal thickness decreased to 524 (27) um after secondary and 516 (27) um after primary DMEK (P = .57). A mean (SD) BCVA of 0.38 (0.36) logMAR (20/50 Snellen equivalents) was achieved after secondary DMEK compared with 0.15 (0.15) logMAR (20/28 Snellen equivalents) after primary DMEK. Histologically, failed DSEK graft lenticels presented condensations of collagen layers. Fibronectin and cytokeratin were accumulated along the stroma-to-stroma interface; vimentin was found in loosened graft stroma. CONCLUSIONS AND RELEVANCE: These data suggest that DMEK might be considered a feasible choice in patients with graft failure after DSEK. However, the visual restitution might be impeded because of preceded depositions of matrix proteins within the corneal stroma and the stroma-to-stroma interface, which are associated with corneal fibrosis. Thereby, fibrotic processes might be avoided by performing a secondary DMEK in an early phase of graft failure. PMID- 25928904 TI - The effect of metamizole and tolfenamic acid on canine and equine adipose-derived mesenchymal stem cells (ASCs) an in vitro research. AB - The influences of NSAIDs (Nonsteroidal Anti-inflammatory Drugs)--non-selective metamizole and selectively-acting tolfenamic acid were estimated on morphology, ultrastructure, and cytophysiological activity of canine (Ca) and equine (Eq) adipose-derived mesenchymal stem cells (ASCs). The lowest concentration of metamizole (0.01 mg/mL) stimulated the viability and cytophysiological activity of Ca ASCs and did not affect cell morphology. Stimulated cells possessed a proper, fibroblastic shape, with large, eccentrically located nuclei. Similar effects to those observed in Ca ASCs were found in Eq cells treated with both drugs. Cells cultivated with the intermediate (0.1 mg/mL) doses of NSAIDs displayed proper cell morphology, whereas cells cultivated in intermediate dose (0.1 mg/mL) became more flattened. The highest concentrations (1 mg/mL) of both drugs resulted in a cytotoxic effect in Ca and Eq ASCs. Based on these results, we conclude that stimulation of Ca and Eq ASCs with metamizole as well as Eq ASCs with tolfenamic acid can lead to positive effects only when the lowest drug concentrations are applied. This study indicates a different cellular response of canine and equine ASCs treated with metamizole and tolfenamic acid. The obtained data might be potentially useful in the study of functionalized veterinary biomaterials. PMID- 25928905 TI - Semen characteristics and selected biochemical markers of canine seminal plasma in various seasons of the year. AB - The aim of this study was to evaluate the influence of season on selected qualitative semen characteristics and biochemical markers of canine seminal plasma. Whole ejaculates were collected from 5 crossbred dogs aged 2-8 years. The study covered a period of one year divided into four seasons: spring (March, April, May), summer (June, July, August), autumn (September, October, November) and winter (December, January, February). Semen samples were subjected to macroscopic and microscopic analyses to determine semen volume, total sperm counts and sperm morphology parameters. The study also involved the determination of sperm motility parameters (CASA system), sperm plasma membrane integrity (SPMI, fluorescent staining SYBR-14/PI), sperm mitochondrial membrane potential (MMP, fluorescent staining JC-1/PI) and the ATP content of sperm cells. Total protein content (TPC) and the activity of alkaline phosphatase (AP) and acid phosphatase (AcP) were determined in biochemical analyses of seminal plasma. No significant differences in ejaculate volume, SMPI or ATP content of sperm cells were observed between seasons. The highest total sperm counts were reported in ejaculates acquired in summer and autumn. The lowest MMP values were determined in summer ejaculates. No significant differences in sperm motility (MOT) were observed throughout the experiment, but ejaculates collected in autumn and winter were characterized by the highest progressive motility (PMOT). AP activity and TPC were not significantly affected by season. However, AcP activity levels were significantly lower in autumn than in the remaining seasons. Seasonal variations in the analyzed macroscopic and microscopic parameters of ejaculates and biochemical markers of seminal plasma did not exert a clear negative effect on the quality of canine semen. PMID- 25928906 TI - Natural immunity factors in Polish mixed breed rabbits. AB - Mixed-breed rabbits in Poland are widely used for diagnostic and scientific research and as utility animals, therefore there is a need to know their immunological status, as well as their haematological status. In this study natural immunity factors were analyzed in Polish mixed-breed rabbits and Polish mixed-breed rabbits with addition of blood of meet-breed, considering the impact of sex and season of the year (spring, summer, autumn, winter) using measurement of non-specific cellular and humoral immunity parameters in peripheral blood. The study has revealed that there is a variety between the two commonly used mixed breed types of rabbits, especially when sex and season is concerned, which is crucial for using these animals in experiments. PMID- 25928907 TI - MicroRNA expression profiles in liver and colon of sexually immature gilts after exposure to Fusarium mycotoxins. AB - To improve our knowledge of the role of microRNAs (miRs) in responses of the porcine digestive system to two Fusarium mycotoxins, zearalenone (ZEN) and deoxynivalenol (DON), we examined the expression of 7 miRs (miR-9, miR-15a, miR 21, miR-34a, miR-122, miR-125b, and miR-192), previously found to be deregulated in diseased liver and colon cells. In this study, immature gilts were exposed to NOEL doses of ZEN (40 MUg/kg/d), DON (12 MUg/kg/d), ZEN + DON (40 + 12 MUg/kg/d), andplacebo (negative control group) for 7, 14, 21, 28, 35, and 42 days. Before the treatment, expression levels of the selected miRs were measured in the liver, the duodenum, the jejunum, and the ascending and the descending colon of the gilts. Hierarchical clustering of the tissues by their miR expression profiles was consistent with what would be expected based on the anatomical locations and the physiological functions of the organs, suggesting that functions of the miRs are related to the specificities of the tissues in which they are expressed. A subset of 2 pairs of miRs (miR-21+miR-192 and miR-15a+miR-34a), which were assigned to two distinct clusters based on their tissue abundance, was then evaluated in the liver and the ascending and the descending colon during the treatment. The most meaningful results were obtained from the ascending colon, where a significant effect of the treatment was observed, suggesting that during the exposure to mycotoxins, the pathways involved in cell proliferation and survival were disordered. Changes in miR expression in the liver and the descending colon of the treated gilts were smaller, and were associated more with treatment duration than the exposure to ZEN, DON, or ZEN + DON. Further research should focus on identification of genes whose expression is regulated by these aberrantly expressed miRs. This should facili- tate understanding of the miRNA regulated biological effects of mycotoxins. PMID- 25928908 TI - Modeling the kinetics of survival of Staphylococcus aureus in regional yogurt from goat's milk. AB - The aim of this study was to determine the kinetics of the survival of the test strain of Staphylococcus aureus in the product investigated. Yogurt samples were contaminated with S. aure to an initial level of 10(3)-10(4) cfu/g. The samples were then stored at four temperatures: 4, 6, 20, 22 degrees C. During storage, the number of S. aureus forming colonies in a gram of yogurt was determined every two hours. Based on the results of the analysis culture the curves of survival were plotted. Three primary models were selected to describe the kinetics of changes in the count of bacteria: Cole's model, a modified model of Gompertz and the model of Baranyi and Roberts. Analysis of the model fit carried out based on the average values of Pearson's correlation coefficient, between the modeled and measured values, showed that the Cole's model had the worst fit. The modified Gompertz model showed the count of S. aureus as a negative value. These drawbacks were not observed in the model of Baranyi and Roberts. For this reason, this model best reflects the kinetics of changes in the number of staphylococci in yogurt. PMID- 25928909 TI - Detection of rabies antibodies in dog sera. AB - In the presented work, we compared the results of determination of rabies antibodies using three in vitro methods: rapid fluorescent focus inhibition test (RFFIT), fluorescent antibody virus neutralisation test (FAVNT) and the immunoenzymatic assay (ELISA). 196 dog sera samples were examined with FAVNT, RFFIT methods and the ELISA test. Sera with low and sufficiently high titre of antibodies had a similar result in determining by all methods. A critical level of rabies antibodies close to the required protection level (0.5 IU/cm3) was seen in sera of 18 dogs (9.18%); these were the sera obtained after primary vaccination of dogs. At this level, even small differences can cause a change in the assessment of the patient's serum seronegativity or seropositivity. Therefore, it is important to choose the appropriate method that has sufficiently strict criteria while having a good reproducibility. PMID- 25928910 TI - Neuropeptide Y as a presynaptic modulator of norepinephrine release from the sympathetic nerve fibers in the pig pineal gland. AB - Norepinephrine (NE) released from the sympathetic nerve endings is the main neurotransmitter controlling melatonin synthesis in the mammalian pineal gland. Although neuropeptide Y (NPY) co-exists with NE in the pineal sympathetic nerve fibers it also occurs in a population of non-adrenergic nerve fibers located in this gland. The role of NPY in pineal physiology is still enigmatic. The present study characterizes the effect of NPY on the depolarization-evoked 3H-NE release from the pig pineal explants. The explants of the pig pineal gland were loaded with 3H-NE in the presence of pargyline and superfused with Tyrode medium. They were exposed twice to the modified Tyrode medium containing 60 mM of K+ to evoke the 3H-NE release via depolarization. NPY, specific agonists of Y1- and Y2- receptors and pharmacologically active ligands of alpha2-adrenoceptors were added to the medium before and during the second depolarization. The radioactivity was measured in medium fractions collected every 2 minutes during the superfusion. NPY (0.1-10 MUM) significantly decreased the depolarization-induced 3H-NE release. Similar effect was observed after the treatment with Y2-agonist: NPY13 36, but not with Y1-agonist: [Leu31,Pro34]-NPY. The tritium overflow was lower in the explants exposed to the 5 MUM NPY and 1 MUM rauwolscine than to rauwolscine only. The effects of 5 MUM NPY and 0.05 MUM UK 14,304 on the depolarization evoked 3H-NE release were additive. The results show that NPY is involved in the regulation of NE release from the sympathetic terminals in the pig pineal gland, inhibiting this process via Y2-receptors. PMID- 25928911 TI - Prevalence and antimicrobial resistance of Arcobacter butzleri and Arcobacter cryaerophilus isolates from retail meat in Lower Silesia region, Poland. AB - Arcobacter butzleri and A. cryaerophilus are considered potential foodborne pathogens. Consumption of Arcobacter-contaminated food is regarded the most likely source of human poisoning. We investigated the prevalence and antimicrobial resistance of Arcobacter isolates in 210 retail meat samples. Seventy-nine A. butzleri and 6 A. cryaerophilus were isolated from pork, beef and chicken meat. Incidence ofA. butzleri was found to be the highest in chicken meat (83%). Less of A. butzleri was isolated from beef (16%) and pork (14%). Most of the A. butzleri isolates were resistant to beta-lactams, like ampicillin (85%), amoxicillin with clavulonic acid (63%), cefotaxime (66%) and mac- rolides, i.e., erythromycin (62%). In contrast, all except one A. cryaerophilus isolates were susceptible to erythromycin. Tetracycline and aminoglycosides showed the highest efficacy against A. butzleri and A. cryaerophilus since almost 80% of their population was susceptible to these agents. All, except one A. cryaerophilus and the majority ofA. butzleri isolates (70%) were susceptible to fluoroquinolones. The incidence of multiresistant isolates was found in forty two (53%) A. butzleri, and one (16%) A. cryaerophilus isolates Eight A. butzleri isolates were resistant to all antimicrobials tested. These results indicate significant incidence of potential foodborne zoonotic agents, i.e. A. butzleri and A. cryaerophilus including multiresistant isolates in retail meat in Poland. PMID- 25928912 TI - Sex-dependent differences in the effect of early weaning on the chosen hormones secretion in sheep during the postnatal transition to puberty--preliminary results. AB - The influence of early weaning on the cortisol, follicle-stimulating hormone (FSH), luteinizing hormone (LH) and growth hormone (GH) secretion in lambs of both sexes and testosterone (T4) level in male lambs during the postnatal transition to puberty was investigated by radioimmunoassay. It was hypothesized that this influence is long-term and sexually dimorphic. Hence, the effect of weaning at 5 weeks of age in comparison with the weaning at 9 weeks of age on hormone concentra- tions in peripheral blood plasma of 5-, 9-, 12-, and 16-week old lambs of both sexes was investigated. The cortisol concentrations were greater (P < 0.05) in control and early weaned female lambs than in male lambs at investigated stages. Weaning at 5 weeks of age resulted in the lover (P < 0.05) cortisol secretion in male lambs in contrast to the greater (P < 0.05) cortisol secretion in female lambs at 16 weeks of age. Weaning at 5 weeks of age stimulated (P < 0.001) the FSH secretion, but reduced (P < 0.001) the LH, GH and T4 secretion in 16-week-old male lambs. In female lambs early weaning inhibited (P < 0.05) the FSH secretion at 9 weeks of age, LH secretion after 9 weeks of age and GH secretion after 12 weeks of age. Thus, early weaning results in the sexually dimorphic stress reaction that is more potent and long-lasting in female in contrast to male lambs. This maternal deprivation stress contributes to the inhibition of LH and GH secretion in lambs of both sexes and T4 secretion in male lambs during the postnatal transition to puberty. PMID- 25928913 TI - Biochemical parameters in Japanese quails Coturnix coturnix japonica infected with coccidia and treated with Toltrazuril. AB - The activity of aspartate aminotransferase, alanine aminotransferase and lactate dehydrogenase, total protein, albumin and cholesterol levels were determined in the blood serum of Japanese quails infected with coccidia and treated with Baycox (active ingredient: toltrazuril). Lower levels of AST and ALT activity were noted in treated birds regardless of the applied Baycox dose. The biochemical changes observed in the blood serum of Japanese quails point to coccidia-induced damage of digestive system tissues despite an absence of pronounced clinical symptoms. Significantly lower levels of AST activity and higher levels of LDH activity in treated birds indicate that coccidiosis treatment with toltrazuril contributed to the regeneration of digestive system tissues. An insignificant increase in cholesterol levels was noted, whereas the other serum biochemical parameters remained within the reference ranges. PMID- 25928914 TI - Experimental laparoscopic pyloromyotomy in pigs. AB - The objective of this study was to evaluate and compare laparoscopic pyloromyotomy methods involving the laparoscopic scalpel and the harmonic scalpel in pigs. The experiment was conducted on 4 subgroups of 12 animals subjected to laparoscopic-assisted pyloromyotomy with a surgical scalpel and the harmonic scalpel, as well as laparoscopic pyloromyotomy with Berci's laparoscopic scalpel and the harmonic scalpel. No postsurgical complications were observed. Four weeks after the surgery, the animals were sacrificed and autopsy was performed. In one animal peritoneal adhesions between the intestines and the mini-laparotomy incision were found. Laparoscopic pyloromyotomy and laparoscopic-assisted pyloromyotomy performed in pigs enabled the selection of laparoscopic entry sites, instruments for pyloromyotomy and evaluation of the applied surgical procedures in animals. The results of this study indicate that the methods applied can be safely used in clinical practice in dogs and cats due to minimal post-operative complications and fast healing of laparoscopic incisions in comparison with classical surgical wounds, and that the harmonic scalpel is a safe surgical instru- ment. PMID- 25928915 TI - Feeding milk replacer instead of whole milk affects blood plasma proteome and lipid profile in preruminant calves. AB - The study was undertaken to determine the effect of feeding milk or milk-replacer on the blood plasma proteome and lipid profile in calves during the second week of life. Feeding milk-replacer significantly decreased the expression of plasma apoA-I. Age of calves affected apoA-I expression, which was higher on the 8th than on the 11th and 14th day of life. A significant effect of interaction between diet and age was also observed. The expression of apoA-IV, was significantly affected by diet and was lower in calves fed milk replacer. Expression of this protein was significantly lower at the 8th day of life and was up-regulated in the calves fed milk-replacer at the second week of life. Calves fed milk-replacer had greater expression of haptoglobin, which differed significantly between days of blood sampling, being higher on the 8th than on the 11th and 14th day. The interactive effect of diet and age affected haptoglobin expression, which was successively down-regulated in calves fed milk re- placer. Diet had a significant effect on the plasma lipid profile. Animals fed milk had a greater concentration of TC, HDLC and LDLC. The composition of milk-replacer, especially fat source, is probably the main factor that affects expression of proteins involved in cholesterol metabolism and level of components of lipid profile in calves fed formula. We claim that the initially increased level of haptoglobin, followed by its decrease during the second week of life in calves fed milk-replacer may indicate the presence of short-term stress induced by changes in the feeding system. PMID- 25928916 TI - Poultry flocks as a source of Campylobacter contamination of broiler carcasses. AB - Campylobacter infection is the leading foodborne bacterial gastroenteritis worldwide and the bacteria are frequently isolated from the intestines of chickens. The broiler meat contamination with C. jejuni or C. coli may occur during slaughter processing. The aim of the study was to investigate the prevalence of Campylobacter in poultry flocks and the corresponding broiler carcasses in 15 districts (voivodeships) all over Poland. A total of 128 samples from broiler flocks and the corresponding carcasses were collected between February 2011 and April 2013. The Campylobacter isolation and species identification were performed according to ISO 10272-1 standard and with PCR. It was found that 112 flock (96.5%) were contaminated with campylobacters, either C. jejuni (77 samples; 68.7%) or C. coli (35 flocks; 31.3%). Analysis of the corresponding chicken carcasses tested after chilling revealed that 77 out of 128 (60.2%) samples were positive for Campylobacter, either C. jejuni (58; 75.3%) or C. coli (19; 24.7%). Most of the carcasses were contaminated with the same Campylobacter species as identified in the corresponding flock before slaughter. As tested by PCR, out of the 77 crops with C. jejuni 58 were positive for the same bacterial species. On the other hand, out of the remaining 35 flocks infected with C. coli, only 19 corresponding carcass samples were contaminated with C. coli. In three cases in the slaughtered flocks C. jejuni was identified but in the same carcasses C. coli was found. The opposite findings (flock positive for C. coli but the corresponding carcasses contaminated with C. jejuni) were seen in six voivodeships. It was also observed that several carcass samples were negative for C. jejuni and C. coli although the original flocks were Campylobacter-positive before slaughter (total 36 of the 77 samples; 46.7%). On the other hand, some carcasses were contaminated with Campylobacter although the flocks were negative for these bacteria (9 samples; 11.7%) which may also be due to internal contamination during slaughter of broilers. PMID- 25928917 TI - Equid herpesvirus type 1 (EHV-1) disrupts actin cytoskeleton during productive infection in equine leukocytes. AB - Equid herpesvirus type 1 (EHV-1) is a prevalent causative agent of equine diseases worldwide. After primary replication in the respiratory epithelium the virus disseminates systemically through a peripheral blood mononuclear cell (PBMC)-associated viraemia. EHV-1 is the only alphaherpes- virus known so far which is capable of establishing latent infection not only in neurons but also in immune system cells (mainly in lymphocytes and macrophages). Since leukocytes are not the target cells for viral replication but are used to transport EHV-1 to the internal organs, the questionremains how the virus avoids the immune response and whether it could potentially be associated with virus-induced cytoskeletal rearrangements. Therefore, the aim of this study was to investigate the progress of EHV-1 replication in leukocytes stimulated by phytohemagglutinin and the impact of EHV-1 infection on the actin cytoskeleton. Using the real-time PCR method we evaluated the quantity of viral DNA from samples collected at indicated time points post infection. In order to examine possible changes in actin cytoskeleton organization due to EHV-1 infection, we performed immunofluorescent staining using TRITC-phalloidin conjugate. The results showed that EHV-1 rep- licates in leukocytes at a restricted level but with the accompaniment of chromatin degradation. Simultaneously, infection with EHV-1 caused disruption of the actin cytoskeleton; this was particularly apparent in further stages of infection. Disruption of the actin cytoskeleton may lead to the limited release of the virus from the cells, but may be also beneficial for the virus, since at the same time it potentially impairs the immune function of leukocytes. PMID- 25928918 TI - Survivin expression in canine lymphomas in relation with proliferative markers. AB - Survivin is a member of apoptosis inhibiting proteins family. Apart from its antiapoptotic activity it plays a critical role in regulating the cell cycle and mitosis. It is overexpressed in most human malignancies. While the prognostic significance of survivin expression is widely investigated in human non-Hodgkin's lymphomas, little is known about its expression in canine lymphomas. The aim of the study was to evaluate the expression of survivin in canine lymphomas in relation to proliferation markers (mitotic index and percentage of Ki67-positive cells). Survivin was found in all examined lymphomas belonging to 6 different morphological subtypes with nuclear immunoreactivity. In most of lymphomas (18/25) survivin expression ranged 10%-25% of positive cells. Only single cases had lower (0-10% positive cells, 1/25) or higher (25-50% and > 50% positive cells, 5/25 and 1/25, respectively) index of survivin. Neither mitotic index nor proliferative index correlated with survivin expression when the values quantified randomly in whole specimens were compared. However, when survivin expression were quantified in selected tumor areas of low and high proliferation activity the high correlations between survivin expression and proliferation index were found. The results indicated that survivin is commonly expressed in canine lymphomas. Nuclear labelling together with the relation of its expression and proliferative activity in highly proliferative areas of neoplastic tissue suggest a potential role of survivin in cell cycle activation in canine lymphoma cells. However, further studies of the relation between expression of survivin and other proteins involved in cell cycle regulation are needed. Moreover, the results suggest that survivin may pose the therapeutic target in canine lymphomas. PMID- 25928919 TI - Immunohistochemical detection of P-glycoprotein in various subtypes of canine lymphomas. AB - Combination chemiotherapy is the current standard of care for dogs with lymphoma. Multidrug resistance is one of the most important factors contributing to the efficacy of chemiotherapy. The major protein responsible for this phenomenon is P glycoprotein. Little is known about P-glycoprotein expression in particular subtypes of lymphomas. The aim of the study was evaluation of P-glycoprotein expression in various subtypes of canine lymphomas. Positive reaction with P glycoprotein was found in 12/25 cases of various morphological subtypes of lymphomas, however, in 3/11 lymphomas the percentage of positively weakly stained cells was < 10% and those tumors were also considered negative. Tumors with 10 50% P-glycoprotein positive cells were found in single cases of centroblastic and centroblastic-centrocytic tumors. In 5 lymphomas P-glycoprotein expression exceeded 50% of tumor cells. Those cases were found among centroblastic, centroblastic-centrocytic, lymphoblastic and Burkitt-like subtypes. Positive reaction was observed mainly in the cell cytoplasm, however, in some cases prominent perinuclear dot-like staining pattern was found. In 2 cases focal staining pattern comprised dominant type of immunolabelling. Among all lymphomas containing P-glycoprotein positive cells intensity of imunolabelling was assessed as weak (6/25), moderate (2/25) and strong (3/25). Our results indicate that P glycoprotein expression is present in nearly one third of newly diagnosed canine lymphomas of different morphological subtypes including those most commonly occurring, such as cenroblastic lymphomas. Hence, determination of P-glycoprotein expression at the time of diagnosis could provide valuable information for the design of treatment protocols. Moreover, our results have shown that P glycoprotein expression in canine tumors could be located in Golgi-zone. PMID- 25928920 TI - Effect of humic-plant feed preparations on biochemical blood parameters of laying hens in deep litter housing system. AB - An influence of various humic-plant feed additives based on some herbs (nettle, chamomile, yarrow, perforatum), lucerne and humic materials on biochemical indices of Lohmann Brown (LB) layers blood plasma was estimated. Hens were housed in deep litter system, 20 birds in a group. Four groups were formed: control (C - standard feeding), and experimental, supplemented with prepara- tions: E-1 herbal humic, E-2 humic-herbal and E-3--humic-lucerne. Hens were placed in the pens on the 16th week of life, addition of preparations with standard food mixture started at the 22nd wk and lasted until 66th wk of life. Blood for analyses was collected four times in the following periods: 27, 37, 54 and 65th wk of life. The applied humic-plant preparations to a limited degree affected the values of examined biochemical parameters in serum: total protein (TP), albumins (Albs), glucose (Glu), urea, triacylglycerols (TAG), total cholesterol (TCh), alanine aminotransferase (ALT), aspartate aminot- ransferase (AST) and alkaline phosphatase (ALP). It is difficult to determine based on these study, which preparation is one the most active biologically, however is seems that humic lucerne prepara- tion affected the examined blood parameters to the highest degree. The reference values ranges in hens blood serum LB hens were proposed for: TP (43-65 g/l), Albs (15-22 g/l), urea (0.5-1.2 mmol/l), Glu 10-15 mmol/l), TCh (2.2-4.5 mmol/l), TAG (10-24 mmol/l), AST (4-12 U/l), ALT (150-280 mmol/l) and ALP (190-350 U/l). PMID- 25928921 TI - Detection of the bovine viral diarrhoea virus (BVDV) in young beef cattle in eastern and south-eastern regions of Poland. AB - In view of the scarcity of information concerning viral diarrhoea virus (BVDV) infections in beef cattle in Poland, the aim of this study was to evaluate the presence of the BVDV in young beef cattle from selected herds in eastern and south-eastern regions of Poland. The material consisted of 78 sera obtained from beef cattle from 15 farms, aged 6-12 months. The anti-BVDV antibody level in the sera was estimated with an ELISA kit, and detection of the BVDV was carried out by standard PCR and one step Real-Time RT-PCR. The ELISA results showed a high degree (80%) of positivity in 5 of the 78 samples. In 7 samples the degree of positivity was in the very low range: < 40%. Of the 78 cDNA samples, the presence of genetic material with a length of 288 bp was found by standard PCR in 3 sera. The genetic material of BVDV was also found in the sera of the same three calves by Real-Time HRM PCR. BVDV infection in young beef cattle in south-eastern Poland is not a significant problem. This was confirmed by the positive ELISA results for 6.4% of the animals and the positive PCR results for 3.9%. The percentage of positive beef herds was about 8.6%. However, due to the severe nature of the disease and rapid transmission of the virus, regular monitoring of BVDV should be carried out. PMID- 25928922 TI - Pharmacokinetics of propofol in rainbow trout following bath exposure. AB - Propofol, 2,6-diisopropylphenol, seems to be a good candidate as a fish anaesthetic, however, no study regarding propofol influence on fish has yet been reported. The aim of this study was to examine propofol pharmacokinetics in rainbow trout (Oncorhynchus mykiss) following bath exposure. Fish (n = 100) were exposed to an aqueous propofol bath at 12 degrees C and 17 degrees C; propofol concentration in the bath was 10 mg L(-1). Plasma concentration-time profiles were determined using LC-MS, and pharmacokinetic parameters were calculated. Propofol was absorbed quickly at both temperatures. Its concentration reached 13.8 +/- 2.7 MUg mL(-1) and 16.1 +/- 2.1 MUg mL(-1) at 12 degrees C and 17 degrees C, respectively, during the first minute of exposure. Blood plasma propofol decreased rapidly to 6.8 +/- 0.7 MUg mL(-1) and 6.3 +/- 2.2 MUg mL(-1) at 12 degrees C and 17 degrees C respectively, during the first 10 minutes of the recovery. The half-life time of propofol was 1.5 h and 1.1 h at 12 degrees C and 17 degrees C, respectively. We found propofol anaesthesia in trout effective and safe. However, it caused a gradual decrease of respiratory rate, and therefore a specific anaesthesia protocol should be developed. PMID- 25928923 TI - Zearalenone induces apoptosis and inhibits proliferation in porcine ileal Peyer's patch lymphocytes. AB - Zearalenone (ZEN) is one of the most active natural estrogenic compounds that induces apoptosis. This study has been prompted by the widespread occurrence of ZEN in food and feed and limited knowledge about the effects of exposure to low doses of ZEN on the immune system. The aim of the study was to verify the hypothesis that low doses of ZEN contribute to induction of apoptosis and inhibition of proliferation in lymphocytes of the germinal centers (GC) of ileal Peyer's patches (IPP) in pigs. The experiment was performed on 30 female Polish Large White pigs, aged 2 months, with body weight of 15-18 kg, divided into two groups: control (C, n = 15) and experimental (Z, n = 15). On days 14, 28 and 42 of exposure to ZEN (100 MUg kg(-1) feed day(-1)), apoptosis in IPP GC was evaluated histologically in HE-stained specimens, immunohistochemically by active caspase-3 staining and in mononucleosome and oligonucleosome detection-based ELISA. Proliferation was evaluated histologically by mitosis detection in HE stained specimens, immunohistochemically by PCNA staining and in the MTT tetrazolium salt colorimetric assay detecting mitogenic responses of B cells to LPS. Exposure to low doses of ZEN for several weeks intensified apoptosis and weakened proliferation in IPP lymphocytes. ZEN influences gut-associated lymphoid tissue (GALT) by decreasing the expression of CD21+ on B cells and by increasing the percentage of B1 cell populations. PMID- 25928924 TI - Large granular lymphoma in six cats. AB - Large granular lymphomas (LGLs) comprise a specific group of lymphomas regardless of classifi- cation scheme. An LGL consists of cells that show less or more mature morphology, but typically neoplastic cells possess cytoplasmic azurophilic granules clearly visible during cytological examin- ation. The aim of the present study was to present clinical and cytological data on large granular lymphomas in cats and to analyses the therapeutic responses in treated cases. During the period from 2012 to 2014 six cats were as having large granular lymphoma. In one cat a nasal form of LGL was recognized, a systemic form was recognized in another cat, and in four cases an alimentary form was recognized. Cellular samples for cytopathology were collected from the cat with nasal cavity mass, from the enlarged mandibular lymph node and thoracic cavity from second cat, and in four cats from the abdominal mass during ultrasound-assisted fine-needle biopsy. Therapy was introduced in 5 of the 6 cats. In two cases palliative therapy with glucocorticoids was conducted, in two cases chemotherapy with COP protocol, and therapy with masitinib in one case. The median of survival time for cats treated with anticancer therapy was 9 months, the median of survival time for cats treated with glucocorticoids was 1.5 months. In conclusion, large granular lymphomas, especially the alimentary form, are a relatively common type of lymphoma in cats. Simple diagnostic methods such as clinical examination, imaging techniques and routine cytology are sufficient in majority of cases. Despite aggressive behavior and poor general prognosis, conventional chemotherapy lead to a good response in some treated cats regardless of anatomic form and histologic grade of malignancy. PMID- 25928925 TI - Assessment of lipid and protein peroxidation markers in non-pregnant and pregnant female dogs. AB - The aim of the study was to investigate oxidative stress during normal pregnancy in female dogs based on an evaluation of plasma markers for lipid and protein peroxidation. Twenty clinically healthy female dogs (10 non-pregnant and 10 pregnant) were used in the study. Blood samples from the pregnant animals were collected at 19-21, 38-40, and 56-58 days of pregnancy. Blood samples from non pregnant female dogs were obtained between 20 and 35 days after ineffective breeding. As indicators of oxidative stress, we measured the following using spectrophotometric and spectrof- luorimetric methods: thiobarbituric acid reactive substances (TBARS), radical cations of N,N, diethylparaphenylene diamine (RC-DEPPD), sulfhydryl groups (SH groups), bityrosine and formylkynurenine. The mean plasma TBARS concentration in the pregnant dogs (0.486 +/- 0.071-0.581 +/- 0.191 MUmol/g protein) was significantly higher (p < 0.05) than that found in the non-pregnant animals (0.274 +/- 0.111 MUmol/g protein). A marked, although not significant, decrease in SH group content, as well as an increase in bityrosine and formylkynurenine concentration were concurrently observed in the pregnant dogs. No significant differences were found in terms of the studied markers in the pregnant animals when comparing the values obtained during the investigated periods of pregnancy, although there was a progressive decrease in TBARS concentration and a progressive increase in RC-DEPPD, bityrosine and formylkynurenine contents. Our findings suggest that normal pregnancy in female dogs is associated with oxidative stress. Further studies are necessary to establish the physiological ranges of antioxidative/oxidative profiles in pregnant dogs and to explain if and how the intensity of oxidative stress might contribute to the risk of the complications of pregnancy. PMID- 25928926 TI - The splenocyte proliferative response and cytokine secretion in mice after oral administration of commercial gold nanocolloid. AB - Owing to their unique physicochemical properties, gold nanoparticles find numerous biomedical applications. Experiments on rodents prove that the main target organs of gold nanoparticles entering an organism are the liver and spleen, whose reticuloendothelial system removes foreign particles from the bloodstream. Through interactions with resident tissue macrophages, nanoparticles can evoke a systemic immunological response. The aim of this study has been to determine the effect of oral administration of commercial gold nanocolloid, recommended by the producer inter alia as a dietary supplement, on the proliferative activity and cytokine secretion by murine splenocytes. The colloid was given to the animals in three different doses (0.25, 2.5, 25 ppm), for three different time periods (7, 14, 28 days). The influence of nanogold on splenocyte functions was time-dependent and the various doses were distinguished by distinct modes of action. The lowest dose had a pro-inflammatory or immunostimulating effect, enhancing the synthesis of pro-inflammatory cytokines (IL-1beta, IL-6, TNF-alpha). The effect of the highest dose can be considered as a pro inflammatory, or immunotoxic one, because the stimulated cytokine synthesis was accompanied by a drastic decline in the proliferative activity of lymphocytes. The medium dose, while inhibiting the synthesis of pro-inflammatory cytokines of macrophages, simultaneously stimulated the proliferation of lymphocytes. All the doses also modulated the synthesis of IL-2, which may implicate their effect on the immunoregulatory mechanisms of an organism. The effect of alimentary administration of gold nanocolloid on the immune system seems to be difficult to predict, hence a risk that this type of dietary supplements might have some adverse impact on the immunity cannot be excluded, especially after their chronic administration. PMID- 25928927 TI - Cecal enzyme activity in gilts following experimentally induced Fusarium mycotoxicosis. AB - The objective of the presented study was to examine the influence of Fusarium mycotoxins (zearalenone--ZEN and deoxynivalenol--DON), administered separately and in combination, on the activity of cecal enzymes (beta-glucosidase and beta glucuronidase) in gilts which were fed fodder con- taminated with these mycotoxins. The activity of beta-glucosidase and beta-glucuronidase varied in the range of 0.170-1.236 MUmol . h(-1) . mg(-1) and 8.701-96.704 MUmol . h(-1) . mg( 1), respectively. In the first two weeks, the toxins had no significant effect on the activity of beta-glucosidase and beta-glucuronidase in the ascending and descending colon. After week 3 and later on, ZEN and DON administered as a mix- ture led to the highest increase in the activity of both enzymes. Administered separately, DON affected the activity of enzymes more than ZEN. From the third week of the experiment, an increase in the activity of CW beta-glucosidase and beta-glucuronidase was observed. PMID- 25928928 TI - Expression of VPAC1 receptor at the level of mRNA and protein in the porcine female reproductive system. AB - The presence and distribution of vasoactive intestinal polypeptide (VIP) receptor VPAC1 was studied in the ovary, oviduct and uterus (uterine horn and cervix) of the domestic pig using methods of molecular biology (RT-PCR and immunoblot) and immunohistochemistry. The expression of VPAC1 receptor at mRNA level was confirmed with RT-PCR in all the studied parts of the porcine female reproductive system by the presence of 525 bp PCR product and at the level of proteins by the detection of 46 kDa protein band in immunoblot. Immunohistochemical stainings revealed the cellular distribution of VPAC1 receptor protein. In the ovary it was present in the wall of arterial blood vessels, as well as in the ovarian follicles of different stages. In the tubular organs the VPAC1 receptor immunohistochemical stainings were observed in the wall of the arterial blood vessels, in the muscular membrane, as well as in the mucosal epithelium. The study confirmed the presence of VPAC1 receptor in the tissues of the porcine female reproductive tract what clearly shows the possibility of influence of VIP on the porcine ovary, oviduct and uterus. PMID- 25928929 TI - Acid-base disorders in calves with chronic diarrhea. AB - The aim of this study was to analyze disorders of acid-base balance in calves with chronic diarrhea caused by mixed, viral, bacterial and Cryptosporydium parvum infection. We compared results ob- tained with the classic model (Henderson-Hasselbalch) and strong ion approach (the Steward model). The study included 36 calves aged between 14 and 21 days. The calves were allocated to three groups: I - (control) non-diarrheic calves, group II - animals with compensated acid-base imbalance and group III calves with compensated acid-base disorders and hypoalbuminemia. Plasma concentrations of Na+, K+, Cl-, C12+, Mg2+, P, albumin and lactate were measured. In the classic model, acid-base balance was determined on the basis of blood pH, pCO2, HCO3-, BE and anion gap. In the strong ion model, strong ion difference (SID), effective strong anion difference, total plasma concentration of nonvolatile buffers (A(Tot)) and strong ion gap (SIG) were measured. The control calves and the animals from groups II and III did not differ significantly in terms of their blood pH. The plasma concentration of HCO3 , BE and partial pressure of CO2 in animals from the two groups with chronic diarrhea were significantly higher than those found in the controls. The highest BE (6.03 mmol/l) was documented in calves from group II. The animals from this group presented compensation resulted from activation of metabolic mechanisms. The calves with hypoal- buminemia (group III) showed lower plasma concentrations of albumin (15.37 g/L), Cl (74.94 mmol/L), Mg2+ (0.53 mmol/L), P (1.41 mmol/L) and higher value of anion gap (39.03 mmol/L). This group III presented significantly higher SID3 (71.89 mmol/L), SID7 (72.92 mmol/L) and SIG (43.53 mmol/L) values than animals from the remaining groups (P < 0.01), whereas A(Tot) (6.82 mmol/L) were significantly lower. The main finding of the correlation study was the excellent relationship between the AGcorr and SID3, SID7, SIG. In conclusion, chronic diarrhea leads to numerous water-electrolyte disorders. Characterization of acid-base disturbance in these cases suggests that classic model have some limitations. This model can not be recommended for use whenever serum albumin or phosphate concentrations are markedly abnormal. PMID- 25928930 TI - The use of elements of the Stewart model (Strong Ion Approach) for the diagnostics of respiratory acidosis on the basis of the calculation of a value of a modified anion gap (AGm) in brachycephalic dogs. AB - Apart from the HH equation, the acid-base balance of an organism is also described by the Stewart model, which assumes that the proper insight into the ABB of the organism is given by an analysis of: pCO2, the difference of concentrations of strong cations and anions in the blood serum - SID, and the total concentration of nonvolatile weak acids - Acid total. The notion of an anion gap (AG), or the apparent lack of ions, is closely related to the acid-base balance described according to the HH equation. Its value mainly consists of negatively charged proteins, phosphates, and sulphates in blood. In the human medicine, a modified anion gap is used, which, including the concentration of the protein buffer of blood, is, in fact, the combination of the apparent lack of ions derived from the classic model and the Stewart model. In brachycephalic dogs, respiratory acidosis often occurs, which is caused by an overgrowth of the soft palate, making it impossible for a free air flow and causing an increase in pCO2--carbonic acid anhydride The aim of the present paper was an attempt to answer the question whether, in the case of systemic respiratory acidosis, changes in the concentration of buffering ions can also be seen. The study was carried out on 60 adult dogs of boxer breed in which, on the basis of the results of endoscopic examination, a strong overgrowth of the soft palate requiring a surgical correction was found. For each dog, the value of the anion gap before and after the palate correction procedure was calculated according to the following equation: AG = ([Na+ mmol/l] + [K+ mmol/l])--([Cl- mmol/l]+ [HCO3- mmol/l]) as well as the value of the modified AG--according to the following equation: AGm = calculated AG + 2.5 x (albumins(r)--albumins(d)). The values of AG calculated for the dogs before and after the procedure fell within the limits of the reference values and did not differ significantly whereas the values of AGm calculated for the dogs before and after the procedure differed from each other significantly. CONCLUSIONS: 1) On the basis of the values of AGm obtained it should be stated that in spite of finding respiratory acidosis in the examined dogs, changes in ion concentration can also be seen, which, according to the Stewart theory, compensate metabolic ABB disorders 2) In spite of the fact that all the values used for calculation of AGm were within the limits of reference values, the values of AGm in dogs before and after the soft palate correction procedure differed from each other significantly, which proves high sensitivity and usefulness of the AGm calculation as a diagnostic method. PMID- 25928931 TI - The effects of dietary deoxynivalenol (DON) on selected blood biochemical and hematological parameters in pre-pubertal gilts. AB - The aim of this study was to determine whether exposure to low doses of DON leads to changes in serum hematological and biochemical profiles. In the experiment, pre-pubertal gilts (with body weight of up to 25 kg) were administered DON per os at a daily dose of 12 MUg/kg BW (group E, n=18) or a placebo (group C, n=21) over a period of 42 days. Blood for analysis was sampled seven times at weekly intervals. Minor, but statistically significant changes were observed in selected indicators, particularly in weeks 2 and 3 in values of biochemical parameters such AlAT, AspAT, Pin and Fe, and in values of hematological parameters such as RBC, MCV, MCHC, PLT, MPV, WBC, neutrophil, eosinophil, lymphocyte and monocyte counts. In group E, a decreasing trend of the values was observed in most cases, except for RBC, PLT, eosinophil, lymphocyte and monocyte counts. Similar results were obtained in the last two weeks of the experiment. Initially, exposure to DON has a stimulating effect, which is eliminated when adaptive mechanisms are triggered. The results of the study indicate that the intensity of biotransformation processes varies subjected to the body's energy resources. PMID- 25928932 TI - Immunohistochemical diagnostic of hibernoma in dog. AB - The diagnosis of hibernoma is uncommon in veterinary medicine. In this report, we present an attempt to confirm hibernoma diagnosed in dogs by applying immunohistochemical tests routinely used in human pathology i.e. antibodies specific to protein S100, protein CD31, or smooth muscle actin (SMA). PMID- 25928933 TI - Selected qualitative and biochemical parameters of cryopreserved semen of Holstein-Friesian (HF) AI bulls. AB - Selected qualitative and biochemical parameters were determined in cryopreserved semen used for artificial insemination, sampled from 120 bulls reared at the Animal Breeding and Insemination Center in Bydgoszcz. The total average motility of the analyzed sperm samples was determined at 62.51%. The percentage of motile spermatozoa displaying progressive forward motility was 21.65%. Analyzed samples were characterized by a high percentage of sperm cells with a intact plasma membrane (71.21%) and active mitochondria (71.32%). High efficiency of the enzymatic antioxidant system of the evaluated sperm cells was demonstrated by high activity of CAT, GPx and SOD (494.37, 2847.83 and 5.31U/1x10(9) spermatozoa, respectively) values and low values of the DNA Fragmentation Index (9.32). The results of the study, obtained with the involvement of advanced analytical methods, indicate a high fertilizing capability of the analyzed sperm samples. PMID- 25928934 TI - Reply: To PMID 25611425. PMID- 25928935 TI - New possibilities in primary care and reimbursement. PMID- 25928936 TI - Moving toward value-based care in diabetes: stakeholders weigh in. PMID- 25928937 TI - In diabetes care, mixed news on payment reform. PMID- 25928938 TI - Neuroscience study uncovers new player in obesity. PMID- 25928939 TI - Understanding the connections between race and bariatric surgery. PMID- 25928940 TI - Getting an earlier diagnosis of diabetes starts with better screening. PMID- 25928941 TI - Daschle: What lies ahead for healthcare and health reform. PMID- 25928942 TI - Making ACOs work amid the changing healthcare landscape. PMID- 25928943 TI - [Issue dedicated to Horvath Attila]. PMID- 25928946 TI - [Belgium Royal Academy of Medicine membership list]. PMID- 25928945 TI - Abstracts of the 12th Workshop on Costs and Assessment in Psychiatry 'Mental Health Policy and Economics Research: Improving Access, Quality and Outcomes', March 27-29, 2015, Venice, Italy. PMID- 25928948 TI - A biography of my father, Graham Glancy, upon his induction to the presidency of the American Academy of Psychiatry and the Law. PMID- 25928949 TI - The new age of much older age. PMID- 25928947 TI - The motivational drive to natural rewards is modulated by prenatal glucocorticoid exposure. AB - Exposure to elevated levels of glucocorticoids (GCs) during neurodevelopment has been identified as a triggering factor for the development of reward-associated disorders in adulthood. Disturbances in the neural networks responsible for the complex processes that assign value to rewards and associated stimuli are critical for disorders such as depression, obsessive-compulsive disorders, obesity and addiction. Essential in the understanding on how cues influence behavior is the Pavlovian-instrumental transfer (PIT), a phenomenon that refers to the capacity of a Pavlovian stimulus that predicts a reward to elicit instrumental responses for that same reward. Here, we demonstrate that in utero exposure to GCs (iuGC) impairs both general and selective versions of the PIT paradigm, suggestive of deficits in motivational drive. The iuGC animals presented impaired neuronal activation pattern upon PIT performance in cortical and limbic regions, as well as morphometric changes and reduced levels of dopamine in prefrontal and orbitofrontal cortices, key regions involved in the integration of Pavlovian and instrumental stimuli. Normalization of dopamine levels rescued this behavior, a process that relied on D2/D3, but not D1, dopamine receptor activation. In summary, iuGC exposure programs the mesocorticolimbic dopaminergic circuitry, leading to a reduction in the attribution of the incentive salience to cues, in a dopamine-D2/D3-dependent manner. Ultimately, these results are important to understand how GCs bias incentive processes, a fact that is particularly relevant for disorders where differential attribution of incentive salience is critical. PMID- 25928950 TI - Age disrupters. PMID- 25928951 TI - Stretch your timeline. PMID- 25928952 TI - Get your head in the game how. PMID- 25928953 TI - Can brain games keep my mind young? PMID- 25928954 TI - What diet helps people live the longest? PMID- 25928957 TI - Zombie dentistry? PMID- 25928956 TI - It's time to embrace lifestyle medicine. PMID- 25928955 TI - Do married people really live longer? PMID- 25928958 TI - Does the ADA have a Code of Ethics? PMID- 25928959 TI - Teeth in the era of implant dentistry. PMID- 25928960 TI - Review of models for titanium as a foreign body. AB - A growing number of theories has evolved attempting to explain the process of dental implant failure. Titanium implants utilized outside of the mouth have exhibited breakdown through a foreign body reaction. Phenomena occurring in the body, such as passive dissolution, osteolysis and metallosis, have not been discussed relative to dental implants. The dental community must consider the full spectrum of implant interactions within the body to understand the differences and similarities within the mouth. PMID- 25928961 TI - Implant treatment planning: endodontic considerations. AB - Implants are a predictable and effective method for replacing missing teeth. Some clinicians have advocated extraction and replacement of compromised but treatable teeth on the assumption that implants will outperform endodontically and/or periodontally treated teeth. However, evidence shows that conventional therapy is as effective as implant treatment. With data on implants developing complications long term and a lack of predictable treatment for peri-implantitis, retaining and restoring the natural dentition should be the first choice when possible. PMID- 25928962 TI - Teeth versus implants: mucogingival considerations and management of soft tissue complications. AB - Soft tissue complications around dental implants occur with an incidence between 1 and 7 percent, and the treatments for these have not been as well studied, understood or as predictable as with similar complications associated with teeth. These complications include recession, fenestration/dehiscence defects, gingival inflammation/proliferation and fistulas. This paper compares and contrasts important mucogingival considerations between teeth and implants. Diagnosis, treatment and prevention of some of the more common soft tissue complications are presented. PMID- 25928963 TI - Treatment planning decisions: implant placement versus preserving natural teeth. AB - Dental implants are routinely used as a treatment modality for replacing missing teeth. An assessment of whether to extract teeth and place implants or preserve natural dentition can be a complex decision-making process. The purpose of this article is to review some of the factors that influence prosthetic planning of functional and esthetic rehabilitation for patients with diseased dentition either with conventional treatment options or with extractions and replacement with implant-supported prosthesis. PMID- 25928964 TI - Email in the age of privacy. PMID- 25928965 TI - HIPAA safeguards. PMID- 25928966 TI - Breathing new life into organized dentistry. PMID- 25928967 TI - Dental hygiene collaborative practice has arrived. PMID- 25928968 TI - Follow-up problems with fixed appliances in pediatric dentistry. AB - Fixed appliances are commonly used in managing early orthodontic problems. Despite their widespread use, they have the potential to impinge on the soft tissues, interfere with the eruption of adjacent teeth and become dislodged or broken. These two case reports present the poor outcomes of fixed appliance treatments if the patient fails to attend follow-up appointments. A successful outcome of treatment with fixed appliances depends upon proper patient selection and the communication skills of the dentist to help patients/parents understand the importance of regular checkups. PMID- 25928969 TI - Successful nonsurgical management of post-orthodontic gingival enlargement with intensive cause-related periodontal therapy. AB - Successful nonsurgical management of severe postorthodontic gingival enlargement and erythema in a 24-year-old male is presented. The patient received an intensive cause-related periodontal therapy, consisting of oral hygiene instruction, scaling and root planing, and weekly recall visits. At week five, complete resolution of the lesions was achieved. By targeting the primary etiologic factor, i.e., plaque, periodontal health was restored without needing surgical intervention. Reducing the bacterial load will give the biologic natural healing capacity of the body the opportunity to stabilize the periodontal condition and, thus, should be considered as the first line of intervention before a surgical approach is taken. PMID- 25928970 TI - What it means to be a doctor. Sensitizing the dentist and the student to professionalism. AB - Professional demeanor and the inter-personal behavior of the dentist play a large part in building the trust patients measure as they gain confidence in their choice of practitioner. Most of the time, patients experience comfort through the competent, compassionate care of a genuinely respected provider. That important im- age is determined by the ethical and proper relationships every patient encounters. The following discussion brings to the forefront image-damaging episodes that have occurred as a result of unwise or unthinking circumstances playing out not only in the office, but in the community and in private life as well. Can a professional shield the public from disappointing legal, unprofessional entanglements that could cast doubt on the good judgment and safety expected of the doctor? What effects on a practice may be seen? PMID- 25928971 TI - Surgical and prosthetic management of a complex edentulous patient for fabrication of complete dentures. AB - Fabrication of well-fitting complete dentures becomes a challenge in the presence of epulis fissuratum in the maxilla or severely resorbed alveolar tissue in the mandible. This clinical report describes the surgical and prosthetic treatment of a patient who presented with both problems. The neutral zone technique was used to improve the stability of the mandibular complete denture. Both dentures were fabricated prior to surgical excision of the epulis fissuratum and inserted immediately following the surgery. PMID- 25928972 TI - Maxillary implant-retained partial overdenture with Dolder bar attachment: a clinical report. AB - This article describes a technique for maintaining a maxillary Kennedy III partial removable dental prosthesis design in a patient who had non-restorable failing abutments by replacing the abutments with dental implants. Two implants were placed immediately after extraction of the abutment teeth in the anterior maxilla. After the implants were fully integrated, a Dolder bar attachment was fitted onto the implants. A new maxillary partial removable dental prosthesis was fabricated using the implants and the remaining natural teeth as abutments to restore function and esthetics. With the aid of dental implants, this Kennedy III maxillary removable dental prosthesis design could provide additional retention and support by promoting cross-arch stability and tissue, implant and tooth support. The patient's satisfaction was significantly increased. PMID- 25928973 TI - An Analysis of the hemophilia of the royal families of Europe, its startling implication and dentistry's role in treating the hemophiliac patient. AB - Hemophilia is an inherited x-linked recessive disorder. It is known popularly as "The Royal Disease," as it has affected many of the royal families of Europe by virtue of Queen Victoria being a carrier for the gene and, subsequently, passing it on to her offspring. They, in turn, married and had children with other royal families of Europe. Hemophilia is certainly not limited to royalty. There are many hemophiliacs living in our communities, and they must receive both proper dental home-care education and dental treatment in order to prevent possibly life threatening emergency dental episodes. Individuals with hemophilia pose different management issues to the dental professional. The various precautions and modifications that must be taken in order to ensure the safe delivery of dental care to hemophiliac dental patients are discussed. PMID- 25928974 TI - Effect of apically separated rotary instruments on bacterial leakage of obturated root canals using resilon. AB - The purpose of this study was to determine the effect of a separated rotary instrument on the time required for bacterial penetration of obturated root canals using Resilon. Eighty-four extracted human maxillary premolars with single canals were used in this study. Group 1 consisted of teeth obturated with gutta percha and AH-26 sealer (n=15); Group 2 consisted of teeth obturated similarly to Group 1 but without a separated file; Group 3 consisted of teeth obturated with Resilon and Epiphany sealer (n=15); and Group 4 consisted of teeth obturated similarly to Group 3 but without a separated file. Six teeth were used as positive controls, and six teeth were used as negative controls for each experimental group. Negative controls were obturated similarly to experimental teeth. On the other hand, positive controls were obturated with gutta-percha or Resilon without sealer. A suspension of Enterococcus faecalis was placed in the access chamber daily, and penetration was determined when turbidity was noted in the culture broth during a three-month period. No significant difference between experimental groups was observed. However, differences between experimental groups and control groups were statistically significant. PMID- 25928975 TI - Pediatric blunt abdominal trauma in the emergency department: evidence-based management techniques. AB - Blunt abdominal trauma is the third most common cause of pediatric trauma deaths, but it is the most common unrecognized fatal injury. This issue discusses common mechanisms and injuries seen in children with blunt abdominal trauma and takes a closer look at current evaluation and management techniques. The main-stays of diagnostic evaluation include laboratory, sonography, and computed tomography studies. However, the routine use of these studies may not be necessary, and controversy exists as to which studies are beneficial and which are less valuable. The concern for radiation-induced malignancy has led to increased efforts to limit radiation exposure by decreasing the use of unnecessary computed tomography scans. The history and physical examination, combined with the mechanism of injury, should be used to develop a thoughtful and directed diagnostic workup. PMID- 25928976 TI - Evidence-based management of neonatal vomiting in the emergency department. AB - Vomiting accounts for up to 36% of neonatal visits to the emergency department. The causes of vomiting can range from benign to life-threatening. Evidence to guide the diagnosis and management of neonatal vomiting in the emergency department is limited. History and physical examination are extremely important in these cases, especially in identifying red flags such as bilious or projectile emesis. A thorough review is presented, discussing various imaging modalities, including plain abdominal radiography, upper gastrointestinal studies, ultrasonography, and contrast enema. A systematic approach in the emergency department, as outlined in this review, is required to identify the serious causes of vomiting in the neonate. PMID- 25928977 TI - [Developing the methodology of examining the lower limb veins in cosmonauts for the space medicine practice]. AB - The article centres on development of a methodology for evaluating the function of lower limb veins of cosmonauts in microgravity. The whys and wherefores of the choice of occlusive plethysmography equipment and procedure are explained. Much place is given to arguments for the requisite body and limb positioning during venous plethysmography pre launch and on return from space flight. To minimize the gravity effect on venous blood flow, the body should be in the level position and the calf aligned with the hydrodynamically indifferent point. Determining the type of test occlusion, occlusion adjustments, venous parameters of interest, and data processing procedure constitute the methodology. PMID- 25928978 TI - [Status of the osteoclast-activating system in cosmonauts after long-duration missions to the International Space Station]. AB - The results of studying the system of osteoprotegerin/ receptor activator of nuclear factor kappa-B ligand (OPG/RANKL) in 22 cosmonauts after long-duration (124 to 199 days) ISS missions are presented. Immediately on return to 1 g, changes were observed in OPG and RANKL serum levels and the ability to produce unstimulated and stimulated PGA of peripheral blood mononuclear cells in vitro. Individual variability of these changes was noticed. Our findings suggest that the cytokine OPG/RANKL-system is involved in bone remodeling in members of long duration space missions. PMID- 25928979 TI - [Use of the prenosology approach for attaining the objectives of pilot medical expertise]. AB - Early diagnostics of senior pilots for diseases and conditions undesirable in terms of flight safety is tightly linked with evaluation of risks of their development. Prenosology diagnostics is focused on borderline states that may pass from health to disease (prenosology and premorbidity) and, vice versa, from disease to recovery (postnosology). Regarding health as a vital adaptation reserve, prenosology diagnostics is concerned with the ability of organism to adapt to an environment rather than probability of disease. Constant drain of adaptation reserves may become a reason for increased risks of disease. Heart rate variability analysis is one of the instruments of prenosology diagnostics. Authors of the paper discuss applicability of the space medicine oriented probabilistic approach to evaluation of adaptation risks by medical expertise boards certifying civil pilots. Results of 2 series of investigations showed increased adaptation risks and reduced functional reserves in pilots found unfit to continue career. PMID- 25928980 TI - [Cytochrome C content and mitochondrial activity in rat's cardiac and skeletal muscle cells in the course of 3-day gravitational unloading]. AB - Purpose of the investigation was to determine the cytochrome c content and associated gene expression in cardiomyocytes and m. soleus fibers obtained from rats following 6, 12, 18, 24 and 72 hours of tail suspension. Cellular respiration was measured using Sax's polarography as a parameter reflecting the mitochondrial activity. In cardiomyocytes, cytochrome c in the protein membrane mitochondrial fraction grew 34.6% (p < 0.05) after 18 hours of suspension relative the control. Cycs and gapdh expression was not altered, while parameters of the cardiomyocyte cellular respiration were increased. In m. soleus fibers, cytochrome c made a fall following 24-hr suspension. mRNA cycs was found reduced significantly after 6 hours and cellular respiration intensity declined reliably after 72 hours of gravitational unloading. PMID- 25928981 TI - [Effects of vestibuloprotectors mexidol and melatonin on animal cerebellum]. AB - In experiments with cats, air-assisted microinjections of mexidol and melatonin had a direct effect on 71-81% Purkinje cells inducing the inhibitory response 4.2 6.3 times more often than exiting. In case of concurrent action of MK-801 (a specific noncompetitive NMDA-receptor antagonist) the mexidol effect on the spontaneous activity was suppressed fully or abated significantly in 88% Purkinje cells. Lusindol (a specific melatonin MT2- and MT2-receptor antagonist) and GABA negative bicuculline prevented the inhibiting effect of melatonin fully or abated significantly the spontaneous activity of 86% and 71% Purkinje cells, respectively. This means that melatonin-produced inhibition recruits both melatonin MT1- and MT2-receptors, and also the GABA-ergic component (stimulation of GABAA-receptors). Investigation of rat's cerebellum slices with prolonged survival showed that 5 mM of mexidol inhibited reliably Purkinje cells population responses by 93 +/- 4%; the presence of MK-801 (100 microMM) weakened this effect by 82 +/- 3%. Consequently, mexidol is capable to inhibit strongly the parallel fibers--Purkinje cells synaptic transmission in the rat's cerebellum, whereas MK- 801 abates this effect appreciably. PMID- 25928982 TI - [Oxidative stress resistance of multipotent mesenchymal stromal cells cultivated under different oxygen tension]. AB - Studies of the reaction of multipotent mesenchymal stromal cells (MMSCs) derived from human adipose tissue to oxidative stress showed that cells cultivated at 5% O2 possessed much lower resistance to hydrogen peroxide. This could be consequent to low basal activities of superoxide dismutase (SOD) and glutathione peroxidase (GP) in these cells when compared to MMSCs exposed to 20 % 02 and 1% O2. Twenty four-hour exposure of stromal precursors in a medium containing H2O2 in a minimal concentration (LD5) stimulated an oxygen-dependent rise of the SOD activity, whereas catalase and GP concentrations did not change. Activation of the antioxidant system in response to equally a weak hypoxic (1% O2) and weak hyperoxic (20% O2) stress in vitro enhances the MMSCs resistance to H2O2. PMID- 25928983 TI - [Alteration of the QRS complex in electrocardiograms of healthy people in the course of test loading]. AB - QRS amplitudes were analyzed in ECG records obtained from exercising healthy people to evaluate the sensitivity of QRS waves to exaggerated pulmonary ventilation, blood pressure (BP) and heart rate (HR). Seventeen normal subjects aged >35 years were involved in a series of three test loading sessions aimed to define QRS alterations caused by shifting and rotation of the heart, and changes in conductivity of thoracic organs and tissues as a consequence of a different respiration pattern. They also participated in a second series of three loading sessions aimed to trace QRS alterations stemming from changes in central hemodynamics (systolic and diastolic BP and HR). Both series demonstrated a reliable S-wave rise that did not relate to the heart rotation caused by the diaphragm displacement due to deep respiration and change in body positioning but correlated with increases in systolic BP. These observations could have been induced by growth of the transmural myocadial pressure produced by isovolumic contractions during heavy test loading. PMID- 25928984 TI - [System analysis of heart rate variability, hemodynamics and bioelectrical activity of the human brain at moderate altitudes]. AB - Heart rate variability (HRV), hemodynamics, cerebral alpha-rhythm and systemic relations between them were investigated in 35 normal human subjects at the age of 37.2 +/- 3.8 years. Results of comprehensive clinical, functional and instrumental HRV investigations, electroencephalography (EEG) using 21 monopolar electrodes and blood pressure (BP) monitoring were embodied in mathematical models describing the relations of these parameters, multiple regression equations, and generated 3-D diagrams. It was found that relative increase of LF and reductions of HF ranges occurred on the background of BP elevation. The EEG alpha amplitude was depressed and alpha index decreased. The HRV reduction and modification of the alpha-rhythm structure were demonstrated to affect BP values. These data point to interactions and tight relations between the vegetative and central nervous systems and BP. PMID- 25928985 TI - [Effect of branched-chain amino acids mixture on repair of atrophied rats' skeletal muscles]. AB - Loss of muscle mass (atrophy) is a regular consequence of gravitational unloading. In hypogravity, muscle atrophy ensues from depression of protein synthesis and increase of its degradation. Both of these processes underlie also atrophy caused by muscle immobilization, cancer cachexia, cardiomyopathy and age related sarcopenia. At the same time, atrophy of skeletal muscles due to chronic alcohol intoxication is the outcome of protein synthesis depression primarily. The study was part of a program aimed to develop a technique for atrophied muscle recovery by activation of anabolic signal pathways. A similar approach is applied to correct hypogravity-induced atrophy; however, analysis of effectiveness of this approach to the treatment of alcoholic muscle atrophy will be more "pure", as proteolytic processes in intoxicated animals are on the level typical of the intact ones. The issue in hand was whether injection of branched-chain amino acids (BCAA) would facilitate repair of m. gastrocnemius medialis in rats in the period of 30 days after 16-week alcoholic intoxication. BCAA was shown to enhance regain size by fast muscular fibers, full recovery of phosphorylated p90RSK concentrations without consequential effects on general proliferative processes and myonuclear number in rat's m. gastrocnemius medialis. PMID- 25928986 TI - [Consequences of disregarding the recommended strength training regimes in space flight: a unique case of seat liner emergency modification at the final stage of a mission]. PMID- 25928987 TI - [On the functional potential evaluation and selection of skiing--specific training load for shoulder girdle muscles]. PMID- 25928988 TI - Malohani, bula vinaka, fakalofa lahi atu, kia orana, talofa lava, malo e lelei, greetings. PMID- 25928989 TI - Rheumatic fever in New Zealand: what are the teeth trying to tell us? AB - Rheumatic fever remains an important disease of childhood in New Zealand, despite increasing access and awareness of the need for preventive antibiotic treatment. Maori and Pacific children have an incidence rate about 30 times and 70 times higher than European children, from annual notification data (77.7 per 100,000 for Pacific, 30.4 per 100,000 for Maori, and 1 per 100,000 for European). In the early 20th century, a Canadian dentist, Weston A. Price, noted that 95% of children who presented with acute rheumatic fever also had advanced dental caries. Oral health surveys show that Maori and Pacific children are disproportionately affected by dental caries compared to European. Excess dietary sugar intake is widely recognised to cause dental decay and also provides energy to some species of bacteria implicated in the pathogenesis of dental decay and rheumatic fever. We suggest that a case-control study be conducted to evaluate the evidence for an association between sugar intake, dental decay and incidence of disease. PMID- 25928990 TI - Fat storage syndrome in Pacific peoples: a combination of environment and genetics? AB - Pacific people (especially Micronesian and Polynesian) have some of the highest rates of obesity and diabetes in the world that largely developed since the introduction of western culture and diet. Recent studies suggest that much of the risk relates to the excessive intake of sugar (sucrose) and carbohydrates, leading to a type of fat storage syndrome (metabolic syndrome). Here we discuss some of the environmental. genetic and epigenetic reasons why this group might be especially prone to developing obesity and diabetes compared to other ethnic groups. Indirect evidence suggests that the higher endogenous uric acid levels in the Polynesian-Micronesian population may represent a predisposing factor for the development of obesity and diabetes in the context of Western diets and lifestyles. Pacific people may be an ideal group to study the role of "thrifty genes" in the pathogenesis of the current obesity epidemic. PMID- 25928991 TI - The case to ban sugary food and drink from schools: these products are addictive, and kids will learn best without them. AB - In New Zealand, schools have been a battleground as a setting to address the obesity epidemic, with successive governments enforcing, and then repealing laws to ban junk food from canteen menus. Just what is considered 'junk food' remains controversial, but recently sugar sweetened beverages have become a target of public health groups. The adverse health consequences of their intake have been the principal arguments to reduce their availability. Here, we argue that the advantages of reducing intake of sugar in schools are very likely to lead to educational and other social benefits. Indices of sugar intake have been associated with aggressive behaviour, attention deficit, dysphoria and suicidal thoughts in cross-sectional studies. Longitudinal studies have also linked soft drink intake with impaired cognitive development. We believe that banning sugary drinks from schools will assist teachers and students to better achieve their learning goals, with a side effect of improving their health status. PMID- 25928992 TI - An 'end-game' for sugar sweetened beverages? AB - OBJECTIVE: The epidemic of unhealthy weight is now in its third decade. The multitude of initiatives designed to address this issue (globally) have predominantly been ineffective as the prevalence of unhealthy weight has continued to rise. Public health professionals have proposed an 'endgame' for tobacco smoking in New Zealand by 2025, which has received widespread support. Similarly, here, to control the prevalence of unhealthy weight, we consider whether a similar approach to tobacco is justified to restrict the intake of sweetened beverages. APPROACH: This paper reviews the evidence relating sugar sweetened beverages to unhealthy weight and adverse health effects. Current initiatives aimed at reducing sugar sweetened beverage consumption both internationally and in New Zealand are reviewed. FINDINGS: Epidemiological evidence consistently links sugar-sweetened drink intake with unhealthy weight and other risk factors for cardiovascular disease, such as diabetes, gout, and raised blood pressure. Food disappearance data suggests that sugar intake continues to increase in New Zealand, and that a subtle addiction to sugar may underlie this trend. A number of successful initiatives to reduce sugary drink intake are described. IMPLICATION/CONCLUSION: We argue that an 'endgame' to the consumption of sugar-sweetened beverages be supported as a means to address the issue of unhealthy weight at a population level. Finally, a preliminary draft endgame plan is presented for consideration, dialogue and debate. PMID- 25928993 TI - Sugar-sweetened beverages, urate, gout and genetic interaction. AB - The clinical manifestations of gout occur as a result of immune responses to monosodium urate crystals. Elevated serum levels of urate (hyperuricemia) are a prerequisite for the development of gout with reduced fractional renal excretion of uric acid (FEUA) an important cause. In New Zealand, Maori and Pacific Island people have inherently raised urate levels with one consequence a higher prevalence of more severe gout. One characteristic metabolic effect of fructose, present in sugar-sweetened beverages (SSB), is raised urate from hepatic processing of fructose. Here we discuss, and place in a biological context evidence, linking consumption of SSB with hyperuricemia and gout, including the first review of recent ecological and clinical studies of the impact of fructose and SSB exposure in Pacific Island people. Both increased serum urate and increased FEUA are observed in clinical studies examining the effects of an acute fructose load. In contrast, chronic exposure to increased fructose in the diet also leads to increased serum urate concentrations, but reduced FEUA. Epidemiological studies have consistently associated SSB consumption with increased serum urate levels and increased risk of gout. Non-additive interaction of SSB consumption with a genetic variant of a uric acid transporter in serum urate levels and gout risk emphasizes the causality of SSB in gout. Taken together these data demonstrate the hyperuricemic effect of SSB and fructose, with biochemical pathways reasonably well understood. The evidence that dietary fructose increases urate is strong. The evidence summarized here is of sufficient weight to recommend reduction of SSB consumption, particularly in Pacific Island and Maori people, to reduce the burden of gout. PMID- 25928994 TI - Sugar sweetened beverages, obesity, diabetes and oral health: a preventable crisis. PMID- 25928995 TI - Sugar-sweetened beverages in Pacific Island countries and territories: problems and solutions? AB - Non-communicable diseases are a major problem in the Pacific Islands, with poor diets an important contributing factor. Available data suggests high levels of intake of sugar-sweetened beverages (SSBs) across the region, and particularly in adolescents. Due to concerns about the risks to health of high intakes, efforts have been made across the region to reduce the intake of SSBs. French Polynesia, Nauru, Cook Islands, Tonga and Fiji have implemented sales or excise taxes on SSBs to increase the price to the consumer. Many countries in the region have adopted school food policies which intend to limit or ban access to SSBs in schools. Guam also adopted legislation to ensure that healthier foods and beverages were available in all vending machines in schools. Efforts to control advertising and sponsorship of SSBs have been limited to-date in the region, although some school food policies do restrict advertising and sponsorship in schools, school grounds and school vehicles. Efforts around education and awareness raising have shown mixed success in terms of changing behaviour. Greater attention is needed to evaluate the impact of these measures to ensure that actions are effective, and to increase the evidence regionally of the most effective approaches to tackle SSBs. PMID- 25928996 TI - Sugar added to foods consumed in New Zealand and Tokelau. PMID- 25928997 TI - Sweetened and unsweetened non-alcoholic beverages in New Zealand: assessment of relative availability, price, serve size, and sugar content. AB - BACKGROUND: Sweetened beverages are a major contributor to sugar intakes in New Zealand, yet little information exists regarding the retail environment and the characteristics of sweetened and unsweetened beverages available for purchase. AIM: Our aim was to assess the availability, price, serve size and sugar content of sweetened and unsweetened non-alcoholic beverages available for purchase in New Zealand supermarkets. We also review and summarise the evidence for policy options relating to beverage availability, price, serve size and sugar content. METHODS: Data on all non-alcoholic beverages available for purchase in two large Auckland supermarkets were sourced from Nutritrack, a brand- specific packaged food composition database. RESULTS: Of 680 beverages available for sale in 2012, less than one in five (17%) was low-energy or unsweetened. However, low-energy options were cheaper, on average, than their sugar-sweetened counterparts (by approximately one third). The sugar content of beverages available ranged from zero to 23 g/100 mL. Some beverages contained more than 80 g of sugar (16 teaspoons) per single serve. National and international evidence suggests that increasing prices of fizzy drinks could reduce consumption, but long-term impacts on obesity and population health are unknown. Little evidence exists regarding other strategies to create healthier retail food environments. CONCLUSION: The vast majority of beverages available for purchase in New Zealand supermarkets are either sugar-sweetened or contain naturally occurring sugars. Options to decrease availability and reduce consumption of sweetened beverages should be urgently explored. PMID- 25928998 TI - Soft drink consumption in Pacific Island countries and territories: a review of trade data. AB - INTRODUCTION: Pacific Islands Countries and Territories (PICTs) have some of the highest rates of obesity and diabetes in the world. Research has demonstrated a strong link between sugar-sweetened beverage (SSB) consumption and subsequent risk of overweight, obesity, dental caries and type II diabetes. To address the impact of SSBs on noncommunicable diseases, it is crucial to understand the level of SSB consumption in PICTs. METHODS: The volume of soft drinks imported and exported was requested from PICTs to estimate the litres of soft drink consumption per head of population. Analysis was confined to PICTs who did not produce their own soft drinks because production data was limited. The Harmonised Commodity Description and Coding System (HS) category 22.02 was used which includes both diet and sugar-sweetened soft drinks. The trade data estimates were then compared with school survey data to explore how the data sources corresponded given the strengths and weaknesses of each. RESULTS: Soft drink import volumes were a feasible way of estimating total soft drink consumption in PICTs and look at trends over time. Seven out of eleven non-producing PICTs contacted were able to provide volume of soft drinks imported. In 2011, estimates of soft drink consumption per person were 84L in Palau, 47L in the Commonwealth of the Northern Mariana Islands (CNMI), 41L in Niue, 31L in Tonga, 22L in Federates States of Micronesia, 8L in Tuvalu and 1L in Kiribati. CONCLUSIONS: Trade data is a feasible way of monitoring soft drink consumption and may be useful to evaluate the impact of changes in government policy on importation of soft drinks. Data quality could be maximised by including export data, adjusting for visitor numbers and cross-checking exports from corresponding countries. To monitor SSB consumption, a wider range of categories could be included such as categories for sugar-sweetened juice and sweetened-milk drinks. PMID- 25928999 TI - The utility of serving size in the measurement of soft drink consumption. AB - BACKGROUND: Many studies examining population differences in soft drink consumption or the association it has with fatness have not included serving size in its assessment. It is not clear what effect this has on their findings and our study aimed to investigate this by comparing the relationships that days (serving size unaccounted for) and cans/day (serving size accounted for) of consumption have with ethnicity/country and fatness. METHODS: Daily nutrient intakes were calculated from a self-administered food frequency questionnaire from a cross sectional health screening study. Participants were Pacific (n=954) and New Zealand European (n=1745) people aged 35 to 74 years. RESULTS: Compared to Australian youth, NZ Pacific youth consumed soft drinks more frequently but a larger difference was observed for cans/day. In a dose-dependent manner, FMI was positively associated with days (P=0.015) and cans/day (P=0.024) of consumption. However, cans/day showed a stronger relationship, with a standardised regression coefficient of 0.066, compared to 0.033 for days of consumption. CONCLUSIONS: It is useful to include serving size in the assessment of soft drink consumption. Excluding it leads to underestimation of both ethnic/country differences in daily volume of intake and associations with fatness. PMID- 25929000 TI - Dietary intakes of Pacific ethnic groups and European people. AB - OBJECTIVE: To compare dietary intakes, food servings, and cooking practices of Pacific ethnic groups with New Zealand Europeans. METHODS: Daily nutrient intakes were calculated from a self-administered food frequency questionnaire from a cross-sectional health screening study. Participants were Pacific (n=954) and New Zealand European (n=1.745) people aged 35 to 74 years. RESULTS: Total energy intakes in Samoan and Niuean men were higher than European men, while for women, total energy intakes were significantly higher in all Pacific ethnic groups compared to New Zealand European women. Pacific men and women had lower alcohol and calcium intakes compared to New Zealand Europeans, and Pacific men had higher protein and cholesterol intakes. Pacific adults reported eating more servings of fish, chicken and bread, fewer servings of cheese and breakfast cereal per month, and boiled their meat more often than European adults. CONCLUSIONS: Substantial differences in dietary habits and cooking practices exist between European and the different Pacific adult groups mainly related to the frequency of consumption of certain food/nutrient groups and greater serving sizes in Pacific compared to New Zealand European adults. Implications Strategies targeting serving sizes and frequency of consumption of specific food groups may help address the major ethnic disparities in nutrition-related health problems in New Zealand. PMID- 25929001 TI - Carbonated beverages consumption among New Zealand youth and associations with BMI and waist circumference. AB - AIM: The primary aim of this study was to describe the carbonated beverage (soft drink) consumption patterns of New Zealand (NZ) youth and to investigate the influence that home availability of soft drinks had on their consumption. A secondary aim was to determine if there was an association between soft drink consumption and body mass index (BMI) or waist circumference. METHODS: Data from Youth '07, a nationally representative survey of the health and well-being of NZ youth, including 8,697 NZ students aged 13 to 17 years, were analysed. RESULTS: The relevant data was available for 8697 students of whom 4633 identified as NZ European. 1621 Maori, 1.098 Asian, 834 Pacific, and 504 Other. Twenty nine percent (29%) were categorised as high consumers of soft drinks (>4 times a week), 45.4% were moderate consumers (1-3 times a week), and 25.6% were low consumers (had not consumed soft drinks in the past week). Male gender, Pacific ethnicity, and high deprivation were all significantly associated with being in the high consumer group. Fifty eight percent (58%) of children who reported that soft drinks were 'usually' available at home were in the high consumption group, compared to 15.1% of children who reported that these drinks were never available at home. After adjusting for possible confounders, waist circumference was significantly associated with soft drink consumption (p<0.05), however, BMI was not. Mean soft drink consumption for boys was 3.5 times per week and was 2.0 for girls. CONCLUSION: This study provides detailed information on soft drink consumption patterns of NZ youth and highlights factors associated with high consumption. Moderating the availability of soft drinks in the home is likely to significantly reduce their consumption among NZ youth. PMID- 25929002 TI - Carbonated beverage consumption in New Zealand adults. PMID- 25929003 TI - Kelston Beverages Pilot Study: Rationale, design and implementation of a community and school based intervention to reduce sugary drink consumption among children and youth. AB - The Kelston Beverages Study was designed to increase awareness of the sugar content of sugary drinks, the poor health consequences that high intake of these drinks have, and inform on ways to reduce intake of students. The aims of this pilot study were to refine interventions and processes designed to raise awareness of the harms that sugar sweetened beverages (SSBs) have on health, and to reduce their consumption among the youth of a small West Auckland suburb. There were three arms to this interventional study, one in schools, another in community organisations (churches, sports clubs and community groups), and the final arm is in the local retail sector. The school arm was the most extensive component and initially involved a survey of children's knowledge and consumption of sugar sweetened beverages (SSBs) using a brief questionnaire. The study evaluated any SSB policies in schools and for schools that did not have policies, opportunities were scoped to develop and implement them; a canteen AUDIT focussed particularly on beverages was carried out; and finally a student partnered social marketing exercise was undertaken that comprised 2 competitions, one to design a poster, and another to write and perform a rap. Children were re-surveyed at the completion of the intervention (7 months later) to determine change in knowledge and self-reported consumption of SSBs. Both the community organisations and retail arms of this study focussed on raising awareness into the harmful effects of SSBs and establishing healthy beverage policy in the respective organisations. Promising results with regards to acceptability, feasibility, and recruitment as well as valuable learnings with regard to process support the development of a proposal to conduct a cluster randomised trial of the interventions successfully tested in this pilot study. PMID- 25929004 TI - The story of FiZZ: an advocacy group to end the sale of sugar sweetened beverages in New Zealand. AB - FIZZ (which stands for fighting sugar in soft-drinks) is a new advocacy group started to reduce population consumption of sugar-sweetened soft drinks in New Zealand. The vision of FIZZ is for New Zealand to be sugary drink free by 2025. This means that sugar sweetened beverages will comprise < or = 5% of the total beverage market, and sugar free drinks will be the norm. In this paper, we outline the story of FIZZ: to reiterate why we believe the group is needed, reflect on what the group has achieved to date, consider what it aims to accomplish, and outline what methods it will seek to achieve these aims. Put simply, we believe that the epidemiological evidence that sugar intake, particularly in liquid form, causes poor physical and mental health is overwhelming. Swapping sugar sweetened drinks for sugar free alternatives, water or milk, is, in our view, an urgently needed and important step which is likely to reduce the epidemic of unhealthy weight (obesity) and its sequelae. The nutrition environment in New Zealand is now out of step with scientific evidence, with virtually unrestricted access to, and sales and marketing of, sugary drinks to both children and adults. FIZZ is seeking the implementation of local and nationwide policy, similar to those implemented for tobacco, to limit advertising, restrict marketing, raise purchase prices and ultimately curb the sales of sugary drinks in New Zealand. FIZZ is also working in communities to raise people's awareness of the harms sugary drinks pose to health. We at FIZZ also acknowledge that the beverage industry may play an important role in accomplishing this vision, and have established that there is common ground upon which FIZZ and industry can engage to reduce the sugary drink intake. PMID- 25929005 TI - Policy brief: Options to reduce sugar sweetened beverage (SSB) consumption in New Zealand. AB - The purpose of this document is to identify key policy recommendations to relevant settings that impact on the availability, marketing price, and knowledge of SSBs and ultimately the consumption of SSBs in New Zealand, particularly in youth. These recommendations will provide achievable goals to various stakeholders and settings of influence, aiming to reduce SSBs intake. The ideal outcome is that water and milk (unflavoured) become preferred beverage options for New Zealand children and adults. These goals align to the vision articulated by the advocacy group 'FIZZ' to achieve a Sugary Drink Free New Zealand by 2025. This means that SSBs should be only rarely consumed, and comprise less than 5% of total population beverage intake. Addressing SSBs in particular is an important step to addressing New Zealand's obesity epidemic, especially among children. PMID- 25929006 TI - Speech: Sugary drink free Pacific by 2030? NZ by 2025? Tariana Turia. PMID- 25929007 TI - A call for social work activism. PMID- 25929008 TI - Men's mental health: a call to social workers. AB - Substantial attention is paid to the mental health needs of women and children by social work researchers, educators, and practitioners--and with good reason, as these are two vulnerable populations in U.S. society. However, the status of men's mental health; its resulting effect on individuals, families, and communities; and the various challenges associated with it are often overlooked by social workers. The authors document the prevalence of common mental health issues among men in the United States, the unique problems that men face, and help-seeking behaviors. They also discuss how social work is in an exceptional position to help men, and the systemic effects that social work practice with men can have. The authors assert that helping improve men's mental health is critical for social work, particularly given its values recognizing the dignity and worth of all individuals. Their goal is to raise awareness and spark an open dialogue about social work practice with men. PMID- 25929009 TI - Gender differences in depression across parental roles. AB - Prior research has focused on the relationship between parenthood and psychological well-being, with mixed results. Some studies have also addressed potential gender differences in this relationship, again yielding varied findings. One reason may be methodological choices pursued in these studies, including the lack of focus on combined parental roles (for example, biological parent and stepparent). The authors used data from the National Longitudinal Survey of Youth, 1979 (N = 6,276) and multinomial treatment models to address how combined roles influence depressive symptoms in mothers and fathers. Further, they explored potential gender differences. Their results indicated that having multiple parental roles is negatively associated with psychological well-being for both men and women, whereas childlessness is more negative for women, and specific parental role combinations affect mothers and fathers differently. Within the context of changing family structure in the United States, these results have important implications for social workers and other mental health professionals-particularly with regard to screening for depression among parents, who are less likely to seek mental health counseling than childless adults. PMID- 25929010 TI - Shaping the future of prevention in social work: an analysis of the professional literature from 2000 through 2010. AB - In light of the Patient Protection and Affordable Care Act's goals of better patient care, cost control, and improved population outcomes, prevention has emerged as an important component of health reform. Social work, with its extensive involvement in the health system and deep roots in public health, can benefit from a better understanding of its role in prevention. This study builds on the Social Work Interest in Prevention Study (SWIPS), which evaluated extent, type, and levels of prevention content in nine social work journals from 2000 to 2005. The goal of the expanded study, the SWIPS-Expansion, was to assess whether interest in prevention increased over the years in which health reform was enacted. Of the 3,745 articles reviewed, 9.0 percent (n = 336) met the criteria for "prevention articles." Between 2000 and 2010, prevention articles rose from 4.1 percent to 14.3 percent of all articles. A secondary analysis focused on topics within social work prevention, with violence, aging, and disease as primary focal areas. The findings suggest that although prevention interest appears to be growing, it remains a minority focus in the profession's journals. A national conversation on prevention can help expand the profession's role in health reform at this critical time. PMID- 25929011 TI - Which strengths-based practice? Reconciling strengths-based practice and mandated authority in child protection work. AB - The recent application of strengths-based practice in child protection settings has been accompanied by evidence of inconsistent implementation and concerns that the approach is incompatible with statutory work. Few studies have moved beyond asking whether child protection workers are implementing strengths-based practice to explore why the approach is enacted as it is. This article describes a mixed methods study using an online survey and interviews to elicit from 225 statutory child protection workers in a large Canadian agency how they applied strengths based ideas and why they did what they did. The authors found that although strengths-based practice was popular, 70 percent of participants believed that it was not always applicable to child protection work. Participants described five distinct versions of the approach, only one of which was fully congruent with their mandated role. The study suggests that the common conflation of strengths based and solution-focused approaches ignores important differences in the conceptualization of practitioner authority and leaves practitioners attempting to implement versions ofstrengths-based practice that do not fit statutory child protection work. Only when practitioners choose solution-focused models that support their use of mandated authority is consistent implementation a reasonable expectation. PMID- 25929012 TI - Vulnerable families as active agents of their own change process: a bidirectional perspective. AB - The literature on successful practice with vulnerable families reports social workers' efforts in forging therapeutic bonds with clients, their ability to both recognize clients' strengths and pain and support them as they work through adversity. Vulnerable families' own contribu- tions to their change process, however, have remained largely opaque. This article offers concrete conceptual tools to consider both social workers and clients from vulnerable families as active agents in the change process. Empirical evidence collected by practitioner researchers through in-depth discussions with 10 vulnerable families illustrates clients' agentic capacities for autonomy, construction, and action as well as joint construction and maintenance of the helping relationships with social workers, thereby illustrating their active contribution to the process of change. PMID- 25929013 TI - Spirituality, hope, and self-sufficiency among low-income job seekers. AB - Self-sufficiency (SS) is an important social welfare policy goal in the United States, yet little is known about the process that leads to SS. To address this gap in the literature, this study examined the relationship between spirituality, hope, and SS among a sample of low-income job seekers (N = 116). It was hypothesized that spirituality would be related to hope, and that hope, in turn, would be related to SS. Using survey data from two workforce development agencies, this hypothesis was confirmed-hope fully mediated the relationship between spirituality and SS. Of the two factors through which hope is commonly operationalized-agency and pathways-supplemental analysis suggested that spirituality only affects SS through the agency channel. To help foster hope in direct practice settings, it is suggested that social workers might employ spiritually modified cognitive-behavioral therapy protocols. Macrostructural interventions that block the pathway component of hope are also suggested to help reverse exclusion from labor market entry. As such, hope needs to be addressed comprehensively-intrapsychically and macrostructurally-to effect bottom-up change for SS. Engendering hope may assist clients overcome some of the many challenges they encounter on the journey to SS. PMID- 25929014 TI - Immigration detention and faith-based organizations. AB - Immigration detention is a hot contemporary issue in the United States, with over 33,000 individuals held in detention facilities daily and reports of poor conditions and human rights abuses. Building on a growing body of theory exploring the role of faith-based organizations (FBOs) in social services provision, and seeking to address a gap in the literature concerning services provided to immigrants in detention, this qualitative study explored the responses of FBOs to immigration detainees. Twenty in-depth interviews with volunteers and staff members of FBOs as well as field notes from participant observation were analyzed using thematic coding techniques. Findings suggest that FBOs are active leaders in this area of social work practice and provide significant resources to isolated and vulnerable detained immigrants in a variety of ways. Simultaneously, they face challenges surrounding access and constricted activity. The study indicates that considerable scope exists for expanding and enhancing faith-based and other social work engagement in this crucial field. PMID- 25929015 TI - Removing barriers to promote more positive thinking for people with diabetes: implications for social work. AB - The purpose of this study is to understand changes in thinking in patients with diabetes and factors related to the health care providers and significant others that would mediate changes in thinking. Cross-sectional data were collected from three sites. Adults age 21 and older with type 2 diabetes were asked about their thinking regarding diabetes at diagnosis and the present time. In addition, respondents were asked questions about their perceptions of health care providers (that is, physicians, nurses, diabetes educators), significant others, and manage ment of diabetes. Significant other blame and self-efficacy were found to be partial mediators in thinking about diabetes; the model explained 29 percent of the variance. Social workers are uniquely trained in the person-in-environment framework, which allows flexibility in creating interventions to provide patients with diabetes the support necessary to have a more positive orientation toward diabetes self-management, increase self-efficacy, and reduce feelings of blame from significant others. Improving the support of significant others and the patients' level of self-efficacy can provide mediation of negative thinking, which may result in an environment that supports improved diabetes self management behaviors. PMID- 25929016 TI - Finding joy in social work. PMID- 25929017 TI - [Fat component in the diet and providing with fat-soluble vitamins]. AB - Information about the content of polyunsaturated fats (PUFAs) and vitamin E and D in fish, vegetable oils, trend data on consumption of the main fat products, the consumption of saturated and polyunsaturated fatty acids by patients with diseases which risk factor is the excessive consumption of fat and insufficient content of PUFA omega-3 in the diet. Nutrition of the Russian population is characterized by excessive consumption of fat, including saturated fatty acids. Despite increased consumption of PUFA at the present time the ratio of omega-6 and omega-3 fatty acids in the diet is not optimal. This is due to high consumption of vegetable oils (mainly sunflower oil), that are the major source of alpha-lino- lenic acid, only a small portion of which is converted in the body into DHA and EPA, and insufficient consumption offish and seafood containing a high level of DHA and EPA. Taking into account the data that inadequate intake of PUFA omega-3 is a risk factor for many nutrition-related diseases, there is no doubt necessary to modify the fat component of the diet. But the problems arise how to select the source of PUFA and avoid possible unwanted effects. Enrichment of the diet with PUFA omega-3 by inclusion offish oil and/ or linseed oil in the diet may lead to a deterioration of sufficiency with vitamin E. The way out of this situation is to create a fat module containing several fats and tocopherol, that will prevent the peroxidation of fat components of the product and prevent the deterioration of sufficiency with vitamin E. PMID- 25929018 TI - [Stress-induced indicators of hydrolytic function of the stomach and the pancreas in persons with various type of autonomic nervous system]. AB - The purpose of research is to study the influence of emotional stress on the activity of digestive enzymes in blood serum of individuals with different initial tone of the autonomic nervous system. Students' session acted as a model of emotional stress. Based on ritm-cardiografic testing according to the indicators of heart rate variability (HRV) 120 healthy young people (18-22 years old) were divided into 3 groups. Hardware-software complex "Varikard 2.51" has been applied to record the electrocardiography and heart rate variability analysis. Regulatory system tension has been selected as an indicator of autonomic balance index, that did not exceed 30 conventional units in student with vagotonia, ranged from 31 to 120 conventional units in normotonics and values from 121 conventional units characterized sympathicotonia. The interpretation of these parameters was carried out in accordance with the recommendations of the European Cardiology and North-American Society for electrophysiology, as well as the guidelines of Russian authors. The level of serum hydrolytic enzymes: 1 pepsinogen (PG 1), 2 pepsinogen (PG 2), amylase, lipase has been determined, the ratio PG 1/PG 2 was calculated. Investigations were carried out on an empty stomach in the day of workshops and during the examination session (emotional stress). The obtained data were statistically processed by variance analysis using the Student's t test. Individual variations were identified in hydrolytic activity of serum enzymes, depending on the original background level of the autonomic nervous system. It has been found that stress factors lead to opposite changes of digestive enzymes activity of blood serum, which were more pronounced in students with high baseline tone of sympatic nervous system. It has been determined that the amylolytic activity was increased in stress in all groups. A reduction in pepsinogen 2 level and lipolytic activity of blood serum has been showed in the group with simpathotony; while endocrine function of the gastric glands in the parasympatic and normotonic groups in terms of pepsinogen 2 increased. PMID- 25929019 TI - [Genetic rat models of type 2 diabetes for evaluation the effectiveness of minor biologically active food substances]. AB - The purposeful use of plant minor biologically active food substances (with demonstrated evident hypoglycemic, hypocholesterolemic and antioxidant action) in the composition of specialized dietary products can become the inno- vative approach for the dietary treatment of type 2 diabetes mellitus. Clinical testing of minor biologically active food substances of plant origin and their further use in the composition of specialized dietary products should be preceded by the stage of complex physiological and biochemical studies in vivo. It all turns on the question: to which extent the results obtained with the biomodel can be extrapolated on the human body. Hence, this review comparatively evaluates the rat models of type 2 diabetes. In this paper, we overview the most frequently used monogenic models of obesity with the damage of the leptin signaling path- way, when the animal loses control over saturation, hyperphagia and subsequent obesity appear. We describe polygenic models of obesity-related diabetes with fatty rats, which are more approximated to type 2 diabetes mellitus in humans. The characteristic of the type 2 diabetes model without obesity is given in the article: the SDT (Spontaneously Diabetic Torii) rats are genetically predisposed to glucose intolerance. Spontaneously Diabetic Torii-fa/fa (SDT fatty) rat is a new model of obese type 2 diabetes. Both male and female SDT fatty rats show overt obesity, and hyperglycemia and hyperlipidemia are observed at a younger age as compared with SDTrats. In conclusion, the SDT fatty rats are useful as a model for the development of new drugs and/or specialized dietary products to reduce body fat mass. PMID- 25929020 TI - [Evaluating the effectiveness of dietary management of patients with varying degrees of obesity]. AB - The purpose of the research is to study the efficiency of a low-calorie diet in treatment of patients with various degree of expressiveness of obesity. 605 patients (188 men and 417 women) with a body mass index > 25 kg/m2 at age 18-79 years have been examined. All patients underwent a complex clinical and instrumental and laboratory examination on the "Nutritest IP-2" system, including studying of clinical status dynamics, anthopometrical indicators, composite structure of a body, parameters of a power exchange and the laboratory indicators characterizing a condition of lipid, carbohydrate and protein metabolism. It has been revealed that low-calorie diet in combination with traditional curative measures ("Nutrikor IP-2") in obese patients significantly improved clinical status, central hemodynamics (blood pressure and heart rate), anthropometric parameters and body composition, lipid profile and parameters of metabolic status. In particular, systolic arterial pressure decreased authentically by 18- 19% (p < 0.00I), diastolic arterial pressure--was reliable for 16-17% (p < 0.001), heart rate authentically decreased by 7-12% (p < 0.001). Concentration of blood glucose authentically decreased at patients with obesity of I and II degrees--by 6% (p < 0.01), at patients with obesity of the III degrees--for 8% (p < 0.001). The reduction of fatty body weight in patients without obesity was 2.3%, in patients with I degree of obesity--3.1% (p < 0.001), in patients with II degree of obesity--3.4% (p < 0.001), and in patients with III degree of obesity- 4% (p < 0.001). It has been shown that the effectiveness of therapeutic interventions reduced according to the severity of obesity, that requires changes in the approach to the treatment of these patients, the search for new methods of drug and dietary management of this pathology. PMID- 25929021 TI - [Priorities in the development of specialized food products with optimized composition for patients with type 2 diabetes mellitus]. AB - The medical and biological rationale for the use of food ingredients in the development of specialized food products with optimized composition for patients with type 2 diabetes is given in the review. It is shown that the key aspects of the development of specialized foods for patients with type 2 diabetes are meeting the physiological needs of the patient in nutrients and biologically active substances, providing favorable metabolic effects of functional ingredients included in the product, maintaining the traditional quality of the enriched product, adjustment of the product composition in order to mitigate the possible changes caused by the introduction of functional ingredients. PMID- 25929022 TI - [The role of the Consultative and Diagnostic Centre "Healthy Nutrition" in the diagnosis and nutritional prevention of non-communicable diseases]. AB - In a consultative and diagnostic center "Healthy Nutrition" of Institute of Nutrition the nutritional status of 3500 patients (mean age 48.4 +/- 0.3 years) liv- ing in the Moscow region, using a system Nutritest IP-3, including genomic analysis has been examined. In the analysis of dietary intake by an average review, increased energy intake due to excess intake of the total (44.2% energy) and saturated fat (13.6%) has been shown. 30.0% of patients were overweight and 34.1% were obese. Osteopenia was detected in 31.0% of men and 25.0% women, osteoporosis--20.9% and 30.3%, respectively. Analysis of the results of biochemical studies revealed increased cholesterol in 68.7% of patients, LDL cholesterol--at 63.9%, triglycerides-- at 22.5%, glucose--at 29.4%. The frequency of the occurrence of risk alleles of genes associated with the development of obesity and type 2 diabetes mellitus was: 47.8%--for the polymorphism rs9939609 (FTO gene), 8.3%--for polymorphism rs4994 (gene ADRB3), 60.2%--for the polymorphism rs659366 (gene UCP2), 36.6%--for the rs5219 polymorphism in the gene of ATP-dependent potassium channel. PMID- 25929023 TI - [Bone mineral density in pregnant women from Moscow: possible effects of pregnancy dynamics and nutrient intake]. AB - Supporting of bone health is one of the main approaches to provide health in pregnant women considering intensive calcium and other mineral mobilization from mass bone that is necessary forforming fetus bone. This mobilization may lead to decrease of bone mineral density and development of osteopenia and osteoporosis. The important factors of development of bone impairment in pregnancy are nutrition and particular deficient consumption of protein, Ca, vitamin D. The possible role of reduced intake of pregnant women other nutrients remains unexplored. The aim of the research was estimating the prevalence of bone mineral density decrease in regard to the particular course of pregnancy and studying possible effects of key nutrients on bone mineral density in pregnant women. 131 women at different stages of pregnancy were involved in the survey. The bone density assessment was conducted using Bone Densitometer Omnisense 7000. As a criterion for bone density decrease in women used a Z-score, which was considered as normal to -1.0, as reduced from -1.0 to -2,0, and as significantly reduced when Z-score was less than -2,0. Analysis of the actual nutrition was performed by a 24-hour recording of 58 pregnant women. Normal bone mineral density was detected in 54 women or 41% of the total number of women surveyed. In 51 (39%) pregnant women reduced bone mineral density was discovered, and in 26 (20%) patients--significantly reduced bone density. There was a considerable deviation in pregnant patients' diet from the nutrition guidelines, which include, in particular, the high content of fat and saturated fatty acid, reduced intake of some micronutrients such as calcium, zinc, folic acid, beta-carotene, vitamins A, B1, E. However, differences in the actual consumption of nutrients in women with varying bone mineral density have been identified only in case of consumption of fat and energy value of diets, also Mn and I. So, it may be suggested that the differences in bone mineral density between women in our study are caused by genetic polymorphism, which leads to differences in the actual demand for nutrients, sufficient for prevention of bone decrease, in individuals. PMID- 25929024 TI - [Modification of carbohydrate composition of confectionery for diabetics type 2]. AB - Confectionery products are not staple foods, however, are an integral part of the daily diet of almost all age groups of population, including children and the elderly. Traditional confectionery are high-calorie foods that contain significant amounts of carbohydrates, the bulk of which is sucrose. One of the main requirements to the diet of patients with diabetes mellitus type 2, is limiting of easily digestible carbohydrates in the diet. Modification of the ingredient composition of confectionery products by eliminating or replacing sugar by other functional food ingredients should help to reduce the glycemic index and calorie content of these products. PMID- 25929025 TI - [Biotechnological optimization of nutrient composition of fermented dairy drink]. AB - The receipt based on the results of carried out studies is substantiated and technology of the new fermented dairy drink containing whole milk and whey with inulin (Jerusalem artichoke extract) and optimizing initial mineral composition of raw material has been developed. The starters ascertaining optimal organoleptic properties of the drink have been selected. It has been established that Jerusalem artichoke and its derivatives in the form of syrups and extracts stimulate fermentative processes of technological microflora, with maximum activity observed with Jerusalem artichoke extract. Physical-chemical and microbiological characteristics of the drink have been defined during storage. The possibility to optimize the nutrient composition of fermented dairy product by means of introducing of Jerusalem artichoke extract into milk-protein base has been demonstrated. It has been calculated that consumption of 100 g of fermented dairy drink enriched with Jerusalem artichoke extract makes it possible to satisfy the physiological needs (recommended daily allowance--RDA) for babies from 0 to 3 months in vitamins B1, B2 and B6 by 25-35% and in minerals P, K, and Ca by 20, 68, 34, 26%. For adults receiving 250 g of fermented beverage meets RDA for vitamins B1, B2 and B6 by 10-19% and in the macronutrients P, K, Ca-by 25 35%. Designed fermented dairy drink supplemented with natural plant ingredient possesses increased antioxidant activity and may be recommended for mass consumption without any limitations. PMID- 25929026 TI - [Study of biological value of beef produced by interspecies hybrids of domestic cattle and wild yaks]. AB - The comparative study of the chemical composition and biological values of beef produced by hybrids of Angus cattle with wild yaks (hybrid beef) and pure-bred Angus cattle (traditional beef) has been carried out. Longissimus muscle samples were used for analysis. It was observed, that the hybrid beef samples had the practically equal protein content comparing to traditional beef (21.1 vs. 21.6 per cent) but were characterized by the lower fat content (1.2 vs. 2.5 per cent). The higher biological value of hybrid beef comparing to traditional beef has been shown. The value of protein-quality index, calculated as the ratio of tryptophan amino acid to oxyprolin and characterizing the ratio of high biological value proteins to low biological value proteins was 8.1 vs. 5.7. The values of amino acid indexes [ratio of essential amino acids (EAA) to non-essential amino acids (NAA) and ratio of EAA to the total amount of amino acids (TAA)] were EAA/NAA = 0.77 vs. 0.65 and EAA/TAA = 0.43 vs. 0.39. The protein of hybrid beef was characterized by the higher content of a number of the essential amino acids: by a factor of 1, 77 for threonin, 1.23--for valin, 1.09--for lysin, 1.17--for leucine and 1.19--for tryptophan. The amount of the essential amino acids in 1 gram of protein of the hybrid beef was 434.7 mg against 393.1 mg for traditional beef It has been shown, that the protein of the hybrid beef comparing to traditional beef is characterized by the higher values of the amino acid scores calculated for EAA. PMID- 25929027 TI - [Sensory analysis. Study of influence of assessors training duration on the panel efficiency]. AB - The aim of this study was to evaluate the effectiveness of the assessors group at different stages of training and estimate the influence of the duration of their training on the quality of the data obtained. The optimal training duration to work with descriptive methods, which is necessary and sufficient for reproducible evaluation of sensory properties has been determined. The training was conducted at three stages during 108 hours. It has been demonstrated that statistically significant differences among products can be already determined by assessors after 8 hours of training. By increasing the training duration the effectiveness of assessors was improved. Completion of training course led to a significant reduction in the mean square error for some sensory characteristics of the products and the variability of the scores. PMID- 25929028 TI - [Aleksey Anatolyevich Korolev (to the 50th anniversary of birthday)]. PMID- 25929029 TI - [The Omsk hemorrhagic fever: research results (1946-2013)]. AB - The main aspects of epidemiology and epizootology of the Omsk hemorrhagic fever (OHF) are analyzed. The discovery of the virus OHF in 1947, as well as the first outbreak of new diseases in the districts of the Omsk region, is described. Comprehensive work for decryption of the etiology of the OHF by specialists from the Omsk and Moscow Institutes is carried out. Long-term dynamics of activity of natural foci of OHF contains four periods of variable intensity of epidemic and epizootic processes. The main reservoir of the virus OHF in natural foci and the source of human infection is muskrat. Metaxenosis provides maintaining of the population of the virus, which is of some significance for hosts. Independent position of the virus OHF in the group of the Flaviviruses of mammals transmitted by ticks is established. There are two aenovariants of the virus OHF. PMID- 25929030 TI - [Rubella virus genetic determinant of attenuation]. AB - Vaccination is the most effective and available way to prevent Rubella. Presently, 9 vaccine strains were registered. Nevertheless, the molecular mechanisms of the attenuation were poorly elucidated for the rubella virus. However, the study of these mechanisms identifying genotypic and phenotypic markers of attenuation, which together with sequence analysis could be used for the genetic stability control of vaccine strains, is still of current interest. Common trends of genetic changes in the process of adaptation to cold were found due to comparison of nucleic acid and amino acid sequences of the Russian strain C-77 with corresponding positions of the known rubella virus strains and its wild type progenitors, if available. PMID- 25929031 TI - [Complete genome analysis of the Batai virus (BATV) and the new Anadyr virus (ANADV) of the Bunyamwera group (Bunyaviridae, Orthobunyavirus) isolated in Russia]. AB - Almost complete nucleotide sequences for the S, M, and L segments were obtained for three strains of the Batai virus (Bunyamwera serogroup, genus Orthobunyavirus, Bunyaviridae family). Based on the results of the phylogenetic analysis conducted forthe three genomic segments LEIV Ast507 and LEIV-Ast528 strains were grouped with other European BATV isolates and were found to be almost identical to the strain 42 isolated from Volgograd Region, Russia, 2003. Surprisingly, LEIV-13395 strain isolated from the Aedes sp. mosquitos in Magadan Oblast, 1987, turned out to be a novel genotype inside Bunyamwera serogroup. The highest nucleotide identity levels of LEIV-13395 genomicsegments (86.9%, 80.8%, 79.7% for S, M and L segments respectively) were observed with corresponding segments of the Batai virus. PMID- 25929032 TI - [Engineering by reverse genetics and characterization of the new reassortant influenza virus strain H5N1]. AB - Reverse genetics was applied to engineering of the reassortantvaccine candidate strain against highly pathogenic avian influenza viruses (HPAIVs) of the H5 subtype. The new strain recPR8-H5N1 contains the HA gene from the Russian HPAIV A/Kurgan/05/2005 (H5N1), the NA and internal genes from A/Puerto Rico/8/34 (H1N1). The strain recPR8-H5N1 demonstrated the antigenic specificity (H5), high proliferation rate in 12 days chicken embryos, and was lethal for the embryos in 36 hours. An inactivated emulsified vaccine based on the strain recPR8-H5N1 elicited high antibody titers and protected 6-week-old chickens from lethal challenge with the HPAIV A/Kurgan/05/2005 (H5N1) on day 21 after single immunization. Infection of non-vaccinated birds with the strain recPR8-H5N1 did not cause any pathology, and the virus was not detected using PCR in blood and cloacal swabs on day 7 p.i. Specific weak seroconversion caused by infection with the strain recPR8-H5N1 was detected on day 14 p.i. As a result, a new influenza virus strain was obtained with modified properties. PMID- 25929033 TI - [Epitope analysis of the hemagglutinin molecule of the Victoria lineage influenza B viruses]. AB - A panel of five monoclonal antibodies (MAbs) to the HA1 molecule of the influenza B virus of the Victorian lineage with high virus-neutralizing activity was developed. For identification of the virus neutralizing epitopes in HA1 escape mutants (EM) of the influenza BIShandong/07/97 and B/Malaysia/2506/04 virus were selected using virus- neutralizing antibodies (MAbs). Three EMs had single, two- double and one--triple amino acid substitutions (AAS) in HA1 (H122N, A202E, K203T, K2031, K203N or A317V). In addition, AAS N197S was detected in three EMs. A correlation of AAS identified with peculiarities of interaction of EMs with Mabs was discussed. PMID- 25929034 TI - [Research of suppression of the herpes simplex virus reproduction with drug resistance by combination phosphite of acycloguanosine with some antiherpetic drugs]. AB - The activity of the phosphite of acycloguanosine (P-ACG) and six antivirals was tested individually and in double and triple combinations on two strains of the herpes simplex virus (HSV) type 1 (sensitive to acyclovir and resistant to acyclovir) using the CPE inhibition method in the Vero E6 cell microcultures. These are: phosphite of acycloguanosine (P-ACG), Ara-A, cidofovir (CDV), ribavirin (Rib), phosphonoformate (PFA), glycyrrhizic acid (GLN) and alpha interferon (alpha-IFN). All studied double combinations and triple combinations including P-ACV inhibited replication of both HSV strains more effectively than any drug alone. Various types of interactions depending on the virus type were observed in both viral models: synergistic (double combinations P-ACG with PFA, CDV, Rib, alpha-IFN and triple combinations P-ACG with alpha-IFN +PFA, alpha-IFN +AraA, alpha-IFN +CDV, PFA+CDV, PFA+Rib, CDV+AraA, CDV+Rib, CDV+GLN,PFA+AraA) and additive (P-ACG with AraA and PFA+GLN). Neither antagonism nor interference was noted for any combinations. Adduced results suggest that these combinations might be clinically useful for the treatment of certain herpes simplex virus type 1 infections. PMID- 25929035 TI - [Frequency of the occurrence of spliced variants of the messenger RNA DR3/LARD in herpesviral infection]. AB - Analysis of frequency of the occurrence of membrane and soluble forms of the mRNA DR3/LARD in blood in herpesviral infection of various etiology was studied. Four forms of the mRNA DR3/LARD were detected with various frequencies in blood cells of healthy volunteers. Patients with herpesviral infection of various etiology were studied using RT-PCR. Two forms encoded membrane molecules (mRNA LARD 1a, mRNA DR3beta) and two other forms accorded soluble forms of receptor (mRNA LARD 3, mRNA soluble DR3beta). It was revealed that the frequency of the occurrence of mRNA soluble DR3beta form decreased in patients with the varicella zoster virus (VZV) infection in comparison with healthy volunteers. However, the patients with the Epstein-Barr virus (EBV) and cytomegalovirus (CMV) infection did not display significant change in occurrence of mRNA soluble DR3beta form. As a whole, changes in frequency of occurrence of spliced variants of mRNA DR3/LARD are directed toward modulation of apoptosis and restraint antiviral immune response. PMID- 25929036 TI - [An ELISA system based on the specific class Y (IgY) antibodies from egg yolks for the quantitative determination of D-antigen in inactivated poliovirus vaccines]. AB - The results of the construction of the first Russian ELISA system for the quantitative determination of D-antigen of 1-3 poliovirus types in the preparations of inactivated poliovirus vaccines are presented. For the first time, this kind of system is based on the use of specific antibodies of class Y (IgY) from egg yolks of immunized hens. It was shown that this ELISA system is specific, sufficiently sensitive, and can be used for quantitative determination of D-antigen of 1-3 poliovirus types in inactivated poliovirus vaccines. PMID- 25929037 TI - [Assessment of epidemic manifestations of the West Nile fever in the Volgograd region depending on the climatic conditions]. AB - Results of the analysis of the increase in the incidence of epidemic of the West Nile fever and climate conditions in the Volgograd region were presented. Certain seasonal periods and threshold values of temperature and humidity statistically associated with the epidemic rise were identified. The discussion of the probable mechanisms of indirect effects of atmospheric heat on the elements of the epidemic process was carried out. PMID- 25929038 TI - [Simulation and influencing factors of spatial distribution of PM2.5 concentrations in Chongqing]. AB - Land use regression model (LUR model) was used to simulate the spatial distribution of PM2.5 concentrations in Chongqing with the software of ArcGIS. This research was conducted with a total of 17 PM2.5 concentrations of monitoring points from 17 air quality monitoring stations recorded in the official website of Chongqing Environmental Protection Bureau. Among them, 16 were chosen as the dependent variables, and the last one was chosen for land use regression model validation test. At each site location, we constructed circular buffers with ArcGIS and captured information on roads, population, land use and DEM. Based on the buffer information, 56 potential geographic predictors were built. Finally 3 variables: cropland area within 500 m of the air quality monitoring sites, the site locations' DEM and primary road length within 1 000 m of the 56 predictors were left for predicting 84% of the variation of PM2.5 concentrations and the Pearson coefficients between the 3 variables and PM2.5 concentrations were 0.695, - 0.599 and 0.394, respectively. The validation test result showed that the spatial distribution map of PM2.5 predicted extremely well with an error rate of only 0.027. And the return map results showed: (1 ) PM2.5 concentrations were high in the center of the main city; (2) PM2.5 concentrations were high along the road and (3) the distribution was closely correlated to the DEM of sampling locations. PMID- 25929039 TI - [Correlation, seasonal and temporal variation of water-soluble ions of PM2.5 in Beijing during 2012-2013]. AB - A total of 486 daily PM2.5 samples were collected at a background site, 3 urban sites, 4 suburban sites and a boundary transfer site during August 2012-July 2013. Mass concentrations of 9 water-soluble ions were obtained. The average mass concentration of the 9 ions was 60.5 MUg x m(-3), and the order of concentration of ions was NO3- > SO4(2-) > NH4(+)- > Cl- > Na+ > K+ > Ca2+ > F- > Mg2+; Secondary inorganic species NO3-, SO4(2-) and NH4+ were the major components of water-soluble ions in PM2.5, with a contribution of 88% to the total ions of PM2.5. NO3- was the most fluctuated anion during the sampling period. With the increase of pollution level, the accumulation of SNA was obvious, the components that contained nitrogen, NO3- and NH4+, occupied the dominant position in the formation of the secondary components. NO3- had a relatively higher contribution to the accumulation of heavy pollution. PMID- 25929040 TI - [Characteristics and sources apportionment of OC and EC in PM1.1 from Nanjing]. AB - The concentrations of OC and EC in PM1.1 collected from Nanshi (NS) and Nanhua (NH) in 2011 were analyzed using DRI Model 2001A Thermal Optical Carbon Analyzer. In addition, source apportionment was simultaneously evaluated. The results showed that the annual average concentrations of OC and EC in PM1.1 were 10. 10 MUg x m(-3) and 2.52 MUg x m(-3) in NS area, and 11.22 MUg x m(-3) and 3.12 MUg x m(-3) in NH area, respectively. This result indicated that OC and EC pollution in NH was more serious than that in NS area. Meanwhile, the concentrations of OC and EC in winter and spring were obviously higher compared to those in summer in these two sampling sites, which was mainly ascribed to the increased coal combustion and the unfavorable emission condition of air pollutants in summer and spring. We noted that the SOC/TOC value was the highest in summer and the lowest in winter. In addition, the SOC concentration was observed to show a positive correlation with ozone concentrations, which indicated that the photochemical reaction was a main way of SOC formation in autumn. PMID- 25929041 TI - [Composition and variation characteristics of atmospheric carbonaceous species in PM 2.5 in Taiyuan, China]. AB - Day-night variation characteristics of organic carbon (OC) and elemental carbon (EC) in atmospheric fine particles (PM2.5) collected during winter of 2009 and spring of 2010 in Taiyuan city were analyzed using DRI Model 2001A Thermal/Optical Carbon Analyzer, and the sources of carbonaceous materials in PM2.5 were analyzed. The results showed that the average concentrations of PM2.5, OC, EC and average OC/EC ratios were all higher during winter [(289.2 +/- 104.8) MUg x m(-3), (65.2 +/- 22.1) MUg x m(-3), (23.5 +/- 8.2) MUg x m(-3) and 2.8 +/- 0.3] than during spring [(248.6 +/- 68.6) MUg x m(-3), (29.7 +/- 6.2) MUg x m( 3), (20.2 +/- 5.4) MUg x m(-3) and 1.5 +/- 0.3], higher in nighttime [(309.3 +/- 150.0) MUg x m(-3), (74.6 +/- 19.5) MUg x m(-3), (24.3 +/- 6.6) MUg x m(-3) and 3.1 +/- 0.3] than in daytime [(234.9 +/- 122.1) MUg x m(-3), (54.9 +/- 28.2) MUg x m(-3), (22.6 +/- 10.8) MUg x m(-3) and 2.5 +/- 0. 5] during winter while higher in daytime [(292.5 +/- 120.8) MUg x m(-3), (32.7 +/- 10.5) MUg x m(-3), (22.7 +/- 10.1) MUg x m(-3) and 1.6 +/- 0.5] than in nighttime [(212.3 +/- 36.7) MUg x m( 3), (29.6 +/- 6.6) MUg x m(-3), (20.7 +/- 6.4) MUg x m(-3) and 1.5 +/- 0.2] during spring. This result was explained by the fact that winter is a "heating season", especially in nighttime, emission of carbonaceous particles was increased because of the increase of coal and biomass combustion and diffusion of pollutants was difficult because of low atmospheric temperature and stable atmospheric conditions; and high OC/EC was caused by increase of OC emission but not contribution of secondary organic carbon (SOC) since low temperature and weak solar radiation were not favorable for the formation of SOC. The higher concentrations of PM2.5, OC and EC in daytime than in nighttime during spring might be due to more dust in daytime because of higher wind speed and lower relative humidity in daytime than in nighttime, and the higher OC/EC in daytime than in nighttime might be caused by higher temperature and stronger solar radiation in daytime, which were favorable for the formation of SOC. Comparing with other cities in China, Taiyuan showed high concentrations of PM2.5, OC and EC, indicating serious carbonaceous aerosol pollution which may significantly contribute to the formation of dust-haze. PMID- 25929042 TI - [Characteristics of organic carbon and elemental carbon in PM2.5 in Shuozhou City]. AB - PM2.5 samples were collected at four sampling sites in Shuozhou during the heating and non-heating periods. Organic carbon (OC) and elemental carbon (EC) in PM2.5 were analyzed by Elementar Analysensysteme GmbH vario EL cube and the concentration, spatial and temporal distribution characteristics and main sources of OC and EC were studied. The results were as following: average concentrations of OC and EC in PM2.5 during non-heating period were (14.3 +/- 2.7) MUg x m(-3) and (10.3 +/- 3.1) MUg x m(-3) while (23.3 +/- 5.9) MUg xm(-3) and (20.0 +/- 5.7) MUg x m(-3) during heating period. The concentrations of OC and EC at four sites during the heating period were higher than those during the non-heating period. The concentrations of OC and EC at SW site during heating were the highest which were 28.5 MUg x m(-3) and 28.1 MUg x m(-3) while the concentrations at PS sites during non-heating period were the highest, which were 17.7 MUg x m(-3) and 14.1 MUg x m(-3). The ratios between OC and EC during the heating and non-heating period were all below 2 and the correlation between OC and EC was not good with R2 of 0. 66 during heating period and 0.52 during non-heating period which indicated that sources of carbon aerosols were complex. Carbonaceous aerosol pollution should be reduced by controlling the primary emissions such as coal combustion, vehicle exhaust and biomass burning, and by paying attention to secondary pollution at the same time to improve the air quality in Shuozhou City. The concentrations of SOC during heating and non-heating period were (6.44 +/- 2.77) MUg x m(-3) and (4.11 +/- 1.92) MUg x m(-3). PMID- 25929043 TI - [Satellite retrieval of a heavy pollution process in January 2013 in China]. AB - By simulating vertical stratification data of PM2.5 with the third-generation air quality model CMAQ and high resolution relative humidity data with mesoscale meteorological model WRF, MODIS AOD data were revised by vertical and humidity correcting method, respectively. A linear regression model between revised AOD and PM2.5 was built, and the linear correlation coefficient was r = 0.77 (n = 57, P < 0.01). Based on this model, the average monthly concentrations of PM2.5 in 10 km resolution in January 2013 were firstly retrieved in the country, and the population exposure level was analyzed. The results showed that the areas where average monthly concentrations of PM2.5 was greater than 100 MUg x m(-3) and 200 MUg x m(-3) in January 2013 were 10.99% and 1.34% of the national terrestrial area, respectively, and the ratios of exposed population were as high as 45.01% and 6.31%, respectively. PMID- 25929044 TI - [Meteorological mechanism for the formation of a serious pollution case in Beijing in the background of northerly flow at upper levels]. AB - There is a kind of serious air pollution case occurring in the situation of northerly flow at the levels above 850 hPa in Beijing area. Meteorological data, NCEP reanalysis data and PM2.5 concentration survey were used to analyze the roles of meteorological mechanism in this kind of air pollution case. The results showed that the stable stratification did not exist all the time during the gradual increase of PM2.5 concentration. The favorable meteorological conditions in PM2.5 accumulation came from the layered structure of vertical speed and convergence in vertical direction. From the surface to the middle level of troposphere, the vertical velocity showed an updraft-downdraft-updraft distribution. And the divergence displayed a convergence-divergence-convergence structure. The convergence at lower levels led to the gathering of the polluted air from the surrounding and the ascending current brought it upwards. However, the polluted air could not go further up due to the prolonged downdraft layer above. As the result, PM2.5 near the surface was concentrated gradually. The vertical speed in layer structure was attributed to the high level northerly flow without invading into the boundary layer. In such case, the wind was still in southerly direction or kept calm at the surface. The weak cold air or no cold air at all was the main reason that the northerly flow could not hit the surface. The developed downdraft layer was relative to the convergence above which was resulted from the wind speed pulses in the northerly flow at upper levels. In conclusion, the air dynamical effect played a key role in the pollution type of northerly flow at upper levels. Therefore, it will be beneficial to enhance our capability in the analysis and forecasting of this kind of pollution case by focusing on 24 hours temperature variation at the middle and lower troposphere as well as the vertical distribution of vertical velocity and divergence. PMID- 25929045 TI - [Concentrations and deposition fluxes of different mercury species in precipitation in Jinyun Mountain, Chongqing]. AB - Concentrations of mercury (Hg) species in precipitation were measured during the period from April 2013 to March 2014 in Jinyun Mountain, Chongqing, and corresponding deposition fluxes were also estimated. The result showed that the ranges of concentration of total mercury (THg) , dissolved mercury (DHg), particulate mercury (PHg), reactive mercury (RHg), total methyl mercury (MeHg), dissolved methyl mercury (DMeHg), particulate methyl mercury (PMeHg) were 7.47 120.11, 2.51-43.03, 2.28-77.99, 0.14-15.14, 2.58 x 10(-2)-101.62 x 10(-2), 0.30 x 10(-2)-72.29 x 10(-2), and 1.45 x 10(-2)-63.55 x 10(-2) ng x L(-1), respectively. And their estimated annual deposition fluxes were 42.71, 23.51, 19.20, 5.87, 0.61, 0.34 and 0.27 MUg x (m2 x a)(-1), respectively. The proportion of MeHg in THg ranged from 0.07% to 3.79% with a mean value of 1.34%, and both PHg and PMeHg in precipitation accounted for approximately 50% of THg (ranged from 10.49% to 89.30%) and TMeHg (ranged from 4.31% to 98.86%). Obvious seasonal variations of Hg concentrations and deposition fluxes were observed, with the highest VWM levels of THg, DHg and PHg occurring in winter and the lowest value occurring in summer. And the RHg concentrations in precipitation in winter and spring were significantly higher than those found in summer and autumn. The variations of deposition fluxes of THg, DHg, MeHg, DMeHg had a similar seasonal trend with the rainfall, decreasing from spring to summer and to autumn and then to winter. The maximum deposition fluxes of RHg also appeared in spring and the minimum value occurred in winter. The wet deposition of Hg in Jinyun Mountain was influenced by rain amount, rainfall frequency and other meteorological conditions. Hg levels in the precipitation were also affected by human activities. PMID- 25929046 TI - [Variation characteristics of total gaseous mercury at Wuzhi mountain (Wuzhishan) background station in Hainan]. AB - Total gaseous mercury (TGM) was continuously monitored at Wuzhi mountain (Wuzhishan) using the high-resolution automatic atmospheric mercury vapor analyzer (Tekran 2537B) from May 2011 to May 2012. The annual geometric mean TGM concentration was (1.58 +/- 0.71) ng x m(-3), suggesting that the atmosphere was not obviously polluted. The TGM level at WuZhi mountain remained low from June to August in 2011 and from March to May in 2012, while higher values were observed from September in 2011 to January in 2012. Tropical monsoons played an important role in the monthly variation of TGM. TGM concentrations showed a clear diurnal trend with the minimum concentration occurring at 09:00 AM and the peak concentration at 19:00 PM due to the combined impact of the long-range transport of atmospheric mercury and local meteorological conditions. The temporal trend of TGM highlighted the impact of long-range transport from the mainland of China on the distribution of TGM in ambient air at Wuzhi mountain by the results of backward trajectory analysis using HYSPLIT. PMID- 25929047 TI - [Organic and element carbon in foliar smoke]. AB - A home-made combustion and sampling apparatus was used to burn green leaves under flaming and smoldering conditions and to collect the smoke generated. The smoke was measured with Organic/Elemental Carbon (OC/EC) Analyzer using IMPROVE thermal optical reflectance (TOR) method, to investigate the mass fractions and the distribution of OC, EC and eight carbon fractions in foliar smoke. The results showed that in smoldering condition, the mean OC, EC mass fractions of ten foliar smokes were 48.9% and 4.5%, respectively. The mean mass fraction of char-EC (EC1 POC) was 4.4%. The average emission factors (EF) of particulate matters, OC and EC in smoldering foliar smoke were 102.4 g x kg(-1), 50.0 g x kg(-1) and 4.7 g x kg(-1), respectively. The mean ratios of OC/EC, OC1/OC2 and char-EC/soot-EC (EC1 POC/EC2 + EC3) in this condition were 11.5, 1.9 and 48.1, respectively. For the foliar smoke emitted in flaming condition, the mean mass fractions of OC, EC and char-EC were 44.9%, 10.9% and 10.7%, respectively. The average EF of PM, OC and EC in flaming smoke were 59.2 g x kg(-1), 26.6 g x kg(-1) and 6.0 g x kg(-1). And the three ratios mentioned above in this condition were 4.8, 1.1 and 133.0, respectively. In conclusion, foliar smoke had higher OC1 mass fractions and OC1/OC2 values in smoldering condition. While flaming foliar smoke had higher char-EC mass fractions and char-EC/soot-EC values. The compositions of OC, EC in foliar smoke varied between different tree species and different combustion conditions. The composition was also obviously different from those of other biomass smoke. PMID- 25929048 TI - [Analysis of characteristics and products of chlorobenzene degradation with dielectric barrier discharge]. AB - For non-biodegradable volatile organic compounds (VOCs) with low water solubility, the tradition biological method can not achieve a satisfactory removal efficiency, so development of high efficiency pre-treatment technology is a hot issue of research. In this experiment, using poor biodegradable chlorobenzene as the target pollutant and dielectric barrier discharge (DBD) non thermal plasma as the pretreatment technology for biotrickling filter (BTF) , the effect of DBD on the degradation of chlorobenzene was studied by adjusting the technical parameters of DBD. The effects of the inlet concentration, residence time, humidity and peak voltage on decomposition efficiency were investigated and the decomposition products of chlorobenzene were analyzed. Experimental results showed that DBD could effectively remove waste gaseous chlorobenzene, the removal rate of chlorobenzene increased with the increasing peak voltage. When the peak voltage was >= 12kV, less effect of residence time on the degradation of chlorobenzene was found. The optimal humidity range of degradation chlorobenzene was 65% - 75%. Through the analysis of degradation products, the species and concentrations of degradation products increased with the increase of discharge voltage. The products were mainly consisted of organic acids and chlorinated hydrocarbons. The water solubility of degradation products was preferable. Furthermore, with the increase of discharge voltage, the biodegradability of degradation products became higher and higher and the biological toxicity was reduced. It had a promoting effect on the degradation of chlorobenzene when the voltage reached 20 kV. Meanwhile, the O3 concentration increased with the increasing discharge voltage and also enhanced with the rising humidity under the same voltage. PMID- 25929049 TI - [Distribution, sources and risk assessment of polycyclic aromatic hydrocarbons (PAHs) in surface sediments of Yangtze estuary and Zhejiang coastal areas]. AB - PAHs contents of surface sediments were tested from 62 sampling sites of the Yangtze River estuary and Zhejiang coastal zone in 2013. The results showed that: 16 kinds of PAHs, which are listed as priority pollutants by EPA, were found in all the samples. The total PAHs level (dry weight) reached 31. 8-384 MUg x kg(-1) and the average amount was 131.1 MUg x kg(-1). The distribution of PAHs was affected by terrigenous input and point source pollution, the high-value zones were found at 2# sampling site of the Yangtze River estuary and 21# sampling site of Ningbo. Compared with other sea areas, the survey sea area was at a low PAHs pollution level. PAHs were primarily tetracyclic or tricyclic, and source analysis showed that most of PAHs were originated from combustion of wood and coal. Based on the Sediment Quality Guidelines (SQGs), the assessment result showed that the PAHs content of surface sediments from survey sea area was at a relatively low level of ecological risk; While according to the assessment result of the Sediment Quality Standards (SQSs), PAHs pollution of surface sediments from survey sea area displayed an "Obviously negative ecological effect" to some extent, and some countermeasures are required to control and eliminate pollutions. PMID- 25929050 TI - [Adsorption characteristics of typical PPCPs onto river sediments and its influencing factors]. AB - A batch equilibrium method was used to investigate the adsorption characteristics of ciprofloxacin (CIP), tetracycline (TC), sulfamethoxazole (SMX) and triclosan (TCS) onto Huangpu River sediments. Effects of adsorption time, initial concentration, solution pH and temperature on the adsorption process were studied. The results showed that the adsorption process of these PPCPs onto sediments was a two-step process: a rapid adsorption followed by a slow balance. The equilibrium time was about 4 h. The pH value had a significant effect on the adsorption of CIP, TC and TCS, whereas the effect on SMX adsorption was negligible. The kinetic results indicated that the adsorption processes followed the pseudo-second-order model, with adsorption rate in the range of 4.89 x 10(-3) 1.96 x 10(-2) kg x (min x mg)(-1). Adsorption isotherms were well described by the Freundlich and linear equations. As temperature increased, the amount of SMX and TC adsorbed increased, whereas CIP and TCS decreased. CIP, TC and TCS had a strong tendency to adsorb onto sediments, while the adsorption of SMX was unfavorable. When the initial concentration of PPCPs was 10 mg x L(-1), the equilibrium adsorption capacities of CIP, TC, SMX and TCS reached 702.8, 733.1, 54.7 and 695.0 mg x kg(-1), respectively. PMID- 25929051 TI - [Contamination and ecological risk assessment of polycyclic aromatic hydrocarbons in surface sediment in karst underground river]. AB - In order to understand pollution characteristics and ecological risk of polycyclic aromatic hydrocarbons (PAHs) in surface sediment from Laolongdong underground river, the concentration and composition of 16 priority PAHs were analyzed. The results showed that the total concentrations of PAHs ranged from 58.2 to 3 598 ng x g(-1), and most of the values were between 100 and 5 000 ng x g(-1). It means that sediments in the river were moderately and heavily polluted by PAHs. The PAH composition were dominated by 2-4 rings (accounted for 75.1%) compounds in Laolongdong, while 4-6 rings PAHs accounted for 56.6% in Xiannvdong. Sediments in Laolongdong mainly came from the transportation of the upstream water and surface soil. 2 - 3 rings PAHs had higher transport capability with farther migration distance, while 4-6 rings PAHs had lower transport capability and shorter migration distance in the conduit, because 4-6 rings PAHs could be easily absorbed by sediments. The result of ecological assessment of PAHs showed that the ecological risk level in Laolongdong was low, leading to little negative ecological impact. However, the level in Xiannvdong was high. Once PAHs migrated from upstream to downstream, it would result in ecological threat for the downstream area. PMID- 25929052 TI - [Contamination characteristics and source analysis of polycyclic aromatic hydrocarbons in multimedium in karst underground river]. AB - In order to understand the contamination characteristics of PAHs in different environmental mediums of karst underground river, the authors chose the Qingshuiquan underground river as the study object. Based on the data of air, groundwater, sediment and soil samples collected during the same period from 2013 to 2014, contrastive analysis was conducted in light of the component spectra, the distribution features and the characteristic ratios as well as the chemical and physical properties of 16 kinds of PAHs. The results showed that 3 kinds of PAHs with 2-3 rings (naphthalenes, phenanthrene and fluoranthene) were dominant in the air and underground river water, which accounted for 71.66% and 54.84% of the total PAHs. And PAHs with 4-6 rings were dominant in the soil and sediment of the underground river, which accounted for 54.26% and 65.06% of the total .PAHs. The distribution of PAHs in environmental mediums along the underground river indicated that the mean concentration PAHs in upstream area was less than that of midstream, and that of midstream was less than that of downstream, because of pollution discharge and absorption. The ratios of specific PAHs indicated that the PAHs sources in upstream rural area mainly came from the combustion of grassy, wood and coal, the PAHs sources in Ganhuai village were mainly originated from petroleum, and the PAHs sources in the outlet of the underground river mainly came from both petroleum and its combustion. PMID- 25929053 TI - [Characteristics of absorption and fluorescence spectra of dissolved organic matter from confluence of rivers: case study of Qujiang River-Jialing River and Fujiang River-Jialing River]. AB - Three-dimensional fluorescence spectroscopy combined with ultraviolet-visible (UV Vis) absorption spectra was used to investigate the change characteristics of dissolved organic matter (DOM) in confluences water of Qujiang River-Jialing River and Fujiang River-Jialing River, respectively. The results suggested that DOM showed a significant terrestrial input signal in all the sampling sites, FI < 1.4, HIX > 0.8, possibly representing remarkable signals of humus resulted from humic-like component. Moreover, the mixing zone of this study showed a non conservative mixed behavior, which had a limited contribution, and was not the dominant factor to interpret the change characteristics of DOM in confluences zones. Different land-use types along all the rivers had an obvious impact on DOM inputs. Results of cluster analysis showed that a higher degree of aromaticity and humification components was observed as the predominant contributor to DOM when the land-use type was forest and farmland ecosystem, for example the confluences of Qujiang River-Jialing River. On the other hand, high concentrations of DOM with relative simple structures were found in the water when the urban land-use type was predominant, for example the confluences of Fujiang River-Jialing River. Meanwhile, a new fluorescent signal of protein-like components (peak T) appeared, which manifested a significant effect on the water quality resulted from anthropogenic activities. PMID- 25929054 TI - [Ultraviolet-visible (UV-Vis) and fluorescence spectral characteristics of soil dissolved organic matter (DOM) in typical agricultural watershed of Three Gorges Reservoir Region]. AB - As an important geo-factor to decide the environmental fate of pollutants in watershed, soil dissolved organic matter (DOM) sampled from a typical agricultural watershed in the Three Gorges Reservoir area was investigated using ultraviolet-visible (UV-Vis) and fluorescence spectroscopies, to analyze and discuss the effect of different land uses including forest, cropland, vegetable field and residence, on soil DOM geochemical characteristics. The results showed that significant differences in DOM samples amongst different land uses were observed, and DOM from forest had the highest aromaticity and humification degree, followed by DOM from cropland. Although DOM from vegetable field and residence showed the highest dissolved organic carbon (DOC) concentration (average values 0.81 g x kg(-1) and 0.89 g x kg(-1), respectively), but the aromaticity was lower indicating lower humification, which further suggested that the non-chromophoric component in these DOM samples contributed significantly to total DOM compositions. Additionally, in all DOM samples that were independent of land uses, fluorescence index (FI) values were between 1.4 (terrigenous) and 1.9 (authigenic) , evidently indicating both the allochthonous and autochthonous sources contributed to DOM characteristics. Meanwhile, r(T/C) values in most of samples were higher than 2.0, suggesting that soil DOM in this agricultural watershed was heavily affected by anthropogenic activities such as agricultural cultivation, especially, vegetable field was a good example. Additionally, sensitivities of different special spectral parameters for reflecting the differences of DOM characteristics amongst different land uses were not identical. For example, neither spectral slope ratio (S(R)) nor humification index (HIX) could clearly unveil the various geochemical characteristics of soil DOM from different sources. Thus, simple and single special spectral parameter cannot comprehensively provide the detailed information of DOM, and combined application of UV-Vis and fluorescence spectroscopies is highly recommended. PMID- 25929055 TI - [Absorption and fluorescence characteristics of dissolved organic matter (DOM) in rainwater and sources analysis in summer and winter season]. AB - This study aimed at evaluating the variability of the optical properties including UV-Vis and fluorescence characteristics of dissolved organic matter (DOM) from rainwater in summer and winter seasons. UV-Vis and fluorescence spectroscopy, together with Hybrid Single-Particle Lagrangian Integrated Trajectory (HYSPLIT) model and fire events map, were conducted to characterize DOM and investigate its sources and contributions. The results showed that as compared with aquatic and soil DOM, rainwater DOM showed similar spectral characteristics, suggesting DOM in precipitation was also an important contributor to DOM pool in terrestrial and aquatic systems. The concentrations of DOC in rainwater were 0.88-12.80 mg x L(-1), and the CDOM concentrations were 3.17-21.11 mg x L(-1). Differences of DOM samples between summer and winter were significant (P < 0.05). In comparison to summer, DOM samples in winter had lower molecular weight and aromaticity, and also lower humification. Input of DOM in winter was predominantly derived from local and short-distance distances, while non-special scattering sources were identified as the main contributors in summer. Although absorption and fluorescence spectroscopy could be used to identify DOM composition and sources, there were obvious differences in spectra and sources analysis between rainwater DOM and the others from other sources. Thus, the classic differentiation method by "allochthonous (terrigenous) and autochthonous (authigenic)" is possibly too simple and arbitrary for characterization of DOM in rainwater. PMID- 25929056 TI - [Composition of NOM in raw water of Danjiangkou Reservoir of South-to-North Water Diversion Project and comparison of efficacy of enhanced coagulation]. AB - The best enhanced coagulation conditions for the raw water of Danjiangkou Reservoir of South-to-North Water Diversion Project and the molecular weights as well as hydrophobicity composition of Natural organic matter (NOM) in the water were investigated in this study. The results showed that the NOM in the raw water of Danjiangkou Reservoir of South-to-North Water Diversion Project was mainly composed of the fraction with a molecular weight of < 1 000 and transphilic components. Dissolved organic carbon (DOC, 39.98%) and UV254 (39.10%) were the major components. And the fraction with a molecular weight of < 1 000 had the highest contents of THMFP and N-DBPFP. In the raw water of Danjiangkou Reservoir, the sum of transphilic and hydrophobic fractions was up to 80%, and the hydrophobic fraction was the minimum contributor of the NOM, but the THMFP of the hydrophobic fraction had the highest percentage. And when the raw water of Danjiangkou Reservoir was treated using polymeric ferric sulfate (PFS, 4 mg x L( 1)) and poly-acrylamide (PAM, 0.4 mg x L(-1)) , the optimal removal rates of turbidity, DOC, UV254 and THMFP were 76.33%, 25.57%, 37.78% and 23.16%, respectively. The results of this paper can provide theoretical and technological basis for upgrading of the process and operation optimization of original drinking water treatment plants in the intake area of South-to-North Water Diversion Project. PMID- 25929057 TI - [Denitrification in water of Daliao River estuary in summer and the effect of environmental factors]. AB - Ratios of nitrogen loss and N2O production by denitrification were observed in Daliao River and the estuary in summer 2013. The results showed that the concentrations of N and P in the main stream of Daliao River were significant higher than those in the estuary (P < 0.05). Decrease of nutrients concentration in the estuary might be integrally caused by water diluting and biogeochemical processes. The net increase of dissolved N2 (DeltaN2) ranged between -11.01 and 71.37 MUmol x L(-1), in which the negative values were mostly determined in the main stream of the river, indicating the consumption amount of N2 was higher than the production in the fresh water. The mean ratio of N2O production during the process of denitrification was about 0.007%, and the N2O flux across water-air interface was about 0.04% of the total fluxes (N2O + N2). In this study, DeltaN2 was not related with DO, while exhibited a significant positive correlation with water temperature and salinity, and a negative correlation with NO3-. This suggests that denitrification was not totally regulated by DO level in the estuary, and coupled nitrification-denitrification was the main denitrification process. Finally, we estimated that 26% of the TN, 37% of the DIN, and 43% of the NO3- were removed by denitrification in the Daliao River estuary based on the ratio of DeltaN2 to N concentrations. PMID- 25929058 TI - [Sources of dissolved organic carbon and the bioavailability of dissolved carbohydrates in the tributaries of Lake Taihu]. AB - Surface water samples of Yincungang and Chendonggang Rivers were collected from September 2012 to August 2013 in Lake Taihu. Water temperature, Chlorophyll a and bacterial abundance were analyzed, as well as dissolved organic carbon (DOC) concentrations, stable carbon isotope of DOC (Delta13C(DOC)), specific UV absorbance (SUVA254 ) and dissolved carbohydrates concentrations. Delta13C(DOC) ranged from -27.03% per thousand +/- 0.30% per thousand to -23.38%per thousand +/ 0.20% per thousand, indicating a terrestrial source. Both the autochthonous and allochthonous sources contributed to the carbohydrates pool in the tributaries. Significant differences in PCHO (polysaccharides) and MCHO (monosaccharides) concentrations were observed between spring-summer and autumn-winter (P < 0.01, n = 12; P < 0.01, n = 12), which might be caused by the variation in the sources and bioavailability of carbohydrates. PCHO contributed a major fraction to TCHO (total dissolved carbohydrates) in autumn and winter, which could be explained by the accumulation of undegradable PCHO limited by the low water temperature; MCHO contributed a major fraction to TCHO in spring and summer, which might be caused by the transformation from PCHO by microbes at high water temperature. PMID- 25929059 TI - [Canonical correspondence analysis of summer phytoplankton community and its environmental factors in Hanfeng Lake]. AB - The phytoplankton community in Hanfeng Lake Reservoir, located in the Three Gorges Reservoir Areas of Yangtze River, was investigated from Jun to August 2013. The results showed that 72 species belonging to 7 phyla of phytoplankton were detected in the water. The dominant species were Synedra, Navicula, Melosira, Cocconeis, Scenedesmus, Pseudoanabaena and Merismopedia. The phytoplankton at the entrance of Donghe River was mainly composed of Bacillariophyta, while that at the entrance of Nanhe River was dominated by Cyanophyta and Chlorophyta. Canonical correspondence analysis was applied to investigate the relationships between the distribution of phytoplankton and the environmental factors. The results showed that the species of phytoplankton at the entrance of the Donghe River were influenced by the physiochemical properties of the water, while those at the entrance of Nanhe River were affected by the nutrient status of the water. The key factors influencing the distributions of phytoplankton were temperature, dissolved oxygen (DO), pH, total nitrogen (TN), dissolved nitrogen (DN) and dissolved phosphorus (DP). PMID- 25929060 TI - [Temporal variation of trophic status in drawdown area of Hanfeng Lake in the storage period of Three Gorges Reservoir in China]. AB - In order to explore the temporal variations of nutrient and biomass in drawdown area of Hanfeng Lake of the Three Gorges Reservoir region, this paper continuously observed the water quality in the storage period of 2013 October to 2014 February. And the concentrations of nutrients, water physical parameters and chlorophyll were determined. The results showed that the concentrations of nutrients and chlorophyll increased, and the nutrition degree increased after the flooding. The concentrations of TN, TP, permanganate index and Chl-a in water in February 2014 were 4.7 times, 1.0 time, 0.2 times and 3.27 times the amount in October 2013. It should be noticed that the concentrations of TN and TP were above the algae growth limit value, which would be easy to cause water eutrophication with prolonged residence time. The single-factor evaluation of Chl a reflected that the water quality was changed from poor nutrient to eutrophic. The results of N/P showed that TN in Han Feng Lake was a factor limiting the growth of algae in different period. In October to December 2013 and February 2014, TN limited the growth of algae. In January 2014, TP limited the growth of algae. The Chl-a had a significant positive correlation to pH, DO, NH4(+) -N, NO3(-) -N, TN, permanganate index and TP, but significant negative correlations were observed with SD and TEMP. The water quality was influenced by the same source of pollution during the storage period. The result of factor analysis showed that the water quality in riparian zone of Hanfeng Lake was mainly affected by pH, DO, NO3(-)-N, TN, while Chl-a, TP, NH4(+) -N and aerobic organics pollution could not be ignored. The water had self-purification capacity in the early phase of the storage period, the eutrophication aggravated with the increase of retention time, and it should be controlled. During the storage period of the Three Gorges Reservoir, the nutrition levels of south river and east river were relatively high, and the management should be strengthened. PMID- 25929061 TI - [Spatial distribution pattern and stock estimation of nutrients during bloom season in Lake Taihu]. AB - Based on the data of high density spatial sampling in July 2013, we analyzed the spatial distribution pattern of nutrients and estimated their amount during bloom season in Lake Taihu to discuss the correlation of algal bloom in different types of ecological water and nutrients in large shallow lake and the representative of its sampling sites. The research showed that nutrients and chlorophyll-a concentration (CHL) in Lake Taihu tended to reduce from northwest to southeast in general during bloom season. Nitrogen was mainly present in dissolved form, accounting for 76.28 percent of the total nitrogen (TN), and phosphorus was mainly present in particulate form, accounting for 66.38 percent of the total phosphorus (TP). The sampling points in the whole lake could be divided into four sections with significant difference between each other using principal component analysis and cluster analysis: The first section was located in the district of northwestern Lake Taihu, which represented the heavy eutrophic lake areas with serious blooms; the second section mainly included Meiliang Bay and area of river inflow into lake in South of Lake Taihu, which stood for moderate eutrophication of water quality; The third section included the central area and the southwest of lake, which represented the water area with medium water pollution, but blooms were frequent; And the fourth area was the remainder areas including Gonghu Bay, Xukou Bay, and Eastern Taihu, which stood for the region of weaker blooms and better water quality. Different factors also affected the growth of planktonic algae in different sections: From the point of the whole lake, CHL was significantly correlated with TP, TN, total dissolved nitrogen (TDN) and nitrate nitrogen (NO3(-) -N); while in the first section, CHL was significantly correlated to TP and TDN; CHL was correlated to TN and TDN in the second section; in the third section, the influencing factors were TP, reactive phosphate (PO4(3 ) -P), TDN; PO4(3-)-P, total dissolved phosphorus (TDP) and nitrite nitrogen (NO2(-) -N) were the influencing factors for the fourth section. The study showed that the values of TN, TDN, TP and TDP respectively were 12 800 tons, 9 800 tons, 445 tons and 150 tons during the research period. As a large shallow lake, Lake Taihu showed high spatial heterogeneity in nutrients during bloom season, which was resulted from the space migration accumulation characteristics of cyanobacteria blooms and the alienation characteristics of ecological type. Therefore, when monitoring and evaluating the large shallow lakes, sampling points should be set rationally and the results should be interpreted properly, to avoid overgeneralization due to improper monitoring points and statistical methods. PMID- 25929062 TI - [Phytoplankton community structure and eutrophication risk assessment of Beijiang River]. AB - To study the distribution of phytoplankton and water quality of Beijiang River, the community structure of phytoplankton was investigated and analyzed in wet and dry seasons. The results showed that a total of 74 species belonging to six phyla, 29 family and 48 genera of phytoplankton were identified, including 58 species of five phyla, 23 family and 41 genera in wet season and 59 species of six phyla, 26 family and 40 genera in dry season. Phytoplankton community structure in Beijiang River was represented by Bacillariophyta, Chlorophyta and Cyanophyta. Bacillariophyta dominanted the phytoplankton, and the dominant species were Aulacoseira granulate, Fragilaria virescens, Surirella biseriata, Nitzschia amphibia, Navicula simplex, Cyclotella meneghiniana, Synedra ulna, Gomphonema angustatum and Cymbella tumida. There was little difference in phytoplankton density between both seasons with the mean values being 3.54 x 10(5) and 4.87 x 10(5) cells L(-1) in dry and wet seasons, respectively. Based on the RDA results, DO, permanganate index, nitrogen and phosphorus were the important environmental factors affecting the distribution of phytoplankton in Beijiang River. The water quality of Beijiang River was classified as oligo mesotrophic level even if this river was subjected to nitrogen and phosphorus pollution mainly from agricultural non-point source. PMID- 25929063 TI - [Synergistic effect of physical and Chironomus plumosus combined disturbance on regeneration and transformation of internal phosphorus]. AB - To explain the synergistic effect of physical and Chironomus plumosus combined disturbance on the regeneration and transformation of internal phosphorus, laboratory static incubation experiments were carried out with the sediments and overlying water from a eutrophic river in Suzhou. Rhizon samplers were used to acquire the pore water. In the experiment, we compared the variation of different phosphorus forms in the overlying water, the pore water and sediments under the Chironomus plumosus disturbance and the combined disturbance. The results indicated that the amount of different forms of phosphorus (TP, PP, DTP, DIP) in the overlying water under combined disturbance was higher than that under Chironomus plumosus combination disturbance. It was attributed to the significant increase of the microbial activity in the sediments. Compared with Chironomus plumosus disturbance, the amount of DIP and ferrous decreased with the greater magnitude and range. It was attributed to the superposition effect of the physical and benthos disturbance on the penetration depth of the dissolved oxygen. In addition, the amount of NH4C1-P decreased remarkably in the 0-2 cm sediment while Fe/Al-P increased obviously. Furthermore, the variation magnitude of NH4Cl-P and Fe/Al-P was higher under combined disturbance than that under Chironomus plumosus disturbance, which suggested the superposition effect of the physical and benthos disturbance on the regeneration and migration of phosphorus. PMID- 25929064 TI - [Effect of light and temperature on growth kinetics of Anabaena flosaquae under phosphorus limitation]. AB - Phosphorus, light and temperature are the key environmental factors leading to algae growth. But the effects of interaction between light and temperature on the growth of Anabaena flosaquae under phosphorus limitation were not well documented in literature. Anabaena flosaquae was selected for the study and lab-scale experiment and simulation were carried out. The results showed that the optimal temperature of Anabaena flosaquae was 20 degrees C under phosphorus limitation when the light intensity was constant, and the optimal light intensity (illuminance) of Anabaena flosaquae was 3 000 lx under phosphorus limitation when the temperature was constant. Based on model fitting and parameter calibration, the optimal temperature and light intensity of Anabaena flosaquae were 21.03 degress C +/- 1.55 degrees C and 2 675.12 lx +/- 262.93 lx, respectively. These data were close to the actual water environmental condition at the end of spring. Results of this study will provide important foundation for prediction of Anabaena blooms. PMID- 25929065 TI - [Purification of the wastewater of quartz processing by mineral-based porous granulation material]. AB - A mineral-based porous granulation material (MPGM) was prepared for absorbing the heavy metal ions from quartz processing wastewater. Analytic results of the MPGM were illustrated by the techniques of BET, SEM and FT-IR, which revealed the excellent properties of multi-aperture distribution, large specific surface area, low loss ratio and so on; the N2 adsorption-desorption isotherm was type-III with H4 hysteresis loop; the functional groups were dominated by groups of layer silicate mineral. A batch adsorption study was carried out with varied adsorbent dosage, initial pH and reaction time. The results showed that the residual ion concentrations of Fe, Zn, Mn and As were decreased from 77.760, 3.700, 2.789 and 0.963 mg x L(-1) to 3.421, 0.574, 0.126 and 0.034 mg x L(-1), respectively. MPGM might be re-utilized after desorption by 1.0 mol x L(-1) NaCl for 12 hours, and the ideal adsorption performance was maintained after 5 recyclings. The adsorption equilibrium and kinetics followed Langmuir and typical pseudo-first order/pseudo-second-order adsorption models. Thermodynamic parameters of DeltaG(theta) < 0, DeltaHtheta > 0, DeltaStheta > 0 showed that the adsorptions were spontaneous and endothermic processes in the temperature range of 15-45 degrees C. PMID- 25929066 TI - [Enhanced reductive decoloration of methylene blue by polyacrylic acid modified zero-valent iron nanoparticles]. AB - Nano zerovalent iron ( NZVI) technology has attracted tremendous amount of interests for degrading a number of environmental contaminants found both in surface water and underground water. However, these nanoscale particles are prone to aggregate, which may result in the decrease of its reactivity in liquid phase. Iron nanoparticles (Fe NPs) modified with polyacrylic acid (PAA) has enhanced the dispersion of NZVI and reduced its agglomeration. For the first time, PAA modified NPs (PAA-Fe NPs) were used for degradation of methylene blue in water phase. The PAA-Fe NPs prepared were characterized in terms of TEM, SEM, XRD and specific surface area. The results indicated that, the surface area of PAA-Fe NPs was increased, compared with unmodified pristine zero-valent iron NPs, and PAA-Fe NPs were smoother with smaller particle size. With addition of 0.1 g x L(-1) of PAA, the decolorization efficiency of methylene blue by PAA-Fe NPs was 98.84% in 60 min, which was 27.32% higher than that of pristine Fe NPs. Decolorization efficiencies were also affected by initial pH value, initial concentration of methylene blue, dosage of PAA-Fe NPs, and degradation temperature. Kinetic analyses based on the experimental data illustrated that the decolorization reaction of methylene blue fitted well to the pseudo first-order kinetics model. PMID- 25929067 TI - [Decolorization of reactive blue P-3R with microsphere-supported binuclear Manganese complex as a novel heterogeneous CWPO catalyst]. AB - Binuclear manganese complex (MnL), with high catalytic activity, was encapsulated into ethyl cellulose microspheres via a microencapsulation technique. The characterization of the catalyst through ICP, UV-VIS, SEM and TEM revealed that MnL was well distributed within the ethyl cellulose matrix. The results of UV-VIS confirmed the structural integrity of MnL after the encapsulation process. The MnL loaded microspheres exhibited an excellent catalytic property in the oxidative decolorization of Reactive Blue P-3R, which was used to simulate the dyestuff wastewater. The dye solution was completely decolorized under the catalyzing action of these microspheres. What's more, these MnL loaded microspheres could be reused for at least 4 times and the decolorization degree of Reactive Blue P-3R was maintained above 70%. The results demonstrated the potential application of the microsphere-supported MnL as a novel heterogeneous CWPO catalyst for the decolorization of wastewater containing dyestuff. PMID- 25929068 TI - [Biosynthetic schwertmannite as catalyst in Fenton-like reactions for degradation of methyl orange]. AB - Biosynthesized schwertmannite was used as catalyst in photo-Fenton-like reaction to facilitate the degradation of methyl orange (MO). Schwertmannite was synthesized through the oxidation of FeSO4 by Acidithiobacillus ferrooxidans LX5 cell suspension at an initial pH 2.5 and 28 degress C for 3 days and characterized using X-ray diffraction spectroscopy and scanning electron microscope. The oxidative degradation of MO in the photo-Fenton-like reaction was studied at different initial pH values of suspension, concentrations of H2O2 and dosages of catalyst. The results suggested that the biosynthetic schwertmannite showed a good catalytic activity in the MO degradation via *OH radical mechanism. Considerable degradation efficiency of MO was still obtained in approximately neutral condition or in the presence of high concentrations of chloride, sulfate and nitrate. This work demonstrated that the heterogeneous photo-Fenton-like reaction catalyzed by the biosynthetic schwertmannite is a promising advanced oxidation technology for the treatment of wastewater containing MO. PMID- 25929069 TI - [Enhanced nitrogen and phosphorus removal of wastewater by using sludge anaerobic fermentation liquid as carbon source in a pilot-scale system]. AB - In order to explore the possibility of enhanced nitrogen and phosphorus removal in wastewater using sludge anaerobic fermentation liquid as external carbon source, the present study proposed an A2/O reactor system with a total effective volume of 4 660 L and real municipal wastewater for treatment. The results showed that under the conditions of the influent COD at 243.7 mg x L(-1), NH4(+) -N at 30. 9 mg x L(-1), TN at 42.9 mg'L- , TP at 2.8 mg x L(-1), the backflow ratio of nitrification liquid at 200% and recycle ratio of sludge at 100%, the addition of acetic acid into anoxic tank could enhance the removal efficiency of nitrogen and phosphorus, and the optimal influent quantity and SCOD incremental of carbon were 7 500 L x d(-1) and 50 mg L(-1), respectively. When the sludge fermentation liquid was used as external carbon source and the average effluent COD, NH4(+) N, TN, TP removal efficiency were 81.60%, 88.91%, 64.86% and 87.61%, the effluent concentrations were 42.18, 2.77, 11.92 and 0.19 mg x L(-1), respectively, which met China's first Class (A) criteria specified in the Discharge Standard Urban Sewage Treatment Plant Pollutant (GB 18918-2002). The results of the present study demonstrated that the addition of sludge anaerobic fermented liquid as external carbon source was a feasible way to enhance the removal of nitrogen and phosphorous in municipal wastewater, providing a new feasible strategy for the reuse and recycle of sewage sludge in China. PMID- 25929070 TI - [Transformation characteristics of carbon, nitrogen, phosphorus and sulfur during thermal hydrolysis pretreatment of sludge with high solid content]. AB - The transformation characteristics of carbon, nitrogen, phosphorus and sulfur in dewatering sludge from municipal wastewater treatment plant (WWTP) were investigated after thermal hydrolysis pretreatment at 165 degress C for 50 min. The results showed that the hydrolysis efficiency of VSS could reach as high as 43.35%, 54.36% of protein and 65.12% of carbohydrate were transferred to dissolved organics, respectively, and the main component of dissolved organic matter in hydrolysate was dissolved protein (52.18% ), 54.23% of insoluble organic nitrogen was turned into dissolved nitrogen and 22.13% of dissolved nitrogen in hydrolysate was converted to ammonia. The transformation rate of insoluble phosphorus was 30.52%. Dissolved phosphorus was mostly transformed to phosphate (79.84%) as phosphorus-accumulating bacteria cells were crushed. 50.03% of insoluble organic sulfur was hydrolyzed, and little change was detected in sulfide (0.50%). The analysis results of the organic compounds transformation are valuable for treatment of the thermal hydrolysis pretreated sludge with high solid content. PMID- 25929071 TI - [Characteristics of nitrogen and phosphorus removal and control of membrane fouling in MBR and SMBR]. AB - To improve the efficiency and running stability of wastewater advanced treatment, a sequencing membrane bioreactor (SMBR) and a traditional membrane bioreactor (MBR) were used to investigate the characteristics of nitrogen and phosphorus removal, and the effect of anoxic time on treatment systems and membrane fouling. Simultaneously, molecular biology techniques were applied to analyze the composition of microbial community and the structure of suspended sludge. The results showed that SMBR had higher efficiency in removing TN than MBR, which indicated that intermittent aeration could enhance the ability of nitrogen removal. SMBR and MBR had a similar removal efficiency of NH4(+)-N, TP, COD, and turbidity with the removal rates of 94%, 78%, 80%, and 97%, respectively. Extension of SMBR anoxic time had no effect on COD, NH4(+) -N removal but decreased TN and TP removal rate, dropping from 61% and 74% to 46% and 52%, respectively. Intermittent aeration and powder activated carbon (PAC) could both mitigate membrane fouling. The analysis on microbial community indicated that there was no difference in the composition and structure of microbial community between SMBR and MBR. Nitrospira and Dechloromonas were both highly abundant functional groups, which provided the basis for highly efficient control of bioreactors. PMID- 25929072 TI - [Influence of substrate COD on methane production in single-chambered microbial electrolysis cell]. AB - The chemical oxygen demand (COD) of substrate can affect the microbial activity of both anode and cathode biofilm in the single-chamber methanogenic microbial electrolysis cell (MEC). In order to investigate the effect of COD on the performance of MEC, a single chamber MEC was constructed with biocathode. With the change of initial concentration of COD (700, 1 000 and 1 350 mg x L(-1)), the methane production rate, COD removal and energy efficiency in the MEC were examined under different applied voltages. The results showed that the methane production rate and COD removal increased with the increasing COD. With the applied voltage changing from 0.3 to 0.7 V, the methane production rate increased at the COD of 700 mg x L(-1), while it increased at first and then decreased at the COD of 1000 mg x L(-1) and 1350 mg x L(-1). A similar trend was observed for the COD removal. The cathode potential reached the minimum (- 0.694 +/- 0.001) V as the applied voltage was 0.5 V, which therefore facilitated the growth of methanogenic bacteria and improved the methane production rate and energy efficiency of the MEC. The maximum energy income was 0.44 kJ +/- 0.09 kJ (1450 kJ x m(-3)) in the MEC, which was obtained at the initial COD of 1000 mg x L(-1) and the applied voltage of 0.5 V. Methanogenic MECs could be used for the treatment of wastewaters containing low organic concentrations to achieve positive energy production, which might provide a new method to recover energy from low-strength domestic wastewater. PMID- 25929073 TI - [Ion specificity during ion exchange equilibrium in natural clinoptilolite]. AB - Zeolites have been widely applied in soil improvement and environment protection. The study on ion specificity during ion exchange equilibrium is of important significance for better use of zeolites. The maximum adsorption capacities of alkali ions during ion exchange equilibrium in the clinoptilolite showed obvious specificity. For alkali metal ions with equivalent valence, the differences in adsorption capacity increased with the decrease of ionic concentration. These results cannot be well explained by the classical theories including coulomb force, ionic size, hydration, dispersion force, classic induction force and surface complexation. We found that the coupling of polarization effects resulted from the quantum fluctuation of diverse alkali metal ions and electric field near the zeolite surface should be the primary reason for specific ion effect during ion exchange in zeolite. The result of this coupling effect was that the difference in the ion dipole moment increased with the increase of surface potential, which further expanded the difference in the adsorption ability between zeolite surface and ions, resulting in different ion exchange adsorption ability at the solid/liquid interface. Due to the high surface charge density of zeolite, ionic size also played an important role in the distribution of ions in the double diffuse layer, which led to an interesting result that distinct differences in exchange adsorption ability of various alkali metal ions were only detected at high surface potential (the absolute value was greater than 0.2 V), which was different from the ion exchange equilibrium result on the surface with low charge density. PMID- 25929074 TI - [Assessment of heavy metal pollution and potential ecological risks of urban soils in Kaifeng City, China]. AB - Ninety-nine topsoil (0-15 cm) samples were collected from Kaifeng City, China using the grid method, and then the concentrations of As, Cd, Cr, Cu, Ni, Pb and Zn in the samples were measured by standard methods. Soil pollution levels and potential ecological risks of the heavy metals were assessed using the pollution load index (PLI) and potential ecological risk index (RI), respectively. Ordinary Kriging interpolation technique was employed to investigate the spatial distribution of PLI and RI of the city. The results showed that high pollution of Cd occurred in Kaifeng urban soils, and there was moderate pollution of Zn, slight pollution of Pb and Cu, and no pollution of Ni, Cr and As. Very high ecological risk was posed by Cd and low risk by other metals. The mean PLI of the 7 metals from all sample points was 2.53, which was categorized as moderate pollution. The average RI was 344.58 which represented a considerable ecological risk. PLI and RI shared a similar spatial distribution with high values centralized in the old industrial area in the southeast and railway stations for passengers and goods in the south of the city, followed by the old town within the ancient city wall, and low values located in the north and west areas. Cadmium was the main factor for both soil pollution and potential ecological risk primarily due to farmland topsoil in the eastern suburb of Kaifeng City with high Cd concentrations resulted from sewage irrigation deposited in the urban area by wind, human activities such as soot discharged from the chemical fertilizer plant of Kaifeng, transportation and coal combustion. PMID- 25929075 TI - [Effects of different cultivation patterns on soil aggregates and organic carbon fractions]. AB - Combined with the research in an organic farm in the past 10 years, differences of soil aggregates composition, distribution and organic carbon fractions between organic and conventional cultivation were studied by simultaneous sampling analysis. The results showed that the percentages of aggregates (> 1 mm, 1-0.5 mm, 0.5-0.25 mm and < 0.25 mm) in the conventional cultivation were 23.75%, 15.15%, 19.98% and 38.09%, while those in organic cultivation were 9.73%, 18.41%, 24.46% and 43.90%, respectively. The percentage of < 0.25 mm micro-aggregates was significantly higher in organic cultivation than that in conventional cultivation. Organic cultivation increased soil organic carbon (average of 17.95 g x kg(-1)) and total nitrogen contents (average of 1.51 g x kg(-1)). Among the same aggregates in organic cultivation, the average content of heavy organic carbon fraction was significantly higher than that in conventional cultivation. This fraction accumulated in < 0. 25 mm micro-aggregates, which were main storage sites of stable organic carbon. In organic cultivation, the content of labile organic carbon in > 1 mm macro-aggregates was significantly higher than that in conventional cultivation, while no significant difference was found among the other aggregates, indicating that the labile organic carbon was enriched in > 1 mm macro-aggregates. Organic cultivation increased the amounts of organic carbon and its fractions, reduced tillage damage to aggregates, and enhanced the stability of organic carbon. Organic cultivation was therefore beneficial for soil carbon sequestration. The findings of this research may provide theoretical basis for further acceleration of the organic agriculture development. PMID- 25929076 TI - [Effects of Chinese prickly ash orchard on soil organic carbon mineralization and labile organic carbon in karst rocky desertification region of Guizhou province]. AB - Taking 5-year-old Chinese prickly ash orchard (PO-5), 17-year-old Chinese prickly ash orchard (PO- 17), 30-year-old Chinese prickly ash orchard (PO-30) and the forest land (FL, about 60 years) in typical demonstration area of desertification control test in southwestern Guizhou as our research objects, the aim of this study using a batch incubation experiment was to research the mineralization characteristics of soil organic carbon and changes of the labile soil organic carbon contents at different depths (0-15 cm, 15-30 cm, and 30-50 cm). The results showed that: the cumulative mineralization amounts of soil organic carbon were in the order of 30-year-old Chinese prickly ash orchard, the forest land, 5 year-old Chinese prickly ash orchard and 17-year-old Chinese prickly ash orchard at corresponding depth. Distribution ratios of CO2-C cumulative mineralization amount to SOC contents were higher in Chinese prickly ash orchards than in forest land at each depth. Cultivation of Chinese prickly ash in long-term enhanced the mineralization of soil organic carbon, and decreased the stability of soil organic carbon. Readily oxidized carbon and particulate organic carbon in forest land soils were significantly more than those in Chinese prickly ash orchards at each depth (P < 0.05). With the increasing times of cultivation of Chinese prickly ash, the contents of readily oxidized carbon and particulate organic carbon first increased and then declined at 0-15 cm and 15-30 cm depth, respectively, but an opposite trend was found at 30-50 cm depth. At 0-15 cm and 15-30 cm, cultivation of Chinese prickly ash could be good for improving the contents of labile soil organic carbon in short term, but it was not conducive in long-term. In this study, we found that cultivation of Chinese prickly ash was beneficial for the accumulation of labile organic carbon at the 30-50 cm depth. PMID- 25929077 TI - [Rare earth elements content in farmland soils and crops of the surrounding copper mining and smelting plant in Jiangxi province and evaluation of its ecological risk]. AB - Rare earth elements content in farmland soils and crops of the surrounding copper mining and smelting plant in Jiangxi province was studied. The results showed that copper mining and smelting could increase the content of rare earth elements in soils and crops. Rare earth elements content in farmland soils of the surrounding Yinshan Lead Zinc Copper Mine and Guixi Smelting Plant varied from 112.42 to 397.02 mg x kg(-1) and 48.81 to 250.06 mg x kg(-1), and the average content was 254.84 mg x kg(-1) and 144.21 mg x kg(-1), respectively. The average contents of rare earth elements in soils in these two areas were 1.21 times and 0.68 times of the background value in Jiangxi province, 1.36 times and 0.77 times of the domestic background value, 3.59 times and 2.03 times of the control samples, respectively. Rare earth elements content in 10 crops of the surrounding Guixi Smelting Plant varied from 0.35 to 2.87 mg x kg(-1). The contents of rare earth elements in the leaves of crops were higher than those in stem and root. The contents of rare earth elements in Tomato, lettuce leaves and radish leaves were respectively 2.87 mg x kg(-1), 1.58 mg x kg(-1) and 0.80 mg x kg(-1), which were well above the hygienic standard limit of rare earth elements in vegetables and fruits (0.70 mg x kg(-1)). According to the health risk assessment method recommended by America Environmental Protection Bureau (USEPA), we found that the residents' lifelong average daily intake of rare earth elements was 17.72 mg x (kg x d)(-1), lower than the critical value of rare earth elements damage to human health. The results suggested that people must pay attention to the impact of rare earth elements on the surrounding environment when they mine and smelt copper ore in Jiangxi. PMID- 25929078 TI - [Combined toxicity of cadmium and S-metolachlor to Scenedesmus obliquus]. AB - The single and combined effects of Cd2+ and S-metolachlor on acute toxicity, total soluble protein content, superoxide dismutase (SOD) activity and cell membrane permeability of Scenedesmus obliquus (S. obliquus) were studied using the standard toxic testing methods. The results showed that the EC50 of Cd2+ and S-metolachlor decreased with time, and the acute toxicity of S-metolachlor was higher than that of Cd2+, EC(50-24h) of Cd2+ and S-metolachlor was 0.27 mg x L( 1) and 0.24 mg x L(-1), respectively, and EC(50.96h) was 0.16 mg x L(-1) and 0.13 mg x L(-1), respectively. The combined toxicity of Cd2+ and S-metolachlor showed a synergistic effects at low concentration, and antagonism effects at high concentration. After 96h-exposure, the total soluble protein content of S. obliquus decreased, the SOD activity first increased and then decreased, and the cell membrane permeability increased with the increasing concentration of both single and combined treatment. PMID- 25929079 TI - [Effect of degradation succession process on the temperature sensitivity of ecosystem respiration in alpine Potentilla fruticosa scrub meadow]. AB - Grazing is one of the main artificial driving forces for the degradation succession process of alpine meadow. In order to quantitatively study the temperature sensitivity of alpine meadow ecosystem respiration in different degradation stages, we conducted the research in Haibei Alpine Meadow Ecosystem Research Station, CAS from July 2003 to July 2004. The static chamber chromatography methodology was used to observe the seasonal changes of alpine scrub ecosystem respiration flux during different degradation stages. The results showed that: (1) The seasonal changes of ecosystem respiration flux in different degradation stages of alpine shrub presented a unimodal curve. The maximum appeared in August and the minimum appeared during the period from October to next April. The degradation succession process significantly decreased the ecosystem respiratory CO2 release rate. The respiratory rate ranges of alpine Potentilla fruticosa scrub (GG), Kobresia capillifolia meadow (GC) and bare land (GL) were 34.21-1 168.23, 2.30-1 112.38 and 20.40-509.72 mg (m2 x h)(-1), respectively. The average respiration rate of GG was 1.29 and 2.56 times of that of GC and GL, respectively; (2) Temperature was the main factor that affected the ecosystem respiration rate, and contributed 25% - 79% of the variation of the ecosystem respiration. The degradation succession process significantly changed the correlation between ecosystem respiration rate and temperature. The correlation (R2) between ecosystem respiration rate and each temperature indicator (T(s), T(d) and T(a)) was reduced by 47.23%, 46.95% and 55.28%, respectively when the ground vegetation disappeared and the scrub was degraded into secondary bare land; (3) The difference of Q10 between warm and cool seasons was significant (P < 0.05), and the value of cold season was larger than that of warm season. Degradation succession process apparently changed the temperature sensitivity of ecosystem respiration. The Q10 values of GG, GC and GL were 2.38, 2.91 and 1.62, respectively. Q10 of GC was increased by 22.26% and that of GL was decreased by 31.93% compared with that of GG. PMID- 25929080 TI - [Ecological stoichiometric characteristics in leaf and litter under different vegetation types of Zhifanggou watershed on the Loess Plateau, China]. AB - The purpose was to characterize the effects of vegetation types on plant leaf and litter carbon (C), nitrogen (N), phosphorus (P), potassium (K) and C: N: P: K ecological stoichiometric characteristics in seven dominant plant species, including Robinia pseudoacacia, Syringa, Sophora viciifolia, Hippophae rhamnoides, Rosa xanthina, Artemisia sacrorum, Artemisia giraldii, of Zhifanggou Watershed on the Loess Plateau, China. This paper indicated the differences between the contents of C, N, P and K and the characteristics of ecological stoichiometric in the different vegetation types, including forest type, shrub type and grass type. Concentrations of C, N, P and K were measured, and C: N: P: K was estimated for different vegetation types. There were no significant differences in leaf C, N and P concentrations among the three vegetation types. But significant differences in leaf K concentration existed, and the K concentration in leaf was the highest in grass type, and the lowest in shrub type. The contents of C, N, P and K in leaf were much higher than those in litter, especially in shrub and grass types. The resorption efficiencies of C, N, P and K were different, and their ranges varied 6.16%-22.84%, 24.38%-65.18%, 22.38%-77.16% and 60.99%- 89.35%, respectively. Grass type had the highest C, P and K resorption efficiencies, and the lowest N resorption efficiency. Values of the N: P ratio in leaf varied in the range of 12.14-19.17, and varied in the range of 12.84-30.67 in litter. Values of the N: P ratio in leaf were the highest in shrub type (19. 17), and the lowest in grass (12. 14), indicating that the growth of shrub plants was limited by P, while the growth of grass plants was limited by N. The K concentration in leaf was significantly negatively correlated with values of the N: P ratio in leaf, and the K concentration in litter was significantly negatively correlated with values of the C: P ratio in leaf. Findings in this study highlighted the characteristics of accumulation and and return of leaf and litters nutrients during the different vegetation succession on the Loess Plateau. PMID- 25929081 TI - [Denitration mechanism of monoclinic-phase nano zirconium oxide-based catalysts]. AB - The MnO(x)-CeO2/m-ZrO2 catalyst was prepared by impregnation with nano monoclinic phase zirconium (m-ZrO2) as the supporter. The influence of active component and reaction temperature on the denitration performance of the catalyst was investigated, while the surface properties of the catalyst and the denitration mechanism were discussed. The denitration efficiency was improved as the active component increased and the reaction temperature rose. The denitration efficiency of 2.5% MnO(x)-CeO2/m-ZrO2 catalyst at 110 degrees C was 55.5% while that of 15% MnO(x)-CeO2/m-ZrO2 catalyst was 93.5%. The results of XRD, SEM, BET and H2-TPR showed that the surface structure of the loaded catalyst was beneficial for denitration and oxidation-reduction. NH3-TPD test demonstrated that NH3 was adsorbed at the Lewis acid sites and Bronsted acid sites on the surface of catalysts. Intermediate products NH2NO and NH4NO were generated from a series of reactions between NO and NH3 and finally transformed into N2 and H2O. Most of the denitration process happened at Lewis acid sites. PMID- 25929082 TI - [Characterization of phosphorus forms in different organic materials]. AB - The existing forms of phosphorus in seven organic waste materials including biogas residues of swine manure (ZZ), biogas residues of cattle manure (NZ), compost of cattle manure and corn straw (NJD), compost of sewage sludge (WD) and compost of rural daily garbage (NSLD) were characterized according to phosphorus fractionation procedures developed by DOU et al. The result showed that there was a great difference in the total phosphorus (TP) and the total phosphorus of various forms (P(t)) among different organic materials. ZZ had the highest content of TP with the value of 23.59 g x kg(-1); while NZ had the lowest TP content with the value of 3.61 g x kg(-1). The contents and proportions of phosphorus fractions in ZZ, NZ, NJD and WD followed the order of HCl-P > Residues P > NaHCO3-P > NaOH-P > H2O-P, while followed the order of HC1-P > Residues-P > H2O-P > NaHCO3-P > NaOH-P in the three NSLDs. The proportion of HCl-P in the total fractionated phosphorus (P(tt)) in seven organic materials ranged from 47.75% to 84.96%, which indicated that most of P in organic materials existed in the forms that were easier to be extracted by strong extracting agents like HCl, which was difficult to be absorbed by plants. The inorganic phosphorus accounted for 79.72% -94.76% of the total phosphorus in the organic materials. Of all the phosphorus forms, the NaHCO3-P had the highest inorganic phosphorus fractions, but the inorganic phosphorus was mainly distributed in HCl-P. The organic phosphorus was mainly distributed in HCl-P and Residues-P. In addition, the higher proportions of inorganic phosphorus in NJD than those of NZ demonstrated that the composting process was benefit for the mineralization of organic phosphorus in organic materials and thus improving its availability. PMID- 25929083 TI - [Comparative life cycle environmental assessment between electric taxi and gasoline taxi in Beijing]. AB - Tailpipe emission of internal combustion engine vehicle (ICEV) is one of the main sources leading to atmospheric environmental problems such as haze. Substituting electric vehicles for conventional gasoline vehicles is an important solution for reducing urban air pollution. In 2011, as a pilot city of electric vehicle, Beijing launched a promotion plan of electric vehicle. In order to compare the environmental impacts between Midi electric vehicle (Midi EV) and Hyundai gasoline taxi (ICEV), this study created an inventory with local data and well reasoned assumptions, and contributed a life cycle assessment (LCA) model with GaBi4.4 software and comparative life cycle environmental assessment by Life cycle impact analysis models of CML2001(Problem oriented) and EI99 (Damage oriented), which included the environmental impacts of full life cycle, manufacture phase, use phase and end of life. The sensitivity analysis of lifetime mileage and power structure was also provided. The results indicated that the full life cycle environmental impact of Midi EV was smaller than Hyundai ICEV, which was mainly due to the lower fossil fuel consumption. On the contrary, Midi EV exhibited the potential of increasing the environmental impacts of ecosystem quality influence and Human health influence. By CML2001 model, the results indicated that Midi EV might decrease the impact of Abiotic Depletion Potential, Global Warming Potential, Ozone Layer Depletion Potential and so on. However, in the production phase, the impact of Abiotic Depletion Potential, Acidification Potential, Eutrophication Potential, Global Warming Potential, Photochemical Ozone Creation Potential, Ozone Layer Depletion Potential, Marine Aquatic Ecotoxicity Potential, Terrestric Ecotoxicity Potential, Human Toxicity Potential of Midi EV were increased relative to Hyundai ICEV because of emissions impacts from its power system especially the battery production. Besides, in the use phase, electricity production was the main process leading to the impact of Abiotic Depletion Potential, Acidification Potential, Eutrophication Potential, Global Warming Potential, Photochemical Ozone Creation Potential, Marine Aquatic Ecotoxicity Potential, Freshwater Aquatic Ecotoxicity Potential, Human Toxicity Potential. While for Hyundai ICEV, gasoline production and tailpipe emission were the primary sources of environmental impact in the use phase. Tailpipe emission was a significant cause for increase in Eutrophication Potential and Global Warming Potential, and so forth. On the basis of inventory data analysis and 2010 Beijing electricity mix, the comparative results of haze-induced pollutants emissions showed that the full life cycle emissions of PM2.5, NO(x), SO(x), VOCs of Midi EV were higher than those of Hyundai ICEV, but the emission of NH3 was lower than that of Hyundai ICEV. Different emissions in use phase were the chief reason leading to this trend. In addition, by sensitivity analysis the results indicated that with the increase of lifetime mileage and proportion of cleaning energy, the rate of GHG( Green House Gas) emission reduction per kilometer of Midi EV became higher with respect to Hyundai ICEV. Haze-induced pollutants emission from EV could be significantly reduced using cleaner power energy. According to the assessment results, some management strategies aiming at electric car promotion were proposed. PMID- 25929084 TI - [Characteristics of water soluble inorganic ions in fine particles emitted from coal-fired power plants]. AB - Currently, China suffers from serious pollution of fine particulate matter (PM2.5). Coal-fired power plant is one of the most important sources of PM2.5 in the atmosphere. To achieve the national goals of total emission reductions of sulfur dioxide (SO2) and nitrogen oxides (NO(x)) during the 11th and 12th Five Year Plan, most of coal-fired power plants in China have installed or will install flue gas desulfurization (FGD) and flue gas denitrification (DNO(x)) systems. As a result, the secondary PM2.5, generated from gaseous pollutants in the atmosphere, would be decreased. However, the physical and chemical characteristics of PM2.5 in flue gas would be affected, and the emission of primary PM2.5 might be increased. This paper summarized the size distributions of PM2.5 and its water soluble ions emitted from coal-fired power plants, and highlighted the effects of FGD and DNO(x) on PM2.5 emission, especially on water soluble ions (such as SO4(2-), Ca2+ and NH4+) in PM2.5. Under the current condition of serious PM2.5 pollution and wide application of FGD and DNO(x), quantitative study on the effects of FGD and DNO(x) installation on emission characteristics of PM2.5 from coal-fired power plants is of great necessity. PMID- 25929085 TI - [Underlying mechanisms of the heavy metal tolerance of mycorrhizal fungi]. AB - Mycorrhizal fungi are ubiquitous in natural ecosystems and can form symbiotic associations with the majority of terrestrial plants. They can be detected even in heavy metal-contaminated soils, while some fungal strains show strong heavy metal tolerance and could potentially be used in bioremediation of contaminated soils. We reviewed current research progresses in the underlying mechanisms of heavy metal tolerance of mycorrhizal fungi, with focuses on habitat selection, physiological adaptation and functional genes. Future research perspectives were proposed to promote the basic research and development of mycorrhizal technology for remediation of heavy metal-contaminated soils. PMID- 25929086 TI - [Research progress on microbial properties of nitrite-dependent anaerobic methane oxidising bacteria]. AB - Nitrite-dependent anaerobic methane oxidation (N-DAMO) is a recently discovered process that constitutes a unique association between the two major global elements essential for life, carbon and nitrogen. This process is one of the most important discoveries in the fields of environmental science and microbiology. The discovery of N-DAMO process supplements biogeochemical cycles of carbon and nitrogen in nature, extends microbial diversity and urges development of novel simultaneous carbon and nitrogen removal process. The N-DAMO process is mediated by the bacterium " Candidatus Methylomirabilis oxyfera" (M. oxyfera), which belongs to the candidate phylum NC10. Currently, a series of breakthroughs have been made in the research of M. oxyfera. The properties of M. oxyfera morphology, chemical composition, enrichment culture, physiology and biochemistry, and ecology have been revealed. Most importantly, the special ultrastructure (star like) of the cell shape and unique chemical composition (10MeC(16,1Delta7)) of M. oxyfera have been revealed. In addition, a new intra-aerobic metabolism (the fourth biological pathway to produce oxygen) was discovered in M. oxyfera. It was observed that M. oxyfera bypassed the denitrification intermediate nitrous oxide by the conversion of two nitric oxide molecules to dinitrogen gas and oxygen, which was then used to oxidise methane. The present review summarises various aspects of microbiological properties of M. oxyfera. PMID- 25929087 TI - President's message--expert power. PMID- 25929088 TI - Duke study touts benefits of APRNs in North Carolina. PMID- 25929089 TI - Nursing issues at the state legislature. PMID- 25929090 TI - You are the expert. PMID- 25929091 TI - Battle tested. PMID- 25929092 TI - School nursing legislative issues in North Carolina. PMID- 25929093 TI - The need for RN circulators. PMID- 25929094 TI - A century of legislative accomplishments of North Carolina nurses. PMID- 25929095 TI - Nursing advocacy 101: start where you are to do what you can. PMID- 25929096 TI - 2015--year of ethics. PMID- 25929097 TI - Nutrition education and gardening in elementary and secondary schools. PMID- 25929098 TI - The role of the advanced practice nurse in the treatment of addiction disorders: advocacy, leadership, lobbying to influence public policy. PMID- 25929099 TI - Nursing leadership in Scotland. PMID- 25929100 TI - Transformational leadership in long-term care in Inverness, Scotland. PMID- 25929101 TI - Sue Sloan, nurse leader. PMID- 25929102 TI - Janet Smith: a transformational leader. PMID- 25929103 TI - Ellen Hudson: a transformational leader. PMID- 25929104 TI - The perception by faculty and students on the use of wireless devices, as an active learning tool, in the associate degree nursing (ADN) program. PMID- 25929105 TI - [Peculiarities of the expression, structure, and localization of the subtilisin like protease in the microsporidium Paranosema locustae]. AB - Peculiarities of the expression, localization, and structure of the subtilisin like protease from the microsporidium Paranosema locustae, a parasite of the migratory locust and other orthopteran species, are analyzed. Heterologous expression of the microsporidian ferment in the bacterium Escherichia coli allowed obtaining antibodies to the recombinant protein and to start its examination. In spite of the presence of the N-tail signal peptide in the ferment, potentially able to secret it into the cytoplasm of the infected cell, immunoblotting with obtained antibodies had demonstrated specific accumulation of the protease in the insoluble fraction of spore homogenate. At the same time, the ferment was absent in intracellular stages.of the parasite and also in the cytoplasm of infested host cells. Accumulation of mRNA, coding the studied protein in microsporidian spores was confirmed with the use of RT-PCR method. Heterologous expression of the protease in the methylotrophic yeast Pichiapastoris demonstrated the same result. The ferment of P. locustae was not secreted into a culture medium and was absent in the cytoplasm of yeast cells, accumulating in a dissoluble (membrane) fraction of the homogenate. On the whole, the obtained data testify to the fact that the subtilisin-like protease of P. locustae plays an important role in the physiology of spores rather than participates in host-parasite relations during intra-cellular development. PMID- 25929106 TI - [The study of Balantidium Helenae Bezzenberger, 1904 (Litostomatea, Trichostomatia) inhabiting the intestines of the frog Rana temporaria Linnaeus, 1758, in optical and electron microscopes]. AB - The structure of the ciliate Balantidium helenae Bezzenberger, 1904 was investigated with the use of optical and electron microscopy. It was demonstrated that, together with the basic dimensional characteristics, main distinguishing features of the studied species include the following characters: the presence of a pointed prominence on the posterior margin of the cell; the presence of elongated cilia on the left margin of the vestibulum; and different shape and size of cortical ridges. Two morphologically different types of electron-dense bodies (supposedly hydrogenosoms) and also endobiotic bacteria were also found in the cytoplasm of B. helenae. PMID- 25929107 TI - [Infestation of lower crustaceans (Copepoda, Cladocera) with microsporidians (Microsporidia) in Western Siberia]. AB - The search for intermediate hosts of microsporidians of bloodsucking mosquitoes of the family Culicidae with complicated two-host developmental cycles in Western Siberia resulted in revealing of 19 microsporidian species in crustaceans. Crustacean microsporidians are represented as by specialized parasites of crustacean, being or being not related to microsporidians parasitizing mosquitoes, and by parasites of mosquitoes having only a part of their complicate life cycle in crustaceans. Sequencing of ssrDNA of microsporidins from copepods had demonstrated that Acanthocyclops venustus Norman et Scott can be an intermediate host of Amblyospora rugosa Simakova et Pankova, 2005 .from mosquitoes Oc. cataphylla Dyar., and Acantocyclops reductus (Chappuis) can be an intermediate host of Trichoctosporea pygopellita Larsson, 1994, a parasite of the mosquito Oc. excrucians (Walker). According to their fine structure, microsporidians from Daphnia Muller belong to the genera Bervaldia Larsson, 1981 and Agglomerata Larrson et Yan, 1988. The infestation rate in natural population of crustaceans was low, constituting about 2%. The maximal infestation rate was observed in temporary reservoirs since late April till early May. PMID- 25929108 TI - [Early stages of development of Trypanosoma rotatorium (Mayer, 1843) from peripheral blood and internal organs of Anurans Bufo bufo (Linnaeus) and Rana sp. (Anura)]. AB - The data on the fauna of trypanosomes of Anura of the Leningrad Province are given. The initial development stages of Trypanosoma rotatorium in peripheral blood and internal organs of the frog are described for the first time. PMID- 25929109 TI - [Goussia obstinata sp. n. (Sporozoa: Eimeriidae), a new coccidian species from intestines of the Amur sleeper Perccottus Glenii Dybowski, 1877 (Perciformes: odontobutidae)]. AB - Goussia obstinata sp. n. is described from the intestine epithelium of the Amur sleeper Perccottus glenii Dybowski, 1877 from Russia and Moldova. The species was examined in an optical microscope. Merogonic, gamogonic and sporogonic stages of the species are located in cells of the gut epithelium. Sporulation is endogenous; oocysts are released in the gut lumen. Non-sporulated oocysts are spherical or ellipsoidal; sporulated oocysts are rounded, 6.7-11.4 MUm in diameter, with a colorless, single-layer, very fine and easily ruptured wall. Micropyle and oocyst residuum is absent; 1-2 small polar granules of 1.0-2.5 MUm are sometimes present. Oocysts contain four compact widely oval, slightly narrow ended sporocysts. The sheath of the sporocyst is formed of two folds divided by a slightly S-shaped longitudinal suture. Coarsely granulated, globular or oval compact sporocyst's residuumis located between sporozoites. Sausage-shaped sporozoits are subdivided by a bend into two unequal parts, being 6.4-9.8 MUm (long part) and 2.6-4.8 MUm (short part) long, arranged in a top-to-tail position. Our preliminary data suggests that infestation of the sleeper with the examined parasite is not associated with the morbidity and mortality of the fish. A new combination Goussia marmorata (Molnar, 1996) comb. n. is proposed for a species originally described in the content of the genus Eimeria Schneider, 1875 from the Western tubenose goby Proterorhinus semilunaris. PMID- 25929110 TI - [Fleas (Siphonaptera) of mammals from the mountain area between the Kuban and Great Laba Rivers]. AB - The flea fauna of mammals in the area between the Kuban and Great Laba Rivers contributes 47 species. The majority of mammal fleas parasitize on several hosts. Peculiarities of the species composition and the structure of flea communities dwelling in different altitudinal belts is estimated. The flea Ctenophthalmus wagneri and some other flea species possessing ancient Mediterranean range show the highest dominance indices in foothills. Ctenophthalmus proximus and Leptopsylla taschenbergi, possessing ranges of the Caucasian type, prevail in the middle mountain belt. Megabothris turbidus and some other boreal species dominate among species collected in the high mountain belt. PMID- 25929111 TI - Smooth transitions to adult health care: do all the rules have to change? PMID- 25929112 TI - Communication in autism spectrum disorder: a guide for pediatric nurses. AB - In the United States, one in every 68 children has autism spectrum disorder (ASD) (Centers for Disease Control and Prevention, 2014). ASD is a developmental disorder of the brain that is characterized by impairments in social interaction, communication, and repetitive patterns of behavior (American Psychiatric Association [APA], 2013). Nurses have a duty to provide high quality care to children with ASD. Effective communication is essential to providing quality care. Three main theories attempt to explain how the ASD brain functions and the implications on communication: lack of theory of mind, weak central coherence, and lack of executive function. Children with ASD have difficulties in vocalic, kinesthetic, and proxemic aspects of communication (Notbhom, 2006). Simple adaptations to environment and style can make the communication between nurses and children with ASD easier and more effective (Aylott, 2000; Green et al., 2010). PMID- 25929113 TI - Demystifying pediculosis: school nurses taking the lead. AB - The treatment of Pediculosis capitis, or head lice, is fraught with misinformation, myths, and mismanagement. Common myths include the need to exclude children from school, the need to remove all visible nits ("no-nit" policies), the need for massive environmental cleaning, that head lice live for long periods of time, and that schools are a common location for lice transmission. Head lice are a common childhood nuisance, causing embarrassment and emotional trauma in both children and families. This article explores and challenges the commonly held beliefs about the identification, management, and treatment of Pediculosis by presenting current recommended evidence-based practice. It also challenges pediatric nurses, and school nurses in particular, in alignment with the National Association of School Nurses (NASN) Position Statement on Pediculosis Management in the School Setting, to act as change agents for reasonable and effective school policies and practices. PMID- 25929114 TI - Effects of leadership characteristics on pediatric registered nurses' job satisfaction. AB - Job satisfaction levels among registered nurses (RNs) influence RN recruitment, retention, turnover, and patient outcomes. Researchers examining the relationship between characteristics of nursing leadership and RN job satisfaction have treated RNs as a monolithic group with little research on the satisfaction of hospital-based pediatric RNs. This study assessed the relationship of transformational and transactional nursing leadership characteristics and RN job satisfaction reported by pediatric RNs. This single site study included 935 hospital-based pediatric RNs who completed validated survey items regarding nursing leadership and job satisfaction. A structural equation model (SEM) was applied to assess how autonomy (transformational leadership) and distributive justice (transactional leadership) influence RN job satisfaction, and how RN socio-demographic characteristics influence job satisfaction via autonomy and distributive justice. Findings revealed that both autonomy and distributive justice had significant positive effects on RN job satisfaction but the largest source of influence was autonomy. PMID- 25929115 TI - Searching for job satisfaction. PMID- 25929116 TI - Education given to parents of children newly diagnosed with acute lymphoblastic leukemia: the parent's perspective. AB - Over the last 30 years, diagnosis and treatment of childhood cancers have improved significantly due to medical research and advancements in technology. Increasingly, parents are taking on the role of providing "nursing" care for their children, including managing emergency situations as well as everyday treatment needs. This study investigated the perceptions and experiences of parents caring for newly diagnosed children with acute lymphoblastic leukemia (ALL) in relation to education given prior to the first discharge from hospital. Using a grounded theory approach, 12 parents of children with ALL from a tertiary pediatric hematology and oncology setting in New Zealand were interviewed using a semi-structured interview technique. Key findings of relevance to clinical practice include the importance of recognizing the emotional strain parents experience following diagnosis and the resultant impact upon how education is understood. Findings may also be applicable to other complex child health areas where education is provided, both in a local and international context. Understanding the family perspective is crucial to enabling clinicians to provide appropriate and informative education to children with ALL and their families. PMID- 25929117 TI - Transitioning from pediatric to adult health care: the experience of patients and families. AB - Due to advances in medicine, many young adults with complex chronic conditions are now able.to reach the age when they must transition from pediatric to adult care. But preparation for these transitions is often inadequate--for patients and their families, as well as for adult providers. As a result, many needs (clinical, psychosocial, and educational) may not be met, and patients and their families may feel uncertain about the quality of care. This article is the first in a series addressing this critical issue by providing insights from patients and families who have experienced transitions, as well as information about programs and available resources. In this article two parents and one young adult patient share their stories of transitioning, identify the numerous challenges they faced, and suggest strategies to improve the health care system for other patients and families. PMID- 25929118 TI - Promoting breastfeeding in infants with cow's milk protein allergy: a case study. PMID- 25929119 TI - Case study: the unilateral tear. PMID- 25929120 TI - A brother's perspective. PMID- 25929121 TI - Knowledge and recognition of SIRS and sepsis among pediatric nurses. AB - BACKGROUND: A large amount of research demonstrates the importance of key interventions in reducing mortality rates of pediatric patients with sepsis (Dellinger et al., 2008). Assessment and recognition of declining status must occur for interventions to be initiated. Of health care practitioners, nurses typically spend the most time with patients, and they must be knowledgeable in recognizing the systemic inflammatory response syndrome and sepsis while also being aware of the importance of prompt intervention. The literature does not discuss pediatric nurses' knowledge of systemic inflammatory response syndrome (SIRS)/sepsis recognition. OBJECTIVES: The purpose of this study was to assess the knowledge of acute and critical care pediatric nurses of SIRS diagnostic criteria, sepsis guidelines, and the importance of SIRS recognition. METHODS: This cross-sectional, quantitative, correlational descriptive study included 242 acute and critical care pediatric nurses at a 490-bed urban pediatric hospital. Participants completed an original questionnaire with face and content validity regarding SIRS criteria, sepsis guidelines, priority interventions, and attitude toward the importance of SIRS recognition. RESULTS: Findings demonstrated a significant knowledge deficit among participants in several key areas of SIRS/sepsis recognition. The mean score was 60.8% +/- 7.4%. Item analyses demonstrated nurses easily recognize septic shock but have difficulty recognizing patients in earlier stages of the sepsis continuum. Significant confusion was evident regarding the role of blood pressure and serum lactic acid levels in diagnosing sepsis. CONCLUSION: It is recommended that an educational intervention be created for acute and critical care pediatric nurses to aid them in recognizing sepsis in its earlier stages. PMID- 25929122 TI - Examining nutrition among a sample of 3- to 5-year-old children living in rural Jamaica. AB - BACKGROUND: The period of early childhood, defined as three to five years of age, is an important and distinct stage in childhood development. Changes in dietary patterns and composition of diets are exposing children in developing countries to over-nutrition as well as under-nutrition. OBJECTIVE: To describe the nutritional status, dietary patterns, and socio-economic conditions of three to five-year-old children living in rural Jamaica. SAMPLE: A convenience sample of 142 children was recruited over a three-year period. MEASUREMENTS: Height and weight measurements were collected. Household dietary patterns and socio-economic indicators were available from a small group (n = 6) of parents. RESULTS: Children experiencing both under-nutrition and over-nutrition were identified. Nine percent (n = 13) could be classified as moderately to severely under nourished, and 6.9% (n = 10) classified as overweight. Frying was a common cooking method, and fruits and vegetables were eaten often. CONCLUSIONS: Economic and political changes may place children in developing countries at risk for over nutrition as well as under-nutrition. The school setting may be an important place to address nutritional issues. This analysis describes the nutritional status of a sample of three to five-year-old children living in rural Jamaica and provides suggestions for future research. PMID- 25929123 TI - Evidence of improved quality of life with pediatric palliative care. AB - Pediatric nurses provide holistic family-centered care for children with life limiting illnesses while being sensitive to children's growth and developmental needs. To learn how pediatric palliative care programs benefit children and their families, the following clinical question was asked: Among children with a life limiting illness, does the use of a palliative care program compared with not using a palliative care program improve quality of life for patients and their families? Evidence from two studies found that palliative care services improve quality of life for children with life-limiting illness and their families in the areas of the child's emotional well-being and parental perception of preparation for the child's end of life, resulting in a low grade for the body of evidence. Future research should include high quality studies with larger sample sizes and control groups, and include children's perspectives--from both patients and siblings--to give a more complete picture of how best to improve their quality of life. A reliable tool is needed that includes a spiritual component and sensitive indicators specific to children with a life-limiting illness. Future research using this tool will more fully answer how palliative care services improve children's quality of life. PMID- 25929124 TI - Teen Advisory Committee: lessons learned by adolescents, facilitators, and hospital staff. AB - The Teen Advisory Committee (TAC), Boston Children's Hospital (BCH), began in 2002 and has been meeting monthly since that time. The top lessons learned by adolescents, committee facilitators, and hospital staff incorporate principles of adolescent development, joint decision-making, and a respect and commitment to patient and family-centered care. The program addresses the unique needs of teens with chronic illness from their perspective through special projects that have led to the development of hospital policies, procedures, and quality improvement initiatives. The discussion of the framework of the TAC and lessons learned are intended to support youth-driven initiatives and models for improvement at children's hospitals nationally. PMID- 25929125 TI - The lived experience of pediatric burn nurses following patient death. AB - The purpose of this study is to describe the lived experience of pediatric burn unit nurses who have experienced the death of a patient. A qualitative phenomenological design was used for the interview and analysis. Methods were incorporated into the design to ensure reliability, consistency, and rigor. Using a semi-structured interview guide and phenomenological concepts, the investigators interviewed seven registered nurses who were employed in a pediatric burn unit. Data obtained were analyzed for common themes that emerged during examination of transcribed interviews. Four common themes of feelings were identified: 1) grief and sadness, 2) helplessness, 2) compartmentalization of feelings, and 4) lack of preparedness for dealing with situations involving the death of a pediatric patient. While nurses are emotionally supportive to patients and families, the emotional support available to nurses who are dealing with these situations is lacking. By developing individual coping strategies and seeking peer support, nurses attempt to deal with emotional situations faced in the workplace. Nurses, nurse educators, and administrators must understand the impact of nurses' grief following patient death. By understanding and validating their emotions, it is hoped that nurses will be supported in a way that will enhance a healthy professional environment and personal well-being. PMID- 25929126 TI - An educational intervention to improve pain assessment in preverbal children. AB - PROBLEM: Pediatric nurses often use an inappropriate tool to assess pain in children younger than 36 months of age. OBJECTIVE: This intervention intended to improve the nursing practice of assessing pain in preverbal (less than 36 months of age) children. METHODS: Pain assessment frequency and use of a pain assessment pediatric tool use was evaluated pre- and post-intervention via a retrospective chart review and a survey of pediatric nurses. Parametric and non-parametric statistical tests were used to determine significant differences between pre- and post-intervention data for both approaches. RESULTS: The chart review data showed a significant increase in the number of times pain was assessed and documented post-educational intervention. Similarly, the survey data analysis showed a significant post-intervention increase in the use of a pain assessment tool and that most nurses used the FLACC pain assessment tool when assessing pain in preverbal children. CONCLUSION: Educating staff nurses about the use of an appropriate pain assessment scale altered practice and improved the frequency of pain assessment of preverbal children. PMID- 25929127 TI - Patient- and family-centered transitions from pediatric to adult care. AB - This article is the second in a series addressing the critical issue of the transition from pediatric to adult care for young adults with complex chronic conditions. Using the analogy of her daughter's recent transition from high school to college, the author highlights some of the needs of young adults and their families in a transition process. Then, drawing upon her years of experience in the field, she explains why the core principles of patient- and family-centered care are foundational to successful transitioning from pediatric to adult health care. PMID- 25929128 TI - [Reprogramming of somatic cells. Problems and solutions]. AB - An adult mammal is composed of more than 200 different types of specialized somatic cells whose differentiated state remains stable over the life of the organism. For a long time it was believed that the differentiation process is irreversible, and the transition between the two types of specialized cells is impossible. The possibility of direct conversion of one differentiated cell type to another was first shown in the 80s of the last century in experiments on the conversion of fibroblasts into myoblasts by ectopic expression of the transcription factor MyoD. Surprisingly, this technology has remained unclaimed in cell biology for a long time. Interest in it revived after 200 thanks to the research of Novel Prize winner Shinya Yamanaka who has shown that a small set of transcription factors (Oct4, Sox2, Klf4 and c-Myc) is capable of restoring pluripotency in somatic cells which they lost in the process of differentiation. In 2010, using a similar strategy and the tissue-specific transcription factors Vierbuchen and coauthors showed the possibility of direct conversion of fibroblasts into neurons, i. e. the possibility of transdifferentiation of one type of somatic cells in the other. The works of these authoras were a breakthrough in the field of cell biology and gave a powerful impulse to the development of cell technologies for the needs of regenerative medicine. The present review discusses the main historical discoveries that preceded this work, evaluates the status of the problem and the progress in the development of methods for reprogramming at the moment, describes the main approaches to solving the problems of reprogramming of somatic cells into neuronal, and briefly discusses the prospect of application of reprogramming and transdifferentiation of cells for such important application areas as regenerative medicine, cell replacement therapy and drug screening. PMID- 25929129 TI - [Steadiness of multipotent mesenchymal stromal cells from adipose tissue to anoxia in vitro]. AB - We have compared the effects of anoxia on multipotent mesenchymal stromal cells (MMSCs) preconditioned at 20 and 5 % O2. It has been shown that the lack of oxygen in the growth phase is accompanied by active cell proliferation, the decrease in their size and increasing the homogeneity of the population. At the same time, the anoxia reduced share of CD54-cells and did not change the number of cells expressing CD90 and CD73 surface markers. Preconditioning at 20% O2 increased the proliferative potential of cells, which nevertheless remained significantly, lower than that of the cells preconditioned at 5% O2. The level of lactate production was also significantly higher for cells preconditioned at 20% O2. However, the highest molar ration of lactate production and glucose consumption (Y(La/Glu)) was typical for MMSC pre-cultured at 5% O2. At anoxia, monolayer MMSCs conversely showed a decrease in this ratio by comparison with control cells and the cells cultured in growth phase. While maintaining a high level of viability under anoxia in the growth phase and in monolayer, we detected significant decrease in mitochondrial transmembrane potential. At the same time, the level of reactive oxygen species was increased only for MMSCs placed in anoxia in the active growth phase. PMID- 25929130 TI - [Mitochondria-targeted antioxidant SkQR1 selectively protects MDR-negative cells against ionizing radiation]. AB - Radioprotection appeared to be an important problem of today due to atom energetic development and utilization of radiation material in the industry, science and medicine. It has been shown that mitochondrial targeted antioxidant SkQR1 could attenuate radiation injury of human erythroleukemia K562 cells. Pretreatment with SkQR1 before irradiation decreased DNA double strand breaks formation, diminished the number of chromosomal aberrations and suppressed delayed ROS production. Prevention of oxidative stress and normalization of mitochondrial function by mitochondria-targeted antioxidants may be a potential therapeutic strategy not only against immediate consequences of radiation, but, either against its late consequences such as genomic instability. SkQR1 did not protect against radiation-induced damage the K562 subline with high level of multidrug resistance (MDR) due to SkQR1 extrusion with Pgp 170 MDR pump. We suggest that mitochondria-targeted antioxidants might be used for selective protection of normal cells against radiation-induced damage without interference with radiotherapy of MDR-positive tumors. PMID- 25929131 TI - [Resolution of spatial constraints during replication of peripheral chromatin]. AB - Tight association of peripheral chromatin with nuclear lamina unavoidably creates topological constraints during replication. Additional complications are associated with high stability of lamina meshwork, which may hinder an access of replication factors to the sites of DNA synthesis in highly condensed template with limited mobility. In the current work we studied structural organization and dynamics of lamina as a function of replicative status of associated peripheral heterochromatin. The studies of molecular mobility of laminas at various stages of S-phase in vivo and using super-resolution microscopy showed no correlation between lamina dynamics and replicative status of attached heterochromatin. These data support the hypothesis that lamina-chromatin interactions during S-phase are regulated at the level of adapter proteins. Ultrastructural studies have demonstrated that temporal break of lamina-chromatin connections during replication does not cause noticeable spatial separation of replicating domains from nuclear periphery. PMID- 25929132 TI - [The influence of two-month treatment with bromocryptine on activity of the adenylyl cyclase signaling system in the myocardium and testes of rats with type 2 diabetes mellitus]. AB - One of the common complications of type 2 diabetes mellitus (DM2) are cardiovascular diseases and dysfunctions of the reproductive system, indicating the urgency of developing new approaches to their correction. Last years for the treatment of DM2 began to use bromocryptine (BC), the agonist of type 2 dopamine receptors, which not only restores the energy metabolism, but also prevents the development of cardiovascular diseases. However, the mechanisms and targets of BC action are poorly understood. The purpose of this study was to investigate the effect of BC treatment on functional activity of adenylyl cyclase signaling system (ACSS) in the myocardium and testes of male rats with DM2, which is caused by high-fat diet and treatment with streptozotocin (25 mg/kg). The treatment with BC (60 days, orally at a dose of 0.6 mg/kg once every two days) was started 90 days after the beginning of high-fat diet. Diabetic rats had an increased body weight, elevated triglycerides level, impaired glucose tolerance, and insulin resistance. The treatment with BC resulted in the restoration of glycometabolic indicators and in the improvement of insulin sensitivity. Adenylyl cyclase (AC) stimulating effects of guanylylimidodiphosphate (GppNHp), relaxin, and agonists of beta-adrenergic receptors (beta3-AR)--isoproterenol and norepinephrine were decreased in the miocardium of the diabetic rats. The corresponding effects of the beta-agonists BRL-37344 and CL-316243 was preserved. The inhibitory effect of somatostatin on forskolin-stimulated AC activity was attenuated, while the inhibitory effect of noradrenaline mediated through alpha2-AR increased. The treatment with BC resulted in the normalization of the adrenergic signaling in the myocardium and partially restoration of AC effects of relaxin and somatostatin. In the testes of diabetic rats, the basal and stimulated by GppNHp, forskolin, human chorionic gonadotropin and pituitary AC-activating polypeptide AC activity were decreased, and the inhibitory effect of somatostatin was attenuated. The changes in testicular ACSS in the case of BC treatment were weakly expressed. Thus, long-term BC treatment restores the functional activity of ACSS in the myocardium and testes of diabetic rats that underlies the therapeutic effect of BC on functions of the cardiovascular and reproductive systems disturbed in DM2 and should be considered when developing strategies for treatment type 2 diabetes and its complications. PMID- 25929133 TI - [Peculiarities of neurodegeneration in hippocampus fields after kainic acid action in rats]. AB - Comparison between results of different ways of application of excitotoxin (kainic acid, KA), intrahippocampal (0.2 MUg/MUl) and intraventricular (0.6 MUg/MUl), was carried out in the course of investigations of the prolonged action of KA on the morphological state of various fields in dorsal hippocampus. Light microscopy with Cresyl Violet staining and fluorescent microscopy with staining by fluoro-jade B were used in our researches. The results revealed that KA, being injected intrahippocampally at a dose, which does not result in animal epileptization, caused obvious degenerative phenomena in hippocampus. Two weeks after KA injection the layers of pyramid cells in the fields CA3 and CA4 were absent, and in four weeks, degenerative changes and cell lysis were spread on the CA1 field as well. Four weeks after KA intraventricular administration in rats with epileptic status the damages of various levels were observed in hippocampus, from partial injuries of pyramid neurons in the fields CA3 and CA4 up to full loss of layers of pyramids in the fields CA1, CA3 and CA4. In both ways of KA injection, in the CA2 field the layer of cells mainly remained undamaged what indicates a special role of this field. After a single-time KA administration the both ways of injection led to the long-term damages of a neural tissue, possibly, of a general character, but differing in rates of neuron reactions in different fields to the damaging factor. An explanation of the prolonged action of KA excitotoxicity might be in the activation of GluR6-containing kainate receptors in pyramid neurons in CA3 field which brings to chronic character in single-time KA action and promotes the destruction of the remaining neurons by necrotic way while at the initial stage of KA influence the neurons perish by apoptotic way. PMID- 25929134 TI - [Recellularization of tissue engineered vascular grafts in perfusion bioreactor]. AB - Small diameter tissue engineered vascular grafts could be a potential solution to the shortage of vascular substitutes in reconstructive cardiovascular surgery. Previously, we have developed a decellularization method for human umbilical arteries, which could be used as a scaffold in vascular tissue engineering. Objective of the study was to optimize the recellelularization of decellularized scaffolds with mesenchymal stem cells. In the study, the possibility of cell growth on decellularized vessel has been shown. We also has proved that the use of perfusion-bioreactor improves the results of recellularization. PMID- 25929135 TI - [Some aspects of cytological diagnostics]. AB - In many countries both histological and cytological examinations are performed by pathologists. In Russia and some countries of the former Soviet Union, pathological anatomists usually do not examine cytological specimens. Cytology belong to another specialty: laboratory medicine. Some cytological smears can contain tissue fragments, evaluation of which requires application of histopathological criteria. Comparisons of cytological and histological specimens are of great significance because of the relatively high percentage of inconclusive reports in cytology, when only a suspicion can be expressed. In conclusion, it is proposed to unify the practical specialties "cytology" and "pathological anatomy" in Russia under the designation "pathoology". PMID- 25929136 TI - Patterns of misreporting intimate partner violence using matched pairs. AB - Intimate partner violence (IPV) is an issue of serious public concern. However, policy interventions and theoretical development have been complicated by mixed evidence about whether men or women experience higher levels of IPV. Some of this discrepancy arises from measurement and whether abuse and victimization are asked of one or both partners. This study uses matched partner data from 1,393 heterosexual couples collected in Wave IIIof the National Longitudinal Study of Adolescent to Adult Health to examine partner IIV reporting discrepancies and develop hypotheses for why such discrepancies might exist. Consistent with expectations, the findings suggest that research on the prevalence of IIV should rely on reports from both partners, rather than just one, and that gendered patterns of social desirability create differences in men's and women's IPV reporting. PMID- 25929137 TI - Prevalence and phenomenology of neonaticide in Switzerland 1980-2010: a retrospective study. AB - For a child, the likelihood of being murdered is highest during the first year of life, and many such cases are neonaticides. Although several recent studies have examined neonaticide in different countries and cultures, there has been no in depth analysis of Swiss cases, even though this country has special neonaticide legislation and four "baby hatches" have been opened to prevent such killings. The primary objective of this retrospective study was to analyze the prevalence and phenomenon of neonaticide in Switzerland. Using data from judicial files, 11 cases were identified in 15 German-speaking cantons between 1980 and 2010. The sample included two uncommon cases of nonmaternal neonaticide. The discussion addresses possible prevention strategies. PMID- 25929138 TI - "Just how graphic are graphic novels?" An examination of aggression portrayals in manga and associations with aggressive behavior in adolescents. AB - Manga, a type of graphic novel, represent a widely popular literary genre worldwide and are one of the fastest growing areas of the publishing arena aimed at adolescents in the United States. However, to our knowledge, there has been almost no empirical research examining content or effects of reading manga. This article consists of 2 studies. Study 1 represents a content analysis of aggressive behavior in best-selling manga aimed at adolescents. Results revealed that aggression was common and was often portrayed in ways that may influence subsequent behavior. Study 2 examined the relationship between reading manga and aggressive behavior in 223 adolescents. Manga readers were more physically aggressive than non-manga readers and also reported more peer relationships with lonely individuals and smaller groups. In addition, reading manga with particularly high levels of aggression was associated with physical aggression even after controlling for media violence exposure in other media. Implications regarding these findings are discussed. PMID- 25929139 TI - Interpersonal youth violence perpetration and victimization in a diverse Asian American and Pacific Islander adolescent sample. AB - This study was the first to examine ethnic, sex, and ethnicity-by-sex differences for under-researched, Asian American and Pacific Islander, adolescent groups on youth violence outcomes other than cyberbullying. This effort included the less researched, emotional violence, and included socioeconomic status (SES) measures as covariates. The sample size from 2 high schools in spring 2007 was 881, using an epidemiologic survey design. The pattern of results was higher rates of violence victimization for ethnic groups, with lower representation in the 2 schools' population, and ethnic groups that more recently moved or immigrated to Hawai'i. For emotional victimization, girls of European American and "other", ethnicities self-reported higher rates than boys. Several implications (e.g., need for ethnically and gender-based approaches) and further research (e.g., ethnocultural identity) are discussed. PMID- 25929140 TI - Health implications of partner violence against women in Ghana. AB - This article explores the health implications of partner violence against women in Ghana using data from northern Ghana. Face-to-face structured interviews were conducted with a sample of 443 women contacted at health facilities in the northern region. Results indicate that 7 out of 10 women have experienced intimate partner violence (IPV) within the past 12 months; 62% had experienced psychological violence, 29% had experienced physical violence, and 34% had experienced sexual violence. Participants reported health problems associated with violence, including injury, thoughts of suicide, sleep disruption, and fear of partner (FP). Logistic regression analyses showed that women who reported physical, psychological, and sexual violence, respectively, had 3.94 times, 10.50 times, and 2.21 times the odds of reporting thoughts of suicide, whereas the odds that women who reported physical, psychological, and sexual violence would report sleep disruption were 4.82 times higher, 4.44 times higher, and 2.50 times higher, respectively. However, only physical and psychological violence predicted the odds of FP. This study shows that IPV is a health risk factor among women in Ghana. Measures that should be designed to improve the health of women experiencing marital violence are suggested. PMID- 25929141 TI - Effects of group status and victim sex on female bystanders' responses to a potential party rape. AB - This research examined bystander responses to 1 of 4 potential party rape scenarios. Undergraduate women (N = 249) imagined attending a party either alone or with three friends where a sober man led an intoxicated potential victim (either male or female) into a bedroom. After random assignment to conditions, participants reported on intent to help and barriers to helping the potential victim. In contrast to the classic bystander effect, bystanders in groups intended to offer more help than lone bystanders. Bystanders also intended to offer more help to potential female than male victims and experienced more barriers to helping male victims. Two of these barriers (lack of personal responsibility to help and identifying risk) explained the lower intentions to help potential male victims. Potential male victims were more likely than female victims to be perceived as gay, and bystanders reported the least intentions to help presumably gay men at risk. PMID- 25929142 TI - Violence against teachers in South Korea: negative consequences and factors leading to emotional distress. AB - Empirical studies indicate that violence against teachers is a globally prevalent phenomenon and has damaging negative effects on victimized teachers' physical and emotional well-being and teaching effectiveness. Nevertheless, limited empirical research has been conducted to identify factors affecting emotional distress among victimized teachers. This research contributes to the literature by exploring negative consequence of victimization and factors associated with victimized teachers' emotional distress in a South Korean context. The results indicate that students' verbal and noncontact physical aggression are highly correlated with teachers' emotional distress. Teachers' gender, student-oriented approach, and several incident characteristics (number of offending students, direct settlement with offending students) are significant predictors of emotional distress caused by either students' verbal threat or noncontact aggressive behaviors. Directions for future research and policy implications are discussed. PMID- 25929143 TI - Translational models of workplace violence in health care. AB - Decision makers have little time to study literature on the prevention and management of workplace violence (WPV). In a health care workplace setting, identifying the person, stimulus, and environmental interactions that can lead to violence is a complicated process. Those in positions of leadership make decisions that affect many individuals, agencies, and communities. Often, they come from different professional backgrounds yet need ways of rapidly understanding concepts of violence that transcend their profession, training, or experience. Translational models (TMs) in WPV visually summarize and interprofessionally facilitate this understanding of concepts, enhancing the chances of more effective collaborative solutions to WPV. The purpose of this article is to demonstrate how TM can be used in interprofessional settings to find effective solutions to reduce WPV. PMID- 25929144 TI - Youth involvement in anti-gay and anti-lesbian bias crimes. AB - There is currently little information available about youth who commit bias crimes. This article contributes to the literature by highlighting the similarities and differences between sexual orientation-motivated bias crimes committed by adult and youth suspects. Among 894 reported sexual orientation motivated incidents in Los Angeles County between 2002 and 2008, this study found that, when compared to adult suspects, youth suspects were more likely to target other youths, were more likely to be in mixed-gender groups, were less likely to commit crimes against person, and were most likely to be reported as committing the crime at school. These preliminary findings highlight the need for additional research into bias-motivation among youth and to clarify the links between bullying and bias crimes. PMID- 25929145 TI - Precursors to rape: pressuring behaviors and rape proclivity. AB - We developed measures assessing personal and normative attitudes toward two types of behaviors that are symptomatic of rape culture. We conceptualize sexual violence as existing on a continuum and argue that two types of behaviors may be potential antecedents to (and consequences of) sexual violence: attempts to pressure, which mimic the power dynamics of rape in a less aggressive fashion, and benevolent dating behaviors, which are accepted dating scripts in which men initiate action. We examined individuals' acceptance of these behaviors in relation to their attitudes toward rape victims and among men to rape proclivity. This initial work suggests that these constructs and measures may be useful to investigate in future research. PMID- 25929146 TI - Recent victimization and recidivism: the potential moderating effects of family support. AB - Although various research confirms an overlap between victims and offenders, much less is known about victimization and recidivism. Using data from the Serious and Violent Offender Reentry Initiative evaluation, this study measures the extent to which the frequency of recent victimization influences recidivism in the 15 months following release from prison. Buffering effects are also investigated by examining whether family support moderates the relationship between victimization and recidivism. After controlling for other known predictors of recidivism, logistic regression models using both listwise deletion and multiple imputation reveal that more frequent victimization significantly increases the likelihood of any self-reported recidivism and has a particularly large effect on violent recidivism for those previously convicted of serious and violent offenses. Even at higher levels of family support, victimization still increases the likelihood of reoffending. PMID- 25929147 TI - Revise and resubmit: now what? PMID- 25929148 TI - Developing the infrastructure to support EBP: it takes partnerships. PMID- 25929149 TI - HIV viral load: a concept analysis and critique. AB - In this article, we examine the concept of HIV viral load and how it has evolved over time (1995-2013) in the field of HIV/AIDS. Although the term viral load is used extensively in this field, few efforts have been directed toward the conceptualization of HIV viral load, which is often left unquestioned, undertheorized, and portrayed as a neutral and objective laboratory value that has remained relatively stable over time--with the exception of progressive advancements in technology, techniques, and sensitivity. The purpose of this article is to apply the evolutionary concept analysis method developed by Rodgers (1989, 2000a) to the concept of HIV viral load. To set the stage, we establish the need for a concept analysis of HIV viral load and provide an overview of the evolutionary view. Then, drawing on the steps proposed by Rodgers (2000a), we outline the process of data collection, management, and analysis. We then offer an in-depth discussion of the findings (attributes, antecedents, and consequences) informed by Wuest's (2000) critical approach to concept analysis. We conclude by highlighting the implications of this analysis for clinical practice, research, and theory. PMID- 25929150 TI - Taking the right action in the right way: a comparison of frameworks for assessing the health and quality of life of a postsecondary student campus community. AB - The focus of campus health research, historically, has been on population health at the individual or aggregate level with little effort to examine the health of the students at a community level with a focus on the broader determinants of health and community-level intervention. The purpose of this article is to critique three models or frameworks of campus health, articulate the World Health Organization (WHO) vision of a health-promoting university, and demonstrate the efficacy of adapting the Community Health Action model for use in university and college settings. Foundational within this proposed model is taking the right action using the right process, an inclusive participatory process. Adaptation of the model requires careful attention to student engagement in community, a healthy campus infrastructure and processes, and relationships beyond the campus. Effective student community assessment and improvement of student community health, ultimately, will serve to generate knowledge and build skills at various levels to benefit the health and quality of life of the students, their student community, the educational institution, and the broader community. PMID- 25929151 TI - Abjection in nursing: silently reading the body. AB - AIM: Throughout their careers, nurses must deal with patients that may invoke feelings of dejection, repulsion, or distress. This abjection of the patient is a real issue already established within the literature. This article seeks to enlighten what continues to be silenced in nursing practice. APPROACH: This article will present a paradigm of the nurse, patient's body, and professional caring through the lens of abjection as theoretically defined by Julia Kristeva, using body hair in women as a forum for discussion. CONCLUSION: Abjection is linked, by its very nature, to the definitions of professional caring. The ability to read a body through the abjection of one's own self is a rite of passage for most nurses. PMID- 25929152 TI - Work stress and emotional exhaustion in nurses: the mediating role of internal locus of control. AB - BACKGROUND: Burnout is a major problem for nursing. There is a strong relationship between work stress and emotional exhaustion. Although studies report a negative correlation between the internal locus of control and emotional exhaustion and work stress, the number of studies available on the subject is limited. PURPOSE: This study intends to examine the extent to which the relationship between work stress and emotional exhaustion is mediated by nurses' internal locus of control. METHODS: The study adopted a cross-sectional survey design. The data were analyzed using structural equation modeling techniques. The study sample consisted of 347 nurses who worked in a university hospital in Izmir, Turkey and who agreed to participate in the study. The Work-Related Strain Inventory was used to evaluate the nurses' work stress level, Maslach Burnout Inventory was used to evaluate their emotional exhaustion levels, and the Locus of Control Scale was used to evaluate the internal locus of control. The variables of the study were based on the Neuman Systems Model. RESULTS: Work stress was positively related to internal locus of control (beta3 = .21, p < .001), which was, in turn, negatively associated with emotional exhaustion (beta = -.03, p > 0.1). Internal locus of control was negatively related to emotional exhaustion (beta = -.14, p < .001). Work stress is directly (beta = .87, p < .001) and indirectly related to emotional exhaustion (mediated by internal locus of control beta = .84, p < .001). Work stress is directly (beta = .87, p < .001) and indirectly related to emotional exhaustion (mediated by internal locus of control, beta = .84, p < .001). CONCLUSION: Although the relationship between emotional exhaustion and work stress was mediated, the impact of internal locus of control was limited. It is recommended that different variables be included in future studies so that they can mediate the relationship between work stress and emotional exhaustion. PMID- 25929153 TI - When Is Helping your Partner with Chronic Pain a Burden? The Relation Between Helping Motivation and Personal and Relational Functioning. AB - OBJECTIVE: Self-determination theory (SDT) may be a useful framework to understand why chronic pain affects partners. SDT postulates that individuals can engage in helping behaviors for different motives varying from more autonomous or volitional motives to more controlled or pressured motives. This article examines the relationship between partners' type of motivation to help (i.e., autonomous vs controlled) and their personal and relational functioning. Furthermore, mechanisms underlying this relationship (i.e., helping exhaustion and relationship-based need satisfaction) were examined. METHODS: In a sample of 48 couples, of which one partner had chronic pain (36 female patients), questionnaires measuring life satisfaction, positive and negative affect, anxiety and depressive feelings, relationship quality and relationship-based need satisfaction were filled out. Individuals with chronic pain (ICPs) also reported on pain intensity and disability whereas partners were requested to report on motives for helping and helping exhaustion. RESULTS: Data analysis with Structural Equation Modeling revealed that autonomous, relative to controlled, motives for helping among partners related positively to partners' well-being and relationship quality, and negatively to distress. The experience of helping exhaustion and relationship-based need satisfaction mediated these associations. Moreover, partners' autonomous helping motivation related positively to patient reported relationship quality among ICPs high in pain intensity. CONCLUSIONS: Applying SDT in a context of pain provides new insights into why chronic pain affects partners and how partners impact patient outcome. Directions for future research are outlined. PMID- 25929154 TI - Stereoselectivity of phosphotriesterase with paraoxon derivatives: a computational study. AB - The bacterial enzyme phosphotriesterase (PTE) exhibits stereoselectivity toward hydrolysis of chiral substrates with a preference for the Sp enantiomer. In this work, docking analysis and two explicit-solvent molecular dynamics (MD) simulations were performed to characterize and differentiate the structural dynamics of PTE bound to the Sp and Rp paraoxon derivative enantiomers (Rp-1 and Sp-1) hydrolyzed with distinct catalytic efficiencies. Comparative analysis of the molecular trajectories for PTE bound to Rp-1 and Sp-1 suggested that substrate binding induced conformational changes in the loops near the active site. After 100 ns of MD simulation, the Zn beta(2+) metal ion formed hexacoordinated- and tetracoordinated geometries in the Sp-1-PTE and Rp-1-PTE ensembles, respectively. Simulation results further showed that the hydrogen bond between Asp301 and His254 occurred with a higher probability after Sp-1 binding to PTE (47.5%) than that after Rp-1 binding (22.2%). These results provide a qualitative and molecular-level explanation for the 10 orders of magnitude increase in the catalytic efficiency of PTE toward the Sp enantiomer of paraoxon. PMID- 25929155 TI - Pharmacological characterization and antidiabetic activity of a long-acting glucagon-like peptide-1 analogue conjugated to an antithrombin III-binding pentasaccharide. AB - AIMS: To examine the biological characteristics of a novel glucagon-like peptide 1 (GLP-1) conjugate, in which an antithrombin III (ATIII)-binding pentasaccharide is conjugated to d-Ala(8) GLP-1 using a tetraethylene glycol linker. METHODS: We assessed GLP-1 receptor binding, cAMP generation and insulin secretory activity of the GLP-1 conjugate in vitro. Circulating half-life, glucose homeostatic and subchronic therapeutic effectiveness were then examined in vivo. RESULTS: The half-life of the GLP-1 conjugate in mice was ~11 h. In vitro insulin secretion from clonal beta cells and islets was increased (p < 0.001) by the conjugate. The conjugate had half maximum effective concentration values of 1.3 * 10(-7) and 9.9 * 10(-8) M for displacement of (125) I-GLP-1 in competitive GLP-1 receptor binding and cAMP generation, respectively. Glucose tolerance in normal mice, immediately and 4 h after conjugate injection, resulted in significant (p < 0.001) improvements in blood glucose. These effects persisted for >48 h after administration. Daily treatment (21 days) of high-fat-fed and ob/ob mice with 25 nmol/kg conjugate resulted in significant improvement in glucose tolerance (p < 0.001) and reductions in glycated haemoglobin (HbA1c; p < 0.01) equivalent to or better than with exenatide or liraglutide. Treatment of C57BL/KsJ db/db mice for 15 days with 100 nmol/kg conjugate significantly (p < 0.001) reduced glucose and raised plasma insulin. Oral glucose tolerance was significantly (p < 0.001) improved and both 24-h glucose profile (p < 0.001) and HbA1c levels (p < 0.001) were reduced. Islet size (p < 0.001) and pancreatic insulin content were increased without change of islet cell proliferation or apoptosis. CONCLUSION: These data show that d-Ala(8) GLP-1(Lys(37) ) pentasaccharide exerts significant antidiabetic actions and has a projected pharmacokinetic/pharmacodynamic profile that merits further evaluation in humans for a possible once-weekly dosing regimen. PMID- 25929156 TI - Impact of the 2009 AJCC staging guidelines for melanoma on the number of mitotic figures reported by dermatopathologists at one institution. AB - BACKGROUND: In 2009 the revised seventh staging system for melanoma recommended the use of mitotic count to separate stage T1a from T1b. However, careful scrutiny of cases may lead to an inadvertent selection effect, with consequent increased reporting of mitotic counts. METHODS: We investigated whether there is a significant increase in mitotic counts reported since 2009 for melanomas with a Breslow thickness of 1.0 mm or less. We conducted a retrospective, case controlled study examining invasive melanoma cases at a large academic center. Mitotic counts were compared between pathology reports before 2009 (n = 61) and after 2009 (n = 125), with a subset of slides re-examined in a blinded fashion. RESULTS: Before the 2009 staging guidelines, 51% of cases had one or more mitosis reported compared to 38% after 2009 (p = 0.113). Blinded re-counting did not yield a significant difference when compared with the original pathology reports in either group. CONCLUSIONS: There was not a significant difference in the number of mitoses reported after the implementation of the new guidelines. PMID- 25929157 TI - Thalidomide for treatment of gastrointestinal bleedings due to angiodysplasia: a case report in acquired von Willebrand syndrome and review of the literature. AB - INTRODUCTION: Acquired von Willebrand syndrome is a rare bleeding disorder and treatment of the associated gastrointestinal (GI) bleeding due to angiodysplasia is challenging. AIM: The aim of this study was to present a new case on the successful use of thalidomide in a patient with acquired von Willebrand syndrome and recurrent angiodysplasia-related GI bleedings, and to conduct a literature review on the use of thalidomide in patients with GI angiodysplasia. METHODS: A literature review was conducted, searching the electronic databases PubMed, Embase and Cochrane. RESULTS: We present a 75-year-old woman with IgG MGUS associated acquired von Willebrand syndrome (AVWS) who suffered from recurrent gastrointestinal (GI) bleedings and epistaxis. Treatment with immunoglobulins, desmopressin, Haemate-P and blood transfusions failed to achieve long-term haemostasis. Eventually, after these bleedings relapsed for almost a decade at 1- to 3-month intervals, thalidomide was prescribed. Since then, only one single nose bleed and one single melaena episode had occurred. She currently remains in remission of GI bleeds after 3 years and 3 months follow-up. The literature review revealed a beneficial effect of thalidomide in reducing GI bleeding due to angiodysplasia, including four case reports on inherited von Willebrand disease. CONCLUSION: In conclusion, thalidomide can be a reasonable option for the treatment of recurrent GI bleeding due to angiodysplasia in AVWS and we report for the first time that refractory or relapsing GI bleeding in patients with AVWS can successfully be controlled with thalidomide. PMID- 25929158 TI - Structured literature review of responses of cattle to viral and bacterial pathogens causing bovine respiratory disease complex. AB - Bovine respiratory disease (BRD) is an economically important disease of cattle and continues to be an intensely studied topic. However, literature summarizing the time between pathogen exposure and clinical signs, shedding, and seroconversion is minimal. A structured literature review of the published literature was performed to determine cattle responses (time from pathogen exposure to clinical signs, shedding, and seroconversion) in challenge models using common BRD viral and bacterial pathogens. After review a descriptive analysis of published studies using common BRD pathogen challenge studies was performed. Inclusion criteria were single pathogen challenge studies with no treatment or vaccination evaluating outcomes of interest: clinical signs, shedding, and seroconversion. Pathogens of interest included: bovine viral diarrhea virus (BVDV), bovine herpesvirus type 1 (BHV-1), parainfluenza-3 virus, bovine respiratory syncytial virus, Mannheimia haemolytica, Mycoplasma bovis, Pastuerella multocida, and Histophilus somni. Thirty-five studies and 64 trials were included for analysis. The median days to the resolution of clinical signs after BVDV challenge was 15 and shedding was not detected on day 12 postchallenge. Resolution of BHV-1 shedding resolved on day 12 and clinical signs on day 12 postchallenge. Bovine respiratory syncytial virus ceased shedding on day 9 and median time to resolution of clinical signs was on day 12 postchallenge. M. haemolytica resolved clinical signs 8 days postchallenge. This literature review and descriptive analysis can serve as a resource to assist in designing challenge model studies and potentially aid in estimation of duration of clinical disease and shedding after natural pathogen exposure. PMID- 25929159 TI - Simulated environmental transport distances of Lepeophtheirus salmonis in Loch Linnhe, Scotland, for informing aquaculture area management structures. AB - In the majority of salmon farming countries, production occurs in zones where practices are coordinated to manage disease agents such as Lepeophtheirus salmonis. To inform the structure of zones in specific systems, models have been developed accounting for parasite biology and system hydrodynamics. These models provide individual system farm relationships, and as such, it may be beneficial to produce more generalized principles for informing structures. Here, we use six different forcing scenarios to provide simulations from a previously described model of the Loch Linnhe system, Scotland, to assess the maximum dispersal distance of lice particles released from 12 sites transported over 19 day. Results indicate that the median distance travelled is 6.1 km from release site with <2.5% transported beyond 15 km, which occurs from particles originating from half of the release sites, with an absolute simulated distance of 36 km observed. This provides information suggesting that the disease management areas developed for infectious salmon anaemia control may also have properties appropriate for salmon lice management in Scottish coastal waters. Additionally, general numerical descriptors of the simulated relative lice abundance reduction with increased distance from release location are proposed. PMID- 25929160 TI - Enantioselective beta-Protonation by a Cooperative Catalysis Strategy. AB - An enantioselective N-heterocyclic carbene (NHC)-catalyzed beta-protonation through the orchestration of three distinct organocatalysts has been developed. This cooperative catalyst system enhances both yield and selectivity, compared to only the NHC-catalyzed process. This new method allows for the efficient conversion of a large scope of aryl-oxobutenoates to highly enantioenriched succinate derivatives and demonstrates the benefits of combining different activation modes in organocatalysis. PMID- 25929161 TI - Dizziness: increased risk for fractures. AB - Dizziness is a common problem that can affect a person at any age. One common, easily treatable cause of transient dizziness is called "benign paroxysmal positional vertigo," or BPPV. Dizziness can negatively affect one's quality of life and is associated with an increased risk of falls. This may be especially problematic for older people, who have a greater chance of falling and breaking bones. A study published in the May 2015 issue of JOSPT investigated whether BPPV is associated with an increased risk of falls that result in fractures. PMID- 25929162 TI - Avascular necrosis of the femoral head. AB - The patient was a 51-year-old man who was evaluated by a physical therapist for a chief complaint of right hip pain. The patient was treated with a single bout of nonthrust hip joint mobilizations, but due to the patient's atypical response and long-term use of oral corticosteroid medications, he was referred to his primary care physician. Radiographs and subsequent magnetic resonance imaging revealed findings that were characteristic of avascular necrosis. PMID- 25929163 TI - The psychometric properties of the dash and quickdash. PMID- 25929164 TI - Rapid replacement of prevailing genotype of human respiratory syncytial virus by genotype ON1 in Beijing, 2012-2014. AB - Human respiratory syncytial virus (HRSV) is the most common viral pathogen causing lower respiratory infections in infants and young children worldwide. HRSV ON1 genotype in subgroup A with a characteristic of a 72 nucleotide duplication in the second highly variable region of attachment glycoprotein gene, has been reported in some countries since it was first detected in clinical samples collected in Canada in 2010. In this study, 557 HRSV antigen-positive nasopharyngeal aspirates were randomly selected during 2012/2013 to 2013/2014 HRSV seasons in Beijing for subgroup typing and for ON1 genotype screening by using a PCR based method developed for easily identifying genotype ON1 out of strains of subtype A. It was found that subgroup B was dominant in the 2012/2013 season and sudden shift of subgroup dominance from B to A and rapid replacement of previously prevailing NA1 genotype by ON1 genotype occurred in the 2013/2014 season. Reversible amino acid replacement in the G protein gene was found in a new branch of ON1 genotype. The evolutionary rate of the 351 global ON1 sequences was estimated to 7.34 * 10(-3) nucleotide substitutions per site per year (95% highest probability density intervals, HPD, 5.71 * 10(-3) to 9.04 * 10(-3)), with the time of most recent common ancestor dating back to June 2009. PMID- 25929165 TI - Association of CYBB polymorphisms with tuberculosis susceptibility in the Chinese Han population. AB - OBJECTIVE: Reactive oxygen species (ROS) play a major role in the nonspecific innate immune response to invading microorganisms, such as Mycobacterium tuberculosis (MTB). Gp91phox, encoded by CYBB, serves as a key functional subunit of the Nicotinamide Adenine Dinucleotide Phosphate (NADPH) oxidase complex, which is pivotal to ROS generation. Therefore, the aim of the study was to investigate the association of CYBB polymorphisms with tuberculosis (TB) susceptibility. METHODS: In total, 636 TB patients and 608 healthy, age and gender matched controls were enrolled in this study. All subjects were unrelated ethnic Han Chinese. Two tagSNPs were selected from the HapMap database and genotyped using matrix-assisted laser desorption/ionization time of flight mass spectrometry. RESULTS: After adjusting for confounders including age, gender and smoking, rs5917471 allele T showed significant association with decreased risk of TB (OR 0.745, 95% CI 0.556-0.999) and pulmonary TB (OR 0.618, 95% CI 0.410-0.931). However, no difference in allelic distribution was observed for the rs6610650 G/A polymorphism with respect to TB or different clinical types of TB. Further stratified analyses demonstrated the protective effect of allele T of rs5917471 was stronger among males (OR 0.500, 95% CI 0.295-0.846), smokers (OR 0.462, 95% CI 0.239-0.896), and male smokers (OR 0.372, 95% CI 0.182-0.761); the individuals carrying the A allele of rs6610650 exhibited an decreased risk of TB among males, smokers and male smokers, with OR (95% CI) of 0.535 (0.290-0.984), 0.442 (0.198 0.988), and 0.350 (0.145-0.845), respectively. There were no statistically significant differences in haplotype distribution between TB and control groups. Smoking and rs5917471 formed the best gene-environment interaction model with the testing balanced accuracy of 53.29% and cross-validation consistency of 9/10. CONCLUSIONS: This is the first study of the association of CYBB polymorphisms with TB. Our findings suggest that the CYBB polymorphisms are significantly correlated with reduced risk of TB, especially among male smokers. Further studies are needed to verify this association. PMID- 25929166 TI - Change of prognosis of patients with myelodysplastic syndromes during the last 30 years. AB - During the last years, more and more treatment modalities are available for MDS patients. Therefore, we were interested if this is reflected in an improvement of the outcome of the patients. We analyzed the survival and rate of leukemic progression of 4147 patients from the Duesseldorf MDS registry diagnosed during the last 30 years and found an improvement of survival in those patients diagnosed after 2002 (30 vs. 23 months, p<0.0001). In detail, the improvement of the prognosis was restricted to high-risk MDS patients diagnosed between 2002 and 2014 in comparison to the patient group diagnosed between 1982 and 2001 (19 vs. 13 months, p<0.001), whereas the prognosis of low-risk MDS patients did not change significantly. The improvement of survival was still measurable after exclusion of RAEB-t patients and of those, that received an allogeneic stem cell transplantation. In line with this finding, we found a lower AML progression rate in the later diagnosed group. Unfortunately, we could not identify a clear reason for this finding but rather a multifactorial cause should be assumed. As death due to bleeding complications and infections was significantly lower, an improvement of BSC may be one of the underlying causes. PMID- 25929167 TI - Exploring the need for a new UK occupational therapy intervention for people with dementia and family carers: Community Occupational Therapy in Dementia (COTiD). A focus group study. AB - OBJECTIVES: In the Netherlands, Graff et al. found Community Occupational Therapy in Dementia (COTiD) demonstrated benefits to people with dementia and family carers. In this study, focus groups took place with people with dementia and family carers to explore how to make COTiD relevant to the UK context. METHOD: Six focus groups (three with people living with dementia (n = 18) and three with family carers (n = 21)) took place. Participants were asked for their impressions of the intervention, the extent to which it could meet their needs, and what modifications were needed. Audio-recordings of the groups were transcribed and analysed. RESULTS: Three key themes emerged covering 'loss and living with dementia', 'what helped us', and 'consistency and continuity'. People with dementia and family carers spoke about the impact of their diagnosis on them and their family and what strategies helped. Issues such as timing, follow-up, and the importance of an early intervention in preventing crises were highlighted. There was some concern over the length of the intervention and the disruption it might cause to current schedules. CONCLUSION: Overall, participants were optimistic about COTiD being used in the United Kingdom if it was to be introduced in a flexible and timely manner, incorporating the needs and existing strategies of the person with dementia. These outcomes have led to changes, such as incorporating more flexibility into COTiD, being made to the intervention prior to its implementation in the United Kingdom. PMID- 25929168 TI - Are muscles weaker in children with neurofibromatosis type 1? PMID- 25929169 TI - The novel CGRP receptor antagonist BIBN4096BS alleviates a postoperative intestinal inflammation and prevents postoperative ileus. AB - BACKGROUND: Abdominal surgery results in neuronal mediator release and subsequent acute intestinal hypomotility. This phase is followed by a longer lasting inflammatory phase resulting in postoperative ileus (POI). Calcitonin gene related peptide (CGRP) has been shown to induce motility disturbances and in addition may be a candidate mediator to elicit neurogenic inflammation. We hypothesized that CGRP contributes to intestinal inflammation and POI. METHODS: The effect of CGRP in POI was tested in mice treated with the highly specific CGRP receptor antagonist BIBN4096BS and in CGRP receptor-deficient (RAMP-1(-/-) ) mice. POI severity was analyzed by cytokine expression, muscular inflammation and gastrointestinal (GI) transit. Peritoneal and muscularis macrophages and mast cells were analyzed for CGRP receptor expression and functional response to CGRP stimulation. KEY RESULTS: Intestinal manipulation (IM) resulted in CGRP release from myenteric nerves, and a concurrent increased interleukin (IL)-6 and IL-1beta transcription and leukocyte infiltration in the muscularis externa and increased GI transit time. CGRP potentiates IM-induced cytokine transcription within the muscularis externa and peritoneal macrophages. BIBN4096BS reduced cytokine levels and leukocyte infiltration and normalized GI transit. RAMP1(-/-) mice showed a significantly reduced leukocyte influx. CGRP receptor was expressed in muscularis and peritoneal macrophages but not mast cells. CGRP mediated macrophage activation but failed to induce mast cell degranulation and cytokine expression. CONCLUSIONS & INFERENCES: CGRP is immediately released during abdominal surgery and induces a neurogenic inflammation via activation of abdominal macrophages. BIBN4096BS prevented IM-induced inflammation and restored GI motility. These findings suggest that CGRP receptor antagonism could be instrumental in the prevention of POI. PMID- 25929170 TI - Disparity, Liver Demand, and Access to Transplants. PMID- 25929171 TI - Synergistic inhibition of human dipeptidyl peptidase IV by combinations of peptides. PMID- 25929172 TI - Cysteine-stabilized alphabeta defensins: From a common fold to antibacterial activity. AB - Antimicrobial peptides (AMPs) seem to be promising alternatives to common antibiotics, which are facing increasing bacterial resistance. Among them are the cysteine-stabilized alphabeta defensins. These peptides are small, with a length ranging from 34 to 54 amino acid residues, cysteine-rich and extremely stable, normally composed of an alpha-helix and three beta-strands stabilized by three or four disulfide bonds and commonly found in several organisms. Moreover, animal and plant CSalphabeta defensins present different specificities, the first being mainly active against bacteria and the second against fungi. The role of the CSalphabeta-motif remains unknown, but a common antibacterial mechanism of action, based on the inhibition of the cell-wall formation, has already been observed in some fungal and invertebrate defensins. In this context, the present work aims to group the data about CSalphabeta defensins, highlighting their evolution, conservation, structural characteristics, antibacterial activity and biotechnological perspectives. PMID- 25929173 TI - Different IncI1 plasmids from Escherichia coli carry ISEcp1-blaCTX-M-15 associated with different Tn2-derived elements. AB - The bla(CTX-M-15) gene, encoding the globally dominant CTX-M-15 extended-spectrum beta-lactamase, has generally been found in a 2.971-kb ISEcp1-bla(CTX-M-15) orf477Delta transposition unit, with ISEcp1 providing a promoter. In available IncF plasmid sequences from Escherichia coli, this transposition unit interrupts a truncated copy of transposon Tn2 that lies within larger multiresistance regions. In E. coli, bla(CTX-M-15) is also commonly associated with IncI1 plasmids and here three such plasmids from E. coli clinical isolates from western Sydney 2006-2007 have been sequenced. The plasmid backbones are organised similarly to those of other IncI1 plasmids, but have insertions and/or deletions and sequence differences. Each plasmid also has a different insertion carrying bla(CTX-M-15). pJIE113 (IncI1 sequence type ST31) is almost identical to plasmids isolated from the 2011 E. coli O104:H4 outbreak in Europe, where the typical bla(CTX-M-15) transposition unit interrupts a complete Tn2 inserted directly in the plasmid backbone. In the novel plasmid pJIE139 (ST88), ISEcp1-blaC(TX-M-15) orf477Delta lies within a Tn2/3 hybrid transposon. Homologous recombination could explain movement of ISEcp1-bla(CTX-M-15)-orf477Delta between copies of Tn2 on IncF and IncI1 plasmids and generation of the Tn2/3 hybrid. pJIE174 (ST37) is almost identical to pESBL-12 from the Netherlands and in these plasmids bla(CTX-M 15) is flanked by two copies of IS26 that truncate the transposition unit within a larger region bounded by the ends of Tn2. bla(CTX-M-15) and the associated ISEcp1-derived promoter may be able to move from this structure by the actions of IS26, independently of both ISEcp1 and Tn2. PMID- 25929174 TI - Extrachromosomal and integrated genetic elements in Clostridium difficile. AB - Clostridium difficile is a major nosocomial pathogen, causing gastrointestinal disease in patients undergoing antibiotic therapy. This bacterium contains many extrachromosomal and integrated genetic elements, with recent genomic work giving new insights into their variability and distribution. This review summarises research conducted in this area over the last 30 years and includes a discussion on the functional contributions of these elements to host cell phenotypes, as well as encompassing recent genome sequencing studies that have contributed to our understanding of their evolution and dissemination. Importantly, we also include a review of antibiotic resistance determinants associated with mobile genetic elements since antibiotic use and the spread of antibiotic resistance are currently of significant global clinical importance. PMID- 25929175 TI - Plasmid partitioning systems of conjugative plasmids from Clostridium perfringens. AB - Many pathogenic strains of Clostridium perfringens carry several highly similar toxin or antibiotic resistance plasmids that have 35 to 40 kb of very closely related syntenous sequences, including regions that carry the genes encoding conjugative transfer, plasmid replication and plasmid maintenance functions. Key questions are how are these closely related plasmids stably maintained in the same cell and what is the basis for plasmid incompatibility in C. perfringens. Comparative analysis of the Rep proteins encoded by these plasmids suggested that this protein was not the basis for plasmid incompatibility since plasmids carried in a single strain often encoded an almost identical Rep protein. These plasmids all carried a similar, but not identical, parMRC plasmid partitioning locus. Phylogenetic analysis of the deduced ParM proteins revealed that these proteins could be divided into ten separate groups. Importantly, in every strain that carried more than one of these plasmids, the respective ParM proteins were from different phylogenetic groups. Similar observations were made from the analysis of phylogenetic trees of the ParR proteins and the parC loci. These findings provide evidence that the basis for plasmid incompatibility in the conjugative toxin and resistance plasmid family from C. perfringens resides in subtle differences in the parMRC plasmid partitioning loci carried by these plasmids. PMID- 25929176 TI - Predictors of weight loss 2 years after laparoscopic sleeve gastrectomy. AB - INTRODUCTION: Despite the rapidly increasing popularity of laparoscopic sleeve gastrectomy (LSG), there is limited data examining weight loss more than 1 year after the procedure. There have also been few studies examining baseline predictors of weight loss after LSG. We aimed to examine the percentage of excess weight loss (%EWL) in patients 2 years after LSG and identify baseline predictors of %EWL. METHODS: Electronic records from university hospitals were available for 292 patients who underwent LSG (205 women; mean age, 41.5 +/- 11.1 years; mean weight, 126.5 +/- 27.5 kg; mean BMI, 45.5 +/- 7.5 kg/m(2) ). Variables assessed for predictive effect were baseline age, sex, BMI, presence of comorbidities (diabetes, hypertension, or obstructive sleep apnea), the amount of weight loss induced by a very low-calorie diet before surgery, and the number of clinic appointments attended over the 2 years. We performed linear regression and mixed model analyses between predictor variables and %EWL at 2 years. RESULTS: Adjusted %EWL was 31% at 2 weeks, 49% at 3 months, 64% at 6 months, 70% at 9 months, 76% at 12 months, 79% at 18 months, and 79% at 2 years. Multivariate analysis showed that lower baseline BMI, absence of hypertension, and greater clinic attendance predicted better %EWL (r(2) = 0.11). CONCLUSION: Longer-term follow-up studies of weight loss post LSG are required to assist with patient care and management. PMID- 25929177 TI - Reasoned Decision Making Without Math? Adaptability and Robustness in Response to Surprise. AB - Many real-world planning and decision problems are far too uncertain, too variable, and too complicated to support realistic mathematical models. Nonetheless, we explain the usefulness, in these situations, of qualitative insights from mathematical decision theory. We demonstrate the integration of info-gap robustness in decision problems in which surprise and ignorance are predominant and where personal and collective psychological factors are critical. We present practical guidelines for employing adaptable-choice strategies as a proxy for robustness against uncertainty. These guidelines include being prepared for more surprises than we intuitively expect, retaining sufficiently many options to avoid premature closure and conflicts among preferences, and prioritizing outcomes that are steerable, whose consequences are observable, and that do not entail sunk costs, resource depletion, or high transition costs. We illustrate these concepts and guidelines with the example of the medical management of the 2003 SARS outbreak in Vietnam. PMID- 25929179 TI - Use of the gonadotrophin-releasing hormone antagonist azaline B to control the oestrous cycle in the koala (Phascolarctos cinereus). AB - The present study examined the effectiveness of the gonadotrophin-releasing hormone (GnRH) antagonist azaline B to suppress plasma LH and 17beta-oestradiol concentrations in koalas and its potential application for oestrous synchronisation. In Experiment 1, single subcutaneous injections of azaline B successfully blocked the LH response to exogenous mammalian (m) GnRH in a dose dependent manner; specifically, 0 mg (n = 4) did not suppress the LH response, 1 mg azaline B (n = 6) suppressed the LH response for 24 h (P < 0.05), 3.3 mg azaline B (n = 8) suppressed the LH response significantly in all animals only for 3 h (P < 0.05), although in half the animals LH remained suppressed for up to 3 days, and 10 mg azaline B (n = 4) suppressed the LH response for 7 days (P < 0.05). In Experiment 2, daily 1 mg, s.c., injections of azaline B over a 10-day period during seasonal anoestrus (June-July; n = 6) suppressed (P < 0.01) the LH response to mGnRH consecutively over the 10-day treatment period and, 4 days after cessation of treatment, the LH response had not recovered. Experiment 3 was designed to test the efficacy of daily 1 mg, s.c., azaline B over 10 days to suppress plasma LH and 17beta-oestradiol concentrations and ultimately synchronise timed return to oestrus during the breeding season. Although azaline B treatment did not suppress basal LH or 17beta-oestradiol, oestrus was delayed in all treated females by 24.2 days, but with high variability (range 9-39 days). Overall, the present study demonstrates that the GnRH antagonist azaline B is able to inhibit the LH response in koalas to exogenous mGnRH and successfully delay the return to oestrus. However, although azaline B clearly disrupts folliculogenesis, it has not been able to effectively synchronise return to oestrus in the koala. PMID- 25929180 TI - Zinc- and oxidative property-dependent degradation of pro-caspase-1 and NLRP3 by ziram in mouse macrophages. AB - The NLRP3 inflammasome, composed of caspase-1, NLRP3 and ASC, plays a critical role in the clearance of microbial pathogens. Here, we found that the treatment of mouse macrophages with the zinc-containing dithiocarbamate ziram, a widely used fungicide in agriculture, caused a decrease in pro-caspase-1 and NLRP3 levels while not affecting ASC level. Ziram did not affect levels of pro-caspase 1 and NLRP3 mRNA, and no cleavage products of pro-caspase-1 including p10 subunit, which is an autocleavage product of pro-caspase-1, were detected, indicating that the decrease was associated with degradation of these proteins. The decrease was inhibited by SH-type antioxidants, N-acetyl cysteine, dithiothreitol and 2-mercaptoethanol, or a metal chelator EDTA but not by inhibitors of proteasome, lysosomes, autophagy and matrix metalloproteases. Thiram, a comparator for ziram that does not contain zinc, showed a weaker decrease in protein levels. Furthermore, the zinc-containing dithiocarbamate, zinc diethyldithiocarbamate, efficiently decreased the levels of pro-caspase-1 and NLRP3, whereas dithiocarbamates, dimethyldithiocarbamate and diethyldithiocarbamate without zinc, were less active. The organic zinc compound [3,4-toluenedithiolato(2-)]zinc hydrate did not induce a decrease in protein levels. Ziram also inhibited IL-1beta production by macrophages in response to lipopolysaccharide and bacterial clearance during Salmonella infection of macrophage cells. These results indicate that ziram causes degradation of pro caspase-1 and NLRP3 in a zinc- and oxidative property-dependent manner and suggest that exposure to ziram may compromise the clearance of microbial pathogens. PMID- 25929181 TI - Phosphatidylinositol 3-kinases pathway mediates lung caspase-1 activation and high mobility group box 1 production in a toluene-diisocyanate induced murine asthma model. AB - We have previously demonstrated that downregulating HMGB1 decreases airway neutrophil inflammation in a toluene-diisocyanate (TDI)-induced murine asthma model, yet how HMGB1 is regulated in the lung remains uncertain. In this study, we intended to explore whether PI3K signaling pathway mediates pulmonary HMGB1 production in TDI-induced asthma model and the possible roles of NLRP3 inflammasome and caspase-1 in this process. BALB/c mice were sensitized and challenged with TDI to establish a TDI-induced asthma model. LY294002, a specific inhibitor of PI3K, was given intratracheally 1h before each challenge. Here we showed that airway hypersensitivity, airway infiltration of neutrophils and eosinophils, serum IgE and IL-4 in supernatant of cervical lymphocytes in TDI induced asthmatic mice were all markedly decreased by LY294002, accompanied by suppressed pulmonary expression of HMGB1. At the same time, we observed elevated protein levels of cleaved caspase-1 and IL-1beta after TDI challenge, as well as increased immunoreactivity in lung, all of which were significantly recovered by LY294002. While both the protein expression and immunodistribution of NLRP3 in the lung stayed unchanged. These data suggest that PI3K mediates lung caspase-1 activation and HMGB1 production in TDI-induced murine asthma model. PMID- 25929182 TI - Quantification of co-transcriptional splicing from RNA-Seq data. AB - During gene expression, protein-coding transcripts are shaped by multiple processing events: 5' end capping, pre-mRNA splicing, RNA editing, and 3' end cleavage and polyadenylation. These events are required to produce mature mRNA, which can be subsequently translated. Nearly all of these RNA processing steps occur during transcription, while the nascent RNA is still attached to the DNA template by RNA polymerase II (i.e. co-transcriptionally). Polyadenylation occurs after 3' end cleavage or post-transcriptionally. Pre-mRNA splicing - the removal of introns and ligation of exons - can be initiated and concluded co transcriptionally, although this is not strictly required. Recently, a number of studies using global methods have shown that the majority of splicing is co transcriptional, yet not all published studies agree in their conclusions. Short read sequencing of RNA (RNA-Seq) is the prevailing approach to measuring splicing levels in nascent RNA, mRNA or total RNA. Here, we compare four different strategies for analyzing and quantifying co-transcriptional splicing. To do so, we reanalyze two nascent RNA-Seq datasets of the same species, but different cell type and RNA isolation procedure. Average co-transcriptional splicing values calculated on a per intron basis are similar, independent of the strategy used. We emphasize the technical requirements for identifying co-transcriptional splicing events with high confidence, e.g. how to calculate co-transcriptional splicing from nascent RNA- versus mRNA-Seq data, the number of biological replicates needed, depletion of polyA+RNA, and appropriate normalization. Finally, we present guidelines for planning a nascent RNA-Seq experiment. PMID- 25929184 TI - Increased expression and colocalization of GAP43 and CASP3 after brain ischemic lesion in mouse. AB - GAP43 is a protein involved in neurite outgrowth during development and axon regeneration reflecting its presynaptic localization in developing neurons. Recently, it has been demonstrated that GAP43 is a ligand of CASP3 involved in receptor endocytosis and is also localized post-synaptically. In this study, by using a transgenic mouse strain carrying a bioluminescent reporter for GAP43 combined with an in vivo bioluminescence assay for CASP3, we demonstrated that one day after brain ischemic lesion and, even more pronounced, four days after stroke, expression of both CASP3 and Gap43 in neurons increased more than 40 times. The in vivo approach of CASP3 and GAP43 colocalization imaging was further validated and quantified by immunofluorescence. Importantly, in 82% of GAP43 positive cells, colocalization with CASP3 was present. These findings suggested that one and four days after stroke CASP3 expression, not necessarily associated with neuronal death, increased and suggested that CASP3 and GAP43 might be part of a common molecular pathway involved in early response to ischemic events occurring after onset of stroke. PMID- 25929183 TI - Myristoylated alanine-rich C kinase substrate (MARCKS) regulates the expression of proinflammatory cytokines in macrophages through activation of p38/JNK MAPK and NF-kappaB. AB - MARCKS, a substrate of protein kinase C, is involved in various processes associated with cytoskeletal movement. Although the expression of MARCKS is highly induced in macrophages, its role in macrophage function has not been studied in detail. Notably, the suppression of MARCKS expression in macrophage cell lines blocked LPS-induced expression of TNF-alpha at the transcriptional level. Treatment of macrophages with MARCKS N-terminus sequence (MANS) and effector domain (ED) peptides, which mimic functional domains and block the phosphorylation of MARCKS, suppressed the LPS-induced expression of TNF-alpha through suppression of p38 and JNK MAPKs and NF-kappaB. Treatment of mice with MANS peptide reduced serum TNF-alpha and IL-6 levels and resulted in 40% survival of mice after the administration of a lethal dose of LPS. These data demonstrate that MARCKS is involved in the regulation of proinflammatory cytokine expression in macrophages and that MARCKS-derived peptides can be used to suppress inflammatory responses. PMID- 25929185 TI - Phytic acid attenuates inflammatory responses and the levels of NF-kappaB and p ERK in MPTP-induced Parkinson's disease model of mice. AB - Phytic acid (PA) is a naturally occurring constituent which exhibits protective action in Parkinson's disease (PD). Inflammation in the central nervous system (CNS) is strongly associated with neuronal death in PD. However, the molecular mechanism of the protective effect of PA in PD has not been fully elucidated. In this study, we tried to testify the protection of PA on neuron and inflammatory responses in 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-induced PD model of mice and investigated the mechanism involved in them. Motor behavior test and tyrosine hydroxylase (TH) immunohistochemistry method showed PA significantly inhibited MPTP-induced dopaminergic cell loss in the substantia nigra (SN). Moreover, using immunohistochemistry method and quantitative polymerase chain reaction (qPCR), microglial activation and inducible nitric oxide synthase (iNOS) were found to be markedly repressed by PA. Via western blot assay, expressions of nuclear factor kappaB (NF-kappaB) and phosphorylated extracellular signal regulated kinase (p-ERK) were significantly attenuated by PA. In conclusion, it is suggested that PA has a neuroprotective effect in MPTP-induced PD model and the neuroprotection is correlated with its anti-inflammatory effect which may be associated with suppression of pathways that involved in NF-kappaB and p-ERK. PMID- 25929186 TI - Camk2a-Cre-mediated conditional deletion of chromatin remodeler Brg1 causes perinatal hydrocephalus. AB - Mammalian SWI/SNF-like BAF chromatin remodeling complexes are essential for many aspects of neural development. Mutations in the genes encoding the core subunit Brg1/SmarcA4 or other complex components cause neurodevelopmental diseases and are associated with autism. Congenital hydrocephalus is a serious brain disorder often experienced by these patients. We report a role of Brg1 in the pathogenesis of hydrocephalus disorder. We discovered an unexpected early activity of mouse Camk2a-Cre transgene, which mediates Brg1 deletion in a subset of forebrain neurons beginning in the late embryonic stage. Brg1 deletion in these neurons led to severe congenital hydrocephalus with enlargement of the lateral ventricles and attenuation of the cerebral cortex. The Brg1-deficient mice had significantly smaller subcommissural organs and narrower Sylvian aqueducts than mice that express normal levels of Brg1. Effects were non-cell autonomous and may be responsible for the development of the congenital hydrocephalus phenotype. Our study provides evidence indicating that abnormalities in Brg1 function result in defects associated with neurodevelopmental disorders and autism. PMID- 25929187 TI - S-Nitrosylation of proline-rich tyrosine kinase 2 involves its activation induced by oxygen-glucose deprivation. AB - Previous studies have demonstrated that activation of proline-rich tyrosine kinase 2 (PYK2) in cerebral ischemia is involved in the modulation of N-methyl-d aspartate-type (NMDA) glutamate receptor activity and Ca(2+) dynamics, resulting in ischemic neuron death ultimately. A number of reports indicate that PYK2 is a redox sensitive kinase that must be activated by an estrogen-induced reactive oxygen species (ROS). However, the mechanism of PYK2 activation remains incompletely illustrated. Accumulating attention is focused on nitric oxide (NO, a free radical) which plays a critical role in cellular signal transduction through stimulus-coupled S-nitrosylation of cysteine residues. Here we reported that PYK2 over-expressed in human embryonic kidney (HEK293) cells was S nitrosylated (forming SNO-PYK2) by reacting with GSNO, an exogenous NO donor, at one critical cysteine residue (Cys534) with a biotin switch assay. Moreover, our results showed that S-nitrosylation and phosphorylation of PYK2 over-expressed in SH-SY5Y cells was significantly increased after oxygen-glucose deprivation (OGD). We further investigated whether the activation (phosphorylation) of PYK2 was associated with S-nitrosylation following SH-SY5Y cells OGD. Our results showed that the cysteine534 residue (site of S-nitrosylation) mutant PYK2 over-expressed in SH-SY5Y cells diminished S-nitrosylation of PYK2 and inhibited its phosphorylation induced by OGD. In addition, overexpression of the mutant PYK2 protein could prevent nuclear accumulation and abrogate neuronal cell death compared to wild type PYK2 in SH-SY5Y cells induced by OGD. These data suggest that the activation of PYK2 following OGD may be modulated by S-nitrosylation, which provides a new avenue for stroke therapy by targeting the post translational modification machinery. PMID- 25929189 TI - The two-component signalling networks of Mycobacterium tuberculosis display extensive cross-talk in vitro. AB - Two-component systems (TCSs), which contain paired sensor kinase and response regulator proteins, form the primary apparatus for sensing and responding to environmental cues in bacteria. TCSs are thought to be highly specific, displaying minimal cross-talk, primarily due to the co-evolution of the participating proteins. To assess the level of cross-talk between the TCSs of Mycobacterium tuberculosis, we mapped the complete interactome of the M. tuberculosis TCSs using phosphotransfer profiling. Surprisingly, we found extensive cross-talk among the M. tuberculosis TCSs, significantly more than that in the TCSs in Escherichia coli or Caulobacter crescentus, thereby offering an alternate to specificity paradigm in TCS signalling. Nearly half of the interactions we detected were significant novel cross-interactions, unravelling a potentially complex signalling landscape. We classified the TCSs into specific 'one-to-one' and promiscuous 'one-to-many' and 'many-to-one' circuits. Using mathematical modelling, we deduced that the promiscuous signalling observed can explain several currently confounding observations about M. tuberculosis TCSs. Our findings suggest an alternative paradigm of bacterial signalling with significant cross-talk between TCSs yielding potentially complex signalling landscapes. PMID- 25929188 TI - Akt isoforms in vascular disease. AB - The mammalian serine/threonine Akt kinases comprise three closely related isoforms: Akt1, Akt2 and Akt3. Akt activation has been implicated in both normal and disease processes, including in development and metabolism, as well as cancer and cardiovascular disease. Although Akt signalling has been identified as a promising therapeutic target in cancer, its role in cardiovascular disease is less clear. Importantly, accumulating evidence suggests that the three Akt isoforms exhibit distinct tissue expression profiles, localise to different subcellular compartments, and have unique modes of activation. Consistent with in vitro findings, genetic studies in mice show distinct effects of individual Akt isoforms on the pathophysiology of cardiovascular disease. This review summarises recent studies of individual Akt isoforms in atherosclerosis, vascular remodelling and aneurysm formation, to provide a comprehensive overview of Akt function in vascular disease. PMID- 25929190 TI - [Postpartum herpetic encephalitis complicated by cerebral hematoma]. PMID- 25929191 TI - Cooperativity between remote sites of ectopic spiking allows afterdischarge to be initiated and maintained at different locations. AB - Many symptoms of nerve damage arise from ectopic spiking caused by hyperexcitability. Ectopic spiking can originate at the site of axonal damage and elsewhere within affected neurons. This raises the question of whether localized damage elicits cell-wide changes in excitability and/or if localized changes in excitability can drive abnormal spiking at remote locations. Computer modeling revealed an example of the latter involving afterdischarge (AD)--stimulus-evoked spiking that outlasts stimulation. We found that AD originating in a hyperexcitable region of axon could shift to the soma where it was maintained. This repositioning of ectopic spike initiation was independent of distance between the two sites but relied on the rate and number of ectopic spikes originating from the first site. Nonlinear dynamical analysis of a reduced model demonstrated that properties which rendered the axonal site prone to initiating AD discouraged it from maintaining AD, whereas the soma had the inverse properties thus enabling the two sites to interact cooperatively. A first phase of AD originating in the axon could, by providing sufficient drive to trigger somatic AD, give way to a second phase of AD originating in the soma such that spiking continued when axonal AD failed. Ectopic spikes originating from the soma during phase 2 AD propagated successfully through the defunct site of axonal spike initiation. This novel mechanism whereby ectopic spiking at one site facilitates ectopic spiking at another site is likely to contribute to the chronification of hyperexcitability in conditions such as neuropathic pain. PMID- 25929193 TI - Cystic Fibrosis and Piperacillin-tazobactam: Adverse Reactions. PMID- 25929192 TI - Alendronate sodium/vitamin D3 combination tablet versus calcitriol for osteoporosis in Chinese postmenopausal women: a 6-month, randomized, open-label, active-comparator-controlled study with a 6-month extension. AB - This study compares efficacy of ALN/D5600 versus that of calcitriol in osteoporotic Chinese postmenopausal women. ALN/D5600 produced greater bone mineral density (BMD) increases, greater bone turnover marker decreases, and less vitamin D insufficiency. This study provided detailed clinical information regarding ALN/D5600 treatment versus calcitriol 0.25 MUg/day. The study did not evaluate fracture risk. INTRODUCTION: The aim of this study is to investigate efficacy of alendronate 70 mg/vitamin D3 5600 IU combination tablets (ALN/D5600) versus calcitriol in osteoporotic Chinese postmenopausal women. METHODS: This study is a 6-month, randomized, open-label, active-comparator study with 6-month extension (clinicaltrials.gov number NCT01350934) in postmenopausal women aged >55 years with osteoporosis (low bone mineral density (BMD) with/without prior fragility fracture). Patients were randomized to ALN/D5600 once weekly or calcitriol 0.25 MUg daily. The primary efficacy end point of the base study was percent change from baseline in lumbar spine BMD (month 6). Hypercalcemia and hypercalciuria were safety events of special interest. RESULTS: A total of 219 patients (ALN/D5600 n = 111, calcitriol n = 108) were randomized. Baseline characteristics were similar, 30.3 % baseline 25-hydroxyvitamin D (25(OH)D) <=15 ng/mL. At months 6 and 12, changes in lumbar spine BMD from baseline were 3.5 versus 1.6 % and 5.2 versus 2.3 % for ALN/D5600 versus calcitriol (between-group differences p < 0.001), respectively. Between-group differences for ALN/D5600 versus calcitriol were significant (p < 0.001) at months 6 and 12 for change from baseline in procollagen type 1 N-terminal propeptide (-59.1 versus -16.8 %, -68.1 versus -17.0 %) and serum C-telopeptides (-79.2 versus -27.2 %, -76.2 versus 24.2 %). Drug-related adverse events (AEs) and discontinuations due to drug related AEs occurred in 15 (14.0 %) versus 8 (7.4 %) patients and 3 (2.8 %) versus 0 patients in the ALN/D5600 and calcitriol group, respectively. Hypercalciuria 12-month incidence (24-h urine Ca >300 mg) was 8.4 (ALN/D5600) versus 13.9 % (calcitriol) (p > 0.05). One patient (calcitriol) had hypercalcemia. CONCLUSIONS: ALN/D5600 produced greater increases in lumbar spine BMD and greater decreases in bone turnover markers versus calcitriol in osteoporotic Chinese women. It is not known whether the greater increase in BMD results in fewer fractures. ALN/D5600 was generally well tolerated in Chinese patients. PMID- 25929194 TI - Binding of pixantrone to DNA at CpA dinucleotide sequences and bulge structures. AB - The binding of the anti-cancer drug pixantrone to three oligonucleotide sequences, d(TCATATGA)2, d(CCGAGAATTCCGG)2 {double bulge = DB} and the non-self complementary d(TACGATGAGTA) : d(TACCATCGTA) {single bulge = SB}, has been studied by NMR spectroscopy and molecular modelling. The upfield shifts observed for the aromatic resonances of pixantrone upon addition of the drug to each oligonucleotide confirmed the drug bound by intercalation. For the duplex sequence d(TCATATGA)2, NOEs were observed from the pixantrone aromatic H7/8 and aliphatic Ha/Hb protons to the H6/H8 and H1' protons of the C2, A3, T6 and G7 nucleotides, demonstrating that pixantrone preferentially binds at the symmetric CpA sites. However, weaker NOEs observed to various protons from the T4 and A5 residues indicated alternative minor binding sites. NOEs from the H7/H8 and Ha/Hb protons to both major (H6/H8) and minor groove (H1') protons indicated approximately equal proportions of intercalation was from the major and minor groove at the CpA sites. Intermolecular NOEs were observed between the H7/H8 and H4 protons of pixantrone and the A4H1' and G3H1' protons of the oligonucleotide that contains two symmetrically related bulge sites (DB), indicative of binding at the adenine bulge sites. For the oligonucleotide that only contains a single bulge site (SB), NOEs were observed from pixantrone protons to the SB G7H1', A8H1' and G9H1' protons, confirming that the drug bound selectively at the adenine bulge site. A molecular model of pixantrone-bound SB could be constructed with the drug bound from the minor groove at the A8pG9 site that was consistent with the observed NMR data. The results demonstrate that pixantrone preferentially intercalates at adenine bulge sites, compared to duplex DNA, and predominantly from the minor groove. PMID- 25929195 TI - Personality Predicts Health Declines Through Stressful Life Events During Late Mid-Life. AB - Personality predicts the occurrence of dependent stressful life events (SLE; i.e., events reliant, at least in part, on an individual's behavior). This process, termed stress generation, contributes to psychiatric outcomes, but its role in physical health is unknown. Data were included from 998 participants (aged 55-64) in the St. Louis Personality and Aging Network (SPAN) study. Assessments occurred every 6 months for 18 months. Neuroticism, impulsivity, and agreeableness were measured with the Revised NEO Personality Inventory. Dependent (e.g., divorce) and independent (e.g., family death) SLE occurring within 6 months following baseline were assessed with the List of Threatening Experiences and confirmed by interviews. Health problems occurring within a year after SLE were the outcome. Analyses examined whether neuroticism, impulsivity, and agreeableness indirectly predict the onset of new health problems through exposure to dependent SLE. Each personality trait was associated with dependent, but not independent, SLE. Only dependent SLE predicted new health problems. Each personality trait indirectly predicted the onset of new health problems through dependent SLE. Findings suggest that personality-driven stress generation influences physical health during late mid-life. Addressing personality in interventions may reduce the occurrence of SLE, in turn decreasing health risks. PMID- 25929196 TI - Evaluating participatory research: Framework, methods and implementation results. AB - This paper describes a structured participatory process and associated evaluation protocol developed to detect systems learning by decision makers involved in the management of natural resources. A series of facilitated participatory workshops were conducted to investigate learning when decision makers and influencers were confronted with the multiple, complex interactions arising from decisions concerned with the nexus of water, food and energy security. The participatory process and evaluation of learning were trialled in the Greater Mekong Subregion (GMS), where integrated scientific evidence was systematically presented to challenge existing beliefs concerned with the effectiveness of proposed policy actions and development investments. Consistent with theoretical propositions, individually held values, beliefs and attitudes were deployed as the primary factors (and psychometrics) that underpin and influence environmental management decision making. Observed and statistically significant changes in the three psychometrics expressed by decision makers in response to the facilitated presentation of scientific evidence during the participatory process, provided supportive evidence of systems learning and the evaluation protocol. PMID- 25929197 TI - Optimisation of extraction and sludge dewatering efficiencies of bio-flocculants extracted from Abelmoschus esculentus (okra). AB - The production of natural biopolymers as flocculants for water treatment is highly desirable due to their inherent low toxicity and low environmental footprint. In this study, bio-flocculants were extracted from Hibiscus/Abelmoschus esculentus (okra) by using a water extraction method, and the extract yield and its performance in sludge dewatering were evaluated. Single factor experimental design was employed to obtain the optimum conditions for extraction temperature (25-90 degrees C), time (0.25-5 h), solvent loading (0.5 5 w/w) and agitation speed (0-225 rpm). Results showed that extraction yield was affected non-linearly by all experimental variables, whilst the sludge dewatering ability was only influenced by the temperature of the extraction process. The optimum extraction conditions were obtained at 70 degrees C, 2 h, solvent loading of 2.5 w/w and agitation at 200 rpm. Under the optimal conditions, the extract yield was 2.38%, which is comparable to the extraction of other polysaccharides (0.69-3.66%). The bio-flocculants displayed >98% removal of suspended solids and 68% water recovery during sludge dewatering, and were shown to be comparable with commercial polyacrylamide flocculants. This work shows that bio-flocculants could offer a feasible alternative to synthetic flocculants for water treatment and sludge dewatering applications, and can be extracted using only water as a solvent, minimising the environmental footprint of the extraction process. PMID- 25929198 TI - A de novo Mutation in KMT2A (MLL) in monozygotic twins with Wiedemann-Steiner syndrome. AB - Growth deficiency, psychomotor delay, and facial dysmorphism was originally described in a male patient in 1989 by Wiedemann et al. and later in 2000 by Steiner et al. Wiedemann-Steiner syndrome (WSS) has since been described only a few times in the literature, with the phenotypic spectrum both expanding and becoming more delineated with each patient reported. We report on the clinical and molecular features of monozygotic twins with a de novo mutation in KMT2A. Single nucleotide polymorphism (SNP) microarray was done on both twins and whole exome sequencing was done using both parents and one of the affected twins. SNP microarray confirmed that they were monozygotic twins. A de novo heterozygous variant (p. Arg1083*) in the KMT2A gene was identified through whole-exome sequencing, confirming the diagnosis of WSS. In this study, we have identified a de novo mutation in KMT2A associated with psychomotor developmental delay, facial dysmorphism, short stature, hypertrichosis cubiti, and small kidneys. This finding in monozygotic twins gives specificity to the WSS. The description of more cases of WSS is needed for further delineation of this condition. Small kidneys with normal function have not been described in this condition in the medical literature before. PMID- 25929199 TI - Labyrinthine function after semicircular canal surgery on seventeen patients with cholesteatoma. PMID- 25929200 TI - Comparison of Substance Use Typologies as Predictors of Sexual Risk Outcomes in African American Adolescent Females. AB - African American female adolescents have a disproportionate risk of sexually transmitted infections (STIs) and other adverse sexual health outcomes. Both alcohol and marijuana use have been shown to predict sexual risk among young African American women. However, no studies have attempted to differentiate alcohol and marijuana typologies use as predictors of sexual risk outcomes exclusively among adolescents who use these substances. This study compared recent alcohol and/or marijuana use as predictors of sexual risk outcomes over 18 months among 182 African American female adolescents. African American females (14-20 years) completed interviews at baseline, 6-, 12-, and 18-months. At each assessment, pregnancy testing was conducted and self-collected vaginal swab specimens were assayed for Trichomonas vaginalis, Chlamydia trachomatis, and Neisseria gonorrhoeae using DNA amplification. Logistic subject-specific random intercept models compared sexual risk outcomes during follow-up among adolescents who reported recent use of alcohol only (AO), marijuana only (MO) or both substances (A + M) at the baseline assessment. Relative to baseline AO use, baseline MO use predicted condom non-use at last sex. Relative to AO use, A + M use predicted pregnancy. Relative to MO use, A + M use predicted pregnancy and acquisition of T. vaginalis and any STI. The results suggest that African American female adolescents who use A + M may represent a priority population for STI, HIV, and pregnancy prevention efforts. PMID- 25929201 TI - Development of an online well-being intervention for young people: an evaluation protocol. AB - BACKGROUND: Research has shown that improving well-being using positive mental health interventions can be useful for predicting and preventing mental illness. Implementing online interventions may be an effective way to reach young people, given their familiarity with technology. OBJECTIVE: This study will assess the effectiveness of a website called the "Online Wellbeing Centre (OWC)," designed for the support and improvement of mental health and well-being in young Australians aged between 16 and 25 years. As the active component of the study, the OWC will introduce a self-guided app recommendation service called "The Toolbox: The best apps for your brain and body" developed by ReachOut.com. The Toolbox is a responsive website that serves as a personalized, ongoing recommendation service for technology-based tools and apps to improve well-being. It allows users to personalize their experience according to their individual needs. METHODS: This study will be a two-arm, randomized controlled trial following a wait-list control design. The primary outcome will be changes in psychological well-being measured by the Mental Health Continuum Short Form. The secondary outcomes will be drawn from a subsample of participants and will include depression scores measured by the Center for Epidemiologic Studies Depression Scale, and quality of life measured by the Assessment of Quality of Life-four dimensions (AQOL-4D) index. Cost-effectiveness analysis will be conducted based on a primary outcome of cost per unique visit to the OWC. Utility based outcomes will also be incorporated into the analysis allowing a secondary outcome to be cost per quality-adjusted life year gained (based on the AQOL-4D values). Resource use associated with both the intervention and control groups will be collected using a customized questionnaire. Online- and community-based recruitment strategies will be implemented, and the effectiveness of each approach will be analyzed. Participants will be recruited from the general Australian population and randomized online. The trial will last for 4 weeks. RESULTS: Small but clinically significant increases in well-being symptoms are expected to be detected in the intervention group compared with the control group. CONCLUSIONS: If this intervention proves to be effective, it will have an impact on the future design and implementation of online-based well-being interventions as a valid and cost-effective way to support mental health clinical treatment. Findings regarding recruitment effectiveness will also contribute to developing better ways to engage this population in research. CLINICALTRIAL: This study is registered in the Australian New Zealand Clinical Trials Registry (ANZCTR): ACTRN12614000710628. PMID- 25929202 TI - Effects of mandibular advancement device treatment on arterial stiffness and glucose metabolism in patients with mild to moderate obstructive sleep apnea: a prospective 1 year study. AB - STUDY OBJECTIVES: An independent association between obstructive sleep apnea (OSA) and cardiovascular events has been reported, suggesting that OSA may lead to cardiometabolic dysregulation. We prospectively investigated the effect of mandibular advancement device (MAD) treatment on arterial stiffness, glucose metabolism, and certain inflammatory markers as predictors of cardiometabolic risk in mild to moderate OSA patients. METHODS: A total of 18 patients with mild to moderate OSA were prospectively enrolled in the study to determine the effects of MAD treatment at 3 months and 1 year following initiation of the treatment. Sleep studies, arterial stiffness assessment, and laboratory analyses were obtained at the baseline and at the time of follow-up. The data collected at 1 year were compared to baseline values. RESULTS: There was a significant decrease in apnea-hypopnea index (AHI) after 1 year of treatment when compared to baseline (22.9 +/- 5.9 to 9.7 +/- 4.5, P < 0.001). Furthermore, MAD treatment was associated with reduced levels of fasting plasma glucose values after 1 year of treatment (5.3 +/- 0.5 to 4.9 +/- 0.5 mmol/L, P < 0.001), as well as fasting plasma insulin values (14.1 +/- 7.8 to 10.9 +/- 6.4 MUU/mL, P < 0.05) and HOMA-IR (3.3 +/- 1.8 to 2.4 +/- 1.4, P < 0.001). There was significant improvement in pulse wave velocity (9.3 +/- 1.9 m/s at baseline to 8.1 +/- 1.7 m/s, P < 0.05) after 1 year of treatment. Plasma level of an inflammatory marker fibrinogen decreased significantly from 3.4 +/- 0.7 at baseline to 3.0 +/- 0.9, (P < 0.05) at 1-year follow-up. CONCLUSIONS: The MAD treatment improved arterial stiffness, glucose metabolism, and insulin resistance in mild to moderate OSA patients after 1 year of treatment. PMID- 25929203 TI - Substance P Receptor Antagonist Suppresses Inflammatory Cytokine Expression in Human Disc Cells. AB - STUDY DESIGN: Laboratory study. OBJECTIVE: To evaluate whether blockade of the Substance P (SP) NK1R attenuates its proinflammatory effect on human intervertebral disc cells (IVD), and to evaluate the signaling pathways associated with SP. SUMMARY OF BACKGROUND DATA: SP and its receptors are expressed in human IVD cells, and cause upregulation of inflammatory mediators; however, the effects of blocking these receptors have not been studied in human IVD cells. METHODS: Human annulus fibrosus (AF) and nucleus pulposus (NP) cells were expanded in monolayer, and then suspended in alginate beads. The alginate beads were treated with culture medium first containing a high affinity NK1R antagonist (L-760735) at different concentrations, and then with medium containing both NK1R antagonist and SP at 2 concentrations. Ribonucleic acid was isolated and transcribed into cDNA. Quantitative reverse transcriptase-polymerase chain reaction (RT-PCR) was performed to evaluate expression of interleukin (IL) 1beta, IL-6, and IL-8. Western blot analysis was performed to examine levels of the phosphorylated p38 mitogen-activated protein kinase (MAPK), extracellular signal regulated kinase 1/2 (ERK1/2) and nuclear factor kappa-light-chain enhancer of activated B cells (NFkappaB p65). The cells were pretreated with specific inhibitors of p38 (SB203580), ERK1/2 (PD98059), and p65 (SM7368) and then stimulated with SP. RESULTS: We detected expression of NK1R, neurokinin receptor 2 (NK2R), and neurokinin receptor 3 (NK3R) in AF and NP cells. Treatment of disc cells with the NK1R antagonist was able to suppress expression of IL 1beta, IL-6, and IL-8 in a dose-dependent manner. SP stimulation increased phosphorylation of p38-MAPK and ERK1/2, but not of NFkappaB p65. This indicates that p38-MAPK and ERK1/2 control SP-induced cytokine expression independently from NF-kB p65. Inhibition of p38 and ERK1/2 activation reduced SP-induced IL-6 production in human disc cells. CONCLUSION: NK1R is responsible for the proinflammatory effect of SP on IVD cells and this effect can be blocked by preventing binding of SP to NK1R. This study shows for the first time that SP mediates signaling in disc cells through NK1R and that SP activates the proinflammatory p38-MAPK and ERK1/2 pathways. LEVEL OF EVIDENCE: 4. PMID- 25929204 TI - Cost-effectiveness of cell saver in short-segment lumbar laminectomy and fusion (<=3 levels). AB - STUDY DESIGN: Mixed retrospective-prospective cohort study. OBJECTIVE: To characterize practice patterns for the use of Cell Saver at our institution, investigate its cost-effectiveness, and propose a new tool for patient selection. SUMMARY OF BACKGROUND DATA: Blood loss is an exceedingly common complication of spine surgery, and Cell Saver intraoperative cell salvage has been used to decrease reliance on allogeneic blood transfusions for blood volume replacement. The cost-effectiveness of Cell Saver has not been established for lumbar spinal surgery, and no universal guidelines exist for clinicians to decide when to utilize this tool. Other authors have proposed cutoffs for anticipated blood loss volumes which indicate that Cell Saver should be used. METHODS: Five hundred and eight patients undergoing lumbar laminectomy in 3 or fewer levels were reviewed from our prospective spinal outcomes registry. Cost information for Cell Saver and allogeneic transfusions was collected from our institution's billing and collections department. Logistic regression was used to identify patient characteristics associated with use of Cell Saver. An incremental cost effectiveness ratio was calculated based on transfusion and cost data. A clinical prediction score was derived using logistic regression. RESULTS: Use of Cell Saver correlated with increased age, higher body mass index, diabetes, greater American Society of Anesthesiologists classification, and greater number of previous spine surgeries. Outcomes for patients who did and did not have Cell Saver set up intraoperatively were equivocal. Cell Saver was not cost effective based on current usage patterns, but may become cost effective if used for patients with high expected blood loss. A simple clinical prediction rule is proposed which may aid in selection of patients to have Cell Saver present intraoperatively. CONCLUSION: Cell Saver is not a cost-effective intervention but may become cost effective if a threshold of expected intraoperative blood loss is used to select patients more judiciously. LEVEL OF EVIDENCE: 3. PMID- 25929205 TI - Cervical Disc Protrusion Correlates With the Severity of Cervical Disc Degeneration: A Cross-Sectional Study of 1211 Relatively Healthy Volunteers. AB - STUDY DESIGN: Cross-sectional study. OBJECTIVE: The purposes of this study were (1) to investigate the frequency and degree of cervical disc degeneration and protrusion on cervical spine magnetic resonance (MR) images and (2) to analyze the correlation between the severity of disc degeneration and disc protrusion. SUMMARY OF BACKGROUND DATA: Cervical disc degenerative changes or protrusion is commonly observed on MR images in healthy subjects. However, there are few large scale studies, and the frequency and range of these findings in healthy subjects have not been clarified. Moreover, there are no reports regarding the correlation between cervical disc degeneration and disc protrusion. METHODS: Cervical disc degeneration and protrusion were prospectively measured using magnetic resonance imaging in 1211 relatively healthy volunteers. These included at least 100 males and 100 females in each decade of life between the 20s and the 70s. Cervical disc degeneration was defined according to the modified Pfirrmann classification system, and the amount of disc protrusion was evaluated using the anteroposterior diameter of disc protrusion on sagittal MR image. RESULTS: Mild disc degeneration was very common, including 98.0% of both sexes in their 20s. The severity of cervical disc degeneration significantly increased with age in both sexes at every level. The disc degeneration predominantly occurred at C5-C6 and C6-C7. The difference between sexes was not significant except for individuals in their 50s. The average anteroposterior diameter of disc protrusion increased with aging, especially from the 20s to the 40s. The anteroposterior diameter of disc protrusion increased with a progression in the disc degeneration grade. CONCLUSION: Cervical disc degeneration and protrusion were frequently observed in healthy subjects even in their 20s and deteriorated with age. Cervical disc protrusion was significantly correlated with cervical disc degeneration, and spatial cervical disc protrusion was affected by biochemical degenerative changes as observed on MR images. LEVEL OF EVIDENCE: 2. PMID- 25929206 TI - A Comparison of Anterior Cervical Corpectomy and Fusion Combined With Artificial Disc Replacement and Cage Fusion in Patients With Multilevel Cervical Spondylotic Myelopathy. AB - STUDY DESIGN: A retrospective study. OBJECTIVE: The aim of this study was to compare clinical and radiological outcomes of anterior cervical corpectomy and fusion (ACCF) combined with artificial disc replacement (C-ADR) and ACCF combined with anterior cervical discectomy and fusion (ACDF) in patients with consecutive 3-level cervical spondylotic myelopathy (CSM). SUMMARY OF BACKGROUND DATA: The optimal surgical strategy for multilevel CSM (MCSM) remains undefined. C-ADR maintains motion at the level of the surgical procedure and decreases strain on the adjacent segments. The clinical results of multilevel C-ADR have not yet been elucidated. ACCF combined with 1-level C-ADR for the treatment of consecutive 3 level CSM may be a reasonable alternative to 3-level fusion. METHODS: We retrospectively reviewed the histories of patients who underwent surgery for consecutive 3-level CSM between C3-4 and C6-7 from June 2007 to August 2011. A total of 42 patients were divided into 2 groups. Group A (n = 19) underwent ACCF combined with 1-level C-ADR; group B (n = 23) underwent ACCF combined with 1 level ACDF. We compared perioperative parameters, clinical parameters, and radiological parameters. RESULTS: There were no significant differences in the average age, sex ratio, the preoperative heights of the disc space or average blood loss between the 2 groups. Group A had longer operation times than group B (P < 0.05). During the follow-up period, group A showed a better Neck Dysfunction Index recovery (P < 0.05) at 24 months postoperatively, and less visual analogue scale scores at 12 and 24 months postoperatively (P < 0.05 and P < 0.001, respectively). Moreover, group A exhibited better C2-C7 range of motion recovery at 6, 12, and 24 months postoperatively (P < 0.05, respectively). CONCLUSION: Group A was superior to Group B in terms of better Neck Dysfunction Index recovery, less intermediate term pain, and better C2-C7 ROM recovery. ACCF hybrid 1-level C-ADR may be a suitable choice for the management of 3-level CSM in appropriate patients. LEVEL OF EVIDENCE: 3. PMID- 25929207 TI - Accuracy and safety of fluoroscopic guided percutaneous pedicle screws in thoracic and lumbosacral spine: a review of 2000 screws. AB - STUDY DESIGN: Retrospective study. OBJECTIVE: To investigate the accuracy and safety of percutaneous pedicle screws placed using fluoroscopic guidance in the thoracic and lumbosacral spine. SUMMARY OF BACKGROUND DATA: Several studies had examined the accuracy and safety of percutaneous pedicle screws but provided large variations in their results with small number of patients or few number of pedicle screws evaluated. METHODS: Computerized tomography of patients who had surgery with fluoroscopic guided percutaneous pedicle screws were chosen from 2 centers: (1) European patients from University Medical Center Hamburg-Eppendorf, Germany and (2) Asian patients from University Malaya Medical Centre, Malaysia. Screw perforations were classified into Grade 0, Grade 1 (<2 mm), Grade 2 (2-4 mm), and Grade 3 (>4 mm). RESULTS: In total, 2000 percutaneous pedicle screws from 273 patients were analyzed: 1290 screws from 183 European patients and 710 screws from 90 Asian patients. The mean age was 59.1 +/- 15.6. There were 140 male patients and 133 female patients. The total perforation rate was 9.4% with 151 (7.5%) Grade 1, 31 (1.6%) Grade 2, and 5 (0.3%) Grade 3 perforations. The total perforation rates among Europeans were 9.4% and among Asians were 9.3%. There was no difference between the 2 groups (P > 0.05). There were 3 distinct peaks in perforation rates (trimodal distribution) at T1, midthoracic region (T4 T7), and lumbosacral junction (L5 and S1). The highest perforation rates were at T1 (33.3%), S1 (19.4%), and T4 (18.6%). CONCLUSION: Implantation of percutaneous pedicle screws insertion using fluoroscopic guidance is safe and has the accuracy comparable to open techniques of pedicle screws insertion. LEVEL OF EVIDENCE: 4. PMID- 25929208 TI - Reliability and validity of an adapted Arabic version of the Scoliosis Research Society-22r Questionnaire. AB - STUDY DESIGN: Cross-sectional validation and reliability assessment study of Arabic version of Scoliosis Research Society-22 (SRS-22r) Questionnaire. OBJECTIVE: To develop and validate the Arabic version of the SRS-22r questionnaire. SUMMARY OF BACKGROUND DATA: The diagnosis and treatment of adolescent idiopathic scoliosis may influence patient quality of life. SRS-22r is an internationally validated questionnaire used to assess function/activity, pain, self-image, and mental health of patients with scoliosis. It has been translated into several languages but not into Arabic language. Therefore, a valid health-related quality-of-life outcome questionnaire for patients with spinal deformity is still lacking in Arabic language. METHODS: The English version of SRS-22r questionnaire was translated, back-translated, and culturally adapted to Arabic language. Then, 81 patients with idiopathic adolescent scoliosis were allocated randomly into either the reliability testing group (group 1) or the validity testing group (group 2). Group 1 patients completed Arabic version of SRS-22r questionnaire twice with 1-week interval in-between. Cronbach alpha and intraclass correlation coefficient were measured to determine internal consistency and temporal reliability. Group 2 patients completed the Arabic version of SRS-22r questionnaire and the previously validated Arabic version of 36-Item Short Form Health Survey (Short Form-36) questionnaire concurrently, and Pearson correlation coefficient was obtained to assess validity. RESULTS: Content analysis, internal consistency reliability, test/retest reproducibility (intraclass correlation coefficient range: 0.82 0.90), and test of concurrent validity showed satisfactory results. Function/activity and satisfaction with management domains had a lower Cronbach alpha (0.58 and 0.44, respectively, vs. 0.71-0.85 range for others). Self image/appearance and satisfaction with management had a lower correlation with domains of the 36-Item Short Form Health Survey. CONCLUSION: An Arabic version of the SRS-22r questionnaire has been developed and validated. This questionnaire will aid health care workers and researchers in evaluation of patient perception of the deformity, satisfaction with treatment, and quality of life in Arabic speaking populations. LEVEL OF EVIDENCE: 3. PMID- 25929209 TI - Evaluation of the Time-dependent Contamination of Spinal Implants: Prospective Randomized Trial. AB - STUDY DESIGN: Prospective study OBJECTIVE.: To evaluate contamination in spinal implants using a liquid culture medium and the effect of covering an implant set on contamination. SUMMARY OF BACKGROUND DATA: Postoperative infection rates increase with the use of spinal implants. Because implant contamination may be an important origin for postoperative infections, investigation, evaluation, and taking required precautions to prevent these contaminations are critical. METHODS: Patients operated on for various spinal pathologies were randomized. The patients were divided into groups of covered and uncovered implant sets. The screw samples were placed in liquid culture medium immediately after opening the implant set. The implant set in the covered group was immediately covered with a sterile surgical towel. A new screw was taken from the implant set and cultured in the liquid culture medium every 30 minutes. At the end of 24 hours, swabs with samples from the liquid culture medium were used to culture blood agar. At the end of 48 hours, the samples with growth were considered contaminated. RESULTS: Growth started after 30 minutes in the uncovered group, whereas only a single growth was noted after 60 minutes in the covered group. Contamination increased with time in both groups, but more so in the open group. A statistically significant difference in contamination was found between the groups at and after 30 minutes. CONCLUSION: Contamination increases with time in all implant materials. Contamination rates can be reduced by using simple precautions, such as covering the implant set. Culturing the entire implant samples in liquid culture medium is accepted as a safe and more effective method in evaluating contamination. LEVEL OF EVIDENCE: 2. PMID- 25929210 TI - Side errors in neurosurgery and human factors training. PMID- 25929211 TI - Moyamoya disease concurrent with Graves' disease treated by direct bypass: clinical features and treatment strategies. AB - BACKGROUND: Moyamoya disease (MMD) concurrent with Graves' disease (GD) is rare. There is no guideline about optimizing thyroid hormones and the appropriate timing of surgical treatment for MMD with GD. METHODS: We encountered eight patients with MMD and GD presenting with cerebral ischemia who were treated by direct bypass. Thyroid hormones [free thyroxin (fT4) and free triiodothyronine (fT3)], thyroid-stimulating hormone (TSH), and TSH receptor antibody (TRAb) were measured sequentially. After thyrotoxic conditions were medically optimized, revascularization surgery was performed by superficial temporal artery-middle cerebral artery (STA-MCA) double bypass in all cases. Clinical outcomes were estimated by modified Rankin scale (mRS) at discharge and 3 months after surgery. RESULTS: In six patients with thyrotoxicosis, the fT4, fT3, and TRAb (range) at the onset of cerebral ischemia were 4.81-10.30 pg/ml, 13.08-31.90 pg/ml, and 3.5 83.8 IU/l, respectively. At surgery, mean (range) fT3 and fT4 were optimized to 3.02 (1.01-4.87) pg/ml and 1.09 (0.41-1.68) ng/dl, respectively. In the thyrotoxic cases, it took 70-310 days (mean, 142 days) to optimize thyroid hormones before surgery. There was no neurological aggravation after surgery, and outcome was excellent at 3 months with mRS scores <=2 in all cases. CONCLUSIONS: For MMD concurrent with GD, optimizing thyroid hormones followed by STA-MCA double bypass was successful to prevent cerebral ischemic events. PMID- 25929212 TI - Self-injury among trans individuals and matched controls: prevalence and associated factors. AB - This study aims to determine the prevalence rate of current non-suicidal self injury (NSSI) among trans individuals, in comparison with a control sample of non trans adults. It also aims to compare those with current NSSI and those with no history of NSSI in terms of psychological well-being, self-esteem, body dissatisfaction, social support and demographic factors. Participants were 97 adults, diagnosed with transsexualism (ICD-10, F64.0), attending a national gender clinic in the United Kingdom, and a matched control group. Clinical participants were all engaged on the treatment pathway. Participants completed the following self-report measures: Self-Injury Questionnaire - Treatment Related (SIQ-TR), Symptom Checklist 90 Revised (SCL-90-R), Rosenberg Self-Esteem Scale (RSE), Hamburg Body Drawing Scale (HBDS) and Multidimensional Scale of Perceived Social Support (MSPSS). The results showed that the trans participants had a significantly higher prevalence of current NSSI behaviour than the non-trans group, with 19% currently engaging in NSSI. Current NSSI was also significantly more prevalent among trans men than trans women. Compared with both trans and non trans participants with no history of NSSI, trans participants with current NSSI had significantly higher scores on SCL; significantly lower scores on RSE, HBDS and MSPSS; and were younger in age. The study concludes that trans men, specifically, are more at risk of NSSI than trans women and the general population, even when on the treatment pathway. Those who currently self-injure have greater psychopathology, lower body satisfaction, lower self-esteem, lower social support and tend to be younger, than those who do not engage in NSSI. PMID- 25929213 TI - Educational attainment among long-term survivors of cancer in childhood and adolescence: a Norwegian population-based cohort study. AB - PURPOSE: The number of young cancer survivors has increased over the past few decades due to improvement in treatment regimens, and understanding of long-term effects among the survivors has become even more important. Educational achievements and choice of educational fields were explored here. METHODS: Five year cancer survivors born in Norway during 1965-1985 (diagnosed <19 years) were included in our analysis by linking Norwegian population-based registries. Cox regression was applied to study the educational attainment among survivors of central nervous system (CNS) tumours, those assumed to have received CNS-directed therapy, and other cancer survivors relative to the cancer-free population. Logistic regression was used to compare the choice of educational fields between the cancer survivors at undergraduate and graduate level and the cancer-free population. RESULTS: Overall, a lower proportion of the cancer survivors completed intermediate (67 vs. 70 %), undergraduate (31 vs. 35 %) and graduate education (7 vs. 9 %) compared with the cancer-free population. Deficits in completion of an educational level were mainly observed among survivors of CNS tumours and those assumed to have received CNS-directed therapy. Choices of educational fields among cancer survivors were in general similar with the cancer free population at both undergraduate and graduate levels. CONCLUSION: Survivors of CNS-tumours and those assumed to have received CNS-directed therapy were at increased risk for educational impairments compared with the cancer-free population. Choices of educational fields were in general similar. IMPLICATIONS FOR CANCER SURVIVORS: Careful follow-up of the survivors of CNS-tumours and those assumed to have received CNS-directed therapy is important at each level of education. PMID- 25929214 TI - The impact of changes in national prescribing conditions for statins on their public expenditure and utilization in the Czech Republic 1997-2013. AB - OBJECTIVES: In the Czech Republic (CZ) extensive price regulation and prescribing conditions are common instruments often employed with new drugs. Since the introduction of statins onto the market in 1990s the originally strict conditions gradually relaxed while the prescription rates and public costs were rising. The aim was to analyze long-term utilization trends of statins, changes in their reimbursement prices and prescribing conditions, and the evolution of the market. METHODS: From January 1997 to December 2013 statin use was measured in terms of defined daily doses per 1000 insured per day (DDD/TID). The prescription-based database of the General Health Insurance Company of the Czech Republic in 1997 covering 7825,216 inhabitants, i.e. 76% of CZ population, was used as the administrative data source. Also the overall expenditure, unit prices, and reimbursement criteria were analyzed. RESULTS: Between 1997 and 2013 the utilization of statins rose from 2 to 96 DDD/TID while the expenditure rose 5.5 fold. The rise of prescription for each molecule was always observed after the liberation of the prescribing criteria. In the study period reimbursement prices of simvastatin and atorvastatin gradually decreased to just 5% of their initial values. CONCLUSIONS: The rising consumption of statins in CZ clearly corresponds in time with the liberation of prescribing conditions allowing for prescription by general practitioners and with the introduction of generics accompanied by a swift and repeated reimbursement price cuts. PMID- 25929215 TI - Influences of visual and action information on object identification and action production. AB - To evaluate the impact of semantic information elicited by labels, participants learned to identify or use novel graspable objects associated with novel actions. We identified each object/action pair with labels that elicited visual form or action semantics and varied the congruence between the label's information and the visual form or action of novel objects. In Experiment 1, participants named objects, and in Experiment 2 they produced the action associated with objects. Generally, congruent labels facilitated performance. Furthermore, for participants who learned incongruent associations, the visual form and semantic information elicited by labels influenced performance in opposite patterns. These findings support the notion that naming may be required before actions are produced when object/action associations are novel. Our findings further support the notion that links between the structural properties of objects and their actions may already be stronger than the links between verbal labels and actions in novel object/action associations. PMID- 25929217 TI - Does the incidence of pulmonary embolism increase during pregnancy? AB - A review of recent evidence with translation to practice for the advanced practice nurse role is presented using a case study module for "Systematic Review and Meta-Analysis of Pregnant Patients Investigated for Suspected Pulmonary Embolism in the Emergency Department." The study results showed that there were 25,339 patients evaluated for pulmonary embolism in an emergency department included in the 17 study articles, 2,636 had venous thromboembolism (VTE; 13%; 95% CI [10, 17]), and 506 were pregnant and underwent diagnostic chest imaging (2%; 95% CI [1.5, 2.6]). These data suggest that pregnancy does not appear to increase the incidence of a VTE-positive diagnosis. The implications and clinical relevance of these findings for advanced practice nurses are discussed highlighting best evidence. PMID- 25929218 TI - Steeple sign: a case of croup. AB - Croup, or laryngotracheobronchitis, is a common viral respiratory tract illness seen in the pediatric population (). This article describes the case of a child who presents with croup and the characteristic "steeple sign" seen on the radiograph. The patient received a diagnosis of croup secondary to the parainfluenza virus infection. It is imperative for advanced practice nurses to recognize the signs and symptoms of croup when these patient present to emergency care settings. Advanced practice nurses must also consider possible differential diagnoses, accurately interpret the radiographs, and intervene according with supportive care and appropriate management. PMID- 25929219 TI - Benzodiazepine selection in the management of status epilepticus: a review. AB - The choice and route of administration of benzodiazepines for the treatment of acute status epilepticus (SE) in both prehospital and emergency department (ED) settings often vary by provider and institution. Prehospital and ED care often involves intramuscular, intravenous, or rectal administration of these medications. Diazepam, lorazepam, and midazolam are available as parenteral formulations in the United States. A literature review of clinical trials and SE treatment guidelines was conducted in an attempt to identify which benzodiazepine and route are the best treatment option for adult patients with SE. For initial treatment of SE in adults, intravenous lorazepam is the recommended drug of choice. However, evidence suggests that intramuscular midazolam has at least equal efficacy in prehospital settings and may be more appropriate for use in this environment. Despite the support of multiple clinical trials and treatment guidelines, inconsistencies in the treatment of acute SE continue to occur in both the prehospital and ED settings. PMID- 25929220 TI - Cannabinoid hyperemesis syndrome. AB - Legalization of marijuana use will increase the number of people who will become long-term users. A prior medical record review study in Australia, in 2004, identified 19 chronic marijuana users who entered the emergency department with recurrent vomiting associated with abdominal pain. Routine treatment of the nausea and vomiting, associated with the chronic marijuana abuse, with antiemetics is ineffective in patients with cannabinoid hyperemesis syndrome. Narcotics do not relieve the abdominal pain but may cause worsening rebound pain. The best treatment of cannabinoid hyperemesis syndrome was found to be abstinence from the recreational use of marijuana. It is important for advanced practice nurses to place cannabinoid hyperemesis syndrome in their differentials of patients presenting to the emergency department with recurrent nausea, vomiting, and abdominal pain. They need to be knowledgeable about cannabinoid hyperemesis syndrome to provide the proper management of care for this specific medical condition. PMID- 25929221 TI - Ebola virus disease. AB - Ebola is an unfamiliar disease with a high mortality rate. Until recently, it occurred only in rural tropical regions and most health care providers had only read about it in epidemiology classes. With globalization, international travel, and foreign medical missions, it is possible that a patient with Ebola exposure and/or symptoms may present in any emergency department. All health care providers must be familiar with identifying the signs and symptoms of Ebola and capable of initiating an appropriate response. This article presents an overview of Ebola virus disease for health care providers, covering pathophysiology, identification, treatment, and general considerations for hospitals and providers to consider when developing policies and procedures. PMID- 25929222 TI - Assessment and treatment of depression in gay and bisexual men in emergency settings. AB - Gay and bisexual men are at higher risk for certain mental health disorders, including anxiety, depression, and suicide. These individuals often present to emergency settings in need of evaluation and treatment. Despite the utilization of emergency mental health services by this population, clinicians are often underprepared in responding to their unique needs. This article discusses depression in gay and bisexual men and provides an evidence-based approach in treating these men in emergency settings. Directives for future research and advanced practice nursing education are also presented. PMID- 25929223 TI - Decontamination training: with and without virtual reality simulation. AB - Nurses must be prepared to care for patients following a disaster, including patients exposed to hazardous contaminants. The purpose of this study was to examine the use of virtual reality simulation (VRS) to teach the disaster specific skill of decontamination. A quasi-experimental design was used to assign nursing students from 2 baccalaureate nursing programs to 1 of 2 groups to learn the disaster skill of decontamination-printed written directions or VRS. Performance, knowledge, and self-efficacy were outcome measures. Although students in the treatment group had significantly lower performance scores than the control group (p = 0.004), students taking part in VRS completed the skill in a significantly shorter amount of time (p = 0.008). No significant group differences were found for self-efficacy (p = 0.172) or knowledge (p = 0.631). However, students in the VRS treatment group reported high levels of satisfaction with VRS as a training method. The disaster-specific skill of decontamination is a low-volume, high-risk skill that must be performed with accuracy to protect both exposed patients and providers performing decontamination. As frontline providers for casualties following a disaster event, emergency nurses must be prepared to perform this skill when needed. Preparation requires cost-effective, timely, and evidence-based educational opportunities that promote positive outcomes. Further investigation is needed to determine the benefits and long-term effects of VRS for disaster education. PMID- 25929224 TI - Relationships among moral distress, level of practice independence, and intent to leave of nurse practitioners in emergency departments: results from a national survey. AB - The aims of this research study were to investigate moral distress among emergency department (ED) nurse practitioners (NPs) and examine relationships between moral distress and level of practice independence as well as intent to leave a position. Moral distress has been studied regarding registered nurses and physicians (MDs) but less so in NPs. It is important to explore moral distress in NPs because they tread a unique path between nursing and physician roles. Moral distress may play a significant role in staff nurses' intention to leave practice, and level of practice independence is found to have a relationship with NPs' intention to leave. A convenience sample of ED NPs was obtained from a mailing list of a national nursing specialty organization, the Emergency Nurses Association. Using a correlational design, survey methods assessed moral distress with the Moral Distress Scale-Revised (MDS-R), level of practice independence with the Dempster Practice Behavior Scale, and intent to leave with self-report. Correlational and regression analyses of data were conducted to characterize moral distress among ED NPs and associations between moral distress, level of practice independence, and intent to leave. Results found ED NPs do experience moral distress with poor patient care results from inadequate staff communication and working with incompetent coworkers in their practice. The MDS-R was a significant predictor of intention to leave among respondents. This study is the first of its kind to explore moral distress in ED NPs. Results suggest moral distress influences ED NPs' intent to leave their position. Further studies are needed to explore the findings from this research and to formulate interventions to alleviate moral distress in ED NPs and improve retention in the clinical setting. PMID- 25929226 TI - Comparative sensitivity of field and laboratory populations of Hyalella azteca to the pyrethroid insecticides bifenthrin and cypermethrin. AB - Hyalella azteca are epibenthic invertebrates that are widely used for toxicity studies. They are reported to be more sensitive to pyrethroid insecticides than most other test species, which has prompted considerable use of this species in toxicity testing of ambient surface waters where the presence of pyrethroids is suspected. However, resident H. azteca have been found in some ambient water bodies reported to contain surface water and/or sediment pyrethroid concentrations that are toxic to laboratory reared H. azteca. This observation suggests differences in the sensitivities of laboratory reared and field populations of H. azteca to pyrethroids. The goal of the present study was to determine the sensitivities of laboratory reared and field populations of H. azteca to the pyrethroids bifenthrin and cypermethrin. Specimens of H. azteca were collected from resident populations at field sites that are subject to varied land-use activities as well as from laboratory populations. These organisms were exposed to bifenthrin- or cypermethrin-spiked water in 96-h water only toxicity tests. The resulting data demonstrated that: 1) field-collected populations in urban and agricultural settings can be >2 orders of magnitude less sensitive to the pyrethroids than laboratory reared organisms; 2) field-collected organisms varied in their sensitivity (possibly based on land-use activities), with organisms collected from undeveloped sites exhibiting sensitivities similar to laboratory reared organisms; and 3) the sensitivity of field-collected "tolerant" organisms increased in subsequent generations reared under laboratory conditions. Potential mechanisms for these differences are discussed. PMID- 25929227 TI - Detection limits of organic compounds achievable with intense, short-pulse lasers. AB - Many organic molecules have strong absorption bands which can be accessed by ultraviolet short pulse lasers to produce efficient ionization. This resonant multiphoton ionization scheme has already been exploited as an ionization source in time-of-flight mass spectrometers used for environmental trace analysis. In the present work we quantify the ultimate potential of this technique by measuring absolute ion yields produced from the interaction of 267 nm femtosecond laser pulses with the organic molecules indole and toluene, and gases Xe, N2 and O2. Using multiphoton ionization cross sections extracted from these results, we show that the laser pulse parameters required for real-time detection of aromatic molecules at concentrations of one part per trillion in air and a limit of detection of a few attomoles are achievable with presently available commercial laser systems. The potential applications for the analysis of human breath, blood and tissue samples are discussed. PMID- 25929228 TI - Cell shape change and invagination of the cephalic furrow involves reorganization of F-actin. AB - Invagination of epithelial sheets to form furrows is a fundamental morphogenetic movement and is found in a variety of developmental events including gastrulation and vertebrate neural tube formation. The cephalic furrow is a deep epithelial invagination that forms during Drosophila gastrulation. In the first phase of cephalic furrow formation, the initiator cells that will lead invagination undergo apicobasal shortening and apical constriction in the absence of epithelial invagination. In the second phase of cephalic furrow formation, the epithelium starts to invaginate, accompanied by both basal expansion and continued apicobasal shortening of the initiator cells. The cells adjacent to the initiator cells also adopt wedge shapes, but only after invagination is well underway. Myosin II does not appear to drive apical constriction in cephalic furrow formation. However, cortical F-actin is increased in the apices of the initiator cells and in invaginating cells during both phases of cephalic furrow formation. These findings suggest that a novel mechanism for epithelial invagination is involved in cephalic furrow formation. PMID- 25929229 TI - Impact of prolonged sitting on lower and upper limb micro- and macrovascular dilator function. AB - NEW FINDINGS: What is the central question of this study? The prevalence of sedentary behaviour in the workplace and increased daily sitting time have been associated with the development of cardiovascular disease; however, studies investigating the impact of sitting on vascular function remain limited. What is the main finding and its importance? We demonstrate that there is a marked vulnerability of the vasculature in the lower and upper limbs to prolonged sitting and highlight the importance of physical activity in restoring vascular function in a limb-specific manner. Sedentary behaviour in the workplace and increased daily sitting time are on the rise; however, studies investigating the impact of sitting on vascular function remain limited. Herein, we hypothesized that 6 h of uninterrupted sitting would impair limb micro- and macrovascular dilator function and that this impairment could be improved with a bout of walking. Resting blood flow, reactive hyperaemia to 5 min cuff occlusion (microvascular reactivity) and associated flow-mediated dilatation (FMD; macrovascular reactivity) were assessed in popliteal and brachial arteries of young men at baseline (Pre Sit) and after 6 h of uninterrupted sitting (Post Sit). Measures were then repeated after a 10 min walk (~1000 steps). Sitting resulted in a marked reduction of resting popliteal artery mean blood flow and mean shear rate (6 h mean shear rate, -52 +/- 8 s(-1) versus Pre Sit, P < 0.05). Interestingly, reductions were also found in the brachial artery (6 h mean shear rate, -169 +/- 41 s(-1) versus Pre Sit, P < 0.05). Likewise, after 6 h of sitting, cuff-induced reactive hyperaemia was reduced in both the lower leg (-43 +/- 7% versus Pre Sit, P < 0.05) and forearm (-31 +/- 11% versus Pre Sit, P < 0.05). In contrast, popliteal but not brachial artery FMD was blunted with sitting. Notably, lower leg reactive hyperaemia and FMD were restored after walking. Collectively, these data suggest that prolonged sitting markedly reduces lower leg micro- and macrovascular dilator function, but these impairments can be fully normalized with a short bout of walking. In contrast, upper arm microvascular reactivity is selectively impaired with prolonged sitting, and walking does not influence this effect. PMID- 25929231 TI - De novo formation and rupture of proximal anterior cerebral artery aneurysm associated with middle cerebral artery occlusion. PMID- 25929230 TI - Reversing motor adaptation deficits in the ageing brain using non-invasive stimulation. AB - KEY POINTS: Healthy ageing in man is associated with a decline in motor adaptation. Transcranial direct current stimulation (TDCS) over the primary motor cortex (M1) or the lateral cerebellum can improve motor adaptation in young and older adults, but as yet no direct comparisons of TDCS effects exist between the two age groups and the two stimulation sites. TDCS over M1 enhanced the motor adaptation in both age groups by ~30% relative to their respective non-stimulated groups and improved the performance of older adults to the extent that it compared with that of young adults without stimulation. The study suggests that the plastic mechanisms activated by TDCS that underpin improvements in motor behaviour in young adults remain available in older adults. The results indicate that TDCS may be a useful tool to help combat the normal decline in motor performance seen in normal healthy ageing. ABSTRACT: Healthy ageing is characterised by deterioration of motor performance. In normal circumstances motor adaptation corrects for movements' inaccuracies and as such, it is critical in maintaining optimal motor control. However, motor adaptation performance is also known to decline with age. Anodal transcranial direct current stimulation (TDCS) of the cerebellum and the primary motor cortex (M1) have been found to improve visuomotor adaptation in healthy young and older adults. However, no study has directly compared the effect of TDCS on motor adaptation between the two age populations. The aim of our study was to investigate whether the application of anodal TDCS over the lateral cerebellum and M1 affected motor adaptation in young and older adults similarly. Young and older participants performed a visuomotor rotation task and concurrently received TDCS over the left M1, the right cerebellum or received sham stimulation. Our results replicated the finding that older adults are impaired compared to the young adults in visuomotor adaptation. At the end of the adaptation session, older adults displayed a larger error (-17 deg) than the young adults (-10 deg). The stimulation of the lateral cerebellum did not change the adaptation in both age groups. In contrast, anodal TDCS over M1 improved initial adaptation in both age groups by around 30% compared to sham and this improvement lasted up to 40 min after the end of the stimulation. These results demonstrate that TDCS of M1 can enhance visuomotor adaptation, via mechanisms that remain available in the ageing population. PMID- 25929232 TI - Clinical and perinatal outcomes in eclamptic women with posterior reversible encephalopathy syndrome. AB - PURPOSE: To compare the clinical and perinatal outcomes in eclamptic women with and without posterior reversible encephalopathy syndrome (PRES). METHODS: This single-center, retrospective, cohort study was conducted between 2008 and 2013. The clinical and perinatal outcomes of eclamptic patients were obtained from hospital records. Magnetic resonance imaging was used for the diagnosis of PRES. Eighty-one eclamptic women were divided into two groups: 45 and 36 patients were included in the PRES and non-PRES groups, respectively. RESULTS: In the PRES group, headache and visual impairment together (60.0 %) were the most common presenting symptoms. In the non-PRES group, only headache was the most common (50 %) presenting symptom. Occipital and parietal lobes were the most frequently affected areas in the PRES group. Women in the PRES group had a higher body mass index value (p = 0.005), longer hospitalization time (p = 0.001), and higher level of proteinuria (p = 0.012) than those in the non-PRES group. Women in the non-PRES group had higher Apgar scores (p = 0.002) than those in the PRES group. CONCLUSIONS: This study indicates that PRES manifests predominantly with headache and visual impairment together. Adverse neonatal outcomes are also common in these patients. PMID- 25929233 TI - Emergency peripartum hysterectomy: 2-year experiences in non-tertiary center. AB - PURPOSE: The aim of this study was to evaluate risk factors, indications and materno-fetal outcomes for emergency peripartum hysterectomy. METHODS: Retrospective evaluation was made of 23 cases. Maternal and neonatal outcomes, need for referral to the tertiary center and related complications were compared to those at the initial diagnosis for surgery, location of delivery, type of surgery and the admission diagnosis. The risk factors associated with emergency peripartum hysterectomy were also investigated. Significance was evaluated at p values of <0.01 and <0.05. RESULTS: There was a correlation between peripartum hysterectomy and uterine atony or uterine rupture (p < 0.01). The referral rates of patients with home delivery were significantly higher than those of patients who delivered in hospital (p = 0.02) but no significant difference was observed in the neonatal outcomes (p = 0.38). There was no significant difference in the rates of maternal complications between home and hospital delivery (p = 0.068). According to the indication for surgery, no significant difference was observed between the rates of referral to the tertiary center, maternal outcomes, complications, or need for maternal intensive care (p > 0.05). However, a highly significant difference was observed between the neonatal outcomes (p = 0.001). CONCLUSION: The results of this study showed the most important risk factors associated with peripartum hysterectomy to be uterine atony, grand multiparity, and uterine rupture. Maternal intensive care, maternal death, neonatal death, or neonatal intensive care were associated with home delivery or delayed presentation at hospital. PMID- 25929234 TI - Aminopeptidase N activity predicts 5-year survival in colorectal cancer patients. AB - BACKGROUND: Aminopeptidase N (APN; EC 3.4.11.2) is a membrane dimeric metallopeptidase involved in differentiation, development, and proliferative processes of several tissues. Recent studies have demonstrated the increased expression and activity of this enzyme in several cancers. However, there are no available data about the impact of this peptidase in the biological aggressiveness and the survival of colorectal cancer (CRC) patients. METHODS: The activity and mRNA expression of APN in tumor tissue (n = 81) and plasma (n = 40) of patients with CRC of low and high grades and stages were prospectively analyzed by fluorimetric and quantitative reverse transcriptase-polymerase chain reaction methods. Data obtained in adenoma and CRC were compared with those from the surrounding normal mucosa. Classic clinical and pathological parameters were stratified following APN data and analyzed for 5-year survival. RESULTS: mRNA levels of APN (ANPEP) were lower in colorectal adenomas and adenocarcinomas than in the surrounding uninvolved mucosa (Kruskal-Wallis, P < 0.001). Aminopeptidase N activity in CRC tissue was higher in patients with better overall survival (log rank P < 0.05, Cox analysis P < 0.05). By contrast, higher plasmatic APN activity correlated with worse overall survival (log-rank P < 0.01, Cox analysis P < 0.05). CONCLUSIONS: Aminopeptidase N activity in tissue and plasma from CRC patients is an independent prognostic factor of 5-year survival. The determination of APN activity levels in the plasma may be a safe, minimally invasive, and inexpensive way to define the aggressiveness of CRC in daily practice. PMID- 25929235 TI - Tubal flushing for subfertility. AB - BACKGROUND: Establishing the patency of the fallopian tubes is a commonly undertaken diagnostic investigation for women with subfertility. This is usually achieved by flushing contrast medium through the tubes and taking radiographs. However, it has been noted that many women conceive in the first three to six months after the tubal flushing, which has raised the possibility that tubal flushing could also be a treatment for infertility. There has been debate about which contrast medium should be used (water-soluble or oil-soluble media) as this may influence pregnancy rates. OBJECTIVES: To evaluate the effect of flushing fallopian tubes with oil- or water-soluble contrast media on live birth and pregnancy rates in women with subfertility. SEARCH METHODS: We searched the Cochrane Menstrual Disorders and Subfertility Group Specialised Register of trials, MEDLINE, EMBASE, Biological Abstracts, trial registers and reference lists of identified articles. The most recent search was conducted in June 2014. SELECTION CRITERIA: Randomised controlled trials (RCTs) comparing tubal flushing with oil-soluble or water-soluble contrast media, or with no treatment, in women with subfertility. DATA COLLECTION AND ANALYSIS: Two authors independently selected the trials, assessed risk of bias and extracted data. We contacted study authors for additional information. The overall quality of the evidence was assessed using GRADE methods. MAIN RESULTS: Thirteen trials involving 2914 women were included, of whom 2494 were included in the analysis. Oil-soluble contrast media (OSCM) versus no interventionThe OSCM group had a higher rate of live birth (odds ratio (OR) 3.09, 95% CI 1.39 to 6.91, 1 RCT, 158 women, low quality evidence) and ongoing pregnancy (OR 3.59, 95% CI 2.06 to 6.26, 3 RCTs, 382 women, I(2) = 0%, low quality evidence) than women who had no intervention. Our findings suggest that among subfertile women with a 17% chance of an ongoing pregnancy if they have no intervention, the rate will increase to between 29% and 55% if they have tubal flushing with OSCM. Water-soluble contrast media (WSCM) versus no interventionThere was no evidence of a difference between the groups in rates of live birth (OR 1.13, 95% CI 0.67 to 1.91, 1 RCT, 334 women, very low quality evidence) or ongoing pregnancy (OR 1.14, 95% CI 0.71 to 1.84, 1 RCT, 334 women, very low quality evidence). OSCM versus WSCMTwo RCTs reported live birth: one found a higher live birth rate in the oil-soluble group and the other found no evidence of a difference between the groups. These studies were not pooled due to very high heterogeneity (I(2) = 93%). There was no evidence of a difference between the groups in rates of ongoing pregnancy, however there was high heterogeneity (OR 1.44, 95% CI 0.84 to 2.47, 5 RCTs, 1454 women, I(2) = 76%, random-effects model, very low quality evidence). OSCM plus WSCM versus WSCM aloneThere was no evidence of a difference between the groups in rates of live birth (OR 1.06, 95% CI 0.64 to 1.77, 1 RCT, 393 women, very low quality evidence) or ongoing pregnancy (OR 1.23, 95% CI 0.87 to 1.72, 4 RCTs, 633 women, I(2) = 0%, low quality evidence).There was no evidence of a difference between any of the interventions in rates of adverse events, but such events were poorly reported in most studies. AUTHORS' CONCLUSIONS: The evidence suggests that tubal flushing with oil-soluble contrast media may increase the chance of pregnancy and live birth compared to no intervention. Findings for other comparisons were inconclusive due to inconsistency and lack of statistical power. There was insufficient evidence on adverse events to reach firm conclusions. Further robust randomised controlled trials are needed. PMID- 25929238 TI - Micro-CT scan, electron microscopy and optical microscopy study of insertional traumas of cochlear implants. AB - PURPOSE: Knowledge of cochlear trauma resulting from the implantation of electrodes is important for the development of atraumatic surgical techniques. The purpose of this study was to demonstrate the advantages of micro-CT scanning, back-scattered electron microscopy (BSEM) and optical microscopy (OM) in understanding the mechanisms of cochlear trauma due to cochlear implantation. METHOD: Our study involved six petrous bones removed from fresh human cadavers: one control specimen plus five other specimens that were surgically implanted with Neurelec Digisonic SP EVO electrode arrays. All six specimens underwent glycol methyl methacrylate embedding, were examined via micro-CT scan and were then sectioned for histological analysis of undecalcified samples via BSEM and OM. RESULTS: The 2D micro-CT scan reconstructions did not display cochlear microtrauma due to a limited resolution and the loss of information caused by the metallic artifacts of the intracochlear electrodes. The 3D reconstructions displayed the quality of the electrode array positioning in the cochlea and enabled determining the axes on which to section the specimens for histological examination. BSEM afforded a clear view of the damage to the osseous structures of the cochlea, but did not display the soft tissue injuries. OM enabled viewing and grading the histological lesions resulting from insertion. CONCLUSION: In our opinion, the combination of 3D micro-CT scan reconstructions and histological analysis using OM appears to be the best method to analyze this type of trauma. PMID- 25929239 TI - From synaptic plasticity to spatial maps and sequence learning. AB - The entorhinal-hippocampal circuit is crucial for several forms of learning and memory, especially sequence learning, including spatial navigation. The challenge is to understand the underlying mechanisms. Pioneering discoveries of spatial selectivity in this circuit, i.e. place cells and grid cells, provided a major step forward in tackling this challenge. Considerable research has also shown that sequence learning relies on synaptic plasticity, especially the Hebbian or the NMDAR-dependent synaptic plasticity. This raises several questions: Are spatial maps plastic? If so, what is the contribution of Hebbian plasticity to spatial map plasticity? How does the spatial map plasticity contribute to sequence learning? A combination of computational and experimental studies has shown that NMDAR-mediated plasticity and theta rhythm can have specific effects on the formation and experiential modification of spatial maps to facilitate predictive coding. Advances in transgenic techniques have provided further support for these mechanisms. Although many exciting challenges remain, these findings have brought us closer to solving the puzzle of how the hippocampal system contributes to spatial memory, and point to a way forward. PMID- 25929240 TI - Molecular cloning, characterization, and expression analysis of two different types of lectins from the oriental river prawn, Macrobrachium nipponense. AB - Lectins, which are widely expressed in invertebrates, play important roles in many biological processes, including protein trafficking, cell signaling, pathogen recognition, as effector molecules, and so on (Wang and Wang, 2013). This study identified one novel M-type lectin and one L-Type lectin, designated as MnMTL1 and MnLTL1, from the oriental river prawn Macrobrachium nipponense. The full-length cDNA of MnMTL1 was 2064 bp with a 1761 bp ORF encoding a putative protein of 586 deduced amino acids. The full-length cDNA of MnLTL1 was 1744 bp with a 972 bp ORF encoding a 323-amino acid peptide. The deduced MnMTL1 protein contained a putative type II transmembrane region and a 440-aa Glycoside hydrolase family 47 (GH47) domain. One luminal carbohydrate recognition domain and a 23-aa type I transmembrane region were identified from the MnLTL1. MnMTL1 shared 78% identity with Marsupenaeus japonicus M-type lectin and MnLTL1 shared 83% similarity with M. japonicus L-type lectin. RT-PCR analysis showed that MnMTL1 and MnLTL1 were expressed in all tested tissues. Quantitative real-time PCR analysis revealed that MnMTL1 and MnLTL1 are substantially fluctuant during Aeromonas hydrophila and Aeromonas veronii infections. Based on immune responses and previous literature, we assumed that MnMTL1 and MnLTL1 might be functioned as pattern recognition receptors and play important roles in the immune response of M. nipponense. PMID- 25929241 TI - iTRAQ-based quantitative subcellular proteomic analysis of Avibirnavirus-infected cells. AB - Infectious bursal disease virus (IBDV) enters the host cells via endocytic pathway to achieve viral replication in the cytoplasm. Here, we performed LC MS/MS coupled with isobaric tags for relative and absolute quantification labeling of differentially abundant proteins of IBDV-infected cells using a subcellular fractionation strategy. We show that the viral infection regulates the abundance and/or subcellular localization of 3211 proteins during early infection. In total, 23 cellular proteins in the cytoplasmic proteome and 34 in the nuclear proteome were significantly altered after virus infection. These differentially abundant proteins are involved in such biological processes as immune response, signal transduction, RNA processing, macromolecular biosynthesis, energy metabolism, virus binding, and cellular apoptosis. Moreover, transcriptional profiles of the 25 genes corresponding to the identified proteins were analyzed by quantitative real-time RT-PCR. Ingenuity Pathway Analysis clustered the differentially abundant proteins primarily into the mTOR pathway, PI3K/Akt pathway, and interferon-beta signaling cascades. Confocal microscopy showed colocalization of the viral protein VP3 with host proteins heterogeneous nuclear ribonucleoprotein H1, nuclear factor 45, apoptosis inhibitor 5, nuclear protein localization protein 4 and DEAD-box RNA helicase 42 during the virus infection. Together, these identified subcellular constituents provide important information for understanding host-IBDV interactions and underlying mechanisms of IBDV infection and pathogenesis. PMID- 25929242 TI - The utility of computed tomography in the management of fever and neutropenia in pediatric oncology. AB - BACKGROUND: Despite the frequent use and radiation exposure of computed tomography (CT) scans, there is little information on patterns of CT use and their utility in the management of pediatric patients with fever and neutropenia (FN). We examined the contribution of either the commonly employed pan-CT (multiple anatomical locations) or targeted CT (single location) scanning to identify possible infectious etiologies in this challenging clinical scenario. Procedure Pediatric patients with an underlying malignancy admitted for fever (temperature >= 38.3 degrees C) and an absolute neutrophil count <500 cells/MUL from 2003-2009 were included. Risk factors associated with utilization, results, and effects on clinical management of CT scans were identified. Results Charts for 635 admissions for FN from 263 patients were reviewed. Overall, 139 (22%) admissions (93 individuals) had at least one scan. Of 188 scans, 103 (55%) were pan-scans. Changes in management were most strongly associated with the identification of evidence consistent with infection (OR = 12.64, 95% CI: 5.05 31.60, P < 0.001). Seventy-eight (41%) of all CT scans led to a change in clinical management, most commonly relating to use of antibiotic (N = 41, 53%) or antifungal/antiviral medications (N = 33, 42%). The odds of a change in clinical management did not differ for those receiving a pan-scan compared to those receiving a targeted scan (OR = 1.23; 95% CI, 0.61-2.46; P = 0.57). Conclusions When CT is clinically indicated, it is important for clinicians to strongly consider utilizing a targeted scan to reduce radiation exposure to patients as well as to decrease costs without compromising care. PMID- 25929243 TI - Histomorphologic Features of Biopsy Sites Following Excisional and Core Needle Biopsies of the Breast. AB - Mammographic studies have documented a number of architectural changes occurring around breast biopsy sites. These changes are well described in the radiological literature, but similar studies do not appear to be present in the pathology literature. We reviewed 100 consecutive mastectomy specimens from women who had undergone prior core needle or excisional biopsies. Multiple sections of the needle tract or excisional biopsy site were reviewed and morphologic findings reported. Hemorrhage, fat necrosis, granulation tissue, necrosis of fibrous tissue, and epithelium along with fibrosis and foreign body type giant cells were common features. Less frequent were areas of synovial metaplasia, atypical spindle cells, atypical duct-like structures, single atypical cells, squamous metaplasia, proliferations of abnormal blood vessels, and hemosiderin deposition. The misinterpretation of atypical spindle cells, single atypical cells, atypical duct-like structures and squamous metaplasia could result in the false-positive diagnosis of residual malignancy. Careful attention to the reactive nature of these changes aids in their distinction from carcinoma. PMID- 25929244 TI - Application of an induced field sensor for assessment of electromagnetic exposure from compact fluorescent lamps. AB - The development of scientifically sound instrumentation, methods, and procedures for the electromagnetic exposure assessment of compact fluorescent lamps (CFLs) is investigated. The incident and induced fields from 11 CFLs have been measured in the 10 kHz-1 MHz range, and they are compared with the levels for incandescent and light emitting diode (LED) bulbs. Commercially available equipment was used to measure the incident fields, while a novel sensor was built to assess the induced fields in humans. Incident electric field levels significantly exceed the International Commission on Non-Ionizing Radiation Protection (ICNIRP) reference levels at close distances for some sources, while the induced fields are within the ICNIRP basic restrictions. This demonstrates the importance of assessing the induced fields rather than the incident fields for these sources. Maximum current densities for CFLs are comparable to the limits (in the range of 9% to 56%), demonstrating the need for measurements to establish compliance. For the frequency range investigated, the induced fields were found to be considerably higher for CFLs than for incandescent light bulbs, while the exposure from the two LED bulbs was low. The proposed instrumentation and methods offer several advantages over an existing measurement standard, and the measurement uncertainty is significantly better than the assessment of electric and magnetic fields at close distances. PMID- 25929245 TI - Diethylstilbestrol regulates expression of avian apolipoprotein D during regression and recrudescence of the oviduct and epithelial-derived ovarian carcinogenesis. AB - Apolipoprotein D (APOD) is a glycoprotein which is widely expressed in mammalian tissues. It is structurally and functionally similar to the lipocalins which are multiple lipid-binding proteins that transport hydrophobic ligands and other small hydrophobic molecules, including cholesterol and several steroid hormones. Although multiple functions for APOD in various tissues have been reported, its expression, biological function, and hormonal regulation in the female reproductive system are not known. Thus, in this study, we focused on correlations between APOD and estrogen during development, differentiation, regression, and regeneration of the oviduct in chickens and in the development of ovarian carcinogenesis in laying hens. Results of the present study indicated that APOD messenger RNA (mRNA) expression increased (P < 0.001) in the luminal and glandular (GE) epithelia of the chicken oviduct in response to diethylstilbestrol (a nonsteroidal synthetic estrogen). In addition, the expression of APOD mRNA and protein decreased (P < 0.001) as the oviduct regressed during induced molting, and gradually increased (P < 0.001) with abundant expression in GE of the oviduct during recrudescence after molting. Furthermore, APOD mRNA and protein were predominantly localized in GE of cancerous, but not normal ovaries from laying hens. Collectively, results of the present study suggest that APOD is a novel estrogen-stimulated gene in the chicken oviduct which likely regulates growth, differentiation, and remodeling of the oviduct during oviposition cycles. Moreover, up-regulated expression of APOD in epithelial cell-derived ovarian cancerous tissue suggests that it could be a candidate biomarker for early detection and treatment of ovarian cancer in laying hens and in women. PMID- 25929246 TI - An in situ Raman spectroscopy-based microfluidic "lab-on-a-chip" platform for non destructive and continuous characterization of Pseudomonas aeruginosa biofilms. AB - Pseudomonas aeruginosa biofilm was cultivated and characterized in a microfluidic "lab-on-a-chip" platform coupled with confocal Raman microscopy in a non destructive manner. Biofilm formation could be quantified by this label-free platform and correlated well with confocal laser scanning microscopy. This Raman microfluidic platform could also discriminate biofilms at different developmental stages. PMID- 25929247 TI - Quantitative analysis of acankoreoside A and acankoreagenin in the leaves of Schefflera octophylla and Schefflera actinophylla using pressurized liquid extraction and high-performance liquid chromatography coupled with evaporative light scattering detection. AB - A rapid method based on pressurized liquid extraction followed by high performance liquid chromatography coupled with evaporative light scattering detection was firstly developed for the quantitative analysis of two bioactive triterpenoids (acankoreoside A and acankoreagenin) in the leaves of Schefflera octophylla and Schefflera actinophylla. The analysis was performed on an Agilent Zorbax SB-Aq column (4.6 * 50 mm, 3.5 MUm) with gradient elution of 0.1% formic acid and acetonitrile. Calibration curves of two analytes showed good linearity (R(2) > 0.9990) within the tested ranges. This novel method is simple, rapid and accurate, and the results of quantification showed that contents of each investigated compound is significant high in natural S. octophylla (6.36-14.83%), which indicated that natural S. octophylla as potential medicinal resource. Furthermore, hierarchical clustering analysis based on the typical peaks of acankoreoside A and acankoreagenin from the 17 tested samples showed that natural and cultured Schefflera species were in different clusters, which could provide a means of discriminating between Schefflera species from different origins. Thus, acankoreoside A and acankoreagnin could be selected markers for quality control of S. octophylla and S. actinophylla. PMID- 25929248 TI - Stereoscopic vascular models of the head and neck: A computed tomography angiography visualization. AB - Computer-assisted 3D models are used in some medical and allied health science schools; however, they are often limited to online use and 2D flat screen-based imaging. Few schools take advantage of 3D stereoscopic learning tools in anatomy education and clinically relevant anatomical variations when teaching anatomy. A new approach to teaching anatomy includes use of computed tomography angiography (CTA) images of the head and neck to create clinically relevant 3D stereoscopic virtual models. These high resolution images of the arteries can be used in unique and innovative ways to create 3D virtual models of the vasculature as a tool for teaching anatomy. Blood vessel 3D models are presented stereoscopically in a virtual reality environment, can be rotated 360 degrees in all axes, and magnified according to need. In addition, flexible views of internal structures are possible. Images are displayed in a stereoscopic mode, and students view images in a small theater-like classroom while wearing polarized 3D glasses. Reconstructed 3D models enable students to visualize vascular structures with clinically relevant anatomical variations in the head and neck and appreciate spatial relationships among the blood vessels, the skull and the skin. PMID- 25929249 TI - Slp-76 is a critical determinant of NK-cell mediated recognition of missing-self targets. AB - Absence of MHC class I expression is an important mechanism by which NK cells recognize a variety of target cells, yet the pathways underlying "missing-self" recognition, including the involvement of activating receptors, remain poorly understood. Using ethyl-N-nitrosourea mutagenesis in mice, we identified a germline mutant, designated Ace, with a marked defect in NK cell mediated recognition and elimination of "missing-self" targets. The causative mutation was linked to chromosome 11 and identified as a missense mutation (Thr428Ile) in the SH2 domain of Slp-76-a critical adapter molecule downstream of ITAM-containing surface receptors. The Slp-76 Ace mutation behaved as a hypomorphic allele-while no major defects were observed in conventional T-cell development/function, a marked defect in NK cell mediated elimination of beta2-microglobulin (beta2M) deficient target cells was observed. Further studies revealed Slp-76 to control NK-cell receptor expression and maturation; however, activation of Slp 76(ace/ace) NK cells through ITAM-containing NK-cell receptors or allogeneic/tumor target cells appeared largely unaffected. Imagestream analysis of the NK-beta2M(-/-) target cell synapse revealed a specific defect in actin recruitment to the conjugate synapse in Slp-76(ace/ace) NK cells. Overall these studies establish Slp-76 as a critical determinant of NK-cell development and NK cell mediated elimination of missing-self target cells in mice. PMID- 25929250 TI - Efficacy and safety of nicoboxil/nonivamide ointment for the treatment of acute pain in the low back - A randomized, controlled trial. AB - BACKGROUND: Until now, nonivamide/nicoboxil ointment has not been tested in a randomized trial for the treatment of acute non-specific low back pain. METHODS: This phase III randomized, double-blind, active- and placebo-controlled, multi centre trial investigated efficacy, safety and tolerability of topical nicoboxil 2.5%/nonivamide 0.4% for treatment of acute non-specific low back pain [primary endpoint: pain intensity (PI) difference between pre-dose baseline and 8 h after the first application]. RESULTS: Patients (n = 805), 18-74 years of age were treated for up to 4 days with nicoboxil 2.5%/nonivamide 0.4%, nicoboxil 2.5%, nonivamide 0.4% or placebo ointment. Pre-dose baseline pain intensity (6.6 on a 0 to 10-point numerical rating scale) was reduced by 1.049 points with placebo, by 1.428 points with nicoboxil, by 2.252 points with nonivamide and by 2.410 points with nicoboxil/nonivamide after 8 h (p < 0.0001 for nicoboxil/nonivamide vs. placebo, nicoboxil; p = 0.4171 for nicoboxil/nonivamide vs. nonivamide). At the end of treatment, the combination provided more pronounced PI reduction (3.540 points) compared with nicoboxil (2.371, p < 0.0001), nonivamide (3.074, p = 0.0259) and placebo (1.884, p < 0.0001). Low back mobility scores on Day 1 were better for the combination compared with all other treatments (p < 0.044); on Day 2-4, scores were better than for placebo and nicoboxil (p < 0.003). Patients assessed efficacy of the combination as greater than of the comparators (p <= 0.0129). All treatments were tolerated well. No treatment-related serious adverse events were reported. CONCLUSION: Nicoboxil/nonivamide ointment is an effective, well-tolerated medication for the treatment of acute non-specific low back pain. PMID- 25929252 TI - Predictors of microbial agents in dust and respiratory health in the Ecrhs. AB - BACKGROUND: Dampness and mould exposure have been repeatedly associated with respiratory health. However, less is known about the specific agents provoking or arresting health effects in adult populations. We aimed to assess predictors of microbial agents in mattress dust throughout Europe and to investigate associations between microbial exposures, home characteristics and respiratory health. METHODS: Seven different fungal and bacterial parameters were assessed in mattress dust from 956 adult ECRHS II participants in addition to interview based home characteristics. Associations between microbial parameters and the asthma score and lung function were examined using mixed negative binomial regression and linear mixed models, respectively. RESULTS: Indoor dampness and pet keeping were significant predictors for higher microbial agent concentrations in mattress dust. Current mould and condensation in the bedroom were significantly associated with lung function decline and current mould at home was positively associated with the asthma score. Higher concentrations of muramic acid were associated with higher mean ratios of the asthma score (aMR 1.37, 95%CI 1.17-1.61). There was no evidence for any association between fungal and bacterial components and lung function. CONCLUSION: Indoor dampness was associated with microbial levels in mattress dust which in turn was positively associated with asthma symptoms. PMID- 25929253 TI - A randomized, double-blind, placebo-controlled study of the effect of ezetimibe on glucose metabolism in subjects with type 2 diabetes mellitus and hypercholesterolemia. AB - BACKGROUND: Recent evidence points to an increased incidence of new-onset diabetes and a negative impact on glucose parameters with statin use. This study examined the safety of ezetimibe vs placebo for change from baseline to week 24 in HbA1c (primary endpoint), glycoalbumin, and fasting plasma glucose (secondary endpoints) in Japanese subjects with type 2 diabetes and hypercholesterolemia. METHODS: This was a randomized, double-blind, placebo-controlled, parallel-group, multi-site trial. Adults with type 2 diabetes and hypercholesterolemia whose LDL C measured <140 mg/dl (subjects receiving lipid-lowering drugs) or <160 mg/dl (subjects not receiving lipid-lowering drugs) at the start of the screening phase, were randomized after a 5-week wash-out period to ezetimibe 10 mg or placebo (1:1) for 24 weeks. Changes in HbA1c, glycoalbumin and fasting plasma glucose from baseline to week 24 were evaluated. The non-inferiority margin was set at 0.5% for HbA1c. RESULTS: Overall, 152 subjects were randomized (75 to ezetimibe and 77 to placebo). From baseline to 24 weeks, HbA1c significantly increased in both the ezetimibe and placebo groups (between-treatment difference 0.08 [95% CI: -0.07 to 0.23]). Ezetimibe was statistically non-inferior to placebo. At 24 weeks, the mean change from baseline in glycoalbumin levels (between-treatment differences 0.00 [95% CI: -0.47, 0.47]) and fasting plasma glucose (between-treatment differences -4.8 [95% CI: -12.1, 2.1]) were similar in both treatment groups. CONCLUSIONS: These results suggest that ezetimibe 10 mg does not result in dysregulation of glucose metabolism in Japanese patients with type 2 diabetes and hypercholesterolemia over 24 weeks of treatment. TRIAL REGISTRATION: ClinicalTrials.gov identifier NCT01611883 . PMID- 25929254 TI - Leptin and adiponectin DNA methylation levels in adipose tissues and blood cells are associated with BMI, waist girth and LDL-cholesterol levels in severely obese men and women. AB - BACKGROUND: Leptin (LEP) and adiponectin (ADIPOQ) genes encode adipokines that are mainly secreted by adipose tissues, involved in energy balance and suspected to play a role in the pathways linking adiposity to impaired glucose and insulin homeostasis. We have thus hypothesized that LEP and ADIPOQ DNA methylation changes might be involved in obesity development and its related complications. The objective of this study was to assess whether LEP and ADIPOQ DNA methylation levels measured in subcutaneous (SAT) and visceral adipose tissues (VAT) are associated with anthropometric measures and metabolic profile in severely obese men and women. These analyses were repeated with DNA methylation profiles from blood cells obtained from the same individuals to determine whether they showed similarities. METHODS: Paired SAT, VAT and blood samples were obtained from 73 severely obese patients undergoing a bioliopancreatic diversion with duodenal switch. LEP and ADIPOQ DNA methylation and mRNA levels were quantified using bisulfite-pyrosequencing and qRT-PCR respectively. Pearson's correlation coefficients were computed to determine the associations between LEP and ADIPOQ DNA methylation levels, anthropometric measures and metabolic profile. RESULTS: DNA methylation levels at the ADIPOQ gene locus in SAT was positively associated with BMI and waist girth whereas LEP DNA methylation levels in blood cells were negatively associated with body mass index (BMI). Fasting LDL-C levels were found to be positively correlated with DNA methylation levels at LEP-CpG11 and -CpG17 in blood and SAT and with ADIPOQ DNA methylation levels in SAT (CpGE1 and CpGE3) and VAT (CpGE1). CONCLUSIONS: These results confirm that LEP and ADIPOQ epigenetic profiles are associated with obesity. We also report associations between LDL-C levels and both LEP and ADIPOQ DNA methylation levels suggesting that LDL-C might regulate their epigenetic profiles in adipose tissues. Furthermore, similar correlations were observed between LDL-C and LEP blood DNA methylation levels suggesting a common regulatory pathway of DNA methylation in both adipose tissues and blood. PMID- 25929255 TI - High-frequency oscillation ventilation for hypercapnic failure of conventional ventilation in pulmonary acute respiratory distress syndrome. AB - INTRODUCTION: High-frequency oscillation ventilation (HFOV) is regarded as particularly lung protective. Recently, HFOV has been shown to be not beneficial for acute respiratory distress syndrome (ARDS) patients in general. Due to its special physical effects, it could be beneficial, however, in inhomogeneous ARDS. This study evaluates the effect of HFOV on PaCO2 removal in hypercapnic patients with ARDS of pulmonary origin. METHODS: Between October 2010 and June 2014 patients with ARDS of pulmonary origin with PaO2/FiO2 ratio >60 mmHg, but respiratory acidosis (pH <7.26) under optimized protective ventilation were switched to HFOV, using moderate airway pressure (adopting the mean airway pressure of the prior ventilation). Data from these patients were analyzed retrospectively; PaCO2 and pH before, 1 h and 24 h after the start of HFOV were compared. RESULTS: Twenty-six patients with PaO2/FiO2 ratio 139 +/- 49 and respiratory acidosis (PaCO2 68 +/- 12 mmHg) were put on HFOV after 17 +/- 22 h of conventional ventilation. Mean airway pressure was 19 cm H2O (15 to 28). PaCO2 decreased significantly: after 1 hour the mean difference was -14 +/- 10 mmHg; P <0.01 and after 24 hours -17 +/- 12 mmHg; P <0.01; n = 24. CO2 clearance improved in all but two patients; in those, extracorporeal lung support was initiated. Oxygenation remained unchanged after 1 h and slightly increased after 24 h. No complications related to HFOV were observed. Twenty-two patients improved and could be weaned from HFOV. Twenty patients (77%) were alive on day 30. CONCLUSIONS: HFOV could be a useful alternative in patients with ARDS of pulmonary origin with hypercapnic failure of lung-protective conventional ventilation. PMID- 25929256 TI - Statins as Targeted "Magical Pills" for the Conservative Treatment of Endometriosis: May Potential Adverse Effects on Female Fertility Represent the "Dark Side of the Same Coin"? A Systematic Review of Literature. AB - The aim of the study was to analyze all the available evidence from both in vitro and in vivo studies regarding the efficacy of statin therapy in the treatment of endometriosis, evaluating the potential efficacy, side effects, and contraindications of their administration in humans. We focused on defining the potential benefits that the administration of statins may have on patients affected by endometriosis and the possible adverse effects of such a therapy on ovarian function and fertility profile. According to our article selection criteria, we included in the review in vitro and in vivo studies performed on human or animal models. The systematic review of literature identified 24 eligible articles, 12 of which reported evidence regarding the effects of statins on endometrial/endometriotic cells and 12 regarding their effects on ovarian function and fertility. All articles seem to emphasize the utility of statin administration in the treatment of endometriosis due to their anti proliferative/proapoptotic effects, their ability to reduce cell viability and migration, and the inhibition of angiogenesis and anti-inflammatory activities. Regarding the potential adverse effects on gonadal activities, steroidogenesis and fertility function, no conclusive data were collected in human models (excluding women affected by polycystic ovary syndrome in which significant decline of androgen levels was reported after statin treatment), while contrasting results were reported by studies conducted in in vitro and in vivo in animal models. Despite evidence supporting statins as the potential therapeutic agent for a targeted conservative treatment of endometriosis, the uncertainties regarding their impact on gonadal function may not define them as an appropriate therapy for all young fertile women. PMID- 25929257 TI - Life expectancy gender gap will close in England and Wales, study predicts. PMID- 25929258 TI - Health effects of adopting low greenhouse gas emission diets in the UK. AB - OBJECTIVE: Dietary changes which improve health are also likely to be beneficial for the environment by reducing emissions of greenhouse gases (GHG). However, previous analyses have not accounted for the potential acceptability of low GHG diets to the general public. This study attempted to quantify the health effects associated with adopting low GHG emission diets in the UK. DESIGN: Epidemiological modelling study. SETTING: UK. PARTICIPANTS: UK population. INTERVENTION: Adoption of diets optimised to achieve the WHO nutritional recommendations and reduce GHG emissions while remaining as close as possible to existing dietary patterns. MAIN OUTCOME: Changes in years of life lost due to coronary heart disease, stroke, several cancers and type II diabetes, quantified using life tables. RESULTS: If the average UK dietary intake were optimised to comply with the WHO recommendations, we estimate an incidental reduction of 17% in GHG emissions. Such a dietary pattern would be broadly similar to the current UK average. Our model suggests that it would save almost 7 million years of life lost prematurely in the UK over the next 30 years and increase average life expectancy by over 8 months. Diets that result in additional GHG emission reductions could achieve further net health benefits. For emission reductions greater than 40%, improvements in some health outcomes may decrease and acceptability will diminish. CONCLUSIONS: There are large potential benefits to health from adopting diets with lower associated GHG emissions in the UK. Most of these benefits can be achieved without drastic changes to existing dietary patterns. However, to reduce emissions by more than 40%, major dietary changes that limit both acceptability and the benefits to health are required. PMID- 25929260 TI - The use of a synthetic progesterone, levonorgestrel (LNG), to control the oestrous cycle in the koala. AB - This study investigated the efficacy of a synthetic progestogen, levonorgestrel (LNG), to control koala ovarian activity for the purposes of oestrous synchronisation. Captive koalas were administered either saline control or a 70 mg LNG implant on Day 2 of oestrus. Urogenital cytology, oestrous behaviour and plasma oestradiol-17beta and LH concentrations were monitored over a 6-week period. After LNG implant removal females were monitored to determine if the return to oestrus was synchronised. LNG-treated koalas immediately ceased displaying oestrous behaviour, showed no evidence of cornified epithelial cells in smears of urogenital cytology and exhibited low plasma oestradiol-17beta concentrations throughout the implantation period. In contrast, oestradiol-17beta levels in control koalas showed evidence of continued cyclic activity associated with behavioural oestrus and increased cornified epithelial cells in urogenital smears on Days 33 to 35 after saline injection. After implant removal, LNG treated koalas exhibited oestrus at 13, 14, 17 and 30 days after implant removal. Plasma LH concentrations varied throughout the study period with no significant time (P = 0.49) or treatment (P = 0.13) effect. Overall results from this study suggest that LNG implants in koalas can inhibit oestrous behaviour and reduce circulating oestradiol-17beta levels before oestrus, most likely by preventing development of the pre-ovulatory follicle. However, there was no evidence of LH suppression by the LNG implants. Removal of LNG implants resulted in the synchronous return to oestrus in three of the four treated koalas. Further studies on a larger population are required to validate these findings. PMID- 25929259 TI - Antibiotic treatment of diarrhoea is associated with decreased time to the next diarrhoea episode among young children in Vellore, India. AB - BACKGROUND: Antibiotics are commonly given for the treatment of childhood diarrhoea, but are not indicated in most cases. Antibiotics modify the gastrointestinal microbiota, which may have unanticipated effects on the risk of subsequent diarrhoea. METHODS: In a prospective observational cohort study, we assessed the effect of caregiver-reported antibiotic treatment for diarrhoea on the timing of a child's next episode among 434 children followed from birth to 3 years of age in Vellore, India. We estimated median time differences and time ratios from inverse probability of exposure-weighted Kaplan-Meier curves for the time to next diarrhoea episode, comparing children who did and did not receive antibiotics for the previous episode. RESULTS: Study children had more than five diarrhoea episodes on average in the first 3 years of life, and more than a quarter of all episodes were treated with antibiotics. Children who received antibiotics for their first diarrhoea episode had their second episode on average 8 weeks earlier (median time difference: -8, 95% confidence interval: -10, -3) than children who did not receive antibiotics. The effects of antibiotics on subsequent diarrhoea were greatest at earlier episodes and younger ages, and cefixime had a slightly larger effect compared with cotrimoxazole. CONCLUSIONS: Antibiotic treatment of diarrhoea was associated with reduced time to a subsequent diarrhoea episode, especially among younger infants. Whereas rational use of antibiotics has been advocated to reduce antimicrobial resistance in populations, we show that overuse of antibiotics may also have a direct adverse effect on individual patients. PMID- 25929262 TI - Identification of the novel KIR3DL1*079 allele from a southern Chinese Han individual. AB - The novel KIR3DL1*079 allele differs from KIR3DL1*0150201 by a single mutation at CDS nt1119 G>T. PMID- 25929263 TI - Curcumin specifically binds to the human calcium-calmodulin-dependent protein kinase IV: fluorescence and molecular dynamics simulation studies. AB - Calcium-calmodulin-dependent protein kinase IV (CAMK4) plays significant role in the regulation of calcium-dependent gene expression, and thus, it is involved in varieties of cellular functions such as cell signaling and neuronal survival. On the other hand, curcumin, a naturally occurring yellow bioactive component of turmeric possesses wide spectrum of biological actions, and it is widely used to treat atherosclerosis, diabetes, cancer, and inflammation. It also acts as an antioxidant. Here, we studied the interaction of curcumin with human CAMK4 at pH 7.4 using molecular docking, molecular dynamics (MD) simulations, fluorescence binding, and surface plasmon resonance (SPR) methods. We performed MD simulations for both neutral and anionic forms of CAMK4-curcumin complexes for a reasonably long time (150 ns) to see the overall stability of the protein-ligand complex. Molecular docking studies revealed that the curcumin binds in the large hydrophobic cavity of kinase domain of CAMK4 through several hydrophobic and hydrogen-bonded interactions. Additionally, MD simulations studies contributed in understanding the stability of protein-ligand complex system in aqueous solution and conformational changes in the CAMK4 upon binding of curcumin. A significant increase in the fluorescence intensity at 495 nm was observed (lambdaexc = 425 nm), suggesting a strong interaction of curcumin to the CAMK4. A high binding affinity (KD = 3.7 * 10(-8) +/- .03 M) of curcumin for the CAMK4 was measured by SPR further indicating curcumin as a potential ligand for the CAMK4. This study will provide insights into designing a new inspired curcumin derivatives as therapeutic agents against many life-threatening diseases. PMID- 25929265 TI - Editorial: selling your science: where preparation meets genius. PMID- 25929264 TI - Biophysical influence of airborne carbon nanomaterials on natural pulmonary surfactant. AB - Inhalation of nanoparticles (NP), including lightweight airborne carbonaceous nanomaterials (CNM), poses a direct and systemic health threat to those who handle them. Inhaled NP penetrate deep pulmonary structures in which they first interact with the pulmonary surfactant (PS) lining at the alveolar air-water interface. In spite of many research efforts, there is a gap of knowledge between in vitro biophysical study and in vivo inhalation toxicology since all existing biophysical models handle NP-PS interactions in the liquid phase. This technical limitation, inherent in current in vitro methodologies, makes it impossible to simulate how airborne NP deposit at the PS film and interact with it. Existing in vitro NP-PS studies using liquid-suspended particles have been shown to artificially inflate the no-observed adverse effect level of NP exposure when compared to in vivo inhalation studies and international occupational exposure limits (OELs). Here, we developed an in vitro methodology called the constrained drop surfactometer (CDS) to quantitatively study PS inhibition by airborne CNM. We show that airborne multiwalled carbon nanotubes and graphene nanoplatelets induce a concentration-dependent PS inhibition under physiologically relevant conditions. The CNM aerosol concentrations controlled in the CDS are comparable to those defined in international OELs. Development of the CDS has the potential to advance our understanding of how submicron airborne nanomaterials affect the PS lining of the lung. PMID- 25929268 TI - Impaired development of left anterior heart field by ectopic retinoic acid causes transposition of the great arteries. AB - BACKGROUND: Transposition of the great arteries is one of the most commonly diagnosed conotruncal heart defects at birth, but its etiology is largely unknown. The anterior heart field (AHF) that resides in the anterior pharyngeal arches contributes to conotruncal development, during which heart progenitors that originated from the left and right AHF migrate to form distinct conotruncal regions. The aim of this study is to identify abnormal AHF development that causes the morphology of transposition of the great arteries. METHODS AND RESULTS: We placed a retinoic acid-soaked bead on the left or the right or on both sides of the AHF of stage 12 to 14 chick embryos and examined the conotruncal heart defect at stage 34. Transposition of the great arteries was diagnosed at high incidence in embryos for which a retinoic acid-soaked bead had been placed in the left AHF at stage 12. Fluorescent dye tracing showed that AHF exposed to retinoic acid failed to contribute to conotruncus development. FGF8 and Isl1 expression were downregulated in retinoic acid-exposed AHF, and differentiation and expansion of cardiomyocytes were suppressed in cultured AHF in medium supplemented with retinoic acid. CONCLUSIONS: The left AHF at the early looped heart stage, corresponding to Carnegie stages 10 to 11 (28 to 29 days after fertilization) in human embryos, is the region of the impediment that causes the morphology of transposition of the great arteries. PMID- 25929269 TI - Generalized Pressure Pain Hypersensitivity in the Cervical Muscles in Women with Migraine. AB - OBJECTIVE: To investigate the differences in pressure sensitivity in the cervical musculature including the upper trapezius, sternocleidomastoid, suboccipital, levator scapulae, and anterior scalene muscles between women with migraine and healthy controls. DESIGN: Cross-sectional study. SUBJECTS: Thirty women with migraine and 30 healthy women participated. METHODS: Pressure pain thresholds (PPT) were bilaterally assessed over upper trapezius, sternocleidomastoid, suboccipital, levator scapulae, and anterior scalene muscles in a blinded design. Mean values of both sides were pooled for statistical analysis. Comparison between groups was performed by unpaired Student t-test and correlation with headache features with Spearman's correlation test. RESULTS: Migraine patients exhibited lower PPT in all muscles compared with controls: upper trapezius (P = 0.046); suboccipital (P < 0.001); sternocleidomastoid (P < 0.001); anterior scalene (P < 0.001), and levator scapulae (P < 0001). No associations were observed between the frequency and the intensity of migraine or years with the disease and PPT. CONCLUSION: This study showed generalized pressure pain hypersensitivity in the cervical musculature in women with migraine. Our findings provide support for the physical therapy treatment and evaluation of musculoskeletal cervical spine disorders in individuals with migraine and reinforce that all cervical muscles should be evaluated. PMID- 25929270 TI - Idiopathic epilepsy in the Italian Spinone in the United Kingdom: prevalence, clinical characteristics, and predictors of survival and seizure remission. AB - BACKGROUND: There is lack of data on idiopathic epilepsy (IE) in the Italian Spinone (IS). OBJECTIVES: To estimate the prevalence of IE in the IS in the United Kingdom (UK) and to investigate predictors of survival and seizure remission. ANIMALS: The target population consisted of 3331 IS born between 2000 and 2011 and registered with the UK Kennel Club (KC). The owners of 1192 dogs returned phase I questionnaire. Sixty-three IS had IE. METHODS: Population survey. The owners of all UK KC-registered IS were invited to complete the phase I questionnaire. Information from the phase I questionnaire and veterinary medical records was used to identify IS with IE and obtain data on treatment and survival. Additional information was obtained from owners of epileptic IS who completed the phase II questionnaire. RESULTS: The prevalence of IE in the IS in the UK was estimated as 5.3% (95% CI, 4.03-6.57%). Survival time was significantly shorter in IS euthanized because of poorly controlled IE compared with epileptic IS that died of unrelated disorders (P = 0.001). Survival was significantly longer in IS with no cluster seizures (CS) (P = 0.040) and in IS in which antiepileptic medication was initiated after the second seizure rather than after >=3 seizures (P = 0.044). Seizure remission occurred only in 3 IS. CONCLUSIONS AND CLINICAL IMPORTANCE: The prevalence of IE in IS (5.3%) is higher than in dogs (0.6%) in the UK. Idiopathic epilepsy in IS has a severe phenotype. Antiepileptic medication initiation after the second seizure and aggressive treatment of CS may improve survival. PMID- 25929271 TI - Improved method for measuring the apparent CO2 photocompensation point resolves the impact of multiple internal conductances to CO2 to net gas exchange. AB - There is a growing interest in accurate and comparable measurements of the CO2 photocompensation point (Gamma*), a vital parameter to model leaf photosynthesis. The Gamma* is measured as the common intersection of several CO2 response curves, but this method may incorrectly estimate Gamma* by using linear fits to extrapolate curvilinear responses and single conductances to convert intercellular photocompensation points (Ci *) to chloroplastic Gamma*. To determine the magnitude and minimize the impact of these artefacts on Gamma* determinations, we used a combination of meta-analysis, modelling and original measurements to develop a framework to accurately determine Ci *. Our modelling indicated that the impact of using linear fits could be minimized based on the measurement CO2 range. We also propose a novel method of analysing common intersection measurements using slope-intercept regression. Our modelling indicated that slope-intercept regression is a robust analytical tool that can help determine if a measurement is biased because of multiple internal conductances to CO2 . Application of slope-intercept regression to Nicotiana tabacum and Glycine max revealed that multiple conductances likely have little impact to Ci * measurements in these species. These findings present a robust and easy to apply protocol to help resolve key questions concerning CO2 conductance through leaves. PMID- 25929272 TI - Neuropeptide Y system in accumbens shell mediates ethanol self-administration in posterior ventral tegmental area. AB - Although modulatory effects of neuropeptide Y (NPY) on ethanol consumption are well established, its role in ethanol reward, in the framework of mesolimbic dopaminergic system, has not been studied. We investigated the influence of nucleus accumbens shell (AcbSh) NPYergic system on ethanol self-administration in posterior ventral tegmental area (p-VTA) using intracranial self-administration paradigm. Rats were stereotaxically implanted with cannulae targeted unilaterally at the right p-VTA and trained to self-administer ethanol (200 mg%) in standard two-lever (active/inactive) operant chamber, an animal model with high predictive validity to test the rewarding mechanisms. Over a period of 7 days, these rats showed a significant increase in the number of lever presses for ethanol self administration suggesting reinforcement. While intra-AcbSh NPY (1 or 2 ng/rat) or [Leu(31) , Pro(34) ]-NPY (0.5 or 1 ng/rat) dose-dependently increased ethanol self-administration, BIBP3226 (0.4 or 0.8 ng/rat) produced opposite effect. The rats conditioned to self-administer ethanol showed significant increase in the population of NPY-immunoreactive cells and fibres in the AcbSh, central nucleus of amygdala (CeA), hypothalamic arcuate nucleus (ARC) and lateral part of bed nucleus of stria terminalis as compared with that in the naive rats. Neuronal tracing studies showed that NPY innervations in the AcbSh may derive from the neurons of ARC and CeA. As NPY and dopamine systems in reward areas are known to interact, we suggest that NPY inputs from ARC and CeA may play an important role in modulation of the dopaminergic system in the AcbSh and consequently influence the ethanol induced reward and addiction. PMID- 25929274 TI - Quantifying Adversary Capabilities to Inform Defensive Resource Allocation. AB - We propose a Bayesian Stackelberg game capable of analyzing the joint effects of both attacker intent and capabilities on optimal defensive strategies. The novel feature of our model is the use of contest success functions from economics to capture the extent to which the success of an attack is attributable to the adversary's capability (as well as the level of defensive investment), rather than pure luck. Results of a two-target example suggest that precise assessment of attacker intent may not be necessary if we have poor estimates of attacker capability. PMID- 25929273 TI - A prospective study of the impact of fluorodeoxyglucose positron emission tomography with concurrent non-contrast CT scanning on the management of operable pancreatic and peri-ampullary cancers. AB - BACKGROUND: The role of fluorodeoxyglucose (FDG) positron emission tomography (PET/CT) scanning in operable pancreas cancer is unclear. We, therefore, wanted to investigate the impact of PET/CT on management, by incorporating it into routine work-up. METHODS: This was a single-institution prospective study. Patients with suspected and potentially operable pancreas, distal bile duct or ampullary carcinomas underwent PET/CT in addition to routine work-up. The frequency that PET/CT changed the treatment plan or prompted other investigations was determined. The distribution of standard uptake values (SUV) among primary tumours, and adjacent to biliary stents was characterised. RESULTS: Fifty-six patients were recruited. The surgical plan was abandoned in 9 (16%; 95% CI: 6-26) patients as a result of PET/CT identified metastases. In four patients, metastases were missed and seven were inoperable at surgery, not predicted by PET/CT. Unexpected FDG uptake resulted in seven additional investigations, of which two were useful. Among primary pancreatic cancers, a median SUV was 4.9 (range 2-12.1). SUV was highest around the biliary stent in 17 out of 28 cases. PET/CT detected metastases in five patients whose primary pancreatic tumours demonstrated mild to moderate avidity (SUV < 5). CONCLUSIONS: PET/CT in potentially operable pancreas cancer has limitations. However, as a result of its ability to detect metastases, PET/CT scanning is a useful tool in the selection of such patients for surgery. PMID- 25929275 TI - Dental service utilization and neighborhood characteristics in young adults in the United States: a multilevel approach. AB - OBJECTIVE: To investigate the association between neighborhood level factors and dental visits in young adults in the United States after adjusting for individual level factors. METHODS: The National Longitudinal Study of Adolescent Health Wave 1 (1994-1995) to Wave III (2001-2002) was analyzed. The primary outcome of having had at least one dental visit in the previous 12 months was analyzed via a multilevel random-effects logistic model accounting for geographic clustering in Wave III and survey design clustering from Wave I. Neighborhood level covariates were defined at the census tract level. RESULTS: Overall rate of dental visits was 57 percent, highest among 18-20 year olds (65 percent) and lowest in 23-26 year olds (52 percent). Increased proportion of African-Americans (<=5 percent to >=20 percent) and Hispanics (<=5 percent to >=20 percent) in a neighborhood corresponded with a decrease in dental visits (60 percent versus 52 percent) and (58 percent versus 51 percent), respectively. Neighborhoods with a high proportion of college-educated residents had a higher percentage of dental visits. Similar differences were found when comparing the lowest and highest tertiles defined by poverty level and unemployment with dental visits. Neighborhood education was significantly associated with dental service utilization after adjustment for individual level factors and dental utilization in adolescence (Waves I and II) in the random effects model. CONCLUSIONS: This study demonstrates that the education level of residents within a neighborhood was associated with dental service utilization in young adults in the United States. PMID- 25929276 TI - Retinal axonal loss in very early stages of multiple sclerosis. AB - BACKGROUND AND PURPOSE: The lack of surrogates of clinical progression has limited the design of neuroprotection trials in multiple sclerosis (MS). Our aim was to study the association between time-domain optical coherence tomography measures and clinical and magnetic resonance imaging outcomes in early MS. METHODS: Forty-three relapsing-remitting MS patients within 1 year of onset were followed for up to 3 years. RESULTS: The peripapillary retinal nerve fiber layer (RNFL) decreased annually by 2 MUm (95% confidence interval -3.89, -0.11; P = 0.038). The RNFL tended to be associated with normalized normal appearing white matter volume in cross-sectional (P = 0.08) and longitudinal analyses (P = 0.06). CONCLUSIONS: There is substantial RNFL loss even in very early MS. Our data suggest that retinal axonal atrophy is associated with atrophy in global white matter volume in early MS. PMID- 25929277 TI - Early glycaemic control among patients with type 2 diabetes and initial glucose lowering treatment: a 13-year population-based cohort study. AB - AIM: To examine real-life time trends in early glycaemic control in patients with type 2 diabetes between 2000 and 2012. METHODS: We used population-based medical databases to ascertain the association between achievement of glycaemic control with initial glucose-lowering treatment in patients with incident type 2 diabetes in Northern Denmark. Success in reaching glycated haemoglobin (HbA1c) goals within 3-6 months was examined using regression analysis. RESULTS: Of 38 418 patients, 91% started with oral glucose-lowering drugs in monotherapy. Metformin initiation increased from 32% in 2000-2003 to 90% of all patients in 2010-2012. Pretreatment (interquartile range) HbA1c levels decreased from 8.9 (7.6-10.7)% in 2000-2003 to 7.0 (6.5-8.1)% in 2010-2012. More patients achieved an HbA1c target of <7% (<53 mmol/mol) in 2010-2012 than in 2000-2003 [80 vs 60%, adjusted relative risk (aRR) 1.10, 95% confidence interval (CI) 1.08-1.13], and more achieved an HbA1c target of <6.5% [(<48 mmol/mol) 53 vs 37%, aRR 1.07 95% CI 1.03 1.11)], with similar success rates observed among patients aged <65 years without comorbidities. Achieved HbA1c levels were similar for different initiation therapies, with reductions of 0.8% (from 7.3 to 6.5%) on metformin, 1.5% (from 8.1 to 6.6%) on sulphonylurea, 4.0% (from 10.4 to 6.4%) on non-insulin combination therapies, and 3.8% (from 10.3 to 6.5%) on insulin monotherapy. CONCLUSIONS: Pretreatment HbA1c levels in patients with incident type 2 diabetes have decreased substantially, which is probably related to earlier detection and treatment in accordance with changing guidelines. Achievement of glycaemic control has improved, but 20% of patients still do not attain an HbA1c level of <7% within the first 6 months of initial treatment. PMID- 25929278 TI - The unusual journey of a tooth. Found but not lost? PMID- 25929279 TI - Transcranial Direct Current Stimulation Ameliorates Behavioral Deficits and Reduces Oxidative Stress in 1-Methyl-4-Phenyl-1,2,3,6-Tetrahydropyridine-Induced Mouse Model of Parkinson's Disease. AB - PURPOSE: Oxidative stress is involved in the pathological process of Parkinson's disease (PD). The present study was designed to investigate the effects of transcranial direct current stimulation (tDCS) on the oxidative stress in a mouse model of PD induced by 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP). METHODS: The animals were modulated by tDCS. Behavioral alterations were observed after three weeks of tDCS treatment using rotary performance tests. The mice were sacrificed for the measurement of the level of dopamine (DA), enzymatic tyrosine hydroxylase (TH), nonenzymatic malonaldehyde (MDA), an enzymatic superoxide dismutase (SOD), and glutathione peroxidase (GSH-Px) in the mouse brain and serum. RESULTS: The mice treated with MPTP had an increased MDA level but a decreased SOD and GSH-Px activity, as well as a behavior impairment. These abnormalities were significantly attenuated by tDCS treatment and by levodopa and benserazide. DISCUSSION: The study demonstrated that the tDCS could have a potential for the therapeutic usage in the PD. PMID- 25929280 TI - Australian Middle Eastern parents' perceptions and practices of children's weight related behaviours: Talking with Parents' Study. AB - The home environment is associated with obesity-related behaviours among children, and research in Australia has shown that some of these behaviours are more prevalent among children from particular cultural backgrounds including Middle Eastern. This study presents findings from face-to-face, semi-structured interviews conducted in April 2013 with a convenience sample of Middle Eastern parents of primary school-age children at an Islamic private school in Sydney, Australia. The interviews explored parental perceptions and practices regarding state government health messages addressing children's eating, physical activity and screen time. The purpose of the study was to investigate whether the content of these generic public health messages is relevant and acceptable to Middle Eastern parents of young children, and to identify any enablers and barriers to adopting these healthy practices at home. Thematic analysis identified predominant themes. In total, 21 interviews were conducted (reference children: 12 boys/9 girls, aged 5-12 years). The content of current health messages regarding children's weight-related behaviours was familiar to respondents, and accepted as relevant for guiding their parenting practices. Parents perceived that they typically encouraged healthy behaviours, although they also reported making regular exemptions, in response to various circumstances. Overall, the perceptions and reported practices of the parents were consistent with other studies with Australian parents. There were no apparent culturally specific barriers or enablers to children's weight-related behaviours. There is however scope for health promoters to provide more precise information on health recommendations, health risks and benefits, and to provide more specific ideas for ways in which parents can act on these health messages within the home and family environment, to encourage and support healthy behaviours in their children. PMID- 25929282 TI - Accelerated isotope fine structure calculation using pruned transition trees. AB - A fast and memory-efficient calculation of theoretical isotope patterns is crucial for the routine interpretation of mass spectrometric data. For high resolution experiments, calculations must procure the exact masses and probabilities of relevant isotopologues over a wide range of polyisotopic compounds, while pruning low-probable ones. Here, a novel albeit simple treelike structure is introduced to swiftly derive sets of relevant subisotopologues for each element in a molecule, which are then combined to the isotopologues of the full molecule. In contrast to existing approaches, transitions via single replacements of the most abundant isotope per element are used in separable tree branches to derive subisotopologues from each other. Moreover, the underlying transition trees prevent redundant replacements and permit the detection of the most probable isotopologue in a first phase. A relative threshold can then be exploited in a second parallelized phase for a precise prepruning of large fractions of the remaining subisotopologues. The gain in performance from such early pruning and the lower variation in the distortion of simulated data with use of relative rather than absolute thresholds were validated in a large-scale benchmark simulation, unprecedentedly comprising several thousand molecular formulas. Both the algorithm and a wealth of related features are freely available as R-package enviPat and as a user-friendly Web interface. PMID- 25929281 TI - Bactericidal activity and biocompatibility of ceragenin-coated magnetic nanoparticles. AB - BACKGROUND: Ceragenins, synthetic mimics of endogenous antibacterial peptides, are promising candidate antimicrobial agents. However, in some settings their strong bactericidal activity is associated with toxicity towards host cells. To modulate ceragenin CSA-13 antibacterial activity and biocompatibility, CSA-13 coated magnetic nanoparticles (MNP-CSA-13) were synthesized. Transmission electron microscopy (TEM), Fourier transform infrared spectroscopy (FT-IR), differential scanning calorimetry (DSC) and thermogravimetric analysis (TGA) were used to characterize MNP-CSA-13 physicochemical properties. Bactericidal action and ability of these new compounds to prevent Pseudomonas. aeruginosa biofilm formation were assessed using a bacteria killing assay and crystal violet staining, respectively. Release of hemoglobin from human red blood cells was measured to evaluate MNP-CSA-13 hemolytic activity. In addition, we used surface activity measurements to monitor CSA-13 release from the MNP shell. Zeta potentials of P. aeruginosa cells and MNP-CSA-13 were determined to assess the interactions between the bacteria and nanoparticles. Morphology of P. aeruginosa subjected to MNP-CSA-13 treatment was evaluated using atomic force microscopy (AFM) to determine structural changes indicative of bactericidal activity. RESULTS: Our studies revealed that the MNP-CSA-13 nanosystem is stable and may be used as a pH control system to release CSA-13. MNP-CSA-13 exhibits strong antibacterial activity, and the ability to prevent bacteria biofilm formation in different body fluids. Additionally, a significant decrease in CSA-13 hemolytic activity was observed when the molecule was immobilized on the nanoparticle surface. CONCLUSION: Our results demonstrate that CSA-13 retains bactericidal activity when immobilized on a MNP while biocompatibility increases when CSA-13 is covalently attached to the nanoparticle. PMID- 25929283 TI - Cellular hallmarks reveal restricted aerobic metabolism at thermal limits. AB - All organisms live within a given thermal range, but little is known about the mechanisms setting the limits of this range. We uncovered cellular features exhibiting signature changes at thermal limits in Caenorhabditis elegans embryos. These included changes in embryo size and shape, which were also observed in Caenorhabditis briggsae, indicating evolutionary conservation. We hypothesized that such changes could reflect restricted aerobic capacity at thermal limits. Accordingly, we uncovered that relative respiration in C. elegans embryos decreases at the thermal limits as compared to within the thermal range. Furthermore, by compromising components of the respiratory chain, we demonstrated that the reliance on aerobic metabolism is reduced at thermal limits. Moreover, embryos thus compromised exhibited signature changes in size and shape already within the thermal range. We conclude that restricted aerobic metabolism at the thermal limits contributes to setting the thermal range in a metazoan organism. PMID- 25929284 TI - Detection of a novel HLA-B*15 variant, HLA-B*15:01:37, in a Taiwanese unrelated hematopoietic stem cell donor. AB - One nucleotide substitution at residue 531 of HLA-B*15:01:01:01 results in a new allele, HLA-B*15:01:37. PMID- 25929285 TI - Cell-Based Approaches in Periodontal Regeneration: A Systematic Review and Meta Analysis of Periodontal Defect Models in Animal Experimental Work. AB - Various cell types have been assessed for experimental periodontal tissue regeneration in a variety of animal models. Nonetheless, the efficacy of cell based approaches for periodontal regeneration is still controversial. Therefore, the purpose of this study was to systematically review cell-based approaches for periodontal regeneration in animal studies including a meta-analysis to obtain more clarity on their efficacy. The results of this systematic review and meta analysis revealed that cell-based approaches have a favorable effect on periodontal tissue regeneration, as displayed by the positive effect of cell based approaches on new bone, cementum, and periodontal ligament (PDL) formation in periodontal defects. Moreover, subgroup analysis showed a favorable effect on PDL formation by PDL-derived cells, but not by bone marrow mesenchymal stem cells (BMSCs). However, meta-analysis did not show any statistically significant differences in effect between PDL-derived cells and BMSCs. These results provide important information for the implementation of cell-based approaches in clinical practice as a routine treatment for periodontal regeneration in the future. PMID- 25929286 TI - Low-intensity, short-duration thermal stimulation during the late phase of incubation alters secondary sex ratio in favour of males. AB - 1. In two experiments, two setters and hatchers, with a capacity of 42 240 eggs each, were used to investigate the effect of low-intensity, short-duration thermal stimuli during the late phase of incubation on hatchability, sex ratio and grow-out performance of broilers under field conditions. 2. Eggs in the test group had the same physical environment as eggs in the control group except that incubation temperature was increased by 0.5 degrees C for 2 h/d above the control group from 18 to 20 d of incubation. 3. Thermal stimulation significantly increased the proportion of males hatched in both experiments. In experiment 2, evaluation at 7 d of age showed that the proportion of males in the test group was still significantly higher than in the control group. 4. In experiment 2, hatch residue was examined and the proportion of unhatched male embryos was significantly greater in the control group than in the test group. 5. Thermal stimulation did not have a significant influence on post-hatch performance of broiler chickens to market age. 6. The results demonstrated that thermal stimulation of 0.5 degrees C for 2 h/d above the control during late incubation shifted the sex ratio at hatch and at 7 d in favour of males. The difference in secondary sex ratio was due to increased survival of male embryos in the test group. PMID- 25929288 TI - Cognitive reserve and cognitive function in healthy older people: a meta analysis. AB - The associations between proxy measures of cognitive reserve (CR) and cognition vary across studies and cognitive domains. This meta-analysis aimed to assess the relationship between CR and cognition in multiple domains (memory, executive function, visuospatial ability, and language). CR was considered in terms of three key proxy measures - educational level, occupational status, and engagement in cognitively stimulating activities - individually and in combination. One hundred and thirty-five studies representing 128,328 participants were included. Of these, 109 used a measure of education, 19 used a measure of occupation, 31 used a measure of participation in cognitively stimulating activities, and 6 used a combination of these. All three proxy measures had a modest positive association with cognition; occupational status and cognitive activities showed the most variation across cognitive domains. This supports the view that the commonly used proxy measures of CR share an underlying process but that each additionally provides a unique contribution to CR. PMID- 25929290 TI - Fluctuations of particle motion in granular avalanches - from the microscopic to the macroscopic scales. AB - In this study, we have investigated the fluctuations of particle motion, i.e. the non-affine motion, during the avalanche process, discovering a rich dynamic from the microscopic to the macroscopic scales. We find that there is a strong correlation between the magnitude of the velocity fluctuation and the velocity magnitude in the spatial and temporal domains. The possible connection between this finding and the theory of the shear transformation zones is discussed based on the direct measurement of the T1 events. In addition, the velocity magnitude of the system and the stress fluctuations of the system are strongly temporally correlated. Our finding will pose challenges to the development of more rigorous theories to describe avalanche dynamics based on the microscopic approach. Moreover, our finding presents a plausible mechanism of particle entrainment in a simple system. PMID- 25929289 TI - The Burden of Undiagnosed Opioid Abuse Among Commercially Insured Individuals. AB - OBJECTIVES: Estimate the prevalence and healthcare costs of undiagnosed opioid abuse among commercially insured individuals. STUDY DESIGN: Retrospective analysis of de-identified pharmacy and medical claims data and publicly-available survey data (no IRB approval required). METHODS: This study focused on commercially insured individuals. Rates of prescription pain-reliever abuse/dependence ("abuse") among individuals ages >=12 were calculated using National Survey on Drug Use and Health (NSDUH) public-use data for 2006-2011 and assumed to capture both diagnosed and undiagnosed opioid abuse. Rates of undiagnosed opioid abuse were calculated as the difference between NSDUH rates and published rates of diagnosed opioid abuse. OptumHealth Reporting and Insights claims data were used to estimate the healthcare costs of undiagnosed abuse. Diagnosed abusers ages 12-64 were identified using ICD-9-CM diagnosis codes for opioid abuse/dependence. Pre-diagnosis costs were assumed to be a proxy for undiagnosed opioid abuse costs. The ratio of undiagnosed to diagnosed abuse costs was calculated as the ratio of annual per-patient healthcare costs between pre diagnosis and post-diagnosis periods. RESULTS: While rates of diagnosed opioid abuse among commercially insured individuals increased from 0.07% in 2006 to 0.19% in 2011, rates of undiagnosed abuse decreased from 0.42% to 0.38% over the same time period. Annual per-patient healthcare costs of undiagnosed abusers were 69.2% of those of diagnosed abusers. CONCLUSIONS: Per-patient healthcare costs of undiagnosed abusers among the commercially insured are estimated to be lower than those of diagnosed abusers. However, the higher prevalence of undiagnosed opioid abuse implies that undiagnosed abuse represents a substantial burden to commercial payers. PMID- 25929291 TI - Gating the photochromism of an azobenzene by strong host-guest interactions in a divalent pseudo[2]rotaxane. AB - The ability of an E-configured azobenzene guest to undergo photoisomerisation is controlled by the presence of a complementary host. Addition of base/acid allowed for a weakening/strengthening of the interactions in the divalent pseudo[2]rotaxane complex and hence could switch on/off photochromic activity. PMID- 25929292 TI - Modified deposition process of electron transport layer for efficient inverted planar perovskite solar cells. AB - A highly-efficient inverted heterojunction perovskite solar cell was prepared. A homogeneous and compact perovskite (CH3NH3PbI3) layer was prepared via a two-step solution deposition method, and subsequently a double-layer PCBM film was deposited by a sequential spin-coating/vapor deposition process as the electron transport layer. The optimised device could achieve a 12.2% (average 11.09%) efficiency. PMID- 25929294 TI - The saccharopine pathway in seed development and stress response of maize. AB - Lysine is catabolized in developing plant tissues through the saccharopine pathway. In this pathway, lysine is converted into alpha-aminoadipic semialdehyde (AASA) by the bifunctional enzyme lysine-ketoglutarate reductase/saccharopine dehydrogenase (LKR/SDH). AASA is then converted into aminoadipic acid (AAA) by aminoadipic semialdehyde dehydrogenase (AASADH). Here, we show that LKR/SDH and AASADH are co-expressed in the sub-aleurone cell layers of the developing endosperm; however, although AASADH protein is produced in reproductive and vegetative tissues, the LKR/SDH protein is detectable only in the developing endosperm. AASADH showed an optimum pH of 7.4 and Kms for AASA and NAD(+) in the micromolar range. In the developing endosperm, the saccharopine pathway is induced by exogenous lysine and repressed by salt stress, whereas proline and pipecolic acid synthesis are significantly repressed by lysine. In young coleoptiles, the LKR/SDH and AASADH transcriptions are induced by abiotic stress, but while the AASADH protein accumulates in the stressed tissues, the LKR/SDH protein is not produced. In the developing seeds, the saccharopine pathway is used for pipecolic acid synthesis although proline may play a major role in abiotic stress response. The results indicate that the saccharopine pathway in maize seed development and stress responses significantly differ from that observed for dicot plants. PMID- 25929295 TI - Participation and factors associated with late or non-response to an online survey in primary care. AB - RATIONALE, AIMS AND OBJECTIVES: Online surveys have several advantages, but a low response rate is common and it is uncertain how results are affected. Response inducement techniques can be used to overcome this problem. The objectives of this study were to describe the percentage of change in the response rate after reminders and to analyse the characteristics associated with non-response and late response based on the survey results, as well as by applying archival and extrapolation techniques. METHOD: In the Autonomous Community of Madrid, an online questionnaire about cancer prevention was sent to a random sample of primary care health professionals (3586 physicians and nurses). Two reminders were sent later. The percentage of change in response rates after reminders, global and by demographic and health care characteristics of participants; and factors associated with non-response and late response were analysed using response rates and odds ratios (ORs). RESULTS: After the reminders, the response rate increased from 22.6% to 32.9% and to 39.4%. Non-response was associated with age [OR: 3.14; confidence interval (CI) 95%: 2.23-4.42 for aged >60 years], gender and functional area. Further, a higher response rate after reminders was observed in professionals with heavier workloads (OR: 1.46; CI 95%: 1.08-1.97) and in those who stated a lower relevance of cancer prevention in primary care. CONCLUSIONS: After electronic reminders, the response rate increased, especially among professionals with the highest workloads and a minor interest in the survey topic. However, possible bias associated with non-response remains and the factors behind this should be examined in future research. PMID- 25929293 TI - The immunotherapy of canine osteosarcoma: a historical and systematic review. AB - Osteosarcoma is a malignant mesenchymal neoplasm that accounts for the majority of primary bone tumors in dogs and shares biological and clinical similarities with osteosarcoma in humans. Despite dose intensification with conventional cytotoxic therapies, survival times for dogs and humans diagnosed with high-grade osteosarcoma have not changed in the past 20 years, with the principal cause of mortality being the development of pulmonary metastases. Given the therapeutic plateau reached for delaying metastatic progression with cytotoxic agents, exploration of alterative adjuvant therapies for improving management of osteosarcoma micrometastases is clinically justified. Evidence suggests that osteosarcoma is an immunogenic tumor, and development of immunotherapies for the treatment of microscopic lung metastases might improve long-term outcomes. In this review, the history and foundational knowledge of immune interactions to canine osteosarcoma are highlighted. In parallel, immunotherapeutic strategies that have been explored for the treatment of canine osteosarcoma are summarized. With a greater understanding and awareness for how the immune system might be redirected toward combating osteosarcoma metastases, the rational development of diverse immune strategies for managing osteosarcoma holds substantial promise for transforming the therapeutic landscape and improving disease management in both dogs and human beings. PMID- 25929296 TI - Consent revisited: the impact of return of results on participants' views and expectations about trial participation. AB - BACKGROUND: Increasingly, the sharing of study results with participants is advocated as an element of good research practice. Yet little is known about how receiving the results of trials may impact on participants' perceptions of their original decision to consent. OBJECTIVE: We explored participants' views of their decision to consent to a clinical trial after they received results showing adverse outcomes in some arms of the trial. METHOD: Semi-structured interviews were conducted with a purposive sample of 38 women in the UK who participated in a trial of antibiotics in pregnancy. All had received results from a follow-up study that reported increased risk of adverse outcomes for children of participants in some of the trial intervention arms. Data analysis was based on the constant comparative method. RESULTS: Participants' original decisions to consent to the trial had been based on hope of personal benefit and assumptions of safety. On receiving the results, most made sense of their experience in ways that enabled them to remain content with their decision to take part. But for some, the results provoked recognition that their original expectations might have been mistaken or that they had not understood the implications of their decision to participate. These participants experienced guilt, a sense of betrayal by the maternity staff and researchers involved in the trial, and damage to trust. CONCLUSIONS: Sharing of study results is not a wholly benign practice, and requires careful development of suitable approaches for further evaluation before widespread adoption. PMID- 25929297 TI - Serum fibroblast growth factor 21 in overweight and obese Thai children and adolescents: its relation to glucose metabolism and its change after glucose loading. AB - OBJECTIVES: Fibroblast growth factor 21 (FGF21) has been demonstrated to be beneficial for glucose metabolism in animal and in vitro studies. However, its role in humans is still unclear. This study aimed to determine serum FGF21 in relation to glucose metabolism in obese children and to evaluate serum FGF21 changes during an oral glucose tolerance test (OGTT). DESIGN, PATIENTS AND MEASUREMENTS: A cross-sectional study of 301 obese children was conducted in a tertiary hospital. All children underwent an OGTT and had their fasting serum FGF21 and adiponectin measured. A subgroup of 71 children had their serum FGF21 levels serially measured at 0, 60 and 120 min during the OGTT. RESULTS: Serum FGF21 levels were progressively increased in children with normal glucose tolerance without hyperinsulinaemia, normal glucose tolerance with hyperinsulinaemia and abnormal glucose tolerance [median (IQR): 72 (34-148), 96 (55-182), 122 (75-220) pg/ml, respectively, P = 0.003]. Log serum FGF21 was associated with homoeostatic model assessment of insulin resistance (r = 0.174, P = 0.002). There was no correlation between log serum FGF21 and serum adiponectin level. During the OGTT, there were changes in serum FGF21 levels with a decrease in FGF21 at 60 min from the baseline and an increase above the baseline at 120 min. CONCLUSIONS: Serum FGF21 level was highest in obese children with the highest insulin resistance or abnormal glucose tolerance. Log serum FGF21 was not correlated with serum adiponectin. Changes in serum FGF21 levels during the OGTT were observed. PMID- 25929298 TI - Correlation between OCT-derived intrastent dimensions and fractional flow reserve measurements after coronary stent implantation and impact on clinical outcome. AB - BACKGROUND: Insufficient stent expansion, vessel wall injury, and tissue prolapse, all frequently unrecognized by coronary angiography, are predictors of future major adverse cardiac event (MACE) after percutaneous coronary intervention (PCI). Optical coherence tomography (OCT) provides accurate visualization of these features of inadequate stent deployment, whereas reduced fractional flow reserve (FFR) values after PCI indicate functional significance of a residual intrastent stenosis. OBJECTIVE: To investigate the relationship of OCT-derived intrastent lumen dimensions and FFR-derived hemodynamic relevance immediately after coronary stent implantation and to evaluate the clinical impact of these parameters at follow-up. METHODS: In 66 stable patients with a coronary de novo lesion, treated by stent implantation, post-stenting FFR and OCT data were compared and related to MACE at follow-up. RESULTS: There was a significant correlation between remaining OCT-derived intrastent percent area stenosis (%AS) and post-stent FFR (r2 = 0.491; P<.001). According to receiver operating characteristic (ROC) analysis, both final FFR and intrastent %AS predicted MACE at 20 months (FFR: area under the curve [AUC] = 0.768; 95% confidence interval [CI], 0.562-0.973; and optimal cut-off = 0.905; %AS: AUC = 0.807; 95%CI, 0.613 1.000; and optimal cut-off = 16.85%) with moderate diagnostic efficiency. Intrastent %AS (16.60 +/- 4.75% vs 7.01 +/- 3.49%; P<.001) and the 20-month cumulative incidence of MACE (35.9% vs 5.3%; P=.01) were significantly greater in patients with FFR <=0.905 (n = 26; 39.4%) compared with FFR >0.905 (n = 40; 60.6%). CONCLUSION: OCT-derived residual intrastent %AS is associated with decreased FFR following stent implantation and both are predictors for clinical outcome at follow-up. PMID- 25929299 TI - Expansion of the indication of transcatheter aortic valve implantation- feasibility and outcome in "off-label" patients compared with "on-label" patients. AB - BACKGROUND: We compare the feasibility and outcomes of "off-label" transcatheter aortic valve implantation (TAVI) patients with a standard "on-label" TAVI population. METHODS: A total of 591 high-risk patients (pts) underwent a TAVI procedure at our institution. Of these, 435 pts (73.6%) were treated for an on label indication (group A) and 156 pts (26.4%) were treated for an off-label indication (group B). Group B was further subdivided into patients with pure aortic regurgitation (n = 22; group B.1), anatomical considerations (n = 26; group B.2), very low ejection fraction <=20% (n = 12; group B.3), concomitant severe mitral regurgitation >2+ (n = 44; group B.4), degenerated aortic bioprosthesis (n = 30; group B.5), and hemodynamic instability with the need for cardiopulmonary bypass (n = 22; group B.6). Outcome parameters were classified according to the Valve Academic Research Consortium-2 criteria. RESULTS: The mean log EuroSCORE of the entire study group was 25 +/- 16% (33 +/- 21% in group B vs 22 +/- 14% in group A; P<.001). Overall device success was 90% (91.3% in group A vs 86.5% in group B; P=.02). Overall 30-day mortality was 9.7%. Group B had a higher 30-day mortality compared with group A (14.7% vs 7.8%, respectively; P=.01). Group B.5 had the lowest 30-day mortality (3.3%). CONCLUSION: Corresponding to the higher surgical risk of group B, 30-day mortality was higher for off-label pts. Patients treated as valve-in-valve had the lowest 30-day mortality, emphasizing its great potential as opposed to redo open-heart surgery. PMID- 25929300 TI - Sheathless guide catheter coronary intervention via radial artery: single-center experience with 9658 procedures. AB - OBJECTIVES: To evaluate the efficacy and safety of transradial coronary intervention (TRI) using a sheathless guide catheter (sheathless TRI) in a large, retrospective, single-center study. BACKGROUND: The sheathless guide catheter was designed to be inserted without an introducer sheath to decrease stress to the radial artery. Although the sheathless guide catheter has some potential limitations, such as its procedural complexity or the risk of coronary ostial dissection, no large studies have been reported. METHODS: We retrospectively investigated all TRIs performed at Sendai Kousei Hospital from January 2004 to December 2013. RESULTS: Out of a total of 12,617 percutaneous coronary interventions (PCIs), sheathless TRIs were performed in 9658 cases (76.5%) and TRIs using a conventional sheath (sheath TRI) were performed in 1070 cases (8.5%). Procedural success was achieved in 98.81% of sheathless TRIs and 96.82% of sheath TRIs (P<.001); after propensity matching, the success rate was 98.9% in sheathless TRIs and 97.6% in sheath TRIs (P=.01). The conversion of the guide catheter system occurred in 0.40% of sheathless TRIs and 0.28% in sheath TRIs (P=.54). Coronary ostial dissection occurred in 0.26% of sheathless TRIs and 0.47% in sheath TRIs (P=.22). CONCLUSION: Sheathless TRI was utilized in the majority of cases, and the propensity-matched procedural success was similar but statistically higher as compared with sheath TRI. Complications were rare and equivalent to sheath TRI. Sheathless TRI is effective and safe as an initial PCI technique after the consideration of its benefits and limitations. PMID- 25929301 TI - The safety and efficacy of peripheral vascular procedures performed in the outpatient setting. AB - OBJECTIVES: This study sought to evaluate the safety and efficacy of peripheral vascular interventions performed in a private, outpatient catheterization laboratory. BACKGROUND: Peripheral vascular interventions have been traditionally performed in the inpatient setting. However, there has been a recent shift away from hospital-based vascular interventions toward outpatient-based procedures. Data are scarce on the efficacy and safety of such procedures being performed in the outpatient setting. METHODS: We performed a retrospective chart review of the first 500 consecutive procedures that were performed at an outpatient catheterization laboratory from February 2012 through February 2013. We separated the procedures into arteriovenous fistula (AVF)-related procedures, peripheral arterial disease (PAD)-related procedures, and miscellaneous procedures. The primary endpoint was procedure success rate, defined as postintervention residual stenosis of <30% on angiography. The secondary endpoint was procedure-related adverse events. RESULTS: The success rate for AVF-related interventions was 90%, and 93% when including partially successful interventions. The success rate for PAD-related interventions was 82%, and 92% when including partially successful interventions. The procedure success rate for miscellaneous interventions was 89%. Five AVF-related procedures suffered an adverse event (1.49%). Two PAD related procedures suffered an adverse event (1.3%), while no adverse events were noted among miscellaneous procedures. One patient required immediate postprocedure hospitalization due to iliac artery perforation. CONCLUSION: Peripheral vascular procedures performed in the outpatient setting are safe and effective. A comparison of outcomes between outpatient and inpatient facilities when performing similar peripheral vascular interventions is needed in order to determine whether a transition of further vascular procedures into an outpatient setting is justified. PMID- 25929302 TI - The new occlutech duct occluder: immediate results, procedural challenges, and short-term follow-up. AB - OBJECTIVE: The aim of this study was to assess the immediate and short-term results of transcatheter closure of patent ductus arteriosus (PDA) using the Occlutech duct occluder (ODO). BACKGROUND: The ODO is a new self-expanding nitinol device. Its body is wider at the pulmonary artery end than the aortic end. It is available in longer lengths than the Amplatzer duct occluder. METHODS: Twenty-two ODO implants were attempted in successive children referred for transcatheter device occlusion of PDAs >=1 mm in diameter. RESULTS: Median patient age was 2.4 years (range, 0.7-17.5 years), median weight was 13.1 kg (range, 6.3-40 kg), and median PDA diameter was 1.9 mm (range, 1-4.3 mm). Twenty one out of 22 patients (95%) had successful ODO implantation. One device was withdrawn before release because it did not reach the pulmonary artery end of a long duct. Median procedure time was 40 minutes (range, 26-60 minutes) and fluoroscopy time was 4.5 minutes (range, 2.7-13.3 minutes). Occlusion rates were 19/21 (90%) at the end of the procedure, 20/21 (95%) at 24-48 hours post procedure, and 21/21 (100%) on echocardiography at a median follow-up of 4 weeks (range, 2-16 weeks). There were no device-related complications. Two infants had femoral artery occlusion, successfully treated by heparinization and thrombolysis. CONCLUSION: This first formal clinical evaluation of the ODO indicates that it is safe and effective in occluding small-to-moderate size ducts, up to a diameter of 4.3 mm. The device produced equivalent results to the Amplatzer duct occluder. Further evaluation is required to assess whether its shape and longer length make it superior for closing large and long ducts. PMID- 25929303 TI - Left atrial appendage closure with amplatzer septal occluder in patients with atrial fibrillation: CT-based morphologic considerations. AB - OBJECTIVES: This study analyzed left atrial appendage (LAA) dimensions measured by computed tomography (CT) scan to define optimal selection of Amplatzer septal occluders for LAA closure. BACKGROUND: Patients with atrial fibrillation and contraindications to anticoagulation have limited options for LAA closure until approval of dedicated closure devices. Off-label use of available cardiac devices represents one option. METHODS: All consecutive patients undergoing LAA occlusion with an Amplatzer device who had undergone CT scanning were included. Numerous dimensions of the LAA were measured in order to optimally select a device that would simultaneously provide good anchoring and good sealing of the LAA. RESULTS: Of 11 eligible patients, 8 had successful Amplatzer deployment. In all successful cases, the putative "left atrial" disc was well matched to the "landing zone" of the LAA, proving good anchoring. The proximal (putative "right atrial") disc was sized to cover the LAA orifice. The failed cases shed light on procedural variables. CONCLUSIONS: LAA occlusion with an Amplatzer device is a viable option for patients with atrial fibrillation and contraindications to anticoagulation. Careful attention to LAA dimensions as measured on CT scan assists in optimizing device selection. PMID- 25929304 TI - "Tip-in" technique for retrograde chronic total occlusion revascularization. AB - Use of the retrograde approach significantly improves the success rate of chronic total occlusion (CTO) percutaneous coronary intervention. The most commonly applied retrograde technique is placing a guidewire just distal to the distal cap using collateral vessels, with subsequent retrograde crossing of the occlusive segment. This is followed by advancement of a microcatheter and externalization of a long guidewire to allow antegrade delivery of balloons and stents. However, there are occasions when a microcatheter or balloon cannot be delivered retrogradely through the occlusive segment, resulting in procedure failure. We describe the "tip-in" technique, which involves intubation of the retrograde guidewire with an antegrade microcatheter to allow successful revascularization of a CTO after failure to externalize. PMID- 25929305 TI - Percutaneous treatment of stent-graft (viabahn) thrombosis employing a second stent-graft. AB - Acute thrombosis is the most common mode of stent-graft failure. Thrombectomy and thrombolysis have inadequate medium-term and long-term results. We propose a new technique for treating acute stent-graft thrombosis by "relining" the thrombosed graft with a second stent-graft. Ten patients were treated with this technique and have been free of any repeat intervention for up to 1 year, showing its feasibility. The Viabahn-in-Viabahn technique needs a larger study to confirm its efficacy and safety. PMID- 25929306 TI - Delayed clopidogrel transit during myocardial infarction evident on angiography. AB - We describe the case of a patient with non-ST segment elevation myocardial infarction (NSTEMI) where a limitation of oral clopidogrel loading prior to percutaneous coronary intervention (PCI) was directly visualized on angiography. Clopidogrel is a thienopyridine antiplatelet agent used in acute coronary syndromes. It reduces platelet aggregation via inhibition of the P2Y12 receptor. Clopidogrel is an inactive metabolite that is metabolized into the active metabolite by the cytochrome P450 isoenzymes located mostly in the liver and partly in the gastrointestinal system. As such, it requires at least 2 hours to reach maximal effect. A 63-year-old female went to an outside facility where she was diagnosed with NSTEMI and underwent angiography. She was administered 324 mg of aspirin and 600 mg of clopidogrel, and was transferred to our facility. Upon arrival, approximately 1.5 hours after the oral loading dose, the clopidogrel tablets were visualized intact in the stomach during angiography, implying a very low likelihood of adequate absorption or antiplatelet effect. This observation raises the concern that delayed gastrointestinal transit, apart from other metabolic derangements, may be a factor in achieving optimal platelet inhibition using oral agents. PMID- 25929307 TI - Allen's test: does it have any significance in current practice? AB - Percutaneous coronary intervention (PCI) performed through transradial access (TRA) has been consistently demonstrated to be safer than transfemoral access (TFA), mainly due to significantly reduced bleeding and vascular complications. Despite demonstrating better patient safety, acceptance of TRA as an access site of choice has remained low, with geographical variations. One of the relative contraindications to performing PCI through TRA is an abnormal Allen's test (AT), in which case the access site is usually switched to TFA. Bleeding and vascular complications are the "Achilles heel" for interventions through the TFA. The use of the AT is controversial given its low sensitivity in assessing both the collateral circulation of the hand and predicting ischemic complications. In this article, we present interesting data from the congenital heart and trauma literature that lead us to suggest the AT is an inadequate test to assess the collateral circulation of the hand. We think the case for its routine guideline driven use is flawed. PMID- 25929308 TI - De-implementing the Allen's Test. PMID- 25929309 TI - Bilateral calcaneal stress fractures in two cats. AB - Two cats that developed bilateral calcaneal stress fractures are reported. One cat developed lameness associated with incomplete fractures at the base of both calcanei, both of which progressed to acute, complete fractures 2 months later. The second cat presented with acute complete calcaneal fracture, with evidence of remodelling of the contralateral calcaneus, which subsequently fractured two years later. The calcaneal fractures were successfully stabilised with lateral bone plates in each case. Stress fractures were suspected because of the bilateral nature, the simple and similar configuration, the consistent location of the fractures, the absence of other signs of trauma in both cases and the suspected insidious onset of the lameness. The feline calcaneus is susceptible to stress fracture, and cats presenting with calcaneal fractures without evidence of trauma should be evaluated for concurrent skeletal pathology. PMID- 25929310 TI - Allergic reaction in a cohort of haemophilia A patients using plasma-derived factor VIII (FVIII) concentrate is rare and not necessarily triggered by FVIII. AB - In contrast to haemophilia B, allergic manifestations are rare complications in haemophilia A (HA) patients treated with factor VIII (FVIII) concentrates. Nevertheless, it can be serious and hamper replacement therapy in these cases. The aims of this study were to evaluate the frequency of allergic reaction in a cohort of HA patients treated only with plasma-derived FVIII (pdFVIII) concentrates, and assess the possible immune mechanisms involved. History of allergic reaction was retrospectively assessed. Patients with allergic manifestations were followed, and had plasma samples collected in different timepoints in relation to the allergic episode. These samples were analysed for the presence of inhibitor and anti-FVIII immunoglobulins subclasses. Three of 322 HA patients (0.9%) developed allergic reaction after exposure to pdFVIII products during the last 15 years in our centre. The first patient, with severe HA, without inhibitor, had anti-pdFVIII IgE and IgG4, but no anti-recombinant FVIII (rFVIII) IgE. The second patient, with severe HA, and high-responding inhibitor, presented allergic manifestation with both, pdFVIII concentrate and activated prothrombin complex concentrate. Although anti-pdFVIII and anti-rFVIII IgG4 were detected, no anti-FVIII IgE was present. The third patient, with moderate HA without inhibitor, atopic, had no anti-FVIII immunoglobulin detected, and allergic symptoms disappeared after switching to rFVIII concentrate. This study corroborates the low incidence of allergic reactions in HA patients. In the three cases presented, the anti-FVIII immunoglobulin profile demonstrated that the allergic manifestation was triggered by other proteins contained in pdFVIII products, and not directed to FVIII. PMID- 25929311 TI - Patient-level meta-analysis of the EDITION 1, 2 and 3 studies: glycaemic control and hypoglycaemia with new insulin glargine 300 U/ml versus glargine 100 U/ml in people with type 2 diabetes. AB - AIMS: To conduct a patient-level meta-analysis of the EDITION 1, 2 and 3 studies, which compared the efficacy and safety of new insulin glargine 300 U/ml (Gla-300) with insulin glargine 100 U/ml (Gla-100) in people with type 2 diabetes (T2DM) on basal and mealtime insulin, basal insulin and oral antihyperglycaemic drugs, or no prior insulin, respectively. METHODS: The EDITION studies were multicentre, randomized, open-label, parallel-group, phase IIIa studies, with similar designs and endpoints. A patient-level meta-analysis of the studies enabled these endpoints to be examined over 6 months in a large population with T2DM (Gla-300, n = 1247; Gla-100, n = 1249). RESULTS: No significant study-by-treatment interactions across studies were found, enabling them to be pooled. The mean change in glycated haemoglobin was comparable for Gla-300 and Gla-100 [each -1.02 (standard error 0.03)%; least squares (LS) mean difference 0.00 (95% confidence interval (CI) -0.08 to 0.07)%]. Annualized rates of confirmed (<=3.9 mmol/l) or severe hypoglycaemia were lower with Gla-300 than with Gla-100 during the night (31% difference in rate ratio over 6 months) and at any time (24 h, 14% difference). Consistent reductions were observed in percentage of participants with >=1 hypoglycaemic event. Severe hypoglycaemia at any time (24 h) was rare (Gla-300: 2.3%; Gla-100: 2.6%). Weight gain was low (<1 kg) in both groups, with less gain with Gla-300 [LS mean difference -0.28 kg (95% CI -0.55 to -0.01); p = 0.039]. Both treatments were well tolerated, with similar rates of adverse events. CONCLUSION: Gla-300 provides comparable glycaemic control to Gla-100 in a large population with a broad clinical spectrum of T2DM, with consistently less hypoglycaemia at any time of day and less nocturnal hypoglycaemia. PMID- 25929312 TI - Bayesian estimation on diagnostic performance of Face, Legs, Activity, Cry, and Consolability and Neonatal Infant Pain Scale for infant pain assessment in the absence of a gold standard. AB - BACKGROUND: Nonverbal pediatric patients such as infants are unable to describe their pain, which leads to the lack of a gold standard scale for their pain assessment. The aim of this study was to estimate the diagnostic performance of Face, Legs, Activity, Cry, and Consolability (FLACC) scale and Neonatal Infant Pain Scale (NIPS) for infants' pain in the absence of a gold standard. METHODS: This prospective observational study recruited 202 postoperative infants, aged <12 months. Postoperative pain intensity was evaluated using FLACC and NIPS scales. The diagnostic performance of these two scales was to estimate using a Bayesian latent class model with conditional dependence. McNemar's test was applied to test whether NIPS and FLACC tests differ from each other. RESULTS: Under a combined model with conditional dependence, the median posterior sensitivity and specificity of the FLACC were 89.94% (95% CI: 78.48-96.83%) and 87.82% (95% CI: 78.6-95.23%), respectively. The sensitivity and specificity of the NIPS were 85.94% (95% CI: 72.15-95.6%) and 92.61% (84.05-97.52%), respectively. McNemar's test demonstrated no significant difference between FLACC and NIPS in either sensitivity or specificity. CONCLUSION: Both the FLACC and NIPS have excellent sensitivity and specificity for pain assessment in infants. The comparison test showed that the FLACC scale was no different to the NIPS scale in sensitivity and specificity. PMID- 25929313 TI - Early neurological worsening in acute ischaemic stroke patients. AB - OBJECTIVES: Neurological worsening in acute ischaemic stroke patients is common with significant morbidity and mortality. AIMS: To determine the factors associated with early neurological worsening within the first 9 h after onset of acute ischaemic stroke. MATERIALS & METHODS: The National Institute of Health Stroke Scale (NIHSS) was used to assess stroke severity. Early neurological worsening was defined as NIHSS score increase >=4 NIHSS points within 9 h of symptom onset compared to NIHSS score within 3 h of symptom onset. Patients with early neurological worsening were compared to patients with unchanged or improved NIHSS scores. RESULTS: Of the 2484 patients admitted with ischaemic stroke, 552 patients had NIHSS score within 3 h of symptom onset, and 44 (8.0%) experienced early neurological worsening. The median NIHSS on admission was 8.4 in both groups. Early neurological worsening was associated with low body temperature on admission (P = 0.01), proximal compared to distal MCA occlusion (P = 0.007) and with ipsilateral internal carotid artery stenosis >50% or occlusion (P = 0.04). Early neurological worsening was associated with higher NIHSS day 7 (P < 0.001) and higher mortality within 7 days of stroke onset (P = 0.005). CONCLUSIONS: Early neurological worsening has serious consequences for the short-term outcome for patients with acute ischaemic stroke and is associated with low body temperature on admission, and with extracranially and intracranially large-vessel stenosis or occlusion. PMID- 25929314 TI - Nurse Staffing Levels and Patient-Reported Missed Nursing Care. AB - A total of 729 inpatients were surveyed using the MISSCARE Survey-Patient. Missed timeliness, patient reports of the time it took for them to receive care from nursing staff, was negatively associated with total nursing staff hours of care per patient-day (r = -0.09, P = .015), registered nurse (RN) hours per patient day (r = -0.14, P = .0002), and RN skill mix (r = -0.13, P = .0004). RN skill mix was also a predictor of missed timeliness (P = .01). PMID- 25929315 TI - Antifolates and MTHFR. AB - We describe a patient who developed symptoms of headache, fatigue, and dizziness after administration of terbinafine (Lamisil). Laboratory tests revealed that he is heterozygous for the C677T variation of the methylenetetrahydrofolate reductase genetic mutation. The prescription of Deplin (L-methylfolate) greatly reduced the symptoms. It was later noted that Lamisil's mechanism of action interferes with cells' methylation cycle, which we suspect compromises cellular function in people with the methylenetetrahydrofolate reductase genetic mutation. PMID- 25929316 TI - On the Analytical Superiority of 1D NMR for Fingerprinting the Higher Order Structure of Protein Therapeutics Compared to Multidimensional NMR Methods. AB - An important aspect in the analytical characterization of protein therapeutics is the comprehensive characterization of higher order structure (HOS). Nuclear magnetic resonance (NMR) is arguably the most sensitive method for fingerprinting HOS of a protein in solution. Traditionally, (1)H-(15)N or (1)H-(13)C correlation spectra are used as a "structural fingerprint" of HOS. Here, we demonstrate that protein fingerprint by line shape enhancement (PROFILE), a 1D (1)H NMR spectroscopy fingerprinting approach, is superior to traditional two-dimensional methods using monoclonal antibody samples and a heavily glycosylated protein therapeutic (Epoetin Alfa). PROFILE generates a high resolution structural fingerprint of a therapeutic protein in a fraction of the time required for a 2D NMR experiment. The cross-correlation analysis of PROFILE spectra allows one to distinguish contributions from HOS vs protein heterogeneity, which is difficult to accomplish by 2D NMR. We demonstrate that the major analytical limitation of two-dimensional methods is poor selectivity, which renders these approaches problematic for the purpose of fingerprinting large biological macromolecules. PMID- 25929317 TI - Dual-Purpose Bioreactors to Monitor Noninvasive Physical and Biochemical Markers of Kidney and Liver Scaffold Recellularization. AB - Analysis of perfusion-based bioreactors for organ engineering and a detailed evaluation of physical and biochemical parameters that measure dynamic changes within maturing cell-laden scaffolds are critical components of ex vivo tissue development that remain understudied topics in the tissue and organ engineering literature. Intricately designed bioreactors that house developing tissue are critical to properly recapitulate the in vivo environment, deliver nutrients within perfused media, and monitor physiological parameters of tissue development. Herein, we provide an in-depth description and analysis of two dual purpose perfusion bioreactors that improve upon current bioreactor designs and enable comparative analyses of ex vivo scaffold recellularization strategies and cell growth performance during long-term maintenance culture of engineered kidney or liver tissues. Both bioreactors are effective at maximizing cell seeding of small-animal organ scaffolds and maintaining cell survival in extended culture. We further demonstrate noninvasive monitoring capabilities for tracking dynamic changes within scaffolds as the native cellular component is removed during decellularization and model human cells are introduced into the scaffold during recellularization and proliferate in maintenance culture. We found that hydrodynamic pressure drop (DeltaP) across the retained scaffold vasculature is a noninvasive measurement of scaffold integrity. We further show that DeltaP, and thus resistance to fluid flow through the scaffold, decreases with cell loss during decellularization and correspondingly increases to near normal values for whole organs following recellularization of the kidney or liver scaffolds. Perfused media may be further sampled in real time to measure soluble biomarkers (e.g., resazurin, albumin, or kidney injury molecule-1) that indicate degree of cellular metabolic activity, synthetic function, or engraftment into the scaffold. Cell growth within bioreactors is validated for primary and immortalized cells, and the design of each bioreactor is scalable to accommodate any three-dimensional scaffold (e.g., synthetic or naturally derived matrix) that contains conduits for nutrient perfusion to deliver media to growing cells and monitor noninvasive parameters during scaffold repopulation, broadening the applicability of these bioreactor systems. PMID- 25929318 TI - Psychopathology and the Ability to Do Otherwise. AB - When philosophers want an example of a person who lacks the ability to do otherwise, they turn to psychopathology. Addicts, agoraphobics, kleptomaniacs, neurotics, obsessives, and even psychopathic serial murderers, are all purportedly subject to irresistible desires that compel the person to act: no alternative possibility is supposed to exist. I argue that this conception of psychopathology is false and offer an empirically and clinically informed understanding of disorders of agency which preserves the ability to do otherwise. First, I appeal to standard clinical treatment for disorders of agency and argue that it undermines this conception of psychopathology. Second, I offer a detailed discussion of addiction, where our knowledge of the neurobiological mechanisms underpinning the disorder is relatively advanced. I argue that neurobiology notwithstanding, addiction is not a form of compulsion and I explain how addiction can impair behavioural control without extinguishing it. Third, I step back from addiction, and briefly sketch what the philosophical landscape more generally looks like without psychopathological compulsion: we lose our standard purported real-world example of psychologically determined action. I conclude by reflecting on the centrality of choice and free will to our concept of action, and their potency within clinical treatment for disorders of agency. PMID- 25929319 TI - A Cervical Hemi-Contusion Spinal Cord Injury Model for the Investigation of Novel Therapeutics Targeting Proximal and Distal Forelimb Functional Recovery. AB - Cervical spinal cord contusion is the most common human spinal cord injury, yet few rodent models replicate the pathophysiological and functional sequela of this injury. Here, we modified an electromechanical injury device and characterized the behavioral and histological changes occurring in response to a lateralized C4 contusion injury in rats. A key feature of the model includes a non-injurious touch phase where the spinal cord surface is dimpled with a consistent starting force. Animals were either left intact as a control, received a non-injury producing touch on the surface of the cord ("sham"), or received a 0.6 mm or a 0.8 mm displacement injury. Rats were then tested on the forelimb asymmetry use test, CatWalk, and the Irvine, Beatties, and Bresnahan (IBB) cereal manipulation task to assess proximal and distal upper limb function for 12 weeks. Injuries of moderate (0.6 mm) and large (0.8 mm) displacement showed consistent differences in forelimb asymmetry, metrics of the CatWalk, and sub-scores of the IBB. Overall findings indicated long lasting proximal and distal upper limb deficits following 0.8 mm injury but transient proximal with prolonged distal limb deficits following 0.6 mm injury. Significant differences in loss of ipsilateral unmyelinated and myelinated white matter was detected between injury severities. Demyelination was primarily localized to the dorsolateral region of the hemicord and extended further rostral following 0.8 mm injury. These findings establish the C4 hemi-contusion injury as a consistent, graded model for testing novel treatments targeting forelimb functional recovery. PMID- 25929320 TI - Autonomic, Behavioral, and Subjective Pain Responses in Alzheimer's Disease. AB - OBJECTIVE: To compare autonomic, behavioral, and subjective pain responses of patients with Alzheimer's disease (AD) to those of healthy seniors (HS). As few studies have examined patients with severe Alzheimer's disease (sAD), we emphasized inclusion of these patients together with mild/moderate Alzheimer's disease (mAD) patients to characterize pain responses potentially affected by disease severity. DESIGN: A controlled cross-sectional study involving repeated measures behavioral pain testing. SETTING: An outpatient clinical setting and local nursing facilities. SUBJECTS: Community dwelling HS controls (N = 33) and individuals with chart-confirmed diagnoses of AD (N = 38, Diagnostic and Statistical Manual-IV criteria). METHODS: HS and AD groups were compared in their responses to repeated applications of five pressure intensities (1-5 kg) on the distal forearm. Autonomic responses (heart rate [HR]), pain behaviors (vocal, facial, and bodily as scored by the Pain Assessment in Advanced Dementia [PAINAD] scale), and subjective pain ratings (Faces Pain Scale-Revised) were measured. RESULTS: HR responses to pressure stimuli were differentially affected based on AD severity: sAD patients had generally decreased HR reactivity compared with other groups (P < 0.01). In contrast, pain behaviors were increased in AD regardless of severity (P < 0.001), compared with HS, for all but the lowest pressure intensity. Increased behaviors occurred in all measured domains of the PAINAD (P < 0.005). While sAD were unreliable subjective reporters, mAD patients (N = 17) rated low level pressures as more painful than HS (P < 0.01). CONCLUSION: These findings provide behavioral and subjective-report evidence of increased acute pain sensitivity in AD, which should be taken into consideration with respect to pain management across the spectrum of AD severity. PMID- 25929321 TI - Corrigendum. PMID- 25929324 TI - Heat-induced spinodal decomposition of Ag-Cu nanoparticles. AB - Solvothermal synthesis was used for Ag-Cu nanoparticle (NP) preparation from metallo-organic precursors. The detailed NP characterization was performed to obtain information about nanoparticle microstructure and both phase and chemical compositions. The resulting nanoparticles exhibited chemical composition inside a FCC_Ag + FCC_Cu two-phase region. The microstructure study was performed by various methods of electron microscopy including high-resolution transmission electron microscopy (HRTEM) at an atomic scale. The HRTEM and X-ray diffraction studies showed that the prepared nanoparticles form the face centred cubic (FCC) crystal lattice where the silver atoms are randomly mixed with copper. The CALPHAD approach was used for predicting the phase diagram of the Ag-Cu system in both macro- and nano-scales. The predicted spinodal decomposition of the metastable Ag-Cu nanoparticles was experimentally induced by heating on an X-ray powder diffractometer (HT XRD). The nucleation of the Cu-rich phase was detected and its growth was studied. Changes in the Ag-rich phase were observed in situ by X-ray diffraction under vacuum. The heat treatment was conducted at different maximum temperatures up to 450 degrees C and the resulting particle product was analysed. The experiments were complemented by differential scanning calorimetry (DSC) measurements up to liquidus temperature. The start temperatures of the spinodal phase transformation and particle aggregation were evaluated. PMID- 25929323 TI - Expression of ezrin, CD44, and VEGF in giant cell tumor of bone and its significance. AB - BACKGROUND: This research aimed to study the role of ezrin, CD44, and VEGF in invasion, metastasis, recurrence, and prognosis of giant cell tumor of bone (GCTB) and its association with the clinical and pathological features of GCTB. METHODS: Expression status of ezrin, CD44, and VEGF in 80 GCTB tissues and its adjacent noncancerous tissue samples were measured with immunohistochemical and Elivison staining. Their correlation with the clinical and pathologic factors was statistically analyzed by chi-square test. RESULTS: The expression status of ezrin, CD44, and VEGF were significantly higher in GCTB tissue samples than in its adjacent noncancerous tissue samples and in GCTB at Campanacci stage III than in Campanacci stages I and II (P < 0.05). No significant difference was found in age and sex of the patients and locations of the tumor (P > 0.05). Survival analysis showed that the expression status of ezrin, CD44, VEGF, and Campanacci clinical stages of GCTB were positively associated with the survival rate of GCTB patients and negatively associated with ezrin and Campanacci stages of GCTB, indicating that ezrin, CD44, VEGF, and Campanacci clinical stages of GCTB are the independent factors for GCTB. CONCLUSIONS: Ezrin, CD44, and VEGF are over expressed in GCTB tissue and its adjacent noncancerous tissue samples and may play an important role in the occurrence, invasion, metastasis, and recurrence of GCTB. Measurement of ezrin, CD44, and VEGF expression status may contribute to the judgment of prognosis of GCTB patients. PMID- 25929322 TI - Q-Score: development of a new metric for continuous glucose monitoring that enables stratification of antihyperglycaemic therapies. AB - BACKGROUND: Continuous glucose monitoring (CGM) has revolutionised diabetes management. CGM enables complete visualisation of the glucose profile, and the uncovering of metabolic 'weak points'. A standardised procedure to evaluate the complex data acquired by CGM, and to create patient-tailored recommendations has not yet been developed. We aimed to develop a new patient-tailored approach for the routine clinical evaluation of CGM profiles. We developed a metric allowing screening for profiles that require therapeutic action and a method to identify the individual CGM parameters with improvement potential. METHODS: Fifteen parameters frequently used to assess CGM profiles were calculated for 1,562 historic CGM profiles from subjects with type 1 or type 2 diabetes. Factor analysis and varimax rotation was performed to identify factors that accounted for the quality of the profiles. RESULTS: We identified five primary factors that determined CGM profiles (central tendency, hyperglycaemia, hypoglycaemia, intra- and inter-daily variations). One parameter from each factor was selected for constructing the formula for the screening metric, (the 'Q-Score'). To derive Q Score classifications, three diabetes specialists independently categorised 766 CGM profiles into groups of 'very good', 'good', 'satisfactory', 'fair', and 'poor' metabolic control. The Q-Score was then calculated for all profiles, and limits were defined based on the categorised groups (<4.0, very good; 4.0-5.9, good; 6.0-8.4, satisfactory; 8.5-11.9, fair; and >=12.0, poor). Q-Scores increased significantly (P <0.01) with increasing antihyperglycaemic therapy complexity. Accordingly, the percentage of fair and poor profiles was higher in insulin-treated compared with diet-treated subjects (58.4% vs. 9.3%). In total, 90% of profiles categorised as fair or poor had at least three parameters that could potentially be optimised. The improvement potential of those parameters can be categorised as 'low', 'moderate' and 'high'. CONCLUSIONS: The Q-Score is a new metric suitable to screen for CGM profiles that require therapeutic action. Moreover, because single components of the Q-Score formula respond to individual weak points in glycaemic control, parameters with improvement potential can be identified and used as targets for optimising patient-tailored therapies. PMID- 25929325 TI - TiNb6O17: a new electrode material for lithium-ion batteries. AB - TiNb6O17 shows a similar crystal structure to Ti2Nb10O29 (Wadsley-Roth shear structure) but has larger lattice parameters and 0.49% cation vacancies, leading to its large Li(+) ion diffusion coefficients. It exhibits a large initial discharge capacity of 383 mA h g(-1) at 0.1 C, high rate performance and good cyclability. PMID- 25929326 TI - Affordable uniform isotope labeling with (2)H, (13)C and (15)N in insect cells. AB - For a wide range of proteins of high interest, the major obstacle for NMR studies is the lack of an affordable eukaryotic expression system for isotope labeling. Here, a simple and affordable protocol is presented to produce uniform labeled proteins in the most prevalent eukaryotic expression system for structural biology, namely Spodoptera frugiperda insect cells. Incorporation levels of 80% can be achieved for (15)N and (13)C with yields comparable to expression in full media. For (2)H,(15)N and (2)H,(13)C,(15)N labeling, incorporation is only slightly lower with 75 and 73%, respectively, and yields are typically twofold reduced. The media were optimized for isotope incorporation, reproducibility, simplicity and cost. High isotope incorporation levels for all labeling patterns are achieved by using labeled algal amino acid extracts and exploiting well-known biochemical pathways. The final formulation consists of just five commercially available components, at costs 12-fold lower than labeling media from vendors. The approach was applied to several cytosolic and secreted target proteins. PMID- 25929327 TI - Comparative analysis of Paenibacillus larvae genotypes isolated in Connecticut. AB - Ninety-six strains of Paenibacillus larvae, causative agent of American foulbrood in honey bee (Apis mellifera) larvae, collected from Connecticut, USA (CT), honey bees, and 12 P. larvae strains not from CT, were genotyped via ERIC-PCR and XbaI RFLP analysis. All CT-isolates, five strains isolated in South America, three strains from North America (not CT), and one strain isolated in Australia grouped into the ERIC I genotype. Three P. larvae formerly subsp. pulvifaciens strains grouped into ERIC III and IV genotypes. XbaI-RFLP genotyping showed three genotypes within the CT-isolates, and two were identified as XbaI-RFLP Type I and III. The third XbaI-RFLP genotype (Type Ib) represented one of four new XbaI-RFLP genotypes identified. Comparison of genotype results for the P. larvae strains tested was used to develop a correlation between ERIC-PCR genotyping and XbaI RFLP genotyping. Sixteen CT-isolates were tetracycline-resistant and demonstrated PCR amplification using oligonucleotide primers for tetL. All 16 isolates grouped within XbaI-RFLP Type Ib, suggesting limited introduction of a tetracycline resistant strain into CT. PMID- 25929329 TI - Architecture and health care: a place for sociology. AB - Sociologists of health and illness have tended to overlook the architecture and buildings used in health care. This contrasts with medical geographers who have yielded a body of work on the significance of places and spaces in the experience of health and illness. A review of sociological studies of the role of the built environment in the performance of medical practice uncovers an important vein of work, worthy of further study. Through the historically situated example of hospital architecture, this article seeks to tease out substantive and methodological issues that can inform a distinctive sociology of healthcare architecture. Contemporary healthcare buildings manifest design models developed for hotels, shopping malls and homes. These design features are congruent with neoliberal forms of subjectivity in which patients are constituted as consumers and responsibilised citizens. We conclude that an adequate sociology of healthcare architecture necessitates an appreciation of both the construction and experience of buildings, exploring the briefs and plans of their designers, and observing their everyday uses. Combining approaches and methods from the sociology of health and illness and science and technology studies offers potential for a novel research agenda that takes healthcare buildings as its substantive focus. PMID- 25929330 TI - Bioaugmentation of soil contaminated with high-level crude oil through inoculation with mixed cultures including Acremonium sp. AB - Heavy contamination of soil with crude oil has caused significant negative environmental impacts and presents substantial hazards to human health. To explore a highly efficient bioaugmentation strategy for these contaminations, experiments were conducted over 180 days in soil heavily contaminated with crude oil (50,000 mg kg(-1)), with four treatments comprised of Bacillus subtilis inoculation with no further inoculation (I), or reinoculation after 100 days with either B. subtilis (II), Acremonium sp.(III), or a mixture of both organisms (IV). The removal values of total petroleum hydrocarbons were 60.1 +/- 2.0, 60.05 +/- 3.0, 71.3 +/- 5.2 and 74.2 +/- 2.7 % for treatment (I-IV), respectively. Treatments (III-IV) significantly enhanced the soil bioremediation compared with treatments (I-II) (p < 0.05). Furthermore, significantly (p < 0.05) greater rates of degradation for petroleum hydrocarbon fractions were observed in treatments (III-IV) compared to treatments (I-II), and this was especially the case with the degradative rates for polycyclic aromatic hydrocarbons and crude oil heavy fractions. Dehydrogenase activity in treatment (III-IV) containing Acremonium sp. showed a constant increase until the end of experiments. Therefore reinoculation with pure fungus or fungal-bacterial consortium should be considered as an effective strategy in bioaugmentation for soil heavily contaminated with crude oil. PMID- 25929331 TI - Comparative quantitative study of 'signature' pathological lesions in the hippocampus and adjacent gyri of 12 neurodegenerative disorders. AB - The hippocampus (HC) and adjacent gyri are implicated in dementia in several neurodegenerative disorders. To compare HC pathology among disorders, densities of 'signature' pathological lesions were measured at a standard location in eight brain regions of 12 disorders. Principal components analysis of the data suggested that the disorders could be divided into three groups: (1) Alzheimer's disease (AD), Down's syndrome (DS), sporadic Creutzfeldt-Jakob disease, and variant Creutzfeldt-Jakob disease in which either beta-amyloid (Abeta) or prion protein deposits were distributed in all sectors of the HC and adjacent gyri, with high densities being recorded in the parahippocampal gyrus and subiculum; (2) Pick's disease, sporadic frontotemporal lobar degeneration with TDP-43 immunoreactive inclusions, and neuronal intermediate filament inclusion disease in which relatively high densities of neuronal cytoplasmic inclusions were present in the dentate gyrus (DG) granule cells; and (3) Parkinson's disease dementia, dementia with Lewy bodies, progressive supranuclear palsy, corticobasal degeneration, and multiple system atrophy in which densities of signature lesions were relatively low. Variation in density of signature lesions in DG granule cells and CA1 were the most important sources of neuropathological variation among disorders. Hence, HC and adjacent gyri are differentially affected in dementia reflecting either variation in vulnerability of hippocampal neurons to specific molecular pathologies or in the spread of pathological proteins to the HC. Information regarding the distribution of pathology could ultimately help to explain variations in different cognitive domains, such as memory, observed in various disorders. PMID- 25929333 TI - SILA: not necessarily the next step? Response to: acute appendicitis can be treated with single-incision laparoscopy: a systematic review of randomized controlled trials. PMID- 25929332 TI - Neighbourhood Deprivation, Individual-Level and Familial-Level Socio-demographic Factors and Risk of Congenital Heart Disease: A Nationwide Study from Sweden. AB - OBJECTIVES: The purpose of the study is to examine whether there is an association between neighbourhood deprivation and incidence of congenital heart disease (CHD), after accounting for family- and individual-level potential confounders. METHODS: All children aged 0 to 11 years and living in Sweden (n = 748,951) were followed between January 1, 2000 and December 31, 2010. Data were analysed by multilevel logistic regression, with family- and individual-level characteristics at the first level and level of neighbourhood deprivation at the second level. RESULTS: During the study period, among a total of 748,951 children, 1499 (0.2%) were hospitalised with CHD. Age-adjusted cumulative hospitalisation rates for CHD increased with increasing level of neighbourhood deprivation. In the study population, 1.8 per 1000 and 2.2 per 1000 children in the least and most deprived neighbourhoods, respectively, were hospitalised with CHD. The incidence of hospitalisation for CHD increased with increasing neighbourhood-level deprivation across all family and individual-level socio demographic categories. The odds ratio (OR) for hospitalisation for CHD for those living in high-deprivation neighbourhoods versus those living in low-deprivation neighbourhoods was 1.23 (95% confidence interval (CI) = 1.04-1.46). In the full model, which took account for age, paternal and maternal individual-level socio economic characteristics, comorbidities (e.g. maternal type 2 diabetes, OR = 3.03; maternal hypertension, OR = 2.01), and family history of CHD (OR = 3.27), the odds of CHD were slightly attenuated but did not remain significant in the most deprived neighbourhoods (OR = 1.20, 95% CI = 0.99-1.45, p = 0.057). CONCLUSIONS: This study is the largest so far on neighbourhood influences on CHD, and the results suggest that deprived neighbourhoods have higher rates of CHD, which represents important clinical knowledge. However, the association does not seem to be independent of individual- and family-level characteristics. PMID- 25929334 TI - Carnosic acid as a major bioactive component in rosemary extract ameliorates high fat-diet-induced obesity and metabolic syndrome in mice. AB - In this study, we investigated the preventive effects of carnosic acid (CA) as a major bioactive component in rosemary extract (RE) on high-fat-diet-induced obesity and metabolic syndrome in mice. The mice were given a low-fat diet, a high-fat diet or a high-fat diet supplemented with either 0.14% or 0.28% (w/w) CA enriched RE (containing 80% CA, RE#1L and RE#1H), or 0.5% (w/w) RE (containing 45% CA, RE#2), for a period of 16 weeks. There was the same CA content in the RE#1H and RE#2 diets and half of this amount in the RE#1L diet. The dietary RE supplementation significantly reduced body weight gain, percent of fat, plasma ALT, AST, glucose, insulin levels, liver weight, liver triglyceride, and free fatty acid levels in comparison with the mice fed with a HF diet without RE treatment. RE administration also decreased the levels of plasma and liver malondialdehyde, advanced glycation end products (AGEs), and the liver expression of receptor for AGE (RAGE) in comparison with those for mice of the HF group. Histological analyses of liver samples showed decreased lipid accumulation in hepatocytes in mice administrated with RE in comparison with that of HF-diet-fed mice. Meanwhile, RE administration enhanced fecal lipid excretion to inhibit lipid absorption and increased the liver GSH/GSSG ratio to perform antioxidant activity compared with HF group. Our results demonstrate that rosemary is a promising dietary agent to reduce the risk of obesity and metabolic syndrome. PMID- 25929335 TI - Indications for prognostic gene expression profiling in early breast cancer. AB - OPINION STATEMENT: Breast cancer is a heterogeneous disease. While breast cancer mortality has dropped substantially over the past three decades due to early detection and adjuvant systemic therapy (AST), the risk of recurrence is highly dependent upon numerous factors including tumor size, involvement of regional lymph nodes, histologic grade, expression of hormone receptors (estrogen and progesterone), and human epidermal growth factor receptor 2 (HER2) amplification. We use these factors to determine which early breast cancer (EBC) patients should be treated with AST, including endocrine therapy (ET), chemotherapy, and HER2 directed treatments. While these factors aid in this determination, it remains challenging to identify those patients unlikely to benefit from adjuvant chemotherapy, resulting in over-treatment of patients. Given this dilemma, there has been great interest in the development of prognostic and predictive gene expression profiles. The most extensively studied profile, the 21-gene recurrence score (Oncotype Dx(r)), estimates 10-year risk of breast cancer recurrence in patients with estrogen receptor (ER)-positive, HER2-negative, node-negative EBC and is likely predictive of chemotherapy benefit. This assay has established analytic validity, clinical validity, and clinical utility for this patient group and, therefore, is indicated in this patient population to help inform decisions regarding administration of adjuvant chemotherapy. Several other assays may have utility in this clinical context or perhaps to identify patients who do not require extended adjuvant ET. These assays include the following: PAM 50 Risk of Recurrence (ROR) Score (ProsignaTM), Breast Cancer Index, and EndoPredict(r). PMID- 25929336 TI - Global gene expression in pseudomyxoma peritonei, with parallel development of two immortalized cell lines. AB - Pseudomyxoma peritonei (PMP) is a rare tumor of appendiceal origin. Treatment is major cytoreductive surgery but morbidity is high. PMP is considered chemo resistant; its molecular biology is understudied; and presently, there is no platform for pre-clinical drug testing. Here, we performed exon array analysis from laser micro-dissected PMP tissue and normal colonic epithelia. The array analysis identified 27 up-regulated and 34 down-regulated genes: candidate up regulated genes included SLC16A4, DSC3, Aldolase B, EPHX4, and ARHGAP24; candidate down-regulated genes were MS4A12, TMIGD1 and Caspase-5. We confirmed differential expression of the candidate genes and their protein products using in-situ hybridization and immuno-histochemistry. In parallel, we established two primary PMP cell lines, N14A and N15A, and immortalized with an SV40 T-antigen lentiviral vector. We cross-checked for expression of the candidate genes (from the array analyses) using qPCR in the cell lines and demonstrated that the gene profiles were distinct from those of colorectal tumor libraries and commonly used colon cell lines. N14A and N15A were responsiveness to mitomycin and oxaliplatin. This study characterizes global gene expression in PMP, and the parallel development of the first immortalized PMP cell lines; fit for pre-clinical testing and PMP oncogene discovery. PMID- 25929337 TI - Molecular signatures of sanguinarine in human pancreatic cancer cells: A large scale label-free comparative proteomics approach. AB - Pancreatic cancer remains one of the most lethal of all human malignancies with its incidence nearly equaling its mortality rate. Therefore, it's crucial to identify newer mechanism-based agents and targets to effectively manage pancreatic cancer. Plant-derived agents/drugs have historically been useful in cancer therapeutics. Sanguinarine is a plant alkaloid with anti-proliferative effects against cancers, including pancreatic cancer. This study was designed to determine the mechanism of sanguinarine's effects in pancreatic cancer with a hope to obtain useful information to improve the therapeutic options for the management of this neoplasm. We employed a quantitative proteomics approach to define the mechanism of sanguinarine's effects in human pancreatic cancer cells. Proteins from control and sanguinarine-treated pancreatic cancer cells were digested with trypsin, run by nano-LC/MS/MS, and identified with the help of Swiss-Prot database. Results from replicate injections were processed with the SIEVE software to identify proteins with differential expression. We identified 37 differentially expressed proteins (from a total of 3107), which are known to be involved in variety of cellular processes. Four of these proteins (IL33, CUL5, GPS1 and DUSP4) appear to occupy regulatory nodes in key pathways. Further validation by qRT-PCR and immunoblot analyses demonstrated that the dual specificity phosphatase-4 (DUSP4) was significantly upregulated by sanguinarine in BxPC-3 and MIA PaCa-2 cells. Sanguinarine treatment also caused down regulation of HIF1alpha and PCNA, and increased cleavage of PARP and Caspase-7. Taken together, sanguinarine appears to have pleotropic effects, as it modulates multiple key signaling pathways, supporting the potential usefulness of sanguinarine against pancreatic cancer. PMID- 25929338 TI - Basal and therapy-driven hypoxia-inducible factor-1alpha confers resistance to endocrine therapy in estrogen receptor-positive breast cancer. AB - Resistance is an obstacle to endocrine therapy for breast cancer. We measured levels of hypoxia-inducible factor (HIF)-1alpha in 52 primary breast cancer patients before and after receiving neoadjuvant endocrine therapy with letrozole for at least 3 months. Pre-treatment levels of HIF-1alpha were associated with negative clinical outcome. Furthermore, levels of HIF-1alpha were increased in post-treatment residual tumors compared with those in pre-treatment biopsy samples. In animal studies, xenografts stably expressing HIF-1alpha were resistant to endocrine therapy with fulvestrant compared with the effects in control xenografts. Additionally, HIF-1alpha transcription was inhibited by zoledronic acid, a conventional drug for the treatment of postmenopausal osteoporosis, and was accompanied by a marked inhibition of the RAS/MAPK/ERK1/2 pathway. HIF-1alpha is a determinant of resistance to endocrine therapy and should be considered as a potential therapeutic target for overcoming endocrine resistance in estrogen receptor (ER)-positive breast cancer. In addition, zoledronic acid may overcome endocrine resistance in ER-positive human breast cancer by targeting HIF-1alpha transcription through inhibition of the RAS/MAPK/ERK1/2 pathway. Clinical studies on the administration of zoledronic acid as a second line treatment in patients who failed endocrine therapy should be considered to improve therapeutic outcomes in breast cancer patients. PMID- 25929340 TI - Massive parallel IGHV gene sequencing reveals a germinal center pathway in origins of human multiple myeloma. AB - Human multiple myeloma (MM) is characterized by accumulation of malignant terminally differentiated plasma cells (PCs) in the bone marrow (BM), raising the question when during maturation neoplastic transformation begins. Immunoglobulin IGHV genes carry imprints of clonal tumor history, delineating somatic hypermutation (SHM) events that generally occur in the germinal center (GC). Here, we examine MM-derived IGHV genes using massive parallel deep sequencing, comparing them with profiles in normal BM PCs. In 4/4 presentation IgG MM, monoclonal tumor-derived IGHV sequences revealed significant evidence for intraclonal variation (ICV) in mutation patterns. IGHV sequences of 2/2 normal PC IgG populations revealed dominant oligoclonal expansions, each expansion also displaying mutational ICV. Clonal expansions in MM and in normal BM PCs reveal common IGHV features. In such MM, the data fit a model of tumor origins in which neoplastic transformation is initiated in a GC B-cell committed to terminal differentiation but still targeted by on-going SHM. Strikingly, the data parallel IGHV clonal sequences in some monoclonal gammopathy of undetermined significance (MGUS) known to display on-going SHM imprints. Since MGUS generally precedes MM, these data suggest origins of MGUS and MM with IGHV gene mutational ICV from the same GC B-cell, arising via a distinctive pathway. PMID- 25929341 TI - Medullary position at the craniocervical junction in mature cavalier King Charles spaniels: relationship with neurologic signs and syringomyelia. AB - BACKGROUND: Medullary elevation (ie, medullary kinking) at the craniocervical junction (CCJ) is reported in dogs with Chiari-like malformations (CM), but its diagnostic criteria and clinical relevance are unclear. OBJECTIVE: To describe the position of the medulla at the CCJ in mature cavalier King Charles spaniels (CKCS), and evaluate its relationship with clinical status and the presence of syringomyelia. ANIMALS: Thirty-six CKCS, 5-12 years of age, including 16 asymptomatic dogs. METHODS: Dogs were assigned a neurologic grade; magnetic resonance imaging (MRI) of the CCJ then was performed. The presence of a CM and syringomyelia was recorded and syringomyelia severity was quantified. Medullary position was quantified using the medullary kinking index, the elevation angle and obex position relative to the foramen magnum. The relationship between medullary position measures and presence and severity of neurologic signs and syringomyelia was investigated. RESULTS: Chiari-like malformation was found in 33 dogs; 26 of them had syringomyelia. Mean medullary kinking index was 46.4% (SD, 10.3), elevation angle was 132 degrees (SD, 12) and obex position was 3.5 mm (SD, 0.8). A higher medullary kinking index was associated with the presence of neurologic signs (P = .0368). Obex position was associated with the presence (P = .0018) and severity of syringomyelia (P = .0164). CONCLUSIONS AND CLINICAL IMPORTANCE: There is a significant association between medullary elevation and clinical signs, whereas more caudal brainstem positions appear related to the presence of syringomyelia. PMID- 25929342 TI - Mixed tau and TDP-43 pathology in a patient with unclassifiable primary progressive aphasia. AB - Classifying primary progressive aphasia (PPA) into variants that may predict the underlying pathology is important. However, some PPA patients cannot be classified. A 78-year-old woman had unclassifiable PPA characterized by anomia, dysarthria, and apraxia of speech without agrammatism. Magnetic resonance imaging revealed left mesial temporal atrophy and 18-flourodeoxy-glucose positron emission tomography showed left anterior temporal and posterior frontal (premotor) hypometabolism. Autopsy revealed a mixed tauopathy (argyrophilic grain disease) and transactive response-DNA-binding-protein-43 proteinopathy. Dual pathologies may explain the difficulty classifying some PPA patients and recognizing this will be important as new imaging techniques (particularly tau positron emission tomography) are introduced and patients begin enrollment in clinical trials targeting the underlying proteinopathy. PMID- 25929343 TI - Intraoperative Phase Reversal Monitoring Using a Novel Technique. PMID- 25929344 TI - Emergency Posterior Fossa Surgery in Sitting Position in a Patient With Pheochromocytoma. PMID- 25929345 TI - The Chicken or the Egg: Hypertension Secondary to Intraoperative Subarachnoid Hemorrhage. PMID- 25929346 TI - Intraoperative changes in blood pressure associated with cerebral desaturation in infants. AB - BACKGROUND: Intraoperative hypotension has been linked to poor postoperative neurological outcomes. However, the definition of hypotension remains controversial in children. We sought to determine arterial blood pressure threshold values associated with cerebral desaturation in infants. METHODS: After ethics committee approval, infants younger than 3 months were included in this prospective observational study. Cerebral saturation was assessed using near infrared spectroscopy. The primary goal of the study was to determine percentage reductions in intraoperative systolic blood pressure (SBP) and mean blood pressure (MBP) associated with decreases in cerebral blood oxygen saturation of >20%, when compared to baseline. Analyses were performed using a bootstrap receiving operator characteristic (ROC) curves with determination of the gray zone. RESULTS: Sixty patients were recruited and 960 measurement points were recorded. Fifty-nine data points (6.1%) recorded cerebral desaturation of >20% when compared to baseline. The areas under the ROC curves were 0.79 (0.74-0.84) and 0.67 (0.6-0.75) for percentage decreases in SBP and MBP, respectively. Gray zone values with false-positive and negative rates <10% were SBP decreases of 20.5% and 37.5%, respectively, and MBP decreases of 15.5% and 44.5%, respectively. CONCLUSION: Our results indicate that falls in noninvasive systolic blood pressure of <20% from baseline are associated with a <10% chance of cerebral desaturation in neonates and infants <3 months of age undergoing noncardiac surgery. As such, maintaining systolic blood pressure above this threshold value appears a valid clinical target. PMID- 25929347 TI - Phase II multicenter study of adjuvant S-1 for colorectal liver metastasis: survival analysis of N-SOG 01 trial. AB - PURPOSE: We previously showed that S-1 after curative resection of colorectal liver metastasis had acceptable toxicity and a high rate of completion of therapy in a prospective phase II trial. We here reported the primary endpoint of disease free survival (DFS). METHODS: Between October 2008 and August 2010, 60 patients were eligible for this study and received S-1 for 28 days followed by a 2-week rest period. Treatment was started within 8 weeks after surgery and repeated for eight cycles. RESULTS: Median follow-up was 41 months. Among 60 patients, 45 had solitary metastasis, and the median maximum tumor diameter was 2.6 cm. The 3-year DFS and overall survival were 47.4 and 80.0 %, respectively. Recurrences developed in 31 patients, with the remnant liver the most common site (19 patients). Multivariate analysis showed that positive lymph node metastasis around the primary site (p = 0.013) and early liver metastasis (synchronous disease or metachronous disease within 12 months) (p = 0.041) were independent poor prognostic factors for DFS. Patients having both risk factors had a significantly worse DFS than those without these risk factors (p < 0.001). Early liver metastasis was an independent indicator of early recurrence within 1 year. CONCLUSIONS: S-1 after curative liver resection yielded promising survival in patients with a low tumor burden. Outcome in patients having both positive lymph node metastasis around the primary site and early liver metastasis was much worse than in patients without these conditions; therefore, they might warrant more aggressive therapy. PMID- 25929348 TI - Intraparotid classical and nodular lymphocyte-predominant Hodgkin lymphoma: pattern analysis with emphasis on associated lymphadenoma-like proliferations. AB - Most of the lymphoproliferative diseases involving the salivary glands represent indolent non-Hodgkin B-cell lymphoma (marginal zone lymphoma) related to chronic autoimmune sialadenitis (Sjogren disease). Other types of non-Hodgkin lymphomas involve the salivary glands less frequently. On rare occasions, classical Hodgkin lymphoma (CHL) and nodular lymphocyte-predominant Hodgkin lymphoma (NLPHL) present initially as a primary salivary gland mass. We analyzed a series of CHL (n=3) and NLPHL (n=6) presenting initially as parotid gland tumors concerning their pattern (parenchymal vs. intraparotid lymph node) and the presence of salivary inclusions and epithelial proliferations within the lymphoma infiltrate. The pattern of infiltration was determined on hematoxylin and eosin-stained slides assisted by immunostaining for pancytokeratin to highlight lobular salivary gland parenchyma. Patients included 6 male and 3 female individuals with a mean age of 62 years (range, 36 to 88 y). Lymphoma was localized within intraparotid lymph nodes in 8 cases and was limited to salivary parenchyma in 1 case. Parenchymal involvement in nodal-based cases was scored as absent (3) or minimal (5). Salivary inclusions (acini and ductules) within affected lymph nodes were noted in 6 cases (4/5 NLPHLs and 2/3 CHLs). In 3/6 NLPHL cases, salivary inclusions showed variable proliferative changes ranging from prominent lymphoepithelial lesions to cystic and oncocytic (Warthin-like) epithelial changes. Scanty small lymphoepithelial lesions were seen in 1 of the 3 CHL cases. One NLPHL in the intraparotid lymph node was accompanied by prominent lymphoepithelial sialadenitis in the absence of clinical signs of Sjogren disease. This study highlights that a majority of parotid gland Hodgkin lymphomas arise within intraparotid lymph nodes. Frequent entrapment and proliferation of salivary ducts and acini within the lymphoma infiltrate might mimic a variety of benign lymphoepithelial mass-forming lesions (nonsebaceous lymphadenoma, Warthin tumor, and autoimmune sialadenitis). Pancytokeratin stain is helpful for reliable assessment of the background architecture. PMID- 25929349 TI - Diagnosis of Gleason pattern 5 prostate adenocarcinoma on core needle biopsy: an interobserver reproducibility study among urologic pathologists. AB - Accurate recognition of Gleason pattern 5 (GP5) prostate adenocarcinoma on needle biopsy is critical as it is associated with disease progression and adverse clinical outcome. Despite important implications of this diagnosis, interobserver variation in the diagnosis of GP5 has not been adequately studied. Digital images of 66 prostate adenocarcinoma cases that potentially contained a GP5 component were distributed to 16 urologic pathologists who were asked to classify whether GP5 was present. Each image was initially classified into 1 of 4 morphologic subpatterns by 2 coauthors (R.B.S. and M.Z.): solid nests (15), comedocarcinoma (8), single cells and/or cords (35), and variant morphology (8). Additional features captured included: size (large: >20 cells, medium: 10 to 20 cells, and small: <10 cells) and distribution of nuclei (uniform vs. nonuniform) for nests pattern; intraluminal coagulative tumor necrosis, karyorrhectic debris, and amorphous material for comedocarcinoma pattern; and quantity (<=5, 6 to 10, and >10) and distribution (clustered vs. intermixed with adjacent well-formed glands) for single cells/cords pattern. Interobserver reproducibility of a diagnosis of GP5 was assessed and the morphologic subpatterns and features were correlated with the consensus diagnosis (defined as 75% agreement). Interobserver reproducibility for overall diagnostic agreement was fair (kappa=0.376). Among subpatterns, comedocarcinoma had highest reproducibility (kappa=0.499), followed by variant morphology (kappa=0.443), single cells/cords (kappa=0.369), and nests (kappa=0.347). All cases with the following features achieved consensus for GP5: large nests regardless of nuclear distribution; coagulative necrosis with or without karyorrhectic debris; single cells/cords >10 or 6 to 10 in a cluster; and signet ring-like cells in single cells or within nests pattern. A majority of cases with the following features achieved consensus against GP5: medium-size nests; exclusive intraluminal amorphous material; single cells/cords <=5; and Paneth cell change. Remaining morphologic features did not reach consensus for or against GP5. A majority (86%) of participants would diagnose a small focus of GP5 only when it is present in >1 level. The diagnostic reproducibility of GP5 within certain morphologies was only fair among urologic pathologists. However, the diagnosis of GP5 was more reproducible when certain restrictive morphologic and quantitative criteria were applied. These findings suggest that additional studies are needed to find highly reproducible features of GP5 associated with documented aggressive clinical outcome. PMID- 25929350 TI - Clinicopathologic analysis of 6 lymphomatoid gastropathy cases: expanding the disease spectrum to CD4-CD8+ cases. AB - Lymphomatoid gastropathy, which was first reported in 2010, is a rare NK-cell proliferation of cyCD3, CD4, CD5, CD8, CD56 phenotypes with unknown etiology. The diagnosis is challenging, as there is histopathologic similarity to malignant lymphoma. In the 2010 report on 10 cases, all lesions were located in the stomach, and all regressed without any therapy. In the present study, we analyzed 6 cases of lymphomatoid gastropathy by investigating the clinicopathologic, immunohistochemical, and molecular findings. Endoscopic and morphologic appearances of all cases were consistent with previous reports, but 2 cases showed previously unreported unique immunophenotypes of CD4CD8. Three of 6 patients underwent lower gastrointestinal examination (1 case underwent double balloon endoscopic examination), but no patient had lesions in the lower gastrointestinal tract. No obvious difference of histology was found between the cases of CD4-CD8-typical phenotype and ones of CD4CD8 phenotype. Both cases had similar clinical behavior as the other 4 cases, implying that the spectrum of the disease is broader than initially thought. Careful clinical and endoscopic follow up is required for the diagnosis of lymphomatoid gastropathy, and additional case studies and molecular studies are warranted to further investigate the pathophysiology of this peculiar benign mimic of lymphoma. PMID- 25929351 TI - Malignant peripheral nerve sheath tumor (MPNST) arising in diffuse-type neurofibroma: clinicopathologic characterization in a series of 9 cases. AB - Diffuse-type neurofibroma, an uncommon variant of neurofibroma, is associated with neurofibromatosis type 1 in ~60% of cases. Typically presenting in young adults as ill-defined plaque-like dermal/subcutaneous thickening, most cases are located on the trunk or the head and neck region. Malignant transformation is extremely rare. Nine cases of malignant peripheral nerve sheath tumor (MPNST) arising in diffuse-type neurofibroma (identified in consult files) are described, including clinicopathologic features and follow-up. Five patients were male and 4 female, aged 31 to 59 years (median 49 y). All diffuse-type neurofibromas contained Meissner corpuscles, with tumor sizes ranging between 3.6 and 45 cm (median, 7.4 cm). Five patients had a clinical history of neurofibromatosis type 1, and 1 had Klippel-Trenaunay-Weber syndrome. Six tumors arose on the trunk and 1 each on the leg, arm, and scalp. Increased cellularity, nuclear atypia, and mitoses (range, 1 to 63/50 high-power fields) indicated transition to MPNST, classified as low grade in 5, intermediate to high grade in 1, and high grade in 3 cases, 1 of which exhibited heterologous angiosarcomatous differentiation. S 100 expression was quite strong and diffuse in the neurofibroma components and less extensive or weaker in MPNST. Follow-up, available for all patients (median, 80.5 mo, except 1 recent case), revealed that 1 patient developed local recurrence after 9 months; 1 with metastases at the time of initial diagnosis died 1 month after tumor resection. All other patients were alive without evidence of disease at 15 to 145 months (median, 83 mo). Diffuse-type neurofibroma may show transformation to MPNST in very rare instances. It is important to be aware of possible malignant change, requiring thorough sampling of resection specimens and long-term clinical follow-up of patients with unexcised lesions. PMID- 25929352 TI - Epithelioid Angiosarcoma of the Bladder: A Series of 9 Cases. AB - Primary angiosarcoma of the bladder is very rare, with approximately 30 cases reported in the literature. Those with epithelioid morphology are even rarer, with only single-case reports published. We describe the histopathologic features and clinical follow-up of 9 patients with epithelioid angiosarcoma (EA) of the bladder retrieved from our Surgical Pathology files from 1998 to 2014. Eight cases were consults. The mean age at presentation was 65 years (range, 39 to 85 y). The M:F ratio was 8:1. The clinical presentation was hematuria and bladder mass in all cases. Six patients had a history of radiotherapy to the pelvis, 5 to treat prostate cancer and 1 to treat uterine cervical cancer. The time from radiotherapy to the diagnosis of EA ranged from 6 to 15 years. The average size of the tumor was 4 cm. (range, 1 to 8 cm.). The submitting diagnoses were poorly differentiated carcinoma (n=5), high-grade invasive urothelial carcinoma (n=3), and atypical vascular proliferation (n=1). Morphologically, the tumors were composed of nests and sheets of highly atypical cells with high nuclear to cytoplasmic ratio, occasional intracytoplasmic lumens, and a hemorrhagic background. None of the cases showed any urothelial carcinoma component. Three patients showed in addition usual angiosarcoma in the resection specimen. By immunohistochemistry, 5/9 cases were positive for cytokeratins, including CK7 (n=3), AE1/AE3 (n=3), and Cam5.2 (n=1). All cases were positive for at least 1 endothelial marker, including CD31 (n=7), CD34 (n=2), FVIII (n=3), and ERG (n=2). Urothelial markers (p63 and GATA3) were consistently negative. Surgical treatment included transurethral resection of the bladder (TURB) only (n=5), TURB followed by cystoprostatectomy (n=2), TURB followed by partial cystectomy (n=1), and cystoprostatectomy only (n=1). The tumor involved the muscularis propria in 5/9 patients, the periureteric adipose tissue in 1 patient, and the prostate and seminal vesicles in 1 patient. Five of 9 patients died of disease, with a median survival of 7 months (range, 6 to 14 mo). Two patients were alive with disease at 3 and 6 months of follow-up. One patient who underwent radical cystoprostatectomy was alive with no evidence of disease 12 months after surgery. EA of the bladder is a rare malignancy that is frequently misdiagnosed as high-grade carcinoma, especially due to positive immunostaining for cytokeratins. This tumor is more frequent in older men with a history of radiotherapy to the pelvis. Morphologic features that should suggest the vascular origin of the tumor include highly atypical nuclei with interspersed erythrocytes, hemorrhagic background, and occasional intracytoplasmic lumens. Patients usually present with muscle invasive disease, and the prognosis is dismal. PMID- 25929353 TI - Lipoblastoma-like tumor of the vulva: further characterization in 8 new cases. AB - Lipoblastoma-like tumor of the vulva (LLTV) is an exceptionally rare adipocytic mesenchymal tumor with only 4 cases reported previously. The aim of this study is to help characterize this tumor type. Eight cases of LLTV were identified in the consult files of one of the authors (C.D.M.F.). Clinical data and follow-up information were obtained from the referring pathologists. Detailed clinical information is available in all 8 cases. Patient age ranged from 17 to 46 years (median 27 y). Lesions presented as a vulvar mass with a variable growth rate, sometimes being painful. The most common preoperative clinical diagnosis was a Bartholin gland abnormality (4). The size of the mass ranged from 3.5 to 15 cm (median 5.6 cm). The lesions were described as grossly myxoid, mucoid, or gelatinous (4), well defined (4), and lobulated (3). None of the lesions exhibited necrosis. Histologically, LLTVs were lobulated and composed of variable proportions of mature adipocytes, bland univacuolated and bivacuolated lipoblasts, and spindle cells with short stubby nuclei in a diffusely myxoid background with prominent branching vessels. Nuclear atypia was minimal. No necrosis and only rare mitotic activity was identified. Only 1 of 7 tumors (in a 26-y-old patient) was positive for PLAG1 and retinoblastoma (Rb). Rb was lost, and PLAG1 was not expressed in all other tumors. HMGA2 was negative in 6 of 6 cases tested. Tumors were negative for S100 (5/5), MDM2, and CDK4 (5/6; 1 with just scattered cells positive for both antibodies). Two of 5 cases were positive for CD34. Fluorescence in situ hybridization for DDIT3 gene rearrangement was negative in 5 cases tested. The follow-up interval ranged from 4 months to 11 years (median 2.75 y). Three patients developed 1 local recurrence, 7 months, 2 years, and 8 years, respectively, after excision of the primary tumor. None of the patients has developed metastatic disease. LLTVs are indolent adipocytic mesenchymal tumors arising in adults. Lack of PLAG1 and HMGA2 expression in the majority of LLTV suggests that these lesions are distinct from "true" lipoblastoma. The loss of Rb in the majority of cases suggests a possible role of 13q chromosomal alterations and a possible relationship with the spindle cell lipoma tumor family. PMID- 25929354 TI - Farmed Atlantic salmon Salmo salar L. parr may reduce early survival of wild fish. AB - The study examined the density-mediated effects on growth, survival and dispersal of wild and farmed Atlantic salmon Salmo salar offspring in the period immediately following emergence, using a substitutive design. In small confined stream channels, wild parr coexisting with farmed parr had a significantly poorer survival, than wild parr alone. Density did not affect this relationship. In larger unconfined stream channels, wild parr coexisting with farmed parr entered a downstream trap in higher numbers than wild parr in allopatry. The results suggests that during the earliest life stages, farmed S. salar can outcompete wild S. salar, resulting in a reduced survival of wild S. salar. PMID- 25929355 TI - Complex histories of repeated gene flow in Cameroon crater lake cichlids cast doubt on one of the clearest examples of sympatric speciation. AB - One of the most celebrated examples of sympatric speciation in nature are monophyletic radiations of cichlid fishes endemic to Cameroon crater lakes. However, phylogenetic inference of monophyly may not detect complex colonization histories involving some allopatric isolation, such as double invasions obscured by genome-wide gene flow. Population genomic approaches are better suited to test hypotheses of sympatric speciation in these cases. Here, we use comprehensive sampling from all four sympatric crater lake cichlid radiations in Cameroon and outgroups across Africa combined with next-generation sequencing to genotype tens of thousands of SNPs. We find considerable evidence of gene flow between all four radiations and neighboring riverine populations after initial colonization. In a few cases, some sympatric species are more closely related to outgroups than others, consistent with secondary gene flow facilitating their speciation. Our results do not rule out sympatric speciation in Cameroon cichlids, but rather reveal a complex history of speciation with gene flow, including allopatric and sympatric phases, resulting in both reproductively isolated species and incipient species complexes. The best remaining non-cichlid examples of sympatric speciation all involve assortative mating within microhabitats. We speculate that this feature may be necessary to complete the process of sympatric speciation in nature. PMID- 25929356 TI - Hydration and chemical ingredients in sport drinks: food safety in the European context. AB - Before, during and after physical activity, hydration is a limiting factor in athletic performance. Therefore, adequate hydration provides benefits for health and performance of athletes. Besides, hydration is associated to the intake of carbohydrates, protein, sodium, caffeine and other substances by different dietary aids, during the training and/or competition by athletes. These requirements have led to the development of different products by the food industry, to cover the nutritional needs of athletes. Currently in the European context, the legal framework for the development of products, substances and health claims concerning to sport products is incomplete and scarce. Under these conditions, there are many products with different ingredients out of European Food Safety Authority (EFSA) control where claims are wrong due to no robust scientific evidence and it can be dangerous for the health. Further scientific evidence should be constructed by new clinical trials in order to assist to the Experts Commitees at EFSA for obtaining robust scientific opinions concerning to the functional foods and the individual ingredients for sport population. PMID- 25929357 TI - State of malnutrition in cuban hospitals; a needed update. AB - RATIONALE: The Cuban Study of Hospital Malnutrition, as conducted during 1999 - 2001 with 1,905 patients assisted in 12 hospitals from 6 provinces of the country, revealed a hospital malnutrition rate of 41.2%. Having elapsed a decade after the first edition of the enquiry, update of this estimate is mandatory. OBJECTIVE: To update the state of hospital malnutrition in Cuba. MATERIAL AND METHOD: Presence of malnutrition in 1,664 patients admitted to 12 hospitals from 8 provinces of the country between March 2012 and March 2014 was documented with the Subjective Global Assessment (SGA) survey of the nutritional status. The state of hospital processes of food and nutritional care was assessed by means of the Hospital Nutrition Survey (HNS). RESULTS: Current hospital malnutrition rate was 36.9% (Delta = +4.3%; p < 0.05). Completion rates of hospital exercises of nutritional assessment and of use of nutritional replenishment therapies were higher. CONCLUSIONS: Having elapsed 10 years after the first edition of the ELAN CUBA Study, modest advances are seen in the identification and treatment of malnutrition in Cuban hospitals. It is perceived that formation and insertion of nutritionists verticalized in hospital care has contributed to the observed change. In addition, the activity of the Cuban Society of Clinical Nutrition and Metabolism in the advancement of the disciplines of nutritional therapy, artificial nutrition and metabolism might have served for a better recognition of the health problem posed by hospital malnutrition. PMID- 25929358 TI - [Healthy lifestyles of the university population]. AB - The lifestyle is defined as the set of behavioral patterns and daily habits of a person, which maintained over time may become dimensions of risk or safety depending on their nature. The aim of this study was to know the lifestyles of university students in the following dimensions: diet, exercise, consumption of tobacco, alcohol and other drugs, sex and road safety. We made a literature review in electronic databases: PubMed, SCIELO and CUIDEN, between 2002-2014; using as keywords habits, lifestyle, health behaviors, young adult and university students. From articles found, stand out as most relevant data that university students have a high presence of favorable beliefs about healthy lifestyles and nevertheless not put into practice. We could conclude that according to different authors, university students in general have not a good eating habits, eating unbalanced diets high in calories. Besides the physical exercise is null, knowing that a good diet and doing exercise have beneficial effects on health. To this must be added the high consumption of alcohol, tobacco and marijuana among university students. PMID- 25929359 TI - Inflammatory markers in relation to body composition, physical activity and assessment of nutritional status of the adolescents. AB - INTRODUCTION: The evaluation of inflammatory markers during adolescence can monitor different stages and manifestation of chronic diseases in adulthood. The control of the subclinical inflammation process through changes in lifestyle, especially in the practice of physical activity and dietary education can mitigate the effects of risk factors that trigger the process of atherosclerosis. OBJECTIVE: To do a critical review regarding inflammatory markers as a risk factor of cardiovascular disease in relation to body composition, physical activity and assessment of nutritional status of adolescents. METHODS: A literature review was performed in the following electronic databases: PUBMED, SCIELO and CONCHRANE COLLECTION. The following associated terms were used "inflammation AND cardiovascular diseases AND nutritional status OR body composition OR physical activity". There were topics created for the discussion of subjects: obesity and risk factors for cardiovascular disease during adolescence; expression of inflammatory markers in adolescence; development of cardiovascular disease with inflammatory markers, and finally, inflammatory markers, physical activity and nutritional evaluation. RESULTS: It was observed that the inflammatory markers may manifest in adolescence and be related to risk factors for cardiovascular diseases. Physical activity and nutritional evaluation featured as non-pharmacological measures to control the incidence of inflammatory markers and cardiovascular risk factor. CONCLUSIONS: Intervention studies may clarify how the adoption of a more proper lifestyle can influence the inflammatory process. PMID- 25929360 TI - Tv food advertising geared to children in Latin-American countries and Hispanics in the USA: a review. AB - INTRODUCTION: Obesity is a pandemic disease in Latin America. The purpose of this review was to analyze the studies exploring food advertising in TV conducted in Latin-American countries and in the USA geared to Hispanics. METHODS: An electronic literature search was conducted in the MEDLINE/PubMed, EMBASE, SCIELO, and CINAHL, databases and open access internet, of food advertising directed to children in TV in Latin American countries and Hispanics living in the USA, published from 1985 to January, 2015 RESULTS: Twenty three studies were found, six were conducted in Chile, five in Mexico, four in Brazil, three among Hispanics in the USA, and one in each of the following countries: Argentina, Peru, Colombia, Honduras and Venezuela. A high exposure of TV food advertised is geared toward children and their family. This exposure has been shown to be associated with the preference and purchase of those foods by adults and children with a high BMI, overweight and obesity. CONCLUSION: An alarming high exposure of the TV food advertised directed toward children was reported, which warrants effective regulations, supervision and accountability. PMID- 25929361 TI - [Breastfeeding as a method to prevent cardiovascular diseases in the mother and the child]. AB - INTRODUCTION: Breastfeeding is a recommended practice from all health institutions, both national and international, due to the benefits that it provides for both the nursling's and the mother's health. It has been proved that mothers who breastfeed their children suffer from less cardiovascular disorders, including hypertension, than those women who have never done it. AIM: The goal of this review is to analyse the studies that have done some research on breastfeeding as a protection from cardiovascular diseases in the mother and the infant. METHODS: A systematic search has been carried out and 10 meta-analysis or reviews, 8 original articles of clinical studies, 31 longitudinal or cohort studies and 7 correlational studies of large sample and descriptive were selected. RESULTS/CONCLUSIONS: Cardiovascular disease is the main cause of death for women all over the world. Diet, exercise, quitting smoking and blood pressure control are well-known methods to prevent cardiovascular diseases. It has been shown that breastfeeding has a positive impact on the mother and child's blood pressure level, both in the short term and the long term. It is, thus, necessary to provide further information for the population so as to promote breastfeeding and know its benefits. PMID- 25929362 TI - Hepatic inflammatory biomarkers and its link with obesity and chronic diseases. AB - INTRODUCTION: The low-grade inflammation and insulin resistance are two events that could be present in varying degrees, on obesity and chronic diseases. The degree of subclinical inflammation can be gauged by measuring the concentrations of some inflammatory biomarkers, including the hepatic origin ones. Some of those biomarkers are sialic acid, alpha1-antitrypsin and the C-terminal fragment of alpha1-antitrypsin, ceruloplasmin, fibrinogen, haptoglobin, homocystein and plasminogen activator inhibitor-1. OBJECTIVES: To approach the relation between adiposity and hepatic inflammatory markers, and to assess the possible associations between hepatic inflammatory biomarkers and obesity, as well as their capacity of predicting chronic diseases such as type 2 diabetes and atherotrombotic cardiovascular diseases. METHODS: We used electronic scientific databases to select articles without restricting publication year. RESULTS: The sialic acid predicts the chance increase to become type 2 diabetic independently of BMI. Moreover, the alpha1-antitripsin, ceruloplasmin, fibrinogen and haptoglobulin biomarkers, seem predict the chance increase to become type 2 diabetic, dependently, of BMI. So, this process could be aggravated by obesity. The concentrations of fibrinogen, homocystein and PAI-1 increase proportionally to insulin resistance, showing its relation with metabolic syndrome (insulin resistance state) and with type 2 diabetes. In relation to cardiovascular diseases, every biomarkers reported in this review seem to increase the risk, becoming useful in add important prognostic. CONCLUSION: This review integrates the knowledge concerning the possible interactions of inflammatory mediators, in isolation or in conjunction, with obesity and chronic diseases, since these biomarkers play different functions and follow diverse biochemical routes in human body metabolism. PMID- 25929363 TI - ["In vivo" body composition assessment; part I: a historic overview]. AB - The study of body composition (BC) has gained in relevance over the last decades, mainly because of its important health- and disease- related applications within both the clinical and the sports setting. It is not a new area, and its especial relevance as an area of biology dates from the second half of the nineteenth century. In this paper, we have reviewed the three historic periods of BC, with special reference to the most important advances in in vivo assessment. Even though the earliest findings about human BC date from antiquity, the first (or 'early') stage of discovery began in 1850. Said early stage was mainly characterized by data obtained from the dissection of cadavers and by the application of biochemical methods in vivo. Longitudinal changes in body composition were also a concern. The second (so called 'recent') stage, in the second half of the twentieth century, was marked by milestones such as the formulation of the first mathematical models for the estimation of body components, and technological advances. Within the third ('contemporary' or 'current') stage of research, several groups have focused on validating the classical BC models in specific populations, on analysis of the genetic determinants (i.e. phenotypes and, more recently genotypes) of body composition, and on re-instigating the study of dynamic BC. PMID- 25929364 TI - [Implementation of the food choice questionnaire in young adolescents and their relationship to overweight and other socio-demographic variables]. AB - OBJECTIVE: The aim of this study is to analyze the behavior in choosing food among Spanish young teens, and its effect on the potential problems related to their weight (overweight and obesity) and other socio-demographic variables. METHODOLOGY: In the study included 590 students attended public and private schools in the city of Valencia, aged between 14 and 17 years, randomly selected. A personal questionnaire based on the Food Choice Questionnaire was conducted. RESULTS: In general, young people choose their food based on the sensory aspects and the price thereof, and do not care about the effects on weight have their eating habits. No differences between students in public or private schools, or between those with normal weight or overweight are detected. If there is any difference in terms of gender of the respondent. CONCLUSIONS: Teens, when food choices are not very aware of the possible effects of these on their current and future health. PMID- 25929365 TI - [Validity of an instrument for assessing food consumption, food habits and cooking skills in 8-11 years old students]. AB - INTRODUCTION: An instrument to measure food knowledge, food consumption, cooking skills, food habits and food expenses at school is necessary to assess changes in food practices. OBJECTIVE: To validate an instrument to measure changes in food knowledge, food consumption, cooking skills, food habits and food expenses in Chilean school children 8 - 11 years from third to fifth grade. METHODS: A validation of a questionnaire with 42 questions was conducted in two stages: the first to assess temporal stability, concordance and internal consistency in 45 children. The second one to apply the survey, modified with the results of the first stage, in 90 children assessing internal consistency. RESULTS: The first survey with 42 questions showed a reasonable temporal stability, concordance and internal consistency for cooking skills, habits and food expenditure at school. Internal consistency was good for food consumption, but not so good for food knowledge. In the final validation with 90 children, there was good consistency for food consumption but bad for food knowledge. Besides, children with cooking skills ate more healthy food and those who expended more money at school, consumed less healthy food. CONCLUSIONS: Food knowledge questions were eliminated from the instrument, which was elaborated with 28 questions about food consumption, cooking skills, food habits and food expenses at school. This instrument is useful to assess changes in food and nutrition education interventions in 8 -11 years children, in particular to measure cooking skills and food expenses at school. PMID- 25929366 TI - Obesity-related indicators and their relationship with serum antioxidant activity levels in Mexican adults. AB - INTRODUCTION: Obesity has been associated with an oxidative process, however there are controversies regarding the potential role of circulating antioxidant activity attributed to non-protein compounds. OBJECTIVE: The purpose of the present study was to examine the relation between antioxidant activity levels and obesity related-indicators in Mexican young adults. METHODS: Anthropometric measures, serum lipids and uric acid were determined in 78 men and 90 women (a total of 168 individuals). Serum antioxidant activity in different fractions also was measured by using TEAC assay (TEACNP, TEACP and TEACTotal). RESULTS: TEACNP was positively correlated (p<0.05) BMI (r=0.307), WC (r=0.322), LDL (r=0.274), TC (r=0.293), TG (r=0.409) and UA (r=0.441). The antioxidant activity measured as TEACNP in individuals with obesity related-indicators was higher compared to those individuals without obesity-related indicators. When BMI, WC, HDL, LDL, TC, TG and UA were considered as obesity related-indicators, the higher the number of obesity related indicators (p<0.05) the higher the TEACNP values. However, when TEACP values decreased, the number of obesity related-indicators (p<0.05) increased. CONCLUSION: The positive association between TEACNP and obesity related-indicators suggests that apparently increase in TEACNP may not always indicate a healthier condition. PMID- 25929367 TI - [The influence of healthy lifestyle habits on weight status in school aged children and adolescents]. AB - INTRODUCTION: Overweight and obesity has high prevalence in children and adolescents in Spain. OBJECTIVE: To determine the degree of influence of four modifiable factors (dietary habits, physical activity, sedentary and sleep) jointly on the weight status of a group of school children and adolescents in Madrid. METHODS: 189 schoolchildren aged 6 to 16 years, who underwent an anthropometric study. To exercise the IPAQ questionnaire was used, establishing a minimum of one hour of exercise a day, as a recommendation, and two hours per day in case of sedentary, which took into account the hours of computer, consoles and TV. Sleep quality was assessed by collecting sleeping hours weekdays and weekend nap. Stating that school children should sleep 10 hours a day. The KIDMED Index was used for the diet quality, the score can be accessed from 0-12 and classified into 3 categories, it was regrouped for statistical measure. The first two results (0-7) as "Bad adherence" and >= 8 value as "Good adherence". RESULTS: 27.6% of students had excess weight. CONCLUSION: No significant differences were reported analyzing the four factors studied versus weight status among those who keep recommendations and excess weight, either individually or multifactor analysis was observed. PMID- 25929368 TI - Prevalence of overweight and obesity among secondary school children aged 14 to 18 years (china). AB - BACKGROUND: Prevalence of overweight and obesity in adolescents has been increasing during recent decades. The present study aimed to assess the prevalence of obesity in 14-18 years old Anhui Secondary school children, and provide more comprehensive guidelines for intervention programs. METHODS: This cross-sectional study was conducted among 4788 children in secondary school, and date from the routine health survey was analyzed. Trained health workers took anthropometric measures, height and weight, at the school. Definition of children overweight and obesity children was based on the international age-and sex specific body mass index reference standards proposed by the International Obesity Task Force and National Center for Health Statistics. RESULTS: According to the IOTF standard the prevalence of overweight (including obesity) and obesity revealed decreasing trend with age in male (overweight, from 17.3% at 14-y to 5.3% at 18-y; obesity, from 3.8% at 14-y to 2.3% at 18-y). Depending on the NCHS references used, the overall prevalence of overweight (including obesity) and obesity in male aged 14 to 18 decreases from 16.4% to 11.7% and from 4.6% to 2.8%, respectively. CONCLUSION: The overweight (including obesity) and obesity from 14 to 18 years old have a decreasing trend, and more attention should be taken to male students in China. These findings suggest secondary school and government need to design appropriate guidelines to keep healthy for adolescents in China. PMID- 25929369 TI - [Effects of a multidisciplinary program on morbid obese patients and patients with comorbility who are likely to be candidates for bariatric surgery]. AB - INTRODUCTION: Morbid obesity is a disease that must be treated comprehensively (i.e. multi/interdisciplinary). Bariatric surgery is an effective and secure procedure for treating this health condition; however, the higher the weight is, the greater the risk of morbimortality might be. OBJECTIVE: The aim of this study is to determine the effects of a multidisciplinary treatment program on metabolic and anthropometric parameters and the physical condition of bariatric surgery candidates. MATERIALS AND METHODS: 1 man and 9 women of ~42.5 years old, with morbid obesity ( n = 3) or obesity and comorbilities (diabetes mellitus type II, hypertension, dyslipidemia and insulin resistance) (n = 7), all of them candidates for bariatric surgery, were submitted to physical exercise, psychological support and nutritional education, 3 times a week during 3 months. 72 hours before and after the last intervention session: body mass; fat mass index; BMI; waist circumference; physical condition; glycemia; HDL, LDL and total cholesterol; and triglycerides, were assessed (with a >=12-hour fast). RESULTS: After intervention, body mass (p=0.004), BMI (p=0.002), fat mass index (p=0.047) and physical condition (p=0.000) showed significant changes. Despite their tendency to decrease, remaining variables did not show significant changes. CONCLUSIONS: A comprehensive reasonable-frequent, short intervention (i.e. 3 sessions per week, during 3 months) may lead to significant weight and body fat loss, apart from enhancing considerably the physical condition of candidates for bariatric surgery. Longer time and/ or higher frequency in interventions might be necessary in order to modify significantly plasmatic variables. PMID- 25929370 TI - The variability in adherence to dietary treatment and quality of weight loss: overweight and obesity. AB - OBJECTIVE: Observation of weight loss and the maximum time that individualized dietary treatment qualitative and quantitative is shown to be effective. METHOD: 4625 consultations were conducted with 616 patients over 25 years old, in the nutrition consultation, using the qualitative and quantitative individualized dietary treatment. As a result we controlled the weight loss, the fat and the quality and variability of the loss, monthly according to sex, age and BMI in an urban area of southeastern Spain. RESULTS AND DISCUSSION: A low level of abandonment was proved in men, patients older than 45 years old compared to obese showed a higher degree. The quality of the loss was greater in men under 45 years old, overweight patients, however, more research is needed in this area. Measuring the waist and hips has led to an increasing interest in measuring indicators of body fat. CONCLUSION: The individualized dietary treatment has been proved to be effective for six months and then a multidisciplinary mode of this treatment is recommended. The use of new ways to assess weight loss is proposed taking into consideration the quality and variability of loss, regardless of the treatment used. PMID- 25929371 TI - Independent and combined influence of the FTO rs9939609 and MC4Rrs17782313 polymorphisms on hypocaloric diet induced changes in body mass and composition and energy metabolism in non-morbid obese premenopausal women. AB - PURPOSE: To examine the independent and combined influence of the FTOrs9939609 and the MC4Rrs17782313 polymorphisms on changes in fat mass (FM), resting energy expenditure (REE), leptin, and thyrotropin (TSH) levels, after a 12-week energy restricted diet intervention in non-morbid premenopausal obese women. METHODS: Fat mass (dual X-ray absorptiometry), REE (indirect calorimetry) and plasma leptin and thyrotropin levels were measured (before and after the intervention) in 77 obese (BMI: 33.9 +/- 2.8 kg/m(2)) women (age: 36.8 +/- 7.0y). RESULTS: There were no significant differences across FTOrs9939609 genotype groups (TT vs. A allele carriers, Ps>0.1) on changes in body mass (-8.6 +/- 3.2% vs. -8.7 +/- 3.3 %), FM (12.8 +/- 4.7% vs. -12.9 +/- 6.3%), REE (-11.3 +/- 4.7 vs. -9.4 +/- 8.1%), leptin (-34.1 +/- 25.1% vs. -43.5 +/- 24.1%) or TSH (5.2 +/- 34.5% vs. 1.7 +/- 27.1%) levels. Moreover, it was not observed any significant difference on changes in body mass (-8.6 +/- 3.6% vs. -8.9 +/- 2.6%), FM (-12.7 +/- 6.1% vs. -13.4 +/- 5.3%), REE (-9.8 +/- 7.4% -9.4 +/- 9.4%), leptin (-39.0 +/- 26.9% vs. 44.8 +/- 18.4%) or TSH (-1.0 +/- 30.0% vs. 1.5 +/- 26.5%) levels between non-C allele carriers and C allele carriers of the MC4Rrs17782313 (Ps>0.3). Finally, there were no significant difference on changes in body mass and composition, REE, leptin or TSH levels among non-risk allele carriers, carriers of the C allele risk of the MC4Rrs17782313, carriers of the A allele of the FTOrs9939609 and carriers of both risk alleles after the 12-week energy-restricted diet intervention (Ps>0.1). CONCLUSION: Carrying the A risk allele of the FTOrs9939609 and/or the C risk allele of the MC4Rrs17782313 did not influence body mass and FM loss, or REE decrease in obese women after a 12-week energy-restricted diet intervention. PMID- 25929372 TI - [Quality of life in obese patients and change after bariatric surgery medium and long term]. AB - INTRODUCTION: Morbid obesity has grown enormously in recent decades, representing a serious public health problem. It is characterized by the accumulation of body fat and the presence of diseases associated with it, which affects the physical, psychological and social level. It has been considered bariatric ciguria as the most effective treatment for weight loss, getting the welfare of the obese person in the above-described drawings. OBJECTIVE: To evaluate the impact on the quality of life of obese people before and after bariatric surgery be tapped using the technique of laparoscopic gastrectomy (GVL) in a follow short, medium and long term. METHOD: The study population are all people with morbid obesity and are candidates for surgery, presenting at Torrecardenas Bariatric Surgery Hospital (Almeria). The design is a descriptive, longitudinal study, prospective. RESULTS: After evaluation of the obese patients a year, two years and five years after surgery, there has been decrease in weight, therefore decrease in BMI and the degree of obesity, improvement or disappearance of comorbidities and increased CV variables. DISCUSSION: The GVL gets reduce excess weight and therefore BMI and the degree of obesity, as well as the number of obesity-associated diseases, thus increasing the CV. PMID- 25929373 TI - Modifiable environmental obesity risk factors among elementary school children in a Mexico-us border city. AB - BACKGROUND: The increasing overweight (OW) and obesity (OB) prevalence in Mexican children warrant the assessment of the environmental risk factors. OBJECTIVE: To assess whether there is an association between food availability in children's environments and their food consumption with BMI z-score and waist circumference (WC). METHODS: Six hundred and eighty four children, 264 parents, 22 teachers and cafeteria staff in the schools and street vendors participated in the study. Weight, height, and WC of 5(th) grade children were assessed. Food frequency, physical activity (PA) and eating habits questionnaires were applied to parents, children and teachers. A food inventory questionnaire was applied to parents, cafeteria staff in the schools, street vendors and stores near the schools. RESULTS: The children's mean age was 10.5. Twenty eight per cent of the children were overweight, 26% obese and 25% had abdominal obesity. A positive correlation was found between energy-dense foods (EDF), fruit and vegetable availability at home and their weekly consumption. Also a correlation between consumption of soft drinks and other EDF was found. The largest contributors to food consumption were the availability at home and at school (R2 = 0.11, p = 0.0001). Children's TV viewing was positively correlated with parents TV viewing time. For each hour of increase (from cero to seven) in daily TV viewing children were more likely to be overweight or obese (OR=1.22 95% CI 1.02-1.45, p=0.026). CONCLUSION: EDF, fruit and vegetable availability in and near home and school along with hours of TV viewing were positively associated with obesity. PMID- 25929374 TI - Dietary potential renal Acid load in venezuelan children. AB - OBJECTIVE: Our aim was to determine and analyze the dietary PRAL and food composition pattern in apparently healthy children from 1 to 6 years of age. METHODS: Parents of 52 children were selected by convenience, in an outpatient clinic of healthy children. Dietary quality and pattern was assessed by 24 hour recall and food frequency questionnaire. We focused on the intake of macronutrients and food groups, such as meats, dairy, fruits and vegetables. Nutrient intake was compared with national and international recommendations. PRAL was determined according to the method described by Remer and Manz. Descriptive statistics and correlations were applied. RESULTS: Dietary intake of proteins, milk and meat was high, while fruits and vegetables intake was low. PRAL was positive in 92% of the children and correlated (p<0.05) with intake of energy, proteins, fat, meat and dairy products. Protein intake was above 2.5 g/kg/day in 46.2% of the children. Food groups with the highest unbalance were meat and dairy products for excessive intake and fruits and vegetables regarding low intake, both of which represent risk factors for endogenous acid production. CONCLUSION: The diet of the children studied was characterized by an excessive acid load with the risk for the generation of systemic acidosis and its metabolic consequences. PMID- 25929375 TI - Energy expenditure in children with cerebral palsy and moderate / severe malnutrition during nutritional recovery. AB - OBJECTIVE: To analyze the total energy expenditure (TEE) and resting energy expenditure (REE) in children with cerebral palsy (CP) and moderate or severe malnutrition during nutritional recovery. METHODS: In an intervention study, thirteen subjects with CP (10 females and 3 males with a mean age of 9y11m +/- 2y3m), level V of the Gross Motor Function Classification System and moderate or severe malnutrition were included. Eight were fed by nasogastric tube and five by gastrostomy. They were compared with 57 healthy participants (31 females and 26 males with mean age of 8y7m +/- 10m). Anthropometric measurements, body composition and energy expenditure by bioelectrical impedance analysis (BIA) and indirect calorimetry (IC) were performed in both groups. RESULTS: TEE and REE were higher in healthy children than in children with CP in kcal/d and kcal/cm/d but were lower in kcal/kg/d (p <0.001). Intensive nutritional support for four weeks in children with CP produced a significant increase in energy expenditure. CONCLUSION: TEE and REE, in children with CP, are lower than in healthy children. Estimating the REE in children with CP and malnutrition is better performed in kcal/kg/d than in kcal/cm/d. Fat-free mass (FFM) is a good predictor of the REE in healthy children and children with CP. PMID- 25929376 TI - [Exposition to drugs of abuse in pregnancy and breastfed babies growth in CONIN Valparaiso, Chile]. AB - INTRODUCTION: Consequences related to drugs exposure during fetal life have been extensively studied. The present work explores the Chilean situation about this matter, characterizing growth of infants previously exposed to drugs during fetal life. OBJECTIVES: Compare anthropometric measurements between neonates exposed to drugs due to maternal consumption during pregnancy and an unexposed control group from 0 -6 months of life. METHODOLOGY: Anthropometric data from 74 control infants from a Health Center in Valparaiso, Chile, and 61 infants exposed to drugs during gestation from the Corporation for Infant Nutrition (CONIN, Valparaiso, Chile) were obtained. Data obtained from both groups were subjected to a T-Student statistical analysis by group. RESULTS: According to gestational age there were more pre-term infants in CONIN-exposed group, reaching more than 25 % prevalence. On the contrary, prevalence in unexposed control infants was less than 11 %. In addition, CONIN group showed a higher number of small for gestational age infants of both sex (37% CONIN vs 6% Control), evaluated according to the Chilean intrauterine growth curves. Length and weight showed statistical significant differences between both groups from birth to 6 months of life. Female infants showed significant differences in cephalic circumference until one month of life, while in male infants this difference is maintained until 6 month of life. Z score for indicators such as weight/ length, weight/age and length/age during first 6 months of life, leads to conclude that CONIN group is at risk of undernutrition while control group should be considered as normal. CONCLUSIONS: Maternal drugs consumption during pregnancy results in marked deficient anthropometric characteristics of newborn and until 6 month of life. This fact may have metabolic long term consequences associated to development of chronic non-communicable diseases during adulthood. PMID- 25929377 TI - [Dyslipidemias in school-age chilean children: prevalence and associated factors]. AB - INTRODUCTION: Dyslipidemias are a key cardiovascular risk factor, and are increased since early childhood. The objective of this study was to describe the prevalence, characteristics of dyslipidemias and associated factors in a population of Chilean children. METHODS: Cross-sectional study done in school-age children from Santiago, Chile (2009-2011). Parents answered questions about family medical history and children answered questions about physical activity. Anthropometry was performed and in a blood sample (12 hours fast) lipid profile, glycemia and insulinemia were measured. RESULTS: We recruited 2900 euglycemic children, 11.4 +/- 0.97 years old, 52% girls. According to BMI, 22.5% were overweight and 15,3% had obesity. Considering recommended cut-off points for lipids, 69.3% were in acceptable range, 19.2% at risk and 11.5% at high cardiovascular risk. In total, 32% of the population had any clinical form of dyslipidemia: Isolated hypertriglyceridemia (9.4%), low HDL-C (7.6%), isolated hypercholesterolemia (4.9%), atherogenic dyslipidemia (6.24%) and mixed dyslipidemia (3.9%). Except for isolated hypercholesterolemia, dyslipidemias were more frequent in girls (globally 36.2% vs. 27.4%, p<0.0001). Low HDL-C was associated with sedentary lifestyle. In multiple logistic regression analysis, nutritional status was the most important associated factor, with less influence of age, sex, central obesity, insulin resistance and history of parental cardiovascular risk factors. CONCLUSIONS: In this population of Chilean school age children, we found a high prevalence of dyslipidemia, and the principal determinant was weight excess. PMID- 25929378 TI - [Association between dietary habits and the presence of overweight/obesity in a sample of 21,385 chilean adolescents]. AB - AIM: The main aim of the present study was to explore the potential associations between dietary habits and the presence of overweight and obesity in Chilean adolescents. METHODS: For the present study dietary habits of 21,385 Chilean students were analyzed and weight and height assessed, in order to determine potential associations between eating patterns and body mass index (BMI) values. RESULTS: The majority of participants have lunch and a snack in the afternoon every day a week (81% and 71.2%, respectively), although only a 59.5% have breakfast every day and a 22% have dinner every night. To have breakfast is common for thin and normal weight subjects, but only a half of overweight and obese individuals usually have it. The obese is the group having less dairy products. A 50.2% of all subjects have legumes once or never in a week. Around a 15% have sweets all days and nearly a 50% of all the participants consume fizzy drinks every day of the week. Interestingly, having breakfast was found to be associated with less truancy. CONCLUSIONS: Nutritional education strategies should be carried out within students in Chile, since inadequate dietary habits are related to the higher values of BMI. PMID- 25929379 TI - [Subclinical hypothyroidism and cardiovascular risk]. AB - OBJECTIVE: To assess whether subclinical hypothyroidism can behave as a cardiovascular risk factor or a modifier thereof, identifying epidemiological variables and estimated in a sample of patients diagnosed in the province of Albacete (Spain) cardiovascular risk. METHODOLOGY: Observational, descriptive study was carried out in Albacete during the first half of January 2012 in patients of both genders with subclinical hypothyroidism. The following variables were analyzed: Fasting glucose , total cholesterol , HDL cholesterol, LDL cholesterol , triglycerides , TSH , T4 , weight, height, Body Mass Index , blood pressure, a history of cardiovascular disease , cardiovascular risk factors and estimated cardiovascular risk. RESULTS: 326 patients younger than 65 years at 78% without cardiovascular risk factors in 48.61 %, with female predominance (79.2 %). The prevalence of cardiovascular risk factors was identified: smoking (33.2 %), diabetes mellitus (24.9%), hypertension (23.4 %), lipid abnormalities (28.9%) and atrial fibrillation (4,9%). No association between subclinical hypothyroidism and most lipid profile parameters that determine a pro- atherogenic profile, except with hypertriglyceridemia was found. Likewise, neither association with increased cardiovascular risk was found. DISCUSSION: The profile of patients with subclinical hypothyroidism is a middle-aged woman with no cardiovascular risk factors in half of cases. It has been found relationship between subclinical hypothyroidism and hypertriglyceridemia, but not with the other parameters of lipid profile, other cardiovascular risk factors or with increased risk. However, 25% of diabetics and 22% of non-diabetics are at moderate to high cardiovascular risk. PMID- 25929380 TI - [Behavior of blood glucose level with the administration of micronutrients vitamin d3 and calcium in nondiabetic patients with hyperglycemia in adult intensive care unit]. AB - Hyperglycemia without previous history of diabetes mellitus (DM) is observed in a high percentage of patients in intensive care units (ICU). OBJECTIVE: To determine the behavior of glycemia in nondiabetic patients with hyperglycemia by administering two micronutrients. METHODS: A clinical trial was conducted in 32 patients, 16 in the intervention group and 16 in the control group. To the intervention group was given, since the admission, the micronutrients vitamin D3 in doses of 1.000 international units (IU) and calcium in doses 1.000 mg every 24 hours, for a period of 72 hours. RESULTS: No significant differences were observed in blood glucose income between the intervention and control groups (152,6 and 153,3 mg / dl, respectively p = 0,922), but after 72 hours the behavior of the glycemia decreased significantly in the intervention group compared to the control group (98,41 and 141,6 mg / dl respectively p 100 mg/ dl), showing that 2,29 patients should be treated to decrease an undesirable event (NNT). CONCLUSION: The use of the analyzed micronutrients in critically ill patients with no previous diagnosis of diabetes requires more research that addresses te limitations posed here. Due to the limited literature found about similar studies, this investigation would provide another alternative for reducing hyperglycemia in these patients. PMID- 25929381 TI - [Systolic pressure, abdominal obesity and body fat, metabolic syndrome predictors in Spanish preschoolers]. AB - OBJECTIVE: The aim of this paper is to determine the presence of metabolic syndrome predictors in 2-to-7- year-old children according to nutrition state. METHOD: A descriptive study with quantitative analysis was conducted in 260 2-to 7-year-old children (135 girls and 125 boys), 66% of the total census. Anthropometric parameters and blood pressure were measured and BMI, body fat by Hoffman and waist-to-height ratio (ICT) were calculated. Subgroups according BMI Z-Score by age and gender (low weight, normal weight, overweight and obesity), body fat (normal and excess), ICT (normal and abdominal obesity) and systolic pressure (normotensive and hypertensive by age and gender) were performed. BMI Z Score classification was primary endpoint used. RESULTS: Combined prevalence of overweight and obesity was 27%, with no difference by sex. Nutritional state was significantly associated with blood pressure, body fat and abdominal obesity as waist-to-height ratio. Higher percentage of obese children had high systolic blood pressure versus normal weight children (OR = 4.1; 95% CI 1.7-9.8; p <0.001). Higher hypertension risk was found in abdominal obesity group (OR = 84.4, 95% CI 17.8-194.0; p <0.001). ICT correlates with groups of systolic blood pressure (p <0.001). Distribution by ICT is consistent with the BMI Z-Score ones, increasing abdominal obesity with BMI (in 96.8% of obese match both criteria). CONCLUSION: A direct relation between overweight and obesity with hypertension, body fat and abdominal obesity in preschoolers is presented. It is showed the validity of accessible anthropometric (ICT and body fat percentage) to study metabolic syndrome risk factors. PMID- 25929382 TI - Waist-to-height ratio (WHtR) and triglyceride to HDL-C ratio (TG/HDL-c) as predictors of cardiometabolic risk. AB - INTRODUCTION: The excessive concentration of fat in the abdominal region is related to a higher risk of developing cardiovascular disease (CVD). Studies have been performed to identify simple and effective indicators of abdominal obesity and associated cardiometabolic risk through the use of simple parameters such as anthropometric and biochemical measures. The Triglyceride / High-density Lipoprotein Cholesterol (TG/HDL-c) has been proposed as a more practical and easy to use atherogenic marker, along with the Waist-to-Height Ratio (WHtR), which makes a superior tool for separating cardiometabolic risk related to overweight/obesity when comparing to Body Mass Index (BMI). OBJECTIVE: To verify the applicability of the WHtR and the TG/HDL-c ratio as predictors of cardiometabolic risk. METHODS: This cross-sectional study was performed at the Department of Nutrition of the UNIVATES University Center, where the participant's anthropometric and biochemical data were collected. Statistical analysis was performed by the Statistical Package for the Social Sciences software (SPSS) 20.0, with a significance level of 5% (p < 0.05). RESULTS: A total of 498 individuals took part on this research, 77.5% female and with a mean age of 25.5 +/- 6.5. A high percentage of fat was found in both men and women (19.9 +/- 5.80% and 29.24 +/- 5.43%, respectively). The prevalence of overweight/obesity (BMI >= 25Kg/m(2)) was 35.05%. The WHtR marker was significantly correlated to Low-density Lipoprotein Cholesterol (LDL-c), Triglyceride (TG) and Anthropometric BMI values, waist circumference (WC) and body fat percentage (BF%). For the TG/HDL-c ratio, there was a positive and significant correlation to the same markers, beyond TC. There was also a correlation between WHtR and TG/HDL-c, and both presented a negative and significant correlation with HDL-c. CONCLUSION: WHtR and TG/HDL-c values were found to be good markers for the cardiometabolic risk ratio in the studied sample. Several studies, original articles and academic reviews confirm the use of the WHtR or TG/HDL-c markers for that purpose in adults. PMID- 25929383 TI - Microbiological quality of enteral feeding and infant formula produced in dietary units, according to the triad of Donabedian. AB - INTRODUCTION AND AIMS: Microbial contamination of enteral feeding and infant formulas can result in a risk of worsening of the clinical condition of the patients, who are already weakened and susceptible to pathogens. The objective was to evaluate aspects of the management of quality hygienic - sanitary of enteral feeding and infant formulas in hospitals, focusing on the structure, process and outcome. METHODS: An observational, descriptive, prospective, with quantitative and qualitative variables study was done. The survey was conducted for 12 months and 227 samples of enteral feeding and 176 of infant formula were collected in Nutrition and Dietetic Services of Health Secretary / Federal District. In evaluating the operating conditions, the Tool 2 was applied to: Enteral Nutrition Preparation. Data were analyzed from the unified Donabedian's triad for evaluation of health services. RESULTS: The results obtained with the Tool 2 demonstrated that the Storage Block complies with legal requirements. Moreover, Dressing Block is a risk factor for the contamination. From the 403 samples, 56% corresponded to samples of Enteral Nutrition and 44% to samples of Infant Formulas. The data indicate that from 227 samples of Enteral Nutrition, 6.2% were in disagreement with the legislation, while from 176 samples of Infant Formulas, 4.6% were also in disagreement with the legislation. CONCLUSION: The ineffective implementation of the sanitary and hygienic requirements during the preparation results in a microbiologically unsafe product to patients in debilitated health state, and the count of mesophilic microorganisms can be a good indicator of microbiological safety. PMID- 25929384 TI - [Lipid - lowering effect of mate tea intake in dyslipidemic subjects]. AB - INTRODUCTION: Mate is the national infusion of Argentina and its properties on human health have not been fully elucidated. OBJECTIVE: To evaluate changes in lipid profile in dyslipidemic patients supplemented with yerba mate. METHODS: 121 dyslipidemic subjects (total cholesterol (TC), LDL cholesterol (LDLC) cholesterol and / or triglycerides (TG) elevated) without lipid-lowering therapy, both sexes (74 women and 47 men) between 40 and 60 years old were studied. After six weeks of mate abstinence, lipid profile and atherogenic index (AI), body composition by anthropometry and recent intake of energy, nutrients and food groups by food frequency questionnaire were analyzed. Daily consumption of mate prepared with 50 g or 100 g of yerba mate was indicated, plus the instruction not to alter eating habits, smoking, medication or exercise. All determinations were repeated after six and twelve weeks. Statistical analysis was performed using Student's T test for paired samples or Wilcoxon test according to normality of the variables (p <0.05). RESULTS: At the end of twelve weeks, TC fell 9.49% (21.66 mg/dL), LDLC fell 11.95% (17.96 mg/dL) HDLC fell 3.34% (1.65 mg/dL) and AI dropped 6.58% (0.31 points), p <0.001 for all cases. TG decreased 7.02% (10.74 mg/dl; p = 0.029) only in 50 g yerba mate consumers. Anthropometric and nutritional variables did not change significantly. CONCLUSIONS: Daily consumption of mate produces a time dependent decrease in TC and its fractions in dyslipidemic subjects. PMID- 25929385 TI - Dietary intake of ain-93 standard diet induces Fatty liver with altered hepatic fatty acid profile in Wistar rats. AB - BACKGROUND: There are several standard diets for animals used in scientific research, usually conceived by scientific institutions. The AIN-93 diet is widely used, but there are some reports of fatty liver in Wistar rats fed this diet. OBJECTIVE: We aimed to evaluate the hepatic repercussions of the AIN-93 diet intake in Wistar rats. METHODS: Forty newly-weaned 21-day-old male Wistar rats were fed either the AIN-93 diet or a commercial diet for either 1 month or 4 months. Weight gain, serum biochemistry, hepatic histology, and hepatic fatty acid profile were analyzed. RESULTS: Hepatic steatosis was observed, especially in the group fed the AIN-93 diet. Serum blood glucose, absolute and relative liver weight and hepatic levels of oleic, palmitoleic, stearic, and palmitic fatty acids were related to the observed steatosis, while lipidogram and serum markers of liver function and injury were not. CONCLUSION: AIN-93 diet induced acute hepatic steatosis in Wistar rats, which may compromise its use as a standard diet for experimental studies with rodents. The hepatic fatty acid profile was associated with steatosis, with possible implications for disease prognosis. PMID- 25929386 TI - Impact of a high-fat diet containing canola or soybean oil on body development and bone; parameters in adult male rats. AB - INTRODUCTION: The role of the fatty acid in the prevention or progression of chronic diseases has generated significant interest on the part of researchers. Thus, our objective was to evaluate the long-term effects of high-fat diet containing soybean or canola oil on body development and bone parameters of male rats. METHODS: After weaning, rats were grouped and fed either a control diet (7S) or a high-fat diet containing soybean (19S) or canola oil (19C). Femur and lumbar vertebra (LV4) structure were determined at 180 days by dual-energy X-ray absorptiometry and computed tomography. RESULTS: The groups showed similar food intake, body mass and length development. The bone parameters of the 19C were similar to the control group, while the 19S showed lower bone parameters when compared to the other groups. CONCLUSIONS: The high-fat diet containing soybean oil was unfavorable to bone structure, while the canola oil contributed bone health during the adult stage of life. PMID- 25929387 TI - Sarcopenia in community-dwelling persons over 60 years of age from a northern spanish city: relationship between diagnostic criteria and association with the functional performance. AB - INTRODUCTION: Sarcopenia is a recognized problem in older people. Currently, its diagnosis goes beyond a simple loss of muscle mass. The aim of this study was to determine the frequency of sarcopenia, defined by the European Working Group on Sarcopenia in Older People (EWGSOP), in independent persons over 60 years of age from a northern Spanish city. In addition, this study compared the diagnostic criteria for sarcopenia and assessed the differences in functional performance according to them. METHODS: A cross-sectional study was carried out on 258 members of community centers of both genders. Body composition was assessed with dual-energy X-ray absorptiometry. Appendicular lean mass index (App LMI), hand grip strength (HGS), and 8 foot up-and-go test (8f-UG) were used to diagnose sarcopenia. RESULTS: The frequency of sarcopenia was 2.4% (n=6). In women, the App LMI was correlated with HGS (r= 0.164, p<0.05) and 8f-UG (r= -0.167, p<0.05), while in men, the App LMI was correlated with HGS (r=0.241, p<0.05) but not with 8f-UG (r= -0.173, p=0.117). The subjects with low HGS and low performance in the 8f-UG presented lower values in other functional outcomes than people with low App LMI (p<0.05). CONCLUSIONS: Using the EWGSOP definition, the frequency of sarcopenia was low in a group of individuals over 60 years of age from a northern Spanish city. In clinical practice, greater emphasis should be placed on the decrease in muscle strength and functional performance rather than on low muscle mass alone. PMID- 25929388 TI - Oral physiology and quality of life in cancer patients. AB - INTRODUCTION: Cancer treatment can affect the health of the teeth and support structures, which are essential to the chewing process, which may change the nutritional status of the patient. OBJECTIVE: The aim of this study was to evaluate the impact of oral physiology changes on quality of life (QoL) of patients submitted to cancer treatment. DESIGN: Initially 84 cancer patients were screened and only those presenting at least 15 natural teeth were selected for oral physiology and quality of life tests. The final sample comprised 30 patients. Twenty subjects were selected as controls paired by age and gender. Dental caries status, salivary flow, masticatory performance (MP), location of tumor, duration of chemo and radiotherapy and World Health Organization Quality of Life (WHOQOL- bref) questionnaire were assessed. Linear regression models were used to test the relationship between the WHOQOL-bref domains (physical, psychological, social relationship, environmental and overall QoL) and independent variables under study. RESULTS AND DISCUSSION: Number of teeth, MP and salivary flow were lower in cancer patients, as well as for the scores obtained in Social Relationship, Environment and Overall QoL domains (p<0.050). Breast cancer caused a negative impact on Psychological (p<0.001) and Overall QoL scores (p=0.017). A similar negative effect was found for the duration of radiotherapy on Psychological (p=0.012) and Environmental (p=0.039) domains. On the other hand, the maintenance of teeth had a positive impact on Psychological (p=0.012) and Environmental (p=0.024) scores. CONCLUSION: Oral physiology changes may impact the QoL of oncological patients. The maintenance of teeth was of positive importance, especially for the psychological aspects. PMID- 25929389 TI - Subjective global assessment and prealbumin levels of esophageal cancer patients undergoing concurrent chemoradiotherapy. AB - AIMS: To evaluate the nutritional status of patients undergoing chemoradiotherapy for esophageal cancer using subjective global assessment (SGA) and association of prealbumin levels to nutritional status. METHODS: A prospective study was performed on 154 patients with esophageal cancer who were treated with concurrent chemoradiotherapy at center of radiation oncology in Huai'an First People's Hospital from January 2012 to May 2013. The patients' nutritional status after receiving concurrent chemoradiotherapy were evaluated using SGA tool. Serum total protein, prealbumin, albumin and other biochemical nutrition parameters including triglyceride, total cholesterol, cholesterol and glucose were determined before beginning and after the end of radiotherapy. RESULTS: Malnutrition developed in 129 (83.8%) patients. According to SGA results, 16.2%, 66.2%, and 17.6% of patients were classified as A, B, or C, respectively. Loss of subcutaneous fat or muscle wasting (odds ratio [OR] 11.522); increased metabolic demand/ stress (OR 8.637); ankle, sacral edema, or ascites (OR 3.229) and weight loss >=5% (OR 2.294) were significantly associated with malnutrition (SGA B or C; p < 0.001). Prealbumin level after the end of radiotherapy was significantly lower in patients with malnutrition (17 +/- 5 g/ dl vs. 21 +/- 5 g/dl, p = 0.005), but it showed no difference before beginning radiotherapy (24 +/- 4 g/dl vs. 22 +/- 5 g/ dl, p > 0.05). On the other hand, there was no significant difference in term of other nutrition parameters whether before beginning or after the end of radiotherapy (p > 0.05). CONCLUSIONS: The prevalence of malnutrition was high in esophageal cancer patients undergoing concurrent chemoradiotherapy. The results serve as a basis for implementation of nutrition intervention to patients being treated at radiotherapy departments. Prealbumin showed relation with SGA rating and should be considered as a sensitive nutritional biomarker for evaluating nutritional status of esophageal cancer patients undergoing concurrent chemoradiotherapy. PMID- 25929390 TI - Association between work shift and the practice of physical activity among workers of a poultry processing plant in Southern Brazil. AB - INTRODUCTION: The regular practice of physical activity (PA) has been associated with better health. In addition, job characteristics may determine the PA behaviours of employees, including the work shift. However, relatively few studies have examined the PA behaviour among shift workers. OBJECTIVE: This study aimed to investigate the association between work shift and the practice of PA among workers of a poultry processing plant in Southern Brazil. METHODS: A cross sectional study was conducted with 1206 workers (786 females), ages 18 to 50, working in shifts on a production line that operates 24 hours/day. Workers who engaged in more than 150 minutes/week of PA were considered active. Multivariate analyses were conducted using Poisson regression and all analyses were stratified by gender. RESULTS: Of the total participants studied, 36% (95%CI: 33-39) were considered active and the sociodemographic characteristics associated with PA differed among males and females. Regarding work shift, night shift workers had higher prevalence of PA. However, increased PA was significantly associated with work shift particularly among females. After controlling for potential confounders, women who worked during the night shift were approximately 30% more active than those who worked during the day (PR[prevalence ratio]= 1.32;95%CI: 1.07-1.62;p=0.010). CONCLUSIONS: This study found a low prevalence of PA among the workers and indicated a significantly association between work shift and PA. Working at night was positively associated with regular PA, particularly among females. These results contribute for initiatives that aim to increase PA among the workers, take into account the job characteristics and gender differences. PMID- 25929391 TI - Blood lipid profile and glucose of university students (China). AB - OBJECTIVE: The main objective of this study was to estimate the blood glucose and blood lipid profile of students in a university in China. METHODS: This descriptive study was based on the health screening data for university students in 2013. The blood glucose (GLU), lipid profiles (total cholesterol (TC), triglyceride (TG, and high density lipoprotein (HDL-C)) was measured by using Hitachi model 747 automatic analyzer. The LDL cholesterol values were calculated according to the formula: LDL-C = TC-HDLC- TG/5. RESULTS: The mean of HDL was 51.31 and 56.30 mg/dL for male and female, respectively (p<0.05). The majority of students have normal level of GLU (65-110 mgl/dL). Elevated TC and LDL were observed in 6.92% and 5.82 % of male, similarly, 5.91%and 3.57% of female. High levels of TC, LDL and TG in male university students were 1.02%,0.71% and 1.41%, respectively; in female university students were 1.26%,1.04 and 0.68%, respectively. Reduced levels of HDL were observed in 5.59% of male and 2.62% of female. CONCLUSION: The study shows that the prevalence of blood glucose and blood lipid in university students, especially reduced levels of HDL and elevated TC and LDL in university students has become a critical health issue. Relevant department of school and government should pay more attention to students' physical health. PMID- 25929392 TI - [Performance of entero-insular axis in an athletic population: diet and exercise influence]. AB - INTRODUCTION: The relationship between physical exercise and appetite regulation can lead to improved competitive performance of athletes. Mediators of the entero insular axis generate neurohumoral signals that influence on the appetite regulation and energy homeostasis. AIM: Determine the influence of diet and prolonged exercise on intestinal peptide, ghrelin, resistin, leptin, and incretins (GLP-1 and GIP) in an athlete population. METHODS: It is a prospective intervention study, conducted from October 2012 to March 2013. 32 healthy semiprofessional rugby players, aged 13-39 years were included. Anthropometric measurements and blood samples were taken at time 0 and after six months of study. Athletes were randomized to a protein diet (PD) or Mediterranean diet (MD) and plasma levels of intestinal peptide, ghrelin, resistin, leptin, and incretins were calculated. RESULTS: In the PD group, GLP-1 and GIP plasmatic levels showed a significant decrease (p <0.03; p <0.01 respectively). GLP-1 and ghrelin plasmatic concentration demonstrated a significant decrease (p <0.03 respectively) in those who experienced gain of muscle mass (MM). Finally, the athletes related to the PD who showed increased total weight and muscle mass presented significantly decreased GLP-1 concentration (p <0.03 and p<0.002, respectively). CONCLUSION: GLP-1 plasmatic concentration was decreased, with the PD suggesting to be more beneficial for the athletes in order to avoid hypoglycemia. Furthermore, muscle mass and total weight gain, linked to the PD, could enhance athletic performance in certain sport modalities. PMID- 25929393 TI - Compliance of physical activity guidelines by chilean low-income children: difference between school and weekend days and nutritional status. AB - The main objectives of this study were to compare in 6-9 y Chilean low-income children, daily minutes of moderate/ vigorous physical activity (MVPA) and compliance of the guideline of 60 min of daily MVPA on weekdays versus weekends, by sex and nutritional status (NS). The sample included 250 children (139 boys). Weight and height were measured; MVPA was assessed with NL1000 pedometers during 7 days. The sample was categorized into normal-weight (N) and overweight (OW) according to BMI z score (WHO reference 2007). Comparisons between weekdays and weekends included: a) MVPA by sex, using t-test b) MVPA of N and OW by sex, using ANOVA c) Compliance of guideline by sex and NS, using test of proportions. 66% of the children were OW, accumulating significantly more MVPA on weekdays, 50.5 min versus 40.3; boys more than girls; this result was similar by NS, except for N girls who spent similarly on weekdays as on weekends. Only 33 % boys and 15% girls (p= 0.03) and 17 and 9% (p=0.058) met the guideline on weekdays and weekends respectively, similarly by NS. A very small proportion of children met the MVPA guideline; adopting an active lifestyle is key, considering their high overweight prevalence. PMID- 25929394 TI - The relationship between obesity and forced vital capacity among university students. AB - OBJECTIVE: We sought to explore the relationship between vital capacity and obesity among university students in China. METHODS: A cross-sectional study was designed to collect the routine health screening data for university students in 2013. The height, weight and force vital capacity of students were measured, and BMI was calculated with height and weight, so as to estimate the relationship between force vital capacity and obesity. RESULTS: Based on Working Group on Obesity references in China, obesity has a higher force vital capacity in both male and female university students. No correlation was found between vital capacity and BMI. CONCLUSION: obesity may have effect on pulmonary function among university students, which is a reference for further epidemic study. PMID- 25929395 TI - [Reliability of a questionnaire to assess physical activity in normal weight adolescents and overweight]. AB - INTRODUCTION: In recent years it has reported high levels of obesity associated with low levels of physical activity, which shows the need for assessment as elements of health and quality of life. OBJECTIVE: To verify the ability of reproducibility of a PA questionnaire in school adolescents classified as normal weight, overweight and obese. MATERIAL AND METHODS: A descriptive cross-sectional study was conducted in 1306 adolescent students (562 men and 744 women) from three municipal educational institutions of the province of Talca (Chile). The age range was from 12.0 to 17.9 years. Weight and height were assessed and body mass index was calculated. Cutoff points used CDC-2000 for nutritional classification categories (normal weight, overweight and obesity) was used. A survey of physical activity was applied to the three groups studied. RESULTS: 388 men and 533 women with normal weight were identified, 131 men and 169 overweight women, 43 men and 42 women with obesity. Both sexes showed high Cronbach alpha reliability values. In men (0.80 with normal weight, overweight 0.77 and 0.83 with obesity) and women (0.79 with normal weight, overweight 0.77 and 0.76 with obesity). CONCLUSION: The instrument used showed high reproducibility capacity in both normal weight adolescents, overweight and obesity. These results suggest everyday use in survey to assess the patterns of AF scale, regardless of nutritional status in which they are located. PMID- 25929396 TI - Giving a nutritional fast hug in the intensive care unit. AB - Implementing a nutrition support protocol in critical care is a complex and dynamic process that involves the use of evidence, education programs and constant monitoring. To facilitate this task we developed a mnemonic tool called the Nutritional FAST HUG (F: feeding, A: analgesia, S: stools, T: trace elements, H: head of bed, U: ulcers, G: glucose control) with a process also internally developed (both modified from the mnemonic proposed by Jean Louis Vincent) called MIAR (M: measure, I: interpret, A: act, R: reanalysis) showing an easy form to perform medical rounds at the intensive care unit using a systematic process. PMID- 25929397 TI - [Bioimpedance vector analysis as a tool for the determination and adjustment of dry weight in patients undergoing hemodialysis]. AB - BACKGROUND AND OBJECTIVE: Overhydration in hemodialysis patients is associated with cardiovascular mortality. Adequate removal of liquids and achievement of dry weight is one of the main goals of therapy. So far there are no clinical or laboratory parameters that are reliable, simple and affordable for its determination. The bioelectrical impedance vector analysis (BIVE) is a tool that allows identifying and monitoring hydration status, so the aim of this study was to use BIVE to adjust the intensity of ultrafiltration and achieve dry weight in hemodialysis patients. METHODS: We studied 26 patients on hemodialysis, which were performed monthly measurements of bioelectrical impedance for four months. Corresponding vectors were plotted to know in an individual way the state of hydration, according to which the dry weight was adjusted when necessary. RESULTS: Dry weight adjustment was performed in 13 patients, 7 of which required increase and 6 decrease of dry weight. The displacement of vectors on the ellipses corresponded to the type of intervention made. Dry weight was reached in 84.6% of patients at the end of the study with a significant decrease in mean arterial blood pressure and an increase in phase angle in the group of decrease of dry weight. CONCLUSIONS: Bioelectrical impedance vector analysis is an useful tool for adjusting the dry weight in patients undergoing hemodialysis. PMID- 25929398 TI - [Diet quality in college students with different academic profile]. AB - INTRODUCTION: We can find in Spain several university studies concerning diet and lifestyle, showing them as an effective strategy to prevent chronic diseases. OBJECTIVES: To evaluate the energy and nutrient intake and adherence to the Mediterranean Diet (DM) in a group of college students with different academic profile and to compare the quality of the diet among students attending degrees in Health Science (HS) and those attending other degree courses (not HS). METHODS: 77 students (80.3% female) from the Campus of Soria, 37 HS students and 40 not HS (mean age 21.2 +/- 2.1 years), completed a questionnaire on socio biographical data, the test KIDMED of adhesion to Mediterranean diet and recorded food intake for seven days. The amount of energy and nutrients was estimated using the software Nutriber (version 1.1.1.3r). Student t test or U Mann-Whitney were used to compare means of independent samples and the criterion of significance was set at p <0,05. RESULTS AND DISCUSSION: The respondent students, regardless of their academic profile, follow a low calorie diet with more protein and fat consumption than the recommended amount, and less carbohydrate and fiber, which is reflected in the insufficient intake of some vitamins and minerals. However, we observed a higher percentage of respondents with high adhesion to the parameters of the DM in the HS group (51.4%) than in the No HS group (30.8%). PMID- 25929399 TI - [Efficacy and effectiveness of different nutritional screening tools in a tertiary hospital]. AB - INTRODUCTION: The high prevalence of malnutrition in hospitals and its impact make the use of a nutritional screening tool necessary for its detection, diagnosis and early treatment. OBJECTIVE: To evaluate the most appropriate tool for nutritional screening, globally and by hospital wards, in a tertiary hospital. METHODOLOGY: cross-sectional study in routine clinical practice. Four nutritional screening tools were evaluated: Subjective Global Assessment (SGA), Mini Nutritional Assessment (MNA), Malnutrition Universal Screening Tool (MUST), and Nutritional Risk Screening 2002 (NRS-2002). Hospital wards were grouped into: medical wards, General Surgery, Orthopedics, other surgical wards, and Oncology Hematology. A statistical analysis of sensitivity (S) and specificity (Sp) were performed, and were compared using ROC curve. RESULTS: There were evaluated 201 patients with median age of 71.6 (RIC 21.4) years and 51.2% were women. The prevalence of nutritional risk (NR) and malnutrition (MN) was: SGS 62.1%, 68.6% MNA, MUST 53.7%, and NRS-2002 35.8%. All the evaluated nutritional screening tools, except MNA, detected a higher prevalence of RN and DN in the medical wards than surgical wards. In the overall analysis the MNA obtained S=93.3%, Sp=71.6% and an area under the ROC curve of 0.825; the MUST obtained S=82.4%, Sp=93.4% and an area under the ROC curve of 0.879; NRS-2002 obtained S=56.0%, Sp=97.4% and an area under the ROC curve of 0.766. These results were similar in the analysis by hospital wards. CONCLUSION: MUST could be the recommended nutritional screening tool to use in a tertiary hospital with elderly population, as the overall good results of sensitivity and specificity, as well as its simplicity. PMID- 25929400 TI - [Consumption of fruits and its association with nutritional status in chilean university students career of physical education]. AB - INTRODUCTION: Chile is a country that reaches the highest levels of overweight and obesity worldwide (66.7% of the Chilean population), with a group of college students tending to swell these numbers considered nutritionally vulnerable group. OBJECTIVE: To associate the consumption of fruits with nutritional status of Chilean university students in physical education. METHODS: The study population consisted of all students of the School of Pedagogy in Physical Education from the Autonomous University of Chile, Temuco based (n = 420). The sample included 239 students (56.9%), men (76.5%) with a mean age of 21.5 +/- 2.1 years. Each student nutritional status was determined and applied a validated survey eating habits. RESULTS: An association between fruit consumption (>=2 servings / day) in the model crude OR = 0.528 (from 0.288 to 0.965), Model 1 adjusted OR = 0.496 (0.268 to 0.916) and Model 2 adjusted OR = 0.495 is observed (0.265 to 0.924) CONCLUSION: Consumption >= 2 servings a day of fruits is a protective factor for a good BMI Chilean university students in physical education. PMID- 25929401 TI - Body fat and its relationship with clustering of cardiovascular risk factors. AB - BACKGROUND: Body mass index (BMI) and waist circumference (WC) are the most commonly measured anthropometric parameters given their association with cardiovascular risk factors (RFs). The relationship between percentage body fat (%BF) and cardiovascular risk has not been extensively studied. AIMS: This study evaluated %BF and its relationship with cardiometabolic RFs in healthy subjects and compared these findings with the relationship between BMI/ WC and cardiovascular RFs. METHODS: This was a cross-sectional study of 99 males and 83 females (mean age 38 +/- 10 years) evaluated in a preventive cardiology program. All subjects completed a survey about RFs and lifestyle habits. Anthropometric parameters, systolic blood pressure (SBP), diastolic blood pressure (DBP), fasting lipid profile, and blood glucose were collected. Body fat was determined using four skinfold measurements. Fat mass index (FMI) was also calculated. RESULTS: Percentage body fat was significantly and directly associated with total cholesterol (R(2)=0.11), triglycerides (R(2)=0.14), low-density lipoprotein cholesterol (R(2)=0.16), non-high-density lipoprotein cholesterol (R(2)=0.24), fasting blood glucose (R(2)=0.16), SBP (R(2)=0.22), and DBP (R(2)=0.13) (p<0.001 for all) and inversely related to high-density lipoprotein cholesterol (R(2)=0.32; p<0.001). When the models of %BF, FMI, WC, and BMI were compared, all of them were significantly related to the same cardiometabolic RFs and the clustering of them. CONCLUSION: Percentage body fat and FMI were significantly associated with biochemical variables and to the clustering of RFs. However, these associations were similar but not better than WC and BMI. PMID- 25929402 TI - [Active interventions in hypercholesteroloemia patients with high cardivascular risk in primary care]. AB - INTRODUCTION: Hypercholesterolemia is a major modifiable risk factors for cardiovascular disease (CVD). Its reduction reduces morbidity and mortality from ischemic heart disease and CVD in general, primary prevention and secondary prevention especially. OBJECTIVE: To determine whether a notarized and intensive clinical practice can overcome inertia and achieve the therapeutic goal (OT) LDL C <100 mg / dL in high-risk patients attended in Primary Care (PC) in our country. METHODOLOGY: epidemiological, prospective, multicenter study conducted in centers of different ACs By AP consecutive sampling 310 patients at high cardiovascular risk (diabetic or established CVD) previously treated with statins, which did not reach the OT included c-LDL. RESULTS: The study subjects had a mean age of 65.2 years, of which 60.32% were male. The 41.64% had a previous EVC, acute myocardial infarction (20.33%), angina (16.07%), stroke / TIA (9.19%), arthropathy (5.25%), diabetes (70 , 87%), hypertension (71.01%), and abdominal obesity (69.62%). The 43.57% (95% CI: 37,21; 50,08) of patients who performed the 2nd visit (241) got the OT. 62.50% (95% CI: 55.68, 68.98) of those who took the 3rd (216) got the OT. Finally, 77.56% (95% CI: 72.13, 83.08) patients who performed the last visit (205) got the OT. Throughout the study there was a reduction in LDL-C levels from 135.6 mg / dL at baseline, 107.4 mg / dL in the 2nd visit, 97.3 mg / dL in the 3rd visit, up to 90.7 mg / dL at the final visit (p <0.0001) The increase in HDL-C from baseline (50.9 mg / dL) and final (53.6 mg / dL) was also significant (p = 0.013). CONCLUSIONS: The reassessment and intensification of treatment in patients at high cardiovascular risk treated in primary care, applying the indications of the guides, achieves the OT in more than three quarters of the previously uncontrolled within half a year. These results should encourage us to overcome the therapeutic inertia in the control of CVD by early and energetic performance against hypercholesterolemia. PMID- 25929403 TI - [Analysis of body image perception of university students in navarra]. AB - INTRODUCTION: Current models of beauty represent an extreme thinness in the women and a muscular body in the men. The body image perception will condition the search of ideal beauty through different behaviors and can be transform in eating disorders. The university students, with the changes typical of youth and university transition, are a vulnerable group. OBJECTIVE: The purpose of this study was to evaluate the body image perception of university students in Navarra. METHODS: The study included 1162 subjects of which 64.2% were female. Students asked for a self-managed questionnaire and they were weighted and heighted to calculate the body mass index (BMI). Their body image perception were obtained asking the students to select a picture, according to their perception which corresponded to their current body image from nine different silhouettes for men and women. Their BMI were calculated and compared with their perceived BMI. RESULTS: 43.03% of students, overestimated their body image (10.65% in males and 59.69% in females) and 10.20% of students underestimated it. 46.75% of students had concordance between BMI and body image perception. DISCUSSION: There were more cases the alterations in the body image perception in women. In general, women saw themselves as being fatter than really were while men saw themselves as being thinner than they really were. The results shown that the women were more worried about their weight and body image than the men. PMID- 25929404 TI - [Adherence to a mediterranean diet and sport performance in a elite female athletes futsal population]. AB - INTRODUCTION: Low energy intake may lead to the loss of muscle mass, menstrual dysfunction, increased risk of fatigue, injures and the need for prolonged recovery process. OBJECTIVES: 1) To analyse the adherence to the Mediterranean diet of a elite female athletes futsal population, 2) To analyse the relationship between the Dietary Mediterranean index, body composition and sport performance, and 3) To analyse if the differences in the index of adherence to the Mediterranean diet generates test differences in sports performance and body composition. METHODS: The adherence to a Mediterranean Diet, body composition test, isokinetic test, vertical jump test (CMJ and SJ), kicking ball, speed test and test Repeated Sprint Ability (RSA) was measured. RESULTS: we found that 7 out of 12 players (58.33%) showed a low index and 5 of the 12 players (41.67%) showed a means index. We found that 7 out of 12 players (58.33%) showed a low index and 5 of the 12 players (41.67%) below the optimum index. Moreover, this adhesion index did not correlate with the values of the body composition or athletic performance test. No significant differences between the players that scored below the optimal index with those with a low level of adhesion were observed. However, mass fat (%) correlated to the ability to repeat sprint. CONCLUSIONS: Low levels of adherence to the Mediterranean diet was observed in futsal players, the values shown in the KIDMED questionnaire did not correlate with the performance of the players nor body composition. PMID- 25929405 TI - [Prevalence of eating disorders in adolescents from Gran Canaria]. AB - OBJECTIVES: To assess the prevalence of eating disorders in Spanish students between 12 and 20 years old using standardized methods. MATERIAL AND METHODS: 1342 students were randomly selected from educational centers on Gran Canaria, Spain. We used a two phase cross sectional design which involved the screening (EAT-40 questionnaire at a cutoff score of 20) and a semi-structured interview (EDE). Sociodemographic variables and weight status were also evaluated. RESULTS: In 2013 we studied participants of 15 educational centers on Gran Canaria. In the first phase we found a prevalence of risk of 27.42% (33% of females, 20.6% of males). In the second phase, 538 participants agreed to proceed with clinical evaluation (285 at risk, high scorers; 253 selected sample not at risk). The overall prevalence of eating disorder was 4.11% (5.46% of females, 2.55% of males). Using DSM-IV-TR diagnostic criteria, the prevalence of anorexia nervosa was 0.19%, of bulimia nervosa 0.57% and of eating disorder not otherwise specified 3.34%. CONCLUSIONS: The prevalence of eating disorders diagnosis in Gran Canaria is similar than in the rest of Spain. However, the prevalence of risk of eating disorders in Gran Canaria is especially high considering data of other studies made in Spain and other countries. PMID- 25929406 TI - Purine nucleoside phosphorylase and the enzymatic antioxidant defense system in breast milk from women with different levels of arsenic exposure. AB - Purine nucleoside phosphorylase (PNP) is an ubiquitous enzyme which plays an important role in arsenic (As) detoxification. As is a toxic metalloid present in air, soil and water; is abundant in the environment and is readily transferred along the trophic chain, being found even in human breast milk. Milk is the main nutrient source for the growth and development of neonates. Information on breast milk synthesis and its potential defense mechanism against As toxicity is scarce. In this study, PNP and antioxidant enzymes activities, as well as glutathione (GSH) and total arsenic (TAs) concentrations, were quantified in breast milk samples. PNP, superoxide dismutase (SOD), catalase (CAT), glutathione S transferase (GST), glutathione peroxidase (GPx), glutathione reductase (GR) activities and GSH concentration were determined spectrophotometrically; TAs concentration ([TAs]) was measured by atomic absorption spectrometry. Data suggest an increase in PNP activity (median = 0.034 U mg protein-1) in the presence of TAs (median = 1.16 g L(-1)). To explain the possible association of PNP activity in breast milk with the activity of the antioxidant enzymes as well as with GSH and TAs concentrations, generalized linear models were built. In the adjusted model, GPx and GR activities showed a statistically significant (p<0.01) association with PNP activity. These results may suggest that PNP activity increases in the presence of TAs as part of the detoxification mechanism in breast milk. PMID- 25929407 TI - Magnesium in tap and bottled mineral water in Spain and its contribution to nutritional recommendations. AB - INTRODUCTION: An appropriate magnesium intake has proved to have beneficial effects on bone health, reduce insulin resistance and prevent atherosclerosis. OBJECTIVE: To determine the concentration of magnesium in drinking water and bottled mineral water in Spain and assess its daily contribution to dietary recommendations. METHODS: We used ion chromatography to analyse the magnesium concentrations of public drinking waters in a representative sample of 108 Spanish municipalities (supplying 21,290,707 potential individuals) and 109 natural mineral waters sold in Spain (97 Spanish and 12 imported). RESULTS: The water generally contained between 15 and 45 mg/L of magnesium, but in seven municipalities it contained over 45 mg/L. The average magnesium concentration of 97 brands of Spanish natural mineral water was 16.27 mg/L (range: 0.11-141.2 mg/L). Of these, 33 contained between 15 and 45 mg/L of magnesium and four contained over 45 mg/L. Of the 12 imported brands, 4 contained over 45 mg/L. Assuming water consumption is as recommended by the European Food Safety Agency, water containing 15 to 45 mg/L of magnesium provides between 9 and 76.5% of the recommended intake of magnesium for children aged one to thirteen, up to 25.7% in adolescents, between 7.5 and 25.7% for adults, and up to 27% for lactating women. Water with 60 mg/L of magnesium provides between 30 and 102% of the recommended dietary allowance, depending on the age of the individual. DISCUSSION: The consumption of public drinking water and natural mineral water in a third of Spanish cities can be regarded as an important supplementary source of magnesium. PMID- 25929408 TI - [The finut healthy lifestyles guide: beyond the food pyramid]. AB - The World Health Organization has proposed that health be promoted and protected through the development of an environment that enables sustainable actions at individual, community, national and global levels. Indeed, food-based dietary guidelines, i.e., food pyramids, have been developed in numerous countries to disseminate nutritional information to the general population. However, wider recommendations are needed, with information on an active, healthy lifestyle, not just healthy eating. The objective of the present work is to propose a three dimensional pyramid as a new strategy for promoting adequate nutrition and active healthy lifestyles in a sustainable way. Indeed, the Iberomerican Nutrition Foundation (FINUT) pyramid of healthy lifestyles has been designed as a tetrahedron, its three lateral faces corresponding to the binomials food and nutrition, physical activity and rest, and education and hygiene. Each lateral face is divided into two triangles. These faces show the following: 1. food-based guidelines and healthy eating habits as related to a sustainable environment; 2. recommendations for rest and physical activity and educational, social and cultural issues; 3. selected hygiene and educational guidelines that, in conjunction with the other two faces, would contribute to better health and provide measures to promote environmental sustainability. The new FINUT pyramid is addressed to the general population of all ages and should serve as a guide for living a healthy lifestyle within a defined social and cultural context. It includes an environmental and sustainability dimension providing measures that should contribute to the prevention of non-communicable chronic diseases. PMID- 25929409 TI - [Obesity and high health risk due to beberages consumption and obesity among high school students in mexico]. AB - The purpose of this study was to identify the consumption of beverages among high school Mexican students and to determine obesity (OB) and abdominal obesity (AB). Differences in range and calorie beverage consumption between gender and BMI categories were calculated with the Mann-Whitney test. We assessed 1,677 students 15 to 17 yo. The prevalence of OB and AO was 15% and 53% in men and 12% and 47% in women. The consumption of energy, sugary drinks, and alcohol in milliliters and kilocalories per week, was higher in men (p = 0.001). More than 70% of students consumed per day more than 25 g/day of sugar from beverages, and more than 38% consumed more than 50 g/day of sugar. This high risk food consumption warrants immediate intervention. PMID- 25929411 TI - [Need to assess statistical tools and impact of educational intervention in obese school]. PMID- 25929410 TI - 12-year old adolescent with super morbid obesity, treated with laparoscopic one anastomosis gastric bypass (LOAGB/BAGUA): A case report after 5-year follow-up. AB - The prevalence of morbid obesity among adolescents has being on the increased in the recent decades specifically in developed countries around the world. In Europe, Spain has the highest prevalence of obese adolescents with more than 18% of the population of children and adolescents. There is evidence that the only effective and permanent treatment for morbid obesity and the comorbidities is surgical treatment, however there exists many controversies about which treatment is the best for obese adolescents. We report a case of a 12 year old patient with super obesity (58.5 kg/m(2) of BMI) and metabolic syndrome who underwent LOAGB/BAGUA and monitored during the last 5 year. The patient after five years follow-up maintains a 22.4 kg/m(2) of BMI. We consider that LOAGB/ BAGUA could be an effective and safe procedure as a treatment of obesity and comorbidities as well, for adolescent patients. PMID- 25929412 TI - Obesity in Latin America: the need for a comprehensive approach. PMID- 25929413 TI - Can Epstein-Barr virus DNA load in nasopharyngeal brushings or whole blood predict recurrent nasopharyngeal carcinoma in a non-endemic region? A prospective nationwide study of the Dutch Head and Neck Oncology Cooperative Group. AB - This study estimated the value of quantitative measurements of EBV markers in the clinical management of nasopharyngeal carcinoma in a non-endemic area. The aim was to predict prognosis and detect recurrent and residual disease. In 72 patients, EBV DNA load in blood and nasopharyngeal brushes, and IgA VCA-p18 and EBNA1 in plasma were measured at different time points. At diagnosis and post treatment, a cut-off value was used for detecting disease [positive (PPV) and negative (NPV) predictive value]. The markers were correlated as a continuous variable with tumor stage, disease-free survival (DFS) and overall survival (OS). The Cox hazard ratio model assessed hazard ratios. At diagnosis, the markers were above the COV in 45, 92, 85 and 83 % of the patients, respectively. Post treatment, DNA load test in blood and brush had the best discriminating power (blood DNA load test: PPV 39 % and NPV 97 %, brush for local disease: PPV 75 % and NPV 99 %). Post-treatment, DNA load in blood was the best predictor for OS and DFS [hazard ratio 3.2 (95 % CI 1.51-3.5) and 2.3 (95 % CI 1.72-5.8)]. Assessing the EBV DNA load in blood has significant prognostic value, although the clinical value is for discussion. The EBV DNA load in the brush might improve early detection of local failures post-treatment. PMID- 25929414 TI - Evaluation of nasopharyngeal microbial flora and antibiogram and its relation to otitis media with effusion. AB - Acute otitis media and otitis media with effusion (OME) are the main causes of hearing impairment in children which require proper treatment, mainly antibiotic therapy. Patients whom were appropriate candidates for adenoidectomy were divided into two groups regarding the presence of middle ear effusion. Adenoid tissue specimens were cultured in both groups and the bacterial flora and anti-microbial resistance pattern were determined. 72 patients were studied, 42 % had OME while 58 % did not. The following bacteria were isolated and cultured from both groups with no meaningful difference in prevalence: Streptococcus viridans (p = 0.265), Staphylococcus aureus (p = 0.72), H. influenza (p = 0.806), Entrococcus. spp (0.391), Streptococcus pneumonia (p = 0.391), nonhemolytic Streptococcus (p = 0.230). Bacterial sensitivity was similar for Amoxicillin-clavulanate (p = 0.935), Amoxicillin (p = 0.935), Cephalexin (p = 0.806), Cefixime (p = 0.391) and Azithromycin in both groups. The two groups showed no meaningful difference considering the bacterial flora of nasopharynx and their sensitivity. Bacteria in both groups were sensitive to Amoxicillin and Amoxicillin-clavulanate and resistant to Azithromycin, Cefixime and Cephalexin. PMID- 25929415 TI - Disability perception in Meniere's disease: when, how much and why? AB - The purpose of the study was to evaluate self-perceived handicap in patients with definite Meniere's disease (MD). A cross-sectional study was conducted. To examine the self-perception of disability, participants completed a DHI (Dizziness Handicap Inventory). Parameters compared with DHI scores: sex, age, unilateral/bilateral affectation, time elapsed since the onset of symptoms, pure tone average (PTA), stages of MD, audiometric change (last 6 months), PTA in low frequencies (PTAl) and audiometric change in PTAl, subjective perception of fluctuating hearing threshold, tinnitus between attacks, number of vertiginous episodes (last 6 months), time elapsed since last attack, subjective perception of instability intercrises and Tumarkin attacks. 90 patients were included; they completed a total of 104 questionnaires. DHI scores ranged from 2 to 100 (average: 47.08, SD 24.45). In 29 cases (27.9 %) the disability perception was mild, in 43 (41.3 %) moderate, and in 32 (30.8 %) severe. Correlation between disability perception and some vestibular symptoms was found: number of typical attacks (last 6 months), time elapsed since last attack, instability intercrises and Tumarkin attacks. No relationship was found with the rest of variables. Disability perception in patients with MD depends primarily on vestibular symptoms (particularly, instability and frequency of attacks). So, we suggest to design a new staging system of MD taking into account both auditory criteria and also vestibular symptoms. PMID- 25929416 TI - Histological reassessment of the role of bridging fibrosis in the angioarchitectural features associated with lobular distortion of the liver in chronic viral hepatitis. AB - AIM: To reassess the role of bridging fibrosis in the lobular distortion of the liver from an angioarchitectural aspect. METHODS: Two tissue samples obtained from surgically resected livers with chronic hepatitis and one obtained from an autopsy case with chronic hepatitis were used for the three-dimensional observation of angioarchitecture by histological reconstruction. RESULTS: Samples showed bridging fibrosis with various degrees of severity, without cirrhotic changes. Two different types of portal-portal bridging fibrosis were found. In our samples, the type that developed in the bifurcation region of the portal tracts was more common than the type observed between the distal portions originating from different parent portal tracts. The angioarchitecture tended to be generally maintained in these lesions. Concerning portal-central bridging fibrosis, two types were observed. One type developed in the lesion with partial paucity of the third-step portal branches in the portal tract at a relatively early stage of chronic hepatitis. The other type developed in an advanced lesion with a complete loss of the normal angioarchitecture of the parenchymal portion of the portal veins. The former was likely developed after large-scale necrosis, such as bridging necrosis, while the latter was presumed to be attributable to portal vein damage associated with long standing chronic inflammation. CONCLUSION: As has been previously noted regarding lobular angioarchitecture, portal-central bridging fibrosis clearly affects the lobular structure of the liver more than portal-portal bridging fibrosis. Therefore, portal vein damage may be a critical event in the eventual distortion of the lobular structure. PMID- 25929417 TI - Segmental V-Y flaps for reconstruction of longitudinal defects in the digit. AB - Longitudinal defects of the finger that extend beyond 1 phalangeal segment such as wounds that expose the flexor tendon are challenging to reconstruct because of their elongated shape. We present the use of segmental V-Y flaps to reconstruct these defects. These are >=2 V-Y flaps orientated transversely and advanced segmentally to close the defect avoiding a linear scar. Nineteen patients had soft-tissue defects of the digits successfully reconstructed with segmental V-Y flaps in this retrospective case series. There were no total or partial flap failures and all flaps retained sensation. Segmental V-Y flaps are a safe method for reconstructing digital defects and are particularly useful in the reconstruction of longitudinal defects. They have the advantages of being homodigital, sensate, technically easy; allow direct closure of the donor site and break up linear defects that might otherwise lead to contractures. PMID- 25929418 TI - Triceps fascial tongue exposure for total elbow arthroplasty: surgical technique and case series. AB - During a posterior approach to the elbow, the triceps muscle body and tendon insertion must be addressed during exposure. Several methods exist including performing an olecranon osteotomy. The triceps fascial tongue exposure, originally described by Van Gorder in 1940, provides an excellent view of the joint while causing minimal trauma to the extensor mechanism facilitating tendon healing, and easy intraoperative conversion from fracture fixation to a total elbow arthroplasty if a fracture is not able to be reconstructed. Using a standard posterior approach to the elbow, a triceps tongue is created. A distally based flap of the triceps tendon approximately 10 cm long and 2 to 3 cm wide is created and a remnant of the tendon is kept on all sides to secure a meticulous repair with nonabsorbable figure-of-eight sutures at the conclusion of the case. In our case series, 29 patients underwent 30 total elbow arthroplasties. There were no triceps-related failures. This surgical technique is a useful alternative surgical exposure to the posterior elbow for fractures and arthroplasty. PMID- 25929419 TI - Infections caused by Fusobacterium in children: a 14-year single-center experience. AB - PURPOSE: This study aimed at reviewing our experience with infections caused by Fusobacterium in children. METHODS: A retrospective analysis of medical records of children admitted to Hadassah-Hebrew University Medical Center from 2000 to 2013, in whom Fusobacterium spp. was identified in any specimen. RESULTS: A total of 22 patients (males = 12) at a mean +/- SE age of 5 +/- 1 (range 1-17) years, were identified. The most common complication was abscess formation (n = 11, 50 %). Eight children (36.4 %) had intracranial complications, including brain abscess (n = 4), meningitis (n = 4) and cerebral sinus vein thrombosis (CSVT, n = 5). Seventeen children (77 %) had bacteremia. Primary site of infection was otogenic (n = 9), oropharyngeal (n = 7), respiratory (n = 2), sinuses (n = 2), intra-abdominal (n = 1) and mucositis (n = 1). Fourteen cases were caused by Fusobacterium necrophorum, including four cases with CSVT, 7/8 cases of mastoiditis, four of them with subperiosteal abscess formation; all four cases with meningitis and two brain abscesses. Fifteen (68 %) patients required surgical intervention and 3 (14 %) received anti-coagulation therapy. Excluding one patient with overwhelming sepsis with fatal outcome, all patients recovered. CONCLUSIONS: Fusobacterium infections in children can cause a diverse spectrum of disease and is associated with high rates of abscess formation and intracranial complications. Although Fusobacterium nucleatum is abundant in the oral cavity, F. necrophorum is the main pathogen that causes severe infections in healthy children. PMID- 25929420 TI - Alopecia syphilitica diffusa. PMID- 25929421 TI - Ertapenem usage in cancer patients with and without neutropenia: a report on 97 cases from a comprehensive cancer center. AB - PURPOSE: Ertapenem is being increasingly utilized in cancer patients, but published data regarding its usage are limited. Our objective was to describe the various indications for ertapenem therapy and its safety and efficacy in cancer patients. METHODS: We conducted a retrospective cohort study of cancer patients who received monotherapy with ertapenem for at least 72 h, between January 2007 and February 2013. RESULTS: Among 97 unique patients who received ertapenem monotherapy, the most common indications were: (1) To facilitate discharge from the hospital of stable patients still requiring antimicrobial therapy (46 %). (2) Primary therapy of various documented infections (bacteremia, pneumonia, urinary tract infection, skin and skin structure infection) with ertapenem (28 %). (3) De escalation from a different broad-spectrum agent or regimen to ertapenem within the hospital setting in patients not ready for discharge (25 %). The median age of the 97 patients studied was 59 years (range 9-87 years) with 52 % being men. Most patients had underlying hematologic malignancies (54 %), and 7 % were recipients of hematopoietic stem cell transplantation. Twenty-nine patients (30 %) were neutropenic, 26 % were diabetic, and 6 % had chronic lung disease. Primary ertapenem monotherapy was successful in all patients, de-escalation in 95.8 % of patients, and the strategy of discharge on outpatient therapy with ertapenem in 95.6 % of patients. Patients failing de-escalation or early discharge responded to alternative regimens. We documented no significant ertapenem associated toxicity or adverse events. CONCLUSIONS: Ertapenem appears to be safe and effective for several indications in cancer patients. PMID- 25929422 TI - Preventing postpartum haemorrhage-when guidelines fall short. PMID- 25929423 TI - A survey on the awareness and attitude of pharmacists and doctors towards the application of pharmacogenomics and its challenges in Qatar. AB - RATIONALE, AIMS AND OBJECTIVES: Pharmacists are expected to play an important role in applying pharmacogenomics discoveries to patient care. Despite the increased attention to genetic research in Qatar, clinicians' attitudes towards the application of pharmacogenomics are not yet explored. The aim of this study was to assess the awareness and attitude of pharmacists compared with doctors towards pharmacogenomics and its implications by submitting an electronic-based survey to all pharmacists and doctors currently working in a large medical corporation in Qatar. METHODS: A cross-sectional survey instrument was developed based on literature review. Eligible participants were pharmacists and doctors currently practicing in Hamad Medical Corporation hospitals in Qatar. The survey comprised questions on demographic and professional characteristics. It also evaluated the awareness, attitudes and challenges towards pharmacogenomics and its application. RESULTS: We collected 202 surveys, 108 (53.2%) of which were pharmacists and the remaining 94 (46.5%) were doctors. The overall participants' mean total awareness score percentage was low (39% +/- 22) and there were no difference between the mean score achieved by pharmacists and doctors. Pharmacists had significantly more positive attitudes than doctors towards: (i) taking the responsibility of applying pharmacogenomics to drug therapy selection, dosing and monitoring; (ii) perceiving a positive role of pharmacogenomics testing on the control of drug expenditure; and (iii) their willingness to participate in pharmacogenomics-related training sessions. Both pharmacists and doctors perceived lack of knowledge and guidelines as major challenges towards the application of pharmacogenomics in Qatar. CONCLUSION: Despite doctors' and pharmacists' low level of awareness towards pharmacogenomics, they both have positive attitudes towards the clinical implications of pharmacogenomics. Pharmacists are more motivated to learn about pharmacogenomics and are more willing to take initiatives in its clinical application and patient education. PMID- 25929424 TI - Vitamins and their derivatives in the prevention and treatment of metabolic syndrome diseases (diabetes). AB - A cluster of inter-related conditions such as central obesity, dyslipidemia, impaired glucose metabolism, and hypertension is referred to as Metabolic Syndrome, which is a risk factor for the development of type-2 diabetes. The micro- and macro-vascular complications of diabetes contribute to its morbidity and mortality. In addition to its calcitropic effect, vitamin D is a regulator of gene expression as well as cell proliferation and differentiation. Various cross sectional and longitudinal cohort studies have indicated a beneficial effect from vitamin D supplementation on the development of type-2 diabetes. Binding of retinol-bound retinol-binding protein to a membrane-binding protein suppresses insulin signaling. All-trans retinoic acid, a derivative of vitamin A, reverses these effects, resulting in increased insulin sensitivity, suppression of the phosphoenolpyruvate carboxy kinase (PEPCK) gene, and the induction of the glucokinase gene. Glucokinase and PEPCK are also regulated in opposite directions by the vitamin biotin, acting at the transcriptional level. Biotin also regulates the synthesis of insulin by the islet of Langerhans cells of the pancreas. The increase in advanced glycation end products (AGEs) is implicated in the initiation and progression of diabetes-associated microvascular diseases. Benfotiamine, a derivative of thiamine, and pyridoxamine, a vitamer of vitamin B6, both have anti-AGE properties, making them valuable therapeutic adjuvants in the treatment of diabetic complications. Thus, various vitamins and their derivatives have profound therapeutic potential in the prevention and treatment of type-2 diabetes. PMID- 25929425 TI - The pharmacology of vitamins and beyond. Part 1: Vitamin D. PMID- 25929426 TI - Risk of overall mortality and cardiovascular events in patients with type 2 diabetes on dual drug therapy including metformin: A large database study from the Cleveland Clinic. AB - BACKGROUND: The aim of the present study was to assess the risk of overall mortality, coronary artery disease (CAD), and congestive heart failure (CHF) in patients with type 2 diabetes mellitus (T2DM) treated with metformin (MF) and an additional antidiabetic agent. METHODS: A retrospective cohort study was conducted using an academic health center enterprise-wide electronic health record (EHR) system to identify 13,185 adult patients (>18 years) with T2DM from January 2008 to June 2013 and received a prescription for MF in combination with a sulfonylurea (SU; n = 9419), thiazolidinedione (TZD; n = 1846), dipeptidyl peptidase-4 inhibitor (DPP-4i; n = 1487), or a glucagon-like peptide-1 receptor agonist (GLP-1a; n = 433). Multivariate Cox models with propensity analysis were used to compare cohorts, with MF+SU serving as the comparator group. RESULTS: The mean (+/-SD) age was 60.6 +/- 12.6 years, with 54.6% male and 75.8% Caucasians. The median follow-up was 4 years. There were 1077 deaths, 1733 CAD events, and 528 CHF events in 55,100 person-years of follow-up. A higher risk of CHF was observed with MF+DPP-4i use (hazard ratio [HR] 1.104; 95% confidence interval [CI] 1.04-1.17; P = 0.001). A trend towards improved overall survival for users of MF+TZD (HR 0.86; 95% CI 0.74-1.0; P = 0.05) and MF+GLP-1a (HR 0.569; 95% CI 0.30-1.07; P = 0.08) was observed. No significant differences in the risk of CAD were identified. CONCLUSIONS: Consistent with recent studies, our results raise concern for an increased risk of CHF with use of DPP-4i. PMID- 25929427 TI - Attitudes and Beliefs of Working and Work-Disabled People with Chronic Pain Prescribed Long-Term Opioids. AB - OBJECTIVE: This study was designed to gain insight into the apparent contradiction between the perspectives of researchers and policy makers, who have questioned the efficacy and safety of chronic opioid therapy for non-cancer pain patients, and the patients themselves, who often indicate that the therapy has value. SUBJECTS: A convenience sample of 54 patients on chronic opioid therapy was studied. METHODS: Participants completed a questionnaire specifically designed for the study, and also several standard instruments that addressed functional interference, emotional functioning, and possible misuse of opioids. Their treating physicians rated the participants on the severity of their disability and the success of their opioid therapy. RESULTS: Although participants reported significant ongoing pain, they gave positive global ratings to their opioid therapy, and reported little concern about addiction or side effects of opioids. They strongly endorsed the beliefs that opioids helped them control their pain and allowed them to participate in important activities such as work. They expressed the belief that their pain would be severe if they did not have access to opioids, and reported negative experiences with tapering or discontinuing opioids in the past. Work-disabled participants reported higher levels of affective distress, catastrophizing, and functional interference than working participants, and were judged by their physicians to be relatively less successful in managing their pain. CONCLUSION: The results of this study suggest several tentative hypotheses about why patients on chronic opioid therapy value opioids, and identified several areas for systematic investigation in the future. PMID- 25929428 TI - Women with polycystic ovary syndrome have elevated serum concentrations of and altered GABA(A) receptor sensitivity to allopregnanolone. AB - OBJECTIVE: Several studies have reported that gamma-aminobutyric acid (GABA) ergic circuits are involved in the pathophysiology of polycystic ovary syndrome (PCOS). The progesterone metabolite allopregnanolone is a potent GABA(A) receptor-modulating steroid, and patients may have increased concentrations of allopregnanolone or altered GABAA receptor sensitivity. We investigated both of these possibilities in this study. PATIENTS: We enrolled 9 women with PCOS and 24 age-matched eumenorrhoeic controls, who were divided into two groups by body mass index (BMI) (16 normal weight and 8 overweight). MEASUREMENTS: We investigated the effects of allopregnanolone injection on GABA(A) receptor sensitivity in both groups of women. All women received a single intravenous dose of allopregnanolone (0.050 mg/kg). GABA(A) receptor sensitivity was assessed with the saccadic eye velocity (SEV) over 30 degrees (SEV30 degrees ), the SEV30 degrees /allopregnanolone concentration ([Allo]) ratio, and sedation, which were measured together with serum allopregnanolone at intervals for 180 min after injection. The controls were tested in the follicular phase of the menstrual cycle. RESULTS: Baseline allopregnanolone concentrations were higher in the PCOS women than in the normal-weight (P = 0.034) and overweight controls (P = 0.004). The allopregnanolone concentrations after injection were higher in the PCOS women (P = 0.006) and overweight controls (P = 0.037) than in the normal-weight controls. All groups showed a decline in the SEV30 degrees /[Allo] ratio after injection. Allopregnanolone had a smaller effect on the SEV30 degrees /[Allo] ratio in the overweight women (PCOS, P = 0.032; controls, P = 0.007) than in the normal-weight controls. The sedation score after allopregnanolone injection was lower in the PCOS patients than in the controls, but was not different between the two control groups. CONCLUSIONS: PCOS women had elevated baseline allopregnanolone concentrations compared with follicular-phase controls. All overweight women (PCOS and controls) were less sensitive to allopregnanolone than normal-weight controls. PMID- 25929429 TI - Development of chimeric candidate vaccine against HPV18: a proof of concept. AB - Human papillomaviruses (HPVs) are prerequisite for the development of cervical cancer, with HPV16 and HPV18 being the most prevalent. Despite the fact that two prophylactic vaccines against HPVs are in the market, wide-scale application of the vaccine in developing countries is a major problem as far as cost of the vaccine and lack of therapeutic efficacy are concerned. Hence, the aim of our study was to develop HPV18 L1E7 chimeric virus-like particles (CVLPs) vaccine candidate possessing both, prophylactic and therapeutic potential against HPV18 associated cervical cancer. In this study, we have developed a potential candidate vaccine against HPV18 involving HPV18 L1E7 CVLPs, which was expressed in E. coli and assembled in vitro. These CVLPs were able to induce a neutralizing antibody response as well as a cell-mediated immune response in mice. PMID- 25929430 TI - Mcl-1 is vital for neutrophil survival. AB - Upon entry to the systemic circulation, neutrophils exhibit a short mean time to cell death. The viability of most cell types in a steady state is preserved by the interplay of the Bcl-2 family of proteins, wherein the anti-apoptotic members inhibit the action of their pro-apoptotic counterparts. Neutrophils, however, display absent or severely reduced expression of several anti-apoptotic Bcl-2 family proteins. Hence, they rely on the expression of Mcl-1, an anti-apoptotic member of the Bcl-2 family, for survival. This protein is uniquely short-lived relative to related proteins and its loss likely precipitates the induction of apoptosis in neutrophils. This review describes the role of Mcl-1 in the neutrophil in the context of apoptosis and highlights the proteins' importance to the cell. We also address neutrophil apoptosis in the broader context of the cells' response to pathogens, focussing particularly on the strategies used by pathogens to manipulate the apoptotic pathway to their own ends. PMID- 25929431 TI - Look beyond Catechol-O-Methyltransferase genotype for cathecolamines derangement in migraine: the BioBIM rs4818 and rs4680 polymorphisms study. AB - BACKGROUND: The study of COMT gene polymorphisms in migraine could be of particular interest since impaired catecholaminergic neurotransmission, namely chronic dopaminergic and noradrenergic hypofunction, is a peculiar migraine trait. In this study, for the first time, we focused on the role of COMT rs4818 genetic variant, the polymorphism most strongly affecting COMT activity, in migraine. This study was conducted in a cohort of carefully clinical characterized Caucasian migraineurs recruited in a specifically dedicated migraine biobank, providing also a replication study on rs4680 polymorphism. FINDINGS: Genotyping of rs4680 and rs4818 Catechol-O-Methyltransferase gene polymorphisms was performed on 380 unrelated migraine patients, and 132 healthy subjects matched for age, gender and race-ethnicity, with no clinical evidence or family history of migraine or other neurological diseases. The rs4680 and rs4818 genotypic frequencies did not deviate from those expected for a population in Hardy-Weinberg equilibrium and did not correlate with demographics or clinical migraine features, even when considering migraine subtypes such as dopaminergic migraine, menstrual migraine, and menstrually related migraine . CONCLUSIONS: COMT genotype does not influence migraine susceptibility or phenotype, even considering rs4818 polymorphism and peculiar clinical subtypes. This finding prompts to go over COMT to explain catecholamine derangement in migraine, exploring enzymes involved in catecholamines synthesis and catabolism, such as monoamine-oxidase, dopamine beta-hydroxylase, tyrosine-hydroxylase or tyrosine decarboxylase, among others. PMID- 25929432 TI - Pressure pain sensitivity map of multifocal nummular headache: a case report. AB - BACKGROUND: Nummular headache (NH) is most commonly a localized unifocal headache; however, some patients infrequently exhibit multifocal symptomatic painful head areas retaining all features of NH. We present the pressure pain sensitivity map of an adolescent with multifocal NH. CASE PRESENTATION: We describe a case of a 14 year-old-girl with a 3-year history of continuous pain in four rounded areas, all of them with the same size and shape. Pressure pain thresholds (PPT) were assessed on 21 points over the scalp and over the symptomatic areas. A pressure pain sensitivity map of the head was constructed. The neurological exam was unremarkable, with neither sensory symptoms nor trophic changes within the painful areas. As previously shown, symptomatic points exhibited lower PPTs compared to the surrounding areas. The map reflected 4 restricted areas of mechanical hyperalgesia confined just to the painful areas. Treatment with gabapentin achieved complete remission. CONCLUSION: This is the first pain sensitivity map of a patient with multifocal NH. Our results support peripheral mechanisms are maintained in multifocal NH. PMID- 25929433 TI - Attitude and awareness of medical and dental students towards collaboration between medical and dental practice in Hong Kong. AB - BACKGROUND: Medical-dental collaboration is essential for improving resource efficiency and standards of care. However, few studies have been conducted on it. This study aimed to investigate the attitude and awareness of medical and dental students about collaboration between medical and dental practices in Hong Kong. METHODS: All medical and dental students in Hong Kong were invited to complete a questionnaire survey at their universities, hospitals and residential halls. It contained 8 questions designed to elicit their attitudes about the collaboration between medical and dental practice. Students were also asked about their awareness of the collaboration between dentistry and medicine. The questionnaires were directly distributed to medical and dental students. The finished questionnaires were immediately collected by research assistants on site. RESULTS: A total of 1,857 questionnaires were distributed and 809 (44%) were returned. Their mean attitude score (SD) towards medical-dental collaboration was 6.37 (1.44). Most students (77%) were aware of the collaboration between medical and dental practice in Hong Kong. They considered that Ear, Nose & Throat, General Surgery and Family Medicine were the 3 most common medical disciplines which entailed collaboration between medical and dental practice. CONCLUSION: In this study, the medical and dental students in general demonstrated a good attitude and awareness of the collaboration between medical and dental practice in Hong Kong. This established an essential foundation for fostering medical dental collaboration, which is vital to improving resource efficiency and standards of care. PMID- 25929434 TI - Activation and deformation of immobilized lipase on self-assembled monolayers with tailored wettability. AB - In this work, lipase from Candida rugosa (CRL) was immobilized on self-assembled monolayers (SAMs) with various wettabilities ranging from highly hydrophilic to highly hydrophobic by adsorption in order to clearly elucidate the interfacial activation character of lipases. The SAMs were made of 11-hydroxyundecane-1-thiol and 1-dodecanethiol. The adsorption behavior was monitored in situ by quartz crystal microbalance with dissipation (QCM-D), and the enzyme binding constants indicated a stronger affinity between CRL and more hydrophobic surfaces. Atomic force microscopy (AFM) and X-ray photoelectron spectroscopy (XPS) were used to characterize the morphologies of the adsorbed lipases. Amide I band attenuated total reflection/Fourier transformed infrared (ART/FTIR) spectroscopy showed an increasing fraction of intermolecular beta-sheet content on surfaces with higher hydrophilicities. Moreover, liquid chromatography (LC) verified that the activity of CRL adsorbed on a hydrophobic surface was higher than that of CRL adsorbed on a hydrophilic surface. This work related the enzyme activity to the substrate properties, adsorption behavior, distribution, and morphology of lipases, helping to achieve the external control of both the immobilization process and enzyme utilization. PMID- 25929435 TI - Higenamine regulates Nrf2-HO-1-Hmgb1 axis and attenuates intestinal ischemia reperfusion injury in mice. AB - INTRODUCTION: Intestinal ischemia and reperfusion (IR) syndrome is a life threatening dilemma caused by diverse events. Higenamine (HG), an active ingredient of Aconiti Lateralis Radix Praeparata, has been traditionally used as a heart stimulant and anti-inflammatory agent in oriental countries. But the function of HG on intestine IR injury has never been investigated. MATERIALS AND METHODS: Mice underwent a 2 cm midline laparotomy, and the superior mesenteric artery (SMA) was obstructed by micro-vascular clamp to induce intestinal ischemia. RESULTS: In our current study, HG increases mouse intestinal epithelial (IEC-6) cell viability through induced heme oxygenase-1 (HO-1) production in vitro. In our in vivo murine intestinal IR injury model, the increased HO-1 protein level and activity, decreased intestinal injury score, Myeloperoxidase (MPO) activity, and inflammatory cytokine expression induced by HG were all abolished with additional treatment of HO-1 inhibitor zinc protoporphyrin IX (ZnPPIX). Furthermore, HG reduced high mobility group box-1 (Hmgb1) expression in IR injury-performed intestine which was inhibited by additional administration of ZnPPIX. And HG treatment significantly decreased HO-1 expression in nuclear factor erythroid 2-related factor (Nrf-2) SiRNA-transfected cells but not in control SiRNA-transfected cells. CONCLUSION: Our study provides evidence HG regulates Nrf2-HO-1-Hmgb1 axis and attenuates intestinal IR injury in mice. PMID- 25929436 TI - Knockdown of augmenter of liver regeneration in HK-2 cells inhibits inflammation response via the mitogen-activated protein kinase signaling pathway. AB - OBJECTIVE: Augmenter of liver regeneration (ALR) is a growth factor that is ubiquitously expressed in multiple forms among eukaryotes. The present study focused on the role of endogenous ALR on the hypoxia/reoxygenation (H/R)-induced inflammatory response in human kidney 2 (HK-2) cells, and the underlying molecular mechanisms. METHODS: To determine the relationship between exogenous and endogenous ALR, exogenous ALR was administrated to HK-2 cells, and endogenous ALR protein and mRNA expression was examined by Western blotting and quantitative real-time polymerase chain reaction (qPCR), respectively. In order to knockdown endogenous ALR expression, HK-2 cells were infected with lentiviral shRNA/ALR, after which cell viability was determined by the MTS cell viability assay. Cells were subjected to hypoxia for 6 h and reoxygenation for 12 h. Levels of monocyte chemotactic protein (MCP-1), interleukin-6 (IL-6), and tumor necrosis factor alpha (TNF-alpha) were determined by enzyme-linked immunosorbent assay (ELISA) and qPCR. Cells were harvested, and nuclear and phosphorylated protein extracts were prepared from the HK-2 cell lysates. Nuclear factor kappaB (NF-kappaB), and phosphorylated extracellular signal-regulated kinase (ERK), p38, and c-Jun N terminal kinase (JNK) were analyzed by Western blotting. The translocation of NF kappaB was detected by immunofluorescence. RESULTS: Exogenous ALR inhibited the expression of endogenous ALR. Lentiviral shRNA/ALR markedly downregulated endogenous ALR expression, whereas there were no changes in ALR expression in lentiviral shRNA/control HK-2 cells. The results of the MTS assay showed that silencing ALR expression did not influence cell viability. H/R led to increased production of MCP-1, IL-6, and TNF-alpha. However, knockdown of ALR attenuated the inflammatory response via inhibition of ERK, p38, and JNK phosphorylation. The translocation of NF-kappaB into the nucleus was also decreased. CONCLUSIONS: These results suggest that there is a negative feedback loop involving ALR in HK 2 cells. Knockdown of ALR exerts anti-inflammatory actions via suppression of the mitogen-activated protein kinase signaling pathway. PMID- 25929437 TI - Inflammation, a link between obesity and atrial fibrillation. AB - Despite the long belief that the role of the adipose tissue was restricted to that of a passive store of triglycerides and a rich source of fatty acids, accumulating data demonstrates that the adipose tissue acts as an endocrine organ, capable of producing a large number of cytokines incriminated in generating a systemic inflammatory status. At its turn, this adiposity-related pro-inflammatory status appears to promote a large range of cardiovascular disorders, including atrial fibrillation (AF). Recent studies suggest that, in addition to systemic adiposity, the volume of the pericardial fat of the entire heart, and particularly of that overlying the atria, may represent an even more important risk factor for AF. This review focuses on the most relevant clinical and experimental data that bridge adiposity-induced inflammation and AF, and provides, through a multidisciplinary approach, a discussion that integrates both the current knowledge regarding the prolific activity of systemic and pericardial adipose tissue as sources of inflammatory mediators and the main effects of adiposity-induced inflammation on the most relevant electrophysiological, structural, and autonomic mechanisms responsible for AF. PMID- 25929439 TI - A proposal for unified flow cytometer parameter naming. PMID- 25929438 TI - Nomogram for overall survival of Japanese patients with bone-metastatic prostate cancer. AB - BACKGROUND: We analyzed the relationship between prostate cancer outcomes and pretreatment clinical factors and developed a prognostic nomogram of overall survival (OS) of patients with bone metastasis. METHODS: From 1993 to 2011, 463 consecutive patients were treated for bone-metastatic prostate cancer. Data sets from 361 patients were used to develop a nomogram (training data), and data sets of 102 patients were used for validation of the nomogram (validation data). Using the external validation data set, the nomogram was assessed for discriminatory ability, and the predictions were assessed for calibration accuracy by plotting actual survival against predicted risk. RESULTS: Of the 361 patients in the training data set, 205 (56.8%) patients died, 169 (46.8%) deaths of which were due to prostate cancer. The median follow-up period was 55.2 months. In the multivariate analysis, patient age, serum prostate-specific antigen level, clinical T stage, extent of disease on bone scan, and biopsy Gleason sum were independent prognostic factors. We developed a prognostic model comprising these five factors for patients with bone-metastatic prostate cancer. This nomogram can be used to estimate 1-, 3-, and 5-year survival probability. External validation of this model using 102 validation data sets showed reasonable accuracy (concordance index, 0.719). CONCLUSION: Our pretreatment prognostic nomogram might be useful for Japanese patients with bone-metastatic prostate cancer. PMID- 25929440 TI - Latent Class Analysis of Gambling Activities in a Sample of Young Swiss Men: Association with Gambling Problems, Substance Use Outcomes, Personality Traits and Coping Strategies. AB - The study aimed to identify different patterns of gambling activities (PGAs) and to investigate how PGAs differed in gambling problems, substance use outcomes, personality traits and coping strategies. A representative sample of 4989 young Swiss males completed a questionnaire assessing seven distinct gambling activities, gambling problems, substance use outcomes, personality traits and coping strategies. PGAs were identified using latent class analysis (LCA). Differences between PGAs in gambling and substance use outcomes, personality traits and coping strategies were tested. LCA identified six different PGAs. With regard to gambling and substance use outcomes, the three most problematic PGAs were extensive gamblers, followed by private gamblers, and electronic lottery and casino gamblers, respectively. By contrast, the three least detrimental PGAs were rare or non-gamblers, lottery only gamblers and casino gamblers. With regard to personality traits, compared with rare or non-gamblers, private and casino gamblers reported higher levels of sensation seeking. Electronic lottery and casino gamblers, private gamblers and extensive gamblers had higher levels of aggression-hostility. Extensive and casino gamblers reported higher levels of sociability, whereas casino gamblers reported lower levels of anxiety neuroticism. Extensive gamblers used more maladaptive and less adaptive coping strategies than other groups. Results suggest that gambling is not a homogeneous activity since different types of gamblers exist according to the PGA they are engaged in. Extensive gamblers, electronic and casino gamblers and private gamblers may have the most problematic PGAs. Personality traits and coping skills may predispose individuals to PGAs associated with more or less negative outcomes. PMID- 25929441 TI - Factors associated with delayed recognition of pulmonary tuberculosis in emergency departments in Taiwan. AB - OBJECTIVE: To identify and evaluate factors associated with delayed recognition of pulmonary tuberculosis (TB) in the emergency department (ED). BACKGROUND: Delayed recognition of pulmonary TB in ED may precipitate mortality and morbidity. METHODS: Medical records of newly diagnosed TB patients admitted to four hospitals in Taiwan were retrospectively reviewed. Patients were divided into two groups based on ED physicians' recognition or not of TB and statistically compared to identify differences in their characteristics. RESULTS: 310 newly diagnosed TB patients were identified; 150 were unrecognized in the ED. Cough, chest tightness, general malaise, and body weight loss were more common for those with recognized TB. Older age (>=65 yrs, P = 0.035) and chronic renal insufficiency (P = 0.005) were associated with delayed TB recognition. CONCLUSION: Older age and chronic renal insufficiency are risk factors for delayed TB while in the ED. Typical symptoms should heighten alertness for recognizing TB. PMID- 25929442 TI - Feasibility study on production of a matrix reference material for cyanobacterial toxins. AB - The worldwide increase in cyanobacterial contamination of freshwater lakes and rivers is of great concern as many cyanobacteria produce potent hepatotoxins and neurotoxins (cyanotoxins). Such toxins pose a threat to aquatic ecosystems, livestock, and drinking water supplies. In addition, dietary supplements prepared from cyanobacteria can pose a risk to consumers if they contain toxins. Analytical monitoring for toxins in the environment and in consumer products is essential for the protection of public health. Reference materials (RMs) are an essential tool for the development and validation of analytical methods and are necessary for ongoing quality control of monitoring operations. Since the availability of appropriate RMs for cyanotoxins has been very limited, the present study was undertaken to examine the feasibility of producing a cyanobacterial matrix RM containing various cyanotoxins. The first step was large scale culturing of various cyanobacterial cultures that produce anatoxins, microcystins, and cylindrospermopsins. After harvesting, the biomass was lyophilized, blended, homogenized, milled, and bottled. The moisture content and physical characteristics were assessed in order to evaluate the effectiveness of the production process. Toxin levels were measured by liquid chromatography with tandem mass spectrometry and ultraviolet detection. The reference material was found to be homogeneous for toxin content. Stability studies showed no significant degradation of target toxins over a period of 310 days at temperatures up to +40 degrees C except for the anatoxin-a, which showed some degradation at +40 degrees C. These results show that a fit-for-purpose matrix RM for cyanotoxins can be prepared using the processes and techniques applied in this work. PMID- 25929445 TI - pH-dependent hydrolysis of acetylcholine: Consequences for non-neuronal acetylcholine. AB - Acetylcholine is inactivated by acetylcholinesterase and butyrylcholinesterase and thereby its cellular signalling is stopped. One distinguishing difference between the neuronal and non-neuronal cholinergic system is the high expression level of the esterase activity within the former and a considerably lower level within the latter system. Thus, any situation which limits the activity of both esterases will affect the non-neuronal cholinergic system to a much greater extent than the neuronal one. Both esterases are pH-dependent with an optimum at pH above 7, whereas at pH values below 6 particularly the specific acetylcholinesterase is more or less inactive. Thus, acetylcholine is prevented from hydrolysis at such low pH values. The pH of the surface of the human skin is around 5 and therefore non-neuronal acetylcholine released from keratinocytes can be detected in a non-invasive manner. Several clinical conditions like metabolic acidosis, inflammation, fracture-related haematomas, cardiac ischemia and malignant tumours are associated with local or systemic pH values below 7. Thus, the present article describes some consequences of an impaired inactivation of extracellular non-neuronal acetylcholine. PMID- 25929444 TI - There are things that we know that we know, and there are things that we do not know we do not know: Confidence in decision-making. AB - Metacognition, the ability to think about our own thoughts, is a fundamental component of our mental life and is involved in memory, learning, planning and decision-making. Here we focus on one aspect of metacognition, namely confidence in perceptual decisions. We review the literature in psychophysics, neuropsychology and neuroscience. Although still a very new field, several recent studies suggest there are specific brain circuits devoted to monitoring and reporting confidence, whereas others suggest that confidence information is encoded within decision-making circuits. We provide suggestions, based on interdisciplinary research, to disentangle these disparate results. PMID- 25929446 TI - Phloretin ameliorates chemokines and ICAM-1 expression via blocking of the NF kappaB pathway in the TNF-alpha-induced HaCaT human keratinocytes. AB - Previous studies found that phloretin had anti-oxidant, anti-inflammatory, and anti-tumor properties. In this study, we investigated whether phloretin could suppress the production of the intercellular adhesion molecule (ICAM)-1 and chemokines through downregulation of the nuclear transcription factor kappa-B (NF kappaB) and mitogen-activated protein kinase (MAPK) signaling pathways in TNF alpha-stimulated HaCaT human keratinocytes. HaCaT cells were treated with phloretin and then the cells were stimulated by TNF-alpha. Phloretin treatment decreased the production of IL-6, IL-8, CCL5, MDC, and TARC. Phloretin decreased ICAM-1 protein and mRNA expression, and also suppressed the adhesion of monocyte THP-1 cells to inflammatory HaCaT cells. Phloretin inhibited NF-kappaB translocation into the nucleus and also suppressed the phosphorylation of Akt and MAPK signal. In addition, phloretin increased heme oxygenase-1 production in a concentration-dependent manner. These results demonstrated that phloretin has anti-inflammatory effects to inhibit chemokines and ICAM-1 expressions through suppression of the NF-kappaB and MAPK pathways in human keratinocytes. PMID- 25929447 TI - Ellagic Acid, a Dietary Polyphenol, Inhibits Tautomerase Activity of Human Macrophage Migration Inhibitory Factor and Its Pro-inflammatory Responses in Human Peripheral Blood Mononuclear Cells. AB - Ellagic acid (EA), a phenolic lactone, inhibited tautomerase activity of human macrophage migration inhibitory factor (MIF) noncompetitively (Ki = 1.97 +/- 0.7 MUM). The binding of EA to MIF was determined by following the quenching of tryptophan fluorescence. We synthesized several EA derivatives, and their structure-activity relationship studies indicated that the planar conjugated lactone moiety of EA was essential for MIF inhibition. MIF induces nuclear translocation of NF-kappaB and chemotaxis of peripheral blood mononuclear cells (PBMCs) to promote inflammation. We were interested in evaluating the effect of EA on nuclear translocation of NF-kappaB and chemotactic activity in human PBMCs in the presence of MIF. The results showed that EA inhibited MIF-induced NF kappaB nuclear translocation in PBMCs, as evident from confocal immunofluorescence microscopic data. EA also inhibited MIF-mediated chemotaxis of PBMCs. Thus, we report MIF-inhibitory activity of EA and inhibition of MIF mediated proinflammatory responses in PBMCs by EA. PMID- 25929443 TI - Actions and interactions of estradiol and glucocorticoids in cognition and the brain: Implications for aging women. AB - Menopause involves dramatic declines in estradiol production and levels. Importantly, estradiol and the class of stress hormones known as glucocorticoids exert countervailing effects throughout the body, with estradiol exerting positive effects on the brain and cognition, glucocorticoids exerting negative effects on the brain and cognition, and estradiol able to mitigate negative effects of glucocorticoids. Although the effects of these hormones in isolation have been extensively studied, the effects of estradiol on the stress response and the neuroprotection offered against glucocorticoid exposure in humans are less well known. Here we review evidence suggesting that estradiol-related protection against glucocorticoids mitigates stress-induced interference with cognitive processes. Animal and human research indicates that estradiol-related mitigation of glucocorticoid damage and interference is one benefit of estradiol supplementation during peri-menopause or soon after menopause. The evidence for estradiol-related protection against glucocorticoids suggests that maintaining estradiol levels in post-menopausal women could protect them from stress-induced declines in neural and cognitive integrity. PMID- 25929448 TI - Involvement of peripheral TRPV1 channels in the analgesic effects of thalidomide. AB - Thalidomide was introduced to the market in 1957 as a sedative and antiemetic agent, and returned to the market for the treatment of myelodysplastic syndrome and multiple myeloma. There are reports and studies of thalidomide as an analgesic or analgesic adjuvant in clinic. However, the underlying mechanism is quite elusive. Many studies suggest that the analgesic effect of thalidomide may be due to its immunomodulatory and anti-inflammatory properties as it suppresses the production of tumor necrosis factor alpha (TNF-alpha) selectively. However, it is not clear whether any other mechanisms are implicated in the pain relief. In this study, we demonstrated that the peripheral vanilloid receptor 1 (TRPV1) channel was also involved in the analgesic effect of thalidomide in different cell and animal models. During the activation by its agonist capsaicin, the cation inward influx through TRPV1 channels and the whole-cell current significantly decreased after TRPV1-overexpressed HEK293 cells or dorsal root ganglion (DRG) neurons were pre-treated with thalidomide for 20 minutes. And such attenuation in the TRPV1 activity was in a dose-dependent manner of thalidomide. In an acetic acid writhing test, pre-treatment of thalidomide decreased the writhing number in the wild type mice, while it did not happen in TRPV1 knockout mice, suggesting that the TRPV1 channel was involved in the pain relief by thalidomide. Taken together, the study showed that TRPV1 channels were involved in the analgesic effects of thalidomide. Such alteration in the action of TRPV1 channels by thalidomide may help understand how thalidomide takes analgesic effect in the body in addition to its selective inhibition of TNF-alpha production. PMID- 25929449 TI - Protective effect of a Chinese Medicine formula He-Ying-Qing-Re Formula on diabetic retinopathy. AB - ETHNOPHARMACOLOGY RELEVANCE: He-Ying-Qing-Re Formula (HF) is a formula modified from "Si-Miao-Yong-An Decoction", a traditional Chinese medical classic emerged in the Qing dynasty and has been reported for treatment of vascular diseases. HF, containing 8 herbs, has been used in local hospital for decades as a complementary method for diabetic retinopathy (DR) with retinal vascular dysfunction. Clinical reports revealed HF could ameliorate vision defects, microaneurysms, hemorrhages and macular edema. The aim of this study is to investigate the anti-DR action of HF and its underlying mechanism experimentally. METHODS: Chromatographic fingerprinting of HF and rodent model of DR were established; hypoglycemic effect of HF was measured by fasting, random blood glucose and glucose tolerance test; vascular degeneration was measured by retinal digestion; blood-retina-barrier (BRB) permeability was assessed with Evans Blue leakage assay. Advanced glycation end products (AGEs) were measured in vitro and in vivo level; Migration of retinal vascular endothelial cells were determined by wound healing and transwell chamber assays; permeability of endothelial monolayer was monitored with dextran transport. AGEs-related proteins and signaling were measured with immunoblotting and immunohistochemistry. RESULTS: Chlorogenic acid, ferulic acid and arctin were identified as major components in HF; HF suppresses retinal vasculature degeneration and BRB permeability damage without significant inhibition on hyperglycemia; HF reduces in vitro and in vivo formation of AGEs and AGEs-induced migration as well as permeability of retinal vascular endothelial cells. Expression of tight junction proteins Zo-1 and Claudin-1 was increased while activation of AGEs receptor and downstream signaling Akt were suppressed upon HF treatment. CONCLUSIONS: HF exhibits protective effect against diabetic retinopathy, which may be associated with inhibition on AGEs and recovery on endothelial dysfunction via modulation of tight junction and AGEs downstream signaling. PMID- 25929450 TI - TRAMIL ethnomedicinal survey in Jamaica. AB - ETHNOPHARMACOLOGICAL RELEVANCE: A survey was undertaken in Jamaica to document medicinal plants frequently used in the treatment or prophylaxis of illness and trends in their use, following the methodology established by the TRAMIL network. TRAMIL, a Caribbean-wide applied research programme, scientifically evaluates and documents the efficacy and safety of medicinal plant remedies used for primary health care. Initial results from this survey, on an aspect of safety, focusing on the concomitant use and prevalence of medicinal plant use in combination with pharmaceutical drugs in Jamaica, were published in an earlier paper in 2011. This paper now reports survey results on the ethnobotanical use of medicinal plants by Jamaicans. MATERIALS AND METHODS: A survey using a structured and modified TRAMIL questionnaire was administered to 407 adults selected randomly from systematically selected households within randomly selected clusters. The clusters were selected from each of the three areas that were purposefully selected. KEY FINDINGS: Respondents identified their use of 107 botanically identified medicinal plants distributed in 51 plant families to treat illnesses or maintain health in the previous twelve months. Fourteen plants, with significant use equal to or greater than 20% for a specified health issue were shortlisted, representing Jamaica's first submission to the TRAMIL database. Andrographis paniculata (Burm. f.) Nees (Rice Bitters) was reported as a plant remedy with significant use for the first time in a TRAMIL survey. Informant consensus factor (ICF) values were high for a number of health issues such as mental health (nerves, insomnia, etc.), respiratory system (cold/flu/cough etc.) and for health maintenance with tonics (washout and blood cleanse), indicating strong cultural coherence in medicinal plant selection for these categories. Forty two per cent (113/270) of medicinal plant users utilised mixtures, combining more than one plant. Leaf material was the most commonly used plant part (69%), with fresh material (98%) most commonly prepared as a tea for internal use by decoction (87%). The majority of medicinal plant respondents sourced plants from their backyards (75%) and cited grandmothers (33%) and mothers (32%) as their main sources of information. Jamaicans reported limited use of complementary and alternative medicine (CAM), supporting the assertion that a significant number of citizens in developing countries continue to rely on the use of medicinal plants for primary healthcare. CONCLUSIONS: Medicinal plant use continues to play an important role in primary healthcare in Jamaica. Fourteen plant remedies with significant use are reported, five previously reported elsewhere and recommended (REC) for the same health condition. Eight plant remedies, including one Jamaican endemic, are reported for different health issues for the first time to TRAMIL and will be investigated (INV) for the new health conditions, together with one plant remedy reported for the first time. This latest survey will be followed by literature reviews, appropriate laboratory screens (TRIG) and community outreach activities (TRADIF) in Jamaica. PMID- 25929451 TI - Medicinal plants: An invaluable, dwindling resource in sub-Saharan Africa. AB - ETHNOPHARMACOLOGICAL RELEVANCE: The use of plant species for different therapeutic/medicinal purposes is well-entrenched in sub-Saharan Africa. AIM OF THE REVIEW: To provide a critical and updated review of the enormous medicinal plant heritage in sub-Saharan Africa with regards to the abundance, importance, conservation status and potential means to help sustain their availability for future generations. METHODS: A comprehensive literature search involving different online databases, books and theses were conducted in order to obtain, collate and synthesize available information on various fundamental aspects pertaining to African medicinal plants. RESULTS: African biodiversity hotspots are endowed with a high level of endemic species with a significant portion possessing medicinal value. Apart from the extensive ethnobotanical uses of medicinal plants found in Africa, scientific validation of their biological potential such as antimicrobial, antioxidant, anti-inflammatory and anti-diabetic properties have been recognized. Together with the demand arising from their biological efficacies, other anthropogenic factors are exerting conservation strains of the wild population of these medicinal plants. Even though researchers have acknowledged the importance and value of conserving these medicinal plants, several challenges have hampered these efforts on the Continent as a whole. CONCLUSIONS: The rich flora occurring in sub-Saharan Africa suggests enormous potential for discovery of new chemical entity with therapeutic value. However, concerted efforts focused on documenting the conservation status of African medicinal plants are pertinent. Application of different biotechnological techniques is needed to sustain these valuable botanical entities, especially to meet increasing pharmaceutical demand. Most importantly, increased public enlightenment and awareness may help eradicate the prejudice against cultivation of medicinal plants. PMID- 25929452 TI - Function of the M1 pi-helix in endplate receptor activation and desensitization. AB - KEY POINTS: A conserved proline in M1 causes a kink between alpha and pi helical segments. The kink is under greater tension in the resting versus active conformation. The kink and the agonist do not interact directly. The pi-helix separates the gating functions of the extracellular and transmembrane domains. Mutations of the conserved proline and propofol increase desensitization. ABSTRACT: Nicotinic acetylcholine receptors (AChRs) switch on/off to generate transient membrane currents (C<->O; closed-open 'gating') and enter/recover from long-lived, refractory states (O<->D; 'desensitization'). The M1 transmembrane helix of the muscle endplate AChR is linked to a beta-strand of the extracellular domain that extends to a neurotransmitter binding site. We used electrophysiology to measure the effects of mutations of amino acids that are located at a proline kink in M1 that separates pi and alpha helices, in both alpha (N217, V218 and P221) and non-alpha subunits. In related receptors, the kink is straighter and more stable in O vs. C structures (gating is 'spring-loaded'). None of the AChR kink mutations had a measureable effect on agonist affinity but many influenced the allosteric gating constant substantially. Side chains in the M1 alpha-helix experience extraordinarily large energy differences between C and O structures, probably because of a ~2 A displacement and tilt of M2 relative to M1. There is a discrete break in the character of the gating transition state between alphaN217 and alphaV218, indicating that the pi-helix is a border between extracellular- and transmembrane-domain function. Mutations of the conserved M1 proline, and the anaesthetic propofol, increase a rate constant for desensitization. The results suggest that straightening of the M1 proline kink triggers AChR desensitization. PMID- 25929453 TI - Between stigma and mother-blame: blind mothers' experiences in USA hospital postnatal care. AB - This study examines instances of discrimination that blind mothers in the USA have experienced at the hands of doctors, nurses and social workers during hospital postnatal care. The author identifies postnatal care as the time when blind mothers are likely to face the most stigmatising interactions with medical staff, as it is when scepticism about their competence as mothers is at its height. The author argues these interactions must be understood within their institutional context in which ideologies of risk and mother-blame are embedded in hospital postnatal practices. PMID- 25929454 TI - Pesticide residues in fruit samples: comparison of different QuEChERS methods using liquid chromatography-tandem mass spectrometry. AB - Acetate- and citrate-buffered quick, easy, cheap, effective, rugged, safe (QuEChERS) pretreatment methods were evaluated for the determination of various pesticides in peaches, grapes, apples, bananas, pears, and strawberries from various regions of Greece, using LC-MS/MS. The purposes of this study were (i) to evaluate which type of QuEChERS method was the most appropriate and effective for each matrix; (ii) to apply the selected QuEChERS method for each matrix, in order to detect and quantify pesticide residues in various fruit samples using UPLC MS/MS; (iii) to examine the concentration distribution of pesticide classes among fruit originating from various areas; and (iv) to assess pesticide concentration distribution between peel and flesh of fruit in order to evaluate the penetration of pesticide residues in the fruit flesh. Acetate-buffered QuEChERS was found to be the most suitable technique for most of the fruit matrices. According to the recovery values at two different concentration levels, peaches should preferably be treated by the citrate-buffered type, whereas grapes, bananas, apples, pears, and strawberries are best treated by the acetate-buffered version, although the differences in efficiency were small. The addition of graphitized carbon black significantly decreases the recovery of specific pesticides in all matrices except for strawberries. The majority of values do not exceed the official maximum residue levels set by the European Commission. Organophosphates proved to be the most commonly detected category along with triazines-triazoles-conazoles group and by carbamates. Apples and pears seem to be the most contaminated fruit matrices among those tested. Distribution of pesticide classes shows variations between different regions, suggesting different pesticide application practices. In the case of peaches and pears, there is an equal distribution of detected pesticides between peel and flesh, indicating penetration of contaminants into the fruit flesh. PMID- 25929455 TI - Assessment of arbuscular mycorrhizal fungi status and heavy metal accumulation characteristics of tree species in a lead-zinc mine area: potential applications for phytoremediation. AB - To select suitable tree species associated with arbuscular mycorrhizal fungi (AMF) for phytoremediation of heavy metal (HM) contaminated area, we measured the AMF status and heavy metal accumulation in plant tissues in a lead-zinc mine area, Northwest China. All 15 tree species were colonized by AM fungi in our investigation. The mycorrhizal frequency (F%), mycorrhizal colonization intensity (M%) and spore density (SP) reduced concomitantly with increasing Pb and Zn levels; however, positive correlations were found between arbuscule density (A%) and soil total/DTPA-extractable Pb concentrations. The average concentrations of Pb, Zn, Cu and Cd in plant samples were 168.21, 96.61, 41.06, and 0.79 mg/kg, respectively. Populus purdomii Rehd. accumulated the highest concentrations of Zn (432.08 mg/kg) and Cu (140.85 mg/kg) in its leaves. Considerable amount of Pb (712.37 mg/kg) and Cd (3.86 mg/kg) were concentrated in the roots of Robinia pseudoacacia Linn. and Populus simonii Carr., respectively. Plants developed different strategies to survive in HM stress environment: translocating more essential metals (Zn and Cu) into the aerial parts, while retaining more toxic heavy metals (Pb and Cd) in the roots to protect the above-ground parts from damage. According to the translocation factor (TF), bioconcentration factor (BCF), growth rate and biomass production, five tree species (Ailanthus altissima (Mill.) Swingle, Cotinus coggygria Scop., P. simonii, P. purdomii, and R. pseudoacacia) were considered to be the most suitable candidates for phytoextraction and/or phytostabilization purposes. Redundancy analysis (RDA) showed that the efficiency of phytoremediation was enhanced by AM symbioses, and soil pH, Pb, Zn, and Cd levels were the main factors influencing the HM accumulation characteristics of plants. PMID- 25929456 TI - Linear regression model for predicting interactive mixture toxicity of pesticide and ionic liquid. AB - The nature of most environmental contaminants comes from chemical mixtures rather than from individual chemicals. Most of the existed mixture models are only valid for non-interactive mixture toxicity. Therefore, we built two simple linear regression-based concentration addition (LCA) and independent action (LIA) models that aim to predict the combined toxicities of the interactive mixture. The LCA model was built between the negative log-transformation of experimental and expected effect concentrations of concentration addition (CA), while the LIA model was developed between the negative log-transformation of experimental and expected effect concentrations of independent action (IA). Twenty-four mixtures of pesticide and ionic liquid were used to evaluate the predictive abilities of LCA and LIA models. The models correlated well with the observed responses of the 24 binary mixtures. The values of the coefficient of determination (R (2)) and leave-one-out (LOO) cross-validated correlation coefficient (Q(2)) for LCA and LIA models are larger than 0.99, which indicates high predictive powers of the models. The results showed that the developed LCA and LIA models allow for accurately predicting the mixture toxicities of synergism, additive effect, and antagonism. The proposed LCA and LIA models may serve as a useful tool in ecotoxicological assessment. PMID- 25929457 TI - A novel biopesticide PONNEEM to control human vector mosquitoes Anopheles stephensi L. and Culex quinquefasciatus Say. AB - Organophosphate pesticides are widely used in vector mosquito management and agricultural pest management. These chemicals enter into natural water bodies and soil and cause hazards to the environment. The objective of this study was to prepare a natural pesticide which will not harm the environment and yet control vector mosquitoes. PONNEEM, a novel biopesticide, patented and prepared from the oils of Azadirachta indica and Pongamia glabra, was tested against Anopheles stephensi and Culex quinquefasciatus. One hundred percent larvicidal and ovicidal activities were observed at 0.1-ppm concentration of PONNEEM against the two mosquito species under laboratory and sunlight conditions up to 12 months from the date of manufacture. Very high oviposition reduction of 26.46 and 32.16 % is also recorded. Reductions in alpha-esterase level (0.0818 +/- 0.340 and 0.2188 +/ 0.003), beta-esterase level (0.0866 +/- 0.026 and 0.0398 +/- 0.010 MUg naphthol produced/min/mg larval protein), glutathione S-transferase enzyme (14.2571 +/- 0.51 and 15.3326 +/- 0.51 MUmol/min/mg larval protein) and total protein levels (0.0390 +/- 0.008 and 0.1975 +/- 0.029 mg/individual larva in treated groups of A. stephensi and C. quinquefasciatus at 0.1-ppm concentration, respectively. The non-target organisms such as Gambusia affinis and Diplonychus indicus were not affected. Biopesticides are good alternatives to synthetic pesticides. PONNEEM can be effectively used for the management of human vector mosquitoes. Since it has a biodegradable nature and does not alter the environmental condition of water and soil. PMID- 25929458 TI - Hydroxyurea use in prevention of stroke recurrence in children with sickle cell disease in a developing country: A cost effectiveness analysis. AB - We undertook a cost effectiveness analysis (CEA) of hydroxyurea (HU) in preventing stroke recurrence and/or death. We followed 43 children with sickle cell disease from 2000 to 2009 after having a first clinical stroke, of whom 10 opted for HU therapy. HU use led to decreased stroke recurrence and death without significantly increasing the annual cost of care per patient (J$83,250 vs. J$76,901, P = 0.491). The incremental cost effectiveness ratio (ICER) for prevention of stroke recurrence amounted to J$169,238 (US$1,900), while that for death prevention equalled J$635,843 (US$7,140). HU may be recommended when safe and affordable transfusion therapy is not feasible. PMID- 25929459 TI - Reproducibility of DCE-MRI time-intensity curve-shape analysis in patients with knee arthritis: A comparison with qualitative and pharmacokinetic analyses. AB - PURPOSE: To compare the between-session reproducibility of dynamic contrast enhanced magnetic resonance imaging (DCE-MRI) combined with time-intensity curve (TIC)-shape analysis in arthritis patients, within one scanner and between two different scanners, and to compare this method with qualitative analysis and pharmacokinetic modeling (PKM). MATERIALS AND METHODS: Fifteen knee joint arthritis patients were included and scanned twice on a closed-bore 1.5T scanner (n = 9, group 1), or on a closed-bore 1.5T and on an open-bore 1.0T scanner (n = 6, group 2). DCE-MRI data were postprocessed using in-house developed software ("Dynamo"). Disease activity was assessed. RESULTS: Disease activity was comparable between the two visits. In group 1 qualitative analysis showed the highest reproducibility with intraclass correlation coefficients (ICCs) between 0.78 and 0.98 and root mean square-coefficients of variation (RMS-CoV) of 8.0% 14.9%. TIC-shape analysis showed a slightly lower reproducibility with similar ICCs (0.78-0.97) but higher RMS-CoV (18.3%-42.9%). The PKM analysis showed the lowest reproducibility with ICCs between 0.39 and 0.64 (RMS-CoV 21.5%-51.9%). In group 2 TIC-shape analysis of the two most important TIC-shape types showed the highest reproducibility with ICCs of 0.78 and 0.71 (RMS-CoV 29.8% and 59.4%) and outperformed the reproducibility of the most important qualitative parameter (ICC 0.31, RMS-CoV 45.1%) and the within-scanner reproducibility of PKM analysis. CONCLUSION: TIC-shape analysis is a robust postprocessing method within one scanner, almost as reproducible as the qualitative analysis. Between scanners, the reproducibility of the most important TIC-shapes outperform that of the most important qualitative parameter and the within-scanner reproducibility of PKM analysis. PMID- 25929460 TI - Preface. Biometals 2014--Proceedings of the 9th International Symposium Biometals 2014 at Duke University, Durham, NC, USA. PMID- 25929461 TI - Intrapartum fetal scalp lactate sampling for fetal assessment in the presence of a non-reassuring fetal heart rate trace. AB - BACKGROUND: Fetal scalp blood sampling for lactate estimation may be considered following identification of an abnormal or non-reassuring fetal heart rate pattern. The smaller volume of blood required for this test, compared with the more traditional pH estimation, may improve sampling rates. The appropriate use of this practice mandates systematic review of its safety and clinical effectiveness prior to widespread introduction. OBJECTIVES: To evaluate the effectiveness and risks of fetal scalp lactate sampling in the assessment of fetal well-being during labour, compared with no testing or alternative testing. SEARCH METHODS: We searched the Cochrane Pregnancy and Childbirth Group's Trials Register (31 January 2015). SELECTION CRITERIA: All published and unpublished randomised and quasi-randomised trials that compared fetal scalp lactate testing with no testing or alternative testing to evaluate fetal status in the presence of a non-reassuring cardiotocograph during labour. DATA COLLECTION AND ANALYSIS: We used the standard methodological procedures of the Cochrane Pregnancy and Childbirth Group. Two review authors independently assessed the studies. MAIN RESULTS: The search identified two completed randomised controlled trials (RCTs) and two ongoing trials. The two published RCTs considered outcomes for 3348 mother-baby pairs allocated to either lactate or pH estimation of fetal blood samples when clinically indicated in labour. Overall, the published RCTs were of low or unclear risk of bias. There was a high risk of performance bias, because it would not have been feasible to blind clinicians or participants.No statistically significant between-group differences were found for neonatal encephalopathy (risk ratio (RR) 1.00, 95% confidence interval (CI) 0.32 to 3.09, one study, 2992 infants) or death. No studies reported neonatal seizures. We had planned to report death with other morbidities, for example, neonatal encephalopathy; however, the data were not available in a format suitable for this, therefore death due to congenital abnormality was considered alone. The three reported neonatal deaths occurred in babies with diaphragmatic hernias (n = 2) or congenital cardiac fibrosis (n = 1). All three babies had been randomised to the pH group and were not acidaemic at birth.There were no statistically significant differences for any of the pre-specified secondary fetal/neonatal/infant outcomes for which data were available. This included low Apgar score at five minutes (RR 1.13, 95% CI 0.76 to 1.68, two studies, 3319 infants) and admission to neonatal intensive care units (RR 1.02, 95% CI 0.83 to 1.25, one study, 2992 infants), or metabolic acidaemia (RR 0.91, 95% CI 0.60 to 1.36, one study, 2675 infants) considered within the studies, either overall or where data were available for those where fetal blood sampling had occurred within 60 minutes of delivery.Similar proportions of fetuses underwent additional tests to further evaluate well-being during labour, including scalp pH if in the lactate group or scalp lactate if in the pH group (RR 0.22, 95% CI 0.04 to 1.30, two studies, 3333 infants;Tau2 1.00, I2 = 58%). Fetal blood sampling attempts for lactate and pH estimation were successful in 98.7% and 79.4% of procedures respectively in the one study that reported this outcome.There were no significant between-group differences in mode of birth or operative birth for non reassuring fetal status, either for all women, or within the group where the fetal blood sample had been taken within 60 minutes of delivery (for example, caesarean section for all enrolled, RR 1.09, 95% CI 0.97 to 1.22, two studies, 3319 women; operative delivery for non-reassuring fetal status for all enrolled RR 1.02, 95% CI 0.93 to 1.11, one study, 2992 women).Neither study reported on adverse effects of fetal scalp lacerations or maternal anxiety. AUTHORS' CONCLUSIONS: When further testing to assess fetal well-being in labour is indicated, fetal scalp blood lactate estimation is more likely to be successfully undertaken than pH estimation. Further studies may consider subgroup analysis by gestational age, the stage of labour and sampling within a prolonged second stage of labour. Additionally, we await the findings from the ongoing studies that compare allocation to no fetal blood sample with sampling for lactate and address longer-term neonatal outcomes, maternal satisfaction with intrapartum fetal monitoring and an economic analysis. PMID- 25929462 TI - Waiting for definitive care: An analysis of elapsed time from decision to surgery or transfer in a rural centre. AB - OBJECTIVE: To examine the timing of operative management and interhospital transfer of emergency general surgical patients in a regional setting. DESIGN: Retrospective cohort study. SETTING: The surgical unit at a major rural referral centre for North-Eastern Victoria servicing a population of 90 000. PARTICIPANTS: General surgical patients (n = 649) admitted via the emergency department at Northeast Health Wangaratta between January 2011 and March 2013 undergoing operative management (n = 608) or transfer to a tertiary centre (n = 44). MAIN OUTCOME MEASURES: Timing of operative management, using appendicectomy as a benchmark operation, was measured as time from presentation to decision to operate, time from decision to surgery, percentage after-hours operating and length of stay (LOS). Time to interhospital transfer was calculated and reasons for delay were sought. RESULTS: Two hundred forty-six appendicectomies were performed. Median time from decision to operate to theatre was 3 hours (interquartile range (IQR) 2-8), and total LOS was 43 hours (IQR: 28-56). Two hundred seventy-two procedures (43%) were performed out-of-hours, including 48% of appendicectomies. Median time from decision making to transfer was 10.3 hours (IQR: 4.7-25). Transfer was less likely to be delayed in trauma patients when compared with urgent non-trauma patients (5.3 versus 10.6 hours; P = 0.04). CONCLUSION: Even in the absence of a strict four-hour rule program and a dedicated emergency surgical unit, main outcome measures appear to be comparatively efficient. However, the duration for transfer of patients is suboptimal because of the lack of established pathways for urgent non-trauma transfer from rural centres and bed availability in tertiary hospitals. PMID- 25929463 TI - Postoperative three-dimensional cervical range of motion and neurological outcomes in patients with cervical ossification of the posterior longitudinal ligament: Cervical laminoplasty versus laminectomy with fusion. AB - OBJECTIVE: Laminoplasty (LP) and laminectomy with fusion (LCF) are acceptable surgical options for cervical myelopathy caused by ossification of the posterior longitudinal ligament (OPLL). This study focused on evaluating cervical range of motion (ROM) on a three-dimensional basis as well as neurological outcomes after LP and LCF. METHODS: This prospective cohort study consisted of 38 patients undergoing LP (n=20) or LCF (n=18) from December 2010 to December 2012. Before surgery and at the 3rd, 6th, 12th month follow-up, patients were assessed with three-dimensional cervical ROM, Japanese Orthopaedic Association (JOA) scores, Visual Analogue Scale (VAS) and complications. RESULTS: The patients in both groups had significant ROM loss after surgery in six directions of motion. At the 12th month follow-up, the LP group preserved more ROM than LCF in all directions except bilateral rotations. Major reduction was observed in extension, as with only 59.8% and 54.3% ROM preserved in LP and LCF groups. However, the most preserved ROM was witnessed in rotation, especially in the LP group (90.8%). For JOA and VAS, both groups showed significant improvements postoperatively, and the difference between the two groups was not statistically significant. CONCLUSIONS: Patients with OPLL had an obvious reduction in active cervical ROM following LP and LCF. Major reduction was observed in extension, and less impact was detected on rotation. Compared with LCF, LP had better ROM preserved. Both LP and LCF provided patients with significant neurological improvement. PMID- 25929464 TI - Cobalt and chromium exposure affects osteoblast function and impairs the mineralization of prosthesis surfaces in vitro. AB - Cobalt (Co) and chromium (Cr) ions and nanoparticles equivalent to those released through tribo-corrosion of prosthetic metal-on-metal (MOM) bearings and taper junctions are detrimental to osteoblast activity and function in vitro when examined as individual species. Here we examined the effects of Co(2+):Cr(3+) and Co(2+):Cr(6+) combinations on osteoblast-like SaOS-2 cellular activity, alkaline phosphatase (ALP) activity and mineralization to better reflect clinical exposure conditions in vivo. We also assessed the effect of Co(2+):Cr(3+) combinations and Co:Cr nanoparticles on SaOS-2 cell osteogenic responses on grit-blasted, plasma sprayed titanium-coated, and hydroxyapatite-coated prosthesis surfaces. Cellular activity and ALP activity were reduced to a greater extent with combination treatments compared to individual ions. Co(2+) and Cr(3+) interacted additively and synergistically to reduce cellular activity and ALP activity, respectively, while the Co(2+) with Cr(6+) combination was dominated by the effect of Cr(6+) alone. Mineralization by osteoblasts was greater on hydroxyapatite-coated surfaces compared to grit-blasted and plasma-sprayed titanium-coated surfaces. Treatments with Co(2+):Cr(3+) ions and Co:Cr nanoparticles reduced the percentage mineralization on all surfaces, with hydroxyapatite-coated surfaces having the least reduction. In conclusion, our data suggests that previous studies investigating individual metal ions underestimate their potential clinical effects on osteoblast activity. Furthermore, the data suggests that hydroxyapatite-coated surfaces may modulate osteoblast responses to metal debris. PMID- 25929465 TI - TLR9-induced miR-155 and Ets-1 decrease expression of CD1d on B cells in SLE. AB - B cells present lipid antigens to CD1d-restricted invariant natural killer T (iNKT) cells to maintain autoimmune tolerance, and this process is disrupted in systemic lupus erythematosus (SLE). Inflammation may inhibit CD1d expression to exacerbate the pathology of lupus. However, how inflammation regulates CD1d expression on B cells is unclear in SLE. In the present study, we showed that the surface expression of CD1d on B cells from SLE mice was decreased and that stimulation of inflammatory responses through TLR9 decreased the membrane and total CD1d levels of CD1d on B cells. Moreover, inflammation-related microRNA-155 (miR-155) negatively correlated with the expression of CD1d in B cells. miR-155 directly targeted the 3'-untranslated region (3'-UTR) of CD1d upon TLR9 activation in both humans and mice. The inhibitory effects of miR-155 on CD1d expression in B cells impaired their antigen-presenting capacity to iNKT cells. In addition, Ets-1, a susceptibility gene of SLE, also directly regulated the expression of the CD1d gene at the transcriptional level. These findings provide new insight into the mechanism underlying decreased CD1d expression on B cells in SLE, suggesting that inhibition of inflammation may increase CD1d expression in B cells to ameliorate SLE via modulating iNKT cells. PMID- 25929467 TI - Executive Summary of Key Concepts. PMID- 25929466 TI - VISIONET: intuitive visualisation of overlapping transcription factor networks, with applications in cardiogenic gene discovery. AB - BACKGROUND: Existing de novo software platforms have largely overlooked a valuable resource, the expertise of the intended biologist users. Typical data representations such as long gene lists, or highly dense and overlapping transcription factor networks often hinder biologists from relating these results to their expertise. RESULTS: VISIONET, a streamlined visualisation tool built from experimental needs, enables biologists to transform large and dense overlapping transcription factor networks into sparse human-readable graphs via numerically filtering. The VISIONET interface allows users without a computing background to interactively explore and filter their data, and empowers them to apply their specialist knowledge on far more complex and substantial data sets than is currently possible. Applying VISIONET to the Tbx20-Gata4 transcription factor network led to the discovery and validation of Aldh1a2, an essential developmental gene associated with various important cardiac disorders, as a healthy adult cardiac fibroblast gene co-regulated by cardiogenic transcription factors Gata4 and Tbx20. CONCLUSIONS: We demonstrate with experimental validations the utility of VISIONET for expertise-driven gene discovery that opens new experimental directions that would not otherwise have been identified. PMID- 25929468 TI - Hospitals of the future. PMID- 25929469 TI - The influence of flooring on environmental stressors: a study of three flooring materials in a hospital. AB - OBJECTIVE: Three flooring materials, terrazzo, rubber, and carpet tile, in patient unit corridors were compared for absorption of sound, comfort, light reflectance, employee perceptions and preferences, and patient satisfaction. BACKGROUND: Environmental stressors, such as noise and ergonomic factors, effect healthcare workers and patients, contributing to increased fatigue, anxiety and stress, decreased productivity, and patient safety and satisfaction. METHODS: A longitudinal comparative cohort study comparing three types of flooring assessed sound levels, healthcare worker responses, and patient Hospital Consumer Assessment of Healthcare Providers and Systems (HCAHPS) ratings over 42 weeks. A linear mixed model analysis was conducted to determine significant differences between the means for participant responses and objective sound meter data during all three phases of the study. RESULTS: A significant difference was found for sound levels between flooring type for equivalent continuous sound levels. Carpet tile performed better for sound attenuation by absorption, reducing sound levels 3.14 dBA. Preferences for flooring materials changed over the course of the study. The HCAHPS ratings aligned with the sound meter data showing that patients perceived the noise levels to be lower with carpet tiles, improving patient satisfaction ratings. CONCLUSIONS: Perceptions for healthcare staff and patients were aligned with the sound meter data. Carpet tile provides sound absorption that affects sound levels and influences occupant's perceptions of environmental factors that contribute to the quality of the indoor environment. Flooring that provides comfort underfoot, easy cleanability, and sound absorption influence healthcare worker job satisfaction and patient satisfaction with their patient experience. PMID- 25929470 TI - Art viewing directives in hospital settings effect on mood. AB - OBJECTIVE: The purpose of this study was to determine the effect viewing directives can have when encountering art in hospitals. A secondary objective of the study was to understand the responses of viewers to an art exhibit on the theme of medical student empathy toward patient pain and suffering. BACKGROUND: Displaying art in hospitals has been credited with increasing well-being of patients, visitors, and staff. Generally, hospital curators have focused on the type of art to display (natural, symbolic, and abstract). This focus has neglected the possibility that in addition to the type of art, the way that viewers engage art may also be responsible for the healing effect. METHODS: Participants (n = 97) were randomly allocated into one of the viewing directives: (1) reflecting on one artwork, (2) creating a drawing or poem in response to one artwork, or (3) no direction. Prior to looking at the art and immediately after, participants were administered the Brief Mood Introspection Scale (BMIS) and offered an opportunity to participate in an interview. RESULTS: Pre-post results of the BMIS demonstrated that viewers who received directions achieved some therapeutic effect. Qualitative themes from the post-exhibit interviews identified that the empathy themed exhibit was well received, although there were differences among responses from patients, visitors, and staff. CONCLUSIONS: The results imply that hospitals may consider offering prompts to help viewers engage with art to enhance mood and exhibiting art that demonstrates empathy for patient suffering. PMID- 25929471 TI - Identifying elements of the health care environment that contribute to wayfinding. AB - OBJECTIVES: Identify aspects of the physical environment that inform wayfinding for visitors. Compare and contrast the identified elements in frequency of use. Gain an understanding of the role the different elements and attributes play in the wayfinding process. BACKGROUND: Wayfinding by patients and visitors is a documented problem in healthcare facilities. The few studies that have been conducted have identified some of the environmental elements that influence wayfinding. Moreover, literatures comparing different design strategies are absent. Currently there is limited knowledge to inform prioritization of strategies to optimize wayfinding within capital budget. METHODS: A multi-method, non-experimental, qualitative, exploratory study design was adopted. The study was conducted in a large, acute care facility in Texas. Ten healthy adults in five age groups, representing both sexes, participated in the study as simulated visitors. Data collection included (a) verbal protocols during navigation; (b) questionnaire; and (c) verbal directions from hospital employees. Data were collected during Fall 2013. RESULTS: Physical design elements contributing to wayfinding include signs, architectural features, maps, interior elements (artwork, display boards, information counters, etc.), functional clusters, interior elements pairing, structural elements, and furniture. The information is used in different ways - some for primary navigational information, some for supporting navigational information, and some as familiarity markers. CONCLUSIONS: The physical environment has a critical role in aiding navigation in healthcare facilities. Architectural feature is the top contributor in the domain of architecture. Artwork (painting, sculpture, etc.) is the top contributor in the domain of interior design. PMID- 25929472 TI - Infection control in design and construction work. AB - OBJECTIVE: To clarify how infection control requirements are represented, communicated, and understood in work interactions through the medical facility construction project life cycle. To assist project participants with effective infection control management by highlighting the nature of such requirements and presenting recommendations to aid practice. BACKGROUND: A 4-year study regarding client requirement representation and use on National Health Service construction projects in the United Kingdom provided empirical evidence of infection control requirement communication and understanding through design and construction work interactions. METHODS: An analysis of construction project resources (e.g., infection control regulations and room data sheets) was combined with semi structured interviews with hospital client employees and design and construction professionals to provide valuable insights into the management of infection control issues. RESULTS: Infection control requirements are representationally indistinct but also omnipresent through all phases of the construction project life cycle: Failure to recognize their nature, relevance, and significance can result in delays, stoppages, and redesign work. Construction project resources (e.g., regulatory guidance and room data sheets) can mask or obscure the meaning of infection control issues. CONCLUSIONS: A preemptive identification of issues combined with knowledge sharing activities among project stakeholders can enable infection control requirements to be properly understood and addressed. Such initiatives should also reference existing infection control regulatory guidance and advice. PMID- 25929473 TI - Housing choices and care home design for people with dementia. AB - This article reviews the current state of housing for people with dementia by exploring housing choices available to this group, and identifying potential issues with design of care homes. Older people who wish to age in place are faced with the challenge of adapting their domestic environment to ensure independence, accessibility, and social connectivity. This is even more challenging for people with dementia who continue to live at home, given the risks of self-harm and getting lost. More imaginative and inclusive forms of collective housing are needed. For people with dementia, a move to a new environment is often a stressful experience that causes shock, withdrawal, and anger. Hence, more research is needed to develop more fitting long-term housing options for people with dementia. This article presents a brief review on housing choices and housing design for people with dementia. Interviews with managers of 22 care homes were conducted to explore housing choices and design issues. Results show that the main housing choices available to people with dementia offer different levels of care. The choice of care homes relates to the atmosphere of a home as some occupants favor a homely or relaxing environment and others prefer dynamic settings. A combination of appropriate level of care, a good atmosphere, and design quality within the care home are elements that lead to a more enabling environment. Design of a successful caring environment also requires appropriate care and a positive therapeutic and domestic-looking environment. PMID- 25929474 TI - Evaluating Evidence-Based Studies and Design Projects. PMID- 25929475 TI - Reinventing Emergency Department Flow via Healthcare Delivery Science. AB - Healthcare system flow resulting in emergency departments (EDs) crowding is a quality and access problem. This case study examines an overcrowded academic health center ED with increasing patient volumes and limited physical space for expansion. ED capacity and efficiency improved via engineering principles application, addressing patient and staffing flows, and reinventing the delivery model. Using operational data and staff input, patient and staff flow models were created, identifying bottlenecks (points of inefficiency). A new flow model of emergency care delivery, physician-directed queuing, was developed. Expanding upon physicians in triage, providers passively evaluate all patients upon arrival, actively manage patients requiring fewer resources, and direct patients requiring complex resources to further evaluation in ED areas. Sustained over time, ED efficiency improved as measured by near elimination of "left without being seen" patients and waiting times with improvement in door to doctor, patient satisfaction, and total length of stay. All improvements were in the setting on increased patient volume and no increase in physician staffing. Our experience suggests that practical application of healthcare delivery science can be used to improve ED efficiency. PMID- 25929476 TI - Case study: design may influence use of seclusion and restraint. AB - OBJECTIVE: The psychiatric emergency room is a dynamic and sometimes volatile environment. Its design may be an important variable in patient care, but most design decisions are based on models of thought and treatment with a minimal evidence base. BACKGROUND: The concept of open design, increasing access of patients to nursing staff, for inpatient psychiatric units has recently gained widespread acceptance, despite a dearth of empirical data. METHODS: We examined rates of seclusion and restraint before and after a design change that reduced the openness of the unit in a dedicated emergency psychiatric service in a general university hospital. Quality assurance data regarding the census, occurrence of assaults, and the use of seclusion and restraint were queried. Two independent analyses utilizing a test of proportional data were performed to replicate the findings. RESULTS: After placement of a door to restrict patients' access to the waiting area of the unit, the rate of the use of seclusion and restraint went from 0.03 (44/777) to 0.0185 (27/1,514; z = 2.02, p < .04). Replication over a separate time period saw reduction from 0.029 (67/2,277) to 0.018 (44/2,431), z = 2.44, p < .02). CONCLUSION: A design change that reduced the openness of the unit resulted in the reduction of seclusion and restraint. PMID- 25929477 TI - Overuse leads to the cliche. PMID- 25929479 TI - Early diagnostic value of Bcl-3 localization in colorectal cancer. AB - BACKGROUND: B-cell leukemia 3 (Bcl-3) is a member of the inhibitor of kappaB family, which regulates a wide range of biological processes by functioning as a transcriptional activator or as a repressor of target genes. Elevated expression, sustained nuclear accumulation, and uncontrolled activation of Bcl-3 causes increased cellular proliferation or survival, dependent on the tissue and type of stimuli. METHODS: We retrospectively reviewed patients who were diagnosed with colorectal cancer at Skane University Hospital in Malmo between 1st of January 1990 and 31st of December 1991. Bcl-3 localization in colorectal cancer was assessed by immunohistochemistry on tissue microarray and freshly isolated colon from patients. Correlation between Bcl-3 localization and clinicopathological parameters of the cohort were evaluated using the Spearman rank-order correlation coefficient. In addition, Bcl-3 expression and localization in colon adenocarcinoma cells were analysed by western blot, immunohistochemistry and subcellular fractionation separately. RESULTS: We found that Bcl-3 was mainly localized in the cytoplasm in the tumour tissue isolated from colon cancer patients. Normal colon samples from the same patients showed Bcl-3 localization in the nucleus. In three out of six colon cancer cell lines, we detected elevated levels of Bcl-3. In these cell lines Bcl-3 was accumulated in the cytosol. We confirmed these findings by analysing Bcl-3 localization in a colon tissue micro array consisting of 270 cases. In these samples Bcl-3 localization correlated with the proliferation marker Ki-67, but not with the apoptotic marker Caspase 3. CONCLUSION: These findings indicate that analysis of the subcellular localization of Bcl-3 could be a potential-early diagnostic marker in colon cancer. PMID- 25929480 TI - Interfacing solid-state nanopores with gel media to slow DNA translocations. AB - We demonstrate the ability to slow DNA translocations through solid-state nanopores by interfacing the trans side of the membrane with gel media. In this work, we focus on two reptation regimes: when the DNA molecule is flexible on the length scale of a gel pore, and when the DNA behaves as persistent segments in tight gel pores. The first regime is investigated using agarose gels, which produce a very wide distribution of translocation times for 5 kbp dsDNA fragments, spanning over three orders of magnitude. The second regime is attained with polyacrylamide gels, which can maintain a tight spread and produce a shift in the distribution of the translocation times by an order of magnitude for 100 bp dsDNA fragments, if intermolecular crowding on the trans side is avoided. While previous approaches have proven successful at slowing DNA passage, they have generally been detrimental to the S/N, capture rate, or experimental simplicity. These results establish that by controlling the regime of DNA movement exiting a nanopore interfaced with a gel medium, it is possible to address the issue of rapid biomolecule translocations through nanopores-presently one of the largest hurdles facing nanopore-based analysis-without affecting the signal quality or capture efficiency. PMID- 25929482 TI - Breast feeding reduces risk of breast cancer recurrence, study finds. PMID- 25929481 TI - Assessing cycling-friendly environments for children: are micro-environmental factors equally important across different street settings? AB - BACKGROUND: As physical activity levels decrease as children age, sustainable and accessible forms of physical activity are needed from a young age. Transportation cycling is one such physical activity and has been associated with many benefits. The aims of the study were to identify whether manipulating micro-environmental factors (e.g. speed limits, evenness of cycle path) within a photographed street influences the perceived supportiveness for transportation cycling; and whether changing these micro-environmental factors has the same effect across different street settings. METHODS: We recruited 305 fifth and sixth grade children and their parents from twelve randomly selected primary schools in Flanders, Belgium. They completed a web-based questionnaire including 12 choice-based conjoint tasks, in which they had to choose between two possible routes depicted on manipulated photographs, which the child would cycle along. The routes differed in four attributes: general street setting (enclosed, half open, open), evenness of cycle path (very uneven, moderately uneven, even), speed limit (70 km/h, 50 km/h, 30 km/h) and degree of separation between a cycle path and motorised traffic (no separation, curb, hedge). Hierarchical Bayes analyses revealed the relative importance of each micro-environmental attribute across the three street settings. RESULTS: For each attribute, children and their parents chose routes that had the best alternative (i.e. open street setting, even cycle path, 30 km/h, a hedge separating the cycle path from motorised traffic). The evenness of the cycle path and lower speed limit had the largest effect for the children, while the degree of separation and lower speed limit had the largest effect for their parents. Interactions between micro-scale and macro-scale factors revealed differences in the magnitude but not direction of their effects on route choice. The results held across the different kinds of street settings tested. CONCLUSIONS: Improving micro-scale attributes may increase the supportiveness of a street for children's transportation cycling. We call for on-site research to test effects of changes in micro-environmental attributes on transportation cycling among children. PMID- 25929483 TI - L-Cysteine metabolism and its nutritional implications. AB - L-Cysteine is a nutritionally semiessential amino acid and is present mainly in the form of L-cystine in the extracellular space. With the help of a transport system, extracellular L-cystine crosses the plasma membrane and is reduced to L cysteine within cells by thioredoxin and reduced glutathione (GSH). Intracellular L-cysteine plays an important role in cellular homeostasis as a precursor for protein synthesis, and for production of GSH, hydrogen sulfide (H(2)S), and taurine. L-Cysteine-dependent synthesis of GSH has been investigated in many pathological conditions, while the pathway for L-cysteine metabolism to form H(2)S has received little attention with regard to prevention and treatment of disease in humans. The main objective of this review is to highlight the metabolic pathways of L-cysteine catabolism to GSH, H(2)S, and taurine, with special emphasis on therapeutic and nutritional use of L-cysteine to improve the health and well-being of animals and humans. PMID- 25929484 TI - Long-term digital mobile phone use and cognitive decline in the elderly. AB - Research on long-term exposure to electromagnetic fields on cognition is lacking. We investigated the associations between frequent digital mobile phone use and global and domain-specific cognitive changes in older persons, a vulnerable group experiencing age-associated cognitive decline. We assessed 871 non-demented Chinese participants in the Singapore Longitudinal Ageing Studies cohort on the frequency of digital mobile phone use, neurocognitive performance and confounding variables at baseline, and neurocognitive performance at the 4-year follow-up. Findings showed that digital mobile phone users were typically self-selected to possess characteristics favoring better cognitive functioning and concomitantly demonstrate better performance on cognitive tasks. There was evidently no significant deleterious effect of digital mobile phone use on cognitive functioning in older people. Findings suggest, however, that digital mobile phone use may have an independent facilitating effect on global and executive functioning. PMID- 25929485 TI - Development of a magnetic solid-phase extraction coupled with high-performance liquid chromatography method for the analysis of polyaromatic hydrocarbons. AB - A novel magnetic solid phase extraction coupled with high-performance liquid chromatography method was established to analyze polyaromatic hydrocarbons in environmental water samples. The extraction conditions, including the amount of extraction agent, extraction time, pH and the surface structure of the magnetic extraction agent, were optimized. The results showed that the amount of extraction agent and extraction time significantly influenced the extraction performance. The increase in the specific surface area, the enlargement of pore size, and the reduction of particle size could enhance the extraction performance of the magnetic microsphere. The optimized magnetic extraction agent possessed a high surface area of 1311 m(2) /g, a large pore size of 6-9 nm, and a small particle size of 6-9 MUm. The limit of detection for phenanthrene and benzo[g,h,i]perylene in the developed analysis method was 3.2 and 10.5 ng/L, respectively. When applied to river water samples, the spiked recovery of phenanthrene and benzo[g,h,i]perylene ranged from 89.5-98.6% and 82.9-89.1%, respectively. Phenanthrene was detected over a concentration range of 89-117 ng/L in three water samples withdrawn from the midstream of the Huai River, and benzo[g,h,i]perylene was below the detection limit. PMID- 25929486 TI - Intraocular localization of Onchocerca lupi adult worm in a dog with anterior uveitis: A case report. AB - OBJECTIVE: Canine ocular onchocercosis may represent an important ocular disease with zoonotic potential and widespread geographical distribution. An uncommon localization of Onchocerca lupi adult worm in the anterior chamber of the eye is described for the first time. ANIMAL STUDIED: A 4-year-old, intact, male, mixed breed dog was admitted with profuse lacrimation and severe squinting. On the right eye, there were mucopurulent discharge, chemosis, and all typical signs of anterior uveitis which were attributed to the presence of a moving filarial worm within the anterior chamber. PROCEDURE: Removal of the parasite from the anterior chamber by a limbal incision revealed a mature adult male, 7.65-cm-long O. lupi worm. Periocular skin scrapings for the corresponding microfilariae were negative. Postoperatively, apart from systemic prednisolone and doxycycline hyclate and a topical antibiotic/steroid solution, parenteral melarsomine, followed by ivermectin, was given until the complete disappearance of the ocular lesions. CONCLUSIONS: Intraocular onchocercosis should be included in the differential diagnosis of canine anterior uveitis in endemic areas. This case highlights the atypical localization of O. lupi in the canine eye emphasizing on the possibility for a complete cure after the surgical removal of the parasite and the filaricidal medication subsequently applied. PMID- 25929488 TI - Assuring quality in an age of rapid technological advance. PMID- 25929489 TI - New surgical technology: do we know what we are doing? PMID- 25929490 TI - Pancreatic cancer: gradual rise, increasing relevance. PMID- 25929491 TI - Smartphone app a lifesaver for patients after myocardial infarction. PMID- 25929493 TI - Cataract surgical blitzes: an Australian anachronism. PMID- 25929487 TI - Systems biology of host-microbe metabolomics. AB - The human gut microbiota performs essential functions for host and well-being, but has also been linked to a variety of disease states, e.g., obesity and type 2 diabetes. The mammalian body fluid and tissue metabolomes are greatly influenced by the microbiota, with many health-relevant metabolites being considered 'mammalian-microbial co-metabolites'. To systematically investigate this complex host-microbial co-metabolism, a systems biology approach integrating high throughput data and computational network models is required. Here, we review established top-down and bottom-up systems biology approaches that have successfully elucidated relationships between gut microbiota-derived metabolites and host health and disease. We focus particularly on the constraint-based modeling and analysis approach, which enables the prediction of mechanisms behind metabolic host-microbe interactions on the molecular level. We illustrate that constraint-based models are a useful tool for the contextualization of metabolomic measurements and can further our insight into host-microbe interactions, yielding, e.g., in potential novel drugs and biomarkers. PMID- 25929494 TI - Can magnetic resonance imaging solve the prostate cancer conundrum? PMID- 25929495 TI - Sceptics undermine effective dietary and heart health advice. PMID- 25929496 TI - Reappraising community treatment orders - can there be consensus? PMID- 25929497 TI - Copayments and the evidence-base paradox. PMID- 25929498 TI - Copayments and the evidence-base paradox. PMID- 25929499 TI - Consent, capacity and the right to say no. PMID- 25929500 TI - Let children cry. PMID- 25929501 TI - Let children cry. PMID- 25929502 TI - Point-of-care testing for coeliac disease antibodies - what is the evidence? PMID- 25929503 TI - Cytomegalovirus disease in immunocompetent adults. PMID- 25929504 TI - Acute pancreatitis: update on management. AB - Acute pancreatitis is a common acute surgical condition associated with high morbidity and mortality in severe cases. New guidelines for management have recently been published by the American College of Gastroenterology and by the International Association of Pancreatology in collaboration with the American Pancreatic Association. The main differences between the new and previous versions of the guidelines relate to the use of endoscopic retrograde cholangiopancreatography (ERCP) and the addition of the new severity category of 'moderately severe acute pancreatitis' All patients with pancreatitis should have its cause determined by features of the history, results of laboratory tests (liver function tests, serum calcium triglyceride levels) and findings on transabdominal ultrasound. Those with idiopathic pancreatitis should have endoscopic ultrasound as a first-line investigation. Acute pancreatitis should be managed with aggressive hydration with intravenous fluids and fasting. Oral feeding can be recommenced in mild pancreatitis once pain and nausea and vomiting have resolved. Patients with mild biliary pancreatitis should have a laparoscopic cholecystectomy during their index admission. In addition to aggressive intravenous fluid resuscitation and fasting, patients with severe pancreatitis should have enteral feeding (nasoenteric or nasogastric feeds) commenced 48 hours after presentation. Total parenteral nutrition should be avoided where possible. All patients with organ failure or severe pancreatitis as defined by the revised version of the Atlanta classification should be managed in an intensive care setting. Patients with biliary pancreatitis and concurrent cholangitis should have endoscopic retrograde cholangiopancreatography within 24 hours of presentation. PMID- 25929505 TI - Hospitals should be exemplars of healthy workplaces. AB - As major employers and flagship health care organisations, hospitals can influence the norms of the communities they serve by adopting model policies and practices that promote the health of patients, visitors, employees, students and trainees. Hospitals must become healthy workplaces in every sense and extend their role to focus on health and wellness, not just illness. Reorienting hospital policies can: ensure the provision and stewardship of healthy, ecologically sound and sustainable environments; increase the focus on promoting health and prevention; foster interpersonal safety; and improve workplace safety. Such efforts deliver improvements in health outcomes and savings in hospital budgets. PMID- 25929506 TI - Cost and outcomes of assessing patients with chest pain in an Australian emergency department. AB - OBJECTIVES: We sought to characterise the demographics, length of admission, final diagnoses, long-term outcome and costs associated with the population who presented to an Australian emergency department (ED) with symptoms of possible acute coronary syndrome (ACS). DESIGN, SETTING AND PARTICIPANTS: Prospectively collected data on ED patients presenting with suspected ACS between November 2008 and February 2011 was used, including data on presentation and at 30 days after presentation. Information on patient disposition, length of stay and costs incurred was extracted from hospital administration records. MAIN OUTCOME MEASURES: Primary outcomes were mean and median cost and length of hospital stay. Secondary outcomes were diagnosis of ACS, other cardiovascular conditions or non cardiovascular conditions within 30 days of presentation. RESULTS: An ACS was diagnosed in 103 (11.1%) of the 926 patients recruited. 193 patients (20.8%) were diagnosed with other cardiovascular-related conditions and 622 patients (67.2%) had non-cardiac-related chest pain. ACS events occurred in 0 and 11 (1.9%) of the low-risk and intermediate-risk groups, respectively. Ninety-two (28.0%) of the 329 high-risk patients had an ACS event. Patients with a proven ACS, high-grade atrioventricular block, pulmonary embolism and other respiratory conditions had the longest length of stay. The mean cost was highest in the ACS group ($13 509; 95% CI, $11 794-$15 223) followed by other cardiovascular conditions ($7283; 95% CI, $6152-$8415) and non-cardiovascular conditions ($3331; 95% CI, $2976-$3685). CONCLUSIONS: Most ED patients with symptoms of possible ACS do not have a cardiac cause for their presentation. The current guideline-based process of assessment is lengthy, costly and consumes significant resources. Investigation of strategies to shorten this process or reduce the need for objective cardiac testing in patients at intermediate risk according to the National Heart Foundation and Cardiac Society of Australia and New Zealand guideline is required. PMID- 25929507 TI - Priorities for professionalism: what do surgeons think? AB - OBJECTIVE: To gain an understanding of the relative importance of the nine surgical competencies and their 27 attributes defined by the Royal Australasian College of Surgeons (RACS), which together provide the curriculum framework for today's surgeons. DESIGN, SETTING AND PARTICIPANTS: Between 9 August and 30 September 2010, trainees and Fellows of the RACS across Australia and New Zealand actively involved in educational activities rated, via questionnaire, the importance of the RACS competencies (technical expertise, communication, professionalism, medical expertise, judgement and decision making, scholarship and teaching, collaboration and teamwork, management and leadership, and health advocacy) and associated attributes. MAIN OUTCOME MEASURES: Importance ranking of competencies and their attributes for surgical education and training. RESULTS: Of 3054 questionnaires distributed, 1834 (60%) were returned. We identified clear priorities in the perceived relative importance of the nine competencies and 27 attributes. The most important attributes were competence, insight, and recognising conditions amenable to surgery; least important were responding to community and cultural needs, supporting others, and maintaining personal health and wellbeing. Key differences were noted for the competency of collaboration and teamwork, which was ranked as more important by trainees than by Fellows. Female trainees and Fellows regarded all attributes as more important than did male trainees and Fellows. CONCLUSION: In a complex environment with multiple pressures, the priorities of the competencies are important. Trainees and Fellows had a very similar approach to the prioritisation of the attributes. Of concern is the lesser importance given to attributes beyond individual expertise. PMID- 25929508 TI - A prospective cohort study of trends in self-poisoning, Newcastle, Australia, 1987-2012: plus ca change, plus c'est la meme chose. AB - OBJECTIVE: To examine inhospital mortality and morbidity associated with self poisoning with different drug classes over an extended period. DESIGN, SETTING AND PARTICIPANTS: A prospective cohort study over 26 years (1987-2012) with limited follow-up of patients presenting consecutively to a primary and tertiary referral toxicology centre covering Newcastle, Lake Macquarie and Port Stephens, Australia. MAIN OUTCOME MEASURES: Hospital length of stay, types of drugs ingested, intensive care unit (ICU) admission, requirement for ventilation, inhospital deaths and rates of antidepressant drug use in Australia. RESULTS: Over the study period, there were 17 266 admissions of patients poisoned by 34 342 substances (16 723 drugs available only on prescription). The median length of stay was 16 hours, 12.2% of patients (2101/17 266) were admitted to an ICU, 7.4% (1281/17 266) were ventilated and 78 (0.45%) died in hospital. Patient demographics, social and psychiatric factors remained stable over the 26-year period, but case fatality decreased (from 0.77% [15/1955] to 0.17% [7/4060]) as did ICU admissions (19.2% [376/1955] to 6.9% [280/4060]), ventilation (13.7% [268/1955] to 4.8% [193/4060]) and LOS. The most frequently ingested substances were alcohol, benzodiazepines, paracetamol, antidepressants and antipsychotics. There was a substantial fall in some highly toxic drugs (tricyclic antidepressants, barbiturates, conventional antipsychotics and theophylline), but increases in less toxic selective serotonin reuptake inhibitors, serotonin noradrenaline reuptake inhibitors and paracetamol. A greater than sixfold increase in community antidepressant use was accompanied by only minor changes in overall and antidepressant self-poisoning rates. CONCLUSION: Over two decades, there were decreases in poisonings by many highly toxic drugs which were associated with substantial reductions in morbidity and inhospital deaths. Despite massive increases in the number of antidepressant prescriptions, neither rates of self-harm nor the proportion of antidepressant poisonings increased markedly. PMID- 25929509 TI - Pancreatic adenocarcinoma presenting as first-onset diabetic ketoacidosis. PMID- 25929510 TI - Severe carbon monoxide poisoning from waterpipe smoking: a public health concern. PMID- 25929511 TI - Listeriosis cluster in Sydney linked to hospital food. PMID- 25929512 TI - The whole 9 years. PMID- 25929513 TI - The politician: a public health problem? PMID- 25929514 TI - Signaling networks organizing regenerative growth of the zebrafish fin. AB - In contrast to mammals, adult salamanders and fish can completely regenerate their appendages after amputation. The cellular and molecular mechanisms underlying this fascinating phenomenon are beginning to emerge, including substantial progress in the identification of signals that control regenerative growth of the zebrafish caudal fin. Despite the fairly simple architecture of the fin, the regulation of its regeneration is complex. Many signals, including fibroblast growth factor (FGF), Wnt, Hedgehog (Hh), retinoic acid (RA), Notch, bone morphogenic protein (BMP), activin, and insulin-like growth factor (IGF), are required for regeneration. Much work needs to be done to dissect tissue specific functions of these pathways and how they interact, but Wnt/beta-catenin signaling is already emerging as a central player. Surprisingly, Wnt/beta-catenin signaling appears to largely indirectly control epidermal patterning, progenitor cell proliferation, and osteoblast maturation via regulation of a multitude of secondary signals. PMID- 25929515 TI - A low-cost and advanced SiOx-C composite with hierarchical structure as an anode material for lithium-ion batteries. AB - A cost-efficient and scalable method is designed to prepare a SiOx-C composite with superior cyclability and excellent rate performance. The glucose addition in a two-step way induces a hierarchical structure, where individual SiOx nanoparticles are wrapped by a conductive carbon layer and these agglomerated particles are further wrapped by a carbon shell functioning as an electrolyte blocking layer. Instrumental analysis indicates that the SiOx domains are comprised of SiO2 and SiO. The SiOx-C anode exhibits a high reversible specific capacity of 674.8 mA h g(-1) after 100 cycles at 100 mA g(-1) with a capacity retention of about 83.5%. The excellent electrochemical performance is due to the hierarchical structure, the well-dispersed conductive carbon network, and the Li2O and Li4SiO4 generated in the initial discharge process, all of which can immensely relieve the volume expansion induced by the lithiation of silicon. This hierarchical SiOx-C composite has a promising prospect of practical application given its adequate storage capacity, good cycling stability, commercially available materials and simple equipment. PMID- 25929516 TI - AKIN10 delays flowering by inactivating IDD8 transcription factor through protein phosphorylation in Arabidopsis. AB - BACKGROUND: Sugar plays a central role as a source of carbon metabolism and energy production and a signaling molecule in diverse growth and developmental processes and environmental adaptation in plants. It is known that sugar metabolism and allocation between different physiological functions is intimately associated with flowering transition in many plant species. The INDETERMINATE DOMAIN (IDD)-containing transcription factor IDD8 regulates flowering time by modulating sugar metabolism and transport under sugar-limiting conditions in Arabidopsis. Meanwhile, it has been reported that SUCROSE NONFERMENTING-1-RELATED PROTEIN KINASE 1 (SnRK1), which acts as a sensor of cellular energy metabolism, is activated by sugar deprivation. Notably, SnRK1-overexpressing plants and IDD8 deficient mutants exhibit similar phenotypes, including delayed flowering, suggesting that SnRK1 is involved in the IDD8-mediated metabolic control of flowering. RESULTS: We examined whether the sugar deprivation-sensing SnRK1 is functionally associated with IDD8 in flowering time control through biochemical and molecular genetic approaches. Overproduction of AKIN10, the catalytic subunit of SnRK1, delayed flowering in Arabidopsis, as was observed in IDD8-deficient idd8-3 mutant. We found that AKIN10 interacts with IDD8 in the nucleus. Consequently, AKIN10 phosphorylates IDD8 primarily at two serine (Ser) residues, Ser-178 and Ser-182, which reside in the fourth zinc finger (ZF) domain that mediates DNA binding and protein-protein interactions. AKIN10-mediated phosphorylation did not affect the subcellular localization and DNA-binding property of IDD8. Instead, the transcriptional activation activity of the phosphorylated IDD8 was significantly reduced. Together, these observations indicate that AKIN10 antagonizes the IDD8 function in flowering time control, a notion that is consistent with the delayed flowering phenotypes of AKIN10 overexpressing plants and idd8-3 mutant. CONCLUSION: Our data show that SnRK1 and its substrate IDD8 constitute a sugar metabolic pathway that mediates the timing of flowering under sugar deprivation conditions. In this signaling scheme, the SnRK1 signals are directly integrated into the IDD8-mediated gene regulatory network that governs flowering transition in response to fluctuations in sugar metabolism, further supporting the metabolic control of flowering. PMID- 25929517 TI - Colorectal carcinomas with KRAS codon 12 mutation are associated with more advanced tumor stages. AB - BACKGROUND: KRAS mutation occurs in 35%-40% of colorectal cancer (CRC). The aim of our study was to evaluate the pathological and molecular features of specific KRAS mutated colorectal carcinomas. KRAS and BRAF (V600E) mutation tests were performed in 762 primary tumors from a consecutive cohort study of Chinese CRC patients. METHODS: DNA mismatch repair (MMR) status was determined by immunohistochemistry (IHC) staining. Assessment of KRAS and BRAF V600E mutational status was performed using a multiplex allele-specific PCR-based assay. RESULTS: Mutations of KRAS (34.8%) and BRAF (V600E) (3.1%) were nearly mutually exclusive. Both KRAS- and BRAF- mutated tumors were more likely to be located at proximal colon than wild-type (WT) carcinomas. KRAS-mutated carcinomas were more frequently observed in female patients (47.5% vs 37.1%, p = 0.005) and mucinous differentiation (34.7% vs 24.8%, p = 0.004), but have no difference between lymph node (LN) metastases and among pTNM stages. Whereas, BRAF-mutated carcinomas more frequently demonstrated histologic features such as proximal location (60.9% vs 20.9%, p = 0.001), low-grade histology (43.5% vs 18.0%, p = 0.005), mucinous differentiation (69.6% vs 25.9%, p = 0.001) and deficient MMR (dMMR) (21.7% vs 7.6%, p = 0.03). In particular, KRAS codon 12 mutated carcinomas had increased lymph node metastasis (odds ratio [OR] = 1.31; 95% confidence interval [CI] = 1.04 to 1.65; P = 0.02) and were more likely in higher disease stage (III-IV) than that of WT carcinomas (OR = 1.30; 95% CI = 1.03 to 1.64; P = 0.03). However, there were no significant differences in lymph node metastasis and disease stage between KRAS codon 13 mutated carcinoma and WT carcinoma patients. CONCLUSIONS: In summary, KRAS codon 12 mutation, but not codon 13 mutation, is associated with lymph node metastasis and higher tumor stages. PMID- 25929518 TI - Beneficial effects of quercetin on renal injury and oxidative stress caused by ciprofloxacin in rats: A histological and biochemical study. AB - Ciprofloxacin is a broad-spectrum quinolone antibiotic commonly used in clinical practice. Quercetin is an antioxidant belongs to flavonoid group. It inhibits the production of superoxide anion. In this study, we aimed to evaluate the effects of quercetin on renal injury and oxidative stress caused by ciprofloxacin. Twenty eight female Wistar albino rats were divided into four groups: control, quercetin (20 mg kg(-1) day(-1) gavage for 21 days), ciprofloxacin (20 mg kg(-1) twice a day intraperitoneally for 10 days), and ciprofloxacin + quercetin. Samples were processed for histological and biochemical evaluations. Malondialdehyde (MDA) and glutathione (GSH) levels, superoxide dismutase (SOD), and catalase (CAT) activities were measured in kidney tissue. The ciprofloxacin group showed histopathological changes such as infiltration, dilatation in tubules, tubular atrophy, reduction of Bowman's space, congestion, hemorrhage, and necrosis. In the ciprofloxacin + quercetin group, these histopathological changes markedly reduced. MDA levels increased in the ciprofloxacin group and decreased in the ciptofloxacin + quercetin group. SOD and CAT activities and GSH levels significantly decreased in the ciprofloxacin group. On the other hand, in the ciprofloxacin + quercetin group, SOD and CAT activities and GSH levels significantly increased with regard to the ciprofloxacin group. We concluded that quercetin has antioxidative and therapeutic effects on renal injury and oxidative stress caused by ciprofloxacin in rats. PMID- 25929519 TI - Mechanical properties of normal versus cancerous breast cells. AB - A cell's mechanical properties are important in determining its adhesion, migration, and response to the mechanical properties of its microenvironment and may help explain behavioral differences between normal and cancerous cells. Using fluorescently labeled peroxisomes as microrheological probes, the interior mechanical properties of normal breast cells were compared to a metastatic breast cell line, MDA-MB-231. To estimate the mechanical properties of cell cytoplasms from the motions of their peroxisomes, it was necessary to reduce the contribution of active cytoskeletal motions to peroxisome motion. This was done by treating the cells with blebbistatin, to inhibit myosin II, or with sodium azide and 2-deoxy-D-glucose, to reduce intracellular ATP. Using either treatment, the peroxisomes exhibited normal diffusion or subdiffusion, and their mean squared displacements (MSDs) showed that the MDA-MB-231 cells were significantly softer than normal cells. For these two cell types, peroxisome MSDs in treated and untreated cells converged at high frequencies, indicating that cytoskeletal structure was not altered by the drug treatment. The MSDs from ATP-depleted cells were analyzed by the generalized Stokes-Einstein relation to estimate the interior viscoelastic modulus G* and its components, the elastic shear modulus G' and viscous shear modulus G", at angular frequencies between 0.126 and 628 rad/s. These moduli are the material coefficients that enter into stress-strain relations and relaxation times in quantitative mechanical models such as the poroelastic model of the interior regions of cancerous and non-cancerous cells. PMID- 25929520 TI - Novel aberrant genetic and epigenetic events in Friedreich's ataxia. AB - It is generally accepted that Friedreich's ataxia (FRDA) is caused by a deficiency in frataxin expression, a mitochondrial protein involved in iron homeostasis, which mainly affects the brain, dorsal root ganglia of the spinal cord, heart and in certain cases the pancreas. However, there is little knowledge as to other possible genes that may be affected in this disorder, and which can contribute to its complexity. In the current study we compared human periodontal ligament cells gene expression of healthy individuals and FRDA patients. The expression of active-caspase 3, as well as other apoptosis-related genes, was increased in the FRDA cells. Furthermore, iron-sulphur cluster genes, as well as oxidative stress-related genes were overexpressed in FRDA. Moreover, brain derived neurotrophic factor, neuregulin 1 and miR-132 were all upregulated. These three genes are capable of regulating the expression of each other. Interestingly, when the cells from FRDA patients were co-cultured in the presence of idebenone and deferiprone, caspase expression decreased while antioxidant gene expression, as well as frataxin expression, increased. Regarding epigenetic mechanisms, the frataxin gene was hypermethylated, compared to the healthy counterparts, in the upstream GAA repetitive region. Of the three DNA methyltransferases, DNMT1 but not DNMT3's gene expression was higher in FRDA cells. In conclusion, our data show that FRDA cells present altered expression of genes related to cell cycle, oxidative stress and iron homeostasis which may be implicated in the increased apoptotic levels. Also, the altered expression is in a certain degree normalized in the presence of idebenone and deferiprone. PMID- 25929521 TI - Stabilization of gene expression and cell morphology after explant recycling during fin explant culture in goldfish. AB - The development of fin primary cell cultures for in vitro cellular and physiological studies is hampered by slow cell outgrowth, low proliferation rate, poor viability, and sparse cell characterization. Here, we investigated whether the recycling of fresh explants after a first conventional culture could improve physiological stability and sustainability of the culture. The recycled explants were able to give a supplementary cell culture showing faster outgrowth, cleaner cell layers and higher net cell production. The cells exhibited a highly stabilized profile for marker gene expression including a low cytokeratin 49 (epithelial marker) and a high collagen 1a1 (mesenchymal marker) expression. Added to the cell spindle-shaped morphology, motility behavior, and actin organization, this suggests that the cells bore stable mesenchymal characteristics. This contrast with the time-evolving expression pattern observed in the control fresh explants during the first 2 weeks of culture: a sharp decrease in cytokeratin 49 expression was concomitant with a gradual increase in col1a1. We surmise that such loss of epithelial features for the benefit of mesenchymal ones was triggered by an epithelial to mesenchymal transition (EMT) process or by way of a progressive population replacement process. Overall, our findings provide a comprehensive characterization of this new primary culture model bearing mesenchymal features and whose stability over culture time makes those cells good candidates for cell reprogramming prior to nuclear transfer, in a context of fish genome preservation. PMID- 25929522 TI - The effects of drugs with immunosuppressive or immunomodulatory activities on xenobiotics-metabolizing enzymes expression in primary human hepatocytes. AB - In this paper we investigated the effects of several drugs used in transplant medicine, i.e. cyclosporine A, tacrolimus, rapamycin, everolimus, mycophenolate mofetil, fluvastatin and rosuvastatin, on the expression of major drug metabolizing enzymes in human hepatocytes. Moreover, we tested the ability of these drugs to affect transcriptional activity of glucocorticoid (GR) and aryl hydrocarbon receptor (AhR). We found that most of tested compounds did not induce expression of CYP1A1/1A2/3A4/2A6/2B6/2C9 mRNAs in human hepatocytes. Slight induction was observed for CYP2A6/2C9 mRNAs and CYP2A6 protein in the rapamycin treated hepatocytes. Decrease of CYP2A6 and CYP2B6 proteins was observed in rosuvastatin-treated cells. Mycophenolate mofetil antagonized the effects of dexamethasone on GR but it potentiated the action of dioxin on AhR. Induction of CYP1A1 mRNA in HepG2 cells by dioxin was modestly antagonized by mycophenolate mofetil, while the induction by benzo[a]pyren or S-omeprazole was significantly potentiated by this drug. In general, tested compounds can be considered safe in the terms of possible drug-drug interaction caused by induction of drug metabolizing cytochromes P450. Nevertheless, mycophenolate mofetil is of possible concern and its combination with drugs, environmental pollutants or food constituents, which activate AhR, may represent a significant toxicological risk. PMID- 25929523 TI - Angular Determination of Toolmarks Using a Computer-Generated Virtual Tool. AB - A blind study to determine whether virtual toolmarks created using a computer could be used to identify and characterize angle of incidence of physical toolmarks was conducted. Six sequentially manufactured screwdriver tips and one random screwdriver were used to create toolmarks at various angles. An apparatus controlled tool angle. Resultant toolmarks were randomly coded and sent to the researchers, who scanned both tips and toolmarks using an optical profilometer to obtain 3D topography data. Developed software was used to create virtual marks based on the tool topography data. Virtual marks generated at angles from 30 to 85 degrees (5 degrees increments) were compared to physical toolmarks using a statistical algorithm. Twenty of twenty toolmarks were correctly identified by the algorithm. On average, the algorithm misidentified the correct angle of incidence by -6.12 degrees . This study presents the results, their significance, and offers reasons for the average angular misidentification. PMID- 25929524 TI - Medicines for cancers in children: The WHO model for selection of essential medicines. AB - Pressures to include more cancer medicines in the WHO Model List of Essential Medicines (EML) pose challenges for the Expert Committee responsible for recommending changes to the list. How do medicines for cancer fit within a definition of essential medicines as those meeting the priority health needs of the population? Will identifying a medicine as "essential" offer some leverage to improve access to effective cancer medicines in low and middle-income countries (LMICs)? The addition of a number of medicines for the treatment of cancers in children to the Model List of Essential Medicines for Children (EMLc) in 2011 provides important insights into previous Expert Committee decision-making and offers a platform for future deliberations. As combination chemotherapy is required for effective treatment of many malignancies, a disease-based approach makes more sense than an agent-based approach. Inadequate financing to purchase essential medicines is a reality in many LMICs, thus a consideration of health impact is central to decisions on the selection and procurement of medicines. Inclusion in national EMLs should identify medicines that have priority for procurement in the public sector. This article will discuss some of the factors taken into account by the Expert Committee in developing the WHO EMLc. We argue that the disease-based approach coupled with the assessment of the magnitude of the clinical benefit provides an appropriate approach for considering further additions of medicines for pediatric cancers and for the review of the adult cancer section of the Model List. PMID- 25929525 TI - Healthcare Cost Regressions: Going Beyond the Mean to Estimate the Full Distribution. AB - Understanding the data generating process behind healthcare costs remains a key empirical issue. Although much research to date has focused on the prediction of the conditional mean cost, this can potentially miss important features of the full distribution such as tail probabilities. We conduct a quasi-Monte Carlo experiment using the English National Health Service inpatient data to compare 14 approaches in modelling the distribution of healthcare costs: nine of which are parametric and have commonly been used to fit healthcare costs, and five others are designed specifically to construct a counterfactual distribution. Our results indicate that no one method is clearly dominant and that there is a trade-off between bias and precision of tail probability forecasts. We find that distributional methods demonstrate significant potential, particularly with larger sample sizes where the variability of predictions is reduced. Parametric distributions such as log-normal, generalised gamma and generalised beta of the second kind are found to estimate tail probabilities with high precision but with varying bias depending upon the cost threshold being considered. PMID- 25929526 TI - Highly enantioselective copper(I)-catalyzed conjugate addition of 1,3-diynes to alpha,beta-unsaturated trifluoromethyl ketones. AB - The conjugate diynylation of alpha,beta-unsaturated trifluoromethyl ketones is carried out in the presence of a low catalytic load (2.5 mol%) of a copper(I) MeOBIPHEP complex, triethylamine and a terminal 1,3-diyne. Pre-metalation of the terminal 1,3-diyne with stoichiometric or higher amounts of dialkylzinc reagent is not required. The corresponding internal diynes bearing a propargylic stereogenic center are obtained with good yields and excellent enantioselectivities. PMID- 25929527 TI - Interpreting Effectiveness Evidence in Pain: Short Tour of Contemporary Issues. AB - There is no shortage of treatment approaches offered to people with pain. The maze of options presents patients and clinicians with difficult choices. Key to making those choices is evidence of treatment effectiveness provided by clinical trials and systematic reviews. Recent growth in the number of clinical trials and systematic reviews, of both high and low quality, makes it vital that users of this evidence-clinicians, researchers, patients, and policy makers-have the skills and knowledge to critically interpret these studies. In this review, we discuss some contemporary issues regarding evidence of effectiveness derived from clinical trials and systematic reviews-issues that we think are critical to understanding the field. We focus on evidence of treatment effectiveness in pain, although many of these issues are relevant to and transferable across the spectrum of evidence-based practice. PMID- 25929528 TI - Physical Therapists as Primary Practitioners in the Emergency Department: Six Month Prospective Practice Analysis. AB - BACKGROUND: Increasing pressure on the emergency department (ED) throughout the world has meant the introduction of innovative ways of working. One such innovation is the advanced practice physical therapist (APP) acting as a primary contact practitioner. There has been little research into the role beyond identifying patient satisfaction with management, cost-effectiveness, and time efficiency. In order to give further support and assist in development of an APP service in the ED, an increased exploration of patient caseload demographics, resource utilization, and management outcomes is needed. OBJECTIVES: The purpose of this study was to provide quantitative data regarding patient demographics, time efficiency, resource utilization, and management outcomes to examine the APP role in the ED. DESIGN: This was a prospective observational study of practice. SETTING: The study was conducted in a single ED in Melbourne, Australia. METHOD: Data collection was conducted over a 6-month period. Patient demographics and diagnoses, assessment times, hospital resource utilization, and discharge destinations were recorded. RESULTS: One thousand seventeen patients (45% female; median age=34 years, interquartile range=25-52) were managed by the APPs; 89% had conditions triaged as not serious or life threatening, and 97% had musculoskeletal pathologies, with the most common diagnosis being fracture or dislocation. Four-hour length-of-stay targets were met in 95% of the patients. Forty-six percent of the patients seen were managed independently, without any support from medical colleagues. The most frequent discharge destination was a referral back to the primary care physician or to hospital outpatient clinics. When comparing similar diagnostic groups, the APPs were significantly more time efficient than ED physicians in their patient management. CONCLUSIONS: This study described in detail the caseload managed by the APP in the ED and identified the role as a valuable asset to an ED, managing a great deal of their caseload independently, safely, and time efficiently. PMID- 25929529 TI - Does Kinesiophobia Modify the Effects of Physical Therapy on Outcomes in Patients With Sciatica in Primary Care? Subgroup Analysis From a Randomized Controlled Trial. AB - BACKGROUND: A higher level of kinesiophobia appears to be associated with poor recovery in patients with sciatica. OBJECTIVE: The aim of this study was to investigate whether kinesiophobia modifies the effect of physical therapy on outcomes in patients with sciatica. DESIGN: This was a subgroup analysis from a randomized controlled trial. SETTING: The study was conducted in a primary care setting. PATIENTS: A total of 135 patients with acute sciatica participated. INTERVENTION: Patients were randomly assigned to groups that received (1) physical therapy plus general practitioners' care (intervention group) or (2) general practitioners' care alone (control group). MEASUREMENTS: Kinesiophobia at baseline was measured with the Tampa Scale for Kinesiophobia (TSK) and a single substitute question for kinesiophobia (SQK). Pain and recovery were assessed at 3 and 12-month follow-ups. Regression analysis was used to test for interaction between the level of kinesiophobia at baseline and treatment allocation. Subgroup results were calculated for patients classified with high fear of movement and for those classified with low fear of movement. RESULTS: Kinesiophobia at baseline interacted with physical therapy in the analysis with leg pain intensity at 12-month follow-up. Kinesiophobia at baseline did not interact with physical therapy regarding any outcome at 3-month follow-up or recovery at 12-month follow up. When comparing both treatment groups in the subgroup of patients with high fear of movement (n=73), the only significant result was found for leg pain intensity difference from baseline at 12-month follow-up (intervention group: X= 5.0, SD=2.6; control group: X=-3.6, SD=2.7). LIMITATIONS: The post hoc study design and relatively small sample size were limitations of the study. CONCLUSIONS: In 135 patients with sciatica, evidence shows that patients with a higher level of kinesiophobia at baseline may particularly benefit from physical therapy with regard to decreasing leg pain intensity at 12-month follow-up. PMID- 25929530 TI - Physical Therapists' Views and Experiences of Pregnancy-Related Low Back Pain and the Role of Acupuncture: Qualitative Exploration. AB - BACKGROUND: Low back pain is often accepted as a "normal" part of pregnancy. Despite research suggesting that quality of life for women who are pregnant is adversely affected, most are advised to self-manage. Although the use of acupuncture for the management of persistent nonspecific low back pain has been recommended in recent UK national guidelines, its use in the management of pregnancy-related low back pain remains limited. OBJECTIVES: This study aimed to explore the perceptions and experiences of physical therapists involved in treating women who are pregnant and have low back pain with the objective of informing the pretrial training program for a pilot randomized trial (Evaluating Acupuncture and Standard care for pregnant womEn with Back pain [EASE Back]). DESIGN: A qualitative phenomenological method with purposive sampling was used in the study. METHODS: Three focus groups and 3 individual semistructured interviews were undertaken, and an iterative exploratory thematic analysis was performed. To ensure transparency of the research process and the decisions made, an audit trail was created. RESULTS: Twenty-one physical therapists participated, and emergent issues included: a lack of experience in treating pregnancy-related complaints, mixed messages from previous acupuncture education, a mistrust of the current evidence for acupuncture safety and effectiveness, and personal and professional fear of causing harm. CONCLUSIONS: The findings suggest that UK physical therapists are reluctant to use acupuncture in the management of pregnancy-related low back pain. The explanations for these findings include perceived lack of knowledge and confidence, as well as a pervasive professional culture of caution, particularly fears of inducing early labor and of litigation. These findings have been key to informing the content of the training program for physical therapists delivering acupuncture within the pilot EASE Back trial. PMID- 25929531 TI - Movement System Impairment-Based Classification Versus General Exercise for Chronic Low Back Pain: Protocol of a Randomized Controlled Trial. AB - BACKGROUND: Low back pain (LBP) is an important health problem in all developed countries and is associated with high levels of disability. Evidence-based clinical practice guidelines usually recommend different physical therapy interventions to manage this condition. However, those interventions usually result in small to moderate clinical effects. Recent studies suggest that interventions based on subgroup classifications may improve the effect sizes compared with rehabilitation programs where the same interventions were applied to all patients. OBJECTIVE: This study will investigate the efficacy of treatment based on a Movement System Impairment (MSI)-based classification model for patients with chronic LBP compared with general exercise. The primary outcomes will be pain intensity and disability at 2 months after randomization. DESIGN: The study is a 2-arm, prospectively registered, randomized controlled trial with a blinded assessor. SETTING: The study setting will be a university physical therapy clinic in Brazil. PARTICIPANTS: A total of 148 individuals with chronic LBP will participate in the study. INTERVENTION: Included individuals will be randomly allocated to participate in an 8-week treatment program based on the MSI based classification or a general exercise program of stretching and strengthening exercises. MEASUREMENTS: Pain intensity, disability, and global impression of recovery will be assessed by a blinded assessor at baseline and at follow-up appointments after treatment (2 months) and 4 and 6 months after randomization. LIMITATIONS: Therapists will not be blinded. CONCLUSIONS: The results of this study may contribute to a better understanding of the efficacy of treatments based on classification of participants with chronic LBP into subgroups. PMID- 25929532 TI - Factors Influencing Physical Therapists' Use of Standardized Measures of Walking Capacity Poststroke Across the Care Continuum. AB - BACKGROUND: The use of standardized assessment tools is an element of evidence informed rehabilitation, but physical therapists report administering these tools inconsistently poststroke. An in-depth understanding of physical therapists' approaches to walking assessment is needed to develop strategies to advance assessment practice. OBJECTIVES: The objective of this study was to explore the methods physical therapists use to evaluate walking poststroke, reasons for selecting these methods, and the use of assessment results in clinical practice. DESIGN: A qualitative descriptive study involving semistructured telephone interviews was conducted. METHODS: Registered physical therapists assessing a minimum of 10 people with stroke per year in Ontario, Canada, were purposively recruited from acute care, rehabilitation, and outpatient settings. Interviews were audiotaped and transcribed verbatim. Transcripts were coded line by line by the interviewer. Credibility was optimized through triangulation of analysts, audit trail, and collection of field notes. RESULTS: Study participants worked in acute care (n=8), rehabilitation (n=11), or outpatient (n=9) settings and reported using movement observation and standardized assessment tools to evaluate walking. When selecting methods to evaluate walking, physical therapists described being influenced by a hierarchy of factors. Factors included characteristics of the assessment tool, the therapist, the workplace, and patients, as well as influential individuals or organizations. Familiarity exerted the primary influence on adoption of a tool into a therapist's assessment repertoire, whereas patient factors commonly determined daily use. Participants reported using the results from walking assessments to communicate progress to the patient and health care professionals. CONCLUSIONS: Multilevel factors influence physical therapists' adoption and daily administration of standardized tools to assess walking. Findings will inform knowledge translation efforts aimed at increasing the standardized assessment of walking poststroke. PMID- 25929534 TI - Direct and Indirect Benefits Reported by Users of Transcutaneous Electrical Nerve Stimulation for Chronic Musculoskeletal Pain: Qualitative Exploration Using Patient Interviews. AB - BACKGROUND: There is no consensus regarding the effectiveness of transcutaneous electrical nerve stimulation (TENS) for management of chronic musculoskeletal pain or chronic low back pain. A recent review of previous trial methodology identified significant problems with low treatment fidelity. There is little information available to guide selection of patient-reported outcome measures appropriate for TENS evaluation. OBJECTIVES: The purpose of this study was to explore the experiences of patients at a secondary care pain clinic who successfully used TENS to help manage chronic musculoskeletal pain. These key informants were selected because they had the potential to generate knowledge that could inform research design and clinical practice. DESIGN: A qualitative method using individual semistructured interviews with open questions was selected for its capacity to generate rich data. METHODS: A mini focus group informed the development of a discussion guide for semistructured interviews with 9 patients (6 women, 3 men). Thematic analysis was used as the primary data analysis method, and this analysis was enhanced by a case-level analysis of the context and processes of TENS use of each individual. RESULTS: Data analysis indicated that distraction from pain and a reduction in the sensations associated with muscle tension or spasm should be considered as separate outcomes from pain relief. These direct benefits led to a wide range of indirect benefits dependent on patient decision making, including medication reduction, enhanced function, psychological benefits, and enhanced ability to rest. CONCLUSIONS: The findings indicate that evaluating TENS using a unidimensional pain scale is likely to overlook potential benefits. The complex pattern of TENS usage, as well as multiple direct and indirect outcomes, indicates that TENS could be considered as a complex intervention. PMID- 25929533 TI - Motor and Visuospatial Attention and Motor Planning After Stroke: Considerations for the Rehabilitation of Standing Balance and Gait. AB - Attention and planning can be altered by stroke, which can influence motor performance. Although the influence of these factors on recovery from stroke has been explored for the upper extremity (UE), their impact on balance and gait are unknown. This perspective article presents evidence that altered motor and visuospatial attention influence motor planning of voluntary goal-directed movements poststroke, potentially affecting balance and gait. Additionally, specific strategies for rehabilitation of balance and gait poststroke in the presence of these factors are discussed. Visuospatial attention selects relevant sensory information and supports the preparation of responses to this information. Motor attentional impairments may produce difficulty with selecting appropriate motor feedback, potentially contributing to falls. An original theoretical model is presented for a network of brain regions supporting motor and visuospatial attention, as well as motor planning of voluntary movements. Stroke may influence this functional network both locally and distally, interfering with input or output of the anatomical or functional regions involved and affecting voluntary movements. Although there is limited research directly examining leg function, evidence suggests alterations in motor and visuospatial attention influence motor planning and have a direct impact on performance of gait and balance. This model warrants testing comparing healthy adults with individuals with stroke. PMID- 25929535 TI - Experiences of First-Time Mothers With Persistent Pelvic Girdle Pain After Childbirth: Descriptive Qualitative Study. AB - BACKGROUND: Pelvic girdle pain (PGP) is common during pregnancy and negatively affects women's lives. When PGP persists after the birth, the way it affects women's lives may change, particularly for first-time mothers as they adjust to motherhood, yet the experiences of women with persistent PGP remain largely unexplored. OBJECTIVES: The objective of this study was to explore primiparous women's experiences of persistent PGP and its impact on their lives postpartum, including caring for their infant and their parental role. DESIGN: This was a descriptive qualitative study. METHODS: Following institution ethical approval, 23 consenting primiparous women with PGP that had started during pregnancy and persisted for at least 3 months postpartum participated in individual interviews. These interviews were recorded, transcribed, and analyzed using thematic analysis. RESULTS: Four themes emerged: (1) "Putting up with the pain: coping with everyday life," in which women put up with the pain but had to balance activities and were grateful for support from family and friends to face everyday challenges; (2) "I don't feel back to normal," in which women's feelings of physical limitations, frustration, and a negative impact on their mood were described; (3) "Unexpected," in which persistent symptoms were unexpected for women due to a lack of information given about PGP; and (4) "What next?," in which the future of women's symptoms was met with great uncertainty, and they expressed worry about having another baby. CONCLUSION: For first-time mothers, having persistent PGP postpartum affects their daily lives in many ways. These findings provide important information for health care providers, which will improve their understanding of these women's experiences, will enhance rapport, and can be used to provide information and address concerns to optimize maternity care during pregnancy and beyond. PMID- 25929536 TI - Cognitive Functional Therapy for Disabling Nonspecific Chronic Low Back Pain: Multiple Case-Cohort Study. AB - BACKGROUND: Multiple dimensions across the biopsychosocial spectrum are relevant in the management of nonspecific chronic low back pain (NSCLBP). Cognitive functional therapy is a behaviorally targeted intervention that combines normalization of movement and abolition of pain behaviors with cognitive reconceptualization of the NSCLBP problem while targeting psychosocial and lifestyle barriers to recovery. OBJECTIVE: The purpose of this study was to examine the effectiveness of cognitive functional therapy for people with disabling NSCLBP who were awaiting an appointment with a specialist medical consultant. DESIGN: A multiple case-cohort study (n=26) consisting of 3 phases (A1-B-A2) was conducted. METHODS: Measurement phase A1 was a baseline phase during which measurements of pain and functional disability were collected on 3 occasions over 3 months for all participants. During phase B, participants entered a cognitive functional therapy intervention program involving approximately 8 treatments over an average of 12 weeks. Finally, phase A2 was a 12-month, no-treatment follow-up period. Outcomes were analyzed using repeated measures analysis of variance or Friedman test (with post hoc Bonferroni correction) across 7 time intervals, depending on normality of data distribution. RESULTS: Statistically significant reductions in both functional disability and pain were observed immediately postintervention and were maintained over the 12 month follow-up period. These reductions reached clinical significance for both disability and pain. Secondary psychosocial outcomes, including depression, anxiety, back beliefs, fear of physical activity, catastrophizing, and self efficacy, were significantly improved after the intervention. LIMITATIONS: The study was not a randomized controlled trial. Although primary outcome data were self-reported, the assessor was not blinded. CONCLUSIONS: These promising results suggest that cognitive functional therapy should be compared with other conservative interventions for the management of disabling NSCLBP in secondary care settings in large randomized clinical trials. PMID- 25929537 TI - Put all GPs on a salaried contract. PMID- 25929538 TI - Reducing Risk of Severe Liver Injury in Patients Treated With Isoniazid. PMID- 25929539 TI - Bowel Rest. PMID- 25929540 TI - Increased Detection of Celiac Disease With Measurement of Deamidated Gliadin Peptide Antibody Before Endoscopy. PMID- 25929541 TI - Increased Risk of Venous Thromboembolic Events With Corticosteroid Versus Biologic Therapy for Inflammatory Bowel Disease. PMID- 25929542 TI - Chemical probing suggests redox-regulation of the carbonic anhydrase activity of mycobacterial Rv1284. AB - The mycobacterial enzyme Rv1284 is a member of the beta-carbonic anhydrase family that is considered essential for survival of the pathogen. The active site cavity of this dimeric protein is characterized by an exceptionally small volume and harbours a catalytic zinc ion coordinated by two cysteine and one histidine residue side chains. Using the natural products polycarpine and emodin as chemical probes in crystallographic experiments and stopped-flow enzyme assays, we report that the catalytic activity can be reversibly inhibited by oxidation. Oxidative conditions lead to the removal of one of the active site cysteine residues from the coordination sphere of the catalytic metal ion by engagement in a disulfide bond with another cysteine residue close by. The subsequent loss of the metal ion, which is supported by crystallographic analysis, may thus render the protein catalytically inactive. The oxidative inhibition of Rv1284 can be reversed by exposing the protein to reducing conditions. Because the physical size of the chemical probes used in the present study substantially exceeds the active site volume, we hypothesized that these compounds exert their effects from a surface-bound location and identified Tyr120 as a critical residue for oxidative inactivation. These findings link conditions of oxidative stress to pH homeostasis of the pathogen. Because oxidative stress and acidification are defence mechanisms employed by the innate immune system of the host, we suggest that Rv1284 may be a component of the mycobacterial survival strategy. DATABASE: Atomic coordinates and structure factors have been deposited in the Protein Data Bank under accession numbers 4yf4, 4yf5 and 4yf6. PMID- 25929544 TI - Level of incongruence during cardiac rehabilitation and prediction of future CVD related hospitalizations plus all-cause mortality. AB - Independent of traditional risk factors, psychosocial risk factors increase the risk of cardiovascular disease (CVD). Studies in the field of psychotherapy have shown that the construct of incongruence (meaning a discrepancy between desired and achieved goals) affects the outcome of therapy. We prospectively measured the impact of incongruence in patients after undergoing a cardiac rehabilitation program. We examined 198 CVD patients enrolled in a 8-12 week comprehensive cardiac rehabilitation program. Patients completed the German short version of the Incongruence Questionnaire and the SF-36 Health Questionnaire to measure quality of life (QoL) at discharge of rehabilitation. Endpoints at follow-up were CVD-related hospitalizations plus all-cause mortality. During a mean follow-up period of 54.3 months, 29 patients experienced a CVD-related hospitalization and 3 patients died. Incongruence at discharge of rehabilitation was independent of traditional risk factors a significant predictor for CVD-related hospitalizations plus all-cause mortality (HR 2.03, 95% CI 1.29-3.20, p = .002). We also found a significant interaction of incongruence with mental QoL (HR .96, 95% CI .92-.99, p = .027), i.e. incongruence predicted poor prognosis if QoL was low (p = .017), but not if QoL was high (p = .74). Incongruence at discharge predicted future CVD related hospitalizations plus all-cause mortality and mental QoL moderated this relationship. Therefore, incongruence should be considered for effective treatment planning and outcome measurement. PMID- 25929543 TI - Stenting of coronary bifurcation lesions: a literature and technical review. AB - Newer generation drug-eluting stents have improved outcomes in various subsets of coronary lesions including bifurcation lesions. This article reviews the current literature on various issues in bifurcation percutaneous coronary intervention (PCI). Generally, the provisional approach of placing one stent in the main vessel is the preferred first-line treatment for most bifurcation lesions. However, some lesions require 2-stenting. It is unknown whether 2nd-generation DES have improved outcomes with 2-stenting. The use of fractional flow reserve (FFR) for the assessment of functional significance of the jailed side branch can help avoid unnecessary stenting in complex lesions. Skilled techniques in every step of the 2-stenting process and meticulous use of imaging techniques including IVUS or OCT are warranted to obtain optimal angiographic and clinical results. Dedicated bifurcation stents are feasible treatment options and may change future concepts in bifurcation PCI, although larger trials with control groups are required in order to widely apply these techniques into daily routine practice. PMID- 25929545 TI - Energetic benefits and adaptations in mammalian limbs: Scale effects and selective pressures. AB - Differences in limb size and shape are fundamental to mammalian morphological diversity; however, their relevance to locomotor costs has long been subject to debate. In particular, it remains unknown if scale effects in whole limb morphology could partially underlie decreasing mass-specific locomotor costs with increasing limb length. Whole fore- and hindlimb inertial properties reflecting limb size and shape-moment of inertia (MOI), mass, mass distribution, and natural frequency-were regressed against limb length for 44 species of quadrupedal mammals. Limb mass, MOI, and center of mass position are negatively allometric, having a strong potential for lowering mass-specific locomotor costs in large terrestrial mammals. Negative allometry of limb MOI results in a 40% reduction in MOI relative to isometry's prediction for our largest sampled taxa. However, fitting regression residuals to adaptive diversification models reveals that codiversification of limb mass, limb length, and body mass likely results from selection for differing locomotor modes of running, climbing, digging, and swimming. The observed allometric scaling does not result from selection for energetically beneficial whole limb morphology with increasing size. Instead, our data suggest that it is a consequence of differing morphological adaptations and body size distributions among quadrupedal mammals, highlighting the role of differing limb functions in mammalian evolution. PMID- 25929546 TI - Survey research: it's just a few questions, right? AB - While most anesthesiologists and other physician- or nurse-scientists are familiar with traditional descriptive, observational, and interventional study design, survey research has typically remained the preserve of the social scientists. To that end, this article provides a basic overview of the elements of good survey design and offers some rules of thumb to help guide investigators through the survey process. PMID- 25929547 TI - Intraoperative Mean Arterial Pressure Variability and 30-day Mortality in Patients Having Noncardiac Surgery. AB - BACKGROUND: Little is known about the relationship between intraoperative blood pressure variability and mortality after noncardiac surgery. Therefore, the authors tested the hypothesis that blood pressure variability, independent from absolute blood pressure, is associated with increased 30-day mortality. METHODS: Baseline and intraoperative variables plus 30-day mortality were obtained for 104,401 adults having noncardiac surgery lasting 60 min or longer. In confounder adjusted models, the authors evaluated the associations between 30-day mortality and both time-weighted average intraoperative mean arterial pressure (TWA-MAP) and measures of intraoperative MAP variability--including generalized average real variability of MAP (ARV-MAP) and SD of MAP (SD-MAP). RESULTS: Mean +/- SD TWA-MAP was 84 +/- 10 mmHg, and ARV-MAP was 2.5 +/- 1.3 mmHg/min. TWA-MAP was strongly related to 30-day mortality, which more than tripled as TWA-MAP decreased from 80 to 50 mmHg. ARV-MAP was only marginally related to 30-day mortality (P = 0.033) after adjusting for TWA-MAP. Compared with median ARV-MAP, odds ratio (95% CI) for 30-day mortality was 1.14 (1.03 to 1.25) for low ARV-MAP (first quartile) and 0.94 (0.88 to 0.99) for high ARV-MAP (third quartile). Odds of 30-day mortality decreased as five-level categorized ARV-MAP increased (0.92; 0.87 to 0.99 for one category increase; P = 0.015). Secondarily, cumulative duration of MAP less than 50, 55, 60, 70, and 80 mmHg was associated with increased odds of 30-day mortality (all P < 0.001). CONCLUSION: Although lower mean arterial pressure is strongly associated with mortality, lower intraoperative blood pressure variability per se is only mildly associated with postoperative mortality after noncardiac surgery. PMID- 25929548 TI - Electrophysiological association of spontaneous yawning and swallowing. AB - Yawning and swallowing are fundamental physiological processes that are present from fetal stages throughout life and that involve sequential motor activities in the oropharyngo-larynx making it likely that they may share neuroanatomical pathways. We postulate that yawning and swallowing are controlled by a distributed network of brainstem regions including the central pattern generator of swallowing, and therefore spontaneous swallowing is frequently associated with spontaneous yawning. In this study, we sought to test this hypothesis by evaluating the elementary features of yawning in the facial, masseter and submental muscles, together with laryngeal movement sensor and respiratory recordings for spontaneous swallowing. We investigated 15 healthy, normal control subjects, 10 patients with Parkinson's disease (PD) and 10 patients with brainstem stroke (BSS). Apart from four subjects with PD and two with BSS, who had dysphagia, none of the other study subjects were dysphagic by published criteria. Twenty-five subjects (10 control, 10 BSS, 5 PD) were evaluated by 1-h polygraphic recording, and 10 (5 control, 5 PD) underwent whole-night sleep recordings. One hundred thirty-two yawns were collected, 113 of which were associated with spontaneous swallows, a clear excess of what would be considered as coincidence. The yawns related with swallows could be classified into the following three categories. The characteristics or the duration of swallows and yawns were similar between controls and disease subjects, with the exception of increased duration of yawning in subjects with BSS. Our findings support the presence of common neuroanatomico-physiological pathways for spontaneous swallows and yawning. PMID- 25929549 TI - The senses of active and passive forces at the human ankle joint. AB - The traditional view of the neural basis for the sense of muscle force is that it is generated at least in part within the brain. Recently it has been proposed that force sensations do not arise entirely centrally and that there is a contribution from peripheral receptors within the contracting muscle. Evidence comes from experiments on thumb flexor and elbow flexor muscles. Here we have studied the sense of force in plantar flexor muscles of the human ankle, looking for further evidence for such a mechanism. The active angle-torque curve was measured for muscles of both legs, and for each muscle, ankle angles were identified on the ascending and descending limbs of the curve where active forces were similar. In a plantar flexion force matching task, subjects were asked to match the force in one foot, generated on the ascending limb of the curve, with force in the other foot, generated on the descending limb. It was hypothesised that despite active forces being similar, the sensation generated in the more stretched muscle should be greater because of the contribution from its peripheral stretch receptors, leading to an overestimation of the force in the stretched muscle. It was found that provided that the comparison was between active forces, there was no difference in the forces generated by the two legs, supporting the central hypothesis for the sense of force. When total forces were matched, including a component of passive force due to muscle stretch, subjects seemed to ignore the passive component. Yet subjects had an acute sense of passive force, provided that the muscles remained relaxed. It was concluded that subjects had two senses, a sense of active force, generated centrally, and a sense of passive force, or perhaps muscle stretch, generated within the muscle itself. PMID- 25929550 TI - Independent digit contributions to rotational manipulation in a three-digit pouring task requiring dynamic stability. AB - Many activities of daily living involve multi-digit, voluntary rotational manipulations of grasped objects. Yet, only a few studies have focused on coordination of individual fingertip forces during such tasks. The objective of this study was to investigate individual digit contributions to a three-digit task in which an object was rotationally manipulated against gravity. Center of mass was varied through the use of containers shaped like a water bottle, pint glass, and cocktail glass, from which subjects poured fluid carefully into a nearby receptacle. The center of mass of the grasped object changed continuously as fluid was poured out. Self-selected digit placement and contributions of fingertip forces to rotational manipulation were dependent upon anticipated center of mass location associated with container shape. The thumb resisted the rotation of the top-heavy, cocktail glass container until 79 % of the pouring phase had elapsed, but actively assisted the rotation of the less challenging containers. More directly opposing the thumb, the index finger contributed more to grasp stability. The middle finger contributed more to rotation of the container for pouring. It was found that the thumb, index, and middle fingers acted in unison temporally, but contributed independently to the grip forces and stabilizing moments throughout the dynamic, rotational manipulation task. PMID- 25929551 TI - Transfer of learning between unimanual and bimanual rhythmic movement coordination: transfer is a function of the task dynamic. AB - Under certain conditions, learning can transfer from a trained task to an untrained version of that same task. However, it is as yet unclear what those certain conditions are or why learning transfers when it does. Coordinated rhythmic movement is a valuable model system for investigating transfer because we have a model of the underlying task dynamic that includes perceptual coupling between the limbs being coordinated. The model predicts that (1) coordinated rhythmic movements, both bimanual and unimanual, are organised with respect to relative motion information for relative phase in the coupling function, (2) unimanual is less stable than bimanual coordination because the coupling is unidirectional rather than bidirectional, and (3) learning a new coordination is primarily about learning to perceive and use the relevant information which, with equal perceptual improvement due to training, yields equal transfer of learning from bimanual to unimanual coordination and vice versa [but, given prediction (2), the resulting performance is also conditioned by the intrinsic stability of each task]. In the present study, two groups were trained to produce 90 degrees either unimanually or bimanually, respectively, and tested in respect to learning (namely improved performance in the trained 90 degrees coordination task and improved visual discrimination of 90 degrees ) and transfer of learning (to the other, untrained 90 degrees coordination task). Both groups improved in the task condition in which they were trained and in their ability to visually discriminate 90 degrees , and this learning transferred to the untrained condition. When scaled by the relative intrinsic stability of each task, transfer levels were found to be equal. The results are discussed in the context of the perception-action approach to learning and performance. PMID- 25929552 TI - Structural differences in basal ganglia of elite running versus martial arts athletes: a diffusion tensor imaging study. AB - The aim of this study was to use diffusion tensor imaging (DTI) to characterize and compare microscopic differences in white matter integrity in the basal ganglia between elite professional athletes specializing in running and martial arts. Thirty-three young adults with sport-related skills as elite professional runners (n = 11) or elite professional martial artists (n = 11) were recruited and compared with non-athletic and healthy controls (n = 11). All participants underwent health- and skill-related physical fitness assessments. Fractional anisotropy (FA) and mean diffusivity (MD), the primary indices derived from DTI, were computed for five regions of interest in the bilateral basal ganglia, including the caudate nucleus, putamen, globus pallidus internal segment (GPi), globus pallidus external segment (GPe), and subthalamic nucleus. Results revealed that both athletic groups demonstrated better physical fitness indices compared with their control counterparts, with the running group exhibiting the highest cardiovascular fitness and the martial arts group exhibiting the highest muscular endurance and flexibility. With respect to the basal ganglia, both athletic groups showed significantly lower FA and marginally higher MD values in the GPi compared with the healthy control group. These findings suggest that professional sport or motor skill training is associated with changes in white matter integrity in specific regions of the basal ganglia, although these positive changes did not appear to depend on the type of sport-related motor skill being practiced. PMID- 25929553 TI - Representational momentum reveals visual anticipation differences in the upper and lower visual fields. AB - Recent empirical research has revealed differences in functional capacity between the upper and lower visual fields (VFs), with the lower VF exhibiting superiority in visual perception skills. Similarly, functional differences between the left and right hemispheres elicit a predominance for visuospatial processing in the left visual field (left VF). Both anatomical as well as evolutionary arguments have been adopted in accounting for these variations in function. Preceding upper and lower VF research has typically investigated either static stimulus perception or the visual processing of upper limb action. The aim of the current research was to investigate whether the lower VF benefits associated with limb control transcend to visual anticipation (the perception of motion). Methods were based on Khan and Lawrence (Exp Brain Res 164:395-398, 2005), who investigated upper/lower VF differences in visuomotor control, but utilising a representational momentum paradigm to isolate perceptual processes. Thirty-two participants were randomised into either a left or right VF group and completed a perceptual computer-based task in the upper and lower VF, where they were required to judge the final position of a moving object before it disappeared. Two aspects of the distributions of same responses were then analysed; the central tendency (weighted means) and the variability. Results revealed that in the left VF, weighted means for the lower VF were significantly greater than for the upper VF [t(14) = 2.242, p = 0.042]. In both left and right VFs, variability was greater in the upper compared to lower VF. This provides new findings regarding visual processes in the different visual fields. While visual search and large scene perception has been found to be superior in the upper VF, here we find that visual anticipation, like target-directed visuomotor skill, is superior in the lower VF. PMID- 25929554 TI - Use of early phase online vision for grip configuration is modulated according to movement duration in prehension. AB - Our previous study (Hum Mov Sci 25:349-371, 2006) investigated whether and how online vision in the early phase of movement influences the control of reach-to grasp movements (movement duration: approximately 1000 ms). We used liquid crystal shutter goggles to manipulate the duration of available online vision during the movement and specified that online vision during the early phase influences grasping movements. The current study examined the effect of online early phase vision on the grip configuration according to the movement duration and compared it between two different movement durations (approximately 500 and 1000 ms). We found that non-availability of early phase online vision affected the grip configuration (i.e., inducing a larger peak grip aperture) even in the shorter movement duration. The influential period for online vision for grasping control shifts to an earlier time when movement time is shorter (i.e., from approximately 214 to 106 ms after movement onset), indicating a flexible mechanism for grip configuration according to the movement duration and the available online vision. PMID- 25929555 TI - Selecting object pairs for action: Is the active object always first? AB - Perception is linked to action via two routes: a direct route based on affordance information in the environment and an indirect route based on semantic knowledge about objects. The present study explored the factors modulating the recruitment of the two routes, in particular which factors affecting the selection of paired objects. In Experiment 1, we presented real objects among semantically related or unrelated distracters. Participants had to select two objects that can interact. The presence of distracters affected selection times, but not the semantic relations of the objects with the distracters. Furthermore, participants first selected the active object (e.g. teaspoon) with their right hand, followed by the passive object (e.g. mug), often with their left hand. In Experiment 2, we presented pictures of the same objects with no hand grip, congruent or incongruent hand grip. Participants had to decide whether the two objects can interact. Action decisions were faster when the presentation of the active object preceded the presentation of the passive object, and when the grip was congruent. Interestingly, participants were slower when the objects were semantically but not functionally related; this effect increased with congruently gripped objects. Our data showed that action decisions in the presence of strong affordance cues (real objects, pictures of congruently gripped objects) relied on sensory-motor representation, supporting the direct route from perception-to-action that bypasses semantic knowledge. However, in the case of weak affordance cues (pictures), semantic information interfered with action decisions, indicating that semantic knowledge impacts action decisions. The data support the dual-route account from perception-to-action. PMID- 25929556 TI - Effective multiple oral administration of reverse genetics engineered infectious bursal disease virus in mice in the presence of neutralizing antibodies. AB - BACKGROUND: Despite spectacular successes in hepatitis B and C therapies, severe hepatic impairment is still a major treatment problem. The clinically tested infectious bursal disease virus (IBDV) superinfection therapy promises an innovative, interferon-free solution to this great unmet need, provided that a consistent manufacturing process preventing mutations or reversions to virulent strains is obtained. METHODS: To address safety concerns, a tissue culture adapted IBDV vaccine strain V903/78 was cloned into cDNA plasmids ensuring reproducible production of a reverse engineered virus R903/78. The therapeutic drug candidate was characterized by immunocytochemistry assay, virus particle determination and immunoblot analysis. The biodistribution and potential immunogenicity of the IBDV agent was determined in mice, which is not a natural host of this virus, by quantitative detection of IBDV RNA by a quantitative reverse transcriptase-polymerase chain reaction and virus neutralization test, respectively. RESULTS: Several human cell lines supported IBDV propagation in the absence of visible cytopathic effect. The virus was stable from pH 8 to pH 6 and demonstrated significant resistance to low pH and also proved to be highly resistant to high temperatures. No pathological effects were observed in mice. Single and multiple oral administration of IBDV elicited antibodies with neutralizing activities in vitro. CONCLUSIONS: Repeat oral administration of R903/78 was successful despite the presence of neutralizing antibodies. Single oral and intravenous administration indicated that IBDV does not replicate in mammalian liver alleviating some safety related concerns. These data supports the development of an orally delivered anti-hepatitis B virus/ anti-hepatitis C virus viral agent for human use. PMID- 25929557 TI - Lupus anticoagulant acquired hypoprothrombinemia syndrome in childhood: two distinct patterns and review of the literature. AB - INTRODUCTION: Lupus anticoagulant associated with acquired prothrombin deficiency also known as 'lupus anticoagulant hypoprothrombinemia syndrome' (LAHS) is an entity that is well described in adults and is usually associated with autoimmune conditions (LAHS-AI). However, in children, LAHS has unique features that are distinct from the adult type. AIMS: We report two paediatric cases of LAHS, describe their distinct patterns and review the paediatric literature on LAHS. METHODS: Case studies on two patients with LAHS were reviewed, details on their presentation, work up and management were extracted. A Medline search was conducted on LAHS in children between 1960 and 2014; Articles in languages other than English were excluded. RESULTS: The case studies highlight the differences in the two patterns of childhood LAHS. Additionally the review of the literature reveals that there are 15 case reports and 5 case series that report 25 children with LAHS-AI, 9 case reports and 6 case series report 26 children of LAHS associated with viral infections (LAHS-VI). At presentation, all patients with LAHS-AI had positive laboratory tests for autoimmune diseases, most commonly for systemic lupus erythematosus while these tests were negative in LAHS-VI. All patients with LAHS-AI had a protracted course and needed prolonged treatment with immune-suppressive therapy while patients with LAHS-VI resolved spontaneously or needed short-term immune-modulating therapy. CONCLUSION: In childhood, two distinct patterns of LAHS are observed, either associated with infection or autoimmune disease. Initial diagnostic investigations are critical to differentiating these two patterns as the prognosis and outcome for each is distinct. PMID- 25929558 TI - Comparisons of clinical performance of Guardian laryngeal mask with laryngeal mask airway ProSeal. AB - BACKGROUND: The Guardian Laryngeal Mask Airway (G-LMA) is a new silicone-based single-use extraglottic device with the drainage port and a cuff pilot valve with pressure indicator. The aim of this study is to compare the clinical performance of this laryngeal mask airway with ProSeal laryngeal mask airway (P-LMA). METHODS: In this prospective randomized study, we included adult patients with ASA grading I and II scheduled for elective surgery requiring supine position under total intravenous anesthesia. The patients were randomly allocated to two groups, 40 in each. G-LMA and P-LMA were used in groups G and P respectively. The cuff of each device was air inflated to 60 cmH2O. The primary outcome was to compare the airway sealing pressure and the secondary outcome was to compare the efficacy and safety of these two devices with respect to insertion success, insertion time, ease of insertion, volume of air for cuff inflation to 60 cmH2O, intracuff pressure measurement, gastric tube insertion attempt, gastric tube insertion time, Fiberoptic laryngeal view, and postoperative pharyngolaryngeal morbidity. RESULTS: The airway sealing pressure at 60 cmH2O cuff pressure was significantly greater in G-LMA than P-LMA (p = 0.04).The first successful attempt of both groups were comparable (p = 1.000). Insertion time was significantly shorter in G-LMA than P-LMA (p < 0.0001). The first successful attempt for the gastric tube insertion in both groups was comparable (p = 0.431). Gastric tube insertion time was less in G-LMA than in P-LMA (p < 0.0001). The volume of air for cuff inflation to 60 cmH2O was more in G-LMA than in P-LMA (<0.0001). The intracuff pressure measurement at 30, 60, 90 and 120 minutes were comparable (p = 0.823, 0.182, 0.870, 0.658).We did not find differences in ease of insertion (p = 0.60); Fiber-optic positions of airway devices were comparable (p = 0.83). In addition, blood staining (p = 1.00), sore throat and dysphagia at 1, 2 and 24 hour (p = 1.00) were comparable in both groups. CONCLUSION: The Guardian laryngeal mask airway was associated with high airway sealing pressure with a quicker insertion of the device as well as gastric tube. TRIAL REGISTRATION: Clinical Trial.gov Identifier: NCT02063516. Date: June 2013. PMID- 25929559 TI - How do Hospitals Respond to Price Changes? Evidence from Norway. AB - Many publicly funded health systems use activity-based financing to increase hospital production and efficiency. The aim of this study is to investigate whether price changes for different treatments affect the number of patients treated and the mix of activity provided by hospitals. We exploit the variations in prices created by the changes in the national average treatment cost per diagnosis-related group (DRG) offered to Norwegian hospitals over a period of 5 years (2003-2007). We use the data from Norwegian Patient Register, containing individual-level information on age, gender, type of treatment, diagnosis, number of co-morbidities and the national average treatment costs per DRG. We employ fixed-effect models to examine the changes in the number of patients treated within the DRGs over time. The results suggest that a 10% increase in price leads to about 0.8-1.3% increase in the number of patients treated for DRGs, which are medical (for both emergency and elective patients). In contrast, we find no price effect for DRGs that are surgical (for both emergency and elective patients). Moreover, we find evidence of upcoding. A 10% increase in the ratio of prices between patients with and without complications increases the proportion of patients coded with complications by 0.3-0.4 percentage points. PMID- 25929561 TI - Systems biology in nanosafety research. PMID- 25929560 TI - Pharmacokinetic Drug Interaction Studies with Enzalutamide. AB - BACKGROUND AND OBJECTIVES: Two phase I drug interaction studies were performed with oral enzalutamide, which is approved for the treatment of metastatic castration-resistant prostate cancer (mCRPC). METHODS: A parallel-treatment design (n = 41) was used to evaluate the effects of a strong cytochrome P450 (CYP) 2C8 inhibitor (oral gemfibrozil 600 mg twice daily) or strong CYP3A4 inhibitor (oral itraconazole 200 mg once daily) on the pharmacokinetics of enzalutamide and its active metabolite N-desmethyl enzalutamide after a single dose of enzalutamide (160 mg). A single-sequence crossover design (n = 14) was used to determine the effects of enzalutamide 160 mg/day on the pharmacokinetics of a single oral dose of sensitive substrates for CYP2C8 (pioglitazone 30 mg), CYP2C9 (warfarin 10 mg), CYP2C19 (omeprazole 20 mg), or CYP3A4 (midazolam 2 mg). RESULTS: Coadministration of gemfibrozil increased the composite area under the plasma concentration-time curve from time zero to infinity (AUCinfinity) of enzalutamide plus active metabolite by 2.2-fold, and coadministration of itraconazole increased the composite AUCinfinity by 1.3-fold. Enzalutamide did not affect exposure to oral pioglitazone. Enzalutamide reduced the AUCinfinity of oral S-warfarin, omeprazole, and midazolam by 56, 70, and 86 %, respectively; therefore, enzalutamide is a moderate inducer of CYP2C9 and CYP2C19 and a strong inducer of CYP3A4. CONCLUSIONS: If a patient requires coadministration of a strong CYP2C8 inhibitor with enzalutamide, then the enzalutamide dose should be reduced to 80 mg/day. It is recommended to avoid concomitant use of enzalutamide with narrow therapeutic index drugs metabolized by CYP2C9, CYP2C19, or CYP3A4, as enzalutamide may decrease their exposure. PMID- 25929562 TI - Nanocarriers targeting cancer stem cells: how to help drugs to find their way home. PMID- 25929563 TI - Highlights from the latest articles in technical and technological advancements in nanotherapeutics. PMID- 25929564 TI - Mesoporous silica-coated upconversion nanocrystals for near infrared light triggered control of gene expression in zebrafish. AB - AIM: To develop a platform technology for photoactivation of gene expression in deep tissues. MATERIALS & METHODS: Upconversion nanoparticles (UCNs) were synthesized from rare earth elements like Ytterbium, Yttrium and Thulium. The nanoparticles were then further coated with a layer of mesoporous silica and loaded with photomorpholinos or photocaged plasmids and tested in zebrafish. The UCNs were activated using safe near-infrared (NIR) light which in turn produced UV light locally to enable photoactivation in deep tissues. RESULTS: Light controlled gene knockdown was demonstrated in an in vivo model, namely zebrafish. UCNs loaded with photomorpholinos were used to knockdown a gene - ntl, which is essential for notochord formation and mesoderm patterning in zebrafish using NIR light. UCN-mediated light-controlled gene expression was also achieved by expressing GFP in tumor cells transplanted into adult zebrafish by irradiating the fish with NIR light. Apart from the delivery and control of genes, the UCNs were also used as imaging agents to image both zebrafish embryos and adult zebrafish. enabled excellent background-free, fluorescent imaging of both embryos and adult zebrafish. CONCLUSION: This technique of controlling gene expression/knockdown through NIR using UCNs is a game changer in the field of genetic manipulation and has the potential of being an excellent, safe and easy to implement tool for developmental biologists to investigate the role of specific genes in development. However, this technique is not restricted to be used only in zebrafish and can be extended for use in other animal models and even for clinical use, in various gene therapy applications. PMID- 25929565 TI - Nanoparticles and antigen-specific T-cell therapeutics: a comprehensive study on uptake and release. AB - AIM: T lymphocytes are used as cellular therapeutics in many disease entities including cancer. We investigated the uptake and retention of nanoparticles (NPs) by these nonphagocytic cells. MATERIALS & METHODS: Uptake, release and toxicity of various polymeric NP preparations were analyzed by flow cytometry, confocal laser scanning microscopy and transmission electron microscopy. T-cell effector functions were measured using IFN-gamma-ELISPOT and (51)Chromium-release assays. RESULTS: Amino-functionalized NPs were efficiently ingested by antigen-specific T cells without adversely influencing effector functions. NPs were stored in membrane-surrounded vesicles, with major proportions released extracellularly during 24 h. CONCLUSION: Amino-functionalized polymeric NPs are efficiently taken up by human T cells and could be used to design nanocarriers for direct access and manipulation of antigen-specific T cells in vivo. PMID- 25929566 TI - Development of dual toxoid-loaded layersomes for complete immunostimulatory response following peroral administration. AB - AIM: Present study reports the development of divalent vaccine with enhanced protection, permeation and presentation following peroral immunization. MATERIALS & METHODS: Layersomes were prepared by layer-by-layer tuning of polyelectrolytes on liposomes template. The developed system was evaluated for in vitro stability of antigen and layersomes, cell-based assays and immunization experiments in mice. RESULTS: Layersomes exhibited enhanced stability in simulated biological fluids, still preserving the integrity, biological activity and conformational stability of toxoids. Layersomes also exhibited complete and protective (>0.1 IU/ml) immunostimulatory response include serum IgG titer, mucosal sIgA titer and cytokines (IL-2 and IFN-gamma) levels following peroral administration. CONCLUSION: The positive findings of proposed strategy are expected to contribute significantly in the field of stable liposomes technology and peroral immunization. PMID- 25929567 TI - Targeted chemotherapy of visceral leishmaniasis by lactoferrin-appended amphotericin B-loaded nanoreservoir: in vitro and in vivo studies. AB - AIM: Exploitation of lactoferrin-appended amphotericin B bearing nanoreservoir (LcfPGNP-AmB) for targeted eradication of Leishmania donovani. MATERIALS & METHODS: LcfPGNP-AmB was architechtured through ionic adsorption of lactoferrin over core poly (d,l-lactide-co-glycolide) nanoparticles and characterized. Anti Leishmania activity in visceral leishmaniasis models, immunomodulatory potential, biodistribution and toxicity profile were also assessed. RESULTS: LcfPGNP-AmB (size, 196.0 +/- 5.28 nm; zeta-potential, +21.7 +/- 1.52 mV; encapsulation efficiency, ~89%) showed reduced toxicity, increased protective proinflammatory mediators expression and down-regulation of disease-promoting cytokines. Biodistribution study illustrated preferential accumulation of LcfPGNP-AmB in liver and spleen. LcfPGNP-AmB showed augmented antileishmanial activity by significantly reducing (~88%) splenic parasite burden of infected hamsters, compared with commercial-formulations. CONCLUSION: Superior efficacy, desired stability and reliable safety of cost-effective LcfPGNP-AmB, suggest its potential for leishmaniasis therapeutics. PMID- 25929568 TI - Fluorophore labeling of core-crosslinked polymeric micelles for multimodal in vivo and ex vivo optical imaging. AB - AIM: To enable multimodal in vivo and ex vivo optical imaging of the biodistribution and tumor accumulation of core-crosslinked polymeric micelles (CCPMs). MATERIALS & METHODS: mPEG-b-p(HPMAm-Lac)-based polymeric micelles, core crosslinked via cystamine and covalently labeled with two different fluorophores (Dy-676/488), were synthesized. The CCPMs were intravenously injected into CT26 tumor-bearing mice. RESULTS: Upon intravenous injection, the CCPMs accumulated in CT26 tumors reasonably efficiently, with values reaching approximately 4%ID at 24 h. Ex vivo two-photon laser scanning microscopy confirmed efficient extravasation of the image-guided CCPMs out of tumor blood vessels and relatively deep penetration into the tumor interstitium. CONCLUSION: CCPMs were labeled with multiple fluorophores, and the results obtained exemplify that combining several different in vivo and ex vivo optical imaging techniques is highly useful for analyzing the biodistribution and tumor accumulation of nanomedicines. PMID- 25929569 TI - Improved neuroprotective effects of resveratrol-loaded polysorbate 80-coated poly(lactide) nanoparticles in MPTP-induced Parkinsonism. AB - AIM: This study investigated the neuroprotective effects of resveratrol (RVT) loaded polysorbate 80 (PS80)-coated poly(lactide) nanoparticles in a mouse model of Parkinson's disease (PD), and compared these effects with those from bulk RVT. METHODS: C57BL/6 mice received for 15 days RVT intraperitoneally (nanoparticulate or non-nanoparticulate), as well as single intranasal administration of 1-methyl 4-phenyl-1,2,3,6-tetrahydropyridine (MPTP), a neurotoxin that damages dopaminergic neurons and induces PD-related symptoms. RESULTS: MPTP induced significant impairments on olfactory discrimination and social recognition memory, as well as caused striatal oxidative stress and reduced the expression of tyrosine hydroxylase in striatum. RVT-loaded nanoparticles (but not bulk) displayed significant neuroprotection against MPTP-induced behavioral and neurochemical changes. CONCLUSION: These results point to RVT-loaded poly(lactide)-nanoparticles coated with PS80 a promising nanomedical tool and adjuvant therapy for PD. PMID- 25929570 TI - Photoimmunotherapy of hepatocellular carcinoma-targeting Glypican-3 combined with nanosized albumin-bound paclitaxel. AB - AIM: Effectiveness of Glypican-3 (GPC3)-targeted photoimmunotherapy (PIT) combined with the nanoparticle albumin-bound paclitaxel (nab-paclitaxel) for hepatocellular carcinoma was evaluated. MATERIALS & METHODS: GPC3 expressing A431/G1 cells were incubated with a phthalocyanine-derivative, IRDye700DX (IR700), conjugated to an anti-GPC3 antibody, IR700-YP7 and exposed to near infrared light. Therapeutic experiments combining GPC3-targeted PIT with nab paclitaxel were performed in A431/G1 tumor-bearing mice. RESULTS: IR700-YP7 bound to A431/G1 cells and induced rapid target-specific necrotic cell death by near infrared light exposure in vitro. IR700-YP7 accumulated in A431/G1 tumors. Tumor growth was inhibited by PIT compared with nontreated control. Additionally, PIT dramatically increased nab-paclitaxel delivery and enhanced the therapeutic effect. CONCLUSION: PIT targeting GPC3 combined with nab-paclitaxel is a promising method for treating hepatocellular carcinoma. PMID- 25929571 TI - Nanoscaled boron-containing delivery systems and therapeutic agents for cancer treatment. AB - Significant efforts have recently been made to develop nanoscaled boron containing delivery systems for improving drug delivery in cancer therapy. On one hand, borate ester chemistry has shown importance in ligand-mediated tumor targeting owing to the recognition ability of boronic acid to polyol residues in cell membranes. In particular, the phenylboronic acid-functionalized nanocarriers for specific targeting to sialic acid groups which are overexpressed on tumor cells have made great achievements. On the other hand, nanoscaled boron neutron capture therapy agents show growing potential in efficiently transporting boron to tumor. The current review outlines the recent developments in the application of borate ester chemistry in tumor targeting by nanoparticles, then summarizes recent work on the development of boron-based nanomaterials as boron neutron capture therapy agents. PMID- 25929572 TI - Nanoparticle-mediated delivery of siRNA for effective lung cancer therapy. AB - Lung cancer is one of the most lethal diseases worldwide, and the survival rate is less than 15% even after the treatment. Unfortunately, chemotherapeutic treatments for lung cancer are accompanied by severe side effects, lack of selectivity and multidrug resistance. In order to overcome the limitations of conventional chemotherapy, nanoparticle-mediated RNA interference drugs represent a potential new approach due to selective silencing effect of oncogenes and multidrug resistance related genes. In this review, we provide recent advancements on nanoparticle-mediated siRNA delivery strategies including lipid system, polymeric system and rigid nanoparticles for lung cancer therapies. Importantly, codelivery of siRNA with conventional anticancer drugs and recent theranostic agents that offer great potential for lung cancer therapy is covered. PMID- 25929574 TI - Nanomedicine for the treatment of Alzheimer's disease. AB - Alzheimer's disease affects more than 35 million people worldwide and this number is presumed to double by the year 2050. Currently, there is no efficient therapy for this disorder but a promising approach is represented by nanotechnology, easily multifunctionalizable devices with size in the order of billionth of meter. This review provides a concise survey on the nano-based strategies for Alzheimer's disease treatment, aiming at carrying drugs across the blood-brain barrier, in particular to target the metabolism of beta-amyloid peptide, a pivotal player in this pathology. PMID- 25929575 TI - Mouse ATP-Binding Cassette (ABC) Transporters Conferring Multi-Drug Resistance. AB - The ABC (ATP-binding cassette) transporter is one of the largest and most ancient protein families with members functioning from protozoa to human. The resistance of cancer and tumor cells to anticancer drugs is due to the over-expression of some ABC transporters, which may finally lead to chemotherapy failure. The mouse ABC transporters are classified into seven subfamilies by phylogenetic analysis. The mouse ABC transporter gene, alias, chromosomal location and function have been determined. Within the ABC super-family, the MDR transporters (Abcb1, Abcc1, Abcg2) in mouse models have been proved to be valuable to investigate the biochemistry and physiological functions. This review concentrates on the multidrug resistance of mouse ABC transporters in cancer and tumor cells. PMID- 25929573 TI - Nanotechnology in bladder cancer: current state of development and clinical practice. AB - Nanotechnology is being developed for the diagnosis and treatment of both nonmyoinvasive bladder cancer (NMIBC) and invasive bladder cancer. The diagnostic applications of nanotechnology in NMIBC mainly focus on tumor identification during endoscopy to increase complete resection of bladder cancer while nanotechnology to capture malignant cells or their components continues to be developed. The therapeutic applications of nanotechnology in NMIBC are to reformulate biological and cytotoxic agents for intravesical instillation, combine both diagnostic and therapeutic application in one nanoformulation. In invasive and advanced bladder cancer, magnetic resonance imaging with supraparamagnetic iron oxide nanoparticles can improve the sensitivity and specificity in detecting small metastasis to lymph nodes. Nanoformulation of cytotoxic agents can potentially decrease the toxicity while increasing efficacy. PMID- 25929576 TI - A promising anti-cancer and anti-oxidant agents based on the pyrrole and fused pyrrole: synthesis, docking studies and biological evaluation. AB - A series of N-aryl derivatives of pyrrole and its related derivatives of fused form (namely; tetrahydroindole and dihydroindenopyrroles) were prepared in fair to good yields. The newly synthesized compounds were confirmed using IR, (1)H NMR, Mass spectral and elemental analysis. Tetrahydrobenzo[b] pyrroles Ia-d, 1,4 dihydroindeno[1,2-b]pyrroles IIa,b and pyrroles IIIa-c,e were evaluated for anticancer activity, coinciding with the antioxidant activity; using Di-Phenyl Picryl Hydrazyl (DPPH) tests. The cytotoxicity of the tested compounds (at a concentration of 100 and 200 MUg /mL) was performed against HepG-2 and EACC cell lines. Compounds Ib, d and IIa showed promising antioxidant activity beside their anticancer activity. Docking studies were employed to justify the promising anticancer activity of Ib,d and IIa. Protein kinase (PKase)-PDB entry 1FCQ was chosen as target enzyme for this purpose using the MOLSOFT ICM 3.4-8C program. The docking results of the tested compounds went aligned with the respective anticancer assay results. PMID- 25929577 TI - Beyond nutrition: hunger and its impact on the health of young Canadians. AB - OBJECTIVES: In a large Canadian study, we examined: (1) the prevalence of hunger due to an inadequate food supply at home; (2) relations between this hunger and a range of health outcomes, and; (3) contextual explanations for any observed associations. METHODS: A cross-sectional survey was conducted of 25,912 students aged 11-15 years from 436 Canadian schools. Analyses were descriptive and also involved hierarchical logistic regression models. RESULTS: Hunger was reported by 25 % of participants, with 4 % reporting this experience "often" or "always". Its prevalence was associated with socio-economic disadvantage and family-related factors, but not with whether or not a student had access to school-based food and nutrition programs. The consistency of hunger's associations with the health outcomes was remarkable. Relations between hunger and health were partially explained when models controlled for family practices, but not the socio-economic or school measures. CONCLUSIONS: Societal responses to hunger certainly require the provision of food, but may also consider family contexts and basic essential elements of care that children need to thrive. PMID- 25929578 TI - How can we improve healthcare access and general self-rated health among orphans and vulnerable children? Findings from a Kenyan cross-sectional study. AB - OBJECTIVES: This study analyzes healthcare access and general self-rated health (GSRH) among orphan and vulnerable child (OVC) households enrolled in an empowerment program in Eastern Province, Kenya. Analyses investigate whether reported monthly income mediates the association between program participation and medical security. Predictors of GSRH are also investigated. METHODS: Cross sectional survey data on families (n = 707) participating in a multisectoral empowerment program were collected in June 2012. Regression methods were used to investigate study aims. RESULTS: Monthly income mediated 14.3 % of the total effect of program participation on healthcare accessibility. Program participation was not significantly associated with higher GSRH. CONCLUSIONS: Increased reported monthly income predicted improved healthcare access, but only explained a portion of improved healthcare access in the study population. Partnerships between community-based empowerment programs and clinical providers might successfully target multiple outcomes among OVC, including improved healthcare access, though further research on potential synergies is required. GSRH was associated with increased access to food, medical care, literacy, safe drinking water and household income. Further research on GSRH among OVC should target measurement validity, potential sources of disparity in GSRH between OVC and non-OVC, and targets for improving GSRH among OVC. PMID- 25929579 TI - Usefulness of early rule-in and rule-out biomarker protocols to estimate ischemia induced myocardial injury in early chest pain presenters. AB - Protocols to minimize the time between 2 measurements of troponin or a combination with copeptin have been developed to rapidly rule-in or rule-out myocardial injury (MI) in patients with chest pain. These fast track protocols to rule-in and rule-out MI are not sufficiently validated for early chest pain presenters. The "early presenter" model was tested in 107 stable patients after a short period of myocardial ischemia, induced by stenting of a significant coronary artery stenosis. High-sensitivity troponin T (hsTnT), high-sensitivity troponin I (hsTnI), and copeptin were measured at the start and 90, 180, and 360 minutes after stent implantation. MI was defined as a troponin level more than the upper limit of normal (ULN) and an absolute increase of >50% ULN on the 360 minute sample. A single combined measurement of troponin and copeptin 90 minutes after the onset of ischemia has a low diagnostic value. This increases when serial measurements with 90-minute intervals are included. For ruling in MI, the highest positive predictive value (with a 95% confidence interval [CI]) can be obtained when focusing only on the increase in troponin level, with a positive predictive value of 86% (70, 93) and 80% (67, 90) for hsTnT and hsTnI, respectively. For ruling out MI, a combined absence of any troponin more than the ULN and any significant increase in troponin level perform best with a negative predictive value of 75% (55, 89) and 75% (55, 89) for hsTnT and hsTnI, respectively. In conclusion, in early presenters, rapid biomarker protocols underestimate MI. A standard biomarker assessment after 3 hours is required to adequately rule-in or rule-out myonecrosis. PMID- 25929580 TI - Prevalence of extracoronary vascular abnormalities and fibromuscular dysplasia in patients with spontaneous coronary artery dissection. AB - Spontaneous coronary artery dissection (SCAD) is a cause of acute coronary syndrome, often occurring in young women. The utility of comprehensive imaging and clinical significance of detected vascular abnormalities have yet to be determined. We hypothesized that extracoronary vascular abnormalities (EVAs) are common in SCAD and aimed to study the prevalence and distribution of these findings. We enrolled 115 patients with confirmed SCAD who were evaluated at the Mayo Clinic SCAD Clinic from February 2010 to May 2014 and prospectively underwent comprehensive computed tomography angiography imaging of the neck, chest, abdomen, and pelvis (SCAD computed tomography angiography protocol, n = 95) or had retrospective review of outside studies (n = 20) including head imaging (n = 40). Follow-up was determined by last clinical visit or study correspondence and included review of recurrent SCAD or myocardial infarction, congestive heart failure, and death. We reported EVAs in 66% of patients with SCAD, most frequently in the abdomen (36%), pelvis (28%), and neck (27%). Only 1 patient had EVA in the chest (aortic dissection and Marfan's). Fibromuscular dysplasia (FMD) (exclusively multifocal) was the most common type of EVA (45%). Vascular abnormalities in those with head imaging included intracranial aneurysms (n = 9) and FMD (n = 3). There were no deaths at median follow-up of 21 months (Q1 to Q3 7.7 to 55). The presence of FMD was not associated with SCAD recurrence (relative risk [RR] 1.2; confidence interval [95% CI] 0.60, 2.5), congestive heart failure (RR 0.66; 95% CI 0.20, 2.3), or myocardial infarction (RR 1.34; 95% CI 0.69, 2.6). In conclusion, EVAs including FMD, dissections, aneurysms, and dilation are common in patients with SCAD and occur in a wide anatomic distribution. The presence of EVAs and/or FMD did not correlate with the risk of subsequent clinical events, but future studies with increased power and longer follow-up will be important to further assess the role of EVAs in patients with SCAD. PMID- 25929581 TI - Risk of Mortality Associated With QT and JT Intervals at Different Levels of QRS Duration (from the Third National Health and Nutrition Examination Survey). AB - QT prolongation in the setting of QRS >120 ms is believed to be triggered by prolonged depolarization rather than repolarization. Hence, JT interval is suggested as an alternative to QT interval when QRS duration is prolonged. It is unclear, however, if JT and QT intervals portend similar risk of mortality for different durations of QRS. We examined the association between QT and JT, separately, with all-cause mortality across different levels of QRS duration in 8,025 participants (60 +/- 13 years, 41% white and 54% women) from the Third National Health and Nutrition Examination Survey. At baseline (1986 to 1994), 486 participants (6%) had QRS duration >=120 ms. During a follow-up of up to 18 years, 3,045 deaths (38%) occurred. There were significant nonlinear relations of QT and JT intervals with mortality (p <0.001). Hence, QT and JT were categorized as prolonged (>95th percentile), shortened (<5th percentile), and normal (reference group). In multivariate-adjusted Cox regression models, prolonged JT (hazard ratio [HR] 4.75, 95% confidence interval [CI] 1.86 to 12.11) was associated with increased risk of mortality more than prolonged QT (HR 1.50, 95% CI 1.03 to 2.17) in participants with QRS >=120 ms (interaction p = 0.02). In participants with QRS duration <120 ms, prolonged QT and JT were equally predictive of all-cause mortality (HR 1.27, 95% CI 1.06 to 1.54, and HR 1.31, 95% CI 1.10 to 1.55, respectively). Similar patterns were observed with shortened QT and JT intervals. In conclusion, although both QT and JT intervals are predictive of mortality, JT is more predictive in the setting of QRS duration >120 ms supporting the use of JT interval in patients with prolonged QRS. PMID- 25929582 TI - Phase II study of axitinib with doublet chemotherapy in patients with advanced squamous non-small-cell lung cancer. AB - BACKGROUND: Axitinib is an orally active and potent tyrosine kinase inhibitor of vascular endothelial growth factor receptors 1, 2 and 3. This phase II study assessed the efficacy and safety of axitinib combined with cisplatin/gemcitabine in chemotherapy-naive patients with advanced/metastatic (stage IIIB/IV) squamous non-small-cell lung cancer (NSCLC). METHODS: Axitinib (starting dose 5 mg twice daily [bid]; titrated up or down to 2-10 mg bid) was administered orally on a continuous schedule with cisplatin (80 mg/m(2) intravenously [i.v.] every 3 weeks) and gemcitabine (1,250 mg/m(2) i.v. on days 1 and 8 of each 3-week cycle), and was continued as monotherapy after completion of six cycles (maximum) of chemotherapy. The primary study endpoint was objective response rate, as defined by Response Evaluation Criteria in Solid Tumours. RESULTS: Of the 38 patients treated, one (2.6%) patient achieved a complete response and 14 (36.8%) patients had a partial response; nine (23.7%) patients showed stable disease and three (7.9%) patients had disease progression. Median progression-free survival was 6.2 months, and median overall survival was 14.2 months. The estimated probability of survival at 12 months and 24 months was 63.2% and 30.8%, respectively. The most frequent grade >=3 toxicities were neutropaenia and hypertension (13.2% each). Three (7.9%) patients experienced haemoptysis, of which one case (2.6%) was fatal. CONCLUSIONS: Treatment with the combination of axitinib and cisplatin/gemcitabine demonstrated anti-tumour activity in patients with advanced/metastatic squamous NSCLC and the fatal haemoptysis rate was low. However, without a reference arm (cisplatin/gemcitabine alone), it is not conclusive whether the combination is better than chemotherapy alone. This study was registered at ClinicalTrials.gov, registration # NCT00735904, on August 13, 2008. PMID- 25929583 TI - Association of smoking and concomitant metformin use with cardiovascular events and mortality in people newly diagnosed with type 2 diabetes. AB - BACKGROUND: The cardiovascular and mortality risk in patients with incident type 2 diabetes (T2D) in relation to smoking status and concurrent use of metformin is not well known. METHODS: A cohort study was performed in 82,205 incident T2D patients from the U.K. Clinical Practice Research Datalink. In the present study, the risks of myocardial infarction (MI), stroke, and mortality in incident T2D patients were evaluated in relation to their smoking status with and without concurrent use of metformin. RESULTS: Over a median 5.4 years of follow-up, of patients without a history of cardiovascular disease (CVD) before a diagnosis of diabetes (n = 63,166), current smokers with and without metformin had an 8% (hazard ratio [HR] 1.08; 95% confidence interval [CI] 0.81, 1.45) and 32% (HR 1.32; 95% CI 1.07, 1.65) increased risk of MI or stroke, respectively, compared with non-smokers without metformin treatment. The respective HRs (95% CI) for mortality in these patients were 0.96 (0.83, 1.11) and 1.86 (1.68, 2.07). The HR for mortality among ex-smokers with and without concurrent metformin treatment was 0.92 (95% CI 0.83, 1.11) and 1.19 (95% CI 1.10, 1.30), respectively. Similar beneficial modifiable effects of metformin among ex- and current smokers were observed in patients with CVD before diagnosis of diabetes (n = 19,039). CONCLUSIONS: In T2D patients, concurrent treatment with metformin attenuates the observed higher cardiovascular and mortality risk in ex- and current smokers. In addition to smoking cessation support, treatment with metformin, particularly in ex- and current smokers, should be encouraged. PMID- 25929584 TI - Syntheses of some alpha-cyclic tripeptides as potential inhibitors for HMG-CoA Reductase. AB - alpha-Cyclic tripeptides (CtPs) are the most rigid members of the cyclic peptide family. However, due to their synthetic difficulty, biological activity has remained undisclosed. The incorporation of side-chain-protected natural amino acids into functional CtPs was performed to explore the potential biological functions. Several novel CtPs that consist of protected serine (S(Bn)) and/or glutamate (E(OBn)) were prepared from corresponding linear tripeptides by chemical synthesis. There is a strong possibility for CtPs that contain 3 phenyl groups to correlate with atorvastatin structure. The binding effects in human HMG CoA reductase (hHMGR) activities were first evaluated by molecular docking. High docking scores were received with these CtPs for enzyme. Therefore, enzymatic assays were carried out and the compound cyclo(S(Bn))3 was indeed able to moderately inhibit hHMGR (IC50 = 110 MUM). PMID- 25929585 TI - A review and discussion of platelet nitric oxide and nitric oxide synthase: do blood platelets produce nitric oxide from L-arginine or nitrite? AB - The NO/sGC/cGMP/PKG system is one of the most powerful mechanisms responsible for platelet inhibition. In numerous publications, expression of functional NO synthase (NOS) in human and mouse platelets has been reported. Constitutive and inducible NOS isoforms convert L-arginine to NO and L-citrulline. The importance of this pathway in platelets and in endothelial cells for the regulation of platelet function is discussed since decades. However, there are serious doubts in the literature concerning both expression and functionality of NOS in platelets. In this review, we aim to present and critically evaluate recent data concerning NOS expression and function in platelets, and to especially emphasise potential pitfalls of detection of NOS proteins and measurement of NOS activity. Prevailing analytical problems are probably the main sources of contradictory data on occurrence, activity and function of NOS in platelets. In this review we also address issues of how these problems can be resolved. NO donors including organic nitrites (RONO) and organic nitrate (RONO2) are inhibitors of platelet activation. Endogenous inorganic nitrite (NO2 (-)), the product of NO autoxidation, and exogenous inorganic nitrite are increasingly investigated as NO donors in the circulation. The role of platelets in the generation of NO from nitrite is also discussed. PMID- 25929586 TI - Unexpectedly fast transfer of positron-emittable artificial substrate into N terminus of peptide/protein mediated by wild-type L/F-tRNA-protein transferase. AB - This article demonstrates the fastest enzymatic introduction of a positron emission tomography (PET) probe into acceptor peptides/proteins. It is site specifically introduced at the basic N-terminus of the acceptors by using L/F transferase in combination with aminoacyl-tRNA synthetase, namely the NEXT-A/PET reaction. Estimated from kinetic analysis, the transfer efficiency of O-(2 fluoromethyl)-L-tyrosine as an artificial amino acid PET probe mediated by the wild-type transferase is almost as good as that of the natural substrate, phenylalanine. PMID- 25929587 TI - Homoarginine in the renal and cardiovascular systems. AB - Homoarginine (hArg) is an endogenous, nonproteinogenic amino acid which differs from arginine by an additional methylene (CH2) group in the backbone. In this brief narrative review, we summarize the current literature on hArg in the renal and cardiovascular systems. Epidemiological studies have identified low hArg levels as an independent risk marker for cardiovascular, cerebrovascular, and renal diseases as well as for mortality. The relatively low correlation of hArg with established cardiovascular risk factors underlines its great potential as an emerging biomarker to improve risk prediction because plasma hArg concentrations might reflect previously unrecognized pathophysiological processes. hArg may be involved in the pathogenesis of various diseases due to its effects on nitric oxide (NO) and energy metabolism. In view of its structural similarities with arginine, it has been proposed that hArg impacts on arginine metabolism and subsequently also on NO synthesis. The key enzyme for hArg synthesis, arginine:glycine amidinotransferase (AGAT), is involved in the synthesis of energy metabolites including guanidinoacetate, the precursor of creatine. Therefore, the involvement of hArg in energy metabolism could partially explain the close association between hArg and cardiovascular diseases such as heart failure. Whether hArg supplementation or modification of key enzymes of hArg metabolism such as AGAT activity is effective for the treatment of chronic diseases remains to be elucidated. PMID- 25929588 TI - An essay on superoxide dismutase, 2-methoxyestradiol, and the proper uses of scientific methods. PMID- 25929589 TI - Somatotopical feedback versus non-somatotopical feedback for phantom digit sensation on amputees using electrotactile stimulation. AB - BACKGROUND: Transcutaneous electrical stimulation can provide amputees with tactile feedback for better manipulating an advanced prosthesis. In general, there are two ways to transfer the stimulus to the skin: somatotopical feedback (SF) that stimulates the phantom digit somatotopy on the stump and non somatotopical feedback (NF) that stimulates other positions on the human body. METHODS: To investigate the difference between SF and NF, electrotactile experiments were conducted on seven amputees. Electrical stimulation was applied via a complete phantom map to the residual limb (SF) and to the upper arm (NF) separately. The behavior results of discrimination accuracy and response time were used to examine: 1) performance differences between SF and NF for discriminating position, type and strength of tactile feedback; 2) performance differences between SF and NF for one channel (1C), three channels (3C), and five channels (5C). NASA-TLX standardized testing was used to determine differences in mental workload between SF and NF. RESULTS: The grand-averaged discrimination accuracy for SF was 6% higher than NF, and the average response time for SF was 600 ms faster than NF. SF is better than NF for position, type, strength, and the overall modality regarding both accuracy and response time except for 1C modality (p<0.001). Among the six modalities of stimulation channels, performance of 1C/SF was the best, which was similar to that of 1C/NF and 3C/SF; performance of 3C/NF was similar to that of 5C/SF; performance of 5C/NF was the worst. NASA-TLX scores indicated that mental workload increased as the number of stimulation channels increased. CONCLUSIONS: We quantified the difference between SF and NF, and the influence of different number of stimulation channels. SF was better than NF in general, but the practical issues such as the limited area of stumps could constrain the use of SF. We found that more channels increased the amount and richness of information to the amputee while fewer channels resulted in higher performance, and thus the 3C/SF modality was a good compromise. Based on this study, we provide possible solutions to the practical problems involving the implementation of tactile feedback for amputees. These results are expected to promote the application of SF and NF tactile feedback for amputees in the future. PMID- 25929590 TI - Cervical Distraction-Stabilization Using an Intervertebral Spacer Screw and String-of Pearl (SOPTM) Plates in 16 Dogs With Disc-Associated Wobbler Syndrome. AB - OBJECTIVE: To retrospectively investigate a novel surgical technique using the Fitz Intervertebral Traction Screw (FITS) combined with string-of-pearl (SOPTM) locking plates for the treatment of Disc Associated Wobbler Syndrome (DAWS). STUDY DESIGN: Case series (n = 16). METHODS: Ventral approach and fenestration of the affected disc(s), nuclear extirpation, and insertion of the FITS device to the level of the dorsal annulus was followed by application of one or two 3.5 mm SOPTM plates. Autogenous cancellous bone graft was placed between adjacent vertebrae. Long-term followup (>12months) via telephone or examination was attempted for all dogs. RESULTS: Case records of 16 dogs were reviewed. All dogs had Type II disc disease with a single site in 13 dogs and multiple sites in 3 dogs. Mean +/- SD age was 75 +/- 38 months and body weight was 34 +/- 7 kg. Fifteen of the 16 dogs had significantly improved neurologic status (P =.01) at 6 weeks. Seven of the 16 dogs were examined at 24-36 months with 6 considered normal and 1 had mild ataxia. Postoperative radiographic intervertebral distraction was significant (P = .01). Radiographic bridging was recorded in 10/16 dogs at 6 weeks and in 7 dogs available for follow-up at 5-36 months. Computed tomography in 3 dogs at 24-36 months and postmortem with histology in 1 dog confirmed bone-bridging. Complications were not considered clinically significant and included implant loosening (2 dogs, both single plates) and minor end-plate subsidence (8 dogs). CONCLUSION: Application of the FITS device in combination with 2 ventral SOPTM locking plates and autogenous cancellous bone graft was associated with excellent outcomes in dogs treated for DAWS in this small case series. PMID- 25929591 TI - Challenges of flow-cytometric estimation of nuclear genome size in orchids, a plant group with both whole-genome and progressively partial endoreplication. AB - Nuclear genome size is an inherited quantitative trait of eukaryotic organisms with both practical and biological consequences. A detailed analysis of major families is a promising approach to fully understand the biological meaning of the extensive variation in genome size in plants. Although Orchidaceae accounts for ~10% of the angiosperm diversity, the knowledge of patterns and dynamics of their genome size is limited, in part due to difficulties in flow cytometric analyses. Cells in various somatic tissues of orchids undergo extensive endoreplication, either whole-genome or partial, and the G1-phase nuclei with 2C DNA amounts may be lacking, resulting in overestimated genome size values. Interpretation of DNA content histograms is particularly challenging in species with progressively partial endoreplication, in which the ratios between the positions of two neighboring DNA peaks are lower than two. In order to assess distributions of nuclear DNA amounts and identify tissue suitable for reliable estimation of nuclear DNA content, we analyzed six different tissue types in 48 orchid species belonging to all recognized subfamilies. Although traditionally used leaves may provide incorrect C-values, particularly in species with progressively partial endoreplication, young ovaries and pollinaria consistently yield 2C and 1C peaks of their G1-phase nuclei, respectively, and are, therefore, the most suitable parts for genome size studies in orchids. We also provide new DNA C-values for 22 orchid genera and 42 species. Adhering to the proposed methodology would allow for reliable genome size estimates in this largest plant family. Although our research was limited to orchids, the need to find a suitable tissue with dominant 2C peak of G1-phase nuclei applies to all endopolyploid species. PMID- 25929592 TI - Patentability of human genes: the conceptual differences between the industrialised and Latin American countries. AB - The patenting of human genes has generated considerable controversy, both in the doctrinal field and in the legal and administrative. In the core countries, particularly the USA and the European Union, a favourable criterion to patentability has been increasing, contrasting with the criteria adopted by Latin American countries, which almost unanimously banned the patentability of genes and gene sequences. This issue not only has legal connotations, but also ethical issues come into play. Particularly in the USA, the recent decision of the Supreme Court in the Myriad case is part of a pro-patent movement, even when its superficial reading seems to be oriented in the opposite direction. In the European Union, the criterion that favours human intervention, whatever its gravitation in the results, tips the balance in favour of patentability. PMID- 25929593 TI - Use of Antiepileptic Drugs in Patients with Chronic Kidney Disease and End Stage Renal Disease. AB - Epilepsy is a disorder with an approximate worldwide prevalence of 1%. Due to complexities of metabolism, protein-binding, renal elimination, and other pharmacokinetic parameters, the dosing of antiepileptic drugs (AEDs) in patients with chronic kidney disease (CKD) or end stage renal disease (ESRD) deserves special attention. This is a review of the most commonly prescribed AEDs with special focus on their indication, pharmacokinetics, and unique considerations for use in patients with CKD and ESRD. A review of their renal toxicities is also included. PMID- 25929594 TI - Population Pharmacokinetic and Pharmacodynamic Modeling and Effects on Platelet Counts of Different Dosages of Eltrombopag in Chinese Patients With Chronic Primary Immune Thrombocytopenia. AB - PURPOSE: This study characterized the population pharmacokinetic (pop-PK) and PK/pharmacodynamic (pop-PK/PD) properties of eltrombopag and evaluated platelet count (PLTC) response to different eltrombopag dosages through simulations in Chinese adult patients with chronic primary immune thrombocytopenia (cITP). METHODS: Pop-PK and pop-PK/PD models were developed from Chinese patients with cITP. Model-based simulations were then performed to predict PLTC response. FINDINGS: The pop-PK properties of eltrombopag were described by a 2-compartment model with first-order absorption and elimination and absorption lag time. Steady state exposure in these Chinese patients was ~55% greater than that in non-East Asian patients. The pop-PK/PD properties of eltrombopag were described by a model with 4 transit compartments where the increase in platelet production rate was linearly related to the plasma eltrombopag concentration. Eleven percent of the patients were identified as nonresponders to eltrombopag. Simulations showed that ~70% to 80% of steady-state PLTC response was achieved at week 2, and the percentages of patients who achieved a PLTC of 50 to 150 * 10(9) cells/L were comparable between weeks 2 and 6 with 12.5-, 25-, 50-, and 75-mg once-daily dosing. The 25-mg once-daily dosage was associated with a more balanced response than were the 12.5-, 50-, and 75-mg once-daily dosages with regard to efficacy (percentages of patients with PLTC 50-150 * 10(9) cells/L, 27% vs 20%, 30%, and 30%, respectively) and the risk for thrombocytosis (percentages of patients with PLTC >250 * 10(9) cells/L, 4% vs 1%, 10%, and 16%). Simulations of PLTCs with the dose-titration regimen showed that >=42% of patients achieved a PLTC 50 to 150 * 10(9) cells/L at week 6 or later, compared with <=30% when the 12.5-, 25-, 50-, and 75-mg once-daily fixed doses were given. No more than 5% of patients who underwent dose titration had a PLTC >250 * 10(9) cells/L throughout 24 weeks of treatment, compared with 3%, 7%, 16%, and 24% when the once-daily fixed doses of eltrombopag were given. IMPLICATIONS: The pop-PK and pop-PK/PD properties of eltrombopag in these Chinese adult patients with cITP were adequately characterized in the present analyses. The modeling and simulation results support the eltrombopag dose-titration regimen, with 25 mg once daily as a starting dosage and a 2-week titration interval, in Chinese patients with cITP. PMID- 25929595 TI - A class of kernel based real-time elastography algorithms. AB - In this paper, a novel real-time kernel-based and gradient-based Phase Root Seeking (PRS) algorithm for ultrasound elastography is proposed. The signal-to noise ratio of the strain image resulting from this method is improved by minimizing the cross-correlation discrepancy between the pre- and post compression radio frequency signals with an adaptive temporal stretching method and employing built-in smoothing through an exponentially weighted neighborhood kernel in the displacement calculation. Unlike conventional PRS algorithms, displacement due to tissue compression is estimated from the root of the weighted average of the zero-lag cross-correlation phases of the pair of corresponding analytic pre- and post-compression windows in the neighborhood kernel. In addition to the proposed one, the other time- and frequency-domain elastography algorithms (Ara et al., 2013; Hussain et al., 2012; Hasan et al., 2012) proposed by our group are also implemented in real-time using Java where the computations are serially executed or parallely executed in multiple processors with efficient memory management. Simulation results using finite element modeling simulation phantom show that the proposed method significantly improves the strain image quality in terms of elastographic signal-to-noise ratio (SNRe), elastographic contrast-to-noise ratio (CNRe) and mean structural similarity (MSSIM) for strains as high as 4% as compared to other reported techniques in the literature. Strain images obtained for the experimental phantom as well as in vivo breast data of malignant or benign masses also show the efficacy of our proposed method over the other reported techniques in the literature. PMID- 25929596 TI - Toward high-throughput phenotyping: unbiased automated feature extraction and selection from knowledge sources. AB - OBJECTIVE: Analysis of narrative (text) data from electronic health records (EHRs) can improve population-scale phenotyping for clinical and genetic research. Currently, selection of text features for phenotyping algorithms is slow and laborious, requiring extensive and iterative involvement by domain experts. This paper introduces a method to develop phenotyping algorithms in an unbiased manner by automatically extracting and selecting informative features, which can be comparable to expert-curated ones in classification accuracy. MATERIALS AND METHODS: Comprehensive medical concepts were collected from publicly available knowledge sources in an automated, unbiased fashion. Natural language processing (NLP) revealed the occurrence patterns of these concepts in EHR narrative notes, which enabled selection of informative features for phenotype classification. When combined with additional codified features, a penalized logistic regression model was trained to classify the target phenotype. RESULTS: The authors applied our method to develop algorithms to identify patients with rheumatoid arthritis and coronary artery disease cases among those with rheumatoid arthritis from a large multi-institutional EHR. The area under the receiver operating characteristic curves (AUC) for classifying RA and CAD using models trained with automated features were 0.951 and 0.929, respectively, compared to the AUCs of 0.938 and 0.929 by models trained with expert-curated features. DISCUSSION: Models trained with NLP text features selected through an unbiased, automated procedure achieved comparable or slightly higher accuracy than those trained with expert-curated features. The majority of the selected model features were interpretable. CONCLUSION: The proposed automated feature extraction method, generating highly accurate phenotyping algorithms with improved efficiency, is a significant step toward high-throughput phenotyping. PMID- 25929597 TI - Establishing and maintaining social connectivity: An understanding of the lived experiences of older adults residing in regional and rural communities. AB - OBJECTIVE: To better understand how to plan for an ageing demographic that resides in ever-changing community typologies. DESIGN: Semi-structured in-depth interviews. SETTING: Community settings in rural and regional towns in Queensland. PARTICIPANTS: Twenty-two people aged over 65 years living in regional and rural Australia. INTERVENTIONS: Qualitative study of social connectedness. MAIN OUTCOME MEASURE(S): Thematic qualitative analysis. RESULTS: Formal and informal social contact, through family, friends and social groups, was found to be important to the everyday lives of the participants. CONCLUSIONS: Social connections for older adults are important in maintaining independence and community engagement. PMID- 25929598 TI - Fatal rituximab-associated lung injury syndrome in a patient treated with rituximab for recurrence of post-transplant nephrotic syndrome. AB - Rituximab (anti-B CD20 ab.) in recently widely used in renal transplantation. CASE HISTORY: A 10-yr-old patient with end-stage renal failure due to multidrug resistant NS was transplanted with renal graft from deceased donor and presented immediate recurrence of NS. PF was started on day 3 and patient received MP pulses, however with no effect. Rituximab (4 * 375 mg/m(2)) was administered. Chest radiographs taken at that time were normal. Partial remission was achieved and the patient was discharged in good condition. Sequential recurrence appeared two wk afterward. Twelve sessions of PF were performed and six pulses of MP were given, effecting a partial remission. Three months after the last dose of rituximab, patient was admitted with increasing respiratory failure, requiring mechanical ventilation. Infectious background, including CMV, BKV, mycoplasma, and pneumocystis, was not confirmed. The patient was treated with MP pulses, IVIG, and a variety of antibiotics. Ground-glass opacity was confirmed on lung CT images. Respiratory failure worsened, despite aggressive ventilation and patient passed away after three wk at ICU. A destruction of alveolar epithelium and extended pulmonary fibrosis was confirmed in the autopsy report. The case represents a fatal RALI. PMID- 25929599 TI - Distinct neural processes are engaged in the modulation of mimicry by social group-membership and emotional expressions. AB - People often spontaneously engage in copying each other's postures and mannerisms, a phenomenon referred to as behavioral mimicry. Social psychology experiments indicate that mimicry denotes an implicit affiliative signal flexibly regulated in response to social requirements. Yet, the mediating processes and neural underpinnings of such regulation are largely unexplored. The present functional magnetic resonance imaging (fMRI) study examined mimicry regulation by combining an automatic imitation task with facial stimuli, varied on two social affective dimensions: emotional expression (angry vs happy) and ethnic group membership (in- vs out-group). Behavioral data revealed increased mimicry when happy and when out-group faces were shown. Imaging results revealed that mimicry regulation in response to happy faces was associated with increased activation in the right temporo-parietal junction (TPJ), right dorsal premotor cortex (dPMC), and right superior parietal lobule (SPL). Mimicry regulation in response to out group faces was related to increased activation in the left ventral premotor cortex (vPMC) and inferior parietal lobule (IPL), bilateral anterior insula, and mid-cingulate cortex (MCC). We suggest that mimicry in response to happy and to out-group faces is driven by distinct affiliative goals, and that mimicry regulation to attain these goals is mediated by distinct neuro-cognitive processes. Higher mimicry in response to happy faces seems to denote reciprocation of an affiliative signal. Higher mimicry in response to out-group faces, reflects an appeasement attempt towards an interaction partner perceived as threatening (an interpretation supported by implicit measures showing that out group members are more strongly associated with threat). Our findings show that subtle social cues can result in the implicit regulation of mimicry. This regulation serves to achieve distinct affiliative goals, is mediated by different regulatory processes, and relies on distinct parts of an overarching network of task-related brain areas. Our findings shed new light on the neural mechanisms underlying the interplay between implicit action control and social cognition. PMID- 25929600 TI - Ventral transpalpebral anterior orbitotomy: surgical description and report of 3 cases. AB - PURPOSE: To describe a surgical approach to allow access to the ventral anterior canine orbit and report outcomes of three cases. SURGICAL TECHNIQUE: After induction of general anesthesia and aseptic preparation of the surgical site, a 2.5- to 3-cm curvilinear skin incision was created through the inferior eyelid at the level of the ventral orbital rim. A combination of sharp and blunt dissection facilitated entrance into the ventral anterior orbital space for the removal of diseased tissues or allows for drainage of purulent debris. Two-layer closure was performed, and postoperative lateral temporary tarsorrhaphy sutures were retained to provide globe protection. RESULTS: Three dogs underwent unilateral ventral transpalpebral anterior orbitotomy. Prior to surgery, apart from a complete ophthalmic examination, ocular ultrasound was used to diagnose orbital disease in two cases, and MRI was utilized in the third case. Exploratory orbitotomy revealed a large mucocele in case 1, orbital bacterial abscessation in case 2, and necrotizing zygomatic sialoadenitis in case 3. Clinical exophthalmos resolved immediately after surgery. The surgical site in all cases healed within 2 weeks. One patient had a superficial corneal ulceration 2 weeks after surgery which healed uneventfully. Recurrence of orbital disease was not noted in any case. CONCLUSIONS: Ventral transpalpebral anterior orbitotomy is a simple procedure that allows easy access to the ventral anterior orbit to allow for removal of diseased tissues or to facilitate drainage of abscessation. Recurrence of orbital disease was not seen in any patient, with one patient experiencing blindness as a long-term complication following the procedure. PMID- 25929601 TI - A framework for the atrial fibrillation prediction in electrophysiological studies. AB - BACKGROUND AND OBJECTIVE: Cardiac arrhythmias are disorders in terms of speed or rhythm in the heart's electrical system. Atrial fibrillation (AFib) is the most common sustained arrhythmia that affects a large number of persons. Electrophysiologic study (EPS) procedures are used to study fibrillation in patients; they consist of inducing a controlled fibrillation in surgical room to analyze electrical heart reactions or to decide for implanting medical devices (i.e., pacemaker). Nevertheless, the spontaneous induction may generate an undesired AFib, which may induce risk for patient and thus a critical issue for physicians. We study the unexpected AFib onset, aiming to identify signal patterns occurring in time interval preceding an event of spontaneous (i.e., not inducted) fibrillation. Profiling such signal patterns allowed to design and implement an AFib prediction algorithm able to early identify a spontaneous fibrillation. The objective is to increase the reliability of EPS procedures. METHODS: We gathered data signals collected by a General Electric Healthcare's CardioLab electrophysiology recording system (i.e., a polygraph). We extracted superficial and intracavitary cardiac signals regarding 50 different patients studied at the University Magna Graecia Cardiology Department. By studying waveform (i.e., amplitude and energy) of intracavitary signals before the onset of the arrhythmia, we were able to define patterns related to AFib onsets that are side effects of an inducted fibrillation. RESULTS: A framework for atrial fibrillation prediction during electrophysiological studies has been developed. It includes a prediction algorithm to alert an upcoming AFib onset. Tests have been performed on an intracavitary cardiac signals data set, related to patients studied in electrophysiological room. Also, results have been validated by the clinicians, proving that the framework can be useful in case of integration with the polygraph, helping physicians in managing and controlling of patient status during EPS. PMID- 25929602 TI - Analysis of Forensic Autopsy in 120 Cases of Medical Disputes Among Different Levels of Institutional Settings. AB - Despite advances in medical science, the causes of death can sometimes only be determined by pathologists after a complete autopsy. Few studies have investigated the importance of forensic autopsy in medically disputed cases among different levels of institutional settings. Our study aimed to analyze forensic autopsy in 120 cases of medical disputes among five levels of institutional settings between 2001 and 2012 in Wenzhou, China. The results showed an overall concordance rate of 55%. Of the 39% of clinically missed diagnosis, cardiovascular pathology comprises 55.32%, while respiratory pathology accounts for the remaining 44. 68%. Factors that increase the likelihood of missed diagnoses were private clinics, community settings, and county hospitals. These results support that autopsy remains an important tool in establishing causes of death in medically disputed case, which may directly determine or exclude the fault of medical care and therefore in helping in resolving these cases. PMID- 25929603 TI - Enzymatic Pre-treatment of Wastewater to Minimize Recovery by Reverse Transcriptase PCR of RNA from Inactive Bacteriophages. AB - Quantitative viral risk assessments for wastewaters are notoriously difficult. The often considered quantitative reverse transcriptase PCR reflects poorly on virus infectivity rates leading to inaccurate risk interpretations. Various techniques focused on the degradation of the nucleic acids of non-infective viruses were previously employed. We comparatively assessed the effectiveness of such enzymatic treatments for MS2 bacteriophage in treated wastewaters. The single use of RNase A at an appropriate concentration may be as effective as the combination of RNase followed by Proteinase K and more rapid. While all tested enzymatic treatments minimized recovery of RNA (>95 %) in the absence of infective MS2, none completely eliminated the signal recovery. Selection of any enzymatic protocol for minimizing recovery of RNA from degraded, non-infective viruses should balance the methods efficacy with its expediency. PMID- 25929604 TI - Subclinical Lesions and Donor-Specific Antibodies in Kidney Transplant Recipients Receiving Tacrolimus-Based Immunosuppressive Regimen Followed by Early Conversion to Sirolimus. AB - BACKGROUND: There is no evidence on the incidence of subclinical inflammation and scaring lesions in patients receiving tacrolimus (TAC) minimization and elimination immunosuppressive regimens. METHODS: This study analyzed preimplantation, 3 and 24 months protocol biopsies and anti-HLA donor-specific antibodies (DSA) in 140 low immunological risk kidney transplant recipients receiving reduced TAC exposure, prednisone, and mycophenolate, randomized at 3 months to be converted or not to sirolimus (SRL). RESULTS: Mean TAC concentrations were 6.0 +/- 2.4 ng/mL and 5.8 +/- 2.2 ng/mL at 3 and 24 months. The incidence of subclinical inflammation lesions at 3 months was 9.3%. The incidence of (interstitial fibrosis) IF/(tubular atrophy) TA at month 24 was 57.6%, higher in SRL compared to TAC group (68.8 vs 44.4%; P = 0.022). Patients converted to SRL showed higher incidence of acute rejection (7.3% vs 0%), proteinuria (59.6% vs 25%; P = 0.001), and DSA (17.8% vs 7.3%; P = 0.201), respectively. Biopsy-proven acute rejection (odds ratio [OR] 2.32, 95% confidence interval [95% CI], 0.979-5.518, P = 0.056), subclinical inflammation lesions at 3 months (OR, 11.75; 95% CI, 1.286-107.474; P = 0.029) and conversion to SRL (OR, 2.72; 95% CI, 1.155-6.383; P = 0.022) were associated with IF/TA at month 24. Black ethnicity (OR, 0.22; 95% CI, 0.058-0.873; P = 0.031), donor age (OR, 2.74; 95% CI, 1.329-5.649; P = 0.006), and conversion to SRL (OR, 2.34; 95% CI, 1.043 5.267; P = 0.039) were associated with inferior renal function at 24 months. CONCLUSIONS: In kidney transplant recipients receiving reduced TAC exposure, subclinical inflammation lesions at 3 months were associated with IF/TA at 24 months. Conversion from TAC to SRL was associated with inferior renal function, higher incidence of IF/TA, and trends to higher incidence of DSA at 24 months. PMID- 25929605 TI - Successful Catheter Ablation of Right Atrial Tachycardia After Bilateral Lung Transplantation. PMID- 25929606 TI - Ex Situ Limb Perfusion System to Extend Vascularized Composite Tissue Allograft Survival in Swine. AB - BACKGROUND: Organ perfusion systems have successfully been applied in solid organ transplantations. Their use in limb transplantation and replantation has not been widely investigated. In this study, we tested the potential for ex situ perfusion system to prolong limb allograft viability in a swine forelimb amputation/replantation model. METHODS: Fourteen swine were used. In group 1 (n = 4), we perfused 4 amputated limbs for 12 hours using warm (27 degrees C-32 degrees C) autologous blood. Group 2 (n = 3) served as a cold preservation control group, preserving limbs for 6 hours at 4 degrees C. All limbs were transplanted into healthy swine (n = 7) and observed for another 12 hours. Hemodynamic variables of circulation, as well as perfusate gases and electrolytes (pH, pCO2, pO2, O2 saturation, Na(+), K(+), Cl(-), Ca(2+), HCO3(-), glucose, lactate) were measured. Muscle samples were used to measure single-muscle fiber contractility. RESULTS: In the control group, no microcirculation was observed after 6 hours of cold storage. In the pump perfusion group, all limbs displayed a gradual increase in lactate levels (P < 0.05) during ex situ perfusion that returned to normal after transplantation and reperfusion (P = 0.05). The pH and potassium remained stable throughout the experiment. Single-muscle fiber contractility testing showed near normal contractility at the end of the reperfusion period (P > 0.05). Limb weight did not increase significantly between the end of pump perfusion and reperfusion (P > 0.05). CONCLUSIONS: We demonstrated the potential to preserve limb allograft using ex vivo circulation. This approach promises to extend the narrow time frame for revascularization of procured extremities in limb transplantation. PMID- 25929607 TI - Uncommon but devastating event: total fertilisation failure following intracytoplasmic sperm injection. AB - Fertilisation with intracytoplasmic sperm injection (ICSI) is a consequence of complex molecular interactions between spermatozoon and oocyte. Disruption of the process obviously prompts a frustrating event called total fertilisation failure (TFF). Up to 3% of ICSI cycles may result in TFF, and brief counselling for subsequent cycle management is indispensable. Within this perspective, ICSI cycles of a centre over a 10-year period were analysed to document TFF cases. Initial TFF after ICSI and subsequent ICSI cycle of the same cases were documented to clarify predictive factors of successful outcomes after initial TFF. In subsequent cycles, assisted oocyte activation (AOA) with calcium ionophore and Hypo-osmotic swelling test (HOST)/pentoxifilline for sperm selection was used. In the current analysis, successful fertilisation was achieved in 85% of the cases with previous TFF. The significant contributing factors for successful fertilisation in the latter cycle were: improved oocyte quantity and better sperm morphology. In conclusion, sporadic TFF event in the first and only cycle is usually a technically modifiable condition, but repeated TFF could indicate possible gamete defects, which might not be overcomed in the next modified ICSI cycle. PMID- 25929608 TI - Multimodality Treatment of Pediatric and Adult Patients With Ewing Sarcoma: A Single-institution Experience. AB - INTRODUCTION: The treatment of Ewing Sarcoma family of tumors is multimodal, both in children and adults. Axial location and metastases are classic prognostic factors. However, the worse prognosis in older patients is more controversial. METHODS: Retrospective analysis was performed of pediatric and adult patients treated with the 2001 SEOP protocol: 6 cycles of VIDE chemotherapy (CT). If no progression was observed, local (surgery and/or radiotherapy) and consolidation treatments were performed adjusted to prognosis: 8 cycles of VAC in standard-risk patients or 1 cycle of VAC and high-dose CT and autologous transplant in the case of increased risk.We analyzed induction CT toxicity, type of consolidation treatment, and disease-free (DFS) and overall (OS) survival by the Kaplan-Meier method, with a log-rank analysis of prognostic factors with regard to OS. RESULTS: Thirty-six patients were analyzed (2003 to 2011). Sixty percent were male, with a median age of 16 years (range, 7 to 57 y). The most frequent location was axial (43%), followed by extremities (34%), extraosseous (18%), and ribs (9%). Fifty-four percent of patients had metastases, of which, 58% were pulmonary.The median follow-up period was 36 months (5 to 101 mo). Median DFS was 25 months (16 to 34 mo) and median OS 29 months (19 to 40 mo), with a 3-year OS of 40%. Median OS from progression was 7 months (0.4 to 15 mo). Age <15 years and normal lactate dehydrogenase levels were associated with prolonged OS. CONCLUSIONS: Induction CT with the VIDE regimen was feasible in most patients, with a low risk for early progression. Hematological toxicity was substantial but manageable. Adult patients had a worse prognosis. Survival after progression was dismal. PMID- 25929609 TI - Imatinib-induced Severe Hepatitis in a 9-Year-old Girl With Philadelphia Chromosome-positive Acute Lymphoblastic Leukemia. AB - Imatinib mesylate has dramatically improved the outcome of children with Philadelphia chromosome-positive acute lymphoblastic leukemia (Ph* ALL) and is now included as first-line therapy. Uncommon adverse effects of this drug for pediatric use, however, are largely unknown. We report the first case of a 9-year old child who developed severe acute hepatitis with grade 4 transaminases and bilirubin elevation during imatinib treatment for Ph* ALL. Liver biopsy showed extensive lobular and pericentral necrosis of hepatocytes. Liver function recovered after discontinuing imatinib with a 4-week prednisolone. Extensive hepatic necrosis should be considered not only in adults but also in children under imatinib administration. PMID- 25929610 TI - Building a National Pediatric Cancer Center and Network in Paraguay: Lessons for Addressing Challenges in a Low-income Country. AB - In Paraguay, cancer is among the leading causes of death among children. We report challenges and solutions for building the country's first pediatric cancer center at the National University School of Medicine (PCC-SM) and describe the outcomes of the National Network for Pediatric Cancer. We found that children with acute lymphoblastic leukemia treated between 2008 and 2012 had higher 3-year survival rates and lower treatment abandonment rates than did children treated between 2000 and 2007 before the network was established. This improvement directly coincided with the increased treatment capacity of the PCC-SM. Herein, we describe the role of local, national, and international contributors in improving the health care at Paraguay's PCC-SM and discuss how expediting access to specialized cancer diagnosis and care and implementing a system for referral and follow-up visits can improve cancer outcomes in other low-resource countries. PMID- 25929611 TI - Anti-M Antibody Induced Prolonged Anemia Following Hemolytic Disease of the Newborn Due to Erythropoietic Suppression in 2 Siblings. AB - Hemolytic disease of the newborn (HDN) arising from MNSs incompatibility is rare, with few reports of prolonged anemia and reticulocytopenia following HDN. We report the younger of 2 male siblings, both of whom had anti-M-induced HDN and anemia persisting for over a month. Peripheral reticulocytes remained inappropriately low for the degree of anemia, and they needed multiple red cell transfusions. Viral infections were ruled out. Corticosteroids were given for suspected pure red cell aplasia. Anemia and reticulocytopenia subsequently improved. Colony-forming unit erythroid assay revealed erythropoietic suppression of M antigen-positive erythroid precursor cells cultured with maternal or infant sera containing anti-M. In conclusion, maternal anti-M caused HDN and prolonged anemia by erythropoietic suppression in 2 siblings. PMID- 25929612 TI - Safety and Effectiveness of Micafungin in Japanese Pediatric Patients: Results of a Postmarketing Surveillance Study. AB - Limited data are available about the safety and efficacy of micafungin in children. A postmarketing surveillance study was conducted to assess the safety and effectiveness of micafungin, an echinocandin antifungal, in pediatric patients. A prospective multicenter postmarketing observational study was carried out between October 2006 and September 2008 in Japan. Pediatric patients under 16 years received an intravenous infusion of micafungin at a dose of 1 mg/kg for candidiasis and 1 to 3 mg/kg for aspergillosis, with the option of increasing the dose if required to 6 mg/kg once daily. All adverse events were recorded. A total of 201 pediatric patients were enrolled. There were 55 adverse drug reactions reported among 42 of 190 patients evaluated for safety (22.1%); the most frequently reported adverse drug reaction was hepatobiliary disorders. No adverse drug reactions were reported in 18 neonates (aged below 4 wk). The overall clinical response rate in 91 patients evaluated for efficacy was 86.8%. The response rate in neonates was 90.0%, and there were no differences in the response rate by age. Micafungin was found to have sufficient safety and effectiveness for the treatment of fungal infections in pediatric patients with various backgrounds. PMID- 25929613 TI - Childhood Ewing Sarcoma of the Orbit. AB - In the span of the last 48 years, only 33 cases of children with orbital Ewing sarcoma have been reported. This study is to present 3 cases that were admitted to Children's Cancer Hospital Egypt 57357, during the period from 2009 to 2013. We have 2 cases treated using the hospital standard Ewing sarcoma treatment protocol, to completion, whereas the third discontinued treatment. All tumors have confirmed CD99 positivity, although translocation (11;22) was positive in 1 patient and negative in the third. With earlier diagnosis and adequate surgical resection and integration of chemotherapy and radiotherapy 1 patient survived for about 4 years, whereas the other 2 cases died due to disease progression or recurrence. PMID- 25929614 TI - Pediatric Vaginal Yolk Sac Tumor: Reappraisal of Treatment Strategy in a Rare Tumor at a Unique Location. AB - Review of the management of 6 young girls with vaginal yolk sac tumor over 25 years showed that the alpha-fetoprotein levels normalized in 5/6 within 4 cycles of primary cisplatin, bleomycin, etoposide (PEB)/carboplatin, etoposide, bleomycin (JEB)/cisplatin, vinblastine, bleomycin (PVB) chemotherapy. Radioimaging revealed residual tissue but viable tumor was found in only 1 of 2 biopsied. Resection/biopsy is necessary to avoid giving additional primary chemotherapy or to identify patients who need different treatment. If markers do not decay appropriately, PEB/JEB/PVB chemotherapy should not be continued. Taxol containing salvage chemotherapy regimens, adjuvant modern radiotherapeutic treatment, and fertility-saving curative surgery should then be considered. Despite having mostly advanced disease, 5/6 patients were cured, 2 with chemotherapy alone. PMID- 25929615 TI - The Risk of Serious Bacterial Infection in Neutropenic Immunocompetent Febrile Children. AB - Only few reports have looked into the risk of invasive bacterial infection in children with neutropenia that is not malignancy related. The objective of the current study was to determine the clinical significance of neutropenia as a predictor of serious bacterial infection (SBI) in immunocompetent children. We conducted a retrospective case-control study including children 3 months to 18 years of age with fever >= 38 degrees C hospitalized or presenting to the emergency department. Patients who had neutropenia <= 1000 ANC/MUL and had a blood culture taken were matched for age with the consecutive febrile patients for whom a blood culture was taken. The main outcome was the rate of SBI. SBIs were more prevalent among the control group than in the group of children with neutropenia, 19/71 and 6/71, respectively (P = 0.0005). More children were treated with antibiotics among the control group than in the group of children with neutropenia, 39/71 and 20/71, respectively (P < 0.0001). Acute-phase reactants including CRP and platelets were higher in the control group. We concluded that immunocompetent patients with fever and moderate neutropenia do not carry a higher risk for SBIs compared with patients with fever who do not have neutropenia. PMID- 25929616 TI - E-cigarette use and relations to tobacco and alcohol use among adolescents. AB - Electronic cigarette (EC) use is currently subject to a debate concerning safety, regulation need, and probable contribution to smoking cessation. An important gap in this debate is the lack of distinction between minors and adults. This is problematic because other principles of prevention apply to long-term users (such as most adult smokers) and experimental or probable users (more common in minors). This commentary focuses on two less discussed aspects of the EC debate: 1) whether EC use is likely to be additive to conventional cigarette and other tobacco use among minors, and 2) if EC use is likely to contribute to an overall increase in alcohol consumption and other drug use among minors. We find the results by Hughes et al. and others indeed suggestive of both. We conclude that EC use is likely to be additive to other tobacco use and increase the risk for alcohol use, therefore serving as another potential route to hazard for even mildly risk-prone minors. Policies to restrict the access and use of EC among minors are encouraged. PMID- 25929617 TI - Toxicological risk assessment of elemental gold following oral exposure to sheets and nanoparticles - A review. AB - Elemental gold is used as a food coloring agent and in dental fillings. In addition, gold nanoparticles are gaining increasing attention due to their potential use as inert carriers for medical purposes. Although elemental gold is considered to be inert, there is evidence to suggest the release of gold ions from its surface. Elemental gold, or the released ions, is, to some extent, absorbed in the gastrointestinal tract. Gold is distributed to organs such as the liver, heart, kidneys and lungs. The main excretion route of absorbed gold is through urine. Data on the oral toxicity of elemental gold is limited. The acute toxicity of elemental gold seems to be low, as rats were unaffected by a single dose of 2000mg nanoparticles/kg of body weight. Information on repeated dose toxicity is very limited. Skin rashes have been reported in humans following the ingestion of liquors containing gold. In addition, gold released from dental restorations has been reported to increase the risk of developing gold hypersensitivity. Regarding genotoxicity, in vitro studies indicate that gold nanoparticles induce DNA damage in mammalian cells. In vivo, gold nanoparticles induce genotoxic effects in Drosophila melanogaster; however, genotoxicity studies in mammals are lacking. Overall, based on the literature and taking low human exposure into account, elemental gold via the oral route is not considered to pose a health concern to humans in general. PMID- 25929618 TI - Modernizing problem formulation for risk assessment necessitates articulation of mode of action. AB - The process of scientific hypothesis formulation affects the experimental designs, methods and interpretations applied, but to be testable, the hypotheses posed must conform to the state of scientific knowledge and available technology. An analogous situation exists in risk assessment, where the questions addressed are typically articulated in the problem formulation phase. Decades ago, regulatory agencies couched problem formulation according to the questions answerable by the science of the day. As regulatory requirements for risk assessment became codified, so too did the rudiments of problem formulation. Unfortunately, codifying problem formulation prevented it from evolving to keep pace with scientific advancements. Today's more advanced science is not always being used effectively and efficiently in risk assessment because the risk assessment problem formulation step still typically poses antiquated questions. Problem formulation needs to be improved so that modern science can inform risk considerations. Based on recent developments in the Human Relevance Framework and using well-studied example chemicals - chloroform and carbon tetrachloride - an approach is proposed for focusing problem formulation on human-relevant hypotheses. We contend that modernizing problem formulation in this way will make risk assessment more scientifically accurate, more practical, and more relevant for protecting human health and the environment. PMID- 25929619 TI - Using within-subject pattern classification to understand lifespan age differences in oscillatory mechanisms of working memory selection and maintenance. AB - In lifespan studies, large within-group heterogeneity with regard to behavioral and neuronal data is observed. This casts doubt on the validity of group statistics-based approaches to understand age-related changes on cognitive and neural levels. Recent progress in brain-computer interface research demonstrates the potential of machine learning techniques to derive reliable person-specific models, representing brain behavior mappings. The present study now proposes a supervised learning approach to derive person-specific models for the identification and quantification of interindividual differences in oscillatory EEG responses related to working memory selection and maintenance mechanisms in a heterogeneous lifespan sample. EEG data were used to discriminate different levels of working memory load and the focus of visual attention. We demonstrate that our approach leads to person-specific models with better discrimination performance compared to classical person-nonspecific models. We show how these models can be interpreted both on an individual as well as on a group level. One of the key findings is that, with regard to the time dimension, the between person variance of the obtained person-specific models is smaller in older than in younger adults. This is contrary to what we expected because of increased behavioral and neuronal heterogeneity in older adults. PMID- 25929621 TI - Reach, treat and cure pediatric tuberculosis: raising the voice for children. PMID- 25929620 TI - 3D Cortical electrophysiology of ballistic upper limb movement in humans. AB - Precise motor control requires the ability to scale the parameters of movement. Theta oscillations across the cortex have been associated with changes in memory, attention, and sensorimotor processing. What has proven more elusive is pinpointing the region-specific frequency band oscillations that are associated with specific parameters of movement during the acceleration and deceleration phases. We report a study using 3D analytic techniques for high density electroencephalography that examines electrocortical dynamics while participants produce upper limb movements to different distances at varying rates. During fast ballistic movements, we observed increased theta band activity in the left motor area contralateral to the moving limb during the acceleration phase of the movement, and theta power correlated with the acceleration of movement. In contrast, beta band activity scaled with the type of movement during the deceleration phase near the end of the movement and correlated with movement time. In the ipsilateral motor and somatosensory area, alpha band activity decreased with the type of movement near the end of the movement, and gamma band activity in visual cortex increased with the type of movement near the end of the movement. Our results suggest that humans use distinct lateralized cortical activity for distance and speed dependent arm movements. We provide new evidence that a temporary increase in theta band power relates to movement acceleration and is important during movement execution. Further, the theta power increase is coupled with desychronization of beta band power and alpha band power which are modulated by the task near the end of movement. PMID- 25929622 TI - Indias last battle in the war against polio. AB - Knowledge and training in evidence-based medicine is essential for informed clinical decision-making and treatment choices. Systematic reviews identify, appraise and synthesize research-based evidence and present it in accessible format. The Indian Council of Medical Research has promoted evidence-based medicine in India by establishing an Advanced Center for evidence based medicine that hosted the South Asian Cochrane Network and Center at the Christian Medical College, Vellore; procuring a national subscription to The Cochrane Library making it accessible to all Indian scientists; and establishing a Center for Advanced research on evidence-based child health at Post Graduate Institute of Medical Education and Research, Chandigarh. This article informs about a national level initiative by ICMR that aims to harness the translational potential of secondary research, by funding systematic reviews aligned to national health priorities selected through a national competitive process; and to provide training, mentoring, and quality assurance. A continuing scheme of funding high quality systematic reviews on priority areas of Child Health may follow. PMID- 25929623 TI - Scorpion envenoming,a step ahead. PMID- 25929624 TI - Myocardial dysfunction in children with scorpion sting envenomation. PMID- 25929625 TI - Early Infant Diagnosis of HIV. PMID- 25929626 TI - Predictors of Myocardial Dysfunction in Children with Indian Red Scorpion (Mesobuthus tamulus) Sting Envenomation. AB - OBJECTIVE: To identify predictive risk factors for myocardial dysfunction in children with scorpion sting envenomation and to evaluate the effects of Scorpion antivenom and prazosin combination therapy on occurrence of myocardial dysfunction. DESIGN: Observational. SETTING: Tertiary care hospital in Southern India. PARTICIPANTS: 85 children aged <13 years with scorpion sting envenomation. OUTCOME MEASURES: Frequency of myocardial dysfunction; predictors of myocardial dysfunction. RESULTS: 24 children (28.2%) developed myocardial dysfunction. Hypotension at admission (P=0.003) and increased time (>4h) between sting and administration of appropriate therapy (P=0.001) were independent predictors of myocardial dysfunction on logistic regression. Scorpion antivenom plus prazosin combination therapy led to an increase in cumulative proportion of children without myocardial dysfunction. CONCLUSIONS: Early (<4 hours) administration of Scorpion antivenom along with prazosin increases the cumulative percentage of children not developing myocardial dysfunction. PMID- 25929627 TI - Blood lead levels and childhood asthma. AB - OBJECTIVE: To measure blood lead levels in children (5-14 y) with bronchial asthma, and correlate with asthma severity. DESIGN: Cross-sectional analytical. SETTING: Pediatric Allergy and Immunology Clinic of a Childrens hospital in Cairo, Egypt. PARTICIPANTS: 200 children (127 males) with bronchial asthma and 125 age- and sex-matched healthy controls (80 males). PROCEDURE: Blood lead levels were measured by atomic absorption spectrophotometer technique, and were subsequently correlated with asthma severity. RESULTS: No significant difference in mean (SD) blood lead levels was observed between children with asthma [13.3 (4.8) ug/dL] and control group [11.4 (3.9) ug/dL]. 190 children (58.5%) had elevated blood lead levels (>10 ug/dL), with no significant difference between patients (60%) and controls (56%). Patients with elevated blood lead levels had significantly higher frequency of eosinophilia (66.7%) and increased total immunoglobulin E (83.3%) compared to other patients with blood lead levels <10ug/dL (10% and 43.8%, respectively). Patients of asthma with elevated blood lead levels had higher grades of severity of asthma compared to those with blood lead levels <10 ug/dL. CONCLUSIONS: Blood lead levels are not significantly associated with diagnosis of asthma but elevated blood lead levels seem to be associated with increased asthma severity and higher frequency of eosinophilia and elevated immunoglobulin E levels. PMID- 25929628 TI - Challenges in the Early Diagnosis of HIV Infection in Infants: Experience from Tamil Nadu, India. AB - OBJECTIVE: To analyze critical steps in the testing algorithm of the National Early Infant Diagnosis (EID) program in India. METHODS: A retrospective analysis of data on cases enrolled in the EID program during 2010-2012 from Tamil Nadu was undertaken. RESULTS: 2745 dried blood spots were tested; 9% of these tested positive. Median age of infants at the time of testing was 4 months. Second specimen for confirmation was received from 67% of cases with a turn-around time of 10-270 days. CONCLUSIONS: Even with high levels of uptake into the program, huge delays and loss-to-follow-up observed between the first and second sampling, suggests need for revision of the current testing algorithm. PMID- 25929629 TI - Association between vasoactive-inotropic score and mortality in pediatric septic shock. AB - OBJECTIVE: To assess the association between Vasoactive Inotrope Score (vis) and mortality in children with fluid-refractory septic shock. METHODS: A retrospective chart review of 71 children (age 1 mo-16y) admitted with fluid refractory septic shock in pediatric intensive care unit during a two year period was done. We divided our cohort into two groups viz High vasoactive inotrope score (Group-H) and Low-vasoactive inotrope score (Group-L) based on a cut-off value of 20. RESULTS: 73% of the children were in Group-L. The mortality rate was 44% and 100% in Group L and Group H, respectively. CONCLUSIONS: High inotropic score in children with septic shock is associated with high mortality rate. PMID- 25929630 TI - Early dimercaptosuccinic acid renal scan in children with first febrile urinary tract infection. AB - OBJECTIVE: To determine use of early Tc-99m dimercaptosuccinic acid scintigraphy in screening for vesicoureteral reflux following first febrile urinary tract infection. METHODS: 43 children (1 mo-5 yr) with first febrile urinary tract infection underwent micturating cystourethrography, abdominal sonogram and early dimercaptosuccinic acid scintigraphy. RESULTS: Early dimercaptosuccinic acid scintigraphy had 72% sensitivity and 76% specificity for vesicoureteral reflux. For dilating vesicoureteral reflux, sensitivity and specificity were 100% and 75%, respectively. CONCLUSIONS: Early dimercaptosuccinic acid scintigraphy has the potential to replace micturating cystourethrography in initial evaluation of febrile urinary tract infection. PMID- 25929631 TI - Continuous positive airway pressure in preterm neonates: an update of current evidence and implications for developing countries. AB - CONTEXT: Continuous Positive Airway Pressure (CPAP) is a cost-effective and minimal invasive respiratory support for the newborn. OBJECTIVE: To review the evidence related to various aspects of CPAP usage and its applicability for developing countries. EVIDENCE ACQUISITION: We conducted a literature search on PubMed, CENTRAL, and Cochrane Database of Systematic Reviews using the terms CPAP OR continuous positive airway pressure OR, non-invasive ventilation AND newborn OR neonate OR infant. We also searched the reference lists from the above articles and of review articles. Extracted manuscripts and reviews were analyzed and results related to various aspects of CPAP usage were summarized in narrative form. RESULTS: Early use of CPAP with early rescue surfactant (InSurE) is the ideal approach for management of respiratory distress syndrome in preterm and extremely preterm infants. Delivery room CPAP is feasible and reduces the need for surfactant and mechanical ventilation by nearly 50%. Prophylactic surfactant for extreme preterms should be discouraged. Heated humidified high flow nasal cannula is best utilized for post-extubation respiratory support. The search for ideal interface still continues and binasal prongs or nasal masks are the good contenders. Evidence on the ideal CPAP delivery is still inconclusive. CONCLUSIONS: CPAP, if used early and judiciously, is an effective intervention and need immediate scaling-up in resource-limited settings. Future research should focus on the ideal interface and the CPAP delivery methods. PMID- 25929632 TI - Does early neonatal vitamin A supplementation reduce infant mortality? PMID- 25929633 TI - Childhood lupus with microangiopathic antiphospholipid syndrome and pulmonary hemorrhage. AB - BACKGROUND: Concurrent thrombotic and hemorrhagic manifestations are uncommon in patients with Antiphospholipid Syndrome. CASE CHARACTERISTICS: A 10-year-old girl with fever, edema, rash and joint pains, who later developed deep venous thrombosis (DVT), stroke, thrombotic microangiopathic hemolytic anemia and pulmonary hemorrhage. Investigations confirmed Antiphospholipid syndrome associated with systemic lupus erythematosus. OUTCOME: She went into complete remission with intravenous immunoglobulins, plasmapheresis, immunosuppression and anticoagulation. MESSAGE: Thrombotic microangiopathic hemolytic anemia and anti phospholipid syndrome can be the presenting manifestations of systemic lupus erythematosus. PMID- 25929634 TI - Ophelia syndrome: Hodgkin lymphoma with limbic encephalitis. AB - BACKGROUND: Limbic encephalitis, an immune-mediated encephalitis, results from inflammation in the medial temporal lobes. The paraneoplastic form is rare in pediatric population, and frequently precedes tumor diagnosis. CASE CHARACTERISTICS: A 9-year-old boy receiving chemotherapy for Hodgkin lymphoma, developed headache, temporal lobe seizures, anxiety, hallucinations, short-term memory loss and autonomic disturbances. Magnetic resonance imaging of brain showed features suggestive of limbic encephalitis. Electro-encephalography showed diffuse slowing with no epileptiform discharges. OUTCOME: We diagnosed paraneoplastic form of limbic encephalitis. Treatment with steroids and intravenous immunoglobulin failed, and the child died 4 weeks after onset of symptoms. MESSAGE: Limbic encephalitis should be kept as differential diagnosis in a child with sub-acutely evolving neuropsychiatric symptoms. PMID- 25929635 TI - Chromhidrosis--colored sweat in a toddler. AB - BACKGROUND: Chromhidrosis means production of coloured sweat. CASE CHARACTERISTICS: A toddler who presented with colored sweat was diagnosed to have chromhidrosis based on skin biopsy. No treatment was attempted considering the young age. OUTCOME: Parents were counselled about the benign nature of this disorder. MESSAGE: Identification of causes of colored sweat requires appropriate investigations. PMID- 25929636 TI - Respiratory Syncytial Virus in Children with Influenza-like Illness. PMID- 25929637 TI - Tenofovir in Indian children. AB - We describe our experience with tenofovir-based antiretroviral therapy in seven HIV-infected children after failure of first line antiretroviral drugs, or due to adverse effects to other antiretrovirals. For follow-up period of average 3.4 years, none had adverse effects or failure of treatment, indicating that tenofovir has good renal and gastrointestinal safety profile in HIV-infected Indian children and adolescents. PMID- 25929638 TI - Late decompensation after a prolonged lucid interval in chronic posterior fossa extradural hematoma. PMID- 25929639 TI - New mutation haplotypes in non-syndromic hearing loss. PMID- 25929640 TI - Maternal profile of children with severe acute malnutrition. PMID- 25929641 TI - Kawasaki disease in an infant, missed clues. PMID- 25929642 TI - Childhood Rhupus syndrome. PMID- 25929643 TI - Caffeine in a term neonate with apnea. PMID- 25929644 TI - Grave's disease following aplastic anemia: predisposition or coincidence? PMID- 25929645 TI - Can Rashtriya Bal Swasthya Karyakram give impetus and direction to Japanese encephalitis vaccination program? PMID- 25929646 TI - Reduced volume isotonic saline 0.9% as maintenance fluid in children. PMID- 25929647 TI - Reduced Volume Isotonic Saline as Maintenance Fluids in Children: Authors reply. PMID- 25929648 TI - Atypical features of severe dengue: probable pathogenesis. PMID- 25929649 TI - Cutaneous polyarteritis nodosa. PMID- 25929650 TI - Nicolau's syndrome. PMID- 25929651 TI - Erythema annulare centrifugum. PMID- 25929652 TI - Congenital platelike osteoma cutis. PMID- 25929653 TI - Infant motor development and cognitive performance in early old age: the Helsinki Birth Cohort Study. AB - Motor development and cognitive development in childhood have been found to be fundamentally interrelated, but less is known about the association extending over the life course. The aim of this study was to examine the association between early motor development and cognitive performance in early old age. From men and women belonging to the Helsinki Birth Cohort Study, who were born between 1934 and 1944 and resided in Finland in 1971, 1279 participated in cognitive performance tests (CogState(r), version 3.0.5) between 2001 and 2006 at an average age of 64.2 years (SD 3.0). Of these, age at first walking extracted from child welfare clinic records was available for 398 participants. Longer reaction times in cognitive tasks measuring simple reaction time (SRT), choice reaction time (CRT), working memory (WM), divided attention (DA), and associated learning (AL) indicated poorer cognitive performance. Adjustment was made for sex, age at testing, father's occupational status and own highest attained education, and occupation in adulthood. Average age of learning to walk was 12.2 months (SD 2.1). After adjusting for covariates, earlier attainment of learning to walk was associated with shorter reaction times in cognitive performance tasks (SRT 10.32 % per month, 95 % CI 0.48-21.12, p = 0.039; CRT 14.17 % per month, 95 % CI 3.75 25.63, p = 0.007; WM 15.14 % per month, 95 % CI 4.95-26.32, p = 0.003). People who learned to walk earlier had better cognitive performance in early old age. The earlier attainment of motor skills may track over to early old age and possibly reflect greater cognitive reserve in older age. PMID- 25929654 TI - Upregulation of cytochrome c oxidase subunit 6b1 (Cox6b1) and formation of mitochondrial supercomplexes: implication of Cox6b1 in the effect of calorie restriction. AB - Calorie restriction (CR), a non-genetic intervention that promotes longevity in animals, may exert anti-aging effects by modulating mitochondrial function. Based on our prior mitochondrial proteome analysis, we focused on the potential roles of cytochrome c oxidase (Cox or Complex IV) subunit 6b1 on formation of mitochondrial supercomplexes comprised of Complex I, III, and IV. Blue native polyacrylamide gel electrophoresis followed by immunoblotting showed that the amount of Cox6b1 and the proportion of high molecular weight supercomplexes (SCs) comprised of Complexes I, III, and IV were increased in the liver of mice subjected to 30 % CR, compared with the liver of mice fed ad libitum. In in vitro experiments, in Cox6b1-overexpressing NIH3T3 (Cox6b1-3T3) cells, Cox6b1 was increased in the SC, III2IV1, and III2IV2 complexes and Cox was concomitantly recruited abundantly into the SC, compared with control (Con)-3T3 cells. The proportions of III2IV1, and III2IV2, relative to IV monomer were also increased in Cox6b1-3T3 cells. Cox6b1-3T3 cells showed increased oxygen consumption rates, Cox activity, and intracellular ATP concentrations, indicating enhanced mitochondrial respiration, compared with Con-3T3 cells. Despite the increased basal level of mitochondrial reactive oxygen species (ROS), cell viability after inducing oxidative stress was greater in Cox6b1-3T3 cells than in Con-3T3 cells, probably because of prompt activation of protective mechanisms, such as nuclear translocation of nuclear factor E2-related factor-2. These in vivo and in vitro studies show that Cox6b1 is involved in regulation of mitochondrial function by promoting the formation of SC, suggesting that Cox6b1 contributes to the anti aging effects of CR. PMID- 25929655 TI - The effect of dexmedetomidine on inflammatory response of septic rats. AB - BACKGROUND: Some studies have demonstrated dexmedetomidine has anti-inflammatory effect on septic rats. However, the mechanism of how dexmedetomidine exerts these effects is still remained unknown. This study was designed to investigate the mechanism of how dexmedetomidine inhibits the production of inflammatory mediators in cecal ligation and puncturinduced septic rats. METHODS: 48 Sprague Dawley rats were randomly divided into six groups: sham-operated (sham) group, cecal ligation and puncture (CLP) group, dexmedetomidine 5 MUg/kg (DEX5) group, dexmedetomidine 10 MUg/kg (DEX10) group,dexmedetomidine + yohimbine (DEX10 + Yoh) group and yohimibine group (Yoh). Blood, bronchoalveolarlavage fluid (BALF) and lung tissues in each group were collected at six hours after dexmedetomidine or yohimbine treatment,. Tumor necrosis factor-alpha (TNF-alpha) and interleukin-6 (IL-6) in BALF and plasma were measured by enzyme-linked immunosorbent assay (ELISA). Toll-like receptor-4(TLR4) and myeloid differerntiation factor(MyD88) expression were measuredby quantitative PCR, and extracellular signal-regulated kinase (ERK) 1/2 phosphorylation were determined by western blott. RESULTS: Compared with CLP group, dexmedetomidine significantly decreased not only the production of TNF-alpha and IL-6 both in plasma and BALF, but also inhibited the expression of TLR4 and MyD88 in mRNA level and the activation of ERK1/2 and NF kappaB in the lung tissues of CLP-induced septic rats. All these effects could not be reversed by yohimibine. CONCLUSIONS: Dexmedetomidine treatment can effectively reduce the generation of inflammatory mediators in the plasma and BALF of CLP-induced septic rats. These effects of dexmedetomidine rely on TLR4/MyD88/MAPK/ NF-kappaB signaling pathway and are independent of alpha2 adrenoceptor. PMID- 25929656 TI - MRI of lumbar trunk muscles in patients with Parkinson's disease and camptocormia. AB - Camptocormia in Parkinson's disease (PD) is an axial postural disorder usually accompanied by histopathological changes in the paravertebral muscles of unknown etiology. The diagnostic potential of magnetic resonance imaging (MRI) of back muscles in camptocormia has not been systematically assessed. Our objective was to characterize pathological muscle changes with MRI and to develop radiological criteria for camptocormia. The criteria edema, swelling and fatty degeneration in 20 idiopathic PD patients with camptocormia were assessed using MRI (T1w and short tau inversion recovery (STIR) sequences) of the lumbar trunk muscles and compared with 20 group-matched PD patients without camptocormia. Edema and fatty degeneration of the paravertebral muscles were significantly more frequent in camptocormia. Edema correlated negatively and fatty degeneration positively with the duration of camptocormia and not PD. Swelling of the paravertebral muscles, edema and swelling of the quadratus lumborum muscle and rare edema of the psoas muscle were only found in camptocormia patients. In this case-control study the defined MRI criteria distinguish the group of PD patients with camptocormia versus those without. Our findings suggest dynamic changes in the MRI signals over time in the paravertebral muscles: edema and swelling are found initially, followed by fatty atrophic degeneration 2-3 years after the beginning of camptocormia. Muscle MRI qualifies as a tool for categorizing phases of camptocormia as acute or chronic, with potential consequences for therapeutic approaches. The involvement of muscles beyond an isolated impairment of the paravertebral muscles implies a more systemic view with a deregulation of lumbar trunk muscles. PMID- 25929657 TI - 25-Hydroxyvitamin D levels in acute monosymptomatic optic neuritis: relation to clinical severity, paraclinical findings and risk of multiple sclerosis. AB - Optic neuritis (ON) is a common first symptom of MS and only few studies have thus far investigated vitamin D at this early stage of MS. The objectives of the study were to examine total 25-hydroxyvitamin D levels (25HVITDL) in patients in acute (A) ON and to determine whether 25HVITD levels in AON (1) predict risk of RRMS and (2) are associated with visual tests of ON severity. A cross-sectional study was conducted of mean 25HVITDL differences between ON (n = 164) and MS (n = 948) patients and of prevalence of 25HVITDL deficiency (<50 nmol/L) in ON and MS (two-sample t test, chi (2) test). Associations between 25HVITDL and (1) clinical ON severity, (2) paraclinical findings suggestive of MS [logistic regression (LRA), Spearman correlation] and (3) hazard of MS development [Cox (C) RA] in ON patients were assessed. 25HVITDL were deseasonalized before analysis. The mean levels were 47.6 (ON) and 63.9 (MS) nmol/L (p < 0.0001), and a significantly higher prevalence of 25HVITD deficiency in ON (56 %; 35 %) (p < 0.0001), most pronounced in females, was shown. Associations were found between 25HVITDL and both CSF leukocyte count (rho = -0.177, p = 0.028) and IgG index elevation (OR 0.980, p = 0.031). Forty-one ON patients developed MS during the study. Multivariate CRA showed no effect on hazard of MS (HR: 0.991, p 0.284). No association was found between 25HVITDL and visual tests (acuity, contrast vision) or OCT RNFL or GCL thickness. The study indicates a high prevalence of 25HVITD deficiency in AON. 25HVITDL was significantly associated with CSF leukocyte count, but not ON severity. The study indicates a possible role of vitamin D in the early stages of MS, but does not support the use of 25HVITDL as a predictor of MS development in acute ON. PMID- 25929659 TI - Brainstem raphe and substantia nigra echogenicity in idiopathic REM sleep behavior disorder with comorbid depression. AB - In Parkinson disease (PD), REM sleep behavior disorder (RBD) and depression may occur before the onset of parkinsonism. Transcranial sonography (TCS) shows that hyperechogenicity of the substantia nigra (SN+) and hypoechogenicity of the brainstem raphe (BR+) are frequent in PD, particularly when depression is associated. Combined SN+ and BR+ identify PD subjects in whom depression antedates parkinsonism onset. It can be speculated that SN+ and BR+ may also identify idiopathic RBD (IRBD) subjects with comorbid depression, supporting the clinical diagnosis of this mood disorder. We aimed to study the brainstem raphe and substantia nigra echogenicity and their ability to predict comorbid depression in IRBD. Seventy-two IRBD patients and 71 age and sex-matched controls underwent TCS. Depression was diagnosed by means of DSM-IV criteria. Depression was more frequent in IRBD patients than in controls (44.4 vs. 18.3 %; p = 0.001). BR+ was more frequent in depressed than in nondepressed IRBD patients (32.0 vs. 11.4 %; p = 0.050). Sensitivity of BR+ to predict depression in IRBD was 32.0 %, specificity was 88.6 %, and relative risk was 1.88. Sensitivity of SN+ to predict depression in IRBD was 72.0 %, specificity was 44.1 %, and relative risk was 1.53. Sensitivity of combined BR+ and SN+ to predict depression in IRBD was 23.1 %, specificity 97.1 %, and relative risk was 2.31. Hypoechogenicity of the brainstem raphe, particularly when combined with hyperechogenicity of the substantia nigra, detects comorbid depression in IRBD. This finding suggests that dysfunction of the serotonergic dorsal raphe may be involved in the pathophysiology of depression in IRBD. PMID- 25929658 TI - Prevalence and timeline of nonmotor symptoms in idiopathic rapid eye movement sleep behavior disorder. AB - Parkinson disease (PD) patients may experience nonmotor symptoms (NMS) before Parkinsonism onset. Patients with idiopathic REM sleep behavior disorder (IRBD) eventually develop PD and may represent premotor PD. We aimed to evaluate the prevalence and perceived timeline of NMS in IRBD through validated scales and questionnaires used in PD research. In 44 IRBD patients and 40 matched controls, overall NMS evaluation was assessed by NMS questionnaire for Parkinson disease, olfaction by University of Pennsylvania Smell Identification Test, dysautonomia by scales for outcomes in Parkinson's disease-autonomic, constipation by Rome III criteria, depression by Hospital Anxiety and Depression Scale, cognitive impairment by Montreal cognitive assessment (MoCA) and hypersomnia by Epworth Sleepiness Scale. Patients were asked to report the perceived time of onset of hyposmia, constipation, and depression. Hyposmia (52.3 vs. 20.0 %, p = 0.002) and constipation (56.8 vs. 20.0 %, p = 0.001) were more frequent in patients than in controls. Patients reported more memory problems and showed a trend toward lower score in MoCA. Depression and hypersomnia were not more frequent in patients. The first symptom perceived was RBD in 38.6 % patients, hyposmia in 15.9 %, constipation in 11.4 %, and depression in 6.8 %. The temporal course of the NMS studied was heterogeneous. The three most common presentations were RBD followed by hyposmia; hyposmia followed by RBD; and hyposmia followed by RBD and constipation occurring at the same time span. IRBD patients frequently exhibit NMS that occur in premotor PD, particularly hyposmia and constipation. In IRBD, the perceived timeline of NMS is highly variable. This variability may suggest that pathological changes occurring in IRBD subjects are also heterogeneous and not restricted to the structures that regulate REM sleep. PMID- 25929660 TI - Two cases of early dystonia of the trunk in Parkinson's disease. PMID- 25929661 TI - Alleviation of myoclonus after bilateral pallidal deep brain stimulation for Lance-Adams syndrome. PMID- 25929662 TI - Deep brain stimulation of the subthalamic nucleus modulates reward processing and action selection in Parkinson patients. AB - Deep brain stimulation (DBS) of the subthalamic nucleus (STN) is an effective treatment for motor impairments in Parkinson's disease (PD) but its effect on the motivational regulation of action control is still not fully understood. We investigated whether DBS of the STN influences the ability of PD patients to act for anticipated reward or loss, or whether DBS improves action execution independent of motivational valence. 16 PD patients (12 male, mean age = 58.5 +/- 10.17 years) treated with bilateral STN-DBS and an age- and gender-matched group of healthy controls (HC) performed a go/no-go task whose contingencies explicitly decouple valence and action. Patients were tested with (ON) and without (OFF) active STN stimulation. For HC, there was a benefit in performing rewarded actions when compared to actions that avoided punishment. PD patients showed such a benefit reliably only when STN stimulation was ON. In fact, the relative behavioral benefit for go for reward over go to avoid losing was stronger in the PD patients under DBS ON than in HC. In PD patients, rather than generally improving motor functions independent of motivational valence, modulation of the STN by DBS improves action execution specifically when rewards are anticipated. Thus, STN-DBS establishes a reliable congruency between action and reward ("Pavlovian congruency") and remarkably enhances it over the level observed in HC. PMID- 25929663 TI - Functional connectome assessed using graph theory in drug-naive Parkinson's disease. AB - The purpose of this study is to investigate whether the topological organization of whole-brain functional network is disrupted in patients with Parkinson's disease (PD). We employed resting-state functional MRI (R-fMRI) and graph theory to investigate the topological organization of the functional connectome in 47 early-stage drug-naive PD patients and 47 healthy control subjects. Correlations between network properties and clinical variables were tested. Both the PD and control groups showed small-world architecture in brain functional networks. However, the PD patients had lower clustering coefficient and local efficiency relative to control subjects, indicating disrupted topologic organization and a shift toward randomization in their functional brain network. At node and connection level, reduced node centralities and connectivity strength were found mainly in temporal-occipital regions and also in sensorimotor regions of PD patients. In PD patients, altered global network properties correlated with cognitive function, while motor impairment was correlated with local connection changes. This study demonstrates a disruption of whole-brain topological organization of the functional brain networks in early-stage drug-naive PD patients and this disruption might contribute to preclinical changes in cognitive process in these patients. PMID- 25929664 TI - Alcohol responsiveness in laryngeal dystonia: a survey study. AB - Laryngeal dystonia (LD) is a task-specific focal dystonia of unknown pathophysiology affecting speech production. We examined the demographics of anecdotally reported alcohol use and its effects on LD symptoms using an online survey based on Research Electronic Data Capture (REDCapTM) and National Spasmodic Dysphonia Association's patient registry. From 641 participants, 531 were selected for data analysis, and 110 were excluded because of unconfirmed diagnosis. A total of 406 patients (76.5 %) had LD and 125 (23.5 %) had LD and voice tremor (LD/VT). The consumption of alcohol was reported by 374 LD (92.1 %) and 109 LD/VT (87.2 %) patients. Improvement of voice symptoms after alcohol ingestion was noted by 227 LD (55.9 % of all patients) and 73 LD/VT (58.4 %), which paralleled the improvement observed by patient's family and/or friends in 214 LD (57.2 %) and 69 LD/VT (63.3 %) patients. The benefits lasted 1-3 h in both groups with the maximum effect after 2 drinks in LD patients (p = 0.002), whereas LD/VT symptoms improved independent of the consumed amount (p = 0.48). Our data suggest that isolated dystonic symptoms, such as in LD, are responsive to alcohol intake and this responsiveness is not attributed to the presence of VT, which is known to have significant benefits from alcohol ingestion. Alcohol may modulate the pathophysiological mechanisms underlying abnormal neurotransmission of gamma aminobutyric acid (GABA) in dystonia and as such provide new avenues for novel therapeutic options in these patients. PMID- 25929665 TI - A longitudinal MRI study of cervical cord atrophy in multiple sclerosis. AB - There is an urgent need of fast and accurate methods for the longitudinal quantification of cervical cord atrophy in multiple sclerosis (MS). Aim of this study was to compare a new semi-automatic method [the active surface (AS) method] with an existing cord segmentation method (the Losseff method) to measure cervical cord atrophy progression in MS patients. Using the AS and Losseff methods, normalized cervical cord cross-sectional area (CSA) was compared between 35 MS patients and 9 healthy controls (HC) at baseline and after 2.3 years of follow-up. Correlations with clinical/conventional MRI variables and a power calculation study were also performed. At follow-up, the Losseff method detected a 1 % CSA increase in HC and a 3.5 % decrease in MS patients (p = 0.01), while the AS method detected a 0.1 % decrease in HC and 3 % decrease in MS patients (p = 0.02). The AS method was more sensitive to associations with disability/conventional MRI variables and also provided lower numbers of subjects per arm compared to the Losseff method in a putative clinical trial scenario. Cord AS CSA measurements were more sensitive to longitudinal changes in MS patients than Losseff measurements. Cord AS CSA might be a valuable surrogate outcome measure for monitoring neuroprotection in MS. PMID- 25929666 TI - Isolated tumefactive demyelinating lesions: diagnosis and long-term evolution of 16 patients in a multicentric study. AB - Isolated tumefactive demyelinating lesion (TDL) is a rare disease and a challenging entity especially for the differential diagnosis, biopsy indications, and therapeutic decisions. Long-term evolution is not well known. The objective of the study is to describe clinical and MRI characteristics and long-term follow up of patients with isolated TDL. We performed a retrospective study including patients (1) with one TDL radiologically defined by a >=20 mm FLAIR hyperintensity involving the white matter associated with T1 hypointensity that enhanced after gadolinium injection and (2) without any other MS lesion on the first MRI. Tumor, abscess, or other inflammatory diseases (ADEM, Balo's concentric sclerosis, systemic disease) were excluded. Sixteen patients (11 females/5 males) were included. The mean age of onset was 35.7 years (range 20 65). MRI disclosed supratentorial lesions with a mean size of 39.4 mm and usually mild edema/mass effect. Peripheral (mainly open-ring pattern) and central (mainly heterogeneous) enhancement were respectively seen in 9/16 and 11/16 patients. CSF study (n = 15) found oligoclonal bands (OCB) in seven. A cerebral biopsy was performed in 11 cases showing acute inflammatory demyelination. Thirteen patients were treated by pulse steroids with marked improvement in ten. At last clinical follow-up (mean 65.8 months, range 6-181), diagnosis was MS in 5 (31 %), isolated TDL in 10 (63 %) and one patient had a second TDL (6 %). Isolated tumefactive demyelinating lesions are a rare diagnostic entity. After a mean follow-up of 5 years, almost one-third became MS whereas most of the patients had no further event. PMID- 25929667 TI - Disentangling perceptual judgment and online feedback deficits in Parkinson's freezing of gait. AB - Although the underlying mechanisms of freezing of gait in Parkinson's disease (PD) are not fully understood, impaired sensory-perceptual processing has been proposed as an important contributor to freezing episodes. The aims of this cross sectional study were to disentangle how sensory-perceptual deficits involved in planning (prior to movement) and sensory-perceptual feedback processing (during movement execution) contribute to freezing of gait in narrow spaces. Thirteen PD participants with freezing (PD FOG), 14 PD participants without freezing (PD non FOG), and 15 healthy individuals made a perceptual estimate of the width of the distal opening of a corridor in two conditions: parallel and narrowing walls. Gait characteristics and number of freezing episodes were then compared while participants walked in baseline (no corridor), and through parallel walls and narrowing walls corridors. Visuospatial abilities were also assessed using neuropsychological tests. PD FOG had lower scores in the copy of the pentagons (p = 0.044) and had greater error variability in the perceptual judgment task (p = 0.008) than healthy participants. Although a similar number of freezing episodes occurred in both corridor conditions, PD FOG had greater step length variability while walking through the parallel walls corridor compared to healthy (p < 0.001) and PD non-FOG (p = 0.017) participants. Regression analysis revealed that error variability in perceptual judgment predicted the percentage of time spent in double support (R (2) = 0.347) only in the narrowing walls condition for PD FOG. These results support the notion that sensory-perceptual deficits both prior to movement planning and during movement execution are important factors contributing to freezing of gait. PMID- 25929668 TI - Henri Gastaut (1915-1995). PMID- 25929670 TI - Science academies of G7 nations call for action on antibiotic resistance and neglected tropical diseases. PMID- 25929669 TI - Physiological relevance of food grade microcapsules: Impact of milk protein based microcapsules on inflammation in mouse models for inflammatory bowel diseases. AB - In order to increase beneficial effects of bioactive compounds in functional food and dietary supplements, enormous efforts are put in the technological development of microcapsules. Although these products are often tailor-made for disease susceptible consumer, the physiological impact of microcapsule uptake on the respective target consumer has never been addressed. The present study aimed to assess the relevance of this aspect by analyzing the impact of milk protein based microcapsules on experimental inflammatory bowel disease. Long-term feeding of sodium caseinate or rennet gel microcapsules resulted in significant alterations in the intestinal microbiota of healthy mice. In TNFDeltaARE/wt mice, a model for chronic ileal inflammation, rennet gel microcapsules resulted in further increased splenomegaly, whereas ileal inflammation was unchanged. In IL10(-/-) mice, a model for chronic colitis, both types of microcapsules induced a local increase of the intestinal inflammation. The present study is the first to demonstrate that, independent of their cargo, microcapsules have the potential to affect the intestinal microbiota and to exert unprecedented detrimental effects on disease-susceptible individuals. In conclusion, the impact of microcapsule uptake on the respective target consumer groups should be thoroughly investigated in advance to their commercial use in functional food or dietary supplements. PMID- 25929671 TI - Boosting the Open Circuit Voltage and Fill Factor of QDSSCs Using Hierarchically Assembled ITO@Cu2S Nanowire Array Counter Electrodes. AB - The key challenges in enhancing the power conversion efficiency (PCE) of a quantum dot-sensitized solar cell (QDSSC) are efficiently achieving charge separation at the photoanode and improving the charge transfer, which is limited by the interface between the electrolyte and the counter electrode (CE). Here, hierarchically assembled ITO@Cu2S nanowire arrays with conductive single crystalline ITO cores and Cu2S nanocrystal shells were designed as efficient QDSSCs CEs. These arrays not only provided an efficient three-dimensional charge transport network but also allowed for the effective deposition of more Cu2S nanocrystals as active sites to catalyze the electrolyte reaction. This design considerably reduced the sheet and charge transfer resistance of the CE, thus decreasing the series resistance and increasing the shunt resistance of the QDSSC. As a result, QDSSCs with this CE exhibited an unprecedentedly high Voc of 0.688 V, a fill factor of 58.39%, and a PCE of 6.12%, which is 21.2% higher than that of the conventional brass/Cu2S CE. PMID- 25929672 TI - Automatic analysis of the trunk thermal images from healthy subjects and patients with faulty posture. AB - BACKGROUND: This paper presents an automatic method for assessing temperature distribution on the patient's back using thermal imaging. It discusses the advantages and disadvantages of thermal imaging and presents an algorithm for image analysis and processing that runs automatically and reproducibly. METHOD: The proposed new method of image analysis relates to automatic and reproducible analysis of temperature distribution on the patient's back. It includes the following steps: (1) detection of the external contours of the human body, (2) identification and recognition of the position of the arms, hips and shoulders, (3) application of a mesh having a fixed number of fields (which automatically adapts to the size of the patient's back), (4) analysis of the paraspinal muscles. These steps are preceded by image pre-processing. RESULTS: Based on a thermal image, this new fully automated algorithm enables to: (1) evaluate temperature distribution in the paraspinal area; (2) pre-assess the degree of lateral spinal curvature in screening, and (3) evaluate anomalies (deviations from the norm) in temperature distribution. The algorithm was practically implemented in Matlab Image Processing Toolbox. PMID- 25929673 TI - Bioanalytical evidence that chemicals in tattoo ink can induce adaptive stress responses. AB - Tattooing is becoming increasingly popular, particularly amongst young people. However, tattoo inks contain a complex mixture of chemical impurities that may pose a long-term risk for human health. As a first step towards the risk assessment of these complex mixtures we propose to assess the toxicological hazard potential of tattoo ink chemicals with cell-based bioassays. Targeted modes of toxic action and cellular endpoints included cytotoxicity, genotoxicity and adaptive stress response pathways. The studied tattoo inks, which were extracted with hexane as a proxy for the bioavailable fraction, caused effects in all bioassays, with the red and yellow tattoo inks having the greatest response, particularly inducing genotoxicity and oxidative stress response endpoints. Chemical analysis revealed the presence of polycyclic aromatic hydrocarbons in the tested black tattoo ink at concentrations twice the recommended level. The detected polycyclic aromatic hydrocarbons only explained 0.06% of the oxidative stress response of the black tattoo ink, thus the majority of the effect was caused by unidentified components. The study indicates that currently available tattoo inks contain components that induce adaptive stress response pathways, but to evaluate the risk to human health further work is required to understand the toxicokinetics of tattoo ink chemicals in the body. PMID- 25929674 TI - Fe-doped cryptomelane synthesized by refluxing at atmosphere: Structure, properties and photocatalytic degradation of phenol. AB - Fe-doped cryptomelanes were synthesized by refluxing at ambient pressure, followed by characterization with multiple techniques and test in photocatalytic degradation of phenol. The introduction of Fe(III) into the structure of cryptomelane results in a decrease in particle size and the contents of Mn and K(+), and an increase in the Mn average oxidation state (AOS), specific surface area and UV-vis light absorption ability. Mn and Fe K-edge extended X-ray absorption fine structure spectroscopy analysis indicates that some Fe(III) is incorporated into the framework of cryptomelane by replacing Mn(III) while the remaining Fe(3+) is adsorbed in the tunnel cavity. These Fe-doped cryptomelanes have significantly improved the photocatalytic degradation rate of phenol, with the sample of ~3.04 wt.% Fe doping being the most reactive and achieving a degradation rate of 36% higher than that of the un-doped one. The enhanced reactivity can be ascribed to the increase in the coherent scattering domain size of the crystals, Mn AOS and light absorption, as well as the presence of sufficient K(+) in the tunnel. The results imply that metal doping is an effective way to improve the performance of cryptomelane in pollutants removal and has the potential for modification of Mn oxide materials. PMID- 25929675 TI - Pain-Related Brain Activity Evoked by Active and Dynamic Arm Movement: Delayed Onset Muscle Soreness as a Promising Model for Studying Movement-Related Pain in Humans. AB - OBJECTIVE: To demonstrate delayed-onset muscle soreness (DOMS) is a suitable model for the study of movement-evoked pain, we attempted to identify brain regions specifically involved in pain evoked by active and dynamic movement under DOMS condition. SUBJECT: Twelve healthy volunteers METHODS: DOMS was induced in the left upper-arm flexor muscles by an eccentric elbow contraction exercise. Movement-evoked pain in the affected muscles was evaluated just before (day 0) and after (days 1-7 and 30) the exercise using a visual analog scale. Subjects underwent functional magnetic resonance imaging scans while performing repeated elbow flexion on day 2 (DOMS condition) and day 30 (painless condition). We compared brain activity between the DOMS and painless conditions. RESULTS: Movement-evoked pain reached peak intensity on day 2 and disappeared by day 30 in all subjects. No subject felt pain at rest on either of these days. Contralateral primary motor cortex (M1), parietal operculum and bilateral presupplementary motor area (pre-SMA) showed greater activity during active and dynamic arm movement with DOMS than during the same movement without pain. There was no difference in activation of brain regions known collectively as the "pain matrix," except for the parietal operculum, between the two conditions. CONCLUSION: Active and dynamic movement with pain selectively evoked activation of M1, pre-SMA, and parietal operculum, as assessed using DOMS. Our results demonstrate that DOMS is a promising experimental model for the study of movement evoked pain in humans. PMID- 25929676 TI - Scope of partial least-squares regression applied to the enantiomeric composition determination of ketoprofen from strongly overlapped chromatographic profiles. AB - Valuable quantitative information could be obtained from strongly overlapped chromatographic profiles of two enantiomers by using proper chemometric methods. Complete separation profiles where the peaks are fully resolved are difficult to achieve in chiral separation methods, and this becomes a particularly severe problem in case that the analyst needs to measure the chiral purity, i.e., when one of the enantiomers is present in the sample in very low concentrations. In this report, we explore the scope of a multivariate chemometric technique based on unfolded partial least-squares regression, as a mathematical tool to solve this quite frequent difficulty. This technique was applied to obtain quantitative results from partially overlapped chromatographic profiles of R- and S ketoprofen, with different values of enantioresolution factors (from 0.81 down to less than 0.2 resolution units), and also at several different S:R enantiomeric ratios. Enantiomeric purity below 1% was determined with excellent precision even from almost completely overlapped signals. All these assays were tested on the most demanding condition, i.e., when the minor peak elutes immediately after the main peak. The results were validated using univariate calibration of completely resolved profiles and the method applied to the determination of enantiomeric purity of commercial pharmaceuticals. PMID- 25929677 TI - Age Differences in the Trends of Smoking Among California Adults: Results from the California Health Interview Survey 2001-2012. AB - The aim is to study the trends of cigarette smoking from 2001 to 2012 using a California representative sample in the US. Data was taken from the California Health Interview Survey (CHIS) from 2001 to 2012, which is a population-based, biennial, random digit-dial telephone survey of the non-institutionalized population. The CHIS is the largest telephone survey in California and the largest state health survey in the US. 282,931 adults (n = 184,454 with age 18-60 and n = 98,477 with age >60) were included in the analysis. Data were weighted to be representative and adjusted for potential covariance and non-response biases. During 2001-2012, the prevalence of current smoking decreased from 18.86 to 15.4 % among adults age 18-60 (beta = -0.8, p = 0.0041). As for adults age >60, the prevalence of current smoking trend decreased with variations, started from 9.66 % in 2001, slightly increased to 9.74 % in 2003, but then gradually decreased, falling to 8.18 % in 2012. In 2012, there was a 14 % reduction of daily smoking adults age 18-60 (OR 0.84, 95 % CI 0.76-0.93, p = 0.0006) compared to 2001, while no significant reduction of daily smoking was observed for those age >60. The reductions of smoking prevalence for adults younger than 60 are encouraging. However, there is a concern for smoking cessation rates among those older than 60 years of age, particularly for African Americans. PMID- 25929678 TI - Phenolic and microbial-targeted metabolomics to discovering and evaluating wine intake biomarkers in human urine and plasma. AB - The discovery of biomarkers of intake in nutritional epidemiological studies is essential in establishing an association between dietary intake (considering their bioavailability) and diet-related risk factors for diseases. The aim is to study urine and plasma phenolic and microbial profile by targeted metabolomics approach in a wine intervention clinical trial for discovering and evaluating food intake biomarkers. High-risk male volunteers (n = 36) were included in a randomized, crossover intervention clinical trial. After a washout period, subjects received red wine or gin, or dealcoholized red wine over four weeks. Fasting plasma and 24-h urine were collected at baseline and after each intervention period. A targeted metabolomic analysis of 70 host and microbial phenolic metabolites was performed using ultra performance liquid chromatography tandem mass spectrometer (UPLC-MS/MS). Metabolites were subjected to stepwise logistic regression to establish prediction models and received operation curves were performed to evaluate biomarkers. Prediction models based mainly on gallic acid metabolites, obtained sensitivity, specificity and area under the curve (AUC) for the training and validation sets of between 91 and 98% for urine and between 74 and 91% for plasma. Resveratrol, ethylgallate and gallic acid metabolite groups in urine samples also resulted in being good predictors of wine intake (AUC>87%). However, lower values for metabolites were obtained in plasma samples. The highest correlations between fasting plasma and urine were obtained for the prediction model score (r = 0.6, P<0.001), followed by gallic acid metabolites (r = 0.5-0.6, P<0.001). This study provides new insights into the discovery of food biomarkers in different biological samples. PMID- 25929679 TI - Sir Joseph Barcroft: one victorian physiologist's contributions to a half century of discovery. AB - During the first half of the 20th Century, Joseph Barcroft, KBE, FRS of Cambridge University became a world leader in respiratory physiology. He determined the role of neural stimulation in the oxygen consumption of several organs, established many of the factors that regulate the binding of oxygen to haemoglobin, explored the determinants of a human's acclimatization to high altitude and developed the field of fetal cardiovascular physiology. Chair of the Cambridge Department of Physiology from 1925 to 1937, he served as a consultant and member of many UK governmental committees. During World War I, he led a British research unit exploring the effects of poisonous gases on pulmonary function and related problems. In addition to his almost 300 publications, several of his monographs are considered as classics. PMID- 25929680 TI - Reduced interhemispheric resting-state functional connectivity in unmedicated bipolar II disorder. AB - OBJECTIVE: Abnormalities in structural and functional brain connectivity have been increasingly reported in patients with bipolar disorder (BD) by recent neuroimaging studies. However, relatively little is known about the changes in functional interaction between the cerebral hemispheres in BD. The present study aimed to examine the interhemispheric functional connectivity of the whole brain in patients with BD II during resting state. METHOD: Twenty-six patients with unmedicated BD II depression and 40 normal controls underwent the resting-state functional magnetic resonance imaging. The functional connectivity between any pair of symmetrical interhemispheric voxels (i.e., functional homotopy) was measured by voxel-mirrored homotopic connectivity (VMHC). RESULTS: The patients with BD II showed lower VMHC than normal controls in the medial prefrontal cortex and inferior temporal gyrus. No regions of increased VMHC were detected in patients. There were no significant correlations between the VMHC values in these regions and clinical severity of BD symptoms. CONCLUSION: These findings suggest substantial impairment of interhemispheric coordination in BD II. PMID- 25929681 TI - Cucurbit[6]uril is an ultrasensitive (129)Xe NMR contrast agent. AB - A lack of molecular contrast agents has slowed the application of ultrasensitive hyperpolarized (129)Xe NMR methods. Here, we report that commercially available cucurbit[6]uril (CB[6]) undergoes rapid xenon exchange kinetics at 300 K, and is detectable by Hyper-CEST NMR at 1.8 pM in PBS and at 1 MUM in human plasma where many molecules, including polyamines, can compete with xenon for CB[6] binding. PMID- 25929682 TI - Improvement of thermoelectric efficiency of the polyaniline molecular junction by the doping process. AB - Thermoelectric properties of a polyaniline molecular junction with face centered cubic electrodes are investigated using the Green function formalism in a linear response regime in the presence of the doping process. Doping causes the increase of thermopower and the figure of merit (ZT) and the decrease of electrical conductance as found experimentally in the work of Li et al., (Synthetic. Metals, 2010, 160, 1153-1158). We also find that the ZT increases with the molecular length in short polyanilines. [Golsanamlou et al., Phys. Chem. Chem. Phys., 2000, 35, 3523]. PMID- 25929683 TI - Effects of low-level sarin and cyclosarin exposure on white matter integrity in Gulf War Veterans. AB - BACKGROUND: We previously found evidence of reduced gray and white matter volume in Gulf War (GW) veterans with predicted low-level exposure to sarin (GB) and cyclosarin (GF). Because loss of white matter tissue integrity has been linked to both gray and white matter atrophy, the current study sought to test the hypothesis that GW veterans with predicted GB/GF exposure have evidence of disrupted white matter microstructural integrity. METHODS: Measures of fractional anisotropy and directional (i.e., axial and radial) diffusivity were assessed from the 4T diffusion tensor images (DTI) of 59 GW veterans with predicted GB/GF exposure and 59 "matched" unexposed GW veterans (mean age: 48 +/- 7 years). The DTI data were analyzed using regions of interest (ROI) analyses that accounted for age, sex, total brain gray and white matter volume, trauma exposure, posttraumatic stress disorder, current major depression, and chronic multisymptom illness status. RESULTS: There were no significant group differences in fractional anisotropy or radial diffusivity. However, there was increased axial diffusivity in GW veterans with predicted GB/GF exposure compared to matched, unexposed veterans throughout the brain, including the temporal stem, corona radiata, superior and inferior (hippocampal) cingulum, inferior and superior fronto-occipital fasciculus, internal and external capsule, and superficial cortical white matter blades. Post hoc analysis revealed significant correlations between higher fractional anisotropy and lower radial diffusivity with better neurobehavioral performance in unexposed GW veterans. In contrast, only increased axial diffusivity in posterior limb of the internal capsule was associated with better psychomotor function in GW veterans with predicted GB/GF exposure. CONCLUSIONS: The finding that increased axial diffusivity in a region of the brain that contains descending corticospinal fibers was associated with better psychomotor function and the lack of significant neurobehavioral deficits in veterans with predicted GB/GF exposure hint at the possibility that the widespread increases in axial diffusivity that we observed in GW veterans with predicted GB/GF exposure relative to unexposed controls may reflect white matter reorganization after brain injury (i.e., exposure to GB/GF). PMID- 25929684 TI - Nutraceuticals: Definition and Epidemiological Rationale for Their Use in Clinical Practice. AB - Cardiometabolic risk factors, such as hypercholesterolemia, hypertriglyceridemia, metabolic syndrome, diabetes, and arterial hypertension, are major predictors of the premature development of cardiovascular diseases (CVD). Since CVD prevention needs a life-course approach, beyond dietary and pharmacological treatment, non pharmacological treatment should be considered an important alternative for patients in primary prevention with mild-moderate cardiometabolic risk factors at low-moderate global risk of CVD. Several functional foods and nutraceuticals are efficacious, safe and well tolerated. However, only some (monacolins of red yeast rice and omega-3 fatty acids) have showed, in long-term randomized clinical trials, a reduction of cardiovascular events. PMID- 25929685 TI - Different strategies from monotherapies to dual or triple fixed dose combination therapies to achieve blood pressure goals: a summary of a satellite symposium from the European Society of Hypertension, June 13-16, 2014 Athens, Greece. Introduction. PMID- 25929686 TI - Lack of vincristine infiltrates in patients with retinoblastoma receiving chemotherapy by peripheral intravenous lines. AB - The delivery route of chemotherapy for intraocular retinoblastoma has become controversial. One objection to systemic delivery is the need for central venous access. We cross-referenced a hospital vascular access database with our tumor registry to determine the incidence of chemotherapy infiltrates. Sixty-five patients received 270 cycles of chemotherapy via peripheral intravenous access. Vincristine infiltration was 0% (95% confidence interval [CI] 0-0.16%) while that of non-vesicant chemotherapy was 0.7% (95%CI 0.1-2.6%). Giving chemotherapy via peripheral access to patients with retinoblastoma is safe. It can decrease therapy costs and prevent central line associated blood stream infections. PMID- 25929687 TI - Wilms' tumor gene 1 regulates p63 and promotes cell proliferation in squamous cell carcinoma of the head and neck. AB - BACKGROUND: Wilms' tumor gene 1 (WT1) can act as a suppressor or activator of tumourigenesis in different types of human malignancies. The role of WT1 in squamous cell carcinoma of the head and neck (SCCHN) is not clear. Overexpression of WT1 has been reported in SCCHN, suggesting a possible oncogenic role for WT1. In the present study we aimed at investigating the function of WT1 and its previously identified protein partners p63 and p53 in the SCCHN cell line FaDu. METHODS: Silencing RNA (siRNA) technology was applied to knockdown of WT1, p63 and p53 in FaDu cells. Cell proliferation was detected using MTT assay. Chromatin immunoprecipitation (ChIP)/PCR analysis was performed to confirm the effect of WT1 on the p63 promoter. Protein co-immunoprecipitation (co-IP) was used to find protein interaction between WT1 and p53/p63. Microarray analysis was used to identify changes of gene expression in response to knockdown of either WT1 or p63. WT1 RNA level was detected using real-time quantitative PCR (RT-qPCR) in patients with SCCHN. RESULTS: We found that WT1 and p63 promoted cell proliferation, while mutant p53 (R248L) possessed the ability to suppress cell proliferation. We reported a novel positive correlation between WT1 and p63 expression. Subsequently, p63 was identified as a WT1 target gene. Furthermore, expression of 18 genes involved in cell proliferation, cell cycle regulation and DNA replication was significantly altered by downregulation of WT1 and p63 expression. Several known WT1 and p63 target genes were affected by WT1 knockdown. Protein interaction was demonstrated between WT1 and p53 but not between WT1 and p63. Additionally, high WT1 mRNA levels were detected in SCCHN patient samples. CONCLUSIONS: Our findings suggest that WT1 and p63 act as oncogenes in SCCHN, affecting multiple genes involved in cancer cell growth. PMID- 25929688 TI - Cannabinoid functions in the amygdala contribute to conditioned fear memory in streptozotocin-induced diabetic mice: Interaction with glutamatergic functions. AB - The role of cannabinoid systems in conditioned fear memory was investigated in streptozotocin (STZ)-induced diabetic mice. The cannabinoid receptor agonist WIN 55,212-2 (1mg/kg, i.p.), when injected into normal mice after conditioning, significantly prolonged the duration of freezing behavior. This effect was significantly inhibited by the cannabinoid CB1 receptor antagonist AM 251 (3mg/kg, s.c.), but not by the cannabinoid CB2 receptor antagonist AM 630 (1mg/kg, s.c.). The duration of freezing in STZ-induced diabetic mice was significantly longer than that in non-diabetic mice. The injection of WIN-55,212 2 (1mg/kg, i.p.) after conditioning significantly prolonged the duration of freezing in non-diabetic mice, but not in STZ-induced diabetic mice. In contrast, the injection of AM 251 (3mg/kg, s.c.) after conditioning significantly shortened the duration of freezing in STZ-induced diabetic mice, but not in non-diabetic mice. The injection of AM 251 (3mg/kg, s.c.) before conditioning or before testing did not significantly affect the duration of freezing in STZ-induced diabetic mice. The protein levels of cannabinoid CB1 receptors in the amygdala were increased in STZ-induced diabetic mice. In contrast, the protein levels of cannabinoid CB2 receptors and diacylglycerol lipase alpha, the enzyme that synthesizes endocannabinoid 2-arachidonoylglycerol, in the amygdala did not differ between non-diabetic and STZ-induced diabetic mice. None of these proteins in the hippocampus was different between non-diabetic and STZ-induced diabetic mice. The injection of AM 251 (50 ng/side) into the basolateral amygdala significantly inhibited the duration of freezing in STZ-induced diabetic mice. Since endocannabinoid is controlled by glutamatergic function, we further examined the role of glutamatergic function in the increased fear memory in STZ induced diabetic mice. The amounts of glutamine and glutamic acid in the amygdala of STZ-induced diabetic mice were significantly increased compared to those in non-diabetic mice. The AMPA receptor antagonist NBQX (4 0ng/side), when injected into the basolateral amygdala, significantly inhibited the duration of freezing in STZ-induced diabetic mice. Finally, AMPA (40 ng, i.c.v.) significantly prolonged the duration of freezing in normal mice, and this effect was inhibited by AM 251 (3mg/kg, s.c.). These results suggest that cannabinoid functions in the amygdala are increased in diabetic mice and that enhanced glutamatergic function in the amygdala of diabetic mice activates the endocannabinoid system, which enhances fear memory via cannabinoid CB1 receptors. PMID- 25929689 TI - Androgen-dependent loss of muscle BDNF mRNA in two mouse models of SBMA. AB - Transgenic expression of neurotrophic factors in skeletal muscle has been found to protect mice from neuromuscular disease, including spinal bulbar muscular atrophy (SBMA), triggering renewed interest in neurotrophic factors as therapeutic agents for treating neuromuscular disease. Because SBMA is an androgen-dependent disease, and brain-derived neurotrophic factor (BDNF) mediates effects of androgens on neuromuscular systems, we asked whether BDNF expression is impaired in two different transgenic (Tg) mouse models of SBMA, the so called "97Q" and "myogenic" SBMA models. The 97Q model globally overexpresses a full length human AR with 97 glutamine repeats whereas the myogenic model of SBMA overexpresses a wild-type rat androgen receptor (AR) only in skeletal muscle fibers. Using quantitative PCR, we find that muscle BDNF mRNA declines in an androgen-dependent manner in both models, paralleling changes in motor function, with robust deficits (6-8 fold) in both fast and slow twitch muscles of impaired Tg males. Castration rescues or reverses disease-related deficits in muscle BDNF mRNA in both models, paralleling its effect on motor function. Moreover, when disease is acutely induced in Tg females, both motor function and muscle BDNF mRNA expression plummet, with the deficit in muscle BDNF emerging before overt motor dysfunction. That androgen-dependent motor dysfunction is tightly associated with a robust and early down-regulation of muscle BDNF mRNA suggests that BDNF delivered to skeletal muscle may have therapeutic value for SBMA. PMID- 25929691 TI - Peri-implant stress correlates with bone and cement morphology: Micro-FE modeling of implanted cadaveric glenoids. AB - Aseptic loosening of cemented joint replacements is a complex biological and mechanical process, and remains a clinical concern especially in patients with poor bone quality. Utilizing high resolution finite element analysis of a series of implanted cadaver glenoids, the objective of this study was to quantify relationships between construct morphology and resulting mechanical stresses in cement and trabeculae. Eight glenoid cadavers were implanted with a cemented central peg implant. Specimens were imaged by micro-CT, and subject-specific finite element models were developed. Bone volume fraction, glenoid width, implant-cortex distance, cement volume, cement-cortex contact, and cement-bone interface area were measured. Axial loading was applied to the implant of each model and stress distributions were characterized. Correlation analysis was completed across all specimens for pairs of morphological and mechanical variables. The amount of trabecular bone with high stress was strongly negatively correlated with both cement volume and contact between the cement and cortex (r = -0.85 and -0.84, p < 0.05). Bone with high stress was also correlated with both glenoid width and implant-cortex distance. Contact between the cement and underlying cortex may dramatically reduce trabecular bone stresses surrounding the cement, and this contact depends on bone shape, cement amount, and implant positioning. PMID- 25929690 TI - Tailoring of self-management interventions in patients with heart failure. AB - The effectiveness of heart failure (HF) self-management interventions varies within patients suggesting that one size does not fit all. It is expected that effectiveness can be optimized when interventions are tailored to individual patients. The aim of this review was to synthesize the literature on current use of tailoring in self-management interventions and patient characteristics associated with self-management capacity and success of interventions, as building blocks for tailoring. Within available trials, the degree to which interventions are explicitly tailored is marginal and often limited to content. We found that certain patient characteristics that are associated with poor self management capacity do not influence effectiveness of a given intervention (i.e., age, gender, ethnicity, disease severity, number of comorbidities) and that other characteristics (low: income, literacy, education, baseline self-management capacity) in fact are indicators of patients with a high likelihood for success. Increased scientific efforts are needed to continue unraveling success of self management interventions and to validate the modifying impact of currently known patient characteristics. PMID- 25929692 TI - Detection of the neuropathogenic variant of equine herpesvirus 1 associated with abortions in mares in Poland. AB - BACKGROUND: The incidence of reported cases of equine herpesvirus myeloencephalopathy (EHM) caused by infection with neuropathogenic strains of equine herpesvirus 1 (EHV-1) has markedly increased over the last decade in many Western countries. The purpose of this study was to estimate the prevalence of the neuropathogenic (G2254) and non-neuropathogenic (A2254) variants of EHV-1 among isolates associated with abortions in Polish stud farms. RESULTS: The results of polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) and sequencing were consistent, and showed that two out of 64 abortions (3.1%) were induced by the neuropathogenic genotype G2254. All remaining 18 EHV-1 positive abortion cases (28.1%) were caused by the non neuropathogenic genotype A2254. CONCLUSIONS: Most of the abortions in mares in Poland from 1999 to 2012 were associated with non-neuropathogenic strains of EHV 1. However, the presented data indicate that the neuropathogenic genotype of the virus is also present in Polish stud farms. Such a presence suggests that the future emergence of EHM in Poland is probable. PMID- 25929693 TI - Genital image, sexual anxiety, and erectile dysfunction among young male military personnel. AB - INTRODUCTION: More than a third of young military personnel report experiencing some level of erectile dysfunction (ED). Preoccupation with body image, particularly genitals, is a distraction that can influence sexual anxiety (SA) and sexual functioning problems (SFPs), particularly ED. AIMS: This study assessed the relationships between male genital self-image (MGSI), SA, and ED in a sample of male military personnel age 40 or younger. METHODS: Data were from a larger study on SFPs in military populations. This sample consisted of 367 male military personnel age 40 or younger. Hierarchical regression analyses and process modeling using mediation analysis were performed to examine the effects of MGSI on ED with SA as an intermediate variable. We predicted that SA would mediate the relationship between MGSI and ED. MAIN OUTCOME MEASURES: ED severity was assessed with the International Index of Erectile Function. MGSI was assessed using the MGSI Scale. SA was assessed with the SA subscale of the Sexual Needs Scale. RESULTS: As hypothesized, greater satisfaction with MGSI was predictive of significantly lower SA (F[8, 352] = 4.07, P = 0.001) and lower ED (F[8, 352] = 13.20, P = 0.001). Lower levels of SA were predictive of lower levels of ED (F[8, 354] = 21.35, P < 0.001). Additionally, results also revealed a significant indirect effect of MGSI on ED through SA (b = -0.07, standard error = 0.03, confidence interval = [-0.14,-0.02], P < 0.05), indicating mediation of MGSI on ED via SA. CONCLUSIONS: This study underscores the complex etiologic basis of SFPs, particularly ED, and highlights the importance of considering psychologic contributors to ED, such as SA and MGSI. Strategies aimed at reducing SA may be useful in improving ED in young military populations and are worth considering as complements to strategies that improve SFPs. PMID- 25929694 TI - Transcranial direct current stimulation (tDCS) for improving aphasia in patients with aphasia after stroke. AB - BACKGROUND: Stroke is one of the leading causes of disability worldwide and aphasia among survivors is common. Current speech and language therapy (SLT) strategies have only limited effectiveness in improving aphasia. A possible adjunct to SLT for improving SLT outcomes might be non-invasive brain stimulation by transcranial direct current stimulation (tDCS) to modulate cortical excitability and hence to improve aphasia. OBJECTIVES: To assess the effects of tDCS for improving aphasia in people who have had a stroke. SEARCH METHODS: We searched the Cochrane Stroke Group Trials Register (November 2014), the Cochrane Central Register of Controlled Trials (CENTRAL) (The Cochrane Library, November 2014), MEDLINE (1948 to November 2014), EMBASE (1980 to November 2014), CINAHL (1982 to November 2014), AMED (1985 to November 2014), Science Citation Index (1899 to November 2014) and seven additional databases. We also searched trials registers and reference lists, handsearched conference proceedings and contacted authors and equipment manufacturers. SELECTION CRITERIA: We included only randomised controlled trials (RCTs) and randomised controlled cross-over trials (from which we only analysed the first period as a parallel group design) comparing tDCS versus control in adults with aphasia due to stroke. DATA COLLECTION AND ANALYSIS: Two review authors independently assessed trial quality and risk of bias, and extracted data. If necessary, we contacted study authors for additional information. We collected information on dropouts and adverse events from the trials. MAIN RESULTS: We included 12 trials involving 136 participants for qualitative assessment. None of the included studies used any formal outcome measure for our primary outcome measure of functional communication - that is, measuring aphasia in a real-life communicative setting. We did a meta-analysis of six trials with 66 participants of correct picture naming as our secondary outcome measure, which demonstrated that tDCS may not enhance SLT outcomes (standardised mean difference (SMD) 0.37, 95% CI -0.18 to 0.92; P = 0.19; I2 = 0%; inverse variance method with random-effects model; with a higher SMD reflecting benefit from tDCS). We found no studies examining the effect of tDCS on cognition in stroke patients with aphasia. We did not find reported adverse events and the proportion of dropouts was comparable between groups. AUTHORS' CONCLUSIONS: Currently there is no evidence of the effectiveness of tDCS (anodal tDCS, cathodal tDCS and bihemispheric tDCS) versus control (sham tDCS) for improving functional communication, language impairment and cognition in people with aphasia after stroke. Further RCTs are needed in this area to determine the effectiveness of this intervention. Authors of future research should adhere to the CONSORT Statement. PMID- 25929695 TI - Body mass index and mortality in men with prostate cancer. AB - BACKGROUND: Body Mass index (BMI) has been shown to affect risk and mortality of several cancers. Prostate cancer and obesity are major public health concerns for middle-aged and older men. Previous studies of pre-diagnostic BMI have found an increased risk of prostate cancer mortality in obese patients. OBJECTIVE: To study the associations between BMI at time of prostate cancer diagnosis and prostate cancer specific and overall mortality. METHODS: BMI was analyzed both as a continuous variable and categorized into four groups based on the observed distribution in the cohort (BMI < 22.5, 22.5 < 25, 25 < 27.5 and >=27.5 kg/m2). The association between BMI and mortality was assessed using stratified Cox proportional hazards models and by fitting regression splines for dose response analysis in 3,161 men diagnosed with prostate cancer. After 11 years of follow up via linkage to the population-based cause of death registry, we identified 1,161 (37%) deaths off which 690 (59%) were due to prostate cancer. RESULTS: High BMI (BMI >= 27.5 kg/m2) was associated with a statistically significant increased risk of prostate cancer specific mortality (HR:1.44, 95% CI: 1.09-1.90) and overall mortality (HR:1.33, 95% CI: 1.09-1.63) compared to the reference group (BMI 22.5 < 25 kg/m2). Additionally, men with a low BMI (<22.5 kg/m2 ), had a statistically significant increased risk of prostate cancer specific mortality (HR:1.33, 95% CI: 1.02-1.74) and overall mortality (HR:1.36, 95% CI: 1.11-1.67) compared to the reference. However, this effect disappeared when men who died within the first two years of follow-up were excluded from the analyses while the increased risk of prostate cancer specific mortality and overall mortality remained statistically significant for men with a BMI >= 27.5 kg/m2 (HR:1.44, 95% CI: 1.09-1.90 and HR: 1.33, 95% CI: 1.09-1.63, respectively). CONCLUSION: This study showed that a high BMI at time of prostate cancer diagnosis was associated with increased overall mortality. PMID- 25929696 TI - Eliciting positive, negative and mixed emotional states: A film library for affective scientists. AB - We describe the creation of a film library designed for researchers interested in positive (amusing), negative (repulsive), mixed (amusing and repulsive) and neutral emotional states. Three hundred 20- to 33-second film clips videotaped by amateurs were selected from video-hosting websites and screened in laboratory studies by 75 female participants on self-reported amusement and repulsion (Experiments 1 and 2). On the basis of pre-defined cut-off values, 51 positive, 39 negative, 59 mixed and 50 neutral film clips were selected. These film clips were then presented to 411 male and female participants in a large online study to identify film clips that reliably induced the target emotions (Experiment 3). Depending on the goal of the study, researchers may choose positive, negative, mixed or neutral emotional film clips on the basis of Experiments 1 and 2 or Experiment 3 ratings. PMID- 25929697 TI - The cell-surface proteome of cultured adipose stromal cells. AB - In this technical note we describe a method to evaluate the cell surface proteome of human primary cell cultures and cell lines. The method utilizes the BD Biosciences lyoplate, a system covering 242 surface proteins, glycoproteins, and glycosphingolipids plus relevant isotype controls, automated plate-based flow cytometry, conventional file-level analysis and unsupervised K-means clustering of markers on the basis of percent of positive events and mean fluorescence intensity of positive and total clean events. As an example, we determined the cell surface proteome of cultured adipose stromal cells (ASC) derived from 5 independent clinical isolates. Between-sample agreement of very strongly expressed (n = 32) and strongly expressed (n =16) markers was excellent, constituting a reliable profile for ASC identification and determination of functional properties. Known mesenchymal markers (CD29, CD44, CD73, CD90, CD105) were among the identified strongly expressed determinants. Among other strongly expressed markers are several that are potentially immunomodulatory including three proteins that protect from complement mediated effects (CD46, CD55, and CD59), two that regulate apoptosis (CD77 and CD95) and several with ectoenzymatic (CD10, CD26, CD13, CD73, and CD143) or receptor tyrosine kinase (CD140b (PDGFR), CD340 (Her-2), EGFR) activity, suggesting mechanisms for the anti-inflammatory and tissue remodeling properties of ASC. Because variables are standardized for K means clustering, results generated using this methodology should be comparable between instrumentation platforms. It is widely generalizable to human primary explant cultures and cells lines and will prove useful to determine how cell passage, culture interventions, and gene expression and silencing affect the cell surface proteome. PMID- 25929698 TI - Association between general practice characteristics and use of out-of-hours GP cooperatives. AB - BACKGROUND: The use of out-of-hours healthcare services for non-urgent health problems is believed to be related to the organisation of daytime primary care but insight into underlying mechanisms is limited. Our objective was to examine the association between daytime general practice characteristics and the use of out-of-hours care GP cooperatives. METHODS: A cross-sectional observational study in 100 general practices in the Netherlands, connected to five GP cooperatives. In each GP cooperative, we took a purposeful sample of the 10 general practices with the highest use of out-of-hours care and the 10 practices with the lowest use. Practice and population characteristics were obtained by questionnaires, interviews, data extraction from patient registration systems and telephone accessibility measurements. To examine which aspects of practice organisation were associated with patients' use of out-of-hours care, we performed logistic regression analyses (low versus high out-of-hours care use), correcting for population characteristics. RESULTS: The mean out-of-hours care use in the high use group of general practices was 1.8 times higher than in the low use group. Day time primary care practices with more young children and foreigners in their patient populations and with a shorter distance to the GP cooperative had higher out-of-hours primary care use. In addition, longer telephone waiting times and lower personal availability for palliative patients in daily practice were associated with higher use of out-of-hours care. Moreover, out-of-hours care use was higher when practices performed more diagnostic tests and therapeutic procedures and had more assistant employment hours per 1000 patients. Several other aspects of practice management showed some non-significant trends: high utilising general practices tended to have longer waiting times for non-urgent appointments, lower availability of a telephone consulting hour, lower availability for consultations after 5 p.m., and less frequent holiday openings. CONCLUSIONS: Besides patient population characteristics, organisational characteristics of general practices are associated with lower use of out-of hours care. Improving accessibility and availability of day time primary day care might be a potential effective way to improve the efficient use of out-of-hours care services. PMID- 25929699 TI - Sex Differences in Device Therapies for Ventricular Arrhythmias or Death in the Multicenter Automatic Defibrillator Implantation Trial With Cardiac Resynchronization Therapy (MADIT-CRT) Trial. AB - INTRODUCTION: Studies suggest that women with ischemic heart disease are less likely to experience appropriate ICD therapies for ventricular arrhythmias (VT/VF). We evaluated the influence of sex on arrhythmic events or death in subjects enrolled in MADIT-CRT. METHODS AND RESULTS: Arrhythmic event rates, defined as VT/VF treated with defibrillator therapy or all-cause death, were determined among 1,790 subjects enrolled in MADIT-CRT with documented 3-year follow-up. Predictors of VT/VF/death were identified using multivariate analysis. Ninety-one (21%) women and 466 (35%) men experienced VT/VF/death over the follow up period. The overall probability of VT/VF/death was significantly lower in women versus men (HR 0.62; P < 0.001). The probability of VT/VF/death was the lowest in women with ischemic heart disease (HR 0.51; P = 0.003). In ICD subjects, the 3-year risk of VT/VF was lower in ischemic women versus men (P = 0.021), and in nonischemic women versus men (P = 0.049). The probability of VT/VF/death was significantly lower in women (HR 0.52; P = 0.007) and men (HR 0.74; P = 0.018) with LBBB who received CRT-D. Appropriate shock therapy strongly correlated with increased risk of death during postshock follow-up in women (HR 5.18; P = 0.001) and men (HR 1.63; P = 0.033); interaction P value of 0.034. CONCLUSION: In this substudy of MADIT-CRT, sex, etiology of heart disease and type of device implanted significantly influenced subsequent risk for VT/VF or death. Women with ischemic heart disease and women with LBBB who received CRT-D had the lowest incidence of VT/VF or death when compared to men. Appropriate shock therapy was a strong predictor of death, particularly in women. PMID- 25929700 TI - An online study combining the constructs from the theory of planned behaviour and protection motivation theory in predicting intention to test for chlamydia in two testing contexts. AB - Chlamydia is a common sexually transmitted infection that has potentially serious consequences unless detected and treated early. The health service in the UK offers clinic-based testing for chlamydia but uptake is low. Identifying the predictors of testing behaviours may inform interventions to increase uptake. Self-tests for chlamydia may facilitate testing and treatment in people who avoid clinic-based testing. Self-testing and being tested by a health care professional (HCP) involve two contrasting contexts that may influence testing behaviour. However, little is known about how predictors of behaviour differ as a function of context. In this study, theoretical models of behaviour were used to assess factors that may predict intention to test in two different contexts: self testing and being tested by a HCP. Individuals searching for or reading about chlamydia testing online were recruited using Google Adwords. Participants completed an online questionnaire that addressed previous testing behaviour and measured constructs of the Theory of Planned Behaviour and Protection Motivation Theory, which propose a total of eight possible predictors of intention. The questionnaire was completed by 310 participants. Sufficient data for multiple regression were provided by 102 and 118 respondents for self-testing and testing by a HCP respectively. Intention to self-test was predicted by vulnerability and self-efficacy, with a trend-level effect for response efficacy. Intention to be tested by a HCP was predicted by vulnerability, attitude and subjective norm. Thus, intentions to carry out two testing behaviours with very similar goals can have different predictors depending on test context. We conclude that interventions to increase self-testing should be based on evidence specifically related to test context. PMID- 25929701 TI - Frequency and severity of hypoglycemia in children with beta-blocker-treated long QT syndrome. AB - BACKGROUND: Hypoglycemia is a potential side effect of beta-blockers; however, no cases have been reported in children with long QT syndrome (LQTS). OBJECTIVE: The purpose of this study was to determine the frequency and severity of hypoglycemia among children with beta-blocker-treated LQTS. METHODS: A retrospective study was performed to identify children with LQTS evaluated from 2000 to 2014 who developed symptomatic hypoglycemia while being treated with a beta-blocker. RESULTS: Nine children (3%; 7 boys; average corrected QT interval 486 +/- 35 ms) developed 13 episodes (0.005 events per 100 treatment years) of beta-blocker associated hypoglycemia (mean initial glucose 21 +/- 7 mg/dL), including 3 of 157 patients with LQTS type 1 (LQT1; 1.9%) and 6 of 105 with LQTS type 2 (LQT2; 5.7%). The mean age at hypoglycemic event was 3.5 +/- 2 years (range 7 months to 9 years), involving nadolol in 6 cases (mean dose 1.4 +/- 0.2 mg/kg/d) and propranolol in 3 (mean dose 2.7+/-1 mg/kg/d). Hypoglycemic events were more frequent in patients with LQT2 than in those with LQT1 (10 vs. 3 events; P = .02). Hypoglycemia-triggered seizures were observed in 6 patients, fasting ketoacidosis in 5, and 7 patients required hospitalization (mean of 3 +/- 2 days). Decreased caloric intake before the event was identified in all patients and a concomitant viral infection in 3. CONCLUSION: This is the largest single center case series of beta-blocker-induced hypoglycemia. Clinicians should be cognizant of hypoglycemia symptoms in younger children during periods of poor appetite and during viral illness, and parents of these children should be educated about the signs and symptoms of hypoglycemia. A potential LQT2 hypoglycemia genotype-phenotype relationship warrants further investigation. PMID- 25929702 TI - Editorial: Advances in cheminformatics: drug discovery, computational toxicology and nanomaterials (part I). PMID- 25929703 TI - Positive Association Between Adipose Tissue and Bone Stiffness. AB - Obesity is often considered to have a protective effect against osteoporosis. On the other hand, several recent studies suggest that adipose tissue may have detrimental effects on bone quality. We therefore aimed to investigate the associations between body mass index (BMI), waist circumference (WC), visceral adipose tissue (VAT) or abdominal subcutaneous adipose tissue (SAT), and bone stiffness. The study involved 2685 German adults aged 20-79 years, who participated in either the second follow-up of the population-based Study of Health in Pomerania (SHIP-2) or the baseline examination of the SHIP-Trend cohort. VAT and abdominal SAT were quantified by magnetic resonance imaging. Bone stiffness was assessed by quantitative ultrasound (QUS) at the heel (Achilles InSight, GE Healthcare). The individual risk for osteoporotic fractures was determined based on the QUS-derived stiffness index and classified in low, medium, and high risk. Linear regression models, adjusted for sex, age, physical activity, smoking status, risky alcohol consumption, diabetes, and height (in models with VAT or abdominal SAT as exposure), revealed positive associations between BMI, WC, VAT or abdominal SAT, and the QUS variables broadband-ultrasound attenuation or stiffness index. Moreover, BMI was positively associated with speed of sound. Our study shows that all anthropometric measures including BMI and, WC as well as abdominal fat volume are positively associated with bone stiffness in the general population. As potential predictors of bone stiffness, VAT and abdominal SAT are not superior to easily available measures like BMI or WC. PMID- 25929704 TI - Drugs, Dialysis, Decisions, and Data: A Walk through the Minefield of Nephropharmacology. PMID- 25929705 TI - Cardiorespiratory parameters in the awake pigeon and during anaesthesia with isoflurane. AB - OBJECTIVE: To determine baseline cardiovascular and respiratory variables in the awake pigeon, and to assess those variables during anaesthesia at the individual minimal anaesthetic concentration (MAC) of isoflurane during spontaneous breathing. STUDY DESIGN: Prospective, experimental trial. ANIMALS: Seven healthy adult pigeons weighing a mean +/- standard deviation (SD) of 438 +/- 38 g. METHODS: Heart rate (HR), heart rhythm, respiratory rate (fR), end-expired carbon dioxide tension (Pe'CO2), indirect systolic arterial pressure (SAP) and cloacal temperature (T) were measured in birds in the awake state (after acclimatization to handling). Two weeks later, the pigeons were anaesthetized with isoflurane in order to determine their MAC and evaluate the same cardiovascular and respiratory variables during a further 40 minutes of isoflurane anaesthesia. RESULTS: In the awake pigeon, mean +/- SD HR, SAP, fR, Pe'CO2 and T were, respectively, 155 +/- 28 beats minute(-1), 155 +/- 21 mmHg, 34 +/- 6 breaths minute(-1), 38 +/- 8 mmHg (5.1 +/- 1.1 kPa) and 41.8 +/- 0.5 degrees C. Mean isoflurane MAC was 1.8 +/- 0.4%. During maintenance of anaesthesia at MAC, although no significant decreases between values obtained in the awake and anaesthetized states emerged in HR or respiratory rate, significant decreases in SAP and cloacal temperature and an increase in Pe'CO2 were observed. No arrhythmia was identified in awake pigeons, whereas second- and third-degree atrioventricular blocks occurred under isoflurane. CONCLUSIONS AND CLINICAL RELEVANCE: Isoflurane MAC in pigeons appeared to be higher than in other avian species. Isoflurane anaesthesia in pigeons resulted in hypercapnia, hypotension, mild hypothermia and second- and third-degree atrioventricular blocks. PMID- 25929706 TI - Taphonomy of the Tianyuandong human skeleton and faunal remains. AB - Tianyuan Cave is an Upper Palaeolithic site, 6 km from the core area of the Zhoukoudian Site Complex. Tianyuandong (or Tianyuan Cave) yielded one ancient (though not the earliest) fossil skeleton of Homo sapiens in China (42-39 ka cal BP). Together with the human skeleton, abundant animal remains were found, but no stone tools were recovered. The animal fossil remains are extremely fragmentary, in contrast to human skeletal elements that are, for the most part, complete. We undertook a taphonomic study to investigate the circumstances of preservation of the human skeleton in Tianyuan Cave, and in course of this we considered four hypotheses: funerary ritual, cannibalism, carnivore activity or natural death. Taphonomic results characterize the role of human action in the site and how these agents acted in the past. Because of disturbance of the human skeleton during its initial excavation, it is not known if it was in a grave cut or if there was any funerary ritual. No evidence was found for cannibalism or carnivore activity in relation to the human skeleton, suggesting natural death as the most reasonable possibility. PMID- 25929708 TI - Rates of caesarean vary widely across Europe. PMID- 25929707 TI - A geometric morphometric analysis of acetabular shape of the primate hip joint in relation to locomotor behaviour. AB - The description of acetabular shape variation among primates is essential for our understanding of the locomotor behaviour and ecology of both extant and fossil species. In this study, we use two-dimensional geometric morphometrics to examine variation in acetabular shape in human and non-human primates and to determine the degree to which it co-varies with locomotor behaviour, while taking both intra and inter-specific variation into account. To these ends, we examined the acetabulum of 303 left hip bones of 27 extant genera of primates (including humans) with different locomotor behaviours. After accounting for shape variation due to sex, size, and phylogeny, the results confirm that acetabular shape varies significantly across locomotor groups. The two most differentiated locomotor groups are leapers and slow-climbing quadrupeds, which exhibit a unique acetabular shape. Furthermore, the acetabulum of humans differed significantly from all other groups, while no significant differences existed between chimpanzees and gorillas. The most noticeable differences are detected in both cranial and dorsal areas and around the acetabular horns. This variation in acetabular morphology may have biomechanical implications at the level of the hip joint, potentially determining joint range motion and load distribution during locomotion. Given the increasing number of published studies on fossil pelves, our results are widely applicable to fossil analyses, with critical implications for paleoanthropological analyses about the complex locomotor behaviour of fossil specimens and their classification into locomotor groups, which may enhance our understanding of their ecological habits. PMID- 25929709 TI - Orthodontic forces add to nicotine-induced loss of periodontal bone : An in vivo and in vitro study. AB - OBJECTIVES: Nicotine is considered an etiologic factor for chronic inflammatory phenomena within the periodontal ligament that may result in loss of periodontal attachment. Considering that smokers account for 26% of adult and 12% of adolescent patients in orthodontic practice, we performed in vivo and in vitro studies as to whether orthodontic forces may add to the nicotine-induced loss of periodontal bone. METHODS: Fourteen male rats (Fischer 344 inbred) were used. Seven of these served as controls, while the other seven received daily subcutaneous injections of 1.89 mg L-nicotine per kg body weight. Both groups were exposed to orthodontic mesialization of the first two upper left molars using a NiTi closed-coil spring, the contralateral side serving as control. Periodontal bone loss was assessed by cone-beam computed tomography (CBCT). Human periodontal fibroblasts were stressed by compression (2 g/cm(2)) and/or nicotine (3/5/7.5 umol), and the expression of cyclooxygenase-2 (COX-2), prostaglandin E2 (PGE2), interleukin-6 (IL-6), osteoprotegerin (OPG), and receptor activator of nuclear factor kappaB ligand (RANKL) was determined at the transcriptional level by quantitative real-time polymerase chain reaction (qRT-PCR) and at the translational level by enzyme-linked immunosorbent assay (ELISA). In addition, differentiation of co-cultured murine RAW264.7 cells to osteoclast-like cells was quantified by tartrate-resistant acid phosphatase (TRAP) staining. RESULTS: Orthodontic force application in vivo led to a significant increase in nicotine induced periodontal bone loss, and cell compression in vitro to increased COX-2, PGE2, IL-6, and RANKL expression, reduced OPG expression, and enhanced differentiation of RAW264.7 cells to osteoclast-like cells compared to nicotine alone. CONCLUSION: Additional loss of periodontal bone must be expected during orthodontic treatment of smokers. Clinicians should inform their patients of this increased risk and refrain from performing tooth movements before cessation of smoking. PMID- 25929710 TI - Periodontal health in teenagers treated with removable aligners and fixed orthodontic appliances. AB - OBJECTIVES: The purpose of this study was to explore the microbiological and periodontal changes occurring in adolescents during 12 months of orthodontic therapy with removable aligners and with fixed appliances. MATERIAL AND METHODS: During the years 2012-2013, 50 teenagers aged 10-18 years with similar initial orthodontic conditions participated in this trial in a university clinic in northern Italy. After receiving professional oral hygiene and instructions on a standardized oral hygiene protocol, the adolescents were randomly assigned to either orthodontic treatment with traditional fixed brackets (n = 25) or to treatment with Invisalign(r) aligners (n = 25). Subgingival microbiological samples, probing depth (PD), plaque index (PI), and bleeding on probing (BOP) were obtained and documented from the mesiovestibular subgingival sulcus of the upper right first molar and left central incisor at the beginning of treatment and 3, 6, and 12 months later. Compliance with oral hygiene procedures, full mouth plaque score (FMPS), and full mouth bleeding score (FMBS) were assessed at the beginning of treatment and 12 months later. Two sample independent t-tests and the chi(2) test were used to study whether the indices of periodontal health differed in the teenagers due to the experimental conditions. RESULTS: None of the patients was positive for the periodontal anaerobes analyzed. The PI, PD, BOP, FMPS, and FMBS scores were significantly lower and compliance with oral hygiene was significantly higher in the group treated with Invisalign(r) than in the group treated with fixed brackets. CONCLUSION: Teenagers treated with removable appliances display better compliance with oral hygiene, less plaque, and fewer gingival inflammatory reactions than their peers with fixed appliances. PMID- 25929711 TI - Association between changes in soft and hard tissue after early chin cup treatment. AB - OBJECTIVE: To assess the soft tissue and to determine the potential association between changes in soft and hard tissue after early chin cup treatment in prognathic children. MATERIALS AND METHODS: A total of 42 children (21 boys, 21 girls) with skeletal Class III malocclusion due to mandibular prognathism were examined before (mean age, 8.5 +/- 0.5 years) and after (mean age, 11.4 +/- 0.6 years) chin cup treatment. Data were compared with 25 untreated matched controls (12 boys, 13 girls) with mean ages of 8.5 +/- 0.5 years at the first and 11.7 +/- 0.5 years at the second observation. Lateral cephalograms were taken before and after 36 months of treatment/observation. We evaluated the changes in hard and soft tissue and the correlations between these changes in both groups. RESULTS: The skeletal and soft-tissue facial profiles improved significantly in the treated patients, mainly due to changes in the mandible. The chin cup group revealed significant reductions in the facial-convexity angle and lower-lip inclination, leading to a remarkable improvement in the soft-tissue facial profile. We noted similar correlations between changes in the hard and soft tissue in both groups, except for a significant correlation between a pogonion retrusion and reduction in the facial-convexity angle detected only in the chin cup group. Various correlations were observed between corresponding soft and dentoalveolar changes between groups. CONCLUSION: Soft-tissue changes accompanied the underlying skeletal and dentoalveolar tissue changes after chin cup treatment. PMID- 25929712 TI - Dental compensation for skeletal Class III malocclusion by isolated extraction of mandibular teeth. Part 1: Occlusal situation 12 years after completion of active treatment. AB - OBJECTIVES: The purpose of this work was to statistically evaluate the outcomes achieved by isolated extraction of mandibular teeth (second premolars or first molars) for Class III compensation. MATERIALS AND METHODS: Part A of the study dealt with the quality of outcomes at the end of active treatment, using weighted Peer Assessment Rating (PAR) scores determined on the basis of casts for 25 (14 female and 11 male) consecutive patients aged 16 +/- 1.7 years at the time of debonding. These results were compared to the scores in a randomly selected control group of 25 (14 female and 11 male) patients who were 14.7 +/- 1.9 years old at debonding. Part B evaluated the long-term stability of the outcomes based on 12 (all of them female) patients available for examination after a mean of 11.8 years. The mean weighted PAR scores obtained in both study parts were analyzed for statistical differences using a two-tailed paired Student's t-test at a significance level of p <= 0.05. RESULTS: Mean weighted PAR scores of 4.76 +/- 3.94 and 3.92 +/- 3.44 were obtained in the Class III extraction group and the control group, respectively, at the end of active treatment. This difference was not significant (p = 0.49). Among the 12 longitudinal patients, the mean score increased from 4 +/- 3.46 at debonding to 6.25 +/- 3.67 by the end of the 11.8-year follow-up period. This difference was significant (p = 0.0008). CONCLUSION: Treatment of Class III anomalies by isolated extraction of lower premolars or molars can yield PAR scores similar to those achieved by standard therapies. These scores, while increasing significantly, remained at a clinically acceptable level over 11.8 years. Hence this treatment modality--intended for cases that border on requiring orthognathic surgery--may also be recommended from a long-term point of view. PMID- 25929713 TI - Effect of untreated and treated temporomandibular joint arthritis on mandibular volume development in growing rabbits. AB - OBJECTIVES: The goal of this work was to investigate the volume development of the mandible in growing rabbits with bilaterally induced temporomandibular joint (TMJ) arthritis that was either left untreated or treated with the tumor necrosis factor-alpha (TNF-alpha) antagonist etanercept. METHODS: A total of 18 New Zealand White rabbits aged 8 weeks were randomized to three groups of 6 animals each. Two of these groups were used as arthritis groups by sensitizing the 12 animals to ovalbumin (OA) at 10 weeks, followed by intraarticular OA injections to induce bilateral TMJ arthritis and repeating these injections every 3 weeks to maintain the inflammation. One of the two arthritis groups was treated by weekly subcutaneous etanercept injections, whereas the other group was left untreated. The remaining 6 animals served as controls. Maxillofacial CT scans were obtained at 3-week intervals (from week 10 of the rabbits' lives to the end of the experiment at 22 weeks) to volumetrically track the development of the mandibles after segmentation. RESULTS: The mandibles did not grow at a continuous rate, but the rate of development was found to decrease in all groups over the course of the study (weeks 10-22). The most extensive volume increases were noted during weeks 10-13. Severe growth deficiencies, especially of the condylar processes, were observed in the arthritis group not receiving treatment. The arthritis group treated with etanercept showed better rates of growth without, however, reaching the normal range of the control group. CONCLUSION: Antigen-induced TMJ arthritis was found to involve severe problems of growth similar to those in juvenile idiopathic arthritis. Etanercept can improve the volume development but does not reestablish an entirely normal rate of growth. PMID- 25929714 TI - Morphology of open bite. AB - OBJECTIVES: The purpose of this work was to define and illustrate the skeletal morphology of open-bite patients against the background of sagittal jaw relationships on the basis of lateral cephalograms. MATERIALS AND METHODS: Lateral cephalograms of 197 untreated adults were analyzed in dental imaging software (Onyx Ceph 3TM; Image Instruments, Chemnitz, Germany). Four groups were formed based on vertical (Index scores) and sagittal (individualized ANB values) parameters. Ninety-nine patients were defined as the control group due to their neutral sagittal and vertical relationships. The remaining patients were found by their vertical relationships to represent open-bite cases and were divided by their sagittal relationships into three study groups: neutral (Class I, n = 34), distal (Class II, n = 26), and mesial (Class III, n = 38). A geometric morphometric approach was used to analyze the x,y-coordinates of 28 skeletal landmarks on each cephalogram. Relative size was captured based on centroid size (CS). The shape-determining factors in the groups were compared by permutation testing after Procrustes transformation, and intergroup differences were visualized in the form of thin-plate splines. RESULTS: While size (CS) was significantly increased in the Class III group, the other two groups were not different from the control group. After Procrustes transformation, characteristic and invariably significant (p < 0.001) differences in shape were detected. Neutral (Class I) open bite involved compression in the mandibular ramus and the upper anterior facial third, including vertical expansion in the lower molar and anterior nasal spine areas. Mesial (Class III) open bite was associated with pronounced vertical and sagittal size reductions in the upper posterior segments and reduced lengths of the mandibular ramus. Distal (Class II) open bite involved expansion in the pterygoid area and compression in the mandibular ramus. CONCLUSION: Open bite is not a homogeneous group. Our geometric techniques of morphometric analysis revealed typical patterns, thus, confirming the differences observed by traditional morphometry. True skeletal overdevelopment appears to be present only in open-bite cases having a mesial jaw relationship. All open-bite groups have in common that the mandibular ramus is compressed, but marked differences are seen in terms of vertical development of the maxilla. This differentiated view of open-bite cases should be taken into consideration during individual etiology assessment and treatment planning. PMID- 25929715 TI - The Influence of Pre-stimulus EEG Activity on Reaction Time During a Verbal Sternberg Task is Related to Musical Expertise. AB - Previous work highlighted the possibility that musical training has an influence on cognitive functioning. The suggested reason for this influence is the strong recruitment of attention, planning, and working memory functions during playing a musical instrument. The purpose of the present work was twofold, namely to evaluate the general relationship between pre-stimulus electrophysiological activity and cognition, and more specifically the influence of musical expertise on working memory functions. With this purpose in mind, we used covariance mapping analyses to evaluate whether pre-stimulus electroencephalographic activity is predictive for reaction time during a visual working memory task (Sternberg paradigm) in musicians and non-musicians. In line with our hypothesis, we replicated previous findings pointing to a general predictive value of pre stimulus activity for working memory performance. Most importantly, we also provide first evidence for an influence of musical expertise on working memory performance that could distinctively be predicted by pre-stimulus spectral power. Our results open novel perspectives for better comprehending the vast influences of musical expertise on cognition. PMID- 25929716 TI - Elevated plasma levels of TL1A in newly diagnosed systemic lupus erythematosus patients. AB - Systemic lupus erythematosus (SLE) is an autoimmune disease. Cytokine-mediated immunity plays an important role in the pathogenesis of SLE. TNF-like ligand 1A (TL1A) belongs to the TNF superfamily of cytokines and has been found to perform significantly in autoimmune diseases, such as rheumatoid arthritis and inflammatory bowel disease. To date, no study has discussed the expression levels of TL1A in SLE. We found that plasma levels of TL1A were significantly higher in newly diagnosed SLE patients compared with controls. Correlation analysis showed that plasma levels of TL1A were positively associated with SLE disease activity index. These data indicated that TL1A may play a role in SLE and may reflect the disease activity for SLE. PMID- 25929718 TI - B-cell acquisition of antigen: Sensing the surface. AB - B-cell antigen receptor (BCR) recognition and acquisition of antigen by B cells is the essential first step in the generation of effective antibody responses. As B-cell-mediated antigen presentation is also believed to play a significant role in the activation of CD4(+) Th-cell responses, considerable effort has focused on clarifying the nature of antigen/BCR interactions. Following earlier descriptions of interactions of soluble antigens with the BCR, it is now clear that B cells also recognize, physically extract and present antigens that are tethered to, or integral components of, the surfaces or extracellular matrix of other cells. In this issue of the European Journal of Immunology, Zeng et al. [Eur. J. Immunol. 2015. 45: XXXX-XXXX] examine how the physical property or "stiffness" of the surface displaying antigens to B cells influences the B-cell response. This commentary reports that antigen tethered on "less stiff" surfaces induces increased B-cell activation and antibody responses. I then infer how "sensing the surface" by B cells may represent a new component of the immune system's ability to detect "damage," and how this understanding may influence approaches to clinical therapies where immune activity is either unwanted or desired. PMID- 25929719 TI - Factors predicting the probability of initiating sexual intercourse by context and sex. AB - Despite men initiating sex more than women there is considerable variance within the sexes. This study is the first to consider the impact of multiple predictors from the literature, and investigates how factors, such as relationship length, sociosexuality, and different aspects of self-perceived mate value among others, independently and interactively predict initiation of sexual intercourse in both short-term sexual and long-term romantic mating contexts, testing predictions from Sexual strategies theory. For long-term relationships, positive partner bond increased initiative to sexual intercourse for women. For men, self-perceived independence increased probability of taking the initiative, while relationship attachment decreased probability. For short-term relations, the desire component of the sociosexual orientation inventory increased probability of initiation for both sexes, while male initiative was increased by pleasure reasons for sex. The impact of individual predictors on initiating intercourse is influenced by being included in a multidimensional model, and relationship context affects the impact of the predictors. PMID- 25929717 TI - Auditory hedonic phenotypes in dementia: A behavioural and neuroanatomical analysis. AB - Patients with dementia may exhibit abnormally altered liking for environmental sounds and music but such altered auditory hedonic responses have not been studied systematically. Here we addressed this issue in a cohort of 73 patients representing major canonical dementia syndromes (behavioural variant frontotemporal dementia (bvFTD), semantic dementia (SD), progressive nonfluent aphasia (PNFA) amnestic Alzheimer's disease (AD)) using a semi-structured caregiver behavioural questionnaire and voxel-based morphometry (VBM) of patients' brain MR images. Behavioural responses signalling abnormal aversion to environmental sounds, aversion to music or heightened pleasure in music ('musicophilia') occurred in around half of the cohort but showed clear syndromic and genetic segregation, occurring in most patients with bvFTD but infrequently in PNFA and more commonly in association with MAPT than C9orf72 mutations. Aversion to sounds was the exclusive auditory phenotype in AD whereas more complex phenotypes including musicophilia were common in bvFTD and SD. Auditory hedonic alterations correlated with grey matter loss in a common, distributed, right-lateralised network including antero-mesial temporal lobe, insula, anterior cingulate and nucleus accumbens. Our findings suggest that abnormalities of auditory hedonic processing are a significant issue in common dementias. Sounds may constitute a novel probe of brain mechanisms for emotional salience coding that are targeted by neurodegenerative disease. PMID- 25929720 TI - Cutaneous malignant melanoma in the Swedish organ transplantation cohort: A study of clinicopathological characteristics and mortality. AB - BACKGROUND: Risk of cutaneous melanoma is increased among organ transplant recipients (OTRs) but outcome has rarely been evaluated. OBJECTIVE: We sought to assess melanoma characteristics and prognosis among OTRs versus the general population. METHODS: Using Swedish health care registers, we identified melanomas in OTRs (n = 49) and in the general population (n = 22,496), given a diagnosis between 1984 and 2008 and followed up through December 31, 2012. Tumor slides of posttransplantation melanomas were reviewed. Odds ratios for comparison of histopathological characteristics and hazard ratios of melanoma-specific death were calculated. RESULTS: Among OTRs the trunk was the most common anatomic melanoma site (50% among female vs 51% among male) and 73% (n = 36) of all melanomas were histologically associated with a melanocytic nevus, 63% (n = 31) atypical/dysplastic. Compared with population melanomas, posttransplantation melanomas were more advanced at diagnosis (Clark level III-V: odds ratio 2.2 [95% confidence interval 1.01-4.7, P = .03], clinical stages III-IV: odds ratio 4.2 [1.6-10.8, P = .003]). Risk of melanoma-specific death was increased among OTRs: adjusted hazard ratio 3.0 (1.7-5.3, P = .0002). LIMITATIONS: Only posttransplantation melanoma slides were reviewed. CONCLUSIONS: Melanomas were more advanced at diagnosis and melanoma-specific survival was poorer in OTRs than in the general population. Prophylactic excision of truncal nevi among OTRs may be advised. PMID- 25929721 TI - Coronary artery bypass grafting in young patients--insights into a distinct entity. AB - OBJECTIVES: Coronary artery bypass grafting (CABG) is the 'Gold Standard' for patients with multiple vessel coronary artery disease (CAD). Younger patients presenting with coronary artery disease requiring surgery may represent a distinct subgroup with the main goal for coronary revascularization being long term patency of the performed grafts to improve outcome. METHODS: Between January 2010 and August 2013, 126 patients below the age of 50 years underwent CABG for CAD in our hospital. We retrospectively analyzed the perioperative data and evaluated patients' outcome. RESULTS: In 25% of the patients CABG was performed as an emergency procedure for STEMI or NSTEMI within 36 hours. Another 27% of the patients were operated urgently for unstable angina or myocardial infarction within the last weeks and only 48% of the patients were purely elective cases. We performed only venous bypass grafts in 12%, total arterial revascularisation in 52% of all cases and combined venous and arterial revascularization in 43%. Six patients needed cardiac support using an extracorporeal membrane oxygenation (Mortality n = 1 out of 6) and 17 patients received an intraaortic ballon pump perioperativly. Patients received 2.8 +/- 1 bypass grafts overall. Overall in hospital mortality in this cohort was low with 1% (n = 1). CONCLUSIONS: In conclusion, the majority of the young patients below the age of 50 years present urgently for operative revascularization. Besides the potential advances regarding long term patency using total arterial revascularization, only about half of the young patients are feasible for this approach. Overall early outcome in this group is excellent with mortality below one percent. PMID- 25929722 TI - Metal-Ion Metathesis and Properties of Triarylboron-Functionalized Metal-Organic Frameworks. AB - An anionic metal-organic framework, H3[(Mn4Cl)3L8]?30H2O?2.5 DMF?5 Diox (UPC-15), was successfully prepared by the reaction of MnCl2 with tris(p-carboxylic acid)tridurylborane (H3 L) under solvothermal conditions. UPC-15 with wide-open pores (~18.8 A) is constructed by packing of octahedral and cuboctahedral cages, and exhibits high gas-sorption capabilities. Notably, UPC-15 shows selective adsorption of cationic dyes due to the anion framework. Moreover, the catalytic and magnetic properties were investigated, and UPC-15 can highly catalyze the cyanosilylation of aromatic aldehydes. UPC-15 exhibits the exchange of metal ions from Mn to Cu in a single-crystal-to-single-crystal manner to generate UPC-16, which could not be obtained by the direct solvothermal reaction of CuCl2 and H3L. UPC-16 exhibits similar properties for gas sorption, dye separation, and catalytic activity. However, the magnetic behaviors for UPC-15 and UPC-16 are distinct due to the metal-specific properties. Below 47 K, UPC-15 exhibits a ferromagnetic coupling but UPC-16 shows a dominant antiferromagnetic behavior. PMID- 25929723 TI - Discovery of serum biomarkers predicting development of a subsequent depressive episode in social anxiety disorder. AB - Although social anxiety disorder (SAD) is strongly associated with the subsequent development of a depressive disorder (major depressive disorder or dysthymia), no underlying biological risk factors are known. We aimed to identify biomarkers which predict depressive episodes in SAD patients over a 2-year follow-up period. One hundred sixty-five multiplexed immunoassay analytes were investigated in blood serum of 143 SAD patients without co-morbid depressive disorders, recruited within the Netherlands Study of Depression and Anxiety (NESDA). Predictive performance of identified biomarkers, clinical variables and self-report inventories was assessed using receiver operating characteristics curves (ROC) and represented by the area under the ROC curve (AUC). Stepwise logistic regression resulted in the selection of four serum analytes (AXL receptor tyrosine kinase, vascular cell adhesion molecule 1, vitronectin, collagen IV) and four additional variables (Inventory of Depressive Symptomatology, Beck Anxiety Inventory somatic subscale, depressive disorder lifetime diagnosis, BMI) as optimal set of patient parameters. When combined, an AUC of 0.86 was achieved for the identification of SAD individuals who later developed a depressive disorder. Throughout our analyses, biomarkers yielded superior discriminative performance compared to clinical variables and self-report inventories alone. We report the discovery of a serum marker panel with good predictive performance to identify SAD individuals prone to develop subsequent depressive episodes in a naturalistic cohort design. Furthermore, we emphasise the importance to combine biological markers, clinical variables and self-report inventories for disease course predictions in psychiatry. Following replication in independent cohorts, validated biomarkers could help to identify SAD patients at risk of developing a depressive disorder, thus facilitating early intervention. PMID- 25929724 TI - Influence of dietary supplementation with flaxseed and lactobacilli on the mucosal morphology and proliferative cell rate in the jejunal mucosa of piglets after weaning. AB - The aim of the study was to investigate the influence of flaxseed and lactobacilli supplementation to the diet of piglets during the time period between 10 days before and 21 days after weaning. The morphometry of the jejunal mucosa and proliferative ratio of both epithelial and lamina propria cells were compared with those found in a group of piglets fed with the usual diet added with sunflower oil during the same time period. The addition of flaxseed oil to the diet significantly increased the crypt depth in comparison with both groups supplemented with sunflower (P < 0.05 and 0.001 respectively) on the weaning day. Moreover, the flaxseed addition caused a significant decrease in villus height (P < 0.01) and crypt depth (P < 0.01) 21 days postweaning in comparison with the sunflower group. The proliferative ratio of the epithelial cells in the sunflower group on the weaning day was significantly higher than in both flaxseed groups (P < 0.01). Paradoxically, significantly higher proliferative activity in the mucosal connective tissue in the group with flaxseed supplementation in comparison with the sunflower group was observed on the day of weaning, as well as 3 days later (P < 0.05 both). A combination of flaxseed with lactobacilli showed significantly lower proliferative activity in the connective tissue cells from weaning up to 7 days after weaning (P < 0.05 all) in comparison with the flaxseed group. PMID- 25929725 TI - Clinical features of 32 new Japanese cases with autoimmune haemorrha-philia due to anti-factor XIII antibodies. AB - INTRODUCTION: Autoimmune haemophilia-like disease (or haemorrha-philia) due to anti-factor XIII (FXIII; F13 to avoid confusion with FVIII or FXII) antibodies (termed AH13) is a severe bleeding disorder. Although AH13 is thought to be rare, 'the number of its diagnosed patients' has recently increased in Japan. However, its prevalence remains unknown. AIM: To improve understanding of this disease, we examined and diagnosed 32 'new' Japanese patients with AH13. METHODS: The presence of antibodies against F13-A subunit and/or F13-B subunit was confirmed by using a dot blot test and enzyme-linked immunosorbent assays. RESULTS: Most of our patients had autoantibodies against the F13-A subunit (88%). A predominance of men (59%) was observed. The mean age and residual F13 activity of our AH13 cohort were 71.7 years and 10.5% of normal, respectively, and 53% of cases were idiopathic. Autoimmune disorders and malignancies were the leading underlying disease (both 16%). Intramuscular and subcutaneous bleeding were the leading symptoms (both 72%). Most of our patients were treated with F13 concentrates (72%) to arrest bleeding and with prednisolone (81%) to eradicate anti-F13 autoantibodies. Cyclophosphamide and rituximab (both 25%) were also administered. The mortality of AH13 was high (22%), and haemorrhage was the major cause of death (71%). Moreover, 13% of our AH13 patients were diagnosed after haemorrhagic death. CONCLUSION: Physicians/haematologists must raise the awareness of AH13 as a life-threatening disease. This report represents the only experience of a nationwide survey, and may contribute to a diagnosis on potentially overlooked non-Japanese AH13 patients in other countries in the world. PMID- 25929726 TI - Vitamin D attenuates pro-inflammatory TNF-alpha cytokine expression by inhibiting NF-kB/p65 signaling in hypertrophied rat hearts. AB - A growing body of evidence suggests that immune activation and inflammatory mediators may play a key role in the development and progression of left ventricle (LV) hypertrophy. The present study was designed to test the hypothesis that the cardioprotective effect of cholecalciferol (Vit-D3) is mediated via the regulation of messenger RNA (mRNA) expression of pro-inflammatory cytokines. Rats were randomly divided into four groups: control group received normal saline (0.9 % NaCl) i.p. for 14 days; Vit-D3 group received Vit-D3 at a dose of 12 MUg/kg/day by gavage for 14 days; ISO group received saline for 7 days, and at day 7, ISO (5 mg/kg/day) was injected i.p. for 7 consecutive days to induce cardiac hypertrophy; and Vit-D3 + ISO group was treated with Vit-D3 for 14 days, and at day 7, ISO was administered for 7 consecutive days. Heart/body weight ratio, troponin-T, creatine kinase-MB, and tumor necrosis factor-alpha (TNF-alpha) levels of LV tissue were estimated. Levels of mRNA expression of NF-kB (NF kB)/p65 and inhibitory kappa B (IkB)-alpha were determined by real-time PCR. Vit D3 administration before and during induction of cardiac hypertrophy significantly reduced (P < 0.001) cardiac biomarkers. The histopathological examination further confirmed these results. In addition, Vit-D3 significantly decreased (P < 0.001) NF-kB-p65 mRNA expression and increased (P < 0.01) IkB alpha mRNA expression in LV tissues compared to ISO group. Based on these findings, it was concluded that the administration of cholecalciferol markedly attenuated the development of ISO-induced cardiac hypertrophy likely through downregulation of TNF-alpha /NF-kb/p65 signaling pathways. However, it should be pointed out that other signaling pathways may contribute to the cardioprotective effect of Vit-D3 which requires further investigation. PMID- 25929727 TI - A signature of microRNA-155 in the pathogenesis of diabetic complications. AB - The current study was designed to explore the potential involvement of miR-155 in the pathogenesis of diabetes complications. Male rats were divided into control and diabetic groups (n = 6). Type 2 diabetes was induced by a single-dose injection of nicotinamide (110 mg/kg; intraperitoneal (i.p.)), 15 min before injection of streptozotocin (STZ; 50 mg/kg; i.p.) in 12-h fasted rats. Two months after induction of diabetes, the rats were sacrificed for subsequent measurements. The nuclear factor kappa B (NF-kappaB) activity was higher in diabetic peripheral blood mononuclear cells (PBMCs), aorta, heart, kidney, liver, and sciatic nerve, than the control counterparts. Also, apoptosis rate was increased in these tissues, except the aorta. NF-kappaB messenger RNA (mRNA) expression level was higher in the kidney, heart, PBMCs, and sciatic nerve of diabetic rats than their control counterparts. Except the liver, the miR-155 expression level was significantly decreased in diabetic kidney, heart, aorta, PBMCs, and sciatic nerve versus the controls. Moreover, the expression of miR-155 was negatively correlated with NF-kappaB activity and apoptosis rate. These results suggest that changes in the expression of miR-155 may participate in the pathogenesis of diabetes-related complications, but causal relationship between miR-155 dysregulation and diabetic complications is unknown. PMID- 25929728 TI - Synthesis and characterization of bismuth(III) and antimony(V) porphyrins: high antileishmanial activity against antimony-resistant parasite. AB - Two bismuth(III) porphyrins-5,10,15,20-tetrakis(phenyl)porphyrinatobismuth(III) nitrate, [Bi(III)(TPP)]NO3, and the unprecedent 5,10,15,20-tetrakis(4 carbomethoxyphenyl)porphyrinatobismuth(III) nitrate, [Bi(III)(T4CMPP)]NO3, and two unprecedented antimony(V) porphyrins dichlorido(5,10,15,20 tetrakis(phenyl)porphyrinato)antimony(V) bromide, [Sb(V)(TPP)Cl2]Br, and dibromido(5,10,15,20-tetrakis(4-carbomethoxyphenyl)porphyrinato)antimony(V) bromide, [Sb(V)(T4CMPP)Br2]Br,-were synthesized by reacting the corresponding porphyrin ligand with Bi(NO3)3.5H2O or SbCl3. All compounds were characterized by UV-vis, (1)H NMR spectroscopy, and mass spectrometry. The new compounds were also characterized by elemental analysis. Because antimony and bismuth compounds have been widely applied in medicine, the activity of these complexes was tested against Sb-sensitive and -resistant Leishmania amazonensis parasites. [Sb(V)(T4CMPP)Br2]Br was more active against the promastigote form of Sb resistant mutant strain as compared to the sensitive parental strain, with IC50 in the micromolar range. These data contrasted with those obtained using the Sb(III) drug potassium antimony tartrate, which displayed IC50 of 110 MUmol L(-1) against the Sb-sensitive parasite and was almost inactive against the Sb resistant strain. The H2T4CMPP ligand also showed antileishmanial activity against Sb-resistant and -sensitive strains, but with IC50 at least tenfold greater than that of the complex. The Sb(V)-porphyrin complex was also active against intracellular amastigotes and showed a higher selectivity index than the conventional Sb(V) drug glucantime, in both Sb-sensitive and -resistant strains. The greater antileishmanial activity of this complex could be attributed to an increased cellular uptake of Sb. Thus, [Sb(V)(T4CMPP)Br2]Br constitutes a new antileishmanial drug candidate. PMID- 25929729 TI - Plasma cell leukemia: Clinicopathologic, immunophenotypic and cytogenetic characteristics of 4 cases. AB - Plasma cell leukemia (PCL) is a rare hematologic malignancy with very poor outcome. It is defined by the presence of >2 * 10(9)/L plasma cells or >20% plasmacytosis of the differential white cell count in the peripheral blood. Primary PCL is first diagnosed in the leukemic phase, while secondary PCL corresponds to the leukemic transformation of a previously diagnosed multiple myeloma (MM). The incidence of PCL ranges between 2-4% of patients with MM and 0.9% of patients with acute leukemia. In this case series, we describe the clinicopathologic, immunophenotypic, and cytogenetic findings of four patients diagnosed with PCL within a ten-year period (2002-2012) at King Faisal Specialist Hospital and Research Centre (General Organization), Riyadh, Saudi Arabia. PMID- 25929730 TI - Detection of 14q32 rearrangements in multiple myeloma, using simultaneous FISH analysis combined with immunofluorescence. AB - BACKGROUND: 14q32 rearrangement has been identified as a recurrent hotspot of translocations in multiple myeloma (MM). The Fluorescence Immunophenotyping and Interphase Cytogenetics as a tool for the Investigation of Neoplasms (known as FICTION technique) for evaluation of chromosomal changes in MM. The aim of this work is to detect 14q32 rearrangement, using FICTION technique, on archival bone marrow (BM) slides of MM patients, and to study its prognostic value. METHOD: This study was conducted at Ain Shams University Hospital. The FICTION technique, which uses CD138 and dual color, and the break-apart 14q32 rearrangement probe, was performed on archived smears of BM slides for 50 MM patients at the time of diagnosis. RESULTS: A significantly higher percentage of cases were positive for 14q32 rearrangement by FICTION (32%) compared to fluorescence in situ hybridization (FISH) (12%) (p=0.04). Cases positive by FICTION for the rearrangement were designated as Group A, while negative cases were designated as Group B. Significantly lower Hb and CRP levels were found among Group B when compared to Group A patients (p=0.001 and 0.01, respectively). Serum albumin level and Bence Jones protein (BJP) significantly affect overall survival (OS) (p=0.01, 0.007, respectively). However, a statistically non-significant shorter mean survival time was found in positive cases through FICTION versus negative cases. CONCLUSION: FICTION technique provides a sensitive tool for establishing clonal plasma cells (PC) infiltration of BM aspirates, and is amenable for use on archived as well as fresh smears. PMID- 25929731 TI - Clinical characteristics of human immunodeficiency virus patients being referred for liver transplant evaluation: a descriptive cohort study. AB - BACKGROUND: Liver transplantation (LT) is a treatment option for select human immunodeficiency virus (HIV)-infected patients with advanced liver disease. The aim of this study was to describe LT evaluation outcomes in HIV-infected patients. METHODS: All HIV-infected patients referred for their first LT evaluation at the Mount Sinai Medical Center were included in this retrospective, descriptive cohort study. Multivariable logistic regression was used to identify factors independently associated with listing. RESULTS: Between February 2000 and April 2012, 366 patients were evaluated for LT, with 66 (18.0%) listed for LT and 300 (82.0%) not listed. Fifty-one patients (13.9%) died before completing evaluation and 85 (23.2%) were too early for listing. Reasons patients were declined for listing were psychosocial (15.8%), HIV-related (10.4%), loss to follow-up (9.6%), surgical/medical (6.0%), liver-related (4.4%), patient choice (3.4%), and financial (1.6%). Listed patients were more likely to have hepatocellular carcinoma (HCC) (43.1% vs. 17.1%; P < 0.0001) and less likely to have hepatitis B (6.2% vs. 15.7%; P = 0.04) or a psychiatric history (19.7% vs. 35.2%; P = 0.02) than those not listed. In multivariable analysis, HCC (odds ratio [OR] 5.79; 95% confidence interval [95% CI]: 2.97-11.28), model for end stage liver disease (MELD) score at referral (OR 1.06; 95% CI 1.01-1.11), and hepatitis B (OR 0.26; 95% CI 0.08-0.79) were associated with listing. CONCLUSION: MELD score and HCC were positive predictors of listing in HIV-infected patients referred for LT evaluation and, therefore, timely referrals are vital in these patients. As MELD is a predictor for death while undergoing evaluation, rapid evaluation should be performed in HIV-infected patients with a higher MELD score. PMID- 25929732 TI - Acutely Trapped Ventricle: Clinical Significance and Benefit from Surgical Decompression. AB - BACKGROUND: Focal ventricular obstruction--trapped ventricle--results in cerebrospinal fluid accumulation, mass effect and possible clinical deterioration. There are no systematic studies on the benefit of surgical decompression in adults. METHODS: We reviewed patients admitted with acutely trapped ventricle on brain imaging to assess their prognosis and the effect of surgical intervention on 30-day mortality. RESULTS: Of the 392 patients with trapped ventricle, the most common causes were brain tumor (45%), intracerebral hemorrhage (ICH) (20%), and subdural hematoma (SDH) (14%). Lateral ventricle trapping accounted for 97% of cases. Two hundred and twenty-one patients (56%) received a surgical intervention for trapped ventricle or its causes; 126 (83%) were treated with craniotomy, 26 (17%) with craniectomy, 30 (14%) with external ventricular drain (EVD) alone, 23 (10%) with ventriculoperitoneal shunt alone, and 16 (7%) with endoscopic fenestration of the septum pellucidum. Surgical intervention was associated with mortality reduction from 95% (n = 54) to 48% (n = 11) in the ICH group, from 47% (n = 27) to 12% (n = 15) in the tumor group and from 90% (n = 18) to 20% (n = 7) in the SDH group (p < 0.001 for all comparisons). Univariate logistic analysis showed that surgical intervention and tumor etiology were associated with decreased mortality while age, ICH etiology, intraventricular hemorrhage, midline shift, and anticoagulation were associated with increased mortality. On multivariate logistic regression, surgical intervention remained associated with decreased mortality (p < 0.0001; OR 0.20, 95% CI 0.09-0.42). On subgroup analysis of the ICH cohort, surgical intervention was also associated with decreased mortality (p = 0.028). CONCLUSIONS: Neurosurgical intervention for decompression in patients with trapped ventricle can have a measurable beneficial effect on early mortality. PMID- 25929733 TI - The role of complement in C3 glomerulopathy. AB - C3 glomerulopathy describes a spectrum of disorders with glomerular pathology associated with C3 cleavage product deposition and with defective complement action and regulation (Fakhouri et al., 2010; Sethi et al., 2012b). Kidney biopsies from these patients show glomerular accumulation or deposition of C3 cleavage fragments, but no or minor deposition of immunoglobulins (Appel et al., 2005; D'Agati and Bomback, 2012; Servais et al., 2007; Sethi and Fervenza, 2011). At present the current situation asks for a better definition of the underlining disease mechanisms, for precise biomarkers, and for a treatment for this disease. The complement system is a self activating and propelling enzymatic cascade type system in which inactive, soluble plasma components are activated spontaneously and lead into an amplification loop (Zipfel and Skerka, 2009). Activation of the alternative pathway is spontaneous, occurs by default, and cascade progression leads to amplification by complement activators. The system however is self controlled by multiple regulators and inhibitors, like Factor H that control cascade progression in fluid phase and on surfaces. The activated complement system generates a series of potent effector components and activation products, which damage foreign-, as well as modified self cells, recruit innate immune cells to the site of action, coordinate inflammation and the response of the adaptive immune system in form of B cells and T lymphocytes (Kohl, 2006; Medzhitov and Janeway, 2002; Ogden and Elkon, 2006; Carroll, 2004; Kemper and Atkinson, 2007; Morgan, 1999; Muller-Eberhard, 1986; Ricklin et al., 2010). Complement controls homeostasis and multiple reactions in the vertebrate organism including defense against microbial infections (Diaz-Guillen et al., 1999; Mastellos and Lambris, 2002; Nordahl et al., 2004; Ricklin et al., 2010). In consequence defective control of the spontaneous self amplifying cascade or regulation is associated with numerous human disorders (Ricklin and Lambris, 2007; Skerka and Zipfel, 2008; Zipfel et al., 2006). Understanding the exact action and regulation of this sophisticated homeotic cascade system is relevant to understand disease pathology of various complement associated human disorders. Furthermore this knowledge is relevant for a better diagnosis and appropriate therapy. At present diagnosis of C3 glomerulopathy is primarily based on the kidney biopsy, and histological, immmunohistological and electron microscopical evaluation (D'Agati and Bomback, 2012; Fakhouri et al., 2010; Medjeral-Thomas et al., 2014a,b; Sethi et al., 2012b). The challenge is to define the actual cause of the diverse glomerular changes or damages, to define how C3 deposition results in the reported glomerular changes, the location of the cell damage and the formation of deposits. PMID- 25929734 TI - A trade-off between precopulatory and postcopulatory trait investment in male cetaceans. AB - Mating with multiple partners is common across species, and understanding how individual males secure fertilization in the face of competition remains a fundamental goal of evolutionary biology. Game theory stipulates that males have a fixed budget for reproduction that can lead to a trade-off between investment in precopulatory traits such as body size, armaments, and ornaments, and postcopulatory traits such as testis size and spermatogenic efficiency. Recent theoretical and empirical studies have shown that if males can monopolize access to multiple females, they will invest disproportionately in precopulatory traits and less in postcopulatory traits. Using phylogenetically controlled comparative methods, we demonstrate that across 58 cetacean species with the most prominent sexual dimorphism in size, shape, teeth, tusks, and singing invest significantly less in relative testes mass. In support of theoretical predictions, these species tend to show evidence of male contests, suggesting there is opportunity for winners to monopolize access to multiple females. Our approach provides a robust dataset with which to make predictions about male mating strategies for the many cetacean species for which adequate behavioral observations do not exist. PMID- 25929735 TI - Powdered Activated Carbon: An Alternative Approach to Genomic DNA Purification. AB - Forensic evidence samples are routinely found as stains on various substrates, which may contain substances known to inhibit polymerase chain reaction (PCR). The goal of this study was to evaluate post-Chelex((r)) 100 purification using powdered activated carbon (PAC). Mock crime scene DNA extracts were analyzed using quantitative PCR and short tandem repeat (STR) profiling to test the DNA recovery and inhibitor removal using PAC with those of the Amicon((r)) Ultra 100K. For extracted bloodstains on soil and wood substrates, PAC and Amicon((r)) Ultra 100K generated similar DNA yield and quality. Moreover, the two methods significantly decreased the concentration of humic substances and tannins compared to nonpurified extracts (p < 0.001). In instances where extracts contained indigo dye (bloodstains on denim), Amicon((r)) Ultra 100K performed better than PAC due to improved amplifiability. Efficient adsorption of humic substances and tannins, which are common inhibitors, indicates PAC's potential application in the purification of high-template DNA extracts. PMID- 25929736 TI - Metastatic melanoma of the gallbladder: report of two cases and a review of the literature. AB - Melanoma is one of the most aggressive and highly metastatic cancers. The most common sites of distant metastases are soft tissues, lung, liver, skin and brain, whereas only few patients develop gastrointestinal metastases. Metastatic involvement of the gallbladder is rare and more often part of a widespread disease than a solitary lesion. The "gold-standard" treatment of metastatic melanoma of the gallbladder remains unclear. We report two cases of patients with past history of cutaneous melanoma who developed visceral metastases. The first patient was asymptomatic and had a widespread disease with metastatic involvement of both the spleen and the gallbladder. The second patient had an isolated metastasis of the gallbladder and complained of upper abdominal pain. The chosen treatment was open cholecystectomy (and splenectomy) in the first case and laparoscopic cholecystectomy in the second. A review of the literature is provided. PMID- 25929737 TI - MTA2 enhances colony formation and tumor growth of gastric cancer cells through IL-11. AB - BACKGROUND: We have preliminarily reported MTA2 expression in gastric cancer and its biological functions by using knockdown cell models, while the molecular mechanisms of MTA2 in regulating malignant behaviors are still unclear. METHODS: MTA2 overexpression models were established by transfection assay in gastric cancer cells BGC-823 and MKN28. Cell proliferation assay, colony formation in soft agar, wound-healing assay and transwell migration assay were performed with MTA2 overexpression and negative control (NC) cells. Subcutaneous xenografts and pulmonary metastasis models by BGC-823/MTA2 and BGC-823/NC cells were used to observe the capacity of growth and metastasis in vivo. Differential gene expression in MTA2 knockdown and overexpression cells was analyzed by microarrays. IL-11, which demonstrated as differential expression in microarray, was detected by real-time PCR, western blot, ELISA and immunohistochemistry staining. Recombinant human IL-11 (rhIL-11) was administrated in cell proliferation and colony formation as rescue assay. RESULTS: The numbers of colonies in soft agar were significantly more in BGC-823/MTA2 and MKN28/MTA2 cells, comparing with those in their NC cells. Capabilities of cell proliferation, wound-healing and cell migration were not significantly changed in MTA2 overexpression cells. The sizes of subcutaneous xenografts and pulmonary metastases of BGC-832/MTA2 cells were significantly larger than those in BGC 823/NC group. Differential expression of IL-11 was identified by genome expression microarray both in MTA2 knockdown and overexpression cells. IL-11 expression was elevated in BGC-823/MTA2 cells, whereas reduced in SGC-7901/shMTA2 cells. Administration of rhIL-11 recovered colony formation capacity of SGC 7901/shMTA2 cells. CONCLUSIONS: MTA2 overexpression enhances colony formation and tumor growth of gastric cancer cells, but not plays important role in cancer cell migration and metastasis. IL-11 is one of the downstream effectors of MTA2 in regulating gastric cancer cells growth. PMID- 25929738 TI - Concise Access to 2-Aroylbenzothiazoles by Redox Condensation Reaction between o Halonitrobenzenes, Acetophenones, and Elemental Sulfur. AB - A wide range of 2-aroylbenzothiazoles 3 including some pharmacologically relevant derivatives can be obtained in high yields by simply heating o-halonitrobenzenes 1, acetophenones 2, elemental sulfur, and N-methylmorpholine. This three component nitro methyl coupling was found to occur in an excellent atom-, step-, and redox-efficient manner in which elemental sulfur played the role of nucleophile building block and redox moderating agent to fulfill electronic requirements of the global reaction. PMID- 25929739 TI - Vildagliptin as add-on therapy to insulin improves glycemic control without increasing risk of hypoglycemia in Asian, predominantly Chinese, patients with type 2 diabetes mellitus. AB - BACKGROUND: The aim of the present study was to investigate the efficacy and safety of vildagliptin added onto insulin with or without metformin in an Asian, predominantly Chinese, population with type 2 diabetes mellitus (T2DM). METHODS: In this 24-week, multicenter, double-blind, placebo-controlled trial, patients with T2DM inadequately controlled (HbA1c 7.5%-11.0%) on stable therapy with long acting, intermediate-acting, or premixed insulin, with or without concomitant metformin, were randomized to receive vildagliptin 50 mg b.i.d. or placebo. RESULTS: Of 293 patients randomized, 146 received vildagliptin and 147 received placebo treatment. At baseline, the overall mean age of patients was 58.1 years, mean T2DM duration was 11.3 years, and mean HbA1c was 8.7%. The adjusted mean (+/ SE) change in HbA1c at Week 24 in the vildagliptin and placebo groups was -1.08 +/- 0.12% and -0.38 +/- 0.12%, respectively (between-treatment difference -0.70 +/- 0.16%; P < 0.001). The between-group difference in fasting plasma glucose was -0.43 +/- 0.38 mmol/L (P = 0.259). Significantly, more patients achieved HbA1c <7.0% with vildagliptin than with placebo (23.6% vs. 11.2%; P = 0.006). The incidence of adverse events in the vildagliptin and placebo groups was 43.8% and 46.3%, whereas that of serious adverse events was 3.4% and 6.8%, respectively. The frequency of hypoglycemia was lower in the vildagliptin than placebo group (2.7% vs. 5.4%). CONCLUSION: The addition of vildagliptin 50 mg b.i.d. significantly improved glycemic control without an increased risk of hypoglycemia in Asian, predominantly Chinese, patients with T2DM inadequately controlled on insulin, with or without metformin. PMID- 25929740 TI - Identifying the Rate-Limiting Step in Total Laparoscopic Hysterectomy in a Training Hospital. AB - STUDY OBJECTIVE: To identify the lengthiest step of total laparoscopic hysterectomy (TLH) in a teaching hospital and to determine which clinical factors affect the duration of this step. SETTING: The University of Louisville Hospital. DESIGN: Single institution retrospective case series. METHODS AND MAIN RESULTS: This is a retrospective chart and video review that included 135 benign, elective TLHs performed at The University of Louisville. TLH was divided into 5 steps: (1) insertion of laparoscopic ports and adhesiolysis to restore normal anatomy; (2) identification of the ureter and resection of adnexal structures to transection of the round ligament; (3) transection of the round ligament to transection of the uterine artery; (4) lateralization of the uterine vessel pedicle to completion of colpotomy; and (5) completion of vaginal cuff closure. The random intercept and slope model was used to identify the lengthiest step of TLH, and the backward elimination procedure was used to evaluate which clinical factors affected this step. Mean +/- SD total length of TLH was 81 +/- 30 min. The lengthiest step was colpotomy, with a mean duration of 24 +/- 13 min. Uterine weight significantly increased the length of time required for colpotomy (p = .001). The primary energy source (ultrasonic scalpel vs monopolar hook) used to perform colpotomy did not influence the length of time (p = .539 vs p = .583). Uterine weight (p < .001) and adhesiolysis (p = .003) significantly increased the total time of TLH. CONCLUSIONS: At a teaching institution where surgeries are performed by residents and fellows, colpotomy is the lengthiest step of TLH and is influenced by uterine weight. This finding may reflect the training levels of the surgeons performing these cases and the learning curve associated with a challenging surgical skill. Further research should focus on simulation models and/or tools for colpotomy that may result in greater efficiency in the operating room. PMID- 25929741 TI - Laparoscopic Radical Hysterectomy After Concomitant Chemoradiation in Locally Advanced Cervical Cancer: A Prospective Phase II Study. AB - OBJECTIVE: To assess the feasibility of laparoscopic radical surgery in patients with locally advanced cervical cancer (LACC) who receive chemoradiation therapy (CT/RT). DESIGN: Prospective phase II study (Canadian Task Force classification II-1). INTERVENTION: Patients with LACC (FIGO stage IB2-III) were evaluated for accrual at the Gynecologic Oncology Unit of Catholic University, Rome/Campobasso. Neoadjuvant CT/RT included whole-pelvic irradiation (total dose, 45.0-50.4 Gy) combined with cisplatin and 5-fluorouracil. Objective response to treatment was evaluated according to Response Evaluation Criteria in Solid Tumors criteria. Laparoscopic radical hysterectomy (RH) plus pelvic and/or aortic lymphadenectomy was attempted within 6 to 8 weeks after CT/RT. The feasibility of laparoscopic RH, as well as the rate, pattern, and severity of early and late postoperative complications, were analyzed. RESULTS: Between January 2010 and October 2013, a total of 58 patients were enrolled into the study. After CT/RT, 23 patients (39.6%) underwent type B2 RH, 31 (53.4%) underwent type C1 RH, and 4 (6.9%) underwent type C2 RH. Pelvic lymphadenectomy was performed in all cases. Laparoscopic RH was feasible in 55 of 58 cases (feasibility rate, 94.8%). No intraoperative complications were recorded. During the observation period (median, 22 months; range, 5-50 months), there were 28 complications, of which only 21.4% were grade 2 complications and 14.3% were grade 3 complications. As of January 2015, disease recurrence was documented in 4 cases (6.9%). CONCLUSION: Total laparoscopic radical surgery is feasible in patients with LACC receiving preoperative CT/RT, providing perioperative outcomes comparable to those registered in early-stage disease. PMID- 25929742 TI - The minimum alveolar concentration of sevoflurane in ring-tailed lemurs (Lemur catta) and aye-ayes (Daubentonia madagascariensis). AB - OBJECTIVE: To determine the minimum alveolar concentration (MAC) of sevoflurane for ring-tailed lemurs (Lemur catta) and aye-ayes (Daubentonia madagascariensis). STUDY DESIGN: Prospective experimental trial. ANIMALS: Six adult ring-tailed lemurs, aged 1.3-11.2 years (median age: 8.26) and weighing a mean +/- standard deviation (SD) of 2283 +/- 254 g. Five adult aye-ayes, aged 4.4-19.3 years (median age: 8.0) and weighing 2712 +/- 191 g. METHODS: Minimum alveolar concentration of sevoflurane was determined using a tail-clamp stimulus. The end tidal sevoflurane (Fe'Sevo) concentration was increased or decreased by approximately 10% after a positive or negative response to tail clamping, respectively. This procedure was repeated until a positive and negative result were seen on two consecutive trials (i.e. a negative result was achieved and a single 10% decrease in Fe'Sevo concentration resulted in a positive test). The MAC for that animal was determined to be the mean of the concentrations at the two consecutive trials. RESULTS: The mean +/- SD MAC of sevoflurane for ring tailed lemurs was 3.48 +/- 0.55% and 1.84 +/- 0.17 for aye-ayes. This represents a 47.1% higher MAC in ring-tailed lemurs compared to aye-ayes. CONCLUSIONS AND CLINICAL RELEVANCE: The sevoflurane MAC was significantly higher in ring-tailed lemurs, compared to aye-ayes. The MAC of sevoflurane in aye-ayes is consistent with reported MAC values in other species. Extrapolation of sevoflurane anesthetic dose between different species of lemurs could lead to significant errors in anesthetic dosing. PMID- 25929743 TI - Percent amino-acid identity thresholds are not necessarily conservative for predicting allergenic cross-reactivity. AB - International guidance on assessing amino-acid sequences for allergenic cross reactivity, such as that provided by Codex, relies on percent amino-acid identity across local alignments. Previous work has shown this approach to exhibit poor selectivity for true allergen cross-reactivity. Here we provide a hypothetical example illustrating that this approach is also not necessarily conservative in detecting high similarity across amino acid sequences, and thus, is not necessarily conservative in detecting potential allergenic cross reactivity among proteins. It is recommended that an established local-alignment bioinformatic tool like FASTA be used in conjunction with statistical measures of similarity to detect the risk of a protein cross-reacting with an allergen. PMID- 25929744 TI - Supremacy of modern morphometry in typing renal oncocytoma and malignant look alikes. AB - In the era of tumour type-specific therapies, the correct typing of renal tumours is of prime importance. As immunotyping and genotyping approaches are laborious and fall short of standardization, we used whole-scale computer-assisted morphometry instead. Three different types of renal tumours with different prognoses and therapies, notoriously prone to mistyping, were analysed . The sample of 335 tumours included clear cell renal cell carcinoma, chromophobe renal cell carcinoma and renal oncocytoma. The sample was analysed using H&E stains of tissue microarrrays in combination with an image-scanning software. Nuclear and cytoplasmic features were registered with the aid of computer-assisted morphometry. Features included shape, texture, colour and colour intensity for different cell compartments, e.g. nuclei and cytoplasm. The software passed several training steps for final validation. Using morphometry, we were able to classify the three renal tumour types correctly, with a 100 % specificity compared to the WHO typing. Nuclear features dominated the typing of chromophobe renal cell carcinoma, whereas cytoplasmic features were the leading classificators for renal oncocytoma. The grading of clear cell renal cell carcinoma attained a specificity of 80 %. In conclusion, modern morphometry may serve as a tool for typing renal epithelial tumours and additionally draws the attention to future nuclear research in chromophobe renal cell carcinoma. PMID- 25929746 TI - Tachycardia, Both Narrow and Broad Complex: What are the Mechanisms? How to Treat? PMID- 25929745 TI - Inhibition of hyaluronan synthesis alters sulfated glycosaminoglycans deposition during chondrogenic differentiation in ATDC5 cells. AB - In chondrogenic differentiation, expression and collaboration of specific molecules, such as aggrecan and type II collagen, in extracellular matrix (ECM) are crucial. However, few studies have clarified the roles of hyaluronan (HA) in proteoglycan aggregation during chondrogenic differentiation. We assessed the roles of HA in sulfated glycosaminoglycans deposition during chondrogenic differentiation by means of 4-methylumbelliferone (4-MU), an HA synthase inhibitor, using ATDC5 cells. ATDC5 cells were treated with 0.5 mM 4-MU for 7 or 21 days after induction of chondrogenic differentiation with insulin. Depositions of sulfated glycosaminoglycans were evaluated with Alcian blue staining. mRNA expression of ECM molecules was determined using real-time RT-PCR. The deposition of aggrecan and versican was investigated with immunohistochemical staining using specific antibodies. Effects of 4-MU on HA concentrations were analyzed by HA binding assay. 4-MU suppressed the positivity of Alcian blue staining, although this delay was reversible. Interestingly, stronger positivity of Alcian blue staining was observed at day 21 in cultures with 4-MU discontinuation than in the control. 4-MU significantly increased the mRNA expression of aggrecan, versican, and type II collagen, which was consistent with increased deposition of aggrecan and versican. The HA concentration in ECM and cell-associated region was significantly suppressed with 4-MU treatment. We conclude that the inhibition of HA synthesis slows sulfated glycosaminoglycans deposition during chondrogenic differentiation despite the increased deposition of other ECM molecules. Transient starvation of HA with 4-MU accelerates chondrogenic ECM formation, suggesting its potential to stimulate chondrogenic differentiation with adequate use. PMID- 25929747 TI - Nonlinear Effects of Noxious Thermal Stimulation and Working Memory Demands on Subjective Pain Perception. AB - OBJECTIVE: A bidirectional relationship between working memory (WM) and acute pain has long been assumed, but equivocal evidence exists regarding this relationship. This study characterized the relationship between WM and acute pain processing in healthy individuals using an adapted Sternberg WM task. DESIGN: Participants completed a Sternberg task while receiving noxious thermal stimulation. Participants received a pseudorandom presentation of four different temperatures (baseline temperatures and individually determined low-, medium-, and high-temperature stimuli) and four levels of Sternberg task difficulty (0-, 3 , 6-, and 9-letter strings). SUBJECTS: Twenty-eight healthy participants were recruited from Stanford University and the surrounding community to complete this study. RESULTS: A nonlinear interaction between intensity of thermal stimulation and difficulty of the Sternberg task was noted. Increased cognitive load from the Sternberg task resulted in increased perception of pain in low-intensity thermal stimulation but suppressed pain perception in high-intensity thermal stimulation. Thermal stimulation had no significant effect on participants' response time or accuracy on the Sternberg task regardless of intensity level. CONCLUSIONS: Pain perception appears to decrease as a function of WM load only for sufficiently noxious stimuli. However, increasing noxious stimuli did not affect cognitive performance. These complex relationships may reflect a shared cognitive space that can become "overloaded" with input of multiple stimuli of sufficient intensity. PMID- 25929748 TI - Characteristics of IL-25 and allergen-induced airway fibrosis in a murine model of asthma. AB - BACKGROUND AND OBJECTIVE: Interleukin (IL)-25 has been implicated in the pathogenesis of human asthma by inducing a Th2 cytokine response, but its possible role in the development of airway remodelling is less clear. METHODS: We developed a murine surrogate of chronic airway inflammation induced by intranasal application of IL-25 alone. Comparison was with the 'classical' surrogate of ovalbumin (OVA) intranasal instillation into previously sensitized animals. Airway fibrotic biomarkers were analysed by immunohistochemistry and enzyme linked immunosorbent assay. Additionally, proliferation assay and real-time polymerase chain reaction analysis were performed to assess IL-25's effects on primary human bronchial fibroblasts in vitro. RESULTS: In Balb/c mice, intranasal instillation of IL-25 alone induced florid airway fibrosis, including increased lay down of extracellular matrix proteins such as collagen I, III, V and fibronectin, increased numbers of fibroblasts/myofibroblasts, a profibrotic imbalance in matrix metalloproteinase/tissue inhibitor of metalloproteinase production and increased expression of profibrotic mediators including connective tissue growth factor and transforming growth factor-beta1. These changes broadly reproduced those seen with classical intranasal OVA challenge in OVA-sensitized animals. Furthermore, IL-25 induced proliferation and expression of collagen I and III and smooth muscle alpha-actin in primary human lung fibroblasts. CONCLUSIONS: We conclude that chronic exposure of the airways to IL-25 alone is sufficient to cause functionally relevant airway remodelling, with the corollary that targeting of IL-25 may attenuate bronchial remodelling and fibrosis in human asthmatics. PMID- 25929749 TI - Hydrophobic charge-induction resin with 5-aminobenzimidazol as the functional ligand: preparation, protein adsorption and immunoglobulin G purification. AB - A new hydrophobic charge-induction chromatography resin was prepared with 5 aminobenzimidazol as functional ligand and polyacrylic ester beads as matrix. Adsorption isotherms and adsorption in columns were investigated using human immunoglobulin G and bovine serum albumin as model proteins, and the influence of pH and NaCl concentration was discussed. Results showed that the ligand density was 195 MUmol/mL gel, and protein selectivity can be improved by controlling pH and salt addition. An optimized purification process (sample loading at pH 8.0 with 0.2 M NaCl and elution at pH 5.0) was performed to purify human immunoglobulin G from bovine serum albumin containing feedstock, which resulted in human immunoglobulin G purity of 99.7% and recovery of 94.6%. A similar process was applied for the purification of monoclonal antibody from cell culture supernatant, which showed antibody purity of 94.9% and recovery of 92.5%. The results indicated that the new resin developed had comparable performance as Protein A chromatography and would be suitable for antibody purification from complex feedstock. PMID- 25929750 TI - Radiation dose reduction thanks to split-bolus multi-detector computer tomography (MDCT) in children with non-thoracic neuroblastoma. PMID- 25929751 TI - Dealing with workplace violence in emergency primary health care: a focus group study. AB - BACKGROUND: Prevention and management of workplace violence among health workers has been described in different health care settings. However, little is known about which phenomena the emergency primary health care (EPC) organization should attend to in their strategies for preventing and managing it. In the current study, we therefore explored how EPC personnel have dealt with threats and violence from visitors or patients, focusing on how organizational factors affected the incidents. METHODS: A focus group study was performed with a sample of 37 nurses and physicians aged 25-69 years. Eight focus group interviews were conducted, and the participants were invited to talk about their experiences of violence in EPC. Analysis was conducted by systematic text condensation, searching for themes describing the participants' experiences. RESULTS: Four main themes emerged for anticipating or dealing with incidents of threats or violence within the system: (1) minimizing the risk of working alone, (2) being prepared, (3) resolving the mismatch between patient expectations and the service offered, and (4) supportive manager response. CONCLUSION: Our study shows a potential for development of better organizational strategies for protecting EPC personnel who are at risk from workplace violence. PMID- 25929753 TI - The preferred upconversion pathway for the red emission of lanthanide-doped upconverting nanoparticles, NaYF4:Yb(3+),Er(3.). AB - Lanthanide-doped upconverting nanoparticles (UCNPs, NaYF4:Yb(3+),Er(3+)) are well known for emitting visible photons upon absorption of two or more near-infrared (NIR) photons through energy transfer from the sensitizer (Yb(3+)) to the activator (Er(3+)). Of the visible emission bands (two green and one red band), it has been suggested that the red emission results from two competing upconversion pathways where the non-radiative relaxation occurs after the second energy transfer (pathway A, (4)I15/2 -> (4)I11/2 -> (4)F7/2 -> (2)H11/2 -> (4)S3/2 -> (4)F9/2 -> (4)I15/2) or between the first and the second energy transfer (pathway B, (4)I15/2 -> (4)I11/2 -> (4)I13/2 -> (4)F9/2 -> (4)I15/2). However, there has been no clear evidence or thorough analysis of the partitioning between the two pathways. We examined the spectra, power dependence, and time profiles of UCNP emission at either 980 nm or 488 nm excitation, to address which pathway is preferred. It turned out that the pathway B is predominant for the red emission over a wide range of excitation powers. PMID- 25929752 TI - The fish embryo toxicity test as a replacement for the larval growth and survival test: A comparison of test sensitivity and identification of alternative endpoints in zebrafish and fathead minnows. AB - The fish embryo toxicity (FET) test has been proposed as an alternative to the larval growth and survival (LGS) test. The objectives of the present study were to evaluate the sensitivity of the FET and LGS tests in fathead minnows (Pimephales promelas) and zebrafish (Danio rerio) and to determine if the inclusion of sublethal metrics as test endpoints could enhance test utility. In both species, LGS and FET tests were conducted using 2 simulated effluents. A comparison of median lethal concentrations determined via each test revealed significant differences between test types; however, it could not be determined which test was the least and/or most sensitive. At the conclusion of each test, developmental abnormalities and the expression of genes related to growth and toxicity were evaluated. Fathead minnows and zebrafish exposed to mock municipal wastewater-treatment plant effluent in a FET test experienced an increased incidence of pericardial edema and significant alterations in the expression of genes including insulin-like growth factors 1 and 2, heat shock protein 70, and cytochrome P4501A, suggesting that the inclusion of these endpoints could enhance test utility. The results not only show the utility of the fathead minnow FET test as a replacement for the LGS test but also provide evidence that inclusion of additional endpoints could improve the predictive power of the FET test. PMID- 25929754 TI - Vitamin E intake and pancreatic cancer risk: a meta-analysis of observational studies. AB - BACKGROUND: Some epidemiological studies have suggested that vitamin E intake reduces the risk of pancreatic cancer; however, this conclusion has not been supported by all the published studies. We conducted a meta-analysis to assess the relationship between vitamin E intake and the risk of pancreatic cancer by combining the results from published articles. MATERIAL/METHODS: We searched the published studies that reported the relationship between vitamin E intake and pancreatic cancer risk using the PubMed, Web of Science, and Embase databases through December 31st, 2014. Based on a fixed-effects or random-effects model, the RR and 95% CI were used to assess the combined risk. RESULTS: In total, 10 observational studies (6 case-control studies and 4 cohort studies) were included. The overall RR (95% CI) of pancreatic cancer for the highest vs. the lowest level of vitamin E intake was 0.81 (0.73, 0.89). We found little evidence of heterogeneity (I2=19.8%, P=0.255). In the subgroup analyses, we found an inverse association between vitamin E intake and pancreatic cancer risk both in the case-control and cohort studies. Additionally, this inverse association was not modified by different populations. CONCLUSIONS: In our meta-analysis, there was an inverse association between vitamin E intake and the risk of pancreatic cancer. A high level of vitamin E might be a protective factor for populations at risk for pancreatic cancer. PMID- 25929755 TI - Cucumispora ornata n. sp. (Fungi: Microsporidia) infecting invasive 'demon shrimp' (Dikerogammarus haemobaphes) in the United Kingdom. AB - Dikerogammarus haemobaphes, the 'demon shrimp', is an amphipod native to the Ponto-Caspian region. This species invaded the UK in 2012 and has become widely established. Dikerogammarus haemobaphes has the potential to introduce non-native pathogens into the UK, creating a potential threat to native fauna. This study describes a novel species of microsporidian parasite infecting 72.8% of invasive D. haemobaphes located in the River Trent, UK. The microsporidium infection was systemic throughout the host; mainly targeting the sarcolemma of muscle tissues. Electron microscopy revealed this parasite to be diplokaryotic and have 7-9 turns of the polar filament. The microsporidium is placed into the 'Cucumispora' genus based on host histopathology, fine detail parasite ultrastructure, a highly similar life-cycle and SSU rDNA sequence phylogeny. Using this data this novel microsporidian species is named Cucumispora ornata, where 'ornata' refers to the external beading present on the mature spore stage of this organism. Alongside a taxonomic discussion, the presence of a novel Cucumispora sp. in the United Kingdom is discussed and related to the potential control of invasive Dikerogammarus spp. in the UK and the health of native species which may come into contact with this parasite. PMID- 25929756 TI - Trabecular bone strength is not an independent predictive factor for dynamic hip screw migration--A prospective multicenter cohort study. AB - This study assessed whether mechanically measured trabecular bone strength is an independent predictor of dynamic hip screw (DHS) stability, i.e., DHS migration (DHSM) after the fixation of proximal femoral fractures. One-hundred and seven patients older than 50 years with proximal femoral fractures were included. During fracture fixation, a mechanical probe (DensiProbeTM Hip) was inserted at the site where the DHS tip would ultimately be positioned. Peak torque to breakaway the trabecular bone was measured. Fracture reduction, primary implant position and postoperative DHSM were assessed by radiographs taken postoperatively, at 6 and 12 weeks after surgery. Univariate regression analysis revealed no association between peak torque and DHSM (R(2) = 0.025, p = 0.135). DHSM correlated with the primary DHS position, i.e., the distance between the DHS and (i) the central femoral neck axis (CNFAD, R(2) = 0.230; p < 0.0001) and (ii) the apex of the femoral head (R(2) = 0.110; p = 0.001). DHSM did not correlate with areal BMD of the contralateral proximal femur. Multivariable regression modeling revealed the CFNAD as predictive factor for screw migration. The primary implant position measured by the CFNAD, rather than DensiProbeTM Hip measured bone strength, is an independent predictor of DHSM. PMID- 25929757 TI - Outcome of testicular sperm extraction in nonmosaic Klinefelter syndrome patients: what is the best approach? AB - Klinefelter syndrome (KS) is the most common chromosomal disorder associated with male hypogonadism and infertility. Parenthood can be achieved in men with KS by intracytoplasmic sperm injection (ICSI) using testicular spermatozoon. The aim of this study was to evaluate surgical sperm retrieval (SSR) rate in patients with KS and to investigate the approach associated with the highest SSR. This is a retrospective study where all medical records of patients with KS who underwent SSR for ICSI, in our centre in the past 14 years, were reviewed. Forty-three patients were included in this study. Twenty-three underwent conventional testicular sperm extraction (TESE), while 20 patients underwent microsurgical TESE (Micro-TESE). The SSR was significantly higher in the Micro-TESE group when compared with the TESE group (30% versus 0% respectively). In the Micro-TESE group, hormonal stimulation was given to 16 patients, while no treatment was given to four patients. SSR was only successful in hormonally treated patients (6/16). When the type of hormone stimulation was evaluated, SSR was higher in patients receiving aromatase inhibitors (27.8%). SSR in patients with KS is significantly higher when using hormonal stimulation by aromatase inhibitors followed by microsurgical testicular sperm extraction. PMID- 25929758 TI - Method of stimulus combination impacts resistance to extinction. AB - Reinforcing an alternative response in the presence of the stimuli governing a target response increases resistance to extinction of target responding, relative to training target responding on its own. Conversely, training alternative and target responses in the presence of different stimuli and combining those stimuli only decreases resistance to extinction of target responding, relative to target responding on its own. The present study assessed how different methods of combining discriminative stimuli influence resistance to extinction of responding in pigeons. As in previous studies, combining stimuli across different keys only decreased resistance to extinction of target responding relative to target responding on its own. In comparison, combining stimuli on the same key initially increased resistance to extinction of target responding, but repeated tests resulted in similar levels of responding as target responding with stimuli combined on separate keys. Moreover, greater overall reinforcement rates produced greater resistance to extinction with both methods of combining stimuli, consistent with behavioral momentum theory. These findings reveal several behavioral processes influence the outcome of combining stimuli--including perceptual processes, discriminative control by contingencies, response competition, and behavioral momentum. PMID- 25929759 TI - Comparison of PCDD/F levels and profiles in fly ash samples from multiple industrial thermal sources. AB - A comprehensive comparison of the levels and profiles of polychlorinated dibenzo p-dioxins and dibenzofurans (PCDD/F) in fly ash samples from multiple industrial sources may help to prioritize sources and to understand discrepancies in profiles. In this study, PCDD/F data from 113 fly ash samples from 14 sources reported in previous studies were summarized and compared. The highest PCDD/F levels occurred in samples from secondary copper smelting (SCu). Although PCDD/F levels from secondary zinc smelting (SZn) were slightly lower than those of SCu, the PCDD/F profiles varied widely between the two sources. For SCu, more chlorinated homologs were dominant, with highest degrees of chlorination being 6.6 for PCDF and 7.2 for PCDD. For SZn, less chlorinated homologs were dominant, with lowest degrees of chlorination being 4.4 for PCDF and 4.8 for PCDD. We speculate that copper and zinc might promote PCDD/F formation by catalyzing different pathways of thermal reactions. Diagnostic ratios of specific PCDD/F congeners for different sources were suggested to identify potential sources of PCDD/Fs in the environment. Equations describing correlations between congeners and PCDD/F toxic equivalents were established, which may be useful for rapid and inexpensive screening of the toxic levels of PCDD/Fs in fly ash samples. PMID- 25929760 TI - Pulmonary arterial hypertension in systemic lupus erythematosus may benefit by addition of immunosuppression to vasodilator therapy: an observational study. AB - OBJECTIVE: To document changes in pulmonary arterial systolic pressure (PASP) in patients with SLE who have received CYC for any indication. METHODS: Twenty-four patients with SLE pulmonary arterial hypertension (PAH) with a PASP of >30 mmHg by transthoracic echocardiography received i.v. CYC (n = 24) or steroids (n = 24) with or without vasodilators (n = 20). Baseline clinical characteristics and PASP were evaluated before and after therapy at 6 months. Responders were defined as those who had a decrease in PASP of >15 mmHg from baseline along with improvement in their New York Heart Association functional class. RESULTS: There were 11 responders (45.83%), with a decrease in mean PASP from 59.33 mmHg at baseline to 43.29 mmHg at the end of 6 months (P < 0.0001). The decrease in mean PASP from 39.75 mmHg at baseline to 34.4 mmHg at the end of 6 months was significant in four patients who received immunosuppression alone (P = 0.04). There was no difference in baseline PASP and disease activity between responders and non responders. Two deaths were noted. CONCLUSION: Immunosuppression and vasodilators produced significant improvement in SLE PAH over 6 months. PMID- 25929761 TI - Fabrication of Highly Ordered and Well-Aligned PbTiO3/TiN Core-Shell Nanotube Arrays. AB - Highly ordered and well-aligned PbTiO3/TiN core-shell nanotubes are fabricated via an anodic aluminum oxide templating route followed by TiN and TiO2 atomic layer deposition deposition and a subsequent PbO vapor reaction. PbTiO3/TiN nanotubes keep their original shape after the vapor phase reaction, and they display well-defined piezoresponse hysteresis curves with remnant piezoresponse of 38 pm V(-1) . PMID- 25929763 TI - Retraction Note to: Suppression of the xCT-CD44v antiporter system sensitizes triple-negative breast cancer cells to doxorubicin. Breast Cancer Res Treat (2014) 147:203-10. PMID- 25929762 TI - Tuberculosis Treatment Completion Rates in Southern New Mexico Colonias. AB - TB medication completion treatment rates for active TB patients living in impoverished US-Mexico border communities called colonias in southern New Mexico counties are unknown. It might be suspected that residents of colonias have lower completion rates than those living in incorporated and medically more accessible areas. A retrospective record review of closed TB case records from 1993 to 2010 of southern New Mexico border counties, was conducted using a modified version of the New Mexico Department of Health Tuberculosis Targeted Health Assessment/History form (Appendix 1). Study findings reveal that despite their unincorporated status, poorer living conditions and questionable legal status, colonia TB patients had a higher medication completion rate than their non colonia counterparts. A robust New Mexico TB treatment program contributed to high completion rates with death being the number-one reason for treatment non completion in both colonia and non-colonias. PMID- 25929764 TI - Incidental radiation to uninvolved internal mammary lymph nodes in breast cancer. AB - Routine treatment of clinically uninvolved internal mammary nodes in breast cancer patients requiring post-mastectomy radiation therapy is controversial. The purpose of this study was to measure the incidental radiation dose to the internal mammary lymph nodes not included in the planning target volume (PTV) in women with breast cancer receiving post-mastectomy radiation therapy. This retrospective protocol utilized CT-based 3D conformal treatment plans. Fifty consecutive patients were included in the analysis: 25 left breast and 25 right breast patients. 3D conformal treatment plans chest wall tangent fields and matched supraclavicular were used. All plans were prescribed to a total dose of 50 Gy in 25 fractions to the chest wall and 46 Gy in 23 fractions to the supraclavicular field. The internal mammary node chain was intentionally not included in the target volume. For purposes of this study, internal mammary vessels were contoured following the Radiation Therapy Oncologist Group atlas with a 7-mm PTV expansion, utilizing original CT simulation images. The internal mammary nodes were contoured in between the first 3 and first 5 intercostal spaces for comparison. Percent volume of internal mammary node PTV receiving 95 % of the prescribed dose (47.5 Gy) with 7-mm expansion and first 5 intercostal spaces for all patients was 25.2 % (range 0.04-97.6 %, standard deviation (SD) 23.5). The mean internal mammary node dose for all patients was 24.98 Gy (range 3.54-55.93 Gy, SD 16). Results of this study suggest the incidental dose to the internal mammary nodes does not achieve clinically significant therapeutic levels in post-mastectomy breast cancer patients treated with standard 3D conformal radiation therapy chest wall irradiation. If risk factors for microscopic involvement are present, internal mammary nodes must be specifically included in target volumes in order to be adequately treated. PMID- 25929765 TI - Incidental primary breast cancer detected on PET-CT. AB - The purpose of this study is to determine the incidence of primary breast cancer (PBC) detected on (18) F-fluorodeoxyglucose (FDG) positron emission tomography (PET)-computed tomography (CT) in patients with a known diagnosis of non-mammary malignancies. A database search was performed to identify patients with non mammary malignancies who had undergone staging with FDG PET-CT at a single institution between September 2005 and September 2011 and with the word "breast" reported in the PET-CT dictation. Additional breast imaging studies, clinical data, and the final histopathology of the breast lesions were correlated with the PET-CT images. Of 1951 patients who underwent PET/CT, 440 incidental breast lesions were identified in 438 patients. Of these 440 lesions, 195 (45 %) were benign, 160 (37 %) malignant, and 85 (19 %) missing data. A total of 25 PBCs were diagnosed; with a median size of 1.8 cm (range 0.8-10.7 cm); and a median SUVmax of 4.4 (range 1.7-17.6). There were 19 invasive ductal cancers, 1 invasive lobular cancer, 2 papillary cancers, 1 tubular cancer, 1 sarcomatoid cancer, and 1 ductal carcinoma in situ. Eight patients had regional nodal disease. Mammography revealed the PBC in 19 of 23 tumors (83 %), sonography in 22 of 23 (96 %). Six percent (25 of 440) of incidental breast lesions identified on FDG PET-CT represent PBCs; more than half were at an early stage and potentially curable. PMID- 25929766 TI - Recent trends in National Institutes of Health funding for surgery: 2003 to 2013. AB - BACKGROUND: The purpose of this study is to compare the compositions of federally funded surgical research between 2003 and 2013, and to assess differences in funding trends between surgery and other medical specialties. DATA SOURCES: The National Institutes of Health (NIH) Research Portfolio Online Reporting Tool database was queried for grants within core surgical disciplines during 2003 and 2013. Funding was categorized by award type, methodology, and discipline. Application success rates for surgery and 5 nonsurgical departments were trended over time. CONCLUSIONS: Inflation-adjusted NIH funding for surgical research decreased 19% from $270 M in 2003 to $219 M in 2013, with a shift from R-awards to U-awards. Proportional funding to outcomes research almost tripled, while translational research diminished. Nonsurgical departments have increased NIH application volume over the last 10 years; however, surgery's application volume has been stagnant. To preserve surgery's role in innovative research, new efforts are needed to incentivize an increase in application volume. PMID- 25929767 TI - The FDA-approved drug irbesartan inhibits HBV-infection in HepG2 cells stably expressing sodium taurocholate co-transporting polypeptide. AB - BACKGROUND: Little is known about the early steps of the HBV life cycle due to the lack of susceptible cells permissive for viral infection. Hence, viral entry has not been exploited for antiviral targets, but the recent seminal discovery of sodium taurocholate co-transporting polypeptide (NTCP) as the cellular receptor for HBV entry opened up many avenues of investigation, making HBV entry amenable to therapeutic intervention. METHODS: In order to exploit HBV entry, we established a HepG2-NTCP cell line that supports HBV infection. Over 70% of cells were infected at a dose of 10(4) genome equivalents (GEq) per cell. Several FDA approved drugs with NTCP-inhibiting activity were tested for their ability to inhibit HBV infection of the cell line. RESULTS: Consistent with their NTCP inhibitory activities, our results showed that several of them inhibit HBV infection. In particular, irbesartan, a drug used for the treatment of hypertension, inhibits HBV infection at the 50% effective concentration value of 35 MUM. CONCLUSIONS: The observation that the pharmacological inhibitors of the NTCP transporter could block HBV entry suggests that NTCP represents an attractive molecular target for therapeutic intervention in HBV infection. PMID- 25929769 TI - Minimal Residual Disease Monitoring in Adult ALL to Determine Therapy. AB - Almost 90 % of children and 50 % of adults with acute lymphoblastic leukemia (ALL) are cured by modern treatment regimens, with significant variations due to several disease- and host-related characteristics. The attainment of an early remission and the avoidance of relapse and treatment-related mortality are the fundamental therapeutic steps. In remission patients, the assessment of the disease response to early intensive therapy through the detection and monitoring of minimal residual disease (MRD) can accurately refine the individual prognosis and is increasingly used to support a risk-oriented treatment strategy. In this way, only the patients with an unfavorable MRD response are preferably selected for allogeneic stem cell transplantation, irrespective of their clinical risk class. This choice spares transplant-related toxicities to MRD responsive cases. Further advancement is expected by integrating the MRD analysis with improved pediatric-type regimens and novel targeting agents for ALL subsets at higher risk of relapse. PMID- 25929770 TI - Current Practice in the Management of Slipped Capital Femoral Epiphysis. AB - BACKGROUND: The most widely used treatment for slipped capital femoral epiphysis (SCFE) is in situ fixation. In an attempt to reduce the chances of impingement, osteoarthritis, and osteonecrosis, surgeons have started adopting newer surgical techniques. The purpose of this study was to determine the current pattern of treating SCFE. METHODS: A questionnaire was sent electronically to all of the members of the Pediatric Orthopaedic Society of North America. The data were analyzed dividing surgeons into academic versus private practice, years of practice, and number of SCFEs treated per year. RESULTS: Of 990 members, 277 (28%) responded to the survey.Type of practice (academic, n=181 vs. private, n=51): For unstable severe SCFE, surgeons in academic practice use the surgical hip dislocation (SHD) approach significantly more frequently (35.7% vs. 14.9%; P=0.02). A radiolucent table is used significantly more frequently in academic practice for both stable (50.6% vs. 29.8%; P=0.01) and unstable (39.6% vs. 15.2%; P=0.002) SCFE. Fully threaded cannulated screws (44.4% vs. 27.1%; P=0.03), open capsular decompression (63.9% vs. 32.4%; P=0.001), contralateral pinning (79% vs. 58.7%; P=0.005), and postoperative magnetic resonance imaging (MRI) (15.5% vs. 3.9%; P=0.03) are significantly more frequent in academic practice.Years of practice (<=15 y, n=124 vs. >15 y, n=140): For severe stable SCFE, surgeons practicing for <=15 years do acute osteotomies significantly less frequently (1.8% vs. 9%; P=0.004) and perform SHD significantly more frequently (20.2% vs. 8.2%; P=0.004). For unstable moderate SCFE, SHD is utilized significantly more frequently by surgeons <=15 years in practice (29.8% vs. 16.5%; P=0.04). Bilateral frog-leg lateral views (86.4% vs. 73.7%; P=0.04), preoperative MRI (36.1% vs. 20.6%; P=0.006), open capsular decompression (69.3% vs. 51.7%; P=0.01) are significantly more frequent among surgeons <=15 years in practice.Number of SCFE treated per year (<10, n=129 vs. >=10, n=136): For unstable severe SCFE, surgeons treating >=10/y perform SHD significantly more frequently (38.6% vs. 26.1%; P=0.02) and do in situ fixation with manual reduction significantly less frequently (11.8% vs. 21.8%; P=0.02). Radiolucent table (54.3% vs. 38%; P=0.01), 7.5 mm screw versus 6.5 mm (62% vs. 45.4%; P=0.01), contralateral pinning (78.9% vs. 67.8%; P=0.04), postoperative MRI (17.6% vs. 9.3%; P=0.04), and postoperative computed tomography (14.7% vs. 7%; 0.04) are significantly more frequent among surgeons doing >=10/y. Elective implant removal is more common among surgeons treating <10/y (16.2% vs. 6.9%; P=0.02). CONCLUSIONS: Treatment of SCFE varies significantly depending on the surgeon's type of practice, years in practice, and numbers treated per year. Surgeons in academic practice, surgeons with <=15 years in practice, and surgeons treating greater number of SCFEs are more likely to use SHD to acutely reduce the slip. PMID- 25929768 TI - Management of advanced-phase chronic myeloid leukemia. AB - The management of chronic myeloid leukemia (CML) in accelerated or blast phase (advanced phase) remains a significant challenge despite the introduction of very effective tyrosine kinase inhibitors (TKIs). The biology of advanced-phase CML is complex and engages several pathways that are not optimally targeted by TKIs. Allogeneic stem cell transplantation remains the only potentially curative therapy, but the effectiveness of this conventional approach is limited. New strategies are required to improve the outlook for these patients. PMID- 25929772 TI - In Reply: Percutaneous Screw Fixation promotes Healing of Lateral Condyle Non union in Children. PMID- 25929771 TI - Correction of Brachymetatarsia and Medial Angulation of the Great Toe of Apert Foot By Distraction Osteogenesis: A Review of 7 Years of Experience. AB - BACKGROUND: Apert foot anomalies may cause severe problems such as pain and development of callus formation related to weight redistribution, problems with footwear, and gait disturbances that may limit their daily activities. The main purpose of this study was to review our experience with distraction osteogenesis for the correction of brachymetatarsia and the great toe angulation of the patients with Apert syndrome. METHODS: This study retrospectively reviewed 7 patients (14 extremities) followed up for Apert syndrome who underwent distraction for the correction of bilateral congenital brachymetatarsia and angulation of the great toe between 2004 and 2008. Correction of the metatarsal inclination angle, the medial angulation of the great toe, the percentage of lengthening, and lengthening rates of distracted bones were evaluated. RESULTS: Patients ranged in age from 4 to 8 years at the distraction operation, with a mean age of 5.4+/-1.3 years, and the average length of follow-up was 86.6+/-21.0 months. The length of the first metatarsal bone increased significantly from the average length of 32.6+/-5.7 mm to an average of 46.7+/-6.5 mm (P<0.001). The mean lengthening rate and lengthening percentages of distracted bones were 0.4%+/ 0.1%/month and 30.2%+/-6.4%/month, respectively. Preoperative and postoperative metatarsal inclination angles were at a mean of 43.8+/-5.12 and 32.6+/-3.8, respectively, and the correction of metatarsal inclination was considered as statistically significant (P<0.001). The mean angulation of the great toe reduced significantly from 49.8+/-11.76 to 13.2+/-8.5 degrees after distraction (P<0.001). Minor complications such as pin loosening, pin-tract infection, and early union that required reoperation were observed in 5 extremities (35.7%). CONCLUSIONS: Anatomic features of Apert foot may lead to complaints that may limit patients' daily activities and require as much attention as associated hand and craniofacial anomalies. Distraction appears to be an effective and safe approach for the simultaneous correction of the shortness of the first ray and medial angulation of the great toe. LEVEL OF EVIDENCE: Level IV. PMID- 25929773 TI - Incomplete Follow-up After Growth Modulation Surgery: Incidence and Associated Complications. AB - BACKGROUND: Extraperiosteal tension plates have become the predominant method for angular deformity correction in skeletally immature patients, with some surgeons using them in very young children with the intent of removing the implants once the correction is complete. The purpose of this study is to determine the incidence of incomplete follow-up and to assess the outcomes of children who were lost to follow-up with retained implants. METHODS: A quality initiative survey was performed at 2 institutions on children treated with extraperiosteal tension plates around the knee because of sentinel events that occurred at each institution. Compliance with follow-up was noted, and children with open perigenicular physes on latest radiograph with retained implants were identified with attempts to reestablish care. Subsequent review of those children was performed, including clinical results, radiographic results, and the need for second deformity surgery. RESULTS: A total of 200 children treated with tension plates were identified (116 at institution #1, 84 at institution #2). The most common indication for surgery was genu valgum (54%), and the mean age at initial surgery was 11.7 years (range, 3.1 to 16.8 y). A high rate of retained implants with incomplete follow-up was identified at both institutions, where a total of 23 patients (12%) were lost with implants still in place. Only 7 of 23 patients returned for evaluation: 3 reached skeletal maturity with no complications, but 4 overcorrected creating the opposite angular deformity. Two of those children required osteotomies to remedy their overcorrection. Two additional patients were reachable, but failed to return for follow-up and the remaining patients were unreachable. CONCLUSIONS: The incidence of incomplete follow-up was significant at both institutions (12% combined incidence). Of those who were found for follow up, nearly one third required a surgery beyond simple implant removal. Incomplete follow-up among this cohort was identified as a significant quality of care issue, and an EMR system has been established to actively follow children receiving growth modulation surgery. LEVEL OF EVIDENCE: Level IV. PMID- 25929774 TI - Traumatic, Posterior Pediatric Hip Dislocations With Associated Posterior Labrum Osteochondral Avulsion: Recognizing the Acetabular "Fleck" Sign. AB - BACKGROUND: Traumatic dislocation of the hip is uncommon in the pediatric population. Concentric reduction is usually achieved by closed means. Open reduction may be needed if there is femoral head fracture, incarcerated fragment, or incomplete reduction due to soft tissue entrapment. We present a series of 10 patients who sustained a posterior hip dislocation or subluxation with associated osteochondral avulsion of the posterior labrum. During surgery they were noted to have a labral injury pattern not previously recognized. Such treatment was dictated by postreduction advanced imaging, which revealed a consistent acetabular "fleck" sign indicative of this labral injury, which has not been previously described in literature. METHODS: We performed a retrospective case review of patients with traumatic posterior hip dislocation/subluxation, treated operatively for a suspected associated labral tear and fractures. RESULTS: Ten patients (2 girls and 8 boys) were identified. Average age was 12.7 years. Eight patients had postreduction computed tomography scans, which revealed a posterior acetabular wall "fleck" sign, suggestive of osteochondral injury. The small bony fragment was consistently displaced at least 2 to 3 mm in all patients with majority of the posterior wall remaining intact. Closed reduction was felt to be congruent in 7 of the 10 patients. All patients were treated operatively for exploration and stabilization of the suspected posterior labrum pathology and associated injuries using a surgical hip dislocation. A consistent pattern of labral pathology was seen in all patients, with disruption of the posterior labrum from the superior 12 o'clock attachment to detachment at the inferior 6 o'clock location. Reattachment of the osteochondral labral avulsion was performed with suture anchors along the posterior rim, and the associated femoral head fractures were also addressed with internal fixation. Two patients had inadequate follow-up and were excluded, the average follow-up for the remaining 8 patients was 9.8 months (range, 6 to 26 mo). There were no findings of avascular necrosis in any of the 8 patients. CONCLUSIONS: Posterior hip dislocation in children may produce an acetabular "fleck" sign on advanced imaging, which in a stable, concentrically reduced hip has been treated without surgery in the past. Acetabular fleck sign may represent a near-complete avulsion of the posterior labrum as seen in our series. We recommend a high suspicion for this type of labral pathology and surgical repair when acetabular "fleck" sign is identified with hip subluxation or dislocation. Traumatic, posterior hip dislocations in young patients may be associated with significant labral pathology. Acetabular "fleck" sign on advanced imaging may predict such pathology. LEVEL OF EVIDENCE: IV, retrospective study. PMID- 25929775 TI - The Effect of Body Mass Index on Postoperative Morbidity After Orthopaedic Surgery in Children With Cerebral Palsy. AB - BACKGROUND: Although a plethora of literature exists on the impact of body mass index (BMI) in orthopaedic surgery, few have examined its implications in the pediatric cerebral palsy (CP) population. The aim of this study is to evaluate the effect of BMI class on 30-day complications after orthopaedic surgery on children with CP. METHODS: A retrospective analysis of the American College of Surgeons National Surgical Quality Improvement Program (NSQIP) Pediatric participant use files from 2012 to 2013 was conducted. Patients with a diagnosis of CP undergoing any orthopaedic procedure were included and subclassified according to BMI classes: underweight, normal weight, overweight, and obese. Multivariate logistic regressions were performed to evaluate the independent effect of BMI class on total, surgical site, and medical complications as well as unplanned reoperations. RESULTS: A total of 1746 patients were included in our study. These included 345 (19.8%) underweight, 952 (54.5%) normal weight, 209 (12.8%) overweight, and 240 (13.7%) obese children and adolescents. In hip and lower extremity osteotomies, underweight class was an independent risk factor for total complications (P=0.037) and medical complications (P=0.031). Similarly, underweight class was a risk factor for total complications (P=0.022) and medical complications (P=0.019) in spine procedures. Weight class was not independently associated with complications in tendon procedures. Overweight and obesity classes were not associated with any independent increased risk for complications. CONCLUSIONS: With respect to the pediatric CP population, underweight status was deemed an independent predictor of increased complications in osteotomies and spine surgery with no independent increased risk in the overweight or obese cohorts. This information can greatly aid providers with risk stratification, preoperative counseling, and postoperative monitoring as it relates to orthopaedic surgery. LEVEL OF EVIDENCE: Level III-Prognostic. PMID- 25929776 TI - Correction of Cubitus Varus After Pediatric Supracondylar Elbow Fracture: Alternative Method Using the Taylor Spatial Frame. AB - BACKGROUND: Cubitus varus is a well-reported complication of supracondylar fracture of the humerus potentially resulting in cosmetic problems, impaired function, and malpractice claims. Traditional methods of correcting malunited distal humeral fractures involve complex osteotomies that have a high complication rate, require a large exposure, and challenging fixation. We present a technique of gradual correction using a percutaneous transverse osteotomy and 3 dimensional correction with a Taylor Spatial Frame. METHODS: This was a retrospective, IRB-approved study of 12 patients between 2006 and 2010, with cubitus varus after a malunited pediatric supracondylar fracture. The average age at initial injury was 5+8 years. The average age of the patients at surgery was 8+8 years. We measured technical (radiographic parameters and complications), functional (clinical carrying angle, range of motion, QuickDash), and satisfaction domain (questionnaire) outcomes at a minimum follow-up of 6 months. RESULTS: The osteotomy healed in all patients by 10 weeks after the index surgery. The mean external fixator time was 10 weeks. The average preoperative and postoperative humeroulnar angles for the affected elbow were 23 degrees varus and 5.8 degrees valgus, respectively. This was statistically significant (P<0.001). The mean preoperative and postoperative carrying angles were 22 degrees of varus and 5.8 degrees of valgus. This was statistically significant (P<0.001). The results of the QuickDash assessment showed that patients were doing very well with regard to the use of their upper extremity. The mean symptom/disability score was 0.80. No major complications or neurovascular complications were encountered. Overall satisfaction with the procedure was high. CONCLUSIONS: The Taylor Spatial Frame as used in this case series provides the experienced surgeon another safe, accurate, and reliable method to correct cubitus varus after pediatric supracondylar fracture. We used in 7 of our 12 cases, a previously unreported pattern of distal humeral pin fixation that allows for a very distal metaphyseal osteotomy, close to the deformity apex. This is a biplanar delta configuration that straddles the olecranon fossa and is appropriate for both children and adults. LEVEL OF EVIDENCE: Level IV. PMID- 25929777 TI - The Use of C-reactive Protein as a Guide for Transitioning to Oral Antibiotics in Pediatric Osteoarticular Infections. AB - BACKGROUND: In the treatment of pediatric osteoarticular infections, early transition to oral antibiotics is desirable to shorten hospital stays and complications of prolonged intravenous therapy. C-reactive protein (CRP) is an acute phase reactant with a short half-life and is utilized at our institution to monitor progress and determine the transition to oral antibiotics. We hypothesized that patients can be safely transitioned from parenteral antibiotics to oral antibiotics when patients improve clinically and CRP halves over a period of 4 days. MATERIALS AND METHODS: A retrospective review was conducted of all pediatric patients between the ages of 1 month and 18 years admitted and treated for acute bacterial osteomyelitis and/or septic arthritis at the authors' institution. We recorded all relevant data, inpatient progress, and outpatient follow-up. RESULTS: Thirty-seven patients fulfilled the selection criteria and were reviewed for this study. Patients were an average of 8.37+/-4.91 years old. Surgery was performed in 33 patients (89.2%). The average duration of intravenous antibiotics was 11.00+/-5.61 days and the average duration of oral antibiotics was 28.76+/-8.69 days, with an average total duration of antibiotics of 39.16+/ 9.08 days. The average peak CRP was 156.91+/-97.81 mg/L and the average CRP at discharge was 24.94+/-22.36 mg/L. Thirty-four patients (91.89%) experienced a 50% decline in CRP over 4 days. Of these patients, only 1 (2.94%) went on develop complications in the follow-up period. The average hospitalization period was 11.50+/-6.55 days. The average duration of follow-up was 7.83+/-6.56 months. CONCLUSIONS: We found that the combination of clinical improvement and a specific reduction of 50% in CRP levels over 4 days, or 5 CRP half lives, could be used to determine when to transition children with osteoarticular infections from parenteral to oral therapy. Complicated outcomes were associated with negative cultures, longer hospitalizations, and persistently elevated CRP levels. PMID- 25929778 TI - Variation in 60-day Readmission for Surgical-site Infections (SSIs) and Reoperation Following Spinal Fusion Operations for Neuromuscular Scoliosis. AB - BACKGROUND: Readmission for surgical-site infection (SSIs) following spinal fusion for NMS impacts costs, patient risk, and family burden; however, it may be preventable. The purpose of this study was to examine variation in hospital performance based on risk-standardized 60-day readmission rates for SSI and reoperation across 39 US Children's Hospitals. METHODS: Retrospective cohort study using the Pediatric Health Information Systems (PHIS) database involving children aged 10 to 18 years with ICD9 codes indicating spinal fusion, scoliosis, and neuromuscular disease discharged from 39 US children's hospitals between January 1, 2007 and September 1, 2012. Readmissions within 60 days for SSI were identified based on the presence of ICD9 codes for (1) infectious complication of device or procedure, or (2) sepsis or specific bacterial infection with an accompanying reoperation. Logistic regression models accounting for patient-level risk factors for SSI were used to estimate expected (patient-level risk across all hospitals) and predicted (weighted average of hospital-specific and all hospital estimates) outcomes. Relative performance was determined using the hospital-specific predicted versus expected (pe) ratios. RESULTS: Average volume across hospitals ranged from 2 to 23 fusions/quarter and was not associated with readmissions. Of the 7560 children in the cohort, 534 (7%) were readmitted for reoperation and 451 (6%) were readmitted for SSI within 60 days of discharge. Reoperations were associated with an SSI in 70% of cases. Across hospitals, SSI and reoperation rates ranged from 1% to 11% and 1% to 12%, respectively. After adjusting for age, sex, insurance, presence of a gastric tube, ventriculoperitoneal shunt, tracheostomy, prior admissions, number of chronic conditions, procedure type (anterior/posterior), and level (>9 or <9 vertebrae), pe ratios indicating hospital performance varied by 2-fold for each outcome. CONCLUSIONS: After standardizing outcomes using patient-level factors and relative case mix, several hospitals in this cohort were more successful at preventing readmissions for SSIs and reoperations. Closer examination of the organization and implementation of strategies for SSI prevention at high performing centers may offer valuable clues for improving care at lower performing institutions. LEVEL OF EVIDENCE: Level III. PMID- 25929779 TI - Socioeconomic Factors Are Associated With Trends in Treatment of Pediatric Femoral Shaft Fractures, and Subsequent Implant Removal in New York State. AB - BACKGROUND: Disparities exist in access to outpatient pediatric orthopaedic care. The purpose of this study was to assess whether disparities also exist in elective pediatric orthopaedic surgical procedures such as implant removal, and to determine which demographic and socioeconomic factors may be associated with differences in treatment. METHODS: Children aged 7 to 18 inclusive who sustained femoral shaft fractures between the years 1997 and 2010 were identified in the New York State SPARCS database. Patient age, sex, race/ethnicity, insurance status, education, and poverty were identified. Factors associated with the method of fracture treatment were assessed through multivariate regression analysis. The subset of patients that received internal fixation were followed up until 2011 inclusive for implant removal. Factors associated with implant removal were assessed using a Cox proportional hazards survival analysis (time to implant removal). RESULTS: Of the 3220 closed femoral shaft fractures identified, 2609 (81%) were treated with internal fixation, 9 (0.3%) had open treatment without implants, 203 (6.3%) were treated with external fixation, and 399 (12.4%) with closed methods. Patients with No Fault/Accident insurance by No Fault/Accident insurance were more likely to undergo internal fixation compared with patients with private insurance (P<0.001). Of the 3220 patients, 2572 were included in the implant removal subanalysis. Implant removal was performed in 725 (28.2%) patients. In the multivariate model, patients were more likely to undergo removal if they were younger (P<0.001), white [vs. black (P<0.001), vs. Hispanic (P=0.035), vs. other (P=0.001)], and lived in neighborhoods with less poverty (P=0.016). Insurance status was not a statistically significant predictor of implant removal. CONCLUSIONS: There is an association between implant removal and younger age, white race, and higher socioeconomic status in children. Awareness of these disparities should prompt further evaluation of causation, whether it be from lack of evidence-based guidelines for implant removal, surgeon bias, variations in reimbursement, or disparities in access to care. Further study is recommended to better elucidate the indications for implant removal in children and the causes for the disparities identified here. LEVEL OF EVIDENCE: Level III retrospective cohort study. PMID- 25929780 TI - Bent Telescopic Rods in Patients With Osteogenesis Imperfecta. AB - BACKGROUND: Telescopic rods require alignment of 2 rods to enable lengthening. A telescopic rod converts functionally into a solid rod if either rod bends, preventing proper engagement. Our goal was to characterize implant bending as a mode of failure of telescopic rods used in the treatment of osteogenesis imperfecta in children. METHODS: We conducted a retrospective review of our osteogenesis imperfecta database for patients treated with intramedullary telescopic rods at our institution from 1992 through 2010 and identified 12 patients with bent rods. The 6 boys and 6 girls had an average age at the time of initial surgery of 3.1 years (range, 1.8 to 8.3 y) and a total of 51 telescoping rods. Clinic notes, operative reports, and radiographs were reviewed. The rods were analyzed for amount of lengthening, characteristics of bending, presence of cut out, or disengagement from an anchor point. Bends in the rods were characterized by their location on the implant component. The bent and straight rods were compared. Data were analyzed with the Mann-Whitney test (statistical significance set at P<=0.05). RESULTS: Of the 51 telescoping rods, 17 constructs (33%) bent. The average interval between surgery and rod bending was 4.0 years (range, 0.9 to 8.2 y). Before bending, 11 of 17 telescoping rods had routine follow-up radiographs for review. In 10 of the rods, bending was present when early signs of rod failure were first detected. Rod bending did not seem to be related to rod size. There was no area on the rod itself that seemed more susceptible to bending. CONCLUSIONS: Rod bending can be an early sign of impending rod failure. When rod bending is first noted, it may predispose the rod to other subsequent failures such as loss of proximal and distal fixation and cut out. Rod bending should be viewed as an indicator for closer monitoring of the patient and discussions regarding future need for rod exchange. LEVEL OF EVIDENCE: Level III-retrospective review. PMID- 25929781 TI - RE: Is There a Correlation Between Androgens and Sexual Desire in Women? PMID- 25929782 TI - Spontaneous hypokalaemia in a man with treated hypertension. PMID- 25929783 TI - PTEN over-expression by resveratrol in acute lymphoblastic leukemia cells along with suppression of AKT/PKB and ERK1/2 in genotoxic stress. AB - The bioactive components of dietary phytochemicals are in the spotlight of research institutes, due to their significant antioxidant activities and health promoting properties. Resveratrol is a polyphenol which is found abundantly in grapes and berries and has long been known as a chemo-preventive agent. The main purpose of this study was to provide a new mechanistic insight into the growth inhibition of acute lymphoblastic leukemia cells by resveratrol along with a DNA damage agent. It was found that the treatment of pre-B ALL cells by resveratrol in the presence or absence of doxorubicin resulted in decreased cell viability and a synergistic increase in cytotoxicity. Cell death was accompanied by a significant increase in phosphorylated p53 at serine 15 and accumulation of PTEN. In addition, resveratrol inhibited the over-expression of p-AKT and p-ERK1/2. These findings clearly demonstrated that resveratrol and doxorubicin synergistically increase the cytotoxicity of pre-B ALL cells via the hyper activation of two important tumor suppressor proteins and two major signal transduction pathways. PMID- 25929785 TI - Phenotypic switch of CD8(+) T cells reactivated under hypoxia toward IL-10 secreting, poorly proliferative effector cells. AB - CD8(+) T cells controlling pathogens or tumors must function at sites where oxygen tension is frequently low, and never as high as under atmospheric culture conditions. However, T-cell function in vivo is generally analyzed indirectly, or is extrapolated from in vitro studies under nonphysiologic oxygen tensions. In this study, we delineate the role of physiologic and pathologic oxygen tension in vitro during reactivation and differentiation of tumor-specific CD8(+) T cells. Using CD8(+) T cells from pmel-1 mice, we observed that the generation of CTLs under 5% O2, which corresponds to physioxia in lymph nodes, gave rise to a higher effector signature than those generated under atmospheric oxygen fractions (21% O2). Hypoxia (1% O2) did not modify cytotoxicity, but decreasing O2 tensions during CTL and CD8(+) tumor-infiltrating lymphocyte reactivation dose-dependently decreased proliferation, induced secretion of the immunosuppressive cytokine IL 10, and upregulated the expression of CD137 (4-1BB) and CD25. Overall, our data indicate that oxygen tension is a key regulator of CD8(+) T-cell function and fate and suggest that IL-10 release may be an unanticipated component of CD8(+) T cell-mediated immune responses in most in vivo microenvironments. PMID- 25929784 TI - The role of piRNA and its potential clinical implications in cancer. AB - Epigenetic mechanisms work in an orchestrated fashion to control gene expression in both homeostasis and diseases. Among small noncoding RNAs, piRNAs seem to meet the necessary requirements to be included in this epigenetic network due to their role in both transcriptional and post-transcriptional regulation. piRNAs and PIWI proteins might play important roles in cancer occurrence, prognosis and treatment as reported previously. Nevertheless, the potential clinical relevance of these molecules has yet been elucidated. A brief overview of piRNA biogenesis and their potential roles as part of an epigenetic network that is possibly involved in cancer is provided. Moreover, potential strategies based on the use of piRNAs and PIWI proteins as diagnostic and prognostic biomarkers as well as for cancer therapeutics are discussed. PMID- 25929786 TI - Molecular phylogenetics suggests a New Guinean origin and frequent episodes of founder-event speciation in the nectarivorous lories and lorikeets (Aves: Psittaciformes). AB - The lories and lorikeets (Aves: Loriinae: Loriini) are a readily recognizable, discrete group of nectarivorous parrots confined to the Indo-Pacific region between Wallace's Line and the Pitcairn Island group in the central-east Pacific Ocean. We present the first phylogenetic analysis of all currently recognized genera in the group using two mitochondrial and five nuclear loci. Our analyses suggest a New Guinean origin for the group at about 10million years ago (95% HPD 4.8-14.8) but this origin must be interpreted within the context of that island's complicated, recent geological history. That is, the origin and early diversification of the group may have taken place as New Guinea's Central Cordillera arose and the final constituent terranes that form present-day New Guinea were accreted. The latter activity may have promoted dispersal as a key element in the group's history. We have detected several instances of dispersal out of New Guinea that we argue constitute instances of founder-event speciation. Some phenotypically cohesive genera are affirmed as monophyletic but other genera are clearly in need of taxonomic dismantlement and reclassification. We recognize Parvipsitta Mathews, 1916 for two species usually placed in Glossopsitta and we advocate transfer of Chalcopsitta cardinalis into Pseudeos Peters, 1935. Other non-monophyletic genera such as Charmosyna, Psitteuteles and, probably, Trichoglossus, require improved taxon sampling and further phylogenetic analysis before their systematics can be resolved. Cursory examination of trait mapping across the group suggests that many traits are ancestral and of little use in determining genus-level systematics. PMID- 25929787 TI - Continental-scale analysis reveals deep diversification within the polytypic Red crowned Ant Tanager (Habia rubica, Cardinalidae). AB - We explored the phylogeographic patterns of intraspecific diversity in the Red crowned Ant Tanager (Habia rubica) throughout its continent-wide distribution, in order to understand its evolutionary history and the role of evolutionary drivers that are considered to promote avian diversification in the Neotropics. We sampled 100 individuals of H. rubica from Mexico to Argentina covering the main areas of its disjunct distribution. We inferred phylogenetic relationships through Bayesian and maximum parsimony methodologies based on mitochondrial and nuclear markers, and complemented genetic analyses with the assessment of coloration and behavioral differentiation. We found four deeply divergent phylogroups within H. rubica: two South American lineages and two Mexican and Middle American lineages. The divergence event between the northern and southern phylogroups was dated to c. 5.0 Ma, seemingly related to the final uplift of the Northern Andes. Subsequently, the two South American phylogroups split c. 3.5 Ma possibly due to the development of the open vegetation corridor that currently isolates the Amazonian and Atlantic forests. Diversification throughout Mexico and Middle America, following dispersion across the Isthmus of Panama, was presumably more recent and coincident with Pleistocene climatic fluctuations and habitat fragmentations. The analyses of vocalizations and plumage coloration showed significant differences among main lineages that were consistent with the phylogenetic evidence. Our findings suggest that the evolutionary history of H. rubica has been shaped by an assortment of diversification drivers at different temporal and spatial scales resulting in deeply divergent lineages that we recommend should be treated as different species. PMID- 25929788 TI - Phylogeny, hybridization, and life history evolution of Rhinogobius gobies in Japan, inferred from multiple nuclear gene sequences. AB - Rhinogobius fishes (Gobiidae) are distributed widely in East and Southeast Asia, and represent the most species-rich group of freshwater gobies with diversified life histories (i.e., amphidromous, fluvial, and lentic). To reveal their phylogenetic relationships and life history evolution patterns, we sequenced six nuclear and three mitochondrial DNA (mtDNA) loci from 18 species, mainly from the mainland of Japan and the Ryukyu Archipelago. Our phylogenetic tree based on nuclear genes resolved three major clades, including several distinct subclades. The mtDNA and nuclear DNA phylogenies showed large discordance, which strongly suggested mitochondrial introgression through large-scale interspecific hybridization in these regions. On the basis of the molecular dating using geological data as calibration points, the hybridization occurred in the early to middle Pleistocene. Reconstruction of the ancestral states of life history traits based on nuclear DNA phylogeny suggests that the evolutionary change from amphidromous to freshwater life, accompanied by egg size change, occurred independently in at least three lineages. One of these lineages showed two life history alterations, i.e., from amphidromous (small egg) to fluvial (large egg) to lentic (small egg). Although more inclusive analysis using species outside Japan should be further conducted, the present results suggest the importance of the life history evolution associated with high adaptability to freshwater environments in the remarkable species diversification in this group. Such life history divergences may have contributed to the development of reproductive isolation. PMID- 25929789 TI - Molecular phylogeny and a modified approach of character-based barcoding refining the taxonomy of New Caledonian freshwater gastropods (Caenogastropoda, Truncatelloidea, Tateidae). AB - The islands of New Caledonia represent one of the world's biodiversity hotspots with many endemic species including freshwater gastropods of the family Tateidae. A phylogenetic analysis based on the mitochondrial COI and 16S rRNA and the nuclear ITS2 genes revealed two cryptic genera, Crosseana gen. n. and Novacaledonia gen. n. In order to provide character-based diagnoses we modified a DNA barcoding approach identifying strings of pairwise diagnostic characters, i.e. alignment positions, at which two genera are alternatively fixed for different nucleotides. The combination or string of all pairwise diagnostic characters was unique for each genus. Inconsistent mitochondrial and nuclear topologies suggest that Hemistomia cockerelli Haase and Bouchet, 1998 and H. fabrorum Haase and Bouchet, 1998, two morphologically well-defined species, hybridize. The age of the most recent common ancestor of the New Caledonian radiation of Tateidae was estimated at 24.6+/-9.5 MY. These findings are in line with the notion that New Caledonia is rather a Darwinian island that was colonized after an extended phase of submergence - in case of the tateids probably from Australia - despite being a fragment of Gondwanaland. PMID- 25929790 TI - Hand-touch contact assessment of high-touch and mutual-touch surfaces among healthcare workers, patients, and visitors. AB - BACKGROUND: Unlike direct contact with patients' body, hand hygiene practice is often neglected by healthcare workers (HCWs) and visitors after contact with patients' environment. Contact with hospital environmental items may increase risk of pathogen transmission. AIM: To enumerate the number of hand-touch contacts by patients, HCWs and visitors with any hospital environmental items. METHODS: All contact-episodes between person and item were recorded by direct observation in a six-bed cubicle of acute wards for 33 working days. High-touch and mutual-touch items with high contact frequencies by HCWs, patients, and visitors were analysed. FINDINGS: In total, 1107 person-episodes with 6144 contact-episodes were observed in 66 observation hours (average: 16.8 person episodes and 93.1 contact-episodes per hour). Eight of the top 10 high-touch items, including bedside rails, bedside tables, patients' bodies, patients' files, linen, bed curtains, bed frames, and lockers were mutually touched by HCWs, patients, and visitors. Bedside rails topped the list with 13.6 contact episodes per hour (mean), followed by bedside tables (12.3 contact-episodes per hour). Using patients' body contacts as a reference, it was found that medical staff and nursing staff contacted bedside tables [rate ratio (RR): 1.741, 1.427, respectively] and patients' files (RR: 1.358, 1.324, respectively) more than patients' bodies, and nursing staff also contacted bedside rails (RR: 1.490) more than patients' bodies. CONCLUSION: Patients' surroundings may be links in the transmission of nosocomial infections because many are frequently touched and mutually contacted by HCWs, patients, and visitors. Therefore, the focus of hand hygiene education, environmental disinfection, and other system changes should be enhanced with respect to high-touch and mutual-touch items. PMID- 25929791 TI - NMR crystallography of monovalent cations in inorganic matrixes: Li(+) siting and the local structure of Li(+) sites in ferrierites. AB - (7)Li-(7)Li correlation MAS NMR spectroscopy, interpreted using periodic DFT including molecular dynamics conformational sampling of Li(+) sites, is employed to obtain the siting of Li(+) at exchangeable positions of ferrierites and the local structure of these Li(+) sites. The former is controlled by the Al siting in the zeolite framework. PMID- 25929792 TI - Saturation vapor pressures and transition enthalpies of low-volatility organic molecules of atmospheric relevance: from dicarboxylic acids to complex mixtures. PMID- 25929793 TI - Rhabdomyolysis: a genetic perspective. AB - Rhabdomyolysis (RM) is a clinical emergency characterized by fulminant skeletal muscle damage and release of intracellular muscle components into the blood stream leading to myoglobinuria and, in severe cases, acute renal failure. Apart from trauma, a wide range of causes have been reported including drug abuse and infections. Underlying genetic disorders are also a cause of RM and can often pose a diagnostic challenge, considering their marked heterogeneity and comparative rarity.In this paper we review the range of rare genetic defects known to be associated with RM. Each gene has been reviewed for the following: clinical phenotype, typical triggers for RM and recommended diagnostic approach. The purpose of this review is to highlight the most important features associated with specific genetic defects in order to aid the diagnosis of patients presenting with hereditary causes of recurrent RM. PMID- 25929794 TI - PCaP2 regulates nuclear positioning in growing Arabidopsis thaliana root hairs by modulating filamentous actin organization. AB - KEY MESSAGE: PCaP2 plays a key role in maintaining the nucleus at a relatively fixed distance from the apex during root hair growth by modulating actin filaments. During root hair growth, the nucleus localizes at a relatively fixed distance from the apex. In Arabidopsis thaliana, the position of the nucleus is mainly dependent on the configuration of microfilaments (filamentous actin). However, the mechanisms underlying the regulation of actin dynamics and organization for nuclear positioning are largely unknown. In the present study, we demonstrated that plasma membrane-associated Ca(2+) binding protein 2 (PCaP2) influences the position of the nucleus during root hair growth. Abnormal expression of PCaP2 in pcap2 and PCaP2 over-expression plants led to the disorganization of actin filaments, rather than microtubules, in the apex and sub apical regions of root hairs, which resulted in aberrant root hair growth patterns and misplaced nuclei. Analyses using a PCaP2 mutant protein revealed that actin-severing activity is essential for the function of PCaP2 in root hairs. We demonstrated that PCaP2 plays a key role in maintaining nuclear position in growing root hairs by modulating actin filaments. PMID- 25929795 TI - Overexpression of 3-deoxy-7-phosphoheptulonate synthase gene from Gossypium hirsutum enhances Arabidopsis resistance to Verticillium wilt. AB - KEY MESSAGE: Expression of DHS1 in cotton is induced upon infection by Verticillium dahliae , and overexpression of GhDHS1 endows transgenic Arabidopsis plants excellent Verticillium resistance. Verticillium wilt is caused by a soil borne fungus Verticillium dahliae. Resistance in most cotton cultivars is either scarce or unavailable, making Verticillium wilt a major obstacle in cotton production. Here, we identified a 3-deoxy-7-phosphoheptulonate synthase (DHS, EC 4.1.2.15) gene from Gossypium hirsutum, named GhDHS1. Its 1620 bp open reading frame encodes a putative 59.4 kDa protein. Phylogenetic analysis indicated that GhDHS1 is clustered in a clade with potato and tomato DHSs that can be induced by wounding and elicitors, respectively. Expression analysis demonstrated that GhDHS1 is constitutively expressed in cotton roots and stems, but transcripts are rare or non-existent in the leaves. Subcellular localization showed that GhDHS1 occurs in the plastids. When plants of three cultivars were inoculated with V. dahliae, DHS1 expression was more significantly up-regulated in the roots of resistant G. barbadense cv. Pima90-53 and G. hirsutum cv. Jimian20 than in the susceptible G. hirsutum cv. Han208. This suggested that DHS1 is involved in the cotton resistance to Verticillium wilt. Furthermore, GhDHS1 overexpressing transgenic lines of Arabidopsis were developed via Agrobacterium tumefaciens mediated transformation. Compared with the untransformed WT (wild type), these transgenic plants showed excellent Verticillium wilt resistance with a significantly lower disease index. The overexpressing transgenic lines also had significantly longer primary roots and greatly increased xylem areas under V. dahliae infection. Overall, our results indicate that GhDHS1 performs a role in the cotton resistance to V. dahliae and would be potential to breeding cottons of Verticillium wilt resistance. PMID- 25929796 TI - Analysis of metabolites in single cells-what is the best micro-platform? AB - This review covers new innovations and developments in the field of single-cell level analysis of metabolites, involving the role of microfluidic and microarray platforms to manipulate and handle the cells prior their detection. Microfluidic and microarray platforms have shown great promise. The latest developments demonstrate their potential to identify a particular cell or even an ensemble of cells (sharing a common property or phenotype) that co-exist in a much larger cell population. The reason for this is the capability of these platforms to perform several complex analytical processes, such as: cleanup, sorting, derivatization, separation, and detection, with great robustness, speed, and reduced sample/reagent consumption. Here, we present several examples that illustrate the rapid strides that have been made for the routine analysis of metabolites by coupling different microfluidics and microarrays devices to a wide range of analytical detectors (e.g. fluorescent microscopy, electrochemical, and mass spectrometry). Herein, we also present selected examples detailing the use of microfluidics and microarrays in the visualization of the natural occurring cell-to-cell heterogeneity in isogenic populations, in particular during the response to external cues. The possibility to accurate monitor the cell-to-cell heterogeneity based on different levels of key metabolites is of clinical relevance, since cell-to-cell heterogeneity can influence, for example, the outcome of a drug treatment. PMID- 25929797 TI - Diagnosis and management of intradiaphragmatic extralobar pulmonary sequestration: a report of 11 cases. AB - Evaluate the diagnosis and management of intradiaphragmatic extralobar pulmonary sequestration (IDEPS). We retrospectively reviewed cases of bronchopulmonary sequestrations (BPS) diagnosed in our hospital from March 2011 to May 2014, in order to identify patients with IDEPS. Diagnosis of IDEPS was confirmed using prenatal Doppler ultrasound, postnatal intravascular enhanced computed tomography, and surgery. The 11 cases diagnosed with IDEPSs were confirmed with histopathology. In our first case we did not find any mass from abdominal surgery; we then turned to transthoracic surgery. Three patients underwent thoracoscopy, and seven underwent thoracotomy. IDEPS is better approached through the chest. Thoracoscopy in experienced hands a favorable approach. PMID- 25929798 TI - Trans-amniotic stem cell therapy (TRASCET) minimizes Chiari-II malformation in experimental spina bifida. AB - PURPOSE: We sought to study the impact of trans-amniotic stem cell therapy (TRASCET) in the Chiari-II malformation in experimental spina bifida. METHODS: Sprague-Dawley fetuses (n=62) exposed to retinoic acid were divided into three groups at term (21-22 days gestation): untreated isolated spina bifida (n=21), isolated spina bifida treated with intra-amniotic injection of concentrated, syngeneic, labeled amniotic fluid mesenchymal stem cells (afMSCs) on gestational day 17 (n=28), and normal controls (n=13). Analyses included measurements of brainstem and cerebellar placement on high resolution MRI and histology. Statistical comparisons included ANOVA. RESULTS: In parallel to the expected induced coverage of the spina bifida in the afMSC-treated group (P<0.001), there were statistically significant differences in brainstem displacement across the groups (P<0.001), with the highest caudal displacement in the untreated group. Significant differences in cerebellar displacement were also noted, albeit less pronounced. Pairwise comparisons were statistically significant, with P=0.014 between treated and normal controls in caudal brainstem displacement and P<0.001 for all other comparisons. Labeled afMSCs were identified in 71% of treated fetuses. CONCLUSIONS: Induced coverage of spina bifida by TRASCET minimizes the Chiari-II malformation in the retinoic acid rodent model, further suggesting it as a practical alternative for the prenatal management of spina bifida. PMID- 25929800 TI - Platinum-Catalyzed Cascade Rearrangement Reaction of 1,5-Diynyl Esters: Unusual Regioselective 1,5-Hydride Migration. AB - A highly regioselective sequential 1,3-acyloxy migration/pentannulation/1,5 hydride migration reaction is disclosed which provides an efficient access to (E) 2-vinyl-3-oxo-1-methyleneindenes under neutral and mild reaction conditions. The migrated hydrogen atom was derived from an unactivated alkyl group, and the long range 1,5-H shift was confirmed through related deuterium experiments. PMID- 25929799 TI - Environmental perception and epigenetic memory: mechanistic insight through FLC. AB - Chromatin plays a central role in orchestrating gene regulation at the transcriptional level. However, our understanding of how chromatin states are altered in response to environmental and developmental cues, and then maintained epigenetically over many cell divisions, remains poor. The floral repressor gene FLOWERING LOCUS C (FLC) in Arabidopsis thaliana is a useful system to address these questions. FLC is transcriptionally repressed during exposure to cold temperatures, allowing studies of how environmental conditions alter expression states at the chromatin level. FLC repression is also epigenetically maintained during subsequent development in warm conditions, so that exposure to cold may be remembered. This memory depends on molecular complexes that are highly conserved among eukaryotes, making FLC not only interesting as a paradigm for understanding biological decision-making in plants, but also an important system for elucidating chromatin-based gene regulation more generally. In this review, we summarize our understanding of how cold temperature induces a switch in the FLC chromatin state, and how this state is epigenetically remembered. We also discuss how the epigenetic state of FLC is reprogrammed in the seed to ensure a requirement for cold exposure in the next generation. PMID- 25929801 TI - Exposure to select phthalates and phenols through use of personal care products among Californian adults and their children. AB - INTRODUCTION: Certain phenols and phthalates are used in many consumer products including personal care products (PCPs). AIMS: We aimed to study the associations between the use of PCPs and urinary concentrations of biomarkers of select phenols and phthalates among Californian adults and their children. As an additional aim we compared phenols and phthalate metabolites concentrations measured in adults and children urine samples collected the same day. METHODS: Our study relied on a subsample of 90 adult-child pairs participating in the Study of Use of Products and Exposure Related Behavior (SUPERB). Each adult and child provided one to two urine samples in which we measured concentrations of selected phenols and phthalate metabolites. We computed Spearman correlation coefficients to compare concentrations measured in adults and children urine samples collected the same day. We used adjusted linear and Tobit regression models to study the associations between the use of PCPs in the past 24h and biomarker concentrations. RESULTS: Benzophenone-3 and parabens concentrations were higher in adults compared to their children. Conversely children had higher mono-n-butyl phthalate and mono-isobutyl phthalate concentrations. No significant difference was observed for the other compounds. The total number of different PCPs used was positively associated with urinary concentrations of methyl, propyl and butyl parabens and the main metabolite of diethyl phthalate in adults. Among children, the use of a few specific products including liquid soap, hair care products and sunscreen was positively associated with urinary concentrations of some phenols or phthalate metabolites. DISCUSSION: These results strengthen the body of evidence suggesting that use of PCPs is an important source of exposure to parabens and diethyl phthalate in adults and provide data on exposure to selected phenols and phthalates through use of PCPs in children. PMID- 25929802 TI - 'Weather Value at Risk': A uniform approach to describe and compare sectoral income risks from climate change. AB - We extend the concept of 'Weather Value at Risk' - initially introduced to measure the economic risks resulting from current weather fluctuations - to describe and compare sectoral income risks from climate change. This is illustrated using the examples of wheat cultivation and summer tourism in (parts of) Sardinia. Based on climate scenario data from four different regional climate models we study the change in the risk of weather-related income losses between some reference (1971-2000) and some future (2041-2070) period. Results from both examples suggest an increase in weather-related risks of income losses due to climate change, which is somewhat more pronounced for summer tourism. Nevertheless, income from wheat cultivation is at much higher risk of weather related losses than income from summer tourism, both under reference and future climatic conditions. A weather-induced loss of at least 5% - compared to the income associated with average reference weather conditions - shows a 40% (80%) probability of occurrence in the case of wheat cultivation, but only a 0.4% (16%) probability of occurrence in the case of summer tourism, given reference (future) climatic conditions. Whereas in the agricultural example increases in the weather related income risks mainly result from an overall decrease in average wheat yields, the heightened risk in the tourism example stems mostly from a change in the weather-induced variability of tourism incomes. With the extended 'Weather Value at Risk' concept being able to capture both, impacts from changes in the mean and the variability of the climate, it is a powerful tool for presenting and disseminating the results of climate change impact assessments. Due to its flexibility, the concept can be applied to any economic sector and therefore provides a valuable tool for cross-sectoral comparisons of climate change impacts, but also for the assessment of the costs and benefits of adaptation measures. PMID- 25929803 TI - The mannose-6-phosphate analogue, PXS64, inhibits fibrosis via TGF-beta1 pathway in human lung fibroblasts. AB - Idiopathic pulmonary fibrosis (IPF) is a chronic disease characterised by a progressive decline in lung function which can be attributed to excessive scarring, inflammation and airway remodelling. Mannose-6-phosphate (M6P) is a strong inhibitor of fibrosis and its administration has been associated with beneficial effects in tendon repair surgery as well as nerve repair after injury. Given this promising therapeutic approach we developed an improved analogue of M6P, namely PXS64, and explored its anti-fibrotic effects in vitro. Normal human lung fibroblasts (NHLF) and human lung fibroblast 19 cells (HF19) were exposed to active recombinant human TGF-beta1 to induce increases in fibrotic markers. rhTGF beta1 increased constitutive protein levels of fibronectin and collagen in the NHLF cells, whereas HF19 cells showed increased levels of fibronectin, collagen as well as alphaSMA (alpha smooth muscle actin). PXS64 demonstrated a robust inhibitory effect on all proteins analysed. IPF patient fibroblasts treated with PXS64 presented an improved phenotype in terms of their morphological appearance, as well as a decrease in fibrotic markers (collagen, CTGF, TGF-beta3, tenascin C, alphaSMA and THBS1). To explore the cell signalling pathways involved in the anti fibrotic effects of PXS64, proteomics analysis with iTRAQ labelling was performed and the data demonstrated a specific antagonistic effect on the TGF-beta1 pathway. This study shows that PXS64 effectively inhibits the production of extracellular matrix, as well as myofibroblast differentiation during fibrosis. These results suggest that PXS64 influences tissue remodelling by inhibiting TGF beta1 signalling in NHLF and HF19 cell lines, as well as in IPF patient fibroblasts. Thus PXS64 is a potential candidate for preclinical application in pulmonary fibrosis. PMID- 25929804 TI - Endogenous VSIG4 negatively regulates the helper T cell-mediated antibody response. AB - VSIG4 acts as a co-inhibitory ligand to negatively regulate T cell proliferation and cytokine production, and its expression is restricted to macrophages. We hypothesized that endogenous VSIG4 impairs helper T cell functions and then inhibits the subsequent antibody response. Isotype switching of ovalbumin (OVA) specific antibody subclasses to IgG1, IgG2a, IgG2b, and IgG3 was enhanced in OVA immunized VSIG4 knockout (KO) mice. 2,4,6-Trinitrophenyl hapten (TNP) - Keyhole Limpet Hemocyanin (KLH)-primed B cells cocultured with OVA-primed CD4(+) T cells from OVA-immunized VSIG4 KO mice in the presence of TNP-OVA showed enhanced isotype switching to IgG subclasses compared to those cocultured with cells isolated from OVA-immunized wild-type (WT) mice. Furthermore, the levels of CD40L expression, the frequency of memory CD4(+) T cells, and the production of isotype switching-inducing cytokines increased significantly in OVA-primed CD4(+) T cells from VSIG4 KO mice. T cells from OVA-specific T cell receptor (TCR) transgenic mice produced more IFN-gamma when cocultured with macrophages from VSIG4 KO mice compared to WT mice. Thus, our results demonstrate that macrophage-associated VSIG4 plays a negative role in helper T cell-dependent isotype switching by inhibiting helper T cell activation and differentiation, and suppressing the isotype switching-inducing cytokine production in antigen-primed CD4(+) helper T cells. PMID- 25929805 TI - Impact of passive smoke and/or atopy on adenoid immunoglobulin production in children. AB - The adenoids are exposed to a wide number and variety of microbes, environmental pollutants, and food antigens. Atopy and passive smoke may significantly affect immune responses, mainly in children. The aim of the present study was to investigate whether passive exposure to tobacco smoke and/or atopy could affect immunoglobulin production by adenoidal lymphocytes in a cohort of children presenting with adenoid hypertrophy. A total of 277 children (151 males and 126 females; median age 5.5 years), with adenoidal hypertrophy requiring adenoidectomy and or adeno-tonsillectomy, were consecutively enrolled in the study. Adenoid mononuclear cells were in vitro stimulated with LPS or CpG. When considering both the presence of smoke exposure and atopy, we observed that the CpG-induced decrease in IgA and IgM production was significantly associated with this combination of risk factors. In the T-independent immunoglobulin production assay we found a positive association between the two risk factors and IgA and IgM production. In particular, the presence of both risk factors, showed a significant increase in IgA and IgM production after stimulation. In conclusion, this is the first study that investigated the in vitro adenoidal B cell response after different stimuli in children, also evaluating possible exposure to passive smoke and/or an atopic condition. PMID- 25929806 TI - Lithium modulates the production of peripheral and cerebral cytokines in an animal model of mania induced by dextroamphetamine. AB - OBJECTIVES: Several recent studies have suggested that the physiopathology of bipolar disorder (BD) is related to immune system alterations and inflammation. Lithium (Li) is a mood stabilizer that is considered the first-line treatment for this mood disorder. The goal of the present study was to investigate the effects of Li administration on behavior and cytokine levels [interleukin (IL)-1beta, IL 4, IL-6, IL-10, and tumor necrosis factor-alpha (TNF-alpha)] in the periphery and brains of rats subjected to an animal model of mania induced by amphetamine (d AMPH). METHODS: Male Wistar rats were treated with d-AMPH or saline (Sal) for 14 days; on Day 8 of treatment, the rats were administered Li or Sal for the final seven days. Cytokine (IL-1beta, IL-4, IL-6, IL-10, and TNF-alpha) levels were evaluated in the cerebrospinal fluid (CSF), serum, frontal cortex, striatum, and hippocampus. RESULTS: The present study showed that d-AMPH induced hyperactivity in rats (p < 0.001), and Li treatment reversed this behavioral alteration (p < 0.001). In addition, d-AMPH increased the levels of IL-4, IL-6, IL-10, and TNF alpha in the frontal cortex (p < 0.001), striatum (p < 0.001), and serum (p < 0.001), and treatment with Li reversed these cytokine alterations (p < 0.001). CONCLUSIONS: Li modulates peripheral and cerebral cytokine production in an animal model of mania induced by d-AMPH, suggesting that its action on the inflammatory system may contribute to its therapeutic efficacy. PMID- 25929807 TI - Factor IX-deficient plasma spiked with N9-GP behaves similarly to N9-GP post administration clinical samples in N9-GP ELISA and FIX activity assays. AB - INTRODUCTION: Evaluation of assay performance with new modified coagulation factors, such as N9-GP, may require testing of different assays and assay conditions. Validation of assays used for clinical monitoring of haemophilia B patients is challenging due to limited availability of blood samples from patients exposed to these new agents. AIM: The aim of the study is to investigate correlations between assays measuring N9-GP concentration and factor IX (FIX) activity, and to evaluate whether in vitro FIX-deficient plasma samples spiked with N9-GP and in vivo post-administration samples from patients exposed to N9-GP perform similarly in these assays. METHODS: In vitro samples, prepared by adding N9-GP to FIX-deficient plasma, were compared to samples from haemophilia B patients participating in the phase 3 paradigm 2(TM) clinical trial (in vivo samples), in assays measuring N9-GP concentration (ELISA) and FIX activity (one stage clotting assay and chromogenic assay). The results of the FIX activity assays and ELISAs were compared and analysed to determine the similarity between the in vitro and in vivo sample analyses. RESULTS: Regression analysis demonstrated a linear relationship between N9-GP concentration and FIX activity. Furthermore, there was no significant difference between the regression lines for the in vitro and in vivo sample analyses. CONCLUSION: The one-stage clot assay using SynthAFax and the chromogenic assay show promise for use in measuring FIX activity in haemophilia B patients treated with N9-GP. Since in vitro and in vivo samples performed similarly in these assays, N9-GP-spiked FIX-deficient plasma could be used as controls in routine measurements of N9-GP activity in haemophilia B patients. PMID- 25929808 TI - Clinical significance of high expression of circulating serum lncRNA RP11 445H22.4 in breast cancer patients: a Chinese population-based study. AB - Long noncoding RNAs (lncRNAs) have been gradually confirmed to be tumor associated biological molecules and became interesting new diagnostic targets of cancer. However, the clinical significances of most cancer-related lncRNAs are largely unknown. Here, we evaluated, for the first time, the feasibility and clinical significances of circulating serum lncRNA RP11-445H22.4 as biomarker for the detection of breast cancer (BC). In this study, the relative concentrations of breast cancer-associated lncRNA RP11-445H22.4 were investigated in a total of 136 serum samples by real-time quantitative reverse transcriptase-polymerase chain reaction (qRT-PCR). The correlations between the levels of serum lncRNA RP11-445H22.4 in breast cancer patients and the clinicopathological factors of these patients were further analyzed. Receiver operating characteristic (ROC) curve was constructed to evaluate the diagnostic values. In breast cancer patients, the expression level of lncRNA RP11-445H22.4 is significantly increased (p < 0.001). The sensitivity and specificity of RP11-445H22.4 for BC were 92 and 74 %, respectively. Its expression levels were correlated with estrogen receptor (ER), progesterone receptor (PR), and menopausal status of the breast cancer patients (p < 0.05). For the detection of breast cancer, the use of RP11-445H22.4 showed a remarkable improvement compared with the clinical serum carcinoembryonic antigen. In conclusions, lncRNA RP11-445H22.4 may be a new potential biomarker of breast cancer. PMID- 25929809 TI - HCC-DETECT: a combination of nuclear, cytoplasmic, and oncofetal proteins as biomarkers for hepatocellular carcinoma. AB - Currently, the search for suitable hepatocellular carcinoma (HCC) biomarkers is very intensive. Besides, efficacy and cost/effectiveness of screening and surveillance of cirrhotics for the diagnosis of HCC is still debated. So, the present study is concerned with the evaluation of cytokeratin-1 (CK-1) and nuclear matrix protein-52 (NMP-52) for identifying HCC. Two-hundred and eighty individuals categorized into three groups [liver fibrosis (F1-F3), cirrhosis (F4), and HCC] constituted this study. Western blot was used for identifying CK-1 and NMP-52 in serum samples. As a result, a single immunoreactive band was shown at 67 and 52 kDa corresponding to CK-1 and NMP-52, respectively. Both CK-1 and NMP-52 bands were cut and electroeluted separately. These markers were quantified in sera using ELISA. Patients with HCC were associated with higher concentrations of CK-1 and NMP-52 than those without HCC with a significant difference (P < 0.0001). CK-1 showed an area under receiver-operating characteristic curve (AUC) of 0.83 with 75 % sensitivity and 82 % specificity while NMP-52 yielded 0.72 AUC with 62 % sensitivity and 70 % specificity for identifying HCC. HCC-DETECT comprising CK-1 and NMP-52 together with AFP was then constructed yielding 0.90 AUC for identifying HCC with 80 % sensitivity and 92 % specificity. HCC-DETECT was then tested for separating HCC from F1-F3 showing 0.94 AUC with 80 % sensitivity and 93 % specificity. In conclusion, CK-1 in conjunction with NMP-52 and AFP could have a potential role for improving the detection of HCC with a high degree of accuracy. PMID- 25929810 TI - The prognostic impact of lipid biosynthesis-associated markers, HSD17B2 and HMGCS2, in rectal cancer treated with neoadjuvant concurrent chemoradiotherapy. AB - Neoadjuvant concurrent chemoradiotherapy has been widely used for rectal cancer to improve local tumor control. The varied response of individual tumors encouraged us to search for useful biomarkers to predict the therapeutic response. The study was aimed to evaluate the prognostic impact of lipid biosynthesis-associated biomarkers in rectal cancer patients treated with preoperative chemoradiotherapy. Through analysis of the previously published gene expression profiling database focusing on genes associated with lipid biosynthesis, we found that HSD17B2 and HMGCS2 were the top two significantly upregulated genes in the non-responders. We further evaluated their expression by immunohistochemistry in the pre-treatment tumor specimens from 172 patients with rectal cancer and statistically analyzed the associations between their expression and various clinicopathological factors, as well as survival. High expression of HMGCS2 or HSD17B2 was significantly associated with advanced pre- and post-treatment tumor or nodal status (P < 0.001) and lower tumor regression grade (P < 0.001). More importantly, high expression of either HMGCS2 or HSD17B2 was of prognostic significance, with HMGCS2 overexpression indicating poor prognosis for disease-free survival (P = 0.0003), local recurrence-free survival (P = 0.0115), and metastasis-free survival (P = 0.0119), while HSD17B2 overexpression was associated with poor prognosis for disease-free survival (P <0.0001), local recurrence-free survival (P = 0.0009), and metastasis-free survival (P < 0.0001). In multivariate analysis, only HSD17B2 overexpression remained as an independent prognosticator for shorter disease-free survival (P < 0.001) and metastasis-free survival (P = 0.008). In conclusion, high expression of either HSD17B2 or HMGCS2 predicted poor susceptibility of rectal cancer to preoperative chemoradiotherapy. Both acted as promising prognostic factors, particularly HSD17B2. PMID- 25929812 TI - Statements about true and false intentions: using the Cognitive Interview to magnify the differences. AB - This study investigates the combined effect of the Cognitive Interview (CI) and the unanticipated questions approach on the magnitude of the elicited cues to true and false intentions. The participants (N = 125) planned for either a mock crime or a non-criminal event, half of them were interviewed with a standard interview (SI) and half with the CI. All participants were asked one set of questions targeting their intentions (anticipated questions) and one set of questions targeting the phase in which they planned their stated intentions (unanticipated questions). As predicted, the questions about the planning phase were perceived as unanticipated by both liars and truth-tellers. Furthermore, and as predicted, the truth-tellers' (vs. the liars') answers to the unanticipated questions were significantly more detailed. Importantly, and in line with our predictions, for the answers given to questions about the planning-phase, liars and truth-tellers differed more clearly in the CI-condition than in the SI condition, indicating that the CI indeed magnified the differences between liars and truth-tellers. In addition, and as predicted, the truth-tellers' (vs. the liars') descriptions of their intentions were more characterized by information related to how to attain the stated goal. PMID- 25929811 TI - The association of urine arsenic with prevalent and incident chronic kidney disease: evidence from the Strong Heart Study. AB - BACKGROUND: Few studies have evaluated associations between low to moderate arsenic levels and chronic kidney disease (CKD). The objective was to evaluate the associations of inorganic arsenic exposure with prevalent and incident CKD in American Indian adults. METHODS: We evaluated the associations of inorganic arsenic exposure with CKD in American Indians who participated in the Strong Heart Study in 3,851 adults ages 45-74 years in a cross-sectional analysis, and 3,119 adults with follow-up data in a prospective analysis. Inorganic arsenic, monomethylarsonate, and dimethylarsinate were measured in urine at baseline. CKD was defined as estimated glomerular filtration rate <= 60 ml/min/1.73 m, kidney transplant or dialysis. RESULTS: CKD prevalence was 10.3%. The median (IQR) concentration of inorganic plus methylated arsenic species (total arsenic) in urine was 9.7 (5.8, 15.7) MUg/L. The adjusted odds ratio (OR; 95% confidence interval) of prevalent CKD for an interquartile range in total arsenic was 0.7 (0.6, 0.8), mostly due to an inverse association with inorganic arsenic (OR: 0.4 [0.3, 0.4]). Monomethylarsonate and dimethylarsinate were positively associated with prevalent CKD after adjustment for inorganic arsenic (OR: 3.8 and 1.8). The adjusted hazard ratio of incident CKD for an IQR in sum of inorganic and methylated arsenic was 1.2 (1.03, 1.41). The corresponding HRs for inorganic arsenic, monomethylarsonate, and dimethylarsinate were 1.0 (0.9, 1.2), 1.2 (1.00, 1.3), and 1.2 (1.0, 1.4). CONCLUSIONS: The inverse association of urine inorganic arsenic with prevalent CKD suggests that kidney disease affects excretion of inorganic arsenic. Arsenic species were positively associated with incident CKD. Studies with repeated measures are needed to further characterize the relation between arsenic and kidney disease development. PMID- 25929813 TI - Expression of cdk6 in head and neck squamous cell carcinoma. AB - OBJECTIVE: Cdk6 is a key regulator during the G1/S cell cycle transition. Aberrant expression of cdk6 protein has been observed in many cancer types. However, little is known about the expression of cdk6 in head and neck squamous cell carcinoma (HNSCC) and its clinical significance. This study evaluated the expression of cdk6 in HNSCC and analyzed the relationship between cdk6 expression and clinicopathological parameters of HNSCC. MATERIALS AND METHODS: Expression of cdk6 was immunohistochemically investigated in 98 HNSCCs. Nuclear and cytoplasmic positive cells were counted separately. Data were presented as the percentage of positive cells. The correlation between the percentage of positive cells and clinicopathological factors was determined. RESULTS: Nuclear and cytoplasmic staining for cdk6 were detected in 91 cases and 97 cases, respectively. A significant correlation was found only between the percentage of nuclear positive cells and T classification (p value = 0.0410). Tumors with high nuclear cdk6 positive cells showed a linear trend toward advanced tumor status (p value = 0.0064). CONCLUSIONS: Cdk6 was highly expressed in HNSCC. Tumors with high nuclear cdk6 expression tended to have advanced tumor status. These results suggest that cdk6 plays a vital role in HNSCC and is involved in tumor progression of this cancer. CLINICAL RELEVANCE: An increased nuclear cdk6 expression is an unfavorable factor for HNSCC. Cdk6 may serve as a therapeutic target in this cancer. PMID- 25929814 TI - Release and pharmacokinetics of near-infrared labeled albumin from monodisperse poly(d,l-lactic-co-hydroxymethyl glycolic acid) microspheres after subcapsular renal injection. AB - Subcapsular renal injection is a novel administration method for local delivery of therapeutics for the treatment of kidney related diseases. The aim of this study was to investigate the feasibility of polymeric microspheres for sustained release of protein therapeutics in the kidney and study the subsequent redistribution of the released protein. For this purpose, monodisperse poly(d,l lactic-co-hydroxymethyl glycolic acid) (PLHMGA) microspheres (40 MUm in diameter) loaded with near-infrared dye-labeled bovine serum albumin (NIR-BSA) were prepared by a membrane emulsification method. Rats were injected with either free NIR-BSA or with NIR-BSA loaded microspheres (NIR-BSA-ms) and the pharmacokinetics of the released NIR-BSA was studied for 3 weeks by ex vivo imaging of organs and blood. Quantitative release data were obtained from kidney homogenates and possible metabolism of the protein was investigated by SDS-PAGE analysis of the samples. The ex vivo images showed a rapid decrease of the NIR signal within 24h in kidneys injected with free NIR-BSA, while, importantly, the signal of the labeled protein was still visible at day 21 in kidneys injected with NIR-BSA-ms. SDS-PAGE analysis of the kidney homogenates showed that intact NIR-BSA was released from the microspheres. The locally released NIR-BSA drained to the systemic circulation and subsequently accumulated in the liver, where it was degraded and excreted renally. The in vivo release of NIR-BSA was calculated after extracting the protein from the remaining microspheres in kidney homogenates. The in vivo release rate was faster (89 +/- 4% of the loading in 2 weeks) compared to the in vitro release of NIR-BSA (38 +/- 1% in 2 weeks). In conclusion, PLHMGA microspheres injected under the kidney capsule provide a local depot from which a formulated protein is released over a prolonged time-period. PMID- 25929815 TI - Implementation of a manual for working with wobbler mice and criteria for discontinuation of the experiment. AB - Mouse breeding is of importance to a whole range of medical and biological research. There are many known mouse models for motor neuron diseases. However, it must be kept in mind that especially mouse models for amyotrophic lateral sclerosis develop severe symptoms causing intense stress. This article is designed to summarize conscientious work with the wobbler mouse, a model for the sporadic form of amyotrophic lateral sclerosis. This mouse model is characterized by a degeneration of alpha-motor-neurons leading to head tremor, loss of body weight and rapidly progressive paralysis. Although this mouse model has been known since 1956, there are no guidelines for breeding wobbler mice. Due to the lack of such guidelines the present study tries to close this gap and implements a manual for further studies. It includes the whole workflow in regard to wobbler mice from breeding and animal care taking, genotyping and phenotype analysis, but also gives some examples for the use of various neuronal tissues for histological investigation. Beside the progress in research a second aim should always be the enhancement of mouse welfare and reduction of stress for the laboratory animals. PMID- 25929816 TI - Monetite granules versus particulate autologous bone in bone regeneration. AB - OBJECTIVE: The aim of this study was to test bone tissue response to monetite granules in comparison with intramembranous autologous bone graft in a rabbit calvaria critical size defect model. MATERIALS AND METHODS: Novel monetite granules were synthesized by thermal conversion of set brushite cement. Eight female New Zealand rabbits were used for this study. Two identical 10mm diameter bicortical cranial defects were created in each animal. One of the defects was grafted with monetite granules while the contralateral was grafted with granules of intramembranous autologous bone as control. Animals were sacrificed 8 weeks after surgery and biopsies were taken for histological and histomorphometrical evaluation under light microscopy. Wilcoxon test was used for statistical analysis. RESULTS: The bone defects treated with either autologous bone or monetite granules were able to heal within the study period. Upon histological observation the defects treated with autologous bone granules resembled the adjacent intact calvaria, whereas the defects treated with monetite showed a high infiltration of new bone and only 13.4+/-8.4% of remaining granules. The percentage of bone volume in the defects of the control group (71+/-9%) was 16% higher than in the study group (55+/-10%) (p<0.05). The percentage of augmented mineralized tissue volume in the study group (68+/-18%) was not significantly different from the control group (p>0.05). CONCLUSION: The amount of augmented mineralized tissue in the bone defects obtained with monetite granules was not significantly different from that obtained with autologous bone. This study confirms the potential of monetite based biomaterials as an alternative to autologous bone graft. PMID- 25929818 TI - Developing osteoblasts as an endpoint for the mouse embryonic stem cell test. AB - The mouse Embryonic Stem cell Test (EST) using cardiomyocyte differentiation is a promising in vitro assay for detecting potential embryotoxicity; however, the addition of another differentiation endpoint, such as osteoblasts, may improve the predictive value of the test. A number of variables such as culture conditions and starting cell number were investigated. A 14 day direct plating method of D3 mouse embryonic stem cells (mESCs) was used to test the predictivity of osteoblast differentiation as an endpoint in the EST. Twelve compounds were tested using the prediction model developed in the ECVAM validation study. Eight of the compounds selected from the EST validation study served as model compounds; four additional compounds known to produce skeletal defects were also tested. Our results indicate comparable chemical classification between the validated cardiomyocyte endpoint and the osteoblast endpoint. These results suggest that differentiation to osteoblasts may provide confirmatory information in predicting embryotoxicity. PMID- 25929817 TI - Novel flow cytometric analysis of the blood-brain barrier. AB - The blood-brain barrier (BBB) is primarily comprised of brain microvascular endothelial cells (BMVEC) and astrocytes and serves as a physical and chemical barrier that separates the periphery from the brain. We describe a flow cytometric method using our in vitro model of the human BBB to characterize BMVEC surface junctional proteins critical for maintenance of barrier function, cell viability, and leukocyte adhesion. For this methodology, BMVEC are cocultured with astrocytes in a transwell tissue culture insert to establish the barrier, after which time the BBB are treated with specific agents, and the BMVEC collected for flow cytometric analyses. We use a standard and optimized method to recover the BMVEC from the coculture model that maintains junctional protein expression and cell viability. A novel leukocyte adhesion assay enables a quantitative analysis of peripheral blood mononuclear cell (PBMC) interactions with the BMVEC and can be used to assess the adhesion of many cell types to the BBB. Furthermore, this method enables the concomitant analysis of a large number of adhesion molecules and tight junction proteins on both the BMVEC and adherent PBMC under homeostatic and pathologic conditions. Flow cytometry is an extremely powerful tool, and this technique can also be applied to assess variables not performed in this study, including cell cycle progression, and calcium flux. PMID- 25929819 TI - Maternal predictors of RBC folate levels in an urban Canadian population. AB - OBJECTIVE: To assess factors associated with low Red Blood Cell folate (RBCf) levels in an obstetric population in a tertiary centre. METHODS: Cross-sectional study. Three hundred and fifty women completed a questionnaire detailing use of folic acid supplementation, and had their RBCf levels measured. Values >= 906 nmol/L were considered optimal. Factors associated with optimal RBCf were assessed, individually and in a logistic regression model. RESULTS: Median RBCf was 1282 nmol/L. Thirty-five women (10%) had suboptimal levels. Predictors of suboptimal RBCf were non-Caucasian ethnicity, non-consumption of folic acid supplementations, and inadequate health care provider information regarding the benefits of folic acid consumption. CONCLUSION: Although, in our population, a high proportion of women achieved optimal levels of RBCf, some women remain at risk due to inadequate folate consumption. Patient and health care provider education regarding folate can still be improved, particularly in the groups identified to be at greater risk. PMID- 25929820 TI - Vinclozolin modulates hepatic cytochrome P450 isoforms during pregnancy. AB - Vinclozolin (V) is classified as a potent endocrine disruptor. The aim of the present study was to determine the effects of V on rat liver CYP regulation and on serum levels of testosterone and estradiol during pregnancy. Pregnancy decreased the liver total CYP content by 65%, enzyme activities of MROD, PROD, and PNPH, and testosterone hydroxylation activities, as well as the protein content of CYP2A and 3A. V exposure remarkably induced the protein content and enzyme activities of CYP1A, 2A, 2B and 3A subfamilies. Testosterone and estradiol were affected in an opposite manner, provoking a 3.5-fold increase in the estradiol/testosterone ratio. These results suggest that V could regulate the hepatic CYP expression through interaction with receptors and coactivators involved in its expression and may play an important role in hormonal balance during pregnancy. In addition, the results may also contribute to understanding the toxicity of V by in utero exposure. PMID- 25929821 TI - Exogenous nitric oxide enhances calcification in embryonic stem cell-derived osteogenic cultures. AB - While the involvement of nitric oxide in bone formation, homeostasis and healing has been extensively characterized, its role in directing pluripotent stem cells to the osteogenic lineage has not been described. Yet, the identification of chemical inducers that improve differentiation output to a particular lineage is highly valuable to the development of such cells for the cell-based treatment of osteo-degenerative diseases. This study aimed at investigating the instructive role of nitric oxide (NO) and its synthesizing enzymes on embryonic stem cell (ESC) osteogenic differentiation. Our findings showed that NO levels may support osteogenesis, but that the effect of nitric oxide on osteoblast differentiation may be specific to a particular time phase during the development of osteoblasts in vitro. Endogenously, nitric oxide was specifically secreted by osteogenic cultures during the calcification period. Simultaneously, messenger RNAs for both the endothelial and inducible nitric oxide synthase isoforms (eNOS and iNOS) were upregulated during this late phase development. However, the specific eNOS inhibitor L-N(5)-(1-Iminoethyl)ornithine dihydrochloride attenuated calcification more so than the specific iNOS inhibitor diphenyleneiodonium. Exogenous stage specific supplementation of culture medium with the NO donor S-nitroso-N-acetyl penicillamine increased the percentage of cells differentiating into osteoblasts and enhanced calcification. Our results point to a primary role for eNOS as a pro osteogenic trigger in ESC differentiation and expand on the variety of supplements that may be used to direct ESC fate to the osteogenic lineage, which will be important in the development of cell-based therapies for osteo degenerative diseases. PMID- 25929822 TI - Hard and soft selection on phenology through seasonal shifts in the general and social environments: A study on plant emergence time. AB - The timing of transition out of one life-history phase determines where in the seasonal succession of environments the next phase is spent. Shifts in the general environment (e.g., seasonal climate) affect the expected fitness for particular transition dates. Variation in transition date also leads to temporal variation in the social environment. For instance, early transition may confer a competitive advantage over later individuals. If so, the social environment will impose frequency- and density-dependent selection components. In effect, the general environment imposes hard selection, whereas the social environment imposes soft selection on phenology. We examined hard and soft selection on seedling emergence time in an experiment on Brassica rapa. In monoculture (uniform social environment), early emergence results in up to a 1.5-fold increase in seed production. In bicultures (heterogeneous social environment), early-emerging plants capitalized on their head start, suppressing their late neighbors and increasing their fitness advantage to as much as 38-fold, depending on density. We devised a novel adaptation of contextual analysis to partition total selection (i.e., cov(omega, z)) into the hard and soft components. Hard and soft components had similar strengths at low density, whereas soft selection was five times stronger than hard at high density. PMID- 25929823 TI - Quality of care for pregnant women and newborns-the WHO vision. PMID- 25929824 TI - Determination of formaldehyde in hair creams by gas chromatography-mass spectrometry. PMID- 25929825 TI - 5-HTTLPR differentially predicts brain network responses to emotional faces. AB - The effects of the 5-HTTLPR polymorphism on neural responses to emotionally salient faces have been studied extensively, focusing on amygdala reactivity and amygdala-prefrontal interactions. Despite compelling evidence that emotional face paradigms engage a distributed network of brain regions involved in emotion, cognitive and visual processing, less is known about 5-HTTLPR effects on broader network responses. To address this, we evaluated 5-HTTLPR differences in the whole-brain response to an emotional faces paradigm including neutral, angry and fearful faces using functional magnetic resonance imaging in 76 healthy adults. We observed robust increased response to emotional faces in the amygdala, hippocampus, caudate, fusiform gyrus, superior temporal sulcus and lateral prefrontal and occipito-parietal cortices. We observed dissociation between 5 HTTLPR groups such that LA LA individuals had increased response to only angry faces, relative to neutral ones, but S' carriers had increased activity for both angry and fearful faces relative to neutral. Additionally, the response to angry faces was significantly greater in LA LA individuals compared to S' carriers and the response to fearful faces was significantly greater in S' carriers compared to LA LA individuals. These findings provide novel evidence for emotion-specific 5-HTTLPR effects on the response of a distributed set of brain regions including areas responsive to emotionally salient stimuli and critical components of the face-processing network. These findings provide additional insight into neurobiological mechanisms through which 5-HTTLPR genotype may affect personality and related risk for neuropsychiatric illness. PMID- 25929826 TI - Sleep-deprivation reduces NK cell number and function mediated by beta-adrenergic signalling. AB - Reduction of sleep time triggers a stress response, leading to augmented levels of glucocorticoids and adrenaline. These hormones regulate components of the innate immune system such as natural killer (NK) and NKT cells. In the present study, we sought to investigate whether and how stress hormones could alter the population and function of NK and NKT cells of mice submitted to different lengths of paradoxical sleep deprivation (PSD, from 24 to 72 h). Results showed that 72h of PSD decreased not only NK and NKT cell counts, but also their cytotoxic activity against B16F10 melanoma cells in vitro. Propranolol treatment during PSD reversed these effects, indicating a major inhibitory role of beta adrenergic receptors (beta-AR) on NK cells function. Moreover, both corticosterone plasma levels and expression of beta 2-adrenergic receptors (beta2 AR) in NK cells increased by 48 h of PSD. In vitro incubation of NK cells with dexamethasone augmented the level of beta2-AR in the cell surface, suggesting that glucocorticoids could induce beta2-AR expression. In summary, we propose that reduction of NK and NKT cell number and cytotoxic activity appears to be mediated by glucocorticoids-induced increased expression of beta2-AR in these cells. PMID- 25929827 TI - Modeling Bone Surface Morphology: A Fully Quantitative Method for Age-at-Death Estimation Using the Pubic Symphysis. AB - The pubic symphysis is widely used in age estimation for the adult skeleton. Standard practice requires the visual comparison of surface morphology against criteria representing predefined phases and the estimation of case-specific age from an age range associated with the chosen phase. Known problems of method and observer error necessitate alternative tools to quantify age-related change in pubic morphology. This paper presents an objective, fully quantitative method for estimating age-at-death from the skeleton, which exploits a variance-based score of surface complexity computed from vertices obtained from a scanner sampling the pubic symphysis. For laser scans from 41 modern American male skeletons, this method produces results that are significantly associated with known age-at-death (RMSE = 17.15 years). Chronological age is predicted, therefore, equally well, if not, better, with this robust, objective, and fully quantitative method than with prevailing phase-aging systems. This method contributes to forensic casework by responding to medico-legal expectations for evidence standards. PMID- 25929828 TI - Optimal indication of neoadjuvant chemoradiotherapy for pancreatic cancer. AB - PURPOSE: Much attention has been paid to preoperative treatment as a new strategy especially for borderline resectable pancreatic cancer (BRPC). The purpose of this study was to define the optimal indication of neoadjuvant chemoradiotherapy (NACRT) for pancreatic cancer. METHODS: We analyzed consecutive 184 patients who had undergone pancreatic resection in Nara Medical University Hospital. Resectability status was classified by NCCN guidelines. Full-dose gemcitabine with concurrent radiation was used as NACRT. We evaluated 85 patients treated with NACRT in comparison with 99 patients without NACRT as control. RESULTS: The regimen of NACRT was well tolerated and feasible. The perioperative outcomes were almost comparable. The postoperative complications were significantly less frequent in NACRT group than non-NACRT group. The pathological effects on both resectable and borderline tumors were favorable in NACRT group compared to non NACRT group. The overall survival of resectable pancreatic cancer was significantly better than that of BRPC regardless of whether the patients were treated with or without NACRT. The prognosis of the patients with NACRT in resectable tumors was significantly better than without, while there was no significant difference in BRPC. Furthermore, multivariate analysis of various factors in the patients with NACRT identified resectability status and completion of adjuvant chemotherapy as independent prognostic factors. CONCLUSIONS: NACRT did not improve the prognosis of the patients with BRPC, although it induced substantial pathological antitumor effect. In contrast, the prognosis of resectable pancreatic cancer treated with NACRT was favorable. Therefore, resectable pancreatic cancer may be good indication for multimodal treatment including NACRT. PMID- 25929829 TI - Poor medication adherence in diabetes: What's the problem? PMID- 25929830 TI - Analysis of phylogenetic and functional diverge in plant nine-cis epoxycarotenoid dioxygenase gene family. AB - During different environmental stress conditions, plant growth is regulated by the hormone abscisic acid (an apocarotenoid). In the biosynthesis of abscisic acid, the oxidative cleavage of cis-epoxycarotenoid catalyzed by 9-cis epoxycarotenoid dioxygenase (NCED) is the crucial step. The NCED genes were isolated in numerous plant species and those genes were phylogenetically investigated to understand the evolution of NCED genes in various plant lineages comprising lycophyte, gymnosperm, dicot and monocot. A total of 93 genes were obtained from 48 plant species to statistically estimate their sequence conservation and functional divergence. Selaginella moellendorffii appeared to be evolutionarily distinct from those of the angiosperms, insisting the substantial influence of natural selection pressure on NCED genes. Further, using exon-intron structure analysis, the gene structures of NCED were found to be conserved across some species. In addition, the substitution rate ratio of non-synonymous (Ka) versus synonymous (Ks) mutations using the Bayesian inference approach, depicted the critical amino acid residues for functional divergence. A significant functional divergence was found between some subgroups through the co-efficient of type-I functional divergence. Our results suggest that the evolution of NCED genes occurred by duplication, diversification and exon intron loss events. The site-specific profile and functional diverge analysis revealed NCED genes might facilitate the tissue-specific functional divergence in NCED sub-families, that could combat different environmental stress conditions aiding plant survival. PMID- 25929831 TI - A Next-Generation Sequencing of the NOTCH3 and HTRA1 Genes in CADASIL Patients. AB - Our purpose was to develop a next-generation sequencing procedure to search for NOTCH3 and HTRA1 mutations in patients with cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) features. A total of 70 patients were sequenced with semiconductor chips in an Ion Torrent Personal Genome Machine. The putative mutations were confirmed through Sanger sequencing of the corresponding patient. Six patients had a typical cysteine-involving NOTCH3 mutation. A new non-reported NOTCH3 variant (p.Pro2178Ser) was found in two patients. One patient was heterozygous for a non reported HTRA1 variant, likely non-pathogenic (p.Ser139Ala). We found a typical NOTCH3 mutation in 9 % of the patients. None of the patients had HTRA1 variants with likely pathogenic effect. The next-generation sequencing (NGS) procedure here described would facilitate the rapid and cost-effective screening of large cohorts of CADASIL patients. PMID- 25929832 TI - Neuroprotective Effects of Rutin in Streptozotocin-Induced Diabetic Rat Retina. AB - Diabetic retinopathy is widely recognized as a neurodegenerative disease of the eye. Increased oxidative stress has been considered the central factor in damaging neural retina in diabetes. Flavonoids, being powerful antioxidants, play protective roles in several oxidative stress-mediated neurodegenerative diseases. In this study, we analyzed the neuroprotective effects of a potential flavonoid, rutin, in the diabetic rat retina. Diabetes was induced in male Wistar rats by single injection of streptozotocin (65 mg/kg). In age-matched control (non diabetic) and 1 week of diabetic rats, rutin (100 mg/kg/day) was orally administered and continued for 5 weeks. In another group of diabetic rats, only saline was supplemented. After treatments, retinas from all the groups were isolated and analyzed for potential neurotrophic factors and apoptotic and oxidative stress markers using biochemical and immunoblotting techniques. Our results indicate that rutin possesses antidiabetic activity, as blood glucose level decreased and insulin level increased in diabetic rats. In the diabetic retina, rutin supplementation enhanced the reduced levels of brain-derived neurotrophic factor (BDNF), nerve growth factor (NGF), and glutathione (GSH) (P < 0.05), and reduced the level of thiobarbituric acid-reactive substances (TBARS) (P < 0.05). In addition, rutin treatment showed antiapoptotic activity by decreasing the level of caspase-3 and increasing the level of Bcl-2 in the diabetic retina. These results suggest the effectiveness of rutin in ameliorating the levels of neuroprotective factors in diabetic retina. Therefore, rutin might be a potential flavonoid that can prevent the retinal damage and subsequently the development of diabetic retinopathy. PMID- 25929833 TI - Parkinson's Disease Genetic Loci in Rapid Eye Movement Sleep Behavior Disorder. AB - Rapid eye movement (REM) sleep behavior disorder (RBD) is a prodromal condition for Parkinson's disease (PD) and other synucleinopathies, which often occurs many years before the onset of PD. We analyzed 261 RBD patients and 379 controls for nine PD-associated SNPs and examined their effects, first upon on RBD risk and second, on eventual progression to synucleinopathies in a prospective follow-up in a subset of patients. The SCARB2 rs6812193 (OR = 0.67, 95 % CI = 0.51-0.88, p = 0.004) and the MAPT rs12185268 (OR-0.43, 95 % CI-0.26-0.72, p = 0.001) were associated with RBD in different models. Kaplan-Meier survival analysis in a subset of RBD patients (n = 56), demonstrated that homozygous carriers of the USP25 rs2823357 SNP had progressed to synucleinopathies faster than others (log rank p = 0.003, Breslow p = 0.005, Tarone-Ware p = 0.004). As a proof-of-concept study, these results suggest that RBD may be associated with at least a subset of PD-associated genes, and demonstrate that combining genetic and prodromal clinical data may help identifying individuals that are either more or less susceptible to develop synucleinopathies. More studies are necessary to replicate these results, and identify more genetic factors affecting progression from RBD to synucleinopathies. PMID- 25929834 TI - FOXO1, FOXO3, AND FOXO4 are differently expressed during mouse oocyte maturation and preimplantation embryo development. AB - Preimplantation embryo development is affected by its environment. FoxO transcription factors are regulated by PI3K/Akt signaling pathway that essentially supports growth and development. FoxO transcription factors are at the interface of crucial cellular processes, orchestrating programs of gene expression that regulate apoptosis, cell-cycle arrest, oxidative stress resistance, DNA repair, glucose metabolism, and differentiation. In the presence of growth factors, FoxO transcription factors are localized in the cytoplasm, whereas under stress conditions they move to the nucleus and trigger transcriptional activities of their target genes. The aim of the present study is to investigate whether FoxO transcription factors are present during in vivo oocyte maturation and preimplantation embryo development. Presence and localizations of FoxO1, FoxO3 and FoxO4 proteins have been determined with immunofluorescence staining. Our results have confirmed that FoxO1, FoxO3 and FoxO4 proteins are differentially expressed in prophase I, metaphase I, metaphase II oocytes, as well as in fertilized oocyte, 2-cell embryo, 4-cell embryo, 8-cell embryo, morula, and blastocyst. FoxOs translocate to nucleus in embryos with developmental delay. Our findings indicate that FoxO transcription factors are present during both oocyte and embryo in vivo maturation and provide fundamental knowledge that FoxOs may regulate in vitro embryo development under stress conditions. PMID- 25929835 TI - Extensive metabolism and route-dependent pharmacokinetics of bisphenol A (BPA) in neonatal mice following oral or subcutaneous administration. AB - Orally administered bisphenol A (BPA) undergoes efficient first-pass metabolism to produce the inactive conjugates BPA-glucuronide (BPA-G) and BPA-sulfate (BPA S). This study was conducted to evaluate the pharmacokinetics of BPA, BPA-G and BPA-S in neonatal mice following the administration of a single oral or subcutaneous (SC) dose. This study consisted of 3 phases: (1) mass-balance phase in which effective dose delivery procedures for oral or SC administration of (3)H BPA to postnatal day three (PND3) mice were developed; (2) pharmacokinetic phase during which systemic exposure to total (3)H-BPA-derived radioactivity in female PND3 mice was established; and (3) metabolite profiling phase in which 50 female PND3 pups received either a single oral or SC dose of (3)H-BPA. Blood was collected from 5 pups/route/time-point at various times post-dosing, the blood plasma samples were pooled by group, and time-point and samples were profiled by HPLC with fraction collection. Fractions were analyzed for total radioactivity and data used to reconstruct radiochromatograms and to integrate individual peaks. The identity of the BPA, BPA-G, and BPA-S peaks was confirmed using authentic standards and LC-MS/MS analysis. The result of this study revealed that female PND3 mice have the capacity to metabolize BPA to BPA-G, BPA-S and other metabolites after both routes of administration. Systemic exposure to free BPA is route-dependent as the plasma concentrations were lower following oral administration compared to SC injection. PMID- 25929837 TI - Chronic Pain Patients' Impressions of an Emergency Department Opioid Prescribing Guideline Poster. AB - OBJECTIVE: To determine if an opioid prescribing guideline poster, meant to be posted in an emergency department (ED) triage area, would deter patients with chronic pain from seeking care. METHODS: We prospectively enrolled patients presenting to a chronic craniofacial pain clinic affiliated with an urban academic Level I trauma center. Patients were surveyed with a close-ended, structured questionnaire. Included patients were aged 18 and older with pain lasting 12 weeks or longer. Patients were shown a sample pain poster. The primary outcome was determination if such a poster would prevent the patient from staying to receive care in the ED. RESULTS: One hundred patients were surveyed. Most patients (77%) reported having been a patient in the ED in the past, and of these, 23% reported visiting the ED for worsening of chronic pain. After being shown the poster, 97% believed the recommendations in the poster were reasonable and 97% thought that the poster should be displayed in the ED. Seven patients (7%) reported that seeing the poster in the ED waiting room or triage area would intimidate them, and two patients within this group (2% of total sample) reported that it would prevent them from staying to get care. CONCLUSIONS: The vast majority of patients with chronic pain in this cohort believes that a pain guideline poster is reasonable and should be posted in the ED. However, a small percentage of patients reported that they would feel intimidated by such a poster and that it would prevent them from staying to get care, a result meant to inform hospitals and policy-makers deciding if such posters should be displayed. PMID- 25929836 TI - Developmental origins of neurotransmitter and transcriptome alterations in adult female zebrafish exposed to atrazine during embryogenesis. AB - Atrazine is an herbicide applied to agricultural crops and is indicated to be an endocrine disruptor. Atrazine is frequently found to contaminate potable water supplies above the maximum contaminant level of 3MUg/L as defined by the U.S. Environmental Protection Agency. The developmental origin of adult disease hypothesis suggests that toxicant exposure during development can increase the risk of certain diseases during adulthood. However, the molecular mechanisms underlying disease progression are still unknown. In this study, zebrafish embryos were exposed to 0, 0.3, 3, or 30MUg/L atrazine throughout embryogenesis. Larvae were then allowed to mature under normal laboratory conditions with no further chemical treatment until 7 days post fertilization (dpf) or adulthood and neurotransmitter analysis completed. No significant alterations in neurotransmitter levels was observed at 7dpf or in adult males, but a significant decrease in 5-hydroxyindoleacetic acid (5-HIAA) and serotonin turnover was seen in adult female brain tissue. Transcriptomic analysis was completed on adult female brain tissue to identify molecular pathways underlying the observed neurological alterations. Altered expression of 1928, 89, and 435 genes in the females exposed to 0.3, 3, or 30MUg/L atrazine during embryogenesis were identified, respectively. There was a high level of overlap between the biological processes and molecular pathways in which the altered genes were associated. Moreover, a subset of genes was down regulated throughout the serotonergic pathway. These results provide support of the developmental origins of neurological alterations observed in adult female zebrafish exposed to atrazine during embryogenesis. PMID- 25929838 TI - Effect of breast-feeding frequency on hyperbilirubinemia in breast-fed term neonate. AB - BACKGROUND: Hyperbilirubinemic neonates have significantly less bodyweight gain from nursery discharge to outpatient department (OPD) follow up. We tested the hypothesis that discharge instructions encouraging frequent breast-feeding given in the nursery would increase infant bodyweight gain and decrease the incidence of hyperbilirubinemia. METHODS: We enrolled consecutively live-born neonates who were discharged from the nursery and who received OPD follow up within the first 2 weeks of birth in 2011. The nursing staff discussed the discharge instructions with the parents at the time of nursery discharge. Parents were asked to fill in a nursing information form to record the frequency of breast-feeding and diaper change per day. RESULTS: Parents of 98 breast-fed term neonates provided complete nursing information forms. These 98 neonates were classified into two groups according to breast-feeding frequency, namely <8 times/day (63 neonates) and >=8 times/day (35 neonates). A significant positive correlation between breast feeding frequency and diaper change frequency per day indicated that the data were highly reliable. The gestational age, Apgar score, birthweight, and bodyweight at nursery discharge and at OPD were similar between the two groups. Neonates who were breast-fed >=8 times/day had a significantly lower incidence of hyperbilirubinemia. CONCLUSIONS: Nursery discharge instructions that encouraged mothers to breast-feed their newborns frequently decreased the rate of hyperbilirubinemia in exclusively breast-fed term neonates. PMID- 25929839 TI - Broad Complex Tachycardia in a Structurally Normal Heart. PMID- 25929841 TI - Reply. PMID- 25929840 TI - A pilot randomized controlled trial of a stepped care intervention package for depression in primary care in Nigeria. AB - BACKGROUND: Depression is common in primary care and is often unrecognized and untreated. Studies are needed to demonstrate the feasibility of implementing evidence-based depression care provided by primary health care workers (PHCWs) in sub-Saharan Africa. We carried out a pilot two-parallel arm cluster randomized controlled trial of a package of care for depression in primary care. METHODS: Six primary health care centers (PHCC) in two Local Government Areas of Oyo State, South West Nigeria were randomized into 3 intervention and 3 control clinics. Three PHCWs were selected for training from each of the participating clinics. The PHCWs from the intervention clinics were trained to deliver a manualized multicomponent stepped care intervention package for depression consisting of psychoeducation, activity scheduling, problem solving treatment and medication for severe depression. Providers from the control clinics delivered care as usual, enhanced by a refresher training on depression diagnosis and management. Outcome measures Patient's Health Questionnaire (PHQ-9), WHO quality of Life instrument (WHOQOL-Bref) and the WHO disability assessment schedule (WHODAS) were administered in the participants' home at baseline, 3 and 6 months. RESULTS: About 98% of the consecutive attendees to the clinics agreed to have the screening interview. Of those screened, 284 (22.7%) were positive (PHQ-9 score >= 8) and 234 gave consent for inclusion in the study: 165 from intervention and 69 from control clinics. The rates of eligible and consenting participants were similar in the control and intervention arms. In all 85.9% (92.8% in intervention and 83% in control) of the participants were successfully administered outcome assessments at 6 months. The PHCWs had little difficulty in delivering the intervention package. At 6 months follow up, depression symptoms had improved in 73.0% from the intervention arm compared to 51.6% control. Compared to the mean scores at baseline, there was improvement in the mean scores on all outcome measures in both arms at six months. CONCLUSION: The results provide support for the feasibility of conducting a fully-powered randomized study in this setting and suggest that the instruments used may have the potential to detect differences between the arms. TRIAL REGISTRATION NUMBER: ISRCTN46754188 (ISRTCN registry at isrtcn.com); registered 23 September 2013, details of the pilot study added 12/02/2015. PMID- 25929842 TI - Protein identification and quantification from riverbank grape, Vitis riparia: Comparing SDS-PAGE and FASP-GPF techniques for shotgun proteomic analysis. AB - Protein sample preparation optimisation is critical for establishing reproducible high throughput proteomic analysis. In this study, two different fractionation sample preparation techniques (in-gel digestion and in-solution digestion) for shotgun proteomics were used to quantitatively compare proteins identified in Vitis riparia leaf samples. The total number of proteins and peptides identified were compared between filter aided sample preparation (FASP) coupled with gas phase fractionation (GPF) and SDS-PAGE methods. There was a 24% increase in the total number of reproducibly identified proteins when FASP-GPF was used. FASP-GPF is more reproducible, less expensive and a better method than SDS-PAGE for shotgun proteomics of grapevine samples as it significantly increases protein identification across biological replicates. Total peptide and protein information from the two fractionation techniques is available in PRIDE with the identifier PXD001399 (http://proteomecentral.proteomexchange.org/dataset/PXD001399). PMID- 25929843 TI - Dose-level response rates of mTor inhibition in tuberous sclerosis complex (TSC) related subependymal giant cell astrocytoma (SEGA). AB - BACKGROUND: Tuberous sclerosis complex (TSC) is an autosomal dominant multisystem disease usually diagnosed in childhood. Subependymal giant cell astrocytomas (SEGA) are benign brain lesions occurring in up to 20% of patients with TSC. Treatment with mTOR inhibitors has been proven effective in inducing SEGA shrinkage, but discontinuation results in re-growth. Evidence suggests that mTOR inhibition seems a disease-modifying treatment for TSC beyond inducing SEGA shrinkage; however concerns remain regarding negative long-term effects. METHODS: Through this retrospective case series, an attempt was made to determine the minimal mTOR inhibitor dose needed to maintain radiological response of SEGA in six pediatric patients treated at The Hospital for Sick Children since 2007. This study reviews medication doses and blood levels as related to SEGA size on MRIs at 3-month intervals. Blood levels were monitored every 3 months and 2 weeks after dose adjustment. Total dose reduction by 25% was considered after SEGA shrinkage was maintained on two consecutive MRIs. RESULTS: All patients demonstrated SEGA shrinkage greater than 50% when treated with mTOR inhibition at therapeutic doses (4-5 mg/m(2)). When sirolimus doses were weaned in two patients by 50%, SEGAs regrew by 84% and 32%. In two patients, responses have been maintained with 30% decrease in sirolimus dose. One patient underwent SEGA resection and one remains on therapeutic dose. CONCLUSIONS: Therapeutic dose of mTOR inhibitor is effective in shrinking TSC-related SEGAs. Doses less than 2.5 mg/m(2) were insufficient to maintain response in this limited series. PMID- 25929849 TI - NCI Posts New "Provocative Questions". AB - The NCI has earmarked another $40 million over the next 2 years for its Provocative Questions Initiative, aimed at funding neglected or understudied areas of cancer research that relate to gaps in current knowledge or address unresolved questions. PMID- 25929848 TI - Next-Generation Sequencing of Stage IV Squamous Cell Lung Cancers Reveals an Association of PI3K Aberrations and Evidence of Clonal Heterogeneity in Patients with Brain Metastases. AB - Large-scale genomic characterization of squamous cell lung cancers (SQCLC) has revealed several putative oncogenic drivers. There are, however, little data to suggest that these alterations have clinical relevance. We performed comprehensive genomic profiling (including next-generation sequencing) of 79 stage IV SQCLCs and analyzed differences in the clinical characteristics of two major SQCLC subtypes: FGFR1 amplified and PI3K aberrant. Patients with PI3K aberrant tumors had aggressive disease marked by worse survival (median overall survival, 8.6 vs. 19.1 months, P < 0.001), higher metastatic burden (>3 organs, 18% vs. 3%, P = 0.025), and greater incidence of brain metastases (27% vs. 0% in others, P < 0.001). We performed whole-exome and RNA sequencing on paired brain metastases and primary lung cancers to elucidate the metastatic process to brain. SQCLC primaries that gave rise to brain metastases exhibited truncal PTEN loss. SQCLC brain metastases exhibited a high degree of genetic heterogeneity and evidence of clonal differences between their primary sites. SIGNIFICANCE: We performed next-generation sequencing of metastatic SQCLCs and primary lung-brain metastasis pairs, identifying PI3K-aberrant tumors as an aggressive subset associated with brain metastases. We identified genetic heterogeneity between lung primaries-brain metastases as well as clonal populations that may highlight alterations important in the metastatic process. PMID- 25929850 TI - Tumor-Only Sequencing Has Limitations. PMID- 25929851 TI - Compensatory Structural and Functional Adaptation after Radical Nephrectomy for Renal Cell Carcinoma According to Preoperative Stage of Chronic Kidney Disease. AB - PURPOSE: We investigated structural hypertrophy and functional hyperfiltration as compensatory adaptations after radical nephrectomy in patients with renal cell carcinoma according to the preoperative chronic kidney disease stage. MATERIALS AND METHODS: We retrospectively identified 543 patients who underwent radical nephrectomy for renal cell carcinoma between 1997 and 2012. Patients were classified according to preoperative glomerular filtration rate as no chronic kidney disease--glomerular filtration rate 90 ml/minute/1.73 m(2) or greater (230, 42.4%), chronic kidney disease stage II--glomerular filtration rate 60 to less than 90 ml/minute/1.73 m(2) (227, 41.8%) and chronic kidney disease stage III--glomerular filtration rate 30 to less than 60 ml/minute/1.73 m(2) (86, 15.8%). Computerized tomography performed within 2 months before surgery and 1 year after surgery was used to assess functional renal volume for measuring the degree of hypertrophy of the remnant kidney, and the preoperative and postoperative glomerular filtration rate per unit volume of functional renal volume was used to calculate the degree of hyperfiltration. RESULTS: Among all patients (mean age 56.0 years) mean preoperative glomerular filtration rate, functional renal volume and glomerular filtration rate/functional renal volume were 83.2 ml/minute/1.73 m(2), 340.6 cm(3) and 0.25 ml/minute/1.73 m(2)/cm(3), respectively. The percent reduction in glomerular filtration rate was statistically significant according to chronic kidney disease stage (no chronic kidney disease 31.2% vs stage II 26.5% vs stage III 12.8%, p <0.001). However, the degree of hypertrophic functional renal volume in the remnant kidney was not statistically significant (no chronic kidney disease 18.5% vs stage II 17.3% vs stage III 16.5%, p=0.250). The change in glomerular filtration rate/functional renal volume was statistically significant (no chronic kidney disease 18.5% vs stage II 20.1% vs stage III 45.9%, p <0.001). Factors that increased glomerular filtration rate/functional renal volume above the mean value were body mass index (p=0.012), diabetes mellitus (p=0.023), hypertension (p=0.015) and chronic kidney disease stage (p <0.001). CONCLUSIONS: Patients with a lower preoperative glomerular filtration rate had a smaller reduction in postoperative renal function than those with a higher preoperative glomerular filtration rate due to greater degrees of functional hyperfiltration. PMID- 25929852 TI - THE ENDOPARASITOID Campoletis chlorideae INDUCES A HEMOLYTIC FACTOR IN THE HERBIVOROUS INSECT Helicoverpa armigera. AB - Although lysis of invading organisms is a major innate form of immunity used by invertebrates, it remains unclear whether herbivorous insects have hemolysin or not. To address this general question, we tested the hemolytic (HL) activity of the hemolymph and tissue extracts from various stages of the polyphagous insect Helicoverpa armigera (Hubner) against the erythrocytes from chicken, duck, and rabbit. An HL activity was identified in the hemolymph of H. armigera larvae. Further studies demonstrated that the HL activity is proteinaceous as it was precipitable by deproteinizing agents. Hemolysins were found in Helicoverpa egg, larva, pupa, and adult, but the activity was higher in feeding larvae than in molting or newly molted larvae. Hemolysins were distributed among a variety of larval tissues including salivary gland, fat body, epidermis, midgut, or testes, but the highest activity was found in salivary gland and fat body. Relative to nonparasitized larvae, parasitization of H. armigera larvae by the endoparasitoid Campoletis chlorideae Uchida induced a 3.4-fold increase in the HL activity in the plasma of parasitized host at day two postparasitization. The present study shows the presence of a parasitoid inducible HL factor in the parasitized insect. The HL activity increased significantly in H. armigera larvae at 12 and 24 h postinjection with Escherichia coli. We infer the HL factor(s) is inducible or due to de novo synthesis, which means that the HL factor(s) is associated with insect immune response by inhibiting or clearance of invading organisms. PMID- 25929853 TI - Pharmacometabonomics in humans: a new tool for personalized medicine. AB - Pharmacogenomics is now over 50 years old and has had some impact in clinical practice, through its use to select patient subgroups who will enjoy efficacy without side effects when treated with certain drugs. However, pharmacogenomics, has had less impact than initially predicted. One reason for this is that many diseases, and the way in which the patients respond to drug treatments, have both genetic and environmental elements. Pure genomics is almost blind to the environmental elements. A new methodology has emerged, termed pharmacometabonomics that is concerned with the prediction of drug effects through the analysis of predose, biofluid metabolite profiles, which reflect both genetic and environmental influences on human physiology. In this review we will cover what pharmacometabonomics is, how it works, what applications exist and what the future might hold in this exciting new area. PMID- 25929854 TI - Population pharmacogenetics of Ibero-Latinoamerican populations (MESTIFAR 2014). AB - MESTIFAR 2014 28-30 November 2014, Panama City, Panama The CEIBA consortium was created within the Ibero-American network of Pharmacogenetics (RIBEF) to study population pharmacogenetics. The current status of these initiatives and results of the MESTIFAR project were analyzed in Panama, 28-30 November 2014. The MESTIFAR project focused on studying CYPs genetic polymorphisms in populations of different ethnic origin. So far, more than 6000 healthy volunteers have been evaluated, making this one of the largest population pharmacogenomic studies worldwide. Three symposia were organized, 'Pharmacogenetics of indigenous and mestizos populations and its clinical implications', 'Methodological innovation in pharmacogenetics and its application in health', and 'General discussion and concluding remarks', about mechanisms and proposals for training, diffusion of pharmacogenetics for Spanish- and Portuguese-speaking health professionals, and 'bench to bedside' pilot projects. PMID- 25929855 TI - GenoChip CYP2D6 macroarray as a method to genotype for CYP2D6 variants: results of a validation study in a Caucasian population. AB - AIM: The aim of this study was to investigate the concordance between the novel GenoChip CYP2D6 macroarray and the AmpliChip, which is considered the gold standard in CYP2D6 genotyping. MATERIALS & METHODS: Germline DNA of 200 patients was genotyped with both the AmpliChip and the GenoChip CYP2D6 macroarray. RESULTS: One hundred and ninety-eight samples (99%) showed concordance. In two discordant samples the AmpliChip identified a *41 allele while the GenoChip CYP2D6 macroarray did not. Sanger sequencing showed that the 2988G>A mutation and thus the *41 allele was not present in both samples. CONCLUSION: We conclude that that the GenoChip CYP2D6 macroarray is a valid method for detecting genetic variants of CYP2D6 in a Caucasian population. Original submitted 10 November 2014; Revision submitted 23 February 2015. PMID- 25929856 TI - Generating hydrated electrons through photoredox catalysis with 9-anthrolate. AB - Hydrated electrons are among the strongest reductants known. Adding the ascorbate dianion as a sacrificial donor turns the photoionization of 9-anthrolate in water into a catalytic cycle for their in situ production with near-UV light (355 nm). The photoionization step is exclusively biphotonic and occurs via the first excited singlet state of the catalyst. Neither triplet formation nor any photochemical side reactions interfere. The ionization by-product, the anthroxy radical, is inert towards the ascorbate monoanion but is rapidly reduced by the dianion, thereby recovering the starting catalyst. A sufficient amount of the sacrificial donor makes that reduction quantitative and leads to a sustainable generation of hydrated electrons, as is evidenced by electron yields greatly surpassing the catalyst concentration. Control experiments established that the superincrease is indeed due to the catalyst regeneration and not to an ionization of other species involved in the reaction. PMID- 25929857 TI - Effect of etodolac hydrazone, a new compound synthesised from etodolac, on spermatozoon quality, testicular lipid peroxidation, apoptosis and spermatozoon DNA integrity. AB - The aim of this study was to investigate the effect of etodolac hydrazone (EH), a new compound synthesised from etodolac, on spermatozoon quality, testicular lipid peroxidation, apoptosis and spermatozoon DNA integrity in rats. Group 1 (n = 8) received 1 ml dimethyl sulfoxide (DMSO) daily (Control); group 2 (n = 8) was treated with 5 mg kg(-1) day(-1) EH, dissolved in 1 ml DMSO (EH-5); and group 3 (n = 8) was treated with 10 mg kg(-1) day(-1) EH, dissolved in 1 ml DMSO (EH 10). All administrations were performed by gavage and maintained for 8 weeks. Both doses of EH administration caused significant decreases in absolute and relative weights of testis, whole epididymis, right cauda epididymis, and spermatozoon motility, spermatozoon count in comparison with the control group. Only 10 mg kg(-1) day(-1) EH administration caused significant decreases in absolute and relative weights of seminal vesicles and serum testosterone level, and significant increases in testicular lipid peroxidation level, and numbers of TUNEL+ apoptotic germ cells and spermatozoa with damaged DNA along with some histopathological damages when compared to the control group. However, body and ventral prostate weight, and testicular antioxidant markers (glutathione, glutathione-peroxidase and catalase), were unaffected significantly by both doses of EH administration. In conclusion, two different doses of EH, in particular its high dose, damage to testicular spermatogenic cells and spermatozoon DNA and, it decreases spermatozoon motility, count and testosterone level in healthy rats. PMID- 25929858 TI - Live imaging the phagocytic activity of inner ear supporting cells in response to hair cell death. AB - Hearing loss and balance disorders affect millions of people worldwide. Sensory transduction in the inner ear requires both mechanosensory hair cells (HCs) and surrounding glia-like supporting cells (SCs). HCs are susceptible to death from aging, noise overexposure, and treatment with therapeutic drugs that have ototoxic side effects; these ototoxic drugs include the aminoglycoside antibiotics and the antineoplastic drug cisplatin. Although both classes of drugs are known to kill HCs, their effects on SCs are less well understood. Recent data indicate that SCs sense and respond to HC stress, and that their responses can influence HC death, survival, and phagocytosis. These responses to HC stress and death are critical to the health of the inner ear. Here we have used live confocal imaging of the adult mouse utricle, to examine the SC responses to HC death caused by aminoglycosides or cisplatin. Our data indicate that when HCs are killed by aminoglycosides, SCs efficiently remove HC corpses from the sensory epithelium in a process that includes constricting the apical portion of the HC after loss of membrane integrity. SCs then form a phagosome, which can completely engulf the remaining HC body, a phenomenon not previously reported in mammals. In contrast, cisplatin treatment results in accumulation of dead HCs in the sensory epithelium, accompanied by an increase in SC death. The surviving SCs constrict fewer HCs and display impaired phagocytosis. These data are supported by in vivo experiments, in which cochlear SCs show reduced capacity for scar formation in cisplatin-treated mice compared with those treated with aminoglycosides. Together, these data point to a broader defect in the ability of the cisplatin treated SCs, to preserve tissue health in the mature mammalian inner ear. PMID- 25929860 TI - Editorial: perspectives on strategies for overcoming cancer therapy resistance. PMID- 25929859 TI - DRAM-3 modulates autophagy and promotes cell survival in the absence of glucose. AB - Macroautophagy is a membrane-trafficking process that delivers cytoplasmic constituents to lysosomes for degradation. The process operates under basal conditions as a mechanism to turnover damaged or misfolded proteins and organelles. As a result, it has a major role in preserving cellular integrity and viability. In addition to this basal function, macroautophagy can also be modulated in response to various forms of cellular stress, and the rate and cargoes of macroautophagy can be tailored to facilitate appropriate cellular responses in particular situations. The macroautophagy machinery is regulated by a group of evolutionarily conserved autophagy-related (ATG) proteins and by several other autophagy regulators, which either have tissue-restricted expression or operate in specific contexts. We report here the characterization of a novel autophagy regulator that we have termed DRAM-3 due to its significant homology to damage-regulated autophagy modulator (DRAM-1). DRAM-3 is expressed in a broad spectrum of normal tissues and tumor cells, but different from DRAM-1, DRAM-3 is not induced by p53 or DNA-damaging agents. Immunofluorescence studies revealed that DRAM-3 localizes to lysosomes/autolysosomes, endosomes and the plasma membrane, but not the endoplasmic reticulum, phagophores, autophagosomes or Golgi, indicating significant overlap with DRAM-1 localization and with organelles associated with macroautophagy. In this regard, we further proceed to show that DRAM-3 expression causes accumulation of autophagosomes under basal conditions and enhances autophagic flux. Reciprocally, CRISPR/Cas9-mediated disruption of DRAM-3 impairs autophagic flux confirming that DRAM-3 is a modulator of macroautophagy. As macroautophagy can be cytoprotective under starvation conditions, we also tested whether DRAM-3 could promote survival on nutrient deprivation. This revealed that DRAM-3 can repress cell death and promote long-term clonogenic survival of cells grown in the absence of glucose. Interestingly, however, this effect is macroautophagy-independent. In summary, these findings constitute the primary characterization of DRAM-3 as a modulator of both macroautophagy and cell survival under starvation conditions. PMID- 25929861 TI - Eliminating ovarian cancer stem cells: a potential therapeutic target for ovarian cancer chemoresistance. AB - Tumor recurrence followed by chemoresistance is a major cause of the poor survival rates for ovarian cancer. Despite advances in ovarian cancer chemotherapies and increased knowledge of the characteristics of ovarian cancer, chemoresistance is still an enormous clinical challenge. Current research suggests that ovarian cancer stem cells (OCSCs) might be involved in the occurrence of chemoresistance in ovarian cancer. In this review, we focus on the relationship of ovarian cancer stem cells with drug-resistant ovarian cancer phenotypes. We also discuss the current knowledge regarding ovarian cancer stem cell-based therapeutic strategies as attempts to overcome chemoresistance, the largest obstacle for successful treatment. Finally, we discuss methods for improving the treatment outcomes of ovarian cancer patients with chemoresistance. PMID- 25929862 TI - The Accomplices of NF-kappaB Lead to Radioresistance. AB - Ionizing radiation (IR) plays an important role in the treatment of epithelial tumors, such as lung and prostate cancer, by wounding and killing cancer cells. However, IR also activates sophisticated anti-apoptotic transcriptional factors such that cancer cells fail to repair DNA damage and obtain resistance to apoptosis under conditions of radiotherapy. Among these transcription factors, the transcription factor nuclear factor kappa B (NF-kappaB) is recognized as a key feature for protecting cells from apoptosis in most cell types. Moreover, the induction of radioresistance is mediated by several genes that are regulated by NF- kappaB. The primary purpose of this review is to introduce the studies of the signaling mechanisms of IR in NF-kappaB activation, such as ROS/NF-kappaB, ATM or DNA-PK/MAPKK/ p90rsk, PI3K/AKT/IKK and k-ras/c-raf/ MEKK/ NF-kappaB pathways. Moreover, we describe how the expression of the target genes (e.g., XIAP, A20, FLIP, Bcl-xL) are induced by NF-kappaB to regulate the activation of survival signaling pathways and to inhibit apoptotic signaling pathways. In addition, IR activates NF-kappaB to express cell cycle-specific genes, for example cyclin D1, which is associated with reinforcing radioresistance. We exhibit the signaling pathways that are induced by IR stimulation of NF-kappaB and illustrate the molecular mechanisms of radioresistance. PMID- 25929863 TI - The LPS-Pretreated MSCs Supply a Positive Microenvironment for Tumor Cell Proliferation and Clone Formation. AB - In this study, the culture supernatant of LPS-treated MSCs was collected and served as a conditioned medium (CM). It was found that the LPS-CM promoted the proliferation of tumor cells (SKBR3, MDA-MB-231, A549, 95D and HepG2). In addition, the colony formation ability was also enhanced by LPS-CM incubation. The inflammatory cytokines, IL-6 and IL-8, were demonstrated to be up-regulated in the LPS-CM, which we supposed to function in the tumor-growth promotion in vitro. PMID- 25929864 TI - Elevated microRNA-23a Expression Enhances the Chemoresistance of Colorectal Cancer Cells with Microsatellite Instability to 5-Fluorouracil by Directly Targeting ABCF1. AB - Colorectal cancer (CRC) is one of the most common tumor types worldwide. A frequent subtype of CRC is defined by a deficiency in the mismatch repair (MMR) pathway, constantly found in combination with microsatellite instability (MSI), which not only contributes to the pathogenesis of a large proportion of CRC, but also controls the response to multiple drugs used to treat CRCs. The most commonly used chemotherapeutic agent for CRC is 5-fluorouracil (5-FU). However, CRC with MSI frequently acquires 5-FU resistance, and the exact mechanism underlying how CRC cells acquire chemoresistance to 5-FU remains incompletely understood. Recently, emerging evidence has demonstrated that microRNAs (miRNAs) are key players in multidrug resistance. In this study, we aimed to characterize the expression profiles and functions of miRNAs in 5-FU-resistant CRC with MSI. We found that miR-23a was significantly elevated in MSI CRC cells and tissues compared to microsatellite stability (MSS) CRC cells and tissues. Ectopic expression of miR-23a increased the viability and survival of MSS CRC cells. Inversely, downregulation of miR-23a reduced viability in and promoted cell apoptosis in MSI CRC cells treated with 5-FU. Moreover, we demonstrated that ABCF1 is a direct target of miR-23a. Additionally, the expression of miR-23a was inversely correlated with the expression of ABCF1 in CRC tissues. Interestingly, repressing ABCF1 expression by either miR-23a overexpression or siABCF1 led to recovery of 5-FU sensitivity in MSI CRC cells. These data demonstrated that miR 23a enhances 5-FU resistance in MSI CRC cells through targeting ABCF1 and thus provided important implications for therapeutic approaches aiming to overcome MSI CRC resistance to 5-FU. PMID- 25929865 TI - miRNA-497 Enhances the Sensitivity of Colorectal Cancer Cells to Neoadjuvant Chemotherapeutic Drug. AB - The neoadjuvant therapy has significantly improved the outcome of locally advanced resectable T3 rectal cancer patients. Actually, only a portion of patients show sensitivity to the preoperative chemoradiation and benefit markedly from this treatment. However, biomarkers for predicting neoadjuvant therapy sensitivity remain unclear. In this study, through screening of a series of microRNAs dysregulated in colorectal cancer patients, we observed that miRNA-497 expression was downregulated in tumor tissues of neoadjuvant chemotherapy responders as compared to that in non-responders. MiRNA-497 level was correlated with chemotherapeutic drug 5-fluorouracil (5-FU) sensitivity in colorectal cancer cells. Functional studies showed that restoration of miRNA-497 expression inhibited cell viability and enhanced 5-FU sensitivity in SW480 cells. By contrast, miRNA inhibitors-mediated silence of miRNA-497 promoted cell growth and reduced the sensitivity of LoVo cells to 5-FU. In addition, miRNA-497 targeted Smurf1 in CRC cells and the Smurf1 expression level was dramatically increased in neoadjuvant therapy-resistant patients compared with treatment-sensitive patients. These results indicate that down-regulation of miRNA-497 in colorectal cancer may contribute to the resistance of CRC cells to 5-FU treatment. Thus, miRNA-497 has the potential to be a novel biomarker for predicting the neoadjuvant chemotherapy sensitivity in CRC patients. PMID- 25929866 TI - Silencing GPX3 Expression Promotes Tumor Metastasis in Human Thyroid Cancer. AB - The incidence of thyroid cancer has been increased in the past few decades. GPX3 gene is located in 5q23, which is frequently deleted in prostate cancer. Methylation of GPX3 was found frequently in prostate, esophagus, gastric and breast cancers. To detect the expression and analyze the mechanism of GPX3 in human thyroid cancer, 94 cases of primary papillary thyroid cancer (PTC) which coupled with adjacent tissue samples, as well as 15 cases of normal thyroid epithelial tissue samples were collected. Methylation specific PCR (MSP), immunohistochemistry staining, transwell assay and siRNA knockdown technique were employed. GPX3 was methylated in 46.8% (44 of 94) of PTC and methylation of GPX3 was associated with tumor size (P<0.05) and regional lymph node metastasis (P<0.01) significantly. Consistent expression of GPX3 was observed in the adjacent tissue samples and absent/reduced expression of GPX3 was found frequently in primary PTC samples. In 44 cases of methylated cancer samples, loss of/ reduced expression was found in 36 cases and expression of GPX3 was found in 8 cases. In 50 cases of unmethylated PTC samples, loss of/ reduced expression was found in 31 cases and expression of GPX3 was found in 19 cases. Lost/ reduced expression of GPX3 is associated with promoter region hypermethylation (P<0.05). Wnt signaling was inhibited by GPX3 in TPC-1 and FTC133 cells. In conclusion, GPX3 is frequently methylated in human papillary thyroid cancer and the expression of GPX3 was regulated by promoter region methylation. Methylation of GPX3 is related to tumor size and lymph node metastasis. Metastasis of thyroid cancer was suppressed by GPX3 through inhibition Wnt/beta-catenin signaling. PMID- 25929867 TI - Methylation of ZNF331 Promotes Cell Invasion and Migration in Human Esophageal Cancer. AB - Loss of zinc-finger protein 331 (ZNF331) expression was reported in gastric cancer. To explore the regulation of expression and the function of ZNF331 in human esophageal cancer, 11 esophageal cancer cell lines, 7 cases of normal esophageal mucosa and 99 cases of primary esophageal squamous cancer were employed. Methylation specific PCR, semi-quantitive reverse transcriptase PCR, immunohistochemistry, western blot, flow cytometry, wound healing and transwell assay were used. The expression of ZNF331 was silenced by promoter region hypermethylation in 8 of 11 esophageal cancer cell lines. 56.5% (56/99) of primary human esophageal cancer was methylated, but no methylation was found in 7 cases of normal esophageal mucosa. The expression of ZNF331 was reduced in human primary esophageal cancer and reduced expression was associated with promoter region methylation. No significant change was found in cell viability (P>0.05) and cell phase distribution (P>0.05) before and after re-expression in KYSE150 and KYSE410 cells. The migration was suppressed by ZNF331 apparently under wound healing experiment. Re-expression of ZNF331 expression significantly suppressed cell migration and invasion (P<0.05). In conclusion, ZNF331 is frequently methylated in human esophageal cancer. The expression of ZNF331 is regulated by promoter region methylation. ZNF331 may suppress esophageal cancer metastasis. PMID- 25929868 TI - Low Dose Decitabine Combined with Taxol and Platinum Chemotherapy to Treat Refractory/Recurrent Ovarian Cancer: An Open-Label, Single-Arm, Phase I/II Study. AB - PURPOSE: Previous research has proposed that the hypomethylating agent decitabine can sensitize ovarian cancer cells to chemical agents. In this open-label, phase I/II clinical study, we analyzed the toxicity and efficacy of low dose decitabine combined with taxol and platinum chemotherapy in treatment of refractory and recurrent ovarian cancer. METHODS: Decitabine was administered intravenously at 7 mg/m(2) for 30 minutes over five consecutive days and followed by reduced dose taxol and platinum chemotherapy treatment (TC) every 28 days for at least four cycles. Adverse events (AEs) were graded according to the Common Terminology Criteria for AEs (NCI-CTCAE), and efficacy was assessed using the Response Evaluation Criteria in Solid Tumors assessment (RECIST). RESULTS: Twenty-one patients diagnosed with relapsed/refractory ovarian cancer were initially enrolled in this study, and 17 patients were able to be evaluated. The combination of low dose decitabine and TC was well-tolerated. The most common adverse effects were nausea (77.8%) and neutropenia (66.7%), and adverse events greater than Grade 4 were not observed. The clinical benefit rate (CBR) was 70.6% (12/17), and the partial response (PR) and stable disease (SD) rates were 17.6% (3/17) and 52.9% (9/17), respectively. A significant decrease in serum CA125 levels was observed in many of the responsive cases even after completing the first treatment cycle. CONCLUSION: Low dose decitabine combined with taxol and platinum was well-tolerated and suitable for treating refractory/refractory ovarian cancer. The change in CA125 levels might be a potential predictor for patient clinical response. The efficacy of low dose decitabine for treatment of ovarian cancer requires more volunteers for further investigation. PMID- 25929869 TI - A review of fish lectins. AB - Lectins have been reported from various tissues of a diversity of fish species including Japanese eel, conger eel, electric eel, bighead carp, gibel carp, grass carp, Arabian Gulf catfish, channel catfish, blue catfish, catfish, pike perch, perch, powan, zebrafish, toxic moray, cobia fish, steelhead trout, Japanese trout, Atlantic salmon, chinook salmon, olive rainbow smelt, rainbow smelt, white spotted charr, tilapia, blue gourami, ayu, Potca fish, Spanish mackerel, gilt head bream, tench, roach, rudd, common skate, and sea lamprey. The tissues from which the lectins were isolated comprise gills, eggs, electric organ, stomach, intestine, and liver. Lectins have also been isolated from skin, mucus serum, and plasma. The lectins differ in molecular weight, number of subunits, glycosylation, sugar binding specificity and amino acid sequence. Their activities include antimicrobial, antitumor, immunoregulatory and a role in development. PMID- 25929870 TI - Beta-Sheet-Forming, Self-Assembled Peptide Nanomaterials towards Optical, Energy, and Healthcare Applications. AB - Peptide self-assembly is an attractive route for the synthesis of intricate organic nanostructures that possess remarkable structural variety and biocompatibility. Recent studies on peptide-based, self-assembled materials have expanded beyond the construction of high-order architectures; they are now reporting new functional materials that have application in the emerging fields such as artificial photosynthesis and rechargeable batteries. Nevertheless, there have been few reviews particularly concentrating on such versatile, emerging applications. Herein, recent advances in the synthesis of self-assembled peptide nanomaterials (e.g., cross beta-sheet-based amyloid nanostructures, peptide amphiphiles) are selectively reviewed and their new applications in diverse, interdisciplinary fields are described, ranging from optics and energy storage/conversion to healthcare. The applications of peptide-based self assembled materials in unconventional fields are also highlighted, such as photoluminescent peptide nanostructures, artificial photosynthetic peptide nanomaterials, and lithium-ion battery components. The relation of such functional materials to the rapidly progressing biomedical applications of peptide self-assembly, which include biosensors/chips and regenerative medicine, are discussed. The combination of strategies shown in these applications would further promote the discovery of novel, functional, small materials. PMID- 25929871 TI - Accumulation of polycyclic aromatic hydrocarbons (PAHs) and oxygenated PAHs (OPAHs) in organic and mineral soil horizons from four U.S. remote forests. AB - We characterized distributions of 23 polycyclic aromatic hydrocarbons (Sigma23PAH) and nine oxygenated PAHs (Sigma9OPAH) in four remote forests. We observed highest Sigma23PAH and Sigma9OPAH concentrations in a coniferous forest in Florida, particularly in organic layers which we attributed to frequent prescribed burning. Across sites, Sigma23PAH and Sigma9OPAH concentrations strongly increased from surface to humidified organic layers (+1626%) where concentrations reached up to 584 ng g(-1). Concentrations in mineral soils were lower (average 37 +/- 8 ng g(-1)); but when standardized per unit organic carbon (OC), PAH/OC and OPAH/OC ratios were at or above levels observed in organic layers. Accumulation in litter and soils (i.e., enrichment factors with depth) negatively correlated with octanol-water partition coefficients (Kow) and therefore was linked to water solubility of compounds. Concentrations of Sigma9OPAHs ranged from 6 +/- 6 ng g(-1) to 39 +/- 25 ng g(-1) in organic layers, and from 3 +/- 1 ng g(-1) to 11 +/- 3 ng g(-1) in mineral soils, and were significantly and positively correlated to Sigma23PAHs concentrations (r(2) of 0.90) across sites and horizons. While OPAH concentrations generally decreased from organic layers to mineral soil horizons, OPAH/OC ratios increased more strongly with depth compared to PAHs, in particular for anthrone, anthraquinone, fluorenone, and acenaphthenequinone. The strong vertical accumulation of OPAH relative to OC was exponentially and negatively correlated to C/N ratios (r(2)=0.67), a measure that often is used for tissue age. In fact, C/N ratios alone explained two-thirds of the variability in OPAH/OC ratios suggesting particularly high retention, sorption, and persistency of OPAHs in old, decomposed carbon fractions. PMID- 25929872 TI - Fresh and weathered crude oil effects on potential denitrification rates of coastal marsh soil. AB - On April 20, 2010, the Deepwater Horizon oil platform experienced an explosion which triggered the largest marine oil spill in US history, resulting in the release of ~795 million L of crude oil into the Gulf of Mexico. Once oil reached the surface, changes in overall chemical composition occurred due to volatilization of the smaller carbon chain compounds as the oil was transported onshore by winds and currents. In this study, the toxic effects of both fresh and weathered crude oil on denitrification rates of coastal marsh soil were determined using soil samples collected from an unimpacted coastal marsh site proximal to areas that were oiled in Barataria Bay, LA. The 1:10 ratio of crude oil:field moist soil fully coated the soil surface mimicking a heavy oiling scenario. Potential denitrification rates at the 1:10 ratio, for weathered crude oil, were 46 +/- 18.4% of the control immediately after exposure and 62 +/- 8.0% of the control following a two week incubation period, suggesting some adaptation of the denitrifying microbial consortium over time. Denitrification rates of soil exposed to fresh crude oil were 51.5 +/- 5.3% of the control after immediate exposure and significantly lower at 10.9 +/- 1.1% after a 2 week exposure period. Results suggest that fresh crude oil has the potential to more severely impact the important marsh soil process of denitrification following longer term exposure. Future studies should focus on longer-term denitrification as well as changes in the microbial consortia in response to oil exposure. PMID- 25929873 TI - Combination of powdered activated carbon and powdered zeolite for enhancing ammonium removal in micro-polluted raw water. AB - Even zeolite is promising in ammonia pollution disposing, its removal efficiency is frequently interfered by organics. As activated carbon has good removal efficiency on organic contaminants, combination of two adsorbents may allow their respective adsorption characteristics into full play. This paper provides a performance assessment of the combination for enhancing ammonium removal in micro polluted raw water. Gel-filtration chromatography (GFC) was carried out to quantify the molecular weight (MW) range of organic contaminants that powdered activated carbon (PAC) and powdered zeolite (PZ) can remove. The polydispersity difference which also calculated from GFC may indicate the wider organic contaminants removal range of PAC and the relatively centralized removal range of PZ. The jar tests of combination dosing confirm a synergistic effect which promotes ammonium removing. Nevertheless, it also shows an antagonism hindering the due removal performance of the two adsorbents on CODMn, while it is not much evident on UV254. Furthermore, a comparison study with simulated coagulation sedimentation process was conducted to evaluate the optimum dosing points (spatial and temporal) of PAC and PZ among follows: suction well, pipeline mixer, early and middle phase of flocculation. We suggest to dose both two adsorbents into the early phase of flocculation to maximize the versatile removal efficiency on turbidity, ammonium and organic contaminants. PMID- 25929874 TI - The enhancement effect of pre-reduction using zero-valent iron on the solidification of chromite ore processing residue by blast furnace slag and calcium hydroxide. AB - A bench scale study was performed to assess the effectiveness of the solidification of chromite ore processing residue (COPR) by blast furnace slag and calcium hydroxide, and investigate the enhancement effect of pre-reduction using zero-valent iron (ZVI) on the solidification treatment. The degree of Cr immobilization was evaluated using the Toxicity Characteristic Leaching Procedure (TCLP) as well as the solid waste-extraction procedure for leaching toxicity sulfuric acid & nitric acid method (Chinese standard HJ/T299-2007). Strength tests and semi-dynamic leaching tests were implemented to investigate the potential for reusing the final treatment product as a readily available construction material. The experimental results showed that the performance of pre-reduction/solidification (S/S) was superior to that of solidification alone. After pre-reduction, all of the S/S treated COPR samples met the TCLP limit for total Cr (5 mg L(-1)), whereas the samples with a COPR content below 40% met the pollution control limit of bricks and building block products (Chinese standard HJ/T 301-2007) produced with COPR for total Cr (0.3 mg L(-1)). At the same time, all of the S/S treated specimens tested were suitable for utilization at certain levels. PMID- 25929875 TI - The Transitive-Unaccusative Alternation: A Cross-Modal Priming Study. AB - The relationship between different linguistic manifestations of an eventuality denoting concept, referred to in the literature as diatheses or voices, is well studied in theoretical linguistics. Among researchers studying this phenomenon, it is widely agreed that there is a systematic relationship between the various diatheses of a concept. However, when a specific alternation is addressed, the nature of this relationship, namely, its directionality, is at debate. This research employs the much-debated transitive-unaccusative alternation as a case study and reports the results of two cross-modal priming experiments designed to explore how Hebrew speakers perceive it. The results reveal an asymmetry between the facilitating effects of transitives and unaccusatives, thus suggesting that the relationship between these diatheses is directional. As a whole, this study demonstrates that theoretical debates regarding derivational relationships can be addressed by means of psycholinguistic research. PMID- 25929876 TI - India's rural medical practitioners are reluctant to refer in severe cases, study finds. PMID- 25929878 TI - Intracranial Aneurysms: Wall Motion Analysis for Prediction of Rupture. AB - Intracranial aneurysms are a common pathologic condition with a potential severe complication: rupture. Effective treatment options exist, neurosurgical clipping and endovascular techniques, but guidelines for treatment are unclear and focus mainly on patient age, aneurysm size, and localization. New criteria to define the risk of rupture are needed to refine these guidelines. One potential candidate is aneurysm wall motion, known to be associated with rupture but difficult to detect and quantify. We review what is known about the association between aneurysm wall motion and rupture, which structural changes may explain wall motion patterns, and available imaging techniques able to analyze wall motion. PMID- 25929877 TI - Are mesenchymal stem cells in rheumatoid arthritis the good or bad guys? AB - The advancements in our understanding of the inflammatory and immune mechanisms in rheumatoid arthritis (RA) have fuelled the development of targeted therapies that block cytokine networks and pathogenic immune cells, leading to a considerable improvement in the management of RA patients. Nonetheless, no therapy is curative and clinical remission does not necessarily correspond to non progression of joint damage. Hence, the biomedical community has redirected scientific efforts and resources towards the investigation of other biological aspects of the disease, including the mechanisms driving tissue remodelling and repair. In this regard, stem cell research has attracted extraordinary attention, with the ultimate goal to develop interventions for the biological repair of damaged tissues in joint disorders, including RA. The recent evidence that mesenchymal stem cells (MSCs) with the ability to differentiate into cartilage are present in joint tissues raises an opportunity for therapeutic interventions via targeting intrinsic repair mechanisms. Under physiological conditions, MSCs in the joint are believed to contribute to the maintenance and repair of joint tissues. In RA, however, the repair function of MSCs appears to be repressed by the inflammatory milieu. In addition to being passive targets, MSCs could interact with the immune system and play an active role in the perpetuation of arthritis and progression of joint damage. Like MSCs, fibroblast-like synoviocytes (FLSs) are part of the stroma of the synovial membrane. During RA, FLSs undergo proliferation and contribute to the formation of the deleterious pannus, which mediates damage to articular cartilage and bone. Both FLSs and MSCs are contained within the mononuclear cell fraction in vitro, from which they can be culture expanded as plastic-adherent fibroblast-like cells. An important question to address relates to the relationship between MSCs and FLSs. MSCs and FLSs could be the same cell type with functional specialisation or represent different functional stages of the same stromal lineage. This review will discuss the roles of MSCs in RA and will address current knowledge of the relative identity between MSCs and FLSs. It will also examine the immunomodulatory properties of the MSCs and the potential to harness such properties for the treatment of RA. PMID- 25929879 TI - White matter alterations in the brains of patients with active, remitted, and cured cushing syndrome: a DTI study. AB - BACKGROUND AND PURPOSE: Cushing syndrome appears after chronic exposure to elevated glucocorticoid levels. Cortisol excess may alter white matter microstructure. Our purpose was to study WM changes in patients with Cushing syndrome compared with controls by using DTI and the influence of hypercortisolism. MATERIALS AND METHODS: Thirty-five patients with Cushing syndrome and 35 healthy controls, matched for age, education, and sex, were analyzed through DTI (tract-based spatial statistics) for fractional anisotropy, mean diffusivity, axial diffusivity, and radial diffusivity (general linear model, family-wise error, and threshold-free cluster enhancement corrections, P < .05). Furthermore, the influence of hypercortisolism on WM DTI changes was studied by comparing 4 subgroups: 8 patients with Cushing syndrome with active hypercortisolism, 7 with Cushing syndrome with medication-remitted cortisol, 20 surgically cured, and 35 controls. Cardiovascular risk factors were used as covariates. In addition, correlations were analyzed among DTI values, concomitant 24-hour urinary free cortisol levels, and disease duration. RESULTS: There were widespread alterations (reduced fractional anisotropy, and increased mean diffusivity, axial diffusivity, and radial diffusivity values; P < .05) in patients with Cushing syndrome compared with controls, independent of the cardiovascular risk factors present. Both active and cured Cushing syndrome subgroups showed similar changes compared with controls. Patients with medically remitted Cushing syndrome also had reduced fractional anisotropy and increased mean diffusivity and radial diffusivity values, compared with controls. No correlations were found between DTI maps and 24-hour urinary free cortisol levels or with disease duration. CONCLUSIONS: Diffuse WM alterations in patients with Cushing syndrome suggest underlying loss of WM integrity and demyelination. Once present, they seem to be independent of concomitant hypercortisolism, persisting after remission/cure. PMID- 25929880 TI - Tract-Based Spatial Statistics in Preterm-Born Neonates Predicts Cognitive and Motor Outcomes at 18 Months. AB - BACKGROUND AND PURPOSE: Adverse neurodevelopmental outcome is common in children born preterm. Early sensitive predictors of neurodevelopmental outcome such as MR imaging are needed. Tract-based spatial statistics, a diffusion MR imaging analysis method, performed at term-equivalent age (40 weeks) is a promising predictor of neurodevelopmental outcomes in children born very preterm. We sought to determine the association of tract-based spatial statistics findings before term-equivalent age with neurodevelopmental outcome at 18-months corrected age. MATERIALS AND METHODS: Of 180 neonates (born at 24-32-weeks' gestation) enrolled, 153 had DTI acquired early at 32 weeks' postmenstrual age and 105 had DTI acquired later at 39.6 weeks' postmenstrual age. Voxelwise statistics were calculated by performing tract-based spatial statistics on DTI that was aligned to age-appropriate templates. At 18-month corrected age, 166 neonates underwent neurodevelopmental assessment by using the Bayley Scales of Infant Development, 3rd ed, and the Peabody Developmental Motor Scales, 2nd ed. RESULTS: Tract-based spatial statistics analysis applied to early-acquired scans (postmenstrual age of 30-33 weeks) indicated a limited significant positive association between motor skills and axial diffusivity and radial diffusivity values in the corpus callosum, internal and external/extreme capsules, and midbrain (P < .05, corrected). In contrast, for term scans (postmenstrual age of 37-41 weeks), tract based spatial statistics analysis showed a significant relationship between both motor and cognitive scores with fractional anisotropy in the corpus callosum and corticospinal tracts (P < .05, corrected). Tract-based spatial statistics in a limited subset of neonates (n = 22) scanned at <30 weeks did not significantly predict neurodevelopmental outcomes. CONCLUSIONS: The strength of the association between fractional anisotropy values and neurodevelopmental outcome scores increased from early-to-late-acquired scans in preterm-born neonates, consistent with brain dysmaturation in this population. PMID- 25929881 TI - Vascular Wall Imaging of Unruptured Cerebral Aneurysms with a Hybrid of Opposite Contrast MR Angiography. AB - BACKGROUND AND PURPOSE: Inflammation and degeneration of the intracranial saccular aneurysm wall play a major role in aneurysm formation, development and subsequent rupture. The aim of this study was to characterize the walls of unruptured intracranial aneurysms by using a hybrid of opposite-contrast MRA at 3T. MATERIALS AND METHODS: Fourteen consecutive patients with 17 unruptured intracranial aneurysms who initially underwent clipping surgery were prospectively evaluated. All aneurysms were scanned preoperatively by using a hybrid of opposite-contrast MRA in 3T high-resolution MR imaging. We classified intraoperative findings of atherosclerotic plaques in the aneurysms into 3 grades: grade A (major plaques), grade B (minor plaques), and grade C (no plaques). The contrast ratio of the high-intensity area was also measured relative to the background low-intensity area inside the carotid artery. RESULTS: Findings from preoperative plaque imaging of the aneurysm corresponded to the intraoperative findings in 15 of 16 aneurysms (excluding 1 that was impossible to visualize in its entirety due to anatomic reasons). Overall sensitivity and specificity of the hybrid of opposite-contrast MRA were 88.9% and 100%, respectively. During the operation, 4 aneurysms were classified as grade A; 5, as grade B; and 7, as grade C. The means of the contrast ratio for grades A, B, and C were 0.72 +/- 0.03, 0.34 +/- 0.30, and -0.02 +/- 0.09, respectively. CONCLUSIONS: The hybrid of opposite-contrast MRA can detect visible atherosclerotic plaques in the unruptured aneurysm wall, and the contrast ratio in intracranial aneurysms correlated with their presence and extent. A study including a larger series is needed to validate the diagnostic potential of this imaging technique. PMID- 25929882 TI - The Role of Core Needle Biopsy and Its Impact on Surgical Management in Patients with Medullary Thyroid Cancer: Clinical Experience at 3 Medical Institutions. AB - BACKGROUND AND PURPOSE: Medullary thyroid carcinoma is an uncommon malignancy that is challenging to diagnose. Our aim was to present our experience using core needle biopsy for the diagnosis of medullary thyroid carcinoma compared with fine needle aspiration. MATERIALS AND METHODS: Between January 2000 and March 2012, 202 thyroid nodules in 191 patients were diagnosed as medullary thyroid cancer by using sonography-guided fine-needle aspiration, core needle biopsy, or surgery. One hundred eighty-three thyroid nodules in 172 patients were included on the basis of the final diagnosis. We evaluated the sensitivity and positive predictive value of fine-needle aspiration and core needle biopsy for the diagnosis of medullary thyroid cancer. We compared the rate of a delayed diagnosis, a diagnostic surgery, and surgery with an incorrect diagnosis for fine needle aspiration and core needle biopsy and investigated the factors related to the fine-needle aspiration misdiagnosis of medullary thyroid cancer. RESULTS: Fine-needle aspiration showed 43.8% sensitivity and 85.1% positive predictive value for the diagnosis of medullary thyroid cancer; 25.7% (44/171) of patients had a delayed diagnosis, while 18.7% (32/171) underwent an operation for accurate diagnosis, and 20.5% (35/171) underwent an operation with an incorrect diagnosis. Core needle biopsy achieved 100% sensitivity and positive predictive value without a delay in diagnosis (0/22), the need for a diagnostic operation (0/22), or an operation for an incorrect diagnosis (0/22). A calcitonin level of <100 pg/mL was the only significant factor for predicting the fine-needle aspiration misdiagnosis of medullary thyroid cancer (P = .034). CONCLUSIONS: Core needle biopsy showed a superior sensitivity and positive predictive value to fine-needle aspiration and could optimize the surgical management in patients with medullary thyroid cancer. Because the ability of fine-needle aspiration to diagnose medullary thyroid cancer significantly decreases in patients with serum calcitonin levels of <100 pg/mL, core needle biopsy could be indicated for these patients to optimize their surgical management. PMID- 25929883 TI - Climate change overruns resilience conferred by temperature-dependent sex determination in sea turtles and threatens their survival. AB - Temperature-dependent sex determination (TSD) is the predominant form of environmental sex determination (ESD) in reptiles, but the adaptive significance of TSD in this group remains unclear. Additionally, the viability of species with TSD may be compromised as climate gets warmer. We simulated population responses in a turtle with TSD to increasing nest temperatures and compared the results to those of a virtual population with genotypic sex determination (GSD) and fixed sex ratios. Then, we assessed the effectiveness of TSD as a mechanism to maintain populations under climate change scenarios. TSD populations were more resilient to increased nest temperatures and mitigated the negative effects of high temperatures by increasing production of female offspring and therefore, future fecundity. That buffered the negative effect of temperature on the population growth. TSD provides an evolutionary advantage to sea turtles. However, this mechanism was only effective over a range of temperatures and will become inefficient as temperatures rise to levels projected by current climate change models. Projected global warming threatens survival of sea turtles, and the IPCC high gas concentration scenario may result in extirpation of the studied population in 50 years. PMID- 25929884 TI - Erratum to: The reach and health impacts of the National Breast and Cervical Cancer Early Detection Program. PMID- 25929885 TI - Erratum to: Cervical cancer screening of underserved women in the United States: results from the National Breast and Cervical Cancer Early Detection Program, 1997-2012. PMID- 25929886 TI - Erratum to: Explaining variation across grantees in breast and cervical cancer screening proportions in the NBCCEDP. PMID- 25929887 TI - Erratum to: Breast cancer screening of underserved women in the USA: results from the National Breast and Cervical Cancer Early Detection Program, 1998-2012. PMID- 25929888 TI - Predictors of Lymph Node Metastasis in Surgically Resected T1 Esophageal Cancer. AB - BACKGROUND: The application of endoscopic therapies for early cancers of the esophagus is limited by the possible presence of regional lymph node metastases. Our objective was to determine the prevalence and predictors of lymph node metastases in patients with pT1 carcinoma of the esophagus and the gastric cardia. METHODS: The National Cancer Institute's Surveillance Epidemiology and End Results Database (2004 to 2010) was used to identify all patients with pT1 carcinomas who underwent primary surgical resection for squamous cell carcinoma (SCC) or adenocarcinoma (EAC) of the esophagus and of the esophagogastric junction (AEG). Prevalence of lymph node metastases was assessed, and survival in all types of cancer was calculated. Multivariate logistic regression was used to identify factors predicting positive lymph node status. RESULTS: There were 1,225 patients (84% male), with a mean age of 64 +/- 10 years, and 90% were white. Intramucosal disease was present in 44% of patients, and submucosal invasion (T1b) was present in 692 (56%). Prevalence of lymph node metastases in EAC, SCC, and AEG was 6.4%, 6.9%, and 9.5% for pT1a tumors and 19.6%, 20%, and 22.9% for pT1b tumors, respectively. In patients with more than 23 lymph nodes removed during resection, prevalence of lymph node metastases in EAC, SCC, and AEG was 8.1%, 25%, and 7.4% for pT1a tumors and 27.8%, 33.3%, and 22% for pT1b tumors, respectively. Positive lymph node status was associated with worse overall 5-year survival in EAC (N0 vs N+: 78% vs 52%) and AEG (N0 vs N+: 83% vs 44%) but did not have a significant effect on the long-term survival of patients with SCC. Infiltration of the submucosa, tumor size exceeding 10 mm, and poor tumor differentiation were independently associated with the risk of nodal disease. Prevalence of lymph node metastasis negative for these three risk factors was only 4.8%. CONCLUSIONS: Prevalence of lymph node metastasis in early esophageal cancer is high in patients with T1 cancer. Inadequate lymphadenectomy underestimates lymph node status. Endoscopic treatment can be considered only in a select group of patients with early esophageal cancer. PMID- 25929889 TI - [Role of vitamin D in allergic diseases: Current research status]. AB - BACKGROUND: Recent research has focused on the relationship between vitamin D and allergy development. Results show that on the one hand a vitamin D deficiency can be responsible for the emergence of allergies, however, on the other hand a vitamin-D (over-) substitution was also seen in context with an increased allergy development. OBJECTIVE: This article provides an overview on the current state of research and points at the problematic aspects that accompany the assessment of these studies. RESULTS: The paradoxic effect of vitamin D is currently being explained by epigenetic programming in pregnancy, by too low vitamin-D levels or excessive supplementation in newborns. Very recently, a gender-specific impact of vitamin D is also being discussed. CONCLUSION: For a final assessment of vitamin D effects on the emergence of allergies, further research is necessary. Due to a high level of heterogeneity among current observational studies regarding central aspects of the discussion, randomised clinical trials are recommended. PMID- 25929890 TI - [Allergen specific immunotherapy for rhinitis allergica : New applications]. AB - BACKGROUND: Allergic diseases are among the most common diseases of humans. The immune response towards allergens is regulated by T-lymphozytes and characterized by an interleukin (IL)-4, IL-5 and IL-13 dominated Th2 cytokine profile. RESULTS: Allergen-specific immunotherapy (AIT) is the only causative treatment option and able to change the course of disease, e. g. to prevent the development of asthma and new sensitizations. The intralymphatic delivery of allergenes named intralymphatic immunotherapy (ILIT) has been evaluated in clinical trials and was demonstrated to be a highly potent application route with low effort and side effects while having equal efficacy if compared with current standard AIT forms. However, studies that verify important questions like optimal dose, new allergen forms, use of adjuvants etc. are still missing. Moreover, it has to be evaluated, whether different indications like rhinitis, or atopic dermatitis are suitable for ILIT and whether it is useful in children. Epicutaneous immunotherapy (EPIT) is a possible alternative application form. It is minimally invasive and basically consists of the affixation of allergen containing patches to the epidermis over 6 weeks. From the studies performed so far, the authors concluded, that epicutaneous immunotherapy is safe and efficacious in a dose-dependent manner after 6 patches only. CONCLUSIONS: AIT is accepted to be the only causative treatment option for allergies. New application routes in ILIT and EPIT may become more important and allow for different delivery methods in the future, however further clinical studies are required and in preparation. PMID- 25929891 TI - [Local allergic rhinitis to Alternaria alternata : Evidence for local IgE production exclusively in the nasal mucosa]. AB - In a subgroup of patients with symptoms of allergic rhinitis (AR), no systemic sensitization can be detected in skin tests or serum. These patients are considered to be afflicted with so-called "local allergic rhinitis" (LAR) with IgE-production exclusively at the site of the nasal mucosa. Patients without any positive allergy test results but seasonal (intermittent) or perennial (persistent) allergic symptoms were often misdiagnosed as having "non-allergic rhinitis" (NAR) in the past.However, there is evidence for a specific IgE production in the nasal mucosa in these patients without systemic sensitization. The diagnosis of LAR is confirmed by clinical symptoms, the detection of specific IgE production in the nasal mucosa and/or nasal provocation tests.We report on two cases of LAR to Alternaria alternata with symptoms of persistent allergic rhinitis that have been diagnosed by positive allergenspecific nasal challenge tests and specific IgE determinations in nasal secretions.According to an actual literature research, this is the second report published on LAR caused by Alternaria alternata. PMID- 25929892 TI - [The latest findings about allergies in ENT medicine]. PMID- 25929893 TI - [ASA-intolerance syndrome and persistent rhinosinusitis : Differential diagnosis and treatment]. AB - BACKGROUND: A differential diagnosis of persistent chronic rhinosinusitis is ASA intolerance syndrome (AIS), also known as Aspirin(r)-exacerbated respiratory disease (AERD), Samter-Trias (Samter's disease, Morbus Widal). Particularly in cases of frequent recurrency of nasal polyps in combination with bronchial asthma and hypersensitivity reactions to acetylsalicylic acid (ASA) and other nonsteroidal anti-inflammatory drugs (NSAR) can often be referred to an underlying AIS. The pathogenesis of this syndrome is attributed to a misallocation of the arachidonic acid metabolism, resulting in an increased leukotriene production. METHODS: The diagnosis may be difficult in the early stages of the disease with incomplete triad of symptoms. RESULTS: Therapy may consist of paranasal sinuses surgery, drug therapy and adaptive deactivation as the only causal treatment option for patients with AIS. CONCLUSION: For adaptive desactivation, positive effects were actually shown even in patients with long term recurrent or persistent complaints of chronic rhinosinusitis. PMID- 25929895 TI - Metaplastic breast carcinoma with multiple muscle metastasis: a case report. AB - Metaplastic breast carcinoma (MBC) is a rare type of breast carcinoma. Recurrence presenting as chest wall invasion is common but rarely as metastasis to distal skeletal muscle in which most patients present with a painful mass. Herein, we report a rare case of 65-year-old woman, with MBC and recurrence presenting as distal multiple muscle metastasis. The patient received surgical excision for symptomatic relief. Unfortunately, she died 12 months postoperatively due to disease progression with multiple lung metastasis.In addition to radiotherapy and chemotherapy, surgical excision is an alternative option in selected patients such as those with painful, isolated, and easily approachable mass. PMID- 25929894 TI - 1H-NMR-based metabolomic analysis of cerebrospinal fluid from adult bilateral moyamoya disease: comparison with unilateral moyamoya disease and atherosclerotic stenosis. AB - Although metabolomics has been increasingly used to observe metabolic pattern and disease-specific metabolic markers, metabolite profiling for moyamoya disease (MMD) has not yet been done in adults. This study investigated cerebrospinal fluid (CSF) metabolites specific to bilateral MMD (B-MMD) and compared them to those of unilateral MMD (U-MMD) or atherosclerotic stenosis with hydrogen-1 nuclear magnetic resonance spectroscopy to identify metabolic biomarkers associated with MMD in adults.CSF samples of B-MMD (n = 29), U-MMD (n = 11), and atherosclerotic cerebrovascular disease (ACVD) (n = 8) were recruited. Principal component analysis, partial least square discriminant analysis, and orthogonal projections to latent structure discriminant analysis (OPLS-DA) were done for the comparisons. Diagnostic performance was acquired by prediction of 1 left-out sample from the distinction model constructed with the rest of the samples.B-MMD showed an increase in glutamine (P < 0.001) and taurine (P = 0.004), and a decrease in glucose (P < 0.001), citrate (P = 0.002), and myo-inositol (P = 0.006) than those in ACVD. U-MMD showed a higher level of glutamine (P = 0.005) and taurine (P = 0.034), and a lower level of glutamate (P < 0.004) than those in ACVD. No difference at the metabolite level was observed between B-MMD and U-MMD. Cross-validation with the OPLS-DA model showed a high accuracy for the prediction of MMD.The results of the study suggest that a metabolomics approach may be helpful in confirming MMD and providing a better understanding of MMD pathogenesis. Elevated glutamine in the CSF may be associated with MMD pathogenesis, which was different from ACVD. PMID- 25929896 TI - Exploring spatial overlap of high-uptake regions derived from dual tracer positron emission tomography-computer tomography imaging using 18F fluorodeoxyglucose and 18F-fluorodeoxythymidine in nonsmall cell lung cancer patients: a prospective pilot study. AB - Interest is growing in radiotherapy to nonuniformly boost radioresistant regions within nonsmall cell lung cancer (NSCLC) using molecular imaging techniques. The complexity of tumor behavior is beyond the ability of any single radiotracer to reveal. We hold dual tracer positron emission tomography-computer tomography (PET/CT) imaging with fluorodeoxyglucose (FDG) and fluorodeoxythymidine (FLT) for NSCLC patients to offer an integrated overlook of tumor biological behaviors quantitatively and localizationally, which may help biological target volume delineation and subvolume boost.Pathological confirmed that NSCLC patients were eligible. FDG and FLT PET/CT were performed for each patient before anticancer treatment and coregistrated for analysis. Maximum and mean standardized uptake values (SUVmax and SUVmean) were calculated automatically. Metabolic volumes (MVs) were delineated by a fixed 50% of SUVmax in FDG PET/CT and proliferative volumes (PVs) were delineated by 50% to 90% of SUVmax with 10% interval in FLT PET/CT. Overlap ratio (OR) were determined as overlapped volume between MV and PV divided PV. Conventional contrast-enhanced CT-based intensity-modulated radiotherapy (IMRT) plans with and without additional PET/CT-guided subtarget boost were made for each of the 5 typical NSCLC patients. Dosimetric parameters derived from dose-volume histogram, tumor control probability (TCP), and normal tissue complication probability (NTCP) of lung, esophagus, heart, and spinal cord were calculated and compared.Thirty-one patients were prospectively included and 23 were selected for analysis. Totally, 23 primary diseases, 41 metastatic lymph nodes, and 15 metastatic lesions were positive in dual PET/CTs and included for analysis. Median ORs increased from 58.61% to 93.12% under thresholds of 50% of SUVmax in FDG PET/CT and increased thresholds from 50% to 90% of SUVmax in FLT PET/CT. Based on conventional IMRT, additional boost to union of high FDG (determined by 50% SUVmax) and FLT (determined by 80% SUVmax) uptake subtargets exhibited higher TCP without significant elevated NTCP of lung, esophagus, spinal cord, and heart.Dual tracer PET/CT of FDG and FLT is suggested for NSCLC patients to guide tumor target delineation in clinical practice. FDG PET/CT is necessary whereas FLT PET/CT may be optional when guiding tumor target delineation clinically. Additional information from randomized trials is required to validate. PMID- 25929897 TI - Probiotics for standard triple Helicobacter pylori eradication: a randomized, double-blind, placebo-controlled trial. AB - The primary objective in the study is determination of efficacy of probiotic preparation as a supportive therapy in eradication of Helicobacter pylori.The study was multicenter, prospective, randomized, placebo controlled, and double blind. The subjects first filled out a specially designed questionnaire to assess the severity of the 10 symptoms, which can be related to eradication therapy to be monitored during the trial. Each subject then received 28 capsules of probiotic preparation or matching placebo capsules, which they were supposed to take over the following 14 days, twice a day, at least 2 hours prior to or after the antibiotic therapy administration.A total of 804 patients were enrolled in the trial, of which 650 (80.85%) were included in the analysis. The results show a significantly larger share of cured subjects in the probiotic arm versus the placebo arm (87.38% vs 72.55%; P < 0.001). Additionally, presence and intensity of epigastric pain, bloating, flatulence, taste disturbance, loss of appetite, nausea, vomiting, heartburn, rash, and diarrhea were monitored over the study period. At 15 days postinclusion, probiotic treatment was found superior to placebo in 7 of 10 mentioned symptoms. Average intensity for symptoms potentially related to antibiotic therapy was significantly higher in the placebo group, 0.76 vs 0.55 (P < 0.001).Adding probiotics to the standard triple therapy for H pylori eradication significantly contributes to treatment efficacy and distinctly decreases the adverse effects of therapy and the symptoms of the underlying disease. PMID- 25929898 TI - A novel skull clamp positioning system and technique for posterior cervical surgery: clinical impact on cervical sagittal alignment. AB - A prospective radiographic study.The purpose of this study was to analyze whether a novel skull clamp positioning system and technique is useful for obtaining good, quantitative cervical sagittal alignment during posterior cervical surgery.Different surgical procedures depend on cervical spine positioning. However, maneuver of the device and cervical position depends on the skill of the operator.This study included 21 male and 10 female patients with cervical spondylotic myelopathy and ossification of the posterior longitudinal ligament of the cervical spine, undergoing posterior cervical surgery using the novel skull clamp positioning system. The average patient age was 68.6 years (range: 56-87 years). The novel system has a scale to adjust the neck position and to enable intended cervical sagittal alignment. First, the patient was placed on the operating table in the prone position with preplanned head-neck sagittal alignment (neutral position in general). The head was rotated sagittally, and the head was positioned in the military tuck position with the novel device that was used to widen the interlaminar space. After completing the decompression procedure, the head was rotated again back to the initial preplanned position. During this position change, the scale equipped with the device was useful in determining accurate positions. The C0-C1, C0-C2, C1-C2, C2-C7, and C0-C7 angles were measured on lateral radiographs taken pre-, intra-, and postoperatively.This novel system allowed us to obtain adequate, quantitative cervical sagittal alignment during posterior cervical surgery. There were no clinically significant differences observed between the pre- and postoperative angles for C1-C2 and C2 C7.Sagittal neck position was quantitatively changed during posterior cervical surgery using a novel skull clamp positioning system, enabling adequate final cervical sagittal alignment identical to the preplanned neck position. PMID- 25929899 TI - Impact of adjuvant chemotherapy in patients with curatively resected stage IV colorectal cancer. AB - The aim of this study was to investigate the impact of adjuvant chemotherapy on survival of patients who had curative resection for stage IV colorectal cancer.The efficacy of adjuvant chemotherapy after curative resection for stage IV colorectal cancer remains unclear.The database of 3695 patients with stage IV colorectal cancer between 1991 and 2007 collected from 16 member hospitals of the Japanese Society for Cancer of the Colon and Rectum was used for this investigation. The survivals of patients with and without adjuvant chemotherapy after curative resection for stage IV colorectal cancer were evaluated using a propensity score matching method.The data of 689 patients who underwent curative resection for both primary and synchronous metastatic tumors were extracted from the database and used for analysis in this study. The 5-year overall survival rates of the patients with and without adjuvant chemotherapy were 41.8% and 33.9%, respectively. A Cox proportional hazards model showed that adjuvant chemotherapy (P = 0.0042), regional lymph node metastasis (P < 0.0001), and peritoneal metastasis (P = 0.0006) were independent factors for overall survival. In the propensity score-matched cohort, patients with adjuvant chemotherapy had better overall survival than those without (P = 0.026).The present study demonstrated that adjuvant chemotherapy improved overall survival after curative resection for stage IV colorectal cancer. The efficacy of each chemotherapeutic regimen in the adjuvant setting for stage IV colorectal cancer should be clarified in the future. PMID- 25929900 TI - Congenital scoliosis in Smith-Magenis syndrome: a case report and review of the literature. AB - The Smith-Magenis syndrome (SMS) is a complex and rare congenital condition that is characterized by minor craniofacial anomalies, short stature, sleep disturbances, behavioral, and neurocognitive abnormalities, as well as variable multisystemic manifestations. Little is reported about spinal deformity associated with this syndrome.This study is to present a case of scoliosis occurring in the setting of SMS and explore the possible mechanisms between the 2 diseases.The patient is a 13-year-old Chinese female with congenital scoliosis and Tetralogy of Fallot, mental retardation, obstructive sleep apnea, hypertrophy of tonsil, conductive hearing loss, and agenesis of the epiglottis. An interphase fluorescent in situ hybridization at chromosome 17p11.2 revealed a heterozygous deletion, confirming a molecular diagnosis of SMS. She underwent a posterior correction at thoracic 1-lumbar 1 (T1-L1) levels, using the Moss-SI spinal system. At 6-month follow-up, the patient was clinically pain free and well balanced. Plain radiographs showed solid spine fusion with no loss of correction.Congenital cardiac disease, immunodeficiency, and severe behavioral problems can affect the surgical outcome following spine fusion and need to be taken into consideration for the surgeon and anesthesiologist. Scoliosis is not uncommon among patients with SMS, and there is a potential association between congenital scoliosis and SMS. The potential mechanisms in the pathogenesis of congenital scoliosis of SMS included retinoic acid-induced 1 (RAI1) microdeletion and RAI1 gene point mutation. PMID- 25929901 TI - Pseudoclavibacter otitis media in a 3-year-old boy with pulmonary and spinal tuberculosis. AB - Pseudoclavibacter has rarely been documented as an etiologic agent of infection in humans. We presented the first case report of Pseudoclavibacter otitis media in a boy with pulmonary and spinal tuberculosis.A 3-year-old boy was referred to our hospital due to prolonged fever and progressive paraplegia for 3 months. He had yellowish discharge from both ear canals. The pleural fluid culture was positive for Mycobacterium tuberculosis. The discharge from both ears culture yielded yellow colonies of gram-positive bacilli with branching. This organism was positive for modified acid-fast bacilli stain but negative for acid-fast bacilli stain. Biochemical characteristics of this isolate were positive for catalase test but negative for oxidase, nitrate, esculin, and sugar utilization tests. The organism was further subjected to be identified by 16S ribosomal deoxyribonucleic acid gene sequencing. The result yielded Pseudoclavibacter species (99.4% identical), which could be most likely a potential pathogen in immunocompromised host like this patient. He responded well with intravenous trimetroprim-sulfamethoxazole for 6 weeks.This is the first case report of Pseudoclavibacter otitis media in children, and this case could emphasize Pseudoclavibacter species as a potential pathogen in immunocompromised host. PMID- 25929902 TI - The association between gastric endoscopic findings and histologic premalignant lesions in the Iranian rural population. AB - Atrophic gastritis, intestinal metaplasia, and gastric dysplasia are histologic premalignant lesions (PMLs). Correlation between the gastric endoscopic findings and histologic PMLs is not clear. This study was designed to determine the possible association of endoscopic findings and histologic PMLs.Over 28 months gastric endoscopic findings of consecutive rural patients with dyspepsia were categorized into 3 groups: 1-normal, 2-ulcerative with or without concurrent abnormality, 3-abnormal non-ulcerative. Biopsies of antrum and body were taken from all included patients and examined for the presence of histologic PMLs. Any mucosal abnormality was also biopsied.From 7340 evaluated patients, an overall of 1973 patients were included. 55.7% of patients were in group 1; 3.8% in group 2 and 40.5% in group 3. A within sex analysis showed that the majority of male patients were in PMLs subgroup (P < 0.001) likewise in groups 2 and 3 (P < 0.001). The prevalence of histologic PMLs in groups 2 and 3 was significantly higher than group 1 (P < 0:001) but the difference was not significant between groups 2 and 3 (P = 0.484). Mean (+/-SD) age of patient with PMLs was 50.25 +/- 17.71 whereas in patients without PMLs was 41.16 +/- 16.48 (P < 0.001).This study has showed that abnormal gastric endoscopic findings, male sex and increased age can be considered as risk factors of the formation of histologic PMLs. Until further investigations we propose that any abnormality on gastric mucosa (ulcerative or non-ulcerative) could be biopsied for the evaluation of probable histologic PMLs especially in old men. PMID- 25929903 TI - Deltoid branch of thoracoacromial vein: a safe alternative entry vessel for intravenous port implantation. AB - An entry vessel is crucial for intravenous port implantation. A safe alternative entry vessel that can be easily explored is crucial for patients without feasible cephalic vein or for those who need port reimplantation because of disease relapse. In this study, we tried to analyze the safety and feasibility of catheter implantation via the deltoid branch of the thoracoacromial vein.From March 2012 to November 2013, 802 consecutive oncology patients who had received intravenous port implantation via the superior vena cava were enrolled in this study. The functional results and complications of different entry vessels were compared.The majority of patients (93.6%) could be identified as thoracoacromial vessel. The deltoid branch of the thoracoacromial vein is located on the medial aspect of the deltopectoral groove beneath the pectoralis major muscle (85.8%) and in the deep part of the deltopectoral groove (14.2%). Due to the various calibers employed and tortuous routes followed, we utilized 3 different methods for catheter implantation, including vessel cutdown (47.4%), wire assisted (17.9%), and modified puncture method (34.6%). The functional results and complication rate were similar to other entry vessels.The deltoid branch of the thoracoacromial vein is located in the neighborhood of the cephalic vein. The functional results of intravenous port implantation via the deltoid branch of the thoracoacromial vein are similar to other entry vessels. It is a safe alternative entry vessel for intravenous port implantation. PMID- 25929904 TI - Improved Efficacy of a pegylated interferon-alpha-2a stepwise optimization treatment strategy in the treatment of hepatitis B e antigen-positive chronic hepatitis B patients. AB - Current pegylated interferon-alpha (PEG-IFN) treatment for chronic hepatitis B (CHB) e-antigen (HBeAg)-positive patients are suboptimal, and effective ways of improving PEG-IFN treatment efficacy are needed.This retrospective cohort study compared the efficacy of a PEG-IFN stepwise optimization treatment (PEG-IFN SOT) strategy with that of a 48-week PEG-IFN standard therapy (PEG-IFN ST) in HBeAg positive CHB patients.A total of 110 patients were included in our study. Of these, 70 received the PEG-IFN SOT and 40 received the PEG-IFN ST (control group). We based the decision whether to add adefovir and/or extend the PEG-IFN based treatment to 96 weeks on the patients' 12-week or 24-week early virological response (12W EVR, at least a 2 log10 reduction in HBV DNA copies/mL at week 12; 24W EVR, at least 1 log10 reduction in HBsAg IU/mL or HBsAg <1500 IU/mL at week 24) and their 48-week partial response (48W PR, 1.0 <=HBeAg <=10.0 S/CO or HBeAg >10.0 S/CO but HBsAg <1000 IU/mL).The HBeAg seroconversion rate 24 weeks post-PEG IFN treatment was significantly higher in the PEG-IFN SOT than the PEG-IFN ST group (50% vs 22.5%, P = 0.005). The HBsAg clearance rates in the PEG-IFN SOT and ST groups were 10% and 0% (P = 0.04), respectively. Receiving PEG-IFN SOT (OR = 0.26, P = 0.01), ALT * ULN at baseline (OR = 0.74, P = 0.003), and achieving 12 and 24W EVR (OR = 0.29, P = 0.03) were independent factors associated with HBeAg seroconversion.PEG-IFN SOT is a promising strategy for achieving high rates of serological response in HBeAg-positive CHB patients. PMID- 25929905 TI - Exposure to air pollution increases the risk of osteoporosis: a nationwide longitudinal study. AB - Several studies have indicated that air pollution induces systemic as well as tissue-specific inflammation. Chronic inflammatory diseases such as rheumatoid arthritis and chronic obstructive pulmonary disease reduce bone mineral density (BMD), leading to increased release of immune cells from the bone marrow. However, the association between air pollution and osteoporosis remains poorly defined. Therefore, we conducted this population-based retrospective cohort study to evaluate the risk of osteoporosis in Taiwanese residents exposed to air pollution.We combined 2 nationwide databases in this study. The National Health Insurance Research Database of Taiwan was available from 2000 to 2010. Detailed daily data on air pollution were collected by Taiwan Environmental Protection Agency (EPA) from 1998 to 2010. We calculated the yearly average concentrations of air pollutants from the study start to the date of osteoporosis occurrence, or withdrawal from the NHI program, or December 31, 2010. The yearly average concentrations of air pollutants were categorized into quartiles, and the risks of osteoporosis were evaluated among 4 stages of air pollutants.Among Q1, Q2, Q3, and Q4 of pollutants in all subjects, the adjusted hazard ratios (HRs) of osteoporosis in Q2, Q3, and Q4 were compared with Q1. For carbon monoxide (CO), the adjusted HRs were 1.05 (95% confidence interval [CI], 0.97-1.14), 1.78 (95% CI, 1.65-1.92), and 1.84 (95% CI, 1.71-1.98), respectively. For nitrogen dioxide (NO2), the adjusted HRs were 1.35 (95% CI, 1.25-1.45), 1.24 (95% CI, 1.15-1.35), and 1.60 (95% CI, 1.48-1.73), respectively, in all subjects.The findings of the present study show that CO and NO2 exposure is associated with an increased risk of osteoporosis in the Taiwanese population. PMID- 25929906 TI - Self-reported physical health associations of traumatic events in medical and dental outpatients: a cross-sectional study. AB - The purpose of this cross-sectional study was to understand the prevalence and severity of health-related sequelae of traumatic exposure in a nonpsychiatric, outpatient sample.Self-report surveys were completed by patients seeking outpatient medical (n = 123) and dental care (n = 125) at a large, urban academic medical center.Results suggested that trauma exposure was associated with a decrease in perceptions of overall health and an increase in pain interference at work. Contrary to prediction, a history of interpersonal trauma was associated with less physical and emotional interference with social activities. A history of trauma exposure was associated with an increase in time elapsed since last medical visit. Depression and anxiety did not mediate the relationship between trauma history and medical care.Based on these results, clinical and research implications in relation to the health effects of trauma are discussed. The results suggest that routine screening for traumatic events may be important, particularly when providers have long-term relationships with patients. PMID- 25929907 TI - Statins can delay insulin use and reduce diabetes-related diseases in Asian patients with type 2 diabetes. AB - We evaluated the role of statins in delaying insulin use and diabetes-related diseases in Asian patients with type 2 diabetes mellitus (T2DM) because statins can cause new-onset diabetes.We used data from the Longitudinal Health Insurance Database in this retrospective cohort study. The 12,470 T2DM patients were categorized into 2 cohorts: a statin cohort comprising 2545 patients who received statin therapy for at least 6 months (180 days) before the index date and a nonstatin cohort comprising 9925 patients who did not receive statin therapy. The control-to-case ratio was set at approximately 4:1. Univariable and multivariable Cox proportional hazards regression analyses were performed to evaluate the risk of diabetes-related events and insulin use on receiving statin treatment.Patients in the statin cohort had a 48% lower risk of diabetes-related coma than those in the nonstatin cohort (95% confidence interval = 0.29-0.92). Patients with >730 days of statin therapy had a significantly lower risk of insulin use, diabetes related disorders of the eye and neurons, and peripheral circulatory disorders. Compared with patients in the nonstatin cohort, the risk of insulin use, diabetes related coma, and diabetes-related disorders of the eye and neurons was lower in patients on a cumulative defined daily dose (cDDD) of statins for >475 days.These results suggest that longer duration of statin use and higher cDDD of statins can delay insulin use in Asian patients with T2DM. PMID- 25929908 TI - Comparison of equimolar doses of mannitol and hypertonic saline for the treatment of elevated intracranial pressure after traumatic brain injury: a systematic review and meta-analysis. AB - The purpose of this meta-analysis was to compare the effectiveness of mannitol and hypertonic saline for reducing intracranial pressure (ICP) after traumatic brain injury (TBI).PubMed, Cochrane, Embase, and ISI Web of Knowledge databases were searched until July 3, 2014 using the terms intracranial hypertension, mannitol, and hypertonic saline. Randomized controlled trials and 2-arm prospective studies in which elevated ICP was present after TBI treated with mannitol or hypertonic saline were included. The primary outcome was the change of ICP from baseline to termination of the infusion, while the secondary outcomes were change from baseline to 30, 60, and 120 minutes after terminating the infusion and change of osmolarity from baseline to termination.A total 7 studies with 169 patients were included. The mean age of patients receiving mannitol ranged from 30.8 to 47 years, and for patients receiving hypertonic saline ranged from 35 to 47 years. A pooled difference in means = -1.69 (95% confidence interval [CI]: -2.95 to -0.44, P = 0.008) indicated that hypertonic saline reduced ICP more effectively than mannitol when compared from the baseline value to the last measurement after treatment. At 30 minutes after intervention, there was no difference in the mean ICP change between the groups, whereas at 60 minutes after intervention (pooled difference in means = -2.58, 95% CI: -4.37 to 0.80, P = .005) and 120 min after intervention (pooled difference in means = 4.04, 95% CI: -6.75 to -1.32, P = .004) hypertonic saline resulted in a significantly greater decrease in ICP. The pooled difference in means = 1.84 (95% CI: -1.64 to 5.31, P = .301) indicated no difference in serum osmolarity between patients treated with hypertonic saline or mannitol.Hypertonic saline is more effective than mannitol for reducing ICP in cases of TBI. PMID- 25929909 TI - Radiotherapy- and chemotherapy-induced myelodysplasia syndrome: a nationwide population-based nested case-control study. AB - This study explored which kinds of cancer are related to a higher incidence of subsequent myelodysplastic syndrome (MDS) after radiotherapy (RT) and chemotherapy (CT).We performed a nested case-control study by using data from the Taiwanese National Health Insurance (NHI) system. The case group included cancer patients who developed MDS. For the control group, 4 cancer patients without MDS were frequency-matched with each MDS case by age, sex, year of cancer diagnosis, and MDS index year. A multivariable logistic regression analysis was conducted, and odds ratios (ORs) and 95% confidence intervals (CIs) were estimated.Overall, cancer patients who received RT or CT exhibited secondary MDS more frequently than did those who did not (RT: OR = 1.53; 95% CI = 1.33-1.77; CT: OR = 1.51; 95% CI = 1.25-1.82). Analysis by cancer site showed that RT increased the risk of MDS for patients with stomach, colorectal, liver, breast, endometrial, prostate, and kidney cancers. By contrast, CT was more likely to increase the risk of MDS for patients with lung, endometrial, and cervical cancers. Further analysis revealed that RT and CT seemed to have a positive interaction. The major limitation of this study was the lack of certain essential data in the NHI Research Database, such as data regarding cancer stage and treatment dose details.This population based nested case-control study determined that RT and CT predisposed patients in Taiwan to the development of MDS. This effect was more prominent when both modalities were used. PMID- 25929910 TI - Comparing treatment plan in all locations of esophageal cancer: volumetric modulated arc therapy versus intensity-modulated radiotherapy. AB - The aim of this study was to compare treatment plans of volumetric modulated arc therapy (VMAT) with intensity-modulated radiotherapy (IMRT) for all esophageal cancer (EC) tumor locations.This retrospective study from July 2009 to June 2014 included 20 patients with EC who received definitive concurrent chemoradiotherapy with radiation doses >50.4 Gy. Version 9.2 of Pinnacle with SmartArc was used for treatment planning. Dosimetric quality was evaluated based on doses to several organs at risk, including the spinal cord, heart, and lung, over the same coverage of gross tumor volume.In upper thoracic EC, the IMRT treatment plan had a lower lung mean dose (P = 0.0126) and lung V5 (P = 0.0037) compared with VMAT; both techniques had similar coverage of the planning target volumes (PTVs) (P = 0.3575). In middle thoracic EC, a lower lung mean dose (P = 0.0010) and V5 (P = 0.0145), but higher lung V20 (P = 0.0034), spinal cord Dmax (P = 0.0262), and heart mean dose (P = 0.0054), were observed for IMRT compared with VMAT; IMRT provided better PTV coverage. Patients with lower thoracic ECs had a lower lung mean dose (P = 0.0469) and V5 (P = 0.0039), but higher spinal cord Dmax (P = 0.0301) and heart mean dose (P = 0.0020), with IMRT compared with VMAT. PTV coverage was similar (P = 0.0858) for the 2 techniques.IMRT provided a lower mean dose and lung V5 in upper thoracic EC compared with VMAT, but exhibited different advantages and disadvantages in patients with middle or lower thoracic ECs. Thus, choosing different techniques for different EC locations is warranted. PMID- 25929911 TI - Comparison of acute respiratory events between asthma-COPD overlap syndrome and COPD patients: a population-based cohort study. AB - Epidemiologic studies investigating the differences in respiratory outcomes between asthma-chronic obstructive pulmonary disease overlap syndrome (ACOS) and chronic obstructive pulmonary disease (COPD) in an Asian population are lacking.We conducted a population-based cohort study to compare the incidence of acute respiratory events between ACOS and COPD cohorts in Taiwan. This study investigated the incidence of acute respiratory events, namely, pneumonia, acute exacerbation, acute respiratory failure, and cardiopulmonary arrest, in 8571 patients with physician-diagnosed ACOS between 2000 and 2007 from the Longitudinal Health Insurance Database. The comparison cohort comprised 17,088 COPD patients, frequency-matched according to age, sex, and the index-year. The duration of follow-up was measured for each patient from the index date to 5 years thereafter. We used univariable and multivariable Poisson regression models to analyze the risk of acute respiratory events by including the variables of sex, age, and comorbidity.The overall prevalence of ACOS was approximately 17.4% in patients with COPD. The prevalence of ACOS increased with age. During the 5 year follow-up, a greater incidence of acute respiratory events was observed in the ACOS cohort than in the COPD cohort (11.5 and 4.62, per 100 person-years, respectively) with an adjusted incidence rate ratio (IRR) of 1.72 (95% confidence interval [CI] = 1.63-1.81). Compared with the COPD cohort, the ACOS patients had a 1.13-fold adjusted IRR of pneumonia (95% CI = 1.07-1.20) and a 2.58-fold adjusted IRR of acute exacerbation (95% CI = 2.43-2.74). Clinicians should be aware of frequent exacerbation of ACOS and prescribe appropriate treatment. PMID- 25929912 TI - Fruits and vegetables intake and risk of bladder cancer: a PRISMA-compliant systematic review and dose-response meta-analysis of prospective cohort studies. AB - Clinical practice recommends eating >=2.5 cups of fruits and vegetables (FVs) each day for cancer prevention, in which the evidence from epidemiological studies for the association between FVs intake and bladder cancer (BC) prevention is inconsistent.We searched the PubMed, Embase, and Willy online Library for relevant studies published up to September 27, 2014. Prospective cohort studies investigated FVs intake, and the risk of BC with >=3 categories of exposure was included. A dose-response meta-analysis was carried out to evaluate the association between FVs intake and risk of BC.Fourteen cohorts with 17 studies including 9447 cases were identified. No evidence of nonlinear association was examined between FVs intake and risk of BC. The summarized relevant risk (RR) of every 0.2 serving increment a day was 1.00 (95%CI: 0.99, 1.00; P = 0.17; I = 41.7%; n = 14) for total fruits; 0.99 (95%CI: 0.96, 1.01; P = 0.28; I = 37.0%; n = 13) for total vegetables; and 0.99 (95%CI: 0.97, 1.01; P = 0.24; I = 57.5%; n = 8) for both FVs. In further analysis, we observed inverse association between every 0.2 serving increment of green leafy vegetables intake a day and risk of BC (RR = 0.98, 95%CI: 0.96, 0.99; I = 0.0%; P < 0.01; Power = 0.76; n = 6), but neither for cruciferous vegetables (RR = 0.97, 95%CI: 0.93, 1.01; P = 0.19; I = 55.8%; n = 8) nor for citrus (RR = 1.00, 95%CI: 1.00, 1.00; P = 0.83; I = 0.0%; n = 7). Subgroup analysis showed consistent results.Little evidence supports a beneficial effect for total fruits, vegetables, both FVs, and citrus intake against bladder cancer. Green leafy vegetables may help prevent bladder cancer. PMID- 25929913 TI - Kawasaki disease mimicking a parapharyngeal abscess: a case report. AB - Parapharyngeal abscess (PPA)-like lesion is a very rare manifestation of Kawasaki disease (KD). Here we report a Chinese case of KD initially mimicking PPA, which is the first one reported in Asia.A 3-year-old male patient presented with fever, drooling, and bilateral painful cervical lymphadenopathy for 3 days. Chest X-ray and echocardiogram were normal. With substantial elevation of white blood count and C-reactive protein, purulent cervical lymphadenitis was considered. Symptoms did not improve after treatment with vancomycin, and the patient further developed trismus and restricted neck movement. Neck CT revealed a 2 * 1.5 cm hypodense lesion in the right parapharyngeal space with peripheral enhancement. PPA was suspected and on the 3rd day following admission, the patient received surgical incision and drainage. One milliliter of serous fluid was drained without bacterial growth on cultures. Fever persisted after surgery. As the clinical course proceeded, additional major signs of KD gradually evolved, and on the 6th day following admission the patient completely fulfilled the diagnostic criteria for KD. Rapid clinical improvement was observed following treatment with high-dose immunoglobulin and aspirin. Due to the parapharyngeal operation, the patient was fed milk through a nasogastric tube for 15 days. His neck incision became infected but healed gradually following dressing change and antibiotic treatment. Currently he remains asymptomatic during regular follow-up and repeated echocardiograms are normal.Both pediatricians and otolaryngologists can learn from this case that KD may initially manifest as PPA. Careful observation for major signs of KD during the clinical course can help to achieve a prompt and correct diagnosis. Thus, unnecessary surgery and cardiac complications of KD may be avoided. PMID- 25929914 TI - Radiation exposure of ovarian cancer patients: contribution of CT examinations performed on different MDCT (16 and 64 slices) scanners and image quality evaluation: an observational study. AB - The objective of this study is to compare radiation doses given to ovarian cancer patients by different computed tomographies (CTs) and to evaluate association between doses and subjective and objective image quality.CT examinations included were performed either on a 16-slice CT, equipped with automatic z-axis tube current modulation, or on a 64-slice CT, equipped with z-axis, xy-axis modulation, and adaptive statistical iterative algorithm (ASIR). Evaluation of dose included the following dose descriptors: volumetric CT dose index (CTDIvol), dose length product (DLP), and effective dose (E). Objective image noise was evaluated in abdominal aorta and liver. Subjective image quality was evaluated by assessment of image noise, spatial resolution and diagnostic acceptability.Mean and median CTDIvol, DLP, and E; correlation between CTDIvol and DLP and patients' weight; comparison of objective noise for the 2 scanners; association between dose descriptors and subjective image quality.The 64-slice CT delivered to patients 24.5% lower dose (P < 0.0001) than 16-slice CT. There was a significant correlation between all dose descriptors (CTDIvol, DLP, E) and weight (P < 0.0001). Objective noise was comparable for the 2 CT scanners. There was a significant correlation between dose descriptors and image noise for the 64-slice CT, and between dose descriptors and spatial resolution for the 16-slice CT.Current dose reduction systems may reduce radiation dose without significantly affecting image quality and diagnostic acceptability of CT exams. PMID- 25929915 TI - Painful lumbosacral plexopathy: a case report. AB - Patients frequently suffer from lumbosacral plexus disorder. When conducting a neurological examination, it is essential to assess the extent of muscle paresis, sensory disorder distribution, pain occurrence, and blocked spine. An electromyography (EMG) can confirm axonal lesions and their severity and extent, root affliction (including dorsal branches), and disorders of motor and sensory fiber conduction. Imaging examination, particularly gadolinium magnetic resonance imaging (MRI) examination, ensues. Cerebrospinal fluid examination is of diagnostic importance with radiculopathy, neuroinfections, and for evidence of immunoglobulin synthesis. Differential diagnostics of lumbosacral plexopathy (LSP) include metabolic, oncological, inflammatory, ischemic, and autoimmune disorders.In the presented case study, a 64-year-old man developed an acute onset of painful LSP with a specific EMG finding, MRI showing evidence of plexus affliction but not in the proximal part of the roots. Painful plexopathy presented itself with severe muscle paresis in the femoral nerve and the obturator nerve innervation areas, and gradual remission occurred after 3 months. Autoimmune origin of painful LSP is presumed.We describe a rare case of patient with painful lumbar plexopathy, with EMG findings of axonal type, we suppose of autoimmune etiology. PMID- 25929916 TI - Successful treatment of treatment-resistant schizophrenia in a 10-year-catatonic patient by augmentation of selective serotonin reuptake inhibitors: a case report. AB - Although catatonia is a well defined syndrome, the treatment of chronic catatonia remains an unresolved issue. Here, we report a successful treatment of a 30-year old patient with treatment-resistant catatonic schizophrenia in 10 years by augmentation of selective serotonin reuptake inhibitors (SSRIs).We present a 30 year-old man with treatment-resistant catatonic schizophrenia who failed to respond to the treatment of benzodiazepines and antipsychotics for 10 years. He markedly improved after taking SSRIs. Now, he does not hold odd postures and begins to talk and show more facial expressions.We postulate that the therapeutic effect is related to the enhancement of 5-HT neurotransmission. SSRIs can be a considerable choice to treat chronic catatonia. PMID- 25929917 TI - Repeated occurrence of second primary lung cancer at different sites in trachea: a case report. AB - Multiple or second primary lung cancers can develop at any sites in the lung with same or different histologic types, synchronously and/or metachronously. In case of metachronous occurrence of the second primary lung cancer, it is easy to confuse with the primary lung cancer as a recurrence of precedent lung malignancy treated successfully or metastasis. Previous reports have demonstrated that majority of the second primary lung malignancies have same histologic types regardless of their developing time and location. However, the repeated occurrence of the second primary lung malignancy, in particular with the different histologic features, is a very rare condition.A 62-year-old male who had past history of squamous cell carcinoma treated with surgery and adjuvant chemotherapy and the recurrence of lung malignancy on the trachea, which was also resected successfully visited our hospital due to blood tinged sputum. Evaluation using bronchoscopy and chest computed tomography revealed the tracheal mass looked similar grossly to the previous recurred tracheal mass that was resected surgically. Unexpectedly, the newly developed tracheal mass was confirmed as small cell lung cancer, the different histologic type from previous ones.In this report, we describe an interesting case of subsequent occurrence of second primary lung cancers showing histologic shifting at different sites in trachea, suggesting that it is important for physician to make an effort to identify the histologic characteristics of second primary lung cancers for the correct and adequate treatment no matter what they exhibit similar gross morphology. PMID- 25929918 TI - Target therapy of unresectable or metastatic dermatofibrosarcoma protuberans with imatinib mesylate: an analysis on 22 Chinese patients. AB - Dermatofibrosarcoma protuberans (DFSP) is a rare, plaque-like tumor of the cutaneous tissue occurring more on the trunk than the extremities and neck. More than 95% of DFSP present anomalies on the 17q22 and 22q13 chromosomal regions leading to the fusion of COL1A1 and PDGFB genes. Surgery is the optimal treatment for DFSP, but less effective in locally advanced or metastatic patients, as is the case with chemotherapy and radiotherapy. The aim of this study was to assess retrospectively the therapeutic activity and safety of imatinib on 22 Chinese patients with locally inoperative or metastatic DFSP at a single institution.In the collected data of 367 Chinese patients with DFSP, we analyzed retrospectively 22 patients with locally advanced or metastatic DFSP, all of whom received imatinib therapy at 1 center from January 2009 to October 2014. Patients were administered with imatinib at an initial dose of 400 mg and escalated to 800 mg daily after they developed imatinib resistance. The median follow-up time was 36 months, and the median treatment time was 15 months.The results showed that 10 locally advanced DFSP patients and 12 metastatic DFSP patients received imatinib therapy. Apart from 1 patient who developed primary imatinib resistance, 15 patients achieved partial remission (PR), and 6 patients achieved stable disease (SD). Both fibrosarcomatous DFSP and classic DFSP patients demonstrated similar response to imatinib. Median PFS was estimated to be 19 months. Median overall survival (OS) has not been reached, and estimated 1- and 3-year OS rates were 95.5% (21/22) and 77.3% (17/22), respectively. Four out of 10 patients with primarily unresectable DFSP received complete surgical resection after neoadjuvant treatment of imatinib.Imatinib therapy is well tolerated with a safety profile and is the therapy of choice in locally inoperative or metastatic DFSP. Neoadjuvant treatment of locally advanced or metastatic DFSP with imatinib improves surgical outcomes and may facilitate resection of difficult tumors. PMID- 25929919 TI - Efficacy of oral Etoposide in pretreated metastatic breast cancer: a multicenter phase 2 study. AB - No standard chemotherapy has been defined for metastatic breast cancer (MBC) patients pretreated with anthracyclines and taxanes. A multicenter phase 2 study was conducted to evaluate the safety and efficacy of oral etoposide in patients with MBC.Eligible patients were treated with repeated cycles of oral etoposide (60 mg/m/d on days 1-10, followed by 11 days of rest). The primary endpoint was progression-free survival (PFS). The secondary endpoints were objective response rate, clinical benefit rate (CBR), and toxicity profiles.Seventy-five women with MBC were enrolled at 10 centers in China. Seven (9.3%) patients achieved partial response (PR) and 29 (38.7%) had stable disease (SD). Nine patients (12%) had SD for >24 weeks and the CBR was 21.3% (16/75). The median PFS was 4.5 (range, 1.3 7.7) months. Of the 38 patients who received >=3 regimens prior to this study, 2 (5.3%) had PR and 3 (7.9%) had SD for >24 weeks, with a CBR of 13.2%. The reported grade 3/4 adverse events included leukopenia (13.3%, n = 10), neutropenia (17.9%, n = 14), anemia (2.7%, n = 2), vomiting (2.6%, n = 2), and alopecia (1.3%, n = 1).Oral etoposide was effective and well tolerated in Chinese women with pretreated MBC. PMID- 25929920 TI - Bilateral kidney infarction due to primary Al amyloidosis: a first case report. AB - Primary Amyloid Light-chain (AL) amyloidosis is a rare form of plasma cell dyscrasia characterized by tissue deposition of monoclonal immunoglobulin light chain. Kidney involvement is the most frequent manifestation, and patients usually present with glomerular disease.We report an exceptional case of bilateral kidney infarcts caused by AL amyloidosis. A 34-years-old man presented with progressive dyspnea, loin pain, recurrent macroscopic hematuria, and acute kidney injury. Computed tomography showed bilateral kidney infarcts.The diagnosis of AL amyloidosis was established on the kidney biopsy with the characterization of major vascular amyloid deposits that selectively stained with antilambda light chain antibody. An amyloid restrictive cardiomyopathy was also present, responsible for the life-threatening conduction disturbance, but without patent cardioembolic disease. The patient then underwent emergency heart transplantation, followed by a conventional chemotherapy with bortezomib, melphalan, and dexamethasone. More than 3 years later, the patient has subnormal renal function, a well-functioning heart transplant, and a sustained hematologic response.In addition to the very uncommon presentation, this case illustrates the tremendous progress that has occurred in the management of severe forms of AL amyloidosis. PMID- 25929921 TI - Statin withdrawal beyond acute phase affected outcome of thrombolytic stroke patients: an observational retrospective study. AB - Statin withdrawal is associated with deleterious outcome on stroke patients. Whether risk changes over time, depends on concomitant treatment of intravenous thrombolysis, or both remains to be clarified. We assessed the influence of statin withdrawal within 3 weeks while initiated in acute phase (72 hours) among patients receiving intravenous thrombolysis.This was a monocentered retrospective observational study enrolling intravenous thrombolytic stroke patients from June 2009 to May 2014. Consecutive patients were distinguished into 3 groups according to the initiation and withdrawal of statin: the reference group (not received statin in 72 hours after stroke onset); the continued group (initiated statin therapy in 72 hours and continued for at least 3 weeks); the withdrawal group (initiated statin in 72 hours and discontinued within 3 weeks). All reasons for cessation were recorded. The effects of statin withdrawal on short-, mid-, and long-term outcomes were evaluated as neurologic improvement (NIH Stroke Scale [NIHSS] score improvement >=4 from baseline or later NIHSS = 0), death or poor outcome (modified Rankin Scale [mRS] >=4), and favorable outcome (mRS <=2). We further evaluate statin withdrawal effects in cardioembolic stroke patients for these outcomes.Among 443 IVT patients enrolled, 367 were included in the final study population. There were 88, 188, and 91 patients in the reference, continued, and withdrawal groups, respectively. Multivariable logistic regression showed that statin withdrawal compared with the reference was related to a lower possibility of long-term favorable outcome (OR = 0.45, 95% CI [0.22, 0.90], P = 0.024). Compared with the continued group, the adjusted OR of statin withdrawal was 0.40 (95% CI [0.22, 0.72], P = 0.002) and 2.52 (95% CI [1.34, 4.75], P = 0.004) for long-term favorable and poor/death outcomes, respectively. Also, results were similar for cardioembolic stroke patients (OR = 0.35, 95% CI [0.14, 0.89], P = 0.027 of favorable outcome and OR = 3.62, 95% CI [1.37, 9.62], P = 0.010 of poor/death outcome).In a real-world setting, for stroke patients receiving intravenous thrombolysis, statin withdrawal within 3 weeks initiating in 72 hours may have a harmful effect on the long-term neurologic outcome, even in cardioembolic stroke patients. PMID- 25929922 TI - Differential effects of viremia and microbial translocation on immune activation in HIV-infected patients throughout ritonavir-boosted darunavir monotherapy. AB - The purpose of this article is to evaluate the evolution of microbial translocation (MT) and its role in CD4 and CD8 T cells immune activation (IA) in HIV-1-infected patients on ritonavir-boosted darunavir monotherapy (mtDRV/rtv).Prospective study of consecutive HIV-1-infected patients switched to mtDRV/rtv as a simplification regimen. Subjects were classified according to the virological behavior during a 24-month follow-up as continuous undetectable viral load, blips, intermittent viremia, and virological failure (VF). MT was evaluated by plasma LPS and 16S genomic rDNA (16S rDNA) levels, whereas IA was assessed by the coexpression of HLA-DR and CD38 in CD4 and CD8 T cells, and plasma sCD14 levels.Seventy-one patients were included in this substudy of the MonDar cohort (ClinicalTrials.gov: NCT01505722). At baseline, CD4 (rho = -0.352, P = 0.01) and CD8 T-cell activation (rho = -0.468, P < 0.001) were correlated with time with viral suppression, but not with MT markers. A significant decrease in plasma LPS levels was found only in patients without VF (baseline, 77.8 vs month 24, 60.4 pg/mL; P < 0.001]. Both plasma 16S rDNA and sCD14 levels were unchanged irrespective of the viral behavior. The only variable independently associated with a decrease in CD4 and CD8 T cells activation was an undetectable HIV-1 viremia (beta = 4.78, P < 0.001 and beta = 2.93, P = 0.005, respectively).MT does not have a pivotal role in T-cell activation, at least in patients with long-term viral suppression. The viremic episodes and VF are the main factors related to CD4 and CD8 T-cells IA, even during mtDRV/rtv. PMID- 25929923 TI - Prevalence and risk factors of cognitive impairment in Parkinson disease: a population-based case-control study in Taiwan. AB - The aim of this study was to evaluate the Parkinson disease (PD) prevalence of cognitive impairment in Taiwan.The case-control study consisted of 6177 cognitive impairment patients and 24,708 noncognitive impairment as controls for the period of 2006 to 2010 and both of the groups aged >=50 years. The multivariable logistic regression analyses were used to estimate the odds ratio (OR) for cognitive impairment, and the 95% confidence intervals (CIs) among patients with PD were compared with those of non-PD patients.PD (adjusted odds ratio [aOR] is 3.07, 95% CI 2.76-3.41) is the one of the most contributed risk factors for cognitive impairment. Besides, we found a remarkable result of the diagnosed cognitive impairment of PD that was found highest in the first 6 months (aOR 11.98, 95% CI 8.51-16.86) and then decrease the incident year by year. The PD prevalence in a patient with cognitive impairment in our data present is 12.1% lower than those with truly dementia published previously and documented by western studies.We found a remarkable result of the diagnosed cognitive impairment of PD that was found highest in the first 6 months and then decrease the incident year by year. PMID- 25929924 TI - A comprehensive method for predicting fatal liver failure of patients with liver cancer resection. AB - There are many methods to assess liver function, but none of them has been verified as fully effective. The purpose of this study is to establish a comprehensive method evaluating perioperative liver reserve function (LRF) in patients with primary liver cancer (PLC).In this study, 310 PLC patients who underwent liver resection were included. The cohort was divided into a training set (n = 235) and a validation set (n = 75). The factors affecting postoperative liver dysfunction (POLD) during preoperative, intraoperative, and postoperative periods were confirmed by logistic regression analysis. The equation for calculating the preoperative liver functional evaluation index (PLFEI) was established; the cutoff value of PLFEI determined through analysis by receiver operating characteristic curve was used to predict postoperative liver function.The data showed that body mass index, international normalized ratio, indocyanine green (ICG) retention rate at 15 minutes (ICGR15), ICG elimination rate, standard remnant liver volume (SRLV), operative bleeding volume (OBV), blood transfusion volume, and operative time were statistically different (all P < 0.05) between 2 groups of patients with and without POLD. The relationship among PLFEI, ICGR15, OBV, and SRLV is expressed as an equation of "PLFEI = 0.181 * ICGR15 + 0.001 * OBV - 0.008 * SRLV." The cutoff value of PLFEI to predict POLD was -2.16 whose sensitivity and specificity were 90.3% and 73.5%, respectively. However, when predicting fatal liver failure (FLF), the cutoff value of PLFEI was switched to -1.97 whose sensitivity and specificity were 100% and 68.8%, respectively.PLFEI will be a more comprehensive, sensitive, and accurate index assessing perioperative LRF in liver cancer patients who receive liver resection. And keeping PLFEI <-1.97 is a safety margin for preventing FLF in PLC patients who underwent liver resection. PMID- 25929926 TI - Paraoxonase and arylesterase activities in dipper and non-dipper prehypertensive subjects. AB - Paraoxonase-1, a high-density lipoprotein linked enzyme complex, was shown to be decreased in several cardiovascular diseases. We aimed to explore whether serum paraoxonase and arylesterase activities differ in dipper and non-dipper prehypertensive subjects compared to healthy controls.Sixty prehypertensive subjects and 30 controls were enrolled. All subjects underwent echocardiographic assessment and 24-hour ambulatory blood pressure monitoring (ABPM). According to the blood pressure (BP) course on ABPM, prehypertensive subjects were categorized into two: non-dipper prehypertensive (NDPH) and dipper prehypertensive (DPH) groups. Serum paraoxonase and arylesterase activities were detected spectrophotometrically.Paraoxonase and arylesterase activities were significantly lower in patients with NDPH compared to both DPH and control groups. Both paraoxonase and arylesterase activities showed significant negative correlations with BP and left ventricular mass index.We have demonstrated that NDPH subjects have lower paraoxonase and arylesterase activities compared to DPH subjects and normotensives. Further prospective studies are needed to clarify the role of paraoxonase and arylesterase activities in the development of overt hypertension in prehypertensive subjects. PMID- 25929927 TI - The pathologic findings of skin, lymph node, liver, and bone marrow in patients with adult-onset still disease: a comprehensive analysis of 40 cases. AB - Adult-onset Still disease (AOSD) is characterized by fever, skin rash, and lymphadenopathy with leukocytosis and anemia as common laboratory findings. We investigated the characteristic pathologic findings of skin, lymph node, liver, and bone marrow to assist in proper diagnosis of AOSD.Forty AOSD patients were included in the study. The skin (26 patients), lymph node (8 patients), liver (8 patients), or bone marrow biopsies (22 patients) between 1998 and 2013 were retrospectively analyzed. AOSD patients were diagnosed according to the Yamaguchi criteria after excluding common infections, hematological and autoimmune diseases. Immunohistochemistry, immunofluorescence, and Epstein-Barr virus encoded RNA (EBER) in situ hybridization were performed.Most skin biopsies revealed mild lymphocytic or histiocytic infiltration in the upper dermis. Nuclear debris was frequently found in the dermis in 14 cases (53.8%). More than half of the cases (n = 14, 53.8%) showed interstitial mucin deposition. Some cases showed interface dermatitis with keratinocyte necrosis or basal vacuolization (n = 10; 38.5%). The lymph node biopsies showed a paracortical or diffuse hyperplasia pattern with immunoblastic and vascular proliferation. The liver biopsies showed sparse portal and sinusoidal inflammatory cell infiltration. All cases showed various degrees of Kupffer cell hyperplasia. The cellularity of bone marrow varied from 20% to 80%. Myeloid cell hyperplasia was found in 14 out of the 22 cases (63.6%). On immunohistochemistry, the number of CD8-positive lymphocytes was greater than that of CD4-positive lymphocytes in the skin, liver, and bone marrow, but the number of CD4-positive lymphocytes was greater than that of CD8-positive lymphocytes in the lymph nodes.The relatively specific findings with respect to the cutaneous manifestation of AOSD were mild inflammatory cell infiltration in the upper dermis, basal vacuolization, keratinocyte necrosis, presence of karyorrhexis, and mucin in the dermis. In all cases, pathologic findings in the lymph nodes included paracortical hyperplasia with vascular and immunoblastic proliferation. Skin and lymph node pathology in addition to clinical findings can aid in the diagnosis of AOSD. PMID- 25929925 TI - Hemoglobin a1c levels and the risk of cardiovascular disease in people without known diabetes: a population-based cohort study in Japan. AB - High hemoglobin A1c (HbA1c) levels are strongly associated with an increased risk of cardiovascular disease (CVD) in people with and without diabetes. However, information regarding the relationship between low HbA1c levels and the risk of CVD among people without known diabetes is limited. The aim of this large-scale, prospective, population-based cohort study was to clarify the association between HbA1c levels and CVD risk among people without known diabetes.We followed-up 10,980 men and 18,079 women (46-80 years old and free of CVD and cancer at baseline) in the Japan Public Health Center-based Prospective Study. Using Cox models, we estimated the hazard ratios for CVD risk with adjustments for age, sex, geographic areas, body mass index, smoking status, sports and physical exercise, alcohol intake, systolic blood pressure, non-high-density lipoprotein cholesterol, and high-density lipoprotein cholesterol.During the median follow-up of 9.4 years, 935 CVD events (770 strokes and 165 coronary heart diseases) occurred. We observed a nonlinear association between HbA1c levels and CVD risk in participants without known diabetes. Compared with HbA1c levels of 5.0 to 5.4% (31-36 mmol/mol), the hazard ratios for CVD in participants without known diabetes were 1.50 (95% confidence interval: 1.15-1.95), 1.01 (0.85-1.20), 1.04 (0.82-1.32), and 1.77 (1.32-2.38) for HbA1c levels of <5.0% (<31 mmol/mol), 5.5 to 5.9% (37-41 mmol/mol), 6.0 to 6.4% (42-47 mmol/mol), and >=6.5% (>=48 mmol/mol), respectively (P value for nonlinear trend: <0.001). In addition, the hazard ratio for CVD was 1.81 (1.43-2.29) in patients with known diabetes compared with participants with HbA1c levels of 5.0 to 5.4% and without known diabetes. This nonlinear relation persisted after excluding people with kidney dysfunction, liver dysfunction, anemia, body mass index <18.5 kg/m, or early events within 3 years of follow-up (P value for nonlinear trend: <0.01 for all tests).In conclusion, both low and high levels of HbA1c were associated with a higher risk of CVD in a Japanese general population without known diabetes. PMID- 25929928 TI - Mucosa-associated lymphoid tissue lymphoma of the larynx: a case report and literature review. AB - The clinicopathological characteristics and rational treatment of primary laryngeal mucosa-associated lymphoid tissue (MALT) lymphoma are still unclear and need to be further defined due to the paucity of this separate lymphoma.Herein, a supraglottic primary MALT lymphoma was described with detailed clinical course, intervention, and follow-up. To date, research of laryngeal MALT lymphoma has seldom been initiated. Our experience in this case will help to expand our understanding of this unique disease. A 58-year-old female presented with a history of progressive hoarseness for about 10 months. Multiple laryngoscopy examinations revealed severe hypertrophy of left ventricular band. She was admitted to our department with residual MALT lymphoma of supraglottic region after partial resection by laser. After systemic evaluation, she was staged as IEA, International Prognostic Index score 0. Irradiation of intensity modulated radiotherapy technique with a dose of 30.6 Gy/17f to the tumor and 25.5 Gy/17f to the related lymphatic drainage area achieved a complete remission. The disease free survival has reached to 4 years. The irradiation related acute and late side effects were mild.Radiotherapy is the first option for limited-stage primary laryngeal MALT lymphoma because of excellent treatment outcome. PMID- 25929929 TI - Pheochromocytoma crisis with severe cyclic blood pressure fluctuations in a cardiac pheochromocytoma patient successfully resuscitated by extracorporeal membrane oxygenation: a case report. AB - Cardiac pheochromocytoma is relatively rare. Few reports describe the intraoperative and postoperative progression of patients experiencing a life threatening pheochromocytoma crisis treated with extracorporeal membrane oxygenation (ECMO).A 35-year-old man was referred to our facility for paroxysmal hypertension with a 10-year history of sweating, headaches, cardiac palpitations, and postexercise dyspnea. The patient initially underwent urine catecholamine measurement and an isotope scan, somatostatin receptor scintigraphy, and 18F fluorodeoxyglucose positron emission tomography/computer tomography (CT), which indicated a multiple, cardiac pheochromocytoma. Echocardiography, cardiac magnetic resonance imaging (MRI), CT reconstruction, and a coronary CT angiography revealed several lesions at the aortic root and along the cardiac vasculature.Multifocal cardiac pheochromocytoma was diagnosed and pheochromocytoma crisis with severe cyclic blood pressure fluctuation occurred during surgery.Surgical resection of multiple pheochromocytomas in the right medial carotid sheath, mediastinum between the main and pulmonary arteries, and between the abdominal aorta and inferior vena artery was performed. To ensure cardiac perfusion and avoid severe circulatory fluctuation, the cardiac paraganglioma resection was prioritized. After resecting the cardiac pheochromocytoma, a severe pheochromocytoma crisis with rapid cyclic blood pressure fluctuation developed. ECMO and intraaortic balloon pump (IABP) were initiated to stabilize circulation and perfusion. Phenoxybenzamine, norepinephrine, epinephrine, and fluid resuscitation were administered to support cardiovascular function.The magnitude of blood pressure fluctuation steadily decreased with treatment. IABP was discontinued after 3 days, and ECMO was discontinued after 16 days. The patient was discharged 3 months postoperatively.This case indicates that mechanical life support with ECMO is a valuable option for pheochromocytoma-induced cardiac shock and should be considered as an effective therapeutic choice in patients with highly unstable hemodynamic function. PMID- 25929930 TI - Long-term survival and death causes of systemic lupus erythematosus in China: a systemic review of observational studies. AB - Systemic lupus erythematosus (SLE) is a chronic autoimmune disease with an increased risk of death compared to general population. Although previous studies showed improvement in survival of SLE, the long-term prognosis has not been elaborated in China.This study aims to integrate the observational studies estimating current long-term survival of Chinese SLE patients and analyze the death-cause situation of SLE in China.The study is a systemic review of English and non-English articles using MEDLINE, EMBASE, CNKI, WANFANG, and SINOMED databases. Additional studies were found by consultation with clinical experts, browse of references in selected papers, and search of related textbooks. Our major search terms were SLE, follow-up, prognosis, survival, mortality, and China.We included cohort studies for survival analysis, and both cohort studies and case series for death-cause analysis in China.The extraction of the articles were done by 2 authors independently using predesigned charts, including characteristics of study, clinical data, analyzing data, and study quality indicators.All pooled analyses were conducted both for random-effects model and fixed-effects model. Funnel plots and Egger regression tests were applied to check potential publication bias. Heterogeneity was tested by sensitivity analysis. We identified 5 studies for survival analysis comprising 4469 Chinese patients with SLE (380 observed deaths). Thirty-six studies were suitable for death-cause analysis with 2179 observed deaths (derived from more than 20,000 Chinese patients with SLE). The overall pooled survival rates for SLE in China were 94% for 5-year survival rate and 89% for 10-year survival rate after disease onset from the year 1995 to 2013, which were similar with previous publications in Asia-Pacific area. The proportions of different causes of death showed infection (33.2%), renal involvement (18.7%), lupus encephalopathy (13.8%), and cardiovascular disease (11.5%) as the top 4 causes.The overall survival rates for Chinese patients with SLE resembled previous publications in Asia-Pacific area. But the death causes of SLE in China were of some differences indicating relatively higher proportion of infection and lupus encephalopathy and lower cardiovascular disease. Ethnicity and more aggressive treatment might have contributed to the difference in death composition. PMID- 25929931 TI - Incidence of branching patterns variations of the arch in aortic dissection in Chinese patients. AB - Several authors have described anatomic variations of the aortic arch in 13% to 20% of the patients who do not have aortic disease. However, few studies have evaluated these patterns in the thoracic aortic dissection (TAD). In the authors' knowledge, this is the first survey that specifically investigates the frequency of these variations in a broad, nonselected group of Chinese patients with aortic dissection. Furthermore, it compares this group with a group of patients without aortic disease.The objective of this study was to define the variation frequency of the aortic arch branches pattern using the tomographic studies of 525 Chinese patients with a diagnosis of TAD. The Stanford classification was used to set the site of the initial tear of the dissection. In addition, we performed an epidemiological analysis of the aortic arch anatomic variations in TAD, and its possible implications for surgical or endovascular treatment. The general hypothesis proposal asserted that Chinese patients with dissection of the aorta have a similar incidence of variations of the aortic arch to the patients without aortic disease.A retrospective study of cases and controls was carried out using the tomographic studies (CT) of all patients admitted to the First Affiliated Hospital of Zhengzhou University, located at Henan-China, with a confirmed diagnosis of aortic dissection from January 2012 until December 2014. The group of cases consisted of 525 patients: 374 men and 151 women, with a mean age of 52.27 years (range, 20-89). The average age of the patients with Stanford A and B aortic dissection was 49.46 and 53.67, respectively. The control group consisted of 525 unselected patients without TAD who underwent a CT scan of the chest due to other indications. This group consisted of 286 men and 239 women, with a mean age of 53.60 years (range, 18-89). All the patients with aneurysm or dissection were excluded from the control group. We performed a statistical analysis of demographic data.The study found 7 different patterns of the aortic arch on both groups of cases and controls. Within the 525 patients with TAD were observed 85 (16.19%) anatomical variations, while the control group showed 112 variations (21.33%); P = 0.033. The most common anatomical variant was the bovine arch, found in 62 (11.80%) cases of TAD compared with 77 (14.66%) in the control group; P = 0.172. Anatomical variations were observed in 14.32% of the patients with Stanford A dissection and 17.09% of the patients with Stanford B dissection; P = 0.425. Patients with Stanford A dissection showed the pattern of bovine arch in 23 (13.21%) of 174 cases. In contrast, the patients with Stanford B dissection showed it in 39 (11.11%) of 351 cases; P = 0.481. The anatomical variant defined as vertebral artery of direct origin of the aortic arch was more frequent in the patients with Stanford B dissection (5.12%). The patients with Stanford A dissection presented this pattern in 1.14% of the cases; P = 0.025. This study observed an increased frequency of aortic dissection in the subgroup from 41 to 60 years old. In the subgroup from 41 to 60 years old without TAD, a greater frequency of anatomical variations were found than in the patients with TAD (20.81% vs 14.23%; P = 0.050). The same fashion was seen in patients older than 80 years (27.27% vs 0%; P = 0.030). The anatomical variations of the aortic arch with TAD occurred in 14.97% of the male patients and 19.20% of the female patients compared to 21.67% to 20.92% in the control group; P = 0.026 and P = 0.681, respectively.The aortic arch variations were found less frequently in the TAD group than in the control group in the present Chinese series. The bovine arch was considered the variant pattern of the major frequency in the patients with TAD and the control group. The anatomical variant of 4 branches, defined as vertebral artery of direct origin of the aortic arch, was more frequent in patients with Stanford B aortic dissection than in the patients with Stanford A.This finding might show an association between the geometry of the aortic arch and the site of onset of first intimal tear of dissection. PMID- 25929932 TI - Novel low-cost endoscopic cap for esophageal foreign objects: a case report. AB - A 57-year-old man presented to the hospital because of swallowing of a small marble precipitated by a hallucination. He subsequently developed chest discomfort. He had a history of psychiatric problem and an esophageal corrosive injury complicated by stricture of the middle esophagus.This report describes the novel idea of endoscopic intervention for the retrieval of an esophageal foreign body. Its inventiveness and the use of limited resources, by adapting a 30-mm aseptic common tubing into an endoscopic retrieving device, make the method novel. This novel low-cost endoscopic cap (NLCEC) was adapted to 25 mm of the front end of the endoscope, with 5 mm maintained for the soft part to prevent esophageal mucosal injury during the retrieval process. An 8-mm green marble was found impacted in the esophagus 32 cm from the incisors. The use of forced suction allowed for the successful retrieval of the marble within minutes. The patient had an uneventful recovery without any serious complications.This NLCEC may be a viable and safe tool for the endoscopic retrieval of esophageal foreign objects without general anesthesia. This innovative design is beneficial in terms of patient safety, easy preparation, and low cost. PMID- 25929933 TI - Diagnostic pitfalls of discriminating lymphoma-associated effusions. AB - High serum lactate dehydrogenase (LDH) level, immunologic defects, enlarged mediastinal lymph nodes, and frequent hydration and diuresis in lymphoma patients may affect the development of pleural effusion (PE). The study was to assess the clinical utility of "Light criteria" and the "recommended algorithm for investigating PEs" in patients with lymphoma.The characteristics of 126 PEs of lymphoma patients who underwent diagnostic thoracentesis between January 1, 2003, and April 30, 2012, were reviewed. Using Light criteria, 29 (23%) PEs were incorrectly classified. The sensitivity for exudates in Light criteria was 88% and the specificity was only 44%. In 32 transudates, PE LDH correlated with blood LDH concentration (P < 0.001, r = 0.66). Nine transudates were misclassified as exudates (50%; 9/18) just due to PE LDH more than two-thirds the upper limits. Among the 56 bilateral PEs, 33 (59%) were exudates. Ten (63%) polymorphonuclear (PMN)-predominant exudative PEs were malignant. Infective PEs were often mononuclear (67%) rather than PMN predominant.When a patient has lymphoma with either unilateral or bilateral PE, thoracentesis for microbiological testing and cytology is imperative. Carefully clinical correlation in addition to the result from Light criteria and differential cell count is essential for prompt management. PMID- 25929934 TI - Association between sex-specific serum uric acid and non-alcoholic fatty liver disease in Chinese adults: a large population-based study. AB - The aim of this study was to examine the association between sex-specific serum uric acid (sUA) levels and NAFLD in a large population-based study.A total of 60,455 subjects from 2 separate medical centers were included. Sex-specific sUA quartiles (Q1-Q4) were defined: <=330, 331-380, 381-435, and >=436 MUmol/L for male; <=230, 231-270, 271-310, and >=311 MUmol/L for female. The odds ratios (ORs), hazard ratios (HRs), and 95% confidence intervals (CIs) for NAFLD were calculated across each quartile of sUA, using the Q1 as reference.After adjusting for known confounding variables in this study, the ORs for NAFLD in the cross sectional population were 1.211 (95% CI 1.109-1.322), 1.519 (95% CI 1.395-1.654), 1.903 (95% CI 1.748-2.072) for Q2, Q3, and Q4, respectively. In the longitudinal population, compared with the reference group, those in Q2, Q3, and Q4 had HRs of 1.127 (95% CI 0.956-1.330), 1.380 (95% CI 1.157-1.644), 1.589 (95% CI 1.310 1.927) for NAFLD, respectively. Analysis for the sex-specific subgroup showed the adjusted ORs for Q4 versus Q1 were 2.898 (95% CI 2.36-3.588) in female and 1.887 (95% CI 1.718-2.072) in male in the cross-sectional population. In the longitudinal population, the HRs for the Q4 were 2.355 (95% CI 1.702-3.259) in female and 1.249 (95% CI 0.975-1.601) in male, compared with Q1.We report that a sex-specific sUA level is independently associated with NAFLD. The association between sUA and NAFLD was significantly greater in females than in males. PMID- 25929935 TI - Role of taxane and anthracycline combination regimens in the management of advanced breast cancer: a meta-analysis of randomized trials. AB - The clinical benefits provided by using combined taxanes and anthracyclines in first-line chemotherapy for metastatic breast carcinoma (MBC) remain uncertain. This meta-analysis compares the benefits of using a combination of anthracyclines along with taxanes versus using single-agent-based chemotherapeutic regimens in the treatment of MBC.Relevant clinical trials as well as abstracts from articles presented at major cancer conferences were searched in various databases including PubMed, Embase, and Cochrane Library. The relevant studies had a primary endpoint of overall survival (OS) and secondary endpoints that included progression-free survival (PFS), time-to-treatment failure (TTF), time to progression (TTP), objective response rate (ORR), disease control rate (DCR), and safety. The hazard ratios of OS, PFS, TTF, and TTP, the odds ratios of ORR and DCR, and the risk ratios (RRs) for grades 1-2 and 3-4 toxicities were extracted from the retrieved studies and analyzed using various statistical methods. Meta analytic estimates were derived from a random-effect model.Fifteen trials were included in the final meta-analysis, and the results suggest that chemotherapy with combined anthracyclines and taxanes does not significantly improve the OS of MBC patients when compared with the OS achieved using separate taxane or anthracycline-based regimens. Compared with taxane-based regimens, combined taxane along with anthracycline regimens failed to significantly improve TTP, ORR, or DCR, but did significantly improve TTP and ORR when compared with anthracycline-based regimens. Furthermore, both individual taxane-based and anthracycline-based regimens produced fewer toxic reactions compared to combined taxane along with anthracycline regimens. Taxane-based regimens had lower RRs for side effects of neutropenia, infection/febrile neutropenia, nausea, and vomiting, whereas patients receiving anthracycline-based regimens had lower RRs for neutropenia, infection/febrile neutropenia, anorexia, stomatitis/mucosal inflammation, diarrhea, and sensory neuropathy. In contrast, patients receiving taxane-based regimens were at higher RRs for hand-foot syndrome and diarrhea, whereas patients receiving anthracycline-based regimens had higher RRs for nausea and vomiting.A taxane-based treatment regimen may be a better option than a combined taxane/anthracycline regimen for managing patients with advanced breast cancer, as it produces equivalent clinical outcomes and has less toxicity compared to other similar regimens. PMID- 25929936 TI - Virtual intravascular endoscopy visualization of calcified coronary plaques: a novel approach of identifying plaque features for more accurate assessment of coronary lumen stenosis. AB - This study was conducted to investigate the feasibility of using 3D virtual intravascular endoscopy (VIE) as a novel approach for characterization of calcified coronary plaques with the aim of differentiating superficial from deep calcified plaques, thus improving assessment of coronary stenosis.A total of 61 patients with suspected coronary artery disease were included in the study. Minimal lumen diameter (MLD) was measured and compared between coronary CT angiography (CCTA) (>=64-slice) and invasive coronary angiography (ICA) with regard to the measurement bias, whereas VIE findings were correlated with CCTA with respect to the diagnostic performance of coronary stenosis and the area under the curve (AUC) by receiver-operating characteristic curve analysis (ROC).In all 3 coronary arteries, the CCTA consistently underestimated the MLD relative to the ICA (P < 0.001). On a per-vessel assessment, the sensitivity, specificity, positive predictive value, and negative predictive value and 95% confidence interval (CI) were 94% (95% CI: 61%, 100%), 27% (95% CI: 18%, 38%), 33% (95% CI: 23%, 43%), and 92% (95% CI: 74%, 99%) for CCTA, and 100% (95% CI: 89%, 100%), 85% (95% CI: 75%, 92%), 71% (95% CI: 56%, 84%), and 100% (95% CI: 95%, 100%) for VIE, respectively. The AUC by ROC analysis for VIE demonstrated significant improvement in analysis of left anterior descending calcified plaques compared with CCTA (0.99 vs 0.60, P < 0.001), with better performance in the left circumflex and right coronary arteries (0.98 vs 0.84 and 0.77 vs 0.77, respectively; P = 0.07 and P = 0.96, respectively). There are no significant differences between 64-, 128-, and 640-slice CCTA and VIE in terms of sensitivity, specificity, positive and negative predictive value in the diagnosis of coronary stenosis.This study shows the feasibility of using VIE for characterizing morphological features of calcified plaques, therefore, significantly improving assessment of coronary stenosis. PMID- 25929937 TI - An increased risk of reversible dementia may occur after zolpidem derivative use in the elderly population: a population-based case-control study. AB - We evaluate the effects of zolpidem use to develop dementia or Alzheimer disease from the Taiwan National Health Insurance Research Database (NHIRD).A retrospective population-based nested case-control study. Newly diagnosed dementia patients 65 years and older and controls were sampled. A total of 8406 dementia and 16,812 control subjects were enrolled from Taiwan NHIRD during 2006 to 2010. The relationships between zolpidem use and dementia were measured using odds and adjusted odds ratios. The relationship between the average cumulative doses for zolpidem and dementia was also analyzed.Zolpidem alone or with other underlying diseases, such as hypertension, diabetes, and stroke, was significantly associated with dementia after controlling for potential confounders, such as age, sex, coronary artery disease, diabetes, anti hypertension drugs, stroke, anticholesterol statin drugs, depression, anxiety, benzodiazepine, anti-psychotic, and anti-depressant agents' use (Adjusted OR = 1.33, 95% CI 1.24-1.41). Zolpidem use also has significant dose-response effects for most of the types of dementia. In patient with Alzheimer diseases, the effects of zolpidem among patients with Alzheimer's disease remained obscure. The adjusted OR for patients whose cumulative exposure doses were between 170 and 819 mg/year (adjusted OR: 1.65, 95% CI 1.08-2.51, P = 0.0199) was significant; however, the effects for lower and higher cumulative dose were not significant.Zolpidem used might be associated with increased risk for dementia in elderly population. Increased accumulative dose might have higher risk to develop dementia, especially in patients with underlying diseases such as hypertension, diabetes, and stroke. PMID- 25929938 TI - A scoring system to predict the risk of postoperative complications after laparoscopic gastrectomy for gastric cancer based on a large-scale retrospective study. AB - To investigate the risk factors for postoperative complications following laparoscopic gastrectomy (LG) for gastric cancer and to use the risk factors to develop a predictive scoring system.Few studies have been designed to develop scoring systems to predict complications after LG for gastric cancer.We analyzed records of 2170 patients who underwent a LG for gastric cancer. A logistic regression model was used to identify the determinant variables and develop a predictive score.There were 2170 patients, of whom 299 (13.8%) developed overall complications and 78 (3.6%) developed major complications. A multivariate analysis showed the following adverse risk factors for overall complications: age >=65 years, body mass index (BMI) >= 28 kg/m, tumor with pyloric obstruction, tumor with bleeding, and intraoperative blood loss >=75 mL; age >=65 years, a Charlson comorbidity score >=3, tumor with bleeding and intraoperative blood loss >=75 mL were identified as independent risk factors for major complications. Based on these factors, the authors developed the following predictive score: low risk (no risk factors), intermediate risk (1 risk factor), and high risk (>=2 risk factors). The overall complication rates were 8.3%, 15.6%, and 29.9% for the low-, intermediate-, and high-risk categories, respectively (P < 0.001); the major complication rates in the 3 respective groups were 1.2%, 4.7%, and 10.0% (P < 0.001).This simple scoring system could accurately predict the risk of postoperative complications after LG for gastric cancer. The score might be helpful in the selection of risk-adapted interventions to improve surgical safety. PMID- 25929940 TI - Survival Prognostic Value of Morphological and Metabolic variables in Patients with Stage I and II Non-Small Cell Lung Cancer. AB - BACKGROUND: The prognosis of patients with non-small cell lung cancer (NSCLC) is important, as patients with resectable disease and poor prognostic variables might benefit from neoadjuvant therapy. The goal of this study is to evaluate SUVmax, SUVmax ratio, CT volume (CTvol), metabolic tumour volume (MTV) and total lesion glycolisis (TLG) as survival prognostic markers. In addition, we defined two variables; MTV x SUVmax (MTVmax) and CTvol x SUVmax (CTvolmax) and assessed whether they can be used as prognostic markers. METHODS: Patients with stage I-II NSCLC who underwent 18 F FDG PET/CT and surgery were evaluated. Cox proportional hazard model was used to determine the association between variables and survival. Similar analysis was performed in cases with no lymph node (LN) involvement. RESULTS: One hundred and eighty-one patients were included (at the end of the study, 140 patients were alive). SUVmax with a cut-off value of 8.2 was significant survival prognostic factor regardless of LN involvement (P = 0.012). In cases with no LN involvement, SUVmax and CTvol (>=7.1 ml) were significant survival prognostic factors with P = 0.004 and 0.03, respectively. CONCLUSIONS: SUVmax may be a useful prognostic variable in stage I-II NSCLC while morphologic tumour volume might be useful in cases with no lymph node involvement. KEY POINTS: * Identifying variables that predict the prognosis of patients with NSCLC is important. * SUVmax in primary lung tumour is a useful independent prognostic variable. * (CTvol) is an independent prognostic variable if no lymph nodes are involved. PMID- 25929939 TI - ESR/ERS white paper on lung cancer screening. AB - Lung cancer is the most frequently fatal cancer, with poor survival once the disease is advanced. Annual low-dose computed tomography has shown a survival benefit in screening individuals at high risk for lung cancer. Based on the available evidence, the European Society of Radiology and the European Respiratory Society recommend lung cancer screening in comprehensive, quality assured, longitudinal programmes within a clinical trial or in routine clinical practice at certified multidisciplinary medical centres. Minimum requirements include: standardised operating procedures for low-dose image acquisition, computer-assisted nodule evaluation, and positive screening results and their management; inclusion/exclusion criteria; expectation management; and smoking cessation programmes. Further refinements are recommended to increase quality, outcome and cost-effectiveness of lung cancer screening: inclusion of risk models, reduction of effective radiation dose, computer-assisted volumetric measurements and assessment of comorbidities (chronic obstructive pulmonary disease and vascular calcification). All these requirements should be adjusted to the regional infrastructure and healthcare system, in order to exactly define eligibility using a risk model, nodule management and a quality assurance plan. The establishment of a central registry, including a biobank and an image bank, and preferably on a European level, is strongly encouraged. KEY POINTS: * Lung cancer screening using low dose computed tomography reduces mortality. * Leading US medical societies recommend large scale screening for high-risk individuals. * There are no lung cancer screening recommendations or reimbursed screening programmes in Europe as of yet. * The European Society of Radiology and the European Respiratory Society recommend lung cancer screening within a clinical trial or in routine clinical practice at certified multidisciplinary medical centres. * High risk, eligible individuals should be enrolled in comprehensive, quality-controlled longitudinal programmes. PMID- 25929941 TI - Upright CT of the knee: the effect of weight-bearing on joint alignment. AB - OBJECTIVES: To prospectively compare patellofemoral and femorotibial alignment in supine non-weight-bearing computed tomography (NWBCT) and upright weight-bearing CT (WBCT) and assess the differences in joint alignment. METHODS: NWBCT and WBCT images of the knee were obtained in 26 patients (mean age, 57.0 +/- 15.9 years; range, 21-81) using multiple detector CT for NWBCT and cone-beam extremity CT for WBCT. Two musculoskeletal radiologists independently quantified joint alignment by measuring femorotibial rotation, tibial tuberosity-trochlear groove distance (TTTG), lateral patellar tilt angle, lateral patellar shift, and medial and lateral femorotibial joint space widths. Significant differences between NWBCT and WBCT were sought using Wilcoxon signed-rank test (P-value < 0.05). RESULTS: Significant differences were found for femorotibial rotation (the NWBCT mean changed from 2.7 degrees +/- 5.1 (reader 1)/2.6 degrees +/- 5.6 (reader 2) external rotation to WBCT 0.4 degrees +/- 7.7/0.2 degrees +/- 7.5 internal rotation; P = 0.009/P = 0.004), TTTG (decrease from NWBCT (13.8 mm +/- 5.1/13.9 mm +/- 3.9) to WBCT (10.5 mm +/- 5.0/10.9 mm +/- 5.2; P = 0.008/P = 0.002), lateral patellar tilt angle (decrease from NWBCT (15.6 degrees +/- 6.7/16.9 degrees +/- 7.4) to WBCT (12.5 degrees +/- 7.7/15.0 degrees +/- 6.2; P = 0.011/P = 0.188). The medial femorotibial joint space decreased from NWBCT (3.9 mm +/- 1.4/4.5 mm +/- 1.3) to WBCT (2.9 mm +/- 2.2/3.5 mm +/- 2.2; P = 0.003/P = 0.004). Inter-reader agreement ranged from 0.52-0.97. CONCLUSION: Knee joint alignment changes significantly in the upright weight-bearing position using CT when compared to supine non-weight-bearing CT. KEY POINTS: * Cone-beam extremity CT offers upright weight-bearing examinations of the lower extremities. * Knee alignment changes significantly in an upright position compared to supine position. * Tibial tuberosity-trochlear groove distance (TTTG) is less pronounced in a weight-bearing position. * The weight-bearing position leads to a decrease of the lateral patellar tilt angle. PMID- 25929942 TI - Contrast enhancement of intracranial lesions at 1.5 T: comparison among 2D spin echo, black-blood (BB) Cube, and BB Cube-FLAIR sequences. AB - OBJECTIVES: The purpose of this study was to investigate the usefulness of T1W black-blood Cube (BB Cube) and T1W BB Cube fluid-attenuated inversion recovery (BB Cube-FLAIR) sequences for contrast-enhanced brain imaging, by evaluating flow related artefacts, detectability, and contrast ratio (CR) of intracranial lesions among these sequences and T1W-SE. METHODS: Phantom studies were performed to determine the optimal parameters of BB Cube and BB Cube-FLAIR. A clinical study in 23 patients with intracranial lesions was performed to evaluate the usefulness of these two sequences for the diagnosis of intracranial lesions compared with the conventional 2D T1W-SE sequence. RESULTS: The phantom study revealed that the optimal parameters for contrast-enhanced T1W imaging were TR/TE = 500 ms/minimum in BB Cube and TR/TE/TI = 600 ms/minimum/300 ms in BB Cube-FLAIR imaging. In the clinical study, the degree of flow-related artefacts was significantly lower in BB Cube and BB Cube-FLAIR than in T1W-SE. Regarding tumour detection, BB Cube showed the best detectability; however, there were no significant differences in CR among the sequences. CONCLUSIONS: At 1.5 T, contrast-enhanced BB Cube was a better imaging sequence for detecting brain lesions than T1W-SE or BB Cube-FLAIR. KEY POINTS: * Cube is a single-slab 3D FSE imaging sequence. * We applied a black blood (BB) imaging technique to T1W Cube. * At 1.5 T, contrast-enhanced T1W BB Cube was valuable for detecting brain lesions. PMID- 25929943 TI - The proliferation of multidisciplinary team meetings (MDTMs): how can radiology departments continue to support them all? AB - OBJECTIVES: To quantify the changes in multidisciplinary team meeting (MDTM) workload for consultant radiologists working in a single UK tertiary referral cancer institution, assess its impact and suggest solutions to these challenges. METHODS: The annual number of MDTM cases was collated over a 5-year period (2009 2013). Qualitative information was obtained through questionnaire-based interviews of 47 consultant radiologists. Data analysed included number of MDTMs involved with, type of MDTM (oncological or non-oncological), time allocation for preparation and perceived deficiencies in the current MDTM. RESULTS: Thirteen thousand and forty-nine cases were discussed in MDTMs in 2009 with a continued yearly increase over the 5-year period. Fifty-five percent of MDTM attendances were at oncological MDTMs. Consultant radiologists attended a median of two MDTMs per week, each requiring 4 hours time commitment; 60 % used out-of-hours time for MDTM preparation. The most frequently cited MDTM deficiency was lack of sufficient clinical input. CONCLUSIONS: The MDTM is a challenging but worthwhile demand on the modern radiologist's time. Solutions to the increasing MDTM workload include demonstration of the benefits of MDTMs to hospital administrators to justify additional resources required, improving MDTM efficiency and ensuring this increased workload is accurately represented and remunerated in individual job plans. KEY POINTS: * MDTMs improve cancer outcomes and are being recommended for non-oncological conditions. * MDTM cases have more than doubled over 5 years at our institution. * Incorporating MDTM workload into current consultant radiologist job plans is difficult. * Solutions include demonstrating MDTM related benefits, improved efficiency, and accurate job planning. PMID- 25929944 TI - Changes in structural lung disease in cystic fibrosis children over 4 years as evaluated by high-resolution computed tomography. AB - OBJECTIVES: To compare the worsening of structural lung disease on high resolution computed tomography (HRCT) with changes in spirometry results in cystic fibrosis (CF) patients, and analyse factors associated with the worsening of structural lung disease over time. METHODS: A total of 31 CF subjects (mean age 11.03 +/- 3.67 years old) were prospectively evaluated by two HRCT and spirometry tests performed 4 years apart. HRCT abnormalities were scored using the Bhalla scoring system. Comparisons between changes on HRCT and spirometry were made for all patients, and also for groups categorized by age, sex, genotypic alterations and lung obstruction. RESULTS: The mean HRCT Bhalla scoring, forced expiratory volume in 1 s (FEV1 %pred.) and forced vital capacity (FVC %pred.) were 7.92 +/- 3.59, 87.76 +/- 20.52 and 96.54 +/- 15.12, respectively. There was a significant deterioration in the Bhalla score (p < 0.01) and in certain categories: severity of bronchiectasis, peribronchial thickening, mucous plugging and bronchial divisions. Females had a more pronounced worsening of the Bhalla score than males (p = 0.048). No change over time was found in FEV1 and FVC. Only sex was associated with a deterioration in HRCT. CONCLUSIONS: HRCT Bhalla scoring changes statistically significantly over 4 years, but spirometry results do not. Worsening on HRCT is more evident in females. KEY POINTS: * HRCT Bhalla scoring changes significantly over 4 years, spirometry results do not. * Females experience faster respiratory deterioration than males. * Spirometry results are not associated with deterioration in HRCT. PMID- 25929945 TI - Mammographic density: Comparison of visual assessment with fully automatic calculation on a multivendor dataset. AB - OBJECTIVES: To compare breast density (BD) assessment provided by an automated BD evaluator (ABDE) with that provided by a panel of experienced breast radiologists, on a multivendor dataset. METHODS: Twenty-one radiologists assessed 613 screening/diagnostic digital mammograms from nine centers and six different vendors, using the BI-RADS a, b, c, and d density classification. The same mammograms were also evaluated by an ABDE providing the ratio between fibroglandular and total breast area on a continuous scale and, automatically, the BI-RADS score. A panel majority report (PMR) was used as reference standard. Agreement (kappa) and accuracy (proportion of cases correctly classified) were calculated for binary (BI-RADS a-b versus c-d) and 4-class classification. RESULTS: While the agreement of individual radiologists with the PMR ranged from kappa = 0.483 to kappa = 0.885, the ABDE correctly classified 563/613 mammograms (92 %). A substantial agreement for binary classification was found for individual reader pairs (kappa = 0.620, standard deviation [SD] = 0.140), individual versus PMR (kappa = 0.736, SD = 0.117), and individual versus ABDE (kappa = 0.674, SD = 0.095). Agreement between ABDE and PMR was almost perfect (kappa = 0.831). CONCLUSIONS: The ABDE showed an almost perfect agreement with a 21-radiologist panel in binary BD classification on a multivendor dataset, earning a chance as a reproducible alternative to visual evaluation. KEY POINTS: Individual BD assessment differs from PMR with kappa as low as 0.483. An ABDE correctly classified 92 % of mammograms with almost perfect agreement (kappa = 0.831). An ABDE can be a valid alternative to subjective BD assessment. PMID- 25929946 TI - Performance of one-view breast tomosynthesis as a stand-alone breast cancer screening modality: results from the Malmo Breast Tomosynthesis Screening Trial, a population-based study. AB - OBJECTIVE: To assess the performance of one-view digital breast tomosynthesis (DBT) in breast cancer screening. METHODS: The Malmo Breast Tomosynthesis Screening Trial is a prospective population-based one-arm study with a planned inclusion of 15000 participants; a random sample of women aged 40-74 years eligible for the screening programme. This is an explorative analysis of the first half of the study population (n = 7500). Participants underwent one-view DBT and two-view digital mammography (DM), with independent double reading and scoring. Primary outcome measures were detection rate, recall rate and positive predictive value (PPV). McNemar's test with 95 % confidence intervals was used. RESULTS: Breast cancer was found in sixty-eight women. Of these, 46 cases were detected by both modalities, 21 by DBT alone and one by DM alone. The detection rate for one-view DBT was 8.9/1000 screens (95 % CI 6.9 to 11.3) and 6.3/1000 screens (4.6 to 8.3) for two-view DM (p < 0.0001). The recall rate after arbitration was 3.8 % (3.3 to 4.2) for DBT and 2.6 % (2.3 to 3.0) for DM (p < 0.0001). The PPV was 24 % for both DBT and DM. CONCLUSION: Our results suggest that one-view DBT might be feasible as a stand-alone screening modality. KEY POINTS: One-view DBT as a stand-alone breast cancer screening modality has not been investigated. One-view DBT increased the cancer detection rate significantly. The recall rate increased significantly but was still low. Breast cancer screening with one-view DBT as a stand-alone modality seems feasible. PMID- 25929947 TI - Coeliac disease and asthma association in children: the role of antibiotic consumption. AB - The relationship between coeliac disease and asthma has been scarcely investigated. Infant antibiotic exposure has been linked to both diseases. We evaluated the association between childhood coeliac disease and asthma and the role of antibiotics in the first year of life. We followed a cohort of children born in 1995-2011 in the Friuli-Venezia Giulia region (Italy). Prescriptions for antibiotics in the first year of life and subsequent treated asthma were retrieved from drug prescription records; coeliac disease incident cases were identified from pathology reports, hospital discharges and exemption from prescription charges for clinical tests. We estimated incidence rate ratios (IRRs) using multivariate Poisson regression models. Among the 143,144 children, we identified 717 coeliac children and 34,969 asthmatics. Children with asthma were at increased risk of coeliac disease (IRR 1.46, 95% CI 1.25-1.67). Restricting the analysis to asthma that occurred before the diagnosis of coeliac disease, the excess risk disappeared, except for coeliac disease diagnosed after 5 years of age (IRR 1.37, 95% CI 1.09-1.71). Antibiotics were not a confounding factor in these associations. Childhood treated asthma and coeliac disease are significantly associated. This association is not confounded by antibiotic exposure in the first year of life and may be explained by other shared risk factors. PMID- 25929948 TI - Serodiagnosis of Mycobacterium abscessus complex infection in cystic fibrosis. AB - Early signs of pulmonary disease with Mycobacterium abscessus complex (MABSC) can be missed in patients with cystic fibrosis (CF). A serological method could help stratify patients according to risk. The objective of this study was to test the diagnostic accuracy of a novel method for investigating IgG activity against MABSC.A prospective study of all patients attending the Copenhagen CF Centre was conducted by culturing for MABSC during a 22-month period and then screening patients with an anti-MABSC IgG ELISA. Culture-positive patients had stored serum examined for antibody kinetics before and after culture conversion.307 patients had 3480 respiratory samples cultured and were then tested with the anti-MABSC IgG ELISA. Patients with MABSC pulmonary disease had median anti-MABSC IgG levels six-fold higher than patients with no history of infection (434 versus 64 ELISA units; p<0.001). The test sensitivity was 95% (95% CI 74-99%) and the specificity was 73% (95% CI 67-78%). A diagnostic algorithm was constructed to stratify patients according to risk.The test accurately identified patients with pulmonary disease caused by MABSC and was suited to be used as a complement to mycobacterial culture. PMID- 25929949 TI - Oral vasopressin receptor antagonist tolvaptan in right heart failure due to pulmonary hypertension. PMID- 25929950 TI - Preclinical validation and imaging of Wnt-induced repair in human 3D lung tissue cultures. AB - Chronic obstructive pulmonary disease (COPD) is characterised by a progressive loss of lung tissue. Inducing repair processes within the adult diseased lung is of major interest and Wnt/beta-catenin signalling represents a promising target for lung repair. However, the translation of novel therapeutic targets from model systems into clinical use remains a major challenge.We generated murine and patient-derived three-dimensional (3D) ex vivo lung tissue cultures (LTCs), which closely mimic the 3D lung microenvironment in vivo. Using two well-known glycogen synthase kinase-3beta inhibitors, lithium chloride (LiCl) and CHIR 99021 (CT), we determined Wnt/beta-catenin-driven lung repair processes in high spatiotemporal resolution using quantitative PCR, Western blotting, ELISA, (immuno)histological assessment, and four-dimensional confocal live tissue imaging.Viable 3D-LTCs exhibited preserved lung structure and function for up to 5 days. We demonstrate successful Wnt/beta-catenin signal activation in murine and patient-derived 3D LTCs from COPD patients. Wnt/beta-catenin signalling led to increased alveolar epithelial cell marker expression, decreased matrix metalloproteinase-12 expression, as well as altered macrophage activity and elastin remodelling. Importantly, induction of surfactant protein C significantly correlated with disease stage (per cent predicted forced expiratory volume in 1 s) in patient derived 3D-LTCs.Patient-derived 3D-LTCs represent a valuable tool to analyse potential targets and drugs for lung repair. Enhanced Wnt/beta-catenin signalling attenuated pathological features of patient-derived COPD 3D-LTCs. PMID- 25929951 TI - Sildenafil in a cigarette smoke-induced model of COPD in the guinea-pig. AB - Sildenafil, a phosphodiesterase-5 inhibitor used to treat pulmonary hypertension, may have effects on pulmonary vessel structure and function. We evaluated the effects of sildenafil in a cigarette smoke (CS)-exposed model of chronic obstructive pulmonary disease (COPD).42 guinea-pigs were exposed to cigarette smoke or sham-exposed and treated with sildenafil or vehicle for 12 weeks, divided into four groups. Assessments included respiratory resistance, pulmonary artery pressure (PAP), right ventricle (RV) hypertrophy, endothelial function of the pulmonary artery and lung vessel and parenchymal morphometry.CS-exposed animals showed increased PAP, RV hypertrophy, raised respiratory resistance, airspace enlargement and intrapulmonary vessel remodelling. CS exposure also produced wall thickening, increased contractility and endothelial dysfunction in the main pulmonary artery. CS-exposed animals treated with sildenafil showed lower PAP and a trend to less RV hypertrophy than CS-exposed only animals. Furthermore, sildenafil preserved the intrapulmonary vessel density and attenuated the airspace enlargement induced by CS. No differences in gas exchange, respiratory resistance, endothelial function and vessel remodelling were observed.We conclude that in this experimental model of COPD, sildenafil prevents the development of pulmonary hypertension and contributes to preserve the parenchymal and vascular integrity, reinforcing the notion that the nitric oxide-cyclic guanosine monophosphate axis is perturbed by CS exposure. PMID- 25929952 TI - CXCR4+ granulocytes reflect fungal cystic fibrosis lung disease. AB - Cystic fibrosis airways are frequently colonised with fungi. However, the interaction of these fungi with immune cells and the clinical relevance in cystic fibrosis lung disease are incompletely understood.We characterised granulocytes in airway fluids and peripheral blood from cystic fibrosis patients with and without fungal colonisation, non-cystic fibrosis disease controls and healthy control subjects cross-sectionally and longitudinally and correlated these findings with lung function parameters.Cystic fibrosis patients with chronic fungal colonisation by Aspergillus fumigatus were characterised by an accumulation of a distinct granulocyte subset, expressing the HIV coreceptor CXCR4. Percentages of airway CXCR4(+) granulocytes correlated with lung disease severity in patients with cystic fibrosis.These studies demonstrate that chronic fungal colonisation with A. fumigatus in cystic fibrosis patients is associated with CXCR4(+) airway granulocytes, which may serve as a potential biomarker and therapeutic target in fungal cystic fibrosis lung disease. PMID- 25929953 TI - Therapeutic management of ALK+ nonsmall cell lung cancer patients. AB - With therapeutic approaches based on oncogene addiction offering significant anticancer benefit, the identification of anaplastic lymphoma kinase (ALK) rearrangements is a key aspect of the management of lung cancers. The EML4-ALK gene fusion is detected in 4-8% of all lung cancers, predominantly in light smokers or nonsmokers. Crizotinib, the first agent to be approved in this indication, is associated with a median progression-free survival of 10.9 months when given as first-line treatment and 7.7 months when administered after chemotherapy. Median overall survival with crizotinib in the second-line setting is 20.3 months. Second-generation ALK inhibitors are currently being evaluated, with early studies giving impressive results, notably in patients resistant to crizotinib or with brain metastases. Among available chemotherapies, pemetrexed appears to be particularly active in this population. Despite this progress, several questions remain unanswered. What detection strategies should be favoured? What underlies the mechanisms of resistance and what options are available to overcome them? What are the best approaches for progressing patients? This review provides an overview of current data in the literature and addresses these questions. PMID- 25929954 TI - Matrix metalloproteinase activation by free neutrophil elastase contributes to bronchiectasis progression in early cystic fibrosis. AB - Neutrophil elastase is the most significant predictor of bronchiectasis in early life cystic fibrosis; however, the causal link between neutrophil elastase and airway damage is not well understood. Matrix metalloproteinases (MMPs) play a crucial role in extracellular matrix modelling and are activated by neutrophil elastase. The aim of this study was to assess if MMP activation positively correlates with neutrophil elastase activity, disease severity and bronchiectasis in young children with cystic fibrosis.Total MMP-1, MMP-2, MMP-7, MMP-9, tissue inhibitor of metalloproteinase (TIMP)-2 and TIMP-1 levels were measured in bronchoalveolar lavage fluid collected from young children with cystic fibrosis during annual clinical assessment. Active/pro-enzyme ratio of MMP-9 was determined by gelatin zymography. Annual chest computed tomography imaging was scored for bronchiectasis.A higher MMP-9/TIMP-1 ratio was associated with free neutrophil elastase activity. In contrast, MMP-2/TIMP-2 ratio decreased and MMP-1 and MMP-7 were not detected in the majority of samples. Ratio of active/pro enzyme MMP-9 was also higher in the presence of free neutrophil elastase activity, but not infection. Across the study cohort, both MMP-9/TIMP-1 and active MMP-9 were associated with progression of bronchiectasis.Both MMP-9/TIMP-1 and active MMP-9 increased with free neutrophil elastase and were associated with bronchiectasis, further demonstrating that free neutrophil elastase activity should be considered an important precursor to cystic fibrosis structural disease. PMID- 25929955 TI - Effectiveness of infliximab in refractory FDG PET-positive sarcoidosis. AB - Inconclusive evidence for the efficacy of infliximab in sarcoidosis hinders the global use of this potentially beneficial drug. To study infliximab efficacy in a clinical setting, we performed a prospective open-label trial in patients refractory to conventional treatment. Patients (n=56) received eight infusions of 5 mg.kg(-1) infliximab. Pulmonary function, disease activity measured by (18)F fluorodeoxyglucose (FDG) by positron emission tomography (PET) and quality of life were part of the clinical work-up. Infliximab levels were measured before every infusion. After 26 weeks of infliximab treatment, mean improvement in forced vital capacity (FVC) was 6.6% predicted (p=0.0007), whereas in the 6 months before start of treatment, lung function decreased. Maximum standardised uptake value (SUVmax) of pulmonary parenchyma on (18)F-FDG PET decreased by 3.93 (p<0.0001). High SUVmax of pulmonary parenchyma at baseline predicted FVC improvement (R=0.62, p=0.0004). An overall beneficial response was seen in 79% of patients and a partial response was seen in 17% of patients. No correlation between infliximab trough level (mean 18.0 ug.mL(-1)) and initial response was found. In conclusion, infliximab causes significant improvement in FVC in refractory (18)F-FDG PET positive sarcoidosis. Especially in pulmonary disease, high (18)F-FDG PET SUVmax values at treatment initiation predict clinically relevant lung function improvement. These results suggest that inclusion of (18)F FDG PET is useful in therapeutic decision-making in complex sarcoidosis. PMID- 25929956 TI - ESR/ERS white paper on lung cancer screening. AB - Lung cancer is the most frequently fatal cancer, with poor survival once the disease is advanced. Annual low dose computed tomography has shown a survival benefit in screening individuals at high risk for lung cancer. Based on the available evidence, the European Society of Radiology and the European Respiratory Society recommend lung cancer screening in comprehensive, quality assured, longitudinal programmes within a clinical trial or in routine clinical practice at certified multidisciplinary medical centres. Minimum requirements include: standardised operating procedures for low dose image acquisition, computer-assisted nodule evaluation, and positive screening results and their management; inclusion/exclusion criteria; expectation management; and smoking cessation programmes. Further refinements are recommended to increase quality, outcome and cost-effectiveness of lung cancer screening: inclusion of risk models, reduction of effective radiation dose, computer-assisted volumetric measurements and assessment of comorbidities (chronic obstructive pulmonary disease and vascular calcification). All these requirements should be adjusted to the regional infrastructure and healthcare system, in order to exactly define eligibility using a risk model, nodule management and quality assurance plan. The establishment of a central registry, including biobank and image bank, and preferably on a European level, is strongly encouraged. PMID- 25929957 TI - French multicentric validation of ALK rearrangement diagnostic in 547 lung adenocarcinomas. AB - Anaplastic lymphoma kinase (ALK) gene rearrangements in lung adenocarcinoma result in kinase activity targetable by crizotinib. Although fluorescence in situ hybridisation (FISH) is the reference diagnostic technique, immunohistochemistry (IHC) could be useful for pre-screening. Diagnostic yields of ALK IHC, FISH and quantitative reverse transcriptase PCR performed in 14 French pathology/molecular genetics platforms were compared. 547 lung adenocarcinoma specimens were analysed using 5A4 and D5F3 antibodies, two break-apart FISH probes and TaqMan kits. Clinicopathological data were recorded. 140 tumours were ALK rearranged (FISH with >=15% of rearranged cells) and 400 were ALK FISH negative (<15%). FISH was not interpretable for seven cases. ALK patients were young (p=0.003), mostly females (p=0.007) and light/nonsmokers (p<0.0001). 13 cases were IHC negative but FISH >=15%, including six cases with FISH between 15% and 20%; eight were IHC positive with FISH between 10% and 14%. Sensitivity and specificity for 5A4 and D5F3 were 87% and 92%, and 89% and 76%, respectively. False-negative IHC, observed in 2.4% of cases, dropped to 1.3% for FISH >20%. Variants were undetected in 36% of ALK tumours. Discordances predominated with FISH ranging from 10% to 20% of rearranged cells and were centre dependent. IHC remains a reliable pre-screening method for ALK rearrangement detection. PMID- 25929958 TI - Synthesis of radiolabelled aryl azides from diazonium salts: experimental and computational results permit the identification of the preferred mechanism. AB - Experimental and computational studies on the formation of aryl azides from the corresponding diazonium salts support a stepwise mechanism via acyclic zwitterionic intermediates. The low energy barriers associated with both transition structures are compatible with very fast and efficient processes, thus making this method suitable for the chemical synthesis of radiolabelled aryl azides. PMID- 25929959 TI - A Political and Social History of HIV in South Africa. AB - For the past 25 years, South Africa has had to deal with the inexorable and monumental rise of HIV. From one or two isolated cases, in the late 1980s, South Africa now has an estimated 6.4 million people infected with HIV, with high rates of concomitant tuberculosis, which will profoundly affect the country for decades to come. For nearly 10 years, the South African government's response to the HIV epidemic was described as denialist, which was estimated to have resulted in the deaths of 330,000 people because lifesaving antiretroviral therapy (ART) was not provided (Chigwedere et al. J Acquir Immune Defic Syndr. 49:410-15, 2008; Heywood 2004). However, the story of the HIV and AIDS response in South Africa over the past 5 years is one of great progress after almost a decade of complex and tragic denialism that united civil society in a way not seen since the opposition to apartheid. Today, South Africa can boast of close to 3 million people on ART, by far the largest number in the world. Prevention efforts appear to be yielding results but there continues to be large numbers of new infections, with a profound peak in incidence in young women aged 15 to 24 years. In addition, infections occur across the gender spectrum in older age groups. As a result of the massive increase in access to ART after 2004 and particularly after 2008 as political will towards the HIV ART programme improved, there has been a marked increase in life expectancy, from 56 to 61 years in the period 2009-2012 alone; the aggressive expansion of the prevention of mother to child transmission (PMTCT) to HIV-positive pregnant women has been accompanied by dramatic decrease in HIV transmission to infants; and a 25 % decrease in child and infant mortality rates in the period 2009-2012. This progress in access is significantly due to a civil society movement that was prepared to pose a rights-based challenge to a governing party in denial and to brave health officials, politicians and clinicians working in a hostile system to bring about change. PMID- 25929960 TI - Innovative Strategies for Scale up of Effective Combination HIV Prevention Interventions in Sub-Saharan Africa. AB - For the last three decades, sub-Saharan Africa has been the epicentre of the HIV epidemic. Some key drivers of the epidemic are specific to this region and there is an urgent need to develop context-specific strategies to reduce HIV-related burden. Implementation frameworks should endeavour to combine structural, behavioural and biomedical interventions and the future of the HIV response involves embracing different approaches for different populations; it is not 'one size fits all approach'. Expanded use of community-based interventions will be key in expanding the role of antiretroviral treatment as prevention (TasP) in the region. For TasP to be effective, high antiretroviral therapy (ART) coverage rates need to be attained. Data from programmatic trials currently underway will provide crucial data to guide the future implementation of TasP. PMID- 25929961 TI - Epidemiological Trends for HIV in Southern Africa: Implications for Reaching the Elimination Targets. AB - Southern Africa is the region worst affected by HIV in the world and accounts for one third of the global burden of HIV. Achieving the UNAIDS 90-90-90 target by 2020 and ending the AIDS epidemic by 2030 depend on success in this region. We review epidemiological trends in each country in southern Africa with respect to the prevalence, incidence, mortality, coverage of anti-retroviral therapy (ART) and TB notification rates, to better understand progress in controlling HIV and TB and to determine what needs to be done to reach the UNAIDS targets. Significant progress has been made in controlling HIV. In all countries in the region, the prevalence of HIV in people not on ART, the incidence of HIV, AIDS related mortality and, in most countries, TB notification rates, are falling. In some countries, the risk of infection began to fall before biomedical interventions such as ART became widely available as a result of effective prevention measures or people's awareness of, and response to, the epidemic but the reasons for these declines remain uncertain. Some countries have achieved better levels of ART coverage than others, but all are in a position to reach the 2020 and 2030 targets if they accelerate the roll-out of ART and of targeted prevention efforts. Achieving the HIV treatment targets will further reduce the incidence of HIV-related TB, but efforts to control TB in HIV-negative people must be improved and strengthened. PMID- 25929962 TI - Introduction: craniosynostosis: modern treatment strategies. PMID- 25929963 TI - Enzyme replacement therapy for congenital hypophosphatasia allows for surgical treatment of related complex craniosynostosis: a case series. AB - Hypophosphatasia (HPP) is a rare inherited disorder of bone metabolism that results in the loss of function of the gene coding for tissue-nonspecific alkaline phosphatase (TNSALP). Patients with HPP have defective bone mineralization as well as craniosynostosis that can be seen in the infantile and childhood forms of this disease. Traditionally, HPP has had a poor prognosis, with few children surviving to exhibit the phenotype of clinical craniosynostosis that requires surgical intervention. Here, the authors report on new advancements in enzyme replacement therapy (ERT) for children affected by HPP, allowing these patients to survive and undergo surgery to address complex craniosynostosis. The authors discuss their case series of 4 HPP patients treated at their institution with ERT who have undergone successful surgical intervention for craniosynostosis. These children had no complications related to their surgeries and exhibited decreased neurological symptoms following cranial vault remodeling. This study reveals that ERT administered either pre- or post- operatively paired with cranial vault remodeling strategies can yield improved neurological outcomes in children affected by HPP. PMID- 25929964 TI - Insights into the development of molecular therapies for craniosynostosis. AB - For the past 2 decades, clinical and basic science researchers have gained significant insights into the molecular and genetic pathways associated with common forms of craniosynostosis. This has led to invaluable information for families and physicians in their attempts to understand the heterogeneity of craniosynostosis. Genetic mutations have been identified in the fibroblast growth factor receptors (FGFRs) as well as in other targets, including TWIST1, BMP, and RUNX2. Greater understanding of these and other pathways has led to the development of innovative approaches for applying medical therapies to the treatment of craniosynostosis, in particular by maintaining suture patency. In this article, the authors discuss the molecular pathophysiological mechanisms underlying various forms of craniosynostosis. They also highlight recent developments in the field of molecular craniosynostosis research with the hope of identifying targets for medical therapies that might augment the results of surgical intervention. PMID- 25929965 TI - The influence of surgical correction on white matter microstructural integrity in rabbits with familial coronal suture craniosynostosis. AB - OBJECT Craniosynostosis is a condition in which one or more of the calvarial sutures fuses prematurely. In addition to the cosmetic ramifications attributable to premature suture fusion, aberrations in neurophysiological parameters are seen, which may result in more significant damage. This work examines the microstructural integrity of white matter, using diffusion tensor imaging (DTI) in a homogeneous strain of rabbits with simple, familial coronal suture synostosis before and after surgical correction. METHODS After diagnosis, rabbits were assigned to different groups: wild-type (WT), rabbits with early-onset complete fusion of the coronal suture (BC), and rabbits that had undergone surgical correction with suturectomy (BC-SU) at 10 days of age. Fixed rabbit heads were imaged at 12, 25, or 42 days of life using a 4.7-T, 40-cm bore Avance scanner with a 7.2-cm radiofrequency coil. For DTI, a 3D spin echo sequence was used with a diffusion gradient (b = 2000 sec/mm(2)) applied in 6 directions. RESULTS As age increased from 12 to 42 days, the DTI differences between WT and BC groups became more pronounced (p < 0.05, 1-way ANOVA), especially in the corpus callosum, cingulum, and fimbriae. Suturectomy resulted in rabbits with no significant differences compared with WT animals, as assessed by DTI of white matter tracts. Also, it was possible to predict to which group an animal belonged (WT, BC, and BC-SU) with high accuracy based on imaging data alone using a linear support vector machine classifier. The ability to predict to which group the animal belonged improved as the age of the animal increased (71% accurate at 12 days and 100% accurate at 42 days). CONCLUSIONS Craniosynostosis results in characteristic changes of major white matter tracts, with differences becoming more apparent as the age of the rabbits increases. Early suturectomy (at 10 days of life) appears to mitigate these differences. PMID- 25929966 TI - The cranial orbital buttress technique for nonsyndromic unicoronal and metopic craniosynostosis. AB - OBJECT Current craniosynostosis procedures can result in complications due to absorbable plates and screws or other specialized expensive hardware. The authors propose the cranial orbital buttress (COB) technique of frontoorbital remodeling for metopic and unicoronal synostoses, wherein no plates or screws are used. They hypothesize that, with this technique, aesthetically acceptable outcomes for unicoronal and metopic synostosis can be achieved. In this article, they present this technique and compare the results with current frontoorbital remodeling practices. METHODS The authors conducted a retrospective chart review of cases in which patients with nonsyndromic unicoronal or metopic synostosis underwent cranio-orbital surgery at their institution from 1985 through 2009. Operative parameters, surgical variations, and complications were analyzed. The COB technique uses a 1-piece switch, hemiforeheads, or multiple pieces for forehead remodeling. The supraorbital bar is reconstructed in patients with metopic synostosis using a double wedge or greenstick fracture technique, and in patients with unicoronal synostosis a hinge procedure based on a 1.5-orbital osteotomy is used. The supraorbital bar is advanced and supported in place by bone graft(s) inserted at the lateral aspect(s) of the orbit(s) to form a buttress, with fixation done using absorbable sutures. RESULTS A total of 79 cases met the criteria for inclusion in the study. Twenty-nine patients had metopic synostosis, 3 had combined metopic and sagittal synostoses, and 47 had unicoronal synostosis. The patients' mean age at surgery was 11.4 +/- 10.1 months and the mean operative time was 183.4 +/- 41.0 minutes. The mean length of hospital stay was 3.7 +/- 1.2 days. The mean blood loss was 150.0 +/- 125.6 ml, and 33% of patients required a blood transfusion (mean volume 206.9 +/- 102.3 ml). In metopic synostosis, hemiforeheads were used most often (24/29, 83%), and the supraorbital bar was remodeled using a bilateral intracranial orbital osteotomy followed by a double wedge modification (23/29, 79%) or a greenstick fracture (4/29 14%) for milder cases. Forehead remodeling for unicoronal synostosis was by a forehead switch (39/47, 83%) and the supraorbital bar was remodeled using a 1.5-orbital intracranial orbital osteotomy (34/47, 72%) such that the bar was advanced on the abnormal side and hinged at the midline of the normal orbit. Perioperative complications occurred in 19% of cases and included dural tears (16%), inconsequential subdural hematoma (1.3%), and nasal greenstick fracture (1.3%). The total reoperation rate was 7.6% (cranioplasties for irregular contours, 6.3%; scar revision, 1.3%). CONCLUSIONS The COB remodeling technique is simple and efficient, gives acceptable outcomes, and is less resource intensive than previous techniques reported in the literature. PMID- 25929967 TI - Computer-assisted virtual planning and surgical template fabrication for frontoorbital advancement. AB - OBJECT The authors describe a novel technique using computer-assisted design (CAD) and computed-assisted manufacturing (CAM) for the fabrication of individualized 3D printed surgical templates for frontoorbital advancement surgery. METHODS Two patients underwent frontoorbital advancement surgery for unilateral coronal synostosis. Virtual surgical planning (SurgiCase-CMF, version 5.0, Materialise) was done by virtual mirroring techniques and superposition of an age-matched normative 3D pediatric skull model. Based on these measurements, surgical templates were fabricated using a 3D printer. Bifrontal craniotomy and the osteotomies for the orbital bandeau were performed based on the sterilized 3D templates. The remodeling was then done placing the bone plates within the negative 3D templates and fixing them using absorbable poly-dl-lactic acid plates and screws. RESULTS Both patients exhibited a satisfying head shape postoperatively and at follow-up. No surgery-related complications occurred. The cutting and positioning of the 3D surgical templates proved to be very accurate and easy to use as well as reproducible and efficient. CONCLUSIONS Computer assisted virtual planning and 3D template fabrication for frontoorbital advancement surgery leads to reconstructions based on standardizedmeasurements, precludes subjective remodeling, and seems to be overall safe and feasible. A larger series of patients with long-term follow-up is needed for further evaluation of this novel technique. PMID- 25929968 TI - Intracranial hypertension after surgical correction for craniosynostosis: a systematic review. AB - OBJECT The authors' aim was perform a systematic review on the incidence of intracranial hypertension (IH) after surgery for craniosynostosis. METHODS A systematic literature review was conducted using PubMed to assess the rate of postoperative IH in studies published between 1985 and 2014. Inclusion criteria were 1) English-language literature; 2) human subjects; 3) pediatric cases; and 4) postoperative IH confirmed with invasive intracranial pressure monitoring. RESULTS Seven studies met inclusion criteria. IH was reported to be present in 5% of patients postoperatively with sagittal synostosis and 4% of patients with all forms of nonsyndromic craniosynostosis. Inadequate numbers were available to determine the incidence of postoperative IH for syndromic and individual nonsyndromic sutural synostosis based on the inclusion criteria. Surgical groups were subdivided into cranial remodeling procedures without orbital advancement and craniofacial procedures with orbital advancement. IH was reported to be present in 5% of patients with all forms of nonsyndromic sutural stenosis after cranial remodeling procedures and 1% after craniofacial advancement. CONCLUSIONS Postoperative development of elevated intracranial pressure has been described by multiple institutions, but the variation in how IH is determined and the multiple surgical procedures to correct craniosynostosis has limited the number of studies subject to a meta-analysis. Nonetheless, this entity deserves special attention, and further studies are required to determine the true incidence of postoperative IH, including the role of various surgical procedures on its incidence. The long term consequences of chronic IH in this group of patients also need to be evaluated. PMID- 25929969 TI - Spring-mediated sagittal craniosynostosis treatment at the Children's Hospital of Philadelphia: technical notes and literature review. AB - OBJECT Sagittal craniosynostosis has been treated using both cranial remodeling techniques and modification of the sagittal strip craniectomy. A more recent technique is to implant springs in conjunction with a suturectomy to transversely expand the parietal bones to accommodate the growing brain. In this paper the authors describe and evaluate several modifications to the spring-mediated cranioplasty (SMC) technique, most notably use of an ultrasonic scalpel to limit dural dissection and maximize opening of the stenosed suture by placement of multiple spring devices. In addition, the literature is reviewed comparing SMC to other surgical treatments of sagittal synostosis. METHODS The authors retrospectively reviewed patients who presented to the Children's Hospital of Philadelphia with a diagnosis of sagittal synostosis from August 2011 to November 2014. A pooled data set was created to compare our institutional data to previously published work. A comprehensive literature review was performed of all previous studies describing the SMC technique, as well as other techniques for sagittal synostosis correction. RESULTS Twenty-two patients underwent SMC at our institution during the study period. Patients were 4.2 months of age on average, had a mean blood loss of 56.3 ml, and average intensive care unit and total hospital stays of 29.5 hours and 2.2 days, respectively. The cranial index was corrected to an average of 73.7 (SD 5.2) for patients who received long-term radiological follow-up. When comparing the authors' institutional data to pooled SMC data, blood loss and length of stay were both significantly less (p = 0.005 and p < 0.001, respectively), but the preoperative cranial index was significantly larger (p = 0.01). A review of the SMC technique compared with other techniques to actively expand the skull of patients with sagittal synostosis demonstrated that SMC can be performed at a significantly earlier age compared with cranial vault reconstruction (CVR). CONCLUSIONS The authors found that their institutional modifications of the SMC technique were safe and effective in correcting the cranial index. In addition, this technique can be performed at a younger age than CVRs. SMC, therefore, has the potential to maximize the cognitive benefits of early intervention, with lower morbidity than the traditional CVR. PMID- 25929970 TI - Upward transtentorial herniation following frontoorbital advancement for syndromic craniosynostosis: case report. AB - The authors describe the case of a boy with Muenke syndrome, an autosomal dominant disorder associated with craniosynostosis. The family history was significant for syndromic craniosynostosis in the patient's maternal grandmother, who died in adulthood after a craniofacial reconstruction. The patient, her grandson, underwent craniofacial reconstruction surgery at the age of 9 months and developed upward transtentorial herniation. Imaging findings revealed remote cerebellar hemorrhage after a large quantity of supratentorial CSF was drained during postoperative Day 1. The clinical course was further complicated by cerebral sinus thrombosis, which was diagnosed after a fourth surgical procedure. Upward transtentorial herniation can occur when a significant increase in intracranial pressure in the posterior fossa causes displacement of the central lobule and superior surfaces of the cerebellum upward through the incisura tentorii. This is a rare but well-documented phenomenon that commonly occurs in the setting of an expansive posterior fossa lesion or excessive supratentorial CSF loss. To help clinicians recognize and prevent this rare but potentially fatal complication, the authors review the postulated mechanisms by which this process may occur. PMID- 25929971 TI - The occipitofrontal circumference: reliable prediction of the intracranial volume in children with syndromic and complex craniosynostosis. AB - OBJECT Patients with syndromic and complex craniosynostosis are characterized by the premature fusion of one or more cranial sutures. These patients are at risk for developing elevated intracranial pressure (ICP). There are several factors known to contribute to elevated ICP in these patients, including craniocerebral disproportion, hydrocephalus, venous hypertension, and obstructive sleep apnea. However, the causal mechanism is unknown, and patients develop elevated ICP even after skull surgery. In clinical practice, the occipitofrontal circumference (OFC) is used as an indirect measure for intracranial volume (ICV), to evaluate skull growth. However, it remains unknown whether OFC is a reliable predictor of ICV in patients with a severe skull deformity. Therefore, in this study the authors evaluated the relation between ICV and OFC. METHODS Eighty-four CT scans obtained in 69 patients with syndromic and complex craniosynostosis treated at the Erasmus University Medical Center-Sophia Children's Hospital were included. The ICV was calculated based on CT scans by using autosegmentation with an HU threshold < 150. The OFC was collected from electronic patient files. The CT scans and OFC measurements were matched based on a maximum amount of the time that was allowed between these examinations, which was dependent on age. A Pearson correlation coefficient was calculated to evaluate the correlations between OFC and ICV. The predictive value of OFC, age, and sex on ICV was then further evaluated using a univariate linear mixed model. The significant factors in the univariate analysis were subsequently entered in a multivariate mixed model. RESULTS The correlations found between OFC and ICV were r = 0.908 for the total group (p < 0.001), r = 0.981 for Apert (p < 0.001), r = 0.867 for Crouzon Pfeiffer (p < 0.001), r = 0.989 for Muenke (p < 0.001), r = 0.858 for Saethre- Chotzen syndrome (p = 0.001), and r = 0.917 for complex craniosynostosis (p < 0.001). Age and OFC were significant predictors of ICV in the univariate linear mixed model (p < 0.001 for both factors). The OFC was the only predictor that remained significant in the multivariate analysis (p < 0.001). CONCLUSIONS The OFC is a significant predictor of ICV in patients with syndromic and complex craniosynostosis. Therefore, measuring the OFC during clinical practice is very useful in determining which patients are at risk for impaired skull growth. PMID- 25929972 TI - Whole genome sequencing of cotton--a new chapter in cotton genomics. PMID- 25929973 TI - Severe radiographic knee osteoarthritis--does Kellgren and Lawrence grade 4 represent end stage disease?--the MOST study. AB - OBJECTIVE: To determine what MRI-detectable osteoarthritis features that are not visualized on radiography demonstrate progression longitudinally in Kellgren and Lawrence (KL) grade 4 knees. METHODS: We studied subjects from the Multicenter Osteoarthritis Study who had KL grade 4 knees at baseline and had baseline and 30 month MRI. Cartilage damage, bone marrow lesions (BMLs), meniscal damage, synovitis (signal changes in Hoffa fat pad), and effusion (fluid equivalent signal in the joint cavity) were semiquantitatively scored using the Whole Organ MRI Score (WORMS) system in five subregions of the medial and lateral tibiofemoral (TF) compartments. Analysis was performed for the compartment showing bone-on-bone appearance ("index") on radiograph and also for the other TF compartment of the same knee. Synovitis and effusion were assessed for the whole knee. Changes in scores at follow-up were noted for each feature. For cartilage and BML, within-grade changes were also recorded. RESULTS: 140 subjects (164 knees) were included (50% women, mean age 66.0 +/- 8.6 years, mean BMI 30.4 +/- 5.1 kg/m(2)). Longitudinally, 51 index compartments (34%) showed an increase in the sum of cartilage scores from all subregions. In the other compartment, 25% showed an increase in the sum score for cartilage damage. For BMLs in the index compartment, 50 knees (33%) showed an increase in maximum score and 32 (21%) showed a decrease. Meniscal status mostly remained stable. Effusion worsened in 36 knees (25%) and improved in 13 knees (9%). Synovitis worsened in 14 knees (10%) and improved in six knees (4%). CONCLUSION: In KL grade 4 knees, MRI detected cartilage loss and fluctuation of BMLs, effusion, and synovitis occurred frequently over a 30-month period. PMID- 25929974 TI - High-performance TiO2 nanoparticle/DOPA-polymer composites. AB - Many natural materials are complex composites whose mechanical properties are often outstanding considering the weak constituents from which they are assembled. Nacre, made of inorganic (CaCO3 ) and organic constituents, is a textbook example because of its strength and toughness, which are related to its hierarchical structure and its well-defined organic-inorganic interface. Emulating the construction principles of nacre using simple inorganic materials and polymers is essential for understanding how chemical composition and structure determine biomaterial functions. A hard multilayered nanocomposite is assembled based on alternating layers of TiO2 nanoparticles and a 3-hydroxy tyramine (DOPA) substituted polymer (DOPA-polymer), strongly cemented together by chelation through infiltration of the polymer into the TiO2 mesocrystal. With a Young's modulus of 17.5 +/- 2.5 GPa and a hardness of 1.1 +/- 0.3 GPa the resulting material exhibits high resistance against elastic as well as plastic deformation. A key feature leading to the high strength is the strong adhesion of the DOPA-polymer to the TiO2 nanoparticles. PMID- 25929975 TI - The CYP17 MspA1 Polymorphism and the Gender Dysphoria. AB - INTRODUCTION: The A2 allele of the CYP17 MspA1 polymorphism has been linked to higher levels of serum testosterone, progesterone, and estradiol. AIM: To determine whether the CYP17 MspA1 polymorphism is associated with transsexualism. METHODS: We analyzed 151 male-to-female (MtF), 142 female-to-male (FtM), 167 control male, and 168 control female individuals. Fragments that included the mutation were amplified by PCR and digested with MspA1. Our data were compared with the allele/genotype frequencies provided by the 1000 Genomes Data Base, and contrasted with a MEDLINE search of the CYP17 MspA1 polymorphism in the literature. MAIN OUTCOME MEASURES: We investigated the association between transsexualism and the CYP17 MspA1 polymorphism. RESULTS: A2 frequency was higher in the FtM (0.45) than the female control (0.38) and male control (0.39) groups, or the MtF group (0.36). This FtM > MtF pattern reached statistical significance (P = 0.041), although allele frequencies were not gender specific in the general population (P = 0.887). This observation concurred with the 1000 Genomes Data Base and the MEDLINE search. CONCLUSION: Our data confirm a sex-dependent allele distribution of the CYP17 MspA1 polymorphism in the transsexual population, FtM > MtF, suggestive of a hypothetical A2 involvement in transsexualism since the allele frequencies in the general population seem to be clearly related to geographic origin and ethnic background, but not sex. PMID- 25929976 TI - Features of coexisting granulomatosis with polyangiitis in a patient with pemphigus vulgaris: a case report. AB - Pemphigus vulgaris (PV) and granulomatosis with polyangiitis (Wegener's or GPA) are two rare autoimmune disorders. Both can involve the upper airways, and diagnosis can be difficult in the absence of extra-airway symptoms. We report the case of a patient with well-controlled PV but persistent upper respiratory tract symptoms. Further evaluation revealed perforation of the nasal septum and elevated serologies consistent with GPA. The patient improved with rituximab treatments. This case demonstrates that alternative concomitant diagnosis should be considered in patients with symptoms suggestive of recalcitrant PV and/or GPA, since these patients may require more aggressive initial treatment. PMID- 25929977 TI - Facial nerve stimulation associated with cochlear implant use following temporal bone fractures. AB - OBJECTIVE: To describe the incidence and management of patients with facial nerve stimulation (FNS) associated with cochlear implant (CI) use in the setting of a prior temporal bone fracture. PATIENTS: One adult CI recipient is reported who experienced implant associated FNS with a history of a temporal bone fracture. Additionally, a literature search was performed to identify similar patients from previous descriptions of CI related FNS. MAIN OUTCOME MEASURES: Presence of FNS after implantation and ability to modify implant programming to avoid FNS. RESULTS: The patient in the present report experienced FNS for middle and basal electrodes during intraoperative neural response telemetry (NRT) in the absence of any surgical exposure or manipulation of the facial nerve. FNS was absent during device activation, but it recurred during follow-up programming sessions. However, additional programming has prevented further FNS during regular implant use. Four other patients with FNS after temporal bone fracture were identified from the literature, and the present case represents the one of two cases in which reprogramming allowed for implant use without FNS. CONCLUSIONS: CI associated FNS is uncommon in patients with a history of a temporal bone fracture, but it is likely that fracture lines provide a lower impedance pathway to the adjacent facial nerve and thus reduce the threshold for FNS. The present report suggests that, in the setting of a prior temporal bone fracture, NRT is not always a reliable predictor of FNS during implant use, and programming changes can help to mitigate FNS when it occurs. PMID- 25929978 TI - Prevention of Cerebral Palsy: Which Infants Will Benefit from Therapeutic Hypothermia? PMID- 25929979 TI - Testing for Infectious Diseases in Sudden Unexpected Infant Death: A Survey of Medical Examiner and Coroner Offices in the United States. AB - OBJECTIVES: To determine interoffice variability in routinely performed sudden unexpected infant death (SUID) postmortem studies for infection and to assess availability and perceived utility of various tests of infectious diseases. STUDY DESIGN: Online surveys were sent to all 154 offices of US medical examiners and coroners serving populations >300,000 people. Surveys included a set of potential laboratory tests for infectious disease. Respondents were asked to select which tests were available in their offices, and which tests were performed routinely in SUIDs vs which tests should be performed routinely. RESULTS: Of the 45 complete responses, 4.4% did not routinely perform histology, 8.9% did not routinely perform viral studies (ie, culture or molecular diagnostics), 22.2% did not routinely perform blood cultures, 26.7% did not routinely perform lung bacterial cultures, and 44.4% did not routinely perform cerebrospinal fluid cultures. CONCLUSIONS: Our findings suggest that there is considerable interoffice variability with testing for infectious diseases in SUIDs. This appeared to be largely the result of a perceived lack of testing utility rather than a lack of test availability. Evidence-based practice guidelines regarding the interpretation of microbial testing results, as well as common testing protocols/algorithms, may lead to more accurate and standardized data, thus improving SUID investigation and surveillance. PMID- 25929981 TI - Editorial Comment. PMID- 25929980 TI - Hand drawing of pencil electrodes on paper platforms for contactless conductivity detection of inorganic cations in human tear samples using electrophoresis chips. AB - This paper describes for the first time the fabrication of pencil drawn electrodes (PDE) on paper platforms for capacitively coupled contactless conductivity detection (C(4) D) on electrophoresis microchips. PDE-C(4) D devices were attached on PMMA electrophoresis chips and used for detection of K(+) and Na(+) in human tear samples. PDE-C(4) D devices were produced on office paper and chromatographic paper platforms and their performance were thoroughly investigated using a model mixture containing K(+) , Na(+) , and Li(+) . In comparison with chromatographic paper, PDE-C(4) D fabricated on office paper has exhibited better performance due to its higher electrical conductivity. Furthermore, the detector response was similar to that recorded with electrodes prepared with copper adhesive tape. The fabrication of PDE-C(4) D on office paper has offered great advantages including extremely low cost (< $ 0.004 per unit), reduced fabrication time (< 5 min), and minimal instrumentation (pencil and paper). The proposed electrodes demonstrated excellent analytical performance with good reproducibility. For an inter-PDE comparison (n = 7), the RSD values for migration time, peak area, and separation efficiency were lower than 2.5, 10.5, and 14%, respectively. The LOD's achieved for K(+) , Na(+) , and Li(+) were 4.9, 6.8, and 9.0 MUM, respectively. The clinical feasibility of the proposed approach was successfully demonstrated with the quantitative analysis of K(+) and Na(+) in tear samples. The concentration levels found for K(+) and Na(+) were, respectively, 20.8 +/- 0.1 mM and 101.2 +/- 0.1 mM for sample #1, and 20.4 +/- 0.1 mM and 111.4 +/- 0.1 mM for sample #2. PMID- 25929982 TI - Analysis of metal artifact reduction tools for dental hardware in CT scans of the oral cavity: kVp, iterative reconstruction, dual-energy CT, metal artifact reduction software: does it make a difference? AB - INTRODUCTION: Metal artifacts may negatively affect radiologic assessment in the oral cavity. The aim of this study was to evaluate different metal artifact reduction techniques for metal artifacts induced by dental hardware in CT scans of the oral cavity. METHODS: Clinical image quality was assessed using a Thiel embalmed cadaver. A Catphan phantom and a polymethylmethacrylate (PMMA) phantom were used to evaluate physical-technical image quality parameters such as artifact area, artifact index (AI), and contrast detail (IQFinv). Metal cylinders were inserted in each phantom to create metal artifacts. CT images of both phantoms and the Thiel-embalmed cadaver were acquired on a multislice CT scanner using 80, 100, 120, and 140 kVp; model-based iterative reconstruction (Veo); and synthesized monochromatic keV images with and without metal artifact reduction software (MARs). Four radiologists assessed the clinical image quality, using an image criteria score (ICS). RESULTS: Significant influence of increasing kVp and the use of Veo was found on clinical image quality (p = 0.007 and p = 0.014, respectively). Application of MARs resulted in a smaller artifact area (p < 0.05). However, MARs reconstructed images resulted in lower ICS. CONCLUSION: Of all investigated techniques, Veo shows to be most promising, with a significant improvement of both the clinical and physical-technical image quality without adversely affecting contrast detail. MARs reconstruction in CT images of the oral cavity to reduce dental hardware metallic artifacts is not sufficient and may even adversely influence the image quality. PMID- 25929983 TI - Body size overestimation and its association with body mass index, body dissatisfaction, and drive for thinness in anorexia nervosa. AB - BACKGROUND: Body size overestimation is a fundamental feature in anorexia nervosa (AN). There have been inconclusive findings about the extent to which this feature distinguishes psychopathology and some authors have argued that overestimation may be a function of lower body mass index (BMI). METHODS: We examine body size estimation accuracy and body dissatisfaction in 74 females with AN and 11 age-matched female controls using two well-established psychophysical procedures. RESULTS: Participants with AN overestimated their body size more and had greater body dissatisfaction than controls. Size accuracy was found to be independent of BMI and correlated with body dissatisfaction and drive for thinness in participants with AN. CONCLUSIONS: We conclude that overestimation of body size in AN is related to the psychopathology associated with the disorder and is not due to any perceptual tendency for people with lower BMI to overestimate their body size. We discuss the implications of these findings for treatment of AN. PMID- 25929984 TI - Calorimetric evidence of interaction of brominated flame retardants with membrane model. AB - The presence of polybrominated flame retardants in the environment seems to be increasing in the past decade. Considering the toxic effects of these pollutants, it is important evaluating the potential interaction with biological membranes for a risk assessment. In this study low and high brominated biphenyls and biphenyl ethers were used to investigate their interaction with biological membrane models constituted by liposomes, using differential scanning calorimetry (DSC) technique. The medium influence on membrane absorption was also assessed. The findings indicate that membrane interaction is controlled by compound structural characteristics. The membrane absorption is allowed by lipophilic medium; instead hydrophilic medium prevents membrane permeation. PMID- 25929985 TI - Delivery of self training and education for stressful situations (DESTRESS-PC): a randomized trial of nurse assisted online self-management for PTSD in primary care. AB - OBJECTIVE: This randomized controlled trial examined the effectiveness of a nurse assisted online cognitive-behavioral self-management intervention for war-related posttraumatic stress disorder (PTSD), compared to optimized usual primary care PTSD Treatment (OUC) to reduce PTSD symptoms. METHOD: Participants were 80 veterans of recent military conflicts with PTSD as assessed by the PTSD Checklist (PCL) seeking primary care treatment at one of three Veterans Affairs (VA) and four Army clinics. DESTRESS-PC consisted of logins to a secure website three times per week for 6 weeks with monitoring by a study nurse. All participants received nurse care management in the form of phone check-ins every two weeks and feedback to their primary care providers. Blinded raters assessed outcomes 6, 12, and 18 weeks post-randomization. RESULTS: DESTRESS-PC was associated with a significantly greater decrease in PTSD symptoms compared to OUC (F(3, 186)=3.72, p=.012). The effect was largest at the 12-week assessment (?PCL=12.6+/-16.6 versus 5.7+/-12.5, p<0.05) with the treatment effect disappearing by the 18-week follow-up. Notably, there was a dose effect; number of logins correlated significantly with PTSD outcomes, with more logins associated with greater PTSD symptom improvement. None of the secondary outcomes (depression, anxiety, somatic symptoms, and functional status) showed statistically significant improvement; however, the treatment effect on depression approached significance (F(3, 186)=2.17, p=.093). CONCLUSIONS: DESTRESS-PC shows promise as a means of delivering effective, early PTSD treatment in primary care. Larger trials are needed. PMID- 25929986 TI - Postpartum electroconvulsive therapy: a systematic review and case report. AB - OBJECTIVE: Postpartum depression can have devastating consequences on the mother and child. Prompt treatment is challenging. Whereas electroconvulsive therapy (ECT) is considered to be an effective treatment modality in severe depression and brings about rapid clinical improvement, little is known about ECT during the postpartum period. METHOD: We systematically reviewed the literature on the use of ECT during the postpartum period using PubMed, Institute for Scientific Information Web of Knowledge and PsycINFO databases until September 2014, using the search terms "electroconvulsive therapy" or "ECT" and "postpartum". Then, we described the successful treatment with ECT and the joint mother-baby hospitalization of a woman with severe depression. RESULTS: Eight case reports and 8 studies were identified. All of the studies reported that ECT is effective in the postpartum period. It is well tolerated, provides a fast response and allows for breastfeeding. In addition, our case report showed the benefits of the hospitalization of the mother-baby unit. CONCLUSIONS: Combined ECT and joint mother-baby hospitalization could be a valuable treatment by targeting both the mother-infant relationship and the maternal depressive symptoms. PMID- 25929987 TI - Risk factors associated with inhibitor development in Chinese patients with haemophilia B. AB - INTRODUCTION: Inhibitor development is a severe complication of factor IX substitution treatment for haemophilia B (HB). Current research examined the association between inhibitor development and F9 genotypes and polymorphisms in immune response genes in Chinese HB patients. MATERIALS AND METHODS: 11 inhibitor positive HB patients and 41 inhibitor-negative HB patients were enrolled. Direct sequencing, copy number variation (CNV) detection and fragment length analysis were applied to identify F9 genotypes and 15 polymorphisms in immune response genes. RESULTS: 7 patients developed high titer inhibitors, with 5 of them having histories of consecutive exposure to FIX products on demand for at least 5 days. Allergic reactions/anaphylaxis to prothrombin complex concentrates (PCC) occurred in 3 patients before inhibitors were detected. Five nonsense mutations (E54X, R75X, Q185X, R298X and R379X), two large deletions (E1~6del and E1~8del) and one missense mutation (S411G) were identified in patients with inhibitors. Missense mutations had a low odds ratio for FIX inhibitors development (IOR) of 0.078 (P = 0.02), while nonsense mutation presented a high IOR of 8.500 (P = 0.0044). The frequency of allele T in CD44(95102) (A/T) was significantly higher in inhibitor negative patients, with OR of 0.324 (P = 0.04). CONCLUSIONS: Nonsense mutations conferred a higher risk for while allele T in CD44(95102) (A/T) might play a protective role against inhibitor development in Chinese HB patients. PMID- 25929988 TI - Experiencing transformation: the case of Jordanian nurse immigrating to the UK. AB - AIMS AND OBJECTIVES: This study explored how Jordanian nurses experienced the transition from home to host country to illuminate the elements of transformation. BACKGROUND: Much research has been conducted on topics such as the current international nursing shortage and the recruitment of nurses from various countries. International nurses have unique needs with regard to adapting to new host cultures and workplaces; furthermore, the literature has revealed little evidence of nurses' professional and personal experiences related to migration. DESIGN: A qualitative study was conducted, collecting data via individual interviews. METHODS: Twenty-five face-to-face and telephone interviews with Jordanian migrant nurses. RESULT: This study showed that living and working in a host country changes the personal, social and professional attributes of migrant nurses. When nurses migrate, they encounter opportunities and significant challenges in their professional and personal lives. Although Jordanian nurses contributed their knowledge and skills to the UK healthcare system, they encountered enormous professional adaptation demands. Work setting discrepancies between source and host country are likely a major element behind the required nursing profession alteration. nurses' lives are transformed in terms of their personal and social networks in the host country. CONCLUSIONS: Social transformation is an integral and inseparable part of engagement with professional organisation(s) in the host community. Professional integration likely has far-reaching effects and consequences involving not only the individual but also their home and host country families and their professional networks. RELEVANCE TO CLINICAL PRACTICE: To provide high-quality nursing care, we must learn about the transformation experience, expand our sense of who we are and gain a degree of control over how we perform our nursing roles when we move away from our home. PMID- 25929989 TI - Sample preparation for avian and porcine influenza virus cDNA amplification simplified: Boiling vs. conventional RNA extraction. AB - RNA extraction and purification is a fundamental step that allows for highly sensitive amplification of specific RNA targets in PCR applications. However, commercial extraction kits that are broadly used because of their robustness and high yield of purified RNA are expensive and labor-intensive. In this study, boiling in distilled water or a commercial lysis buffer of different sample matrices containing avian or porcine influenza viruses was tested as an alternative. Real-time PCR (RTqPCR) for nucleoprotein gene fragment was used as read out. Results were compared with freshly extracted RNA by use of a commercial extraction kit. Different batches of virus containing materials, including diluted virus positive allantoic fluid or cell culture supernatant, and avian faecal, cloacal or oropharyngeal swab samples were used in this study. Simple boiling of samples without any additional purification steps can be used as an alternative RNA preparation method to detect influenza A virus nucleoprotein RNA in oropharyngeal swab samples, allantoic fluid or cell-culture supernatant. The boiling method is not applicable for sample matrices containing faecal material. PMID- 25929990 TI - Non-ionic detergents facilitate non-specific binding of M13 bacteriophage to polystyrene surfaces. AB - Phage-displayed random peptide libraries are widely used for identifying peptide interactions with proteins and other substrates. Selection of peptide ligands involves iterative rounds of affinity enrichment. The binding properties of the selected phage clones are routinely tested using immunoassay after propagation to high titre in a bacterial host and precipitation using polyethylene glycol (PEG) and high salt concentration. These immunoassays can suffer from low sensitivity and high background signals. Polysorbate 20 (Tween((r)) 20) is a non-ionic detergent commonly used in immunoassay washing buffers to reduce non-specific binding, and is also used as a blocking reagent. We have observed that Tween 20 enhances non-specific M13 library phage binding in a peptide-independent manner. Other non-ionic detergents were also found to promote significant, dose-dependent non-specific phage binding in ELISA. This effect was not observed for assays using phage concentrated by ultracentrifugation, suggesting that interactions occur between detergents and the PEG-precipitated phage, irrespective of the displayed peptide motif. This artefact may impact on successful affinity selection of peptides from phage-display libraries. We propose alternative methods for screening phage libraries for identifying binding interactions with target ligands. PMID- 25929991 TI - Organophosphate and phthalate esters in settled dust from apartment buildings in Stockholm. AB - In this study, the occurrence of nine phthalate diesters (phthalates) and 14 organophosphorus flame retardants (PFRs) was investigated in 62 house dust samples collected from 19 buildings in Stockholm area during the year 2008. Eight phthalates were detected in almost all samples, with median concentrations ranging from 0.47 MUg/g to 449 MUg/g with di(2-ethylhexyl) phthalate being the most abundant compound. Twelve PFRs were detected with median concentrations ranging from 0.19 MUg/g to 11 MUg/g. Within this class of compounds, the most abundant were tris(2-chloroisopropyl) and tris(2-butoxyethyl) phosphate. Both classes of compounds were also measured in the air of the apartments, but no correlation between air and dust concentrations could be found. Based on these measurements, exposure, via house dust ingestion and air inhalation, was calculated for adults and toddlers, and compared to published limit values in order to estimate potential health risks. In an extreme exposure scenario for toddlers, di(2-ethylhexyl) phthalate, tris(2-chloroethyl) phosphate, tris(2 butoxyethyl) phosphate, and tributyl phosphate were close to the reference dose for chronic oral exposure or the tolerable daily intake. Standard Reference Material SRM 2585 was used as a quality control sample, and the levels of diisononyl and diisodecyl phthalates were determined in this material. PMID- 25929992 TI - The reactivity of phenancyl bromide under beta-cyclodextrin as supramolecular catalyst: a computational survey. AB - Phenacyl bromide as one starting material in multicomponent reactions (MCRs) with beta-cyclodextrin (beta-CD) as catalyst can get an excellent yield in short reaction times. The interaction of beta-CD with phenacyl bromide plays an important role in this process. This paper studies the complex of beta-CD with phenacyl bromide using density functional theory (DFT) method. Energy is investigated to find out the lowest energy of two possible complexation models. Hydrogen bonds are researched on the basis of natural bonding orbital (NBO) analysis. The relative position between phenacyl bromide and beta-CD is confirmed by (1)H nuclear magnetic resonance ((1)HNMR). The results of frontier molecular orbitals and charge distribution reveal that beta-CD catalyst improves the reactivity and electrophilicity of phenacyl bromide, meanwhile, the carbonyl group of phenacyl bromide more easily gives a carbocationic intermediate in the presence of beta-CD as catalyst. The reactivity of phenancyl bromide under beta CD as supramolecular catalysis is improved. PMID- 25929993 TI - Insight into the genomic diversity and relationship of Astragalus glycyphyllos symbionts by RAPD, ERIC-PCR, and AFLP fingerprinting. AB - We assessed the genomic diversity and genomic relationship of 28 Astragalus glycyphyllos symbionts by three methodologies based on PCR reaction, i.e., RAPD, ERIC-PCR, and AFLP. The AFLP method with one PstI restriction enzyme and selective PstI-GC primer pair had a comparable discriminatory power as ERIC-PCR one and these fingerprinting techniques distinguished among the studied 28 A. glycyphyllos symbionts 18 and 17 genomotypes, respectively. RAPD method was less discriminatory in the genomotyping of rhizobia analyzed and it efficiently resolved nine genomotypes. The cluster analysis of RAPD, ERIC-PCR, and AFLP profiles resulted in a generally similar grouping of the test strains on generated dendrograms supporting a great potential of these DNA fingerprinting techniques for study of genomic polymorphism and evolutionary relationship of A. glycyphyllos nodulators. The RAPD, ERIC-PCR, and AFLP pattern similarity coefficients between A. glycyphyllos symbionts studied was in the ranges 8-100, 18-100, and 23-100%, respectively. PMID- 25929994 TI - Decreased expression of gastric gland mucin-specific glycan alpha1,4-linked N acetylglucosamine on its scaffold mucin 6 is associated with malignant potential of pyloric gland adenoma of the stomach. AB - AIMS: Pyloric gland adenoma (PGA) is a unique gastric neoplasm expressing mucin 6 (MUC6), and is often associated with high-grade dysplasia and/or adenocarcinoma. MUC6 secreted from the gastric gland mucous cells, such as pyloric gland cells, carries unique O-glycans with terminal alpha1,4-linked N-acetylglucosamine (alphaGlcNAc) residues on its molecule. As we recently demonstrated that alphaGlcNAc serves as a tumour suppressor for gastric adenocarcinoma, this study aimed to investigate the significance of alphaGlcNAc expression in PGA. METHODS AND RESULTS: Eighteen patients with PGA were examined with immunohistochemistry for alphaGlcNAc and MUC6. alphaGlcNAc and MUC6 were coexpressed in 12 of 18 PGAs. However, reduced alphaGlcNAc expression relative to MUC6 expression was observed in six cases. When the MIB-1 labelling index (LI) of tumour cells was examined with respect to reduced alphaGlcNAc expression, the MIB-1 LI was significantly higher in PGAs showing decreased alphaGlcNAc expression relative to MUC6 expression than in PGAs with unchanged alphaGlcNAc expression (P = 0.023). CONCLUSIONS: The present study indicates that coexpression of alphaGlcNAc and MUC6 in PGA suggests the presence of fully glycosylated MUC6 on tumour cells, consistent with pyloric gland differentiation. However, the decreased glycosylation of alphaGlcNAc on MUC6 is associated with high mitotic activity of tumour cells, indicative of malignant potential of PGA. PMID- 25929995 TI - Histotripsy Lesion Formation Using an Ultrasound Imaging Probe Enabled by a Low Frequency Pump Transducer. AB - When histotripsy pulses shorter than 2 cycles are applied, the formation of a dense bubble cloud relies only on the applied peak negative pressure (p-) exceeding the "intrinsic threshold" of the medium (absolute value of 26-30 MPa in most soft tissues). It has been found that a sub-threshold high-frequency probe pulse (3 MHz) can be enabled by a sub-threshold low-frequency pump pulse (500 kHz) where the sum exceeds the intrinsic threshold, thus generating lesion producing dense bubble clouds ("dual-beam histotripsy"). Here, the feasibility of using an imaging transducer to provide the high-frequency probe pulse in the dual beam histotripsy approach is investigated. More specifically, an ATL L7-4 imaging transducer (Philips Healthcare, Andover, MA, USA), pulsed by a V-1 Data Acquisition System (Verasonics, Redmond, WA, USA), was used to generate the high frequency probe pulses. The low-frequency pump pulses were generated by a 20 element 345-kHz array transducer, driven by a custom high-voltage pulser. These dual-beam histotripsy pulses were applied to red blood cell tissue-mimicking phantoms at a pulse repetition frequency of 1 Hz, and optical imaging was used to visualize bubble clouds and lesions generated in the red blood cell phantoms. The results indicated that dense bubble clouds (and resulting lesions) were generated when the p- of the sub-threshold pump and probe pulses combined constructively to exceed the intrinsic threshold. The average size of the smallest reproducible lesions using the imaging probe pulse enabled by the sub-threshold pump pulse was 0.7 * 1.7 mm, whereas that using the supra-threshold pump pulse alone was 1.4 * 3.7 mm. When the imaging transducer was steered laterally, bubble clouds and lesions were steered correspondingly until the combined p- no longer exceeded the intrinsic threshold. These results were also validated with ex vivo porcine liver experiments. Using an imaging transducer for dual-beam histotripsy can have two advantages: (i) lesion steering can be achieved using the steering of the imaging transducer (implemented with the beamformer of the accompanying programmable ultrasound system), and (ii) treatment can be simultaneously monitored when the imaging transducer is used in conjunction with an ultrasound imaging system. PMID- 25929996 TI - Efficient Gene Delivery by Sonoporation Is Associated with Microbubble Entry into Cells and the Clathrin-Dependent Endocytosis Pathway. AB - Microbubble oscillation at specific ultrasound settings leads to permeabilization of surrounding cells. This phenomenon, referred to as sonoporation, allows for the in vitro and in vivo delivery of extracellular molecules, including plasmid DNA. To date, the biological and physical mechanisms underlying this phenomenon are not fully understood. The aim of this study was to investigate the interactions between microbubbles and cells, as well as the intracellular routing of plasmid DNA and microbubbles, during and after sonoporation. High-speed imaging and fluorescence confocal microscopy of HeLa cells stably expressing enhanced green fluorescent protein fused with markers of cellular compartments were used for this investigation. Soft-shelled microbubbles were observed to enter cells during sonoporation using experimental parameters that led to optimal gene transfer. They interacted with the plasma membrane in a specific area stained with fluorescent cholera subunit B, a marker of lipid rafts. This process was not observed with hard-shelled microbubbles, which were not efficient in gene delivery under our conditions. The plasmid DNA was delivered to late endosomes after 3 h post-sonoporation, and a few were found in the nucleus after 6 h. Gene transfer efficacy was greatly inhibited when cells were treated with chlorpromazine, an inhibitor of the clathrin-dependent endocytosis pathway. In contrast, no significant alteration was observed when cells were treated with filipin III or genistein, both inhibitors of the caveolin-dependent pathway. This study emphasizes that microbubble-cell interactions do not occur randomly during sonoporation; microbubble penetration inside cells affects the efficacy of gene transfer at specific ultrasound settings; and plasmid DNA uptake is an active mechanism that involves the clathrin-dependent pathway. PMID- 25929997 TI - Needle Trajectory and Tip Localization in Real-Time 3-D Ultrasound Using a Moving Stylus. AB - Described here is a novel approach to needle localization in 3-D ultrasound based on automatic detection of small changes in appearance on movement of the needle stylus. By stylus oscillation, including its full insertion into the cannula to the tip, the image processing techniques can localize the needle trajectory and the tip in the 3-D ultrasound volume. The 3-D needle localization task is reduced to two 2-D localizations using orthogonal projections. To evaluate our method, we tested it on three different ex vivo tissue types, and the preliminary results indicated that the method accuracy lies within clinical acceptance, with average error ranges of 0.9 degrees -1.4 degrees in needle trajectory and 0.8-1.1 mm in needle tip. Results also indicate that method performance is independent of the echogenicity of the tissue. This technique is a safe way of producing ultrasonic intensity changes and appears to introduce negligible risk to the patient, as the outer cannula remains fixed. PMID- 25929998 TI - Induction of HLA-B*40:02-restricted T cells possessing cytotoxic and suppressive functions against haematopoietic progenitor cells from a patient with severe aplastic anaemia. PMID- 25930000 TI - Estimation of the infectious viral load required for transfusion-transmitted human T-lymphotropic virus type 1 infection (TT-HTLV-1) and of the effectiveness of leukocyte reduction in preventing TT-HTLV-1. AB - BACKGROUND AND OBJECTIVES: The risk of transfusion-transmitted human T lymphotropic virus type 1 infection (TT-HTLV-1) after prestorage leucocyte reduction (LR) remains unknown, as the proviral load in the blood component that would cause TT-HTLV-1 is undetermined. On the basis of the distribution of HTLV-1 proviral load among HTLV-1-sero-positive blood donors, we attempted to estimate the proviral load for transfusion-related infectivity. We also discuss the effectiveness of LR in preventing TT-HTLV-1. MATERIALS AND METHODS: The HTLV-1 proviral load in 300 HTLV-1-sero-positive blood donors was determined by real time polymerase chain reaction analysis. The proviral load required for transfusion-related infectivity was estimated using historical TT-HTLV-1 frequency data from a retrospective study on patients who had received blood from HTLV-1-sero-positive blood donors and the distribution pattern of HTLV-1 proviral load among blood donors. RESULTS: HTLV-1 proviral loads ranged between < 0.01 and 25.0 copies per 100 leucocytes. Historical data showed TT-HTLV-1 frequency to be 80%. Assuming that 80% of the 300 sero-positive samples are infectious, it is estimated that the transfer of >= 9 * 10(4) cells containing the HTLV-1 provirus is required to establish TT-HTLV-1. CONCLUSION: The residual number of HTLV-1 infected cells after LR is substantially lower than the viral load necessary for TT-HTLV-1. LR therefore appears to be effective in minimizing the incidence of TT HTLV-1. PMID- 25930001 TI - New photostable naphthalimide-based fluorescent probe for mitochondrial imaging and tracking. AB - Monitoring mitochondria morphological changes temporally and spatially exhibits significant importance for diagnosing, preventing and treating various diseases related to mitochondrial dysfunction. However, the application of commercially available mitochondria trackers is limited due to their poor photostability. To overcome these disadvantages, we designed and synthesized a mitochondria localized fluorescent probe by conjugating 1,8-naphthalimide with triphenylphosphonium (i.e. NPA-TPP). The structure and characteristic of NPA-TPP was characterized by UV-vis, fluorescence spectroscopy, (1)HNMR, (13)CNMR, FTIR, MS, etc. The photostability and cell imaging were performed on the laser scanning confocal microscopy. Moreover, the cytotoxicity of NPA-TPP on cells was evaluated using (3-[4,5-dimethylthiazol-2-yl]-2,5 diphenyl tetrazolium bromide) assay. The results showed that NPA-TPP not only has high sensitivity and specificity to mitochondria, but also exhibits super-high photostability, negligible cytotoxicity and good water solubility. In short, NPA-TPP indicates great potential for targeting mitochondria and enables a real-time and long-term tracking mitochondrial dynamics changes. PMID- 25929999 TI - Speciation by genome duplication: Repeated origins and genomic composition of the recently formed allopolyploid species Mimulus peregrinus. AB - Whole genome duplication (polyploidization) is a mechanism of "instantaneous" species formation that has played a major role in the evolutionary history of plants. Much of what we know about the early evolution of polyploids is based upon studies of a handful of recently formed species. A new polyploid hybrid (allopolyploid) species Mimulus peregrinus, formed within the last 140 years, was recently discovered on the Scottish mainland and corroborated by chromosome counts. Here, using targeted, high-depth sequencing of 1200 genic regions, we confirm the parental origins of this new species from M. x robertsii, a sterile triploid hybrid between the two introduced species M. guttatus and M. luteus that are naturalized and widespread in the United Kingdom. We also report a new population of M. peregrinus on the Orkney Islands and demonstrate that populations on the Scottish mainland and Orkney Islands arose independently via genome duplication from local populations of M. x robertsii. Our data raise the possibility that some alleles are already being lost in the evolving M. peregrinus genomes. The recent origins of a new species of the ecological model genus Mimulus via allopolyploidization provide a powerful opportunity to explore the early stages of hybridization and genome duplication in naturally evolved lineages. PMID- 25930002 TI - Amplification-based method for microRNA detection. AB - Over the last two decades, the study of miRNAs has attracted tremendous attention since they regulate gene expression post-transcriptionally and have been demonstrated to be dysregulated in many diseases. Detection methods with higher sensitivity, specificity and selectivity between precursors and mature microRNAs are urgently needed and widely studied. This review gave an overview of the amplification-based technologies including traditional methods, current modified methods and the cross-platforms of them combined with other techniques. Many progresses were found in the modified amplification-based microRNA detection methods, while traditional platforms could not be replaced until now. Several sample-specific normalizers had been validated, suggesting that the different normalizers should be established for different sample types and the combination of several normalizers might be more appropriate than a single universal normalizer. This systematic overview would be useful to provide comprehensive information for subsequent related studies and could reduce the un-necessary repetition in the future. PMID- 25930003 TI - Development of an electrochemical RNA-aptasensor to detect human osteopontin. AB - Electrochemical aptasensors may be used to detect protein biomarkers related to tumor activity. Osteopontin (OPN), a protein present in several body fluids, has been suggested as a potential biomarker since its overexpression seems to be associated with breast cancer progression and metastasis. In this work, a simple and label-free voltammetric aptasensor for the detection of OPN, using an RNA aptamer previously reported to have affinity for human OPN as the molecular recognition element, and the ferro/ferricyanide solution as a redox probe, was developed. The RNA aptamer was synthetized and immobilized in a working microelectrode gold surface (diameter of 0.8mm) of a screen-printed strip with a silver pseudo-reference electrode and a gold counter electrode. The electrochemical behavior of the electrode surface after each preparation step of the aptasensor was studied using cyclic voltammetry and square wave voltammetry. The resulting voltammetric aptasensor was used to detect OPN in standard solutions. Cyclic voltammetry results showed that the aptasensor has reasonable detection and quantification limits (3.7 +/- 0.6 nM and 11 +/- 2 nM, respectively). Indeed, the detection limit falls within the osteopontin levels reported in the literature for patients with metastatic breast cancer. Moreover, the aptasensor is able to selectively detect the target protein in the presence of other interfering proteins, except for thrombin. Considering the overall results, a possible application of the aptasensor for cancer prognosis may be foreseen in a near future. PMID- 25930004 TI - Selective detection of fenaminosulf via a molecularly imprinted fluorescence switch and silver nano-film amplification. AB - A novel fluorescence switch sensor was constructed for detecting the fungicide fenaminosulf (FM), based on a dye-doped molecularly imprinted polymer (MIP) and silver nanofilm amplification. The MIP was prepared by electropolymerization of hydroquinone doped with neutral red on the silver nanofilm modified electrode. A fluorescence signal was produced by the neutral red and the fluorescence intensity was diminished by the ion pair that formed via electrostatic forces between FM and the dye. Therefore, elution and adsorption of FM by the MIP acted as a switch to control the fluorescence intensity, which was effectively amplified by the silver nanofilm. The decrease in fluorescence intensity was linear with the FM concentration, establishing a new method for FM detection. Under optimal conditions, good linear correlation was obtained for FM concentrations over the range from 2.0 * 10(-10) to 4.0 * 10(-8)mol/L, with a detection limit of 1.6 * 10(-11)mol/L. This method was utilized to determine residual FM in vegetable samples, and recoveries ranging from 92.0% to 110% were obtained. PMID- 25930005 TI - Trauma, social support, family conflict, and chronic pain in recent service veterans: does gender matter? AB - OBJECTIVE: Women veterans have a higher prevalence of chronic pain relative to men. One hypothesis is that differential combat and traumatic sexual experiences and attenuated levels of social support between men and women may differentially contribute to the development and perpetuation of pain. This investigation examined [1] gender differences in trauma, social support, and family conflict among veterans with chronic pain, and [2] whether trauma, social support, and family conflict were differentially associated with pain severity, pain interference, and depressive symptom severity as a function of gender. METHODS: Participants included 460 veterans (56% female) who served in support of recent conflicts, and who endorsed pain lasting 3 months or longer. Participants completed a baseline survey during participation in a longitudinal investigation. Self-report measures included pain severity, pain interference, depressive symptom severity, exposure to traumatic life events, emotional and tangible support, and family conflict. RESULTS: Relative to men, women veterans reporting chronic pain evidenced higher rates of childhood interpersonal trauma (51% vs 34%; P < 0.001) and military sexual trauma (54% vs 3%; P < 0.001), along with lower levels of combat exposure (10.00 vs 16.85, P < 0.001). Gender was found to be a moderator of the association of marital status, combat exposure, childhood interpersonal trauma, and family conflict with pain interference. It also moderated family conflict in the prediction of depressive symptoms. CONCLUSIONS: Results underscore the potential importance of developing and testing gender specific models of chronic pain that consider the relative roles of trauma, social support, and family conflict. PMID- 25930006 TI - Synthesis and Characterization of Two-Photon Active Chromophores Based on Tetrathienoacene (TTA) and Dithienothiophene (DTT). AB - Three new donor-pi-donor (D-pi-D) tetrathienoacene (thieno[2',3':4,5]thieno[3,2 b]thieno[2,3-d]thiophene (TTA))-cored chromophores, end-functionalized with electron-donating triphenylamine (TPA) groups, were developed and characterized for their two-photon-related properties by using both nano- and femtosecond laser pulses as the probing tools. TTA-based chromophores exhibit stronger and more widely dispersed two-photon absorption (2PA) than those of dithienothiophene (DTT)-based congeners. As a consequence, the bithiophene-conjugated TTA chromophore exhibits the highest maximum 2PA cross-section value (up to 2500 GM) with good thermal stability, and thus, it is the best performing two-photon chromophore among the studied model compounds. The bithiophene-conjugated DTT analogue exhibits the second highest maximum two-photon absorptivity of 1950 GM, which is nearly 7 times larger than that of previously reported DTT-based chromophores. PMID- 25930007 TI - Dose-dependent deleterious and salutary actions of the Nrf2 inducer dh404 in chronic kidney disease. AB - Oxidative stress and inflammation play a central role in the progression and complications of chronic kidney disease (CKD) and are, in part, due to impairment of the Nrf2 system, which regulates the expression of antioxidant and detoxifying molecules. Natural Nrf2-inducing phytochemicals have been shown to ameliorate kidney disease in experimental animals. However, owing to adverse outcomes a clinical trial of a synthetic Nrf2 activator, bardoxolone methyl (BARD), in CKD patients was terminated. BARD activates Nrf2 via covalent modification of reactive cysteine residues in the Nrf2 repressor molecule, Keap1. In addition to Nrf2, Keap1 suppresses IKKB, the positive regulator of NF-kappaB. Treatment with a BARD analog, dh404, at 5-20mg/kg/day in diabetic obese Zucker rats exacerbates, whereas its use at 2mg/kg/day in 5/6 nephrectomized rats attenuates, CKD progression. We, therefore, hypothesized that deleterious effects of high-dose BARD are mediated by the activation of NF-kappaB. CKD (5/6 nephrectomized) rats were randomized to receive dh404 (2 or 10mg/kg/day) or vehicle for 12 weeks. The vehicle-treated group exhibited glomerulosclerosis; interstitial fibrosis and inflammation; activation of NF-kappaB; upregulation of oxidative, inflammatory, and fibrotic pathways; and suppression of Nrf2 activity and its key target gene products. Treatment with low-dose dh404 restored Nrf2 activity and expression of its target genes, attenuated activation of NF-kappaB and fibrotic pathways, and reduced glomerulosclerosis, interstitial fibrosis, and inflammation. In contrast, treatment with a high dh404 dosage intensified proteinuria, renal dysfunction, and histological abnormalities; amplified upregulation of NF-kappaB and fibrotic pathways; and suppressed the Nrf2 system. Thus therapy with BARD analogs exerts a dose-dependent dimorphic impact on CKD progression. PMID- 25930008 TI - Near-ultraviolet laser diodes for brilliant ultraviolet fluorophore excitation. AB - Although multiple lasers are now standard equipment on most modern flow cytometers, ultraviolet (UV) lasers (325-365 nm) remain an uncommon excitation source for cytometry. Nd:YVO4 frequency-tripled diode pumped solid-state lasers emitting at 355 nm are now the primary means of providing UV excitation on multilaser flow cytometers. Although a number of UV excited fluorochromes are available for flow cytometry, the cost of solid-state UV lasers remains prohibitively high, limiting their use to all but the most sophisticated multilaser instruments. The recent introduction of the brilliant ultraviolet (BUV) series of fluorochromes for cell surface marker detection and their importance in increasing the number of simultaneous parameters for high dimensional analysis has increased the urgency of including UV sources in cytometer designs; however, these lasers remain expensive. Near-UV laser diodes (NUVLDs), a direct diode laser source emitting in the 370-380 nm range, have been previously validated for flow cytometric analysis of most UV-excited probes, including quantum nanocrystals, the Hoechst dyes, and 4',6-diamidino-2 phenylindole. However, they remain a little-used laser source for cytometry, despite their significantly lower cost. In this study, the ability of NUVLDs to excite the BUV dyes was assessed, along with their compatibility with simultaneous brilliant violet (BV) labeling. A NUVLD emitting at 375 nm was found to excite most of the available BUV dyes at least as well as a UV 355 nm source. This slightly longer wavelength did produce some unwanted excitation of BV dyes, but at sufficiently low levels to require minimal additional compensation. NUVLDs are compact, relatively inexpensive lasers that have higher power levels than the newest generation of small 355 nm lasers. They can, therefore, make a useful, cost-effective substitute for traditional UV lasers in multicolor analysis involving the BUV and BV dyes. PMID- 25930009 TI - Changes in puffing behavior among smokers who switched from tobacco to electronic cigarettes. AB - INTRODUCTION: Nicotine intake from electronic cigarette (e-cigarettes) increases with user's experience. This suggests that smokers who switched from tobacco to electronic cigarettes compensate for nicotine over time to get as much nicotine as they need. One of the mechanisms by which smokers may compensate for nicotine is by modifying their puffing behavior. The aim of the study was to assess the changes in puffing behavior after switching from conventional to electronic cigarettes among regular smokers. MATERIALS AND METHODS: Twenty smokers (11 female, aged 31+/-10, CPD 16+/-8, FTND 4+/-3, and exhaled CO 16+/-17 (mean+/-SD)) who were naive to e-cigarettes participated in this study. They were asked to substitute their regular tobacco cigarettes with first generation e-cigarettes (labeled 18mg nicotine) for two weeks. Puffing topography (number of puffs, puff volume, intervals between puffs, and average puff flow rate) was measured at the initial use (baseline), as well as after one and two weeks of product use. We tested changes in puffing topography outcomes using repeated measures ANOVA. RESULTS: We found that after one week of using e-cigarettes, participants significantly increased the average time they puffed on e-cigarettes from 2.2+/ 0.1 (mean+/-SEM) to 3.1+/-0.3s (p<0.05). The average puff flow rate decreased from 30.6+/-2.3 to 25.1+/-1.8ml/s after one week of e-cigarette use (p<0.05). CONCLUSIONS: Our data show that smokers modify their puffing behavior after switching from tobacco to electronic cigarettes by taking longer and slower puffs. The potential reason for changing puffing behavior is to compensate for less efficient nicotine delivery from e-cigarettes. PMID- 25930010 TI - Belief incongruence and the intention-behavior gap in persons with at-risk alcohol use. AB - INTRODUCTION: When intentions are expressed, e.g., when filling in a health questionnaire, people may have unrealistic beliefs towards behavior change resulting in strong intentions to change. These may fail to correspond to reality when the behavior actually should be performed. Belief incongruence was tested as a possible source of the intention-behavior gap. METHODS: The study sample consisted of 433 job agency clients with at-risk alcohol use (64% men, mean age=30.6 (SD=11.6) years). Behavioral, normative, and control beliefs, intention, and alcohol use were assessed at baseline and three months later. The influence of belief incongruence on the intention-behavior gap was examined using latent interaction models. RESULTS: The gap between stated intentions and at-risk alcohol use three months later was larger when the according normative beliefs were incongruent (total effect: b=-0.44, p<0.05 for persons with congruent beliefs vs. b=-0.06, p>0.10 for persons with incongruent beliefs). When controlling for the mediating effect of changes in intentions, the association between belief incongruence and intention-behavior gap was attenuated (direct effect: b=-0.56, p<0.01 for persons with congruent beliefs vs. b=-0.28, p<0.05 for persons with incongruent beliefs). Neither behavioral belief incongruence nor control belief incongruence was significantly associated with the intention behavior gap. CONCLUSIONS: Normative belief incongruence may contribute to the gap between intentions to adhere to recommended drinking limits and subsequent at risk alcohol use. Focusing on the reduction of misperceptions about drinking norms could help to increase the proportion of persons who succeed in translating their intentions into behavior. PMID- 25930011 TI - Brain bases of morphological processing in young children. AB - How does the developing brain support the transition from spoken language to print? Two spoken language abilities form the initial base of child literacy across languages: knowledge of language sounds (phonology) and knowledge of the smallest units that carry meaning (morphology). While phonology has received much attention from the field, the brain mechanisms that support morphological competence for learning to read remain largely unknown. In the present study, young English-speaking children completed an auditory morphological awareness task behaviorally (n = 69, ages 6-12) and in fMRI (n = 16). The data revealed two findings: First, children with better morphological abilities showed greater activation in left temporoparietal regions previously thought to be important for supporting phonological reading skills, suggesting that this region supports multiple language abilities for successful reading acquisition. Second, children showed activation in left frontal regions previously found active in young Chinese readers, suggesting morphological processes for reading acquisition might be similar across languages. These findings offer new insights for developing a comprehensive model of how spoken language abilities support children's reading acquisition across languages. PMID- 25930012 TI - Polystyrene as a model system to probe the impact of ambient gas chemistry on polymer surface modifications using remote atmospheric pressure plasma under well controlled conditions. AB - An atmospheric pressure plasma jet (APPJ) was used to treat polystyrene (PS) films under remote conditions where neither the plume nor visible afterglow interacts with the film surface. Carefully controlled conditions were achieved by mounting the APPJ inside a vacuum chamber interfaced to a UHV surface analysis system. PS was chosen as a model system as it contains neither oxygen nor nitrogen, has been extensively studied, and provides insight into how the aromatic structures widespread in biological systems are modified by atmospheric plasma. These remote treatments cause negligible etching and surface roughening, which is promising for treatment of sensitive materials. The surface chemistry was measured by X-ray photoelectron spectroscopy to evaluate how ambient chemistry, feed gas chemistry, and plasma-ambient interaction impact the formation of specific moieties. A variety of oxidized carbon species and low concentrations of NOx species were measured after APPJ treatment. In the remote conditions used in this work, modifications are not attributed to short-lived species, e.g., O atoms. It was found that O3 does not correlate with modifications, suggesting that other long-lived species such as singlet delta oxygen or NOx are important. Indeed, surface-bound NO3 was observed after treatment, which must originate from gas phase NOx as neither N nor O are found in the pristine film. By varying the ambient and feed gas chemistry to produce O rich and O-poor conditions, a possible correlation between the oxygen and nitrogen composition was established. When oxygen is present in the feed gas or ambient, high levels of oxidation with low concentrations of NO3 on the surface were observed. For O-poor conditions, NO and NO2 were measured, suggesting that these species contribute to the oxidation process, but are easily oxidized when oxygen is present. That is, surface oxidation limits and competes with surface nitridation. Overall, surface oxidation takes place easily, but nitridation only occurs under specific conditions with the overall nitrogen content never exceeding 3%. Possible mechanisms for these processes are discussed. This work demonstrates the need to control plasma-ambient interactions and indicates a potential to take advantage of plasma-ambient interactions to fine-tune the reactive species output of APP sources, which is required for specialized applications, including polymer surface modifications and plasma medicine. PMID- 25930013 TI - Anti-androgenic activities of diuron and its metabolites in male Nile tilapia (Oreochromis niloticus). AB - Diuron (3-(3,4-dichlorophenyl)-1,1-dimethylurea) is a widely used herbicide which has been frequently detected in surface waters throughout the world. In vivo bioassay guided fractionation studies indicated that diuron may have estrogenic activity augmented by biotransformation. This study evaluated the effects of diuron and three of its metabolites on plasma hormone concentrations and spermatogenesis of the freshwater fish Nile tilapia (Oreochromis niloticus). Sexually mature male fish were exposed for 25 days to diuron, as well to its metabolites 3,4-dichloroaniline (DCA), 3,4-dichlorophenylurea (DCPU) and 3,4 dichlorophenyl-N-methylurea (DCPMU), at concentrations of 200ng/L. Testosterone levels were decreased by diuron, but had limited effects on gonadal histology. Diuron metabolites, however, caused significant decreases in testosterone and in 11-ketotestosterone, gonadosomatic index, diameter of seminiferous tubules and in the mean percentages of germ cells (spermatids and spermatozoa). We conclude that these metabolites have antiandrogenic activity to male Nile tilapia, potentially causing reproductive impairment in male fish. PMID- 25930014 TI - Mammalian cadherins DCHS1-FAT4 affect functional cerebral architecture. AB - Cortical development is a complex process where a multitude of factors, including cadherins, plays an important role and where disruptions are known to have far reaching effects in neural development and cortical patterning. Cadherins play a central role in structural left-right differentiation during brain and body development, but their effect on a functional level remains elusive. We addressed this question by examining functional cerebral asymmetries in a patient with Van Maldergem Syndrome (VMS) (MIM#601390), which is caused by mutations in DCHS1-FAT4 cadherins, using a dichotic listening task. Using neurophysiological (EEG) data, we show that when key regulators during mammalian cerebral cortical development are disrupted due to DCHS1-FAT4 mutations, functional cerebral asymmetries are stronger. Basic perceptual processing of biaurally presented auditory stimuli was unaffected. This suggests that the strength and emergence of functional cerebral asymmetries is a direct function of proliferation and differentiation of neuronal stem cells. Moreover, these results support the recent assumption that the molecular mechanisms establishing early left-right differentiation are an important factor in the ontogenesis of functional lateralization. PMID- 25930016 TI - (1)H, (13)C and (15)N assignments of EGF domains 8-11 of human Notch-1. AB - The Notch receptor is part of a core cell-cell signaling system crucial for development and tissue homeostasis in Metazoa. Structural information is available for the negative regulatory region, the ligand-binding region and the intracellular domain of Notch, but data for the remaining portions of the extracellular region which determine its overall shape at the cell surface are still lacking. This region consists of 36 EGF-like domains arranged as multiple tandem repeats. Most EGF-like domains near the ligand-binding domains EGF11 and 12 are of the calcium-binding type, with well-described, rigid and near-linear interdomain interfaces. However, EGF10 is a conserved, non-calcium-binding domain which may confer flexibility or a non-linear organization to the receptor. To probe this, we have expressed and purified a four-domain construct, EGF8-11, from human Notch-1, and report here the (1)H, (13)C and (15)N resonance assignments. Differences in EGF11 chemical shifts between this construct and a previously assigned construct, EGF11-13, confirm the presence of hydrophobic interdomain contacts between the hairpin turn of the major beta-sheet in EGF11 and the conserved aromatic residue within the C-terminal region of EGF10. This suggests that the EGF10-11 interface is rigid. PMID- 25930015 TI - Vulvar cancer: a review for dermatologists. AB - Vulvar malignancies are important tumors of the female reproductive system. They represent a serious health issue with an incidence between 2 and 7 per 100,000 and year. We provide a review about most important cancer entities, i.e., melanoma, squamous cell carcinoma, basal cell carcinoma, neuroendocrine cancer, and skin adnexal malignancies.Squamous cell carcinoma is the most common vulvar malignancy that can develop from vulvar intraepithelial neoplasia or de novo. Basal cell carcinoma represents only 2% of all vulvar cancers. Melanoma of the vulva exists in two major types-superficial spreading and acral lentiginous. A special feature is the occurrence of multiple vulvar melanomas. Of the adnexal cancer types Paget's disease and carcinoma are seen more frequently than other adnexal malignancies. The dermatologist should be aware of this problem, since he might be the first to be consulted by patients for vulvar disease. Treatment should be interdisciplinary in close association to gynecologists, oncologists, and radiologists. PMID- 25930017 TI - In vitro comparison of polymerisation kinetics and the micro-mechanical properties of low and high viscosity giomers and RBC materials. AB - OBJECTIVES: The study aims to characterise a low and high viscosity giomer bulk fill resin restorative with established low and high viscosity resin-based composite (RBC) restoratives at simulated clinical relevant specimen depths. METHODS: The irradiance of a light curing unit (Bluephase 20i) was measured on a laboratory-grade spectrometer at distances up to 10mm from the light tip (in 1mm increments). Polymerization kinetics (real-time decrease of CC double bond and degree of cure, DC) and micro-mechanical properties (Vickers hardness/HV; Depth of cure/DOC; Indentation modulus/E) were assessed at varying specimen depths (0.1 6mm in 100MUm steps for E, DOC and HV and 0.1, 2, 4 and 6mm for DC) for a 20s irradiation. RESULTS: One and two-way ANOVA (alpha=0.05) were performed. The parameter material has a significant (p<0.001) effect on DC (etaP(2)=0.839), HV (etaP(2)=0.683), and E (etaP(2)=0.536), whereas the specimen depth influenced only DC (etaP(2)=0.584) but not HV (p=0.093) or E (p=0.133). The polymerisation kinetic could be described by an exponential sum function, distinguishing between the gel and the glass phase. The hardness drop out was lower than 20%, indicated a depth of cure of 6mm for all materials. CONCLUSIONS: The low and high viscosity giomer bulk-fill restoratives fulfil the requirements of bulk-fill placement, since under the analysed irradiation conditions an adequate depth of cure of >4mm was identified. Variation of DC with specimen depth was low, with little variation at specimen depths of <4mm. The micro-mechanical properties of the giomer materials were higher compared with the conventional RBC materials. PMID- 25930018 TI - Menstrual-Cycle and Menstruation Disorders in Episodic vs Chronic Migraine: An Exploratory Study. AB - OBJECTIVE: Migraine is a chronic condition of recurring moderate-to-severe headaches that affects an estimated 6% of men and 18% of women. The highest prevalence is in those 18-49 years of age, generally when women menstruate. It is divided into episodic and chronic migraine depending on the total number of headache days per month being 14 or less or 15 or more, respectively. Migraine has been associated with menorrhagia, dysmenorrhea, and endometriosis, the latter particularly in chronic migraine. METHODS: We conducted a questionnaire survey of 96 women with migraine, 18-45 years old, to determine the occurrence of the menstrual-cycle disorders, oligomenorrhea, polymenorrhea, and irregular cycle, and the menstruation disorders, dysmenorrhea and menorrhagia, in episodic vs chronic migraine. RESULTS: The prevalence of menstrual-cycle disorders in general (41.2 vs 22.2%) and dysmenorrhea (51.0 vs 28.9%) was statistically significantly higher in the women with chronic migraine than in those with episodic migraine (P <= 0.05) (not corrected for multiple comparisons). Whether the migraine was menstruation sensitive, that is, the headaches consistently occurred or worsened with menstruation, did not impact the prevalence of menstrual disorders. CONCLUSION: We conclude that chronic migraine is possibly more often than episodic migraine associated with menstrual-cycle disorders in general and dysmenorrhea, without impact on menstruation sensitivity of the headaches. PMID- 25930019 TI - Predictive value of routine esophageal high-resolution manometry for gastro esophageal reflux disease. AB - BACKGROUND: Using conventional manometry, gastro-esophageal reflux disease (GERD) was associated with a reduced lower esophageal sphincter (LES) pressure and impaired peristalsis. However, with a large overlap between GERD patients and controls, these findings are of limited clinical relevance. It is uncertain whether the more detailed information of high-resolution manometry (HRM) can discriminate GERD patients. Therefore, we aimed to determine to which extent HRM findings can predict GERD. METHODS: HRM measurements in 69 patients with GERD and 40 healthy subjects were compared and the predictive value of HRM for the diagnosis of GERD was explored. KEY RESULTS: GERD patients had a significantly lower contraction amplitude (55 vs 64 mmHg; p = 0.045) and basal LES pressure (10 vs 13.2 mmHg; p = 0.034) than healthy controls. GERD patients more often had a hiatal hernia than healthy subjects (30% vs 7%; p = 0.005). Patients with reflux esophagitis had a lower DCI than patients without reflux esophagitis (558 vs 782 mmHg cm s; p = 0.045). No significant difference was seen in contractile front velocity, distal latency, number of peristaltic breaks, residual LES pressure and LES length. On multivariate logistic regression analysis, both esophagogastric junction type I (OR 4.971; 95% CI 1.33-18.59; p = 0.017) and mean wave amplitude (OR 0.95; 95% CI 0.90-0.98; p = 0.013) were found to be independent predictors of GERD. However, the sensitivity and specificity of these findings were low. CONCLUSIONS & INFERENCES: Hiatal hernia, low contraction amplitude and LES pressure are associated with GERD, but do not predict the disease with sufficient accuracy. Routine esophageal HRM can therefore not be used to distinguish GERD patients from healthy subjects. PMID- 25930020 TI - Decennial Analysis of Interventional Left Atrial Appendage Closure. AB - INTRODUCTION: Data on long-term follow-up (LTFU) after interventional closure of the left atrial appendage (LAAC) in patients with nonvalvular atrial fibrillation (AF) are scarce. We sought to determine the outcome of patients after LAAC with the first generation device. METHODS AND RESULTS: The Cardioangiologisches Centrum Bethanien (CCB) LAAC registry database was analyzed. Between October 2001 and July 2007, 45 AF patients (23 male, mean age 71 +/- 6 years; mean CHA2 DS2 VaSc 4.3 +/- 1.7 [range 1-7]; mean HASBLED score 3.3 +/- 1.2 [1-5]) received LAAC. Postimplant dual-platelet inhibition with clopidogrel 75 mg/day and aspirine (ASA) 300 mg/day was prescribed for 6 months, followed by ASA 300 mg indefinitely. The primary endpoint was defined as any thrombembolic complication and/or any bleeding complication. The median FU was 7.4 years (1-12.4 years) resulting in 292 patient years. Fourteen patients died due to heart failure (n = 4), noncardiac reasons (n = 7), or due to unknown etiology (n = 3). No patient died from a bleeding or a stroke. Five ischemic strokes occurred at a median of 794 days (range 304-3,706 days) after LAAC. The observed annual stroke rate was 1.7% (RR 0.43; 95% CI 0.24-0.74; P = 0.0028). In 6 patients bleeding occurred (2 acute procedural, 4 during follow-up). The observed annual bleeding rate was 2.1% (RR 0.56; 95% CI 0.48-0.66; P < 0.0001). CONCLUSION: During LTFU after LAAC in patients with nonvalvular AF, lower event rates than expected are observed for both thrombembolic and bleeding complications. PMID- 25930021 TI - Chronic hindlimb suspension unloading markedly decreases turnover rates of skeletal and cardiac muscle proteins and adipose tissue triglycerides. AB - We previously showed that a single bolus of "doubly-labeled" water ((2)H2 (18)O) can be used to simultaneously determine energy expenditure and turnover rates (synthesis and degradation) of tissue-specific lipids and proteins by modeling labeling patterns of protein-bound alanine and triglyceride-bound glycerol (Bederman IR, Dufner DA, Alexander JC, Previs SF. Am J Physiol Endocrinol Metab 290: E1048-E1056, 2006). Using this novel method, we quantified changes in the whole body and tissue-specific energy balance in a rat model of simulated "microgravity" induced by hindlimb suspension unloading (HSU). After chronic HSU (3 wk), rats exhibited marked atrophy of skeletal and cardiac muscles and significant decrease in adipose tissue mass. For example, soleus muscle mass progressively decreased 11, 43, and 52%. We found similar energy expenditure between control (90 +/- 3 kcal . kg(-1). day(-1)) and hindlimb suspended (81 +/- 6 kcal/kg day) animals. By comparing food intake (~ 112 kcal . kg(-1) . day(-1)) and expenditure, we found that animals maintained positive calorie balance proportional to their body weight. From multicompartmental fitting of (2)H labeling patterns, we found significantly (P < 0.005) decreased rates of synthesis (percent decrease from control: cardiac, 25.5%; soleus, 70.3%; extensor digitorum longus, 44.9%; gastrocnemius, 52.5%; and adipose tissue, 39.5%) and rates of degradation (muscles: cardiac, 9.7%; soleus, 52.0%; extensor digitorum longus, 27.8%; gastrocnemius, 37.4%; and adipose tissue, 50.2%). Overall, HSU affected growth of young rats by decreasing the turnover rates of proteins in skeletal and cardiac muscles and adipose tissue triglycerides. Specifically, we found that synthesis rates of skeletal and cardiac muscle proteins were affected to a much greater degree compared with the decrease in degradation rates, resulting in large negative balance and significant tissue loss. In contrast, we found a small decrease in adipose tissue triglyceride synthesis paired with a large decrease in degradation, resulting in smaller negative energy balance and loss of fat mass. We conclude that HSU in rats differentially affects turnover of muscle proteins vs. adipose tissue triglycerides. PMID- 25930022 TI - Lower-body negative pressure restores leg bone microvascular flow to supine levels during head-down tilt. AB - Skeletal unloading and cephalic fluid shifts in microgravity may alter the bone microvascular flow and may be associated with the 1-2% bone loss per month during spaceflight. The purpose of this study was to determine if lower-body negative pressure (LBNP) can prevent microgravity-induced alterations of tibial microvascular flow. Head-down tilt (HDT) simulates the cephalad fluid shift and microvascular flow responses that may occur in microgravity. We hypothesized that LBNP prevents HDT-induced increases in tibial microvascular flow. Tibial bone microvascular flow, oxygenation, and calf circumference were measured during 5 min sitting, 5 min supine, 5 min 15 degrees HDT, and 10 min 15 degrees HDT with 25 mmHg LBNP using photoplethysmography (PPG), near-infrared spectroscopy (NIRS), and strain-gauge plethysmography (SGP). Measurements were made simultaneously. Tibial microvascular flow increased by 36% with 5 min 15 degrees HDT [2.2 +/- 1.1 V; repeated-measures ANOVA (RMANOVA) P < 0.0001] from supine (1.4 +/- 0.8 V). After 10 min of LBNP in the 15 degrees HDT position, tibial microvascular flow returned to supine levels (1.1 +/- 0.5 V; RMANOVA P < 0.001). Tibial oxygenation did not change significantly during sitting, supine, HDT, or HDT with LBNP. However, calf circumference decreased with 5 min 15 degrees HDT (-0.7 +/- 0.4 V; RMANOVA P < 0.0001) from supine (-0.5 +/- 0.4 V). However, with LBNP calf circumference returned to supine levels (-0.4 +/- 0.1 V; RMANOVA P = 0.002). These data establish that simulated microgravity increases tibial microvascular flow and LBNP prevents these increases. The results suggest that LBNP may provide a suitable countermeasure to normalize the bone microvascular flow during spaceflight. PMID- 25930023 TI - Modulation of motor unit activity in biceps brachii by neuromuscular electrical stimulation applied to the contralateral arm. AB - The purpose of the study was to determine the influence of neuromuscular electrical stimulation (NMES) current intensity and pulse width applied to the right elbow flexors on the discharge characteristics of motor units in the left biceps brachii. Three NMES current intensities were applied for 5 s with either narrow (0.2 ms) or wide (1 ms) stimulus pulses: one at 80% of motor threshold and two that evoked contractions at either ~10% or ~20% of maximal voluntary contraction (MVC) force. The discharge times of 28 low-threshold (0.4-21.6% MVC force) and 16 high-threshold (31.7-56.3% MVC force) motor units in the short head of biceps brachii were determined before, during, and after NMES. NMES elicited two main effects: one involved transient deflections in the left-arm force at the onset and offset of NMES and the other consisted of nonuniform modulation of motor unit activity. The force deflections, which were influenced by NMES current intensity and pulse width, were observed only when low-threshold motor units were tracked. NMES did not significantly influence the discharge characteristics of tracked single-threshold motor units. However, a qualitative analysis indicated that there was an increase in the number of unique waveforms detected during and after NMES. The findings indicate that activity of motor units in the left elbow flexors can be modulated by NMES current and pulse width applied to right elbow flexors, but the effects are not distributed uniformly to the involved motor units. PMID- 25930024 TI - Females have a blunted cardiovascular response to one year of intensive supervised endurance training. AB - Cross-sectional studies in athletes suggest that endurance training augments cardiovascular structure and function with apparently different phenotypes in athletic males and females. It is unclear whether the longitudinal response to endurance training leads to similar cardiovascular adaptations between sexes. We sought to determine whether males and females demonstrate similar cardiovascular adaptations to 1 yr of endurance training, matched for training volume and intensity. Twelve previously sedentary males (26 +/- 7, n = 7) and females (31 +/ 6, n = 5) completed 1 yr of progressive endurance training. All participants underwent a battery of tests every 3 mo to determine maximal oxygen uptake (Vo2max) and left ventricle (LV) function and morphology (cardiac magnetic resonance imaging). Pulmonary artery catheterization was performed before and after 1 yr of training, and pressure-volume and Starling curves were constructed during decreases (lower-body negative pressure) and increases (saline infusion) in cardiac volume. Males progressively increased Vo2max, LV mass, and mean wall thickness, before reaching a plateau from month 9 to 12 of training. In contrast, despite exactly the same training, the response in females was markedly blunted, with Vo2max, LV mass, and mean wall thickness plateauing after only 3 mo of training. The response of LV end-diastolic volume was not influenced by sex (males +20% and females +18%). After training Starling curves were shifted upward and left, but the effect was greatest in males (interaction P = 0.06). We demonstrate for the first time clear sex differences in response to 1 yr of matched endurance training, such that the development of ventricular hypertrophy and increase in Vo2max in females is markedly blunted compared with males. PMID- 25930025 TI - Heat acclimation improves heat exercise tolerance and heat dissipation in individuals with extensive skin grafts. AB - Burn survivors with extensive skin grafts have impaired heat dissipation and thus heat tolerance. This study tested the hypothesis that heat acclimation (HA) improves these factors in this population. Thirty-four burn survivors were stratified into highly [>40% body surface area (BSA) grafted, n = 15] and moderately (17-40% BSA grafted, n = 19) grafted groups. Nine healthy nonburned subjects served as controls. Subjects underwent 7 days of HA involving 90 min of exercise at ~ 50% peak oxygen uptake in 40 degrees C, 30% relative humidity. On days 1 and 7, subjects exercised in the heat at a fixed rate of metabolic heat production. Pre-HA, all controls and 18/19 subjects in the 17-40% group completed 90 min of exercise. Conversely, heat exercise tolerance was lower (P < 0.01) in the > 40% group, with 7/15 subjects not completing 90 min of exercise. Post-HA, heat exercise tolerance was similar between groups (P = 0.39) as all subjects, except one, completed 90 min of exercise. Pre-HA, the magnitude of the increase in internal temperature during exercise occurred sequentially (P <= 0.03) according to BSA grafted (>40%: 1.6 +/- 0.5 degrees C; 17-40%: 1.2 +/- 0.3 degrees C; control: 0.9 +/- 0.2 degrees C). HA attenuated (P < 0.01) increases in internal temperature in the control (by 0.2 +/- 0.3 degrees C), 17-40% (by 0.3 +/ 0.3 degrees C), and > 40% (by 0.3 +/- 0.4 degrees C) groups, the magnitude of which was similar between groups (P = 0.42). These data indicate that HA improves heat tolerance and dissipation in burn survivors with grafted skin, and the magnitude of these improvements are not influenced by the extent of skin grafting. PMID- 25930026 TI - Ventilatory, metabolic, and thermal responses to hypercapnia in female rats: effects of estrous cycle, ovariectomy, and hormonal replacement. AB - The aim of this study was to examine how estrous cycle, ovariectomy, and hormonal replacement affect the respiratory [ventilation (Ve), tidal volume, and respiratory frequency], metabolic (Vo2), and thermoregulatory (body temperature) responses to hypercapnia (7% CO2) in female Wistar rats. The parameters were measured in rats during different phases of the estrous cycle, and also in ovariectomized (OVX) rats supplemented with 17beta-estradiol (OVX+E2), with a combination of E2 and progesterone (OVX+E2P), or with corn oil (OVX+O, vehicle). All experiments were conducted on day 8 after ovariectomy. The intact animals did not present alterations during normocapnia or under hypercapnia in Ve, tidal volume, respiratory frequency, Vo2, and Ve/Vo2 in the different phases of the estrous cycle. However, body temperature was higher in female rats on estrus. Hormonal replacement did not change the ventilatory, thermoregulatory, or metabolic parameters during hypercapnia, compared with the OVX animals. Nevertheless, OVX+E2, OVX+E2P, and OVX+O presented lower hypercapnic ventilatory responses compared with intact females on the day of estrus. Also, rats in estrus showed higher Ve and Ve/Vo2 during hypercapnia than OVX animals. The data suggest that other gonadal factors, besides E2 and P, are possibly involved in these responses. PMID- 25930027 TI - Metabolic reprogramming and inflammation act in concert to control vascular remodeling in hypoxic pulmonary hypertension. AB - Pulmonary hypertension (PH) is a complex, multifactorial syndrome that remains poorly understood despite decades of research. PH is characterized by profound pulmonary artery (PA) remodeling that includes significant fibro-proliferative and inflammatory changes of the PA adventitia. In line with the emerging concept that PH shares key features with cancer, recent work centers on the idea that PH results from a multistep process driven by reprogramming of gene-expression patterns that govern changes in cell metabolism, inflammation, and proliferation. Data demonstrate that in addition to PA endothelial cells and smooth muscle cells, adventitial fibroblasts from animals with experimental hypoxic PH and from humans with PH (hereafter, termed PH-Fibs) exhibit proinflammatory activation, increased proliferation, and apoptosis resistance, all in the context of metabolic reprogramming to aerobic glycolysis. PH-Fibs can also recruit, retain, and activate naive macrophages (Mphi) toward a proinflammatory/proremodeling phenotype through secretion of chemokines, cytokines, and glycolytic metabolites, among which IL-6 and lactate play key roles. Furthermore, these fibroblast activated Mphi (hereafter, termed FAMphi) exhibit aerobic glycolysis together with high expression of arginase 1, Vegfa, and I1lb, all of which require hypoxia inducible factor 1alpha and STAT3 signaling. Strikingly, in situ, the adventitial Mphi phenotype in the remodeled PA closely resembles the Mphi phenotype induced by fibroblasts in vitro (FAMphi), suggesting that FAMphi crosstalk involving metabolic and inflammatory signals is a critical, pathogenetic component of vascular remodeling. This review discusses metabolic and inflammatory changes in fibroblasts and Mphi in PH with the goal of raising ideas about new interventions to abrogate remodeling in hypoxic forms of PH. PMID- 25930029 TI - Skipping vs. running as the bipedal gait of choice in hypogravity. AB - Hypogravity challenges bipedal locomotion in its common forms. However, as previously theoretically and empirically suggested, humans can rely on "skipping," a less common gait available as a functional analog (perhaps a vestigium) of quadrupedal gallop, to confidently move when gravity is much lower than on Earth. We set up a 17-m-tall cavaedium (skylight shaft) with a bungee rubber body-suspension system and a treadmill to investigate the metabolic cost and the biomechanics of low-gravity (Mars, Moon) locomotion. Although skipping is never more metabolically economical than running, the difference becomes marginal at lunar gravities, with both bouncing gaits approaching values of walking on Earth (cost ~ 2 J . kg(-1). m(-1)). Nonmetabolic factors may thus be allowed to dominate the choice of skipping on the Moon. On the basis of center of pressure measurements and body segments kinetics, we can speculate that these factors may include a further reduction of mechanical work to move the limbs when wearing space suits and a more effective motor control during the ground (regoliths)-boot interaction. PMID- 25930028 TI - Diminished satellite cells and elevated adipogenic gene expression in muscle as caused by ovariectomy are averted by low-magnitude mechanical signals. AB - Age-related degeneration of the musculoskeletal system, accelerated by menopause, is further complicated by increased systemic and muscular adiposity. The purpose of this study was to identify at the molecular, cellular, and tissue levels the impact of ovariectomy on adiposity and satellite cell populations in mice and whether mechanical signals could influence any outcomes. Eight-week-old C57BL/6 mice were ovariectomized, with one half subjected to low-intensity vibration (LIV; 0.3 g/90 Hz, 15 min/day, 5 day/wk; n = 10) for 6 wk and the others sham vibrated (OVX; n = 10). Data are compared with age-matched, intact controls (AC; n = 10). In vivo MUCT analysis showed that OVX mice gained 43% total (P < 0.001) and 125% visceral adiposity (P < 0.001) compared with their baseline after 6 wk, whereas LIV gained only 21% total (P = 0.01) and 70% visceral adiposity (P < 0.01). Relative to AC, expression of adipogenic genes (PPARgamma, FABP4, PPARdelta, and FoxO1) was upregulated in OVX muscle (P < 0.05), whereas LIV reduced these levels (P < 0.05). Adipogenic gene expression was inversely related to the percentage of total and reserve satellite cell populations in the muscle, with both declining in OVX compared with AC (-21 and -28%, respectively, P < 0.01). LIV mitigated these declines (-11 and -17%, respectively). These results provide further evidence of the negative consequences of estrogen depletion and demonstrate that mechanical signals have the potential to interrupt subsequent adipogenic gene expression and satellite cell suppression, emphasizing the importance of physical signals in protecting musculoskeletal integrity and slowing the fat phenotype. PMID- 25930030 TI - Identification of proteins involved in inhibition of spheroid formation under microgravity. AB - Many types of cells transit in vitro from a two- to a three-dimensional growth, when they are exposed to microgravity. The underlying mechanisms are not yet understood. Hence, we investigated the impact of microgravity on protein content and growth behavior. For this purpose, the human thyroid cancer cells FTC-133 were seeded either in recently developed cell containers that can endure enhanced physical forces and perform media changes and cell harvesting automatically or in T-25 culture flasks. All cells were cultured for five days at 1g. Afterwards, a part of the cell containers were flown to the International Space Station, while another part was kept on the ground. T-25 flasks were mounted on and next to a Random Positioning Machine. The cells were cultured for 12 days under the various conditions, before they were fixed with RNAlater. All fixed cultures showed monolayers, but three-dimensional aggregates were not detected. In a subsequent protein analysis, 180 proteins were identified by mass spectrometry. These proteins did not indicate significant differences between cells exposed to microgravity and their 1g controls. However, they suggest that an enhanced production of proteins related to the extracellular matrix could detain the cells from spheroid formation, while profilin-1 is phosphorylated. PMID- 25930031 TI - Serum alkaline phosphatase in multidrug resistance 2 (Mdr2(-/-) ) knockout mice is strain specific. PMID- 25930032 TI - Inappropriate rightward saccades after right hemisphere damage: Oculomotor analysis and anatomical correlates. AB - Patients with right hemisphere damage and visual neglect have severe problems to orient attention towards left-sided objects, often associated with the tendency to produce inappropriate rightward saccades. In its most severe form, this tendency can assume the compulsive character of a rightward deviation of gaze as soon as the visual scene deploys (so-called "magnetic attraction of gaze"). However, little is known about the exact nature of inappropriate rightward saccades, their relation with impaired conscious perception of left-sided stimuli, and their lesional correlates. To explore these issues, we studied three groups of patients with right brain damage: patients with signs of left visual neglect associated to left homonymous hemianopia, neglect patients without hemianopia, and patients without neglect or hemianopia. Participants searched for a gap missing within a target, presented among distractors. Manual responses for target detection were required, while participants were encouraged to move their eyes during search. Endogenous attention could be summoned to the target location by a central cue. All the three groups of patients produced inappropriate rightward saccades, which could not be completely overcome by the endogenous orienting of attention induced by the cues. Anatomical analysis indicated a specific implication of damage to the right frontal eye field and to a long-range white matter tract, the fronto-parietal superior longitudinal fasciculus. Fronto parietal networks in the right hemisphere appear thus to be essential to integrate covert and overt orienting of attention, and to thoroughly explore space in order to become aware of the multiple competing objects around us. PMID- 25930033 TI - IMPACT OF IMMUNE RESPONSE OF A PARASITIC BEETLE Dastarcus helophoroides ON ITS HOST BEETLE Monochamus alternatus. AB - Dastarcus helophoroides is an ectoparasitoid beetle of Monochamus alternatus, and the parasitism by D. helophoroides larvae remarkably influenced on the immune responses of M. alternatus larvae in many aspects. The hemolymph melanization reactions in the hosts were inhibited 1 h and 24 h postparasitization. The phenoloxidase activities of hemolymph were significantly stimulated 4 h postparasitization and inhibited 12 h postparasitization, and back to control level. The antibacterial activities of hemolymph in the parasitized hosts were significantly lower than that in the unparasitized ones 1 h postparasitization. By 72 h postparasitism, the total hemocyte numbers of the parasitized larvae declined to not more than one-seconds of the number collected from the unparasitized larvae. All sampled hemolymph held the capability of nodulation, and there were fluctuations in the number of nodules the hemocytes made. However, there were no significant differences between unparasitized and parasitized larvae at each time point in the hemagglutination activity and the ratios of spreading hemocytes. In conclusion, D. helophoroides larvae could regulate M. alternatus immune system and resulted in the changes in host immune responses. PMID- 25930034 TI - Exposure to and experiences of violence among adolescents in lower socio-economic groups in Johannesburg, South Africa. AB - BACKGROUND: We explored exposure to and experiences of violence and their risk factors amongst ethnically diverse adolescents from lower socio economic groups in Johannesburg. METHODS: This cross-sectional study recruited a stratified sample of 16-18 year old adolescents from four low socio-economic suburbs in Johannesburg to reflect ethnic group clustering. We collected socio-demographic, sexual behaviour, alcohol and drug use and trauma events data. Proportions and risk factors were assessed by chi-square and logistic regression. RESULTS: Of 822 adolescents, 57% (n = 469) were female. Approximately 62% (n = 506) were Black, 13% (n = 107) Coloured, 13% (n = 106) Indian and 13% (n = 103) White. Approximately 67% (n = 552) witnessed violence to a non-family member, 28% (n = 228) experienced violence by a non-family member, and 10% (n = 83) reported sexual abuse. Multivariate analysis determined that witnessing violence in the community was associated with being Black (OR: 4.6, 95%CI: 2.7-7.9), Coloured (OR: 3.9, 95%CI: 2.0-7.4) or White (OR: 8.0, 95%CI:4.0-16.2), repeating a grade (OR: 1.5, 95%CI: 1.01-2.1), having more than one sexual partner (OR: 1.7, 95%CI: 1.1-2.5) and ever taking alcohol (OR: 2.1, 95%CI: 1.5-2.9). Witnessing violence in the family was associated with being female (OR: 1.8, 95%CI: 1.3-2.6), being Black (OR: 2.2, 95%CI: 1.1-4.1), or White (OR: 3.0, 95%CI: 1.4-6.4), repeating a grade (OR: 1.6, 95%CI: 1.1-2.2) and ever taking alcohol (OR: 2.9, 95%CI: 2.0 4.3). CONCLUSIONS: In low socio-economic areas in Johannesburg, Black, White and Coloured adolescents experience a high burden of violence. Interventions to mitigate the effects of violence are urgently required. PMID- 25930035 TI - How to treat fungal infections in ICU patients. AB - Fungal infections represent a major burden in the critical care setting with increasing morbidity and mortality. Candidiasis is the leading cause of such infections, with C. albicans being the most common causative agent, followed by Aspergillosis and Mucormycosis. The diagnosis of such infections is cumbersome requiring increased clinical vigilance and extensive laboratory testing, including radiology, cultures, biopsies and other indirect methods. However, it is not uncommon for definitive evidence to be unavailable. Risk and host factors indicating the probability of infections may greatly help in the diagnostic approach. Timely and adequate intervention is important for their successful treatment. The available therapeutic armamentarium, although not very extensive, is effective with low resistance rates for the newer antifungal agents. However, timely and prudent use is necessary to maximize favorable outcomes. PMID- 25930036 TI - Changes in Suicide Mortality for Veterans and Nonveterans by Gender and History of VHA Service Use, 2000-2010. AB - OBJECTIVE: Veterans are believed to be at high risk of suicide. However, research comparing suicide rates between veterans and nonveterans is limited, and even less is known regarding differences by history of Veterans Health Administration (VHA) service use. This study directly compared veteran and nonveteran suicide risk while for the first time differentiating veterans by VHA service use. METHODS: The cross-sectional study analyzed data from 173,969 adult suicide decedents from 23 states (2000-2010) included in the U.S. Department of Veterans Affairs suicide data archive. Annual standardized mortality ratios (SMRs) were computed for veterans compared with nonveterans and for veterans who used VHA services compared with veterans who did not, overall and separately for males and females. RESULTS: After the analysis controlled for age and gender differences, the number of observed veteran suicides was approximately 20% higher than expected in 2000 (SMR=1.19, 95% confidence interval [CI]=1.10-1.28), and this increased to 60% higher by 2010 (SMR=1.63, CI=1.58-1.68). The elevated risk for female veterans (2010 SMR=5.89) was higher than that observed for male veterans (2010 SMR=1.54). Trends for non-VHA-utilizing veterans mirrored those of the veteran population as a whole, and the SMR for VHA-utilizing veterans declined. Since 2003, the number of suicides among VHA-utilizing veterans was less than expected when compared directly with the suicide rate among non-VHA-utilizing veterans. CONCLUSIONS: Veterans are members of the community and, as such, are an important part of observed increases in U.S. suicide rates. Not all veterans are at equal or increasing risk of suicide, however. VHA-utilizing veterans appear to have declining absolute and relative suicide rates. PMID- 25930037 TI - Participation in Training for Depression Care Quality Improvement: A Randomized Trial of Community Engagement or Technical Support. AB - OBJECTIVE: Community engagement and planning (CEP) could improve dissemination of depression care quality improvement in underresourced communities, but whether its effects on provider training participation differ from those of standard technical assistance, or resources for services (RS), is unknown. This study compared program- and staff-level participation in depression care quality improvement training among programs enrolled in CEP, which trained networks of health care and social-community agencies jointly, and RS, which provided technical support to individual programs. METHODS: Matched programs from health care and social-community service sectors in two communities were randomly assigned to RS or CEP. Data were from 1,622 eligible staff members from 95 enrolled programs. Primary outcomes were any staff trained (for programs) and total hours of training (for staff). Secondary staff-level outcomes were hours of training in specific depression collaborative care components. RESULTS: CEP programs were more likely than RS programs to participate in any training (p=.006). Within health care sectors, CEP programs were more likely than RS programs to participate in training (p=.016), but within social-community sectors, there was no difference in training by intervention. Among staff who participated in training, mean training hours were greater among CEP programs versus RS programs for any type of training (p<.001) and for training related to each component of depression care (p<.001) except medication management. CONCLUSIONS: CEP may be an effective strategy to promote staff participation in depression care improvement efforts in underresourced communities. PMID- 25930038 TI - Five-Year Mental Health Care Use by Patients Referred to Collaborative Care or to Specialized Care. AB - OBJECTIVE: This study compared long-term use of mental health care by two groups of patients who had common mental disorders in the Netherlands-those treated in a collaborative care setting and those referred to off-site specialized mental health services if indicated. METHODS: The study was a retrospective analysis of use of mental health care over five years by 139 patients who participated in a cluster-randomized parent study. The parent study involved 27 general practitioners (GPs) who provided either collaborative care or usual care. In the collaborative care condition, a mental health professional worked on site at the GP's practice and was available to provide short-term treatment. In the usual care condition, the GP referred the patient to off-site specialized mental health services if indicated; if not indicated, the GP provided usual care. The two treatment groups were compared on the number of mental health care contacts and total treatment duration, the proportion that initiated a new treatment episode after termination of the initial treatment, and time to new treatment. RESULTS: Patients in the collaborative care condition received about half the number of mental health care contacts as those in the usual-care condition, and no differences were found in the rate of initiation of new treatment episodes after initial treatment, time to new treatment, and total treatment duration. CONCLUSIONS: Referral of patients with common mental disorders to collaborative mental health care as a first intervention led to fewer contacts with a mental health care professional over the long term, compared with referral to specialized mental health care. PMID- 25930039 TI - The New York State Office of Mental Health Positive Alternatives to Restraint and Seclusion (PARS) Project. AB - OBJECTIVE: The Positive Alternatives to Restraint and Seclusion (PARS) project of the New York State Office of Mental Health (OMH) was designed to build capacity to use alternatives to restraint and seclusion within state-operated and licensed inpatient and residential treatment programs serving children with severe emotional disturbances. Its long-term goal was to eliminate the use of these restrictive interventions throughout the state's mental health system of care by creating coercion- and violence-free treatment environments governed by a philosophy of recovery, resiliency, and wellness. METHODS: The central feature of the PARS project was training in, implementation of, and engagement with the Six Core Strategies to Reduce the Use of Seclusion and Restraint, a comprehensive approach developed by the National Association of State Mental Health Program Directors. This report provides an overview of the project, results from January 2007 through December 2011, and lessons learned by OMH. RESULTS: The three participating mental health treatment facilities demonstrated significant decreases in restraint and seclusion episodes per 1,000 client-days. Each identified specific activities that contributed to success, including ways to facilitate open, respectful two-way communication between management and staff and between staff and youths and greater involvement of youths in program decision making. CONCLUSIONS: All three facilities continued to implement key components of the PARS initiative after termination of grant-funded activities, and OMH initiated multiple activities to disseminate lessons learned during the project to all inpatient and residential treatment programs throughout the state mental health system. PMID- 25930040 TI - Health Care Utilization Patterns Among High-Cost VA Patients With Mental Health Conditions. AB - OBJECTIVE: To inform development of intensive management programs for high-cost patients, this study investigated the relationship between psychiatric diagnoses and patterns of health care utilization among high-cost patients in the Department of Veterans Affairs (VA) health care system. METHODS: The costliest 5% of patients who received care in the VA in fiscal year 2010 were assigned to five mutually exclusive hierarchical groups on the basis of diagnosis codes: no mental health condition, serious mental illness, substance use disorder, posttraumatic stress disorder (PTSD), and depression. Multivariable linear regression was used to examine associations between diagnostic groups and use of mental health and non-mental health care and costs of care, with adjustment for sociodemographic characteristics. The proportion of costs generated by mental health care was estimated for each group. RESULTS: Among 261,515 high-cost VA patients, rates of depression, substance use disorder, PTSD, and serious mental illness were 29%, 20%, 17%, and 13%, respectively. Individuals in the serious mental illness and substance use disorder groups were younger and had fewer chronic general medical conditions and higher adjusted rates of mental health care utilization; they also had a greater proportion of costs generated by mental health care (41% and 31%, respectively) compared with individuals in the PTSD and depression groups (18% and 11%, respectively). CONCLUSIONS: Optimal management of high-risk, high-cost patients may require stratification by psychiatric diagnoses, with integrated care models for patients with multiple chronic conditions and comorbid mental health conditions and intensive mental health services for patients whose primary needs stem from mental health conditions. PMID- 25930041 TI - Implementing a Web-Based Intervention to Train Community Clinicians in an Evidence-Based Psychotherapy: A Pilot Study. AB - OBJECTIVE: The authors conducted a feasibility assessment of online training plus an online learning collaborative to support implementation of an evidence-based psychosocial treatment in a community mental health system. METHODS: Two mental health centers were randomly allocated to in-person training with local supervision, and three were assigned to online training plus an online learning collaborative supported by expert clinicians. Participants (N=36) were clinicians interested in interpersonal and social rhythm therapy (IPSRT), an evidence-based psychotherapy for bipolar disorder. After training, 136 patients reported monthly on the extent to which clinicians used 19 IPSRT techniques. RESULTS: Clinicians from both training groups increased use of IPSRT techniques. Patients of clinicians receiving Internet-supported e-learning and of those receiving in person training reported comparable clinician use of IPSRT techniques. CONCLUSIONS: Internet-supported e-learning by community clinicians was found to be feasible and led to uptake of an evidence-based psychotherapy comparable to that by clinicians who received face-to-face training. PMID- 25930042 TI - Socioeconomic Status and Mental Health Service Use Among National Guard Soldiers. AB - OBJECTIVE: Convergent evidence suggests that low socioeconomic status (SES) may be related to reduced mental health service use. However, this relationship has not been tested in the National Guard (NG) population, in which the prevalence of mental health symptoms is high. METHODS: Surveys were completed by 1,262 NG soldiers. SES was measured by education and income. Adjusted multivariable regression models assessed associations between SES, overall service use, and use of specific types of services. RESULTS: SES was not associated with overall use but was associated with use of certain types of services. Higher SES was associated with lower likelihood of psychotropic medication use (odds ratio=.83, 95% confidence interval=.72-.96), and higher SES strengthened the positive relationship between PTSD and use of individual therapy. CONCLUSIONS: Higher SES may increase the use of individual therapy among soldiers with PTSD. Barriers to care among individuals with low SES merit continued attention and outreach efforts. PMID- 25930043 TI - Language Barriers and Access to Psychiatric Care: A Systematic Review. AB - OBJECTIVE: The objective of this study was to synthesize the available evidence regarding the impact of patients' language proficiency on access to psychiatric care. METHODS: A systematic literature search of PubMed, EMBASE, Medline, and PsycINFO was performed to identify studies published between January 1950 and July 2014 that examined the impact of language proficiency on access to and utilization of psychiatric services in the general population or among patients with psychiatric disorders. The keywords were psychiatry, language, utilization, access, and mental health care. Only articles in English were included. Cross referencing of the identified articles was also performed. RESULTS: Eighteen articles from four countries were identified, including 13 from the United States, two from Australia, two from Canada, and one from the Netherlands. These reports were generally consistent in showing a clear association between insufficient language proficiency and underutilization of psychiatric services; 15 studies reported that limited language proficiency was significantly associated with less frequent mental health care visits. Only one article showed an inverse relationship between limited language proficiency and use of mental health services, and two articles reported no association. No published data were found on the effects of linguistic interventions on access to mental health care among people with limited language proficiency. CONCLUSIONS: It is plausible that limited language proficiency is closely associated with underutilization of psychiatric services. Still, the lack of prospective interventional data clearly highlights the need for further investigations of the impact of language barriers on access to psychiatric care. PMID- 25930044 TI - Acceptability and Receipt of Preventive Care for Chronic-Disease Health Risk Behaviors Reported by Clients of Community Mental Health Services. AB - OBJECTIVE: Compared with the general population, people with a mental illness have a greater prevalence of behaviors that contribute to higher chronic disease rates. Mental health clinical guidelines recommend preventive care to address such behaviors; however, little information is available about whether clients consider preventive care acceptable or about the prevalence of such care in mental health services. This article describes acceptability and receipt of assessment, advice, and referral for smoking, inadequate fruit and vegetable consumption, harmful alcohol consumption, and physical inactivity, as reported by community mental health service clients. The association between preventive care, diagnosis, and number of clinical appointments was examined. METHODS: A cross sectional telephone interview was conducted with clients (N=558) of community mental health services in Australia. RESULTS: Although preventive care was highly acceptable to clients (86%-97%), receipt of preventive care was low. Client receipt of risk assessment ranged from 26% (assessment of fruit or vegetable intake) to 76% (assessment of alcohol consumption). The proportion of clients at risk of and assessed for unhealthy behavior who then received brief advice ranged from 69% (fruit or vegetable intake) to 85% (physical activity), whereas only 38% (alcohol consumption) to 49% (smoking) received any referral. A greater number of mental health appointments were associated with higher prevalence of preventive care, as were diagnoses of diabetes or respiratory conditions and not having a schizophrenia diagnosis. CONCLUSIONS: Practice change strategies are required to increase the delivery of routine preventive care within mental health services if clients are to benefit from clinical guidelines. PMID- 25930045 TI - Applicability of the Risk-Need-Responsivity Model to Persons With Mental Illness Involved in the Criminal Justice System. AB - OBJECTIVE: National efforts to improve responses to persons with mental illness involved with the criminal justice system have traditionally focused on providing mental health services under court supervision. However, a new policy emphasis has emerged that focuses on providing correctional treatment services consistent with the risk-need-responsivity (RNR) model to reduce recidivism. The objective of this review was to evaluate empirical support for following the RNR model (developed with general offenders) with this group and to pose major questions that the field needs to address. METHODS: A comprehensive search using PubMed and PsycINFO yielded 18 studies that addressed the applicability of the RNR model to the target population. The results of these studies were synthesized. RESULTS: There is strong support for using general risk assessment tools to assess this group's risk of recidivism. Preliminary evidence indicates that cognitive behavioral programs targeting general risk factors are more effective than psychiatric treatment alone. However, there is as yet no direct support for the applicability of the three core RNR principles to treat this population. CONCLUSIONS: Although the new policy emphasis shows substantial promise, the field must avoid rushing to the next "evidence base" too rapidly and with too little data. There must be explicit recognition that RNR principles are being applied to a new population with unique characteristics (mental illness combined with justice system involvement), such that generalizability from general offender samples is uncertain. Moreover, public safety goals for the target population should not eclipse those related to public health. This group's unique features may affect both the process and outcomes of treatment. PMID- 25930046 TI - How Can We Link General Medical and Behavioral Health Care? International Models for Practice and Policy. AB - A range of integration models for providing effective care to individuals with comorbid general medical and behavioral health conditions have been described and tested in varied settings internationally for several subsets of this population. This column examines models in three countries selected to showcase implementation in a variety of health systems: the national health system in England, nationally regulated individual insurance market in the Netherlands, and a mixture of employer-sponsored and government-funded health insurance plans in Japan. The authors describe a set of key practices for and challenges to the successful implementation of these models. PMID- 25930047 TI - Trends in antidepressant use among U.S. cancer survivors, 1999-2012. PMID- 25930048 TI - The Maryland Resilience Breakthrough Series Collaborative: A Quality Improvement Initiative for Children's Mental Health Services Providers. AB - The Maryland Resilience Breakthrough Series Collaborative (BSC), a recent quality improvement initiative for children's mental health services providers, is aimed at bridging the gap between resilience theory and mental health service practices. Six provider teams across the state attended resilience training sessions and incrementally implemented practice improvements at their agencies. Group discussions and surveys administered to teams before and after the BSC indicate that the BSC facilitated breakthrough changes in the areas of resilience enhanced assessment and treatment practices, as well as family and community resilience. This column presents quantitative and anecdotal outcomes and makes recommendations for the provider community. PMID- 25930049 TI - Consumers' Valuation of Primary Care-Based Treatment Options for Mental and Substance Use Disorders. AB - Most individuals with substance use disorders and with mental disorders do not receive treatment. If treatment options were more attractive, treatment rates might increase. The advantages of novel approaches, including primary care-based treatment and collaborative care in a primary care setting, have been documented. However, less is known about consumers' valuation of these options. The authors assessed monetary valuation of these treatment types compared with usual care in a specialty treatment setting. Contingent valuation methods were used in a Web based randomized vignette experiment that involved 2,146 individuals who screened positive for a drug or alcohol use disorder or a mental disorder. Participants valued a primary care-based treatment visit over usual care in a specialty treatment setting by $9.00 and a collaborative care visit over usual care in a specialty treatment setting by $5.85. PMID- 25930051 TI - Stage-dependent ethoxyresorufin-O-deethylase (EROD) in vivo activity in medaka (Oryzias latipes) embryos. AB - Using medaka (Oryzias latipes) embryos, this study aimed to quantitatively characterize the stage-dependent in vivo ethoxyresorufin-O-deethylase (EROD) as indicator of cytochrome P4501A (CYP1A) activity. Embryos were challenged for 24-h to an agonist (beta-naphthoflavone [BNF], 2.5, 5, 10, and 20 MUg L(-1)) or to its combination (2.5 MUg L(-1)) with an antagonist (alpha-naphthoflavone [ANF], 25, 50, 100, and 200 MUg L(-1)), initiated at four different developmental time points (1, 3, 6, and 9 d post-fertilization [dpf]). Respective induction and competitive inhibition were evaluated over fluorescent images of whole embryo (nonorgan-specific [NOS] EROD activity) and gallbladder (organ-specific [OS] EROD activity). Both flavonoids showed signs of stability in solution. Generally speaking, the mean fluorescence intensity (MFI) values for NOS EROD increased with BNF concentration and exposure challenge. BNF co-exposure with ?50 MUg ANF L(-1) during the 1-2 and 3-4 dpf challenges lowered NOS EROD to undetectably induced levels. Significant increments in MFIs for OS-EROD were seen from exposures to ?2.5 MUg BNF L(-1), peaking during the 6-7 dpf challenge regardless of BNF concentration. The simultaneous BNF/ANF incubation showed competitive inhibition for OS EROD activity, although levels were generally detectably induced during all challenges and at all ANF concentrations. The morphometric in vivo gallbladder analysis indicated significant dilation in the 10 dpf-old embryos co-exposed to BNF and 200 MUg ANF L(-1). This quantitative approach can be used successfully at 4 dpf at the NOS-EROD or OS-EROD levels, although the NOS EROD response was sensitive enough to induction or inhibition, even at 2 dpf. PMID- 25930050 TI - Adulthood Weight Change and Risk of Colorectal Cancer in the Nurses' Health Study and Health Professionals Follow-up Study. AB - We investigated the association between adulthood weight change and colorectal cancer risk in a prospective study with 24 to 34 years of follow-up among 90,988 women and 46,679 men. The primary exposures included weight change from early adulthood (age = 18 years for women, 21 years for men) to baseline enrollment (median age = 43 years for women, 52 years for men), and from baseline to present. In the secondary analyses, we also assessed 4-year weight change during follow-up, and during premenopausal (from age 18 years to menopause) and postmenopausal (from menopause to present) periods in women. Compared to men maintaining their weight from age 21 to baseline, those who gained 20 kg or more were at a higher risk of colorectal cancer (relative risk [RR], 1.64; 95% confidence interval [CI], 1.15-2.35, Ptrend < 0.001), whereas those who lost 8 kg or more had a lower risk (RR, 0.61; 95% CI, 0.30-1.22, Ptrend = 0.003). Similar but weaker associations were found in women and the corresponding RRs were 1.38 (95% CI, 1.13-1.69, Ptrend < 0.001) and 0.80 (95% CI, 0.58-1.09, Ptrend = 0.21). Weight change from baseline to present was not associated with colorectal cancer risk. Four-year weight change during follow-up was positively associated with colorectal cancer risk in men (Ptrend = 0.03) but not in women (Ptrend = 0.42). In addition, in women, weight change before, but not after, menopause was associated with colorectal cancer risk. Our findings provide further scientific rationale for recommendations to maintain a healthy body weight during adulthood. A potential differential association according to sex and timing of weight change warrants further investigation. PMID- 25930052 TI - Effects of NaCl and seawater induced salinity on survival and reproduction of three soil invertebrate species. AB - The increase of global mean temperature is raising serious concerns worldwide due to its potential negative effects such as droughts and melting of glaciers and ice caps leading to sea level rise. Expected impacts on soil compartment include floodings, seawater intrusions and use of saltwater for irrigation, with unknown effects on soil ecosystems and their inhabitants. The present study aimed at evaluating the effects of salinisation on soil ecosystems due to sea level rise. The reproduction and mortality of three standard soil invertebrate species (Folsomia candida, Enchytraeus crypticus, Hypoaspis aculeifer) in standard artificial OECD soil spiked with serial dilutions of seawater/gradient of NaCl were evaluated according to standard guidelines. An increased sensitivity was observed in the following order: H. aculeifer?E. crypticus~F. candida consistent with the different exposure pathways: springtails and enchytraeids are exposed by ingestion and contact while mites are mainly exposed by ingestion due to a continuous and thick exoskeleton. Although small differences were observed in the calculated effect electrical conductivity values, seawater and NaCl induced the same overall effects (with a difference in the enchytraeid tests where a higher sensitivity was found in relation to NaCl). The adverse effects described in the present study are observed on soils not considered saline. Therefore, the actual limit to define saline soils (4000 MUS cm(-1)) does not reflect the existing knowledge when considering soil fauna. PMID- 25930053 TI - Internal distribution of Cd in lettuce and resulting effects on Cd trophic transfer to the snail: Achatina fulica. AB - The mechanisms underlying Cd trophic transfer along the soil-lettuce-snail food chain were investigated. The fate of Cd within cells, revealed by assessment of Cd chemical forms and of subcellular partitioning, differed between the two examined lettuce species that we examined (L. longifolia and L. crispa). The species-specific internal Cd fate not only influenced Cd burdens in lettuce, with higher Cd levels in L. crispa, but also affected Cd transfer efficiency to the consumer snail (Achatina fulica). Especially, the incorporation of Cd chemical forms (Cd in the inorganic, water-soluble and pectates and protein-integrated forms) in lettuce could best explain Cd trophic transfer, when compared to dietary Cd levels alone and/or subcellular Cd partitioning. Trophically available metal on the subcellular partitioning base failed to shed light on Cd transfer in this study. After 28-d of exposure, most Cd was trapped in the viscera of Achatina fulica, and cadmium bio-magnification was noted in the snails, as the transfer factor of lettuce-to-snail soft tissue was larger than one. This study provides a first step to apply a chemical speciation approach to dictate the trophic bioavailability of Cd through the soil-plant-snail system, which might be an important pre-requisite for mechanistic understanding of metal trophic transfer. PMID- 25930054 TI - Carotenoid intake and head and neck cancer: a pooled analysis in the International Head and Neck Cancer Epidemiology Consortium. AB - Food and nutrition play an important role in head and neck cancer (HNC) etiology; however, the role of carotenoids remains largely undefined. We explored the relation of HNC risk with the intake of carotenoids within the International Head and Neck Cancer Epidemiology Consortium. We pooled individual-level data from 10 case-control studies conducted in Europe, North America, and Japan. The analysis included 18,207 subjects (4414 with oral and pharyngeal cancer, 1545 with laryngeal cancer, and 12,248 controls), categorized by quintiles of carotenoid intake from natural sources. Comparing the highest with the lowest quintile, the risk reduction associated with total carotenoid intake was 39 % (95 % CI 29-47 %) for oral/pharyngeal cancer and 39 % (95 % CI 24-50 %) for laryngeal cancer. Intakes of beta-carotene equivalents, beta-cryptoxanthin, lycopene, and lutein plus zeaxanthin were associated with at least 18 % reduction in the rate of oral and pharyngeal cancer (95 % CI 6-29 %) and 17 % reduction in the rate of laryngeal cancer (95 % CI 0-32 %). The overall protective effect of carotenoids on HNC was stronger for subjects reporting greater alcohol consumption (p < 0.05). The odds ratio for the combined effect of low carotenoid intake and high alcohol or tobacco consumption versus high carotenoid intake and low alcohol or tobacco consumption ranged from 7 (95 % CI 5-9) to 33 (95 % CI 23-49). A diet rich in carotenoids may protect against HNC. Persons with both low carotenoid intake and high tobacco or alcohol are at substantially higher risk of HNC. PMID- 25930056 TI - Genetic analysis of glucosinolate variability in broccoli florets using genome anchored single nucleotide polymorphisms. AB - KEY MESSAGE: The identification of genetic factors influencing the accumulation of individual glucosinolates in broccoli florets provides novel insight into the regulation of glucosinolate levels in Brassica vegetables and will accelerate the development of vegetables with glucosinolate profiles tailored to promote human health. Quantitative trait loci analysis of glucosinolate (GSL) variability was conducted with a B. oleracea (broccoli) mapping population, saturated with single nucleotide polymorphism markers from a high-density array designed for rapeseed (Brassica napus). In 4 years of analysis, 14 QTLs were associated with the accumulation of aliphatic, indolic, or aromatic GSLs in floret tissue. The accumulation of 3-carbon aliphatic GSLs (2-propenyl and 3-methylsulfinylpropyl) was primarily associated with a single QTL on C05, but common regulation of 4 carbon aliphatic GSLs was not observed. A single locus on C09, associated with up to 40 % of the phenotypic variability of 2-hydroxy-3-butenyl GSL over multiple years, was not associated with the variability of precursor compounds. Similarly, QTLs on C02, C04, and C09 were associated with 4-methylsulfinylbutyl GSL concentration over multiple years but were not significantly associated with downstream compounds. Genome-specific SNP markers were used to identify candidate genes that co-localized to marker intervals and previously sequenced Brassica oleracea BAC clones containing known GSL genes (GSL-ALK, GSL-PRO, and GSL-ELONG) were aligned to the genomic sequence, providing support that at least three of our 14 QTLs likely correspond to previously identified GSL loci. The results demonstrate that previously identified loci do not fully explain GSL variation in broccoli. The identification of additional genetic factors influencing the accumulation of GSL in broccoli florets provides novel insight into the regulation of GSL levels in Brassicaceae and will accelerate development of vegetables with modified or enhanced GSL profiles. PMID- 25930055 TI - The Bangladesh Risk of Acute Vascular Events (BRAVE) Study: objectives and design. AB - During recent decades, Bangladesh has experienced a rapid epidemiological transition from communicable to non-communicable diseases. Coronary heart disease (CHD), with myocardial infarction (MI) as its main manifestation, is a major cause of death in the country. However, there is limited reliable evidence about its determinants in this population. The Bangladesh Risk of Acute Vascular Events (BRAVE) study is an epidemiological bioresource established to examine environmental, genetic, lifestyle and biochemical determinants of CHD among the Bangladeshi population. By early 2015, the ongoing BRAVE study had recruited over 5000 confirmed first-ever MI cases, and over 5000 controls "frequency-matched" by age and sex. For each participant, information has been recorded on demographic factors, lifestyle, socioeconomic, clinical, and anthropometric characteristics. A 12-lead electrocardiogram has been recorded. Biological samples have been collected and stored, including extracted DNA, plasma, serum and whole blood. Additionally, for the 3000 cases and 3000 controls initially recruited, genotyping has been done using the CardioMetabochip+ and the Exome+ arrays. The mean age (standard deviation) of MI cases is 53 (10) years, with 88 % of cases being male and 46 % aged 50 years or younger. The median interval between reported onset of symptoms and hospital admission is 5 h. Initial analyses indicate that Bangladeshis are genetically distinct from major non-South Asian ethnicities, as well as distinct from other South Asian ethnicities. The BRAVE study is well-placed to serve as a powerful resource to investigate current and future hypotheses relating to environmental, biochemical and genetic causes of CHD in an important but under-studied South Asian population. PMID- 25930058 TI - Erratum to: The Influence of God and Providence on Happiness and the Quality of Life of Patients Benefiting from Aesthetic Medicine Treatments in Poland. PMID- 25930057 TI - Characterization of Soybean mosaic virus resistance derived from inverted repeat SMV-HC-Pro genes in multiple soybean cultivars. AB - KEY MESSAGE: Soybean mosaic virus resistance was significantly improved in multiple soybean cultivars through genetic transformation induced by inverted repeat-SMV- HC - Pro genes based on RNAi and post-transcriptional gene silencing. Here, we demonstrate Soybean mosaic virus (SMV) resistance in transgenic soybean plants. Transformation of five soybean genotypes with a construct containing inverted repeat-SMV-HC-Pro genes-induced high-level SMV resistance. Through leaf painting assays, polymerase chain reaction (PCR) verification and LibertyLink((r)) strip detection, 105 T0 and 1059 T1 plants were confirmed as transgene-positive. Southern blotting confirmed insertion of the T-DNA into the genomic DNA and revealed a low-copy integration pattern. Most T0 plants were fertile and transmitted the exogenous genes to their progenies (ratios of 3:1 or 15:1). In the T1 generation, virus resistance was evaluated visually after inoculation with SMV (strain SC3) and 441 plants were highly resistant (HR). SMV disease rating was classified on a scale with 0 = symptomless and 4 = mosaic symptoms with severe leaf curl. In the positive T1 plants, the disease rating on average was 1.42 (range 0.45-2.14) versus 3.2 (range 2-4) for the nontransformed plants. With the T2 generation, 75 transgene-positive plants were inoculated with SC3, and 57 HR plants were identified. Virus-induced seed coat mottling was eliminated in the resistant lines. Analysis of SMV levels in the plants was performed using quantitative real-time PCR and double-antibody sandwich enzyme linked immunosorbent assays; the results revealed no virus or a gradual reduction over time in the viral content, thereby supporting the visual examination results. This is the first report demonstrating pathogen-derived resistance to SMV induced by inverted repeat-SMV-HC-Pro genes in multiple soybean cultivars. Our findings contribute positively to the study of transgenic SMV-resistance using RNA interference. PMID- 25930059 TI - Mental Health and Self-Esteem of Institutionalized Adolescents Affected by Armed Conflict. AB - The primary purpose of this paper was to compare the epidemiology of mental health problems and self-esteem of conflict hit adolescents living in charitable seminaries with their counterparts brought up in natural homes. Substantive body of the literature illustrates the emotional and behavioral issues experienced by these adolescents. In this study, 27 adolescents from a charitable Muslim seminary and 30 adolescents from a regular school were recruited. Self-report measures and clinical interview were used to measure mental health and self esteem. The findings indicate that adolescents in institution setting may not be having mental health and self-esteem-related issues when compared to adolescents living in intact by parent homes. While the authors acknowledge the limitations of the study, these findings need further research to examine the causes for these differences. PMID- 25930060 TI - Modulating the correlation and squeezing of phase-conjugate four-wave mixing via the polarizable dressing states. AB - We report the experimental observation of the intensity noise correlation and squeezing between counter propagating Stokes and anti-Stokes signals in Pr(3+):Y2SiO5 crystals. Both the degree of correlation and squeezing as well as the oscillation frequency of correlation curves are modulated by changing the polarization states and powers of the dressing fields. The double-dressed effect and the triple-dressed effect in V-type three-level, Lambda-type three-level and N-type four-level systems are compared. The polarization and power dependencies in these systems are different, and the oscillation frequency of the correlation curve in the triple-dressed process is greater than that of the double-dressed process. Our results show that the correlation and squeezing of photon pairs can be controlled via polarized dark states. PMID- 25930062 TI - Self-assembled organic nanostructures in medicinal chemistry: advances and applications. PMID- 25930063 TI - Women's health team of the year. PMID- 25930061 TI - Mammalian Cells Exhibit a Range of Sensitivities to Silver Nanoparticles that are Partially Explicable by Variations in Antioxidant Defense and Metallothionein Expression. AB - While it is well known that there are interspecies differences in Ag sensitivity, differences in the cytotoxic responses of mammalian cells to silver nanoparticles (Ag NPs) are also observed. In order to explore these response outcomes, six cell lines, including epithelial cells (Caco-2, NHBE, RLE-6TN, and BEAS-2B) and macrophages (RAW 264.7 and THP-1) of human and rodent origin, are exposed to 20 nm citrate- and PVP-coated Ag NPs with Au cores, as well as 20 nm citrate-coated particles without cores. An MTS assay shows that while Caco-2 and NHBE cells are resistant to particles over a 0.1-50 MUg mL(-1) dose range, RAW 264.7, THP-1, RLE 6TN, and BEAS-2B cells are more susceptible. While there are small differences in dissolution rates, there are no major differences in the cytotoxic potential of the different particles. However, differences in anti-oxidant defense and metallothionein expression among different cell types are observed, which can partially explain differential Ag NP sensitivity. So, it is important to consider these differences in understanding the potential heterogeneous effects of nano Ag on mammalian biological systems. PMID- 25930064 TI - Neurocognitive Function in Newly Diagnosed Low-grade Glioma Patients Undergoing Surgical Resection With Awake Mapping Techniques. AB - BACKGROUND: Low-grade glioma (LGG) patients have increased life expectancy, so interest is high in the treatments that maximize cognition and quality of life. OBJECTIVE: To examine presurgical baseline cognitive deficits in a case series of LGG patients and determine cognitive effects of surgical resection with awake mapping. METHODS: We retrospectively assessed neurological deficits, subjective concerns from patient or caregiver, and cognitive deficits at baseline and postsurgery for 22 patients with newly diagnosed LGG who underwent baseline neuropsychological evaluation and magnetic resonance imaging before awake surgical resection with mapping. Twelve of the 22 patients returned for postoperative evaluation approximately 7 months after surgery. RESULTS: At baseline, 92% of patients/caregivers reported changes in cognition or mood. Neurological examinations and Montreal Cognitive Assessment Scale scores were largely normal; however, on many tests of memory and language, nearly half of individuals showed deficits. After surgery, 45% had no deficits on neurological examination, whereas 55% had only transient or mild difficulties. Follow-up neuropsychological testing found most performances stable to improved, particularly in language, although some patients showed declines on memory tasks. CONCLUSION: Most LGG patients in this series presented with normal neurological examinations and cognitive screening, but showed subjective cognitive and mood concerns and cognitive decline on neuropsychological testing, suggesting the importance of comprehensive evaluation. After awake mapping, language tended to be preserved, but memory demonstrated decline in some patients. These results highlight the importance of establishing a cognitive baseline before surgical resection and further suggest that awake mapping techniques provide reasonable language outcomes in individuals with LGG in eloquent regions. PMID- 25930065 TI - Successful salvage treatment of myxoid liposarcoma with multiple peritoneal seeding using helical tomotherapy-based intraperitoneal radiotherapy: a case report. AB - BACKGROUND: Myxoid liposarcoma is the most common soft-tissue sarcoma that metastasizes to the peritoneal cavity. Recently, an advanced intensity-modulated radiotherapy, known as helical tomotherapy, has been introduced to improve target coverage, while reducing normal tissue radiation. Here, we report a case of myxoid liposarcoma with multiple peritoneal seeding that was chemotherapy refractory, but was successfully salvaged by helical tomotherapy-based intraperitoneal radiotherapy. CASE PRESENTATION: A 71-year-old East-Asian male was initially diagnosed with myxoid liposarcoma in his left thigh by excision. Six years later, the patient underwent a left pneumonectomy for metastatic myxoid liposarcoma in the left lung. Since then, the patient was treated with two segmental resections, and multiple lines of chemotherapy, for repeated recurrences in the peritoneal cavity. The patient underwent intraperitoneal radiotherapy followed by tumor boost radiotherapy, as salvage treatment for chemotherapy-resistant metastatic peritoneal myxoid liposarcoma. The prescribed dose was 24 Gy delivered in 15 fractions of 1.6 Gy over 3 weeks, followed by a 16 Gy boost dose administered in eight fractions of 2 Gy, to multifocal peritoneal lesions. A positron emission tomography scan obtained 8 weeks after completion of radiotherapy, showed a complete metabolic response of metastatic peritoneal lesions. Radiotherapy was well tolerated, without any side effects. In a computed tomography scan obtained 20 weeks after completion of radiotherapy, most of the peritoneal metastatic lesions had disappeared, except for two small residual nodules. CONCLUSION: This case suggests that low fraction-sized intraperitoneal radiotherapy (1.6 Gy administered once daily), followed by a focal boost using helical tomotherapy, is a feasible treatment without side effects. It produced an excellent tumor response, and durable intraperitoneal control for metastatic peritoneal myxoid liposarcoma. PMID- 25930066 TI - Increased evapotranspiration demand in a Mediterranean climate might cause a decline in fungal yields under global warming. AB - Wild fungi play a critical role in forest ecosystems, and its recollection is a relevant economic activity. Understanding fungal response to climate is necessary in order to predict future fungal production in Mediterranean forests under climate change scenarios. We used a 15-year data set to model the relationship between climate and epigeous fungal abundance and productivity, for mycorrhizal and saprotrophic guilds in a Mediterranean pine forest. The obtained models were used to predict fungal productivity for the 2021-2080 period by means of regional climate change models. Simple models based on early spring temperature and summer autumn rainfall could provide accurate estimates for fungal abundance and productivity. Models including rainfall and climatic water balance showed similar results and explanatory power for the analyzed 15-year period. However, their predictions for the 2021-2080 period diverged. Rainfall-based models predicted a maintenance of fungal yield, whereas water balance-based models predicted a steady decrease of fungal productivity under a global warming scenario. Under Mediterranean conditions fungi responded to weather conditions in two distinct periods: early spring and late summer-autumn, suggesting a bimodal pattern of growth. Saprotrophic and mycorrhizal fungi showed differences in the climatic control. Increased atmospheric evaporative demand due to global warming might lead to a drop in fungal yields during the 21st century. PMID- 25930067 TI - The role of expanded testing for Lynch syndrome in women with endometrial cancer. PMID- 25930068 TI - Plasma citrulline in the critically ill: intriguing biomarker, cautious interpretation. AB - In a recent issue of Critical Care, Poole and colleagues found that plasma citrulline concentration and glucose absorption were reduced in 20 critically ill patients compared with 15 controls; however, the authors found no correlation between these two variables. This study highlights the question of the accuracy of plasma citrulline for assessing small bowel function in critically ill patients. Future studies should take into account the type of intestinal failure considered, the particular metabolism of citrulline, the time of plasma citrulline measurement, as well as the range of citrullinemia considered. PMID- 25930069 TI - A self-healing PDMS polymer with solvatochromic properties. AB - Coordination bonds are effective for constructing functional self-healing materials due to their tunable bond strength and metal-ion-induced functionalities. In this work, we incorporate a cobalt(II) triazole complex into a polydimethylsiloxane (PDMS) matrix. The resulting polymers show solvatochromic behaviour as well as self-healing properties. PMID- 25930071 TI - Targeted disruption of CD1d prevents NKT cell development in pigs. AB - Studies in mice genetically lacking natural killer T (NKT) cells show that these lymphocytes make important contributions to both innate and adaptive immune responses. However, the usefulness of murine models to study human NKT cells is limited by the many differences between mice and humans, including that their NKT cell frequencies, subsets, and distribution are dissimilar. A more suitable model may be swine that share many metabolic, physiological, and growth characteristics with humans and are also similar for NKT cells. Thus, we analyzed genetically modified pigs made deficient for CD1d that is required for the development of Type I invariant NKT (iNKT) cells that express a semi-invariant T-cell receptor (TCR) and Type II NKT cells that use variable TCRs. Peripheral blood analyzed by flow cytometry and interferon-gamma enzyme-linked immuno spot assays demonstrated that CD1d-knockout pigs completely lack iNKT cells, while other leukocyte populations remain intact. CD1d and NKT cells have been shown to be involved in shaping the composition of the commensal microbiota in mice. Therefore, we also compared the fecal microbiota profile between pigs expressing and lacking NKT cells. However, no differences were found between pigs lacking or expressing CD1d. Our results are the first to show that knocking-out CD1d prevents the development of NKT cells in a non-rodent species. CD1d-deficient pigs should offer a useful model to more accurately determine the contribution of NKT cells for human immune responses. They also have potential for understanding how NKT cells impact the health of commercial swine. PMID- 25930072 TI - Targeted disruption of the spermatid-specific gene Spata31 causes male infertility. AB - Spata31, a novel testis-specific gene, was first isolated from the testis of a vitamin A-deficient rat model. To gain insight into its physiological function, Spata31-targeted knockout mice were generated by homologous recombination. Spata31-deficient (Spata31(flox/flox) ; Vasa-Cre) male mice exhibited low sperm count and premature shedding of germ cells into the lumen, ultimately causing azoospermia and male sterility. Mechanistically, the Spata31 deficiency resulted in reduced expression of the adhesion protein nectin-3 and cytoskeletal protein beta-actin at the apical ectoplasmic specialization. Our findings demonstrate that the disruptions to the SPATA31 ortholog could be linked to human male infertility. PMID- 25930073 TI - Identifying single electron charge sensor events using wavelet edge detection. AB - The operation of solid-state qubits often relies on single-shot readout using a nanoelectronic charge sensor, and the detection of events in a noisy sensor signal is crucial for high fidelity readout of such qubits. The most common detection scheme, comparing the signal to a threshold value, is accurate at low noise levels but is not robust to low-frequency noise and signal drift. We describe an alternative method for identifying charge sensor events using wavelet edge detection. The technique is convenient to use and we show that, with realistic signals and a single tunable parameter, wavelet detection can outperform thresholding and is significantly more tolerant to 1/f and low frequency noise. PMID- 25930074 TI - Poor sleep quality is associated with impaired glucose tolerance in women after gestational diabetes. AB - We analyzed the association of sleep quality and glucose metabolism in women after gestational diabetes (pGDM) and in women after normoglycemic pregnancy (controls). Data during pregnancy and a visit within the first 15 months after delivery were collected from 61 pGDM and 30 controls in a prospective cohort study. This included a medical history, physical examination, questionnaires (Pittsburgh Sleep Quality Index (PSQI), and Perceived Stress Scale (PSS)), and 5 point oral glucose tolerance test with insulin measurements to determine indices of insulin sensitivity and insulin secretion. We used Spearman correlation coefficients and multivariate regression models for analysis.9.3 +/- 3.2 months after delivery, pGDM had significantly higher fasting and 2 h glucose levels and lower insulin sensitivity than controls. There was no significant difference in age, BMI and sleep quality as assessed with the PSQI between the two groups. The PSQI score correlated with the ogtt-2 h plasma glucose in pGDM (delta = 0.41; p = 0.0012), but not in controls. This association was confirmed with a multivariate linear regression model with adjustment for age, BMI and months post-delivery. Perceived stress was an independent risk factor (OR 1.12; 95% CI 1.02-1.23) for impaired sleep. Our findings suggest that post-delivery sleep quality significantly influences glucose tolerance in women after GDM and that impaired sleep is associated with increased stress perception. Measures to improve of sleep quality and reduce perceived stress should therefore be tested as additional strategies to prevent progression to type 2 diabetes after GDM. PMID- 25930076 TI - Unresolved trauma in fibromyalgia: A cross-sectional study. AB - This study examined the prevalence of unresolved attachment-related trauma and its association with physical and psychological health status in 34 patients with fibromyalgia. Unresolved trauma was assessed with the Adult Attachment Interview. In addition, participants completed self-report measures of childhood trauma, fibromyalgia-related health status and depression. Of the sample, 50 per cent was classified as unresolved on the Adult Attachment Interview. Neither interview based ratings of unresolved trauma nor self-reported childhood sexual or physical abuse were associated with health outcomes. Only for self-reported emotional abuse, a positive correlation with depression emerged. The implications of the findings are discussed. PMID- 25930077 TI - A longitudinal interpretative phenomenological analysis of the process of kidney recipients' resolution of complex ambiguities within relationships with their living donors. AB - Much previous research into living kidney donation has focused on the decision making of the donor, despite evidence suggesting this may be a more psychologically challenging time for the recipient. This longitudinal study explores the experiences of four recipients of kidneys from living donors throughout the transplant process. Transcripts were analysed using interpretative phenomenological analysis. Three themes arose from the data, which were as follows: changing perceptions of relationships with kidney donors; upbeat, temporal strategies for remaining positive and journey of the self. Findings from the first theme are presented in detail here. It was found that each participants' relationship with their donor grew and developed in different ways, presenting their own complex challenges in terms of developing relationships and ambiguity around the decision to use the chosen donor. PMID- 25930075 TI - Oligodendrocyte morphometry and expression of myelin - Related mRNA in ventral prefrontal white matter in major depressive disorder. AB - White matter disturbance in the ventral prefrontal cortex (vPFC) in major depressive disorder (MDD) has been noted with diffusion tensor imaging (DTI). However, the cellular and molecular pathology of prefrontal white matter in MDD and potential influence of antidepressant medications is not fully understood. Oligodendrocyte morphometry and myelin-related mRNA and protein expression was examined in the white matter of the vPFC in MDD. Sections of deep and gyral white matter from the vPFC were collected from 20 subjects with MDD and 16 control subjects. Density and size of CNPase-immunoreactive (-IR) oligodendrocytes were estimated using 3-dimensional cell counting. While neither density nor soma size of oligodendrocytes was significantly affected in deep white matter, soma size was significantly decreased in the gyral white matter in MDD. In rhesus monkeys treated chronically with fluoxetine there was no significant effect on oligodendrocyte morphometry. Using quantitative RT-PCR to measure oligodendrocyte related mRNA for CNPase, PLP1, MBP, MOG, MOBP, Olig1 and Olig2, in MDD there was a significantly reduced expression of PLP1 mRNA (which positively correlated with smaller sizes) and increased expression of mRNA for CNPase, OLIG1 and MOG. The expression of CNPase protein was significantly decreased in MDD. Altered expression of four myelin genes and CNPase protein suggests a mechanism for the degeneration of cortical axons and dysfunctional maturation of oligodendrocytes in MDD. The change in oligodendrocyte morphology in gyral white matter may parallel altered axonal integrity as revealed by DTI. PMID- 25930078 TI - A qualitative study of the experience of psychological distress post-stroke. AB - There is little qualitative data on the emotional effect of stroke upon which to base hypotheses for psychological interventions. We used Interpretative Phenomenological Analysis of semi-structured interviews with 10 individuals in the clinical range for psychological distress on the Hospital Anxiety and Depression Scale to explore their experiences of psychological distress. Three super-ordinate themes (the fear of stroke, loss of self and sense of isolation and aloneness) emerged. Processes involving a lack of acceptance and self compassion underlined these themes. Internal isolation was found as a great problem. These themes may indicate targets for directed psychological interventions in people following stroke. PMID- 25930079 TI - Effects of emotion regulation strategies on anxiety during job interviews in Chinese college students. AB - BACKGROUND AND OBJECTIVES: Few studies related to the impact of different emotion regulation strategies on anxiety have used externally and ecologically valid emotion-eliciting stimuli or Eastern populations. The present study compares the effects of reappraisal, suppression, and acceptance on anxiety induced by a simulated job interview in a Chinese sample. METHODS: Eighty-two subjects were randomly assigned to one of four instructions: reappraisal, suppression, acceptance, or no-regulation strategies during a simulated job interview. Anxiety was assessed with an observer-based behavior rating scale during the interview and the State Anxiety Inventory before, during, and after the interview. RESULTS: A repeated-measures MANOVA indicated a significantly greater reduction in anxiety in the reappraisal and acceptance groups compared to the control group during the interview (reappraisal: d = 1.42; acceptance: d = 1.30; each p < .001), but not during the recovery stage. The suppression and control group did not differ in any stage. Suppression led to a higher (pmax < .04) anxiety than reappraisal/acceptance in the anticipation (d = 0.65/0.68), interview (d = 0.87/0.79), and recovery stages (d = 0.94/1.03). No significant differences were found between reappraisal and acceptance. CONCLUSIONS: In Chinese students reappraisal and acceptance seem to be more effective anxiety regulation strategies than suppression. PMID- 25930080 TI - TLR2 and TLR9 contribute to alcohol-mediated liver injury through induction of CXCL1 and neutrophil infiltration. AB - Although previous studies reported the involvement of the TLR4-TRIF pathway in alcohol-induced liver injury, the role of TLR2 and TLR9 signaling in alcohol mediated neutrophil infiltration and liver injury has not been elucidated. Since alcohol binge drinking is recognized to induce more severe form of alcohol liver disease, we used a chronic-binge ethanol-feeding model as a mouse model for early stage of alcoholic hepatitis. Whereas a chronic-binge ethanol feeding induced alcohol-mediated liver injury in wild-type mice, TLR2- and TLR9-deficient mice showed reduced liver injury. Induction of neutrophil-recruiting chemokines, including Cxcl1, Cxcl2, and Cxcl5, and hepatic neutrophil infiltration were increased in wild-type mice, but not in TLR2- and TLR9-deficient mice. In vivo depletion of Kupffer cells (KCs) by liposomal clodronate reduced liver injury and the expression of Il1b, but not Cxcl1, Cxcl2, and Cxcl5, suggesting that KCs are partly associated with liver injury, but not neutrophil recruitment, in a chronic binge ethanol-feeding model. Notably, hepatocytes and hepatic stellate cells (HSCs) produce high amounts of CXCL1 in ethanol-treated mice. The treatment with TLR2 and TLR9 ligands synergistically upregulated CXCL1 expression in hepatocytes. Moreover, the inhibitors for CXCR2, a receptor for CXCL1, and MyD88 suppressed neutrophil infiltration and liver injury induced by chronic-binge ethanol treatment. Consistent with the above findings, hepatic CXCL1 expression was highly upregulated in patients with alcoholic hepatitis. In a chronic-binge ethanol-feeding model, the TLR2 and TLR9-dependent MyD88-dependent pathway mediates CXCL1 production in hepatocytes and HSCs; the CXCL1 then promotes neutrophil infiltration into the liver via CXCR2, resulting in the development of alcohol-mediated liver injury. PMID- 25930081 TI - Colonic mucosal gene expression and genotype in irritable bowel syndrome patients with normal or elevated fecal bile acid excretion. AB - The mucosal gene expression in rectosigmoid mucosa (RSM) in irritable bowel syndrome with diarrhea (IBS-D) is unknown. Our objectives were, first, to study mRNA expression [by RT(2) PCR of 19 genes pertaining to tight junctions, immune activation, intestinal ion transport and bile acid (BA) homeostasis] in RSM in IBS-D patients (n = 47) and healthy controls (n = 17) and study expression of a selected protein (PDZD3) in 10 IBS-D patients and 4 healthy controls; second, to assess RSM mRNA expression according to genotype and fecal BA excretion (high >= 2,337 MUmol/48 h); and third, to determine whether genotype or mucosal mRNA expression is associated with colonic transit or BA parameters. Fold changes were corrected for false detection rate for 19 genes studied (P < 0.00263). In RSM in IBS-D patients compared with controls, mRNA expression of GUC2AB, PDZD3, and PR2Y4 was increased, whereas CLDN1 and FN1 were decreased. One immune-related gene was upregulated (C4BP4) and one downregulated (CCL20). There was increased expression of a selected ion transport protein (PDZD3) on immunohistochemistry and Western blot in IBS-D compared with controls (P = 0.02). There were no significant differences in mucosal mRNA in 20 IBS-D patients with high compared with 27 IBS-D patients with normal BA excretion. GPBAR1 (P < 0.05) was associated with colonic transit. We concluded that mucosal ion transport mRNA (for several genes and PDZD3 protein) is upregulated and barrier protein mRNA downregulated in IBS-D compared with healthy controls, independent of genotype. There are no differences in gene expression in IBS-D with high compared with normal fecal BA excretion. PMID- 25930082 TI - Noninvasive biomagnetic detection of intestinal slow wave dysrhythmias in chronic mesenteric ischemia. AB - Chronic mesenteric ischemia (CMI) is a challenging clinical problem that is difficult to diagnose noninvasively. Diagnosis early in the disease process would enable life-saving early surgical intervention. Previous studies established that superconducting quantum interference device (SQUID) magnetometers detect the slow wave changes in the magnetoenterogram (MENG) noninvasively following induction of mesenteric ischemia in animal models. The purpose of this study was to assess functional physiological changes in the intestinal slow wave MENG of patients with chronic mesenteric ischemia. Pre- and postoperative studies were conducted on CMI patients using MENG and intraoperative recordings using invasive serosal electromyograms (EMG). Our preoperative MENG recordings showed that patients with CMI exhibited a significant decrease in intestinal slow wave frequency from 8.9 +/- 0.3 cpm preprandial to 7.4 +/- 0.1 cpm postprandial (P < 0.01) that was not observed in postoperative recordings (9.3 +/- 0.2 cpm preprandial and 9.4 +/- 0.4 cpm postprandial, P = 0.86). Intraoperative recording detected multiple frequencies from the ischemic portion of jejunum before revascularization, whereas normal serosal intestinal slow wave frequencies were observed after revascularization. The preoperative MENG data also showed signals with multiple frequencies suggestive of uncoupling and intestinal ischemia similar to intraoperative serosal EMG. Our results showed that multichannel MENG can identify intestinal slow wave dysrhythmias in CMI patients. PMID- 25930083 TI - A Qualitative Study of Medical Mistrust, Perceived Discrimination, and Risk Behavior Disclosure to Clinicians by U.S. Male Sex Workers and Other Men Who Have Sex with Men: Implications for Biomedical HIV Prevention. AB - Access to biomedical HIV prevention technologies such as pre-exposure prophylaxis (PrEP) requires individuals to disclose risk behavior to clinicians, but experiences of discrimination and medical mistrust may limit disclosure among male sex workers and other MSM. We explored experiences of perceived discrimination, medical mistrust, and behavior disclosure among male sex workers compared to other men who have sex with men (MSM). We conducted 56 interviews with MSM and compared findings about medical mistrust, discrimination, and disclosure for 31 men who engaged in sex work vs. 25 men who did not. MSM who engaged in sex work reported more medical mistrust and healthcare discrimination due to issues beyond MSM behavior/identity (e.g., homelessness, substance use, poverty). MSM who did not report sex work described disclosing sex with men to clinicians more often. Both subgroups reported low PrEP awareness, but willingness to disclose behavior to obtain PrEP. Medical mistrust and perceived discrimination create barriers for sexual behavior disclosure to clinicians, potentially impeding access to PrEP and other forms of biomedical HIV prevention. These barriers may be higher among male sex workers compared to other MSM, given overlapping stigmas including sex work, substance use, homelessness, and poverty. An intersectionality framework for understanding multiple stigmas can help to identify how these dynamics may limit access to biomedical HIV prevention among male sex workers, as well as suggesting strategies for addressing stigmas to improve the delivery of PrEP and other HIV prevention approaches in this population. PMID- 25930084 TI - Contrast-enhanced voiding urosonography: in vitro evaluation of a second generation ultrasound contrast agent for in vivo optimization. AB - BACKGROUND: Pediatric contrast-enhanced ultrasound (CEUS) is primarily performed outside the United States where a track record for safety in intravenous and intravesical applications has been established. Contrast-enhanced voiding urosonography (ceVUS) has also been shown to have a much higher rate of vesicoureteral reflux detection compared to voiding cystourethrography. US contrast agents available in the United States differ from those abroad. Optison(r) (GE Healthcare, Princeton, NJ) is such an US contrast agent. While Optison(r) has similar characteristics to other second-generation agents, it has never been used for ceVUS. In vitro optimization of dose and imaging parameters as well as assessment of contrast visualization when delivered in conditions similar to ceVUS are necessary starting points prior to in vivo applications. OBJECTIVE: To optimize the intravesical use of Optison(r) in vitro for ceVUS before its use in pediatric studies. MATERIALS AND METHODS: The experimental design simulated intravesical use. Using 9- and 12-MHz linear transducers, we scanned 20-mL syringes varying mechanical index, US contrast agent concentration (0.25%, 0.5%, 1.0%), solvent (saline, urine, radiographic contrast agent) and time out of refrigeration. We evaluated mechanical index settings and contrast duration, optimized the contrast dose, measured the effect of urine and radiographic contrast agent, and the impact of length of time of contrast outside of the refrigerator on US contrast appearance. We scanned 50-ml saline bags to assess the appearance and duration of US contrast with different delivery systems (injection vs. infusion). RESULTS: Consistent contrast visualization was achieved at a mechanical index of 0.06-0.17 and 0.11-0.48 for the L9 and L12 MHz transducers (P < 0.01), respectively. Thus, it was necessary to increase the mechanical index for better contrast visualization of the microbubbles with a higher transducer frequency. The lowest mechanical index for earliest visible microbubble destruction was 0.21 for the 9 MHz and 0.39 for the 12 MHz (P < 0.01) transducers. The 0.5% US contrast agent volume to bladder filling was the most optimal. At this concentration, the mean time to visualize homogenous contrast was 2 min and destruction of approximately half of the microbubbles in the field of view occurred in 7.8 min using the 9-MHz transducer. During contrast infusion, the contrast dose needed to be reduced to 0.12% for maintenance of optimal visualization of microbubbles. There was no deleterious effect on the visualization of contrast in the presence of urine or radiographic contrast agent. Infusion of the US contrast agent speeded visualization of homogeneous enhancement compared with injection. Time outside refrigeration did not affect contrast performance. CONCLUSION: Transducer mechanical index settings need to be optimized. A very low dose of the US contrast agent Optison(r) will suffice for intravesical application, i.e. 0.12% to 0.50% of the bladder filling volume. The presence of urine or radiographic contrast agent did not compromise contrast visualization. The best mode of administration is the infusion method due to fast homogenous distribution at the lowest dose of 0.12%. Leaving the US contrast agent outside the refrigerator for an hour does not affect the microbubbles. PMID- 25930085 TI - Anticholinergic drugs and negative outcomes in the older population: from biological plausibility to clinical evidence. AB - The use of medication with anticholinergic properties is widespread among older subjects. Many drugs of common use such as antispasmodics, bronchodilators, antiarrhythmics, antihistamines, anti-hypertensive drugs, antiparkinson agents, skeletal muscle relaxants, and psychotropic drugs have been demonstrated to have an anticholinergic activity. The most frequent adverse effects are dry mouth, nausea, vomiting, constipation, abdominal pain, urinary retention, blurred vision, tachycardia and neurologic impairment such as confusion, agitation and coma. A growing evidence from experimental studies and clinical observations suggests that drugs with anticholinergic properties can cause physical and mental impairment in the elderly population. However, the morbidity and management issues associated with unwanted anticholinergic activity are underestimated and frequently overlooked. Moreover, their possible relation with specific negative outcome in the elderly population is still not firmly established. The aim of the present review was to evaluate the relationship between the use of drugs with anticholinergic activity and negative outcomes in older persons. We searched PubMed and Cochrane combining the search terms "anticholinergic", "delirium", "cognitive impairment", "falls", "mortality" and "discontinuation". Medicines with anticholinergic properties may increase the risks of functional and cognitive decline, morbidity, institutionalization and mortality in older people. However, such evidences are still not conclusive probably due to possible confounding factors. In particular, more studies are needed to investigate the effects of discontinuation of drug with anticholinergic properties. Overall, minimizing anticholinergic burden should always be encouraged in clinical practice to improve short-term memory, confusion and delirium, quality of life and daily functioning. PMID- 25930086 TI - Should cardiac resynchronization therapy be a rescue therapy for inotrope dependent patients with advanced heart failure? AB - BACKGROUND: Although the "off-label usage" of cardiac resynchronization therapy with defibrillator (CRT-D) has spread recently in advanced heart failure (HF) patients in the real-world practice, its clinical effect remained uncertain. METHODS AND RESULTS: A total of 84 in-hospital <65-year old patients with advanced HF undergoing CRT-D were enrolled. Seventeen patients (20%) had been dependent on inotropes at the time of CRT-D implantation, and 17 suffered cardiac death within a year. Both inotrope dependence and elevated plasma levels of B type natriuretic peptide (BNP) (>690 pg/mL) at the time of CRT-D implantation were independent predictors of cardiac death within a year by Cox regression analyses (P < 0.05 for both). These 2 parameters could significantly stratify 1 year ventricular assist device (VAD)-free survival: inotrope-free low (1) or high BNP (2), or inotrope-dependent low (3) or high BNP groups (4) (98, 77, 57, and 17%, respectively, P < 0.001). In contrast, there were no significant differences in actual 1-year survival among the four groups. CONCLUSION: Patients dependent on inotropes sometimes receive CRT-D therapy as the last treatment resort in clinical practice, but LVAD implantation should be considered instead of CRT-D in advanced HF patients because of their poor prognosis with CRT-D therapy. PMID- 25930087 TI - The nanochannel delivery system for constant testosterone replacement therapy. AB - INTRODUCTION: The goal of testosterone replacement is to provide long-term physiological supplementation at sufficient levels to mitigate the symptoms of hypogonadism. AIM: The objective of this work is to determine if the implantable nanochannel delivery system (nDS) can present an alternative delivery strategy for the long-term sustained and constant release of testosterone. METHODS: A formulation of common testosterone esters (F1) was developed to enable nanochannel delivery of the low water soluble hormone. In vivo evaluation of testosterone, luteinizing hormone (LH) and follicle stimulating hormone (FSH) levels by liquid chromatography/mass spectrometry and a multiplex assay, respectively, in castrated Sprague-Dawley rats implanted with nDS-F1 implants or polymeric pellets was performed over a 6-month period. The percent of testosterone concentrations observed that fell within the normal range of testosterone levels for each animal was calculated and used to compare the study groups. MAIN OUTCOME MEASURES: Sustain release of testosterone in vivo for over 6 months. RESULTS: The subcutaneous release of F1 from nDS implants exhibited sustained in vivo release kinetics and attained stable clinically relevant plasma testosterone levels. Plasma LH and FSH levels were significantly diminished in nDS-F1 implant-treated animals, confirming biological activity of the released testosterone. CONCLUSIONS: In conclusion, we demonstrate that nDS-F1 implants represents a novel approach for the treatment of male hypogonadism. Further studies will be performed in view of translating the technology to clinical use. PMID- 25930088 TI - Identification of different species of Bacillus isolated from Nisargruna Biogas Plant by FTIR, UV-Vis and NIR spectroscopy. AB - Definitive identification of microorganisms, including pathogenic and non pathogenic bacteria, is extremely important for a wide variety of applications including food safety, environmental studies, bio-terrorism threats, microbial forensics, criminal investigations and above all disease diagnosis. Although extremely powerful techniques such as those based on PCR and microarrays exist, they require sophisticated laboratory facilities along with elaborate sample preparation by trained researchers. Among different spectroscopic techniques, FTIR was used in the 1980s and 90s for bacterial identification. In the present study five species of Bacillus were isolated from the aerobic predigester chamber of Nisargruna Biogas Plant (NBP) and were identified to the species level by biochemical and molecular biological (16S ribosomal DNA sequence) methods. Those organisms were further checked by solid state spectroscopic absorbance measurements using a wide range of electromagnetic radiation (wavelength 200 nm to 25,000 nm) encompassing UV, visible, near Infrared and Infrared regions. UV Vis and NIR spectroscopy was performed on dried bacterial cell suspension on silicon wafer in specular mode while FTIR was performed on KBr pellets containing the bacterial cells. Consistent and reproducible species specific spectra were obtained and sensitivity up to a level of 1000 cells was observed in FTIR with a DTGS detector. This clearly shows the potential of solid state spectroscopic techniques for simple, easy to implement, reliable and sensitive detection of bacteria from environmental samples. PMID- 25930089 TI - CYP3A5 and ABCB1 polymorphisms as predictors for sunitinib outcome in metastatic renal cell carcinoma. AB - BACKGROUND: In our exploratory studies, we associated single nucleotide polymorphisms (SNPs) in candidate genes with the efficacy and toxicities of sunitinib in metastatic renal cell carcinoma (mRCC). OBJECTIVE: To see whether previously reported associations of SNPs with sunitinib-induced toxicities and efficacy in mRCC can be confirmed in a large cohort of patients. DESIGN, SETTING, AND PARTICIPANTS: The mRCC patients treated with sunitinib and a DNA sample available were pooled from three exploratory studies conducted in the United States, Spain, and the Netherlands. A total of 22 SNPs and 6 haplotypes in 10 candidate genes related to the pharmacokinetics and pharmacodynamics of sunitinib were selected for association testing. OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS: SNPs and haplotypes were tested for associations with toxicity, dose reductions, progression-free survival (PFS), overall survival (OS), and best objective response. RESULTS AND LIMITATIONS: A total of 333 patients were included. We confirmed 2 of the 22 previously reported SNP associations. The presence of CYP3A5*1 was associated with dose reductions (odds ratio: 2.0; 95% confidence interval [CI], 1.0-4.0, p=0.039). The presence of CGT in the ABCB1 haplotype was associated with an increased PFS (hazard ratio: 1.9; 95% CI, 1.3 2.6; p<0.001) and remained significant after Bonferroni correction. These associations are consistent with prior observations. CONCLUSIONS: The confirmation of previously reported associations between polymorphisms in CYP3A5 and ABCB1 with sunitinib toxicity and efficacy, respectively, indicates that genotyping of these genetic variants will be useful for guiding sunitinib treatment. A prospective validation study is needed to confirm our findings on ABCB1 and CYP3A5 genetic polymorphisms. PATIENT SUMMARY: We confirmed that variants in genes involved in processing sunitinib through the body have an effect on sunitinib treatment outcome. These findings confirm the potential of testing for these genetic variants to improve individual patient care for patients with metastatic renal cell carcinoma treated with sunitinib. PMID- 25930090 TI - Preoperative psychological distress, coping and quality of life in Chinese patients with newly diagnosed gastric cancer. AB - AIMS AND OBJECTIVES: The purpose of this study was to investigate the prevalence of preoperative psychological distress and its relationship with coping style and quality of life in Chinese patients with newly diagnosed gastric cancer. BACKGROUND: Being newly diagnosed with cancer can be a source of psychological distress. Understanding the preoperative psychological distress may contribute to the development of appropriate interventions. DESIGN: This is a descriptive correlational survey study. METHODS: The study was conducted in two teaching hospitals in Anhui province, China. A total of 165 patients with gastric cancer completed a battery of self-report questionnaires including the Distress Thermometer, the revised Chinese version of the Quality of Life Questionnaire Stomach 22 and the Cancer Coping Modes Questionnaire. RESULTS: The prevalence of clinically significant preoperative psychological distress was 76.97% in this group. Statistically significant correlations were identified between the distress score and stomach pain, eating restrictions and anxiety subscale. Positive associations were found between the distress scores and four subdimensions of coping (avoidance and suppression, resignation, fantasy and catharsis), whereas a negative association was found between the distress scores and one subdimension of coping (Confrontation). There were also significant differences in the quality of life and coping style of patients who had different psychological distress statuses. CONCLUSION: These findings indicate a relatively high prevalence of preoperative psychological distress among Chinese patients with gastric cancer. Patients with clinically psychological distress were more likely to have poor quality of life and to demonstrate negative coping styles. RELEVANCE TO CLINICAL PRACTICE: Nursing professionals need to carefully assess the psychological status of patients with gastric cancer. Tailored interventions can be administered to help these patients appropriately cope with the disease and to enhance their quality of life. PMID- 25930091 TI - New associations: INFG and TGFB1 genes and the inhibitor development in severe haemophilia A. AB - INTRODUCTION: The development of factor VIII (FVIII) inhibitor is the main complication of replacement therapy in patients with haemophilia A (HA). A ratio of 5-7% of individuals HA develops antibodies (inhibitors) against the FVIII infused during the treatment, thereby reducing their pro-coagulant activity. The immunomodulatory cytokine genes have been related to the risk of development of alloantibodies in several studies, mainly in HA with severe form. AIM: We investigated the polymorphisms in regulatory regions of cytokine genes (IL1A, IL1B, IL1R, IL1RA, IL4RA, IL12, INFG, TGFB1, TNF, IL2, IL4, IL6, IL10) that could influence the risk of developing inhibitors in patients with severe HA. METHODS: The genotyping of cytokine genes of 117 patients with HA was performed by polymerase chain reaction with sequence-specific primers (PCR-SSP) using the protocol recommended by the manufacturer (Invitrogen kit Cytokines((r)) , Canoga Park, USA) RESULTS: From the cohort of 117 patients with severe HA, 35 developed inhibitors. There was a higher frequency of +874 T allele in INFG and of +869 TT and TG/TG in TGFB1 genes on patients with inhibitors. CONCLUSION: This suggests that polymorphisms in INFG and in TGFB1 genes are related to risk of developing inhibitor, and could contribute to a genetic profile of the individual HA for the risk of inhibitors development to FVIII. PMID- 25930092 TI - Highly sensitive fluorescent stain for detecting lipopolysaccharides in sodium dodecyl sulfate polyacrylamide gel electrophoresis. AB - A sensitive and simple technique was developed for the visualization of gel separated lipopolysaccharides by using a hydrazide derivative, UGF202. As low as 0.5-1 ng total LPS could be detected by UGF202 stain, which is 2- and 16-fold more sensitive than that of the commonly used Pro-Q Emerald 300 and Keenan et al. developed silver stain, respectively. The results indicated that UGF202 stain could be a good choice for LPS determination in polyacrylamide gels. PMID- 25930093 TI - UP-HILIC-MS/MS to Determine the Action Pattern of Penicillium sp. Dextranase. AB - Investigation of the action pattern of enzymes acting on carbohydrates is challenging, as both the substrate and the digestion products are complex mixtures. Dextran and its enzyme-derived oligosaccharides are widely used for many industrial applications. In this work, a new method relying on ultra performance hydrophilic interaction liquid chromatography quadrupole time-of flight tandem mass spectrometry (UP-HILIC-Q/TOF-MS/MS) was developed to analyze a complex mixture of dextran oligosaccharide products to determine the action pattern of dextranase. No derivatization of oligosaccharides was required and the impact of the alpha- and beta-configurations of the native oligosaccharides on the chromatographic separation was eliminated. The 1->6, 1->3, 1->4 backbone linkages and the branch linkages of these oligosaccharides were all distinguished from diagnostic ions in their MS/MS spectra, including fragments corresponding to (0,2)A, (0,3)A, (0,4)A, B-H2O, (2,5)A, and (3,5)A. The sequences of the oligosaccharide products were similarly established. Thus, the complex oligosaccharide mixtures in dextran digestion products were profiled and identified using this method. The more enzyme-resistant structures in dextran were established using much less sample, labor, time, and uncertainty than in previous studies. This method provides an efficient, sensitive, and straightforward way to monitor the entire process of digestion, establish the action pattern of the dextranase from Penicillium sp., and to support the proper industrial application of dextranase. PMID- 25930094 TI - Determination of Dicyandiamide in Powdered Milk Using Direct Analysis in Real Time Quadrupole Time-of-Flight Tandem Mass Spectrometry. AB - The direct analysis in real time (DART) ionization source coupled with quadrupole time-of-flight tandem mass spectrometry (Q-TOF MS/MS) system has the capability to desorb analytes directly from samples without sample cleanup or chromatographic separation. In this work, a method based on DART/Q-TOF MS/MS has been developed for rapid identification of dicyandiamide (DCD) present in powdered milk. Simple sample extraction procedure employing acetonitrile-water (80:20, v/v) mixture was followed by direct, high-throughput determination of sample extracts spread on a steel mesh of the transmission module by mass spectrometry under ambient conditions. The method has been evaluated for both qualitative and quantitative analysis of DCD in powdered milk. Variables including experimental apparatus, DART gas heater temperature, sample presentation speed, and vacuum pressure were investigated. The quantitative method was validated with respect to linearity, sensitivity, repeatability, precision, and accuracy by using external standards. After optimization of these parameters, a limit of detection (LOD) of 100 MUg kg(-1) was obtained for DCD with a linear working range from 100 to 10000 MUg kg(-1) and a satisfactory correlation coefficient (R(2)) of 0.9997. Good recovery (80.08%-106.47%) and repeatability (RSD = 3.0%-5.4%) were achieved for DCD. The DART/Q-TOF MS/MS-based method provides a rapid, efficient, and powerful scheme to analyze DCD in powdered milk with limited sample preparation, thus reducing time and complexity of quality control. PMID- 25930095 TI - Three-Dimensional Evaluation of Alveolar Bone and Soft Tissue Dimensions of Maxillary Central Incisors for Immediate Implant Placement: A Cone-Beam Computed Tomography Assisted Analysis. AB - INTRODUCTION: This study explored the relationship between the thickness of bone and soft tissue along the labial and palatal aspect of maxillary central incisors. The influence of overall socket width, labiopalatal positioning of the incisor on the bone, and soft tissue thickness were also investigated. MATERIALS AND METHODS: This study used cone-beam computed tomography of 150 patients to determine labial, palatal soft and hard tissue thickness, labiopalatal (B-P) socket width and corelated the same to the labiopalatal positioning of maxillary central incisors. RESULTS: Mean (SD) thicknesses of the labial soft tissue at cervical (C), midroot (M), and apical (A) locations and the corresponding bone thicknesses were 1.07 (0.28), 0.987 (0.27), 1.240 (0.41), and 0.928 (0.39), 0.894 (0.52), 1.57 (0.88), respectively. Similarly, palatal soft tissue and bone thicknesses at locations C, M, A were 1.807 (0.66), 1.557 (0.62), 1.639 (0.66), and 1.679 (0.62), 3.439 (1.28), 6.038 (1.63), respectively. Mean (SD) thicknesses of the B-P socket width at location C was 8.047 (0.963). CONCLUSIONS: There is a positive correlation between the labial and palatal bone and corresponding soft tissue thickness, between thickness of the labial bone and the labiopalatal thickness of the alveolar socket. No correlation was observed between the thickness of the labial cortical bone and the labiopalatal positioning of the tooth. PMID- 25930096 TI - Mitochondrial reactive oxygen species modulate innate immune response to influenza A virus in human nasal epithelium. AB - The innate immune system of the nasal epithelium serves as a first line of defense against invading respiratory viruses including influenza A virus (IAV). Recently, it was verified that interferon (IFN)-related immune responses play a critical role in local antiviral innate immunity. Reactive oxygen species (ROS) generation by exogenous pathogens has also been demonstrated in respiratory epithelial cells and modulation of ROS has been reported to be important for respiratory virus-induced innate immune mechanisms. Passage-2 normal human nasal epithelial (NHNE) cells were inoculated with IAV (WS/33, H1N1) to assess the sources of IAV-induced ROS and the relationship between ROS and IFN-related innate immune responses. Both STAT1 and STAT2 phosphorylation and the mRNA levels of IFN-stimulated genes, including Mx1, 2,5-OAS1, IFIT1, and CXCL10, were induced after IAV infection up to three days post infection. Similarly, we observed that mitochondrial ROS generation increased maximally at 2 days after IAV infection. After suppression of mitochondrial ROS generation, IAV-induced phosphorylation of STAT and mRNA levels of IFN-stimulated genes were attenuated and actually, viral titers of IAV were significantly higher in cases with scavenging ROS. Our findings suggest that mitochondrial ROS might be responsible for controlling IAV infection and may be potential sources of ROS generation, which is required to initiate an innate immune response in NHNE cells. PMID- 25930097 TI - Linear-array EUS improves detection of pancreatic lesions in high-risk individuals: a randomized tandem study. AB - BACKGROUND: Studies comparing linear and radial EUS for the detection of pancreatic lesions in an asymptomatic population with increased risk for pancreatic cancer are lacking. OBJECTIVES: To compare pancreatic lesion detection rates between radial and linear EUS and to determine the incremental diagnostic yield of a second EUS examination. DESIGN: Randomized controlled tandem study. SETTING: Five academic centers in the United States. PATIENTS: Asymptomatic high risk individuals (HRIs) for pancreatic cancer undergoing screening EUS. INTERVENTIONS: Linear and radial EUS performed in randomized order. MAIN OUTCOME MEASUREMENTS: Pancreatic lesion detection rate by type of EUS, miss rate of 1 EUS examination, and incremental diagnostic yield of a second EUS examination (second pass effect). RESULTS: Two hundred seventy-eight HRIs were enrolled, mean age 56 years (43.2%), and 90% were familial pancreatic cancer relatives. Two hundred twenty-four HRIs underwent tandem radial and linear EUS. When we used per-patient analysis, the overall prevalence of any pancreatic lesion was 45%. Overall, 16 of 224 HRIs (7.1%) had lesions missed during the initial EUS that were detected by the second EUS examination. The per-patient lesion miss rate was significantly greater for radial followed by linear EUS (9.8%) than for linear followed by radial EUS (4.5%) (P = .03). When we used per-lesion analysis, 73 of 109 lesions (67%) were detected by radial EUS and 99 of 120 lesions (82%) were detected by linear EUS (P < .001) during the first examination. The overall miss rate for a pancreatic lesion after 1 EUS examination was 47 of 229 (25%). The miss rate was significantly lower for linear EUS compared with radial EUS (17.5% vs 33.0%, P = .007). LIMITATIONS: Most detected pancreatic lesions were not confirmed by pathology. CONCLUSION: Linear EUS detects more pancreatic lesions than radial EUS. There was a "second-pass effect" with additional lesions detected with a second EUS examination. This effect was significantly greater when linear EUS was used after an initial radial EUS examination. PMID- 25930099 TI - Two Virtual Reality Pilot Studies for the Treatment of Pediatric CRPS. PMID- 25930098 TI - Protocol guided bleeding management improves cardiac surgery patient outcomes. AB - BACKGROUND AND OBJECTIVES: Excessive bleeding is a risk associated with cardiac surgery. Treatment invariably requires transfusion of blood products; however, the transfusion itself may contribute to postoperative sequelae. Our objective was to analyse a quality initiative designed to provide an evidenced-based approach to bleeding management. MATERIALS AND METHODS: A retrospective analysis compared blood product transfusion and patient outcomes 15 months before and after implementation of a bleeding management protocol. The protocol incorporated point-of-care coagulation testing (POCCT) with ROTEM and Multiplate to diagnose the cause of bleeding and monitor treatment. RESULTS: Use of the protocol led to decreases in the incidence of transfusion of PRBCs (47.3% vs. 32.4%; P < 0.0001), FFP (26.9% vs. 7.3%; P < 0.0001) and platelets (36.1% vs. 13.5%; P < 0.0001). During the intra-operative period, the percentage of patients receiving cryoprecipitate increased (2.7% vs. 5.1%; P = 0.002), as did the number of units transfused (248 vs. 692; P < 0.0001). The proportion of patients who received tranexamic acid increased (13.7% to 68.2%; P < 0.0001). There were reductions in re-exploration for bleeding (5.6% vs. 3.4; P = 0.01), superficial chest wound (3.3% vs. 1.4%; P = 0.002), leg wound infection (4.6% vs. 2.0%; P < 0.0001) and a 12% reduction in mean length of stay from operation to discharge (95%: 9-16%, P < 0.0001). Acquisition cost of blood products decreased by $1 029 118 in the 15 month period with the protocol. CONCLUSIONS: The implementation of a bleeding management protocol supported by POCCT in a cardiac surgery programme was associated with significant reductions in the transfusion of allogeneic blood products, improved outcomes and reduced cost. PMID- 25930100 TI - Health-related employer support, recurring pain, and direct insurance costs for a self-insured employer. AB - BACKGROUND: Poor psychosocial workplace factors have been found to cause or exacerbate a variety of health problems, including pain. However, little work has focused on how psychosocial workplace factors, such as health-related employer support, relate to future medical expenditures after controlling for health. Health-related support has also not been well explored in previous literature as a psychosocial factor. This study estimated the association of health-related employer support and pain with future medical expenditures, after including many additional controls. METHODS: This study used a restricted data set comprised of medical claims and survey data for one company in the U.S. Participants were included in the sample if they had worked for their employer for at least 12 months prior to the survey and if they were continuously eligible for health insurance (N=1,570). Future medical expenditures were measured using administrative claims data covering inpatient, outpatient, mental health and pharmaceutical insurance claims during a year. Health-related employer support was measured using participants' answers about whether the employer would support their efforts to positively change their emotional or physical health. Pain was measured as recurring pain from any condition over the previous year. RESULTS: Having any physical health-related employer support was associated with a 0.06 increase in the probability of having future medical expenditures greater than zero, 95% CI [0.01, 0.11], but not with total expenditures. Having pain was associated with a 0.06 increase, 95% CI [0.04, 0.09], in the probability of having future medical expenditures greater than zero and with $3,027 additional total expenditures, 95% CI [$1,077, $4,987]. CONCLUSIONS: After controlling for health and pain, psychosocial workplace factors were not robustly associated with future medical expenditures. Pain was associated with increased medical expenditures for the self-insured employer in this study, adjusting for a variety of factors. PMID- 25930102 TI - The Autonomous Developmental Pathway: The Primacy of Subjective Mental States for Human Behavior and Experience. AB - This review focuses on infants' emerging awareness of mental states and demonstrates how cultural models-consisting of parenting beliefs and practices interact dynamically with biologically prepared developmental potentialities in shaping infant behavior and development. Contrasting very different cultural contexts, it is suggested that caregivers' visual contingent responsiveness and associated processes are key features of early mother-infant interaction. They (a) are informed by intuitive parenting and culture-specific ethnotheories that, as a consequence, (b) differentially sensitize infants for internal mental states in the 1st year and beyond, and thereby (c) provide mechanisms that specify how culture not only shapes human behavior and experience but also produces culture specific developmental pathways. PMID- 25930101 TI - Patterns of mixed Plasmodium species infections among children six years and under in selected malaria hyper-endemic communities of Zambia: population-based survey observations. AB - BACKGROUND: Although malaria is preventable and treatable, it still claims 660,000 lives every year globally with children under five years of age having the highest burden. In Zambia, malaria rapid diagnostic tests (RDTs) that only detect Plasmodium falciparum are the main confirmatory means for malaria diagnosis in most health facilities without microscopy services. As a consequence of this P. falciparum species diagnostic approach, non-falciparum malaria is not only under-diagnosed but entirely missed, thereby making the exact disease burden unknown. We thus investigated the prevalence of various Plasmodium spp. and associated burden of infection in selected communities in Zambia. METHODS: Data from two malaria hyper-endemic provinces (Eastern and Luapula) of the 2012 National Malaria Indicator Survey (MIS), conducted between April and May 2012, were used. The MIS is a nationally representative, two-stage cluster survey conducted to coincide with the end of the malaria transmission season. Social, behavioural and background information were collected from households as part of the survey. Thick blood smears, RDTs and dried blood spots (DBS) were collected from children below six years of age. Slides were stained using Giemsa and examined by microscopy while polymerase chain reaction (PCR) was used to analyse the DBS for malaria Plasmodium spp. Multivariate logistic regression was employed to examine the association between background factors and malaria. RESULTS: Overall, 873 children younger than six years of age were surveyed. The overall prevalence of Plasmodium spp. by PCR was 54.3% (95% CI 51-57.6%). Of the total Plasmodium isolates, 88% were P. falciparum, 10.6% were mixed infections and 1.4% were non-falciparum mono infections. Among the mixed infections, the majority were a combination of P. falciparum and P. malariae (6.5% of all mixed infections). Children two years and older (2-5 years) had three-fold higher risk of mixed malaria infections (aOR 2.8 CI 1.31-5.69) than children younger than two years of age. CONCLUSION: The high prevalence of mixed Plasmodium spp. infections in this population stresses review of the current malaria RDT diagnostic approaches. The observed less incidence of mixed infections in children under two years of age compared to their older two-to-five-year-old counterparts is probably due to the protective maternal passive immunity, among other factors, in that age group. PMID- 25930103 TI - Involvement of epimutations in meningioma. AB - Epimutations are heritable and reversible cell markers, which can influence cell function going beyond the effects of DNA mutations. They result from multiple and coordinated mechanisms able to modulate gene expression. Regarding the significance of epigenetics in meningioma, few and somehow contradictory results are available, although promising information has been obtained. Here we highlight the most recent advances about the impact of DNA methylation, histone modifications, and microRNA regulation on meningioma development as well as the interplay between genetic and epigenetic alterations. Data indicate that epigenetics can help to identify novel candidate genes for the management and treatment of meningioma. PMID- 25930105 TI - Preparation of Sheet-like Polymer-Encapsulated Composite Particles by Seeded Polymerization from Sub-micrometer Sheets. AB - Seeded polymerization has been widely used to fabricate polymer-encapsulated inorganic particles (IPs). The most frequently used seeds are spherical, whereas nonspherical particles are not well documented. Recently, sheet-like IPs have attracted much attention in the context of polymer composites. This article is therefore dedicated to understanding seeded polymerization from submicron sheets and focuses on the control of the overall morphology of the composite particles obtained. However, it was found that the composite particles only maintained the sheet-like morphology of the seeds at a low polymer content, whereas they became hamburger-like at a high polymer content owing to minimization of the interfacial energy. Interestingly, when cross-linked, the sheet-like morphology could be well preserved, even at a rather high polymer content. With the encapsulating polymer layer, the obtained sheet-like composite particles showed improved compatibility with the polymer matrix and could be well dispersed in polymer matrix when simply blended. PMID- 25930104 TI - Epigenetic regulation of germ cells-remember or forget? AB - Unlike somatic cells, germ cells retain the potential to reproduce an entire new organism upon fertilization. In order to accomplish the process of fertilization, germ cells undergo an extreme cellular differentiation process known as gametogenesis in order to produce morphologically and functionally distinct oocyte and sperm. In addition to changes in genetic content changes from diploid to haploid, epigenetic mechanisms that modify chromatin state without altering primary DNA sequences have profound influence on germ cell differentiation and moreover, the transgenerational effect. In this review, we will go over the most recent discoveries on epigenetic regulations in germline differentiation and transgenerational inheritance across different metazoan species. PMID- 25930106 TI - An introgressed wing pattern acts as a mating cue. AB - Heliconius butterflies provide good examples of both homoploid hybrid speciation and ecological speciation. In particular, examples of adaptive introgression have been detected among the subspecies of Heliconius timareta, which acquired red color pattern elements from H. melpomene. We tested whether the introgression of red wing pattern elements into H. timareta florencia might also be associated with incipient reproductive isolation (RI) from its close relative, H. timareta subsp. nov., found in the eastern Andes. No choice experiments show a 50% reduction in mating between females of H. t. subsp. nov. and males of H .t. florencia, but not in the reciprocal direction. In choice experiments using wing models, males of H. timareta subsp. nov. approach and court red phenotypes less than their own, whereas males of H. t. florencia prefer models with a red phenotype. Intrinsic postzygotic isolation was not detected in crosses between these H. timareta races. These results suggest that a color pattern trait gained by introgression is triggering RI between H. timareta subsp. nov. and H. t. florencia. PMID- 25930107 TI - Secondary cutaneous involvement by systemic anaplastic lymphoma kinase-negative anaplastic large-cell lymphoma with 6p25.3 rearrangement. PMID- 25930109 TI - Predictive model for the growth kinetics of Staphylococcus aureus in raw pork developed using Integrated Pathogen Modeling Program (IPMP) 2013. AB - A predictive model was performed to describe the growth of Staphylococcus aureus in raw pork by using Integrated Pathogen Modeling Program 2013 and a polynomial model as a secondary predictive model. S. aureus requires approximately 180 h to reach 5-6 log CFU/g at 10 degrees C. At 15 degrees C and 25 degrees C, approximately 48 and 20 h, respectively, are required to cause food poisoning. Predicted data using the Gompertz model was the most accurate in this study. For lag time (LT) model, bias factor (Bf) and accuracy factor (Af) values were both 1.014, showing that the predictions were within a reliable range. For specific growth rate (SGR) model, Bf and Af were 1.188 and 1.190, respectively. Additionally, both Bf and Af values of the LT and SGR models were close to 1, indicating that IPMP Gompertz model is more adequate for predicting the growth of S. aureus on raw pork than other models. PMID- 25930108 TI - Kallistatin treatment attenuates lethality and organ injury in mouse models of established sepsis. AB - INTRODUCTION: Kallistatin levels in the circulation are reduced in patients with sepsis and liver disease. Transgenic mice expressing kallistatin are resistant to lipopolysaccharide (LPS)-induced mortality. Here, we investigated the effect of kallistatin on survival and organ damage in mouse models of established sepsis. METHODS: Mice were rendered septic by cecal ligation and puncture (CLP), or endotoxemic by LPS injection. Recombinant human kallistatin was administered intravenously six hours after CLP, or intraperitoneally four hours after LPS challenge. The effect of kallistatin treatment on organ damage was examined one day after sepsis initiation, and mouse survival was monitored for four to six days. RESULTS: Human kallistatin was detected in mouse serum of kallistatin treated mice. Kallistatin significantly reduced CLP-induced renal injury as well as blood urea nitrogen, serum creatinine, interleukin-6 (IL-6), and high mobility group box-1 (HMGB1) levels. In the lung, kallistatin decreased malondialdehyde levels and HMGB1 and toll-like receptor-4 (TLR4) synthesis, but increased suppressor of cytokine signaling-3 (SOCS3) expression. Moreover, kallistatin attenuated liver injury, serum alanine transaminase (ALT) levels and hepatic tumor necrosis factor-alpha (TNF-alpha) synthesis. Furthermore, delayed kallistatin administration improved survival in CLP mice by 38%, and LPS-treated mice by 42%. In LPS-induced endotoxemic mice, kallistatin attenuated kidney damage in association with reduced serum creatinine, IL-6 and HMGB1 levels, and increased renal SOCS3 expression. Kallistatin also decreased liver injury in conjunction with diminished serum ALT levels and hepatic TNF-alpha and TLR4 expression. In cultured macrophages, kallistatin through its active site increased SOCS3 expression, but this effect was blocked by inhibitors of tyrosine kinase, protein kinase C and extracellular signal-regulated kinase (ERK), indicating that kallistatin stimulates a tyrosine-kinase-protein kinase C-ERK signaling pathway. CONCLUSIONS: This is the first study to demonstrate that delayed human kallistatin administration is effective in attenuating multi-organ injury, inflammation and mortality in mouse models of polymicrobial infection and endotoxemia. Thus, kallistatin therapy may provide a promising approach for the treatment of sepsis in humans. PMID- 25930110 TI - Perspective on multi-target antiplatelet therapies: high content phenotypic screening as an unbiased source of novel polypharmacological strategies. AB - Platelets play an important role in cardiovascular thrombosis as well as in many other pathological conditions such as inflammation, atherosclerosis and cancer. While multi-target strategies to treat complex diseases are gaining considerable attention, current development of antiplatelet therapies is mostly oriented towards several single targets, arising from our present understanding of the regulation of platelet activation. Limited efforts to develop multi-target agents or multidrug therapies are mostly due to a lack of a systematic basis to define target combinations with synergistic effects. Here we discuss the perspective to use high content phenotypic screening of in vitro models as a potential source for inference of synergetic multi-target strategies to control platelet activation. PMID- 25930111 TI - The burden of pertussis in low- and middle-income countries since the inception of the Expanded Programme on Immunization (EPI) in 1974: a systematic review protocol. AB - BACKGROUND: Vaccine against pertussis has been in use for several decades. Despite the widespread use of pertussis vaccine, evidence shows resurgence of pertussis in high-income countries. Pertussis surveillance data is largely missing from low- and middle-income countries (LMICs). Without data on trends of pertussis, it is difficult to review and amend pertussis control policies in any country. We propose conducting a systematic review to evaluate the burden and trends of pertussis in LMICs since 1974. METHODS/DESIGN: Common and medical subject heading (MeSH) terms for pertussis and LMICs will be used to search electronic databases for the relevant literature published between 1974 and December 2014. Only studies from LMICs that fulfils World Health Organisation (WHO) or CDC pertussis case definitions will be included. The studies must have a clear numerator and denominator in a well-defined population. Risk of bias will be evaluated by assessing all qualifying full-text articles for quality and eligibility using a modified quality score assessment tool. Standardised data extraction will be carried out after which descriptions of trends in the prevalence, incidence, as well as mortality rate and case fatality rate, will be done. Where sufficient data is available, the results will be stratified by age group, geography, location, vaccination and HIV status. DISCUSSION: The systematic review proposed by this protocol seeks to address the knowledge gap in the epidemiology of pertussis in LMICs for the first time. It is anticipated that the background epidemiological trends of pertussis in LMICs that our study will provide could be used in the planning for the control of pertussis. SYSTEMATIC REVIEW REGISTRATION: PROSPERO CRD42015015159. PMID- 25930112 TI - Faunal analysis of chigger mites (Acari: Prostigmata) on small mammals in Yunnan province, southwest China. AB - This paper studied the species diversity and fauna distribution of chigger mites on small mammals in Yunnan province, southwest Yunnan. In total, 120,138 individuals of chigger mites were collected from 13,760 individual small mammals, and these mites were identified as comprising two families, 26 genera, and 274 species. Of the five zoogeographical subregions, the mite species diversity in subregions I and II was higher than that in subregions III, IV, and V. Four mite species (Leptotrombidium scutellare, Leptotrombidium sinicum, Leptotrombidium deliense, and Helenicula simena) were the most dominant species in the whole province. Several vector species of chigger mites co-existed in Yunnan, and L. deliense (a main vector of scrub typhus in China) was mainly distributed in subregions IV and V with lower latitude and average altitude whereas L. scutellare (also a main vector in China) was mainly distributed in subregions I, II, and III with higher latitude and average altitude. Some geographically widely distributed mite species were also the mites with wide host ranges and low host specificity. The dominant mite species and their clustering tendency in the dendrogram of hierarchical clustering analysis were highly in accordance with the zoogeographical divisions. The species diversity of chigger mites showed a parabolic tendency from the low altitude (<500 m) to the high altitude (>3,500 m) along the vertical gradients and reached the highest value in the middle altitude regions in 2,000-2,500 m. The highest species diversity of the mites and their small mammal hosts happened in the regions around the Hengduan Mountains, which is a hotspot of biodiversity in Asia continent. The host and its sample size, geographical scope, landscape, topography, and some other factors comprehensively influence the species diversity and faunal distribution of chigger mites. A systematic field investigation with a wide geographical scope and large host sample is strongly recommended in the fauna study of chigger mites and other ectoparasites. PMID- 25930113 TI - Tenuigenin ameliorates acute lung injury by inhibiting NF-kappaB and MAPK signalling pathways. AB - We aimed to explore the protective effect of tenuigenin (TNG) on lipopolysaccharide (LPS)-stimulated inflammatory responses in acute lung injury (ALI). Thus, we assessed the effects of TNG on the LPS-induced production of tumour necrosis factor (TNF)-alpha, interleukin (IL)-6, and IL-1beta in the culture supernatants of RAW 264.7 cells. Male BALB/c mice were pretreated with commercial TNG (2, 4 and 8 mg/kg) and dexamethasone (Dex, 5mg/kg) for 1h prior to LPS (0.5 mg/kg) challenge. After 12h, airway inflammation was assessed. Our results showed that TNG dramatically decreased the production of TNF-alpha, IL 1beta, and IL-6 in vitro and in vivo as well as the expression of COX-2 protein in vivo. Treatment with TNG not only significantly ameliorated LPS-stimulated histopathological changes but also reduced the myeloperoxidase (MPO) activity and the wet-to-dry weight ratio of the lungs. Furthermore, TNG blocked IkappaBalpha phosphorylation and degradation and inhibited p38/ERK phosphorylation in LPS induced ALI. These findings suggest that TNG may have a protective effect on LPS induced ALI and may be useful for the prevention and treatment of ALI in the clinical setting. PMID- 25930114 TI - Recombinant L7/L12 protein entrapping PLGA (poly lactide-co-glycolide) micro particles protect BALB/c mice against the virulent B. abortus 544 infection. AB - Brucella abortus is the etiologic agent of Brucellosis, a zoonotic infection affecting a wide range of animals. It is a highly infectious disease of pandemic potential reporting over 500,000 new human cases annually. Till date, there is no reported vaccine for humans and the available animal vaccines are unsafe, therefore a safe and effective subunit vaccine is highly sought for. In this study, we have evaluated rL7/L12 protein encapsulated in microparticles of PLGA (85:15), a biocompatible and biodegradable polymer approved by FDA for human use. In this work, BALB/c mice have been immunized with rL7/L12 entrapped in microparticles in a prime-boost regimen. Further, evaluation of the immunogenicity of the formulation showed that the IgG antibody titre reached a maxima of 2.2*10(5) (p value 0.0001 v/s control) after the injection of the booster dose. A mixed IgG isotype profile (IgG1/IgG2a) indicated the stimulation of both the cellular as well as humoral immunity which has increased parallely and gradually since the first immunization. High levels of IFN-gamma, 815+/ 55pg/ml were recorded depicting an optimal elicitation of the cellular wing of immunity leading to clearance of splenic bacteria upto 1.69 log units. PMID- 25930115 TI - Smallpox vaccine, ACAM2000: Sites and duration of viral shedding and effect of povidone iodine on scarification site shedding and immune response. AB - The U.S. Department of Defense vaccinates personnel deployed to high-risk areas with the vaccinia virus (VACV)-based smallpox vaccine. Autoinoculations and secondary and tertiary transmissions due to VACV shedding from the vaccination site continue to occur despite education of vaccinees on the risks of such infections. The objectives of this study were to investigate, in naive smallpox vaccinees, (a) whether the vaccination site can remain contagious after the scab separates and (b) whether the application of povidone iodine ointment (PIO) to the vaccination site inactivates VACV without affecting the immune response. These objectives were tested in 60 individuals scheduled to receive smallpox vaccine. Thirty individuals (control) did not receive PIO; 30 subjects (treatment) received PIO starting on post-vaccination day 7. Counter to current dogma, this study showed that VACV continues to shed from the vaccination site after the scab separates. Overall viral shedding levels in the PIO group were significantly lower than those in the control group (p=0.0045), and PIO significantly reduced the duration of viral shedding (median duration 14.5 days and 21 days in the PIO and control groups, respectively; p=0.0444). At least 10% of control subjects continued to shed VACV at day 28, and 3.4% continued to shed the virus at day 42. PIO reduced the proportion of subjects shedding virus from the vaccination site from day 8 until days 21-23 compared with control subjects. Groups did not differ significantly in the proportion of subjects mounting an immune response, as measured by neutralizing antibodies, IgM, IgG, and interferon gamma enzyme-linked immunospot assay. When applied to the vaccination site starting on day 7, PIO reduced viral shedding without altering the immune response. The use of PIO in addition to a semipermeable dressing may reduce the rates of autoinoculation and contact transmission originating from the vaccination site in smallpox-vaccinated individuals. PMID- 25930116 TI - Intra-serotype SAT2 chimeric foot-and-mouth disease vaccine protects cattle against FMDV challenge. AB - The genetic diversity of the three Southern African Territories (SAT) types of foot-and-mouth disease virus (FMDV) reflects high antigenic variation, and indications are that vaccines targeting each SAT-specific topotype may be needed. This has serious implications for control of FMD using vaccines as well as the choice of strains to include in regional antigen banks. Here, we investigated an intra-serotype chimeric virus, vSAT2(ZIM14)-SAT2, which was engineered by replacing the surface-exposed capsid-coding region (1B-1D/2A) of a SAT2 genome length clone, pSAT2, with that of the field isolate, SAT2/ZIM/14/90. The chimeric FMDV produced by this technique was viable, grew to high titres and stably maintained the 1B-1D/2A sequence upon passage. Chemically inactivated, oil adjuvanted vaccines of both the chimeric and parental immunogens were used to vaccinate cattle. The serological response to vaccination showed the production of strong neutralizing antibody titres that correlated with protection against homologous FMDV challenge. We also predicted a good likelihood that cattle vaccinated with an intra-serotype chimeric vaccine would be protected against challenge with viruses that caused recent outbreaks in southern Africa. These results provide support that chimeric vaccines containing the external capsid of field isolates induce protective immune responses in FMD host species similar to the parental vaccine. PMID- 25930117 TI - Increasing Vero viable cell densities for yellow fever virus production in stirred-tank bioreactors using serum-free medium. AB - In this work, changes in Vero cell cultivation methods have been employed in order to improve cell growth conditions to obtain higher viable cell densities and to increase viral titers. The propagation of the 17DD yellow fever virus (YFV) in Vero cells grown on Cytodex I microcarriers was evaluated in 3-L bioreactor vessels. Prior to the current changes, Vero cells were repeatedly displaying insufficient microcarrier colonization. A modified cultivation process with four changes has resulted in higher cell densities and higher virus titers than previously observed for 17DD YFV. PMID- 25930118 TI - Fabrication of cell culture-derived influenza vaccine dissolvable microstructures and evaluation of immunogenicity in guinea pigs. AB - Microstructure patches provide an opportunity for simple, effective, and safe vaccine administration, while achieving the desired immune response. We have evaluated the MicroCor transdermal system for cell culture-derived trivalent influenza vaccine administration. Influenza monovalent purified bulk vaccines (monobulks) (H1N1, H3N2, B) were concentrated by tangential flow filtration, lyophilized, and formulated with biocompatible excipients to form the microstructure array dissolvable tips. Standard single radial immunodiffusion (SRID) determined that the influenza antigens retained potency through the formulation and microstructure array fabrication processes. Array stability was evaluated for storage in both refrigerated and room temperature conditions. Microstructure mechanical strength was confirmed by application to excised pig skin, resulting in successful skin penetration and tip dissolution within 5 min of microstructure insertion. Guinea pigs immunized with influenza vaccine-loaded microstructures had hemagglutinin inhibition (HI) and IgG titers comparable to those obtained by intramuscular injection. After two immunizations, serum HI titers for all immunized groups were greater than 40 (>4-fold higher than the untreated group). These data demonstrate the feasibility for the development of skin delivery technologies that are compatible with cell culture-derived influenza vaccines. PMID- 25930119 TI - Ursolic acid derivatives as bone anabolic agents targeted to tryptophan hydroxylase 1 (Tph-1). AB - Tryptophan hydroxylase 1 (Tph-1) initiates the biosynthesis of peripheral serotonin. As peripheral serotonin suppresses bone formation, inhibitor of Tph-1 provides a useful tool to discover anabolic agents for osteoporosis. In the present study, series of ursolic acid (UA) derivatives were synthesized, and their inhibitory activity on serotonin biosynthesis and cytotoxicity were evaluated. Among the derivatives, 8d with potent inhibitory activity on serotonin was applied for further research. The data revealed that 8d significantly inhibited protein and mRNA expressions of Tph-1, and an SPR study indicated that 8d directly interacted to Tph-1 with a binding affinity of KD=15.09MUM. Oral administration of 8d significantly prevented bone loss via suppressing serotonin biosynthesis without estrogenic side-effects in ovariectomized (OVX) rats. PMID- 25930120 TI - Cetuximab directly inhibits P-glycoprotein function in vitro independently of EGFR binding. AB - PURPOSE: Cancer chemotherapy typically combines anticancer drugs from different mechanisms of action. However, cancer cells could become resistant to chemotherapy via P-gp or other ATP binding cassette proteins. The objective of this study was to evaluate whether cetuximab, monoclonal antibody directed toward epidermal growth factor receptor, could increase intracellular concentration of conventional chemotherapy by interacting with P-gp. METHODS: Two human ovarian carcinoma (IGROV1) and two human embryonary kidney (HEK) cell lines, overexpressing or weakly expressing P-gp, were used. Their EGFR expressions were compared. Cetuximab effect on P-gp functionality was evaluated by measuring doxorubicin (P-gp fluorescent substrate) intracellular accumulation. Cetuximab ability to increase doxorubicin cytotoxicity was evaluated by MTT test. A quaternary structure model of the P-gp-Cetuximab complex was established. RESULTS: Exposure of cetuximab in therapeutic concentrations range with doxorubicin led to significant doxorubicin accumulation and reversion of doxorubicin resistance in P-gp expressing cells lines. Molecular modeling of P-gp cetuximab interactions showed that cetuximab is able to bind P-gp extracellular part. CONCLUSIONS: Cetuximab increases a P-gp substrate intracellular accumulation in both P-gp expressing cell lines, independently of their EGFR expression. One hypothesis is that cetuximab binding on P-gp could hamper the conformational changes that occur during drugs efflux. Our results offer new possibilities of research on monoclonal antibodies influence in MDR phenomena. PMID- 25930121 TI - Lactate dehydrogenase inhibitors sensitize lymphoma cells to cisplatin without enhancing the drug effects on immortalized normal lymphocytes. AB - Up-regulation of glycolysis, a well recognized hallmark of cancer cells, was also found to be predictive of poor chemotherapy response. This observation suggested the attempt of sensitizing cancer cells to conventional chemotherapeutic agents by inhibiting glucose metabolism. Lactate dehydrogenase (LDH) inhibition can be a way to hinder glycolysis of cancer cells without affecting the metabolism of normal tissues, which usually does not require this enzymatic activity. In this paper, we showed that two LDH inhibitors (oxamate and galloflavin) can increase the efficacy of cisplatin in cultured Burkitt's lymphoma (BL) cells and that this potentiating effect is not exerted in proliferating normal lymphocytes. This result was explained by the finding that in BL cells LDH inhibition induced reactive oxygen species (ROS) generation, which was not evidenced in proliferating normal lymphocytes. In BL cells treated with the association of cisplatin and LDH inhibitors, these ROS can be a further cause of DNA damage, to be added to that produced by cisplatin, leading to the failure of the response repair. At present LDH inhibitors suitable for clinical use are actively searched; our results can allow a better understanding of the potentiality of LDH as a possible target to develop innovative anticancer treatments. PMID- 25930122 TI - Synthesis of trapezohedral indium oxide nanoparticles with high-index {211} facets and high gas sensing activity. AB - Nanocrystals with high-index facets usually exhibit higher catalytic activities than those with only low-index facets. Trapezohedron-shaped (TS) In2O3 particles with exposed high-index {211} facets were successfully synthesized in an oleic acid (OA) and trioctylamine (TOA) system. It has been demonstrated that the gas sensing activity of TS In2O3 particles with exposed high-index {211} facets is higher than that of octahedron-shaped In2O3 particles with exposed low-index {111} facets. PMID- 25930123 TI - Promises of "jam tomorrow" are not enough for the NHS, two think tank leaders say. PMID- 25930124 TI - Fate of volatile aromatic hydrocarbons in the wastewater from six textile dyeing wastewater treatment plants. AB - The occurrence and removal of benzene, toluene, ethylbenzene, xylenes, styrene and isopropylbenzene (BTEXSI) from 6 textile dyeing wastewater treatment plants (TDWTPs) were investigated in this study. The practical capacities of the 6 representative plants, which used the activated sludge process, ranged from 1200 to 26000 m(3) d(-1). The results indicated that BTEXSI were ubiquitous in the raw textile dyeing wastewater, except for isopropylbenzene, and that toluene and xylenes were predominant in raw wastewaters (RWs). TDWTP-E was selected to study the residual BTEXSI at different stages. The total BTEXSI reduction on the aerobic process of TDWTP-E accounted for 82.2% of the entire process. The total BTEXSI concentrations from the final effluents (FEs) were observed to be below 1 MUg L(-1), except for TDWTP-F (2.12 MUg L(-1)). Volatilization and biodegradation rather than sludge sorption contributed significantly to BTEXSI removal in the treatment system. BTEXSI were not found to be the main contaminants in textile dyeing wastewater. PMID- 25930125 TI - Fluoride bioaccumulation by hydroponic cultures of camellia (Camellia japonica spp.) and sugar cane (Saccharum officinarum spp.). AB - The ability of hydroponic cultures of camellia and sugar cane adult plants to remove fluoride was investigated. Plants were grown in a 50% Steiner nutrient solution. After an adaptation period to hydroponic conditions, plants were exposed to different fluoride concentrations (0, 2.5, 5 and 10 mg L(-1)). Fluoride concentration in the culture medium and in tissues was measured. In sugar cane, fluoride was mainly located in roots, with 86% of it absorbed and 14% adsorbed. Sugar cane plants removed 1000-1200 mg fluoride kg(-1) dry weight. In camellia plants the highest fluoride concentration was found in leaf. Roots accumulated fluoride mainly through absorption, which was 2-5 times higher than adsorption. At the end of the experiment, fluoride accumulation in camellia plants was 1000-1400 mgk g(-1) dry weight. Estimated concentration factors revealed that fluoride bioaccumulation is 74-221-fold in camellia plants and 100 500-fold in sugar cane plants. Thus, the latter appear as a suitable candidate for removing fluoride from water due to their bioaccumulation capacity and vigorous growth rate; therefore, sugar cane might be used for phytoremediation. PMID- 25930126 TI - Improving Relationships in Trauma Victims: The Case for Interpersonal Psychotherapy and PTSD. PMID- 25930127 TI - Good news in the battle against military suicide. PMID- 25930128 TI - Effect of Treating Mothers' Depression on Children's Well-Being. PMID- 25930129 TI - Neuropsychiatric symptoms in dementia: a cause or consequence? PMID- 25930130 TI - Three paths to drug discovery in psychiatry. PMID- 25930131 TI - Narcissistic personality disorder: diagnostic and clinical challenges. PMID- 25930132 TI - Reflections on Ferguson. PMID- 25930133 TI - Images in psychiatry. The 2,000 yard stare. PMID- 25930134 TI - The clinical discovery of imipramine. AB - The major classes of psychotropic drugs were introduced in an extraordinary decade of discovery between the late 1940s and late 1950s. In the present climate of pessimism about the absence of new drug development, it may be instructive to look back at the research methods used during that era. The study that identified the first antidepressant is a case in point. It was conducted by Roland Kuhn, a Swiss psychiatrist working in a remote psychiatric hospital. Kuhn, like the other pioneering researchers of his day, was given access to new drug entities, and the method he used to discover their clinical effects was open-minded, exploratory, comprehensive, clinical observation. The paper that reported the results of his study has not been available in English, but because of its historical significance and because Kuhn's achievement stands in such contrast to the present impasse in drug development, the authors thought that it might be informative to read about his discovery in his own words. Accordingly, one of the authors (M.R.) translated the paper into English, and they now present excerpts of that translation with the intent of encouraging reevaluation of contemporary approaches to drug discovery. By today's clinical research standards, Kuhn's method of unfettered, exploratory, clinical observation was substandard, haphazard, even messy. Yet it produced a major breakthrough-the discovery that a drug can alleviate depression-that has had a lasting impact on the treatment of depression and on the development of antidepressant drugs. Kuhn's experience might usefully inform our strategies of drug development. PMID- 25930135 TI - Abuse and diversion of gabapentin among nonmedical prescription opioid users in Appalachian Kentucky. PMID- 25930137 TI - Correction. PMID- 25930136 TI - Augmentation of Clozapine With ECT: Observations From India. PMID- 25930143 TI - Predictive factors of subjective outcomes after septoplasty with and without turbinoplasty: can individual perceptual differences of the air passage be a main factor? AB - BACKGROUND: Although septoplasty provides adequate correction of septal deviation, patients are not always satisfied with the procedure. The degree of satisfaction after septal surgery may be affected by individual differences in the perception of one's nasal passage changes and emotional factors. The aim of this study is to identify the predictive factors that influence subjective septoplasty outcomes. METHODS: Forty-nine patients with septal deviation and nasal obstruction were enrolled. Forty-three patients completed the study 3 months after surgery. Age, gender, allergies, smoking, and degree of septal deviation were evaluated. The differences in the visual analogue scale for nasal obstruction and nasal volume measured by acoustic rhinometry between pre decongestant and post-decongestant states were analyzed. A stress questionnaire (SQ) and Beck's depression index (BDI) were also used to evaluate the emotional factors. Subjective satisfaction was evaluated as the difference in nasal obstruction symptom evaluation (NOSE) scores between baseline and 3 months postoperation. RESULTS: Subjective satisfaction was not related to individual perceptual differences in nasal passage changes, depression index, age, gender, allergy status, smoking, or degree of septal deviation (p > 0.05 in all; univariate analysis). The baseline SQ and NOSE scores were significant predictive factors in univariate analysis. However, on multiple regression, only the baseline NOSE scores were related to subjective satisfaction after septoplasty. CONCLUSION: Individual perceptual differences of air passage changes and emotional factors do not predict subjective symptom improvement after septoplasty. Baseline symptoms were the only predictive factor for patient satisfaction after septoplasty. PMID- 25930145 TI - Advantageous effect of biventricular pacing on cardiac function and coronary flow: A case report. PMID- 25930144 TI - A novel hydrogen sulfide prodrug, SG1002, promotes hydrogen sulfide and nitric oxide bioavailability in heart failure patients. AB - Recent studies demonstrate robust molecular cross talk and signaling between hydrogen sulfide (H2 S) and nitric oxide (NO). Heart failure (HF) patients are deficient in both H2 S and NO, two molecules that are critical for cardiovascular homeostasis. A phase I clinical trial of a novel H2 S prodrug (SG1002) was designed to assess safety and changes in H2 S and NO bioavailability in healthy and HF subjects. Healthy subjects (n = 7) and heart failure patients (n = 8) received oral SG1002 treatment in escalating dosages of 200, 400, and 800 mg twice daily for 7 days for each dose. Safety and tolerability were assessed by physical examination, vital signs, and ECG analysis. Plasma samples were collected during a 24-h period each week for H2 S and NO analysis. BNP and glutathione levels were analyzed as markers of cardiac health and redox status. Administration of SG1002 resulted in increased H2 S levels in healthy subjects. We also observed increased H2 S levels in HF subjects following 400 mg SG1002. Nitrite, a metabolite of NO, was increased in both healthy and HF patients receiving 400 mg and 800 mg SG1002. HF subjects treated with SG1002 displayed stable drug levels over the course of the trial. SG1002 was safe and well tolerated at all doses in both healthy and HF subjects. These data suggest that SG1002 increases blood H2 S levels and circulating NO bioavailability. The finding that SG1002 attenuates increases in BNP in HF patients suggests that this novel agent warrants further study in a larger clinical study. PMID- 25930146 TI - Gastroesophageal reflux and atrial fibrillation: A chicken and egg situation. PMID- 25930148 TI - Power-law dynamics in neuronal and behavioral data introduce spurious correlations. AB - Relating behavioral and neuroimaging measures is essential to understanding human brain function. Often, this is achieved by computing a correlation between behavioral measures, e.g., reaction times, and neurophysiological recordings, e.g., prestimulus EEG alpha-power, on a single-trial-basis. This approach treats individual trials as independent measurements and ignores the fact that data are acquired in a temporal order. It has already been shown that behavioral measures as well as neurophysiological recordings display power-law dynamics, which implies that trials are not in fact independent. Critically, computing the correlation coefficient between two measures exhibiting long-range temporal dependencies may introduce spurious correlations, thus leading to erroneous conclusions about the relationship between brain activity and behavioral measures. Here, we address data-analytic pitfalls which may arise when long-range temporal dependencies in neural as well as behavioral measures are ignored. We quantify the influence of temporal dependencies of neural and behavioral measures on the observed correlations through simulations. Results are further supported in analysis of real EEG data recorded in a simple reaction time task, where the aim is to predict the latency of responses on the basis of prestimulus alpha oscillations. We show that it is possible to "predict" reaction times from one subject on the basis of EEG activity recorded in another subject simply owing to the fact that both measures display power-law dynamics. The same is true when correlating EEG activity obtained from different subjects. A surrogate-data procedure is described which correctly tests for the presence of correlation while controlling for the effect of power-law dynamics. PMID- 25930149 TI - Soft repulsive interactions, particle rearrangements and size selection in the self-assembly of nanoparticles at liquid interfaces. AB - In the adsorption of nanoparticles at liquid interfaces, soft and short ranged repulsive effective interactions between the nanoparticles at the interface may eventually induce crowding, slow dynamics and jamming at high surface coverage. These phenomena can interfere during the adsorption process, significantly slowing down its kinetics. Here, by means of numerical simulations, we find that modifying the effective interactions, which can be achieved for example by grafting differently functionalized polymer shells on the bare nanoparticles, may qualitatively change such interplay. In particular our results suggest that, in the presence of ultrasoft particle interactions such as the ones described by a Gaussian Core Model potential, a small size polydispersity can be sufficient to decouple the adsorption kinetics from the slow dynamics that develops at the interface, due to a qualitative change from an irreversible adsorption controlled by particle rearrangements at the interface to one dominated by size selection mechanisms. These findings may be useful to achieve higher surface coverages and faster adsorption kinetics. PMID- 25930147 TI - Race-Ethnicity, Poverty, Urban Stressors, and Telomere Length in a Detroit Community-based Sample. AB - Residents of distressed urban areas suffer early aging-related disease and excess mortality. Using a community-based participatory research approach in a collaboration between social researchers and cellular biologists, we collected a unique data set of 239 black, white, or Mexican adults from a stratified, multistage probability sample of three Detroit neighborhoods. We drew venous blood and measured telomere length (TL), an indicator of stress-mediated biological aging, linking respondents' TL to their community survey responses. We regressed TL on socioeconomic, psychosocial, neighborhood, and behavioral stressors, hypothesizing and finding an interaction between poverty and racial ethnic group. Poor whites had shorter TL than nonpoor whites; poor and nonpoor blacks had equivalent TL; and poor Mexicans had longer TL than nonpoor Mexicans. Findings suggest unobserved heterogeneity bias is an important threat to the validity of estimates of TL differences by race-ethnicity. They point to health impacts of social identity as contingent, the products of structurally rooted biopsychosocial processes. PMID- 25930150 TI - Tipping the scales toward population health. PMID- 25930151 TI - Frequent marijuana use, binge drinking and mental health problems among undergraduates. AB - BACKGROUND AND OBJECTIVES: In light of the rapidly changing legal status of marijuana in the U.S., there has been increased interest in the potentially adverse outcomes of heavy marijuana use among young persons. The goal of this study was to investigate frequent marijuana use among undergraduates, and its association with the use of illicit substances, mental health problems, and stress. METHODS: Undergraduates from one university in the Northeast were surveyed using a questionnaire derived from the American College Health Association-National College Health Assessment (N = 1,776). Logistic regression analyses were used to examine relationships between frequency of marijuana use and other substance use, binge drinking, negative consequences of drinking, mental health problems, and perceived stress. Analyses were adjusted for demographics differences such as gender, race, year in school, and sorority/fraternity membership. RESULTS: Approximately 1 in 12 undergraduates (8.5%) reported using marijuana more than 10 days in the past month. Frequent marijuana use was associated with increased likelihood of other substance use and alcohol-related negative outcomes. Marijuana use was associated with increased reports of anxiety, and frequent use was associated with depression and substance use problems. Perceived stress was not associated with marijuana use. CONCLUSIONS AND SCIENTIFIC SIGNIFICANCE: These findings, indicating that frequent use is related to depression, other substance use and negative outcomes, contribute to our understanding of marijuana use among undergraduates. Given the relatively high prevalence of marijuana use among young persons, future studies should seek to uncover potentially causal relationships between frequent marijuana use and a variety of negative outcomes. PMID- 25930152 TI - Prevalence and impact of Streptococcus pneumoniae in adult cystic fibrosis patients: a retrospective chart review and capsular serotyping study. AB - BACKGROUND: Cystic fibrosis (CF) is a genetic disease characterized by complex polymicrobial communities within the lower respiratory tract. S. pneumoniae, while a well-defined pathogen in the general population, has rarely been identified in CF. Furthermore, prevalence studies on Pneumococcus in CF have predominantly focused on the infant and pediatric populations, and outcome data is lacking. METHODS: Through a review of our comprehensive clinical and microbiologic database from a single adult CF center in Canada from 1978-2013 we sought to determine the incidence, prevalence, serotype and clinical impact of Pneumococcus in adults with CF. RESULTS: Only fifteen of 318 adult CF patients (5%) were ever found to have transient Pneumococcus colonization, and none developed persistent infection although length of carriage varied. As all isolates were stored, capsular serotyping could be performed using a multiplex PCR panel. Capsular serotyping revealed a varied distribution of several serotypes within these isolates. Lung function testing at time of incident Pneumococcus isolation was compared with values before and after isolation and showed no significant reduction in spirometry values, nor was there an increased need for rescue antibacterial therapy. CONCLUSION: Within our center, incident Pneumococcus infection is neither common, associated with a disproportionate clinical deterioration nor results in chronic infection. PMID- 25930153 TI - Label-free quantitative analysis of the casein kinase 2-responsive phosphoproteome of the marine minimal model species Ostreococcus tauri. AB - Casein kinase 2 (CK2) is a protein kinase that phosphorylates a plethora of cellular target proteins involved in processes including DNA repair, cell cycle control, and circadian timekeeping. CK2 is functionally conserved across eukaryotes, although the substrate proteins identified in a range of complex tissues are often different. The marine alga Ostreococcus tauri is a unicellular eukaryotic model organism ideally suited to efficiently study generic roles of CK2 in the cellular circadian clock. Overexpression of CK2 leads to a slow circadian rhythm, verifying functional conservation of CK2 in timekeeping. The proteome was analysed in wild-type and CK2-overexpressing algae at dawn and dusk, revealing that differential abundance of the global proteome across the day is largely unaffected by overexpression. However, CK2 activity contributed more strongly to timekeeping at dusk than at dawn. The phosphoproteome of a CK2 overexpression line and cells treated with CK2 inhibitor was therefore analysed and compared to control cells at dusk. We report an extensive catalogue of 447 unique CK2-responsive differential phosphopeptide motifs to inform future studies into CK2 activity in the circadian clock of more complex tissues. All MS data have been deposited in the ProteomeXchange with identifier PXD000975 (http://proteomecentral.proteomexchange.org/dataset/PXD000975). PMID- 25930154 TI - Primary High-Grade Poorly Differentiated Angiosarcoma of an Intra-parotid Lymph Node. AB - Head and neck angiosarcoma is an infrequent malignant vascular tumor most commonly found in the skin and soft tissue of the head and neck. Most head and neck angiosarcomas are metastatic to cervical lymph nodes from other primitive location. We describe herein a case of primary high-grade poorly differentiated angiosarcoma arising in an intra-parotid lymph node, discuss the value of immunohistochemical stains for differential diagnosis, and review the literature concerning head and neck angiosarcoma. A 47-year-old man presented with a painless mass that had grown for a period of 6 months in the parotid area. The CT scan revealed a left parotid lesion of 17 mm. Fine needle aspiration was considered suspicious for lymphoma or poorly differentiated carcinoma. A superficial parotidectomy was performed. On gross examination, the lesion was a well-defined, gray, homogeneous mass of 15 mm of diameter. Microscopic examination showed a normal parotid tissue and a poorly differentiated malignant neoplasm in an intra-parotid lymph node. The tumor had a pseudo-alveolar pattern, with large pleomorphic epithelioid cells, abundant eosinophilic cytoplasm, large vesicular nuclei, and one or more prominent nucleoli. Atypical mitoses were seen. Neoplastic malignant cells stained positive for Vimentin, CD31, D2-40, factor VIII, ERG, and partially for CD34. A positron emission tomography scan was made to search for a primary neoplasia, but no other tumor was localized. The diagnosis of primary high-grade, poorly differentiated, intra-parotid lymph node angiosarcoma was established. PMID- 25930155 TI - Prophylaxis escalation in severe von Willebrand disease: a prospective study from the von Willebrand Disease Prophylaxis Network. AB - BACKGROUND: Treatment of mucosal bleeding (epistaxis, gastrointestinal bleeding, and menorrhagia) and joint bleeding remains problematic in clinically severe von Willebrand disease (VWD). Patients are often unresponsive to treatment (e.g. desmopressin or antifibrinolytic therapy) and may require von Willebrand factor (VWF) replacement therapy. There are little data on the use of prophylaxis in VWD, and none have been applied in a prospective, treatment escalation design. OBJECTIVE: Evaluate the effect of escalating dose prophylaxis in severe VWD. METHODS: Patients eligible for enrollment in this prospective study included those with type 1 VWD with VW factor activity-ristocetin cofactor ratio <= 20% and unresponsive to desmopressin, patients with type 2 VWD not responsive to desmopressin and all subjects with type 2B and type 3 VWD. Entry criteria were strictly defined, as were therapy escalation parameters and clinical data collection. RESULTS: Eleven subjects completed the study. Six had type 2A, and five had type 3 VWD. Six patients presented with epistaxis, three with GI bleeding, and two with joint bleeding. Seven had dose escalation above the first level. Among the 10 subjects with evaluable bleeding log data, use of prophylaxis decreased the median annualized bleeding rate from 25 to 6.1 (95% confidence interval of the rate difference: -51.6 to -1.7), and the median annualized bleeding rate was even lower (4.0; 95% confidence interval: -57.5 to -5.3) when the subjects reached their final dosing level. CONCLUSION: This is the first prospective study to demonstrate that prophylaxis with VW factor concentrates is highly effective in reducing mucosal and joint bleeding rates in clinically severe VWD. PMID- 25930157 TI - Measurement of peak esophageal luminal cross-sectional area utilizing nadir intraluminal impedance. AB - BACKGROUND: Multichannel intraluminal impedance (MII) is currently used to monitor gastroesophageal reflux and esophageal bolus clearance. We describe a novel methodology to measure maximal luminal cross-sectional area (CSA) during bolus transport from MII measurements. METHODS: Studies were conducted in-vitro (test tubes) and in-vivo (healthy subjects). Concurrent MII, high resolution manometry, and intraluminal ultrasound (US) images were recorded 7-cm above the lower esophageal sphincter. Swallows with two concentrations of saline, 0.1 and 0.5 N, of bolus volumes 5, 10, and 15 cc were performed. The CSA was estimated by solving two algebraic Ohm's law equations, resulting from the two saline solutions. The CSA calculated from impedance method was compared with the CSA measured from the intraluminal US images. KEY RESULTS: The CSA measured in duplicate from B-mode US images showed a mean difference between the two manual delineations to be near zero, and the repeatability coefficient was within 7.7% of the mean of the two CSA measurements. The calculated CSA from the impedance measurements strongly correlated with the US measured CSA (R(2) ? 0.98). A detailed statistical analysis of the impedance and US measured CSA data indicated that the 95% limits of agreement between the two methods ranged from -9.1 to 13 mm(2) . The root mean square error of the two measurements was 4.8% of the mean US-measured CSA. CONCLUSIONS & INFERENCES: We describe a novel methodology to measure peak esophageal luminal CSA from the nadir impedance during peristalsis. Further studies are needed to determine if it is possible to measure patterns of luminal distension during peristalsis across the entire length of the esophagus from the MII recordings. PMID- 25930156 TI - Human islet function following 20 years of cryogenic biobanking. AB - AIMS/HYPOTHESIS: There are potential advantages to the low-temperature (-196 degrees C) banking of isolated islets, including the maintenance of viable islets for future research. We therefore assessed the in vitro and in vivo function of islets cryopreserved for nearly 20 years. METHODS: Human islets were cryopreserved from 1991 to 2001 and thawed between 2012 and 2014. These were characterised by immunostaining, patch-clamp electrophysiology, insulin secretion, transcriptome analysis and transplantation into a streptozotocin (STZ) induced mouse model of diabetes. RESULTS: The cryopreservation time was 17.6 +/- 0.4 years (n = 43). The thawed islets stained positive with dithizone, contained insulin-positive and glucagon-positive cells, and displayed levels of apoptosis and transcriptome profiles similar to those of freshly isolated islets, although their insulin content was lower. The cryopreserved beta cells possessed ion channels and exocytotic responses identical to those of freshly isolated beta cells. Cells from a subset of five donors demonstrated similar perifusion insulin secretion profiles pre- and post-cryopreservation. The transplantation of cryopreserved islets into the diabetic mice improved their glucose tolerance but did not completely normalise their blood glucose levels. Circulating human insulin and insulin-positive grafts were detectable at 10 weeks post transplantation. CONCLUSIONS/INTERPRETATION: We have demonstrated the potential for long-term banking of human islets for research, which could enable the use of tissue from a large number of donors with future technologies to gain new insight into diabetes. PMID- 25930158 TI - Porous Hybrid Network of Graphene and Metal Oxide Nanosheets as Useful Matrix for Improving the Electrode Performance of Layered Double Hydroxides. AB - Mesoporous hybrid network of reduced graphene oxide (rG-O) and layered MnO(2) nanosheets could act as an efficient immobilization matrix for improving the electrochemical activity of layered double hydroxide (LDH). The control of MnO(2) /rG-O ratio is crucial in optimizing the porous structure and electrical conductivity of the resulting hybrid structure. The immobilization of Co-Al-LDH on hybrid MnO(2) /rG-O network is more effective in enhancing its electrode activity compared with that of on pure rG-O network. The Co-Al-LDH-rG-O-MnO(2) nanohybrid deliveres a greater specific capacitance than does MnO(2) -free Co-Al LDH-rG-O nanohybrid. The beneficial effect of MnO(2) incorporation on the electrode performance of nanohybrid is more prominent for higher current density and faster scan rate, underscoring the significant enhancement of the electron transport of Co-Al-LDH-rG-O. This is supported by electrochemical impedance spectroscopy. The present study clearly demonstrates the usefulness of the porously assembled hybrid network of graphene and metal oxide nanosheets as an effective platform for exploring efficient LDH-based functional materials. PMID- 25930160 TI - Indirect effects of primary prey population dynamics on alternative prey. AB - We develop a theory of generalist predation showing how alternative prey species are affected by changes in both mean abundance and variability (coefficient of variation) of their predator's primary prey. The theory is motivated by the indirect effects of cyclic rodent populations on ground-breeding birds, and developed through progressive analytic simplifications of an empirically-based model. It applies nonetheless to many other systems where primary prey have fast life-histories and can become superabundant, thus facilitating impact on alternative prey species and generating highly asymmetric interactions. Our results suggest that predator effects on alternative prey should generally decrease with mean primary prey abundance, and increase with primary prey variability (low to high CV)-unless predators have strong aggregative responses, in which case these results can be reversed. Approximations of models including predator dynamics (general numerical response with possible delays) confirm these results but further suggest that negative temporal correlation between predator and primary prey is harmful to alternative prey. Finally, we find that measurements of predator numerical responses are crucial to predict-even qualitatively-the response of ecosystems to changes in the dynamics of outbreaking prey species. PMID- 25930159 TI - Human polyomavirus JC replication and non-coding control region analysis in multiple sclerosis patients under natalizumab treatment. AB - In the last years, the treatment of multiple sclerosis (MS) patients with natalizumab has been associated with the occurrence of progressive multifocal leukoencephalopathy (PML) caused by human polyomavirus JC (JCV). Here, we have shown a significant correlation between patients with JC viruria and positive JC specific antibody response and patients without JCV-specific antibodies after 1 year of natalizumab (p = 0.0006). Furthermore, JCV-specific quantitative PCR on urine and plasma samples, collected at the enrollment (t0) and every 4 months (t1, t2, t3) in the first year and at two time points (t4 and t5) in the second year of natalizumab treatment, indicated the prevalence of JC viremia rather than JC viruria only in the second year of treatment (p = 0.04). Moreover, the analysis of JCV non-coding control region (NCCR) sequences in peripheral blood mononuclear cells of patients with JC-specific antibodies after 12 natalizumab infusions (t3) revealed the presence of rearranged sequences, whereas the prevalence of genotypes 1A, 1B, and 4 was detected in these patients by VP1 sequence analysis. In summary, JC viruria evaluation seems to be useful to identify early those patients who do not already develop a humoral immune response against JCV. It may also be interesting to study the JCV NCCR rearrangements since they could give us new insights on the onset of neuro invasive viral variants. PMID- 25930161 TI - Safety and diagnostic performance of image-guided lung biopsy in the targeted therapy era. AB - OBJECTIVE OF THE STUDY: To identify risk factors for the adverse events and determine the diagnostic yield of a large series of image-guided thoracic biopsies performed in a single institution. MATERIALS AND METHODS: We reviewed a consecutive series of 811 patients (546 males; average age: 68 years.) who underwent 824 image-guided biopsies of pulmonary lesions performed between 2009 and 2013. Indications for biopsy were always evaluated by a multidisciplinary board. All complications were registered. The diagnostic accuracy was calculated on the basis of histology after surgery, response to medical therapy, or outcome at imaging follow-up. Safety and accuracy was correlated with patient-related and lesion-related factors. RESULTS: 61 biopsies were performed under US-guidance, 750 under CT-guidance, and 13 under combined guidance. The average lesion size was 36.4 mm (6-150 mm). FNAB was exclusively performed in 247 patients, whereas 577 patients underwent also or only core biopsy (CB). 40 (4.8 %) major complications and 172 (20.8 %) minor complications occurred. US-guidance, absence of perilesional emphysema and minor depth of the target lesion from the skin resulted as favorable predictors against major complications. According to the gold standard criteria, we demonstrated 497 true positives, 72 true negatives, 18 false negatives, 0 false positives. Sensitivity, specificity and diagnostic accuracy were 96.5, 100 and 97 %. No predictors for accuracy were found, but the number of samples largely related to the pathologist on site. CONCLUSIONS: Image guided lung biopsy is safe and highly accurate for diagnosing thoracic lesions. In the targeted therapy era, CB with larger needles can be safely applied when the need for larger amounts of tumor tissue is presumed. PMID- 25930163 TI - Animal studies of neonatal hypothermic neuroprotection have translated well in to practice. AB - The discovery that mild, induced hypothermia can improve neurological recovery after global moderate to severe hypoxia-ischemia has been a dramatic validation of the strong foundation of preclinical studies that informed current protocols. The major challenge is to find ways to further improve outcomes. As discussed in this review, the findings from large clinical trials of extended cooling are highly concordant with recent animal studies. These findings support the use of precise, carefully selected animal models to refine our strategies to protect babies with moderate to severe encephalopathy before instigating further large trials. PMID- 25930162 TI - Prevalence and Measurement of Anxiety in Samples of Patients With Heart Failure: Meta-analysis. AB - OBJECTIVES: Rates of anxiety in patients with heart failure (HF) vary widely, and not all assessment instruments used in this patient population are appropriate. It is timely to consolidate the evidence base and establish the prevalence and variance of anxiety in HF samples. METHODS: A systematic review, meta-analysis, and meta-regression were conducted to identify the prevalence, variance, and measurement of anxiety in patients with HF. RESULTS: A total of 14,367 citations were identified, with 73 studies meeting inclusion criteria. A random effects pooled prevalence of 13.1% (95% confidence interval [CI], 9.25%-16.86%) for anxiety disorders, 28.79% (95% CI, 23.30%-34.29) for probable clinically significant anxiety, and 55.5% (95% CI, 48.08%-62.83%) for elevated symptoms of anxiety was identified. Rates of anxiety were highest when measured using the Brief Symptom Scale-Anxiety scale (72.3%) and lowest when measured using the Generalised Anxiety Disorder-7 (6.3%). CONCLUSION: Many patients with HF would benefit if screened for anxiety and treated. The conceptualization and measurement of anxiety accounted for most variance in prevalence rates. The Generalised Anxiety Disorder-7 or the Hospital Anxiety and Depression Scale appear to be the most appropriate instruments for this clinical population, with evidence to suggest they can discriminate between depression and anxiety, omit somatic items that may contaminate identification of anxiety in a population with physical comorbidities, and provide thresholds with which to differentiate patients and target treatments. Although there are limitations with the collation of diverse measurement methods, the current review provides researchers and clinicians with a more granular knowledge of prevalence estimates of anxiety in a population of HF patients. PMID- 25930164 TI - Ischaemic stroke after exposure to aflibercept: interaction with vitamin K antagonist and/or direct pharmacodynamic effect? AB - WHAT IS KNOWN AND OBJECTIVE: Vascular endothelial growth factor (VEGF) proteins are involved in the regulation of vascular endothelium, and their inhibition led to the development of a number of drugs used for malignancies or exudative neo vascular age-related macular degeneration (AMD). CASE SUMMARY: We report a case of ischemic stroke in an 87-year-old woman having received intravitreal aflibercept, a new anti-VEGF for AMD. She had been treated with ranibizumab since 2007. In 2013, ranibizumab was replaced with aflibercept, followed by a decrease in the International Normalized Ratio, complicated by a stroke a few days later. The rechallenge was positive. WHAT IS NEW AND CONCLUSION: A potential time dependent interaction between aflibercept and VKA antagonist and/or a direct effect of aflibercept may have contributed to the occurrence of the ischaemic stroke. Currently available data suggest some pharmacokinetic and pharmacodynamic effects of aflibercept by explaining its pro-thrombotic profile. PMID- 25930166 TI - Medical Students in a Dementia Care Facility: an Enhanced Geriatric Psychiatry Experience. PMID- 25930165 TI - Lineage-specific sequence evolution and exon edge conservation partially explain the relationship between evolutionary rate and expression level in A. thaliana. AB - Rapidly evolving proteins can aid the identification of genes underlying phenotypic adaptation across taxa, but functional and structural elements of genes can also affect evolutionary rates. In plants, the 'edges' of exons, flanking intron junctions, are known to contain splice enhancers and to have a higher degree of conservation compared to the remainder of the coding region. However, the extent to which these regions may be masking indicators of positive selection or account for the relationship between dN/dS and other genomic parameters is unclear. We investigate the effects of exon edge conservation on the relationship of dN/dS to various sequence characteristics and gene expression parameters in the model plant Arabidopsis thaliana. We also obtain lineage specific dN/dS estimates, making use of the recently sequenced genome of Thellungiella parvula, the second closest sequenced relative after the sister species Arabidopsis lyrata. Overall, we find that the effect of exon edge conservation, as well as the use of lineage-specific substitution estimates, upon dN/dS ratios partly explains the relationship between the rates of protein evolution and expression level. Furthermore, the removal of exon edges shifts dN/dS estimates upwards, increasing the proportion of genes potentially under adaptive selection. We conclude that lineage-specific substitutions and exon edge conservation have an important effect on dN/dS ratios and should be considered when assessing their relationship with other genomic parameters. PMID- 25930167 TI - Thyroglobulin antibody resolution after total thyroidectomy for cancer. AB - BACKGROUND: Thyroglobulin antibodies (TgAb) are produced by 10%-25% of thyroid cancer patients and interfere with thyroglobulin measurement, a marker of residual or recurrent cancer after surgery. Our purpose was to describe the TgAb resolution time course and the significance of persistent antibody elevation after thyroidectomy. METHODS: A database of 247 consecutive patients with TgAb measured preoperatively who underwent thyroidectomy for differentiated thyroid cancer between January 2007 and May 2013 was reviewed. Patients were stratified by TgAb status (positive or negative) and recurrence (defined as biopsy proven disease or unplanned second surgery). Survival and regression analysis was used to determine TgAb resolution time course. Log-rank was used to determine an association between persistent antibody elevation and recurrence. RESULTS: Of 247 patients (77% women, 23% men; mean 45.7 +/- 1.0 y) with TgAb measured preoperatively, 34 (14%) were TgAb+ (>=20 IU/mL; mean 298.1 +/- 99.2 IU/mL). Median time to TgAb resolution was 11.0 +/- 2.3 mo, and the majority resolved by 32.4 mo. Regression analysis of patients with antibody resolution yielded an average decline of -11% IU/mL per month +/- 2.2%. Disease-free survival was equivalent between TgAb-positive and TgAb-negative groups (P = 0.8). In 9 of 34 patients, antibodies had not resolved at the last follow-up and imaging could not identify recurrent disease. CONCLUSIONS: TgAb are common in patients with thyroid cancer but resolve after treatment at approximately -11% IU/mL per month from preoperative levels with median resolution at 11.0 mo. Persistently elevated levels after thyroidectomy were not associated with disease recurrence in our series. PMID- 25930168 TI - Pharmacologic investigations on the role of Sirt-1 in neuroprotective mechanism of postconditioning in mice. AB - BACKGROUND: Cerebral ischemia-reperfusion (I-R) injury is one of the primary causes of ischemic stroke. Ischemic postconditioning (iPoCo) is evolving as an important adaptive technique to contain I-R injury. Some recent studies have shown neuroprotective effects of iPoCo. However, the neuroprotective mechanism of iPoCo is not clear. So, the present study has been undertaken to investigate the possible role of Sirtinol, a selective class III histone deacetylase (HDAC) inhibitor in the neuroprotective mechanism of iPoCo in mice. MATERIAL AND METHODS: Bilateral carotid artery occlusion (BCAO) for 12 min followed by reperfusion for 24 h was used to produce I-R-induced cerebral injury in Swiss albino mice. iPoCo involving three episodes of 10-s carotid artery occlusion and reperfusion instituted immediately after BCAO just before prolonged reperfusion of 24 h. Cerebral infarct size was measured using triphenyltetrazolium chloride staining. Memory was evaluated using a Morris water maze test. Rotarod test, inclined beam-walking test, and neurologic severity score (NSS) were used to assess motor incoordination. Acetylcholine esterase levels, brain thiobarbituric acid reactive species (TBARS), and glutathione level were also estimated. RESULTS: BCAO for 12 min followed by reperfusion for 24 h produced a significant rise in cerebral infarct size and NSS along with impairment of memory and motor coordination and biochemical alteration (?acetylcholine esterase, ?glutathione, and ?TBARS). iPoCo, involving three episodes of 10-s carotid artery occlusion with intermittent reperfusion of 10 s applied just after ischemic insult of 12 min produced a significant decrease in cerebral infarct size and NSS along with the reversal of I-R-induced impairment of memory and motor coordination. iPoCo induced neuroprotective effects were significantly abolished by pretreatment with selective SIRT 1 (class III HDAC) blocker Sirtinol (10 mg/kg intraperitoneal). CONCLUSIONS: It may be concluded that the neuroprotective effect of iPoCo probably involves activation of SIRT 1 (class III HDAC) enzyme. PMID- 25930170 TI - Portal vein thrombosis and chronic liver disease progression: The closer you look the more you see. PMID- 25930169 TI - Pulmonary complications after major abdominal surgery: National Surgical Quality Improvement Program analysis. AB - BACKGROUND: Postoperative pulmonary complications (PPCs) after major abdominal surgery are common and associated with significant morbidity and high cost of care. The objective of this study was to identify the risk factors for PPCs after major abdominal surgery. MATERIALS AND METHODS: The American College of Surgeons' National Surgical Quality Improvement Program database from 2005-2012 was queried for patients who underwent major abdominal surgery (esophagectomy, gastrectomy, pacnreatectomy, enterectomy, hepatectomy, colectomy, and proctectomy). Predictors of PPCs were identified using multivariate logistic regression. RESULTS: Of 165,196 patients who underwent major abdominal surgery 9595 (5.8%) suffered PPCs (pneumonia 3.2%, prolonged ventilator support >=48 h 3.0%, and unplanned intubation 2.8%). On multivariate analysis, significant predictors of overall and individual PPCs include esophagectomy, advanced American Society of Anesthesiology Classification System, dependent functional status, prolonged operative time, age >=80 y, severe chronic obstructive pulmonary disease, preoperative shock, ascites, and smoking. Obesity was not a risk factor. Female gender was overall protective for PPCs. CONCLUSIONS: PPCs after abdominal procedures are associated with a number of clinical variables. Esophageal operations and American Society of Anesthesiology Classification System were the strongest predictors. These results provide a framework for identifying patients at risk for developing pulmonary complications after major abdominal surgery. PMID- 25930171 TI - Sweep frequency impedance measures in Australian Aboriginal and Caucasian neonates. AB - OBJECTIVE: Despite high prevalence of otitis media in Aboriginal children, the acoustic-mechanical properties of their outer and middle ear during the neonatal period remain obscured. The objective of this study was to compare the acoustic mechanical properties of outer and middle ear using Sweep Frequency Impedance (SFI) measures between Australian Aboriginal and Caucasian neonates. METHODS: SFI data from 40 ears of 24 Aboriginal neonates (16 males, 8 females) with mean gestational age of 39.57 weeks (SD = 1.25) and 160 ears of 119 Caucasian neonates (57 males, 62 females) with mean gestational age of 39.28 weeks (SD = 1.25) serving as controls were analysed. SFI data in terms of resonance frequency (RF) and mobility of the outer and middle ear (DeltaSPL) were collected from neonates who passed a test battery that included automated auditory brainstem response, distortion product otoacoustic emissions test and 1000-Hz tympanometry. SFI data were analysed using descriptive statistics and analysis of variance. RESULTS: There was no significant difference in mean gestational age, age of testing and birth weight between the Aboriginal and Caucasian neonates. The mean resonance frequencies for the outer ear (mean RF1 = 264.9 Hz, SD = 58.6 Hz) and middle ear (mean RF2 = 1144 Hz, SD = 228.8 Hz) for Aboriginal neonates were significantly lower than that of Caucasian neonates (mean RF1 = 295.3 Hz, SD = 78.4 Hz and mean RF2 = 1241.8 Hz, SD = 216.6 Hz). However, no significant difference in the mobility of outer ear (DeltaSPL1) and middle ear (DeltaSPL2) between the two groups was found. Middle ear resonance was absent in 22.5% (9 ears) of Aboriginal ears but present in all Caucasian ears. CONCLUSIONS: This study provided evidence that despite passing the test battery, Aboriginal neonates had significantly lower resonance frequencies of the outer and middle ear than Caucasian neonates. Furthermore, 22.5% of Aboriginal neonates showed no middle ear resonance, indicating the possibility of subtle middle ear issues not detected by the test battery. Reasons for the different acoustic-mechanical properties between the two ethnic groups remain unclear and require further investigation. PMID- 25930172 TI - Novel mutation located in EC7 domain of protocadherin-15 uncovered by targeted massively parallel sequencing in a family segregating non-syndromic deafness DFNB23. AB - OBJECTIVE: Hereditary hearing loss is a clinically and genetically heterogeneous disorder associated with mutations of a large number of diverse genes. In this study we applied targeted capture and massively parallel sequencing to identify the disease-causing gene of a Chinese family segregating recessive inherited deafness. METHODS: After excluding mutations in common deafness genes GJB2, SLC26A4, mitochondrial m.1555A>G, genomic DNA of the proband of family GDSW24 was subjected to targeted next-generation sequencing. Subsequently, a candidate homozygous mutation was confirmed by Sanger sequencing. RESULTS: A novel PCDH15 c.2367_2369delTGT/p.V788-homozygous mutation was detected. In this family, no obvious vestibular disorder was found. The in-frame mutation c.2367_2369delTGT is located in the evolutionarily conserved EC7 domain of Protocadherin-15 and was predicted to be pathogenic. CONCLUSION: The novel homozygous mutation in a family segregating non-syndromic hearing loss family supports previous reported observations that PCDH15 does not only causes Usher syndrome type 1F, but also DFNB23. PMID- 25930173 TI - Surgery or implantable hearing devices in children with congenital aural atresia: 25 years of our experience. AB - OBJECTIVES: Congenital aural atresia and ear deformities have been the subject of serious discussions for centuries. These malformations are associated with significant aesthetic and functional problems. Outcome of the surgical solution is rarely optimal. Despite the gradual improvement of surgical techniques the surgery still remains associated with very limited short-term and mainly long term functional outcome. Therefore, the priority treatment in modern otology becomes implantable devices--BAHA, Bonebridge and active middle ear implants. METHODS: The functional and aesthetic outcomes of aural atresia reconstruction performed at Pediatric ENT Department of Children's University Hospital were retrospectively evaluated and compared with the results prospectively obtained from implantable hearing devices (BAHA, Vibrant Soundbridge, Bonebridge), which have been implanted in patients with aural atresia at Department of ORL HNS, University Hospital Bratislava. RESULTS: Aural atresia reconstruction has been performed in 34 patients during last 25 years. Results of the surgery could be viewed as excellent only in three patients (gain above 30 dB). Air conduction threshold has decreased after the surgery in seven patients, and in two cases total deafness occurred after the surgery. Patients gain on average 12 dB in auditory threshold after surgery. Hearing devices were implanted to the group of 11 children in order to improve their hearing. All of them were the patients with bilateral aural atresia. After implantation a significant improvement in hearing threshold occurred in all children (30-35 dB on average). Together with results of air conduction threshold in patient with aural atresia before and after surgery and implantation we also present a standard deviation. CONCLUSION: The functional outcome of implantable hearing devices in patients with bilateral aural atresia clearly dominates over the traditional reconstructive surgery. Aesthetic results in pinna deformity management remain a major concern for patients and parents. Implantable epithesis bring promising results. Since there is no universal solution to this disorder, the final selection of the treatment is upon the patient. Patients should opt for the most suitable solution through consultation with the surgeon, after clarifying the advantages and disadvantages of each option. PMID- 25930174 TI - Haemophilia A carriers experience reduced health-related quality of life. AB - INTRODUCTION: Haemophilia A is an X-linked recessive bleeding disorder that primarily affects males. Emerging data support evidence for increased bleeding in female haemophilia A carriers despite factor VIII activity within the normal range. AIM: Data regarding the effect of increased bleeding on health-related quality of life (HR-QOL) in haemophilia A carriers is sparse. We tested the hypothesis that haemophilia A carriers have reduced HR-QOL related to bleeding symptoms. METHODS: We conducted a cross-sectional study at Vanderbilt University. Case subjects were obligate or genetically verified haemophilia A carriers age 18 60 years. Control subjects were mothers of children with cancer who receive care at the Vanderbilt paediatric haematology-oncology clinic. Trained interviewers administered the Rand 36-Item Health Survey 1.0, a validated questionnaire evaluating eight health concepts that may affect HR-QOL, to each study participant. Mann-Whitney U-tests were used to compare median scores for the eight health domains between the case and control groups. RESULT: Forty-two haemophilia A carriers and 36 control subjects were included in analyses. Haemophilia A carriers had significantly lower median scores for the domains of 'Pain' (73.75 vs. 90; P = 0.02) and 'General health' (75 vs. 85; P = 0.01) compared to control subjects. CONCLUSION: Haemophilia A carriers in our study demonstrated significantly lower median scores on the Rand 36-item Health Survey 1.0 in the domains of 'Pain' and 'General Health' compared to women in the control group. Our findings highlight the need for further investigation of the effect of bleeding on HR-QOL in this population. PMID- 25930175 TI - Differential effects of stress-induced cortisol responses on recollection and familiarity-based recognition memory. AB - Stress-induced changes in cortisol can impact memory in various ways. However, the precise relationship between cortisol and recognition memory is still poorly understood. For instance, there is reason to believe that stress could differentially affect recollection-based memory, which depends on the hippocampus, and familiarity-based recognition, which can be supported by neocortical areas alone. Accordingly, in the current study we examined the effects of stress-related changes in cortisol on the processes underlying recognition memory. Stress was induced with a cold-pressor test after incidental encoding of emotional and neutral pictures, and recollection and familiarity based recognition memory were measured one day later. The relationship between stress-induced cortisol responses and recollection was non-monotonic, such that subjects with moderate stress-related increases in cortisol had the highest levels of recollection. In contrast, stress-related cortisol responses were linearly related to increases in familiarity. In addition, measures of cortisol taken at the onset of the experiment showed that individuals with higher levels of pre-learning cortisol had lower levels of both recollection and familiarity. The results are consistent with the proposition that hippocampal-dependent memory processes such as recollection function optimally under moderate levels of stress, whereas more cortically-based processes such as familiarity are enhanced even with higher levels of stress. These results indicate that whether post encoding stress improves or disrupts recognition memory depends on the specific memory process examined as well as the magnitude of the stress-induced cortisol response. PMID- 25930176 TI - Functional analysis of problem behavior: A systematic approach for identifying idiosyncratic variables. AB - When inconclusive functional analysis (FA) outcomes occur, a number of modifications have been made to enhance the putative establishing operation or consequence associated with behavioral maintenance. However, a systematic method for identifying relevant events to test during modified FAs has not been evaluated. The purpose of this study was to develop and evaluate a technology for systematically identifying events to test in a modified FA after an initial FA led to inconclusive outcomes. Six individuals, whose initial FA showed little or no responding or high levels only in the control condition, participated. An indirect assessment (IA) questionnaire developed for identifying idiosyncratic variables was administered, and a descriptive analysis (DA) was conducted. Results from the IA only or a combination of the IA and DA were used to inform modified FA test and control conditions. Conclusive FA outcomes were obtained with 5 of the 6 participants during the modified FA phase. PMID- 25930177 TI - A matching pursuit algorithm for inferring tonic sympathetic arousal from spontaneous skin conductance fluctuations. AB - Tonic sympathetic arousal is often inferred from spontaneous fluctuations in skin conductance, and this relies on assumptions about the shape of these fluctuations and how they are generated. We have previously furnished a psychophysiological model for this relation, and an efficient and reliable inversion method to estimate tonic arousal from given data in the framework of dynamic causal modeling (DCM). Here, we provide a fast alternative inversion method in the form of a matching pursuit (MP) algorithm. Analyzing simulated data, this algorithm approximates the true underlying arousal up to about 10 spontaneous fluctuations per minute of data. For empirical data, we assess predictive validity as the ability to differentiate two known psychological arousal states. Predictive validity is comparable between the methods for three datasets, and also comparable to visual peak scoring. Computation time of the MP algorithm is 2-3 orders of magnitude faster for the MP than the DCM algorithm. In summary, the new MP algorithm provides a fast and reliable alternative to DCM inversion for SF data, in particular when the expected number of fluctuations is lower than 10 per minute, as in typical experimental situations. PMID- 25930178 TI - Evidence for enhanced oxygen surface exchange reaction in nanostructured Gd2O3 doped CeO2 films. AB - The effect of microstructure of Gd2O3-doped CeO2 (GDC) films on oxygen surface exchange and diffusion is reported. Epitaxial GDC (10 mol% Gd) films up to 1 MUm in thickness are prepared using pulsed laser deposition on (100) yttria stabilized zirconia single-crystal substrates and subjected to high-temperature annealing at 1300 degrees C in air to induce microstructural modifications. Characterization using atomic force microscopy and transmission electron microscopy reveals granular morphologies comprised of densely packed columnar nanostructures for the as-grown GDC films; however, significant microstructural reconstruction of the entire GDC layer occurs after high-temperature annealing. (18)O isotope exchange depth profiling with dynamic secondary ion mass spectroscopy is employed to evaluate the oxygen surface exchange coefficient k* and the diffusion coefficient D* at T = 600 degrees C. The as-grown GDC exhibits up to 10 times higher k* than the annealed film. The strong differences in oxygen surface reaction are correlated to the observed film properties including surface microstructure and cerium oxidation state as evaluated using electron energy loss spectroscopy in scanning transmission electron microscopy. PMID- 25930179 TI - [Prolapse of the upper lacrimal punctum]. PMID- 25930180 TI - [Progressive scotoma with perception of photopsia]. AB - Acute annular outer retinopathy (AAOR) is a very rare variant of acute zonal occult outer retinopathy (AZOOR). Both variants are characterized by the perception of a progressive visual field defect and can be accompanied by photopsia. In contrast to AZOOR, a progressive whitish and annular demarcation of the involved retina is observed in AAOR using ophthalmoscopy. Optical coherence tomography (OCT) reveals morphological changes predominantly in the outer retinal layers. Although there is no proof of an effective therapy, in the case presented here further progression could be stopped by a combination of antiviral and immunosuppressive therapy. PMID- 25930181 TI - [In Process Citation]. PMID- 25930183 TI - [Chronic bilateral orbital tumors in IgG4-related disease]. AB - BACKGROUND: The IgG4-related disease describes a new multisystem disorder, which can also be manifested in the orbit. This syndrome is characterized by a multifocal chronic fibroinflammation with high levels of plasma cells expressing IgG4. CASE REPORT: This article reports the case of a patient with advanced bilateral tumors of the upper eyelid and orbit. The diagnosis of IgG4-related disease was only revealed after many years and after many biopsies of the tumors had been carried out. The initiation of a systemic steroid therapy led to a rapid reduction of the tumors and an improvement in the general condition of the patient. PMID- 25930182 TI - [Functional disorders in the chronological progression of glaucoma]. AB - BACKGROUND: Glaucomatous optic neuropathy is a complex process, which not only leads to destruction of the retinal ganglion cells but also negatively influences the third and fourth neurons. Therefore, in histological studies of glaucoma a significant cell loss in both the lateral geniculate nucleus and in the visual cortex could be detected. OBJECTIVE: The involvement of the entire visual pathway in glaucoma leads to a variety of functional disturbances, which are presented in this overview. RESULTS: Besides the well-known visual field defects in glaucomatous optic neuropathy, additional disturbances occur in contrast sensitivity, color vision, stereo vision and increased sensitivity to glare. As a result, faces are less easily recognized , the reading speed is reduced, the location of objects is more complicated and the reaction rate decreases. All these alterations are increased with the progression of glaucomatous damage. DISCUSSION: The consequences of these visual impairments lead to an increasing social isolation and to an increased risk of falls and driving accidents, thereby significantly reducing the quality of life of glaucoma patients. Therefore, increasing awareness of these visual difficulties is necessary in the special care of patients with glaucoma and the domestic environment should be transformed accordingly. PMID- 25930184 TI - STAT3 inhibition reduces toxicity of oncolytic VSV and provides a potentially synergistic combination therapy for hepatocellular carcinoma. AB - Hepatocellular carcinoma (HCC) is a refractory malignancy with a high mortality and increasing worldwide incidence rates, including the United States and central Europe. In this study, we demonstrate that a specific inhibitor of signal transducer and activator of transcription 3 (STAT3), NSC74859, efficiently reduces HCC cell proliferation and can be successfully combined with oncolytic virotherapy using vesicular stomatitis virus (VSV). The potential benefits of this combination treatment are strengthened by the ability of NSC74859 to protect primary hepatocytes and nervous system cells against virus-induced cytotoxicity, with an elevation of the VSV maximum tolerated dose in mice. Hereby we propose a strategy for improving the current regimen for HCC treatment and seek to further explore the molecular mechanisms underlying selective oncolytic specificity of VSV. PMID- 25930185 TI - Metastasectomy for metachronous pulmonary and hepatic metastases from nasopharyngeal carcinoma: Report of 6 cases and review of the literature. AB - BACKGROUND: Metastatic nasopharyngeal carcinoma (NPC) is commonly treated with palliative chemotherapy. The purpose of this study was to review the feasibility of metastasectomy for metachronous pulmonary and hepatic metastases from NPC. METHODS: We present 6 patients who developed metachronous metastases from NPC (4 patients with pulmonary metastases and 2 patients with hepatic metastases) and underwent curative resection. RESULTS: Four patients are still alive with no recurrence of NPC after metastasectomy. Two patients died with postoperative survival periods of 57 and 70 months and recurrence-free intervals of 14 and 39 months, respectively. CONCLUSION: Metastasectomy is a feasible option for the treatment of metachronous and resectable oligometastatic NPC to the lung and liver. Application of appropriate selection criteria would be required. PMID- 25930186 TI - Pathogenesis of amoebic encephalitis: Are the amoebae being credited to an 'inside job' done by the host immune response? AB - Pathogenic free living amoeba like Naegleria fowleri, Acanthamoeba spp., and Balamuthia mandrillaris are known to cause fatal "amoebic meningoencephalitis" by acquiring different route of entries to the brain. The host immune response to these protist pathogens differs from each another, as evidenced by the postmortem gross and microscopic findings from the brains of the affected patients. Cited with the expression of 'brain eating amoeba' when the infection is caused by N. fowleri, this expression is making its way into parasitology journals and books. The impression that it imparts is, as if the brain damage is substantially due to the enzymes and toxins produced by this amoeba. A detailed review of the literature, analysis of archived specimens and with our experimental assays, here we establish that with N. fowleri, Acanthamoeba and Balamuthia spp., the infections result in an extensive brain damage that in fact is substantially caused by the host immune response rather than the amoeba. Due to the comparatively larger sizes of these pathogens and the prior exposure of the amoebal antigen to the human body, the host immune system launches an amplified response that not only breaches the blood brain barrier (BBB), but also becomes the major cause of brain damage in Amoebic meningoencephalitis. It is our understanding that for N. fowleri the host immune response is dominated by acute inflammatory cytokines and that, in cases of Acanthamoeba and Balamuthia spp., it is the type IV hypersensitivity reaction that fundamentally not only contributes to disruption and leakiness of the blood brain barrier (BBB) but also causes the neuronal damage. The further intensification of brain damage is done by toxins and enzymes secreted by the amoeba, which causes the irreversible brain damage. PMID- 25930187 TI - Molecular phylogeography of Angiostrongylus cantonensis (Nematoda: Angiostrongylidae) and genetic relationships with congeners using cytochrome b gene marker. AB - Angiostrongylus cantonensis is an important emerging zoonotic parasite causing human eosinophilic meningitis (or meningoencephalitis) in many parts of the world. To-date there is only a single study using mitochondrial cytochrome b (CYTB) gene to determine its genetic structure in eight geographical localities in Thailand. The present study examined the molecular phylogeography of this rat lungworm and its phylogenetic relationship with congeners using CYTB gene marker. A total of 15 CYTB haplotypes was found in 37 sequences from 14 geographical localities (covering north, west, east, central and south regions) in Thailand. These CYTB haplotypes were distinct from those of A. cantonensis for China and Hawaii. In Thailand, some CYTB haplotypes appeared to be confined to specific geographical localities. The partial CYTB DNA nucleotide sequences separated unequivocally the A. cantonensis isolates of Thailand, China and Hawaii as well as the congeners Angiostrongylus malaysiensis, A. costaricensis and Angiostrongylus vasorum, with A. malaysiensis grouped with A. cantonensis and A. costaricensis grouped with A. vasorum. Likewise the congeners of Metastrongylus and Onchocerca genera could also be clearly differentiated. The present study added two new definitive hosts (Bandicota savilei and Rattus losea) and three new localities (Mae Hong Son in the north, Tak in the west, and Phang Nga in the south) for A. malaysiensis in Thailand, indicating its wide occurrence in the country. Three CYTB haplotypes were found in the Thailand samples of A. malaysiensis. In addition to differentiation of congeners, CYTB gene marker could be used for determining the genetic diversity of a given population/taxon. PMID- 25930188 TI - Species composition of phlebotomine sand fly fauna in an area with sporadic cases of Leishmania infantum human visceral leishmaniasis, Morocco. AB - Visceral and cutaneous leishmaniases are the main endemic vector-born diseases in Morocco. Human visceral leishmaniasis (HVL), by Leishmania infantum, currently presents a significant health problem throughout the country and may constitute factor for death, especially among children with less than 15 years old. In the past, HVL has been basically absent or at least sporadic in Marrakesh-Tensift-Al Haouz region; however it became significant during the last decade. An entomological survey and a retrospective study on L. infantum HVL cases had been carried out to assess the risk of the disease apparition in this region. 7046 sand flies (Diptera: Psychodidae) were collected and studied from twelve localities within Marrakesh-Tensift-Al Haouz region. The result shows the presence of ten sand fly species, 58.76% from the genus Phlebotomus and 41.24% from genus Sergentomyia. A further analysis indicates that Phlebotomus perniciosus, Phlebotomus longicuspis and Phlebotomus ariasi species, incriminated vectors of L. infantum, are dominant (35.56%), so, we describe their spatial (according to altitude and biotopes) and temporal (seasonal activity) distribution in study area. PMID- 25930189 TI - Sensitivity improvement of kukoamine determination by complexation with dihydrogen phosphate anions in capillary zone electrophoresis. AB - A novel complexation between kukoamines and dihydrogen phosphate ions (DPI) during CZE was discovered to improve the UV signal of kukoamine by around 30 fold. This complexation formed by electric current was attributed to the hydrogen bonding of hydroxyl and amino (or amide) groups between the analyte and electrolyte anions. The established CZE method is low-cost, easy to operate, and eco-friendly, and it was shown to be superior to HPLC in terms of separation capability, efficiency, specificity, and sensitivity. We believe that our CZE method can be applied as an alternative to HPLC for kukoamine assay. The approach described here can be also extended for analyzing other compounds with similar functional groups. PMID- 25930190 TI - Breath-Holding During Exhalation as a Simple Manipulation to Reduce Pain Perception. AB - OBJECTIVE: Baroreceptor stimulation yields antinociceptive effects. In this study, baroreceptors were stimulated by a respiratory maneuver, with the effect of this manipulation on pain perception subsequently measured. METHODS: Thirty eight healthy participants were instructed to inhale slowly (control condition) and to hold the air in lungs after a deep inhalation (experimental condition). It was expected that breath-holding would increases blood pressure (BP) and thus stimulate the baroreceptors, which in turn would reduce pain perception. Pain was induced by pressure algometry on the nail of the left-index finger, at three different pressure intensities, and quantified by visual analogue scales. Heart rate (HR) and BP were continuously recorded. RESULTS: Pain perception was lower when pain pressure was administered during the breath-holding phase versus the slow inhalation phase, regardless of the pressure intensity. During breath holding, a rapid increase in BP and decrease in HR were observed, demonstrating activation of the baroreceptor reflex. CONCLUSION: Pain perception is reduced when painful stimulation is applied during breath-holding immediately following a deep inhalation. These results suggest that a simple and easy-to-perform respiratory maneuver could be used to reduce acute pain perception. PMID- 25930191 TI - Polymorphisms related to ORMDL3 are associated with asthma susceptibility, alterations in transcriptional regulation of ORMDL3, and changes in TH2 cytokine levels. AB - BACKGROUND: Chromosome 17q21, harboring the orosomucoid 1-like 3 (ORMDL3) gene, has been consistently associated with childhood asthma in genome-wide association studies. OBJECTIVE: We investigated genetic variants in and around ORMDL3 that can change the function of ORMDL3 and thus contribute to asthma susceptibility. METHODS: We performed haplotype analyses and fine mapping of the ORMDL3 locus in a cross-sectional (International Study of Asthma and Allergies in Childhood Phase II, n = 3557 total subjects, n = 281 asthmatic patients) and case-control (Multicenter Asthma Genetics in Childhood Study/International Study of Asthma and Allergies in Childhood Phase II, n = 1446 total subjects, n = 763 asthmatic patients) data set to identify putative causal single nucleotide polymorphisms (SNPs) in the locus. Top asthma-associated polymorphisms were analyzed for allele specific effects on transcription factor binding and promoter activity in vitro and gene expression in PBMCs after stimulation ex vivo. RESULTS: Two haplotypes (H1 and H2) were significantly associated with asthma in the cross-sectional (P = 9.9 * 10(-5) and P = .0035, respectively) and case-control (P = 3.15 * 10(-8) and P = .0021, respectively) populations. Polymorphisms rs8076131 and rs4065275 were identified to drive these effects. For rs4065275, a quantitative difference in transcription factor binding was found, whereas for rs8076131, changes in upstream stimulatory factor 1 and 2 transcription factor binding were observed in vitro by using different cell lines and PBMCs. This might contribute to detected alterations in luciferase activity paralleled with changes in ORMDL3 gene expression and IL-4 and IL-13 cytokine levels ex vivo in response to innate and adaptive stimuli in an allele-specific manner. Both SNPs were in strong linkage disequilibrium with asthma-associated 17q21 SNPs previously related to altered ORMDL3 gene expression. CONCLUSION: Polymorphisms in a putative promoter region of ORMDL3, which are associated with childhood asthma, alter transcriptional regulation of ORMDL3, correlate with changes in TH2 cytokines levels, and therefore might contribute to the childhood asthma susceptibility signal from 17q21. PMID- 25930192 TI - Changes in peanut-specific T-cell clonotype with oral immunotherapy. PMID- 25930193 TI - Allergen-induced IL-6 trans-signaling activates gammadelta T cells to promote type 2 and type 17 airway inflammation. AB - BACKGROUND: A variant in the IL-6 receptor (IL-6R) gene increases asthma risk and is predicted to decrease IL-6 classic signaling and increase IL-6 trans signaling. This suggests that inhibition of IL-6 trans-signaling, but not classic signaling, might suppress allergic airway inflammation. OBJECTIVES: We sought to determine whether IL-6 signaling contributes to (1) acute experimental asthma induced by clinically relevant allergens and (2) variation in asthma clinical phenotypes in asthmatic patients. METHODS: Mice were sensitized to house dust mite (HDM) or cockroach at day 0, treated with IL-6R inhibitors at day 13, and challenged with the same allergen at days 14 to 17. End points were measured 3 hours after the final challenge. IL-6 and soluble IL-6 receptor (sIL-6R) expression in induced sputum of asthmatic patients was correlated with asthma clinical phenotypes. RESULTS: Both HDM and cockroach induced a type 2/type 17 cytokine profile and mixed granulocytic inflammation in the airways. Both allergens increased IL-6 expression in the airways, but only cockroach induced sIL-6R expression. Therefore HDM challenge promoted IL-6 classic signaling but not trans-signaling; in this model treatment with anti-IL-6R did not suppress airway inflammation. In contrast, cockroach-induced inflammation involved activation of IL-6 trans-signaling and production of IL-17A by gammadelta T cells. Anti-IL-6R, selective blockade of sIL-6R, or gammadelta T-cell deficiency significantly attenuated cockroach-induced inflammation. Asthmatic patients with high airway IL-6 and sIL-6R levels were enriched for the neutrophilic and mixed granulocytic subtypes. CONCLUSION: Experimental asthma associated with both high IL-6 and high sIL-6R levels in the airways is attenuated by treatment with IL-6R inhibitors. PMID- 25930194 TI - Monoclonal antibodies in excess: A simple way to avoid immunogenicity in patients? PMID- 25930195 TI - Analysis of glutathione S-transferase allergen cross-reactivity in a North American population: Relevance for molecular diagnosis. AB - BACKGROUND: It is not clear whether cross-reactivity or cosensitization to glutathione S-transferases (GSTs) occurs in tropical and subtropical environments. In the United States, Bla g 5 is the most important GST allergen and lack of coexposure to GSTs from certain species allows a better assessment of cross-reactivity. OBJECTIVES: To examine the molecular structure of GST allergens from cockroach (Bla g 5), dust mites (Der p 8 and Blo t 8), and helminth (Asc s 13) for potential cross-reactive sites, and to assess the IgE cross-reactivity of sensitized patients from a temperate climate for these allergens for molecular diagnostic purposes. METHODS: Four crystal structures were determined. Sera from patients allergic to cockroach and mite were tested for IgE reactivity to these GSTs. A panel of 6 murine anti-Bla g 5 mAb was assessed for cross-reactivity with the other 3 GSTs using antibody binding assays. RESULTS: Comparisons of the allergen structures, formed by 2-domain monomers that dimerize, revealed few contiguous regions of similar exposed residues, rendering cross-reactivity unlikely. Accordingly, anti-Bla g 5 or anti-Der p 8 IgE from North American patients did not recognize Der p 8 or Bla g 5, respectively, and neither showed binding to Blo t 8 or Asc s 13. A weaker binding of anti-Bla g 5 IgE to Der p 8 versus Bla g 5 (~ 100-fold) was observed by inhibition assays, similar to a weak recognition of Der p 8 by anti-Bla g 5 mAb. Patients from tropical Colombia had IgE to all 4 GSTs. CONCLUSIONS: The lack of significant IgE cross-reactivity among the 4 GSTs is in agreement with the low shared amino acid identity at the molecular surface. Each GST is needed for accurate molecular diagnosis in different geographic areas. PMID- 25930196 TI - IgE-mediated hypersensitivity to cephalosporins: Cross-reactivity and tolerability of alternative cephalosporins. AB - BACKGROUND: Studies regarding the cross-reactivity and tolerability of alternative cephalosporins in large samples of subjects with an IgE-mediated hypersensitivity to cephalosporins are lacking. OBJECTIVE: We sought to evaluate the possibility of using alternative cephalosporins in subjects with cephalosporin allergy who especially require them. METHODS: One hundred two subjects with immediate reactions to cephalosporins and positive skin test results to the responsible drugs underwent serum specific IgE assays with cefaclor and skin tests with different cephalosporins. Subjects were classified in 4 groups: group A, positive responses to 1 or more of ceftriaxone, cefuroxime, cefotaxime, cefepime, cefodizime, and ceftazidime; group B, positive responses to aminocephalosporins; group C, positive responses to cephalosporins other than those belonging to the aforementioned groups; and group D, positive responses to cephalosporins belonging to 2 different groups. Group A subjects underwent challenges with cefaclor, cefazolin, and ceftibuten; group B participants underwent challenges with cefuroxime axetil, ceftriaxone, cefazolin, and ceftibuten; and group C and D subjects underwent challenges with some of the aforementioned cephalosporins selected on the basis of their patterns of positivity. RESULTS: There were 73 subjects in group A, 13 in group B, 7 in group C, and 9 in group D. Challenges with alternative cephalosporins (ceftibuten in 101, cefazolin in 96, cefaclor in 82, and cefuroxime axetil and ceftriaxone in 22 subjects) were well tolerated. CONCLUSIONS: Cephalosporin hypersensitivity does not seem to be a class hypersensitivity. Subjects with cephalosporin allergy who especially require alternative cephalosporins might be treated with compounds that have side-chain determinants different from those of the responsible cephalosporins and have negative pretreatment skin test responses. PMID- 25930199 TI - Drug interactions in cancer patients receiving antidepressants are common, researchers report. PMID- 25930197 TI - Pulmonary receptor for advanced glycation end-products promotes asthma pathogenesis through IL-33 and accumulation of group 2 innate lymphoid cells. AB - BACKGROUND: Single nucleotide polymorphisms in the human gene for the receptor for advanced glycation end-products (RAGE) are associated with an increased incidence of asthma. RAGE is highly expressed in the lung and has been reported to play a vital role in the pathogenesis of murine models of asthma/allergic airway inflammation (AAI) by promoting expression of the type 2 cytokines IL-5 and IL-13. IL-5 and IL-13 are prominently secreted by group 2 innate lymphoid cells (ILC2s), which are stimulated by the proallergic cytokine IL-33. OBJECTIVE: We sought to test the hypothesis that pulmonary RAGE is necessary for allergen induced ILC2 accumulation in the lung. METHODS: AAI was induced in wild-type and RAGE knockout mice by using IL-33, house dust mite extract, or Alternaria alternata extract. RAGE's lung-specific role in type 2 responses was explored with bone marrow chimeras and induction of gastrointestinal type 2 immune responses. RESULTS: RAGE was found to drive AAI by promoting IL-33 expression in response to allergen and by coordinating the inflammatory response downstream of IL-33. Absence of RAGE impedes pulmonary accumulation of ILC2s in models of AAI. Bone marrow chimera studies suggest that pulmonary parenchymal, but not hematopoietic, RAGE has a central role in promoting AAI. In contrast to the lung, the absence of RAGE does not affect IL-33-induced ILC2 influx in the spleen, type 2 cytokine production in the peritoneum, or mucus hypersecretion in the gastrointestinal tract. CONCLUSIONS: For the first time, this study demonstrates that a parenchymal factor, RAGE, mediates lung-specific accumulation of ILC2s. PMID- 25930198 TI - Mild B-cell lymphocytosis in patients with a CARD11 C49Y mutation. PMID- 25930200 TI - The Impact of Interpersonal Style and Interpersonal Complementarity on the Therapeutic Alliance Between Therapists and Offenders in Sex Offender Treatment. AB - Therapist and treatment process variables affect the effectiveness of offender rehabilitation programs. This study examined the influence of therapists' and offenders' interpersonal styles (IPSs) and interpersonal complementarity on therapeutic alliance (TA). Seventy-five sex offenders and their therapists evaluated each other's IPSs and the TA after 3 weeks of treatment. Offenders evaluated the TA more positively than therapists. Regarding the impact of IPS, therapist affiliation was positively correlated and therapist control was negatively correlated with offenders' ratings of the TA; in other words, offenders evaluated the TA more strongly when therapists were perceived as affiliative, and weaker when therapists were viewed as controlling. Offender affiliation was positively correlated with therapists' ratings of TA; in other words, therapists evaluated the TA more strongly when offenders were viewed as more affiliative; perceptions of offender control were unrelated to offenders' ratings of TA. Complementarity in IPS between offenders and therapists did not affect TA. PMID- 25930201 TI - Primary Prevention of Sexual Violence in Aotearoa New Zealand. AB - The extensive and sometimes profoundly damaging effects of sexual violence and large numbers of victims necessitate dedicated attention to primary prevention efforts. Few studies have examined the scope of current prevention activities or their fit with empirical research into effective prevention strategies. The current article presents findings from a survey of primary prevention activities in non-Maori and bicultural communities within Aotearoa New Zealand. Forty-four respondents representing 42 agencies responded to a comprehensive survey that canvased types of sexual violence primary prevention activities undertaken, sexual violence primary prevention programs, and barriers and supports to sexual violence prevention work. Consistent with findings from previous international surveys, the focus of primary prevention work in New Zealand was on sexual violence education and increasing awareness. Findings are discussed in the context of the sexual violence prevention literature and what works in prevention more broadly to help identify promising initiatives as well as gaps in current practices. Recommendations for advancing sexual violence primary prevention research are also provided. PMID- 25930202 TI - Childhood Sexual Abuse, Attachments in Childhood and Adulthood, and Coercive Sexual Behaviors in Community Males. AB - Associations between self-reported coercive sexual behavior against adult females, childhood sexual abuse (CSA), and child-parent attachment styles, as well as attachment with adult romantic partners, were examined among 176 adult community males. Attachment style with each parent and with romantic partners was also investigated as a potential moderator. Using hierarchical multiple regression analysis, avoidant attachment with mothers in childhood (and also with fathers, in a second model) accounted for a significant amount of the variance in coercive sexual behavior controlling for scores on anxious ambivalent and disorganized/disoriented attachment scales, as predicted. Similarly, in a third model, avoidance attachment in adulthood was a significant predictor of coercive sexual behavior controlling for scores on the anxiety attachment in adulthood scale. These main effects for avoidant and avoidance attachment were not statistically significant when CSA and control variables (other types of childhood adversity, aggression, antisociality, and response bias) were added in each of the models. But the interaction between scales for CSA and avoidance attachment in adulthood was significant, demonstrating incremental validity in a final step, consistent with a hypothesized moderating function for attachment in adulthood. The correlation between CSA and coercive sexual behavior was .60 for those with the highest third of avoidance attachment scores (i.e., the most insecurely attached on this scale), .24 for those with scores in the middle range on the scale, and .01 for those with the lowest third of avoidance attachment scores (i.e., the most securely attached). Implications for study design and theory were discussed. PMID- 25930203 TI - Bacterial Community Diversity in Soil Under two Tillage Practices as Determined by Pyrosequencing. AB - The ability of soil to provide ecosystem services is dependent on microbial diversity, with 80-90 % of the processes in soil being mediated by microbes. There still exists a knowledge gap in the types of microorganisms present in soil and how soil management affects them. However, identification of microorganisms is severely limited by classical culturing techniques that have been traditionally used in laboratories. Metagenomic approaches are increasingly becoming common, with current high-throughput sequencing approaches allowing for more in-depth analysis. We conducted a preliminary analysis of bacterial diversity in soils from the longest continuously maintained no-till (NT) plots in the world (52 years) and in adjacent plow-till (PT) plots in Ohio, USA managed similarly except for tillage. Bacterial diversity was determined using a culture independent approach of high-throughput pyrosequencing of the 16S rRNA gene. Proteobacteria and Acidobacteria were predominant in both samples but the NT soil had a higher number of reads, bacterial richness, and five unique phyla. Four unique phyla were observed in PT and 99 % of the community had relative abundance of <1 %. Plowing and secondary tillage tend to homogenize the soil and reduces the unique (i.e., diverse) microenvironments where microbial populations can reside. We conclude that tillage leads to fewer dominant species being present in soil and that these species contribute to a higher percentage of the total community. PMID- 25930205 TI - Mapping aboveground woody biomass using forest inventory, remote sensing and geostatistical techniques. AB - Mapping forest biomass is fundamental for estimating CO2 emissions, and planning and monitoring of forests and ecosystem productivity. The present study attempted to map aboveground woody biomass (AGWB) integrating forest inventory, remote sensing and geostatistical techniques, viz., direct radiometric relationships (DRR), k-nearest neighbours (k-NN) and cokriging (CoK) and to evaluate their accuracy. A part of the Timli Forest Range of Kalsi Soil and Water Conservation Division, Uttarakhand, India was selected for the present study. Stratified random sampling was used to collect biophysical data from 36 sample plots of 0.1 ha (31.62 m * 31.62 m) size. Species-specific volumetric equations were used for calculating volume and multiplied by specific gravity to get biomass. Three forest-type density classes, viz. 10-40, 40-70 and >70% of Shorea robusta forest and four non-forest classes were delineated using on-screen visual interpretation of IRS P6 LISS-III data of December 2012. The volume in different strata of forest-type density ranged from 189.84 to 484.36 m(3) ha(-1). The total growing stock of the forest was found to be 2,024,652.88 m(3). The AGWB ranged from 143 to 421 Mgha(-1). Spectral bands and vegetation indices were used as independent variables and biomass as dependent variable for DRR, k-NN and CoK. After validation and comparison, k-NN method of Mahalanobis distance (root mean square error (RMSE) = 42.25 Mgha(-1)) was found to be the best method followed by fuzzy distance and Euclidean distance with RMSE of 44.23 and 45.13 Mgha(-1) respectively. DRR was found to be the least accurate method with RMSE of 67.17 Mgha(-1). The study highlighted the potential of integrating of forest inventory, remote sensing and geostatistical techniques for forest biomass mapping. PMID- 25930204 TI - Preconcentration and determination of lead and cadmium levels in blood samples of adolescent workers consuming smokeless tobacco products in Pakistan. AB - The present study was aimed to evaluate the cadmium (Cd) and lead (Pb) levels in the blood samples of adolescent boys, chewing different smokeless tobacco (SLT) products in Pakistan. For comparative purpose, boys of the same age group (12-15 years), not consumed any SLT products were selected as referents. To determine trace levels of Cd and Pb in blood samples, a preconcentration method, vortex assisted liquid-liquid microextraction (VLLME) has been developed, prior to analysis by flame atomic absorption spectrometry. The hydrophobic chelates of Cd and Pb with ammonium pyrrolidinedithiocarbamate were extracted into the fine droplets of ionic liquid (IL) 1-butyl-3-methylimidazolium hexafluorophosphate, while nonionic surfactant, Triton X-114 was used as a dispersing medium. The main factors affecting the recoveries of Cd and Pb, such as concentration of APDC, centrifugation time, volume of IL and TX-114, were investigated in detail. It was also observed that adolescent boys who consumed different SLT products have 2- to 3-fold higher levels of Cd and Pb in their blood samples as compared to referent boys (p < 0.001). PMID- 25930206 TI - Chlamydiae interaction with the endoplasmic reticulum: contact, function and consequences. AB - Chlamydiae and chlamydiae-related organisms are obligate intracellular bacterial pathogens. They reside in a membrane-bound compartment termed the inclusion and have evolved sophisticated mechanisms to interact with cellular organelles. This review focuses on the nature, the function(s) and the consequences of chlamydiae inclusion interaction with the endoplasmic reticulum (ER). The inclusion membrane establishes very close contact with the ER at specific sites termed ER-inclusion membrane contact sites (MCSs). These MCSs are constituted of a specific set of factors, including the C. trachomatis effector protein IncD and the host cell proteins CERT and VAPA/B. Because CERT and VAPA/B have a demonstrated role in the non-vesicular trafficking of lipids between the ER and the Golgi, it was proposed that Chlamydia establish MCSs with the ER to acquire host lipids. However, the recruitment of additional factors to ER-inclusion MCSs, such as the ER calcium sensor STIM1, may suggest additional functions unrelated to lipid acquisition. Finally, chlamydiae interaction with the ER appears to induce the ER stress response, but this response is quickly dampened by chlamydiae to promote host cell survival. PMID- 25930207 TI - A UHPLC-MS/MS bioanalytical assay for the determination of BMS-911543, a JAK2 inhibitor, in human plasma. AB - Herein we report a rapid, accurate and robust UHPLC-MS/MS assay for the quantitation of BMS-911453, a Janus kinase 2 inhibitor under clinical development for the treatment of myeloproliferative disorders, in human plasma. A systematic method development approach was used to optimize the mass spectrometry, chromatography, and sample extraction conditions, and to minimize potential bioanalytical risks. The validated method utilizes stable-isotope labeled (13)C4 BMS-911543 as the internal standard. Liquid-liquid extraction was used for sample preparation. Chromatographic separation was achieved within 2min on a Zorbax Extend-C18 column with an isocratic elution. BMS-911543 and its internal standard were detected by positive ion electrospray tandem mass spectrometry. The assay range was from 1 to 500ng/mL, and the standard curve was fitted with 1/x(2) weighted linear regression. The intra-assay precision was within 5.0% CV and the inter-assay precision was within 2.6% CV. The inter-assay mean accuracy, expressed as percents of theoretical, was between 99.8% and 102.3%. The assay has high recovery (~80%) and minimal matrix effect (0.95-1.00). BMS-911543 was stable in human plasma for at least 24h at room temperature, 90 days at -20 degrees C, and following three freeze-thaw cycles. The validated method was successfully applied to sample analysis in clinical studies. PMID- 25930208 TI - Global variation in clinical profile, management, and post-discharge outcomes among patients hospitalized for worsening chronic heart failure: findings from the ASTRONAUT trial. AB - AIMS: This study sought to investigate regional variation in clinical characteristics, therapy utilization, and post-discharge outcomes among patients hospitalized for heart failure (HHF) enrolled in the multinational ASTRONAUT (Aliskiren Trial on Acute Heart Failure Outcomes) trial. METHODS AND RESULTS: The ASTRONAUT trial randomized 1615 HHF patients with ejection fraction <=40% to aliskiren or placebo. Enrolled patients were from Eastern Europe (n = 495, 30.7%), Asia/Pacific (n = 439, 27.2%), Western Europe (n = 395, 24.5%), Latin America (n = 163, 10.1%), and North America (n = 123, 7.6%). Marked differences were seen across geographic regions in terms of baseline demographics, vital signs, laboratory tests, co-morbidity burden, and use of guideline-recommended therapies. All-cause death at 12 months ranged from 7.3% in North America to 26.7% in Asia/Pacific, with differences largely driven by sudden cardiac death. Rates of repeat HHF at 12 months ranged from 22.7% in Latin America to 43.9% in North America. After adjustment for patient characteristics, region was an independent predictor of death at 12 months, with highest risk in Asia/Pacific (hazard ratio 3.04, 95% confidence interval 1.47-6.29, compared with North America) and lowest risk in North America and Western Europe. There was no association between region and the composite of cardiovascular mortality or HHF. CONCLUSION: For patients enrolled in this HHF trial, baseline characteristics and risk of death differed markedly by geographic region. Rates of death and repeat HHF demonstrated a general inverse relationship. Global differences in patient characteristics and outcomes should be accounted for when designing future HHF clinical trials. PMID- 25930209 TI - Whole slurry saccharification and fermentation of maleic acid-pretreated rice straw for ethanol production. AB - We evaluated the feasibility of whole slurry (pretreated lignocellulose) saccharification and fermentation for producing ethanol from maleic acid pretreated rice straw. The optimized conditions for pretreatment were to treat rice straw at a high temperature (190 degrees C) with 1 % (w/v) maleic acid for a short duration (3 min ramping to 190 degrees C and 3 min holding at 190 degrees C). Enzymatic digestibility (based on theoretical glucose yield) of cellulose in the pretreated rice straw was 91.5 %. Whole slurry saccharification and fermentation of pretreated rice straw resulted in 83.2 % final yield of ethanol based on the initial quantity of glucan in untreated rice straw. These findings indicate that maleic acid pretreatment results in a high yield of ethanol from fermentation of whole slurry even without conditioning or detoxification of the slurry. Additionally, the separation of solids and liquid is not required; therefore, the economics of cellulosic ethanol fuel production are significantly improved. We also demonstrated whole slurry saccharification and fermentation of pretreated lignocellulose, which has rarely been reported. PMID- 25930210 TI - Effects of Mexican Immigrant Parents' Daily Workplace Discrimination on Child Behavior and Family Functioning. AB - This study investigated Mexican immigrant parents' reports of perceived workplace discrimination and their children's behavior, parents' moods, and parent-child interactions. Parents of one hundred and thirty-eight 3- to 5-year-old children were asked to complete one survey daily for 2 weeks (N = 1,592 days). On days when fathers perceived discrimination, fathers and mothers reported more externalizing child behaviors, and mothers reported fewer positive child behaviors. When mothers perceived discrimination, they reported more externalizing child behaviors; fathers reported more internalizing child behaviors. Parents reported worse mood on days with perceived discrimination. Perceived discrimination was not strongly related to parent-child interactions. For fathers, but less so for mothers, those whose psychological acculturation indicated separation had more negative relations between daily perceived workplace discrimination and child and family outcomes. PMID- 25930211 TI - Prevalence, injury rate and, symptom frequency in generalized joint laxity and joint hypermobility syndrome in a "healthy" college population. AB - Generalized joint hypermobility (GJH) and joint hypermobility syndrome (JHS) are gaining increased attention as potential sources of pain and injury. The aims of this study were to evaluate prevalence of GJH and JHS and to determine whether musculoskeletal injuries and symptoms commonly attributed to GJH and JHS were more common within a "healthy" college student population. The study involved a convenience sample of 267 college and graduate students, aged 17-26. GJH was assessed using the Beighton score with a cutoff of 5/9, while JHS was assessed using the Brighton criteria. Injury history and symptoms were assessed by recall. Prevalence of GJH was 26.2 % overall (females 36.7 %, males 13.7 %). Prevalence of JHS was 19.5 % overall (females 24.5 %, males 13.7 %). Injury rates were not significantly different for individuals who had GJH vs. those who did not have GJH. Individuals with JHS were significantly more likely to have had sprains, back pain, and stress fractures. Symptoms were no different between those with GJH and those who did not have GJH. However, individuals with JHS were significantly more likely to report clumsiness, easy bruising, and balance problems than those who did not have JHS. GJH and JHS were relatively common in this healthy college student population; GJH was not associated with increased incidence of injury or symptoms commonly attributed to JHS, but JHS was associated with increased incidence of some injuries and symptoms. PMID- 25930212 TI - Extremity Injury and War: A Historical Reflection. PMID- 25930213 TI - Heat-related cardiovascular mortality risk in Cyprus: a case-crossover study using a distributed lag non-linear model. AB - BACKGROUND: The frequency and intensity of heat waves is projected to increase in many parts of the world, particularly in regions such as the Eastern Mediterranean and Middle East (EMME), where the warming trends are much larger than the global average. The relationship between air temperature and premature mortality is widely recognized, however, it is not well defined in the aforementioned region. The objective of this study is to assess the relationship between cardiovascular mortality risk and air temperature in Cyprus, an island located centrally in the EMME. METHODS: Daily cardiovascular mortality data and spatially aggregated daily mean, maximum, and minimum temperatures for the period 2004-2010 were analyzed using a case-crossover design combined with a distributed lag non-linear model. RESULTS: A relationship between high temperatures and cardiovascular mortality was observed for cerebrovascular diseases, ischaemic and other heart diseases; this relationship was exacerbated on days with high temperatures. The highest relative risk was observed on the day of the heat event and remained significantly elevated for another day. The results were consistent regardless whether the minimum, maximum, or mean temperatures were used, although the association seems to be more pronounced with the mean temperatures, which suggests that consecutive high day- and night-time temperatures are the most hazardous. CONCLUSIONS: The identification of a positive relationship between high temperatures and cardiovascular mortality in Cyprus raises concerns. In view of the projected climate changes and strong increases in extreme heat events in the region, appropriate interventions need to be developed. PMID- 25930215 TI - Choline acetyltransferase in the hippocampus is associated with learning strategy preference in adult male rats. AB - One principle of the multiple memory systems hypothesis posits that the hippocampus-based and striatum-based memory systems compete for control over learning. Consistent with this notion, previous research indicates that the cholinergic system of the hippocampus plays a role in modulating the preference for a hippocampus-based place learning strategy over a striatum-based stimulus- response learning strategy. Interestingly, in the hippocampus, greater activity and higher protein levels of choline acetyltransferase (ChAT), the enzyme that synthesizes acetylcholine, are associated with better performance on hippocampus based learning and memory tasks. With this in mind, the primary aim of the current study was to determine if higher levels of ChAT and the high-affinity choline uptake transporter (CHT) in the hippocampus were associated with a preference for a hippocampus-based place learning strategy on a task that also could be solved by relying on a striatum-based stimulus--response learning strategy. Results confirmed that levels of ChAT in the dorsal region of the hippocampus were associated with a preference for a place learning strategy on a water maze task that could also be solved by adopting a stimulus-response learning strategy. Consistent with previous studies, the current results support the hypothesis that the cholinergic system of the hippocampus plays a role in balancing competition between memory systems that modulate learning strategy preference. PMID- 25930214 TI - Contraindications to anticoagulation therapy and eligibility for novel anticoagulants in older patients with atrial fibrillation. AB - AIMS: Oral anticoagulation therapy prevents stroke and improves survival in patients with atrial fibrillation, but the therapy is underutilized. We sought to identify the prevalence of contraindications for oral anticoagulation and the proportion of patients potentially eligible for different agents. METHODS: We identified patients with nonacute atrial fibrillation in a nationally representative 5% sample of 2009 Medicare data. We divided the population into patients ineligible for any oral anticoagulant, patients eligible for warfarin only, and patients eligible for any anticoagulant. We compared patient characteristics and the use of anticoagulation among the subgroups. RESULTS: Among 86,671 patients with atrial fibrillation, 1872 (2.2%) were ineligible for anticoagulation because of an absolute contraindication, most frequently a history of intracranial hemorrhage (60%). Patients ineligible for any anticoagulant were the same age as the overall group (mean age, 80.5 vs. 80.4 years). However, they had higher rates of dementia (19% vs. 8.6%) and heart failure (59% vs. 43%) and higher mean CHADS2 scores (3.8 vs. 2.8). Of the remaining 84,799 patients eligible for anticoagulation, 7146 (8.4%) were eligible for warfarin only (most commonly because of mechanical heart valves [66%] and end stage renal disease [12%]). Sixty-five percent of patients eligible for anticoagulation received warfarin, and the proportion was similar for patients with a relatively high risk of bleeding. CONCLUSIONS: Older adults with atrial fibrillation rarely have absolute contraindications to oral anticoagulation therapy. Among patients without contraindications, most appeared to be eligible for any anticoagulant, and relatively high-risk features appeared not to influence warfarin use. PMID- 25930216 TI - Spatial learning by mice in three dimensions. AB - We tested whether mice can represent locations distributed throughout three dimensional space, by developing a novel three-dimensional radial arm maze. The three-dimensional radial maze, or "radiolarian" maze, consists of a central spherical core from which arms project in all directions. Mice learn to retrieve food from the ends of the arms without omitting any arms or re-visiting depleted ones. We show here that mice can learn both a standard working memory task, in which all arms are initially baited, and also a reference memory version in which only a subset are ever baited. Comparison with a two-dimensional analogue of the radiolarian maze, the hexagon maze, revealed equally good working-memory performance in both mazes if all the arms were initially baited, but reduced working and reference memory in the partially baited radiolarian maze. This suggests intact three-dimensional spatial representation in mice over short timescales but impairment of the formation and/or use of long-term spatial memory of the maze. We discuss potential mechanisms for how mice solve the three dimensional task, and reasons for the impairment relative to its two-dimensional counterpart, concluding with some speculations about how mammals may represent three-dimensional space. PMID- 25930217 TI - Brain asymmetry modulates perception of biological motion in newborn chicks (Gallus gallus). AB - Few light-points on the joints of a moving animal give the impression of biological motion (BM). Day-old chicks prefer BM to non-BM, suggesting a conserved predisposition to attend to moving animals. In humans and other mammals a network of regions, primarily in the right hemisphere, provides the neural substrate for BM perception. However, this has not been investigated in avians. In birds the information from each eye is mainly feeding to the contralateral hemisphere. To study brain asymmetry, we recorded the eye spontaneously used by chicks to inspect a BM stimulus. We also investigated the effect of lateralization following light exposure of the embryos. In Experiment 1, highly lateralized chicks aligned with the apparent direction of motion only when they were exposed to a BM-stimulus moving rightward first, monitoring it with the left eye-system. In Experiment 2 weakly lateralized chicks did not show any behavioral asymmetry. Moreover, they counter aligned with the apparent direction of motion. Brain lateralization affects chicks behavior while processing and approaching a BM stimulus. Highly lateralized chicks aligned their body with the apparent direction of the BM, a behavior akin to a following response, monitoring the stimulus preferentially with their left eye. This suggests a right hemisphere dominance in BM processing. Weakly lateralized chicks counter-aligned with the apparent direction of the BM, facing it during interaction, and monitored it equally with both eyes. Environmental factors (light stimulation) seem to affect the development of lateralization, and consequently social behavior. PMID- 25930218 TI - Behavioral inhibition during a conflict state elicits a transient decline in hippocampal theta power. AB - Although it has been shown that hippocampal theta power transiently declines during response inhibition in a simultaneous feature negative (FN: A+, AB-) task, observations of additional changes after this initial decline have been inconsistent across subjects. We hypothesized that the cause of these inconsistencies might be that variations in the learning speed for the FN task differentially affect the changes in hippocampal theta activity observed during the task. In this study, we classified rats into three groups (fast, intermediate, and slow FN-learning groups) based on the number of sessions required to complete learning of the FN task. We then examined whether there was a difference in hippocampal theta power among the fast, intermediate, and slow FN learning groups, and rats that learned a simple discrimination task (SD group). We observed that compared to the SD group, the slow FN-learning group, but not the fast FN-learning group, showed an increase in hippocampal theta power. In addition, a transient decline of hippocampal theta power occurred in the fast FN learning group, but not in the slow FN-learning group. These results indicate that the hippocampal theta activity during response inhibition in the FN task differed between fast- and slow-learning rats. Thus, we propose that a difference in learning speed affected hippocampal theta activity during response inhibition under a conflict state. PMID- 25930219 TI - Effects of the selective 5-HT7 receptor antagonist SB-269970 on premature responding in the five-choice serial reaction time test in rats. AB - The antagonists of serotonin 5-HT7 receptors have been demonstrated to ameliorate cognitive impairments in pharmacological animal models of schizophrenia that involve blockade of N-methyl-D-aspartate receptors (NMDARs). The administration of NMDAR antagonists evokes a broad range of cognitive deficits, including a loss of impulse control. The involvement of 5-HT7 receptors in the modulation of impulsivity has been recently suggested but has not been studied in great detail. The aim of the present study was to examine the effect of a selective 5-HT7 receptor antagonist SB-269970 on a measure of impulsive action, i.e., premature responding on the five-choice serial reaction time task (5-CSRTT) in rats. The antagonist of 5-HT2A receptor M100,907 was used as a positive control. The efficacies of both compounds were assessed in conditions of increased impulsivity that were produced by the administration of the NMDAR antagonist MK-801 or/and non-drug stimuli, i.e., using variable inter-trial intervals (vITIs). To examine the general ability of SB-269970 to counteract the MK-801-induced impairments, a discrete paired-trial delayed alternation task in a T-maze was employed. MK-801 significantly increased the number of premature responses in 5-CSRTT, and this effect was abolished by the administration of M100,907 (0.5 mg/kg) and SB-269970 (1 mg/kg). In addition, M100,907, but not SB-269970, reduced premature responding in the prolonged ITI trials. Both M100,907 and SB-269970 attenuated MK-801 induced working memory impairment in a T-maze. The present study demonstrated the efficacy of SB-269970 against MK-801-induced premature responding in the 5-CSRTT. This anti-impulsive action may offer additional benefits to the cognitive enhancing effects of pharmacological blockade of 5-HT7 receptors. PMID- 25930220 TI - Frontal cortex and hippocampus neurotransmitter receptor complex level parallels spatial memory performance in the radial arm maze. AB - Several neurotransmitter receptors have been proposed to be involved in memory formation. However, information on receptor complexes (RCs) in the radial arm maze (RAM) is missing. It was therefore the aim of this study to determine major neurotransmitter RCs levels that are modulated by RAM training because receptors are known to work in homo-or heteromeric assemblies. Immediate early gene Arc expression was determined by immunohistochemistry to show if prefrontal cortices (PFC) and hippocampi were activated following RAM training as these regions are known to be mainly implicated in spatial memory. Twelve rats per group, trained and untrained in the twelve arm RAM were used, frontal cortices and hippocampi were taken, RCs in membrane protein were quantified by blue-native PAGE immunoblotting. RCs components were characterised by co-immunoprecipitation followed by mass spectrometrical analysis and by the use of the proximity ligation assay. Arc expression was significantly higher in PFC of trained as compared to untrained rats whereas it was comparable in hippocampi. Frontal cortical levels of RCs containing AMPA receptors GluA1, GluA2, NMDA receptors GluN1 and GluN2A, dopamine receptor D1, acetylcholine nicotinic receptor alpha 7 (nAChR-alpha7) and hippocampal levels of RCs containing D1, GluN1, GluN2B and nAChR-alpha7 were increased in the trained group; phosphorylated dopamine transporter levels were decreased in the trained group. D1 and GluN1 receptors were shown to be in the same complex. Taken together, distinct RCs were paralleling performance in the RAM which is relevant for interpretation of previous and design of future work on RCs in memory studies. PMID- 25930221 TI - Bringing antidepressant self-discontinuation into view. PMID- 25930223 TI - Antidepressant self-discontinuation: results from the collaborative psychiatric epidemiology surveys. AB - OBJECTIVE: The goal of this study was to examine the extent and correlates of self-discontinuation of antidepressant medications without physician advice. METHODS: Among 1,411 participants of the nationally representative Collaborative Psychiatric Epidemiology Surveys who reported using antidepressants in the past year, sociodemographic and clinical correlates of self-discontinuation of medication without physician advice or approval were examined, along with participants' reasons for discontinuation. RESULTS: A total of 313 (22%) antidepressant users in the preceding year reported discontinuing their antidepressant medication without physician advice or approval. Older individuals had reduced odds of self-discontinuing antidepressants. Participants with an anxiety or substance use disorder and those prescribed an antidepressant by a provider other than a psychiatrist had higher odds of self-discontinuation. Participants with public insurance had lower odds of self-discontinuation than those with private insurance. The two most commonly reported reasons for self discontinuation of antidepressants were side effects and experiencing no benefit from the medication. CONCLUSIONS: Physicians prescribing antidepressants need to clearly communicate the expected benefits of treatment, the minimum duration of use required to experience benefits, and the potential side effects of these medications, particularly to younger patients, those with anxiety disorders, and patients treated in general medical settings, all of whom have increased odds of self-discontinuation. PMID- 25930224 TI - Correction. PMID- 25930225 TI - An integrated geriatric program for persons experiencing homelessness. PMID- 25930226 TI - ACE Pathways Project: therapeutic catharsis in digital storytelling. PMID- 25930227 TI - Behavioral strategies to mitigate violent behavior among inpatients: a literature review. PMID- 25930228 TI - Peer-administered motivational interviewing: conceptualizing a new practice. PMID- 25930233 TI - Process monitoring using kernel density estimation and Bayesian networking with an industrial case study. AB - Principal component analysis has been widely used in the process industries for the purpose of monitoring abnormal behaviour. The process of reducing dimension is obtained through PCA, while T-tests are used to test for abnormality. Some of the main contributions to the success of PCA is its ability to not only detect problems, but to also give some indication as to where these problems are located. However, PCA and the T-test make use of Gaussian assumptions which may not be suitable in process fault detection. A previous modification of this method is the use of independent component analysis (ICA) for dimension reduction combined with kernel density estimation for detecting abnormality; like PCA, this method points out location of the problems based on linear data-driven methods, but without the Gaussian assumptions. Both ICA and PCA, however, suffer from challenges in interpreting results, which can make it difficult to quickly act once a fault has been detected online. This paper proposes the use of Bayesian networks for dimension reduction which allows the use of process knowledge enabling more intelligent dimension reduction and easier interpretation of results. The dimension reduction technique is combined with multivariate kernel density estimation, making this technique effective for non-linear relationships with non-Gaussian variables. The performance of PCA, ICA and Bayesian networks are compared on data from an industrial scale plant. PMID- 25930234 TI - Nanocrystal superlattices that exhibit improved order on heating: an example of inverse melting? AB - Grazing incidence small angle X-ray scattering (GISAXS) measurements reveal that superlattices of 1.7 nm diameter, gold (Au) nanocrystals capped with octadecanethiol become significantly more ordered when heated to moderate temperatures (50-60 degrees C). This enhancement in order is reversible and the superlattice returns to its initially disordered structure when cooled back to room temperature. Disorder-order transition temperatures were estimated from the GISAXS data using the Hansen-Verlet criterion. Differential scanning calorimetry (DSC) measurements of the superlattices exhibited exotherms (associated with disordering during cooling) and endotherms (associated with ordering during heating) near the transition temperatures. The superlattice transition temperatures also correspond approximately to the melting and solidification points of octadecanethiol. Therefore, it appears that a change in capping ligand packing that occurs upon ligand melting underlies the structural transition of the superlattices. We liken the heat-induced ordering of the superlattices to an inverse melting transition. PMID- 25930235 TI - Acyl-coenzyme A:cholesterol acyltransferase 1 blockage enhances autophagy in the neurons of triple transgenic Alzheimer's disease mouse and reduces human P301L tau content at the presymptomatic stage. AB - Patients with Alzheimer's disease (AD) display amyloidopathy and tauopathy. In mouse models of AD, pharmacological inhibition using small molecule enzyme inhibitors or genetic inactivation of acyl-coenzyme A (Acyl-CoA):cholesterol acyltransferase 1 (ACAT1) diminished amyloidopathy and restored cognitive deficits. In microglia, ACAT1 blockage increases autophagosome formation and stimulates amyloid beta peptide1-42 degradation. Here, we hypothesize that in neurons ACAT1 blockage augments autophagy and increases autophagy-mediated degradation of P301L-tau protein. We tested this possibility in murine neuroblastoma cells ectopically expressing human tau and in primary neurons isolated from triple transgenic AD mice that express mutant forms of amyloid precursor protein, presenilin-1, and human tau. The results show that ACAT1 blockage increases autophagosome formation and decreases P301L-tau protein content without affecting endogenous mouse tau protein content. In vivo, lacking Acat1 decreases P301L-tau protein content in the brains of young triple transgenic AD mice but not in those of old mice, where extensive hyperphosphorylations and aggregation of P301L-tau take place. These results suggest that, in addition to ameliorating amyloidopathy in both young and old AD mice, ACAT1 blockage may benefit AD by reducing tauopathy at early stage. PMID- 25930236 TI - HIV infection and related risk behaviors: does school support level the playing field between orphans and nonorphans in Zimbabwe? AB - Research is limited on whether providing school support to female adolescent orphans mitigates their HIV risk disadvantage compared to other female adolescents. This paper examines 2011 Zimbabwe Demographic and Health Survey (ZDHS) HIV-related biomarker and behavior data for orphaned and nonorphaned rural adolescent females to compare findings from a similar sample participating in a randomized controlled trial (RCT) testing school support as HIV prevention. HIV status, marriage, pregnancy, sexual debut, school dropout, years of schooling, and socioeconomic status were analyzed with the combined data-sets. Bivariate analyses compared variables between RCT comprehensive intervention and delayed partial intervention conditions, and between ZDHS orphan and nonorphan groups. Multivariable analyses included a series of group comparisons as follows: ZDHS orphans vs. ZDHS nonorphans; RCT orphans in each condition vs. ZDHS nonorphans; RCT orphans in each condition vs. ZDHS orphans. Analyses methods accounted for the complex survey sampling design within each data-set. A total of 751 observations were included. All orphan groups had consistently higher odds of HIV infection than ZDHS nonorphans. ZDHS orphans had higher odds of marriage, pregnancy, and sexual debut than ZDHS nonorphans. Comprehensive intervention participants had lower odds of marriage, sexual debut, and school dropout than ZDHS nonorphans. RCT participants in both conditions had lower odds of marriage, sexual debut, and school dropout than ZDHS orphans. The findings indicate that orphans are at a distinct disadvantage to HIV risk compared to nonorphans, and much of this is likely related to vertical transmission. We found no evidence that provision of school fees to orphans will reduce their risk of HIV infection relative to nonorphans but further evidence that such programs may reduce risk behaviors including early sexual debut, child marriage, and school dropout. Further research is needed to determine how these programs can be sustainably scaled-up in resource-limited settings. PMID- 25930237 TI - Nanoparticle-stabilized microbubbles for multimodal imaging and drug delivery. AB - Microbubbles (MBs) are routinely used as contrast agents for ultrasound imaging. The use of ultrasound in combination with MBs has also attracted attention as a method to enhance drug delivery. We have developed a technology platform incorporating multiple functionalities, including imaging and therapy in a single system consisting of MBs stabilized by polyethylene glycol (PEG)-coated polymeric nanoparticles (NPs). The NPs, containing lipophilic drugs and/or contrast agents, are composed of the widely used poly(butyl cyanoacrylate) (PBCA) polymer and prepared in a single step. MBs stabilized by these NPs are subsequently prepared by self-assembly of NPs at the MB air-liquid interface. Here we show that these MBs can act as contrast agents for conventional ultrasound imaging. Successful encapsulation of iron oxide NPs inside the PBCA NPs is demonstrated, potentially enabling the NP-MBs to be used as magnetic resonance imaging (MRI) and/or molecular ultrasound imaging contrast agents. By precise tuning of the applied ultrasound pulse, the MBs burst and the NPs constituting the shell are released. This could result in increased local deposit of NPs into target tissue, providing improved therapy and imaging contrast compared with freely distributed NPs. PMID- 25930238 TI - High ethanol fermentation performance of the dry dilute acid pretreated corn stover by an evolutionarily adapted Saccharomyces cerevisiae strain. AB - Ethanol fermentation was investigated at the high solids content of the dry dilute sulfuric acid pretreated corn stover feedstock using an evolutionary adapted Saccharomyces cerevisiae DQ1 strain. The evolutionary adaptation was conducted by successively transferring the S. cerevisiae DQ1 cells into the inhibitors containing corn stover hydrolysate every 12h and finally a stable yeast strain was obtained after 65 days' continuous adaptation. The ethanol fermentation performance using the adapted strain was significantly improved with the high ethanol titer of 71.40 g/L and the high yield of 80.34% in the simultaneous saccharification and fermentation (SSF) at 30% solids content. No wastewater was generated from pretreatment to fermentation steps. The results were compared with the published cellulosic ethanol fermentation cases, and the obvious advantages of the present work were demonstrated not only at the high ethanol titer and yield, but also the significant reduction of wastewater generation and potential cost reduction. PMID- 25930239 TI - Is the cellular uptake of respiratory aerosols delivered from different devices equivalent? AB - The study focuses on the application of a cell integrated modified Andersen Cascade Impactor (ACI) as an in vitro lung model for the evaluation of aerosols' behaviour of different formulation devices, containing the same active drug, specifically nebuliser, pressurised metered dose inhaler (pMDI) and dry powder inhaler (DPI). Deposition and transport profiles of the three different inhaled salbutamol sulphate (SS) formulations with clinically relevant doses were evaluated using a modified ACI coupled with the air interface Calu-3 bronchial cell model. Reproducible amounts of SS were deposited on Snapwells for the different formulations, with no significant difference in SS deposition found between the standard ACI plate and modified plate. The transport of SS aerosols produced from pMDI formulation had similar transport kinetics to nebulised SS but significantly higher compared to the DPI, which could have led to the differences in clinical outcomes. Furthermore, drug absorption of different inhaled formulation devices of the same aerodynamic fraction was found not to be equivalent due to their physical chemical properties upon aerosolisation. This study has established an in vitro platform for the evaluation of the different inhaled formulations in physiologically relevant pulmonary conditions. PMID- 25930240 TI - Supreme Court tells UK government to cut nitrogen dioxide levels. PMID- 25930241 TI - Environmental risks and problems of the optimal management of an oil shale semi coke and ash landfill in Kohtla-Jarve, Estonia. AB - The main wastes of the Estonian shale oil industry - oil shale semi-coke and ashes - are deposited in landfills. The Kohtla-Jarve oil shale semi-coke and ash landfill, which is likely the largest of its kind in the World, was started in 1938. The environmental risks connected with the landfill were assessed and prioritized. The most significant hazard to human health is emission of harmful landfill gases and the water contamination in the local river network is harmful for aqueous organisms. The spatial expansion of subsurface contamination predicted by the groundwater transport model completed is practically insignificant from the viewpoint of health services. The landfill's leachates must be captured and purified, and the closed part of the landfill should be covered by greenery. The partial landfill capping recently executed is useless. The EU Landfill Directive requirements imposed on the hydraulic resistance of geological barriers cannot prevent the leakage of contaminants from a landfill. PMID- 25930242 TI - Spatial resolution of anthropogenic heat fluxes into urban aquifers. AB - Urban heat islands in the subsurface contain large quantities of energy in the form of elevated groundwater temperatures caused by anthropogenic heat fluxes (AHFS) into the subsurface. The objective of this study is to quantify these AHFS and the heat flow they generate in two German cities, Karlsruhe and Cologne. Thus, statistical and spatial analytical heat flux models were developed for both cities. The models include the spatial representation of various sources of AHFS: (1) elevated ground surface temperatures, (2) basements, (3) sewage systems, (4) sewage leakage, (5) subway tunnels, and (6) district heating networks. The results show that the district heating networks induce the largest AHFS with values greater than 60 W/m(2) and one order of magnitude higher than fluxes from other sources. A covariance analysis indicates that the spatial distribution of the total flux depends mainly on the thermal gradient in the unsaturated zone. On a citywide scale, basements and elevated ground surface temperatures are the dominant sources of heat flow. Overall, 2.1 PJ/a and 1.0 PJ/a of heat are accumulated on average in Karlsruhe and the western part of Cologne, respectively. Extracting this anthropogenically originated energy could sustainably supply significant parts of the urban heating demand. Furthermore, using this heat could also keep groundwater temperatures from rising further. PMID- 25930243 TI - Perspectives of Canadian Stakeholders on Criteria for Appropriateness for Total Joint Arthroplasty in Patients With Hip and Knee Osteoarthritis. AB - OBJECTIVE: As rates of total joint arthroplasty (TJA) for osteoarthritis (OA) rise, there is a need to ensure appropriate use. We undertook this study to develop criteria for appropriate use of TJA. METHODS: In prior work, we used qualitative methods to separately assess OA patients' and arthroplasty surgeons' perceptions regarding appropriateness of patient candidates for TJA. The current study reviewed the appropriateness themes that emerged from each group, and a series of statements were developed to reflect each unique theme or criterion. A group of arthroplasty surgeons then indicated their level of agreement with each statement using electronic voting. Where <=70% agreed or disagreed, the criterion was discussed and revised, and revoting occurred. In standardized telephone interviews, OA patient focus group participants indicated their level of agreement with each revised criterion. RESULTS: Qualitative research in 58 OA patients and 14 arthroplasty surgeons identified 11 appropriateness criteria. Member-checking in 15 surgeons (including 5 who had participated in the qualitative study) resulted in agreement on 6 revised criteria. These included evidence of arthritis on joint examination, patient-reported symptoms negatively impacting quality of life, an adequate trial of appropriate nonsurgical treatment, realistic patient expectations of surgery, mental and physical readiness of patient for surgery, and patient-surgeon agreement that potential benefits exceed risks. Thirty-six of the original 58 OA patient focus group participants (62.1%) participated in the member-check interviews and endorsed all 6 criteria. CONCLUSION: Patients and surgeons jointly endorsed 6 criteria for assessment of TJA appropriateness in OA patients. Prospective validation of these criteria (assessed preoperatively) as predictive of postoperative patient reported outcomes is under way and will inform development of a surgeon-patient decision-support tool for assessment of TJA appropriateness. PMID- 25930244 TI - Pyridyl-Amides as a Multimode Self-Assembly Driver for the Design of a Stimuli Responsive pi-Gelator. AB - An oligo(p-phenylenevinylene) (OPV) derivative connected to pyridyl end groups through an amide linkage (OPV-Py) resulted in a multistimuli-responsive pi gelator. When compared to the corresponding OPV pi-gelator terminated by a phenyl amide (OPV-Ph), the aggregation properties of OPV-Py were found to be significantly different, leading to multistimuli gelation and other morphological properties. The pyridyl moiety in OPV-Py initially interferes with the amide H bonded assembly and gelation, however, protonation of the pyridyl moiety with trifluoroacetic acid (TFA) facilitated the formation of amide H-bonded assembly leading to gelation, which is reversible by the addition of N,N diisopropyethylamine (DiPEA). Interestingly, addition of Ag(+) ions to a solution of OPV-Py facilitated the formation of a metallo-supramolecular assembly leading to gelation. Surprisingly, ultrasound-induced gelation was observed when OPV-Py was mixed with a dicarboxylic acid (A1). A detailed study using different spectroscopic and microscopic experimental techniques revealed the difference in the mode of assembly in the two molecules and the multistimuli-responsive nature of the OPV-Py gelation. PMID- 25930245 TI - A Compressible Bulla on the Upper Back of a Teen. PMID- 25930246 TI - Synthesis of single-walled carbon nanotubes on graphene layers. AB - Here, we report the synthesis of semiconducting single-walled carbon nanotubes with a narrow diameter distribution between 0.67 and 1.1 nm via chemical vapour deposition on graphene layers using Pt catalysts. PMID- 25930247 TI - Local Therapy Decision-Making and Contralateral Prophylactic Mastectomy in Young Women with Early-Stage Breast Cancer. AB - BACKGROUND: Rates of contralateral prophylactic mastectomy (CPM) have increased in the United States, with younger women with breast cancer the most likely to have CPM. METHODS: As part of an ongoing cohort study of young women diagnosed with breast cancer at age <=40 years, we conducted multinomial logistic regression of data from 560 women with unilateral Stage I-III disease to identify factors associated with: (1) CPM versus unilateral mastectomy (UM); (2) CPM versus breast-conserving surgery (BCS). RESULTS: Median age at diagnosis was 37 years; 66 % of women indicated that their doctor said that BCS was an option or was recommended. Of all women, 42.9 % had CPM, 26.8 % UM, and 30.4 % BCS. Among women who said the surgical decision was patient-driven, 59.9 % had CPM, 22.8 % BCS, and 17.3 % UM. Clinical characteristics associated with CPM versus BCS included HER2 positivity, nodal involvement, larger tumor size, lower BMI, parity, and testing positive for a BRCA mutation. Emotional and decisional factors associated with CPM versus UM and BCS included anxiety, less fear of recurrence, and reporting a patient-driven decision. Women who reported a physician-driven decision were less likely to have had CPM than both of the other surgeries, whereas higher confidence with the decision was associated with having CPM versus BCS. CONCLUSIONS: Many young women with early-stage breast cancer are choosing CPM. The association between CPM and emotional and decisional factors suggest that improved communication together with better psychosocial support may improve the decision-making process. PMID- 25930660 TI - Sub-hubs of baseline functional brain networks are related to early improvement following two-week pharmacological therapy for major depressive disorder. AB - Accumulating evidence suggests that early improvement after two-week antidepressant treatment is predictive of later outcomes of patients with major depressive disorder (MDD); however, whether this early improvement is associated with baseline neural architecture remains largely unknown. Utilizing resting state functional MRI data and graph-based network approaches, this study calculated voxel-wise degree centrality maps for 24 MDD patients at baseline and linked them with changes in the Hamilton Rating Scale for Depression (HAMD) scores after two weeks of medication. Six clusters exhibited significant correlations of their baseline degree centrality with treatment-induced HAMD changes for the patients, which were mainly categorized into the posterior default-mode network (i.e., the left precuneus, supramarginal gyrus, middle temporal gyrus, and right angular gyrus) and frontal regions. Receiver operating characteristic curve and logistic regression analyses convergently revealed excellent performance of these regions in discriminating the early improvement status for the patients, especially the angular gyrus (sensitivity and specificity of 100%). Moreover, the angular gyrus was identified as the optimal regressor as determined by stepwise regression. Interestingly, these regions possessed higher centrality than others in the brain (P < 10(-3)) although they were not the most highly connected hubs. Finally, we demonstrate a high reproducibility of our findings across several factors (e.g., threshold choice, anatomical distance, and temporal cutting) in our analyses. Together, these preliminary exploratory analyses demonstrate the potential of neuroimaging-based network analysis in predicting the early therapeutic improvement of MDD patients and have important implications in guiding earlier personalized therapeutic regimens for possible treatment-refractory depression. PMID- 25930661 TI - Validity and reliability of the Internalized Stigma of Smoking Inventory: An exploration of shame, isolation, and discrimination in smokers with mental health diagnoses. AB - BACKGROUND AND OBJECTIVES: De-normalization of smoking as a public health strategy may create shame and isolation in vulnerable groups unable to quit. To examine the nature and impact of smoking stigma, we developed the Internalized Stigma of Smoking Inventory (ISSI), tested its validity and reliability, and explored factors that may contribute to smoking stigma. METHODS: We evaluated the ISSI in a sample of smokers with mental health diagnoses (N = 956), using exploratory and confirmatory factor analysis, and assessed construct validity. RESULTS: Results reduced the ISSI to eight items with three subscales: smoking self-stigma related to shame, felt stigma related to social isolation, and discrimination experiences. Discrimination was the most commonly endorsed of the three subscales. A multivariate generalized linear model predicted 21-30% of the variance in the smoking stigma subscales. Self-stigma was greatest among those intending to quit; felt stigma was highest among those experiencing stigma in other domains, namely ethnicity and mental illness-based; and smoking-related discrimination was highest among women, Caucasians, and those with more education. DISCUSSION AND CONCLUSION: Smoking stigma may compound stigma experiences in other areas. Aspects of smoking stigma in the domains of shame, isolation, and discrimination were related to modeled stigma responses, particularly readiness to quit and cigarette addiction, and were found to be more salient for groups where tobacco use is least prevalent. SCIENTIFIC SIGNIFICANCE: The ISSI measure is useful for quantifying smoking-related stigma in multiple domains. PMID- 25930662 TI - Combination of herbivore removal and nitrogen deposition increases upland carbon storage. AB - Ecosystem carbon (C) accrual and storage can be enhanced by removing large herbivores as well as by the fertilizing effect of atmospheric nitrogen (N) deposition. These drivers are unlikely to operate independently, yet their combined effect on aboveground and belowground C storage remains largely unexplored. We sampled inside and outside 19 upland grazing exclosures, established for up to 80 years, across an N deposition gradient (5-24 kg N ha(-1) yr(-1) ) and found that herbivore removal increased aboveground plant C stocks, particularly in moss, shrubs and litter. Soil C storage increased with atmospheric N deposition, and this was moderated by the presence or absence of herbivores. In exclosures receiving above 11 kg N ha(-1) year(-1) , herbivore removal resulted in increased soil C stocks. This effect was typically greater for exclosures dominated by dwarf shrubs (Calluna vulgaris) than by grasses (Molinia caerulea). The same pattern was observed for ecosystem C storage. We used our data to predict C storage for a scenario of removing all large herbivores from UK heathlands. Predictions were made considering herbivore removal only (ignoring N deposition) and the combined effects of herbivore removal and current N deposition rates. Predictions including N deposition resulted in a smaller increase in UK heathland C storage than predictions using herbivore removal only. This finding was driven by the fact that the majority of UK heathlands receive low N deposition rates at which herbivore removal has little effect on C storage. Our findings demonstrate the crucial link between herbivory by large mammals and atmospheric N deposition, and this interaction needs to be considered in models of biogeochemical cycling. PMID- 25930663 TI - Evaluation of the accuracy of protein quantification using isotope TMPP-labeled peptides. AB - N-succinimidyloxycarbonylmethyl tris(2,4,6-trimethoxyphenyl) phosphonium bromide (TMPP-Ac-OSu) reacts rapidly, mildly, and specifically with the N-terminals of proteins and peptides. Thus, it can be developed as an ideal isotope-coded tag to be used in quantitative proteomics. Here, we present a strategy for light and heavy TMPP-based quantitative proteomic analysis, in which peptides in a mixture can be quantified using an on-tip TMPP derivatization approach. To demonstrate the accuracy of this strategy, light and heavy TMPP-labeled peptides were combined at different ratios and subsequently analyzed by LC-MS/MS. The MS spectra and scatter plots show that peptide and protein ratios were both consistent with the mixed ratios. We observed a linear correlation between protein ratios and the predicted ratios. In comparison with SILAC method, the TMPP labeling method produced similarly accurate quantitative results with low CVs. In conclusion, our results suggest that this isotope-coded TMPP method achieved accurate quantification and compatibility with IEF-based separation. With the inherent advantages of TMPP derivatization, we believe that it holds great promise for future applications in quantitative proteomics analysis. PMID- 25930664 TI - Characteristics and outcomes of patients diagnosed with norovirus gastroenteritis after allogeneic hematopoietic stem cell transplantation based on immunochromatography. AB - Norovirus gastroenteritis (NV-GE) is a highly transmittable disease that can lead to fatal outcomes in vulnerable populations including patients after hematopoietic stem cell transplantation (HSCT). Prompt detection of NV is therefore important for HSCT recipients. Immunochromatography (IC) can be used to easily and rapidly diagnose NV-GE by detecting NV antigens. In this study, we examined 642 stool specimens in patients who developed diarrhea after allogeneic HSCT between January 2007 and June 2011. NV was detected in 10 of 350 (2.9 %) HSCT recipients. The median onset of symptoms was 36 days (range 3-93) after HSCT. The median duration of symptoms was 42 days (3-135). A second or subsequent allogeneic HSCT was associated with a higher incidence of NV-GE (P = 0.034). Of four patients who underwent colonoscopy, two showed intestinal graft-versus-host disease (GVHD) histopathology, whereas the other two showed no evidence of GVHD, and thus no need for intensified immunosuppression. None of the patients died of NV-GE. In conclusion, IC may be useful in the differential diagnosis of diarrhea after allogeneic HSCT, and could enable the appropriate adjustment of immunosuppressive drugs and prompt preventive measures. PMID- 25930665 TI - alpha-Hispanolol sensitizes hepatocellular carcinoma cells to TRAIL-induced apoptosis via death receptor up-regulation. AB - Hispanolone derivatives have been previously described as anti-inflammatory and antitumoral agents. However, their effects on overcoming Tumor necrosis factor related apoptosis-inducing ligand (TRAIL) resistance remain to be elucidated. In this study, we analyzed the cytotoxic effects of the synthetic hispanolone derivative alpha-hispanolol (alpha-H) in several tumor cell lines, and we evaluated the induction of apoptosis, as well as the TRAIL-sensitizing potential of alpha-H in the hepatocellular carcinoma cell line HepG2. Our data show that alpha-H decreased cell viability in a dose-dependent manner in HeLa, MDA-MB231, U87 and HepG2 cell lines, with a more prominent effect in HepG2 cells. Interestingly, alpha-H had no effect on non-tumoral cells. alpha-H induced activation of caspase-8 and caspase-9 and also increased levels of the proapoptotic protein Bax, decreasing antiapoptotic proteins (Bcl-2, X-IAP and IAP 1) in HepG2 cells. Specific inhibition of caspase-8 abrogated the cascade of caspase activation, suggesting that the extrinsic pathway has a critical role in the apoptotic events induced by alpha-H. Furthermore, combined treatment of alpha H with TRAIL enhanced apoptosis in HepG2 cells, activating caspase-8 and caspase 9. This correlated with up-regulation of both the TRAIL death receptor DR4 and DR5. DR4 or DR5 neutralizing antibodies abolished the effect of alpha-H on TRAIL induced apoptosis, suggesting that sensitization was mediated through the death receptor pathway. Our results demonstrate that alpha-H induced apoptosis in the human hepatocellular carcinoma cell line HepG2 through activation of caspases and induction of the death receptor pathway. In addition, we describe a novel function of alpha-H as a sensitizer on TRAIL-induced apoptotic cell death in HepG2 cells. PMID- 25930666 TI - Role of Sphingosine-1-Phosphate in Transplant Vasculopathy Evoked by Anti-HLA Antibody. AB - Transplant vasculopathy (TV) represents the main cause of late graft failure and limits the long-term success of organ transplantation. Cellular and humoral immune responses contribute to the pathogenesis of the concentric and diffuse intimal hyperplasia of arteries of the grafted organ. We recently reported that the mitogenic signaling, evoked in human vascular smooth muscle cells (hmSMC) by the anti-HLA class I monoclonal antibody W6/32, implicates neutral sphingomyelinase-2, suggesting a role for sphingolipids in intimal hyperplasia of TV. Here, we investigated whether the mitogenic sphingolipid, sphingosine-1 phosphate (S1P), is involved in intimal hyperplasia elicited by W6/32. Studies were done on cultured hmSMC and on an in vivo model of TV, consisting of human mesenteric arteries grafted into SCID/beige mice, injected weekly with W6/32. hmSMC migration and DNA synthesis elicited by W6/32 were inhibited by the sphingosine kinase-1 (SK1) inhibitor dimethylsphingosine, the anti-S1P antibody Sphingomab and the S1PR1/R3 inhibitor VPC23019. W6/32 stimulated SK1 activity, while siRNA silencing SK1, S1PR1 and S1PR3 inhibited hmSMC migration. In vivo, Sphingomab significantly reduced the intimal thickening induced by W6/32. These data emphasize the role of S1P in intimal hyperplasia elicited by the humoral immune response, and open perspectives for preventing TV with S1P inhibitors. PMID- 25930667 TI - Emerging treatments in Neurogastroenterology: Perspectives of guanylyl cyclase C agonists use in functional gastrointestinal disorders and inflammatory bowel diseases. AB - BACKGROUND: Functional gastrointestinal disorders (FGID) and inflammatory bowel diseases (IBD) are the most frequent pathologic conditions affecting the gastrointestinal (GI) tract and both significantly reduce patients' quality of life. Recent studies suggest that guanylyl cyclase C (GC-C) expressed in the GI tract constitutes a novel pharmacological target in the treatment of FGID and IBD. Endogenous GC-C agonists - guanylin peptides: guanylin and uroguanylin, by the regulation of water and electrolyte transport, are involved in the maintenance of homeostasis in the intestines and integrity of the intestinal mucosa. Linaclotide, a synthetic agonist of GC-C was approved by Food and Drug Administration and European Medicines Agency as a therapeutic in constipation predominant irritable bowel syndrome (IBS-C) and chronic idiopathic constipation (CIC). Lately, several preclinical and clinical trials focused on assessment of therapeutic properties of synthetic agonists of uroguanylin, plecanatide, and SP 333. Plecanatide is currently tested as a potential therapeutic in diseases related to constipation and SP-333 is a promising drug in ulcerative colitis treatment. PURPOSE: Here, we discuss the most recent findings and future trends on the development of GC-C agonists and their use in clinical trials. PMID- 25930668 TI - Photodynamic therapy in colorectal cancer treatment: the state of the art in clinical trials. AB - BACKGROUND: Photodynamic therapy (PDT) is used in many different oncologic fields. Also in gastroenterology, where have been a few attempts to treat both the premalignant lesion and advanced colorectal cancer. This review aims to give a general overview of the PDT application to colorectal cancer in the field of clinical trials to emphasize its curative, and insufficiently exploited potential. MATERIALS AND METHODS: Literature on PDT for colorectal cancer with the following medical subject headings search terms: colorectal cancer, photodynamic therapy, clinical trials was reviewed. The articles were selected by their relevance to the topic. RESULTS: There are many positive and promising trial results from I to II/III phase for the use of PDT in colorectal cancer both in less advanced tumors as well as in the palliative therapy of advanced lesions. CONCLUDING REMARKS: PDT seems to be a safe and a feasible treatment option for colorectal cancer. Theoretical assumptions confirmed by many results of preclinical studies taking into consideration an increasing number of analyzed clinical trials, should lead to the development of optimized standards by using PDT in colorectal cancer treatment. PMID- 25930669 TI - Life cycle assessment of innovative technology for energy production from automotive shredder residue. AB - Automotive Shredder Residue (ASR) is a problematic waste material remaining after shredding and recovery processes of end-of-life vehicles (ELVs). Its heterogeneous grain size and composition make difficult its recovery or disposal. Although ASR accounts for approximately 20% to 25% of the weight of an ELV, the European Union (EU)'s ELV Directive (2000/53/EC) requires that by 2015 a minimum 95% of the weight of an ELV must be reused or recovered, including a 10% weight energy recovery. The quantity of ASR is relevant: Approximately 2.4 million tons are generated in the EU each year and most of it is sent to landfills. This article describes a life cycle model of the "TEKNE-Fluff" process designed to make beneficial use of ASR that is based on the results of an experimental pilot plant for pyro-gasification, combustion, cogeneration, and emissions treatment of ASR. The goal of the research was the application of life cycle assessment (LCA) methodology to identify the environmental hot spots of the "TEKNE system" and use scenario analysis to check solutions to improve its environmental profile, supporting the design and industrialization process. The LCA was conducted based on data modeled from the experimental campaign. Moreover, different scenarios on shares of electricity and thermal energy produced by the cogeneration system and alternative treatment processes for the waste produced by the technology were compared. Despite the limitation of the research (results based on scaling up experimental data by modeling), impact assessment results are promising and sufficiently robust, as shown by Monte Carlo analysis. The TEKNE technology may become an interesting solution for the problem of ASR management: Besides representing an alternative to landfill disposal, the energy produced could avoid significant impacts on fossil resources depletion (a plant of 40,000 tons/y capacity could produce ~ 147,000 GJ/yr, covering the annual need of ~ 13,500 households). PMID- 25930670 TI - Solvent-Induced Facile Synthesis of Cubic-, Spherical-, and Honeycomb-Shape Palladium N-Heterocyclic Carbene Particles and Catalytic Applications in Cyanosilylation. AB - The facile synthesis of palladium N-heterocyclic carbene (NHC) particles with spherical, cubic, and honeycomb morphologies is accomplished. The structures of cubic and honeycomb particles are defined as an unprecedented trinuclear palladium-NHC complex. An obvious effect of particle morphologies on catalytic activity and recyclability is observed in hetero-geneous cyanosilylation. PMID- 25930671 TI - N-terminal truncation contributed to increasing thermal stability of mannanase Man1312 without activity loss. AB - BACKGROUND: The disordered residues on distal loops affect the molecular structural stability and on some occasions have regulatory roles in catalytic reaction. To increase understanding of the influence of distal residue mutation, this study explored the thermostability and enzymatic activity of mannanase Man1312 deletion mutants. The focus was on residues located on the N-terminal region because they are more disordered and changeable. The effects of N-terminal truncation on enzymatic activity and thermal dynamics were investigated by spectrophotometry, circular dichroism and differential scanning calorimetry assays. RESULTS: The deletion mutants on V3, N7 and Q11 showed a marked increase in stability, while the enzymatic activity was significantly improved when triplet deletion was carried out. Triplet deletion MandVNQ showed around double the stability of its corresponding single-site and double-site deletion mutants. The Tm value of MandVNP was about 8 degrees C higher than that of Man1312. MandVNP had improved characteristics of Topt by 10 degrees C, t1/2 by 10 min and catalytic activity by 11% in comparison with Man1312. Analysis of spectra and modeling showed that MandVNQ had increased helix and strand contents. CONCLUSION: N-terminal truncation had positive effects on the thermostability and activity of mannanase. PMID- 25930672 TI - Economic Analyses in Anterior Cruciate Ligament Reconstruction: A Qualitative and Systematic Review. AB - BACKGROUND: As the health care system in the United States (US) transitions toward value-based care, there is an increased emphasis on understanding the cost drivers and high-value procedures within orthopaedics. To date, there has been no systematic review of the economic literature on anterior cruciate ligament reconstruction (ACLR). PURPOSE: To evaluate the overall evidence base for economic studies published on ACLR in the orthopaedic literature. Data available on the economics of ACLR are summarized and cost drivers associated with the procedure are identified. STUDY DESIGN: Systematic review. METHODS: All economic studies (including US-based and non-US-based) published between inception of the MEDLINE database and October 3, 2014, were identified. Given the heterogeneity of the existing evidence base, a qualitative, descriptive approach was used to assess the collective results from the economic studies on ACLR. When applicable, comparisons were made for the following cost-related variables associated with the procedure for economic implications: outpatient versus inpatient surgery (or outpatient vs overnight hospital stay vs >1-night stay); bone-patellar tendon bone (BPTB) graft versus hamstring (HS) graft source; autograft versus allograft source; staged unilateral ACLR versus bilateral ACLR in a single setting; single- versus double-bundle technique; ACLR versus nonoperative treatment; and other unique comparisons reported in single studies, including computer-assisted navigation surgery (CANS) versus traditional surgery, early versus delayed ACLR, single- versus double-incision technique, and finally the costs of ACLR without comparison of variables. RESULTS: A total of 24 studies were identified and included; of these, 17 included studies were cost identification studies. The remaining 7 studies were cost utility analyses that used economic models to investigate the effect of variables such as the cost of allograft tissue, fixation devices, and physical therapy, the percentage and timing of revision surgery, and the cost of revision surgery. Of the 24 studies, there were 3 studies with level 1 evidence, 8 with level 2 evidence, 6 with level 3 evidence, and 7 with level 4 evidence. The following economic comparisons were demonstrated: (1) ACLR is more cost-effective than nonoperative treatment with rehabilitation only (per 3 cost utility analyses); (2) autograft use had lower total costs than allograft use, with operating room supply costs and allograft costs most significant (per 5 cost identification studies and 1 cost utility analysis); (3) results on hamstring versus BPTB graft source are conflicting (per 2 cost identification studies); (4) there is significant cost reduction with an outpatient versus inpatient setting (per 5 studies using cost identification analyses); (5) bilateral ACLR is more cost efficient than 2 unilateral ACLRs in separate settings (per 2 cost identification studies); (6) there are lower costs with similarly successful outcomes between single- and double-bundle technique (per 3 cost identification studies and 2 cost utility analyses). CONCLUSION: Results from this review suggest that early single-bundle, single (endoscopic) incision outpatient ACLR using either BPTB or HS autograft provides the most value. In the setting of bilateral ACL rupture, single-setting bilateral ACLR is more cost-effective than staged unilateral ACLR. Procedures using CANS technology do not yet yield results that are superior to the results of a standard surgical procedure, and CANS has substantially greater costs. PMID- 25930673 TI - Epidemiology of Overuse Injuries in Collegiate and High School Athletics in the United States. AB - BACKGROUND: Overuse injuries result from microtrauma due to repetitive loading combined with insufficient tissue recovery time and can result in both immediate and long-term time loss from sports. HYPOTHESIS: Overuse injury rates and patterns differ across college and high school populations, sport, and sex. STUDY DESIGN: Descriptive epidemiology study. METHODS: Surveillance data for 16 sports from the National Collegiate Athletic Association's Injury Surveillance System (NCAA ISS; 2004-2005 through 2008-2009) and 14 sports from High School Reporting Information Online (High School RIO; 2006-2007 through 2012-2013) were analyzed. All reported injuries had an injury mechanism of overuse/gradual onset (college) or overuse/chronic (high school). Overuse injury incidence rates were calculated, and rate ratios with 95% CIs were used to compare subgroups. RESULTS: The rate of overuse injury was 3.28 times higher in college than high school sports (95% CI, 3.12-3.44). The rate of overuse injury among sex-comparable sports was higher in female than male athletes in both populations (college rate ratio, 1.25; 95% CI, 1.16-1.35; high school rate ratio, 1.55; 95% CI, 1.43-1.68). The lower extremity was the most commonly injured body site (college, 69.4%; high school, 70.4%). A larger proportion of overuse injuries among college athletes resulted in time loss of more than 21 days (college, 20.4%; high school, 7.7%) and surgery (college, 5.2%, high school, 2.5%). CONCLUSION: Overuse injuries can impose a significant burden on college and high school athletes. Interventions addressing prevention of overuse injury are needed. PMID- 25930674 TI - Injury Risk Estimation Expertise: Assessing the ACL Injury Risk Estimation Quiz. AB - BACKGROUND: Available methods for screening anterior cruciate ligament (ACL) injury risk are effective but limited in application as they generally rely on expensive and time-consuming biomechanical movement analysis. A potentially efficient alternative to biomechanical screening is skilled movement analysis via visual inspection (ie, having experts estimate injury risk factors based on observations of athletes' movements). PURPOSE: To develop a brief, valid psychometric assessment of ACL injury risk factor estimation skill: the ACL Injury Risk Estimation Quiz (ACL-IQ). STUDY DESIGN: Cohort study (diagnosis); Level of evidence, 3. METHODS: A total of 660 individuals participated in various stages of the study, including athletes, physicians, physical therapists, athletic trainers, exercise science researchers/students, and members of the general public in the United States. The ACL-IQ was fully computerized and made available online (www.ACL-IQ.org). Item sampling/reduction, reliability analysis, cross-validation, and convergent/discriminant validity analyses were conducted to refine the efficiency and validity of the assessment. RESULTS: Psychometric optimization techniques identified a short (mean time, 2 min 24 s), robust, 5 item assessment with high reliability (test-retest: r = 0.90) and high test sensitivity (average difference of exercise science professionals vs general population: Cohen d = 2). Exercise science professionals and individuals from the general population scored 74% and 53% correct, respectively. Convergent and discriminant validity was demonstrated. Scores on the ACL-IQ were best predicted by ACL knowledge and specific judgment strategies (ie, cue use) and were largely unrelated to domain-general spatial/decision-making ability, personality, or other demographic variables. Overall, 23% of the total sample (40% of exercise science professionals; 6% of general population) performed better than or equal to the ACL nomogram. CONCLUSION: This study presents the results of a systematic approach to assess individual differences in ACL injury risk factor estimation skill; the assessment approach is efficient (ie, it can be completed in <3 min) and psychometrically robust. The results provide evidence that some individuals have the ability to visually estimate ACL injury risk factors more accurately than other instrument-based ACL risk estimation methods (ie, ACL nomogram). The ACL-IQ provides the foundation for assessing the efficacy of observational ACL injury risk factor assessment (ie, does simple skilled visual inspection reduce ACL injuries?). The ACL-IQ can also be used to increase our understanding of the perceptual-cognitive mechanisms underlying injury risk assessment expertise, which can be leveraged to accelerate learning and improve performance. PMID- 25930676 TI - Is there a role for albumin and C-reactive protein levels for prognostication in acute heart failure? PMID- 25930675 TI - Human renal carcinoma cells respond to Newcastle disease virus infection through activation of the p38 MAPK/NF-kappaB/IkappaBalpha pathway. AB - PURPOSE: Newcastle disease virus (NDV) is an oncolytic virus that is known to have a higher preference to cancer cells than to normal cells. It has been proposed that this higher preference may be due to defects in the interferon (IFN) responses of cancer cells. The exact mechanism underlying this process, however, remains to be resolved. In the present study, we examined the antiviral response towards NDV infection of clear cell renal cell carcinoma (ccRCC) cells. ccRCC is associated with mutations of the von Hippel-Lindau tumor suppressor gene VHL, whose protein product is important for eliciting cellular responses to changes in oxygen levels. The most common first line treatment strategy of ccRCC includes IFN. Unfortunately, most ccRCC cases are diagnosed at a late stage and often are resistant to IFN-based therapies. Alternative treatment approaches, including virotherapy using oncolytic viruses, are currently being investigated. The present study was designed to investigate the mechanistic pathways underlying the response of ccRCC cells to oncolytic NDV infection. METHODS AND RESULTS: We found that NDV induces activation of NF-kappaB in ccRCC cells by inducing phosphorylation and subsequent degradation of IkappaBalpha. IkappaBalpha was found to be phosphorylated as early as 1 hour post-infection and to result in rapid NF-kappaB nuclear translocation and activation. Importantly, p38 MAPK phosphorylation was found to occur upstream of the NDV-induced NF-kappaB activation. Restoration of VHL in ccRCC cells did not result in a reduction of this phosphorylation. A similar phenomenon was also observed in several other cancer-derived cell lines. CONCLUSION: Our data provide evidence for involvement of the p38 MAPK/NF-kappaB/IkappaBalpha pathway in NDV infection and subsequent induction of apoptosis in ccRCC cells. PMID- 25930677 TI - Osteoprotegerin in patients with degenerative aortic stenosis and preserved left ventricular ejection fraction. AB - OBJECTIVES: The aim of the present study was to evaluate value of osteoprotegerin (OPG) in patients with degenerative aortic stenosis and preserved left ventricular ejection fraction. METHODS: We have prospectively followed 70 patients with aortic stenosis (mean aortic gradient >=15 mmHg) and preserved left ventricular ejection fraction for 1 year. In all patients, echocardiography and blood tests (OPG, lipids, high-sensitivity C-reactive protein) were performed at baseline and after 1 year of follow-up. Detailed medical history including atherosclerotic risk factors was obtained. The control group consisted of 20 healthy individuals with normal echocardiographic findings. Rapid progression of aortic stenosis was defined as more than 7 mmHg increase in mean aortic gradient per year. RESULTS: Osteoprotegerin concentrations were significantly higher in patients with aortic stenosis (P < 0.0001) and correlated with the degree of aortic stenosis. In multivariable regression model analysis, age (beta = 0.015, P < 0.0001), mean aortic gradient (beta = 0.04, P = 0.0078) and presence of coronary artery disease (beta = 0.111, P = 0.0408) were the only independent determinants of plasma OPG concentrations. There was no association between OPG concentrations and coronary artery disease risk factors: male sex, smoking, hypertension and hypercholesterolemia. Concentrations of high-sensitivity C reactive protein correlated positively with OPG levels only in nonsurgical patients (with lower degree of stenosis) (r = 0.34, P = 0.01). Aortic stenosis progression was related to body mass, diabetes, triglyceride concentrations, metabolic syndrome and left-ventricular systolic volume. In multivariate analysis, only metabolic syndrome was an independent predictor of aortic stenosis progression. CONCLUSION: Osteoprotegerin concentrations are linked to the presence and severity of aortic stenosis. Metabolic syndrome was the only independent predictor of degenerative aortic stenosis progression. PMID- 25930678 TI - Children's inference generation: The role of vocabulary and working memory. AB - Inferences are crucial to successful discourse comprehension. We assessed the contributions of vocabulary and working memory to inference making in children aged 5 and 6years (n=44), 7 and 8years (n=43), and 9 and 10years (n=43). Children listened to short narratives and answered questions to assess local and global coherence inferences after each one. Analysis of variance (ANOVA) confirmed developmental improvements on both types of inference. Although standardized measures of both vocabulary and working memory were correlated with inference making, multiple regression analyses determined that vocabulary was the key predictor. For local coherence inferences, only vocabulary predicted unique variance for the 6- and 8-year-olds; in contrast, none of the variables predicted performance for the 10-year-olds. For global coherence inferences, vocabulary was the only unique predictor for each age group. Mediation analysis confirmed that although working memory was associated with the ability to generate local and global coherence inferences in 6- to 10-year-olds, the effect was mediated by vocabulary. We conclude that vocabulary knowledge supports inference making in two ways: through knowledge of word meanings required to generate inferences and through its contribution to memory processes. PMID- 25930679 TI - Revisiting the Iberian honey bee (Apis mellifera iberiensis) contact zone: maternal and genome-wide nuclear variations provide support for secondary contact from historical refugia. AB - Dissecting diversity patterns of organisms endemic to Iberia has been truly challenging for a variety of taxa, and the Iberian honey bee is no exception. Surveys of genetic variation in the Iberian honey bee are among the most extensive for any honey bee subspecies. From these, differential and complex patterns of diversity have emerged, which have yet to be fully resolved. Here, we used a genome-wide data set of 309 neutrally tested single nucleotide polymorphisms (SNPs), scattered across the 16 honey bee chromosomes, which were genotyped in 711 haploid males. These SNPs were analysed along with an intergenic locus of the mtDNA, to reveal historical patterns of population structure across the entire range of the Iberian honey bee. Overall, patterns of population structure inferred from nuclear loci by multiple clustering approaches and geographic cline analysis were consistent with two major clusters forming a well defined cline that bisects Iberia along a northeastern-southwestern axis, a pattern that remarkably parallels that of the mtDNA. While a mechanism of primary intergradation or isolation by distance could explain the observed clinal variation, our results are more consistent with an alternative model of secondary contact between divergent populations previously isolated in glacial refugia, as proposed for a growing list of other Iberian taxa. Despite current intense honey bee management, human-mediated processes have seemingly played a minor role in shaping Iberian honey bee genetic structure. This study highlights the complexity of the Iberian honey bee patterns and reinforces the importance of Iberia as a reservoir of Apis mellifera diversity. PMID- 25930680 TI - Tailoring the nucleation of domain walls along multi-segmented cylindrical nanoelements. AB - The magnetization reversal of three-segment cylindrical nanoelements comprising alternating nanowire and nanotube sections is investigated by means of Monte Carlo simulations. Such nanoelements may feature a three-state behaviour with an intermediate plateau in the hysteresis curve due to a metastable pinning of the domain walls (DWs) at the wire-tube interfaces. It turns out that vortex as well as transverse DWs contribute to the magnetization reversal. By varying the geometric parameters, the sequence, or the material of the elements the nucleation location of DWs, as well as their nucleation field, can be tailored. Especially interesting is the novel possibility to drive DWs coherently in the same or in opposite directions by changing the geometry of the hybrid nanoelement. This important feature provides additional flexibility to the construction of logical devices based on DW movement. Another prominent outcome is that DWs can be nucleated near the centre of the element and then traverse to the outer tips of the cylindrical structure when the applied field is increased, which also opens the possibility to use these three-segment nanoelements for the field-induced delivery of DWs as substitutes for large nucleation pads. PMID- 25930681 TI - Astrocyte physiopathology: At the crossroads of intercellular networking, inflammation and cell death. AB - Recent breakthroughs in neuroscience have led to the awareness that we should revise our traditional mode of thinking and studying the CNS, i.e. by isolating the privileged network of "intelligent" synaptic contacts. We may instead need to contemplate all the variegate communications occurring between the different neural cell types, and centrally involving the astrocytes. Basically, it appears that a single astrocyte should be considered as a core that receives and integrates information from thousands of synapses, other glial cells and the blood vessels. In turn, it generates complex outputs that control the neural circuitry and coordinate it with the local microcirculation. Astrocytes thus emerge as the possible fulcrum of the functional homeostasis of the healthy CNS. Yet, evidence indicates that the bridging properties of the astrocytes can change in parallel with, or as a result of, the morphological, biochemical and functional alterations these cells undergo upon injury or disease. As a consequence, they have the potential to transform from supportive friends and interactive partners for neurons into noxious foes. In this review, we summarize the currently available knowledge on the contribution of astrocytes to the functioning of the CNS and what goes wrong in various pathological conditions, with a particular focus on Amyotrophic Lateral Sclerosis, Alzheimer's Disease and ischemia. The observations described convincingly demonstrate that the development and progression of several neurological disorders involve the de regulation of a finely tuned interplay between multiple cell populations. Thus, it seems that a better understanding of the mechanisms governing the integrated communication and detrimental responses of the astrocytes as well as their impact towards the homeostasis and performance of the CNS is fundamental to open novel therapeutic perspectives. PMID- 25930682 TI - The brain acid-base homeostasis and serotonin: A perspective on the use of carbon dioxide as human and rodent experimental model of panic. AB - Panic attacks (PAs), the core feature of panic disorder, represent a common phenomenon in the general adult population and are associated with a considerable decrease in quality of life and high health care costs. To date, the underlying pathophysiology of PAs is not well understood. A unique feature of PAs is that they represent a rare example of a psychopathological phenomenon that can be reliably modeled in the laboratory in panic disorder patients and healthy volunteers. The most effective techniques to experimentally trigger PAs are those that acutely disturb the acid-base homeostasis in the brain: inhalation of carbon dioxide (CO2), hyperventilation, and lactate infusion. This review particularly focuses on the use of CO2 inhalation in humans and rodents as an experimental model of panic. Besides highlighting the different methodological approaches, the cardio-respiratory and the endocrine responses to CO2 inhalation are summarized. In addition, the relationships between CO2 level, changes in brain pH, the serotonergic system, and adaptive physiological and behavioral responses to CO2 exposure are presented. We aim to present an integrated psychological and neurobiological perspective. Remaining gaps in the literature and future perspectives are discussed. PMID- 25930683 TI - A critical appraisal of the what-where-when episodic-like memory test in rodents: Achievements, caveats and future directions. AB - During the last decade the what, where and when (WWWhen) episodic-like memory (ELM) task, which is based on the object recognition paradigm, has been utilized for the cognitive phenotyping of mouse mutants and transgenic mouse models of neuropsychiatric diseases. It was also widely used to identify the neuroanatomical, electrophysiological and pharmacological foundations of ELM formation, retention and retrieval. Findings from these studies have helped to increase our understanding of the neurobiology and neuropathology of episodic memory in the context of neurodegenerative and neuropsychiatric diseases. Pharmacological studies identified novel targets that might facilitate episodic memory formation in patients with memory problems. In this review, we attempt to delineate the cognitive operations and processes that might underlie rodent performance in the WWWhen/ELM task. We discuss major issues of the object recognition paradigm, including the problem of familiarity vs. recollection-based object recognition, the problem of novel object-induced neophobia, and propose novel methodological solutions to these issues. In conclusion, the WWWhen/ELM task has proven to be a useful tool in the fields of behavioral and translational clinical neuroscience and has the potential to be further refined to address major problems in animal memory research. PMID- 25930684 TI - Transcatheter aortic valve implantation in a person with haemophilia. PMID- 25930685 TI - Amine-Assisted Delamination of Nb2C MXene for Li-Ion Energy Storage Devices. AB - 2D Nb2CTx MXene flakes are produced using an amine-assisted delamination process. Upon mixing with carbon nanotubes and filtration, freestanding, flexible paper is produced. The latter exhibits high capacity and excellent stability when used as the electrode for Li-ion batteries and capacitors. PMID- 25930687 TI - Antibacterial activity of Lactobacillus spp. isolated from the feces of healthy infants against enteropathogenic bacteria. AB - Lactobacilli are normal microflora of the gastrointestinal (GI) tract and are a heterogeneous group of lactic acid bacteria (LAB). Lactobacillus strains with Probiotic activity may have health Benefits for human. This study investigates the probiotic potential of Lactobacillus strains obtained from the feces of healthy infants and also explores antibacterial activity of Lactobacillus strains with probiotic potential against enteropathogenic bacteria. Fecal samples were collected from 95 healthy infants younger than 18 months. Two hundred and ninety Lactobacillus strains were isolated and assessed for probiotic potential properties including ability to survive in gastrointestinal conditions (pH 2.0, 0.3% oxgall), adherence to HT-29 cells and antibiotic resistance. Six strains including Lactobacillus fermentum (4 strains), Lactobacillus paracasei and Lactobacillus plantarum showed good probiotic potential and inhibited the growth of enteropathogenic bacteria including ETEC H10407, Shigella flexneri ATCC 12022, Shigella sonnei ATCC 9290, Salmonella enteritidis H7 and Yersinia enterocolitica ATCC 23715. These Lactobacillus strains with probiotic potential may be useful for prevention or treatment of diarrhea, but further in vitro and in vivo studies on these strains are still required. PMID- 25930688 TI - Introduction. Cross-cultural autism studies, neurodiversity, and conceptualizations of autism. PMID- 25930686 TI - Recurrent Clostridium difficile infection: From colonization to cure. AB - Clostridium difficile infection (CDI) is increasingly prevalent, dangerous and challenging to prevent and manage. Despite intense national and international attention the incidence of primary and of recurrent CDI (PCDI and RCDI, respectively) have risen rapidly throughout the past decade. Of major concern is the increase in cases of RCDI resulting in substantial morbidity, morality and economic burden. RCDI management remains challenging as there is no uniformly effective therapy, no firm consensus on optimal treatment, and reliable data regarding RCDI-specific treatment options is scant. Novel therapeutic strategies are critically needed to rapidly, accurately, and effectively identify and treat patients with, or at-risk for, RCDI. In this review we consider the factors implicated in the epidemiology, pathogenesis and clinical presentation of RCDI, evaluate current management options for RCDI and explore novel and emerging therapies. PMID- 25930689 TI - On the Need for Rethinking Current Practice that Highlights Goal Achievement Risk in an Enterprise Context. AB - This article addresses the issue of how performance and risk management can complement each other in order to enhance the management of an enterprise. Often, we see that risk management focuses on goal achievements and not the enterprise risk related to its activities in the value chain. The statement "no goal, no risk" is a common misconception. The main aim of the article is to present a normative model for describing the links between performance and risk, and to use this model to give recommendations on how to best structure and plan the management of an enterprise in situations involving risk and uncertainties. The model, which has several novel features, is based on the interaction between different types of risk management (enterprise risk management, task risk management, and personal risk management) and a structure where the enterprise risk management overrules both the task and personal risk management. To illustrate the model we use the metaphor of a ship, where the ship is loaded with cash-generating activities and has a direction over time determined by the overall strategic objectives. Compared to the current enterprise risk management practice, the model and related analysis are founded on a new perspective on risk, highlighting knowledge and uncertainties beyond probabilities. PMID- 25930690 TI - The plant kinome. AB - Plant kinases are one of the largest protein families in Arabidopsis. There are almost 600 membrane-located receptor kinases and almost 400 soluble kinases with distinct functions in signal transduction. In this minireview we discuss phylogeny and functional context of prominent members from major protein kinase subfamilies in plants. PMID- 25930691 TI - Phosphatases in plants. AB - Reversible protein phosphorylation is an essential posttranslational modification mechanism executed by opposing actions of protein phosphatases and protein kinases. About 1,000 predicted kinases in Arabidopsis thaliana kinome predominate the number of protein phosphatases, of which there are only ~150 members in Arabidopsis. Protein phosphatases were often referred to as "housekeeping" enzymes, which act to keep eukaryotic systems in balance by counteracting the activity of protein kinases. However, recent investigations reveal the crucial and specific regulatory functions of phosphatases in cell signaling. Phosphatases operate in a coordinated manner with the protein kinases, to execute their important function in determining the cellular response to a physiological stimulus. Closer examination has established high specificity of phosphatases in substrate recognition and important roles in plant signaling pathways, such as pathogen defense and stress regulation, light and hormonal signaling, cell cycle and differentiation, metabolism, and plant growth. In this minireview we provide a compact overview about Arabidopsis protein phosphatase families, as well as members of phosphoglucan and lipid phosphatases, and highlight the recent discoveries in phosphatase research. PMID- 25930692 TI - Phosphoproteomics in cereals. AB - Cereals are the most important crop plant supplying staple food throughout the world. The economic importance and continued breeding of crop plants such as rice, maize, wheat, or barley require a detailed scientific understanding of adaptive and developmental processes. Protein phosphorylation is one of the most important regulatory posttranslational modifications and its analysis allows deriving functional and regulatory principles in plants. This minireview summarizes the current knowledge of phosphoproteomic studies in cereals. PMID- 25930693 TI - Screening of kinase substrates using kinase knockout mutants. AB - Protein kinases are widely known to be major regulators of various signaling processes, particularly in eukaryotes, including plants. To understand their role in signal transduction pathways, it is necessary to determine which proteins are phosphorylated by these enzymes. Recent studies have applied a comparative phosphoproteomic approach to identify protein kinase substrates in plants. The results demonstrated that kinase knockout mutants are useful for screening protein kinase substrates via such a comparative analysis. Here some technical points are described for the experimental design and comparative analysis using kinase knockout mutants. PMID- 25930694 TI - Phosphopeptide profiling of receptor kinase mutants. AB - The family of transmembrane receptor kinase is the largest protein kinase family in Arabidopsis. However many of these kinases have yet uncharacterized functions and little is known about direct substrates of these kinases. Here, we present a large-scale phosphoproteomics method involving label-free quantitation-based comparative phosphopeptide profiling of knockout mutants in receptor-like kinases. This approach, among other physiological and cell biological experiments, is one step in understanding the functional roles of plant kinases in the context of their signaling networks. PMID- 25930695 TI - Combining Metabolic 15N Labeling with Improved Tandem MOAC for Enhanced Probing of the Phosphoproteome. AB - In eukaryotic cells many diverse cellular functions are regulated by reversible protein phosphorylation. In recent years, phosphoproteomics has become a powerful tool for studying protein phosphorylation because it enables unbiased localization, and site-specific quantification of in vivo phosphorylation of hundreds of proteins in a single experiment. A common strategy for identifying phosphoproteins and their phosphorylation sites from complex biological samples is the enrichment of phosphopeptides from digested cellular lysates followed by mass spectrometry. However, despite high sensitivity of modern mass spectrometers the large dynamic range of protein abundance and the transient nature of protein phosphorylation remained major pitfalls in MS-based phosphoproteomics. This is particularly true for plants in which the presence of secondary metabolites and endogenous compounds, the overabundance of ribulose-1,5-bisphosphate carboxylase and other components of the photosynthetic apparatus, and the concurrent difficulties in protein extraction necessitate two-step phosphoprotein/phosphopeptide enrichment strategies (Nakagami et al., Plant Cell Physiol 53:118-124, 2012).Approaches for label-free peptide quantification are advantageous due to their low cost and experimental simplicity, but they lack precision. These drawbacks can be overcome by metabolic labeling of whole plants with heavy nitrogen ((15)N) which allows combining two samples very early in the phosphoprotein enrichment workflow. This avoids sample-to-sample variation introduced by the analytical procedures and it results in robust relative quantification values that need no further standardization. The integration of (15)N metabolic labeling into tandem metal-oxide affinity chromatography (MOAC) (Hoehenwarter et al., Mol Cell Proteomics 12:369-380, 2013) presents an improved and highly selective approach for the identification and accurate site-specific quantification of low-abundance phosphoproteins that is based on the successive enrichment of light and heavy nitrogen-labeled phosphoproteins and peptides. This improved strategy combines metabolic labeling of whole plants with the stable heavy nitrogen isotope ((15)N), protein extraction under denaturing conditions, phosphoprotein enrichment using Al(OH)3-based MOAC, and tryptic digest of enriched phosphoproteins followed by TiO2-based MOAC of phosphopeptides and quantitative phosphopeptide measurement by liquid chromatography (LC) and high resolution accurate mass (HR/AM) mass spectrometry (MS). Thus, tandem MOAC effectively targets the phosphate moiety of phosphoproteins and phosphopeptides and allows probing of the phosphoproteome to unprecedented depth, while (15)N metabolic labeling enables accurate relative quantification of measured peptides and direct comparison between samples. PMID- 25930696 TI - Kinase activity and specificity assay using synthetic peptides. AB - Phosphorylation of substrate proteins by protein kinases can lead to activation or inactivation of signaling pathways or metabolic processes. Precise understanding of activity and specificity of protein kinases are important questions in characterization of kinase functions. Here, we describe a procedure to study kinase activity and specificity using kinase-GFP complexes purified from plant material and synthetic peptides as substrates. Magnetic GFP beads allow purifying receptor-like kinase-GFP complexes from microsomal fractions. Kinase GFP complexes are then incubated with ATP and the synthetic peptides for kinase reaction. Phosphorylation of substrate peptides is then identified and quantified by mass spectrometry. PMID- 25930697 TI - Absolute quantitation of protein posttranslational modification isoform. AB - Mass spectrometry has been widely applied in characterization and quantification of proteins from complex biological samples. Because the numbers of absolute amounts of proteins are needed in construction of mathematical models for molecular systems of various biological phenotypes and phenomena, a number of quantitative proteomic methods have been adopted to measure absolute quantities of proteins using mass spectrometry. The liquid chromatography-tandem mass spectrometry (LC-MS/MS) coupled with internal peptide standards, i.e., the stable isotope-coded peptide dilution series, which was originated from the field of analytical chemistry, becomes a widely applied method in absolute quantitative proteomics research. This approach provides more and more absolute protein quantitation results of high confidence. As quantitative study of posttranslational modification (PTM) that modulates the biological activity of proteins is crucial for biological science and each isoform may contribute a unique biological function, degradation, and/or subcellular location, the absolute quantitation of protein PTM isoforms has become more relevant to its biological significance. In order to obtain the absolute cellular amount of a PTM isoform of a protein accurately, impacts of protein fractionation, protein enrichment, and proteolytic digestion yield should be taken into consideration and those effects before differentially stable isotope-coded PTM peptide standards are spiked into sample peptides have to be corrected. Assisted with stable isotope-labeled peptide standards, the absolute quantitation of isoforms of posttranslationally modified protein (AQUIP) method takes all these factors into account and determines the absolute amount of a protein PTM isoform from the absolute amount of the protein of interest and the PTM occupancy at the site of the protein. The absolute amount of the protein of interest is inferred by quantifying both the absolute amounts of a few PTM-site-independent peptides in the total cellular protein and their peptide yields. The PTM occupancy determination is achieved by measuring the absolute amounts of both PTM and non PTM peptides from the highly purified protein sample expressed in transgenic organisms or directly isolated from an organism using affinity purification. The absolute amount of each PTM isoform in the total cellular protein extract is finally calculated from these two variables. Following this approach, the ion intensities given by mass spectrometers are used to calculated the peptide amounts, from which the amounts of protein isoforms are then deduced. In this chapter, we describe the principles underlying the experimental design and procedures used in AQUIP method. This quantitation method basically employs stable isotope-labeled peptide standards and affinity purification from a tagged recombinant protein of interest. Other quantitation strategies and purification techniques related to this method are also discussed. PMID- 25930698 TI - Phosphorylation stoichiometry determination in plant photosynthetic membranes. AB - This chapter describes different strategies for the study of phosphorylation dynamics and stoichiometry in photosynthetic membranes. Detailed procedures for the detection, large-scale identification, and quantification of phosphorylated proteins optimized for plant thylakoid proteins are given. PMID- 25930699 TI - Phosphopeptide immuno-affinity enrichment to enhance detection of tyrosine phosphorylation in plants. AB - Tyrosine (Tyr) phosphorylation plays an essential role in signaling in animal systems, but the relative contribution of Tyr phosphorylation to plant signal transduction has, until recently, remained an open question. One of the major issues hampering the analysis is the low abundance of Tyr phosphorylation and therefore underrepresentation in most mass spec-based proteomic studies. Here, we describe a working approach to selectively enrich Tyr-phosphorylated peptides from complex plant tissue samples. We describe a detailed protocol that is based on immuno-affinity enrichment step using an anti-phospho-tyrosine (pTyr)-specific antibody. This single enrichment strategy effectively enriches pTyr-containing peptides from complex total plant cell extracts, which can be measured by LC MS/MS without further fractionation or enrichment. PMID- 25930700 TI - The Peptide Microarray ChloroPhos1.0: A Screening Tool for the Identification of Arabidopsis thaliana Chloroplast Protein Kinase Substrates. AB - We designed the peptide microarray ChloroPhos1.0 to screen for substrates of chloroplast protein kinases. The peptides represented on the microarray were selected from phosphoproteomics data, and the identified chloroplast phosphopeptides were spotted as 15-mers on a glass slide with the phosphorylation site centered. Altogether, 905 distinct peptides from chloroplast proteins are present on the array. Here we describe how the array can be used to identify the target protein spectrum of chloroplast kinases. We present the method and discuss limitations and challenges associated with the determination of phosphorylation activity on peptide substrates in vitro. PMID- 25930701 TI - Plant protein kinase substrates identification using protein microarrays. AB - Protein kinases regulate signaling pathways by phosphorylating their targets. They play critical roles in plant signaling networks. Although many important protein kinases have been identified in plants, their substrates are largely unknown. We have developed and produced plant protein microarrays with more than 15,000 purified plant proteins. Here, we describe a detailed protocol to use these microarrays to identify plant protein kinase substrates via in vitro phosphorylation assays on these arrays. PMID- 25930702 TI - Targeted Analysis of Protein Phosphorylation by 2D Electrophoresis. AB - Two-dimensional (2D) gel electrophoresis combines isoelectric focusing in the first and SDS polyacrylamide gel electrophoresis in the second dimension to separate complex mixtures of proteins with unequalled resolution and sensitivity. It is well suited for the analysis of posttranslational protein modifications as most of them affect the isoelectric point and, therefore, the focusing behavior of the protein in the first dimension. It is particularly useful for low abundance proteins, as it provides a first indication of PTMs, before establishing methods for protein isolation. For targeted proteomics of more abundant proteins, 2D electrophoresis itself may be the method of choice for the isolation of posttranslationally modified isoforms of the protein of interest for mass spectrometric analyses. Protein phosphorylation can be detected by use of phospho-specific stains or antibodies, or by comparing spot patterns of a protein sample before and after phosphatase treatment. Here we describe a simple method, combining 2D gel electrophoresis and western blot analysis with dephosphorylation by lambda-phosphatase to analyze the phosphorylation status of oxophytodienoic acid reductase 3 in protein extracts from different organs of tomato and Arabidopsis plants. PMID- 25930703 TI - Computational phosphorylation network reconstruction: methods and resources. AB - The succession of protein activation and deactivation mediated by phosphorylation and dephosphorylation events constitutes a key mechanism of molecular information transfer in cellular systems. To deduce the details of those molecular information cascades and networks has been a central goal pursued by both experimental and computational approaches. Many computational network reconstruction methods employing an array of different statistical learning methods have been developed to infer phosphorylation networks based on different types of molecular data sets such as protein sequence, protein structure, or phosphoproteomics data. In this chapter, different computational network inference methods and resources for biological network reconstruction with a particular focus on phosphorylation networks are surveyed. PMID- 25930704 TI - Computational identification of protein kinases and kinase-specific substrates in plants. AB - The protein phosphorylation catalyzed by protein kinases (PKs) plays an essential role in almost all biological progresses in plants. Thus, the identification of PKs and kinase-specific substrates is fundamental for understanding the regulatory mechanisms of protein phosphorylation especially in controlling plant growth and development. In this chapter, we describe the computational methods and protocols for the identification of PKs and kinase-specific substrates in plants, by using Vitis vinifera as an example. First, the proteome sequences and experimentally identified phosphorylation sites (p-sites) in Vitis vinifera were downloaded. The potential PKs were computationally identified based on preconstructed Hidden Markov Model (HMM) profiles and ortholog searches, whereas the kinase-specific p-sites, or site-specific kinase-substrate relations (ssKSRs) were initially predicted by the software package of Group-based Prediction System (GPS) and further processed by the iGPS algorithm (in vivo GPS) to filter potentially false positive hits. All primary data sets and prediction results of Vitis vinifera are available at: http://ekpd.biocuckoo.org/protocol.php. PMID- 25930705 TI - Databases for plant phosphoproteomics. AB - Phosphorylation is the most studied posttranslational modification involved in signal transduction in stress responses, development, and growth. In the recent years large-scale phosphoproteomic studies were carried out using various model plants and several growth and stress conditions. Here we present an overview of online resources for plant phosphoproteomic databases: PhosPhAt as a resource for Arabidopsis phosphoproteins, P3DB as a resource expanding to crop plants, and Medicago PhosphoProtein Database as a resource for the model plant Medicago trunculata. PMID- 25930706 TI - Phosphorylation site prediction in plants. AB - Protein phosphorylation events on serine, threonine, and tyrosine residues are the most pervasive protein covalent bond modifications in plant signaling. Both low and high throughput studies reveal the importance of phosphorylation in plant molecular biology. Although becoming more and more common, the proteome-wide screening on phosphorylation by experiments remains time consuming and costly. Therefore, in silico prediction methods are proposed as a complementary analysis tool to enhance the phosphorylation site identification, develop biological hypothesis, or help experimental design. These methods build statistical models based on the experimental data, and they do not have some of the technical specific bias, which may have advantage in proteome-wide analysis. More importantly computational methods are very fast and cheap to run, which makes large-scale phosphorylation identifications very practical for any types of biological study. Thus, the phosphorylation prediction tools become more and more popular. In this chapter, we will focus on plant specific phosphorylation site prediction tools, with essential illustration of technical details and application guidelines. We will use Musite, PhosPhAt and PlantPhos as the representative tools. We will present the results on the prediction of the Arabidopsis protein phosphorylation events to give users a general idea of the performance range of the three tools, together with their strengths and limitations. We believe these prediction tools will contribute more and more to the plant phosphorylation research community. PMID- 25930709 TI - Cushing's disease: towards precision medicine. AB - The pathogenesis of Cushing's disease is poorly understood; two recent reports identifying somatic mutations in USP8 in pituitary corticotroph tumors provide exciting advances in this field. These mutations alter EGFR trafficking and signaling, raising the prospect that EGFR inhibitors may move the treatment of this disease into the era of precision medicine. PMID- 25930707 TI - A new model of reverse cholesterol transport: enTICEing strategies to stimulate intestinal cholesterol excretion. AB - Cardiovascular disease (CVD) remains the largest cause of mortality in most developed countries. Although recent failed clinical trials and Mendelian randomization studies have called into question the high-density lipoprotein (HDL) hypothesis, it remains well accepted that stimulating the process of reverse cholesterol transport (RCT) can prevent or even regress atherosclerosis. The prevailing model for RCT is that cholesterol from the artery wall must be delivered to the liver where it is secreted into bile before leaving the body through fecal excretion. However, many studies have demonstrated that RCT can proceed through a non-biliary pathway known as transintestinal cholesterol excretion (TICE). The goal of this review is to discuss the current state of knowledge of the TICE pathway, with emphasis on points of therapeutic intervention. PMID- 25930710 TI - AChE for DNA degradation. AB - DNA hydrolysis is a biochemical process often associated with different forms of cell death, including apoptosis. In a recent paper published in Cell Discovery, Du et al. report that synaptic acetylcholinesterase (AChE-S) shows an unexpected enzymatic activity as DNase switched on after cytotoxic insults. PMID- 25930708 TI - Arginase: an old enzyme with new tricks. AB - Arginase has roots in early life-forms. It converts L-arginine to urea and ornithine. The former provides protection against NH3; the latter serves to stimulate cell growth and other physiological functions. Excessive arginase activity in mammals has been associated with cardiovascular and nervous system dysfunction and disease. Two relevant aspects of this elevated activity may be involved in these disease states. First, excessive arginase activity reduces the supply of L-arginine needed by nitric oxide (NO) synthase to produce NO. Second, excessive production of ornithine leads to vascular structural problems and neural toxicity. Recent research has identified inflammatory agents and reactive oxygen species (ROS) as drivers of this pathologic elevation of arginase activity and expression. We review the involvement of arginase in cardiovascular and nervous system dysfunction, and discuss potential therapeutic interventions targeting excess arginase. PMID- 25930712 TI - BIPCO: ultrasound feature points based on phase congruency detector and binary pattern descriptor. AB - PURPOSE: Detection of feature points in medical ultrasound (US) images is the starting point of many clinical tasks, such as segmentation of lesions in pathological areas, estimation of organ deformation, and multimodality image fusion. However, obtaining a reliable feature point localization is a complex task even for an expert radiologist due to the US image characteristics: strong presence of noise, insidious artifacts, and low contrast. In this work, we describe a feature detector based on phase congruency (PhC) combined with a binary pattern descriptor. METHODS: We introduce a feature detector specifically designed for US images and based on PhC analysis. We also introduce a descriptor based on local binary pattern (LBP) operator to improve and simplify the matching between feature points extracted from different images. LBP is not applied directly to the intensity values; instead, it is applied to the PhC output obtained during the detection step to improve robustness to intensity transformation, and the rejection of noise. RESULTS: We tested the proposed approach compared to state-of- the-art methods applied to real US images subject to realistic synthetic transformations. The results of the proposed method, in terms of accuracy and precision, outperform the state-of-the-art approaches that are not designed for US data. CONCLUSIONS: The methods described in this work will enable the development of US-based navigation system, which supports automatic feature point detection and matching from US images acquired at different times during the procedure. PMID- 25930711 TI - B-1 lymphocytes in mice and nonhuman primates. AB - B-1 cells comprise subpopulations of B lymphocytes in mice that display developmental, phenotypic, and functional characteristics that are distinct from those of conventional B cell populations (B-2 cells). Despite the known importance of murine B-1a (CD5(+) ) and B-1b (CD5(-) ) cells in the production of natural antibodies and rapid antigen-specific humoral responses to infection, evidence for B-1 cells in primates, including humans, is very limited. Identifying these cells in humans proves challenging given the limited number of cells that can be obtained from sites expected to harbor increased frequencies of these cells (i.e., peritoneal and pleural cavities) and the need to perform functional analyses on these cells, which, in the case of B-1b cells, must be carried out in vivo. My laboratory has used cynomolgus macaques and African green monkeys to bypass these limitations and to identify and extensively analyze primate B cell populations with the phenotypic and functional characteristics of mouse B-1a and B-1b cells. Our results reveal striking similarities between primate and murine B-1 cells, including a conserved functional role for primate B 1b-like cells in immunity to T cell-independent type 2 antigens. PMID- 25930713 TI - Computer-assisted hip resurfacing planning using Lie group shape models. AB - INTRODUCTION: Hip resurfacing is a surgical option for osteoarthritis young and active patients. Early failures has been reported due to improper implant placement. Computer-assisted surgery is a promising avenue for more successful procedures. PURPOSE: This paper presents a novel automatic surgical planning for computer-assisted hip resurfacing procedures. The plan defined the femoral head axis that was used to place the implant. The automatic planning was based on a Lie group statistical shape model. METHODS: A statistical shape model was constructed using 50 femurs from osteoarthritis patients who underwent computer assisted hip resurfacing. The model was constructed using product Lie groups representation of shapes and nonlinear analysis on the manifold of shapes. A surgical plan was drawn for the derived base shape. The base shape was transformed to 14 femurs with known manual plans. The transformed base plan was used as the computed plan for each femur. Both actual and computed plans were compared. RESULTS: The method showed a success by computing plans that differ from the actual plans within the surgical admissible ranges. The minimum crossing distance between the two plans had a mean of 0.75 mm with a standard deviation of 0.54 mm. The angular difference between the two plans had the mean of 5.94 degrees with a standard deviation of 2.145.94 degrees . CONCLUSION: Product Lie groups shape models were proved to be successful in automatic planning for hip resurfacing computer-assisted surgeries. The method can be extended to other orthopedic and general surgeries. PMID- 25930714 TI - Disruption of melatonin circadian rhythm production is related to multiple sclerosis severity: A preliminary study. AB - Sunlight can influence the immune system independently of vitamin D, such as through melatonin production in the pineal gland. Inflammatory disorders can suppress nocturnal melatonin production, but only a few studies have investigated melatonin status in multiple sclerosis (MS). We aimed to study melatonin production in association with clinical and immunological data in MS patients. Eleven treated relapsing-remitting MS (RRMS) patients and eight controls underwent neurological examination and were assessed for fatigue severity and depressive symptoms. Inflammatory cytokines were analyzed in blood samples and concentration of 6-sulfatoxymelatonin (6-SMT) was determined in 24h urine. Patients with an abnormal proportion of overnight 6-SMT (n=8, 72.7%) had higher disability and fatigue severity (p<0.05). Overnight 6-SMT was inversely related with fatigue severity (p=0.016), number of relapses in the previous 12 months (p=0.010) and EDSS scores (p=0.049). In conclusion, disruption of melatonin circadian rhythm production is frequent among RRMS patients and seemingly related to higher disability and fatigue scores. Future studies with larger sample size are necessary to establish melatonin status as a biomarker of disease severity in MS. PMID- 25930715 TI - Day case hemithyroidectomy is safe and feasible: experience in Scotland. AB - BACKGROUND AND AIMS: We aimed to analyse the safety and feasibility of day case hemithyroidectomy. METHODS AND RESULTS: We reviewed all hemithyroidectomies led by two surgeons across two sites between 2010 and the end of 2013. Patients were divided into 'planned inpatient' or 'planned day case'. RESULTS: Day of discharge, conversion to inpatient procedure, intraoperative and postoperative complications and postoperative presentations or readmission to hospital were analysed. Age, gender, American Society of Anaesthesiologists score and indication for surgery were also recorded. One-hundred and eighty hemithyroidectomy cases were analysed, 35 (19.5%) were planned as inpatient procedures. Of the remaining 145 (80.5%) planned day case: 106 (73.1%) were successfully discharged on the same day and 39 (26.9%) were not; 11 (7.6%) were converted to inpatient procedures perioperatively; 8 (5.5%) had additional procedures; 6 (4.1%) had wound infections; 7 (4.8%) presented to ER; 1 (0.7%) of which required readmission to hospital for a reason unrelated to the surgery. None had laryngeal nerve palsy, compressive haematoma or symptomatic hypocalcaemia. CONCLUSION: This study showed that hemithyroidectomy by experienced surgeons can be performed safely as a day surgery. No 'planned day case patients' in this study developed laryngeal nerve palsy, compressive haematoma or symptomatic hypocalcaemia. PMID- 25930716 TI - Evaluation of the Head-Mounted Display for Ultrasound-Guided Peripheral Nerve Blocks in Simulated Regional Anesthesia. AB - BACKGROUND AND OBJECTIVES: Anesthesiologists performing peripheral nerve blocks under ultrasound guidance look frequently back and forth between the patient and the ultrasound screen during the procedure. These head movements add time and complexity to the procedure. The head-mounted display (HMD) device is a commercially available head-mounted video display that is connected to the ultrasound machine and projects the ultrasound image onto the HMD glasses, enabling the anesthesiologist to monitor the screen without ever needing to look away from the patient. We hypothesized that the use of the HMD device would decrease the total procedure time as well as operator head and ultrasound probe movements during a simulated nerve block. METHODS: The Blue Phantom was used to simulate a nerve block target. After IRB approval, verbal consent was obtained. Twenty participants, at different levels of training/experience, were asked to perform a simulated nerve block under ultrasound guidance with and without the HMD. The number of ultrasound probe and head movements and the time required to place the needle with and without the HMD were recorded. Results were analyzed using a paired t-test and significance was accepted with P < 0.05. RESULTS: Participants were significantly faster (7.1 vs 10.9 seconds) performing the simulated block with the HMD than without. Additionally, the HMD significantly decreased the number of operator head and ultrasound probe movements. CONCLUSIONS: Use of a HMD improved efficiency and human factors during simulated nerve blocks. This suggests that a clinical study to see if this observation translates into a clinical setting is warranted. PMID- 25930717 TI - When one receptor closes, another opens: claudins and the hepatitis C virus E1 glycoprotein. PMID- 25930718 TI - Assessing the value of token reinforcement for individuals with autism. AB - The use of token systems has been supported across a variety of populations, but little research has evaluated the reinforcing value of token systems for individuals with autism. We used progressive-ratio schedules to compare the reinforcing value of an established token system, primary reinforcement, and tokens unpaired with reinforcement. Token systems were variably reinforcing for 2 students with autism and more so than primary reinforcement for 1 student. Results support formal assessment of the effectiveness of token systems. PMID- 25930719 TI - 5-year follow-up of a randomized controlled trial of immediate versus delayed zoledronic acid for the prevention of bone loss in postmenopausal women with breast cancer starting letrozole after tamoxifen: N03CC (Alliance) trial. AB - BACKGROUND: Postmenopausal women with breast cancer receiving aromatase inhibitors are at an increased risk of bone loss. The current study was undertaken to determine whether upfront versus delayed treatment with zoledronic acid (ZA) impacted bone loss. This report described the 5-year follow-up results. METHODS: A total of 551 postmenopausal women with breast cancer who completed tamoxifen treatment and were undergoing daily letrozole treatment were randomized to either upfront (274 patients) or delayed (277 patients) ZA at a dose of 4 mg intravenously every 6 months. In the patients on the delayed treatment arm, ZA was initiated for a postbaseline bone mineral density T-score of <-2.0 or fracture. RESULTS: The incidence of a 5% decrease in the total lumbar spine bone mineral density at 5 years was 10.2% in the upfront treatment arm versus 41.2% in the delayed treatment arm (P<.0001). A total of 41 patients in the delayed treatment arm were eventually started on ZA. With the exception of increased NCI Common Toxicity Criteria (CTC) grade 1/2 elevated creatinine and fever in the patients treated on the upfront arm and cerebrovascular ischemia among those in the delayed treatment arm, there were no significant differences observed between arms with respect to the most common adverse events of arthralgia and back pain. Osteoporosis occurred less frequently in the upfront treatment arm (2 vs 8 cumulative cases), although this difference was not found to be statistically significant. Bone fractures occurred in 24 patients in the upfront treatment arm versus 25 patients in the delayed treatment arm. CONCLUSIONS: Immediate treatment with ZA prevented bone loss compared with delayed treatment in postmenopausal women receiving letrozole and these differences were maintained at 5 years. The incidence of osteoporosis or fractures was not found to be significantly different between treatment arms. PMID- 25930720 TI - Streptococcal infection and immune response in children with Tourette's syndrome. AB - BACKGROUND: Streptococcal infection and basal ganglia inflammation are hypothesized to be involved in Tourette's syndrome (TS). There is a need for effective therapies for managing TS. We studied streptococcal infection and immunity in TS following immunomodulator (pidotimod) therapy. METHODS: Blood samples from 58 patients with TS and 128 age-matched healthy controls enabled measurement of antistreptolysin O (ASO), T cells, natural killer (NK) cells, interleukin-6 (IL-6) and interleukin-8 (IL-8), and tumor necrosis factor-alpha (TNF-alpha). Forty-four patients with abnormal T cell numbers were divided into two groups and treated with pidotimod granules (pidotimod group, n = 20) or pidotimod plus dopaminergic receptor antagonists (combination group, n = 24). Yale Global Tic Severity Scale (YGTSS) scores and immunologic indices were assessed after treatment. RESULTS: An ASO >1:200 was found in 22.4% of children with TS, 7.5% of controls, and 38.9% of children with both TS and attention deficit hyperactivity disorder (ADHD) compared to 15.0% of children with TS alone (P < 0.05). Children with TS showed decreased CD3(+) and CD4(+) T cells, CD4(+)/CD8(+) ratio, IL-6 and IL-8, increased NKC and TNF-alpha (P < 0.05) as compared to controls. ASO-positive children with TS had lower CD4(+) T cells as compared to ASO-negative children with TS, and lower IL-6 and IL-8 levels as compared to controls (P < 0.05). After 8 weeks of pidotimod treatment, IL-8 was increased compared to either tiapride hydrochloride or haloperidol and pidotimod (P < 0.05). CONCLUSIONS: Streptococcal infection in TS patients is associated with immune and cytokine dysfunction, which can be potentially managed with immunomodulator therapy. PMID- 25930721 TI - Desmoplastic infantile astrocytoma with multiple intracranial and intraspinal localizations at presentation. AB - PURPOSE: Desmoplastic infantile gliomas (DIG) are rare tumors that occur in infants aged between 1 and 24 months. The tumor in general has a favorable prognosis after surgical resection. There are no treatment algorithms, however, for patients with multiple intracranial and intraspinal presentations. CASE REPORT: In an 11-month-old girl with a history of nystagmus, magnetic resonance imaging (MRI) demonstrated contrast-enhancing lesions in the suprasellar region, the cerebellar vermis, and the spinal axis. The tumor in the cerebellar vermis was removed via a suboccipital midline approach. The histological examination revealed a desmoplastic infantile astrocytoma (DIA) WHO grade I. Postoperatively, it was decided to adopt a wait-and-see strategy. Further development, up to 16 months after surgery, was unremarkable. Follow-up MRI showed no recurrence of the posterior fossa tumor, mild progress of the suprasellar tumor, and significant regression of the spinal tumors. CONCLUSION: DIA is a rare mostly benign brain tumor found in infants. The final diagnosis always relies on histology. Surgical resection is the recommended therapy for symptomatic tumors; however, more experience is needed to develop treatment recommendations for multiple-site tumors. PMID- 25930722 TI - Development and content validation of performance assessments for endoscopic third ventriculostomy. AB - PURPOSE: This study aims to develop and establish the content validity of multiple expert rating instruments to assess performance in endoscopic third ventriculostomy (ETV), collectively called the Neuro-Endoscopic Ventriculostomy Assessment Tool (NEVAT). METHODS: The important aspects of ETV were identified through a review of current literature, ETV videos, and discussion with neurosurgeons, fellows, and residents. Three assessment measures were subsequently developed: a procedure-specific checklist (CL), a CL of surgical errors, and a global rating scale (GRS). Neurosurgeons from various countries, all identified as experts in ETV, were then invited to participate in a modified Delphi survey to establish the content validity of these instruments. In each Delphi round, experts rated their agreement including each procedural step, error, and GRS item in the respective instruments on a 5-point Likert scale. RESULTS: Seventeen experts agreed to participate in the study and completed all Delphi rounds. After item generation, a total of 27 procedural CL items, 26 error CL items, and 9 GRS items were posed to Delphi panelists for rating. An additional 17 procedural CL items, 12 error CL items, and 1 GRS item were added by panelists. After three rounds, strong consensus (>80% agreement) was achieved on 35 procedural CL items, 29 error CL items, and 10 GRS items. Moderate consensus (50-80% agreement) was achieved on an additional 7 procedural CL items and 1 error CL item. The final procedural and error checklist contained 42 and 30 items, respectively (divided into setup, exposure, navigation, ventriculostomy, and closure). The final GRS contained 10 items. CONCLUSIONS: We have established the content validity of three ETV assessment measures by iterative consensus of an international expert panel. Each measure provides unique assessment information and thus can be used individually or in combination, depending on the characteristics of the learner and the purpose of the assessment. These instruments must now be evaluated in both the simulated and operative settings, to determine their construct validity and reliability. Ultimately, the measures contained in the NEVAT may prove suitable for formative assessment during ETV training and potentially as summative assessment measures during certification. PMID- 25930723 TI - Awareness and uptake of measures for preventing CNS birth defects among mothers of affected children in a sub-Saharan African neurosurgeon's practice. AB - BACKGROUND: The two main measures used in the reduction of the birth prevalence of CNS birth defects are (i) folic acid, FA, supplementation/food fortification for reproductively active women as the primary one, and (ii) timely screening/intrauterine diagnosis, and possibly termination of the affected pregnancies. MATERIALS AND METHODS: We performed a cross-sectional survey of the levels of awareness and uptake of these measures in a consecutive cohort of mothers of children with CNS birth defects presenting for neurosurgical treatment in an African clinical practice. RESULTS: There were 151 cases, 101 of them neural tube defects, NTDs. The level of awareness of the role of FA in prevention of these defects was low, 18.8%, and dietary multivitamin supplementation was ingested by only10.7% of the study subjects. The mothers' obstetric behavior in the index pregnancies was suboptimal: pregnancy registration and commencement of obstetric supplements were at median gestational age of 4 months, and obstetric ultrasonography was obtained infrequently, and in an unregulated milieu. Only 17.8% of these CNS birth defects were diagnosed prenatally, but >80% of the mothers would have liked to have the intrauterine diagnosis, and about 23% might have asked for termination of these pregnancies. CONCLUSIONS: The levels of awareness and uptake of measures for preventing CNS birth defects among mothers of affected children in this sub-Saharan African women cohort are low. Interestingly, many of the mothers were very favorably disposed to receiving, and acting on, the information about the screen detected CNS birth defects in their fetuses. PMID- 25930724 TI - Phase I trial of weekly MK-0752 in children with refractory central nervous system malignancies: a pediatric brain tumor consortium study. AB - PURPOSE: Amplification and high levels of NOTCH ligand expression have been identified in several types of pediatric brain tumors. A phase I trial of weekly MK-0752, an oral inhibitor of gamma-secretase, was conducted in children with recurrent central nervous system (CNS) malignancies to estimate the maximum tolerated dose, dose-limiting toxicities (DLT), pharmacokinetics (PK), and pharmacodynamics of weekly MK-0752. METHODS: MK-0752 was administered once weekly at 1000 and 1400 mg/m(2) using a rolling-6 design. PK analysis was performed during the first course. NOTCH and HES expression was assessed by immunohistochemistry and Western blot. RESULTS: Ten eligible patients were enrolled (median age 8.8 years; range 3.1-19.2) with diagnoses of brain stem glioma (n = 3), ependymoma (n = 2), anaplastic astrocytoma (n = 1), choroid plexus carcinoma (n = 2), medulloblastoma (n = 1), and primitive neuroectodermal tumor (n = 1). Nine were evaluable for toxicity. One DLT of fatigue occurred in the six evaluable patients enrolled at 1000 mg/m(2)/dose. No DLTs were experienced by three patients treated at 1400 mg/m(2)/dose. Non-dose-limiting grade 3 toxicities included lymphopenia, neutropenia, and anemia. Median number of treatment courses was 2 (range 1-10). Two patients continued on therapy for at least 6 months. The median (range) C(max) of MK-0752 was 88.2 MUg/mL (40.6 to 109 MUg/mL) and 60.3 MUg/mL (59.2 to 91.9 MUg/mL) in patients receiving 1000 and 1400 mg/m(2)/week, respectively. NOTCH expression was decreased in six of seven patients for whom tissue was available at 24 h post-MK-0752. CONCLUSION: MK-0752 is well tolerated and exhibits target inhibition at 1000 and 1400 mg/m(2)/week in children with recurrent CNS malignancies. PMID- 25930725 TI - Risk of fracture prevention in spina bifida patients: correlation between bone mineral density, vitamin D, and electrolyte values. AB - PURPOSE: The aim of our study was to investigate the relationship between bone mineral density (BMD), vitamin D, and electrolyte blood values in patients with spina bifida, to find a possible therapeutic regimen and an intervention to reduce the risk of fractures in this population. METHODS: BMD values were measured in 49 patients (32 females, 17 males; aged 14.1 +/- 3.86 years; range 5 20 years) using dual-energy X-ray absorptiometry (DEXA) and were analyzed based on sex, the level of spinal involvement, vitamin D, and electrolyte values, physical activity, body mass index (BMI), and ambulatory status [patients were divided into three subgroups: full-time wheelchair (FTWC), limited ambulator (LA), and full-time ambulator (FTA)]. These data were analyzed considering sex-, age-, and BMD-matched values and compared with those of normal population. RESULTS: BMD was significantly lower in these patients compared with that in the general healthy population (Z-score: -1.2 +/- 1.8); in particular, females had Z score values significantly lower that of the males (Z-score: -2.43 +/- 2.02; P < 0.0004). In FTWC subgroup, Z-score was lower than that of the other two subgroups (P < 0.009). Vitamin D values were significantly lower compared with those in the general healthy population (vitamin D spina bifida group: 14.6 +/- 8.7 mg/dL; normal subjects: 35 +/- 9.8 mg/dL; P < 0.001). Subjects with spina bifida showed hypophosphatemia (<3 mg/dL) because of the lower levels of vitamin D (3.1 +/- 0.9 mg/dL; P < 0.001). CONCLUSIONS: Spina bifida patients showed lower BMD, vitamin D, and electrolyte values than the healthy population; hence, they have an increase risk of developing pathological fractures. Vitamin D supplementation for a longer time period could reduce this risk. PMID- 25930726 TI - A rare and unexpected clinical progress and location on a primary extradural spinal hydatid cyst in a pediatric patient: a case report. AB - BACKGROUND: Involvement of spine in patients with hydatid disease (HD) is less than 1% and primary intra-spinal extradural HD is extremely rare. Although this disease is introduced as benign pathology according to its clinical presentation and biological behavior, intraoperative rupture of the cyst may aggravate the patients' outcome in the long-term especially in pediatric patient population. CASE PRESENTATION: We report a 9-year-old girl who presented a progressive neurological deterioration due to an enlargement of a ventrally located extradural hydatid cyst within the thoracic spinal canal. Total removal of the cyst was achieved by preserving the capsule integrity for preventing potential seeding. Our preoperative initial diagnosis based on the radiological findings was confirmed as cyst hydatid histopathologically. CONCLUSION: Cyst hydatid should be considered in the differential diagnosis of the presence of homogenous cystic lesions with regular shape inside the spinal canal especially in patients from endemic region. To our knowledge, this pediatric patient is the first case of cyst hydatid located ventral side of the spinal cord extradurally located inside the spinal canal showing no extension. PMID- 25930728 TI - Strategies of fluorescence staining for trace total ribonucleic acid analysis by capillary electrophoresis with argon ion laser-induced fluorescence. AB - In this work, five fluorescent dyes (SYTO-9, SYBR Green I, SYBR Green II, SYBR Safe, and SYBR Gold) were used as both on-column and precolumn stains for total RNA analysis by CE-LIF with Ar ion laser excitation. In the on-column RNA stain, the SYTO-9 provided the highest fluorescence intensity and the lowest detectable concentration, as low as 10 pg/MUL, while the SYBR Green II and SYBR Gold were adsorbed on the poly(ethylene oxide) thus affected the separation efficiency. As a precolumn stain, SYBR Gold was the most sensitive among the five dyes due to the strong affinity between the dye and RNA molecules. As a result, a single-cell quantity of RNA (10-30 pg per cell) could be detected by CE-LIF with precolumn staining by SYBR Gold. Because of the great savings of fluorescent dye using precolumn stain (one button dye may use for one million stain), this method is the best strategy for RNA staining in terms of cost-effectiveness and sensitivity. PMID- 25930727 TI - A comprehensive review of the sub-axial ligaments of the vertebral column: part I anatomy and function. AB - BACKGROUND: As important as the vertebral ligaments are in maintaining the integrity of the spinal column and protecting the contents of the spinal canal, a single detailed review of their anatomy and function is missing in the literature. METHODS: A literature search using online search engines was conducted. RESULTS: Single comprehensive reviews of the spinal ligaments are not found in the extant medical literature. CONCLUSIONS: This review will be useful to those who treat patients with pathology of the spine or who interpret imaging or investigate the anatomy of the ligaments of the vertebral column. PMID- 25930729 TI - College issues guidance to identify substance misuse among older people. PMID- 25930730 TI - Hepatocyte growth factor activator is a potential target proteinase for Kazal type inhibitor in turkey (Meleagris gallopavo) seminal plasma. AB - A peculiar characteristic of turkey seminal plasma is the increased activity of serine proteinases. It is of interest if the single-domain Kazal-type inhibitor controls the activity of turkey seminal plasma proteinases. Pure preparations of the Kazal-type inhibitor and anti-Kazal-type inhibitor monospecific immunoglobulin Gs were used as ligands in affinity chromatography for proteinase isolation from turkey seminal plasma. Gene expression and the immunohistochemical detection of the single-domain Kazal-type inhibitor in the reproductive tract of turkey toms are described. The hepatocyte growth factor activator (HGFA) was identified in the binding fraction in affinity chromatography. Hepatocyte growth factor activator activity was inhibited by the Kazal-type inhibitor in a dose dependent manner. This protease was a primary physiological target for the single domain Kazal-type inhibitor. Numerous proteoforms of HGFA were present in turkey seminal plasma, and phosphorylation was the primary posttranslational modification of HGFA. In addition to HGFA, acrosin was a target proteinase for the single-domain Kazal-type inhibitor. In seminal plasma, acrosin was present only in complexes with the Kazal-type inhibitor and was not present as a free enzyme. The single-domain Kazal-type inhibitor was specific for the reproductive tract. The germ cell-specific expression of Kazal-type inhibitors in the testis indicated an important function in spermatogenesis; secretion by the epithelial cells of the epididymis and the ductus deferens indicated that the Kazal-type inhibitor was an important factor involved in the changes in sperm membranes during maturation and in the maintenance of the microenvironment in which sperm maturation occurred and sperm was stored. The role of HGFA in these processes remains to be established. PMID- 25930731 TI - Effect of luteinizing hormone on rabbit ovarian superstimulation and embryo developmental potential. AB - Assisted reproduction technologies require ovarian stimulation to increase the number of oocytes and embryos. Currently, superstimulation is achieved by gonadotropin treatment, but the embryo yield and quality are highly variable. Commonly, commercial preparations derived from pituitary and urinary origin are used to superovulate. Hence, ovarian superstimulation protocols have usually included both FSH and LH. The appearance of recombinant gonadotropins manufactured by genetic engineering techniques has ensured high quality and batch to-batch consistency. Moreover, this enables us to assess the importance of LH in the ovarian stimulation. The main aim of this study was to evaluate the effect of recombinant human LH supplementation (10%) on embryonic development produced by rabbit does superovulated with low or high concentration (18.75 or 37.50 IU) of recombinant human FSH (rhFSH). Females treated with rhFSH increased the ovulation rate, and it was significantly higher when the high FSH dose was supplemented with LH. The superstimulation treatment used did not significantly affect in vitro development rate until the expanded blastocyst stage. The results of this study seem to suggest that, in terms of superovulatory response, when rabbit does are treated with 37.5-IU rhFSH, the use of LH supplementation allows an increase in the number of follicles recruited and the quality of embryos, in terms of ability to develop in vitro until blastocyst, and the expression profile of OCT4, NANOG, and SOX2 genes is not affected. PMID- 25930732 TI - Fibroblast growth factor 17 and bone morphogenetic protein 15 enhance cumulus expansion and improve quality of in vitro-produced embryos in cattle. AB - Bone morphogenetic protein 15 (BMP15) and members of the fibroblast growth factor (FGF) family are expressed by the oocyte and are involved in the control of cumulus cell function. We tested the hypothesis that FGF17, alone or combined with BMP15 in the maturation medium, enhances cumulus expansion, meiosis progression, embryonic development, and expression of mRNA encoding key genes regulating expansion (prostaglandin-endoperoxide synthase 2 [PTGS2], hyaluronan synthase 2 [HAS2], tumor necrosis factor-stimulated gene 6 [TNFAIP6], and pentraxin 3 [PTX3]) and markers of oocyte developmental competence (phosphofructokinase [PFKP], gremlin [GREM1], versican [VCAN], and the genomic progesterone receptor [nPR]) in cumulus cells. Fibroblast growth factor 17 and BMP15 increased the percentage of fully expanded cumulus-oocyte complexes (COCs), but there was no additive effect when both were combined. Neither FGF17 nor BMP15 altered the percentage of oocytes reaching meiosis II at the end of COC culture or cleavage and blastocyst rates after IVF. However, embryo quality, as assessed by the number of cells in the inner cell mass, was improved by the combination of FGF17 with BMP15. Fibroblast growth factor 17 alone did not alter gene expression in cumulus cells at the end of IVM, whereas BMP15 increased PTGS2 and PTX3 mRNA levels. The combination of FGF17 and BMP15 increased nPR mRNA abundance in cumulus cells but did not change the expression of other markers of developmental competence. This study provides novel evidence that FGF17 enhances cumulus expansion in bovine COCs submitted to IVM and that the supplementation of the IVM medium with FGF17 and BMP15 may improve embryo quality. PMID- 25930733 TI - Steady-state level of messenger RNA and immunolocalization of aquaporins 3, 7, and 9 during in vitro growth of ovine preantral follicles. AB - Aquaporins (AQPs) are a well-conserved family of small (approximately 30 kDa) membrane channel proteins that facilitate rapid movement of fluids and have a unique tissue-specific pattern of expression. These proteins have been found in the female reproductive systems of humans, rats, and mice. However, the expression and cellular localization of AQPs have not extensively been studied in the female reproductive system of sheep. Therefore, this study aimed to evaluate, by real-time polymerase chain reaction and immunohistochemistry respectively, the levels of messenger RNA and the immunolocalization of AQP3, AQP7, and AQP9 in large isolated ovine secondary follicles over a period of IVC. Our analysis revealed that AQP3 and AQP9 were present predominately in follicles that exhibited antrum formation, suggesting a crucial role of these AQPs in the formation of the antrum. Interestingly, AQP7 was only expressed in follicles that had not formed an antrum by Day 12 of culture. In conclusion, the presence of protein channels (AQP3 and AQP9) seems to be essential for the formation of the antrum in isolated ovine secondary follicles cultured in vitro and thus plays an important role during folliculogenesis in this species. PMID- 25930734 TI - Quality of life in rheumatological patients: The impact of personality disorders. AB - OBJECTIVE: Rheumatological diseases are associated with lower quality of life (QoL) levels. Psychiatric disturbances are frequently observed in these patients. This study examined the impact of personality disorders on the QoL of patients with rheumatological diseases. METHOD: The study sample consisted of 142 participants including patients suffering from rheumatological disease with a personality disorder (n = 30), without any personality disorder (n = 112), and healthy control participants without physical or psychiatric disorders (n = 60). The Structured Clinical Interview for Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition (SCID-I) and the Structured Clinical Interview for DSM, Revised Third Edition Personality Disorders (SCID-II) were used to determine Axis I and Axis II psychiatric disorders, respectively. QoL levels were assessed by means of the World Health Organization QoL Assessment-Brief. RESULTS: The subscale scores of physical health, psychological health, and social relationships were significantly lower in patients with rheumatological disease regardless of the existence of personality disorder compared with the control participants. Rheumatological patients with a personality disorder had significantly lower subscale scores of psychological health (p = 0.003) and social relationships (p < 0.003) compared with patients without any personality disorder. CONCLUSIONS: Personality disorders seem to be a relevant factor that maybe associated with QoL in patients suffering from rheumatological disease. PMID- 25930735 TI - Increased serum prolactin in borderline personality disorder. AB - Although there is an important interaction between serotonergic system, prolactin and suicidal behavior, and impulsivity, no investigation examined the prolactin values in borderline personality disorder in which suicidal behavior and impulsivity are core symptom dimensions. In this context, in the present investigation, we planned to measure serum prolactin levels in the patients with borderline personality disorder. The study comprised 15 patients with borderline personality disorder and 15 healthy controls. Prolactin values were measured in both patients and control subjects. The patients had abnormally higher mean value of prolactin compared to those of healthy controls (48.66 +/- 36.48 mg/dl for patients vs. 15.20 +/- 7.81 mg/dl for healthy controls). There was no correlation between prolactin values and any demographic variables for both the patients and control subjects. In conclusion, our present results suggest that prolactin values increased in the patients with borderline personality disorder and are required to be replicated by more comprehensive and detailed further studies to decipher the exact roles of prolactin increase. PMID- 25930736 TI - Depression: An important factor associated with disability among patients with chronic low back pain. AB - OBJECTIVE: The study aimed to compare the associations of pain indices, depression, anxiety, and somatic symptoms with disability among outpatients with chronic low back pain (CLBP). METHOD: Consecutive orthopedics outpatients with CLBP in a medical center were enrolled. The Oswestry Disability Index and physical functioning and role limitations-physical of the Short-Form 36 were used as disability indices. The Hospital Anxiety and Depression Scale (HADS) and the Depression and Somatic Symptoms Scale were employed. Pain intensity was rated using a visual analogue scale. Multiple linear regressions were used to determine the impacts of these independent factors related to disability. RESULTS: Among 225 participants (122 male, 103 female) with CLBP, patients with major depressive disorder and associated leg symptoms of CLBP had higher disability indices. A tendency was noted that depression (HADS-depression) had the highest correlation to the three disability indices, followed by pain intensity, anxiety, and somatic symptoms. After controlling for demographic variables, HADS-depression explained the highest variance of disability, followed by pain intensity. CONCLUSION: Depression was the most powerful factor associated with disability of CLBP among depression, anxiety, and somatic symptoms. Depression should be evaluated when investigating disability among patients with CLBP. PMID- 25930737 TI - Perception of social exclusion, neuropathy, and quality of life among Hansen's disease patients. AB - BACKGROUND: Leprosy subjects are strongly affected not only by physical issues such as peripheral neuropathy but also by massive social exclusion that may be related to quality of life (QoL) impairment. However, there are as yet no studies evaluating the impact of perceived stigma in conjunction with neuropathy on QoL and the respective role of each one on QoL. OBJECTIVE: The present study aims to investigate the variations in clinical and socio-demographic profile of Hansen's disease patients with/without perception of social exclusion (PSE) and neuropathy as the impact of both conditions on their QoL. METHODS: A sample of 160 consecutive leprosy outpatients seeking treatment in two reference centers for leprosy in Brazil was recruited. Patients were assessed using a socio-demographic questionnaire, M.I.N.I. PLUS and SF-36. Data from medical records were also collected. Participants were divided into four groups: control group, perceived stigma, neuropathy, and stigma neuropathy. RESULTS: Of the 160 patients who consented to participate, 78.75% completed the survey. All four groups were similar in terms of demographic parameters, except for occupational status, which was compensated statistically. The group with neuropathy and PSE reported the worst QoL in half of the evaluated domains. The cross-sectional design does not allow cause and effect to be established between variables, and the relatively small sample size may limit the ability to demonstrate a relative decrease in QoL scores from the isolated variables analyzed. CONCLUSIONS: The results of this survey show that the presence of both neuropathy and PSE significantly increases impairment in QoL, especially in some specific domains. PMID- 25930739 TI - Salinipyrone and Pacificanone Are Biosynthetic By-products of the Rosamicin Polyketide Synthase. AB - Salinipyrones and pacificanones are structurally related polyketides from Salinispora pacifica CNS-237 that are proposed to arise from the same modular polyketide synthase (PKS) assembly line. Genome sequencing revealed a large macrolide PKS gene cluster that codes for the biosynthesis of rosamicin A and a series of new macrolide antibiotics. Mutagenesis experiments unexpectedly correlated salinipyrone and pacificanone biosynthesis to the rosamicin octamodule Spr PKS. Remarkably, this bifurcated polyketide pathway illuminates a series of enzymatic domain- and module-skipping reactions that give rise to natural polyketide product diversity. Our findings enlarge the growing knowledge of polyketide biochemistry and illuminate potential challenges in PKS bioengineering. PMID- 25930740 TI - Direct insertion of an ultra-slim upper endoscope for cholangioscopy in patients undergoing choledochoduodenostomy. AB - Direct peroral cholangioscopy (POC) using an ultra-slim upper endoscope is one modality of POC for intraductal endoscopic evaluation and treatment of the bile duct. Choledochoduodenostomy (CDS) is one modality of biliary bypass surgery that provides a new route to the bile duct. We carried out direct POC using an ultra slim upper endoscope without the use of accessories in 10 patients (four sump syndromes, three bile duct strictures and three intrahepatic duct stones) previously undergoing surgical CDS. Direct POC was successful in all patients. The use of an intraductal balloon catheter was required in one patient for advancement of the endoscope into the bile duct. Distal bile ducts with sump syndromes were cleared using baskets and water irrigation under direct POC. Cholangiocarcinoma was diagnosed in one patient with hilar bile duct stricture after cholangioscopic evaluation and a targeting forceps biopsy under direct POC. Intrahepatic duct stones were successfully extracted after intraductal fragmentation under direct POC. Oozing bleeding occurred during intraductal lithotripsy but stopped spontaneously. Direct POC using an ultra-slim upper endoscope without the assistance of accessories can easily be carried out in patients undergoing CDS. PMID- 25930742 TI - The non-motor heterogeneity of Parkinson disease. PMID- 25930741 TI - Treatment with 8-OH-modified adenine (TLR7 ligand)-allergen conjugates decreases T helper type 2-oriented murine airway inflammation. AB - A strategy to improve allergen-specific immunotherapy is to employ new adjuvants stably linked to allergens. The study is addressed to evaluate the in vivo and in vitro effects of allergens [natural Dermatophagoides pteronyssinus 2 (nDer p 2) and ovalbumin (OVA)] chemically bound to an 8-OH-modified adenine. Humoral and cellular responses were analysed in allergen-sensitized and challenged mice by using conjugates (Conj) in a therapeutic setting. The in vitro activity of the conjugates on cytokine production induced by bone marrow dendritic cells and the co-culture system was also investigated. The nDer p 2-Conj treatment in nDer p 2 primed and challenged BALB/c mice reduced the numbers of eosinophils in bronchoalveolar lavage fluid and lung, airway allergen-driven interleukin-13 (IL 13) production in lung mononuclear cells and IgE, in comparison with nDer p 2 treated mice. The increase of IgG2a paralleled that of interferon-gamma (IFN gamma) and IL-10 in allergen-stimulated spleen cells. Similar effects were elicited by treatment with OVA-Conj in an OVA-driven BALB/c model. The nDer p 2 Conj or OVA-Conj redirected memory T helper type 2 cells towards the production of IL-10 and IFN-gamma also in C57BL/6 mice and when subcutaneously administered. Interleukin-10, IL-12 and IL-27 were produced in vitro by Conj-stimulated bone marrow dendritic cells, whereas IL-10 and IFN-gamma were up-regulated in co cultures of CD11c(+) and CD4(+) T cells from Conj-treated mice stimulated with allergen. Cytofluorometric analysis indicated that the Conj expanded IFN-gamma- and IL-10- producing memory T cells. The Conj effects on IL-10(-/-) and IL-12(-/ ) mice confirmed the role of IL-10 and IFN-gamma in inducing a protective and balanced redirection the T helper type 2-mediated airway inflammation. PMID- 25930743 TI - Unique clonal relationship between T-cell acute lymphoblastic leukemia and subsequent Langerhans cell histiocytosis with TCR rearrangement and NOTCH1 mutation. AB - Acute lymphoblastic leukemia (ALL) occasionally develops before or after the onset of Langerhans cell histiocytosis (LCH). The mechanism of LCH developing after ALL remains unclear; thus the clonality of LCH developing during maintenance chemotherapy for T-cell ALL (T-ALL) was investigated. The T-ALL and LCH cells tested had the same T-cell receptor (TCR) gamma rearrangement. Mutation analysis of the NOTCH1 gene revealed 7213C>T (Q2405X) in exon 34 in T-ALL and LCH cells, but 5156T>C (I1719T) in exon 27 only in T-ALL. Polymerase chain reaction restriction fragment length polymorphism analysis revealed three patterns of NOTCH1 mutations in T-ALL cells. The results suggest that the T-ALL and LCH cells were derived from a common precursor with TCR rearrangement and a single NOTCH1 mutation, rather than LCH cells developing from a minor clone of T-ALL with single NOTCH1 mutation. PMID- 25930744 TI - 3'-UTR poly(T/U) repeat of EWSR1 is altered in microsatellite unstable colorectal cancer with nearly perfect sensitivity. AB - Approximately 15% of colorectal cancers exhibit instability of short nucleotide repeat regions, microsatellites. These tumors display a unique clinicopathologic profile and the microsatellite instability status is increasingly used to guide clinical management as it is known to predict better prognosis as well as resistance to certain chemotherapeutics. A panel of five repeats determined by the National Cancer Institute, the Bethesda panel, is currently the standard for determining the microsatellite instability status in colorectal cancer. Recently, a quasimonomorphic mononucleotide repeat 16T/U at the 3' untranslated region of the Ewing sarcoma breakpoint region 1 gene was reported to show perfect sensitivity and specificity in detecting mismatch repair deficient colorectal, endometrial, and gastric cancers in two independent populations. To confirm this finding, we replicated the analysis in 213 microsatellite unstable colorectal cancers from two independent populations, 148 microsatellite stable colorectal cancers, and the respective normal samples by PCR and fragment analysis. The repeat showed nearly perfect sensitivity for microsatellite unstable colorectal cancer as it was altered in 212 of the 213 microsatellite unstable (99.5%) and none of the microsatellite stable colorectal tumors. This repeat thus represents the first potential single marker for detecting microsatellite instability. PMID- 25930745 TI - (S001) Tumor Control and Toxicity Outcomes for Head and Neck Cancer Patients Re Treated With Intensity-Modulated Radiation Therapy (IMRT)-A Fifteen-Year Experience. PMID- 25930746 TI - (S002) Prognostic Value of Intraradiation Treatment FDG-PET Parameters in Locally Advanced Oropharyngeal Cancer. PMID- 25930747 TI - (S018) intensity-modulated radiation therapy or conformal radiation therapy and cardiopulmonary mortality risk in the elderly with esophageal cancer. PMID- 25930748 TI - (S036) Circulating Tumor DNA and Implications for Clinical Decision-Making in Stage I NSCLC. PMID- 25930749 TI - (S019) Radiation-Induced Liver Disease Following Liver SBRT for Primary Hepatic Malignancies: Analysis of a Prospective Institutional Study. PMID- 25930750 TI - (S003) Weekly IGRT Volumetric Response Analysis as a Predictive Tool for Locoregional Control in Head and Neck Cancer Radiotherapy. PMID- 25930751 TI - (S020) predictors of local-regional failure and the impact on overall survival in patients with resected exocrine pancreatic cancer. PMID- 25930752 TI - (S037) Phenotypic Diversity Measured in PET/CT Scans Predicts Overall Survival in Early-Stage Lung Adenocarcinoma. PMID- 25930753 TI - (S004) Combination of radiotherapy and cetuximab for aggressive, high-risk cutaneous squamous cell cancer of the head and neck: a propensity score analysis. PMID- 25930754 TI - (S005) Radiotherapy for carcinoma of the hypopharynx over five decades: experience at a single institution. PMID- 25930755 TI - (S038) pulmonary dose-volume predictors of radiation pneumonitis following stereotactic body radiation therapy. PMID- 25930756 TI - (S039) High-Resolution 4D Ventilation and Perfusion PET/CT Facilitates Functionally Adapted Intensity-Modulated Radiation Therapy (IMRT) in Lung Cancer. PMID- 25930757 TI - (S006) Impact of delays to adjuvant radiation therapy on survival in squamous cell carcinoma of the oral cavity and oropharynx. PMID- 25930758 TI - (S021) the role of neoadjuvant stereotactic body radiation therapy in pancreatic cancer. PMID- 25930759 TI - (S007) Intensity of Follow-Up After Radiotherapy for HPV-Positive Oropharyngeal Cancer. PMID- 25930760 TI - (S040) has severe acute esophagitis been reduced by 21st century treatment modalities among patients with limited-stage small-cell lung cancer? PMID- 25930761 TI - (S022) Experimental Insight Into the Preferential Cytotoxicity of Cancerous vs Noncancerous Cells of Metformin. PMID- 25930762 TI - (S023) ultrasound tissue characterization of breast fibrosis following hypofractionated breast radiotherapy. PMID- 25930763 TI - (S041) the role of chemoradiation in elderly limited-stage small-cell lung cancer patients. PMID- 25930764 TI - (S024) impact of pelvic radiotherapy on sexuality reported by women surviving cancer. PMID- 25930765 TI - (S025) discovery and validation of predictive factors for safety incident reports in patients receiving radiation therapy: comparative results from a large safety variance database. PMID- 25930766 TI - (S026) a novel method for detecting serious cardiac device errors in patients receiving radiotherapy using daily pulse checks. PMID- 25930767 TI - (S027) novel mechanisms of adaptive resistance in head and neck cancer. PMID- 25930768 TI - (S028) patient-level DNA damage and repair pathway profiles are prognostic after prostatectomy for high-risk prostate cancer. PMID- 25930769 TI - (S029) evaluating the role of a 21-gene expression assay in directing adjuvant radiotherapy decisions for elderly women with early-stage breast cancer. PMID- 25930771 TI - (S030) breast conservation in young women in the modern era. PMID- 25930770 TI - (S008) The Impact of HPV, HIV, and Smoking on Oncologic and Functional Outcomes in Patients With Head and Neck Cancer. PMID- 25930773 TI - (S009) Radiation therapy improves outcomes with desmoplastic melanoma of the head and neck. PMID- 25930772 TI - (S031) Dosimetric Analysis of Left-Sided Breast Cancer Treatment With Tomotherapy IMRT, IMRT, VMAT, and 3D-CRT. PMID- 25930774 TI - (S032) complications of contralateral prophylactic mastectomy with tissue expander reconstruction and potential impact on adjuvant oncologic therapy. PMID- 25930775 TI - (S033) predictive capacity of three comorbidity indices in estimating survival endpoints in women with early-stage endometrial carcinoma. PMID- 25930776 TI - (S010) A Phase III Randomized Trial of MRI-Mapped Dose-Escalated Salvage Radiotherapy Post-Prostatectomy: The MAPS Trial-Feasibility and Acute Toxicity. PMID- 25930777 TI - (S034) Pilot Phase II Trial of "Sandwich" Radiation and Combination Carboplatin and Paclitaxel Chemotherapy in Patients With High-Risk Endometrial Cancer. PMID- 25930778 TI - (S035) cervical cancer outcome prediction to high-dose-rate brachytherapy using quantitative magnetic resonance imaging analysis of tumor response to external beam radiotherapy. PMID- 25930779 TI - (S011) Hypofractionated vs Standard Fractionated Proton Beam Therapy for Early Stage Prostate Cancer: Interim Results of a Randomized Prospective Trial. PMID- 25930780 TI - (S042) Factors Influencing Brain Recurrence After PCI Among Patients With Limited Small-Cell Lung Cancer. PMID- 25930781 TI - (S012) Trends in the Selection of Definitive Treatment for Newly Diagnosed Prostate Cancer in Men < 60 Years Old. PMID- 25930782 TI - (S013) Heterogeneity Within the Prostate and Risk-Adapting Dose-Volume Analysis With SBRT for Prostate Cancer. PMID- 25930783 TI - (S014) pN+ Prostate Cancer (CaP) Does Not Imply Incurable Disease. PMID- 25930784 TI - (S015) Impact of health insurance status on prostate cancer treatment modality selection in the United States. PMID- 25930785 TI - (S043) changes in quality of life after radiation therapy for localized prostate cancer after dissemination of intensity-modulated radiation therapy. PMID- 25930786 TI - (S016) Intermediate-risk prostate cancer: a medicare-based cost comparison of five radiotherapy regimens. PMID- 25930787 TI - (S044) Patient-Reported Quality of Life After Stereotactic Body Radiotherapy (SBRT), Intensity-Modulated Radiotherapy (IMRT), and Brachytherapy. PMID- 25930788 TI - (S045) Equivalent Survival With Breast-Conserving Therapy and Mastectomy in Young Women Under the Age of 40 With Early-Stage Breast Cancer: A National Registry Based Stage-by-Stage Comparison. PMID- 25930789 TI - (S046) Prognosis for Patients With Metastatic Breast Cancer Who Achieve 'No Evidence-of-Disease' Status After Systemic or Local Therapy. PMID- 25930790 TI - (S047) Radiotherapy vs Chemotherapy Effects on Neuronal Architecture and Spine Density in the Hippocampus. PMID- 25930791 TI - (S048) identification of excellent and poor prognostic groups after stereotactic radiosurgery for spinal metastasis: secondary analyses of mature prospective trials. PMID- 25930792 TI - (S049) salvage stereotactic radiosurgery for locally recurrent brain metastases treated previously with stereotactic radiosurgery. PMID- 25930793 TI - (S050) cost-effectiveness of neurocognitive preservation for whole-brain radiotherapy. PMID- 25930794 TI - (S051) the role of temozolomide in the treatment of low-grade glioma. PMID- 25930795 TI - (S052) Inverse Optimization for Correlating 4DCT Ventilation Imaging and Radiation Dose. PMID- 25930796 TI - (S053) Nodal Surveillance With Diffusion-Weighted MRI After Definitive (Chemo) Radiotherapy for HPV-Predominant Squamous Cell Cancers of the Oropharynx and Unknown Primary. PMID- 25930797 TI - (S054) long-term survival and racial differences in pediatric hodgkin lymphoma patients from the state of Florida: three decades of experience. PMID- 25930798 TI - (S017) Factors associated with regional recurrence following lymphadenectomy for penile squamous cell carcinoma. PMID- 25930799 TI - (P001) Disparities in the local management of breast cancer in the United States according to health insurance status. PMID- 25930800 TI - (P002) Predictors of CNS disease in metastatic melanoma: desmoplastic subtype associated with higher risk. PMID- 25930801 TI - (P003) identification of somatic mutations using fine needle aspiration: correlation with clinical outcomes in patients with locally advanced pancreatic cancer. PMID- 25930802 TI - (P004) A Retrospective Study to Assess Disparities in the Utilization of Intensity-Modulated Radiotherapy (IMRT) and Proton Therapy (PT) in the Treatment of Prostate Cancer (PCa). PMID- 25930803 TI - (P047) the role of radiation therapy following adjuvant chemotherapy in pancreatic adenocarcinoma. PMID- 25930804 TI - (P048) mutational analysis by next-generation sequencing in patients with pancreatic adenocarcinoma. PMID- 25930805 TI - (P049) increased portal venous enhancement of hepatocellular carcinoma following transcatheter arterial chemoembolization. PMID- 25930806 TI - (P005) Ultrasensitive PSA Identifies Patients With Organ-Confined Prostate Cancer Requiring Postop Radiotherapy. PMID- 25930807 TI - (P006) the role of sequential imaging in cervical cancer management. PMID- 25930808 TI - (P050) Yttrium-90 Radioembolization for Unresectable, Chemorefractory Colorectal Cancer Liver Metastases in KRAS Wild-type and Mutant Patients. PMID- 25930809 TI - (P051) Intraductal Papillary Neoplasm of the Bile Duct: Prognostic Factors in SEER Outcomes of Benign and Malignant Cases. PMID- 25930810 TI - (P052) human papillomavirus in esophageal cancer: an institutional retrospective analysis. PMID- 25930811 TI - (P008) Pretreatment FDG Uptake of Nontarget Lung Tissue Correlates With Symptomatic Pneumonitis Following Stereotactic Ablative Radiotherapy (SABR). PMID- 25930812 TI - (P053) Esophageal Cancer Pathologic Complete Response Rate After Neoadjuvant Chemoradiation: Is There a Difference Between Academic Centers vs Community Centers. PMID- 25930813 TI - (P009) monte carlo dosimetry evaluation of lung stereotactic body radiosurgery. PMID- 25930814 TI - (P054) carbon ion therapy for chinese patients with prostate cancer: primary reports. PMID- 25930815 TI - (P055) can high-grade prostate cancer (Gleason 8-10) be cured with definitive local therapy without testosterone suppression? Five-year outcomes employing up front prostatectomy in patients with clinically localized, nonmetastatic disease. PMID- 25930816 TI - (P010) stereotactic body radiotherapy for treatment of adrenal gland metastasis: toxicity, outcomes, and patterns of failure. PMID- 25930817 TI - (P011) Stereotactic Radiosurgery and BRAF Inhibitor Therapy for Melanoma Brain Metastases Is Associated With Increased Risk for Radiation Necrosis. PMID- 25930818 TI - (P012) characteristics of mentorship during radiation oncology residency. PMID- 25930819 TI - (P056) ten-year outcomes of patients with Gleason score 9/10 prostate cancer treated with trimodality therapy. PMID- 25930820 TI - (P013) perioperative mortality in nonelderly adult patients with cancer: a population-based study evaluating healthcare disparities in the United States according to insurance status. PMID- 25930821 TI - (P057) a population-based study of men with low-volume, low-risk prostate cancer: does african-american race predict for more aggressive disease? PMID- 25930822 TI - (P058) the long-term economic value of hypofractionated prostate radiation: a cost minimization analysis of a randomized trial. PMID- 25930823 TI - (P059) trends in the utilization of radiotherapy in the management of renal cell carcinoma. PMID- 25930824 TI - (P015) Radiation Biological Responses of MRI-Linac vs Linac in Human Head and Neck and Lung Cancer Cells. PMID- 25930825 TI - (P016) The Cell Cycle Inhibitor P21 Regulates Langerhans Cell Radiation Resistance and PromotesT Regulatory Cell Induction Upon Exposure to Radiotherapy. PMID- 25930826 TI - (P017) dosimetric evaluation of respiratory-gated radiotherapy for left-sided breast cancer. PMID- 25930827 TI - (P060) impact of major psychiatric disorders on tolerance and outcomes for men with prostate cancer undergoing dose-escalated radiation therapy. PMID- 25930828 TI - (P018) Accelerated Partial Breast Radiotherapy Using VMAT-A Preliminary Dosimetric Comparison to Single-Entry Brachytherapy. PMID- 25930829 TI - (P061) anticoagulation use and improved outcomes in a predominantly african american population with high-risk prostate cancer. PMID- 25930830 TI - (P019) predictors of outcomes in breast cancer patients with oligometastases. PMID- 25930831 TI - (P062) Comparison of Stereotactic Body Radiotherapy (SBRT) and Conventional External Beam Radiotherapy (EBRT) in Renal Cell Carcinoma (RCC). PMID- 25930832 TI - (P063) Can Some High-Risk Prostate Cancer Patients Be Treated With a Shorter Course of Androgen Deprivation Therapy (ADT)? PMID- 25930833 TI - (P064) outcomes after adjuvant radiation therapy for prostate cancer at a comprehensive cancer center. PMID- 25930834 TI - (P065) lack of variation in pathologic upgrading and upstaging by race among patients with low-risk prostate cancer. PMID- 25930837 TI - (P096) Late Radiation-Associated Dysphagia (Late-RAD) With Lower Cranial Neuropathy After Oropharyngeal IMRT. PMID- 25930835 TI - (P020) 3D Conformal External Beam Radiation Therapy May Result in Lower Heart Dose and Risk of Radiation-Induced Major Coronary Events Compared With Multicatheter Balloon High-Dose-Rate Brachytherapy for Left-Sided Breast Cancer Patients. PMID- 25930836 TI - (P066) dosimetric analysis of proton therapy for prostate cancer: a single institutional experience. PMID- 25930839 TI - (P068) VMAT vs Eight-Field IMRT: Dosimetric Comparison of Pelvic Radiotherapy for High-Risk Prostate Cancer Patients in Terms of Bone Marrow Sparing. PMID- 25930838 TI - (P067) The Role of Offline PET-CT Imaging in Evaluating the Particle Beam Range and Beam Stop for Prostate Cancer Treated With Heavy Ion Therapy. PMID- 25930840 TI - (P069) Gleason 7 Prostate Adenocarcinoma Treated With High- or Low-Dose-Rate Brachytherapy: Impact of External Beam Radiotherapy and/or Androgen Deprivation Therapy. PMID- 25930841 TI - (P070) High-Risk Prostate Adenocarcinoma Treated With Whole-Pelvis Radiotherapy HDR Brachytherapy Boost Results in Very High Disease-Specific Survival. PMID- 25930842 TI - (P071) Socioeconomic Disparities in Baseline Magnetic Resonance Imaging (MRI) Utilization and Imaging Characteristics for Prostate Cancer (PCa) Patients Undergoing Radiotherapy. PMID- 25930843 TI - (P072) Analysis of Composite EQD2 Dose Distribution in Radiotherapy for Cervical Cancer Using Central Shielding Technique. PMID- 25930844 TI - (P073) optimal epidural analgesia during interstitial brachytherapy for treatment of gynecological cancer. PMID- 25930845 TI - (P074) the use of stereotactic body radiotherapy in lieu of brachytherapy in patients with cervical or endometrial cancer. PMID- 25930846 TI - (P075) Management of Nodal Recurrences of Endometrial Cancer With IMRT. PMID- 25930847 TI - (P076) postoperative treatment recommendations for stage I endometrial cancer: a survey of society of gynecologic oncology members. PMID- 25930848 TI - (P077) Defining the Pendulum Swing From Whole-Pelvic Radiation Therapy (WPRT) Alone to Vaginal Brachytherapy (VB) in the Adjuvant Setting for Endometrial Cancer: A SEER-Based Analysis From Years 2000-2011. PMID- 25930849 TI - (P097) tumor density, size, and histology in the outcome of stereotactic body radiation therapy for early-stage non-small-cell lung cancer: a single institution experience. PMID- 25930850 TI - (P098) dosimetric predictors of pulmonary toxicity in patients with malignant pleural mesothelioma receiving radiation therapy to the intact lungs. PMID- 25930851 TI - (P099) Influence of Surveillance PET/CT on Detection of Early Recurrence Following Definitive Radiation in Stage III Non-Small-Cell Lung Cancer. PMID- 25930852 TI - (P100) intensity-modulated radiation therapy after extrapleural pneumonectomy with and without chemotherapy for malignant pleural mesothelioma: no fatal pulmonary toxicity and long-term survival. PMID- 25930853 TI - (P101) Does Maximum SUV From F-18 PET Scan Predict Outcomes for Early-Stage Non Small-Cell Lung Cancer Treated With Stereotactic Body Radiotherapy (SBRT)? PMID- 25930854 TI - (P102) surgery improves survival in 14,228 patients with malignant pleural mesothelioma. PMID- 25930855 TI - (P103) a new score predicts survival in patients with non-small-cell lung cancer. PMID- 25930856 TI - (P104) Esophagus- and Contralateral Lung-Sparing IMRT for Locally Advanced Lung Cancer in the Community Hospital Setting. PMID- 25930857 TI - (P105) Community-Based Early-Stage Treatment (BEST) Outcomes for NSCLC. PMID- 25930858 TI - (P106) Dosimetric Comparisons of Treatment by Different Radiotherapy Techniques for Stage III Non-Small-Cell Lung Cancer. PMID- 25930859 TI - (P107) Vero SBRT Treatment of Moving Lung Tumors. PMID- 25930860 TI - (P108) Stereotactic Body Radiation Therapy for the Treatment of Large (> 5 cm) Primary Non-Small-Cell Carcinoma. PMID- 25930861 TI - (P109) Standard Immunochemotherapy Plus Radiation vs Dose-Intense Chemotherapy With Rituximab in Stage I/II Primary Mediastinal Large B-Cell Lymphoma: A Single Institution Experience. PMID- 25930862 TI - (P110) hodgkin lymphoma and pregnancy: treatment patterns and survival outcomes of women treated with modern chemotherapy and radiotherapy. PMID- 25930863 TI - (P111) single-isocenter frameless volumetric-modulated arc radiosurgery for multiple intracranial metastases. PMID- 25930864 TI - (P112) spine stereotactic radiosurgery in the treatment of metastatic pheochromocytoma: a case series. PMID- 25930866 TI - (P079) retrospective review of chemoradiation in the preoperative or definitive management of locally advanced vulvar cancer. PMID- 25930865 TI - (P078) radiation therapy in the management of carcinosarcoma of the uterus. PMID- 25930867 TI - (P080) favorable outcomes using radiation therapy after chemotherapy in the management of primary, recurrent, and metastatic ovarian cancer. PMID- 25930868 TI - (P081) SBRT Boost as a Substitute for Brachytherapy in the Definitive Treatment of Gynecologic Malignancies With Radiotherapy. PMID- 25930869 TI - (P082) Outcomes of Definitive Radiotherapy for T2N0 Squamous Cell Carcinoma of the Glottis: A Single-Institution Retrospective Study. PMID- 25930870 TI - (P083) Concurrent Chemotherapy + IMRT in Locally Advanced Squamous Cell Carcinoma of Head and Neck: What Is the Appropriate Chemotherapy? PMID- 25930871 TI - (P084) long-term functional and oncologic outcomes of esthesioneuroblastoma. PMID- 25930872 TI - (P085) Oncologic and Functional Outcomes of Salivary Gland Tumors (SGTs) With Pathologically Proven Perineural Invasion (PNI). PMID- 25930873 TI - (P021) improving clinical documentation and prospectively populating a research database through an electronic data capture system for routine clinical care. PMID- 25930874 TI - (P022) proton therapy on an incline beam line: acute toxicity outcomes in locally advanced breast cancer patients. PMID- 25930875 TI - (P023) Dosimetric Evaluation of Accelerated Partial Breast Irradiation Utilizing the ViewRay Magnetic Resonance Image-Guided Radiation Therapy System. PMID- 25930876 TI - (P024) predictors of radiation-induced skin toxicity: data from a prospective cohort receiving breast radiation. PMID- 25930877 TI - (P025) t3 tumors and breast conservation. PMID- 25930878 TI - (P026) Is Cause-Specific Survival Similar for Estrogen Receptor- and Progesterone Receptor-Negative Early-Stage Invasive Lobular and Invasive Ductal Cancers? A National Registry SEER Database Study. PMID- 25930879 TI - (P027) increasing use of postlumpectomy radiotherapy for ductal carcinoma in situ of the breast in the United States. PMID- 25930880 TI - (P028) adjuvant radiation therapy after lumpectomy according to insurance status. PMID- 25930881 TI - (P029) A Comparison of CT- and MRI-Defined Lumpectomy Cavity for Radiotherapy Planning of Breast Cancer. PMID- 25930882 TI - (P030) metaplastic breast carcinoma at a single institution: clinical-pathologic characteristics and outcome. PMID- 25930883 TI - (P113) posttreatment sequelae for long-term survivors of brain metastases. PMID- 25930884 TI - (P114) Radiotherapeutic Care Within the Veterans Health Administration of US Veterans With Metastatic Cancer to the Brain: Supportive Measures (Part 1 of 2 Reports). PMID- 25930885 TI - (P115) the experience of a radiation oncology center in gauging the use of single fraction radiotherapy for painful bone metastases. PMID- 25930886 TI - (P116) pain and radiographic control after stereotactic radiosurgery for spinal metastases from hepatocellular carcinoma: a comparison with other radioresistant histologies. PMID- 25930887 TI - (P117) Outcomes, Patterns of Failures, and Toxicity for Patients Diagnosed With Pulmonary Metastases Treated With Stereotactic Body Ablative Radiotherapy (SABR). PMID- 25930888 TI - (P118) Radiotherapeutic Care Within the Veterans Health Administration of US Veterans With Metastatic Cancer to the Brain: Part 2 Clinical Treatment Patterns. PMID- 25930889 TI - (P119) electronic brachytherapy management of atypical fibroxanthoma: report of seven cases. PMID- 25930890 TI - (P120) Pregnancy and Parenthood in Radiation Oncology, Views and Experiences Survey (PROVES): Results of a Blinded Prospective Trainee Parenting and Career Development Assessment. PMID- 25930891 TI - (P121) Image-Guided Radiation Therapy Utilization and Practice Patterns: Results From a National Survey of ASTRO Membership. PMID- 25930892 TI - (P122) older african americans' use of religious music to cope with cancer. PMID- 25930893 TI - (P123) Reducing Time From Patient CT Simulation (CT SIM) Appointment Time to Start of Actual CT Scan: Lean Thinking in the VA System. PMID- 25930894 TI - (P124) dosimetric comparison of three-dimensional conformal proton radiotherapy and intensity-modulated proton therapy for treatment of pediatric hodgkin lymphoma. PMID- 25930895 TI - (P125) glioblastoma multiforme outcome comparison between pediatrics and adults: is there a difference? PMID- 25930896 TI - (P126) long-term volumetric follow-up of juvenile pilocytic astrocytomas treated with proton beam radiotherapy. PMID- 25930897 TI - (P127) Stereotactic Accelerated Partial Breast Irradiation (SAPBI) for Early Stage Breast Cancer: Rationale, Feasibility, and Early Experience Using the CyberKnife Radiosurgery Delivery Platform. PMID- 25930899 TI - (P129) Bone Marrow Aspiration Under CT Guidance: Technique and Value. PMID- 25930898 TI - (P128) Statistically Significant Calibration Curve for Ir-192 HDR Source Using Multichannel Gafchromic Film Analysis. PMID- 25930900 TI - (P130) An Exploratory Pilot Study of Perfusion Patterns in Locoregionally Advanced Head and Neck Cancer Using a Novel Analysis Technique of Dynamic Contrast-Enhanced (DCE)-MRI. PMID- 25930901 TI - (P131) Improved Prostate Delineation in Prostate HDR Brachytherapy With TRUS-CT Deformable Registration Technology. PMID- 25930902 TI - (P132) Evaluation of the Chest Wall Skin Dose Associated With Bolus Application in Postmastectomy Radiation Therapy (PMRT) Using Nanodot OSLD. PMID- 25930903 TI - (P086) Proton vs Photon/Electron-Based Therapy in the Treatment of Pediatric Salivary Gland Tumors: A Comparison of Dosimetric Data and Acute Toxicities. PMID- 25930904 TI - (P087) Proton Therapy Results in Low Rates of Acute GI Toxicity for Parotid Cancers. PMID- 25930905 TI - (P088) Nonadherence to NCCN Guidelines Negatively Impacts Survival in Early-Stage Squamous Cell Carcinoma of the Larynx. PMID- 25930906 TI - (P089) p16 as a Complementary Prognostic Marker for EBV-Positive Nasopharyngeal Carcinoma. PMID- 25930907 TI - (P090) pediatric metastatic odontogenic ghost cell carcinoma: a multimodal treatment approach. PMID- 25930908 TI - (P091) sarcopenia/cachexia is associated with reduced survival and locoregional control in head and neck cancer patients receiving radiotherapy: results from quantitative imaging analysis of lean body mass. PMID- 25930909 TI - (P092) definitive chemoradiotherapy or radiotherapy for unresectable, very locally advanced, or medically inoperable paranasal sinus and nasal cavity cancer. PMID- 25930910 TI - (P093) Cesium-131 Brachytherapy in High-Risk and Recurrent Head and Neck (HN) Cancers: Long-Term Results of a Pilot Study. PMID- 25930911 TI - (P094) treatment outcomes of sinonasal neuroendocrine cancer: a retrospective review. PMID- 25930912 TI - (P133) Spinal Cord Dose Comparison With and Without Contrast Density Correction on CT Myelogram Simulations for Patients Treated With Stereotactic Body or Conventional Radiotherapy. PMID- 25930913 TI - (P134) an overview of the first one hundred patients treated with a new cutting edge, frameless, image-guided, stereotactic radiosurgery system. PMID- 25930914 TI - (P135) quantitative assessment of target delineation variability for thymic cancers: agreement evaluation of a prospective segmentation challenge. PMID- 25930915 TI - (P136) quantitative measurement of contrast enhancement in myxoid liposarcomas: response to neoadjuvant therapy with volumetric and pathologic correlates. PMID- 25930917 TI - (P138) Dosimetric Evaluation of Parotid Dose in Whole-Brain Radiation Plans Covering C1 vs C2. PMID- 25930916 TI - (P137) seeing is believing: concerns and solutions in implementing magnetic resonance image-guided radiation therapy. PMID- 25930918 TI - (P139) clinical outcomes and patient-reported outcomes after local treatment for high-risk, localized prostate cancer. PMID- 25930919 TI - (P140) Clinical Predictors of Survival for Patients With Stage IV Cancer Referred to Radiation Oncology. PMID- 25930920 TI - (P141) rectal spacer injection in postprostatectomy patients undergoing high-dose salvage external beam radiation. PMID- 25930921 TI - (P142) older patients derive greater benefit from adjuvant and neoadjuvant radiotherapy in diverse solid malignancies. PMID- 25930922 TI - (P031) effects of oncoplastic surgery on delivery of standard adjuvant radiotherapy. PMID- 25930923 TI - (P143) multisite review of twenty-six head and neck cancer patients who have developed osteoradionecrosis: location, etiology, and treatment. PMID- 25930924 TI - (P144) Radiation-Associated Toxicities in Obese Women With Endometrial Cancer: More Than Just BMI? PMID- 25930925 TI - (P032) current management of low-grade central nervous system glioma. PMID- 25930926 TI - (P033) MRI resection cavity dynamics following brain metastasis resection and permanent iodine-125 brachytherapy. PMID- 25930927 TI - (P034) Proton Therapy (PT) Large-Volume Re-Irradiation for Recurrent Glioma: Overall Survival (OS) and Toxicity Outcomes. PMID- 25930928 TI - (P035) Prognostic Factors of Early Deaths in Patients With Craniopharyngioma From the SEER Registry. PMID- 25930929 TI - (P036) patterns of care and outcomes of adjuvant radiotherapy for meningiomas: a surveillance, epidemiology, and end results and medicare-linked analysis. PMID- 25930930 TI - (P037) analysis of survival outcomes in patients with multifocal glioblastoma. PMID- 25930932 TI - (P039) outcomes of patients with glioblastoma receiving concurrent radiation treatment and antiepileptic agents with histone deacetylase inhibitor activity. PMID- 25930931 TI - (P038) leukoencephalopathy following stereotactic radiosurgery for brain metastases. PMID- 25930933 TI - (P040) Radiosurgery for primary central nervous system lymphoma. PMID- 25930934 TI - (P041) Clinical Outcomes of Gamma Knife Stereotactic Radiosurgery (GK-SRS) for Painful Trigeminal Neuropathy (TNP). PMID- 25930935 TI - (P042) Toxicity and Treatment Outcomes in Single vs Multifractionated Radiotherapy for Acoustic Neuromas. PMID- 25930936 TI - (P044) Treatment Outcomes of WHO Grade III Malignant Meningioma With and Without Postoperative Radiation Therapy. PMID- 25930937 TI - (P043) Central neurocytoma: impact of resection extent and adjuvant radiotherapy on survival outcomes. PMID- 25930938 TI - (P045) Multimodality therapy with intensity-modulated radiotherapy for locally advanced esophageal cancer. PMID- 25930939 TI - (P046) Prediction of pathologic complete response after neoadjuvant chemoradiation therapy for rectal cancer using radiographic texture analysis. PMID- 25930940 TI - Identification of alcohol abuse and transition from long-term unemployment to disability pension. AB - AIMS: The aim of the study was to reveal potential gaps and inconsistencies in the identification of alcohol abuse in health care and in employment services and to analyse the granting of disability pensions with respect to the alcohol abuse identification pattern. METHODS: The material consisted of documentary information on 505 long-term unemployed subjects with low employability sent to the development project entitled 'Eligibility for a Disability Pension' in 2001 2006 in Finland. The dichotomous variables 'Alcohol abuse identified in employment services' and 'Alcohol abuse identified in health care' were cross tabulated to obtain a four-class variable 'Alcohol abuse identification pattern'. Logistic regression analyses were conducted to ascertain the association of alcohol abuse identification pattern with the granting of disability pensions. RESULTS: Alcohol abuse was detected by both health care and employment services in 47% of those identified as abusers (41% of examinees). Each service systems also identified cases that the other did not. When alcohol abuse was identified in health care only, the OR for a disability pension being granted was 2.8 (95% CI 1.5-5.2) compared with applicants without identified alcohol abuse. The result remained the same and statistically significant after adjusting for confounders. CONCLUSIONS: Alcohol abuse identified in health care was positively associated with the granting of a disability pension. Closer co-operation between employment services and health care could help to identify those long-term unemployed individuals with impaired work ability in need of thorough medical examination. PMID- 25930941 TI - Biorefining of by-product streams from sunflower-based biodiesel production plants for integrated synthesis of microbial oil and value-added co-products. AB - This study focuses on the valorisation of crude glycerol and sunflower meal (SFM) from conventional biodiesel production plants for the separation of value-added co-products (antioxidant-rich extracts and protein isolate) and for enhancing biodiesel production through microbial oil synthesis. Microbial oil production was evaluated using three oleaginous yeast strains (Rhodosporidium toruloides, Lipomyces starkeyi and Cryptococcus curvatus) cultivated on crude glycerol and nutrient-rich hydrolysates derived from either whole SFM or SFM fractions that remained after separation of value-added co-products. Fed-batch bioreactor cultures with R. toruloides led to the production of 37.4gL(-1) of total dry weight with a microbial oil content of 51.3% (ww(-1)) when a biorefinery concept based on SFM fractionation was employed. The estimated biodiesel properties conformed with the limits set by the EN 14214 and ASTM D 6751 standards. The estimated cold filter plugging point (7.3-8.6 degrees C) of the lipids produced by R. toruloides is closer to that of biodiesel derived from palm oil. PMID- 25930942 TI - Biogas stripping of ammonia from fresh digestate from a food waste digester. AB - The efficiency of ammonia removal from fresh source-segregated domestic food waste digestate using biogas as a stripping agent was studied in batch experiments at 35, 55 and 70 degrees C, at gas flow rates of 0.125 and 0.250Lbiogasmin(-1)L(-1)digestate with and without pH adjustment. Higher temperatures and alkaline conditions were required for effective ammonia removal, and at 35 degrees C with or without pH adjustment or 55 degrees C with unadjusted pH there was little or no removal. Results were compared to those from earlier studies with digestate that had been stored prior to stripping and showed that ammonia removal from fresh digestate was more difficult, with time constants 1.6 5.7 times higher than those previously reported. This has implications for the design of large-scale systems where continuous stripping of fresh digestate is likely to be the normal operating mode. A mass balance approach showed that thermal-alkaline stripping improved hydrolysis. PMID- 25930944 TI - Shoulder pain and intra-articular interleukin-8 levels in patients with rotator cuff tears. AB - AIM: Rotator cuff disease (RCD) is one of the most common disorders in the shoulder joint and causes joint pain and functional disability. In this study, we investigated the associations among cytokine levels and clinical symptoms in patients with RCD. METHOD: Joint fluid specimens of the shoulder joint were obtained from 38 patients with RCD before arthroscopic surgery. The levels of inflammatory cytokines, including interleukin (IL)-1beta, IL-6 and IL-8, were evaluated using enzyme-linked immunosorbent assay kits, and the associations between these cytokine levels and the clinical symptoms were determined. A multiple linear regression analysis was performed to identify the parameters accounting for the visual analogue scale (VAS) score at rest. RESULTS: IL-8 level was correlated with IL-6 (r = 0.434, P = 0.006) and IL-1beta (r = 0.575, P < 0.001) levels. The cuff tear size was inversely correlated with the VAS score at rest. A multiple stepwise linear regression analysis revealed that the VAS score at rest could be explained by the VAS score at night, the VAS score during movement and the intra-articular IL-8 level (adjusted R2 = 0.544, P < 0.001). The intra-articular IL-8 level is associated with resting pain in rotator cuff tear patients. CONCLUSION: These results suggest that an increased concentration of IL 8 is associated with resting pain in rotator cuff tear patients. PMID- 25930945 TI - Fluoroscopy-guided infiltration for pain reduction in patients with Baastrup's disease: clinical experience and results. AB - OBJECTIVE: Baastrup disease refers to degenerative changes of adjacent spinous processes with resultant back pain. The purpose of this study is to assess the safety and efficacy of percutaneous, fluoroscopy-guided infiltrations in a consecutive series of patients suffering from Baastrup disease. MATERIALS AND METHODS: From January 2009 until December 2013, 55 patients suffering from Baastrup disease (diagnosed clinically and by imaging findings) underwent percutaneous, fluoroscopy-guided infiltration. The position of the needle (22 gauge spinal needle) was fluoroscopically verified at the level of interspinous ligament. Then a mixture of long-acting corticosteroid with local anesthetic (1.5/1 cc) was injected. A questionnaire with NVS scale helped in assessing pain relief degree, life quality, and mobility improvement. RESULTS: In the patients of our study, a total of 67 sessions was performed. In 12/55 patients (22%), a second infiltration was performed within 7-10 days apart from the first one. The end point was 1 year post-treatment. Patients were followed 1 week after the first injection for a subsequent treatment and then if asymptomatic re-controlled in 3-6 and 12 months. Comparing the pain scores prior (mean value, 8.18 +/- 1.44 NVS units) and after (mean value, 0.62 +/- 0.93 NVS units) there was a mean decrease of 7.56 +/- 1.68 NVS units (p < 0.001) on terms of pain reduction, effect upon mobility and life quality. There were no clinically significant complications noted in our study. CONCLUSIONS: Fluoroscopy-guided infiltrations seem to be a feasible, efficacious, and safe approach for pain reduction and mobility improvement in patients with Baastrup disease. PMID- 25930943 TI - The (dys)functional extracellular matrix. AB - The extracellular matrix (ECM) is a major component of the biomechanical environment with which cells interact, and it plays important roles in both normal development and disease progression. Mechanical and biochemical factors alter the biomechanical properties of tissues by driving cellular remodeling of the ECM. This review provides an overview of the structural, compositional, and mechanical properties of the ECM that instruct cell behaviors. Case studies are reviewed that highlight mechanotransduction in the context of two distinct tissues: tendons and the heart. Although these two tissues demonstrate differences in relative cell-ECM composition and mechanical environment, they share similar mechanisms underlying ECM dysfunction and cell mechanotransduction. Together, these topics provide a framework for a fundamental understanding of the ECM and how it may vary across normal and diseased tissues in response to mechanical and biochemical cues. This article is part of a Special Issue entitled: Mechanobiology. PMID- 25930946 TI - Evaluation of finger A3 pulley rupture in the crimp grip position-a magnetic resonance imaging cadaver study. AB - PURPOSE: The correct diagnosis of an A3 pulley rupture is challenging for musculoskeletal radiologists. An A3 pulley rupture should in theory influence the shape of the proximal interphalangeal joint volar plate (VP) and the amount of bowstringing at level of the VP during finger flexion. The purpose of this study was to perform MRI with metric analysis of the VP configuration and VP bowstringing in cadaver fingers in the crimp grip position and to determine cut points for A3 pulley rupture. MATERIALS AND METHODS: MRI in the crimp grip position was performed in 21 cadaver fingers with artificially created flexor tendon pulley tears (fingers with A3 pulley rupture n = 16, fingers without A3 pulley rupture n = 5). The distances of the translation of the VP relative to the middle phalanx base, the distances between the flexor tendons and the VP body, and the distances between the flexor tendon and bone (TB) were measured. RESULTS: Statistical analysis showed significantly lower VP translation distances and significantly higher VP tendon distances if the A3 pulley was ruptured. A2 TB and A4 TB distances did not differ significantly in specimens with and without A3 pulley rupture. The optimal cut points for A3 pulley rupture were a VP translation distance <2.8 mm and a VP tendon distance >1.4 mm. CONCLUSION: Reduction of the VP translation distance and augmentation of the VP tendon distance are suitable indirect signs of A3 pulley rupture. PMID- 25930947 TI - Neurometabolic coupling between neural activity, glucose, and lactate in activated visual cortex. AB - Neural activity is closely coupled with energy metabolism but details of the association remain to be identified. One basic area involves the relationships between neural activity and the main supportive substrates of glucose and lactate. This is of fundamental significance for the interpretation of non invasive neural imaging. Here, we use microelectrodes with high spatial and temporal resolution to determine simultaneous co-localized changes in glucose, lactate, and neural activity during visual activation of the cerebral cortex in the cat. Tissue glucose and lactate concentration levels are measured with electrochemical microelectrodes while neural spiking activity and local field potentials are sampled by a microelectrode. These measurements are performed simultaneously while neurons are activated by visual stimuli of different contrast levels, orientations, and sizes. We find immediate decreases in tissue glucose concentration and simultaneous increases in lactate during neural activation. Both glucose and lactate signals return to their baseline levels instantly as neurons cease firing. No sustained changes or initial dips in glucose or lactate signals are elicited by visual stimulation. However, co localized measurements of cerebral blood flow and neural activity demonstrate a clear delay in the cerebral blood flow signal such that it does not correlate temporally with the neural response. These results provide direct real-time evidence regarding the coupling between co-localized energy metabolism and neural activity during physiological stimulation. They are also relevant to a current question regarding the role of lactate in energy metabolism in the brain during neural activation. Dynamic changes in energy metabolites can be measured directly with high spatial and temporal resolution by use of enzyme-based microelectrodes. Here, to examine neuro-metabolic coupling during brain activation, we use combined microelectrodes to simultaneously measure extracellular glucose, lactate, and neural responses in the primary visual cortex to visual stimulation. We demonstrate rapid decreases in glucose and increases in lactate during neural activation. Changes in glucose and lactate signals are transient and closely coupled with neuronal firing. PMID- 25930948 TI - Comparative proteomic analysis of oil palm leaves infected with Ganoderma boninense revealed changes in proteins involved in photosynthesis, carbohydrate metabolism, and immunity and defense. AB - The basidiomycete fungal pathogen Ganoderma boninense is the causative agent for the incurable basal stem rot (BSR) disease in oil palm. This disease causes significant annual crop losses in the oil palm industry. Currently, there is no effective method for disease control and elimination, nor is any molecular marker for early detection of the disease available. An understanding of how BSR affects protein expression in plants may help identify and/or assist in the development of an early detection protocol. Although the mode of infection of BSR disease is primarily via the root system, defense-related genes have been shown to be expressed in both the root and leafs. Thus, to provide an insight into the changes in the global protein expression profile in infected plants, comparative 2DE was performed on leaf tissues sampled from palms with and without artificial inoculation of the Ganoderma fungus. Comparative 2DE revealed that 54 protein spots changed in abundance. A total of 51 protein spots were successfully identified by LC-QTOF MS/MS. The majority of these proteins were those involved in photosynthesis, carbohydrate metabolism as well as immunity and defense. PMID- 25930950 TI - A Recombinant Collagen-mRNA Platform for Controllable Protein Synthesis. AB - We have developed a collagen-mRNA platform for controllable protein production that is intended to be less prone to the problems associated with commonly used mRNA therapy as well as with collagen skin-healing procedures. A collagen mimic was constructed according to a recombinant method and was used as scaffold for translating mRNA chains into proteins. Cysteines were genetically inserted into the collagen chain at positions allowing efficient ribosome translation activity while minimizing mRNA misfolding and degradation. Enhanced green fluorescence protein (eGFP) mRNA bound to collagen was successfully translated by cell-free Escherichia coli ribosomes. This system enabled an accurate control of specific protein synthesis by monitoring expression time and level. Luciferase-mRNA was also translated on collagen scaffold by eukaryotic cell extracts. Thus we have demonstrated the feasibility of controllable protein synthesis on collagen scaffolds by ribosomal machinery. PMID- 25930951 TI - Brief Report: Miscarriages in Female Rheumatoid Arthritis Patients: Associations With Serologic Findings, Disease Activity, and Antirheumatic Drug Treatment. AB - OBJECTIVE: To study the association between miscarriage in rheumatoid arthritis (RA) patients and serologic findings, disease activity, and antirheumatic drug treatment, and to study disease activity and reproductive outcomes after a miscarriage. METHODS: Within a nationwide prospective cohort study (Pregnancy Induced Amelioration of RA study), patients with RA were followed up from preconception until 6 months after delivery or miscarriage. Univariate and logistic regression analyses were performed to assess variables of interest, with covariates included in the models if the P value for association with miscarriage was <0.20 and subsequently excluded if the P value was >0.10. RESULTS: Among 162 pregnancies, 28 miscarriages occurred (17.3%; 95% confidence interval 12.2 24.0%). Women who miscarried were older than women with an ongoing pregnancy. Women who miscarried tended to be more often positive for anti-citrullinated protein antibodies (ACPAs), to have higher disease activity scores, and to have more often received methotrexate (MTX) therapy in the past. Logistic regression showed a tendency toward a higher likelihood of miscarriage in association with increasing age (P = 0.065) and presence of ACPAs (P = 0.092). After miscarriage, 33% of women had a flare of RA. Within 1 year, 68% of women became pregnant again, 14% stopped trying to conceive, and 11% were lost to followup. The live birth rate of the subsequent pregnancy was 90%. CONCLUSION: The miscarriage rate in the PARA cohort is comparable to that in the general population. Due to the low frequency of miscarriages in this study, the associations between miscarriage in RA and the presence of ACPAs, disease activity, and MTX use did not reach statistical significance. Within 1 year after miscarriage, the majority of patients who continued trying to conceive achieved a pregnancy resulting in a live birth. PMID- 25930953 TI - Three-Dimensional Evaluation of Implant Bed Preparation and the Influence on Primary Implant Stability After Using 2 Different Surgical Techniques. AB - PURPOSE: Surgical techniques affect primary implant stability, which is required for osseointegration. The aim of this study was to investigate the influence of full-guided surgery on the dimension of implant site in relation to primary stability. MATERIALS AND METHODS: After implant site preparation in artificial bone by full-guided (FG) or non-guided (NG) workflows to create final diameters of 3.3, 4.1, and 4.8mm and depths of 8 or 12 mm, computed tomograms were obtained and the volume of the osteotomies was analyzed 3 dimensionally. After comparing implant insertions, the implant stability quotient (ISQ) was measured by resonance frequency analysis (RFA). RESULTS: Volume analysis of the implant site showed significant differences (P < .0001) between surgical procedures (FG vs NG) at a depth of 12 mm for all diameters (3.3 mm, 61.98 +/- 5.84 vs 80.96 +/- 9.65 mm(3); 4.1 mm, 107.45 +/- 6.91 vs 132.07 +/- 5.16 mm(3); 4.8 mm, 158.62 +/- 10.21 vs 182.00 +/- 6.25 mm(3)) and at a depth of 8 mm for diameters of 4.1 mm (71.76 +/- 8.38 vs 83.64 +/- 7.54 mm(3)) and 4.8 mm (103.84 +/- 6.73 vs 120.55 +/- 14.63 mm(3)). RFA showed significant differences for implants with a diameter of 4.8 mm and lengths of 12 mm (ISQ, 69.3 +/- 4.09 for FG vs 65.05 +/- 5.61 for NG; P = .0007) and 8 mm (64.5 +/- 4.16 for FG vs 58.85 +/- 6.72 for NG; P = .0107). CONCLUSIONS: The use of FG implant surgery decreases the bone volume removed during osteotomy preparation, which can lead to greater primary stability. PMID- 25930952 TI - Catehol-o-methyltransferase gene Val158met polymorphism as a potential predictor of response to computer-assisted delivery of cognitive-behavioral therapy among cocaine-dependent individuals: Preliminary findings from a randomized controlled trial. AB - BACKGROUND: Findings from uncontrolled studies suggest that the COMT Val108/158Met polymorphism may affect response to cognitive behavioral therapy (CBT) in some populations. Using data from a randomized controlled trial evaluating computerized CBT (CBT4CBT), we evaluated treatment response by COMT genotype, with the a priori hypothesis that Val carriers would have improved response to computerized delivery of CBT. METHODS: 101 cocaine-dependent individuals, of whom 81 contributed analyzable genetic samples, were randomized to standard methadone maintenance treatment plus CBT4CBT or standard treatment alone in an 8 week trial. RESULTS: There was a significant genotype by time effect on frequency of cocaine use from baseline to the end of the 6 month follow up, suggesting greater reductions over time for Val carriers relative to individuals with the Met/Met genotype. There was a significant treatment condition by genotype interactions for rates of participants attaining 21 or more days of continuous abstinence as well as self-reported percent days of abstinence, suggesting less cocaine use among Val carriers when assigned to CBT compared to standard treatment. Exploration of possible mechanisms using measures of attentional biased also pointed to greater change over time in these measures among the Val carriers assigned to CBT. CONCLUSION: These are the first data from a randomized controlled trial indicating significant interactions of COMT polymorphism and behavioral therapy condition on treatment outcome, where Val carriers appeared to respond particularly well to computerized CBT. These preliminary data point to a potential biomarker of response to CBT linked to its putative mechanism of action, enhanced cognitive control. PMID- 25930954 TI - Cytotoxicity Evaluation of Bioresorbable Fixation Screws on Human Gingival Fibroblasts and Mouse Osteoblasts by Real-Time Cell Analysis. AB - PURPOSE: To evaluate the effects of bioresorbable fixation screws (BFSs) on human gingival fibroblast (HGF) and mouse osteoblast (MC3T3-E1) cell viability. MATERIALS AND METHODS: The KLS Martin SonicPins Rx, Synthes RapidSorb Cortex Screws, and Inion CPS Bioabsorbable Fixation System each were incubated in Dulbecco's Modified Eagle Medium for 72 hours according to ISO 10993-5 standards. A real-time cell analyzer was used to evaluate cell survival. After seeding 200 MUL cell suspensions in the wells of an E-plate View 96, HGF and MC3T3-E1 cells were treated with the bioactive components released by the bioresorbable materials and monitored every 15 minutes for 96 hours. Statistical significance was determined using 1-way analysis of variance and Tukey-Kramer tests. RESULTS: There were significant differences in the HGF responses to the untreated control conditions and the Synthes (P < .01), Inion (P < .05), and KLS Martin (P < .05) treatments over 48 hours. The Synthes (P < .01) and Inion (P < .01) treatments produced lower HGF cell index values than the untreated control at 72 hours, whereas the KLS Martin treatment did not. When left to elute for 96 hours, there were no significant differences in values among the control and study groups for HGFs (P > .05). All tested BFSs decreased cell survival rates of M3T3C1 cells for 48 hours (P < .01), 72 hours (P < .001), and 96 hours (P < .001). CONCLUSION: Differences in the sensitivities of the 2 tested cell lines to the different BFSs might be the result of the different materials used to manufacture the screws. These results provide fundamental knowledge and new insights for the future design and development of new biocompatible BFSs for oral and maxillofacial surgery. PMID- 25930955 TI - Is There Enough Evidence to Regularly Apply Bone Screws for Intermaxillary Fixation in Mandibular Fractures? AB - PURPOSE: Intermaxillary fixation (IMF) is traditionally achieved with arch bars; however, this method has several well-known disadvantages and other techniques, such as bone screws, are available. This study evaluated current evidence regarding these IMF screws (IMFSs) for mandibular trauma and to assess whether this allows a change of treatment protocol for IMF. MATERIALS AND METHODS: A systematic electronic literature search was conducted in the PubMed, Embase, and Cochrane databases. Titles and abstracts retrieved from the search were screened and evaluated for inclusion and exclusion criteria. The full text of all relevant articles was read and citation lists were checked for any missing references. All randomized controlled trials (RCTs) were subjected to a quality assessment. Included articles were checked for outcome measurements concerning occlusion, operative time, oral hygiene, root trauma, wire-stick injuries, and mucosa overgrowth. RESULTS: Twenty-two articles (17 case series, 4 RCTs, and 1 cohort study) were included. None of the RCTs scored high methodologic results in the quality assessment. The results suggest IMFSs have similar malocclusion rates as arch bars, fewer wire-stick injuries, improved oral hygiene, and shorter operative time. Root damage is less likely to occur with self-drilling screws and seldom requires treatment. CONCLUSIONS: Although the methodologic quality of the included studies is poor, self-drilling IMFSs are recommended for temporary per operative IMF of noncomminuted mandibular fractures. More high-quality studies are required to allow an evidence-based change of protocol. PMID- 25930956 TI - Coronectomy of the Mandibular Third Molar: A Retrospective Study of 185 Procedures and the Decision to Repeat the Coronectomy in Cases of Failure (J Oral Maxillofac Surg 73:587, 2015). PMID- 25930957 TI - Anatomic Study of the Dorsalis Pedis Artery, First Metatarsal Artery, and Second Metatarsal Bone for Mandibular Reconstruction. AB - PURPOSE: The purpose of this study was to clarify the anatomic variation of the dorsalis pedis and first metatarsal arteries and to define the trabecular-to cortical bone ratio (TBR) of the second metatarsal bone to ascertain their suitability as implants. MATERIALS AND METHODS: Fifty-two specimens were prepared for this study. Each specimen was dissected on the dorsal side of the foot to search for the dorsalis pedis artery. RESULTS: Three types of dorsalis pedis artery were found: in type A, which was the most common, the artery continuously formed the first metatarsal artery; in type C, which was the second most common, the artery coursed below the first dorsal interosseous muscle; and in type B, the artery coursed from the lateral side. Five variations of the first metatarsal artery were identified: the most common was type IIb, in which the artery coursed below the first dorsal interosseous muscle; followed by type Ib, in which the artery coursed obliquely through the muscle; type Ic, in which the artery coursed parallel to the muscle; type IIa, in which the artery coursed above and below the muscle; and type Ia, in which the artery coursed only above the muscle. The second metatarsal bone was divided into 5 regions. There was no trabecular bone in regions 1 and 5. The TBR appeared to be lower in region 3 than in regions 2 and 4 and highest in region 2. CONCLUSION: All regions of the second metatarsal bone appear to be suitable as implants, but when placing the implant in the proximal end, care should be taken not to overheat the bone and to be wary of perforation when placing it on the middle side. PMID- 25930958 TI - Is It Safe and Effective to Lengthen a Chin With Interpositional Allogenic (Iliac) Graft? AB - PURPOSE: This is a retrospective review of a consecutive series of patients undergoing chin lengthening at the time of orthognathic surgery over a 3-year timeframe. MATERIALS AND METHODS: The genioplasty procedures studied included lengthening to the extent that an interpositional graft was deemed necessary (n = 19). Allogenic (iliac) corticocancellous bone was used in all cases. Each patient underwent lateral cephalometric radiography within 2 months before and 5 weeks after surgery. From the radiographs, quantitative measurements (millimeters) were made to document the vertical lengthening and horizontal advancement achieved. Chin region wound healing parameters were reviewed to document evidence of infection, sequestra, need for reoperation, and evidence of fibrous union. Inpatient hospital and outpatient office records were reviewed for any evidence of sepsis or viral transmission. RESULTS: The patients' mean age at operation was 35 years (range, 15 to 58 yr). Analysis of preoperative and 5-week postoperative radiographs documented a mean vertical lengthening of 7 mm (range, 4 to 10 mm). The mean horizontal advancement at the pogonion was confirmed to be 2 mm (range, 1 to 3 mm). None of the study patients sustained chin region infection graft sequestra, fibrous union, or need for reoperation. There were no cases of postoperative sepsis or viral illness to indicate systemic infectious sequelae. CONCLUSION: The study confirms the safety of allogenic (iliac) corticocancellous grafting to fill interpositional defects associated with a transverse symphyseal lengthening osteotomy. PMID- 25930959 TI - C-Terminal Telopeptide-Science or Politics? PMID- 25930960 TI - Application of 3-Dimensional Printing Technology to Kirschner Wire Fixation of Adolescent Condyle Fracture. AB - Condyle fractures are common in children and are increasingly treated with open reduction. Three-dimensional printing has developed into an important method of assisting surgical treatment. This report describes the case of a 14-year-old patient treated for a right condyle fracture at the authors' hospital. Preoperatively, the authors designed a surgical guide using 3-dimensional printing and virtual surgery. The 3-dimensional surgical guide allowed accurate alignment of the fracture using Kirschner wire without additional dissection and tissue injury. Kirschner wire fixation augmented by 3-dimensional printing technology produced a good outcome in this adolescent condyle fracture. PMID- 25930961 TI - Oral verruciform xanthoma: a clinicopathologic and immunohistochemical study of 20 cases. AB - Verruciform xanthoma of the oral cavity is an uncommon benign lesion that usually affects the palate and gingiva mainly as a well-circumscribed solitary yellowish to whitish plaque or nodule, which is promptly recognized microscopically by identification of sub-epithelial foamy macrophages. The aim of this study was to evaluate the clinicopathologic and immunohistochemical features of 20 cases of oral verruciform xanthoma. All cases were evaluated by conventional hematoxylin/eosin staining and six of those were submitted to immunohistochemical reactions for CD68, CD63, CD163, syndecan-1 (CD138), S-100 protein and cytokeratins (CK) 8, 14 and 19. Oral verruciform xanthoma presented as yellowish papillary nodules affecting mainly the palate (30%), buccal mucosa (30%) and gingiva (25%) of middle-aged male patients. Most cases presented papillary epithelial hyperplasia and sub-epithelial foamy cells, which were immunopositive for CD68, CD63 and CD163 in all cases. The orange parakeratin superficial layer was negative for CK14 and presented a distinct granular membrane pattern of positivity for CD138. S-100 protein, CK8, and CK19 were negative. PMID- 25930962 TI - Countries are ill prepared to fight antimicrobial resistance, WHO says. PMID- 25930963 TI - Modeling the enzyme kinetic reaction. AB - The Enzymatic control reactions model was presented within the scope of fractional calculus. In order to accommodate the usual initial conditions, the fractional derivative used is in Caputo sense. The methodologies of the three analytical methods were used to derive approximate solution of the fractional nonlinear system of differential equations. Two methods use integral operator and the other one uses just an integral. Numerical results obtained exhibit biological behavior of real world problem. PMID- 25930964 TI - Erratum to: Maternal vitamin C deficiency during pregnancy results in transient fetal and placental growth retardation in guinea pigs. PMID- 25930966 TI - Longitudinal associations of serum fatty acid composition with type 2 diabetes risk and markers of insulin secretion and sensitivity in the Finnish Diabetes Prevention Study. AB - PURPOSE: To examine the longitudinal associations of serum fatty acid composition with type 2 diabetes, insulin secretion and insulin sensitivity over several years. METHODS: We conducted a prospective cohort study derived from the randomized Finnish Diabetes Prevention Study. Total serum fatty acid composition was measured using gas chromatography in 407 overweight, middle-aged people with impaired glucose tolerance at baseline (1993-1998) and annually during the intervention period (1994-2000). Longitudinal associations of 20 fatty acids and three desaturase activities (Delta5 (20:4n-6/20:3n-6, D5D), Delta6 (18:3n-6/18:2n 6, D6D), stearoyl-CoA desaturase-1 (16:1n-7/16:0, SCD-1)) with type 2 diabetes incidence, and estimates of insulin sensitivity (Matsuda), secretion (ratio of insulin and glucose concentrations) and beta-cell function (disposition index) by an oral glucose tolerance test were analyzed using Cox regression and linear mixed models. We validated estimated D5D and D6D using a known FADS1 gene variant, rs174550. RESULTS: The baseline proportions of 20:5n-3, 22:5n-3 and 22:6n-3, and D5D were associated with lower incidence of type 2 diabetes during a median follow-up of 11 years (HR per 1SD: 0.72, 0.74, 0.73, 0.78, respectively, P <= 0.01). These long-chain omega-3 fatty acids and D5D were associated with higher insulin sensitivity in subsequent years but not with disposition index. Saturated, monounsaturated and trans fatty acids and 18:3n-3, 18:2n-6, SCD-1 and D6D were inconsistently associated with type 2 diabetes or related traits. CONCLUSIONS: Serum long-chain omega-3 fatty acids and D5D predicted lower type 2 diabetes incidence in people at a high risk of diabetes attending to an intervention study; a putative mechanism behind these associations was higher insulin sensitivity. PMID- 25930967 TI - Synthesis of Highly Functionalized Decalins via Metallacycle-Mediated Cross Coupling. AB - Bridged bicyclic metallacyclopentenes generated from the [4 + 2] cycloaddition of metallacyclopentadienes with alkenes have been proposed as reactive intermediates in the course of [2 + 2 + 2] annulation reactions. Recently a collection of alkoxide-directed Ti-mediated [2 + 2 + 2] annulation reactions have been discovered for the synthesis of densely functionalized hydrindanes, where the bridged bicyclic metallacyclopentenes from intramolecular [4 + 2] were treated as fleeting intermediates en route to cyclohexadiene products formed by formal cheletropic extrusion of Ti(Oi-Pr)2. In studies aimed at understanding the course of these organometallic cascade reactions it was later discovered that these bridged bicyclic intermediates can be trapped by various elimination processes. Here, we have realized metallacycle-mediated annulation reactions for the assembly of angularly substituted decalins--structural motifs that are ubiquitous in natural products and molecules of pharmaceutical relevance. In addition to defining the basic annulation reaction we have discovered a surprising stability associated with the complex organometallic intermediates generated in the course of this coupling process and document here the ability to control the fate of such species. Ligand-induced cheletropic extrusion of the titanium center delivers cyclohexadiene-containing products, while several distinct protonation events have been identified to realize polycyclic products that contain three new stereocenters (one of which is the angular quaternary center that is a hallmark of alkoxide-directed titanium-mediated [2 + 2 + 2] annulation reactions). Examples of this metallacycle-mediated annulation reaction are provided to demonstrate that a range of stereodefined fused bicyclo[4.4.0]decanes are accessible, including those that contain aromatic and aliphatic substituents, and an empirical model is presented to accompany the observations made. PMID- 25930965 TI - Fruit peel polyphenols demonstrate substantial anti-tumour effects in the model of breast cancer. AB - PURPOSE: Fruit and vegetable intake is inversely correlated with cancer; thus, it is proposed that an extract of phytochemicals as present in whole fruits, vegetables, or grains may have anti-carcinogenic properties. Thus, the anti tumour effects of fruit peel polyphenols (Flavin7) in the chemoprevention of N methyl-N-nitrosourea-induced mammary carcinogenesis in female rats were evaluated. METHODS: Lyophilized substance of Flavin7 (F7) was administered at two concentrations of 0.3 and 3 % through diet. The experiment was terminated 14 weeks after carcinogen administration, and mammary tumours were removed and prepared for histopathological and immunohistochemical analysis. In addition, using an in vitro cytotoxicity assay, apoptosis and proliferation after F7 treatment in human breast adenocarcinoma (MCF-7) cells were performed. RESULTS: High-dose F7 suppressed tumour frequency by 58 % (P < 0.001), tumour incidence by 24 % (P < 0.05), and lengthened latency by 8 days (P > 0.05) in comparison with the control rats, whereas lower dose of F7 was less effective. Histopathological analysis of tumours showed significant decrease in the ratio of high-/low-grade carcinomas after high-dose F7 treatment. Immunohistochemical analysis of rat carcinoma cells in vivo found a significant increase in caspase-3 expression and significant decrease in Bcl-2, Ki67, and VEGFR-2 expression in the high-dose group. Both doses demonstrated significant positive effects on plasma lipid metabolism in rats. F7 significantly decreased survival of MCF-7 cells in vitro in MTT assay by dose- and time-dependent manner compared to control. F7 prevented cell cycle progression by significant enrichment in G1 cell populations. Incubation with F7 showed significant increase in the percentage of annexin V-/PI positive MCF-7 cells and DNA fragmentation. CONCLUSIONS: Our results reveal a substantial tumour-suppressive effect of F7 in the breast cancer model. We propose that the effects of phytochemicals present in this fruit extract are responsible for observed potent anti-cancer activities. PMID- 25930968 TI - Development of a peptide-functionalized imaging nanoprobe for the targeting of (FXYD2)gammaa as a highly specific biomarker of pancreatic beta cells. AB - Diabetes is characterized by a progressive decline of the pancreatic beta cell mass (BCM), which is responsible for insufficient insulin secretion and hyperglycaemia. There are currently no reliable methods to measure non-invasively the BCM in diabetic patients. Our work describes a phage display-derived peptide (P88) that is highly specific to (FXYD2)gammaa expressed by human beta cells and is proposed as a molecular vector for the development of functionalized imaging probes. P88 does not bind to the exocrine pancreas and is able to detect down to ~156 human pancreatic islets/mm(3) in vitro after conjugation to ultra-small particles of iron oxide (USPIO), as proven by the R2 measured on MR images. For in vivo evaluation, MRI studies were carried out on nude mice bearing Capan-2 tumours that also express (FXYD2)gammaa. A strong negative contrast was obtained subsequent to the injection of USPIO-P88, but not in negative controls. On human histological sections, USPIO-P88 seems to be specific to pancreatic beta cells, but not to duodenum, stomach or kidney tissues. USPIO-P88 thus represents a novel and promising tool for monitoring pancreatic BCM in diabetic patients. The quantitative correlation between BCM and R2 remains to be demonstrated in vivo, but the T2 mapping and the black pixel estimation after USPIO-P88 injection could provide important information for the future pancreatic BCM evaluation by MRI. PMID- 25930969 TI - A new method with variable injection parameters in contrast-enhanced CT: a phantom study for evaluating an aortic peak enhancement. AB - Contrast-enhanced CT employs a standard uniphasic single-injection method (SIM), wherein administration is based on two parameters: the iodine administration rate (mgI/s) and the injection duration (s). However, as the SIM uses a fixed iodine administration rate, only a uniform contrast enhancement can be achieved with this method. The iodine administration rate can be increased only by increasing the iodine dose or shortening the injection duration, and no arbitrary adjustments can be made to the peak enhancement characteristics of the time enhancement curves (TECs) at the fixed injection parameters used in the SIM. To address this problem, we developed a variable injection method (VIM) with a new parameter, the variation factor (VF), to adjust the TECs. A phantom study with the VIM indicated that arbitrary adjustments to the iodine administration rate could be made without changing the injection duration or increasing the iodine load. In our study, VFs of 0.3 and 0.5, which showed earlier achievement of peak enhancements, showed better temporal separation between arterial vasculature and parenchyma or the venous vasculature than that obtained with the SIM. The higher peak enhancement provided by the VF of 0.3 was also considered to improve the contrast in qualitative diagnostic examinations. A VF of 0.5 increased the duration of the enhancement and was considered to produce stable enhancement of contrast in vascular investigations. The VF is now an essential parameter, and the VIM is useful as a reasonable contrast method that may contribute to both improved visualization and improvement in the accuracy of morphologic diagnosis. PMID- 25930970 TI - Infective Endocarditis Complicated by Mitral Valve Aneurysm: Pathologic and Echocardiographic Correlations. AB - Infective endocarditis is a well-described cardiovascular disease that causes significant morbidity and mortality despite medical and surgical advances. Complications of endocarditis include heart failure, systemic embolization, and valvular destruction including valve aneurysms which increase morbidity and mortality. Mitral valve aneurysms are rarely encountered in the clinical setting. We present eight mitral valve aneurysm cases and discuss a new potential pathogenesis of this deadly endocarditis complication. Pathologic evaluation suggests that neovascularization of the anterior mitral valve leaflet predisposes this territory to abscess and aneurysm formation. In conclusion, mitral valve aneurysms appear to be another form of intravalvular abscess which has expanded and should be approached aggressively with surgical intervention if indicated. PMID- 25930971 TI - A homozygous mutation in SLC1A4 in siblings with severe intellectual disability and microcephaly. AB - We performed exome analysis in two affected siblings with severe intellectual disability (ID), microcephaly and spasticity from an Ashkenazi Jewish consanguineous family. We identified only one rare variant, a missense in SLC1A4 (c. 766G>A [p. E256K]), that is homozygous in both siblings but not in any of their 11 unaffected siblings or their parents (Logarithm of odds, LOD score: 2.6). This variant is predicted damaging. We genotyped 450 controls of Ashkenazi Jewish ancestry and identified only 5 individuals who are heterozygous for this variant (minor allele frequency: 0.0056). SLC1A4 (ASCT1) encodes a transporter for neutral aminoacids such as alanine, serine, cysteine and threonine. L-Serine is essential for neuronal survival and differentiation. Indeed, L-serine biosynthesis disorders affect brain development and cause severe ID. In the brain, L-serine is synthesized in astrocytes but not in neurons. It has been proposed that ASCT1 mediates the uptake of L-serine into neurons and the release of glia-borne L-serine to neighboring cells. SLC1A4 disruption may thus impair brain development and function by decreasing the levels of L-serine in neurons. The identification of additional families with mutations in SLC1A4 would be necessary to confirm its involvement in ID. PMID- 25930972 TI - Improvement of Refractory Ulcerative Proctitis With Sacral Nerve Stimulation. AB - BACKGROUND AND AIMS: Sacral nerve stimulation (SNS) is recognized for its efficiency and safety for anal incontinence, preventing high morbidity. Evidence from the literature suggests extending SNS to diseases associated with problems of intestinal barrier permeability. The aim of this study was to highlight clinical evidence of the beneficial impact of SNS in a refractory proctitis case report. MATERIALS AND METHODS: A permanent SNS was performed successfully in a patient with proctitis after implantation of the neuromodulator. Despite immunosuppressive drugs, the patient was experiencing mucus and blood discharge, pain, and fecal incontinence. To relieve fecal incontinence, SNS was tested without modification of medications. Disease activity, endoscopic and histologic score, ex vivo barrier permeability, expression of inflammatory cytokines (transforming growth factor-beta, tumor necrosis factor alpha, Interleukin-6, Interleukin-8), and junctional proteins (ZO-1, claudin-1, occludin) were assessed before and after SNS to observe the impact of SNS other than for incontinence. RESULTS: After a 3-week period of temporary stimulation, the patient experienced significant improvement with a decrease in fecal incontinence and disease activity scores. Both endoscopic and histologic scores showed improvement. The rectal barrier permeability decreased with SNS, whereas junctional protein mRNA expression transiently increased. Clinical and histologic improvement was sustained over time. After 18 months of permanent stimulation, the patient remained improved by SNS. CONCLUSION: This work demonstrates the relevance to explore further indications of SNS beyond fecal incontinence. PMID- 25930974 TI - Retrieval of Retained Capsule Endoscopy at Small Bowel Stricture by Double Balloon Endoscopy Significantly Decreases Surgical Treatment. AB - GOALS: The aim is to elucidate the efficacy and safety of double-balloon endoscopy (DBE) for small bowel capsule endoscopy (SBCE) retrieval from small bowel stricture and to follow the outcome of the stricture where the SBCE was entrapped. BACKGROUND: The retention of SBCE is a serious adverse event and most retained capsules are retrieved by surgery. There is still no report analyzing the follow-up of patients with stricture after retrieval of entrapped SBCEs by DBE. METHODS: This study was designed a retrospective cohort study. Subjects were 12 consecutive patients with small bowel stricture where retrieval of entrapped SBCE was attempted using DBE. Success rate of the SBCE retrieval by DBE, surgical rate of the small bowel stricture, adverse events of DBE, and outcomes in the follow-up period were evaluated. RESULTS: Diagnoses were Crohn's disease, nonsteroidal anti-inflammatory drugs-induced enteropathy, ischemic enteritis, and carcinoma in 8, 2, 1, and 1 patients, respectively. SBCE was successfully retrieved in 11 of the 12 patients (92%). No adverse events were encountered in all endoscopic procedures such as retrieval of SBCEs and dilation of the strictures. Nine of the 12 patients (75%) did not undergo surgical treatment for the stricture where SBCE was entrapped through the follow-up period (mean, 1675+/ 847 d). CONCLUSIONS: Retrieval of SBCEs using DBE was safe, had a high success rate, and was useful to evaluate the need for surgery. Seventy-five percent of patients with small bowel stricture where the SBCE was entrapped did not require surgery through approximately 5 years. PMID- 25930973 TI - High-sensitive C-Reactive Protein as a Marker for Inflammation in Irritable Bowel Syndrome. AB - BACKGROUND: Recent studies demonstrated low-grade inflammation in patients with irritable bowel syndrome (IBS). However, these studies have been relatively small and do not enable examination of this factor in different subtypes of IBS and the possibility of confounding effects of comorbidities that may be associated with inflammatory responses. GOALS: To investigate the association between high sensitive C-reactive protein (hs-CRP) and the diagnosis of IBS, IBS subtypes, symptoms' severity, and IBS-associated comorbidities. STUDY: This cross-sectional study uses data from a large matched case-control study of IBS subjects and healthy controls (HC). hs-CRP levels were measured in all subjects. IBS diagnosis was determined by Rome III criteria, negative screening blood tests, and normal colonoscopy. Subjects were evaluated for IBS severity and associated pain and psychological comorbidities. RESULTS: A total of 242 IBS patients and 244 HC were studied. Median hs-CRP levels in the IBS group were significantly higher than in HC (1.80; interquartile range, 0.7 to 4.04 mg/L vs. 1.20, interquartile range, 0.5 to 2.97 mg/L respectively, P<0.006). Levels were highest in IBS-D patients with greater disease severity. Hs-CRP levels mildly correlated with symptoms severity (r=0.169, P=0.009); this correlation was stronger for the IBS-D patients (r=0.27, P=0.006). IBS was a significant independent predictor (P=0.025) for higher hs-CRP levels, whereas other pain and psychological comorbidities were not. CONCLUSIONS: Given these observations of cross-sectional differences in hs CRP between IBS subtypes and severity, independent of pain and comorbidities, more research is needed to explore a possible role of low-grade inflammation in the pathogenesis and/or clinical presentation of IBS. PMID- 25930975 TI - Does an Upper Endoscopy Before Transesophageal Echocardiography Change Patient Management? AB - GOAL: To determine if esophagogastroduodenoscopy (EGD) before transesophageal echocardiography (TEE) will change patient management. BACKGROUND: Before TEE gastroenterologists are often consulted to evaluate patients with a history of dysphagia, known gastrointestinal (GI) disease, or GI bleed. There are no known published data on the clinical utility of EGD before TEE. DESIGN AND SETTING: Retrospective study at an inner city tertiary-care center. PATIENTS: A total of 134 patients were included who were at least 18 years old and underwent an EGD to evaluate the safety of the blind passage of a TEE probe. RESULTS: In total, 134 patients were identified. Twenty patients (15%) were not cleared for TEE due to esophageal surface abnormalities (n=3; esophagitis, ulcer, mucosal tear), esophageal structural abnormalities (n=10; varices, stricture, ring, web, hernia, Zenker), and combinations thereof (n=7). Of the 20 patients not cleared for TEE, 17 never underwent a TEE and 3 patients underwent a TEE 7 to 180 days later. Two patients undergoing EGD and 5 patients undergoing TEE experienced adverse cardiopulmonary events. CONCLUSIONS: Our results demonstrate that an EGD before TEE can elucidate findings that may preclude the passage of a blind probe in patients with upper GI symptoms or known esophageal disease. Therefore, we propose that an EGD is clinically beneficial before TEE and can change patient management. PMID- 25930976 TI - Inhomogeneity in barrier height at graphene/Si (GaAs) Schottky junctions. AB - Graphene (Gr) interfaced with a semiconductor forms a Schottky junction with rectifying properties, however, fluctuations in the Schottky barrier height are often observed. In this work, Schottky junctions are fabricated by transferring chemical vapor deposited monolayer Gr onto n-type Si and GaAs substrates. Temperature dependence of the barrier height and ideality factor are obtained by current-voltage measurements between 215 and 350 K. An increase in the zero bias barrier height and decrease in the ideality factor are observed with increasing temperature for both junctions. Such behavior is attributed to barrier inhomogeneities that arise from interfacial disorders as revealed by scanning tunneling microscopy/spectroscopy. Assuming a Gaussian distribution of the barrier heights, mean values of 1.14 +/- 0.14 eV and 0.76 +/- 0.10 eV are found for Gr/Si and Gr/GaAs junctions, respectively. These findings resolve the origin of barrier height inhomogeneities in these Schottky junctions. PMID- 25930977 TI - Organized sports participation and the association with injury in paediatric patients with haemophilia. AB - INTRODUCTION: With the wide availability of factor and the routine use of prophylaxis boys with haemophilia are now able to participate in regular physical activity, including organized sports. Current guidelines vary regarding specific recommendations for sports participation and concerns remain regarding safety. AIM: To determine if participation in organized sports is associated with an increased risk for injury in paediatric subjects with haemophilia. METHODS: Retrospective single-centre cohort study from January 1, 2008 to December 31, 2010 in male subjects ages 10-18 years with a factor VIII (FVIII) or FIX level <40%. The number of injuries per subject and participation in organized sports was recorded. RESULTS: 48 male subjects with a mean age of 14.3 +/- 2.6 years (range: 10-18.8) were included; 64.6% (31/48) FVIII deficiency, 54.2% (26/48) severe haemophilia, 18.8% (9/48) moderate and 27.1% (13/48) mild. The majority [62.5% (30/48)] of subjects participated in at least one season of organized sport. There were 77 injuries in 36/48 (75%) subjects. The mean number of injuries per subject was 1.6 +/- 1.5. There was no statistical difference in the mean number of injuries (P = 0.44) or target joint formation (P = 0.52) between the subjects who participated in organized sports compared to those who did not. CONCLUSION: In this study, participation in organized sports by boys with haemophilia, ages 10-18 years, is common and not associated with an increased number of injuries or the development of a target joint. As injuries occurred equally in both groups, concerted efforts should be directed at reducing injuries in all patients. PMID- 25930978 TI - Fear of falling in vision impairment. AB - Falls are the leading cause of injury-related morbidity and mortality among older adults. In addition to the resulting physical injury and potential disability after a fall, there are also important psychological consequences, including depression, anxiety, activity restriction, and fear of falling. Fear of falling affects 20 to 43% of community-dwelling older adults and is not limited to those who have previously experienced a fall. About half of older adults who experience fear of falling subsequently restrict their physical and everyday activities, which can lead to functional decline, depression, increased falls risk, and reduced quality of life. Although there is clear evidence that older adults with visual impairment have higher falls risk, only a limited number of studies have investigated fear of falling in older adults with visual impairment and the findings have been mixed. Recent studies suggest increased levels of fear of falling among older adults with various eye conditions, including glaucoma and age-related macular degeneration, whereas other studies have failed to find differences. Interventions, which are still in their infancy in the general population, are also largely unexplored in those with visual impairment. The major aims of this review were to provide an overview of the literature on fear of falling, its measurement, and risk factors among older populations, with specific focus on older adults with visual impairment, and to identify directions for future research in this area. PMID- 25930979 TI - Contributions of Visuo-oculomotor Abilities to Interceptive Skills in Sports. AB - PURPOSE: Monitoring and intercepting a fast approaching object is a critical skill for many sports. Athletes might be distinguished from nonathletes based on their ability to access various visual abilities to accomplish interceptive actions. Here, we examined whether interceptive visuomotor skills of athletes and nonathletes are differently correlated to a hierarchy of visuo-oculomotor abilities related to the perception of motion in depth. METHODS: Eighty-six athletes in interceptive sports, as well as 60 nonathletes, were recruited based on their sport performance and prior experiences. Their basic visual abilities (dominant eye acuity, contrast sensitivity, visual span, and visual memory) and complex visuo-oculomotor abilities (dynamic acuity, accommodative facility, near point of convergence, and near/far phoria) were analyzed in relation to critical visuomotor skills (manual interception, visually guided locomotion, and depth judgment). RESULTS: Discriminant analysis revealed that athletes and nonathletes can be accurately differentiated based on measured visuomotor skills (91.3% accuracy, p < 0.0001). Near point of convergence, accommodative facility, and dynamic acuity were moderately effective in identifying athletes (71.3%, p = 0.002) and in predicting the three visuomotor skills (all r(2) >= 0.096, all p <= 0.022). Dominant eye acuity and contrast sensitivity also identified athletes (61.4%, p = 0.021) and contributed to complex visuo-oculomotor abilities (all r(2) >= 0.046, all p <= 0.039). The correlations among measured abilities were more significant for athletes than nonathletes. CONCLUSIONS: Athletes in interceptive sports are superior to nonathletes in their visuomotor skills. They also have broader access to various visual and complex visuo-oculomotor abilities than nonathletes. This likely allows athletes to more effectively coordinate visual and oculomotor abilities under demanding conditions when some visual cues are degraded. The present findings are consistent with a pyramid of sports vision and suggest a top-down process for athlete screening and training. PMID- 25930980 TI - A study on the effect of cimetidine and L-carnitine on myoglobinuric acute kidney injury in male rats. AB - Myoglobinuric acute renal failure is the most important life threatening complication of rhabdomyolysis. Iron, free radicals, nitric oxide and cytochrome p450 are involved in the pathogenesis of mARF. The aim of this study is to compare the effect of cimetidine, l-carnitine and both agents together on mARF in rats. Forty rats were divided into 5 groups; group I: control rats, group II: myoglobinuric ARF rats, group III: mARF rats received l-carnitine (200mg/kg, i.p.), group IV: mARF rats received cimetidine (150mg/kg i.p.) and group V: mARF rats received both agents together. 48h after glycerol injection, systolic blood pressure was measured. Urine and blood samples were collected to evaluate urine volume, GFR, BUN, creatinine, K, Na, serum creatine kinase, NO and glutathione levels. Kidney specimens were taken to investigate renal cytochrome p450 and for histological examinations. Cimetidine treatment significantly decreased creatinine, BUN, K, Na, SBP and creatine kinase and increased GFR and urine volume compared to group II. l-carnitine exerted similar changes except for the effect on K and GFR. NO was significantly decreased, while renal glutathione and cytochrome p450 were significantly increased in groups treated with l-carnitine or cimetidine as compared to group II. Combined treatment further improved renal functions, creatine kinase, oxidative stress parameters and SBP as compared to each therapy alone. The histological changes confirmed the biochemical findings. Cimetidine and l-carnitine have protective effects - almost equally - against mARF. Using both agents together, minimises the renal injury. PMID- 25930981 TI - Renal formulas pretreated with medications alters the nutrient profile. AB - BACKGROUND: Pretreating renal formulas with medications to lower the potassium and phosphorus content is common in clinical practice; however, the effect of this treatment on other nutrients is relatively unstudied. We examine whether nutrient composition is affected by pretreating renal formulas with sodium polystyrene sulfonate (SPS) suspension and sevelamer carbonate. METHODS: Fixed medication doses and treatment times were utilized to determine changes in the nutrient composition of Suplena(r) and Similac(r) PM 60/40. The effect of simultaneously adding both medications (co-administration) to the formula on the nutrient composition of Suplena(r) was also evaluated. RESULTS: Pretreatment of Suplena(r) with SPS reduced the concentrations of calcium (11-38 %), copper (3-11 %), manganese (3-16 %), phosphorus (0-7 %), potassium (6-34 %), and zinc (5-20 %) and increased those of iron (9-34 %), sodium (89-260 %), and sulfur (19-45 %) and the pH (0.20-0.50 units). Pretreatment of Similac(r) PM 60/40 with SPS reduced the concentrations of calcium (8-29 %), copper (5-19 %), magnesium (3-26 %), and potassium (33-63 %) and increased those of iron (13-87 %) and sodium (86-247 %) and the pH (0.40-0.81 units). Pretreatment of both formulas with the SPS suspension led to significant increases in the aluminum concentration in both formulas (507-3957 %). No differences in potassium concentration were observed between treatment times. Unexpectedly, the levels of neither phosphorus nor potassium were effectively reduced in Suplena(r) pretreated with sevelamer carbonate alone or when co-administered with SPS. CONCLUSIONS: Pretreating formula with medications alters nutrients other than the intended target(s). Future studies should be aimed at predicting the loss of these nutrients or identifying alternative methods for managing serum potassium and phosphorus levels in formula-fed infants. The safety of pretreating formula with SPS suspension should also be examined. PMID- 25930982 TI - Substance use and its impact on care outcomes among HIV-infected individuals in Manitoba. AB - The high prevalence of substance use among HIV-infected individuals creates numerous challenges to patient care. This study was undertaken in order to understand the impact of substance use on care outcomes for HIV-infected individuals in Manitoba. Clinical records of 564 HIV-infected individuals in care at Health Sciences Centre in Winnipeg, Manitoba were reviewed. Clinical data were extracted from patient charts for substance users (illicit substance users, alcohol abusers and chronic users of opioids or benzodiazepines) and non-users. Substance users and non-users were analysed using chi-square analysis and logistic regression models to compare basic socio-demographic and clinic variables. Chi-square and analysis of variance were used to compare a subset of substance users based on similar socio-demographic and clinical characteristics. Among HIV-infected individuals in Manitoba, 38% were substance users with over representation by Aboriginals, females, young adults and residents of Winnipeg's core areas. Opioids and benzodiazepines were the most commonly used substances with the majority of substance users having used multiple classes of substances in their lifetime. Substance users were more likely than non-users to have missed clinic appointments. Among substance users, missed appointments were more common among those who self-identified as Aboriginal, female, young adults, residents of Winnipeg's core areas, heterosexuals and those who had abused alcohol or cocaine/crack. Aboriginal substance users were also less likely to achieve viral load suppression compared to non-Aboriginal substance users. With the high prevalence of substance use among HIV-infected individuals in Manitoba, it is important to identify at-risk individuals in order to implement appropriate care strategies and improve treatment adherence and health outcomes. PMID- 25930983 TI - Increased risk of additional cancers among patients with gastrointestinal stromal tumors: A population-based study. AB - BACKGROUND: Most gastrointestinal stromal tumors (GISTs) are considered nonhereditary or sporadic. However, single-institution studies suggest that GIST patients develop additional malignancies at increased frequencies. It was hypothesized that greater insight could be gained into possible associations between GISTs and other malignancies with a national cancer database inquiry. METHODS: Patients diagnosed with GISTs (2001-2011) in the Surveillance, Epidemiology, and End Results database were included. Standardized prevalence ratios (SPRs) and standardized incidence ratios (SIRs) were used to quantify cancer risks incurred by GIST patients before and after GIST diagnoses, respectively, in comparison with the general US population. RESULTS: There were 6112 GIST patients, and 1047 (17.1%) had additional cancers. There were significant increases in overall cancer rates: 44% (SPR, 1.44) before the GIST diagnosis and 66% (SIR, 1.66) after the GIST diagnosis. Malignancies with significantly increased occurrence both before and after diagnoses included other sarcomas (SPR, 5.24; SIR, 4.02), neuroendocrine-carcinoid tumors (SPR, 3.56; SIR, 4.79), non-Hodgkin lymphoma (SPR, 1.69; SIR, 1.76), and colorectal adenocarcinoma (SPR, 1.51; SIR, 2.16). Esophageal adenocarcinoma (SPR, 12.0), bladder adenocarcinoma (SPR, 7.51), melanoma (SPR, 1.46), and prostate adenocarcinoma (SPR, 1.20) were significantly more common only before the GIST diagnosis. Ovarian carcinoma (SIR, 8.72), small intestine adenocarcinoma (SIR, 5.89), papillary thyroid cancer (SIR, 5.16), renal cell carcinoma (SIR, 4.46), hepatobiliary adenocarcinoma (SIR, 3.10), gastric adenocarcinoma (SIR, 2.70), pancreatic adenocarcinoma (SIR, 2.03), uterine adenocarcinoma (SIR, 1.96), non small cell lung cancer (SIR, 1.74), and transitional cell carcinoma of the bladder (SIR, 1.65) were significantly more common only after the GIST diagnosis. CONCLUSIONS: This is the first population-based study to characterize the associations and temporal relations between GISTs and other cancers by both site and histological type. These associations may carry important clinical implications for future cancer screening and treatment strategies. PMID- 25930984 TI - Assessing Antibody Strength: Comparison of MFI, C1q, and Titer Information. AB - The presence of donor-specific HLA antibodies before or after transplantation may have different implications based on the antibody strength. Yet, current approaches do not provide information regarding the true antibody strength as defined by antigen-antibody dissociation rate. To assess currently available methods, we compared between neat mean fluorescence intensity (MFI) values, C1q MFI values, ethylenediaminetetraacetic acid (EDTA)-treated samples, as well as titration studies and peak MFI values of over 7000 Luminex-based single-antigen HLA antibody data points. Our results indicate that neat MFI values do not always accurately depict antibody strength. We further showed that EDTA treatment (6%) does not always remove all inhibitory factors compared with C1q or titration studies. In this study of patients presenting with multiple antibody specificities, a prozone effect was observed in 71% of the cohort (usually not affecting all antibody specificities within a single serum sample, though). Similar to titration studies, the C1q assay was able to address the issue of potential inhibition; however, its limitation is its low sensitivity and inability to detect the presence of weak antibodies. Titration studies are the only method among the approaches used in this study to provide information suggesting antigen-antibody dissociation rates and are, therefore, likely to provide better indication of true antibody strength. PMID- 25930985 TI - Cloning and Characterization of an Enantioselective l-Menthyl Benzoate Hydrolase from Acinetobacter sp. ECU2040. AB - A new esterase gene abmbh, encoding a benzoate hydrolase which can enantioselectively hydrolyze l-menthyl benzoate to l-menthol, was recently identified from the genomic library of a soil isolate Acinetobacter sp. ECU2040. The abmbh gene contains a 1080-bp open reading frame encoding a protein of 360 amino acids with a calculated molecular mass of 40.7 kDa. The corresponding enzyme AbMBH was functionally expressed in Escherichia coli BL21 (DE3), purified, and characterized. The AbMBH displayed the maximum activity towards p-nitrophenyl butyrate at 50 degrees C, and an optimum pH of 8.5. A K M of 2.6 mM and a k cat of 0.26 s(-1) were observed towards dl-menthyl benzoate. The AbMBH exhibited a moderate enantioselectivity (E = 27.5) towards dl-menthyl benzoate. It can also catalyze the enantioselective hydrolysis of a variety of racemic menthyl esters, including dl-menthyl acetate, dl-menthyl chloroacetate, and dl-menthyl butyrate. PMID- 25930986 TI - Dealing with deficient and missing data. AB - Disease control decisions require two types of data: data describing the disease frequency (incidence and prevalence) along with characteristics of the population and environment in which the disease occurs (hereafter called "descriptive data"); and, data for analytical studies (hereafter called "analytical data") documenting the effects of risk factors for the disease. Both may be either deficient or missing. Descriptive data may be completely missing if the disease is a new and unknown entity with no diagnostic procedures or if there has been no surveillance activity in the population of interest. Methods for dealing with this complete absence of data are limited, but the possible use of surrogate measures of disease will be discussed. More often, data are deficient because of limitations in diagnostic capabilities (imperfect sensitivity and specificity). Developments in methods for dealing with this form of information bias make this a more tractable problem. Deficiencies in analytical data leading to biased estimates of effects of risk factors are a common problem, and one which is increasingly being recognized, but options for correction of known or suspected biases are still limited. Data about risk factors may be completely missing if studies of risk factors have not been carried out. Alternatively, data for evaluation of risk factors may be available but have "item missingness" where some (or many) observations have some pieces of information missing. There has been tremendous development in the methods to deal with this problem of "item missingness" over the past decade, with multiple imputation being the most prominent method. The use of multiple imputation to deal with the problem of item missing data will be compared to the use of complete-case analysis, and limitations to the applicability of imputation will be presented. PMID- 25930987 TI - Homology modeling, vasorelaxant and bradykinin-potentiating activities of a novel hypotensin found in the scorpion venom from Tityus stigmurus. AB - In a recent work by our group involving a transcriptomics approach applied to the venom glands from Tityus stigmurus we identified a new family of peptides called Hypotensins (TSTI0006C) (Almeida et al., 2012). The cluster TSTI0006C was analyzed in the main 25 amino acid residues and named T. stigmurus Hypotensin (TistH), showing a molecular mass of 2.7 kDa, an absence of cysteines and the presence of two C-terminal proline residues, which are a bradykinin-potentiating peptide (BPP) signature. Here, we describe the homology modeling of the three dimensional structure of TistH. In addition, we evaluated the cardiovascular effects elicited by TistH in normotensive rats. Firstly, TistH showed no cytotoxic effect on horse erythrocyte. Furthermore, in normotensive rats TistH was able to potentiate the hypotensive action of bradykinin (BK) and induced a vasorelaxant effect in mesenteric artery rings by endothelium-dependent release of nitric oxide (NO) and demonstrated independent inhibition of angiotensin converting enzyme (ACE). Our data can contribute to a better understanding of the structural and functional characteristics of TistH and suggest its potential use in cardiovascular diseases. PMID- 25930988 TI - Proteomic analysis of host brain components that bind to infectious particles in Creutzfeldt-Jakob disease. AB - Transmissible encephalopathies (TSEs), such as Creutzfeldt-Jakob disease (CJD) and scrapie, are caused by infectious agents that provoke strain-specific patterns of disease. Misfolded host prion protein (PrP-res amyloid) is believed to be the causal infectious agent. However, particles that are stripped of PrP retain both high infectivity and viral proteins not detectable in uninfected mouse controls. We here detail host proteins bound with FU-CJD agent infectious brain particles by proteomic analysis. More than 98 proteins were differentially regulated, and 56 FU-CJD exclusive proteins were revealed after PrP, GFAP, C1q, ApoE, and other late pathologic response proteins were removed. Stripped FU-CJD particles revealed HSC70 (144* the uninfected control), cyclophilin B, an FU-CJD exclusive protein required by many viruses, and early endosome-membrane pathways known to facilitate viral processing, replication, and spread. Synaptosomal elements including synapsin-2 (at 33*) and AP180 (a major FU-CJD exclusive protein) paralleled the known ultrastructural location of 25 nm virus-like TSE particles and infectivity in synapses. Proteins without apparent viral or neurodegenerative links (copine-3), and others involved in viral-induced protein misfolding and aggregation, were also identified. Human sCJD brain particles contained 146 exclusive proteins, and heat shock, synaptic, and viral pathways were again prominent, in addition to Alzheimer, Parkinson, and Huntington aggregation proteins. Host proteins that bind TSE infectious particles can prevent host immune recognition and contribute to prolonged cross-species transmissions (the species barrier). Our infectious particle strategy, which reduces background sequences by >99%, emphasizes host targets for new therapeutic initiatives. Such therapies can simultaneously subvert common pathways of neurodegeneration. PMID- 25930989 TI - Effects of luseogliflozin, a sodium-glucose co-transporter 2 inhibitor, on 24-h glucose variability assessed by continuous glucose monitoring in Japanese patients with type 2 diabetes mellitus: a randomized, double-blind, placebo controlled, crossover study. AB - The aim of the present study was to determine the effects of luseogliflozin on 24 h glucose levels, assessed by continuous glucose monitoring, and on pharmacodynamic variables measured throughout the day. In this double-blind, placebo-controlled, crossover study, 37 patients with type 2 diabetes mellitus inadequately controlled with diet and exercise were randomized into two groups. Patients in each group first received luseogliflozin then placebo for 7 days each, or vice versa. After 7 days of treatment, the mean 24-h glucose level was significantly lower with luseogliflozin than with placebo [mean (95% confidence interval) 145.9 (134.4-157.5) mg/dl vs 168.5 (156.9-180.0) mg/dl; p < 0.001]. The proportion of time spent with glucose levels >=70 to <=180 mg/dl was significantly greater with luseogliflozin than with placebo [median (interquartile range) 83.2 (67.7-96.5)% vs 71.9 (46.9-83.3)%; p < 0.001] without inducing hypoglycaemia. The decrease in glucose levels was accompanied by reductions in serum insulin levels throughout the day. PMID- 25930991 TI - The role of Mott-Schottky heterojunctions in PtCo-Cu2ZnGeS4 as counter electrodes in dye-sensitized solar cells. AB - Metastable wurtzstannite Cu2ZnGeS4 (CZGS) nanocrystals were synthesized via a hot injection method and then used as matrixes to fabricate PtCo-CZGS heterostructured nano-particles. The formed Mott-Schottky heterojunctions in the hybrid nanocrystals promote the transfer of electrons from semiconducting CZGS to metallic PtCo, which accelerates the reduction of I3(-) to I(-) in dye-sensitized solar cells. PMID- 25930990 TI - The macrophage migration inhibitory factor protein superfamily in obesity and wound repair. AB - The rising number of obese individuals has become a major burden to the healthcare systems worldwide. Obesity includes not only the increase of adipose tissue mass but importantly also the altered cellular functions that collectively lead to a chronic state of adipose tissue inflammation, insulin resistance and impaired wound healing. Adipose tissue undergoing chronic inflammation shows altered cytokine expression and an accumulation of adipose tissue macrophages (ATM). The macrophage migration inhibitory factor (MIF) superfamily consists of MIF and the recently identified homolog D-dopachrome tautomerase (D-DT or MIF-2). MIF and D-DT, which both bind to the CD74/CD44 receptor complex, are differentially expressed in adipose tissue and have distinct roles in adipogenesis. MIF positively correlates with obesity as well as insulin resistance and contributes to adipose tissue inflammation by modulating ATM functions. D-DT, however, is negatively correlated with obesity and reverses glucose intolerance. In this review, their respective roles in adipose tissue homeostasis, adipose tissue inflammation, insulin resistance and impaired wound healing will be reviewed. PMID- 25930992 TI - A computed tomography radiogenomic biomarker predicts microvascular invasion and clinical outcomes in hepatocellular carcinoma. AB - Microvascular invasion (MVI) in hepatocellular carcinoma (HCC) is an independent predictor of poor outcomes subsequent to surgical resection or liver transplantation (LT); however, MVI currently cannot be adequately determined preoperatively. Radiogenomic venous invasion (RVI) is a contrast-enhanced computed tomography (CECT) biomarker of MVI derived from a 91-gene HCC "venous invasion" gene expression signature. Preoperative CECTs of 157 HCC patients who underwent surgical resection (N = 72) or LT (N = 85) between 2000 and 2009 at three institutions were evaluated for the presence or absence of RVI. RVI was assessed for its ability to predict MVI and outcomes. Interobserver agreement for scoring RVI was substantial among five radiologists (kappa = 0.705; P < 0.001). The diagnostic accuracy, sensitivity, and specificity of RVI in predicting MVI was 89%, 76%, and 94%, respectively. Positive RVI score was associated with lower overall survival (OS) than negative RVI score in the overall cohort (P < 0.001; 48 vs. >147 months), American Joint Committee on Cancer tumor-node-metastasis stage II (P < 0.001; 34 vs. >147 months), and in LT patients within Milan criteria (P < 0.001; 69 vs. >147 months). Positive RVI score also portended lower recurrence-free survival at 3 years versus negative RVI score (P = 0.001; 27% vs. 62%). CONCLUSION: RVI is a noninvasive radiogenomic biomarker that accurately predicts histological MVI in HCC surgical candidates. Its presence on preoperative CECT is associated with early disease recurrence and poor OS and may be useful for identifying patients less likely to derive a durable benefit from surgical treatment. PMID- 25930995 TI - Osteocalcin protects pancreatic beta cell function and survival under high glucose conditions. AB - Diabetes is characterized by progressive beta cell dysfunction and loss due in part to oxidative stress that occurs from gluco/lipotoxicity. Treatments that directly protect beta cell function and survival in the diabetic milieu are of particular interest. A growing body of evidence suggests that osteocalcin, an abundant non-collagenous protein of bone, supports beta cell function and proliferation. Based on previous gene expression data by microarray, we hypothesized that osteocalcin protects beta cells from glucose-induced oxidative stress. To test our hypothesis we cultured isolated rat islets and INS-1E cells in the presence of normal, high, or high glucose +/- osteocalcin for up to 72 h. Oxidative stress and viability/mitochondrial function were measured by H2O2 assay and Alamar Blue assay, respectively. Caspase 3/7 activity was also measured as a marker of apoptosis. A functional test, glucose stimulated insulin release, was conducted and expression of genes/protein was measured by qRT-PCR/western blot/ELISA. Osteocalcin treatment significantly reduced high glucose-induced H2O2 levels while maintaining viability/mitochondrial function. Osteocalcin also significantly improved glucose stimulated insulin secretion and insulin content in rat islets after 48 h of high glucose exposure compared to untreated islets. As expected sustained high glucose down-regulated gene/protein expression of INS1 and BCL2 while increasing TXNIP expression. Interestingly, osteocalcin treatment reversed the effects of high glucose on gene/protein expression. We conclude that osteocalcin can protect beta cells from the negative effects of glucose-induced oxidative stress, in part, by reducing TXNIP expression, thereby preserving beta cell function and survival. PMID- 25930994 TI - Changes in nitrergic and tachykininergic pathways in rat proximal colon in response to chronic treatment with otilonium bromide. AB - BACKGROUND: Otilonium bromide (OB) is used as a spasmolytic drug in the treatment of the functional bowel disorder irritable bowel syndrome. Although its acute effects on colonic relaxation are well-characterized, little is known about the effects of chronic administration of OB on enteric neurons, neuromuscular transmission, and interstitial cells of Cajal (ICC), key regulators of the gut function. METHODS: Adult Sprague-Dawley rats were treated with OB in drinking water at a dose of 2 mg/kg for 30 days. The colons of OB-treated and age-matched control rats were studied by confocal immunohistochemistry to detect immunoreactivity (IR) in myenteric plexus neurons for nitrergic and tachykininergic markers, and also by microelectrode electrophysiology. KEY RESULTS: Using immunohistochemistry, chronic OB administration did not change total neuron number, assessed by anti-Hu IR, but resulted in a significant increase in NK1 receptor positive neurons, a decrease in neuronal nitric oxide synthase expressing neurons, and a reduction in volume of substance P in nerve fibers in the myenteric plexus. Chronic OB administration potentiated inhibitory and excitatory junction potentials evoked by repetitive electrical field stimulation. The various types of colonic ICC, detected by Kit IR, were not altered nor were slow waves or smooth muscle membrane potential. CONCLUSIONS & INFERENCES: Chronic treatment with OB caused significant changes in the nitrergic and tachykinergic components of the myenteric plexus and in both inhibitory and excitatory neurotransmission in the rat colon. PMID- 25930996 TI - Fenoterol inhibits LPS-induced AMPK activation and inflammatory cytokine production through beta-arrestin-2 in THP-1 cell line. AB - The AMP-activated protein kinase (AMPK) pathway is involved in regulating inflammation in several cell lines. We reported that fenoterol, a beta2 adrenergic receptor (beta2-AR) agonist, had anti-inflammatory effects in THP-1 cells, a monocytic cell line. Whether the fenoterol anti-inflammatory effect involves the AMPK pathway is unknown. In this study, we explored the mechanism of beta2-AR stimulation with fenoterol in a lipopolysaccharide (LPS)-induced inflammatory cytokine secretion in THP-1 cells. We studied whether fenoterol and beta-arrestin-2 or AMPKalpha1 subunit knockdown could affect LPS-induced AMPK activation, nuclear factor-kappa B (NF-kappaB) activation and inflammatory cytokine secretion. LPS-induced AMPK activation and interleukin 1beta (IL-1beta) release were reduced with fenoterol pretreatment of THP-1 cells. SiRNA knockdown of beta-arrestin-2 abolished the fenoterol inhibition of LPS-induced AMPK activation and interleukin 1beta (IL-1beta) release, thus beta-arrestin-2 mediated the anti-inflammatory effects of fenoterol on LPS-treated THP-1 cells. In addition, siRNA knockdown of AMPKalpha1 significantly attenuated the LPS induced NF-kappaB activation and IL-1beta release, so AMPKalpha1 was a key signaling molecule involved in LPS-induced inflammatory cytokine production. These results suggested the beta2-AR agonist fenoterol inhibited LPS-induced AMPK activation and IL-1beta release via beta-arrestin-2 in THP-1 cells. The exploration of these mechanisms may help optimize therapeutic agents targeting these pathways in inflammatory diseases. PMID- 25930993 TI - Toll-like receptor signaling in primary immune deficiencies. AB - Toll-like receptors (TLRs) recognize common microbial or host-derived macromolecules and have important roles in early activation of the immune system. Patients with primary immune deficiencies (PIDs) affecting TLR signaling can elucidate the importance of these proteins to the human immune system. Defects in interleukin-1 receptor-associated kinase-4 and myeloid differentiation factor 88 (MyD88) lead to susceptibility to infections with bacteria, while mutations in nuclear factor-kappaB essential modulator (NEMO) and other downstream mediators generally induce broader susceptibility to bacteria, viruses, and fungi. In contrast, TLR3 signaling defects are specific for susceptibility to herpes simplex virus type 1 encephalitis. Other PIDs induce functional alterations of TLR signaling pathways, such as common variable immunodeficiency in which plasmacytoid dendritic cell defects enhance defective responses of B cells to shared TLR agonists. Dampening of TLR responses is seen for TLRs 2 and 4 in chronic granulomatous disease (CGD) and X-linked agammaglobulinemia (XLA). Enhanced TLR responses, meanwhile, are seen for TLRs 5 and 9 in CGD, TLRs 4, 7/8, and 9 in XLA, TLRs 2 and 4 in hyper IgE syndrome, and for most TLRs in adenosine deaminase deficiency. PMID- 25930997 TI - Essential role of POLDIP2 in Tau aggregation and neurotoxicity via autophagy/proteasome inhibition. AB - In Alzheimer's disease and other tauopathy, abnormal Tau proteins form intracellular aggregates and Tau filaments. However, the mechanisms that regulate Tau aggregation are not fully understood. In this paper, we show that POLDIP2 is a novel regulator of Tau aggregation. From a cell-based screening using cDNA expression library, we isolated POLDIP2 which increased Tau aggregation. Expression of POLDIP2 was increased in neuronal cells by the multiple stresses, including Abeta, TNF-alpha and H2O2. Accordingly, ectopic expression of POLDIP2 enhanced the formation of Tau aggregates without affecting Tau phosphorylation, while down-regulation of POLDIP2 alleviated ROS-induced Tau aggregation. Interestingly, we found that POLDIP2 overexpression induced impairments of autophagy activity and partially proteasome activity and this activities were retained in DUF525 domain of POLDIP2. In a drosophila model of human tauopathy, knockdown of the drosophila POLDIP2 homolog, CG12162, attenuated rough eye phenotype induced by Tau overexpression. Further, the lifespan of neural Tau(R406W) transgenic files were recovered by CG12162 knockdown. Together, these observations indicate that POLDIP2 plays a crucial role in Tau aggregation via the impairment of autophagy activity, providing insight into Tau aggregation in Tau pathology. PMID- 25930998 TI - Application of dynamic metabolomics to examine in vivo skeletal muscle glucose metabolism in the chronically high-fat fed mouse. AB - RATIONALE: Defects in muscle glucose metabolism are linked to type 2 diabetes. Mechanistic studies examining these defects rely on the use of high fat-fed rodent models and typically involve the determination of muscle glucose uptake under insulin-stimulated conditions. While insightful, they do not necessarily reflect the physiology of the postprandial state. In addition, most studies do not examine aspects of glucose metabolism beyond the uptake process. Here we present an approach to study rodent muscle glucose and intermediary metabolism under the dynamic and physiologically relevant setting of the oral glucose tolerance test (OGTT). METHODS AND RESULTS: In vivo muscle glucose and intermediary metabolism was investigated following oral administration of [U (13)C] glucose. Quadriceps muscles were collected 15 and 60 min after glucose administration and metabolite flux profiling was determined by measuring (13)C mass isotopomers in glycolytic and tricarboxylic acid (TCA) cycle intermediates via gas chromatography-mass spectrometry. While no dietary effects were noted in the glycolytic pathway, muscle from mice fed a high fat diet (HFD) exhibited a reduction in labelling in TCA intermediates. Interestingly, this appeared to be independent of alterations in flux through pyruvate dehydrogenase. In addition, our findings suggest that TCA cycle anaplerosis is negligible in muscle during an OGTT. CONCLUSIONS: Under the dynamic physiologically relevant conditions of the OGTT, skeletal muscle from HFD fed mice exhibits alterations in glucose metabolism at the level of the TCA cycle. PMID- 25930999 TI - Nesfatin-1 stimulates glucagon-like peptide-1 and glucose-dependent insulinotropic polypeptide secretion from STC-1 cells in vitro. AB - Nesfatin-1 is an 82 amino acid peptide encoded in a secreted precursor, nucleobindin 2. It is an anorexigenic and insulinotropic peptide found abundantly in the hypothalamus, pancreas and gastric oxyntic mucosa. NUCB2 mRNA expression is 10 fold higher in the gastric mucosa than in brain, suggesting gastrointestinal tract as a main source of nesfatin-1. Meal responsive insulin secretion is regulated by incretins glucagon-like peptide-1 (GLP-1) and glucose dependent insulinotropic polypeptide (GIP). Since both nesfatin-1 and incretins modulate insulin secretion, we hypothesized that nesfatin-1 is present in the enteroendocrine cells, and that it regulates incretin secretion. RT-PCR analysis found NUCB2 mRNA expression, and immunofluorescence microscopy determined nesfatin-1 immunoreactivity in STC-1, an enteroendocrine cell line. NUCB2/nesfatin-1 is co-localized with GLP-1 and GIP in mouse small intestinal cells. Static incubation of STC-1 cells with nesfatin-1 upregulated preproglucagon (GLP-1 precursor) mRNA (0.01, 0.1, 1 and 10 nM) and GLP-1 secretion (0.1, 1 and 10 nM). Nesfatin-1 also enhanced GIP mRNA (0.1, 1 and 10 nM) and GIP secretion (1 and 10 nM). Together, our data support the hypothesis that nesfatin-1 is present in enteroendocrine cells and that it stimulates incretin secretion. Future studies should aim for nesfatin-1 and incretin interactions in vivo. PMID- 25931000 TI - Fat and carbohydrate in western diet contribute differently to hepatic lipid accumulation. AB - We investigated the contributions of dietary fat and dietary carbohydrate to the development of fatty liver induced by western diet (WD). Compared with WD-fed wild type (WT) mice, livers of WD-fed ChREBP(-/-) mice showed lipid droplets of varying sizes around the hepatic lobules, while hepatic triglyceride and cholesterol contents were only modestly decreased. Inflammation and fibrosis were suppressed in ChREBP(-/-) mice. In addition, compared with WD-fed WT mice, ChREBP(-/-) mice showed decreased beta-oxidation, ketogenesis and FGF21 production, increased intestinal lipid absorption, and decreased VLDL secretion. These findings suggest that dietary fat and carbohydrate contribute differently to the development of fatty liver. PMID- 25931001 TI - ShRNA-mediated gene silencing of lipoprotein lipase improves insulin sensitivity in L6 skeletal muscle cells. AB - In previous studies, we demonstrated that down-regulation of lipoprotein lipase in L6 muscle cells increased insulin-stimulated glucose uptake. In the current study, we used RNA interference technology to silence the LPL gene in L6 cells and generate a LPL-knock-down (LPL-KD) cell line. ShRNA transfected cells showed a 88% reduction in the level of LPL expression. The metabolic response to insulin was compared in wild-type (WT) and LPL-KD cells. Insulin-stimulated glycogen synthesis and glucose oxidation were respectively, 2.4-fold and 2.6-fold greater in LPL-KD cells compared to WT cells. Oxidation of oleic acid was reduced by 50% in LPL-KD cells compared to WT cells even in the absence of insulin. The contribution of LPL in regulating fuel metabolism was confirmed by adding back purified LPL to the culture media of LPL-KD cells. The presence of 10 MUg/mL LPL resulted in LPL-KD cells reverting back to lower glycogen synthesis and glucose oxidation and increased fatty acid oxidation. Thus, LPL depletion appeared to mimic the action of insulin. These finding suggests an inverse correlation between muscle LPL levels and insulin-stimulated fuel homeostasis. PMID- 25931002 TI - Neural correlates of personal goal processing during episodic future thinking and mind-wandering: An ALE meta-analysis. AB - The ability to imagine the future is a complex mental faculty that depends on an ensemble of cognitive processes supported by an extended set of brain regions. Our aim here was to shed light on one key component of future thinking--personal goal processing--and to determine its neural correlates during both directed and spontaneous forms of thoughts. To address this question, we performed separate ALE meta-analyses of neuroimaging studies of episodic future thinking (EFT), mind wandering, and personal goal processing, and then investigated the commonalities and differences in brain activity between these three domains. The results showed that the three domains activated a common set of brain regions within the default network and, most notably, the medial prefrontal cortex. This finding suggests that the medial prefrontal cortex mediates the processing of personal goals during both EFT and mind-wandering. Differences in activation were also observed, and notably regions supporting cognitive control processes (the dorsolateral prefrontal cortex) were recruited to a lesser extent during mind-wandering than experimentally directed future thinking, suggesting that different kinds of self generated thoughts may recruit varying levels of attentional control abilities. PMID- 25931003 TI - Guidelines of care for vascular lasers and intense pulse light sources from the European Society for Laser Dermatology. AB - AIM: Lasers and non-coherent intense pulse light sources (IPLS) are based on the principle of selective photothermolysis and can be used for the treatment of many vascular skin lesions. A variety of lasers has been developed for the treatment of congenital and acquired vascular lesions which incorporate these concepts into their design. Although laser and light sources are very popular due to their non invasive nature, caution should be considered by practitioners and patients to avoid permanent side-effects. The aim of these guidelines is to give evidence based recommendations for the use of lasers and IPLS in the treatment of vascular lesions. METHODS: These guidelines were produced by a Consensus Panel made up of experts in the field of vascular laser surgery under the auspices of the European Society of Laser Dermatology. Recommendations on the use of vascular lasers and IPLS were made based on the quality of evidence for efficacy, safety, tolerability, cosmetic outcome, patient satisfaction/preference and, where appropriate, on the experts' opinion. The recommendations of these guidelines are graded according to the American College of Chest Physicians Task Force recommendations on Grading Strength of Recommendations and Quality of Evidence in Clinical Guidelines. RESULTS: Lasers and IPLS are very useful and sometimes the only available method to treat various vascular lesions. It is of a paramount importance that the type of laser or IPLS and their specific parameters are adapted to the indication but also that the treating physician is familiar with the device to be used. The crucial issue in treating vascular lesions is to recognize the immediate end-point after laser treatment. This is the single most important factor to ensure both the efficacy of the treatment and avoidance of serious side-effects. PMID- 25931004 TI - Genistein increases estrogen receptor beta expression in prostate cancer via reducing its promoter methylation. AB - Genistein has protective effects against prostate cancer (PCa) but whether this protection involves an estrogen receptor (ER) beta dependent mechanism has yet to be elucidated. ER-beta has a tumor suppressor role in PCa and its levels decline with cancer progression which was linked to ER-beta promoter hypermethylation. Genistein has been suggested to have demethylating activities in cancer. However, the ability of genistein to reverse ER-beta promoter hypermethylation in PCa has not been studied. In addition, there are great discrepancies among studies that examined the effect of genistein on ER-beta gene expression. Therefore, we sought to explore effects of genistein on ER-beta promoter methylation as a mechanism of modulating ER-beta expression using three PCa cell lines, LNCaP, LAPC-4 and PC-3. We also examined the role of ER-beta in mediating the preventive action of genistein. Our data demonstrated that genistein at physiological ranges (0.5-10 MUmol/L) reduced ER-beta promoter methylation significantly with corresponding dose-dependent increases in ER-beta expression in LNCaP and LAPC-4 but not in PC 3 cells, which could be attributed to the low basal levels of ER-beta promoter methylation in PC-3 cell line. Genistein induced phosphorylation, nuclear translocation and transcriptional activity of ER-beta in all three PCa cell lines. Inhibitory effects of genistein on LAPC-4 and PC-3 cell proliferation were diminished using a specific ER-beta antagonist. In conclusion, genistein and ER beta act together to prevent PCa cell proliferation; genistein increases ER-beta levels via reducing its promoter methylation and ER-beta, in turn, mediates the preventive action of genistein. PMID- 25931005 TI - Medical Student Perceptions of Cost-Conscious Care in an Internal Medicine Clerkship: A Thematic Analysis. AB - BACKGROUND: Although as much as 87 % of all healthcare spending is directed by physicians, studies have demonstrated that they lack knowledge about the costs of medical care. Similarly, learners have not traditionally received instruction on cost-conscious care. OBJECTIVE: To examine medical students' perceptions of healthcare delivery as it relates to cost consciousness DESIGN: Retrospective qualitative analysis of medical student narratives PARTICIPANTS: Third-year medical students during their inpatient internal medicine clerkship MAIN MEASURES: Students completed a reflective exercise wherein they were asked to describe a scenario in which a patient experienced lack of attention to cost conscious care, and were asked to identify solutions and barriers. We analyzed these reflections to learn more about students' awareness and perceptions regarding the practice of cost-conscious care within our medical center. KEY RESULTS: Eighty students submitted the assignment between July and December 2012. The most common problems identified included unnecessary tests and treatments (n = 69) and duplicative tests and treatments (n = 20.) With regards to solutions, students described 82 scenarios, with 125 potential solutions identified. Students most commonly used discussion with the team (speak up, ask why) as the process they would use (n = 28) and most often wanted to focus lab testing (n = 38) as the intervention. The most common barriers to high-value care included increased time and effort (n = 19), ingrained practices (n = 17), and defensive medicine or fear of missing something (n = 18.) CONCLUSIONS: Even with minimal clinical experience, medical students were able to identify instances of lack of attention to cost-conscious care as well as potential solutions. Although students identified the hierarchy in healthcare teams as a potential barrier to improving high value care, most students stated they would feel comfortable engaging the team in discussion. Future efforts to empower learners at all levels to question value decisions and to develop and implement solutions may result in improved healthcare. PMID- 25931006 TI - Inpatient Hospital Charge Variability of U.S. Hospitals. AB - BACKGROUND: The range of hospital charges for similar diagnoses show tremendous variability across U.S. hospitals. This charge variability remains unexplained. OBJECTIVE: We aimed to describe hospital charge variability in the U.S. and examine its relationship to local health factors. DESIGN: This was a descriptive study of the 2011 Medicare Inpatient Charge data summarizing inpatient hospital charges billed to Medicare. This data was evaluated using 29 county-level measures of health status, health behavior, clinical access and quality, built environment, and socioeconomic status in a clustered, multivariate linear regression. PARTICIPANTS: 2871 U.S. hospitals registered with Medicare and with at least ten discharges for diagnosis-related groups (DRGs) of six common inpatient conditions. MAIN MEASURE: Inpatient hospital charges were assessed. KEY RESULTS: No community health measures were associated with hospital charges. The one notable exception associated with higher charges was higher rates of uninsured status ($344.84 higher charges for every one-percentage point increase in prevalence (p < 0.001)). One variable was associated with lower hospital charges: the percentage of children living in poverty [$309.30 lower charges for every one-percentage point increase in prevalence (p < 0.001)]. CONCLUSIONS: Overall, hospital charges lacked an association with population health measures, and their variability remains largely unexplained. However, the association of higher charges with uninsured status raises concerns about hospitals' price setting strategies, such as price discrimination and cost-shifting strategies that expose vulnerable populations to great financial risks. PMID- 25931007 TI - Fast determination of octinoxate and oxybenzone uv filters in swimming pool waters by gas chromatography/mass spectrometry after solid-phase microextraction. AB - A fast gas chromatography/mass spectrometry method was developed and validated for the analysis of the potential endocrine disrupters octinoxate and oxybenzone in swimming pool water samples based on the solvent-free solid-phase microextraction technique. The low-pressure gas chromatography/mass spectrometry method used for the fast identification of UV filter substances was compared to a conventional method in terms of sensitivity and speed. The fast method proposed resulted in 2 min runs, leading to an eightfold decrease in the total analysis time and a sevenfold improvement in detection limits. The main parameters affecting the solid-phase microextraction process were also studied in detail and the optimized conditions were as follows: fiber coating, polyacrylate; extraction mode, direct immersion; extraction temperature, 25 degrees C; sample volume, 5 mL; extraction time 45 min; pH 6.5. Under the optimized conditions, a linear response was obtained in the concentration range of 0.5-25 MUg/L with correlation coefficients in the range 0.990-0.999. The limits of detection were 0.17-0.29 MUg/L, and the recoveries were 80-83%. Combined method uncertainty was assessed and found to be less than 7% for both analytes for concentrations equal to or higher than 5 MUg/L. Pool water samples were analyzed to demonstrate the applicability of the proposed method. Neither octinoxate nor oxybenzone were detected in the swimming pool water samples at concentrations above the respective limits of detection. PMID- 25931008 TI - Identifying corrections-is there a better way? PMID- 25931009 TI - Transparency in Europe: A Quantitative Study. AB - In recent years, European pharmaceutical regulators have increasingly committed to heightening access to raw safety-related data as part of a wave of transparency initiatives (e.g., providing public Internet-mediated access to clinical trials data). Yet, the regulators--who are under significant pressure- have not yet benefited from a systematic review of this new policy. In seeking to inject much needed evidence, this article explores the effects of new transparency policies designed to promote meaningful communication of risks and benefits to patients. Results of a cross-national European survey with respondents from Great Britain, the Netherlands, Spain, France, Germany, and Sweden (N = 5,648) shed light on how patients and the public are likely to react to the regulators' new transparency policies. The findings demonstrate clear national variations in how European citizens are likely to react and emphasize the need to develop evidence-based, reasoned transparency policies that integrate benefit-risk communication. The authors conclude by providing six specific recommendations, informed by the study, that seek to improve the European transparency model both within the medical field and across health, safety, and environmental policy domains. PMID- 25931010 TI - [Metastatic screening before adjuvant chemotherapy in breast cancer]. AB - INTRODUCTION: Systematic metastasis staging in early breast cancer is no longer recommended. However, it is still performed before adjuvant chemotherapy. MATERIALS AND METHODS: We assessed metastasis screening of asymptomatic women with a local breast cancer without lymph node involvement when adjuvant chemotherapy was indicated. The screening result was classified in 3 groups: "non metastatic", "metastatic" and "suspect". For suspect screening, we analyzed the checking period and the consequences on cares. RESULTS: Out of 1545 patients with possible indication of chemotherapy, 690 indications of chemotherapy were validated by multidisciplinary meeting. Six hundred and thirty-nine metastasis screening were done. Five hundred and fifty-five screenings (86.9 %) were "non metastatic", 3 screenings (0.5 %) were "metastatic" and 81 screenings (12.7 %) were "suspect". Out of this 81 suspect screening, only 47 screening have been checked, using 61 further investigations. No breast cancer metastasis was finally identified. CONCLUSION: Low rate of metastasis suggest reassessing metastasis screening before adjuvant chemotherapy for patients without lymph node involvement. PMID- 25931011 TI - An assessment of preventive care offered to orthodontic patients by oral health therapists in NSW Australia. AB - OBJECTIVE: The aim of this study was to record preventive oral health care planned by dental therapists and oral health therapists (therapists) for patients with poor oral hygiene undergoing orthodontic treatment. MATERIALS AND METHODS: A cross-sectional survey, using a clinical vignette of a patient with poor oral hygiene undergoing therapy with a fixed appliance, was undertaken to record the preventive care offered to this individual by therapists working across 15 Local Health Districts (LHDs). This orthodontic vignette was inserted between two dental caries-related vignettes. Data were coded and descriptive statistics were used to report the findings. RESULTS: One-hundred and seventeen therapists returned questionnaires (giving a response rate of 64.6%), of whom 82.0% (n = 95) completed the orthodontic vignette. Adopting motivational interviewing techniques to facilitate communication with the patient and their parent was recommended by 88.4% (n = 84) respondents, 98.0% (n = 93) offered oral-hygiene instruction, 70.5% (n = 67) recorded plaque levels and used disclosing solution and 60.0% (n = 57) offered dietary advice. Products recommended for use at home included fluoride toothpaste [1,450 ppm F (80.0%; n = 76) and 5,000 ppm F (59.0%; n = 24)] and casein phosphopeptide amorphous phosphates plus fluoride (CPP-ACPF) paste (33.3%; n = 32). Less than 20% offered fissure sealants. CONCLUSION: Preventive advice and care was offered inconsistently by therapists in this study. To ensure that all therapists adopt a scientifically based approach to prevention, LHD clinical directors should implement continuous professional education programmes for therapists to improve patient's health outcomes. PMID- 25931012 TI - Lack of topoisomerase copy number changes in patients with de novo and relapsed diffuse large B-cell lymphoma. AB - Topoisomerase (TOP) gene copy number changes may predict response to treatment with TOP-targeting drugs in cancer treatment. This was first described in patients with breast cancer and is currently being investigated in other malignant diseases. TOP-targeting drugs may induce TOP gene copy number changes at relapse, with possible implications for relapse therapy efficacy. TOP gene alterations in lymphoma are poorly investigated. In this study, TOP1 and TOP2A gene alterations were investigated in patients with de novo diffuse large B-cell lymphoma (DLBCL) (n = 33) and relapsed DLBCL treated with chemotherapy regimens including TOP2-targeting drugs (n = 16). No TOP1 or TOP2A copy number changes were found. Polysomy of chromosomes 20 and 17 was seen in 3 of 25 patients (12%) and 2 of 32 patients (6%) with de novo DLBCL. Among relapsed patients, chromosome polysomy was more frequently observed in 5 of 13 patients (38%) and 4 of 16 patients (25%) harboring chromosome 20 and 17 polysomy, respectively; however, these differences only tended to be significant (p = 0.09 and p = 0.09, respectively). The results suggest that TOP gene copy number changes are very infrequent in DLBCL and not likely induced by TOP2-targeting drugs. Increased polyploidy of chromosomes 17 and 20 among patients with relapsed DLBCL may reflect genetic compensation in the tumor cells after TOP2 inhibition, but is more likely due to the increased genetic instability often seen in progressed cancers. Therefore, it is unlikely that TOP1 and TOP2A gene alterations can be used as predictive markers for response to treatment with TOP2-targeting drugs in patients with DLBCL. PMID- 25931013 TI - RN-1, a potent and selective lysine-specific demethylase 1 inhibitor, increases gamma-globin expression, F reticulocytes, and F cells in a sickle cell disease mouse model. AB - Increased levels of fetal hemoglobin are associated with decreased symptoms and increased lifespan in patients with sickle cell disease (SCD). Hydroxyurea, the only drug currently approved for SCD, is not effective in a large fraction of patients, and therefore, new agents are urgently needed. Recently it was found that lysine demethylase 1, an enzyme that removes monomethyl and dimethyl residues from the lysine 4 residue of histone H3, is a repressor of gamma-globin gene expression. In this article, we have compared the ability of tranylcypromine (TCP) and a more potent TCP derivative, RN-1, to increase gamma-globin expression in cultured baboon erythroid progenitor cells and in the SCD mouse model. The results indicate that the ability of RN-1 to induce F cells and gamma-globin mRNA in SCD mice is similar to that of decitabine, the most powerful fetal hemoglobin inducing drug known, and greater than that of either TCP or hydroxyurea. We conclude that RN-1 and other lysine demethylase 1 inhibitors may be promising new gamma-globin-inducing agents for the treatment of SCD that warrant further studies in other preclinical models, such as nonhuman primates. PMID- 25931014 TI - Coexpression of hyperactivated AKT1 with additional genes activated in leukemia drives hematopoietic progenitor cells to cell cycle block and apoptosis. AB - The phosphatidylinositol 3-kinase/AKT pathway is an integral component of signaling involved in the development of many cancers, including myeloid leukemias such as chronic myeloid leukemia and acute myeloid leukemia (AML). Increased AKT1 activity is frequently seen in AML patients, providing leukemic cells with growth and survival promoting signals. An important aspect of AKT1 function is its involvement in cellular metabolism and energy production. Under some circumstances, strong activation of AKT1 increases oxidative stress, which can cause apoptosis when cells progressively build up excess free radicals. This has been described in hematopoietic cells overexpressing activated AKT1; however, whether this is true in cells coexpressing other genetic events involved in leukemia is not known. This prompted us to investigate the effect of constitutively active AKT1 (myristoylated AKT1) in hematopoietic progenitor cells expressing constitutively active signal transducer and activator of transcription 5, Fms-related tyrosine kinase 3-internal tandem duplication, or antiapoptotic B cell lymphoma 2. Surprisingly, myristoylated AKT1 was incompatible with proliferation driven by both signal transducer and activator of transcription 5 and Fms-related tyrosine kinase 3-internal tandem duplication, which triggered cell cycle block and apoptosis. Moreover, transplantable cells of B-cell lymphoma 2-transgenic mice were impaired in their engraftment ability to recipient mice when expressing hyperactivated AKT1. This was linked to AKT1-mediated proapoptotic functions and not to impairment in homing to the bone marrow. Although cells expressing hyperactivated AKT1 displayed higher levels of reactive oxygen species both in vitro and in vivo, the addition of the antioxidant N acetyl-L-cysteine significantly reduced apoptosis. Taken together, the results indicate that constitutive AKT1 activity is incompatible with growth- and survival-promoting ability of other activated genes in AML. PMID- 25931015 TI - Improving pancreatic islet in vitro functionality and transplantation efficiency by using heparin mimetic peptide nanofiber gels. AB - Pancreatic islet transplantation is a promising treatment for type 1 diabetes. However, viability and functionality of the islets after transplantation are limited due to loss of integrity and destruction of blood vessel networks. Thus, it is important to provide a proper mechanically and biologically supportive environment for enhancing both in vitro islet culture and transplantation efficiency. Here, we demonstrate that heparin mimetic peptide amphiphile (HM-PA) nanofibrous network is a promising platform for these purposes. The islets cultured with peptide nanofiber gel containing growth factors exhibited a similar glucose stimulation index as that of the freshly isolated islets even after 7 days. After transplantation of islets to STZ-induced diabetic rats, 28 day-long monitoring displayed that islets that were transplanted in HM-PA nanofiber gels maintained better blood glucose levels at normal levels compared to the only islet transplantation group. In addition, intraperitoneal glucose tolerance test revealed that animals that were transplanted with islets within peptide gels showed a similar pattern with the healthy control group. Histological assessment showed that islets transplanted within peptide nanofiber gels demonstrated better islet integrity due to increased blood vessel density. This work demonstrates that using the HM-PA nanofiber gel platform enhances the islets function and islet transplantation efficiency both in vitro and in vivo. PMID- 25931016 TI - Development of human corneal epithelium on organized fibrillated transparent collagen matrices synthesized at high concentration. AB - Several diseases can lead to opacification of cornea requiring transplantation of donor tissue to restore vision. In this context, transparent collagen I fibrillated matrices have been synthesized at 15, 30, 60 and 90 mg/mL. The matrices were evaluated for fibril organizations, transparency, mechanical properties and ability to support corneal epithelial cell culture. The best results were obtained with 90 mg/mL scaffolds. At this concentration, the fibril organization presented some similarities to that found in corneal stroma. Matrices had a mean Young's modulus of 570 kPa and acellular scaffolds had a transparency of 87% in the 380-780 nm wavelength range. Human corneal epithelial cells successfully colonized the surface of the scaffolds and generated an epithelium with characteristics of corneal epithelial cells (i.e. expression of cytokeratin 3 and presence of desmosomes) and maintenance of stemness during culture (i.e. expression of DeltaNp63alpha and formation of holoclones in colony formation assay). Presence of cultured epithelium on the matrices was associated with increased transparency (89%). PMID- 25931017 TI - Coupling of olfactory receptor and ion channel for rapid and sensitive visualization of odorant response. AB - In the human smell sensing system, there are about 390 kinds of olfactory receptors (ORs) which bind to various odorants with different affinities and specificities. Characterization and odorant binding pattern analysis of the ORs are essential for understanding of human olfaction and to mimic the olfactory system in various applications. Although various cell-based odorant screening systems have been developed for this purpose, many human ORs (hORs) still remain orphan because of the time-consuming and labor-intensive experimental procedures of the available screening methods. In this study, we constructed an ion channel coupled hOR for simple odorant detection by rapidly visualizing the odorant response to overcome the limitations of conventional screening systems. The hORs were coupled to the Kir6.2 potassium channel and the fusion proteins were expressed in HEK293 cells. In this system, when an odorant binds to the hORs coupled to the ion channel, a conformational change in the OR occurs, which consequently opens the ion channel to result in ion influx into the cell. This ion influx was then visualized using a membrane potential dye. Cells expressing ion channel-coupled hORs showed high sensitivity and selectivity to their specific odorants, and the odorant-hOR binding pattern was visualized to identify the response of individual hORs to various odorants, as well as the response of various hORs to various odorants. These results indicate that the ion channel coupled hOR system can be effectively used not only for simple and fast high throughput odorant screening, but also to visualize the odorant-hOR response pattern. PMID- 25931018 TI - Optimization of adhesive conditions for neural differentiation of murine embryonic stem cells using hydrogels functionalized with continuous Ile-Lys-Val Ala-Val concentration gradients. AB - Stem cell therapies, which aim to restore neurological function after central nervous system injury, have shown increased efficacy when a tissue engineering matrix is implanted with cells compared to implantation of the cells alone. However, much work still needs to be done to characterize materials that can be used to facilitate and direct the differentiation of implanted cells. In the current study, polyethylene glycol hydrogels functionalized with continuous Ile Lys-Val-Ala-Val (IKVAV) concentration gradients were fabricated and utilized to systematically study and optimize the adhesive conditions for neural differentiation of mouse embryonic stem cells in two- and three-dimensional environments. The results suggest that 570 MUM and 60 MUM are the optimal IKVAV concentrations for 2D and 3D neural differentiation, respectively, to maximize mRNA expression of neuron-specific markers and neurite extension while minimizing apoptotic activities in cultured cells compared to those exposed to higher IKVAV concentrations. The combinatorial approach presented in this work demonstrates that hydrogels functionalized with bioactive peptides provide a defined and tunable platform that can be employed to characterize and improve culture conditions for superior survival, maturation and integration of implanted cells, leading to enhanced restoration of neurological function for those receiving stem cell therapies after traumatic brain and spinal cord injuries. PMID- 25931019 TI - Multilayered thin films from poly(amido amine)s and DNA. AB - Dip-coated multilayered thin films of poly(amido amine)s (PAAs) and DNA have been developed to provide surfaces with cell-transfecting capabilities. Three types of PAAs, differing in side chain functional groups, were synthesized and characterized for their properties in forming multilayered structures with ultrasonicated calf thymus DNA (CTDNA) as model DNA. All three polymers display a multilayer build-up in linear profiles as demonstrated by UV spectroscopy. More highly charged side chains were found to provide the lowest deposition of DNA. Surface profiles of the obtained films were investigated by atomic force microscopy (AFM) and static water contact angle measurements to reveal complete surface coverage after at least four layer pair depositions, where alternating patterns of surface profiles were observed depending on whether the cationic polymer or the anionic DNA layer was on top. The stability of the formed surfaces was investigated in vitro under physiological and reductive conditions. Owing to the presence of disulfide bonds in the PAA main chain, the films were readily degraded in the presence of 1mM of DTT in vitro. Under non-reductive physiological conditions, two of the thicker films underwent thermodynamic rearrangement, which resulted in release of approximately half of the incorporated material within 1h, which was caused by the physiological salt concentration. Further, this unpacking phenomenon proved useful in transfecting COS-7 cells seeded on top of these multilayers containing functional plasmid DNA encoding for green fluorescence protein (GFP). Two out of the three different multilayers facilitated good COS-7 cell attachment, proliferation, and transfection in vitro within 2d ays of culture. Fluorescence staining further revealed the presence of DNA-containing released film material among cultured cells. The present work demonstrates the possibility of coating surfaces with thin films that are conveniently adjustable in thickness and amount of active agent to provide cell-transfecting functionality. In this manner transfection can be achieved by simply culturing cells on a multilayer-coated surface in their optimal culture condition (in the presence of serum) and without the need of removing the transfection agent to avoid cytotoxicity. PMID- 25931020 TI - De novo SHANK3 mutation causes Rett syndrome-like phenotype in a female patient. AB - Rett syndrome (RTT) is a neurodevelopmental disorder predominantly affecting females. Females with the MECP2 mutations exhibit a broad spectrum of clinical manifestations ranging from classical Rett syndrome to asymptomatic carriers. Mutations of genes encoding cyclin-dependent kinase-like 5 (CDKL5) and forkhead box G1 (FOXG1) are also found in early onset RTT variants. Here, we present the first report of a female patient with RTT-like phenotype caused by SHANK3 (SH3 and multiple ankylin repeat domain 3) mutation, indicating that the clinical spectrum of SHANK3 mutations may extend to RTT-like phenotype in addition to (severe) developmental delay, absence of expressive speech, autistic behaviors and intellectual disability. PMID- 25931021 TI - Increasing self-drinking for children with feeding disorders. AB - Children with feeding disorders often do not self-drink without treatment. Unfortunately, the literature on self-drinking is scarce. We evaluated differential positive reinforcement to increase self-drinking for 2 children with feeding disorders. Results showed that differential positive reinforcement with tangible items increased self-drinking for both children in the absence of nonremoval of the cup. PMID- 25931022 TI - Indication of metal homeostasis disturbance in earthworm Eisenia fetida after exposure to semi-solid depot sludge. AB - Treated sewage sludge is commonly used in agriculture as fertilizer. It is, therefore, necessary to determine possible detrimental influences of sludge application on soil contamination and accumulation of contaminants in tissues of terrestrial animals, which in the long run could also have undesirable effects on humans. With that aim, the study was performed using earthworm Eisenia fetida as test organism and semi-solid depot sludge from a wastewater treatment plant as exposure media. The concentrations of 26 metals/metalloids were determined in depot sludge, and their bioaccumulation was estimated in whole tissue of E. fetida, and for the first time in the soluble tissue fraction, which represents metal fraction available for metabolic requirements and toxic effects. Obtained results have revealed acceptable levels of several elements (Cd, Cr, Cu, Ni, Pb, Zn) in depot sludge, when compared to currently valid regulations, and only moderate accumulation of some elements (e.g. As, Ba, Cd, Co, Fe, Tl, V, and Zn) in earthworms, as a consequence of exposure to depot sludge. However, a concentration increase after exposure to depot sludge was observed in E. fetida for several elements (Cd, Mo, and Zn), which were present in lower concentrations in the exposure mixtures than in soil. Contrary, a concentration decrease was observed for Cs, Mn, and Rb, although they were present in higher concentrations in depot sludge than in soil. It was an indication of disturbance in metal homeostasis in earthworms, possibly caused by exposure to complex mixture of contaminants present in depot sludge. The cumulative effect of exposure to a number of various contaminants (inorganic, organic, microbiological and pharmaceutical), even if each of them was not present in very high concentrations, could have caused distress in earthworms exposed to depot sludge. PMID- 25931023 TI - Synthesising the effects of land use on natural and managed landscapes. AB - To properly manage our natural and managed landscapes, and to restore or repair degraded areas, it is important to know the changes that have taken place over time, particularly with respect to land use and its cumulative effect on ecological function. In common with many places in the world, where the industrial revolution resulted in profound changes to land use and management, Australia's landscapes have been transformed in the last 200 years. Initially the VAST (Vegetation Assets, States and Transitions) system was developed to describe and map changes in vegetation over time through a series of condition states or classes; here we describe an enhancement to the VAST method which will enable identification of the factors contributing to those changes in state as a result of changes in management practice. The 'VAST-2' system provides a structure in which to compile, interpret and sequence a range of data about past management practices, their effect on site and vegetation condition. Alongside a systematic chronology of land use and management, a hierarchy of indices is used to build a picture of the condition of the vegetation through time: 22 indicators within ten criteria representing three components of vegetation condition-regenerative capacity, vegetation structure and species composition-are scored using information from a variety of sources. These indicators are assessed relative to a pre-European reference state, either actual or synthetic. Each component is weighted proportionally to its contribution to the whole, determined through expert opinion. These weighted condition components are used to produce an aggregated transformation score for the vegetation. The application of this system to a range of sites selected across Australia's tropical, sub-tropical and temperate bioregions is presented, illustrating the utility of the system. Notably, the method accommodates a range of different types of information to be aggregated. PMID- 25931024 TI - Microbial risk assessment of drinking water based on hydrodynamic modelling of pathogen concentrations in source water. AB - Norovirus contamination of drinking water sources is an important cause of waterborne disease outbreaks. Knowledge on pathogen concentrations in source water is needed to assess the ability of a drinking water treatment plant (DWTP) to provide safe drinking water. However, pathogen enumeration in source water samples is often not sufficient to describe the source water quality. In this study, the norovirus concentrations were characterised at the contamination source, i.e. in sewage discharges. Then, the transport of norovirus within the water source (the river Gota alv in Sweden) under different loading conditions was simulated using a hydrodynamic model. Based on the estimated concentrations in source water, the required reduction of norovirus at the DWTP was calculated using quantitative microbial risk assessment (QMRA). The required reduction was compared with the estimated treatment performance at the DWTP. The average estimated concentration in source water varied between 4.8*10(2) and 7.5*10(3) genome equivalents L(-1); and the average required reduction by treatment was between 7.6 and 8.8 Log10. The treatment performance at the DWTP was estimated to be adequate to deal with all tested loading conditions, but was heavily dependent on chlorine disinfection, with the risk of poor reduction by conventional treatment and slow sand filtration. To our knowledge, this is the first article to employ discharge-based QMRA, combined with hydrodynamic modelling, in the context of drinking water. PMID- 25931025 TI - Radon survey in caves from Mallorca Island, Spain. AB - This study reports radon concentration in the most representative caves of Mallorca, identifying those in which the recommended action level is exceeded, thus posing health risks. Two show caves (Campanet and Arta) and three non touristic caves (Font, Drac, Vallgornera) were investigated. Data were collected at several locations within each cave for three different periods, from March 2013 to March 2014. Except for Vallgornera, where only one monitoring period was possible, and Arta in which low values were recorded throughout the year, a clear seasonal variability, with higher values during the warm seasons and lower during winter time is prominent. Radon concentrations differed markedly from one cave to another, as well as within the same cave, ranging from below detection limit up to 3060 Bq.m(-3). The results of this study have significant practical implications, making it possible to provide some recommendation to cave administrators and other agencies involved in granting access to the investigated caves. PMID- 25931026 TI - Improved monitoring framework for local planning in the water, sanitation and hygiene sector: From data to decision-making. AB - Today, a vast proportion of people still lack a simple pit latrine and a source of safe drinking water. To help end this appalling state of affairs, there is a pressing need to provide policymakers with evidences which may be the basis of effective planning, targeting and prioritization. Two major challenges often hinder this process: i) lack of reliable data to identify which areas are most in need; and ii) inadequate instruments for decision-making support. In tackling previous shortcomings, this paper proposes a monitoring framework to compile, analyze, interpret and disseminate water, sanitation and hygiene information. In an era of decentralization, where decision-making moves to local governments, we apply such framework at the local level. The ultimate goal is to develop appropriate tools for decentralized planning support. To this end, the study first implements a methodology for primary data collection, which combines the household and the waterpoint as information sources. In doing so, we provide a complete picture of the context in which domestic WASH services are delivered. Second, the collected data are analyzed to underline the emerging development challenges. The use of simple planning indicators serves as the basis to i) reveal which areas require policy attention, and to ii) identify the neediest. Third, a classification process is proposed to prioritize among various populations. Three different case studies from East and Southern African countries are presented. Results indicate that accurate and comprehensive data, if adequately exploited through simple instruments, may be the basis of effective targeting and prioritization, which are central to sector planning. The application of the proposed framework in the real world, however, is to a certain extent elusive; and we point out to conclude two specific challenges that remain unaddressed, namely the upgrade of existing decision-making processes to enhance transparency and inclusiveness, and the development of data updating mechanisms. PMID- 25931027 TI - Toward improved peptide feature detection in quantitative proteomics using stable isotope labeling. AB - Reliable detection of peptides in LC-MS data is a key algorithmic step in the analysis of quantitative proteomics experiments. While highly abundant peptides can be detected reliably by most modern software tools, there is much less agreement on medium and low-intensity peptides in a sample. The choice of software tools can have a big impact on the quantification of proteins, especially for proteins that appear in lower concentrations. However, in many experiments, it is precisely this region of less abundant but substantially regulated proteins that holds the biggest potential for discoveries. This is particularly true for discovery proteomics in the pharmacological sector with a specific interest in key regulatory proteins. In this viewpoint article, we discuss how the development of novel software algorithms allows us to study this region of the proteome with increased confidence. Reliable results are one of many aspects to be considered when deciding on a bioinformatics software platform. Deployment into existing IT infrastructures, compatibility with other software packages, scalability, automation, flexibility, and support need to be considered and are briefly addressed in this viewpoint article. PMID- 25931028 TI - Rapid infection and proliferation of dactylogyrid monogeneans on gills of spotted rose snapper (Lutjanus guttatus) after transfer to a sea-cage. AB - Finfish mariculture is typically threatened by parasite and disease outbreaks. Therefore, it is important to identify parasite species of potential risk for this activity. Snappers are valuable food fish worldwide. In the Eastern Pacific, spotted rose snapper (Lutjanus guttatus [Steindachner, 1869]) is a firm candidate for sea-cage aquaculture. In the current study, the parasitism of caged L. guttatus by dactylogyrids was evaluated for the first time during a complete farming period. Twenty five thousand juvenile fish produced at the Research Center for Food and Development (CIAD, Mazatlan Unit) were reared in a sentinel sea-cage from February to November 2012 in Mazatlan Bay, Mexico. A fish sample (n=15) was obtained every month. Dactylogyrids from the left second gill arch were identified and quantified. A total of 18,704 dactylogyrids distributed in three species, Euryhaliotrema perezponcei Garcia-Vargas, Fajer-Avila and Lamothe Argumedo, 2008, E. mehen (Soler-Jimenez, Garcia-Gasca and Fajer-Avila, 2012), and Haliotrematoides guttati Garcia-Vargas, Fajer-Avila and Lamothe-Argumedo, 2008 (Monogenea: Dactylogyridae) was found, which were able to infect caged L. guttatus since the first month of the farming period. Prevalence of these parasite species was 100% all the time, except for initial low values for E. mehen and H. guttati. The mean intensity of infection of each dactylogyrid species varied significantly between sampling months. Euryhaliotrema perezponcei was the most abundant parasite, reaching the highest mean intensity in May, June and July (154.3, 296.9 and 176.6 parasites/host, respectively). No clear seasonality of infection was observed; however, the influence of the water temperature on the observed infection levels is discussed. There was no mortality, change on behavior or pathological signs. However, given the rapid infection and proliferation of dactylogyrids, particularly E. perezponcei on L. guttaus reared in a sentinel sea-cage, outbreak of these parasites could be expected when this fish species is cultured on a large scale. PMID- 25931029 TI - Histologic and Immunohistochemical Findings of a Human Immature Permanent Tooth with Apical Periodontitis after Regenerative Endodontic Treatment. AB - Specimens of human immature permanent teeth after regenerative endodontic treatment (RET) are sparse. This case report describes the histologic and immunohistochemical findings of tissue formed in the canal space of a human immature permanent tooth with apical periodontitis after RET. A patient presenting with immature human permanent tooth #29 with apical periodontitis underwent RET. At the 10-month follow-up visit, radiographic examination revealed complete resolution of the periapical lesion, marked narrowing of the apical foramen, increased thickness of the canal walls, and minimal lengthening of the root. Notably, the tooth regained pulp sensibility. Tooth #29 was extracted for orthodontic reasons and processed for histologic and immunohistochemical examination. The canal space was filled with newly formed cementumlike tissue, bonelike tissue, and fibrous connective tissue. The apical closure, thickness, and length increment of the root were caused by the deposition of cementumlike tissue without dentin. Furthermore, neurons and nerve fibers were observed in the canal space; this observation was confirmed by immunohistochemistry. Based on the findings in the present case, after RET, the newly formed tissues in the canal space of the human immature permanent tooth with apical periodontitis were primarily fibrous connective tissue, cementumlike tissue, and bonelike tissue. Nerve regeneration was identified. PMID- 25931030 TI - Hydrophilic Hierarchical Nitrogen-Doped Carbon Nanocages for Ultrahigh Supercapacitive Performance. AB - The synergism of large surface area, multiscale porous structure, and good conductivity endows hierarchical carbon nanocages with high-level supercapacitive performances. Further nitrogen doping greatly improves the hydrophilicity, which boosts the supercapacitive performances to an ultrahigh specific capacitance of up to 313 F g(-1) at 1 A g(-1). PMID- 25931031 TI - Association of lymphotoxin alpha polymorphism with systemic lupus erythematosus and rheumatoid arthritis: a meta-analysis. AB - AIM: The aim of this study was to perform a meta-analysis of eligible studies to derive precise estimation of the associations of lymphotoxin alpha (LTA) 252 A>G polymorphism (rs909253) with systemic lupus erythematosus (SLE) and rheumatoid arthritis (RA) risk. METHOD: Data were collected from the following electronic databases, including EMBASE, PubMed and China National Knowledge Infrastructure (CNKI). A total of 19 studies (13 studies involving 1346 SLE patients and 1951 controls, six studies involving 1079 RA patients and 1057 controls) were included. RESULTS: This meta-analysis showed no evidence of significant association of the A allele with SLE susceptibility (odds ratio [OR] 1.26; 95% confidence interval [CI] 0.98-1.62, P = 0.073), but it showed a weaker association under an additive model (OR 1.63, 95%CI 1.01-2.65, P = 0.047). Stratification by ethnicity indicated that the variant A allele carriers increased the risk of SLE in Asians (OR 1.91, 95%CI 1.44-2.53, P < 0.001). However, we failed to reveal any association between LTA gene 252 A>G polymorphism and RA risk under all models (for A vs. G: OR 1.02, 95%CI 0.79-1.33, P = 0.853; for AA + AG vs. GG: OR 0.86, 95%CI 0.52-1.41, P = 0.542; for AA vs. AG + GG: OR 1.19, 95%CI 0.80-1.78, P = 0.394, for AA vs. GG: OR 1.03, 95%CI 0.58 1.84, P = 0.919). Similar results were obtained in the subgroup analysis based on ethnicity. CONCLUSION: The present study suggests that LTA 252 A>G polymorphism is associated with SLE susceptibility in Asians, and there is no significant association between LTA 252 A>G polymorphism and RA. PMID- 25931033 TI - Identification of beta1,3-galactosyltransferases responsible for biosynthesis of insect complex-type N-glycans containing a T-antigen unit in the honeybee. AB - Honeybees (Apis mellifera) produce unique complex-type N-glycans bearing a Galbeta1-3GalNAc (T-antigen) unit, and honeybee-specific N-glycans are linked to royal jelly glycoproteins. In this study, we identified two novel honeybee beta1,3-galactosyltransferase (beta1,3-GalT) genes responsible for biosynthesis of the T-antigen in insect N-glycans. The products of the two putative beta1,3 GalT genes (beta1,3-GalT1 and beta1,3-GalT2), which were expressed in Sf21 insect cells, transferred galactose (Gal) residues to GalNAc2GlcNAc2Man3GlcNAc2-PA to form the Galbeta1-3GalNAc unit, indicating that the identified genes were involved in biosynthesis of the beta1-3 Gal-containing N-glycan. Therefore, using biochemistry and molecular biology techniques, we revealed a unique N-glycan biosynthesis mechanism in the cephalic region of honeybees, which has not previously been found in other animal or plant cells. PMID- 25931034 TI - Structural and dynamic views of GM1 ganglioside. AB - The ganglioside GM1 mediates various physiological and pathological processes mainly through the formation of GM1 clusters on cell surfaces. Therefore, detailed characterization of conformational properties of the glycan moiety of GM1 and the structures and interactions of this glycosphingolipid in membrane environments is necessary for better understanding of the clustering-coupled functional promotion. Nuclear magnetic resonance (NMR) spectroscopy has provided conformational information of GM1 in solution as well as in membrane-like environments. Recently, sophisticated paramagnetism-assisted NMR approaches combined with molecular dynamics simulations have enabled the quantitative exploration of conformational spaces of a series of gangliosides, including GM1, taking into account their minor conformations. NMR techniques have also been successfully applied to investigations of the dynamic interactions of GM1 clusters with amyloidogenic proteins such as amyloid beta and alpha-synuclein associated with neurodegenerative disorders. Further integration of experimental and computational approaches will open up new possibilities to provide structural views of the more complicated heterogeneous systems exemplified by microdomains involving GM1. PMID- 25931032 TI - Metabolic glycoengineering bacteria for therapeutic, recombinant protein, and metabolite production applications. AB - Metabolic glycoengineering is a specialization of metabolic engineering that focuses on using small molecule metabolites to manipulate biosynthetic pathways responsible for oligosaccharide and glycoconjugate production. As outlined in this article, this technique has blossomed in mammalian systems over the past three decades but has made only modest progress in prokaryotes. Nevertheless, a sufficient foundation now exists to support several important applications of metabolic glycoengineering in bacteria based on methods to preferentially direct metabolic intermediates into pathways involved in lipopolysaccharide, peptidoglycan, teichoic acid, or capsule polysaccharide production. An overview of current applications and future prospects for this technology are provided in this report. PMID- 25931035 TI - A method for incorporating three-dimensional residual stretches/stresses into patient-specific finite element simulations of arteries. AB - The existence of residual stresses in human arteries has long been shown experimentally. Researchers have also demonstrated that residual stresses have a significant effect on the distribution of physiological stresses within arterial tissues, and hence on their development, e.g., stress-modulated remodeling. Through progress in medical imaging, image analysis and finite element (FE) meshing tools it is now possible to construct in vivo patient-specific geometries and thus to study specific, clinically relevant problems in arterial mechanics via FE simulations. Classical continuum mechanics and FE methods assume that constitutive models and the corresponding simulations start from unloaded, stress free reference configurations while the boundary-value problem of interest represents a loaded geometry and includes residual stresses. We present a pragmatic methodology to simultaneously account for both (i) the three dimensional (3-D) residual stress distributions in the arterial tissue layers, and (ii) the equilibrium of the in vivo patient-specific geometry with the known boundary conditions. We base our methodology on analytically determined residual stress distributions (Holzapfel and Ogden, 2010, J. R. Soc. Interface 7, 787-799) and calibrate it using data on residual deformations (Holzapfel et al., 2007, Ann. Biomed. Eng. 35, 530-545). We demonstrate our methodology on three patient specific FE simulations calibrated using experimental data. All data employed here are generated from human tissues - both the aorta and thrombus, and their respective layers - including the geometries determined from magnetic resonance images, and material properties and 3-D residual stretches determined from mechanical experiments. We study the effect of 3-D residual stresses on the distribution of physiological stresses in the aortic layers (intima, media, adventitia) and the layers of the intraluminal thrombus (luminal, medial, abluminal) by comparing three types of FE simulations: (i) conventional calculations; (ii) calculations accounting only for prestresses; (iii) calculations including both 3-D residual stresses and prestresses. Our results show that including residual stresses in patient-specific simulations of arterial tissues significantly impacts both the global (organ-level) deformations and the stress distributions within the arterial tissue (and its layers). Our method produces circumferential Cauchy stress distributions that are more uniform through the tissue thickness (i.e., smaller stress gradients in the local radial directions) compared to both the conventional and prestressing calculations. Such methods, combined with appropriate experimental data, aim at increasing the accuracy of classical FE analyses for patient-specific studies in computational biomechanics and may lead to increased clinical application of simulation tools. PMID- 25931036 TI - 68Ga-PSMA imaging of metastatic breast cancer. PMID- 25931037 TI - Polypyrrole nanoparticles for tunable, pH-sensitive and sustained drug release. AB - We report the development of a generalized pH-sensitive drug delivery system that can release any charged drug preferentially at the pH range of interest. Our system is based on polypyrrole nanoparticles (PPy NPs), synthesized via a simple one-step microemulsion technique. These nanoparticles are highly monodisperse, stable in solution over the period of a month, and have good drug loading capacity (~15 wt%). We show that PPy NPs can be tuned to release drugs at both acidic and basic pH by varying the pH, the charge of the drug, as well as by adding small amounts of charged amphiphiles. Moreover, these NPs may be delivered locally by immobilizing them in a hydrogel. Our studies show encapsulation within a calcium alginate hydrogel results in sustained release of the incorporated drug for more than 21 days. Such a nanoparticle-hydrogel composite drug delivery system is promising for treatment of long-lasting conditions such as cancer and chronic pain which require controlled, localized, and sustained drug release. PMID- 25931038 TI - Evaluation of adipocytokines in children with chronic kidney disease. AB - INTRODUCTION: Adipose tissue through the many secreted adipocytokines creates a highly active metabolic and endocrine organ. The evaluation of serum adipocytokine concentration in children with chronic kidney disease (CKD) could serve as a marker of cardio-vascular complication progression and an index of outcome in adulthood and after kidney transplantation. MATERIAL AND METHODS: The aim of the study was to evaluate simultaneously the serum concentrations of six different adipocytokines: adiponectin, apelin, chemerin, omentin, resistin, and vaspin, in 28 children with CKD stage 5 on haemodialysis and peritoneal dialysis. RESULTS: The concentration of apelin, omentin, and resistin in children with CKD was significantly higher and the concentration of vaspin, adiponectin, and chemerin was significantly lower than in the control group. After adjusting to body mass index (BMI), the same results were obtained. After adjusting to body surface area (BSA), the concentration of vaspin, adiponectin, and chemerin did not differ between children with CKD and the control group. In analysis of the correlation between serum total adipocytokine levels in children with CKD we found a negative relationship in pairs: omentin-apelin and omentin-vaspin, and positive in pairs: adiponectin-chemerin and adiponectin-resistin. CONCLUSIONS: Our results show that changes in serum adipocytokines concentration are associated with the kidney dysfunction in CKD in children. Longitudinal studies on larger groups of paediatric cohorts would be helpful in investigating whether adipocytokines play a harmful role in the development of CKD and would enable further understanding of the risk factors for CKD progression. PMID- 25931039 TI - Visfatin concentrations in obese patients in relation to the presence of newly diagnosed glucose metabolism disorders. AB - INTRODUCTION: Visfatin, protein secreted by visceral adipose tissue, exerts insulin-mimetic actions. Visfatin concentration increases in patients with longer standing diabetes type 2 with progressive b-cell dysfunction. Data about the role of visfatin in newly diagnosed glucose metabolism abnormalities are limited. Evaluation of visfatin concentration in patients with obesity, in relation to the presence of newly diagnosed glucose metabolism disorders. MATERIAL AND METHODS: The study included 68 subjects with obesity, without a previous diagnosis of abnormal glucose metabolism. In all subjects we performed an oral glucose tolerance test, and according to the results the group was divided into the subgroups: A (n = 31), with glucose metabolism disorders (impaired fasting glucose, impaired glucose tolerance and type 2 diabetes); and B (n = 37), without abnormalities. In all subjects serum lipids, uric acid, C-peptide, glycated haemoglobin (HbA1c), creatinine, and serum visfatin concentrations were measured. The control group comprised 30 lean, healthy individuals with normal glucose tolerance. RESULTS: We found elevated visfatin levels in obese individuals versus the control group (50.0 +/- 48 vs. 26.7 +/- 22.1 ng/mL; p = 0.01). Visfatin concentrations in both subgroups, A and B, did not differ (40.86 +/- 27.84 vs. 57.7 +/- 59.79 ng/mL; p = 0.19). In subgroup A visfatin concentration correlated significantly with triglycerides (r = 0.37, p = 0.038), HbA1c (r = -0.43, p = 0.02), C-peptide (r = -0.38,p = 0.048), and waist-hip ratio (r = -0.41, p = 0.036). CONCLUSIONS: The presence of newly diagnosed glucose metabolism abnormalities in obese subjects had no influence on the visfatin level, probably due to preserved endogenous insulin secretion and relatively short exposure to hyperglycaemia in patients with prediabetes or at early stage of type 2 diabetes. PMID- 25931040 TI - Comparison of the effects of short-term hypolipidaemic treatment on plasma adipokine levels in men and women with isolated hypercholesterolaemia. AB - INTRODUCTION: Hypolipidaemic agents were found to affect plasma adipokine levels, but no previous study has investigated whether this effect is sex-dependent. MATERIAL AND METHODS: We retrospectively analysed 61 patients participating in our previous studies, who because of isolated hypercholesterolaemia were treated with simvastatin (40 mg daily), ezetimibe (10 mg daily) or simvastatin (40 mg daily) plus ezetimibe (10 mg daily). Plasma levels of leptin, adiponectin, visfatin, tumour necrosis factor-alpha (TNF-alpha), free fatty acids (FFA), and high-sensitivity C-reactive protein (hsCRP) were assessed separately for men and women before and after 30 days of treatment. RESULTS: At baseline, plasma levels of adiponectin and leptin were lower, while plasma levels of TNF-alpha were higher in men than in women. Administration of simvastatin and statin/ezetimibe combination for 30 days reduced plasma levels of hsCRP, FFA, leptin, visfatin, and TNF-alpha but increased plasma levels of adiponectin, while the effect of ezetimibe was much more limited. The effect of simvastatin and ezetimibe, administered alone or in combination, on plasma hsCRP, FFA, leptin, adiponectin, visfatin, and TNF-alpha did not differ between men and women. Irrespectively of sex, the changes in plasma adipokines and systemic-anti-inflammatory effects were more expressed in simvastatin - than in ezetimibe-treated patients and were strongest when both these agents were administered together. CONCLUSIONS: Our results show that sex differences do not determine the effect of hypolipidaemic agents on adipose tissue and low-grade inflammation. PMID- 25931041 TI - The prevalence of somatic RAS mutations in medullary thyroid cancer - a Polish population study. AB - INTRODUCTION: Somatic RET mutations are detectable in two-thirds of sporadic cases of medullary thyroid cancer (MTC). Recent studies reported a high proportion of RAS somatic mutations in RET negative tumours, which may indicate RAS mutation as a possible alternative genetic event in sporadic MTC tumorigenesis. Thus, the aim of the study was to evaluate the frequency of somatic RAS mutations in sporadic medullary thyroid cancer in the Polish population and to relate the obtained data to the presence of somatic RET mutations. MATERIAL AND METHODS: Somatic mutations (RET, RAS genes) were evaluated in 78 snap-frozen MTC samples (57 sporadic and 21 hereditary) by direct sequencing. Next, three randomly selected RET-negative MTC samples were analysed by the next generation sequencing. RESULTS: RAS mutation was detected in 26.5% of 49 sporadic MTC tumours. None of all the analysed samples showed N-RAS mutation. When only RET-negative samples were considered, the prevalence of RAS mutation was 68.7%, compared to 6% observed in RET-positive samples. Most of these mutations were located in H-RAS codon 61 (72%). None of 21 hereditary MTC samples showed any RAS mutations. CONCLUSIONS: RAS mutations constitute a frequent molecular event in RET-negative sporadic medullary thyroid carcinoma in Polish patients. However, their role in MTC tumorigenesis remains unclear. PMID- 25931042 TI - Radioiodine therapy for Graves' disease - retrospective analysis of efficacy factors. AB - INTRODUCTION: Radioiodine ((131)I) isotope therapy is the method of choice in the treatment of Graves' disease relapse. The efficiency of this method is dependent on many factors; therefore, the present paper aims to identify the parameters that have a crucial impact on the efficacy of radioiodine therapy for Graves' disease. MATERIAL AND METHODS: The authors performed a retrospective analysis of the medical documentation of 700 Graves' disease sufferers treated with (131)I. The patients were divided into three groups depending on the thyroid-absorbed dose of (131)I: group I - 100 Gy, II - 150 Gy, and III - 200 Gy. The authors assessed the influence of gender, age, presence of orbitopathy, TRab titres, thyroid mass, iodine uptake after 24 and 48 hours, and the absorbed dose on the treatment efficacy at one year post-(131)I administration. RESULTS: The volume of thyroid gland (P < 0.002) and the thyroid-absorbed dose (P < 0.001) were the only factors that had a significant impact on the outcome of the treatment. The likelihood of hyperthyroidism persisting (odds ratio: 3.71, 95% confidence interval: 2.4-5.87) was greatest in patients from group I. In group II, with thyroid volume amounting both to 25 mL and to 25-50 mL, the percentage of hyperthyroidism was lowest (1 and 0%). However, with thyroid volume > 50 mL, the percentage of hyperthyroidism was lowest in group III (10%). CONCLUSIONS: The absorbed dose of (131)I and the volume of the thyroid gland are two parameters that have a significant influence on the efficacy of radioiodine therapy for Graves' disease. 150 Gy is the optimal dose for glands < 50 mL. A goitre > 50 mL requires an absorbed dose of 200 Gy in order to minimise the risk of recurrent hyperthyroidism. PMID- 25931043 TI - The role of Epstein-Barr virus infection in the development of autoimmune thyroid diseases. AB - INTRODUCTION: Autoimmune thyroid diseases, including Graves' and Hashimoto's thyroiditis, are the most frequent autoimmune disorders. Viral infection, including Epstein-Barr virus (EBV), is one of the most frequently considered environmental factors involved in autoimmunity. Its role in the development of AITD has not been confirmed so far. MATERIAL AND METHODS: Surgical specimens of Graves' and Hashimoto's diseases and nodular goitres were included in the study. The expression of EBV latent membrane protein 1 (LMP1) was analysed by immunohistochemistry, with the parallel detection of virus-encoded small nuclear non-polyadenylated RNAs (EBER) by in situ hybridisation. RESULTS: In none of the Graves' disease specimens but in 34.5% of Hashimoto's thyroiditis cases the cytoplasmic expression of LMP1 was detected in follicular epithelial cells and in infiltrating lymphocytes. EBER nuclear expression was detected in 80.7% of Hashimoto's thyroiditis cases and 62.5% of Graves' disease cases, with positive correlation between LMP1 and EBER positivity in all Hashimoto's thyroiditis LMP1 positive cases. CONCLUSIONS: We assume that high prevalence of EBV infection in cases of Hashimoto's and Graves' diseases imply a potential aetiological role of EBV in autoimmune thyroiditis. The initiation of autoimmune thyroiditis could start with EBV latency type III infection of follicular epithelium characterised by LMP1 expression involving the production of inflammatory mediators leading to recruitment of lymphocytes. The EBV positivity of the infiltrating lymphocytes could be only the presentation of a carrier state, but in cases with EBER+/ LMP1+ lymphocytes (transforming latent infection) it could represent a negative prognostic marker pointing to a higher risk of primary thyroid lymphoma development. PMID- 25931044 TI - The usefulness of the GHRH stimulation test in the diagnostics of growth hormone deficiency in children. AB - INTRODUCTION: Stimulation tests form the basis for the diagnostic process in growth hormone deficiency (GHD). One of these tests uses the GH releasing hormone (GHRH). This provides the potential to differentiate patients with pituitary dysfunction from patients with hypothalamus abnormalities. However, the routine use of the GHRH test is still being debated. The aim of this study was to assess the diagnostic usefulness of the GHRH test in the diagnostics of GHD. MATERIAL AND METHODS: The study group consisted of 20 prepubertal children with GHD. In all the children, one of the performed stimulation tests was the GHRH test. RESULTS: The results showed that the mean peak concentration of GH in the GHRH test was 14.7 +/- 11.3 ng/mL. In eight children the MRI showed pituitary hypoplasia, in one patient pituitary hypoplasia and pituitary stalk agenesis, and in one patient septo-optic dysplasia. All patients with pituitary malformations, except for one patient with a hypoplastic pituitary gland, presented GH levels < 10 ng/mL in the GHRH test. The sensitivity of the GHRH test in the diagnostics of GHD was 45%. CONCLUSIONS: The high correlation between the GHRH test and anatomical changes in the pituitary provides this test with a high predictive value. In individual clinical cases, knowledge about the level of damage in the hypothalamic-pituitary area can determine diagnostic and therapeutic procedures. PMID- 25931045 TI - Dosage and costs of lanreotide Autogel 120 mg administered as part of routine acromegaly care in Poland - two years of data from Lanro-Study. AB - INTRODUCTION: To evaluate, over 24 months of prospective follow-up, the dosage and costs of lanreotide AUTOGEL 120 mg (ATG120) administered as part of routine acromegaly care in Poland. MATERIAL AND METHODS: A multicentre, non interventional, observational prospective study on resource utilisation in Polish acromegalic patients treated with ATG120 at 4-week or extended (> 4 weeks) dosing interval. The study population consisted of adult acromegalic patients treated for at least 3 injections of ATG120. The endpoints were: percentage of patients treated with ATG120 at an extended dosing interval (> 4 weeks), mean time between injections, and the cost of ATG120 during a 24-month prospective observation. Costs were calculated in PLN from the public health-care payer and patient perspective for the year 2014. RESULTS: 143 patients were enrolled in, and 132 completed (70% women, 81% macroadenoma, 75% previous surgery) the analysis. During two years, changes in the treatment pattern were reported in 41 patients: 17% of them had increased injection interval and 10% switched to octreotide LAR and then returned to ATG120. Sixty-three patients (48%) received ATG120 at an extended dosing interval. ATG120 was predominantly administered in an out-patient setting (84%) by a health care professional (97%). CONCLUSIONS: The results demonstrated that extended dosing interval of ATG120 is used in a substantial proportion of patients in routine clinical practice in Poland. Such findings support the potential for ATG120 in reducing treatment burden in the real-world clinical environment. PMID- 25931046 TI - [Primary hyperparathyroidism due to parathyroid cancer - a diagnostic and management challenge]. AB - Parathyroid carcinoma (PC) is a rare endocrine malignancy and the cause of primary hyperparathyroidism. It is usually associated with a high rate of local and distant recurrence. Laboratory findings and clinical symptoms may be similar to those in parathyroid adenoma. The histological features of PC may also be non specific and the affected gland is often indistinguishable from a benign lesion. The proper diagnosis is commonly made months to years later when the disease recurs or metastases are present. Therefore, parathyroid carcinoma still remains a diagnostic and management challenge for many physicians. However, there are some features that, in combination, may help in diagnosis. Surgery still remains the only curative treatment, even in metastatic disease. In advanced, non operable subjects, managing hypercalcaemia and controlling a tumour are the main goals. Morbidity is caused by hypercalcaemia rather than metastases. A multidisciplinary approach with experienced endocrinologists, pathologists, radiologists, nuclear medicine doctors, oncologists, and surgeons is needed to optimize patient outcome. PMID- 25931047 TI - Bruck syndrome - a rare syndrome of bone fragility and joint contracture and novel homozygous FKBP10 mutation. AB - Bruck syndrome is an autosomal recessive syndrome consisting of bone fragility and congenital joint contractures. According to the genotype, it has been classified into types 1 and 2. Recently, mutations in FKBP10, localised to chromosome 17q21, have been identified in some patients of Bruck syndrome. Twenty seven patients of this syndrome have been reported so far. We present a new patient of this syndrome, with frequent fractures, congenital joint contractures, kyphoscoliosis, bilateral clubfoot, and pectus carinatum. The clinical and genetic features of all previously reported cases are also reviewed. PMID- 25931048 TI - Amiodarone and the thyroid. AB - Amiodarone, a benzofuranic iodine-rich antiarrhythmic drug, causes thyroid dysfunction in 15-20% of cases. Amiodarone can cause both hypothyroidism (AIH, amiodarone-induced hypothyroidism) and thyrotoxicosis (AIT, amiodarone-induced thyrotoxicosis). AIH is treated by L-thyroxin replacement and does not need amiodarone discontinuation. There are two main forms of AIT: type 1, a form of true iodine-induced hyperthyroidism; and type 2, a drug-induced destructive thyroiditis. However, mixed/indefinite forms exist, contributed to by both pathogenic mechanisms. Type 1 AIT usually occurs in diseased thyroid glands, whereas type 2 AIT develops in substantially normal thyroid glands. Thioamides represent the first-line treatment for type 1 AIT, but iodine-replete glands are poorly responsive; sodium/potassium perchlorate, by inhibiting thyroidal iodine uptake, may increase the response to thioamides. Type 2 AIT is best treated by oral glucocorticoids. Response depends on thyroid volume and severity of thyrotoxicosis. Mixed/indefinite forms may require a combination of thioamides, potassium perchlorate, and steroids. Radioiodine treatment is usually not feasible because amiodarone-related iodine load decreases thyroidal radioiodine uptake. Thyroidectomy represents an important and helpful option in cases resistant to medical therapy. Surgery performed by a skilled surgeon may represent an emergent treatment in patients who have severe cardiac dysfunction. PMID- 25931049 TI - Endemic rubella is eliminated from Americas, PAHO announces. PMID- 25931050 TI - Challenges of glycoprotein analysis by microchip capillary gel electrophoresis. AB - Glycosylations severely influence a protein's biological and physicochemical properties. Five exemplary proteins with varying glycan moieties were chosen to establish molecular weight (MW) determination (sizing), quantitation, and sensitivity of detection for microchip capillary gel electrophoresis (MCGE). Although sizing showed increasing deviations from literature values (SDS-PAGE or MALDI-MS) with a concomitant higher degree of analyte glycosylation, the reproducibility of MW determination and accuracy of quantitation with high sensitivity and reliability were demonstrated. Additionally, speed of analysis together with the low level of analyte consumption render MCGE attractive as an alternative to conventional SDS-PAGE. PMID- 25931052 TI - Erratum to: Sequential distribution of pTDP-43 pathology in behavioral variant frontotemporal dementia (bvFTD). PMID- 25931051 TI - Molecular profiling of long-term survivors identifies a subgroup of glioblastoma characterized by chromosome 19/20 co-gain. AB - Glioblastoma (GBM) is a devastating tumor and few patients survive beyond 3 years. Defining the molecular determinants underlying long-term survival is essential for insights into tumor biology and biomarker identification. We therefore investigated homogeneously treated, IDH (wt) long-term (LTS, n = 10) and short-term survivors (STS, n = 6) by microarray transcription profiling. While there was no association of clinical parameters and molecular subtypes with long-term survival, STS tumors were characterized by differential polarization of infiltrating microglia with predominance of the M2 phenotype detectable both on the mRNA and protein level. Furthermore, transcriptional signatures of LTS and STS predicted patient outcome in a large, IDH (wt) cohort (n = 468). Interrogation of overlapping genomic alterations identified concurrent gain of chromosomes 19 and 20 as a favorable prognostic marker. The strong association of this co-gain with survival was validated by aCGH in a second, independent cohort (n = 124). Finally, FISH and gene expression data revealed gains to constitute low-amplitude, clonal events with a strong impact on transcription. In conclusion, these findings provide important insights into the manipulation of the innate immune system by particularly aggressive GBM tumors. Furthermore, we genomically characterize a previously unknown, clinically relevant subgroup of glioblastoma, which can easily be identified through modern neuropathological workup. PMID- 25931054 TI - An introduction to the special issue on X-ray free-electron lasers. PMID- 25931053 TI - Zebrafish models for nemaline myopathy reveal a spectrum of nemaline bodies contributing to reduced muscle function. AB - Nemaline myopathy is characterized by muscle weakness and the presence of rod like (nemaline) bodies. The genetic etiology of nemaline myopathy is becoming increasingly understood with mutations in ten genes now known to cause the disease. Despite this, the mechanism by which skeletal muscle weakness occurs remains elusive, with previous studies showing no correlation between the frequency of nemaline bodies and disease severity. To investigate the formation of nemaline bodies and their role in pathogenesis, we generated overexpression and loss-of-function zebrafish models for skeletal muscle alpha-actin (ACTA1) and nebulin (NEB). We identify three distinct types of nemaline bodies and visualize their formation in vivo, demonstrating these nemaline bodies not only exhibit different subcellular origins, but also have distinct pathological consequences within the skeletal muscle. One subtype is highly dynamic and upon breakdown leads to the accumulation of cytoplasmic actin contributing to muscle weakness. Examination of a Neb-deficient model suggests this mechanism may be common in nemaline myopathy. Another subtype results from a reduction of actin and forms a more stable cytoplasmic body. In contrast, the final type originates at the Z disk and is associated with myofibrillar disorganization. Analysis of zebrafish and muscle biopsies from ACTA1 nemaline myopathy patients demonstrates that nemaline bodies also possess a different protein signature. In addition, we show that the ACTA1(D286G) mutation causes impaired actin incorporation and localization in the sarcomere. Together these data provide a novel examination of nemaline body origins and dynamics in vivo and identifies pathological changes that correlate with muscle weakness. PMID- 25931055 TI - The Linac Coherent Light Source. AB - The Linac Coherent Light Source (LCLS) at the SLAC National Accelerator Laboratory was the first hard X-ray free-electron laser (FEL) to operate as a user facility. After five years of operation, LCLS is now a mature FEL user facility. Our personal views about opportunities and challenges inherent to these unique light sources are discussed. PMID- 25931056 TI - Overview of the SACLA facility. AB - In March 2012, SACLA started user operations of the first compact X-ray free electron laser (XFEL) facility. SACLA has been routinely providing users with stable XFEL light over a wide photon energy range from 4 to 15 keV and an ultrafast pulse duration below 10 fs. The facility supports experimental activities in broad fields by offering high-quality X-ray optics and diagnostics, as well as reliable multiport charge-coupled-device detectors, with flexible experimental configurations. A two-stage X-ray focusing system was developed that enables the highest intensity of 10(20) W cm(-2). Key scientific results published in 2013 and 2014 in diverse fields are reviewed. The main experimental systems developed for these applications are summarized. A perspective on the facility upgrade is presented. PMID- 25931057 TI - The FERMI free-electron lasers. AB - FERMI is a seeded free-electron laser (FEL) facility located at the Elettra laboratory in Trieste, Italy, and is now in user operation with its first FEL line, FEL-1, covering the wavelength range between 100 and 20 nm. The second FEL line, FEL-2, a high-gain harmonic generation double-stage cascade covering the wavelength range 20-4 nm, has also completed commissioning and the first user call has been recently opened. An overview of the typical operating modes of the facility is presented. PMID- 25931058 TI - The Atomic, Molecular and Optical Science instrument at the Linac Coherent Light Source. AB - The Atomic, Molecular and Optical Science (AMO) instrument at the Linac Coherent Light Source (LCLS) provides a tight soft X-ray focus into one of three experimental endstations. The flexible instrument design is optimized for studying a wide variety of phenomena requiring peak intensity. There is a suite of spectrometers and two photon area detectors available. An optional mirror based split-and-delay unit can be used for X-ray pump-probe experiments. Recent scientific highlights illustrate the imaging, time-resolved spectroscopy and high power density capabilities of the AMO instrument. PMID- 25931059 TI - The Soft X-ray Research instrument at the Linac Coherent Light Source. AB - The Soft X-ray Research instrument provides intense ultrashort X-ray pulses in the energy range 280-2000 eV. A diverse set of experimental stations may be installed to investigate a broad range of scientific topics such as ultrafast chemistry, highly correlated materials, magnetism, surface science, and matter under extreme conditions. A brief description of the main instrument components will be given, followed by some selected scientific highlights. PMID- 25931060 TI - The X-ray Pump-Probe instrument at the Linac Coherent Light Source. AB - The X-ray Pump-Probe instrument achieves femtosecond time-resolution with hard X ray methods using a free-electron laser source. It covers a photon energy range of 4-24 keV. A femtosecond optical laser system is available across a broad spectrum of wavelengths for generating transient states of matter. The instrument is designed to emphasize versatility and the scientific goals encompass ultrafast physical, chemical and biological processes involved in the transformation of matter and transfer of energy at the atomic scale. PMID- 25931061 TI - The X-ray Correlation Spectroscopy instrument at the Linac Coherent Light Source. AB - The X-ray Correlation Spectroscopy instrument is dedicated to the study of dynamics in condensed matter systems using the unique coherence properties of free-electron lasers. It covers a photon energy range of 4-25 keV. The intrinsic temporal characteristics of the Linac Coherent Light Source, in particular the 120 Hz repetition rate, allow for the investigation of slow dynamics (milliseconds) by means of X-ray photon correlation spectroscopy. Double-pulse schemes could probe dynamics on the picosecond timescale. A description of the instrument capabilities and recent achievements is presented. PMID- 25931062 TI - The Coherent X-ray Imaging instrument at the Linac Coherent Light Source. AB - The Coherent X-ray Imaging (CXI) instrument specializes in hard X-ray, in-vacuum, high power density experiments in all areas of science. Two main sample chambers, one containing a 100 nm focus and one a 1 um focus, are available, each with multiple diagnostics, sample injection, pump-probe and detector capabilities. The flexibility of CXI has enabled it to host a diverse range of experiments, from biological to extreme matter. PMID- 25931063 TI - The Matter in Extreme Conditions instrument at the Linac Coherent Light Source. AB - The LCLS beam provides revolutionary capabilities for studying the transient behavior of matter in extreme conditions. The particular strength of the Matter in Extreme Conditions instrument is that it combines the unique LCLS beam with high-power optical laser beams, and a suite of dedicated diagnostics tailored for this field of science. In this paper an overview of the beamline, the capabilities of the instrumentation, and selected highlights of experiments and commissioning results are presented. PMID- 25931064 TI - Optical laser systems at the Linac Coherent Light Source. AB - Ultrafast optical lasers play an essential role in exploiting the unique capabilities of recently commissioned X-ray free-electron laser facilities such as the Linac Coherent Light Source (LCLS). Pump-probe experimental techniques reveal ultrafast dynamics in atomic and molecular processes and reveal new insights in chemistry, biology, material science and high-energy-density physics. This manuscript describes the laser systems and experimental methods that enable cutting-edge optical laser/X-ray pump-probe experiments to be performed at LCLS. PMID- 25931065 TI - Diverse application platform for hard X-ray diffraction in SACLA (DAPHNIS): application to serial protein crystallography using an X-ray free-electron laser. AB - An experimental system for serial femtosecond crystallography using an X-ray free electron laser (XFEL) has been developed. It basically consists of a sample chamber, fluid injectors and a two-dimensional detector. The chamber and the injectors are operated under helium atmosphere at 1 atm. The ambient pressure operation facilitates applications to fluid samples. Three kinds of injectors are employed to feed randomly oriented crystals in aqueous solution or highly viscous fluid. Experiments on lysozyme crystals were performed by using the 10 keV XFEL of the SPring-8 Angstrom Compact free-electron LAser (SACLA). The structure of model protein lysozyme from 1 um crystals at a resolution of 2.4 A was obtained. PMID- 25931066 TI - The Low Density Matter (LDM) beamline at FERMI: optical layout and first commissioning. AB - The Low Density Matter (LDM) beamline has been built as part of the FERMI free electron laser (FEL) facility to serve the atomic, molecular and cluster physics community. After the commissioning phase, it received the first external users at the end of 2012. The design and characterization of the LDM photon transport system is described, detailing the optical components of the beamline. PMID- 25931067 TI - Multipurpose end-station for coherent diffraction imaging and scattering at FERMI@Elettra free-electron laser facility. AB - The Diffraction and Projection Imaging (DiProI) beamline at FERMI, the Elettra free-electron laser (FEL), hosts a multi-purpose station that has been opened to users since the end of 2012. This paper describes the core capabilities of the station, designed to make use of the unique features of the FERMI-FEL for performing a wide range of static and dynamic scattering experiments. The various schemes for time-resolved experiments, employing both soft X-ray FEL and seed laser IR radiation are presented by using selected recent results. The ongoing upgrade is adding a reflection geometry setup for scattering experiments, expanding the application fields by providing both high lateral and depth resolution. PMID- 25931068 TI - EIS: the scattering beamline at FERMI. AB - The Elastic and Inelastic Scattering (EIS) beamline at the free-electron laser FERMI is presented. It consists of two separate end-stations: EIS-TIMEX, dedicated to ultrafast time-resolved studies of matter under extreme and metastable conditions, and EIS-TIMER, dedicated to time-resolved spectroscopy of mesoscopic dynamics in condensed matter. The scientific objectives are discussed and the instrument layout illustrated, together with the results from first exemplifying experiments. PMID- 25931069 TI - Recent results of PADReS, the Photon Analysis Delivery and REduction System, from the FERMI FEL commissioning and user operations. AB - The Photon Analysis Delivery and REduction System of FERMI (PADReS) has been routinely used during the machine commissioning and operations of FERMI since 2011. It has also served the needs of several user runs at the facility from late 2012. The system is endowed with online and shot-to-shot diagnostics giving information about intensity, spatial-angular distribution, spectral content, as well as other diagnostics to determine coherence, pulse length etc. Moreover, PADReS is capable of manipulating the beam in terms of intensity and optical parameters. Regarding the optics, besides a standard refocusing system based on an ellipsoidal mirror, the Kirkpatrick-Baez active optics systems are key elements and have been used intensively to meet users' requirements. A general description of the system is given, together with some selected results from the commissioning/operations/user beam time. PMID- 25931070 TI - Data acquisition system for X-ray free-electron laser experiments at SACLA. AB - A data acquisition system for X-ray free-electron laser experiments at SACLA has been developed. The system has been designed for reliable shot-to-shot data storage with a high data stream greater than 4 Gbps and massive data analysis. Configuration of the system and examples of prompt data analysis during experiments are presented. Upgrade plans for the system to extend flexibility are described. PMID- 25931071 TI - X-ray detectors at the Linac Coherent Light Source. AB - Free-electron lasers (FELs) present new challenges for camera development compared with conventional light sources. At SLAC a variety of technologies are being used to match the demands of the Linac Coherent Light Source (LCLS) and to support a wide range of scientific applications. In this paper an overview of X ray detector design requirements at FELs is presented and the various cameras in use at SLAC are described for the benefit of users planning experiments or analysts looking at data. Features and operation of the CSPAD camera, which is currently deployed at LCLS, are discussed, and the ePix family, a new generation of cameras under development at SLAC, is introduced. PMID- 25931072 TI - Correction of complex nonlinear signal response from a pixel array detector. AB - The pulsed free-electron laser light sources represent a new challenge to photon area detectors due to the intrinsic spontaneous X-ray photon generation process that makes single-pulse detection necessary. Intensity fluctuations up to 100% between individual pulses lead to high linearity requirements in order to distinguish small signal changes. In real detectors, signal distortions as a function of the intensity distribution on the entire detector can occur. Here a robust method to correct this nonlinear response in an area detector is presented for the case of exposures to similar signals. The method is tested for the case of diffuse scattering from liquids where relevant sub-1% signal changes appear on the same order as artifacts induced by the detector electronics. PMID- 25931073 TI - Nanofocusing of X-ray free-electron lasers by grazing-incidence reflective optics. AB - Total-reflection mirror devices for X-ray free-electron laser focusing are discussed in terms of optical design, mirror-fabrication technology, a wavefront diagnosis method and radiation-damage testing, as a review of the present status of the focusing optics at the SPring-8 angstrom compact free-electron laser (SACLA). Designed beam sizes of 1 um and 50 nm, and spot sizes almost matching prediction have been achieved and used to explore topics at the forefront of natural science. The feasibility of these devices is determined to be sufficient for long-term and stable operation at SACLA by investigating the radiation-damage threshold and achievable accuracies in the mirror figure and alignment. PMID- 25931074 TI - Focus characterization at an X-ray free-electron laser by coherent scattering and speckle analysis. AB - X-ray focus optimization and characterization based on coherent scattering and quantitative speckle size measurements was demonstrated at the Linac Coherent Light Source. Its performance as a single-pulse free-electron laser beam diagnostic was tested for two typical focusing configurations. The results derived from the speckle size/shape analysis show the effectiveness of this technique in finding the focus' location, size and shape. In addition, its single pulse compatibility enables users to capture pulse-to-pulse fluctuations in focus properties compared with other techniques that require scanning and averaging. PMID- 25931075 TI - Pulse energy measurement at the SXR instrument. AB - A gas monitor detector was implemented and characterized at the Soft X-ray Research (SXR) instrument to measure the average, absolute and pulse-resolved photon flux of the LCLS beam in the energy range between 280 and 2000 eV. The detector is placed after the monochromator and addresses the need to provide reliable absolute pulse energy as well as pulse-resolved measurements for the various experiments at this instrument. This detector provides a reliable non invasive measurement for determining flux levels on the samples in the downstream experimental chamber and for optimizing signal levels of secondary detectors and for the essential need of data normalization. The design, integration into the instrument and operation are described, and examples of its performance are given. PMID- 25931076 TI - Photon-in photon-out hard X-ray spectroscopy at the Linac Coherent Light Source. AB - X-ray free-electron lasers (FELs) have opened unprecedented possibilities to study the structure and dynamics of matter at an atomic level and ultra-fast timescale. Many of the techniques routinely used at storage ring facilities are being adapted for experiments conducted at FELs. In order to take full advantage of these new sources several challenges have to be overcome. They are related to the very different source characteristics and its resulting impact on sample delivery, X-ray optics, X-ray detection and data acquisition. Here it is described how photon-in photon-out hard X-ray spectroscopy techniques can be applied to study the electronic structure and its dynamics of transition metal systems with ultra-bright and ultra-short FEL X-ray pulses. In particular, some of the experimental details that are different compared with synchrotron-based setups are discussed and illustrated by recent measurements performed at the Linac Coherent Light Source. PMID- 25931077 TI - Combining THz laser excitation with resonant soft X-ray scattering at the Linac Coherent Light Source. AB - This paper describes the development of new instrumentation at the Linac Coherent Light Source for conducting THz excitation experiments in an ultra high vacuum environment probed by soft X-ray diffraction. This consists of a cantilevered, fully motorized mirror system which can provide 600 kV cm(-1) electric field strengths across the sample and an X-ray detector that can span the full Ewald sphere with in-vacuum motion. The scientific applications motivated by this development, the details of the instrument, and spectra demonstrating the field strengths achieved using this newly developed system are discussed. PMID- 25931078 TI - Demonstration of simultaneous experiments using thin crystal multiplexing at the Linac Coherent Light Source. AB - Multiplexing of the Linac Coherent Light Source beam was demonstrated for hard X rays by spectral division using a near-perfect diamond thin-crystal monochromator operating in the Bragg geometry. The wavefront and coherence properties of both the reflected and transmitted beams were well preserved, thus allowing simultaneous measurements at two separate instruments. In this report, the structure determination of a prototypical protein was performed using serial femtosecond crystallography simultaneously with a femtosecond time-resolved XANES studies of photoexcited spin transition dynamics in an iron spin-crossover system. The results of both experiments using the multiplexed beams are similar to those obtained separately, using a dedicated beam, with no significant differences in quality. PMID- 25931079 TI - Characterization and use of the spent beam for serial operation of LCLS. AB - X-ray free-electron laser sources such as the Linac Coherent Light Source offer very exciting possibilities for unique research. However, beam time at such facilities is very limited and in high demand. This has led to significant efforts towards beam multiplexing of various forms. One such effort involves re using the so-called spent beam that passes through the hole in an area detector after a weak interaction with a primary sample. This beam can be refocused into a secondary interaction region and used for a second, independent experiment operating in series. The beam profile of this refocused beam was characterized for a particular experimental geometry at the Coherent X-ray Imaging instrument at LCLS. A demonstration of this multiplexing capability was performed with two simultaneous serial femtosecond crystallography experiments, both yielding interpretable data of sufficient quality to produce electron density maps. PMID- 25931080 TI - Effects of self-seeding and crystal post-selection on the quality of Monte Carlo integrated SFX data. AB - Serial femtosecond crystallography (SFX) is an emerging method for data collection at free-electron lasers (FELs) in which single diffraction snapshots are taken from a large number of crystals. The partial intensities collected in this way are then combined in a scheme called Monte Carlo integration, which provides the full diffraction intensities. However, apart from having to perform this merging, the Monte Carlo integration must also average out all variations in crystal quality, crystal size, X-ray beam properties and other factors, necessitating data collection from thousands of crystals. Because the pulses provided by FELs running in the typical self-amplified spontaneous emission (SASE) mode of operation have very irregular, spiky spectra that vary strongly from pulse to pulse, it has been suggested that this is an important source of variation contributing to inaccuracies in the intensities, and that, by using monochromatic pulses produced through a process called self-seeding, fewer images might be needed for Monte Carlo integration to converge, resulting in more accurate data. This paper reports the results of two experiments performed at the Linac Coherent Light Source in which data collected in both SASE and self-seeded mode were compared. Importantly, no improvement attributable to the use of self seeding was detected. In addition, other possible sources of variation that affect SFX data quality were investigated, such as crystal-to-crystal variations reflected in the unit-cell parameters; however, these factors were found to have no influence on data quality either. Possibly, there is another source of variation as yet undetected that affects SFX data quality much more than any of the factors investigated here. PMID- 25931081 TI - Simultaneous multiplexed materials characterization using a high-precision hard X ray micro-slit array. AB - The needs both for increased experimental throughput and for in operando characterization of functional materials under increasingly realistic experimental conditions have emerged as major challenges across the whole of crystallography. A novel measurement scheme that allows multiplexed simultaneous measurements from multiple nearby sample volumes is presented. This new approach enables better measurement statistics or direct probing of heterogeneous structure, dynamics or elemental composition. To illustrate, the submicrometer precision that optical lithography provides has been exploited to create a multiplexed form of ultra-small-angle scattering based X-ray photon correlation spectroscopy (USAXS-XPCS) using micro-slit arrays fabricated by photolithography. Multiplexed USAXS-XPCS is applied to follow the equilibrium dynamics of a simple colloidal suspension. While the dependence of the relaxation time on momentum transfer, and its relationship with the diffusion constant and the static structure factor, follow previous findings, this measurements-in-parallel approach reduces the statistical uncertainties of this photon-starved technique to below those associated with the instrument resolution. More importantly, we note the potential of the multiplexed scheme to elucidate the response of different components of a heterogeneous sample under identical experimental conditions in simultaneous measurements. In the context of the X-ray synchrotron community, this scheme is, in principle, applicable to all in-line synchrotron techniques. Indeed, it has the potential to open a new paradigm for in operando characterization of heterogeneous functional materials, a situation that will be even further enhanced by the ongoing development of multi-bend achromat storage ring designs as the next evolution of large-scale X-ray synchrotron facilities around the world. PMID- 25931082 TI - General method for automatic on-line beamline optimization based on genetic algorithm. AB - It is essential but inconvenient to perform high-quality on-line optimization for synchrotron radiation beamlines. Usually, synchrotron radiation beamlines are optimized manually, which is time-consuming and difficult to obtain global optimization for all optical elements of the beamline. In this contribution a general method based on the genetic algorithm for automatic beamline optimization is introduced. This method can optimize all optical components of any beamline simultaneously and efficiently. To test this method, a program developed using LabVIEW is examined at the XAFCA beamline of the Singapore Synchrotron Light Source to optimize the beam flux at the sample position. The results demonstrate that the beamline can be optimized within 17 generations even when the initial flux is as low as 4% of its maximum value. PMID- 25931083 TI - Performance optimization of a bendable parabolic cylinder collimating X-ray mirror for the ALS micro-XAS beamline 10.3.2. AB - The Advanced Light Source (ALS) beamline (BL) 10.3.2 is an apparatus for X-ray microprobe spectroscopy and diffraction experiments, operating in the energy range 2.4-17 keV. The performance of the beamline, namely the spatial and energy resolutions of the measurements, depends significantly on the collimation quality of light incident on the monochromator. In the BL 10.3.2 end-station, the synchrotron source is imaged 1:1 onto a set of roll slits which form a virtual source. The light from this source is collimated in the vertical direction by a bendable parabolic cylinder mirror. Details are presented of the mirror design, which allows for precision assembly, alignment and shaping of the mirror, as well as for extending of the mirror operating lifetime by a factor of ~10. Assembly, mirror optimal shaping and preliminary alignment were performed ex situ in the ALS X-ray Optics Laboratory (XROL). Using an original method for optimal ex situ characterization and setting of bendable X-ray optics developed at the XROL, a root-mean-square (RMS) residual surface slope error of 0.31 urad with respect to the desired parabola, and an RMS residual height error of less than 3 nm were achieved. Once in place at the beamline, deviations from the designed optical geometry (e.g. due to the tolerances for setting the distance to the virtual source, the grazing incidence angle, the transverse position) and/or mirror shape (e.g. due to a heat load deformation) may appear. Due to the errors, on installation the energy spread from the monochromator is typically a few electron volts. Here, a new technique developed and successfully implemented for at wavelength (in situ) fine optimal tuning of the mirror, enabling us to reduce the collimation-induced energy spread to ~0.05 eV, is described. PMID- 25931084 TI - Beamline P02.1 at PETRA III for high-resolution and high-energy powder diffraction. AB - Powder X-ray diffraction techniques largely benefit from the superior beam quality provided by high-brilliance synchrotron light sources in terms of photon flux and angular resolution. The High Resolution Powder Diffraction Beamline P02.1 at the storage ring PETRA III (DESY, Hamburg, Germany) combines these strengths with the power of high-energy X-rays for materials research. The beamline is operated at a fixed photon energy of 60 keV (0.207 A wavelength). A high-resolution monochromator generates the highly collimated X-ray beam of narrow energy bandwidth. Classic crystal structure determination in reciprocal space at standard and non-ambient conditions are an essential part of the scientific scope as well as total scattering analysis using the real space information of the pair distribution function. Both methods are complemented by in situ capabilities with time-resolution in the sub-second regime owing to the high beam intensity and the advanced detector technology for high-energy X-rays. P02.1's efficiency in solving chemical and crystallographic problems is illustrated by presenting key experiments that were carried out within these fields during the early stage of beamline operation. PMID- 25931085 TI - The In situ growth of Nanostructures on Surfaces (INS) endstation of the ESRF BM32 beamline: a combined UHV-CVD and MBE reactor for in situ X-ray scattering investigations of growing nanoparticles and semiconductor nanowires. AB - This paper presents the upgraded 'In situ growth of Nanoscructures on Surfaces' (INS) endstation of the InterFace beamline IF-BM32 at the European Synchrotron Radiation Facility (ESRF). This instrument, originally designed to investigate the structure of clean surfaces/interfaces/thin-films by surface X-ray diffraction, has been further developed to investigate the formation and evolution of nanostructures by combining small- and wide-angle X-ray scattering methodologies, i.e. grazing-incidence small-angle X-ray scattering (GISAXS) and grazing-incidence X-ray diffraction (GIXD). It consists of a UHV chamber mounted on a z-axis type goniometer, equipped with residual gas analysis, reflection high energy electron diffraction (RHEED) and Auger electron spectroscopy (AES) to complete the X-ray scattering investigations. The chamber has been developed so as up to eight sources of molecular beam epitaxy (MBE) can be simultaneously mounted to elaborate the nanostructures. A chemical vapor deposition (CVD) set-up has been added to expand the range of growing possibilities, in particular to investigate in situ the growth of semiconductor nanowires. This setup is presented in some detail, as well as the first in situ X-ray scattering measurements during the growth of silicon nanowires. PMID- 25931086 TI - Bunch mode specific rate corrections for PILATUS3 detectors. AB - PILATUS X-ray detectors are in operation at many synchrotron beamlines around the world. This article reports on the characterization of the new PILATUS3 detector generation at high count rates. As for all counting detectors, the measured intensities have to be corrected for the dead-time of the counting mechanism at high photon fluxes. The large number of different bunch modes at these synchrotrons as well as the wide range of detector settings presents a challenge for providing accurate corrections. To avoid the intricate measurement of the count rate behaviour for every bunch mode, a Monte Carlo simulation of the counting mechanism has been implemented, which is able to predict the corrections for arbitrary bunch modes and a wide range of detector settings. This article compares the simulated results with experimental data acquired at different synchrotrons. It is found that the usage of bunch mode specific corrections based on this simulation improves the accuracy of the measured intensities by up to 40% for high photon rates and highly structured bunch modes. For less structured bunch modes, the instant retrigger technology of PILATUS3 detectors substantially reduces the dependency of the rate correction on the bunch mode. The acquired data also demonstrate that the instant retrigger technology allows for data acquisition up to 15 million photons per second per pixel. PMID- 25931087 TI - Concept of a multichannel spin-resolving electron analyzer based on Mott scattering. AB - The concept of a multichannel electron spin detector based on optical imaging principles and Mott scattering (iMott) is presented. A multichannel electron image produced by a standard angle-resolving (photo) electron analyzer or microscope is re-imaged by an electrostatic lens at an accelerating voltage of 40 kV onto the Au target. Quasi-elastic electrons bearing spin asymmetry of the Mott scattering are imaged by magnetic lenses onto position-sensitive electron CCDs whose differential signals yield the multichannel spin asymmetry image. Fundamental advantages of this concept include acceptance of inherently divergent electron sources from the electron analyzer or microscope focal plane as well as small aberrations achieved by virtue of high accelerating voltages, as demonstrated by extensive ray-tracing analysis. The efficiency gain compared with the single-channel Mott detector can be a factor of more than 10(4) which opens new prospects of spin-resolved spectroscopies in application not only to standard bulk and surface systems (Rashba effect, topological insulators, etc.) but also to buried heterostructures. The simultaneous spin detection combined with fast CCD readout enables efficient use of the iMott detectors at X-ray free-electron laser facilities. PMID- 25931088 TI - Simultaneous nanocalorimetry and fast XRD measurements to study the silicide formation in Pd/a-Si bilayers. AB - The use of a membrane-based chip nanocalorimeter in a powder diffraction beamline is described. Simultaneous wide-angle X-ray scattering and scanning nanocalorimetric measurements are performed on a thin-film stack of palladium/amorphous silicon (Pd/a-Si) at heating rates from 0.1 to 10 K s(-1). The nanocalorimeter works under a power-compensation scheme previously developed by the authors. Kinetic and structural information of the consumed and created phases can be obtained from the combined techniques. The formation of Pd2Si produces a broad calorimetric peak that contains overlapping individual processes. It is shown that Pd consumption precedes the formation of the crystalline Pd2Si phase and that the crystallite size depends on the heating rate of the experiment. PMID- 25931089 TI - Synchrotron radiation Mossbauer spectra of a rotating absorber with implications for testing velocity and acceleration time dilation. AB - Many Mossbauer spectroscopy (MS) experiments have used a rotating absorber in order to measure the second-order transverse Doppler (TD) shift, and to test the validity of the Einstein time dilation theory. From these experiments, one may also test the clock hypothesis (CH) and the time dilation caused by acceleration. In such experiments the absorption curves must be obtained, since it cannot be assumed that there is no broadening of the curve during the rotation. For technical reasons, it is very complicated to keep the balance of a fast rotating disk if there are moving parts on it. Thus, the Mossbauer source on a transducer should be outside the disk. Friedman and Nowik have already predicted that the X ray beam finite size dramatically affects the MS absorption line and causes its broadening. We provide here explicit formulas to evaluate this broadening for a synchrotron Mossbauer source (SMS) beam. The broadening is linearly proportional to the rotation frequency and to the SMS beam width at the rotation axis. In addition, it is shown that the TD shift and the MS line broadening are affected by an additional factor assigned as the alignment shift which is proportional to the frequency of rotation and to the distance between the X-ray beam center and the rotation axis. This new shift helps to align the disk's axis of rotation to the X-ray beam's center. To minimize the broadening, one must focus the X-ray on the axis of the rotating disk and/or to add a slit positioned at the center, to block the rays distant from the rotation axis of the disk. Our experiment, using the (57)Fe SMS, currently available at the Nuclear Resonance beamline (ID18) at the ESRF, with a rotating stainless steel foil, confirmed our predictions. With a slit installed at the rotation axis (reducing the effective beam width from 15.6 um to 5.4 um), one can measure a statistically meaningful absorption spectrum up to 300 Hz, while, without a slit, such spectra could be obtained up to 100 Hz only. Thus, both the broadening and the alignment shift are very significant and must be taken into consideration in any rotating absorber experiment. Here a method is offered to measure accurately the TD shift and to test the CH. PMID- 25931090 TI - X-rays only when you want them: optimized pump-probe experiments using pseudo single-bunch operation. AB - Laser pump-X-ray probe experiments require control over the X-ray pulse pattern and timing. Here, the first use of pseudo-single-bunch mode at the Advanced Light Source in picosecond time-resolved X-ray absorption experiments on solutions and solids is reported. In this mode the X-ray repetition rate is fully adjustable from single shot to 500 kHz, allowing it to be matched to typical laser excitation pulse rates. Suppressing undesired X-ray pulses considerably reduces detector noise and improves signal to noise in time-resolved experiments. In addition, dose-induced sample damage is considerably reduced, easing experimental setup and allowing the investigation of less robust samples. Single-shot X-ray exposures of a streak camera detector using a conventional non-gated charge coupled device (CCD) camera are also demonstrated. PMID- 25931091 TI - A dispenser-reactor apparatus applied for in situ XAS monitoring of Pt nanoparticle formation. AB - In situ time-resolved X-ray absorption spectroscopy (XAS) measurements collected at the Pt L3-edge during the synthesis of Pt nanoparticles (NPs) in aqueous solution are reported. A specially designed dispenser-reactor apparatus allowed for monitoring changes in the XAS spectra from the earliest moments of Pt ions in solution until the formation of metallic nanoparticles with a mean diameter of 4.9 +/- 1.1 nm. By monitoring the changes in the local chemical environment of the Pt atoms in real time, it was possible to observe that the NPs formation kinetics involved two stages: a reduction-nucleation burst followed by a slow growth and stabilization of NPs. Subsequently, the synthesized Pt NPs were supported on activated carbon and characterized by synchrotron-radiation-excited X-ray photoelectron spectroscopy (XPS), X-ray diffraction (XRD) and extended X ray absorption fine structure (EXAFS). The supported Pt NPs remained in the metallic chemical state and with a reduced size, presenting slight lattice parameter contraction in comparison with the bulk Pt values. PMID- 25931092 TI - The ALBA spectroscopic LEEM-PEEM experimental station: layout and performance. AB - The spectroscopic LEEM-PEEM experimental station at the CIRCE helical undulator beamline, which started user operation at the ALBA Synchrotron Light Facility in 2012, is presented. This station, based on an Elmitec LEEM III microscope with electron imaging energy analyzer, permits surfaces to be imaged with chemical, structural and magnetic sensitivity down to a lateral spatial resolution better than 20 nm with X-ray excited photoelectrons and 10 nm in LEEM and UV-PEEM modes. Rotation around the surface normal and application of electric and (weak) magnetic fields are possible in the microscope chamber. In situ surface preparation capabilities include ion sputtering, high-temperature flashing, exposure to gases, and metal evaporation with quick evaporator exchange. Results from experiments in a variety of fields and imaging modes will be presented in order to illustrate the ALBA XPEEM capabilities. PMID- 25931093 TI - XAS and XMCD studies of magnetic properties modifications of Pt/Co/Au and Pt/Co/Pt trilayers induced by Ga+ ions irradiation. AB - Magnetic and magneto-optical properties of Pt/Co/Au and Pt/Co/Pt trilayers subjected to 30 keV Ga(+) ion irradiation are compared. In two-dimensional maps of these properties as a function of cobalt thickness and ion fluence, two branches with perpendicular magnetic anisotropy (PMA) for Pt/Co/Pt trilayers are well distinguished. The replacement of the Pt capping layer with Au results in the two branches still being visible but the in-plane anisotropy for the low fluence branch is suppressed whereas the high-fluence branch displays PMA. The X ray absorption spectra and X-ray magnetic circular dichroism (XMCD) spectra are discussed and compared with non-irradiated reference samples. The changes of their shapes and peak amplitude, particularly for the high-fluence branch, are related to the modifications of the local environment of Co(Pt) atoms and the etching effects induced by ion irradiation. Additionally, in irradiated trilayers the XMCD measurements at the Pt L2,3-edge reveal an increase of the magnetic moment induced in Pt atoms. PMID- 25931094 TI - Nuclear resonant inelastic X-ray scattering at high pressure and low temperature. AB - A new synchrotron radiation experimental capability of coupling nuclear resonant inelastic X-ray scattering with the cryogenically cooled high-pressure diamond anvil cell technique is presented. The new technique permits measurements of phonon density of states at low temperature and high pressure simultaneously, and can be applied to studies of phonon contribution to pressure- and temperature induced magnetic, superconducting and metal-insulator transitions in resonant isotope-bearing materials. In this report, a pnictide sample, EuFe2As2, is used as an example to demonstrate this new capability at beamline 3-ID of the Advanced Photon Source, Argonne National Laboratory. A detailed description of the technical development is given. The Fe-specific phonon density of states and magnetism from the Fe sublattice in Eu(57)Fe2As2 at high pressure and low temperature were derived by using this new capability. PMID- 25931095 TI - High-resolution X-ray emission spectroscopy with transition-edge sensors: present performance and future potential. AB - X-ray emission spectroscopy (XES) is a powerful element-selective tool to analyze the oxidation states of atoms in complex compounds, determine their electronic configuration, and identify unknown compounds in challenging environments. Until now the low efficiency of wavelength-dispersive X-ray spectrometer technology has limited the use of XES, especially in combination with weaker laboratory X-ray sources. More efficient energy-dispersive detectors have either insufficient energy resolution because of the statistical limits described by Fano or too low counting rates to be of practical use. This paper updates an approach to high resolution X-ray emission spectroscopy that uses a microcalorimeter detector array of superconducting transition-edge sensors (TESs). TES arrays are discussed and compared with conventional methods, and shown under which circumstances they are superior. It is also shown that a TES array can be integrated into a table top time-resolved X-ray source and a soft X-ray synchrotron beamline to perform emission spectroscopy with good chemical sensitivity over a very wide range of energies. PMID- 25931096 TI - Soft X-ray angle-resolved photoemission with micro-positioning techniques for metallic V2O3. AB - Soft X-ray angle-resolved photoemission has been performed for metallic V2O3. By combining a microfocus beam (40 um * 65 um) and micro-positioning techniques with a long-working-distance microscope, it has been possible to observe band dispersions from tiny cleavage surfaces with a typical size of several tens of um. The photoemission spectra show a clear position dependence, reflecting the morphology of the cleaved sample surface. By selecting high-quality flat regions on the sample surface, it has been possible to perform band mapping using both photon-energy and polar-angle dependences, opening the door to three-dimensional angle-resolved photoemission spectroscopy for typical three-dimensional correlated materials where large cleavage planes are rarely obtained. PMID- 25931097 TI - Direct-write X-ray lithography using a hard X-ray Fresnel zone plate. AB - Results are reported of direct-write X-ray lithography using a hard X-ray beam focused by a Fresnel zone plate with an outermost zone width of 40 nm. An X-ray beam at 7.5 keV focused to a nano-spot was employed to write arbitrary patterns on a photoresist thin film with a resolution better than 25 nm. The resulting pattern dimension depended significantly on the kind of underlying substrate, which was attributed to the lateral spread of electrons generated during X-ray irradiation. The proximity effect originated from the diffuse scattering near the focus and electron blur was also observed, which led to an increase in pattern dimension. Since focusing hard X-rays to below a 10 nm spot is currently available, the direct-write hard X-ray lithography developed in this work has the potential to be a promising future lithographic method. PMID- 25931098 TI - A novel crystal-analyzer phase retrieval algorithm and its noise property. AB - A description of the rocking curve in diffraction enhanced imaging (DEI) is presented in terms of the angular signal response function and a simple multi information retrieval algorithm based on the cosine function fitting. A comprehensive analysis of noise properties of DEI is also given considering the noise transfer characteristic of the X-ray source. The validation has been performed with synchrotron radiation experimental data and Monte Carlo simulations based on the Geant4 toolkit combined with the refractive process of X rays, which show good agreement with each other. Moreover, results indicate that the signal-to-noise ratios of the refraction and scattering images are about one order of magnitude better than that of the absorption image at the edges of low-Z samples. The noise penalty is drastically reduced with the increasing photon flux and visibility. Finally, this work demonstrates that the analytical method can build an interesting connection between DEI and GDPCI (grating-based differential phase contrast imaging) and is widely suitable for a variety of measurement noise in the angular signal response imaging prototype. The analysis significantly contributes to the understanding of noise characteristics of DEI images and may allow improvements to the signal-to-noise ratio in biomedical and material science imaging. PMID- 25931099 TI - Highly porous nanoberyllium for X-ray beam speckle suppression. AB - This paper reports a special device called a 'speckle suppressor', which contains a highly porous nanoberyllium plate squeezed between two beryllium windows. The insertion of the speckle suppressor in an X-ray beam allows manipulation of the spatial coherence length, thus changing the effective source size and removing the undesirable speckle structure in X-ray imaging experiments almost without beam attenuation. The absorption of the nanoberyllium plate is below 1% for 1 mm thickness at 12 keV. The speckle suppressor was tested on the ID06 ESRF beamline with X-rays in the energy range from 9 to 15 keV. It was applied for the transformation of the phase-amplitude contrast to the pure amplitude contrast in full-field microscopy. PMID- 25931100 TI - Phase-preserving beam expander for biomedical X-ray imaging. AB - The BioMedical Imaging and Therapy beamlines at the Canadian Light Source are used by many researchers to capture phase-based imaging data. These experiments have so far been limited by the small vertical beam size, requiring vertical scanning of biological samples in order to image their full vertical extent. Previous work has been carried out to develop a bent Laue beam-expanding monochromator for use at these beamlines. However, the first attempts exhibited significant distortion in the diffraction plane, increasing the beam divergence and eliminating the usefulness of the monochromator for phase-related imaging techniques. Recent work has been carried out to more carefully match the polychromatic and geometric focal lengths in a so-called 'magic condition' that preserves the divergence of the beam and enables full-field phase-based imaging techniques. The new experimental parameters, namely asymmetry and Bragg angles, were evaluated by analysing knife-edge and in-line phase images to determine the effect on beam divergence in both vertical and horizontal directions, using the flat Bragg double-crystal monochromator at the beamline as a baseline. The results show that by using the magic condition, the difference between the two monochromator types is less than 10% in the diffraction plane. Phase fringes visible in test images of a biological sample demonstrate that this difference is small enough to enable in-line phase imaging, despite operating at a sub-optimal energy for the wafer and asymmetry angle that was used. PMID- 25931101 TI - Dual-energy X-ray analysis using synchrotron computed tomography at 35 and 60 keV for the estimation of photon interaction coefficients describing attenuation and energy absorption. AB - A novel method for dual-energy X-ray analysis (DEXA) is tested using measurements of the X-ray linear attenuation coefficient MU. The key is a mathematical model that describes elemental cross sections using a polynomial in atomic number. The model is combined with the mixture rule to describe MU for materials, using the same polynomial coefficients. Materials are characterized by their electron density Ne and statistical moments Rk describing their distribution of elements, analogous to the concept of effective atomic number. In an experiment with materials of known density and composition, measurements of MU are written as a system of linear simultaneous equations, which is solved for the polynomial coefficients. DEXA itself involves computed tomography (CT) scans at two energies to provide a system of non-linear simultaneous equations that are solved for Ne and the fourth statistical moment R4. Results are presented for phantoms containing dilute salt solutions and for a biological specimen. The experiment identifies 1% systematic errors in the CT measurements, arising from third harmonic radiation, and 20-30% noise, which is reduced to 3-5% by pre-processing with the median filter and careful choice of reconstruction parameters. DEXA accuracy is quantified for the phantom as the mean absolute differences for Ne and R4: 0.8% and 1.0% for soft tissue and 1.2% and 0.8% for bone-like samples, respectively. The DEXA results for the biological specimen are combined with model coefficients obtained from the tabulations to predict MU and the mass energy absorption coefficient at energies of 10 keV to 20 MeV. PMID- 25931102 TI - Water window ptychographic imaging with characterized coherent X-rays. AB - A ptychographical coherent diffractive imaging experiment in the water window with focused soft X-rays at 500 eV is reported. An X-ray beam with high degree of coherence was selected for ptychography at the P04 beamline of PETRA III synchrotron radiation source. The beam coherence was measured with the newly developed non-redundant array method, and a coherence length of 4.1 um and global degree of coherence of 35% at 100 um exit slit opening in the vertical direction were determined. A pinhole, 2.6 um in size, selected the coherent part of the beam that was used to obtain ptychographic reconstruction results of a lithographically manufactured test sample and a fossil diatom. The achieved resolution was 53 nm for the test sample and was only limited by the size of the detector. The diatom was imaged at a resolution better than 90 nm. PMID- 25931103 TI - I12: the Joint Engineering, Environment and Processing (JEEP) beamline at Diamond Light Source. AB - I12 is the Joint Engineering, Environmental and Processing (JEEP) beamline, constructed during Phase II of the Diamond Light Source. I12 is located on a short (5 m) straight section of the Diamond storage ring and uses a 4.2 T superconducting wiggler to provide polychromatic and monochromatic X-rays in the energy range 50-150 keV. The beam energy enables good penetration through large or dense samples, combined with a large beam size (1 mrad horizontally * 0.3 mrad vertically). The beam characteristics permit the study of materials and processes inside environmental chambers without unacceptable attenuation of the beam and without the need to use sample sizes which are atypically small for the process under study. X-ray techniques available to users are radiography, tomography, energy-dispersive diffraction, monochromatic and white-beam two-dimensional diffraction/scattering and small-angle X-ray scattering. Since commencing operations in November 2009, I12 has established a broad user community in materials science and processing, chemical processing, biomedical engineering, civil engineering, environmental science, palaeontology and physics. PMID- 25931104 TI - XAFCA: a new XAFS beamline for catalysis research. AB - A new X-ray absorption fine-structure (XAFS) spectroscopy beamline for fundamental and applied catalysis research, called XAFCA, has been built by the Institute of Chemical and Engineering Sciences, and the Singapore Synchrotron Light Source. XAFCA covers the photon energy range from 1.2 to 12.8 keV, making use of two sets of monochromator crystals, an Si (111) crystal for the range from 2.1 to 12.8 keV and a KTiOPO4 crystal [KTP (011)] for the range between 1.2 and 2.8 keV. Experiments can be carried out in the temperature range from 4.2 to 1000 K and pressures up to 30 bar for catalysis research. A safety system has been incorporated, allowing the use of flammable and toxic gases such as H2 and CO. PMID- 25931105 TI - UV-CD12: synchrotron radiation circular dichroism beamline at ANKA. AB - Synchrotron radiation circular dichroism (SRCD) is a rapidly growing technique for structure analysis of proteins and other chiral biomaterials. UV-CD12 is a high-flux SRCD beamline installed at the ANKA synchrotron, to which it had been transferred after the closure of the SRS Daresbury. The beamline covers an extended vacuum-UV to near-UV spectral range and has been open for users since October 2011. The current end-station allows for temperature-controlled steady state SRCD spectroscopy, including routine automated thermal scans of microlitre volumes of water-soluble proteins down to 170 nm. It offers an excellent signal to-noise ratio over the whole accessible spectral range. The technique of oriented circular dichroism (OCD) was recently implemented for determining the membrane alignment of alpha-helical peptides and proteins in macroscopically oriented lipid bilayers as mimics of cellular membranes. It offers improved spectral quality <200 nm compared with an OCD setup adapted to a bench-top instrument, and accelerated data collection by a factor of ~3. In addition, it permits investigations of low hydrated protein films down to 130 nm using a rotatable sample cell that avoids linear dichroism artifacts. PMID- 25931106 TI - Data Analysis WorkbeNch (DAWN). AB - Synchrotron light source facilities worldwide generate terabytes of data in numerous incompatible data formats from a wide range of experiment types. The Data Analysis WorkbeNch (DAWN) was developed to address the challenge of providing a single visualization and analysis platform for data from any synchrotron experiment (including single-crystal and powder diffraction, tomography and spectroscopy), whilst also being sufficiently extensible for new specific use case analysis environments to be incorporated (e.g. ARPES, PEEM). In this work, the history and current state of DAWN are presented, with two case studies to demonstrate specific functionality. The first is an example of a data processing and reduction problem using the generic tools, whilst the second shows how these tools can be targeted to a specific scientific area. PMID- 25931107 TI - Characterization of a Pt mirror to be used to deflect synchrotron radiation beam onto Langmuir monolayers. AB - A homemade mirror for X-rays has been built to prepare a diffraction beamline for liquid surface diffraction and scattering measurements. This simple approach is in operation at the XRD2 bending-magnet beamline at the Brazilian Synchrotron Light Laboratory. PMID- 25931108 TI - CDApps: integrated software for experimental planning and data processing at beamline B23, Diamond Light Source. Corrigendum. AB - In the paper by Hussain et al. [(2015), J. Synchrotron Rad. 22, 465-468], Daniel Myatt is missing from the list of authors. The complete list of authors should be Rohanah Hussain, Kristian Benning, Daniel Myatt, Tamas Javorfi, Edoardo Longo, Timothy R. Rudd, Bill Pulford and Giuliano Siligardi. PMID- 25931109 TI - In situ synchrotron X-ray diffraction investigation of the evolution of a PbO2/PbSO4 surface layer on a copper electrowinning Pb anode in a novel electrochemical flow cell. Corrigendum. AB - Figures 7 and 8 of the article by Clancy et al. [(2015), J. Synchrotron Rad. 22, 366-375] are corrected. PMID- 25931111 TI - Systematic investigation of CMTM family genes suggests relevance to glioblastoma pathogenesis and CMTM1 and CMTM3 as priority targets. AB - The novel CKLF-like Marvel Transmembrane Domain-containing gene family (CMTM) consists of 8 members (CMTM1-8). As little is known about the oncogenic impact of these genes, we aimed to systematically investigate the relevance of CMTMs to glioblastoma pathogenesis. We performed mRNA expression analyses and survival correlations in glioblastoma patients. Moreover, we analyzed the impact of RNAi based silencing and overexpression of CMTM family genes on tumor cell proliferation and invasion in vitro. CMTMs appeared to be widely regulated in the group of glioblastomas relative to non-neoplastic brain (NB) tissue (significant upregulation for CMTM2, 3, and 6 and significant downregulation for CMTM 4 and 8). For CMTM1, 5 and 7, we found aberrant expression levels in individual tumors. Functionally, CMTM1, 3, and 7 promoted tumor cell invasion, while CMTM1 additionally enhanced cell proliferation. In a large clinically annotated dataset, higher CMTM1 and 3 expression was significantly correlated with shorter overall survival. Our data thus suggest CMTM1 and 3 as priority targets in glioblastomas. Using a human phosphokinase protein expression profiling assay, we can provide first insights into signalling of these two genes that might be conveyed by growth factor receptor, Src family kinase and WNT activation. PMID- 25931112 TI - Reduced emotional and cardiovascular reactivity to emotionally evocative stimuli in major depressive disorder. AB - Major Depressive Disorder (MDD) is a highly debilitating mental health concern that affects a large number of adults in the United States. The emotional context insensitivity (ECI) hypothesis argues that individuals with MDD disengage from the environment to defend themselves from futile activity. In the current study, electrocardiogram and pupillometry were recorded from 50 participants (MDD n=25, never depressed control n=25) during the display of emotionally evocative images, sounds, and movie clips. Individuals with MDD reported reduced change in happiness to positively- and negatively-valenced images and sounds. Heart rate reactivity also was reduced in individuals with MDD when viewing images and watching movie clips. These results suggest that individuals with MDD may have some difficulty engaging with certain environmental stimuli. PMID- 25931113 TI - Modulation of resource allocation by intelligent individuals in linguistic, mathematical and visuo-spatial tasks. AB - This study investigates two questions: first, how individuals with high intelligence allocate cognitive resources while solving linguistic, mathematical and visuo-spatial tasks with varying degree of difficulty as compared to individuals with low intelligence? Second, how to distinguish between high and low intelligent individuals by analyzing pupil dilation and eye blink together? We measured the response time, error rates along with pupil dilation and eye blink rate that indicate resource allocation. We divided the whole processing into three stages namely: pre-stimuli (5s prior to stimuli onset), during stimuli and post stimuli (until 5s after the response) for better assessment of preparation and resource allocation strategies. Individuals with high intelligence showed greater task evoked pupil dilation, decreased eye blink with less response time and error rates during-stimuli stage (processing) of tough linguistic and visuo-spatial tasks but not during mathematical tasks. The finding suggests that individuals with high intelligence allocate more resources if the task demands are high else they allocate less resources. Greater pre-stimuli pupil dilation and increased eye blink of high intelligent individuals in all tasks indicated their attentiveness and preparedness. The result of our study shows that individuals with high intelligence are more attentive and flexible in terms of altering the resource allocation strategy according to task demand. Eye blinks along with pupil dilation and other behavioral parameters can be reliably used to assess the intelligence of an individual and the analysis of pupil dilation and blink rate at pre-stimuli stage can be crucial in distinguishing individuals with varying intelligence. PMID- 25931114 TI - Capturing the cardiac effects of racial discrimination: Do the effects "keep going"? AB - Racial discrimination negatively impacts cardiac functioning, but few studies examine the more distal cardiac effects of racial discrimination experiences. The present study examined the momentary and prolonged impact of lab-based intergroup and intragroup racial discrimination on heart rate variability (HRV) and heart rate (HR) in a sample (N = 42) of African American (AA) women across two days. On day one, the women were exposed to simulated racial discrimination from either a European American (EA) or AA confederate in the lab. On day two, the women returned to the lab for additional physiological recording and debriefing. Women insulted by the EA confederate exhibited lower HRV on day one and marginally lower HRV on day two. These women also exhibited marginally higher HR on day two. The HRV and HR effects on day two were not mediated by differences in perseveration about the stressor. The findings indicate that racial discrimination - particularly intergroup racial discrimination - may have both momentary and prolonged effects on cardiac activity in AAs. PMID- 25931115 TI - p62/Sequestosome-1, Autophagy-related Gene 8, and Autophagy in Drosophila Are Regulated by Nuclear Factor Erythroid 2-related Factor 2 (NRF2), Independent of Transcription Factor TFEB. AB - The selective autophagy receptor p62/sequestosome 1 (SQSTM1) interacts directly with LC3 and is involved in oxidative stress signaling in two ways in mammals. First, p62 is transcriptionally induced upon oxidative stress by the NF-E2 related factor 2 (NRF2) by direct binding to an antioxidant response element in the p62 promoter. Second, p62 accumulation, occurring when autophagy is impaired, leads to increased p62 binding to the NRF2 inhibitor KEAP1, resulting in reduced proteasomal turnover of NRF2. This gives chronic oxidative stress signaling through a feed forward loop. Here, we show that the Drosophila p62/SQSTM1 orthologue, Ref(2)P, interacts directly with DmAtg8a via an LC3-interacting region motif, supporting a role for Ref(2)P in selective autophagy. The ref(2)P promoter also contains a functional antioxidant response element that is directly bound by the NRF2 orthologue, CncC, which can induce ref(2)P expression along with the oxidative stress-associated gene gstD1. However, distinct from the situation in mammals, Ref(2)P does not interact directly with DmKeap1 via a KEAP1 interacting region motif; nor does ectopically expressed Ref(2)P or autophagy deficiency activate the oxidative stress response. Instead, DmAtg8a interacts directly with DmKeap1, and DmKeap1 is removed upon programmed autophagy in Drosophila gut cells. Strikingly, CncC induced increased Atg8a levels and autophagy independent of TFEB/MitF in fat body and larval gut tissues. Thus, these results extend the intimate relationship between oxidative stress-sensing NRF2/CncC transcription factors and autophagy and suggest that NRF2/CncC may regulate autophagic activity in other organisms too. PMID- 25931116 TI - Transcriptional Repressor TrmBL2 from Thermococcus kodakarensis Forms Filamentous Nucleoprotein Structures and Competes with Histones for DNA Binding in a Salt- and DNA Supercoiling-dependent Manner. AB - Architectural DNA proteins play important roles in the chromosomal DNA organization and global gene regulation in living cells. However, physiological functions of some DNA-binding proteins from archaea remain unclear. Recently, several abundant DNA-architectural proteins including histones, Alba, and TrmBL2 have been identified in model euryarchaeon Thermococcus kodakarensis. Although histones and Alba proteins have been previously characterized, the DNA binding properties of TrmBL2 and its interplay with the other major architectural proteins in the chromosomal DNA organization and gene transcription regulation remain largely unexplored. Here, we report single-DNA studies showing that at low ionic strength (<300 mM KCl), TrmBL2 binds to DNA largely in non-sequence specific manner with positive cooperativity, resulting in formation of stiff nucleoprotein filamentous patches, whereas at high ionic strength (>300 mM KCl) TrmBL2 switches to more sequence-specific interaction, suggesting the presence of high affinity TrmBL2-filament nucleation sites. Furthermore, in vitro assays indicate the existence of DNA binding competition between TrmBL2 and archaeal histones B from T. kodakarensis, which can be strongly modulated by DNA supercoiling and ionic strength of surrounding solution. Overall, these results advance our understanding of TrmBL2 DNA binding properties and provide important insights into potential functions of architectural proteins in nucleoid organization and gene regulation in T. kodakarensis. PMID- 25931117 TI - Endoglin Regulation of Smad2 Function Mediates Beclin1 Expression and Endothelial Autophagy. AB - Autophagy is the targeted degradation of proteins and organelles critical for homeostasis and cell survival. Transforming growth factor beta (TGF-beta) differentially regulates autophagy in a context-specific manner, although the precise intracellular mechanisms remain less clear. Importantly, how TGF-beta controls autophagic responses in endothelial cells (EC) during angiogenesis is unknown. Here we identified endoglin, an EC-specific TGF-beta co-receptor essential for angiogenesis, as a key determinant of autophagy. Among the two opposing TGF-beta Smad pathways in the EC system (Smad1/5/8 and Smad2/3), we found Smad2 as the major transcriptional regulator of autophagy that targets beclin1 (BECN1) gene expression. Smad2, but not Smad3, acts as a repressor upstream of the BECN1 promoter region. Overall, endoglin promotes autophagy by impeding Smad2 transcriptional repressor activity. Notably, increased beclin1 levels upon Smad2 knockdown directly correlated with enhanced autophagy during angiogenesis. Taken together, these results establish endoglin as a critical mediator of autophagy and demonstrate a new transcriptional mechanism by which Smad2 inhibits angiogenesis. PMID- 25931118 TI - Analysis of Human Dopamine D3 Receptor Quaternary Structure. AB - The dopamine D3 receptor is a class A, rhodopsin-like G protein-coupled receptor that can form dimers and/or higher order oligomers. However, the molecular basis for production of these complexes is not well defined. Using combinations of molecular modeling, site-directed mutagenesis, and homogenous time-resolved FRET, the interfaces that allow dopamine D3 receptor monomers to interact were defined and used to describe likely quaternary arrangements of the receptor. These were then compared with published crystal structures of dimeric beta1-adrenoreceptor, MU-opioid, and CXCR4 receptors. The data indicate important contributions of residues from within each of transmembrane domains I, II, IV, V, VI, and VII as well as the intracellular helix VIII in the formation of D3-D3 receptor interfaces within homo-oligomers and are consistent with the D3 receptor adopting a beta1-adrenoreceptor-like quaternary arrangement. Specifically, results suggest that D3 protomers can interact with each other via at least two distinct interfaces: the first one comprising residues from transmembrane domains I and II along with those from helix VIII and a second one involving transmembrane domains IV and V. Moreover, rather than existing only as distinct dimeric species, the results are consistent with the D3 receptor also assuming a quaternary structure in which two transmembrane domain I-II-helix VIII dimers interact to form a "rhombic" tetramer via an interface involving residues from transmembrane domains VI and VII. In addition, the results also provide insights into the potential contribution of molecules of cholesterol to the overall organization and potential stability of the D3 receptor and possibly other GPCR quaternary structures. PMID- 25931119 TI - The Helicase Activity of Ribonuclease R Is Essential for Efficient Nuclease Activity. AB - RNase R, which belongs to the RNB family of enzymes, is a 3' to 5' hydrolytic exoribonuclease able to digest highly structured RNA. It was previously reported that RNase R possesses an intrinsic helicase activity that is independent of its ribonuclease activity. However, the properties of this helicase activity and its relationship to the ribonuclease activity were not clear. Here, we show that helicase activity is dependent on ATP and have identified ATP-binding Walker A and Walker B motifs that are present in Escherichia coli RNase R and in 88% of mesophilic bacterial genera analyzed, but absent from thermophilic bacteria. We also show by mutational analysis that both of these motifs are required for helicase activity. Interestingly, the Walker A motif is located in the C-terminal region of RNase R, whereas the Walker B motif is in its N-terminal region implying that the two parts of the protein must come together to generate a functional ATP-binding site. Direct measurement of ATP binding confirmed that ATP binds only when double-stranded RNA is present. Detailed analysis of the helicase activity revealed that ATP hydrolysis is not required because both adenosine 5'-O (thiotriphosphate) and adenosine 5'-(beta,gamma-imino)triphosphate can stimulate helicase activity, as can other nucleoside triphosphates. Although the nuclease activity of RNase R is not needed for its helicase activity, the helicase activity is important for effective nuclease activity against a dsRNA substrate, particularly at lower temperatures and with more stable duplexes. Moreover, competition experiments and mutational analysis revealed that the helicase activity utilizes the same catalytic channel as the nuclease activity. These findings indicate that the helicase activity plays an essential role in the catalytic efficiency of RNase R. PMID- 25931120 TI - Muscle Segment Homeobox Genes Direct Embryonic Diapause by Limiting Inflammation in the Uterus. AB - Embryonic diapause is a reproductive strategy widespread in the animal kingdom. This phenomenon is defined by a temporary arrest in blastocyst growth and metabolic activity within a quiescent uterus without implantation until the environmental and maternal milieu become favorable for pregnancy to progress. We found that uterine Msx expression persists during diapause across species; their inactivation in the mouse uterus results in termination of diapause with the development of implantation-like responses ("pseudoimplantation") that ultimately succumbed to resorption. To understand the cause of this failure, we compared proteome profiles between floxed and Msx-deleted uteri. In deleted uteri, several functional networks, including transcription/translation, ubiquitin-proteasome, inflammation, and endoplasmic reticulum stress, were dysregulated. Computational modeling predicted intersection of these pathways on an enhanced inflammatory signature. Further studies showed that this signature was reflected in increased phosphorylated IkappaB levels and nuclear NFkappaB in deleted uteri. This was associated with enhanced proteasome activity and endoplasmic reticulum stress. Interestingly, treatment with anti-inflammatory glucocorticoid (dexamethasone) reduced the inflammatory signature with improvement of the diapause phenotype. These findings highlight an unexpected role of uterine Msx in limiting aberrant inflammatory responses to maintain embryonic diapause. PMID- 25931121 TI - Inhibition of Cav3.2 T-type Calcium Channels by Its Intracellular I-II Loop. AB - Voltage-dependent calcium channels (Cav) of the T-type family (Cav3.1, Cav3.2, and Cav3.3) are activated by low threshold membrane depolarization and contribute greatly to neuronal network excitability. Enhanced T-type channel activity, especially Cav3.2, contributes to disease states, including absence epilepsy. Interestingly, the intracellular loop connecting domains I and II (I-II loop) of Cav3.2 channels is implicated in the control of both surface expression and channel gating, indicating that this I-II loop plays an important regulatory role in T-type current. Here we describe that co-expression of this I-II loop or its proximal region (Delta1-Cav3.2; Ser(423)-Pro(542)) together with recombinant full length Cav3.2 channel inhibited T-type current without affecting channel expression and membrane incorporation. Similar T-type current inhibition was obtained in NG 108-15 neuroblastoma cells that constitutively express Cav3.2 channels. Of interest, Delta1-Cav3.2 inhibited both Cav3.2 and Cav3.1 but not Cav3.3 currents. Efficacy of Delta1-Cav3.2 to inhibit native T-type channels was assessed in thalamic neurons using viral transduction. We describe that T-type current was significantly inhibited in the ventrobasal neurons that express Cav3.1, whereas in nucleus reticularis thalami neurons that express Cav3.2 and Cav3.3 channels, only the fast inactivating T-type current (Cav3.2 component) was significantly inhibited. Altogether, these data describe a new strategy to differentially inhibit Cav3 isoforms of the T-type calcium channels. PMID- 25931122 TI - MicroRNA-193a-3p Reduces Intestinal Inflammation in Response to Microbiota via Down-regulation of Colonic PepT1. AB - Intestinal inflammation is characterized by epithelial disruption, leading to the loss of barrier function, recruitment of immune cells, and host immune responses to gut microbiota. PepT1, a di/tripeptide transporter that uptakes bacterial products, is up-regulated in inflamed colon tissue, which implies its role in bacterium-associated intestinal inflammation. Although microRNA (miRNA)-mediated gene regulation has been found to be involved in various processes of inflammatory bowel disease (IBD), the biological function of miRNAs in the pathogenesis of IBD remains to be explored. In this study we detected miRNA expression patterns in colon tissues during colitis and investigated the mechanism underlying the regulation of colonic PepT1 by miRNAs. We observed an inverse correlation between PepT1 and miR-193a-3p in inflamed colon tissues with active ulcerative colitis, and we further demonstrated that miR-193a-3p reduced PepT1 expression and activity as a target gene and subsequently suppressed the NF kappaB pathway. Intracolonic delivery of miR-193a-3p significantly ameliorated dextran sodium sulfate-induced colitis, whereas the overexpression of colonic PepT1 via PepT1 3'-untranslated region mutant lentivirus vector abolished the anti-inflammatory effect of miR-193a-3p. Furthermore, antibiotic treatment eliminated the difference in the dextran sodium sulfate-induced inflammation between the presence and absence of miR-193a-3p. These findings suggest that miR 193a-3p regulation of PepT1 mediates the uptake of bacterial products and is a potent mechanism during the colonic inflammation process. Overall, we believe miR 193a-3p may be a potent regulator of colonic PepT1 for maintaining intestinal homeostasis. PMID- 25931123 TI - 2-O-Sulfated Domains in Syndecan-1 Heparan Sulfate Inhibit Neutrophil Cathelicidin and Promote Staphylococcus aureus Corneal Infection. AB - Ablation of syndecan-1 in mice is a gain of function mutation that enables mice to significantly resist infection by several bacterial pathogens. Syndecan-1 shedding is induced by bacterial virulence factors, and inhibition of shedding attenuates bacterial virulence, whereas administration of purified syndecan-1 ectodomain enhances virulence, suggesting that bacteria subvert syndecan-1 ectodomains released by shedding for their pathogenesis. However, the pro pathogenic functions of syndecan-1 ectodomain have yet to be clearly defined. Here, we examined how syndecan-1 ectodomain enhances Staphylococcus aureus virulence in injured mouse corneas. We found that syndecan-1 ectodomain promotes S. aureus corneal infection in an HS-dependent manner. Surprisingly, we found that this pro-pathogenic activity is dependent on 2-O-sulfated domains in HS, indicating that the effects of syndecan-1 ectodomain are structure-based. Our results also showed that purified syndecan-1 ectodomain and heparan compounds containing 2-O-sulfate motifs inhibit S. aureus killing by antimicrobial factors secreted by degranulated neutrophils, but does not affect intracellular phagocytic killing by neutrophils. Immunodepletion of antimicrobial factors with staphylocidal activities demonstrated that CRAMP, a cationic antimicrobial peptide, is primarily responsible for S. aureus killing among other factors secreted by degranulated neutrophils. Furthermore, we found that purified syndecan-1 ectodomain and heparan compounds containing 2-O-sulfate units potently and specifically inhibit S. aureus killing by synthetic CRAMP. These results provide compelling evidence that a specific subclass of sulfate groups, and not the overall charge of HS, permits syndecan-1 ectodomains to promote S. aureus corneal infection by inhibiting a key arm of neutrophil host defense. PMID- 25931124 TI - Apelin Enhances Brown Adipogenesis and Browning of White Adipocytes. AB - Brown adipose tissue expends energy in the form of heat via the mitochondrial uncoupling protein UCP1. Recent studies showed that brown adipose tissue is present in adult humans and may be exploited for its anti-obesity and anti diabetes actions. Apelin is an adipocyte-derived hormone that plays important roles in energy metabolism. Here, we report that apelin-APJ signaling promotes brown adipocyte differentiation by increasing the expressions of brown adipogenic and thermogenic transcriptional factors via the PI3K/Akt and AMPK signaling pathways. It is also found that apelin relieves the TNFalpha inhibition on brown adipogenesis. In addition, apelin increases the basal activity of brown adipocytes, as evidenced by the increased PGC1alpha and UCP1 expressions, mitochondrial biogenesis, and oxygen consumption. Finally, we provide both in vitro and in vivo evidence that apelin is able to increase the brown-like characteristics in white adipocytes. This study, for the first time, reveals the brown adipogenic and browning effects of apelin and suggests a potential therapeutic route to combat obesity and related metabolic disorders. PMID- 25931125 TI - Granulocyte/Macrophage Colony-stimulating Factor-dependent Dendritic Cells Restrain Lean Adipose Tissue Expansion. AB - The physiological roles of macrophages and dendritic cells (DCs) in lean white adipose tissue homeostasis have received little attention. Because DCs are generated from bone marrow progenitors in the presence of granulocyte/macrophage colony-stimulating factor (GM-CSF), we used GM-CSF-deficient (Csf2(-/-)) mice fed a low fat diet to test the hypothesis that adipose tissue DCs regulate the development of adipose tissue. At 4 weeks of age, Csf2(-/-) mice had 75% fewer CD45(+)Cd11b(+)Cd11c(+)MHCII(+) F4/80(-) DCs in white adipose tissue than did wild-type controls. Furthermore, the Csf2(-/-) mice showed a 30% increase in whole body adiposity, which persisted to adulthood. Adipocytes from Csf2(-/-) mice were 50% larger by volume and contained higher levels of adipogenesis gene transcripts, indicating enhanced adipocyte differentiation. In contrast, adipogenesis/adipocyte lipid accumulation was inhibited when preadipocytes were co-cultured with CD45(+)Cd11b(+)Cd11c(+)MHCII(+)F4/80(-) DCs. Medium conditioned by DCs, but not by macrophages, also inhibited adipocyte lipid accumulation. Proteomic analysis revealed that matrix metalloproteinase 12 and fibronectin 1 were greatly enriched in the medium conditioned by DCs compared with that conditioned by macrophages. Silencing fibronectin or genetic deletion of matrix metalloproteinase 12 in DCs partially reversed the inhibition of adipocyte lipid accumulation. Our observations indicate that DCs residing in adipose tissue play a critical role in suppressing normal adipose tissue expansion. PMID- 25931126 TI - Reconstitution of Formylglycine-generating Enzyme with Copper(II) for Aldehyde Tag Conversion. AB - To further our aim of synthesizing aldehyde-tagged proteins for research and biotechnology applications, we developed methods for recombinant production of aerobic formylglycine-generating enzyme (FGE) in good yield. We then optimized the FGE biocatalytic reaction conditions for conversion of cysteine to formylglycine in aldehyde tags on intact monoclonal antibodies. During the development of these conditions, we discovered that pretreating FGE with copper(II) is required for high turnover rates and yields. After further investigation, we confirmed that both aerobic prokaryotic (Streptomyces coelicolor) and eukaryotic (Homo sapiens) FGEs contain a copper cofactor. The complete kinetic parameters for both forms of FGE are described, along with a proposed mechanism for FGE catalysis that accounts for the copper-dependent activity. PMID- 25931127 TI - Human CHAC1 Protein Degrades Glutathione, and mRNA Induction Is Regulated by the Transcription Factors ATF4 and ATF3 and a Bipartite ATF/CRE Regulatory Element. AB - Using an unbiased systems genetics approach, we previously predicted a role for CHAC1 in the endoplasmic reticulum stress pathway, linked functionally to activating transcription factor 4 (ATF4) following treatment with oxidized phospholipids, a model for atherosclerosis. Mouse and yeast CHAC1 homologs have been shown to degrade glutathione in yeast and a cell-free system. In this report, we further defined the ATF4-CHAC1 interaction by cloning the human CHAC1 promoter upstream of a luciferase reporter system for in vitro assays in HEK293 and U2OS cells. Mutation and deletion analyses defined two major cis DNA elements necessary and sufficient for CHAC1 promoter-driven luciferase transcription under conditions of ER stress or ATF4 coexpression: the -267 ATF/cAMP response element (CRE) site and a novel -248 ATF/CRE modifier (ACM) element. We also examined the ability of the CHAC1 ATF/CRE and ACM sequences to bind ATF4 and ATF3 using immunoblot-EMSA and confirmed ATF4, ATF3, and CCAAT/enhancer-binding protein beta binding at the human CHAC1 promoter in the proximity of the ATF/CRE and ACM using ChIP. To further validate the function of CHAC1 in a human cell model, we measured glutathione levels in HEK293 cells with enhanced CHAC1 expression. Overexpression of CHAC1 led to a robust depletion of glutathione, which was alleviated in a CHAC1 catalytic mutant. These results suggest an important role for CHAC1 in oxidative stress and apoptosis with implications for human health and disease. PMID- 25931128 TI - Lower extremity rotational deformities and patellofemoral alignment parameters in patients with anterior knee pain. AB - PURPOSE: Anterior knee pain is a common musculoskeletal condition amongst young adult population. Lower extremity structural factors, such as increased femoral anteversion and lateral tibial torsion, may contribute to patellofemoral malalignment and anterior knee pain. The aim of this study was to evaluate the lower extremity structural factors and related patellofemoral alignment parameters that play a role in the aetiology of anterior knee pain. METHODS: This study involved three groups: patients with unilateral symptomatic knees (n = 35), asymptomatic contralateral knees in the same patients and a control group (n = 40). All subjects were physically examined, and Q-angles were measured. The lower extremities of all subjects were imaged by a very low-dose CT scan, and the symptomatic knees of patients were compared with their asymptomatic contralateral knees and with the healthy knees of controls regarding femoral anteversion, tibial torsion, sulcus angle, patellar tilt angle and lateral patellar displacement. RESULTS: Regarding the Q-angle, femoral anteversion and lateral tibial torsion, no significant differences were found between the symptomatic and asymptomatic knees, whereas significant differences were found between the symptomatic knees and controls. The symptomatic group demonstrated significantly greater sulcus angle only in 30 degrees of knee flexion than did the controls. CONCLUSION: Patients with unilateral anterior knee pain may have similar morphology at their contralateral asymptomatic lower extremity, and different morphology compared with healthy controls. Lower extremity rotational deformities may increase the risk of anterior knee pain; however, these deformities alone are not sufficient to cause knee pain, and may be predisposing factor rather than a direct aetiology. LEVEL OF EVIDENCE: Diagnostic study, Level III. PMID- 25931129 TI - Effects of boric acid on the healing of Achilles tendons of rats. AB - PURPOSE: Tendinous lesions are among the most frequent pathologies encountered in sportsmen. The objectives of new treatments are to improve the healing process and reduce the recovery time. Boron plays an important role in the wound repair process by increasing components of extracellular matrix and angiogenesis. This animal study aimed to investigate the effect of boric acid on healing of the Achilles tendon. METHODS: The right Achilles tendons of 40 rats were completely sectioned, and the rats were randomly divided into five groups. Each group consisted of eight rats. Groups 1 and 2 were oral boric acid groups with the doses of 4 and 8 mg/kg/day boric acid, respectively. Group 3 was the local boric acid group (8 mg/kg boric acid intratendinous injection). Group 4 was administered both oral and local boric acid (8 mg/kg/day orally and 8 mg/kg boric acid intratendinous injection), and group 5 was the control group with no boric acid application. At the end of the fourth week, all the rats were killed and histopathological examination of the Achilles tendon repair site was made. RESULTS: Histopathological examination of the tissue sections revealed more properly oriented collagen fibres, more normal cellular distribution of tenocytes and more properly organized vascular bundles in group 1 and group 2, which were the groups administered oral boric acid. Pathological sum scores of groups 1 and 2 were less than those of the other groups, and the differences between the oral boric acid groups (group 1 and group 2) and the other three groups (groups 3, 4 and 5) were statistically significant (p = 0.001). CONCLUSION: As boric acid is safe and toxicity even after very high doses is unusual, oral boric acid may be used as an agent to improve the healing process of tendon injuries. However, biomechanical tests should also be performed to show the effect of boric acid on strength and endurance of the tendon before it can be used in clinical practice. PMID- 25931130 TI - Indirect payments: when the Mental Capacity Act interacts with the personalisation agenda. AB - This paper reports findings from a study that aimed to explore how practitioners were bringing together the demands of the personalisation agenda, in particular the offer of direct payments (DPs), with the Mental Capacity Act, and to investigate current practices of offering and administering indirect payments for people who lack capacity to consent to them, including the use of 'suitable person' proxies under the new regulations (DH, 2009). The study adopted a qualitative interview-based design; participants were social work practitioners (67) and recipients of 'indirect' payments (18) in six local authorities in England in 2011-2012. The paper reports on five key decision-making points in the indirect payments process: the decision to take on an indirect payment, the assessment of mental capacity, the identification of a suitable person, the establishment of the care recipient's best interests and the decisions about how to execute the indirect payment. We found that practitioners and suitable people had different experiences of the system, although in both cases, there was overarching support for the benefits of enabling people who lack capacity to consent to a DP to receive their social care funding in the form of an 'indirect' payment via a proxy suitable person. PMID- 25931132 TI - The first case of actinide triple helices: pH-dependent structural evolution and kinetically-controlled transformation of two supramolecular conformational isomers. AB - The first actinide triple helices, including two supramolecular conformational isomers of uranium(VI), have been synthesized with the aid of a flexible V-shaped ligand and a rigid aromatic base. The isomers exhibit an intriguing pH-dependent structural evolution and a kinetically-controlled transformation via a novel conformational rearrangement of the organic base. PMID- 25931131 TI - Staphylococcus aureus nasal carriage among healthcare workers in Kisangani, the Democratic Republic of the Congo. AB - Methicillin-resistant Staphylococcus aureus (MRSA) is a global health concern, but there are few data from Central Africa. The objective of our study was to characterise S. aureus colonisation isolates from healthcare-exposed professionals in the Democratic Republic of the Congo (DRC). Healthcare workers and medical students (n = 380) in Kisangani, DRC were screened for S. aureus nasal carriage in a single-centre cross-sectional study in the University Hospital of Kisangani. The isolates were identified and characterised using phenotypic and genotypic methods. The nasal carriage rate of S. aureus was 16.6 % and 10 out of 63 isolates (15.9 %) were MRSA. We found 28 different spa types. Most MRSA isolates belonged to ST8-spa t1476-SCCmec V. The majority of MRSA were multidrug-resistant to non-beta-lactam antibiotics. Overall, 28.5 % of S. aureus carried Panton-Valentine leucocidin (PVL)-encoding genes (all methicillin sensitive) and 17.5 % carried toxic shock syndrome toxin-1 (TSST-1)-encoding genes. The finding of MRSA carriage among healthcare workers in a setting with limited access to diagnostic microbiology and appropriate therapy calls for improved education on infection control practices and supports the introduction of surveillance programmes. PMID- 25931133 TI - The two domains of Mycobacterium tuberculosis NusG protein are dynamically independent. AB - Transcription elongation factor NusG from Escherichia coli couples transcription and translation. It is the only conserved transcription factor in all three kingdoms of life, playing a variety of roles in gene expression. E. coli NusG consists of two non-interacting domains. While the N-terminal domain interacts with RNA polymerase, the C-terminal domain contacts NusE (S10), or the Rho transcription termination factor. The two corresponding domains of Thermotoga maritima NusG are mutually interacting. Therefore, NusG here forms an autoinhibited state, where the binding sites to RNAP, NusE, and the Rho factor are masked. Recent functional studies showed differences between NusG from E. coli and Mycobacterium tuberculosis. In contrast to E. coli NusG, M. tuberculosis NusG is able to stimulate intrinsic termination, but is not able to bind the Rho factor. To analyze whether this has structural reasons, we determined the solution structure of the carboxyterminal domain of M. tuberculosis NusG by nuclear magnetic resonance spectroscopy. Furthermore, we modeled the wild-type full-length protein, and present evidence that the two domains of this protein do not interact in solution by NMR dynamics measurements. PMID- 25931135 TI - Physicians' exodus: why medical graduates leave Austria or do not work in clinical practice. AB - BACKGROUND: Austria has the highest number of medical graduates of all Organisation for Economic Co-operation and Development (OECD) countries in relation to its population size, but over 30% choose not to pursue a career as physicians in the country. OBJECTIVE AND RESEARCH DESIGN: This article describes under- and postgraduate medical education in Austria and analyses reasons for the exodus of physicians. MEDICAL EDUCATION: In Austria, medicine is a 5- or 6-year degree offered at four public and two private medical schools. Medical graduates have to complete training in general medicine or a speciality to attain a licence to practice. While not compulsory for speciality training, board certification in general medicine has often been regarded as a prerequisite for access to speciality training posts. ANALYSIS: Unstructured postgraduate training curricula, large amounts of administrative tasks, low basic salaries and long working hours present for incentives for medical graduates to move abroad or to work in a non-clinical setting. The scope of current reforms, such as the establishment of a new medical faculty and the implementation of a common trunk, is possibly insufficient in addressing the issue. CONCLUSION: Extensive reforms regarding occupational conditions and the structure of postgraduate medical education are necessary to avoid a further exodus of junior doctors. PMID- 25931136 TI - Sc-47 production from titanium targets using electron linacs. AB - In this work we have studied the feasibility of photonuclear production of (47)Sc from (48)Ti via (48)Ti(gamma,p)(47)Sc reaction. Photon flux distribution for electron beams of different energies incident on tungsten converter was calculated using MCNPX radiation transport code. (47)Sc production rate dependence on electron beam energy was found and (47)Sc yields were estimated. It was shown that irradiating a natural Ti target results in numerous scandium isotopes which can reduce the specific activity of (47)Sc. Irradiating enriched (48)Ti targets with a 22MeV 1mA beam will result in hundreds of MBq/g activity of (47)Sc and no other isotopes of scandium. Decreasing the size of the target will result in much higher average photon flux through the target and tens of GBq/g levels of specific activity of (47)Sc. Increasing the beam energy will also result in higher yields, but as soon as the electron energy exceeds the (48)Ti(gamma,np)(46)Sc reaction threshold, (46)Sc starts being produced and its fraction in total scandium atoms grows as beam energy increases. The results of the simulations were benchmarked by irradiating natural titanium foil with 22MeV electron beam incident on the tungsten converter. Measured (47)Sc activities were found to be in very good agreement with the predictions. PMID- 25931137 TI - A practical process for the preparation of [(32)P]S1P and binding assay for S1P receptor ligands. AB - Sphingosine-1-phosphate receptors (S1PRs) are important regulators of vascular permeability, inflammation, angiogenesis and vascular maturation. Identifying a specific S1PR PET radioligand is imperative, but it is hindered by the complexity and variability of current for binding affinity measurement procedures. Herein, we report a streamlined protocol for radiosynthesis of [(32)P]S1P with good radiochemical yield (36-50%) and high radiochemical purity (>99%). We also report a reproducible procedure for determining the binding affinity for compounds targeting S1PRs in vitro. PMID- 25931138 TI - Effect of Nozzle Geometry on Characteristics of Submerged Gas Jet and Bubble Noise. AB - Submerged exhaust noise is one of the main noise sources of underwater vehicles. The nozzle features of pipe discharging systems have a great influence on exhaust noise, especially on the noise produced by gas-liquid two-phase flow outside the nozzle. To study the influence of nozzle geometry on underwater jet noises, a theoretical study was performed on the critical weber number at which the jet flow field morphology changes. The underwater jet noise experiments of different nozzles under various working conditions were carried out. The experimental results implied that the critical weber number at which the jet flow transformed from bubbling regime to jetting regime was basically identical with the theoretical analysis. In the condition of jetting regime, the generated cavity of elliptical and triangular nozzles was smaller than that of the circular nozzle, and the middle- and high-frequency bands increased nonlinearly. The radiated noise decreased with the decrease in nozzle diameter. Combined with theoretical analysis and experimental research, three different submerged exhaust noise reduction devices were designed, and the validation tests proved that the noise reduction device with folds and diversion cone was the most effective. PMID- 25931139 TI - Small-molecule compounds exhibiting target-mediated drug disposition - A case example of ABT-384. AB - Nonlinearities are frequently encountered in pharmacokinetics, and they can occur when 1 or more processes of absorption, distribution, metabolism, and excretion are saturable. One special source of nonlinearity that has been noticed recently is the saturable binding of the drug to a high-affinity-low-capacity target, a phenomenon known as target-mediated drug disposition (TMDD). Although TMDD can occur in both small-molecule compounds and large-molecule compounds, the latter has received much more attention because of its high prevalence. With the development of more potent small-molecule drugs acting on highly specific targets and the availability of increasingly sensitive analytical techniques, small molecule compounds exhibiting TMDD have been increasingly reported in the past several years. ABT-384 is a small-molecule drug candidate that exhibited significant nonlinear pharmacokinetics, potentially imparted by TMDD, in a first in-human clinical trial conducted in healthy volunteers. Compared with published small-molecule compounds exhibiting TMDD, ABT-384 pharmacokinetic characteristics are more consistent with TMDD. To expand current knowledge of TMDD of small molecule compounds and increase awareness of this interesting and clinically important phenomenon, in this review the general features of small-molecule compounds exhibiting TMDD are highlighted, with ABT-384 provided as an example. PMID- 25931140 TI - Contribution of longitudinal follow up and clinical pathological correlation in the diagnosis CD30-positive skin infiltrates. AB - The diagnosis of a CD30+ cutaneous infiltrate is often difficult and requires clinicopathologic correlation. To further evaluate this challenge, initial clinical and histopathologic diagnoses were correlated with final clinicopathologic diagnosis in 44 cases with CD30 immunopositivity. Dermatopathologic evaluation confirmed the initial clinical diagnosis in 65% of the suspected benign cases, all cases of suspected lymphomatoid papulosis (LyP), and 72% of clinically malignant cases. In the 25 patients with clinical suspicion for lymphoma, the histopathologic diagnoses included lymphoma in 18, LyP in 2, CD30+ lymphoproliferative disorder (CD30 LPD) in 3 and hypersensitivity reaction in 2 patients. Clinicopathologic correlation led to a change in three cases diagnosed histopathologically as anaplastic large cell lymphoma (ALCL) reclassified as LyP type C, and one patient diagnosed as CD30 LPD clinically evolved as herpes virus infection. Furthermore, five cases reported as CD30 LPD received more specific diagnoses after clinicopathologic correlation (LyP type C in three, and ALCL in two patients). Clinicopathologic correlation is essential in establishing the correct diagnosis of CD30 LPD, in particular the distinction of ALCL from LyP type C. In this setting, the histopathologic diagnosis of CD30 LPD is advisable in the absence of clinical data. PMID- 25931141 TI - Similar efficacy and safety of LY2963016 insulin glargine and insulin glargine (Lantus(r)) in patients with type 2 diabetes who were insulin-naive or previously treated with insulin glargine: a randomized, double-blind controlled trial (the ELEMENT 2 study). AB - AIMS: To compare the efficacy and safety of LY2963016 insulin glargine (LY IGlar) and the reference product (Lantus((r))) insulin glargine (IGlar) in combination with oral antihyperglycaemic medications in patients with type 2 diabetes (T2D). METHODS: This phase III, randomized, double-blind, 24-week study enrolled patients with T2D who were insulin-naive [glycated haemoglobin (HbA1c) >=7 and <=11.0%] or previously on IGlar (HbA1c <=11%) and treated with >=2 oral antihyperglycaemic medications. Patients were randomized to receive once-daily LY IGlar (n = 376) or IGlar (n = 380) for 24 weeks. The primary efficacy outcome was to test the non-inferiority (0.4% and then 0.3% margin) of LY IGlar to IGlar, as measured by change in HbA1c from baseline to 24 weeks. RESULTS: Both treatment groups had similar and significant (p < 0.001) within-group decreases in mean HbA1c values from baseline. LY IGlar met non-inferiority criteria compared with IGlar for change in HbA1c from baseline [-1.29 vs -1.34%; respectively, least squares mean difference 0.052% (95% confidence interval -0.070 to 0.175); p > 0.05]. There were no treatment differences (p > 0.05) in fasting plasma glucose, proportion of patients reaching HbA1c <7% or insulin dose at 24 weeks. Adverse events, allergic reactions, weight change, hypoglycaemia and insulin antibodies were similar between treatment groups. Similar findings were observed in patients who were insulin-naive or previously treated with IGlar at baseline. CONCLUSIONS: Both LY IGlar and IGlar, when used in combination with oral antihyperglycaemic medications, provided effective and similar glucose control with similar safety profiles in patients with T2D. PMID- 25931142 TI - Formation of functionalized nanoclusters by solvent evaporation and their effect on the physicochemical properties of dental composite resins. AB - OBJECTIVE: The aim of this work was to study the effect of silica nanoclusters (SiNC), obtained by a solvent evaporation method and functionalized by 3 methacryloxypropyltrimethoxysilane (MPS) and MPS+octyltrimethoxysilane (OTMS) (50/50wt/wt), on the rheological, mechanical and sorption properties of urethane dimethylacrylate (UDMA)/triethylenglycol dimethacrylate (TEGDMA) (80/20wt/wt) resins blend. METHODS: Silica nanoparticles (SiNP) were silanized with MPS or MPS+OTMS (50/50wt/wt) and incorporated in an UDMA-isopropanol mix to produce functionalized silica nanoclusters after evaporating the isopropanol. The effect of functionalized SiNC on resins rheological properties was determined by large and small deformation tests. Mechanical, thermal, sorption and solubility properties were evaluated for composite materials. RESULTS: The UDMA/TEGDMA (80/20wt/wt) resins blend with added SiNC (ca. 350nm) and functionalized with MPS showed a Newtonian flow behavior associated to their spheroidal shape, whereas the resins blend with nanoclusters silanized with MPS+OTMS (50/50wt/wt) (ca. 400nm) showed a shear-thinning behavior due to nanoclusters irregular shape. Composite materials prepared with bare silica nanoclusters showed lower compressive strength than functionalized silica nanoclusters. MPS functionalized nanoclusters showed better mechanical properties but higher water sorption than functionalized nanoclusters with both silane coupling agents, MPS and OTMS. SIGNIFICANCE: The solvent evaporation method applied to functionalized nanoparticles showed to be an alternative way to the sinterization method for producing nanoclusters, which improved some dental composite mechanical properties and reduced water sorption. The shape of functionalized silica nanoclusters showed to have influence on the rheological properties of SiNC resin suspensions and the mechanical and sorption properties of light cured composites. PMID- 25931143 TI - Role of defective methylation reactions in ethanol-induced dysregulation of intestinal barrier integrity. AB - Alcoholic liver disease (ALD) is a major healthcare challenge worldwide. Emerging evidence reveals that ethanol administration disrupts the intestinal epithelial tight junction (TJ) complex; this defect allows for the paracellular translocation of gut-derived pathogenic molecules to reach the liver to cause inflammation and progressive liver injury. We have previously demonstrated a causative role of impairments in liver transmethylation reactions in the pathogenesis of ALD. We have further shown that treatment with betaine, a methylation agent that normalizes liver methylation potential, can attenuate ethanol-induced liver injury. Herein, we explored whether alterations in methylation reactions play a causative role in disrupting intestinal mucosal barrier function by employing an intestinal epithelial cell line. Monolayers of Caco-2 cells were exposed to ethanol or a-pan methylation reaction inhibitor, tubercidin, in the presence and absence of betaine. The structural and functional integrity of intestinal epithelial barrier was then examined. We observed that exposure to either ethanol or tubercidin disrupted TJ integrity and function by decreasing the localization of TJ protein occludin-1 to the intracellular junctions, reducing transepithelial electrical resistance and increasing dextran influx. All these detrimental effects of ethanol and tubercidin were attenuated by co-treatment with betaine. We further show that the mechanism of betaine protection was through BHMT-mediated catalysis. Collectively, our data suggest a novel mechanism for alcohol-induced gut leakiness and identifies the importance of normal methylation reactions in maintaining TJ integrity. We also propose betaine as a potential therapeutic option for leaky gut in alcohol-consuming patients who are at the risk of developing ALD. PMID- 25931144 TI - The role of alpha5 nicotinic acetylcholine receptors in mouse models of chronic inflammatory and neuropathic pain. AB - The aim of the present study was to determine the impact of alpha5 nicotinic acetylcholine receptor (nAChR) subunit deletion in the mouse on the development and intensity of nociceptive behavior in various chronic pain models. The role of alpha5-containing nAChRs was explored in mouse models of chronic pain, including peripheral neuropathy (chronic constriction nerve injury, CCI), tonic inflammatory pain (the formalin test) and short and long-term inflammatory pain (complete Freund's adjuvant, CFA and carrageenan tests) in alpha5 knock-out (KO) and wild-type (WT) mice. The results showed that paw-licking time was decreased in the formalin test, and the hyperalgesic and allodynic responses to carrageenan and CFA injections were also reduced. In addition, paw edema in formalin-, carrageenan- or CFA-treated mice were attenuated in alpha5-KO mice significantly. Furthermore, tumor necrosis factor-alpha (TNF-alpha) levels of carrageenan treated paws were lower in alpha5-KO mice. The antinociceptive effects of nicotine and sazetidine-A but not varenicline were alpha5-dependent in the formalin test. Both hyperalgesia and allodynia observed in the CCI test were reduced in alpha5-KO mice. Nicotine reversal of mechanical allodynia in the CCI test was mediated through alpha5-nAChRs at spinal and peripheral sites. In summary, our results highlight the involvement of the alpha5 nAChR subunit in the development of hyperalgesia, allodynia and inflammation associated with chronic neuropathic and inflammatory pain models. They also suggest the importance of alpha5-nAChRs as a target for the treatment of chronic pain. PMID- 25931145 TI - JAK1/STAT3 activation directly inhibits IL-12 production in dendritic cells by preventing CDK9/P-TEFb recruitment to the p35 promoter. AB - Inhibition of Janus-activated kinase-1 (JAK1) is a promising clinical concept for post-transplant immunosuppression and autoimmunity. However, it also raises concerns regarding possible immunosuppressive side effects. Our study investigates JAK1 signalling in the context of CD40L and bacterially activated human MoDC using siRNA and biological inhibitors. We demonstrate that strong stimuli (e.g. intact Escherichia coli or LPS in addition to IL-1beta) induce IL 12p70 via a ROS/RELA/CDK9 pathway that is inhibited by simultaneous JAK1/STAT3 signalling. Transcription is effective if RELA recruits the positive transcription elongation factor b (P-TEFb) component CDK9 to a combined RELA/STAT3 binding site -50 to -20bp upstream of the start site of the IL-12p35 promoter. STAT3 simultaneously attaches to this site and inhibits CDK9 binding. In the presence of IFNgamma, JAK1/2 inhibitors block STAT1/IRF1/IRF8-dependent activation and simultaneously enhance CDK9-dependent activation signals. This inverse regulation of IFNgamma- vs. E. coli-induced cytokine production by JAK inhibitors including Ruxolitinib was similarly observed for IL-6 and TNF-alpha production, but not for IL-10 production. Thus, JAK1 inhibition enhances IL-12p70 production in this context by increased DNA binding of CDK9. In contrast, weak RELA-activation signals (CD40L, LPS) depended on IFN-gamma induced STAT1/IRF1/IRF8 co-signalling, which was completely blocked by JAK inhibitors as reported before. Our results suggest a novel molecular mechanism of how cytokine responses to invading pathogens are separable from IFNgamma-dependent autoimmunity by targeting JAK1/STAT3 activation. PMID- 25931146 TI - GCDCA down-regulates gene expression by increasing Sp1 binding to the NOS-3 promoter in an oxidative stress dependent manner. AB - During the course of cholestatic liver diseases, the toxic effect of bile acids accumulation has been related to the decreased expression of endothelial nitric oxide synthase (NOS-3) and cellular oxidative stress increase. In the present study, we have investigated the relationship between these two biological events. In the human hepatocarcinoma cell line HepG2, cytotoxic response to GCDCA was characterized by the reduced activity of the respiratory complexes II+III, the increased expression and activation of the transcription factor Sp1, and a higher binding capacity of this at positions -1386, -632 and -104 of the NOS-3 promoter (pNOS-3). This was associated with a decreased promoter activity and a consequent reduction of NOS-3 expression. The use of antioxidants in GCDCA-treated cells caused a lower activation of Sp1 and the recovery of the pNOS-3 activity and NOS 3 expression and activity. Similarly, the specific inhibition of Sp1 resulted in the improvement of NOS-3 expression. Both, antioxidant treatment and Sp1 inhibition were associated with the reduction of cell death-related parameters. Bile duct ligation in rats confirmed in vitro results concerning the activation of Sp1 and the reduction of NOS-3 expression. Our results provide direct evidence for the involvement of Sp1 in the regulation of NOS-3 expression during cholestasis. Thus, the identification of Sp1 as a potential negative regulator of NOS-3 expression represents a new mechanism by which the accumulation of bile acids causes a cytotoxic effect through the oxidative stress increase, and provides a new potential target in cholestatic liver diseases. PMID- 25931147 TI - Genetic ablation of PRAS40 improves glucose homeostasis via linking the AKT and mTOR pathways. AB - Alterations in PI3K-AKT-mTOR signaling have been implicated in diabetes. This study assessed whether disruption of PRAS40, a substrate of AKT and component of mTORC1, would alter glucose homeostasis and prevent hyperglycemia in the streptozotocin (STZ)-induced diabetes mouse model. PRAS40 ablation resulted in a mild lowering of blood glucose levels and glycated hemoglobin (HbA1C), a lowered insulin requirement, and improved glucose tolerance in untreated PRAS40 gene knockout (PRAS40(-/-)) as compared to wild-type (PRAS40(+/+)) mice. Diabetes was then induced in these mice using STZ at 50mg/kg/day over five days. Following STZ treatment, PRAS40(-/-) mice exhibited significantly lower blood glucose and HbA1C levels than PRAS40(+/+) mice. Liver tissue of PRAS40(-/-) mice and shPRAS40 Hep3B cells showed increased activation of AKT (p-AKT T308) and mTORC1 (p-p70S6K) signaling as well as decreased p-AKT (S473) and increased p-IRS1 (S612) protein levels. Altered tissue gene expression of several glucose transporters (GLUT) and increased hepatic GLUT4 protein levels were observed in PRAS40(-/-) as compared to PRAS40(+/+) mice. In summary, PRAS40 deletion significantly attenuates hyperglycemia in STZ-induced PRAS40(-/-) mice through increased hepatic AKT and mTORC1 signaling, a lowered serum insulin requirement, and altered hepatic GLUT4 levels. PMID- 25931148 TI - PKC-mediated cerebral vasoconstriction: Role of myosin light chain phosphorylation versus actin cytoskeleton reorganization. AB - Defective protein kinase C (PKC) signaling has been suggested to contribute to abnormal vascular contraction in disease conditions including hypertension and diabetes. Our previous work on agonist and pressure-induced cerebral vasoconstriction implicated PKC as a major contributor to force production in a myosin light chain (LC20) phosphorylation-independent manner. Here, we used phorbol dibutyrate to selectively induce a PKC-dependent constriction in rat middle cerebral arteries and delineate the relative contribution of different contractile mechanisms involved. Specifically, we employed an ultra-sensitive 3 step western blotting approach to detect changes in the content of phosphoproteins that regulate myosin light chain phosphatase (MLCP) activity, thin filament activation, and actin cytoskeleton reorganization. Data indicate that PKC activation evoked a greater constriction at a similar level of LC20 phosphorylation achieved by 5-HT. PDBu-evoked constriction persisted in the presence of Go6976, a selective inhibitor of Ca(2+)-dependent PKC, and in the absence of extracellular Ca(2+). Biochemical evidence indicates that either + or extracellular Ca(2+), PDBu (i) inhibits MLCP activity via the phosphorylation of myosin targeting subunit of myosin phosphatase (MYPT1) and C-kinase potentiated protein phosphatase-1 inhibitor (CPI-17), (ii) increases the phosphorylation of paxillin and heat shock protein 27 (HSP27), and reduces G-actin content, and (iii) does not change the phospho-content of the thin filament proteins, calponin and caldesmon. PDBu-induced constriction was more sensitive to disruption of actin cytoskeleton compared to inhibition of cross-bridge cycling. In conclusion, this study provided evidence for the pivotal contribution of cytoskeletal actin polymerization in force generation following PKC activation in cerebral resistance arteries. PMID- 25931149 TI - A tribute to David Triggle. AB - "A gentleman and a scholar" is how many would characterize David Triggle. His insightful, thoughtful approaches to professional pursuits, both personal research and collaborative relationships, stand out by any measure. He has shaped students, colleagues, and whole fields, calcium ion channels and ligands being most representative of the latter. In recent years, he has expanded his contributions to important commentaries on politics and social challenges in the sciences. David is the rare intellect able to do all this and more, as outlined herein. PMID- 25931150 TI - Short-term patient-centered nutrition counseling impacts weight and nutrient intake in patients with systemic lupus erythematosus. AB - BACKGROUND: Patients with systemic lupus erythematosus (SLE) are at a high risk for cardiovascular disease (CVD) due to increased prevalence of traditional and nontraditional CVD risks factors. OBJECTIVE: To evaluate the effect of patient centered nutrition counseling methods on changes in select nutrient, anthropometric, and clinical outcomes in SLE patients enrolled in a CVD prevention counseling program (CVD PCP). METHODS: From March 2009 to June 2011 a subgroup of SLE patients enrolled in our CVD PCP were referred to a registered dietitian for individualized nutrition counseling. Outcomes of interest were assessed at baseline and six months. A primary analysis evaluated the six-month changes in nutrient intake, weight, body mass index (BMI), waist circumference, and lipid levels. A secondary analysis compared the same measurements between the nutrition counseling patients and the group that was referred but did not attend. RESULTS: Of 71 referrals, 41 (58%) attended nutrition counseling (female: 89%, African American/Hispanic: 72%, mean age of 39.7 +/- 12.82 years, and a mean disease duration of 11.49 +/- 8.02 years). Over a six-month period, patients attending nutritional counseling: (a) reduced their intake of sodium (p = 0.006), total calories (p = 0.07), and percent calories from fat (p = 0.011) and saturated fat (p = 0.068); (b) had decreased weight (-1.64 kg, p = 0.025); and (c) were more likely to report increases in eating a diet rich in fruits and vegetables (p < 0.001), a high fiber diet (p = 0.011), >=two servings of fish/week (p = 0.002), and a low cholesterol diet (p = 0.034). There were no significant changes observed over the six months in BMI and clinical outcomes among nutrition counseling patients. When comparing nutrition counseling patients to those who were referred but did not attend, we found at six months a higher percentage of nutrition counseling patients reportedly followed a high-fiber diet (p = 0.03), consumed two or more servings of fish per week (p = 0.01), followed a low-cholesterol diet (p = 0.03), and achieved a greater weight loss (p = 0.04) compared to the group that did not attend. CONCLUSION: At six months we found that nutrition counseling using patient-centered methods appears to be an effective method for promoting changes in nutrient intake, diet habits, and, possibly, anthropometric measures in SLE patients. However, the counseling did not show a significant improvement in lipid levels, possibly due to short follow up and/or SLE related factors. PMID- 25931151 TI - Stimulus conflict triggers behavioral avoidance. AB - According to a recent extension of the conflict-monitoring theory, conflict between two competing response tendencies is registered as an aversive event and triggers a motivation to avoid the source of conflict. In the present study, we tested this assumption. Over five experiments, we examined whether conflict is associated with an avoidance motivation and whether stimulus conflict or response conflict triggers an avoidance tendency. Participants first performed a color Stroop task. In a subsequent motivation test, participants responded to Stroop stimuli with approach- and avoidance-related lever movements. These results showed that Stroop-conflict stimuli increased the frequency of avoidance responses in a free-choice motivation test, and also increased the speed of avoidance relative to approach responses in a forced-choice test. High and low proportions of response conflict in the Stroop task had no effect on avoidance in the motivation test. Avoidance of conflict was, however, obtained even with new conflict stimuli that had not been presented before in a Stroop task, and when the Stroop task was replaced with an unrelated filler task. Taken together, these results suggest that stimulus conflict is sufficient to trigger avoidance. PMID- 25931152 TI - Does low bone density influence symptoms and functional status in patients with fibromyalgia? Observations from rural South India. AB - INTRODUCTION: The presence of more than one musculoskeletal disease has been found to impair quality of life (QoL). The influence of low bone mineral density (BMD) on symptoms and function in those with fibromyalgia syndrome (FMS) is unknown. METHODOLOGY: A cross sectional study was carried out on 158 patients attending camps in rural South India. BMD was determined using quantitative ultrasound of the distal radius. Symptoms and function were assessed using a visual analogue scale (VAS) and the Fibromyalgia Impact Questionnaire (FIQ). RESULTS: Low BMD was seen in 81.6% (129/158) of the persons screened. FMS was seen in 37/158 persons, of which 31/37 (83.7%) had low BMD. CONCLUSION: FMS with low bone density leads to higher levels of pain and a poorer QoL compared to those without FMS. Coexisting musculoskeletal problems could also contribute to this. Therefore, medical practitioners and rehabilitation specialists should consider screening for bone density among those with FMS and should use this information to decide appropriate therapies to reduce pain and improve QoL. PMID- 25931153 TI - The effect of range changes on the functional turnover, structure and diversity of bird assemblages under future climate scenarios. AB - Animal assemblages fulfill a critical set of ecological functions for ecosystems that may be altered substantially as climate change-induced distribution changes lead to community disaggregation and reassembly. We combine species and community perspectives to assess the consequences of projected geographic range changes for the diverse functional attributes of avian assemblages worldwide. Assemblage functional structure is projected to change highly unevenly across space. These differences arise from both changes in the number of species and changes in species' relative local functional redundancy or distinctness. They sometimes result in substantial losses of functional diversity that could have severe consequences for ecosystem health. Range expansions may counter functional losses in high-latitude regions, but offer little compensation in many tropical and subtropical biomes. Future management of local community function and ecosystem services thus relies on understanding the global dynamics of species distributions and multiscale approaches that include the biogeographic context of species traits. PMID- 25931154 TI - Keeping workers safe: does provision of personal protective equipment match supervisor risk perceptions? AB - BACKGROUND: Although farm management may understand agriculture's risks, they may not provide personal protective equipment (PPE). This study describes thoroughbred farm management's risk perceptions, provision of PPE, and factors that influence its provision. METHODS: Thirty-five representatives from 26 farms participated in a 1-4hr semi-structured interview covering perceived risks associated with horse work and perspectives and provision of PPE. Interviews were audio-recorded, transcribed, entered into ATLAS.ti, and analyzed by three coders. RESULTS: Management cited horse-related tasks as most dangerous, yet horse related PPE as least provided because of 1) differences in farm context, 2) the belief that workers were most important agents in their safety, 3) lack of confidence in its effectiveness, and 4) the perception that risk could never be eliminated. CONCLUSIONS: PPE provision was limited by management's poor perceptions of its efficacy relative to other factors. Future research should explore workers' perceptions and PPE's effectiveness in averting horse-related injury. PMID- 25931156 TI - Why did Alfred Blalock and Helen Taussig not receive the nobel prize? AB - BACKGROUND: From the 1940s to the 1960s, the number of cardiac surgeons nominated for the Nobel Prize for Physiology or Medicine grew rapidly. These nominations pinpoint major developments ranging from the first closed extracardiac operations to the era of complete intracardiac repair and treatment of congenital heart diseases. The aim of this article is to present the motivations for the numerous Nobel Prize nominations for the cardiac surgeon Alfred Blalock and the pediatric cardiologist Helen B. Taussig, and to show why the Nobel committee finally chose not to award them for the development of the Blalock-Taussig shunt. METHODS: The authors have gathered and analyzed files on Blalock and Taussig from the Nobel Prize archive for Physiology and Medicine in Solna, Sweden. RESULTS AND CONCLUSIONS: More than forty scholars, primarily from the United States and Europe, nominated Blalock and Taussig for the Nobel Prize for Physiology or Medicine. Such a strong transatlantic support is rare for nominated surgeons. The authors discuss why the number of Nobel Prize nominations for cardiac surgeons in general reached a climax around the 1950s and formulate open research questions on why relatively few surgeons have received the prestigious prize for the development of surgical procedures. PMID- 25931155 TI - Proteomic analysis of cellular soluble proteins from human bronchial smooth muscle cells by combining nondenaturing micro 2DE and quantitative LC-MS/MS. 1. Preparation of more than 4000 native protein maps. AB - Soluble proteins of human bronchial smooth muscle cells (HBSMC) were separated by nondenaturing micro 2DE and a 30 mm * 40 mm area of the CBB-stained slab gel (1.0 mm thick) was cut into 1.1 mm * 1.1 mm squares, then the proteins in the 972 gel pieces (squares) were applied to quantitative LC-MS/MS. Grid-cutting of the gel was employed to; (i) ensure the total analysis of the proteins in the area, (ii) standardize the conditions of analysis by LC-MS/MS, (iii) reconstruct the protein distribution patterns from the quantity data [1]. Totally 4323 proteins were identified in successfully analyzed 967 squares and the quantity distribution of each was reconstructed as a color density pattern (a native protein map). The quantity of the proteins distributed from 3.6% to 1 * 10(-5) % of the total protein quantity in the grid area. Each protein map was characterized by several features, including the position of quantity peak square, number of detected squares, and degree of concentration (focused or dispersed). About 4% of the proteins were detected in 100 or more squares, suggesting that they might be ubiquitous and interacting with other proteins. In contrast, many proteins showed more concentrated quantity distribution and the quantity peak positions of 565 proteins with a defined degree of concentration were summarized into a quantity peak map. These results for the first time visualized the distribution patterns of cellular proteins on a nondenaturing 2D gel. PMID- 25931157 TI - Development of a low-density-solvent dispersive liquid-liquid microextraction with gas chromatography and mass spectrometry method for the quantitation of tetrabromobisphenol-A from dust. AB - The development of an alternative dispersive liquid-liquid microextraction protocol utilizing a low-density extraction solvent, toluene, is described here for the extraction of the brominated flame retardant, tetrabromobisphenol-A, from dust prior to selected ion monitoring analysis by gas chromatography with mass spectrometry. Method parameters of dispersive solvent type and extraction solvent type were optimized. Excellent recovery (88.9%; n = 5 spike replicates) with good precision was achieved in a spike and recovery study. This developed method was utilized to survey tetrabromobisphenol-A concentrations in dust sampled from a local electronics recycling facility from the ambient environment and 20 computer towers undergoing recycling. Concentrations of tetrabromobisphenol-A from dust in computer towers ranged from not detected (n = 2) up to 64 MUg/g with a mean value of 11 MUg/g and median of 4.1 MUg/g tetrabromobisphenol-A. A composite sample of dust collected from the ambient indoor environment was analyzed with a resulting concentration of 36 MUg/g. This is the first application of this novel green method for pre-concentrating flame retardants from dust and the first report of tetrabromobisphenol-A concentrations at a U.S.-based electronics recycling facility. PMID- 25931158 TI - Mortality risk prediction in burn injury: Comparison of logistic regression with machine learning approaches. AB - INTRODUCTION: Predicting mortality from burn injury has traditionally employed logistic regression models. Alternative machine learning methods have been introduced in some areas of clinical prediction as the necessary software and computational facilities have become accessible. Here we compare logistic regression and machine learning predictions of mortality from burn. METHODS: An established logistic mortality model was compared to machine learning methods (artificial neural network, support vector machine, random forests and naive Bayes) using a population-based (England & Wales) case-cohort registry. Predictive evaluation used: area under the receiver operating characteristic curve; sensitivity; specificity; positive predictive value and Youden's index. RESULTS: All methods had comparable discriminatory abilities, similar sensitivities, specificities and positive predictive values. Although some machine learning methods performed marginally better than logistic regression the differences were seldom statistically significant and clinically insubstantial. Random forests were marginally better for high positive predictive value and reasonable sensitivity. Neural networks yielded slightly better prediction overall. Logistic regression gives an optimal mix of performance and interpretability. DISCUSSION: The established logistic regression model of burn mortality performs well against more complex alternatives. Clinical prediction with a small set of strong, stable, independent predictors is unlikely to gain much from machine learning outside specialist research contexts. PMID- 25931159 TI - Response to the Comment on "Bariatric Surgery can Lead to Net Cost Savings to Health Care Systems: Results from a Comprehensive European Decision Analytic Model". PMID- 25931160 TI - The cyclical nature of depressed mood and future risk: Depression, rumination, and deficits in emotional clarity in adolescent girls. AB - Deficits in emotional clarity, the understanding and awareness of one's own emotions and the ability to label them appropriately, are associated with increased depressive symptoms. Surprisingly, few studies have examined factors associated with reduction in emotional clarity for adolescents, such as depressed mood and ruminative response styles. The present study examined rumination as a potential mediator of the relationship between depressive symptoms and changes in emotional clarity, focusing on sex differences. Participants included 223 adolescents (51.60% female, Mean age = 12.39). Controlling for baseline levels of emotional clarity, initial depressive symptoms predicted decreases in emotional clarity. Further, rumination prospectively mediated the relationship between baseline depressive symptoms and follow-up emotional clarity for girls, but not boys. Findings suggest that depressive symptoms may increase girls' tendencies to engage in repetitive, negative thinking, which may reduce the ability to understand and label emotions, a potentially cyclical process that confers vulnerability to future depression. PMID- 25931161 TI - Anti-Apoptotic Effects of Dapsone After Spinal Cord Injury in Rats. AB - Spinal cord injury (SCI) is a condition producing irreversible damage to the neurological function. Among the leading mechanisms associated to cell death after SCI, excitotoxicity, oxidative stress, inflammatory response and apoptosis are considered potential targets to prevent tissue damage. We recently reported that dapsone an anti-inflammatory drug, decreases the activity of myeloperoxidase, lipid peroxidation, improve neurological function and increase the amount of spared tissue after SCI in rats. In this study, we characterized the anti-apoptotic effect of dapsone administered at 12.5 mg/kg/24 h dose, starting at 3 and 5 h after SCI. We monitored the activity of caspases-8, 9, and 3 and quantitated Annexin V and TUNEL positive cells in the core of the lesion. Results showed increased activities of caspase-8, 9 and 3 at 72 h by SCI to reach increments of 69, 143 and 293 %, respectively, as compared to sham group. Meanwhile, dapsone, administered at 3 and 5 after SCI, reduced caspase-8 activity by 36 and 44 % respectively, whereas the activity of caspase-9 was diminished by 37 %. Likewise, the activity of caspase-3 showed a decrease of 38 %. Finally, both Annexin V and TUNEL-positive cells were significantly reduced by DDS as compared to untreated SCI animals. Results showed that dapsone exerted anti apoptotic effect after SCI. PMID- 25931163 TI - No increase in prevalence of somatization in functional vs organic dyspepsia: a cross-sectional survey. AB - BACKGROUND: Psychological factors are associated with functional gastrointestinal (GI) disorders. Literature suggests that somatization is associated with functional dyspepsia (FD). However, the relationship between organic dyspepsia (OD), FD, and FD subtypes and somatization is poorly described. We aimed to examine this issue in a cross-sectional study of secondary care patients. METHODS: Demographic and GI symptom data were collected from 4224 adult patients via the Rome III questionnaire. Somatization data were collected using the patient health questionnaire-12. Mean somatization score and number of somatic symptoms were compared between patients with organic and FD, and between FD subtypes using analysis of variance. The same comparison was undertaken for the proportion of patients reporting individual somatic symptoms. KEY RESULTS: Exactly, 783 patients met criteria for dyspepsia, of whom 231 (29.5%) had organic disease following upper GI endoscopy. Mean somatization scores and number of somatic symptoms were no higher in functional vs OD (p = 0.23; p = 0.19). In addition, while the prevalence of somatization in FD was relatively high, there was no difference in severity of somatization in FD subgroups. CONCLUSIONS & INFERENCES: Somatization is associated with functional and OD to the same degree. Overall severity of somatization did not appear to vary according to FD subtype. PMID- 25931162 TI - Insights into Enzyme Catalysis and Thyroid Hormone Regulation of Cerebral Ketimine Reductase/MU-Crystallin Under Physiological Conditions. AB - Mammalian ketimine reductase is identical to MU-crystallin (CRYM)-a protein that is also an important thyroid hormone binding protein. This dual functionality implies a role for thyroid hormones in ketimine reductase regulation and also a reciprocal role for enzyme catalysis in thyroid hormone bioavailability. In this research we demonstrate potent sub-nanomolar inhibition of enzyme catalysis at neutral pH by the thyroid hormones L-thyroxine and 3,5,3'-triiodothyronine, whereas other thyroid hormone analogues were shown to be far weaker inhibitors. We also investigated (a) enzyme inhibition by the substrate analogues pyrrole-2 carboxylate, 4,5-dibromopyrrole-2-carboxylate and picolinate, and (b) enzyme catalysis at neutral pH of the cyclic ketimines S-(2-aminoethyl)-L-cysteine ketimine (owing to the complex nomenclature trivial names are used for the sulfur containing cyclic ketimines as per the original authors' descriptions) (AECK), Delta(1)-piperideine-2-carboxylate (P2C), Delta(1)-pyrroline-2-carboxylate (Pyr2C) and Delta(2)-thiazoline-2-carboxylate. Kinetic data obtained at neutral pH suggests that ketimine reductase/CRYM plays a major role as a P2C/Pyr2C reductase and that AECK is not a major substrate at this pH. Thus, ketimine reductase is a key enzyme in the pipecolate pathway, which is the main lysine degradation pathway in the brain. In silico docking of various ligands into the active site of the X-ray structure of the enzyme suggests an unusual catalytic mechanism involving an arginine residue as a proton donor. Given the critical importance of thyroid hormones in brain function this research further expands on our knowledge of the connection between amino acid metabolism and regulation of thyroid hormone levels. PMID- 25931164 TI - In Silico Analysis of NF2 Gene Missense Mutations in Neurofibromatosis Type 2: From Genotype to Phenotype. AB - HYPOTHESIS: Computer-based (in silico) protein modeling to examine genotype phenotype relationships for a given mutation has been applied to many genes but never to NF2. BACKGROUND: Missense mutations in the merlin protein occur in approximately 9% of patients with neurofibromatosis type 2 (NF2). Within this subset of patients, no genotype-phenotype correlations have been established. The aim of this study was to determine if genotype correlates with phenotype in the cohort of NF2 patients with missense mutations as a first step to defining a method to predict clinical phenotype from genotype for these patients. METHODS: We analyzed 45 patients with NF2 as a result of missense mutations drawn from the United Kingdom NF2 registry. Our analysis included 17 different NF2 mutations from NF2 patients and six single-nucleotide polymorphisms (SNP)--presumed benign because they are observed in the dbSNP National Center for Biotechnology Information database and 1000 Genomes. We analyzed the mutations using three mutation tolerance prediction approaches: Align GVGD, SIFT, and PolyPhen-2. The mutation sites were also modeled on the three-dimensional crystal structure of merlin to investigate the spatial relationship of NF2-causing mutations. RESULTS: Two mutation tolerance predictors (SIFT and PolyPhen-2) were able to distinguish NF2-causing mutations from non-NF2-causing SNPs (p < 0.05). Mapping mutations on the molecular structure of merlin suggest that mutations resulting in greater structural conflicts within the protein are more likely to correlate with severe phenotypes. CONCLUSION: This work is a step toward a better understanding of genotype-phenotype relationships in NF2 caused by missense mutations using a computer-based methodology. PMID- 25931165 TI - Magnetic Resonance Imaging With Cochlear Implant Magnet in Place: Safety and Imaging Quality. AB - OBJECTIVE: To evaluate the safety and image quality of 1.5-T MRI in patients with cochlear implants and retained internal magnets. STUDY DESIGN: Retrospective case series from 2012 to 2014. SETTING: Single tertiary academic referral center. PATIENTS: All cochlear implant recipients undergoing 1.5-T MRI without internal magnet removal. INTERVENTION(S): MRI after tight headwrap application. MAIN OUTCOME MEASURES: Patient tolerance, complications, and characteristics of imaging artifact. RESULTS: Nineteen ears underwent a total of 34 MRI scans. Two patients did not tolerate imaging with the headwrap in place and required magnet removal before rescanning. One subject experienced two separate episodes of polarity reversal in the same device from physical realignment (i.e., flipping) of the internal magnet requiring surgical repositioning. Three patients were discovered to have canting of the internal magnet after imaging. In all three cases, the magnet could be reseated by applying gentle firm pressure to the scalp until the magnet "popped" back into place. These patients continue to use their device without difficulty and have not required surgical replacement. In patients receiving head MRI, the ipsilateral internal auditory canal and cerebellopontine angle could be visualized without difficulty in 94% of cases. There were no episodes of cochlear implant device failure or soft tissue complications. CONCLUSION: Under controlled conditions, 1.5-T MRI can be successfully performed in most patients without the need for cochlear implant magnet removal. In nearly all cases, imaging artifact does not impede evaluation of the ipsilateral skull base. Patients should be counseled regarding the risk of internal magnet movement that may occur in up to 15% of cases, even with tight headwrap application. If internal magnet polarity reversal occurs, a trial of reversing the external magnet can be considered. If canting or mild displacement of the internal magnet occurs, an attempt at reseating can be made by applying gentle firm pressure to the scalp over the internal magnet. If conservative measures fail, the magnet should be surgically repositioned to minimize interruption of device use and to prevent scalp complications. PMID- 25931167 TI - Vitreoretinal surgery for shotgun eye injuries: outcomes and complications. AB - PURPOSE: To analyse the postoperative anatomic and functional outcomes in addition to complications after vitreoretinal surgery for patients with shotgun eye injuries related to hunting accidents. MATERIALS: Retrospective review of the clinical records of all cases of shotgun eye injuries presented between January 2000 and January 2011 and with a minimum follow-up of 1 year. Collection of demographics, type of injury, choice of management, complications and final surgical success with final visual acuity is reported. RESULTS: Twenty eyes of 19 patients (all male) with a mean age of 36.1 years (range 16-60 years) were included in the study. Mean postoperative follow-up was 47.5 months (range 15-118 months). Best corrected visual acuity (BCVA) at presentation ranged from perception of light to 20/200. Ten eyes had a penetrating injury and 10 others had a perforating injury. All the eyes underwent an initial vitrectomy and the intraocular pellet was removed in all the 10 penetrating injuries. Concurrent cataract surgery was performed in 12 cases, internal tamponade was used in 15 cases and a supplemental encircling scleral buckle was inserted in 12 cases. One additional vitreoretinal surgery was required in seven cases (35%) and two additional surgeries required in two other cases (10%). At last follow-up BCVA ranged from NPL to 20/20 and was 20/100 or better in 10 eyes (50%). All patients had a flat retina except for two cases (10%) that developed severe proliferative vitreoretinopathy. CONCLUSION: These results suggest that vitreoretinal surgery can offer good visual rehabilitation in patients with shotgun eye injuries. PMID- 25931168 TI - Chorio-retinal thickness measurements in patients with acromegaly. PMID- 25931166 TI - Keratoconus: an inflammatory disorder? AB - Keratoconus has been classically defined as a progressive, non-inflammatory condition, which produces a thinning and steepening of the cornea. Its pathophysiological mechanisms have been investigated for a long time. Both genetic and environmental factors have been associated with the disease. Recent studies have shown a significant role of proteolytic enzymes, cytokines, and free radicals; therefore, although keratoconus does not meet all the classic criteria for an inflammatory disease, the lack of inflammation has been questioned. The majority of studies in the tears of patients with keratoconus have found increased levels of interleukin-6 (IL-6), tumor necrosis factor-alpha(TNF-alpha), and matrix metalloproteinase (MMP)-9. Eye rubbing, a proven risk factor for keratoconus, has been also shown recently to increase the tear levels of MMP-13, IL-6, and TNF-alpha. In the tear fluid of patients with ocular rosacea, IL-1alpha and MMP-9 have been reported to be significantly elevated, and cases of inferior corneal thinning, resembling keratoconus, have been reported. We performed a literature review of published biochemical changes in keratoconus that would support that this could be, at least in part, an inflammatory condition. PMID- 25931169 TI - Topiramate maculopathy secondary to dose titration: first reported case. PMID- 25931170 TI - The Eye Phone Study: reliability and accuracy of assessing Snellen visual acuity using smartphone technology. AB - PURPOSE: Smartphone-based Snellen visual acuity charts has become popularized; however, their accuracy has not been established. This study aimed to evaluate the equivalence of a smartphone-based visual acuity chart with a standard 6-m Snellen visual acuity (6SVA) chart. METHODS: First, a review of available Snellen chart applications on iPhone was performed to determine the most accurate application based on optotype size. Subsequently, a prospective comparative study was performed by measuring conventional 6SVA and then iPhone visual acuity using the 'Snellen' application on an Apple iPhone 4. RESULTS: Eleven applications were identified, with accuracy of optotype size ranging from 4.4-39.9%. Eighty-eight patients from general medical and surgical wards in a tertiary hospital took part in the second part of the study. The mean difference in logMAR visual acuity between the two charts was 0.02 logMAR (95% limit of agreement -0.332, 0.372 logMAR). The largest mean difference in logMAR acuity was noted in the subgroup of patients with 6SVA worse than 6/18 (n=5), who had a mean difference of two Snellen visual acuity lines between the charts (0.276 logMAR). CONCLUSION: We did not identify a Snellen visual acuity app at the time of study, which could predict a patients standard Snellen visual acuity within one line. There was considerable variability in the optotype accuracy of apps. Further validation is required for assessment of acuity in patients with severe vision impairment. PMID- 25931171 TI - Polymerase epsilon (POLE) ultra-mutated tumors induce robust tumor-specific CD4+ T cell responses in endometrial cancer patients. AB - OBJECTIVE: Around 7-10% of endometrial carcinomas are characterized by polymerase epsilon-(POLE) exonuclease-domain-mutations, an ultra-mutated-phenotype and a favorable prognosis. It is currently unknown whether POLE ultra-mutated-tumors are more immunogenic when compared to the other groups of endometrial cancers. METHODS: We used autologous-dendritic-cells (DC) pulsed with whole-tumor-extracts to assess the level of CD8+ and CD4+ T-cell-activation induced by POLE ultramutated (+) and POLE wild-type (-) endometrial cancer cells in vitro. T lymphocyte-proliferations were evaluated using CFSE and/or ([3H])thymidine incorporation-assays while the ability to specifically kill autologous-tumor cells by cytotoxic-T-lymphocyte (CTL) was tested in standard 4-h-(51)Cr cytotoxicity-assays. In order to correlate cytotoxic activity and proliferation by CD4+ and CD8+ T-lymphocytes, respectively, with a particular lymphoid subset, two-color-flow-cytometric analysis of intracellular-cytokine-expression (IFN gamma vs IL-4) at the single cell level was also performed. RESULTS: DC-pulsed with tumor extracts were able to induce CTL-responses against autologous-tumor cells in both POLE (+) and POLE (-) cancer patients (P=0.305). These CD8+ T-cell populations were cytotoxic against tumor-cells but they did not lyse PHA stimulated-autologous-lymphocytes or autologous-EBV-transformed-lymphoblastoid control-cell-lines. In contrast, only POLE (+) tumor-lysate-pulsed-DC were able to induce significant proliferation and high IFN-gamma expression (i.e., Th1 cytokine-bias) in autologous in vitro DC-stimulated CD4+ T-cells as well as naive CD4+ and CD8+ T-cells from patients-peripheral-blood (P<0.05). CONCLUSIONS: POLE ultra-mutated-tumors are significantly more immunogenic when compared to POLE (-) tumors, in particular to the helper arm of the immune system. These data lend support to the hypothesis that the better prognosis of patients with POLE (+) tumors may at least in part be linked to their enhanced immunogenicity. PMID- 25931172 TI - Nutrition behavior of the middle-aged and elderly: Compliance with dietary recommendations of the food pyramid. AB - BACKGROUND & AIMS: During the aging process, human physiology changes noticeably, mostly to the disadvantage of the individual. A healthy lifestyle that includes sufficient physical activity as well as a balanced and diverse diet contributes to healthy aging. One key factor that elderly people need to be aware of is compliance with nutritional recommendations. There is very little data concerning eating patterns, consumption behavior, and compliance with food guides (food pyramid) and nutritional recommendations among the Swiss, particularly for the middle-aged and elderly. The objective of this study was to gather new and representative information about these issues, concentrating on people aged 50+ and living in Switzerland. METHODS: A questionnaire in online and written form was distributed to a representative sample of middle-aged and elderly people living in Switzerland. RESULTS: In total, 632 people returned the survey. Of those respondents, 71% knew the Swiss Food Pyramid but only 38% said they comply with it. Based on self-reports, only a few participants met the recommendations for the different food groups listed in the food pyramid, whether in the pyramid comply or pyramid-non-comply group. CONCLUSION: The survey shows that the middle aged and elderly living in Switzerland need more nutritional guidance to help them to meet dietary recommendations. As usage and understanding of food guides seem limited among this population group, new tools must be explored for transfer of recommendations to real applications. PMID- 25931173 TI - Influence of nutrients pollution on the growth and organic matter output of Ulva prolifera in the southern Yellow Sea, China. AB - The influence of nutrients on the growth of Ulva prolifera was studied in the SYS by field experiments. The wet weight of U. prolifera gradiently increased from 11.94% to 25.92% in proportion to contents of DIN supply, which indicated DIN content was essentially decisive for the output of U. prolifera blooms. Continuous nutrient supply could promote the growth of U. prolifera, indicated by the increase of growth rate from 10.46% of the batch culture to 42.17% of the in situ culture. The higher P utilized rate in all treatments showed P was the potential limited factor for the growth of U. prolifera. Moreover, it was calculated about 4.1*10(5)t organic matter was begot by U. prolifera in the whole Yellow Sea based on the statistical relationship between output of U. prolifera and DIN content. This work could be convenient to evaluate biomass and prepare enough tools to manage U. prolifera. PMID- 25931174 TI - An almost completed pollution-recovery cycle reflected by sediment geochemistry and benthic foraminiferal assemblages in a Swedish-Norwegian Skagerrak fjord. AB - During the 20th century Idefjord was considered one of the most polluted marine areas in Scandinavia. For decades it received high discharges from paper/pulp industry, which made it anoxic and extremely polluted by heavy metals and organic contaminants. Today the fjord is close to fulfil a complete pollution-recovery cycle, which is recorded in its sediment archives. Here we report results from five sediment cores studied for TC, C/N, heavy metals and benthic foraminifera. All of the cores have laminations deposited during 1940-1980s and indicative of long-lasting anoxia; high TC and heavy metal content, poor foraminiferal faunas and lack of macrofauna. The upper part of the cores deposited since 1980s shows a gradual pollutant decrease and partial foraminiferal recovery. The majority of foraminiferal species in Idefjord are agglutinated opportunistic and stress tolerant taxa, which to some extent tolerate hypoxia and are early colonisers of previously disturbed environments. The current study demonstrates a value of benthic foraminiferal stratigraphy as a useful tool in understanding processes driving environmental degradation and recovery of coastal ecosystems. PMID- 25931175 TI - Arsenic fractionation in estuarine sediments: Does coastal eutrophication influence As behavior? AB - The Paranagua Estuarine Complex (PEC) includes the naturally oligotrophic (NO) Mel Island which is surrounded by sea grasses, a naturally eutrophic (NE) Benito Inlet adjacent to mangrove wetlands and the highly impacted eutrophic (IE) Paranagua Bay, home of one of Brazil's largest ports. The results from this study indicate that reactive As and pyrite increase with sediment depth near Paranagua port in the IE region. At the NE region, near a mangrove fringe, the reactive As, Fe, Mn and pyrite remained relatively high along the sediment column while near the sea grasses at NO the As contents were low. The degree of trace metal pyritization (DTMP) and the degree of pyritization (DOP) was highest at the IE site, slightly increasing with depth. These baseline results indicate that influence of trophic conditions and presence of marine vegetation may be directly related to As behavior in coastal systems. PMID- 25931176 TI - Distribution, enrichment and sources of thallium in the surface sediments of the southwestern coastal Laizhou Bay, Bohai Sea. AB - The concentrations of thallium (Tl) in the surface sediments of the southwestern coastal Laizhou Bay and the rivers it connects were determined. In riverine sediments, the Tl concentrations ranged from 0.34 to 0.76 MUg g(-1) in summer; in autumn, the corresponding data were 0.35-1.08 MUg g(-1). In marine sediments, the Tl concentrations ranged from 0.36 to 0.58 MUg g(-1) in summer; and from 0.30 to 0.56 MUg g(-1) in autumn. The grain size, Al and Fe oxides were major factors affecting Tl distribution. Tl in the surface sediments of the studied area was mainly from the natural input with the non-natural input as a subsidiary source. The low concentrations of Tl made it hard to cause potential negative environmental effects in this area. PMID- 25931177 TI - Contaminant profiles for surface water, sediment, flora and fauna associated with the mangrove fringe along middle and lower eastern Tampa Bay. AB - Contaminant concentrations are reported for surface water, sediment, flora and fauna collected during 2010-2011 from the mangrove fringe along eastern Tampa Bay, Florida. Concentrations of trace metals, chlorinated pesticides, atrazine, total polycyclic aromatic hydrocarbons, and polychlorinated biphenyls were species-, chemical- and location-specific. Contaminants in sediments did not exceed proposed individual sediment quality guidelines. Most sediment quality assessment quotients were less than one indicating the likelihood of no inhibitory effect based on chemical measurements alone. Faunal species typically contained more contaminants than plant species; seagrass usually contained more chemicals than mangroves. Bioconcentration factors for marine angiosperms were usually less than 10 and ranged between 1 and 31. Mercury concentrations (ppm) in blue crabs and fish did not exceed the U.S. Environmental Protection Agency fish tissue criterion of 0.3 and the U.S. Food and Drug Administration action level of 1.0. In contrast, total mercury concentrations in faunal species often exceeded guideline values for wildlife consumers of aquatic biota. PMID- 25931178 TI - Non-immunoglobulin scaffolds: a focus on their targets. AB - Non-immunoglobulin (non-Ig) scaffolds are, in contrast to antibodies, small single-domain proteins that require no post-translational modification, often lack disulfide bonds, and can undergo straightforward multimerization. Among the 20 different types of non-Ig scaffolds, Adhirons, Alphabodies, Centyrins, Pronectins, Repebodies, Affimers, and Obodies have been introduced in the past 4 years. 102 proteins have been specifically targeted by 139 different non-Ig scaffold binders. The most frequent application of non-Ig scaffolds is in the treatment and diagnosis of cancer and inflammatory diseases, and 10 non-Ig scaffolds have already been tested in clinical trials. Recently, non-Ig scaffolds have often been used in research as structure determination chaperones, for intracellular monitoring of post-translational modifications, and as antibody alternatives for microscopy, flow cytometry, and Western blotting. PMID- 25931180 TI - Persistent Sleep Disturbances Independently Predict Poorer Functional and Social Outcomes 1 Year After Mild Traumatic Brain Injury. AB - OBJECTIVE: To investigate the effect of sleep disturbances on functional and social outcomes after mild traumatic brain injury. SETTING: Outpatient traumatic brain injury clinic in a tertiary trauma center. PARTICIPANTS: A total of 374 mild traumatic brain injury patients were assessed within 3 months of injury and followed up every 3 months for 1 year. DESIGN: Analysis of a historical cohort in a naturalistic clinical setting. MAIN MEASURES: At each visit, symptoms of concussion and psychological distress and indices of functional and social outcomes were measured with the Rivermead Postconcussion Questionnaire, 28-item General Health Questionnaire, and Rivermead Head Injury Follow-up Questionnaire, respectively. Changes in outcome scores over time were explored using repeated measures analysis of variance and compared between subjects with persistent (SD) and recovered (SR) sleep disturbances. Predictors of functional/social outcome were determined using linear regression. RESULTS: The percentages of subjects reporting sleep disturbances at each time point were 71.9%, 57.2%, 55.1%, and 53.7%, respectively. For functional and social outcomes, significant effects of time (F3,315 = 9.54; P < .001), group (SD vs SR) F1,317 = 5.32; P = .022, and time X group interaction F3,315 = 4.14; P = .007 were found. Persistent sleep disturbance (P = 0.011) and higher symptom burden at 6 months postinjury (P < .0001) were independent predictors of poorer outcome. CONCLUSION: Sleep disturbance, independent of psychological distress, is an important prognostic factor of functional and social outcomes after mild traumatic brain injury. PMID- 25931179 TI - Posttraumatic Brain Injury Cognitive Performance Is Moderated by Variation Within ANKK1 and DRD2 Genes. AB - OBJECTIVE: As dopamine neurotransmission impacts cognition, we hypothesized that variants in the linked dopamine D2 receptor (DRD2) and ankyrin repeat and kinase domain (ANKK1) genes might account for some individual variability in cognitive recovery following traumatic brain injury (TBI). PARTICIPANTS: Prospective cohort of 108 survivors of severe TBI, recruited consecutively from a level 1 trauma center. DESIGN: We examined relationships between DRD2 genetic variation and functional recovery at 6 and 12 months post-TBI. MAIN MEASURES: Cognitive performance was evaluated using 8 neuropsychological tests targeting different cognitive domains. An overall cognitive composite was developed using normative data. We also assessed functional cognition, depression status, and global outcome. Subjects were genotyped for 6 DRD2 tagging single-nucleotide polymorphisms and Taq1A within ANKK1. RESULTS: ANKK1 Taq1A heterozygotes performed better than homozygotes across several cognitive domains at both time points postinjury. When adjusting for age, Glasgow Coma Scale score, and education, the Taq1A (ANKK1) and rs6279 (DRD2) variants were associated with overall composite scores at 6 months post-TBI (P = .0453 and P = .0452, respectively). At 12 months, only Taq1A remained a significant genetic predictor of cognition (P = .0128). Following multiple-comparisons correction, there were no significant associations between examined genetic variants and functional cognition, depression status, and global outcome. CONCLUSION: These data suggest that genetic variation within DRD2 influences cognitive recovery post-TBI. Understanding genetic influences on dopaminergic systems post-TBI may impact current treatment paradigms. PMID- 25931181 TI - Decreased Movement Path Tortuosity Is Associated With Improved Functional Status in Patients With Traumatic Brain Injury. AB - OBJECTIVE: To determine if movement path tortuosity in everyday ambulation decreases in Veterans being treated in a residential setting for traumatic brain injury. Elevated path tortuosity is observed in assisted living facility residents with cognitive impairment and at risk for falls, and tortuosity may decrease over the course of cognitive rehabilitation received by the Veterans. If observed, decreased tortuosity may be linked to improved clinical outcomes. DESIGN: Longitudinal observational study without random assignment. SETTING: Veterans Affairs Medical Center inpatient residential polytrauma treatment facility. PATIENTS: Twenty-two Veterans enrolled in a postacute predischarge residential polytrauma treatment facility. INTERVENTIONS: None, observation-only. MAIN OUTCOME MEASURE: Mayo-Portland Adaptability Index-4, and movement path tortuosity measured by Fractal Dimension (Fractal D). Fractal D was obtained continuously from an indoor movement tracking system primarily used to provide machine-generated prompts and reminders to facilitate activities of daily living. Patients were deemed "responders" (N = 10) if a significant linear decline in Fractal D occurred over the course of treatment, or nonresponders (N = 12) if no significant decline was observed. RESULTS: Responders had lower discharge Mayo Portland Adaptability Inventory scores (mean = 32.6, SD = 9.53) than non responders (mean = 39.5, SD = 6.02) (F = 2.07, df = 20, P = .05). Responders and nonresponders did not differ on initial injury severity or other demographic measures. CONCLUSIONS: Fractal D, a relatively simple measure of movement path tortuosity can be linked to functional recovery from traumatic brain injury. PMID- 25931182 TI - Movement Path Tortuosity Predicts Compliance With Therapeutic Behavioral Prompts in Patients With Traumatic Brain Injury. AB - OBJECTIVE: Rehabilitation of patients with traumatic brain injury typically includes therapeutic prompts for keeping appointments and adhering to medication regimens. Level of cognitive impairment may significantly affect a traumatic brain injury victim's ability to benefit from text-based prompting. We tested the hypothesis that spatial disorientation as measured by movement path tortuosity during ambulation would be associated with poorer compliance with automated prompts by veterans actively being treated for traumatic brain injury. SETTING: Clinical polytrauma center. PARTICIPANTS: Ten (1 female) veteran patients mean age = 35.4 (SD = 12.4) years. DESIGN: Small group correlational study without random assignment. MAIN MEASURES: Fractal Dimension, a measure of movement path tortuosity derived from a GPS logging device used to record casual outdoor ambulation at the start of the study. Compliance with smart home machine generated therapeutic prompts received during rehabilitation at the James A. Haley Veterans Administration Hospital Polytrauma Transitional Rehabilitation Program. A patient was compliant with a prompt if they transited from where the prompt was presented to the prescribed destination (both within the Polytrauma Transitional Rehabilitation Program) within 30 minutes. Noncompliance was failure to appear at the destination within the allotted time. RESULTS: Fractal dimension was significantly inversely related to overall prompt compliance (r = -0.603, n = 10, P = .032; 1-tailed). CONCLUSIONS: The findings support the hypothesis that increased spatial disorientation adversely impacts compliance with automated prompts throughout therapy. The results are consistent with previous studies linking elevated path tortuosity to cognitive impairment and increased risk for falls in assisted living facility residents. PMID- 25931183 TI - Global Outcome and Late Seizures After Penetrating Versus Closed Traumatic Brain Injury: A NIDRR TBI Model Systems Study. AB - BACKGROUND: If and how much dural penetration influences long-term outcome after traumatic brain injury (TBI) is understudied, especially within the civilian population. OBJECTIVES: Using the large TBI Model Systems cohort, this study assessed and compared penetrating TBI (PTBI) and closed TBI with respect to global outcome and late seizures 2 years after injury. METHODS: After performing unadjusted PTBI versus closed TBI comparisons, multivariate regression models were built and analyzed for both outcomes by including the following additional predictors: length of unconsciousness, posttraumatic amnesia duration, hospital length of stay, age, gender, race, marital status, education level, problem substance abuse, and preinjury employment status. RESULTS: The collapsed Glasgow Outcome Scale model (n = 6111) showed significant secondary effects of PTBI with employment status. When employed before injury, individuals with PTBI were 2.62 times more likely (95% confidence interval, 1.92-3.57) to have a lower Glasgow Outcome Scale category. The final model for late seizures (n = 6737) showed a significant main effect for PTBI. Adjusting for other predictors, individuals with PTBI were 2.78 times more likely (95% confidence interval, 1.93-3.99) than those with closed TBI to be rehospitalized for a seizure. CONCLUSION: This study empirically demonstrates that penetrating injury mechanism has important prognostic implications. PMID- 25931185 TI - Relationship Between Resilience, Adjustment, and Psychological Functioning After Traumatic Brain Injury: A Preliminary Report. AB - OBJECTIVE: To examine the relationship between resilience, psychological distress, adjustment, and community participation after traumatic brain injury (TBI). SETTING: Large university health system. PARTICIPANTS: Adult survivors of mild to severe TBI (N = 96). DESIGN: Descriptive, preliminary. MAIN MEASURES: The Connor-Davidson Resilience Scale (10-item version) was used to assess resilience, the Brief Symptom Inventory (BSI-18) was used to characterize psychological distress, and the Mayo-Portland Adaptability Index (MPAI-4) was used to measure ability, adjustment, and participation. RESULTS: Resilience scores were substantially lower than those of the general population. Significant relationships were found between resilience, psychological distress, and adjustment. Partial correlations (adjusting for the other MPAI-4 indices) showed significant correlation (P < .05) between MPAI-4 Adjustment and resilience. Partial correlations (adjusting for the other BSI-18 scales) also showed significance for Depression (P < .01) and resilience. Resilience scores differed significantly (P < .001) between individuals meeting BSI-18 caseness criteria for psychological distress (n = 55) and those not meeting criteria (n = 41). CONCLUSIONS: Individuals with TBI are at risk for low resilience, which was found to correlate with psychological distress and psychosocial maladjustment. Developing interventions to strengthen resilience skills has the potential to improve postinjury psychosocial adjustment, an important area for future research. PMID- 25931184 TI - TBI-QOL: Development and Calibration of Item Banks to Measure Patient Reported Outcomes Following Traumatic Brain Injury. AB - OBJECTIVE: To use a patient-centered approach or participatory action research design combined with advanced psychometrics to develop a comprehensive patient reported outcomes (PRO) measurement system specifically for individuals with traumatic brain injury (TBI). This TBI Quality-of-Life (TBI-QOL) measurement system expands the work of other large PRO measurement initiatives, that is, the Patient-Reported Outcomes Measurement Information System and the Neurology Quality-of-Life measurement initiative. SETTING: Five TBI Model Systems centers across the United States. PARTICIPANTS: Adults with TBI. DESIGN: Classical and modern test development methodologies were used. Qualitative input was obtained from individuals with TBI, TBI clinicians, and caregivers of individuals with TBI through multiple methods, including focus groups, individual interviews, patient consultation, and cognitive debriefing interviews. Item pools were field tested in a large multisite sample (n = 675) and calibrated using item response theory methods. MAIN OUTCOMES MEASURES: Twenty-two TBI-QOL item banks/scales. RESULTS: The TBI-QOL consists of 20 independent calibrated item banks and 2 uncalibrated scales that measure physical, emotional, cognitive, and social aspects of health related quality of life. CONCLUSIONS: The TBI-QOL measurement system has potential as a common data element in TBI research and to enhance collection of health-related quality-of-life and PRO data in rehabilitation research and clinical settings. PMID- 25931186 TI - Subconcussive Blows to the Head: A Formative Review of Short-term Clinical Outcomes. AB - BACKGROUND: Given questions about "lower thresholds" for concussion, as well as possible effects of repetitive concussion and chronic traumatic encephalopathy (CTE), and associated controversy, there is increasing interest in "subconcussive" blows and their potential significance. OBJECTIVE: A formative review with critical examination of the developing literature on subconcussive blows in athletes with an emphasis on clinical outcomes. METHODS: Studies of biomechanical, performance and/or symptom-based, and neuroimaging data were identified via PubMed search and critically reviewed. Five studies of symptom reporting/performance and 4 studies of neuroimaging were included. RESULTS: The relation between biomechanical parameters and diagnosed concussion is not straightforward (ie, it is not the case that greater and more force leads to more severe injury or cognitive/behavioral sequelae). Neuropsychological studies of subconcussive blows within a single athletic season have failed to demonstrate any strong and consistent relations between number and severity of subconcussive events and cognitive change. Recent studies using neuroimaging have demonstrated a potential cumulative effect of subconcussive blows, at least in a subset of individuals. CONCLUSION: Human studies of the neurological/neuropsychological impact of subconcussive blows are currently quite limited. Subconcussive blows, in the short-term, have not been shown to cause significant clinical effects. To date, findings suggest that any effect of subconcussive blows is likely to be small or nonexistent, perhaps evident in a subset of individuals on select measures, and maybe even beneficial in some cases. Longer-term prospective studies are needed to determine if there is a cumulative dose effect. PMID- 25931187 TI - Prevalence of Self-Reported Lifetime History of Traumatic Brain Injury and Associated Disability: A Statewide Population-Based Survey. AB - OBJECTIVE: To investigate the prevalence of all severities of traumatic brain injury (TBI), regardless of treatment setting, and their associated negative outcomes. PARTICIPANTS: A total of 2701 adult Coloradoans. DESIGN: A statewide, population-based, random digit-dialed telephone survey. MAIN MEASURES: The lifetime history of TBI was assessed by a modification of the Ohio State University TBI Identification Method; activity limitation and life satisfaction were also assessed. RESULTS: The distribution of self-reported lifetime injury was as follows: 19.8%, no injury; 37.7%, injury but no TBI; 36.4%, mild TBI; and 6.0%, moderate-severe TBI. Of those reporting a TBI, 23.1% were hospitalized, 38.5% were treated in an emergency department, 9.8% were treated in a physician's office, and 27.5% did not seek medical care. A clear gradient of activity limitations and low life satisfaction was seen, with the highest proportions of these negative outcomes occurring in people reporting more severe TBI and the lowest proportions in those not reporting a TBI. Approximately twice as many people reported activity limitations and low life satisfaction after nonhospitalized TBI compared with hospitalized TBI. CONCLUSIONS: This investigation highlights the seriousness of TBI as a public health problem and the importance of including all severities of TBI, no matter where, or if treated, in estimating the prevalence of disability co-occurring with TBI. PMID- 25931188 TI - Risk of Negative Outcomes After Traumatic Brain Injury: A Statewide Population Based Survey. AB - OBJECTIVE: To investigate the rates of negative outcomes associated with all severities of traumatic brain injury (TBI), treated in all settings or not treated at all, in comparison to the general population. PARTICIPANTS: Coloradoans without injury, with injury but no TBI, with mild TBI but no loss of consciousness (LOC), mild TBI with LOC, moderate TBI, or severe TBI. DESIGN: Statewide population-based survey. MAIN MEASURES: Computer-assisted, modified Ohio State University TBI Identification Method; Behavioral Risk Factor Surveillance System and National Health Interview Survey questions; Satisfaction with Life Scale; and postconcussive symptoms. RESULTS: Up to 42.5% of participants reported a lifetime history of at least 1 TBI. Multiple negative outcomes were found to increase in prevalence in a stepwise fashion in association with greater TBI severity, with the clearest patterns observed for disability, poor life satisfaction, and impaired memory. CONCLUSIONS: Traumatic brain injury was found to be associated with disability and other negative outcomes in a general population survey. This study does not allow us to examine the proximate causes of disability, but it suggests that TBI may serve to both cause disability directly and exacerbate the influence of other etiologies. These relations should be examined in subsequent studies. PMID- 25931189 TI - Outcome after total knee arthroplasty in haemophilic patients with stiff knees. AB - INTRODUCTION: Advanced haemophilic arthropathy of the knee is associated with progressive joint stiffness. Results after total knee arthroplasty (TKA) in stiff knees are considered to be inferior compared to those with less restricted preoperative range of motion (ROM). There is only very limited data on the results of primary TKA in haemophilic patients with stiff knees. AIM: The purpose of this retrospective study was to evaluate the clinical outcome after TKA performed in haemophilic patients with preoperative ROM of 50 degrees or less. METHODS: Twenty one patients (23 knees) undergoing TKA with stiff knees were retrospectively evaluated. Mean follow-up was 8.3 years (range, 2-25). Clinical assessment included ROM, degree of flexion contracture and complication rate. Functional evaluation and pain status were assessed using the Knee Society's Scoring System (KSS). RESULTS: Range of motion improved from 26.7 degrees preoperatively to 73.0 degrees postoperatively. Flexion contracture decreased from 21.7 degrees to 8.3 degrees . KSS increased from 22.9 to 72.9 points. Evaluation of pain revealed a decrease from 8.4 points preoperatively to 2.1 points postoperatively. All these differences were statistically significant (P < 0.005). The complication rate was 8.7% including one late periprosthetic infection, and one aseptic implant loosening. Nine patients who required VY quadricepsplasty for knee exposure developed a mean postoperative extensor lag of 7 degrees . CONCLUSION: Total knee arthroplasty in haemophilic patients presenting with stiff knees results in significant improvement of function and reduction in pain. Although the clinical outcome is inferior compared to nonstiff knees reported in the literature, joint replacement surgery can be successfully performed in this particular group of patients. PMID- 25931190 TI - Video-based 3D reconstruction, laparoscope localization and deformation recovery for abdominal minimally invasive surgery: a survey. AB - BACKGROUND: The intra-operative three-dimensional (3D) structure of tissue organs and laparoscope motion are the basis for many tasks in computer-assisted surgery (CAS), such as safe surgical navigation and registration of pre-operative and intra-operative data for soft tissues. METHODS: This article provides a literature review on laparoscopic video-based intra-operative techniques of 3D surface reconstruction, laparoscope localization and tissue deformation recovery for abdominal minimally invasive surgery (MIS). RESULTS: This article introduces a classification scheme based on the motions of a laparoscope and the motions of tissues. In each category, comprehensive discussion is provided on the evolution of both classic and state-of-the-art methods. CONCLUSIONS: Video-based approaches have many advantages, such as providing intra-operative information without introducing extra hardware to the current surgical platform. However, an extensive discussion on this important topic is still lacking. This survey paper is therefore beneficial for researchers in this field. Copyright (c) 2015 John Wiley & Sons, Ltd. PMID- 25931191 TI - Effect of Selenium Supplementation on Apoptosis and Cell Cycle Blockage of Renal Cells in Broilers Fed a Diet Containing Aflatoxin B1. AB - The aim of the study was to investigate the competency of selenium (Se) in counteracting the adverse effects of aflatoxin B1 (AFB1) on apoptosis, cell cycle, and proliferation of nephritic cells. Two hundred forty 1-day-old healthy male avian broilers were randomly divided into four groups and fed basal diet (control group), 0.3 mg/kg AFB1 diet (AFB1 group), 0.4 mg/kg Se diet (+Se group), and 0.3 mg/kg AFB1 + 0.4 mg/kg Se diet (AFB1 + Se group), respectively. Compared to the control group, the number of apoptotic renal cells and expressions of Bax and caspase-3 messenger RNA (mRNA) were significantly increased, while the expression of Bcl-2 was significantly decreased in the AFB1 and the +Se groups (p < 0.01). A significantly decreased proliferating cell nuclear antigen (PCNA) expression and arrested G0/G1 phases of the cell cycle were also seen in the AFB1 and the +Se groups when compared with those of the control group. Moreover, these parameters were restored to the control group levels in the AFB1 + Se group. These results suggested that sodium selenite supplied in the diet could effectively inhibit AFB1-induced apoptosis and cell cycle blockage in renal cells of broiler. PMID- 25931192 TI - Why solid-state fermentation is more advantageous over submerged fermentation for converting high concentration of glycerol into Monacolin K by Monascus purpureus 9901: A mechanistic study. AB - The underlying mechanisms by which solid-state fermentation (SSF) was more advantageous over submerged fermentation (SmF) for converting high concentration of glycerol into Monacolin K by Monascus purpureus were investigated innovatively. First, the established kinetic models and kinetic parameters showed that the cell growth, Monacolin K formation and glycerol consumption in SSF were more rapid than those in SmF. Secondly, the comparison of fatty acid composition of mycelial cells indicated a better fluidity and permeability of the cell membrane in SSF than that of SmF, which was also consistent with the difference in the ratio of extracellular/intracellular Monacolin K between the two systems. Thirdly, the phenomenon of glycerol concentration gradient was verified in SSF, which could well explain the resistance effect to high concentration of glycerol in SSF. These new findings provide some important insights to the elucidation of the advantages of SSF for the synthesis of fungal secondary metabolites. PMID- 25931193 TI - Genome sequence of Xanthomonas sacchari R1, a biocontrol bacterium isolated from the rice seed. AB - Xanthomonas sacchari, was first identified as a pathogenic bacterium isolated from diseased sugarcane in Guadeloupe. In this study, R1 was first isolated from rice seed samples from Philippines in 2002. The antagonistic ability against several rice pathogens raises our attention. The genomic feature of this strain was described in this paper. The total genome size of X. sacchari R1 is 5,000,479 bp with 4315 coding sequences (CDS), 59 tRNAs, 2rRNAs and one plasmid. PMID- 25931195 TI - Prevalence of thoracic aortopathy in patients with juvenile Polyposis Syndrome Hereditary Hemorrhagic Telangiectasia due to SMAD4. AB - Hereditary hemorrhagic telangiectasia (HHT) is characterized by abnormal vascular structures that may present as epistaxis, telangiectasias, and/or arteriovenous malformations. The genes associated with HHT (ACVRL1, ENG, and SMAD4) are members of the TGFbeta pathway. Other syndromes associated with abnormalities in TGFbeta signaling include Marfan syndrome, Loeys-Dietz syndrome and related disorders. These disorders have aortic disease as a prominent finding. While there are case reports of patients with HHT and aortopathy (dilatation/aneurysm, dissection, and rupture), this has not been systematically investigated. We conducted a retrospective chart review to determine the prevalence of aortopathy in an HHT cohort. Patients from a single institution were identified who met the Curacao Criteria for a clinical diagnosis of HHT and/or had a mutation in ACVRL1, ENG, or SMAD4 and underwent echocardiogram. Two-dimensional echocardiograms were reviewed by a single pediatric cardiologist, and data were collected on demographics, genotype, HHT features, aortic root measurements, past medical history, and family history. Z scores and nomograms were utilized to identify abnormal results. Twenty-six patients from 15 families (one ACVRL1, four ENG, eight SMAD4, and two clinical diagnoses) were included in the analysis. Aortopathy was found in 6/26 (23%) patients; all had SMAD4 mutations. In our cohort, 6/16 (38%) SMAD4 mutation carriers had evidence of aortopathy. These data suggest that aortopathy could be part of the spectrum of SMAD4-induced HHT manifestations. Routine aortic imaging, including measurements of the aorta, should be considered in patients with SMAD4 mutations to allow for appropriate medical and surgical recommendations. PMID- 25931194 TI - Input-specific regulation of hippocampal circuit maturation by non-muscle myosin IIB. AB - Myh9 and Myh10, which encode two major isoforms of non-muscle myosin II expressed in the brain, have emerged as risk factors for developmental brain disorders. Myosin II motors regulate neuronal cytoskeletal dynamics leading to optimization of synaptic plasticity and memory formation. However, the role of these motor complexes in brain development remains poorly understood. Here, we disrupted the in vivo expression of Myh9 and/or Myh10 in developing hippocampal neurons to determine how these motors contribute to circuit maturation in this brain area important for cognition. We found that Myh10 ablation in early postnatal, but not mature, CA1 pyramidal neurons reduced excitatory synaptic function in the Schaffer collateral pathway, whereas more distal inputs to CA1 neurons were relatively unaffected. Myh10 ablation in young neurons also selectively impaired the elongation of oblique dendrites that receive Schaffer collateral inputs, whereas the structure of distal dendrites was normal. We observed normal spine density and spontaneous excitatory currents in these neurons, indicating that Myh10 KO impaired proximal pathway synaptic maturation through disruptions to dendritic development rather than post-synaptic strength or spine morphogenesis. To address possible redundancy and/or compensation by other Myosin II motors expressed in neurons, we performed similar experiments in Myh9 null neurons. In contrast to findings in Myh10 mutants, evoked synaptic function in young Myh9 KO hippocampal neurons was normal. Data obtained from double Myh9/Myh10 KO neurons largely resembled the MyH10 KO synaptic phenotype. These data indicate that Myosin IIB is a key molecular factor that guides input-specific circuit maturation in the developing hippocampus. Non-muscle myosin II is an actin binding protein with three isoforms in the brain (IIA, IIB and IIC) encoded by the myh9, myh10, and myh14 genes in mice, respectively. We have studied the structure and the function of hippocampal CA1 neurons missing NMIIB and/or NMIIA proteins at different times during development. We have discovered that NMIIB is the major isoform regulating Schaffer collateral inputs, and that this regulation is restricted to early postnatal development. PMID- 25931196 TI - A Prospective Observational Study of Antibiotic Therapy in Febrile Neutropenia Patients with Hematological Malignances from Multiple centers in Northeast China. AB - OBJECTIVES: Febrile neutropenia (FN) is a common but lethal complication of chemotherapy in hematological malignance. The aim of this study was to identify the prognostic risk factors for antibiotic treatment outcome in PN patients, and provide the optimal choice for the initial empirical antibiotic treatment. METHODS: 227 consecutive FN hematologic malignancies from four hospitals in Northeast China were enrolled. The outcome of antibiotic therapy was investigated until 14 days after the onset of FN. The factors affecting antibiotic therapy outcome were evaluated using Univariate analysis and Multivariate logistic regression analysis. RESULTS: Among all patients, 27 patients did not achieve favorable outcome either clinically or bacteriologically. It was shown that the risk factors for poor FN therapy outcome were associated with prolonged duration of neutropenia over 9 days during FN (P=0.019), slow neutrophil recovery (P=0.039), respiratory infection (P=0.005), and that initial monotherapy with drugs recommended by the guidelines indicated better outcome (P=0.009). Additionally, patients with multi-bacterial infection, as well as further ANC decrease after fever, had a poor prognosis. CONCLUSIONS: Our results indicate that early application of antibiotics and prevention of respiratory infection as well as good clinical care are able to improve clinical outcomes from empirical antibiotic treatment in FN patients with hematological malignances. PMID- 25931197 TI - Diagnosis and Treatment of Typhoid Fever and Associated Prevailing Drug Resistance in Northern Ethiopia. AB - OBJECTIVE: To determine diagnostic value of the Widal test, treatment pattern of febrile patients and antimicrobial drug susceptibility pattern of blood isolates. METHODS: Using cross sectional methods, blood samples were collected for culture and Widal test from 502 febrile outpatients attending Mekelle hospital and Mekelle health center with similar symptoms to typhoid. Sensitivity, specificity for anti-TH and anti-TO titers using culture confirmed typhoid fever cases, and Kappa agreement between Titer and slide Widal tests were calculated. Treatment pattern of patients and antimicrobial susceptibility pattern of the blood isolates was assessed. RESULTS: From the 502 febrile patients, 8(1.6%) of them had culture-proven typhoid fever. However, patients who have results indicative of recent infection by O and H antigens of the Widal slide agglutination test were 343 (68.5%), with specificity and sensitivity of 33% and 100%, respectively. Over prescription of antibiotics was seen by Widal slide test for Ciprofloxacin 268 (76.1%), Amoxicillin- Clavulanic acid 9(2.6%), Amoxicillin 8(2.4%) and Chloranphenicol 8(2.4%). Tube titer positivity was seen in 23(5.3%) patients with 75% sensitivity and 95.8% specificity. Widal slide and Tube titer tests showed poor agreement for both antigens (kappa=0.02 for O) and (Kappa=0.09 for H). A single anti-TH titer of >= 1:160 and anti-TO titer >= 1:80 higher in our study showed an indication for typhoid fever infection. Drug resistance pattern of blood isolates ranges from 0-89.7% for gram positive and 0-100% for Gram negative, with an overall multi-drug resistance rate of 61.7%. CONCLUSION: Patients were wrongly diagnosed and treated for typhoid fever by Widal test. The tube titration method was relatively good but still had poor sensitivity. Blood isolates showed multi drug resistance, which may be due to the indiscriminate prescription as seen in this study. Based on our results, the slide Widal test is not helpful in the diagnosis of typhoid, hence other tests with rapid, feasible, better sensitivity and specificity are urgently needed in Ethiopia. PMID- 25931198 TI - Severe Sepsis Secondary to Persistent Lysinibacillus sphaericus, Lysinibacillus fusiformis and Paenibacillus amylolyticus Bacteremia. AB - Lysinibacillus and Paenibacillus are pervasive bacteria rarely associated with human disease. Less sophisticated microbiology techniques may frequently incorrectly identify these genera as Bacillus spp., often regarded as environmental contamination. This report describes a case of severe sepsis due to persistent Lysinibacillus and Paenibacillus bacteremia, identified by matrix assisted laser desorption and ionization time-of-flight mass spectroscopy and 16S rRNA gene sequencing. PMID- 25931199 TI - Distribution of MED12 mutations in fibroadenomas and phyllodes tumors of the breast--implications for tumor biology and pathological diagnosis. AB - Somatic mutations in exon 2 of MED12 have been described in benign and malignant smooth muscle cell tumors suggesting a functional role in these neoplasms. Recently fibroadenomas of the breast were also reported to harbor MED12 mutations. Hence, we explored MED12 mutations in fibroepithelial tumors of the breast, histological subtypes of fibroadenomas and phyllodes tumors, to validate and extend previous efforts. Using conventional Sanger sequencing, we profiled 39 cases of fibroepithelial breast tumors comprising classic histological subtypes of fibroadenomas as well as benign and malignant phyllodes tumors for mutations in exon 2 of MED12. MED12 mutations were detected in 60% of all tumor samples with the majority being missense mutations affecting codon 44. Additionally, we report novel in-frame deletions that have not been described previously. Sixty two percent of the fibroadenomas harbored mutated MED12 with intracanalicular fibroadenomas being the most frequently mutated histological subtype (82%). Of note, 8/11 of benign phyllodes tumors had MED12 mutations while only 1/5 of malignant phyllodes tumors showed mutations in exon 2 of MED12. In conclusion, we confirm the frequent occurrence of MED12 mutations in fibroadenomas, provide evidence that most intracanalicular fibroadenomas closely resembling benign phyllodes as well as benign phyllodes tumors harbor MED12 mutations, and conclude that MED12 mutations in malignant phyllodes tumors appear to be relatively rare. PMID- 25931200 TI - Role of Patient Factors and Practice Patterns in Determining Access to Liver Waitlist. AB - Geographic variability in access to care is a persistent challenge in transplantation. Little is known about how patients with end-stage liver disease are chosen for referral, evaluation and listing. Utilizing death certificate data from the Centers for Disease Control and Prevention from 2002 to 2009, estimated liver demand (ELD) was measured by aggregating annual deaths from liver disease and liver transplants performed in each donor service area (DSA). In DSAs with higher ELD, more patients per capita were listed for transplantation (p < 0.001). In addition, listing rates per ELD varied fivefold across DSAs, with more patients per ELD being transplanted in DSAs with higher listing rates (p < 0.001). After adjusting for liver donor risk index and MELD at transplant, there was no association between listing rate and posttransplant survival (HR 1.002, p = 0.77). In addition, DSAs with lower listing rates were more likely to export organs (p < 0.001) of lower liver donor risk index (p < 0.001). Listing sicker patients was associated with increased access to the waitlist and transplantation and more efficient organ utilization, but had minimal effect on posttransplant outcomes after adjusting for the resulting organ shortage. PMID- 25931201 TI - Effects of impaired membrane interactions on alpha-synuclein aggregation and neurotoxicity. AB - The post-mortem brains of individuals with Parkinson's disease (PD) and other synucleinopathy disorders are characterized by the presence of aggregated forms of the presynaptic protein alpha-synuclein (aSyn). Understanding the molecular mechanism of aSyn aggregation is essential for the development of neuroprotective strategies to treat these diseases. In this study, we examined how interactions between aSyn and phospholipid vesicles influence the protein's aggregation and toxicity to dopaminergic neurons. Two-dimensional NMR data revealed that two familial aSyn mutants, A30P and G51D, populated an exposed, membrane-bound conformer in which the central hydrophobic region was dissociated from the bilayer to a greater extent than in the case of wild-type aSyn. A30P and G51D had a greater propensity to undergo membrane-induced aggregation and elicited greater toxicity to primary dopaminergic neurons compared to the wild-type protein. In contrast, the non-familial aSyn mutant A29E exhibited a weak propensity to aggregate in the presence of phospholipid vesicles or to elicit neurotoxicity, despite adopting a relatively exposed membrane-bound conformation. Our findings suggest that the aggregation of exposed, membrane-bound aSyn conformers plays a key role in the protein's neurotoxicity in PD and other synucleinopathy disorders. PMID- 25931202 TI - Massive rotator cuff tears: definition and treatment. AB - PURPOSE: The aim of this review is to summarise tear pattern classification and management options for massive rotator cuff tears (MRCT), as well as to propose a treatment paradigm for patients with a MRCT. METHOD: Data from 70 significant papers were reviewed in order to define the character of reparability and the possibility of alternative techniques in the management of MRCT. RESULTS: Massive rotator cuff tears (MRCT) include a wide panoply of lesions in terms of tear pattern, functional impairment, and reparability. Pre-operative evaluation is critical to successful treatment. With the advancement of medical technology, arthroscopy has become a frequently used method of treatment, even in cases of pseudoparalytic shoulders. Tendon transfer is limited to young patients with an irreparable MRCT and loss of active rotation. Arthroplasty can be considered for the treatment of a MRCT with associated arthritis. CONCLUSION: There is insufficient evidence to establish an evidence-based treatment algorithm for MRCTs. Treatment is based on patient factors and associated pathology, and includes personal experience and data from case series. PMID- 25931203 TI - Takayasu arteritis and ulcerative colitis: high rate of co-occurrence and genetic overlap. AB - OBJECTIVE: Takayasu arteritis (TAK) is a systemic vasculitis affecting large arteries and large branches of the aorta. Ulcerative colitis (UC) is a prevalent autoimmune colitis. Since TAK and UC share HLA-B*52:01 and IL12B as genetic determinants, and since there are case reports of the co-occurrence of these diseases, we hypothesized that UC is a common complication of TAK. We undertook this study to perform a large-scale analysis of TAK, both to evaluate the prevalence of concurrent cases of TAK and UC and to identify and estimate susceptibility genes shared between the 2 diseases. METHODS: We analyzed a total of 470 consecutive patients with TAK from 14 institutions. We characterized patients with TAK and UC by analyzing clinical manifestations and genetic components. Genetic overlapping of TAK and UC was evaluated with the use of UC susceptibility single-nucleotide polymorphisms by comparing risk directions and effect sizes between susceptibility to the 2 diseases. RESULTS: Thirty of 470 patients with TAK had UC (6.4% [95% confidence interval 4.3-9.0]). This percentage was strikingly higher than that expected from the prevalence of UC in Japan. Patients with TAK complicated with UC developed TAK at an earlier stage of life (P = 0.0070) and showed significant enrichment of HLA-B*52:01 compared to TAK patients without UC (P = 1.0 * 10(-5) ) (odds ratio 12.14 [95% confidence interval 2.96-107.23]). The 110 non-HLA markers of susceptibility to UC significantly displayed common risk directions with susceptibility to TAK (P = 0.0054) and showed significant departure of permutation P values from expected P values (P < 1.0 * 10(-10) ). CONCLUSION: UC is a major complication of TAK. These 2 diseases share a significant proportion of their genetic background, and HLA B*52:01 may play a central role in their co-occurrence. PMID- 25931204 TI - Circadian exosomal expression of renal thiazide-sensitive NaCl cotransporter (NCC) and prostasin in healthy individuals. AB - PURPOSE: A circadian timing system is involved in the maintenance of fluid and electrolyte balance and blood pressure control. Aldosterone and vasopressin modulate ion transporters and channels crucial in sodium (Na) and water reabsorption such as the epithelium Na channel and the renal thiazide-sensitive NaCl cotransporter (NCC). We analyzed in urinary exosomes the intraday variations of NCC and prostasin expression and the association with electrolytes and water balance parameters. EXPERIMENTAL DESIGN: Blood and urine samples were collected at five time points during the day from five healthy subjects. Blood renin, aldosterone, cortisol, ACTH, and plasmatic and urinary Na, potassium, creatinine, adiuretin (ADH), NCC, and prostasin were evaluated. RESULTS: ACTH and cortisol showed a circadian pattern, similarly to aldosterone, while exosomal NCC and prostasin pattern were similar to urinary ADH, decreased in the morning and subsequently increased in the afternoon and evening. CONCLUSIONS AND CLINICAL RELEVANCE: In urinary exosomes, NCC and prostasin had a diurnal pattern parallel to ADH and aquaporin 2, confirming that, in healthy subjects, both prostasin and NCC relate to water balance. These results provide suggestions for a possible chronotherapeutic approach in patients treated with thiazides, diuretic drugs acting as specific inhibitors of NCC-mediated Na reabsorption. PMID- 25931205 TI - A developmental switch between fetal and adult B lymphopoiesis. AB - Fluorescence-activated cell sorting (FACS)-purified pro-B cells from fetal liver and adult bone marrow generate B cells with distinct phenotypes: fetal cells generate few IgD(high) B cells and half express CD5, whereas adult cells generate mostly IgD(high) cells and few express CD5. These results led us to propose a model of a developmental switch in B lymphopoiesis, similar to the well-known switch in fetal to adult erythropoiesis. More recent global analysis of mRNA and microRNA expression comparing these two types of pro-B cells revealed differential expression of Lin28b and microRNAs from the Let-7 family, indicating that this regulatory axis plays a role in the switch. Further analysis has provided data supporting this model, implicating Arid3a as a key transcription factor in mediating fetal-type B cell development. Function of this regulatory axis in human B lineage precursors may also explain the predominance of CD5(+) B cells in cord blood. We suggest that Lin28b-promoted B cell development generates many cells expressing CD5 as a consequence of positively selected self reactivity. While such cells serve a useful role in clearance of senescent cells and in certain immune responses, they also carry the risk of progression to leukemia/lymphoma later in life. PMID- 25931206 TI - A case of inflammatory myofibroblastic tumour of the right labium majus. PMID- 25931207 TI - And the GIST is: When one has a GIST, think of an association! PMID- 25931208 TI - "A Cold Spring Harbor in Europe." EURATOM, UNESCO and the Foundation of EMBO. AB - This article explores the problem of the foundation of the European Molecular Biology Organization (EMBO), by reconstructing a broader institutional framework, which includes other international actors--EURATOM, UNESCO and the International Laboratory of Genetics and Biophysics (ILGB) in Naples--and a relevant, but still neglected figure, the Italian geneticist Adriano Buzzati-Traverso (1913-1983). The article considers the tension between centralized and federal models of organization in the field of life sciences not just as an EMBO internal controversy, but rather as a structural issue of European scientific cooperation in fundamental biology in the early 1960s. Along with EMBO, the article analyzes in particular the EURATOM Biology Division Program and the constitution of UNESCO International Cell Research Organization (ICRO). Adriano Buzzati-Traverso, as founder of ILGB and scientific consultant of EURATOM and UNESCO, played a crucial role in the complex negotiation which ultimately led to the foundation of EMBO. A synchronic treatment of ILGB, EURATOM, UNESCO-ICRO and EMBO opens a window on the early 1960s institutional configuration of molecular biology in Europe, showing how it basically incorporated the "Cold Spring Harbor" decentralized model rather than reproducing the "CERN" centralized model. PMID- 25931209 TI - Update on transient cardiac standstill in cerebrovascular surgery. AB - Transient cardiac standstill is a complementary procedure used with microsurgery to treat patients with particularly complex aneurysms, such as large or giant cerebral aneurysms. These procedures allow the aneurysms to be decompressed while maintaining a bloodless field and increased surgical exposure. Deep hypothermia combined with circulatory arrest provides cerebroprotection with optimal surgical conditions. However, its disadvantage is the relatively high risk of the procedure, which requires extensive expertise and infrastructure. Thus, its use is typically limited to patients with complex posterior circulation aneurysms. Adenosine-induced transient asystole is an easily applied technique in a variety of clinical situations. Its use requires minimal advanced preparation and no complex logistical coordination with other subspecialties. However, patient specific dose-response relationships must be determined by exposure, so the relationship may not be known in an emergent situation. Persistent hypotension is a potentially major complication. Rapid ventricular pacing (RVP) has recently been reintroduced into cerebrovascular surgery. It is more predictable than adenosine in response time and, thus, can be used during unanticipated complications, such as aneurysmal rupture. It also induces a shorter period of hypotension compared with adenosine. However, RVP is more invasive and more complex from an anesthesia standpoint. Vascular neurosurgeons should be familiar with these techniques and know their applications and limitations. PMID- 25931210 TI - MiR-429 increases the metastatic capability of HCC via regulating classic Wnt pathway rather than epithelial-mesenchymal transition. AB - Epigenetic modification of miR-429 can manipulate liver T-ICs via targeting the RBBP4/E2F1/Oct4 axis, which might be crucial for hepatocarcinogenesis. However, whether miR-429 plays a role in regulating metastasis of hepatocellular carcinoma is still unclear. Using quantitative methylation analysis and real-time PCR, we have identified the hypomethylated status and upregulation of miR-429 in portal vein metastasis samples in comparison with their matched primary tumor. The ectopic expression of miR-429 dramatically induced the expression of MMP2/7/9 and enhanced HCC migration and invasion in vitro and in vivo in an EMT-independent manner. Both bioinformatics and functional studies elucidated the direct regulation of miR-429 on the 3'UTR of the PTEN gene, which leads to the activation of PI3K/AKT signaling and the nuclear translocation of beta-catenin, eventually. Conversely, the knockdown of miR-429 efficiently recovered the expression of PTEN and attenuated PI3K/AKT/beta-catenin-mediated cell metastasis. Clinically, the higher expression of miR-429 and nucleus relocation of beta catenin were identified as the adverse prognosis factors for recurrence-free survival (RFS) and overall survival (OS). In summary, our results here defined miR-429 as a key inducer for HCC pathogenesis and metastasis with potential utility for tumor intervention. PMID- 25931211 TI - Identification of orthologous target pairs with shared active compounds and comparison of organism-specific activity patterns. AB - A systematic search for active small molecules shared by orthologous targets was carried out, leading to the identification of 803 compound-based orthologous target pairs covering a total of 938 orthologues, 358 unique targets and 98 organisms. Many orthologous target pairs were found to have substantial compound coverage, enabling the introduction of an orthologous target pairs classification including 'organism cliffs' and 'potency-retaining' pairs. A total of 158 orthologous target pairs involving human orthologues were identified, which were typically associated with drug discovery-relevant targets, organism combinations and compound data. Orthologous target pairs with human orthologues included 83 potency-retaining orthologous target pairs covering a variety of targets and organisms. On the basis of these orthologous target pairs, the compound search was further extended and 1149 potent compounds were identified that only had reported activities for non-human orthologues of 48 therapeutic targets, but not their human counterparts, hence providing a large pool of candidate compounds for further evaluation. The complete set of orthologous target pairs identified in our analysis, the orthologous target pairs classification including associated data and all candidate compounds are made freely available. PMID- 25931212 TI - [Treatment of vascular Parkinson's syndrome after stroke by ultralow frequency and high frequency repetitive transcranial magnetic stimulation]. AB - OBJECTIVE: To determine effect and safety of ultra-low frequency and high frequency repetitive transcranial magnetic stimulation on treating vascular Parkinson's syndrome (VPS) after stroke. METHODS: The 0.1 Hz low frequency (n=21) and 5 Hz high frequency (n=21) rTMS were used to treat patients with VPS, and the false stimulation servered as a control group (n=18). The UPDRS score and Parkinson's Disease Questionnaire (PDQ) were chosen to evaluate the curative effect on PD. The patients were given anti-PD drugs continuously during the treatment. RESULTS: UPDRS scores as well as I, II, and III scores after the treatment were significantly decreased in both the ultra-low frequency group and the high frequency group compared with those before the treatment (all P<0.05). The scores at the third month after the treatment were still lower than those before the treatment (P<0.05), but there was no significant difference between the ultra-low frequency and the high frequency group at the same time point before and after the treatment (P>0.05). There was no significant difference in UPDRS scores between before and after the treatment in the control group (P>0.05), but PDQ scores were significantly decreased at the third month after the treatment compared with those of before and after treatment (P<0.05). CONCLUSION: The low frequency and high frequency repetitive transcranial magnetic stimulation can safely improve the clinical symptoms and life quality of patients with VPS. PMID- 25931213 TI - [Effects of benzo(a)pyrene exposure on the ATPase activity and content of Ca2+ in the hippocampus of neonatal SD rats]. AB - OBJECTIVE: To investigate the effect of benzo(alpha)pyrene on the ATPase activity and content of Ca2+ in the hippocampus of neonatal SD rats. METHODS: Sixty male and 60 female 4-days-old neonatal SD rats were randomly divided into 5 groups (n=24): a blank control group, a vehicle control group (peanut oil), 3 benzo(alpha)pyrene groups (0.02, 0.2 and 2 mg/kg, respectively). SD rats were given benzo(alpha)pyrene (dissolved in peanut oil) by gavage daily from postnatal day 4 (PND4) to PND20. The nerve reflex, the condition of neuro-muscle development and motion function were examined in the period of treatment. The colorimetric technique was used to detect the activity of Ca2+-ATPase and Ca2+ Mg2+-ATPase in hippocampus after the treatment. The concentration of Ca2+ of synapse in the hippocampus of rats was detected by fluorescent labeling. RESULTS: The results from the behavior tests showed that duration of surface reflex latency in rats with medium dose of benzo(alpha)pyrene was longer compared with that in the control group in PND12. The duration of surface reflex latency in rats with high dose of benzo(alpha) pyrene is longer in PND 14 and PND 16 compared with that in the control group (P<0.05). Compared with the rats in the control group, the activities of Ca2+-Mg2+-ATPase and Ca2+-ATPase in hippocampus in rats with high dose benzo(alpha) pyrene were significantly decreased, and the degree in the decrease of Ca2+-ATPase activity was dose-dependent (P<0.05). The contents of Ca2+ in the hippocampus in rats with medium or high dose of benzo(alpha) pyrene were significantly increased compared with that in the control group (P<0.05), which showed a dose-dependent manner (P<0.05). CONCLUSION: Benzo(alpha)pyrene exposure led to the decrease in ATPase activity as well as Ca2+ overload of the synapse in the hippocampal tissue, which in turn results in the nerve damage of newborn SD rats. PMID- 25931214 TI - [Circulating miR-214 level and its correlation with the extent of coronary lesion in patients with acute myocardial infarction]. AB - OBJECTIVE: To examine the circulating levels of miR-214 in acute myocardial infarction (AMI) patients and to explore the relationship between the circulating levels of miR-214 and the degree of coronary lesion. METHODS: A total of 45 patients with AMI (AMI group) were enrolled from Xiangya Hospital of Central South University between September, 2011 and January, 2012. Twenty healthy volunteers served as a normal control group (n=20). According to the coronary artery lesion area, AMI group was also divided into a single-branch group, a double-branch group and a triple-branch group (n=20, 13, 12 respectively). Circulating levels of miR-214 and plasma levels of placental growth factor (PLGF) were measured by real time-PCR assay and enzyme-linked immunosorbent assay respectively on the day when the patients admitted to the hospital. The plasma levels of miR-214 and PLGF were compared among the various branch groups. The correlation between miR-214 and PLGF was analyzed in AMI subgroups. RESULTS: The miR-214 levels in the AMI subgroups were lower than that in the control group. The more decrease in miR-214 level, the larger size of coronary lesion. There was significant difference in the different groups (all P<0.05). Compared with the control group, the levels of plasma PLGF were significantly higher in the AMI subgroups. The more increase in PLGF level, the larger size of coronary lesion. There was significant difference in the different groups (all P<0.05). The plasma levels of miR- 214 were negatively correlated with that of PLGF in the AMI group (r=-0.588, P<0.01). CONCLUSION: The circulating level of miR-214 was significantly decreased in the AMI group, which might be correlated with the extent of the coronary lesion. Circulating miR-214 may be a promising biomarker for the diagnosis and prognosis of severe AMI. PMID- 25931215 TI - [Association of serum level of apolipoprotein M with disease activity in systemic lupus erythematosus]. AB - OBJECTIVE: To explore the association of serum level of apolipoprotein M with disease activity in systemic lupus erythematosus (SLE). METHODS: A total of 65 patients with SLE, who came to Second Xiangya Hospital for treatment from April to November in 2013 (SLE group) and 120 age-and sex-matched controls (control group) were studied. The SLE group was further divided into three groups according to systemic lupus erythematosus disease activity index (SLEDAI): a mild activity group, a moderate activity group and a severe activity group (n=16, 16, 33, respectively). The control group was also divided into a disease control group (n=60) and a healthy control group (n=60). The serum levels of apo M were measured by enzyme-linked immunosorbent assay (ELISA). Other indicators including TC, TG, HDL, LDL, apo A1, apo B, and anti-dsDNA antibody were detected. The correlation between SLEDAI or anti-dsDNA antibody and apo M was assessed. RESULTS: Compared with the healthy control group, the expression levels of apo M and HDL were decreased significantly (both P<0.05), and the expression levels of anti-dsDNA antibody, TG, apo B were increased significantly in the SLE group (all P<0.05). Comparison among the three subgroups, no significant differences in apo M were found (all P>0.05). The serum concentration of apo M was significant negatively correlated with SLEDAI and anti-dsDNA antibody (r=-0.551, -0.562, both P<0.01). CONCLUSION: Compared with the healthy control group, the serum levels of apo M in patients with SLE are significantly decreased. The apo M is closely correlated with disease activity of SLE and it might be used as an indicator to monitor the disease activity of SLE. PMID- 25931216 TI - [Transient stopping immunosuppressive agents during the post-transplant pulmonary infection does not affect the long-term outcome of renal transplantation]. AB - OBJECTIVE: To determine the effect of transient withdrawal of immunosuppressive agents during the treatment of pulmonary infection on long-term survival of patients and graft s. METHODS: A total of 104 patients with post-transplant pulmonary infection were enrolled in this study. These patients received renal transplantation in Center for Organ Transplantation, Xiangya Hospital, Central South University, during December 2005 and August 2014. Among them, 50 patients stopped immunosuppressive agents during the treatment of infection. These patients served as stopping drug (SD) group, whereas the remaining patients who served as a control group did not stop immunosuppressive drugs. The five-year cumulative patient survival, graft survival, and laboratory results were compared between the 2 groups. RESULTS: The five-year cumulative patient survival rates in the SD group were significantly lower than those in the control group [(69.8 +/- 7.0)% vs (94.2 +/- 3.2)%, P=0.001]. There was no significant difference in the allograft survival rates between the 2 groups [(81.7 +/- 6.6)% vs (90.9 +/- 4.3)%, P=0.113]. In patients who survived from pulmonary infection, there was no significant difference in long-term survival rates between the 2 groups (P=0.979). CONCLUSION: Pulmonary infection impacts allograft survival after patients underwent renal transplantation. Transient stopping immunosuppressive agents during the treatment of infection is a safe and necessary treatment strategy for patients with serious post-transplant pulmonary infection. PMID- 25931217 TI - [Expression of perforin and granzyme-B in peripheral blood lymphocyte in patients with prostate cancer and the clinical significance]. AB - OBJECTIVE: To explore the expression of perforin and granzyme-B in peripheral blood lymphocyte (PBL) in patients with prostate cancer (PCa) and the clinical significance. METHODS: The expressions of perforin and granzyme-B in PBL were detected by fluorescence quantitative reverse transcription polymerase chain reaction. The results of perforin and granzyme-B expression were compared among patients with PCa (n=60), patients with BPH (benign prostatic hyperplasia, n=40) and healthy controls (n=20). RESULTS: Th e expressions of perforin and granzyme-B in patients with PCa were significantly lower than that in patients with BPH or that in the healthy controls (P<0.05), respectively. Furthermore, in PCa patients with low pathological grade, the expressions of perforin and granzyme-B in PBL was statistically higher than that in patients with high pathological grade (P<0.05). The expressions of perforin and granzyme-B in PCa patients at high clinical stage was statistically lower than that in PCa patients at low clinical stage (P<0.05). CONCLUSION: The results of this study suggest that development and progression of PCa might be associated with poor immune status of patients. PMID- 25931218 TI - [MRI features of phyllodes tumor of the breast and the pathological study]. AB - OBJECTIVE: To analyze the features of MRI and pathology for phyllodes tumor of the breast and to improve the diagnosis level. METHODS: The MRI data of 11 patients with phyllodes tumor of the breast were analyzed. The MRI features included morphology, signal intensity on pre-enhanced T1WI, appearance of dynamic contrast enhancement (DCE-MRI) and the type of time-signal intensity curve (TIC). RESULTS: The pathologic diagnosis for the 11 phyllodes tumor included 6 benign, 2 borderline and 3 malignant. All of the 11 tumors showed well-defined margins and lobulated lump. The signal intensity of tumor was lower (4 cases) than or equal (7 cases) to that of normal breast tissue on T1-weighted images. On T2-weighted images, 5 cases presented variegated appearance, 6 cases displayed high signal. Four cases showed patchy high signal on T1WI and T2WI. All patients underwent DCE MRI and showed uneven enhancement. There were 7 cases in type I of TIC and 4 cases in type II. CONCLUSION: The imaging findings of phyllodes tumor on MR is characteristic but not specific, the final diagnosis still depends on the histopathologic examination. PMID- 25931219 TI - [Clinical research on the application of trans-esophageal echocardiography in monitoring Nuss surgery]. AB - OBJECTIVE: To investigate the validity and safety of trans-esophageal echocardiography (TEE) in monitoring of Nuss surgery. METHODS: A total of 140 patients with pectus excavatum from Sichuan Provincial People's Hospital underwent Nuss surgery from August, 2011 to AMUgust, 2013. Among them, 72 patients received TEE monitoring while 68 patients didn't. The injury of heart and large vessels by the introducer and Nuss steel bar was observed by intraoperative TEE monitoring under middle-esophageal four chamber view and middle-esophageal aortic short axis view. RESULTS: The operation in all patients had been performed successfully without any severe complications. Satisfactory TEE images were obtained in all patients. The procedure of inserting the inducer and Nuss steel bar behind sternum and steel bar overturn could be seen clearly. No injury in heart and large vessels was detected. Local streak-like hemorrhage in 3 patients was observed under intra-operative TEE screen, but no further new bleeding was found in postoperative TEE examination. The blood was absorbed and couldn't see under trans-thoracic echocardiography in 1 month after the operation. CONCLUSION: The TEE is a non-invasive monitoring method. It is sensitive to detect the status of the heart and large vessels and can prevent the severe complications due to Nuss surgery. PMID- 25931220 TI - [Impact of pre-pregnancy body mass index on baby's physical growth and nutritional status]. AB - OBJECTIVE: To explore the impact of pre-pregnancy body mass index on baby's physical growth and nutritional status. METHODS: A total of 491 pairs of mother infant were divided into 3 groups according to mother's pre-pregnancy body mass index (BMI): a pre-pregnancy low BMI group (BMI<18.5 kg/m2, n=93), a pre pregnancy normal BMI group (18.5 kg/m2 <= BMI<24.0 kg/m2, n=326), and a pre pregnancy high BMI group (BMI >= 24.0 kg/m2, n=72). Analysis of variance of repeated measurement data and the median percentage methods were used to compare the physical growth and nutritional status of babies in different groups. RESULTS: Baby's weight in the high BMI group were higher than that in the normal BMI and the low BMI group (F=3.958, P=0.020). The incidence of malnutrition in the low BMI group showed a tendency to decline along with the months (chi2=5.611, P=0.018), the incidence of overweight and obesity in the high and the normal BMI groups displayed a tendency to decline along with the months (chi2=18.773, 53.248, all P<0.001). Baby in the low BMI group had higher incidence of malnutrition while baby in the high BMI group had higher incidence of overweight and obesity. CONCLUSION: Pregnancy BMI was correlated with the growth of baby. Too high or too low prepregnancy BMI exerts harmful effect on baby's weight and nutritional status. Medical workers should strengthen the education on women's pre-pregnancy to remind them keeping BMI at normal level. PMID- 25931221 TI - [Evaluation index system for equalization of basic public health services]. AB - OBJECTIVE: To establish the evaluation index system for equalization of basic public health services and to test its value in practice. METHODS: We developed the index system through expert scored evaluation and then chose a city in Hunan for the research object. The sources of data and the methods of collection for each indicator were identified. The reliability and validity of index system was tested. The methods of AHP (analytic hierarchy process) and TOPSIS (technique for order preference by similarity to an ideal solution) were applied to comprehensively evaluate the public health services among nine counties in the city. RESULTS: The Cronbach's alpha coefficient, which described reliability test result on evaluation index system for equalization of basic public health services, was 0.750. The cumulative contribution rate reached 89.32% after validity test with extraction of 5 common factors through factor-analysis. The sorting results from AHP or TOPSIS method are very close except two districts. CONCLUSION: Evaluation index system for equalization of basic public health services established in this study is in good validity and reliability, which can be objectively applied to analyze the current status of basic public health services. PMID- 25931222 TI - [Gene therapy and Alzheimer's disease]. AB - Alzheimer's disease (AD) is a progressive neurodegenerative disease characterized by the presence of extracellular beta-amyloid in the senile plaques, intracellular aggregates of abnormal phosphorylation of tau protein in the neurofibrillary tangles, neuronal loss and cerebrovascular amyloidosis. The manifestations of clinical symptoms include memory impairment, cognitive decline, altered behavior and language deficit. Currently available drugs in AD therapy consist of acetylcholinesterase inhibitors, NMDA receptor antagonists, non steroidal anti-inflammatory drugs, etc. These drugs can only alleviate the symptoms of AD. Gene therapy is achieved by vector-mediated gene transfer technology, which can delivery DNA or RNA into target cells to promote the expression of a protective or therapeutic protein and silence certain virulence genes. PMID- 25931223 TI - [Progress in regulatory T cells and hepatocellular carcinoma]. AB - As a functionally unique subset of T cells, regulatory T cells (Treg) suppress tumor immune responses effectively through a variety of mechanisms and play an important role in tumorigenesis and tumor progression. There is growing evidence to suggest that Treg participates in the formation and development of hepatic tumor, especially the HCC. Elucidation of the mechanisms for involvement of Treg in HCC progression may provide new ideas for liver cancer therapy through a point of view regarding immunology. PMID- 25931224 TI - [Expression of 5-lipoxygenase in human tissues and its association with disease]. AB - 5-Lipoxygenase, one of lipoxygenase isozymes, is a well-studied oxidative metabolism enzyme. It widely exists in various human tissues and cells, participates in the oxidative metabolism of endogenous and exogenous chemicals, and produces a variety of metabolites, all of which contribute to the occurrence of human diseases, such as inflammation, asthma, atherosclerosis, and tumor and so on. The expression of 5-lipoxygenase is at low level in normal human tissues while at high level in abnormal tissues. 5-Lipoxygenase is closely related to many kinds of diseases in human ovary, brain, cardiovascular system, lung, liver, pancreas and other tissues. The abnormal expression of 5-lipoxygenase tends to promote the development of the disease. PMID- 25931225 TI - [Experience of treatment for accumulation of extra-axil cerebrospinal fluid after skull surgery]. AB - OBJECTIVE: To explore the treatment and pathophysiology of extra-axil cerebrospinal fluid accumulation aft er skull surgery. METHODS: The treatment of 46 cases of pineal regional tumor was retrospectively studied. RESULTS: The CT showed that all patients had postoperative extra-axil cerebrospinal fluid accumulation in 6 hours after operation. 5 cases displayed symptomatic accumulation of extra-axil cerebrospinal fluid. 1 died 30 days aft er discharge, 4 performed S-P shunt and 3 of them switched to V-P shunt after S-P shunt failed. CONCLUSION: Much more attention should be paid to postoperative accumulation of extra-axil cerebrospinal fluid. Both V-P and S-P are the effective strategies of therapy. PMID- 25931226 TI - [Perioperative nursing for gastric perforation repair operation performed by the first domestic surgical robot]. AB - We reported a case of gastric perforation repair operation performed by the first domestic surgical robot, named Miaoshou. The comprehensive and accurate nursing assessments and targeted psychological care were performed before the surgery. Close observation and care, effective prevention and treatment of complications, and nice guidance of diet were conducted after the surgery. All of these measures exerted positive effects on successful operation and early rehabilitation for patients. PMID- 25931227 TI - [Expression and purification of DNA binding domain of NR4A1]. AB - OBJECTIVE: To express and purify NR4A1-DNA binding domain (DBD) protein of nuclear receptors. METHODS: The fusion protein PET28a-NR4A1-DBD was constructed and purified with the nickel affinity chromatography, cation-exchange chromatography and gel filtration chromatography. RESULTS: The protein PET28a NR4A1-DBD was mostly soluable at 24 degrees C. A total of 2-3 mg/L pure NR4A1 proteins were yielded in bacterial culture and the purity for final fractions of NR4A1-DBD protein were great than 95% by SDS-PAGE analysis. CONCLUSION: Nickel affinity chromatography is effective to purify protein. The protein purity can be further improved by the following methods including cation-exchange chromatography and gel filtration chromatography. PMID- 25931228 TI - [Analysis of human papillomavirus infection in 16 320 patients from gynecologic clinic]. AB - OBJECTIVE: To evaluate the genital human papillomavirus (HPV) infection in patients from gynecology clinic, and to investigate the association of persistent HPV infection with cervical lesions. METHODS: From January, 2009 to December, 2013, clinical data of 16 320 patients in Third Xiangya Hospital were collected. A retrospective analysis was carried out to evaluate the overall prevalence of HPV infection. The prevalence of HPV infection in different ages and subtypes were compared. The prevalence of persistent HPV infection and results of cervical cytology were analyzed. RESULTS: The overall HPV prevalence was 26.54%. The lowest overall and high-risk HPV prevalence were found in women at the age of 30 39 years old (P<0.05); the highest ones were found at the age of over 60 years old, with significant difference among the aged groups (P<0.05). There was no significant difference in low-risk HPV prevalence among the aged groups (P=0.693). The clearance rate of HPV was 87.65% one year later. There was no significant difference in high-risk and low-risk HPV infection between the non persistent positive group and the persistent positive group (P=0.545), but the difference in single and multiple subtypes infection between these 2 groups was significant (P<0.05). In the persistent positive group, the most common genotypes were HPV 16, 52, 58, CP8304, and 33. The incidence of ASC-US, HSIL or SCC was significantly increased in the persistent positive group. CONCLUSION: Persistent HPV infection mainly consists of multiple and high-risk HPV infection. It is necessary to focus on the prevention of HPV 16, 52 and 58 persistent infection in our region. PMID- 25931229 TI - [Cephalometric analysis of the soft tissue profile in Hunan Han adults with normal occlusion]. AB - OBJECTIVE: To analyze the characteristics soft tissue profile in Hunan Han adults with normal occlusion and to explore the differences of the soft tissue profile in gender, region and race. METHODS: Lateral cephalometric radiographs were performed for 323 volunteers (164 females and 159 males) from Hunan Province. The digital cephalometric radiographs were imported into the WinCeph8.0 measurement and analysis system in a same computer. According to the Holdaway analysis method, the mean and standard deviation were calculated. Then the results were compared to the data from Liaoning, Nepalese, Japanese, North American Caucasians. RESULTS: The normal value of cephalometric facial soft tissue profile in Han population adults with normal occlusion in Hunan Province were obtained. There were significant differences in subnasale to H line (Sn-H), upper lip tension, lower lip sulcus depth (Si-PgsLs), and soft tissue chin thickness (Pg Pgs) between males and females (all P<0.05). Compared with Liaoning Province, significant regional differences in soft tissue facial angle (FH-NsPgs), upper lip sulcus depth (Ss-Ls), Sn-H, lower lip thickness, upper lip thickness, H angle, lower lip to H line (Li-PgsLs), Si-PgsLs, and Pg-Pgs were found in Hunan Province (all P<0.05). Compared with the Japan, significant regional differences in FH-NsPgs, nose prominence (Sn-Pn), lower lip thickness, upper lip tensity, H angle, Li-PgsLs, Si-PgsLs, and Pg-Pgs were found in Hunan Province (all P<0.05). Compared with the Nepalese, significant regional differences in Sn-Pn, Ss-Ls, Sn H, skeletal profile convexity (A-NPs), basic upper lip thickness, upper lip tensity, H angle, Li-PgsLs and Pg-Pgs were found in Hunan Province (all P<0.05). Compared with the North America, significant regional differences in Sn-Pn, Ss Ls, Sn-H, A-NPs, basic upper lip thickness, upper lip tensity, H angle, Li-PgsLs, Si-PgsLs and Pg-Pgs were found in Hunan Province (all P<0.05). CONCLUSION: There are both similarities and differences in facial soft tissue profile between males and females with normal occlusion in Hunan Province. The characteristics of facial soft tissue profile in Hunan Province are different from that in Liaoning area, Nepal, Japan and North America. PMID- 25931230 TI - [Clinical analysis of bone flap craniotomy for 17 patients with chronic subdural hematomas]. AB - OBJECTIVE: To deepen the understanding of chronic subdural hematoma and to seek the effective treatment for chronic subdural hematoma (CSDH). METHODS: We retrospectively reviewed a series of 17 consecutive patients with CSDH, who received the treatment of bone flap craniotomy. To explore the surgical indications for CSDH, the data of imaging appearance, intraoperative findings and postoperative complications were analyzed. RESULTS: Among the patients, 13 were septated CSDH, with the characteristic imaging features such as anti-"3" impression in the inner edge of the hematoma and fibrous strap structure in the hematoma. Four patients were organized CSDH, with strong signals of T1 and T2 as well as hypointense netlike structure within the hematoma cavity while low signal on MRI in the thickened inner membrane. Burr hole trepanation was performed, but no improvement were achieved, whereas the bone flap craniotomy removed the hematoma completely without serious surgical complication except 1 case. CONCLUSION: Based on the preoperative imaging data, flap bone craniotomy seems to be the first choice for treatment of CSDH. PMID- 25931231 TI - Hydrogel Retaining Toxin-Absorbing Nanosponges for Local Treatment of Methicillin Resistant Staphylococcus aureus Infection. PMID- 25931232 TI - Risk of thiamine deficiency and Wernicke's encephalopathy after gastrointestinal surgery for cancer. AB - BACKGROUND: Cancer patients submitted to gastrointestinal surgery are at risk of thiamine deficiency (TD) and Wernicke's encephalopathy (WE). Although permanent neurological damage and death could be prevented by a timely replacement therapy, they often remain undiagnosed and untreated. We hypothesized that WE remains unrecognized because most cases may manifest several months after hospital discharge. METHODS: WE frequency was investigated in a sample of cancer patients who underwent gastrointestinal surgery, by using the diagnostic criteria proposed to improve diagnosis among alcoholics. Patients were evaluated at discharge through the examination of medical records and 6 months after by telephonic interview. RESULTS: Forty-five patients were selected. Signs of WE resulted in 4.4% at discharge. At 6 months, 21 patients were interviewed. Among them, 90.4% had signs of WE. The number of affected patients was significantly higher 6 months after discharge than at discharge (90.4 vs 9.5%, p < 0.0001). CONCLUSIONS: Further studies with larger samples are needed to establish the prevalence of TD and related WE in cancer patients after gastrointestinal surgery. This study suggests that the problem is understated. Even in absence of symptoms of TD, the use of prophylactic thiamine supplementation should be taken in consideration, as consequences of misdiagnosis can be severe. PMID- 25931233 TI - Influence of roughness and tilt on nanoindentation measurements: A quantitative model. AB - A model, which takes into account the indentation size effect, was proposed to relate hardness and its standard deviation to the quality of the sample surface, i.e., the roughness and the tilt. Stainless steel samples were mechanically polished so as to obtain various roughness and tilt. Then the quality of the surface and the hardness were measured respectively by scanning probe microscopy and by nanoindentation. The model was fitted according to those experimental data. It was shown that the standard deviation only depends on the ratio of the arithmetic roughness over the contact depth of the indent while the average hardness also depends on the contact depth and on the tilt. It was deduced that hardness measurements are performed with an uncertainty lower than 10% if: (i) the ratio of the arithmetic roughness over the contact depth of the indent is lower than 0.05, (ii) the tilt of the sample is lower than 2 degrees and (iii) the difference of roughness between samples is lower than 50%. PMID- 25931234 TI - Intravascular NK/T-cell lymphoma: a report of five cases with cutaneous manifestation from China. AB - BACKGROUND: Intravascular lymphoma is a rare type of lymphoma that frequently affects the skin and is usually of B-cell origin. This lymphoma type is very rare and not recognized as a separate entity in the 2008 World Health Organization classification of hematopoietic and lymphoid tissue tumors. METHODS: We reported five cases of intravascular NK/T cell lymphoma with cutaneous manifestation and reviewed 12 published cases involving Chinese patients with similar characteristics. RESULTS: All five patients were adults who exhibited red or brown patches or plaques on the lower extremities or trunk; four cases were associated with B symptoms; one case developed subsequent to a lymphoma on the face (possibly extranodal NK/T cell lymphoma, nasal type). Histopathologically, all patients exhibited abnormal, medium-sized intravascular lymphocytes in the dermis and subcutaneous tissues. All patients were positive for CD2, CD3epsilon, CD56 and cytotoxic proteins. All cases were Epstein-Barr virus (EBV) positive. Four of FIVE patients died of lymphoma within a few months of diagnosis. CONCLUSIONS: Intravascular NK/T-cell lymphoma is a rare highly aggressive and EBV associated lymphoma that is prone to develop in Chinese patients. The relationship between intravascular NK/T-cell lymphoma and extranodal NK/T-cell lymphoma, nasal type, requires clarification. PMID- 25931235 TI - Chlamydia testing: Reaching high-risk sexually active young people in the community. PMID- 25931236 TI - Five years' real-life experience with raltegravir in a large HIV centre. AB - Raltegravir was the first licensed integrase inhibitor. Real-life experience is informative and complements trial data. We therefore evaluated raltegravir use in adults in a large HIV treatment centre. From pharmacy and departmental HIV database records, we identified all adults taking >=1 dose of raltegravir from first availability to the end of November 2012. Data were collected using a standardised case report form. Two hundred and fifteen individuals provided 502 patient-years (median 2.6 years/person) of raltegravir use. Of 215 individuals, 166 (77%) were male, median age 43 years; 189 (88%) were antiretroviral therapy (ART)-experienced and 26 (12%) ART-naive, with median baseline CD4 counts of 324 and 54 cells/uL, respectively. Of ten individuals using once-daily raltegravir, four, with good adherence remained virologically suppressed after a median 28 months, four stopped against medical advice, one stopped to simplify and one failed virologically. In hepatitis co-infection, 35 individuals (92 patient years) took raltegravir without evidence of hepatotoxicity. Six women started raltegravir during pregnancy for intensification (5/6) or switch for tolerability without complications. Of ten individuals stopping raltegravir after virological failure, 2/4 with successful sequencing showed resistance. Raltegravir appears safe and effective, without evidence of toxicity above that in published trials, including in pregnancy and co-infections. Once-daily dosing seems effective where adherence is good. PMID- 25931237 TI - Distance from care predicts in-hospital mortality in HIV-infected patients with severe sepsis from rural and semi-rural Virginia, USA. AB - There are few data regarding outcomes from severe sepsis for HIV-infected patients living in rural or semi-rural settings. We aim to describe the characteristics and predictors of mortality in HIV-infected patients admitted with severe sepsis to the University of Virginia located in semi-rural Charlottesville, Virginia, USA. We queried the University of Virginia Clinical Data Repository for cases with ICD-9 codes that included: (1) infection, (2) acute organ dysfunction, and (3) HIV infection. We reviewed each case to confirm the presence of HIV infection and severe sepsis. We recorded socio-demographic, clinical, and laboratory data. We used a generalised linear mixed-effects model to assess pre-specified predictors of mortality. We identified 74 cases of severe sepsis in HIV-infected patients admitted to University of Virginia since 2001. The median (IQR) age was 44 (36-49), 32 (43%) were women, and 56 (76%) were from ethnic minorities. The median (IQR) CD4+ T-cell count was 81 (7-281) cells/uL. In hospital mortality was 20%. When adjusted for severity of illness and respiratory failure, patients who lived >40 miles away from care or had a CD4+ T cell count <50 cells/uL had > four-fold increased risk of death compared to the rest of the study population (AOR = 4.18, 95% CI: 1.09-16.07, p = 0.037; AOR = 4.33, 95% CI: 1.15-16.29, p = 0.03). In HIV-infected patients from rural and semi-rural Virginia with severe sepsis, mortality was increased in those that lived far from University of Virginia or had a low CD4+ T cell counts. Our data suggest that rural HIV-infected patients may have limited access to care, which predisposes them to critical illness and a high associated mortality. PMID- 25931238 TI - Long-term postpartum adherence to antiretroviral drugs among women in Latin America. AB - Antiretroviral adherence in the postpartum period is crucial for maternal health and decreasing the risk of mother-to-child HIV transmission and transmission to sexual partners. Self-reported antiretroviral adherence was examined between 6- to 12-weeks and 30 months postpartum among 270 HIV-infected women enrolled in a prospective cohort study from 2008 to 2010 at multiple sites in Latin America. Adherence data were collected at each study visit to quantify the proportion of prescribed antiretrovirals taken during the previous three days, assess the timing of the last missed dose, and identify predictors of adherence. Mean adherence rates were 89.5% at 6-12 weeks and 92.4% at 30 months; the proportions with perfect adherence were 80.3% and 83.6%, respectively. The overall trend for perfect adherence was not significant (p = 0.71). In adjusted regression modelling, younger age was associated with an increased probability of non perfect adherence at 18 and 24 months postpartum. Other factors associated with increased probability of non-perfect adherence were higher parity, current use of alcohol and tobacco, and more advanced HIV disease. Women with perfect adherence had lower viral loads. Interventions for alcohol and tobacco use cessation, and support for young women and those with advanced HIV disease should be considered to improve postpartum adherence. PMID- 25931239 TI - A Randomized Controlled Evaluation of the Efficacy of an Ankle-Foot Cast on Walking Recovery Early After Stroke: SWIFT Cast Trial. AB - BACKGROUND: Timely provision of an ankle-foot orthosis (AFO) orthotist customized for individuals early after stroke can be problematic. OBJECTIVE: To evaluate the efficacy of a therapist-made AFO (SWIFT Cast) for walking recovery. METHODS: This was a randomized controlled, observer-blind trial. Participants (n = 105) were recruited 3 to 42 days poststroke. All received conventional physical therapy (CPT) that included use of "off-the-shelf" and orthotist-made AFOs. People allocated to the experimental group also received a SWIFT Cast for up to 6 weeks. Measures were undertaken before randomization, 6 weeks thereafter (outcome), and at 6 months after stroke (follow-up). The primary measure was walking speed. Clinical efficacy evaluation used analysis of covariance. RESULTS: Use of a SWIFT Cast during CPT sessions was significantly higher (P < .001) for the SWIFT Cast (55%) than the CPT group (3%). The CPT group used an AFO in 26% of CPT sessions, compared with 11% for the SWIFT Cast group (P = .005). At outcome, walking speed was 0.42 (standard deviation [SD] = 0.37) m/s for the CPT group and 0.32 (SD = 0.34) m/s for the SWIFT Cast group. Follow-up walking speed was 0.53 (SD = 0.38) m/s for the CPT group and 0.43 (0.34) m/s for the SWIFT Cast group. Differences, after accounting for minimization factors, were insignificant at outcome (P = .345) and follow-up (P = .360). CONCLUSION AND IMPLICATIONS: SWIFT Cast did not enhance the benefit of CPT, but the control group had greater use of another AFO. However, SWIFT Cast remains a clinical option because it is low cost and custom made by therapists who can readily adapt it during the rehabilitation period. PMID- 25931240 TI - Characteristics Associated with HIV Drug Resistance Among Women Screening for an HIV Prevention Trial in KwaZulu-Natal, South Africa. AB - While the expansion of antiretroviral therapy (ART) in sub-Saharan Africa has reduced morbidity and mortality from HIV/AIDS, it has increased concern about drug resistance. The Microbicide Trials Network 009 study assessed the prevalence of drug-resistance mutations among women at clinical sites in Durban, South Africa who tested seropositive for HIV-1 at screening for the VOICE trial. The objective of this paper was to identify characteristics and behaviors associated with drug resistance. Factors found to be significantly associated with increased resistance were high perceived risk of getting HIV and prior participation in a microbicide trial, a likely proxy for familiarity with the health care system. Two factors were found to be significantly associated with reduced resistance: having a primary sex partner and testing negative for HIV in the past year. Other variables hypothesized to be important in identifying women with resistant virus, including partner or friend on ART who shared with the participant and being given antiretrovirals during pregnancy or labor, or the proxy variable-number of times given birth in a health facility-were not significantly associated. The small number of participants with resistant virus and the probable underreporting of sensitive behaviors likely affected our ability to construct a comprehensive profile of the type of HIV-positive women at greatest risk of developing resistance mutations. PMID- 25931241 TI - Socio-demographic, Behavioral and Health Characteristics of Underage Female Sex Workers in Mozambique: The Need to Protect a Generation from HIV Risk. AB - Characteristics, HIV risk, and program coverage for underage female sex workers (FSW) are rarely systematically described worldwide. We compared characteristics of underage (15-17 years old) and adult (>=18 years old) FSW in three main urban areas of Mozambique (Maputo, Beira and Nampula) using data from three respondent driven sampling surveys implemented in 2011-2012. Among survey participants, 9.8 % (39/400) in Maputo, 17.0 % (70/411) in Beira and 25.6 % (110/429) in Nampula were underage. Over half reported performing sex work to afford daily living, and 29.7-50.0 % had unprotected sex with their last client. The proportion of underage FSW having accessed care and prevention services was lower compared to adult FSW. While HIV prevalence among underage FSW was lower than in adults, it increased markedly with age. Our results point to the urgency of expanding prevention and care programs geared towards underage FSW. PMID- 25931242 TI - Female Partner Acceptance as a Predictor of Men's Readiness to Undergo Voluntary Medical Male Circumcision in Zambia: The Spear and Shield Project. AB - The World Health Organization has recommended the scale-up of voluntary medical male circumcision (VMMC) for HIV prevention in sub-Saharan Africa; however, men are often uninterested in undergoing VMMC. The Spear & Shield project enrolled 668 men and female partners from ten Zambian community health centers into parallel interventions promoting VMMC for HIV prevention or time-matched control conditions. A mediation model was utilized to examine the relationships between changes in women's acceptance of VMMC and men's readiness to undergo the procedure. Results demonstrated that, at 12 months post-intervention, a 5.9 % increase in the likelihood of undergoing VMMC among men in the experimental condition could be attributed to increased women's acceptance. From a public health perspective, involving women in VMMC promotion interventions such as the Spear & Shield project could significantly impact the demand for VMMC in Zambia. PMID- 25931243 TI - Health Outcomes of HIV-Infected People with Mental Illness. AB - Improving outcomes for people with HIV and mental illness will be critical to meeting the goals of the US National HIV/AIDS Strategy. In a retrospective analysis of the 2008-2010 cycles of the locally representative Philadelphia Medical Monitoring Project, we compared the proportions of HIV-infected adults with and without mental illness: (1) retained in care (>=2 primary HIV visits separated by >=90 days in a 12-month period); (2) prescribed antiretroviral therapy (ART) at any point in a 12-month period; and (3) virally suppressed (HIV 1 RNA <=200 copies/mL at the last measure in the 12-month period). Multivariable regression assessed associations between mental illness and the outcomes, adjusting for age, gender, race/ethnicity, insurance, alcohol abuse, injection drug use, CD4 count, and calendar year. Of 730 HIV-infected persons, representative of 9409 persons in care for HIV in Philadelphia, 49.0 % had mental illness. In adjusted analyses, there were no significant differences in retention (91.3 vs. 90.3 %; AOR 1.30, 95 % CI 0.63-2.56) and prescription of ART (83.2 vs. 88.7 %; AOR 0.79, 95 % CI 0.49-1.25) between those with and without mental illness. However, mentally ill patients were less likely to achieve viral suppression than those without mental illness (65.9 vs. 74.4 %; AOR 0.64, 95 % CI 0.46-0.90). These findings argue for the need to optimize ART adherence in this population. PMID- 25931244 TI - Ceftolozane-tazobactam compared with levofloxacin in the treatment of complicated urinary-tract infections, including pyelonephritis: a randomised, double-blind, phase 3 trial (ASPECT-cUTI). AB - BACKGROUND: Treatment of complicated urinary-tract infections is challenging due to rising antimicrobial resistance. We assessed the efficacy and safety of ceftolozane-tazobactam, a novel antibacterial with Gram-negative activity, in the treatment of patients with complicated lower-urinary-tract infections or pyelonephritis. METHODS: ASPECT-cUTI was a randomised, double-blind, double dummy, non-inferiority trial done in 209 centres in 25 countries. Between July, 2011, and September, 2013, hospital inpatients aged 18 years or older who had pyuria and a diagnosis of a complicated lower-urinary-tract infection or pyelonephritis were randomly assigned in a 1:1 ratio to receive intravenous 1.5 g ceftolozane-tazobactam every 8 h or intravenous high-dose (750 mg) levofloxacin once daily for 7 days. The randomisation schedule was computer generated in blocks of four and stratified by study site. The next allocation was obtained by the study site pharmacist via an interactive voice-response system. The primary endpoint was a composite of microbiological eradication and clinical cure 5-9 days after treatment in the microbiological modified intention-to-treat (MITT) population, with a non-inferiority margin of 10%. This study is registered with ClinicalTrials.gov, numbers NCT01345929 and NCT01345955. FINDINGS: Of 1083 patients enrolled, 800 (73.9%), of whom 656 (82.0%) had pyelonephritis, were included in the microbiological MITT population. Ceftolozane-tazobactam was non inferior to levofloxacin for composite cure (306 [76.9%] of 398 vs 275 [68.4%] of 402, 95% CI 2.3-14.6) and, as the lower bound of the two-sided 95% CI around the treatment difference was positive and greater than zero, superiority was indicated. Adverse event profiles were similar in the two treatment groups and were mainly non-serious. INTERPRETATION: Treatment with ceftolozane-tazobactam led to better responses than high-dose levofloxacin in patients with complicated lower-urinary-tract infections or pyelonephritis. FUNDING: Cubist Pharmaceuticals. PMID- 25931245 TI - A new ASPECT for complicated urinary tract infections. PMID- 25931246 TI - CO2 , NOx and SOx removal from flue gas via microalgae cultivation: a critical review. AB - Flue gas refers to the gas emitting from the combustion processes, and it contains CO2 , NOx , SOx and other potentially hazardous compounds. Due to the increasing concerns of CO2 emissions and environmental pollution, the cleaning process of flue gas has attracted much attention. Using microalgae to clean up flue gas via photosynthesis is considered a promising CO2 mitigation process for flue gas. However, the impurities in the flue gas may inhibit microalgal growth, leading to a lower microalgae-based CO2 fixation rate. The inhibition effects of SOx that contribute to the low pH could be alleviated by maintaining a stable pH level, while NOx can be utilized as a nitrogen source to promote microalgae growth when it dissolves and is oxidized in the culture medium. The yielded microalgal biomass from fixing flue gas CO2 and utilizing NOx and SOx as nutrients would become suitable feedstock to produce biofuels and bio-based chemicals. In addition to the removal of SOx , NOx and CO2 , using microalgae to remove heavy metals from flue gas is also quite attractive. In conclusion, the use of microalgae for simultaneous removal of CO2 , SOx and NOx from flue gas is an environmentally benign process and represents an ideal platform for CO2 reutilization. PMID- 25931247 TI - The protective function of galectin-9 in liver ischemia and reperfusion injury in mice. AB - Galectin-9 (Gal-9) has gained attention as a multifaceted player in adaptive and innate immunity. To elucidate the role of Gal-9, we used a mouse model of partial liver ischemia/reperfusion injury (IRI) with wild type (WT) and Gal-9 knockout (KO) mice as well as a recombinant galectin-9 (reGal-9) protein. We found that the expression of Gal-9 was enhanced endogenously in the liver especially by hepatocytes and Kupffer cells during warm IRI for a mouse liver, which causes massive destruction of liver tissue. Gal-9 was released into the extracellular space in the liver and the highest levels in the plasma at 1 hour after reperfusion. The present study elucidates a novel role of Gal-9 signaling in mouse liver IRI, by using Gal-9-deficient mice and a stable form of reGal-9 protein. In the circumstance of Gal-9 absence, liver damage due to ischemia/reperfusion (IR) exacerbated the severity as compared with WT. On the other hand, exogenously administered reGal-9 significantly ameliorated hepatocellular damage. It decreased the local infiltration of the inflammatory cells such as T cells, neutrophils, and macrophages, and it reduced the expression of proinflammatory cytokines/chemokines; then, it strongly suppressed the apoptosis of the liver cells. Interestingly, severe liver damage due to IR in Gal-9 KO mice was improved by the administration of reGal-9. In conclusion, Gal-9 engagement ameliorated local inflammation and liver damage induced by IR, and the present study suggests a significant role of Gal-9 in the maintenance of hepatic homeostasis. In conclusion, targeting Gal-9 represents a novel approach to protect from inflammation such as liver IRI. Exogenous Gal-9 treatment will be a new therapeutic strategy against innate immunity-dominated liver tissue damage. PMID- 25931249 TI - Sex Differences in Affective Expression Among Individuals with Psychometrically Defined Schizotypy: Diagnostic Implications. AB - The present investigation uses facial electromyography (fEMG) to measure patterns of affective expression in individuals with psychometrically defined schizotypy during presentation of neutral and negative visual images. Twenty-eight individuals with elevated schizotypal features and 20 healthy controls observed a series of images from the International Affective Picture System (IAPS) and provided self-report ratings of affective valence and arousal while their physiological responses were recorded. The groups were evenly divided by sex. A three-way interaction in fEMG measurement revealed that while males with psychometrically defined schizotypy demonstrated the expected pattern of blunted/constricted facial affective expression relative to male controls in the context of negative images, females displayed the opposite pattern. That is, females with psychometrically defined schizotypy demonstrated significant elevations in negative facial affective expression relative to female controls while viewing negative images. We argue that these findings corroborate previously reported impressions of sex differences in affective expression in schizotypy. We discuss implications for assessment and diagnostic procedures among individuals with disorders along the schizophrenia spectrum. PMID- 25931248 TI - Cannabinoid Receptor-2 Regulates Embryonic Hematopoietic Stem Cell Development via Prostaglandin E2 and P-Selectin Activity. AB - Cannabinoids (CB) modulate adult hematopoietic stem and progenitor cell (HSPCs) function, however, impact on the production, expansion, or migration of embryonic HSCs is currently uncharacterized. Here, using chemical and genetic approaches targeting CB-signaling in zebrafish, we show that CB receptor (CNR) 2, but not CNR1, regulates embryonic HSC development. During HSC specification in the aorta gonad-mesonephros (AGM) region, CNR2 stimulation by AM1241 increased runx1;cmyb(+) HSPCs, through heightened proliferation, whereas CNR2 antagonism decreased HSPC number; FACS analysis and absolute HSC counts confirmed and quantified these effects. Epistatic investigations showed AM1241 significantly upregulated PGE2 synthesis in a Ptgs2-dependent manner to increase AGM HSCs. During the phases of HSC production and colonization of secondary niches, AM1241 accelerated migration to the caudal hematopoietic tissue (CHT), the site of embryonic HSC expansion, and the thymus; however these effects occurred independently of PGE2. Using a candidate approach for HSC migration and retention factors, P-selectin was identified as the functional target of CNR2 regulation. Epistatic analyses confirmed migration of HSCs into the CHT and thymus was dependent on CNR2-regulated P-selectin activity. Together, these data suggest CNR2-signaling optimizes the production, expansion, and migration of embryonic HSCs by modulating multiple downstream signaling pathways. PMID- 25931250 TI - Open-Loop Neurofeedback Audiovisual Stimulation: A Pilot Study of Its Potential for Sleep Induction in Older Adults. AB - This pilot study tested the efficacy of a 30-min audio-visual stimulation (AVS) program for the treatment of chronic insomnia in older adults. Chronic insomnia has been conceptualized as entailing increased cortical high frequency EEG activity at sleep onset and during NREM sleep. We hypothesized that an AVS program gradually descending from 8 to 1 Hz would potentially reduce the excessive cortical activation that is thought to contribute to difficulties with initiating and maintaining sleep. Accordingly, we conducted an intervention study of AVS using a pre-post design. Eight older adults (88 +/- 8.7 years) complaining of chronic insomnia self-administered a 30-min AVS program nightly at bedtime for one month. Sleep was assessed at baseline and throughout the 4-week intervention. After using AVS for 4 weeks, significant improvement was reported in insomnia symptoms (ISI, p = 0.002) and sleep quality (PSQI, p = 0.004); with moderate to large effect sizes (Partial Eta2: 0.20-0.55)(Cohen's d: 0.7-2.3). The training effect (self-reported sleep improvement) was observed at the end of week one and persisted through the 1-month intervention. The results from this pilot study suggest that further exploration of AVS as a treatment for insomnia is warranted. PMID- 25931251 TI - Acetabular fracture assessment in four different pelvic trauma centers: have the Judet views become superfluous? AB - INTRODUCTION: The present study was designed to examine whether oblique radiographs (Judet views) in addition to 2D and 3D CT scans improved the intra- and interobserver reliability when assessing acetabular fractures. MATERIALS AND METHODS: Four international orthopedic pelvic trauma centers reviewed the radiological images for 20 acetabular fracture patients. Three different image sets were made; one set containing plain radiographs including oblique (Judet) views and 2D axial CT scans. The second set contained an AP radiograph of the pelvis, without oblique views, 2D and 3D CT scans. The third set contained all the images. The image sets were evaluated in three separate sessions, for each session the raters were asked to classify the fracture according to Letournel, as well as record a number of other important radiological features concerning the fracture. RESULTS: The interobserver agreement for the Letournel classification was found to be moderate for all image sets. The image set without oblique views showed the best agreement with a kappa value of 0.60. The intra- and interobserver agreement for important modifiers were found to be substantial. The addition of oblique radiographs did not seem to increase the intra- or interobserver agreement for any of the factors evaluated except for the roof arc score. CONCLUSION: The moderate agreement found for the Letournel classification is to be expected given the complexity of the classification. The addition of oblique radiographs to the image sets does not seem to improve the reliability and thus its routine use for classification and decision making may be debated. PMID- 25931252 TI - Irreversible electroporation of the pancreas is feasible and safe in a porcine survival model. AB - OBJECTIVES: Use of thermal tumor ablation in the pancreatic parenchyma is limited because of the risk of pancreatitis, pancreatic fistula, or hemorrhage. This study aimed to evaluate the feasibility and safety of irreversible electroporation (IRE) in a porcine model. METHODS: Ten pigs were divided into 2 study groups. In the first group, animals received IRE of the pancreatic tail and were killed after 60 minutes. In the second group, animals received IRE at the head of the pancreas and were followed up for 7 days. Clinical parameters, computed tomography imaging, laboratory results, and histology were obtained. RESULTS: All animals survived IRE ablation, and no cardiac adverse effects were noted. Sixty minutes after IRE, a hypodense lesion on computed tomography imaging indicated the ablation zone. None of the animals developed clinical signs of acute pancreatitis. Only small amounts of ascites fluid, with a transient increase in amylase and lipase levels, were observed, indicating that no pancreatic fistula occurred. CONCLUSIONS: This porcine model shows that IRE is feasible and safe in the pancreatic parenchyma. Computed tomography imaging reveals significant changes at 60 minutes after IRE and therefore might serve as an early indicator of therapeutic success. Clinical studies are needed to evaluate the efficacy of IRE in pancreatic cancer. PMID- 25931253 TI - Dysbiosis of Intestinal Microbiota Associated With Inflammation Involved in the Progression of Acute Pancreatitis. AB - OBJECTIVES: To evaluate alterations of the intestinal bacteria and its associations with the inflammation in acute pancreatitis (AP). METHODS: A multihospital prospective clinical study was conducted, and a total of 108 participants were enrolled in our study, including 44 with severe AP (SAP), 32 with mild AP (MAP), and 32 healthy volunteers. The structure of intestinal microbiota, 10 predominant bacteria, plasma endotoxin, and serum cytokines were investigated by polymerase chain reaction-denaturing gradient gel electrophoresis, real-time quantitative polymerase chain reaction, Limulus amebocyte lysate tests, and enzyme-linked immunosorbent assays, respectively. RESULTS: Dramatic alterations in the predominant fecal microbiota were observed in most of both MAP and SAP patients. In addition, the rates of the multiorgan failures and infectious complications in the patients with SAP with altered intestinal microbiota were significantly higher than in those whose intestinal microbiota remained unaltered. Enterococcus increased and Bifidobacterium decreased in the patients with SAP compared to the patients with MAP. Serum IL-6 were positively correlated with Enterobacteriaceae and Enterococcus and negatively correlated with Bifidobacterium, whereas plasma endotoxin positively correlated with Enterococcus (P < 0.05). CONCLUSIONS: The intestinal bacteria most frequently altered in both the patients with MAP and those with SAP significantly correlated with inflammation, which indicated that the intestinal microbiota may be involved in the progression of AP. PMID- 25931254 TI - Early detection of sporadic pancreatic cancer: summative review. AB - Pancreatic cancer (PC) is estimated to become the second leading cause of cancer death in the United States by 2020. Early detection is the key to improving survival in PC. Addressing this urgent need, the Kenner Family Research Fund conducted the inaugural Early Detection of Sporadic Pancreatic Cancer Summit Conference in 2014 in conjunction with the 45th Anniversary Meeting of the American Pancreatic Association and Japan Pancreas Society. This seminal convening of international representatives from science, practice, and clinical research was designed to facilitate challenging interdisciplinary conversations to generate innovative ideas leading to the creation of a defined collaborative strategic pathway for the future of the field. An in-depth summary of current efforts in the field, analysis of gaps in specific areas of expertise, and challenges that exist in early detection is presented within distinct areas of inquiry: Case for Early Detection: Definitions, Detection, Survival, and Challenges; Biomarkers for Early Detection; Imaging; and Collaborative Studies. In addition, an overview of efforts in familial PC is presented in an addendum to this article. It is clear from the summit deliberations that only strategically designed collaboration among investigators, institutions, and funders will lead to significant progress in early detection of sporadic PC. PMID- 25931255 TI - Characterization of patients with advanced pancreatic cancer and high serum interleukin-6 levels. AB - OBJECTIVES: High serum level of interleukin 6 (IL-6) is associated with high degree of tumor progression and systemic weakness. Anti-IL-6 therapy possibly improves the deterioration of clinical characteristics in patients with high IL-6 level. However, IL-6-related factors in patients with treatment-naive advanced pancreatic cancer (PC) have not been established. The goal of this study was to identify IL-6-related factors in patients with advanced PC who were scheduled to undergo first-line chemotherapy. METHODS: Patients with treatment-naive advanced PC were eligible for inclusion in this study. Patients who did not receive first line chemotherapy were excluded. Serum IL-6 levels and clinical parameters were prospectively recorded. Analyses were performed to identify risk factors for high IL-6 levels. RESULTS: Eighty patients were analyzed. IL-6-related factors were advanced age (P < 0.01), the presence of liver metastasis (P < 0.01), the large volume of liver metastasis (P < 0.01), severe fatigue (P = 0.02), high carcinoembryonic antigen levels (P = 0.02), anemia (P < 0.01), and high C reactive protein levels (P = 0.02) in multivariate analyses. Decreased skeletal muscle mass tended to be associated with high IL-6 levels. CONCLUSIONS: High serum IL-6 was related to advanced age, the presence of hepatic metastasis, large tumor burden in liver, severe fatigue, high carcinoembryonic antigen, high C reactive protein, and anemia in patients with treatment-naive advanced PC. PMID- 25931256 TI - Effects of rhubarb on intestinal flora and toll-like receptors of intestinal mucosa in rats with severe acute pancreatitis. AB - OBJECTIVE: The aim of this study was to examine the effects of rhubarb on intestinal flora and toll-like receptors (TLRs) of intestinal mucosa in rats with severe acute pancreatitis (SAP). METHODS: Healthy male Sprague-Dawley rats were randomly allocated into sham-operated surgical model of SAP without or with postoperative rhubarb treatment groups (7 in each group). Rats in with rhubarb group received 10% rhubarb decoction (1 mL/200 g) through tube feeding at every 8 hours during postoperative 24 hours. Serum amylase, amount of intestinal flora, and TLR2/TLR4 messenger RNA expression in intestinal mucosa were tested among 3 groups at postoperative 24 hours. RESULTS: TLR2 and TLR4 messenger RNA expression levels in intestinal mucosa in SAP without rhubarb group were significantly higher than those in sham-operated or SAP with rhubarb groups (P < 0.05). The amount of intestinal lactobacilli and bifidobacteria in SAP without rhubarb group were significantly fewer than in those sham-operated group (P < 0.05) but not significantly different from those in SAP with rhubarb group (P > 0.05). The amount of intestinal Escherichia coli was relatively higher in SAP group than in sham-operated group (P > 0.05) but lesser in rhubarb treatment group (P > 0.05). CONCLUSIONS: Rhubarb might maintain the intestinal mucosal barrier through regulating intestinal flora and inhibiting intestinal inflammatory response in rats with SAP. PMID- 25931257 TI - Pancreatic retransplantation is associated with poor allograft survival: an update of the United Network for Organ Sharing database. AB - The aim of the study was to assess outcomes of pancreas retransplantation versus primary pancreas transplantation. METHODS: Data from the United Network for Organ Sharing database on all adult (age, >=18 years) subjects who received pancreas and kidney-pancreas transplants between 1996 and 2012 were analyzed (n = 20,854). The subjects were analyzed in the following 2 groups: retransplant (n = 1149) and primary transplant (n = 19,705). RESULTS: Kaplan-Meier analysis demonstrated significantly different patient survival (P < 0.0001) and death-censored graft survival (P < 0.0001) between the primary transplant versus retransplant subjects. Allograft survival was significantly poorer in the retransplantation group. Patient survival was greater in the retransplant group. CONCLUSIONS: The results of our study differ from previous studies, which showed similar allograft survival in primary and secondary pancreas transplants. Further studies may elucidate specific patients who will benefit from retransplantation. At the present time, it would appear that pancreas retransplantation is associated with poor graft survival and that retransplantation should not be considered for all patients with primary pancreatic allograft failure. PMID- 25931258 TI - Hyperfibrinogen Is Associated With the Systemic Inflammatory Response and Predicts Poor Prognosis in Advanced Pancreatic Cancer. AB - OBJECTIVE: The aim of this study was to examine the prognostic prediction value of plasma fibrinogen level for overall survival (OS) in patients with advanced pancreatic cancer. METHODS: A total of 321 patients with locally advanced or metastatic pancreatic adenocarcinoma were retrospectively recruited. The association between plasma fibrinogen level and OS was analyzed. We also evaluated the relationship between plasma fibrinogen level and the systemic inflammatory response markers: the neutrophil-lymphocyte ratio, platelets/lymphocyte ratio, and lymphocyte/monocyte ratio. RESULTS: High plasma fibrinogen levels were significantly correlated with shorter OS in patients with advanced pancreatic cancer (175 days for patients with high fibrinogen levels vs 357 days for patients with low fibrinogen levels; log rank, 22.949; P < 0.001). Multivariate analyses confirmed that plasma fibrinogen level was an independent prognostic predictor for OS (hazard ratio, 2.184; 95% confidence interval, 1.574 3.032; P < 0.001). Receiver operating characteristic analyses showed that including plasma fibrinogen level alongside traditional factors (tumor stage and CA 19-9) significantly improved prognostic prediction capability (traditional model area under the curve of 0.62 versus combined model area under the curve of 0.708; P = 0.016). In addition, plasma fibrinogen level was positively correlated with neutrophil-lymphocyte ratio and platelets/lymphocyte ratio and negatively correlated with lymphocyte/monocyte ratio. CONCLUSIONS: Hyperfibrinogen is associated with the systemic inflammatory response and predicts poor prognosis for advanced pancreatic cancer. PMID- 25931259 TI - Neoplastic spindle cells are an independent prognostic factor in pancreatic cancer. AB - OBJECTIVE: Several reports showed that neoplastic spindle cells (NSCs) may be strongly involved in the invasion, metastasis, and poor prognosis, as well as in epithelial-mesenchymal transition (EMT). It has not yet been investigated that NSCs relate to the recurrence and prognosis in various cancers. Furthermore, NSCs participate in EMT in pancreatic cancer (PC) too. We clinicopathologically investigated the association between NSCs and the recurrence, prognosis, and EMT in PC. METHODS: We studied 68 PC patients. Cancer cells with a spindle or oval shape that do not exhibit luminal structures were defined as NSCs. We graded NSCs regarding to an area of NSCs at hematoxylin and eosin stain (NSC grade) and examined the participation in NSCs and EMT by immunohistostaining of snail antibody and E-cadherin antibody. RESULTS: In multivariate analysis, NSC grade was an independent risk factor for disease-free survival and overall survival. This was independent of TNM stage and histological grade. Neoplastic spindle cells were related to EMT pattern in immunohistostaining significantly. CONCLUSIONS: Neoplastic spindle cell grade significantly related to the recurrence and prognosis of PC. The NSC grade assessment can be not only performed inexpensively and conveniently, but also used to guide future individualized therapeutic approaches. Furthermore, NSCs were found to relate to EMT profoundly. PMID- 25931260 TI - Cytoreductive Surgery for Pancreatic Cancer Improves Overall Outcome of Gemcitabine-Based Chemotherapy. AB - OBJECTIVES: Pancreatoduodenectomy is feasible also in patients with locally advanced pancreatic adenocarcinoma (PA) nowadays. Data on risk and survival analysis of palliative pancreatic resections followed by gemcitabine-based chemotherapy (Cx) are limited. METHODS: Between 2000 and 2009, a total of 45 patients had primary cytoreductive surgery (cS) (pancreaticoduodenectomy or total pancreatectomy) followed by gemcitabine-based Cx (cS + Cx) for advanced PA. We matched 1:1 the cS + Cx group with 45 contemporaneous patients who primarily started palliative gemcitabine-based Cx for age, sex, performance status, and body mass index. Overall, survival was evaluated. RESULTS: Local R0 and R1 resection in metastatic patients was achieved in 27% and 27%, respectively. The R2 resection status without distant metastasis resulted in 33%, whereas 13% showed a local R2 status with additional metastasis (M1). Median overall survival was 10.4 months after cytoreductive pancreatic surgery and consecutive gemcitabine-based Cx versus 7.2 months after upfront gemcitabine-based Cx (P = 0.009). Median survival for R0/M1 patients was 14.4 months and 11.0 months for R2/M0 patients, whereas the median survival for R1/M1 and for R2/M1 patients was 7.3 months and 6.1 months, respectively. CONCLUSIONS: Individual patients with advanced PA had a significantly longer overall survival after palliative pancreaticoduodenectomy followed by Cx than patients in a matched control group who underwent primarily palliative Cx. PMID- 25931261 TI - Pancreatic Endocrine Effects of Dopamine Receptors in Human Islet Cells. AB - OBJECTIVE: To date, there are no reports on the cellular localization of dopamine receptors in the human pancreas. In our study, we determined the localization and expression of 5 dopamine receptors (D(1), D(2), D(3), D(4), and D(5)) in normal human pancreas tissue. METHODS: Human nonpathological pancreas tissues were fixed with 4% paraformaldehyde, paraffin-embedded, and processed for immunohistochemical analysis to detect dopamine receptors in the human pancreas tissue by using double immunofluorescent labeling and confocal microscopy. RESULTS: We found that the D(1) receptor is present in beta cells; the D(2) receptor is expressed by alpha, delta, and pancreatic polypeptide cells; the D(4) receptor is expressed by beta and polypeptide cells; whereas the D(5) receptor is expressed only by delta cells. CONCLUSIONS: Our results identify the dopamine receptors (D(1)-D(5)) in normal pancreas tissue and provide a morphological basis for studying the pancreatic endocrine effects of dopamine and suggest a new target for the clinical treatment of diabetes. PMID- 25931262 TI - Classic and novel stem cell niches in brain homeostasis and repair. AB - Neural stem cells (NSCs) critical for the continued production of new neurons and glia are sequestered in distinct areas of the brain called stem cell niches. Until recently, only two forebrain sites, the subventricular zone (SVZ) of the anterolateral ventricle and the subgranular zone (SGZ) of the hippocampus, have been recognized adult stem cell niches (Alvarez-Buylla and Lim, 2004; Doetsch et al., 1999a, 1999b; Doetsch, 2003a, 2003b; Lie et al., 2004; Ming and Song, 2005). Nonetheless, the last decade has been witness to a growing literature suggesting that in fact the adult brain contains stem cell niches along the entire extent of the ventricular system. These niches are capable of widespread neurogenesis and gliogenesis, particularly after injury (Barnabe-Heider et al., 2010; Carlen et al., 2009; Decimo et al., 2012; Lin et al., 2015; Lindvall and Kokaia, 2008; Robins et al., 2013) or other inductive stimuli (Bennett et al., 2009; Cunningham et al., 2012; Decimo et al., 2011; Kokoeva et al., 2007, 2005; Lee et al., 2012a, 2012b; Migaud et al., 2010; Pencea et al., 2001b; Sanin et al., 2013; Suh et al., 2007; Sundholm-Peters et al., 2004; Xu et al., 2005; Zhang et al., 2007). This review focuses on the role of these novel and classic brain niches in maintaining adult neurogenesis and gliogenesis in response to normal physiological and injury related pathological cues. This article is part of a Special Issue entitled SI: Neuroprotection. PMID- 25931263 TI - Social monogamy in wild owl monkeys (Aotus azarae) of Argentina: the potential influences of resource distribution and ranging patterns. AB - Using published and new data from a population of monogamous owl monkeys in the Argentinean Chaco, I examine the hypothesis that social monogamy is a default social system imposed upon males because the spatial and/or temporal distribution of resources and females makes it difficult for a single male to defend access to more than one mate. First, I examine a set of predictions on ranging patterns, use of space, and population density. This first section is followed by a second one considering predictions related to the abundance and distribution of food. Finally, I conclude with a section attempting to link the ranging and ecological data to demographic and life-history parameters as proxies for reproductive success. In support of the hypothesis, owl monkey species do live at densities (7 64 ind/km(2) ) that are predicted for monogamous species, but groups occupy home ranges and core areas that vary substantially in size, with pronounced overlap of home ranges, but not of core areas. There are strong indications that the availability of food sources in the core areas during the dry season may be of substantial importance for regulating social monogamy in owl monkeys. Finally, none of the proxies for the success of groups were strongly related to the size of the home range or core area. The results I present do not support conclusively any single explanation for the evolution of social monogamy in owl monkeys, but they help us to better understand how it may function. Moreover, the absence of conclusive answers linking ranging, ecology, and reproductive success with the evolution of social monogamy in primates, offer renewed motivation for continuing to explore the evolution of monogamy in owl monkeys. PMID- 25931264 TI - Successful generation of structural information for fragment-based drug discovery. AB - Fragment-based drug discovery relies upon structural information for efficient compound progression, yet it is often challenging to generate structures with bound fragments. A summary of recent literature reveals that a wide repertoire of experimental procedures is employed to generate ligand-bound crystal structures successfully. We share in-house experience from setting up and executing fragment crystallography in a project that resulted in 55 complex structures. The ligands span five orders of magnitude in affinity and the resulting structures are made available to be of use, for example, for development of computational methods. Analysis of the results revealed that ligand properties such as potency, ligand efficiency (LE) and, to some degree, clogP influence the success of complex structure generation. PMID- 25931265 TI - Do Orexins contribute to impulsivity-driven binge consumption of rewarding stimulus and transition to drug/food dependence? AB - Orexins (OX) are neuropeptides synthesized in the lateral hypothalamic region which play a fundamental role in a wide range of physiological and psychological functions including arousal, stress, motivation or eating behaviors. This paper reviews under the addiction cycle framework (Koob, 2010), the role of the OX system as a key modulator in compulsivity-driven consumption of rewarding stimulus including ethanol, palatable food and drugs and their role in impulsivity and binge-like consumption in non dependent organisms as well. We propose here that drug/food binge-like consumption in vulnerable organisms increases OX activity which, in turn, elicits enhanced impulsivity and further impulsivity-driven binge consumption in a positive loop that would promote compulsive-driven binge-consumption and the transition to drug/food disorders over time. PMID- 25931266 TI - Central administration of oxytocin differentially increases yawning, penile erections and scratching in high- (HY) and low-yawning (LY) sublines of Sprague Dawley rats. AB - Central administration of oxytocin has been shown to induce yawning, penile erection, grooming and scratching. Yawning and penile erections are due to activation of oxytocinergic neurons in the paraventricular nucleus of the hypothalamus. We selectively bred two sublines from Sprague-Dawley rats, one with a high-yawning frequency (HY) of 20yawns/h, and one with a low-yawning (LY) frequency of 2yawns/h. The aim of the current study was to analyze the behavioral effects of centrally-administered oxytocin [15ng-10MUg; intracerebroventricularly (i.c.v.)] on yawning, penile erections, grooming and scratching in adult male rats from both sublines. Oxytocin produced a dose-dependent increase in yawning and penile erection frequencies and this effect was significantly higher in the HY, compared to the LY, subline. However, the number of oxytocin-induced scratching bouts was significantly higher in the LY, compared to the HY group. In conclusion, these sublines represent a suitable model for detailed analysis of behavior induced by oxytocin and other neuropeptides in animals with different spontaneous expression of behavioral traits. PMID- 25931267 TI - Flavonoid Chrysin prevents age-related cognitive decline via attenuation of oxidative stress and modulation of BDNF levels in aged mouse brain. AB - In this study, the effect of Chrysin (5,7-dihydroxyflavone), an important member of the flavonoid family, on memory impairment, oxidative stress and BDNF reduction generated by aging in mice were investigated. Young and aged mice were treated daily per 60days with Chrysin (1 and 10mg/kg; per oral, p.o.) or veichle (10ml/kg; p.o.). Mice were trained and tested in Morris Water Maze task. After the behavioural test, the levels of reactive species (RS), the activity of superoxide dismutase (SOD), catalase (CAT) and glutathione peroxidase (GPx), as well as the activity of Na(+), K(+)-ATPase and the levels of brain-derived neurotrophic factor (BDNF) were determined in the prefrontal cortex (PFC) and hippocampus (HC) of mice. Results demonstrated that the age-related memory decline was partially protected by Chrysin at a dose of 1mg/kg, and normalized at the dose of 10mg/kg (p<0.001). Treatment with Chrysin significantly attenuated the increase of RS levels and the inhibition of SOD, CAT and GPx activities of aged mice. Inhibition of Na(+), K(+)-ATPase activity in PFC and HP of aged mice was also attenuated by Chrysin treatment. Moreover, Chrysin marked mitigated the decrease of BDNF levels in the PFC and HC of aged mice. These results demonstrated that flavonoid Chrysin, an antioxidant compound, was able to prevent age-associated memory probably by their free radical scavenger action and modulation of BDNF production. Thus, this study indicates that Chrysin may represent a new pharmacological approach to alleviate the age-related declines during normal age, acting as an anti-aging agent. PMID- 25931268 TI - Lacosamide reduces HDAC levels in the brain and improves memory: Potential for treatment of Alzheimer's disease. AB - Lacosamide, a histone deacetylase (HDAC) inhibitor, has been approved for the treatment of epilepsy. Some HDAC inhibitors have been proven effective for the treatment of memory disorders. The present investigation was designed to evaluate the effect of lacosamide on memory and brain HDAC levels. The effect on memory was evaluated in animals with scopolamine-induced amnesia using the elevated plus maze, object recognition test, and radial arm maze. The levels of acetylcholinesterase and HDAC in the cerebral cortex were evaluated. Lacosamide at doses of 10 and 30mg/kg significantly reduced the transfer latency in the elevated plus maze. Lacosamide at a dose of 30mg/kg significantly increased the time spent with a familiar object in the object recognition test at the 24h interval and decreased the time spent in the baited arm. Moreover, at this dose, the number of errors in the radial arm maze at 3 and 24h intervals was minimized and a reduction in the level of HDAC1, but not acetylcholinesterase, was observed in the cerebral cortex. These effects of lacosamide are equivalent to those of piracetam at a dose of 300mg/kg. These results suggest that lacosamide at a 30mg/kg dose improves disrupted memory, possibly by inhibiting HDAC, and could be used to treat amnesic symptoms of Alzheimer's disease. PMID- 25931269 TI - Promoter DNA methylation is associated with KLF11 expression in epithelial ovarian cancer. AB - As a transforming growth factor-beta (TGF-beta)-inducible gene, the expression of Kruppel-like transcription factor 11 (KLF11) is altered in several types of cancer. In the current study, through using human 9K CpG island array, KLF11 was identified as one of hypermethylated genes in RAS-transformed ovarian T29H cells. Methylation of the KLF11 promoter was also observed in ovarian cancer tissue samples accompanied by significantly reduced KLF11 gene expression. Interestingly, the expression of SMAD2, SMAD3, and SMAD7 genes was reduced in the tumour, whilst no change was found in TGF-beta expression. Our data suggest a relationship between promoter DNA methylation and KLF11 gene expression in ovarian cancer tumorigenesis. PMID- 25931270 TI - Childhood interstitial lung disease: A systematic review. AB - OBJECTIVES: Childhood interstitial lung disease (chILD) is a group of rare chronic and complex disorders of variable pathology. There has been no systematic review of published chILD research. This study aimed to describe chILD classification systems, epidemiology, morbidity, treatments, outcomes, and the impact of chILD on families and the burden on health services. METHODS: A systematic literature search for original studies on chILD was undertaken in the major biomedical databases to the end of December 2013. Epidemiological studies, case series and studies describing classification systems were included. Single case studies were excluded. RESULTS: The search yielded 37 publications that met study criteria. Four different chILD classification systems have been proposed in the past decade. The incidence of chILD has been estimated at 0.13-16.2 cases/100,000 children/year. One to five new cases presented to individual hospitals each year. In developed countries, the median mortality was 13% (6 19%). Morbidity and outcomes were highly variable and not systematically reported. Corticosteroids and hydroxychloroquine were the most common treatments. The impact of chILD on families and the burden on health services has not been studied. CONCLUSIONS: The heterogeneity of the chILD group of disorders, different determinations of what constitutes a chILD disorder and, a paucity of large epidemiological studies precludes consolidation of results across studies. Consensus on chILD classification is needed to support diagnosis and allow direct comparisons of research evidence. Active disease surveillance and international patient registries are required to advance understanding and management of chILD. PMID- 25931271 TI - Effects of unweighting and speed on in-shoe regional loading during running on a lower body positive pressure treadmill. AB - The purpose of this study was to determine how unweighted running on a lower body positive pressure treadmill (LBPPT) modifies in-shoe regional loading. Ten experienced runners were fit with pressure distribution measurement insoles and ran at 100%, 120%, and 140% of self-reported easy training pace on a LBPPT at 20%, 40%, 60%, 80%, and 100% body weight percentage settings (BWSet). Speeds and BWSet were in random order. A linear mixed effect model (p<0.05 significance level) was used to compare differences in whole foot and regional maximum in-shoe plantar force (FMAX), impulse, and relative load distribution across speeds and BWSet. There were significant main effects (p<0.001) for running speed and BWSet for whole foot Fmax and impulse. The model revealed 1.4% and 0.24% increases in whole foot FMAX (times body weight) and impulse, respectively, for every unit increase in body weight percentage. There was a significant main effect for BWSet on Fmax and relative load (p<0.05) for each of the nine foot regions examined, though four regions were not different between 80% and 100% BWSet. There was a significant (p<0.001) main effect for BWSet on forefoot to rear foot relative load. Linear relationships were found between increases in BWSet and increases in shoe Fmax and impulse, resulting from regional changes in foot pressure which represent a shift towards forefoot loading, most evident <80% BWSet. Estimating in-shoe regional loading parameters may be useful during rehabilitation and training to appropriately prescribe specific speed and body weight levels, without exceeding certain critical peak force levels while running. PMID- 25931272 TI - Comparison of the malnutrition-inflammation score in chronic kidney disease patients and kidney transplant recipients. AB - BACKGROUND: Protein-energy wasting (PEW) is a common condition in patients with chronic kidney disease (CKD) including dialysis and kidney transplant recipients (TX) and frequently assessed with malnutrition-inflammation score (MIS). We hypothesized that (1) the MIS and PEW parameters are correlated with kidney function and (2) the MIS and PEW parameters are more severe in TX than in non dialysis (ND) CKD patients with similar eGFR. METHODS: In this study, we matched 203 ND-CKD and 203 TX patients from two independently assembled cohorts of patients based on estimated glomerular filtration rate (eGFR) and compared various PEW parameters between the two groups using unadjusted and case-mix adjusted linear regression and conditional logistic regression analysis models. RESULTS: In the combined cohort (n = 406) of patients, the mean +/- SD age was 57 +/- 12 years; included 55 % men and 35 % diabetics; and demonstrated a mean +/- SD baseline eGFR of 29 +/- 11 ml/min/1.73 m(2). The eGFR correlated positively with serum albumin (rho = 0.26, p < 0.001) and negatively (rho = -0.33, p < 0.001) with MIS. ND-CKD and TX patients had similar MIS, PEW parameters such as waist circumference, serum CRP, albumin, and leptin levels. After case-mix adjustment, TX status was associated with higher waist circumference (standardized coefficient: 0.187, p < 0.001), lower BMI (standardized coefficient: -0.204, p < 0.001), and lower SGA score (standardized coefficient: 0.156, p = 0.006). CONCLUSIONS: We found associations between lower eGFR and various PEW measures in both the ND-CKD and TX populations. Additionally, we did not observe significant differences in the burden of PEW parameters between the CKD and TX populations. PMID- 25931273 TI - Histomorphometric diagnostics of renal osteopathy in chronic dialysis patients at high risk of cardiovascular disease. AB - Chronic kidney disease-mineral and bone disorder (CKD-MBD) ranks among clinically and pathogenetically significant complications in patients with CKD. Numerous factors are involved in its development, and histomorphometric analysis of the bone tissue is still necessary for accurate diagnosis. METHODS: The open, pilot, prospective study aimed at performing a comprehensive histomorphometric bone analysis in 26 dialysis patients and assessing the relationships of different types of CKD-MBD to selected parameters of calcium and phosphate metabolism, densitometry, activity of parathyroid glands, presence of diabetes mellitus, and duration of dialysis treatment. RESULTS: Comparison of the histomorphometric characteristics demonstrated statistically significant correlations between the volume of bone trabeculae and s-procollagen 1 (.754) as well as s-calcitonin (.856). Similarly, there was a positive correlation between the size of tetracycline lines and volume of bone trabeculae (.705) and a strong negative correlation with the thickness of trabeculae (-.442). When assessing the serum levels of s-osteoprotegerin and serum RANKL, there was a correlation with osteoid thickness and bone trabeculae thickness. In case of s-osteoprotegerin, a statistical power was demonstrated in relation to osteoid thickness (.880); in case of s-RANKL, a statistical power was demonstrated in relation to the thickness of trabeculae (.830). When assessing the influence of dialysis duration, relationships to the volume of trabecular bone (.665) and volume of bone trabeculae (.949) were demonstrated. Finally, a relationship between s-1,25 hydroxyvitamin D and s-osteoprotegerin was observed (.739); also the relationships demonstrated were significantly lower volume of bone trabeculae in men (p = 0.067) and lower values of s-osteocalcin and s-procollagen 1 in diabetic patients (p = 0.014). CONCLUSION: The results provide new noninvasive possibilities of CKD-MBD detection that are based on selected serum parameters of bone metabolism. Presented are possibilities of noninvasive assessment of different types of CKD-MBD using serum osteomarkers in relation to comprehensive CKD-MBD histomorphometry. PMID- 25931274 TI - Impact of trisomy 8 on treatment response and survival of patients with chronic myelogenous leukemia in the era of tyrosine kinase inhibitors. PMID- 25931275 TI - Women-centred interventions to increase vaginal birth after caesarean section (VBAC): A systematic review. AB - OBJECTIVE: to evaluate the effectiveness of women-centred interventions during pregnancy and birth to increase rates of vaginal birth after caesarean. DESIGN: we searched bibliographic databases for randomised trials or cluster randomised trials on women-centred interventions during pregnancy and birth designed to increase VBAC rates in women with at least one previous caesarean section. Comparator groups included standard or usual care or an alternative treatment aimed at increasing VBAC rates. The methodological quality of included studies was assessed independently by two authors using the Effective Public Health Practice Project quality assessment tool. Outcome data were extracted independently from each included study by two review authors. FINDINGS: in total, 821 citations were identified and screened by title and abstract; 806 were excluded and full text of 15 assessed. Of these, 12 were excluded leaving three papers included in the review. Two studies evaluated the effectiveness of decision aids for mode of birth and one evaluated the effectiveness of an antenatal education programme. The findings demonstrate that neither the use of decision aids nor information/education of women have a significant effect on VBAC rates. Nevertheless, decision-aids significantly decrease women's decisional conflict about mode of birth, and information programmes significantly increase their knowledge about the risks and benefits of possible modes of birth. KEY CONCLUSIONS: few studies evaluated women-centred interventions designed to improve VBAC rates, and all interventions were applied in pregnancy only, none during the birth. There is an urgent need to develop and evaluate the effectiveness of all types of women-centred interventions during pregnancy and birth, designed to improve VBAC rates. IMPLICATIONS FOR PRACTICE: decision-aids and information programmes during pregnancy should be provided for women as, even though they do not affect the rate of VBAC, they decrease women's decisional conflict and increase their knowledge about possible modes of birth. PMID- 25931276 TI - Healthcare professionals experience with motivational interviewing in their encounter with obese pregnant women. AB - OBJECTIVE: to explore and describe how healthcare professionals in the Southern Region of Denmark experienced motivational interviewing as a communication method when working with pregnant women with obesity. DESIGN: a qualitative, descriptive study based on face-to-face interviews with 11 obstetric healthcare professionals working in a perinatal setting. METHODS: a thematic descriptive method was applied to semi-structured interviews. The healthcare professional's experiences were recorded verbatim during individual semi-structured qualitative interviews, transcribed, and analysed using a descriptive analysis methodology. FINDINGS: motivational interviewing was found to be a useful method when communicating with obese pregnant women. The method made the healthcare professionals more aware of their own communication style both when encountering pregnant women and in their interaction with colleagues. However, most of the healthcare professionals emphasised that time was crucial and they had to be dedicated to the motivational interviewing method. The healthcare professionals further stated that it enabled them to become more professional in their daily work and made some of them feel less 'burned out', 'powerless' and 'stressed' as they felt they had a communication method in handling difficult workloads. CONCLUSION: healthcare professionals experienced motivational interviewing to be a useful method when working perinatally. The motivational interviewing method permitted heightened awareness of the healthcare professionals communication method with the patients and increased their ability to handle a difficult workload. Overall, lack of time restricted the use of the motivational interviewing method on a daily basis. PMID- 25931277 TI - Selective serotonin reuptake inhibitors (SSRIs) and serotonin-norepinephrine reuptake inhibitors (SNRIs) for the prevention of tension-type headache in adults. AB - BACKGROUND: This is an updated version of the Cochrane review published in 2005 on selective serotonin re-uptake inhibitors (SSRIs) for preventing migraine and tension-type headache. The original review has been split in two parts and this review now only regards tension-type headache prevention. Another updated review covers migraine. Tension-type headache is the second most common disorder worldwide and has high social and economic relevance. As serotonin and other neurotransmitters may have a role in pain mechanisms, SSRIs and serotonin norepinephrine reuptake inhibitors (SNRIs) have been evaluated for the prevention of tension-type headache. OBJECTIVES: To determine the efficacy and tolerability of SSRIs and SNRIs compared to placebo and other active interventions in the prevention of episodic and chronic tension-type headache in adults. SEARCH METHODS: For the original review, we searched the Cochrane Central Register of Controlled Trials (CENTRAL 2003, Issue 4), MEDLINE (1966 to January 2004), EMBASE (1994 to May 2003), and Headache Quarterly (1990 to 2003). For this update, we revised the original search strategy to reflect the broader type of intervention (SSRIs and SNRIs). We searched CENTRAL (2014, Issue 10) on the Cochrane Library, MEDLINE (1946 to November 2014), EMBASE (1980 to November 2014), and PsycINFO (1987 to November 2014). We also checked the reference lists of retrieved articles and searched trial registries for ongoing trials. SELECTION CRITERIA: We included randomised controlled trials comparing SSRIs or SNRIs with any type of control intervention in participants 18 years and older, of either sex, with tension-type headache. DATA COLLECTION AND ANALYSIS: Two authors independently extracted data (headache frequency, index, intensity, and duration; use of symptomatic/analgesic medication; quality of life; and withdrawals) and assessed the risk of bias of trials. The primary outcome is tension-type headache frequency, measured by the number of headache attacks or the number of days with headache per evaluation period. MAIN RESULTS: The original review included six studies on tension-type headache. We now include eight studies with a total of 412 participants with chronic forms of tension-type headache. These studies evaluated five SSRIs (citalopram, sertraline, fluoxetine, paroxetine, fluvoxamine) and one SNRI (venlafaxine). The two new studies included in this update are placebo controlled trials, one evaluated sertraline and one venlafaxine. Six studies, already included in the previous version of this review, compared SSRIs to other antidepressants (amitriptyline, desipramine, sulpiride, mianserin). Most of the included studies had methodological and/or reporting shortcomings and lacked adequate power. Follow-up ranged between two and four months.Six studies explored the effect of SSRIs or SNRIs on tension-type headache frequency, the primary endpoint. At eight weeks of follow-up, we found no difference when compared to placebo (two studies, N = 127; mean difference (MD) -0.96, 95% confidence interval (CI) -3.95 to 2.03; I(2)= 0%) or amitriptyline (two studies, N = 152; MD 0.76, 95% CI -2.05 to 3.57; I(2)= 44%).When considering secondary outcomes, SSRIs reduce the symptomatic/analgesic medication use for acute headache attacks compared to placebo (two studies, N = 118; MD -1.87, 95% CI -2.09 to -1.65; I(2)= 0%). However, amitriptyline appeared to reduce the intake of analgesic more efficiently than SSRIs (MD 4.98, 95% CI 1.12 to 8.84; I(2)= 0%). The studies supporting these findings were considered at unclear risk of bias. We found no differences compared to placebo or other antidepressants in headache duration and intensity.SSRIs or SNRI were generally more tolerable than tricyclics. However, the two groups did not differ in terms of number of participants who withdrew due to adverse events or for other reasons (four studies, N = 257; odds ratio (OR) 1.04; 95% CI 0.41 to 2.60; I(2)= 25% and OR 1.55, 95% CI 0.71 to 3.38; I(2)= 0%).We did not find any study comparing SSRIs or SNRIs with pharmacological treatments other than antidepressants (e.g. botulinum toxin) or non-drug therapies (e.g. psycho-behavioural treatments, manual therapy, acupuncture). AUTHORS' CONCLUSIONS: Since the last version of this review, the new included studies have not added high quality evidence to support the use of SSRIs or venlafaxine (a SNRI) as preventive drugs for tension type headache. Over two months of treatment, SSRIs or venlafaxine are no more effective than placebo or amitriptyline in reducing headache frequency in patients with chronic tension-type headache. SSRIs seem to be less effective than tricyclic antidepressants in terms of intake of analgesic medications. Tricyclic antidepressants are associated with more adverse events; however, this did not cause a greater number of withdrawals. No reliable information is available at longer follow-up. Our conclusion is that the use of SSRIs and venlafaxine for the prevention of chronic tension-type headache is not supported by evidence. PMID- 25931279 TI - Estimating the distribution of sensorimotor synchronization data: A Bayesian hierarchical modeling approach. AB - The sensorimotor synchronization paradigm is used when studying the coordination of rhythmic motor responses with a pacing stimulus and is an important paradigm in the study of human timing and time perception. Two measures of performance frequently calculated using sensorimotor synchronization data are the average offset and variability of the stimulus-to-response asynchronies-the offsets between the stimuli and the motor responses. Here it is shown that assuming that asynchronies are normally distributed when estimating these measures can result in considerable underestimation of both the average offset and variability. This is due to a tendency for the distribution of the asynchronies to be bimodal and left skewed when the interstimulus interval is longer than 2 s. It is argued that (1) this asymmetry is the result of the distribution of the asynchronies being a mixture of two types of responses-predictive and reactive-and (2) the main interest in a sensorimotor synchronization study is the predictive responses. A Bayesian hierarchical modeling approach is proposed in which sensorimotor synchronization data are modeled as coming from a right-censored normal distribution that effectively separates the predictive responses from the reactive responses. Evaluation using both simulated data and experimental data from a study by Repp and Doggett (2007) showed that the proposed approach produces more precise estimates of the average offset and variability, with considerably less underestimation. PMID- 25931278 TI - Increased In Vitro Osteopotential in SHED Associated with Higher IGF2 Expression When Compared with hASCs. AB - Mesenchymal stem cell (MSC) osteogenic differentiation potential varies according to factors such as tissue source and cell population heterogeneity. Pre-selection of cell subpopulations harboring higher osteopotential is a promising strategy to achieve a thorough translation of MSC-based therapies to the clinic. Here, we searched for novel molecular markers predictive of osteopotential by comparing MSC populations from two sources harboring different osteogenic potentials. We show that MSCs from human deciduous teeth (SHED) have an intrinsically higher osteogenic potential when compared with MSCs from human adipose tissue (hASCs) under the same in vitro controlled induction system. Transcriptome profiling revealed IGF2 to be one of the top upregulated transcripts before and during early in vitro osteogenic differentiation. Further, exogenous IGF2 supplementation enhanced alkaline phosphatase activity and matrix mineralization, and inhibition of IGF2 lessened these parameters in SHED and hASCs, validating IGF2 as an osteogenic factor in these MSCs. Further, we found IGF2 to be biallelically expressed in SHED, but not in hASCs. We observed a 4 % methylation increase in the imprinting control region within the IGF2-H19 locus in SHED, and this is mainly due to 2 specific CpG sites. Thus, we suggest that IGF2 upregulation in SHED is due to loss of imprinting. This study unravels osteogenic properties in SHED, implying IGF2 as a potential biomarker of MSCs with higher osteopotential, and unveils IGF2 loss-of-imprinting in SHED. PMID- 25931280 TI - Elucidation of the absolute configuration of rhizopine by chiral supercritical fluid chromatography and vibrational circular dichroism. AB - The absolute configuration of rhizopine, an opine-like natural product present in nitrogen-fixing nodules of alfalfa infected by rhizobia, is elucidated using a combination of state-of-the-art analytical and semi-preparative supercritical fluid chromatography and vibrational circular dichroism spectroscopy. A synthetic peracetylated racemate was fractionated into its enantiomers and subjected to absolute configuration analysis revealing that natural rhizopine exists as a single enantiomer. The stereochemistry of non-derivatized natural rhizopine corresponds to (1R,2S,3R,4R,5S,6R)-4-amino-6-methoxycyclohexane-1,2,3,5-tetraol. PMID- 25931281 TI - Screening for people with abnormal glucose metabolism in the European DE-PLAN project. AB - AIMS: The aim of this report is to describe the application of the FINDRISC in clinical practice within the DE-PLAN project as a step to screen for Type 2 diabetes. METHODS: Nine out of 24 possible centers were included. Six centers used opportunistic screening methods for participant recruitment whereas three centers provided study participants of a random population sample. Men (n=1621) and women (n=2483) were evaluated separately. In order to assess the prevalence of abnormal glucose tolerance (AGT) disorders across different risk categories, the FINDRISC was used. Anthropometric measurements included blood pressure, height, weight, and waist circumference. Blood lipids and an oral glucose tolerance test were performed in all participants. The primary outcome was identified risk of AGT and type 2 diabetes. RESULTS: There was no difference in the prevalence of smoking between the FINDRISC categories, people with a FINDRISC below 15 points tend to be more physically active and to eat more frequently fruits and vegetables. Men with a FINDRISC from 15 to 19 points had a prevalence of abnormal glucose tolerance of approximately 60% and women 50%. The prevalence for men and women with a FINDRISC >20 points was 80%. 30% of men and 20% of women with a FINDRISC between 15 and 19 points had Type 2 diabetes. Among people with a FINDRISC more than 20 points, 50% had previously undiagnosed Type 2 diabetes. CONCLUSIONS: The FINDRISC may be a practical tool to be used in primary health care systems throughout the European population. PMID- 25931283 TI - World Diabetes Congress 2015: Living with diabetes stream: Triumphing over complexity and flourishing with diabetes. PMID- 25931282 TI - Family history and body mass index predict perceived risks of diabetes and heart attack among community-dwelling Caucasian, Filipino, Korean, and Latino Americans -DiLH Survey. AB - AIM: The purpose of the study was to explore the perceived risk for diabetes and heart attack and associated health status of Caucasian, Filipino, Korean, and Latino Americans without diabetes. METHODS: A cross-sectional survey was conducted with 904 urban adults (mean age 44.3+/-16.1 years; 64.3% female) in English, Spanish or Korean between August and December 2013. RESULTS: Perceived risk for developing diabetes was indicated by 46.5% (n=421), and 14.3% (n=129) perceived themselves to be at risk for having a heart attack in their lifetime. Significant predictors of pessimistic diabetes risk perceptions: Filipino (adjusted odds ratio [AOR]=1.7; 95% CI: 1.04-2.86) and Korean (AOR=2.4; 1.33 4.48) ethnicity, family history of diabetes (AOR=1.4; 1.00-1.84), female gender (AOR=1.4; 1.04-1.96), high cholesterol (AOR= 1.6; 1.09-2.37) and higher body mass index (BMI) (AOR=1.1; 1.08-1.15). Predictors of pessimistic heart attack risk perceptions were family history of an early heart attack (AOR=2.9; 1.69-5.02), high blood pressure (AOR=2.4; 1.45-3.84), and higher BMI (AOR=1.1; 1.04-1.12) after controlling for socio-demographic factors. Older age, physical inactivity, smoking, and low HDL levels were not associated with risk perceptions. CONCLUSION: Multiple risk factors were predictive of greater perceived diabetes risk, whereas, only family history of heart attack, high blood pressure and increases in BMI significantly contributed to perceived risk of heart attack among ethnically diverse at risk middle-aged adults. It is important that healthcare providers address the discordance between an individual's risk perceptions and the presence of actual risk factors. PMID- 25931284 TI - Watching orientational ordering at the nanoscale with coherent anti-stokes Raman microscopy. AB - Whether in lipid membranes, liquid crystals or solid-state catalysts, the orientational ordering of molecules greatly influences the overall system behaviour. However, watching molecular alignment is a huge technical challenge. This article introduces nonlinear Raman (coherent anti-Stokes Raman scattering; CARS) microscopy as a promising tool for fast, label-free 3D chemical and structural sample characterization at the nanoscale in real time. PMID- 25931285 TI - DNA damage in cancer therapeutics: a boon or a curse? AB - Millions of DNA-damaging lesions occur every day in each cell of our bodies due to various stresses. The failure to detect and accurately repair these lesions can give rise to cells with high levels of endogenous DNA damage, deleterious mutations, or genomic aberrations. Such genomic instability can lead to the activation of specific signaling pathways, including the DNA damage response (DDR) pathway. Constitutive activation of DDR proteins has been observed in human tumor specimens from different cancer stages, including precancerous and metastatic cancers, although not in normal tissues. The tumor-suppressive role of DDR activity during the premalignant stage has been studied, and strong evidence is emerging for an oncogenic role for DDR proteins such as DNA-PK and CHK1 during the later stages of tumor development. However, the majority of current cancer therapies induce DNA damage, potentially exacerbating protumorigenic genomic instability and enabling the development of resistance. Therefore, elucidating the molecular basis of DNA damage-mediated genomic instability and its role in tumorigenesis is critical. Finally, I discuss the potential existence of distinct DNA damage thresholds at various stages of tumorigenesis and what the ramifications of such thresholds would be, including the ambiguous role of the DDR pathway in human cancers, therapy-induced malignancies, and enhanced therapies. PMID- 25931286 TI - High-Frequency Targetable EGFR Mutations in Sinonasal Squamous Cell Carcinomas Arising from Inverted Sinonasal Papilloma. AB - Inverted sinonasal papilloma (ISP) is a locally aggressive neoplasm associated with sinonasal squamous cell carcinoma (SNSCC) in 10% to 25% of cases. To date, no recurrent mutations have been identified in ISP or SNSCC. Using targeted next generation sequencing and Sanger sequencing, we identified activating EGFR mutations in 88% of ISP and 77% of ISP-associated SNSCC. Identical EGFR genotypes were found in matched pairs of ISP and associated SNSCC, providing the first genetic evidence of a biologic link between these tumors. EGFR mutations were not identified in exophytic or oncocytic papillomas or non-ISP-associated SNSCC, suggesting that the ISP/SNSCC spectrum is biologically distinct among sinonasal squamous tumors. Patients with ISP harboring EGFR mutations also exhibited an increased progression-free survival compared with those with wild-type EGFR. Finally, treatment of ISP-associated carcinoma cells with irreversible EGFR inhibitors resulted in inactivation of EGFR signaling and growth inhibition. These findings implicate a prominent role for activating EGFR mutations in the pathogenesis of ISP and associated SNSCC and rationalize consideration of irreversible EGFR inhibitors in the therapy of these tumors. PMID- 25931287 TI - Living in "survival mode:" Intergenerational transmission of trauma from the Holodomor genocide of 1932-1933 in Ukraine. AB - Qualitative methodology was used to investigate the intergenerational impact of the 1932-1933 Holodomor genocide on three generations in 15 Ukrainian families. Each family, residing in Ukraine, consisted of a first generation survivor, a second generation adult child and a third generation adult grandchild of the same line. The findings show that the Holodomor, a genocide that claimed millions of lives by forced starvation, still exerts substantial effects on generations born decades later. Specifically, thematic analysis of the 45 semi-structured, in depth interviews, done between July and November 2010, revealed that a constellation of emotions, inner states and trauma-based coping strategies emerged in the survivors during the genocide period and were subsequently transmitted into the second and third generations. This constellation, summarized by participants as living in "survival mode," included horror, fear, mistrust, sadness, shame, anger, stress and anxiety, decreased self-worth, stockpiling of food, reverence for food, overemphasis on food and overeating, inability to discard unneeded items, an indifference toward others, social hostility and risky health behaviours. Since both the family and community-society were found to be involved in trauma transmission, the findings highlight the importance of multi framework approaches for studying and healing collective trauma. PMID- 25931288 TI - Ethnic differences in children's socioemotional difficulties: Findings from the Millennium Cohort Study. AB - This paper investigates ethnic differences in children's socioemotional difficulties and possible explanations for any observed inequalities. We used data collected from the fourth sweep of the Millennium Cohort Study when children were aged 7 years. We found that Pakistani, Bangladeshi, and Black Caribbean children had significantly more socioemotional difficulties than White children. These differences were partially explained by the relative socioeconomic disadvantage of their families. After accounting for maternal and family environment factors, the differences for Pakistani children remained unexplained. In contrast, Black African children were the only ethnic minority group to have significantly fewer socioemotional difficulties. We investigated the role of four indicators of socioeconomic position in explaining these differences and found equivalised household income had the strongest influence on socioemotional difficulties, and that socioeconomic position associations with socioemotional difficulties were less apparent among Pakistani and Bangladeshi children. The association between adverse economic conditions and socioemotional difficulties was partially mediated by maternal psychological distress. In conclusion, unexplained ethnic differences in socioemotional difficulties were seen, with a disadvantage among Pakistani children and an advantage among Black African children. Our results point to the need to address economic deprivation among ethnic minority groups to reduce children's socioemotional difficulties. PMID- 25931289 TI - Effect of gaseous ozone and light-activated disinfection on the surface hardness of resin-based root canal sealers. AB - Although root canal instruments remove most of the content from the main root canal space, disinfection or irrigation plays an indispensable role in all areas of the root canal system, especially in parts that are inaccessible by instruments. The originality of this study was to investigate the effect of two novel disinfection techniques on the surface hardness of resin-based endodontic sealers using atomic force microscopy (AFM). Forty extracted single-rooted maxillary central human teeth were prepared and divided into four groups according to treatment methods. The first group was irrigated with saline and served as a control, other groups irrigated with sodium hypochlorite (NaClO); gaseous ozone; and light-activated disinfection (LAD). The groups were divided into two subgroups, according to the obturation method used: subgroup A: gutta percha and AH plus; and subgroup B: EndoREZ/resin-coated cones. After obturation, atomic force microscopy (AFM) measurement was performed to analyze the surface hardness of the sealers. There was a significant difference between group 1A and group 3A (p < 0.05). Group 3B had the highest surface hardness values that were statistically different (p < 0.05). When disregarding the sealers, the ozone possessed statistically higher surface hardness values than the other groups in all root thirds (p < 0.05). The use of ozone and LAD may alter the surface hardness of resin-based sealers. The use of AFM can be considered an alternative hardness test techonology for sealing material. PMID- 25931290 TI - Sensory Adapted Dental Environments to Enhance Oral Care for Children with Autism Spectrum Disorders: A Randomized Controlled Pilot Study. AB - This pilot and feasibility study examined the impact of a sensory adapted dental environment (SADE) to reduce distress, sensory discomfort, and perception of pain during oral prophylaxis for children with autism spectrum disorder (ASD). Participants were 44 children ages 6-12 (n = 22 typical, n = 22 ASD). In an experimental crossover design, each participant underwent two professional dental cleanings, one in a regular dental environment (RDE) and one in a SADE, administered in a randomized and counterbalanced order 3-4 months apart. Outcomes included measures of physiological anxiety, behavioral distress, pain intensity, and sensory discomfort. Both groups exhibited decreased physiological anxiety and reported lower pain and sensory discomfort in the SADE condition compared to RDE, indicating a beneficial effect of the SADE. PMID- 25931291 TI - Hypogammaglobulinemia in newly diagnosed chronic lymphocytic leukemia: Natural history, clinical correlates, and outcomes. AB - BACKGROUND: Although hypogammaglobulinemia is a well recognized complication in patients with chronic lymphocytic leukemia (CLL), its prevalence at the time of CLL diagnosis, and association with novel prognostic markers and clinical outcome is not well understood. METHODS: All patients at the Mayo Clinic between January 1999 and July 2013 who had newly diagnosed CLL and had a baseline assessment of serum immunoglobulin G (IgG) were included. The relation between hypogammaglobulinemia at diagnosis and the novel prognostic parameters time to first treatment (TFT) and overall survival (OS) were evaluated. RESULTS: Of 1485 patients who met the eligibility criteria, 382 (26%) had hypogammaglobulinemia (median IgG, 624 mg/dL), whereas the remaining 1103 patients (74%) had normal serum IgG levels (median IgG, 1040 mg/dL). Patients who had hypogammaglobulinemia at diagnosis were more likely to have advanced Rai stage (III-IV; P = .001) and higher expression of CD49d (P < .001) compared with patients who had normal IgG levels. Although the median TFT for patients who had hypogammaglobulinemia was shorter compared with that for patients who had normal IgG levels (3.8 years vs 7.4 years; P < .001), on multivariable analysis, there was no difference in OS between these 2 groups (12.8 years vs 11.3 years, respectively; P = .73). Of 1103 patients who had CLL with normal IgG levels at diagnosis and who did not receive CLL therapy, the risk of acquired hypogammaglobulinemia was 11% at 5 years and 23% at 10 years. CONCLUSIONS: Hypogammaglobulinemia is present in 25% of patients with newly diagnosed CLL. Approximately 25% of patients who have CLL with normal IgG levels at diagnosis will subsequently develop hypogammaglobulinemia on long term follow-up. The presence of hypogammaglobulinemia does not appear to impact overall survival. PMID- 25931293 TI - Efficacy of Spinal Needle Aspiration in Patients with Epiglottic Abscess: A Prospective, Randomized, Controlled Study. AB - OBJECTIVE/HYPOTHESIS: To evaluate the efficacy of spinal needle aspiration for symptom improvement in awake patients with epiglottic abscess (EA). STUDY DESIGN: Prospective randomized controlled study. SETTING: Tertiary center. SUBJECTS AND METHODS: Twenty-two patients who were diagnosed with EA were randomly allocated to group A (needle aspiration and antibiotics) or group B (antibiotics only). Patients' characteristics, laryngoscopic findings of epiglottic swelling and arytenoid swelling by scope classification, and initial laboratory findings were analyzed. Needle aspiration was done under local anesthesia in awake patients using an 18-gauge spinal needle and indirect laryngoscope. Changes in the following symptoms during hospital stay were assessed: sore throat, hoarseness, dyspnea, odynophagia, and dysphagia. RESULTS: Eleven patients were treated with needle aspiration and antibiotics, and 11 patients were treated with antibiotics only. There was no statistically significant difference between the 2 groups regarding age, sex, white blood cell count, C-reactive protein, presenting clinical symptoms, abscess size, and scope classification at time of diagnosis. Patients in both groups had significant improvement in all clinical symptoms. While there were no between-group differences in improvement for any of the symptoms, the length of hospitalization was significantly lower in group A (4.0 +/- 1.9 days) than in group B (5.7 +/- 1.2 days) (P = .037). CONCLUSION: We did not find any significant additional benefit of needle aspiration for the treatment of EA, with the exception that needle aspiration reduced the length of hospitalization. Further proof with a large-scale study is needed. PMID- 25931294 TI - Vocal Fold Paralysis as a Delayed Consequence of Neck and Chest Radiotherapy. AB - OBJECTIVE: To describe a series of cases of vocal fold paralysis years after radiation therapy, including presentation, clinical course, and treatment. STUDY DESIGN: Case series with chart review. SETTING: Tertiary care center. SUBJECTS AND METHODS: A review of 8 years of patient records yielded 10 patients (8 male and 2 female; average age 57 years [range, 29-76 years]) with vocal fold paralysis and a history of radiation therapy to the head, neck, or mediastinum. These patients did not have other possible etiologies of vocal fold paralysis. Demographic, diagnostic, clinical course, and treatment data were collected. RESULTS: On average, 21 years (range, 1-27 years) elapsed between completion of radiation and presentation with vocal fold paralysis. Original pathologies included Hodgkin lymphoma (5), squamous cell carcinoma of the head and neck (4), and peripheral T-cell lymphoma (1). Eight patients had unilateral left vocal fold paralysis, and 2 had bilateral neuropathy; none recovered spontaneously. All patients had dysphonia, and nearly all patients also complained of dysphagia. Six elected not to be treated. Four underwent injection augmentation with resolution of voice complaints. CONCLUSIONS: Radiation therapy has the potential to cause laryngeal neuropathy years to decades after treatment. The potential for recovery is low, but injection augmentation can relieve symptoms. Development of contralateral neuropathy and altered tissue response are considerations in treatment. PMID- 25931295 TI - Hospital and Surgeon Adherence to Pediatric Tonsillectomy Guidelines Regarding Perioperative Dexamethasone and Antibiotic Administration. AB - OBJECTIVES: To (1) determine adherence to American Academy of Otolaryngology-Head and Neck Surgery Foundation guidelines for pediatric tonsillectomy recommending routine administration of perioperative dexamethasone and against routine antibiotic administration among surgeons and hospitals in a multihospital network and (2) evaluate the impact of adherence on the risk of complications. STUDY DESIGN: Case series with chart review. SETTING: Multihospital network. SUBJECTS AND METHODS: A case series of 15,950 children aged 1 to 18 years undergoing same day surgery adenotonsillectomy (T&A) within a multihospital network from 2008 to 2014 was reviewed to determine whether dexamethasone and/or antibiotics were given in the hospital. The frequency of dexamethasone and antibiotic administration was compared among surgeons and hospitals in the years before and after the guidelines were published. The frequency of complications was compared in adhering vs nonadhering surgeons. RESULTS: The study cohort included 15,950 children undergoing T&A at 19 hospitals by 74 surgeons. Of the patients before guideline publication, 98.4% (n = 7432) received dexamethasone compared with 98.9% of subjects after guideline publication (n = 8518). In total, 16.1% received antibiotics before the guidelines compared with 13.8% after. Prior to the guidelines, 27 of 74 surgeons (36%) routinely gave antibiotics. After the guidelines were published, 19 surgeons (26%) continued to give antibiotics more than 50% of the time. There was no difference in complication visits between adhering and nonadhering surgeons. CONCLUSIONS: Most hospitals and surgeons administered perioperative dexamethasone routinely. While the overall frequency of antibiotic administration decreased after the guidelines were published, a significant percentage of surgeons continued to give antibiotics routinely, suggesting the need for improved dissemination and implementation of guidelines to promote adherence. PMID- 25931296 TI - Validation of rapid assessment methods to determine streamflow duration classes in the Pacific Northwest, USA. AB - United States Supreme Court rulings have created uncertainty regarding U.S. Clean Water Act (CWA) authority over certain waters, and established new data and analytical requirements for determining CWA jurisdiction. Thus, rapid assessment methods are needed that can differentiate between ephemeral, intermittent, and perennial streams. We report on the validation of several methods. The first (Interim Method) was developed through best professional judgment (BPJ); an alternative (Revised Method) resulted from statistical analysis. We tested the Interim Method on 178 study reaches in Oregon, and constructed the Revised Method based on statistical analysis of the Oregon data. Next, we evaluated the regional applicability of the methods on 86 study reaches across a variety of hydrologic landscapes in Washington and Idaho. During the second phase, we also compared the Revised Method with a similar approach (Combined Method) based on combined field data from Oregon, Washington, and Idaho. We further compared field-based methods with a GIS-based approach (GIS Method) that used the National Hydrography Dataset and a synthetic stream network. Evaluations of all methods compared results with actual streamflow duration classes. The Revised Method correctly determined known streamflow duration 83.9% of the time, versus 62.3% accuracy of the Interim Method and 43.6% accuracy for the GIS-based approach. The Combined Method did not significantly outperform the Revised Method. Analysis showed biological indicators most accurately discriminate streamflow duration classes. While BPJ established a testable hypothesis, this study illustrates the importance of quantitative field testing of rapid assessment methods. Results support a consistent method applicable across the Pacific Northwest. PMID- 25931297 TI - Displacement, Deprivation and Development: The Impact of Relocation on Income and Livelihood of Tribes in Similipal Tiger and Biosphere Reserve, India. AB - A large volume of literature describes adverse consequences of conservation induced displacement on indigenous communities depended on natural resources of wildlife habitat. Resettlement policies in protected areas the world over are mainly designed and implemented without consideration of social and economic costs of exclusion. This study examined income and poverty profile of tribal residents in Similipal Tiger and Biosphere Reserve in India, relative to the households relocated out of the reserve. The income from different sources and livelihood diversification of displaced reserve dwellers reflected changes resulting from the loss of access to natural and household assets. The results contradicted common perception about impoverishment outcome of relocation. It showed an increase in the per capita income for poorer segments with an overall 8% increase in absolute household income and corresponding improvement in the poverty ratio (head count ratio) and FGT index (0.241) for the relocated community. Contrary to other studies, the finding did not observe social alignment or marginalization; however, on-farm livelihood diversification reduced with increased dependence on off-farm sources. Expulsion of people from forest reserves to support conservation is inadequate in restricting habitat use of locals unless suitable alternative livelihood options are available for forest dependent was proven from the study. PMID- 25931298 TI - Quantifying Variability in Four U.S. Streams Using a Long-Term Dataset: Patterns in Biotic Endpoints. AB - Effective water resources assessment and management requires quantitative information on the variability of ambient and biological conditions in aquatic communities. Although it is understood that natural systems are variable, robust estimates of long-term variation in community-based structure and function metrics are rare in U.S. waters. We used a multi-year, seasonally sampled dataset from multiple sites (n = 5-6) in four streams (Codorus Creek, PA; Leaf River, MS; McKenzie and Willamette Rivers, OR) to examine spatial and temporal variation in periphyton chlorophyll a, and fish and macroinvertebrate metrics commonly used in bioassessment programs. Within-site variation of macroinvertebrate metrics and benthic chlorophyll a concentration showed coefficient of variation ranging from 16 to 136%. Scale-specific variability patterns (stream-wide, season, site, and site-season patterns) in standardized biotic endpoints showed that within-site variability patterns extended across sites with variability greatest in chlorophyll a and lowest in Hilsenhoff's Biotic Index. Across streams, variance components models showed that variance attributed to the interaction of space and time and sample variance accounted for the majority of variation in macroinvertebrate metrics and chlorophyll a, while most variation in fish metrics was attributed to sample variance. Clear temporal patterns in measured endpoints were rare and not specific to any one stream or assemblage, while apparent shifts in metric variability related to point source discharges were seen only in McKenzie River macroinvertebrate metrics in the fall. Results from this study demonstrate the need to consider and understand spatial, seasonal, and longer term variability in the development of bioassessment programs and subsequent decisions. PMID- 25931299 TI - From Paper to Forest: Local Motives for Participation in Different Conservation Initiatives. Case Studies in Southeastern Mexico. AB - Under the assumption that local participation can contribute toward conservation, various policies have sought to increase the participation of local communities in conservation, but not always with success. Despite this failure, the drivers that explain local participation remain unclear and few studies have attempted to understand the motivations behind involvement (or lack of it) in different conservation initiatives and adopting the perspective of the local stakeholder. In this study, we analyze the motives behind the participation (or lack thereof) of local populations in three conservation schemes: Protected Areas, Areas Voluntary Devoted to Conservation, and areas under Payment for Environmental Services. The study, conducted in 6 communities of southeastern Mexico, comprises an ethnographic stage and the application of a survey exploring the motives for participation. Our results show similarities among the motives for participation in these three initiatives, predominantly the obligation to comply with acquired commitments and a desire to "care for the land". Results also show that 77 % of the people interviewed did not participate in any conservation initiatives, often due to the lack of mechanisms by which to participate. We conclude by questioning the feasibility of achieving local participation in conservation as currently proposed and for the aims that are outlined. PMID- 25931300 TI - A case of fever of unknown origin? PMID- 25931301 TI - Metastatic ovarian carcinoma presenting as an incarcerated femoral hernia. AB - INTRODUCTION: Incarcerated femoral hernias usually contain a simple loop of bowel. Occasionally other abdominal structures may be found within the hernial sac. Rarely femoral hernias may contain metastatic tumour deposits. PRESENTATION OF CASE: We report the case of an 82 year old lady with a background of ovarian carcinoma, who presented with acute small bowel obstruction and an irreducible right groin mass. CT imaging revealed an incarcerated loop of small bowel within a femoral hernia sac. The patient proceeded to theatre for hernia repair. Upon opening the hernial sac an adherent incarcerated small bowel loop was discovered. Interestingly, the sac itself was lined with metastatic deposits, which were later histologically proven to be ovarian in origin. The sac was reduced and the hernia was repaired. The patient's post-operative course was uneventful. DISCUSSION: As abdominal wall hernias communicate with the abdominal cavity there is the potential for malignant cells to seed the peritoneal lining of the hernia sac. If the sac also contains bowel wall, this may become involved in the tumour mass. This may result in small bowel incarceration & obstruction. CONCLUSION: In cases, where there is a known intra-abdominal malignancy & the presence of an incarcerated hernia, there should be a high index of suspicion for the presence of tumour within the hernial contents. PMID- 25931302 TI - Delayed presentation of compartment syndrome of the thigh secondary to quadriceps trauma and vascular injury in a soccer athlete. AB - INTRODUCTION: Compartment syndrome isolated to the anterior thigh is a rare complication of soccer injury. Previous reports in the English literature on sports trauma-related compartment syndrome of the thigh are vague in their description of the response of thigh musculature to blunt trauma, magnetic resonance imaging (MRI) findings of high-risk features of compartment syndrome, vascular injury in quadriceps trauma, and the role of vascular study in blunt thigh injury. CASE REPORT: We present herein the rare case of a 30-year-old man who developed thigh compartment syndrome 8 days after soccer injury due to severe edema of vastus intermedius and large thigh hematoma secondary to rupture of the profunda femoris vein. MRI revealed "blow-out" rupture of the vastus lateralis. Decompressive fasciotomy and vein repair performed with subsequent split-skin grafting of the wound defect resulted in a good functional outcome at 2-years follow-up. CONCLUSION: A high index of suspicion for compartment syndrome is needed in all severe quadriceps contusion. Vascular injury can cause thigh compartment syndrome in sports trauma. MRI findings of deep thigh muscle swelling and "blow-out" tear of the vastus lateralis are strongly suggestive of severe quadriceps injury, and may be a harbinger of delayed thigh compartment syndrome. PMID- 25931303 TI - Bile acids activate ryanodine receptors in pancreatic acinar cells via a direct allosteric mechanism. AB - The earliest critical event of pancreatitis is a long lasting high amplitude rise of intracellular Ca(2+) concentration of the acinar cell, which can be triggered by high concentration of bile acids. Although, Ca(2+)-release through ryanodine receptors (RyR) is involved in the process, the significance and the exact mechanism of bile acid's action on RyR has not been fully elucidated yet. Therefore, we aimed to test with various techniques and aspects whether bile acids exert a direct effect on RyR and SERCA pump. Our data show that taurocholic acid (TCA)-induced Ca(2+) release in pancreatic acinar cells was significantly reduced by the RyR antagonist dantrolene. Further, we show that TCA enhanced RyR's (3)H-ryanodine binding and triggered robust Ca(2+)-release from RyR enriched vesicles in the pathologically relevant concentration range. RyR single channel current analysis demonstrated that 200MUM TCA induced a 5-fold increase in the channel's open probability and caused a significant lengthening of the mean open time. TCA also suppressed Ca(2+)-uptake rate and ATP-ase activity of SERCA-enriched vesicles, but interestingly, failed to decrease Ca(2+) elimination rate in intact cells. Overall, our results strongly suggest that TCA opens RyR by an allosteric mechanism, which contribute significantly to bile acid-induced pathologic Ca(2+)-leak from the endoplasmic reticulum in pancreatic acinar cells. PMID- 25931304 TI - The development of thromboembolism may increase the risk of osteonecrosis in children with acute lymphoblastic leukemia. AB - Previous studies indicate pathophysiological and epidemiological parallels between osteonecrosis (ON) and thromboembolism (TE), two common treatment-related morbidities in acute lymphoblastic leukemia (ALL). To elucidate risk factors for ON and explore the relationship between ON and TE, we undertook a retrospective study of children (n = 208) with ALL. Twenty-one (10.1%) children developed ON and 42 (20.2%) TE on therapy. Thromboembolism was a significant predictor of ON on univariate (OR 8.85) and multivariate analysis, along with older age and PEGylated asparaginase. This observation supports a role for hypercoagulability in the pathogenesis of ON. Larger prospective studies are needed to further test these findings. PMID- 25931305 TI - Improved nonclinical pharmacokinetics and biodistribution of a new PPAR pan agonist and COX inhibitor in nanocapsule formulation. AB - We report the in vitro release profile and comparative pharmacokinetics and biodistribution of a new peroxisome proliferator-activated receptor-gamma agonist and cyclooxygenase inhibitor (Lyso-7) free or associated to poly(D,L-lactic acid) nanocapsules (NC) after intravenous administration in mice. Lyso-7 pertains to the class of insulin-sensitizing agents that shows potential beneficial effects in diabetes therapy. Monodispersed Lyso-7 NC with a mean diameter of 273 nm with high encapsulation efficiency (83%) were obtained. Lyso-7 dissolution rate was reduced (2.6-fold) upon loading in NC. The pharmacokinetic parameters were determined using a non-compartmental approach. In comparison with Lyso-7 in solution, the plasma-AUC increased 14-fold, the mean residence time 2.6-fold and the mean half-life (t1/2) 1.5-fold for Lyso-7-NC; the Lyso-7 plasma clearance, distribution volume and elimination rate were reduced 13, 10 and 1.4 fold, respectively, which indicates higher retention of encapsulated Lyso-7 in the blood compartment. Upon association with NC, organ exposure to Lyso-7 was higher in the heart (3.6-fold), lung (2.8-fold), spleen (2.3-fold), kidney (2-fold) and liver (1.8-fold) compared to Lyso-7 in solution. The analysis of whole data clearly indicates that body exposure to Lyso-7 was enhanced and the general toxicity reduced upon nanoencapsulation, allowing further evaluation of Lyso-7 in nonclinical and clinical studies. PMID- 25931306 TI - Molecular weight and concentration of heparin in hyaluronic acid-based matrices modulates growth factor retention kinetics and stem cell fate. AB - Growth factors are critical for regulating and inducing various stem cell functions. To study the effects of growth factor delivery kinetics and presentation on stem cell fate, we developed a series of heparin-containing hyaluronic acid (HyA)-based hydrogels with various degrees of growth factor affinity and retention. To characterize this system, we investigated the effect of heparin molecular weight, fractionation, and relative concentration on the loading efficiency and retention kinetics of TGFbeta1 as a model growth factor. At equal concentrations, high MW heparin both loaded and retained the greatest amount of TGFbeta1, and had the slowest release kinetics, primarily due to the higher affinity with TGFbeta1 compared to low MW or unfractionated heparin. Subsequently, we tested the effect of TGFbeta1, presented from various heparin containing matrices, to differentiate a versatile population of Sca-1(+)/CD45(-) cardiac progenitor cells (CPCs) into endothelial cells and form vascular-like networks in vitro. High MW heparin HyA hydrogels stimulated more robust differentiation of CPCs into endothelial cells, which formed vascular-like networks within the hydrogel. This observation was attributed to the ability of high MW heparin HyA hydrogels to sequester endogenously synthesized angiogenic factors within the matrix. These results demonstrate the importance of molecular weight, fractionation, and concentration of heparin on presentation of heparin binding growth factors and their effect on stem cell differentiation and lineage specification. PMID- 25931307 TI - Fluorescence Lifetime Imaging Combined with Conventional Intravascular Ultrasound for Enhanced Assessment of Atherosclerotic Plaques: an Ex Vivo Study in Human Coronary Arteries. AB - This study evaluates the ability of label-free fluorescence lifetime imaging (FLIm) to complement intravascular ultrasound (IVUS) for concurrent visualization of human coronary vessel composition, structure, and pathology. Co-registered FLIm and IVUS data from 16 coronary segments were correlated to eight distinct pathological features including thin-cap fibroatheroma (TCFA). The sensitivity, specificity, and positive predictive value for combined FLIm-IVUS (89, 99, 89 %) were better than FLIm (70, 98, 88 %) and IVUS (45, 94, 62 %) alone in distinguishing between pathologies. FLIm can assess compositional changes in luminal surface through variations in fluorescence lifetime values (<3.5 ns for lipid-rich areas; >4 ns for collagen-rich areas) enabling detection of macrophages in fibrous caps (sensitivity, 86 %) and distinguishing between relatively stable thick-cap fibroatheromas and rupture-prone TCFA (sensitivity, 80 %) amongst other features. Current results demonstrate the potential of FLIm IVUS as a new intravascular method for improved evaluation of plaques that may subsequently aid in guiding coronary intervention. PMID- 25931308 TI - Multisession Gamma Knife Radiosurgery for Orbital Apex Tumors. AB - OBJECTIVE: This study was performed to analyze the outcome of multisession gamma knife radiosurgery (GKS) in benign tumors located at the orbital apex. METHODS: Medical records of 23 patients who underwent multisession GKS for benign orbital apex tumors were reviewed retrospectively. Three patients were diagnosed by histology, and the other 20 patients were given the diagnoses on the basis of clinical and radiological findings. Diagnoses included cavernous hemangioma (8 cases), meningioma (8 cases), and schwannoma (7 cases). All patients were treated with 4 sessions of GKS with 12 hours of interval. Median marginal dose in each session was 5 Gy (range, 4.5-5.5 Gy) at the 50% isodose line (range, 50%-55%). RESULTS: Mean clinical and imaging follow-up duration after treatment were 52.1 and 34.2 months, respectively. Tumor control was achieved in 22 patients (95.7%). Significant tumor shrinkage was observed in 17 patients (73.9%), and mean tumor volume reduction rate was 53.9%. Visual function was improved in 16 patients (69.6%) and stable in 4 patients (17.4%). Deterioration of visual acuity was reported by 3 patients (13.0%). Clinical and radiological response to multisession GKS was most excellent in cavernous hemangiomas with tumor control in all patients, and the mean tumor volume reduction rate was 68.3%. CONCLUSIONS: Multisession GKS proved to be an effective and safe management strategy for benign orbital apex tumors. Response to treatment was different according to the pathology, and multisession GKS may be considered as the initial treatment of choice for specific pathology such as cavernous hemangioma. PMID- 25931309 TI - A Rare Complication of Spine Surgery: Guillain-Barre Syndrome. AB - OBJECTIVE: Since little has been reported about Guillain-Barre syndrome (GBS) after spine surgery, we sought to determine some of the clinical features and the management of the condition. METHODS: A total of 4 cases of GBS after spine surgery were included. The medical charts of the patients were reviewed to obtain demographic and clinical details. All the patients underwent neurologic and electrophysiologic examinations and were followed up after surgery. RESULTS: The onset of symptoms about GBS was 2-7 days after the operation. Neurologic evaluation showed weaknesses of upper and lower extremities and repeal of tendon reflexes. The patients exhibited typical clinical symptoms and signs of GBS and electromyographic findings. Lumbar puncture was performed in 2 cases, and cerebrospinal fluid examination showed albuminocytological dissociation. All the 4 patients were diagnosed as GBS on the basis of typical clinical, laboratory, and electrophysiologic findings. Intravenous immunoglobulin was instituted. At follow-up, one patient needed ventilator support; one patient could transfer from bed to chair; one walked with assistive devices; and the remaining patient had residual minor neurologic deficits. CONCLUSIONS: These cases warn surgeons to be alert to the association of GBS and spine surgery. On the basis of our experience, we recommend consideration of this rare diagnosis in patients with paralysis after spine surgery. PMID- 25931310 TI - Posterior Cerebral Artery Pseudoaneurysm, a Rare Complication of Pituitary Tumor Transsphenoidal Surgery: Case Report and Literature Review. AB - Endoscopic endonasal transsphenoidal surgery for pituitary tumors has been the standard therapy for decades. This approach offers surgeons an effective, safe, and wide exposure to the pituitary gland, with a relatively low mortality rate and acceptable complication rates. However, severe complications, including cerebrospinal fistula, meningitis, neural component injury, and vascular injury, may occur. One of the most common and severe complications is carotid artery injury; however, only 2 posterior cerebral artery injuries with pseudoaneurysm formation have been reported previously. One of them received bypass surgery and recovered well, but the other received endovascular treatment and died of intracranial hypertension. Herein, we report a rare case of iatrogenic pseudoaneurysm formation with hemorrhage after transsphenoidal surgery, in which tumor traction-related adjacent vessel injury was most likely. Aneurysm clipping, vascular bypass, and embolization are considered reasonable choices depending on the patient's condition for iatrogenic aneurysm formation. In our case, no surgical or endovascular intervention was performed, and the aneurysm healed spontaneously 3 weeks later. PMID- 25931311 TI - Myopericytoma: A Series of 5 Cases Affecting the Nervous System. AB - BACKGROUND: Myopericytomas are benign vascular tumors composed of perivascular myoid cells that usually arise in superficial soft tissues of the extremities. METHODS: We here report on 5 cases of myopericytoma, malignant myopericytoma, and glomangiopericytoma arising from subcutaneous, paraspinal, orbital, and sellar regions that secondarily involved the nervous system. Patients experienced orbital swelling, progressing neuropathic pain, dermatoma specific pain, and oculomotor paresis. RESULTS: Mean age at diagnosis was 56.8 years (range, 38-74 years). After a mean follow-up of 38 months, no recurrence was detected. All tumors were unencapsulated but relatively well-circumscribed lesions, showing typical histologic and immunohistochemical features of soft-tissue myopericytoma, including one malignant case. CONCLUSION: We conclude that myopericytoma may affect the nervous system and for prognostic and therapeutic reasons, needs to be differentiated from other vascular tumors. PMID- 25931312 TI - Aneurysm Clip Compression Technique in the Surgery of Aneurysms with Hard/Calcified Neck. AB - OBJECTIVE: One of the most important technical problems in surgery to repair aneurysms is the presence of a hard/calcified neck. In this situation, various techniques can be used for proper clipping. In addition to well-known techniques, we have used a different technique for more than 10 years. This technique probably also has been used by other neurosurgeons, but we could not find any publications about it in the English literature. Therefore, we would like to report the details of this technique and our own experience. METHODS: More than 600 anterior circulation aneurysms were clipped between January 2003 and December 2014. It was necessary to apply this technique in 25 aneurysms because of a hard/calcified neck. This series was reviewed retrospectively. If the hard calcified plaque at the neck does not allow for full closure of the clip and the known techniques are not sufficient for clipping, we carefully and slowly compress the aneurysm clip itself at the neck with a hemostatic clamp. The hard plaque usually is crushed with this technique, and full closure of the clip is immediately obtained. RESULTS: Complete occlusion of the neck was achieved in 16 aneurysms (64%) with this technique. Technique-related complication developed as intraoperative rupture of the aneurysm in two patients (8%). However, this complication was managed with other techniques in both cases. No distal thromboembolism developed in any patient. CONCLUSIONS: Our aneurysm clip compression technique may be a viable option in surgery of aneurysms with hard calcified neck. PMID- 25931313 TI - AutomiRDB: a web resource connecting microRNAs and autophagy in cancer. PMID- 25931314 TI - Duration of symptoms does not correlate with results of T-cell gene rearrangement studies in patients evaluated for cutaneous T-cell lymphoma. AB - OBJECTIVES: We aimed to determine if clonality on T-cell gene rearrangement studies correlated with duration of cutaneous symptoms in patients with skin disease who are being evaluated for cutaneous T-cell lymphoma (CTCL). Specifically, our goal was to determine if symptom duration could help better optimize sample selection for T-cell gene rearrangement studies. METHODS: Biopsies were reviewed from patients within both general dermatology clinic and CTCL specialty clinic for clonality results in relation to disease duration. RESULTS: We did not find an association between duration and clonality in any group. CONCLUSIONS: The yield of T-cell gene rearrangement studies is similar between shorter and longer duration of disease implying that there is not an optimal duration range in which T-cell gene rearrangement studies are more likely to give a positive result. PMID- 25931315 TI - Feasibility and safety of dose-dense modified docetaxel-cisplatin or carboplatin and 5-fluorouracil regimen (mTPF) in locally advanced or metastatic head and neck cancers: a retrospective monocentric study. AB - BACKGROUND: Docetaxel-cisplatin and 5-fluorouracil (TPF) chemotherapy (days 1-21) represents a standard but toxic regimen for advanced head and neck cancer (HNC). We report a retrospective monocentric study evaluating the safety and the efficacy of a dose-dense modified TPF (mTPF) regimen (days 1-14) in patients with stage III-IV HNC. METHODS: Thirty-seven patients retrospectively included from May 2011 to May 2014 were treated with a bimonthly dose-dense mTPF regimen (40 mg/m(2) docetaxel, 40 mg/m(2) cisplatin or AUC2 carboplatin, folinic acid 400 mg/m(2) for 2 h, bolus 5-FU 400 mg/m(2) for 10 min and 5-FU 1,000 mg/m(2)/day) by continuous infusion over 46 h). RESULTS: Chemotherapy was used as induction or palliative treatment in 12 and 25 patients, respectively, with a median age of 60 years (range 46-83). Median follow-up time was 7.4 months (2.53-16.7 months). There was no intestinal toxicity in 25 patients (68 %). Grade 3-4 hematological toxicity was noticed for 5 (13.5 %) patients. Granulocyte-colony stimulating factor was used as primary prophylaxis in 30 patients (81 %). After at least 4 delivered cycles, complete responses, partial responses and stable diseases were reported in 5 (15 %), 13 (39 %) and 5 (15 %) of the 33 evaluable patients, respectively, yielding an objective response rate of 54.5 % (39 % for palliative chemotherapy and 90 % for induction chemotherapy). CONCLUSION: Dose-dense mTPF (days 1-14) is safe and seems to be as effective as TPF (days 1-21). Future prospective trials are required to confirm our results. PMID- 25931317 TI - Clinical results of islet transplantation. AB - Islet transplantation is considered an advanced therapy in the treatment of type 1 diabetes, with a progressive improvement of clinical results as seen in the Collaborative Islet Transplant Registry (CITR) report. It is an accepted method for the stabilization of frequent hypoglycemia, or severe glycemic lability, in patients with hypoglycemic unawareness, poor diabetic control, or a resistance to intensive insulin-based therapies. Worldwide data confirm a positive trend in this field, with the integrated management of pivotal factors: adequate islet mass, immunosuppressive protocols, additional anti-inflammatory therapy, and pre transplant allo-immunity assessment. Insulin independence has been observed in several clinical trials with different rate, ranging 100-65% of patients; the maintenance of this condition during the follow-up progressively decreased, actually arranged on 44% 3 years after the last infusion, according to data reported from the CITR. Successful duration is progressively increasing, with >=13 years being the longest reported insulin-free condition on record. The immediate results of functioning islet transplantation are an improvement in hypoglycemic awareness and a reduction in the glycated hemoglobin level. Furthermore, many studies have shown its influence on the chronic complications of diabetes, such as peripheral neuropathy, retinopathy, and macroangiopathy. Pre transplant nephropathy remains an exclusion criterion as immunosuppressive therapy can exacerbate kidney-function deterioration. The problems linked to immunosuppression following islet transplantation for the treatment of type-1 diabetes need to be considered in order to achieve the correct risk/benefit ratio for each patient. PMID- 25931316 TI - Pidotimod for the prevention of acute respiratory infections in healthy children entering into daycare: A double blind randomized placebo-controlled study. AB - Acute respiratory tract infections (ARTIs) are very common in pediatric age and reach a peak in the first 4 years of life, especially in children attending daycare. Pidotimod, a synthetic immunostimulant, may reduce the incidence of ARTIs in children with predisposing risk factors. Nevertheless studies on healthy children are presently lacking. We performed a double-blinded randomized placebo controlled trial study to assess the efficacy of Pidotimod in a population of 3 year-old healthy children who just entered kindergarten. The main outcome was the incidence of respiratory infections in this population and the secondary outcome was the prescription of antibiotics. The study group consisted of healthy 3-year old children who had not yet attended day-care centers. Patients were enrolled by a convenience sample of 17 family pediatricians (FP). Children were randomized to receive either Pidotimod 400 mg per os or placebo twice daily for the last 10 days of each month from October 2013 to April 2014. Any time a child presented to his/her FP with fever and ARTI was diagnosed, clinical and therapeutic data were collected. A total of 800 children were pre-screened, 733 did not meet the inclusion criteria and 10 refused to participate. Of the 67 eligible subjects, 57 were successfully enrolled within the study recruitment period and randomized to receive Pidotimod (n = 29) or placebo (n = 28). Eight children were lost to follow-up. In the final analysis were thus included 24 children who received Pidotimod and 25 who received placebo. The incidence rate ratio for respiratory infections was 0.78 (95%CI 0.53 to 1.15, p = 0.211) for Pidotimod vs. placebo. The corresponding risk ratio for antibiotic usage was 0.56 (95%CI 0.27 to 1.16, p = 0.120). In our trial, Pidotimod did not prove to be statistically superior to placebo for the prevention of ARTI in a population of healthy children who entered kindergarten. However, Pidotimod showed some potential as a means for reducing antibiotic usage in these children. PMID- 25931319 TI - Testing parallel laser image scaling for remotely measuring body dimensions on mantled howling monkeys (Alouatta palliata). AB - Body size is a fundamental variable for many studies in primate biology. However, obtaining body dimensions of wild primates through live capture is difficult and costly, so developing an alternative inexpensive and non-invasive method is crucial. Parallel laser image scaling for remotely measuring body size has been used with some success in marine and terrestrial animals, but only one arboreal primate. We further tested the efficacy of this method on the arboreal mantled howling monkey (Alouatta palliata) in La Pacifica, Costa Rica. We calculated interobserver error, as well as the method's repeatability when measuring the same animal on different occasions. We also compared measurements obtained physically through live capture with measurements obtained remotely using parallel laser image scaling. Our results show that the different types of error for the remote technique are minimal and comparable with the error rates observed in physical methods, with the exception of some dimensions that vary depending on the animals' posture. We conclude that parallel laser image scaling can be used to remotely obtain body dimensions if careful consideration is given to factors such as species-specific morphology and postural habits. PMID- 25931318 TI - Sarpogrelate hydrochloride, a serotonin 5HT2A receptor antagonist, ameliorates the development of chronic hypoxic pulmonary hypertension in rats. AB - PURPOSE: The purpose of the present study was to determine if sarpogrelate hydrochloride (SPG), a serotonin 5HT2A receptor antagonist, prevented the development of chronic hypoxia-induced pulmonary hypertension (PH) and hypertensive pulmonary vascular remodeling. METHODS: Forty-one male Sprague Dawley rats were exposed to hypobaric hypoxia (380 mmHg, 10 % oxygen) or room air and administered 50 mg/kg SPG or vehicle by gavage once daily from day -2 to day 14. The mean pulmonary artery pressure (PAP) and right ventricular hypertrophy (RVH) were measured. Hypertensive pulmonary vascular remodelings were assessed morphometrically by light microscopy. Serotonin-induced contraction was determined in isolated pulmonary artery rings from 24 rats. In another set of rats, Western blotting, real-time polymerase chain reaction and immunofluorescent staining (n = 9) for lung tissue were performed. RESULTS: Chronic hypoxia induced a rise in mean PAP and RVH, increased the percentage of muscularized arteries in peripheral pulmonary arteries and medial wall thickness in small muscular arteries, and potentiated serotonin-induced contraction, each of which was significantly (p < 0.05) ameliorated by SPG. Chronic hypoxia significantly increased the expression of endothelial nitric oxide synthase (eNOS) and phosphorylated eNOS (peNOS) protein levels, cyclic guanosine monophosphate, and matrix metalloproteinase-13 (MMP-13) mRNA levels in whole lung tissues. SPG increased peNOS expression in the immunofluorescent staining of peripheral pulmonary arteries from chronic hypoxic rats and decreased the MMP-13 mRNA in lung tissue in chronic hypoxic rats. CONCLUSIONS: The administration of SPG ameliorated the development of chronic hypoxic PH and hypertensive pulmonary vascular changes. PMID- 25931320 TI - Histological and transcript analyses of intact somatic embryos in an elite maize (Zea mays L.) inbred line Y423. AB - Intact somatic embryos were obtained from an elite maize inbred line Y423, bred in our laboratory. Using 13-day immature embryos after self-pollination as explants, and after 4-5 times subculture, a large number of somatic embryos were detected on the surface of the embryonic calli on the medium. The intact somatic embryos were transferred into the differential medium, where the plantlets regenerated with shoots and roots forming simultaneously. Histological analysis and scanning electron micrographs confirmed the different developmental stages of somatic embryogenesis, including globular-shaped embryo, pear-shaped embryo, scutiform embryo, and mature embryo. cDNA-amplified fragment length polymorphism (cDNA-AFLP) was used for comparative transcript profiling between embryogenic and non-embryogenic calli of a new elite maize inbred line Y423 during somatic embryogenesis. Differentially expressed genes were cloned and sequenced. Gene Ontology analysis of 117 candidate genes indicated their involvement in cellular component, biological process and molecular function. Nine of the candidate genes were selected. The changes in their expression levels during embryo induction and regeneration were analyzed in detail using quantitative real-time PCR. Two full length cDNA sequences, encoding ZmSUF4 (suppressor of fir 4-like protein) and ZmDRP3A (dynamin-related protein), were cloned successfully from intact somatic embryos of the elite inbred maize line Y423. Here, a procedure for maize plant regeneration from somatic embryos is described. Additionally, the possible roles of some of these genes during the somatic embryogenesis has been discussed. This study is a systematic analysis of the cellular and molecular mechanism during the formation of intact somatic embryos in maize. PMID- 25931321 TI - Molecular characterization of BZR transcription factor family and abiotic stress induced expression profiling in Brassica rapa. AB - BRASSINAZOLE-RESISTANT (BZR) transcription factors (TFs) are primarily well known as positive regulators of Brassinosteroid (BR) signal transduction in different plants. BR is a plant specific steroid hormone, which has multiple stress resistance functions besides various growth regulatory roles. Being an important regulator of the BR synthesis, BZR TFs might have stress resistance related activities. However, no stress resistance related functional study of BZR TFs has been reported in any crop plants so far. Therefore, this study identified 15 BZR TFs of Brassica rapa (BrBZR) from a genome-wide survey and characterized them through sequence analysis and expression profiling against several abiotic stresses. Various systematic in silico analysis of these TFs validated the fundamental properties of BZRs, where a high degree of similarity also observed with recognized BZRs of other plant species from the comparison studies. In the organ specific expression analyses, 6 BrBZR TFs constitutively expressed in flower developmental stages indicating their flower specific functions. Subsequently, from the stress resistance related expression profiles differential transcript abundance levels were observed by 6 and 11 BrBZRs against salt and drought stresses, respectively. All BrBZRs showed several folds up-regulation against exogenous ABA treatment. All BrBZRs also showed differential expression against low temperature stress treatments and these TFs were proposed as transcriptional activators of CBF cold response pathway of B. rapa. Notably, three BrBZRs gave co-responsive expression against all the stresses tested here, suggesting their multiple stress resistance related functions. Thus, the findings would be helpful in resolving the complex regulatory mechanism of BZRs in stress resistance and further functional genomics study of these potential TFs in different Brassica crops. PMID- 25931322 TI - Inhibition of beta-amyloid peptide self-assembly and cytotoxicity by poly(LVFF-co beta-amino ester). AB - The beta-amyloid (Abeta) peptide plays an important role in the onset and progress of Alzheimer's disease (AD). Therefore, studies on inhibiting fibril formation and thus neurotoxicity of Abeta could be beneficial for the prevention and treatment of AD. We report a convenient synthetic approach for one-pot preparation of poly-(beta-amino ester) copolymerized with the GGLVFF peptide, which is based on the frequently used inhibitor LVFF. The copolymer was found to efficiently inhibit the aggregation and fibrillation of Abeta42 by using fluorescence assay and atomic force microscopy. Reduced beta-sheet formation of Abeta42 peptide after addition of copolymer was observed by circular dichroism. Furthermore, the cell viability assay confirmed that the toxicity of Abeta42 for SH-SY5Y cells was markedly reduced in the presence of copolymer. This could be beneficial for AD prevention and treatment and also for the molecular design of inhibitory agents for other amyloidoses. PMID- 25931323 TI - The larval head of Exechia (Mycetophilidae) and Bibio (Bibionidae) (Diptera). AB - Exechia and Bibio have retained several plesiomorphic groundplan features of Diptera and Bibionomorpha, including a fully exposed and sclerotized head capsule, the transverse undivided labrum, the absence of movable premandibles, and undivided mandibles without combs. The fusion of the hypostomal bridge with the head capsule and largely reduced antennae are derived features shared by both taxa. The absence of teeth at the anterior hypostomal margin is a potential autapomorphy of Bibionomorpha. A basal position of Anisopodidae is suggested by a number of plesiomorphies retained in this family. Apomorphies of Bibionomorpha excluding Anisopodidae are the reduction of tentorial elements, the partial fusion of the labrum and clypeus, one-segmented antennae, the absence of a separate submental sclerite, the loss of the labial palpus, and the reduction of the pharyngeal filter apparatus. Head structures of Bibio are largely unmodified. The subprognathous orientation is one of few autapomorphic features. In contrast, the mouthparts of Exechia are highly modified in correlation with the specialized food uptake. The rasping counterrotating movements of maxillae and mandibles with teeth oriented in opposite directions are carried out by strongly developed extensors and flexors of the paired mouthparts. The modified labium mechanically supports the "drill head" formed by the mandibles und maxillae. The necessary stability of the head capsule is provided by the hypostomal bridge which also compensates the far-reaching reduction of the tentorium. PMID- 25931324 TI - Tuning aerosol performance using the multibreath Orbital(r) dry powder inhaler device: controlling delivery parameters and aerosol performance via modification of puck orifice geometry. AB - The current study presents a new approach to tackle high-dose lung delivery using a prototype multibreath Orbital(r) dry powder inhaler (DPI). One of the key device components is the "puck" (aerosol sample chamber) with precision engineered outlet orifice(s) that control the dosing rate. The influence of puck orifice geometry and number of orifices on the performance of mannitol aerosols were studied. Pucks with different orifice configurations were filled with 400 mg of spray-dried mannitol and tested in the Orbital(r) DPI prototype. The emitted dose and overall aerodynamic performance across a number of "breaths" were studied using a multistage liquid impinger. The aerosol performances of the individual actuations were investigated using in-line laser diffraction. The emptying rate of all pucks was linear between 20% and 80% cumulative drug released (R(2) > 0.98), and the amount of formulation released per breath could be controlled such that the device was empty after 2 to 11 breath maneuvers. The puck-emptying rate linearly related to the orifice hole length (R(2) > 0.95). Mass median aerodynamic diameters of the emitted aerosol ranged from 4.03 to 4.62 MUm and fine particle fraction (<=6.4 MUm) were 50%-66%. Laser diffraction suggested that the aerosol performance and emptying rates were not dependent on breath number, showing consistent size distribution profiles. PMID- 25931326 TI - Hb M-Iwate in an Indian family. AB - BACKGROUND: High performance liquid chromatography in a newborn girl with congenital cyanosis and a unilateral cleft palate revealed a variant hemoglobin with retention time of 4.8 min, similar to hemoglobin Q-India. Since hemoglobin Q India did not explain the cyanosis, further investigations were initiated. METHODS: Sequencing of alpha-globin genes revealed hemoglobin M-Iwate ([alpha87 (F8) His -> Tyr]) that was confirmed on restriction enzyme analysis. RESULTS: Hemoglobin M-Iwate is a rare methemoglobinemic variant formed due to a point mutation in the alpha-globin gene. Primarily reported from the Iwate prefecture of Japan, there have been occasional case reports from other regions as well. Inherited methemoglobinemia finds only rare mention in Indian literature while hemoglobin M-Iwate has not been reported from India. CONCLUSIONS: This case illustrates the step-wise logical diagnostic approaches necessary to elucidate the cause of methemoglobinemia in an otherwise healthy child with cyanosis. PMID- 25931332 TI - Differential effects of GABA in modulating nociceptive vs. non-nociceptive synapses. AB - GABA (gamma-amino-butyric acid) -mediated signaling is normally associated with synaptic inhibition due to ionotropic GABA receptors that gate an inward Cl(-) current, hyperpolarizing the membrane potential. However, there are also situations where ionotropic GABA receptors trigger a Cl(-) efflux that results in depolarization. The well-characterized central nervous system of the medicinal leech was used to study the functional significance of opposing effects of GABA at the synaptic circuit level. Specifically, we focused on synapses made by the nociceptive N cell and the non-nociceptive P (pressure) cell that converge onto a common postsynaptic target. It is already known that GABA hyperpolarizes the P cell, but depolarizes the N cell and that inhibition of ionotropic GABA receptors by bicuculline (BIC) has opposing effects on the synapses made by these two inputs; enhancing P cell synaptic transmission, but depressing N cell synapses. The goal of the present study was to determine whether the opposing effects of GABA were due to differences in Cl(-) homeostasis between the two presynaptic neurons. VU 0240551 (VU), an inhibitor of the Cl(-) exporter K-Cl co-transporter isoform 2 (KCC2), attenuated GABA-mediated hyperpolarization of the non nociceptive afferent while bumetanide (BUM), an inhibitor of the Cl(-) importer Na-K-Cl co-transporter isoform 1 (NKCC1), reduced GABA-mediated depolarization of the nociceptive neuron. VU treatment also enhanced P cell synaptic signaling, similar to the previously observed effects of BIC and consistent with the idea that GABA inhibits synaptic signaling at the presynaptic level. BUM treatment depressed N cell synapses, again similar to what is observed following BIC treatment and suggests that GABA has an excitatory effect on these synapses. The opposing effects of GABA could also be observed at the behavioral level with BIC and VU increasing responsiveness to non-nociceptive stimulation while BIC and BUM decreased responsiveness to nociceptive stimulation. These findings demonstrate that distinct synaptic inputs within a shared neural circuit can be differentially modulated by GABA in a functionally relevant manner. PMID- 25931333 TI - Butyrylcholinesterase-knockout reduces brain deposition of fibrillar beta-amyloid in an Alzheimer mouse model. AB - In Alzheimer's disease (AD), numerous beta-amyloid (Abeta) plaques are associated with butyrylcholinesterase (BChE) activity, the significance of which is unclear. A mouse model, containing five human familial AD genes (5XFAD), also develops Abeta plaques with BChE activity. Knock-out of BChE in this model showed diminished fibrillar Abeta plaque deposition, more so in males than females. This suggests that lack of BChE reduces deposition of fibrillar Abeta in AD and this effect may be influenced by sex. PMID- 25931327 TI - The Healthy Brains and Behavior Study: objectives, design, recruitment, and population coverage. AB - Violence is increasingly viewed as a public health issue that may be ameliorated by health-based interventions. The Healthy Brains and Behavior Study (HBBS) aims to identify environmental and biological risk factors for aggression in late childhood and to reduce aggression through psychological and nutritional treatments. Utilizing a cross-disciplinary collaborative research approach, the HBBS has both human and animal components. The human component has two stages consisting of risk assessment followed by treatment. The risk assessment is based on 451 community-residing children aged 11-12 years and their caregivers, during which genetic, brain imaging, neuroendocrine, psychophysiology, environment toxicology, neurocognitive, nutrition, psychological, social and demographic risk variables are collected. Children who met criteria (N = 219) for problematic aggressive behaviors were assigned to one of four treatment groups: cognitive behavior therapy (CBT) alone, nutritional supplements alone, both CBT and nutrition, or treatment-as-usual. Treatment duration was 12 weeks and all children whether in treatment or not were followed-up at three, six, and 12 months. The animal component assessed the effects of dietary omega-3 fatty acids on the development of aggression. This study contributes knowledge on how biological factors interact with social factors in shaping proactive and reactive aggression and assesses the efficacy of treatment approaches to reduce childhood aggression. PMID- 25931334 TI - The diagnostic value of next generation sequencing in familial nonsyndromic congenital heart defects. AB - To determine the diagnostic value of massive parallel sequencing of a panel of known cardiac genes in familial nonsyndromic congenital heart defects (CHD), targeted sequencing of the coding regions of 57 genes previously implicated in CHD was performed in 36 patients from 13 nonsyndromic CHD families with probable autosomal dominant inheritance. Following variant analysis and Sanger validation, we identified six potential disease causing variants in three genes (MYH6, NOTCH1, and TBX5), which may explain the defects in six families. Several problematic situations were encountered when performing genotype-phenotype correlations in the families to confirm the causality of these variants. In conclusion, by screening known CHD-associated genes in well-selected nonsyndromic CHD families and cautious variant interpretation, potential causative variants were identified in less than half of the families (6 out of 13; 46%). Variant interpretation remains a major challenge reflecting the complex genetic cause of CHD. PMID- 25931335 TI - The association between N-terminal pro B-type natriuretic peptide and lipoprotein particle concentration plateaus at higher N-terminal pro B-type natriuretic peptide values: Multi-Ethnic Study on Atherosclerosis. AB - BACKGROUND: The association between N-terminal pro B-type natriuretic peptide (NT proBNP) and blood levels of small and large LDL- and HDL- particle (P) concentration may not be linear throughout the whole range of NT-proBNP values. METHODS: Linear spline regression analysis between NT-proBNP and lipoprotein particle concentrations was performed cross-sectionally in 5597 individuals from the Multi-Ethnic Study of Atherosclerosis adjusted for age, race, sex, body mass index, % of energy from saturated fats, intentional exercise, statin use, antihypertensive medication use, diabetes, IL-6 and estimated glomerular filtration rate. Spline knots were selected as the point at which the linear slope changed in these associations. RESULTS: NT-proBNP was positively associated with large LDL-P and HDL-P, but inversely associated with small LDL-P and HDL-P, but only for NT-proBNP values below the knot (range: 100-200 pg/mL). CONCLUSION: These results suggest the presence of two distinct biological mechanisms above and below the knot determining the association between NT-proBNP and lipoprotein particle concentrations. PMID- 25931337 TI - An analysis of the biomechanics of interference screw fixation and sheathed devices for biceps tenodesis. AB - BACKGROUND: This study aimed to evaluate the differences in biomechanical properties of biceps tenodesis when performed with sheathed versus unsheathed screws and also to investigate the effect of altering the pre-tension. METHODS: Tenodesis was performed in an in vitro model using biomechanical test blocks and ovine tendons. Blocks were allocated to 1 of 5 groups which varied by method of tenodesis and cyclical loading protocol: Group A, Biosure PK screw (10-100 N), Group B: 7-8 mm Biosure Sync and Biosure PK screw (10-100 N), Group C: Biosure PK screw (10-70 N), Group D: Biosure PK (20-100 N), and Group E: custom sheath and Biosure PK screw (10-100 N). If tenodeses remained intact after 500 cycles maximum load to failure testing was performed. FINDINGS: 30% of tenodeses in Group A failed prior to 500 cycles whereas none failed in the sheathed device groups (P=0.02). Using a sheathed device prevented mal-rotation. However, tenodeses in Group B were more likely to fail immediately distal to the tenodesis at a load below the anticipated maximum load to failure suggesting tendon damage during fixation. Using the custom sheath, which did not have sharp edges, resulted in a statistically significant increased maximum load to failure in Group E (348 N) when compared to Group A (228 N, mean difference 120 N, P=0.01) and Group B (253N, mean difference 95 N, P=0.0007). INTERPRETATION: Sheathed devices prevent mal-rotation and increase stiffness and maximum load to failure. This is further improved by reducing tendon damage at the time of tenodesis. PMID- 25931325 TI - Mediators of Chronic Pruritus in Atopic Dermatitis: Getting the Itch Out? AB - For centuries, itch was categorized as a submodality of pain. Recent research over the last decade has led to the realization that itch is in fact a separate and distinct, albeit closely related, sensation. Chronic itch is a common complaint and has numerous etiologies. Various receptors (TRPA1, TRPV1, PAR2, gastrin-releasing peptide receptor (GRPR), Mas-related G proteins), secreted molecules (histamine, nerve growth factor (NGF), substance P (SP), proteases), and cytokines/chemokines (thymic stromal lymphopoietin (TSLP), IL-2, IL-4, IL-13, and IL-31) are implicated as mediators of chronic pruritus. While much remains unknown regarding the mechanisms of chronic itch, this much is certain: there is no singular cause of itch. Rather, itch is caused by a complex interface between skin, keratinocytes, cutaneous nerve fibers, pruritogenic molecules, and the peripheral and central nervous systems. Atopic dermatitis is one of the most itchy skin dermatoses and affects millions worldwide. The sensation of atopic itch is mediated by the interplay between epidermal barrier dysfunction, upregulated immune cascades, and the activation of structures in the central nervous system. Clinicians are in possession of an arsenal of different treatment options ranging from moisturizers, topical immunomodulators, topical anesthetic ion channel inhibitors, systemic immunomodulators, as well as oral drugs capable of reducing neural hypersensitization. Emerging targeted therapies on the horizon, such as dupilumab, promise to usher in a new era of highly specific and efficacious treatments. Alternative medicine, stress reduction techniques, and patient education are also important treatment modalities. This review will focus on the mediators of chronic pruritus mainly associated with atopic dermatitis (atopic itch), as well as numerous different therapeutic options. PMID- 25931336 TI - Results of a transparent expert consultation on patient and public involvement in palliative care research. AB - BACKGROUND: Support and evidence for patient, unpaid caregiver and public involvement in research (user involvement) are growing. Consensus on how best to involve users in palliative care research is lacking. AIM: To determine an optimal user-involvement model for palliative care research. DESIGN: We hosted a consultation workshop using expert presentations, discussion and nominal group technique to generate recommendations and consensus on agreement of importance. A total of 35 users and 32 researchers were approached to attend the workshop, which included break-out groups and a ranking exercise. Descriptive statistical analysis to establish consensus and highlight divergence was applied. Qualitative analysis of discussions was completed to aid interpretation of findings. SETTING/PARTICIPANTS: Participants involved in palliative care research were invited to a global research institute, UK. RESULTS: A total of 12 users and 5 researchers participated. Users wanted their involvement to be more visible, including during dissemination, with a greater emphasis on the difference their involvement makes. Researchers wanted to improve productivity, relevance and quality through involvement. Users and researchers agreed that an optimal model should consist of (a) early involvement to ensure meaningful involvement and impact and (b) diverse virtual and face-to-face involvement methods to ensure flexibility. CONCLUSION: For involvement in palliative care research to succeed, early and flexible involvement is required. Researchers should advertise opportunities for involvement and promote impact of involvement via dissemination plans. Users should prioritise adding value to research through enhancing productivity, quality and relevance. More research is needed not only to inform implementation and ensure effectiveness but also to investigate the cost effectiveness of involvement in palliative care research. PMID- 25931339 TI - A seashell by the seashore. PMID- 25931340 TI - Diaphragmatic hernia in a pediatric emergency department. AB - Diaphragmatic hernia in pediatric emergency department poses a diagnostic challenge because of the acute or subtle timing of onset and the wide variety of clinical features. We describe 3 different late presentations of Bochdalek diaphragmatic hernia in a pediatric emergency department. These reports may help physicians avoid delayed diagnosis of late-presenting congenital diaphragmatic hernia, thereby reducing the risk of inappropriate treatments and life threatening conditions in children. PMID- 25931341 TI - A rare cause of respiratory distress in the emergency department: anomalous origin of the left coronary artery from the pulmonary artery. AB - Anomalous origin of the left coronary artery from the pulmonary artery is the most common cause of myocardial ischemia and infarction in children and infants. Most of the affected individuals become symptomatic, owing to dilated cardiomyopathy during the infant period. Because of congestive heart failure, pulmonary congestion and respiratory distress can be seen. Herein, we report a 35 day-old infant with anomalous origin of the left coronary artery from the pulmonary artery who presented with respiratory distress and dilated cardiomyopathy to draw attention to this rare surgically treatable anomaly. PMID- 25931342 TI - "Bucking" for a diagnosis. AB - Foreign body ingestions are all too common in children. The adverse effects of many of these ingestions are well known. We present an interesting case report of "Buckyballs" and the implications of ingesting or placing in other orifices these strong rare-earth magnets. We illustrate that these toys can be of possible disastrous consequences. Although these products were removed from the marketplace, there is still the possibility of negative consequences. Our aim was to inform the physician population of their persistence and negative effects. PMID- 25931343 TI - Electronic prescription writing errors in the pediatric emergency department. PMID- 25931344 TI - Pediatric emergency medicine: legal briefs. PMID- 25931345 TI - Management of a patient with diabetic ketoacidosis in the emergency department. AB - Diabetic ketoacidosis is a common problem among known and newly diagnosed diabetic children and adolescents for which they will often seek care in the emergency department (ED). Technological advances are leading to changes in outpatient management of diabetes. The ED physician needs to be aware of the new technologies in the care of diabetic children and comfortable managing patients using continuous subcutaneous insulin infusions. This article reviews the ED management of diabetic ketoacidosis and its associated complications, as well as the specific recommendations in caring for patients using the continuous subcutaneous insulin infusion, serum ketone monitoring, and continuous glucose monitoring. PMID- 25931346 TI - Circular right upper quadrant mass, not intussusception. AB - Point-of-care ultrasound is fast becoming a routine diagnostic tool in the pediatric emergency department, including in resource-limited settings. We describe a case where a patient was initially diagnosed with intussusception and admitted to a hospital. While serving as a patient model for a point-of-care ultrasound course, he was found to have a liver abscess. We discuss the manner in which the ultrasound study for ileocolic intussusception is performed and potential mimickers of ileocolic intussusception. PMID- 25931347 TI - ECGs in the ED. PMID- 25931348 TI - Current and emerging therapies for adrenocortical carcinoma--review. AB - Adrenocortical carcinoma (ACC) is a rare malignancy with poor prognosis. Patients may present with hormone excess or a local mass effect. The most common imaging techniques (CT and MRI) use both size and appearance to distinguish between benign and malignant tumors. Open surgery by an expert surgeon with R0 target is the treatment of choice. Mitotane (alone or in combination with cytotoxic drugs) may be administered after surgery or in patients not amenable to surgery. The role of radiotherapy as an adjuvant treatment is uncertain whereas targeted radionuclide therapy seems to be a promising option. New adjuvant treatment options, even after complete tumor removal, are desired because postoperative disease-free survival at 5 yrs is only around 30%. The establishment of detailed guidelines with the purpose of optimizing therapy with only mitotane but also in combination with other antineoplasmatic drugs is still a task to be done. Future advances in the management of ACC will probably be connected with better understanding of the molecular pathogenesis. PMID- 25931349 TI - Pro-Apoptotic Activity of Ruxolitinib Alone and in Combination with Hydroxyurea, Busulphan, and PI3K/mTOR Inhibitors in JAK2-Positive Human Cell Lines. AB - BACKGROUND: The JAK2V617F mutation plays a crucial role in the pathogenesis of myeloproliferative neoplasms (MPNs). Inhibition of JAK2 activity by ruxolitinib (RX) results in growth inhibition and apoptosis of cells carrying the JAK2V617F mutation however the exact mechanisms regulating apoptosis have not been fully elucidated. OBJECTIVES: This study assessed the potential cytotoxicity of RX against JAK2-positive human cell lines (SET-2 and HEL), either alone or in combination with hydroxyurea, busulphan, rapamycin or LY294002. MATERIAL AND METHODS: Cell viability, the apoptosis rate (annexin-V staining), drop of mitochondrial transmembrane potential (Deltapsim) and caspase activation, were measured using flow cytometry. Additionally, the expression of several apoptosis regulating proteins was evaluated. RESULTS: RX showed cytotoxicity against both SET-2 and HEL cell lines. The main mechanism of this action was apoptosis, with significant drop of Deltapsim, caspase-3 and -9 activation, and moderate activation of caspase-8 (only for SET-2 cells). Corresponding to enhanced apoptosis, the expression levels of some apoptosis-regulating proteins were changed, the most pronounced in both cell lines being up-regulation of Bax and down-regulation of Bcl-2 proteins. Additionally, up-regulation of Bak and Bad (SET-2) and down-regulation of Mcl-1 (HEL) were observed. Of the studied compounds, a combination of RX + LY294002 induced the greatest cytotoxicity in both SET-2 and HEL cell lines, and rapamycin the least. CONCLUSIONS: This study shows that the combination of RX and a PI3K kinase inhibitor provokes a significant pro-apoptotic effect in JAK2V617F mutated cells, which may justify the beginning of clinical trials based on the combination of these drugs. PMID- 25931350 TI - The Ethanol Extract of Polish Propolis Exhibits Anti-Proliferative and/or Pro Apoptotic Effect on HCT 116 Colon Cancer and Me45 Malignant Melanoma Cells In Vitro Conditions. AB - BACKGROUND: Propolis is a natural product widely consumed in folk medicine. Different biological activities, such as anticancer, antioxidant, anti inflammatory, antibiotic and antifungal effects have been reported for propolis and its constituents. OBJECTIVES: An in vitro study focused on an evaluation of the biological activity of EEPP, including its anti-proliferative influence on selected neoplastic cells, considering qualitative-quantitative chemical characterization of Polish propolis. MATERIAL AND METHODS: Cytotoxicity was evaluated by means of the MTT and LDH assays. The apoptosis was determined using fluorescence microscopy with annexin V-FITC. Additional EEPP composition was analyzed by a High Performance Liquid Chromatography (HPLC) method. The antimicrobial activity was evaluated by minimal inhibitory concentrations (MIC) against Streptococcus aureus, Enetecoccus faecalis, Escherichia coli, Pseudomonas aeruginosa and Candida albicans.??. RESULTS: The total content of flavonoids per quercetin in the examined propolis extract amounted to 0.442+/-0.091 mg/mL. The flavonoid compounds identified in Polish propolis included flavones, flavonones, flavonolols, flavonols and phenolic acids. The multi-directional interactions among the various chemical compounds in propolis seem to be the essential biological activities when considering its anticancer effects. The results showed that in case of Me45 and HCT 116 cell lines, the ethanol extract of propolis could inhibit cell growth as well as cell size reduction. Regarding antimicrobial activity, EEPP showed MICs ranging from 0.39 to 6.25 mg/mL. CONCLUSIONS: Ethanol extract of propolis from Poland obtained in the study exhibits anti-proliferative activity in different carcinoma cells. PMID- 25931351 TI - Effects of oleuropein on serum inflammatory cytokines and histopathological changes in rats with pancreatitis. AB - OBJECTIVES: Acute pancreatitis is a severe debilitating disease with high morbidity and mortality. The severity of the disease is largely due to the actions of various inflammatory mediators. No specific therapy is indicated for AP and its treatment remains largely supportive. This study investigated the effect of oleuropein on serum inflammatory cytokines and distant organ injury in rats with acute pancreatitis induced by bile-pancreatic duct obstruction. MATERIAL AND METHODS: Thirty adult male Wistar rats were randomly assigned to 3 groups of 10 rats each: group I: sham, group II: pancreatitis and group III: pancreatitis+oleuropein. Rats in Group III received oleuropein 20 mg/kg intragastrically during 10 days before surgery. The rats were sacrificed at 24 h after surgery and venous blood, pancreatic and lung tissue samples were obtained for analysis. RESULTS: A statistically significant difference was found between groups regarding serum amylase, LDH, lipase, pancreatic amylase, IL-6, IL-10 and TNF-alpha values with a Kruskal-Wallis test (p<0.05). No statistically significant difference was found between Group II and III regarding pairwise comparison of amylase, LDH, lipase, pancreatic amylase, IL-6, IL-10 and TNF-alpha value by using pairwise comparisons with a Mann-Whitney U test (p>0.01). A statistically significant difference between groups was found regarding edema, inflammation, hemorrhage and acinar cell necrosis in histopathological examination of the pancreas (p<0.05). No difference was found between group II and III (p>0.01). A difference was found between the groups in terms of lung tissue edema (p<0.05) but no difference was found regarding hemorrhage and inflammation (p>0.05). No statistically significant difference was found between group II and III with pairwise comparison (p>0.01). CONCLUSIONS: The experimental model used in this study showed to be appropriate for creation of acute pancreatitis. It was concluded that oleuropein as a prophylactic treatment has no protective effect on serum proinflammatory and anti-inflammatory cytokines as well as pancreatic tissue. PMID- 25931352 TI - The Conductivity and pH Values of Dispersions of Nanospheres for Targeted Drug Delivery in the Course of Forced Equilibrium Dialysis. AB - BACKGROUND: In the available literature, the problem of pH and conductivity in FED is evaluated separately, and limited mainly to the final purity of the synthesized polymer. In this study data from conductivity and pH measurements were evaluated in the context of the structure of the macromolecule. OBJECTIVES: The aim of the study was to evaluate the conductivity and pH of dispersions of nanospheres synthesized with the use of N-isopropyl acrylamide (NIPA) as the main monomer, N,N'-methylenebisacrylamide (MBA) as the cross-linker and acrylic acid (AcA) as the anionic comonomer during the purification of dispersions via forced equilibrium dialysis (FED). MATERIAL AND METHODS: Six batches of nanospheres were obtained in the process of surfactant free precipitation polymerization (SFPP) under inert nitrogen. The conductivity and pH of the dispersions of nanospheres were measured at the beginning of FED and after finishing that process. The conductivity in the systems being studied decreased significantly in the process of FED. The initial values of conductivity ranged from 736.85+/-8.13 MUS*cm(-1) to 1048.90+/-67.53 MUS*cm(-1) After 10 days, when the systems being assessed gained stability in terms of conductivity level, the values of conductivity were between 4.29+/-0.01 MUS*cm(-1) and 33.56+/-0.04 MUS*cm(-1). The pH values inreased significantly after FED. The resulting pH was between 6.92+/-0.07 and 8.21+/-0.07, while the initial values were between 3.42+/-0.23 MUS*cm(-1) and 4.30+/-0.22 MUS*cm(-1). CONCLUSIONS: Conductivity and pH measurements performed during purification via FED provide important information on the composition of the resulting nanospheres, including the functional groups embedded in the structure of the polymer in the course of the synthesis, as well as the purity of the structures. The presence of a cross-linker and acidic comonomer in the poly-N isopropyl acrylamide (polyNIPA) macromolecule may be confirmed by both the pH and the conductivity measurements. PMID- 25931353 TI - Antioxidant Effect of Ethanolic Extract of Propolis in Liver of L-NAME Treated Rats. AB - BACKGROUND: The blocking of nitric oxide synthase (NOS) activity may cause vasoconstriction with formation of reactive oxygen species. Propolis is a natural product collected from plants by honeybees. Propolis has biological and pharmacological properties. OBJECTIVES: This study was designed to investigate the effects of propolis on catalase (CAT) activity, nitric oxide (NO) and malondialdehyde (MDA) levels in the liver tissues of NOS inhibited rats by Nomega Nitro-L-arginine methyl ester (L-NAME). MATERIAL AND METHODS: Rats were given a NOS inhibitor (L-NAME, 40 mg/kg, intraperitoneally) for 15 days to provoke hypertension and propolis (200 mg/kg, by gavage) the last 5 of the 15 days. RESULTS: Nitric oxide levels in the liver tissue of the rats given L-NAME significantly decreased (p<0.01). That parameter did not significantly alter in the liver of rats treated with propolis compared to the control group. CAT activity and MDA levels in the liver of the rats administrated L-NAME significantly increased compared to the control group (p<0.01). These parameters significantly decreased in the liver of the rats given L-NAME + propolis compared to the L-NAME group (p<0.01). CONCLUSIONS: The present data shows that L-NAME in the liver may enhance oxidative stress via inhibited nitric oxide synthase. Our results also suggest that this effect is suppressed by the antioxidant properties of propolis in the liver tissue of NOS inhibited rats. PMID- 25931354 TI - Association of endogenous melatonin with uric acid and traditional cardiovascular risk factors in healthy young male. AB - BACKGROUND: Uric acid may act as an antioxidant; high serum uric acid levels are often associated with cardiovascular disease, such as coronary artery disease. Melatonin plays a role as a direct free radical scavenger and indirect antioxidant. No study has examined the relationships between endogenous melatonin and uric acid in order to predict the risk of future cardiovascular disease in males so far. To better characterize a possible relationship, we studied the association of endogenous melatonin with uric acid and traditional cardiovascular risk factors such as plasma lipids, and glucose in healthy young males. MATERIAL AND METHODS: Twenty-one male participants [mean age: 22.6 2.5 (18-26) year], non smoking; their medication or alcohol consumption history were studied. Blood samples for measuring melatonin concentrations were collected in the supine position between 13:30-14:30 hours. After centrifugation, plasma samples were immediately frozen at -20 degrees C until analysis. RESULTS: Although we found a significant negative correlation between the levels of endogeneous melatonin and uric acid (p=0.01, r=-0.51), we did not find any correlation among the melatonin and other antropometric, hemodynamic and biochemical parameters in male subjects (p>0.41). CONCLUSIONS: The present study demonstrated a significant negative correlation between the levels of endogeneous melatonin and uric acid in healthy young males. PMID- 25931355 TI - Toll-Like Receptor 4 Gene Polymorphism C1196T in Polish Women with Postmenopausal Osteoporosis - Preliminary Investigation. AB - BACKGROUND: Postmenopausal osteoporosis is a systemic bone disease characterized by low bone mass after menopause. Bone remodeling is regulated by a number of factors, including the immune system. Toll-like receptors 4 (TLR4) are expressed on bone cells and modify the immune response. TLR4 gene polymorphism may take part in the development of chronic inflammation in women after menopause, which is the cause of severe bone resorption. OBJECTIVES: To examine the frequency of TLR4 C1196T genotypes in postmenopausal osteoporotic and non-osteoporotic Polish women and to investigate the possible relationship between C1196T polymorphism, bone mineral density (BMD) and the incidence of osteoporotic fractures in this group of patients. MATERIAL AND METHODS: The study involved 40 postmenopausal women with osteoporosis and 63 healthy postmenopausal non-osteoporotic women. BMD measurements were performed by dual-energy X-ray absorptiometry. DNA was extracted from peripheral blood. Genotyping was performed by real-time PCR using LightSNiP tests with SimpleProbe probes. Melting curve analysis of PCR amplicons enabled the identification of individual C1196T genotypes. RESULTS: C1196T genotype frequencies in the osteoporotic group were 88% for CC and 12% for CT. In the control group, respectively 86% and 14%. We did not observe the TT genotype. There was no association of C1196T genotypes and BMD nor the incidence of fractures but there was a correlation between genotypes and body height (p=0.035, r=0.415). Homozygous subjects for the C-allele had a lower body height with respect to heterozygous subjects. CONCLUSIONS: It is unlikely that TLR4 C1196T polymorphism is related to bone mineral density and fracture incidence in Polish osteoporotic women after menopause. However, our data suggests that the C allele may be associated with lower body height in this group. Due to the small number of participants, our observations should be considered as preliminary. Larger studies are needed to confirm our findings. PMID- 25931356 TI - Serum vitamin D and the metabolic syndrome among osteoporotic postmenopausal female patients of a family practice clinic in Jordan. AB - BACKGROUND: Vitamin D deficiency and insufficiency and the metabolic syndrome are two common health issues worldwide. The association between these two health problems is subject to debate. OBJECTIVES: This study aims to investigate the association between vitamin D deficiency or insufficiency and the metabolic syndrome in a sample of osteoporotic postmenopausal women attending a family practice clinic in Amman-Jordan. MATERIAL AND METHODS: This was an observational cross sectional study. It was carried out in the family practice clinic in Jordan University Hospital. The study included all postmenopausal osteoporotic women attending the clinic between June 2011 and May 2012, yielding a total of 326 subjects. The association between metabolic syndrome and serum vitamin D levels was investigated. RESULTS: Waist circumference, body mass index, triglycerides and fasting blood sugar were significantly higher among postmenopausal women with metabolic syndrome, but HDL cholesterol was significantly lower (p<0.05). The prevalence of metabolic syndrome among all study participants was 42.9%. Triglycerides and LDL cholesterol were significantly higher among women deficiency or insufficiency (p<0.05). The prevalence of vitamin D deficiency or insufficiency was 45.7%. Among patients with metabolic syndrome, the prevalence of vitamin D deficiency or insufficiency was 50.7%. CONCLUSIONS: Findings of the current study suggest a lack of relationship between serum vitamin D and metabolic syndrome. However, a significant inverse relationship was found between serum vitamin D levels and both serum triglycerides and LDL levels. PMID- 25931357 TI - Gene polymorphisms of tumor necrosis factor alpha and antioxidant enzymes in bronchial asthma. AB - BACKGROUND: Bronchial asthma is an inflammatory disease resulting from a combination of genetic and environmental factors. Single nucleotide polymorphisms in the regulatory regions of cytokine and antioxidant enzyme genes may affect cytokine production and enzyme activity, and thus play a contributory role in asthma pathogenesis. OBJECTIVES: The aim of this study was to examine the association of manganese superoxide dismutase (MnSOD) Ala16Val, catalase (CAT) A 21T and tumor necrosis factor alpha (TNF-alpha) G-308A polymorphisms with bronchial asthma. MATERIAL AND METHODS: A total of 79 patients with asthma and 95 healthy controls were screened for MnSOD Ala16Val, CAT A-21T and TNF-alpha G-308A polymorphisms using the polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) method. RESULTS: The results obtained showed significantly higher prevalence of the MnSOD ValVal genotype (chi2=14.463, df=2, p=0.001) and MnSOD 16Val allele (chi2=12.862, p=0.026, OR=0.451, 95% CI=0.291 0.699) in patients with asthma compared to controls. The genotype and allele frequencies distribution of CAT A-21T and TNF-alpha G-308A gene polymorphisms did not show differences between patients and controls. CONCLUSIONS: Our results show an association of MnSOD Ala16Val genetic polymorphism with asthma in a Serbian population and suggest a protective role of the MnSOD 16Ala allele. PMID- 25931358 TI - Differentiation of Monocyte Derived Dendritic Cells in End Stage Renal Disease is Skewed Towards Accelerated Maturation. AB - BACKGROUND: Dendritic cells (DC) play an important role in the induction of immune responses. Patients with end stage renal disease (ESRD) suffer from chronic inflammation, leading to a secondary, uremic immunodeficiency associated with alterations in monocyte subpopulations with increased proinflammatory capacities. OBJECTIVES: The aim of this study was to examine, under isolated conditions, whether alterations in monocyte subpopulations may affect in vitro maturation of dendritic cells (DC) in patients with ESRD, thus allowing us to draw conclusions for the situation in vivo. MATERIAL AND METHODS: Monocytes from 30 patients undergoing hemodialysis (HD) and 15 healthy volunteers were enriched from peripheral blood leukocytes, differentiated into immature DC (iDC) in medium containing IL-4 and GM-CSF, and were induced with LPS to differentiate into mature DC (mDC). Monocyte subpopulations and DC maturation stages were phenotypically characterized using flow-cytometry. RESULTS: Although phenotypically indistinguishable, the number of both iDC and mDC that were generated from uremic monocytes was significantly higher compared to those from healthy controls (p=0.02 and p=0.03, respectively). This was associated with an increased number of CD14+ CD16+ monocytes (p=0.02) and by a higher maturation efficiency of mDC in patients (p=0.04). CONCLUSIONS: A high percentage of CD14+ CD16+ monocytes in patients with ESRD is associated with an increased propensity to differentiate into DC. This indicates that chronic inflammation may substantiate the biased consistence of monocyte subpopulations leading to profound alteration in DC generation and maturation in ESRD. PMID- 25931359 TI - Ileal pouch morphology and microbiology in ulcerative colitis patients. AB - BACKGROUND: Ideal pouch created during restorative proctocolectomy is a new gastrointestinal organ--"neorectum". Although it is made from the ileum, it takes over function of the removed rectum. This new function results in significant morphological changes in pouch's mucous membrane, which becomes similar to the large bowel mucosa. The most common pathology of the ileal pouch is its inflammation--pouchitis. One of the suspected causes of pouchitis is bacterial flora disturbance. OBJECTIVES: The aim of the study was to analyze the morphological and microbiological changes in ileal pouches in different time periods after ileostomy closure and to evaluate the influence of certain bacterial strains on the degree of inflammation. MATERIAL AND METHODS: The study involved 47 patients who had been treated surgically; they were investigated before and at different stages after ileostomy closure. They underwent repeated rectoscopies with biopsies of pouch mucosa and swabs for microbiological examination. In total 89 rectoscopies were performed, which provided 70 histopathological results according to the Heidelberg Pouchitis Activity Score and 87 microbiological test results. RESULTS: The assessment of the morphology of intestinal pouches showed increased signs of chronic inflammation as the length of time after the closure of a protective ileostomy increased. There was no correlation between the signs of acute inflammation and the length of time after surgery; there were more signs of acute inflammation in cases of pouchitis. The composition of the bacterial flora of intestinal pouches changed as the length of time after ileostomy closure increased, with significant increases in the number of enterobacteriaceae species. The presence of Staphylococcus aureus significantly correlates with a higher degree of chronic inflammation; this bacterium may be a potential infectious factor in pouchitis. CONCLUSIONS: Microbiological analysis of intestinal pouch lumen is a useful tool that can be used in routine follow-up assessment of intestinal pouches as well as in diagnosing pouchitis. PMID- 25931360 TI - The assessment of the influence of the method for obtaining hemostasis on the occurrence of postoperative complications after thyroid surgery. AB - BACKGROUND: The need to obtain successful surgical hemostasis had a significant impact on the development of electrosurgery. Innovative technical solutions necessitate the continuous training of surgeons in the use of more modern technologies. The diversity of solutions is also associated with the need to adapt the methods for obtaining hemostasis to the type of operation. Each time, the introduction of new technologies requires a critical evaluation of the results of surgical treatment. The most important measure of quality in thyroid surgery is the presence of chronic complications, such as the recurrent laryngeal nerve palsy and parathyroid insufficiency. Transient disorders also have a significant impact on the patient's comfort and quality of life. The report is preliminary in nature and it requires further investigation. OBJECTIVES: The aim of the study was to evaluate the effect of three methods for obtaining hemostasis on the occurrence of hypoparathyroidism, recurrent laryngeal nerve palsy, bleeding and the surgical site infection after thyroid surgery. MATERIAL AND METHODS: A retrospective analysis included patients who underwent thyroidectomy (n=654). Three methods of hemostasis were used. The first group (n=339) had blood vessels tied off. In the second (n=192) bipolar electrocoagulation was used and in the third one (n=123) bipolar electrocoagulation with integrated cutting mechanism. RESULTS: The transient hypoparathyroidism was found in 1.4% patients in the first group, 8.3% in the second and 27.6% in the third one. Chronic hypoparathyroidism was found in 0.29% in the first group, 0% in the second group and 2.4% in the third group. Significantly statistical differences were found in the incidence of transient hypoparathyroidism. CONCLUSIONS: Significant statistical differences were found in incidences of transient hypoparthyroidism in the group where bipolar electrosurgery was used. PMID- 25931362 TI - Motor cortex stimulation in patients with chronic central pain. AB - BACKGROUND: Motor cortex stimulation is one of the neuromodulation methods of treating refractory central neurogenic pain. OBJECTIVES: The aim of this study was to retrospectively evaluate the effects of motor cortex stimulation. MATERIAL AND METHODS: The study group consisted of 14 consecutive patients with thalamic pain, atypical facial pain, post-brachial plexus avulsion injury pain, phantom pain and pain in syringomyelia who were treated with motor cortex stimulation at the Department of Neurosurgery of the Military Research Hospital in Bydgoszcz, Poland, from 2005 to 2013. The procedures were conducted with the use of neurosurgical navigation and intraoperative neurophysiological monitoring. The outcomes were assessed in terms of visual analog scale scores. The long-term follow-up ranged from one to six years. RESULTS: A statistically significant reduction in the intensity of pain was noted in patients treated with motor cortex stimulation (pre-surgery median visual analog scale=9, short-term result median visual analog scale=3, p=0.0009; long-term result median visual analog scale=5, p=0.0036). Over the long term, with follow-ups ranging from one to six years, the results were excellent (over 80% reduction in pain) in 31% of the patients and satisfactory (50-80% reduction in pain) in 23% of the patients. Unsatisfactory pain control (less than 50%) was noted in 31% of the patients and no improvement was noted in 15%. Significantly better relief of pain was observed in the early postoperative period. In this series of patients, the highest efficacy of motor cortex stimulation was observed in post-stroke or post hemorrhagic thalamic pain (5/7 patients-71%). Long-term outcomes were not related to the age or sex of the patient, the preoperative duration of the pain, or to the position or number of implanted electrodes. CONCLUSIONS: MCS significantly reduces the intensity of neurogenic pain. The best long-term results in the present study were achieved in patients with thalamic syndrome. No significant predictors were found for a successful final outcome. The authors consider appropriate selection of patients, accurate placement of the electrodes and frequent adjusting of the stimulation parameters to be important factors increasing the efficacy of MCS. PMID- 25931361 TI - The impact of surgery on the efficacy of adjuvant therapy in glioblastoma multiforme. AB - BACKGROUND: Glioblastoma multiforme (GBM) is the most malignant brain tumor. Surgery still remains a fundamental part of treatment in GBM, followed by radiotherapy and chemotherapy. OBJECTIVES: The aim of the study was to assess the impact of surgery on the efficacy of adjuvant therapy in patients with glioblastoma multiforme. MATERIAL AND METHODS: The study involved 181 patients: 50 treated with adjuvant radiotherapy (RTH) only (60 Gy in daily 2Gy fractions) and 131 treated with postoperative radiochemotherapy (RTH-CHT) (60 Gy, 2Gy/d)+75 mg/m2 temozolomide for 42 days of radiotherapy, followed by 6 courses every 28 days; the first course was 150 mg/m2 for 1-5 days, and the subsequent courses were 200 mg/m2 for 1-5 days). Overall survival (OS) and disease-free survival (DFS) were assessed. The statistical analysis entailed the log-rank test, Kaplan Meier curves and Cox proportional hazards regression; the threshold of statistical significance was set at p=0.05. RESULTS: Median OS and DFS were significantly increased (p=0.001) in the RTH-CHT group compared with the RTH group: 9.77 months vs 6.38 months for OS, and 8.4 months vs 4.33 months for DFS. After radical surgery, RTH-CHT extended OS by 5.3 months and DFS by 4.5 months in comparison to RTH. In patients who underwent non-radical surgery, the type of adjuvant therapy made no difference in either OS or DFS. In the RTH-CHT group, OS and DFS depended on the extent of the surgery, and were significantly longer in patients who underwent radical surgery (OS: p=0.03128; DFS: p=0.01206). In the RTH group, the type of surgery had no effect on survival. CONCLUSIONS: Radiochemotherapy significantly prolongs OS and DFS compared with radiotherapy alone in GBM patients who have undergone radical removal of the tumor. Among patients who had non-radical surgery, the type of adjuvant treatment has no effect on OS or DFS. PMID- 25931363 TI - Dorsal onlay buccal mucosal graft urethroplasty in the treatment of urethral strictures - does the stricture length affect success? AB - BACKGROUND: Treatment of urethral strictures can be challenging, but, with appropriate preoperative evaluation and surgical planning it is possible to achieve successful results. OBJECTIVES: To analyze if the stricture length affects the success with dorsal onlay buccal mucosal graft urethroplasty technique. MATERIAL AND METHODS: Between January 2004 and June 2010 a total of 40 patients with anterior urethral stricture were treated with dorsal onlay buccal mucosal graft urethroplasty. Age, etiology of the stricture, stricture length (<=7 cm, and >7 cm), and localization of the stricture were assessed as the factors affecting success rate. RESULTS: The clinical outcome was defined as a failure when any operative instrumentation including dilatation was needed or the urine flow rate was less than 14 mL per second at the sixth month, postoperatively. The mean follow-up period was 43.44 months. Of 40 patients, 28 (70%) were successful and 12 (30%) were a failure. There was no statistically significant difference between the age groups, etiology of the stricture and success rate (p=0.26 and p=0.41). The statistical difference was significant for the localization and length of the stricture by means of success (p=0.002 and p=0.025). CONCLUSIONS: Our results show that the stricture length and localization are the most important variables for desirable success. Even though surgical techniques are constantly evolving, long strictures stay as a problem for urologists. Studies with larger number of patients with long urethral strictures may support our findings, and may prove the efficiency of these surgical techniques. PMID- 25931364 TI - Rehabilitation of the orofacial complex by means of a stimulating plate in children with Down syndrome. AB - BACKGROUND: Disorders in the orofacial complex as well as muscle hypotension in children with Down syndrome can be corrected through orofacial therapy that makes use of a palatal plate. OBJECTIVES: The aim of this paper was to present how parents of children with DS assess the availability of treatment and the therapeutic effects of orthodontic palatal plate therapy on the tongue position and mimetic muscle tension in their children; and to determine whether implementing full Castillo-Morales therapy and using only a palatal plate lead to substantially different results. MATERIAL AND METHODS: The study was conducted on 100 children with DS between the ages of two months and two years (44 boys, 56 girls) who were treated by means of stimulating plate therapy. The study analyzed responses obtained from the parents to questions included in a questionnaire completed at every visit over a period of two years. RESULTS: The study found that in 50 patients with DS who underwent palatal plate rehabilitation there was a visible improvement of the mimetic muscles, tongue retraction and lip closure. CONCLUSIONS: Early orthodontic palatal plate therapy ought to be an integral part of the multidisciplinary rehabilitation of patients with DS. PMID- 25931365 TI - Dimethylarginines as risk markers of atherosclerosis and chronic kidney disease in children with nephrotic syndrome. AB - BACKGROUND: Nephrotic syndrome in children is commonly associated with dyslipidemia, which is considered a risk factor for endothelial dysfunction and atherosclerosis. Recently new markers of endothelial dysfunction, such as asymmetric dimethylarginine (ADMA), have gained importance. Another L-arginine derivative--symmetric dimethylarginine (SDMA)--may reflect the glomerular filtration rate (GFR). OBJECTIVES: The main aim of this study was to assess ADMA as a marker of atherosclerosis. Secondly, SDMA was examined for GFR assessment. MATERIAL AND METHODS: The study involved 32 children with nephrotic syndrome. Several parameters were examined in the remission and relapse phases of nephrotic syndrome, including ADMA, SDMA, cholesterol, triglycerides and GFR. RESULTS: In the relapse phase there was a negative correlation between ADMA and lipids (cholesterol and triglycerides). In both phases SDMA was negatively correlated with GFR. CONCLUSIONS: The role of ADMA as a marker for endothelial dysfunction is not significant. SDMA may be utilized to monitor GFR in children with nephrotic syndrome. PMID- 25931366 TI - The Pitfalls and Important Distances in Temporal Bone HRCT of the Subjects with High Jugular Bulbs - Preliminary Report. AB - BACKGROUND: High jugular bulb (HJB) may be detected unilaterally or bilaterally in temporal bone high resolution computerized tomography (HRCT). OBJECTIVES: In this retrospective study, we investigated the pitfalls and important surgical distances in patients with unilateral and bilateral HJB via temporal bone HRCT. MATERIAL AND METHODS: In this preliminary report, the study group consisted of 20 adult patients (12 male, 8 female), or 40 ears, all of which underwent temporal bone HRCT. We divided them into groups that consisted of bilateral HJB (14 ears), unilateral HJB (13 ears), and control (No HJB, 13 ears). The anotomical relationships of the sigmoid sinus, jugular bulb, and carotid artery with several landmarks in the temporal bone were studied via temporal bone axial and coronal HRCT. The shortest distances between certain points were measured. These measurements were analyzed in respect to pneumatization. Dehiscence on the jugular bulb (JB) and internal carotid artery (ICA) and the dominance of JB were also evaluated for all of the groups. RESULTS: In the axial sections of the temporal bone HRCTs, the sigmois sinus (SS)-external auditory canal (EAC) distance of the bilateral HJB group (14.00+/-1.17 mm) was significantly lower than that of the control group (16.46+/-2.14 mm). The JB-posteromedial points of the umbo on the ear drum (ED) distance of the bilateral HJB (6.28+/-1.72 mm) and the unilateral HJB groups (7.23+/-2.00 mm) were significantly lower than that of the control group (11.15+/-2.30 mm). In the coronal sections of the temporal bone HRCT, the JB-F distance of the bilateral HJB group (5.42+/-2.10 mm) was significantly lower than that of the control group (8.30+/-2.28 mm). As the mastoid pneumatisation and mastoid volume increased, the percentage of ICA dehiscence and the percentage of JB-dehiscence increased. CONCLUSIONS: In subjects with well-pneumatised mastoids, the doctors should be aware of the increased risk of ICA-dehiscence and JB-dehiscence. These measurements should be done in greater series to yield more thorough knowledge. PMID- 25931367 TI - PET/CT Assessment of Follicular Lymphoma and High Grade B Cell Lymphoma - Good Correlation with Clinical and Histological Features at Diagnosis. AB - BACKGROUND: Follicular lymphoma is a common type of non-Hodgkin's lymphoma observed in Western countries. The diagnosis of this disease is based primarily on morphological and immunohistochemical assessment. The proliferative index Ki67 correlates with histological grading and clinical aggressiveness. Currently, positron emission tomography/computed tomography scanning are not applied for standard staging at diagnosis of follicular lymphoma and its use is limited to those patients for whom the identification of residual disease is crucial for therapeutic decisions and only when transformation to a high-grade lymphoma is suspected. OBJECTIVES: Our aim was to assess whether a correlation exists between the maximal standardized uptake value (SUVmax) at the biopsy site as detected via positron emission tomography/computed tomography and pathological (Ki67 and FL histological grade) and clinico-biological features (e.g. LDH, beta-2 microglobulin, Ann Arbor stage and FL International Prognostic Index--FLIPI) at diagnosis. MATERIAL AND METHODS: We retrospectively identified 16 patients during the previous 3.5 years in whom node biopsies were guided, taking into account the SUVmax as detected upon PET/CT scan at diagnosis. The results of these biopsies were diagnostic of follicular lymphoma. We also included 6 patients with high grade B cell lymphoma: 5 diffuse large B cell lymphoma (DLBCL) and 1 FL 3b histological grade. A 2-tailed non-parametric Spearman's correlation analysis of the SUVmax with Ki67, histological grade, LDH and b-2-microglobuline was performed. RESULTS: The Ki67 (r=0.73) and follicular lymphoma histological grade (r=0.75) at the biopsy displayed a significant correlation with the SUVmax at diagnosis (p<0.01). CONCLUSIONS: Our results suggest that SUV detected by positron emission tomography/computed tomography correlates with histological grade in follicular lymphoma/high grade B cell lymphoma, Ki67 and LDH. Positron emission tomography/computed tomography should be considered for guiding lymph node biopsy when transformation to a high-grade B cell lymphoma is suspected. PMID- 25931368 TI - Effect of adjuvant interferon therapy on hepatitis b/c virus-related hepatocellular carcinoma after curative therapy - meta-analysis. AB - BACKGROUND: Hepatocellular carcinoma is the fifth most common malignant cancer in the world. Liver resection and local ablation are the most effective therapeutic approaches for most HCC patients. Recurrence after curative therapy is very common. Some studies reveal that IFNs have an effect on recurrence. While the opinion is disagreement. OBJECTIVES: The aim of this meta-analysis was to evaluate whether interferon therapy could reduce the recurrence of patients of hepatitis B/C virus-related hepatocellular carcinoma after curative therapy. MATERIAL AND METHODS: All randomized controlled trials about interferon on recurrence of hepatitis B/C virus-related hepatocellular carcinoma patients after curative surgery treatment were searched from PubMed, Embase, Cochrane library (all from 1977 to January 2014). Two reviewers independently assessed the quality of each included study and extracted data. RevMan 5.1 was used for meta-analysis. RESULTS: Pooled data analysis revealed that the interferon group had no statistical significance on the recurrence of hepatitis-related hepatocellular carcinoma compared to the control group (RR=0.91, 95% CI, 0.82 to 1.00; p=0.11). While from the subgroup analysis of adjuvant interferon can reduce the recurrence of the median tumor size below 3 cm (RR 0.50, 95% CI 0.35-0.72; p=0.00002). CONCLUSIONS: Adjuvant IFN after curative treatment of hepatitis-related HCC can improve the survival of HCC patients. In addition, IFN could decrease the recurrence rate of HCC patient with median tumor size below 3 cm but not exceeding 3 cm. PMID- 25931369 TI - Comparison of autologous and heterologous bone graft stability effects for filling maxillary bone gap after Le Fort I osteotomy. AB - BACKGROUND: The amount of postoperative maxillary relapse of two different bone graft materials after Le Fort I osteotomy were compared in this study. OBJECTIVES: The aim of this study is to compare postoperative maxillary relapse rates using heterologous and autologous graft materials after Le Fort I osteotomy. MATERIAL AND METHODS: A total of 80 patients who had developmental malocclusion were analyzed retrospectively in this study. Twenty nine (36.2%) and 51 (63.8%) patients underwent Le Fort I osteotomy, and Le Fort I and bilateral sagittal split ramus osteotomy (two-jaw surgery), respectively. Forty two (52.5%) maxillary bone gaps were filled with heterologous bone grafts (group A) and 38 (47.5%) were filled with autologous bone grafts (group B) after Le Fort I osteotomy. The cephalometric graphics and measurements were taken before (T1), 1 week after (T2), and 1 year after (T3) the surgery. The results were documented and determined by the Dolphin imaging 10.5 (Dolphin Imaging, Chatsworth, Calif.) computer program for skeletal relapse. Whether or not the relationship between group A's and B's maxillary relapse rates was evaluated in the postoperative period. RESULTS: It was observed that both graft materials have positive effects on maxillary relapse rate in the postoperative period. When the groups are compared to each other, the relapse rates were similar between group A (8.3%) and group B (10.8%) (p>0.05). CONCLUSIONS: Heterologous bone graft material (Osteoplant(r)-Flex) is thought to be a good alternative to autologous grafts in decreasing the relapse rates and reducing the morbidity of the donor area of the patients who underwent Le Fort I osteotomy. PMID- 25931370 TI - Alternative right ventricular pacing sites. AB - BACKGROUND: The main adverse effect of chronic stimulation is stimulation-induced heart failure in case of ventricular contraction dyssynchrony. Because of this fact, new techniques of stimulation should be considered to optimize electrotherapy. One of these methods is pacing from alternative right ventricular sites. OBJECTIVES: The purpose of this article is to review currently accumulated data about alternative sites of cardiac pacing. MATERIAL AND METHODS: Medline and PubMed bases were used to search English and Polish reports published recently. RESULTS: Recent studies report a deleterious effect of long term apical pacing. It is suggested that permanent apical stimulation, by omitting physiological conduction pattern with His-Purkinie network, may lead to electrical and mechanical dyssynchrony of heart muscle contraction. In the long term this pathological situation can lead to severe heart failure and death. Because of this, scientists began to search for some alternative sites of cardiac pacing to reduce the deleterious effect of stimulation. Based on current accumulated data, it is suggested that the right ventricular outflow tract, right ventricular septum, direct His-bundle or biventricular pacing are better alternatives due to more physiological electrical impulse propagation within the heart and the reduction of the dyssynchrony effect. These methods should preserve a better left ventricular function and prevent the development of heart failure in permanent paced patients. As there is still not enough, long-term, randomized, prospective, cross-over and multicenter studies, further research is required to validate the benefits of using this kind of therapy. CONCLUSIONS: The article should pay attention to new sites of cardiac stimulation as a better and safer method of treatment. PMID- 25931371 TI - Psychiatric aspects of herpes simplex encephalitis, tick-borne encephalitis and herpes zoster encephalitis among immunocompetent patients. AB - The psychopathological symptoms occurring in the course of diseases associated with infections are often initially isolated and non-characteristic, and may cause diagnostic difficulties. Moreover, such disorders tend to be less responsive to psychiatric management. Among possible causes such as trauma, neoplasm and vascular changes, inflammatory changes of the brain as a result of a viral infection should also be considered. There were 452 registered cases of viral encephalitis in Poland in 2010, and although not very prevalent they remain a severe and life-threatening condition. What is more, the frequently occurring neurological and psychiatric complications of viral encephalitis often result in permanent disabilities, causing a significant decrease in the quality of life. This article presents the three types of encephalitis that are most prevalent among immunocompetent patients in Poland, i.e. herpes simplex encephalitis (HSE), tick-borne encephalitis (TBE) and herpes zoster encephalitis (HZE). The psychopathology of the acute phase of the infection, the residual symptoms, features apparent in imaging studies and some neuropathological aspects are also presented. The paper also focuses on psychiatric aspects of the diagnostics and treatment of the described conditions. The clinical pictures of these infections are quite specific, although they cover a wide range of symptoms, and these characteristic features are described. The aim of this review is also to show the significance of thorough diagnostics and a multidisciplinary approach to patients with viral CNS infections. PMID- 25931372 TI - Ultrasensitive anion detection by NMR spectroscopy: a supramolecular strategy based on modulation of chemical exchange rate. AB - NMR spectroscopy is a powerful tool for monitoring molecular interactions and is widely used to characterize supramolecular systems at the atomic level. NMR is limited for sensing purposes, however, due to low sensitivity. Dynamic processes such as conformational changes or binding events can induce drastic effects on NMR spectra in response to variations in chemical exchange (CE) rate, which can lead to new strategies in the design of supramolecular sensors through the control and monitoring of CE rate. Here, we present an indirect NMR anion sensing technique in which increased CE rate, due to anion-induced conformational flexibility of a relatively rigid structure of a novel sensor, allows ultrasensitive anion detection as low as 120 nM. PMID- 25931373 TI - A new class of bacterial quorum sensing antagonists: glycomonoterpenols synthesized using linalool and alpha terpineol. AB - With increasing burden of antibiotic resistant microorganism search for newer drug targets and potent drug molecules is a never ending scenario. Quorum sensing (QS), the phenomenon of bacterial cross-talk, is one such target that has captured the attention of many and has been touted as the future of new age antimicrobials. Quorum sensing has the potential to regulate a plethora of bacterial virulence phenotypes and search of molecules with powerful quorum sensing inhibitory (QSI) capacity are underway. Monoterpene alcohols like linalool and alpha terpineol have been shown to possess antimicrobial and anti biofilm activity. However in this article we attempt to bring forth a new class of compounds, glycomonoterpenols, derived from monoterpenoids alcohols. These glycomonoterpenols have been synthesized using Candida bombicola ATCC 22214 by feeding the cells with linalool and alpha terpineol respectively as substrates in 10% glucose, production medium. The advantage of these molecules over their parent compound is their additional surfactant like property, increased solubility and enhanced QSI potential. A variety of gram-negative bacteria capable of elaborating quorum sensing mediated phenotypes have been selected and both these glycoterpenoid derivatives have been shown to possess strong anti-QS activity. PMID- 25931374 TI - Characterization of the cellulolytic bacteria communities along the gastrointestinal tract of Chinese Mongolian sheep by using PCR-DGGE and real-time PCR analysis. AB - A balanced gastrointestinal microbial ecosystem is crucial for the health and growth of animals. In the gastrointestinal tract (GIT) of ruminants, cellulolytic bacteria aid in the digestion and absorption of nutrients. Rumen contents and feces in ruminants are often used to assess gastrointestinal microbial communities; however, these sites do not guarantee to represent the diversity of microbes found in the entire GIT. In this study, we investigated the microbiota along the GIT of five Chinese Mongolian sheep using PCR-denaturing gradient gel electrophoresis (DGGE) and real-time PCR analysis. Results indicated that microbiota were more abundant in the stomach and large intestine than in the small intestine. DGGE and real-time PCR revealed the predominance of Firmicutes and Bacteroidetes in the GIT. Meanwhile, Ruminococcus flavefaciens and Clostridium cluster IV showed significant difference in their abundance along the GIT (P < 0.05). Fibrobacter succinogenes was the most dominant species, followed by Ruminococcus albus and R. flavefaciens. The ileum harbored a larger number of cellulolytic bacteria, particularly-Clostridium cluster IV, than reported previously. In addition, comparisons between microbiota in the rumen and rectum indicated similar number of total bacteria, Firmicutes, Bacteroidetes, F. succinogenes, Butyrivibrio fibrisolvens, Clostridium cluster IV, and Clostridium cluster XIVa, whereas the number of R. albus and R. flavefaciens was higher in the rumen. This study investigated the composition and quantification of GIT microbial community in Chinese Mongolian sheep, and revealed for the first time the cellulolytic bacterial community in these sheep. PMID- 25931375 TI - Galactose supplementation enhance sialylation of recombinant Fc-fusion protein in CHO cell: an insight into the role of galactosylation in sialylation. AB - Sialic acid levels of therapeutic glycoprotein play an important role in plasma half-life. An undesirable decrease of sialic acid content was observed when we increased Fc-fusion protein productivity fourfold in a GS-CHO cell line by bioprocess optimization. We investigated the potential mechanism for the sialic acid content reduction. We found that limited nucleotide sugar precursor and the extracellular sialidase were not responsible for the reduction of the sialic acid content after titer improvement. Oligosaccharide analysis revealed that the lack of protein galactosylation was the potential cause for the reduction of sialic acid content. Thus we validated this notion by evaluated galactose supplementation in 2 L bioreactors. Cell culture performance was not impacted by addition of up to 40 mM galactose except for the glucose consumption rate. Addition of 20 mM galactose to the bioreactor resulted in the increase of 44 % for total sialic acid content and 20.3 % for sialylated glycans. These data were further validated when the process was run on 200 L scaled bioreactor. These data together show that the galactosylation plays an apparent role in sialylation in our current system. PMID- 25931376 TI - Application of carbon nanotubes modified with a Keggin polyoxometalate as a new sorbent for the hollow-fiber micro-solid-phase extraction of trace naproxen in hair samples with fluorescence spectrophotometry using factorial experimental design. AB - A sensitive technique to determinate naproxen in hair samples was developed using hollow-fiber micro-solid-phase combined with fluorescence spectrophotometry. The incorporation of multi-walled carbon nanotubes modified with a Keggin polyoxometalate into a silica matrix prepared by the sol-gel method was reported. In this research, the Keggin carbon nanotubes /silica composite was used in the pores and lumen of a hollow fiber as the hollow-fiber micro-solid-phase extraction device. The device was used for the microextraction of the analyte from hair and water samples under the optimized conditions. An orthogonal array experimental design with an OA24 (4(6) ) matrix was employed to optimize the conditions. The effect of six factors influencing the extraction efficiency was investigated: pH, salt, volume of donor and desorption phase, extraction and desorption time. The effect of each factor was estimated using individual contributions as response functions in the screening process. Analysis of variance was employed for estimating the main significant factors and their contributions in the extraction. Calibration curve plot displayed linearity over a range of 0.2-10 ng/mL with detection limits of 0.072 and 0.08 ng/mL for hair and aqueous samples, respectively. The relative recoveries in the hair and aqueous matrices ranged from 103-95%. The relative standard deviation for fiber to-fiber repeatability was 3.9%. PMID- 25931377 TI - Exploring the use of social network analysis to measure communication between disease programme and district managers at sub-national level in South Africa. AB - With increasing interest in maximising synergies between disease control programmes (DCP) and general health services (GHS), methods are needed to measure interactions between DCP and GHS actors. In South Africa, administrative integration reforms make GHS managers at decentralised level (district managers) responsible for the oversight of DCP operations within districts, with DCP managers (programme managers) providing specialist support. The reforms necessitate interdependence, but these actors work together ineffectively. Communication is crucial for joint working, but no research to assess communication between these actors has been done. This study explores the use of social network analysis (SNA) to measure the extent to which programme and district managers in South Africa communicate, using HIV monitoring and evaluation (M&E) as an exemplar. Data were collected from fifty one managers in two provinces during 2010-2011, to measure: a) one-on-one task-related communication - talking about the collation (verification, reporting) and use of HIV data for monitoring HIV interventions; and b) group communication through co participating in management committees where HIV data are used for monitoring HIV interventions in districts. SNA measures were computed to describe actor centrality, network density (cohesion), and communication within and between respective manager groups. Block modelling was applied to identify management committees that connect respective manager groups. Results show HIV programme managers located at higher level communicated largely amongst themselves as a group (homophily), seldom talked to the district managers to whom they are supposed to provide specialist HIV M&E support, and rarely participated with them in management committees. This research demonstrates the utility of SNA as a tool for measuring the extent of communication between DCP and GHS actors at sub national level. Actions are needed to bridge observed communication gaps in order to promote collaborative monitoring of HIV programme interventions within districts. PMID- 25931378 TI - Simultaneous determination of 40 novel psychoactive stimulants in urine by liquid chromatography-high resolution mass spectrometry and library matching. AB - The emergence of novel psychoactive substances is an ongoing challenge for analytical toxicologists. Different analogs are continuously introduced in the market to circumvent legislation and to enhance their pharmacological activity. Although detection of drugs in blood indicates recent exposure and link intoxication to the causative agent, urine is still the most preferred testing matrix in clinical and forensic settings. We developed a method for the simultaneous quantification of 8 piperazines, 4 designer amphetamines and 28 synthetic cathinones and 4 metabolites, in urine by liquid chromatography coupled to high-resolution mass spectrometry (LC-HRMS). Data were acquired in full scan and data dependent MS(2) mode. Compounds were quantified by precursor ion exact mass, and confirmed by product ion spectra library matching, taking into account product ions' exact mass and intensities. One-hundred MUL urine was subjected to solid phase cation exchange extraction (SOLA SCX). The chromatographic reverse phase separation was achieved with gradient mobile phase of 0.1% formic acid in water and in acetonitrile in 20 min. The assay was linear from 2.5 or 5 to 500 MUg/L. Imprecision (n=15) was <15.4%, and accuracy (n=15) 84.2-118.5%. Extraction efficiency was 51.2-111.2%, process efficiency 57.7-104.9% and matrix effect ranged from -41.9% to 238.5% (CV<23.3%, except MDBZP CV<34%). Authentic urine specimens (n=62) were analyzed with the method that provides a comprehensive confirmation for 40 new stimulant drugs with specificity and sensitivity. PMID- 25931379 TI - Using quantitative structure activity relationship models to predict an appropriate solvent system from a common solvent system family for countercurrent chromatography separation. AB - Countercurrent chromatography (CCC) is a form of liquid-liquid chromatography. It works by running one immiscible solvent (mobile phase) over another solvent (stationary phase) being held in a CCC column using centrifugal force. The concentration of compound in each phase is characterised by the partition coefficient (Kd), which is the concentration in the stationary phase divided by the concentration in the mobile phase. When Kd is between approximately 0.2 and 2, it is most likely that optimal separation will be achieved. Having the Kd in this range allows the compound enough time in the column to be separated without resulting in a broad peak and long run time. In this paper we report the development of quantitative structure activity relationship (QSAR) models to predict logKd. The QSAR models use only the molecule's 2D structure to predict the molecular property logKd. PMID- 25931380 TI - What is the container/contained when there are ghosts in the nursery?: Joining Bion and Fraiberg in dyadic interventions with mother and infant. AB - "Ghosts in the nursery." "Visitors from the unremembered past." Fraiberg, Adelson, and Shapiro's (1975) words convey the relational "intruders" that they perceived while working with mothers and infants. A mother's unresolved past is a driving force within the treatment of mother-infant dyads. Working with these families, the therapist strives to process and metabolize the distress of the dyad while enabling the mother to contain the infant more fully. This article proposes that Fraiberg et al.'s metaphor may be newly elaborated utilizing Bion's (1962) original theoretical conceptualization of the "container and contained." He posited that an infant projects distressing affective states upon the mother, who contains the experience, transforms the feelings, and then enables the infant to reintroject a more tolerable experience. This lays the foundation for the relational experience of being known by another and facilitates the infant's development of self-knowledge and emotional regulation. We utilize Fraiberg et al.'s original case material to identify ways in which ghosts in the nursery disrupt the processes of the container and contained. Bion's ideas may help enrich our understanding of how the therapeutic relationship enables cycles of containment, transitioning the material "ghosts" from being contained by the infant to being contained by the therapist, and to ultimately being transformed so that the mother can reattribute them to the past. PMID- 25931381 TI - Selective detection and quantification of carbon nanotubes in soil. AB - Carbon nanotubes (CNTs) have been widely applied in many industrial fields. As world production of CNTs increases, the risk of environmental exposure to CNTs also increases. Therefore, to evaluate the impact on the environment, many cell and animal studies have reported on the toxicity of CNTs. It is important to determine the degree of contamination of CNTs in soil and to find the pollution pathways for assessment of the environmental toxicity of CNTs. However, selective detection methods for CNTs in soil or water have rarely been reported. In the present study, a novel technique was developed to quantify the amount of CNTs in soil mixtures using fluorescent SYBR Green I dye after isolation of the CNTs with specific DNA oligomers. As a result, a limit of detection of CNTs in soil was obtained in the range of 250 ppb. This limit can easily be extended to the level of 10 ppb using magnetic well plates with a greater capacity. This method also worked well in the presence of graphene oxide and could be applied to the detection of CNTs in a variety of surroundings (e.g., fish and other tissues). PMID- 25931382 TI - Acute intake of plant stanol esters induces changes in lipid and lipoprotein metabolism-related gene expression in the liver and intestines of mice. AB - The kinetics of plant stanol uptake and routing in 8-week-old C57BL/6J mice were determined after a plant stanol ester gavage. In addition, acute changes in intestinal and hepatic gene expression were investigated. Mice were fed a plant sterol/stanol poor diet from weaning. At the age of 8 weeks, they received an oral gavage consisting of 0.25 mg cholesterol + 50 mg plant stanol esters dissolved in olive oil. Animals were euthanized at different time points. In a second comparable set-up, mesenteric lymph-cannulated versus sham-operated mice received the same oral gavage, which was now deuterium labeled. Intestinal and hepatic sitostanol concentrations increased within 15 min post-gavage. This rapid hepatic appearance was absent in lymph-cannulated mice, suggesting a very fast lymph-mediated uptake. Hepatic mRNA expression of SREBP2 and its target genes rapidly decreased, whereas expression of LXR target genes increased. The intestinal SREBP2 pathway was increased, whereas the expression of LXR target genes hardly changed. The fivefold and sixfold increased expression of intestinal LDLr and PCSK9 is suggestive of TICE activation. We conclude that in C57BL/6J mice plant stanol kinetics are fast, and affect intestinal and hepatic gene expression within 15 min postprandial after lymph-mediated uptake. PMID- 25931383 TI - Correlation between B7-H3 expression and rheumatoid arthritis: A new polymorphism haplotype is associated with increased disease risk. AB - CD276 (B7-H3) is a costimulatory molecule that plays a potent role in T cell responses, however, the role of B7-H3 in autoimmune diseases has not been elucidated. We analyzed B7-H3 expression in rheumatoid arthritis (RA) for the first time and found B7-H3 was significantly up-regulated on monocytes in RA patients, while the levels of soluble B7-H3 in serum were lower than in controls (P < 0.0001). These differences correlated with clinical and laboratory disease parameters and informatory factor TNF-alpha. Through in vitro experiments, we demonstrated that B7-H3 promoted TNF-alpha secretion. In addition, a new polymorphism variant, B7-H3-T-A-C-T, was identified and shown to be associated with the incidence of RA and the decreased release of sB7-H3. These results suggest that B7-H3 may be a promising biomarker associated with the pathogenesis of RA. Notably, the new B7-H3-T-A-C-T polymorphism variant is associated with RA risk and might be associated with the release of soluble B7-H3. PMID- 25931384 TI - Polarization diversity of human CD4+ stem cell memory T cells. AB - T cells are considered to develop through three stages, from naive T (Tn) into central memory T (Tcm) and finally into effector memory T (Tem). Among the subsets of Tn, stem cell memory T (Tscm) were recently found to be the least developed memory subset. While this subset was revealed to possess self reproducibility and multipotentiality, little is known about the relationship between development and polarity. We conducted transcriptome analysis of human CD4(+) T subsets and found that Tscm was a clearly distinct subset, located between Tn and Tcm. Surface antigen analysis and differentiation assay showed that the flexibility of polarity and the cytokine production progressively changed as the differentiation of CD4(+) T cells advanced. Interestingly, we found that most cells of the CD45RO(-)CCR7(+)CCR6(+) subset, hitherto considered the naive precursor of Th17, were in fact Tscm. These findings may advance our understanding of the highly heterogeneous human helper T cells. PMID- 25931385 TI - Differential expression of CD57 in antigen-reactive CD4+ T cells between active and latent tuberculosis infection. AB - The development of diagnostic tests that predict the progression of latent tuberculosis infection to active disease is pivotal for the eradication of tuberculosis. As an initial step to achieve this goal, our study's aim was to identify biomarkers that differentiate active from latent tuberculosis infection. We compared active and latent tuberculosis infection groups in terms of the precursor frequency, functional subset differentiation, and senescence/exhaustion surface marker expression of antigen-specific CD4(+) T cells, which were defined as dividing cells upon their encountering with Mycobacterium (M.) tuberculosis antigens. Among several parameters shown to have statistically significant differences between the two groups, the frequency of CD57-expressing cells could differentiate effectively between active disease and latent infection. Our results suggest that the expression of CD57 in M. tuberculosis-reactive CD4(+) T cells could be a promising candidate biomarker with which to identify individuals with latent tuberculosis infection prone to progression to active disease. PMID- 25931386 TI - Autoimmune lymphoproliferative syndrome-like disease in patients with LRBA mutation. AB - Mutations in LPS-responsive and beige-like anchor (LRBA) gene were recently described in patients with combined immunodeficiency, enteropathy and autoimmune cytopenia. Here, we extend the clinical and immunological phenotypic spectrum of LRBA associated disorders by reporting on three patients from two unrelated families who presented with splenomegaly and lymphadenopathy, cytopenia, elevated double negative T cells and raised serum Fas ligand levels resembling autoimmune lymphoproliferative syndrome (ALPS) and one asymptomatic patient. Homozygous loss of function mutations in LRBA were identified by whole exome analysis. Similar to ALPS patients, Fas mediated apoptosis was impaired in LRBA deficient patients, while apoptosis in response to stimuli of the intrinsic mitochondria mediated apoptotic pathway was even enhanced. This manuscript illustrates the phenotypic overlap of other primary immunodeficiencies with ALPS-like disorders and strongly underlines the necessity of genetic diagnosis in order to provide early correct diagnosis and subsequent care. PMID- 25931387 TI - Evaluation of a youth agency's supervision practices: A mixed-method approach. AB - This research presents the findings from an evaluation and organizational development initiative that was requested by a Canadian youth agency working in a large urban setting. A team of four researchers affiliated with the Center for Research on Educational and Community Services (CRECS) at the University of Ottawa conducted the evaluation. The purpose of the evaluation was to identify the supervision needs and challenges of coordinators and front line staff, assess the efficiency of the current supervision practices, and evaluate the supervisors' and supervisees' satisfaction with these current practices. A literature review was performed to help provide a clear definition of 'supervision' and the different professional roles it encompasses. Additionally, research evidence pertaining both to what contributes to supervision efficacy and supervisor competency was reviewed to distill the most robust findings in the existing literature. The lines of evidence consisted of a document and file review, an online employee survey, group discussions (i.e. focus groups), and interviews with key informants. The results of the evaluation helped the research team formulate recommendations to the agency for the development of enhanced supervision practices across its various service areas. PMID- 25931388 TI - ER proteostasis addiction in cancer biology: Novel concepts. AB - Endoplasmic reticulum (ER) stress is generated by various physiological and pathological conditions that induce an accumulation of misfolded proteins in its lumen. ER stress activates the unfolded protein response (UPR), an adaptive reaction to cope with protein misfolding to and restore proteostasis. However, chronic ER stress results in apoptosis. In solid tumors, the UPR mediates adaptation to various environmental stressors, including hypoxia, low in pH and low nutrients availability, driving positive selection. Recent findings support the concept that UPR signaling also contributes to other relevant cancer-related event that may not be related to ER stress, including angiogenesis, genomic instability, metastasis and immunomodulation. In this article, we overview novel discoveries highlighting the impact of the UPR to different aspects of cancer biology beyond its known role as a survival factor to the hypoxic environment observed in solid tumors. PMID- 25931389 TI - How tumour cell identity is established? PMID- 25931390 TI - ER stress and hexosamine pathway during tumourigenesis: A pas de deux? AB - Both the hexosamine biosynthetic pathway (HBP) and the endoplasmic reticulum (ER) are considered sensors for the nutritional state of the cell. The former is a branch of the glucose metabolic pathway that provides donor molecules for glycosylation processes, whereas the second requires co-translational N glycosylation to ensure proper protein folding. It has become clear that the microenvironment of solid tumours, characterised by poor oxygen and nutrient supply, challenges optimal functions of the ER and the HBP. Here, we review recent advances demonstrating that the ER stress (ERS) response and HBP pathways are interconnected to promote cell viability. We then develop the idea that communication between ER and HBP is a survival feature of neoplastic cells that plays a prominent role during tumourigenesis. PMID- 25931391 TI - Embryonic neural stem cells in a 3D bioassay for trophic stimulation studies. AB - Progenitors were discovered in the corpus striatum several years ago, but little is known about their proliferation and differentiation. The aim of this study was to analyze embryonic progenitor cells from the corpus striatum using a bioassay with trophic stimulation. Primary cells obtained from brains of rat embryos at E13-14 were dissected from striatum niches and cultured in stem cell media. These floating dispersed cells clumped together to forming floating bodies like irregular spheres (spheroids), which were placed in type I collagen gel and cultured under basal conditions or with the addition of NGF, NT-3, or NTN. Optimum growth of neurites was obtained, and after 24 and 48 h, they were measured for number and length. The expression of proliferation markers such as PCNA and Ki67, and of neural progenitor markers such as GFAP, nestin, vimentin, O4, A2B5, Pax6, S100, TubIII, and NeuN, was then analyzed. The initial behavior in cell cultures showed distinguishable spheroids that, when placed in 3D gels and with trophic support, generated neurites. A similar effect was observed in glial cell outgrowth from the spheroids. Our assay showed high reproducibility, short culture time, and high resolution for tracing neuron-neurite outgrowth or visualizing glial outgrowth in a few hours. PMID- 25931393 TI - Penicillin V acylase from Pectobacterium atrosepticum exhibits high specific activity and unique kinetics. AB - Penicillin V acylases (PVAs, E.C.3.5.11) belong to the Ntn hydrolase super family of enzymes that catalyze the deacylation of the side chain from phenoxymethyl penicillin (penicillin V). Penicillin acylases find use in the pharmaceutical industry for the production of semi-synthetic antibiotics. PVAs employ the N terminal cysteine residue as catalytic nucleophile and are structurally and evolutionarily related to bile salt hydrolases (BSHs). Here, we report the cloning and characterization of a PVA enzyme from the Gram-negative plant pathogen, Pectobacterium atrosepticum (PaPVA). The enzyme was cloned and expressed in Escherichia coli attaining a very high yield (250 mg/l) and a comparatively high specific activity (430 IU/mg). The enzyme showed marginally better pH and thermo-stability over PVAs characterized from Gram-positive bacteria. The enzyme also showed enhanced activity in presence of organic solvents and detergents. The enzyme kinetics turned out to be significantly different from that of previously reported PVAs, displaying positive cooperativity and substrate inhibition. The presence of bile salts had a modulating effect on PaPVA activity. Sequence analysis and characterization reveal the distinctive nature of these enzymes and underscore the need to study PVAs from Gram-negative bacteria. PMID- 25931392 TI - Past, present and future of spike sorting techniques. AB - Spike sorting is a crucial step to extract information from extracellular recordings. With new recording opportunities provided by the development of new electrodes that allow monitoring hundreds of neurons simultaneously, the scenario for the new generation of algorithms is both exciting and challenging. However, this will require a new approach to the problem and the development of a common reference framework to quickly assess the performance of new algorithms. In this work, we review the basic concepts of spike sorting, including the requirements for different applications, together with the problems faced by presently available algorithms. We conclude by proposing a roadmap stressing the crucial points to be addressed to support the neuroscientific research of the near future. PMID- 25931395 TI - Chondroitin nanocapsules enhanced doxorubicin induced apoptosis against leishmaniasis via Th1 immune response. AB - Current leishmaniasis treatment is strangled due to concealed residence of parasite and reduced host cell mediated immune response. To circumvent above challenges, novel macrophage targeted oily core polymeric shell based doxorubicin (DOX) loaded nanocapsules (NCAPs) were fabricated employing chondroitin sulphate (CHD) for complimentary immunotherapy coupled chemotherapy against leishmaniasis. Excellent encapsulation efficiency along with pH dependent drug release was demonstrated by NCAPs. Improved cell cycle arrest at G1-S phase (1.56 folds) and apoptosis against promastigotes (6.26 folds), support the remarkable in-vitro antileishmanial activity of NCAPs (IC50: 0.254+/-0.038 MUg/ml) compared to free DOX (IC50: 0.543+/-0.012 MUg/ml). In-vivo antileishmanial activity in hamsters represented a significantly enhanced parasitic inhibition by NCAPs (1.42 folds). Improved activity was mediated via immunotherapeutic activity of NCAPs which up regulated Th1 immune response (IL-12, INF-gamma, and TNF-alpha) and down regulated Th2 immune response (IL-4, IL-10, and TGF-beta). In conclusion, current novel nano-formulation could be a viable option against leishmaniasis. PMID- 25931394 TI - Codon optimization and expression of irisin in Pichia pastoris GS115. AB - Irisin is a novel hormone which is related to many metabolic diseases. In order to illuminate the function and therapeutic effect of irisin, gaining active irisin is necessary. In this work, a codon-optimized irisin gene was designed according to Pichia pastoris synonymous codon usage bias and cloned into the pPIC9K expression vector. Sequencing result indicating that the sequence of irisin was consistent with the modified irisin and the irisin was in frame with alpha-factor secretion signal ATG. The plasmid pPIC9K-irisin was transformed into GS115 P. pastoris cells through electroporation. The positive transformants were screened on MD medium and analyzed by PCR. Five recombinant GS115/pPIC9K-irisin strains were obtained, but only one strain expressed irisin successfully. SDS PAGE and Western blot were used to assess the expression level and purity of irisin. The irisin was also simply purified and the effect of pH value, methanol concentration and induction time on the production of irisin was investigated. The results showed that the best conditions of irisin expression were as follows: pH 6.0, 2.0% methanol and induction for 96 h. This work laid the basis for further investigation into the therapeutic and pharmacological effects of irisin, as well as development of irisin-based therapy. PMID- 25931396 TI - Physicochemical study of the formation of complexes between pancreatic proteases and polyanions. AB - The formation of insoluble complexes between proteins and oppositely charged polyelectrolytes was assessed. Two pancreatic enzymes: trypsin and chymotrypsin, and two anionic synthetic polyelectrolytes: polyacrylate and polyvinylsulfonate, were used for the study at the pH range between 3.00 and 5.00. Two different titration curve shapes, representing two insoluble complexes formation mechanisms, were found. The turbidity of enzyme-polyelectrolyte mixtures is related to the increase either in the size or in the quantity of the insoluble complexes. Ionic strength destabilized insoluble complex formation. Finally, the kinetics of the process of insoluble complex formation at different conditions was studied. PMID- 25931397 TI - Quinopeptide formation associated with the disruptive effect of epigallocatechin gallate on lysozyme fibrils. AB - Numerous studies demonstrate that natural polyphenols can inhibit amyloid formation and disrupt preformed amyloid fibrils. In the present study, the fibril disruptive effects of epigallocatechin-3-gallate (EGCG) were examined using lysozyme as a model protein. The results indicated that EGCG dose dependently inhibited lysozyme fibrillation and modified the peptide chains with quinonoid moieties under acidic conditions, as measured by ThT fluorescence, transmission electron microscopy, and an NBT-staining assay. Moreover, EGCG transformed the preformed lysozyme fibrils to amorphous aggregates through quinopeptide formation. The thiol blocker, N-ethylmaleimide, inhibited the disruptive effect of EGCG on preformed fibrils, suggesting that thiol groups are the binding sites for EGCG. We propose that the formation of quinone intermediates via oxidation and subsequent binding to lysozyme chains are the main processes driving the inhibition of amyloid formation and disruption of preformed fibrils by EGCG. The information presented in this study may provide fresh insight into the link between the antioxidant capacity and anti-amyloid activity of polyphenols. PMID- 25931398 TI - Effects of the P20 protein from Bacillus thuringiensis israelensis on insecticidal crystal protein Cry4Ba. AB - The accessory protein P20 from Bacillus thuringiensis israelensis has been defined as an important molecular chaperone for forming crystal Cyt1Aa, and enhancing Cry11Aa and Cry4Aa expression. To investigate its putative role in Cry4Ba delta-endotoxin production and toxicity, a p20 gene was cloned and introduced into B. thuringiensis recombinant strain expressing cry4Ba type gene (cry4BLB). The delta-endotoxin synthesis was enhanced by 262%. The generated inclusions were assayed against third instar larvae of Aedes aegypti. The combination of P20 protein with Cry4BLB delta-endotoxin led to a stable mortality rate of 25% with doses ranging from 0.2 mg l(-1) to 0.6 mg l(-1). Cry4BLB crystals produced in the presence of P20 were much less soluble than those produced by the control strain lacking P20 at pH lower than or equal to 10.5. The observed toxicity perturbation correlates with a decrease of Cry4BLB inclusions solubility. The presence of P20 protein has affected Cry4BLB crystallization and altered greatly its solubility properties. Cry4Ba effectiveness against A. aegypti larvae is related to the solubilization step in larval guts environment. PMID- 25931399 TI - One-pot synthesis of antibacterial chitosan/silver bio-nanocomposite hydrogel beads as drug delivery systems. AB - Silver nanoparticles were synthesized in situ during the formation of physically crosslinked chitosan hydrogel beads using sodium tripolyphosphate as the crosslinker. The aim of the study was to investigate whether these nanocomposite beads have the potential to be used in drug delivery applications. The formation of silver nanoparticles (AgNPs) in the hydrogels was confirmed by X-ray diffraction and scanning electron microscopy studies. Furthermore, the antibacterial and swelling properties of the beads were studied. The nanocomposite hydrogels demonstrated good antibacterial effects against Escherichia coli and Staphylococcus aureus bacteria. AgNPs caused an increase in the swelling capacity of the beads. In vitro drug release test was carried out to prove the effectiveness of this novel type of nanocomposite beads as a controlled drug delivery system. Prolonged and more controlled drug releases were observed for AgNPs containing chitosan beads, which increased by the increase in AgNPs content. PMID- 25931400 TI - Inhibition of amyloid fibril formation and cytotoxicity by a chemical analog of Curcumin as a stable inhibitor. AB - Clinical application of curcumin for Alzheimer's disease treatment is severely limited with regard to its poor bioavailability, high rate of metabolism, and instability under neutral condition. In the current study, we designed three compounds in which the diketone moiety of curcumin was replaced by cyclohexanone. In these compounds, the linker length of the molecules was optimal; and substitution of dioxolane for hydroxyl groups on compound 3 should prevent metabolic inactivation. The inhibitory effect of the compounds was investigated against hen egg white lysozyme (HEWL) fibrillation using AFM (atomic force microscope), ThT (thioflavin T) and MTT assay. We found that all three compounds were able to inhibit HEWL aggregation in a dose-dependent manner and inhibit the cytotoxic activity of aggregated HEWL. Docking results demonstrated that the compounds could bind into lysozyme and occupy the whole active site groove. In conclusion, we present chemical analogs of curcumin with various modifications in the spacer and the phenolic rings as improved inhibitors of amyloid aggregation. PMID- 25931401 TI - DNA interaction and efficient antimicrobial activities of 4N chelating metal complexes. AB - A new series of metal(II) complexes using a symmetric Schiff base ligand, obtained by the condensation reaction of 4-formyl-N,N-dimethylaniline with benzene-1,2-diamine were synthesized and characterized. The various physico chemical data indicate that the complexes have octahedral geometry. The intrinsic binding constant of the complexes with DNA is explored. The UV-Vis., circular dichorism, fluorescence emission spectral data and the viscosity measurements indicate that the complexes bind to calf thymus DNA (CT DNA) by intercalative mode. The intrinsic binding constants of Cu(II), Ni(II), Co(II) and Zn(II) complexes are found to be 7.1*10(4), 5.2*10(4), 1.8*10(5) and 6.3*10(4) M(-1), respectively. The cleavage studies of these complexes are investigated by gel electrophoresis method in the presence of peroxide. The complexes exhibit enhanced biological activities compared to the free ligand. PMID- 25931402 TI - Wiskott-Aldrich syndrome/X-linked thrombocytopenia in China: Clinical characteristic and genotype-phenotype correlation. AB - BACKGROUND: Wiskott-Aldrich syndrome (WAS) and X-linked thrombocytopenia (XLT) are caused by mutations of the WAS gene. The genotype-phenotype association of WAS and XLT have not been fully elucidated. Here, we established the largest database of WAS in China to further determine the potential correlation between genotype and phenotype and long-term outcome. PROCEDURES: We collected clinical data of 81 WAS/XLT patients, analyzed mutations of WAS gene at the genomic DNA and transcriptional/translational levels, and quantified three different patterns of WAS protein (WASp) expression in PBMCs by flow cytometry. RESULTS: There were 60 unique mutations identified, including 20 novel mutations and eight hotspots, from 75 unrelated families with a total of 81 affected members. Nearly all the patients with XLT had missense mutations and were WASp-positive in the peripheral cells, while only half of the patients with missense mutations exhibited the XLT phenotype and detectable WASp. In contrast, patients with nonsense mutations, deletions, insertions, and complex mutations were WASp-negative and developed the classic WAS phenotype. An equal number of patients with splice anomalies were either WASp-positive or WASp-negative. Long-term survival rates were lower in WASp-negative patients compared to WASp-positive patients. CONCLUSIONS: The clinical phenotype of classic WAS or milder XLT and long-term outcome are potentially influenced by the effect of these defects on gene transcription and translation. Patients with missense mutations allowing expression of mutated WASp and those with splice anomalies, which result in generation of multiple products, including normal WASp, present the attenuated XLT phenotype and show better prognosis. PMID- 25931404 TI - Efficiency of energy transfer during exercise: what are the limiting factors? PMID- 25931403 TI - Mineral and bone disorders in kidney transplant recipients: reversible, irreversible, and de novo abnormalities. AB - Given the advances in medical technologies related to kidney transplantation, the post-transplant graft survival rate and quality of life have improved dramatically. Nevertheless, post-transplant mortality rate still remains high as compared to the general population due to the development of cardiovascular events. It has recently been widely recognized that chronic kidney disease mineral and bone disorders (CKD-MBD) significantly contribute to such poor prognosis at least in part. In the majority of kidney recipients, abnormal serum parameters for mineral and bone disorder (MBD), such as phosphorus, calcium, 1,25 dihydroxyvitamin D, parathyroid hormone and fibroblast growth factor 23, gradually return toward acceptable levels following the re-establishment of kidney function after transplantation; however, some irreversible abnormalities, developed as the result of long-term dialysis, persist, require treatment, or even progress after kidney transplantation. Thus, better management of CKD-MBD during pre-dialysis and dialysis period as well as after kidney transplantation is highly appreciated. PMID- 25931405 TI - More than mitochondrial biogenesis: alternative roles of PGC-1alpha in exercise adaptation. PMID- 25931406 TI - The role of muscle sympathetic nerve activity in limiting exercise capacity in heart failure. PMID- 25931407 TI - Uncovering the mechanisms for statin-mediated dysglycaemia: role of Rac1? PMID- 25931408 TI - Reply from Lykke Sylow, Lisbeth L. V. Moller, Maximilian Kleinert, Erik A. Richter and Thomas E. Jensen. PMID- 25931409 TI - From a basic principle of evolution to the heart rate of mammals. PMID- 25931410 TI - Physiology and evolution at the crossroads of plasticity and inheritance. PMID- 25931411 TI - Medical treatment of acromegaly in pregnancy, highlights on new reports. PMID- 25931413 TI - Hypovitaminosis D: a novel risk factor for coronary heart disease in type 2 diabetes? AB - Vitamin D (25(OH)D) levels have been associated with cardiovascular disease. Thus, the aim of our study was to investigate the association of 25(OH)D levels with coronary heart disease (CHD) in 698 consecutive type 2 diabetic outpatients. 698 consecutive type 2 diabetic outpatients (25.2 % men, age 66 +/- 9 years) and 100 (90 % men, age 65 +/- 13 years) age-matched non-diabetic volunteers were enrolled. 25(OH)D assay and the main cardiovascular risk factors were explored. 25(OH)D concentration was 22 +/- 10 ng/ml in control subjects and 18.23 +/- 10 ng/ml in diabetic patients (p < 0.01). The prevalence of hypovitaminosis D was higher in diabetic patients than in control subjects (90 vs. 83 %, p < 0.01). Diabetic subjects with hypovitaminosis D had higher prevalence of high values of A1C (p < 0.01), BMI (p < 0.01), LDL cholesterol (p < 0.01), triglycerides (p < 0.01), and glycemia (p < 0.01) than their vitamin D-sufficient counterparts. 25(OH)D and HDL cholesterol were lower (p < 0.01), while BMI (p < 0.01), age (p < 0.01), systolic (p < 0.01) and diastolic blood pressure (p < 0.01), diabetes duration (p < 0.01), A1C (p < 0.01), glycemia (p < 0.01), fibrinogen (p < 0.01), triglycerides (p < 0.01), and total (p < 0.01) and LDL cholesterol (p < 0.01) were higher in diabetic subjects with CHD than diabetic subjects without CHD. At the logistic regression analysis, the association of vitamin D with CHD was lost, while sex (p = 0.026), diabetes duration (p = 0.023), and age (p = 0.024) were the most powerful predictors of CHD. The current study demonstrates that 25(OH)D does not have a direct effect on CHD but may have an indirect effect mediated by cardiovascular risk factors such as diabetes duration, age, and sex. PMID- 25931412 TI - The clinical use of vitamin D metabolites and their potential developments: a position statement from the European Society for Clinical and Economic Aspects of Osteoporosis and Osteoarthritis (ESCEO) and the International Osteoporosis Foundation (IOF). AB - Several compounds are produced along the complex pathways of vitamin D3 metabolism, and synthetic analogs have been generated to improve kinetics and/or vitamin D receptor activation. These metabolites display different chemical properties with respect to the parental or native vitamin D3, i.e., cholecalciferol, which has been, so far, the supplement most employed in the treatment of vitamin D inadequacy. Hydrophilic properties of vitamin D3 derivatives facilitate their intestinal absorption and their manageability in the case of intoxication because of the shorter half-life. Calcidiol is a more hydrophilic compound than parental vitamin D3. Active vitamin D analogs, capable of binding the vitamin D receptor evoking vitamin D-related biological effects, are mandatorily employed in hypoparathyroidism and kidney failure with impaired 1alpha-hydroxylation. They have been shown to increase BMD, supposedly ameliorating calcium absorption and/or directly affecting bone cells, although their use in these conditions is jeopardized by the development of hypercalciuria and mild hypercalcemia. Further studies are needed to assess their overall safety and effectiveness in the long-term and new intermittent regimens, especially when combined with the most effective antifracture agents. PMID- 25931414 TI - Shortened saline infusion test for subtype prediction in primary aldosteronism. PMID- 25931415 TI - Morphology of the Nasal Apparatus in Pygmy (Kogia Breviceps) and Dwarf (K. Sima) Sperm Whales. AB - Odontocete echolocation clicks are generated by pneumatically driven phonic lips within the nasal passage, and propagated through specialized structures within the forehead. This study investigated the highly derived echolocation structures of the pygmy (Kogia breviceps) and dwarf (K. sima) sperm whales through careful dissections (N = 18 K. breviceps, 6 K. sima) and histological examinations (N = 5 K. breviceps). This study is the first to show that the entire kogiid sound production and transmission pathway is acted upon by complex facial muscles (likely derivations of the m. maxillonasolabialis). Muscles appear capable of tensing and separating the solitary pair of phonic lips, which would control echolocation click frequencies. The phonic lips are enveloped by the "vocal cap," a morphologically complex, connective tissue structure unique to kogiids. Extensive facial muscles appear to control the position of this structure and its spatial relationship to the phonic lips. The vocal cap's numerous air crypts suggest that it may reflect sounds. Muscles encircling the connective tissue case that surrounds the spermaceti organ may change its shape and/or internal pressure. These actions may influence the acoustic energy transmitted from the phonic lips, through this lipid body, to the melon. Facial and rostral muscles act upon the length of the melon, suggesting that the sound "beam" can be focused as it travels through the melon and into the environment. This study suggests that the kogiid echolocation system is highly tunable. Future acoustic studies are required to test these hypotheses and gain further insight into the kogiid echolocation system. PMID- 25931416 TI - Heatstroke induces liver injury via IL-1beta and HMGB1-induced pyroptosis. AB - BACKGROUND & AIMS: Liver injury is a common complication of heat stroke (HS), and often constitutes a direct cause for patient death. The cellular and molecular mechanism underlying HS-induced liver injury remains unclear. Recent evidence indicates that inflammasome plays an important role in mediating sterile inflammation triggered by tissue damage. Using a rat HS model, we identified a novel mechanism by which inflammasome-dependent interleukin-1beta (IL-1beta) activation and hepatocyte pyroptosis mediate HS-induced liver injury. METHODS: To induce HS, rats were subjected to heat exposure. Inhibition of inflammasomes was achieved by RNA silencing and pharmacologic inhibitor prior to heat exposure. Inflammasome assembly, caspase-1 activation, histological changes, as well as serum levels of liver enzymes were measured. RESULTS: We demonstrated that the onset of HS activated inflammasome in the liver as evidenced by increased capase 1 activity and the association of inflammasome components NOD-like receptor family pyrin domain containing 3 (Nlrp3) and apoptosis speck-like protein containing a caspase-recruitment domain (ASC); and the activated inflammasome, in turn, induced IL-1beta activation and hepatocyte pyroptosis, and subsequent augmented liver injury. HS-induced hepatocyte inflammasome activation seems to be high-mobility group box 1 (HMGB1) dependent. Inhibition of Nlrp3, caspase-1, or HMGB1 prevented HS-induced liver inflammation and ameliorated liver injury. CONCLUSIONS: These findings demonstrate an important role of HMGB1 in mediating inflammasome activation in the development of liver injury following HS, and suggest that targeting inflammasome may represent a novel therapeutic strategy to limit cell death and prevent liver failure after HS. PMID- 25931417 TI - Morphological, genetic and phytochemical variation of the endemic Teucrium arduini L. (Lamiaceae). AB - Analysis of the morphological traits of leaves, genetic variability (analyzed by AFLP) and chemical composition of essential oils (analyzed by GC-MS) was conducted on eleven populations of the endemic Illyric-Balcanic species Teucrium arduini L. in Croatia, Bosnia and Herzegovina, and Montenegro. Average blade length and width ranged from 20.00 to 31.47mm and from 11.58 to 15.66mm, respectively. Multivariate analysis (PCA, UPGMA) of morphological traits distinguished two continental Bosnian populations from the remaining populations. AFLP analysis separated the investigated populations into two groups based primarily on geographical distance. Essential oil analysis showed a total of 52 compounds, with two chemotypes distinguished based on the essential oil profile. The first was a sesquiterpene chemotype, with beta-caryophyllene, germacrene D or caryophyllene oxide as the major compounds, while the second was an oxygenated monoterpene chemotype, with pulegone and piperitone oxide as the main components. The Mantel test showed a stronger correlation between the morphological traits and AFLP than between the essential oil profile and AFLP. The test also showed a stronger association between the essential oil profile and geographical position than between the morphological traits and geographical position. PMID- 25931418 TI - Sarcopenic obesity is associated with lower indicators of psychological health and quality of life in Koreans. AB - Sarcopenic obesity (SO) is known to contribute to morbidity and mortality from chronic diseases. However, there exists limited information regarding its effect on psychological health. The aim of this study was to evaluate association of SO with several indices of psychological health and quality of life (QoL) in Korean adults. This cross-sectional study was conducted with 11521 participants older than 20 years from the Korea National Health and Nutrition Examination Survey 2008-2011. Sarcopenic obesity was defined by a low appendicular skeletal muscle mass divided by body weight less than 1 standard deviation below the sex-specific mean for the young reference group, and by a high waist circumference of at least 90 cm for men and at least 85 cm for women. Psychological health status, including depressive symptoms, perceived stress, and suicidal ideation, as well as QoL, was assessed by a self-reporting questionnaire. Association between SO and psychological health status was assessed under a logistic regression model. After multivariate adjustment for demographics and lifestyle factors, SO was significantly associated with perceived stress (odds ratio, 1.24; 95% confidence interval, 1.07-1.44; P value = .004) and suicidal ideation (odds ratio, 1.26; 95% confidence interval, 1.06-1.50; P value = .010). In addition, SO was found to have a negative association with a range of QoL indicators. Interestingly, these association patterns were more significant in participants younger than 60 years. In conclusion, our results suggest that SO was associated with adverse psychological health and lower QoL more than body mass index-based general obesity. PMID- 25931419 TI - Kiwifruit-derived supplements increase stool frequency in healthy adults: a randomized, double-blind, placebo-controlled study. AB - The worldwide growth in the incidence of gastrointestinal disorders has created an immediate need to identify safe and effective interventions. In this randomized, double-blind, placebo-controlled study, we examined the effects of Actazin and Gold, kiwifruit-derived nutritional ingredients, on stool frequency, stool form, and gastrointestinal comfort in healthy and functionally constipated (Rome III criteria for C3 functional constipation) individuals. Using a crossover design, all participants consumed all 4 dietary interventions (Placebo, Actazin low dose [Actazin-L] [600 mg/day], Actazin high dose [Actazin-H] [2400 mg/day], and Gold [2400 mg/day]). Each intervention was taken for 28 days followed by a 14 day washout period between interventions. Participants recorded their daily bowel movements and well-being parameters in daily questionnaires. In the healthy cohort (n = 19), the Actazin-H (P = .014) and Gold (P = .009) interventions significantly increased the mean daily bowel movements compared with the washout. No significant differences were observed in stool form as determined by use of the Bristol stool scale. In a subgroup analysis of responders in the healthy cohort, Actazin-L (P = .005), Actazin-H (P < .001), and Gold (P = .001) consumption significantly increased the number of daily bowel movements by greater than 1 bowel movement per week. In the functionally constipated cohort (n = 9), there were no significant differences between interventions for bowel movements and the Bristol stool scale values or in the subsequent subgroup analysis of responders. This study demonstrated that Actazin and Gold produced clinically meaningful increases in bowel movements in healthy individuals. PMID- 25931420 TI - Experience of a skeletal dysplasia registry in Turkey: a five-years retrospective analysis. AB - This study shares data on 417 patients with genetic disorders of skeleton including 10 fetal autopsies encountered in a 5-year period at a tertiary university hospital in Ankara, Turkey. We included patients with osteochondrodysplasias, excluding overgrowth syndromes, dysostoses, and craniofacial syndromes. When grouped according to the "International Skeletal Dysplasia Society 2010 classification" the most frequent group is "FGFR3 group" (achondroplasia). "Decreased bone density group" takes the second place, consistent with the literature. We also demonstrated, a relatively higher frequency of recessively inherited skeletal dysplasias when the diagnosis is an entity other than achondroplasia or osteogenesis imperfecta. The literature on the incidence of genetic disorders of skeleton from the Middle East and Eastern Mediterranean is limited to fetal and neonatal autopsies or birth prevelance reports. The higher rate of consanguineous marriages which increases the frequency of autosomal recessive entities makes it difficult to apply data from other parts of the world. Total consanguinity rate among parents in our study was 53% and there were regional differences. The highest (79%) was among parents from South-east Anatolia. This study is the first broad retrospective analysis of genetic disorders of skeleton from our region. We aim to provide a descriptive source for future studies and discuss our findings in comparison to reports from other parts of the world. PMID- 25931421 TI - Pycnogenol(r) in Metabolic Syndrome and Related Disorders. AB - The present review provides an update of the biological actions of Pycnogenol(r) in the treatment of metabolic syndrome and related disorders such as obesity, dyslipidaemia, diabetes and hypertension. Pycnogenol(r) is a French maritime pine bark extract produced from the outer bark of Pinus pinaster Ait. Subsp. atlantica. Its strong antioxidant, antiinflammatory, endothelium-dependent vasodilator activity, and also its anti-thrombotic effects make it appropriate for targeting the multifaceted pathophysiology of metabolic syndrome. Clinical studies have shown that it can reduce blood glucose levels in people with diabetes, blood pressure in mild to moderate hypertensive patients, and waist circumference, and improve lipid profile, renal and endothelial functions in metabolic syndrome. This review highlights the pathophysiology of metabolic syndrome and related clinical research findings on the safety and efficacy of Pycnogenol(r). The results of clinical research studies performed with Pycnogenol(r) are discussed using an evidence-based, target-oriented approach following the pathophysiology of individual components as well as in metabolic syndrome overall. PMID- 25931422 TI - Graphene oxide decorated with silver nanoparticles as a coating on a stainless steel fiber for solid-phase microextraction. AB - A novel graphene oxide decorated with silver nanoparticles coating on a stainless steel fiber for solid-phase microextraction was prepared. Scanning electron microscopy and X-ray photoelectron spectroscopy were used to characterize the coating surface and showed that silver nanoparticles were dispersed on the wrinkled graphene oxide surface. Coupled to gas chromatography with flame ionization detection, the extraction abilities of the fiber for polycyclic aromatic hydrocarbons were examined in the headspace solid-phase microextraction mode. The extraction parameters including adsorption time, adsorption temperature, salt concentration, desorption time and desorption temperature were investigated. Under the optimized condition, wide linearity with low limits of detection from 2 to 10 ng/L was obtained. The relative standard deviations for single-fiber repeatability and fiber-to-fiber reproducibility were less than 10.6 and 17.5%, respectively. The enrichment factors were from 1712.5 to 4503.7, showing the fiber has good extraction abilities. Moreover, the fiber exhibited a good stability and could be reused for more than 120 times. The established method was also applied for determination of polycyclic aromatic hydrocarbons in two real water samples and the recoveries of analytes ranged from 84.4-116.3% with relative standard deviations less than 16.2%. PMID- 25931423 TI - The relationship between excess body weight and the risk of death from unnatural causes. AB - OBJECTIVE: The purpose is to exam whether excess body weight is associated with an increased risk of death from unnatural causes, particularly, injury. METHOD: We analyzed nationally representative data of 14,453 adults (19 and older) who participated in the third National Health and Nutrition Examination Survey, 1988 1994, and were followed up with vital statuses through December 31, 2006. We used Cox proportional hazard regression to estimate the hazard ratio (HR) of death from all unnatural causes combined and specific ones. Gray's test was performed to assess the equality of cumulative incidence functions between body mass index (BMI) levels. RESULTS: A total of 128 unnatural deaths were recorded during an 18 year follow-up with 193,019 person-years accumulated. Compared with healthy weight participants, a person with excess body weight had a low hazard of death from unnatural causes [HR=1.00 (reference), 0.58 (0.39-0.87), and 0.50 (0.30 0.82) for healthy weight, overweight and obese participants, respectively]. Injuries, including motor vehicle accidents and falls, were the major types of unnatural deaths (n=91, 71% of all unnatural deaths), and the risk of death from injuries was linearly and reversely associated with BMI. The HRs of injury were 1.00 (reference), 0.57 (0.36-0.91), and 0.36 (0.19-0.69) for healthy weight, overweight and obese participants, respectively. All these estimates were obtained after adjustment of socio-demographic variables. DISCUSSION: Excess body weight appears to be associated with a low risk of death from unnatural causes, particularly, injuries. Additional investigations on the mechanism underlying the relationship between BMI and unnatural deaths are warranted. PMID- 25931424 TI - The six blind men and the elephant: Are episodic memory tasks tests of different things or different tests of the same thing? AB - The development of episodic memory in children has been of interest to researchers for more than a century. Current behavioral tests that have been developed to assess episodic memory differ substantially in their surface features. Therefore, it is possible that these tests are assessing different memory processes. In this study, 106 children aged 3 to 6 years were tested on four putative tests of episodic memory. Covariation in performance was investigated in order to address two conflicting hypotheses: (a) that the high level of difference between the tests will result in little covariation in performance despite their being designed to assess the same ability and (b) that the conceptual similarity of these tasks will lead to high levels of covariation despite surface differences. The results indicated a gradual improvement with age on all tests. Performances on many of the tests were related, but not after controlling for age. A principal component analysis found that a single principal component was able to satisfactorily fit the observed data. This principal component produced a marginally stronger correlation with age than any test alone. As such, it might be concluded that different tests of episodic memory are too different to be used in parallel. Nevertheless, if used together, these tests may offer a robust assessment of episodic memory as a complex multifaceted process. PMID- 25931425 TI - Nanopharmaceuticals: Tiny challenges for the environmental risk assessment of pharmaceuticals. AB - Many new developments and innovations in health care are based on nanotechnology. The field of nanopharmaceuticals is diverse and not as new as one might think; indeed, nanopharmaceuticals have been marketed for many years, and the future is likely to bring more nanosized compounds to the market. Therefore, it is time to examine whether the environmental risk assessment for human pharmaceuticals is prepared to assess the exposure, fate, and effects of nanopharmaceuticals in an adequate way. Challenges include the different definitions for nanomaterials and nanopharmaceuticals, different regulatory frameworks, the diversity of nanopharmaceuticals, the scope of current regulatory guidelines, and the applicability of test protocols. Based on the current environmental risk assessment for human medicinal products in the European Union, necessary adaptations for the assessment procedures and underlying study protocols are discussed and emerging solutions identified. PMID- 25931426 TI - TRAF2 regulates peripheral CD8(+) T-cell and NKT-cell homeostasis by modulating sensitivity to IL-15. AB - In this study, a critical and novel role for TNF receptor (TNFR) associated factor 2 (TRAF2) is elucidated for peripheral CD8(+) T-cell and NKT-cell homeostasis. Mice deficient in TRAF2 only in their T cells (TRAF2TKO) show ~40% reduction in effector memory and ~50% reduction in naive CD8(+) T-cell subsets. IL-15-dependent populations were reduced further, as TRAF2TKO mice displayed a marked ~70% reduction in central memory CD8(+) CD44(hi) CD122(+) T cells and ~80% decrease in NKT cells. TRAF2TKO CD8(+) CD44(hi) T cells exhibited impaired dose dependent proliferation to exogenous IL-15. In contrast, TRAF2TKO CD8(+) T cells proliferated normally to anti-CD3 and TRAF2TKO CD8(+) CD44(hi) T cells exhibited normal proliferation to exogenous IL-2. TRAF2TKO CD8(+) T cells expressed normal levels of IL-15-associated receptors and possessed functional IL-15-mediated STAT5 phosphorylation, however TRAF2 deletion caused increased AKT activation. Loss of CD8(+) CD44(hi) CD122(+) and NKT cells was mechanistically linked to an inability to respond to IL-15. The reduced CD8(+) CD44(hi) CD122(+) T-cell and NKT-cell populations in TRAF2TKO mice were rescued in the presence of high dose IL-15 by IL-15/IL-15Ralpha complex administration. These studies demonstrate a critical role for TRAF2 in the maintenance of peripheral CD8(+) CD44(hi) CD122(+) T-cell and NKT-cell homeostasis by modulating sensitivity to T-cell intrinsic growth factors such as IL-15. PMID- 25931427 TI - Age-related morphologic changes of the vertebral artery in the transverse process. Analysis by multidetector computed tomography angiography. AB - BACKGROUND CONTEXT: The V2 segment of the vertebral artery (VA) ascends and passes through the transverse foramen (TF) of the C6-C1 vertebrae. Atherosclerosis of the VA and degenerative changes in the cervical spine are likely to occur with aging, and subsequent morphologic changes may alter the normal anatomy. PURPOSE: The aim was to determine the morphologic changes of TF and VA in relation to aging. STUDY DESIGN/SETTING: This was a retrospective cross sectional study. PATIENT SAMPLE: One hundred ten consecutive patients who had undergone computed tomography angiography were included. METHODS: The subjects were then divided into three groups according to age: Group A, less than 45 years; Group B, from 45 to 65 years; and Group C, older than 65 years. Cases with stenosis and dissection of the VA were excluded from the quantitative analysis. The areas of the VA and TF were measured, and the VA/TF occupation ratio (OR) was calculated accordingly. The presence of VAs tortuosity within the TF was also noted. RESULTS: The TF was larger in the oldest group, but the difference was not statistically significant. There was also no significant statistical difference among the age groups in terms of the VA and VA/TF ORs (p>.05). In the Group C, the rate of overall tortuosity of the VA was 73%, and arterial tortuosity in the TF was 28.6%. In cases with tortuous VA, C6 and C4 TFs were found to be significantly larger. CONCLUSIONS: Tortuous VAs tend to be associated with enlargement of C6 and C4 TFs. Knowledge of such changes in the anatomy is crucial during instrumentation used for cervical spine surgeries, to prevent serious complications in patients aged older than 65 years. PMID- 25931428 TI - A method for preparation of hydrogel microcapsules for stem cell bioprocessing and stem cell therapy. AB - A method for the preparation of suspension culture microcapsules used in the bioprocessing of human mesenchymal stem cells (hMSCs) is reported. The microcapsules are prepared from a semi-synthetic hydrogel comprising Pluronic(r)F127 conjugated to denatured fibrinogen. The Pluronic-fibrinogen adducts display a lower critical solubility temperature (LCST) at ~30 degrees C, thus enabling mild, cell-compatible physical crosslinking of the microcapsules in a warm gelation bath. Cell-laden microgels were prepared from a solution of Pluronic-fibrinogen hydrogel precursor and hMSCs; these were cultivated for up to 15 days in laboratory-scale suspension bioreactors and harvested by reducing the temperature of the microcapsules to disassemble the physical polymer network. The viability, proliferation and cell recovery yields of the hMSCs were shown to be better than photo-chemically crosslinked microcapsules made from a similar material. The cell culture yields, which exceeded 300% after 15 days in suspension culture, were comparable to other microcarrier systems used for the mass production of hMSCs. The simplicity of this methodology, both in terms of the cell inoculation and mild recovery conditions, represent distinct advantages for stem cell bioprocessing with suspension culture bioreactors. PMID- 25931429 TI - Characterization of a MAVS ortholog from the Chinese tree shrew (Tupaia belangeri chinensis). AB - Human mitochondrial antiviral signaling protein (hMAVS, also known as IPS-1, VISA, or Cardif) is essential for antiviral innate immunity. The Chinese tree shrew (Tupaia belangeri chinenses), a close relative of primates, is emerging as a potential animal model for investigating viral infection. However, there is a lack of biological knowledge about the antiviral innate immunity of the tree shrew. In this study, we identified and characterized the function of the Chinese tree shrew MAVS gene (tMAVS). The cDNA of tMAVS was 2771 bp in length and encoded a polypeptide of 501 amino acids. Phylogenetic analyses based on the amino acid sequences revealed a closer affinity of tMAVS with those of primates. Quantitative real-time PCR analysis indicated that tMAVS mRNA was constitutively expressed in all seven tissues analyzed in this study. The tMAVS mRNA expression was rapidly and significantly increased after RNA virus infections. Ectopic expression of tMAVS significantly potentiated the virus-triggered activation of IRF3, NF-kappaB and interferon-beta (IFN-beta), whereas knockdown of tMAVS displayed the opposite effect. Furthermore, tMAVS mutants lacking the caspase activation and recruitment (CARD) domains or the transmembrane (TM) domain were unable to induce IFN-beta. Similar with hMAVS, mitochondrial localization of tMAVS was dependent on its domain. Collectively, this study revealed evolutionary conservation of the MAVS antiviral signaling pathway in the Chinese tree shrew. PMID- 25931431 TI - The Pap test and Bethesda 2014. PMID- 25931430 TI - Childcare service centers' preferences and intentions to use a web-based program to implement healthy eating and physical activity policies and practices: a cross sectional study. AB - BACKGROUND: Overweight and obesity is a significant public health problem that impacts a large number of children globally. Supporting childcare centers to deliver healthy eating and physical activity-promoting policies and practices is a recommended strategy for obesity prevention, given that such services provide access to a substantial proportion of children during a key developmental period. Electronic Web-based interventions represent a novel way to support childcare service providers to implement such policies and practices. OBJECTIVE: This study aimed to assess: (1) childcare centers' current use of technology, (2) factors associated with intention to use electronic Web-based interventions, and (3) Web based features that managers rated as useful to support staff with implementing healthy eating and physical activity-promoting policies and practices. METHODS: A computer-assisted telephone interview (CATI) was conducted with service managers from long day care centers and preschools. The CATI assessed the following: (1) childcare center characteristics, (2) childcare centers' use of electronic devices, (3) intention to use a hypothetical electronic Web-based program assessed using the Technology Acceptance Model (TAM) with ratings between 1 (strongly disagree) and 7 (strongly agree), and (4) features rated as useful to include in a Web-based program. RESULTS: Overall, 214 service centers out of 277 (77.3%) consented to participate. All service centers except 2 reported using computers (212/214, 99.1%), whereas 40.2% (86/214) used portable tablets. A total of 71.9% (151/210) of childcare service managers reported a score of 6 or more for intention to use a hypothetical electronic Web-based program. In a multivariable logistic regression analysis, intention to use the program was significantly associated with perceived ease of use (P=.002, odds ratio [OR] 3.9, 95% CI 1.6-9.2) and perceived usefulness (P<.001, OR 28,95% CI 8.0-95.2). Features reported by service managers as useful or very useful for a Web-based program included decision-support tools to support staff with menu planning (117/129, 90.7%), links to relevant resources (212/212, 100%), updated information on guidelines (208/212, 98.1%), and feedback regarding childcare center performance in relation to other childcare centers (212/212, 100%). CONCLUSIONS: Childcare service managers reported high intention to use a Web based program and identified several useful features to support staff to implement healthy eating and physical activity policies and practices. Further descriptive and intervention research examining the development and use of such a program to support childcare centers with the implementation of healthy eating and physical activity-promoting policies and practices is warranted. PMID- 25931432 TI - Temperamental factors in severe weight cycling. A cross-sectional study. AB - OBJECTIVE: Weight cycling is a prevalent phenomenon in obese individuals. There is evidence that temperamental factors are associated with obesity and subgroups among the obese have been identified based on reactive and regulative aspects of temperament. METHODS: We aimed at investigating the association between reactive and regulative aspects of temperament and severe weight cycling in overweight and obese individuals of a representative German population sample (n = 923). Participants completed questionnaires assessing weight parameters including BMI and weight cycling, sensitivity to punishment and to reward (BIS/BAS scales), self-regulatory abilities (effortful control scale), depressive symptoms, and binge eating. RESULTS: Severe weight cycling was more common in women, and was associated with higher reward sensitivity, higher current and maximum-ever BMI, higher weight suppression, more depressive symptoms, and a higher prevalence of binge eating. In contrast, sensitivity to punishment and effortful control were not associated with severe weight cycling. Also, the interaction between sensitivity to reward and effortful control did not predict weight cycling. DISCUSSION: Higher reward sensitivity might not only render individuals vulnerable for weight regain but might also be associated with a higher frequency of weight loss attempts due to the putative rewarding properties of the initial success in weight loss at the early stages of a diet. Temperamental factors should be considered in the treatment of obesity. PMID- 25931434 TI - Assessment of knowledge, attitude and practice of food allergies among food handlers in the state of Penang, Malaysia. AB - OBJECTIVES: Food handler's knowledge, attitude and practice regarding food allergies are important to prevent debilitating and sometimes fatal reactions. This study aimed to assess their food allergy knowledge, attitude and practice, which could help to maintain the safety and hygiene of food consumed by the public. STUDY DESIGN: Cross-sectional survey. METHODS: A cross-sectional survey involving 121 conveniently sampled (81.76% response rate) respondents among the food handlers in the state of Penang, Malaysia, was conducted using a validated self-administered questionnaire. Their knowledge, attitude and work practice were captured using a 37-item questionnaire that elicited their responses using a mixture of closed-ended and Likert scale techniques. RESULTS: The mean knowledge score for respondents was 50.23 (SD = 14.03), attitude score was 54.26 (SD = 11.67) and practice score was 45.90 (SD = 24.78). Only 1.79% of the respondents were considered to have excellent knowledge, 21.37% had a low risk practice and 4.27% had positive attitudes towards food allergies. Most of the respondents (70%) knew about food allergies and their seriousness. There was a statistically significant correlation between the attitude and practice of respondents (r = 0.51). The type of establishment was the only characteristic significantly associated (P < 0.05) with food handler allergy knowledge, attitude and practice. CONCLUSIONS: More than half of food handlers in Penang have moderate levels of food allergy knowledge, practice and attitude. Only a small proportion of them have excellent food allergy knowledge, practice and attitude. Integration of food allergy training into compulsory food safety training programmes is needed to reduce food allergy risks and prevent fatal allergic reactions to food among their customers. PMID- 25931433 TI - Acute responses to opioidergic blockade as a biomarker of hedonic eating among obese women enrolled in a mindfulness-based weight loss intervention trial. AB - There are currently no commonly used or easily accessible 'biomarkers' of hedonic eating. Physiologic responses to acute opioidergic blockade, indexed by cortisol changes and nausea, may represent indirect functional measures of opioid-mediated hedonic eating drive and predict weight loss following a mindfulness-based intervention for stress eating. In the current study, we tested whether cortisol and nausea responses induced by oral ingestion of an opioidergic antagonist (naltrexone) correlated with weight and self-report measures of hedonic eating and predicted changes in these measures following a mindfulness-based weight loss intervention. Obese women (N = 88; age = 46.7 +/- 13.2 years; BMI = 35.8 +/- 3.8) elected to complete an optional sub-study prior to a 5.5-month weight loss intervention with or without mindfulness training. On two separate days, participants ingested naltrexone and placebo pills, collected saliva samples, and reported nausea levels. Supporting previous findings, naltrexone-induced cortisol increases were associated with greater hedonic eating (greater food addiction symptoms and reward-driven eating) and less mindful eating. Among participants with larger cortisol increases (+1 SD above mean), mindfulness participants (relative to control participants) reported greater reductions in food addiction symptoms, b = -0.95, SE(b) = 0.40, 95% CI [-1.74, -0.15], p = .021. Naltrexone induced nausea was marginally associated with reward-based eating. Among participants who endorsed naltrexone-induced nausea (n = 38), mindfulness participants (relative to control participants) reported greater reductions in food addiction symptoms, b = -1.00, 95% CI [-1.85, -0.77], p = .024, and trended toward reduced reward-based eating, binge eating, and weight, post-intervention. Single assessments of naltrexone-induced cortisol increases and nausea responses may be useful time- and cost-effective biological markers to identify obese individuals with greater opioid-mediated hedonic eating drive who may benefit from weight loss interventions with adjuvant mindfulness training that targets hedonic eating. PMID- 25931435 TI - The effects of calorie labels on those at high-risk of eating pathologies: a pre post intervention study in a University cafeteria. AB - OBJECTIVES: The aim of the study was to examine the effect of a public policy (menu labelling) on those at high-risk for eating pathologies. Specifically, the study looked for any adverse effects related to eating disturbance level. STUDY DESIGN: The study employed a pre-post intervention design. Baseline collection took place in October 2012. One week prior to follow-up in November 2012, calorie labels were displayed next to virtually all menu items in a University cafeteria. Labels remained throughout the entire duration of follow-up. METHODS: Participants were female undergraduates (N = 299). At baseline and follow-up, a survey assessed eating disturbance level (Eating Attitudes Test-26), emotional state, frequency of engaging in unhealthy weight-related behaviours, and calorie consumption. RESULTS: Generalized estimating equations were used to test changes in negative outcomes over time in response to calorie labels. Calorie consumption did not significantly decrease from baseline (mean = 660.5 kcal) to follow-up (mean = 600.5 kcal; P = 0.104). There were no changes in emotional states such as body image satisfaction (P = 0.447), anxiety (P = 0.595), positive affect (P = 0.966), negative affect (P = 0.576), and unhealthy weight-related behaviours such as binging (P = 0.268), exercising excessively (P = 0.847), or restricting calories (P = 0.504). Additionally, there were no interactions between eating disturbance level and time. CONCLUSIONS: Overall, no adverse outcomes were found for this at-risk population. Calorie labels did not differentially affect those with higher levels of eating disturbance. Future research should focus on examining the impact of calorie labels among those with clinical eating disorders. PMID- 25931436 TI - The prevalence and characteristics of fast food outlets in Ontario hospitals. PMID- 25931437 TI - Treatment outcome and its attributes in TB-HIV co-infected patients registered under Revised National TB Control Program: a retrospective cohort analysis. AB - OBJECTIVES: DOTS treatment has shown to be effective in TB patients with or without HIV infection although there have been some conflicting evidence. This may be due to various factors associated with HIV-TB co-infection and its treatment. Thus the present study was planned to study the outcome of DOTS and factors associated with same in TB-HIV co-infected patients. STUDY DESIGN: A retrospective cohort analysis was done. METHODS: 886 TB-HIV co-infected patients who were registered under RNTCP were the subjects. Data from RNTCP was obtained on diagnosis of TB, HIV and TB therapy and some attributes. RESULTS: Average cure rate for NSP TB-HIV co-infected patients was 72% compared with 83% of total NSP registered patients (P < 0.001). Death rate in NSP TB-HIV co-infected patients was 16% (P < 0.001). In non-NSP TB-HIV co-infected patients, success rate was 80%. Death rate was significantly higher i.e. 12% in non-NSP TB-HIV co-infected cases as compared with 6% in total registered patients. Death rate was 19% in RT TB-HIV co-infected patients while 11% in all registered RT cases (P < 0.001). In TB-HIV co-infected patients paediatric patients, patients with extra pulmonary TB and new patients without any history of previous treatment had a higher chance of success at treatment. Patients with Pulmonary TB had higher chance of death. CONCLUSION: Success rate was significantly lower and death rate was significantly higher among the TB-HIV co-infected cohort with age, type of TB and history of previous treatment affecting the success rate of treatment and type of TB affecting the death rate. PMID- 25931438 TI - Financial burden on the families of patients with hepatitis B virus-related liver diseases and the role of public health insurance in Yunnan province of China. AB - OBJECTIVE: To investigate the financial burden of patients who had various stages of hepatitis B virus-related diseases and the level of alleviation from financial burden by health insurance schemes in Yunnan province of China. STUDY DESIGN: A cross-sectional survey. METHODS: Patients' information was consecutively recorded at the First Affiliated Hospital of Kunming Medical University, from December 2012 to June 2013. Consecutive cases of hepatitis B virus (HBV) (520), compensated cirrhosis (91), decompensated cirrhosis (198) and hepatocellular carcinoma (HCC) (131) were recruited from the outpatient and inpatient departments. The total direct costs, hospital charge, outpatient costs, hospitalization fees being reimbursed and household catastrophic health expenditure were estimated for each disease group. RESULTS: The average annual direct costs for each disease group were 19,496 RMB for HBV, 28,466 RMB in compensated cirrhosis, 46,061 RMB for decompensated cirrhosis, and 33,044 RMB for HCC patients. Catastrophic health expenditure occurred in all four groups. Health insurance reimbursement released the financial burden incurred by medical expenses of patients under a high level of household economic status. Public health insurance schemes helped the patients to various extents. CONCLUSIONS: Among these patient groups, direct costs represent a significant economic burden. Health expenditure and financing systems must be considered to prevent the increase of household catastrophe, particularly among the poor. PMID- 25931439 TI - Linking health states to subjective well-being: an empirical study of 5854 rural residents in China. AB - OBJECTIVES: Despite a maturing literature on the association between subjective well-being (SWB) and health status of the general population in Western countries, little is known regarding the happiness-health relation in China, and rural populations in particular. This study was aimed to explore the correlation between SWB and health states of China's rural residents. STUDY DESIGN: Cross sectional survey. METHODS: Data derived from a household survey conducted in 2010 with 5854 rural residents included. The single-item self-reported happiness measure used in the World Values Survey was employed to measure SWB. EQ-5D dimensions and visual analogue scale (VAS) were applied to measure subjective health status. The number of chronic diseases was used as proxy of objective health status. OLS regressions were performed to estimate the variation in SWB by health status and beta coefficients were employed as effect size measures. RESULTS: Among EQ-5D dimensions, anxiety/depression had the strongest negative effect on SWB. Having severe anxiety/depression problems could reduce SWB by 1.65 on a scale 1-4. Reporting severe problems in pain/discomfort could also reduce SWB by 0.41, while the impact of other dimensions was insignificant. The coefficient on VAS implied a difference in SWB of 1.60 between the worst health state and the best health state. And suffering from three chronic diseases could reduce SWB by 0.62, but the effect turned insignificant when all measures of subjective health status were entered in the regression. CONCLUSIONS: The results from this study verify the strongly negative effect of the mental health dimension on SWB in the context of rural China. And suffering from chronic diseases has substantial negative effect on SWB even after subjective health status is controlled for. But the impact of chronic diseases on SWB could be fully captured when all measures of subjective health status are taken into account. PMID- 25931441 TI - Identification of the metabolites of TCM prescription Sinisan, found in miniature pig urine via intragastric administration. AB - The metabolic profile of the traditional Chinese medicine, Sinisan, in miniature pig urine via intragastric administration was investigated. In total, 50 compounds, including 10 unchanged parent glycosides, which were not found from Sinisan's metabolic profile in rats' urine, were identified. Among these, 36 compounds were characterized by HPLC-SPE-NMR coupled with HPLC-HRESIMS, five of which are new and nine are endogenous metabolites of miniature pig. Most of phase I and phase II metabolites are hydrolytic products of parent glycosides and glucuronide conjugates, respectively, the latter having been reported as sulfate conjugates while the experimental animal is rat. Benzoic acid, obtained from hydrolysis of albiflorin and paeoniflorin, and phenylpropenoic acids, obtained from oxidative cleavage of flavones, formed phase II glycine conjugates. PMID- 25931440 TI - The Role of Gastroesophageal Reflux and Other Factors during Progression to Esophageal Adenocarcinoma. AB - BACKGROUND: U.S. esophageal adenocarcinoma (EAC) incidence increased over 5-fold between 1975 and 2009. Symptomatic gastroesophageal reflux disease (sGERD) elevates the risk for EAC. However, a simple calculation suggests that changes in sGERD prevalence can explain at most approximately 16% of this trend. Importantly, a mechanistic understanding of the influence of sGERD and other factors (OF) on EAC is lacking. METHODS: A multiscale model was developed to estimate temporal trends for sGERD and OF, and their mechanistic role during carcinogenesis. Model calibration was to Surveillance, Epidemiology, and End Results (SEER) incidence and age-dependent sGERD data using maximum likelihood and Markov chain Monte Carlo (MCMC) methods. RESULTS: Among men, 77.8% [95% credibility interval (CI), 64.9%-85.6%] of the incidence trend is attributable to OF, 13.4% (95% CI, 11.4%-17.3%) to sGERD, and 8.8% (95% CI, 4.2%-13.7%) to sGERD OF interactions. Among women, 32.6% (95% CI, 27.0%-39.9%) of the trend is attributable to OF, 13.6% (95% CI, 12.5%-15.9%) to sGERD, and 47.4% (95% CI, 30.7%-64.6%) to interactions. The predicted trends were compared with historical trends for obesity, smoking, and proton pump inhibitor use. Interestingly, predicted OF cohort trends correlated most highly with median body mass index (BMI) at age 50 (r = 0.988 for men; r = 0.998 for women). CONCLUSIONS: sGERD and OF mechanistically increase premalignant cell promotion, which increases EAC risk exponentially with exposure duration. IMPACT: Surveillance should target individuals with long-duration sGERD and OF exposures. PMID- 25931443 TI - Rapid on-site evaluation of EBUS-TBNA specimens of lymph nodes: Comparative analysis and recommendations for standardization. AB - BACKGROUND: There is no widely accepted rapid on-site evaluation (ROSE) reporting system for endobronchial ultrasound-guided transbronchial needle aspiration. At the University of Arkansas for Medical Sciences, ROSE reporting was unstructured. The goal was to evaluate, compare, and improve upon 2 structured approaches proposed in the literature. METHODS: One hundred eighteen consecutive nodal aspirates were retrospectively reviewed by a pathology resident and a staff cytopathologist, both of whom were blinded to the original unstructured readings. Each reviewer interpreted every specimen with 2 different structured criteria proposed in the literature: criteria from the University of Minnesota (the Minnesota [MN] criteria) and criteria from the North Shore Long Island Jewish Health System (the New York [NY] criteria). The data allowed a comparison of the original unstructured ROSE system with the MN and NY scoring schemes and the final diagnosis. RESULTS: Original on-site adequacy (OSA) had been assessed at 96%. Three cases were false-adequate according to the original unstructured approach; these had been called adequate on site, but a subsequent slide review including cell blocks did not show definite nodal tissue. OSA dropped to 86% with the MN criteria and to 85% with the NY criteria. No false-adequate on-site diagnoses would have been rendered with the application of either structured criteria. There were no significant differences between the MN and NY criteria with respect to the determination of OSA. An assessment of ease of application favored the NY criteria. With respect to diagnostic categories, each of the systems (MN and NY) was felt to have a category of value not used by the other system. CONCLUSIONS: A standardized intra- and inter-institutional system for ROSE reporting is needed. On the basis of comparative analyses and consensus, modifications to prior criteria have been proposed in the hope of approaching this goal. PMID- 25931442 TI - Early gene Broad complex plays a key role in regulating the immune response triggered by ecdysone in the Malpighian tubules of Drosophila melanogaster. AB - In insects, humoral response to injury is accomplished by the production of antimicrobial peptides (AMPs) which are secreted in the hemolymph to eliminate the pathogen. Drosophila Malpighian tubules (MTs), however, are unique immune organs that show constitutive expression of AMPs even in unchallenged conditions and the onset of immune response is developmental stage dependent. Earlier reports have shown ecdysone positively regulates immune response after pathogenic challenge however, a robust response requires prior potentiation by the hormone. Here we provide evidence to show that MTs do not require prior potentiation with ecdysone hormone for expression of AMPs and they respond to ecdysone very fast even without immune challenge, although the different AMPs Diptericin, Cecropin, Attacin, Drosocin show differential expression in response to ecdysone. We show that early gene Broad complex (BR-C) could be regulating the IMD pathway by activating Relish and physically interacting with it to activate AMPs expression. BR-C depletion from Malpighian tubules renders the flies susceptible to infection. We also show that in MTs ecdysone signaling is transduced by EcR-B1 and B2. In the absence of ecdysone signaling the IMD pathway associated genes are down regulated and activation and translocation of transcription factor Relish is also affected. PMID- 25931444 TI - Swine Farming Is a Risk Factor for Infection With and High Prevalence of Carriage of Multidrug-Resistant Staphylococcus aureus. AB - BACKGROUND: Livestock-associated Staphylococcus aureus (LA-SA) has been documented worldwide. However, much remains unknown about LA-SA colonization and infection, especially in rural environments. METHODS: We conducted a large-scale prospective study of 1342 Iowans, including individuals with livestock contact and a community-based comparison group. Nasal and throat swabs were collected to determine colonization at enrollment, and skin infection swabs over 17 months were assessed for S. aureus. Outcomes included carriage of S. aureus, methicillin resistant S. aureus (MRSA), tetracycline-resistant S. aureus (TRSA), multidrug resistant S. aureus (MDRSA), and LA-SA. RESULTS: Of 1342 participants, 351 (26.2%; 95% confidence interval [CI], 23.8%-28.6%) carried S. aureus. MRSA was isolated from 34 (2.5%; 95% CI, 1.8%-3.5%) and LA-SA from 131 (9.8%; 95% CI, 8.3% 11.5%) of the 1342 participants. Individuals with current swine exposure were significantly more likely to carry S. aureus (prevalence ratio [PR], 1.8; 95% CI, 1.4-2.2), TRSA (PR, 8.4; 95% CI, 5.6-12.6), MDRSA (PR, 6.1; 95% CI, 3.8-10.0), and LA-SA (PR, 5.8; 95% CI, 3.9-8.4) than those lacking exposure. Skin infections (n = 103) were reported from 67 individuals, yielding an incidence rate of 6.6 (95% CI, 4.9-8.9) per 1000 person-months. CONCLUSIONS: Current swine workers are 6 times more likely to carry MDRSA than those without current swine exposure. We observed active infections caused by LA-SA. This finding suggests that individuals with livestock contact may have a high prevalence of exposure to, and potentially infection with, antibiotic-resistant S. aureus strains, including LA SA strains. PMID- 25931446 TI - Solar cells. Impact of microstructure on local carrier lifetime in perovskite solar cells. AB - The remarkable performance of hybrid perovskite photovoltaics is attributed to their long carrier lifetimes and high photoluminescence (PL) efficiencies. High quality films are associated with slower PL decays, and it has been claimed that grain boundaries have a negligible impact on performance. We used confocal fluorescence microscopy correlated with scanning electron microscopy to spatially resolve the PL decay dynamics from films of nonstoichiometric organic-inorganic perovskites, CH3NH3PbI3(Cl). The PL intensities and lifetimes varied between different grains in the same film, even for films that exhibited long bulk lifetimes. The grain boundaries were dimmer and exhibited faster nonradiative decay. Energy-dispersive x-ray spectroscopy showed a positive correlation between chlorine concentration and regions of brighter PL, whereas PL imaging revealed that chemical treatment with pyridine could activate previously dark grains. PMID- 25931445 TI - Cell biology. Reversible centriole depletion with an inhibitor of Polo-like kinase 4. AB - Centrioles are ancient organelles that build centrosomes, the major microtubule organizing centers of animal cells. Extra centrosomes are a common feature of cancer cells. To investigate the importance of centrosomes in the proliferation of normal and cancer cells, we developed centrinone, a reversible inhibitor of Polo-like kinase 4 (Plk4), a serine-threonine protein kinase that initiates centriole assembly. Centrinone treatment caused centrosome depletion in human and other vertebrate cells. Centrosome loss irreversibly arrested normal cells in a senescence-like G1 state by a p53-dependent mechanism that was independent of DNA damage, stress, Hippo signaling, extended mitotic duration, or segregation errors. In contrast, cancer cell lines with normal or amplified centrosome numbers could proliferate indefinitely after centrosome loss. Upon centrinone washout, each cancer cell line returned to an intrinsic centrosome number "set point." Thus, cells with cancer-associated mutations fundamentally differ from normal cells in their response to centrosome loss. PMID- 25931447 TI - DEVELOPMENTAL BIOLOGY. It's about time for neural crest. PMID- 25931448 TI - Aging stem cells. A Werner syndrome stem cell model unveils heterochromatin alterations as a driver of human aging. AB - Werner syndrome (WS) is a premature aging disorder caused by WRN protein deficiency. Here, we report on the generation of a human WS model in human embryonic stem cells (ESCs). Differentiation of WRN-null ESCs to mesenchymal stem cells (MSCs) recapitulates features of premature cellular aging, a global loss of H3K9me3, and changes in heterochromatin architecture. We show that WRN associates with heterochromatin proteins SUV39H1 and HP1alpha and nuclear lamina heterochromatin anchoring protein LAP2beta. Targeted knock-in of catalytically inactive SUV39H1 in wild-type MSCs recapitulates accelerated cellular senescence, resembling WRN-deficient MSCs. Moreover, decrease in WRN and heterochromatin marks are detected in MSCs from older individuals. Our observations uncover a role for WRN in maintaining heterochromatin stability and highlight heterochromatin disorganization as a potential determinant of human aging. PMID- 25931449 TI - NEURODEVELOPMENT. Shared regulatory programs suggest retention of blastula-stage potential in neural crest cells. AB - Neural crest cells, which are specific to vertebrates, arise in the ectoderm but can generate cell types that are typically categorized as mesodermal. This broad developmental potential persists past the time when most ectoderm-derived cells become lineage-restricted. The ability of neural crest to contribute mesodermal derivatives to the bauplan has raised questions about how this apparent gain in potential is achieved. Here, we describe shared molecular underpinnings of potency in neural crest and blastula cells. We show that in Xenopus, key neural crest regulatory factors are also expressed in blastula animal pole cells and promote pluripotency in both cell types. We suggest that neural crest cells may have evolved as a consequence of a subset of blastula cells retaining activity of the regulatory network underlying pluripotency. PMID- 25931450 TI - State-of-the-Art Methods for Evaluation of Angiogenesis and Tissue Vascularization: A Scientific Statement From the American Heart Association. PMID- 25931451 TI - Pembrolizumab for Treatment of Patients with Advanced or Unresectable Melanoma. AB - From Coley's toxin to combination immune checkpoint inhibition, strategies to activate the immune system and generate anticancer immunity have been ongoing for well over a century. Over the past decade, the so-called immune checkpoint inhibitors, generally monoclonal antibodies that target key regulators of T-cell activation, emerged as the most effective immune-targeted agents. Pembrolizumab is the first anti-programmed death 1 (PD-1) antibody approved by the FDA for the treatment of metastatic melanoma. With responses seen in 25% to 40% of patients, depending on dose and setting (i.e., before or after ipilimumab), pembrolizumab specifically and anti-PD-1 antibodies generally are revolutionizing the treatment of melanoma. However, in the setting of other recent advances in the field, a number of practical issues are emerging that need to be addressed to optimize the care of patients with melanoma. First, the optimal sequencing of therapy (first line immunotherapy over molecular targeted therapy, ipilimumab versus pembrolizumab as initial immune checkpoint inhibitor) is unknown and must be evaluated through randomized trials. Second, there is a strong rationale to combine immune checkpoint inhibitors (i.e., anti-PD-1 with ipilimumab) and to combine immune therapies with targeted therapy agents, so determining whether combination therapy is better than direct sequencing is another critical issue that needs to be addressed in carefully carried out studies. PMID- 25931452 TI - PET Imaging in Head and Neck Cancer Patients to Monitor Treatment Response: A Future Role for EGFR-Targeted Imaging. AB - Approximately 50,000 new cases of head and neck squamous cell carcinoma (HNSCC) are diagnosed worldwide each year and subsequently treated with surgery, chemotherapy, radiotherapy, and/or targeted therapy. The heterogeneity of the patient population in terms of treatment response drives the search for tumor specific biomarkers. Imaging of biomarkers can reveal patient-specific responses to therapies and, if assessed early after the start of treatment, may allow adaptation of treatment regimens. In this review, tracers that have been tested to monitor treatment efficacy in HNSCC by PET scanning prior to and early after the onset of treatment are discussed. An important imaging target for this application in HNSCC patients is the EGFR. It steers the pathways related to proliferation, hypoxia, DNA damage repair, and apoptosis, all treatment resistance mechanisms. The anti-EGFR antibody cetuximab has been labeled with various radionuclides and has been tested as an imaging biomarker in several HNSCC models. These studies suggest that EGFR-targeting tracers can be used to monitor EGFR receptor expression in HNSCC and have the potential to noninvasively monitor cetuximab treatment and steer individualized treatment regimens. Multiple factors can influence the uptake of EGFR-targeting tracers. Here, we discuss the relevance of gene and protein overexpression, mutations, and amplifications related to EGFR signaling. In addition, monoclonal antibody properties and the effect on the host immune system are reviewed in light of the future role of EGFR targeted imaging in HNSCC. PMID- 25931453 TI - Synergistic Leukemia Eradication by Combined Treatment with Retinoic Acid and HIF Inhibition by EZN-2208 (PEG-SN38) in Preclinical Models of PML-RARalpha and PLZF RARalpha-Driven Leukemia. AB - PURPOSE: Retinoic acid-arsenic trioxide (ATRA-ATO) combination therapy is the current standard of care for patients with acute promyelocytic leukemia (APL) carrying the oncogenic fusion protein PML-RARalpha. Despite the high cure rates obtained with this drug combination, resistance to arsenic is recently emerging. Moreover, patients with APL carrying the PLZF-RARalpha fusion protein are partially resistant to ATRA treatment. Hypoxia-inducible factor-1alpha (HIF 1alpha) activation has been recently reported in APL, and EZN-2208 (PEG-SN38) is a compound with HIF-1alpha inhibitory function currently tested in clinical trials. This study investigates the effect of EZN-2208 in different preclinical APL models, either alone or in combination with ATRA. EXPERIMENTAL DESIGN: Efficacy of EZN-2208 in APL was measured in vitro by assessing expression of HIF 1alpha target genes, cell migration, clonogenicity, and differentiation, vis a vis the cytotoxic and cytostatic effects of this compound. In vivo, EZN-2208 was used in mouse models of APL driven by PML-RARalpha or PLZF-RARalpha, either alone or in combination with ATRA. RESULTS: Treatment of APL cell lines with noncytotoxic doses of EZN-2208 causes dose-dependent downregulation of HIF-1alpha bona fide target genes and affects cell migration and clonogenicity in methylcellulose. In vivo, EZN-2208 impairs leukemia progression and prolongs mice survival in APL mouse models. More importantly, when used in combination with ATRA, EZN-2208 synergizes in debulking leukemia and eradicating leukemia initiating cells. CONCLUSIONS: Our preclinical data suggest that the combination ATRA-EZN-2208 may be tested to treat patients with APL who develop resistance to ATO or patients carrying the PLZF-RARalpha fusion protein. PMID- 25931454 TI - Interference from 3-O-methyldopa with ultra-high performance LC-MS/MS measurements of plasma metanephrines: chromatographic separation remains important. PMID- 25931455 TI - Tandem mass spectrometric determination of atypical 3beta-hydroxy-Delta5-bile acids in patients with 3beta-hydroxy-Delta5-C27-steroid oxidoreductase deficiency: application to diagnosis and monitoring of bile acid therapeutic response. AB - BACKGROUND: 3beta-Hydroxy-Delta(5)-C27-steroid oxidoreductase (HSD3B7) deficiency, a progressive cholestatic liver disease, is the most common genetic defect in bile acid synthesis. Early diagnosis is important because patients respond to oral primary bile acid therapy, which targets the negative feedback regulation for bile acid synthesis to reduce the production of hepatotoxic 3beta hydroxy-Delta(5)-bile acids. These atypical bile acids are highly labile and difficult to accurately measure, yet a method for accurate determination of 3beta hydroxy-Delta(5)-bile acid sulfates is critical for dose titration and monitoring response to therapy. METHODS: We describe a electrospray ionization LC-MS/MS method for the direct measurement of atypical 3beta-hydroxy-Delta(5)-bile acid sulfates in urine from patients with HSD3B7 deficiency that overcomes the deficiencies of previously used GC-MS methods. RESULTS: Separation of sulfated 3beta-hydroxy-Delta(5)-bile acids was achieved by reversed-phase HPLC in a 12-min analytical run. The mean (SE) urinary concentration of the total 3beta-sulfated Delta(5)-cholenoic acids in patients with HSD3B7 deficiency was 4650 (1711) MUmol/L, approximately 1000-fold higher than in noncholestatic and cholestatic patients with intact primary bile acid synthesis. GC-MS was not reliable for measuring 3beta-hydroxy-Delta(5)-bile acid sulfates; however, direct analysis of urine by fast atom bombardment mass spectrometry yielded meaningful semiquantitative assessment of urinary excretion. CONCLUSIONS: The tandem mass spectrometry method described here for the measurement of 3beta-hydroxy-Delta(5) bile acid sulfates in urine can be applied to the diagnosis and accurate monitoring of responses to primary bile acid therapy in HSD3B7 patients. PMID- 25931456 TI - Light-intensity physical activities and mortality in the United States general population and CKD subpopulation. AB - BACKGROUND AND OBJECTIVES: Sedentary behavior is associated with increased mortality in the general population. Whether replacing sedentary behavior with low- or light-intensity activities confers a survival benefit in the general or CKD populations is unknown. DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS: This observational analysis of the 2003-2004 National Health and Nutrition Examination Survey examined the associations of low- and light-intensity activities with mortality. On the basis of the number of counts/min recorded by an accelerometer, durations of sedentary (<100/min), low (100-499/min), light (500-2019/min), and moderate/vigorous (>=2020/min) activity were defined and normalized to 60 minutes. The mortality associations of 2 min/hr less sedentary duration in conjunction with 2 min/hr more (tradeoff) spent in one of the low, light, or moderate/vigorous activity durations while controlling for the other two activity durations were examined in multivariable Cox regression models in the entire cohort and in the CKD subgroup. RESULTS: Of the 3626 participants included, 383 had CKD. The mean sedentary duration was 34.4+/-7.9 min/hr in the entire cohort and 40.8+/-6.8 in the CKD subgroup. Tradeoff of sedentary duration with low activity duration was not associated with mortality in the entire cohort or the CKD subgroup. Tradeoff of sedentary duration with light activity duration was associated with a lower hazard of death in the entire cohort (hazard ratio, 0.67; 95% confidence interval, 0.48 to 0.93) and CKD subgroup (hazard ratio, 0.59; 95% confidence interval, 0.35 to 0.98). Tradeoff of sedentary duration with moderate/vigorous activity duration had a nonsignificant lower hazard in the entire cohort and CKD subgroup. CONCLUSIONS: Patients with CKD are sedentary nearly two thirds of the time. Interventions that replace sedentary duration with an increase in light activity duration might confer a survival benefit. PMID- 25931457 TI - Follicle Online: an integrated database of follicle assembly, development and ovulation. AB - Folliculogenesis is an important part of ovarian function as it provides the oocytes for female reproductive life. Characterizing genes/proteins involved in folliculogenesis is fundamental for understanding the mechanisms associated with this biological function and to cure the diseases associated with folliculogenesis. A large number of genes/proteins associated with folliculogenesis have been identified from different species. However, no dedicated public resource is currently available for folliculogenesis-related genes/proteins that are validated by experiments. Here, we are reporting a database 'Follicle Online' that provides the experimentally validated gene/protein map of the folliculogenesis in a number of species. Follicle Online is a web-based database system for storing and retrieving folliculogenesis related experimental data. It provides detailed information for 580 genes/proteins (from 23 model organisms, including Homo sapiens, Mus musculus, Rattus norvegicus, Mesocricetus auratus, Bos Taurus, Drosophila and Xenopus laevis) that have been reported to be involved in folliculogenesis, POF (premature ovarian failure) and PCOS (polycystic ovary syndrome). The literature was manually curated from more than 43,000 published articles (till 1 March 2014). The Follicle Online database is implemented in PHP + MySQL + JavaScript and this user-friendly web application provides access to the stored data. In summary, we have developed a centralized database that provides users with comprehensive information about genes/proteins involved in folliculogenesis. This database can be accessed freely and all the stored data can be viewed without any registration. Database URL: http://mcg.ustc.edu.cn/sdap1/follicle/index.php PMID- 25931458 TI - NeuroPep: a comprehensive resource of neuropeptides. AB - Neuropeptides play a variety of roles in many physiological processes and serve as potential therapeutic targets for the treatment of some nervous-system disorders. In recent years, there has been a tremendous increase in the number of identified neuropeptides. Therefore, we have developed NeuroPep, a comprehensive resource of neuropeptides, which holds 5949 non-redundant neuropeptide entries originating from 493 organisms belonging to 65 neuropeptide families. In NeuroPep, the number of neuropeptides in invertebrates and vertebrates is 3455 and 2406, respectively. It is currently the most complete neuropeptide database. We extracted entries deposited in UniProt, the database (www.neuropeptides.nl) and NeuroPedia, and used text mining methods to retrieve entries from the MEDLINE abstracts and full text articles. All the entries in NeuroPep have been manually checked. 2069 of the 5949 (35%) neuropeptide sequences were collected from the scientific literature. Moreover, NeuroPep contains detailed annotations for each entry, including source organisms, tissue specificity, families, names, post translational modifications, 3D structures (if available) and literature references. Information derived from these peptide sequences such as amino acid compositions, isoelectric points, molecular weight and other physicochemical properties of peptides are also provided. A quick search feature allows users to search the database with keywords such as sequence, name, family, etc., and an advanced search page helps users to combine queries with logical operators like AND/OR. In addition, user-friendly web tools like browsing, sequence alignment and mapping are also integrated into the NeuroPep database. Database URL: http://isyslab.info/NeuroPep PMID- 25931460 TI - Sulcal effacement with preserved gray-white junction: a sign of reversible ischemia. AB - BACKGROUND AND PURPOSE: Sulcal effacement with preserved underlying gray-white matter junction (isolated sulcal effacement [ISE]) in acute ischemic stroke may not represent irreversible parenchymal injury. We aimed to evaluate the frequency and significance of ISE in patients with large vessel occlusion acute ischemic stroke. METHODS: Consecutive acute ischemic stroke patients with middle cerebral artery M1 or internal carotid artery terminus occlusions who underwent computed tomography angiogram/perfusion followed by intra-arterial therapy were screened for ISE. RESULTS: Out of the 568 patients who underwent intra-arterial therapy between March 2011 and September 2014, 108 fulfilled inclusion criteria. ISE was present in 8 (7.4%) patients (age 55.7+/-10.5 years, 6 female, baseline National Institutes of Health Stroke Scale 16.1+/-3.8, 5 middle cerebral artery-M1, and 3 internal carotid artery terminus occlusions). Computed tomography angiogram revealed engorged/dilated leptomeningeal vessels obliterating the sulci within the areas of effacement, whereas computed tomography perfusion indicated normal to-increased cerebral blood volume and prolonged Tmax in all patients. Modified treatment in cerebral ischemia (mTICI) 2b-3 reperfusion was achieved in all patients. Follow-up imaging confirmed no infarct in the ISE area in all patients, and 5 (62%) had modified Rankin Scale 0 to 2 at 3 months. CONCLUSIONS: Sulcal effacement with preserved gray-white delineation is occasionally visualized in patients with proximal occlusion strokes, relates to robust leptomeningeal collaterals, and indicates preserved underlying parenchyma. ISE should not be used to exclude patients from thrombectomy. PMID- 25931461 TI - Letter by Yang and Bai regarding article, "Safety of intravenous thrombolysis in stroke mimics: prospective 5-year study and comprehensive meta-analysis". PMID- 25931459 TI - novPTMenzy: a database for enzymes involved in novel post-translational modifications. AB - With the recent discoveries of novel post-translational modifications (PTMs) which play important roles in signaling and biosynthetic pathways, identification of such PTM catalyzing enzymes by genome mining has been an area of major interest. Unlike well-known PTMs like phosphorylation, glycosylation, SUMOylation, no bioinformatics resources are available for enzymes associated with novel and unusual PTMs. Therefore, we have developed the novPTMenzy database which catalogs information on the sequence, structure, active site and genomic neighborhood of experimentally characterized enzymes involved in five novel PTMs, namely AMPylation, Eliminylation, Sulfation, Hydroxylation and Deamidation. Based on a comprehensive analysis of the sequence and structural features of these known PTM catalyzing enzymes, we have created Hidden Markov Model profiles for the identification of similar PTM catalyzing enzymatic domains in genomic sequences. We have also created predictive rules for grouping them into functional subfamilies and deciphering their mechanistic details by structure based analysis of their active site pockets. These analytical modules have been made available as user friendly search interfaces of novPTMenzy database. It also has a specialized analysis interface for some PTMs like AMPylation and Eliminylation. The novPTMenzy database is a unique resource that can aid in discovery of unusual PTM catalyzing enzymes in newly sequenced genomes. Database URL: http://www.nii.ac.in/novptmenzy.html PMID- 25931462 TI - Effects of postinfarct myelin-associated glycoprotein antibody treatment on motor recovery and motor map plasticity in squirrel monkeys. AB - BACKGROUND AND PURPOSE: New insights into the brain's ability to reorganize after injury are beginning to suggest novel restorative therapy targets. Potential therapies include pharmacological agents designed to promote axonal growth. The purpose of this study was to test the efficacy of one such drug, GSK249320, a monoclonal antibody that blocks the axon outgrowth inhibition molecule, myelin associated glycoprotein, to facilitate recovery of motor skills in a nonhuman primate model of ischemic cortical damage. METHODS: Using a between-groups repeated-measures design, squirrel monkeys were randomized to 1 of 2 groups: an experimental group received intravenous GSK249320 beginning 24 hours after an ischemic infarct in motor cortex with repeated dosages given at 1-week intervals for 6 weeks and a control group received only the vehicle at matched time periods. The primary end point was a motor performance index based on a distal forelimb reach-and-retrieval task. Neurophysiological mapping techniques were used to determine changes in spared motor representations. RESULTS: All monkeys recovered to baseline motor performance levels by postinfarct day 16. Functional recovery in the experimental group was significantly facilitated on the primary end point, albeit using slower movements. At 7 weeks post infarct, motor maps in the spared ventral premotor cortex in the experimental group decreased in area compared with the control group. CONCLUSIONS: GSK249320, initiated 24 hours after a focal cortical ischemic infarct, facilitated functional recovery. Together with the neurophysiological data, these results suggest that GSK249320 has a substantial biological effect on spared cortical tissue. However, its mechanisms of action may be widespread and not strictly limited to peri-infarct cortex and nearby premotor areas. PMID- 25931463 TI - Circulating Tissue Factor Levels and Risk of Stroke: Findings From the EPICOR Study. AB - BACKGROUND AND PURPOSE: Tissue factor (TF) expression is increased in inflammatory atherosclerotic plaques and has been related to their thrombogenicity. Blood-borne TF has been also demonstrated to contribute to thrombogenesis. However, few studies have evaluated the association of circulating levels of TF with stroke. We investigated the association of baseline circulating levels of TF with stroke events occurred in the European Prospective Investigation into Cancer and Nutrition-Italy cohort. METHODS: Using a nested case-cohort design, a center-stratified random sample of 839 subjects (66% women; age range, 35-71 years) was selected as subcohort and compared with 292 strokes in a mean follow-up of 9 years. Blood samples were collected at baseline in citrate, plasma was stored in liquid nitrogen and TF was measured by ELISA (IMUBIND, TF ELISA, Instrumentation Laboratory, Milan, Italy). The odd ratios and 95% confidence intervals, adjusted by relevant confounders (covariates of TF) and stratified by center, were estimated by a Cox regression model using Prentice method. RESULTS: Individuals in the highest compared with the lowest quartile of TF plasma levels had significantly increased risk of stroke (odds ratioIVvsI quartile, 2.01; 95% confidence interval, 1.25-3.23). The association was independent from several potential confounders (odds ratioIVvsI quartile, 1.91; 95% confidence interval, 1.15-3.19). No differences were observed between men and women. The increase in risk was restricted to ischemic strokes (odds ratioIVvsI quartile, 2.13; 95% confidence interval, 1.10-4.12; fully adjusted model), whereas high levels of TF were not associated with the risk of hemorrhagic stroke (odds ratioIVvsI quartile, 1.12; 95% confidence interval, 0.49-2.55; fully adjusted model). CONCLUSIONS: Our data provide evidence that elevated levels of circulating TF are potential risk factors for ischemic strokes. PMID- 25931464 TI - Response to letter regarding article, "Safety of intravenous thrombolysis in stroke mimics: prospective 5-year study and comprehensive meta-analysis". PMID- 25931466 TI - Needed dialog: regionalization of stroke systems of care along the trauma model. PMID- 25931465 TI - Protective Role of Peroxisome Proliferator-Activated Receptor-gamma in the Development of Intracranial Aneurysm Rupture. AB - BACKGROUND AND PURPOSE: Inflammation is emerging as a key component of the pathophysiology of intracranial aneurysms. Peroxisome proliferator-activated receptor-gamma (PPARgamma) is a nuclear hormone receptor of which activation modulates various aspects of inflammation. METHODS: Using a mouse model of intracranial aneurysm, we examined the potential roles of PPARgamma in the development of rupture of intracranial aneurysm. RESULTS: A PPARgamma agonist, pioglitazone, significantly reduced the incidence of ruptured aneurysms and the rupture rate without affecting the total incidence aneurysm (unruptured aneurysms and ruptured aneurysms). PPARgamma antagonist (GW9662) abolished the protective effect of pioglitazone. The protective effect of pioglitazone was absent in mice lacking macrophage PPARgamma. Pioglitazone treatment reduced the mRNA levels of inflammatory cytokines (monocyte chemoattractant factor-1, interleukin-1, and interleukin-6) that are primarily produced by macrophages in the cerebral arteries. Pioglitazone treatment reduced the infiltration of M1 macrophage into the cerebral arteries and the macrophage M1/M2 ratio. Depletion of macrophages significantly reduced the rupture rate. CONCLUSIONS: Our data showed that the activation of macrophage PPARgamma protects against the development of aneurysmal rupture. PPARgamma in inflammatory cells may be a potential therapeutic target for the prevention of aneurysmal rupture. PMID- 25931467 TI - Diagnostic work-up for detection of paroxysmal atrial fibrillation after acute ischemic stroke: cross-sectional survey on German stroke units. AB - BACKGROUND AND PURPOSE: Multiple methods to detect paroxysmal atrial fibrillation (pAF) in patients with acute stroke are available. However, it is unknown which approaches are currently used in clinical routine and guidelines remain vague to the extent of cardiac monitoring. We characterize diagnostic efforts for pAF detection on German stroke units (SU). METHODS: A standardized anonymous questionnaire was sent to all clinical leads of certified SUs in Germany. The questionnaire focused on basic characteristics of SUs, procedures to detect AF, and estimates on AF detection. RESULTS: One hundred seventy-nine SU leads participated (response rate 71.6%). All patients undergo continuous bedside ECG monitoring. A percentage of 77.6 SUs initiate additional 24-hour Holter ECG in >50% of patients without known AF. Patients with transient ischemic attack are monitored significantly shorter than patients with ischemic stroke. Independent of SU type or size, 67.6% of leads assumed to fail detecting pAF in 5% to 20% of patients. In cryptogenic stroke, additional ECG monitoring is recommended by 90.2% but only 13.8% of SUs perform routine ECG follow-up visits. The use of implanted event recorders is low (1-10 patients/y by 60.7% of SUs; 28.1%: no use). A percentage of 83.9 do not use external event recorders. CONCLUSIONS: Our survey demonstrates substantial heterogeneity among German SUs on diagnostic work up for pAF. Future prospective multicenter studies should systematically evaluate the impact of different methods to uncover pAF. PMID- 25931468 TI - Protease-activated receptor 1 and 4 signal inhibition reduces preterm neonatal hemorrhagic brain injury. AB - BACKGROUND AND PURPOSE: This study examines the role of thrombin's protease activated receptor (PAR)-1, PAR-4 in mediating cyclooxygenase-2 and mammalian target of rapamycin after germinal matrix hemorrhage. METHODS: Germinal matrix hemorrhage was induced by intraparenchymal infusion of bacterial collagenase into the right ganglionic eminence of P7 rat pups. Animals were treated with PAR-1, PAR-4, cyclooxygenase-2, or mammalian target of rapamycin inhibitors by 1 hour, and <=5 days. RESULTS: We found increased thrombin activity 6 to 24 hours after germinal matrix hemorrhage, and PAR-1, PAR-4, inhibition normalized cyclooxygenase-2, and mammalian target of rapamycin by 72 hours. Early treatment with NS398 or rapamycin substantially improved long-term outcomes in juvenile animals. CONCLUSIONS: Suppressing early PAR signal transduction, and postnatal NS398 or rapamycin treatment, may help reduce germinal matrix hemorrhage severity in susceptible preterm infants. PMID- 25931469 TI - Raw arterial spin labeling data can help identify arterial occlusion in acute ischemic stroke. PMID- 25931470 TI - Motor control summer school: the first ten years. PMID- 25931471 TI - Hand motor control: maturing an immature science. AB - In the target article Mark Latash has argued that there is but a single bona-fide theory for hand motor control (referent configuration theory). If this is true, and research is often phenomenological, then we must admit that the science of hand motor control is immature. While describing observations under varying conditions is a crucial (but early) stage of the science of any field, it is also true that the key to maturing any science is to vigorously subject extant theories and budding laws to critical experimentation. If competing theories are absent at the present time is it time for scientists to focus their efforts on maturing the science of hand motor control through critical testing of this long standing theory (and related collections of knowledge such as the uncontrolled manifold)? PMID- 25931472 TI - Neural control of hand movements. AB - Most of our daily actions involve movements of the hand. The neuronal pathway contributing to the control of hand movements are complex and not yet completely understood. Recent studies highlight how task-dependent changes in cortical and subcortical pathways driven by contralateral and ipsilateral influences may open avenues to further understand the complexity of hand actions in healthy and disease. In the following section studies using transcranial magnetic and electrical stimulation in healthy subjects and in individuals with chronic incomplete spinal cord injury will be highlighted to further understand neuronal pathways involved in the control of voluntary activity by hand muscles. PMID- 25931473 TI - Novel Observations From Next-Generation RNA Sequencing of Highly Purified Human Adult and Fetal Islet Cell Subsets. AB - Understanding distinct gene expression patterns of normal adult and developing fetal human pancreatic alpha- and beta-cells is crucial for developing stem cell therapies, islet regeneration strategies, and therapies designed to increase beta cell function in patients with diabetes (type 1 or 2). Toward that end, we have developed methods to highly purify alpha-, beta-, and delta-cells from human fetal and adult pancreata by intracellular staining for the cell-specific hormone content, sorting the subpopulations by flow cytometry, and, using next-generation RNA sequencing, we report the detailed transcriptomes of fetal and adult alpha- and beta-cells. We observed that human islet composition was not influenced by age, sex, or BMI, and transcripts for inflammatory gene products were noted in fetal beta-cells. In addition, within highly purified adult glucagon-expressing alpha-cells, we observed surprisingly high insulin mRNA expression, but not insulin protein expression. This transcriptome analysis from highly purified islet alpha- and beta-cell subsets from fetal and adult pancreata offers clear implications for strategies that seek to increase insulin expression in type 1 and type 2 diabetes. PMID- 25931474 TI - Altered Phenotype of beta-Cells and Other Pancreatic Cell Lineages in Patients With Diffuse Congenital Hyperinsulinism in Infancy Caused by Mutations in the ATP Sensitive K-Channel. AB - Diffuse congenital hyperinsulinism in infancy (CHI-D) arises from mutations inactivating the KATP channel; however, the phenotype is difficult to explain from electrophysiology alone. Here we studied wider abnormalities in the beta cell and other pancreatic lineages. Islets were disorganized in CHI-D compared with controls. PAX4 and ARX expression was decreased. A tendency toward increased NKX2.2 expression was consistent with its detection in two-thirds of CHI-D delta cell nuclei, similar to the fetal pancreas, and implied immature delta-cell function. CHI-D delta-cells also comprised 10% of cells displaying nucleomegaly. In CHI-D, increased proliferation was most elevated in duct (5- to 11-fold) and acinar (7- to 47-fold) lineages. Increased beta-cell proliferation observed in some cases was offset by an increase in apoptosis; this is in keeping with no difference in INSULIN expression or surface area stained for insulin between CHI D and control pancreas. However, nuclear localization of CDK6 and P27 was markedly enhanced in CHI-D beta-cells compared with cytoplasmic localization in control cells. These combined data support normal beta-cell mass in CHI-D, but with G1/S molecules positioned in favor of cell cycle progression. New molecular abnormalities in delta-cells and marked proliferative increases in other pancreatic lineages indicate CHI-D is not solely a beta-cell disorder. PMID- 25931475 TI - Circulating TGF-beta1-Regulated miRNAs and the Risk of Rapid Progression to ESRD in Type 1 Diabetes. AB - We investigated whether circulating TGF-beta1-regulated miRNAs detectable in plasma are associated with the risk of rapid progression to end-stage renal disease (ESRD) in a cohort of proteinuric patients with type 1 diabetes (T1D) and normal eGFR. Plasma specimens obtained at entry to the study were examined in two prospective subgroups that were followed for 7-20 years (rapid progressors and nonprogressors), as well as a reference panel of normoalbuminuric T1D patients. Of the five miRNAs examined in this study, let-7c-5p and miR-29a-3p were significantly associated with protection against rapid progression and let-7b-5p and miR-21-5p were significantly associated with the increased risk of ESRD. In logistic analysis, controlling for HbA1c and other covariates, let-7c-5p and miR 29a-3p were associated with more than a 50% reduction in the risk of rapid progression (P <= 0.001), while let-7b-5p and miR-21-5p were associated with a >2.5-fold increase in the risk of ESRD (P <= 0.005). This study is the first prospective study to demonstrate that circulating TGF-beta1-regulated miRNAs are deregulated early in T1D patients who are at risk for rapid progression to ESRD. PMID- 25931476 TI - Encapsulation of alpha-Particle-Emitting 225Ac3+ Ions Within Carbon Nanotubes. AB - (225)Ac(3+) is a generator of alpha-particle-emitting radionuclides with 4 net alpha-particle decays that can be used therapeutically. Targeting (225)Ac(3+) by use of ligands conjugated to traditional bifunctional chelates limits the amount of (225)Ac(3+) that can be delivered. Ultrashort, single-walled carbon nanotubes (US-tubes), previously demonstrated as sequestering agents of trivalent lanthanide ions and small molecules, also successfully incorporate (225)Ac(3+). METHODS: Aqueous loading of both (225)Ac(3+) ions and Gd(3+) ions via bath sonication was used to construct (225)Ac@gadonanotubes ((225)Ac@GNTs). The (225)Ac@GNTs were subsequently challenged with heat, time, and human serum. RESULTS: US-tubes internally loaded with both (225)Ac(3+) ions and Gd(3+) ions show 2 distinct populations of (225)Ac(3+) ions: one rapidly lost in human serum and one that remains bound to the US-tubes despite additional challenge with heat, time, and serum. The presence of the latter population depended on cosequestration of Gd(3+) and (225)Ac(3+) ions. CONCLUSION: US-tubes successfully sequester (225)Ac(3+) ions in the presence of Gd(3+) ions and retain them after a human serum challenge, rendering (225)Ac@GNTs candidates for radioimmunotherapy for delivery of (225)Ac(3+) ions at higher concentrations than is currently possible for traditional ligand carriers. PMID- 25931477 TI - Safety of a Scout Dose Preceding Hepatic Radioembolization with 166Ho Microspheres. AB - Before (166)Ho radioembolization, a small batch of the same type of microspheres is administered as a scout dose instead of the conventional (99m)Tc macroaggregated albumin ((99m)Tc-MAA). The (166)Ho scout dose provides a more accurate and precise lung shunt assessment. However, in contrast to (99m)Tc-MAA, an unintended extrahepatic deposition of this beta-emitting scout dose could inflict radiation damage, the extent of which we aimed to quantify in this study. METHODS: All patients eligible for radioembolization in our institute between January 2011 and March 2014 were reviewed. Of the extrahepatic depositions of (99m)Tc-MAA on SPECT, the amount and volume were measured. These were used to calculate the theoretic absorbed dose in the case a (166)Ho scout dose had been used. The extrahepatic activity was measured as the sum of all voxels of the deposition. Volumes were measured using a threshold technique including all voxels from the maximum voxel intensity up to a certain percentage. The threshold needed to obtain the true volume was studied in a phantom study. RESULTS: In the phantom study, a threshold of 40% was found to overestimate the volume, with the consequence of underestimating the absorbed dose. Of 160 patients, 32 patients (34 cases) of extrahepatic deposition were identified. The depositions contained a median of 1.3% (range, 0.1%-19.5%) of the administered activity in a median volume of 6.8 mL (range, 1.1-42 mL). The use of a scout dose of 250 MBq of (166)Ho microspheres in these cases would theoretically have resulted in a median absorbed dose of 6.0 Gy (range, 0.9-374 Gy). The dose exceeded a limit of 49 Gy (reported in 2013) in 2 of 34 cases (5.9%; 95% confidence interval, 0.7%-20.1%) or 2 of 160 (1.3%; 95% confidence interval, 0.1%-4.7%) of all patients. In these 2 patients with a large absorbed dose (112 and 374 Gy), the culprit vessel was identified in 1 case. CONCLUSION: Extrahepatic deposition of a (166)Ho scout dose seems to be theoretically safe in most patients. Its safety in clinical practice is being evaluated in ongoing clinical trials. PMID- 25931478 TI - Lymphoscintigraphy and sentinel nodes. AB - It has been validated that sentinel lymph node biopsy (SLNB) shows whether a patient's breast cancer or melanoma has spread to regional lymph nodes. As a result, management of patients with these cancers has been revolutionized. SLNB has replaced axillary lymph node dissection (ALND) as the staging modality of choice for early breast cancer and has replaced complete lymph node dissection as the staging modality of choice for melanoma in patients whose SLNBs indicate no metastases. Recently concluded multicenter, randomized trials for breast cancer with 5- to 10-y outcome data have shown no significant differences in disease free survival rates or overall survival rates between SLNB and ALND groups but have shown significantly lower morbidity with SLNB than with ALND. The lowest false-negative rates (5.5%-6.7%) were seen in studies that used preoperative lymphoscintigraphy and dual mapping during surgery. To assess the survival impact of SLNB in melanoma, the Multicenter Selective Lymphadenectomy Trial I was performed. Melanoma-specific survival rates were not different between subjects randomized to SLNB with lymphadenectomy for nodal metastasis on biopsy and subjects randomized to observation with lymphadenectomy for nodal relapse. However, the 10-y disease-free survival rates were better for the SLNB group than for the observation group, specifically among patients with intermediate thickness melanomas or thick melanomas. PMID- 25931479 TI - Effects of Image Gently and the North American guidelines: administered activities in children at 13 North American pediatric hospitals. AB - The goal of this investigation was to assess the impact of the publication of the 2010 North American guidelines on the practice of nuclear medicine in children at 13 dedicated pediatric institutions within the United States and Canada by comparing results of similar surveys from 2007 and 2013. METHODS: In 2013, a follow-up survey was performed of the original 13 dedicated pediatric institutions initially surveyed in 2007. Both surveys inquired about the administered activities for 16 nuclear medicine procedures commonly performed on children. The administered activity per body mass, the maximum activity, and the minimum activity for patients for each procedure were requested from each site. For each parameter the minimum and maximum reported values, as well as the median and the mean, were tabulated. The mean difference in the mean between 2007 and 2013 was calculated, as well as the 95% confidence intervals for the mean administered activity per body mass for both years. The factor of variation used with the previous survey for each parameter was calculated by taking the ratio of the maximum and minimum reported values. For the 8 procedures addressed in the 2010 North American guidelines, the percentage of institutions that were compliant (defined as within 20%) for each parameter were noted for both surveys. Institutions were asked whether they were familiar with "Image Gently," the North American guidelines, and the "Go with the Guidelines" campaign and whether they adjusted their administered activities on the basis of these guidelines. RESULTS: In general, the 13 pediatric institutions have reduced their administered activities in children, particularly for those procedures addressed by the 2010 North American guidelines. The average variability in the activity per body mass and the minimum activity as measured by the factor of variation were substantially reduced by 9.7% (from 3.1 to 2.8) and 24% (from 10.0 to 7.6). The average variability of the maximum activity was increased by 6.1% (from 3.3 to 3.5), but the increase was mostly due to some sites reducing their limits while others maintained their previous values. For the 8 procedures addressed by the guidelines, half or more of the institutions were compliant (within 20%) with the associated parameters in 66% of the cases. Ten of the 13 institutions reported that they adjusted their administered activities according to the North American guidelines. CONCLUSION: The publication of these guidelines and the associated public relations program appear to have had a positive effect with regard to both dose optimization and procedure standardization in pediatric nuclear medicine. PMID- 25931480 TI - Human Radiation Dosimetry for the N-Methyl-D-Aspartate Receptor Radioligand 11C CNS5161. AB - (11)C-CNS5161 (N-(2-chloro-5-methylthiophenyl)-N'-(3-methylthiophenyl)-N'-(11)C methylguanidine) has been successfully used in PET imaging of N-methyl-d aspartate (NMDA) receptors. However, no human dosimetry data have been published. We are planning to use this radiotracer for investigating NMDA receptor function in systemic lupus erythematosus, traumatic brain injury, and Parkinson disease. We have therefore undertaken (11)C-CNS5161 PET imaging to measure the whole-body distribution of this radionuclide and to estimate radiation dose to various organs. METHODS: Dynamic PET studies of the whole body were performed on 5 healthy adults. Regions of interest were drawn over the visualized structures. Resultant time-activity curves were generated and used to determine residence times for dosimetry calculations. S factors were implemented within the OLINDA/EXM software for each structure or organ. RESULTS: For (11)C-CNS5161, organ doses ranged from 0.0002 to 0.0393 mGy/MBq (0.0006-0.1455 rad/mCi). The critical organ for radiation burden was the lungs, with a dose of 0.0393 mGy/MBq (0.1455 rad/mCi). Radiation doses to the reproductive and blood-forming organs were 0.0023, 0.0002, and 0.0020 mGy/MBq (0.0086, 0.0006, and 0.0074 rad/mCi) for the ovaries, testes, and red marrow, respectively. The effective dose equivalent was 0.0106 mSv/MBq (0.0392 rem/mCi). CONCLUSION: The radiation dosimetry for (11)C-CNS5161 for a standard single injection of 555 MBq (15 mCi) will result in an effective dose equivalent of 5.9 mSv (0.59 rem) and a lung dose of 21.8 mGy (2.18 rad) in young, healthy subjects. PMID- 25931481 TI - Barriers to new drug development in respiratory disease. PMID- 25931482 TI - Combination therapy in idiopathic pulmonary fibrosis: the way ahead will be hard. PMID- 25931483 TI - What is new about Rio? PMID- 25931484 TI - Lung cancer in never-smokers. PMID- 25931485 TI - Where do we go from here? Clinical drug development in idiopathic pulmonary fibrosis. PMID- 25931486 TI - Development of a syllabus for postgraduate respiratory physiotherapy education: the Respiratory Physiotherapy HERMES project. PMID- 25931487 TI - A free lung health check for the European Parliament: Healthy Lungs for Life. PMID- 25931489 TI - Increased serum levels of LL37, HMGB1 and S100A9 during exacerbation in COPD patients. PMID- 25931490 TI - Inspiratory muscle function, dynamic hyperinflation and exertional dyspnoea in pulmonary arterial hypertension. PMID- 25931491 TI - Cough hypersensitivity syndrome: clinical measurement is the key to progress. PMID- 25931492 TI - Cough hypersensitivity syndrome: clinical measurement is the key to progress. PMID- 25931493 TI - Screening for latent tuberculosis before tumour necrosis factor antagonist therapy. PMID- 25931494 TI - Screening for latent tuberculosis before tumour necrosis factor antagonist therapy. PMID- 25931495 TI - Are C-reactive protein levels associated with bacteria in COPD exacerbations? PMID- 25931496 TI - Are C-reactive protein levels associated with bacteria in COPD exacerbations? PMID- 25931497 TI - Erratum. PMID- 25931499 TI - Backward- and forward-looking responsibility for obesity: policies from WHO, the EU and England. AB - BACKGROUND: In assigning responsibility for obesity prevention a distinction may be drawn between who is responsible for the rise in obesity prevalence ('backward looking responsibility'), and who is responsible for reducing it ('forward looking responsibility'). METHODS: We study how the two aspects of responsibility figure in the obesity policies of WHO (European Region), the EU and the Department of Health (England). RESULTS: Responsibility for the emergence and reduction of obesity is assigned to both individuals and other actors to different degrees in the policies, combining an individual and a systemic view. The policies assign backward-looking responsibility to individuals, the social environment, the authorities and businesses. When it comes to forward-looking responsibility, individuals are expected to play a central role in reducing and preventing obesity, but other actors are also urged to act. WHO assigns to individuals the lowest degree of backward- and forward-looking responsibility, and the Department of Health (England) assigns them the highest degree of responsibility. DISCUSSION: Differences in the assignment of backward- and above all forward-looking responsibility could be explained to some extent by the different roles of the three authorities making the plans. WHO is a UN agency with health as its goal, the EU is a liberal economic union with optimization of the internal European market as an important task, and England, as an independent sovereign country, has its own economic responsibilities. PMID- 25931500 TI - Play ball! PMID- 25931501 TI - Association of equipment worn and concussion injury rates in National Collegiate Athletic Association football practices: 2004-2005 to 2008-2009 academic years. AB - BACKGROUND: The epidemiology of football-related concussions has been extensively examined. However, although football players experience more at-risk exposure time during practices than competitions, there is a dearth of literature examining the nature of the activities or equipment worn during practice. In particular, varying levels of equipment worn during practices may place players at varying levels of risk for concussion. PURPOSE: To describe the epidemiology of NCAA men's football concussions that occurred during practices from the 2004 2005 to 2008-2009 academic years by amount of equipment worn. STUDY DESIGN: Descriptive epidemiology study. METHODS: Men's collegiate football data from the National Collegiate Athletic Association Injury Surveillance System (NCAA ISS) during the 5-year study period were analyzed. Injury rates and injury rate ratios (RRs) were reported with 95% confidence intervals. RESULTS: During the study period, 795 concussions were reported during practices, resulting in an injury rate of 0.39 per 1000 athlete-exposures (AEs) (95% CI, 0.36-0.42). Among NCAA divisions, Division III had the highest concussion rate (0.54/1000 AEs), followed by Division I (0.34/1000 AEs) and Division II (0.24/1000 AEs) (all P values for RRs comparing divisions<.001). Most concussions in practice occurred when players were fully padded (69.9%), followed by wearing shells (23.5%) and helmets only (1.9%). The practice concussion rate was higher in fully padded practices (0.66/1000 AEs) compared with practices when shells were worn (0.33/1000 AEs; RR=1.99 [95% CI, 1.69-2.35]; P<.001) and practices when only helmets were worn (0.03/1000 AEs; RR=22.39 [95% CI, 13.41-37.39]; P<.001). The practice concussion rate of the preseason (0.76/1000 AEs) was higher than that of the regular season (0.18/1000 AEs; RR=4.14 [95% CI, 3.55-4.83]; P<.001) and that of postseason (0.25/1000 AEs; RR=3.02 [95% CI, 1.95-4.67]; P<.001). The types of practice with the highest concussion rate were scrimmages (1.55/1000 AEs). Although only 3 concussions were sustained during scrimmage practices in which players wore shells, the concussion rate (2.84/1000 AEs) was higher than all other reported rates. CONCLUSION: Practice concussion rates are highest during fully padded practices, preseason practices, and scrimmages, suggesting that the nature, focus, and intensity of football practices affect concussion risk. In addition, coaching staff should continue to closely monitor player safety during scrimmages. Meanwhile, future surveillance should examine whether removing scrimmages, particularly those that are not fully padded, will meaningfully reduce the incidence and rate of concussions. PMID- 25931502 TI - In memoriam: Cyril B. Frank, MD (1949-2015). PMID- 25931505 TI - Corrigendum. PMID- 25931506 TI - Immediate versus delayed meniscus allograft transplantation: letter to the editor. PMID- 25931507 TI - Immediate versus delayed meniscus allograft transplantation: response. PMID- 25931508 TI - Sequential Elution Interactome Analysis of the Mind Bomb 1 Ubiquitin Ligase Reveals a Novel Role in Dendritic Spine Outgrowth. AB - The mind bomb 1 (Mib1) ubiquitin ligase is essential for controlling metazoan development by Notch signaling and possibly the Wnt pathway. It is also expressed in postmitotic neurons and regulates neuronal morphogenesis and synaptic activity by mechanisms that are largely unknown. We sought to comprehensively characterize the Mib1 interactome and study its potential function in neuron development utilizing a novel sequential elution strategy for affinity purification, in which Mib1 binding proteins were eluted under different stringency and then quantified by the isobaric labeling method. The strategy identified the Mib1 interactome with both deep coverage and the ability to distinguish high-affinity partners from low-affinity partners. A total of 817 proteins were identified during the Mib1 affinity purification, including 56 high-affinity partners and 335 low affinity partners, whereas the remaining 426 proteins are likely copurified contaminants or extremely weak binding proteins. The analysis detected all previously known Mib1-interacting proteins and revealed a large number of novel components involved in Notch and Wnt pathways, endocytosis and vesicle transport, the ubiquitin-proteasome system, cellular morphogenesis, and synaptic activities. Immunofluorescence studies further showed colocalization of Mib1 with five selected proteins: the Usp9x (FAM) deubiquitinating enzyme, alpha-, beta-, and delta-catenins, and CDKL5. Mutations of CDKL5 are associated with early infantile epileptic encephalopathy-2 (EIEE2), a severe form of mental retardation. We found that the expression of Mib1 down-regulated the protein level of CDKL5 by ubiquitination, and antagonized CDKL5 function during the formation of dendritic spines. Thus, the sequential elution strategy enables biochemical characterization of protein interactomes; and Mib1 analysis provides a comprehensive interactome for investigating its role in signaling networks and neuronal development. PMID- 25931510 TI - Adenylyl cyclases 5 and 6 underlie PIP3-dependent regulation. AB - Many different neurotransmitters and hormones control intracellular signaling by regulating the production of the second messenger cAMP. The function of the broadly expressed adenylyl cyclases (ACs) 5 and 6 is regulated by either stimulatory or inhibitory G proteins. By analyzing a well-known rebound stimulation phenomenon after withdrawal of Gi protein in atrial myocytes, we discovered that AC5 and -6 are tightly regulated by the second messenger PIP3. By monitoring cAMP levels in real time by means of Forster resonance energy transfer (FRET)-based biosensors, we reproduced the rebound stimulation in a heterologous expression system specifically for AC5 or -6. Strikingly, this cAMP rebound stimulation was completely blocked by the PI3K inhibitor wortmannin, both in atrial myocytes and in transfected human embryonic kidney cells. Similar effects were observed by heterologous expression of the PIP3 phosphatase and tensin homolog (PTEN). However, general kinase inhibitors or inhibitors of Akt had no effect, suggesting a PIP3-dependent mechanism. These findings demonstrate the existence of a novel general pathway for regulation of AC5 and -6 activity via PIP3 that leads to pronounced alterations of cytosolic cAMP levels. PMID- 25931509 TI - Architecture of a Host-Parasite Interface: Complex Targeting Mechanisms Revealed Through Proteomics. AB - Surface membrane organization and composition is key to cellular function, and membrane proteins serve many essential roles in endocytosis, secretion, and cell recognition. The surface of parasitic organisms, however, is a double-edged sword; this is the primary interface between parasites and their hosts, and those crucial cellular processes must be carried out while avoiding elimination by the host immune defenses. For extracellular African trypanosomes, the surface is partitioned such that all endo- and exocytosis is directed through a specific membrane region, the flagellar pocket, in which it is thought the majority of invariant surface proteins reside. However, very few of these proteins have been identified, severely limiting functional studies, and hampering the development of potential treatments. Here we used an integrated biochemical, proteomic and bioinformatic strategy to identify surface components of the human parasite Trypanosoma brucei. This surface proteome contains previously known flagellar pocket proteins as well as multiple novel components, and is significantly enriched in proteins that are essential for parasite survival. Molecules with receptor-like properties are almost exclusively parasite-specific, whereas transporter-like proteins are conserved in model organisms. Validation shows that the majority of surface proteome constituents are bona fide surface-associated proteins and, as expected, most present at the flagellar pocket. Moreover, the largest systematic analysis of trypanosome surface molecules to date provides evidence that the cell surface is compartmentalized into three distinct domains with free diffusion of molecules in each, but selective, asymmetric traffic between. This work provides a paradigm for the compartmentalization of a cell surface and a resource for its analysis. PMID- 25931511 TI - Choline Transporter-Like Protein-2: New von Willebrand Factor-Binding Partner Involved in Antibody-Mediated Neutrophil Activation and Transfusion-Related Acute Lung Injury. AB - OBJECTIVE: In contrast to other antibodies involved in transfusion-related acute lung injury, anti-HNA-3a antibodies are incapable of inducing direct neutrophil activation and seem to interact with endothelial cells (ECs) primarily. In animal studies, anti-HNA-3a-mediated transfusion-related acute lung injury could be precipitated in the absence of neutrophils, but was stronger when neutrophils were present. In a different context the target protein of these antibodies, choline transporter-like protein-2 (CTL-2), was reported to interact with a protein of the inner ear carrying 2 von Willebrand factor (VWF) A-domains. These observations prompted us to investigate whether VWF might be involved in anti-HNA 3a-mediated neutrophil activation, and whether signaling via CD11b/CD18 is involved, as in various other experimental settings. APPROACH AND RESULTS: Cell adhesion demonstrated specific binding of CTL-2 to VWF. Immunoprecipitation analysis of CTL-2/CD11b/CD18 coexpressing cells indicated that anti-HNA-3a colocalizes CTL-2 and CD11b/CD18 when VWF is present. Functional studies revealed that anti-HNA-3a-mediated neutrophil agglutination is an active, protein kinase C dependent and partially Fc-dependent process. Agglutination and the production of reactive oxygen species seem to require the formation of a trimolecular complex between the target antigen (CTL-2), CD11b/CD18 and VWF. In line with these observations, anti-HNA-3a induced less severe transfusion-related acute lung injury and less neutrophil recruitment to the alveolar space in VWF knockout mice. CONCLUSIONS: We introduce CTL-2 as a new binding partner for VWF. Interaction of neutrophils with VWF via CTL-2 allows anti-HNA-3a to induce signal transduction via CD11b/CD18, which leads to neutrophil activation and agglutination. In transfusion-related acute lung injury, this mechanism may further aggravate endothelial leakage. PMID- 25931512 TI - Deficiency in Melanocortin 1 Receptor Signaling Predisposes to Vascular Endothelial Dysfunction and Increased Arterial Stiffness in Mice and Humans. AB - OBJECTIVE: The melanocortin 1 receptor (MC1-R) is expressed by vascular endothelial cells and shown to enhance nitric oxide (NO) availability and vasodilator function on pharmacological stimulation. However, the physiological role of MC1-R in the endothelium and its contribution to vascular homeostasis remain unresolved. We investigated whether a lack of functional MC1-R signaling carries a phenotype with predisposition to vascular abnormalities. APPROACH AND RESULTS: Recessive yellow mice (MC1R(e/e)), deficient in MC1-R signaling, and their wild-type littermates were studied for morphology and functional characteristics of the aorta. MC1R(e/e) mice showed increased collagen deposition and arterial stiffness accompanied by an elevation in pulse pressure. Contractile capacity and NO-dependent vasodilatation were impaired in the aorta of MC1R(e/e) mice supported by findings of decreased NO availability. These mice also displayed elevated levels of systemic and local cytokines. Exposing the mice to high-sodium diet or acute endotoxemia revealed increased susceptibility to inflammation-driven vascular dysfunction. Finally, we investigated whether a similar phenotype can be found in healthy human subjects carrying variant MC1-R alleles known to attenuate receptor function. In a longitudinal analysis of 2001 subjects with genotype and ultrasound data (The Cardiovascular Risk in Young Finns Study), weak MC1-R function was associated with lower flow-mediated dilatation response of the brachial artery and increased carotid artery stiffness. CONCLUSIONS: The present study demonstrates that deficiency in MC1-R signaling is associated with increased arterial stiffness and impairment in endothelium-dependent vasodilatation, suggesting a physiological role for MC1-R in the regulation of arterial tone. PMID- 25931513 TI - Key Role of Amino Acid Repeat Expansions in the Functional Diversification of Duplicated Transcription Factors. AB - The high regulatory complexity of vertebrates has been related to two rounds of whole genome duplication (2R-WGD) that occurred before the divergence of the major vertebrate groups. Following these events, many developmental transcription factors (TFs) were retained in multiple copies and subsequently specialized in diverse functions, whereas others reverted to their singleton state. TFs are known to be generally rich in amino acid repeats or low-complexity regions (LCRs), such as polyalanine or polyglutamine runs, which can evolve rapidly and potentially influence the transcriptional activity of the protein. Here we test the hypothesis that LCRs have played a major role in the diversification of TF gene duplicates. We find that nearly half of the TF gene families originated during the 2R-WGD contains LCRs. The number of gene duplicates with LCRs is 155 out of 550 analyzed (28%), about twice as many as the number of single copy genes with LCRs (15 out of 115, 13%). In addition, duplicated TFs preferentially accumulate certain LCR types, the most prominent of which are alanine repeats. We experimentally test the role of alanine-rich LCRs in two different TF gene families, PHOX2A/PHOX2B and LHX2/LHX9. In both cases, the presence of the alanine rich LCR in one of the copies (PHOX2B and LHX2) significantly increases the capacity of the TF to activate transcription. Taken together, the results provide strong evidence that LCRs are important driving forces of evolutionary change in duplicated genes. PMID- 25931515 TI - Relaxing the Molecular Clock to Different Degrees for Different Substitution Types. AB - Rates of molecular evolution can vary over time. Diverse statistical techniques for divergence time estimation have been developed to accommodate this variation. These typically require that all sequence (or codon) positions at a locus change independently of one another. They also generally assume that the rates of different types of nucleotide substitutions vary across a phylogeny in the same way. This permits divergence time estimation procedures to employ an instantaneous rate matrix with relative rates that do not differ among branches. However, previous studies have suggested that some substitution types (e.g., CpG to TpG changes in mammals) are more clock-like than others. As has been previously noted, this is biologically plausible given the mutational mechanism of CpG to TpG changes. Through stochastic mapping of sequence histories from context-independent substitution models, our approach allows for context dependent nucleotide substitutions to change their relative rates over time. We apply our approach to the analysis of a 0.15 Mb intergenic region from eight primates. In accord with previous findings, we find comparatively little rate variation over time for CpG to TpG substitutions but we find more for other substitution types. We conclude by discussing the limitations and prospects of our approach. PMID- 25931514 TI - Mitonuclear Ecology. AB - Eukaryotes were born of a chimeric union between two prokaryotes--the progenitors of the mitochondrial and nuclear genomes. Early in eukaryote evolution, most mitochondrial genes were lost or transferred to the nucleus, but a core set of genes that code exclusively for products associated with the electron transport system remained in the mitochondrion. The products of these mitochondrial genes work in intimate association with the products of nuclear genes to enable oxidative phosphorylation and core energy production. The need for coadaptation, the challenge of cotransmission, and the possibility of genomic conflict between mitochondrial and nuclear genes have profound consequences for the ecology and evolution of eukaryotic life. An emerging interdisciplinary field that I call "mitonuclear ecology" is reassessing core concepts in evolutionary ecology including sexual reproduction, two sexes, sexual selection, adaptation, and speciation in light of the interactions of mitochondrial and nuclear genomes. PMID- 25931516 TI - 'Flatten plus': a recent implementation in WSxM for biological research. AB - Scanning probe microscopy (SPM) is already a relevant tool in biological research at the nanoscale. We present 'Flatten plus', a recent and helpful implementation in the well-known WSxM free software package. 'Flatten plus' allows reducing low frequency noise in SPM images in a semi-automated way preventing the appearance of typical artifacts associated with such filters. AVAILABILITY AND IMPLEMENTATION: WSxM is a free software implemented in C++ supported on MS Windows, but it can also be run under Mac or Linux using emulators such as Wine or Parallels. WSxM can be downloaded from http://www.wsxmsolutions.com/. CONTACT: ignacio.horcas@wsxmsolutions.com. PMID- 25931517 TI - RVD2: an ultra-sensitive variant detection model for low-depth heterogeneous next generation sequencing data. AB - MOTIVATION: Next-generation sequencing technology is increasingly being used for clinical diagnostic tests. Clinical samples are often genomically heterogeneous due to low sample purity or the presence of genetic subpopulations. Therefore, a variant calling algorithm for calling low-frequency polymorphisms in heterogeneous samples is needed. RESULTS: We present a novel variant calling algorithm that uses a hierarchical Bayesian model to estimate allele frequency and call variants in heterogeneous samples. We show that our algorithm improves upon current classifiers and has higher sensitivity and specificity over a wide range of median read depth and minor allele fraction. We apply our model and identify 15 mutated loci in the PAXP1 gene in a matched clinical breast ductal carcinoma tumor sample; two of which are likely loss-of-heterozygosity events. AVAILABILITY AND IMPLEMENTATION: http://genomics.wpi.edu/rvd2/. CONTACT: pjflaherty@wpi.edu SUPPLEMENTARY INFORMATION: Supplementary data are available at Bioinformatics online. PMID- 25931519 TI - AMG 595, an Anti-EGFRvIII Antibody-Drug Conjugate, Induces Potent Antitumor Activity against EGFRvIII-Expressing Glioblastoma. AB - Epidermal growth factor receptor variant III (EGFRvIII) is a cancer-specific deletion mutant observed in approximately 25% to 50% of glioblastoma multiforme (GBM) patients. An antibody drug conjugate, AMG 595, composed of the maytansinoid DM1 attached to a highly selective anti-EGFRvIII antibody via a noncleavable linker, was developed to treat EGFRvIII-positive GBM patients. AMG 595 binds to the cell surface and internalizes into the endo-lysosomal pathway of EGFRvIII expressing cells. Incubation of AMG 595 with U251 cells expressing EGFRvIII led to potent growth inhibition. AMG 595 treatment induced significant tumor mitotic arrest, as measured by phospho-histone H3, in GBM subcutaneous xenografts expressing EGFRvIII. A single intravenous injection of AMG 595 at 17 mg/kg (250 MUg DM1/kg) generated complete tumor regression in the U251vIII subcutaneous xenograft model. AMG 595 mediated tumor regression in the D317 subcutaneous xenograft model that endogenously expresses EGFRvIII. Finally, AMG 595 treatment inhibited the growth of D317 xenografts orthotopically implanted into the brain as determined by magnetic resonance imaging. These results demonstrate that AMG 595 is a promising candidate to evaluate in EGFRvIII-expressing GBM patients. PMID- 25931518 TI - Combined Inhibition of Cyclin-Dependent Kinases (Dinaciclib) and AKT (MK-2206) Blocks Pancreatic Tumor Growth and Metastases in Patient-Derived Xenograft Models. AB - KRAS is activated by mutation in the vast majority of cases of pancreatic cancer; unfortunately, therapeutic attempts to inhibit KRAS directly have been unsuccessful. Our previous studies showed that inhibition of cyclin-dependent kinase 5 (CDK5) reduces pancreatic cancer growth and progression, through blockage of the centrally important RAL effector pathway, downstream of KRAS. In the current study, the therapeutic effects of combining the CDK inhibitor dinaciclib (SCH727965; MK-7965) with the pan-AKT inhibitor MK-2206 were evaluated using orthotopic and subcutaneous patient-derived human pancreatic cancer xenograft models. The combination of dinaciclib (20 mg/kg, i.p., three times a week) and MK-2206 (60 mg/kg, orally, three times a week) dramatically blocked tumor growth and metastasis in all eight pancreatic cancer models examined. Remarkably, several complete responses were induced by the combination treatment of dinaciclib and MK-2206. The striking results obtained in these models demonstrate that the combination of dinaciclib with the pan-AKT inhibitor MK-2206 is promising for therapeutic evaluation in pancreatic cancer, and strongly suggest that blocking RAL in combination with other effector pathways downstream from KRAS may provide increased efficacy in pancreatic cancer. Based on these data, an NCI-CTEP-approved multicenter phase I clinical trial for pancreatic cancer of the combination of dinaciclib and MK-2206 (NCT01783171) has now been opened. PMID- 25931520 TI - 13C Tracking after 13CO2 Supply Revealed Diurnal Patterns of Wood Formation in Aspen. AB - Wood of trees is formed from carbon assimilated in the photosynthetic tissues. Determining the temporal dynamics of carbon assimilation, subsequent transport into developing wood, and incorporation to cell walls would further our understanding of wood formation in particular and tree growth in general. To investigate these questions, we designed a (13)CO2 labeling system to study carbon transport and incorporation to developing wood of hybrid aspen (Populus tremula * tremuloides). Tracking of (13)C incorporation to wood over a time course using nuclear magnetic resonance spectroscopy revealed diurnal patterns in wood cell wall biosynthesis. The dark period had a differential effect on (13)C incorporation to lignin and cell wall carbohydrates. No (13)C was incorporated into aromatic amino acids of cell wall proteins in the dark, suggesting that cell wall protein biosynthesis ceased during the night. The results show previously unrecognized temporal patterns in wood cell wall biosynthesis, suggest diurnal cycle as a possible cue in the regulation of carbon incorporation to wood, and establish a unique (13)C labeling method for the analysis of wood formation and secondary growth in trees. PMID- 25931521 TI - Induction of Photosynthetic Carbon Fixation in Anoxia Relies on Hydrogenase Activity and Proton-Gradient Regulation-Like1-Mediated Cyclic Electron Flow in Chlamydomonas reinhardtii. AB - The model green microalga Chlamydomonas reinhardtii is frequently subject to periods of dark and anoxia in its natural environment. Here, by resorting to mutants defective in the maturation of the chloroplastic oxygen-sensitive hydrogenases or in Proton-Gradient Regulation-Like1 (PGRL1)-dependent cyclic electron flow around photosystem I (PSI-CEF), we demonstrate the sequential contribution of these alternative electron flows (AEFs) in the reactivation of photosynthetic carbon fixation during a shift from dark anoxia to light. At light onset, hydrogenase activity sustains a linear electron flow from photosystem II, which is followed by a transient PSI-CEF in the wild type. By promoting ATP synthesis without net generation of photosynthetic reductants, the two AEF are critical for restoration of the capacity for carbon dioxide fixation in the light. Our data also suggest that the decrease in hydrogen evolution with time of illumination might be due to competition for reduced ferredoxins between ferredoxin-NADP(+) oxidoreductase and hydrogenases, rather than due to the sensitivity of hydrogenase activity to oxygen. Finally, the absence of the two alternative pathways in a double mutant pgrl1 hydrogenase maturation factor G-2 is detrimental for photosynthesis and growth and cannot be compensated by any other AEF or anoxic metabolic responses. This highlights the role of hydrogenase activity and PSI-CEF in the ecological success of microalgae in low-oxygen environments. PMID- 25931523 TI - Soundscapes offer unique opportunities for studies of fish communities. PMID- 25931522 TI - An R2R3-MYB Transcription Factor Regulates Eugenol Production in Ripe Strawberry Fruit Receptacles. AB - Eugenol is a volatile phenylpropanoid that contributes to flower and ripe fruit scent. In ripe strawberry (Fragaria * ananassa) fruit receptacles, eugenol is biosynthesized by eugenol synthase (FaEGS2). However, the transcriptional regulation of this process is still unknown. We have identified and functionally characterized an R2R3 MYB transcription factor (emission of benzenoid II [FaEOBII]) that seems to be the orthologous gene of PhEOBII from Petunia hybrida, which contributes to the regulation of eugenol biosynthesis in petals. The expression of FaEOBII was ripening related and fruit receptacle specific, although high expression values were also found in petals. This expression pattern of FaEOBII correlated with eugenol content in both fruit receptacle and petals. The expression of FaEOBII was repressed by auxins and activated by abscisic acid, in parallel to the ripening process. In ripe strawberry receptacles, where the expression of FaEOBII was silenced, the expression of cinnamyl alcohol dehydrogenase1 and FaEGS2, two structural genes involved in eugenol production, was down-regulated. A subsequent decrease in eugenol content in ripe receptacles was also observed, confirming the involvement of FaEOBII in eugenol metabolism. Additionally, the expression of FaEOBII was under the control of FaMYB10, another R2R3 MYB transcription factor that regulates the early and late biosynthetic genes from the flavonoid/phenylpropanoid pathway. In parallel, the amount of eugenol in FaMYB10-silenced receptacles was also diminished. Taken together, these data indicate that FaEOBII plays a regulating role in the volatile phenylpropanoid pathway gene expression that gives rise to eugenol production in ripe strawberry receptacles. PMID- 25931524 TI - Pools and Pols: Mechanism of a mutator phenotype. PMID- 25931525 TI - Structural details of the OxyR peroxide-sensing mechanism. AB - OxyR, a bacterial peroxide sensor, is a LysR-type transcriptional regulator (LTTR) that regulates the transcription of defense genes in response to a low level of cellular H2O2. Consisting of an N-terminal DNA-binding domain (DBD) and a C-terminal regulatory domain (RD), OxyR senses H2O2 with conserved cysteine residues in the RD. However, the precise mechanism of OxyR is not yet known due to the absence of the full-length (FL) protein structure. Here we determined the crystal structures of the FL protein and RD of Pseudomonas aeruginosa OxyR and its C199D mutant proteins. The FL crystal structures revealed that OxyR has a tetrameric arrangement assembled via two distinct dimerization interfaces. The C199D mutant structures suggested that new interactions that are mediated by cysteine hydroxylation induce a large conformational change, facilitating intramolecular disulfide-bond formation. More importantly, a bound H2O2 molecule was found near the Cys199 site, suggesting the H2O2-driven oxidation mechanism of OxyR. Combined with the crystal structures, a modeling study suggested that a large movement of the DBD is triggered by structural changes in the regulatory domains upon oxidation. Taken together, these findings provide novel concepts for answering key questions regarding OxyR in the H2O2-sensing and oxidation dependent regulation of antioxidant genes. PMID- 25931527 TI - Transparency versus harassment. PMID- 25931529 TI - Seismology. Nepal disaster presages a coming megaquake. PMID- 25931526 TI - Genetically encoded sensors of protein hydrodynamics and molecular proximity. AB - The specialized light organ of the ponyfish supports the growth of the bioluminescent symbiont Photobacterium leiognathi. The bioluminescence of P. leiognathi is generated within a heteromeric protein complex composed of the bacterial luciferase and a 20-kDa lumazine binding protein (LUMP), which serves as a Forster resonance energy transfer (FRET) acceptor protein, emitting a cyan colored fluorescence with an unusually long excited state lifetime of 13.6 ns. The long fluorescence lifetime and small mass of LUMP are exploited for the design of highly optimized encoded sensors for quantitative fluorescence anisotropy (FA) measurements of protein hydrodynamics. In particular, large differences in the FA values of the free and target-bound states of LUMP fusions appended with capture sequences of up to 20 kDa are used in quantitative FA imaging and analysis of target proteins. For example, a fusion protein composed of LUMP and a 5-kDa G protein binding domain is used as an FA sensor to quantify the binding of the GTP-bound cell division control protein 42 homolog (Cdc42) (21 kDa) in solution and within Escherichia coli. Additionally, the long fluorescence lifetime and the surface-bound fluorescent cofactor 6,7-dimethyl-8- (1'-dimethyl ribityl) lumazine in LUMP are utilized in the design of highly optimized FRET probes that use Venus as an acceptor probe. The efficiency of FRET in a zero length LUMP-Venus fusion is 62% compared to ~ 31% in a related CFP-Venus fusion. The improved FRET efficiency obtained by using LUMP as a donor probe is used in the design of a FRET-optimized genetically encoded LUMP-Venus substrate for thrombin. PMID- 25931530 TI - Infectious diseases. In Guinea, a long, difficult road to zero Ebola cases. PMID- 25931531 TI - Bioethics. Embryo engineering study splits scientific community. PMID- 25931533 TI - Funding. Greece raids research funds to pay salaries. PMID- 25931532 TI - Nutrition. Have a sweet tooth? New blood test could tell. PMID- 25931534 TI - Beyond graphene. PMID- 25931535 TI - What is Jeopardy!? PMID- 25931536 TI - Put yourself in Jeopardy! PMID- 25931537 TI - Ecology. 1000 dams down and counting. PMID- 25931538 TI - Chemical physics. The quantum halo state of the helium trimer. PMID- 25931539 TI - Medicine. Brain disorders? Precisely. PMID- 25931540 TI - Ecology. Extinction risks from climate change. PMID- 25931541 TI - Ecology. Human-wildlife conflicts in a crowded airspace. PMID- 25931542 TI - Sustainability. Secure sustainable seafood from developing countries. PMID- 25931543 TI - Immunology. Early life Aire. PMID- 25931544 TI - America's crisis of faith in science. PMID- 25931545 TI - Outside the tower. Bringing science inside prison walls. PMID- 25931547 TI - Light and Optics. Frontiers in light & optics. Introduction. PMID- 25931546 TI - Beware study design measurement errors. PMID- 25931548 TI - Nanophotonics: shrinking light-based technology. AB - The study of light at the nanoscale has become a vibrant field of research, as researchers now master the flow of light at length scales far below the optical wavelength, largely surpassing the classical limits imposed by diffraction. Using metallic and dielectric nanostructures precisely sculpted into two-dimensional (2D) and 3D nanoarchitectures, light can be scattered, refracted, confined, filtered, and processed in fascinating new ways that are impossible to achieve with natural materials and in conventional geometries. This control over light at the nanoscale has not only unveiled a plethora of new phenomena but has also led to a variety of relevant applications, including new venues for integrated circuitry, optical computing, solar, and medical technologies, setting high expectations for many novel discoveries in the years to come. PMID- 25931549 TI - Transforming the optical landscape. AB - Electromagnetism provides us with some of the most powerful tools in science, encompassing lasers, optical microscopes, magnetic resonance imaging scanners, radar, and a host of other techniques. To understand and develop the technology requires more than a set of formal equations. Scientists and engineers have to form a vivid picture that fires their imaginations and enables intuition to play a full role in the process of invention. It is to this end that transformation optics has been developed, exploiting Faraday's picture of electric and magnetic fields as lines of force, which can be manipulated by the electrical permittivity and magnetic permeability of surrounding materials. Transformation optics says what has to be done to place the lines of force where we want them to be. PMID- 25931550 TI - Quantum optics: science and technology in a new light. AB - Light facilitates exploration of quantum phenomena that illuminate the basic properties of nature and also enables radical new technologies based on these phenomena. The critical features of quantum light that underpin the opportunities for discovery and application are exceptionally low noise and strong correlations. Rapid progress in both science and technology has been stimulated by adopting components developed for optical telecommunications and networking, such as highly efficient detectors, integrated photonic circuits, and waveguide- or nanostructure-based nonlinear optical devices. These provide the means to generate new quantum states of light and matter of unprecedented scale, containing many photons with quantum correlations across space and time. Notably, networks with only several tens of photons are already beyond what can be efficiently analyzed by current computers. PMID- 25931551 TI - Beyond crystallography: diffractive imaging using coherent x-ray light sources. AB - X-ray crystallography has been central to the development of many fields of science over the past century. It has now matured to a point that as long as good quality crystals are available, their atomic structure can be routinely determined in three dimensions. However, many samples in physics, chemistry, materials science, nanoscience, geology, and biology are noncrystalline, and thus their three-dimensional structures are not accessible by traditional x-ray crystallography. Overcoming this hurdle has required the development of new coherent imaging methods to harness new coherent x-ray light sources. Here we review the revolutionary advances that are transforming x-ray sources and imaging in the 21st century. PMID- 25931552 TI - Quantum simulation. Two-dimensional superexchange-mediated magnetization dynamics in an optical lattice. AB - The interplay of magnetic exchange interactions and tunneling underlies many complex quantum phenomena observed in real materials. We study nonequilibrium magnetization dynamics in an extended two-dimensional (2D) system by loading effective spin-1/2 bosons into a spin-dependent optical lattice and use the lattice to separately control the resonance conditions for tunneling and superexchange. After preparing a nonequilibrium antiferromagnetically ordered state, we observe relaxation dynamics governed by two well-separated rates, which scale with the parameters associated with superexchange and tunneling. With tunneling off-resonantly suppressed, we observe superexchange-dominated dynamics over two orders of magnitude in magnetic coupling strength. Our experiment will serve as a benchmark for future theoretical work as the detailed dynamics of this 2D, strongly correlated, and far-from-equilibrium quantum system remain out of reach of current computational techniques. PMID- 25931553 TI - Quantum gases. Observation of isolated monopoles in a quantum field. AB - Topological defects play important roles throughout nature, appearing in contexts as diverse as cosmology, particle physics, superfluidity, liquid crystals, and metallurgy. Point defects can arise naturally as magnetic monopoles resulting from symmetry breaking in grand unified theories. We devised an experiment to create and detect quantum mechanical analogs of such monopoles in a spin-1 Bose Einstein condensate. The defects, which were stable on the time scale of our experiments, were identified from spin-resolved images of the condensate density profile that exhibit a characteristic dependence on the choice of quantization axis. Our observations lay the foundation for experimental studies of the dynamics and stability of topological point defects in quantum systems. PMID- 25931554 TI - Three-body physics. Observation of the Efimov state of the helium trimer. AB - Quantum theory dictates that upon weakening the two-body interaction in a three body system, an infinite number of three-body bound states of a huge spatial extent emerge just before these three-body states become unbound. Three helium (He) atoms have been predicted to form a molecular system that manifests this peculiarity under natural conditions without artificial tuning of the attraction between particles by an external field. Here we report experimental observation of this long-predicted but experimentally elusive Efimov state of (4)He3 by means of Coulomb explosion imaging. We show spatial images of an Efimov state, confirming the predicted size and a typical structure where two atoms are close to each other while the third is far away. PMID- 25931555 TI - Ionic interactions. Subnanoscale hydrophobic modulation of salt bridges in aqueous media. AB - Polar interactions such as electrostatic forces and hydrogen bonds play an essential role in biological molecular recognition. On a protein surface, polar interactions occur mostly in a hydrophobic environment because nonpolar amino acid residues cover ~75% of the protein surface. We report that ionic interactions on a hydrophobic surface are modulated by their subnanoscale distance to the surface. We developed a series of ionic head groups-appended self assembled monolayers with C2, C6, C8, and C12 space-filling alkyl chains, which capture a dendritic guest via the formation of multiple salt bridges. The guest release upon protonolysis is progressively suppressed when its distance from the background hydrophobe changes from 1.2 (C2) to 0.2 (C12) nanometers, with an increase in salt bridge strength of ~3.9 kilocalories per mole. PMID- 25931556 TI - Brain computation. Selective information routing by ventral hippocampal CA1 projection neurons. AB - The hippocampus computes diverse information involving spatial memory, anxiety, or reward and directly projects to several brain areas. Are different computations transmitted to all downstream targets uniformly, or does the hippocampus selectively route information according to content and target region? By recording from ventral hippocampal CA1 neurons in rats during different behavioral tasks and determining axonal projections with optogenetics, we observed subsets of neurons changing firing at places of elevated anxiety or changing activity during goal approach. Anxiety-related firing was selectively increased in neurons projecting to the prefrontal cortex. Goal-directed firing was most prominent in neurons targeting the nucleus accumbens; and triple projecting neurons, targeting the prefrontal cortex, amygdala, and nucleus accumbens, were most active during tasks and sharp wave/ripples. Thus, hippocampal neurons route distinct behavior-contingent information selectively to different target areas. PMID- 25931557 TI - Biomechanics. Mechanistic origins of bombardier beetle (Brachinini) explosion induced defensive spray pulsation. AB - Bombardier beetles (Brachinini) use a rapid series of discrete explosions inside their pygidial gland reaction chambers to produce a hot, pulsed, quinone-based defensive spray. The mechanism of brachinines' spray pulsation was explored using anatomical studies and direct observation of explosions inside living beetles using synchrotron x-ray imaging. Quantification of the dynamics of vapor inside the reaction chamber indicates that spray pulsation is controlled by specialized, contiguous cuticular structures located at the junction between the reservoir (reactant) and reaction chambers. Kinematics models suggest passive mediation of spray pulsation by mechanical feedback from the explosion, causing displacement of these structures. PMID- 25931558 TI - Extinctions. Paleontological baselines for evaluating extinction risk in the modern oceans. AB - Marine taxa are threatened by anthropogenic impacts, but knowledge of their extinction vulnerabilities is limited. The fossil record provides rich information on past extinctions that can help predict biotic responses. We show that over 23 million years, taxonomic membership and geographic range size consistently explain a large proportion of extinction risk variation in six major taxonomic groups. We assess intrinsic risk-extinction risk predicted by paleontologically calibrated models-for modern genera in these groups. Mapping the geographic distribution of these genera identifies coastal biogeographic provinces where fauna with high intrinsic risk are strongly affected by human activity or climate change. Such regions are disproportionately in the tropics, raising the possibility that these ecosystems may be particularly vulnerable to future extinctions. Intrinsic risk provides a prehuman baseline for considering current threats to marine biodiversity. PMID- 25931559 TI - Climate change. Accelerating extinction risk from climate change. AB - Current predictions of extinction risks from climate change vary widely depending on the specific assumptions and geographic and taxonomic focus of each study. I synthesized published studies in order to estimate a global mean extinction rate and determine which factors contribute the greatest uncertainty to climate change induced extinction risks. Results suggest that extinction risks will accelerate with future global temperatures, threatening up to one in six species under current policies. Extinction risks were highest in South America, Australia, and New Zealand, and risks did not vary by taxonomic group. Realistic assumptions about extinction debt and dispersal capacity substantially increased extinction risks. We urgently need to adopt strategies that limit further climate change if we are to avoid an acceleration of global extinctions. PMID- 25931560 TI - Bacterial division. Mechanical crack propagation drives millisecond daughter cell separation in Staphylococcus aureus. AB - When Staphylococcus aureus undergoes cytokinesis, it builds a septum, generating two hemispherical daughters whose cell walls are only connected via a narrow peripheral ring. We found that resolution of this ring occurred within milliseconds ("popping"), without detectable changes in cell volume. The likelihood of popping depended on cell-wall stress, and the separating cells split open asymmetrically, leaving the daughters connected by a hinge. An elastostatic model of the wall indicated high circumferential stress in the peripheral ring before popping. Last, we observed small perforations in the peripheral ring that are likely initial points of mechanical failure. Thus, the ultrafast daughter cell separation in S. aureus appears to be driven by accumulation of stress in the peripheral ring and exhibits hallmarks of mechanical crack propagation. PMID- 25931561 TI - Protein dynamics. Direct observation of hierarchical protein dynamics. AB - One of the fundamental challenges of physical biology is to understand the relationship between protein dynamics and function. At physiological temperatures, functional motions arise from the complex interplay of thermal motions of proteins and their environments. Here, we determine the hierarchy in the protein conformational energy landscape that underlies these motions, based on a series of temperature-dependent magic-angle spinning multinuclear nuclear magnetic-resonance relaxation measurements in a hydrated nanocrystalline protein. The results support strong coupling between protein and solvent dynamics above 160 kelvin, with fast solvent motions, slow protein side-chain motions, and fast protein backbone motions being activated consecutively. Low activation energy, small-amplitude local motions dominate at low temperatures, with larger amplitude, anisotropic, and functionally relevant motions involving entire peptide units becoming dominant at temperatures above 220 kelvin. PMID- 25931562 TI - Retrotransposons. An RNA polymerase III subunit determines sites of retrotransposon integration. AB - Mobile genetic elements are ubiquitous. Their integration site influences genome stability and gene expression. The Ty1 retrotransposon of the yeast Saccharomyces cerevisiae integrates upstream of RNA polymerase III (Pol III)-transcribed genes, yet the primary determinant of target specificity has remained elusive. Here we describe an interaction between Ty1 integrase and the AC40 subunit of Pol III and demonstrate that AC40 is the predominant determinant targeting Ty1 integration upstream of Pol III-transcribed genes. Lack of an integrase-AC40 interaction dramatically alters target site choice, leading to a redistribution of Ty1 insertions in the genome, mainly to chromosome ends. The mechanism of target specificity allows Ty1 to proliferate and yet minimizes genetic damage to its host. PMID- 25931563 TI - From war to science paradise. PMID- 25931564 TI - Erratum for the report "Molten uranium dioxide structure and dynamics" by L. B. Skinner, C. J. Benmore, J. K. R. Weber, M. A. Williamson, A. Tamalonis, A. Hebden, T. Wiencek, O. L. G. Alderman, M. Guthrie, L. Leibowitz, J. B. Parise. PMID- 25931566 TI - Endoscopic stenting for double bronco-pleural fistula after lobectomy. AB - Bronchial fistula is one of the most serious complications after pulmonary resection. It presents a challenge in terms of treatment, with a high risk of perioperative mortality. We describe a patient who underwent a right upper lobectomy and systematic hilar-mediastinal lymphadenectomy for lung adenocarcinoma complicated by 2 bronchopleural fistulas. The lesions were sited at the upper lobar stump and the pars membranacea of the intermediate bronchus. The patient was successfully treated by placement of an endobronchial prosthesis (initially a self-expanding prosthesis and subsequently, a Dumon prosthesis) and a pleural chest drain, to avoid a potential right pneumonectomy. PMID- 25931565 TI - DNA repair. Proteomics reveals dynamic assembly of repair complexes during bypass of DNA cross-links. AB - DNA interstrand cross-links (ICLs) block replication fork progression by inhibiting DNA strand separation. Repair of ICLs requires sequential incisions, translesion DNA synthesis, and homologous recombination, but the full set of factors involved in these transactions remains unknown. We devised a technique called chromatin mass spectrometry (CHROMASS) to study protein recruitment dynamics during perturbed DNA replication in Xenopus egg extracts. Using CHROMASS, we systematically monitored protein assembly and disassembly on ICL containing chromatin. Among numerous prospective DNA repair factors, we identified SLF1 and SLF2, which form a complex with RAD18 and together define a pathway that suppresses genome instability by recruiting the SMC5/6 cohesion complex to DNA lesions. Our study provides a global analysis of an entire DNA repair pathway and reveals the mechanism of SMC5/6 relocalization to damaged DNA in vertebrate cells. PMID- 25931567 TI - Hemodynamics of 17-mm vs. 19-mm St. Jude Medical Regent and annulus enlargement. AB - OBJECTIVE: We aimed to compare early and midterm clinical and hemodynamic outcomes of 17-mm vs. 19-mm St. Jude Medical Regent valves with concomitant aortic annulus enlargement. METHODS: Between 1999 and 2012, 20 patients (group 1) underwent first-time aortic valve replacement with a 17-mm St. Jude Medical Regent valve, and 35 patients (group 2) had a 19-mm valve and concomitant aortic annulus enlargement. The mean follow-up was 81 +/- 37 months (range 20-110 months). RESULTS: There was one death in group 1 vs. 4 in group 2 (p > 0.05). The mean postoperative transprosthetic gradient was 17.5 +/- 4.5 in group 1 and 17 +/ 6.4 mm Hg in group 2 (p = 0.83), and 37 +/- 10.7 and 32 +/- 13 mm Hg, respectively, under stress (p = 0.17). Left ventricular mass and left ventricular mass index were reduced and similar in both groups. Postoperative effective orifice area index was higher in group 2 (0.85 +/- 0.17 cm(2 )m(-2)) than group 1 (0.76 +/- 0.2 cm(2 )m(-2); p > 0.05). A multivariate Cox model identified a 19-mm valve with aortic annulus enlargement (p = 0.032), functional class (p = 0.025), reoperation (p = 0.04), ejection fraction < 35% (p = 0.042), and combined surgery (p = 0.04) as strong predictors of poorer overall event-free survival. CONCLUSIONS: The 17-mm St. Jude Medical Regent valve may be employed with satisfactory postoperative clinical and hemodynamic outcomes in patients with a small aortic annulus, as an alternative to a larger prothesis with aortic annulus enlargement. PMID- 25931568 TI - NR2 antibody is associated with quality of life in aortic valve replacement. AB - BACKGROUND: The relationship between the potential brain injury biomarker N methyl-D-aspartate receptor antibody and quality of life has never been assessed. METHODS: We measured serum N-methyl-D-aspartate receptor antibody levels preoperatively in patients undergoing aortic valve replacement. Quality of life was scored using the Short Form-36 and European Quality of Life 5-Dimensions questionnaires pre- and postoperatively. We analyzed the antibody levels as a continuous variable and as a dichotomous variable with 1.8 ng mL(-1) as the cutoff. RESULTS: Fifty-two patients (15 females) with a mean age of 71 +/- 8.4 years were recruited for this study. Forty-eight (92%) patients attended the follow-up visit (405 +/- 161 days). No mortality or severe neurological event was recorded. In both quality-of-life instruments, the low antibody level group (n = 35) had significantly better scores than the high antibody level group (n = 17) preoperatively. Postoperatively, the scores for both groups improved; however, the low antibody level group continued to score significantly better in most of the physical and mental health domains (p = 0.04 to <0.001). Multiple regression analyses revealed that antibody level and the 1.8 ng mL(-1) cutoff were independently related to quality of life (pre- and postoperatively). CONCLUSIONS: Higher N-methyl-D-aspartate receptor antibody levels in aortic valve replacement patients are independently related to poorer quality of life pre- and postoperatively. PMID- 25931569 TI - Pseudo-horseshoe lung due to compensatory hyperinflation. PMID- 25931570 TI - Diagnostic images of cardiac papillary fibroelastoma and video-assisted surgery. PMID- 25931571 TI - Sharma's clamp for sequential coronary artery grafting. AB - Sequential coronary artery grafting is a common procedure. Holding the graft in the correct alignment and orientation in a limited pericardial space and taking a suture at the correct place on the graft is difficult. Graft slippage from the assistant can be distracting to the surgeon, unnecessarily increasing the anastomosis time and also affecting graft patency due to improperly placed sutures. We describe a simple device (Sharma's clamp) for graft holding and stabilization for sequential bypass grafting in coronary artery bypass surgery. PMID- 25931572 TI - Anterior mediastinal tumor associated with symmetrical hypertrophy of the kidneys. PMID- 25931573 TI - Outcomes in patients undergoing percutaneous ventricular assist device implantation for cardiogenic shock. AB - BACKGROUND: Percutaneous ventricular assist devices (PVADs) offer an important but resource-intensive option for management of severe cardiogenic shock (CS). Optimal selection of patients for PVAD support remains undefined. We investigated outcomes, including characteristics associated with in-hospital survival, during PVAD support for CS. METHODS: We established a prospective quality improvement program among patients undergoing TandemHeart PVAD implantation for CS at Brigham and Women's Hospital (Boston, MA). We evaluated 65 consecutive patients between 2006 and 2014, analyzing demographic, clinical, laboratory, hemodynamic, and survival data. RESULTS: Thirty-two patients (49.2%) survived to hospital discharge, of which 12 received destination surgical therapy. Baseline characteristics associated with survival included younger age (47 +/- 15 years vs 61 +/- 11 years; p<0.001), non-ischemic cardiomyopathy (NICMP) vs ischemic CMP (survival 70.4% vs 34.2%, p=0.004), and, paradoxically, lower presenting left ventricular ejection fraction (LVEF) (survival 66.7% for LVEF ?15%, 41.2% for LVEF 16-25%, 25.0% for LVEF >25%; p=0.010). Younger age (p=0.026) and NICMP (p=0.034) remained independent predictors of survival. Twenty-four hours after PVAD placement, a more modest increase in cardiac index (?0.75 L/min/m(2)) was associated with higher in-hospital mortality (OR 6.3, 95% CI 1.8-22.1), as was lack of improvement in serum anion gap (?2 mEq/L; OR 5.1, 95% CI 1.6-16.6). CONCLUSIONS: Despite intensive care and provision of circulatory support, survival is poor in severe CS. Patients in CS with younger age and NICMP were more likely to survive to hospital discharge. Less robust hemodynamic improvement and persistent acidosis after 24 hours of PVAD support also identified patients less likely to survive. PMID- 25931574 TI - Agitation for recognition by DSM-5 mixed features specifier signals fatigue? PMID- 25931575 TI - Clinical outcomes and adherence to guideline recommendations during the initial treatment of acute venous thromboembolism. AB - BACKGROUND: Adherence to American College of Chest Physicians (CHEST) guidelines for treatment of acute venous thromboembolism (VTE) has not been formally assessed in the United States, specifically in the subset of patients with renal impairment. OBJECTIVE: Evaluate adherence to CHEST VTE treatment guidelines. METHODS: This retrospective cohort study evaluated patients with acute VTE between January 1, 2010, and December 31, 2011, for the primary outcome of adherence to CHEST VTE treatment guidelines defined as (1) patients receiving an appropriate parenteral anticoagulant and dose based on renal function and weight, (2) at least 5 days of parenteral anticoagulation during warfarin initiation, and (3) an international normalized ratio (INR) value >=2 documented before discontinuing parenteral agents. Secondary outcomes included recurrent thromboembolism and major bleeding across renal function categories. RESULTS: Of the 1683 patients included in the final analysis, 1483 (88%) had complete data for all 3 elements of the primary outcome (dose, overlap duration, and INR >=2.0). VTE guideline adherence was identified in 95% (1408/1483) of these patients. There were 20 major bleeds overall, which occurred in 1.1%, 1.1%, and 1.3% in patients with CrCl <30 mL/min, 30 to 59 mL/min, and >=60 mL/min, respectively (P = 0.929). Also, 7 recurrent VTE events occurred-3 in patients with CrCl values of 30 to 59 mL/min (0.5%) and 4 in patients with CrCl >=60 mL/min (0.4%; P = 0.797 across groups). CONCLUSIONS: Adherence to CHEST guidelines was high and resulted in low rates of bleeding and recurrent VTE complications across renal function categories. Further studies of patients with CrCl <30 mL/min are needed. PMID- 25931576 TI - IL-13 as a novel growth factor in CTCL. PMID- 25931577 TI - INPP4B, a new player in the chemoresistance of AML. PMID- 25931578 TI - Toward a BETter grasp of acetyl-lysine readers. PMID- 25931579 TI - HLA class II meets beta2-glycoprotein I. PMID- 25931580 TI - A maturing understanding of naive T cells. PMID- 25931581 TI - Hypo- and Hyperglycemic Alarms: Devices and Algorithms. AB - Soon after the discovery that insulin regulates blood glucose by Banting and Best in 1922, the symptoms and risks associated with hypoglycemia became widely recognized. This article reviews devices to warn individuals of impending hypo- and hyperglycemia; biosignals used by these devices include electroencephalography, electrocardiography, skin galvanic resistance, diabetes alert dogs, and continuous glucose monitors (CGMs). While systems based on other technology are increasing in performance and decreasing in size, CGM technology remains the best method for both reactive and predictive alarming of hypo- or hyperglycemia. PMID- 25931582 TI - Clonal hematopoiesis of indeterminate potential and its distinction from myelodysplastic syndromes. AB - Recent genetic analyses of large populations have revealed that somatic mutations in hematopoietic cells leading to clonal expansion are commonly acquired during human aging. Clonally restricted hematopoiesis is associated with an increased risk of subsequent diagnosis of myeloid or lymphoid neoplasia and increased all cause mortality. Although myelodysplastic syndromes (MDS) are defined by cytopenias, dysplastic morphology of blood and marrow cells, and clonal hematopoiesis, most individuals who acquire clonal hematopoiesis during aging will never develop MDS. Therefore, acquisition of somatic mutations that drive clonal expansion in the absence of cytopenias and dysplastic hematopoiesis can be considered clonal hematopoiesis of indeterminate potential (CHIP), analogous to monoclonal gammopathy of undetermined significance and monoclonal B-cell lymphocytosis, which are precursor states for hematologic neoplasms but are usually benign and do not progress. Because mutations are frequently observed in healthy older persons, detection of an MDS-associated somatic mutation in a cytopenic patient without other evidence of MDS may cause diagnostic uncertainty. Here we discuss the nature and prevalence of CHIP, distinction of this state from MDS, and current areas of uncertainty regarding diagnostic criteria for myeloid malignancies. PMID- 25931583 TI - Altered lymphopoiesis and immunodeficiency in miR-142 null mice. AB - MicroRNAs (miRNAs) are a class of powerful posttranscriptional regulators implicated in the control of diverse biological processes, including regulation of hematopoiesis and the immune response. To define the biological functions of miR-142, which is preferentially and abundantly expressed in immune cells, we created a mouse line with a targeted deletion of this gene. Our analysis of miR 142(-/-) mice revealed a critical role for this miRNA in the development and homeostasis of lymphocytes. Marginal zone B cells expand in the knockout spleen, whereas the number of T and B1 B cells in the periphery is reduced. Abnormal development of hematopoietic lineages in miR-142(-/-) animals is accompanied by a profound immunodeficiency, manifested by hypoimmunoglobulinemia and failure to mount a productive immune response to soluble antigens and virus. miR-142(-/-) B cells express elevated levels of B-cell-activating factor (BAFF) receptor (BAFF R) and as a result proliferate more robustly in response to BAFF stimulation. Lowering the BAFF-R gene dose in miR-142(-/-) mice rescues the B-cell expansion defect, suggesting that BAFF-R is a bona fide miR-142 target through which it controls B-cell homeostasis. Collectively, our results uncover miR-142 as an essential regulator of lymphopoiesis, and suggest that lesions in this miRNA gene may lead to primary immunodeficiency. PMID- 25931584 TI - A systematic review of transfusion-associated graft-versus-host disease. AB - Transfusion-associated graft-versus-host disease (TA-GVHD) is a rare complication of blood transfusion. The clinicolaboratory features of TA-GVHD and the relative contributions of recipient and component factors remain poorly understood. We conducted a systematic review of TA-GVHD reports. The HLA relationship between donor and recipient was classified as D = 0 when no donor antigens were foreign to the recipient vs D >= 1 when >=1 donor antigen disparity occurred. We identified 348 unique cases. Criteria for component irradiation were met in 48.9% of cases (34.5% immune-compromised, 14.4% related-donor), although nonirradiated components were transfused in the vast majority of these (97.6%). Components were typically whole blood and red cells. When reported, component storage duration was <=10 days in 94%, and 23 (6.6%) were leukoreduced (10 bedside, 2 prestorage, and 11 unknown). Among 84 cases with HLA data available, the category of D = 0 was present in 60 patients (71%) at either HLA class I or II loci and was more common among recipients without traditional indications for component irradiation. These data challenge the historic emphasis on host immune defects in the pathogenesis of TA-GVHD. The dominant mechanism of TA-GVHD in both immunocompetent and compromised hosts is exposure to viable donor lymphocytes not recognized as foreign by, but able to respond against, the recipient. PMID- 25931585 TI - Lyn sustains oncogenic signaling in chronic lymphocytic leukemia by strengthening SET-mediated inhibition of PP2A. AB - Aberrant protein kinase activities, and the consequent dramatic increase of Ser/Thr and -Tyr phosphorylation, promote the deregulation of the survival pathways in chronic lymphocytic leukemia (CLL), which is crucial to the pathogenesis and progression of the disease. In this study, we show that the tumor suppressor protein phosphatase 2A (PP2A), one of the major Ser/Thr phosphatases, is in an inhibited form because of the synergistic contribution of 2 events, the interaction with its physiologic inhibitor SET and the phosphorylation of Y307 of the catalytic subunit of PP2A. The latter event is mediated by Lyn, a Src family kinase previously found to be overexpressed, delocalized, and constitutively active in CLL cells. This Lyn/PP2A axis accounts for the persistent high level of phosphorylation of the phosphatase's targets and represents a key connection linking phosphotyrosine- and phosphoserine/threonine mediated oncogenic signals. The data herein presented show that the disruption of the SET/PP2A complex by a novel FTY720-analog (MP07-66) devoid of immunosuppressive effects leads to the reactivation of PP2A, which in turn triggers apoptosis of CLL cells. When used in combination with SFK inhibitors, the action of MP07-66 is synergistically amplified, providing a new option in the therapeutic strategy for CLL patients. PMID- 25931586 TI - RNAi profiling of primary human AML cells identifies ROCK1 as a therapeutic target and nominates fasudil as an antileukemic drug. AB - Acute myeloid leukemia (AML) is characterized by a marked genetic heterogeneity, which complicates the development of novel therapeutics. The delineation of pathways essential within an individual patient's mutational background might overcome this limitation and facilitate personalized treatment. We report the results of a large-scale lentiviral loss-of-function RNA interference (RNAi) screen in primary leukemic cells. Stringent validation identified 6 genes (BNIPL1, ROCK1, RPS13, STK3, SNX27, WDHD1) whose knockdown impaired growth and viability of the cells. Dependence on these genes was not caused by mutation or overexpression, and although some of the candidates seemed to be rather patient specific, others were essential in cells isolated from other AML patients. In addition to the phenotype observed after ROCK1 knockdown, treatment with the approved ROCK inhibitor fasudil resulted in increased apoptosis and decreased viability of primary AML cells. In contrast to observations in some other malignancies, ROCK1 inhibition did not foster growth of immature malignant progenitors but was toxic to this cell fraction in feeder coculture and xenotransplant experiments, indicating a distinct effect of ROCK1 inhibition on leukemic progenitors. We conclude that large-scale RNAi screens in primary patient-derived cells are feasible and can complement other methods for personalized cancer therapies, such as expression and mutation profiling. PMID- 25931588 TI - Satisfaction with out of hours primary care. PMID- 25931587 TI - Resolving the multifaceted mechanisms of the ferric chloride thrombosis model using an interdisciplinary microfluidic approach. AB - The mechanism of action of the widely used in vivo ferric chloride (FeCl3) thrombosis model remains poorly understood; although endothelial cell denudation is historically cited, a recent study refutes this and implicates a role for erythrocytes. Given the complexity of the in vivo environment, an in vitro reductionist approach is required to systematically isolate and analyze the biochemical, mass transfer, and biological phenomena that govern the system. To this end, we designed an "endothelial-ized" microfluidic device to introduce controlled FeCl3 concentrations to the molecular and cellular components of blood and vasculature. FeCl3 induces aggregation of all plasma proteins and blood cells, independent of endothelial cells, by colloidal chemistry principles: initial aggregation is due to binding of negatively charged blood components to positively charged iron, independent of biological receptor/ligand interactions. Full occlusion of the microchannel proceeds by conventional pathways, and can be attenuated by antithrombotic agents and loss-of-function proteins (as in IL4 R/Iba mice). As elevated FeCl3 concentrations overcome protective effects, the overlap between charge-based aggregation and clotting is a function of mass transfer. Our physiologically relevant in vitro system allows us to discern the multifaceted mechanism of FeCl3-induced thrombosis, thereby reconciling literature findings and cautioning researchers in using the FeCl3 model. PMID- 25931589 TI - Genome sequencing of 18 francisella strains to aid in assay development and testing. AB - Francisella tularensis is a highly infectious bacterium with the potential to cause high fatality rates if infections are untreated. To aid in the development of rapid and accurate detection assays, we have sequenced and annotated the genomes of 18 F. tularensis and Francisella philomiragia strains. PMID- 25931590 TI - Thirty-Two Complete Genome Assemblies of Nine Yersinia Species, Including Y. pestis, Y. pseudotuberculosis, and Y. enterocolitica. AB - The genus Yersinia includes three human pathogens, of which Yersinia pestis is responsible for >2,000 illnesses each year. To aid in the development of detection assays and aid further phylogenetic elucidation, we sequenced and assembled the complete genomes of 32 strains (across 9 Yersinia species). PMID- 25931591 TI - Complete genome sequences for 35 biothreat assay-relevant bacillus species. AB - In 2011, the Association of Analytical Communities (AOAC) International released a list of Bacillus strains relevant to biothreat molecular detection assays. We present the complete and annotated genome assemblies for the 15 strains listed on the inclusivity panel, as well as the 20 strains listed on the exclusivity panel. PMID- 25931592 TI - Complete genome sequences for 59 burkholderia isolates, both pathogenic and near neighbor. AB - The genus Burkholderia encompasses both pathogenic (including Burkholderia mallei and Burkholderia pseudomallei, U.S. Centers for Disease Control and Prevention Category B listed), and nonpathogenic Gram-negative bacilli. Here we present full genome sequences for a panel of 59 Burkholderia strains, selected to aid in detection assay development. PMID- 25931593 TI - Genome Sequences of Three Strains of Lactobacillus paracasei of Different Origins and with Different Cholate Sensitivities. AB - We report here the draft genome sequences of three strains of Lactobacillus paracasei (NRIC 0644, NRIC 1781, and NRIC 1917) isolated from different sources. The three genomes range from 2.95 to 3.15 Mb with a G+C content of 46% and contain approximately 2,700 protein coding sequences. PMID- 25931594 TI - Draft Genome Sequence of Clostridium aceticum DSM 1496, a Potential Butanol Producer through Syngas Fermentation. AB - Clostridium aceticum DSM 1496 is a Gram-negative anaerobic chemolithoautotrophic acetogenic bacterium that is capable of producing commodity chemicals from syngas fermentation. In this study, we report the draft genome sequence of the C. aceticum DSM 1496 strain (4.16 Mb) to elucidate the syngas fermentation metabolic pathway. PMID- 25931595 TI - Genome Sequence of a Novel Iflavirus from the Leafhopper Graminella nigrifrons. AB - A novel iflavirus was discovered from the transcriptome of the leafhopper Graminella nigrifrons. The assembled virus genome has 9,700 nucleotides (nt) and encodes a 3,035-amino-acid polyprotein. Sanger sequencing was used to confirm the sequence encoding the polyprotein and indicated a genome length of 9,617 nt with a polyadenylated tail. PMID- 25931596 TI - Complete Genome Sequence of Rhodococcus sp. B7740, a Carotenoid-Producing Bacterium Isolated from the Arctic Sea. AB - Rhodococcus sp. B7740 was isolated from Arctic seawater and selected for its capacity to synthesize carotenoids. Here, we report the complete genome sequence of Rhodococcus sp. B7740 to provide the genetic basis for a better understanding of its carotenoid-accumulating capabilities, and we describe the major features of the genome. PMID- 25931597 TI - Draft Genome Sequence of Isolate Staphylococcus aureus LHSKBClinical, Isolated from an Infected Hip. AB - We report here the genome sequence of a clinical isolate of Staphylococcus aureus from an orthopedic infection. Phenotypically diverse Staphylococcus aureus strains are associated with orthopedic infections and subsequent implant failure, and some are highly resistant to antibiotics. This genome sequence will support further analyses of strains causing orthopedic infections. PMID- 25931598 TI - Metagenome sequencing of a coastal marine microbial community from monterey bay, california. AB - Heterotrophic microbes are critical components of aquatic food webs. Linkages between populations and the substrates they utilize are not well defined. We present the metagenome of microbial communities from the coastal Pacific Ocean exposed to various nutrient additions in order to better understand substrate utilization and partitioning in this environment. PMID- 25931599 TI - Whole-Genome Sequence of an Epidemic Strain of Burkholderia pseudomallei vgh07 in Taiwan. AB - Here, we report the complete genome sequence of B. pseudomallei vgh07. This is an epidemic strain that was isolated from a melioidosis patient with arthro osteomyelitis in Taiwan. PMID- 25931600 TI - Complete Genome Sequence of the Clinical Beijing-Like Strain Mycobacterium tuberculosis 323 Using the PacBio Real-Time Sequencing Platform. AB - We report here the whole-genome sequence of the multidrug-resistant Beijing-like strain Mycobacterium tuberculosis 323, isolated from a 15-year-old female patient who died shortly after the initiation of second-line drug treatment. This strain is representative of the Beijing-like isolates from Colombia, where this lineage is becoming a public health concern. PMID- 25931601 TI - Genome sequence of classical Swine Fever virus genotype 1.1 with a genetic marker of attenuation detected in a continuous porcine cell line. AB - The complete genome sequencing and analysis of a classical swine fever virus (CSFV) detected in a porcine kidney cell line revealed a close relationship with genotype 1.1 viruses circulating in India and China. The presence of consecutive T insertions in the 3' untranslated region (UTR), as seen in vaccine strains of CSFV, suggested some degree of attenuation. PMID- 25931602 TI - Whole-Genome Sequencing of 10 Pseudomonas syringae Strains Representing Different Host Range Spectra. AB - Pseudomonas syringae is a ubiquitous bacterium that readily persists in environmental habitats as a saprophyte and also is responsible for numerous diseases of crops. Here, we report the whole-genome sequences of 10 strains isolated from both woody and herbaceous plants that will contribute to the elucidation of the determinants of their host ranges. PMID- 25931603 TI - Genome Sequence of the Acidophilic Ferrous Iron-Oxidizing Isolate Acidithrix ferrooxidans Strain Py-F3, the Proposed Type Strain of the Novel Actinobacterial Genus Acidithrix. AB - Extremely acidophilic iron-oxidizing Gram-positive bacteria comprise species within the phyla Firmicutes and Actinobacteria. Here, we report the 4.02-Mb draft genome of Acidithrix ferrooxidans Py-F3, which was isolated from a stream draining an abandoned copper mine and proposed as the type species of a new genus of Actinobacteria. PMID- 25931604 TI - Genome Sequence of the Acidophilic Iron Oxidizer Ferrimicrobium acidiphilum Strain T23T. AB - Extremely acidophilic iron-oxidizing bacteria have largely been characterized for the phyla Proteobacteria and Nitrospira. Here, we report the draft genome of an iron-oxidizing and -reducing heterotrophic mesophile of the Actinobacteria, Ferrimicrobium acidiphilum, which was isolated from an abandoned pyrite mine. The genome sequence comprises 3.08 Mb. PMID- 25931605 TI - Complete Genome Sequence of Cyanobacterium Geminocystis sp. Strain NIES-3709, Which Harbors a Phycoerythrin-Rich Phycobilisome. AB - The cyanobacterium Geminocystis sp. strain NIES-3709 accumulates a larger amount of phycoerythrin than the related NIES-3708 strain does. Here, we determined the complete genome sequence of the NIES-3709 strain. Our genome data suggest that the different copy number of rod linker genes for phycoerythrin leads to the different phycoerythrin contents between the two strains. PMID- 25931606 TI - Complete Genome Sequence of Rhodovulum sulfidophilum DSM 2351, an Extracellular Nucleic Acid-Producing Bacterium. AB - Rhodovulum sulfidophilum DSM 2351 is the nonsulfur photosynthetic bacterium that efficiently releases nucleic acids into the extracellular milieu, which leads to flocculation. In this study, we determined the complete genome sequence of R. sulfidophilum DSM 2351, which will provide new insights into the mechanism of its unique nucleic acid release. PMID- 25931607 TI - Complete genome sequence of a coxsackievirus a16 strain, isolated from a fatal case in shenzhen, southern china, in 2014. AB - We determined the complete genome sequence of a coxsackievirus A16 strain (CVA16/SZ29/CHN/2014) from a fatal case in Shenzhen, southern China, in 2014. The strain was assigned to subgenotype B1b based on phylogenetic analysis of the VP1 gene. PMID- 25931608 TI - First Insights into the Genome of the N-Methylhydantoin-Degrading Clostridium sp. Strain FS41 (DSM 6877). AB - Clostridium sp. strain FS41 (DSM 6877) is a strictly anaerobic and Gram-positive spindle-shaped rod. This spore-forming bacterium is able to degrade N methylhydantoin, with N-carbamoylsarcosine and sarcosine as intermediates. The genome consists of one replicon (6.28 Mb) and harbors 5,735 predicted protein coding genes. PMID- 25931609 TI - Draft Genome Sequences of Histamine-Producing Photobacterium kishitanii and Photobacterium angustum, Isolated from Albacore (Thunnus alalunga) and Yellowfin (Thunnus albacares) Tuna. AB - Histamine-producing bacteria are responsible for scombrotoxin (histamine) fish poisoning, a leading cause of fish poisoning in the United States. We report here the draft genome sequences of four histamine-producing (HP) Photobacterium kishitanii strains and nine HP Photobacterium angustum strains isolated from tuna. PMID- 25931610 TI - The evolutionary fate of alternatively spliced homologous exons after gene duplication. AB - Alternative splicing and gene duplication are the two main processes responsible for expanding protein functional diversity. Although gene duplication can generate new genes and alternative splicing can introduce variation through alternative gene products, the interplay between the two processes is complex and poorly understood. Here, we have carried out a study of the evolution of alternatively spliced exons after gene duplication to better understand the interaction between the two processes. We created a manually curated set of 97 human genes with mutually exclusively spliced homologous exons and analyzed the evolution of these exons across five distantly related vertebrates (lamprey, spotted gar, zebrafish, fugu, and coelacanth). Most of these exons had an ancient origin (more than 400 Ma). We found examples supporting two extreme evolutionary models for the behaviour of homologous axons after gene duplication. We observed 11 events in which gene duplication was accompanied by splice isoform separation, that is, each paralog specifically conserved just one distinct ancestral homologous exon. At other extreme, we identified genes in which the homologous exons were always conserved within paralogs, suggesting that the alternative splicing event cannot easily be separated from the function in these genes. That many homologous exons fall in between these two extremes highlights the diversity of biological systems and suggests that the subtle balance between alternative splicing and gene duplication is adjusted to the specific cellular context of each gene. PMID- 25931612 TI - Linking Landscape-Scale Disturbances to Stress and Condition of Fish: Implications for Restoration and Conservation. AB - Humans have dramatically altered landscapes as a result of urban and agricultural development, which has led to decreases in the quality and quantity of habitats for animals. This is particularly the case for freshwater fish that reside in fluvial systems, given that changes to adjacent lands have direct impacts on the structure and function of watersheds. Because choices of habitat have physiological consequences for organisms, animals that occupy sub-optimal habitats may experience increased expenditure of energy or homeostatic overload that can cause negative outcomes for individuals and populations. With the imperiled and threatened status of many freshwater fish, there is a critical need to define relationships between land use, quality of the habitat, and physiological performance for resident fish as an aid to restoration and management. Here, we synthesize existing literature to relate variation in land use at the scale of watersheds to the physiological status of resident fish. This examination revealed that landscape-level disturbances can influence a host of physiological properties of resident fishes, ranging from cellular and genomic levels to the hormonal and whole-animal levels. More importantly, these physiological responses have been integrated into traditional field-based monitoring protocols to provide a mechanistic understanding of how organisms interact with their environment, and to enhance restoration. We also generated a conceptual model that provides a basis for relating landscape-level changes to physiological responses in fish. We conclude that physiological sampling of resident fish has the potential to assess the effects of landscape-scale disturbances on freshwater fish and to enhance restoration and conservation. PMID- 25931611 TI - Composite Selection Signals for Complex Traits Exemplified Through Bovine Stature Using Multibreed Cohorts of European and African Bos taurus. AB - Understanding the evolution and molecular architecture of complex traits is important in domestic animals. Due to phenotypic selection, genomic regions develop unique patterns of genetic diversity called signatures of selection, which are challenging to detect, especially for complex polygenic traits. In this study, we applied the composite selection signals (CSS) method to investigate evidence of positive selection in a complex polygenic trait by examining stature in phenotypically diverse cattle comprising 47 European and 8 African Bos taurus breeds, utilizing a panel of 38,033 SNPs genotyped on 1106 animals. CSS were computed for phenotypic contrasts between multibreed cohorts of cattle by classifying the breeds according to their documented wither height to detect the candidate regions under selection. Using the CSS method, clusters of signatures of selection were detected at 26 regions (9 in European and 17 in African cohorts) on 13 bovine autosomes. Using comparative mapping information on human height, 30 candidate genes mapped at 12 selection regions (on 8 autosomes) could be linked to bovine stature diversity. Of these 12 candidate gene regions, three contained known genes (i.e., NCAPG-LCORL, FBP2-PTCH1, and PLAG1-CHCHD7) related to bovine stature, and nine were not previously described in cattle (five in European and four in African cohorts). Overall, this study demonstrates the utility of CSS coupled with strategies of combining multibreed datasets in the identification and discovery of genomic regions underlying complex traits. Characterization of multiple signatures of selection and their underlying candidate genes will elucidate the polygenic nature of stature across cattle breeds. PMID- 25931613 TI - Economics of alcohol-involved traffic crashes in the USA: an input-output analysis. AB - BACKGROUND: Preventing traffic crashes reduces crash costs paid by employers and employees. The related savings filter through the economy, impacting its performance. This study is the first to measure the impact of traffic crash reduction on a national economy. It focuses on impaired driving crashes. METHODS: We analysed the impact of the almost 50% alcohol-involved driving crash rate reduction from 1984-1986 to 2010 and the impact if such crashes in 2010 had not occurred. The analysis entered published estimates of costs that employers, consumers and governments paid because of US impaired-driving crashes as production costs and demand changes in Rutgers University's input-output model of the US economy. For example, reducing medical costs paid by employers lowers the cost of labour inputs to production while reducing vehicle repairs raises demand for other goods. Running the model at current and alternative crash rates revealed the impacts of crash reductions on economic output, gross domestic product (GDP), national income and employment. RESULTS: Alcohol-involved crash reductions since 1984-1986 increased economic output in 2010 by an estimated $20 billion, raised GDP by $10 billion, increased US income by $6.5 billion, and created 215 000 jobs. GDP gains from alcohol-involved crash reduction contributed 5% of the $200 million compounded average annual growth in US GDP from 1985 to 2013. Eliminating remaining alcohol-involved crashes would result in similar economic gains. CONCLUSIONS: Alcohol-involved crashes drag down the US economy. On average, each of the 25.5 billion miles Americans drove impaired in 2010 reduced economic output by $0.80. Those losses are preventable. PMID- 25931614 TI - Numerical Method of Characteristics for One-Dimensional Blood Flow. AB - Mathematical modeling at the level of the full cardiovascular system requires the numerical approximation of solutions to a one-dimensional nonlinear hyperbolic system describing flow in a single vessel. This model is often simulated by computationally intensive methods like finite elements and discontinuous Galerkin, while some recent applications require more efficient approaches (e.g. for real-time clinical decision support, phenomena occurring over multiple cardiac cycles, iterative solutions to optimization/inverse problems, and uncertainty quantification). Further, the high speed of pressure waves in blood vessels greatly restricts the time step needed for stability in explicit schemes. We address both cost and stability by presenting an efficient and unconditionally stable method for approximating solutions to diagonal nonlinear hyperbolic systems. Theoretical analysis of the algorithm is given along with a comparison of our method to a discontinuous Galerkin implementation. Lastly, we demonstrate the utility of the proposed method by implementing it on small and large arterial networks of vessels whose elastic and geometrical parameters are physiologically relevant. PMID- 25931615 TI - Time-Domain Optimal Experimental Design in Human Seated Postural Control Testing. AB - We are developing a series of systems science-based clinical tools that will assist in modeling, diagnosing, and quantifying postural control deficits in human subjects. In line with this goal, we have designed and constructed a seated balance device and associated experimental task for identification of the human seated postural control system. In this work, we present a quadratic programming (QP) technique for optimizing a time-domain experimental input signal for this device. The goal of this optimization is to maximize the information present in the experiment, and therefore its ability to produce accurate estimates of several desired seated postural control parameters. To achieve this, we formulate the problem as a nonconvex QP and attempt to locally maximize a measure (T optimality condition) of the experiment's Fisher information matrix (FIM) under several constraints. These constraints include limits on the input amplitude, physiological output magnitude, subject control amplitude, and input signal autocorrelation. Because the autocorrelation constraint takes the form of a quadratic constraint (QC), we replace it with a conservative linear relaxation about a nominal point, which is iteratively updated during the course of optimization. We show that this iterative descent algorithm generates a convergent suboptimal solution that guarantees monotonic nonincreasing of the cost function value while satisfying all constraints during iterations. Finally, we present successful experimental results using an optimized input sequence. PMID- 25931617 TI - Erratum. PMID- 25931616 TI - A message from the editor. PMID- 25931618 TI - Surgeon General's perspectives. PMID- 25931620 TI - Adolescent health and teen pregnancy in the United States: a progress report. PMID- 25931622 TI - Integrating ethics for the nation's health. PMID- 25931623 TI - Successful implementation and results of an HPV vaccination program in Geneva Canton, Switzerland. AB - We describe a human papillomavirus (HPV) vaccination program implemented since 2007 in Geneva Canton, Switzerland, that used school services, a public hospital, and private physicians as vaccination providers. We assessed program performance with the evolution of immunization coverage during the first four years of program implementation. We measured vaccination coverage of the target population using individual records of vaccination status collected by service providers and transmitted to the Geneva Canton Medical Office. The target population was 20,541 adolescent girls aged 11-19 years as of September 1, 2008, who resided in the canton when the program began. As of June 30, 2012, HPV vaccination coverage was 72.6% and 74.8% in targeted cohorts for three and two doses, respectively. The global coverage for three doses increased by 27 percentage points from December 2009 to June 2012. Coverage for girls aged 16-18 years at the beginning of the program reached 80% or more four years into the program. High coverage by this HPV vaccination program in Geneva was likely related to free vaccination and easy access to the vaccine using a combination of delivery services, including school health services, a public hospital, and private physicians, covering most eligible adolescent girls. PMID- 25931624 TI - Self-reported use of Supplemental Nutrition Assistance Program benefits to purchase soda in a public health center population: Los Angeles County, California, 2012. AB - To better inform local program planning for the Supplemental Nutrition Assistance Program (SNAP), the Los Angeles County Department of Public Health used self reported data from a public health center population to examine the prevalence of benefits used to purchase soda. We performed statistical analyses, including multivariable regression modeling, using data from a local health and nutrition examination survey. The survey response rate was 69% (n=1,503). More than one third of survey participants reported receiving, or living in a household where someone receives, nutrition assistance benefits. When asked, 33% (n=170) reported using these benefits to purchase soda "sometimes" and 18% (n=91) reported "often" or "always," suggesting that the use of program benefits to purchase soda was not uncommon in this subpopulation. These findings have meaningful policy and planning implications, as they contribute to ongoing dialogue about strategies for optimizing nutrition among SNAP recipients. PMID- 25931625 TI - Developmental disabilities and socioeconomic outcomes in young adulthood. AB - OBJECTIVE: We assessed the associations between developmental disabilities and indicators of socioeconomic outcomes (i.e., educational attainment, employment status, occupation type, subjective perception of socioeconomic status [SES], income, and wage rate) among young U.S. adults aged 24-33 years. METHODS: We used data from the National Longitudinal Study of Adolescent Health (n=13,040), a nationally representative study of U.S. adolescents in grades 7-12 during the 1994-1995 school year. Young adult outcomes (i.e., educational attainment, employment status, income, occupation, and subjective SES) were measured in Wave IV (2008 for those aged 24-33 years). Multivariate methods controlled for sociodemographic characteristics and other relevant variables. RESULTS: Nearly 12% of this sample presented with a physical or cognitive disability. Respondents with physical disabilities had lower educational attainment (odds ratio [OR] = 0.69, 95% confidence interval [CI] 0.57, 0.85) and ranked themselves in lower positions on the subjective SES ladder (OR=0.71, 95% CI 0.57, 0.87) than those without a physical disability. Compared with individuals without disabilities, young adults with a cognitive disability also had lower educational attainment (OR=0.41, 95% CI 0.33, 0.52) and, when employed, were less likely to have a professional/managerial occupation (OR=0.50, 95% CI 0.39, 0.64). Young adults with disabilities also earned less annually (-$10,419.05, 95% CI -$4,954.79, $5,883.37) and hourly (-$5.38, 95% CI -$7.64, -$3.12) than their non-disabled counterparts. CONCLUSION: This study highlights the importance of considering multiple developmental experiences that may contribute to learning and work achievements through the transition from adolescence to young adulthood. PMID- 25931626 TI - Legionnaires' disease and associated comorbid conditions as causes of death in the U.S., 2000-2010. AB - OBJECTIVE: Recent U.S. outbreaks of Legionnaires' disease (LD) underscore the virulent nature of this infectious pneumonia. To date, only a paucity of literature has described the mortality burden of LD. This study updates LD mortality using U.S. multiple-cause-of-death data from 2000-2010. METHODS: We calculated crude and age-adjusted rates for LD mortality for age, sex, race, state, Census region, and year. We conducted Poisson regression to assess seasonal and temporal trends. We generated matched odds ratios (MORs) to describe the association between LD-related deaths and other comorbid conditions listed on the death certificates. RESULTS: We identified a total of 1,171 LD-related deaths during 2000-2010. The age-adjusted mortality rate remained relatively static from 2000 (0.038 per 100,000 population, 95% confidence interval [CI] 0.031, 0.046) to 2010 (0.040 per 100,000 population, 95% CI 0.033, 0.047). The absolute number increased from 107 to 135 deaths during this period, with adults >=45 years of age having the highest caseload. Overall, LD mortality rates were 2.2 times higher in men than in women. White people accounted for nearly 83.3% of all LD related deaths, but the age-adjusted mortality rates for black and white people were similar. Comorbid conditions such as leukemia (MOR=4.8, 95% CI 3.5, 6.6) and rheumatoid arthritis (MOR=5.6, 95% CI 3.3, 9.4) were associated with LD diagnosis on death certificates. CONCLUSION: Comorbid conditions that could lead to an immunocompromised state were associated with fatal LD on U.S. death certificates. Characterization of LD mortality burden and related comorbidities has practice implications for clinical medicine and public health surveillance. PMID- 25931627 TI - The economic burden of exposure to secondhand smoke for child and adult never smokers residing in U.S. public housing. AB - OBJECTIVE: The World Health Organization (WHO) reports that nonsmokers experience disease and death due to secondhand smoke (SHS) exposure in the home. We estimated the total excess burden and costs to society due to SHS exposure in U.S. public housing. METHODS: We quantified the public health burden for outcomes causally related to SHS exposure for nationally representative never-smoking residents in U.S. public housing using (1) WHO-recommended health outcomes and methodology, (2) publicly available and other large databases, and (3) published estimates of morbidity and mortality rates. We used published estimates of direct medical and nonmedical care costs and the value of productivity losses to estimate SHS-related societal costs for disease and death. We estimated the public health and economic burden for two serum cotinine limits of detection (LODs): 0.05 nanograms per milliliter (ng/mL) and 0.015 ng/mL. RESULTS: In 2011, an estimated 37,791 never-smoking child and adult U.S. public housing residents experienced illness and death due to SHS exposure at home based on an LOD=0.05 ng/mL (50,967 residents at LOD=0.015 ng/mL). Costs incurred by society for these illnesses and deaths totaled $183 million (LOD=0.05 ng/mL) and $267 million (LOD=0.015 ng/mL) annually. Of the total costs, direct costs (medical and nonmedical) accounted for $128 million and $176 million for LOD=0.05 ng/mL and LOD=0.015 ng/mL, respectively. Medical care accounted for the majority of direct costs-$110 million at LOD=0.05 ng/mL and $153 million at LOD=0.015 ng/mL. Adverse respiratory health outcomes accounted for approximately one-half (56% at LOD=0.05 ng/mL and 52% at LOD=0.015 ng/mL) of total societal costs. CONCLUSION: Implementing smoke-free policies in all U.S. public housing could save lives and decrease SHS-related morbidity and mortality in never-smoking residents, resulting in annual societal savings of $183 million at LOD=0.05 ng/mL and $267 million at LOD=0.015 ng/mL. PMID- 25931629 TI - Comparative mortality among people diagnosed with HIV infection or AIDS in the U.S., 2001-2010. AB - OBJECTIVE: The comparative mortality figure (CMF) is the expected number of deaths in the standard population compared with those observed. We assessed state based CMFs for people with HIV infection to allow standardized assessment of mortality in all states. METHODS: We used National HIV Surveillance System data to compute CMFs for people diagnosed with HIV and AIDS from 2001 to 2010 who met the CDC HIV case definition; were alive on December 31, 2009; and died during 2010. RESULTS: In 33 U.S. states with name-based HIV reporting since 2001, the 2010 CMF for people with an HIV diagnosis was 2.8 compared with 4.5 for those with an AIDS diagnosis. CMFs for males were higher than for females (3.4 vs. 3.1) and black people had higher CMFs than white people for HIV (3.2 vs. 2.2) and AIDS (4.7 vs. 4.3). CMFs by state ranged from 0.9 to 4.2 for HIV and 1.9 to 9.7 for AIDS. In 50 states and the District of Columbia with AIDS reporting, CMFs for males and females were similar (4.5 and 4.6, respectively), CMFs for black people remained higher than for white people (5.0 and 3.9, respectively), and the range for states remained broad (1.2-9.4). CONCLUSION: State mortality figures varied based on population composition and disease stage at diagnosis, possibly indicating a need for state-specific testing, linkage to care, and viral suppression strategies to reduce mortality. PMID- 25931628 TI - Using smartphone apps in STD interviews to find sexual partners. AB - OBJECTIVES: Smartphone applications (apps) are increasingly used to facilitate casual sexual relationships, increasing the risk of sexually transmitted diseases (STDs). In STD investigations, traditional contact elicitation methods can be enhanced with smartphone technology during field interviews. METHODS: In 2013, the Monroe County Department of Public Health conducted a large, multi-infection STD investigation among men who have sex with men (MSM) using both index case and cluster interviews. When patients indicated meeting sexual partners online, disease intervention specialists (DISs) had access to smartphone apps and were able to elicit partners through access to inboxes and profiles where traditional contact information was lacking. Social network mapping was used to display the extent of the investigation and the impact of access to smartphones on the investigation. RESULTS: A total of 14 index patient interviews and two cluster interviews were conducted; 97 individuals were identified among 117 sexual dyads. On average, eight partners were elicited per interview (range: 1-31). The seven individuals who used apps to find partners had an average of three Internet partners (range: 1-5). Thirty-six individuals either had a new STD (n=7) or were previously known to be HIV-positive (n=29). Of the 117 sexual dyads, 21 (18%) originated either online (n=8) or with a smartphone app (n=13). Of those originating online or with a smartphone app, six (29%) partners were located using the smartphone and two (10%) were notified of their exposure via a website. Three of the new STD/HIV cases were among partners who met online. CONCLUSION: Smartphone technology used by DISs in the field improved contact elicitation and resulted in successful partner notification and case finding. PMID- 25931630 TI - Food insecurity and health: data from the Veterans Aging Cohort Study. AB - OBJECTIVE: Food insecurity may be a modifiable and independent risk factor for worse control of medical conditions, but it has not been explored among veterans. We determined the prevalence of, and factors independently associated with, food insecurity among veterans in the Veterans Aging Cohort Study (VACS). METHODS: Using data from VACS from 2002-2008, we determined the prevalence of food insecurity among veterans who have accessed health care in the Veterans Health Administration (VA) as defined by "concern about having enough food for you or your family in the past month." We used multivariable logistic regression to determine factors independently associated with food insecurity and tests of trend to measure the association between food insecurity and control of hypertension, diabetes, HIV, and depression. RESULTS: Of the 6,709 veterans enrolled in VACS, 1,624 (24%) reported being food insecure. Food insecurity was independently associated with being African American, earning <$25,000/year, recent homelessness, marijuana use, and depression. Being food insecure was also associated with worse control of hypertension, diabetes, HIV, and depression (p<0.001). CONCLUSION: Food insecurity is prevalent and associated with worse control of medical conditions among veterans who have accessed care in the VA. PMID- 25931631 TI - The descriptive epidemiology of yersiniosis: a multistate study, 2005-2011. AB - OBJECTIVES: Yersiniosis, a foodborne infection of zoonotic origin caused by the bacteria Yersinia enterocolitica and Yersinia pseudotuberculosis, is a reportable disease in 38 states. Both sporadic and foodborne outbreaks of yersiniosis have been reported in the U.S., with annual occurrence of an estimated 98,000 episodes of illness, 533 hospitalizations, and 29 deaths. We analyzed surveillance data from nine non-FoodNet-participating U.S. states during the period 2005-2011 to describe the epidemiology of this disease. METHODS: As part of a passive surveillance system, laboratory-confirmed cases of yersiniosis were reported to state health departments in Arizona, Illinois, Michigan, Missouri, Nebraska, North Carolina, South Carolina, Washington, and Wisconsin. We calculated overall, age-, and race-specific annual incidence rates per 100,000 population using 2010 Census data as the denominator. We used Poisson regression to examine seasonal variation and annual incidence trends by race, age group, and overall. RESULTS: The average annual incidence of yersiniosis was 0.16 cases per 100,000 population during 2005-2011. We observed a statistically significant decreasing annual trend of yersiniosis incidence among African Americans <5 years of age (p<0.01), whereas white people aged 19-64 years (p=0.08) and Hispanic people (p=0.05) had an overall increasing annual incidence of yersiniosis. We observed higher incidence during October-December (p<0.01) and January-March (p=0.03) quarters among African Americans, whereas white people had a higher incidence during April June (p=0.05). CONCLUSION: This multistate analysis revealed differences in the epidemiology of yersiniosis by race/ethnicity that may be useful for future research and prevention efforts. While this study was consistent with the FoodNet report in recognizing the high and declining incidence among African American children and winter seasonality among African Americans, our study also identified April-June seasonality among the white population. PMID- 25931635 TI - Integrating classroom, community, mixed-methods research, and community-based participatory research to teach public health practice. PMID- 25931642 TI - Study on the Effect of Inlet Fluctuation on Cavitation in a Cone Flow Channel. AB - A mathematical method was conducted to investigate the mechanism of formation of cavitation cloud, while the inlet stream contains a fluctuating flow. Based on the Rayleigh-Plesset equation and the static pressure distribution in a cone flow channel, parameters related to cavitation cloud are estimated, and the collapse pressure of the cavitation cloud is obtained by solving the equation of Morch's model. Moreover, the effect of the amplitude and frequency of inlet fluctuation on cavitation is studied. Results revealed that the smaller the amplitude, the smaller the cloud and the lower the collapse pressure. And frequency of fluctuating stream was found to have a relative great effect on frequency of peak pressure but not so significant on peak collapse pressure and size of cloud. It is concluded that limiting the inlet fluctuation reduces the erosion and noise generated by cavitation collapse. PMID- 25931633 TI - Taken to court: defending public health authority to access medical records during an outbreak investigation. PMID- 25931643 TI - Dye-Enhanced imaging of mammalian cells with SIMS. AB - A major limitation of SIMS studies of cells is the limited number of molecules available for detection. This study examines the possibility of utilizing a molecular tag which is easily identifiable using SIMS and does not interfere with the mass spectra of commonly identified cellular components, to aid in the visualization of specific cellular organelles. Here, a fluorescent, nuclear stain (Hoechst 33342) was used to allow for verification of the staining protocols prior to SIMS analysis. The stain was successfully chemically imaged within the nuclear region of a glutaraldehyde fixed bovine aortic endothelial cell. The ability to chemically map a larger variety of organelles and cellular components will allow for further possible study of a greater number of biological pathways and processes, as well as make cell-drug studies more feasible using SIMS. PMID- 25931644 TI - Teen responses when a younger school-age sibling has been bullied. AB - The prevalence of bullying among children, and the sometimes tragic consequences as a result, has become a major concern in schools. The larger research for this study reported on in-depth interviews with 28 elementary and middle school-age boys and girls (7-12 years) who had experienced various forms of bullying and relational aggression by their peers, mostly on school grounds, and the responses of their parents and teachers. Responses of the children's teen siblings to the younger child's revelations of being bullied are the focus of this report. In depth interviews with each teen sibling (n = 28) and with each bullied child revealed how the children viewed the teen siblings' supportive strategies. Almost all the children (89%) reported that their older siblings talked with them and offered advice. The teen siblings shared with the younger ones that they too (71%) had been bullied, or they knew someone who had been bullied (18%). Teens gave the advice to 'bully back' to 11% and advice to 'tell someone' to 32% of the younger children. The children felt quite positive about their older siblings' advice (89%), which did differ depending on the bullied child's gender. Teen siblings gave advice to 'avoid bullies' to 77% of female and to 27% of male younger children. PMID- 25931645 TI - Using reflective poems to describe the lived experiences of street children and adolescents in Ghana. AB - These two poems emerged from my qualitative research with homeless youth in Accra Central, Ghana. I was overwhelmed at how this method of research rarely used in Ghana offers a researcher the opportunity to capture participants' subjective feelings, and the complexities of their perceptions and experiences of a phenomenon. The aim of the study was to examine the lived experiences of street youth and to explore factors that enhance their survival on the street. These reflective poems shed light on the experiences of both the street youth and researcher, as captured in my reflective journal during the research. It was difficult winning the trust of the street youth, but when the trust was won, it became a worthy journey to understanding the complexities of their daily lives. PMID- 25931646 TI - Development and aetiology of body dissatisfaction in adolescent boys and girls. AB - This longitudinal study aims to describe the development of body dissatisfaction (BD), measured with the Contour Drawing Rating Scale, between the ages of 14 and 18, and to identify factors associated with BD at age 18, among 413 adolescents. Between the ages of 14 and 18, the proportion of girls wanting to be thinner increased, although it remained unchanged among boys. A ratio of 1:2 girls and 1:5 boys reported having seriously tried to lose weight. Factors associated with BD in girls at age 18 were (1) wanting to be thinner, (2) body mass index (BMI), (3) weight control behaviours and (4) negative comments about weight. Factors associated with BD in boys at age 18 were (1) wanting to be thinner or bigger, (2) BMI, (3) having experienced sexual intercourse and (4) negative comments about weight. The high prevalence of BD and weight-related concerns suggest a need for early interventions. PMID- 25931647 TI - Culture Circles in adolescent empowerment for the prevention of violence. AB - An action research based on Paulo Freire's Culture Circles was developed to implement a health education intervention involving adolescents, in collective knowledge construction about strategies for the prevention of violence. The data collection in the Culture Circles involved 11 adolescents and included observation and field diary, photographic records and recording. The educational action aroused a critical socio-political and cultural position in the adolescents towards the situations of vulnerability to violence, including the guarantee of human rights, justice and the combat of inequities; changes in the social relations, combat against discrimination and intolerance; expansion of access and reorientation of health services through intersectoral public policies. The intervention empowered the group of adolescents for the prevention of violence and permitted the inclusion of health professionals in the school context, from an interdisciplinary perspective, contributing to the establishment of social support and protection networks. PMID- 25931648 TI - Incorporating research technology into the clinical assessment of balance and mobility: perspectives of physiotherapists and people with stroke. AB - PURPOSE: To describe the perspectives of people with stroke and their physiotherapists on the use of biomechanics technology to assess balance and mobility. METHODS: This qualitative study used semi-structured interviews with patients with stroke and a focus group with their physiotherapists. Coding of interview and focus-group data used a line-by-line inductive approach, with qualitative software to develop codes into themes. RESULTS: The quantitative data from the assessment were seen as beneficial to providing patients with insight into balance and mobility problems. Physiotherapists found that the assessment confirmed clinical reasoning and aided in precise evaluation of progress but expressed mixed opinions as to whether treatment choice was influenced. Patients would have liked more communication regarding the purpose of the assessment. Patients also stated that trust in their physiotherapists helped them overcome anxieties and that confidence was gained through exposure to more challenging balance assessments. Physiotherapists advocated for the use of a harness system to safely incorporate reactive balance control assessment and training into practice. CONCLUSION: Both patients and therapists saw value in the quantitative data provided by the assessment. Regardless of the technology used, patients value a strong physiotherapist-patient relationship. Ongoing collaboration between clinicians and researchers should guide the evolution of technology into clinically useful tools. PMID- 25931649 TI - Survey of a pelvic health physiotherapy community of practice: a pilot study to gain member input to help sustain and advance the group. AB - PURPOSE: To gather input and perspectives from members of the Calgary Pelvic Health Physiotherapists' Community of Practice (PHPT CoP) to ensure common goals that help sustain and advance the group. METHOD: An online survey grounded in CoP theory was used to elicit feedback from 23 PHPTs. Descriptive statistics summarized survey results. RESULTS: The response rate was 96%; all respondents worked in women's pelvic health. Respondents expressed interest in continuing regular face-to-face meetings, a speaker series, case studies, and connecting with other PHPTs. CONCLUSION: The findings suggest continuation of regular meetings, with a focus on clinical skill development, and an annual Alberta PHPT conference. Members of this community of practice seek a strategy to promote PHPT to the public and develop referral sources. PMID- 25931650 TI - Observations and Performances "with distinction" by Physical Therapy Students in Clinical Education: Analysis of Checkboxes on the Physical Therapist Clinical Performance Instrument (PT-CPI) over a 4-Year Period. AB - PURPOSE: To describe how often the 24 performance criteria of the Physical Therapist Clinical Performance Instrument (PT-CPI) were not observed and how often they were rated exceptionally well for physical therapy (PT) students in relation to clinical placement descriptors. METHODS: Indicators of "not observed," performance "with distinction," and "significant concerns" were tabulated from 1,460 clinical placements between 2008 and 2012. The rates for these indicators were evaluated with respect to catchment area, practice setting (hospital/institutional or community-based), practice area (musculoskeletal, cardiorespiratory, neurology, paediatrics, geriatrics, or variety), and level (junior to senior). RESULTS: Of the 24 PT-CPI criteria, 15 had observation rates >95%. Of the other nine criteria, some showed significant differences in observation rates across level, practice setting, and practice area. Ratings of "with distinction" were awarded most often for criteria related to professionalism and communication and were awarded more often in community-based settings than in hospital/institutional settings. For some criteria, "with distinction" was awarded more often in paediatrics placements than in other areas. The "significant concerns" checkboxes were rarely used. CONCLUSIONS: The overall observation rates were very similar to those reported elsewhere. The findings related to performance "with distinction" and observation rates relative to setting and practice area are new contributions to physical therapy knowledge. PMID- 25931651 TI - An Exploratory Study to Determine the Relationship between Cervical Dysfunction and Perimenstrual Migraines. AB - PURPOSE: To determine whether an association between cervical dysfunction and perimenstrual migraines exists. METHODS: Forty perimenstrual migraine sufferers and 46 controls were compared. Information on the participants' ages and perceptions of neck pain and stiffness were solicited. The blinded physical examination of the cervical area consisted of postural, range of motion, muscle strength, muscle length, trigger point, neural mobility, and segmental cervical joint movement assessment. RESULTS: The migraine group had increased perception of neck pain and stiffness (p<0.001); reduced bilateral rotation (p=0.013); decreased muscle length in both trapezii, left sternocleidomastoid, and right occipitals (p=0.045); more pain on muscle stretch in both levator scapulae, both trapezii, left sternocleidomastoid, and both occipitals (p=0.013); increased trigger points bilaterally in the left trapezius (p=0.021), right trapezius (p=0.023), left sternocleidomastoid (p=0.0.004), and right sternocleidomastoid (p=0.021); reduced neural mobility with bilateral elbow lag (p=0.043); greater C4 C6 pain (p=0.045); and increased cervical stiffness in C5-C7 (p=0.023). There were no differences in posture and muscle strength. Decreased muscle length increased the risk of perimenstrual migraines 2.4-6.7 fold, reduced neural mobility 5.8-10.7 fold, and increased C7 stiffness 17.0 fold. CONCLUSION: The results suggest that an association between cervical dysfunction and perimenstrual headaches should be further explored. PMID- 25931652 TI - Impact of using physiotherapy self-referral in the medical-surgical neurological intensive care unit. AB - PURPOSE: To describe physiotherapy (PT) referral practice in a medical-surgical neurological intensive care unit (MSNICU) of a large quaternary teaching hospital before and after the implementation of PT self-referral. METHODS: Charts were reviewed for MSNICU patients who received PT pre-implementation (Pre; n=90) and post-implementation (Post; n=100) to collect data on timeliness, number of referrals, and MSNICU length of stay (LOS); t-tests were conducted to determine group differences. RESULTS: The mean age of MSNICU patients referred to PT was 60.6 (SD=18.6) years; 59.5% were male. PT treatment consisted of cardiorespiratory (39% Pre, 51.1% Post), mobility (22% Pre, 28.8% Post), and combined (39% Pre, 20% Post) interventions. Overall, the number of days between MSNICU admission and PT initiation and MSNICU LOS did not differ significantly from Pre to Post. However, for patients (n=50) receiving early (within 7 days of MSNICU admission) PT self-referral Post versus patients receiving physician referral only Pre (n=83), there was a significant decrease (p=0.01) in time to PT initiation of 1.4 days (3.2 Pre, 1.8 Post). CONCLUSIONS: PT self-referral increased both the number of patients receiving more timely access to PT and the provision of treatment of a deferred group of patients previously not referred. Future studies need to evaluate the impact of referral methods across a variety of clinical populations. PMID- 25931653 TI - Device or ice: the effect of consistent cooling using a device compared with intermittent cooling using an ice bag after total knee arthroplasty. AB - Purpose : To determine the comparative effectiveness of consistent cooling using an icing device (DonJoy Iceman, DJO Canada, Mississauga, ON) versus intermittent cooling using an ice bag (usual care) for the first 48 hours after total knee arthroplasty (TKA). Method : A sample of 78 patients (intervention group, n=37; control group, n=34) undergoing primary TKA were randomized to intervention (device) or control (ice) groups. The primary outcome was pain intensity, measured by numerical pain rating scale (NPRS). Secondary outcomes were passive range of motion (PROM), nausea or vomiting, opioid use, blood loss, lower limb function, hospital length of stay, and patient-reported compliance and satisfaction. Results : No significant differences in the primary outcome (pain intensity measured via NPRS) were observed between control and intervention groups. Patients in the intervention group were significantly more satisfied (8.4 vs. 6.0, p=0.002); used the device more consistently, day and night (85.7% vs. 29.6% and 87.6% vs. 30.8%, respectively, p<0.001); and were more likely to recommend this method of cooling (96.8% vs. 68.0%, p=0.004). Conclusion : The study found no additional benefit of consistent cryotherapy using the icing device over intermittent ice bags on postoperative pain, PROM, nausea or vomiting, opioid use, blood loss, lower limb function, or length of stay, despite significant differences in patient-reported compliance and satisfaction. PMID- 25931654 TI - Evaluating the reliability of a novel neck-strength assessment protocol for healthy adults using self-generated resistance with a hand-held dynamometer. AB - PURPOSE: To evaluate the intra- and inter-session test-retest agreement of a novel neck-strength assessment protocol using a hand-held dynamometer. BACKGROUND: A literature review found a lack of neck-strength assessment protocols that are both portable and reliable. Hand-held dynamometry is a portable and inexpensive method of assessing muscle strength, but it is not commonly used for neck-strength assessment. METHODS: A hand-held dynamometer was used to evaluate neck strength in 30 healthy participants. The device measured maximum force in cervical flexion, extension, side flexion, side flexion with rotation, and pure rotation, using the ipsilateral hand to apply isometric resistance over 3 seconds. Three measurements were taken over 6-8 days. RESULTS: Test-retest intra-class correlation coefficients (ICCs) showed high reliability, ranging from 0.94 to 0.97 for all tested directions from Trial 1 to Trial 2 (intra-session reliability, ICC [2,1], absolute). ICC values demonstrated good to high inter-session reliability, ranging from 0.87 to 0.95 for all tested directions from Trial 1 to Trial 3 (ICC [2,1], absolute). CONCLUSION: The results suggest that the five test positions of the neck and upper-quadrant strength assessment protocol can be performed using hand-held dynamometry with good to high reliability. PMID- 25931655 TI - Physical therapy for an adult with chronic stroke after botulinum toxin injection for spasticity: a case report. AB - PURPOSE: In this case report, we describe the type and duration of a physical therapy and botulinum toxin type A (BoNTA) intervention directed at lower limb spasticity and the gait and balance improvement in a patient post-stroke. Treatment of focal spasticity with BoNTA intramuscular injections combined with physical therapy is recommended by rehabilitation experts. However, the optimal type and duration of physical therapy intervention to optimize any functional gains that follow chemodenervation induced by BoNTA has not been established. METHOD: One individual with chronic stroke who received BoNTA injections for upper and lower extremity spasticity was included. Physical therapy intervention consisted of 45- to 60-min sessions twice weekly for 12 weeks, based on the Bobath-neurodevelopmental therapy approach, and an activity-based home program. RESULTS: After BoNTA injections and physical therapy, the patient made clinically significant improvements in balance and gait speed and became more independent with his ambulation. CONCLUSIONS: This case report demonstrates that physical therapy after BoNTA injections can result in significant functional improvements for individuals with spasticity after chronic stroke that may not be possible with BoNTA injections alone. PMID- 25931656 TI - Measuring professional behaviour in canadian physical therapy students' objective structured clinical examinations: an environmental scan. AB - PURPOSE: To identify professional behaviours measured in objective structured clinical examinations (OSCEs) by Canadian university physical therapy (PT) programs. METHOD: A cross-sectional telephone survey was conducted to review current practice and determine which OSCE items Canadian PT programs are using to measure PT students' professional behaviours. Telephone interviews using semi structured questions were conducted with individual instructors responsible for courses that included an OSCE as part of the assessment component. RESULTS: Nine PT programmes agreed to take part in the study, and all reported conducting at least one OSCE. The number and characteristics of OSCEs varied both within and across programs. Participants identified 31 professional behaviour items for use in an OSCE; these items clustered into four categories: communication (n=14), respect (n=10), patient safety (n=4), and physical therapists' characteristics (n=3). CONCLUSIONS: All Canadian entry-level PT programmes surveyed assess professional behaviours in OSCE-type examinations; however, the content and style of assessment is variable. The local environment should be considered when determining what professional behaviours are appropriate to assess in the OSCE context in individual programmes. PMID- 25931657 TI - Bibliometric Analyses of Physical and Occupational Therapy Faculty across Canada Indicate Productivity and Impact of Rehabilitation Research. AB - PURPOSE: This study examines physical and occupational therapy faculty across Canada, using bibliometrics and federal funding as indicators of academic impact, and considers the validity of various bibliometric indices. METHODS: Faculty members were identified and their rank, professional designation, and department obtained from faculty Web sites. Bibliometric indicators were determined using Publish or Perish software. An independent author (not a faculty member) inspected the data to remove any incorrectly attributed publications. The h index, citation years, g-index, and total number of citations for each faculty member were retrieved. The Canadian Institutes of Health Research (CIHR) funding database was used to determine the amount of research funding provided to each faculty member as a principal investigator (PI) and his or her total CIHR funding received. Mean faculty indicators by university, rank, gender, and profession were determined. Analysis of variance (ANOVA) was used to detect differences by rank and gender, and measures of association (Pearson correlation coefficients and multiple regression) were used to identify factors that affected h-index and PI funding received. RESULTS: A total of 347 physical and occupational therapy faculty were identified. The median h-index was 5 (inter-quartile range [IQR] 2 8) for assistant professors, 11 (IQR 7-15) for associate professors, and 18 (IQR 12-26) for full professors. ANOVA indicated no significant differences between male and female faculty in terms of h-index or funding received. Regression analysis indicated that 58% of h-index variance could be explained by gender (p=0.039), appointment within a department that provides a (rehabilitation science) PhD programme (p<0.001), rank (p<0.001), CIHR PI funding (p=0.001), or total CIHR funding (p<0.001). Significant predictors of the amount of CIHR funding received as a PI included h-index (p<0.001) and total number of citations (p=0.023), which together explained 27% of the variation in funding received. CONCLUSION: The h-index, although not without flaws, provides a useful metric that indicates that physical and occupational faculty in Canada are productive scientists having a measurable impact and that this impact increases with rank and greater funding. PMID- 25931658 TI - Sustainability of outcomes after a randomized crossover trial of resistance exercise for shoulder dysfunction in survivors of head and neck cancer. AB - PURPOSE: Shoulder pain and dysfunction may occur after surgery for head and neck cancer (HNC) as a result of damage to or resection of the spinal accessory nerve. Previous research found that 12 weeks of upper extremity progressive resistance exercise training (PRET) improved shoulder outcomes in survivors of HNC; the purpose of this study was to determine whether benefits persisted over the longer term. METHODS: Survivors of HNC were assigned at random to PRET (n=27) or a standard therapeutic protocol (TP; n=25), with an opportunity for crossover in the TP group after 12 weeks. At 12-month follow-up, participants were mailed a questionnaire that assessed quality of life (QOL), shoulder outcomes, and exercise behaviour. RESULTS: Of the 52 participants enrolled in the study, 44 were eligible at 12-month follow-up, and 37 (71%) completed the questionnaires. Overall, self-reported outcomes were largely sustained over the follow-up period. After 12 months, regardless of original group allocation, participants who continued resistance exercise training during the follow-up period reported better neck dissection-related functioning (p=0.021) and better QOL (p=0.011) than those who did not. CONCLUSIONS: Benefits of PRET were sustained at 12-month follow-up. Ongoing participation in resistance exercise training may prove valuable as a supportive care intervention for survivors of HNC. PMID- 25931659 TI - The future of chronic disease management: melting pot or mosaic? PMID- 25931660 TI - Coordination and balance in children with birth-related brachial plexus injury: a preliminary study. AB - PURPOSE: Most children with severe birth-related brachial plexus injury (BRBPI) have some functional impairment, but information on the impact of BRBPI on coordination and balance is limited. The study's purpose was to determine whether children with BRBPI exhibit deficits in body coordination and balance. METHOD: A prospective cohort study involving 39 children with BRBPI aged 5-15 years was conducted. Range of motion, strength, active movement, and balance and coordination motor skills were assessed using the Bruininks-Oseretsky Test of Motor Proficiency, Second Edition (BOT-2), and the Movement Assessment Battery for Children-Second Edition (MABC-2). A self-report measure of physical disability, the Activities Scale for Kids-Performance Version (ASKp), was also administered. RESULTS: Participants scored a mean of 44.72 on the BOT-2 Body Coordination composite subtest; scores can range from 20 to 80. Eleven participants (28.2%) scored below average on this test. Participants scored a mean of 7.3 on the Balance subtest of the MABC-2; scores can range from 1 to 19. Twenty-six participants (66.7%) scored below average on this test. Of 38 participants, 25 (65.8%) had an ASKp score indicating some level of disability (<95/100); we found a statistically significant difference in balance (p=0.007) between these 25 participants and those without disability (ASKp score 95-100). CONCLUSIONS: The majority of our study population scored in the categories of at risk or significant difficulty for balance on the MABC-2. Balance rehabilitation may be a valuable treatment adjunct for children with BRBPI. PMID- 25931661 TI - Who receives rehabilitation in canadian long-term care facilities? A cross sectional study. AB - PURPOSE: To describe the proportion of residents receiving occupational therapy (OT) and physical therapy (PT) and the factors associated with receiving PT in long-term care (LTC) facilities across five provinces and one territory in Canada. METHODS: Using a population-based, retrospective analysis of cross sectional data, the proportion of LTC facility residents in each province or territory receiving three different amounts (time and frequency) of PT, OT, or both before July 1, 2013, was calculated according to the Resource Utilization Groups-III rehabilitation classifications. Twenty-three variables from the Resident Assessment Instrument 2.0, such as age and cognition, were examined as correlates; those significant at p<0.01 were included in a multivariate logistic regression. RESULTS: Between 63.7% and 88.6% of residents did not receive any PT or OT; 0.8%-12.6% received both PT and OT; 5.8%-29.5% received an unspecified amount of PT; 1.9%-7.0% received 45 minutes or more of PT 3 days or more per week; and fewer than 1% received 150 minutes or more of PT on 5 or more days per week. Province, age, cognitive status, depression, clinical status, fracture, multiple sclerosis, and self-rated potential for improvement were associated with PT irrespective of time intensity. CONCLUSIONS: The proportion of LTC residents receiving rehabilitation services varies across Canada and appears to be associated with physical impairments and the potential for improvement; older residents with cognitive impairment or mood disorders are less likely to receive rehabilitation services. Future recommendations should consider what is driving the patterns of service use, determine whether the resources available are appropriate, and address the most appropriate goals for residents in LTC. PMID- 25931662 TI - Clinician's Commentary on McArthur et al.(1). PMID- 25931663 TI - Ethical issues raised by private practice physiotherapy are more diverse than first meets the eye: recommendations from a literature review. AB - PURPOSE: Physiotherapy in private practice differs from physiotherapy practised in a public setting in several ways, the most evident of which is the for-profit nature of private physiotherapy clinics; these differences can generate distinct and challenging ethical issues. The objectives of this article are to identify ethical issues encountered by physiotherapists in private practice settings and to identify potential solutions and recommendations to address these issues. METHOD: After a literature search of eight databases, 39 studies addressing ethical issues in a private practice context were analyzed. RESULTS: A total of 25 ethical issues emerging from the included studies were classified into three main categories: (1) business and economic issues (e.g., conflicts of interests, inequity in a managed care context, lack of time affecting quality of care); (2) professional issues (e.g., professional autonomy, clinical judgment, treatment effectiveness, professional conduct); and (3) patients' rights and welfare issues (e.g., confidentiality, power asymmetries, paternalism vs. patient autonomy, informed consent). Recommendations as to how physiotherapists could better manage these issues were then identified and categorized. CONCLUSIONS: The physiotherapy community should reflect on the challenges raised by private practice so that professionals can be supported-through education, research, and good governance in providing the best possible care for their patients. PMID- 25931665 TI - Clinician's Commentary on Gibson and Shields(1). PMID- 25931664 TI - Effects of Aquatic Therapy and Land-Based Therapy versus Land-Based Therapy Alone on Range of Motion, Edema, and Function after Hip or Knee Replacement: A Systematic Review and Meta-analysis. AB - PURPOSE: To determine whether aquatic therapy in combination with land-based therapy improves patient outcomes after hip or knee arthroplasty compared with land-based therapy alone. METHODS: For this systematic review, six online databases (MEDLINE, CINAHL, AMED, EMBASE, Cochrane, and PEDro) were searched from the earliest date available until September 2013. Controlled trials published in English in a peer-reviewed journal that compared aquatic therapy in combination with land-based therapy with land-based therapy alone were included; trial quality was assessed using the PEDro scale. Data were presented as standardized mean differences (SMDs), their associated 95% CIs, and meta-analyses. RESULTS: Three small trials of moderate quality were included in the qualitative analysis. Meta-analysis of two of these studies found moderate-quality evidence that aquatic therapy in combination with land-based therapy improves functional outcomes (SMD=0.53; 95% CI, 0.03-1.03), knee range of motion (measured in knee or hip arthroplasty; SMD=0.78; 95% CI, 0.27-1.29), and edema (SMD=-0.66; 95% CI, 1.16 to -0.15) compared with land-based therapy alone. The results for improved functional outcomes were not considered clinically significant. CONCLUSIONS: It is not possible to draw confident conclusions from this review because of the small number of studies of limited quality and the modest differences found. Further studies of sound methodological quality are required to confirm the results. Economic analysis alongside randomized controlled trials is needed to examine the cost-effectiveness of these clinical outcomes. PMID- 25931666 TI - Ordering diagnostic imaging: a survey of ontario physiotherapists' opinions on an expanded scope of practice. AB - PURPOSE: To explore Ontario physiotherapists' opinions on their ability to order diagnostic imaging (DI). METHODS: An online questionnaire was sent to all registered members of the College of Physiotherapists of Ontario. Descriptive statistics were calculated using response frequencies. Practice characteristics were compared using chi(2) tests and Wilcoxon rank-sum tests. RESULTS: Of 1,574 respondents (21% response rate), 42% practised in orthopaedics and 53% in the public sector. Most physiotherapists were interested in ordering DI (72% MRI/diagnostic ultrasound, 78% X-rays/computed tomography scans). Respondents with an orthopaedic caseload of 50% or more (p<0.001) and those in the private sector (p<0.001) were more interested in ordering DI. Respondents preferred a DI course that combined face-to-face and Web-based components and one that was specific to their area of practice. Most respondents perceived minimal barriers to the uptake of ordering DI, and most agreed that support from other health care professionals would facilitate uptake. CONCLUSION: The majority of Ontario physiotherapists are interested in ordering DI. For successful implementation of a health care change, such as physiotherapists' ability to order DI, educational needs and barriers to and facilitators of the uptake of the authorized activity should be considered. PMID- 25931668 TI - Clinician's Commentary on Cheung et al.(1). PMID- 25931667 TI - Patient-identified factors that influence spasticity in people with stroke and multiple sclerosis receiving botulinum toxin injection treatments. AB - PURPOSE: To describe the nature, extent, and impact of spasticity; determine factors that are perceived to influence its severity; and examine the relationship between time since diagnosis and impact of spasticity on daily activities in people with stroke and multiple sclerosis (MS) who are receiving botulinum toxin injection treatments. METHODS: After a cross-sectional telephone survey, descriptive statistics and correlations were analyzed separately for the stroke and MS groups. RESULTS: A total of 29 people with stroke and 10 with MS were surveyed. Both groups perceived increased spasticity with outdoor cold (69% stroke, 60% MS), muscle fatigue (59% stroke, 80% MS), and mental stress (59% stroke, 90% MS). No statistically significant correlations were found between time since diagnosis and perceived impact of spasticity on function in the stroke (r=0.07, p=0.37) or MS (r=0.16, p=0.33) groups. The MS group experienced bilateral and more severe perception of spasticity in the legs than the stroke group and identified more factors as worsening their spasticity (p<0.05). Severity of leg (but not arm) spasticity was significantly correlated with severity of impact of the following factors in the MS group only: lying on the back (r=0.70, p<0.05), outdoor heat (r=0.61, p<0.05), and morning (r=0.59, p<0.05). CONCLUSION: Intrinsic and extrinsic triggers can influence the perception of spasticity differently depending on individual factors, severity, location (arm vs. leg), and distribution of spasticity (unilateral vs. bilateral). Clinicians can use the findings to better understand, educate, and treat people with stroke and MS. PMID- 25931669 TI - Inter- and Intra-observer Agreement of the Motion Palpation Test for Lumbar Vertebral Rotational Asymmetry. AB - PURPOSE: To investigate inter- and intra-observer agreement in the assessment of lumbar vertebral rotational (VR) asymmetry by a motion palpation test. METHODS: For this prospective and descriptive test-retest study, 51 asymptomatic participants (40 women, 11 men; mean age 23.3 [SD 5.6] years) were recruited from the community. Each participant was assessed in two sessions by the same three observers, who assessed VR by means of a palpatory test for movement asymmetry. This test is performed by applying posteroanterior pressure in an alternating manner to the left and right transverse processes of a vertebra to determine motion asymmetry in the transverse plane and thus the vertebral position. Observers classified the vertebral position as neutral, rotation to the right, and rotation to the left; they were blinded to which participant was being assessed and to any previous results. RESULTS: Intra- and inter-observer agreement was verified by the kappa coefficient (kappa) and the weighted kappa coefficient (kappa w ). Values of kappa and kappa w varied from 0.07 (95% CI, 0.10 to 0.245) to 0.37 (95% CI, 0.11-0.63) for intra-observer agreement and from 0.12 (95% CI, -0.06 to 0.29) to 0.30 (95% CI, 0.08-0.52) for inter-observer agreement. CONCLUSION: The motion palpation test used to assess VR asymmetry has low agreement levels; therefore, its clinical significance for measuring vertebral position is questionable. PMID- 25931670 TI - Impact of college-administered quality practice assessments: a longitudinal evaluation of repeat peer assessments of continuing competence in physiotherapists. AB - PURPOSE: The College of Physiotherapists of Ontario (CPO) developed its peer practice assessment (PA) process under statutory requirements for quality assurance. Each year, a small percentage of physiotherapists, most selected at random, undergo PA. To shed light on continuing competence, we report outcomes from physiotherapists who have had two PAs. METHODS: Records were extracted for physiotherapists with two unrelated PAs. Demographic features, peer assessors' scores, and consequent outcome decisions were examined. Outcomes were examined cross-sectionally (vs. other PAs in the same time period) and longitudinally (within cohort). RESULTS: Between 2004 and 2012, 117 Ontario physiotherapists underwent two unrelated PAs, typically 5-7 years apart. This cohort was representative of Ontario physiotherapists in terms of sex ratios, education, and years in practice. At the first PA (PA1), this cohort's outcomes were similar to those of other physiotherapists; at the second PA (PA2), they were better than others undergoing PA1 in the same period (p=0.02). The cohort's outcomes were better at PA2 than at PA1 (p<0.001). CONCLUSIONS: Physiotherapists are likely to meet professional standards in a repeat PA 5-7 years after an initial one. Additional research is required to identify risk factors for not meeting standards. The findings provide empirical evidence to guide ongoing development of the CPO's quality management program. PMID- 25931671 TI - How Well Do Functional Assessments of Mobility and Balance Discriminate Fallers and Recurrent Fallers from Non-Fallers among Ambulatory Older Adults in the Community? AB - PURPOSE: 1) To compare the ability of functional mobility and balance assessments in discriminating fallers from non-fallers and recurrent fallers from those with fewer or no falls. 2) To compare the discriminatory accuracy of cut-off scores specific to this study sample with that of cut-off scores proposed in the literature for community-dwelling older adults. METHODS: In a sample of 39 ambulatory older adults living independently in the community, fallers were identified on the basis of number of falls in the past year. Seven functional tests of mobility and balance were used to identify fallers and recurrent fallers on the basis of their fall history. RESULTS: Discrimination of fallers from non fallers was poor: Only a high-level balance assessment significantly discriminated these groups (p=0.0498, area under the curve [AUC]=0.68). Four assessments significantly discriminated recurrent fallers from those with fewer or no falls (ps=0.006-0.009), but their discriminatory powers were not significantly different from one another (AUCs=0.77-0.80, p>0.05). For two assessments, cutoff scores based on the study sample enhanced discriminatory accuracy relative to the literature-based cutoff scores. CONCLUSIONS: To improve fall prediction for ambulatory community-dwelling older adults, future prospective studies should consider including high-level mobility and balance assessments and targeting cutoff scores to the level of function of this relatively high-functioning population. PMID- 25931672 TI - Use of Simulation Learning Experiences in Physical Therapy Entry-to-Practice Curricula: A Systematic Review. AB - PURPOSE: To review the literature on simulation-based learning experiences and to examine their potential to have a positive impact on physiotherapy (PT) learners' knowledge, skills, and attitudes in entry-to-practice curricula. METHOD: A systematic literature search was conducted in the MEDLINE, CINAHL, Embase Classic+Embase, Scopus, and Web of Science databases, using keywords such as physical therapy, simulation, education, and students. RESULTS: A total of 820 abstracts were screened, and 23 articles were included in the systematic review. While there were few randomized controlled trials with validated outcome measures, some discoveries about simulation can positively affect the design of the PT entry-to-practice curricula. Using simulators to provide specific output feedback can help students learn specific skills. Computer simulations can also augment students' learning experience. Human simulation experiences in managing the acute patient in the ICU are well received by students, positively influence their confidence, and decrease their anxiety. There is evidence that simulated learning environments can replace a portion of a full-time 4-week clinical rotation without impairing learning. CONCLUSIONS: Simulation-based learning activities are being effectively incorporated into PT curricula. More rigorously designed experimental studies that include a cost-benefit analysis are necessary to help curriculum developers make informed choices in curriculum design. PMID- 25931673 TI - Clinician's Commentary on Mori et al.(1). PMID- 25931675 TI - What Does the Cochrane Collaboration Say about Falls Prevention? PMID- 25931674 TI - Feasibility of a pedometer-based walking program for survivors of breast and head and neck cancer undergoing radiation therapy. AB - PURPOSE: This pilot study assessed the feasibility and acceptability of a pedometer-based walking program for people with breast cancer and head and neck cancer (HNC) undergoing radiation therapy treatment. METHODS: Participants were given a pedometer and prescribed a home-based walking program that included an individualized weekly step-count goal during the 3- to 5-week course of radiation therapy. Feasibility was determined by calculating recruitment rate, completion rate, and rate of adherence. Secondary outcomes included 6-minute walk test (6MWT) distance, step count, physical activity level, and psychological outcomes of depression, happiness, self-esteem, and sleep quality. RESULTS: A total of 21 participants were recruited. All participants completed the study; adherence to prescribed step counts was 91% at follow-up. Analysis found a significant improvement in happiness, as measured by the Oxford Happiness Questionnaire (mean difference 0.3, p=0.003), and a borderline significant improvement in 6MWT distance (mean difference 35 m, p=0.008). CONCLUSION: This pilot study demonstrated the feasibility of a pedometer-based walking program for survivors of breast cancer and HNC undergoing radiation therapy. PMID- 25931677 TI - Muscle activities of the rectus abdominis and rectus femoris and their ratio during leg raises performed by healthy adults. AB - [Purpose] The purpose of this study was to analyze muscle activation during hip flexion in the supine position to examine the activation characteristics of the rectus abdominis and rectus femoris. [Subjects] The subjects of this study were 20 healthy adults (10 males and 10 females). [Methods] Muscle activities of the rectus abdominis and rectus femoris while raising the leg from 0 degrees -60 degrees were measured in 15-degree divisions and their ratio was calculated. [Results] Statistically significant differences were found in the muscle activities of the rectus femoris and rectus abdominis were found among each division of during hip flexion in the supine position. The rectus abdominis and rectus femoris ratios increased as the angle of hip flexion increased. [Conclusion] During hip flexion from 0 degrees -45 degrees in the supine position, femur motion caused hip flexion. At angles greater than or equal to 45 degrees hip flexion was accompanied by pelvic motion. PMID- 25931676 TI - Pentameric Ligand-gated Ion Channels : Insights from Computation. AB - Pentameric ligand-gated ion channels (pLGICs) conduct upon the binding of an agonist and are fundamental to neurotransmission. New insights into the complex mechanisms underlying pLGIC gating, ion selectivity, and modulation have recently been gained via a series of crystal structures in prokaryotes and C .elegans, as well as computational studies relying on these structures. Here we review contributions from a variety of computational approaches, including normal mode analysis, automated docking, and fully atomistic molecular dynamics simulation. Examples from our own research, particularly concerning interactions with general anesthetics and lipids, are used to illustrate predictive results complementary to crystallographic studies. PMID- 25931678 TI - Comparisons of changes in the two-point discrimination test following muscle fatigue in healthy adults. AB - [Purpose] This study aimed to examine the effects of muscle fatigue on skin sensation by looking at changes in two-point discrimination (2PD) after inducing muscle fatigue. [Subjects] Thirty-four young and healthy adults with no pathological symptoms (17 males; 17 females) participated in this study. [Methods] Continuous isometric contraction was applied to the upper and lower extremities with an intensity of 50% of the maximal muscle strength to trigger muscle fatigue, and then the 2PD test was conducted on the 3 cm medial area of the elbow and 5 cm area of the knee bone. [Results] After muscle fatigue was induced, the 2PD distance significantly increased in the upper and lower extremities of both males and females. Before triggering muscle fatigue, the 2PD distance was longer in males than females, but after causing muscle fatigue, there was no difference between males and females. The increase in 2PD distance after the experiment was more significant in females than males. [Conclusion] Muscle fatigue has an effect of reducing the skin's sensory faculty by increasing the 2PD distance in the skin. There is a difference in the response of the skin according to body area and gender; therefore, caution is needed to avoid triggering fatigue during exercise. PMID- 25931679 TI - Lifestyle-related factors and their association with metabolic syndrome in Korean adults: a population-based study. AB - [Purpose] The aim of this study was to investigate whether lifestyle-related factors are associated with metabolic syndrome (MetS) in community-dwelling Korean adults. [Subjects and Methods] The subjects comprised 590 men and 1,138 women aged 20 years and above. The subjects visited a public health promotion center in Seoul, Republic of Korea to participate in a survey regarding sleep duration, mental stress, educational level, economic status, and frequency of alcohol consumption and smoking. MetS was defined according to the standard definition of the National Cholesterol Education Program's Adult Treatment Panel III report. The relationship between lifestyle-related factors and MetS was assessed using multivariate logistic regression analysis after adjustments for age and sex. [Results] Sleep duration, educational level, economic status, and frequency of alcohol consumption and smoking were not associated with MetS. Mental stress was the only lifestyle-related factor associated with MetS. [Conclusion] Well-designed studies will be necessary in order to establish the lifestyle-related factors of MetS. PMID- 25931680 TI - Effects of brain-computer interface-based functional electrical stimulation on brain activation in stroke patients: a pilot randomized controlled trial. AB - [Purpose] This study sought to determine the effects of brain-computer interface based functional electrical stimulation (BCI-FES) on brain activation in patients with stroke. [Subjects] The subjects were randomized to in a BCI-FES group (n=5) and a functional electrical stimulation (FES) group (n=5). [Methods] Patients in the BCI-FES group received ankle dorsiflexion training with FES for 30 minutes per day, 5 times under the brain-computer interface-based program. The FES group received ankle dorsiflexion training with FES for the same amount of time. [Results] The BCI-FES group demonstrated significant differences in the frontopolar regions 1 and 2 attention indexes, and frontopolar 1 activation index. The FES group demonstrated no significant differences. There were significant differences in the frontopolar 1 region activation index between the two groups after the interventions. [Conclusion] The results of this study suggest that BCI-FES training may be more effective in stimulating brain activation than only FES training in patients recovering from stroke. PMID- 25931681 TI - Relationship between the phases of the menstrual cycle and the transversus abdominis muscle. AB - [Purpose] This study investigated changes in the thickness of the transversus abdominis muscle at various stages of the menstrual cycle. [Subjects] The subjects were 15 young healthy females with regular menstrual cycles. [Methods] A regular menstrual cycle was defined as a 28-day cycle comprising 3 phases: the menstrual phase, the follicular phase, and the luteal phase. For the purpose of the study, measurements were taken at day 3 (menstrual phase), day 12 (follicular phase), and day 21 (luteal phase) of the cycle. An ultrasonic imaging diagnostic device (MyLab 25) and a linear expression probe were used for measurement of the transversus abdominis muscle. [Results] There were no significant differences in the variation rate of the thickness of the muscle at any phase of the menstrual cycle. [Conclusion] The results suggested that the sex hormones associated with the menstrual cycle do not affect the contractility or changes in the thickness of the transversus abdominis muscle. For the reasons stated above, there is little need to consider the menstrual cycle when measuring muscle thickness in physical therapy scenarios because the transversus abdominis muscle does not depend on the menstrual cycle. PMID- 25931682 TI - The effect of Kinesio Taping on handgrip strength. AB - [Purpose] The purpose of this research was to evaluate the change in muscle function induced by a Kinesio Tape application with no or moderate tension, to the dominant and non-dominant arms. [Subjects and Methods] This research was a quantitative study, in which 75 women participated. The subjects, aged 18-30 years, were divided into 3 groups, Kinesio, Kinesio without Tension, and Control, and they were assessed before the taping intervention and after 30 minutes, 24 hours, and 48 hours of taping. [Results] The Kinesio group subjects demonstrated an increase in handgrip strength after 30 minutes, 24 hours, and 48 hours of tape application compared to control. A statistically significant increase in strength was observed in the Kinesio group comparison to the Control after 24 hours and 48 hours for the right hand, and after 48 hours for the left hand. Improvement in the Kinesio group compared to the Kinesio without Tension was observed only after 24 hours of taping application, and only in the right hand. [Conclusion] The Kinesio Taping method augmented the handgrip strength of healthy women, and the increase in grip strength was maintained for 48 hours after its application; the dominant hand demonstrated the greatest strength values. PMID- 25931683 TI - The effect of foot position on erector spinae and gluteus maximus muscle activation during sit-to-stand performed by chronic stroke patients. AB - [Purpose] The aim of this study was to use surface electromyography (EMG) to investigate the effects of different foot positioning on bilateral erector spinae (ES) and gluteus maximus (GM) activation during sit-to-stand performed by individuals with stroke. [Subjects] Fifteen randomly selected participants with stroke were enrolled in this study. [Methods] All the participants were asked to perform sit-to-stand (STS) using three different strategies: (1) symmetric foot position, (2) unaffected foot placed behind the affected foot position (asymmetric-1), (3) affected foot placed behind the unaffected foot position (asymmetric-2). An EMG system was used to measure ES and GM muscle activities. The strategies were performed in a random order, and the mean values of five measurements were used in the analysis. One-way repeated measure ANOVA was used to determine the statistical significance of differences between the conditions. [Results] The affected ES muscle activity was significantly greater in asymmetric 2 (180.7+/-73.4) than in symmetrical foot placement (149.8+/-54.2). In addition, the affected ES, unaffected ES, and affected GM muscle activity were significantly greater in asymmetric-2 (180.7+/-73.4, 173.5+/-83.1, 98.3+/-90.3 respectively) than in asymmetric-1 foot placement (147.3+/-53.8, 151.2+/-76.5, 84.9+/-73.8 respectively). [Conclusion] Our results suggest that it may be more desirable for persons with stroke to place the affected foot behind the unaffected foot when performing STS to increase affected ES and GM muscle activation. PMID- 25931684 TI - The relationship between smartphone use and subjective musculoskeletal symptoms and university students. AB - [Purpose] The purpose of this study was to investigate the use of smartphones by university students in selected areas, their musculoskeletal symptoms, and the associated hazard ratio. [Subjects and Methods] This involved the completion of a self-administered questionnaire by dental hygiene students in Seoul, Gyeonggido, and Gyeongsangbukdo. The 292 completed copies of the questionnaire were then analyzed. [Results] The most painful body regions after the use of smartphones were found to be the shoulders and neck. In the musculoskeletal system, back pain was found to have a positive correlation with the size of the smartphone's liquid crystal display (LCD) screen, and pain in legs and feet were found to have a negative correlation with the length of time that the smartphone was used. As a result, it was revealed that the use of a smartphone was correlated with musculoskeletal symptoms. [Conclusion] Therefore, in today's environment, where the use of smartphones is on the rise, it is necessary to improve the ways that they are used and to develop a preventive program to alleviate the symptoms of musculoskeletal damage. PMID- 25931685 TI - Effects of exercise therapy on muscular strength in firefighters with back pain. AB - [Purpose] The purpose of this study was to determine how an exercise program focusing on muscular strength could aid firefighters with chronic lower back pain. [Subjects] The research subjects were randomly assigned to two groups, the experimental group (n=8) and the control (n=8). [Methods] The experimental group performed two types of exercise programs four times per week for 8 weeks under supervision. Tests were performed before and after the 8 weeks of exercise in accordance with the Korea Occupational Safety and Health Agency's program. [Results] At the end of the 8 weeks of the rehabilitation program, abdominal muscular strength were significantly increased in the experimental group, and this indicates that the exercise therapy was effective for improvement of muscular strength. [Conclusion] We found that exercise therapy is an effective intervention that can reduce the pain of patients with chronic lower back pain. The firefighters with chronic lower back pain who participated in this study exhibited enhanced lower back muscular strength and obtained some additional benefits. They need regular exercise. PMID- 25931686 TI - Aerobic exercise training in modulation of aerobic physical fitness and balance of burned patients. AB - [Purpose] This study aimed to determine the impact of aerobic exercise on aerobic capacity, balance, and treadmill time in patients with thermal burn injury. [Subjects and Methods] Burned adult patients, aged 20-40 years (n=30), from both sexes, with second degree thermal burn injuries covering 20-40% of the total body surface area (TBSA), were enrolled in this trial for 3 months. Patients were randomly divided into; group A (n=15), which performed an aerobic exercise program 3 days/week for 60 min and participated in a traditional physical therapy program, and group B (n=15), which only participated in a traditional exercise program 3 days/week. Maximal aerobic capacity, treadmill time, and Berg balance scale were measured before and after the study. [Results] In both groups, the results revealed significant improvements after treatment in all measurements; however, the improvement in group A was superior to that in group B. [Conclusion] The results provide evidence that aerobic exercises for adults with healed burn injuries improve aerobic physical fitness and balance. PMID- 25931687 TI - Gait analysis of elderly women after total knee arthroplasty. AB - [Purpose] The purpose of this study was to investigate ability and muscle activities of elderly women after total knee arthroplasty (TKA) and compare them with those of healthy ones. [Subjects and Methods] Fifteen female patients with TKA due to advanced degenerative arthritis of the measured on knee joint and 19 healthy elderly females participated. Tibiofemoral angles of TKA patients were using a gait analysis system anterioposterior X-rays of the weight-bearing knee. The knee flexion angle and gait parameters were measured. Muscle activities and prolongation time were EMG system. The gait of the treated limb of each participant was evaluated in three consecutive trials at fast speed and comfortable speed. [Results] The knee flexion angle %stance phase, stride length, step length, speed, cadence, and gait cycle significantly decreased at both the fast speed and comfortable speeds, and the onset and duration time of rectus femoris activity was significantly increased at the comfortable speed in the TKA group. [Conclusion] In conclusion, elderly women who received TKA showed decreased gait ability and muscle activity compared to the healthy elderly women. PMID- 25931688 TI - Motion analysis of wheelchair propulsion movements in hemiplegic patients: effect of a wheelchair cushion on suppressing posterior pelvic tilt. AB - [Purpose] This study sought to ascertain whether, in hemiplegic patients, the effect of a wheelchair cushion to suppress pelvic posterior tilt when initiating wheelchair propulsion would continue in subsequent propulsions. [Subjects] Eighteen hemiplegic patients who were able to propel a wheelchair in a seated position participated in this study. [Methods] An adjustable wheelchair was fitted with a cushion that had an anchoring function, and a thigh pad on the propulsion side was removed. Propulsion movements from the seated position without moving through three propulsion cycles were measured using a three dimensional motion analysis system, and electromyography was used to determine the angle of pelvic posterior tilt, muscle activity of the biceps femoris long head, and propulsion speed. [Results] Pelvic posterior tilt could be suppressed through the three propulsion cycles, which served to increase propulsion speed. Muscle activity of the biceps femoris long head was highest when initiating propulsion and decreased thereafter. [Conclusion] The effect of the wheelchair cushion on suppressing pelvic posterior tilt continued through three propulsion cycles. PMID- 25931689 TI - Rasch validation of the SF-36 for assessing the health status of Korean older adults. AB - [Purpose] To verify, using Rasch analysis, the applicability of the 36-Item Short Form Health Survey (SF-36) to elderly Koreans, as this instrument would be useful for determining elderly individuals' overall performance and providing them with health information. [Subjects and Methods] The SF-36 was administered to a sample of 510 individuals aged over 60 living in the Seoul and Gyeonggi areas of South Korea. When testing for goodness-of-fit, we considered items with infit and outfit indexes of over 1.30 or less than 0.70 to be incongruent. SF-36 factors that contained over three items, including physical functioning, role limitations (physical and emotional), mental health, vitality, and general health, were analyzed. Each factor was examined through step calibration of the response categories in the probability curve. [Results] The response categories were found to be appropriate because the adjustment values of each factor increased. We found five items in physical functioning, two items in role limitation-emotion, one item in mental health, and one item in general health to be incongruent; all items in the role limitation-physical and vitality factors were congruent. [Conclusion] We conclude that the SF-36 could be revised to more accurately measure the health status of elderly Koreans. PMID- 25931690 TI - Effects of horse-riding exercise on balance, gait, and activities of daily living in stroke patients. AB - [Purpose] This study aimed to investigate the effects of horse-riding exercise on balance, gait, and activities of daily living (ADLs) in stroke patients. [Subjects] Among 20 participants with stroke, 10 were randomly assigned to the experimental group, and 10 were randomly assigned to the control group. The experimental group participated in horse-riding exercise for 30 minutes per day, 5 days a week for 6 weeks. Balance was tested with the Berg Balance Scale (BBS). Gait was measured using the 10-Meter Walk Test (10MWT). ADLs were tested with the Modified Barthel Index (MBI). Differences between pre- and post-experiment values within the two groups were compared using paired t-tests. Between-group differences were compared using independent t-tests. [Results] The experimental group showed significant improvements in balance, gait, and ADLs following horse riding exercise. Additionally, the experimental group showed significant differences in balance, gait, and ADLs compared with in the control group. [Conclusion] These results support that horse-riding exercise enhances balance, gait, and ADLs in stroke patients. This study supports the need for further research on horse-riding exercise programs. PMID- 25931691 TI - Effect of gait training with constrained-induced movement therapy (CIMT) on the balance of stroke patients. AB - [Purpose] The purpose of the present study was to examine the effect of intensive gait training using a constrained induced movement therapy (CIMT) technique applied to the non-paretic upper extremity on the balance ability of stroke patients. [Subjects and Methods] Twenty stroke patients were randomly assigned to an experimental group or a control group. The experimental group received gait training with CIMT for 30 minutes per session, three sessions per week for four weeks, and the control group received gait training alone. [Results] The experimental group showed improvements in dynamic balance and the degree of improvement in this group was greater than that observed in the control group. Furthermore, the experimental group showed improvements in movement distances to the paretic side. On the other hand, the control group showed no significant improvements in balance indices after the intervention. [Conclusion] Gait training of stroke patients using CIMT techniques should be regarded as a treatment that can improve the balance of stroke patients. PMID- 25931692 TI - Body balance under ametropic conditions induced by spherical lenses in an upright position. AB - [Purpose] To investigate the changes in body balance under ametropic conditions induced by spherical lenses in an upright position. [Subjects and Methods] Twenty subjects (10 males, 10 females) of average age 23.4+/-2.70 years participated and they were fully corrected by subjective refraction. To induce ametropic conditions (binocular myopia and hyperopia), lenses of +/-0.50 D, +/-1.00 D, +/ 1.50 D, +/-2.00 D, +/-3.00 D, +/-4.00 D and +/-5.00 D were used. General stability (ST), fall risk index (FI), and sway path (SP) were analyzed through changes in synchronization of left/right and toe/heel, as measured by the biofeedback system, TETRAX. Measurement was performed for 32 seconds for each condition. [Results] ST increased significantly from +0.50 D-induced myopia and from -1.00 D-induced hyperopia as compared with corrected emmetropia. FI increased significantly from +4.00 D-induced myopia and from -1.50 D-induced hyperopia as compared with corrected emmetropia. In SP, which means a change of body balance, toe/heel was significantly greater than left/right in all ametropic conditions. SP of right/left synchronization was not affected by the side of the dominant eye. [Conclusion] An uncorrected hyperope may cause subjects to have a higher risk of falling than an uncorrected myope. Therefore, clinical specialists should consider the refractive condition, especially hyperopia, when analyzing body balance. PMID- 25931693 TI - Core strength training for patients with chronic low back pain. AB - [Purpose] Through core strength training, patients with chronic low back pain can strengthen their deep trunk muscles. However, independent training remains challenging, despite the existence of numerous core strength training strategies. Currently, no standardized system has been established analyzing and comparing the results of core strength training and typical resistance training. Therefore, we conducted a systematic review of the results of previous studies to explore the effectiveness of various core strength training strategies for patients with chronic low back pain. [Methods] We searched for relevant studies using electronic databases. Subsequently, we evaluated their quality by analyzing the reported data. [Results] We compared four methods of evaluating core strength training: trunk balance, stabilization, segmental stabilization, and motor control exercises. According to the results of various scales and evaluation instruments, core strength training is more effective than typical resistance training for alleviating chronic low back pain. [Conclusion] All of the core strength training strategies examined in this study assist in the alleviation of chronic low back pain; however, we recommend focusing on training the deep trunk muscles to alleviate chronic low back pain. PMID- 25931694 TI - Effect of application of transcranial direct current stimulation during task related training on gait ability of patients with stroke. AB - [Purpose] The objective of this study was to determine the effect of transcranial direct current stimulation (tDCS) during task-related training (TRT) on the gait ability of patients with chronic stroke. [Subjects and Methods] The participants were 24 patients who were diagnosed with hemiplegia due to stroke. Three groups were created: subjects who performed TRT for general exercise therapy (TRT), subjects who received sham tDCS during TRT for general exercise therapy (TST), and subjects who received tDCS during TRT for general exercise therapy (TT). [Results] The stance phase symmetry profile, the swing phase symmetry profile, and gait velocity all decreased significantly in the TT group compared with the TRT group. However, there was no significant difference in the step length symmetry profile among the groups. [Conclusion] A application of tDCS, that affects the excitatory regulation in the cortical motor area, is an effective rehabilitation method for gait improvement. PMID- 25931695 TI - Effect of exercise at light loads with manipulative resistance on infraspinatus, trapezius (upper fiber) and deltoid (middle fiber) muscle activities in shoulder joint elevation. AB - [Purpose] To clarify rotator cuff muscular activity in the raised position of the closed kinetic chain (CKC) exercise. [Subjects] Twenty-nine cases were studied, 19 men and 10 women (average age 21.5 +/-4.7 years old, average body weight 60.1 kg +/-11.4). [Methods] To determine the effects of the closed kinetic chain exercise on the upper limb, we measured the surface EMG of the infraspinatus muscle, the trapezius (upper fiber) and the deltoid (middle fiber) with the arm elevated. [Results] Our results show that at an elevation angle of 150 degrees in the scapular plane of the upper limb, with 5% body weight load, the EMG activities of the infraspinatus muscle are approximately 30% of maximum voluntary contraction (MVC). [Conclusion] The raised position of the CKC exercise is effective in physical therapy for functional recovery of the infraspinatus muscle. PMID- 25931696 TI - EMG and peak force responses to PNF stretching and the relationship between stretching-induced force deficits and bilateral deficits. AB - [Purpose] The aim of the present study was to investigate the possibility of an interaction between stretching induced deficit (SFD) and bilateral deficits (BLD) during maximal voluntary isometric hand flexion under PNF stretch and no-stretch conditions through measurement of EMG and force production. [Subjects and Methods] Ten physically active male Caucasian students (age, 24.1+/-2.38 years; body mass, 79.48+/-11.40 kg; height, 174.15+/-0.8 cm) volunteered to participate in this study. EMG and force measurements of the subjects were recorded during either unilateral or bilateral 3-second maximal voluntary isometric hand flexion (MVC) against a force transducer. The paired sample t-test was used to examine the significance of differences among several conditions. Pearson product-moment correlation was used to evaluate the associations between different parameters. [Results] Stretching-induced deficits correlated with bilateral deficits in both force (r=0.85) and iEMG (r=0.89). PNF stretching caused significant decrements in the bilateral and unilateral conditions for both the right and left sides. [Conclusion] Since both force and iEMG decreases were observed in most measurements; it suggests there is a neural mechanism behinnd both the BLD and the SFD. PMID- 25931697 TI - Effect of anticipation triggered by a prior dyspnea experience on brain activity. AB - [Purpose] Oxygenated hemoglobin (oxy-Hb) concentrations in the prefrontal cortex are closely associated with dyspnea. Dyspnea is influenced not only by physical activity, but also by visual stimuli, and several studies suggest that oxy-Hb concentrations change in response to certain external stimuli. However, the effects of internal psychological states on dyspnea have not been reported. This study explored the influence of anticipation triggered by previous episodes of dyspnea on brain activity. [Subjects] The subjects were 15 healthy volunteers with a mean age of 25.0 +/- 3.0 years. [Methods] The subjects were shown a variety of photographs and instructed to expect breathing resistance matched to the affective nature of the particular photograph. After viewing the images, varying intensities of breathing resistance that were identical to, easier than, or harder than those shown in the images were randomly administered to the subjects; in fact, the image and resistance were identical 33% of the time and discordant 66% of the time. [Results] The concentrations of oxy-Hb in the right medial prefrontal cortex (rMPFC) increased significantly with an inspiratory pressure that was 30% of the maximum intensity in the subjects shown a pleasant image compared to the concentrations in subjects shown an unpleasant image. Moreover, rMPFC activity was significantly correlated with the magnitude of the dyspnea experienced. [Conclusion] These results suggest that a correlation exists between increased oxy-Hb in the rMPFC and the effects of expectations on dyspnea. PMID- 25931698 TI - Effect of a muscle strengthening exercise program for pelvic control on gait function of stroke patients. AB - [Purpose] The purpose of this study was to investigate the effects of strengthening exercises for the hip extensors on the gait performance and stability of patients with hemiplegia. [Subjects and Methods] The subjects were fifteen stroke patients (ten males, five females). The experimental subjects performed a hip extensor strengthening exercise (HESE) program for a total of four weeks. [Results] The experimental subjects showed significant improvements after the HESE program. Especially, walking speed and the affected side stance phase time significantly increased after the HESE program. Furthermore, the affected side stride length and symmetry index in the stance phase significantly increased after HESE program. [Conclusion] These results suggest that the HESE program may, in part, help to improve gait performance ability and stabilize physical disability after stroke. PMID- 25931699 TI - Exercise intensity criteria for routine rehabilitation therapy for stroke patients. AB - [Purpose] The aim of this study was to observe the relationships among heart rate, rate of perceived exertion, and oxygen consumption in stroke patients and the effectiveness of improving aerobic capacity during routine rehabilitation therapy. [Subjects and Methods] Thirty-six stroke patients participated in the study. A K4b(2) pulmonary function device was used to record heart rate (beats per minute), oxygen consumption (Equation Section (Next)ml.min(-1).kg(-1)), and rate of perceived exertion. Results were recorded after completing the following activities continuously: (1) silent sitting, (2) sit-to-stand transfers, (3) hip extension while standing against a wall, (4) weight loading on the affected leg, (5) upward and downward leg movements on a stall bar, (6) walking up and down a flight of stairs, and (7) a 60-meter walk. Correlation analyses were performed to demonstrate the relationship of oxygen consumption with HR and RPE. [Results] Moderate correlation was found between HR and oxygen consumption, and low correlation was found between rate of perceived exertion and oxygen consumption. The routine rehabilitation therapy could reduce the accumulation of lactate. [Conclusion] HR is a better index than rate of perceived exertion in evaluating exercise intensity in stroke patients. The routine rehabilitation therapy can improve the aerobic capacity of stroke patients. PMID- 25931700 TI - Improvement of pulmonary function with arm swing exercise in patients with type 2 diabetes. AB - [Purpose] Obesity and hyperglycemia play roles in the impairment of pulmonary function in type 2 diabetes mellitus (T2DM) patients. Low-intensity exercise is known to reduce body fat and improve hyperglycemia. The arm swing exercise (ASE), a low-intensity exercise, is easy and convenient to perform without any equipment and is suitable for daily practice. Therefore, we aimed to investigate the effects of ASE on lung function and obesity in overweight T2DM patients. [Subjects and Methods] Twenty-four subjects continued their daily life routines for 8 weeks (control period), and then performed ASE for 8 weeks (30 minutes per day, 3 days per week) (ASE period). Pulmonary function tests were performed, and fasting blood glucose, haemoglobin A1c (HbA1c), lipid profiles, high-sensitive C reactive protein (HSCRP), insulin concentration, and anthropometric parameters were measured before and after each period. [Results] After the ASE period, the forced vital capacity, forced expiratory volume in the first second of expiration, and maximal voluntary ventilation were increased when compared with after the control period. HbA1c, a low-density lipoprotein, malondialdehyde, oxidized glutathione, and the percent body fat were significantly decreased when compared with after the control period. However, other parameters, such as lung volume, anthropometric parameters, and fasting blood glucose, insulin, high density lipoprotein, triglycerides, total cholesterol and glutathione concentrations, showed no differences between the two periods. [Conclusion] These data suggest that there is improvement of pulmonary functions in T2DM patients after ASE training. PMID- 25931701 TI - Effects of community-based virtual reality treadmill training on balance ability in patients with chronic stroke. AB - [Purpose] We aimed to examine the effectiveness of a community-based virtual reality treadmill training (CVRTT) program on static balance abilities in patients with stroke. [Subjects and Methods] Patients (n = 20) who suffered a stroke at least 6 months prior to the study were recruited. All subjects underwent conventional physical therapy for 60 min/day, 5 days/week, for 4 weeks. Additionally, the CVRTT group underwent community-based virtual reality scene exposure combined with treadmill training for 30 min/day, 3 days/week, for 4 weeks, whereas the control group underwent conventional physical therapy, including muscle strengthening, balance training, and indoor and outdoor gait training, for 30 min/day, 3 days/week, for 4 weeks. Outcome measurements included the anteroposterior, mediolateral, and total postural sway path lengths and speed, which were recorded using the Balancia Software on a Wii Fit(TM) balance board. [Results] The postural sway speed and anteroposterior and total postural sway path lengths were significantly decreased in the CVRTT group. Overall, the CVRTT group showed significantly greater improvement than the control group. [Conclusions] The present study results can be used to support the use of CVRTT for effectively improving balance in stroke patients. Moreover, we determined that a CVRTT program for stroke patients is both feasible and suitable. PMID- 25931702 TI - The effect of cocontraction of the masticatory muscles during neck stabilization exercises on thickness of the neck flexors. AB - [Purpose] The purpose of this study was to determine the effect of the cocontraction of masticatory muscles during neck stabilization exercises on changes in the thickness of the neck flexors. [Subjects and Methods] Twenty subjects performed neck stabilization only exercise and neck stabilization exercise with simultaneous contraction of the masticatory muscles. Changes in the thickness of the longus colli and sternocleidomastoid were then measured by ultrasound. [Results] The thickness of the longus colli increased significantly fallowing cocontraction of the masticatory muscles and neck stabilization exercise, whereas the exercise method used had no significant effect on the thickness of the sternocleidomastoid. [Conclusion] Cocontraction of the masticatory muscles during neck stabilization exercise is helpful in increasing the thickness of longus colli muscle. PMID- 25931703 TI - The relationship between obesity and health-related quality of life of office workers. AB - [Purpose] This study aimed to understand how office workers' obesity, anxiety and health-related quality of life (HRQOL) affect each other. [Subjects] The study was conducted from February 1 of 2013 to March 31 of 2014 and targeted a total of 143 office workers working in Seoul, Republic of Korea. [Methods] The study collected data using both an assessment tool and questionnaire in order to learn the subjects' obesity index, anxiety and HRQOL. [Results] The study revealed a significant difference in the total scores in regard to how the obesity index influences anxiety, mental HRQOL and total HRQOL. The more overweight and the heavier the subjects were, the more severe was the anxiety observed, which resulted in decreased scores for mental HRQOL and total HRQOL. Obesity turned out to be significantly correlated with anxiety, mental HRQOL and total HRQOL, and in terms of how much anxiety the subjects felt, there was a significant correlation with the total scores for physical HRQOL, mental HRQOL and total HRQOL. [Conclusion] The present study found that overweight and obese office workers are more anxious than office workers with normal weights, as the former have a lower mental HRQOL. It also suggests that overweight and obese office workers should improve their mental HRQOL through professional workout programs, which would help with their obesity problem. The study also suggests that subsequent research should be carried out to observe the results of any such workout programs applied in the future. PMID- 25931704 TI - Effects of Ving Tsun Chinese martial art training on musculoskeletal health, balance performance, and self-efficacy in community-dwelling older adults. AB - [Purpose] The aim of this study was to investigate the effects of Ving Tsun (VT) Chinese martial art training on radial bone strength, upper- and lower-limb muscular strength, shoulder joint mobility, balance performance, and self efficacy in elderly participants. [Subjects and Methods] Twelve seniors voluntarily joined the VT training group, and twenty-seven seniors voluntarily joined the control group. The VT group received VT training for three months, while the control group received no training. The bone strength of the distal radius was assessed using an ultrasound bone sonometer. Muscular strength in the limbs was evaluated using a Jamar handgrip dynamometer and the five times sit-to stand test. Shoulder joint mobility was examined using a goniometer. Balance performance and self-efficacy were evaluated using the Berg Balance Scale and the Chinese version of the Activities-specific Balance Confidence Scale, respectively. [Results] The results revealed a nonsignificant group-by-time interaction effect, group effect, and time effect for all outcome variables. However, general trends of maintenance or improvement in all outcome parameters were observed to a greater extent in the VT group than in the control group. [Conclusion] VT training might be a potential fall-prevention exercise that can be used to maintain general physique, balance, and confidence in the elderly population. A further randomized controlled trial is needed to confirm this postulation. PMID- 25931705 TI - The effect of neurofeedback on a brain wave and visual perception in stroke: a randomized control trial. AB - [Purpose] This study investigated a brain wave and visual perception changes in stroke subjects using neurofeedback (NFB) training. [Subjects] Twenty-seven stroke subjects were randomly allocated to the NFB (n = 13) group and the control group (n=14). [Methods] Two expert therapists provided the NFB and CON groups with traditional rehabilitation therapy in 30 thirst-minute sessions over the course of 6 weeks. NFB training was provided only to the NFB group. The CON group received traditional rehabilitation therapy only. Before and after the 6-week intervention, a brain wave test and motor free visual perception test (MVPT) were performed. [Results] Both groups showed significant differences in their relative beta wave values and attention concentration quotients. Moreover, the NFB group showed a significant difference in MVPT visual discrimination, form constancy, visual memory, visual closure, spatial relation, raw score, and processing time. [Conclusion] This study demonstrated that NFB training is more effective for increasing concentration and visual perception changes than traditional rehabilitation. In further studies, detailed and diverse investigations should be performed considering the number and characteristics of subjects, and the NFB training period. PMID- 25931706 TI - Effects of upper limb robot-assisted therapy in the rehabilitation of stroke patients. AB - [Purpose] The aim of this study was to examine the effects of upper limb robot assisted therapy in the rehabilitation of stroke patients. [Subjects and Methods] Fifteen stroke patients with no visual or cognitive problems were enrolled. All subjects received robot-assisted therapy and comprehensive rehabilitation therapy for 30 minutes each. The experimental group received a conventional therapy and an additional half hour per weekday of robot therapy. The patients participated in a total of 20 sessions, each lasting 60 minutes (conventional therapy 30 min, robot-assisted therapy 30 min), which were held 5 days a week for 4 weeks. [Result] The patients showed a significant difference in smoothness and reach error of the point to point test, circle size and independence of the circle in the circle test, and hold deviation of the playback static test between before and after the intervention. On the other hand, no significant difference was observed in the displacement of the round dynamic test. The patients also showed significant improvement in the Fugl-Meyer Assessment and Modified Barthel Index after the intervention. [Conclusion] These kinematic factors can provide good information when analyzing the upper limb function of stroke patients in robot assisted therapy. Nevertheless, further research on technology-based kinematic information will be necessary. PMID- 25931708 TI - Improved underpants to reduce toileting problems in patients with poor standing balance. AB - [Purpose] We developed and assessed improved underpants allowing patients to easily and completely open the crotch by pulling upward a string on the back of the underpants while seated. [Subjects and Methods] Healthy subjects tested commercial open-crotch underpants for disabled people and our improved open crotch underpants by opening the crotch while seated. Measurement parameters included the percentage of crotch opening and the degree of genital or anal exposure before and after opening the crotch, as well as fit. The percentage of crotch opening and the degree of genital or anal exposure were recorded with a digital camera, and fit was determined with a visual analog scale. The measurements for both types of underpants were then compared. [Results] The commercial underpants for disabled people allowed opening of the crotch while seated, but the exposure of the genital and anal areas was insufficient to allow waste elimination. The improved underpants allowed sufficient opening of the crotch while seated and adequately exposed the genital and anal areas. The fit score of the improved underpants was significantly better than that of the commercial underpants. [Conclusion] The improved open-crotch underpants may allow for more effective opening of the crotch while seated than commercial open-crotch underpants for disabled people. PMID- 25931707 TI - Effects of a cognitive-enhancement group training program on daily living activities, cognition, and depression in the demented elderly. AB - [Purpose] The effects of a cognitive enhancement group training program on daily living activities, cognition, and depression in the demented elderly population of a local Korean community were investigated. [Subjects and Methods] The study included 22 elderly subjects who were 65 years of age or older, had been diagnosed with dementia, and were attending a daily care center in K City, Republic of Korea. Eleven subjects participated in the program, which was conducted twice a week for 8 weeks for a total of 16 sessions. Eleven subjects in a non-training group did not receive any interventions. [Results] The MMSE-K, MBI and KDS scores of all of the eleven subjects who participated in the program improved, and the improvements were statistically significant. [Conclusion] Cognitive enhancement group training programs may have positive effects on daily living activities, cognition, and depression. PMID- 25931709 TI - The effect of simulating a leg-length discrepancy on pelvic position and spinal posture. AB - [Purpose] The purpose of this study was to examine how a leg-length discrepancy contributes to the pelvic position and spinal posture. [Subjects and Methods] A total of 20 subjects (10 males, 10 females) were examined during different artificially created leg-length inequalities (0-4 cm) using a platform. The pelvic tilt and torsion and the sagittal deviation of the spine were measured using the rasterstereographic device formetric 4D. [Results] Changes in platform height led to an increase in pelvic tilt and torsion, while no changes in the spinal posture were found with the different simulated leg-length inequalities. [Conclusion] Our study showed that a leg-length discrepancy may cause pelvic deviation and torsion, but may not lead to kyphosis and lordosis. Therefore, we consider that an artificially created leg-length discrepancy has a greater effect on pelvic position than spine position. PMID- 25931710 TI - The perioperative changes in physical function and physique of patients with gastrointestinal cancer. AB - [Purpose] The purpose of this study was to observe the long-term change in physical function and physique from perioperative to discharge of patients with gastrointestinal cancer. [Subjects and Methods] Subjects were 47 perioperative patients with gastrointestinal cancer [25 men and 22 women aged 61.3 +/- 11.0 years (mean +/- SD)]. Six-minute walk distance was measured for physical function and body mass index and calf circumference were measured for physique. These items were evaluated at three time points: before surgery, after surgery, and after discharge. [Results] Significant declines in physical function and physique were observed temporarily after surgery. Physical function improved equally before surgery in after discharge. On the other hand, postoperative physique was significantly lower than that observed pre-operatively. [Conclusion] These results suggest that the perioperative changes in physical function and physique follow different courses in patients with gastrointestinal cancer. PMID- 25931711 TI - Comparison of energy expenditure during the Y-balance test in older adults with different visual acuities. AB - [Purpose] This study compared the energy expenditure during the Y-balance test (YBT) between elderly women with good binocular visual acuity (BVA) and those with poor BVA. [Subjects] Twenty-one elderly women who could walk independently were recruited from a community dwelling. Eleven participants had a BVA equal to or less than 0.4 logarithm of the minimum angle of resolution (logMAR), and the other 10 participants had a BVA equal to or better than 0.3 logMAR. [Methods] The participants had an accelerometer attached over the L3 spinous process for measurement of energy expenditure and performed the YBT in the anterior, posteromedial, and posterolateral directions. [Results] The normalized reach distance in the good BVA group during the YBT in three directions and composite reach distance were significantly longer compared with the values in the poor BVA group. The energy expenditure in the good BVA group during the YBT in the three directions was significantly reduced compared with the values in the poor BVA group. [Conclusion] We suggest that visual acuity in the elderly influences dynamic balance and energy expenditure. Elderly subjects with poor BVA showed poor dynamic balance control and an inefficient biomechanical cost strategy compared to subjects with good BVA. PMID- 25931712 TI - Upper extremity muscle activation during drinking from a glass in subjects with chronic stroke. AB - [Purpose] The purpose of this study was to compare the muscle activities of upper extremities during a drinking task between the stroke-affected and less-affected sides. [Subjects] Eight stroke patients (8 men; age 45.3 years; stroke duration 21.9 months) participated in this study. [Methods] Electromyography (EMG) was used to measure nine muscle activities of the upper extremity. The drinking task was divided into 5 phases. [Results] Analysis of the EMG data showed that the percentage of maximum voluntary isometric contraction (%MVIC) across all phases of drinking differed between the affected and less-affected sides. Participants used relatively higher levels of %MVIC in the anterior deltoid, flexor muscles, brachioradialis, and infraspinatus on the stoke-affected side. [Conclusion] The difference in muscle activation across all phases of the drinking movement allowed us to determine how upper extremity muscle activation may influence drinking performance on the stroke-affected and less-affected sides. PMID- 25931713 TI - Relationship between foot posture measurements and force platform parameters during two balance tasks in older and younger subjects. AB - [Purpose] The aim of this study was to compare age-related differences in balance and anthropometric posture measurements of the foot and to determine any relationship between them. [Subjects and Methods] Sixty-eight older and 42 younger adults participated in this study. Foot posture was tested for four domains: 1) hallux flexion and extension range of motion using a goniometer, 2) navicular height and 3) length of the foot using a pachymeter, and 4) footprint (width of forefoot, arch index and hallux valgus). Balance was tested under two conditions on a force platform: bipodal in 60-s trials and unipodal in 30-s trials. The sway area of the center of pressure and velocity in the anteroposterior and mediolateral directions were computed. [Results] Older individuals showed significantly poorer balance compared with younger adults under in the unipodal condition (center of pressure area 9.97 vs. 7.72 cm(2)). Older people presented a significantly lower hallux mobility and higher values for width of the forefoot and transverse arch index than younger adults. The correlations between all foot posture and center of pressure parameters varied across groups, from weak to moderate (r -0.01 to -0.46). Low hallux mobility was significantly related to higher center of pressure values in older people. [Conclusion] These results have clinical implications for balance and foot posture assessments. PMID- 25931714 TI - The effect of superficial trunk muscle exercise and deep trunk muscle exercise on the foot pressure of healthy adults. AB - [Purpose] The purpose of this study was to analyze the effect of superficial trunk muscle exercise and deep trunk muscle exercise on the foot pressure of healthy adults. [Subjects] The subjects were 30 healthy females and males who agreed to participate in this study. There were two groups, a superficial trunk muscle exercise group and a deep trunk muscle exercise group, with 15 participants in each. [Methods] The exercises were conducted 5 times a week for 4 weeks for both groups. A gait analyzer was used to measure foot plantar pressure while walking on a plate. Participants were measured before starting the exercise and after 4 weeks. The paired t-test was used to analyze the pre-and post-test results. [Results] There were no significant differences in foot pressure in any region in the superficial trunk muscle exercise group. In the deep trunk muscle exercise group, there were statistically significant increase in F1, F4, F5, R1 and R3. In addition, there were significant decreases in R2 and R4. [Conclusion] After the 4-week deep trunk muscle exercise group decreases in foot pressure on the inner foot and increases on the outside of the feet indicate normal and overall even distribution of body weight on the feet. PMID- 25931715 TI - Difficulty levels of OSCE items related to examination and measurement skills. AB - [Purpose] The difficulty levels of level-2 OSCE (examination and measurement skills) items were examined, with a view to providing reference data for the determination of students' skills. [Subjects] A total of 284 graduates of physical (PT) and occupational (OT) therapy classes of 2011 (59 and 40), 2012 (46 and 36), and 2013 (61 and 42, respectively) were studied, with PT or OT faculty members as OSCE examiners and a simulated patient. [Methods] Scores for 11 level 2 OSCE items were compared between before and after clinical training. [Results] Scores markedly increased after clinical training. On comparison among the items, scores for sensory examination were the highest, and those for interviews were the lowest. [Conclusion] The results of this study indicate the necessity of considering an appropriate combination of different difficulty levels when adopting OSCE-based educational approaches. PMID- 25931716 TI - What is the effect of peripheral muscle fatigue, pulmonary function, and body composition on functional exercise capacity in acromegalic patients? AB - [Purpose] The six-minute walk test (6MWT) is increasingly being used as an important tool for analyzing functional capacity in patients with multisystem disorders. The aim of this study was to evaluate the effect of body composition, peripheral muscle function, and pulmonary function on the six-minute walk distance (6MWD) in acromegalic patients. [Subjects and Methods] Thirty-two patients with active acromegaly, with a mean age of 48.6 +/- 12.1 years, underwent an evaluation of body composition using electrical bioimpedance, isometric dynamometry with surface electromyography, tests of pulmonary function, and the 6MWT. [Results] The mean +/- SD values for the 6MWD, fat-free mass (FFM), and maximal expiratory pressure (MEP) were 65.5 +/- 11.7% predicted, 55.1 +/- 10.6 kg, and 55.2 +/- 16.8% predicted, respectively. There was a significant correlation between the 6MWD and the following parameters: the angle of the linear regression line obtained using the values of the median frequency electromyography signal over time during the fatigability test for the vastus medialis muscle (MDF, r=0.65), FFM (r=0.62), MEP (r=0.60), height((2))/resistance index (r=0.52), resistance (r=-0.50), and forced expiratory volume in 1 second (r=0.50). Multivariate analysis showed that MDF, FFM, and MEP were independent predictors of the 6MWD (R(2)=0.52). [Conclusion] The fatigability of the peripheral muscles, FFM, and MEP are the primary determinants of the 6MWD in acromegalics. PMID- 25931717 TI - The effects of t'ai chi on muscle activity, pain, and balance in females in their 20s with acute low back pain. AB - [Purpose] This study was conducted in order to examine the effects of t'ai chi on females in their 20s with acute low back pain. The subjects were 30 females in their 20s with acute low back pain. [Subjects and Methods] They were equally and randomly divided into a t'ai chi group and a stretching group. The intervention was applied three times per week, one hour each time, for a total of eight weeks. During the one hour, the subjects conducted warm-up exercises for 10 min, primary exercises for 40 min, and cool-down exercises for 10 min. In order to examine changes in low back pain in the patients according to the intervention method, muscle activity, pain, and balance elements (left and right side movement distance, forward and backward movement distance) were measured. [Results] Muscle activity and the visual analog scale score significantly decreased in both the t'ai chi group and the stretching group. Regarding changes in balance elements, the t'ai chi group's left and right side movement distance decreased, which was statistically significant. However, the t'ai chi group's forward and backward movement distance and the stretching group's forward and backward movement distance and left and right side movement distance did not change. [Conclusion] According to the results of this study, t'ai chi is considered an appropriate exercise program to reduce acute low back pain in females in their 20s. This is because when compared with stretching, it enables posture maintenance with lesser force due to decreased muscle activity, it is more helpful for improvements in balance ability, and it is effective in decreasing pain. PMID- 25931718 TI - Effects of combined application of progressive resistance training and Russian electrical stimulation on quadriceps femoris muscle strength in elderly women with knee osteoarthritis. AB - [Purpose] The aim of this study was to investigate the effects of combined application of progressive resistance training and Russian electrical stimulation on quadriceps femoris muscle strength in elderly women with osteoarthritis of the knee. [Subjects] Thirty women over 65 years of age diagnosed with knee osteoarthritis participated in the present study. The subjects were randomly assigned to a control group (n=10), a progressive resistance training group (n=10), or a Russian electrical stimulation group (n=10). [Methods] Each group was treated 3 times weekly for 8 weeks, and each session lasted 45 minutes. Muscle strength was assessed by measuring the peak torque of the quadriceps femoris muscle. Outcome measurements were performed at baseline and at the fourth and eighth weeks of the treatment period. [Results] All groups showed significant intragroup differences in the quadriceps femoris muscle peak torque after the treatment intervention. There were significant intergroup differences between the Russian electrical stimulation group and the other groups. [Conclusion] The results of this study suggest that combined application of progressive resistance training and Russian electrical stimulation can be effective in strengthening the quadriceps femoris muscle in elderly women with knee osteoarthritis. PMID- 25931719 TI - Effects of gait training with horizontal impeding force on gait and balance of stroke patients. AB - [Purpose] The purpose of this study was to investigate the effects of treadmill training with a horizontal impeding force applied to the center of upper body mass on the gait and balance of post-stroke patients. [Subjects and Methods] Twenty-four subjects with hemiplegia less than 3 months after stroke onset were randomly assigned to 2 groups: an applied horizontal impeding force on treadmill training (experimental) group (n = 12), and a control group (n = 12). Both groups walked on a treadmill at a comfortable or moderate speed for 20 minutes per day, 3 sessions per week for 8 weeks after a pre-test. The experimental group also had a horizontal impeding force applied to the center of their upper body mass. [Results] All groups demonstrated significant improvement after 8 weeks compared to baseline measurements. In intra-group comparisons, the subjects' gait ability (CGS, MGS, cadence, and step length) and balance ability (TUG, BBS, and FRT) significantly improved. In inter-group comparisons, the experimental group's improvement was significantly better in CGS MGS, cadence, step length, TUG, and BBS, but not in FRT. [Conclusion] Treadmill training was identified as an effective training method that improved gait and balance ability. A horizontal impeding force applied during treadmill training was more effective than treadmill walking training alone at improving the gait and dynamic balance of patients with stroke. PMID- 25931720 TI - Expression of brain-derived neurotrophic factor, IGF-1 and cortisol elicited by regular aerobic exercise in adolescents. AB - [Purpose] This study was conducted on adolescent subjects whose brains are still developing with the purpose of identifying the effect of 8 weeks duration of aerobic exercises on the expression of BDNF, IGF-1 and cortisol, to identify effect of aerobic exercise on the expression of cortisol, BDNF and IGF-1 related to nerve cell growth. [Subjects and Methods] The subjects were 20 junior-high school students with no history of physical illness. The students were divided into an exercise group and a control group. The exercise group performed 3 treadmill exercise times per week for 8 weeks. The exercise time for the consumption of 200 kcal was calculated and the exercises were performed by each individual for 8 weeks. [Results] The exercise group showed statistically significant in increases serum BDNF and IGF-1 after 8 weeks, but cortisol showed no significant change. There were statistically significant differences between the groups in serum BDNF and IGF-1 after 8 weeks, but the difference in cortisol levels was not significant. [Conclusion] We found that long-term regular aerobic exercises has a positive effect on the enhancement of serum BDNF levels at rest and IGF-1 of adolescents who are still undergoing through brain developments. PMID- 25931721 TI - Effects of a therapeutic climbing program on muscle activation and SF-36 scores of patients with lower back pain. AB - [Purpose] This study examined the effects of lumbar stability exercises on chronic lower back pain by using a therapeutic climbing program on lumbar muscle activity and function. [Subjects and Methods] Thirty adult subjects with chronic back pain participated. The subjects were assigned to 2 exercise groups, namely the lumbar stabilization (Mat Ex) and therapeutic climbing exercise groups (TC Ex). Each group trained for 30 minutes, 3 times a week for 4 weeks. The Short form 36-item Questionnaire (SF-36) was administered and the surface electromyographic (sEMG) activities of the lumbar muscles were measured. [Results] Both therapy groups showed significant increases in the SF-36 score, and the increase was greater in the TC Ex group. Significant increases in the sEMG activities of the lumbar muscles were found in both groups. The increases in the sEMG activities of the rectus abdominis and internal and external oblique muscles of the abdomen were greater in the TC Ex group than in the Mat Ex group. [Conclusion] These findings demonstrate that TC Ex, which is similar to normal lumbar stabilization exercise, is effective at activating and improving the function of the lumbar muscles. These results suggest that TC Ex has a positive impact on the stabilization of the lumbar region. PMID- 25931722 TI - Effect of backpack position on foot weight distribution of school-aged children. AB - [Purpose] In the present study, we aimed to determine the effects of backpack position on foot weight distribution of standing school-aged children. [Subjects] Thirty school-aged children volunteered to participate in this study. [Methods] The subjects randomly performed four types of carrying a backpack: no backpack (condition-1), carrying a backpack at C7 (condition-2), carrying a backpack at 10 cm below C7 (condition-3), and carrying a backpack at 20 cm below C7 (condition 4). [Results] Statistically significant differences were noted in the anterior and posterior pressure values, and in the anterior-to-posterior ratio, among the four conditions (p < 0.05). Post-hoc analysis indicated that the pressure value of condition-4 was significantly lower in the anterior foot region and higher in the posterior foot region than in condition-2 and condition-3. In addition, the anterior-to-posterior ratio was lower in condition-4 than in condition-2 and condition-3. [Conclusion] These findings suggest that carrying a backpack in a higher position, with fastening of the shoulder strap, may be more favorable for normalizing the foot weight distribution. PMID- 25931723 TI - Effects of bilateral training on motor function, amount of activity and activity intensity measured with an accelerometer of patients with stroke. AB - [Purpose] This study investigated the recovery of arm function and the functional use of the affected limb in real life of stroke patients after bilateral arm training. [Subjects] Twenty patients with stroke were randomly allocated to the BT (bilateral training group, n=10) and UT (unilateral training group, n=10) groups. [Methods] The BT group performed functional tasks with both hand symmetrically, the UT group performed tasks with only the affected hand for 30 minutes a session 5 times a week over 6 weeks. Before and after the intervention, accelerometers (Actisleep), functional independence measure (FIM) and manual function test (MFT) were used to assess subjects' abilities. [Results] The BT group showed a significant improvement in FIM total score, motor subtotal score and MFT score of affected side compared to the UT group. The BT group showed a more quantitative increase in the amount of activity of the affected side than the UT group. Regarding activity intensity, the BT group showed a decrease in the sedentary level and an increase of the moderate level on the affected side compared to the UT group. [Conclusion] We found that programs tailored to the characteristics of stroke patients and continuous monitoring of physical activity using an accelerometer minimized possible future disability and improved the patients' quality of life. PMID- 25931724 TI - Effect of rehabilitational sliding machine and ergometer bicycle training on patients with hemiplegia. AB - [Purpose] The purpose of the study was to investigate the effects of exercise using rehabilitational sliding machine training and ergometer bicycle training on the balance and gait of patients with stroke. [Subjects] Forty patients with hemiplegia resulting from stroke were divided into a sliding training group (STG, n=20) and ergometer bicycle training group (ETG, n=20). [Methods] STG and ETG respectively performed rehabilitational sliding training and cycle ergometer training in 30 minute sessions, five times a week, for a total of eight weeks. [Results] The balance and gait ability of both groups significantly improved. Both groups showed improvements in balance and gait ability, and the ETG showed anterior and posterior ranges of the limit of stability following standing. [Conclusion] Training on a rehabilitational sliding machine and an ergometer is effective at increasing a patient's balance and gait ability during nontreatment time in their daily time without therapist. PMID- 25931725 TI - Gait improvement by low-dose botulinum toxin A injection treatment of the lower limbs in subacute stroke patients. AB - [Purpose] Lower-limb spasticity after stroke may be associated with worse functional outcome. Our study aim was to establish whether a low-dose botulinum toxin A (BTX-A) injection in subacute stroke patients can improve spasticity, gait, and daily living abilities. [Subjects] Twenty-three subacute stroke patients were randomly allocated to BTX-A treatment group (11 patients) and control group (12 patients). [Methods] In the BTX-A treatment group patients, 200 units BTX-A was injected into the triceps surae (150 iu) and posterior tibial (50 iu) by electrical stimulation-guided. The patients in the control group received the same volume of placebo solution into the same injection locations. Gait analysis (step length, cadence, speed), the 6-min walking test, Fugl-Meyer Assessment (FMA) of the lower limbs, modified Ashworth scale assess (MAS) assessment of the lower limbs, surface electromyography (sEMG), and modified Barthel index (MBI) assessment were performed before and at 4,8 weeks after treatment. [Results] We found that the FMA of the low limbs and MBI were significantly improved in both groups. The gait analysis, FMA, and MBI results in the BTX-A treatment group were better than those in the control group. MAS and surface electromyography (sEMG) showed better improvement of spasticity in the treatment group. [Conclusion] Early low-dose botulinum toxin A (BTX-A) injection in subacute stroke patients into the lower-limb may improve gait, spasticity, and daily living abilities. PMID- 25931726 TI - Effect of a single session of transcranial direct-current stimulation combined with virtual reality training on the balance of children with cerebral palsy: a randomized, controlled, double-blind trial. AB - [Purpose] The aim of the present study was to investigate the effects of a single session of transcranial direct current stimulation combined with virtual reality training on the balance of children with cerebral palsy. [Subjetcs and Methods] Children with cerebral palsy between four and 12 years of age were randomly allocated to two groups: an experimental group which performed a single session of mobility training with virtual reality combined with active transcranial direct current stimulation; and a control group which performed a single session of mobility training with virtual reality combined with placebo transcranial direct current stimulation. The children were evaluated before and after the training protocols. Static balance (sway area, displacement, velocity and frequency of oscillations of the center of pressure on the anteroposterior and mediolateral axes) was evaluated using a force plate under four conditions (30 second measurements for each condition): feet on the force plate with the eyes open, and with the eyes closed; feet on a foam mat with the eyes open, and with the eyes closed. [Results] An increase in sway velocity was the only significant difference found. [Conclusion] A single session of anodal transcranial direct current stimulation combined with mobility training elicited to lead to an increase in the body sway velocity of children with cerebral palsy. PMID- 25931727 TI - Effectiveness of motor sequential learning according to practice schedules in healthy adults; distributed practice versus massed practice. AB - [Purpose] The purpose of the current study was to compare the effectiveness of motor sequential learning according to two different types of practice schedules, distributed practice schedule (two 12-hour inter-trial intervals) and massed practice schedule (two 10-minute inter-trial intervals) using a serial reaction time (SRT) task. [Subjects and Methods] Thirty healthy subjects were recruited and then randomly and evenly assigned to either the distributed practice group or the massed practice group. All subjects performed three consecutive sessions of the SRT task following one of the two different types of practice schedules. Distributed practice was scheduled for two 12-hour inter-session intervals including sleeping time, whereas massed practice was administered for two 10 minute inter-session intervals. Response time (RT) and response accuracy (RA) were measured in at pre-test, mid-test, and post-test. [Results] For RT, univariate analysis demonstrated significant main effects in the within-group comparison of the three tests as well as the interaction effect of two groups * three tests, whereas the between-group comparison showed no significant effect. The results for RA showed no significant differences in neither the between-group comparison nor the interaction effect of two groups * three tests, whereas the within-group comparison of the three tests showed a significant main effect. [Conclusion] Distributed practice led to enhancement of motor skill acquisition at the first inter-session interval as well as at the second inter-interval the following day, compared to massed practice. Consequentially, the results of this study suggest that a distributed practice schedule can enhance the effectiveness of motor sequential learning in 1-day learning as well as for two days learning formats compared to massed practice. PMID- 25931728 TI - The effect of computer-assisted cognitive rehabilitation and repetitive transcranial magnetic stimulation on cognitive function for stroke patients. AB - [Purpose] This study investigated the effects of computer-assisted cognitive rehabilitation (CACR) and repetitive transcranial magnetic stimulation (rTMS) on cognitive function in patients with stroke. [Subjects and Methods] We enrolled 20 patients and divided them into CACR and rTMS groups. CACR and rTMS were performed thrice a week for 4 weeks. Cognitive function was measured with the Korean Mini Mental State Examination (K-MMSE) and Lowenstein Occupational Therapy Cognitive Assessment-Geriatric (LOTCA-G) before and after treatment. The independent samples t-test was performed to test the homogeneity of K-MMSE and LOTCA-G before treatment and compare the differences in cognitive improvement between the CACR and rTMS groups. A paired samples t-test was used to compare cognitive function before and after treatment. [Results] Cognitive function of both the groups significantly improved after the intervention based on the K-MMSE and LOTCA-G scores. While the LOTCA-G score improved significantly more in the CACR group than in the rTMS group, no significant difference was seen in the K-MMSE scores. [Conclusion] We showed that CACR is more effective than rTMS in improving cognitive function after stroke. PMID- 25931729 TI - Effect of constrained weight shift on the static balance and muscle activation of stroke patients. AB - [Purpose] The purpose of this study was to evaluate the effects of constrained weight shift induced by shoe lift beneath the unaffected lower extremity, on balance functions and electromyography of the affected lower extremity of stroke patients. [Subjects and Methods] Twelve patients with unilateral stroke were recruited as volunteers for this study. The subjects were repeatedly measured in a randomized order under three conditions: no-shoe lift, and shoe lifts of 5 mm and 10 mm heights beneath the unaffected lower extremity. [Results] Standing with a 10 mm shoe lift for the unaffected lower extremity decreased the mean velocity of mediolateral sway compared to no-shoe lift. Regarding the velocity of anteroposterior sway, standing with 5 mm and 10 mm shoe lifts decreased the mean velocity of anteroposterior sway. The muscle activation of the affected lower extremity was not significantly different among the no-shoe lift, 5 mm shoe lift and 10 mm shoe lift conditions; however, the muscle activities of the rectus femoris, biceps femoris, tibialis anterior, and medial gastrocnemius of the affected lower extremity progressively improved with increasing height of the shoe lift. [Conclusion] A constrained weight shift to the affected side elicited by a shoe insole of 10 mm height on the unaffected side can improve the static standing balance of stroke patients, and it resulted in 14-24% increases in the muscle activities of the affected leg. PMID- 25931730 TI - The relationship between stroke patients' socio-economic conditions and their quality of life: the 2010 Korean community health survey. AB - [Purpose] The relationship between stroke patients' socio-economic conditions and quality of life (QOL) using the 2010 Korean Community Health Survey (KCHS) statistics was examined. [Subjects and Methods] A total of 4,604 stroke patients were analyzed. Socio-economic conditions were sex, age, educational level, monthly household income, occupation, residential area, and living with family. [Results] The results show a statistically significant lower QOL for men than for women, for those aged 75 years or over compared to individuals between 19 years and 64 years, and for elementary (or lower) or middle school graduates compared to higher education graduates. QOL was also significant lower among patients whose household income was KRW4 million (US$3,746.72) or less a month. Finally, QOL was significantly lower for patients without an occupation compared to those with an occupation, for patients in rural areas compared to urban areas, and for patients who did not live with family compared to those who lived with family. [Conclusion] We showed the importance of the relationships between socio-economic conditions and QOL of stroke patient. PMID- 25931731 TI - Concomitance of fibromyalgia syndrome and cervical disc herniation. AB - [Purpose] Fibromyalgia syndrome (FMS) and cervical disc herniation (CDH) are a common diseases commonly encountered in physical therapy clinics. There are also patients who have both of these diseases. In this study we aim to investigated whether FMS is a risk factor for cervical disc herniation and the frequency of their coincident occurrence. [Subjects and Methods] Thirty-five patients having a primary FMS diagnosis according to the American Rheumatism Association criteria are taken into consideration and a control group were the subjects of this study. The two groups were compared with respect to cervical disc hernia using cervical region MRI. [Results] The distribution of disc hernia of 6 fibromyalgia patients who had cervical discopathy was: 16.6% C2-3, 16.6% C5-6, 16.6% C6-7, 33.3% C4-5, C5-6 (two levels in two patients) and 16.6% C4-5, C5-6, C7-1 (three levels in one patient) . The herniation directions were given as: central in 5 levels, right paramedian in 1 level, and left paramedian disc hernia in 1 level. There were 4 cervical disk hernia in the control group. The herniation direction were central in two, right paramedian in one, and left paramedian in one patient. [Conclusion] In this study, the existence of cervical disc herniation in fibromyalgia patients was found to be not different from the normal population. PMID- 25931732 TI - Tidal volume and diaphragm muscle activity in rats with cervical spinal cord injury. AB - [Purpose] The purpose of this study was to make an experimental model of cervical spinal cord injury (CSCI) using Wistar rats, in order to analyze the influence of CSCI on the respiratory function. [Subjects] Thirty-two male 12-week-old Wistar rats were used. [Methods] The CSCI was made at the levels from C3 to C7, and we performed pneumotachography and electromyography (EMG) on the diaphragm. Computed tomography was used to determine the level of spinal cord damage. [Results] After the operation, the tidal volume of the rats with a C3 level injury decreased to approximately 22.3% of its pre-injury value. In addition, in the same rats, the diaphragmatic electromyogram activity decreased remarkably. Compared with before CSCI, the tidal volume decreased to 78.6% of its pre-injury value in CSCI at the C5 level, and it decreased to 94.1% of its pre-injury value in CSCI at the C7 level. [Conclusion] In the rats that sustained a CSCI in this study, the group of respiratory muscles that receive innervation from the thoracic spinal cord was paralyzed. Therefore, the EMG signal of the diaphragm increased. These results demonstrate that there is a relationship between respiratory function and the level of CSCI. PMID- 25931733 TI - Changes in proprioception and pain in patients with neck pain after upper thoracic manipulation. AB - [Purpose] The purpose of this study was to conduct cervical stability training and upper thoracic manipulation for patients with chronic neck pain and then investigate the changes of cervical proprioception and pain. [Subjects and Methods] Subjects were 30 workers with mechanical neck pain, who were randomly divided into an upper thoracic manipulation group and a cervical stability training group. Upper thoracic manipulation after cervical stability training was conducted for the upper thoracic manipulation group, and only stability training was conducted for the cervical stability training group. The intervention period was six weeks, and consisted of three sessions a week, each of which lasted for 30 minutes. For proprioception measurement, an electro-goniometer was used to measure reposition sense before and after the intervention. The visual analogue scale was used to assess pain. [Results] After the intervention, the error angle was significantly smaller in flexion and right left side-bending, and pain was significantly reduced in the upper thoracic manipulation group. According to the post intervention comparison of the two groups, there were significant differences in the proprioception and pain values. [Conclusion] Conducting both cervical stability training and upper thoracic manipulation for patients with chronic neck pain was more helpful for the improvement of proprioception and pain than cervical stability training alone. PMID- 25931734 TI - Analysis of variation in length of stay (LOS) after ischemic and hemorrhagic stroke using the Charlson Comorbidity Index (CCI). AB - [Purpose] The purpose of this study was to understand factors present at baseline that affect outcome and healthcare utilization post-stroke. We investigated the association between the Charlson Comorbidity Index (CCI) score and functional outcome (length of stay) after hemorrhagic and ischemic stroke. [Subjects and Methods] Data from the Korean National Hospital Discharge In-depth Injury Survey for 6 years, from 2005 to 2010, were used. The t-test and analysis of variance were carried out to compare average differences in the length of stay with the general characteristics in accordance with CCI. Multiple regression analysis was carried out using dummy variables to look at factors affecting stroke patients' length of stay. [Results] Independent variables with significant relationships with the log-transformed length of stay included gender, type of insurance, the size of city of residence, the number of beds in the hospital, the location of the medical institution, hospitalization path, receipt of physical therapy, treatment involving brain surgery, death, the type of stroke, and CCI. [Conclusion] The results of the present study suggests that CCI independently influences the length of stay after ischemic and hemorrhagic stroke and that variables with significant relationships with the log-transformed length of stay need to be continuously managed. PMID- 25931735 TI - The effects of whole body vibration on static balance, spinal curvature, pain, and disability of patients with low back pain. AB - [Purpose] The purpose of this study was to investigate the impact of whole body vibration (WBV) on static balance, spinal curvature, pain, and the disability of patients with chronic lower back pain. [Subjects and Methods] The subjects were of 40 patients, who were randomly assigned to WBV and control groups. Twenty-five minutes of lumbar stability training and 5 minutes of WBV were conducted for the WBV group, and 30 minutes of lumbar stability training was conducted for the control group. The training was conducted three times per week for a total of 6 weeks. Static balance, spinal curvature, pain, and disability were measured before and after the intervention. [Results] After the intervention, the WBV group showed a significant differences in static balance, spinal curvature, pain, and disability. The control group presented significant differences in pain, and disability. In the comparison of the two groups, the WBV group showed more significant improvements in the fall index and pain. [Conclusion] WBV can be recommended for the improvement of the balance ability and pain of chronic lower back pain patients. PMID- 25931736 TI - Knee muscle strength in multiple sclerosis: relationship with gait characteristics. AB - [Purpose] To investigate the relationship between isokinetic knee muscle strength and kinematic, kinetic and spatiotemporal gait parameters of patients with multiple sclerosis (MS). [Subjects and Methods] Twenty-nine MS patients (mean age 31.5+/-6.5) were investigated in this study. The isokinetic knee muscle strength and gait parameters of MS patients with moderate and severe disability, as determined by the expanded disability status scale (EDSS): EDSS=1-4.5 (n=22, moderate disability) and EDSS>4.5 (n=7, severe disability) were measured. [Results] Isokinetic knee muscle strength, kinematic, kinetic and spatiotemporal gait parameters differed between moderate (EDSS=1-4.5, n=22) and severe disability (EDSS>4.5, n=7). The correlation between each of gait speed, stride length, total range of knee joint movement and the four strength parameters (minimum and maximum quadriceps and hamstring muscle strengths) were significant for the MS group as a whole. Within subgroups, the correlation between minimum hamstring strength and total range of knee movement was significant only in group EDSS>4.5; minimum hamstring correlated with peak knee extensor moment in group EDSS=1-4.5, but at a reduced level of significance. [Conclusion] The present study revealed significant correlations between gait characteristics and isokinetic strength parameters of the quadriceps and hamstring muscles. Our study suggests that rehabilitation protocols for MS patients should include a critical strength training programme particularly for the hamstring and quadriceps muscles. PMID- 25931737 TI - Contribution of abdominal muscle strength to various activities of daily living of stroke patients with mild paralysis. AB - [Purpose] The trunk muscles frequently become weak after stroke, thus impacting overall activities of daily living. However, activities of daily living items closely related with trunk strength remain unclear. This study aimed to clarify the influence of trunk muscle weakness on activities of daily living items. [Subjects] The subjects were 24 stroke patients who fulfilled the following inclusion criteria: first stroke and the absence of severe paralysis, marked cognitive function deterioration, unilateral spatial neglect or apathy. [Methods] According to abdominal strength, the 24 patients were divided into a nonweakness group and a weakness group. For the assessment, we used the stroke impairment assessment set, the Berg balance scale, a simple test for evaluating hand function, grip strength, and functional independence measure scale scores and the results were compared between the groups. [Results] The Berg balance scale score and scores for dressing, toilet use, transfer to bed, and walk items of the functional independence measure were significantly lower in the weakness group than in the nonweakness group. [Conclusion] Our results suggest that weakness of the abdominal muscles adversely impacts the balance of patients with mild stroke as well as their ability to dress, use a toilet, transfer, and walk. Trunk training, including abdominal muscle exercises, can effectively improve the performance of these activities of daily living items. PMID- 25931738 TI - Factors influencing sexual function of middle-aged married Korean women. AB - [Purpose] This study investigated the status of women's sexual function and relevant factors given the fact that women's health is crucial to the national health, and in particular that women's sexual health has a significant impact on their overall health. [Subjects and Methods] This study surveyed 353 women living in South Korea's P and K metropolitan regions from July 2012 to August 10, 2013. The Female Sexual Functional Index (FSFI), the Sexual Attitude Scale (SAS), sexual knowledge and questionnaires were used. [Results] Two groups based on FSFI scores above and below a cutoff value of 25 were compared with each other, and significant differences were found in age, male friends, menstrual status, sex status, and frequency of sex, experience of forced sex, personal health, husband's health and sexual knowledge. Male friends, sex status, experience of forced sex, husband's healths and sexual knowledge explained women's sexual function. [Conclusion] The finding that women's sexual function is associated with multiple factors suggests an intervention program for improving women's sexual function should be developed to reflect the factors influencing the target groups' sexual function. PMID- 25931739 TI - Changes in angular kinematics of the paretic lower limb at different orthotic angles of plantar flexion limitation of an ankle-foot-orthosis for stroke patients. AB - [Purpose] An ankle-foot-orthosis (AFO) is an assistive brace that allows stroke patients to achieve an independent gait. Therefore, we examined whether or not the orthotic angle for plantar flexion limitation affects the kinematic parameters of the hip and knee joints on the affected side of patients with stroke. [Subjects and Methods] Fifteen patients with chronic hemiplegia were recruited for this study. Kinematic three-dimensional data was acquired, while patients walked along a walkway wearing AFOs under five different conditions of 0 degrees , 5 degrees , 10 degrees , 15 degrees , and 20 degrees of plantar stop limitation angle in the orthotic joint. Peak angles of the hip and knee joints on the affected side were analyzed. [Results] At the peak angle of the knee joint, statistically significant differences were found only at mid-stance in the sagittal plane and the horizontal plane. However, no significant differences were observed among any of the orthotic limitation angles in the frontal plane. [Conclusion] According to the results, an orthotic limitation angle of more than 10 degrees elicits changes in the knee joint angle at mid-stance in the sagittal and horizontal planes. This study provided basic data on postural changes of patients with stroke. PMID- 25931740 TI - New design of home-based dynamic hand splint for hemiplegic hands: a preliminary study. AB - [Purpose] Hemiplegia following a stroke can affect hand movement; therefore, reconstructing hand function is the most desired outcome for stroke patients. The purpose of this study was to explore the application of rehabilitation through the use of a dynamic hand splint and observes its effects on the muscle strength and functional activity of the affected hands. [Subjects and Methods] Chronic stroke patients who underwent a 3-month conventional rehabilitation using the dynamic hand splint were recruited . Evaluations (e.g., electromyography, grip and finger strength appraisals, and Fugl-Meyer assessment) were conducted before the test, and after the 1 and 3 month's intervention. The hemiplegic hands intermediately and after the treatment to assess improvement in hand-muscle strength and functional increase of the hand movements were evaluated. Patient response to use of the dynamic hand splint was assessed using a satisfaction scale after treatment. [Results] The results for maximal voluntary contraction of the extensor and flexor muscles and wrist and finger strength showed a statistically significant increase from the pretest to after 1 and 3 month's intervention. [Conclusion] Wearing a dynamic hand splint for home-use as a supplementary training program in addition to hospital-based rehabilitation can effectively increase the muscle strength of hemiplegic hands. PMID- 25931741 TI - Effect of handrail use while performing treadmill walking on the gait of stroke patients. AB - [Purpose] The purpose of this study was to investigate how the use of handrails during treadmill walking affects the gait parameters of stroke patients. [Subjects and Methods] The participants, 30 hemiplegic stroke patients, were randomly allocated to one of three groups: the NHG group (No Handrail group, n=10), the FHG group (Front handrail group, n=10), and BHG group (Bilateral Handrail group, n=10). All the subjects' performed treadmill walking for 30 min, five days a week, for a period of eight weeks. Gait parameters were evaluated using the RS-scan system. [Results] A statistically significant difference in the HM (heel-medial) area of plantar foot pressure was observed between BHG and NHG. Statistically significant difference in the HL (heel-lateral) area of plantar foot pressure was observed between BHG and NHG, and between FHG and NHG. A statistically significant difference in contact area of the rear foot was observed between BHG and NHG. [Conclusion] The results of this study show that holding handrails during treadmill training may enhance the improvement in the quality of patients' gait (plantar foot pressure, contact area of foot). PMID- 25931742 TI - Relation between functional ability and health-related quality of life of children with juvenile rheumatoid arthritis. AB - [Purpose] The aim of this study was to assess patients' health-related quality of life, compare it with a healthy age-matched population, and examine associations between functional ability and quality of life among juvenile rheumatoid arthritis (JRA) patients. [Subjects and Methods] The study participants were 26 JRA patients and 25 controls. The Childhood Health Assessment Questionnaire and the Pediatric Quality of Life Inventory 4.0 Generic Core Scales were used to evaluate functional ability and health-related quality of life, respectively. [Results] Functional ability scores averaged 0.37 in the JRA group and 0.08 in the control group. There were significant between-group differences in functional ability scores in the overall cohort and in the subgroup of participants aged 14 16 years. Health-related quality of life scores were significantly lower in the JRA group than in the control group (68.39 vs. 85.17). In the JRA group, functional ability was statistically positively correlated with health-related quality of life. [Conclusion] We conclude that the mental state of adolescents with JRA affects their particular functional abilities. Subjects in the 14-16 age group who had a longer disease duration and higher difficulty scores showed a lower health-related quality of life than children in the other age groups. PMID- 25931743 TI - Study of the physical condition of middle-aged workers by gender. AB - [Purpose] The purpose of this research was to investigate the physical condition of middle-aged workers in Korea by gender. [Subjects] In total, 2,644 middle-aged workers (male, n = 2,175; female, n =469) >=50 years of age from eight geographical areas were evaluated from 2007 to 2008. [Methods] The subjects' physical condition, muscular endurance, reaction, flexibility, agility and age of physical strength were evaluated. [Results] The physical condition and exercise status of males were superior to those of female workers. Male workers exhibited a higher rate of smoking than female workers, but had better muscular endurance, reaction, agility and age of physical strength. [Conclusion] Middle-aged female workers in Korea have a poorer overall physical condition than middle-aged male workers. The physical condition of middle-aged and elderly workers must be managed through various health management programs to maintain a productive aging society. PMID- 25931744 TI - Effects of virtual reality-based ankle exercise on the dynamic balance, muscle tone, and gait of stroke patients. AB - [Purpose] The purpose of this study was to investigate the therapeutic effects of virtual reality-based ankle exercise on the dynamic balance, muscle tone, and gait ability of stroke subjects. [Subjects and Methods] Twenty persons who were in the chronic stroke subjects of this study and they were included and assigned to two groups: experimental (VRAE; Virtual Reality-based Ankle Exercise group) (n=10) and control groups (n=10). The VRAE group performed virtual environment system ankle exercise, and the control group watched a video. Both groups performed their respective interventions for 30 minutes per day, 5 times per week over a 6-week period. To confirm the effects of the intervention, dynamic balance, muscle tone, and spatiotemporal gait were evaluated. [Results] The results showed that the dynamic balance and muscle tone was significantly more improved after the intervention compared to before in the VRAE group (dynamic balance: 5.50+/-2.57; muscle tone: 0.90+/-0.39), and the improvements were more significant than those in the control (dynamic balance: 1.22+/-2.05; muscle tone: 0.10+/-0.21). Spatiotemporal gait measures were significantly more increased in the paretic limb after the intervention compared to before in the VRAE group and the improvements were more significant than those in the control group. [Conclusion] This study demonstrated that virtual reality-based ankle exercise effectively improves the dynamic balance, muscle tone, and gait ability of stroke patients. PMID- 25931745 TI - Reliability of isometric knee extension muscle strength measurements made by a hand-held dynamometer and a belt: a comparison of two types of device. AB - [Purpose] The purpose of the present study was to compare the reliability of 2 hand-held dynamometers (HHD-1, 2) with different designs, by performing isometric knee muscle extension measurements two times each. [Subjects] The subjects were 40 young healthy adults. [Methods] The reliability of the measurements was examined using Bland-Altman analysis. [Results] Bland-Altman analysis found a fixed bias in measurements made by HHD-1 with an average limits of agreement (LOA) value of -2.1 kgf. For HHD-2, only random errors were detected, and the minimal detectable change (MDC) was 11.4 kgf. Fixed biases were observed between the two devices with an average LOA value of 2.2 kgf. When the bodyweight ratio was used, fixed biases were observed in measurements made by both devices, and the average value of LOA was -0.03 kgf/kg. The comparison of the two devices revealed only random errors, and MDC was 0.22 kgf/kg. [Conclusion] For HHD measurements using these two devices, the appropriate number of measurements is two times, and comparison of measurement values between the two devices should be avoided. PMID- 25931746 TI - The effects of symmetric center of pressure displacement training with feedback on the gait of stroke patients. AB - [Purpose] This study investigated the effects of COP displacement training using visual feedback had on the gait of patients with hemiplegia due to stroke. [Subjects and Methods] This study was conducted with 20 patients with hemiplegia due to stroke. The training consisted of five training sets repeated 10 times and the activity was conducted for 15 minutes each session, three times per week for six weeks immediately after completion of central nervous system developmental treatment. [Results] A comparison of the results of before and after the experiment found that the COP displacement training group showed significant improvements in step length, stride length, gait velocity, and the functional reach test, while the control group showed significant improvement only in the functional reach test. In the intergroup comparison, the COP displacement training group showed significant improvements in paretic side step length, paretic side stride length, gait velocity, and the functional reach test compared to the control group. [Conclusion] In conclusion, according to the results of this study, visual feedback training for COP displacement is more effective at enhancing the gait and balance of hemiplegic patients due to stroke than only performing feedback training for even weight distribution. PMID- 25931747 TI - Effect of early mobilization on discharge disposition of mechanically ventilated patients. AB - [Purpose] The purpose of this study was to clarify the benefits of early mobilization for mechanically ventilated patients for their survival to discharge to home from the hospital. [Subjects and Methods] Medical records were retrospectively analyzed of patients who satisfied the following criteria: age >= 18 years; performance status 0-2 and independent living at their home before admission; mechanical ventilation for more than 48 h; and survival after mechanical ventilation. Mechanically ventilated patients in the early mobilization (EM) group (n = 48) received mobilization therapy, limb exercise and chest physiotherapy, whereas those in the control group (n = 60) received bed rest alone. Univariate and multivariate logistic regression analyses were performed to identify clinical variables associated with discharge disposition. [Results] Early mobilization was a positive independent factor and the presence of neurological deficits was a negative factor contributing to discharge to home. Among patients surviving mechanical ventilation without neurological deficits, the rate of discharge to home was significantly higher among patients in the EM group that in the control group (76% vs. 40%). [Conclusion] Early mobilization can improve the rate of discharge to home of patients requiring mechanical ventilation because of non-neurological deficits. PMID- 25931748 TI - Effects of phase I complex decongestive physiotherapy on physical functions and depression levels in breast cancer related lymph edema. AB - [Purpose] Breast cancer-related upper extremity lymph edema is known to cause physical, functional and psychological impairments in women after modified radical mastectomy. The aim of this study was to investigate the effects of phase I Complex Decongestive Physiotherapy (CDP) on physical functions and depression levels in women with breast cancer-related upper extremity lymph edema. [Subjects and Methods] Fifty-eight subjects with breast cancer-related upper extremity lymph edema were the subjects of this study. The arm circumference, shoulder range of motion (ROM), muscle strength and depression levels of the subjects were assessed before and after phase I CDP treatment. [Results] After phase I CDP, there was a statistically significant reduction in circumference measurements at all levels of the affected arm. There was not any statistically significant difference in muscle strength after CDP. The shoulder ROM improved after treatment. There was a significant reduction in the Beck Depression Inventory score. A significant positive correlation was found between depression levels and circumference measurement. [Conclusion] Based on the results we suggest that by reducing limb volume, beside improving physical functions, phase I CDP can affect psychological status, especially depression which is very common in women with breast cancer-related upper extremity lymph edema. PMID- 25931749 TI - Effects of Pilates on muscle strength, postural balance and quality of life of older adults: a randomized, controlled, clinical trial. AB - [Purpose] The aim of the present study was to determine the effects of Pilates on lower leg strength, postural balance and the health-related quality of life (HRQoL) of older adults. [Subjects and Methods] Thirty-two older adults were randomly allocated either to the experimental group (EG, n = 16; mean age, 63.62 +/- 1.02 years), which performed two sessions of Pilates per week for 12 weeks, or to the control group (CG, n = 16; mean age, 64.21 +/- 0.80), which performed two sessions of static stretching per week for 12 weeks. The following evaluations were performed before and after the interventions: isokinetic torque of knee extensors and flexors at 300 degrees /s, the Timed Up and Go (TUG) test, the Berg Balance Scale, and the Health Survey assessment (SF-36). [Results] In the intra-group analysis, the EG demonstrated significant improvement in all variables. In the inter-group analysis, the EG demonstrated significant improvement in most variables. [Conclusion] Pilates exercises led to significant improvement in isokinetic torque of the knee extensors and flexors, postural balance and aspects of the health-related quality of life of older adults. PMID- 25931750 TI - Approaches for improving the toileting problems of hemiplegic stroke patients with poor standing balance. AB - [Purpose] Our objective was to evaluate the residual dynamic and static functionality in the sitting position of hemiplegic stroke patients who require help to pull their lower garments up and down during toileting. [Subjects and Methods] The subjects were 11 hemiplegic patients. We gathered data on the patients' motor paralysis, sensory capacity, lower extremity muscle strength, trunk control, ability to roll and sit up from a lying position, sitting balance, and ability to pull the lower garments up and down. We then compared 2 groups: those able to pull the lower garments up and down independently while standing (the "independent group"), and those who were unable to do so (the "non independent group"). [Results] Though the non-independent group had severely and significantly reduced trunk control and abilities as a whole, there was no significant difference from the independent group in static and dynamic sitting balance. [Conclusion] We conclude that, to enable hemiplegic patients with poor standing balance to pull their lower garments up and down, it is necessary to do these maneuvers in a sitting, rather than a standing, position, or to develop garments that are easier to put on and take off. PMID- 25931751 TI - Temperament of premature infants with cerebral palsy. AB - [Purpose] The purpose of this study was to examine the infant temperaments of children with cerebral palsy due to premature birth. [Subjects and Methods] Data were collected through questionnaires sent to 118 mothers of infants diagnosed with cerebral palsy due to premature birth. [Results] Different infant temperament scores were obtained according to the degrees of disability, type of palsy, birth weights, gestational age, and periods of hospitalization in an NICU; however, the differences were not statistically significant. [Conclusion] Additional comprehensive studies are necessary in order to understand the infant temperaments of newborns with cerebral palsy due to premature birth, as a prerequisite to providing efficient intervention programs supporting the children's development and growth, and to verify statistical significance. PMID- 25931752 TI - Impact in oral health and the prevalence of temporomandibular disorder in individuals with Parkinson's disease. AB - The aims of the present study were to investigate the prevalence of temporomandibular disorder (TMD) in a group of patients with Parkinson's disease (PD), and to analyze oral health according to the severity of the disease. [Methods] Signs and symptoms of TMD were evaluated using the Research Diagnostic Criteria for Temporomandibular Disorders, and oral health impact was measured using the Oral Health Impact Profile. The unpaired Student's t-test was used to compare groups with and without TMD. Pearson's correlation coefficients were calculated to determine correlations between the level of functional independence and oral health impact. Fisher's exact test was used to test the association between TMD and the severity of symptoms of PD. [Results] Fifty-nine individuals with PD were analyzed. The prevalence of TMD was 20.33%. No statistically significant associations were found between TMD and the severity of PD. Oral health impact was considered weak, but a statistically significant difference between groups with and without TMD was found for psychological disability (p = 0.003). No significant correlation was found between the level of functional independence and oral health impact. [Conclusion] The prevalence of TMD among patients with Parkinson's disease was 20.33%. A statistically significant difference between groups with and without TMD was found regarding the psychological disability domain. PMID- 25931753 TI - Activation of the vastus medialis oblique and vastus lateralis muscles in asymptomatic subjects during the sit-to-stand procedure. AB - [Purpose] The purpose of this study was to examine the vastus medialis oblique to vastus lateralis ratio in two pelvic tilt positions while performing the sit-to stand task. [Subjects and Methods] Activation of the vastus medialis oblique and the vastus lateralis muscles of 46 healthy subjects (25 males, 21 females) were recorded by surface electromyography during the STS task with anterior pelvic tilt (sit with thoracolumbar spine extended and pelvis in an anterior tilt) and neutral pelvic tilt (sit with thoracolumbar spine relaxed and pelvis in the neutral tilt position) positions. Changes in vastus medialis oblique, vastus lateralis activation and the vastus medialis oblique/vastus lateralis ratio were analyzed. [Results] Vastus medialis oblique and vastus lateralis muscle activation significantly increased in neutral pelvic tilt position, but the vastus medialis oblique/vastus lateralis ratio was not statistically different. [Conclusion] The sit-to-stand procedure with neutral pelvic tilt position increased activation of the vastus medialis oblique and vastus lateralis, usefully strengthening the quadriceps, but did not selectively activate the vastus medialis oblique muscle. PMID- 25931754 TI - Effect of blocked vision treadmill training on knee joint proprioception of patients with chronic stroke. AB - [Purpose] The purpose of this study was to compare the effect of treadmill training with the eyes closed and eyes open on the joint position sense of chronic stroke patients. [Subjects and Methods] Thirty patients with chronic stroke participated in this study. Patients performed the timed up and go test and were assigned to one of two treadmill training groups with and without visual deprivation. The treadmill gait training for each group lasted 40 minutes, and sessions were held 3 times a week for 4 weeks. The knee joint proprioception was measured using the Biodex System Pro 3 before and after the intervention. [Results] The knee joint proprioception of the treadmill training with blocked vision group showed more significant improvement after the treadmill training sessions than that of the eyes open group. [Conclusion] This study demonstrated that treadmill training with blocked vision may be useful for the proprioceptive sensory rehabilitation of patients with chronic stroke. PMID- 25931755 TI - Is hypertension a risk factor for poor balance control in elderly adults? AB - [Purpose] The aim of this study was to investigate whether hypertension negatively affects the postural balance control of elderly adults under different sensory conditions. [Subjects and Methods] Fifty-four healthy elderly adults who were residents in a Geriatric Home Care Center were recruited for this study. Height, weight, body mass index and age of the volunteers were recorded. After applying the exclusion criteria, the final study group included 16 hypertensive (HT) and the control group included 10 non-hypertensive (Non-HT) healthy elderly adults. To evaluate postural balance control objectively, the modified Clinical Test of Sensory Interaction on Balance (modified CTSIB) test was performed under four different conditions: 1) eyes open on a stable surface; 2) eyes closed on a stable surface; 3) eyes open on an unstable surface; and 4) eyes closed on an unstable surface. [Results] The postural balance scores (center of gravity sway) of the HT group were slightly higher than those of the Non-HT group under conditions 1 (HT group=0.3 degrees /sec, Non-HT group=0.2 degrees /sec), 2 (HT group=0.8 degrees /sec, Non-HT group=0.4 degrees /sec) and 4 (HT group=4.5 degrees /sec, Non-HT group=3.5 degrees /sec), but no statistically significant differences were found between the HT and Non-HT groups under any sensory condition. [Conclusion] The result of this study indicate that controlled hypertension in elderly adults is not a cause of worse balance performance than controls on stable or unstable surfaces with the eyes open or closed. PMID- 25931756 TI - The characteristics of multi-directional step distance and the association between stepping laterality and walking ability of patients with stroke. AB - [Purpose] The purpose of this study was to determine the effect of stepping limb and step direction on step distance and the association of step distance and stepping laterality in step difference with walking ability and motor dysfunction. [Subjects and Methods] The subjects were thirty-nine patients with chronic hemiparesis as a result of stroke, who performed the MSL (Maximum Step Length) test along with tests of motor impairment, gait speed and Functional Ambulation Category. The MSL test is a clinical test of stepping distance in which participants step to the front, side, and back. The subjects were classified into three groups according to the stepping laterality in front step distance. [Results] Step distance did not differ across stepping limbs but did differ across step directions. Front step distance was significantly longer than side and back step distance. Participants with forward paretic step length shorter than forward non-paretic step length had significantly higher walking ability than participants with symmetric forward step length or forward paretic step length longer than forward non-paretic step length [Conclusion] Patients with stroke have characteristic step distances in each direction. Adequate weight shift toward the paretic limb when stepping with the non-paretic limb is associated with walking ability. PMID- 25931757 TI - Multicomponent exercise for physical fitness of community-dwelling elderly women. AB - [Purpose] The purpose of this study was to identify whether a 4-week multicomponent exercise program could improve the level of physical fitness of community-dwelling elderly women. [Subjects and Methods] Twenty-two healthy community-dwelling elderly women were randomly allocated to either an experimental or a control group. Experimental subjects performed a multicomponent exercise program that consisted of balance, strengthening, and stretching exercises for 4 weeks, whereas the control subjects did not perform any specific exercise. The subjects' level of physical fitness was assessed prior to and after training using the Senior Fitness Test which assesses muscle strength, flexibility, dynamic balance/agility, aerobic endurance, and body composition. [Results] Subjects in the experimental group showed significant improvements in lower and upper body strength, lower and upper body flexibility, dynamic balance/agility following training, but not in aerobic endurance or body composition. Significant group differences were shown in lower and upper body strength, lower body flexibility, and dynamic balance/agility. [Conclusion] The results suggest that a multicomponent training program that consists of balance, strengthening, and stretching exercises is a relevant intervention for the improvement of the level of physical fitness of community-dwelling elderly women. PMID- 25931758 TI - Changes in foot pressure elicited by 3D air balance exercise and pelvic stability exercise for functional leg-length discrepancy in adult women. AB - [Purpose] This study was conducted to examine the effect of pelvic stabilization exercise and 3D equipment exercise on adult women with Functional Leg-Length Discrepancy (FLLD). [Subjects and Methods] Twenty female students in their 20's having FLLD without Structural Leg Length Discrepancy were selected. Exercise was performed for 50 min per session, three times a week, for six weeks. The Pelvic stabilization exercise (PSE) group performed pelvic stabilization exercises for 50 minutes, and the 3D exercise (3DE) group performed 3D Air Balance exercise for 10 minutes after performing the pelvic stabilization exercise program for 40 minutes. [Results] The PSE group showed statistically significant differences in tape measure method (TMM) and maximum pressure between pre-test and post-test, and 3DE showed statistically significant differences in TMM, the difference in maximum pressure, the difference in average pressure, and the difference in support area. At the end of the 6-week intervention, TMM, difference in maximum pressure, difference in average pressure, and difference in support area showed significantly greater reduction in the 3DE group. [Conclusion] The results show that 3D stabilization exercise was more effective at improving the stabilization of the deep muscles surrounding the pelvis and left-right muscular balance. We consider that 3D exercise should be included in exercise programs for improving pelvic cavity and spinal stability in the future. PMID- 25931759 TI - The effects of gait velocity on the gait characteristics of hemiplegic patients. AB - [Purpose] The present study investigated the effects of gait speed on temporal and spatial gait characteristics of hemiplegic stroke patients. [Subjects and Methods] Twenty post-stroke hemiplegic patients participated in the present study. To enhance the reliability of the analysis of the gait characteristics, the assessments were conducted three days per week at the same time every day. Each subject walked maintaining a comfortable speed for the first minute, and measurement was conducted for 30 seconds at a treadmill speed of 1 km/hour thereafter. Then, the subjects walked at a treadmill speed of 2 km/hour for 30 seconds after a 30-minute rest. The differences in the measurements were tested for significance using the paired t-test. [Results] The measures of foot rotation, step width, load response, mid stance, pre-swing, swing phase, and double stance phase showed significant difference between the gait velocities. [Conclusion] The present study provides basic data for gait velocity changes for hemiplegic patients. PMID- 25931760 TI - Effects of kinesio taping on lumbopelvic-hip complex kinematics during forward bending. AB - [Purpose] The aim of this study was to investigate the effect of kinesio taping (KT) on the kinematics of the lumbo-pelvic-hip complex during forward bending by individuals with reduced hamstring extensibility. [Subjects] Eighteen males with reduced hamstring extensibility were randomly assigned to one of two groups:, the hamstring KT group (n=9), or the sham KT group (n=9). [Methods] The kinematics of the lumbopelvic-hip complex during lumbar forward bending was measured using a motion capture system before and after applying KT. [Results] The angle of lumbar flexion during late lumbar forward bending increased significantly post-KT compared to pre-KT measurements in the hamstring KT group. [Conclusion] These findings suggest that KT does not directly affect an individual's movement during lumbar forward bending. PMID- 25931761 TI - Seasonal changes in activity levels among nursing care insurance service users in areas with different climates. AB - [Purpose] To clarify seasonal changes in activity levels among nursing care insurance service users in areas with different climates using the Life Space Assessment. [Subjects] A total of 72 nursing care insurance service users aged >=65 years, who were from areas along the Sea of Japan or those around the Inland Sea. [Methods] The subjects were divided into 2 groups according to their home prefecture, and each survey was conducted over two successive seasons (Survey I: fall and winter, n=48, Survey II: winter and spring, n=24). We investigated the subjects' basic information, and determined their FIM, the Life Space Assessment, and Modified Falls Efficacy Scale scores. These scores were subjected to between group and -season comparisons. [Results] In Survey I, there were no significant differences in any investigation item between the 2 groups, but the Japan Sea group showed decreases in the Life Space Assessment, Independent Life space, and Minimal Life space scores in winter. In Survey II, we did not note any between group or -season differences. [Conclusion] Our findings suggest that the Life Space Assessment, whose scores are influenced by outdoor environments, may be used as a tool to clarify seasonal changes in activity levels of nursing care insurance service users. PMID- 25931762 TI - 3D motion analysis comparison of left handers' wrist flexion and cutting accuracy according to scissors type. AB - [Purpose] The purpose of this study was to research the difference in wrist flexion and accuracy of left-handers when using regular scissors made for right handed persons versus scissors made for left-handers. [Subjects and Methods] Eighteen left-handers participated in the experiment. There were ten males and eight females subjects. The degree of wrist flexion of 18 left-handers was analyzed when using scissors designed for left-handers and when using scissors designed for right-handers. [Results] When left-handers used left-handed scissors, they carried out the task while extending the wrist at 4.67+/-14.60 degrees , but when they used right-handed scissors, they carried out the task while flexing the wrist at 1.19+/-12.41 degrees . When left-handers used left handed scissors, the error rate was 1.39+/-1.29 times on average, but when they used right-handed scissors, the rate was 0.72+/-0.67 times on average. [Conclusion] When left-hand dominant persons used left-handed scissors rather than right-handed scissors, the degree of wrist flexion decreased, which created more functionality, and the accuracy of the cutting increased. For improved cutting accuracy and wrist stability and to protect the wrist from extensive flexion, it is necessary for left-handers to use scissors that are made for left handed people. PMID- 25931763 TI - Effects of physical exercise on the functional recovery of rat hindlimbs with impairments of the sciatic nerve as assessed by 2D video analysis. AB - [Purpose] The purpose of this study was to investigate the effects of treadmill training on functional recovery by analyzing the ankle joint as well as the knee and hip joints with 2D video analysis during gait by rats with sciatic nerve injury. [Subjects and Methods] Twenty-four male Sprague-Dawley rats were used in this study. The sham group (SG) received only a sham operation without any sciatic injury; the training group (TG) performed treadmill training for 4 weeks after sciatic injury; and the control group (CG) wasn't provided with any therapeutic intervention after sciatic injury. [Results] The ankle, knee, and hip ROM of TG and CG during the initial, mid stance, and toe-off phases of gait at post-test were significantly different from SG. [Conclusion] Physical exercise, like treadmill training, is beneficial for the improvement of the ankle, knee and hip joints of rats with crushed sciatic nerve injury. PMID- 25931764 TI - Daily sit-to-stands performed by adults: a systematic review. AB - [Purpose] The sit-to-stand (STS) maneuver is a component of everyday mobility. The purpose of this review was to summarize the number of daily STSs performed by adults with or without pathology. [Methods] Four bibliographic databases were searched followed by a consultation with experts and a search by hand to locate articles reporting daily STSs. Information on measurement procedures, tested populations, and daily STSs was extracted. Methodological quality was rated. [Results] Ten articles were identified. The mean number of daily STSs ranged from 33 to 71. The mean number was at least 45 for all groups except patients with congestive heart failure, residents of a hospital ward and one group of older adults. [Conclusion] Individuals performing fewer than 45 daily STSs may be experiencing a work deficit and benefit from additional intentional STS repetitions. PMID- 25931765 TI - Exercise and tropism of the multifidus muscle in low back pain: a short review. AB - [Purpose] The purpose of this review was to investigate the types of exercises that can improve the tropism of the multifidus muscles, based on clinical evidence. [Methods] Following to the PICO (Problem, Intervention, Comparison, Outcome) model, we considered studies of subjects with specific or non-specific LBP that used exercises aimed at activating the lumbar multifidus muscle and measured its cross-sectional area or thickness with ultrasound, computed tomography or magnetic resonance imaging. [Results] This review found that most studies compared different types of exercises for lumbar muscles, but without specifically investigating the multifidus muscle. However, a few studies showed that the cross-sectional area and thickness of the multifidus muscle can be increased by activating this muscle, and they progressed from motor control to increased static and dynamic loads. [Conclusion] A review of the literature revealed that specific supervised and home exercises may improve the symmetry of the multifidus muscle. PMID- 25931766 TI - Seating arrangements for children with insufficient head control: lessons from trials using the i2i head & neck positioning & support system. AB - [Purpose] An insufficient head control is the most troublesome condition for children with impaired mobility who require optimal seating. [Subjects and Methods] We report on the clinical trial of the newly developed i2i head & neck positioning & support system called i2i for locomotively disabled children with periventricular leukomalacia (PVL). [Results] Two major advantages of the i2i were observed in the trial. The first was its favorable effect on the alignment of the spine to prevent scoliosis and to provide stable breathing and optimal seating, which resulted in improvement of the children's activities of daily living (ADL). The second was its direct application of force to the head rather than indirectly to the pelvis in a conventional seat arrangement. The conventional way of head support is based on stabilization of the trunk which is based on stabilization of the pelvis by some seating arrangement. [Conclusion] The trial of the i2i device demonstrated its usefulness in helping PVL children with insufficient head control develop their abilities while preventing secondary disability. PMID- 25931767 TI - The effect of complex rehabilitation training for 12 weeks on trunk muscle function and spine deformation of patients with SCI. AB - [Purpose] It is important for patients with incomplete spinal cord injury (SCI) to strengthen their muscle strength and return to the work force one of the ultimate objectives of rehabilitation. This study reports how a single patient with SCI became stabilized in terms of abdominal muscles and back extension muscles, as well as returning the back to the neutral position from spinal deformation, as result of complex exercises performed for 12 weeks. [Subjects] The degree of damage of the subject was rated as C grade. The subject of this study had unstable posture due to paralysis in the lower extremities of the left side after removal of a malignant tumor by surgical operation, and tilting and torsion in the pelvis increased followed by increase of kyphosis in the thoracolumbar spine. The subject was more than two years since diagnosis of incomplete SCI after surgery. [Methods] Using isokinetic lumbar muscle strength measurement equipment, peak torque/weight, total work and average power in flexion and extension of the lumbar region were measured. A trunk measurement system (Formetric 4D, DIERS, Germany), which is a 3D image processing apparatus with high resolution for vertebrae, was used in order to measure 3D vertebrae and pelvis deformation as well as static balance abilities. As an exercise method, a foam roller was used to conduct fascia relaxation massage for warming-up, and postural kyphosis was changed into postural lordosis by lat pull-down using equipment, performed in 5 sets of 15 times preset at 60% intensity of 1RM 4 set of 10 crunch exercises per set using Togu's were done while sitting at the end of Balance pad, and 4 sets of 15 bridge exercises. [Results] All angular speed tests showed a gradual increase in muscle strength. Flexion and extension showed 10% and 3% improvements, respectively. The spine deformation test showed that isokinetic exercise and lat pull-down exercise for 12 weeks resulted in improved spinal shape. [Conclusion] In this study, core stability exercise for deep muscle training and lat pull-down exercise had positive effects on lower extremity muscle strength and the spinal shape of a patient with SCI. PMID- 25931768 TI - Effects of a single session of transcranial direct current stimulation on static balance in a patient with hemiparesis: a case study. AB - [Purpose] Cerebrovascular accident (stroke) is characterized by an abrupt onset of focal or global neurological signs and symptoms. Asymmetry of the limbs is common following a stroke due to hemiplegia or hemiparesis. [Subject and Methods] A male patient having suffered an ischemic stroke was initially evaluated using the Timed Up-and-Go Test and the Six-Minute Walk Test. Static balance was evaluated using a force plate (Kistler model 9286BA) for the stabilometry analysis of center of pressure (COP) sway. The data were interpreted using the SWAY software program (BTS Engineering) synchronized with the SMART-D 140((r)) system. Anodal transcranial direct current stimulation (tDCS; 2 mA) was applied over the primary motor cortex for 20 minutes during gait training on a treadmill. [Results] Under the condition of eyes open, reductions were found in anteroposterior sway (6.18%), trace length (3.3%) and sway velocity (3.3%) immediately following tDCS. [Conclusion] A single session of anodal tDCS combined with treadmill training had a positive effect on the static balance of a subject with chronic hemiparesis stemming from a stroke. PMID- 25931769 TI - Hippotherapy as a treatment for socialization after sexual abuse and emotional stress. AB - [Purpose] Hippotherapy is a therapeutic resource that uses the horse as a kinesiotherapy instrument to elicit motor and cognitive improvements in individuals with special needs. [Subjects and Methods] This research evaluated two women aged 18 and 21 years, who had suffered sexual violence when they were children between the ages of 6 and 7 years old. The subjects did not have mental dysfunction but they were regular students registered at a school of special education. The patients presented severe motor limitation, difficulty with coordination, significant muscular retractions, thoracic and cervical kyphosis, cervical protrusion wich was basically a function of the postures they had adopted when victims of the sexual violence suffered in childhood. The patients performed twenty sessions of 30 minutes of hippotherapy on a horse. The activities were structured to stimulate coordination, proprioception, the vestibular and motor-sensorial systems for the improvement of posture, muscle activity and cognition. [Results] The activities provided during the hippotherapy sessions elicited alterations in postural adjustment resulting in 30% improvement, 80% improvement in coordination in, 50% improvement in corporal balance and in sociability and self-esteem. [Conclusion] Hippotherapy proved to be an effective treatment method for coordination, balance and postural correction, and also improved the patients' self-esteem that had suffered serious emotional stress. PMID- 25931770 TI - Modified constraint-induced movement therapy for clients with chronic stroke: interrupted time series (ITS) design. AB - [Purpose] The purpose of this study was to investigate the impact that modified constraint-induced movement therapy has on upper extremity function and the daily life of chronic stroke patients. [Subjects and Methods] Modified constraint induced movement therapy was conduct for 2 stroke patients with hemiplegia. It was performed 5 days a week for 2 weeks, and the participants performed their daily living activities wearing mittens for 6 hours a day, including the 2 hours of the therapy program. The assessment was conducted 5 times in 3 weeks before and after intervention. The upper extremity function was measured using the box and block test and a dynamometer, and performance daily of living activities was assessed using the modified Barthel index. The results were analyzed using a scatterplot and linear regression. [Results] All the upper extremity functions of the participants all improved after the modified constraint-induced movement therapy. Performance of daily living activities by participant 1 showed no change, but the results of participant 2 had improved after the intervention. [Conclusion] Through the results of this research, it was identified that modified constraint-induced movement therapy is effective at improving the upper extremity functions and the performance of daily living activities of chronic stroke patients. PMID- 25931771 TI - Reliability of measurements of knee extensor muscle strength using a pull-type hand-held dynamometer. AB - [Purpose] The purpose of this study was to examine the intra-examiner and inter examiner reliabilities of measurements of knee extensor muscle strength using a pull-type hand-held dynamometer (HHD). [Subjects] Fifty-four healthy adults (35 males; average age, 23 years) participated in this study. [Methods] Knee extensor muscle strength of each leg was measured three times using the HHD. To examine the intra- and inter-examiner reliabilities, measurements were performed by two examiners, a physical therapist and a physical therapy student. [Results] The intra-examiner reliabilities, ICC (1, 1) and ICC (1, 3) ranged from 0.94-0.99. The inter-examiner reliabilities, ICC (2, 1) and ICC (3, 1) ranged from 0.90-0.92 for the right leg, and 0.88-0.90 for the left leg. Neither constant nor proportional errors were found by Bland-Altman analysis. [Conclusion] Intra examiner and inter-examiner reliabilities were acceptable, indicating that muscle strength can be measured with the pull-type HHD without dependence on skill of measurement. Pain was not caused by measurements with the pull-type HHD. PMID- 25931772 TI - Changes in the activity of the muscles surrounding the neck according to the angles of movement of the neck in adults in their 20s. AB - [Purpose] The aim of this study was to examine changes in the muscle activity around the neck according to the neck movement angle during neck flexion and extension. [Subjects and Methods] Activities of the sternocleidomastoid muscle (SCM), splenius capitis and splenius cervicis muscles, upper trapezius muscle, and middle trapezius muscle during flexion and extension were assessed in 24 college students. [Results] SCM muscle activation significantly increased at every angle during flexion and extension. The activities of the splenius capitis and splenius cervicis muscles increased significantly during flexion. The activity of the upper trapezius muscle also increased significantly. [Conclusion] The results highlight the need for individuals not to adopt a neck flexion posture for extended periods. PMID- 25931773 TI - The effect of forward head posture on muscle activity during neck protraction and retraction. AB - [Purpose] The present study was performed to investigate whether forward head posture (FHP) affects muscle activity. [Subjects and Methods] Twenty subjects attending Y university in Gyeongsangnam-do, Republic of Korea. They were divided into two groups according to craniovertebral angle: a control group (n=10) and a FHP group (n=10). Electromyography electrodes were attached to the upper fibers of the trapezius, middle fibers of the trapezius, the splenii (splenius capitis and splenius cervicis), and the sternocleidomastoid (SCM) muscle to measure muscle activity during the neck protraction and retraction. [Results] EMG activities of the middle trapezius, splenii, and SCM muscle showed significant differences between the control group and the FHP group. However, the EMG activity of the upper trapezius muscle showed no significant difference between the two groups during neck protraction and retraction. [Conclusion] The results suggest that FHP alters the muscle activity in neck protraction and retraction. PMID- 25931774 TI - Impact of electrode sequence on electrochemical removal of trichloroethylene from aqueous solution. AB - The electrode sequence in a mixed flow-through electrochemical cell is evaluated to improve the hydrodechlorination (HDC) of trichloroethylene (TCE) in aqueous solutions. In a mixed (undivided) electrochemical cell, oxygen generated at the anode competes with the transformation of target contaminants at the cathode. In this study, we evaluate the effect of placing the anode downstream from the cathode and using multiple electrodes to promote TCE reduction. Experiments with a cathode followed by an anode (C->A) and an anode followed by a cathode (A->C) were conducted using mixed metal oxide (MMO) and iron as electrode materials. The TCE removal rates when the anode is placed downstream of the cathode (C->A) were 54% by MMO->MMO, 64% by MMO->Fe and 87% by Fe->MMO sequence. Removal rates when the anode is placed upstream of the cathode (A->C) were 38% by MMO->MMO, 58% by Fe->MMO and 69% by MMO->Fe sequence. Placing the anode downstream of the cathode positively improves (by 26%) the degradation of aqueous TCE in a mixed flow through cell as it minimizes the influence of oxygen generated at the MMO anode on TCE reduction at the cathode. Furthermore, placing the MMO anode downstream of the cathode neutralizes pH and redox potential of the treated solution. Higher flow velocity under the C->A setup increases TCE mass flux reduction rate. Using multiple cathodes and an iron foam cathode up stream of the anode increase the removal rate by 1.6 and 2.4 times, respectively. More than 99% of TCE was removed in the presence of Pd catalyst on carbon and as an iron foam coating. Enhanced reaction rates found in this study imply that a mixed flow-through electrochemical cell with multiple cathodes up stream of an anode is an effective method to promote the reduction of TCE in groundwater. PMID- 25931775 TI - 'A Burden on the County': Madness, Institutions of Confinement and the Irish Patient in Victorian Lancashire. AB - This article explores the responses of the Poor Law authorities, asylum superintendents and Lunacy Commissioners to the huge influx of Irish patients into the Lancashire public asylum system, a system facing intense pressure in terms of numbers and costs, in the latter half of the nineteenth century. In particular, it examines the ways in which patients were passed, bartered and exchanged between two sets of institution-workhouses and asylums. In the mid nineteenth century removal to asylums was advocated for all cases of mental disorder by asylum medical superintendents and the Lunacy Commissioners; by its end, asylum doctors were resisting the attempts of Poor Law officials to 'dump' increasing numbers of chronic cases into their wards. The article situates the Irish patient at the centre of tussles between those with a stake in lunacy provision as a group recognised as numerous, disruptive and isolated. PMID- 25931776 TI - Abiotic stress induces change in Cinnamoyl CoA Reductase (CCR) protein abundance and lignin deposition in developing seedlings of Leucaena leucocephala. AB - Aboitic stress such as drought and salinity are class of major threats, which plants undergo through their lifetime. Lignin deposition is one of the responses to such abiotic stresses. The gene encoding Cinnamoyl CoA Reductase (CCR) is a key gene for lignin biosynthesis, which has been shown to be over-expressed under stress conditions. In the present study, developing seedlings of Leucaena leucocephala (Vernacular name: Subabul, White popinac) were treated with 1 % mannitol and 200 mM NaCl to mimic drought and salinity stress conditions, respectively. Enzyme linked immunosorbant assay (ELISA) based expression pattern of CCR protein was monitored coupled with Phlorogucinol/HCl activity staining of lignin in transverse sections of developing L. leucocephala seedlings under stress. Our result suggests a differential lignification pattern in developing root and stem under stress conditions. Increase in lignification was observed in mannitol treated stems and corresponding CCR protein accumulation was also higher than control and salt stress treated samples. On the contrary CCR protein was lower in NaCl treated stems and corresponding lignin deposition was also low. Developing root tissue showed a high level of CCR content and lignin deposition than stem samples under all conditions tested. Overall result suggested that lignin accumulation was not affected much in case of developing root however developing stems were significantly affected under drought and salinity stress condition. PMID- 25931777 TI - Increased rate of drying reduces metabolic inequity and critical water content in radicles of Cicer arietinum L. AB - Orthodox seed serves as easily accessible model to study desiccation-sensitivity in plant tissues because once they undergo germination, they become sensitive to desiccation imposed injuries. In the proposed study, effects of rate of drying on the viability, electrolyte leakage, superoxide accumulation, lipid-protein oxidation and antioxidant enzymes were explored in excised radicles of Cicer arietinum L. under dehydration and wet storage. For both the drying conditions, desiccation could be explained by exponential and inverse functions. Under rapid drying tissue viability as scored by germination efficiency and tetrazolium staining remained 100 % all through the analysis (24 h) but declined remarkably after 0.30 g g(-1) fresh mass water content (4 days) under slow drying. Moreover, precipitous fall in tissue viability was observed after 2 weeks of wet storage. Rapid drying was also accompanied with limited amounts of electrolyte leakage, superoxide radical, malondialdehyde and protein hydroperoxide, together with enhanced level of protein. Additionally, activities of both superoxide dismutase and ascorbate peroxidase were increased in rapidly dried radicles, but guaiacol peroxidase was declined. In contrary, above referred biomarkers were observed to perform either inversely or poorly during slow drying and wet storage suggesting that above documented alterations might be the resultant of ageing and not desiccation. Gathered data demonstrated that increased drying lowers the critical water content for tissue survival and also reduces the risk of damage resulting from aqueous-based deleterious reactions. Additionally, it also showed that growing radicles are a popular model to explore desiccation-sensitivity in plant tissues and/or seeds. PMID- 25931778 TI - Antiproliferative and Apoptosis Inducing Effects of Non-Polar Fractions from Lawsonia inermis L. in Cervical (HeLa) Cancer Cells. AB - Two non-polar fractions viz. hexane (Hex-LI) and chloroform fraction (CHCl3-LI) of Lawsonia inermis were studied for their antiproliferative potential in various cancer cell lines viz. HeLa, MCF-7, A549 and C6 glioma cells. Both the fractions showed more than 60 % of growth inhibition in all the tested cell lines at highest tested concentration. In clonogenic assay, different concentrations of Hex-LI and CHCl3-LI decreased the number and size of colonies as compared to control in HeLa cells. The apoptotic effects as nuclear condensation, fragmentation were visualized with Hoechst-33342 staining of HeLa cells using confocal microscope. Both fractions induced apoptotic cell death in human cervical carcinoma (HeLa) cells as evident from flow cytometric analysis carried out using Annexin V-FITC and propidium iodide dyes. CHCl3-LI treated cells significantly induced apoptosis (25.43 %) in comparison to control. Results from Neutral Comet assay demonstrated that both fractions induced double stranded breaks (DSB's) in HeLa cells. Our data indicated that Hex-LI and CHCl3-LI treated cells showed significant increase of 32.2 and 18.56 % reactive oxygen species (ROS) levels in DCFH-DA assay respectively. Further, experimental studies to decipher exact pathway via which these fractions induce cell death are in progress. PMID- 25931779 TI - Stem cell therapy for bronchopulmonary dysplasia: bench to bedside translation. AB - Bronchopulmonary dysplasia (BPD), a chronic lung disease affecting very premature infants, is a major cause of mortality and long-term morbidities despite of current progress in neonatal intensive care medicine. Though there has not been any effective treatment or preventive strategy for BPD, recent stem cell research seems to support the assumption that stem cell therapy could be a promising and novel therapeutic modality for attenuating BPD severity. This review summarizes the recent advances in stem cell research for treating BPD. In particular, we focused on the preclinical data about stem cell transplantation to improve the lung injury using animal models of neonatal BPD. These translational research provided the data related with the safety issue, optimal type of stem cells, optimal timing, route, and dose of cell transplantation, and potency marker of cells as a therapeutic agent. Those are essential subjects for the approval and clinical translation. In addition, the successful phase I clinical trial results of stem cell therapies for BPD are also discussed. PMID- 25931780 TI - Perforator Flap versus Conventional Flap. AB - The introduction of perforator flaps represented a significant advance in microsurgical reconstruction. However, confusion has developed due to the erroneous belief that perforator flaps are different from conventional flaps. The concept of the perforator is not new, but is an idea that evolved from the conventional flap. In fact, some of the flaps used by microsurgeons were perforator flaps. The only difference is the anatomical level of the blood vessels involved; the perforator concept is focused on the distal circulation, so called 'perforator'. Therefore, thinner sections of tissue can be taken from the conventional donor sites of myocutaneous flaps. With the use of perforators, there are no longer "flap of choice" for specific reconstructions, because conventional donor sites have become universal donor sites, enabling the harvesting of a variety of flaps. Moreover, depending on the surgeon's ability, any flap can be utilized as a perforator-based island flap whose source vessel has been completely preserved. Therefore, tissues can be efficiently customized and tailored into any configuration required for reconstruction. The application of perforator flap technique enables more precise dissection, and allows more selective harvesting of thinner flaps, which will expand options in reconstructive surgery. No doubt the technique will continue to evolve. PMID- 25931781 TI - General internists' perspectives regarding primary care and currently related issues in Korea. AB - Although primary care has been recognized as an essential element of the healthcare system, the primary healthcare of Korea has not been highly valued. Listening to the voices of physicians who are engaged in primary care should be the first step for improving the level of primary care in Korea. In this study, we conducted a questionnaire survey of general internists to investigate their perspectives regarding primary care, and which included the evaluation of current primary care, perception of the five, key attributes of primary care, and their opinions regarding the management system of chronic diseases. A total of 466 general internists' responses were used in this analysis. The results showed that primary care is considered to have an important role, according to general internists, although their evaluation of the overall status of primary care in Korea indicated that it is poor. The respondents also indicated that the functions of coordination and comprehensiveness in primary care, which can be integral for treating patients with chronic diseases, are most vulnerable. Given the high level of agreement regarding the need for a new medical management system for chronic diseases, based on physicians' autonomy and provided by clinics, establishing a policy encouraging the participation of general internists should be emphasized. PMID- 25931782 TI - Expression of Peroxisome Proliferator Activated Receptor gamma in Prostatic Adenocarcinoma. AB - Peroxisome proliferator-activated receptor gamma (PPAR-gamma), a ligand-activated transcription factor has been investigated as the target for cancer treatment as well as metabolic disorders. Recent studies have demonstrated that PPAR-gamma ligands are anti-tumorigenic in prostate cancer due to anti-proliferative and pro differentiation effects. The aim of this study was to validate PPAR-gamma expression in malignant and benign prostate tissues by immunohistochemistry and quantitative real-time polymerase chain reaction (PCR). A total of 730 prostatic adenocarcinomas (PCAs) including 63 whole sections from radical prostatectomy specimens and tissue microarrays containing 667 PCAs were subject to immunostaining for two PPAR-gamma antibodies. Twenty-five benign prostate tissues and PCAs were selected for investigating mRNA expression by quantitative real time PCR. 10.7% of PCAs (78/730) showed cytoplasmic immunoreactivity of PPAR gamma and no nuclear immunoreactivity was noted in PCAs. Most benign prostatic glands showed negative immunoreactivity of PPAR-gamma except for variable weak cytoplasmic staining in some glands. Nuclear immunoreactivity of PPAR-gamma was noted some central zone and verumontanum mucosal epithelium. The constitutive PPAR-gamma mRNA showed significantly lower level in PCAs compared to that in the benign tissues. There was no difference of PPAR-gamma mRNA expression between low (<=7) and high (>7) Gleason score groups. There was no association of PPAR-gamma mRNA level or cytoplasmic immunostaining with Gleason grade or pathologic stage. Our study supported the evidence of extra-nuclear localization and nongenomic actions of PPAR-gamma. Further studies are needed to assess the functional role of PPAR-gamma and to validate its therapeutic implication in prostate cancer. PMID- 25931783 TI - Risks of Lung Cancer due to Radon Exposure among the Regions of Korea. AB - Radon is likely the second most common cause of lung cancer after smoking. We estimated the lung cancer risk due to radon using common risk models. Based on national radon survey data, we estimated the population-attributable fraction (PAF) and the number of lung cancer deaths attributable to radon. The exposure age duration (EAD) and exposure-age concentration (EAC) models were used. The regional average indoor radon concentration was 37.5 95 Bq/m(3). The PAF for lung cancer was 8.3% (European Pooling Study model), 13.5% in males and 20.4% in females by EAD model, and 19.5% in males and 28.2% in females by EAC model. Due to differences in smoking by gender, the PAF of radon-induced lung cancer deaths was higher in females. In the Republic of Korea, the risk of radon is not widely recognized. Thus, information about radon health risks is important and efforts are needed to decrease the associated health problems. PMID- 25931784 TI - Cross-reactivity of Toxocariasis with Crude Antigen of Toxascaris leonina Larvae by ELISA. AB - Roundworms of Toxocara canis and Toxascaris leonina are common gastrointestinal helminths of canids over the world. Humans are infected with T. canis larvae through ingestion of infective eggs in contaminated environments or larvae by consumption of raw or uncooked meat or livers. Recently, patients of clinically diagnosed toxocariasis are increasing and require correct diagnosis in Korea. The present study investigated serological cross-reactivity between crude antigens of T. canis (TCLA) and T. leonina (TLLA) larvae. We collected serum specimens from 177 toxocariasis patients who were clinically suspected in the Seoul National University Hospital and 115 healthy controls. An ELISA method for toxocariasis was used to evaluate diagnostic efficacy of TLLA for serodiagnosis of human toxocariasis. The IgG ELISA using TLLA gave 14 (14.3%) positives of 98 TCLA positive specimens among 177 suspected toxocariasis patients. Most of them showed high absorbances with TCLA. In conclusion, there is a partial cross reaction between serum specimens of toxocariasis and TLLA. PMID- 25931785 TI - Infliximab partially alleviates the bite force reduction in a mouse model of temporomandibular joint pain. AB - Temporomandibular joint (TMJ) disorder is clinically important because of its prevalence, chronicity, and therapy-refractoriness of the pain. In this study, we investigated the effect of infliximab in a mouse model of TMJ pain using a specially-engineered transducer for evaluating the changes in bite force (BF). The mice were randomly divided into three groups (7 mice per group): the control group, the complete Freund's adjuvant (CFA) group, and the infliximab group. BF was measured at day 0 (baseline BF). After measuring the baseline BF, CFA or incomplete Freund's adjuvant was injected into both TMJs and then the changes in BF were measured at days 1, 3, 5, 7, 9, and 13 after the TMJ injection. For measuring the BF, we used a custom-built BF transducer. Control, CFA, and infliximab groups showed similar baseline BF at day 0. From day 1, a significant reduction in BF was observed in the CFA group, and this reduction in BF was statistically significant compared to that in the control group (P < 0.05). This reduction in BF was maintained until day 7, and BF started to recover gradually from day 9. In the infliximab group also, the reduction in BF was observed on day 1, and this reduction was maintained until day 7. However, the degree of reduction in BF was less remarkable compared to that in the CFA group. The reduction in BF caused by injection of CFA into the TMJ could be partially alleviated by the injection of anti-tumor necrosis factor alpha, infliximab. PMID- 25931786 TI - A Novel Angiotensin Type I Receptor Antagonist, Fimasartan, Prevents Doxorubicin induced Cardiotoxicity in Rats. AB - Angiotensin receptor blockers (ARBs) have organ-protective effects in heart failure and may be also effective in doxorubicin-induced cardiomyopathy (DOX CMP); however, the efficacy of ARBs on the prevention of DOX-CMP have not been investigated. We performed a preclinical experiment to evaluate the preventive effect of a novel ARB, fimasartan, in DOX-CMP. All animals underwent echocardiography and were randomly assigned into three groups: treated daily with vehicle (DOX-only group, n=22), 5 mg/kg of fimasartan (Low-fima group, n=22), and 10 mg/kg of fimasartan (High-fima group, n=19). DOX was injected once a week for six weeks. Echocardiography and hemodynamic assessment was performed at the 8th week using a miniaturized conductance catheter. Survival rate of the High-fima group was greater (100%) than that of the Low-fima (75%) and DOX-only groups (50%). Echocardiography showed preserved left ventricular (LV) ejection fraction in the High-fima group, but not in the DOX-only group (P=0.002). LV dimensions increased in the DOX-only group; however, remodeling was attenuated in the Low fima and High-fima groups. Hemodynamic assessment showed higher dP/dt in the High fima group compared with the DOX-only group. A novel ARB, fimasartan, may prevent DOX-CMP and improve survival rate in a dose-dependent manner in a rat model of DOX-CMP and could be a treatment option for the prevention of DOX-CMP. PMID- 25931787 TI - Role of Soluble ST2 as a Prognostic Marker in Patients with Acute Heart Failure and Renal Insufficiency. AB - This study sought to assess the relationship between serum concentrations of the soluble ST2 (sST2) and B-type natriuretic peptide (BNP) and investigate the role of sST2 as a prognosticator in patients hospitalized with acute heart failure (HF) and renal insufficiency. sST2 was measured at admission and discharge in 66 patients hospitalized with acute decompensated HF and renal insufficiency (estimated glomerular filtration rate [eGFR] < 90 mL/min/1.73 m(2)) using a high sensitivity immunoassay. BNP was sampled at the same time and compared to sST2. Demographical, biochemical, and echocardiographic data were also obtained during hospitalization.There were positive correlations between sST2 and BNP levels at admission (r = 0.330, P = 0.007) and at discharge (r = 0.320, P = 0.009) in overall patients. However, there was no correlation between them at each timepoint in patients with severe renal insufficiency (eGFR < 30 mL/min/1.73 m(2), n = 17). sST2 level was not changed with the degree of renal function, even though BNP level was much higher in patients with severe renal insufficiency. During 3 month follow-up, 9 (13.6%) died and 16 (24.2%) were readmitted due to HF aggravation.On multivariate analysis, sST2 at discharge was independently associated with death or HF readmission during 3 months after discharge (hazard ratio, 1.038; 95% confidence interval, 1.011-1.066, P = 0.006). In conclusion, sST2 is not affected by renal function compared with BNP in acute HF patients. The measurement of predischarge sST2 can be helpful in predicting short-term outcomes in acute decompensated HF patients with renal insufficiency. PMID- 25931788 TI - The Effect of Umbilical Cord Blood Derived Mesenchymal Stem Cells in Monocrotaline-induced Pulmonary Artery Hypertension Rats. AB - Pulmonary arterial hypertension (PAH) causes right ventricular failure due to a gradual increase in pulmonary vascular resistance. The purposes of this study were to confirm the engraftment of human umbilical cord blood-mesenchymal stem cells (hUCB-MSCs) placed in the correct place in the lung and research on changes of hemodynamics, pulmonary pathology, immunomodulation and several gene expressions in monocrotaline (MCT)-induced PAH rat models after hUCB-MSCs transfusion. The rats were grouped as follows: the control (C) group; the M group (MCT 60 mg/kg); the U group (hUCB-MSCs transfusion). They received transfusions via the external jugular vein a week after MCT injection. The mean right ventricular pressure (RVP) was significantly reduced in the U group after the 2 week. The indicators of RV hypertrophy were significantly reduced in the U group at week 4. Reduced medial wall thickness in the pulmonary arteriole was noted in the U group at week 4. Reduced number of intra-acinar muscular pulmonary arteries was observed in the U group after 2 week. Protein expressions such as endothelin (ET)-1, endothelin receptor A (ERA), endothelial nitric oxide synthase (eNOS) and matrix metalloproteinase (MMP)-2 significantly decreased at week 4. The decreased levels of ERA, eNOS and MMP-2 immunoreactivity were noted by immnohistochemical staining. After hUCB-MSCs were administered, there were the improvement of RVH and mean RVP. Reductions in several protein expressions and immunomodulation were also detected. It is suggested that hUCB-MSCs may be a promising therapeutic option for PAH. PMID- 25931789 TI - Association between Serum Fibroblast Growth Factor 21 and Coronary Artery Disease in Patients with Type 2 Diabetes. AB - The aim of this study was to evaluate the association of plasma fibroblast growth factor (FGF)-21 with angiographically significant coronary artery disease (CAD) in patients with type 2 diabetes mellitus. Serum FGF-21 was measured in 120 patients undergoing coronary angiography. Patients were divided into 4 groups based on the presence/absence of type 2 diabetes mellitus and of significant CAD. The atherosclerotic burden was obtained by two angiographic scores: Gensini score (GS) and Extent score (ES). FGF-21 levels were higher in type 2 diabetes mellitus than in non-diabetic patients (P = 0.014). FGF-21 levels were significantly correlated with GS (r = 0.358, P < 0.001) and ES (r = 0.324, P < 0.001) in univariate analysis with all patients. After adjusting for several confounding factors, both GS and ES were associated with FGF-21 in all patients (r = 0.271, P = 0.014; r = 0.217, P = 0.041, respectively). However, FGF-21 lost significant correlation with both GS and ES with type 2 diabetes mellitus in the final model. The patients with type 2 diabetes mellitus and CAD feature had elevated FGF-21 levels. Despite of a limited role in diabetic patients, FGF-21 levels are independently associated with angiographic severity and extent of CAD. PMID- 25931790 TI - Radiological findings and outcomes of bronchial artery embolization in cryptogenic hemoptysis. AB - Management of cryptogenic massive hemoptysis is difficult, and conservative treatment may be inadequate to stop the hemorrhage. Surgery is not a reasonable option because there is no underlying identifiable pathology. This study aimed to investigate the radiologic findings and bronchial artery embolization outcomes in cryptogenic hemoptysis, and to compare the results with non-cryptogenic hemoptysis. We evaluated 26 patients with cryptogenic hemoptysis and 152 patients with non-cryptogenic hemoptysis. A comparison of the bronchial artery abnormalities between the cryptogenic and non-cryptogenic hemoptysis groups showed that only extravasation was more statistically significant in the cryptogenic hemoptysis group than in the non-cryptogenic hemoptysis group, while the other bronchial artery abnormalities, such as bronchial artery dilatation, hypervascularity, and bronchial-to-pulmonary shunting, showed no significant difference between groups. Involvement of the non-bronchial systemic artery was significantly greater in the non-cryptogenic hemoptysis group than in the cryptogenic hemoptysis group. While 69.2% of patients with cryptogenic hemoptysis also had hypervascularity in the contralateral bronchial arteries and/or ipsilateral bronchial artery branches other than the bleeding lobar branches, this finding was not detected in non-cryptogenic hemoptysis. Embolization was performed on all patients using polyvinyl alcohol particles of 355-500 um. Hemoptysis ceased in all patients immediately after embolization. While recurrence of hemoptysis showed no statistically significant difference between the cryptogenic and non-cryptogenic hemoptysis groups, it was mild in cryptogenic hemoptysis in contrast to mostly severe in non-cryptogenic hemoptysis. Transarterial embolization is a safe and effective technique to manage cryptogenic hemoptysis. PMID- 25931791 TI - Clinical characteristics and prognostic impact of bacterial infection in hospitalized patients with alcoholic liver disease. AB - Bacterial infection is an important cause of death in patients with liver cirrhosis. The aim of this study was to investigate the clinical characteristics and prognostic impact of bacterial infection in hospitalized patients with alcoholic liver disease (ALD). We retrospectively analyzed data from 409 patients consecutively admitted to a tertiary referral center with ALD diagnosis. Of a total of 544 admissions, 133 (24.4%) cases presented with bacterial infection, of which 116 were community-acquired whereas 17 were hospital-acquired. The common types of infection were pneumonia (38%), biliary tract infection (17%), soft tissue infection (12%), and spontaneous bacterial peritonitis (9%). Diabetes, serum Na <135 mM/L, albumin <2.5 g/dL, C-reactive protein >=20 mg/L, systemic inflammatory response syndrome (SIRS) positivity were independently associated with bacterial infection in patients with ALD. Overall 30-day and 90-day mortalities in patients with bacterial infection were significantly (P < 0.001) higher than those without infection (22.3% vs. 5.1% and 32.3% vs. 8.2%, respectively). Furthermore, bacterial infection (HR, 2.2; 95% CI, 1.049-4.579, P = 0.037), SIRS positivity (HR, 2.5; 95% CI, 1.240-4.861, P = 0.010), Maddrey's discriminant function score >=32 (HR, 2.3; 95% CI, 1.036-5.222, P = 0.041), and hemoglobin <12 g/dL (HR, 2.4; 95% CI, 1.081-5.450, P = 0.032) were independent predictors of short-term mortality. In conclusion, bacterial infection and SIRS positivity predicted short-term prognosis in hospitalized patients with ALD. A thorough evaluation at admission or on clinical deterioration is required to detect possible infection with prompt management. PMID- 25931792 TI - Deficiencies of Circulating Mucosal-associated Invariant T Cells and Natural Killer T Cells in Patients with Acute Cholecystitis. AB - Mucosal-associated invariant T (MAIT) cells and natural killer T (NKT) cells are known to play crucial roles in a variety of diseases, including autoimmunity, infectious diseases, and cancers. However, little is known about the roles of these invariant T cells in acute cholecystitis. The purposes of this study were to examine the levels of MAIT cells and NKT cells in patients with acute cholecystitis and to investigate potential relationships between clinical parameters and these cell levels. Thirty patients with pathologically proven acute cholecystitis and 47 age- and sex-matched healthy controls were enrolled. Disease grades were classified according to the revised Tokyo guidelines (TG13) for the severity assessment for acute cholecystitis. Levels of MAIT and NKT cells in peripheral blood were measured by flow cytometry. Circulating MAIT and NKT cell numbers were significantly lower in acute cholecystitis patients than in healthy controls, and these deficiencies in MAIT cells and NKT cell numbers were associated with aging in acute cholecystitis patients. Notably, a reduction in NKT cell numbers was found to be associated with severe TG13 grade, death, and high blood urea nitrogen levels. The study shows numerical deficiencies of circulating MAIT and NKT cells and age-related decline of these invariant T cells. In addition, NKT cell deficiency was associated with acute cholecystitis severity and outcome. These findings provide an information regarding the monitoring of these changes in circulating MAIT and NKT cell numbers during the course of acute cholecystitis and predicting prognosis. PMID- 25931793 TI - The Immunogenicity and Safety of the Live-attenuated SA 14-14-2 Japanese Encephalitis Vaccine Given with a Two-dose Primary Schedule in Children. AB - Effective and tolerable vaccination is an essential strategy to prevent Japanese encephalitis (JE) in endemic areas. Although the live attenuated SA 14-14-2 JE vaccine (LAJEV) has been widely used since its introduction, the systemic data of LAJEV was very rarely available in Korea. We conducted the open-label, prospective cohort study to assess the immunogenicity and safety of this vaccine. Ninety subjects were enrolled, and LAJEV in a 2-dose primary series was given with a 12-month interval. Neutralizing antibody titers were measured before and after each vaccination, and active monitoring for adverse events was performed. After the first dose, 91.1% of subjects had seroprotection with a geometric mean titer (GMT) of 40.9. Seroprotection rate after the second dose was 97%, and GMT showed an increase of 6.5-fold. Most adverse events following immunization were self-limited, and no serious adverse events were reported until 42 days after each dose. The 2-dose administration of LAJEV in the primary immunization schedule appeared to be highly immunogenic and safe. PMID- 25931794 TI - Prevalence of antibiotic use for pediatric acute upper respiratory tract infections in Korea. AB - This study was conducted to estimate the prevalence of antimicrobial prescribing for acute upper respiratory tract infections (URI) among pediatric outpatients and to identify the national patterns of its use from 2009 to 2011 in Korea. Using National Patients Sample database from 2009 to 2011, we estimated the frequency of antibiotics prescribing for URI in pediatric outpatients with diagnoses of acute nasopharyngitis (common cold), acute sinusitis, acute pharyngitis, acute tonsillitis, acute laryngitis/tracheitis, acute obstructive laryngitis/epiglottitis, and acute upper respiratory infections of multiple and unspecified sites. The proportions of each antibiotic class were calculated by year and absolute and relative differences were estimated. Also, we investigated daily amount of prescribed antibiotics per defined population according to the type of medical care institution, physician specialty, and geographic region. The overall antibiotic prescribing proportion was 58.7% and its annual proportion slightly decreased (55.4% in 2011 vs. 60.5% in 2009; adjusted odds ratio, 0.82; 95% confidence interval, 0.82-0.83). Variations by the type of medical care institution were observed. Tertiary hospitals (45.0%) were less likely to prescribe antibiotics than primary care clinics (59.4%), hospitals (59.0%), and general hospitals (61.2%); they showed different tendencies in choosing antibiotics. Variations by physician specialty and region were also observed. Prevalence of antimicrobial prescribing for pediatric URI is still considered higher than that of western countries and varies by the type of medical care institution, physician specialty, and geographic region. PMID- 25931795 TI - Functional magnetic resonance imaging of motor cortex activation in schizophrenia. AB - Previous fMRI studies of sensorimotor activation in schizophrenia have found in some cases hypoactivity, no difference, or hyperactivity when comparing patients with controls; similar disagreement exists in studies of motor laterality. In this multi-site fMRI study of a sensorimotor task in individuals with chronic schizophrenia and matched healthy controls, subjects responded with a right handed finger press to an irregularly flashing visual checker board. The analysis includes eighty-five subjects with schizophrenia diagnosed according to the DSM IV criteria and eighty-six healthy volunteer subjects. Voxel-wise statistical parametric maps were generated for each subject and analyzed for group differences; the percent Blood Oxygenation Level Dependent (BOLD) signal changes were also calculated over predefined anatomical regions of the primary sensory, motor, and visual cortex. Both healthy controls and subjects with schizophrenia showed strongly lateralized activation in the precentral gyrus, inferior frontal gyrus, and inferior parietal lobule, and strong activations in the visual cortex. There were no significant differences between subjects with schizophrenia and controls in this multi-site fMRI study. Furthermore, there was no significant difference in laterality found between healthy controls and schizophrenic subjects. This study can serve as a baseline measurement of schizophrenic dysfunction in other cognitive processes. PMID- 25931796 TI - A Korean survey on qualities and definition of a good psychiatrist. AB - The definition of a "good" psychiatrist has varied over the past decades due to changing roles of psychiatrists. Studies on the qualities of "good" psychiatrists have been completed in many countries. However, no such study has been undertaken in Korea. In Korea, recent growing interest in psychiatry demands the identification of qualities for a good psychiatrist. The purpose of this study was to define the qualities of a good psychiatrist in Korea, subsequently facilitating the improvement of psychiatric training programs. The questionnaire was based on a Singaporean survey with the permission from the original authors. Respondents were divided into patient group and psychiatrist group. The 40-item questionnaire contained items grouped into four themes: Professional, Personal Values, Academic Executive and Relationship. Of the four themes, both patient and psychiatrist groups considered Professional as the most important, whereas Academic Executive as the least important. The mean scores for all items of each theme in the patient group were higher than those in the psychiatrist group, reflecting higher expectations for good psychiatrist in the patient group. Patients emphasized Relationship more than psychiatrists did. It is concluded that a good psychiatrist in Korea can be defined as "a good communicator and listener with a professional manner, who respects confidentiality and has good doctor-patient relationships." PMID- 25931797 TI - Increasing Prevalence of Trichophyton rubrum Identified through an Analysis of 115,846 Cases over the Last 37 Years. AB - Trichophyton rubrum is the most common dermatophyte in the world with the highest prevalence in Korea. There are few reports about epidemiological and mycological characteristics of T. rubrum based on long-term, large-scale studies. The purpose of this study was to investigate the clinical and epidemiological characteristics of T. rubrum infections in Korea. We retrospectively investigated with patients' records about the epidemiological and mycological status of 115,846 cases with T. rubrum infection that was mycologically diagnosed at Catholic Skin Disease Clinic from 1979 to 2013. Direct microscopy in 15% KOH solution and culture was done in each case. The annual incidence of patients with T. rubrum infection had been increasing during the period; and of 131,122 patients with dermatophytosis, 115,846 patients (88.35%) had T. rubrum infection. Disease was most prevalent among patients in their twenties in the 1970s and 1980s; in their thirties in the 1990s; in their forties in the 2000s; and in their fifties in the 2010s. The sex ratio was 1.5:1. T. rubrum infection was most commonly seen in summer and was found predominantly in patients living in urban areas. Toe webs were most frequently involved, followed by toenails and groin. This epidemiologic findings provide useful information for prevention of T. rubrum infection and future dermatophytosis prospects. PMID- 25931798 TI - Inpatient stroke rehabilitation outcomes in Korea derived from the Korean Brain Rehabilitation Centers' online database system for the years 2007 to 2011. AB - The purpose of this report was to provide information for patients receiving inpatient rehabilitation after stroke and to identify the possible factors influencing functional outcome after inpatient rehabilitation. Stroke patients (n = 5,212) who were discharged from the Departments of Rehabilitation Medicine (RM) of university hospitals and rehabilitation hospitals from 2007 through 2011 were participants. Prevalence, age, transfer time after onset, length of stay (LOS), functional status at admission and discharge were analyzed. In all stroke subjects, cerebral infarctions (67%) were more common than hemorrhages. Cerebral infarctions in the middle cerebral artery territory were most common, while the basal ganglia and cerebral cortex were the most common areas for hemorrhagic stroke. The LOS decreased from 45 to 28 days. Transfer time after onset decreased from 44 to 30 days. Shorter transfer time after onset was correlated with better discharge functional status and shorter LOS. Initial functional status was correlated with discharge functional status. In ischemic stroke subtypes, cerebellar and brainstem strokes predicted better outcomes, while strokes with more than one territory predicted poorer outcomes with more disabilities. In hemorrhagic stroke subtypes, initial and discharge functional status was the lowest for cortical hemorrhages and highest for brainstem hemorrhages. This report shows that LOS and transfer time after onset has been decreased over time and initial functional status and shorter transfer after onset are predictors of better functional outcome at discharge. PMID- 25931799 TI - Effects of u-Opioid Receptor Gene Polymorphism on Postoperative Nausea and Vomiting in Patients Undergoing General Anesthesia with Remifentanil: Double Blinded Randomized Trial. AB - Association between postoperative nausea and vomiting (PONV) and u-opioid receptor A118G single nucleotide polymorphism (SNP) is undefined and might underlie inconsistent results of studies on PONV occurrence in patients undergoing general anesthesia with the opioid, remifentanil. Four hundred and sixteen Korean women undergoing breast surgery with general anesthesia were randomized to receive remifentanil 10 ng/mL (plasma-site, Minto model) using a target-controlled infusion device and either propofol for total intravenous anesthesia (T group) or sevoflurane for inhalation anesthesia (I group) with bispectral index values maintained between 40 and 60. Blood specimens were collected after anesthesia induction for A118G SNP analysis. PONV and postoperative pain were evaluated. A118G SNP type distribution among Korean female adults studied was AG (n=195)>AA (n=158)>GG (n=63). Regardless of anesthetic technique, patients with GG types had lower PONV scale on arrival at postoperative care unit (PACU) (P=0.002), while T group showed lower PONV scale than I group up to 6 hr after PACU discharge in AA and AG types. No differences were apparent for postoperative pain among opioid receptor polymorphism. PONV occurrence differs according to opioid receptor polymorphism and anesthetic technique in patients undergoing general anesthesia with remifentanil. PMID- 25931800 TI - Virtual Endoscopic and Laparoscopic Exploration of Stomach Wall Based on a Cadaver's Sectioned Images. AB - We intended to determine that virtual endoscopy and laparoscopy of the stomach based on serially sectioned cadaver images is beneficial. Therefore, the outlines between the gastric wall and lumen were traced using the new female data of the Visible Korean to build a volume model. While the outlines were expanded at appropriate thicknesses, the stomach was observed endoscopically and laparoscopically in comparison with a chosen sectioned image. Four layers (mucosa, submucosa, muscular layer, and serosa) of the stomach were discernible by their proper colors in the sectioned images. All layers except the submucosa were identified in the endoscopic and laparoscopic views by using consistent colors. The stepwise expansion of the outlines revealed thickness of each layer as well as whether the thickness was uniform. Our ideas and the Visible Korean images could be a robust resource of virtual reality learning for medical students and clinicians. PMID- 25931801 TI - Cluster of serogroup W-135 meningococcal disease in 3 military recruits. AB - We describe a group of 3 cases of invasive meningococcal disease that occurred in a military training camp in April 2011. All three patients were hospitalized. Ultimately, two patients recovered and one died. One patient had meningitis, one patient had septicemia and meningitis, and the other had no definite septicemia or meningitis. Neisseria meningitidis serogroup W-135 was detected in the serum and cerebrospinal fluid (CSF) of all patients by real-time polymerase chain reaction. In the one case of mortality, two strains were isolated from the patient's blood and CSF. Using multilocus sequence typing analysis, these strains were identified as a novel sequence type, ST-8912. Special attention is required for the meningococcal disease in military camp because the military personnels are in high risk of contact transmission. PMID- 25931802 TI - Cancer Risk among Population near Nuclear Power Plants in Korea. PMID- 25931803 TI - "We weren't the sort that wanted intimacy every night": Birth control and abstinence in England, c.1930-60. AB - This article presents an exploration of qualitative evidence on the relationship between birth control and abstinence from an oral history project, which interviewed middle and working-class English men and women, who had married between the late 1920s and the early 1950s. Among the working classes the assumption that men were responsible for birth control choices and the disadvantages that contraceptive methods of all types posed, combined with the fear of pregnancy, acted as a disincentive to have sex and resulted in forms of partial abstinence. Among the middle classes, women had much more access to birth control information and as a consequence a greater range of methods was used, including more female methods. However, the reluctance of couples to discuss sexual matters, and some continued preference for male methods meant that while condoms were the most regularly used middle-class male method, both withdrawal and abstinence were also in evidence. Moreover, although partners were more likely to discuss birth control at the start of their marriages, they were less likely to agree that contraception was a male responsibility and there was greater potential for conflict over contraceptive methods, not infrequently resulting in abstinence. The evidence suggests that sexual and contraceptive practices in marriages in England at the end of the secular fertility decline do not present a picture which straightforwardly correlates with the assumptions represented by the popular thesis that this period of increased fertility control was closely associated with the rise of companionate marriage. PMID- 25931804 TI - Toolbox for mobile-element insertion detection on cancer genomes. AB - Mobile elements constitute greater than 45% of the human genome as a result of repeated insertion events during human genome evolution. Although most of mobile elements are fixed within the human population, some elements (including ALU, long interspersed elements (LINE) 1 (L1), and SVA) are still actively duplicating and may result in life-threatening human diseases such as cancer, motivating the need for accurate mobile-element insertion (MEI) detection tools. We developed a software package, TANGRAM, for MEI detection in next-generation sequencing data, currently serving as the primary MEI detection tool in the 1000 Genomes Project. TANGRAM takes advantage of valuable mapping information provided by our own MOSAIK mapper, and until recently required MOSAIK mappings as its input. In this study, we report a new feature that enables TANGRAM to be used on alignments generated by any mainstream short-read mapper, making it accessible for many genomic users. To demonstrate its utility for cancer genome analysis, we have applied TANGRAM to the TCGA (The Cancer Genome Atlas) mutation calling benchmark 4 dataset. TANGRAM is fast, accurate, easy to use, and open source on https://github.com/jiantao/Tangram. PMID- 25931805 TI - Infrared imaging enhances retinal crystals in Bietti's crystalline dystrophy. AB - Infrared imaging dramatically increased the number of crystalline deposits visualized compared with clinical examination, standard color fundus photography, and red free imaging in patients with Bietti's crystalline dystrophy. We believe that this imaging modality significantly improves the sensitivity with which these lesions are detected, facilitating earlier diagnosis and may potentially serve as a prognostic indicator when examined over time. PMID- 25931806 TI - Comparison of novel lipid-based eye drops with aqueous eye drops for dry eye: a multicenter, randomized controlled trial. AB - BACKGROUND: Dry eye may be caused or exacerbated by deficient lipid secretion. Recently, lipid-containing artificial tears have been developed to alleviate this deficiency. Our study compared the efficacy, safety, and acceptability of lipid containing eye drops with that of aqueous eye drops. METHODS: A non-inferiority, randomized, parallel-group, investigator-masked multicenter trial was conducted. Subjects with signs and symptoms of dry eye were randomized to use one of two lipid-containing artificial tears, or one of two aqueous artificial tears. Subjects instilled assigned drops in each eye at least twice daily for 30 days. The primary efficacy analysis tested non-inferiority of a preservative-free lipid tear formulation (LT UD) to a preservative-free aqueous tear formulation (AqT UD) for change in Ocular Surface Disease Index (OSDI) score from baseline at day 30. Secondary measures included OSDI at day 7, tear break-up time (TBUT), corneal and conjunctival staining, Schirmer's test, acceptability and usage questionnaires, and safety assessments. RESULTS: A total of 315 subjects were randomized and included in the analyses. Subjects reported instilling a median of three doses of study eye drops per day in all groups. At days 7 and 30, all groups showed statistically significant improvements from baseline in OSDI (P<0.001) and TBUT (P<=0.005). LT UD was non-inferior to AqT UD for mean change from baseline in OSDI score at day 30. No consistent or clinically relevant differences for the other efficacy variables were observed. Acceptability was generally similar across the groups and there was a low incidence of adverse events. CONCLUSION: In this heterogeneous population of dry eye subjects, there were no clinically significant differences in safety, effectiveness, and acceptability between lipid containing artificial tears and aqueous eye drops. The results suggest that lipid containing artificial tears can be used to counteract lipid deficiency that is common in dry eye, without compromising overall acceptability. PMID- 25931808 TI - A review of the iStent((r)) trabecular micro-bypass stent: safety and efficacy. AB - There is a significant demand for procedures that can effectively treat glaucoma with low risk and good visual outcomes. To fill this void, procedures termed "minimally invasive glaucoma surgery", are gaining in popularity. This review will focus on the safety and efficacy of one such minimally invasive glaucoma surgery procedure, the trabecular micro-bypass stent. This stent is intended to lower intraocular pressure by directly cannulating Schlemm's canal and thereby enhancing aqueous outflow. Recent randomized controlled trials and case series have demonstrated the micro-bypass stent to be a relatively safe procedure, with limited complications and no serious adverse sequelae. The most common complication across all studies was stent obstruction or malposition, which generally did not result in any adverse outcome in vision or pressure control. In addition, increased rates of hypotony, choroidal hemorrhage, or infection were not seen with the micro-bypass stent in comparison to cataract surgery alone. PMID- 25931807 TI - Efficacy and safety of two new formulations of artificial tears in subjects with dry eye disease: a 3-month, multicenter, active-controlled, randomized trial. AB - PURPOSE: To evaluate and compare the efficacy and safety of two investigational artificial tear formulations (CHO-1 and CHO-2) containing carmellose sodium, hyaluronic acid at different concentrations, and osmoprotectants, with a standard carmellose sodium-containing formulation (Refresh Tears [RT]) in the treatment of dry eye disease. SUBJECTS AND METHODS: In this 3-month, double-masked, multicenter study, subjects (n=305) were randomized 1:1:1 to receive CHO-1, CHO 2, or RT, used as needed but at least twice daily. The primary endpoint was change in ocular surface disease index (OSDI) score from baseline to day 90. Other key outcomes included symptoms evaluated on a visual analog scale, corneal and conjunctival staining, and adverse events. RESULTS: OSDI scores and dry eye symptoms showed a rapid and sustained reduction from baseline in each group. Both CHO-1 and CHO-2 met the primary efficacy endpoint of noninferiority to RT in day 90 OSDI score change from baseline. OSDI ocular symptoms subscale improved more with CHO-1 than CHO-2 (P=0.048). In subjects with clinically relevant baseline ocular surface staining (>14 total score of a maximum of 55), day 90 improvements were greater with CHO-1 and CHO-2 than RT (P<=0.044). Day 90 improvements in OSDI ocular symptoms subscale scores were also greater with CHO-1 than RT (P<0.007) in subjects with clinically relevant ocular staining. All treatments were well tolerated. CONCLUSION: Both combination artificial tear formulations were efficacious and well tolerated in subjects with dry eye. CHO-1 demonstrated the best performance in improving ocular symptoms and reducing ocular staining in this heterogeneous study population. PMID- 25931809 TI - A pharmacological modification of pain and epithelial healing in contemporary transepithelial all-surface laser ablation (ASLA). AB - PURPOSE: We report our experience with the use of the matrix regenerating agent (RGTA) Cacicol((r)) after reverse transepithelial all-surface laser ablation (ASLA)-SCHWIND to assess the safety, efficacy, pain, and epithelial healing. METHODS: Forty eyes of 20 myopic patients were prospectively recruited to a randomized fellow eye study. Patients underwent transepithelial ASLA in both eyes, with one of the eyes randomly assigned to the use of the RGTA Cacicol. Postoperative pain and vision were subjectively assessed with the use of a questionnaire on the operative day, at 24 hours, 48 hours and 72 hours. Epithelial defect area size was measured at 24 hours, 48 hours, and 72 hours. Uncorrected distance visual acuity (UDVA) and corrected distance visual acuity (CDVA) were assessed at 1 month. RESULTS: Mean UDVA at 1 month was LogMAR 0.028. The epithelial defect area was 10.91 mm(2) and 13.28 mm(2) at 24 hours and 1.39 mm(2) and 1.24 mm(2) at 48 hours for treated and nontreated eyes, respectively. Overall, 50% and 65% of treated and nontreated eyes healed by 48 hours. There was no statistically significant difference in the subjective vision between the groups, although vision of patients in the RGTA group was reported to be better. Pain scores were better at 24 hours and 48 hours in the RGTA group but with no statistically significant difference. CONCLUSION: The use of RGTA Cacicol shows faster epithelial recovery after transepithelial ASLA for myopia. Subjectively reported scores of pain and subjective vision were better in the RGTA group, although the difference was not statistically significant. There seems to be a consensual acceleration of epithelial healing even in eyes that did not receive treatment. There were no adverse events and no incidents of inflammation, delayed healing, or haze. PMID- 25931810 TI - Paclitaxel attenuates renal interstitial fibroblast activation and interstitial fibrosis by inhibiting STAT3 signaling. AB - Recent studies have demonstrated that paclitaxel might inhibit renal fibrosis. However, the underlying molecular mechanism remains unclear. In this study, we hypothesized that low-dose paclitaxel may block the STAT3 (signal transducer and activator of transcription 3) signaling to attenuate fibrosis in a mouse model with unilateral ureteral obstruction. Both NRK-49F cells and mice with unilateral ureteral obstruction were treated with paclitaxel. The results showed that paclitaxel treatment resulted in a dose- and time-dependent decrease in tyrosine phosphorylated STAT3, and inhibited the expression of fibronectin, alpha-smooth muscle actin (alpha-SMA), and collagen I in cultured NRK-49F cells. S3I-201, an STAT3 inhibitor, also suppressed the expression of fibronectin, alpha-SMA, and collagen I in cultured NRK-49F cells. Mechanistically, paclitaxel treatment blocked the STAT3 activity by disrupting the association of STAT3 with tubulin and inhibiting STAT3 nucleus translocation. Furthermore, paclitaxel also ameliorated renal fibrosis by down-regulating the expression of fibronectin, alpha-SMA, and collagen I, and suppressed the infiltration of macrophages and production of TNF-alpha, IL-1beta, TGF-beta, and ICAM-1 (intercellular adhesion molecule 1) by inhibition of STAT3 activity in obstructive nephropathy. These results suggest that paclitaxel may block the STAT3 activity by disrupting the association of STAT3 with tubulin and inhibiting STAT3 nucleus translocation, consequently leading to the suppression of renal interstitial fibroblast activation and the development of renal fibrosis, and inhibition of proinflammatory cytokine production. PMID- 25931811 TI - Clinicopathological significance and potential drug targeting of CDH1 in lung cancer: a meta-analysis and literature review. AB - BACKGROUND: CDH1 is a protein encoded by the CDH1 gene in humans. Mutations in this gene are linked with several types of cancer. Loss of CDH1 function contributes to the progression of cancer by increasing proliferation, invasion, and/or metastasis. However, the association between and clinicopathological significance of CDH1 promoter methylation and lung cancer remains unclear. In this study, we systematically reviewed the studies of CDH1 promoter methylation and lung cancer, and evaluated the association between CDH1 promoter methylation and lung cancer using meta-analysis methods. METHODS: A comprehensive search of the PubMed and Embase databases was performed up to July 2014. The methodological quality of the studies was also evaluated. The data were extracted and assessed by two reviewers independently. Analyses of pooled data were performed. Odds ratios (ORs) were calculated and summarized. RESULTS: Finally, an analysis of 866 patients with non-small cell lung cancer from 13 eligible studies was performed. The CDH1 methylation level in the cancer group was significantly higher than in the controls (OR 3.89, 95% confidence interval [CI] 2.87-5.27, P<0.00001). However, there were no correlations between CDH1 promoter methylation and clinicopathological characteristics (sex status, OR 0.78, 95% CI 0.41-1.50, P=0.46; smoking history, OR 0.97, 95% CI 0.53-1.79, P=0.93; pathological type, OR 0.97, 95% CI 0.59-1.60, P=0.91; clinical staging, OR 1.48, 95% CI 0.81-2.68, P=0.2; lymph node metastasis, OR 0.68, 95% CI 0.13-3.63, P=0.65; or differentiation degree, OR 1.01, 95% CI 0.34-3.02, P=0.99). CONCLUSION: The results of this meta-analysis suggest that CDH1 methylation is associated with an increased risk of lung cancer. CDH1 hypermethylation, which induces inactivation of the CDH1 gene, plays an important role in carcinogenesis and may serve as a potential drug target in lung cancer. However, CDH1 methylation does not correlate with other factors, such as smoking history, clinical stage, pathological type, sex status, lymph node metastasis, or degree of differentiation. PMID- 25931812 TI - Transgenic animal models for study of the pathogenesis of Huntington's disease and therapy. AB - Huntington's disease (HD) is caused by a genetic mutation that results in polyglutamine expansion in the N-terminal regions of huntingtin. As a result, this polyQ expansion leads to the misfolding and aggregation of mutant huntingtin as well as age-dependent neurodegeneration. The genetic mutation in HD allows for generating a variety of animal models that express different forms of mutant huntingtin and show differential pathology. Studies of these animal models have provided an important insight into the pathogenesis of HD. Mouse models of HD include transgenic mice, which express N-terminal or full-length mutant huntingtin ubiquitously or selectively in different cell types, and knock-in mice that express full-length mutant Htt at the endogenous level. Large animals, such as pig, sheep, and monkeys, have also been used to generate animal HD models. This review focuses on the different features of commonly used transgenic HD mouse models as well as transgenic large animal models of HD, and also discusses how to use them to identify potential therapeutics. Since HD shares many pathological features with other neurodegenerative diseases, identification of therapies for HD would also help to develop effective treatment for different neurodegenerative diseases that are also caused by protein misfolding and occur in an age-dependent manner. PMID- 25931813 TI - Nanoparticle albumin-bound paclitaxel (nab-paclitaxel) as second-line chemotherapy in HER2-negative, taxane-pretreated metastatic breast cancer patients: prospective evaluation of activity, safety, and quality of life. AB - BACKGROUND: A prospective, multicenter trial was undertaken to assess the activity, safety, and quality of life of nanoparticle albumin-bound paclitaxel (nab-paclitaxel) as second-line chemotherapy in HER2-negative, taxane-pretreated metastatic breast cancer (MBC). PATIENTS AND METHODS: Fifty-two women with HER2 negative MBC who were candidates for second-line chemotherapy for the metastatic disease were enrolled and treated at three centers in Northern Italy. All patients had previously received taxane-based chemotherapy in the adjuvant or first-line metastatic setting. Single-agent nab-paclitaxel was given at the dose of 260 mg/m(2) as a 30-minute intravenous infusion on day 1 each treatment cycle, which lasted 3 weeks, in the outpatient setting. No steroid or antihistamine premedication was provided. Treatment was stopped for documented disease progression, unacceptable toxicity, or patient refusal. RESULTS: All of the enrolled patients were evaluable for the study endpoints. The objective response rate was 48% (95% CI, 31.5%-61.3%) and included complete responses from 13.5%. Disease stabilization was obtained in 19 patients and lasted >6 months in 15 of them; the overall clinical benefit rate was 77%. The median time to response was 70 days (range 52-86 days). The median progression-free survival time was 8.9 months (95% CI, 8.0-11.6 months, range 5-21+ months). The median overall survival point has not yet been reached. Toxicities were expected and manageable with good patient compliance and preserved quality of life in patients given long-term treatment. CONCLUSION: Our results showed that single-agent nab-paclitaxel 260 mg/m(2) every 3 weeks is an effective and well tolerated regimen as second-line chemotherapy in HER2-negative, taxane-pretreated MBC patients, and that it produced interesting values of objective response rate and progression-free survival without the concern of significant toxicity. Specifically, the present study shows that such a regimen is a valid therapeutic option for that 'difficult to treat' patient population represented by women who at the time of disease relapse have already received the most active agents in the adjuvant and/or metastatic setting (ie, conventional taxanes). PMID- 25931814 TI - Anticancer activity of streptochlorin, a novel antineoplastic agent, in cholangiocarcinoma. AB - BACKGROUND: The aim of this study is to investigate the anticancer activity of streptochlorin, a novel antineoplastic agent, in cholangiocarcinoma. METHODS: The anticancer activity of streptochlorin was evaluated in vitro in various cholangiocarcinoma cell lines for apoptosis, proliferation, invasiveness, and expression of various protein levels. A liver metastasis model was prepared by splenic injection of HuCC-T1 cholangiocarcinoma cells using a BALB/c nude mouse model to study the systemic antimetastatic efficacy of streptochlorin 5 mg/kg at 8 weeks. The antitumor efficacy of subcutaneously injected streptochlorin was also assessed using a solid tumor xenograft model of SNU478 cells for 22 days in the BALB/c nude mouse. RESULTS: Streptochlorin inhibited growth and secretion of vascular endothelial growth factor by cholangiocarcinoma cells in a dose dependent manner and induced apoptosis in vitro. In addition, streptochlorin effectively inhibited invasion and migration of cholangiocarcinoma cells. Secretion of vascular endothelial growth factor and activity of matrix metalloproteinase-9 in cholangiocarcinoma cells were also suppressed by treatment with streptochlorin. Streptochlorin effectively regulated metastasis of HuCC-T1 cells in a mouse model of liver metastasis. In a tumor xenograft study using SNU478 cells, streptochlorin significantly inhibited tumor growth without changes in body weight when compared with the control. CONCLUSION: These results reveal that streptochlorin is a promising chemotherapeutic agent to the treatment of cholangiocarcinoma. PMID- 25931816 TI - Benefit-risk assessment of pitavastatin for the treatment of hypercholesterolemia in older patients. AB - With the practice-shifting changes made with the most recent guidelines for treating blood cholesterol, more older patients may be prescribed statin therapy. Therefore, it is imperative that practitioners have not only a working knowledge of information related to statins, but more specifically to their efficacy and safety in elderly populations. Pitavastatin is the most recent statin to receive regulatory approval. It is indicated for the treatment of primary hyperlipidemia or mixed dyslipidemia as an adjunctive therapy to diet. The overall body of evidence for the efficacy and safety of pitavastatin in elderly patients is small. The available data suggest that the ability of pitavastatin to lower low density lipoprotein cholesterol in elderly patients is at least similar, and may be greater than that seen in comparatively younger cohorts. Taken together, the limited available data suggest that pitavastatin is effective at improving lipid parameters in elderly patients with a similar safety profile to other agents in the class. Until data become available distinguishing pitavastatin from the other available options, its ultimate role in the hyperlipidemia treatment armamentarium remains unclear. PMID- 25931815 TI - Emerging therapies for patients with symptoms of opioid-induced bowel dysfunction. AB - Opioid-induced bowel dysfunction (OIBD) comprises gastrointestinal (GI) symptoms, including dry mouth, nausea, vomiting, gastric stasis, bloating, abdominal pain, and opioid-induced constipation, which significantly impair patients' quality of life and may lead to undertreatment of pain. Traditional laxatives are often prescribed for OIBD symptoms, although they display limited efficacy and exert adverse effects. Other strategies include prokinetics and change of opioids or their administration route. However, these approaches do not address underlying causes of OIBD associated with opioid effects on mostly peripheral opioid receptors located in the GI tract. Targeted management of OIBD comprises purely peripherally acting opioid receptor antagonists and a combination of opioid receptor agonist and antagonist. Methylnaltrexone induces laxation in 50%-60% of patients with advanced diseases and OIBD who do not respond to traditional oral laxatives without inducing opioid withdrawal symptoms with similar response (45% 50%) after an oral administration of naloxegol. A combination of prolonged release oxycodone with prolonged-release naloxone (OXN) in one tablet (a ratio of 2:1) provides analgesia with limited negative effect on the bowel function, as oxycodone displays high oral bioavailability and naloxone demonstrates local antagonist effect on opioid receptors in the GI tract and is totally inactivated in the liver. OXN in daily doses of up to 80 mg/40 mg provides equally effective analgesia with improved bowel function compared to oxycodone administered alone in patients with chronic non-malignant and cancer-related pain. OIBD is a common complication of long-term opioid therapy and may lead to quality of life deterioration and undertreatment of pain. Thus, a complex assessment and management that addresses underlying causes and patomechanisms of OIBD is recommended. Newer strategies comprise methylnaltrexone or OXN administration in the management of OIBD, and OXN may be also considered as a preventive measure of OIBD development in patients who require opioid administration. PMID- 25931817 TI - Physical activity and all-cause mortality among older Brazilian adults: 11-year follow-up of the Bambui Health and Aging Study. AB - OBJECTIVE: To investigate the association between physical activity (eg, energy expenditure) and survival over 11 years of follow-up in a large representative community sample of older Brazilian adults with a low level of education. Furthermore, we assessed sex as a potential effect modifier of this association. MATERIALS AND METHODS: A population-based prospective cohort study was conducted on all the >=60-year-old residents in Bambui city (Brazil). A total of 1,606 subjects (92.2% of the population) enrolled, and 1,378 (85.8%) were included in this study. Type, frequency, and duration of physical activity were assessed in the baseline survey questionnaire, and the metabolic equivalent task tertiles were estimated. The follow-up time was 11 years (1997-2007), and the end point was mortality. Deaths were reported by next of kin during the annual follow-up interview and ascertained through the Brazilian System of Information on Mortality, Brazilian Ministry of Health. Hazard ratios (95% confidence intervals [CIs]) were estimated by Cox proportional-hazard models, and potential confounders were considered. RESULTS: A statistically significant interaction (P<0.03) was found between sex and energy expenditure. Among older men, increases in levels of physical activity were associated with reduced mortality risk. The hazard ratios were 0.59 (95% CI 0.43-0.81) and 0.47 (95% CI 0.34-0.66) for the second and third tertiles, respectively. Among older women, there was no significant association between physical activity and mortality. CONCLUSION: It was possible to observe the effect of physical activity in reducing mortality risk, and there was a significant interaction between sex and energy expenditure, which should be considered in the analysis of this association in different populations. PMID- 25931818 TI - Polymeric nanoparticle-based delivery of microRNA-199a-3p inhibits proliferation and growth of osteosarcoma cells. AB - Our prior screening of microRNAs (miRs) identified that miR-199a-3p expression is reduced in osteosarcoma cells, one of the most common types of bone tumor. miR 199a-3p exhibited functions of tumor cell growth inhibition, suggesting the potential application of miR-199a-3p as an anticancer agent. In the study reported here, we designed and developed a lipid-modified dextran-based polymeric nanoparticle platform for encapsulation of miRs, and determined the efficiency and efficacy of delivering miR-199a-3p into osteosarcoma cells. In addition, another potent miR, let-7a, which also displayed tumor suppressive ability, was selected as a candidate miR for evaluation. Fluorescence microscopy studies and real-time polymerase chain reaction results showed that dextran nanoparticles could deliver both miR-199a-3p and let-7a into osteosarcoma cell lines (KHOS and U-2OS) successfully. Western blotting analysis and 3-(4,5-dimethylthiazol-2-yl) 2,5-diphenyltetrazolium bromide (MTT) assays demonstrated that dextran nanoparticles loaded with miRs could efficiently downregulate the expression of target proteins and effectively inhibit the growth and proliferation of osteosarcoma cells. These results demonstrate that a lipid-modified dextran-based polymeric nanoparticle platform may be an effective nonviral carrier for potential miR-based anticancer therapeutics. PMID- 25931819 TI - Cu(2+)-RGDFRGDS: exploring the mechanism and high efficacy of the nanoparticle in antithrombotic therapy. AB - Thrombosis disease has been the leading cause of morbidity and mortality worldwide. In the discovery of antithrombotic agents, three complexes of Cu(2+) and repetitive arginine-glycine-aspartic acid (RGD) sequences, Cu(II)-Arg-Gly-Asp Ser-Arg-Gly-Asp-Ser (Cu[II]-4a), Cu(II)-Arg-Gly-Asp-Val-Arg-Gly-Asp-Val (Cu[II] 4b), and Cu(II)-Arg-Gly-Asp-Phe-Arg-Gly-Asp-Phe (Cu[II]-4c), were previously reported, of which Cu(II)-4a and Cu(II)-4c possessed the highest in vitro and in vivo activity, respectively. Transmission electron microscopy (TEM) images visualized that Cu(II)-4a and Cu(II)-4c formed nanoaggregates and nanoparticles, respectively. However, the details of the formation of the nanospecies complexes and of the mechanism for inhibiting thrombosis remain to be clarified. For this purpose, this study designed a novel complex of Cu(II) and the RGD octapeptide, Arg-Gly-Asp-Phe-Arg-Gly-Asp-Ser (RGDFRGDS), consisting of Arg-Gly-Asp-Phe of Cu(II)-4c and Arg-Gly-Asp-Ser of Cu(II)-4a, to colligate their biological and nanostructural benefits. In contrast with Cu(II)-4a, -4b, and -4c, Cu(II) RGDFRGDS (Cu(2+)-FS) had high antiplatelet and antithrombotic activities, with the formed nanoparticles having a porous surface. Additionally, this paper evidenced the dimer had the basic structural unit of Cu(2+)-FS in water, theoretically simulated the formation of Cu(2+)-FS nanoparticles, and identified that Cu(2+)-FS activity in decreasing glycoprotein IIb/IIIa, P-selectin, and IL-8 was responsible for the antithrombotic action. Finally, adherence onto the surface and entry into the cytoplasm were considered the steps of a two-step model for the blocking of platelet activation by Cu(2+)-FS nanoparticles. Findings indicated that the antiplatelet aggregation activity of Cu(2+)-FS was 10 52 times higher than that of RGDFRGDS, while the effective dose for antithrombotic action was 5,000 times lower than that of RGDFRGDS. PMID- 25931820 TI - Tungsten oxide-Au nanosized film composites for glucose oxidation and sensing in neutral medium. AB - In this work, we report for the first time the use of tungsten oxide (WOx) as catalyst support for Au toward the direct electrooxidation of glucose. The nanostructured WOx/Au electrodes were synthesized by means of laser-ablation technique. Both micro-Raman spectroscopy and transmission electron microscopy showed that the produced WOx thin film is amorphous and made of ultrafine particles of subnanometer size. X-ray diffraction and X-ray photoelectron spectroscopy revealed that only metallic Au was present at the surface of the WOx/Au composite, suggesting that the WOx support did not alter the electronic structure of Au. The direct electrocatalytic oxidation of glucose in neutral medium such as phosphate buffered saline (pH 7.2) solution has been investigated with cyclic voltammetry, chronoamperometry, and square-wave voltammetry. Sensitivity as high as 65.7 MUA cm(-2) mM(-1) up to 10 mM of glucose and a low detection limit of 10 MUM were obtained with square-wave voltammetry. This interesting analytical performance makes the laser-fabricated WOx/Au electrode potentially promising for implantable glucose fuel cells and biomedical analysis as the evaluation of glucose concentration in biological fluids. Finally, owing to its unique capabilities proven in this work, it is anticipated that the laser ablation technique will develop as a fabrication tool for chip miniature-sized sensors in the near future. PMID- 25931821 TI - Reduction of graphene oxide by resveratrol: a novel and simple biological method for the synthesis of an effective anticancer nanotherapeutic molecule. AB - OBJECTIVE: Graphene represents a monolayer or a few layers of sp2-bonded carbon atoms with a honeycomb lattice structure. Unique physical, chemical, and biological properties of graphene have attracted great interest in various fields including electronics, energy, material industry, and medicine, where it is used for tissue engineering and scaffolding, drug delivery, and as an antibacterial and anticancer agent. However, graphene cytotoxicity for ovarian cancer cells is still not fully investigated. The objective of this study was to synthesize graphene using a natural polyphenol compound resveratrol and to investigate its toxicity for ovarian cancer cells. METHODS: The successful reduction of graphene oxide (GO) to graphene was confirmed by UV-vis and Fourier transform infrared spectroscopy. Dynamic light scattering and scanning electron microscopy were employed to evaluate particle size and surface morphology of GO and resveratrol reduced GO (RES-rGO). Raman spectroscopy was used to determine the removal of oxygen-containing functional groups from GO surface and to ensure the formation of graphene. We also performed a comprehensive analysis of GO and RES-rGO cytotoxicity by examining the morphology, viability, membrane integrity, activation of caspase-3, apoptosis, and alkaline phosphatase activity of ovarian cancer cells. RESULTS: The results also show that resveratrol effectively reduced GO to graphene and the properties of RES-rGO nanosheets were comparable to those of chemically reduced graphene. Biological experiments showed that GO and RES-rGO caused a dose-dependent membrane leakage and oxidative stress in cancer cells, and reduced their viability via apoptosis confirmed by the upregulation of apoptosis executioner caspase-3. CONCLUSION: Our data demonstrate a single, simple green approach for the synthesis of highly water-dispersible functionalized graphene nanosheets, suggesting a possibility of replacing toxic hydrazine by a natural and safe phenolic compound resveratrol, which has similar efficacy in the reduction of GO to rGO. Resveratrol-based GO reduction would facilitate large-scale production of graphene-based materials for the emerging graphene-based technologies and biomedical applications. PMID- 25931822 TI - Chloramphenicol encapsulated in poly-epsilon-caprolactone-pluronic composite: nanoparticles for treatment of MRSA-infected burn wounds. AB - The emergence of methicillin-resistant Staphylococcus aureus (MRSA) infection has increased precipitously over the past several decades, with far-reaching health care and societal costs. MRSA infections in the context of burn wounds lead to invasive disease that could potentially cause mortality. Chloramphenicol is a well-known broad-spectrum bacteriostatic antibiotic that has been used since 1949, but due to its hydrophobicity, poor penetration in skin, fast degradation, and toxicity, its application has been hindered. Furthermore, it has been demonstrated that old antibiotics such as chloramphenicol remained active against a large number of currently prevalent resistant bacterial isolates due to their low-level use in the past. Recently, the novel nanoparticulate drug-delivery system has been used and reported to be exceptionally useful for topical therapeutics, due to its distinctive physical characteristics such as a high surface-to-volume ratio and minuscule size. It helps to achieve better hydrophilicity, bioavailability, and controlled delivery with enhanced therapeutic index, which has resulted in decreased toxicity levels compared to the crude drug. Here, we report a novel chloramphenicol loaded with poly(epsilon caprolactone) (PCL)-pluronic composite nanoparticles (CAM-PCL-P NPs), physicochemical characterizations, and its bioactivity evaluation in a MRSA infected burn-wound animal model. CAM-PCL-P NPs could encapsulate 98.3% of the drug in the nanoparticles and release 81% of the encapsulated drug over 36 days with a time to 50% drug release of 72 hours (51%). Nanoparticle suspensions maintained the initial properties with respect to size and encapsulation efficiency, even after 6 months of storage at 4 degrees C and 25 degrees C, respectively (P>0.05). Significant reduction in the level of toxicity was observed for CAM-PCL-P NPs compared with that of free drug as confirmed from hemolytic activity against human blood erythrocytes and cytotoxicity assay against an MCF-7 breast cancer cell line. In vitro antibacterial activities were performed by zone of inhibition, minimum inhibitory concentrations, minimum bacterial concentration, and time-kill assays, which showed that CAM-PCL-P NPs exhibited significantly enhanced anti-MRSA activity against ten clinical isolates of MRSA strains. The augmented activity of CAM-PCL-P NPs was further tested on a MRSA-infected burn-wound animal model and achieved quicker efficacy in MRSA clearance and improved the survival rate compared with free-chloramphenicol treatment. Thus, we propose CAM-PCL-P NPs as a promising novel antimicrobial candidate that may have a good potential for preclinical applications. PMID- 25931823 TI - Strategies to improve medication adherence in patients with schizophrenia: the role of support services. AB - The purpose of this review is to describe research over the past 10 years on the role of support services in promoting medication adherence in mental health consumers diagnosed with schizophrenia. A literature search was conducted using the terms "medication adherence," "schizophrenia," and "support services," using Medline, PubMed, and CINAHL. Reference lists from published studies were also reviewed to identify additional research studies. Twenty-two articles focused on support-service intervention studies, and these were selected for review. Available support-service interventions include adherence therapy, electronic reminders via text messages and telephones, cognitive-behavioral and motivational strategies, and financial incentives. Support-service intervention strategies need to be tailored to the specific needs of mental health consumers with schizophrenia. More research is needed to investigate effective support services to enhance long-term adherence and adherence to medications for medical illnesses in this population. PMID- 25931825 TI - Selecting, adapting, and sustaining programs in health care systems. AB - Practitioners and researchers often design behavioral programs that are effective for a specific population or problem. Despite their success in a controlled setting, relatively few programs are scaled up and implemented in health care systems. Planning for scale-up is a critical, yet often overlooked, element in the process of program design. Equally as important is understanding how to select a program that has already been developed, and adapt and implement the program to meet specific organizational goals. This adaptation and implementation requires attention to organizational goals, available resources, and program cost. We assert that translational behavioral medicine necessitates expanding successful programs beyond a stand-alone research study. This paper describes key factors to consider when selecting, adapting, and sustaining programs for scale up in large health care systems and applies the Knowledge to Action (KTA) Framework to a case study, illustrating knowledge creation and an action cycle of implementation and evaluation activities. PMID- 25931824 TI - Continual evolution of type 2 diabetes: an update on pathophysiology and emerging treatment options. AB - Diabetes is a complex and progressive disease that has a major societal and economic impact. The most common form of diabetes, type 2 diabetes mellitus (T2DM), is a multifactorial disease, the pathophysiology of which involves not only the pancreas but also the liver, skeletal muscle, adipose tissue, gastrointestinal tract, brain, and kidney. Novel therapies with mechanisms of action that are different from most existing drugs are emerging. One such class consists of compounds that inhibit renal sodium-glucose cotransporter 2, which is responsible for the bulk of glucose reabsorption by the kidneys. This new class of compounds improves glycemic control independently of insulin and promotes weight reduction, providing an additional tool to treat patients with T2DM. This review discusses the underlying pathophysiology of T2DM, clinical guidelines, and available and emerging treatment options, with particular emphasis on sodium glucose cotransporter 2 inhibitors. PMID- 25931826 TI - Fasting during Ramadan: efficacy, safety, and patient acceptability of vildagliptin in diabetic patients. AB - Diabetes management during Ramadan fasting is challenging to the physician in terms of minimizing the risk of hypoglycemia. As compared to oral hypoglycemic agents (OHAs) and sulfonylureas (SUs), which carry a higher and significant risk of hypoglycemia, newer antidiabetic agents such as dipeptidyl peptidase-4 (DPP-4) inhibitors have demonstrated lower risk of hypoglycemia during Ramadan fasting, with better patient compliance. In addition to diabetes education and pre-Ramadan assessments, the physician should also consider use of DPP-4 inhibitors (such as vildagliptin) during Ramadan fasting to minimize the risk of hypoglycemia in type 2 diabetic subjects. Severe episodes of hypoglycemia have been demonstrated in recent research and clinical trials with OHAs/SUs. Conversely, these research observations have also demonstrated comparative safety and efficacy with lower risk of hypoglycemia associated with vildagliptin. Current research review has collected evidence-based clinical trials and observations for the drug vildagliptin to minimize the risk of hypoglycemia during Ramadan fasting, while at the same time focusing the role of diabetes self-management education (DSME), pre-Ramadan assessments, and patient care. PMID- 25931827 TI - The genetic basis of familial adenomatous polyposis and its implications for clinical practice and risk management. AB - Familial adenomatous polyposis (FAP) is an inherited disorder that represents the most common gastrointestinal polyposis syndrome. Germline mutations in the APC gene were initially identified as responsible for FAP, and later, several studies have also implicated the MUTYH gene as responsible for this disease, usually referred to as MUTYH-associated polyposis (MAP). FAP and MAP are characterized by the early onset of multiple adenomatous colorectal polyps, a high lifetime risk of colorectal cancer (CRC), and in some patients the development of extracolonic manifestations. The goal of colorectal management in these patients is to prevent CRC mortality through endoscopic and surgical approaches. Individuals with FAP and their relatives should receive appropriate genetic counseling and join surveillance programs when indicated. This review is focused on the description of the main clinical and genetic aspects of FAP associated with germline APC mutations and MAP. PMID- 25931828 TI - Incidence of dizziness and vertigo in Japanese primary care clinic patients with lifestyle-related diseases: an observational study. AB - OBJECTIVE: Dizziness and vertigo are highly prevalent symptoms among patients presenting at primary care clinics, and peripheral vestibular disorder (PVD) is their most frequent cause. However, the incidence of PVD has not been well documented. This study aimed to investigate the incidence of dizziness, vertigo, and PVD among patients presenting at a primary care clinic. DESIGN: This was an observational study. SETTING AND PARTICIPANTS: Between November 2011 and March 2013, we observed 393 patients, all at least 20 years old, who had been treated for chronic diseases such as hypertension, dyslipidemia, and diabetes mellitus for at least 6 months at a primary clinic (Oki Clinic) in Japan. OUTCOME: The main outcome of interest was new incidence of dizziness, vertigo, and PVD events. During the 1-year follow-up period, the otorhinolaryngologist diagnosed and reported new PVD events. RESULTS: The mean age of the 393 participants at entry was 65.5 years. Of the study participants, 12.7%, 82.4%, and 92.6% had diabetes mellitus, hypertension, and dyslipidemia, respectively. We followed up all the participants (100%). During the 662.5 person-years of follow-up, 121 cases of dizziness or vertigo (dizziness/vertigo) and 76 cases of PVD were observed. The incidence of dizziness/vertigo and PVD was 194.7 (95% confidence interval: 161.6 232.6) per 1,000 person-years and 115.7 (95% confidence interval: 92.2-142.6) per 1,000 person-years, respectively. There were 61 cases of acute peripheral vestibulopathy, 12 of benign paroxysmal positional vertigo, and three of Meniere's disease among the 76 PVD patients. CONCLUSION: We reported the incidence of dizziness/vertigo among Japanese primary care clinic patients, which was higher than that usually observed in the general population. Furthermore, we described the incidence of PVD and found that it was a major cause of dizziness/vertigo. PMID- 25931829 TI - A simplified approach to the pooled analysis of calibration of clinical prediction rules for systematic reviews of validation studies. AB - OBJECTIVE: Estimating calibration performance of clinical prediction rules (CPRs) in systematic reviews of validation studies is not possible when predicted values are neither published nor accessible or sufficient or no individual participant or patient data are available. Our aims were to describe a simplified approach for outcomes prediction and calibration assessment and evaluate its functionality and validity. STUDY DESIGN AND METHODS: Methodological study of systematic reviews of validation studies of CPRs: a) ABCD(2) rule for prediction of 7 day stroke; and b) CRB-65 rule for prediction of 30 day mortality. Predicted outcomes in a sample validation study were computed by CPR distribution patterns ("derivation model"). As confirmation, a logistic regression model (with derivation study coefficients) was applied to CPR-based dummy variables in the validation study. Meta-analysis of validation studies provided pooled estimates of "predicted:observed" risk ratios (RRs), 95% confidence intervals (CIs), and indexes of heterogeneity (I(2) ) on forest plots (fixed and random effects models), with and without adjustment of intercepts. The above approach was also applied to the CRB-65 rule. RESULTS: Our simplified method, applied to ABCD(2) rule in three risk strata (low, 0-3; intermediate, 4-5; high, 6-7 points), indicated that predictions are identical to those computed by univariate, CPR based logistic regression model. Discrimination was good (c-statistics =0.61 0.82), however, calibration in some studies was low. In such cases with miscalibration, the under-prediction (RRs =0.73-0.91, 95% CIs 0.41-1.48) could be further corrected by intercept adjustment to account for incidence differences. An improvement of both heterogeneities and P-values (Hosmer-Lemeshow goodness-of fit test) was observed. Better calibration and improved pooled RRs (0.90-1.06), with narrower 95% CIs (0.57-1.41) were achieved. CONCLUSION: Our results have an immediate clinical implication in situations when predicted outcomes in CPR validation studies are lacking or deficient by describing how such predictions can be obtained by everyone using the derivation study alone, without any need for highly specialized knowledge or sophisticated statistics. PMID- 25931830 TI - Epidemiology of cervical cancer with special focus on India. AB - Cervical cancer is on the declining trend in India according to the population based registries; yet it continues to be a major public health problem for women in India. Multifactorial causation, potential for prevention, and the sheer threat it poses make cervical cancer an important disease for in-depth studies, as has been attempted by this paper. This paper attempts to review the available knowledge regarding the epidemiology and pattern of cervical cancer; types of HPV (human papilloma virus) prevalent among cervical cancer patients and among women in general, high-risk groups such as commercial sex workers, and HIV (human immunodeficiency virus)-positive women; and the role of the national program on cancer in control efforts. The peak age of incidence of cervical cancer is 55-59 years, and a considerable proportion of women report in the late stages of disease. Specific types of oncogenic HPV-16, 18 have been identified in patients with cervical cancer. Other epidemiological risk factors are early age at marriage, multiple sexual partners, multiple pregnancies, poor genital hygiene, malnutrition, use of oral contraceptives, and lack of awareness. A multipronged approach is necessary which can target areas of high prevalence identified by registries with a combination of behavior change communication exercises and routine early screening with VIA. Sensitizing the people of the area, including menfolk, is necessary to increase uptake levels. Vaccination against types 16 and 18 can also be undertaken after taking into confidence all stakeholders, including the parents of adolescent girls. Preventing and treating cervical cancer and reducing the burden are possible by targeting resources to the areas with high prevalence. PMID- 25931831 TI - Differences in injury distribution in professional and recreational snowboarding. AB - INTRODUCTION: Little is known about the distribution of injuries in competitive snowboarding and there are no reports describing long-term complications of professional snowboarding. To examine the injury distribution and long-term impairments in active and retired professional snowboarders, a retrospective data analysis was performed using a questionnaire. As a control group, injuries of recreational snowboarders of a southern German university clinic were examined. METHODS: Retired and active snowboarders were identified from the result lists of the International Ski Federation (FIS) and from the current team lists of the German-speaking European national snowboard teams. After identification, a questionnaire regarding injury distribution/treatment was sent to the athletes and the filled-in questionnaires were subsequently evaluated. Injuries in recreational snowboarding were evaluated by analyzing the medical records and surgical reports for a seven-year period. RESULTS: Compared to the available literature, significantly more severe injuries that necessitated surgical treatment in recreational snowboarders were documented. Most injuries accounted for wrist fractures but also many nonunions and spinal fractures were recorded. Between active professionals, distinct differences in injury distribution were found. The number of days off differed greatly with less days in speed disciplines (35.5 days) and the maximum number of days off in snowboardcross (51 days). Injury distribution varied clearly with more injuries of the upper extremity and ankle in speed disciplines compared to snowboardcross and freestyle professionals, who exhibited more injuries to the lower extremity and head. Freestyle athletes used significantly less protectors compared to speed (P=0.01) and snowboardcross athletes (P=0.00). An analysis of retired professionals revealed a higher number of impairments in daily life and a significantly higher number of days off snowboarding (P=0.018). CONCLUSION: Knowledge about snowboard specific injuries is a requirement for an appropriate treatment of these patients. This first description of long-term impairments after professional snowboarding highlights the importance of the development of specific strategies to prevent daily life impairments after a professional sports career. PMID- 25931832 TI - Management of acute attacks of hereditary angioedema: role of ecallantide. AB - Hereditary angioedema (HAE) is characterized as an episodic swelling disorder with autosomal dominant inheritance. Clinical features include nonpitting edema of external or mucosal body surfaces, and patients often present with swelling of the extremities, abdominal pain, and swelling of the mouth and throat, which can lead to asphyxiation. Patients with HAE classically have no associated urticaria, which is often referred to as nonhistaminergic angioedema. Treatment for HAE involves long-term prophylaxis, short-term prophylaxis, and management of acute attacks. Up until the past few years, acute HAE episodes were predominately treated with supportive measures. Three classes of medications have recently been approved by the US Food and Drug Administration (FDA) for the management of acute HAE attacks. Ecallantide, a recombinant protein that acts as a reversible inhibitor of kallikrein, is currently indicated for acute attacks of HAE in those aged >=12 years. In two randomized, double-blind, placebo-controlled, multicenter trials, EDEMA3 and EDEMA4, patients treated with 30 mg of ecallantide demonstrated statistically significant improvement in symptoms compared to those on placebo. In addition to its use as treatment for HAE, ecallantide has been used off label in the management of nonhistaminergic angioedema, not due to HAE. Ecallantide has shown promise in the treatment of these other forms; however, data are limited to mainly case reports at this time. Ecallantide is generally a safe and well-tolerated medication; however, based on reports of anaphylaxis, ecallantide does contain a black box warning. Due to the risk of anaphylaxis, ecallantide cannot be self-administered and must be given by a health care professional. Overall, ecallantide is a safe and effective medication for the treatment of acute attacks of HAE. PMID- 25931833 TI - D1 versus D2 dissection in gastric carcinoma: Evaluation of postoperative mortality and complications. AB - OBJECTIVE: Surgery is the only curative treatment for patients with gastric cancer. However, the extent of lymph node dissection is still debated. The aim of the study was to evaluate complications, postoperative length of hospital stay and postoperative mortality after D1 or D2 lymph node dissection for gastric cancer in a non-specialized hospital. MATERIAL AND METHODS: All patients who underwent surgery for pathologically confirmed gastric cancer at our 3rd General Surgery Department, Ankara Numune Training Hospital between January 1999 and 2007 were retrospectively reviewed. A consecutive series of 71 gastric cancer patients was identified. D1 resection (level 1 lymphadenectomy) was compared with D2 resection (levels 1 and 2 lymphadenectomy). RESULTS: The D2 group had higher postoperative mortality (16% vs. 8%; p<0.005) and morbidity (54% vs. 34%; p<0.005), and their postoperative length of stay was longer. Splenectomy did not have an effect on postoperative morbidity and mortality in either the D1 or the D2 group. CONCLUSION: The D2 procedure was associated with significantly higher postoperative mortality, morbidity, and postoperative length of hospital stay. PMID- 25931834 TI - The importance of staging systems for the determination of prognosis of well differentiated thyroid cancer. AB - OBJECTIVE: In this study, we aimed to determine the significance of the staging systems (EORTC, De Groot, MACIS, and TNM) on the prognosis of well-differentiated thyroid cancer patients who underwent surgery in our clinics. MATERIAL AND METHODS: This retrospective study included 181 patients who were operated between December 1995-December 2007, with a diagnosis of thyroid cancer. In order to obtain data related to cancer staging, a computer program for PDA was developed to facilitate parameter recording. Survival analysis was performed. The findings were compared to the predicted rates by the staging systems. RESULTS: According to the De Groot staging system, stage 1 and stage 2 patients' results were compatible, but stage 3 and 4 patients' results were different (stage 3; 87% versus 66.6%, stage 4; 35% versus 100%, p=0.04). In the MACIS staging system, 20 year survival rates are determined and comparison should not be made due to insufficient follow-up period in this study. When compared to the EORTC staging system, stage 3 and stage 4 patients' results were determined different (stage 3; 51% versus 100%, stage 4; 33% versus 50%, p=0.02). The most consistent results in terms of prognosis was determined in comparison with the TNM staging system (stage 1; 100% versus 97.8%, stage 4; 45.3% versus 50%). CONCLUSION: Many classification systems are proposed for well-differentiated thyroid cancer, to predict the behavior of the tumor. In this study, we concluded that for determination of prognosis in well-differentiated thyroid cancer, the TNM staging system could best predict prognosis consistent with clinical findings. PMID- 25931835 TI - Evaluation of controlled prescriptions with a diagnosis of surgical intervention. AB - OBJECTIVE: Drugs subject to control (DSC) are commonly used in the preoperative, per-operative and postoperative periods. In this study, details of DSC use, that are required to be prescribed to green prescriptions (GP) or red prescriptions (RP), for a surgical diagnosis were evaluated. MATERIAL AND METHODS: Controlled drug prescriptions (CDP) between January to December 2009 were investigated in the archives of the Istanbul Local Health Authority. 660 CDPs indicating a surgical diagnosis were retrospectively evaluated and those prescribed by surgical departments (SD)were compared to those written by internal medicine departments (ID). RESULTS: SD physicians prescribed 72.7% of CDPs and 89.5% of prescriptions were for GP, and 10.5% were for RP. The physicians of SD were found to prescribe more RP than ID physicians. Most of the CDPs were written for women (58.8%) and mostly in private hospitals (40.9%). Among all the physicians, orthopedic surgeons prescribed these drugs the most (20.9%). Tramadol was the most common drug found in CDPs (55.5%). CONCLUSION: DSCs, which have difficult prescription procedures, are used frequently in surgical interventions. The study shows that not only SD physicians, but also ID physicians prefer CDP. The study provides important clues to the usage patterns of DSCs. Recently evolving health care systems including prescriptions should use these findings obtained from the study. PMID- 25931836 TI - Mastodynia: is imaging necessary in young patients? AB - OBJECTIVE: Mastalgia is the most frequent symptom seen in patients who undergo breast imaging. There are various medical treatment methods in the literature. However, malignancy should be excluded before starting treatment. This is a prospective study, evaluating the necessity of imaging in patients who have applied for cyclic or non-cyclic breast pain, with normal physical examination, and without a family history. MATERIAL AND METHODS: Two hundred women, younger than 30 years of age, who applied to Igdir State Hospital general surgery department with complaint of cyclic or non-cyclic breast pain, were prospectively studied. Patients with nipple discharge, complaint of lump in their breast, who were pregnant or lactating, who had breast cancer history in their family and those who were found to have lumps on examination were excluded from the study. All patients underwent ultrasound imaging and the same radiologist evaluated them. RESULTS: The breast examination was normal in all patients. Ultrasound imaging results were completely normal in 98 (48%) patients. 47 (23.5%) patients were found to have fibroadenoma, with a mean diameter of 9.6 mm (5 mm-14 mm). 45 (22.5%) patients had simple cysts with a mean diameter of 7.8 mm (3 mm-11 mm). 6 (3%) patients were found to have intraductal papillomas and 4 (2%) to have lipomas. All patients were classified as either BI-RADS 1 or BI-RADS 2. CONCLUSION: It is recommended that malignancy should be eliminated before starting treatment in patients with breast pain. In this study, the necessity of imaging in patients younger than 30 years and who applied to the general surgery department for only breast pain, was investigated. None of the patients with a normal breast examination were found to have any lesions considered suspicious for malignancy. We believe that if breast examination is normal, the patient is equal to or younger than 30 years of age and there is no family history, imaging is not necessary and that medical therapy can be started directly after the patient is informed. PMID- 25931837 TI - The role of general surgery consultations in patient management. AB - OBJECTIVE: Consultation results of patients who were thought to require a surgical intervention and were evaluated in the General Surgery Department for diagnostic support and treatment, upon detection of pathology in clinical and/or laboratory tests. MATERIAL AND METHODS: In a six-months period, 221 patients were retrospectively analyzed. There were 121 male (54.75%) and 100 female (45.25%) patients and the mean age was 46 years (15-102). The departments which requested consultation, the reason for consultation, test and physical examination findings before consultation, required additional tests after consultation and results of consultations were recorded as well as performed interventions. RESULTS: The majority of consultations were from the emergency department (91.9%) and the most frequent reason was abdominal pain (29.9%). No tests were performed before consultation in 21% of cases. Physical examination was completely fulfilled in 100% of judicial cases, but this ratio was 35% in perianal diseases and 30% in patients with bowel obstruction. Additional tests were required in 54.3% of the patients after consults. Out of the whole group with surgical consultation, 21% were operated under general anesthesia, 9% under local anesthesia, while an elective operation was suggested in 3%. CONCLUSION: Currently, it is mandatory that patient management is carried out with a multidisciplinary approach; however, we believe that consultations should be asked in a more selective manner. PMID- 25931839 TI - A case of multiorgan resection for locally advanced stomach cancer. AB - Extensive surgical resection may be required in locally advanced gastric cancers, with involvement of other organs. Our purpose was to present a case where vascular reconstruction was performed during multiple organ resections in a patient with locally advanced gastric cancer. An emergent laparotomy was performed on a patient who presented with upper gastrointestinal system hemorrhage; and he was diagnosed with locally advanced gastric cancer. Total gastrectomy, D II dissection, pancreaticoduodenectomy, transverse colectomy and end-to-end anastomosis were performed. Additionally, the superior mesenteric vein was partially excised and re-implanted to the portal vein. Neither recurrence nor distant metastasis was observed during the post-operative follow-up. Adjacent organ resections may be necessary for a curative treatment in locally advanced gastric cancer. In addition, partial resection and reconstruction may be required for extensive vascular invasion. PMID- 25931838 TI - A prospective evaluation of the risk factors for development of wound dehiscence and incisional hernia. AB - OBJECTIVE: Post-laparotomy wound dehiscence, evantration and evisceration are important complications leading to an increase in both morbidity and mortality. Incisional hernias are frequently observed following abdominal surgeries and their occurrence is related to various local and systemic factors. This study aims to analyze the factors affecting wound healing by investigating the parameters that may cause wound dehiscence, incisional hernia, sinus formation and chronic incisional pain. MATERIAL AND METHODS: The records of 265 patients who underwent major abdominal surgery were analyzed. The data on patient characteristics, medication, surgical procedure type, type of suture and surgical instruments used and complications were recorded. The patients were followed up with respect to sinus formation, incisional hernia occurrence and presence of chronic incision pain. Statistical analysis was performed using SPSS 10.00 program. The groups were compared via chi-square tests. Significance was determined as p<0.05. Multi-variate analysis was done by forward logistic regression analysis. RESULTS: 115 (43.4%) patients were female and 150 (56.6%) were male. Ninety-four (35.5%) patients were under 50 years old and 171 (64.5%) were older than 50 years. The median follow-up period was 28 months (0-48). Factors affecting wound dehiscence were found to be; creation of an ostomy (p=0.002), postoperative pulmonary problems (p=0.001) and wound infection (p=0.001). Factors leading to incisional hernia were; incision type (p=0.002), formation of an ostomy (p=0.002), postoperative bowel obstruction (p=0.027), postoperative pulmonary problems (p=0.017) and wound infection (p=0.011). CONCLUSION: Awareness of the factors causing wound dehiscence and incisional hernia in abdominal surgery, means of intervention to the risk factors and taking relevant measures may prevent complications. Surgical complications that occur in the postoperative period are especially related to wound healing problems. PMID- 25931840 TI - Two cases of non-recurrent laryngeal nerve: routine nerve exploration in total thyroidectomy. AB - Recurrent laryngeal nerve injury is one of the main complications of thyroidectomy. Since variability in the course of the nerve increases the risk of injury, routine nerve exploration is recommended. In this report, we present two cases of non-recurrent laryngeal nerve found during total thyroidectomy performed for benign pathologies. Total thyroidectomy was performed on two female patients (52 and 54 years old) with a diagnosis of multi-nodular goiter in our clinics. Nerve exploration was performed routinely and non-recurrent laryngeal nerve was noted in both patients. Patients were discharged on the first postoperative day without any complications. Recurrent laryngeal nerve exploration does not increase the risk of nerve injury and ensures safety in case of non-recurrent laryngeal nerve presence, despite its rarity. PMID- 25931841 TI - Gastric duplication (bronchogenic) cyst mimicking a gastrointestinal stromal tumour. AB - Gastric duplication cysts (GDC) lined with pseudostratified columnar ciliated epithelium (PCCE) are uncommon lesions that stem from a foregut developmental malformation. The clinical and radiological diagnosis is usually difficult. Definitive diagnosis can be established by histopathological examination. In this study, we report a rare case of a peri-gastric mass that was operated and reported as a bronchogenic cyst. Microscopically, the gastric cyst was lined by PCCE. Although rare, GDC should be included in the differential diagnosis of gastric wall masses. Surgical intervention is recommended in patients who have clinical symptoms. PMID- 25931842 TI - Cortex sparing laparoscopic adrenalectomy in a patient with Conn's syndrome. AB - Conn's syndrome, an aldosterone producing adenoma, is a surgically curable cause of primary aldosteronism, classically treated by unilateral adrenalectomy. With the advent of laparoscopic surgery in the recent decade, laparoscopic adrenalectomy is currently accepted as the gold standard of treatment for Conn's syndrome. Cortical sparing adrenalectomy is especially an ideal operation for patients with bilateral pheochromocytoma. This case report describes a successful laparoscopic adrenal cortex sparing surgery on the left side and anesthetic approach in a patient with Conn's syndrome, who had a history of previous right surrenalectomy. Laparoscopic surgery without dividing the central adrenal vein can also be performed successfully in patients with Conn's syndrome. PMID- 25931843 TI - An atypically localized gastrointestinal stromal tumor: a case report of pancreas gastrointestinal stromal tumor. AB - Gastrointestinal stromal tumors (GISTs) are the most common mesenchymal tumors of the gastrointestinal tract. They can arise from any part of the tract as well as the omentum, mesentery or retroperitoneum. In this study, we present a case of a GIST originating from an extraordinary site, the pancreas. Evaluation of 30-year old man with complaints of abdominal distension revealed a cystic, distal pancreatic lesion 13 cm in diameter. There were no intra-abdominal or distant organ metastases. The patient was operated with a diagnosis of cystic pancreas tumor, distal pancreatectomy and splenectomy was performed. The lesion was diagnosed as gastrointestinal stromal tumor upon histopathological examination. He was discharged on the sixth postoperative day without any complications and is being followed up for 21 months without systemic or local recurrence. Extragastrointestinal GISTs are reported rarely. To our knowledge, only one pancreatic GIST has been reported previously in the English literature. PMID- 25931844 TI - Acute abdomen and hemorrhagic shock caused by spontaneous rupture of renal cyst in autosomal dominant polycystic kidney disease. AB - Autosomal dominant polycystic kidney disease is an important cause of end stage renal failure. Rarely, these patients may present with hemorrhagic shock caused by rupture of the renal cyst. The aim of this study was to report a rare case of a patient who arrived at the emergency department with autosomal dominant polycystic kidney disease presenting with acute abdominal pain and hemorrhagic shock. A 58-year-old male with chronic renal failure was admitted to the emergency department with acute abdominal pain and hemorrhagic shock. The patient was admitted to the Department of Surgery with diagnosis of acute abdomen and perirenal hematoma. Although the patient was on conservative treatment, his symptoms did not improve and the patient was operated emergently. During exploration, there was bleeding from the right polycystic kidney, which was 30*20 cm in dimension. The patient underwent nephrectomy and drainage of the hematoma, and was discharged on the fifth postoperative day without any problems. Bleeding due to rupture of a cyst in autosomal dominant polycystic kidney disease occurs rarely but it may be life threatening. Although conservative methods are often preferable in treatment, surgery can be life saving for patients in whom the clinical situation does not improve. PMID- 25931845 TI - Biochemical and histopathological changes of intra-abdominal hypertension on the kidneys: Experimental study in rats. AB - OBJECTIVE: This study aimed to evaluate the effects of experimentally induced intra-abdominal hypertension on renal functions, with the combination of biochemical and histopathological properties. MATERIAL AND METHODS: Thirty male Wistar albino rats were used in this experimental study. Rats were divided into four groups. Group 1 (control group, n=6) only received anesthesia. After the induction of anesthesia, a 20 G catheter was introduced intraperitoneally to Group 2 (sham group, n=8), Group 3 (n=8) and Group 4 (n=8). The intra-abdominal pressure was not increased in Group 2. We applied 20 mmHg intra-peritoneal pressure to Group 3 and 30 mmHg to Group 4 for 3 hours. After withdrawing 3 mL intracardiac blood from all groups, the kidneys were removed for histopathological examination. Serum urea and creatinine levels were measured in all groups. RESULTS: Biochemical examination showed that blood urea and creatinine levels were statistically different among all groups (p<0.05). Serum creatinine levels in Group 3 and serum urea and creatinine levels in Group 4 were significantly increased. In the histopathological examination, the kidneys in Group 1 and Group 2 were classified as normal. In Group 3, areas with congestion were detected in the glomeruli and interstitial regions. In addition to these findings seen in Group 3, dilatation of the pelvi-caliceal structures and proximal ureters were noticed in Group 4. CONCLUSION: The levels of serum urea and creatinine are elevated when intra-abdominal pressure is increased due to kidney damage. Foci of hemorrhage in the interstitial area, dilatations in the proximal ureter, renal pelvis, and lymphatics were the pathologic findings seen in the kidneys under such circumstances. PMID- 25931846 TI - Does topical rifampicin reduce the risk of surgical field infection in hernia repair? AB - OBJECTIVE: Inguinal hernia operations are common procedures in general surgery. There have been many approaches in the historical development of hernia repair; tension free repair with mesh being the most commonly used technique today. Although it is a clean wound, antibiotic use is still controversial due to concerns about infection related to synthetic mesh. We aimed to determine the probable role of topical rifampicin in patients with tension-free hernia repair and mesh support. MATERIAL AND METHODS: The charts of patients who underwent tension-free inguinal hernia repair were retrospectively analyzed. Information and operative notes on patients, in whom synthetic materials were used, were identified. The patients were divided into two groups, placebo group (G1) and patients with application of topical rifampicin on the mesh (G2). Infection rates between the groups in the early postoperative period were compared. RESULTS: The mean age of the 278 patients who were included in the study was 49.6+/-15.39 and the female/male ratio was 10/268. There were recurrent hernias in four patients and superficial wound infections in 22 patients in the early period. One patient had testicle torsion and underwent an orchiectomy. There were no significant differences between the groups in terms of age and gender. The types of hernia and body mass index were homogenous between the two groups. In the early postoperative period the infection rates were 16/144 (11.1%) and 6/134 (4.48%) in the groups, respectively, with the difference being statistically significant (p=0.041). CONCLUSION: We suggest that applying rifampicin locally can decrease surgical site infection in hernia operations where meshes are used. PMID- 25931847 TI - Quality of life after stapler haemorrhoidectomy evaluated by SF-36 questionnaire. AB - OBJECTIVE: Hemorrhoids are normal elements of the anal canal anatomy and they become symptomatic with potential factors such as gravity or strain. When symptomatic, hemorrhoidal disease can be costly measured in time away from productive activities. The aim of the study was to assess changes in the quality of life of patients after hemorrhoidectomy using Short Form-36. MATERIAL AND METHODS: Thirty patients, 24 male and 6 female (age 28 to 65), who were diagnosed with grade III and IV internal hemorrhoidal disease at the general surgery outpatient clinic and treated with stapled hemorrhoidectomy were enrolled in the study. They filled out Short Form-36 a week before surgery and four weeks after surgery. Post-Hoc tests were evaluated with Bonferroni correction after Kruskal Wallis analysis. Wilcoxon test, Student-t-test and Mann-Whitney U test were used for statistical analysis using SPSS 15. RESULTS: Physical health (Physical functioning, Physical role restriction, Bodily pain) scores were significantly improved after surgery. CONCLUSION: Success of hemorrhoidectomy operations can be evaluated by postoperative recovery, incidence of complications or relapses. Quality of life questionnaires are another method to evaluate the success of the treatment from the patient's perspective. PMID- 25931848 TI - Complicated Meckel's diverticulum and therapeutic management. AB - OBJECTIVE: This study aimed to investigate the treatment options and compare patient management with the literature for patients operated on for an acute abdomen who had complications due to inflammation of the Meckel's diverticulum at our clinics. MATERIAL AND METHODS: This study retrospectively evaluated 14 patients who had been operated on for acute abdomen and had been diagnosed with Meckel's diverticulitis (MD) in Ege University Medical Faculty Department of General Surgery, between October 2007 and October 2012. RESULTS: Fourteen patients with a diagnosis of Meckel's diverticulitis (MD) were retrospectively analyzed. Radiologically, the abdominal computer tomography showed pathologies compatible with mechanical intestinal obstruction, Meckel's diverticulitis and peridiverticular abscess, as well as detection of free air within the abdomen on direct abdominal X-ray. Among patients diagnosed with complicated Meckel's diverticuli (obstruction, diverticulitis, perforation) 10 patients had partial small bowel resection and end-to-end anastomosis (71.5%), three patients underwent diverticulum excision (21.4%), and one patient underwent right hemicolectomy+ileotransversostomy (7.1%). CONCLUSION: Meckel's diverticulum is a vestigial remnant of an omphalomesenteric channel in the small bowel. It is a real congenital diverticular abnormality that contains all three layers of the small bowel. Surgical excision should be performed if Meckel's diverticulum is detected in order to avoid incidental complications such as ulceration, bleeding, bowel obstruction, diverticulitis or perforation. Meckel's diverticulitis does not have specific clinical and radiological findings. Delayed diagnosis can lead to lethal septic complications. Complications associated with Meckel's diverticulitis, especially if a definite diagnosis is not made during the preoperative period, should be considered in the differential diagnosis. In the presence of a complicated diverticulum the appropriate treatment should be emergent surgical intervention. PMID- 25931849 TI - The diagnostic importance of evaluation of solid breast masses by sonoelastography. AB - OBJECTIVE: The aim of this study was to determine whether the use of a scoring method by sonoelastography in solid breast masses is helpful in differentiating benign and malignant lesions. MATERIAL AND METHODS: One hundred and eighty solid breast masses in 155 patients (147 benign, 33 malignant) were prospectively evaluated in a two-year period. For each lesion, B-mode sonography and sonoelastography images were obtained. Elasticity scores of the lesions were determined with a 5-point scoring method by sonoelastography. The findings were compared with histopathology. The diagnostic performances of the sonoelastographic scoring and B-mode sonography methods were determined. RESULTS: The mean scores on sonoelastography were 2.61+/-0.62 for benign lesions and 3.73+/-0.69 for malignant lesions. When a cutoff point between scores 3 and 4 was used, accuracy, sensitivity, specificity, positive and negative predictive values for B-mode sonography were found as 81%, 89%, 79%, 46% and 97%, respectively; these were 87%, 73%, 91%, 69% and 92% for the sonoelastographic scoring method. CONCLUSION: After B-mode sonography analysis, the evaluation with the 5-point scoring method by sonoelastography might be a complementary method that increases specificity when differentiating between benign and malignant solid breast masses. PMID- 25931850 TI - Spontaneous intestinal intramural hematoma: What to do and not to do. AB - OBJECTIVE: Spontaneous intestinal intramural hematoma is a rare complication of anticoagulant treatment. In this study, we retrospectively evaluated 14 patients with the diagnosis of intramural hematoma of the small intestine who were followed-up and treated in our clinic, and we aimed to determine current approaches in the diagnosis and treatment of intramural hematoma. MATERIAL AND METHODS: Between February 2010-October 2012, 14 patients diagnosed with small intestinal intramural hematoma were retrospectively analyzed. Nine patients were followed due to clinical findings and 5 patients underwent operation with a histopathological diagnosis of intramural hematoma. RESULTS: Abdominal computed tomography demonstrated ileal and jejunal wall thickening in 10 patients, while findings were consistent with mesenteric vascular disease in four. Five patients were operated due to mechanical bowel obstruction and acute abdomen. The other 9 patients were followed up with medical treatment and 8 of these patients were already using warfarin due to cardiac bypass and valve replacement. CONCLUSION: Spontaneous intestinal intramural hematoma is a rare cause of small bowel obstruction due to intramural hematoma, which is encountered even more rarely. An intramural hematoma should be considered among differential diagnosis of patients who present with abdominal pain and symptoms of obstruction with a history of anticoagulant drug use and elevated International Normalized Ratio (INR) levels. Early diagnosis and medical follow-up can provide a good response to treatment in the majority of patients without requiring surgery. PMID- 25931852 TI - A rare cause of acute abdomen: Splenic hematoma and rupture resulting from pancreatitis. AB - Splenic subcapsular hematoma and splenic rupture due to pancreatitis are rare causes of acute abdomen. Here we report a case of splenic hematoma and rupture resulting from a second attack of pancreatitis in a 38 year-old woman with chronic pancreatitis due to alcoholism. Her first pancreatitis attack, 4 months before the second, was complicated with a pancreatic pseudocyst that was drained and acute renal failure. The patient underwent pancreatic necrosectomy and splenectomy, and was discharged on the sixth postoperative day without any further complication. We conclude that splenic hematoma, a complication of pancreatitis attack, which may require emergency surgical intervention, must be kept in mind in order to make an early diagnosis. Considering a possible subsequent attack of pancreatitis and determining follow-up criteria, radical treatment must be planned immediately. PMID- 25931851 TI - Restaging of colorectal cancer and PET/CT. AB - Positron Emission Tomography/Computerized Tomography (PET/CT) is an important assessment method in restaging of oncology patients. Its ability to detect the metabolic/functional changes in patients with colorectal cancer during the early stages, in which morphological changes cannot be documented, is significantly superior to other imaging modalities. PMID- 25931853 TI - Portomesenteric venous thrombosis as a rare cause of acute abdomen in a young patient: What should be the process of diagnosis and management? AB - This report aimed to discuss indications for radiological evaluation, laboratory investigation for thrombophilic risk factors, and the duration of anticoagulation therapy in porto-mesenteric venous thrombosis, based on a young patient who presented with acute abdomen and ascites. We investigated the acquired and genetic thrombophilic risk factors and the diagnostic process. Abdominal CT and Doppler US were found to be useful radiological tools in both diagnosis and follow-up of portomesenteric thrombosis. The investigated thrombophilic factors, PT G20210A, MTHFR C677T and MTHFR A1298C, were positive for heterozygous mutations and high levels of lupus anticoagulant and factor VIII were detected. Rapid ascites resolution and an improvement in abdominal pain after meals were observed following anticoagulation. Follow-up examination after six months showed that the portomesenteric thrombosis had completely resolved. Evaluation by CT is recommended for patients with acute abdomen and ascites, especially if ultrasonography failed to show any specific pathology. Several acquired or genetic thrombophilic factors were identified in a patient in whom local precipitating factors were absent. For patients with genetic thrombophilic risk factors and thrombosis at an uncommon site in the body, lifelong treatment with anticoagulants is recommended. PMID- 25931854 TI - Appendiceal mucocele mimicking urolithiasis. AB - Appendiceal mucocele is a rare clinical condition that results from distension of the appendix lumen with mucus. It is only found in 0.1-0.3% of all appendectomy specimens. Twenty-five per cent of these cases are asymptomatic and are incidentally discovered either during surgery or upon radiological examination. The treatment of appendiceal mucocele is surgical, and while appendectomy is usually sufficient in some cases right hemicolectomy may be considered as a treatment option. Mucoceles are histologically subdivided into four types: retention cysts, mucosal hyperplasia, cystadenomas and cystadenocarcinomas. Herein, we present a case of appendiceal mucocele clinically mimicking urolithiasis in a 62-year-old female patient with a complaint of colicky right flank pain and a single episode of macroscopic hematuria. The patient's abdominal ultrasonography and abdominal CT scan showed a mass consistent with mucocele in the right lower quadrant of the abdomen. Colonoscopy gave the impression of a mass lesion exerting pressure from the outside. The patient was electively operated. Histopathological diagnosis was reported as mucinous cystadenoma. Appendiceal mucocele or mucinous cystadenomas are usually seen in patients undergoing surgery with a diagnosis of appendicitis but, as in our case, these lesions may rarely occur with a clinical picture that mimics urological disease. PMID- 25931855 TI - A rare pathology that caused high-level intestinal obstruction: Left paraduodenal hernia. AB - The aim of this report is to assess clinical findings and surgical treatment of left paraduodenal hernia, which is an unusual type of internal herniation, in light of the literature. The diagnosis and treatment course of a 42-year-old male patient with findings of intestinal obstruction was assessed and presented together with literature search. The patient underwent surgery with a preliminary diagnosis of intestinal obstruction and the definitive diagnosis of internal herniation was made intraoperatively. Nearly two-thirds of the small intestine was found to be herniated into the retroperitoneal space from the left paraduodenal region. Small bowel loops were pulled out of the hernia sac and anatomically positioned in the intraperitoneal area. The hernia sac was repaired primarily. The patient was discharged on the fourth postoperative day, uneventfully. Left paraduodenal hernia should be considered as a part of differential diagnosis in patients who have recurring abdominal pain episodes accompanied by symptoms suggestive of intestinal obstruction. Timely diagnosis is important to prevent complications. Reduction of hernia content followed by primary repair of the defect appears to be a safe and effective treatment. PMID- 25931856 TI - Ectopic breast cancer: A case report. AB - Ectopic breast may be present at any site, from the axilla to the vulva, other than its normal location. Cysts, adenofibromas and rarely carcinomas have been reported in ectopic breasts. In this case report, we present a patient with ectopic breast cancer. The patient had a thickening and enlarging of her ectopic breast tissue, on the left arcus costarium. Tru-cut biopsy revealed "invasive lobular carcinoma". Left ectopic mastectomy and level I-II axillary dissection were performed and then chemotherapy+radiotherapy+endocrine therapy treatment was commenced. During follow up, the patient is doing well; in spite of R1 resection, she has no evidence of local recurrences or distant metastases. PMID- 25931857 TI - Bezoars and surgery. PMID- 25931858 TI - Patient oriented management for the creation of arteriovenous fistula for hemodialysis. AB - OBJECTIVE: Hemodialysis access is of paramount importance for end-stage renal failure (ESRF) patients. Creation and maintenance of arteriovenous fistula (AVF) by a dedicated team increases the success and duration of the hemodialysis. The aim of this study is to report a patient oriented standardized surgical technique performed by a single surgeon on the success of AVF creation. MATERIAL AND METHODS: A single surgeon performed all AVF operations. The records of all patients who were operated for AVF creation without using synthetic grafts through a 3 year period (2009-2011) were included. The patients were examined and operated on by a previously defined standard protocol. RESULTS: A total of 221 procedures were done for 209 patients. The mean age was 65+/-11,4 years. Immediate function rate was 95.9% (n=212). Follow-up was possible for 182 patients (82.3%). For an average follow-up time of 11,3 months, the death rate was 20.8% (n=38) and the rate of AVF patency was 73.7% (n=134). CONCLUSION: Sustaining patency of AVF is difficult in these systemically deranged patients. A focused approach by a dedicated team will increase the success rate. PMID- 25931859 TI - Turkey's contribution to medicine: Main institutions, fields and publications. AB - OBJECTIVE: To identify and disclose publications from Turkey with the greatest "genuine" contributons to medicine in the past 50 years. MATERIAL AND METHODS: Based on the data of Web of Science, publications originating from Turkey's institutions that were received by May, 2013, >=72 citations were identified, after excluding papers having more than a minor share by international authors. RESULTS: Primary authors numbering 223 generated 271 medical papers, each receiving >=72 (95% CI 72; 263) citations. The articles cited herein were of a level of top global 8-10% papers. Half of the articles were published in 1997 2004. Compared with about 25-28 papers annually 10 years previously, it is estimated that currently only 20 papers are generated in Turkey annually, representing a global share of only 1.5 per thousand. The rate of rise registered in the period 1995-2004 may be anticipated to attenuate. Internal medicine, led by rheumatology, cardiology and hematology, and neurosciences were represented at 1.8-fold odds higher than the overall average. Led by Behcet's disease, health issues encountered more widely than in other populations, formed frequent topics of contribution. Led by the Medical Faculties of Istanbul, Hacettepe, Ankara Universities and the Military Medical Academy, only 33 medical faculties and 14 public and private hospitals constituted sources. CONCLUSION: Since the elicited results are unsatisfactory, compared with Turkey's potential, much more concerted efforts should be directed to rebuild a milieu favorable to promote research likely to contribute to medicine. PMID- 25931860 TI - Symptom-histopathology relation in upper GI endoscopy. AB - OBJECTIVE: The purpose of this article is to examine the correlation between information obtained from patients before endoscopy and histopathological findings. MATERIAL AND METHODS: One thousand, five hundred and thirty-six patients underwent upper GI endoscopy between January 2011-September 2012, without distinction of age and sex were included in the study. Patients with alarm symptoms, dyspepsia, epigastric pain, gastroesophageal reflux were recorded. Tissue samples taken for histopathological examination and H. pylori screening were evaluated by Giemsa stain. The information given by the patients and histopathological findings were comparatively evaluated. RESULTS: Six hundred and twenty-four patients (40.6%) were male and 912 (59.4%) were female. Mean age was 45 years (18-90). H. pylori was positive in 416 patients with dyspepsia (58.8%), 172 patients with epigastric pain (54.4%), 52 patients with GER symptoms (28.3%) and 128 patients with alarm symptoms (50.8%). Four patients with dyspepsia (0.6%) and 20 patients with alarm symptoms (7.9%) were diagnosed with stomach cancer. CONCLUSION: The main factor should be considered as the presence of at least one of the alarm symptoms when planning an upper GI endoscopy in a patient. In the presence of at least one of the alarm symptoms, an upper GI endoscopy should be performed regardless of age. Under the age of 50 and for patients without alarm symptoms, medical treatment can be tried before performing upper GI endoscopy. Patients with GER symptoms but not diagnosed as reflux esophagitis, should be treated long-term even when symptoms decline with initial treatment. PMID- 25931861 TI - Single-incision (with multi-input single-port) laparoscopic colorectal procedures: Early results. AB - OBJECTIVE: Single incision laparoscopic surgery (SILS) is a "scar-less" new surgical technique which has been gaining popularity over recent years. In comparison to conventional multiport laparoscopic surgery, SILS is introduced as a less invasive method. This technique has also been applied to colorectal surgery. The aim of the presenting study is to investigate the applicability of SILS and report short term results. MATERIAL AND METHODS: We evaluated prospectively collected data of 24 patients who had been operated with "Single Incision Laparoscopic Colon Resection (SILCR)" in our clinic between June 2011 June 2013. Informed consent was obtained from all patients before surgery. Patient data such as ASA and BMI values, need for additional surgery, tumors, number of lymph nodes resected, length of hospital stay, length of surgery, timing of flatus, time to start oral feeding and complications were recorded. RESULTS: SILCR was performed in 24 patients. In 13 patients, SILCR was performed for cancer treatment. There was no need for extra ports, conversion to open surgery and stoma creation was also not necessary. Drain was placed in 4 patients. Overall complication rate was 12.5%. The mean number of lymph nodes in 13 patients who underwent SILCR for tumor was found to be 23 (14-33). The mean operative time and length of hospital stay was 177 minutes (110-363) and 5.35 days (4-11) respectively. Anastomotic leakage was not seen in any of the patients. In one patient, urinoma formation due to ureteral leakage was seen which resulted from thermal injury. CONCLUSION: When we compare other series with almost the same number of patients' reported SILS results in the literature, we believe that we could draw conclusions from our data. SILS appears to have comparable results to conventional multiport laparoscopic surgery in the hands of experienced surgeons. It seems advantegous as it can be done with conventional laparoscopic instruments in a "scar-less" manner. Prospective randomized trials are necessary to define the benefits of one procedure over the other. PMID- 25931862 TI - Predictors of mortality and morbidity in peritonitis in a developing country. AB - OBJECTIVE: Generalized peritonitis is still a common emergency managed by most general surgeons throughout the world. If the outcome in these patients can be correctly predicted, then better management can be instituted to those patients in need. This study aims to identify factors in patients with peritonitis which have a significant bearing on morbidity and mortality. These factors could be later used to predict the outcome in patients with generalized peritonitis. MATERIAL AND METHODS: A total of one hundred patients with peritonitis were studied. Factors including age, pulse and respiratory rate, temperature, hemoglobin, total leukocyte count, hematocrit, urea, creatinine, sodium, potassium, pH, PaO2 levels at the time of surgery along with peritoneal contamination and duration of surgery were noted. Using the Students t test, factors were identified which had a statistically significant influence on the outcome. RESULTS: Thirty-six patients in the study developed complications and 17 died. Statistics showed that 8 factors influenced morbidity and 11 influenced mortality. CONCLUSION: Identifying variables which influence the outcome of patients with peritonitis is an important initial step. Once these factors have been identified, the outcome of patients can be correctly predicted and better management can be instituted to those patients in need. PMID- 25931863 TI - Rene Leriche and "Philosophy of Surgery" in the light of contemporary medical ethics. AB - Prof. Dr. Rene Leriche was a famous French surgeon who lived between 1879 and 1955. After working as a vascular surgeon in Lyon, he was appointed professor at the University of Strasbourg in 1924 and later the Paris College de France in 1937. Leriche had proposed vascular patches as the ideal treatment for obliterated vascular segments and advocated the necessity of sympathectomy in arterial diseases in the 1920s. He defined "Leriche Syndrome" in 1923 which is known by his name and which develops as a result of incomplete obstruction of the aortic bifurcation. Rene Leriche wrote a monograph entitled "La Chirurgie de la Douleur-Pain Surgery" in 1940 and he also became a pioneer in the sympathectomy procedure for pain treatment. Rene Leriche focused on topics that must be remembered again today, including surgery advanced into science, the physiological basis of surgery, research methods, as well as issues such as business technology, humanity in surgery, surgical essence and surgeon's qualifications in the book entitled "La Philosophie de la Chirurgie-Philosophy of Surgery" that he wrote in 1951. In this review, the issues that Prof. Dr. Rene Leriche addressed in middle of the 20(th) century were revised in the light of contemporary medical ethics. PMID- 25931864 TI - Spleen-preserving laparoscopic distal pancreatectomy: Two cases and review of the technique. AB - In this study, we aimed to assess the technique and results of spleen-preserving laparoscopic distal pancreatectomy (SPLDP) on the basis of two cases. The first case was a woman with a large cystic papillary lesion of the distal pancreas. The other patient was a woman with a pancreatic mass on the tail of the pancreas. Both patients were operated on using SPLDP. Five trocars were used in the first case and four trocars were used in the second case. Thirty degree telescope visualization and LigaSure dissection were used during the operation. The splenic vessels were dissected, but the short gastric vessels were preserved. The pancreas was transected by one Endo GIA stapler and the cut edge of the pancreas was reinforced with sutures to prevent a pancreatic fistula. We performed the same technique in both cases. However, in the first case, we aspirated the content of the cystic mass of the pancreas before removing it to avoid making a large incision. The duration of the operation was 190 and 135 minutes, respectively. There were no postoperative complications. SPLDP is a safe, effective modality for managing lesions of the distal pancreas. If the splenic vessels are transected, the short gastric vessels must be protected to ensure the viability of the spleen. PMID- 25931865 TI - Breast hydatid cyst mimicking fibroadenoma and malignancy: A case report. AB - Echinococcus granulosis is known as the cause of hydatid cyst disease. It is often seen in many regions of the world, and can cause serious health problems. This parasite can invade tissues in all parts of the body and produce hydatid cysts, although it has been mainly observed in the liver and the lungs. Breast hydatid cysts are encountered rarely. After physical examination, radiological and serological tests are performed on patients with breast hydatid disease. These examinations are helpful for an early diagnosis, but they are insufficient to make a definitive diagnosis, which can only be made according to the results of histopathological examinations. We had a primary diagnosis of either fibroadenoma or malignancy in the breast during the preoperative period of the present case. A precise diagnosis could only be made by histopathological examinations in the postoperative period. PMID- 25931866 TI - Bilateral breast metastasis as the first sign of recurrence of a cutaneous melanoma: A case report. AB - Breast skin and parenchyma are metastatic sites for various tumours. Metastasis to the breast is rare, but it must be considered in the differential diagnosis of a breast mass. Melanoma is among the most commonly reported metastatic tumours of the breast. With the increasing incidence of melanoma, this complication is being encountered with greater frequency. Melanoma has different manifestations in the breast. All these manifestations are important not only as initial presentations of the disease, but also as indicators of the progression period of the disease. Along with a brief review of the literature, we report the case of a woman who presented with breast metastasis after 17 years as the first sign of recurrence of a melanoma. The aim of this study was to report the clinico-pathological features of a patient with metastatic melanoma to the breast. Metastasis can mimic either benign disease or primary malignancy and is often an unexpected diagnosis in a patient presenting with a breast mass. These masses generally indicate disseminated disease with very short survival. Metastasis should be suspected in patients with a breast mass and a prior history of melanoma even if the primary was removed a long time ago (17 years in our case). Fine needle aspiration cytology combined with immunohistochemistry is essential for the diagnosis of metastasis. PMID- 25931867 TI - Fusion of a cervical sympathetic ganglion with the recurrent inferior laryngeal nerve: a case of false positive non-recurrent inferior laryngeal nerve. AB - An anastomosis between the recurrent inferior laryngeal nerve (RILN) and the cervical sympathetic ganglion is seen rarely and might be confused with non recurrent inferior laryngeal nerve (NRILN) in patients undergoing thyroidectomy and parathyroidectomy. In spite of the fact that NRILN is rarely seen and is an important anatomical structure, when damaged, the quality of life of the patient is negatively affected. This case report describes a connection between the RILN and the sympathetic nerve ganglion encountered during nerve dissection in a 43 year old female patient undergoing thyroidectomy and central zone dissection. Key points in the differential diagnosis are discussed. PMID- 25931868 TI - Conservative management of abdominal injuries. AB - OBJECTIVE: Non-operative management of abdominal injuries has recently become more common. Especially non-operative treatment of blunt abdominal trauma is gaining wide acceptance. In this study, the efficacy of non-operative treatment in abdominal trauma (blunt penetrating) is discussed. MATERIAL AND METHODS: All patients who received treatment due to abdominal trauma from November 2008 to January 2013 were retrospectively analyzed. The demographic characteristics, type of injury, injured organ, type of treatment (operative vs. nonoperative) and mortality data were evaluated. RESULTS: The study includes 115 patients treated for abdominal trauma in our department. The mechanism of trauma was stab wounds in 60%, blunt abdominal trauma in 23.5% and gunshot wounds in 16.5%. Forty-two patients (36.5%) were operated for hemodynamic instability and/or peritonitis on admission. The remaining 63.5% of patients (n=73) were treated nonoperatively, 10 of whom required laparotomy during follow-up. The remaining 63 patients were treated with non-operative management. The success rate for non-operative treatment was 86.3% and there was no difference in terms of the types of injuries. The mortality rate was 4.3% (n= 5) in the whole series, but there were no deaths among the patients who had received non-operative treatment. In the whole patient group 54.2% (n=63) were treated nonoperatively. CONCLUSION: Nonoperative treatment in abdominal trauma is safe and effective. Patients with clinical stability and normal physical examination findings can be treated nonoperatively with close monitoring. PMID- 25931869 TI - The efficacy of fibrin glue to control hemorrhage from the gallbladder bed during laparoscopic cholecystectomy. AB - OBJECTIVE: The aim of the study is to report our experience with fibrin glue application in the management of bleeding from the gallbladder bed during laparoscopic cholecystectomy, which could not be controlled by conventional methods. MATERIAL AND METHODS: Three hundred eighty-two patients underwent laparoscopic cholecystectomy. Fourteen patients with bleeding from the gallbladder bed, which could not be controlled by conventional methods, were analyzed retrospectively. RESULTS: Fibrin glue was used in 10 patients. Six (71%) were female and 4 were (29%) male. The mean age was 55.7 years. Fourteen patients were operated for the presence of symptomatic gallstones. Thirteen patients (92%) had a concomitant pathology. The mean time spent to maintain hemostasis was 23.9 minutes (15-35). Blood products were used in two patients with hemoglobin values under 8 mg/dL. Hemostasis could not be achieved in a patient despite fibrin glue application, and the operation was converted to open surgery. CONCLUSION: The application of fibrin glue for bleeding from the gallbladder bed during laparoscopic cholecystectomy can reduce conversion rates, further studies including more patients are required. PMID- 25931870 TI - Comparison of surgical Limberg flap technique and crystallized phenol application in the treatment of pilonidal sinus disease: a retrospective study. AB - OBJECTIVE: This study was designed to compare the efficacy of crystallized phenol method with Limberg flap in pilonidal sinus treatment. MATERIAL AND METHODS: Patients with a diagnosis of pilonidal sinus disease treated with surgical excision + Limberg rhomboid flap technique and crystallized phenol method between 2010-2011 in the Sevket Yilmaz Training and Research Hospital, Department of General Surgery were evaluated retrospectively. Patients' age, sex, length of hospital stay, complications and recurrence rates were evaluated. RESULTS: Eighty eight percent of patients were male and mean age was 26.84+/-6.41 in the Limberg group, and 24.72+/-5.00 in the crystallized phenol group. Sinus orifice locations and nature, and duration of symptoms before surgery were similar in the two groups. Length of hospital stay in the Limberg group was 1.46+/-0.61 days; whereas all patients in the crystallized phenol group were discharged on the same day. Infection, hematoma, wound dehiscence, and cosmetic problems were significantly higher in the Limberg group. There was no difference between the two groups in terms of recurrence and seroma formation. CONCLUSION: The less invasive method of crystallized phenol application may be an alternative approach to rhomboid excision and Limberg flap in patients with non-complicated pilonidal sinus disease, yielding acceptable recurrence rates. PMID- 25931871 TI - What should be done in thyroid nodules less than two centimeters, ultrasonographically suspicious and cytologically benign? AB - OBJECTIVE: Although fine needle aspiration biopsy has a high sensitivity in thyroid nodule assessment, ultrasonography findings should not be underestimated. With this study, we aimed to evaluate cytologically benign nodules smaller than two centimeters, where ultrasonography findings were suspicious. MATERIAL AND METHODS: Thirty-one patients undergoing thyroidectomy between January 2009 and January 2013 were included in this retrospectively designed study. Thyroid ultrasonography and thyroid fine needle aspiration biopsy (FNAB) results were evaluated. Ultrasonographically, all patients had multinodular tissue formation and nodules had at least one of the suspicious features (nodules with hypoechogenicity, irregular margins, absence of halo, taller-than-wide, increased vascularity and microcalcifications). Maximum size of the nodules was 2 cm. Thyroidectomy was performed in this ultrasonographically suspicious, but cytologically benign group due to clinical suspicion, cosmetic reasons or patient preference. RESULTS: All patients underwent a total thyroidectomy. The group consisted of 27 female and 4 male patients, with a mean age of 49.5 years. According to the final pathology reports, there were 13 (41.9%) multinodular goiters, 2 (6.4%) follicular adenomas, 1 (3.2%) Hashimoto's thyroiditis and 15 (48.3%) thyroid cancers. Patients with cancer had at least two suspicious ultrasound findings. Except five patients with papillary microcarcinoma, cancer was diagnosed in ultrasonographically suspicious nodules in all patients. The percentage of patients with benign FNAB results, but with at least two suspicious ultrasound findings of malignancy in the biopsied nodules, was 32.2%. CONCLUSION: FNAB remains to be the gold standard in the management of ultrasonographically suspicious nodules smaller than 2 centimeters. Nevertheless, due to its high sensitivity, in case of presence of suspicious features on ultrasonography, we believe that thyroidectomy should be a treatment option if there is a clinical suspicion and the patient carries at least two suspicious ultrasonography findings. PMID- 25931872 TI - Analysis of the factors that have an effect on hypocalcemia following thyroidectomy. AB - OBJECTIVE: The incidence of and risk factors for hypocalcemia following thyroidectomy were evaluated in this study. MATERIAL AND METHODS: One hundred and ninety thyroidectomy patients were evaluated retrospectively for factors that might contribute to postoperative hypocalcemia; age, hyperthyroidism, malignancy, the extent of surgery (total/near total/subtotal thyroidectomy), cervical lymph node dissection, and incidental parathyroidectomy. RESULTS: The rate of transient hypocalcemia/hypoparathyroidism was 19.47%, with a permanent hypoparathyroidism rate of 4.74%. Factors affecting the development of transient hypocalcemia were found as being operated for hyperthyroidism, and use of total thyroidectomy as the surgical method. Total thyroidectomy increased the risk of postoperative hypocalcemia by 3.16 fold. Patients undergoing operations for hyperthyroidism had a 2.3 fold increase, and those undergoing total thyroidectomy had a 3.16 fold risk of postoperative hypocalcemia. CONCLUSION: Hyperthyroidism surgery and total thyroidectomy lead to a higher risk of developing early postoperative or transient hypocalcemia. According to our results, no significant relationship could be established between any of the study parameters and persistent hypocalcemia. PMID- 25931873 TI - Clinical nutrition and drug interactions. AB - A drug's plasma level, pharmacological effects or side effects, elimination, physicochemical properties or stability could be changed by interactions of drug drug or drug-nutrition products in patients who receive enteral or parenteral nutritional support. As a result, patients might experience ineffective outcomes or unexpected effects of therapy (such as drug toxicity, embolism). Stability or incompatibility problems between parenteral nutrition admixtures and drugs might lead to alterations in expected therapeutic responses from drug and/or parenteral nutrition, occlusion in venous catheter or symptoms or mortality due to infusion of composed particles. Compatibilities between parenteral nutrition and drugs are not always guaranteed in clinical practice. Although the list of compatibility or incompatibilities of drugs are published for the use of clinicians in their practices, factors such as composition of parenteral nutrition admixture, drug concentration, contact time in catheter, temperature of the environment and exposure to light could change the status of compatibilities between drugs and nutrition admixtures. There could be substantial clinical changes occurring in the patient's nutritional status and pharmacological effects of drugs due to interactions between enteral nutrition and drugs. Drug toxicity and ineffective nutritional support might occur as a result of those predictable interactions. Although administration of drugs via feeding tube is a complex and problematic route for drug usage, it is possible to minimise the risk of tube occlusion, decreased effects of drug and drug toxicity by using an appropriate technique. Therefore, it is important to consider pharmacological dosage forms of drugs while administering drugs via a feeding tube. In conclusion, since the pharmacists are well-experienced and more knowledgeable professionals in drugs and drug usage compared to other healthcare providers, it is suggested that provision of information and drug counselling by pharmacists in terms of detection and prevention of problems (such as interactions, stability, incompatibility) related with enteral/parenteral nutrition and drugs are invaluable in clinical practice. PMID- 25931874 TI - Robot assisted laparoscopic (RAL) gastrectomy: case series and a review of the literature. AB - Gastric cancer is the fourth most common cancer type and is the second leading cause of cancer deaths worldwide. The contemporary treatment is gastrectomy and lymphadenectomy, which can be accomplished by either conventional (open), or laparoscopic surgery. With the advances in technology, there is a paradigm shift from conventional laparoscopy. As a result, single incision laparoscopic surgery (SILS), natural orifice transluminal endoscopic surgery (NOTES), and robot assisted laparoscopic surgery (RALS) have evolved as new treatment options for minimal invasive surgery. Herein five patients who were treated via robot assisted laparoscopic gastrectomy were reported together with review of the literature. PMID- 25931875 TI - Abdominal aortic injury due to lumbar disc surgery: A case report. AB - Complications arising from lumbar intervertebral disc surgery are rare but fatal. Major vascular injury is one complication that may end in death unless it is diagnosed and treated immediately. Herein we report an abdominal aortic injury due to L3-L4 intervertebral disc surgery that was treated successfully and discuss it in light of current literature. Diagnosis and treatment of an abdominal aortic injury in a 31-year-old male patient operated on for L3-L4 intervertebral disc degeneration is discussed. Interestingly, in spite of abdominal aortic injury this particular patient was hemodynamically stable. The diagnosis was made 12 hours after disc surgery and laparotomy was performed immediately. As the injury in the aorta was large and had irregular margins, it could not be repaired with primary repair but an end-to-end anastomosis with partial resection was performed. In lumbar intervertebral disc hernia surgery, peroperative hemodynamic instability should raise suspicion of major vascular injury with high mortality and appropriate surgical treatment should be done as soon as possible. If there is any finding suggesting an intraoperative vascular injury, the patient should be kept under close monitoring in order not to delay diagnosis and treatment. It should not be forgotten that hemodynamic stability does not rule out major vascular injury. PMID- 25931876 TI - A rare clinical manifestation of rectal adenocarcinoma and synchronous scalp metastasis: A case report. AB - In this case report, our aim was to emphasize that cutaneous involvement can be seen at the time of diagnosis or during the clinical course of visceral organ cancers in general and in colorectal cancers particularly. We also aimed to demonstrate that cutaneous lesions occurring in patients under follow up for visceral organ cancers could be metastases. A rapid progressing scalp lesion was detected in a newly diagnosed rectal cancer patient and the tru-cut biopsy revealed adenocarcinoma metastasis. This patient died due to a myocardial infarction during neoadjuvant chemotherapy. Cutaneous metastatic lesions in colorectal cancers must be evaluated as a sign of advanced disease and treatment protocols should be determined accordingly. PMID- 25931877 TI - Torsion of wandering spleen as a rare reason for acute abdomen: A presentation of two cases. AB - Wandering spleen is a rare disease that is clinically characterized by torsion of the pedicle. The congenital absence of ligaments anchoring the spleen to the left sub-phrenic area or an acquired looseness is the major reason behind its mobilization. Unless splenic torsion occurs and acute abdominal clinical symptomatology develops, clinical diagnosis is highly challenging due to lack of symptoms. This study aims to share the information acquired from two encountered cases accompanied by the relevant literature. PMID- 25931878 TI - Quality of life after stapler haemorrhoidectomy evaluated by SF-36 questionnaire. PMID- 25931879 TI - Minimally invasive surgery for gastric cancer. AB - The interest in minimally invasive surgery (MIS) has rapidly increased in recent decades and surgeons have adopted minimally invasive techniques due to its reduced invasiveness and numerous advantages for patients. With increased surgical experience and newly developed surgical instruments, MIS has become the preferred approach not only for benign disease but also for oncologic surgery. Recently, robotic systems have been developed to overcome difficulties of standard laparoscopic instruments during complex procedures. Its advantages including three-dimensional images, tremor filtering, motion scaling, articulated instruments, and stable retraction have created the opportunity to use robotic technology in many procedures including cancer surgery. Gastric cancer is one of the most common causes of cancer-related deaths worldwide. While its overall incidence has decreased worldwide, the proportion of early gastric cancer has increased mainly in eastern countries following mass screening programs. The shift in the paradigm of gastric cancer treatment is toward less invasive approaches in order to improve the patient's quality of life while adhering to oncological principles. In this review, we aimed to summarize the operative strategy and current literature in laparoscopic and robotic surgery for gastric cancer. PMID- 25931880 TI - A rare cause of acute mesenteric ischemia: JAK2 positivity and chronic active hepatitis B. AB - Short bowel syndrome occurs as a result of insufficiency in the total length of the small intestine to provide adequate supply of nutrients. Seventy-five percent of cases are due to massive intestinal resection. A 35-year-old male complaining of abdominal pain was admitted to the gastroenterology department. A CT scan was performed, showing total occlusion of the portal vein and superior mesenteric vein. During the operation, widespread edema and necrosis of the small intestine were found. The necrotic segments of the small intestine were resected. The spleen was larger than normal and, in some parts, infarcts were evident, thus asplenectomy was also performed during surgery. A second-look procedure was performed 24 hours later, and an additional 10 cm jejunal resection and anastomosis was performed. His further evaluations revealed myeloproliferative disease and chronic active hepatitis B leading to thrombosis. Essential thrombocytosis and portal vein thrombosis are common in hepatitis B infection. Patients with complaints of abdominal pain in the context of essential thrombocytosis and hepatitis B should be handled with caution as they are at risk of developing portal vein thrombosis. PMID- 25931881 TI - The importance of clinical suspicion in the diagnosis of a successfully managed case with De Bakey Type 1 acute aortic dissection: A case report. AB - Type 1 aortic dissection is a catastrophic clinical entity originating from the ascending aorta. Clinical suspicion in patients with epigastric pain, chest pain and gastrointestinal symptoms might be life saving. Aortic dissection and acute mesenteric ischemia might be confusing in diagnosis of patients with epigastric pain, chest pain, gastrointestinal symptoms and high white blood cell count and D dimer. In this case report of a patient who was admitted to the emergency room with a presentation resembling acute mesenteric ischemia, this diagnosis was excluded within the first 24 hours as a result of clinical suspicion. In this case report, the successful management in diagnosis and treatment of a 30-year old male patient with type 1 aortic dissection is discussed in light of the literature. PMID- 25931882 TI - Metaplastic carcinoma of the breast: A rare carcinoma with chondroid metaplasia. AB - Metaplastic breast carcinoma accounts for less than 1% of breast malignancies. Huvos et al. first introduced the term metaplastic carcinoma in 1974. It is usually seen together with poorly differentiated ductal carcinoma of the breast. Within its mesenchymal components, undifferentiated connective tissue cells, fibroblasts, osteoblasts and chondroblasts can be found. Metaplastic breast carcinoma is an aggressive disease with a poor prognosis. In this report, a case of a 45-year-old female patient who underwent segmental mastectomy with a diagnosis of metaplastic carcinoma of the breast is presented. PMID- 25931883 TI - Timing of cholecystectomy in biliary pancreatitis treatment. AB - OBJECTIVE: Gallstone pancreatitis constitutes 40% of all cases with pancreatitis while it constitutes up to 90% of cases with acute pancreatitis. The treatment modality in this patient population is still controversial. In this study, we aimed to compare the results of early and late cholecystectomy for patients with biliary pancreatitis. MATERIAL AND METHODS: Patients treated with a diagnosis of acute biliary pancreatitis in our clinics between January 2000 and December 2011 were retrospectively reviewed. Patients were divided into two groups: Group A, patients who underwent cholecystectomy during the first pancreatitis attack, Group B, patients who underwent an interval cholecystectomy at least 8 weeks after the first pancreatitis episode. The demographic characteristics, clinical symptoms, number of episodes, length of hospital stay, morbidity and mortality data were recorded. All data were evaluated with Statistical Package for the Social Sciences (SPSS) 13.0 for windows and p <0.05 was considered as statistically significant. RESULTS: During the last 12 years, a total of 91 patients with surgical treatment for acute biliary pancreatitis were included into the study. There were 62 female and 29 male patients, with a mean age of 57.9+/-14.6 years (range: 21-89). A concomitant acute cholecystitis was present in 46.2% of the patients. Group A and B included 48 and 43 patients, respectively. The length of hospital stay was significantly higher in group B (9.4 vs. 6.8 days) (p<0,05). More than half of the patients in Group B were readmitted to the hospital for various reasons. No significant difference was observed between the two groups, one patient died due to heart failure in the postoperative period in group B. CONCLUSION: In-hospital cholecystectomy after remission of acute pancreatitis is feasible. It will not only result in lower recurrence and complication rates but also shorten length of hospital stay. We recommend performing cholecystectomy during the course of the first episode in patients with acute pancreatitis. PMID- 25931884 TI - The results of 21-year experience of treating anal squamous cell carcinomas. AB - OBJECTIVE: Anal squamous cell carcinomas are one of the rare cancer types. Due to the developments in the past 35 years, surgery is no longer the first treatment of choice. The aim of this study was to retrospectively examine the outcomes of 24 patients treated in a single center in the last 21 years in terms of applied treatment, local relapse, distant metastasis, post-treatment complications, and survival. MATERIAL AND METHODS: Data obtained from 24 anal squamous cell carcinoma patients, who were treated in Ankara Oncology Research and Education Hospital between 1990 and 2010, were retrospectively evaluated. RESULTS: Of the 24 patients, 16 had anal canal squamous cell carcinoma and eight had perianal squamous cell carcinoma. All of the patients with anal canal squamous cell carcinoma (n=16) received chemoradiotherapy. Three of these patients who did not respond to treatment, underwent abdominoperineal resection. The patients with perianal squamous cell tumors were treated by local excision. During the follow ups, seven patients experienced local relapse, and one patient had distant organ metastasis. Only one patient died. Five-year disease free survival rate was found as 66%. CONCLUSION: Our findings suggest that the first alternative in the treatment of anal squamous cell tumors should be chemoradiotherapy; and surgery seems to be the appropriate approach for the non-responsive and relapsing cases. PMID- 25931885 TI - Completion thyroidectomy in differentiated thyroid cancer: When to perform? AB - OBJECTIVE: Completion thyroidectomy is recommended in patients who have been diagnosed with differentiated thyroid cancer on histopathological evaluation, if their first operation was a conservative approach. The critical issue is when to do the second operation. MATERIAL AND METHODS: The medical records of 66 patients who underwent completion thyroidectomy for the treatment of differentiated thyroid cancer in our clinic between 2006-2013 were retrospectively analyzed. All data were compared after patients were divided into two groups according to the interval between the first surgery and completion thyroidectomy. RESULTS: Fifty two patients (78.8%) were women and 14 patients (21.2%) were male. Completion thyroidectomy was performed 10-90 days after the initial surgery (group 1) in 26 patients, whereas it was performed later than 90 days in 40 patients (group 2). Temporary hypoparathyroidism occurred in two patients (7.7%) in group 1, and in 3 patients (7.5%) in group 2. Transient recurrent laryngeal nerve palsy was observed in 1 patient (3.9%) in group 1, and in 1 patient (2.5%) in group 2. There were no permanent morbidities in both groups. Residual tumor rate after completion thyroidectomy was 45.5%. There was no statistically significant difference between the two groups in terms of complications after completion thyroidectomy. CONCLUSION: Although in some studies it is recommended that completion thyroidectomy should be performed either before scar tissue development or after clinical remission of scar tissue, edema and inflammation, we believe that timing of surgery has no effect on morbidity. PMID- 25931886 TI - Effect of surgeon's judgement on the diagnosis of acute appendicitis. AB - OBJECTIVE: The accuracy of a surgeon's judgement still remains to be controversial in the diagnosis of acute appendicitis, which is a diagnosis usually based on laboratory data and imaging tests. MATERIAL AND METHODS: Patients with a possible diagnosis of acute appendicitis were reviewed retrospectively with regard to demographic variables, laboratory and imaging results, and treatment modalities. RESULTS: There were 128 patients with a mean age of 31.2+/-14 years. The mean white blood cell count and the proportion of polymorphonuclear leukocytes were 11403+/-4669/mm(3) and 75+/-11%, respectively. Appendectomy was performed on 66 (51.6%) patients. Conservative management was applied to 62 (48.4%) patients. Statistical analysis showed that patients with appendicitis have a higher white blood cell count (p=0.015) and a higher proportion of polymorphonuclear leukocytes (p=0.023). Sensitivity, specificity and accuracy rates were 84.6%, 63.7% and 74.3% for ultrasound and 100%, 86.7% and 92.2% for computed tomography, respectively. CONCLUSION: Diagnosis based on patients' laboratory and imaging data, in combination with, the surgeon's judgement appears to yield the best outcomes in patients with suspicion of acute appendicitis. PMID- 25931887 TI - The early results of our initial experience with robotic adrenalectomy. AB - OBJECTIVE: Robotic adrenalectomy is one of the minimally invasive surgical methods gaining wide acceptance due to the three-dimensional imaging system and ergonomics of the equipment. We aimed to present the early data on patients who underwent robotic adrenalectomy due to adrenal masses in our hospital. MATERIAL AND METHODS: The records of eight cases, in which a unilateral robotic trans peritoneal adrenalectomy was conducted due to an adrenal mass between 2011 and 2013, have been evaluated. Demographic characteristics of cases, body mass index (BMI), American Society of Anesthesiologists (ASA) score, preoperative diagnosis, diameter and localization of the adrenal mass, operative time, blood loss, conversion rate to open surgery, morbidity and mortality rates, length of hospital stay, total hospital charges and postoperative pathologic results were considered. RESULTS: The female to male ratio was 6:2, the median age was 49.5 (26-71) and the median BMI was 29.7 (21.7-38.5). An adrenalectomy was performed in six cases for a right adrenal mass and in two cases for a left adrenal mass. The mean tumor diameter was 53.6 mm (20-90). The average surgical time (including docking) was 98 min. (55-175 min.) and the average blood loss was 50 mL. The only complication was a diaphragm injury which was repaired robotically. There were no conversions to traditional laparoscopic or open surgery and there have not been any mortality in the series. The median length of hospital stay was 4.1 days (range 2-11) and the average cost was 3617.12 TL ($1808.56). CONCLUSION: Robotic adrenalectomy is an effective and safe surgical alternative to laparoscopic adrenalectomy. However its high cost has emerged as its main disadvantage. PMID- 25931888 TI - Comparison of fructus agni casti and flurbiprofen in the treatment of cyclic mastalgia in premenopausal women. AB - OBJECTIVE: Cyclic mastalgia is described as a diffuse, periodic and bilateral breast pain that can not be localized. Although there are several methods of treatment, the most efficient treatment method is still controversial. The aim of this study is to determine, compare and discuss the results of the patients under 40 years old age with a complaint of cyclic mastalgia and without any clinical signs, family history and ultrasonography finding, treated with fructus agni casti extract or flurbiprofen. MATERIAL AND METHODS: One hundred and fourteen premenapousal patients younger than 40 years old with a complaint of cyclic mastalgia and without any clinical, family or ultrasonography findings were analyzed prospectively. Fructus agni casti extract (Group 1) or flurbiprofen (Group 2) were administered to the patients. VAS scores were accepted as full recovery whit a score of zero, as significant healing when the score improved more than 50%, as mild-moderate healing when the improvement was less than 50% and as no healing in case of no improvement. RESULTS: The mean age in group 1 was 28.29+/-5.81, and in group 2 was 29.09+/-4.49. The mean number of days with pain was 6.0+/-1.70 days in group 1, and was 6.3+/-1.63 in group 2. There was no significant difference in VAS scores between the two groups after treatment. CONCLUSION: Fructus agni casti extract and flurbiprofen are commonly used medications in the treatment of cyclic mastalgia. Both of these medications significantly reduce the complaints and have acceptable side-effects. There is no proven superiority over each other. Further clinical and laboratory studies are necessary to determine the ideal medication fort he treatment of cyclic mastalgia. PMID- 25931889 TI - The techniques of sphincter-saving extrasphincteric dissection and proximal segmental sphincteric excision in low rectal cancer surgery. AB - OBJECTIVE: To define the techniques used in lower rectal cancer surgery, by transvaginal and transperineal approach; extrasphincteric dissection, proximal segmental sphincteric excision and transsphincteric rectal resection. MATERIAL AND METHODS: Between 2007 and 2013, 7 patients (4 female, 3 male with lower rectal cancer were operated by sphincter-saving extrasphincteric disection and proksimal sphincteric excision techniques. After completion of the rectosigmoid dissection and total mesorectal excision up to the puborectal muscle level; extrasphincteric rectal dissection, transsphincteric rectal resection and ultra low coloanal anastomosis were performed by using the transvaginal and transperineal approach in the sublevator phase of the operation. RESULTS: Seven patients were operated with sublevator access for lower rectal cancer. Bowel contiunity has been provided in all patients. One patient died due to surgical complications in the early postoperative period. One patient deceveloped anastomotic leakage and there were two patients with anastomotic stricture. Circumferential resection margin and tumoral perforation were found negative in all of the patients. Tumoral deposits at the distal resection line was observed in one patient. CONCLUSION: The techniques of sublevator rectal resection may be considered as an alternative sphincter-saving surgical method, especially in lower rectal cancer surgery. PMID- 25931890 TI - Videoscopic total extraperitoneal approach to an adult patient with undescended testicle accompanied by a contra-lateral inguinal hernia. AB - A 22 year-old male patient was admitted to our clinic with complaints of swelling and pain at the left groin area as well as inability to palpate his right testicle. The patient was diagnosed as right undescended testicle accompanied by left indirect inguinal hernia. According to the scrotal Doppler ultrasonography the right undescended testicle was localized in the inguinal canal very close to the inner ring. As totally extra peritoneal (TEP) approach is widely used for inguinal hernia repair by hernia surgeons, the same technique was planned for both inguinal hernia repair and orchiectomy simultaneously. Using videoscopic TEP approach, left inguinal hernia repair and right prophylactic inguinal hernia repair with polypropylene mesh was carried out following successful laparoscopic right orchiectomy. In patients with undescended testicle who are indicated for orchiectomy and accompanied by inguinal hernia, videoscopic TEP operation is a safe procedure, also providing the oppurtunity for prophylactic hernia repair at the orchiectomy site. PMID- 25931891 TI - A case report of primary breast angiosarcoma causing hemorrhagic shock in pregnancy. AB - Angiosarcoma is a rare breast tumor. In contrary to other breast tumors, primary breast angiosarcomas are seen in the third and fourth decades. Clinically, they present as rapidly growing masses. They can also be seen during pregnancy. The aim of this article is to report on a primary breast angiosarcoma case that occured during pregnancy and resulted in hemorrhagic shock. PMID- 25931892 TI - Laparoscopic treatment of ileal intussusception due to heterotopic gastric mucosa in an adult patient. AB - Adult intussusception, which is a rare condition, generally requires surgical treatment. A 25-year-old-male with abdominal pain was diagnosed as ileal intussusception with computerized tomography. The patient underwent diagnostic laparoscopy, laparoscopic small bowel resection and anastomosis. The pathologic evaluation revealed heterotopic gastric mucosa. Heterotopic gastric mucosa is rarely seen in ileum and is difficult to diagnose preoperatively. Excision is the choice of treatment. Laparoscopic treatment can be preferred in adult intussusception even in urgent cases. PMID- 25931893 TI - Bowel obstruction due to diaphragmatic injury after penetrating thoracic trauma. AB - Diaphragmatic injuries due to penetrating traumas to the thorax progress insidiously. Proper diagnosis might only be performed after months. Delayed diagnosis increases morbidity and mortality. Herein, we present a case of diaphragm injury due to penetrating thoracic trauma that was diagnosed 2 years later. The case was referred to emergency service with bowel obstruction symptoms and after the examinations, first laparotomy and then thoracotomy were performed. The trace of the injury tract should be evaluated in all penetrating thoracic traumas and diaphragmatic injury should be taken into consideration. It is important to keep in mind that thoracic symptoms could be obscured and, if needed, further evaluation and surgical exploration should be performed. In the absence of early symptoms, failure to recognize diaphragmatic injuries can result in mortality. PMID- 25931894 TI - Invagination of the appendix due to endometriosis presenting as acute appendicitis. AB - Appendicitis and endometriosis are commonly encountered surgical problems. Endometrial involvement of the appendix is rare and very few cases have been reported in the literature. True diagnosis of appendix invagination is highly difficult due to variable symptoms. Noting the findings which are in favour of invagination in patients diagnosed with acute appendicitis is of great significance in order to be prepared for changing surgical attempts. This case describes a 34 year old female patient diagnosed with infertility who was operated on for acute appendicitis. In the pathological assessment, endometrial involvement of the appendix was seen. The classification, symptoms, radiological appearance and treatment of appendix invagination described in the literature are discussed. PMID- 25931895 TI - Non-recurrent laryngeal nerve. AB - Injury to the recurrent laryngeal nerve is a serious complication in thyroid and parathyroid surgery. The anatomy of the recurrent laryngeal nerve is variable. Non-recurrent nerve is a very rare variation of the inferior laryngeal nerve. Because of the anatomical variations of the nerve, preservation of the nerve is the optimal strategy during surgery. In this case report, we present a non recurrent laryngeal nerve abnormality in a patient who underwent parathyroidectomy, thyroidectomy and functional neck dissection for malignant parathyroid disease. A non-recurrent laryngeal nerve was identified during nerve exploration. PMID- 25931896 TI - Controversies in familial thyroid cancer 2014. AB - Thyroid cancer is the sixth most common cancer in women, and the majority of patients with thyroid cancer has sporadic disease. However, about 25% of patients with medullary thyroid cancer and 5% with papillary thyroid cancer have familial tumors. Currently, there are numerous controversies regarding the mode of inheritance, tumor behavior, extent of surgical resection for optimal results, coexisting thyroid pathology, risk of other cancers, and extent of postoperative treatment of patients with familial thyroid cancer. This review aimed to give insight to surgeons on this interesting topic. PMID- 25931897 TI - The effect of the endoscopist on the wait-time for colorectal cancer surgery. AB - OBJECTIVE: The effect of the specialty of physicians who perform endoscopy on preoperative wait-time of colorectal cancer patients was evaluated. MATERIAL AND METHODS: Data from 86 patients who have been operated with a diagnosis of colorectal cancer from January 2011-February 2013 regarding age, sex, tumor location, colonoscopy date, surgery date, the expertise and institution of the endoscopist were retrospectively examined. The time between colonoscopy and surgery was accepted as the pre-operative wait time (PWT). RESULTS: Out of 86 patients, 24 (27.9%) colonoscopies were performed by general surgeons (GS), and 62 (72.1%) by gastroenterologists (GE). When patients who underwent colonoscopy in other centers were extracted, the PWT for our center was 20.4+/-10.8 days. When grouped according to specialties, the PWT of patients who had their colonoscopy performed by GS was significantly shorter than patients who underwent colonoscopy by GE at the same center (p<0.05). Patient's age, sex and location of the tumor had no effect on PWT (p>0.05). CONCLUSION: The preparation time for surgery in colorectal cancer patients is influenced by the specialty of the physician performing the procedure. In order to standardize this period, a common flow diagram after endoscopy should be established for patients with suspected malignancy. PMID- 25931898 TI - Our results of lower gastrointestinal endoscopy: evaluation of 700 patients. AB - OBJECTIVE: Although radiological imaging modalities like barium enema and computed tomography provide some clues, endoscopic methods still maintain superiority in assessment and differential diagnosis of large intestinal symptoms and complaints that require biopsy. We aimed to present the results of colonoscopic procedures performed in our general surgery clinic in detail. MATERIAL AND METHODS: Seven hundred patients who presented to Afyon Kocatepe University, Faculty of Medicine, Department of General Surgery Endoscopy Unit between January 2011 and July 2012 with an indication for colonoscopy were retrospectively evaluated. RESULTS: Out of the 700 patients enrolled in the study 356 (50.8%) were male while 344 patients (49.2%) were female. The mean age of the patients was found to be 49 years. Within the group of 700 patients who underwent colonoscopic examinations, the terminal ileum and cecum have been reached on the first attempt in 432 patients (61.7%) and colonoscopic success has been achieved. Results of colonoscopies performed on 700 patients in our clinic revealed malignancy in 42 (6%) patients, and all of these patients were treated surgically in our clinic. Mortality was not observed in this series. Procedure-related bleeding and perforation developed in 6 patients. One patient developed respiratory arrest due to sedation and patient was responsive to resuscitation. The complication rate in our series was 1%. CONCLUSION: In the study where we revised our own clinical experience, we found that our success rate was lower than the literature, and our complication rate was higher. The main reasons are accepted as our colonoscopy unit's being young and the low patient volume. PMID- 25931899 TI - The evaluation of gallstone formation in patients undergoing Roux-en-Y gastric bypass due to morbid obesity. AB - OBJECTIVE: This study aimed to evaluate gallstone formation, prophylactic and selective cholecystectomy and the effectiveness of ursodeoxycholic acid treatment following laparoscopic Roux-en-Y gastric bypass (LRYGB) in morbid obese patients. MATERIAL AND METHODS: Files of 60 patients who underwent LRYGB between October 2006 and March 2011 were retrospectively reviewed. Patients were evaluated for formation of gallstones. RESULTS: Fifty-three (88.3%) patients were female and seven (11.7%) were male. Eight of the 60 patients (13.3%) had previously undergone cholecystectomy. Six patients (11.5%) underwent cholecystectomy in addition to LRYGB due to preoperatively detected gallstones by ultrasonography. The remaining 46 patients were followed up for a mean duration of 28.57 months (5 56 months). In 10 (21.7%) of these patients, gallstones were detected and five patients with symptomatic gallstones underwent cholecystectomy. Patients who did and did not develop gallstones after LRYGB did not show a significant difference regarding age, gender and the new body mass index (BMI). Three patients were started on ursodeoxycholic acid and the treatment was continued for six months. Gallstones were not detected in these patients. CONCLUSION: In light of these data, since only a very small portion of patients develops symptomatic gallstones after LRYGB, we recommend cholecystectomy in patients with symptomatic gallstones or the use of ursodeoxycholic acid rather than a prophylactic approach. Prospective randomized controlled studies in larger series are required to support these results. PMID- 25931900 TI - Increased interleukin 1 and tumor necrosis factor alpha levels after thyroid surgery. AB - OBJECTIVE: The aim of this study was to consider levels of the proinflammatory cytokines IL-1 and TNFalpha after thyroid surgery. MATERIAL AND METHODS: A total of 200 patients who underwent total thyroidectomy enrolled in this study. Drain fluid samples were taken. IL-1 and TNFalpha results and their relationship with other factors were analyzed. RESULTS: There was a positive correlation between IL 1 and hyperthyroidism (rs=0.614, p<0.001), operative time (rs=0.770, p<0.001), and excised thyroid volume (rs=0.829, p<0.001). Moreover, there was a positive correlation between TNFalpha and hyperthyroidism (rs=0.430, p<0.001), operative time (rs=0.392, p<0.001), and excised thyroid volume (rs=0.398, p<0.001). CONCLUSION: The results of this study showed us that the parameters related to increased proinflammatory cytokine levels after thyroid surgery were hyperthyroidism, operative time, and excised thyroid volume, but this increase did not show us any clinical outcomes related to these parameters. PMID- 25931901 TI - Evaluation of factors affecting mortality in Fournier's Gangrene: Retrospective clinical study of sixteen cases. AB - OBJECTIVE: Fournier's gangrene is a progressive, necrotizing fasciitis due to synergistic infection of the perineum and external genitalia that is associated with high mortality and morbidity. The purpose of this study is to review the diagnostic and treatment methods that effect mortality in Fournier's gangrene. MATERIAL AND METHODS: Sixteen patients who were diagnosed and treated at our clinic between 2011 and 2013 due to Fournier's gangrene were retrospectively analyzed. The surviving and non-surviving patient groups were compared in terms of age, sex, onset time of symptoms, isolated microorganisms, concomitant diseases, Fournier's gangrene severity index (FGSI), and length of hospital stay. RESULTS: Ten of our cases (62.5%) were male and six (37.5%) were female, with a mean age of 61.2+/-12.3 (42-73) years. The mortality rate was 18.8% (3 cases). The mean duration of symptoms before admission was 4.31+/-1.81 (2-8) days. This period was 6.67+/-1.52 days in patients who succumbed to death, and 3.77+/-1.42 days in patients who survived (p=0.007). Ten cases (62.5%) had concomitant diabetes mellitus. The most common organism isolated in wound cultures was Escherichia coli (68.7%), and Acinetobacter baumannii, Proteus mirabilis, methicillin-resistant Staphylococcus aureus and Enterococcus spp. in the remaining patients. The mean FGSI of surviving patients was 3.84+/-1.77, and 7.66+/-0.57 in fatal cases (p=0.003). The mean length of hospital stay was 25.5 days (2-57) and duration of hospitalization was significantly longer in survivors (p<0.05). CONCLUSION: The delay in diagnosis and higher FGSI may be responsible for worsening of prognosis and mortality in Fournier's gangrene. Early diagnosis and determination of the severity of the disease, aggressive surgical debridement and appropriate antimicrobial therapy may improve prognosis. PMID- 25931902 TI - Factors affecting the safety of drains and catheters in surgical patients. AB - OBJECTIVE: Drains and catheters are used for both prophylactic and therapeutic reasons in clinical practice. This study aimed to investigate the factors that affect safety of drains, catheters, nasogastric tube and central venous line in patients who underwent surgery. MATERIAL AND METHODS: Two hundred and four consecutive patients who were operated at the general surgery clinics under general anesthesia were included in the study. Factors that affect the safety of drains and catheter were followed and recorded prospectively. RESULTS: During follow-up period, 12 (5.8%) patients have experienced problems regarding safety of drains/catheters. The mean age of patients who were followed-up in terms of security problems was 63.1 (39-86) years. Eight (66.7%) patients had been operated emergently, and four (33.3%) patients electively. Three (25%) patients had psychiatric/neurological co-morbidities and 3 (25%) patients were confused due to anesthesia/intensive care unit treatment when the drain safety was broken. Eight (66.7%) patients withdrew the drains or catheters by themselves, in 2 (16.7%) patients the drains spontaneously came out and in 2 (16.7%) patients the wrong drain was withdrawn. One patient had dementia, one patient had Alzheimer's disease and one patient was being followed-up with a diagnosis of schizophrenia. In three (25%) patients the abdominal drain, in four (33.3%) patients nasogastric tube, in one (8.3%) patient intubation tube, in one (8.3%) patient central venous catheter, and in three (25%) patients multiple drains were removed. CONCLUSION: The inaccurate use of drains or re-intervention for an unintentionally removed drain causes problems regarding patient safety. Close monitoring of surgical patients in terms of security, and submission of additional measures for patients with confusion and neurological/psychiatric disorders are of great importance. PMID- 25931903 TI - How informed are endocrine surgery patients about the risks of surgery after approving an informed consent? AB - OBJECTIVE: The aim is to evaluate if patients reach the level of competence that enables them to make the best decision for themselves with oral and written informed consent process that is legally valid. MATERIAL AND METHODS: This study included 62 patients who applied to Ege University Hospital Department of General Surgery Endocrine Surgery Clinics and in whom oral and written informed consent was obtained by a surgeon. Patients who were willing to participate in the study were asked to fill in a questionnaire containing questions regarding the concept of consent. RESULTS: Seventy-one percent of patients were female and 29% were male, with a mean age of 50.4+/-17.9 years. Six percent of patients were illiterate, 51.6% had primary education and 16.1% were college graduates. One in every two patients stated that they have never heard of informed consent concept before, 16% stated that they signed the consent without reading it. Among these patients, 88% reported that they trusted the physician and did not bother reading because they have already been verbally informed. Verbal briefing by the doctor was detected as 92%. Similarly, 91% of the patients reported that the time allocated to read and fill-in the form was enough. CONCLUSION: Informing is not composed simply of conveying information, but also to elevate patients to a proficiency level where they could decide with their best interest. It is thought that the results obtained in this study might guide studies to improve the quality of information in patients undergoing surgery. PMID- 25931904 TI - Four mucinous cystadenoma of the appendix treated by different approaches. AB - Appendiceal mucocele is a rare clinical entity characterized by dilatation of the appendiceal lumen due to abnormal mucinous secretion. It may be of inflammatory or tumoral origin. It may occur as a result of mucoceles, mucosal hyperplasia, mucinous cystadenoma or mucinous cystadenocarcinoma. Mucinous cystadenoma of the appendix is the most common form, although it manifests itself in many different clinical presentations. It is detected in 0.6% of appendectomy specimens. Preoperative diagnosis is difficult, and it is often detected at laparotomy. Despite existing reservations due to the risk of rupture, laparoscopic surgery is gaining acceptance. Although there is no consensus on the choice of surgery, either appendectomy or right hemicolectomy is applied. In this article, we discussed four patients with appendix mucinous cystadenoma where different surgical methods were applied in light of the literature. PMID- 25931905 TI - Symptomatic duodenal lipoma with endoscopic snare polypectomy. AB - Duodenal lipomas are extremely rare benign tumors. 90% arise from the submucosa and is usually localized in the second portion. They are usually asymptomatic and are detected incidentally during endoscopy or surgery. Appearance of symptoms are related to lesion size, those greater than four centimeters frequently may cause intussusception, obstruction or bleeding. A 59- year-old woman presented with complaints of abdominal fullness in the upper quadrants after meals, and heartburn symptoms. She had been under treatment for iron deficiency anemia during the last five months. The upper gastrointestinal endoscopy revealed a mobile, 4*2 cm polypoid mass extending from the second portion of the duodenum to the third portion, with a regular mucosa and wide pedicle. Saline and epinephrine was injected to polyp base and "snare" polypectomy was performed. Patient's complaint of fullness in the upper part of the abdomen declined after polypectomy and the treatment of anemia was discontinued after a month, with normal blood count values in the fourth month. PMID- 25931906 TI - Diffuse idiopathic varices in the colon characterized by lower gastrointestinal bleeding. AB - Colon varices are very rare lesions that usually present as secondary to portal hypertension. Idiopathic colon varices are even rarer, and should be considered especially in the etiology of massive lower gastrointestinal bleeding. Forty-five year old male presented to our hospital with complaints of recurrent rectal bleeding for one week and severe anemia. The patient was transfused with 4 units of blood. His colonoscopy revealed diffuse submucosal varices. The tests performed for investigation of etiology did not reveal any portal pathology. The patient did not experience another episode of active bleeding during follow-up and was discharged with conservative recommendations. Idiopathic colon varices are rare but should be considered in the differential diagnosis of patients presenting with massive rectal bleeding. Conservative approach is first line of treatment, reserving segmental or total colectomy only for ongoing hemorrhage. PMID- 25931907 TI - The chain of postoperative complications after laparoscopic cholecystectomy. AB - Bile duct injuries are among the most dreadful complications of cholecystectomy. As laparoscopic cholecystectomy has become increasingly popular, the incidence of this complication increased and has remained unchanged in spite the learning curve being completed. A 50-year-old female underwent elective laparoscopic cholecystectomy for gallstone disease. A complicated bile duct injury occurred during the procedure. As the injury was immediately recognized, it was treated with concomitant hepaticojejunostomy. In the postoperative period, biliary fistula, which was assumed to be the result of an anastomotic leak, was encountered. Diagnostic and therapeutic percutaneous transhepatic biliary drainage was considered. It revealed that the anastomosis was intact and the source of biliary leak was an aberrant right posterior sectorial branch. A severe bleeding through the biliary catheter occurred due to transmigration of the catheter into the portal vein. Bleeding was controlled with embolization by the interventional radiologist. The patient thereafter was re-operated, and the leakage was sealed by ligation of the aberrant right posterior sectorial branch. The postoperative period was uneventful. As long as cholecystectomy is performed, bile duct injuries will always exist. Therefore, every abdominal surgeon should be aware of possible consequences of complications related to this procedure. PMID- 25931908 TI - A rare cause of mechanical obstruction: Intestinal myeloid sarcoma. AB - Myeloid sarcoma is a rare aggressive tumour that originates from immature extramedullary myeloid cells. It can be seen as a relapse in patients with acute myeloid leukaemia. Sometimes it can be seen in the form of a solid tumour without any evidence of leukaemia. A case of a 44-year-old male patient who was admitted with symptoms and signs of mechanical intestinal bowel obstruction was operated on. The operation findings showed small bowel obstruction due to a mass. The mass was then resected with end-to-end intestinal anastomosis. The resected mass pathology results were consistent with myeloid sarcoma. The post-operative period was uneventful and adjuvant therapy was applied. In this case report we aimed to evaluate the clinical signs and treatment modalities of small intestinal myeloid sarcoma. PMID- 25931909 TI - Gastric necrosis and perforation caused by acute gastric dilatation. AB - Acute gastric dilatation was first defined by Duplay in 1833. We herein present the case of a 55-year-old male patient diagnosed with gastric necrosis and perforation caused by acute gastric dilatation. Since the stomach has a rich blood circulation, necrosis and perforation are rarely seen. Clinically, more than 90% of cases have complaints of vomiting. The most useful method in revealing the diagnosis and aetiology is computerized tomography. Medical treatment is appropriate for cases where no necrosis and peritonitis findings are detected through endoscopy. Delays in surgical treatment increase the risk of mortality. PMID- 25931910 TI - Can horizontal diameter of colorectal tumor help predict prognosis? AB - OBJECTIVE: We aimed to investigate the relationship between the horizontal tumor diameter and prognosis. MATERIAL AND METHODS: Patients' records were analyzed retrospectively. Patient data, including age, gender, vertical penetration, anatomic location, differentiation of the tumor, tumor node metastasis (TNM) stage, survival rate, and disease-free survival, were analyzed to find out if there was any correlation with horizontal tumor diameter. RESULTS: A total of 439 colorectal cancer patients were enrolled. Patients were stratified into two groups according to the horizontal tumor diameter (<=4.5 cm vs. >4.5 cm). Poorly differentiated tumors were significantly larger than other differentiation groups (p=0.003). The horizontal diameter increased with increase in T-stage (p<0.001). Similarly, the number of positive lymph nodes increased significantly as the size of the horizontal tumor diameter increased (p<0.001). The relationship between TNM staging and the horizontal diameter of tumors in both groups was examined, and it was found that the progression of tumor stage was accompanied by increased horizontal diameter (p<0.001). It was also found that the horizontal tumor diameter was not correlated with local recurrence (p=0.063). However, distant metastasis was higher in patients with a tumor larger than 4.5 cm (p=0.02). Although the disease-free survival was shorter in patients with a horizontal tumor diameter more than 4.5 cm, the difference was not statistically significant. CONCLUSION: There is a significant relation between horizontal diameter of the tumor and depth of the tumor, lymph node involvement, overall survival, and distant metastasis. Horizontal diameter of the tumor can possibly be used as a prognostic factor in colorectal cancer patients. PMID- 25931911 TI - The growing role of laparoscopic repair in patients with early diagnosed peptic ulcer perforation. AB - OBJECTIVE: Laparoscopy is gaining more importance in emergency abdominal surgery. Peptic ulcer perforation (PUP) constitutes a significant portion of surgical emergencies. The aim of this study was to evaluate the methods and results of patients who underwent surgery due to PUP in our department. MATERIAL AND METHODS: Patients who were admitted to the hospital in the early period and received Graham-patch (GP) repair due to PUP from January 2009 to January 2013 were divided into two groups as laparoscopic (group L) or open (group O) surgery. Demographic data of the patients, duration of the operation, conversion to open surgery, length of hospital stay, secondary interventions, re-admissions, morbidity and mortality rates were retrospectively evaluated. Patients with conversion to open surgery were included in Group O. RESULTS: Two hundred and nineteen patients were included in the study, 148 of which were in Group O (including the 47 patients with conversion), and 71 in group L. In patients with early admission, the rate of laparoscopically completed GP was 19.6% in the first year of the study, whereas this rate was 61.8% in the fourth year (p<0.001). The rate of conversion to open surgery was 50% in 2009, and 24.4% in 2012 (p=0.028). Length of hospital stay was shorter in group L (p=0.35). The complication rate was 4.2% in patients who had laparoscopic procedures, and was 6.1% in patients who underwent open surgery (p=0.57). Seventy-three percent (n=11) of re hospitalized patients in the perioperative period (n=15) were treated conservatively. When costs related to secondary interventions and re hospitalization were included, there was no significant difference between laparoscopic and open surgery groups in terms of cost (p=0.06). CONCLUSION: Laparoscopic surgery for PUP is a reliable method and has been used increasingly over the years in our department. The operative time is longer, the length of hospital stay is shorter, the complication rates are less than open surgery, and the conversion rate is significantly reduced. Laparoscopic GP is feasible in early-admitted patients with PUP, due to the above-mentioned advantages. We believe the rate of conversion to open surgery decreases with increasing experience in laparoscopy. PMID- 25931912 TI - Thyroid pathologies accompanying primary hyperparathyroidism: a high rate of papillary thyroid microcarcinoma. AB - OBJECTIVE: Thyroid pathologies and non-medullary thyroid cancer often accompany primary hyperparathyroidism (PHPT). The purpose of this study was to examine the association between thyroid diseases, especially micropapillary thyroid cancer, with PHPT. MATERIAL AND METHODS: Data regarding 46 patients who were operated on with a diagnosis of PHPT at Inonu University Faculty of Medicine, General Surgery Clinic between June 2009 and March 2013 were retrospectively analyzed. Age, gender, levels of preoperative calcium, parathyroid hormone and phosphorus, and the histopathological results of the removed parathyroid and thyroid tissues were evaluated. All of the patients had a preoperative diagnosis of PHPT and there was no history of radiation to the head and neck region in any of the patients. RESULTS: Out of the 46 patients who were operated on for PHPT, 39 were female and 7 were male. The mean age was 52.8 years (25-76). Simultaneous thyroidectomy was performed in 35 patients (76.1%) due to an accompanying thyroid disorder. Papillary microcarcinoma was detected in 5 of these 35 (10.9%) patients who underwent thyroidectomy, two of which (40%) were multifocal tumors. The benign thyroid pathologies detected in the remaining 30 (65.2%) cases included lymphocytic thyroiditis in 3, Hashimoto thyroiditis in 1, follicular adenoma in 3 (two of which was Hurtle cell), and nodular colloidal goiter in 23 patients. The preoperative serum phosphate level was significantly higher in the group with papillary thyroid microcarcinoma (p=0.013). CONCLUSION: In regions where goiter is endemic, thyroid diseases and thyroid papillary microcarcinoma occur in association with PHPT at a higher rate compared to the normal population. Therefore, we believe that patients who are planned for surgery due to PHPT should be thoroughly investigated for the presence of any concomitant malignant thyroid pathologies in the preoperative period. It should also be kept in mind that patients with high blood serum phosphate values may have an increased risk of papillary thyroid microcarcinoma. PMID- 25931913 TI - Analysis of patients with phyllodes tumor of the breast. AB - OBJECTIVE: The diagnosis and management of phyllodes tumors is challenging due to its low incidence. The treatment of these tumors is surgery, however the extent of surgery, the application of adjuvant chemotherapy and radiotherapy are still controversial. Therefore, we aimed to evaluate patients who were treated with a diagnosis of phyllodes tumor of the breast in our clinic. MATERIAL AND METHODS: Patients who were treated with a diagnosis of phyllodes tumor of the breast between June 2011 and June 2013 were reviewed retrospectively. Patient demographic characteristics (age, gender), menopausal status, symptoms, radiologic and surgical methods used for diagnosis and treatment, histopathologic features of the tumor and type of adjuvant therapy were evaluated. Patients were grouped as benign or borderline/malignant according to histopathological diagnosis. Patients in these groups were compared in terms of age, menopausal status, tumor size and the number of mitosis within the tumor. RESULTS: The median age was 26 years (17-59), and 30 patients were female. The surgical treatment of choice was wide local excision with tumor-free surgical margins in 29 patients and mastectomy in one patient. Histopathological diagnosis after surgery was benign in 21 patients (70%), borderline in 6 patients (20%) and malignant phyllodes tumor in 3 patients (10%). Patients with borderline and malignant phyllodes tumors were significantly older (p=0.002) and had higher mitotic counts (p<0.0001). There was no significant relationship between histopathologic subtypes of phyllodes tumors and menopausal status (p=0.06) or tumor size (p=0.1). CONCLUSION: Surgery is the treatment of choice for phyllodes tumors, and obtaining tumor-free margins is important. Since phyllodes tumors might recur as borderline/malignant tumors, local control with surgery and adjuvant radiotherapy should be provided when required. In this way, distant metastases and death that may arise due to possible malignant recurrences might be avoided. PMID- 25931914 TI - First-line therapy in Helicobacter pylori eradication therapy: experience of a surgical clinic. AB - OBJECTIVE: Helicobacter pylori (HP) is the world's most common infectious agent. Despite conventional therapy consisting of proton pump inhibitor (PPI), amoxicillin (AMO) and clarithromycin (CLA), approximately half of the patients remain infected. We compared the PPI-based triple therapy with quadruple treatment (BPMT) including bismuth citrate (BS), PPI, metronidazole (MET) and tetracycline (TET). MATERIAL AND METHODS: Forty-three patients who used triple therapy (LAC) consisting of lansoprazole (L), AMO and CLA and 42 patients who used quadruple therapy (BPMT) for 14 days between May 2008 and November 2013 were included in the study. The LAC group included patients who received 30 mg L 2*1, 1000 mg AMO 2*1, and 500 mg CLA 2*1 for 14 days, whereas the BPMT group was designed from patients who received 600 mg BS 2*1, 40 mg omeprazole (O) 2*1 or 30 mg L 2*1, 500 mg MET 3*1 and 500 mg TET 4*1. RESULTS: Demographic characteristics and endoscopic findings were similar in both groups. The eradication rate was 53.4% in the LAC group and 78.5% in the BPMT group (p<0.05). Compliance problems and side effects were significantly higher in the BPMT group as compared to the LAC group (p<0.05). CONCLUSION: Due to high antibiotic resistance in Turkey, the efficacy of LAC treatment has reduced. The BPMT protocol should be kept in mind in the first line of treatment, since it provides a higher eradication rate. PMID- 25931915 TI - Evaluation of reporting quality of the 2010 and 2012 National Surgical Congress oral presentations by CONSORT, STROBE and Timmer criteria. AB - OBJECTIVE: This study aimed to evaluate the abstracts of oral presentations that were accepted to the National Surgical Congress by CONSORT, STROBE and Timmer criteria and to recommend development of a national abstract assessment system. MATERIAL AND METHODS: Presentation scores were calculated for oral presentations that have been accepted to the 2010 and 2012 National Surgical Congresses and have been included in the digital congress abstract booklets by two independent reviewers who were blinded to information regarding both the author and the institution. The CONSORT and Timmer criteria were used for randomized controlled trials, and for observational studies the STROBE and Timmer criteria were used. The presentation score that was obtained by three different evaluation systems was accepted as the main variable. The score changes according to the two congresses, the influence of the reviewers on the presentation scores, and compatibility between the two reviewers were evaluated. Comparisons regarding study types and total presentation number were made by using the chi-square test, the compatibility between the total score of the presentations were made by the Mann-Whitney U test and the compatibility between the reviewers were evaluated by the Wilcoxon signed ranks test. RESULTS: There was no difference between the two Congresses in terms of study type distribution and total number of accepted presentations (p=0.844). The total scores of randomized controlled trials and observational studies from the 2010 and 2012 National Surgical Congresses that were evaluated by two independent reviewers with different assessment tools did not show any significant difference (p>0.05). A significant difference was observed between the reviewers in their evaluation by CONSORT, STROBE and Timmer criteria (p<0.05). CONCLUSION: Implementation of standard criteria for the evaluation of abstracts that are sent to congresses is important in terms of presentation reporting quality. The existing criteria should be revised according to national factors, in order to reduce the significant differences between reviewers. It is believed that discussions on a new evaluation system will be beneficial in terms of the development of a national assessment system. PMID- 25931916 TI - The predictive value of elastography in thyroid nodules and its comparison with fine-needle aspiration biopsy results. AB - OBJECTIVE: We aimed to evaluate the predictive value of elastography in determining malignancy during preoperative investigation of thyroid nodules and to compare its results with preoperative fine-needle aspiration biopsy (FNA) and postoperative histopathology results. MATERIAL AND METHODS: Among the group of patients who had indications for thyroidectomy between January 2013- September 2013 in the department of general surgery 86 euthyroid patients were prospectively included in the study. Informed consent was obtained from all patients. All patients received simultaneous thyroid ultrasonography and elastography by an experienced radiologist. The patients were classified into five scores according to Tsukuba scoring. Score 1 and 2 were evaluated as soft nodules (benign), score 3 as medium consistency (usually benign), and scores 4 and 5 as hard nodules (malignant). For statistical purposes, the FNA results were classified as benign, probably benign or malignant. The histopathological results were classified as benign or malignant. The results were compared with FNA and elastography findings. RESULTS: The fine-needle aspiration biopsy of the nodules revealed 60.5% benign, 17.4% high probability of benign, and 22.1% malignant cases; and the elastography diagnosed 38.4% benign, 23.3% high probability of benign, and 38.4% malignant nodules. The postoperative pathology evaluation diagnosed 67.4% of patients as benign, and 32.6% as malignant. The rate of detection of thyroid cancer cases (sensitivity) by elastography was 67.9%, the ability to distinguish healthy individuals (specificity) was 75.9%, and the overall adequacy of the method (accuracy) was determined as 73.3%. CONCLUSION: Elastography overlaps with especially benign cytology-pathology at a high rate, and provides definite diagnosis in 58% of malignant cases. In our study, elastography provided more reliable results than FNA, in terms of diagnosing malignancy. PMID- 25931917 TI - Response to trauma and metabolic changes: posttraumatic metabolism. AB - Stress response caused by events such as surgical trauma includes endocrine, metabolic and immunological changes. Stress hormones and cytokines play a role in these reactions. More reactions are induced by greater stress, ultimately leading to greater catabolic effects. Cuthbertson reported the characteristic response that occurs in trauma patients: protein and fat consumption and protection of body fluids and electrolytes because of hypermetabolism in the early period. The oxygen and energy requirement increases in proportion to the severity of trauma. The awareness of alterations in amino acid, lipid, and carbohydrate metabolism changes in surgical patients is important in determining metabolic and nutritional support. The main metabolic change in response to injury that leads to a series of reactions is the reduction of the normal anabolic effect of insulin, i.e. the development of insulin resistance. Free fatty acids are primary sources of energy after trauma. Triglycerides meet 50 to 80 % of the consumed energy after trauma and in critical illness. Surgical stress and trauma result in a reduction in protein synthesis and moderate protein degradation. Severe trauma, burns and sepsis result in increased protein degradation. The aim of glucose administration to surgical patients during fasting is to reduce proteolysis and to prevent loss of muscle mass. In major stress such as sepsis and trauma, it is important both to reduce the catabolic response that is the key to faster healing after surgery and to obtain a balanced metabolism in the shortest possible time with minimum loss. For these reasons, the details of metabolic response to trauma should be known in managing these situations and patients should be treated accordingly. PMID- 25931918 TI - Retrohepatic inferior vena cava reconstruction with saphenous vein patch in advanced stage cholangiocarcinoma. AB - Hepatic resection is the only known curative treatment option in primary and metastatic liver tumors. Unlike other types of malignancies, the response rate to even the best chemotherapy protocols is quite low in liver malignancies. Survival is expressed in months in untreated liver malignancies or in patients with residual tumor after resection. The optimal survival can be achieved only by liver resection with negative surgical margins. In order to increase the number of patients suitable for hepatic resection, techniques such as portal vein embolization, neoadjuvant chemotherapy, two-step hepatectomy, re-do hepatectomy, hypothermic liver perfusion have been developed and newer modalities are still being investigated. Primary liver malignancies like hepatocellular carcinoma and cholangiocarcinoma, and metastatic liver tumors can invade the retrohepatic vena cava due to anatomical proximity. Invasion of either the hepatocaval confluence or vena cava are often considered as contraindications for liver resection due to the risk of intraoperative massive air embolism or hemorrhage. In this article, we present a patient who underwent left hepatectomy together with vena cava resection and reconstruction with saphenous vein patch due to cholangiocarcinoma. PMID- 25931919 TI - Endometriosis externa within the rectus abdominis muscle. AB - The presence of endometrial glands and stroma outside the uterine cavity is called "endometriosis". Recklinghausen first defined this entity in 1896, and Sampson first named it in detail in 1921. Endometriosis is most often seen in the pelvis. Although extrapelvic endometriosis is rare, it can be seen in almost every organ. Endometriosis localized in the rectus abdominis muscle is very rare. A patient who had two previous cesarean sections presented with a 23 mm heterogeneous hypoechoic mass within the rectus abdominis muscle, approximately 1 cm superior to the Pfannenstiel incision that was diagnosed as endometriosis externa by fine-needle biopsy and excisional biopsy. Herein, we report this patient along with the literature. PMID- 25931920 TI - Treatment of sleeve gastrectomy leak with an endoscopic stent. AB - Laparoscopic sleeve gastrectomy is used increasingly for obesity treatment. The most important complications of this procedure are bleeding and staple line leak. In this article, a 44-year-old female patient who developed a leak at the gastro oesophageal junction following a revision laparoscopic sleeve gastrectomy is presented. The leak was recognized by computerized tomography and fluoroscopy that were performed during endoscopy. A fully expandable covered stent was inserted to the leak site. The stent was removed endoscopically after three weeks and the fistula healed completely. Early use of stents is an effective treatment method in leaks that have developed after sleeve gastrectomy. PMID- 25931921 TI - General surgeons and endoscopy training. PMID- 25931922 TI - Migration of two swallowed foreign bodies to different locations in the same case. AB - Foreign body ingestion can be seen at all ages, especially in childhood. Most swallowed foreign objects are disposed from the body without any health problems through defecation. It is rare that a foreign object perforates the intestine and migrates into the liver or peritoneum. In our case two unintentionally swallowed needles pierced the intestine and were located in the left lobe of the liver and small intestine mesentery. Foreign objects were detected in the abdomen of a 20 year-old female patient during examination performed for abdominal pain that lasted for three months. After a follow up period of three weeks the patient's complaints continued. She underwent laparotomy and both needles were removed in one session. It should be kept in mind that swallowed foreign objects can sometimes perforate the gastrointestinal system and may be located in different organs in the abdomen. PMID- 25931923 TI - Extramedullary plasmacytoma of the colon: a case report. AB - Extramedullary plasmacytoma is a rare cause of nonobstructive colonic masses, which is often disregarded. Plasmacytoma is a neoplastic proliferation of plasma cells; when systemic involvement occurs, the disease is named multiple myeloma. Extramedullary plasmacytomas comprise 4% of all plasma cell tumours and occur mainly in the upper respiratory tract; gastrointestinal system involvement is rare. In this case we describe a rare cause of gastrointestinal system mass: extramedullary plasmacytoma involving the left colon. PMID- 25931924 TI - Iatrogenic Zenker's diverticulum perforation: A conservatively treated case. AB - Zenker's diverticulum is the most common type of diverticulum in the esophagus. Most patients are elderly. Typical symptoms are regurgitation, dysphagia, halitosis and chronic cough. The most common treatments are open surgical diverticulectomy with cricopharyngeal myotomy or diverticulopexy. Most instances of esophageal perforation are iatrogenic. Rapid diagnosis and therapy provide the best chance for survival. If diagnosed early, cervical esophageal perforations can be treated conservatively if there are no signs of systemic sepsis. In this case report a conservatively treated cervical esophageal diverticulum perforation is presented. PMID- 25931925 TI - The importance of defecography in the assessment of the etiology of chronic constipation: An analysis of 630 patients. AB - OBJECTIVE: Chronic constipation is an entity with a high prevalence in the community. In our study, we analyzed the importance of defecography in the assessment of the etiology of chronic constipation. MATERIAL AND METHODS: Patients who were admitted to our hospital outpatient general surgery clinic with complaints of constipation between July 2010 and January 2014, and who had their demographic data and defecography results recorded were included in the study. The demographic data of patients who underwent defecography and their results were recorded along with patient gender and age. RESULTS: The defecography was abnormal in 573 patients (90.9%) while it was normal in 57 patients (9.1%). CONCLUSION: Defecography is the current standard method of examination in etiological investigations for constipation, and it should be performed in each patient with a diagnosis of chronic constipation. PMID- 25931926 TI - Does extracellular matrix of the varicose vein wall change according to clinical stage? AB - OBJECTIVE: The etiology and pathophysiology of chronic venous disease is not fully understood. This study aimed to determine the variation of the extracellular matrix proteins in varicose vein wall according to clinical stage. MATERIAL AND METHODS: Forty varicose and 10 control veins were sampled from the saphenofemoral junction. The Clinical Etiologic Anatomic Pathophysiologic (CEAP) classification was used in patients with varicose veins. Samples were stained with hematoxylin-eosin, Masson's trichrome, EVG (Elastica-van Gieson) stain and with laminin, fibronectin, tenascin antibodies. Stained samples were examined immuno-histochemically. Changes in extracellular matrix were determined semi quantitatively using light microscopy. RESULTS: It was observed that in the early stages (C2-C3) of chronic venous disease, fibrosis is increased in the intima and media layers, with fragmentation in lamina elastica interna, and increased tenascin expression in the intima layer. In advanced stages (C4-C6), the accumulation of tenascin in the intima continued along with fibrosis in the media layer, the thickness of the media layer increased and fibronectin deposition was observed. CONCLUSION: This study showed that changes first occur in the intima during the early stages of the disease with addition of alterations in the media layer at later stages. PMID- 25931927 TI - A comparison of single-port laparoscopic cholecystectomy and an alternative technique without a suspension suture. AB - OBJECTIVE: Many surgeons face difficulties during single-incision laparoscopic cholecystectomy (SILC) surgery and are forced to use an additional port. We compared the results of a technique that we developed with SILC. MATERIAL AND METHODS: Fifty-four patients who were diagnosed with chronic cholelithiasis were prospectively randomized and divided into two groups. An additional 5-mm port (MCAP: with an additional port using a multi-channel device through the umbilicus) was placed in the subxiphoid area instead of a transabdominal suspension suture in one group of patients. The other group was operated on with the SILC technique. The demographic and surgical data of the patients were compared. RESULTS: The MCAP technique shortened the surgery duration by more than half (MCAP: 35.0+/-12.3, SILC: 79.1+/-27.7 min) (p<0.05). No difference was found between the two methods in terms of estimated blood loss, length of hospitalization, postoperative day 1 and 7 visual analog scale scores, need for analgesia in the postoperative period, and rate of changing to another technique due to inadequacy of the surgical technique. CONCLUSION: MCAP is as safe as SILC for cholecystectomy and is easier for the surgeon to perform. PMID- 25931928 TI - The approach of general surgeons to the use of vessel sealing device in thyroid surgery. AB - OBJECTIVE: Vascular sealing devices (VSD) can be safely used in thyroid surgery. The purpose of this survey was to investigate general surgeons' approach to the use of VSD in thyroid surgery in Turkey. MATERIAL AND METHODS: A questionnaire containing 10 items was prepared and announced via the Dialogue in Endocrinology Society website. The results were then analyzed. RESULTS: Fifty surgeons (65.8%) stated that they always use VSD, 20 (26.3%) stated that they sometimes use these devices and six (7.9%) declared that they never use VSD. Thirty-six surgeons (47.4%) reported that they use ligation all the time, and 42 (55.3%) stated that upper pole vessels should be ligated at least once. Twenty two point four percent of the responders stated that they faced a complication, which they thought was related to VSD. CONCLUSION: The vast majority of surgeons routinely uses VSD and accepts it as a safe tool. However, the observed complication rate was very high. PMID- 25931929 TI - Is three-gland-or-less parathyroidectomy a clinical failure for secondary hyperparathyroidism? AB - OBJECTIVE: To compare the clinical and biochemical outcomes between adequate and inadequate parathyroidectomies in patients with chronic renal failure. MATERIAL AND METHODS: All secondary hyperparathyroidism patients who were previously operated in the Marmara University Hospital Breast and Endocrine Surgery Unit were planned to be included in the study. Patients were divided into two groups according to their extent of surgery: "adequate" and "inadequate" surgery groups. "Adequate surgery" was regarded as either subtotal (31/2) or total parathyroidectomy. Removing fewer than 31/2 parathyroids was defined as "inadequate surgery." Demographic, preoperative clinical symptoms, and their severity, as well as biochemical (e.g., tCa, PTH) findings, were recorded. Patients were followed monthly. The course of biochemical findings (tCa, PTH, P, ALP) and symptoms (by a scoring system of 1-4) was determined by comparing preoperative findings to those at the patient's last follow-up. Primary outcome of the study was treatment failure (biochemical persistence/recurrence) rates in both study cohorts. Secondary outcomes of the study were the levels of biochemical findings and improvement rates of clinical symptoms after parathyroidectomy, as well as complication rates related to the initial surgery in each surgery cohort. RESULTS: Forty-two patients with secondary hyperparathyroidism who underwent parathyroidectomy were included into the study. Twenty-six were male and 16 were female. Median age was 46. Forty (95%) patients had at least one symptom as the indication for surgery, whereas only 2 (5%) patients were asymptomatic, but biochemical findings were the indication. Twenty two (52%) patients underwent adequate operation, whereas 20 (48%) patients had inadequate operation. Mean follow-up duration after initial parathyroidectomy was 60 [3-244] months. Significantly more patients (n=15; 75%) in the inadequate surgery group had biochemical persistence/recurrence when compared with those (n=8; 36%) who underwent adequate surgery (OR [odds ratio] 5.25; 95% CI 1.38 19.93; p=0.012). However, symptom improvement rates were similar in both adequate and inadequate surgery groups. CONCLUSION: Although there is high biochemical treatment failure after inadequate parathyroidectomy in patients with renal hyperparathyroidism, clinical symptom improvement rates are also surprisingly high in this patient group. On the other hand, the adequate surgery group also had an increased biochemical failure rate well above expected in longer follow ups. PMID- 25931930 TI - The management of penetrating abdominal stab wounds with organ or omentum evisceration: The results of a clinical trial. AB - OBJECTIVE: The therapeutic approach to abdominal penetrating stab injuries has changed over the years from routine laparotomy to non-operative treatment. In case of organ or omental evisceration, although the laparotomy need is greater, non-operative treatment may be applied in selected cases. The aim of our study was to assess the follow-up and treatment outcomes of patients with organ or omental evisceration due to penetrating abdominal injuries. MATERIAL AND METHODS: Patients with organ or omental evisceration due to penetrating abdominal stab injuries were prospectively evaluated between April 2009 and July 2012. Emergent laparotomy was performed in cases that were hemodynamically unstable or had signs of organ evisceration or peritonitis, while other patients were managed conservatively. Patients' follow-up and treatment outcomes were assessed. RESULTS: A total of 18 patients with organ or omental evisceration were assessed. Six (33.3%) patients underwent emergent laparotomy, and 12 (66.7%) patients underwent conservative follow-up. Three patients in the emergent laparotomy group had signs of organ evisceration, and 3 had signs of peritonitis; five of these 6 patients underwent therapeutic laparotomy and 1 negative laparotomy. In the non operative follow-up group, therapeutic laparotomy was carried out in a total of 7 patients, 4 being early and 3 late, due to development of peritonitis, whereas 5 (27.8%) patients were managed non-operatively. CONCLUSION: Although organ or omental eviscerations due to penetrating abdominal stab injuries have a high rate of therapeutic laparotomy, selective conservative therapy is a safe method in selected cases. PMID- 25931931 TI - The retrospective documentation of legal cases with bile duct injury that were submitted for consideration to Istanbul Forensic Medicine Institute by the courts between 2008-2012. AB - OBJECTIVE: The aim was to evaluate the parameters that were considered by Forensic Medicine in bile duct injury as well as the issues that the physicians were found to be faulty. MATERIAL AND METHODS: The following parameters were investigated in 21 files that were referred to Istanbul Forensic Medicine Institute with request of expert opinion between 2008-2012; expert decisions, patient's age, gender, written patient consent, diagnosis, type of first surgery, surgical complications, timing of complication diagnosis within the scope of complication management, patient's referral timing, troubleshooting procedures and mortality rate. RESULTS: Physicians were found to be faulty in all files. The reason for physician fault was failure to show the necessary professional care and attention in one (4.7%) file, late recognition of injury and late transfer of the patient in 20 (95.3%) files. Written consent had not been obtained in any of the files. Thirteen patients were female (61.9%) and 8 (30.1%) were male, with a mean age of 43.3 years. Nineteen patients had cholelithiasis (90.4%), and two patients (9.5%) had a mass in the head of the pancreas. Cholecystectomy was performed laparoscopically in 15 patients (78.9%), and with open surgery in 4 patients (21.1%). The Whipple procedure was performed in two patients. The diagnosis was made during the operation in one patient (4.7%), and in the post operative period in 20 patients (95.3%). The time to diagnosis after surgery was between 3-6 days. All of the patients had been referred to third level health care facilities. The timing of transfer was 1 day in the patient who was diagnosed during the operation, and ranged between 4-10 days in those who were diagnosed postoperatively. Reasons for late referral were delays related to pending test results in 12 patients, vague signs in 3 patients, and following-up patients with the thought that the biliary fistula will heal by itself in 5 patients. Mortality was not observed in any of the examined files. CONCLUSION: The issues where physicians were most frequently found to be faulty were failure to obtain written patient consent, late recognition of injury and late transfer of the patient. PMID- 25931932 TI - Isolated cecal necrosis: our surgical experience and a review of the literature. AB - OBJECTIVE: Isolated cecal necrosis is a rare cause of ischemic colitis. Ischemic colitis is further divided into two groups: occlusive mesenteric ischemia and non occlusive mesenteric ischemia. The aim of this study was to investigate the cause of isolated cecal necrosis. MATERIAL AND METHODS: We operated on 3 male and 3 female patients with a mean age of 60.3+/-18.7 (38-85) years with a preliminary diagnosis of acute appendicitis between 2007 and 2012. Four of these patients were on hemodialysis, 1 patient had an aortofemoral bypass, and 1 patient had coronary artery disease with atrial fibrillation. RESULTS: The diagnosis was made intraoperatively in all cases. Five patients died postoperatively. One patient survived. CONCLUSION: In the case of right lower quadrant pain, the possibility of isolated cecal necrosis should be kept in mind, especially in patients on hemodialysis, elderly patients with diabetes, and heart disease; surgical strategies should be planned accordingly, and it should be understood that a high mortality rate will be inevitable. PMID- 25931933 TI - Organ preservation in rectal cancer patients following complete clinical response to neoadjuvant chemoradiotherapy: Long-term results in three patients. AB - Rectal cancer patients following complete clinical response to neoadjuvant chemoradiotherapy (CRT) can be followed up without surgery. Those patients in particular who needed abdominoperineal resection before CRT choose the follow-up protocol, should they be given the necessary information. The purpose of this study was to demonstrate the long-term follow-up results of patients following neoadjuvant CRT without surgery. PMID- 25931934 TI - A real mycotic aneurysm-mycotic aneurysm of the abdominal aorta due to fungal infection. AB - A 53-year-old male who was being followed up by a nephrology department because of type V crescentic glomerulonephritis was admitted with abdominal pain to our clinic. He was diagnosed with abdominal aortic aneurysm after the examinations. Aortic repair with a tubular graft was performed. Pathological examination of the aneurysm tissue showed fungal hyphae. We started antifungal chemotherapy with amphotericin B. A separation of the graft body occurred, and the patient was reoperated on. An excision of the graft, ligation of the aorta, and axillobifemoral graft by-pass was performed. At the 15(th) month of his discharge, the patient was readmitted to the emergency room of our clinic suffering from hematemesis. According to the examinations, an aortoduodenal fistula was diagnosed, and we performed a partial duodenal resection and end-to end duodenoduodenostomy. We want to share this unusual, interesting, and complicated case, operated on several times because of a mycotic aneurysm due to a fungal infection. PMID- 25931935 TI - Massive lower gastrointestinal bleeding from a jejunal Dieulafoy lesion. AB - Dieulafoy lesion should be considered in massive gastrointestinal bleeding that may be difficult to localize. If the endoscopic and angiographic approaches fail, surgery must be considered according to the patient's clinical condition within an appropriate time. Although mostly seen in the stomach of old male patients with co-morbidities, here we presented a Dieulafoy lesion in the jejunum of a 21 year-old female patient without any significant comorbidity. After endoscopic and angiographic attempts, surgical resection with the help of intraoperative endoscopy was performed. It was shown that perioperative endoscopy may reveal the localization of jejunal bleedings and may guide the definitive treatment. PMID- 25931936 TI - Malignant rhabdoid tumour in the stomach. AB - In this case report, a rare tumoral morphology in the gastrointestinal system is introduced. Malignant rhabdoid features are rarely observed in the gastrointestinal system but this discrimination is important due to the tumor's poor prognosis, aggressive behavior and early metastasis. PMID- 25931937 TI - Appendix mucocele mimicking a complex ovarian cyst. AB - Appendiceal mucocele is a rare entity which is characterized by cystic dilatation due to abnormal accumulation of mucus in the lumen of the appendix. Patients are often diagnosed incidentally by abdominal screening or abdominal surgery for other causes. Pain in the right lower quadrant of the abdomen, which may present as acute or chronic appendicitis, is the most common symptom of appendix mucocele, when the patient is symptomatic. This study describes the case of a 26 year-old female for whom surgical intervention for a complex ovarian cyst was planned, but who instead underwent laparoscopic appendectomy because appendiceal mucocele was determined during laparoscopic exploration. PMID- 25931938 TI - A retrospective analysis of 93 cases with anorectal abscess in a rural state hospital. AB - OBJECTIVE: Anorectal abscess is a clinical condition frequently encountered in daily surgical practice and recurrences may occur despite treatment with adequate incision and drainage. The primary aim of this study was to analyze the variables that may have resulted in recurrent anorectal abscess, retrospectively. MATERIAL AND METHODS: Ninety-three patients out of 149 patients who underwent surgery for anorectal abscess at our center between 2011-2012 were included in this study. Data regarding age, gender, presence of recurrence, time to recurrence, abscess type, presence of fistula, fistula type, drain usage, length of hospital stay and follow-up duration were retrospectively recorded. RESULTS: Patients were divided into two groups: the recurrence group and the treatment group. Eleven patients (11.8%) had a recurrence and the median time to recurrence was 3 months. None of the variables evaluated were found to be significantly associated with the presence of recurrence. CONCLUSION: Variables such as age, gender, type of abscess, presence of fistula or drain usage were not associated with the development of recurrence in patients who underwent incision and drainage of an anorectal abscess. PMID- 25931939 TI - A retrospective analysis of early and late term complications in patients who underwent application of retention sutures for gastrointestinal tract malignancies. AB - OBJECTIVE: Complications associated with wound healing after abdominal tumor operations continue to be a significant problem. This study aimed to determine the significance of retention sutures in preventing these complications. For this purpose, early and late term results of patients who underwent application of polydioxanone (PDS) and additional retention sutures for abdominal closure were retrospectively evaluated. MATERIAL AND METHODS: Clinical files of 172 patients who were operated due to gastrointestinal tract malignancies in our clinic between January 2007 and January 2011 were retrospectively analyzed. Patients in whom the fascia was repaired only with PDS (Group 1) were compared to patients in whom the fascia was repaired with PDS and retention sutures (Group 2) in terms of age, gender, postoperative evisceration-wound infection (<1 month), incisional hernia (>1 month), incision type, co-morbid factors, and operative time. RESULTS: There was no significant difference between the two groups in terms of age or gender (p=0.680 and p=0.763). No significant difference was detected in terms of postoperative incisional hernia (p=0.064). Evisceration and post-operative wound infection were significantly lower in Group 2 as compared to Group 1 (p=0.008 and p=0.002). Operative time was significantly longer in Group 1 than in Group 2 (p<0.0001). Co-morbid features were significantly higher in Group 2 than in Group 1 (p<0.0001). There were no significant differences between the groups in terms of incision type (p=0.743). CONCLUSION: In the presence of co-morbid factors that disrupt wound healing in surgical patients with gastrointestinal malignancy, retention suture can be safely used as a supplement for optimal wound care. PMID- 25931940 TI - Risk factors influencing morbidity and mortality in perforated peptic ulcer disease. AB - OBJECTIVE: Peptic ulcer perforation continues to be a major surgical problem. In this study, risk factors that influence morbidity and mortality in perforated peptic ulcer disease were examined. MATERIAL AND METHODS: Files of 148 patients who were included in the study due to peptic ulcer perforation between January 2006 and December 2010 were retrospectively analyzed. Data regarding age, gender, complaints, time elapsed between onset of symptoms and hospital admission, physical examination findings, co-morbid diseases, laboratory and imaging findings, length of hospital stay, morbidity and mortality were recorded. RESULTS: The study group included 129 (87.2%) male and 19 (12.8%) female patients. The mean age was 51.7+/-20 (15-88) years. Forty five patients (30.4%) had at least one co-morbid disease. In the postoperative period, 30 patients (20.3%) had complications. The most common complication was wound infection. Mortality was observed in 27 patients (18.2%). The most common cause of mortality was sepsis. Multivariate analysis revealed age over 60 years, presence of co morbidities and Mannheim peritonitis index as independent risk factors for morbidity. Age over 60 years, time to admission and Mannheim peritonitis index were detected as independent risk factors for mortality. CONCLUSION: Early diagnosis and proper treatment are important in patients presenting with peptic ulcer perforation. PMID- 25931941 TI - The effectiveness of gastric tonometry in the diagnosis of acute mesenteric ischemia in cases where a contrast-enhanced computed tomography cannot be obtained. AB - OBJECTIVE: The aim of the study was to evaluate the effectiveness of gastric tonometry in the diagnosis of acute mesenteric ischemia in cases where a contrast enhanced computed tomography cannot be obtained. MATERIAL AND METHODS: The gastric pH (pHi) and gastric CO2 (gpCO2) were measured with gastric tonometry catheter, preoperatively and postoperatively at 24 hours, in patients with suspicion of acute mesenteric ischemia. Simultaneous evaluation of blood gases and blood lactate levels were performed. Patients were divided into two groups after surgery. Group 1 included patients with mesenteric ischemia, and Group 2 consisted of patients without mesenteric ischemia. RESULTS: Forty-two patients (26 males, 16 females) were evaluated. The mean age was 61.4+/-13.3 years. There was no significant difference between the groups in terms of demographic factors and co-morbid diseases. There were no significant differences between groups in terms of pHi and gpCO2 levels (7.24+/-0.2 and -3+/-12.0 in Group 1, 7.18+/-0.06 and -3+/-1.9 in Group 2, respectively), intra-abdominal pressure, lactate levels, and survival. Among all the study parameters, only arterial pH had statistical significance in the diagnosis of acute mesenteric ischemia (7.23+/-0.21 versus 7.35+/-0.07 for Groups 1 and 2, respectively,) (p<0.05). CONCLUSION: Gastric tonometry is not a useful method in the early diagnosis of acute mesenteric ischemia. PMID- 25931942 TI - The adaptation process of a teaching and research hospital to changing trends in modern breast surgery. AB - OBJECTIVE: Minimally invasive surgery is increasingly gaining importance in breast surgery parallel to other surgical branches. Sentinel lymph node biopsy (SLNB) is a method that has radically changed the approach to breast surgery in the last decade of the 20(th) century. In this study, we aimed to evaluate the adaptation process to these alterations in breast surgery at our clinic. MATERIAL AND METHODS: Patients who underwent surgery with a diagnosis of breast cancer in our clinic between April 2010 and November 2013 were retrospectively evaluated in terms of demographic characteristics, the number of operations and type of surgical methods applied according to years, SLNB performance rate, and results of frozen section and histopathological analysis. The first year of SLNB practice was accepted as part of the learning curve, and 24 patients who were operated during that period underwent routine axillary dissection. RESULTS: The median age of 198 patients who were included in the study was 55 years (25-89). It was detected that the number of cases who underwent surgery for breast cancer increased in years, that the SLNB application rate increased from 37% to 66% between 2010 and 2013 (p=0.01), and SLNB staining rates increased from 70% to 94% (p=0.03). When only results from the last four years were evaluated, the mean staining rate in patients with SLNB (n=105) was 88% (n=92), with positive histopathology in 32% of these cases (n=30). Despite a decreasing trend over the years, a metastatic axillary lymph node was detected in paraffin block evaluation in spite of negative frozen section examination of SLNB in five cases, and 5 patients (5%) out of 97 patients who underwent breast conserving surgery required re-excision. The histopathological diagnosis was invasive ductal carcinoma in 84% (n=167) of patients. CONCLUSION: It was observed that during the four-year period of adaptation, the application rate of breast conserving surgery and SLNB reached accepted standards, and that both the technical problems encountered in SLNB and the requirement for re-excision after breast conserving surgery significantly decreased with increasing case volume and experience. PMID- 25931943 TI - Multidisciplinary breast cancer teams and proposed standards. AB - Multidisciplinary approach is recommended for the diagnosis and treatment of cancer, in order to optimize quality of life and survival. Multidisciplinary cancer teams that are used for this purpose enable communication between professionals. Multidisciplinary cancer meetings are pre-programmed regular meetings where cancer patients are evaluated on an individual basis, and where the multidisciplinary treatment of patients is planned based on evidence. Currently, application of appropriate treatment in a timely manner carries as great significance as early diagnosis. For this purpose, standards of multidisciplinary approach are significant. Disease specific multidisciplinary breast cancer meetings are essential in the treatment of breast cancer. The standards and organization of these teams have been scientifically determined. It is recommended that these multidisciplinary breast cancer meetings should be held regularly and the required infrastructure should be provided. PMID- 25931944 TI - Diagnosis of acute pancreatitis by diffusion-weighted magnetic resonance imaging. AB - Diffusion-weighted magnetic resonance imaging has emerged as a successful technique in the early diagnosis of acute pancreatitis. An 82-year-old male patient suspected of acute pancreatitis refused to undergo intravenous contrast enhanced abdominal computed tomography due to a history of previous allergic reactions to contrast medium. He was imaged with diffusion-weighted magnetic resonance imaging without the use of oral or intravenous contrast material. Diffuse hyperintensity in the pancreas with a relevant apparent diffusion coefficient map showing diffuse hypointensity was demonstrated. The findings were interpreted as restricted diffusion and were diagnostic for acute pancreatitis. Diffusion-weighted magnetic resonance imaging, an imaging modality that does not involve ionizing radiation and does not require the use of contrast material, can successfully demonstrate the manifestations of acute pancreatitis. PMID- 25931945 TI - Neonatal colonic perforation. AB - Neonatal colonic perforation is a rarely seen condition. Plain abdominal radiography of a 28-hour newborn consulted for vomiting and bloody stool revealed the presence of subdiaphragmatic free air, which necessitated surgical exploration. Transverse colonic perforation was detected during the exploration, and subsequently, a colostomy and appendectomy were performed. The postoperative follow-up period was uneventful. Necrotizing enterocolitis, Hirschsprung disease, and mechanical obstruction are some of the causes of colonic perforation during the neonatal period. Herein, we have shared a case of colonic perforation in an asphyctic newborn delivered after prolonged labor. PMID- 25931946 TI - Old-scar mass and changing surgical perspective: Sarcoidosis. AB - Sarcoidosis is a systemic inflammatory disease of an unknown etiology. Skin is involved in 25% of all cases, and 29% of them present as a scar sarcoidosis. Asymptomatic old-scar masses are generally regarded as a foreign body reaction by surgeons and often result in excisional biopsy. We describe a case of a patient who developed sarcoidosis in a 34-year-old appendectomy scar and adjacent inguinal lymph nodes without any local or systemic symptom and radiologic finding. Surgeons should not underestimate the importance of such lesions as a simple condition. Scar sarcoidosis may resolve spontaneously, or the treatment with some topical agents is effective. Furthermore, scar sarcoidosis may be the initial manifestation of systemic sarcoidosis. PMID- 25931947 TI - Papillary thyroid cancer located in the carotid bifurcation mimicking carotid body tumor. AB - The symptoms and examination findings of masses that are located in the neck region can mimic each other. Although conventional radiological methods are useful for diagnosis, the distinction between carotid body tumors and papillary thyroid cancer may be challenging. In order to eliminate this situation that may lead to technical problems during surgery, the differential diagnosis must be made carefully. The definitive diagnostic method is pathological evaluation of the excised lesion. Herein, a patient with papillary thyroid cancer mimicking carotid body tumor is presented along with the literature. PMID- 25931948 TI - What is the effect of treatment modality on red blood cell distribution width in patients with acute cholecystitis? AB - OBJECTIVE: The red blood cell distribution width (RDW) has recently been used as a marker to predict outcome in various patient groups. In this study, we aimed to examine how RDW is influenced during the treatment and follow-up of cases of acute cholecystitis which is a common inflammatory disease. MATERIAL AND METHODS: Seventy-two patients who were treated for acute cholecystitis, were included into the study. The demographic data, leukocyte count, RDW, C-reactive protein (CRP) values and treatment protocols of these patients were prospectively recorded. The patients who received medical treatment for acute cholecystitis (Group A, n=33) and those who underwent surgery (Group B, n=39) were examined in separate groups. RESULTS: There were 27 male and 45 female patients with a mean age of 50.1+/-18 years (min-max: 21-94). In Group B, 33 patients underwent laparoscopic cholecystectomy, whereas 6 patients underwent open cholecystectomy. The RDW values on admission were not significantly different between two groups. However the post-treatment/pre-discharge RDW values were significantly lower in the surgical group (14.4+/-1.9 to 13.6+/-1.1, respectively, p<0.05). Also, no significant RDW change was identified in the medical treatment group based on an intra-group assessment, whereas a significant decrease was observed in Group B (on admission and following surgical treatment: 14.3+/-1.3, 13.6+/-1.1, respectively, p=0.015). No significant differences were observed between groups in terms of CRP and leucocyte values. CONCLUSION: There was a significant decrease in RDW values in patients who were treated with surgery for acute cholecystitis, while this response could not be observed with medical treatment. PMID- 25931949 TI - Minimally invasive parathyroidectomy without using intraoperative parathyroid hormone monitoring or gamma probe. AB - OBJECTIVE: Minimal invasive parathyroidectomy (MIP) is a common surgical technique for the treatment of primary hyperparathyroidism (PHPT) and is usually done in conjunction with positive imaging techniques. We aimed to assess the results of this technique, performed without the use of intraoperative tests, in cases with PHPT caused by a single parathyroid adenoma. MATERIAL AND METHODS: The data for patients who were diagnosed with PHPT were assessed retrospectively. Only those who had undergone a parathyroid adenoma localization study with ultrasonography (US) and parathyroid scintigraphy (PS) before the surgery, along with those patients for whom the MIP technique was routinely performed with frozen pathology, were included. RESULTS: The study group was made up of 65 patients who had undergone the MIP technique. The mean age of the patients was 56+/-14 (20-81), with most being females [M/F: 19 (29.2%)/46 (70.8%)]. The mean calcium values before the operation were 11.24+/-1.26 mg/dL (8-15.5) (normal range: 8.4-10.2), and the parathyroid hormone (PTH) values were 388 pg/mL (249 707.75). These same values, measured 24 hours after the operation, were determined as 9.04+/-1.04 mg/dL (6.8-13.9) and 27 pg/mL (6-86), respectively. The follow-up period for the patients was an average of 26.6+/-9.4 (3-76) months, and only 3 (4.6%) cases of persistent hyperparathyroidism were detected within this period. CONCLUSION: Our success rate with MIP in PHPT cases was determined to be 95.4%; therefore, this technique may be applied with a high success rate without any assistance from intraoperative tests, such as rapid serum PTH (rPTH) assays or gamma probes, in the presence of localization results of PS and US. PMID- 25931950 TI - Review of our ileal pouch experience in the light of literature. AB - OBJECTIVE: Retrospective proctocolectomy is a distinguished, sphincter saving treatment used for the treatment of ulcerative colitis and FAP disease. We aimed to evaluate ileal pouch interventions performed at our clinic and their results in the light of literature. MATERIAL AND METHODS: Medical records of 35 restorative proctocolectomy and J pouch ileo-anal anastomosis surgeries performed at Necmettin Erbakan University, Meram School of Medicine between the years 2006 2013 were retrospectively examined. The patients were assessed according to their age, gender, length of hospital stay, diagnosis, follow-up duration and pouch related complications. All patients were contacted by phone and they were scheduled for controls at the outpatient clinic. RESULTS: Nineteen patients were male (54%) and 16 were female (46%). Their mean age was 45 years (21-74). The mean length of hospital stay was 11 (5-20) days. Twenty two (63%) patients were operated on due to FAP, 12 (34%) due to synchronous rectum cancer and colon tumor or polyp, and one (3%) due to ulcerative colitis. All patients received J pouch and protective ileostomy. After the closure of ileostomy, two cases were identified to have J pouch fistulas. The patients were followed up for 6 months to 7 years. They were contacted by phone and they were questioned about their active complaints, number of defecations, urinary and sexual dysfunctions. It was identified that they had 5 (3-8) defecations per day on average and that 4 (11%) cases had one nocturnal defecation. No pouchitis was identified in the follow-up endoscopic examinations. CONCLUSION: Restorative proctocolectomy and ileo-anal anastomosis technique is a surgical procedure that can be performed with low rates of morbidity and mortality, including the elderly. PMID- 25931951 TI - Unresectable pancreatic adenocarcinoma with complete clinical response following chemoradiotherapy. AB - Locally advanced or metastatic disease is present in 2/3s of patients with pancreatic cancer. Pancreatic cancer patients are assessed as resectable, potentially resectable (borderline) and unresectable according to pre-operative examinations. The chance for operability may be enhanced by using adjuvant neoadjuvant systemic chemotherapy, radiotherapy or both. The rates of R0 resection may be increased by means of treatment delivered this way. This case report presents a pancreatic adenocarcinoma case that was assessed to be resectable but was identified to be unresectable during surgical exploration, thus received adjuvant chemoradiotherapy. The patient was then re-evaluated, identified as resectable and received pancreaticoduodenectomy. PMID- 25931952 TI - Cyphastreakausti sp. n. (Cnidaria, Anthozoa, Scleractinia), a new species of reef coral from the Red Sea. AB - A new scleractinian coral species, Cyphastreakausti sp. n., is described from 13 specimens from the Red Sea. It is characterised by the presence of eight primary septa, unlike the other species of the genus, which have six, ten or 12 primary septa. The new species has morphological affinities with Cyphastreamicrophthalma, from which it can be distinguished by the lower number of septa (on average eight instead of ten), and smaller calices and corallites. This species was observed in the northern and central Red Sea and appears to be absent from the southern Red Sea. PMID- 25931953 TI - Two new species of the Clubionacorticalis-group from Yunnan Province, China (Araneae, Clubionidae). AB - The present paper describes two new Clubionacorticalis-group species collected from Xishuangbanna, Yunnan Province of China: Clubionasubmoralis sp. n. (??) and Clubionapollicaris sp. n. (??). PMID- 25931954 TI - A faunistic study on the leafhoppers of northwestern Iran (Hemiptera, Cicadellidae). AB - The leafhopper fauna of northwestern Iran: Azarbaijan-e-Sharghi, Azarbaijan-e Gharbi and Ardabil provinces is listed from previously published records and from our current work. Sixty-nine species are included with four species (Mogangellastraminea Dlabola, 1957, Doraturastylata (Boheman, 1847), Macrostelessordidipennis (Stal, 1858) and Psammotettixseriphidii Emeljanov, 1962) listed as new for Iran and Balcluthapunctata (Fabricius, 1775), as a new record for the region. A distribution map of the species in northwestern Iran is given. PMID- 25931955 TI - First record of Jacobsoniidae (Coleoptera) from China with description of a new species of Sarothrias Grouvelle. AB - The family Jacobsoniidae Heller () is newly recorded from China upon the discovery of Sarothriassinicus Bi & Chen, sp. n. () from Motuo, Southeast Xizang. Description and illustrations of the habitus and major diagnostic features of the new taxon are provided. A key to the species of Sarothrias and some ecological notes on the new species are presented. PMID- 25931956 TI - Description of a new species of Wormaldia from Sardinia and a new Drusus species from the Western Balkans (Trichoptera, Philopotamidae, Limnephilidae). AB - New species are described in the genera Wormaldia (Trichoptera, Philopotamidae) and Drusus (Trichoptera, Limnephilidae, Drusinae). Additionally, the larva of the new species Drususcrenophylax sp. n. is described, and a key provided to larval Drusus species of the bosnicus-group, in which the new species belongs. Observations on the threats to regional freshwater biodiversity and caddisfly endemism are discussed. The new species Wormaldiasarda sp. n. is an endemic of the Tyrrhenian island of Sardinia and differs most conspicuously from its congeners in the shape of segment X, which is trilobate in lateral view. The new species Drususcrenophylax sp. n. is a micro-endemic of the Western Balkans, and increases the endemism rate of Balkan Drusinae to 79% of 39 species. Compared to other Western Balkan Drusus, males of the new species are morphologically most similar to Drususdiscophorus Radovanovic and Drususvernonensis Malicky, but differ in the shape of superior and intermediate appendages. The females of Drususcrenophylax sp. n. are most similar to those of Drususvernonensis, but differ distinctly in the outline of segment X. Larvae of Drususcrenophylax sp. n. exhibit toothless mandibles, indicating a scraping grazing-feeding ecology. PMID- 25931957 TI - Two new Neuratelia Rondani (Diptera, Mycetophilidae) species from Western Palaearctic: a case of limited congruence between morphology and DNA sequence data. AB - Two new Mycetophilidae species, Neurateliajabalmoussae sp. n. and Neurateliasalmelai sp. n. are described on the basis of material collected from Lebanon, Estonia and Finland. Detailed figures of male terminalia and photographs of general facies are provided along with discussions of their morphological distinction from sibling species. For the first time molecular characters are used to distinguish new fungus gnat species. Molecular analysis relies on cytochrome oxidase subunit one (COI) but has additionally been corroborated by information from the 28S and ITS2 regions of nuclear ribosomal DNA. Situations where morphological and molecular data provide conflicting evidence for species delimitation are discussed. A new country record from Georgia is provided for Neurateliacaucasica. PMID- 25931958 TI - New records of Muscidae (Diptera) from Mediterranean countries. AB - New records are provided for Muscidae from four different Mediterranean countries, with new distribution records for species in ten different genera. Seven species are newly recorded for Croatia, four species for Montenegro and one species for Bosnia & Herzegovina. In this paper we give the first confirmation of an aquatic larval stage for Lispocephalabrachialis (Rondani, 1877), Lispocephalaspuria (Zetterstedt, 1838) and Lispocephalamikii (Strobl, 1893). A first record of the species Coenosialyneborgi Pont, 1972 since its original description is also provided. PMID- 25931959 TI - Identification guide to some Diaptomid species (Crustacea, Copepoda, Calanoida, Diaptomidae) of "de la Plata" River Basin (South America). AB - An identification guide is presented for species of calanoid copepod family Diaptomidae from "de la Plata" River Basin (Argentina, Brazil, Bolivia, Paraguay and Uruguay). It was based on material collected during the summer and winter of 2010 from 43 sites across the eastern part and the lower stretches of this basin, the second largest in South America and the fourth in the world. The guide contains identification keys and species diagnoses for males and females, richly supported by scanning electronic micrographs and/or line drawings of 19 species. It also includes some general remarks on the taxonomy and phylogenetic relationships of these species. The key was adjusted to be useful for these species only, with separate keys for each sex, and is the first for females of South America. One species classified herein as incertae sedis was not included in the analysis. At least ten other species have previously been recorded in the basin but were not present in our samples. This is the first attempt to compile comprehensive taxonomic information on this group of copepods in this region, and it is expected to become a useful tool for biologists and young taxonomists interested in the crustacean biota of the Neotropical region. PMID- 25931960 TI - One new species of the genus Savarna Huber, 2005 (Araneae, Pholcidae) from southern Thailand. AB - One new species Savarnakraburiensis sp. n. (??) is reported from southern Thailand. PMID- 25931961 TI - A new genus and species of native exotic millipede in Australia (Diplopoda, Polydesmida, Paradoxosomatidae). AB - Taxidiotisomaportabile gen. n., sp. n. is described from scattered populations in New South Wales, Victoria and Tasmania, Australia. Populations of Taxidiotisomaportabile in Victoria, Tasmania and parts of New South Wales occur in urban, suburban and agricultural areas, with no collections of the species in natural habitats in the same district. Taxidiotisomaportabile is likely to be a native exotic species whose home range is in eastern New South Wales. PMID- 25931962 TI - Two new species of Coecobrya (Collembola, Entomobryidae) from China, with an updated key to the Chinese species of the genus. AB - Two new Coecobrya species, which were newly collected in 2014, are described from China. Coecobryasanmingensis sp. n. from southeast China (Fujian) is the fourth 1+1 eyed species in the genus; it can be distinguished from other three species by the ciliate chaetae X and X2-4 on the ventral side of head, the abundant chaetae on the trochanteral organ, a large outer tooth on the unguiculus, the absence of smooth manubrial chaetae, and the dorsal chaetotaxy. Coecobryaqinae sp. n. from southwest China (Yunnan) is characterized by paddle-like S-chaetae of Ant. III organ, ciliate chaetae X, X2 and X4 posterior to labium, medial macrochaetae on the mesothorax, and 5+5 central and 2+2 lateral macrochaetae on the fourth abdominal segment. An updated key to the Chinese species of Coecobrya is given. PMID- 25931963 TI - Two new species of Oobius Trjapitzin (Hymenoptera, Encyrtidae) egg parasitoids of Agrilus spp. (Coleoptera, Buprestidae) from the USA, including a key and taxonomic notes on other congeneric Nearctic taxa. AB - Oobius Trjapitzin (Hymenoptera, Encyrtidae) species are egg parasitoids that are important for the biological control of some Buprestidae and Cerambycidae (Coleoptera). Two species, Oobiusagrili Zhang & Huang and Oobiuslongoi (Siscaro), were introduced into North America for classical biocontrol and have successfully established. Two new native North American species that parasitize eggs of Agrilus spp. (Buprestidae) are described and illustrated from the USA: Oobiusminusculus Triapitsyn & Petrice, sp. n. (Michigan), an egg parasitoid of both Agrilussubcinctus Gory on ash (Fraxinus spp.) and Agrilusegenus Gory on black locust (Robiniapseudoacacia L.) trees, and Oobiuswhiteorum Triapitsyn, sp. n. (Pennsylvania), an egg parasitoid of Agrilusanxius Gory on European white birch (Betulapendula Roth). A taxonomic key and notes on the Nearctic native and introduced Oobius species are also included. PMID- 25931964 TI - New distribution records for Canadian Aleocharinae (Coleoptera, Staphylinidae), and new synonymies for Trichiusa. AB - Fifty-four new Canadian provincial records of aleocharine beetles (Staphylinidae), including three new Canadian records and one new North American record, are presented. Of these, 33 are new provincial records for Saskatchewan, 14 for Alberta, two for British Columbia, three for Manitoba, two for the Northwest Territories and one for the Yukon Territory. The following are new Canadian records: Trichiusapilosa Casey [formerly reported from Nova Scotia and Ontario as Trichiusapostica Casey], Acrotonarecondita (Erichson) and the adventive Palaearctic Athetanigra (Kraatz), which is also a new North American record. Bionomics information and new locality records are provided. The following new synonyms of Trichiusapilosa Casey are established: Trichiusaatra Casey, Trichiusamonticola Casey, Trichiusaparviceps Casey, and Trichiusapostica Casey. The numbers of Aleocharinae remaining to be discovered in Canadian provinces and territories are discussed. PMID- 25931965 TI - Rediscovery of Rhabdomastix (Rhabdomastix) incapax Stary, 2005 (Diptera, Limoniidae), a crane fly species flightless in both sexes and probably endemic to Sardinia. AB - Rediscovery of Rhabdomastix (Rhabdomastix) incapax Stary, 2005 in Sardinia made it possible to update the description of the male and to provide the first description of the female of this species. Notes on the wing reduction, ecology, and behaviour of this species are appended. PMID- 25931966 TI - Reptiles of Chubut province, Argentina: richness, diversity, conservation status and geographic distribution maps. AB - An accurate estimation of species and population geographic ranges is essential for species-focused studies and conservation and management plans. Knowledge of the geographic distributions of reptiles from Patagonian Argentina is in general limited and dispersed over manuscripts from a wide variety of topics. We completed an extensive review of reptile species of central Patagonia (Argentina) based on information from a wide variety of sources. We compiled and checked geographic distribution records from published literature and museum records, including extensive new data from the LJAMM-CNP (CENPAT-CONICET) herpetological collection. Our results show that there are 52 taxa recorded for this region and the highest species richness was seen in the families Liolaemidae and Dipsadidae with 31 and 10 species, respectively. The Patagonica was the phytogeographic province most diverse in species and Phymaturus was the genus of conservation concern most strongly associated with it. We present a detailed species list with geographical information, richness species, diversity analyses with comparisons across phytogeographical provinces, conservation status, taxonomic comments and distribution maps for all of these taxa. PMID- 25931968 TI - A revision of the Neotropical caddisfly genus Leucotrichia Mosely, 1934 (Hydroptilidae, Leucotrichiinae). AB - A revision of Leucotrichia (Trichoptera, Hydroptilidae) is provided, including a generic diagnosis, illustrations, a key, and descriptions of males. A total of 43 species are treated, 13 described as new: Leucotrichiaangelinae sp. n. (Venezuela), Leucotrichiadenticulata sp. n. (Mexico), Leucotrichiadianeae sp. n (Costa Rica), Leucotrichiafulminea sp. n. (Ecuador), Leucotrichiahispida sp. n. (Costa Rica), Leucotrichiakateae sp. n. (Venezuela), Leucotrichiapectinata sp. n. (Ecuador), Leucotrichiaprocera sp. n. (Brazil), Leucotrichiarepanda sp. n. (Venezuela), Leucotrichiarhomba sp. n. (Costa Rica), Leucotrichiariostoumae sp. n. (Ecuador), Leucotrichiasidneyi sp. n. (Venezuela), and Leucotrichiatapantia sp. n. (Costa Rica). PMID- 25931967 TI - A new species of Hisonotus (Siluriformes, Loricariidae) from rio Sao Francisco basin, Brazil. AB - A new species of Hisonotus is described from the rio Sao Francisco basin. The new species can be distinguished from congeners by having (1) a unique coloration pattern of caudal fin with one black spot extending from its origin to the ventral lobe and two dark spots at the end of the lobe's rays; (2) odontodes forming longitudinally aligned rows on head and trunk; (3) a functional V-shaped spinelet; (4) a single rostral plate at the tip of the snout; (5) by lacking contrasting dark geometric spots on the anterodorsal region of the body; (6) a lower caudal-peduncle depth; and (7) lower counts of the lateral median plates and (8) higher premaxillary and dentary teeth. The new species is the second described species of the genus Hisonotus in the rio Sao Francisco basin. It was found inhabiting the marginal vegetation of the rio Sao Francisco and three of its tributary, rio das Velhas, rio Paraopeba and rio Formoso. PMID- 25931969 TI - Two new species of endemic Ecuadorean Amaryllidaceae (Asparagales, Amaryllidaceae, Amarylloideae, Eucharideae). AB - New species of the genera Stenomesson and Eucharis (Amaryllidaceae) are described from Ecuador. Stenomessonecuadorense is the second species of the genus reported from that country, and the only endemic one. It is related to Stenomessonminiatum and Stenomessoncampanulatum, both from Peru, with which it shares orange flower color and the fusion of the staminal corona to the perianth tube. It differs from Stenomessonminiatum by the non-urceolate perianth, from Stenomessoncampanulatum by its shorter stamens and longer perianth, and from both by its lower montane, cloud forest habitat. Eucharisruthiana, found in the vicinity of Zamora, is related to Eucharismoorei from which it differs by the narrower leaves and tepals; short, deeply cleft staminal corona; the long teeth on either side of the free filaments; the narrowly subulate, incurved free filaments; and the shorter style. The green mature fruit and campanulate floral morphology place it in Eucharissubg.Heterocharis. PMID- 25931970 TI - Psephellusvanensis (Asteraceae), a new species from east Turkey. AB - A new species, Psephellusvanensis A.Duran, Behcet & B.Dogan (Asteraceae) from Anatolia, Turkey, is described and illustrated. The species grows on the serpentine stony field of the village of Caldiran in the district of Baskale (Van province) in eastern Anatolia. It is morphologically similar to Psephelluspyrrhoblepharus (Boiss.) Wagenitz. Diagnostic characters are discussed, and a key to the most similar species is provided. Ecology, conservation status and notes on biogeography of the species are also presented. In addition, the geographical distribution of the new species and other related species in Turkey is mapped. PMID- 25931971 TI - Dianthusaticii, a new species from Turkey (Caryophyllaceae). AB - During the taxonomic revision of the Turkish Dianthus species, specimens collected from Bilecik, Seben (Bolu), and Nallihan (Ankara) were discovered that represent a new species. Its description, images, chorology, ecology, and threat category are provided. It was compared with a closely related species, Dianthuszonatus, and differences are based on its general morphology and seed micromorphology. PMID- 25931972 TI - Paepalanthusserpens, a new microendemic species of Eriocaulaceae from the Espinhaco Range, Minas Gerais, Brazil. AB - We describe and illustrate Paepalanthusserpens, a microendemic species of Eriocaulaceae from the Espinhaco Range. The species is known from a single population growing in rocky areas of the Serra do Cipo, Minas Gerais. It is placed in Paepalanthusser.Paepalanthus, and is easily distinguished from its congeneric species by its elongated, lignescent stem, thickened by the marcescent sheaths of the linear leaves, which are arranged in a rosette at the stem apex, scapes equalling the leaf height, and capitulae with straw-coloured involucral bracts. Comparisons with the morphologically similar species are provided, as well as comments on distribution, ecology, phenology and conservation status. PMID- 25931973 TI - Clarifying the Dioscoreabuchananii Benth. species complex: a new potentially extinct subspecies for South Africa. AB - The Dioscoreabuchananii complex is shown to comprise three species, one of which is divided into two subspecies, based on morphological data. Two species, Dioscorearupicola Kunth and Dioscoreamultiloba Kunth, are endemic or subendemic to South Africa and of widespread occurrence in KwaZulu Natal. They differ markedly from each other in inflorescence and floral morphology and appear to be ecologically differentiated. The third species, Dioscoreabuchananii Benth., is primarily found in southeastern tropical Africa, but a small number of specimens collected in South Africa in the late 19(th) and early 20(th) centuries are placed in an endemic subspecies, Dioscoreabuchananiisubsp.undatiloba (Baker) Wilkin. The latter taxon is a high priority in terms of rediscovery and conservation. Keys, descriptions, supporting information and illustrations are provided and made available online through eMonocot biodiversity informatics tools. Three nomenclatural acts are undertaken: two names are placed in synonymy and a new combination made. PMID- 25931975 TI - Potato research achievement and challenges. PMID- 25931974 TI - A refined concept of the Critoniopsisbogotana species group in Colombia with two new species (Vernonieae, Asteraceae). AB - Critoniopsisbogotana is more precisely delimited, and two related Colombian species are described as new. The form of trichomes on the abaxial surfaces of the leaves is found to be of major importance. A short key to the Critoniopsisbogotana group is provided. PMID- 25931976 TI - Challenges of breeding potato cultivars to grow in various environments and to meet different demands. AB - The potato (Solanum tuberosum L.) is cultivated all year round in Japan by using four types of cropping: summer and winter croppings, and double cropping in spring and fall. In each cropping season, growth conditions such as temperature, day length, and growing period, differ drastically; thus, different cultivars adapted to each environment are required. Breeding stations are located in both summer cropping areas and double cropping areas, and cultivars suitable for each cropping system are developed. The required cultivars differ according to cropping type and according to use such as table use, food processing, and starch production. The qualities necessary for each purpose differ and are therefore evaluated accordingly. Improvements in pest and disease resistance and in yield abilities are important as common breeding targets for all purposes. To develop potato cultivars that meet different needs, breeders have continued efforts to improve these traits. In this review, we introduce our approaches to developing new potato cultivars. We also discuss problems predicted in the future and introduce our efforts on broadening genetic diversity. PMID- 25931977 TI - Seed potato production system in Japan, starting from foundation seed of potato. AB - Potato is one of the staple crops cultivated in upland farming in Japan and is propagated vegetatively by means of tubers. However once infected with diseases, potato yield decreases significantly. And one seed potato can produce approximately only 10 potato tubers. To improve the production system of seed potatoes in Japan, Japanese government established a three-stage propagation system for the production and distribution of healthy and disease-free seed potatoes. The National Center for Seeds and Seedlings (NCSS) has a role for the production of foundation seed potatoes and strictly manages the production in isolated fields that are treated thoroughly to control pests and diseases. Recently though the distribution of foundation seed potatoes is decreasing, the number of varieties of foundation seed potatoes has increased steadily. And new varieties of potato adapted various requirements, including resistance of the golden potato cyst nematode, have been increasing. Therefore, NCSS is introducing a new method of producing minitubers (MnTs) by using hydroponic cultivation greenhouse to increase the efficiency of propagation and to rapidly disseminate these new potato varieties. In this review, we describe a seed potato production system in Japan and the production of foundation seed potatoes as an important role of NCSS. PMID- 25931978 TI - Diversity of potato genetic resources. AB - A considerable number of highly diverse species exist in genus Solanum. Because they can adapt to a broad range of habitats, potato wild relatives are promising sources of desirable agricultural traits. Potato taxonomy is quite complex because of introgression, interspecific hybridization, auto- and allopolyploidy, sexual compatibility among many species, a mixture of sexual and asexual reproduction, possible recent species divergence, phenotypic plasticity, and the consequent high morphological similarity among species. Recent researchers using molecular tools have contributed to the identification of genes controlling several types of resistance as well as to the revision of taxonomical relationships among potato species. Historically, primitive forms of cultivated potato and its wild relatives have been used in breeding programs and there is still an enormous and unimaginable potential for discovering desirable characteristics, particularly in wild species Different methods have been developed to incorporate useful alleles from these wild species into the improved cultivars. Potato germplasm comprising of useful alleles for different breeding objectives is preserved in various gene banks worldwide. These materials, with their invaluable information, are accessible for research and breeding purposes. Precise identification of species base on the new taxonomy is essential for effective use of the germplasm collection. PMID- 25931979 TI - Cryopreservation for preservation of potato genetic resources. AB - Cryopreservation is becoming a very important tool for the long-term storage of plant genetic resources and efficient cryopreservation protocols have been developed for a large number of plant species. Practical procedures, developed using in vitro tissue culture, can be a simple and reliable preservation option of potato genetic resources rather than maintaining by vegetative propagation in genebanks due their allogamous nature. Cryopreserved materials insure a long-term backup of field collections against loss of plant germplasm. Occurrence of genetic variation, in tissue culture cells during prolonged subcultures, can be avoided with suitable cryopreservation protocols that provide high regrowth, leading and facilitating a systematic and strategic cryo-banking of plant genetic resources. Cryopreservation protocols for potato reviewed here, can efficiently complement field and in vitro conservation, providing for preservation of genotypes difficult to preserve by other methods, wild types and other species decided as priority collections. PMID- 25931980 TI - Potato genetics, genomics, and applications. AB - Potato has a variety of reproductive uniquenesses besides its clonal propagation by tubers. These traits are controlled by a different kind of genetic control. The reproductive information has been applied to enable interspecific hybridization to enhance valuable traits, such as disease and pest resistances, from the tuber-bearing Solanum gene pool. While progress has been made in potato breeding, many resources have been invested due to the requirements of large populations and long time frame. This is not only due to the general pitfalls in plant breeding, but also due to the complexity of polyploid genetics. Tetraploid genetics is the most prominent aspect associated with potato breeding. Genetic maps and markers have contributed to potato breeding, and genome information further elucidates questions in potato evolution and supports comprehensive potato breeding. Challenges yet remain on recognizing intellectual property rights to breeding and germplasm, and also on regulatory aspects to incorporate modern biotechnology for increasing genetic variation in potato breeding. PMID- 25931981 TI - Elucidation of virus-host interactions to enhance resistance breeding for control of virus diseases in potato. AB - Potato virus Y (PVY) and Potato mop-top virus (PMTV) are viruses whose geographical distribution is expanding and economic losses are increasing, in contrast to most of other viruses infecting potato crops. Most potato cultivars lack broad-spectrum resistance to the new, genetically complex strains of PVY, and no efficient resistance to PMTV is known in potato. Control of the vectors of these viruses is not an efficient or possible strategy to prevent infections. Studies on molecular virus-host interactions can discover plant genes that are important to viral infection or antiviral defence. Both types of genes may be utilized in resistance breeding, which is discussed in this paper. The advanced gene technologies provide means to fortify potato cultivars with effective virus resistance genes or mutated, non-functional host factors that interfere with virus infection. PMID- 25931982 TI - Potato yield enhancement through intensification of sink and source performances. AB - The combined total annual yield of six major crops (maize, rice, wheat, cassava, soybean, and potato; Solanum tuberosum L.) amounts to 3.1 billion tons. In recent years, staple crops have begun to be used as substitutes for fossil fuel and feedstocks. The diversion of crop products to fuels and industrial feedstocks has become a concern in many countries because of competition for arable lands and increased food prices. These concerns are definitely justified; however, if plant biotechnology succeeds in increasing crop yields to double the current yields, it will be possible to divert the surplus to purposes other than food without detrimental effects. Maize, rice, wheat, and soybean bear their sink organs in the aerial parts of the plant, and potato in the underground parts. Plants with aerial storage organs cannot accumulate products beyond their capacity to support the weight of these organs. In contrast, potato has heavy storage organs that are supported by the soil. In this mini-review, we introduce strategies of intensifying potato productivity and discuss recent advances in this research area. PMID- 25931984 TI - Molecular and genealogical analysis of grain dormancy in Japanese wheat varieties, with specific focus on MOTHER OF FT AND TFL1 on chromosome 3A. AB - In the wheat (Triticum aestivum L.) cultivar 'Zenkoujikomugi', a single nucleotide polymorphism (SNP) in the promoter of MOTHER OF FT AND TFL1 on chromosome 3A (MFT-3A) causes an increase in the level of gene expression, resulting in strong grain dormancy. We used a DNA marker to detect the 'Zenkoujikomugi'-type (Zen-type) SNP and examined the genotype of MFT-3A in Japanese wheat varieties, and we found that 169 of 324 varieties carry the Zen type SNP. In Japanese commercial varieties, the frequency of the Zen-type SNP was remarkably high in the southern part of Japan, but low in the northern part. To examine the relationship between MFT-3A genotype and grain dormancy, we performed a germination assay in three wheat-growing seasons. On average, the varieties carrying the Zen-type SNP showed stronger grain dormancy than the varieties carrying the non-Zen-type SNP. Among commercial cultivars, 'Iwainodaichi' (Kyushu), 'Junreikomugi' (Kinki-Chugoku-Shikoku), 'Kinuhime' (Kanto-Tokai), 'Nebarigoshi' (Tohoku-Hokuriku), and 'Kitamoe' (Hokkaido) showed the strongest grain dormancy in each geographical group, and all these varieties, except for 'Kitamoe', were found to carry the Zen-type SNP. In recent years, the number of varieties carrying the Zen-type SNP has increased in the Tohoku-Hokuriku region, but not in the Hokkaido region. PMID- 25931983 TI - Review of recent transgenic studies on abiotic stress tolerance and future molecular breeding in potato. AB - Global warming has become a major issue within the last decade. Traditional breeding programs for potato have focused on increasing productivity and quality and disease resistance, thus, modern cultivars have limited tolerance of abiotic stresses. The introgression of abiotic stress tolerance into modern cultivars is essential work for the future. Recently, many studies have investigated abiotic stress using transgenic techniques. This manuscript focuses on the study of abiotic stress, in particular drought, salinity and low temperature, during this century. Dividing studies into these three stress categories for this review was difficult. Thus, based on the study title and the transgene property, transgenic studies were classified into five categories in this review; oxidative scavengers, transcriptional factors, and above three abiotic categories. The review focuses on studies that investigate confer of stress tolerance and the identification of responsible factors, including wild relatives. From a practical application perspective, further evaluation of transgenic potato with abiotic stress tolerance is required. Although potato plants, including wild species, have a large potential for abiotic stress tolerance, exploration of the factors responsible for conferring this tolerance is still developing. Molecular breeding, including genetic engineering and conventional breeding using DNA markers, is expected to develop in the future. PMID- 25931985 TI - Zn isotope fractionation in a pristine larch forest on permafrost-dominated soils in Central Siberia. AB - Stable Zn isotopes fractionation was studied in main biogeochemical compartments of a pristine larch forest of Central Siberia developed over continuous permafrost basalt rocks. Two north- and south-oriented watershed slopes having distinctly different vegetation biomass and active layer depth were used as natural proxy for predicting possible future climate changes occurring in this region. In addition, peat bog zone exhibiting totally different vegetation, hydrology and soil temperature regime has been studied. The isotopic composition of soil profile from Central Siberia is rather constant with a delta(66)Zn value around 0.20/00 close to the value of various basalts. Zn isotopic composition in mosses (Sphagnum fuscum and Pleurozium schreberi) exhibits differences between surface layers presenting values from 0.14 to 0.20/00 and bottom layers presenting significantly higher values (0.5 - 0.70/00) than the underlain mineral surface. The humification of both dead moss and larch needles leads to retain the fraction where Zn bound most strongly thus releasing the lighter isotopes in solution and preserving the heavy isotopes in the humification products, in general accord with previous experimental and modeling works [GCA 75:7632-7643, 2011]. The larch (Larix gmelinii) from North and South-facing slopes is enriched in heavy isotopes compared to soil reservoir while larch from Sphagnum peatbog is enriched in light isotopes. This difference may result from stronger complexation of Zn by organic ligands and humification products in the peat bog compared to mineral surfaces in North- and South-facing slope. During the course of the growing period, Zn followed the behavior of macronutrients with a decrease of concentration from June to September. During this period, an enrichment of larch needles by heavier Zn isotopes is observed in the various habitats. We suggest that the increase of the depth of rooting zone, and the decrease of DOC and Zn concentration in soil solution from the root uptake zone with progressively thawing soil could provoke heavy isotopes to become more available for the larch roots at the end of the vegetative season compared to the beginning of the season, because the decrease of DOC will facilitate the uptake of heavy isotope as it will be less retained in strong organic complexes. PMID- 25931986 TI - I am only a nurse: a biographical narrative study of a nurse's self-understanding and its implication for practice. AB - BACKGROUND: The personal is a vital part of professional nursing practice. From a psycho-social perspective, nurses produce and reproduce conceptions of the Self through experience. A literature search on nurses' self-understanding in a psycho social perspective yields no results. Hence, the aim of this study was to investigate personal and professional experiences that may have formed the self understanding of a nurse, and how this self-understanding may have influenced her professional practice. METHODS: Using a single case approach, I conducted a Biographical Narrative Interview with a 50-year-old experienced Norwegian nurse. I asked the nurse to tell me the story of her life and how her work has affected her and possibly changed the way she saw herself. The overall aim of the interpretation was to understand the historically situated subjectivity in terms of the nurse's personal, social and professional constraints and chosen options. RESULTS: The nurse's narrative of her life story made it possible to trace a common theme throughout her experiences, the experience of being "only a nurse". The nurse experienced a low status, as well as a downgrade in the competence needed to deliver quality care in professional relationships. She felt it difficult to identify with the experience of being on the bottom of the social ladder and to identify with the female, mothering ideal connected to nursing. She desired a better position, and wanted to identify with strong women. In contrast to reality, her self-understanding influenced her relationship with her patients, her professional pride and her further professional development. CONCLUSIONS: This study shows that the professional practice of a nurse was informed by her self-understanding. This study suggests that the individual nurse must be given the opportunity to explore her professional vulnerability based on the assumption that it is both personally and socially constituted. This study indicates that the exploration of a nurse's self-understanding is one way to contribute to professional development. PMID- 25931987 TI - TLR2 and AP-1/NF-kappaB are involved in the regulation of MMP-9 elicited by heat killed Listeria monocytogenes in human monocytic THP-1 cells. AB - BACKGROUND: MMP-9 is crucial for a normal immune response, but excessive release of this enzyme leads to severe tissue damage. Listeria monocytogenes (LM) is an opportunistic food-borne pathogen causing listerosis, meningitis and sepsis. Heat killed Listeria monocytogenes (HKLM) activates immune system and leads production of cytokines and chemokines. However, nothing is known about the involvement of HKLM in MMP-9 regulation. Therefore we investigated the role of HKLM in the regulation of MMP-9 gene expression in THP-1 cells. METHODS: Commercially available heat killed Listeria monocytogenes was used in this study. HKLM-induced MMP-9 expression was assessed with quantitative real-time qPCR and ELISA. Action of HKLM in different signaling pathways were studied by using THP-1-XBlueTM cells (THP-1-cells with NF-kappaB/AP-1 reporter construct), THP-1-XBlueTM-defMyD cells (MyD88(-/-) THP-1 cells), anti-TLR2 mAb and pharmacological inhibitors. Phospho and total proteins were determined by Western blotting. RESULTS: Increased MMP-9 production (mRNA: 395-Fold; Protein: 8141 pg/ml; P < 0.05) was observed in HKLM stimulated THP-1 cells as compared to the un-stimulated THP-1 cells. This production of MMP-9 was completely abrogated by anti-TLR2 blocking mAb (P = 0.0024). Furthermore, THP-1-XBlueTM-defMyD cells were unable to produce MMP-9 in response to HKLM. HKLM- induced activation of NF-kappaB/AP-1 was also observed in THP-1-XBlueTM Cells. In addition, inhibitors of JNK (SP600125), MEK/ERK (U0126; PD98056), p38 MAPK (SB203580) and NF-kappaB (BAY 11-7085, Triptolide and Resveratrol) significantly suppressed (P < 0.05) HKLM-stimulated MMP-9 expression. CONCLUSION: Our results indicate that HKLM activates TLR2 and NF kappaB/AP-1 signaling pathways, leading to up-regulation of MMP-9 production in THP-1 cells. Thus, MMP-9 could be an appropriate therapeutic target to stop severe tissue damage caused by infection or chronic inflammation. PMID- 25931988 TI - The County Health Rankings: rationale and methods. AB - BACKGROUND: Annually since 2010, the University of Wisconsin Population Health Institute and the Robert Wood Johnson Foundation have produced the County Health Rankings-a "population health checkup" for the nation's over 3,000 counties. The purpose of this paper is to review the background and rationale for the Rankings, explain in detail the methods we use to create the health rankings in each state, and discuss the strengths and limitations associated with ranking the health of communities. METHODS: We base the Rankings on a conceptual model of population health that includes both health outcomes (mortality and morbidity) and health factors (health behaviors, clinical care, social and economic factors, and the physical environment). Data for over 30 measures available at the county level are assembled from a number of national sources. Z-scores are calculated for each measure, multiplied by their assigned weights, and summed to create composite measure scores. Composite scores are then ordered and counties are ranked from best to worst health within each state. RESULTS: Health outcomes and related health factors vary significantly within states, with over two-fold differences between the least healthy counties versus the healthiest counties for measures such as premature mortality, teen birth rates, and percent of children living in poverty. Ranking within each state depicts disparities that are not apparent when counties are ranked across the entire nation. DISCUSSION: The County Health Rankings can be used to clearly demonstrate differences in health by place, raise awareness of the many factors that influence health, and stimulate community health improvement efforts. The Rankings draws upon the human instinct to compete by facilitating comparisons between neighboring or peer counties within states. Since no population health model, or rankings based off such models, will ever perfectly describe the health of its population, we encourage users to look to local sources of data to understand more about the health of their community. PMID- 25931989 TI - Erratum to: Model of Cation Transportation Mediated by High-Affinity Potassium Transporters (HKTs) in Higher Plants. AB - [This corrects the article DOI: 10.1186/s12575-014-0013-3.]. PMID- 25931990 TI - Clinical Treatment Options Infectious Diseases: Update on PrEP Implementation, Adherence, and Advances in Delivery. AB - Pre-exposure prophylaxis (PrEP) is an effective and evidence-based HIV-prevention option and is recommended for individuals with substantial risk for HIV infection [1]. Randomized controlled trials have demonstrated that daily oral PrEP dramatically reduces the risk of HIV infection when it is taken as directed. Concerns regarding widespread emergence of antiretroviral resistance attributable to PrEP and behavioral disinhibition have to date not been observed in clinical trials and open-label demonstration projects. PrEP has great potential as part of an HIV risk reduction strategy and barriers to wider implementation including community education, prescriber availability, and elimination of financial barriers should be aggressively pursued. Adherence is critical to PrEP efficacy and has varied across study populations; developing and refining ways of measuring and supporting adherence is essential to the success of PrEP. Evaluation of long-acting medications and alternative formulations for PrEP is underway and may lead to the wider implementation and impact of PrEP. PMID- 25931992 TI - Application of endoscopic ultrasonography in the diagnosis and treatment of lower gastrointestinal disease. PMID- 25931991 TI - Identification of Nocardia species using matrix-assisted laser desorption/ionization-time-of-flight mass spectrometry. AB - BACKGROUND: The MALDI (matrix-assisted laser desorption/ionization) Biotyper system for bacterial identification has already been utilized in clinical microbiology laboratories as a successful clinical application of protoemics. However, in cases of Nocardia, mass spectra suitable for MALDI Biotyper identification are often not obtained if such specimens are processed like general bacteria. This problem is related to the insufficiencies in bacterial spectrum databases that preclude accurate specimen identification. Here, we developed a bacterial processing method to improve mass spectra from specimens of the genus Nocardia. In addition, with the new processing method, we constructed a novel in-house bacterial database that combines a commercial database and mass spectra of Nocardia strains from the Department of Clinical Laboratory at Chiba University Hospital (DCLC) and the Medical Mycology Research Center at Chiba University (MMRC). RESULTS: The newly developed method (Nocardia Extraction Method at DCLC [NECLC]) based on ethanol-formic acid extraction (EFAE) improved mass spectra obtained from Nocardia specimens. The Nocardia in-house database at Chiba University Hospital (NDCUH) was then successfully validated. In brief, prior to introduction of the NECLC and NDCUH, 10 of 64 (15.6%) clinical isolates were identified at the species level and 16 isolates (25.0%) could only be identified at the genus level. In contrast, after the introduction, 58 isolates (90.6%) were identified at the species level and 6 isolates (9.4%) were identified at the genus level. CONCLUSIONS: The results of this study suggest that MALDI-TOF (time-of-flight) Biotyper system can identify Nocardia accurately in a short time in combination with a simple processing method and an in-house database. PMID- 25931993 TI - Are small rectal neuroendocrine tumors safe? PMID- 25931994 TI - Myeloid-derived suppressor cells in inflammatory bowel disease. AB - Immature myeloid cells, also known as myeloid-derived suppressor cells (MDSCs), include neutrophilic and monocytic myeloid cells, and are found in inflammatory loci and secondary lymphoid organs in mice with intestinal inflammation, inflammatory bowel disease (IBD) patients, and tumor tissues. However, the roles of MDSCs in IBD are not yet well understood, and there are controversies regarding their immunosuppressive functions in IBD. In addition, recent studies have suggested that endoplasmic reticulum (ER) stress in intestinal epithelial cells, especially in Paneth cells, is closely associated with the induction of IBD. However, the ER stress in MDSCs accumulated in the inflamed tissues of IBD patients is not yet fully understood. In the current review, we discuss the presence of accumulated MDSCs in the intestines of IBD patients, and further speculate on their physiological roles in the inflammatory condition with interleukin 17-producing cells, including Th17 cells. In particular, we will discuss the divergent functions of MDSCs in ER stressed intestinal environments, including their pro-inflammatory or immunosuppressive roles, based on the consideration of unfolded protein responses initiated in intestinal epithelial cells by ER stress. PMID- 25931995 TI - Epigenetic alterations in inflammatory bowel disease and cancer. AB - Overwhelming evidences supports the idea that inflammatory bowel disease (IBD) is caused by a complex interplay between genetic alterations of multiple genes and an aberrant interaction with environmental factors. There is growing evidence that epigenetic factors can play a significant part in the pathogenesis of IBD. Significant effort has been invested in uncovering genetic and epigenetic factors, which may increase the risk of IBD, but progress has been slow, and few IBD-specific factors have been detected so far. It has been known for decades that DNA methylation is the most well studied epigenetic modification, and analysis of DNA methylation is leading to a new generation of cancer biomarkers. Therefore, in this review, we summarize the role of DNA methylation alteration in IBD pathogenesis, and discuss specific genes or genetic loci using recent molecular technology advances. Here, we suggest that DNA methylation should be studied in depth to understand the molecular pathways of IBD pathogenesis, and discuss epigenetic studies of IBD that may have a significant impact on the field of IBD research. PMID- 25931996 TI - Increased risk of asymptomatic gallstones in patients with ulcerative colitis. AB - BACKGROUND/AIMS: The relationship between Crohn's disease and gallstones is established. However, the prevalence and risk factors for gallstones in patients with ulcerative colitis (UC) are not yet well understood. The aim of this study was to evaluate the prevalence and risk factors of gallstones in patients with UC. METHODS: This study was a retrospective single center study. A total of 87 patients with UC and 261 healthy controls were enrolled. Age, sex, and body mass index were matched. To investigate risk factors, the extent of UC, duration of disease, number of hospital admissions, and number of steroid treatments in patients with UC were evaluated. RESULTS: The prevalence of gallstones in patients with UC was 13.8%, whereas that in healthy controls was only 3.1% (P<0.001). For patients with UC, patients >=50 years of age had a 3.6-times higher risk of gallstones compared to that in those <50 years of age, and the difference was statistically significant (odds ratio, 3.60; confidence interval, 1.03-12.61) in univariate analysis. There were no statistically significant disease-related risk factors for gallstones in UC patients. CONCLUSIONS: This is the first study of gallstone prevalence in Korean UC patients. In this study, patients with UC had a higher prevalence of gallstones compared to that in well matched healthy controls. Age seemed to be a possible risk factor, and more studies are needed. Further prospective, large-scale studies will be required to confirm the risk factors for gallstones in UC patients. PMID- 25931997 TI - What's the Clinical Features of Colitis in Elderly People in Long-Term Care Facilities? AB - BACKGROUND/AIMS: As life expectancy has increased, the number of elderly patients who need long-term care has grown rapidly. Mortality in patients with colitis in long-term care facilities (LTCFs) is increasing. We intend to investigate the main causes of colitis in LTCFs compared to those of colitis in local communities, and to identify the clinical features and risk factors of patients with colitis in LTCFs. METHODS: We retrospectively analyzed epidemiology, medical conditions, laboratory values, diagnoses, and clinical courses of elderly patients aged >=65 who were admitted to the Ewha Womans University hospital with colitis between January 2007 and July 2012. RESULTS: Patients with colitis in LTCFs (n=20) were compared with elderly patients with colitis in local communities (n=154). Fifty-five percent of colitis in LTCFs was caused by Clostridium difficile infection (CDI), 30% was due to ischemic colitis, and 15% was due to non-specific colitis. Non-specific colitis was the most common (63%) in the community group. Clinical outcomes were also significantly different between both groups: higher mortality (10.0% vs. 0.64%, P=0.021), higher requirement for intensive care units care (50.0% vs. 18.8%, P<0.01) in LTCFs group. In univariate analysis, the most significant risk factor for death in patients in LTCFs was decreased mental faculties. CONCLUSIONS: Patients in LTCFs showed worse clinical outcomes and a much higher prevalence of CDI compared to patients from local communities. We suggest early and active evaluation, such as endoscopic examination, for differential diagnosis in patients in LTCFs. PMID- 25931998 TI - The clinical usefulness of endoscopic ultrasound-guided fine needle aspiration and biopsy for rectal and perirectal lesions. AB - BACKGROUND/AIMS: Endoscopic ultrasound-guided fine needle aspiration and/or biopsy (EUS-FNA/B) have been used to diagnose subepithelial tumors (SETs) and extraluminal lesions in the gastrointestinal tract. Our group previously reported the usefulness of EUS-FNA/B for rectal and perirectal lesions. This study reports our expanded experience with EUS-FNA/B for rectal and perirectal lesions in terms of diagnostic accuracy and safety. We also included our new experience with EUS FNB using the recently introduced ProCore needle. METHODS: From April 2009 to March 2014, EUS-FNA/B for rectal and perirectal lesions was performed in 30 consecutive patients. We evaluated EUS-FNA/B performance by comparing histological diagnoses with final results. We also investigated factors affecting diagnostic accuracy. RESULTS: Among 10 patients with SETs, EUS-FNA/B specimen results revealed a gastrointestinal stromal tumor in 4 patients and malignant lymphoma in 1 patient. The diagnostic accuracy of EUS-FNA/B was 50% for SETs (5/10). Among 20 patients with non-SET lesions, 8 patients were diagnosed with malignant disease and 7 were diagnosed with benign disease based on both EUS FNA/B and the final results. The diagnostic accuracy of EUS-FNA/B for non-SET lesions was 75% (15/20). The size of lesions was the only factor related to diagnostic accuracy (P=0.027). Two complications of mild fever and asymptomatic pneumoperitoneum occurred after EUS-FNA/B. CONCLUSIONS: The overall diagnostic accuracy of EUS-FNA/B for rectal and perirectal lesions was 67% (20/30). EUS FNA/B is a clinically useful method for cytological and histological diagnoses of rectal and perirectal lesions. PMID- 25931999 TI - Inhibitory effect of metformin therapy on the incidence of colorectal advanced adenomas in patients with diabetes. AB - BACKGROUND/AIMS: Metformin use has been associated with decreased colorectal cancer risk and mortality among diabetic patients. Recent research suggests that metformin use may decrease the incidence of colorectal adenomas in diabetic patients with previous colorectal cancer. This study aimed to assess the clinical effect of metformin use on the development of colorectal adenomas in diabetic patients without previous colorectal cancer. METHODS: Among 604 consecutive diabetic patients who underwent colonoscopic surveillance after initial colonoscopy between January 2002 and June 2012, 240 patients without previous colorectal cancer were enrolled in this study and were divided in two groups: 151 patients receiving metformin and 89 patients not receiving metformin. Patient demographics and clinical characteristics as well as the colorectal adenoma incidence rate were retrospectively analyzed. RESULTS: The incidence rate of total colorectal adenomas was not different according to metformin use (P=0.349). However, the advanced adenoma incidence rate was significantly lower in the metformin group compared with the non-metformin group (relative risk [RR], 0.09; P=0.011). Metformin use was independently associated with a decreased incidence of advanced colorectal adenomas after adjustment for clinically relevant factors (RR, 0.072; P=0.016). In addition, the cumulative development rate of advanced adenomas during follow-up was significantly lower in the metformin group compared with the non-metformin group (P=0.007). CONCLUSIONS: Metformin use in diabetic patients without previous colorectal cancer is associated with a lower risk of advanced colorectal adenomas. PMID- 25932000 TI - Patient descriptions of rectal effluents may help to predict the quality of bowel preparation with photographic examples. AB - BACKGROUND/AIMS: Previous studies have suggested a weak correlation between self reported rectal effluent status and bowel preparation quality. We aim to evaluate whether photographic examples of rectal effluents could improve the correlation between patient descriptions of rectal effluents and bowel preparation quality. METHODS: Before colonoscopy, patients were asked to describe the nature of their last three rectal effluents. Photographic examples of rectal effluents were provided as a reference for scoring. Bowel preparation was subsequently assessed by a single endoscopist using a global preparation assessment scale. Preparation outcomes were grouped into two levels (excellent to good vs. fair to inadequate). Both univariate and multivariate logistic regression models were used to find any association between bowel preparation quality and patient characteristics. RESULTS: A total of 138 patients completed the questionnaires. The mean age was 56.5+/-10.4 years. The mean sum of the last three rectal effluent scores was 5.9+/-2.0. Higher rectal effluent scores (odds ratio [OR], 0.82; P=0.043) and the presence of diverticula (OR, 0.16; P<0.001) were risk factors for suboptimal preparation. CONCLUSIONS: Photographic example-guided patient descriptions of rectal effluents showed a statistically significant association with bowel preparation quality. However, clinical significance seemed to be low. The presence of diverticula was an independent predictive factor for suboptimal bowel preparation quality. PMID- 25932001 TI - Risk factors for delayed post-polypectomy bleeding. AB - BACKGROUND/AIMS: Among the many complications that can occur following therapeutic endoscopy, bleeding is the most serious, which occurs in 1.0-6.1% of all colonoscopic polypectomies. The aim of this study was to identify risk factors of delayed post-polypectomy bleeding (PPB). METHODS: We retrospectively reviewed the data of patients who underwent colonoscopic polypectomy between January 2003 and December 2012. We compared patients who experienced delayed PPB with those who did not. The control-to-patient ratio was 3:1. The clinical data analyzed included polyp size, number, location, and shape, patient' body mass index (BMI), preventive hemostasis, and endoscopist experience. RESULTS: Of 1,745 patients undergoing colonoscopic polypectomy, 21 (1.2%) experienced significant delayed PPB. We selected 63 age- and sex-matched controls. Multivariate logistic regression analysis showed that polyps >10 mm (odds ratio [OR], 2.605; 95% confidence interval [CI], 1.035-4.528; P=0.049), a pedunculated polyp (OR, 3.517; 95% CI, 1.428-7.176; P=0.045), a polyp located in the right hemicolon (OR, 3.10; 95% CI, 1.291-5.761; P=0.013), and a high BMI (OR, 3.681; 95% CI, 1.876-8.613; P=0.013) were significantly associated with delayed PPB. CONCLUSIONS: Although delayed PPB is a rare event, more caution is needed during colonoscopic polypectomies performed in patients with high BMI or large polyps, pedunculated polyps, or polyps located in the right hemicolon. PMID- 25932002 TI - Usefulness of Adalimumab for Treating a Case of Intestinal Behcet's Disease With Trisomy 8 Myelodysplastic Syndrome. AB - Behcet's disease (BD) is a systemic vasculitis, while myelodysplastic syndrome (MDS) is a heterogeneous group of clonal hematologic disorders characterized by ineffective hematopoiesis. Some studies suggest a relationship between MDS and BD, especially intestinal BD, and trisomy 8 seems to play an important role in both diseases. There are several reports on patients with BD comorbid with MDS involving trisomy 8 that frequently have intestinal lesions refractory to conventional medical therapies. Tumor necrosis factor (TNF)-alpha is strongly involved in the pathophysiology of several autoimmune diseases such as rheumatoid arthritis, inflammatory bowel disease, and BD. In addition, TNF-alpha plays an important role in the pathophysiology of MDS by inhibiting normal hematopoiesis and inducing the programmed cell death of normal total bone marrow cells and normal CD34+ cells. Recent clinical reports demonstrate the favorable effect of TNF-alpha antagonists in patients with refractory intestinal BD and in those with MDS. We present the case of a patient with intestinal BD and MDS involving trisomy 8 who was successfully treated with adalimumab. PMID- 25932003 TI - Primary anorectal malignant melanoma treated with endoscopic mucosal resection. AB - Anorectal melanoma is a rare neoplasm that accounts for less than 1-4% of anorectal malignant tumors. The main therapeutic modality for anorectal melanoma is surgical treatment, with abdominoperineal resection or wide local excision being the most common approaches. A 77-year-old male with a history of cerebral infarction and hypertension presented with anal bleeding. Here, we report a case of anorectal melanoma treated by endoscopic mucosal resection with adjuvant interferon therapy rather than surgical resection. The patient has been disease free for 5 years after endoscopic treatment. PMID- 25932004 TI - Natural course of an untreated metastatic perirectal lymph node after the endoscopic resection of a rectal neuroendocrine tumor. AB - Lymph node metastasis is rare in small (i.e., <10 mm) rectal neuroendocrine tumors (NETs). In addition to tumor size, pathological features such as the mitotic or Ki-67 proliferation index are associated with lymph node metastasis in rectal NETs. We recently treated a patient who underwent endoscopic treatment of a small, grade 1 rectal NET that recurred in the form of perirectal lymph node metastasis 7 years later. A 7-mm-sized perirectal lymph node was noted at the time of the initial endoscopic treatment. The same lymph node was found to be slightly enlarged on follow-up and finally confirmed as a metastatic NET. Therefore, the perirectal lymph node metastasis might have been present at the time of the initial diagnosis. However, the growth rate of the lymph node was extremely low, and it took 7 years to increase in size from 7 to 10 mm. NETs with low Ki-67 proliferation index and without mitotic activity may grow extremely slowly even if they are metastatic. PMID- 25932005 TI - A patient experiencing bloody diarrhea and tenesmus for three weeks. PMID- 25932006 TI - When is an Assay of Cytomegalovirus Antigenemia Useful in Detecting Cytomegalovirus Colitis? PMID- 25932007 TI - Author's Reply. PMID- 25932008 TI - Brain-derived neurotrophic factor: a biomarker for obsessive-compulsive disorder? PMID- 25932009 TI - Rapid adaptation of multisensory integration in vestibular pathways. AB - Sensing gravity is vital for our perception of spatial orientation, the control of upright posture, and generation of our everyday activities. When an astronaut transitions to microgravity or returns to earth, the vestibular input arising from self-motion will not match the brain's expectation. Our recent neurophysiological studies have provided insight into how the nervous system rapidly reorganizes when vestibular input becomes unreliable by both (1) updating its internal model of the sensory consequences of motion and (2) up-weighting more reliable extra-vestibular information. These neural strategies, in turn, are linked to improvements in sensorimotor performance (e.g., gaze and postural stability, locomotion, orienting) and perception characterized by similar time courses. We suggest that furthering our understanding of the neural mechanisms that underlie sensorimotor adaptation will have important implications for optimizing training programs for astronauts before and after space exploration missions and for the design of goal-oriented rehabilitation for patients. PMID- 25932010 TI - Neurocognitive poetics: methods and models for investigating the neuronal and cognitive-affective bases of literature reception. AB - A long tradition of research including classical rhetoric, esthetics and poetics theory, formalism and structuralism, as well as current perspectives in (neuro)cognitive poetics has investigated structural and functional aspects of literature reception. Despite a wealth of literature published in specialized journals like Poetics, however, still little is known about how the brain processes and creates literary and poetic texts. Still, such stimulus material might be suited better than other genres for demonstrating the complexities with which our brain constructs the world in and around us, because it unifies thought and language, music and imagery in a clear, manageable way, most often with play, pleasure, and emotion (Schrott and Jacobs, 2011). In this paper, I discuss methods and models for investigating the neuronal and cognitive-affective bases of literary reading together with pertinent results from studies on poetics, text processing, emotion, or neuroaesthetics, and outline current challenges and future perspectives. PMID- 25932011 TI - Neural representation of three-dimensional acoustic space in the human temporal lobe. AB - Sound localization is an important function of the human brain, but the underlying cortical mechanisms remain unclear. In this study, we recorded auditory stimuli in three-dimensional space and then replayed the stimuli through earphones during functional magnetic resonance imaging (fMRI). By employing a machine learning algorithm, we successfully decoded sound location from the blood oxygenation level-dependent signals in the temporal lobe. Analysis of the data revealed that different cortical patterns were evoked by sounds from different locations. Specifically, discrimination of sound location along the abscissa axis evoked robust responses in the left posterior superior temporal gyrus (STG) and right mid-STG, discrimination along the elevation (EL) axis evoked robust responses in the left posterior middle temporal lobe (MTL) and right STG, and discrimination along the ordinate axis evoked robust responses in the left mid MTL and right mid-STG. These results support a distributed representation of acoustic space in human cortex. PMID- 25932012 TI - Historic evidence to support a causal relationship between spirochetal infections and Alzheimer's disease. AB - Following previous observations a statistically significant association between various types of spirochetes and Alzheimer's disease (AD) fulfilled Hill's criteria in favor of a causal relationship. If spirochetal infections can indeed cause AD, the pathological and biological hallmarks of AD should also occur in syphilitic dementia. To answer this question, observations and illustrations on the detection of spirochetes in the atrophic form of general paresis, which is known to be associated with slowly progressive dementia, were reviewed and compared with the characteristic pathology of AD. Historic observations and illustrations published in the first half of the 20th Century indeed confirm that the pathological hallmarks, which define AD, are also present in syphilitic dementia. Cortical spirochetal colonies are made up by innumerable tightly spiraled Treponema pallidum spirochetes, which are morphologically indistinguishable from senile plaques, using conventional light microscopy. Local brain amyloidosis also occurs in general paresis and, as in AD, corresponds to amyloid beta. These historic observations enable us to conclude that chronic spirochetal infections can cause dementia and reproduce the defining hallmarks of AD. They represent further evidence in support a causal relationship between various spirochetal infections and AD. They also indicate that local invasion of the brain by these helically shaped bacteria reproduce the filamentous pathology characteristic of AD. Chronic infection by spirochetes, and co-infection with other bacteria and viruses should be included in our current view on the etiology of AD. Prompt action is needed as AD might be prevented. PMID- 25932013 TI - Dopaminergic signaling within the primary cilia in the renovascular system. AB - Activation of dopamine receptor type-5 (DR5) has been known to reduce systemic blood pressure, most likely by increasing renal vasodilation and enhancing natriuresis in the kidney. However, the mechanism of DR5 in natriuresis and vasodilation was not clearly known. We have previously shown that DR5 is localized to primary cilia of proximal renal epithelial and vascular endothelial cells. We here show that selective activation of DR5 specifically induces calcium influx only in the primary cilia, whereas non-selective activation of dopamine receptor induces calcium fluxes in both cilioplasm and cytoplasm. Cilia independent signaling induced by thrombin only shows calcium signaling within cytoplasm. Furthermore, calcium activation in the cilioplasm by DR5 increases length and mechanosensory function of primary cilia, leading to a greater response to fluid-shear stress. We therefore propose a new mechanism by which DR5 induces vasodilation via chemical and mechanical properties that are specific to primary cilia. PMID- 25932014 TI - Discourse-voice regulatory strategies in the psychotherapeutic interaction: a state-space dynamics analysis. AB - This study seeks to provide evidence of the dynamics associated with the configurations of discourse-voice regulatory strategies in patient-therapist interactions in relevant episodes within psychotherapeutic sessions. Its central assumption is that discourses manifest themselves differently in terms of their prosodic characteristics according to their regulatory functions in a system of interactions. The association between discourse and vocal quality in patients and therapists was analyzed in a sample of 153 relevant episodes taken from 164 sessions of five psychotherapies using the state space grid (SSG) method, a graphical tool based on the dynamic systems theory (DST). The results showed eight recurrent and stable discourse-voice regulatory strategies of the patients and three of the therapists. Also, four specific groups of these discourse-voice strategies were identified. The latter were interpreted as regulatory configurations, that is to say, as emergent self-organized groups of discourse voice regulatory strategies constituting specific interactional systems. Both regulatory strategies and their configurations differed between two types of relevant episodes: Change Episodes and Rupture Episodes. As a whole, these results support the assumption that speaking and listening, as dimensions of the interaction that takes place during therapeutic conversation, occur at different levels. The study not only shows that these dimensions are dependent on each other, but also that they function as a complex and dynamic whole in therapeutic dialog, generating relational offers which allow the patient and the therapist to regulate each other and shape the psychotherapeutic process that characterizes each type of relevant episode. PMID- 25932015 TI - Associations between visual perception accuracy and confidence in a dopaminergic manipulation study. AB - Delusions are defined as fixed erroneous beliefs that are based on misinterpretation of events or perception, and cannot be corrected by argumentation to the opposite. Cognitive theories of delusions regard this symptom as resulting from specific distorted thinking styles that lead to biased integration and interpretation of perceived stimuli (i.e., reasoning biases). In previous studies, we were able to show that one of these reasoning biases, overconfidence in errors, can be modulated by drugs that act on the dopamine system, a major neurotransmitter system implicated in the pathogenesis of delusions and other psychotic symptoms. Another processing domain suggested to involve the dopamine system and to be abnormal in psychotic disorders is sensory perception. The present study aimed to investigate whether (lower-order) sensory perception and (higher-order) overconfidence in errors are similarly affected by dopaminergic modulation in healthy subjects. Thirty-four healthy individuals were assessed upon administration of l-dopa, placebo, or haloperidol within a randomized, double-blind, cross-over design. Variables of interest were hits and false alarms in an illusory perception paradigm requiring speeded detection of pictures over a noisy background, and subjective confidence ratings for correct and incorrect responses. There was a significant linear increase of false alarm rates from haloperidol to placebo to l-dopa, whereas hit rates were not affected by dopaminergic manipulation. As hypothesized, confidence in error responses was significantly higher with l-dopa compared to placebo. Moreover, confidence in erroneous responses significantly correlated with false alarm rates. These findings suggest that overconfidence in errors and aberrant sensory processing might be both interdependent and related to dopaminergic transmission abnormalities in patients with psychosis. PMID- 25932016 TI - Social incentives improve deliberative but not procedural learning in older adults. AB - Age-related deficits are seen across tasks where learning depends on asocial feedback processing, however plasticity has been observed in some of the same tasks in social contexts suggesting a novel way to attenuate deficits. Socioemotional selectivity theory suggests this plasticity is due to a deliberative motivational shift toward achieving well-being with age (positivity effect) that reverses when executive processes are limited (negativity effect). The present study examined the interaction of feedback valence (positive, negative) and social salience (emotional face feedback - happy; angry, asocial point feedback - gain; loss) on learning in a deliberative task that challenges executive processes and a procedural task that does not. We predict that angry face feedback will improve learning in a deliberative task when executive function is challenged. We tested two competing hypotheses regarding the interactive effects of deliberative emotional biases on automatic feedback processing: (1) If deliberative emotion regulation and automatic feedback are interactive we expect happy face feedback to improve learning and angry face feedback to impair learning in older adults because cognitive control is available. (2) If deliberative emotion regulation and automatic feedback are not interactive we predict that emotional face feedback will not improve procedural learning regardless of valence. Results demonstrate that older adults show persistent deficits relative to younger adults during procedural category learning suggesting that deliberative emotional biases do not interact with automatic feedback processing. Interestingly, a subgroup of older adults identified as potentially using deliberative strategies tended to learn as well as younger adults with angry relative to happy feedback, matching the pattern observed in the deliberative task. Results suggest that deliberative emotional biases can improve deliberative learning, but have no effect on procedural learning. PMID- 25932017 TI - The calming effect of maternal carrying in different mammalian species. AB - Attachment theory postulates that mothers and their infants possess some basic physiological mechanisms that favor their dyadic interaction and bonding. Many studies have focused on the maternal physiological mechanisms that promote attachment (e.g., mothers' automatic responses to infant faces and/or cries), and relatively less have examined infant physiology. Thus, the physiological mechanisms regulating infant bonding behaviors remain largely undefined. This review elucidates some of the neurobiological mechanisms governing social bonding and cooperation in humans by focusing on maternal carrying and its beneficial effect on mother-infant interaction in mammalian species (e.g., in humans, big cats, and rodents). These studies show that infants have a specific calming response to maternal carrying. A human infant carried by his/her walking mother exhibits a rapid heart rate decrease, and immediately stops voluntary movement and crying compared to when he/she is held in a sitting position. Furthermore, strikingly similar responses were identified in mouse rodents, who exhibit immobility, diminished ultra-sonic vocalizations and heart rate. In general, the studies described in the current review demonstrate the calming effect of maternal carrying to be comprised of a complex set of behavioral and physiological components, each of which has a specific postnatal time window and is orchestrated in a well-matched manner with the maturation of the infants. Such reactions could have been evolutionarily adaptive in mammalian mother-infant interactions. The findings have implications for parenting practices in developmentally normal populations. In addition, we propose that infants' physiological response may be useful in clinical assessments as we discuss possible implications on early screening for child psychopathology (e.g., autism spectrum disorders and perinatal brain disorders). PMID- 25932018 TI - How language affects children's use of derivational morphology in visual word and pseudoword processing: evidence from a cross-language study. AB - Developing readers have been shown to rely on morphemes in visual word recognition across several naming, lexical decision and priming experiments. However, the impact of morphology in reading is not consistent across studies with differing results emerging not only between but also within writing systems. Here, we report a cross-language experiment involving the English and French languages, which aims to compare directly the impact of morphology in word recognition in the two languages. Monolingual French-speaking and English speaking children matched for grade level (Part 1) and for age (Part 2) participated in the study. Two lexical decision tasks (one in French, one in English) featured words and pseudowords with exactly the same structure in each language. The presence of a root (R+) and a suffix ending (S+) was manipulated orthogonally, leading to four possible combinations in words (R+S+: e.g., postal; R+S-: e.g., turnip; R-S+: e.g., rascal; and R-S-: e.g., bishop) and in pseudowords (R+S+: e.g., pondal; R+S-: e.g., curlip; R-S+: e.g., vosnal; and R-S : e.g., hethop). Results indicate that the presence of morphemes facilitates children's recognition of words and impedes their ability to reject pseudowords in both languages. Nevertheless, effects extend across accuracy and latencies in French but are restricted to accuracy in English, suggesting a higher degree of morphological processing efficiency in French. We argue that the inconsistencies found between languages emphasize the need for developmental models of word recognition to integrate a morpheme level whose elaboration is tuned by the productivity and transparency of the derivational system. PMID- 25932019 TI - Embodied cognition of aging. AB - Embodiment is revolutionizing the way we consider cognition by incorporating the influence of our body and of the current context within cognitive processing. A growing number of studies which support this view of cognition in young adults stands in stark contrast with the lack of evidence in favor of this view in the field of normal aging and neurocognitive disorders. Nonetheless, the validation of embodiment assumptions on the whole spectrum of cognition is a mandatory step in order for embodied cognition theories to become theories of human cognition. More pragmatically, aging populations represent a perfect target to test embodied cognition theories due to concomitant changes in sensory, motor and cognitive functioning that occur in aging, since these theories predict direct interactions between them. Finally, the new perspectives on cognition provided by these theories might also open new research avenues and new clinical applications in the field of aging. The present article aims at showing the value and interest to explore embodiment in normal and abnormal aging as well as introducing some potential theoretical and clinical applications. PMID- 25932021 TI - Functional categorization of carbapenemase-mediated resistance by a combined genotyping and two-tiered Modified Hodge Test approach. AB - The functional relationship between the detection of carbapenemase activity and phenotypic resistance in Gram-negative bacterial pathogens is often ill-defined. To address this issue, we developed a two-tiered Modified Hodge Test approach for carbapenemase detection and typing, in which the use of Pseudomonas aeruginosa strain PAO1 and Escherichia coli as indicator strains conferred two levels of sensitivities to carbapenemases. When applied alongside PCR genotyping tests for existence of known carbapenemase genes in 92 carbapenem resistant clinical isolates, this method is extremely useful in elucidating the relative role by which different enzymes contributed to the prevalent carbapenem-resistance phenotypes. With this study approach, we showed that the proportion of P. aeruginosa and Acinetobacter baumannii strains whose carbapenem resistance phenotypes could at least be partially attributed to carbapenemase were 34 and 89%, respectively. Our data also facilitates detailed functional categorization of carbapenem resistance phenotypes on the basis of the types and activities of detectable carbapenemase produced by the test organism. For example, six A. baumannii isolates harboring the bla OXA-51/23-like gene without detectable enzymatic activities were identified, suggesting that other resistance mechanisms may be involved. On the other hand, there were seven P. aeruginosa strains which produced carbapenemase phenotype without harboring known carbapenemase genes, inferring the existence of some hitherto unknown resistance determinants. Findings in this work therefore provide a comprehensive view on the cellular basis of carbapenem resistance phenotypes in major Gram-negative bacterial species, paving the way for development of novel strategies to reverse the effects of the major resistance mechanisms concerned. PMID- 25932020 TI - Phenotypic heterogeneity in metabolic traits among single cells of a rare bacterial species in its natural environment quantified with a combination of flow cell sorting and NanoSIMS. AB - Populations of genetically identical microorganisms residing in the same environment can display marked variability in their phenotypic traits; this phenomenon is termed phenotypic heterogeneity. The relevance of such heterogeneity in natural habitats is unknown, because phenotypic characterization of a sufficient number of single cells of the same species in complex microbial communities is technically difficult. We report a procedure that allows to measure phenotypic heterogeneity in bacterial populations from natural environments, and use it to analyze N2 and CO2 fixation of single cells of the green sulfur bacterium Chlorobium phaeobacteroides from the meromictic lake Lago di Cadagno. We incubated lake water with (15)N2 and (13)CO2 under in situ conditions with and without NH4 (+). Subsequently, we used flow cell sorting with auto-fluorescence gating based on a pure culture isolate to concentrate C. phaeobacteroides from its natural abundance of 0.2% to now 26.5% of total bacteria. C. phaeobacteroides cells were identified using catalyzed-reporter deposition fluorescence in situ hybridization (CARD-FISH) targeting the 16S rRNA in the sorted population with a species-specific probe. In a last step, we used nanometer-scale secondary ion mass spectrometry to measure the incorporation (15)N and (13)C stable isotopes in more than 252 cells. We found that C. phaeobacteroides fixes N2 in the absence of NH4 (+), but not in the presence of NH4 (+) as has previously been suggested. N2 and CO2 fixation were heterogeneous among cells and positively correlated indicating that N2 and CO2 fixation activity interact and positively facilitate each other in individual cells. However, because CARD-FISH identification cannot detect genetic variability among cells of the same species, we cannot exclude genetic variability as a source for phenotypic heterogeneity in this natural population. Our study demonstrates the technical feasibility of measuring phenotypic heterogeneity in a rare bacterial species in its natural habitat, thus opening the door to study the occurrence and relevance of phenotypic heterogeneity in nature. PMID- 25932022 TI - Inactivated E. coli transformed with plasmids that produce dsRNA against infectious salmon anemia virus hemagglutinin show antiviral activity when added to infected ASK cells. AB - Infectious salmon anemia virus (ISAV) has caused great losses to the Chilean salmon industry, and the success of prevention and treatment strategies is uncertain. The use of RNA interference (RNAi) is a promising approach because during the replication cycle, the ISAV genome must be transcribed to mRNA in the cytoplasm. We explored the capacity of E. coli transformed with plasmids that produce double-stranded RNA (dsRNA) to induce antiviral activity when added to infected ASK cells. We transformed the non-pathogenic Escherichia coli HT115 (DE3) with plasmids that expressed highly conserved regions of the ISAV genes encoding the nucleoprotein (NP), fusion (F), hemagglutinin (HE), and matrix (M) proteins as dsRNA, which is the precursor of the RNAi mechanism. The inactivated transformed bacteria carrying dsRNA were tested for their capacity to silence the target ISAV genes, and the dsRNA that were able to inhibit gene expression were subsequently tested for their ability to attenuate the cytopathic effect (CPE) and reduce the viral load. Of the four target genes tested, inactivated E. coli transformed with plasmids producing dsRNA targeting HE showed antiviral activity when added to infected ASK cells. PMID- 25932023 TI - Bacterial community of cushion plant Thylacospermum ceaspitosum on elevational gradient in the Himalayan cold desert. AB - Although bacterial assemblages are important components of soils in arid ecosystems, the knowledge about composition, life-strategies, and environmental drivers is still fragmentary, especially in remote high-elevation mountains. We compared the quality and quantity of heterotrophic bacterial assemblages between the rhizosphere of the dominant cushion-forming plant Thylacospermum ceaspitosum and its surrounding bulk soil in two mountain ranges (East Karakoram: 4850-5250 m and Little Tibet: 5350-5850 m), in communities from cold steppes to the subnival zone in Ladakh, arid Trans-Himalaya, northwest India. Bacterial communities were characterized by molecular fingerprinting in combination with culture-dependent methods. The effects of environmental factors (elevation, mountain range, and soil physico-chemical parameters) on the bacterial community composition and structure were tested by multivariate redundancy analysis and conditional inference trees. Actinobacteria dominate the cultivable part of community and represent a major bacterial lineage of cold desert soils. The most abundant genera were Streptomyces, Arthrobacter, and Paenibacillus, representing both r- and K-strategists. The soil texture is the most important factor for the community structure and the total bacteria counts. Less abundant and diverse assemblages are found in East Karakoram with coarser soils derived from leucogranite bedrock, while more diverse assemblages in Little Tibet are associated with finer soils derived from easily weathering gneisses. Cushion rhizosphere is in general less diverse than bulk soil, and contains more r strategists. K-strategists are more associated with the extremes of the gradient, with drought at lowest elevations (4850-5000 m) and frost at the highest elevations (5750-5850 m). The present study illuminates the composition of soil bacterial assemblages in relation to the cushion plant T. ceaspitosum in a xeric environment and brings important information about heterotrophic bacteria in Himalayan soil. PMID- 25932024 TI - Financial evaluations of antibiotic stewardship programs-a systematic review. AB - INTRODUCTION: There is an increasing awareness to counteract problems due to incorrect antimicrobial use. Interventions that are implemented are often part of an Antimicrobial Stewardship Program (ASPs). Studies publishing results from these interventions are increasing, including reports on the economical effects of ASPs. This review will look at the economical sections of these studies and the methods that were used. METHODS: A systematic review was performed of articles found in the PubMed and EMBASE databases published from 2000 until November 2014. Included studies found were scored for various aspects and the quality of the papers was assessed following an appropriate check list (CHEC criteria list). RESULTS: 1233 studies were found, of which 149 were read completely. Ninety-nine were included in the final review. Of these studies, 57 only mentioned the costs associated with the antimicrobial medication. Others also included operational costs (n = 23), costs for hospital stay (n = 18), and/or other costs (n = 19). Nine studies were further assessed for their quality. These studies scored between 2 and 14 out of a potential total score of 19. CONCLUSIONS: This review gives an extensive overview of the current financial evaluation of ASPs and the quality of these economical studies. We show that there is still major potential to improve financial evaluations of ASPs. Studies do not use similar nor consistent methods or outcome measures, making it impossible draw sound conclusions and compare different studies. Finally, we make some recommendations for the future. PMID- 25932025 TI - Why do bacteria divide? AB - The problem of not only how but also why cells divide can be tackled using recent ideas. One idea from the origins of life - Life as independent of its constituents - is that a living entity like a cell is a particular pattern of connectivity between its constituents. This means that if the growing cell were just to get bigger the average connectivity between its constituents per unit mass - its cellular connectivity - would decrease and the cell would lose its identity. The solution is division which restores connectivity. The corollary is that the cell senses decreasing cellular connectivity and uses this information to trigger division. A second idea from phenotypic diversity - Life on the Scales of Equilibria - is that a bacterium must find strategies that allow it to both survive and grow. This means that it has learnt to reconcile the opposing constraints that these strategies impose. The solution is that the cell cycle generates daughter cells with different phenotypes based on sufficiently complex equilibrium (E) and non-equilibrium (NE) cellular compounds and structures appropriate for survival and growth, respectively, alias 'hyperstructures.' The corollary is that the cell senses both the quantity of E material and the intensity of use of NE material and then uses this information to trigger the cell cycle. A third idea from artificial intelligence - Competitive Coherence - is that a cell selects the active subset of elements that actively determine its phenotype from a much larger set of available elements. This means that the selection of an active subset of a specific size and composition must be done so as to generate both a coherent cell state, in which the cell's contents work together harmoniously, and a coherent sequence of cell states, each coherent with respect to itself and to an unpredictable environment. The solution is the use of a range of mechanisms ranging from hyperstructure dynamics to the cell cycle itself. PMID- 25932026 TI - Editorial: recent discoveries in evolutionary and genomic microbiology. PMID- 25932028 TI - Effects of immunosuppressive drugs on viability and susceptibility of adipose- and bone marrow-derived mesenchymal stem cells. AB - The immunomodulatory potential of cell therapies using adipose-derived stem cells (ASCs) and bone marrow-derived mesenchymal stem cells (BM-MSCs) has been studied in vascularized composite allotransplantation (VCA). Most cell therapy-based experimental and clinical protocols integrate some degree of recipient conditioning/induction with antibodies or other immunosuppressive agents. We investigated the susceptibility of ASCs and BM-MSCs to anti-lymphocyte serum (ALS) and tacrolimus. Rat ASCs and BM-MSCs were exposed to varying concentrations of tacrolimus and ALS in vitro. Serum from ALS-treated animals was added to cell cultures. Viability, susceptibility, and cytotoxicity parameters were evaluated. ALS inhibited ASC and BM-MSC viability and susceptibility in vitro in a dose dependent manner. ASCs were more susceptible to both ALS and tacrolimus than BM MSCs. Trypsinized and adherent ASCs were significantly smaller than BM-MSCs. This is the first report on the viability and susceptibility characteristics of BM MSCs or ASCs to collateral effects of ALS and tacrolimus. These in vitro insights may impact choice of cell type as well as concomitant conditioning agents and the logistical coordination of the timing, dosing, and frequency of drug or cell therapy in solid organ transplantation or VCA protocols. PMID- 25932027 TI - The Aspergillus fumigatus cell wall integrity signaling pathway: drug target, compensatory pathways, and virulence. AB - Aspergillus fumigatus is the most important airborne fungal pathogen, causing severe infections with invasive growth in immunocompromised patients. The fungal cell wall (CW) prevents the cell from lysing and protects the fungus against environmental stress conditions. Because it is absent in humans and because of its essentiality, the fungal CW is a promising target for antifungal drugs. Nowadays, compounds acting on the CW, i.e., echinocandin derivatives, are used to treat A. fumigatus infections. However, studies demonstrating the clinical effectiveness of echinocandins in comparison with antifungals currently recommended for first-line treatment of invasive aspergillosis are still lacking. Therefore, it is important to elucidate CW biosynthesis pathways and their signal transduction cascades, which potentially compensate the inhibition caused by CW- perturbing compounds. Like in other fungi, the central core of the cell wall integrity (CWI) signaling pathway in A. fumigatus is composed of three mitogen activated protein kinases. Deletion of these genes resulted in severely enhanced sensitivity of the mutants against CW-disturbing compounds and in drastic alterations of the fungal morphology. Additionally, several cross-talk interactions between the CWI pathways and other signaling pathways are emerging, raising the question about their role in the CW compensatory mechanisms. In this review we focused on recent advances in understanding the CWI signaling pathway in A. fumigatus and its role during drug stress response and virulence. PMID- 25932029 TI - Comparison of proteome response to saline and zinc stress in lettuce. AB - Zinc salts occurring in soils can exert an osmotic stress toward plants. However, being zinc a heavy metal, some more specific effects on plant metabolisms can be forecast. In this work, lettuce has been used as a model to investigate salt and zinc stresses at proteome level through a shotgun tandem MS proteomic approach. The effect of zinc stress in lettuce, in comparison with NaCl stress, was evaluated to dissect between osmotic/oxidative stress related effects, from those changes specifically related to zinc. The analysis of proteins exhibiting a fold change of 3 as minimum (on log 2 normalized abundances), revealed the involvement of photosynthesis (via stimulation of chlorophyll synthesis and enhanced role of photosystem I) as well as stimulation of photophosphorylation. Increased glycolytic supply of energy substrates and ammonium assimilation [through formation of glutamine synthetase (GS)] were also induced by zinc in soil. Similarly, protein metabolism (at both transcriptional and ribosomal level), heat shock proteins, and proteolysis were affected. According to their biosynthetic enzymes, hormones appear to be altered by both the treatment and the time point considered: ethylene biosynthesis was enhanced, while production of abscisic acid was up-regulated at the earlier time point to decrease markedly and gibberellins were decreased at the later one. Besides aquaporin PIP2 synthesis, other osmotic/oxidative stress related compounds were enhanced under zinc stress, i.e., proline, hydroxycinnamic acids, ascorbate, sesquiterpene lactones, and terpenoids biosynthesis. Although the proteins involved in the response to zinc stress and to salinity were substantially the same, their abundance changed between the two treatments. Lettuce response to zinc was more prominent at the first sampling point, yet showing a faster adaptation than under NaCl stress. Indeed, lettuce plants showed an adaptation after 30 days of stress, in a more pronounced way in the case of zinc. PMID- 25932030 TI - Gamma-glutamyl cycle in plants: a bridge connecting the environment to the plant cell? PMID- 25932031 TI - Editorial: Genetics and epigenetics of fetal alcohol spectrum disorders. PMID- 25932032 TI - Metabolic evaluation of children with global developmental delay. AB - Global developmental delay (GDD) is a relatively common early-onset chronic neurological condition, which may have prenatal, perinatal, postnatal, or undetermined causes. Family history, physical and neurological examinations, and detailed history of environmental risk factors might suggest a specific disease. However, diagnostic laboratory tests, brain imaging, and other evidence-based evaluations are necessary in most cases to elucidate the causes. Diagnosis of GDD has recently improved because of remarkable advances in genetic technology, but this is an exhaustive and expensive evaluation that may not lead to therapeutic benefits in the majority of GDD patients. Inborn metabolic errors are one of the main targets for the treatment of GDD, although only a small proportion of GDD patients have this type of error. Nevertheless, diagnosis is often challenging because the phenotypes of many genetic or metabolic diseases often overlap, and their clinical spectra are much broader than currently known. Appropriate and cost-effective strategies including up-to-date information for the early identification of the "treatable" causes of GDD are needed for the development of well-timed therapeutic applications with the potential to improve neurodevelopmental outcomes. PMID- 25932033 TI - Osteosarcoma in Korean children and adolescents. AB - Osteosarcoma is the most frequent primary bone tumor. Advances in combination chemotherapy and surgical technique have greatly improved the survival of patients with osteosarcoma. In Korea, improvements in osteosarcoma treatment have been made over the past two decades. The 5-year event-free survival rate of Korean children and adolescents with localized disease is 64.6%, comparable to that of American or European patients. This article provides an overview of current therapies for osteosarcoma in Korea. PMID- 25932034 TI - Long-term outcome of patients with p22 (phox) -deficient chronic granulomatous disease on Jeju Island, Korea. AB - PURPOSE: This study investigated the long-term clinical outcomes of patients with p22 (phox) -deficient chronic granulomatous disease (CGD) on Jeju Island and retrospectively evaluated the effects of interferon-gamma (IFN-gamma) prophylaxis. METHODS: The medical records of 15 patients with CGD were retrospectively reviewed. The efficacy of IFN-gamma prophylaxis was evaluated by comparing the frequency of severe infections before and after starting continuous prophylaxis with IFN-gamma. RESULTS: At the time of the analysis, 14 patients were alive, with a median age of 14.3 years. The diagnosis of CGD was made at a median age of 2.4 years, and the median age at onset of severe infection was 0.3 years. Thirteen of the 15 patients had their first severe infection within the first year of life. The overall incidence of severe infection was 1.36 infections per patient-year; pneumonia, suppurative lymphadenitis, and skin and subcutaneous abscesses were the most common infections. Aspergillus species were the most frequently isolated microorganisms, present in 15.8% of isolates. IFN-gamma did not significantly change the rate of severe infection. The survival rate for patients after 2 years of age was 93%; there was a prolonged survival plateau beyond the age of 2. CONCLUSION: Compared with cases of X-linked CGD reported in other studies, patients with CGD on Jeju Island did not show obviously different clinical manifestations, but they had a significantly higher survival rate. Further studies with a substantially longer period of observation, and with more patients under intensive surveillance are necessary to elucidate the prophylactic efficiency of IFN-gamma. PMID- 25932035 TI - Ultrasound-guided internal jugular vein catheterization in critically ill pediatric patients. AB - PURPOSE: Continuous intravenous access is imperative in emergency situations. Ultrasound-guided internal jugular vein (IJV) catheterization was investigated in critically ill pediatric patients to assess the feasibility of the procedure. METHODS: Patients admitted to the pediatric intensive care unit between February 2011 and September 2012 were enrolled in this study. All patients received a central venous catheter from attending house staff under ultrasound guidance. Outcome measures included successful insertion of the catheter, cannulation time, number of cannulation attempts, and number and type of resulting complications. RESULTS: Forty-one central venous catheters (93.2%) were successfully inserted into 44 patients (21 males and 23 females; mean age, 6.54+/-1.06 years). Thirty three patients (75.0%) had neurological disorders. The right IJV was used for catheter insertion in 34 cases (82.9%). The mean number of cannulation attempts and the mean cannulation time was 1.57+/-0.34 and 14.07+/-1.91 minutes, respectively, the mean catheter dwell time was 14.73+/-2.5 days. Accidental catheter removal was observed in 9 patients (22.0%). Six patients (13.6%) reported complications, the most serious being catheter-related sepsis, which affected 1 patient (2.3%). Other complications included 2 reported cases of catheter malposition (4.6%), and 1 case each of arterial puncture (2.3%), pneumothorax (2.3%), and skin infection (2.3%). CONCLUSION: The results suggest that ultrasound-guided IJV catheterization can be performed easily and without any serious complications in pediatric patients, even when performed by visiting house staff. Therefore, ultrasound-guided IJV catheterization is strongly recommended for critically ill pediatric patients. PMID- 25932036 TI - Neuroprotective effects of mild hypoxia in organotypic hippocampal slice cultures. AB - PURPOSE: The aim of this study was to investigate the potential effects of mild hypoxia in the mature and immature brain. METHODS: We prepared organotypic slice cultures of the hippocampus and used hippocampal tissue cultures at 7 and 14 days in vitro (DIV) to represent the immature and mature brain, respectively. Tissue cultures were exposed to 10% oxygen for 60 minutes. Twenty-four hours after this hypoxic insult, propidium iodide fluorescence images were obtained, and the damaged areas in the cornu ammonis 1 (CA1), CA3, and dentate gyrus (DG) were measured using image analysis. RESULTS: In the 7-DIV group compared to control tissue, hypoxia-exposed tissue showed decreased damage in two regions (CA1: 5.59%+/-2.99% vs. 4.80%+/-1.37%, P=0.900; DG: 33.88%+/-12.53% vs. 15.98%+/-2.37%, P=0.166), but this decrease was not statistically significant. In the 14-DIV group, hypoxia-exposed tissue showed decreased damage compared to control tissues; this decrease was not significant in the CA3 (24.51%+/-6.05% vs. 18.31%+/-3.28%, P=0.373) or DG (15.72%+/-3.47% vs. 9.91%+/-2.11%, P=0.134), but was significant in the CA1 (50.91%+/-5.90% vs. 32.30%+/-3.34%, P=0.004). CONCLUSION: Although only CA1 tissues cultured for 14 DIV showed significantly less damage after exposure to hypoxia, the other tissues examined in this study showed a tendency towards less damage after hypoxic exposure. Therefore, mild hypoxia might play a protective role in the brain. PMID- 25932037 TI - Autosomal dominant hypocalcemia with Bartter syndrome due to a novel activating mutation of calcium sensing receptor, Y829C. AB - The calcium sensing receptor (CaSR) plays an important role in calcium homeostasis. Activating mutations of CaSR cause autosomal dominant hypocalcemia by affecting parathyroid hormone secretion in parathyroid gland and calcium resorption in kidney. They can also cause a type 5 Bartter syndrome by inhibiting the apical potassium channel in the thick ascending limb of the loop of Henle in the kidney. This study presents a patient who had autosomal dominant hypocalcemia with Bartter syndrome due to an activating mutation Y829C in the transmembrane domain of the CaSR. Symptoms of hypocalcemia occurred 12 days after birth and medication was started immediately. Medullary nephrocalcinosis and basal ganglia calcification were found at 7 years old and at 17 years old. Three hypercalcemic episodes occurred, one at 14 years old and two at 17 years old. The Bartter syndrome was not severe while the serum calcium concentration was controlled, but during hypercalcemic periods, the symptoms of Bartter syndrome were aggravated. PMID- 25932038 TI - Urosepsis and postrenal acute renal failure in a neonate following circumcision with Plastibell device. AB - Plastibell is one of the three most common devices used for neonatal circumcision in the United States, with a complication rate as low as 1.8%. The Plastibell circumcision device is commonly used under local anesthesia for religious circumcision in male neonates, because of cosmetic reasons and ease of use. Occasionally, instead of falling off, the device may get buried under the skin along the shaft of the penis, thereby obstructing the normal flow of urine. Furthermore, the foreskin of neonates is highly vascularized, and hence, hemorrhage and infection are possible when the skin is cut. Necrosis of penile skin, followed by urethral obstruction and renal failure, is a serious surgical mishap requiring immediate corrective surgery and medical attention. We report a case of fulminant urosepsis, acute renal failure, and pyelonephritis in a 4-day old male neonate secondary to impaction of a Plastibell circumcision device. Immediate medical management was initiated with fluid resuscitation and mechanical ventilation; thereby correcting life threatening complications. Pediatricians and Emergency Department physicians should be cognizant of the complications from Plastibell circumcision device in order to institute appropriate and timely management in neonates. PMID- 25932039 TI - Osteonecrosis of the jaw in an AIDS patient: a case report. AB - We report a rare case of osteonecrosis of the jaw following necrotizing gingivitis in a Japanese AIDS patient. Intraoral examination showed exposed necrotic bone in the left mandible and spontaneous loss of teeth. This patient was successfully treated with highly active anti-retroviral therapy combined with minimally invasive surgical procedures to remove the osteonecrosis of the jaw. PMID- 25932040 TI - Efficacy of the Osaka Medical College (OMC) brace in the treatment of adolescent idiopathic scoliosis following Scoliosis Research Society brace studies criteria. AB - BACKGROUND: The efficacy of brace treatment for patients with adolescent idiopathic scoliosis (AIS) remains controversial. To make comparisons among studies more valid and reliable, the Scoliosis Research Society (SRS) has standardized criteria for brace studies in patients with AIS. The purpose of this study was to evaluate the efficacy of the Osaka Medical College (OMC) brace for AIS in accordance with the modified standardized criteria proposed by the SRS committee on bracing and non-operative management. METHODS: From 1999 through 2010, 31 consecutive patients with AIS who were newly prescribed the OMC brace and met the modified SRS criteria were studied. The study included 2 boys and 29 girls with a mean age of 12 years and 0 month. Patients were instructed to wear the brace for a minimum of 20 hours per day at the beginning of brace treatment. The mean duration of brace treatment was 4 years and 8 months. We examined the initial brace correction rate and the clinical outcomes of main curves evaluated by curve progression and surgical rate, and the compliance evaluated by the instruction adherence rate for all cases. The clinical course of the brace treatment was considered progression if >=6 degrees curvature increase occurred and improvement if >=6 degrees curvature decrease occurred according to SRS judgment criteria. RESULTS: The average initial brace correction rate was 46.8%. In 10 cases the curve progressed, 6 cases the curve improved, and 15 cases the curve remained unchanged (success rate: 67.7%). The mean instruction adherence rate, that was defined the percentage of the visits that patients declared they mostly followed our instruction to total visits, was 53.7%. The success rate was statistically higher in the patient group whose instruction adherence rate was greater than 50% (88.2%) as compared with in those 50% or less (42.8%). CONCLUSIONS: OMC brace treatment for AIS patients could alter the natural history and significantly decreased the progression of curves to the threshold for surgical intervention. Better instruction adherence of brace wear associated with greater success. PMID- 25932041 TI - Psychological impact of identifying character strengths in people with psychosis. AB - A one group pre-post test design investigated the impact of identifying character strengths using the Values In Action Inventory of Strengths (VIA-IS) with individuals with early psychosis (N = 29). Post-test improvements in positive affect and cognitive performance were observed. Neither self-esteem nor self efficacy improved. The technique appears feasible for use within early intervention services. Adverse consequences should be monitored and additional components considered to enhance benefits. PMID- 25932042 TI - Highlights from the 14(th) St Gallen International Breast Cancer Conference 2015 in Vienna: Dealing with classification, prognostication, and prediction refinement to personalize the treatment of patients with early breast cancer. AB - The refinement of the classification, the risk of relapse and the prediction of response to multidisciplinary treatment for early breast cancer has been the major theme of the 14(th) St Gallen International Breast Cancer Consensus Conference 2015. The meeting, held in Vienna, assembled 3500-4000 participants from 134 countries worldwide. It culminated, on the final day, with the International Consensus Session, delivered by 40-50 of the world's most experienced opinion leaders in the field of breast cancer treatment. The panelist addressed the "semantic" classification of breast cancer subtypes by pathology based biomarkers (e.g. estrogen receptor, progesterone receptor and HER2) vs genomic classifiers. They also refined the biomarker prognostication dissecting the impact of the various gene signatures and pathologic variables in predicting the outcome of patients with early breast cancer in terms of early and late relapse. Finally they addressed the challenges stemming from the intra- and inter observer variability in the assessment of pathologic variables and the role of gene signatures for the prediction of response to specific therapeutic approach such as endocrine therapy and chemotherapy and for personalizing local treatment of patients with early breast cancer. The vast majority of the questions asked during the consensus were about controversial issues. The opinion of the panel members has been used to implement guidance for treatment choice. This is the unique feature of the St. Gallen Consensus, ensuring that the resulting recommendations will take due cognizance of the variable resource limitations in different countries. Information derived from evidence based medicine and large meta-analyses is of obvious and enormous value. The weakness of this approach is that it gives particular weight to older trials (which have accumulated more event endpoints) and is frequently unable to collect sufficient detail on the patients and tumors in the trials to allow assessment of whether the treatments which are better on average offer equal value to all currently definable patient subgroups. What St Gallen can provide is clinically useful updated breast cancer treatment consensus for the majority of patients treated outside of clinical trials (>90%) in most countries. PMID- 25932043 TI - OECI-EACR precision medicine for cancer: Conference report 1-4 March 2015, Luxembourg. AB - The 'Precision Medicine for Cancer' was the first meeting of a new series of conferences organised biannually by the European Association for Cancer Research (EACR) and the Organisation for European Cancer Institutes (OECI). The main objective of the meeting was to focus on novel topics in precision medicine by allowing strong interactions between participants and to access the speakers easily. As the first implementations of personalised medicine are appreciated in the clinic, the aim of the meeting was to further educate both researchers and clinicians and learn more from the novel approaches in the field. Similarly, the interaction between two organisations-the research-oriented EACR and the clinic oriented OECI-was of a great value for the meeting. This OECI-EACR 2015 report will highlight the major findings of this outstanding meeting. PMID- 25932046 TI - Cancer mutation screening: Comparison of high-resolution melt analysis between two platforms. AB - High-resolution melt analysis (HRMA) is a cheap and reliable post-polymerase chain reaction (PCR) cancer mutation screening technique, which is fast gaining clinical relevance. The HRMA capabilities of the LightScanner (Idaho Technology) have been severally studied. However, the ABI 7500 HRM has not been tested against the purpose-built HRM instrument such as the LightScanner. DNA from formalin-fixed, paraffin-embedded gastric cancer, colorectal cancer, and normal tissue as well as from colorectal cancer cell lines were amplified at exons 2, 3, and 4 of KRAS, and at exons 11 and 15 of BRAF in the ABI 7500 fast real-time PCR machine and subjected to melting both on the ABI and on the LightScanner. HRMA data were analysed with the ABI HRM software v2.0.1 and the LightScanner Call-IT 2.5. We tested the ABI 7500 HRM for internal precision, accuracy, sensitivity, and specificity at mutation screening relative to the LightScanner, using crude percentage concordance, kappa statistics, and the area under the receiver operator characteristics (AUROC) curve on SPSS version 19. The results show that the ABI 7500 HRMA has a high internal precision, and excellent concordance, sensitivity, and specificity at mutation screening compared with the LightScanner. However, in contrast to the LightScanner HRM software analysis, the ABI HRM software v.2.0.1, cannot distinguish real from certain pseudovariations in PCR amplicons that are sometimes brought about by the artefacts of the melting process. In conclusion, the ABI HRM has a comparable performance level with the LightScanner, although in certain respects mentioned previously, the LightScanner has an edge over the ABI. PMID- 25932045 TI - Repurposing Drugs in Oncology (ReDO)-itraconazole as an anti-cancer agent. AB - Itraconazole, a common triazole anti-fungal drug in widespread clinical use, has evidence of clinical activity that is of interest in oncology. There is evidence that at the clinically relevant doses, itraconazole has potent anti-angiogenic activity, and that it can inhibit the Hedgehog signalling pathway and may also induce autophagic growth arrest. The evidence for these anticancer effects, in vitro, in vivo, and clinical are summarised, and the putative mechanisms of their action outlined. Clinical trials have shown that patients with prostate, lung, and basal cell carcinoma have benefited from treatment with itraconazole, and there are additional reports of activity in leukaemia, ovarian, breast, and pancreatic cancers. Given the evidence presented, a case is made that itraconazole warrants further clinical investigation as an anti- cancer agent. Additionally, based on the properties summarised previously, it is proposed that itraconazole may synergise with a range of other drugs to enhance the anti-cancer effect, and some of these possible combinations are presented in the supplementary materials accompanying this paper. PMID- 25932044 TI - Biology of colorectal cancer. AB - Colorectal cancer is a serious health problem, a challenge for research, and a model for studying the molecular mechanisms involved in its development. According to its incidence, this pathology manifests itself in three forms: family, hereditary, and most commonly sporadic, apparently not associated with any hereditary or familial factor. For the types having inheritance patterns and a family predisposition, the tumours develop through defined stages ranging from adenomatous lesions to the manifestation of a malignant tumour. It has been established that environmental and hereditary factors contribute to the development of colorectal cancer, as indicated by the accumulation of mutations in oncogenes, genes which suppress and repair DNA, signaling the existence of various pathways through which the appearance of tumours may occur. In the case of the suppressive and mutating tracks, these are characterised by genetic disorders related to the phenotypical changes of the morphological progression sequence in the adenoma/carcinoma. Moreover, alternate pathways through mutation in BRAF and KRAS genes are associated with the progression of polyps to cancer. This review surveys the research done at the cellular and molecular level aimed at finding specific alternative therapeutic targets for fighting colorectal cancer. PMID- 25932047 TI - Treatment of early-stage HER2+ breast cancer-an evolving field. AB - The evolving field of HER2-targeted therapy has significantly improved the outcome of women diagnosed with HER2-positive invasive breast cancer. In this review, we sought to summarise the efficacy of trastuzumab-based regimens in the adjuvant and neoadjuvant setting with a special emphasis on relevant clinical questions: treatment duration, sequence of trastuzumab administration, toxicity, the role of anthracycline-based regimens, and optimal management of small HER2+ tumours. Controversial topics are discussed taking into consideration the development of modern anti-HER2 agents. PMID- 25932048 TI - A rare presentation of primary leiomyosarcoma of ovary in a young woman. AB - Primary ovarian leiomyosarcoma is a very rare tumour which is most commonly seen in postmenopausal women. A case is described here involving a 30-year-old female who presented with pain in the abdomen. The patient underwent laparotomy with peritoneal lavage, bilateral salpingo-oophorectomy, and total abdominal hysterectomy. Microscopic and immunohistochemical findings established the diagnosis of primary ovarian leiomyosarcoma. Similar to sarcoma of other tissues, an adjuvant chemotherapy regimen consisting of vincristine, epirubicin, and cyclophosphamide was given for this present case. Six months after treatment completion, the patient is on regular follow-up and disease-free on clinical and radiological examination. PMID- 25932049 TI - Curcumin modulates cellular AP-1, NF-kB, and HPV16 E6 proteins in oral cancer. AB - In this study, we investigated the effects of the natural antioxidant curcumin on the HPV16-positive oral carcinoma cell line 93VU147T and demonstrated that curcumin is not only a potent inhibitor for the activity of host nuclear transcription factors AP-1 and NF-kB but it also selectively suppresses transcription of the HPV16/E6 oncogene during the carcinogenic process in oral cancer cells. This study suggests a therapeutic potential of curcumin for high risk human papilloma virus (HPV)-infected oral cancers. PMID- 25932050 TI - Draft genomes of four enterotoxigenic Escherichia coli (ETEC) clinical isolates from China and Bangladesh. AB - BACKGROUND: Enterotoxigenic Escherichia coli (ETEC) is an important pathogen that causes childhood and travelers' diarrhea. Here, we present the draft genomes of four ETEC isolates recovered from stool specimens of patients with diarrhea in Beijing, China and Dhaka, Bangladesh, respectively. RESULTS: We obtained the draft genomes of ETEC strains CE516 and CE549 isolated in China, and E1777 and E2265 isolated in Bangladesh with a length of 5.1 Mbp, 4.9 Mbp, 5.1 Mbp, and 5.0 Mbp, respectively. Phylogenetic analysis indicated that the four strains grouped with the classical Escherichia coli phylogenetic groups A and B1 and three of them including a multi drug-resistant Chinese isolate (CE549) belonged to two major ETEC lineages distributed globally. The heat stable toxin (ST) structural gene (estA) was present in all strains except in strain CE516, and the heat labile toxin (LT) operon (eltAB) was present in all four genomes. Moreover, different resistance gene profiles were found between the ETEC strains. CONCLUSIONS: The draft genomes of the two isolates CE516 and CE549 represent the first genomes of ETEC reported from China. Though we revealed that ETEC is uncommon in Beijing, China, however, when it does occur, multi-drug resistance and ESBL positive isolates might pose a specific public health risk. Furthermore, this study advances our understanding of prevalence and antibiotic resistance of ETEC in China and adds to the number of sequenced strains from Bangladesh. PMID- 25932051 TI - Improving protein-ligand binding site prediction accuracy by classification of inner pocket points using local features. AB - BACKGROUND: Protein-ligand binding site prediction from a 3D protein structure plays a pivotal role in rational drug design and can be helpful in drug side effects prediction or elucidation of protein function. Embedded within the binding site detection problem is the problem of pocket ranking - how to score and sort candidate pockets so that the best scored predictions correspond to true ligand binding sites. Although there exist multiple pocket detection algorithms, they mostly employ a fairly simple ranking function leading to sub-optimal prediction results. RESULTS: We have developed a new pocket scoring approach (named PRANK) that prioritizes putative pockets according to their probability to bind a ligand. The method first carefully selects pocket points and labels them by physico-chemical characteristics of their local neighborhood. Random Forests classifier is subsequently applied to assign a ligandability score to each of the selected pocket point. The ligandability scores are finally merged into the resulting pocket score to be used for prioritization of the putative pockets. With the used of multiple datasets the experimental results demonstrate that the application of our method as a post-processing step greatly increases the quality of the prediction of Fpocket and ConCavity, two state of the art protein-ligand binding site prediction algorithms. CONCLUSIONS: The positive experimental results show that our method can be used to improve the success rate, validity and applicability of existing protein-ligand binding site prediction tools. The method was implemented as a stand-alone program that currently contains support for Fpocket and Concavity out of the box, but is easily extendible to support other tools. PRANK is made freely available at http://siret.ms.mff.cuni.cz/prank. PMID- 25932052 TI - Emergency medical services key performance measurement in Asian cities. AB - BACKGROUND: One of the key principles in the recommended standards is that emergency medical service (EMS) providers should continuously monitor the quality and safety of their services. This requires service providers to implement performance monitoring using appropriate and relevant measures including key performance indicators. In Asia, EMS systems are at different developmental phases and maturity. This will create difficultly in benchmarking or assessing the quality of EMS performance across the region. An attempt was made to compare the EMS performance index based on the structure, process, and outcome analysis. FINDINGS: The data was collected from the Pan-Asian Resuscitation Outcome Study (PAROS) data among few Asian cities, namely, Tokyo, Osaka, Singapore, Bangkok, Kuala Lumpur, Taipei, and Seoul. The parameters of inclusions were broadly divided into structure, process, and outcome measurements. The data was collected by the site investigators from each city and keyed into the electronic web-based data form which is secured strictly by username and passwords. Generally, there seems to be a more uniformity for EMS performance parameters among the more developed EMS systems. The major problem with the EMS agencies in the cities of developing countries like Bangkok and Kuala Lumpur is inadequate or unavailable data pertaining to EMS performance. CONCLUSIONS: There is non-uniformity in the EMS performance measurement across the Asian cities. This creates difficulty for EMS performance index comparison and benchmarking. Hopefully, in the future, collaborative efforts such as the PAROS networking group will further enhance the standardization in EMS performance reporting across the region. PMID- 25932053 TI - Hypertensive emergency presenting as blurry vision in a patient with hypertensive chorioretinopathy. AB - A 42-year-old man presented with 3 weeks of blurry vision in the right eye. His exam was significant for decreased vision in the right eye, diffuse retinopathy in both eyes, and serous retinal detachment in the right eye. The patient was found to be hypertensive with blood pressure of 256/160 mmHg. He was diagnosed with hypertensive emergency with end-organ damage due to features of hypertensive chorioretinopathy. He was admitted with abnormal urinalysis, elevated troponin, and abnormal EKG. After appropriate control of his blood pressure, his vision and his labs normalized. Hypertensive emergencies can be manifested first in the eyes. When the choroid is associated, the hypertensive event is often more acute and associated with increased morbidity. It is imperative to obtain a fundus exam in any patient with elevated blood pressure and concomitant vision complaints. PMID- 25932054 TI - Simultaneous onset of Alzheimer's disease in a husband and wife in their mid fifties: what do we really know about environmental factors? AB - INTRODUCTION: Environmental factors can play a role in the pathogenesis of Alzheimer's disease. We present a case of the simultaneous onset of Alzheimer's disease in two middle aged adults. CASE PRESENTATION: A married couple ages 54 year and 51-year-old female cohabiting together were diagnosed with Alzheimer's disease within the same year. The patient's both developed cognitive decline shortly after a major renovation of their property and followed a similar disease course. The diagnosis was supported by clinical presentation and tissue pathology on autopsy. CONCLUSION: Environmental factors may play a role in the pathogenesis of Alzheimer's disease. Further understanding of the disease cascade is required. PMID- 25932055 TI - Trichoscopy findings in loose anagen hair syndrome: rectangular granular structures and solitary yellow dots. AB - BACKGROUND: Loose anagen hair syndrome (LAHS) is typically diagnosed in girls older than 2 years who present with hair that "will not grow". Hair microscopic examination shows absent inner and outer root sheaths, ruffling of the cuticle on the proximal hair shaft and deformed pigmented anagen bulbs. OBJECTIVE: The aim of the study was to assess whether there are characteristic trichoscopic features favoring the diagnosis of LAHS. PATIENTS AND METHODS: Eighty nine children patients were included into the study (24 girls with LAHS, 25 with alopecia areata, 20 with telogen effluvium and 20 healthy children). In all groups trichoscopy was performed. Trichoscopy images were analyzed for abnormalities in the hairs shafts, the hair follicle openings and the interfollicular area. RESULTS: Dirty dots were present in all groups. A unique feature of LAHS was the presence of rectangular black granular structures which differs from dense black dots seen in patients with alopecia areata. This feature was observed in 71% of patients with LAHS. Follicular units with single hairs constituted 92,9% of hair units in these patients (65,5% in telogen effluvium and 53% in the control group). Solitary yellow dots were found in 50% of patient with LAHS and in 24% of patients with alopecia areata, but was not found in control group or in patients with telogen effluvium. CONCLUSION: The trichoscopy features favoring the diagnosis of LAHS are: rectangular black granular structures, solitary yellow dots and major predominance of follicular units with single hairs. PMID- 25932056 TI - Linear psoriasis following the typical distribution of the sciatic nerve. AB - BACKGROUND: Some studies suggest that the nervous system plays a role in the onset of psoriasis and psoriasis flares including the symmetry of lesions, sparing of denervated skin and the role of stress in inducing lesions. MAIN OBSERVATIONS: We describe an unusual case of psoriasis occurring in the same distribution as sciatic pain from a prolapsed intervertebral disc. The patient, a 45-year-old man with plaque psoriasis was treated with ustekinumab for 104 weeks, at a standard dose. During the eight month of therapy he developed an asymptomatic linear eruption on the left lower extremity along the distribution of the sciatic nerve. On examination, erythematous scaly plaques were noted. Histopathology confirmed the diagnosis of psoriasis. The treatment was continued and clobetasol proprionate 0.05% cream was added. At week 12 after the eruption, the patient reported a pain radiating through the buttock and posterior left leg during jogging. Magnetic resonance imaging showed lumbar disc herniation with compression of the L5-S1 spinal nerve roots. The patient stopped running and the psoriasis spontaneously receded, in a slow but complete fashion, without any local treatment. CONCLUSION: There is substantial evidence that nerves play a key role in the pathogenesis of psoriasis. We hypothesized that local TNF-alpha, neuropeptides and nerve growth factor, which are produced by nerve root compression, played a critical role in this case of psoriasis onset in an area of pain from a bulging lumbar intervertebral disc. To our knowledge, a correlation of psoriasis and nerve root compression has not been described previously. PMID- 25932057 TI - Symmetrical drug-related intertriginous and flexural exanthema (Baboon syndrome) associated with infliximab. AB - BACKGROUND: Symmetrical drug related intertriginous and flexural exanthema (SDRIFE or Baboon syndrome) is a symmetrical contact dermatitis on inverse regions of the body. The disorder is easily differentiated from other drug eruptions by its typical appearance and lack of other concurrent findings. OBSERVATION: A 50-year-old male patient presented to our clinic complaining of a rash that had developed two days after the tenth infliximab infusion for psoriasis and reoccurred after consecutive infusions. The physical examination revealed a bilateral intergluteal, inguinal, abdominal, axillary, antecubital and neck region macular erythematous rash. There were no other systemic findings. The laboratory values were within normal range. The patient was diagnosed with symmetrical drug-related intertriginous and flexural exanthema associated with infliximab treatment based on dermatological findings, histopathology and the results of the provocation test. The lesions resolved permanently after the patient was swiched from infliximab to adalimumab. CONCLUSION: Various cutaneous adverse events of anti-tumor necrosis factor alpha treatment have already been reported. The increased use of these agents can lead to a wider variety of drug induced skin lesions, such as the reported Baboon syndrome. PMID- 25932058 TI - Primary cutaneous gamma/delta T-cell lymphoma. An atypical case with bone marrow granulomas. AB - BACKGROUND: Primary cutaneous gamma/delta T-cell lymphoma is a rare variant of peripheral T-cell lymphoma which has been only recently set apart from subcutaneous panniculitis-like T-cell lymphoma and is known for its aggressive nature. MAIN OBSERVATION: We hereby report a case of primary cutaneous gamma/delta T-cell lymphoma in a 35-year-old man with bone marrow granulomas, an unexpected feature in this lymphoma. The patient was treated with combination chemotherapy. Partial response was obtained, followed by relapse. Allogeneic stem cell transplantation was then carried out, and full remission was achieved. CONCLUSION: Bone marrow granulomas can be an accompanying feature in primary cutaneous gamma/delta T-cell lymphoma. PMID- 25932059 TI - Recalcitrant oral squamous cell papilloma lesions in two HIV-infected patients successfully treated with topical imiquimod. AB - BACKGROUND: Squamous cell papilloma is a benign mucosal disease associated with human papillomavirus. Its presence in human immunodeficiency virus (HIV)-infected patients has rarely been reported. Therapeutic modalities for oral squamous cell papilloma have limited success and recurrences are frequent in HIV-infected subjects. Imiquimod, is a topical immunomodulator successfully used in some human papillomavirus-related oral lesions. However, its use for oral squamous cell papillomas in HIV-infected individuals has never been described. OBSERVATIONS: We report two male adult patients with HIV-infection, B2 and C3 stage respectively, undergoing antiretroviral therapy, with multiple recalcitrant oral squamous cell papillomas, predominantly affecting the masticatory mucosa. These lesions were successfully treated with daily topical imiquimod 5% cream for a few weeks, with only mild and well-tolerated side effects. No recurrences were observed after a follow-up period of over 20 months. CONCLUSIONS: Our cases highlight the value of imiquimod for the non-invasive treatment of multiple persistent oral squamous cell papillomas in two HIV-infected patients. PMID- 25932060 TI - Photoletter to the editor: Psoriatic erythroderma associated with bullous pemphigoid: clinical appearance and histopathology. AB - Psoriasis and bullous pemphigoid represent two clinically well-characterized, chronic, inflammatory skin conditions. The concomitant occurrence of these two entities in a patient is rare. We report a 62-year-old male with personal history of psoriasis vulgaris who developed disseminated bullous pemphigoid associated with psoriatic erythroderma. Skin histopathology from a scaly plaque was consistent with the diagnosis of psoriasis and showed subepidermal blister with inflammatory infiltrate of eosinophils with some neutrophils. PMID- 25932061 TI - Photoletter to the editor: Basal cell carcinoma on the vermilion lip. AB - The vermilion and vermilion border are rare locations for basal cell carcinoma. We report a case of a 72-year-old woman, who presented with an asymptomatic erosive lesion on the vermilion area of the upper lip. Histopathology examination was consistent with basal cell carcinoma. We suggest that basal cell carcinoma should be included in the differential diagnosis of erosive/ulcerative lesions arising on the vermilion area of the lip. PMID- 25932062 TI - Photoletter to the editor: Giant cutaneous horn associated with squamous cell carcinoma. AB - A 90-year-old patient presented with a large cutaneous horn (cornu cutaneum) of nine-year duration arising at her right cheek. The lesion was removed by surgery. Histology was reported as cornu cutaneum with a well-differentiated squamous cell carcinoma at its base. Cutaneous horn is morphological designation for protuberant mass of keratin that resembles the horn of an animal. Such lesions appear on sun-exposed skin areas like upper parts of the face and ears in elderly patients. Large cutaneous horns (> 1 cm) tend to be more commonly associated with squamous cell carcinoma compared to smaller cutaneous horns, particularly when present on the face. PMID- 25932063 TI - [Bilateral choroidal metastases of unknown origin: report of a case]. PMID- 25932064 TI - [Overweight and obesity in the general population of 5-19 years in urban Bamako (Mali)]. PMID- 25932065 TI - [Overweight and obesity in the population over 20 years in urban Bamako (Mali)]. PMID- 25932066 TI - Self inflicted human teeth bites: a case report. AB - Human infighting has been a part of our civilization since times immemorial. These incidences may go unnoticed or may attract attention of law enforcing agencies depending upon the severity of the offence. Though weapons are generally employed to inflict injuries, rare cases have been reported in literature where human teeth have been used to serve this purpose. Human bites may be self inflicted or self suffered in connivance with others to level an allegation against an adversary. We are presenting here such a case where such injuries were produced to bring a false charge against a neighbor. PMID- 25932067 TI - Glycaemic control in diabetic patients in Zambia. AB - INTRODUCTION: The glycaemic control status of diabetic patients affects the management of their disorder. We examined the glycaemic control and clinical factors that may influence the achievement of the glycaemic control targets among diabetic out-patients. METHODS: This was a hospital based cross-sectional study carried out at the University Teaching Hospital diabetic clinic in Lusaka, Zambia. A simple random sample of 198 consenting participants was selected from diabetic out-patients between September and December 2013. A structured interview schedule was used to capture socio-demographic data as well as needed clinical data from clients' medical records and laboratory results. Multivariate binary logistic regression analysis was carried out to examine factors that may be associated with the glycaemic control status of these diabetic patients. RESULTS: Overall (n = 198), mean (SD) age was 53.19 +/- 13.32 years. Majority (61.3%) of the patients had poor glycaemic control status (HbA1c >= 49 mmol/mol). Insulin treatment (OR 0.13, 95% CI: 0.01 - 1.41), systolic blood pressure (OR 1.04, CI: 1.00 - 1.08) and fasting plasma glucose (previous; OR 0.81, CI: 0.72 - 0.90 and current; OR 0.85, CI: 0.78 - 0.93) were statistically significantly associated with glycaemic control. The poor glycaemic control observed in this study is similar to that reported in other published studies. CONCLUSION: We found evidence of poor glycaemic control in the study population suggesting need to explore the reasons for this. Association of Insulin, systolic blood pressure and fasting plasma glucose with glycaemic control further suggests the efficiency of traditional basic monitoring parameters which should be exploited in sharpening primary preventive strategies especially those that support lifestyle modification. Such efforts should also be integrated in all information, education and communication strategies that target but not limited to hospital based patients too. PMID- 25932068 TI - [Morphometric study of the outer ear in young adults]. PMID- 25932069 TI - [Knowledge, attitudes and practices of the population of SAMBWA health area in relation to the treatment of onchocerciasis with ivermectin under community directives]. PMID- 25932070 TI - [Giant calculi on enterocystoplasty]. PMID- 25932071 TI - [Pain associated with health care: the reality in Befelatanana University Hospital Antananarivo, Madagascar]. PMID- 25932072 TI - The prevalence and plasmid profile of non-typhoidal salmonellosis in children in Lagos metropolis, South-western Nigeria. AB - INTRODUCTION: Non-typhoidal Salmonella is the causative agent of gastroenteritis, a food-borne and zoonotic infection which is a major cause of high morbidity and death among children under 5 years of age especially from resource poor settings like the developing countries. METHODS: This study was carried out for 6 months to determine the prevalence and plasmid profile of non-typhoidal salmonellosis in children in Lagos metropolis. A total of 105 stool samples were collected from diarrheal children aged 3 months to 12 years and processed during this period. The isolates were identified using Selenite F Broth, Salmonella-Shigella Agar, Kligler Iron Agar, and Motility-indole-Urea medium, citrate and sugar utilization tests. RESULTS: A total number of 127 isolates were identified, 2 of which are Salmonella enteritidis (1.6%). The non-typhoidal Salmonellae were sensitive to ciprofloxacin, cetotaxime, streptomycin, cotrimxazole and tetracycline. Only one of the 2 isolates (50%) was sensitive to amoxillin and sulphonamide while none of them (0%) was sensitive to cefuroxime. CONCLUSION: The plasmid analysis of the isolates showed that they harboured no detectable plasmids; this suggests that the resistance was chromosomally mediated. PMID- 25932073 TI - Health instruction in Nigerian schools: what are the missing links? AB - INTRODUCTION: School health instruction (SHI) is the instructional aspects of school health programme. It provides information on key health issues to school children who are in their formative years. METHODS: A cross sectional descriptive study of all the primary schools in a focal Local Government Area in Nigeria was carried out to ascertain the implementation of SHI with regards to the contents, methods of delivery and teachers preparation for health teaching using an evaluation checklist for SHI. RESULTS: There were more female pupils enrolled in the study area compared to their male counterparts with a male to female ratio of 0.9:1.0 and only 3.0% of the teachers had In-service training on health related issues in the previous five years preceding the study. 79.4% of the teachers had the recommended qualification to work in the schools. Teachings on emotional health, communicable diseases and safety education were sparingly given by 1.6%, 4.7% and 56% schools respectively. Only three (4.7%) schools (all private) had health instruction given by designated health education staff. No school gave health instruction at least thrice a week as recommended. CONCLUSION: Compliance with the implementation of SHI was very poor in the study area. PMID- 25932074 TI - [Migratory IUD: report of two cases and review of the literature]. PMID- 25932075 TI - [Unusual localization of tuberculosis: tuberculous arthritis of the thumb bone]. PMID- 25932076 TI - Spinal cord compression: an unusual presentation of hepatocellular carcinoma. AB - Hepatocellular carcinoma is the 5(th) most common cancer in men and the 2(nd) common cause of death from cancer worldwide. The tumour commonly metastasizes to the lungs, regional lymph nodes and bone. Spinal cord compression secondary to metastatic disease as a first presentation is uncommon. We describe a patient who presented with paraplegia as a first presentation of hepatocellular carcinoma. 46 year old Namibian man presented with progressive leg weakness that was associated with a dull back ache and inability to pass urine and stool. He had no history of trauma nor did he have chronic cough, night sweats or fevers. He has been treated several times for alcohol dependence. On examination he was wasted, power 0/5 in both lower limbs and a sensory level at T12. He also had a non-tender hepatomegaly with Alpha-fetoprotein of 2000. The Chest X-ray and Chest CT showed nodular opacities indicating metastatic disease and the X-ray and CT of the thoracic spine showed osteolytic lesion with destruction of the pedicle of L1. Liver and spinal biopsy confirmed the hepatocellular carcinoma. The extra hepatic manifestations of HCC are diverse and Spinal cord metastasis is of pertinent clinical importance and should thus be greatly considered. PMID- 25932077 TI - [Diagnosis and prevalence of metabolic syndrome in diabetics followed in a context of limited resources: the case of Burkina Faso]. PMID- 25932078 TI - [Kidney transplantation in Morocco: are hemodialysis caretakers well informed?]. PMID- 25932079 TI - Multicystic tuberculosis pericarditis. PMID- 25932080 TI - Direct observation of outpatient management of malaria in a rural Ghanaian district. AB - INTRODUCTION: In Ghana, malaria continues to top outpatient morbidities; accounting for about 40% of all attendances. Effective case-management is key to its control. We evaluated case-management practices of uncomplicated malaria in Kwahu South District (KSD) health facilities to determine their conformity to guidelines. METHODS: We conducted a cross sectional survey at all public health facilities in three randomly selected sub-districts in KSD. A non-participatory observation of suspected malaria consultations was conducted. Suspected malaria was defined as any person with fever (by history or measured axillary temperature > or equal 37.5 oC) presenting at the selected health facilities between 19th and 29th April 2013. Findings were expressed as frequencies, relative frequencies, mean (+/- standard deviation) and median. RESULTS: Of 70 clinical observations involving 10 prescribers in six health facilities, 40 (57.1%) were females and 16 (22.9%) were below five years. Median age was 18 years (interquartile range: 5 33). Overall, 63 (90.0%) suspected case-patients had diagnostic tests. Two (3.6%) were treated presumptively. All 31 confirmed and 10 (33.3%) of the test negative case-patients received Artemisinin-based Combination Therapies (ACTs). However, only 12 (27.9%) of the 43 case-patients treated with ACT received Artesunate Amodiaquine (AA). Only three (18.8%) of the under-fives were examined for non malarial causes of fever. Mean number of drugs per patient was 3.7 drugs (+/- 1.1). Only 45 (64.3%) patients received at least one counseling message. CONCLUSION: Conformity of malaria case-management practices to guidelines in KSD was suboptimal. Apart from high rate of diagnostic testing and ACT use, prescription of AA, physical examination and counseling needed improvement. PMID- 25932081 TI - [Post cesarean Ogilvie syndrome: a mysterious complication: about a case]. PMID- 25932082 TI - Healthcare in Equatorial Guinea, West Africa: obstacles and barriers to care. AB - INTRODUCTION: The provision of healthcare services in developing countries has received increasing attention, but inequalities persist. One nation with potential inequalities in healthcare services is Equatorial Guinea (Central-West Africa). Mitigating these inequalities is difficult, as the Equatoguinean healthcare system remains relatively understudied. METHODS: In this study, we interviewed members of the healthcare community in order to: 1) learn which diseases are most common and the most common cause of death from the perspective of healthcare workers; and 2) gain an understanding of the healthcare community in Equatorial Guinea by describing how: a) healthcare workers gain their professional knowledge; b) summarizing ongoing healthcare programs aimed at the general public; c) discussing conflicts within the healthcare community and between the public and healthcare providers; d) and addressing opportunities to improve healthcare delivery. RESULTS: We found that some causes of death, such as serious injuries, may not be currently treatable in country, potentially due to a lack of resources and trauma care facilities. In addition, training and informational programs for both healthcare workers and the general public may not be effectively transmitting information to the intended recipients. This presents hurdles to the healthcare community, both in terms of having professional competence in healthcare delivery and in having a community that is receptive to medical care. CONCLUSION: Our data also highlight government-facility communication as an opportunity for improvement. Our research is an important first step in understanding the context of healthcare delivery in Equatorial Guinea, a country that is relatively data poor. PMID- 25932083 TI - Total rupture of hydatid cyst of liver in to common bile duct: a case report. AB - Rupture of hydatid liver cyst into biliary tree is frequent complications that involve the common hepatic duct, lobar biliary branches, the small intrahepatic bile ducts,but rarely rupture into common bile duct. The rupture of hydatid cyst is serious life threating event. The authors are reporting a case of total rupture of hydatid cyst of liver into common bile duct. A 50-year-old male patient who presented with acute cholangitis was diagnosed as a case of totally rupture of hydatid cyst on Abdominal CT Scan. Rupture of hydatid cyst of liver into common bile duct and the gallbladder was confirmed on surgery. Treated by cholecystectomy and T-tube drainage of Common bile duct. PMID- 25932084 TI - The association between the rs11549465 polymorphism in the hif-1alpha gene and cancer risk: a meta-analysis. AB - PURPOSE: The associations between hypoxia-inducible factor-1 alpha (HIF-1alpha) and clinicopathological characteristics of cancers have been evaluated in various studies, with the conflicting results. The common rs11549465 (1772C/T) genetic polymorphism has been reported to be functional and may contribute to genetic susceptibility to cancers. However, the association between rs11549465 (1772C/T) and cancer risk remains inconclusive. METHODS: To better understand the role of rs11549465 (1772C/T) polymorphism in global cancer, we conducted this comprehensive meta-analysis encompassing 7807 cases and 8633 controls. RESULTS: Overall, the rs11549465 (1772C/T) genetic polymorphism was associated with higher cancer risk, especially exists in Asians. In the stratified analysis, significant associations were found between the HIF-1 rs11549465 polymorphism and gynecologic cancer among Caucasian population. We observed that the TT genotype might modulate gynecologic cancer (OR=9.92 [2.15-45.66]) risk comparing with the CC genotype. Moreover, a significantly increased lung and breast cancer risk was found among Asian population comparing with Caucasian population. When stratified by study design, significantly elevated susceptibility to cancer was found among hospital -based studies. CONCLUSIONS: Our meta-analysis suggested that the HIF-1 rs11549465 (1772C/T) genetic polymorphism is significantly associated with higher risk among Asian population and lower risk among Caucasian population in breast and lung cancer, and this SNP was significantly associated with the gynecologic cancer among Caucasian population. The effect of the rs11549465 polymorphism on cancer especially exists in Asians. PMID- 25932085 TI - Posterior reversible encephalopathy syndrome during the peripartum period: report of four cases and review of the literature. AB - Posterior reversible encephalopathy syndrome (PRES) is a cliniconeuroradiologic disorder affecting the brain's occipital and parietal lobes characterized by altered mental status, seizures, headache and blurred vision. Eclampsia is one of the main causes of posterior reversible encephalopathy. We aimed to discuss here literature guided clinical and radiologic findings of four women who had experienced status epilepticus at peripartum period and diagnosed as PRES. PMID- 25932086 TI - Polymorphism of klotho G-395A and susceptibility of coronary artery disease in East-Asia population: a meta-analysis. AB - OBJECTIVE: To investigate the association between polymorphism of Klotho G-395A and susceptibility of coronary artery disease (CAD) in East-Asia population. METHODS: A total of 6 case-control studies involving 1560 patients and 1459 controls were analyzed in the study. PubMed, Embase, CBM disc, Wanfang database were searched for published case-control studies investigating the association between Klotho G-395A and CAD that were available before Dec. 2013. Fixed or random effect models were selected for odds ratio (OR) calculation. A Meta analysis was performed to estimate heterogeneity and the pooled odds ratio (OR) to evaluate the relationship between Klotho G-395A polymorphism and CAD. The sensitivity analysis was also assessed. RESULTS: There was no significant heterogeneity found (dominant genetic model: P = 0.2, I(2) = 30.8%). The pooled OR (95% CI) value of the frequencies of the Klotho G-395A genotype (GA + AA)/GG calculated by fixed effects mode was 1.24 (95% CI:1.06-1.45), P = 0.009. There was no significant heterogeneity among the remaining articles after using random effect model or excluding the article with the largest weight or the article with larger frequencies of the allele A, respectively. And the pooled OR (95% CI) value of the frequencies of the genotype (GA + AA)/GG were similar. Publication bias was not found by Begg's test. CONCLUSION: Klotho G-395A polymorphism may be a susceptible factor of CAD in East-Asia population. PMID- 25932087 TI - Management of primary gastric small cell carcinoma in China. AB - BACKGROUND: Primary gastric small cell carcinomas (GSCCs) are increasingly identified by endoscopy, and account for 15-20% of all gastric neuroendocrine tumors (NETs). GSCCs have the worst prognosis with the highest rate of metastases. PURPOSE: To provide useful information for clinicians and researchers to better manage patients with GSCC, we studied the clinical features of GSCC and explored the corresponding therapies and prognosis. METHODS: A literature search was conducted through PUBMED, EMBASE, CNKI and WanFang Databases using search terms "stomach" or "gastric" and "small cell carcinoma" or "poorly differentiated neuroendocrine carcinoma", for the period 1999 to 2012. And the cases reported were all from China. Relevant articles were identified through manual review. The reference lists of these articles were reviewed to include further appropriate articles. RESULTS: Two hundred and five eligible cases were analyzed. The median age of patients was 62 years, with a male-to-female ratio of 5.4:1. Of the tumors, 53.17% were located in the upper stomach, 25.37% in the mid, 18.54% in the distal stomach, the remaining 2.93% were found in the total stomach. The mean size was 68mm in maximum diameter, with a range of 15-150 mm. Of the one hundred and thirty-five patients, fifty appeared to be pure GSCCs, eighty-five were mixed. The median overall survival time of 195 patients was 18.50 months. The 1-, 2-, and 5-year average survival rates of 142 patients were 66.75%, 37.13%, and 20.15%, respectively. CONCLUSIONS: GSCC is a rare tumor and it is notoriously aggressive with a strong propensity for both regional and distant spread. Therapies including surgical resection, chemotherapy, and local radiotherapy, by itself or in combination with other treatment, have been used to treat GSCCs in China. To identify the most effective treatment modalities for GSCCs, we still need prospective, multicenter, randomized clinical researches. PMID- 25932088 TI - Surgical treatment achieves better outcome in severe traumatic pericallosal aneurysm: case report and literature review. AB - Traumatic pericallosal aneurysm (TPA) is typically seldom yet potentially lethal. Because of its rarity, also complicated by the unpredictable delayed-onset, TPA is more difficult to be diagnosed promptly. Due to the sporadic reports and diverse opinions on the priority of surgical treatment, a consensus about effective management of TPA has not been reached. Here we report a 55 year-old male patient with TPA, who received an emergent craniotomy to clip the pseudoaneurysm and remove the hematoma under intense intracranial pressure (ICP) monitoring. A satisfactory clinical outcome was achieved at a 3-month follow-up. Thereafter, a review was conducted to evaluate the outcomes of different managing modalities. PMID- 25932089 TI - Inflammatory myofibroblastic tumors of the head and nec. AB - Inflammatory myofibroblastic tumors (IMT) rarely affect the head and neck region. IMTs of the head and neck regions account for 14-18% of extra-pulmonary IMTs. Most commonly, they are located in the region of the orbits and upper airways, and less often at other sites. In the present study, we reviewed the English language literature regarding the etiology, clinical features, diagnosis, treatment, and prognosis of IMTs of the head and neck. PMID- 25932090 TI - Tendency for age-specific mortality with hypertension in the European Union from 1980 to 2011. AB - Tendency for mortality in hypertension has not been well-characterized in European Union (EU). Mortality data from 1980 to 2011 in EU were used to calculate age-standardized mortality rate (ASMR, per 100,000), annual percentage change (APC) and average annual percentage change (AAPC). The Joinpoint Regression Program was used to compare the changes in tendency. Mortality rates in the most recent year studied vary between different countries, with the highest rates observed in Slovakia men and Estonia women. A downward trend in ASMR was demonstrated over all age groups. Robust decreases in ASMR were observed for both men (1991-1994, APC = -13.54) and women (1996-1999, APC = -14.80) aged 55-65 years. The tendency of systolic blood pressure (SBP) from 1980 to 2009 was consistent with ASMR, and the largest decrease was observed among Belgium men and France women. In conclusion, SBP associated ASMR decreased significantly on an annual basis from 1980 to 2009 while a slight increase was observed after 2009. Discrepancies in ASMR from one country to another in EU are significant during last three decades. With a better understanding of the tendency of the prevalence of hypertension and its mortality, efforts will be made to improve awareness and help strict control of hypertension. PMID- 25932091 TI - Influence of caspase-3 silencing on the proliferation and apoptosis of rat bone marrow mesenchymal stem cells under hypoxia. AB - AIMS: To investigate the effects of caspase-3 silencing on the proliferation and apoptosis of rat bone marrow mesenchymal stem cells (MSCs) under hypoxia. METHODS: Rat bone marrow MSCs were transfected with a recombinant shRNA lentivirus targeting caspase-3 expression. Protein expression of caspase-3 was measured by western blotting. Cell proliferation was measured with MTS, and the cell cycle was analyzed by flow cytometry. The apoptosis rate was measured at various time points under hypoxia. Apoptotic morphology was assessed by Hoechst 33258 staining. mRNA levels of caspase-3, Bcl-2, and Bax were measured by real time PCR. RESULTS: Western blotting showed that the rat MSCs were stably transfected with the shRNA targeting caspase-3 by a significant reduction of caspase-3 expression. Silencing of caspase-3 expression resulted in a significant increase of MSC proliferation (P < 0.05), an increase of cells in S-phase (52.66 +/- 0.30%), and a significant decrease of apoptotic MSCs (P < 0.05). These effects exhibited a slow increase during hypoxic culture. Furthermore, caspase-3 silencing significantly down-regulated mRNA expression of caspase-3 (P < 0.01) and Bax (P < 0.01), and up-regulated Bcl-2 mRNA expression (p < 0.01), thereby increasing the ratio of Bcl-2/Bax (P < 0.05). CONCLUSION: Caspase-3 silencing modulates the cell cycle of MSCs, promotes cell proliferation, and enhances the anti-apoptotic capacity of MSCs under hypoxia in vitro. PMID- 25932092 TI - Low back pain associated with lumbar disc herniation: role of moderately degenerative disc and annulus fibrous tears. AB - Lumbar disc herniation is one of the most common spinal degenerative disorders which may lead to low back pain (LBP) and radicular leg pain. However, it remains difficult to diagnose a degenerative herniated disc as the LBP generator in clinical practice. The purpose of this study is to explore the characteristic changes of a herniated disc causing LBP on MRI and to clarify the underlying role of inflammatory mediators and annulus fibrous (AF) tears in LBP generation associated with disc herniation. We prospectively collected intervertebral disc specimens and MRI from 57 single-segment disc herniation patients with radiculopathy. All subjects were grouped according to LBP occurrence or disc degeneration severity for the comparison of inflammatory mediators' expression and AF tears occurrence (High Intensity Zone, HIZ, on MRI). LBP incidence under circumstances of different degeneration severity with or without HIZ was further analyzed. Both LBP incidence and Inflammatory mediators expression in moderately degenerated group was higher than mildly and severely degenerative groups. HIZ incidence was higher in moderately and severely degenerated groups. LBP incidence in the patients with both moderately degenerated discs and HIZ was 86.7%, much higher than the rest of the patient population. In conclusion, the high expression of inflammatory mediators with AF tears causes LBP associated with disc herniation. Moderately degenerative disc with HIZ is MRI morphological change of herniated disc causing LBP, which can be applied to diagnose LBP. PMID- 25932093 TI - Can routine oral care with antiseptics prevent ventilator-associated pneumonia in patients receiving mechanical ventilation? An update meta-analysis from 17 randomized controlled trials. AB - BACKGROUND: Whether oral antiseptics could reduce the risk of ventilator associated pneumonia (VAP) in patients receiving mechanical ventilation remains controversial. We performed a meta-analysis to assess the effect of oral care with antiseptics on the prevalence of ventilator associated pneumonia in adult critically ill patients. METHODS: A comprehensive search of PubMed, Embase and Web of Science were performed to identity relevant studies. Eligible studies were randomized controlled trials of mechanically ventilated adult patients receiving oral care with antiseptics. The quality of included studies was assessed by the Jadad score. Relative risks (RRs), weighted mean differences (WMDs), and 95% confidence intervals (CIs) were calculated and pooled using a fixed-effects model or random-effects model. Heterogeneity among the studies was assessed with I (2) test. RESULTS: 17 studies with a total number of 4249 met the inclusion criteria. Of the 17 studies, 14 assessed the effect of chlorhexidine, and 3 investigated the effect of povidone-iodine. Overall, oral care with antiseptics significantly reduced the prevalence of VAP (RR=0.72, 95% CI: 0.57, 0.92; P=0.008). The use of chlorhexidine was shown to be effective (RR=0.73, 95% CI: 0.57, 0.93; P=0.012), whereas this effect was not observed in povidone-iodine (RR=0.51, 95% CI: 0.09, 2.82; P=0.438). Subgroup analyses showed that oral antiseptics were most marked in cardiac surgery patients (RR=0.54, 95% CI: 0.39, 0.74; P=0.00). Patients with oral antiseptics did not have a reduction in intensive care unit (ICU) mortality (RR=1.11, 95% CI: 0.95, 1.29; P=0.201), length of ICU stay (WMD=-0.10 days, 95% CI: -0.25, 0.05; P=0.188), or duration of mechanical ventilation (WMD=-0.05 days, 95% CI: -0.14, 0.04; P=0.260). CONCLUSION: Oral care with antiseptics significantly reduced the prevalence of VAP. Chlorhexidine application prevented the occurrence of VAP in mechanically ventilated patients but povidone-iodine did not. Further large-scale, well-designed randomized controlled trials are needed to identify the findings and determine the effect of povidone-iodine application. PMID- 25932094 TI - Transferrin and cell-penetrating peptide dual-functioned liposome for targeted drug delivery to glioma. AB - A brain drug delivery system for glioma chemotherapy based on transferrin and cell-penetrating peptide dual-functioned liposome, Tf/TAT-lip, was made and evaluated with doxorubicin (DOX) as a model drug. TAT conjugated liposome (TAT lip) loaded with doxorubicin (DOX) were prepared by the thin film hydration methods (lip-DOX) and then conjugated with transferrin (Tf) to yield Tf/TAT-lip DOX which was characterized for their various physicochemical and pharmaceutical properties. Cellular uptakes were explored in both brain capillary endothelial cells (BCECs) of rats and U87 cells. The blood brain barrier model in vitro was established to evaluate the trans-endothelial ability crossing the BBB. The biodistribution of each formulation was further identified. The Tf/TAT-lip-DOX presents the best anti-proliferative activity against U87 cells. The orthotropic glioma model was established for the evaluation of anti-glioma effect. In conclusion, the experimental data in vitro and in vivo indicated that the Tf/TAT lip was a promising brain drug delivery system due to its high delivery efficiency across the BBB. PMID- 25932095 TI - Expression of the P2Y2 receptor in the terminal rectum of fetal rats with anorectal malformation. AB - OBJECTIVE: The expression and distribution of a subtype of purine receptors (P2Y2) in the terminal rectum of fetal rats with anorectal malformations (ARM) were examined to investigate their possible impact on the development of the enteric nervous system (ENS). METHODS: Pregnant Sprague-Dawley rats were randomly divided into a control group (5 rats) and an experimental group (20 rats). The experimental group was treated with ethylene thiourea (ETU). On gestational day 20, the intrauterine fetal rats were collected from both groups of pregnant rats. Sagittal sections of the pelvic perinea were stained with HE. P2Y2 protein and mRNA expression in the terminal recta of the fetal rats in the control group, the ARM group, and the ETU-treated group that exhibited no malformations (the ETU group) were detected by immunohistochemistry, western blot, and qRT-PCR. RESULTS: The fetal rats in the control group showed normal position of the anal opening, with no malformation. The incidence of ARM was 89.2% for the fetal rats in the experimental group. The immunohistochemistry results showed that P2Y2 was expressed in the cytoplasm of the cells in the terminal rectum submucosa and myenteric plexus of the fetus rats in the control group, the ETU group, and the ARM group. The average integrated optical density (IOD) value for the ARM group was significantly lower than the IOD value for the control and ETU groups (186.48 +/- 23.03 vs. 493.18 +/- 19.70; 186.48 +/- 23.03 vs. 479.48 +/- 41.71, P<0.01), while the IOD value for the ETU group was comparable to the control group IOD (493.18 +/- 19.70 vs. 479.48 +/- 41.71, P = 0.360). The western blot and qRT-PCR results showed that the P2Y2 protein and mRNA expressions were significantly lower in the terminal rectum of the fetal rats in the ARM group than in the control and ETU groups (0.28 +/- 0.08 vs. 0.51 +/- 0.10, 0.28 +/- 0.08 vs. 0.48 +/- 0.12; 48.91 +/- 12.17 vs. 98.03 +/- 15.68, 48.91 +/- 12.17 vs. 92.53 +/- 10.43; P<0.01), while the P2Y2 protein and mRNA levels in the control group were comparable to the ETU group (0.51 +/- 0.10 vs. 0.48 +/- 0.12, P = 0.494; 98.03 +/ 15.68 vs. 92.53 +/- 10.43, P = 0.058). CONCLUSION: P2Y2 may participate in and affect the development of ENS in the terminal rectum of fetal rats with ARM. PMID- 25932096 TI - GSTM1 and GSTT1 null genotype and diabetic retinopathy: a meta-analysis. AB - Glutathione S-transferases (GSTs) have proved to be involved in the detoxifying several oxidants and may play an important role in diabetic retinopathy (DR). Previous studies on the association between glutathione S-transferase T1 (GSTT1) and GSTM1 polymorphism and DR risk reported inconclusive results. To clarify the possible association, we conducted a meta-analysis of eligible studies. We searched in the PubMed, Embase, and Wangfang Medicine databases for studies assessing the association between GSTM1 and GSTT1 null genotype and DR risk. Odds ratios (ORs) with 95% confidence intervals (CIs) were used to assess the strength of association between GSTM1 and GSTT1 null genotype and DR risk. Five studies with 3563 subjects were included in this meta-analysis. The null genotypes of GSTT1 and GSTM1 were associated with a significantly increased risk of DR (OR = 1.69; 95% CI, 1.33-2.16; OR = 1.59; 95% CI, 1.22-2.06), respectively. When stratified by the type of DM, a significantly elevated DR risk was observed in T2DM patients. In conclusion, this meta-analysis suggested that an increased risk of DR was associated with the null polymorphism of GSTT1 and GSTT1, respectively. PMID- 25932097 TI - Meta-analysis of the clinical application on gasless laparoscopic cholecystectomy in China. AB - OBJECTIVE: We aim to perform systematic reviews of the clinical effects of the abdominal wall suspension technique in laparoscopic cholecystectomy in China. METHODS: We retrieved databases of literature on randomized controlled trials involving abdominal wall suspension laparoscopic cholecystectomy. Then, we conducted screenings, extracted data, and performed quality assessment and meta analysis. RESULTS: We analyzed 611 patients. Our analysis showed that the abdominal wall suspension group compared to the traditional group had reduced length of hospital stay (SMD = -0.91, 95% CI = -1.76~-0.06, P = 0.04), had shortened postoperative first exhaust time (SMD = -0.65, 95% CI = -1.11~-0.20, P = 0.005), and had diminished incidence of postoperative complications (P < 0.001), which decreased the cost of hospitalization. CONCLUSIONS: Application of abdominal wall suspension endoscopic technique can significantly speed up the rehabilitation of laparoscopic cholecystectomy patients; therefore, it is worthy of further research and clinical application. PMID- 25932098 TI - Oral administration of oleanolic acid, isolated from Swertia mussotii Franch, attenuates liver injury, inflammation, and cholestasis in bile duct-ligated rats. AB - BACKGROUND & AIMS: Oleanolic acid is abundantly distributed in Swertia mussotii Franch, a Chinese traditional herb for the treatment of jaundice. However, the hepatoprotective role of oleanolic acid in obstructive cholestasis and its underlying molecular mechanism are unclear. METHODS: Normal rats and bile duct ligated (BDL) rats were given oleanolic acid and serum biochemistry, bile salts, and pro-inflammatory factors were measured, as well as the expression levels of liver bile acid synthesis and detoxification enzymes, membrane transporters, nuclear receptors, and transcriptional factors. RESULTS: Oral administration of oleanolic acid at 100 mg/kg did not cause rat liver injury. However, it significantly reduced the serum levels of alanine aminotransferase (ALT) on days 7 and 14, aspartate aminotransferase (AST) and TNF-alpha on day 14, and alkaline phosphatase (ALP) and IL-1beta on days 3, 7, and 14 in the BDL rats. Furthermore, the serum levels of total bile acid (TBA) and bile acids, including CDCA, CA, DCA, and Talpha/betaMCA were significantly reduced by oleanolic acid on day 3 in the BDL rats. In addition, the expression levels of detoxification enzymes Cyp3a, Ugt2b, Sult2a1, Gsta1-2, and Gstm1-3, membrane transporters Mrp3, Mrp4, Ostbeta, Mdr1, Mdr2, and Bsep, nuclear receptors Pxr, Vdr, Hnf4alpha, Rxralpha, Raralpha, Lxr, and Lrh-1, and transcriptional factors Nrf2, Hnf3beta, and Ahr were significantly increased in oleanolic acid-treated rats. CONCLUSION: We demonstrated that the oral administration of oleanolic acid attenuates liver injury, inflammation, and cholestasis in BDL rats. The anti-cholestatic effect may be associated with the induction of hepatic detoxification enzymes and efflux transporters mediated by nuclear receptors and transcriptional factors. PMID- 25932099 TI - MiR-16 family as potential diagnostic biomarkers for cancer: a systematic review and meta-analysis. AB - BACKGROUND: Cancer is a main public health problem all over the world with its high morbidity and mortality. MicroRNA-16 (miRNA-16, miR-16) family members have been considered as potential biomarkers in cancer diagnosis in several previous studies, but their results were inconsistent. OBJECTIVE: The present meta analysis was conducted to assess the diagnostic efficacy of miR-16 family for cancer systematically. METHODS: Multiple search strategies and random-effects model were used. Pooled sensitivity, specificity and other parameters were calculated. Totally, 1,259 cancer patients and 855 controls from 16 articles were enrolled in this meta-analysis. RESULTS: The pooled results for sensitivity, specificity, positive likelihood ratios (PLR), negative likelihood ratios (NLR), diagnostic odds ratio (DOR) and the area under the curve (AUC) were 0.80 (95% CI: 0.73-0.85), 0.77 (95% CI: 0.70-0.84), 3.5 (95% CI: 2.5-5.0), 0.26 (95% CI: 0.19 0.36), 14 (95% CI: 8-25) and 0.86 (95% CI: 0.82-0.88), respectively. Our subgroup analyses indicated miR-16 family assay was more appropriate in Asian populations. CONCLUSIONS: Our findings demonstrated that miR-16 family members have a relatively high value as promising biomarkers in diagnosing cancers. Nevertheless, the clinical application of miR-16 family profiling for cancers diagnosis still needs further large-scale studies and additional improvements of substantiation. PMID- 25932100 TI - Association between phosphodiesterase 4D (PDE4D) SNP 87 and ischemic stroke: a meta-analysis. AB - BACKGROUND AND PURPOSE: Data on the association between PDE4D SNP 87 and the risk of ischemic stroke are contentious and debatable. The present meta-analysis was undertaken to systematically summarize the possible association. METHODS: Based on comprehensive search of PubMed, Embase, and CNKI databases, we identified 18 eligible articles examining the relationship between PDE4D SNP 87 and ischemic stroke risk. We evaluated the strength of relationship using odds ratios (ORs) with 95% confidence intervals (CIs). RESULTS: In the overall analysis, PDE4D SNP 87 was not found to have effects on the risk of ischemic stroke. The null association persisted in the subgroup analyses according to ethnicity and sample size. CONCLUSIONS: Our meta-analysis suggests that PDE4D SNP 87 may not represent an independent risk factor for ischemic stroke development. PMID- 25932101 TI - Detection of pulmonary metastases with the novel radiolabeled molecular probe, (99m)Tc-RRL. AB - BACKGROUND: To improve the detection of pulmonary metastases, experimental blood borne pulmonary metastasis mouse models were established using three intravenously administered cell lines. In a previous study we demonstrated that (99m)Tc-radiolabeled arginine-arginine-leucine (RRL) could be used to non invasively image malignant tumors. METHODS: (99m)Tc-RRL was prepared and injected intravenously in mice with pulmonary metastases that arose from the intravenous injection of HepG2, B16, and Hela cells. The bio-distribution and imaging of (99m)Tc-RRL were determined in different pulmonary metastases mouse models and in normal mice. RESULTS: (99m)Tc-RRL exhibited higher uptake values in the lungs of pulmonary metastatic mice compared to normal mice (P<0.05; 3.92+/-0.48% ID/g 2 h post-injection and 3.89+/-0.36% ID/g 4 h post-injection in metastatic hepatic carcinoma [HepG2]-bearing lungs; 5.49+/-0.84% ID/g 2 h post-injection and 5.11+/ 0.75% ID/g 4 h post-injection in metastatic melanoma [B16]-bearing lungs; 3.72+/ 0.52% ID/g 2 h post-injection and 3.51+/-0.35% ID/g 4 h post-injection in metastatic cervical carcinoma [Hela]-bearing lungs; 2.38+/-0.20% ID/g 2 h post injection and 2.11+/-0.24% ID/g 4 h post-injection in normal lungs). The pulmonary metastatic lesions were clearly visualized using (99m)Tc-RRL. CONCLUSIONS: (99m)Tc-RRL exhibited favorable metastatic tumor targeting and imaging properties, thus highlighting its potential as an effective imaging probe for detection of pulmonary metastases. (99m)Tc-RRL can be used as a reasonable supplement to (18)F-FDG imaging in the non-invasive imaging of tumor angiogenesis. PMID- 25932102 TI - Pterostilbene attenuates inflammation in rat heart subjected to ischemia reperfusion: role of TLR4/NF-kappaB signaling pathway. AB - OBJECTIVE: The aim of the present study was to investigate whether pterostilbene could modulate the TLR4/NF-kappaB signaling, reduce neutrophil accumulation and TNF-alpha induction in an ischemia/reperfusion injured rat heart model. MATERIALS AND METHODS: Rats were randomly exposed to sham operation, myocardial ischemia and reperfusion (MI/R), MI/R + pterostilbene, MI/R + pterostilbene + L-NAME. And myocardial infarct size, apoptosis, TLR4 expression, NF-kappaB expression, MPO level and TNF-alpha level were detected. RESULTS: The results demonstrated that after MI/R, the expressions of myocardial TLR4, NF-kappaB and caspase-3 increased significantly in ischemia area. Compared with MI/R, pterostilbene significantly attenuated the expressions of TLR4, NF-kappaB and caspase-3. In addition, it also reduced myeloperoxidase (MPO) levels, both serum and myocardial TNF-alpha production, myocardial infarct sizes (INF/AAR%) and myocardial apoptosis induced by MI/R. All the effects of pterostilbene were abolished by L-NAME, a nitric oxide synthase inhibitor. CONCLUSION: These data provide evidence that pterostilbene inhibits TLR4/NF-kappaB signaling and apoptosis in the rat heart subjected to MI/R, which is associated with NO production. PMID- 25932103 TI - Computer-aided three-dimensional reconstruction of main vessels in hemangiomas. AB - This study aimed to investigate three-dimensional (3-D) morphological features of the main vessel architecture of human hemangioma. Serial sections of specimens from three cases of children hemangioma were stained with hematoxylin and eosin (HE) to visualize the vessels. Serial images were taken and processed with computer-assisted 3-D reconstruction. Partial 3-D structure reconstruction of vessel morphology in hemangioma revealed strange distribution and branching, which were different from normal vessels of the human skin. The 3-5 microvascular was most common in hemangioma. We observed respective characteristics of three cases: 1 case showed uniform artery vein distribution accompanied by running trend; 1 case showed main artery distribution and less vein distribution, and there were many blood sinus in the shallow surface close to the skin; another case showed vein distribution in the middle of antrum. In conclusion, digital vascular model of 3-D structure of main vessel hemangioma provides a new way for the diagnosis and treatment of hemangioma of children. PMID- 25932104 TI - The role of serum AMH and FF AMH in predicting pregnancy outcome in the fresh cycle of IVF/ICSI: a meta-analysis. AB - PURPOSE: This meta-analysis tries to find and confirm the true prognostic value of serum AMH and the follicle fluid AMH (FF AMH) on the outcome of ART. METHOD: We identified all studies published by March 2014 with data related to in vitro fertilization", "intracytoplasmic sperm injection", "assisted reproductive technology" and "antimullerian hormone" in Pubmed database. Studies were included if 2 * 2 tables for outcomes of pregnancy in IVF patients in relation to AMH could be constructed or studies which used T-tests to compare clinical indexes including AMH in pregnant and non-pregnant women. And all the patients were less than 46 years old. RESULTS: A total of 26 studies could be used for this meta analysis. Of these articles 22 studies could be constructed 2 * 2 tables, with 15 for predicting pregnancy and 7 for non-pregnancy. 11 studies used the analysis of T-test, with 7 articles were duplicated. And of the 11 articles, 8 were for the analysis of serum AMH in prediction of pregnancy, 3 were for FF AMH. Because of heterogeneity among studies, calculation of a summary point estimate for sensitivity and specificity was not possible. For the analysis of serum AMH on non-pregnancy, the heterogeneity was moderate (I-squared of 65.9%), the curves indicated positive find (the AUROC is 0.73, 95% CI is 0.69-0.77.). In the T-test group of serum AMH, the DOR for women with pregnancy outcome was 0.232 (95% confidence interval (CI): 0.034-0.43), with less heterogeneity (I-squared of 45.1%). Unfortunately, the predictive value of FF AMH on pregnancy is still unclear because of large heterogeneity (I-squared of 90.5%). CONCLUSION: Serum AMH, as an independent parameter, can predict pregnancy outcome after assisted conception and the positive correlation with serum AMH and non-pregnancy should not be ignored either. The predictive value of FF AMH on pregnancy is still unclear. PMID- 25932105 TI - Protective effect of the traditional Chinese medicine xuesaitong on intestinal ischemia-reperfusion injury in rats. AB - OBJECTIVE: We investigated the effect of xuesaitong on intestinal barrier dysfunction and related mechanisms in a rat model for intestinal ischemia reperfusion. METHODS: Rats were divided into sham-operated, disease-model and Xuesaitong-treated groups. In the disease-model and Xuesaitong-treated rats an intestinal ischemia-reperfusion injury (IRI) model was introduced, which was created by a temporary obstruction of the superior mesenteric artery (SMA). The xuesaitong group was pre-treated with injections into the abdominal cavity prior to the generation of the IRI model. Tissue changes were evaluated using H&E staining and electron microscopy. Samples were analyzed at 0, 3 and 24 h post IRI. Ascites volumes as well as small intestinal mucosa bleeding, injury scores, wet to dry weight ratios, and propulsions were evaluated. Apoptotic rates were determined with TUNNEL assays. Blood serum tumor necrosis factor-alpha (TNF alpha) levels were measured using ELISA, and Bcl-2 and caspase-3 expression in small intestinal mucosa measured using immunohistochemistry. RESULTS: We determined a significant increase of pathological damage to small intestinal tissues, intestinal wet to dry ratios, ascites volume, TNF-alpha levels, apoptosis rates of small intestinal mucosa, and expression of Bcl-2 and caspase-3 proteins in the disease-model group compared to the sham-operated group (P < 0.001), and intestinal motility was significantly decreased (P < 0.001). However, comparisons between disease-model and xuesaitong pre-treated animals revealed, that in the treatment group these changes occurred in significant less severities. CONCLUSIONS: Xuesaitong can effectively alleviate intestinal barrier dysfunction caused by ischemia-reperfusion injury by reducing TNF-alpha, up regulating Bcl-2 and down-regulating caspase-3 expression, in addition to increasing peristalsis. PMID- 25932106 TI - Prognostic role of YB-1 expression in breast cancer: a meta-analysis. AB - OBJECTIVE: In published studies, Y-box binding protein-1 (YB-1) correlated with the prognosis of patients with breast cancer (BC), but the specific role of YB-1 is still unclear. Our study aimed to evaluate the prognostic value of YB-1 in BC patients using meta-analysis based on the published studies. METHODS: We searched the relevant literatures deadline for June 2014 in databases, including PubMed, Embase, Medline and Cochrane library, and finally 8 studies were included in our study. Our study contained 1094 BC patients with 398 YB-1 positive and 696 YB-1 negative. RESULTS: Our results showed that YB-1 abnormal expression did not correlated with the lymph node status [OR = 1.258, 95% CI = 0.895-1.769, P = 0.186], high histological grade [OR = 2.709, 95% CI = 0.861-8.530, P = 0.089], histological type [OR = 0.837, 95% CI = 0.526-1.331, P = 0.452], P53 status [OR = 2.006, 95% CI 0.686-5.865, P = 0.203] and PR [OR = 0.607, 95% CI = 0.347-1.061, P = 0.080] in BC patients. But YB-1 over-expression was associated with other unfavorable factors: ER negativity [OR = 0.604, 95% CI = 0.388-0.941, P = 0.026], HER2 positivity [OR = 3.841, 95% CI = 2.637-5.594, P = 0.000], and high tumorous T stage [OR = 2.169, 95% CI = 1.295-3.632, P = 0.003]. In addition, our data suggested that high YB-1 expression had an adverse impact on 5-year OS [RR = 2.767, 95% CI = 2.054-3.727, P = 0.000] in BC patients. CONCLUSIONS: Our findings implied that YB-1 might a novel biomarker to predict the prognosis of BC, and could be a potential direction for developing diagnostic and therapeutic approaches in BC. PMID- 25932107 TI - Endogenous FOXP3 inhibits cell proliferation, migration and invasion in glioma cells. AB - The transcription factor forkhead box P3 (FOXP3) has been demonstrated to play important roles in the development and function of regulatory T cells (Tregs). In addition, studies had recently demonstrated that FOXP3 also expressed in some tumor cells. However, the exact role and molecular mechanism of FOXP3 function in glioma's cells are still unclear. This study aims to elucidate the functions of FOXP3 in glioma's cells. Expression of FOXP3 in glioma cell U87 and LN229 was up regulated and down-regulated by pCMV6-FOXP3-GFP and pRFP-C-RS shFOXP3 respectively. Then, CCK-8 assay, flow cytometry, migration and invasion assay, and western blot were used to detect cell proliferation, cell cycle, cell migration and invasion and related protein expression. All detection methods demonstrated that over-expression of FOXP3 in glioma cell U87 and LN229 inhibited cell proliferation, reduced cell migration, decreased cell invasion compared with control. Moreover, up-regulation of FOXP3 increased the protein levels of pro apoptotic molecules caspases-3 and caspases-7, resulting in the promotion of cell apoptosis. Conversely down-regulation of the FOXP3 promoted cell growth and inhibited cell apoptosis and reduced the expression of caspases-3 and caspases-7. Our findings suggest that FOXP3 maybe act as a suppressor in glioma cells proliferation, migration and invasion and endogenous FOXP3 transfusion could be a novel approach for inhibiting glioma progression. PMID- 25932108 TI - Tumor-infiltrating memory T-lymphocytes for prognostic prediction in cancer patients: a meta-analysis. AB - PURPOSE: Pathological evidence has continually supported the prognostic value of tumour-infiltrating T lymphocytes for several solid tumours across diverse patient cohorts. To investigate the clinical relevance of tumour-infiltrating memory T lymphocytes, we investigated relevant publications to identify the significance of memory tumour-infiltrating T lymphocytes (TILs) in predicting survival in cancer patients and analysed the influence of variations in the tumour stage and the infiltrated location thereon. METHODS: Relevant publications that assessed the clinical relevance of memory TILs to the patient's overall survival (OS) were investigated. Disease-free survival (DFS) was also evaluated where possible. Hazard ratios (HR) and 95% confidence intervals (CI) were assessed using a random-effects model. Heterogeneity was investigated with stratified analysis and I(2) statistics. RESULTS: In total, 16 relevant publications, including 4248 cancer patients, were analysed. In the pooled analysis, intra-tumour accumulation of memory TILs correlated positively with favourable clinical outcomes for both OS (pooled HR, 2.06; 95% CI, 1.76-2.40) and DFS (pooled HR, 2.31; 95% CI, 1.67-3.19). Various effects of the tumour stage and the anatomical region where the cells infiltrated were identified in survival prediction, using memory TILs. CONCLUSIONS: Overall, infiltration of memory TILs can serve as a biomarker for survival prediction in cancer. Additional heterogeneous effects of the associated factors should be considered when categorizing high-risk patients. PMID- 25932109 TI - Ameliorating effects of low tidal volume ventilation with associated hypercapnia on pneumoperitoneum-induced lung injury by inhibition of Toll-like receptor 4. AB - BACKGROUND: Mechanical ventilation using lower tidal volume ventilation with associated hypercapnia is supported to avoid ventilator-induced lung injury, but the underlying mechanism is not clear. This study was intended to explore whether low tidal volume ventilation with associated hypercapnia would ameliorate pneumoperitoneum-induced lung injury and whether this protection strategy might work through mediating inflammation and oxidative stress via TLR 4 signaling pathway. MATERIALS AND METHODS: 50 anesthetized Wistar Rats were randomized to be mechanically ventilated for 4 h at 7 groups: Group A, ventilated with 12 ml/kg; Group B, similar to Group A but injected with LPS (Toll receptor 4 agonist); Group C, similar to Group A but injected with Pam3Cys (Toll receptor 2 agonist); Group D, ventilated with 12 ml/kg and subjected to pneumoperitoneum; Group E, ventilated with 6 ml/kg and subjected to pneumoperitoneum; Group F, similar to Group E but injected with LPS; Group G, similar to Group E but injected with Pam3Cys. After animals were killed, indices of lung Injury, inflammation markers and oxidative stress markes of the lungs tissues, bronchoalveolar lavage fluid and blood were assessed. RESULTS: The group subjected to pneumoperitoneum (Group D) had elevated values of indices of lung Injury, inflammation oxidative stress markers compared with the controls (Group A). The low tidal volume ventilation group (Group E) had significantly decreased values of markers of lung Injury, inflammation and oxidative stress compared with the high tidal volume ventilation group (Group D). LPS treatment reversed all the results of Group E, while Pam3Cys treatment had no significant effect. CONCLUSIONS: Low tidal volume ventilation with associated hypercapnia ameliorated pneumoperitoneum-induced lung injury by reducing TLR 4-mediated inflammation and oxidative stress. PMID- 25932110 TI - Pycnogenol, a compound isolated from the bark of pinus maritime mill, attenuates ventilator-induced lung injury through inhibiting NF-kappaB-mediated inflammatory response. AB - BACKGROUND: During mechanical ventilation, high end-inspiratory lung volume results in a permeability type pulmonary oedema, called ventilator-induced lung injury (VILI). The pathophysiology of ventilator-induced lung injury involves multiple mechanisms, such as excessive inflammation. And pycnogenol is a mixture of flavonoid compounds extracted from pine tree bark that have anti-inflammatory activity. OBJECTIVE: We investigated the effects of pyncogenol on ventilator induced lung injury in rats. METHODS: Rats were orally administrated with pycnogenol once (30 mg/kg) 2 days before lung injury induction with mechanical ventilation, then the rats were divided into three groups: lung-protective ventilation (LV group, n = 20), injurious ventilation (HV group, n = 20), HV + pycnogenol group (HV + Pyc group, n = 20). Lung specimens and the bronchoalveolar lavage fluid (BALF) were isolated for histopathological examinations and biochemical analyses. RESULTS: Pretreatment with pycnogenol could markedly decrease lung wet/dry ratio, lower myeloperoxidase (MPO) activity and total protein concentration and reduce the production of TNF-alpha, IL-6, IL-1beta and MIP-2 in the BALF in ventilator-induced lung injury rats. Additionally, pycnogenol improved the histology of the lung and significantly inhibited the phosphorylation of NF-kappaB p65 and the degradation of IkappaB-alpha. CONCLUSION: Pycnogenol treatment could attenuate ventilator-induced lung injury in rats, at least in part, through its ability to reduce the production of inflammatory cytokines via inhibiting the activation of NF-kappaB, indicating it as a potential therapeutic candidate for ventilator-induced lung injury. PMID- 25932111 TI - Abnormal expression of NSF, alpha-SNAP and SNAP23 in pulmonary arterial hypertension in rats treated with monocrotaline. AB - BACKGROUND: Recent researches have shown that dysfunctional intracellular vesicular trafficking exists in pulmonary arterial hypertension (PAH). However, the expression of proteins involved in intracellular vesicular trafficking in pulmonary vasculature in PAH remains unclear. OBJECTIVE: To elucidate possible roles of proteins involved in intracellular vesicular trafficking in the development of PAH in rats treated with monocrotaline, changes in the expression of N-ethyl-maleimide-sensitive factor (NSF), alpha-soluble NSF attachment protein (alpha-SNAP) and synaptosome-associated membrane protein (SNAP) 23 were examined together with expression of caveolin-1 (cav-1), endogenous nitric oxide synthase (eNOS), type 2 bone morphogenetic receptor (BMPR2) and cellular apoptosis. METHODS: The mRNA expression was investigated by real time-PCR and protein expression by immunoblot method in rat lung. Caspase-3 was used as an indicator of cellular apoptosis and examined by immunoblot method. RESULTS: During the development of PAH, mRNA and protein expression of NSF, alpha-SNAP and SNAP23 all significantly increased before pulmonary arterial pressure started to increase, then all significantly decreased when PAH established. The expression of eNOS and BMPR2 changed similarly, while the mRNA and protein of cav-1 both downregulated after monocrotaline treatment. Caspase-3 was also increased after exposure to monocrotaline. CONCLUSIONS: Since the expression of NSF, alpha-SNAP and SNAP23 changed greatly during the onset of PAH and accompanied with abnormal expression of eNOS, BMPR2 and cav-1 and with enhanced cellular apoptosis, NSF, alpha-SNAP and SNAP23 appear to be associated with the development of PAH in rats treated with monocrotaline. PMID- 25932112 TI - Functionalized nano-graphene oxide particles for targeted fluorescence imaging and photothermy of glioma U251 cells. AB - AIM: This study was to prepare the functionalized nano-graphene oxide (nano-GO) particles, and observe targeted fluorescence imaging and photothermy of U251 glioma cells under near infrared (NIR) exposure. MATERIAL AND METHODS: The functionalized nano-GO-Tf-FITC particles were prepared and then were incubated with U251 glioma cells. Estimation of CCK8 cell activity was adopted for measurement of cytotoxicity. The effect of fluorescein imaging was detected by fluorescence microscope with anti-CD71-FITC as a control. Finally, we detected the killing efficacy with flow cytometry after an 808 nm NIR exposure. RESULTS: Both nano-GO-Tf-FITC group and CD71-FITC group exhibited green-yellow fluorescence, while the control group without the target molecule nano-GO-FITC was negative. The nano-GO-Tf-FITC was incubated with U251 cells at 0.1 mg/ml, 1.0 mg/ml, 3.0 mg/ml and 5.0 mg/ml. After 48 h of incubation, the absorbance was 0.747 +/- 0.031, 0.732 +/- 0.043, 0.698 +/- 0.051 and 0.682 +/- 0.039, while the absorbance of control group is 0.759 +/- 0.052. There is no significant difference between the nano-GO-FITC groups and control group. In addition, the apoptosis and death index of nano-GO-Tf-FITC group was significantly higher than that of nano-GO-FITC and blank control group (P < 0.05). CONCLUSION: The nano-GO Tf-FITC particles with good biological compatibility and low cytotoxicity are successfully made, which have an observed effect of target imaging and photothermal therapy on glioma U251 cells. PMID- 25932113 TI - Biomechanical comparison of three types of internal fixation in a type C zone II pelvic fracture model. AB - OBJECTIVE: This study aimed to compare the stability of Tile C pelvic fractures fixed with two iliosacral (IS) screws, tension band plate (TBP), and minimally invasive adjustable plate (MIAP). METHODS: Six embalmed specimens of adult pelvis were used. The soft tissue was removed from the specimens, but spines from the fourth lumbar vertebra to the proximal one-third of both femurs were retained. The pubic symphysis, bilateral sacroiliac joints and ligaments, bilateral hip joints, bilateral sacrotuberous ligaments, and bilateral sacrospinous ligaments were intact. Tile C pelvic fractures were created on the specimens. The symphysis pubis was fixed with a plate, and the fracture on the posterior pelvic ring was fixed with three types of internal fixation in a randomized block design. The specimens were placed in a biomechanical machine at a standing neutral posture. A cyclic vertical load of up to 500N was applied, and displacement was recorded. Shifts in the fracture gap were measured by a grating displacement sensor. RESULTS: Under different vertical loads, the shift in the fracture gap and displacement of the pelvic fractures fixed with two IS screws were similar to those in fractures fixed with MIAP. However, the shift in the fracture gap and displacement of fractures fixed with MIAP was significantly smaller than those of fractures fixed with TBP. CONCLUSION: The stability of the Tile C pelvic fractures fixed with MIAP was similar to that of fractures fixed with IS screws. MIAP performed better than TBP under vertical load. PMID- 25932114 TI - MicroRNA-506 suppresses growth and metastasis of oral squamous cell carcinoma via targeting GATA6. AB - Oral squamous cell carcinoma (OSCC) remains the main cause of cancer mortality, accounts for 90% of oral cancers. Increasing evidence reveals that aberrant expression of microRNA contributes to the development and progression of OSCC, but the roles of microRNA-506 (miR-506) in OSCC remain elusive. Here, we found that the expression of miR-506 was decreased in 21 OSCC tissues and SCC-4 and SCC 9 cells. miR-506 overexpression suppressed proliferation, migration and invasion capabilities of OSCC cells. Moreover, miR-506 overexpression suppressed the luciferase activity of the GATA6-Wt 3'-UTR and decreased the mRNA and protein levels of GATA6. GATA6 overexpression attenuated the suppressive effects of miR 506. Furthermore, GATA6 was increased in OSCC tissues compared with the adjacent normal tissues and inversely associated with miR-506. Taken together, these results suggest that miR-506 is an important suppressor and could be a novel prognostic factor and therapeutic target for OSCC patients. PMID- 25932115 TI - Activation of spinal alpha-7 nicotinic acetylcholine receptor attenuates remifentanil-induced postoperative hyperalgesia. AB - The activation of alpha-7 nicotinic acetylcholine receptors (alpha7-nAchRs) are currently being considered as novel therapeutic approaches for managing hyperalgesia in inflammation and chronic neuropathic pain, but the role of a7 nAChRs on opioids induced hyperalgesia remain unknown. The present study investigated the effects of alpha7-nAChRs selective agonists PHA-543613 and type II positive allosteric modulators (PAMs) PNU-120596 in remifentanil induced postoperative hyperalgesia. As the results shown, intrathecal treatment with both alpha7-nAChRs agonists and type II PAMs could attenuate remifentanil induced hyperalgesia by increasing paw withdrawal mechanical threshold (PWMT) and paw withdrawal thermal latency (PWTL). Furthermore, we also investigated the protein level of proinflammatory cytokines and phosphorylation N-methyl-d-aspartate receptor 2B subunit (p-NR2B) in the spinal cord. Our data indicated that activation of alpha7-nAchRs decreased the proinflammatory cytokines (TNF-alpha, IL-6) and p-NR2B protein level in the spinal cord. The depression of the increased levels of proinflammatory cytokines and p-NR2B after remifentanil treatment may contribute to the anti-hyperalgesia effects of PHA-543613and PNU 120596 via alpha7-nAChRs. Therefore, our findings demonstrated that alpha7-nAChRs may be potential candidates for treating opioids induced hyperalgesia. PMID- 25932116 TI - Role of Hsp-70 responses in cold acclimation of HUVEC-12 cells. AB - BACKGROUND: Endothelial recovery is a central feature of tissues after frostbite injuries. Thermo tolerance plays an important role in protecting cells against injury after frozen and thawing. The present study aimed to quantitatively assess the injury of human umbilical vein endothelial cells HUVEC-12 after repeated low temperature. MATERIAL AND METHOD: Pretreatments (HUVEC-12) cells were repeatedly exposed to cold (1 degrees C/min decrement to -20 degrees C). Their proliferation, death, apoptosis, and protein and mRNA expressions of HSP70 were determined. RESULTS: Endothelial cells after repeated cold exposures were more resistant to apoptosis and necrosis than normal cells. The expressions of HSP70 in cells after repeated cold exposures were significantly higher than in normal HUVEC-12 cells (P < 0.05). CONCLUSION: Cold acclimation may induce the expression of HSP-70 which plays a protective role in the temperature tolerance. PMID- 25932117 TI - Polymorphisms of interleukin-10 genes on the risk of ischemic stroke in a meta analysis. AB - BACKGROUND: Previous studies have investigated the associations between polymorphisms of interleukin-10 (IL-10) gene and risk of ischemic stroke (IS). However, the results were inconsistent. The aim of this study was to clarify the relationship between IL-10 polymorphisms and IS risk by a meta-analysis approach. METHODS: The meta-analysis was performed by searching PubMed and Wanfang databases. Odds ratio (OR) and corresponding 95% confidence interval (95% CI) as well as effect size were calculated by a fixed or random-effect model according to the I(2) value. In total, five case-control studies for IL10-1082G/A and four studies for IL10-819C/T were included in this meta-analysis. RESULTS: Combined analysis indicated that IL10-1082G/A polymorphism was associated with risk of IS (A/A vs. G/G+G/A: OR = 1.82, 95% CI = 1.21-2.74, P = 0.004; for A allele vs. G allele: OR = 1.55, 95% CI = 1.14-2.10, P = 0.006). However, there was no significant association between IL10-819C/T polymorphism and IS in any comparison model (C/C vs. T/C+T/T: OR = 0.96, 95% CI = 0.69-1.36, P = 0.84; C allele vs. T allele: OR = 1.00, 95% CI = 0.83-1.21, P = 0.97). CONCLUSIONS: Our results indicated that IL-10-1082G/A polymorphism, but not IL10-819C/T polymorphism was associated with the risk of IS. PMID- 25932118 TI - Cancer-associated fibroblasts are associated with poor prognosis in esophageal squamous cell carcinoma after surgery. AB - OBJECTIVE: Cancer-associated fibroblasts (CAFs; alpha-SMA positivity), as a representative of the tumor microenvironment, play an important role in influencing the proliferation, invasion and metastasis of cancer cells. The objective is to investigate the prognostic value of CAFs density in esophageal squamous cell carcinoma (ESCC) after surgery. METHOD: A total of 95 patients who underwent esophagectomy for ESCC in 2007 were included in this study. These specimens were immunostained with alpha-smooth muscle actin (alpha-SMA) antibodies to quantify CAFs. Antibodies D2-40 and CD34 were used to evaluate the lymphatic vessel density (LVD) and microvessel density (MVD) of the lesions. The Cox proportional hazards model was used to determine the hazard ratio of CAFs density on 3-year overall survival and 3-year disease-free survival. The correlation between CAFs density and lymphatic vessel density (LVD) or microvessel density (MVD) were analyzed. RESULTS: 3-year overall survival rate in the CAF-poor group (63%) was significantly better than those in the CAF-rich group (42%) (P < 0.01). In the Cox univariate and multivariate analysis of 3-year overall survival, the hazard ratio (HR) of CAFs density was 1.870 (95% CI 1.033 3.385; P = 0.039) and 2.196 (95% CI 1.150-4.193; P = 0.017), respectively. CAFs density was proved to be an independent prognostic factor for 3-year overall survival. CAFs density correlated significantly with increased LVD and MVD in ESCC. CONCLUSION: CAFs density may be a marker for predicting prognosis and guiding therapeutic management of ESCC. PMID- 25932119 TI - Actinomycin D inhibits cell proliferations and promotes apoptosis in osteosarcoma cells. AB - Actinomycin D (ActD), a well known transcription inhibitors, has been widely reported to induce cell apoptosis in several types of tumor cells by inhibiting the anti-apoptotic gene transcriptions. However, how ActD affects osteosarcoma cells survival and its molecular mechanism is currently unclear. In the present study, results of proliferation assays and Hoechst stainings suggested that MG63 human osteosarcoma cells showed impaired cell proliferations and significant apoptosis after ActD treatment. Moreover, biochemical results showed that cleaved caspase-3 is gradually increased with the increasing ActD concentrations and treated times. Importantly, results of western blots indicated that protein levels of cyclin factors, such as cyclin A, D1 and E, were all reduced after ActD treatment. And ActD treatments may inhibit mRNA transcription levels of these cyclin factors, which may finally lead to cell cycle arrest and consequently apoptosis. The present study have revealed a novel mechanism by which ActD inhibits osteosarcoma cell proliferations and induces apoptosis, and will provide an useful clue to chemotherapy in future treatment of osteosarcoma. PMID- 25932120 TI - Effect of clipping anterior communicating artery aneurysms via pterional approach contralateral to supply of dominant blood: report of 15 patients. AB - BACKGROUND AND PURPOSE: Anterior communicating artery aneurysm (ACoAA) is a common cerebrovascular disease. This research is to observe the curative effect and safety of clipping anterior communicating artery (ACoA) aneurysms by microsurgery through the pterional approach contralateral to supply of dominant blood. MATERIALS AND METHODS: Before the surgery, three-dimensional-DSA (3D-DSA) was performed to study the regional anatomy of ACoA complexes in all 15 patients with ACoA aneurysms. According to 3D-DSA, the aneurysms and ACoA complexes could be satisfactorily exposed by the microsurgery through the pterional approach contralateral to the supply of dominant blood. And then the microsurgery through the pterional approach contralateral to the supply of dominant blood was performed in 15 patients with ACoA aneurysms. RESULTS: Clipping of ACoA aneurysms were successfully performed in all patients. The aneurysms and ACoA complexes were satisfactorily exposed via 3D-DSA. Among 15 patients with ACoA aneurysms, 14 cases were cured and 1 case need further care. CONCLUSIONS: The ideal side of pterional approach may be cheese via simulation of pterional approach with 3D DSA. The ACoA complex and aneurysm can be clearly exposed, and the aneurysm may be smoothly clipped safely by the microsurgery through the ideal side pterional approach contralateral to supply of dominant blood in the patients with ACoA aneurysms. PMID- 25932121 TI - A modified porous tantalum implant technique for osteonecrosis of the femoral head: survivorship analysis and prognostic factors for radiographic progression and conversion to total hip arthroplasty. AB - Tantalum rod implant following core decompression is reported to be effective in early stage of osteonecrosis of the femoral head (ONFH). The purpose of this study was to assess the survivorship and prognostic factors for radiographic progression and conversion to total hip arthroplasty (THA) after treatment with a modified tantalum implant technology. 59 consecutive hips (45 patients) in whom ONFH was treated with core decompression, impaction bone grafting of 2 mm composite bone filling material, and insertion of a porous tantalum implant. 57 hips (44 patients, mean age 43 years, range 21 to 70 years) with Steinberg Stage I-IVA ONFH were available for follow-up at a mean of 44.8 months (rang, 11 to 62 months). Outcome measures included HHS (Harris Hip Score), radiographic outcome, and survivorship analysis with reversion to THA. Radiographic progression occurred in 17 hips (17/57, 29.82%). 11 hips (11/57, 19.30%) were converted to THA. The overall survival rate was 72.49% at 60 months post-operatively. After logistic regression analysis, corticosteroid use and bone marrow edema were found to be predictors of radiographic progression. The Cox proportional-hazard model revealed that bone marrow edema was an independent prognostic factor for conversion to THA. This modified technology may make patients avoid the use of corticosteroid, especially those without bone marrow edema, and obtains encouraging survival rates and a delay in or prevention of THA. PMID- 25932122 TI - Prognostic role of miR-200c in various malignancies: a systematic review and meta analysis. AB - MiR-200c expression is dysregulated in various malignancies and may predict the survival of patients with cancer, although the results of different studies conflict. Therefore, we conducted a meta-analysis to resolve this discrepancy. We queried the PubMed and Embase using multiple search strategies. Data were extracted from studies comparing overall survival and progression-free survival in patients with cancer with high and low levels of miR-200c expression. Fixed and random models were used where appropriate. A combined hazards ratio (HR) was calculated to estimate the association of high levels of miR-200c with survival. We selected 16 studies of 1485 participants for our final meta-analysis. Upregulated expression of miR-200c predicted significantly worse overall survival in patients with cancer (HR 1.51; 95% confidence interval [CI] 1.06-2.16, P = 0.023). Subgroup analysis indicated that high levels of miR-200c was associated with decreased survival of Caucasians and patients with gynecological tumors with pooled HR values of 1.82 (95% CI 1.27-2.26, P = 0.01) and 3.23 (95% CI 1.11-9.38, P = 0.032), respectively. Because of the absence of apparent heterogeneity, the combined HRs were 1.69 (95% CI 1.24-2.30, P = 0.001) for squamous cell carcinoma and 1.91 (95% CI 1.40-2.59, P < 0.001) for samples from peripheral blood. Increased expression of miR-200c significantly associated with shorter progression-free survival of patients with cancer (HR 2.37; 95% CI 1.47-3.81, P < 0.001). Our meta-analysis indicates that the level of miR-200c expression predicted survival of patients with cancer, particularly for Caucasians and patients with gynecological cancer. Increased expression of miR-200c predicted shorter survival of patients with squamous cell carcinomas. Our findings indicate that monitoring the levels of miR-200c in blood may be useful for following tumor progression as well as patients' prognosis. PMID- 25932123 TI - Prognostic value of rsf-1/hbxap in human solid tumors: a meta-analysis of cohort studies. AB - PURPOSE: Recent studies have investigated remodeling and spacing factor 1 (Rsf-1) as a molecular marker in various solid tumors. However, whether or not Rsf-1 exerts a negative or positive effect on the survival of patients with solid cancers remains controversial. Therefore, this study aims to determine whether or not Rsf-1 may be a predicative marker of poor prognosis and aggressive tumor progression. METHODS: We conducted a meta-analysis of 11 cohort studies (n = 1620 patients) to evaluate the relationship between Rsf-1 and clinical outcome. We included studies with data on overall survival (OS), disease-specific survival (DSS), recurrent-free survival (RFS), metastasis-free survival (MFS), and hazard ratios (HRs) with 95% confidence intervals (CIs). RESULTS: High Rsf-1 expression was significantly associated with poor survival in solid tumors. Overall, the combined HR for OS was 1.49 (95% CI = 1.21-1.84, P < 0.001), DSS 3.07 (95% CI = 1.67-5.62, P < 0.001), RFS 2.51 (95% CI = 1.12-5.63, P = 0.025), and MFS 2.14 (95% CI = 1.49-3.06, P < 0.001). In addition, Rsf-1 overexpression was significantly associated with tumor stage (OR = 4.13, 95% CI = 2.84-6.00, P < 0.001), primary tumor (OR = 2.09, 95% CI = 1.58-2.75, P < 0.001), nodal status (OR = 1.95, 95% CI = 1.40-2.72, P < 0.001), and histological grade (OR = 3.09, 95% CI = 2.10-4.54, P < 0.001). CONCLUSIONS: Rsf-1 may be a predicative marker of poor prognosis and aggressive tumor progression. PMID- 25932124 TI - Association between estrogen receptor-alpha gene PvuII and XbaI polymorphisms and osteoarthritis risk: a meta-analysis. AB - Estrogen receptor-alpha (ER-alpha) gene PvuII (T/C) and XbaI (A/G) polymorphisms have been hypothesized to be associated with osteoarthritis (OA) risk by several epidemiological studies, however, the available results were inconclusive and conflicting. We conducted a meta-analysis of 10 case-control studies that included 3328 osteoarthritis cases and 6390 case-free controls. We assessed the strength of the association, using odds ratios (ORs) with 95% confidence intervals (CIs). This meta-analysis showed that the ER-alpha PvuII and XbaI polymorphisms were not associated with OA risk in overall population. For the PvuII (T/C) polymorphism, however, in the subgroup analysis by country, a significantly reduced risk was observed among Chinese (TC vs. CC: OR = 0.73, 95% CI 0.54-0.99, I (2) = 0%, P heterogeneity = 0.498; dominant model, OR = 0.73, 95% CI = 0.55-0.98, I (2) = 0%, P heterogeneity = 0.555). For the XbaI (A/G) polymorphism, when stratifying by sample size, a significantly elevated risk was found in sample size <= 500 (AA vs. GG: OR = 2.60, 95% CI 1.10-6.18, I (2) = 42.9%, P heterogeneity = 0.135; dominant model: OR = 2.04, 95% CI 1.12-3.71, I (2) = 11.4%, P heterogeneity = 0.341; and recessive model: OR = 1.69, 95% CI 1.12 2.55, I (2) = 40.2%, P heterogeneity = 0.154). No publication bias was found in the present study. This meta-analysis suggests that ER-alpha PvuII (T/C) polymorphism may be associated with a reduced OA risk among Chinese and the XbaI (A/G) polymorphism may not be associated with OA risk, while the observed increase in OA risk for XbaI polymorphism may be due to small-study bias. PMID- 25932125 TI - Nicorandil inhibits oxidative stress and amyloid-beta precursor protein processing in SH-SY5Y cells overexpressing APPsw. AB - It has been demonstrated that ATP-sensitive potassium (KATP) channel activation has neuroprotective effects against neuronal damage induced by hypoxia, ischemia or metabolism stress. This study investigated the multiply protective effects of KATP channel opener nicorandil against neurotoxicity in SH-SY5Y cells transiently transfected with Swedish mutant APP (APPsw) and also the potential involvement of PI3K/Akt/GSK-3beta pathway. Cells were treated with nicorandil (1 mM) for 24 h with and without glibenclamide (10 MUM), a KATP channel inhibitor. Then the cells were collected for Hoechst33342, biochemical assays, real-time PCR, western blot and ELISA assay. Our results showed that nicorandil reduced apoptosis and decreased oxidative stress. Moreover, nicorandil down regulated APP695 mRNA and APP695 protein expression, also reduced Abeta1-42 levels in the medium. In addition, nicorandil increased the protein levels of p-Akt and p-GSK-3beta by PI3K activation. Applying a PI3K inhibitor, LY294002 blocked the protection. These findings suggest nicorandil to be a potential therapeutic agent to treat Alzheimer's disease (AD). PMID- 25932126 TI - The role of Interleukin 15 in protein degradation in skeletal muscles in rats of chronic obstructive pulmonary disease. AB - AIM: The present study aimed to investigate the role of Interleukin 15 (IL-15) in protein degradation in skeletal muscle mediated by the ubiquitin-proteasome pathway (UPP) in a rat model of chronic obstructive pulmonary disease (COPD). METHODS: The COPD model was established in 30 Sprague Dawley (SD) rats through the combination of passive smoking and intratracheal injection of lipopolysaccharide (LPS). The pathological changes in lungs and bronchi of COPD rats (n=30) were compared with that of control rats (n=15). The levels of IL-15 and tumor necrosis factor-alpha (TNF- alpha) in the serum, diaphragm, gastrocnemius, and the intercostal muscles were measured using enzyme-linked immunosorbent assay (ELISA), and compared between the COPD and control rats. In addition, the expression of E2-14K, MAFbx, and ubiquitin (Ub) was evaluated using quantitative real-time PCR and western blot and compared between the COPD and control rats. RESULTS: The levels of IL-15 and TNF-alpha in the serum, diaphragm, gastrocnemius, and the intercostal muscles in COPD rats were significantly higher than that in control rats. The expression of E2-14K, MAFbx, and ubiquitin (Ub) in the diaphragm, gastrocnemius, and the intercostal muscles in COPD rats was also significantly higher than that in the control rats. In addition, we identified positive correlation between the levels of IL-15 and TNF-alpha. Positive correlation was also identified between the levels of IL-15 and E2-14K, MAFbx, and Ub. CONCLUSION: Our results suggest that IL-15 inhibited the protein degradation in skeletal muscle in COPD rats, which may be mediated by the TNF alpha and UPP pathway. PMID- 25932127 TI - Tanshinone IIA protects against methylglyoxal-induced injury in human brain microvascular endothelial cells. AB - Tanshinone IIA is one of the major diterpenes from Salvia miltiorrhiza Bunge and has been shown to possess a protective effect on the endothelial cells. The present study aimed to investigate whether tanshinone IIA could protect against methylglyoxal (MGO)-induced injury in human brain microvascular endothelial cells (HBMEC). Using cultured HBMEC, cell viability was measured by MTT assay and trypan blue dye exclusion test. Cellular oxidative stress was measured by production of reactive oxygen species (ROS), thiobarbituric acid reactive substances (TBARS) and H2O2. AnnexinV/PI staining and western blot were performed to determine cell apoptosis and protein expression. We found that MGO treatment caused a concentration and time-dependent decrease in cell viability, which was inhibited by pretreatment with tanshinone IIA. Exposure to MGO promoted the accumulation of AGEs, and production of ROS, TBARS and H2O2 in the cultured HBMEC, which were inhibited by tanshinone IIA pretreatment. Addition of tanshinone IIA significantly reduced MGO-induced cell apoptosis as shown by flow cytometry. On the molecular level, tanshinone IIA administration altered the expression of apoptosis-related proteins such as p53, Bax, Bcl-2 and cyto C. In addition, MGO treatment remarkably increased the phosphorylation of MAPK family including p38, JNK and ERK. By contrast, addition of tanshinone IIA inhibited the activation of MAPK family members. These data indicated that tanshinone IIA could protect against MGO-induced cell injury through inhibiting MAPK activation in HBMEC. PMID- 25932128 TI - Baicalein alters PI3K/Akt/GSK3beta signaling pathway in rats with diabetes associated cognitive deficits. AB - Our present investigation focused on assessing the neuroprotective potential of baicalein (BAC) against diabetes-associated cognitive deficit (DACD) using a diabetic model and further figure out the potential molecular mechanisms. Diabetic rat model was established by streptozotocin (STZ). Vehicle or BAC by the doses of 2 and 4 mg/kg was intraperitoneally injected once a day for seven consecutive weeks. Memory function was evaluated by Morris water maze test and avoidance passive test. The activities of acetylcholinesterase (AChE), choline acetylase (ChAT), caspase-9 and caspase-3 in STZ-induced diabetic rats' hippocampus were detected via responsive commercial kits. Western blot assay were used to determine the protein levels of phospho-phosphatidylinositol 3-kinase (p PI3K), phospho-Akt (p-Akt), and phospho-glycogen synthase kinase-3beta (p GSK3beta). Our results showed that BAC remarkably increased body weight and ChAT activity, decreased blood glucose level and AChE activity as well as improved cognitive deficits in diabetic rats. Additionally, it was also found that treatment with BAC to diabetes obviously stimulated the p-PI3K and p-Akt and inhibited the level of p-GSK3beta. Furthermore, the neuronal apoptosis was also prevented after BAC treatment by decreasing caspase-9 and caspase-3 activities in diabetic rats' hippocampus. It is concluded that BAC exerted beneficial effects against DACD in rats and its neuroprotection might be linked with activating PI3K and Akt phosphorylation accompanied with suppressing the phosphorylated level of GSK3beta. These results hint that BAC is likely to be served as an adjuvant therapy to conventional anti-hyperglycemic regimens as well as DACD. PMID- 25932129 TI - Chrysin suppresses cigarette smoke-induced airway inflammation in mice. AB - Cigarette smoke-induced airway inflammation is one of the most important features of chronic airway diseases. Studies suggest that chrysin possesses strong anti inflammatory properties and this study aimed to investigate the effect of chrysin on cigarette smoke-induced airway inflammation in mice. Mice with exposure to cigarette smoke were intraperitonealy injected with chrysin (10, 20 mg/kg.d). TNF alpha, IL-1beta and IL-8 levels in bronchoalveolar lavage fluid were determined by ELISA. MPO level in lung homogenates was tested by a MPO kit. The expression of signaling proteins in lung tissue, phosphorylation ERK and p38 was detected using Western Blot. Cigarette smoke exposure increased the release of inflammatory cytokines TNF-alpha, IL-1beta, IL-8 in bronchoalveolar lavage fluid and the expression of MPO in lung tissue. Chrysin pretreatment inhibited cigarette smoke-induced airway inflammation, inflammatory cytokines release, and MPO expression. Cigarette smoke exposure also increased the expression of phosphorylation ERK and p38, meanwhile, chrysin intervention can inhibit such changes. In summary, chrysin inhibits cigarette smoke exposure-induced airway inflammation in mice, which may partly act through inhibition of ERK and p38 phosphorylation. PMID- 25932130 TI - Efficacies of immunotherapy with polypeptide vaccine from ProDer f 1 in asthmatic mice. AB - Allergic asthma is associated with the major house dust mite group 1 allergens Der p 1 and Der f 1, which belongs to the papin-like protease family and is the most potent of indoor allergens and allergen-specific immunotherapy (SIT), is seen as effective intervention for the entity. The current study was designed to verify the SIT efficacies of the enzymatic hydrolysates (papain and trypsin) in mice with asthma. We initially developed the asthmatic mouse models with ProDer f 1, and respectively applied recombinant ProDer f 1 protein and the two kinds of enzymatic hydrolysates for SIT. The results were verified by measuring the contents of IL-4, IL-10, IL-17 and IFN-gamma changed in both bronchoalveolar lavage fluid (BALF) and supernatant of splenocyte culture as well as level changes of specific IgE and IgG2a in the serum. After SIT intervention, the symptoms of allergic inflammation was alleviated significantly in mice treated with ProDer f 1 protein and the two enzymatic hydrolysates via detection of the lung tissue sections, and infiltration of inflammatory cells was also notably depressed as compared with the models, though the epithelial structure in airways remained similar with the PBS group. In addition, we observed lower serum contents of the specific IgE antibody and lower levels of IL-4, IL-17 in BALF and splenic cells in mice undergone SIT, whereas specific IgG2a, IFN-gamma and IL-10 in BALF and supernatant of splenocyte culture were higher as compared to the asthma group. The findings suggest the SIT using the above two kinds of hydrolysates may effectively inhibit the allergic inflammation in the airways of mouse models sensitized with ProDer f 1 protein. PMID- 25932131 TI - Application of the myocardial tissue/silicon substrate microelectrode array technology on detecting the effection of Zhigancao Decoction medicated serum on cardiac electrophysiology. AB - BACKGROUND: Modern pharmacological studies have confirmed that the total extract of Zhigancao Decoction, either as a single active compound or in combination, can inhibit arrhythmia. In this study, the myocardial tissue/silicon substrate microelectrode array (MEA) was used to detect the Zhigancao Decoction medicated serum of the New Zealand white rabbits right atrial appendage after rapid right atrium pacing (RAP). METHODS: New Zealand white rabbits were randomly divided into four groups, with eight rabbits per group. The first group was the control animal group (Group A). The second was the drug-free serum vehicle control group (Group B). The third group used serum-containing f Zhigancao Decoction (Group C) at various concentrations. The fourth group was the Zhigancao Decoction medicated serum group (Group D). After establishing the atrial fibrillation model, the field action potential duration (fAPD) of the right atrial appendage (RAA) in the control group, and in groups after different interventions, were measured. RESULTS: We report of an atrial fibrillation model using by rapid right atrium atrial pacing, in which fAPD was significantly shorter 12 hours after pacing (P < 0.05). The intervention by 10% to 25% of drug-containing serum or decoction could prolong the fAPD of rabbit atrial appendage in atrial fibrillation rabbits in a dose dependent manner (P < 0.05). CONCLUSION: fAPD can be used as an indicator for the change of cardiac electrophysiological properties. 10% to 25% of Zhigancao Decoction medicated serum can prolong fAPD in atrial fibrillation rabbits, which may be the electrophysiological mechanism of atrial fibrillation resistance. PMID- 25932132 TI - MicroRNA-221 promotes human non-small cell lung cancer cell H460 growth. AB - MicroRNA (miRNA-221) has been reported to be a regulator of cell proliferation. Here we intended to investigate the role of miRNA-221 in regulating the growth of human non-small cell lung cancer cell line H460. H460 cells were transfected with miRNA-221 mimics/inhibitors or their respective negative controls. Real-time quantitative PCRs (qRT-PCRs) were used to confirm the effects of miRNA-221 mimics and inhibitors in H460 cells while Cell Counting Kit 8 (CCK-8) and 5-Ethynyl-2' deoxyuridine (EdU) assay were used to access the cell viability and proliferation. P27 and P57, as putative targets of miRNA-221, were determined by qRT-PCRs in H460 cells. We found that overexpression of miRNA-221 led to increased proliferative rate and cell viability in H460 cells while down regulation of miRNA-221 decreased those effects. P27 but not P57 was identified as a potential target gene of miRNA-221 in H460 as P27 was negatively regulated by miRNA-221 in the protein level. In conclusion, this study suggests that miRNA 221 controls human non-small cell lung cancer cell H460 growth potentially by targeting P57. Inhibition of miRNA-221 represents a novel potential treatment for human non-small cell lung cancer. PMID- 25932133 TI - Long term effects on mineral and bone metabolism by low versus standard calcium dialysate in peritoneal dialysis: a meta-analysis. AB - BACKGROUND: Low calcium dialysate with 1.25 mmol/l calcium concentration has been proposed to replace standard calcium dialysate in peritoneal dialysis patients taking calcium-containing phosphate binder to prevent hypercalcaemia. We conducted a meta-analysis to evaluate long term effects on mineral and bone metabolism by low versus standard calcium dialysate in peritoneal dialysis. METHOD: Clinical studies comparing low versus standard calcium dialysate in peritoneal dialysis patients were identified by searching PubMed (from 1990 to October 2013) and EMBASE (from 1990 to October 2013). Major outcomes extracted for meta-analysis were: serum total and ionized calcium, phosphate, parathyroid hormone and bone metabolism. Statistical analyses were performed using the Review Manager, version 5.1.0 (Cochrane Collaboration, Oxford, UK). RESULTS: Four studies were identified for meta-analysis. A total of 240 peritoneal dialysis patients received standard calcium dialysate and 106 patients were given low calcium dialysate. 1-2 year after peritoneal dialysis, both serum total and ionized calcium were lower in low calcium dialysate patients as compared with standard dialysate patients (Total calcium: MD, 0.09; 95% CI, 0.05 0.13; P < 0.0001; Ionized calcium: MD, 0.04; 95% CI, 0.02 0.06; P < 0.0001). No statistical difference was observed in phosphate level between two groups (MD, -0.05; 95% CI, -0.13 0.02; P = 0.19). Intact parathyroid hormone level was significantly increased in low calcium dialysate patients. No clinically significant long term change of bone metabolism was observed between low and standard calcium dialysate treated patients. CONCLUSION: Long term (1-2 year) use of low calcium dialysate with 1.25 mmol/l calcium concentration in peritoneal dialysis patients results in decrease of serum total and ionized calcium level and does not change serum phosphate level. No clinical significance in the change of bone metabolism was observed between low and standard calcium dialysate patients despite the increase of serum parathyroid hormone in low calcium dialysate group. PMID- 25932134 TI - Catalpol protects mice against renal ischemia/reperfusion injury via suppressing PI3K/Akt-eNOS signaling and inflammation. AB - Renal ischemia/reperfusion-injury (IRI) is a common disease in clinic, which is also the most common cause of acute kidney failure. Previous investigations has illustrated that catalpol has neuroprotective, anti-inflammatory, and anti hepatitis virus effects. This study was designed to investigate the protective effect of catalpol on renal IRI mice through suppressing phosphatidylinositol 3 kinase/protein kinase B (PI3K/Akt)-endothelial nitric oxide synthase (eNOS) and against inflammation, and the possible underlying mechanism. Firstly, we used renal IRI model to analyze blood urea nitrogen and serum creatinine levels in renal IRI mice. Next, real-time PCR and western blotting were used to detect the expression of KIM-1 and the expression of PI3K, Akt and eNOS levels in renal IRI, respectively. In addition, activities of tumor necrosis factor alpha (TNF-alpha), interleukin-1beta (IL-1beta), interleukin-6 (IL-6) and interleukin-10 (IL-10) in renal IRI mice were measured with respective TNF-alpha, IL-1beta, IL-6 and IL-10 ELISA kits. Our results showed that catalpol clearly reduced blood urea nitrogen, serum creatinine levels and the expression of KIM-1 in renal IRI mice. Meanwhile, we found that catalpol markedly reduced the expression of PI3K, Akt and eNOS levels in renal IRI group. Suppressing of the PI3K/Akt-eNOS and the TNF-alpha, IL 1beta, IL-6 and IL-10 activities was involved in the protective effect of catalpol on renal IRI. Collectively, catalpol protected renal IRI via inhibiting PI3K/Akt-eNOS signaling and inflammatory responses. PMID- 25932135 TI - Prognostic value of ALDH1 expression in lung cancer: a meta-analysis. AB - OBJECTIVE: ALDH1 has recently been reported as a marker of cancer stem-like cells in lung cancer. However, the predictive value of ALDH1 in lung cancer remains controversial. In this study, we aimed to evaluate the association of ALDH1 expression with the clinicopathological features and outcomes of lung cancer patients through a meta-analysis. METHODS: Publications that assessed the clinical or prognostic significance of ALDH1 in lung cancer up to October 2014 were identified. A meta-analysis was performed to clarify the association between ALDH1 expression and clinical outcomes. RESULTS: Ten eligible publications with 1836 patients were included. The analysis of these data showed that ALDH1 expression was highly correlated with lymph node metastasis (pooled OR = 1.45, 95% CI: 1.04-2.02, P = 0.027), decreased overall survival (pooled RR: 2.25, 95% CI: 1.15-4.41, P = 0.019), and decreased disease-free survival (pooled RR: 1.63, 95% CI: 1.01-2.64, P = 0.047). CONCLUSION: Patients with ALDH1-positive lung cancer had poor prognosis, which was associated with common clinicopathological poor prognostic factors. PMID- 25932136 TI - Association of MYOC and APOE promoter polymorphisms and primary open-angle glaucoma: a meta-analysis. AB - BACKGROUND: Primary open-angle glaucoma (POAG) is the most common form of glaucoma with a genetic predisposition. The relationship between polymorphisms in MYOC or APOE promoter region and POAG has been addressed in many case-control studies, but the published results were not consistent. METHODS: A meta-analysis assessing the association between five single nucleotide polymorphisms (SNPs) (in MYOC promoter: rs12035719 and rs2075648; in APOE promoter: rs405509, rs769446 and rs449647) and the risk of POAG was performed based on included studies from literature research. In fixed effect model or random effect model, the Mantel Haenszel (M-H) pooled odds ratios (ORs) and 95% confidence intervals (95% CIs) were used to evaluate the genetic association. Stratification analysis was also conducted to test the association within Asian or Caucasian populations. RESULTS: Twenty five case-control studies within multiple populations were identified and no publish bias was observed. Significant association was detected between POAG risk and MYOC rs2075648 in Caucasian (GA+AA vs. GG, OR=0.587, 95% CI=0.437-0.788, P < 0.001). For other SNPs and in other ethnic populations, no statistic evidence was detected for significant association between them and the development of POAG. CONCLUSIONS: This meta-analysis suggested a genetic association between one of MYOC polymorphism (rs2075648) and the risk of POAG only in Caucasian population. The significant heterogeneity for this locus might imply the different POAG genetic basis among different populations. PMID- 25932138 TI - Comparative proteomic analysis of serum diagnosis patterns of sputum smear positive pulmonary tuberculosis based on magnetic bead separation and mass spectrometry analysis. AB - A major challenge in pulmonary tuberculosis (TB) control is early and accurate diagnosis of sputum smear negative pulmonary TB (SSN-PTB). The patients with SSN PTB have to wait for a longer period of time before receiving proper treatment than sputum smear positive pulmonary TB (SSP-PTB) patients due to delay in diagnosis. The purpose of this study is to discover potential serum protein biomarkers for SSN-PTB. Surface-enhanced laser desorption/ionization-time of flight mass spectrometry (SELDI-TOF MS) combined with weak cation exchange (WCX) magnetic beads was used to screen serum samples from SSN-PTB patients (N = 66), SSP-PTB patients (N = 49), and healthy volunteers (N = 80). The serum protein profiles were analyzed with Biomarker Wizard system. A classification model was established using Biomarker Pattern Software (BPS). Fifty-eight protein peaks were identified to exhibit significant differences between SSN-PTB, SSP-PTB and healthy control groups (P < 0.05), among which 6 peaks were found to be down regulated, while 10 peaks were up-regulated gradually in the healthy control, SSN PTB, and SSP-PTB groups. Twenty-three discriminating m/z peaks were detected between SSN-PTB patients and healthy controls (P < 0.01, Fold >= 1.5). The classification tree combined with three protein peaks (2747.0, 4480.0, and 9410.1 Da) could distinguish SSN-PTB patients from healthy controls with a sensitivity of 83.33% and a specificity of 82.50%. Early diagnosis of SSN-PTB disease is critical in order to reduce morbidity and mortality associated with TB. The study will help to clarify the role of differential proteins in the pathogenesis of TB. PMID- 25932137 TI - Paroxetine alleviates rat limb post-ischemia induced allodynia through GRK2 upregulation in superior cervical ganglia. AB - Long-lasting neuroplastic changes induced by transient decrease in G protein coupled receptor kinase 2 (GRK2) in nociceptors enhances and prolongs inflammatory hyperalgesia. Here, we investigated the effects of paroxetine (a selective serotonin reuptake inhibitor and GRK2 inhibitor) on GRK2 expression in superior cervical ganglion (SCG) in a rat model of complex regional pain syndrome type I (CRPS-I). After ischemia-reperfusion (I/R) injury, the ipsilateral 50% paw withdrawal thresholds (PWTs) to mechanical stimuli and the expression levels of GRK2 protein and mRNA in the ipsilateral SCGs all decreased significantly; the ipsilateral cold allodynia scores increased significantly. No significant differences were found in the contralateral side except GRK2 mRNA reduced significantly at day 2-day 9 after I/R injury, but still higher than those in ipsilateral SCGs. After paroxetine administration, the ipsilateral 50% PWTs at day 2, 7, 14, and 21 were significantly higher than those in control group; The GRK2 protein and mRNA levels in ipsilateral SCGs were also significantly up regulated after day1; The ipsilateral cold allodynia scores were significantly reduced after day7. No significant differences were found in the contralateral 50% PWTs, cold allodynia scores, and GRK2 protein level except GRK2 mRNA levels increased significantly at day1-day7 after paroxetine administration. Therefore, a transient decrease of GRK2 expression in SCG neurons might be involved in the development and maintenance of allodynia in CRPS-I and paroxetine might alleviate this allodynia through GRK2 protein upregulation in SCGs. PMID- 25932139 TI - Effect of radiotherapy on moderate and severe thyroid associated ophthalmopathy: a double blind and self-controlled study. AB - OBJECTIVE: The effect of radiotherapy on moderate and severe Thyroid associated ophthalmopathy (TAO) was evaluated by various objective and quantitative indexes including T2 signal intensity ratios of orbital MRI inferior rectus and ipsilateral temporal muscle (T2SIR), extraocular muscles (EOM) volume, and the degree of exophthalmos using clinical research with prospective, randomized, double blind, self controlled. METHODS: The patients with TAO who in the moderate and severe active period and had similar double eyes condition in the Outpatient Department of Ophthalmology of Xiangya No. 2 Hospital of Central South University from 2011.2 to 2014.2 were selected as objects in this study. The related body check was finished after the research group was built. For the object, one eye of patient having random radiotherapy was chosen as the experimental eye. The other eye in the same patient with pseudo radiotherapy (merely known by operator, doctors in department of ophthalmology and patients were double blind) was selected as the control eye. The radiotherapy plan was made by the operator according to the CT results. The T2 signal intensity ratios of orbital MRI inferior rectus and ipsilateral temporal muscle (T2SIR), extraocular muscles (EOM) volume, and the exophthalmos degree was compared by MRI check to evaluate the effect of radiotherapy. RESULTS: The T2 signal intensity ratios of orbital MRI inferior rectus and ipsilateral temporal muscle (T2SIR), extraocular muscles (EOM) volume, and the exophthalmos degree between both eyes (experimental and control eyes) had significant differences and these data had statistical significance. CONCLUSIONS: The treatment of radiotherapy is effective for the TAO in the moderate and severe active period. PMID- 25932140 TI - PAI-1 4G/5G polymorphism and coronary artery disease risk: a meta-analysis. AB - Many epidemiologic studies have investigated the plasminogen activator inhibitor 1 (PAI-1) gene 4G/5G polymorphism and this association with coronary artery disease (CAD). But definite conclusions can not be drawn. Related studies were identified from PubMed, Springer Link, Ovid, Chinese Wanfang Data Knowledge Service Platform, Chinese National Knowledge Infrastructure (CNKI), and Chinese Biology Medicine (CBM) till 10 August 2014. Pooled ORs and 95% CIs were used to assess the strength of the associations. A total of 53 studies including 20921 CAD cases and 18434 controls were included. Significantly elevated CAD risk was found in overall analysis (OR = 1.13, 95% CI: 1.05-1.21, P = 0.0009). In the subgroup analysis by races, significantly increased risk was found in Caucasians (OR = 1.11, 95% CI: 1.03-1.20, P = 0.005) and Asians (OR = 1.20, 95% CI: 1.01 1.42, P = 0.04). In the subgroup analysis by gender, significant association was found in males (OR = 1.15, 95% CI: 1.06-1.25, P = 0.0008), but was not found in females (OR = 1.05, 95% CI: 0.92-1.20, P = 0.47). In the subgroup analysis by age, young populations showed increased CAD risk (OR = 1.19, 95% CI: 1.02-1.37, P = 0.02), but old populations did not show this association (OR = 1.01, 95% CI: 0.82-1.24, P = 0.93). This meta-analysis provides the evidence that PAI-1 4G/5G polymorphism may contribute to the CAD development. PMID- 25932141 TI - Association between tumor necrosis factor alpha rs1800629 polymorphism and risk of cervical cancer. AB - PURPOSE: The objective of this study was to evaluate the influence of the TNF alpha rs1800629 polymorphism on the risk of cervical cancer. METHODS: A comprehensive search of EMBASE, PubMed, Wanfang database and China National Knowledge Infrastructure (CNKI) was conducted and the papers published were retrieved. The fixed effects or random effects model was appropriately used to calculate the odds ratio (OR) along with 95% confidence interval (CI). RESULTS: Data from sixteen articles containing nineteen studies were summarized in this meta-analysis. In general, we observed a marginal association between the TNF alpha rs1800629 polymorphism and cervical cancer risk under the AA + AG vs. GG comparison model (OR=1.17, 95% CI=1.00-1.38, P=0.019 for heterogeneity). Interestingly, significantly increased risk was observed in the allele model (A vs. G: OR=1.19, 95% CI=1.02-1.38, P=0.006 for heterogeneity). In the stratified analysis by ethnicity, we found significant results in Caucasians. CONCLUSIONS: Our results reveal that the Caucasian population may be at increased risk of developing invasive cervical cancer associated with the TNF-alpha rs1800629 polymorphism. PMID- 25932142 TI - Hypertensive vascular remodeling was inhibited by Xuezhikang through the regulation of Fibulin-3 and MMPs in spontaneously hypertensive rats. AB - Fibulin-3, an extracellular glycoprotein, has been suggested as having functions in vessels. In hypertension, extracellular matrix, matrix metalloproteinases (MMPs) and tissue inhibitors of metalloproteinases (TIMPs) play important roles in cardiovascular remodeling. However, the role of Fibulin-3 as an extracellular glycoprotein in hypertensive vascular remodeling remains unclear. Our study was to determine whether Fibulin-3 and TIMPs/MMPs would affect vascular structure during hypertension and the treatment of Xuezhikang. Thirty spontaneously hypertensive rats (SHRs) aged 8 weeks were randomized to three groups: SHRs control group (SHRs group, n=10), group treated with low dose Xuezhikang (XZK-L, 20 mg/kg/d, n=10) and group treated with high dose Xuezhikang (XZK-H, 200 mg/kg/d, n=10), the normal group was comprised of ten Wistar-Kyoto (WKY) rats of the same age. We showed that serum nitric oxide (NO) in control group was significantly lower than WKY group (P<0.05). Concomitantly, serum oxidized low density lipoprotein (ox-LDL) was higher than WKY group (P<0.05). The treatment of high dose Xuezhikang significantly dicreased ox-LDL, left ventricular mass index (LVMI) and Wall-to-lumen area ratio (W/L) of thoracic aorta (P<0.05), while serum NO was significantly increasing (P<0.05). Moreover, the expressions of Fibulin-3 and MMP-2, 9 at both protein and mRNA levels were significantly higher in thoracic aorta of SHRs group compared to WKY group by immunohistochemistry and western blotting (P<0.05). However, the levels of Fibulin-3 and MMP-2, 9 were significantly decreased in XZK-H group compared to control group (P<0.05). The level of TIMP-3 had no significance difference between SHRs and WKY groups (P>0.05). So the levels of Fibulin-3 and MMP-2, 9 in SHRs could be inhibited by Xuezhikang. Furthermore, a strong correlation in transcript expression was established between Fibulin-3, and MMP-2 (r=0.81, P<0.05) and MMP-9 (r=0.92, P<0.05) through immunohistochemistry. In summary, the overexpression of Fibulin-3 and MMP-2, 9 levels were associated with hypertension and vascular remodeling and inhibited by Xuezhikang. Fibulin-3 is a candidate in the pathogenesis of cardiovascular remodeling in hypertension. PMID- 25932143 TI - Effects of baicalin cream in two mouse models: 2,4-dinitrofluorobenzene-induced contact hypersensitivity and mouse tail test for psoriasis. AB - BACKGROUND: Scutellaria baicalensis is a Chinese herbal medicine that has been used for centuries to treat psoriasis. Baicalin is one of the major flavonoids and bioactive components of S. baicalensis and is responsible for the pharmacologic actions of the plant. OBJECTIVE: This study aimed to investigate the anti-inflammatory effect and keratinocyte differentiation-inducing activity of baicalin in vivo. METHODS: Baicalin was formulated into topical creams at concentrations of 1%, 3%, and 5%. The anti-inflammatory effect of baicalin cream was evaluated in 2,4-dinitrofluorobenzene (DNFB)-induced contact hypersensitivity (CHS) mice, and its keratinocyte-modulating action was assessed using the mouse tail model for psoriasis. RESULTS: During the topical application of baicalin cream, no evidence of irritant effect was observed in both tests. In the inflammation model, mice exposed to baicalin cream displayed a reduction in DNFB induced CHS responses compared with vehicle-treated animals, showing that the topical application of baicalin cream exerted an anti-inflammatory effect. In the second model, baicalin cream dose-dependently increased the orthokeratosis of granular layers and the relative epidermal thickness of mouse tail skin, indicative of the keratinocyte differentiation-inducing activity of this topical preparation. CONCLUSIONS: Taking the in vivo findings together, the present study indicated that baicalin cream may be a promising antipsoriatic agent worthy of further investigation for psoriasis treatment. PMID- 25932144 TI - A survey on clinical use of propranolol for infantile hemangiomas in mainland China. AB - OBJECTIVE: To provide a guideline for Chinese clinicians regarding oral propranolol treatment on infantile hemangioma (IH). METHODS: A survey for management of propranolol therapy (clinical consultation, dosage initiation, dosage changing, monitoring of complications and effectiveness evaluation) was performed and was delivered to the Division of Vascular Anomalies (DVA), Chinese Stomatological Association (CSA), and to the Division of Hemangioma and Vascular Malformations (DHVM), Chinese Society of Plastic and Reconstructive Surgery. RESULTS: Data from 31 hospitals were collected and analyzed. In all hospitals, IH patients were treated with oral propranolol as a routine. Twenty-two (71%) of the 31 hospitals treated patients with IH as part of a multidisciplinary strategy. Cardiology consultation was routinely sought in 21 (95%) of these 22 hospitals before initiation of propranolol therapy. Sixteen hospitals (52%) recommend an initial propranolol dose of 1 to 1.5 mg/kg/day, in most cases 1.0 mg/kg/day. The dosage frequency of once a day was recommended in 18 (58%) of the surveyed hospitals. The maximum dose of 1.5 mg/kg/day or 2.0 mg/kg/day was suggested in 10 (32%) and 13 (42%) hospitals, respectively. Similarly, the optimal dose of 1.5 mg/kg/day or 2.0 mg/kg/day was recommended in 11 (37%) and 9 (30%) hospitals, respectively. The duration of therapy varied from 1 to 24 months. Tapering was advised by 10 (40%) hospitals and immediate discontinuation was applied in 13 (52%) hospitals. Complications were emphasized by all hospitals. The most common complications were gastrointestinal symptoms (17 of 31 hospitals), whereas the complication most commonly monitored for was changes in heart rate. No rebound effects were reported. CONCLUSIONS: Propranolol has become the first-line agent for IH in mainland China. This is a practical survey which is helpful to standardize and develop a guideline for propranolol therapy. PMID- 25932145 TI - Correlation between triggering receptor expressed on myeloid cells-1 and clinical disease activity in Chinese patients with ulcerative colitis. AB - The need for reliable biomarkers for monitoring disease activity in patients with ulcerative colitis (UC) is increasing. This study aimed at characterizing the correlation between serum sTREM-1 levels and diseases activity in Chinese patients with UC. Consecutive 76 patients with UC and 20 healthy subjects were prospectively enrolled. The disease activity of UC was assessed according to Mayo Score. Expression levels of TREM-1 in peripheral blood mononuclear cells (PBMCs) and serum sTREM-1 levels were evaluated at the time when the disease activity was determined. Other laboratory parameters, including erythrocyte sedimentation rate (ESR) and C-reactive protein (CRP) were also determined. Both TREM-1 expression levels in PBMCs and serum sTREM-1 levels from patients with UC were significantly increased compared to healthy subjects. In addition, the levels of TREM-1 expression and serum sTREM-1 were significantly elevated in UC patients with moderate or severe disease compared to the patients with quiescent or mild disease. More importantly, both levels of TREM-1 expression in PBMCs and serum sTREM-1 levels were significantly correlated with disease activity. The correlation between sTREM-1 and disease activity was higher than the correlations between CRP and disease activity or ESR and disease activity. Our findings suggest that serum sTREM-1 could be a potential serum biomarker for monitoring disease activity in Chinese patients with UC, and could be a promising surrogate for CRP and ESR. PMID- 25932146 TI - Effects of PSCA rs2294008 (C/T) and c-MYC rs9642880 (G/T) polymorphisms on bladder cancer: evidence from a meta-analysis. AB - Previous studies have investigated the associations between the two polymorphisms (prostate stem cell antigen (PSCA) rs2294008 C/T and c-MYC rs9642880 G/T) and bladder cancer (BC) risk. However, the results are inconsistent. We therefore carried out a meta-analysis to estimate the relationship between PSCA/c-MYC polymorphisms and BC risk. We searched PubMed up to November 2014 to identify potentially eligible literatures. Odds ratios (ORs) and 95% confidence intervals (CIs) were used to estimate the strength of the associations, the data were further stratified by ethnicity. Heterogeneity was evaluated by Q test and I(2) statistics. Begg's funnel plot and Egger's test were used to assess the publication bias. 11 studies from 9 articles were identified, including a total of 16,814 cancer cases and 52,868 case-free controls. We found a significant association between PSCA rs2294008 polymorphism and BC risk (the allele contrast model: OR = 1.14, 95% CI = 1.11-1.18; homozygote comparison: OR = 1.28, 95% CI = 1.20-1.37; heterozygote comparison: OR = 1.23, 95% CI = 1.17-1.30; dominant model: OR = 1.25, 95% CI = 1.19-1.31 and recessive model: OR = 1.13, 95% CI = 1.07-1.20). Moreover, a significant increased risk of BC was confirmed both in Caucasian and in Asians. For c-MYC rs9642880 polymorphism, significant increased BC risk was detected under the following genetic models (the allele contrast model: OR = 1.20, 95% CI = 1.13-1.27; homozygote comparison: OR = 1.37, 95% CI = 1.21-1.55; heterozygote comparison: OR = 1.20, 95% CI = 1.09-1.32; dominant model: OR = 1.25, 95% CI = 1.14-1.37 and recessive model: OR = 1.26, 95% CI = 1.13-1.40). Further stratified analysis by ethnicity also observed the same results. This meta-analysis suggested that PSCA rs2294008 and c-MYC rs9642880 polymorphisms may increase the BC risk. Further studies are needed to clarify the effects. PMID- 25932147 TI - Histone demethylase KDM2B inhibits the chondrogenic differentiation potentials of stem cells from apical papilla. AB - Mesenchymal stem cells (MSCs) are a reliable resource for tissue regeneration, but the molecular mechanism underlying directed differentiation remains unclear; this has restricted potential MSC applications. Histone methylation, controlled by histone methyltransferases and demethylases, may play a key role in MSCs differentiation. Previous studies determined that KDM2B can regulate the cell proliferation and osteo/dentinogenic differentiation of MSCs. It is not known whether KDM2B is involved in the other cell lineages differentiation of MSCs. Here we used the stem cells from apical papilla (SCAPs) to study the role of KDM2B on the chondrogenic differentiation potentials in MSCs. In this study, Gain and loss-of-function assays were applied to investigate the role of KDM2B on the chondrogenic differentiation. Alcian Blue Staining and Quantitative Analysis were used to investigate the synthesis of proteoglycans by chondrocytes. Real-time RT PCR was used to detect the expressions of chondrogenesis related genes. The Alcian Blue staining and Quantitative Analysis results revealed that overexpression of KDM2B decreased the proteoglycans production, and real-time RT PCR results showed that the expressions of the chondrogenic differentiation markers, COL1, COL2 and SOX9 were inhibited by overexpression of KDM2B in SCAPs. On the contrary, depletion of KDM2B increased the proteoglycans production, and inhibited the expressions of COL1, COL2 and SOX9. In conclusion, our results indicated that KDM2B is a negative regulator of chondrogenic differentiation in SCAPs and suggest that inhibition of KDM2B might improve MSC mediated cartilage regeneration. PMID- 25932148 TI - Applications of computed tomography pelvimetry and clinical-pathological parameters in sphincter preservation of mid-low rectal cancer. AB - BACKGROUND: This study aims to evaluate the predictive value of pelvic anatomical and clinical-pathological parameters that influence the success of sphincter preservation procedure (SPP). METHODS: We studied 42 consecutive patients who underwent low anterior resection (LAR) with double stapling technique (DST) anastomosis or abdominoperineal resection (APR) for mid-low rectal cancer between June 2009 and April 2014. The surgical procedures were performed by the same surgeon and surgical team at the Department of Surgery of Wenzhou Central Hospital. Pelvic dimensions and angles were measured using three-dimensional reconstruction of spiral computed tomography (CT) images. A number of clinical pathological parameters were also examined. Univariate and multivariate analyses were performed to determine the predictive significance of these variables that might affect a successful SPP for mid-low rectal cancer. RESULTS: Body mass index (BMI), distance of tumor from anal verge, and diameter of upper pubis to coccyx affected the success of SPP. It was the higher distance of tumor from anal verge, the higher BMI, and the larger diameter of upper pubis to coccyx contributed most to the success of SPP. CONCLUSIONS: Diameter of upper pubis to coccyx is the only one of the pelvic anatomical parameters that could affect the success of SPP for mid-low rectal cancer patients. Furthermore, within the normal BMI range, higher BMI seemed to be a favorable factor for the success of SPP. PMID- 25932149 TI - Apoptosis-inducing effects of cetuximab combined with radiotherapy and hypothermia on human nasopharyngeal carcinoma CNE cells. AB - To investigate the apoptosis-inducing effects of cetuximab combined with radiotherapy and hypothermia in human nasopharyngeal carcinoma CNE cells. CNE cells were treated with the radiation monotherapy, the radiation and hypothermia, the cetuximab and radiation, and the triple-combination treatment, respectively. MTT assay was performed to assess cell proliferation following treatments. Hoechst 33258 staining and flow cytometry analyses were used to detect apoptotic process. Western blot analysis was performed to determine the protein expression levels. Cetuximab monotherapy inhibited the proliferation of CNE cells. Hyperthermia alone inhibited EGFR expression, and prolonged hypothermia treatment resulted in declining EGFR expression levels in these cells. Moreover, Hoechst 33258 staining showed obvious apoptotic morphologies in the treatment groups. Flow cytometry analysis showed that the interventions dramatically increased the apoptosis rates in CNE cells, with the most potent effect for the triple combination treatment. Western blot analysis showed that, in the treatment groups, the expression levels of Bax were increased, while the expression levels of Bcl-2 were decreased, leading to significantly elevated Bax/Bcl-2 ratios in these groups, with the highest ratio for the triple-combination treatment. Cetuximab combined with radiotherapy and hypothermia treatments could efficiently inhibit the proliferation of CNE cells, and enhance the cellular apoptotic processes via regulating the expression levels of Bax and Bcl-2. Our findings provide experimental evidence for the application of the combination therapy in clinical treatment of nasopharyngeal carcinoma. PMID- 25932150 TI - As2O3 induces apoptosis in human hepatocellular carcinoma HepG2 cells through a ROS-mediated mitochondrial pathway and activation of caspases. AB - Arsenic trioxide (As2O3) has been shown to induce apoptosis in hepatocellular carcinoma cells. However, the molecular mechanism of As2O3-induced apoptosis in the hepatocellular carcinoma cells remains poorly understood. Here, we investigated the impact of As2O3 exposure on the human hepatocellular carcinoma cell line HepG2 and examined the underlying mechanism of cell death. As2O3 induced apoptosis of HepG2 cells in a dose- and time-dependent manner and caused a massive production of reactive oxygen species (ROS). The antioxidant N acetylcysteine (NAC) was able to prevent As2O3-induced cell death, implying an involvement of ROS in the induction of As2O3-triggered apoptosis. Furthermore, As2O3 initiated apoptosis by triggering of the mitochondria apoptotic pathway as indicated by inhibited Bcl-2 expression, a collapse of the mitochondrial membrane potential (MMP), release of cytochrome c and activation of the caspase cascade. However, these As2O3-induced events can be prevented by NAC. Taken together, these findings suggest that the As2O3 induced apoptosis through a ROS-mediated mitochondrial pathway and activation of caspases. PMID- 25932151 TI - Apparent diffusion coefficient measurements and Gd-DTPA enhanced-imaging in staging hepatic fibrosis in rats. AB - To evaluate the utility of ADC values and Gd-DTPA equilibrium phase MR imaging in staging hepatic fibrosis in rats. 48 rats were allocated into experimental and control groups. Experimental rats were subcutaneously injected with a mixture of CCl4. From 4th-12th weeks, MR images were obtained, which include pre-enhanced phase imaging, DWI and equilibrium phase imaging. Then the rat groups were subdivided according to the stages of fibrosis (S0, S1, S2, S3 and S4) after histopathological analysis. The original MRI data were forwarded to the workstation to obtain apparent diffusion coefficient (ADC) maps at b value of 500 s/mm(2). Pre-enhanced phase and equilibrium phase signal intensities and relative contrast enhancement index (RCEI) were measured as well. Lastly, the ADC values and RCEI of the experimental group were compared with each other and with the control group. All statistical analyses were carried out with SPSS, where P < 0.05 is considered to represent a significant difference. Hepatic ADC values are significantly different between the experimental and control groups (P = 0). There is a statistically significant difference between the experimental and control groups on RCEI (P = 0). Comparing the S1, S2, S3 and S4 groups, there is a statistically significant difference between the mild group (S1 and S2) and the severe group (S4) in terms of ADC values and RCEI (all P < 0.05). A statistically significant difference is also found between the moderate group (S3) and the severe group in ADC values. As the degree of fibrosis increases, there are a reduction in ADC values and an increase in RCEI. Comparing the groups with ADC values and enhancement index, there are statistically significant differences in sensitivity and specificity on diagnosis of hepatic fibrosis. The ADC values have the best sensitivity (93.1%) and specificity (83.3%). Quantitative ADC values and RCEI may be helpful to the staging of rat fibrosis, but their application in human is controversial. PMID- 25932152 TI - Efficacy of edaravone on coronary artery bypass patients with myocardial damage after ischemia and reperfusion: a meta analysis. AB - OBJECTIVES: To assess the efficacy and safety of edaravone for myocardial damage during myocardial ischemia and reperfusion (I/R). METHODS: We included randomized controlled trials that compared edaravone with placebo or no intervention in patients with acute myocardial infarction or undergoing coronary artery bypass. Two authors selected eligible trials, assessed trial quality and independently extracted the data. RESULTS: Seven clinical trials were eventually included and analyzed in this study, involving 148 participants. Four trials were defined as waiting assessment. All of the three remaining trials compared edaravone and another treatment combined with other treatment alone, used the same dose of edaravone injections (60 mg per day) and course of treatment (14 days), evaluated the effect of edaravone at different times, applied different methods, reported adverse events, and showed no differences between the treatment group and the control group. When pooling all of the trials in one dataset, edaravone appeared to decrease the proportion of participant with marked myocardial damage during I/R as compared with the control group. The meta-analysis also revealed decreased CK-MB, cTnI and MDA, and increased content of SOD. CONCLUSIONS: Due to the moderate risk of bias and small sample, our observation of an effective treatment trend of edaravone for I/R requires future larger, high-quality trials to confirm. PMID- 25932153 TI - Chemopreventive effects of 5-amino salicylic acids on inflammatory bowel disease associated colonic cancer and colonic dysplasia: a meta-analysis. AB - PURPOSE: To study the effects of 5-amino salicylic acids (5-ASAs) on the incidence rates of inflammatory bowel disease (IBD)-associated colonic cancer (IBDACa) and colonic dysplasia (IBDADys), as well as to evaluate the chemopreventive effects of 5-ASAs on IBDACa/Dys. METHODS: Searches for officially published clinical studies on the effects of 5-ASAs on the chemoprevention of IBDACa/Dys were conducted in both foreign-language databases, including PubMed (Medline), EMCC, OVID, and the Cochrane Library, and Chinese databases, including Wanfang, Weipu (VIP), and CNKI, as well as using Google Scholar. For literature matching the selection criteria, the statistical software RevMan was employed to calculate odds ratio (OR) values and 95% confidence intervals (CIs). Sub-group analysis was performed for different study design types and IBD types. RESULTS: A total of fourteen papers were included in this study. The results of the analysis showed that compared with patients not using 5-ASAs, patients using 5-ASAs showed only 49% of the occurrence rate of IBDACa and IBDADys, OR = 0.49 (95% CI: 0.33 0.73). The OR of ulcerative colitis (UC) patients using 5-ASAs exhibiting UCCa/Dys was 0.44 (95% CI: 0.26-0.76). CONCLUSION: The use of 5-ASAs exerts a chemopreventive effect against IBDACa/Dys. PMID- 25932154 TI - Association of Leu125Val polymorphisms in the PECAM-1 gene with the risk of coronary heartdisease: a meta-analysis. AB - OBJECTIVE: Several published literatures investigated the relation between a polymorphism (Leul25Val) in platelet endothelial cell adhesion molecule-1 (PECAM 1) gene and risk of coronary heart disease (CHD) and did not reach the same conclusion. To shed light on these inconclusive findings, we performed a meta analysis of studies relating the PECAM-1 genetic polymorphism (Leul25Val) to the risk of CHD. METHODS: We identified literatures by searching PubMed, EMBASE, Chinese National Knowledge Infrastructure databases (CNKI) and Wanfang database in China. Data from eligible studies were extracted for meta-analysis. CHD risk associated with PECAM-1 genetic polymorphism (Leul25Val) was estimated by pooled odds ratios (ORs) and 95% confidence intervals (95% CIs). The software Review Manager (Version 5.2) was used for meta-analysis. Publication bias was tested by funnel plot. RESULTS: A total of 15 studies comprising 3696 cases and 3940 controls fulfilled the inclusion criteria. Our results did not show that Leul25Val polymorphism in PECAM-1 gene was associated with the risk of CHD [(LL+LV) vs VV, OR = 1.15, 95% CI: 0.84-1.56, P = 0.38; (VV+LV) vs LL, OR = 0.96, 95% CI: 0.79-1.17, P = 0.69; V vs L, OR = 1.08, 95% CI: 0.92-1.27, P = 0.80, respectively] by a meta-analysis. CONCLUSION: The results of our meta-analysis suggested that Leul25Val polymorphism in PECAM-1 gene is not a susceptibility marker of CHD. PMID- 25932155 TI - Effects of Shenqi Neijin powder on activation and apoptosis of hepatic stellate cells in rats with hepatic fibrosis. AB - Traditional herbal medicine is usually administrated according to experiences and practices. We aimed to investigate the anti-fibrotic effects of Shenqi Neijin powder (SQNJP) in hepatic fibrosis rats induced by carbon tetrachloride (CCl4). A total of 32 rats were divided into control group, model group, and SQNJP group. The hydroxyproline content was assayed. Histological features of liver tissues were determined with different staining methods. Western blotting analysis and immuno-fluorescence staining were performed to determine the expression of alpha smooth muscle actin (alpha-SMA) and the activation of hepatic stellate cells (HSCs). Serial sections were stained with alpha-SMA immuno-fluorescence staining and the terminal deoxynucleotidyl transferase-mediated dUTP-biotin nick end labeling method (TUNEL) in turn to detect the apoptosis of HSCs. Fatty degeneration, deposition of collagen, and interval of fibers were noticed in rats induced by CCl4. After administration of SQNJP, remarkable decrease of fatty degeneration, deposition of collagen, and hydroxyproline content were noticed. Compared with the model group, significant decrease of alpha-SMA protein was noticed after administration of SQNJP, and remarkable apoptosis of HSCs was noticed after treating with SQNJP. SQNJP showed anti-fibrotic effects through inhibiting HSCs activation and inducing apoptosis of HSCs. PMID- 25932156 TI - TGF-beta1 related inflammation in the posterior longitudinal ligament of cervical spondylotic myelopathy patients. AB - AIM: This study aimed to elucidate the pathogenesis of posterior longitudinal ligament (PLL) hypertrophy. METHODS: Cervical PLL specimens were collected from CSM patients during surgery (n = 30) and during routine autopsy (n = 14), and processed for histological examination (HE staining and Masson's Trichrome staining) and IHC (CD3, CD68, CD31, TGF-beta1 and collagen II). In addition, the mRNA expression of collagen I was detected in cervical PLL specimens from 16 CSM patients (n = 16) and from routine autopsy (n = 16) by RT-PCR. RESULTS: Obvious fibrosis, cartilage metaplasia and calcification were found in the cervical PLL of CSM patients. In the degenerated PLL, CD68(+) macrophages were frequently identified, CD3(+) T lymphocytes were occasionally found, and many newly generated small vessels were also present. In the degenerated PLL, of the number of TGF-beta1 positive cells increased markedly when compared with control group. IHC indicated TGF-beta1 was secreted by macrophages. RT-PCR showed a significantly lower mRNA expression of collagen I in the PLL of CSM patients as compared to control group. CONCLUSIONS: Macrophages are the major type of inflammatory cells involved in the cervical PLL degeneration, and TGF-beta1 is related to the cervical PLL degeneration. TGF-beta1 is mainly secreted by macrophages. Anti-inflammation may serve as an alternative non-surgical treatment and prophylactic strategy for PLL degeneration. PMID- 25932157 TI - OSAHS obstructive plane localization: comparative study between ag200 and friedman classification. AB - OBJECTIVE: To compare AG200 (Sleep Monitoring Obstructive Locator, Apneagraphy) and the result of Friedman classification and evaluate the accuracy of the two testing methods on OSAHS obstructive localization diagnosis. METHODS: 77 patients who were undergoing a treatment in the hospital, with Obstructive sleep apnea hypopnea syndrome (OSAHS) diagnosed by Polysomnography, were selected. Those patients were monitored by ArthroCare AG200 for their upper airway-esophageal pressure. Friedman classification, tongue height scale (Friedman tongue position, FTP), tonsil scale and classification between constituent ratio of upper obstruction >=70% and constituent ratio of lower obstruction >=70% were recorded before analyzing the relations of obstructive planes measured by Friedman classification and AG. RESULT: Friedman clinical classification didn't include type IV patients (no patients had BMI >=40, or had obvious jaw deformity); the comparison between each other within a group showed that the number of type III patients was apparently larger than that of Friedman type I (U=4.689, P<0.05); A common rule was that as the scale of Friedman classification and FTP increases, the lower obstructive constituent ratio also increases. AG systematic analysis showed that 66.23% (51/77) patients mainly complained of upper obstruction, i.e. upper obstructive constituent ratio >=70% while 12.99% (10/77) patients mainly complained of lower obstruction, i.e. lower obstructive constituent ratio >=70%). No obvious difference was detected if classified by tonsil size. If patients were classified by upper obstructive constituent ratio >=70% and lower obstructive constituent ratio >=70%, the condition of the patients, FTP and the size of the tonsil showed no significant difference (P>0.05). CONCLUSION: Friedman classification method is easy to operate and to some extent, it can predict the site of obstructive plane, though the result is not always accurate because the result from Friedman classification of some patients was not consistent with that measured by nasopharyngo-fiberoscope and CT scan. Measuring the upper airway esophageal pressure by AG200 system is the only localizing diagnosis method now to find the dynamic changes of all obstructive sites during the whole night as it can acquire the rough constituent ratio of obstructive plane and complement the shortcomings of physics examination and imaging tests. But it can only provide the location of the lowest plane instead of the accurate cause of obstruction and whether there is another obstruction above the existed obstruction at the same time. Clinically, patients, especially those who are considering surgeries like UPPP should combine different examination methods before the surgery so as to complement their advantages and improve the accuracy of localizing obstructive plane before deciding a proper surgery plan for a successful surgery, thus patients can recover as soon as possible. PMID- 25932159 TI - Osteopontin can decrease the expression of Col-II and COMP in cartilage cells in vitro. AB - OBJECTIVE: To observe the effect of osteopontin (OPN) on the expression of collagen type II (Col-II) and oligomeric matrix protein COMP in cartilage cells of knee osteoarthritis, and explore the mechanism of OPN in the knee osteoarthritis. METHODS: Cartilage cells were isolated from fetal rabbit, they were divided into 3 groups: A (control); B (0.5 MUM OPN) and C (1 MUM OPN). The expression levels of Col-2 and COMP were detected by RT-PCR and Western blotting methods. MMP-13 was detected using ELISA. The proliferation was determined by MTT method. RESULTS: Compared with the group, the expression levels of Col-2 and COMP in cartilage cells decreased in the intervention group with dose dependent (P<0.05). The expression of MMP-13 in culture supernatant and the proliferation increased in the intervention group (P<0.05). CONCLUSION: OPN can down-regulate the expression levels of Col-2 and COMP in cartilage cells and up-regulate the expression of MMP-13 in culture supernatant and promote the proliferation of cells, which could accelerate the pathological process of cartilage cells. PMID- 25932158 TI - Primary intra- and juxta-articular vascular malformations of the temporomandibular joint: a clinical analysis of 8 consecutive patients. AB - OBJECTIVE: To analyze primary intra- and juxta-articular vascular malformations of the temporomandibular joint. PATIENTS AND METHODS: This study retrospectively reviewed eight patients (seven venous malformations and one lymphatico-venous malformation) who were treated for intra- or juxta-articular vascular malformations of the temporomandibular joint from November 2005 to January 2011. All patients underwent magnetic resonance imaging (MRI) preoperatively. RESULTS: According to MRI findings, vascular malformations involving TMJ could be divided into 3 types; homogenous, lacunar and mixed types. All patients underwent surgical resection, and the final clinical diagnoses were confirmed by postoperative histopathology and immunohistochemical examinations. All treated patients had no clinical or radiographic signs of recurrence. CONCLUSION: Owing to the lower incidence and nonspecific clinical presentations, preoperative diagnosis of vascular malformations involving the TMJ region is very difficult. The classification based on MRI manifestations is proposed first, then it may greatly help in the initial diagnosis. Surgical resection is considered the first option for these TMJ lesions with excellent results. PMID- 25932160 TI - Matrix metalloproteinase 2 (MMP2) protein expression and laryngeal cancer prognosis: a meta analysis. AB - OBJECTIVE: To investigate the protein expression of matrix metalloproteinase 2 (MMP2) and its clinical significance in laryngeal cancer. METHODS: A comprehensive search for the related literature published in China and other countries was conducted in a variety of databases, including MEDLINE, Embase, China Academic Journals Full-text Database, Wanfang Data and VIP Database. A total of seven case-control studies were included in the final systematic assessment. A meta-analysis software program was used to statistically analyze the raw data from each study for the calculation of the pooled odds ratio (OR) and 95% confidence interval (95% CI). RESULTS: The meta-analysis indicated that, compared with normal laryngeal tissue, the MMP2 protein was highly expressed in the laryngeal cancer tissue [OR=21.67; 95% CI: 11.61-40.43; P<0.001]. Compared with highly differentiated laryngeal cancer, the MMP2 protein expression level was higher in the moderately and poorly differentiated laryngeal cancers [OR=0.25; 95% CI: 0.13-0.46; P<0.001]. Compared with laryngeal cancers without lymph node metastasis, the laryngeal cancers with lymph node metastasis exhibited a greatly elevated MMP2 protein expression [OR=0.25; 95% CI: 0.14-0.46; P<0.001]. CONCLUSION: High protein expression levels of MMP2 may play an important role in the tumorigenesis, progression and prognosis of laryngeal cancer. PMID- 25932161 TI - Effects of CD14 and TLR4 on LPS-mediated normal human skin fibroblast proliferation. AB - BACKGROUND: This study was designed to elucidate the effects of CD14 and TLR4 on the proliferation of LPS-mediated normal human skin fibroblasts and to gain new insights into the mechanisms underlying LPS-induced scar formation. METHODS: Cell morphology and density were observed using an inverted microscope. Proliferation curves were described by MTT. The number of proliferating cells was counted by staining the cells with trypan blue. Cells were stained with propidium iodide (PI) and the phase of cell generation cycle was determined by flow cytometry. RESULTS: The growth rate detected in groups B, C, D was slower compared to group A after 48 h. All proliferation curves were approximately S shaped and the peak was seen on days 6, followed by a sharp decline on days 7. The proliferation rate of groups B, C, D was significantly slower than group A. After the staining, we found a significantly smaller number of proliferating cells in groups B, C, D as compared to group A. Flow cytometry revealed that the ratio of proliferating cells at S phase was lower in the groups B, C, D as compared to group A. CONCLUSIONS: Both separate and combined use of anti-CD14 and anti-TLR4 enable a significant decline in the rate and capacity of proliferation, with the latter pretreatment resulting in the sharpest reduction. Therefore, it seems likely that anti-CD14 along with anti-TLR4 is significantly engaged in the signaling mechanisms of LPS-mediated fibroblast proliferation. PMID- 25932162 TI - Injuries of myocardial cells and changes of myocardial enzymes after firearm wound-induced intestinal perforation in porcine abdomen. AB - This study aims to observe the changes of myocardial injuries after the firearm wound-induced intestinal perforation in porcine abdomen. 42 healthy Landrace piglets were randomly divided into the control group and the injury group, which was then subdivided into the post-injury 1 h, 2 h, 4 h, 8 h, 12 h and 24 h subgroup. the LDH, CK and CK-MB levels of each group, as well as the plasma endotoxin, were determined and compared. The plasma endotoxin levels of the experimental groups were significantly higher than the control group, and the light microscope observation revealed that the 8 h, 12 h and 24 h subgroup appeared the gradually-aggravated myocardial cell edema and degeneration; the electron microscope revealed that the 4 h, 8 h, 12 h and 24 h subgroup appeared the mitochondrial swelling and dissolution gradually; the serum levels of LDH, CK and CK-MB of each experimental group were higher than the control group. The abdominal firearm wound-induced intestinal perforation would lead to the damaged changes of myocardial morphology and enzymes, which would aggravate as time went along. PMID- 25932163 TI - Ipsilateral total hip arthroplasty in patient with an above-knee amputee for femoral neck fracture: a case report. AB - There is limited literature about the outcomes of total hip arthroplasty (THA) as a surgical option for above-knee amputees. Here, we described one case of femoral neck fracture with above-knee amputation. Two-year follow-up revealed an excellent clinical and radiological outcome. The main challenge of THA posed by the amputation was control of the lower extremity. We recommend inserting a pin at the greater trochanter of the femur to improve control of traction or rotation. PMID- 25932164 TI - Technique and surgical outcome of total resection of lower sacral tumor. AB - OBJECTIVE: To summarize the technique and surgical outcome for total resection of lower sacral tumor. METHODS: This retrospective study included 12 cases of total resection of lower sacral tumor (involving S3 and the below) from January 2010 to February 2013. Seven patients underwent en bloc resection and five cases accepted intralesional curettage. We used extraperitoneal approach to ligature the bilateral internal iliac artery, separated the tumor, and used transverse incision to separate the sacrum from surrounding ligaments and muscles. We then separated the sacrum to S2-S3 junction and ligatured the dural sac, cut off the sacrum at the S2-S3 junction, and remove the tumor out of the envelope. The other five patients underwent posterior surgery, which directly revealed lesions. Curettes were used under direct vision to scrape the tumor tissue. RESULTS: All patients underwent the operation successfully without perioperative death or serious complication. The blood loss ranged from 300-650 mL (460 mL in average) in en bloc resection group. The blood loss ranged from 350-2800 mL (1595 mL in average) in curettage group. One case of transient enteroplegia and one case of transient gatism were respectively reported in en bloc resection group and one case of chronic pain in sacral was reported in curettage group. The postoperative pathological results revealed that there were 4 chordomas, 2 giant cell tumor and 1 metastatic tumor in en bloc resection group. All patients were followed up for 4-36 months (13.6 in average). At the final follow-up there was no recurrence reported. Two cases of local recurrence (40%) in curettage group were reported. CONCLUSION: The surgery combined with anterior-posterior approach helped remove the lower sacral tumor totally, with uncomplicated surgical operations and obviously reduced recurrence rate. The recurrence rate was significantly reduced using curettage method. PMID- 25932165 TI - Prognostic role of vascular endothelial growth factor in prostate cancer: a systematic review and meta-analysis. AB - The objective of this study was to perform a meta-analysis and literature review on the predictive role of vascular endothelial growth factor (VEGF) in prostate cancer. A detailed literature search was performed using PubMed and Embase databases for related research publications written in English. Methodological quality of the studies was also evaluated. Data was collected from studies comparing overall survival (OS), progression-free survival (PFS), disease-free survival (DFS), biomedical failure (BF) and cancer-specific survival (CSS) in patients with elevated VEGF levels and those having lower levels. The hazard ratio (HR) and its 95% confidence interval (CI) were used to assess the strength of associations. A total of 12 studies (n = 1,737) were included in this meta analysis (4 for OS, 3 for CSS, 2 for DFS, 4 for BF, and 4 for PFS). For OS, DFS and PFS, the pooled HR for VEGF was not statistically significant at 1.30 (95% CI, 0.74-2.29), 0.80 (95% CI, 0.57-1.13) and 1.04 (95% CI, 0.93-1.16), respectively. However, for CSS and BF, the pooled HR was 2.32 (95% CI, 1.20-4.46) and 1.30 (95% CI, 1.06-1.59), respectively. Our results demonstrate that VEGF may have a critical prognostic value in patients with prostatic cancer. PMID- 25932166 TI - miR-210, a modulator of hypoxia-induced epithelial-mesenchymal transition in ovarian cancer cell. AB - miR-210 has been found consistently induced by hypoxia and implicated in cancer progression. Despite widespread exploration on miR-210 function, little is known about its action on invasion and metastasis of ovarian cancer. In this study, miR 210 was induced by hypoxia in SKOV3 ovarian cancer cells and then suppressed with its specific inhibitor. Repression of miR-210 in hypoxic cells led to upregulation of E-cadherin, downregulation of vimentin and Snail, and attenuation of wound healing capability. On the other hand, miR-210 was overexpressed in normoxic SKOV3 cells, which resulted in decrease of E-cadherin, increase of vimentin and Snail, and facilitation of wound healing capability. These results revealed that miR-210 promoted ovarian cancer cell mobility by acting as a modulator of epithelial-mesenchymal transition (EMT), highlighting the importance of miR-210 in ovarian cancer progression. PMID- 25932167 TI - Interleukin-1beta rs1143634 polymorphism and aggressive periodontitis susceptibility: a meta-analysis. AB - Multiple studies had focused on the association between interleukin-1 (IL-1) rs1143634 polymorphism and aggressive periodontitis (AgP) susceptibility, but the results remained inconclusive. Therefore, this meta-analysis was conducted to explore its role in the development of AgP. PubMed and Embase databases were searched up to April 15, 2014. After study selection and data extraction form eligible studies, meta-analysis was performed. Odds ratios (ORs) and 95% confidence intervals (CIs) were used to evaluate the association. All the analysis was performed using Comprehensive Meta-Analysis software. Finally a total of 25 case-control studies were included. The pooled results showed non association between AgP susceptibility and IL-1 rs1143634 polymorphism [for T vs. C: OR = 0.99, 95% CI = 0.79-1.23; for TT vs. CC: OR = 1.14, 95% CI = 0.78-1.66; for CT vs. CC: OR = 0.97, 95% CI = 0.70-1.36; for (CT + TT) vs. CC: OR = 1.02, 95% CI = 0.76-1.37; for TT vs. (CT + CC): OR = 1.22, 95% CI = 0.85-1.75]. Subgroup analyses remain did not find any association. No publication bias was detected. Hence, our meta-analysis showed that IL-1beta rs1143634 polymorphism is not linked to AgP susceptibility, regardless of ethnicity. PMID- 25932168 TI - Detection and screening of small molecule agents for overcoming Sorafenib resistance of hepatocellular carcinoma: a bioinformatics study. AB - Sorafenib, a novel orally-available multikinase inhibitor blocking several crucial oncogenic signaling pathways, presented survival benefits and became the first-line drug for treatment of patients with Hepatocellular carcinoma (HCC). However, the acquired resistance to Sorafenib resulted in limited benefits. In this study, we aimed to explore possible agents that might overcome Sorafenib resistance by bioinformatics methods. The gene expression profiles of HCC-3sp (acquired Sorafenib-resistance) and HCC-3p (Sorafenib-sensitive) cell line were downloaded from Gene Expression Omnibus (GEO) database. Then, the differentially expressed genes (DEGs) were selected using dChip software. Furthermore, Gene Ontology (GO) and pathway enrichment analyses were performed by DAVID database. Finally, the Connectivity Map was utilized to predict potential chemicals for reversing Sorafenib resistance. Consequently, a total of 541 DEGs were identified, which were associated with cell extracellular matrix, cell adhesion and binding-related items. KEGG pathway analysis indicated that 8 dysfunctional pathways were enriched. Finally, several small molecules, such as pregnenolone and lomustine, were screened out as potential therapeutic agents capable of overcoming Sorafenib resistance. The data identified some potential small molecule drugs for treatment of Sorafenib resistance and offered a novel strategy for investigation and treatments of HCC. PMID- 25932169 TI - Association between RAD51 polymorphism and breast cancer susceptibility: a meta analysis. AB - BACKGROUND: RAD51 interacting with BRCA1 and BRCA2 could modulate the penetrance of BRCA1/BRCA2 mutations, which may increase susceptibility for breast cancer by inhibiting DNA repair and genome stability. The purpose of this study was to provide refined statistical evidence for the association between RAD51 polymorphism and breast cancer risk. DESIGN AND RESULTS: We conducted a meta analysis of 15 publications with a total of 11,766 cancer cases and 11,227 controls. We summarized the data on the association of RAD51 polymorphism with breast cancer risk and performed subgroup analyses by ethnicity and control source. The pooled ORs based on fixed-effects model did not indicate a modified risk of breast cancer associated with RAD51 polymorphism in the overall population. Nor did we find a significant association in any stratified analysis. CONCLUSIONS: This meta-analysis suggested that RAD51 polymorphism did not appear to represent a significant risk factor for breast cancer. PMID- 25932170 TI - Lentivirus-mediated TPD52L2 depletion inhibits the proliferation of liver cancer cells in vitro. AB - Tumor protein D52-like 2, known as hD54 in previous studies (TPD52L2), is a member of TPD52 family which has been implicated in multiple human cancers. In recent reports, TPD52 proteins were indicated to be associated with several malignancies, but very little is known about the function of TPD52L2 in liver cancers. In our present study, in order to explore the role of TPD52L2 in liver cancer, TPD52L2 was knocked down in SMMC-7721 liver cancer cell line by lentivirus mediated RNA interference. The results demonstrated that depletion of TPD52L2 could remarkably inhibit proliferation and colony forming ability of cancer cell SMMC-7721. Furthermore, cell cycle in TPD52L2 depleted cells was verified to be arrested in G0/G1 phase as determined by FACS assay, in consistence with the observation of cell proliferation inhibition. These results unraveled that TPD52L2 played an important role in tumorigenesis pathways of liver cancer and might serve as a promising target in human liver cancer diagnosis and therapy. PMID- 25932171 TI - Rosuvastatin attenuated contrast-induced nephropathy in diabetes patients with renal dysfunction. AB - BACKGROUND: The protective effect of statins against CIN is still controversial. We investigated the efficacy of pretreatment of rosuvastatin in decreasing the risk of CIN in a high-risk population of patients undergoing coronary angiography. METHODS: We conducted a prospective, randomized, controlled study, involving 120 patients with diabetes and mild to moderate renal dysfunction undergoing coronary angioplasty. Patients were randomly assigned to receive rosuvastatin (n = 60, 10 mg/day) or no statins (n = 60) for at least 2 days before and 3 days after contrast media administration. Serum cystatin (SCysC), serum neutrophil gelatinase-associated lipocalin (NGAL) and urinary N-acetyl-beta D-glucosaminidase/urinary creatinine (NAG/UCr) were also observed before and after procedure. RESULTS: Baseline demographic characteristics and nephropathy risk factors were similar between groups. The NGAL levels after procedure were higher than baseline (P < 0.05). Both the peak NGAL values occurred at 2 hours. In rosuvastatin group the peak NGAL values were lower compared with that in control group [(47.60 +/- 18.72) MUg/L vs (62.19 +/- 44.68) MUg/L, P = 0.014]. No differences of the peak values of SCr were found between the two groups. But the peak levels of SCysC in rosuvastatin group were significantly lower compared with that in control group [(0.96 +/- 0.30) mg/L vs (1.08 +/- 0.34) mg/L, P = 0.043]. There were significant statistical differences of NAG/Cr levels in the two groups. No clinical events occurred within the following 30 days in the two groups. CONCLUSIONS: Rosuvastatin could reduce the effect of degrading glomerular filtration function and renal tubular damage in patients with DM and mild to moderate renal dysfunction. PMID- 25932172 TI - p53 Arg72Pro polymorphism and risk of basal cell carcinoma: a meta analysis. AB - PURPOSE: We attempted to comprehensively assess the possible association between p53 Arg72Pro polymorphism and the risk of basal cell carcinoma (BCC). METHODS: We performed a literature search of case-control association studies on p53 Arg72Pro polymorphism and BCC susceptibility in PubMed and EMBASE. 7 eligible studies were finally identified and their data were extracted for this meta-analysis. BCC risk was determined with the fixed effects model using a pooled odds ratio (OR). RESULTS: Using distinct genetic models, we found that p53 Arg72Pro polymorphism was not associated with the overall risk of BCC. We observed a similar trend towards the association when performing subgroup analysis for Caucasians and Asians. CONCLUSION: Our results suggest that presence of the common p53 Arg72Pro polymorphism may not play a role in the development of BCC. Larger studies are needed to better confirm the association. PMID- 25932173 TI - Genetic association between CD95 rs2234767 polymorphism and cervical cancer risk: a meta analysis. AB - BACKGROUND: CD95 rs2234767 polymorphism in the promotor region of CD95 gene has been implicated in several studies of cervical cancer. However, the results have not been conclusively established. OBJECTIVE: The main aim of this study was to deal with the controversy with respect to the correlation between CD95 rs2234767 polymorphism and risk of cervical cancer through a meta-analysis. METHODS: Association studies that pertain to CD95 rs2234767 polymorphism and risk of cervical cancer were identified up to May 26, 2014. ORs and 95% CIs were calculated assuming AA versus GG, AA + AG versus GG, AA versus AG + GG, A versus G and AG versus GG genetic models. RESULTS: A total of 5 case-control studies were included in this meta-analysis. Overall, no significant effect modification of cervical cancer risk was revealed either at the genotypic or the allelic level for CD95 rs2234767 polymorphism. This null association persisted in the stratified analysis of Asian population. CONCLUSIONS: These findings revealed that CD95 rs2234767 polymorphism may not act as a causative agent of cervical cancer. Further evidence is needed to confirm our findings. PMID- 25932174 TI - Laparoscopic repair of iatrogenic vesicovaginal and rectovaginal fistula. AB - OBJECTIVE: To investigate the clinical efficacy of laparoscopic repair of iatrogenic vesicovaginal fistulas (VVF) and rectovaginal fistulas. METHODS: Seventeen female patients with iatrogenic fistulas (11 cases of VVF and 6 cases of high rectovaginal fistulas) were included. All patients were hospitalized and underwent laparoscopic fistula repair in our hospital between 2008 and 2012. The mean age of the patients was 44.8 +/- 9.1 years. The fistulas and scar tissue were completely excised by laparoscopy, orifices were tension-free closed using absorbable sutures, omental flaps were interposed between the vagina and the bladder or rectum, and drainage was kept after repair. RESULTS: Laparoscopic repair of fistulas was successful in all 17 patients. No complication was found during or after repair. No reoperation was needed after the repair. The operative time was 80.2 +/- 30.0 minutes (range 50-140 minutes). The blood loss was 229.4 +/- 101.6 ml (range 100-400 ml). The double J catheters were placed in 7 patients and removed 1-2 months after repair. Eight VVF patients underwent cystoscopy 3 months after laparoscopic repair and there were no abnormal findings. The follow up time was 17.1 +/- 6.5 months (range 8-29 months). CONCLUSION: Laparoscopic repair of VVF and rectovaginal fistulas is a safe and an effective minimally invasive procedure for treatment of iatrogenic fistula. PMID- 25932175 TI - Prevention and treatment of bone cement-related complications in patients receiving percutaneous kyphoplasty. AB - OBJECTIVE: This study is to investigate the complications and preventive measures of bone cement in percutaneous kyphoplasty for the treatment of osteoporotic vertebral compression fractures. METHODS: A retrospective analysis of 134 cases of osteoporotic vertebral compression fracture patients treated with percutaneous kyphoplasty, which involved 182 vertebral fractures, was performed. The bone cement-related complications, the reasons causing these complications, and the preventive measures were investigated. RESULTS: Successful operation was performed in all patients. Operative bone cement toxic reaction occurred in 1 patient. Different degrees of leakage of bone cement were found in 21 patients with 25 fractures and 1 case needed operation treatment. During the long term follow-up, bone necrosis absorption and cement drifted away which needed operation treatment was found in 1 patient with vertebral fracture. Thirteen adjacent vertebral fractures were found in 11 patients and 10 patients underwent operation treatment again. CONCLUSIONS: With careful surgery, complications associated with bone cement could be greatly reduced. PMID- 25932176 TI - Analysis of association between sunscreens use and risk of malignant melanoma. AB - BACKGROUND: Epidemiological studies evaluating the association between sunscreens use and malignant melanoma risk have produced inconsistent results. Thus, we conducted a meta-analysis to summarize the evidence from epidemiological studies of sunscreens use with the risk of malignant melanoma. METHODS: Pertinent studies were identified by a search in PubMed and Web of Knowledge up to October 2014. Random-effect model was used to combine the results. Publication bias was estimated using Egger's regression asymmetry test. RESULTS: Twenty-one studies including 7150 malignant melanoma cases about sunscreens use with the risk of malignant melanoma were included in this meta-analysis. The combined relative risk (RR) of malignant melanoma associated with sunscreens use was 1.145 (95% CI=0.912-1.438). The association was significant neither in the case-control studies nor in the cohort studies. No publication biases were found. CONCLUSIONS: Our analysis indicated that sunscreens use is not associated with the risk of malignant melanoma. PMID- 25932177 TI - Three-D imaging of dental alveolar bone change after fixed orthodontic treatment in patients with periodontitis. AB - OBJECTIVES: The objective of this study was to radiographically quantify bone height and bone density in patients with periodontitis after fixed orthodontic treatment using cone beam computed tomography (CBCT). MATERIALS AND METHODS: A total of 81 patients including 40 patients with chronic periodontitis (group 1) and 41 patients with normal periodontal tissues (group 2) were selected. CBCT scanning for anterior teeth were taken before and after orthodontic treatment. Measurements of bone height and bone density were performed using CBCT software. RESULTS: The group 1 presented a statistically lesser bone density and bone height when compared to group 2 before treatment. There was a significant loss of bone density for both groups after orthodontic treatment, but bone density loss was significantly greater in the group 1. There was no statistically significant bone height change in two groups after treatment. CONCLUSIONS: This study demonstrated that orthodontic treatment can preserve bone height but not capable of maintaining bone density, especially for patients with periodontitis. It is indicated that the change of bone density may be more susceptible than that of bone height when radiographically evaluating bone status under this combined periodontal and orthodontic therapy. PMID- 25932178 TI - Comparison of two electrophysiological methods for the assessment of progress in a rat model of nerve repair. AB - There are 2 critical steps in neural regeneration: nerve fibres successfully crossing the suture and restoration of neuromuscular transmission. For the second step, the compound muscle action potential (CMAP) is the standard electrophysiological technique used to assess regeneration, but it is difficult to detect changes in the CMAP during early regeneration after nerve repair. There is a need for better, noninvasive quantitative electrophysiological techniques to assess regeneration in an earlier stage after nerve repair. In this study, we utilized 2 measures, CMAP and single-fibre electromyography (SFEMG), in a rat model of nerve repair. The model was generated by separating the sciatic nerve of the rat hindlimb from the tibial nerve in Sprague-Dawley rats. CMAP and SFEMG were measured in each rat at 1, 2, 3, 4, and 6 weeks after the operation. The muscle weight was measured and both the general structure of the muscle and the changes in muscle atrophy were examined using haematoxylin and eosin staining protocols. The nerve electrophysiological data could be detected at 2 weeks after surgery initially and more data could be collected with passing time. During the period ranging from 2 to 4 weeks after surgery, parameters of SFEMG recordings changed significantly while the CMAP amplitude did not increase until 6 weeks after surgery. While the fibre density (FD) at 2 weeks after surgery was 0.27 +/- 0.31, there was a significant increase at 3 weeks relative to 2 weeks (P < 0.01), and the FD increased further at 4 weeks (P < 0.01). The action potential mean consecutive difference (MCD) was significantly higher (60.50 +/- 3.53 MUs) in the second week relative to the third week (41.12 +/- 5.08 MUs) after the operation. The results indicated that SFEMG was more sensitive than CMAP amplitudes in detecting neuromuscular transmission after nerve repair. The findings of nerve electrophysiological experiments were consistent with the observed degree of muscle recovery. The SFEMG can be used to detect the very early reinnervation of the muscle more sensitively than CMAP. The ratio of affected muscle weight to unaffected muscle weight was decreased at 2 weeks after surgery (59.01%), continued to decrease significantly at 3 weeks (51.24%), and was restored at 6 weeks. A combination of SFEMG and CMAP can show the dynamic progression of the muscle reinnervation process. PMID- 25932179 TI - Evaluation of clinical features of elderly epilepsy in China. AB - Recent data indicate that the prevalence and incidence of epilepsy are high among the elderly, many of whom will have concomitant neurodegenerative, cerebrovascular, or neoplastic disease. The aim of this study is to evaluate the clinical characteristics of elderly patients with epilepsy in China. We retrospectively reviewed the clinical records of 104 outpatients over 50 years of age (average: 63.8 years). The results showed that in the total 104 outpatients, 53 men and 51 women were studied. Twenty-seven (26.0%) patients had idiopathic epilepsy syndromes, and 15 (14.4%) patients were considered cryptogenic. Sixty two (59.6%) patients had remote symptomatic epilepsy. According to the known etiological factors, cerebrovascular disease (53.2%) is the most common underlying cause, followed by craniocerebral trauma (16.1%), primary or metastatic neoplastic disease (16.1%), and others (14.5%). The most common type of seizure in the group studied was partial seizures (51.9%), followed by generalized seizures (37.5%). Forty-three patients (41.3%) were used combination medication and 61 patients (58.7%) were used single medication. In conclusions, this study provides important data for clinical and research purposes in China. Further research is indicated to confirm the clinical findings of the elderly people with epilepsy by a larger epidemiological study. PMID- 25932180 TI - Expression of the microRNAs hsa-miR-15a and hsa-miR-16-1 in lens epithelial cells of patients with age-related cataract. AB - This study aimed to examine and analyze the expression levels of hsa-miR-15a and hsa-miR-16-1 in lens epithelial cells from patients with age-related cataract to understand better the roles of these microRNAs in the pathogenesis of this disease. Lens epithelial cells of 60 age-related cataract patients (including 20 with cortical cataracts, 20 with nuclear cataracts, and 20 with posterior subcapsular cataracts) and 20 normal patients were included in the study. Real time PCR was used to detect the expression of hsa-miR-15a-5p, hsa-miR-15a-3p, hsa miR-16-1-5p, and hsa-miR-16-1-3p. Expression of the target genes of these microRNAs, namely bcl-2 and mcl-1, was also evaluated. hsa-miR-15a-5p, hsa-miR 15a-3p, and hsa-miR-16-1-5p were expressed at low levels in normal lens epithelial cells but at significantly higher levels in corresponding cells of patients with cortical, nuclear, or posterior subcapsular cataracts (P < 0.01). hsa-miR-16-1-3p was expressed at relatively high levels in normal lens epithelial cells but significantly decreased expression, or none at all, was detected in cells of patients from each cataract group (P < 0.01). Concerning their target genes bcl-2 and mcl-1, expression was detectable in normal lens epithelial cells, but their levels were significantly decreased in cataract patients, irrespective of type (P < 0.01). Expression of hsa-miR-15a-5p, hsa-miR-15a-3p, and hsa-miR-16 1-5p rose in lens epithelial cells in the three types of age-related cataract, which may suppress the expression of the anti-apoptotic genes bcl-2 and mcl-1, thereby contributing to the pathogenesis of age-related cataract through apoptosis. PMID- 25932181 TI - Ultrasonographic characteristics and BI-RADS-US classification of BRCA1 mutation associated breast cancer in Guangxi, China. AB - OBJECTIVE: To retrospectively analyze and compare the ultrasonographic characteristics and BI-RADS-US classification between patients with BRCA1 mutation-associated breast cancer and those without BRCA1 gene mutation in Guangxi, China. METHODS: The study was performed in 36 lesions from 34 BRCA1 mutation-associated breast cancer patients. A total of 422 lesions from 422 breast cancer patients without BRCA1 mutations served as control group. The comparison of the ultrasonographic features and BI-RADS-US classification between two the groups were reviewed. RESULTS: More complex inner echo was disclosed in BRCA1 mutation-associated breast cancer patients (x(2) = 4.741, P = 0.029). The BI-RADS classification of BRCA1 mutation-associated breast cancer was lower (U = 6094.0, P = 0.022). CONCLUSIONS: BRCA1 mutation-associated breast cancer frequently displays as microlobulated margin and complex echo. It also shows more benign characteristics in morphology, and the BI-RADS classification is prone to be underestimated. PMID- 25932182 TI - Correlation analysis for follicle-stimulating hormone and C-terminal cross-linked telopetides of type i collagen in menopausal transition women with osteoporosis. AB - The sudden drop in estrogen in post-menopausal women can lead to osteoporosis. About one in three women aged more than 50 years experienced an osteoporotic fracture. The aim of this study is to explore function of follicle-stimulating hormone (FSH) in bone metabolism and osteoporosis in menopausal transition women. 164 cases of women in menopausal transition were included, and which were divided into three groups, including < 40 years group, 40-50 years group and > 50 years group. All of patients must with empty stomach, and 5 ml blood was collected from median cubital vein between second day to ninth day in menstruation period. Examination of FSH and C-terminal cross-linked telopetides of type I collagen (CTx) was performed by using ECLIA assay. The results indicated that CTx levels were distinguished among the different aged group, with the increasing level following with the increased age. FSH level in both of < 40 years and 40-50 years old women were positively correlated with CTx level (P < 0.05). The spearman rank correlation analysis results also showed that there were no significant correlation between CTx level and FSH level in > 50 years old women. There were significant differences for the CTx level between 0-40 mIU/ml group and > 40 40 mIU/ml group in all of the three ages group (P < 0.05). In conclusion, it's clinically significant for the combining examination of FSH and CTx in menopausal transition women, which could observe the bone metabolize changes quickly and sensitively, and prevent or therapy the osteoporosis in a further step. PMID- 25932183 TI - Inhibition of glucose-transporter 1 (GLUT-1) expression reversed Warburg effect in gastric cancer cell MKN45. AB - Glucose transporter-1 (GLUT-1) plays critical roles in cancer development and progression. Warburg effect (aerobic glycolysis) contributes greatly to tumorigenesis and could be targeted for tumor therapy. However, published data on the relationship between GLUT-1 and Warburg effect are scarce. In this study, gastric cancer cell, MKN45, was transfected with GLUT-1 shRNA using Lipofectamine 2000. Oxygen consumption, LDH activity, lactate production and cytoplasmic pyruvate were detected after MKN45 cells with GLUT-1 knockdown. In the last, hexokinase 1 (HK1), HK2, and pyruvate kinase M2 (PKM2) expression were detected by using western blot. In this study, we showed that inhibition of GLUT-1 expression reversed Warburg effect in MKN45 cells, and induced apoptosis. PMID- 25932184 TI - Role of CD14 and TLR4 in type I, type III collagen expression, synthesis and secretion in LPS-induced normal human skin fibroblasts. AB - OBJECTIVES: The primary aim of this study was to investigate the role of CD14 and TLR4 in type I, type III collagen expression, synthesis and secretion in LPS induced normal human skin fibroblasts. The secondary aim was to provide theoretical basis for the molecular mechanisms of scar formation induced by LPS. METHODS: The normal skin fibroblasts cultured in vitro were randomly divided into four groups: 0.1 MUg/mL LPS reference group, CD14 pretreatment + LPS, TLR4 pretreatment + LPS, CD14 and TLR4 pretreatment + LPS. The collagen DNA synthesis was assessed by (3)H-proline incorporation method. Real-time Quantitative PCR was used to detect type I, type III collagen mRNA expression. RESULTS: Similar results were revealed for mRNA expression levels. The immunofluorescence staining suggested that type I and type III collagen were expressed in all investigated groups and that the expression was differentially downregulated in groups B, C, D. ELISA demonstrated markedly decreased levels in secreting type I, type III collagens and hydroxyproline in groups B, C, D (P<0.05), and the lowest level was detected in group D (P<0.01). CONCLUSION: Pretreatment with CD14 or TLR4 alone or their combination can significantly reduce the levels of type I and type III collagen expression, synthesis and secretion, with the most notable reduction detected in case of CD14 and TLR4 combined. We could thus conclude that both CD14 and TLR4 are involved in type I and type III collagen expression, synthesis and secretion in LPS-induced skin fibroblasts. PMID- 25932185 TI - Efficacy of Rho kinase inhibitor on cognitive impairment induced by chronic cerebral hypoperfusion in rats. AB - This work aims to explore the efficacy of Rho kinase inhibitor Fasudil on cognitive impairment induced by chronic cerebral hypoperfusion in rats. A total of 32 male adult Sprague Dawley (SD) rats were randomly divided into three groups: treatment group, control group and sham-operated group for severe carotid artery stenosis model. After two weeks, 8.35 mg/kg Fasudil and physiological saline were intraperitoneally applied twice per day in treatment group and control group, respectively. Morris water maze test was performed in each group to detect the changes of cognitive function and observe the hippocampal pathomorphology in rats after eight weeks. The average escape latency distinctly shortened (P < 0.01) and the percentage of swimming distance in the platform quadrant significantly increased (P < 0.01) in treatment group compared with those at corresponding time points in control group. The rate of carotid artery stenosis in rats had no statistical difference between treatment and control groups (P > 0.05). Fasudil effectively improved hippocampal pathomorphology. Rho kinase inhibitor obviously ameliorated cognitive impairment induced by chronic cerebral hypoperfusion in rats. PMID- 25932186 TI - Diagnostic outcomes of magnetocardiography in patients with coronary artery disease. AB - OBJECTIVE: To evaluate the diagnostic outcomes of magnetocardiography (MCG) on the patients with coronary artery disease and compared the outcomes between MCG, ECG and Echocardiography. METHODS: MCG measurements were performed on 101 patients with coronary artery disease and 116 healthy volunteers with a seven channel magnetocardiographic system (MCG7, SQUID AG, Germany) installed in an unshielded room. CAD was diagnosed when stenosis >= 70% in >= 1 vessel. Three quantitative indicators were analyzed, R-max/T-max ratio, R value and a average angle. RESULTS: R-max/T-max ratio of CAD group (6.30 +/- 4.07) was much higher than that of healthy group (3.73 +/- 1.41) (P < 0.001), R value of CAD group (69.16 +/- 27.87)% was significantly higher than that of healthy group (34.96 +/- 19.09)% (P < 0.001), a average angle of CAD group (221.46 degrees +/- 64.53 degrees ) was higher than that of healthy group (24.32 degrees +/- 20.70 degrees ) (P < 0.01). In 75 of 101 CAD patients (74.26%), MCG had abnormal mapping patterns. The resting ECG examination showed ischemic changes, such as abnormal Q waves and ST-T change in 49 patients (48.51%). Echocardiography revealed abnormal left ventricular wall motion and asynergy in 46 patients (45.54%). Thus, the diagnostic outcomes of MCG for the patients with CAD were much significant than those of ECG and echocardiography (P < 0.001). CONCLUSIONS: Our result showed that resting MCG under condition of an advanced data analysis has higher diagnostic outcomes and is superior to ECG or echocardiography for patients with CAD. MCG can detect ST-segment displacement caused by ischemic myocardium, thus helpful in diagnosing coronary artery disease early. PMID- 25932187 TI - Application value of different transformation zone types and its genetic relationship with high-risk HPV type in diagnosis and therapy of cervical disease. AB - This study aims to discuss the influence of different types of transformation zone (TZ) on positive surgical margin of loop electrosurgical excision procedure (LEEP) and the significance of infection of different genetic high-risk HPV for cervical intraepithelial neoplasm. The clinical data of patients who had CIN2+ and received LEEP during January to December 2013 was investigated. The conditions of positive surgical margin of patients of different transformation zone (type I, II, III) were analyzed. The clinical high-risk types of HPV were divided into three groups, including A5/6, A7 and A9, compared with the pathological conditions of pre-operation and post-operation of the patients in respective group. The results indicated that type III transformation zone is more likely to cause positive cutting margin. For CIN2+ patients, sensitivity and specificity are 0.89% and 79.56% in group A5/6, and negative and positive predicted value (NPV, PPV) are 40% and 5%. The sensitivity, specificity, NPV, PPV in group A7 is 12.5%, 44.08%, 29.49% and 21.21%, respectively. The sensitivity, specificity, NPV, PPV in group A9 is 88.99%, 87.09%, 85.26%, 81.51%, respectively. Transformation zone type was correlated positively with positive cutting margin percentage (r = 0.8732, P < 0.05). Compared with type I, type II and III transformation zone is more likely to cause pathological upgrades. In conclusion, different types of transformation zone and high-risk HPV have clinical significance in causing positive cutting margin of surgery and disease extent. PMID- 25932188 TI - Prefabricated partial distal urethral in 2-staged repair of proximal hypospadias with severe chordee. AB - PURPOSE: To describe a new technique for staged hypospadias repair in which the urethral plate is divided and tubularized transverse island flap prefabricated partial distal urethral at the time of the first stage. MATERIALS AND METHODS: Sixteen patients with proximal hypospadias associated with severe chordee were operated on using a new staged technique. At the time of the first stage, the urethral plate was divided and chordee was corrected. Then tubularized transverse island flap was used to prefabricate partial distal urethra. The defective urethra was repaired using the Thiersch-Duplay principle at the second stage. RESULTS: All participants have completed both stages of the operation. The mean follow-up duration was 18.4 months (range from 6 to 72 months). In the first stage surgery, the modified tabularized transverse preputial island flap was performed on 6 patients, whereas the modified preputial double-faced island flap was performed on the other 10 patients. All of the prefabricated partial distal neourethras had no evidence of stenosis or scarring. The result of the second stage procedure was a complete penis with integrated urethral. All patients were satisfied with cosmetic and functional results. Neither stricture nor diverticula was observed. A good urinary stream during the urination was attained in 12 (75.0%) patients. Four cases (25.0%) developed urethrocutaneous fistula after the second stage repair. CONCLUSIONS: In our preliminary series, this procedure improved functional and cosmetic results. It may be applicable to most cases of proximal hypospadias. Even when complications occur, they are less severe compared to those of the traditional staged approach. PMID- 25932189 TI - Expression of cartilage glycoprotein 39 in peripheral blood monocytes of septic rat and its role in TLR 4-NF-kappaB signaling pathways. AB - OBJECTIVE: To investigate Cartilage glycoprotein 39 (Cgp-39) expression in peripheral blood monocytes of septic rats, and analyze the relationship between Toll-like receptor 4 (TLR4)-NF-kappaB signalling pathway and Cgp-39 expression. METHODS: The ligation puncture was performed to establish rat sepsis model, and ELISA was used to measure serum Cgp-39 concentration. Peripheral blood mononuclear cells was isolated and cultured for 72 h. RNA interference technology was used to inhibit TLR4 and NF-kappaB gene expression, and real-time PCR and Western blot were performed to detect mRNA and protein expression of TLR4 and NF kappaB. RESULTS: At 1 h, there was no significant differences in serum Cgp-39 concentration between sepsis group and the control group (P > 0.05), however, at 6 h, 12 h, 24 h and 48 h, serum Cgp-39 concentrations in sepsis group were significantly higher than those in the control group at the corresponding time points (P < 0.05). Compared with the control group, TLR4 mRNA and protein expression were increased significantly in sepsis group and sepsis NF-kappaB interference group; NF-kappaB mRNA and protein expression were increased significantly in sepsis group and sepsis TLR4 interference group. However, compared with sepsis group, Cgp-39 concentrations decreased significantly in either sepsis TLR4 interference group or NF-kappaB interference group (P < 0.05 for both). CONCLUSION: Cgp-39 is highly expressed in peripheral blood monocytes of septic rat and TLR4-NF-kappaB signalling pathways may be involved in the regulation of Cgp-39 expression. PMID- 25932190 TI - Effect of chrysin on nociception in formalin test and serum levels of noradrenalin and corticosterone in rats. AB - OBJECTIVE: The levels of corticosterone and noradrenalin as the two nociception modulators modify after stress condition. The propose of current study was to investigate the effect of chrysin on formalin-induced nociceptive behaviors and serum levels of corticosterone and noradrenalin in rats. MATERIALS AND METHODS: Pain was induced by applying 20 MUL of 5% formalin in distilled water in the subplantar of the right hind paw. Chrysin (50, 100 and 150 mg/kg, intraperitoneally (i.p.) was administered 60 min before formalin injection. Morphine (10 mg/kg, i.p.) was administered 30 min before formalin injection. The control group received the same volume of saline by i.p. injection 30 min before formalin injection. RESULTS: Chrysin treatment can significantly decrease formalin-induced pain in rat in a dose-dependent manner. Chrysin (150 mg/kg) significantly inhibit the first phase (P < 0.01), whereas, the all concentration of chrysin were affected on the later phase of formalin-induced pain (P < 0.05). Chrysin could significantly attenuate the content of corticosterone and noradrenalin in the serum versus to the control rats (P < 0.01). CONCLUSION: The current study confirms that the chrysin decreased the nociceptive behaviors in the formalin test and indicate a correlation with decrease in serum corticosterone and noradrenalin levels. PMID- 25932191 TI - STAT4 rs7574865 polymorphism contributes to the risk of type 1 diabetes: a meta analysis. AB - The signal transducer and activator of transcription 4 (STAT4) rs7574865 polymorphism has been indicated to be correlated with type 1 diabetes (T1D) susceptibility, but study results are still debatable. Thus, a meta-analysis was conducted. The electronic databases PubMed, Embase, CNKI, and Web of Science (ISI) were searched to find eligible studies. Data were extracted and pooled odds ratios (OR) with 95% confidence intervals (CI) were calculated. A significant association was found between STAT4 rs7574865 polymorphism and T1D risk (OR=1.30; 95% CI, 1.13-1.48; P<0.01; I(2) =73%). Significant associations were also found in Asians (OR=1.33; 95% CI, 1.04-1.71; P=0.02; I(2) =60%) and Caucasians (OR=1.26; 95% CI, 1.08-1.47; P<0.01; I(2) =74%), respectively. This association was also positive in the pediatric patients (OR=1.41; 95% CI, 1.19-1.68; P<0.01; I(2) =46%). Moreover, we found that STAT4 rs7574865 polymorphism was associated with early-onset T1D risk (OR=1.43; 95% CI, 1.16-1.77; P<0.01; I(2) =0%). This meta-analysis suggested that the STAT4 rs7574865 polymorphism may be associated with T1D development. PMID- 25932192 TI - Role of SB203580 in the regulation of human esophageal cancer cells under the effection of Diosgenin. AB - In order to investigate the mechanism of human esophageal Eca109 cells induced by Diosgenin (Dio), the p38 specific inhibitor SB203580 was used to inhibit the expression of p38 and Western blot was employed to detect the effect of SB203580 in Eca109 cells. MTT experiments were executed to detect the proliferation of the cells. Western blot was also applied to find the expression of phosphorylated p38 (p-p38). It is found that SB203580 can inhibit the expression of p38 in human esophageal cell Eca109. After treated with 50 MUg/mL of Dio and 10 MUg/mL of SB203580, the proliferation of cells showed significantly increase and the apoptosis of cells showed significantly decrease compared with the proliferation in the cells treated with Dio only. Moreover, p-p38 protein level was significantly decreased after treated by the two drugs. It is concluded that Dio may regulate esophageal Eca109 cells through p-p38 pathway. PMID- 25932193 TI - Melt-metaphyseal and diphyseal osteotomy for correction of infantile Blount's disease: a long-term follow-up study. AB - Blount's disease is an uncommon disorder of postero-medial proximal tibial physis. Blount described infantile and adolescent types. This study aims to describe using femur, tibia and fibula osteotomies to treat infantile Blount's disease. From May 1992 to May 2005, 7 patients of Blount's disease (3 males, 4 females) were included, whose age was range from 17 to 62 months. Femorotibial angle (FTA) was 31 +/- 6 degrees (range from 27 degrees to 41 degrees ). Metaphyseal-diaphyseal angle (MDA) was 16 +/- 4 degrees (range from 13 degrees to 24 degrees ). The femoral vara angle was 10 +/- 4 degrees (range from 2 degrees to 23 degrees ). According to Langenskiold's classification, 3 patients were in stage II, 7 patients in stage III, and 2 patients in stage IV. Five cases were affected bilateral and 2 unilaterally, treated by famur, tibia and fibula valgus osteotomies, and a hip spica cast were used for 6 weeks after operation. Results indicated that all patients were followed up 3 to 16 years. FTA, MDA and femur diaphysis were measured, FTA was 2 +/- 7 degrees valgus (from 4 degrees vara to 13 degrees valgus). MDA was 1 +/- 2 degrees valgus (range from 0 degrees to 12 degrees ). Femoral diaphyseal angle was 1 +/- 3 degrees valgus (range from 3 degrees vara to 7 degrees valgus). Six patients could walk without any knee pain, except for 1 patient with bilateral disorder feels his left genu uncomfortable after long time stand or work. His MDA was 12 degrees , and FAT was -4 degrees . In conclusion, femur, tibia and fibula osteotomies are useful for correction of Blount's disease. Recurrence and complication are less than those reported for Blount's disease. PMID- 25932194 TI - Mechanism of immunosuppressants combined with cord blood for severe aplastic anemia. AB - This study aims to explore the mechanism of immunosuppressants combined with cord blood (IS + CBI) for severe aplastic anemia. Selecting 30 patients with SAA and all treated with IS + CBI (newly diagnosed group). 23 patients who were treated effectively (effective group) while 7 cases were treated invalidly (invalid group). Another 20 healthy individuals were selected as control group. To detect the expression levels of IL-17, IL-22 and other cytokines by ELISA method in each group. To detect the engraftment of cord blood stem cells by using short tandem repeat-polymerase chain reaction (STR-PCR) method. 1. IL-17, IL-22 and other cytokines expressions in newly diagnosed group were significantly higher than in the control group. 2. After 6 months, the level in effective group was significantly lower than pretherapy (P < 0.05).The level in invalid group had no obvious difference than pretherapy. 3. After 1 month and 3 months of treatment, a small amount of engraftment was found in effective group. After 6 months, implant rejection was showed. No effective engraftment was observed in invalid group. 1. IL-17, IL-22 cells in SAA patients increased which might positively correlated with the progression of SAA. 2. During the treatment of IS + CBI, there is a bridging mechanism between the early stage of engraftment and the advanced stage of immunosuppressant adjustment. The first 3 months after treatment, it relies on the engraftment of cord blood stem cells to promote hematopoietic recovery and 3 months later, it relies on immunosuppressants to maintain normal hematopoietic function. PMID- 25932195 TI - Prior exposure to imatinib does not impact outcome of allogeneic hematopoietic transplantation for chronic myeloid leukemia patients: a single-center experience in china. AB - OBJECTIVE: We conducted a retrospective single-center study of 106 patients to investigate the impact of prior exposure to imatinib before allogeneic hematopoietic stem cell transplantation (allo-HSCT) on outcome of HSCT for chronic myeloid leukemia (CML) in china. METHODS: Patients were divided into imatinib and non-imatinib group according to whether receiving imatinib therapy before transplantation or not. Hematopoietic engraftment, prognosis, congestive heart failure (CHF), hepatic veno-occlusive disease (HVOD), graft versus host disease (GVHD), hemorrhagic cystitis and infections were compared between the two groups in early stage of transplantation (within 100 days after transplantation). RESULTS: Compared to non-imatinib group, imatinib group neither had a significantly longer engraftment time nor higher incidence of HVOD, GVHD, hemorrhagic cystitis and infections (P > 0.05). However, imatinib group tended to have a statistically higher incidence of CHF (29.6% vs 8.6%, P = 0.037) and a higher 0.5-year transplant-related mortality (TRM) (27.8% vs 5.9%, P = 0.001). The estimated 10-year relapse-free survival (RFS) and 10-year overall survival (OS) were not statistically significant between the two groups (79.6% vs 62.4% P = 0.432, 68.9% vs 55.5% P = 0.086, respectively). CONCLUSION: Thus, prior exposure to imatinib before transplantation does not influence the hematopoietic engraftment and incidence of early transplant-related complications. While, imatinib therapy pre-HSCT probably increases the risk of CHF and TRM in early stage of post-HSCT, and this effect can be enhanced in older age patients. However, Imatinib therapy doesn't impact RFS and OS on a long view. PMID- 25932196 TI - The expression and functional evidence for voltage-dependent potassium channel Kv1.3 in lymphocytes during aging in spontaneously hypertensive rats. AB - AIMS: Our previous studies showed that expression and functional profile of voltage-dependent potassium channels Kv1.3 were increased in lymphocytes of spontaneously hypertensive rats (SHR) compared to normotensive rats, suggesting a crucial role for lymphocyte Kv1.3 in the development of hypertension. Here, we further investigated whether the expression and functional profile of Kv1.3 was related to increased blood pressure in SHR with age of 4, 8, 16 and 24 wk. METHODS: Systolic blood pressure was measured through pressure device around the tail. mRNA and protein expression were assessed by real-time PCR and western blot in lymphocytes of SHR. Current density of Kv channels in lymphocytes was measured by patch-clamp. RESULTS: Systolic blood pressure was elevated in an age-dependent manner (ANOVA P < 0.05). mRNA and protein level of Kv1.3 were significantly increased in an age-dependent manner in lymphocyte of SHR (ANOVA P < 0.05). Moreover, the current density of Kv was dramatically enhanced in an age-dependent manner (ANOVA P < 0.05). CONCLUSION: The systolic blood pressure positively correlated with expression as well as current density of potassium channels in lymphocytes of SHR at age of 8, 16 and 24 wk. In conclusion, Kv1.3 channels were upregulated in an age-dependent manner in SHR and correlates with systolic blood pressure during aging. The present study implies that Kv1.3 blockers may be applied as a therapeutic treatment for the development of hypertension during aging. PMID- 25932197 TI - Glycated peptides are associated with proximal tubule dysfunction in type 2 diabetes mellitus. AB - BACKGROUND: Advanced glycation end-products have been involved in the pathogenesis of proximal tubule dysfunction which characterizes diabetic tubulopathy. METHODS: A total of 76 Type 2 diabetes mellitus patients and 28 healthy controls were evaluated concerning a potential association of glycated peptides with proximal tubule dysfunction by assessing urine albumin:creatinine ratio, urinary alpha1-microglobulin, urinary neutrophil gelatinase-associated lipocalin, plasma and urinary advanced glycation end-products, plasma asymmetric dimethyl-arginine, serum cystatin C. Fully automated chip-nanoelectrospray ionization and high-capacity ion trap multistage mass spectrometry characterized the urinary proteomic profile. RESULTS: The urinary glycated proteins displayed a molecular weight of 15,121.4 Da in normoalbuminuric patients and of 30,180.4 Da in microalbuminuric patients. Urinary alpha1-microglobulin and neutrophil gelatinase-associated lipocalin correlated with urinary advanced glycation end products (R(2)=0.586; R(2)=0.415), urine albumin: creatinine ratio (R(2)=0.292; R(2)=0.116), estimated glomerular filtration rate (R(2)=0.172; R(2)=0.135), serum cystatin C (R(2)=0.146; R(2)=0.129), but not with asymmetric dimethyl-arginine. In multivariable regression analysis models, the correlations for urinary alpha1 microglobulin and neutrophil gelatinase-associated lipocalin remained significant with urine albumin: creatinine ratio, urinary advanced glycation end-products, estimated glomerular filtration rate (P<0.0001, R(2)=0.674; P<0.0001, R(2)=0.551; P<0.0001, R(2)=0.482). CONCLUSIONS: In patients with Type 2 diabetes mellitus urinary glycated peptides are associated with proximal tubule dysfunction. The proteomic patterns of urinary glycated peptides could differentiate normo- from microalbuminuric patients and may explain a potential relation between the size and the glycation status of glycated peptides, and the extent of proximal tubule dysfunction. The lack of correlation between parameters of endothelial dysfunction and proximal tubule dysfunction cannot exclude glomerular involvement in early diabetic nephropathy. PMID- 25932198 TI - Serum GRObeta: a potential tumor-associated biomarker for colorectal cancer. AB - OBJECTIVE: This study aimed to confirm the potential of growth-related gene product beta (GRObeta) as a biomarker for colorectal cancer. We compared serum GRObeta levels in patients with colorectal cancer, healthy individuals and individuals with non-tumor diseases. METHODS: We measured serum GRObeta levels with enzyme-linked immunosorbent assay in patients with colorectal cancer (123 preoperative samples and 66 postoperative samples), 88 healthy controls and 125 individuals with other diseases. Serum levels of carcinoembryonic antigen (CEA) and carbohydrate antigen 19-9 (CA19-9) were measured in all samples with an immunoluminometric assay. Statistical analyses were performed to determine associations between serum GRObeta levels and clinical parameters for colorectal cancer. A receiver operating characteristic (ROC) curve was analyzed for GRObeta, CEA and CA19-9. RESULTS: The serum GRObeta levels were much higher in patients with colorectal cancer (median: 96.15 pg/ml) than those in healthy controls (median: 43.28 pg/ml, P < 0.01) and other disease controls (median: 57.30 pg/ml, P < 0.01). Serum GRObeta levels in colorectal cancer were correlated positively with tumor-node-metastasis staging (P < 0.01) and the depth of infiltration (P < 0.05), but not with the histological grade, tumor embolus, lymph node metastasis, gross pathologic tumor type, or patient gender. The sensitivity and specificity of the assay for serum GRObeta were 56.1% (69/123) and 95.31% (203/213), respectively. The area under the ROC curve constructed with GRObeta (0.834) was larger than that constructed with CEA (0.739) or CA19-9 (0.676) for discriminating colorectal cancer from matched controls. CONCLUSION: These preliminary results suggested that the serum GRObeta level could be a useful biomarker for colorectal cancer diagnoses. PMID- 25932199 TI - Effects of calcitonin on lumbar spinal stenosis: a systematic review and meta analysis. AB - BACKGROUND: To investigate whether calcitonin can improve walking distance (WD) and visual analog pain scale (VAS) in patients who suffer lumbar spinal stenosis (LSS). METHODS: We performed a search on CENTRAL, PubMed, Embase and Cochrane databases up to July 2014; we finally found 19 original articles, of which only 6 were in full compliance with the RCT criteria. These full articles were carefully reviewed independent and in blinded way by two previously capacitated reviewers for the objective to extract data and score a quality of these articles by the criteria of Cochrane Handbook (5.1.0). RESULTS: We accepted 6 studies with 232 participants. There is no evidence show calcitonin is better than placebo or paracetamol regardless of mode of administration. CONCLUSIONS: This meta-analysis suggest that calcitonin provide no significant improvement in pain symptoms or walking distance in LSS patients. PMID- 25932200 TI - USF-1 genetic polymorphisms confer a high risk of nonalcoholic fatty liver disease in Chinese population. AB - Genetic polymorphisms in upstream transcription factor 1 (USF1) were investigated for their links to increased risk of nonalcoholic fatty liver disease (NAFLD) in Chinese population. Between January 2013 and April 2014, 174 patients with NAFLD in the First Affiliated Hospital of China Medical University were selected for this study. A group of 100 healthy subjects were identified as the control group. The MALDI-TOF-MS, a mass spectrometry based technique, was used to detect USF-1 genetic polymorphisms using PCR amplified DNA products. Furthermore, Automatic Chemistry Analyzer (ACA) was used to determine the clinical indicators. Genotypes, allele frequencies and clinical indicators were measured to assess NAFLD risk in relation to the SNPs. USF-1 rs6427573 genetic polymorphisms were associated with an increased risk of NAFLD (AA vs. GG: OR = 3.16, 95% CI = 1.56 6.43, P = 0.001; GA + AA vs. GG: OR = 1.87, 95% CI = 1.13-3.09, P = 0.015; GG + AA vs. AA: OR = 2.96, 95% CI = 1.49-5.88, P = 0.001; G vs. A: OR = 2.10, 95% CI = 1.43-3.09, P < 0.001). Similarly, rs2516839 polymorphisms also conferred a risk for NAFLD (AA vs. GG: OR = 2.49, 95% CI = 1.43-4.34, P = 0.001; GA + AA vs. GG: OR = 1.69, 95% CI = 1.02-2.78, P = 0.041). On the other hand, rs3737787 and rs2774279 showed no statistical significances in the NAFLD group and control group (P > 0.05). Two USF-1 genetic polymorphisms, rs6427573 and rs2516839, may present an increased risk of NAFLD. PMID- 25932201 TI - High tenascin-C levels cause inadequate myocardial blush grade in patients with acute myocardial infarction. AB - AIM: Coronary artery disease (CAD) and its serious clinical form, ST segment elevated myocardial infarction (STEMI) has been the leader within the death causes around the world and in our country. In STEMI, the main objective is providing the myocardial reperfusion. In our study, it was aimed to investigate the predictive value of tenascin-C level for the degree of myocardial reperfusion in patients with STEMI. METHODS: In our study, 58 patients admitted to our hospital with acute anterior STEMI were included. All the patients had underwent primary percutaneous intervention for the single-vessel disease at left anterior descending coronary artery. After admission to coronary care unit tenascin-C levels were measured. Subjects were classified according to their myocardial blush grades (MBG); MBG 0, MBG 1 and MBG 2 were groupped as Group I, MBG 3 was groupped as Group II. The groups were compared according to their tenascin-C levels and other parameters. RESULTS: Between group I (n = 31, mean age 55 +/- 12.5) and group II (n = 27, mean ages 49.3 +/- 11.1); tenascin-C, troponin I and CK-MB levels were significantly higher in group I compared to the group-II (P < 0.001; P < 0.001 and P < 0.05; respectively). In group I, left ventricular ejection fraction (LVEF) was significantly lower (P < 0.001), left ventricular end-diastolic volume and left ventricular end-systolic volume were significantly higher (P = 0.03) as compared to group II. In group I, ST-segment resolution at ECG was worse (P = 0.003). In correlation analyzes, tenascin-C was significantly positively correlated with troponin-I (r = 0.596; P < 0.001) and CRP (r = 0.615, P < 0.001). Tenascin-C was significantly negatively correlated with MBG, LVEF and ST-segment resolution (r = -0.626, P < 0.001, r = -0.411, P = 0.002 and r = 0.631; P < 0.001, respectively). CONCLUSION: Based on our study, it can be estimated that in patients with high tenascin-C levels myocardial reperfusion was inadequate, even underwent successfull PCI. In this context, increased tenascin-C may help predict not only left ventricular remodelling and prognosis but also the effectiveness of primary PCI. PMID- 25932202 TI - Parameters of prostate cancer at contrast-enhanced ultrasound: correlation with prostate cancer risk. AB - OBJECTIVE: to investigate the correlation between the parameters of prostate cancer (PCa) at contrast-enhanced ultrasound (CEUS) with PCa risk. METHODS: 84 patients (68 +/- 8 years; range, 33-79 years) who had undergone CEUS were included. All the images were offline analyzed. Parameters (maximum intensity (IMAX), rise time (RT), time to peak (TTP) and mean transit time (mTT)) were recorded and compared with PSA level, Gleason score, clinical stages and PCa risk. RESULTS: Age was correlated significantly with PCa risk. RT and mTT of outer gland were associated with PCa risk. No significant correlation was found between PSA and CEUS enhancement parameters. Furthermore, with the exception of IMAX of inner gland and IMAX of outer gland, there were no significant differences of enhancement parameters in Gleason score groups and clinical stages groups. CONCLUSION: The enhancement parameters of PCa at CEUS may be used to predict PCa risk. And it is helpful for the choice of therapeutic options. PMID- 25932203 TI - An application of uterine artery chemoembolization in treating cesarean scar pregnancy. AB - OBJECTIVE: To discuss the feasibility and safety of uterine artery chemoembolization in treating cesarean scar pregnancy (CSP). METHODS: During the period between 1(st) of May 2009 and 17(th) of January 2014, uterine artery chemoembolization with methotrexate (MTX) and gelatin sponge was performed in 31 patients diagnosed with CSP in Xinqiao Hospital. Curettage of uterus was carried out within 24-48 hours after the procedure. RESULTS: The success rate of bilateral uterine artery chemoembolization was 100%. The mean blood loss during curettage procedure was only 8.32+/-4.76 (2-20) ml. The mean time for serum beta HCG normalization was 33.81+/-17.47 (15-82) days, and the mean time for gestational sacs elimination was 29.52+/-20.93 (4-90) days. The mean time of hospital stay was 5.10+/-1.08 (4-8) days. CONCLUSIONS: No serious complications occurred. The uterine artery chemoembolization is an effective and safe treatment for CSP, which greatly reduces the necessity of hysterectomy. PMID- 25932204 TI - The effect of silymarin on hepatic regeneration after partial hepatectomy: is silymarin effective in hepatic regeneration? AB - AIM: Silymarin from Silybum marianum was found to reduce liver injury. The aim of the present study was to investigate the effects of silymarin on hepatic regeneration in partially hepatectomized rats. METHODS: Thirty Wistar-Albino rats were divided into 3 groups of 10 animals as sham, control and experimental groups. In the sham group (n=10) abdominal incision was closed after laparotomy. In the control group (n=10), the rats underwent 70% hepatectomy after laparotomy. In the experimental group (n=10) after partial 70% hepatectomy, silymarin (200 mg/kg/d) were given to rats for 10 days. Rats in three groups were sacrificed on 10 days. Aspartate (AST) and alanine transaminase (ALT), gamma glutamyl transferase (GGT), ALP, LDH and total bilirubin levels were measured using intracardiac blood samples. Tissue malondialdehyde (MDA) and tissue glutathion (GSH) and Superoxide dismutase (SOD) levels were measured. To reveal the increase in the mass of the remnant liver tissue in the control and experimental groups relative weight of the liver was calculated. Histopathological analysis of the liver was performed using a semi-quantitative scoring system. RESULTS: A statistically significant difference among three groups was not shown for AST and ALT levels. A statistically significant difference was found between the groups as for total bilirubin and gamma glutamyl transferase levels. Increases in relative liver weights were seen with time in Groups 2 and 3. A statistically significant difference was not found for tissue malondialdehyde, Glutathion and Superoxide dismutase levels between hepatectomy and hepatectomy + silymarin groups. On liver tissue sections of the rats in the hepatectomy + silymarin group, increased regeneration and lipid peroxidation were observed accompanied by decreased antioxidant response. CONCLUSION: It has been observed that silymarin with many established functions such as antiproliferative, anti-inflammatory and energy antioxidant effects, does not contributed to proliferative regeneration of the liver-which has very important metabolic functions -after partial hepatectomy; instead it will decrease serum levels of transaminases. PMID- 25932205 TI - Cholangiographic features and endoscopic treatment of biliary strictures. AB - OBJECTIVES: The most commonly occurring complications following orthotopic liver transplantation procedures are associated with the biliary tract. Endoscopic technique has become the primary modality for the treatment of biliary strictures after liver transplantation. The objective of this study was to assess the role of cholangiographic features of the initial cholangiogram in endoscopic treatment success and stricture recurrence. METHODS: Patients who underwent endoscopic therapy for biliary strictures after orthotopic liver transplantation (OLT), from 2006 to 2009 were included in this retrospective study. RESULTS: The initial success rate after endoscopic treatment was achieved in 85.53% patients. However, recurrence of biliary strictures occurred in 24.62% of the patients. Patients with successful anastomotic biliary strictures (AS) after treatment were characterized by shorter stricture length as compared to patients who have not achieved success (p < 0.01). Of the 42 patients with AS, patients with recurrence had larger initial stricture length (p < 0.01) and smaller narrowing diameter (p < 0.01) than those without recurrence. Patients treated with NAS for multiple strictures experienced increased rate of recurrence than those with single narrowing, but failed to achieve statistical significance (50% vs. 23.08%, p = 0.18). Patients for whom dilation failed to eliminate the waist, experienced higher recurrence rate than those without stricture waist (70% vs. 16.63%, p < 0.01). CONCLUSIONS: Endoscopic procedure using endoscopic retrograde cholangiopancreatography was found to be an effective modality for treating biliary strictures after OLT. PMID- 25932206 TI - Minimally invasive video-assisted versus conventional open thyroidectomy on immune response: a meta analysis. AB - OBJECTIVES: The aim of this study was to compare the immune response between the minimally invasive video-assisted thyroidectomy (MIVAT) and conventional thyroidectomy (CT). METHODS: An exhaustive literature search was performed in the Medline, Embase, and Cochrane Library to identify the randomized controlled trials comparing the immune response between MIVAT and CT. Relevant data were extracted and statistical analysis was done using RevMan 5.0. RESULTS: Twelve trials including 389 patients were identified. Immune-competent cells demonstrated no significant differences between MIVAT and CT. The including trails were assessed various perioperative plasma cytokine concentrations with no significant differences in interleukin-6 (IL-6), T lymphocytes (CD4(+), CD8(+), CD4/CD8) and NK cells between the MIVAT and CT. However, meta-analysis showed lower counts on postoperative days at 72 h was showed lower C-reactive protein (CRP) level compared to the preoperation levels but showed no significant difference within 24 h in MIVAT S group compared with CT group. Tumor necrosis factor alpha (TNF-alpha) level after surgery within 24 h and 72 h showed lower TNF-alpha level after MIVAT surgery within 24 h and 72 h. CONCLUSIONS: This meta analysis demonstrates that, MIVAT has less immune response outcomes and that it is a more ideal choice for the patients relative to the conventional surgery. PMID- 25932207 TI - Mir-196a-2 C>T polymorphism as a susceptibility factor for colorectal cancer. AB - OBJECTIVE: This study aimed to gain a better insight into the impact of the mir 196a-2 C>T polymorphism on the susceptibility to colorectal cancer (CRC). METHODS: In a meta-analysis of 6 publications with a total of 1,754 cancer cases and 2,430 controls, we summarized the data on the associations between the studied mir-196a-2 C>T polymorphism and CRC risk and conducted subgroup analyses by ethnicity and control sources. RESULTS: We found no overall association between the mir-196a-2 C>T polymorphism and CRC risk. But a significant association was found in the stratified analysis according to ethnicity among Asians (ORCC vs. TT = 1.22, 95% CI = 1.02-1.45, P heterogeneity = 0.718; ORCC vs. TC + TT = 1.22, 95% CI = 1.04-1.44, P heterogeneity = 0.590; ORallele C vs. allele T = 1.10, 95% CI = 1.01-1.20, P heterogeneity = 0.726) rather than Caucasians. CONCLUSIONS: Our results suggested that there was no overall risk of CRC in relation to the mir-196a-2 C>T polymorphism. However, this polymorphism was associated with an increased risk in Asian populations. PMID- 25932208 TI - Clinical outcomes of non-torque pattern double running suture technique for optical penetrating keratoplasty. AB - OBJECTIVE: To validate non-torque pattern double running suture technique for optical penetrating keratoplasty compared with traditional suture method. METHODS: 56 patients (56 eyes) undergoing optical penetrating keratoplasty were divided into two groups. The experimental group (28 cases) underwent non-torque pattern double running suture technique, and the control group (28 cases) underwent interrupted suture. All participants were followed up at 2 weeks, 2 months, 6 months, and 1 year postoperatively. The best corrected visual acuity (BCVA), corneal curvature change and astigmatism change were observed and compared between the two groups, and corneal topographer was used to measure refractive change. RESULTS: BCVA in experimental group was significantly improved (P<0.05); the corneal topographer showed that astigmatism in experimental group was significantly lower than that in control group at the early postoperative phase (P<0.001). Six months later postoperatively, astigmatism gap between the two groups was narrowed, but the differences were still statistically significant (P<0.001). Twelve months later, astigmatism in the experimental group was similar to six months ago, but astigmatism in control group reduced significantly. No significant difference in astigmatism was observed between two groups (P>0.05). CONCLUSION: Non-torque pattern double running suture technique for optical penetrating keratoplasty can achieve the BCVA at the very early phase, with stable postoperative refractive status. This novel suture method is accurate and safe with elegant appearance. PMID- 25932209 TI - Efficacy and safety of acupuncture therapy for nerve deafness: a meta-analysis of randomized controlled trials. AB - BACKGROUND: Acupuncture is one of the important parts of therapeutic methods in traditional Chinese medicine, and has been widely used for the treatment of nerve deafness in recent years. The current study was to evaluate the efficacy and safety of acupuncture therapy for nerve deafness compared with conventional medicine therapy. METHODS: PubMed, the Chinese National Knowledge Infrastructure Database, the Chinese Science and Technology Periodical Database, the Chinese Biomedical Database, the Wanfang Database were searched for articles published to identify randomized controlled trials evaluating efficacy and side effects between acupuncture and conventional medicine therapies up to 2013/06. RESULTS: A total of 12 studies, including 527 patients assessed the efficacy and safety of acupuncture therapy for nerve deafness. Overall, the efficacy of acupuncture was significantly better than that of the conventional western medication (RR: 1.54, 95% CI: 1.36-1.74) or traditional Chinese medicines (RR: 1.51, 95% CI: 1.24 1.84), and the efficacy of acupuncture in combination with conventional western medication or traditional Chinese medicine was better than that of the conventional western medication alone (RR: 1.51, 95% CI: 1.29-1.77) or traditional Chinese medicine alone (RR: 1.59, 95% CI: 1.30-1.95). Based on the comparison of number of deafness patients who were completely cured, the efficacy of acupuncture in combination with traditional Chinese medicines was better than that of traditional Chinese medicine alone (RR: 4.62, 95% CI: 1.38-15.47). CONCLUSIONS: Acupuncture therapy can significantly improve the hearing of patients with nerve deafness, and the efficacy of acupuncture in combination with medication is superior to medication alone. PMID- 25932210 TI - Local thrombolytic therapy in severe cerebral venous sinus thrombosis during puerperium. AB - This study is to explore and evaluate the efficacy and safety of local thrombolytic therapy in superior sagittal sinus in patients with severe cerebral venous sinus thrombosis during puerperium, as well as the efficacy and safety of anti-platelet aggregation treatment for preventing recurrence. Twelve patients during postpartum period with cerebral venous sinus thrombosis were received local thrombolytic therapy by placing a micro-catheter at the distal end of superior sagittal sinus from January 2008 to December 2013. All the patients accepted mechanical thrombus maceration before local intrasinus thrombolytic therapy, and were treated with low molecular weight heparin in the acute phase. After local thrombolytic therapy, anti-platelet aggregation treatment was performed for 6 months. Follow-up data included lumber puncture, fundus examination and magnetic resonance venography (MRV) once per half year for 6-70 months. At discharge, the intracranial pressure of 12 patients reduced to below 200 mmH2O. DSA or MRV confirmed that superior sagittal sinus of 9 patients were smooth. The cortex venous and deep venous were recovered to normal. Superior sagittal sinus of 3 patients recanalized partly. Cortex venous and deep venous was compensated. The follow-up study indicated that no thrombosis and new neurological symptoms occurred among all patients. Local thrombolytic treatment is safe and effective in patients with severe cerebral venous sinus thrombosis during puerperium. The collateral circulation compensation is the main recovery factor. And it is also safe and effective for anti-platelet aggregation treatment to prevent recurrence of cerebral venous sinus thrombosis. PMID- 25932211 TI - Novel impurity-free hexagonal hydroxyapatite nanotubes for local delivery of antibiotics in orthopedic surgery: in vitro release validation. AB - Hydroxyapatite (HA) has been studied recently as a drug carrier in prevent implant infections due to its biocompatibility and osteoconductive properties, but most of these studies failed to control infection. The aim of the present study was to evaluate the potential of this impurity-free novel HA nanotube as a carrier for drug delivery in a controlled manner. Gentamicin was selected as an antibiotic to study the drug-carrier properties of this novel HA nanotube. Gentamicin was introduced into the HA nanotubes through immersion and evaporation process. Gentamicin-loaded HA nanotubes were then placed in phosphate buffered saline (PBS) and drug release profile was then monitored by measuring free genntamicin in the solution. An initial burst release of the drug occurred in the first 24 hours; subsequently, 84.7% of the drug was released from the nanotubes in 9 days. After 13 d, the concentrations of released drug were measured close to 2 MUg/ml. The porosity of the gentamicin-loaded HA nanotubes was also observed using a Hitachi s-4800 high-resolution SEM, further confirming the drug-carrier property of HA nanotubes. Our novel bone substitute is an effective prophylactic tool for the local delivery of gentamicin to prevent periprosthetic infections. PMID- 25932212 TI - The prognostic value of miR-34a expression in completely resected gastric cancer: tumor recurrence and overall survival. AB - The prognosis of gastric cancer is mainly linked to tumor recurrence. MicroRNA 34a (miR-34a) is a direct transcriptional target of p53 and links tumor suppressor function and the oncogenic pathways in some cancers. However, the role of miR-34a in predicting prognosis of gastric cancer has not been fully elucidated. In this study, we aimed to investigate the expression level of miR 34a and its prognostic value in gastric cancer. A total of 137 consecutive gastric cancer patients who underwent gastrectomy with D2 lymph node dissection were included in this study. Quantitative real-time polymerase chain reaction (qRT-PCR) was utilized to detect miR-34a expression in gastric cancer tissues and adjacent normal tissues. The results showed that the levels of miR-34a expression were significantly decreased in the tumor tissues compared with the adjacent normal tissues (P<0.001). Low miR-34a expression level was associated with lymph node involvement (P=0.004), advanced TNM stage (P=0.006), poor tumor differentiation (P=0.024), high tumor recurrence rate (P=0.008), and poor five year survival (P<0.001). The median time to recurrence and median overall survival time were significantly shorter in patients with low miR-34a levels compared with those with high miR-34a levels (P=0.028 and P=0.021, respectively). Furthermore, when analyzed with a multivariate Cox regression model, a low miR 34a level was significantly correlated with high recurrence rate and poor overall survival. Taken together, our results suggest that downregulation of miR-34a in gastric cancer is associated with high recurrence rate and poor overall survival and that miR-34a may be served as a prognostic marker for gastric cancer. PMID- 25932213 TI - Associations between ABO blood groups and biochemical recurrence after radical prostatectomy. AB - BACKGROUND: Recent studies have demonstrated associations between ABO blood groups and prognosis in various types of cancers. The aim of this study was to investigate the association between ABO blood groups and biochemical recurrence (BCR) after radical prostatectomy (RP). METHODS: A total of 555 patients with prostate cancer who underwent RP were included in the study. No patients received neoadjuvant and/or adjuvant therapy. The effect of ABO blood groups on BCR was examined using univariate and multivariate analyses. RESULTS: During the follow up period (mean, 52.0 months), 166 patients (29.9%) experienced BCR, with a 5 year BCR-free rate of 67.3%. Although the ABO blood group was not a significantly associated with BCR in the univariate analysis, it was an independent predictor of BCR in the multivariate analysis: blood type O patients had a significantly lower risk of BCR compared to type A patients (Hazard ratio, 0.608; 95% confidence interval, 0.410-0.902; P = 0.014). Further analyses revealed that surgical margin status confounded the assessment of the association between the ABO blood group and BCR. In the analyses of patients with a negative surgical margin, the 5-year BCR-free rate in blood type O patients was a significantly higher than that in type A patients (91.2% vs. 71.0%; P = 0.026). CONCLUSION: Blood type O is significantly associated with a decreased risk of biochemical recurrence after radical prostatectomy. Further studies are needed to clarify the nature of this association. PMID- 25932214 TI - The effect of polymorphism in DNA repair genes RAD51 and XRCC2 in colorectal cancer in Turkish population. AB - The genes RAD51 and XRCC2 encode proteins that are important for the repair of double-strand DNA breaks by recombination. Therefore, genetic variability in these genes may contribute to the occurrence and progression of carcinoma. We investigated the association of polymorphisms in the DNA repair genes XRCC2-A/G and RAD51-135G/C with the colorectal cancer risk. Genotypes were determined by PCR-RFLP assays in 71 patients with colorectal cancer and 86 age-matched healthy controls. After amplification, we used a restriction enzyme (RAD51; MvaI and XRCC2; HphI) and digested the PCR product. Then, this DNA fragments were passed through gel electrophoresis. By examining these images, we identified changes in the nucleotides in these specific regions. To clarify fragments polymorphisms, the PCR products were sequenced with an Applied Biosystems Automated Sequencer. We observed the Arg188His polymorphism of XRCC2 genes in 42.2%, as shown in 30 of the 71 cancer patients. Only 21 out of 86 controls showed this polymorphism (24.2%). We also observed that 21 of the 71 patients (29.5%) carried the RAD51135G/C polymorphism of this gene. The same polymorphism was observed in 11 of the 86 controls (12.7 %; p < 0.05). The obtained results indicate that the polymorphism of RAD51 and XRCC2 genes may be associated with the incidence of colon cancer in the Turkish population. Further studies, including those on a larger group of patients, are required to further clarify this point. PMID- 25932215 TI - Two novel mutations of ornithine transcarbamylase gene identified from three Chinese neonates with ornithine transcarbamylase deficiency. AB - We aim to analyze the blood metabolic profiling and the gene mutation of ornithine transcarbamylase (OTC) in three neonates with ornithine transcarbamylase deficiency (OTCD). Three neonates with OTCD were included in this study. The profiling of amino acids and acylcarnitine was determined using MS-MS assay. The OTC exons were amplified using PCR amplification. DNA sequencing was performed, based on which mutation analysis of OTC genes was carried out. For the clinical symptoms, all the three neonates showed poor reaction and feeding. In addition, convulsion and neonatal infection were noticed. A remarkable decrease of citrulline concentration was revealed by MS-MS assay. In case 1, a 548A > G substitution was identified in exon 6, which resulted in replacement of cysteine by tyrosine in codon 183. In case 2, a 1016T > G substitution was identified in exon 10, leading to replacement of valine by glycine in codon 339. In case 3, a 995G > C mutation was noted in exon 9, resulting in missense mutation of tryptophane to serine in codon332. Three types of OTC gene mutations were identified in Chinese neonates with OTC deficiency, among which two novel mutations, including 1016T > G and 995G > C, are presented uniquely in our study. PMID- 25932216 TI - A comparison study of immune-inflammatory response in electroacupuncture and transcutaneous electrical nerve stimulation for patients undergoing supratentorial craniotomy. AB - OBJECTIVE: The effect of transcutaneous electrical nerve stimulation (TENS) on immuno-inflammatory response was tested and the differences between electroacupuncture (EA) and TENS in immuno-inflammatory response in patients undergoing supratentorial craniotomy were explored. METHODS: 51 patients received craniotomy were divided randomly into 3 groups: control (group C, n=18), EA (group A, n=19) and TENS (group T, n=14) groups. Blood samples were collected before anesthesia (T0) and 30 min (T1), 2 h (T2) and 4 h (T3) after induction of anesthesia to measure the levels of tumor necrosis factor-alpha (TNF-alpha), interleukin (IL)-8, IL-10, IgM, IgA and IgG.. RESULTS: No significant difference existed between groups A and group T during craniotomy. IgM and IgA decreased significantly in group C compared with groups A and T at T2 and T3 time points. Compared with group C, there were significant difference in TNF-alpha, IgM and IgA level at T0 in groups A and T; no significant difference was found in the levels of IgG, IL-10 and IL-8. CONCLUSION: EA and TENS could reduce immunosuppression in patients undergoing supratentorial craniotomy and it has significance in choice of treatment in immunosuppressive therapy. PMID- 25932217 TI - The effects of laparoscopic sleeve gastrectomy on head, neck, shoulder, low back and knee pain of female patients. AB - As the rise on the prevalence of obesity, it is related with physical impairment of joints, especially in the lumbar spine and knee joints. Losing body weight can reduce or eliminate pain of head, neck, shoulder, lumbar spine and knees. By performing a laparoscopic bariatric surgery we demonstrated a significant improvement on the pain by body weight reduction. In this study we aimed to explore the efficacy and safety of Laparoscopic Sleeve Gastrectomy (LSG) on the relief of pain on head and neck, shoulder, low back and knee among the severely morbid obese female patients. A total of 39 morbidly obese female patients who underwent LSG for morbid obesity were included in this study. Body weight, height, body mass index (BMI), head and neck, shoulder, low back and knee pain intensity were measured with Visual Analog Scale (VAS) before and after LSG at the 6(th) month. 39 morbidly obese female patients were enrolled to this study. The mean age of the patients was 37.69 +/- 11.33 years. Preoperative and postoperative body weights were 127.3 kg and 91.21 kg, respectively. Mean height was 165.23 +/- 5.78 cm. Preoperative and postoperative BMIs were 46.49 kg/m(2) and 32.33 kg/m(2), respectively. A significant correlation between preoperative and postoperative parameters was found according to BMI. Our data showed that LSG is an efficient and safe procedure on severely obese patients and showed a predictive remission of head and neck, shoulder, low back and knee pain intensity of female patients by analyzing with VAS during the first 6 months. PMID- 25932218 TI - Systemic side effects of locally used oxymetazoline. AB - OBJECTIVES: The object of the study is to experimentally investigate the possible systemic side effects of Oxymetazoline including its nasal spray which has been in use for a long time both by the physicians and patients. There is no study in the literature to address the damages of oxymetazoline on the end organ. MATERIALS AND METHODS: The study conducted on 2 groups of rat. Group 1 (n = 8): Control; and Group 2 (n = 8): Oxymetazoline. During 4 week, the control group was applied with 2 drops of saline water on each nasal cavity 3 times a day and the other group was applied with 2 drops of oxymetazoline HCl 3 times a day. At the end of experiment, samples from mandible, parotid and tails of the rats were taken in 10% formalin for histopathological investigations. RESULTS: In histopathological experiments, when compared with the control group, the oxymetazoline group showed significant increase in many of the histopathological parameters (ischemic changes: P = 0.0001; congestion: P = 0.0006; arterial thrombosis: P = Ns; PNL accumulations: P = 0.001; necrosis: P = 0.0001; and ulceration: P = 0.014). The results of histopathologic tests on the samples taken from mandible and parotid gland, in comparison with the control group, showed no significant increase (focal inflammation: P = Ns; and lymphocyte aggregation: P = Ns). CONCLUSION: Due to the damage that the long-term use of nasal spray including oxymetazoline, it may cause injury on the end organ, which we revealed in our histopathological experiments. We believe that it's essential for the physicians to provide information on the side effects of the medicine to their patients who use for a long term. PMID- 25932219 TI - Efficiencies of intracoronary sodium nitroprusside on fractional flow reserve measurement. AB - BACKGROUND: Fractional flow reserve (FFR) has certain advantages of assessing functional severity of coronary stenosis. Adenosine(AD) is the most widely used agents in FFR measurement but has the disadvantages of higher rate of complications. Sodium Nitroprusside (SNP) represents a valuable alternative. METHODS AND RESULTS: In 75 patients with 86 moderate coronary stenosis, FFR values, heart rate and blood pressure were measured at baseline, after 0.6 MUg boluses of intracoronary (IC) SNP, and after 140 MUg/kg /min of continuous intravenous (IV) AD. FFR values decreased significantly after administering IV AD and IC SNP compared with the baseline Pd/Pa values (P < 0.001). Mean FFR induced by IV AD was not significantly different from that by IC SNP (t = 0.577, P = 0.566). The mean kappa value in the evaluation of two methods was 0.973 for FFR. There was a significant correlation between the FFR values of IV AD and IC SNP (R = 0.911, P < 0.001). Significant decreases in the blood pressures were found after agents were given compared to the baseline. No significant difference was found between AD and SNP. In addition, immediate complications occurred in 60.5% patients of IV AD in contrast to no adverse events after IC SNP. CONCLUSION: SNP is a safe and effective agent and easy to use for the FFR measurement. Maximal hyperemia by IC SNP is equivalent to that by IV AD. IC SNP could be considered a potential alternative in patients with contraindications to AD administration. PMID- 25932220 TI - Transvaginal sonographic characteristics of paraovarian borderline tumor. AB - Parovarian cysts are common disorders which constitute 10-20% of adnexal masses in pathologically verified series. Most of these cysts are benign, and borderline parovarian tumors are rare and documented only as case reports in the literature. The study was aim to examine the sonographic features of parovarian borderline tumors for making an accurate preoperative diagnosis. Four patients (mean age 49 years, ranged from 35 to 75 years) with a pathological proven parovarian borderline tumor were retrospectively recruited. Preoperative transvaginal ultrasonography (TVS) and color Doppler ultrasonography were examined, and histological reports were analyzed. All tumors were correctly diagnosed as parovarian tumors at preoperative TVS. The cysts were hypoechoic and showed a variable number of papillary projections growing from the inner wall in 3 patients. Color Doppler examination of the papillae showed the presence of blood vessels in two of those three patients. In addition, histological analysis of the removed tumors demonstrated two parovarian serous borderline cystadenomas and two parovarian serous papillary borderline cystadenomas. TVS might be useful in making a preoperative diagnosis of borderline parovarian tumors. PMID- 25932221 TI - Application of buccal fat pads in pack palate relaxing incisions on maxillary growth: a clinical study. AB - OBJECTIVE: To observe the impact on maxillary growth of the use of buccal fat pads to pack palate relaxing incisions. METHODS: We recruited 30 patients aged 3 4 years with a complete cleft palate. Half (15) of the patients underwent reparative surgery that entailed packing buccal fat pads into the bilateral raw bony surfaces and served as the experimental group. The remaining 15 patients underwent reparative surgery that entailed packing and fixing relaxing incisions with iodoform gauze and served as the control group. After a 5-year follow-up, the differences in data from X-ray cephalometry and upper dental models in the two groups were analyzed using the T test. RESULTS: A significant difference (P < 0.05) in maxillary growth was observed between the two groups of children with cleft palate. CONCLUSION: The results supported the use of buccal fat pads to pack relaxing incisions which led to improved maxillary development in patients with cleft palate. PMID- 25932222 TI - Polymorphisms of COL4A1 gene are associated with arterial pulse wave velocity in healthy Han Chinese and Uygur subjects. AB - Pulse wave velocity (PWV) is a noninvasive index of arterial stiffness and an independent predictor of cardiovascular outcomes. Type IV collagen is an important structural component of the vascular basement membrane, thus it is important for the integrity and functions of basement membrane. However, the relationship between genetic polymorphisms of COL4A1 gene and PWV in healthy Han Chinese and Uygur subjects remains unclear. We aimed to investigate the association between PWV and COL4A1 genetic polymorphisms in healthy Han Chinese and Uygur subjects. A total of 1533 subjects (909 Han, 624 Uygur) were selected from the Cardiovascular Risk Survey (CRS) study. Two SNPs (rs605143 and rs565470) were genotyped by using the polymerase chain reaction-restriction fragment length (PCR-RFLP) method. In the Uygur population, the two SNPs (rs605143 and rs565470) were associated with PWV by analyses of a recessive model (p = 0.002, p = 0.008, respectively), and the difference remained significant after multivariate adjustment (p = 0.004, p = 0.001, respectively); the AA genotype of rs605143 was associated with increased PWV value compared with the AG or GG genotype (1543.36 +/- 324.79 cm/s vs. 1530.45 +/- 314.24 cm/s and 1522.93 +/- 316.00 cm/s); and the CC genotype of rs565470 was associated with increased PWV value compared with the CT or TT genotype (1647.90 +/- 553.27 cm/s vs. 1506.8 +/- 357.35 cm/s and 1488.4 +/- 344.32 cm/s). But for healthy Han Chinese subjects, this association was not observed in rs605143 and rs565470 before and after multivariate adjustment. Both rs605143 and rs565470 in the COL4A1 gene are associated with PWV in healthy Uygur subjects, indicating that carriers of the A allele of rs605143 and the C allele of rs565470 have a high risk of Arterial stiffness. PMID- 25932223 TI - Polymorphisms in UGT2B4 and susceptibility to pancreatic cancer. AB - As an important enzyme in the conjugation phase of drug clearance, UGT2B4 helps metabolize various endogenous and exogenous substances, and polymorphisms in the corresponding gene can influence enzyme activity. This study investigated the association between polymorphisms in UGT2B4 and the risk of developing pancreatic cancer in Han Chinese individuals. A hospital-based case-control study was conducted with 1579 healthy controls and 406 pancreatic cancer patients from China. Genomic DNA was obtained from peripheral blood lymphocytes. Time-of-flight mass spectrometry was used to genotype polymorphic loci in UGT2B4, and the association between these polymorphisms and susceptibility to pancreatic cancer was expressed as odds ratios (ORs) with 95% confidence intervals (CIs), as calculated using multivariable logistic regression analysis. The rs1131878C > T polymorphism (NT_016354.20: g.10558805C > T) in UGT2B4 was associated with an increased pancreatic cancer risk. Compared to the C/C genotype, the C/T genotype conferred 1.39 times higher the pancreatic cancer risk (95% CI = 1.09-1.77; P = 0.007), and the T/T genotype conferred 2.97 times higher the pancreatic cancer risk (95% CI = 1.24-7.08; P = 0.014). In contrast, compared with the A/A genotype, the A/C genotype at the rs3822179 locus in UGT2B4 (NT_016354.20: g.10569096C > A) bestowed a 20% risk reduction (OR = 0.80, 95% CI = 0.67-0.95; P = 0.011). However, the risk was not significantly reduced with the C/C genotype (OR = 0.77, 95% CI = 0.52-1.14, P = 0.191). Polymorphisms in UGT2B4 affect the risk of pancreatic cancer occurrence in Han Chinese individuals. PMID- 25932224 TI - Could pretreatment with oral contraceptives before pituitary down regulation reduce the incidence of ovarian hyperstimulation syndrome in the IVF/ICSI procedure? AB - The long gonadotrophin releasing-hormone agonists (GnRH-a) protocol of pituitary down regulation was widely used in controlled ovarian hyperstimulation (COH). Some clinicians prefer to use one cycle of oral contraceptives (OC) pretreatment before the traditional long GnRH-a protocol. This study was aimed to investigate whether such pretreatment could reduce the incidence of ovarian hyperstimulation syndrome (OHSS) for patients with different ovarian responses in IVF/ICSI treatment. Participants undergoing IVF/ICSI treatment with long GnRH-a protocol of pituitary down regulation in luteal phase were recruited by their potential risk of OHSS into one group of suspected high responders (227 participants) and the other group of suspected normal responders (665 participants). As for the suspected high responders, pretreatment with OC could lower the serum LH level, LH/FSH ratio and E2 level right after 14 days of pituitary down regulation. It could also lower the serum E2 level before oocytes retrieval and the count of oocytes collected. The incidence of severe OHSS was also significantly decreased. Such effect of OC on hormone profile, follicular dynamics and incidence of OHSS was not discovered in the group of suspected normal responders. PMID- 25932225 TI - Diffusion-weighted MR imaging and Doppler ultrasonography in the evaluation of renal parenchyma in acute ureteral obstruction. AB - OBJECTIVE: To compare the efficacy of diffusion-weighted (DW) magnetic resonance (MR) imaging and Doppler ultrasonography (US) by using quantitative markers in acute unilateral obstruction due to renal stones. METHODS: This prospective study included 28 patients with unilateral ureteral obstruction and 18 healthy control subjects. In Doppler US and DW MR imaging, resistive index (RI) and apparent diffusion coefficient (ADC) values were measured respectively. The results were compared in patients and in control subjects. Paired samples test, two-tailed unpaired Student's t test and Spearman analysis were performed for statistical analysis. RESULTS: The mean RI in the 28 obstructed kidneys was significantly higher than the mean RI in unobstructed kidneys and in control subjects (P < 0.05). The ADC of obstructed kidneys in the cortex was significantly lower than the ADC of the contralateral unobstructed kidneys (P < 0.05). The ADC of unobstructed kidneys was significantly higher than the ADC of control subjects in the cortex (P < 0.05). RI and ADC values yielded no significant correlation. CONCLUSION: Doppler US and DW MR imaging provide accurate and noninvasive diagnosis, Doppler US may be preferred as it is a more practical technique compared to DW MR imaging in the evaluation of acute ureteral obstruction due to renal stones. PMID- 25932226 TI - The protective effect of goji berry extract in ischemic reperfusion in testis torsion. AB - This study investigated whether goji berry extract (GBE), a known antioxidant, reduces ischemic reperfusion injury when administered to rats exposed to experimental testis torsion. A total of 32 Sprague-Dawley male rats were randomized into 4 groups, including the control (sham), goji, torsion, and torsion-goji groups. The treatment groups received intraperitoneal GBE prior to torsion. The left testes of the animals were subjected to torsion via 5 hours of ischemia and 6 hours of reperfusion. TAC (total antioxidant capacity), TOS (total oxidant status) and OSI (oxidative stress index) levels were calculated. Approximately 5-MUm-thick sections were stained with hematoxylin-eosin (H&E) and examined under a light microscope. Statistical analyses were performed with the SPSS 15 software package. The mean serum TAC level was significantly increased in Groups 2 and 4 compared with Groups 1 and 3 in biochemical analyses (for both P < 0.001). The mean serum TOS level was significantly increased in Group 3 compared with Groups 1, 2, and 4 (P < 0.001, P < 0.001, and P = 0.003, respectively). Comparison of the groups with regard to histopathological examination revealed that Group 4 exhibited a significantly higher rate of hemorrhage and congestion compared with Groups 1 and 2 (P = 0.038). The groups did not differ significantly with respect to degeneration. Ischemic reperfusion injury associated with testis torsion was reduced by the antioxidant effect of GBE. Further experimental and clinical studies are needed to confirm the agent's efficacy for this indication. PMID- 25932227 TI - Serum and biliary MMP-9 and TIMP-1 concentrations in the diagnosis of cholangiocarcinoma. AB - AIM: Cholangiocarcinoma is generally detected late in the course of disease, and current diagnostic techniques often fail to differentiate benign from malignant disease. Ongoing biomarker studies for early diagnosis of cholangiocarcinoma are still continues. By this study, we analyzed the roles of serum and biliary MMP-9 and TIMP-1 concentrations in the diagnosis of cholangiocarcinoma. MATERIALS AND METHODS: The 113 patients (55 males, 58 females) were included; 33 diagnosed with cholangiocarcinoma (malignant group) and 80 diagnosed with choledocholithiasis (benign group). MMP-9 and TIMP-1 concentrations were analyzed in serum and bile and compared in the malignant and benign groups. Results were evaluated statistically. RESULTS: Biliary MMP-9 concentrations were significantly higher (576 +/- 209 vs. 403 +/- 140 ng/ml, p < 0.01) and biliary TIMP-1 concentrations were significantly lower (22.4 +/- 4.9 vs. 29.4 +/- 6.1 ng/ml, p < 0.01) in the malignant than in the benign group. In contrast, serum MMP-9 and TIMP-1 concentrations were similar in the two groups. Receiver operating curve analysis revealed that the areas under the curve of bile MMP-9 and TIMP-1 were significantly higher than 0.5 (p < 0.001). The sensitivity, specificity, positive and negative predictive values, positive and negative likelihood ratios and accuracy were 0.94, 0.32, 0.36, 0.93, 1.40, 0.19 and 0.5 for biliary MMP-9, respectively, and 0.97, 0.36, 0.39, 0.97, 1.5, 0.08 and 0.54 for biliary TIMP-1, respectively. CONCLUSION: Serum and biliary MMP-9 and TIMP-1 tests do not appear to be useful in the diagnosis of cholangiocarcinoma. PMID- 25932228 TI - Management of pulmonary artery sling with tracheal stenosis: LPA re-implantation without tracheoplasty. AB - OBJECTIVES: Pulmonary artery sling (PA sling) is frequently associated with tracheal and/or bronchial stenosis. Most PA sling patients receive left pulmonary artery (LPA) re-implantation and tracheoplasty under the cardiopulmonary bypass, but the postoperative complications of tracheoplasty remain a great challenge. In this study, we reviewed 14 PA sling children who received surgery in our hospital, and tried to find out whether tracheoplasty could be avoided or not. METHODS: A total of 14 patients receiving surgery due to PA sling/tracheal stenosis were recruited. Complete tracheal ring was confirmed by fiberoptic bronchoscopy in all the patients preoperatively. The clinical outcome and the severity of trachea stenosis (tracheal diameter and length) were evaluated, and effectiveness of various managements was analyzed. RESULTS: Fourteen PA sling/tracheal stenosis children underwent surgical treatment. Three patients needed intubation and mechanical ventilation for severe respiratory symptoms preoperatively. Eight patients received LPA re-implantation alone to relieve the trachea compression, and slide tracheoplasty was performed in one patient for extubation failure who finally died of air leakage. Six patients received LPA re implantation and tracheal intervention simultaneously. Three patients received slide tracheoplasty, and one was discharged after recovery. The remaining 3 patients received tracheal stent implantation, but finally died. The diameter/length (%) in the survivors without tracheal intervention was significantly higher than that in patients with tracheal intervention. CONCLUSIONS: Patients with PA sling undergoing LPA re-implantation achieved a good outcome. Diameter/length (%) may be a more reliable indicator used for determination of tracheal intervention in surgical management of PA sling. PMID- 25932229 TI - Effects of dexmedetomidine on cellular immunity of perioperative period in children with brain neoplasms. AB - OBJECTIVE: To study the effects of dexmedetomidine (Dex) on cellular immunity during the perioperative period in children with brain neoplasms. METHODS: Forty children with brain neoplasms scheduled for selective operation were recruited and divided randomly into two groups. The Dex group was given a loading dose of 1 MUg*kg(-1) Dex 15 minutes before anesthesia induction followed by a continuous infusion of 0.5 MUg * kg(-1) * h(-1) Dex. Patients in control group received a same volume of normal saline for a same time period. Venous blood was collected before anesthesia (T0), 1 h after operation started (T1), immediately after operation ended (T2), 1 day after operation (T3) and 3 days after operation (T4), respectively. RESULTS: CD3 (+), CD4 (+), CD4 (+)/CD8 (+), NK and B cells at T1-T3 decreased significantly (P < 0.05) in both groups compared with those at T0, while the decrease of CD3 (+), CD4 (+), CD4 (+)/CD8 (+) and NK cells at T1-T3 and B cells at T1-T2 in Dex group was significantly less than the control group (P < 0.05). All values at T4 recovered to the level before anesthesia in both groups. CONCLUSION: Dex given by a continuous intravenous infusion during general anesthesia may effectively inhibit the stress responses and reduce the inhibition of cellular immunity in children with brain neoplasms during the perioperative period. PMID- 25932230 TI - Correlations between posterior longitudinal ligament status and size of bone fragment in thoracolumbar burst fractures. AB - This study aim to determine the correlation between the size of bone fragment and injury of posterior longitudinal ligament (PLL). In this study retrospectively analyze medical chart of patients with thoracolumbar burst fractures from June 2010 to December 2012. Patients were divided into two groups (Intact group and Disrupted group) according to the result of MRI assessing status of PLL. All the fractures were classified according to the Arbeit Fuer Osteoosynthese (AO) classification system. Neurological status was classified according to American Spinal Injury Association (ASIA). Mimics measured the height and width of bone fragment (HBF and WBF), transverse canal diameter (TCD) and calculate the height of posterior wall of the injury vertebrae, ratio of height of bone fragment occupying height of posterior wall of vertebrae body (RHBF) and ratio of width of bone fragment occupying transverse canal diameter (RWBF). The results indicated that 52 patients were included in the study. There are 31 patients with intact PLL and 21 patients with disrupted PLL. There was significant difference on the HBF (t = -3.646, P = 0.001), WBF (t = -3.615, P = 0.001), RHBF (t = -4.124, P = 0.000) and RWBF (t = -3.305, P = 0.002) between the intact group and injury group. There was a significant correlation between injury of PLL and ASIA grade (OR = 7.851, P = 0.005), and AO classification (OR = 6.401, P = 0.011), and RHBF (OR = 6.455, P = 0.011), and HBF (OR = 5.208, P = 0.022). In conclusion, the results of this study indicate that AO classification, ASIA grade, HBF and RHBF could act as the predictors of injury of PLL. PMID- 25932231 TI - The cytochrome P450 2D6*10 genetic polymorphism alters postoperative analgesia. AB - The present study was aimed to investigate the effects of the cytochrome P450 (CYP) 2D6*10 genetic polymorphism on postoperative patient-controlled morphine usage. A total of 114 patients were selected, and 102 patients completed the study. Polymerase chain reaction-based restriction fragment length polymorphism (PCR-RFLP) was used to determine the CYP2D6*10 genotype, and patients were categorized into three groups according to CYP2D6 genotype: heterozygous (m/w), wild-type homozygous (w/w), and mutant homozygous (m/m). Total morphine usage and visual analogue score (VAS) were determined 72 hours after the operation and compared across the three genotype groups. Statistical methods used to analyze results were the chi(2) test, analysis of variance, and multiple linear regression analysis; P<0.05 was considered to be statistically significant. The cumulative use of morphine in the m/w group was significantly higher than that in the m/m group between T0.5 and T4h (P<0.05). There were no significant differences in the loading dose of morphine or VAS among the different genotypes within 72 hours of operation. Patients carrying the CYP2D6*10 m/w genotype required higher doses of morphine at T0.5~T4h compared to the m/m group, and therefore received a higher cumulative dose of morphine post-operation. This phenomenon may be due to a decreased ability to synthesize endogenous opioid peptide. PMID- 25932232 TI - SNP rs1511412 in FOXL2 gene as a risk factor for keloid by meta analysis. AB - OBJECTIVE: Determine whether SNP rs1511412 is associated with keloid. DESIGN AND METHODS: One large-scale GWAS identified association between SNP rs1511412 in the FOXL2 gene and keloid disease in the Japanese population. However, researchers didn't observe significant association for keloid in Chinese Han population (PBonferroni>0.05). It's probable that the frequency of this variant in Chinese Han population was relatively low and the sample size was not very large in this study (power =45.5). We performed an independent case control association study in the Chinese Han population and a follow-up large scale meta-analysis for SNP rs1511412. RESULTS: Our study included 309 keloid patients and 1080 controls of the Chinese Han population. A significant association was found between SNP and keloid (P=0.02, OR=2.23). Meta-analysis included 1847 keloid patients and 7229 controls combined from five Asian populations. The association between SNP rs1511412 and keloid became highly significant (P<1*10(-8) OR=1.89). CONCLUSION: We conclude that SNP rs1511412 in FOXL2 is indeed a genetic risk factor for keloid across different ethnic populations. PMID- 25932233 TI - Increased expressions of integrin subunit beta1, beta2 and beta3 in patients with cancer ------correlation analysis between risk factors of VTE and expression of core proteins. AB - OBJECTIVE: Cancer is one of the most common risk factor of venous thromboembolism (VTE). Our previous studies have shown that integrin subunits beta1, beta2 and beta3 were the core proteins of venous thrombi and potential useful biomarker of VTE. This study aimed to explore the expression status of core proteins (integrin subunits beta1, beta2 and beta3) in cancer patients. METHODS: This is a case control study. A total of 144 inpatients (54 females) with clinically proven cancers were recruited into this study, meanwhile 200 inpatients without cancer matched in sex and age were recruited as control group. Flow cytometry was done to measure the expressions of blood integrin beta1, beta2, beta3 and cellular immunity related variables (CD3, CD4, CD8, CD4/CD8, CD16CD56 and CD19). The association degree between increased core proteins and cancers was analyzed by calculating the relative risk (RR). RESULTS: The expression of integrin beta1 and beta3 were markedly increased in patients with cancer (P=0.001 and 0.008). Integrin beta2 was also mildly increased in patients with cancer (P=0.274). The relative risk ratio (RR) of increased integrin beta1, beta2 and beta3 in cancer patients was 1.655 (95% CI: 1.321-2.074, P=0.000), 1.314 (95% CI: 1.052-1.642, P=0.021) and 1.852, (95% CI: 1.097-3.126, P=0.028), respectively. Combined analysis with integrin beta1, beta2 and beta3 showed that the relative risk ratio (RR) of increased in cancer patients was 4.895 (95% CI: 1.645-14.563, P=0.002). CD3, CD4, CD4/CD8 and CD19 were significantly decreased (P=0.004, P=0.000, P=0.000, P=0.000, respectively) in patients with cancer, while CD8 and CD16CD56 were markedly increased in cancer patients (P=0.005, P=0.035). CONCLUSIONS: As the core proteins of venous thrombi, integrin beta1 and beta3 were markedly increased expression in patients with cancer, which maybe explain the increased risk of VTE in cancer patients. A weakened or disordered immune system might be the basis of VTE in condition. PMID- 25932234 TI - Prothrombin complex concentrates utility for warfarin-associated hemorrhage. AB - INTRODUCTION: Prothrombin Complex Concentrate (PCC) for reversal of warfarin is the main therapeutic option in cases of life-threatening bleeding. Aim of the study was to investigate for using 4-factor PCC brought to the therapeutic levels of International Normalized Ratio (INR) values in cases of life-threatening bleeding in Emergency Department. METHODS: This retrospective cohort study was performed in a tertiary care university emergency department. Patients with active bleeding who were taking warfarin with INR levels of >=1.5, and had received 4-factor prothrombin complex concentrate for treatment were included in to study. RESULTS: A total of 75 patients were included in the study. The median age of the study participants was 68 (minimum 23 to maximum 87) years and 45.3% (n = 34) of them were male. INR levels was normalized all patients who were received 4-factor PCC. Red blood cell (RBC) was transfused in 16 patients (21%) because of the low hemoglobin levels. Mean unite of the RBC packet was 2,75. The lengths of hospital stay of receiving 4-factor PCC rate were determined 4.9 +/- 8.7 days. No thrombotic complications or adverse drug reactions were observed after 4-factor PCC administration in any of the patients. CONCLUSIONS: In our study 4-factor PCC was found to be effective and safe in rapidly reversing the effects of warfarin. PMID- 25932235 TI - Alterations of serum brain type natriuretic peptide (BNP) in patients with Crimean-Congo hemorrhagic fever. AB - BACKGROUND: Crimean-Congo hemorrhagic fever (CCHF) is known to be associated with cardiac damage. Brain type natriuretic peptide (BNP) is secreted from stressed myocardium. OBJECTIVES: This study investigated that BNP levels in CCHF and its association with clinical course of disease. METHODS: Consecutive CCHF diagnosis confirmed patients were enrolled to the study. Results of patients were compared with age-sex-matched healthy volunteers. Blood samples for BNP levels were collected from the patients during emergency room applications. Mortality, hospitalization duration and other disease severity predictors (thrombocyte count, hemoglobin, white blood cell count, alanine aminotransferase, aspartate aminotransferase, prothrombin time, lactate dehydrogenase, international normalized ratio, activated partial thromboplastin time) were recorded. These parameters' correlations with BNP levels were analyzed. RESULT: Forty-three CCHF patients and 28 control subjects recruited to the study. Groups were similar for age and gender. There was no mortality. Levels of BNP were found to be significantly higher in patients than control subjects (100.4+/-45.4 vs. 78.0+/ 40.4, P=0.033). But BNP levels were not correlated with duration of hospitalization and disease severity predictors (P > 0.05). CONCLUSIONS: This study showed that BNP levels are modestly increased in CCHF but this increase does not correlated with disease severity predictors. PMID- 25932236 TI - Intertrochanteric hip fracture surgery in Chinese: risk factors for predicting mortality. AB - Surgery is the preferred treatment for intertrochanteric fractures. This study aimed to analyze risk factors for predicting mortality after intertrochanteric hip fracture surgery by arthroplasty and internal fixation. We performed a retrospective analysis of 1,263 patients who received surgical treatment for intertrochanteric fractures from January 2005 to December 2010. The clinical and follow-up data from 491 eligible patients were collected and analyzed. The age, activity before surgery, activity after surgery, anesthesia, medical illness, and the time between fracture and surgery were significantly associated with the mortality as single factor. Multifactor analysis showed that the activity after surgery, medical illness, and the time between fracture and surgery were correlated with postoperative mortality. In conclusion, these data suggest that the age, activity after surgery, medical illness could affect postoperative mortality of patients of intertrochanteric fractures. These factors may be used to predict the postoperative mortality of intertrochanteric fractures. PMID- 25932237 TI - Expression of miR-221 in colon cancer correlates with prognosis. AB - MicroRNAs are increasingly important in the study of cancer because of their ability to down regulate the expression of tumor suppressors and promote tumorigenesis. Here, miR-221, which is dysregulated in various tumors, was investigated for its expression in colon cancer tissues and its correlation with patient prognosis. Colon cancer tissue samples were obtained from 182 individuals who underwent surgical resection in our hospital from June 2008 to September 2009. Real-time PCR was used to detect the expression of miR-221 in these tissues. Patient survival was determined by telephone interview, and survival curves were plotted by using the Kaplan-Meier method and compared by the Log-rank test. Statistical methods also included X(2) test and Cox proportional hazard regression model. Differences in the expression of miR-221 by gender, pathology, and pathological staging were not statistically significant (P>0.05), but differences in the expression of miR-221 among age groups were statistically significant (P<0.05). A survival analysis indicated that high expression of miR 221 was closely associated with a shorter survival time (P<0.05). Further, later p-TNM (hazard ratio, HR=2.973, 95% confidence interval, CI: 1.329-6.519, P=0.003) and high expression of miR-211 (HR=2.394, 95% CI: 1.210-4.910, P=0.006) were identified as risk factors for colon cancer prognosis. Thus, high miRNA-221 expression might be a prognostic marker of colon cancer patients. The high expression of miRNA-221 was associated with poor prognosis of patients with colon cancer. PMID- 25932238 TI - Postadenoidectomy hemorrhage: how we do it? AB - AIMS: Conventionally, adenoidectomy has been performed using blind curettage. Postoperative hemorrhage is the most common complication of surgery. There is no specific management algorithm in the literature. In this study, we described an endoscopic approach in the management of postadenoidectomy hemorrhage. MATERIAL AND METHODS: Between 1995 and 2014, 7946 patients undergoing adenoidectomy under general anesthesia in our clinic were retrospectively analyzed. All patients had a rest adenoid tissue located in the choanae. Endoscopic excision of the tissue was performed without using a post-nasal pack. RESULTS: All patients (100%) had a rest adenoid tissue located in the choanae. Hemorrhage was completely discontinued with endoscopic excision of the hemorrhagic tissue. CONCLUSION: Based on our study findings, we conclude that an endoscopic approach should be applied in all postoperative patients with hemorrhage who are unresponsive to conservative treatment modalities. PMID- 25932239 TI - Comparison of the status of overweight/obesity among the youth of local Shanghai, young rural-to-urban migrants and immigrant origin areas. AB - BACKGROUND: Obesity in adolescents and children has become a global public health problem and lots of factors influence the status of obesity and overweight. The present study aims to compare the health-related factors which could influence the obesity in Chinese children and adolescents in three different groups which including the local developed city group, rural-to-urban migrants group and immigrants origin areas group. METHODS: We conducted a cross-sectional study consisted of 2457 children and adolescents aged 7-10 years old including 914 rural-to-urban migrants subjects, 795 local Shanghai subjects and 748 from immigrant origin areas. Physique measurements and self-reported information on health-related factors, such as physical activities, dietary habits, socio economic factors such as family income, sleep habits, etc. were collected by questionnaire. SPSS16.0 was used in the analysis. RESULTS: Mean level of body height, body weight and sitting height were different among the three groups, local youth group was higher in all the indexes than the other two groups. Grip for both hands were higher in local group also, while the heart rate was lowest in rural-to-ruban migrants group. The mean BMI in three groups showed significant difference, highest for local group. Higher SBP level was found in city and rural to-urban migrants group also. However, no difference of DBP between groups was detected. The distribution of pre-hypertension and hypertension in three groups were significantly different and the distribution of overweight and obesity between genders in all three groups were different. The prevalence of overweight was 19.04% in rural-to-urban migrants group (19.92% for male and 17.64% for female), 28.21% for city group (35.64% for male and 20.72% for female); while no overweight or obesity subjects were found in immigrant origin areas group in this study. When compared the overweight and obesity prevalence between city group and rural-to-urban migrants, we found the overweight was more common in the local youth group. Univariable Logistic regression analysis and multivariable analysis results suggested that the more rice intake, higher family income and SBP higher than 140 mmHg were risk factors to obesity for rural-to-ruban migrants, while good dietary habits (no TV watching during meals) was preventive factor to obesity and SBP higher than 120 mmHg and unsocial factor were associated with obesity for rural-to-urban migrants. CONCLUSIONS: Our study revealed the prevalence of overweight and obesity in developed city children and adolescents and rural-to-urban migrants were relatively high, especially more common in local population and male gender. Lifestyle, dietary and psychological factors offered important contribution in increasing or decreasing the risk of obesity. PMID- 25932240 TI - Caries outcomes after orthodontic treatment with fixed appliances: a longitudinal prospective study. AB - OBJECTIVES: The aim of this study was to assess the relationship between orthodontic and the development of dental caries in the same patients who received single jaw orthodontic treatment. MATERIAL AND METHODS: A consecutive sample consisted of 60 subjects who required single upper jaw orthodontic were recruited consecutively from the Department of Orthodontic at the Stomatology Hospital of Wenzhou Medical University. The dental examinations were routinely carried out by one dentists at the following stages: pre-treatment (T1); post treatment (T2); more than 7 years after T1 (T3). The DMFS count which reflect the caries experience was recorded. RESULTS: There was no significant difference between the treated groups and untreated groups for the DMFS before received fixed orthodontic treatment. The same result was found after orthodontic treatment. However, the average number of DMFS in the treatment jaw after fixed orthodontic treatment was lower than in the without treatment jaw after long-term follow-up period. CONCLUSIONS: Fixed orthodontic appliances significant decrease the patients caries risk after orthodontic treatment. PMID- 25932241 TI - Ethnic differences in acylation stimulating protein (ASP) in Xinjiang Uygur autonomous region, China. AB - BACKGROUND: Acylation Stimulating Protein (ASP) stimulates adipocyte triglyceride synthesis and glucose transport. The aim was to examine ethnic difference in ASP and the relation to lipid profile and other parameters among Han, Uygur, and Kazak healthy populations matched for BMI, age and gender distribution. METHODS: 331 healthy persons were recruited in total (age 30-60 yr): 137 Han, 114 Uygur, and 80 Kazak. Anthropometric measurements including height, weight, waist circumference, hip circumference, blood pressure, ankle brachial index (ABI), and pulse wave velocity (PWV) were measured in all participants. Fasting concentrations of fasting glucose, uric acid, and lipids, including triglyceride (TG), total cholesterol (TC), low density lipoprotein cholesterol (LDL-C), high density lipoprotein cholesterol (HDL-C), ASP, complement C3, insulin, non esterified fatty acid (NEFA) and C-reactive protein (CRP) were measured. RESULTS: ASP in Uygurs was significantly lower than Han subjects (P=0.0003). The Uygurs demonstrated the highest C3 (P<0.001), CRP (P=0.001), and NEFA concentrations (P=0.008), the lowest %ASP/C3 (P<0.001) and TC levels (P=0.0008) vs those in Han and Kazak populations. In the Han group, glucose, the average ABI (an index of peripheral response) and diastolic blood pressure were significantly different from both Uygur and Kazak group (P=0.0007, P=0.0003, P=0.0001) while Kazaks show the lowest waist/hip circumference (WHR) (P=0.0003). CONCLUSION: There are ethnic differences in ASP, C3, CRP and lipid profiles in healthy Han, Uygur, and Kazak populations. Overall, the Uygur populations presents with a disadvantageous metabolic profile as compared to Han and Kazak groups. PMID- 25932242 TI - Analysis of the risk factors and characteristics of coronary artery disease of Han, Uygur and Kazak patients with acute myocardial infarction in Xinjiang district. AB - To discuss the risk factors and characteristics of coronary artery disease of Han, Uygur and Kazak patients with acute myocardial infarction in Xinjiang district. A retrospective analysis of clinical data of 262 cases of Han patients, 166 cases of Uygur patients and 86 cases of Kazak patients was conducted, whose age, body mass index, cholesterol, uric acid, hypertension, type 2 diabetes, smoking, drinking, family history of coronary heart disease, relationship between PCI history and pathogenesis of acute myocardial infarction, and coronary artery disease characteristics were observed and compared in different groups. Between the Han and minority young patients, there were statistically significant differences in the distribution of BMI, lipoprotein a, positive family history of coronary heart disease, uric acid level, the combined aspects of smoking history (P<0.017); there were also statistically significant differences in BMI, TG, HDL C, apolipoprotein B, positive family history of coronary heart disease distribution between minority young patients and older patients (P<0.017). There were statistically significant differences in the distribution of BMI, TC, HDL-C, LDL-C, apolipoprotein AI, positive family history of coronary heart disease between Han and Uygur patients (P<0.017). Han and Kazak patients had statistically significant differences in the distribution of BMI, TC, LDL-C, apolipoprotein B, lipoprotein a, type 2 diabetes and hypertension (P<0.017). Comparison of patients in Uygur and Kazak showed that there were statistically significant differences in the distribution of BMI, TC, LDL-C, apolipoprotein AI, apolipoprotein B and type 2 diabetes between the two groups (P<0.017). The proportion of zero lesions and single-vessel lesions in minority youth patients was higher than that of elderly patients (P<0.001), and the proportion of two and three lesions was less than that of elderly patients (P<0.001). Gensini score of Han patients was greater than that of Uygur patients (P<0.001) and the Kazak patients (P=0.005); The proportion of Han patients with single-vessel disease was less than that of Kazak patients (P=0.003), and the proportion of patients with double-vessel disease was greater than that of Kazak patients (P=0.007). There were ethnic differences in risk factors and the characteristics of coronary artery disease of AMI patients in Xinjiang district; there were differences between minority youth patients and elderly patients, young patients of Han. PMID- 25932243 TI - Clinical and echocardiographic results of the Kalangos biodegradable tricuspid ring for moderate and severe functional tricuspid regurgitation treatment. AB - INTRODUCTION: The Kalangos Biodegradable Tricuspid Ring (Kalangos Biodegradable Tricuspid Ring(r), Bioring SA, Lonay, Switzerland) is a biodegradable prothesis in the treatment of functional tricuspid regurgitation (FTR). In this study, we aimed to determine the clinical and echocardiographic results of this prosthesis for moderate and severe FTR treatment and compare this technique with the results of semicircular DeVega annuloplasty. MATERIALS AND METHODS: From January 2005 through January 2010 we retrospectively studied the data on 64 consecutive patients underwent annuloplasty procedures for FTR treatment. The patients were assigned to 2 groups: (1) Kalangos BTR annuloplasty was performed in 32 patients, and (2) Semicircular DeVega annuloplasty was performed in the 32 patients. All patients were evaluated clinically and by echocardiography preoperatively, at the end of the 1st week, 3rd and 6th month following surgery. RESULTS: No complications related to the prosthesis or the procedures within the follow-up period were recorded. At the follow-up period, systolic pulmonary arterial pressure and tricuspid valve area diameter were found to be significantly lower than the preoperative values in both groups (p < 0.0001). At the follow-up period residual tricuspid regurgitation and the Tei index (Myocardial performance index) was significantly lower in group 1 compared to group 2 (p < 0.05). Three-quarters of the annuloplasty ring had degraded in the postoperative 6-months period. DISCUSSION: We conclude that Kalangos BTR is an efficient and safe prosthesis with easy implantation technique for FTR treatment, with encouraging midterm results. PMID- 25932244 TI - Efficacy assessment of two antibiotic prophylaxis regimens in oral and maxillofacial trauma surgery: preliminary results. AB - The study set out to evaluate the efficacy of two antibiotic prophylaxis regimens in patients with facial fractures admitted to the Oral and Maxillofacial Surgery and Traumatology services of the Onofre Lopes University Hospital attached to the Federal University of Rio Grande do Norte in the period from December 2011 to December 2012. The sample consisted of 74 patients divided into two groups, GI with forty-three patients and GII with 32. Both groups received 2 g of cefazolin, 20 minutes before surgery. The postoperative protocol for each group was randomly determined; group I (single dose) received no antibiotics after surgery but group II (24 h dosage) received 1 g of cefazolin every 6 hours for 24 hours. Postoperative infection incidence was 9.3% (seven patients), six patients in Group I and one in Group II. 85% of the infections were in mandibular fractures. Results were presented qualitatively and quantitatively and the Chi square test (taking the value for p to be < 0.05) showed no statistically significant differences in the efficacies of the two regimens in the comparisons made between the cases of fractures in the upper and middle thirds of the face with those in the lower third (mandibular fractures). Considering mandibular fractures alone, Group II proved to be more efficacious with a p value of 0.02. However, to confirm the tendency shown in the mandibular fracture treatments whereby prolonging antibiotic administration for 24 hours appeared to be beneficial, research needs to be done with much larger sample groups. PMID- 25932245 TI - Lipocalin-2 plasmatic levels are reduced in patients with long-term type 2 diabetes mellitus. AB - BACKGROUND: De-regulation of adipocytokines synthesis and secretion appears to be involved in the pathogenesis of different metabolic diseases. AIMS: We assessed a possible association between plasmatic levels of lipocalin-2 (LCN2) and type 2 diabetes mellitus (T2DM), as well as among levels of LCN2 and those of adiponectin, ghrelin, leptin and resistin, in Mexican diabetic patients. SUBJECTS AND METHODS: Fifty-three healthy individuals and fifty-three with long-term T2DM were included. Measurements from all patients for BMI, fasting glucose, insulin, lipids and adipocytokine profiles were obtained. RESULTS: Comparison of data between the corresponding for diabetic subjects and those of healthy individuals showed significant differences in every anthropometric and metabolic parameter analyzed (P < 0.001). In diabetic subjects, lipocalin-2 and ghrelin plasmatic levels were statistically diminished (P < 0.001) in comparison with the levels registered in healthy subjects. In conclusion, in this study we found that LCN2 plasmatic levels are reduced in Mexican subjects with long-term diabetes and this reduction in circulating concentrations is similar to the one reported for anti inflammatory adipocytokines, which suggests that lipocalin-2 is somehow involved in insulin resistance and cardiometabolic alterations through an uncharacterized mechanism generated by the inflammation process. PMID- 25932246 TI - Adherence to Mediterranean diet and its relation with cardiovascular diseases in Turkish population. AB - Mediterranean diet (MD) is considered a model for healthy eating. However, prospective evidence in Turkey evaluating the relationship between MD and cardiovascular events is scarce. We surveyed the adherence of Alanya population to MD and its association with coronary heart diseases (CHD). The study population consisted of participants in Alanya, a region placed southern Turkey. Followed-up 900 participants (52 percent women) initially free of CHD during 5.1 years. The general dietary habits of study population were detected with a food frequency questionnaire. Data obtained from that questionnaire were tested with Mediterranean diet score in order to find out the relevance to Mediterranean diet. A MD score (scale 0-8) was computed reflecting high ratio of monounsaturated to saturated fat; high intake of legumes, cereals, vegetables, and fruits; low intakes of meat and it's products, milk and dairy products. Scoring < 5 was defined as Low-MD consuming, while 5+ as High-MD consuming. We observed 25 incident cases of CHD. Consumption of High-MD was 21% in men and 19% in women. The risk for myocardial infarction, coronary bypass, coronary angioplasty, and any cardiovascular disease in men increased by 1.3 (P = 0.02), 1.4 (P = 0.03), 1.5 (P = 0.01), and 1.3 (P = 0.02), respectively, for each MD score decrease. In women, the risk for myocardial infarction and angioplasty increased by 1.3 (P = 0.02) and 1.5 (P = 0.01), respectively, for each MD score decrease. The risk for coronary bypass, and any cardiovascular disease in women, crude odds ratios ranged from 1.1 to 1.3 but were not statistically significant. The current rate of MD in Alanya is fairly low. There is an inverse association between adherence to MD and the incidence of fatal and non-fatal CHD in initially healthy adults. PMID- 25932247 TI - Spectrum analysis of Chinese vowels formant in patients with tongue carcinoma underwent hemiglossectomy. AB - OBJECTIVES: Tongue is the most important phonatory organ in stomatognathic system. Radical resection of tongue squamous cell carcinoma can cause tongue defect and result in serious oral dysfunction, especially in phonetic function. This study aims to reveal the influence of tongue cancer, tongue defect and tongue reconstructions to phonetic function of tongue cancer patients. STUDY DESIGN: Formant spectrum analysis of Chinese vowels was performed by linear predictive coding (LPC) in tongue squamous cell carcinoma patients (before surgery and 3 months, 9 months and 2 years after surgery) and normal people. Patients with tongue squamous cell carcinoma were divided into reconstruction group and non-reconstruction group. In reconstruction group, patients underwent tongue reconstruction with radial forearm free flap (RFFF) and lateral arm free flap (LAFF), respectively. RESULTS: 45 patients and 40 normal people were included. Differences were statistically significant between patients and normal persons, between patients before surgery and after surgery, between non reconstruction group and construction group 2 years after operation. No statistical significance was found between patients underwent tongue reconstruction with RFFF or LAFF 2 years after operation. CONCLUSIONS: This study showed that tongue cancer and tongue defect after radical resections affected phonetic function of patients. Tongue reconstruction with free flaps could restore phonetic function to some extent. The efficiency of tongue reconstruction with RFFF and LAFF respectively were similar. PMID- 25932248 TI - Modifying enzymes related aminoglycoside: analyses of resistant Acinetobacter isolates. AB - Enzymatic modification of aminoglycosides by nucleotidyltransferases, acetyltransferases and/or phosphotransferases accounts for the majority of aminoglycoside-resistant Acinetobacter isolates. In this study, we investigated the relationship between aminoglycoside resistance and the presence of aminoglycoside-modifying enzymes in Acinetobacter baumannii clinical isolate groups with different resistance profiles. Thirty-two clinical A. baumannii isolates were included in this study. Acinetobacter isolates were divided into 4 groups according to results of susceptibility testing. The presence of genes encoding the following aminoglycoside-modifying enzymes; aph (3')-V1, aph (3') Ia, aac (3)-Ia, aac (3) IIa, aac (6')-Ih, aac (6')-Ib and ant (2')-Ia responsible for resistance was investigated by PCR in all strains. The acetyltransferase (aac (6')-Ib, aac (3)-Ia) and phosphotransferase (aph (3')-Ia) gene regions were identified in the first group, which comprised nine imipenem, meropenem, and gentamicin-resistant isolates. The acetyltransferase (aac (6')-Ib, aac (3)-Ia), phosphotransferase (aph (3')-VI) and nucleotidyltransferase (ant2-Ia) gene regions were identified in the second group, which was composed of nine imipenem resistant, meropenem-resistant and gentamicin-sensitive isolates. The acetyltransferase (aac (3)-Ia) and phosphotransferase (aph (3')-Ia) regions were identified in the fourth group, which comprised eight imipenem-sensitive, meropenem-sensitive and gentamicin-resistant isolates. Modifying enzyme gene regions were not detected in the third group, which was composed of six imipenem, meropenem and gentamicin-sensitive isolates. Our data are consistent with previous reports, with the exception of four isolates. Both acetyltransferases and phosphotransferases were widespread in A. baumannii clinical isolates in our study. However, the presence of the enzyme alone is insufficient to explain the resistance rates. Therefore, the association between the development of resistance and the presence of the enzyme and other components should be investigated further. PMID- 25932249 TI - Inadequate gestational weight gain and adverse pregnancy outcomes among normal weight women in China. AB - OBJECTIVE: The objective of the paper is to find the association between inadequate gestational weight gain and pregnancy outcomes in normal weight women in China. METHOD: A retrospective study was conducted among 13,776 normal weight pregnant women who received antenatal care and delivered singleton infants at the participating hospital during August, 2009 to July, 2013. Adverse pregnancy outcomes like low birth weight (LBW), preterm birth, birth asphyxia, neonatal intensive care unit (NICU) admission and length of hospital stay were compared and analyzed between two groups with inadequate and adequate gestational weight gain. RESULTS: According to the IOM recommendations, inadequate gestational weight gain was found to be 14.7% in this study. Women with inadequate gestational weight gain (GWG) were found to be at a higher risk for LBW (aOR = 2.13, 95% CI: 1.75, 2.86) and preterm birth (aOR = 1.44, 95% CI: 1.21, 1.67) than those in the adequate gestational weight gain group, after adjusting for monthly family income, maternal education, occupation, and whether they received any advice regarding benefits of gestational weight gain and residential area. However, inadequate GWG was not associated with longer hospital stay (aOR = 1.13, 95% CI: 0.91-1.43) in adjusted model. In addition, the rate of birth asphyxia and NICU admission were similar in both groups (P > 0.05). CONCLUSIONS: Normal weight pregnant women with GWG below the recommended AIOM 2009 guidelines were found to be at an increased risk of low birth weight and preterm birth. PMID- 25932250 TI - The perioperative and convalescence nursing of 5 cases of Monti ileovesicostomy. AB - The main indications of Monti ileovesicostomy is urinary incontinence and urethral injury. Thus, it's very significant for the patients to relieve the vice effects of Moni ileovesicostomy. The aim of this study is to investigate the perioperative nursing care and methods to improve the quality of life in Monti ileovesicostomy. In this study, 5 patients received Monti ileovesicostomy in our department since 2009, each patient was provided with well-designed perioperative nursing care including physical and psychological nursing, care of complications, health education, family rehabilitation guidance, and the quality of life for each patient was followed up after the operation. The results indicated that all of 5 patients recovered successfully Without bloating, vomiting, and severe bleeding; In one year follow-up, 5 patients didn't suffer colostomy narrowing, blockage or dermatitis; 5 patients' satisfaction had been obviously improved in the anxiety status, social function and sexual function. In conclusion, the quality of life can be improved for patients who have to receive the treatment of Monti ileovesicostomy with professional perioperative nursing, health education and rehabilitation guidance. PMID- 25932251 TI - Correlation between polymorphisms of the E-selectin gene, hepatitis B virus DNA copies, pre-S1 antigen and clinical outcomes during chronic hepatitis B. AB - The aim of this study was to investigate the relationships between E-selectin +G98T, +A561C polymorphisms and different progression in Hepatitis B virus (HBV) infection Xinjiang Han population, also to determine the HBV DNA copies and pre S1 antigen (preS1Ag) in this population. Polymorphisms of the E-selectin gene in 200 chronic HBV infection (61 cases of chronic HBV carriers, chronic hepatitis B 75, liver cirrhosis 43, liver cancer 21) and 200 healthy controls were detected using polymerase chain reaction-restriction fragment length polymorphism (PCR RFLP). Real-time quantitative PCR was used to detect the levels of HBV DNA. preS1Ag and five items of hepatitis B were detected by enzyme-linked immunosorbent assay. Liver fibrosis using chemiluminescence, biochemical markers using Roche 7600 automatic biochemical analyzer. E-selectin +A561C polymorphism of A/C genotype and C allele frequency in chronic hepatitis B (CHB) and cirrhosis (LC) group were compared with the control group had significant difference (P < 0.05). The risk of CHB and LC, AC genotype were 2.09, 2.33 times of the AA genotype. In group of CHB, the levels of HBV DNA and preS1Ag in the AC genotype patients were higher than those in the AA genotype (P < 0.05). However, there were no significant differences in comparison of liver function and liver fibrosis index in different genotypes of CHB and LC group. +A561C and +G98T linkage disequilibrium analysis showed: D' = 0.632, r(2) = 0.202, haplotype analysis showed that the G-A haplotype OR = 0.507, G-C haplotype OR = 1.973. E selectin +A561C polymorphism may have some correlation with the occurrence of CHB and LC, and allele C may be one of the predisposing factors. AC polymorphism may affect HBV replication in CHB, but may not play an important and direct effect on liver injury and liver fibrosis after HBV infection. There were some linkage of +A561C and +G98T, G-C haplotype may be a risk factor for chronic HBV infection. PMID- 25932252 TI - Mean platelet volume levels in the presence of angiographically documented peripheral artery disease. AB - AIM: Increased mean platelet volume (MPV) have been shown to be associated with peripheral artery disease (PAD). However in these studies, noninvasive methods for the diagnosis of PAD was used. In the literature, there is no studies examining the values of MPV in the angiographically documented PAD. We aimed to evaluate the relationship between angiographically documented PAD and MPV levels in the peripheral blood samples. METHODS: In this study, retrospective analysis of 1386 patients was performed who underwent peripheral angiography at the cardiology service of the our hospital, between 2006 and 2012 for a suspected diagnosis of lower extremity peripheral arterial disease. Patients with a stenosis percent of 50% or above in the peripheral angiography were considered as having peripheral arterial disease. MPV values are affected by many factor. Only 84 patients who complied with the inclusion criteria were detected. The study patients were divided into 2 groups according to the results of peripheral angiography. 56 patients diagnosed with PAD based on the specified criteria were grouped into Group I (mean age 59 +/- 10 years) while 28 patients without peripheral arterial disease were grouped into Group II (mean age 60 +/- 11 years). Blood tests and angiographic images were analyzed from patients' data. RESULTS: Both groups were similar in terms of basic parameters of anemia including hemoglobin, hematocrit and red cell distribution width levels. There were no significant differences between MPV levels in both groups (8.08 +/- 0.91 vs 8.28 +/- 1.16, P > 0.05). Mean corpuscular volume and mean corpuscular hemoglobin levels, on the other hand, were significantly higher in Group I (P < 0.05). CONCLUSIONS: In our study, we did not found any significant changes in the MPV levels of angiographically documented PAD diseases. The use of MPV level as a risk factor for peripheral arterial disease is impractical due to the fact that MPV is affected by a lot of factors and there are several technical factors. Because of this, in the real life, we are not recommend to use MPV values as an indicator for peripheral artery disease. PMID- 25932253 TI - Association between NKX2-5 rs29784 and infantile hypertrophic pyloric stenosis in Chinese Han population. AB - PURPOSE: The aim of this study was to evaluate the association of three single nucleotide polymorphisms (SNPs, rs11712066 and rs573872 near MBNL1, rs29784 near NKX2-5) with infantile hypertrophic pyloric stenosis (IHPS) in Chinese Han population. METHODS: A total of 47 family trios consisting of infants with IHPS and their healthy biological parents were recruited for this study. Genotypes were determined using direct sequencing. Transmission disequilibrium test (TDT) was performed for family-based association analysis. RESULTS: Genotypic distributions of three SNPs in both groups (patients and proband's parents) were in conformity with Hardy-Weinberg equilibrium (P > 0.05). There were significant preferential transmission of A allele of rs29784 from the parents to affected offspring (TDT: x(2) = 5.444, P = 0.0196). However, other two polymorphism loci (rs11712066 and rs573872) were not significant susceptibility loci for IHPS in Chinese Han population. CONCLUSIONS: We found that there was a significant association between rs29784 and IHPS. PMID- 25932254 TI - De novo malignancies in renal transplant recipients: experience at a single center in China. AB - OBJECTIVE: Post-transplant malignancies are a major cause of morbidity and mortality after renal transplantation. This retrospective study investigated the incidence and outcome of de novo malignancies following kidney transplantation in a single China kidney transplantation center. MATERIALS AND METHODS: Between 1989 and 2010, 1467 patients underwent kidney transplantation at transplantation center of Tianjin First Central Hospital of Tianjin Medical University. Data were analyzed for tumor incidence, clinical characteristics, and outcome. A review of the literature is also summarized. RESULTS: After 1,467 renal transplantations, 5 men and 9 women (sex ratio 5:9) with a mean age of 54 years (21-64) were included for malignancies, an overall incidence of 0.954%. Urinary tract malignancies represented the most frequent malignancies (57%). The time of postoperative tumor occurring varied from 1 to 133 months with an average value of 42.78 months. Among them, 4 died and the mortality rate was 28.6%. CONCLUSIONS: In short, with the increasing of transplant patients and the prolonging of survival time with kidney, the occurrence of malignancies will be increasing. This requires that we should set up perfect transplant follow-up system, and do regular follow-up and careful physical examination, do not overlook any early feature of tumor, at last achieve early diagnosis of tumor, and early treatment to improve the cure rate of postoperative malignancies of renal transplantation. PMID- 25932255 TI - Evaluation of left ventricular systolic and diastolic functions in bipolar patients during lithium therapy. AB - BACKGROUND: Bipolar disorder (BD) is a chronic mental illness that is associated with substantial functional impairment, morbidity and mortality. Lithium is still considered as a first-line therapy in BD. In this study, systolic and diastolic function parameters were measured with echocardiography in BD during lithium therapy and compared to those of a control group. METHODS: Thirty BD under lithium therapy and controls were included in our study. Blood samples were taken 12 hours after receiving the last dose of lithium treatment, in the meantime echocardiography were performed. Left ventricular systolic and diastolic function was assessed by conventional echocardiography and tissue Doppler imaging. Serum lithium level correlation between diastolic function parameters was measured. RESULTS: Baseline demographic and laboratory results did not differ significantly between the groups. Left ventricular ejection fraction (LVEF) (66.7 +/- 7.1% vs 66.7 +/- 4.9%), E/A ratio (1.14 +/- 0.41 vs 1.28 +/- 0.29), and isovolumetric relaxation time (IVRT) (77.8 +/- 14.5 cm/sec vs 75.9 +/- 17.7cm/sec) measured with conventional echocardiography showed no significant difference between the two groups. Em (14.8 +/- 5.2 cm/sec vs 15 +/- 4.6 cm/sec), Am (12.7 +/- 4.0 cm/sec vs 11.1.0 +/- 2.4 cm/sec) and E/Em (5.5 +/- 1.8 vs 5.9 +/- 2.4) measured with tissue Doppler echocardiography showed no significant difference between the two groups. Serum lithium levels were not correlated with LVEF, mitral inflow E velocity, mitral inflow A velocity, E/A ratio, deceleration time (DT), IVRT, or E/Em ratio. CONCLUSION: Left ventricular systolic and diastolic functions were preserved in BD during lithium therapy. PMID- 25932256 TI - Risk factors for depression among elderly subjects with hypertension living at home in China. AB - OBJECTIVE: Studies of factors associated with symptoms of depression in the elderly in China are scarce, especially for those with hypertension residing at home in the general population. METHODS: We conducted a cross-sectional study to determine the risk factors for depression in a hypertensive population residing in Beijing in 2004. The sample population consisted of 1064 people aged >= 60 years dwelling in an urban district, a suburb, and in mountain country. Statistical sampling techniques included cluster, stratification, and random selection. Trained staff using a comprehensive geriatric assessment questionnaire, a standard survey instrument in China, completed the assessments. During person-to-person interviews, data were collected regarding demographic characteristics and living and health conditions. RESULTS: Symptoms of depression were scored according to the Center for Epidemiologic Studies-Depression (CES-D) screening test. We showed that factors that were associated with a higher incidence of depression were living in a rural area, being illiterate, without a mate, low income, experiencing a significant stressful life event, poor sleep pattern, poor functional status, and poor cognitive function. Logistic regression analysis indicated that elderly participants with hypertension were significantly more likely to develop depression symptoms under conditions of illiteracy, experiencing a significant stressful life event, poor sleep habits, and poor functional status. CONCLUSIONS: Our study determined risk factors for depression in elderly patient with hypertension, and these risk factors are modifiable. This indicates that depression in these patients can be prevented by appropriate lifestyle changes and psychological health education. PMID- 25932257 TI - The effect of laser epilation on recurrence and satisfaction in patients with sacrococcygeal pilonidal disease: a prospective randomized controlled trial. AB - BACKGROUND: The primary aim of this prospective study was to investigate the effects of laser epilation on patient satisfaction and recurrence in patients who underwent pilonidal sinus surgery. METHOD: Sixty patients scheduled for pilonidal sinus surgery in our clinic between 2011 and 2012 were enrolled in this prospective randomized controlled study. Patients were divided in two groups of 30 patients each. Only the Karydakis flap reconstruction technique was performed in the first group. Two sessions of laser epilation were applied in the second group in addition to Karydakis flap reconstruction. The patients in the second group underwent laser epilation 2 weeks before and 3 weeks after the surgery for a total of 2 times in a private office. RESULTS: There were no statistically significant differences between the groups in terms of age, gender, smoking usage, ASA Score, duration of patient's complaints, BMI and hospital stay. There were no statistically significant differences between the groups in terms of surgical site infection, wound separation, abscess formation at the any time postoperatively. There were statistically significant differences between the two groups in the first week post operation considering the VAS pain score (P<0.03) and VAS satisfaction score (P<0.01). While there were statistically significant differences between the two groups in the first month post operation considering the VAS pain score (P<0.0001), there were no statistically significant differences between the groups in terms of VAS satisfaction score in the first and three month postoperatively. In the telephone interviews done 1 year after the surgery, recurrence were detected in 4% of first group and in 20% of second group. Recurrence rates were significantly higher in the second group (P=0.045). CONCLUSION: Our results show that laser epilation does not reduce the relapse rates in pilonidal sinus surgery, as expected. It is obvious that prospective randomized studies need to be held on this subject. PMID- 25932258 TI - Correlation of rs1799793 polymorphism in ERCC2 and the clinical response to platinum-based chemotherapy in patients with triple negative breast cancer. AB - BACKGROUND: Polymorphisms of DNA repair genes may affect the repair capacity of DNA damages and cause different responses towards chemotherapy. Excision repair cross-complementing group 2 (ERCC2) plays an important role in the nucleotide excision repair. OBJECTIVES: The aim of this study was to investigate the association between ERCC2 single nucleotide polymorphisms (SNPs) and the response to platinum-based chemotherapy among patients with triple negative breast cancer. METHODS: In total, 60 triple negative breast cancer patients treated with platinum-based chemotherapy were studied. The clinical, pathological and treatment data of them were collected. Sequenom's MassARRAY system was used in the detection of the SNPs of ERCC2. Finally, the association between genotypes and different clinical responses among patients was analyzed. All of the patients received a platinum-based chemotherapy for 4 cycles in median and achieved an overall response rate of 66.7%, showing a comparative good response towards platinum-based chemotherapy among triple negative breast cancer. Fifty-three of the 60 patients had got the results of ERCC2 rs1799793 polymorphisms after MassARRAY detection. RESULTS: The proportion of GG genotype and GA genotype was 81.1% and 18.9% respectively. The response rate of the rs1799793 GG genotype group was 69.8%, while the GA genotype group only had a response rate of 30.0%. It turned out that the GG genotype was associated with better response towards platinum-based chemotherapy (P=0.030). CONCLUSIONS: ERCC2 rs1799793 polymorphism may be associated with the clinical sensitivity of platinum-based chemotherapy and could be a potential predictive biomarker for triple negative breast cancer patients treated with platinum compounds. PMID- 25932259 TI - Invasive group B streptococcal infection in infants in Shenzhen, China. AB - OBJECTIVE: In this study, we aim to investigate the distribution and antibiotic susceptibility of Group B Streptococcus (GBS) in infants younger than 90 days in Shenzhen, China. METHODS: A retrospective study was conducted to evaluate GBS infection over an 4-year period. Starting from January 2010, we evaluated the laboratory data, clinical manifestations, treatment and outcomes of patients admitted to our hospital with invasive GBS infection. Furthermore, we analyzed distribution of isolates from infants < 90 days with GBS or non-GBS invasive infection. RESULTS: The registered cases of invasive GBS infection (n = 40, male: 23, female: 17) were classified as sepsis (n = 24), meningitis (n = 2), or both (n = 14). Patients with sepsis recovered completely. Among patients with meningitis, 1 (6.3%) died from ventricular hemorrhage, and 4 (25%) showed sequelae during the follow up of 3 months. Among the 377 isolates (45 from the 40 infants with invasive GBS infection, 332 from infants with non-GBS invasive infections), the detection rate of GBS was 11.9% (45/377), accounted for 11.2% of sepsis and 18.4% of meningitis cases. All 45 isolates were susceptible to penicillin, vancomycin, linezolid, tigecycline, and quinolones. Resistance to erythromycin, clindamycin, and tetracycline was found in 19 (42%), 29 (64%), and 42 (93%) isolates, respectively. CONCLUSION: GBS is an important pathogen in infants < 90 days in Shenzhen, China, which results in high mortality and neurological sequelae. GBS strains show strong resistance to clindamycin and erythromycin. PMID- 25932260 TI - Comparison of the efficacy of four cholinesterase inhibitors in combination with memantine for the treatment of Alzheimer's disease. AB - BACKGROUND: Combined use of memantine and acetylcholinesterase inhibitors (AChEIs) has shown improved outcomes in patients with Alzheimer's disease (AD). However, it is not clear which AChEI is the optimal for the combined treatment with memantine. METHODS: A total of 110 AD patients were randomized to receive memantine and one of the following add-on drugs: placebo, donepezil, rivastigmine, galantamine, and huperzine A for 24 weeks (n=22). At baseline, 12 weeks, and 24 weeks, the patients were evaluated using mini-mental state examination (MMSE) and Alzheimer Disease Cooperative Study-Activities of Daily Living (ADCS-ADL) scales. Adverse events were recorded to analyze the safety profile. RESULTS: The MMSE scores were significantly increased and the ADL scores were significantly decreased at 12 weeks and 24 weeks in all five groups compared with baseline (all P<0.01). At 24 weeks, patients treated with memantine+huperzine A showed better MMSE and ADL scores than those treated with memantine+placebo. CONCLUSIONS: Huperzine A may be an optimal choice for the combined therapy with memantine in treating AD. PMID- 25932261 TI - Effect of Tai Chi exercise in combination with auricular plaster on patients with lumbar muscle strain. AB - OBJECTIVE: observe the effect of Tai Chi exercise on the patients with the chronic lumbar muscle strain under the intervention treatment of auricular plaster. METHODS: 74 middle-aged and elderly patients, suffering from the chronic lumbar muscle strain, are randomly and equally divided into an observation group and a control group, with 37 patients in each group. The patients in the control group do Tai Chi exercise, while those in the observation group are treated by the auricular plaster therapy in addition to Tai Chi exercise. Evaluate and compare the disease conditions of the patients in the two groups before the treatment and after 12 weeks' treatment. RESULTS: after 12 weeks' treatment, the patients in the two groups have been improved differently in comparison with those before the treatment (P < 0.05). However, the cure rate, the excellence rate and total effective rate of the observation group are superior to those of the control group, respectively P < 0.05 or P < 0.01, thus their difference shows statistic significance. CONCLUSION: after 12 weeks' Tai Chi exercise, it exercises an obvious curative effect on the patients with lumbar muscle strain but the curative effect is more remarkable if it is combined with auricular plaster therapy. PMID- 25932262 TI - Effects of SIBO and rifaximin therapy on MHE caused by hepatic cirrhosis. AB - AIM: To determine the effects of small-intestinal bacterial overgrowth (SIBO) and rifaximin therapy on minimal hepatic encephalopathy (MHE) with liver cirrhosis. METHODS: A total of 60 patients with cirrhosis were included in this study. Patients were evaluated by three neuropsychometric tests including number connection-A (NCT-A), number connection-BC (NCT-BC) and digit symbol test (DST) to diagnose the MHE. Glucose breath testing was used to determine the presence of SIBO. Patients with MHE were then treated with 200 mg of rifaximin orally three times a day for a week. Glucose breath testing and psychometric tests were repeated upon 4 weeks after antibiotic completion. Blood ammonia levels were also monitored before and after rifaximin treatment. RESULTS: Of the 60 patients enrolled, 26 were diagnosed with MHE. The mean blood ammonium level in MHE group was 48.7 +/- 8.8 MUmol/L, while in non-MHE it was 34.9 +/- 7.5 MUmol/L, demonstrating an increase (t = 6.55, P < 0.05). One third of patients had an abnormal glucose hydrogen breath test, indicating the presence of SIBO. Abnormal breath test results were present in 3 of the 34 patients (8%) without MHE, 17 of the 26 patients (65.4%) with MHE. One week after rifaximin antibiotic therapy, the number of the MHE patients reduced from 26 to 11. Among 17 MHE patients with SIBO, 13 became SIBO negative. Blood ammonium level in MHE patients with SIBO decreased from 51.6 +/- 5.4 MUmol/L to 39.1 +/- 7.6 MUmol/L (P < 0.01), while in MHE patients without SIBO decreased from 45.3 +/- 9.8 MUmol/L to 36.9 +/- 8.8 MUmol/L (P < 0.01). Higher reduction was observed in SIBO group. All three psychometric test results showed significant (P < 0.01) improvement after rifaximin treatment. CONCLUSIONS: SIBO is prevalent in MHE patients with liver cirrhosis, and short-term treatment with rifaximin can effectively reduce blood ammonia level and improve psychometric test. PMID- 25932263 TI - Distal fallopian tube recanalization using ozone treatment: a clinical study in two hundred tubal obstruction Chinese patients. AB - A major cause of female infertility is fallopian tube obstruction and traditional conservative and interventional treatments have been largely unsuccessful, especially in patients with distal tubal obstruction. The objective of the current study was to compare the curative outcome of ozone (treatment group) and conventional interventional treatment (comparison group) through comparing the different effects in the infertility cases caused by fallopian tube obstruction, with the purpose to provide future reference for better treatment regimen for tubal obstruction. 400 infertile cases caused by tubal obstruction admitted in the Second Affiliated Hospital of Shaanxi University of Chinese Medicine from August 2006 to January 2012 were enrolled in this study and received either ozone or conventional interventional treatment. No difference was observed between post operative proximal tube recanalization rates in the two groups; however, post operative distal tube recanalization rate and recanalization rate after 6 months were significantly higher in the treatment group. Importantly, the adhesion and conception rates were significantly lower and higher, respectively, in the treatment group compared to the comparison group after six months. Hence, ozone therapy can potentially become a viable treatment modality for far-end tubal obstruction patients. PMID- 25932264 TI - Association of ACE polymorphism and diabetic nephropathy susceptibility. AB - AIM: The study was aimed to analyze whether ACE rs267604983 polymorphism was related to the onset of diabetic nephropathy (DN). METHODS: 80 DN patients and 78 healthy controls were enrolled in the study. The differences of age, sex, body mass index (BMI), systolic blood pressure (SBP) and diastolic blood pressure (DBP) between two groups were analyzed. The genotyping of ACE rs267604983 was conducted by the technology of PCR-HRM. Odds ratio (ORs) with 95% CI were used to evaluate the relationship of ACE rs267604983 with DN susceptibility. RESULTS: The AA genotype of ACE rs267604983 was remarkably associated with the risk for DN (OR = 2.90, 95% CI = 1.12-7.51). In addition, for the A allele carriers, the risk for DN increased 1.87 fold (OR = 1.87, 95% CI = 1.16-3.01). The subgroup analysis showed that the AA genotype was found higher in normal albuminuria group than other groups (P = 0.006), while AG genotype was higher in macro albuminuria group (P = 0.036). CONCLUSION: ACE rs267604983 polymorphism is associated with the risk of DN. AA genotype and A allele may increase the risk for DN. Furthermore, AA and AG genotypes may have effects on the subgroups of DN. PMID- 25932265 TI - Multicentric Castleman's disease with renal amyloidosis and mesangial proliferative glomerulonephritis: a case report. AB - Renal involvement is a significant complication of multicentric Castleman's disease (MCD) and various glomerular involvements have been reported. A 56-year old Chinese woman presented with proteinuria and skin rash, with lymphadenopathy and hypergammaglobulinemia. Lymph nodes and skin biopsy proven the case was multicentric CD with plasma cell pathological pattern. The renal biopsy was performed and six glomeruli were observed and two of these showed global sclerosis. Moderate increasing of mesangial matrix with mesangial cell proliferation were seen in every glomerulus. In addition, one-segmental sclerosis accompanied by adhesion of the Bowman's capsule was revealed. Two of the glomeruli had crescents formation. Under immunofluorescence microscopy, immunofluorescence for anti-IgA, IgM, C3, C1q and FRA showed coarse and fine granular depositions along capillary walls and sparsely in the mesangium. Staining for anti-IgG was negative. Under electron microscopy revealed indiscriminate amyloidal deposits in glomerular basement membrane. The foot process of glomerular podocytes was fusion. Moderate increasing of mesangial matrix and mesangial cell proliferation were found. Subsequently, she was successfully treated with prednisone combined with cyclophosphamide therapy not only for proteinuria but also for renal function. PMID- 25932266 TI - Sympathetic ophthalmia caused by a severe ocular chemical burn: a case report and literature review. AB - We herein presented a case of sympathetic ophthalmia induced by chemical burns. A 39-year-old male was referred to our retinal clinic complaining of sharply decreased vision in his right eye, with photophobia and headache. He had suffered severe chemical burns five months ago, and his left eye underwent amniotic membrane transplantation combined with tarsorrhaphy for persistent corneal ulceration. A comprehensive examination was performed. After excluding other infectious ocular diseases and systemic inflammatory disease, Vogt-Koyanagi Harada was considered. A regimen of 1.5 mg/kg prednisone per day was initiated, and tapered to a weekly dose. The inflammation in the patient's right eye was improved, and the best-corrected visual acuity recovered to 20/50. He continued to be seen by his corneal specialist for follow-up on the left eye. A regular B scan was performed, and atrophy of the left eyeball was detected 2 months later. Upon removal of the left eyelid sutures, corneal perforation with a prolapsed iris was found. Afterwards, the inflammation of the right eye reoccurred, and the diagnosis was revised to sympathetic ophthalmia. The patient underwent an enucleation procedure on the left eye, and a massive prednisolone regimen was initiated, and then tapered slowly over one year. Pathological results showed diffuse epithelioid cells, polymorphonuclear giant cells, and lymphocyte infiltration in the uveal tissue. Sympathetic ophthalmia was confirmed. The right eye remained unremarkable at 41 months of follow-up. An uncommon case is presented of sympathetic ophthalmia following severe chemical burns. It is notable that sympathetic ophthalmia developed after chemical burns to the ocular surface and corneal perforation, despite reconstructive treatment combined with tarsorrhaphy. PMID- 25932267 TI - Squamous cell carcinoma of the middle ear: report of three cases. AB - Squamous cell carcinoma of the middle ear (SCCME) accounts for 1.5% of malignant tumors in the ear. Because of the low incidence and infrequent reports of SCCME, the extent of concordance between CT and MRI results, surgical findings, and pathology reports are not well-characterized. In the present study, we reported CT and MRI images in three SCCME cases, and assessed the relationship between these results and those of surgery and the pathological report. Middle ear carcinoma is frequently misdiagnosed before surgery. In three cases of middle ear carcinoma, CT revealed the following: 1) soft tissue density lesions centered around the middle tympanum, exhibiting increased density, with external auditory canal involvement; 2) damage and absorption in the mastoid area, ossicles, and facial nerve canal, characterized by an irregular, worm-eaten appearance, without sclerotic margins; and 3) lesion infiltration of the surrounding bony substance of the middle ear, temporal squama, temporomandibular joint, anterior wall of the sigmoid sinus, and horizontal segment of the canalis caroticus (in one case lesion invasion into the intracranial cavity occurred through sigmoid sinus walls; no signs of intracranial invasion were seen in the other two cases). Enhanced lesion imaging revealed partial heterogeneous enhancement. In one patient MRI revealed a defined mass in the mastoid area of the middle ear. Signals in the lesion were partially heterogeneous and similar to brain tissue in T1- and T2-weighted images. The lesion was significantly enhanced following application of a contrast agent, while the adjacent meninges also exhibited linear enhancement. No abnormal signals were detected in the brain parenchyma. The destruction of adjacent bone plates was poorly defined. The CT and MRI results were consistent with the invasive features of middle ear cancer documented in the post-surgery pathology report. PMID- 25932268 TI - Cystic echinococcosis accompanied by hepatocellular carcinoma in a female herdsman. AB - Human cystic echinococcosis is a zoonosis caused by the larval cestode Echinococcus granulosus. Hepatocellular carcinoma is one of the most common types of cancer in the whole world including China. A few reports about cystic echinococcosis concurrent with hepatocellular carcinoma were noted until now. In addition, the association between these two diseases is still not well defined as the case with cystic echinococcosis with hepatocellular carcinoma is rare. In this case report, we presented a female herdsman living in Xinjiang Uyghur Autonomous region, China, which may raise the possibility that echinococcosis may play a role in the development of hepatocellular carcinoma. PMID- 25932269 TI - Osteochondroma of bilateral mandibular condyle: a case report. AB - Osteochondroma represents the largest group of benign tumors of bone, which usually develops in long bones and relatively uncommon in the craniofacial region. The condyle and coronoid tip are the most common sites of occurrence in the mandible, but both sides of condyle involved has never been reported. Here, we describe a case of osteochondroma arising from the bilateral mandibular condyle. PMID- 25932270 TI - Placental site trophoblastic tumor presented with vaginal metastasis. AB - Placental site trophoblastic tumor (PSTT) is a rare type of gestational trophoblastic neoplasia (GTN). It is rising from the abnormal proliferation of intermediate trophoblastic cells with occasional multinuclear giant cells, with the potential for local invasion and metastasis. For its untypical and changeable clinical characteristics, the diagnosis and management are still poorly understood. Here we documented a case of PSTT with vaginal lesion as her unique presentation. After surgery and adjuvant chemotherapy, the patient was cured. PMID- 25932271 TI - Lateral wedging of the cemented vertebra after balloon kyphoplasty: a case report. AB - Balloon kyphoplasty has been shown to be safe in treatment of vertebral compression fractures refractory to conservative management. However, few reports have focused on lateral wedging of cemented vertebra after kyphoplasty. A 72-year old woman with a T12 osteoporotic compression fracture underwent kyphoplasty using polymethylmethacrylate (PMMA) via a bipedicular approach. The patient felt pain free, whereas she did not receive anti-osteoporosis treatment after the surgery. The abnormal spatial distribution of PMMA cement within the T12 vertebral body and cement leakage right lateral to the vertebral body was observed in postoperative radiographs. Twelve months later, lateral wedging of the cemented vertebra was detected in plain radiographs. In the kyphoplasty procedure, symmetric cement filling should be achieved to avoid lateral wedging of the cemented vertebra. Postoperative anti-osteoporotic medication treatment is also very important. PMID- 25932272 TI - Massive hemoperitoneum following spontaneous rupture of an arterial aneurysm overlying a uterine myoma. AB - Intraperitoneal hemorrhage caused by a uterine myoma is rare. A 54-year-old woman was admitted to the emergency room; on admission, she was in cardiopulmonary arrest with pulseless electrical activity. Transabdominal ultrasonography revealed hyperechoic fluid filled almost the entire abdominal cavity. On contrast enhanced computed tomography, extravasation of contrast material was observed inside the fluid, although the bleeding site was not identifiable. An emergency operation was performed to stabilize the patient. There was pulsating bleeding from a subserosal myoma on the posterior wall of the uterus; the myoma measured approximately 6 cm in maximum diameter. After resection of the myoma, the bleeding stopped. Pathological assessment of the resected specimen revealed a ruptured arterial aneurysm, approximately 8 mm in diameter, situated on the surface of a leiomyoma without degeneration. Spontaneous rupture of a vein or an artery overlying a myoma has been documented in the English literature, though it is extremely rare. Rupture of a vein is a more frequent occurrence than the rupture of an artery. This is the first reported case documenting a ruptured arterial aneurysm overlying a myoma. PMID- 25932273 TI - Atypical, multilevel and noncontiguous tuberculous spondylitis that affected the vertebrae of thoracic, lumbar and sacrum: a case report. AB - AIM: Tuberculous spondylitis (TS, also called Spinal tuberculosis, Pott's spine or Pott's disease) is a common extrapulmonary manifestation of tuberculosis (TB), but multilevel, noncontiguous TS cases are rare. METHODS: Physical examination, CT, MRI imaging, percutaneous biopsy and other lab tests were used to confirm the diagnosis. RESULT: we report a rare case of atypical, multilevel and noncontiguous TS in a 50-year-old woman. We found four noncontiguous osteolytic lesions in her spine that affected the Intervertebral joints of T10/11, L1/2, L3/4 and L5/S1. Patient was then treated conservatively with anti-TB drugs and was followed-up for about 1 year. The treatment turned out to be successful. CONCLUSION: The conservative anti-TB treatment was enough at least for this particular patient. PMID- 25932274 TI - The diagnosis of gallbladder agenesis: two cases report. AB - Congenital absence of the gallbladder is an extremely rare embryological aberration that is frequently mistaken for cholecystolithiasis; the aim of this study is to investigate the diagnostic methods for agenesis of the gallbladder. Two surgically confirmed gallbladder agenesis cases in our hospital and 75 cases of gallbladder agenesis reported in the literature in China were reviewed. It is extremely difficult to make a correct diagnosis of gallbladder agenesis before operation. When suspected, it may be confirmed by ERCP and MRCP. Interoperate, if no gallbladder can be found during laparoscopy, open surgery should be immediately performed Clinician's understanding of this disease is of great help in avoiding unnecessary surgical exploration and minimizing the risk of complication. Patients with gallbladder agenesis can be classified into two new types, I: Symptomatic, II: Asymptomatic. Type I can be divided into two subtypes: I a with fatal malformations and I b without fatal malformations. PMID- 25932275 TI - High-grade invasive urothelial carcinoma of the ureter with systematic lymph node metastasis successfully treated by nephroureterectomy followed by chemotherapy. AB - We report a case of high-grade invasive urothelial carcinoma with squamous differentiation of the urinary tract. A 72-year-old woman was referred to our hospital because of asymptomatic gross hematuria. A right-sided laparoscopic radical nephroureterectomy with bladder cuff removal and right-sided pelvic lymphadenectomy were performed at our institution. Postoperative pathological examination showed high-grade urothelial carcinoma with squamous differentiation. Five months later, CT scan of the neck diagnosed it as lymph nodes metastasis. Following the laparoscopic radical nephroureterectomy, chemotherapy with gemcitabine and cisplatin or nedaplatin was carried out. After several cycles' chemotherapy, nearly all the enlarged lymph node disappeared. Seven years and five years passed, urothelial carcinoma has not recurred after the surgery and all the lymph node disappeared respectively. PMID- 25932276 TI - Unexpected cause of a right hemiplegia secondary to the painless full-length aortic dissection: a case report and literature review. AB - Painless aortic dissections in general are uncommon and are frequently misdiagnosed. Here we reported a rare case of acute ischemic stroke secondary to completely painless acute full-length dissection (DeBakey I) and provide a brief review of the literature. A 56-year-old man was referred to our department with right hemiplegia. Ischaemic stroke and thrombolytic treatment were considered initially. At the second examination, the patient was found to have decreased blood pressure, asymmetrical blood pressure/pulses between the bilateral limbs, and sudden loss of pulse in a lower extremity. Laboratory results revealed leucocytosis, elevated creatinine and CK without obvious cause. An aortic dissection was subsequently confirmed by contrast enhanced thoracic and abdominal CT scan. Our report provides some clues for the early diagnosis of painless aortic dissections. PMID- 25932277 TI - Successful treatment of a case of acute myeloid leukemia following Langerhans cell histiocytosis in an adolescent: a case report and review of the literature. AB - Langerhans cell histiocytosis (LCH) is a rare histiocytic disorder of unknown etiopathogenesis. Its clinical presentation is variable and ranges from isolated skin or bone disease to a life-threatening multisystem condition. LCH can occur at any age but is more frequent in the pediatric population. The diagnosis depends on clinical, histopathological and radiographic examination and should be confirmed by immunohistochemical study with CD1a, S100 protein and langerin, three markers used widely for identifying Langerhans cells. Herein, we report an adolescent with acute myeloid leukemia (AML-M2) who was treated just with surgical management alone for LCH. As far as we know, this is the first case that the LCH patient without chemotherapy evolved into AML and was successfully cured. Cooperative studies of large numbers of LCH patients are needed to evaluate a possible association between LCH and acute leukemia, and to identify common risk factors or predisposing agents if such be present. The previously reported cases of LCH concomitant with other hematological disorders are also summarized and described compared with the present case. PMID- 25932278 TI - Treatment of hematuria caused by renal arteriovenous malformation in pregnant patients. AB - This study is to investigate hematuria in pregnant patients caused by renal arteriovenous malformation and to evaluate the efficacy of superselective renal angiography and embolization used for treatment of renal arteriovenous malformation. Two cases of hematuria in pregnant patients caused by renal arteriovenous malformation were enrolled. Case 1 was a 28-year-old woman with repeatedly intermittent hematuria at week 7 during gestation. Case 2 was a 30 year-old woman with repeatedly intermittent hematuria at week 8 during gestation. B ultrasound and CT were performed to detect hydronephrosis. Renal arteriovenous malformation was diagnosed by selective angiography. Both the patients were treated with embolization. The 2 cases were successfully embolized with different materials including gelfoam and coils. Both of the 2 patients were recovered well and discharged successful after the operation. In conclusion, superselective renal angiography and embolization are effective methods for diagnosis and treatment of renal arteriovenous malformation in pregnant patients. PMID- 25932279 TI - Intravascular heat exchange technology successfully treats a patient after ultra long cardiopulmonary resuscitation: a case report. AB - OBJECTIVE: To investigate the effect of intravascular heat exchange in saving the lives of patients after cardiopulmonary resuscitation. METHODS: The clinical data of a female patient who was given cardiopulmonary resuscitation for 1.67 h in July 2014 in our hospital was retrospectively analyzed. An intravascular heat exchange procedure was performed on the patient to control her body temperature. Comprehensive treatment measures also included mechanical ventilation, vasoactive agents, and osmotic dehydrating agents to reduce the elevated intracranial pressure, improving cerebral metabolism and anti-infective therapy. RESULTS: After providing an intravascular heat exchange for 6 h, the patient's eyes automatically opened but the patient was unconscious. After 28 h, the patient became conscious. The breathing machine was withdrawn after 2 d and the vasoactive agents were stopped after 5 d. The patient was discharged after 17 d. CONCLUSION: Intravascular heat exchange could be an important complementary treatment to cardiopulmonary resuscitation. PMID- 25932280 TI - The expression and clinical significance of serum miR-205 for breast cancer and its role in detection of human cancers. AB - OBJECTIVE: Our study aims to measure the expression level of serum microRNA-205 (miRNA-205, miR-205) in breast cancer, and evaluate the diagnostic value of miR 205 as a noninvasive biomarker for the early detection of breast cancer and other human cancers through a meta-analysis. METHODS: In the first phase, an experiment based on 58 breast cancer patients and 93 healthy controls was carried out to figure out the diagnostic performance of serum miR-205 for breast cancer. The study was conducted by using Reverse Transcription and quantitative Real-time polymerase Cycle Reaction (RT-qPCR). In the second phase, a meta-analysis was performed to evaluate the diagnostic value of miR-205 for various cancers. RESULTS: The test showed that the normalized expression levels of miR-205 in serum were evidently higher in healthy control than in breast cancer with a sensitivity and specificity at the optimal cutoff of 86.2% and 82.8%, respectively. The meta-analysis received a sensitivity of 75% and a specificity of 84%, and an AUC of 0.87. CONCLUSION: Our study determined that as a noninvasive and accessible biomarker, miR-205 not only has high clinical diagnostic value in the detection of breast cancer, but also plays an important role in clinical utilization of diagnosing various cancers. Further researches based on larger-scale subjects and additional improvement should be carried out to confirm our results. PMID- 25932281 TI - Macrophage functional phenotype can be consecutively and reversibly shifted to adapt to microenvironmental changes. AB - Macrophages are functionally plastic cells, and have developed distinct functional subsets in associa-tion with cancer, autoimmune disease, and chronic infections. As an alternative to the concept of subset development, we hypothesized that macrophages, in response to changes in their tissue environment, can reversibly and progressively change the pattern of functions that they express. We examined the reversible and progressive shift of functional phenotypes of macrophages in response to changes in their tissue environment. As demonstrated herein, macrophages can reversibly shift their functional patterns in response to sequential changes in cytokine environment. After treatment alone or alternative with IL-4, MFCS, IL-12, INF-gamma or LPS, the cells showed various functional patterns. A progression through multiple functional phenotypes was displayed after sequential treatment of macrophages with multiple cytokines. This ability to adapt to changing cytokine microenvironments has significant relevance in vivo, as evidenced by the fact that developed macrophage functional phenotypes in vivo in aged mice or forestomach carcinoma (MFC) tumor-bearing mice can be shifted by modifying their microenvironment. Therefore, a concept of shifted macrophage functional phenotypes has important implications for therapeutic targeting of macrophages in chronic diseases. The dominance of particular functional phenotypes of macrophages in chronic diseases may play an important role in pathogenesis. PMID- 25932282 TI - Effects of tea polyphenols on proliferation and apoptosis of cadmium-transformed cells. AB - To investigate the roles and mechanism(s) of epigallocatechin gallate (EGCG) in carcinogenesis in malignant transformed cell line, cadmium-induced malignant transformed cells were treated with different doses of EGCG. Then cell proliferation, cell apoptosis, hTERT mRNA and protein level, and c-Myc protein levels were measured at different time points. EGCG was found to inhibit cell proliferation in a dose-dependent manner. Cell cycle was changed in the transformed cells after EGCG treatment with significantly increased cell numbers in G0/G1 phase and decreased cell numbers in S phase compared to control group, P < 0.001. EGCG was also found to promote cell apoptosis with a time-dependent manner. Both mRNA and protein levels of hTERT gene were significantly decreased in cells after treated with EGCG, P < 0.001. c-Myc protein level was significantly decreased after EGCG treatment, especially in the highest dose group (i.e. 200 MUg/ml). The decrease in c-Myc protein level was accompanied by the reduction of hTERT protein levels. EGCG can inhibit cell proliferation and promote apoptosis in malignant cadmium-transformed cell line. The mechanism may be its ability to reduce c-Myc gene expression and consequently inhibits hTERT gene expression, which in turn decrease the telomerase activity. PMID- 25932283 TI - Integrin beta-8 (ITGB8) silencing reverses gefitinib resistance of human hepatic cancer HepG2/G cell line. AB - Hepatic cancer is a class of cancer that is relatively insensitive to chemotherapy, and cancers that harbor EGFR active mutations are more sensitive to EGFR-TK inhibitor such as gefitinib, which becomes the first-line treatment of this subtype of cancer. However, almost all patients treated with gefitinib will develop drug resistance. Here we show that a protein called integrin beta-8 (ITGB8) when over-expressed, is correlated with the gefitinib resistance of hepatic cancer cell line HepG2/G. After ITGB8 silencing, the drug resistance is reversed as the cell proliferation decreases and apoptosis rate increases significantly by gefitinib treatment when compared to HepG2/G. We demonstrated that multi-drug resistant proteins ABCB1, ABCC2 and ABCG2, anti-apoptosis proteins like survivin and Bcl-2, and cycle promoting protein CDK1 are involved in drug resistance of HepG2/G. Other drug-resistance relative proteins like SOD, GST, TS and HIF-1 are also modulated by ITGB8 silencing, but their role in this gefitinib resistance might be indirect. TGF beta pathway could be a critical pathway by which ITGB8 modulates the sensitivity of HepG2/G to gefitinib. PMID- 25932284 TI - Phase II multi-center clinical study on using S-1 to treat advanced breast cancer after resistance to anthracycline and taxane drugs in Chinese patients. AB - BACKGROUND: Treatment for metastatic breast cancer (MBC) in patients who have relapsed from anthracycline and taxane is difficult. S-1, an oral 5-FU derivative, has demonstrated a potential antitumor effect in patients with MBC. Thus, we evaluated the efficacy and safety of S-1 as second-line chemotherapy MBC patients in a phase II trial. METHODS: The study was conducted at seven centers in China and enrolled MBC patients who had previously relapsed from one chemotherapy regimen. The median progression-free survival (PFS) was the primary end point. The treatment schedule involved the administration of S-1 at a standard dose based on the body surface area (BSA) in 28-day cycles with consecutive administration followed by a 14-day rest, as follows: 40 mg twice daily if BSA < 1.25 m(2); 50 mg twice daily if 1.25 m(2) <= BSA >= 1.5 m(2); and 60 mg twice daily if BSA > 1.5 m(2). RESULTS: Thirty-three patients were included in the analysis. S-1 demonstrated moderate efficacy with a PFS of 3.3 months, a response rate of 33.3%, and a disease control rate of 72.7%. The treatment was well-tolerated with mild-to-moderate toxicity. Grade 3 adverse events (AEs) occurred in 4 patients (2 with hyperbilirubinemia, 1 with anorexia, and 1 with vomiting). Grade 4 AEs were not observed. CONCLUSION: S-1 demonstrated encouraging efficacy and safety in a prospective trial as second-line treatment in MBC patients. All AEs were manageable; however, bilirubin monitoring is recommended during treatment. PMID- 25932285 TI - Building capacity for dementia care in Latin America and the Caribbean. AB - Latin America and the Caribbean (LAC) have limited facilities and professionals trained to diagnose, treat, and support people with dementia and other forms of cognitive impairment. The situation for people with dementia is poor, and worsening as the proportion of elderly in the general population is rapidly expanding. We reviewed existing initiatives and provided examples of actions taken to build capacity and improve the effectiveness of individuals, organizations, and national systems that provide treatment and support for people with dementia and their caregivers. Regional barriers to capacity building and the importance of public engagement are highlighted. Existing programs need to disseminate their objectives, accomplishments, limitations, and overall lessons learned in order to gain greater recognition of the need for capacity-building programs. PMID- 25932286 TI - Three dimensional time-gated tracking of non-blinking quantum dots in live cells. AB - Single particle tracking has provided a wealth of information about biophysical processes such as motor protein transport and diffusion in cell membranes. However, motion out of the plane of the microscope or blinking of the fluorescent probe used as a label generally limits observation times to several seconds. Here, we overcome these limitations by using novel non-blinking quantum dots as probes and employing a custom 3D tracking microscope to actively follow motion in three dimensions (3D) in live cells. Signal-to-noise is improved in the cellular milieu through the use of pulsed excitation and time-gated detection. PMID- 25932288 TI - Pullout strength after expandable polymethylmethacrylate transpedicular screw augmentation for pedicle screw loosening. AB - OBJECTIVE: Pedicle screw fixation for spine arthrodesis is a useful procedure for the treatment of spinal disorders. However, instrument failure often occurs, and pedicle screw loosening is the initial step of a range of complications. The authors recently used a modified transpedicular polymethylmethacrylate (PMMA) screw augmentation technique to overcome pedicle screw loosening. Here, they report on the laboratory testing of pedicle screws inserted using this modified technique. METHODS: To evaluate pullout strengths three cadaveric spinal columns were used. Three pedicle screw insertion methods were utilized to compare pullout strength; the three methods used were; control (C), traditional transpedicular PMMA augmentation technique (T), and the modified transpedicular augmentation technique (M). After control screws had been pulled out, loosening with instrument was made. Screw augmentations were executed and screw pullout strength was rechecked. RESULTS: Pedicle screws augmented using the modified technique for pedicle screw loosening had higher pullout strengths than the control (1106.2+/ 458.0 N vs. 741.2+/-269.5 N; p=0.001). Traditional transpedicular augmentation achieved a mean pullout strength similar to that of the control group (657.5+/ 172.3 N vs. 724.5+/-234.4 N; p=0.537). The modified technique had higher strength than the traditional PMMA augmentation technique (1070.8+/-358.6 N vs. 652.2+/ 185.5 N; p=0.023). CONCLUSION: The modified PMMA transpedicular screw augmentation technique is a straightforward, effective surgical procedure for treating pedicle screw loosening, and exhibits greater pullout strength than traditional PMMA transpedicular augmentation. However, long-term clinical evaluation is required. PMID- 25932287 TI - Epithelial Mesenchymal Transition: a double-edged sword. AB - Epithelial mesenchymal transition (EMT) is a physiological process necessary to normal embryologic development. However in genesis of pathological situations, this transition can be perverted and signaling pathways have different regulations from those of normal physiology. In cancer invasion, such a mechanism leads to generation of circulating tumor cells. Epithelial cancer cells become motile mesenchymal cells able to shed from the primary tumor and enter in the blood circulation. This is the major part of the invasive way of cancer. EMT is also implicated in chronic diseases like fibrosis and particularly renal fibrosis. In adult organisms, healing is based on EMT which is beneficial to repair wounds even if it can sometimes exceed its goal and elicit fibrosis. In this review, we delineate the clinical significance of EMT in both physiological and pathological circumstances. PMID- 25932289 TI - Correlation of the Beta-trace protein and inflammatory cytokines with magnetic resonance imaging in chronic subdural hematomas : a prospective study. AB - OBJECTIVE: Magnetic resonance imaging (MRI) of chronic subdural hematoma (CSDH) detects various patterns, which can be attributed to many factors. The purpose of this study was to measure the level of interleukin-6 (IL-6), interleukin-8 (IL 8), and highly specific protein [beta-trace protein (betaTP)] for cerebrospinal fluid (CSF) in CSDHs, and correlate the levels of these markers with the MRI findings. METHODS: Thirty one patients, treated surgically for CSDH, were divided on the basis of MRI findings into hyperintense and non-hyperintense groups. The concentrations of IL-6, IL-8, and betaTP in the subdural fluid and serum were measured. The betaTP was considered to indicate an admixture of CSF to the subdural fluid if betaTP in the subdural fluid (betaTPSF)/betaTP in the serum (betaTPSER)>2. RESULTS: The mean concentrations of IL-6 and IL-8 of the hyperintense group (n=17) of T1-WI MRI were 3975.1+/-1040.8 pg/mL and 6873.2+/ 6365.4 pg/mL, whereas them of the non-hyperintense group (n=14) were 2173.5+/ 1042.1 pg/mL and 2851.2+/-6267.5 pg/mL (p<0.001 and p=0.004). The mean concentrations of betaTPSF and the ratio of betaTPSF/betaTPSER of the hyperintense group (n=13) of T2-WI MRI were 7.3+/-2.9 mg/L and 12.6+/-5.4, whereas them of the non-hyperintense group (n=18) were 4.3+/-2.3 mg/L and 7.5+/ 3.9 (p=0.011 and p=0.011). CONCLUSION: The hyperintense group on T1-WI MRI of CSDHs exhibited higher concentrations of IL-6 and IL-8 than non-hyperintense group. And, the hyperintese group on T2-WI MRI exhibited higher concentrations of betaTPSF and the ratio of betaTPSF/betaTPSER than non-hyperintense group. These findings appear to be associated with rebleeding and CSF admixture in the CSDHs. PMID- 25932291 TI - Angiographic results of wide-necked intracranial aneurysms treated with coil embolization : a single center experience. AB - OBJECTIVE: Endovascular treatment of wide-necked intracranial aneurysms is a challenge and the durability and the safety of these treated aneurysms remain unknown. The aim of this study was to evaluate the clinical and long-term angiographic results of wide-necked intracranial aneurysms treated with coil embolization. METHODS: Between January 2002 and December 2012, 53 wide-necked aneurysms treated with coil embolization were selected. Forty were female, and 13 were male. Twenty eight (52.8%) were ruptured aneurysms, and 25 (47.2%) were unruptured aneurysms. The patents' medical and radiological records were reviewed retrospectively. RESULTS: Of the 53 aneurysms, coiling alone was employed in 45 (84.9%) and stent-assisted coiling was done in 8 (15.1%). The initial angiographic results revealed Raymond class 1 (complete occlusion) in 30 (56.6%) cases, Raymond class 2 (residual neck) in 18 (34.0%) cases, and Raymond class 3 (residual sac) in 5 (9.4%) cases. The mean angiographic follow-up period was 37.9 months (12-120 months). At the last angiographies, Raymond class 1 was seen in 26 (49.1%) cases, Raymond class 2 in 16 (30.2%), and Raymond class 3 in 11 (20.8%). Angiographic recurrence occurred in 22 (41.5%) patients, with minor recurrence in 7 (13.2%) cases and major recurrence in 15 (28.3%). Retreatment was performed in 8 cases (15.1%). A suboptimal result on the initial angiography was a significant predictor of recurrence in this study (p=0.03). CONCLUSION: The predictor of recurrence in wide-necked aneurysms is a suboptimal result on the initial angiography. Long-term angiographic follow-up is recommended in wide-necked aneurysms. PMID- 25932290 TI - Analyses Using Micro-CT Scans and Tissue Staining on New Bone Formation and Bone Fusion According to the Timing of Cranioplasty via Frozen Autologous Bone Flaps in Rabbits : A Preliminary Report. AB - OBJECTIVE: The timing of cranioplasty and method of bone flap storage are known risk factors of non-union and resorption of bone flaps. In this animal experimental study, we evaluated the efficacy of cranioplasty using frozen autologous bone flap, and examined whether the timing of cranioplasty after craniectomy affects bone fusion and new bone formation. METHODS: Total 8 rabbits (male, older than 16 weeks) were divided into two groups of early cranioplasty group (EG, 4 rabbits) and delayed cranioplasty group (DG, 4 rabbits). The rabbits of each group were performed cranioplasty via frozen autologous bone flaps 4 weeks (EG) and 8 weeks (DG) after craniectomy. In order to obtain control data, the cranioplasty immediate after craniectomy were made on the contralateral cranial bone of the rabbits (control group, CG).The bone fusion and new bone formation were evaluated by micro-CT scan and histological examination 8 weeks after cranioplasty on both groups. RESULTS: In the micro-CT scans, the mean values of the volume and the surface of new bone were 50.13+/-7.18 mm(3) and 706.23+/-77.26 mm(2) in EG, 53.78+/-10.86 mm(3) and 726.60+/-170.99 mm(2) in DG, and 31.51+/-12.84 mm(3) and 436.65+/-132.24 mm(2) in CG. In the statistical results, significant differences were shown between EG and CG and between DG and CG (volume : p=0.028 and surface : p=0.008). The histological results confirmed new bone formation in all rabbits. CONCLUSION: We observed new bone formation on all the frozen autologous bone flaps that was stored within 8 weeks. The timing of cranioplasty may showed no difference of degree of new bone formation. Not only the healing period after cranioplasty but the time interval from craniectomy to cranioplasty could affect the new bone formation. PMID- 25932292 TI - Intracranial meningioma with leptomeningeal dissemination : retrospective study with review of the literature. AB - OBJECTIVE: The purposes of this article are to present 5 cases of intracranial meningioma with leptomeningeal dissemination (LD) and investigate the characteristics of this disease. METHODS: We present a retrospective case series of 5 females at our institutions (age ranged 21-72 years, mean 54.6 years) diagnosed with LD of an intracranial meningioma after surgery between 1998 and 2013. A database search revealed 45 cases with LD of meningioma in the English literature. Characteristic features were analyzed and compared. RESULTS: The incidence rate at our institutions of LD of meningioma was 0.9% (5/534). World Health Organization (WHO) grade was distributed as follows: I : 2, II : 2, and III : 1. Time to LD ranged from 2.5 months to 6.9 years; the patient with WHO grade III had the shortest interval to LD. The patient with an intraventricular meningioma (WHO grade II) had the second shortest interval to LD (1.7 years), and simultaneously revealed both LD and extraneuronal metastases. Four of 5 patients showed a disease progression, with the survival ranging from 1 month to 3.8 years after LD. Based on the literature, the initial tumor was an intraventricular meningioma in 9 patients, and their time to LD was shorter on average (mean 1.9 years). Histologically, 26 of 45 (58%) were initially diagnosed with a WHO grade II or III meningioma, and 6 of 19 patients (32%) with WHO grade I revealed malignant transformation. CONCLUSION: This study shows that intraventricular location and histologically aggressive features seem to increase the chance of LD of meningioma. PMID- 25932293 TI - Independent predictors for recurrence of chronic subdural hematoma. PMID- 25932294 TI - Incidence and risk factors of chronic subdural hematoma after surgical clipping for unruptured anterior circulation aneurysms. AB - OBJECTIVE: Chronic subdural hematoma (CSDH) is a rare complication of unruptured aneurysm clipping surgery. The purpose of this study was to identify the incidence and risk factors of postoperative CSDH after surgical clipping for unruptured anterior circulation aneurysms. METHODS: This retrospective study included 518 patients from a single tertiary institute from January 2008 to December 2013. CSDH was defined as subdural hemorrhage which needed surgical treatment. The degree of brain atrophy was estimated using the bicaudate ratio (BCR) index. We used uni- and multivariate analyses to identify risk factors correlated with CSDH. RESULTS: Sixteen (3.1%) patients experienced postoperative CSDH that required burr hole drainage surgery. In univariate analyses, male gender (p<0.001), size of aneurysm (p=0.030), higher BCR index (p=0.004), and the use of antithrombotic medication (p=0.006) were associated with postoperative CSDH. In multivariate analyses using logistic regression test, male gender [odds ratio (OR) 4.037, range 1.287-12.688], high BCR index (OR 5.376, range 1.170 25.000), and the use of antithrombotic medication (OR 4.854, range 1.658-14.085) were associated with postoperative CSDH (p<0.05). Postoperative subdural fluid collection and arachnoid plasty were not showed statistically significant difference in this study. CONCLUSION: The incidence of CSDH was 3.1% in unruptured anterior circulation aneurysm surgery. This study shows that male gender, degree of brain atrophy, and the use of antithrombotic medication were associated with postoperative CSDH. PMID- 25932295 TI - Quantification of pediatric cervical spine growth at the cranio-vertebral junction. AB - OBJECTIVE: The purpose of this study was to investigate morphological change at the craniovertebral junction (CVJ) region using computed tomography. METHODS: A total of 238 patients were included in this study, and mean age was 47.8+/-21.3 months. Spinal canal diameter, Power's ratio, McRae line, antero-posterior C1 ring height, atlantoaxial joint space, C2 growth, epidural space from the dens (M PB-C2) and longitudinal distance (basion to C2 lower margin, B-C2) were measured. The mean value of each parameter was assessed for individual age groups. The cohorts were then divided into three larger age groups : infancy (I) (<=2 years), very early (VE) childhood (2-5 years) and early (E) childhood (5>= years). RESULTS: Spinal canal diameter increased with age; however, this value did not increase with statistical significance after VE age. A significant age-related difference was found for all C2 body and odontoid parameters (p<0.05). Mean McRae line was 8.5, 8, and 7.5 mm in the I, VE, and E groups, respectively. The M-PB-C2 line showed up-and-down dynamic change during early pediatric periods. CONCLUSION: Expansion of the spinal canal was restricted to the very early childhood period (less than 5 years) in the CVJ region; however, the C2 body and odontoid process increased continuously with age. The above results induced a dynamic change in the M-PB-C2 line. Although C2 longitudinal growth continued with age, the McRae line showed relatively little change. PMID- 25932296 TI - The effectiveness of infrared thermography in patients with whiplash injury. AB - OBJECTIVE: This study aims to visualize the subjective symptoms before and after the treatment of whiplash injury using infrared (IR) thermography. METHODS: IR thermography was performed for 42 patients who were diagnosed with whiplash injury. There were 19 male and 23 female patients. The mean age was 43.12 years. Thermal differences (DeltaT) in the neck and shoulder and changes in the thermal differences (DeltadT) before and after treatment were analyzed. Pain after injury was evaluated using visual analogue scale (VAS) before and after treatment (DeltaVAS). The correlations between DeltadT and DeltaVAS results before and after the treatment were examined. We used Digital Infrared Thermal Imaging equipment of Dorex company for IR thermography. RESULTS: The skin temperature of the neck and shoulder immediately after injury showed 1-2C hyperthermia than normal. After two weeks, the skin temperature was normal range. DeltaT after immediately injuy was higher than normal value, but it was gradually near the normal value after two weeks. DeltadT before and after treatment were statistically significant (p<0.05). VAS of the neck and shoulder significantly reduced after 2 week (p=0.001). Also, there was significant correlation between DeltadT and reduced DeltaVAS (the neck; r=0.412, p<0.007) (the shoulder; r=0.648, p<0.000). CONCLUSION: The skin temperature of sites with whiplash injury is immediately hyperthermia and gradually decreased after two weeks, finally it got close to normal temperature. These were highly correlated with reduced VAS. IR thermography can be a reliable tool to visualize the symptoms of whiplash injury and the effectiveness of treatment in clinical settings. PMID- 25932297 TI - Pituitary apoplexy following mitral valvuloplasty. AB - Pituitary apoplexy is a rare but potentially life-threatening clinical syndrome caused by the sudden enlargement of a pituitary adenoma secondary to hemorrhage or infarction. Pituitary apoplexy after cardiac surgery is a very rare perioperative complication. Factors associated with open heart surgery that may lead to pituitary apoplexy include hemodynamic instability during cardiopulmonary bypass and systemic heparinization. We report a case of pituitary apoplexy after mitral valvuloplasty with cardiopulmonary bypass. After early pituitary tumor resection and hormonal replacement therapy, the patient made a full recovery. PMID- 25932298 TI - Vestibular schwannoma atypically invading temporal bone. AB - Vestibular schwannoma (VS) usually present the widening of internal auditory canal (IAC), and these bony changes are typically limited to IAC, not extend to temporal bone. Temporal bone invasion by VS is extremely rare. We report 51-year old man who revealed temporal bone destruction beyond IAC by unilateral VS. The bony destruction extended anteriorly to the carotid canal and inferiorly to the jugular foramen. On histopathologic examination, the tumor showed typical benign schwannoma and did not show any unusual vascularity or malignant feature. Facial nerve was severely compressed and distorted by tumor, which unevenly eroded temporal bone in surgical field. Vestibular schwannoma with atypical invasion of temporal bone can be successfully treated with combined translabyrinthine and lateral suboccipiral approach without facial nerve dysfunction. Early detection and careful dissection of facial nerve with intraoperative monitoring should be considered during operation due to severe adhesion and distortion of facial nerve by tumor and eroded temporal bone. PMID- 25932299 TI - Misunderstanding of foot drop in a patient with charcot-marie-tooth disease and lumbar disk herniation. AB - We report the case of 57-year-old woman diagnosed with Charcot-Marie-Tooth (CMT) disease and lumbar disk herniation (LDH). She had left leg weakness and foot numbness, foot deformity (muscle atrophy, high arch, and clawed toes). The lumbar spine MRI showed LDH at L4-5. Additionally, electrophysiology results were consistent with chronic peripheral motor-sensory polyneuropathy (axonopathy). In genetic testing, 17p11.2-p12 duplication/deletions characteristic of CMT disease were observed. We confirmed the patient's diagnosis as CMT disease and used conservative treatment. PMID- 25932300 TI - Cerebrospinal fluid rhinorrhea and seizure caused by temporo-sphenoidal encephalocele. AB - This case report describes the symptoms and clinical course of a 35-year-old female patient who was diagnosed with a temporo-sphenoidal encephalocele. It is characterized by herniation of cerebral tissue of the temporal lobe through a defect of the skull base localized in the middle fossa. At the time of first presentation the patient complained about recurrent nasal discharge of clear fluid which had begun some weeks earlier. She also reported that three months earlier she had for the first time suffered from a generalized seizure. In a first therapeutic attempt an endoscopic endonasal approach to the sphenoid sinus was performed. An attempt to randomly seal the suspicious area failed. After frontotemporal craniotomy, it was possible to localize the encephalocele and the underlying bone defect. The herniated brain tissue was resected and the dural defect was closed with fascia of the temporalis muscle. In summary, the combination of recurrent rhinorrhea and a first-time seizure should alert specialists of otolaryngology, neurology and neurosurgery of a temporo-sphenoidal encephalocele as a possible cause. Treatment is likely to require a neurosurgical approach. PMID- 25932301 TI - Deep brain stimulation of the subthalamic and pedunculopontine nucleus in a patient with Parkinson's disease. AB - Deep brain stimulation (DBS) of the pedunculopontine nucleus (PPN) is a novel therapy developed to treat Parkinson's disease. We report a patient who underwent bilateral DBS of the PPN and subthalamic nucleus (STN). He suffered from freezing of gait (FOG), bradykinesia, rigidity and mild tremors. The patient underwent bilateral DBS of the PPN and STN. We compared the benefits of PPN-DBS and STN-DBS using motor and gait subscores. The PPN-DBS provided modest improvements in the gait disorder and freezing episodes, while the STN-DBS failed to improve the dominant problems. This special case suggests that PPN-DBS may have a unique role in ameliorating the locomotor symptoms and has the potential to provide improvement in FOG. PMID- 25932302 TI - Radiological Follow-up of a Cerebral Tuberculoma with a Paradoxical Response Mimicking a Brain Tumor. AB - We report a case of a paradoxical response of a tuberculoma in the brain mimicking a brain tumor. A 76-year-old woman presented with a 2 week history of headache, dysarthia, and orthopnea. Brain magnetic resonance images (MRI) revealed two rim-enhancing lesions on the pons and occipital lobe, and chest computed tomography showed randomly distributed miliary nodules. The tentative diagnosis was tuberculosis (TB) of the brain and lung. She complained of right hemiparesis and worsening general weakness after taking the anti-TB medication. On the monthly follow-up images, the enhanced lesions were enlarged with increased perfusion and choline/creatinine ratio, suggesting a high grade glioma. A surgical resection was completed to diagnose the occipital lesion, and the tuberculoma was pathologically confirmed by a positive TB-polymerase chain reaction. The anti-TB medication was continued for 13 months. A follow-up MRI showed decreased size of the brain lesions associated with perilesional edema, and the clinical symptoms had improved. Brain tuberculoma could be aggravated mimicking brain malignancy during administration of anti-TB medication. This paradoxical response can be effectively managed by continuing the anti-TB drugs. PMID- 25932303 TI - Treatment of Syringomyelia due to Chiari Type I Malformation with Syringo Subarachnoid-Peritoneal Shunt. AB - Chiari type I malformation is a tonsillar herniation more than 3 mm from the level of foramen magnum, with or without concurrent syringomyelia. Different surgical treatments have been developed for syringomyelia secondary to Chiari's malformations: craniovertebral decompression with or without plugging of the obex, syringo-subarachnoid, syringo-peritoneal, and theco-peritoneal shunt placement. Shunt placement procedures are useful for neurologically symptomatic large-sized syrinx. In this paper, authors define the first successful treatment of a patient with syringomyelia due to Chiari type I malformation using a pre defined new technique of syringo-subarachnoid-peritoneal shunt with T-tube system. PMID- 25932304 TI - Erratum to "Surgical Management with Radiation Therapy for Metastatic Spinal Tumors Located on Cervicothoracic Junction : A Single Center Study" by Park HY, et al. (J Korean Neurosurg Soc 57 : 42-49, 2015). AB - [This corrects the article on p. 42 in vol. 57, PMID: 25674343.]. PMID- 25932305 TI - Efficacy of various cleaning solutions on saliva-contaminated zirconia for improved resin bonding. AB - PURPOSE: This study aimed to investigate the efficacy of cleaning solutions on saliva-contaminated zirconia in comparison to air-abrasion in terms of resin bonding. MATERIALS AND METHODS: For saliva-contaminated airabraded zirconia, seven cleaning methods)-no contamination (NC), water-spray rinsing (WS), additional airabrasion (AA), and cleaning with four solutions (Ivoclean [IC]; 1.0 wt% sodium dodecyl sulfate [SDS], 1.0 wt% hydrogen peroxide [HP], and 1.0 wt% sodium hypochlorite [SHC])-were tested. The zirconia surfaces for each group were characterized using various analytical techniques. Three bonded resin (Panavia F 2.0) cylinders (bonding area: 4.5 mm(2)) were made on one zirconia disk specimen using the Ultradent jig method [four disks (12 cylinders)/group; a total of 28 disks]. After 5,000 thermocycling, all specimens were subjected to a shear bond strength test with a crosshead speed of 1.0 mm/minute. The fractured surfaces were observed using an optical and scanning electron microscope (SEM). RESULTS: Contact angle measurements showed that groups NC, AA, IC, and SHC had hydrophilic surfaces. The X-ray photoelectron spectroscopy (XPS) analysis showed similar elemental distributions between group AA and groups IC and SHC. Groups IC and SHC showed statistically similar bond strengths to groups NC and AA (P>.05), but not groups SDS and HP (P<.05). For groups WS, SDS, and HP, blister-like bubble formations were observed on the surfaces under SEM. CONCLUSION: Within the limitations of this in vitro study, some of the cleaning solutions (IC or SHC) were effective in removing saliva contamination and enhancing the resin bond strength. PMID- 25932306 TI - The effect of two artificial salivas on the adhesion of Candida albicans to heat polymerized acrylic resin. AB - PURPOSE: Xerostomia can diminish the quality of life, leads to changes in normal chemical composition of saliva and oral microbiata, and increases the risk for opportunistic infections, such as Candida albicans. Various artificial salivas have been considered for patients with xerostomia. However, the knowledge on the antifungal and antiadhesive activity of artificial saliva substitutes is limited. The aim of the present study was to evaluate influence of two artificial salivas on the adhesion of Candida albicans to the polymethylmethacrylate disc specimens. MATERIALS AND METHODS: Two commercial artificial salivas (Saliva Orthana and Biotene Oral Balance Gel) were selected. 45 polymethylmethacrylate disc specimens were prepared and randomly allocated into 3 groups; Saliva Orthana, Biotene-Oral Balance gel and distilled water. Specimens were stored in the artificial saliva or in the sterile distilled water for 60 minutes at 37C. Then they were exposed to yeast suspensions including Candida albicans. Yeast cells were counted using *40 magnification under a light microscope and data were analysed. RESULTS: Analysis of data indicated statistically significant difference in adhesion of Candida albicans among all experimental groups (P=.000). Findings indicated that Saliva Orthana had higher adhesion scores than the Biotene Oral Balance gel and distilled water (P<.05). CONCLUSION: In comparison of Saliva Orthana, the use of Biotene Oral Balance Gel including lysozyme, lactoferrin and peroxidase may be an appropriate treatment method to prevent of adhesion of Candida albicans and related infections in patients with xerostomia. PMID- 25932307 TI - Investigation of flexural strength and cytotoxicity of acrylic resin copolymers by using different polymerization methods. AB - PURPOSE: The aim of this study was to appraise the some mechanical properties of polymethyl methacrylate based denture base resin polymerized by copolymerization mechanism, and to investigate the cytotoxic effect of these copolymer resins. MATERIALS AND METHODS: 2-hydroxyethyl methacrylate (HEMA) and isobutyl methacrylate (IBMA) were added to monomers of conventional heat polymerized and injection-molded poly methyl methacrylate (PMMA) resin contents of 2%, 3%, and 5% by volume and polymerization was carried out. Three-point bending test was performed to detect flexural strength and the elasticity modulus of the resins. To determine the statistical differences between the study groups, the Kruskall Wallis test was performed. Then pairwise comparisons were performed between significant groups by Mann-Whitney U test. Agar-overlay test was performed to determine cytotoxic effect of copolymer resins. Chemical analysis was determined by FTIR spectrum. RESULTS: Synthesis of the copolymer was approved by FTIR spectroscopy. Within the conventional heat-polymerized group maximum transverse strength had been seen in the HEMA 2% concentration; however, when the concentration ratio increased, the strength decreased. In the injection-molded group, maximum transverse strength had been seen in the IBMA 2% concentration; also as the concentration ratio increased, the strength decreased. Only IBMA showed no cytotoxic effect at low concentrations when both two polymerization methods applied while HEMA showed cytotoxic effect in the injection-molded resins. CONCLUSION: Within the limitations of this study, it may be concluded that IBMA and HEMA may be used in low concentration and at high temperature to obtain non-cytotoxic and durable copolymer structure. PMID- 25932308 TI - Evaluation of the bond strength between aged composite cores and luting agent. AB - PURPOSE: The aim of this study was to evaluate effect of different surface treatment methods on the bond strength between aged composite-resin core and luting agent. MATERIALS AND METHODS: Seventy-five resin composites and also seventy-five zirconia ceramic discs were prepared. 60 composite samples were exposed to thermal aging (10,000 cycles, 5 to 55C) and different surface treatment. All specimens were separated into 5 groups (n=15): 1) Intact specimens 2) Thermal aging-air polishing 3) Thermal aging- Er:YAG laser irradiation 4) Thermal aging- acid etching 5) Thermal-aging. All specimens were bonded to the zirconia discs with resin cement and fixed to universal testing machine and bond strength testing loaded to failure with a crosshead speed of 0.5 mm/min. The fractured surface was classified as adhesive failure, cohesive failure and adhesive-cohesive failure. The bond strength data was statistically compared by the Kruskal-Wallis method complemented by the Bonferroni correction Mann-Whitney U test. The probability level for statistical significance was set at alpha=.05. RESULTS: Thermal aging and different surface treatment methods have significant effect on the bond strength between composite-resin cores and luting-agent (P<.05). The mean baseline bond strength values ranged between 7.07 +/- 2.11 and 26.05 +/- 6.53 N. The highest bond strength of 26.05 +/- 6.53 N was obtained with Group 3. Group 5 showed the lowest value of bond strength. CONCLUSION: Appropriate surface treatment method should be applied to aged composite resin cores or aged-composites restorations should be replaced for the optimal bond strength and the clinical success. PMID- 25932309 TI - The effect of the thread depth on the mechanical properties of the dental implant. AB - PURPOSE: This study aimed to evaluate the effect of implant thread depth on primary stability in low density bone. MATERIALS AND METHODS: The insertion torque was measured by inserting Ti implants with different thread depths into solid rigid polyurethane blocks (Sawbones) with three different bone densities (0.16 g/cm(3), 0.24 g/cm(3), and 0.32 g/cm(3)). The insertion torque value was evaluated with a surgical engine. The static compressive strength was measured with a universal testing machine (UTM) and the Ti implants were aligned at 30 degrees against the loading direction of the UTM. After the static compressive strength test, the Ti implants were analyzed with a Measurescope. RESULTS: The Ti implants with deeper thread depth showed statistically higher mean insertion torque values (P<.001). Groups A and group B had similar maximum static compressive strengths, as did groups C and D (P>.05). After the static compressive strength, the thread shape of the Ti implants with deeper thread depth did not show any breakage but did show deformation of the implant body and abutment. CONCLUSION: The implants with deeper thread depth had higher mean insertion torque values but not lower compressive strength. The deep threads had a mechanical stability. Implants with deeper thread depth may increase the primary stability in areas of poor quality bone without decreasing mechanical strength. PMID- 25932310 TI - Accuracy evaluation of metal copings fabricated by computer-aided milling and direct metal laser sintering systems. AB - PURPOSE: To assess the marginal and internal gaps of the copings fabricated by computer-aided milling and direct metal laser sintering (DMLS) systems in comparison to casting method. MATERIALS AND METHODS: Ten metal copings were fabricated by casting, computer-aided milling, and DMLS. Seven mesiodistal and labiolingual positions were then measured, and each of these were divided into the categories; marginal gap (MG), cervical gap (CG), axial wall at internal gap (AG), and incisal edge at internal gap (IG). Evaluation was performed by a silicone replica technique. A digital microscope was used for measurement of silicone layer. Statistical analyses included one-way and repeated measure ANOVA to test the difference between the fabrication methods and categories of measured points (alpha=.05), respectively. RESULTS: The mean gap differed significantly with fabrication methods (P<.001). Casting produced the narrowest gap in each of the four measured positions, whereas CG, AG, and IG proved narrower in computer aided milling than in DMLS. Thus, with the exception of MG, all positions exhibited a significant difference between computer-aided milling and DMLS (P<.05). CONCLUSION: Although the gap was found to vary with fabrication methods, the marginal and internal gaps of the copings fabricated by computer-aided milling and DMLS fell within the range of clinical acceptance (<120 um). However, the statistically significant difference to conventional casting indicates that the gaps in computer-aided milling and DMLS fabricated restorations still need to be further reduced. PMID- 25932311 TI - Relationship between squamous cell carcinoma of the tongue and the position of dental prosthesis. AB - PURPOSE: Squamous cell carcinoma (SCC) of the tongue has a relatively high incidence of all oral cancers. Some studies have reported a relationship between intraoral dental prosthesis and SCC of the tongue; however, this relationship remains controversial. The purpose of this study was to investigate the relationship between SCC of the tongue and the positional aspects of dental prosthesis using a retrospective analysis. MATERIALS AND METHODS: A total of 439 patients with SCC of the tongue were diagnosed and treated in the Department of Oral and Maxillofacial Surgery, Seoul National University Dental Hospital. Patients were treated over a 12.5-year period ranging from January 1, 2001 to June 30, 2013. Statistical analysis was performed to examine potential differences between the groups. RESULTS: The number of patients with a crown and/or a bridge (134, 63.5%) was significantly different than the number of patients without a prosthesis (77, 36.5%). Even after accounting for different types of prostheses such as crowns, bridges, and dentures, no significant differences were observed between the position of the prosthesis and the location of the SCC of the tongue, with significance defined as a P-value less than .05 by the Pearson-Chi square test. CONCLUSION: Patients with crowns and/or bridges exhibited more frequent SCC of the tongue compared with patients without these prosthesis. These data support the hypothesis that mechanical trauma and galvanic phenomena play a role in the etiology of SCC of the tongue. PMID- 25932312 TI - Effect of laser-dimpled titanium surfaces on attachment of epithelial-like cells and fibroblasts. AB - PURPOSE: The objective of this study was to conduct an in vitro comparative evaluation of polished and laserdimpled titanium (Ti) surfaces to determine whether either surface has an advantage in promoting the attachment of epithelial like cells and fibroblast to Ti. MATERIALS AND METHODS: Forty-eight coin-shaped samples of commercially pure, grade 4 Ti plates were used in this study. These discs were cleaned to a surface roughness (Ra: roughness centerline average) of 180 nm by polishing and were divided into three groups: SM (n=16) had no dimples and served as the control, SM15 (n=16) had 5-um dimples at 10-um intervals, and SM30 (n=16) had 5-um dimples at 25-um intervals in a 2 * 4 mm(2) area at the center of the disc. Human gingival squamous cell carcinoma cells (YD-38) and human lung fibroblasts (MRC-5) were cultured and used in cell proliferation assays, adhesion assays, immunofluorescent staining of adhesion proteins, and morphological analysis by SEM. The data were analyzed statistically to determine the significance of differences. RESULTS: The adhesion strength of epithelial cells was higher on Ti surfaces with 5-um laser dimples than on polished Ti surfaces, while the adhesion of fibroblasts was not significantly changed by laser treatment of implant surfaces. However, epithelial cells and fibroblasts around the laser dimples appeared larger and showed increased expression of adhesion proteins. CONCLUSION: These findings demonstrate that laser dimpling may contribute to improving the periimplant soft tissue barrier. This study provided helpful information for developing the transmucosal surface of the abutment. PMID- 25932313 TI - The effect of zirconia framework design on the failure of all-ceramic crown under static loading. AB - PURPOSE: This in vitro study aimed to compare the failure load and failure characteristics of two different zirconia framework designs of premolar crowns when subjected to static loading. MATERIALS AND METHODS: Two types of zirconia frameworks, conventional 0.5 mm even thickness framework design (EV) and 0.8 mm cutback of full contour crown anatomy design (CB), were made for 10 samples each. The veneer porcelain was added on under polycarbonate shell crown made by vacuum of full contour crown to obtain the same total thickness of the experiment crowns. The crowns were cemented onto the Cobalt-Chromium die. The dies were tilted 45 degrees from the vertical plane to obtain the shear force to the cusp when loading. All crowns were loaded at the lingual incline of the buccal cusp until fracture using a universal testing machine with cross-head speed 0.5 mm/min. The load to fracture values (N) was recorded and statistically analyzed by independent sample t-test. RESULTS: The mean and standard deviations of the failure load were 1,170.1 +/- 90.9 N for EV design and 1,450.4 +/- 175.7 N for CB design. A significant difference in the compressive failure load was found (P<.05). For the failure characteristic, the EV design was found only cohesive failures within veneering porcelain, while the CB design found more failures through the zirconia framework (8 from 10 samples). CONCLUSION: There was a significant difference in the failure load between two designs, and the design of the framework influences failure characteristic of zirconia crown. PMID- 25932314 TI - Microscopical and chemical surface characterization of CAD/CAM zircona abutments after different cleaning procedures. A qualitative analysis. AB - PURPOSE: To describe and characterize the surface topography and cleanliness of CAD/CAM manufactured zirconia abutments after steaming and ultrasonic cleaning. MATERIALS AND METHODS: A total of 12 ceramic CAD/CAM implant abutments of various manufacturers were produced and randomly divided into two groups of six samples each (control and test group). Four two-piece hybrid abutments and two one-piece abutments made of zirconium-dioxide were assessed per each group. In the control group, cleaning by steam was performed. The test group underwent an ultrasonic cleaning procedure with acetone, ethyl alcohol and antibacterial solution. Groups were subjected to scanning electron microscope (SEM) analysis and Energy dispersive X-ray spectroscopy (EDX) to verify and characterize contaminant chemical characterization non-quantitatively. RESULTS: All zirconia CAD/CAM abutments in the present study displayed production-induced wear particles, debris as well as organic and inorganic contaminants. The abutments of the test group showed reduction of surface contamination after undergoing an ultrasonic cleaning procedure. However, an absolute removal of pollutants could not be achieved. CONCLUSION: The presence of debris on the transmucosal surface of CAD/CAM zirconia abutments of various manufacturers was confirmed. Within the limits of the study design, the results suggest that a defined ultrasonic cleaning process can be advantageously employed to reduce such debris, thus, supposedly enhancing soft tissue healing. Although the adverse long-term influence of abutment contamination on the biological stability of peri-implant tissues has been evidenced, a standardized and validated polishing and cleaning protocol still has to be implemented. PMID- 25932315 TI - In-vitro development of a temporal abutment screw to protect osseointegration in immediate loaded implants. AB - PURPOSE: In this study, a temporal abutment fixation screw, designed to fracture in a controlled way upon application of an occlusal force sufficient to produce critical micromotion was developed. The purpose of the screw was to protect the osseointegration of immediate loaded single implants. MATERIALS AND METHODS: Seven different screw prototypes were examined by fixing titanium abutments to 112 Mozo-Grau external hexagon implants (MG Osseous(r); Mozo-Grau, S.A., Valladolid, Spain). Fracture strength was tested at 30 degrees in two subgroups per screw: one under dynamic loading and the other without prior dynamic loading. Dynamic loading was performed in a single-axis chewing simulator using 150,000 load cycles at 50 N. After normal distribution of obtained data was verified by Kolmogorov-Smirnov test, fracture resistance between samples submitted and not submitted to dynamic loading was compared by the use of Student's t-test. Comparison of fracture resistance among different screw designs was performed by the use of one-way analysis of variance. Confidence interval was set at 95%. RESULTS: Fractures occurred in all screws, allowing easy retrieval. Screw Prototypes 2, 5 and 6 failed during dynamic loading and exhibited statistically significant differences from the other prototypes. CONCLUSION: Prototypes 2, 5 and 6 may offer a useful protective mechanism during occlusal overload in immediate loaded implants. PMID- 25932316 TI - Evaluation of antibacterial activity and osteoblast-like cell viability of TiN, ZrN and (Ti1-xZrx)N coating on titanium. AB - PURPOSE: The aim of this study was to evaluate antibacterial activity and osteoblast-like cell viability according to the ratio of titanium nitride and zirconium nitride coating on commercially pure titanium using an arc ion plating system. MATERIALS AND METHODS: Polished titanium surfaces were used as controls. Surface topography was observed by scanning electron microscopy, and surface roughness was measured using a two-dimensional contact stylus profilometer. Antibacterial activity was evaluated against Streptococcus mutans and Porphyromonas gingivalis with the colony-forming unit assay. Cell compatibility, mRNA expression, and morphology related to human osteoblast-like cells (MG-63) on the coated specimens were determined by the XTT assay and reverse transcriptase polymerase chain reaction. RESULTS: The number of S. mutans colonies on the TiN, ZrN and (Ti1-xZrx)N coated surface decreased significantly compared to those on the non-coated titanium surface (P<0.05). CONCLUSION: The number of P. gingivalis colonies on all surfaces showed no significant differences. TiN, ZrN and (Ti1 xZrx)N coated titanium showed antibacterial activity against S. mutans related to initial biofilm formation but not P. gingivalis associated with advanced periimplantitis, and did not influence osteoblast-like cell viability. PMID- 25932317 TI - Evaluation of effect of galvanic corrosion between nickel-chromium metal and titanium on ion release and cell toxicity. AB - PURPOSE: The purpose of this study was to evaluate cell toxicity due to ion release caused by galvanic corrosion as a result of contact between base metal and titanium. MATERIALS AND METHODS: It was hypothesized that Nickel (Ni) Chromium (Cr) alloys with different compositions possess different corrosion resistances when contacted with titanium abutment, and therefore in this study, specimens (10*10*1.5 mm) were fabricated using commercial pure titanium and 3 different types of Ni-Cr alloys (T3, Tilite, Bella bond plus) commonly used for metal ceramic restorations. The specimens were divided into 6 groups according to the composition of Ni-Cr alloy and contact with titanium. The experimental groups were in direct contact with titanium and the control groups were not. After the samples were immersed in the culture medium - Dulbecco's modified Eagle's medium[DMEM] for 48 hours, the released metal ions were detected using inductively coupled plasma mass spectrometer (ICP-MS) and analyzed by the Kruskal Wallis and Mann-Whitney test (P<.05). Mouse L-929 fibroblast cells were used for cell toxicity evaluation. The cell toxicity of specimens was measured by the 3 {4,5-dimethylthiazol-2yl}-2,5-diphenyltetrazolium bromide (MTT) test. Results of MTT assay were statistically analyzed by the two-way ANOVA test (P<.05). Post-hoc multiple comparisons were conducted using Tukey's tests. RESULTS: The amount of metal ions released by galvanic corrosion due to contact between the base metal alloy and titanium was increased in all of the specimens. In the cytotoxicity test, the two-way ANOVA showed a significant effect of the alloy type and galvanic corrosion for cytotoxicity (P<.001). The relative cell growth rate (RGR) was decreased further on the groups in contact with titanium (P<.05). CONCLUSION: The release of metal ions was increased by galvanic corrosion due to contact between base metal and titanium, and it can cause adverse effects on the tissue around the implant by inducing cytotoxicity. PMID- 25932318 TI - Familial gigantiform cementoma with Ehlers - Danlos syndrome: A report of 2 cases. AB - Ehlers-Danlos syndrome is an autosomal dominant hereditary disorder of connective tissue, while familial gigantiform cementoma is a condition that usually manifests as multiple radiopaque cementum-like masses throughout the jaws. This case report discusses the oral management and prosthetic rehabilitation of two patients presenting familial gigantiform cementoma with Ehlers-Danlos Syndrome. PMID- 25932319 TI - Can severe aortic stenosis be identified by emergency physicians when interpreting a simplified two-view echocardiogram obtained by trained echocardiographers? AB - BACKGROUND: Aortic stenosis (AS) is a common valve problem that causes significant morbidity and mortality. The goal of this study was to determine whether an emergency physician (EP) could determine severe AS by reviewing only two B-mode echocardiographic views (parasternal long axis (PSLA) and parasternal short axis (PSSA)) obtained by trained echocardiographers. METHODS: A convenience sample of 60 patients with no AS, mild/moderate AS or severe AS was selected for health record and echocardiogram review. The echocardiograms were performed in an accredited echocardiography laboratory. An EP blinded to the cardiologist's final report reviewed the PSLA and PSSA views after the cases were randomly sorted. Severe AS was defined as no cusp movement seen by the EP reviewers. A second EP independently reviewed 25% of randomly selected patients for inter-rater reliability. Collected data included patient demographics, EP interpretation and details of each echo view (quality, the number of cusps visualized, presence of calcification) and compared to final cardiology reports. Analyses included descriptive statistics, test characteristics for severe AS and kappa for agreement. RESULTS: The mean age was 75.3 years (range 18 to 90) with 36.7% females. The cardiologist's diagnosis was as follows: 38.3% severe AS, 28.3% mild/moderate AS and 33.3% no AS. The PSSA view was poorer in quality compared with the PSLA (33.3% vs. 13.3%, p = 0.02), but the PSSA view was better than PSLA to visualize all three cusps (83.3% vs. 0%, p = 0.001). There was no difference in the presence of calcification between the mild/moderate and severe AS groups (94.1% vs. 100.0%, p = 0.46). The sensitivity and specificity for EP diagnosis of severe AS was 75.0% (95% CI 56.7% to 85.4%) and 92.5% (83.3% to 97.7%). The kappa for severe AS was 0.69 (0.41 to 0.85), and there was no significant difference between observers in the quality of the view, presence of aortic calcification and the number of cusps visible. CONCLUSIONS: PSLA and PSSA views obtained by trained echocardiographers can be interpreted by an EP with appropriate training to identify severe AS with good specificity. Further larger prospective studies are required before widespread use by EPs. PMID- 25932320 TI - The Cambridge Mindreading Face-Voice Battery for Children (CAM-C): complex emotion recognition in children with and without autism spectrum conditions. AB - BACKGROUND: Difficulties in recognizing emotions and mental states are central characteristics of autism spectrum conditions (ASC). However, emotion recognition (ER) studies have focused mostly on recognition of the six 'basic' emotions, usually using still pictures of faces. METHODS: This study describes a new battery of tasks for testing recognition of nine complex emotions and mental states from video clips of faces and from voice recordings taken from the Mindreading DVD. This battery (the Cambridge Mindreading Face-Voice Battery for Children or CAM-C) was given to 30 high-functioning children with ASC, aged 8 to 11, and to 25 matched controls. RESULTS: The ASC group scored significantly lower than controls on complex ER from faces and voices. In particular, participants with ASC had difficulty with six out of nine complex emotions. Age was positively correlated with all task scores, and verbal IQ was correlated with scores in the voice task. CAM-C scores were negatively correlated with parent-reported level of autism spectrum symptoms. CONCLUSIONS: Children with ASC show deficits in recognition of complex emotions and mental states from both facial and vocal expressions. The CAM-C may be a useful test for endophenotypic studies of ASC and is one of the first to use dynamic stimuli as an assay to reveal the ER profile in ASC. It complements the adult version of the CAM Face-Voice Battery, thus providing opportunities for developmental assessment of social cognition in autism. PMID- 25932321 TI - Person-centric clinical trials: defining the N-of-1 clinical trial utilizing a practice-based translational network. AB - A person-centric clinical trial is inclusive of both the investigator and the person and as such represents point-of-use data generated at the practice level and encompasses both health and disease. Raising the clinical encounter to a research encounter and providing an infrastructure to support a level of quality assurance creates a synergy for efficiency for healthcare delivery. The interface of translational studies and clinical research poses an opportunity, whereby person-centricity can support transparency, facilitate informed consent, improve safety, enhance recruitment and compliance, improve dissemination of results, implement change and help close the translational gap. The model represents robust clinical data from persons of record allowing for improved interpretation of drug/device side-effects and for regulatory reviewers to expedite the approval process. PMID- 25932322 TI - Comparative muscle development of scyphozoan jellyfish with simple and complex life cycles. AB - BACKGROUND: Simple life cycles arise from complex life cycles when one or more developmental stages are lost. This raises a fundamental question - how can an intermediate stage, such as a larva, be removed, and development still produce a normal adult? To address this question, we examined the development in several species of pelagiid jellyfish. Most members of Pelagiidae have a complex life cycle with a sessile polyp that gives rise to ephyrae (juvenile medusae); but one species within Pelagiidae, Pelagia noctiluca, spends its whole life in the water column, developing from a larva directly into an ephyra. In many complex life cycles, adult features develop from cell populations that remain quiescent in larvae, and this is known as life cycle compartmentalization and may facilitate the evolution of direct life cycles. A second type of metamorphic processes, known as remodeling, occurs when adult features are formed through modification of already differentiated larval structures. We examined muscle morphology to determine which of these alternatives may be present in Pelagiidae. RESULTS: We first examined the structure and development of polyp and ephyra musculature in Chrysaora quinquecirrha, a close relative of P. noctiluca with a complex life cycle. Using phallotoxin staining and confocal microscopy, we verified that polyps have four to six cord muscles that persist in strobilae and discovered that cord muscles is physically separated from ephyra muscle. When cord muscle is removed from ephyra segments, normal ephyra muscle still develops. This suggests that polyp cord muscle is not necessary for ephyra muscle formation. We also found no evidence of polyp-like muscle in P. noctiluca. In both species, we discovered that ephyra muscle arises de novo in a similar manner, regardless of the life cycle. CONCLUSIONS: The separate origins of polyp and ephyra muscle in C. quinquecirrha and the absence of polyp-like muscle in P. noctiluca suggest that polyp muscle is not remodeled to form ephyra muscle in Pelagiidae. Life cycle stages in Scyphozoa may instead be compartmentalized. Because polyp muscle is not directly remodeled, this may have facilitated the loss of the polyp stage in the evolution of P. noctiluca. PMID- 25932324 TI - Comparable outcomes for beta-lactam/beta-lactamase inhibitor combinations and carbapenems in definitive treatment of bloodstream infections caused by cefotaxime-resistant Escherichia coli or Klebsiella pneumoniae. AB - BACKGROUND: Extended-spectrum beta-lactamase (ESBL) producing Enterobacteriaceae are often susceptible in vitro to beta-lactam/beta-lactamase inhibitor (BLBLI) combination antibiotics, but their use has been limited by concerns of clinical inefficacy. We aimed to compare outcomes between patients treated with BLBLIs and carbapenems for bloodstream infection (BSI) caused by cefotaxime non-susceptible (likely ESBL- or AmpC beta-lactamase-producing) Escherichia coli and Klebsiella pneumoniae. METHODS: All adult patients with a BSI caused by cefotaxime non susceptible E. coli or K. pneumoniae were included from May 2012-May 2013. We compared outcomes between patients who had definitive monotherapy with a carbapenem to those who had definitive monotherapy with a BLBLI. RESULTS: There were 92 BSIs that fulfilled the microbiological inclusion criteria. 79 (85.9%) were caused by E. coli and 13 (14.1%) by K. pneumoniae. Four out of 23 (17.4%) patients treated with carbapenem monotherapy and 2 out of 24 (8.3%) patients treated with BLBLI monotherapy died (adjusted HR for survival 0.91, 95% CI 0.13 to 6.28; p = 0.92). The time to resolution of systemic inflammatory response syndrome (SIRS) criteria did not vary between the treatment groups (adjusted HR 0.91, 95% CI 0.32 to 2.59; p = 0.97). The length of hospital admission post positive blood culture was slightly longer in patients treated with BLBLIs (median duration 15 vs. 11 days), although this was not significant (adjusted HR 0.62; 95% CI 0.27 to 1.42; p = 0.26). There were no significant differences in subsequent isolation of carbapenem resistant organisms (4.3% vs. 4.2%, p = 1.0), C. difficile infection (13.0% vs. 8.3%, p = 0.67) or relapsed BSI (0% vs. 2%, p = 0.23). CONCLUSIONS: BLBLIs appear to have a similar efficacy to carbapenems in the treatment of cefotaxime-resistant E. coli and K. pneumoniae bloodstream infections. Directed therapy with a BLBLI, when susceptibility is proven, may represent an appropriate carbapenem-sparing option. PMID- 25932325 TI - China, what antibiotics and what volumes are used in food production animals? PMID- 25932323 TI - Calcium sensors of ciliary outer arm dynein: functions and phylogenetic considerations for eukaryotic evolution. AB - The motility of eukaryotic cilia and flagella is modulated in response to several extracellular stimuli. Ca(2+) is the most critical intracellular factor for these changes in motility, directly acting on the axonemes and altering flagellar asymmetry. Calaxin is an opisthokont-specific neuronal calcium sensor protein first described in the sperm of the ascidian Ciona intestinalis. It binds to a heavy chain of two-headed outer arm dynein in a Ca(2+)-dependent manner and regulates 'asymmetric' wave propagation at high concentrations of Ca(2+). A Ca(2+)-binding subunit of outer arm dynein in Chlamydomonas reinhardtii, the light chain 4 (LC4), which is a Ca(2+)-sensor phylogenetically different from calaxin, shows Ca(2+)-dependent binding to a heavy chain of three-headed outer arm dynein. However, LC4 appears to participate in 'symmetric' wave propagation at high concentrations of Ca(2+). LC4-type dynein light chain is present in bikonts, except for some subclasses of the Excavata. Thus, flagellar asymmetry symmetry conversion in response to Ca(2+) concentration represents a 'mirror image' relationship between Ciona and Chlamydomonas. Phylogenetic analyses indicate the duplication, divergence, and loss of heavy chain and Ca(2+)-sensors of outer arm dynein among excavate species. These features imply a divergence point with respect to Ca(2+)-dependent regulation of outer arm dynein in cilia and flagella during the evolution of eukaryotic supergroups. PMID- 25932326 TI - Cognitive dysfunction in severe chronic obstructive pulmonary disease (COPD) with or without Long-Term Oxygen Therapy (LTOT). AB - BACKGROUND: Chronic Obstructive Pulmonary Disease (COPD) is a progressive respiratory condition which can lead to comorbidities of variable severity, cognitive dysfunction included. The role of supplemental oxygen in preventing COPD-induced cognitive deterioration is still debated, but only episodically investigated. The aim of this study was to compare the cognitive pattern of hypoxemic COPD subjects treated with long-term oxygen (LTOT) to that of patients of comparable severity assuming oxygen on irregular basis, and to normal reference values. METHODS: Lung function, arterial blood gases, health status, and cognitive function measured by means of four psychometric tests focusing different domains of cognition (such as: MMSE, Clock test; TMT-A; TMT-B) were assessed in 146 well matched hypoxemic COPD patients (males n = 96, 66%; mean age = 70.5 +/- 12.9). Seventy-three patients were assuming long-term oxygen (LTOT), while the remaining seventy-three were only using oxygen as needed (AN). Regarding statistics, t test and ANOVA (Duncan test) were used to analyze data, assuming a p < 0.05 as the lowest limit of significance. RESULTS: Even though all COPD patients showed a poorer psychometric profile vs corresponding normal reference values, LTOT patients showed a lower prevalence of severe deterioration in cognition. Also the extent of impairment was significantly lower in these patients when assessed by TMT-A and TMT-B (p < 0.012 and 0.001, respectively), but not when measured by MMSE and Clock test (both p = ns). Several domains of cognition are variably affected by persistent hypoxemia in COPD patients. A panel of psychometric tools is needed for identifying the pattern of cognitive dysfunctions in these patients. Memory and attention (functions assessed by MMSE and Clock test) are only mildly-moderately affected, while visual processing, reproduction of numeric sequences, cognition flexibility, and shifting capacity (functions assessed by TMT-A and TMT-B) are much more deteriorated (p < 0.012 and p < 0.001, respectively). CONCLUSIONS: Only LTOT allows to preserve significantly (p < 0.022) cognitive functions from the COPD-induced deterioration. This assumption is of strategic value for COPD patients who are prescribed long-term oxygen because they frequently are not aware of the cognitive risks related to their condition. PMID- 25932327 TI - A systematic review of agomelatine-induced liver injury. AB - Agomelatine is an antidepressant with a unique mechanism of action. Since its marketing in 2009, concerns have been raised regarding its potential to induce liver injury. The authors therefore address the need to comprehensively evaluate the potential risk posed by agomelatine of inducing liver injury by reviewing data from published and unpublished clinical trials in both the pre- and postmarketing settings, as well as data from non-interventional studies, pharmacovigilance database reviews and one case report. Recommendations for clinicians are also provided. In this review, agomelatine was found to be associated with higher rates of liver injury than both placebo and the four active comparator antidepressants used in the clinical trials for agomelatine, with rates as high as 4.6% for agomelatine compared to 2.1% for placebo, 1.4% for escitalopram, 0.6% for paroxetine, 0.4% for fluoxetine, and 0% for sertraline. The review also provides evidence for the existence of a positive relationship between agomelatine dose and liver injury. Furthermore, rates of liver injury were found to be lower in non-interventional studies. Findings from pharmacovigilance database reviews and one case report also highlight the risk of agomelatine-induced liver injury. As agomelatine does pose a risk of liver injury, clinicians must carefully monitor liver function throughout treatment. However, agomelatine's unique mechanism of action and favourable safety profile render it a valuable treatment option. A quantitative analysis of agomelatine induced liver injury is lacking in the literature and would be welcomed. PMID- 25932328 TI - Tenofovir substitution in Namibia based on an analysis of the antiretroviral dispensing database. AB - OBJECTIVES: In the management of HIV infection, tenofovir is preferred to its predecessors - zidovudine and stavudine - in the antiretroviral therapy (ART) nucleoside backbone. Tenofovir's (TDF) preference is based on its safety profile. Nevertheless, TDF causes adverse reactions, some of which warrant its substitution for patients. The rate of TDF-substitution is suggestive of the rate of occurrence of TDF-related adverse reactions. However, the rate of substitution of TDF with another nucleoside reverse transcriptase inhibitor (NRTI) in Namibia was unknown. The objective of this review was to measure the rate of TDF's substitution for the period of January 1, 2008 to November 30, 2011, and to compare the gender difference in the rates of TDF's substitution. METHODS: We accessed antiretroviral medicine dispensing records from the national antiretroviral dispensing database (NDB). We selected patients who were started on a TDF-containing conventional ART regimen - 2NRTI+1NNRT. We used the initial and current ART regimens to identify records of TDF's substitution with another NRTI. RESULTS: A total of 84,741 patients were initiated on ART (Jan-1-2008 to Nov-30-2011). A total of 52,612 patient-records were excluded from the analysis because they did not meet the criteria for inclusion. Of the 32,129 included records, 59.4% (n=19 096) and 40.6% (n=13 033) were for female and male patients, respectively. Of these, 1.2% (n=380) of the patients had their TDF substituted with another NRTI. Of the females and males, respectively, 1.1% (95% CI: 0.9-1.3; n=210) and 1.3% (95% CI: 1.1-1.5; n=170) had TDF substituted with another NRTI. No gender difference was observed (p-value = 0.11). CONCLUSION: The percentage of patients for whom TDF was substituted with another NRTI, possibly due to TDF related adverse reactions, was within the current published limits. However, 1.2% is likely not a true representation of the percentage of patients who experience adverse events because some patients could have been maintained on TDF even in the presence of adverse events. Further investigation is required to determine the clinical reasons for TDF's withdrawal. PMID- 25932329 TI - Immobilized laccase mediated dye decolorization and transformation pathway of azo dye acid red 27. AB - BACKGROUND: Laccases have good potential as bioremediating agents and can be used continuously in the immobilized form like many other enzymes. METHODS: In the present study, laccase from Cyathus bulleri was immobilized by entrapment in Poly Vinyl Alcohol (PVA) beads cross-linked with either nitrate or boric acid. Immobilized laccase was used for dye decolorization in both batch and continuous mode employing a packed bed column. The products of degradation of dye Acid Red 27 were identified by LC MS/MS analysis. RESULTS: The method led to very effective (90%) laccase immobilization and also imparted significant stability to the enzyme (more than 70% after 5 months of storage at 4 degrees C). In batch decolorization, 90-95% decolorization was achieved of the simulated dye effluent for up to 10-20 cycles. Continuous decolorization in a packed bed bioreactor led to nearly 90% decolorization for up to 5 days. The immobilized laccase was also effective in decolorization and degradation of Acid Red 27 in the presence of a mediator. Four products of degradation were identified by LC-MS/MS analysis. CONCLUSIONS: The immobilized laccase in PVA-nitrate was concluded to be an effective agent in treatment of textile dye effluents. PMID- 25932330 TI - Lower levels of 25-hydroxyvitamin D3 are associated with a higher prevalence of microvascular complications in patients with type 2 diabetes. AB - OBJECTIVE: Low levels of serum 25-hydroxyvitamin D [25(OH)D] are commonly found in type 2 diabetes. We examined whether there is an association between circulating 25(OH)D concentrations and the presence of microvascular complications in people with type 2 diabetes. RESEARCH DESIGN AND METHODS: We studied 715 outpatients with type 2 diabetes who regularly attended our clinic. Participants were evaluated for the presence of microvascular complications (namely retinopathy and/or nephropathy) by clinical evaluation, fundus examination, urine examination and biochemical tests. Serum 25(OH)D levels were also measured for each participant. RESULTS: Hypovitaminosis D (ie, a serum 25(OH)D level <30 ng/mL) was found in 75.4%, while deficiency (ie, a 25(OH)D level <20 ng/mL) was found in 36.6% of these patients. Serum 25(OH)D levels decreased significantly in relation to the severity of either retinopathy or nephropathy or both. In multivariate logistic regression analysis, lower 25(OH)D levels were independently associated with the presence of microvascular complications (considered as a composite end point; OR 0.758; 95% CI 0.607 to 0.947, p=0.015). Notably, this association remained significant even after excluding those with an estimated glomerular filtration rate <60 mL/min/1.73 m(2). CONCLUSIONS: We found an inverse and independent relationship between circulating 25(OH)D levels and the prevalence of microvascular complications in patients with type 2 diabetes. However, vitamin D may be simply a marker and causality cannot be implied from our cross-sectional study. Whether vitamin D supplementation in patients with type 2 diabetes may have beneficial effects on the risk of microvascular complications remains to be investigated. PMID- 25932332 TI - The 7-year teesside experience of primary prevention ICD indications following primary PCI (PPCI) and the potential impact of a change in NICE guidance. AB - INTRODUCTION: The recovery of LV function in patients with severe LV impairment in the acute phase following primary percutaneous coronary intervention (PPCI) is not well established. The indication for a primary prevention ICD post-STEMI is dependent on which screening guidance, NICE or ESC, is followed. The potential impact of the new NICE guidance is estimated. METHODS: We performed a retrospective analysis of all patients presenting with a STEMI over a 7-year period (2005-2012) treated with PPCI to determine in-hospital mortality, LV function at index presentation, at 3 months and the predicted primary prevention ICD implantation rate using NICE (TA095) and ESC 2006 guidelines. Predicted implant rates using the new NICE guidance (TA314) and actual implantation rates were also assessed. RESULTS: 3902 patients with a mean age of 65+/-13 years underwent PPCI. Of those patients surviving until discharge, 332 (10%) had LVEF <=35%. 254 of 332 patients (76%) with a severely impaired ventricle were followed up at participating centres. 210 of 254 (83%) patients had a repeat echocardiogram within 3 months post-MI; among these patients, 89 (42%) remained to have LVEF <=35%. The number of patients fulfilling NICE and ESC criteria for primary prevention ICD implantation was 14 (16%) and 84 (94%), respectively. The actual number of patients receiving an ICD was 17 (19%). The number of patients fulfilling the new NICE (TA314) guidance was 84 (94%). CONCLUSIONS: A small proportion of patients with STEMIs undergoing PPCI have a severely impaired LV systolic function. A large proportion of these patients will have improved LV systolic function at 3 months. There is a five-fold difference in the predicted ICD implantation rates depending on which guidance is followed-NICE versus ESC. The potential impact of the new NICE (TA314) guidance on ICD implantation will be a significant increase in ICD implantation rates. PMID- 25932331 TI - Diabetic muscle infarction: a systematic review. AB - CONTEXT: Diabetic muscle infarction (DMI) is a rare complication associated with poorly controlled diabetes mellitus. Less than 200 cases have been reported in the literature since it was first described over 45 years ago. There is no clear 'standard of care' for managing these patients. EVIDENCE ACQUISITION: PubMed searches were conducted for 'diabetic muscle infarction' and 'diabetic myonecrosis' from database inception through July 2014. All articles identified by these searches were reviewed in detail if the article text was available in English. EVIDENCE SYNTHESIS: The current literature exists as case reports or small case series, with no prospective or higher-order treatment studies available. Thus, an evidence-based approach to data synthesis was difficult. The available literature is presented objectively with an attempt to describe clinically relevant trends and findings in the diagnosis and management of DMI. CONCLUSIONS: Early recognition of DMI is key, so appropriate treatment can be initiated. MRI is the radiological study of choice. A combination of bed rest, glycemic control, and non-steroidal anti-inflammatory drug therapy appears to yield the shortest time to symptom resolution and the lowest risk of recurrence. PMID- 25932333 TI - Guilt by association: paradigm for detecting a silent killer (thoracic aortic aneurysm). AB - Recent studies have confirmed a close association between various medical conditions (intracranial aneurysm, abdominal aortic aneurysm, temporal arteritis, autoimmune disorder, renal cysts), certain aortic anatomic variants (bovine aortic arch, direct origin of left vertebral artery from aortic arch, bicuspid aortic valve), and family history of aneurysm disease with thoracic aortic aneurysm and dissection. This paper reviews these associations. We propose to capitalise on these associations as powerful and expanding opportunities to diagnose the virulent but silent disease of thoracic aortic aneurysm. This can be accomplished by recognition of this 'guilt by association' with the other conditions. Thus, patients with associated diseases and anatomic variants should be investigated for silent aortic aneurysms. Such a paradigm holds substantial potential for reducing death from the silent killer represented by thoracic aortic aneurysm disease. PMID- 25932334 TI - MRI using ultrasmall superparamagnetic particles of iron oxide in patients under surveillance for abdominal aortic aneurysms to predict rupture or surgical repair: MRI for abdominal aortic aneurysms to predict rupture or surgery-the MA(3)RS study. AB - INTRODUCTION: Population screening for abdominal aortic aneurysms (AAA) halves the associated mortality and has led to the establishment of national screening programmes. Prediction of aneurysm growth and rupture is challenging and currently relies on serial diameter measurements with ultrasound. Recently, a novel MRI-based technique using ultrasmall superparamagnetic particles of iron oxide (USPIO) has demonstrated considerable promise as a method of identifying aneurysm inflammation and expansion. METHODS AND ANALYSIS: The MA(3)RS study is a prospective observational multicentre cohort study of 350 patients with AAA in three centres across Scotland. All participants will undergo MRI with USPIO and aneurysm expansion will be measured over 2 years with CT in addition to standard clinical ultrasound surveillance. The relationship between mural USPIO uptake and subsequent clinical outcomes, including expansion, rupture and repair, will be evaluated and used to determine whether the technique augments standard risk prediction markers. To ensure adequate sensitivity to answer the primary question, we need to observe 130 events (composite of rupture or repair) with an estimated event rate of 41% over 2 years of follow-up. The MA(3)RS study is currently recruiting and expects to report in 2017. DISCUSSION: This is the first study to evaluate the use of USPIO-enhanced MRI to provide additional information to aid risk prediction models in patients with AAA. If successful, this study will lay the foundation for a large randomised controlled trial targeted at applying this technique to determine clinical management. TRIAL REGISTRATION NUMBER: Current Controlled Trials: ISRCTN76413758. PMID- 25932336 TI - Genes at stake. PMID- 25932335 TI - Current Approaches in the Treatment of Relapsed and Refractory Acute Myeloid Leukemia. AB - The limited sensitivity of the historical treatment response criteria for acute myeloid leukemia (AML) has resulted in a different paradigm for treatment compared with most other cancers presenting with widely disseminated disease. Initial cytotoxic induction chemotherapy is often able to reduce tumor burden to a level sufficient to meet the current criteria for "complete" remission. Nevertheless, most AML patients ultimately die from their disease, most commonly as clinically evident relapsed AML. Despite a variety of available salvage therapy options, prognosis in patients with relapsed or refractory AML is generally poor. In this review, we outline the commonly utilized salvage cytotoxic therapy interventions and then highlight novel investigational efforts currently in clinical trials using both pathway-targeted agents and immunotherapy based approaches. We conclude that there is no current standard of care for adult relapsed or refractory AML other than offering referral to an appropriate clinical trial. PMID- 25932337 TI - The effect of photodynamic therapy on Aggregatibacter actinomycetemcomitans attached to surface-modified titanium. AB - PURPOSE: The purpose of this study was to evaluate the effect of photodynamic therapy (PDT) using erythrosine and a green light emitting diode (LED) light source on biofilms of Aggregatibacter actinomycetemcomitans attached to resorbable blasted media (RBM) and sandblasted, large-grit, acid-etched (SLA) titanium surfaces in vitro. METHODS: RBM and SLA disks were subdivided into four groups, including one control group and three test groups (referred to as E0, E30, E60), in order to evaluate the effect of PDT on each surface. The E0 group was put into 500 uL of 20 uM erythrosine for 60 seconds without irradiation, the E30 group was put into erythrosine for 60 seconds and was then irradiated with a LED for 30 seconds, and the E60 group was put into erythrosine for 60 seconds and then irradiated with a LED for 60 seconds. After PDT, sonication was performed in order to detach the bacteria, the plates were incubated under anaerobic conditions on brucella blood agar plates for 72 hours at 37C, and the number of colony-forming units (CFUs) was determined. RESULTS: Significant differences were found between the control group and the E30 and E60 groups (P<0.05). A significantly lower quantity of CFU/mL was found in the E30 and E60 groups on both titanium disk surfaces. In confocal scanning laser microscopy images, increased bacterial death was observed when disks were irradiated for a longer period of time. CONCLUSIONS: These findings suggest that PDT using erythrosine and a green LED is effective in reducing the viability of A. actinomycetemcomitans attached to surface-modified titanium in vitro. PMID- 25932338 TI - Effectiveness of biphasic calcium phosphate block bone substitutes processed using a modified extrusion method in rabbit calvarial defects. AB - PURPOSE: This study evaluated the mechanical and structural properties of biphasic calcium phosphate (BCP) blocks processed using a modified extrusion method, and assessed their in vivo effectiveness using a rabbit calvarial defect model. METHODS: BCP blocks with three distinct ratios of hydroxyapatite (HA):tricalcium phosphate (TCP) were produced using a modified extrusion method:HA8 (8%:92%), HA48 (48%:52%), and HA80 (80%:20%). The blocks were examined using scanning electron microscopy, X-ray diffractometry, and a universal test machine. Four circular defects 8 mm in diameter were made in 12 rabbits. One defect in each animal served as a control, and the other three defects received the BCP blocks. The rabbits were sacrificed at either two weeks (n=6) or eight weeks (n=6) postoperatively. RESULTS: The pore size, porosity, and compressive strength of the three types of bone block were 140-170 um, >70%, and 4-9 MPa, respectively. Histologic and histomorphometric observations revealed that the augmented space was well maintained, but limited bone formation was observed around the defect base and defect margins. No significant differences were found in the amount of new bone formation, graft material resorption, or bone infiltration among the three types of BCP block at either of the postoperative healing points. CONCLUSIONS: Block bone substitutes with three distinct compositions (i.e., HA:TCP ratios) processed by a modified extrusion method exhibited limited osteoconductive potency, but excellent space-maintaining capability. Further investigations are required to improve the processing method. PMID- 25932339 TI - Efficacy of sonic-powered toothbrushes for plaque removal in patients with peri implant mucositis. AB - PURPOSE: The aim of this study was to evaluate the effectiveness of powered toothbrushes for plaque control in patients with peri-implant mucositis, in comparison with manual toothbrushes. METHODS: This randomized, prospective, controlled, clinical parallel study compared the efficacy of manual and powered toothbrushes for plaque control in implant restorations. Patients with bleeding on probing, no residual pocket depth (as indicated by a pocket probing depth >= 5 mm), and no radiological peri-implant bone loss were eligible for this study. Patients were requested to complete a questionnaire describing their oral hygiene habits. The duration and frequency of tooth brushing were recorded by subjects in order to assess their compliance. Clinical parameters, including the modified plaque index (mPI), the modified sulcus bleeding index (mSBI), and clinical photographs (buccal and lingual views) were recorded at baseline and at one-month and two-month follow-up visits. RESULTS: Statistically significant differences between patients who used manual toothbrushes and those who used powered toothbrushes were found regarding the frequency of tooth brushing per day and the duration of brushing at one-month and two-month follow-up visits, while no statistically significant differences were found relating to other oral hygiene habits. A statistically significant difference in patient compliance for tooth brushing was found at one month, while no difference was found at two months. Statistically significant decreases in the mPI and the mSBI were observed in both groups from baseline to the one- and two-month follow-ups. The overall reduction of these parameters was not significantly different between the two groups, except for mPI reduction between baseline and one month of follow-up. CONCLUSIONS: Sonic-powered toothbrushes may be a useful device for plaque control in patients with peri-implant mucositis. PMID- 25932341 TI - Multiple transcripts of anoctamin genes expressed in the mouse submandibular salivary gland. AB - PURPOSE: Salivary fluid formation is primarily driven by Ca(2+)-activated, apical efflux of chloride into the lumen of the salivary acinus. The anoctamin1 protein is an anion channel with properties resembling the endogenous calcium-activated chloride channels. In order to better understand the role of anoctamin proteins in salivary exocrine secretion, the expression of the ten members of the anoctamin gene family in the mouse submandibular gland was studied. METHODS: Total RNA extracted from mouse submandibular salivary glands was reverse transcribed using primer pairs to amplify the full-length coding regions of each anoctamin gene and was subcloned into plasmid vectors for DNA sequencing. Alternative splice variants were also screened by polymerase chain reaction using primer pairs that amplified six overlapping regions of the complementary DNA of each anoctamin gene, spanning multiple exons. RESULTS: Multiple anoctamin transcripts were found in the mouse submandibular salivary gland, including full length transcripts of anoctamin1, anoctamin3, anoctamin4, anoctamin5, anoctamin6, anoctamin9, and anoctamin10. Exon-skipping splicing in the N-terminal exons of the anoctamins1, anoctamin5, and anoctamin6 genes resulted in multiple alternative splice variants. No expression of anoctamin2, anoctamin7, or anoctamin8 was found. CONCLUSIONS: The predominant anoctamin transcript expressed in the mouse submandibular gland is anoctamin1ac. The chloride channel protein produced by anoctamin1ac is likely responsible for the Ca(2+)-activated chloride efflux, which is the rate-limiting step in salivary exocrine secretion. PMID- 25932340 TI - Histomorphometric analysis of microcrack healing after the installation of mini implants. AB - PURPOSE: The goal of this study was to investigate the histomorphometric characteristics of the healing process of microcracks in the cortical bone after the installation of mini-implants (MIs). METHODS: Self-drilling MIs were inserted into the tibial diaphysis of twelve adult male New Zealand rabbits. Four MIs per rabbit were placed randomly. The animals were divided into four groups according to the length of the healing period: group A was sacrificed immediately, group B was sacrificed after one week, group C was sacrificed after two weeks, and group D was sacrificed after four weeks. Cortical bone thickness was measured using micro-computed tomography, and histomorphometric analyses of the cumulative length of the microcracks (CLCr) and the total number of microcracks (NCr) were performed using hematoxylin and eosin staining. RESULTS: The microcracks were radially and concentrically aligned in the peri-MI bone. The CLCr decreased significantly one week after the surgery, mainly due to healing of the concentrically aligned microcracks. The CLCr showed another significant decrease from two weeks after the surgery to four weeks after the surgery, mainly reflecting healing of the radially aligned microcracks. A statistically significant decrease in the NCr occurred as the microcracks healed from zero weeks to two weeks. However, no significant difference in the NCr was found between groups C and D. CONCLUSIONS: In order to improve the primary stability of MIs, delayed loading and a healing period of a certain length are recommended to ensure the optimal healing of microcracks and bone remodeling. PMID- 25932342 TI - Extensive gingival necrosis and sequestration of the alveolar bone caused by methimazole-induced neutropenia and three-year follow-up. AB - PURPOSE: Methimazole is an anti-thyroid drug that can cause life-threatening neutropenia in rare situations. The aim of this case report is to describe a set of oral complications associated with methimazole-induced neutropenia and the healing of the gingiva after proper treatment. METHODS: A 31-year-old female patient hospitalized for systemic symptoms of sore throat and fever and showing extensive gingival necrosis with pain was referred to the Department of Periodontics from the Department of Endocrinology. Methimazole-induced neutropenia was diagnosed based on blood test results and her medical history. Methimazole was discontinued and a range of treatments was administered, including the injection of granulocyte colony stimulating factor. RESULTS: After systemic treatment, the gingiva began to heal as the neutrophil count increased. Approximately one year later, the gingiva had returned to a normal appearance. Twenty-one months after treatment, sequestra of the alveolar bone that had broken through the gingiva were removed. Periodic supportive periodontal treatment has been continued uneventfully. CONCLUSIONS: The oral manifestations of gingival necrosis and ulcerations, in combination with systemic symptoms such as fever and sore throat, are the critical signs presented in the early stages of drug-induced neutropenia. Therefore, dentists need to be aware of these oral complications in order to make an accurate diagnosis and to ensure that prompt medical intervention is provided. PMID- 25932343 TI - Vulnerability Factors and Pathways Leading to Underage Entry into Sex Work in two Mexican-US Border Cities. PMID- 25932344 TI - Strengthening Interactions between Statisticians and Collaborators: Objectives and Sample Sizes. PMID- 25932345 TI - Managing the Earth's Biggest Mass Gathering Event and WASH Conditions: Maha Kumbh Mela (India). AB - BACKGROUND: Mass gatherings including a large number of people makes the planning and management of the event a difficult task. Kumbh Mela is one such, internationally famous religious mass gathering. It creates the substantial challenge of creating a temporary city in which millions of people can stay for a defined period of time. The arrangements need to allow this very large number of people to reside with proper human waste disposal, medical services, adequate supplies of food and clean water, transportation etc. METHODS: We report a case study of Maha Kumbh, 2013 which focuses on the management and planning that went into the preparation of Kumbh Mela and understanding its water, sanitation and hygiene conditions. It was an observational cross-sectional study, the field work was done for 13 days, from 21 January to 2 February 2013. RESULTS: Our findings suggest that the Mela committee and all other agencies involved in Mela management proved to be successful in supervising the event and making it convenient, efficient and safe. Health care services and water sanitation and hygiene conditions were found to be satisfactory. BhuleBhatke Kendra (Center for helping people who got separated from their families) had the major task of finding missing people and helping them to meet their families. Some of the shortfalls identified were that drainage was a major problem and some fire incidents were reported. Therefore, improvement in drainage facilities and reduction in fire incidents are essential to making Mela cleaner and safer. The number of persons per toilet was high and there were no separate toilets for males and females. Special facilities and separate toilets for men and women will improve their stay in Mela. CONCLUSION: Inculcation of modern methods and technologies are likely to help in supporting crowd management and improving water, sanitation and hygiene conditions in the continuously expanding KumbhMela, in the coming years. PMID- 25932346 TI - The Potential Impact of Directionality, Colour Perceptions and Cultural Associations on Disaster Messages During Heatwaves in the UK. AB - The health risks posed by heatwaves have been well documented. In the UK, before and during a heatwave, alerts are issued to the general public based on a tiered warning system integrating the use of colour and number sequences. There has of yet been no formal assessment of the public response to these messages. Cultural and language barriers make some members of ethnic minority communities particularly hard to reach. These may be less challenging amongst younger community members, who may be well placed to instigate the circulation of warning information to those less able or willing to use conventional channels. This qualitative study assesses the role of age and ethnic and cultural background in the conceptualisation of the number and colour systems used as part of the Heat Health Watch System (HHWS) and the National Severe Weather Warning Service (NSWWS). Young and older participants were recruited from the Bangladeshi and white British populations of Tower Hamlets. All participants were given a cognitive task that required them to identify and draw associations between 12 cards depicting the four colours and numbers used in the warning system and four pictures providing contextualisation in terms of heatwave risk. A qualitative analysis of the heuristics used in the group discussions provided insights into the conceptualisations basic to interpreting colour and number sequences as representations of risk graduations, and how interpretation might be influenced by age and ethnic and cultural background. There were considerable differences in the interpretation of young Bangladeshi and older white British participants, on the one hand, and older Bangladeshi participants, on the other. Young Bangladeshis and older white British participants conceptualised the colours and numbers as a vertical scale, with the numbers/colours at "the top" corresponding to representations of higher temperature. This conceptualisation was mainly based on strong associations between colour and temperature, with risk only associated with the upper limit of the scale. Older Bangladeshi participants, on the other hand, conceptualised the numbers and pictures as a narrative sequence and disassociated the colours from the other cards. The differences between groups suggest potential cultural barriers to the "intended" interpretation of the colour and number sequences for older Bangladeshis but not for young Bangladeshis. The fact that the predominant association for the colour sequence for both young Bangladeshis and older white British participants was with graduations of temperature rather than risk raises questions about the applicability of using colours in a tiered warning system. PMID- 25932347 TI - Services for mothers and newborns during the ebola outbreak in liberia: the need for improvement in emergencies. AB - BACKGROUND: The magnitude of the Ebola outbreak in West Africa is unprecedented. Liberia, Guinea, and Sierra Leone are in the bottom ten countries in the Human Development Index, but all had made gains in child survival prior to the outbreak. With closure of healthcare facilities and the loss of health workers secondary to the outbreak, the region risks reversing survival gains achieved in maternal and newborn health. METHODS: Anonymized service utilization data were downloaded from the Liberia District Health Information Software (DHIS) 2 for selected maternal health services at PHC facilities in Margibi and Bong Counties from March 2014, when the first case of Ebola was reported in Liberia, through December 2014. Absolute numbers are provided instead of percentage measures because of the lack of a population-based denominator. RESULTS: Overall, the data show a decrease in absolute utilization from the start of the outbreak, followed by a slow recovery after October or November. In Bong County, totals were less than 14% of the peak numbers during the outbreak for number of antenatal visits and pregnant women receiving intermittent preventive treatment for malaria in pregnancy (IPTp). For total deliveries, utilization was less than 33% of the highest month. In Margibi County, during what now appears to be the height of the outbreak, numbers dropped to less than 9% of peak utilization for antenatal care visits and 4% for IPTp. Total health facility deliveries dropped to less than 9% of peak utilization. CONCLUSION: It is clear that Bong and Margibi Counties in Liberia experienced a large drop in utilization of maternal health care services during what now appears to be the peak of the Ebola outbreak. As the health of women and their babies is being promoted in the post-2015 sustainable development agenda, it is critical that the issue of maternal and newborn survival in humanitarian emergency settings, like the Ebola outbreak, is prioritized. PMID- 25932348 TI - Feasibility assessment of using geoinformatics technology in disaster disease surveillance in a developing country, iran. AB - BACKGROUND AND PURPOSE: Geoinformatics technology retains an unprecedented trait of performing with a supersonic speed and precision in public health management whereas the existing disease surveillance systems in developing countries lack using this technology. This article aims to assess the feasibility of using geoinformatics technology in disaster disease surveillance in a developing country, Iran. METHODS: A self-administered questionnaire was developed based on technology acceptance model (TAM), and a semi-quantitative survey was conducted in order to collect data. Fifty TUMS & HS personnel, currently involve in disease surveillance and information technology, were included. Initially, a pilot study was conducted to test the validity and reliability of the questionnaire. Cronbach alpha, confirmatory factor analysis (CFA), and standard error of measurement (SEM) were calculated to validate the causal model. RESULTS: The results from structural equation analysis suggested that TAM provided a constructive picture of using geoinformatics technology in disaster disease surveillance at TUMS &HS. The study found attitude (ATT) had a significant influence on participants intention to use (ITU) a new technology, and perceived ease of use (PEOU) was a strong determinant of perceived of usefulness (PU). Subsequently, PU and PEOU explained ATT substantially; even though the analysis showed insignificant statistical association among these constructs. The high R2 (Coefficient of determination) of the constructs described respondents positive instinct towards accepting a new technology. CONCLUSION: The study reveals that personnel intent to adopt geoinformatics technology in disaster disease surveillance; and at the same time, they possess a positive attitude towards the technology. This study also found PEOU has a strong influence on PU, so information sessions and training on geoinformatics technology need to focus primarily on the applications and impacts of technology on disaster disease surveillance. PMID- 25932349 TI - Control of a Reassortant Pandemic 2009 H1N1 Influenza Virus Outbreak in an Intensive Swine Breeding Farm: Effect of Vaccination and Enhanced Farm Management Practices. AB - Influenza A viruses in swine cause considerable economic losses and raise concerns about their zoonotic potential. The current paucity of thorough empirical assessments of influenza A virus infection levels in swine herds under different control interventions hinders our understanding of their effectiveness. Between 2012 and 2013, recurrent outbreaks of respiratory disease caused by a reassortant pandemic 2009 H1N1 (H1N1pdm) virus were registered in a swine breeding farm in North-East Italy, providing the opportunity to assess an outbreak response plan based on vaccination and enhanced farm management. All sows/gilts were vaccinated with a H1N1pdm-specific vaccine, biosecurity was enhanced, weaning cycles were lengthened, and cross-fostering of piglets was banned. All tested piglets had maternally-derived antibodies at 30 days of age and were detectable in 5.3% of ~90 day-old piglets. There was a significant reduction in H1N1pdm RT-PCR detections after the intervention. Although our study could not fully determine the extent to which the observed trends in seropositivity or RT-PCR positivity among piglets were due to the intervention or to the natural course of the disease in the herd, we provided suggestive evidence that the applied measures were useful in controlling the outbreak, even without an all-in/all-out system, while keeping farm productivity at full. PMID- 25932350 TI - Rural-urban migration and mental and sexual health: a case study in Southwestern China. AB - Massive rural-urban temporary migration has taken place amid China's rapid economic growth and development. Much has been written about the economic causes and consequences of this massive migration; less studied are the potential health and behavioral impacts of migration on migrants. Using data from a population based sample survey conducted in southwestern China, this paper examines the potential impact of rural-urban migration and post-migration urban living on migrants' mental health and sexual risk behavior. The results suggest that regardless of places of origin and destination temporary migrants had on average poorer mental health and riskier sexual behavior than non-migrants. Compared to living in rural areas, living in urban areas does not make statistical difference in residents' mental health; it is only marginally associated with riskier sexual behavior. Rural-urban temporary migrants' mental health and health risk sexual behavior deserve more immediate research attention. Both selectivity of temporary migrants and migration-induced psycho-socio-behavioral changes may have contributed to migrants' poorer mental health and riskier sexual behavior. However, more theory-driven research with longitudinal design is needed before firm conclusions can be drawn about the underlying mechanisms that mediate or moderate the impact of temporary migration on migrants' mental health and sexual risk behavior. PMID- 25932351 TI - Non-invasive Ventilation: A Gimmick or Does it Really Affect Outcomes? PMID- 25932352 TI - Stratospheric sulfur and its implications for radiative forcing simulated by the chemistry climate model EMAC. AB - Multiyear simulations with the atmospheric chemistry general circulation model EMAC with a microphysical modal aerosol module at high vertical resolution demonstrate that the sulfur gases COS and SO2, the latter from low-latitude and midlatitude volcanic eruptions, predominantly control the formation of stratospheric aerosol. Marine dimethyl sulfide (DMS) and other SO2 sources, including strong anthropogenic emissions in China, are found to play a minor role except in the lowermost stratosphere. Estimates of volcanic SO2 emissions are based on satellite observations using Total Ozone Mapping Spectrometer and Ozone Monitoring Instrument for total injected mass and Michelson Interferometer for Passive Atmospheric Sounding (MIPAS) on Envisat or Stratospheric Aerosol and Gases Experiment for the spatial distribution. The 10 year SO2 and COS data set of MIPAS is also used for model evaluation. The calculated radiative forcing of stratospheric background aerosol including sulfate from COS and small contributions by DMS oxidation, and organic aerosol from biomass burning, is about 0.07W/m2. For stratospheric sulfate aerosol from medium and small volcanic eruptions between 2005 and 2011 a global radiative forcing up to 0.2W/m2 is calculated, moderating climate warming, while for the major Pinatubo eruption the simulated forcing reaches 5W/m2, leading to temporary climate cooling. The Pinatubo simulation demonstrates the importance of radiative feedback on dynamics, e.g., enhanced tropical upwelling, for large volcanic eruptions. PMID- 25932353 TI - Metabolically active tumour volume segmentation from dynamic [(18)F]FLT PET studies in non-small cell lung cancer. AB - BACKGROUND: Positron emission tomography (PET) with (18)F-3'-deoxy-3' fluorothymidine ([(18)F]FLT) can be used to assess tumour proliferation. A kinetic-filtering (KF) classification algorithm has been suggested for segmentation of tumours in dynamic [(18)F]FLT PET data. The aim of the present study was to evaluate KF segmentation and its test-retest performance in [(18)F]FLT PET in non-small cell lung cancer (NSCLC) patients. METHODS: Nine NSCLC patients underwent two 60-min dynamic [(18)F]FLT PET scans within 7 days prior to treatment. Dynamic scans were reconstructed with filtered back projection (FBP) as well as with ordered subsets expectation maximisation (OSEM). Twenty-eight lesions were identified by an experienced physician. Segmentation was performed using KF applied to the dynamic data set and a source-to-background corrected 50% threshold (A50%) was applied to the sum image of the last three frames (45- to 60-min p.i.). Furthermore, several adaptations of KF were tested. Both for KF and A50% test-retest (TRT) variability of metabolically active tumour volume and standard uptake value (SUV) were evaluated. RESULTS: KF performed better on OSEM- than on FBP-reconstructed PET images. The original KF implementation segmented 15 out of 28 lesions, whereas A50% segmented each lesion. Adapted KF versions, however, were able to segment 26 out of 28 lesions. In the best performing adapted versions, metabolically active tumour volume and SUV TRT variability was similar to those of A50%. KF misclassified certain tumour areas as vertebrae or liver tissue, which was shown to be related to heterogeneous [(18)F]FLT uptake areas within the tumour. CONCLUSIONS: For [(18)F]FLT PET studies in NSCLC patients, KF and A50% show comparable tumour volume segmentation performance. The KF method needs, however, a site-specific optimisation. The A50% is therefore a good alternative for tumour segmentation in NSCLC [(18)F]FLT PET studies in multicentre studies. Yet, it was observed that KF has the potential to subsegment lesions in high and low proliferative areas. PMID- 25932354 TI - GMP-compliant (68)Ga radiolabelling in a conventional small-scale radiopharmacy: a feasible approach for routine clinical use. AB - BACKGROUND: The number of routine care patient examinations with (68)Ga radiopharmaceuticals is still relatively limited, probably caused by the presumed need for large investments in hot cells, automated synthesis modules, laboratory equipment and validation efforts. Our aim was to set up the preparation of (68)Ga DOTA-NOC in compliance with all current European Union-Good Manufacturing Practices (EU-GMP), current Good Radiopharmacy Practice (cGRPP) and European Pharmacopoeia (Ph. Eur.) guidance but without the availability of a hot cell and gas chromatography (GC), high-performance liquid chromatography (HPLC) and atomic absorption spectrometry (AAS) equipment. METHODS: A risk-based approach was applied to align preparation conditions with applicable regulations, together with a validation of a thin-layer chromatography (ITLC) method to replace HPLC as modality for examining radiochemical purity. RESULTS: Using an internally shielded labelling module for manual operation, a (68)Ga-DOTA-NOC labelling procedure was set up that meets all applicable Ph. Eur. specifications. The applied ITLC method showed very good correlation with HPLC results (r = 0.961) and was able to detect relevant deviations in radiolabelling procedures. All identified quality assurance aspects were made compliant with EU-GMP and cGRPP guidance. CONCLUSIONS: We consider the described configuration and validation approach feasible for many conventional small-scale radiopharmacies, something that could help to increase the availability of (68)Ga radiopharmaceuticals to a large number of patients. PMID- 25932355 TI - Fibroblast growth factor-21 enhances mitochondrial functions and increases the activity of PGC-1alpha in human dopaminergic neurons via Sirtuin-1. AB - Mitochondrial dysfunctions accompany several neurodegenerative disorders and contribute to disease pathogenesis among others in Parkinson's disease (PD). Peroxisome proliferator-activated receptor gamma coactivator-1alpha (PGC-1alpha) is a major regulator of mitochondrial functions and biogenesis, and was suggested as a therapeutic target in PD. PGC-1alpha is regulated by both transcriptional and posttranslational events involving also the action of growth factors. Fibroblast growth factor-21 (FGF21) is a regulator of glucose and fatty acid metabolism in the body but little is known about its action in the brain. We show here that FGF21 increased the levels and activity of PGC-1alpha and elevated mitochondrial antioxidants in human dopaminergic cells in culture. The activation of PGC-1alpha by FGF21 occurred via the NAD(+)-dependent deacetylase Sirtuin-1 (SIRT1) subsequent to an increase in the enzyme, nicotinamide phosphoribosyltransferase (Nampt). FGF21 also enhanced mitochondrial respiratory capacity in human dopaminergic neurons as shown in real-time analyses of living cells. FGF21 is present in the brain including midbrain and is expressed by glial cells in culture. These results show that FGF21 activates PGC-1alpha and increases mitochondrial efficacy in human dopaminergic neurons suggesting that FGF21 could potentially play a role in dopaminergic neuron viability and in PD. PMID- 25932356 TI - Breast 3 T-MR imaging: indication for stereotactic vacuum-assisted breast biopsy. AB - PURPOSE: The purpose of this study was to assess indications for stereotactic vacuum-assisted breast biopsy (SVAB) evaluated by breast 3 T-magnetic resonance (3 T-MR) imaging in patients showing suspicious microcalcifications on mammography and negative ultrasound (US) findings. METHODS AND MATERIALS: Fifty five patients with 55 breast lesions showing suspicious microcalcifications on mammography and negative US findings underwent preoperative 3 T-MR examination including dynamic MR imaging. All patients underwent SVAB within 1 month of MR imaging. The pathological diagnosis of each breast lesion was made by examining tissues obtained by SVAB or radical/partial mastectomy. 3 T-MR imaging findings were evaluated by using the American College of Radiology Breast Imaging Reporting and Data System Atlas (BI-RADS-MRI) and then were correlated with the histopathological findings. When BI-RADS 4 and 5 MR imaging lesions were assumed to be malignant, the usefulness of 3 T-MR imaging was evaluated for diagnosis of impalpable breast lesions by SVAB among lesions with microcalcification detected by mammography and negative US findings. RESULTS: There were 21 malignant lesions, including 5 invasive ductal carcinomas, 16 lesions of ductal carcinoma in situ (DCIS). The sensitivity, specificity, positive predictive value, negative predictive value, and accuracy of 3 T-MR imaging for deciding the indications for SVAB was 90.5%, 97.1%, 95.0%, 94.3%, and 94.5%, respectively. The one-false negative case was a DCIS with small enhancing lesions (0.5 mm). The one false positive case was ductal adenoma with a linear ductal pattern of enhancement. CONCLUSIONS: 3 T-MR imaging may be useful for deciding the indications for SVAB in patients who have breast lesions with microcalcification that are impalpable and are detected by mammography and negative US findings. However, our findings should be considered preliminary and further prospective investigation is required. PMID- 25932357 TI - Implications of a novel Pseudomonas species on low density polyethylene biodegradation: an in vitro to in silico approach. AB - Degradation of Petroleum-plastics like Low Density Polyethylene (LDPE) is a budding challenge due to increasing white pollution. The present investigation has focused the aspect through microbial assisted biodegradation. Various indigenous microorganisms were isolated from collected municipal landfill soil. Growth medium enriched with 0.2 g of LDPE powder was used to screen the soil bacteria with biodegradation potential. The screened bacteria were subjected to biodegradation assay in presence of LDPE sheets in growth medium. Four strains gave 5%, 17.8%, 0.9% and 0.6% degradation rate based on weight loss in the conducted in vitro assay for four days. The maximum degraded sheet was analyzed through Scanning Electron Microscopy, Fourier transform infrared spectroscopy and Thermogravimetry, taking undegraded LDPE sheet as control. Results illustrated one-step weight loss with control and three-step weight loss with test. Thus, it proved the efficacy of isolated strain. The strain identification was carried out by genomic DNA isolation followed by PCR and 16S rRNA sequencing. Genotypic identification revealed the bacterium as Pseudomonas citronellolis. BLAST gave a similarity with the database of 96%, thus phylogenetic assessment clarified the bacterium as a novel strain. The isolate was named as Pseudomonas citronellolis EMBS027 and sequence was deposited as LDPE degrading species, in GenBank with accession number KF361478. PMID- 25932358 TI - A PCR method for VKORC1 G-1639A and CYP2C9 A1075C genotyping useful to warfarin therapy among Japanese. AB - Warfarin is widely prescribed for patients with the risk of thromboembolism around the world. The inter-individual and inter-racial differences in appropriate dosage depend highly on age, body weight, and genetic factors. A lot of studies including genome-wide association studies revealed that vitamin K epoxide reductase complex, subunit 1 (VKORC1) G-1639A and Cytochrome P450 (CYP) 2C9 A1075C are the most strong genetic factors for determining warfarin effects in Asians and Africans. Since we developed a quick and inexpensive genotyping method, polymerase chain reaction with confronting two-pair primers (PCR-CTPP), the method was applied for these genotypes to examine the possibility to clinical use. Subjects were 436 examinees (117 males and 319 females, aged 32 to 85 years) who attended a health checkup program in Japan. The PCR-CTPP for VKORC1 G-1639A and CYP2C9 A1075C was conducted for the subjects, as well as the samples genotyped by DigiTag2 method. The allele frequencies of VKORC1 G-1639A were 0.085 for G and 0.915 for A, and those of CYP2C9 A1075C were 0.979 for A and 0.021 for C, being in Hardy-Weinberg equilibrium (p = 0.658 and p = 0.514, respectively). These frequencies were similar to those reported in the HapMap project. Genotyping for both SNPs by PCR-CTPP was replicated by DigiTag2 method. Our results indicated that the PCR-CTPP could be one of the alternative methods for genotyping VKORC1 G-1639A and CYP2C9 A1075C for Asians and Africans with similar allele frequencies to Japanese. PMID- 25932359 TI - Initial experience with use of hydrogel microcoils in embolization of pulmonary arteriovenous malformations. AB - The purpose of this study is to describe our initial experience with embolization of pulmonary arteriovenous malformations (PAVMs) using hydrogel microcoils. The technical and radiological outcomes were retrospectively reviewed in seven patients with nine simple-type PAVMs (median feeder size 4 mm, range 3-6 mm) who underwent embolization. Hydrogel microcoils were mainly used, and detachable bare microcoils were combined as needed to occlude the terminal feeding artery just before the sac. Of a total of 43 microcoils, 30 (69.8%) hydrogel microcoils were deployed in eight PAVMs with the median number 3.5 (range 2 to 6) per lesion. All hydrogel microcoils were successfully deployed without microcatheter stuck or malposition. In the remaining one small PAVM, only soft bare microcoils were used, however, resulting in recanalization requiring additional coils in the second session. The venous sac was substantially shrunk in all lesions treated with hydrogel microcoils with the median size reduction rate 95.0% (range 81.8% to 99.0%) during the median follow-up period 10 months (range 6 to 18 months). In conclusion, hydrogel microcoils were safely and effectively applied for occluding PAVMs with relatively small feeders. PMID- 25932360 TI - Detection of alterations in membrane metabolism during neoadjuvant chemotherapy in patients with breast cancer using phosphorus magnetic resonance spectroscopy at 7 Tesla. AB - Here we investigate the feasibility of tumor metabolism monitoring in T1c to T3 breast cancer during neoadjuvant chemotherapy by means of phosphorus ((31)P) magnetic resonance spectroscopy at 7 tesla (T). Five breast cancer patients were examined using a (31)P MRSI sequence, prior to-, halfway-, and after neoadjuvant chemotherapy. The (31)P MRSI data were analyzed on group and individual level and compared to a spectrum of a group of healthy volunteers. Ratios of phosphomonoesters (PME) to phosphodiesters (PDE) and phosphomonoesters to inorganic phosphate (Pi) were determined. Histopathologic assessment showed four partial responders and one complete responder to chemotherapy. The (31)P spectrum of the patient group was distinctly different from the (31)P spectrum of healthy volunteers and transformed its shape during the course of chemotherapy towards the shape of the spectrum of the healthy volunteers. Prior to chemotherapy the PME to PDE signal ratio and the PME to Pi signal ratio were high, and during the course of the chemotherapy these ratios normalized to the value of the healthy volunteers. Metabolite T 2 values in tumor tissue tended to be lower than those for healthy glandular tissue. Assessment of individual patients showed that four out of five had a significant drop of the PME to Pi ratio by a factor of 2 or more. On average, the pH of the tumor, calculated from chemical shift variation of Pi, was 0.19 units lower before chemotherapy. We have demonstrated that the sensitivity of (31)P MRSI in breast cancer at 7 T is sufficient to detect alterations in membrane metabolism during neoadjuvant chemotherapy, which may be used for early assessment of treatment efficacy. PMID- 25932361 TI - Interactions of antiparasitic sterols with sterol 14alpha-demethylase (CYP51) of human pathogens. AB - Sterol 14alpha-demethylase is a validated and an attractive drug target in human protozoan parasites. Pharmacological inactivation of this important enzyme has proven very effective against fungal infections, and it is a target that is being exploited for new antitrypanosomal and antileishmanial chemotherapy. We have used in silico calculations to identify previously reported antiparasitic sterol-like compounds and their structural congeners that have preferential and high docking affinity for CYP51. The sterol 14alpha-demethylase from Trypanosoma cruzi and Leishmania infantum, in particular, preferentially dock to taraxerol, epi oleanolic acid, and alpha/beta-amyrim structural scaffolds. These structural information and predicted interactions can be exploited for fragment/structure based antiprotozoal drug design. PMID- 25932363 TI - Hypertensive encephalopathy and cerebral infarction. AB - INTRODUCTION: Hypertensive encephalopathy is one cause of posterior reversible encephalopathy syndrome. Hypertensive encephalopathy and cerebral infarction have only been reported in a few individual case reports. CASE DESCRIPTION: A 51-year old woman presented with hypertensive encephalopathy. T2-weighted images from magnetic resonance imaging showed hyperintense lesions in both occipital and parietal lobes. Diffusion-weighted imaging showed that this represented cytotoxic oedema and perfusion magnetic resonance imaging revealed reduced blood volume and flow. The magnetic resonance imaging was repeated 5 months later and subtotal regression of theT2-hyperintensity had occurred. However, small bilateral infarcts were seen on T1-weighted images. Perfusion magnetic resonance imaging presented reduced blood volume and flow on the right side. DISCUSSION AND EVALUATION: The patient in this report had posterior reversible encephalopathy syndrome caused by hypertensive encephalopathy. Magnetic resonance imaging of the brain showed bilateral cytotoxic oedema that partially resolved and resulted in small infarcts. The imaging findings are compatible with posterior reversible encephalopathy syndrome with subtotal resolution and infarct evolution. CONCLUSION: The case report suggests that the presence of hypertensive encephalopathy and posterior reversible encephalopathy syndrome should alert clinicians and lead to prompt treatment in order to prevent cerebral damage. PMID- 25932364 TI - Real life experience on the effect of Belimumab in patients with active systemic lupus. AB - INTRODUCTION: To evaluate real life experience on the effect of Belimumab in patients with active systemic lupus erythematosus. CASE PRESENTATION: Twenty patinets with musclesketal symptoms were evaluated, three were discontinued for different resons and seventeen completed eight injections of Belimumab during a six month period. A fatigue score was also evaluated at the same time. DISCUSSION AND EVALUATION: Marked reduction of disease activity and fatigue score were observed in the patient group. CONCLUSIONS: Belimumab is a novel form of therapy in patients with active systemic lupus erythematosus to be added in the standard of care particularly in patients with skin and joint symptoms. PMID- 25932362 TI - A review of sleep deprivation studies evaluating the brain transcriptome. AB - Epidemiological studies show a positive association between adequate sleep and good health. Further, disrupted sleep may increase the risk for CNS diseases, such as stroke and Alzheimer's disease. However, there has been limited progress in determining how sleep is linked to brain health or how sleep disruption may increase susceptibility to brain insult and disease. Animal studies can aid in understanding these links. In reviewing the animal literature related to the effects of sleep disruption on the brain, we found most of the work was directed toward investigating and characterizing the role of various brain areas or structures in initiating and regulating sleep. In contrast, limited effort has been directed towards understanding how sleep disruption alters the brain's health or susceptibility to insult. We also note many current studies have determined the changes in the brain following compromised sleep by examining, for example, the brain transcriptome or to a more limited extent the proteome. However, these studies have utilized almost exclusively total sleep deprivation (e.g., 24 out of 24 hours) paradigms or single short periods of limited acute sleep deprivation (e.g., 3 out of 24 hours). While such strategies are beneficial in understanding how sleep is controlled, they may not have much translational value for determining links between sleep and brain health or for determining how sleep disruption may increase brain susceptibility to insult. Surprisingly, few studies have determined how the duration and recurrence of sleep deprivation influence the effects seen after sleep deprivation. Our aim in this review was to identify relevant rodent studies from 1980 through 2012 and analyze those that use varying durations of sleep deprivation or restriction in their effort to evaluate the effects of sleep deprivation on the brain transcriptome and to a more limited extent the proteome. We examined how differences in the duration of sleep deprivation affect gene and protein expression to better understand the full consequences of repeated sleep disruption on the brain. Future research needs to consider and emphasize how the type and extent of the sleep deprivation exposure impacts the conclusions reached concerning the influence of sleep disruption on the brain. We identified relevant studies between 1980 and 2012 by searching the electronic databases of PubMed, Medline (Ovid), Embase (Ovid), and Web of Science using the terms "sleep" AND "disrupt", "deprivation", "restrict", "fragment", "loss", "disturb", "disorder", "dysfunction", "brain", "cortex", striatum", hypothalamus", "hippocampus", "gene", "protein", "genomics", "proteomics", "polymerase chain reaction", "pcr", "microarray", "molecular", "rodent" "rat", "rats", "mouse", "mice". All searches were limited to rodent studies in English and the reference lists of retrieved articles were searched for additional pertinent studies. PMID- 25932365 TI - A new approach of presenting reversible logic gate in nanoscale. AB - Conventional lithography-based VLSI design technology deployed to optimize low powered-computing and higher scale integration of semiconductor components. However, this downscaling trend confronts serious challenges of tunneling and leakage current increment to the Complementary Metal-Oxide-Semiconductor (CMOS) technology on nanoscale regimes. To resolve the physical restriction of the CMOS, Quantum-dot Cellular Automata (QCA) technology dedicates for the nanoscale technology that embrace a new information transformation technique. However, QCA is limited to the design of the sequential and combinational circuits only. This paper presents some highly scalable features reversible logic gate for the QCA technology. In addition, proposed layout compared with CMOS technology, offer a better reduction in size up to 233 times. PMID- 25932366 TI - How well do radiographic, clinical and self-reported diagnoses of knee osteoarthritis agree? Findings from the Hertfordshire cohort study. AB - OBJECTIVE: Epidemiological studies of knee osteoarthritis (OA) have often used a radiographic definition. However, the clinical syndrome of OA is influenced by a broad range of factors in addition to the structural changes required for radiographic OA. Hence more recently several studies have adopted a clinical or self-reported approach to OA diagnosis rather than a radiographic approach. The aim of this study was to investigate agreement between radiographic OA and the clinical and self-reported diagnoses of OA. DESIGN: Data were available for 199 men and 196 women in the Hertfordshire Cohort Study (HCS), UK. Participants completed a questionnaire detailing self-reported OA. Clinical OA was defined based on American College of Rheumatology (ACR) criteria. Knee radiographs were taken and graded for overall Kellgren and Lawrence (K&L) score. RESULTS: The mean (standard deviation (SD)) age of study participants was 75.2 (2.6) years and almost identical proportions of men and women. The prevalence of knee OA differed depending on the method employed for diagnosis; 21% of the study participants self-reported knee OA, 18% of the participants had clinical knee OA and 42% of the participants had radiographic OA. Of those 72 study participants with a self reported diagnosis of knee OA 52 (72%) had a radiographic diagnosis of knee OA, while 66% (39 out of 59) of study participants with clinical knee OA had a diagnosis of radiographic knee OA. However 58% of those participants diagnosed with radiographic OA did not have either self-reported knee OA or a diagnosis of clinical OA. Therefore in comparison with the radiographic definition of OA, both the clinical and self-report definitions had high specificity (91.5% & 91.5% respectively) and low sensitivity (24.5% and 32.7% respectively). CONCLUSION: There is modest agreement between the radiographic, clinical and self-report methods of diagnosis of knee OA. PMID- 25932367 TI - The relationship between LAPTM4B polymorphisms and cancer risk in Chinese Han population: a meta-analysis. AB - LAPTM4B is a newly cloned gene that shows an active role in many solid tumors progression in substantial researches, mainly through the autophage function. Accumulated studies have been conducted to determine the association of LAPTM4B polymorphism with cancer risk. While the results are inconsistent, we conducted the meta-analysis to determine the strength of the relationship. Results showed that allele*2 carriers exhibited a significantly increased risk of cancer development with comparison to allele*1 homozygote (for *1/2, OR = 1.55, 95% CI 1.367-1.758; for *2/2, OR = 2.093, 95%CI 1.666-2.629; for *1/2 + *2/2, OR = 1.806, 95%CI 1.527-2.137). We also observed a significant association between *2/2 homozygote and cancer risk with comparison to allele*1 containing genotypes (OR = 1.714, 95%CI 1.408-2.088). Allele*2 is a risk factor for cancer risk (OR = 1.487, 95%CI 1.339-1.651). Stratified analysis by tumor type exhibits the significant association of this genetic variants with various cancers. In conclusion, LAPTM4B polymorphism is associated with cancer risk and allele*2 is a risk factor. PMID- 25932369 TI - The extracellular death factor (EDF) protects Escherichia coli by scavenging hydroxyl radicals induced by bactericidal antibiotics. AB - The newly discovered extracellular death factor (EDF) is a pentapeptide with the sequence NNWNN in Escherichia coli. It was reported that it participated in the cell death process mediated by toxin-antitoxin system mazEF. Reactive oxygen species (ROS) are recently considered as common factors for bactericidal antibiotics-mediated cell death. Previous study indicated that EDF could scavenge hydroxyl radicals and might act as a signal molecule with dual effects, "death" and "survival". But the structure-activity relationship of EDF and the effects of EDF on the activity of antibiotics remain unclear. In the present study, our results indicated that tryptophan could be the key residue to the hydroxyl radicals-scavenging activity of EDF, and EDF could protect Escherichia coli from killing by bactericidal antibiotics, but not by DNA-damaging or bacteriostatic antibiotics. Our results could provide novel evidence to understand the role of EDF in drug-resistance. PMID- 25932370 TI - Identification of tyrosinase inhibitors from traditional Chinese medicines for the management of hyperpigmentation. AB - The inhibition of tyrosinase is the most effective method to decrease melanin synthesis during the process of pigmentation. We aimed to find compounds from traditional Chinese medicines (TCM) that are more effective than the most commonly used tyrosinase inhibitor, arbutin. First, we employed homology modeling to construct a tyrosinase-modeled structure, and structure-based virtual screening to screen from 61,000 TCM compounds. We also adopted the following quantitative structure-activity relationship (QSAR) models for ligand-based validation: support vector machine, multiple linear regression, and Bayesian network. Molecular dynamics (MD) simulation was used to confirm the stability of ligand binding. We found that merresectine C might more effectively bind and inhibit the activity of tyrosinase than arbutin. This study provides useful evidence for the potential development of a novel non-toxic bleaching or whitening ingredient. PMID- 25932368 TI - The mechanisms of action of vaccines containing aluminum adjuvants: an in vitro vs in vivo paradigm. AB - Adjuvants such as the aluminum compounds (alum) have been dominantly used in many vaccines due to their immunopotentiation and safety records since 1920s. However, how these mineral agents influence the immune response to vaccination remains elusive. Many hypotheses exist as to the mode of action of these adjuvants, such as depot formation, antigen (Ag) targeting, and the induction of inflammation. These hypotheses are based on many in vitro and few in vivo studies. Understanding how cells interact with adjuvants in vivo will be crucial to fully understanding the mechanisms of action of these adjuvants. Interestingly, how alum influences the target cell at both the cellular and molecular level, and the consequent innate and adaptive responses, will be critical in the rational design of effective vaccines against many diseases. Thus, in this review, mechanisms of action of alum have been discussed based on available in vitro vs in vivo evidences to date. PMID- 25932371 TI - Social network analysis - centrality parameters and individual network positions of agonistic behavior in pigs over three different age levels. AB - Knowledge of the network structure of agonistic interactions helps to understand the formation and the development of aggressive behavior. Therefore, video observation data of 149 pigs over three different age levels were investigated for 2 days each directly after mixing (65 groups in the rearing area, 24 groups in the growing stable and 12 groups in the breeding stable). The aim of the study was to use network analysis to investigate the development of individual network positions of specific animals and to determine whether centrality parameters in previous mixing situations have an impact on the future behavior of the animals. The results of the weighted degree centrality indicated that weaned pigs had a higher fighting intensity directly after mixing compared to growing pigs and gilts. Also, the number of different opponents (degree centrality) was higher compared to the older age groups. The betweenness centrality showed relatively small values and no significant differences between the different age levels, whereas the closeness centrality showed high values at all observed age levels. Experiences gained in previous agonistic interactions had an impact on the centrality parameters in subsequent mixing situations. It was shown that the position of individual animals in agonistic interaction networks can be characterized using social network analysis and that changes over different age levels can be detected. Therefore, social network analysis provides insights into the formation and evolution of behavioral patterns which could be of particular interest for the identification of key factors with regard to abnormal behavior (e.g. tail biting). PMID- 25932372 TI - A prospective evaluation of the role of Vascular Endothelial Growth Factor (VEGF) and the immune system in stage III/IV melanoma. AB - BACKGROUND: The immune system and vascular endothelial growth factor (VEGF) may be influential in melanoma behavior. We performed a prospective, exploratory analysis in 10 stage III and 22 stage IV melanoma patients to observe factors influencing outcomes. PATIENTS AND METHODS: Patients accrued during 2010 and 2011 were treated according to standard protocols for disease stage. We analyzed selected biomarkers for predictive patterns of clinical response. Survival outcomes were calculated using Kaplan-Meier curves. RESULTS: Baseline LDH was negatively correlated with length of survival and positively correlated to baseline VEGF in stage IV melanoma patients. We found a positive correlation between peripheral blood Treg concentrations and baseline VEGF in stage IV patients. No stage III patients died during the study period; median survival for stage IV patients was 48 months using a Kaplan-Meier survival curve, which illustrates the enrichment for exceptional stage IV survivors. Six stage IV patients remain disease free, including 4 of the 10 patients who received IL-2 +/ metastatectomy. CONCLUSIONS: Recent advances in immunotherapy have demonstrated durable therapeutic responses which may favorably impact survival. Examining T cell characteristics of metastatic melanoma patients may gain further insight into underlying immunomodulation mechanisms to guide improved therapies. PMID- 25932373 TI - Characterization of the goat feeding system among rural small holder farmers in the semi-arid regions of Uganda. AB - Goats (Capra hircus) are widely distributed in Africa and Asia, and are important to the subsistence and economic livelihoods of many people in these areas. The goat feeding system among rural small holder farmers in Buyende district (Uganda) was characterised by determining the goat rearing practices, feed resources fed on by goats and availability of browse species mentioned by small holder farmers. Data was gathered using ethnobotanical and ecological approaches. Results from the ethnobotanical survey revealed that farmers were rearing indigenous goat breeds that are managed by tethering in natural pastures during the rainy season but free ranging during the dry season (i.e. when no crops are susceptible of damage). Major challenges facing goat production in the study area were diseases, shortage of land and inadequate pastures. The reduction of grazing land due to crop farming, has led to tethering of animals which in turn leads to restricted feeding. Goats were known to feed on 48 plant species distributed in 18 families and 39 genera dominated by trees and shrubs. Browse species were known to stay longer in the dry season when the grass and herbaceous species were no longer available. The most frequently mentioned browse species were Ficus natalensis, Harrisonia abyssinica, Acalypha psilostachya, Artocarpus heterophyllus and Lantana camara while Panicum maximum and Impeata cylindrica were the most mentioned herbaceous species. 31 browse species were encountered in the ecological survey. These were dominated by Combretum molle, L. camara, A. zygia, M. indica, and Albizia coriaria. In conclusion, the rearing practices of goats in Buyende district are comprised of indigenous goats tethered in natural pastures especially browses which stay longer through the dry season. However, most of the preferred browses are rare according to the computed IVI (i.e. less than 30%). PMID- 25932374 TI - Implications of expansin-like 3 gene in Dictyostelium morphogenesis. AB - Dictyostelium harbors multiple expansin-like genes with generally unknown functions. Thus, we analyzed the expansin-like 3 (expL3) gene and found that its expression was reduced in a null mutant for a STATa gene encoding a transcription factor. The expression of expL3 was developmentally regulated and its transcript was spliced only in the multicellular stages. The expL3 promoter was activated in the anterior prestalk region of the parental strain and downregulated in the STATa null slug, although the expL3 promoter was still expressed in the prestalk region. The expL3 overexpressing strain exhibited delayed development and occasionally formed an aberrant structure, i.e., a fruiting body-like structure with a short stalk. The ExpL3-myc protein bound cellulose. PMID- 25932375 TI - The primary study of low-dose pancreas perfusion by 640- slice helical CT: a whole-organ perfusion. AB - To discuss the feasibility of low-dose whole-pancreas imaging utilizing 640-slice dynamic volume CT.80 patients (40 cases of normal pancreas and 40 patients supposed of having pancreatic carcinoma or focal pancreatic space-occupying lesions were mainly refered) referred for CT pancreas perfusion were enrolled in the study. 80 patients randomly assigned to 3 groups: Group 1 (whole sequence). Group 2 (odd number sequence). Group 3 (even number group)(Compared to 1, the scanning times and effective radiate dose of 2 and 3 decreased about 50% respectively). The head, body, tail of each normal pancreas without any pancreatic disease, lesion and lesion-surrounding areas of each pancreatic cancer were selected as ROI, and tissue peak, blood flow are measured.According to pathology and clinical materials, 27 patients were diagnosed as pancreatic cancer; 40 patients were diagnosed as normal pancreas. The tissue peak and blood flow of the head, body, tail of normal pancreas without any pancreatic disease are 109.63 +/- 16.60 and 131.90 +/- 41.61, 104.38 +/- 19.39 and 127.78 +/- 42.52, 104.55 +/- 15. 44 and 123.50 +/- 33.44 respectively. The tissue peak and blood flow of pancreatic cancer is 59.59 +/- 18.20 and 60.00 +/- 15.36. For and between each group, there is no significant statistical difference for the tissue peak and blood flow of normal areas of the head, body, tail of normal pancreas. There is statistical difference for the tissue peak and blood flow of lesion and lesion surrounding areas of pancreatic cancer in each group. However, there is no statistical difference for the tissue peak and blood flow of normal and diseasing areas between 3 groups.Low-dose whole-pancreas perfusion with 640-slice dynamic volume CT is feasible. PMID- 25932376 TI - Bilateral synchronous carcinoma breast- a rare case presentation. AB - INTRODUCTION: Bilateral Breast Carcinoma (BBC) is a rare entity with incidence of synchronous carcinoma being 2-5% of all breast malignancies, which is much less than metachronous carcinoma. Synchronicity/ metachronicity are usually associated with local and lymphatic spread and with blood-borne spread to lungs, bones and liver. Moreover BBC are mostly lobular carcinomas but we report a rare case of Infiltrating Ductal Carcinoma (IDC) as the primary carcinoma and Lobular Carcinoma as the secondary. CASE DESCRIPTION: 56 year old female who presented with a Stage IIIB fungating growth around 10x8cm in the lower inner, lower outer and upper outer quadrant of right breast since 6 months and a StageIIA 4x4cm tumour felt in the left breast in the upper inner and lower outer quadrant. Wedge biopsy of the right breast fungating mass showed Ductal Carcinoma and FNAC of the left breast lump suggested Lobular carcinoma which was confirmed on Histopathology after surgery. Patient was subjected to Hormonal therapy (Tab Tamoxifen), chemotherapy (Cyclophosphamide, 5 FU, and Doxorubicin) followed by Radiotherapy. Patient recovered well and shows no recurrence or signs of metastasis in the 8 months of follow up. DISCUSSION AND EVALUATION: Different histological subtypes with different grades of tumour in both breasts suggested two different synchronous primary tumours. Early detection of the contralateral tumour is of utmost importance emphasising the significance of breast self examination. Screening tools like MRI have a greater sensitivity compared to Mammography. There are no clear treatment guidelines for bilateral breast cancer. Patients are often treated with bilateral mastectomy, with breast conservative surgery having unclear importance. CONCLUSION: Meticulous diagnosis and appropriate management help to improve the longitivity with an improved quality of life. PMID- 25932377 TI - Two-stage hepatectomy and associated liver partition and portal vein ligation for staged hepatectomy (ALPPS) in treating liver metastases of rectal cancer: a case report. AB - INTRODUCTION: An innovative approach, called associated liver partition and portal vein ligation for staged hepatectomy(ALPPS), has made possible a marked increase in future liver remnant (FLR) volume over a short period of time, thus permitting extended hepatectomy. CASE DESCRIPTION: This report describes ALPPS in a 63-year-old male patient with rectal cancer and synchronous multiple liver metastases. The primary lesion was resected, followed by chemotherapy. We had planned to completely resect the metastases in both liver lobes, but CT volumetry revealed a very small FLR (364 ml, 29% of the total liver volume, 0.61% of total body weight). His indocyanine green retention rate at 15 minutes was 12.7%. Because of the risk of tumor progression in the interim, we performed ALPPS. During the first stage, the tumor in segment 3 was resected, the right lobe was mobilized, the liver was partitioned, and the right portal vein was ligated. The right hepatic artery, duct and vein were secured with vessel loops. CT on postoperative day 6 showed sufficient FLR increase (from 364 ml to 573 ml, or from 0.61% to 0.96% of total body weight) and ICGR15 improvement to 3.4%. The second stage of ALPPS was on postoperative day 7, completing resection of the metastases. The patient recovered well and was discharged 21 days after the second step. DISCUSSION AND EVALUATION: The ALPPS approach has many advantages, but it lacks evidence of long-term results. Considering the high mortality and morbidity rates of ALPPS, it is essential to evaluate its risks and benefits in individual patients and determine the strict criteria for this surgical method. CONCLUSIONS: ALPPS procedure rapidly increases FLR, permitting extended hepatectomy for patients with initially insufficient FLR. PMID- 25932378 TI - Validity and reliability of the Finnish version of the Functioning Assessment Short Test (FAST) in bipolar disorder. AB - BACKGROUND: The Functioning Assessment Short Test (FAST) was developed for the clinical evaluation of functional impairment of patients suffering from bipolar disorder. The aim of this study was to validate the Finnish version of FAST. METHODS: Translation and back-translation of FAST were performed. Fifty patients with the Diagnostic and Statistical Manual of Mental Disorders-Fourth edition (DSM-IV) bipolar type I and II were interviewed at the Bipolar Disorder Research and Treatment Centre, City of Helsinki, Finland. Participants completed the FAST, the Social and Occupational Functioning Assessment Scale (SOFAS) of DSM-IV, and the Sheehan Disability Scale (SDS) as part of the assessment. Internal consistency and correlations between FAST and SOFAS and SDS were analysed. Twenty five patients participated in a reliability assessment carried out 1 week apart by a different rater. RESULTS AND DISCUSSION: The internal consistency coefficient obtained was very good, with a Cronbach alpha of 0.870. Reliability of FAST was also found excellent (correlation between two measures r = 0.896, p < 0.001). A highly significant negative correlation between FAST and SOFAS scores was found (r = -0.723, p < 0.001). FAST and SDS were also highly significantly correlated (r = 0.742, p < 0.001). CONCLUSIONS: The psychometric validity and reliability of FAST in the Finnish sample of patients with bipolar disorder types I and II were good. PMID- 25932379 TI - Recent Advances in Burkholderia mallei and B. pseudomallei Research. AB - Burkholderia mallei and Burkholderia pseudomallei are Gram-negative organisms, which are etiological agents of glanders and melioidosis, respectively. Although only B. pseudomallei is responsible for a significant number of human cases, both organisms are classified as Tier 1 Select Agents and their diseases lack effective diagnosis and treatment. Despite a recent resurgence in research pertaining to these organisms, there are still a number of knowledge gaps. This article summarizes the latest research progress in the fields of B. mallei and B. pseudomallei pathogenesis, vaccines, and diagnostics. PMID- 25932380 TI - Looking for the elusive lung stem cell niche. AB - This discourse contains three perspectives on various aspects of Stem Cell Biology and tools available to study and translate into Regenerative Medicine. The lung incessantly faces onslaught of the environment, constantly undergoes oxidative stress, and is an important organ of detoxification. In degenerative diseases and inflammation, the lung undergoes irreversible remodeling that is difficult to therapeutically address and/or transplant a dying tissue. The other difficulty is to study its development and regenerative aspects to best address the aforementioned problems. This perspective therefore addresses- firstly, review of types of stem cells, their pathway of action and models in invertebrate organisms vis-a-vis microenvironment and its dynamics; secondly, stem cells in higher organisms and niche; and lastly data and inference on a novel approach to study stem cell destruction patterns in an injury model and information on putative lung stem cell niche. Stem cells are cryptic cells known to retain certain primitive characteristics making them akin to ancient cells of invertebrates, developmental stages in invertebrates and vertebrates and pliant cells of complex creatures like mammals that demonstrate stimulus-specific behavious, whether to clonally propagate or to remain well protected and hidden within specialized niches, or mobilize and differentiate into mature functionally operative cells to house-keep, repair injury or make new tissues. In lung fibrosis, alveolar epithelium degenerates progressively. In keeping with the goal of regenerative medicine, various models and assays to evaluate long and short term identity of stem cells and their niches is the subject of this perspective. We also report identification and characterization of functional lung stem cells to clarify how stem cell niches counteract this degenerative process. Inferences drawn from this injury model of lung degeneration using a short term assay by tracking side population cells and a long term assay tracking label retaining cells have been presented. PMID- 25932381 TI - Paraneoplastic Leukemoid Reaction as a Marker of Tumor Progression in Non-Small Cell Lung Cancer. PMID- 25932382 TI - Comparison of Anorectic Potencies of the Trichothecenes T-2 Toxin, HT-2 Toxin and Satratoxin G to the Ipecac Alkaloid Emetine. AB - Trichothecene mycotoxins, potent translational inhibitors that are associated with human food poisonings and damp-building illnesses, are of considerable concern to animal and human health. Food refusal is a hallmark of exposure of experimental animals to deoxynivalenol (DON) and other Type B trichothecenes but less is known about the anorectic effects of foodborne Type A trichothecenes (e.g., T-2 toxin, HT-2 toxin), airborne Type D trichothecenes (e.g. satratoxin G [SG]) or functionally analogous metabolites that impair protein synthesis. Here, we utilized a well-described mouse model of food intake to compare the anorectic potencies of T-2 toxin, HT-2 toxin, and SG to that of emetine, a medicinal alkaloid derived from ipecac that inhibits translation. Intraperitoneal (IP) administration with T-2 toxin, HT-2 toxin, emetine and SG evoked anorectic responses that occurred within 0.5 h that lasted up to 96, 96, 3 and 96 h, respectively, with lowest observed adverse effect levels (LOAELs) being 0.1, 0.1, 2.5 and 0.25 mg/kg BW, respectively. When delivered via natural routes of exposure, T-2 toxin, HT-2 toxin, emetine (oral) and SG (intranasal) induced anorectic responses that lasted up to 48, 48, 3 and 6 h, respectively with LOAELs being 0.1, 0.1, 0.25, and 0.5 mg/kg BW, respectively. All four compounds were generally much more potent than DON which was previously observed to have LOAELs of 1 and 2.5 mg/kg BW after IP and oral dosing, respectively. Taken together, these anorectic potency data will be valuable in discerning the relative risks from trichothecenes and other translational inhibitors of natural origin. PMID- 25932383 TI - Triple fixed drug combinations in type 2 diabetes. PMID- 25932384 TI - Sulfonylureas: Assets in the past, present and future. PMID- 25932385 TI - Forum for Injection Technique (FIT), India: The Indian recommendations 2.0, for best practice in Insulin Injection Technique, 2015. AB - As injectable therapies such as human insulin, insulin analogs, and glucagon-like peptide-1 receptor agonists are used to manage diabetes, correct injection technique is vital for the achievement of glycemic control. The forum for injection technique India acknowledged this need for the first time in India and worked to develop evidence-based recommendations on insulin injection technique, to assist healthcare practitioners in their clinical practice. PMID- 25932387 TI - Anti-thyroid drugs in pediatric Graves' disease. AB - Graves' disease is the most common cause of hyperthyroidism in children. Most children and adolescents are treated with anti-thyroid drugs as the initial modality. Studies have used Methimazole, Carbimazole and Propylthiouracil (PTU) either as titration regimes or as block and replacement regimes. The various studies of anti-thyroid drug (ATD) treatment of Graves' disease in pediatric patients differ in terms of the regimes, remission rate, duration of therapy for adequate remission, follow up and adverse effects of ATD. Various studies show that lower thyroid hormone levels, prolonged duration of treatment, lower levels of TSH receptor antibodies, smaller goiter and increased age of child predicted higher chance of remission after ATD. A variable number of patients experience minor and major adverse effects limiting initial and long term treatment with ATD. The adverse effects of various ATD seem to more in children compared to that of adults. In view of liver injury including hepatocellular failure need of liver transplantation associated with PTU, the use has been restricted in children. The rate of persistent remission with ATD following discontinuation is about 30%. Radioactive iodine therapy is gaining more acceptance in older children with Graves's disease in view of the limitations of ATD. For individual patients, risk benefit ratio of ATD should be weighed against benefits of radioactive iodine therapy and patient preferences. PMID- 25932386 TI - Feminizing adrenocortical tumors: Literature review. AB - Feminizing adrenal tumors (FAT) are extremely rare tumors prevailing in males. Clinical manifestations are gynecomastia and/or other hypogonadism features in adults. They are rarer in pediatric population and their main manifestation is peripheral sexual precocity. In women genital bleeding, uterus hypertrophy, high blood pressure and/or abdomen mass may be the only manifestations. On the biological point, estrogen overproduction with or without increase in other adrenal hormones are the main abnormalities. Radiological examination usually shows the tumor, describes its limits and its eventual metastases. Adrenal and endocrine origins are confirmed by biochemical assessments and histology, but that one is unable to distinguish between benign and malignant tumors, except if metastases are already present. Immunostaining using anti-aromatase antibodies is the only tool that distinguishes FAT from other adrenocortical tumors. Abdominal surgery is the best and the first line treatment. For large tumors (>=10 cm), an open access is preferred to coeliosurgery, but for the small ones, or when the surgeon is experienced, endoscopic surgery seems to give excellent results. Surgery can be preceded by adrenolytic agents such as ortho paraprime dichloro diphenyl dichloroethane (Mitotane), ketoconazole or by aromatase inhibitors, but till now there is not any controlled study to compare the benefit of different drugs. New anti-estrogens can be used too, but their results need to be confirmed in malignant tumors resistant to classical chemotherapy and to conventional radiotherapy. Targeted therapy can be used too, as in other adrenocortical tumors, but the results need to be confirmed. PMID- 25932388 TI - Turmeric use is associated with reduced goitrogenesis: Thyroid disorder prevalence in Pakistan (THYPAK) study. AB - INTRODUCTION: South Asian population has a particularly high prevalence of thyroid disorders mainly due to iodine deficiency and goitrogen use. There is no data available for prevalence of thyroid disorders in the general population living in nonmountainous regions of Pakistan. MATERIALS AND METHODS: A total of 2335 residents of Pak Pattan, Punjab, Pakistan were interviewed about demographic, dietary, medical and environmental history as well as screened for goiter. Individuals of all ages and either gender were included. RESULTS: Median age was 34 (10-88) years and 1164 (49.9%) were males. Median monthly income was 49 (3.9-137) USD. Six hundred and sixty-nine (28.7%) subjects had palpable goiter. 77.5% (n = 462) and 22.5% (n = 133) had World Health Organization Grade I and Grade II goiters respectively, further screened by measuring thyroid stimulating hormone (TSH). In subjects with TSH <0.4 mg/dL, free T3 and free T4 levels were measured. In 185 goiter subjects when TSH was measured, 50% (n = 93) were euthyroid, 48% (n = 89) were hyperthyroid, and one subject each was hypothyroid and subclinically hyperthyroid. 29/89 hyperthyroid subjects underwent radionuclide scanning. Twelve subjects had heterogeneous uptake consistent with multinodular goiter, 12 subjects had diffuse uptake, two had cold nodules and two had hyperfunctioning single nodules. Goiter was significantly more common among females, unmarried individuals and individuals drinking tube well (subterranean) water. Goiter was less common among those who consumed daily milk, daily ghee (hydrogenated oil), spices, chilies, and turmeric. DISCUSSION: In our study population, goiter was endemic with very high prevalence of hyperthyroidism. Turmeric use was association with reduced goitrogenesis. Further studies to assess iodine sufficiency, thiocyanate exposure and autoimmunity need to be conducted. Masses consuming high goitrogen diets should be educated to incorporate turmeric, spices and green chilies in their cooking recipes, to reduce the risk of goiter development. In addition, use of iodized salt in their daily diet cannot be overemphasized. PMID- 25932389 TI - Efficacy and safety of low dose oral prednisolone as compared to pulse intravenous methylprednisolone in managing moderate severe Graves' orbitopathy: A randomized controlled trial. AB - BACKGROUND: High dose oral prednisolone (100 mg/day) in Graves' orbitopathy (GO) is limited by lesser response, and greater side-effects compared to intravenous (iv) methylprednisolone. Low dose oral prednisolone has not been evaluated in GO. This study aimed to evaluate the safety and efficacy of low dose oral prednisolone in GO. MATERIALS AND METHODS: A total of 114 consecutive GO patients were screened of which 65 patients with previously untreated moderate-severe GO, clinical activity score (CAS) >2, without co-morbid states were randomized into treatment Group-A (iv methylprednisolone 0.5 g for 3 days/month for 4 months) and Group-B (oral prednisolone 1 mg/kg/day for 6 weeks then tapered stopped), and followed-up. Thirty-one patients in each group with at least 1-year follow-up were analyzed. Responders were defined as improvement in >= 1 major response criteria or >= 2 minor response criteria. The trial is registered at ctri.nic.in (CTRI/2013/12/004264). RESULTS: At 1-year, 27/31 (87.10%) patients were responders in Group-A compared to 17/31 (54.84%) in Group-B (P = 0.005). There was a greater improvement in CAS score in patients of Group-A as compared to Group-B (P < 0.001). Responders (n = 44) had significantly higher baseline intra ocular pressures and left eye proptosis as compared to nonresponders. Cox regression revealed baseline T4 levels, diplopia, and smoking history were predictive of remission. Low dose prednisolone was well tolerated, and the occurrence of adverse events were comparable in both groups. CONCLUSIONS: Low dose oral prednisolone is inferior to iv pulse methylprednisolone in managing GO, having a comparable side-effect profile. It can be a safe second line alternative in patients intolerant to pulse iv methylprednisolone. PMID- 25932390 TI - Neurological, psychiatric, ophthalmological, and endocrine complications in giant male prolactinomas: An observational study in Algerian population. AB - INTRODUCTION: Prolactinomas are less frequent, but more invasive in males. Giant ones (>=4 cm) are extremely rare in literature. Their neurological, psychiatric and endocrine complications are life threatening. Our aim was to report the largest mono center series in order to analyze their frequency, their characteristics, and their complications. SUBJECTS AND METHODS: All patients had clinical examination, hormonal, ophthalmological, and radiological assessment based on computed tomography scan and cerebral magnetic resonance imaging. Positive diagnosis was based on clinical symptoms, high prolactin +/- immunohistochemy study. Mixed adenomas were excluded by hormonal exploration and immunohistochemy. For those who received medical treatment only, a reduction in tumor size was considered a supplementary positive point for the diagnosis. RESULTS: Among 154 male prolactinomas seen between 1987 and 2013, we observed 44 giant tumors (28.5%). Median age = 36 years, and 38.3% were under 30. Median tumor height = 53.95 mm (40-130) and median prolactin = 15,715 ng/ml (n < 20). Solid and cystic aspect +/- calcifications was observed in 25%. 42 had cavernous sinuses invasion. Other invasions were: Posterior= 65.9%, anterior= 63.6%, temporal= 15.9% and frontal = 9%. For endocrine complications: Hypogonadism = 98.4%, thyrotroph and corticotroph deficits were seen in respectively 34%, and 32%. Posterior pituitary insufficiency was observed in one case. For ophthalmological complications: Optic atrophy = 46%, Ptosis = 6.8%, diplopia/strabismus = 4.5%. Neurological complications were: Memory loss and/or unconsciousness = 18.2%, epilepsy = 15.9%, frontal syndrome = 9% and obstructive hydrocephalus = 6.8%. CONCLUSION: Giant prolactinomas account for 28% in our population. Severe neurological complications are frequent. But, obstructive hydrocephalus is rare, which argues for a slow progression. PMID- 25932391 TI - Helicobacter pylori infection prevalence: Is it different in diabetics and nondiabetics? AB - BACKGROUND: Helicobacter pylori (HP) infection plays a significant role in the development of gastrointestinal complications and has a significant role in systemic inflammation. It has some extragastrointestinal manifestations like endocrine diseases. In this study, we aimed to compare the prevalence of HP infection in diabetic and nondiabetic individuals. MATERIALS AND METHODS: In this cross-sectional study, 218 nondiabetic and 211 diabetic patients referring to Shahid Beheshti Hospital of Qom between March 2013 and 2014 were studied. The patients were divided into two HP(+) and HP(-) groups based on serological immunoglobulin G antibody against HP and the association between diabetes, and HP infection was evaluated. Data were analyzed using independent t-tests, Chi square, Fisher's exact and Mann-Whitney tests. RESULTS: The prevalence of HP seropositive was 65.9% versus 50.5% in diabetic and nondiabetics, respectively, and the difference was statistically significant (P = 0.001). CONCLUSIONS: This study showed a higher prevalence of HP infection in diabetic patients. PMID- 25932392 TI - Endocrine dysfunction in patients of leprosy. AB - BACKGROUND: Leprosy is a chronic granulomatous disease and affects many internal organs in addition to the skin and peripheral nerves. Endocrine dysfunction is often silent and is often missed in patients of leprosy leading to significant morbidity. We studied the presence of occult endocrine disorders in leprosy patients and compared the same with disease parameters. MATERIALS AND METHODS: We evaluated 40 patients of leprosy (aged 18-70 years, any duration) in this cross sectional, observational study. All subjects were assessed for pituitary, thyroid, adrenal, gonadal function, and dynamic testing was done when deemed necessary. The participants were divided into two groups: Group 1 (Leprosy, n = 40) and Group 2 (Controls, n = 20) and the data were analyzed with appropriate statistical tests. RESULTS: The study participants (35 males, 5 females) had a mean age of 36.4 +/- 11.3 years, and duration of the disease was 2.5 +/- 5.5 years. Eleven out of 40 patients showed results consistent with an endocrine disorder, including subclinical hypothyroidism (n = 4), sick euthyroid syndrome (n = 3), growth hormone (GH) deficiency (n = 2), primary hypogonadism (n = 2) and secondary hypogonadism in one patient. One patient had partial hypopituitarism (GH deficiency and secondary hypogonadism) and none of the controls showed any hormonal dysfunction. Testosterone levels showed inverse correlation with the number of skin patches (P = 0.0006). CONCLUSION: Occult endocrine dysfunction is seen in a quarter of patients with leprosy. Thyroid and gonadal axes abnormalities are common, and the severity is more in lepromatous forms of the disease. Further large studies are required to confirm the findings observed in our study. PMID- 25932393 TI - Association of bilirubin and malondialdehyde levels with retinopathy in type 2 diabetes mellitus. AB - INTRODUCTION: Bilirubin as an antioxidant and malondialdehyde (MDA) as an oxidant have been shown to be associated with various complications of type 2 diabetes mellitus (DM). AIMS AND OBJECTIVES: The aim was to measure the levels of serum bilirubin and MDA in type 2 DM patients with and without diabetic retinopathy (DR) and to correlate them with severity of DR. MATERIALS AND METHODS: A total number of 120 subjects out of which 40 were controls without type 2 DM and the rest 80 were type 2 DM patients were included in the study. Of those 80 diabetics, 44 patients did not have DR and 36 patients had DR. RESULTS: The total bilirubin, direct bilirubin, indirect bilirubin were higher in controls as compared to cases (P = 0.017, 0.033, 0.024). Serum MDA levels were found to be higher in diabetics as compared to controls (P = 0.00). The values of all the three parameters, that is, total bilirubin, direct bilirubin and indirect bilirubin were lower in patients with retinopathy as compared to those without retinopathic changes (P = 0.00, 0.020, and 0.007). Subjects were assigned to quartiles based on serum total bilirubin concentration. The prevalence of DR was significantly lower among persons with the highest bilirubin quartile compared to those with the lowest quartile. The severity of DR was inversely proportional to the total bilirubin levels (P = 0.001). The multiple logistic regression analysis showed total bilirubin to be associated with prevalence of DR (P = 0.035). CONCLUSIONS: The levels of total bilirubin were significantly lower in patients with DR and also in the late stages of retinopathy as compared to those without retinopathy and in controls but MDA levels did not show any association with DR. PMID- 25932394 TI - Knowledge of hypoglycemia and its associated factors among type 2 diabetes mellitus patients in a Tertiary Care Hospital in South India. AB - INTRODUCTION: Hypoglycemia being the rate limiting complication in the attainment of strict glycemic control in diabetes management, in this study, we intended to study the knowledge of its symptoms, target blood levels during treatment and ways of prevention among type 2 diabetes patients attending Outpatient Department (OPD) of a medical college hospital. MATERIALS AND METHODS: Every fifth patient attending the OPD during the 4 months between March and June 2013 was interviewed using a questionnaire. RESULTS: The study included 366 type 2 diabetic patients, of which 76.5% were females. The target fasting and postprandial blood glucose levels while on treatment was known to 135 (36.9%) and 126 (34.4%) patients, respectively. The common symptoms of hypoglycemia known to the study subjects were dizziness (81.4%), weakness (73.8%), and drowsiness (72.1%). Overall, 242 (66.1%) diabetic patients had good knowledge on hypoglycemia (knowledge of at least three symptoms of hypoglycemia together with at least one precipitating factor and at least one remedial measure). Higher age, illiteracy, low socioeconomic status were associated with poor knowledge whereas treatment with insulin along with oral hypoglycemic agents was associated with good knowledge on hypoglycemia. Sex and duration of disease were not associated with knowledge on hypoglycemia. CONCLUSION: Although the knowledge on symptoms of hypoglycemia, precipitating factors, remedial measures are high in this study, the target blood levels, complications were known to just a third of them. There is a knowledge gap on important aspects of hypoglycemia among type 2 diabetic patients. PMID- 25932395 TI - Effect of diabetic education on the knowledge, attitude and practices of diabetic patients towards prevention of hypoglycemia. AB - AIMS: To assess the role of diabetic education in increasing awareness about hypoglycemia and decreasing hypoglycemic symptoms in diabetics. MATERIALS AND METHODS: This is a longitudinal study involving the use of a structured questionnaire for obtaining baseline information related to knowledge, attitude and practices (KAP) of diabetic patients regarding hypoglycemia. Then the patients were given diabetic education by the treating doctor regarding hypoglycemia, its symptoms and prevention; the effect of which was assessed by repeating the same questionnaire after a month. The occurrence of hypoglycemic symptoms was also compared before and after diabetic education. RESULTS: There is a significant improvement in all parameters like KAP with diabetic education. The hypoglycemic episodes also decrease significantly. CONCLUSIONS: Proper diabetic education is seen to improve the knowledge and attitude of the diabetic patients toward hypoglycemia. This leads to improved practices of such patients and decrease hypoglycemic episodes in them. PMID- 25932396 TI - Effect of Vitamin D supplementation on glycemic parameters and progression of prediabetes to diabetes: A 1-year, open-label randomized study. AB - BACKGROUND: Whether Vitamin D supplementation in prediabetes subjects prevents the development of diabetes is a matter of debate, and the results are inconsistent. This open-label, randomized study in subjects with prediabetes evaluated the effect of 12 months of Vitamin D supplementation on glycemic parameters and progression of prediabetes to diabetes in an ethnically homogeneous Kashmiri population. MATERIALS AND METHODS: A total of 147 subjects were diagnosed as prediabetes out of which 137 subjects were randomized to receive in addition to standard lifestyle measures, either Vitamin D 60,000 IU weekly for 4 weeks and then 60,000 IU monthly (n = 69) or no Vitamin D (n = 68). Fasting plasma glucose (FPG), 2-h plasma glucose and A1C levels were estimated at 0, 6 and 12 months. Changes in FPG, 2-h plasma glucose, A1C level and the proportion of subjects developing diabetes were assessed among 129 subjects. RESULTS: At 12 months, A1C levels were significantly lesser (5.7% +/- 0.4%) in the Vitamin D supplemented group when compared with non-Vitamin D supplemented (6.0% +/- 0.3%). Similarly, FPG (97 +/- 7) and 2-h plasma glucose (132 +/- 16) were significantly less in Vitamin D supplemented group as compared with non Vitamin D supplemented group (FPG = 116 +/- 6 and 2-h plasma glucose = 157 +/- 25) at 12 months. Nine out of 65 in non-Vitamin D supplemented and seven out of 64 in the Vitamin D supplemented group developed diabetes. CONCLUSIONS: Vitamin D supplementation in prediabetes subjects significantly lowered FPG, 2-h plasma glucose and A1C levels. PMID- 25932397 TI - Changes in bone mineral density and bone turnover markers in patients undergoing hematopoietic stem cell transplant. AB - INTRODUCTION: Hematopoietic stem cell transplant (HSCT) is frequently complicated by endocrine abnormalities and loss of bone mass. This prospective study was conducted to evaluate the bone loss post-HSCT. MATERIALS AND METHODS: A total of 50 patients was evaluated pretransplantation, and 25 had HSCT (17 males, 8 females; 19 allogenic, 6 autologous). Bone mineral density (BMD) and bone markers were measured at baseline, 3-6 months and 12 months. RESULTS: The mean age and body mass index were 25.1 +/- 16.3 years and 19.4 +/- 4.5 kg/m(2), respectively. There were 15 adults (60%), and 10 adolescents (40%). There was a significant decline in BMD from the baseline at total femur (-8.7%; P < 0.0001), femoral neck (-5.0%; P = 0.003), femoral trochanter (-6.0%; P = 0.001), and Ward's triangle ( 9.9%; P < 0.0001) at 6 months posttransplantation. From the 6 months to 12 months, there was a significant improvement in BMD at above sites except at Ward's triangle. The decline in BMD was nonsignificant at the whole body (-0.3%, P = 0.748) and the lumbar spine (-2.7%, P = 0.130) at 6 months posttransplant. Younger patients with allogenic graft and steroid use are more likely to have significant loss of BMD at hip posttransplant. Serum osteocalcin decreased, and N telopeptide increased at 3-6 months, which return to baseline at 1-year posttransplant. CONCLUSIONS: A significant bone loss is observed at 6 months in patients with post-HSCT. The bone loss occurs predominantly at cortical bone. There is recovery of bone mass at 12 months posttransplant except at Ward's triangle. Bone loss after HSCT is multifactorial. PMID- 25932398 TI - Community health orientation of Indian Journal of Endocrinology and Metabolism: A bibliometric analysis of Indian Journal of Endocrinology and Metabolism. AB - BACKGROUND: Endocrine and metabolic diseases especially diabetes have become focus areas for public health professionals. Indian Journal of Endocrinology and Metabolism (IJEM), a publication of Endocrine Society of India, is a peer reviewed online journal, which covers technical and clinical studies related to health, ethical and social issues in field of diabetes, endocrinology and metabolism. This bibliometric analysis assesses the journal from a community health perspective. MATERIALS AND METHODS: Every article published in IJEM over a period of 4 years (2011-2014) was accessed to review coverage of community health in the field of endocrinology. RESULTS: Seven editorials, 30 review articles, 41 original articles, 12 brief communications, 20 letter to editors, 4 articles on guidelines and 2 in the section "endocrinology and gender" directly or indirectly dealt with community health aspects of endocrinology. Together these amounted to 17% of all articles published through these 4 years. There were 14 articles on general, 60 pertaining to pancreas and diabetes, 10 on thyroid, 7 on pituitary/adrenal/gonads, 21 on obesity and metabolism and 4 on parathyroid and bone; all community medicine related. CONCLUSION: Community health is an integral part of the modern endocrinology diabetology and metabolism practice and it received adequate journal space during the last 4 years. The coverage is broad based involving all the major endocrine disorders. PMID- 25932399 TI - Categories of foot at risk in patients of diabetes at a tertiary care center: Insights into need for foot care. AB - OBJECTIVE: Diabetic foot ulcers and amputations are preventable. Aim of this study was to determine the distribution of categories of foot at risk in patients with diabetes, attending a tertiary care hospital and factors that affect it. MATERIALS AND METHODS: Detail history and examination including neurological and vascular assessment were performed in 100 patients with diabetes attending a Tertiary Care Hospital. Foot at risk was classified according to the task force of foot care interest Group of American Diabetes Association. Category of foot at risk was correlated with demographic and clinical features. RESULTS: Fifty-two percent patients had foot at risk-category 1 and 2. Loss of protective sensation (LOPS) was present in 33% (category 1). Peripheral arterial disease (PAD) was present in 19% (category 2). Both LOPS and PAD were present in 10% patients. 95% had never received foot care advice by health professionals, let alone prescriptive footwear or vascular consultation. CONCLUSIONS: This study brings forth that foot at risk of ulcer is rampant in patients with diabetes. There are lacunae in diabetic foot care at all levels of care. With the increase in diabetes, cost effective steps are required to improve foot care among diabetes in India. Considering the demographic profile of patients in our study, growing number of patients with diabetes, lack of time and staff allocated for foot care in our setup, audiovisual aids seems a good option to spread foot care awareness among diabetes. PMID- 25932400 TI - Hypothyroidism in diabetes mellitus patients in Eastern Nepal. AB - CONTEXT: The coexistence of diabetes mellitus (DM) with hypothyroidism is a known clinical observation. AIMS: To estimate prevalence and co-relate that of hypothyroidism in patients with DM in relation to the age and sex, the lipid profile, body mass index visiting diabetes clinic and inpatients in B. P. Koirala Institute of Health Sciences. SETTINGS AND DESIGN: The hospital-based descriptive study. MATERIALS AND METHODS: Two hundred and seventy-one known or newly detected cases of DM aged more than 15 years were selected randomly from September 2012 to September 2013 and subjected to evaluation for thyroid function - clinically and biochemically and other relevant investigations were done. STATISTICAL ANALYSIS USED: For descriptive statistics mean, standard deviation, percentage, proportion were calculated. For inferential statistics following test were carried out at the level of significant 0.05 where confidence interval is 95%. The statistical operations were done through Statistical Package for the Social Sciences version 10. RESULTS: Of 271 subjects, the prevalence of hypothyroidism (clinical and subclinical) in diabetics was, 4.05% (11/271) with females preponderance, of which 7 (30.4%) were clinically hypothyroid and 4 (17.4%) were subclinical hypothyroid. One (4.3%) patient had subclinical hyperthyroidism. The mean age at diagnosis of type 2 DM was 51-60 years. 8.69% of diabetics with primary hypothyroids were having morbid obesity. High-density lipoprotein among different thyroid status were statistically significant (P = 0.042). CONCLUSIONS: Hypothyroidism is not uncommon in diabetes, and we found body mass index, mean triglyceride and cholesterol levels were more in those diabetic patients having coexisting hypothyroidism. PMID- 25932401 TI - Prevalence of thyroid dysfunction among women during the first trimester of pregnancy at a tertiary care hospital in Haryana. AB - BACKGROUND: Undetected and untreated thyroid disorders are associated with adverse maternal and fetal outcomes. There are limited data on the prevalence of newly diagnosed thyroid disease during pregnancy from India. Therefore, this study was designed to evaluate the prevalence of thyroid dysfunction, especially hypothyroidism during the first trimester of pregnancy. MATERIALS AND METHODS: The present cross-sectional study was conducted at Department of endocrinology and antenatal clinic in the Obstetrics and Gynecology Pt. B.D. Sharma PGIMS, Rohtak over a period of 1-year. The total sample population comprised of 461 pregnant women with uncomplicated intrauterine singleton pregnancies in the first trimester of gestation without any history of thyroid disease or intake of any thyroid medication. Morning blood samples from the participants were analyzed for thyroid function tests, which included FT3, FT4, thyroid-stimulating hormone (TSH) and anti-thyroid peroxidase antibodies (TPO). RESULTS: A total of 461 women were enrolled for this study. Mean maternal age was 23.79 +/- 3.47 years. Median gestational age was 8 weeks 5 days. The median FT3, FT4 and TSH were 3.3 pg/mL, 1.25 ng/dL, and 1.40 mIU/L, respectively. Anti-TPO was elevated in 128 (27.8%) pregnant women. 99 (21.5%) women had sub-clinical hypothyroidism and 39 (39.4%) among them were positive for anti-TPO (P <= 0.001). 2 (0.4%) of women had overt hyperthyroidism, whereas 15 (3.3%) of the women had sub-clinical hyperthyroidism. CONCLUSION: Considering the immense impact that maternal thyroid dysfunction has on maternal and fetal outcomes, prompt identification of thyroid dysfunction and its timely treatment is essential. Thus, universal screening of pregnant women for thyroid dysfunction should be considered especially in a country like India due to the high prevalence of thyroid dysfunction. PMID- 25932402 TI - Improper sharp disposal practices among diabetes patients in home care settings: Need for concern? AB - In the recent years, outbreaks of blood-borne infections have been reported from assisted living facilities, which were traced back to improper blood glucose monitoring practices. Needle-stick injuries have been implicated in many such cases. This directly raises concerns over sharp disposal practices of diabetic patients self-managing their condition in home care settings. With India being home to a huge diabetic population, this issue, if neglected, can cause substantial damage to the health of the population and a marked economic loss. This article discusses the sharp disposal practices prevalent among diabetes patients, the importance of proper sharp disposal, barriers to safe disposal of sharps, and the options available for doing the same. For adopting an environmentally safe wholesome approach, disposal of plastics generated as a result of diabetes self-care at home is important as well. The article also looks at the possible long-term solutions to these issues that are sustainable in an Indian context. PMID- 25932403 TI - Sodium-glucose cotransporter-2 inhibition and the insulin: Glucagon ratio: Unexplored dimensions. AB - The sodium-glucose cotransporter 2 (SGLT-2) inhibitors are a novel class of glucose-lowering drugs which act by inhibiting the reabsorption of filtered glucose from the kidneys. Their effect on insulin and glucagon levels has recently been studied but is not fully explained. This communication proposes various hypotheses: A direct effect of SGLT-2 inhibition on the alpha cell receptors, a paracrine or intra-islet mediated effect on alpha cell sensitivity to glucose, and a calorie restriction mimetic action, to explain the impact of these drugs on the insulin glucagon ratio. PMID- 25932404 TI - Prolonged adrenal insufficiency after unilateral adrenalectomy for Cushing's Syndrome. AB - The contralateral healthy adrenal in patients undergoing unilateral adrenalectomy for Cushing's is known to be suppressed temporarily and forms the basis of peri and postoperative steroids. We present four cases of Cushing's who had prolonged adrenal insufficiency with continued requirement for steroids for periods ranging 1-4 years after unilateral adrenalectomy for Cushing's. We further review literature regarding the recovery of the hypothalamo pituitary adrenal axis postsurgery in patients with Cushing's syndrome. PMID- 25932405 TI - Kumbhakarna: Did he suffer from the disorder of the hypothalamus? AB - Kumbhakarna was brother of the evil Raavana in the mythological tale of Ramayana. According the legend, Kumbhakarna had an insatiable appetite and thirst and used to sleep for great lengths of time. He also had an uncontrollable temper, which was feared by many. It is our assessment that Kumbhakarna possibly suffered from hypothalamic obesity. Hypothalamic obesity can be defined as significant polyphagia and weight gain that occurs because of structural or function involvement of the ventromedial nucleus of the hypothalamus bilaterally. The characteristic features are obesity associated with polyphagia. Somnolence is present in 40% of cases. Sham rage is a characteristic behavioral abnormality seen in these patients. All these symptoms are described in the mythological text while describing Kumbhakarna. The episodic nature of Kumbhakarna's symptoms can also be explained by another hypothalamic syndrome called Klein-Levine syndrome. This syndrome is characterized by with periodic episodes of somnolence, hyperphagia and hypersexuality along with other behavioral and cognitive difficulties. PMID- 25932406 TI - Postpartum screening after gestational diabetes mellitus: Aiming for universal coverage. PMID- 25932407 TI - Comparison of direct versus Friedewald estimation of low density lipoprotein cholesterol in Indian patients: Cost-effectiveness concerns? PMID- 25932408 TI - Congenital Hypothyroidism: Recent Indian data. PMID- 25932409 TI - Yoga: An endocrine therapy. PMID- 25932411 TI - Accuracy of needle placement in cadavers: non-guided versus ultrasound-guided. AB - OBJECTIVE: To compare the accuracy rates of non-guided vs. ultrasound-guided needle placement in four lower limb muscles (tibialis posterior, peroneus longus, and short and long heads of the biceps femoris). METHODS: Two electromyographers examined the four muscles in each of eight lower limbs from four fresh frozen cadavers. Each electromyographer injected an assigned dye into each targeted muscle in a lower limb twice (once without guidance, another under ultrasound guidance). Therefore, four injections were done in each muscle of one lower limb. All injections were performed by two electromyographers using 18 gauge 1.5 inch or 24 gauge 2.4 inch needles to place 0.5 mL of colored acryl solution into the target muscles. The third person was blinded to the injection technique and dissected the lower limbs and determined injection accuracy. RESULTS: A 71.9% accuracy rate was achieved by blind needle placement vs. 96.9% accuracy with ultrasound-guided needle placement (p=0.001). Blind needle placement accuracy ranged from 50% to 93.8%. CONCLUSION: Ultrasound guidance produced superior accuracy compared with that of blind needle placement in most muscles. Clinicians should consider ultrasound guidance to optimize needle placement in these muscles, particularly the tibialis posterior. PMID- 25932410 TI - Aging of skeletal muscle fibers. AB - Aging has become an important topic for scientific research because life expectancy and the number of men and women in older age groups have increased dramatically in the last century. This is true in most countries of the world including the Republic of Korea and the United States. From a rehabilitation perspective, the most important associated issue is a progressive decline in functional capacity and independence. Sarcopenia is partly responsible for this decline. Many changes underlying the loss of muscle mass and force-generating capacity of skeletal muscle can be understood at the cellular and molecular levels. Muscle size and architecture are both altered with advanced adult age. Further, changes in myofibers include impairments in several physiological domains including muscle fiber activation, excitation-contraction coupling, actin myosin cross-bridge interaction, energy production, and repair and regeneration. A thorough understanding of these alterations can lead to the design of improved preventative and rehabilitative interventions, such as personalized exercise training programs. PMID- 25932412 TI - Diagnostic cutoff value for ultrasonography in the ulnar neuropathy at the elbow. AB - OBJECTIVE: To determine the diagnostic cutoff values of ultrasonographic measurements in ulnar neuropathy at the elbow (UNE). METHODS: Twenty-five elbows of 23 patients (9 females, 16 males) diagnosed with UNE and 30 elbows of 30 healthy controls (15 females, 15 males) were included in our study. The ulnar nerve cross-sectional area (CSA) was measured at the Guyon canal, midforearm, and maximal swelling point (MS) around the elbow (the cubital tunnel inlet in healthy controls). CSA measurements of the ulnar nerve at each point, the Guyon canal-to MS ulnar nerve area ratio (MS/G), and the midforearm-to-MS ulnar nerve ratio (MS/F) were calculated. RESULTS: Among the variables, only CSA at MS, MS/G, and MS/F displayed significant differences between the control and patient groups. The cutoff value for diagnosing UNE was 8.95 mm(2) for the CSA at MS (sensitivity 93.8%, specificity 88.3%), 1.99 for the MS/G (sensitivity 75.0%, specificity 73.3%), and 1.48 for the MS/F (sensitivity 93.8%, specificity 95.0%). CONCLUSION: These findings may be helpful to diagnose UNE. PMID- 25932413 TI - Clinical implications of real-time visualized ultrasound-guided injection for the treatment of ulnar neuropathy at the elbow: a pilot study. AB - OBJECTIVE: To investigate the feasibility of ultrasound (US)-guided steroid injection by in-plane approach for cubital tunnel syndrome (CuTS), based on symptomatic, morphologic and electrophysiological outcomes. METHODS: A total of 10 patients, who were clinically diagnosed as CuTS and confirmed by an electrodiagnostic study, participated in this study. US-guided injection into the cubital tunnel was performed with 40 mg triamcinolone and 2 mL of 1% lidocaine. Outcomes of the injections were evaluated at pre-injection, 1st week and 4th week after injection. Visual analog scale, self-administered questionnaire of the ulnar neuropathy at the elbow (SQUNE), and McGowan classification were used for clinical evaluation. Cross-sectional area of the ulnar nerve by US and the electrophysiological severity scale through a nerve conduction study were utilized in the evaluation of morphologic and electrophysiological changes. The cross-sectional area of the ulnar nerve was measured at 3 points of condylar, proximal, and distal level of the cubital tunnel. RESULTS: No side effects were reported during the study period. The visual analog scale and cross-sectional area showed a significant decrease at 1st week and 4th week, as compared to baseline (p<0.05). The electrophysiological severity scale was significantly decreased at the 4th week, as compared with baseline and 1st week (p<0.05). Among the quantitative components of the scale, there were statistically significant improvements with respect to the conduction velocity and block. CONCLUSION: The new approach of US-guided injection may be a safe tool for the treatment of CuTS. Symptomatic and morphologic recoveries preceded the electrophysiological improvement. PMID- 25932414 TI - The effect of glenohumeral internal rotation deficit on the isokinetic strength, pain, and quality of life in male high school baseball players. AB - OBJECTIVE: To investigate the effects of glenohumeral internal rotation deficit (GIRD) on the isokinetic strength, body pain, and the quality of life in male high school baseball players of Korea. METHODS: Fifty-six male high school baseball players were divided into either group A (GIRD>=20 degrees , n=12) or group B (GIRD<20 degrees , n=44). The range of motion in the shoulder and the isokinetic strength were measured. Questionnaires were administered regarding the body pain location by using the visual analogue scale, and the quality of life was measured by using the SF-36 Form. RESULTS: All subjects had increased external rotation range of motion and decreased internal rotation in the throwing shoulder. The incidence of GIRD (>=20 degrees ) was 21.43% in the present study. In the isokinetic strength test, a significantly weaker muscular state at an angular velocity of 180 degrees /s was observed in group A, compared to group B. For the comparison of the pain, the frequency of shoulder pain was higher (33.93%) than other body pain, among the study subjects. CONCLUSION: GIRD is one of the main risk factors of glenohumeral joint damage, and it is correlated with reduced isokinetic strength and quality of life. High school baseball players will need appropriate shoulder rehabilitation programs for the improvement in their quality of life and performance. PMID- 25932415 TI - Effect of Enhanced External Counterpulsation and Cardiac Rehabilitation on Quality of Life, Plasma Nitric Oxide, Endothelin 1 and High Sensitive CRP in Patients With Coronary Artery Disease: A Pilot Study. AB - OBJECTIVE: To investigate the effect of enhanced external counterpulsation (EECP) on plasma nitric oxide (NO), Endothelin 1 (ET1), high sensitive C-reactive protein (HSCRP) and quality of life (QoL) in patients with coronary artery disease (CAD). METHODS: We conducted a pilot randomized clinical trial in order to evaluate plasma NO, ET1, HSCRP and QoL before and after twenty sessions of EECP (group A) and cardiac rehabilitation (CR, group B) in 42 patients with CAD (21 in each group). RESULTS: Forty-two patients (33 male and 9 female) were included in the study. The mean age was 58.2+/-10 years. The mean HSCRP was 1.52+/-0.7 in the EECP group and it was reduced to 1.27+/-0.4 after intervention. The reduction in HSCRP was not statistically significant in EECP and CR groups with p=0.33 and p=0.27, respectively. There was not significant improvement of NO, ET1, and QoL in the EECP and CR groups shortly after therapy (p>0.05). CONCLUSION: Although the short-term EECP treatment in CAD patients improved HSCRP, NO, ET1, and QoL compared with the baseline those improvements are not statistically significant. Further studies are necessary with large study groups and more sessions. PMID- 25932416 TI - Changes in hyolaryngeal movement and swallowing function after neuromuscular electrical stimulation in patients with Dysphagia. AB - OBJECTIVE: To investigate immediate changes in hyolaryngeal movement and swallowing function after a cycle of neuromuscular electrical stimulation (NMES) on both submental and throat regions and submental placement alone in patients with dysphagia. METHODS: Fifteen patients with dysphagia were recruited. First, videofluoroscopic swallowing study (VFSS) was performed before NMES. All patients thereafter received a cycle of NMES by 2 methods of electrode placement: 1) both submental and throat regions and 2) submental placement alone concomitant with VFSS. The Penetration-Aspiration Score (PAS) and the NIH-Swallowing Safety Scale (NIH-SSS) were measured for swallowing function. RESULTS: During swallowing, hyolaryngeal descent significantly occurred by NMES on both submental and throat regions, and anterior displacement of hyolaryngeal complex was significant on submental placement alone. NMES on submental placement alone did not change the PAS and NIH-SSS. However, NMES on both submental and throat regions significantly reduced the NIH-SSS, although it did not change the PAS. Patients with no brainstem lesion and with dysphagia duration of <3 months showed significantly improved the NIH-SSS. CONCLUSION: Immediate hyolaryngeal movement was paradoxically depressed after NMES on both submental and throat regions with significant reductions in the NIH-SSS but not the PAS, suggesting improvement in pharyngeal peristalsis and cricopharyngeal functions at the esophageal entry rather than decreased aspiration and penetration. The results also suggested that patients with dysphagia should be carefully screened when determining motor-level NMES. PMID- 25932417 TI - Dysphagia in tongue cancer patients. AB - OBJECTIVE: To identify risk factors for dysphagia in tongue cancer patients. Dysphagia is a common complication of surgery, radiotherapy, and chemotherapy in tongue cancer patients. Previous studies have attempted to identify risk factors for dysphagia in patients with head and neck cancer, but no studies have focused specifically on tongue cancer patients. METHODS: This study was conducted on 133 patients who were diagnosed with tongue cancer and who underwent a videofluoroscopy swallowing study (VFSS) between January 2007 and June 2012 at the Asan Medical Center. Data collected from the VFSS were analyzed retrospectively. Patients with aspiration were identified. RESULTS: Patients showed a higher incidence of inadequate tongue control, inadequate chewing, delayed oral transit time, aspiration or penetration, vallecular pouch and pyriform residue, and inadequate laryngeal elevation after surgery. Moreover, male gender, extensive tumor resection, a higher node stage, and more extensive lymph node dissection were major risk factors for aspiration in tongue cancer patients. CONCLUSION: Tongue cancer patients have difficulties in the pharyngeal phase as well as the oral phase of swallowing. These difficulties can worsen after tongue cancer surgery. Gender, the extent of tumor resection, and lymph node metastasis affect swallowing in tongue cancer patients. Physicians should take these risk factors into account when administering swallowing therapy to tongue cancer patients. PMID- 25932418 TI - Effect of chronic obstructive pulmonary disease on swallowing function in stroke patients. AB - OBJECTIVE: To investigate the prevalence of chronic obstructive pulmonary disease (COPD) in stroke patients, and to assess the difference in swallowing function between stroke patients with COPD (COPD group) and stroke patients without COPD (control group). METHODS: The subjects included 103 stroke patients. They underwent the pulmonary function test and were assigned to either the COPD group or the control group. Their penetration-aspiration scale (PAS) scores and functional dysphagia scale scores were compared by performing a videofluoroscopic swallowing study. The intergroup differences in lip closure, bolus formation, mastication, and the oral transit time, laryngeal elevation, cricopharyngeal dysfunction, oronasal regurgitation, residue in pyriform sinus and vallecula, pharyngeal transit time, aspiration, and esophageal relaxation were also compared. RESULTS: Thirty patients were diagnosed with COPD. The COPD group showed statistically higher PAS scores (4.67+/-2.15) compared to the control group (2.89+/-1.71). Moreover, aspiration occurred more frequently in the COPD group with statistical significance (p<0.05). The COPD group also showed higher occurrence of cricopharyngeal dysfunction, albeit without statistical significance. CONCLUSION: This study shows that a considerable number of stroke patients had COPD, and stroke patients with COPD had higher risk of aspiration than stroke patients without COPD. PMID- 25932420 TI - Participation in leisure activity and exercise of chronic stroke survivors using community-based rehabilitation services in seongnam city. AB - OBJECTIVE: To clarify how participation in leisure activities and exercise by chronic stroke survivors differs before and after a stroke. METHODS: Sixty chronic stroke survivors receiving community-based rehabilitation services from a health center in Seongnam City were recruited. They completed a questionnaire survey regarding their demographic characteristics and accompanying diseases, and on the status of their leisure activities and exercise. In addition, their level of function (Korean version of Modified Barthel Index score), risk of depression (Beck Depression Inventory), and quality of life (SF-8) were measured. RESULTS: After their stroke, most of the respondents had not returned to their pre-stroke levels of leisure activity participation. The reported number of leisure activities declined from a mean of 3.9 activities before stroke to 1.9 activities post-stroke. In addition, many participants became home-bound, sedentary, and non social after their stroke. The most common barriers to participation in leisure activities were weakness and poor balance, lack of transportation, and cost. The respondents reported a mean daily time spent on exercise of 2.6+/-1.3 hours. Pain was the most common barrier to exercise participation. CONCLUSION: Chronic stroke survivors need information on leisure activities and appropriate pain management. PMID- 25932419 TI - Effect of pneumatic compressing powered orthosis in stroke patients: preliminary study. AB - OBJECTIVE: To evaluate the feasibility and effectiveness of a knee-ankle-foot orthosis powered by artificial pneumatic muscles (PKAFO). METHODS: Twenty-three hemiplegic patients (age, 59.6+/-13.7 years) were assessed 19.7+/-36.6 months after brain lesion. The 10-m walking time was measured as a gait parameter while the individual walked on a treadmill. Walking speed (m/s), step cycle (cycle/s), and step length (m) were also measured on a treadmill with and without PKAFO, and before and after gait training. Clinical parameters measured before and after gait training included Korean version of Modified Bathel Index (K-MBI), manual muscle test (MMT), and Modified Ashworth Scale (MAS) of hemiplegic ankle. Gait training comprised treadmill walking for 20 minutes, 5 days a week for 3 weeks at a comfortable speed. RESULTS: The 10-m walking time, walking speed, step length, and step cycle were significantly greater with PKAFO than without PKAFO, and after gait training (both p<0.05). K-MBI was improved after gait training (p<0.05), but MMT and MAS were not. CONCLUSION: PKAFO may improve gait function in hemiplegic patients. It can be a useful orthosis for gait training in hemiplegic patients. PMID- 25932421 TI - Diagnostic value of plain abdominal radiography in stroke patients with bowel dysfunction. AB - OBJECTIVE: To evaluate the diagnostic value of plain abdominal radiography in stroke patients with bowel dysfunction. METHODS: A total of 59 stroke patients were recruited and assigned into constipation or non-constipation group. Patients were interviewed to obtain clinical information, constipation score, and Bristol stool form scale. The total and segmental colon transit time (CTT) was measured using radio-opaque markers (Kolomark). The degree of stool retention was evaluated by plain abdominal radiography and scored by two different methods (Starreveld score and Leech score). The relationship between the clinical aspects, CTT, and stool retention score using plain abdominal radiography was determined. RESULTS: Average constipation score was 4.59+/-2.16. Average Bristol stool form scale was 3.86+/-1.13. The total and segmental CTTs showed significant differences between the constipation and non-constipation groups. There was statistically significant (p<0.05) correlation between the total CTT and constipation score or between Starreveld score and Leech score. Each segmental CTT showed significant correlation (p<0.05) between segmental stool retention scores. CONCLUSION: The stool retention score showed significant correlation with constipation score as well as total and segmental CTT. Thus, plain abdominal radiography is a simple and convenient method for the evaluation of bowel dysfunction in stroke patients. PMID- 25932422 TI - Can motor evoked potentials be an objective parameter to assess extremity function at the acute or subacute stroke stage? AB - OBJECTIVE: To investigate whether motor evoked potential (MEP) amplitude ratio measurements are sufficiently objective to assess functional activities of the extremities. We also delineated the distribution between the presence or absence of MEPs and the Medical Research Council (MRC) scale for muscle strength of the extremities. METHODS: We enrolled 183 patients with first-ever unilateral hemiplegia after stroke. The MEP parameters were amplitude ratio (amplitude of affected side/amplitude of unaffected side) recorded at the first dorsal interosseous (FDI) and tibialis anterior (TA) muscles. We performed frequency analyses using the MRC scale for muscle strength and the presence or absence of evoked MEPs. Change on the MRC scale, hand function tests (HFTs), and the Modified Barthel Index (MBI) subscore were compared between the evoked MEP and absent MEP groups using the independent t-test. Receiver operating characteristic curves were used to determine the optimal cutoff scores for the MEP amplitude ratio using the HFT results and MBI subscores. Correlations between the MEP amplitude ratio and the MRC scale, HFTs, and MBI subscore were analyzed. RESULTS: About 10% of patients with MRC scale grades 0-2 showed evoked MEPs at the FDI muscle, and 4% of patients with MRC scale grades 3-5 did not show MEPs. About 18% of patients with MRC scale grades 0-2 showed evoked MEPs at the TA muscle, and 4% of patients with MRC scale grades 3-5 did not show MEPs. MEP amplitude increased with increasing MRC scale grade. The evoked MEP group had more significant changes on the MRC scale, HFT, and the climbing stair score on the MBI than those in the group without MEPs. Larger MEP amplitude ratios were observed in patients who had more difficulty with the HFTs and ambulation. The MEP amplitude ratio was significantly correlated with the MRC scale, HFT, and MBI subscore. CONCLUSION: We conclude that the MEP amplitude ratio may be useful to predict functional status of the extremities in patients who suffered stroke. PMID- 25932423 TI - Outcomes of drug-resistant urinary retention in patients in the early stage of stroke. AB - OBJECTIVE: To investigate the prognosis of patients with stroke and urinary retention resistant to alpha blockers and cholinergic agents. METHODS: Post-void residual urine volume (PVR) was measured in 33 patients with stroke (14 men and 19 women) who were admitted to the department of rehabilitation medicine of our hospital within 30 days after stroke onset. An alpha-blocker and cholinergic agent were administered to patients with PVR >100 mL. If urinary retention had not improved despite the maximum drug doses, the patient was diagnosed with drug resistant urinary retention. We retrospectively reviewed patient's charts, including PVR at discharge and prognostic factors for PVR. RESULTS: Ten patients (30.3%) could not void or their PVR was >400 mL at discharge (45.7+/-15.4 days after onset) after rehabilitation. Twelve patients (36.4%) could void, and their PVR was 100-400 mL. PVR was consistently <100 mL in 11 patients (33.3%). These measurements correlated with the Korean version of the Modified Barthel Index score, Functional Ambulation Category, and the presence of a communication disorder. CONCLUSION: The results show that 22 patients (66.7%) had incomplete bladder emptying or required catheterization at discharge. Outcomes correlated with functional status, walking ability, and the presence of a communication disorder. Patients with urinary retention and poor general condition require close observation to prevent complications of urinary retention. PMID- 25932424 TI - Factors associated with upper extremity motor recovery after repetitive transcranial magnetic stimulation in stroke patients. AB - OBJECTIVE: To determine factors associated with motor recovery of the upper extremity after repetitive transcranial magnetic stimulation (rTMS) treatment in stroke patients. METHODS: Twenty-nine patients with subacute stroke participated in this study. rTMS was applied to the hand motor cortex for 10 minutes at a 110% resting motor threshold and 10 Hz frequency for two weeks. We evaluated the biographical, neurological, clinical, and functional variables, in addition to the motor-evoked potential (MEP) response. The Manual Function Test (MFT) was performed before, immediately after, and two weeks after, the treatment. Patients were divided into a responder and non-responder group according to their respective improvements on the MFT. Data were compared between the two groups. RESULTS: Patients with exclusively subcortical stroke, absence of aphasia, the presence of a MEP response, high scores on the Mini-Mental Status Examination, Motricity Index arm score, Functional Independence Measure, and Functional Ambulatory Classification; and a shorter period from stroke onset to rTMS were found to be significantly associated with a response to rTMS. CONCLUSION: The results of this study suggest that rTMS may have a greater effect on upper extremity motor recovery in stroke patients who have a MEP response, suffer an exclusively subcortical stroke, mild paresis, and have good functional status. Applying rTMS early would have additional positive effects in the patients with the identified characteristics. PMID- 25932425 TI - Necessity to develop a tool to evaluate activity of daily living for electric powered indoor/outdoor chair users. AB - OBJECTIVE: To evaluate changes in activity of daily living before and after provision of electric-powered indoor/outdoor chair (EPIOC), discuss problems of current activities of daily living (ADL) evaluating tools for EPIOC users, and provide preliminary data to develop ADL evaluation tool for EPIOC user. METHODS: A total of 70 users who were prescribed EPIOC and had been using for more than 1 year were recruited in this study. Before and after provision of EPIOC, MBI and FIM scores were measured and a questionnaire consisting of six categories (general socioeconomic states, currently using state, whether EPIOC was helpful for social participation and occupational chances, psychiatric influences, self reported degrees of independency, and barriers of using EPIOC) was used. RESULTS: No difference in MBI scores before and after provision of EPIOC was observed. However, the wheelchair ambulation category showed a significant difference. While motor FIM was not significantly different from MBI, FIM score were significantly (p<0.05) higher than MBI. For questions regarding social participation frequency, helpfulness of EPIOC on confidence, refreshing patients' emotions and self-reported degrees of independence, all of them showed positive responses. Especially, EPIOC users' self-reported degree of independency showed favorable results. There was discrepancy in MBI or FIM measured by physicians. CONCLUSION: Our study showed that there was a gap between the existing ADL evaluation tool and the ADL level that EPIOC users were actually feeling. Thus, it is necessary to develop an evaluation tool specifically for EPIOC. PMID- 25932426 TI - Effect of foot orthoses on children with lower extremity growing pains. AB - OBJECTIVE: To evaluate the effect of custom molded foot orthoses on children with growing pains of the lower extremities. METHODS: Children with growing pains were recruited during a clinic visit. None had any bony deformities, inflammatory joint disease or depression. Resting calcaneal stance position (RCSP) and calcaneal pitch angle were measured, and individual custom molded rigid foot orthoses were prescribed using the inverted orthotic technique to control for foot overpronation using the RCSP angle. Pain sites, degree and frequency of pain, and balance ability were evaluated using Balance Master computerized posturography prior to foot orthosis fitting, and 1 and 3 months later. RESULTS: Twenty children completed the study. Seventeen (75%) had overpronated feet. Significant improvements were noted after 1 and 3 months in pain degree and frequency, and after 3 months in balancing ability. CONCLUSION: The use of custom molded foot orthoses is a good method for treating children with multiple musculoskeletal pains in the leg. PMID- 25932427 TI - Quantitative analysis of magnetic resonance imaging of the neck and its usefulness in management of congenital muscular torticollis. AB - OBJECTIVE: To quantify magnetic resonance imaging (MRI) findings of congenital muscular torticollis (CMT) and to demonstrate the usefulness of quantitative MRI findings in the management of CMT. METHODS: This was a retrospective study of 160 subjects with CMT who had undergone neck MRI at the age of 48 months or younger at a tertiary medical center. Among the 160 subjects, 54 had undergone surgical release of CMT and 106 subjects had not undergone surgery. For the quantitative analysis, the ratios of area and intensity of the MRI findings were measured and compared between the two groups (ratio of area = the largest cross-sectional area of the SCM with CMT - the cross-sectional area of the contralateral SCM without CMT / the cross-sectional area of the contralateral SCM without CMT; ratio of intensity = the mean gray color intensity of the contralateral SCM without CMT - the lowest mean gray color intensity of the SCM with CMT / the mean gray color intensity of the contralateral SCM without CMT). Receiver operating characteristic (ROC) curve analysis was conducted for the ratios of area and intensity in order to find the optimal cutoff value for determining the need for surgery in CMT cases. RESULTS: The ratios of area and intensity were significantly higher in the surgical group than in the non-surgical group (p<=0.001), suggesting that the sternocleidomastoid muscle (SCM) was thicker and darker in the surgical group than in the non-surgical group. The optimal cutoff value for the ratio of area was 0.17 and that for the ratio of intensity was 0.05. All subjects with a ratio of intensity less than 0.03 belonged to the non surgical group, and all subjects with a ratio of intensity greater than 0.16 were categorized in the surgical group. CONCLUSION: The quantitative MRI findings, i.e., ratios of area and intensity, may provide a guideline for deciding the need for surgical intervention in CMT patients. Further prospective studies are required to verify these findings. PMID- 25932428 TI - Simultaneous loss of bilateral voluntary eyelid opening and sustained winking response following bilateral posterior cerebral artery infarction. AB - Spontaneous opening and closing of both eyes usually occurs in the normal awake state, unless a deliberate and voluntary attempt is made to open only one eye. We present a rare case of a male patient who was unable to open both eyes simultaneously after bilateral posterior cerebral artery infarction. He was able to close both eyes voluntarily. However, he was unable to keep both eyes open simultaneously and either the right or left eye remained closed. Upon a verbal command to open both eyes, the opened eye closed and the contralateral eye opened. When the closed eye was forced open, the opened eye closed. We thus presented a case of right-left dissociation of voluntary eyelid opening following bilateral posterior cerebral artery infarction, which was treated with botulinum toxin type A injection. Differential diagnosis to other movement disorders of the eyelids was discussed. PMID- 25932429 TI - Paroxysmal autonomic instability with dystonia managed using chemodenervation including alcohol neurolysis and botulinum toxin type a injection: a case report. AB - Paroxysmal autonomic instability with dystonia (PAID) is a rare complication of brain injury. Symptoms of PAID include diaphoresis, hyperthermia, hypertension, tachycardia, and tachypnea accompanied by hypertonic movement. Herein, we present the case of a 44-year-old female patient, who was diagnosed with paraneoplastic limbic encephalopathy caused by thyroid papillary cancer. The patient exhibited all the symptoms of PAID. On the basis that the symptoms were unresponsive to antispastic medication and her liver function test was elevated, we performed alcohol neurolysis of the musculocutaneous nerve followed by botulinum toxin type A (BNT-A) injection into the biceps brachii and brachialis. Unstable vital signs and hypertonia were relieved after chemodenervation. Accordingly, alcohol neurolysis and BNT-A injection are proposed as a treatment option for intractable PAID. PMID- 25932430 TI - Diagnosis of spasmodic dysphonia manifested by swallowing difficulty in videofluoroscopic swallowing study. AB - Spasmodic dysphonia is defined as a focal laryngeal disorder characterized by dystonic spasms of the vocal cord during speech. We described a case of a 22-year old male patient who presented complaining of idiopathic difficulty swallowing that suddenly developed 6 months ago. The patient also reported pharyngolaryngeal pain, throat discomfort, dyspnea, and voice change. Because laryngoscopy found no specific problems, an electrodiagnostic study and videofluoroscopic swallowing study (VFSS) were performed to find the cause of dysphagia. The VFSS revealed continuous twitch-like involuntary movement of the laryngeal muscle around the vocal folds. Then, he was diagnosed with spasmodic dysphonia by VFSS, auditory perceptual voice analysis, and physical examination. So, we report the first case of spasmodic dysphonia accompanied with difficulty swallowing that was confirmed by VFSS. PMID- 25932431 TI - Extracorporeal shock wave therapy for painful chronic neurogenic heterotopic ossification after traumatic brain injury: a case report. AB - Neurogenic heterotopic ossification (NHO) is a process of benign bone formation and growth in soft tissues surrounding major synovial joints and is associated with central nervous system (CNS) injuries. It is a common complication in major CNS injuries, such as traumatic brain injury, spinal cord injury, and stroke. Here, we report the case of a 72-year-old male, who experienced a traumatic brain injury and painful chronic NHO around the left hip joint. Three applications of extracorporeal shock wave therapy (ESWT) were administered to the area of NHO, which resulted in pain relief and an improvement in the loss of motion in the left hip joint. Improvements were also noted in walking performance and activities of daily living, although the size of NHO remained unchanged. Therapeutic effects of ESWT lasted for 12 weeks. PMID- 25932432 TI - Severe, persistent, painful neuropathy relieved immediately after surgical release: case of neurostenalgia of the radial nerve. AB - Neurostenalgia is a neuropathic pain that results from continuing irritation of an anatomically intact nerve by a noxious agent. The pain resolves promptly after surgical release of the nerve. The authors report a case of neurostenalgia of the radial nerve in which the posterior interosseous branch was compressed at the arcade of Frohse, presenting with severe arm and elbow pain. The pain was immediately relieved after surgical release of the nerve. PMID- 25932433 TI - Paralysis developing as a paradoxical response during treatment for tuberculous spondylitis. PMID- 25932434 TI - In reply: paralysis developing as a paradoxical response during the treatment for tuberculous spondylitis. PMID- 25932435 TI - Meta-analysis of genetic association studies. AB - The object of this review is to help readers to understand meta-analysis of genetic association study. Genetic association studies are a powerful approach to identify susceptibility genes for common diseases. However, the results of these studies are not consistently reproducible. In order to overcome the limitations of individual studies, larger sample sizes or meta-analysis is required. Meta analysis is a statistical tool for combining results of different studies on the same topic, thus increasing statistical strength and precision. Meta-analysis of genetic association studies combines the results from independent studies, explores the sources of heterogeneity, and identifies subgroups associated with the factor of interest. Meta-analysis of genetic association studies is an effective tool for garnering a greater understanding of complex diseases and potentially provides new insights into gene-disease associations. PMID- 25932436 TI - Incidences and Prognostic Impact of c-KIT, WT1, CEBPA, and CBL Mutations, and Mutations Associated With Epigenetic Modification in Core Binding Factor Acute Myeloid Leukemia: A Multicenter Study in a Korean Population. AB - BACKGROUND: To identify potential molecular prognostic markers in core binding factor (CBF) AML, we analyzed incidences and prognostic impacts of mutations in c KIT, WT1, CEBPA, CBL, and a number of epigenetic genes in CBF AML. METHODS: Seventy one and 21 AML patients with t(8;21) and inv(16) were enrolled in this study, respectively. NPM1, CEBPA, c-KIT, IDH1/2, DNMT3A, EZH2, WT1, and CBL mutations were analyzed by direct sequencing. Patients were categorized with respect to c-KIT and WT1 mutation status, and both clinical features and prognoses were compared. RESULTS: The incidences of FLT3 internal tandem duplication (ITD), NPM1, CEBPA, IDH1/2, DNMT3A, EZH2, and CBL mutations were low (<=5%) in CBF AML patients. However, c-KIT and WT1 mutations occurred frequently (10.9% and 13.8%, respectively). t(8;21) patients with c-KIT mutations showed significantly shorter overall survival (OS) and disease free survival (DFS) periods than those without mutations (P<0.001, for both); however, although the limited number of t(8;21) patients were analyzed, WT1 mutation status did not affect prognosis significantly. Relapse or death during follow-up occurred more frequently in t(8;21) patients carrying c-KIT mutations than in those without the mutation, although the difference was significant only in a specific patient subgroup with no WT1 mutations (P=0.014). CONCLUSIONS: The incidences of mutations in epigenetic genes are very low in CBF AML; however, c-KIT and WT1 mutations occur more frequently than others. The poor prognostic impact of c-KIT mutation in t(8;21) AML patients only applies in a specific patient subgroup without WT1 mutations. The prognostic impact of WT1 mutation in CBF AML is not evident and further investigation is required. PMID- 25932437 TI - Further Modification of the Modified Hodge Test for Detecting Metallo-beta Lactamase-Producing Carbapenem-Resistant Enterobacteriaceae. AB - BACKGROUND: The modified Hodge test (MHT) was designed to detect carbapenemase producing Enterobacteriaceae (CPE). This study evaluated variables to improve the performance of MHT. METHODS: Carbapenem-resistant Enterobacteriaceae isolated from November 2010 to March 2013 at the Asan Medical Center, were evaluated, including 33 metallo-beta-lactamase (MBL) producers and 103 non-CPEs. MHT was performed by using two carbapenem disks (ertapenem and meropenem; Becton Dickinson, USA), three media (Mueller-Hinton agar (MHA), MacConkey agar (MAC), and zinc-enriched MHA), and two inoculums (0.5-McFarland [McF] suspension and a 10-fold dilution of it.) PCR was performed to detect beta-lactamase genes of the MBL, AmpC, and CTX-M types. RESULTS: The sensitivity of MHT for detecting New Delhi metallo-beta-lactamase (NDM) producers was highest using ertapenem and 0.5 McF, 52.0% on MHA and 68.0% on MAC, respectively. NDM-producing Klebsiella pneumoniae (NDMKP) were detected with higher sensitivity on MAC (78.6%) vs. MHA (28.6%) (P=0.016), but VIM-producing Enterobacter, Citrobacter, and Serratia were detected with higher sensitivity on MHA (78.5%) vs. MAC (14.3%) (P=0.004). MBL producers were consistently identified with lower sensitivity using meropenem vs. ertapenem, 39.4% vs. 60.6% (P=0.0156), respectively. The effects of zinc and inoculum size were insignificant. Enterobacter aerogenes producing unspecified AmpC frequently demonstrated false positives, 66.7% with ertapenem and 22.2% with meropenem. CONCLUSIONS: The MHT should be adjusted for the local distribution of species and the carbapenemase type of MBL producers. MAC and ertapenem are preferable for assessing NDMKP, but MHA is better for VIM. Laboratory physicians should be aware of the limited sensitivity of MHT and its relatively high false positive rate. PMID- 25932438 TI - Multiplex Real-Time PCR Method for Simultaneous Identification and Toxigenic Type Characterization of Clostridium difficile From Stool Samples. AB - BACKGROUND: The aim of this study was to develop and validate a multiplex real time PCR assay for simultaneous identification and toxigenic type characterization of Clostridium difficile. METHODS: The multiplex real-time PCR assay targeted and simultaneously detected triose phosphate isomerase (tpi) and binary toxin (cdtA) genes, and toxin A (tcdA) and B (tcdB) genes in the first and sec tubes, respectively. The results of multiplex real-time PCR were compared to those of the BD GeneOhm Cdiff assay, targeting the tcdB gene alone. The toxigenic culture was used as the reference, where toxin genes were detected by multiplex real-time PCR. RESULTS: A total of 351 stool samples from consecutive patients were included in the study. Fifty-five stool samples (15.6%) were determined to be positive for the presence of C. difficile by using multiplex real-time PCR. Of these, 48 (87.2%) were toxigenic (46 tcdA and tcdB-positive, two positive for only tcdB) and 11 (22.9%) were cdtA-positive. The sensitivity, specificity, negative predictive value (NPV), and positive predictive value (PPV) of the multiplex real-time PCR compared with the toxigenic culture were 95.6%, 98.6%, 91.6%, and 99.3%, respectively. The analytical sensitivity of the multiplex real time PCR assay was determined to be 10(3) colony forming unit (CFU)/g spiked stool sample and 0.0625 pg genomic DNA from culture. Analytical specificity determined by using 15 enteric and non-clostridial reference strains was 100%. CONCLUSIONS: The multiplex real-time PCR assay accurately detected C. difficile isolates from diarrheal stool samples and characterized its toxin genes in a single PCR run. PMID- 25932439 TI - Investigation of Serum Angiotensin II Type 1 Receptor Antibodies at the Time of Renal Allograft Rejection. AB - BACKGROUND: Angiotensin II type 1 receptor (AT1R) is responsible for cardiovascular effects mediated by angiotensin II. This study aimed to investigate the impact of antibodies directed against AT1R (anti-AT1R) in renal allograft rejection. METHODS: We evaluated 53 patients who had biopsy-proven rejection including antibody-mediated rejection (AMR) (N=22), T-cell-mediated rejection (TCMR) (N=29), and mixed AMR and TCMR (N=2). Donor specific HLA antibodies (DSA) and anti-AT1Rs were simultaneously determined. RESULTS: Anti AT1Rs were detected in 9.4% (5/53) of rejection patients (one with acute AMR, two with chronic active AMR, one with acute TCMR, and one with mixed acute AMR & TCMR). HLA antibodies and DSA were detected in 75.5% (40/53) and 49.1% (26/53) of patients, respectively. There was no significant difference in transplant characteristics between anti-AT1R(+) and anti-AT1R(-) patients except for the association of HLA class-I DSA(+) and anti-AT1R(+). Four of five anti-AT1R(+) patients had DSA and were also found to have AMR. A single anti-AT1R(+)/DSA(-) patient developed acute TCMR. Detection rates of DSA, HLA antibodies, or anti AT1R were not different between AMR and TCMR. However, DSA(+)/anti-AT1R(+) was more frequently found in AMR than in TCMR (P=0.036). Patients with anti-AT1R showed a greater tendency to develop high-grade rejection as Banff IIA/IIB or AMR. CONCLUSIONS: The presence of anti-AT1R was significantly associated with HLA class-I DSA in renal allograft rejection patients. Both anti-AT1R and DSA positivity was associated with AMR in patients with renal allograft rejection. PMID- 25932441 TI - Meta-Analysis of the SLCO1B1 c.521T>C Variant Reveals Slight Influence on the Lipid-Lowering Efficacy of Statins. AB - BACKGROUND: Several studies have focused on the association between the lipid lowering efficacy of statins and the SLCO1B1 c.521T>C polymorphism; however, the results are conflicting. The effects of statins show significant variability between individuals. This meta-analysis aimed to investigate the effects of the SLCO1B1 c.521T>C polymorphism on the lipid-lowering effects of statins. METHODS: We systematically searched PubMed and Web of Science to screen relevant studies. Meta-analysis was performed to identify the association between SLCO1B1 c.521 polymorphisms and the lipid-lowering effects of statins on the basis of the standard mean difference (SMD) and 95% confidence intervals (CIs). Additionally, we checked for heterogeneity (I(2)) among studies and evidence of publication bias. We obtained eight studies including 2,012 wild genotype (T/T) and 526 variant genotype (T/C and C/C) cases. RESULTS: No significant difference was observed in the lipid-lowering efficacy of statins between the wild and variant genotypes of SLCO1B1, with a pooled SMD of 0.03 (95% CI: -0.07-0.13). Furthermore, there was no significant effect in the meta-analyses of the variant heterozygote, homozygote, and Chinese populations. Subgroup meta-analysis indicated that the time required for the statin to take effect did not significantly affect the association between lipid-lowering efficacy of statins and SLCO1B1 c.521T>C polymorphism. However, the wild genotype improved the lipid lowering efficacy of simvastatin with a pooled SMD of -0.26 (95% CI: -0.47- 0.05). CONCLUSIONS: No significant association was detected between the lipid lowering efficacy of statins and the SLCO1B1 c.521T>C polymorphism, with the exception of simvastatin. PMID- 25932440 TI - Interlaboratory Comparison of the Results of Lifecodes LSA Class I and Class II Single Antigen Kits for Human Leukocyte Antigen Antibody Detection. AB - BACKGROUND: Although single antigen bead assays (SAB) are approved qualitative tests, the median fluorescence intensity (MFI) values obtained from SAB are frequently used in combination with quantitative significances for diagnostic purposes. To gauge the reproducibility of SAB results, we assessed the interlaboratory variability of MFI values using identical kits with reagents from the same lot and the manufacturer's protocol. METHODS: Six serum samples containing HLA-specific antibodies were analyzed at five laboratories by using Lifecodes LSA Class I and Class II SAB kits (Immucor, USA) from the same lot, according to the manufacturer's protocol. We analyzed the concordance of qualitative results according to distinct MFI cutoffs (1,000, 3,000, 5,000, and 10,000), and the correlation of quantitative MFI values obtained by the participating laboratories. The CV for MFI values were analyzed and grouped by mean MFI values from the five laboratories (<1,000; 1,000-2,999; 3,000-4,999; 5,000-9,999; and >=10,000). RESULTS: The categorical results obtained from the five laboratories exhibited concordance rates of 96.0% and 97.2% for detection of HLA class I and class II antibodies, respectively. The Pearson correlation coefficients for MFI values of class I and class II antibodies were between 0.947 0.991 and 0.992-0.997, respectively. The median CVs for the MFI values among five laboratories in the lower MFI range (<1,000) were significantly higher than those for the other MFI ranges (all P<0.01). CONCLUSIONS: Analysis of SAB performed in five laboratories using identical protocols and reagents from the same lot resulted in high levels of concordance and strong correlation of results. PMID- 25932442 TI - Mutation Analysis of the TGFBI Gene in Consecutive Korean Patients With Corneal Dystrophies. AB - BACKGROUND: Mutations in the transforming growth factor beta-induced gene (TGFBI) are major causes of genetic corneal dystrophies (CDs), which can be grouped into TGFBI CDs. Although a few studies have reported the clinical and genetic features of Korean patients with TGFBI CD, no data are available regarding the frequency and spectrum of TGFBI mutations in a consecutive series of Korean patients with clinically diagnosed CDs. METHODS: Patients with any type of CD, who underwent both ophthalmologic examination and TGFBI gene analysis by Sanger sequencing at a tertiary care hospital in Seoul, Korea from 2006 to 2013, were enrolled in this study. RESULTS: Among a total of 89 patients, 77 (86.5%) were diagnosed as having clinical TGFBI CD. Seventy-three out of 74 patients (98.6%) with granular CD type 2 (GCD2), had the p.R124H mutation. Of particular note, one patient with rapidly progressive CD had the p.R124H mutation as well as a novel nonsense variant with unknown clinical significance (p.A179*). In three patients with lattice CD type 1 (LCD1), one known mutation (p.R124C) and two novel variants (p.L569Q and p.T621P) in the TGFBI gene were identified. CONCLUSIONS: This study provides epidemiological insight into CDs in a Korean population and reaffirms that GCD2 is the most common TGFBI CD phenotype and that p.R124H is the only mutation identified in patients with GCD2. In addition, we broaden the spectrum of TGFBI mutations by identifying two novel missense variants in patients with LCD1. PMID- 25932443 TI - Scoring system for detecting spurious hemolysis in anticoagulated blood specimens. AB - BACKGROUND: The identification of in vitro hemolysis (IVH) using a hematology analyzer is challenging because centrifugation of the specimens cannot be performed for cell counts. In the present study, we aimed to develop a scoring system to help identify the presence of hemolysis in anticoagulated blood specimens. METHODS: Thirty-seven potassium EDTA anticoagulated blood specimens were obtained, and each specimen was divided into 3 aliquots (A, B, and C). Aliquots B and C were mechanically hemolyzed by aspirating 2 and 5 times, respectively, using a 27-gauge needle and then tested; aliquot A was analyzed immediately without any hemolysis. After the cells were counted, aliquots B and C were centrifuged and the supernatants were tested for the hemolytic index and lactate dehydrogenase levels. RESULTS: The 4 hematologic parameters were selected and scored from 0 to 3 as follows:< 34.0, 34.0-36.2, 36.3-38.4, and >=38.5 for mean cell hemoglobin concentration (MCHC, g/dL); <0.02, 0.02, 0.03, and >=0.04 for red blood cell ghosts (10(12)/L); <0.13, 0.13-0.38, 0.39-1.30, and >=1.31 for difference value (g/dL) of measured hemoglobin and calculated hemoglobin; and <0.26, 0.26-0.95, 0.96-3.34, and >=3.35 for difference value (g/dL) of MCHC and cell hemoglobin concentration mean. The hemolysis score was calculated by adding all the scores from the 4 parameters. At the cutoff hemolysis score of 3, the IVH of aliquots B and C were detected as 64.9% and 91.9%, respectively. CONCLUSIONS: The scoring system might provide effective screening for detecting spurious IVH. PMID- 25932444 TI - Risk-Reducing Genetic Variant of Wilms Tumor 1 Gene rs16754 in Korean Patients With BCR-ABL1-Negative Myeloproliferative Neoplasm. AB - The genetic variant rs16754 of Wilms tumor gene 1 (WT1) has recently been described as an independent prognostic factor in AML patients. It is of great interest to test whether WT1 single nucleotide polymorphism can be used as a molecular marker in other types of cancer, to improve risk and treatment stratification. We performed sequencing analysis of exons 7 and 9 of WT1, which are known mutational hotspots, in a total of 73 patients with BCR-ABL1-negative myeloproliferative neoplasm (MPN) and 93 healthy controls. No previously reported WT1 mutations were identified in the present study. In Korean patients with BCR ABL1-negative MPN, WT1 genetic variant rs16754 had no significant impact on clinical outcomes. We observed a significant difference in the allelic frequencies of WT1 rs16754 in Koreans between BCR-ABL1-negative MPN cases and healthy controls. Individuals carrying variant G alleles of WT1 rs16754 showed a relatively low prevalence of BCR-ABL1-negative MPN, compared with those carrying wild A alleles of WT1 rs16754 (Hazard ratio 0.10-0.65, P<0.05). Therefore, possession of the variant G allele of WT1 rs16754 may reduce the risk of developing BCR-ABL1-negative MPN. PMID- 25932445 TI - Report on HbA1c Proficiency Testing in Asia in 2012. AB - In 2010, the Japan Diabetes Society decided to introduce the National Glycohemoglobin Standardization Program (NGSP) values into clinical practice. Accordingly, NGSP Certification of Japanese manufacturers of HbA1c-related diagnostic reagents and instruments was initiated in February, 2012, through an NGSP network laboratory, the Asian Secondary Reference Laboratory (ASRL) #1. Traceability to the NGSP reference system can be endorsed by manufacturer certification, as well as by the College of American Pathologists (CAP) survey. Nevertheless, only a few manufacturers participate in the CAP survey in Japan. Thus, proficiency testing (PT) was proposed and executed by ASRL #1. Single-donor whole-blood samples were used for the PT. The participated measurement systems were NGSP certified. Twenty-two laboratories obtained certification through ASRL #1; 2 through the Secondary Reference Laboratory (SRL) #8; and 9 through the SRL #9. The combination plots of the bias data in this PT and in the NGSP certification performed in March and May in 2012 were consistent with each other: mean NGSP values at each level agreed well with the target value. In conclusion, PT using whole blood is useful in endorsing NGSP certification. PMID- 25932446 TI - Comparison of AdvanSure TB/NTM PCR and COBAS TaqMan MTB PCR for Detection of Mycobacterium tuberculosis Complex in Routine Clinical Practice. AB - The AdvanSure tuberculosis/non-tuberculous mycobacterium (TB/NTM) PCR (LG Life Science, Korea) and COBAS TaqMan Mycobacterium tuberculosis (MTB) PCR (Roche Diagnostics, USA) are commonly used in clinical microbiology laboratories. We aimed to evaluate these two commercial real-time PCR assays for detection of MTB in a large set of clinical samples over a two-year period. AdvanSure TB/NTM PCR and COBAS TaqMan MTB PCR were performed on 9,119 (75.2%) and 3,010 (24.8%) of 12,129 (9,728 respiratory and 2,401 non-respiratory) MTB specimens, with 361 (4.0%) and 102 (3.4%) acid-fast bacilli (AFB)-positive results, respectively. In MTB culture, 788 (6.5%) MTB and 514 (4.2%) NTM were identified. The total sensitivity and specificity of the AdvanSure assay were 67.8% (95% confidence interval [CI], 63.9-71.6) and 98.3% (95% CI, 98.0-98.6), while those of the COBAS TaqMan assay were 67.2% (95% CI, 60.0-73.8) and 98.4% (95% CI, 97.9-98.9), respectively. The sensitivities and specificities of the AdvanSure and COBAS TaqMan assays for AFB-positive and AFB-negative samples were comparable. Furthermore, the AdvanSure assay showed fewer invalid results compared with the COBAS TaqMan assay (5.0 vs. 20.4 invalid results/1,000 tests, P<0.001). AdvanSure assay represents a comparable yet more reliable method than COBAS TaqMan for the identification of mycobacteria in routine clinical microbiology. PMID- 25932447 TI - Identification of a Novel De Novo Variant in the PAX3 Gene in Waardenburg Syndrome by Diagnostic Exome Sequencing: The First Molecular Diagnosis in Korea. AB - Waardenburg syndrome (WS) is a clinically and genetically heterogeneous hereditary auditory pigmentary disorder characterized by congenital sensorineural hearing loss and iris discoloration. Many genes have been linked to WS, including PAX3, MITF, SNAI2, EDNRB, EDN3, and SOX10, and many additional genes have been associated with disorders with phenotypic overlap with WS. To screen all possible genes associated with WS and congenital deafness simultaneously, we performed diagnostic exome sequencing (DES) in a male patient with clinical features consistent with WS. Using DES, we identified a novel missense variant (c.220C>G; p.Arg74Gly) in exon 2 of the PAX3 gene in the patient. Further analysis by Sanger sequencing of the patient and his parents revealed a de novo occurrence of the variant. Our findings show that DES can be a useful tool for the identification of pathogenic gene variants in WS patients and for differentiation between WS and similar disorders. To the best of our knowledge, this is the first report of genetically confirmed WS in Korea. PMID- 25932448 TI - A novel case of extreme thrombocytosis in acute myeloid leukemia associated with isochromosome 17q and copy neutral loss of heterozygosity. PMID- 25932449 TI - A rare case of chronic myelogenous leukemia and plasma cell myeloma in the same patient. PMID- 25932450 TI - A case of pentasomy 21 with two isochromosome 21s in acute megakaryoblastic leukemia associated with Down syndrome. PMID- 25932451 TI - T618I-Mutated Colony Stimulating Factor 3 Receptor in Chronic Neutrophilic Leukemia and Chronic Myelomonocytic Leukemia Patients who Underwent Allogeneic Stem Cell Transplantation. PMID- 25932452 TI - First Case of Pulmonary Mycobacterium parascrofulaceum Infection in a Patient With Bronchiectasis in Korea. PMID- 25932453 TI - The First Klebsiella pneumoniae Isolate Co-Producing OXA-48 and NDM-1 in Turkey. PMID- 25932454 TI - Flavobacterium ceti From Blood Samples of a Korean Patient With Alcoholic Liver Cirrhosis. PMID- 25932455 TI - Identification of p.Glu131Lys Mutation in the IHH Gene in a Korean Patient With Brachydactyly Type A1. PMID- 25932456 TI - XocR, a LuxR solo required for virulence in Xanthomonas oryzae pv. oryzicola. AB - Xanthomonas oryzae pv. oryzicola (Xoc) causes bacterial leaf streak (BLS) in rice, a serious bacterial disease of rice in Asia and parts of Africa. The virulence mechanisms of Xoc are not entirely clear and control measures for BLS are poorly developed. The solo LuxR proteins are widespread and shown to be involved in virulence in some plant associated bacteria (PAB). Here, we have cloned and characterized a PAB LuxR solo from Xoc, named as XocR. Mutation of xocR almost completely impaired the virulence ability of Xoc on host rice, but did not alter the ability to trigger HR (hypersensitive response, a programmed cell death) on non-host (plant) tobacco, suggesting the diversity of function of xocR in host and non-host plants. We also provide evidence to show that xocR is involved in the regulation of growth-independent cell motility in response to a yet-to-be-identified rice signal, as mutation of xocR impaired cell swimming motility of wild-type Rs105 in the presence but not absence of rice macerate. We further found that xocR regulated the transcription of two characterized virulence-associated genes (recN and trpE) in the presence of rice macerate. The promoter regions of recN and trpE possessed a potential binding motif (an imperfect pip box-like element) of XocR, raising the possibility that XocR might directly bind the promoter regions of these two genes to regulate their transcriptional activity. Our studies add a new member of PAB LuxR solos and also provide new insights into the role of PAB LuxR solo in the virulence of Xanthomonas species. PMID- 25932457 TI - Comparison of the adherence to the american diabetes association guidelines of diabetes care in primary care and subspecialty clinics. AB - BACKGROUND: Diabetes mellitus is a major public health problem with significant morbidity and mortality. Evidence based guidelines have been proposed to reduce the micro and macrovascular complications, but studies have shown that these goals are not being met. We sought to compare the adherence to the American Diabetes Association guidelines for measurement and control of glycohemoglobin (A1c), blood pressure (BP), lipids (LDL) and microalbuminuria (MA) by subspecialty and primary care clinics in an academic medical center. METHODS: 390 random charts of patients with diabetes from Family Practice (FP), Internal Medicine (IM) and Diabetes (DM) clinics at Michigan State University were reviewed. RESULTS: We reviewed 131, 134 and 125 charts from the FP, IM and DM clinics, respectively. DM clinic had a higher percentage of patients with type 1 diabetes 43/125 (34.4%) compared with 7/131 (5.3%) in FP and 7/134 (5.2%) in IM clinics. A1c was measured in 99%, 97.8% and 100% subjects in FP, IM and DM clinics respectively. B.P. was measured in all subjects in all three clinics. Lipids were checked in 97.7%, 95.5% and 92% patients in FP, IM and DM clinics respectively. MA was measured at least once during the year preceding the office visit in 85.5%, 82.8% and 76.8% patients in FP, IM and DM clinics respectively. A1C was controlled (<7%) in 38.9, 43.3, 28.8% of patients in the FP, IM and DM clinics, respectively (p = 0.034). LDL was controlled (<100 mg/dl or 2.586 mmol/l) in 71.8, 64.9, 64% of patients in the FP, IM and DM clinics, respectively. MA was controlled (<30 mg/gm creatinine) in 60.3%, 51.5% and 60% patients in FP, IM and DM clinics respectively (P = 0.032). BP was controlled (<130/80) in 59.5, 67.2 and 52.8% patients in the FP, IM and DM clinics, respectively. CONCLUSION: Testing rates for A1C, LDL, and MA were high, in both subspecialty and primary care clinics. However, the degree of control was not optimal. Significantly fewer patients in the DM clinic had A1c <7%, the cause of which may be multifactorial. PMID- 25932458 TI - Corrigendum: Novel TTC37 Mutations in a Patient with Immunodeficiency without Diarrhea: Extending the Phenotype of Trichohepatoenteric Syndrome. AB - [This corrects the article on p. 2 in vol. 3, PMID: 25688341.]. PMID- 25932459 TI - Health disparities and cancer: racial disparities in cancer mortality in the United States, 2000-2010. AB - Declining cancer incidence and mortality rates in the United States (U.S.) have continued through the first decade of the twenty-first century. Reductions in tobacco use, greater uptake of prevention measures, adoption of early detection methods, and improved treatments have resulted in improved outcomes for both men and women. However, Black Americans continue to have the higher cancer mortality rates and shorter survival times. This review discusses and compares the cancer mortality rates and mortality trends for Blacks and Whites. The complex relationship between socioeconomic status and race and its contribution to racial cancer disparities is discussed. Based on current trends and the potential and limitations of the patient protection and affordable care act with its mandate to reduce health care inequities, future trends, and challenges in cancer mortality disparities in the U.S. are explored. PMID- 25932460 TI - Perceptions of social mobility: development of a new psychosocial indicator associated with adolescent risk behaviors. AB - Social class gradients have been explored in adults and children, but not extensively during adolescence. The first objective of this study was to examine the association between adolescent risk behaviors and a new indicator of adolescent relative social position, adolescent "perceived social mobility." Second, it investigated potential underlying demographic, socioeconomic, and psychosocial determinants of this indicator. Data were taken from the 2004 urban adolescent module of Oportunidades, a cross-sectional study of Mexican adolescents living in poverty. Perceived social mobility was calculated for each subject by taking the difference between their rankings on two 10-rung ladder scales that measured (1) projected future social status and (2) current subjective social status within Mexican society. Adolescents with higher perceived social mobility were significantly less likely to report alcohol consumption, drinking with repercussions, compensated sex, police detainment, physical fighting, consumption of junk food or soda, or watching >=4 h of television during the last viewing. They were significantly more likely to report exercising during the past week and using a condom during last sexual intercourse. These associations remained significant with the inclusion of covariates, including parental education and household expenditures. Multiple logistic regression analyses show higher perceived social mobility to be associated with staying in school longer and having higher perceived control. The present study provides evidence for the usefulness of perceived social mobility as an indicator for understanding the social gradient in health during adolescence. This research suggests the possibility of implementing policies and interventions that provide adolescents with real reasons to be hopeful about their trajectories. PMID- 25932461 TI - Flexibility of short ds-DNA intercalated by a dipyridophenazine ligand. AB - We use Forster Resonant Energy Transfer (FRET) in order to measure the increase of flexibility of short ds-DNA induced by the intercalation of dipyridophenazine (dppz) ligand in between DNA base pairs. By using a DNA double strand fluorescently labeled at its extremities, it is shown that the end-to-end length increase of DNA due to the intercalation of one dppz ligand is smaller than the DNA base pair interdistance. This may be explained either by a local bending of the DNA or by an increase of its flexibility. The persistence length of the formed DNA/ligand is evaluated. The described structure may have implications in the photophysical damages induced by the complexation of DNA by organometallic molecules. PMID- 25932462 TI - S-nitrosylation of the thioredoxin-like domains of protein disulfide isomerase and its role in neurodegenerative conditions. AB - Correct protein folding and inhibition of protein aggregation is facilitated by a cellular "quality control system" that engages a network of protein interactions including molecular chaperones and the ubiquitin proteasome system. Key chaperones involved in these regulatory mechanisms are the protein disulfide isomerases (PDI) and their homologs, predominantly expressed in the endoplasmic reticulum of most tissues. Redox changes that disrupt ER homeostasis can lead to modification of these enzymes or chaperones with the loss of their proposed neuroprotective role resulting in an increase in protein misfolding. Misfolded protein aggregates have been observed in several disease states and are considered to play a pivotal role in the pathogenesis of neurodegenerative conditions such as Alzheimer's disease, Parkinson's disease, and Amyotrophic Lateral sclerosis. This review will focus on the importance of the thioredoxin like CGHC active site of PDI and how our understanding of this structural motif will play a key role in unraveling the pathogenic mechanisms that underpin these neurodegenerative conditions. PMID- 25932464 TI - Facilitating emotional processing in depression: the application of exposure principles. AB - Even with the best psychosocial and pharmacological treatments for unipolar depression, relapse is a serious problem. One path to improve treatments for depression is to target fundamental processes that go awry in depression and to enhance new learning by adapting principles and strategies from exposure-based treatments for anxiety and fear-related disorders. I describe basic principles of exposure and emotional processing and illustrate with Exposure-Based Cognitive Therapy (EBCT) for depression, how these principles can be applied, with some adaptation, to address the therapeutic targets of depression. Clinical trial data of EBCT suggest that this application might be fruitful and that the process of change might be similar to that in exposure-based treatments for anxiety and trauma-related disorders. PMID- 25932463 TI - "Don't Want No Risk and Don't Want No Problems": Public Understandings of the Risks and Benefits of Non-Invasive Prenatal Testing in the United States. AB - BACKGROUND: The recent availability of new non-invasive prenatal genetic tests for fetal aneuploidy has raised questions concerning whether and how these new tests will be integrated into prenatal medical care. Among the many factors to be considered are public understandings and preferences about prenatal testing mechanisms and the prospect of fetal aneuploidy. METHODS: To address these issues, we conducted a nation-wide mixed-method survey of 2,960 adults in the United States to explore justifications for choices among prenatal testing mechanisms. Open responses were qualitatively coded and grouped by theme. RESULTS: Respondents cited accuracy, followed by cost, as the most significant aspects of prenatal testing. Acceptance of testing was predicated on differing valuations of knowledge and on personal and religious beliefs. Trust in the medical establishment, attitudes towards risk, and beliefs about health and illness were also considered relevant. CONCLUSIONS: Although a significant portion of the sample population valued the additional accuracy provided by the new non-invasive tests, they nevertheless expressed concerns over high costs. Furthermore, participants continued to express reservations about the value of prenatal genetic information per se, regardless of how it was obtained. PMID- 25932465 TI - Genetic background influences loss of heterozygosity patterns in radiation induced mouse thymic lymphoma. AB - Previous studies have revealed that p53 heterozygous (p53+/-) mice are extremely susceptible to radiation-induced tumorigenesis. To investigate whether genetic background influences radiation induced tumor susceptibility, we crossed p53+/- 129/Sv mice with genetically diverse strains to generate p53+/- F1 hybrids. The results showed that genetic background had a profound impact on tumor latency after exposure to gamma radiation, while the tumor spectrum did not change. We further characterized the thymic lymphomas that arose in the p53+/- mice by genome-wide loss of heterozygosity (LOH) analyses and found that genetic background strongly influenced the frequency of LOH and the loss of which parental allele on different chromosomes. Further research is needed to identify which genetic variations control the LOH patterns in radiation-induced thymic lymphomas and to evaluate its relevance to human cancers. PMID- 25932466 TI - Estimating Diffusion Network Structures: Recovery Conditions, Sample Complexity & Soft-thresholding Algorithm. AB - Information spreads across social and technological networks, but often the network structures are hidden from us and we only observe the traces left by the diffusion processes, called cascades. Can we recover the hidden network structures from these observed cascades? What kind of cascades and how many cascades do we need? Are there some network structures which are more difficult than others to recover? Can we design efficient inference algorithms with provable guarantees? Despite the increasing availability of cascade-data and methods for inferring networks from these data, a thorough theoretical understanding of the above questions remains largely unexplored in the literature. In this paper, we investigate the network structure inference problem for a general family of continuous-time diffusion models using an [Formula: see text]-regularized likelihood maximization framework. We show that, as long as the cascade sampling process satisfies a natural incoherence condition, our framework can recover the correct network structure with high probability if we observe O(d3 log N) cascades, where d is the maximum number of parents of a node and N is the total number of nodes. Moreover, we develop a simple and efficient soft thresholding inference algorithm, which we use to illustrate the consequences of our theoretical results, and show that our framework outperforms other alternatives in practice. PMID- 25932468 TI - Directing the orientational alignment of anisotropic magnetic nanoparticles using dynamic magnetic fields. AB - The structure-directing influence of static and dynamic, i.e. rotating, magnetic fields on the orientational alignment of spindle-type hematite particles with a high aspect ratio is investigated. Structural characterization using electron microscopy and small-angle X-ray scattering confirms a nearly collinear particle arrangement with orientation of the main particle axis either parallel or perpendicular to the substrate as directed by the magnetic field geometry. The combination of large structural and magnetocrystalline anisotropies results in significantly different, strongly anisotropic magnetic properties of the assemblies revealed by directional magnetization measurements. PMID- 25932467 TI - Biologically controlled synthesis and assembly of magnetite nanoparticles. AB - Magnetite nanoparticles have size- and shape-dependent magnetic properties. In addition, assemblies of magnetite nanoparticles forming one-dimensional nanostructures have magnetic properties distinct from zero-dimensional or non organized materials due to strong uniaxial shape anisotropy. However, assemblies of free-standing magnetic nanoparticles tend to collapse and form closed-ring structures rather than chains in order to minimize their energy. Magnetotactic bacteria, ubiquitous microorganisms, have the capability to mineralize magnetite nanoparticles, the so-called magnetosomes, and to direct their assembly in stable chains via biological macromolecules. In this contribution, the synthesis and assembly of biological magnetite to obtain functional magnetic dipoles in magnetotactic bacteria are presented, with a focus on the assembly. We present tomographic reconstructions based on cryo-FIB sectioning and SEM imaging of a magnetotactic bacterium to exemplify that the magnetosome chain is indeed a paradigm of a 1D magnetic nanostructure, based on the assembly of several individual particles. We show that the biological forces are a major player in the formation of the magnetosome chain. Finally, we demonstrate by super resolution fluorescence microscopy that MamK, a protein of the actin family necessary to form the chain backbone in the bacteria, forms a bundle of filaments that are not only found in the vicinity of the magnetosome chain but are widespread within the cytoplasm, illustrating the dynamic localization of the protein within the cells. These very simple microorganisms have thus much to teach us with regards to controlling the design of functional 1D magnetic nanoassembly. PMID- 25932469 TI - Water corrosion of spent nuclear fuel: radiolysis driven dissolution at the UO2/water interface. AB - X-ray diffraction has been used to probe the radiolytic corrosion of uranium dioxide. Single crystal thin films of UO(2) were exposed to an intense X-ray beam at a synchrotron source in the presence of water, in order to simultaneously provide radiation fields required to split the water into highly oxidising radiolytic products, and to probe the crystal structure and composition of the UO(2) layer, and the morphology of the UO(2)/water interface. By modeling the electron density, surface roughness and layer thickness, we have been able to reproduce the observed reflectivity and diffraction profiles and detect changes in oxide composition and rate of dissolution at the Angstrom level, over a timescale of several minutes. A finite element calculation of the highly oxidising hydrogen peroxide product suggests that a more complex surface interaction than simple reaction with H(2)O(2) is responsible for an enhancement in the corrosion rate directly at the interface of water and UO(2), and this may impact on models of long-term storage of spent nuclear fuel. PMID- 25932470 TI - Pressure dependence of Raman spectrum in InAs nanowires. AB - We report on a Raman scattering experiment under high pressure on InAs nanowires with mainly wurtzite crystal structure. The dependence of the phonon modes on applied pressure due to the modification of the lattice parameters has been determined along with the transverse dynamical charge. Contrary to bulk InAs, no structural transition to rock salt phase has been observed in the investigated pressure range, while an anomalous behavior of the full-width at half-maximum has been noted. Our data suggest that wurtzite InAs NWs go through a tetragonal intermediate phase. Furthermore, the resonance profile of the phonon modes as a function of the applied pressure has been investigated, giving insights into the band structure of wurtzite InAs. PMID- 25932471 TI - A metallic carbon consisting of helical carbon triangle chains. AB - Carbon is the basis of life on Earth and many technological applications. We computationally report an sp3-hybridization-assembled carbon allotrope constructed by helical triangle chains through the evolutionary structure prediction method. Different from the previous metallic carbon K4, this carbon, called Tri-carbon, is mechanically and dynamically stable at ambient pressure. High ring strain in the carbon triangle blocks forces the C-C bond in Tri-carbon to be a 'bent bond', rather than the common single bond in diamond or the pi bond in graphite. Unlike the unstrained sp3-hybridization in semiconductive diamond, valence electrons in the 'bent bond' are recombined to form extremely anisotropic sp3-hybridized bonds, thus conferring metallicity to Tri-carbon. Under nonhydrostatic conditions, Tri-carbon shows significantly anisotropic ideal tensile and compressive strength. Tri-carbon is expected to be achieved through chemical methods, such as the synthesis of cyclopropane derivatives (e.g. triangulane and tetrahedrane). These methods eliminate the restriction of ultra high pressure to obtain metallic carbons. PMID- 25932472 TI - Density functional study of electronic structure, elastic and optical properties of MNH2 (M=Li, Na, K, Rb). AB - We report a systematic first principles density functional study on the electronic structure, elastic and optical properties of nitrogen based solid hydrogen storage materials LiNH2, NaNH2, KNH2, and RbNH2. The ground state structural properties are calculated by using standard density functional theory, and also dispersion corrected density functional theory. We find that van der Waals interactions are dominant in LiNH2 whereas they are relatively weak in other alkali metal amides. The calculated elastic constants show that all the compounds are mechanically stable and LiNH2 is found to be a stiffer material among the alkali metal amides. The melting temperatures are calculated and follow the order RbNH2 < KNH2 < NaNH2 < LiNH2. The electronic band structure is calculated by using the Tran-Blaha modified Becke-Johnson potential and found that all the compounds are insulators, with a considerable band gap. The [NH2]- derived states completely dominate in the entire valence band region while the metal atom states occupy the conduction band. The calculated band structure is used to analyze the different interband optical transitions occurring between valence and conduction bands. Our calculations show that these materials have considerable optical anisotropy. PMID- 25932473 TI - Topologically nontrivial narrow bands in ultrathin SnTe films with defect superstructures. AB - It is shown that a two-dimensional topological insulator can be realized and the band topology (equivalently, the edge states) may be further controlled by charge doping in an ultrathin SnTe film with a defect superstructure. Based on first principles density functional theory (DFT), we predict that a Sn-Te bilayer, if exfoliated from three-dimensional bulk SnTe in the (1 1 1) direction, has a trivial band topology in its pristine form, but is made topologically nontrivial by introducing an appropriate array of defects. The emergence of the topological state is ascribed to the formation of topologically nontrivial narrow bands near the Fermi level by spin-orbit splitting of defect-induced bands. In addition, we demonstrate that a transition between a topological insulator and a normal insulator is possible under the electron or hole doping which can be useful for controlling the topological edge states. PMID- 25932474 TI - Spin-orbit coupling induced magnetoresistance oscillation in a dc biased two dimensional electron system. AB - We study dc-current effects on the magnetoresistance oscillation in a two dimensional electron gas with Rashba spin-orbit coupling, using the balance equation approach to nonlinear magnetotransport. In the weak current limit the magnetoresistance exhibits periodical Shubnikov-de Haas oscillation with changing Rashba coupling strength for a fixed magnetic field. At finite dc bias, the period of the oscillation halves when the interbranch contribution to resistivity dominates. With further increasing current density, the oscillatory resistivity exhibits phase inversion, i.e., magnetoresistivity minima (maxima) invert to maxima (minima) at certain values of the dc bias, which is due to the current induced magnetoresistance oscillation. PMID- 25932475 TI - [Rare Disease Day 2015 -- rare diseases -- no longer "orphans"]. PMID- 25932476 TI - [Obituary for Prof. Dr. Hans Peter Clodi (1929-2014)]. PMID- 25932477 TI - [Joint opinion of the German Society of Gastroenterology, Digestive and Metabolic Diseases (DGVS) and the German Society for Internal Medicine (DGIM) to Vedolizumab-benefit assessment according to S 35a SGB V the G-BA]. PMID- 25932478 TI - [BNG positions -- outpatient specialty specialist care]. PMID- 25932479 TI - [Colonoscopy screening from 50 -- A new era in Baden-Wurttemberg]. PMID- 25932480 TI - [Vascular liver diseases - hotline at the bng]. PMID- 25932481 TI - The healthy aged: Descriptive analysis by sex of cognitively functioning elderly patients 80 years and older living independently in the community. AB - OBJECTIVE: To describe a population of cognitively functioning seniors aged 80 years and older who are livingin dependently in the community. DESIGN: Descriptive cross-sectional study based on the enrolment cohort of a randomized controlled trial. SETTING: St John's, Nfld. PARTICIPANTS: A total of 236 cognitively functioning seniors aged 80 years and older living independently in the community. MAIN OUTCOME MEASURES: Demographic characteristics including age, sex, marital status, and education; health status and quality of life measured by the Short Form-36 and the CASP-19 (control, autonomy, self-realization,and pleasure); use of formal and informal community services;satisfaction with family physician care as measured by the Patient Satisfaction Questionnaire-18; and use of health care resources (family physician visits, emergency department visits,hospitalizations, and laboratory and diagnostic imaging tests). RESULTS: Overall, 66.5% of those in the group were women and the average age was 85.5 years. A quarter had postsecondary diplomas or degrees; 54.7% were widowed (69.4% of women and 25.3% of men). The cohort scored well in terms of health status and quality of life, with a range of scores on the Short Form-36 from 57.5 to 93.5 out of 100, and a score of 44 out of 57 on the CASP-19; they were satisfied with the care received from family physicians, with scores between 3.8 and 4.3 out of 5 on the Patient Satisfaction Questionnaire-18; and use of health services was low-70% had no emergency department visits in the previous year and 80% had not used any laboratory or diagnostic services. CONCLUSION: Seniors aged 80 years and older living in dependently are involved in the social fabric of society. They are generally well educated, slightly more than half are widowed,and two-thirds are female. They score well on scales that measure well-being and quality of life, and they use few health services. They are the healthy aged. TRIAL REGISTRATION NUMBER: NCT00452465 (ClinicalTrials.gov). PMID- 25932482 TI - Physicians' perceptions of capacity building for managing chronic disease in seniors using integrated interprofessional care models. AB - OBJECTIVE: To explore the barriers to and facilitators of adapting and expanding a primary care memory clinic model to integrate care of additional complex chronic geriatric conditions (heart failure, falls, chronic obstructive pulmonary disease, and frailty) into care processes with the goal of improving outcomes for seniors. DESIGN: Mixed-methods study using quantitative (questionnaires) and qualitative (interviews) methods. SETTING: Ontario. PARTICIPANTS: Family physicians currently working in primary care memory clinic teams and supporting geriatric specialists. METHODS: Family physicians currently working in memory clinic teams (n = 29) and supporting geriatric specialists(n = 9) were recruited as survey participants. Interviews were conducted with memory clinic lead physicians (n = 16).Statistical analysis was done to assess differences between family physician ratings and geriatric specialist ratings related to the capacity for managing complex chronic geriatric conditions, the role of interprofessional collaboration within primary care, and funding and staffing to support geriatric care. Results from both study methods were compared to identify common findings. MAIN FINDINGS: Results indicate overall support for expanding the memory clinic model to integrate care for other complex conditions. However, the current primary care structure is challenged to support optimal management of patients with multiple comorbidities, particularly as related to limited funding and staffing resources. Structured training, interprofessional teams, and an active role of geriatric specialists within primary care were identified as important facilitators. CONCLUSION: The memory clinic model, as applied to other complex chronic geriatric conditions, has the potential to build capacity for high quality primary care, improve health outcomes,promote efficient use of health care resources, and reduce healthcare costs. PMID- 25932483 TI - Improving awareness, accountability, and access through health coaching: qualitative study of patients' perspectives. AB - OBJECTIVE: To assess patients' experiences with and perceptions of health coaching as part of their ongoing care. DESIGN: A qualitative research design using semistructured interviews that were recorded and transcribed verbatim.Setting Ottawa, Ont. PARTICIPANTS: Eleven patients (> 18 years of age) enrolled in a health coaching pilot program who were at risk of or diagnosed with type 2 diabetes. METHODS: Patients' perspectives were assessed with semistructured interviews. Interviews were conducted with 11 patients at the end of the pilot program, using a stratified sampling approach to ensure maximum variation. MAIN FINDINGS: All patients found the overall experience with the health coaching program to be positive. Patients believed the health coaching program was effective in increasing awareness of how diabetes affected their bodies and health, in building accountability for their health-related actions, and in improving access to care and other health resources. CONCLUSION: Patients perceive one-on-one health coaching as an acceptable intervention in their ongoing care. Patients enrolled in the health coaching pilot program believed that there was an improvement in access to care, health literacy, and accountability,all factors considered to be precursors to behavioural change. PMID- 25932485 TI - Proceedings of The International Symposium on the "Biochemical Role of Eukaryotic Cell Surface Macromolecules", Jan 2014, Kolkata, India. PMID- 25932484 TI - On "using a team-centered approach to evaluate effectiveness of nurse-physician communications": in response. PMID- 25932486 TI - [Not Available]. PMID- 25932487 TI - [The new psychiatric patient care regulation in Baden-Wurttemberg]. PMID- 25932488 TI - Aligning the 3Rs with new paradigms in the safety assessment of chemicals. AB - There are currently several factors driving a move away from the reliance on in vivo toxicity testing for the purposes of chemical safety assessment. Progress has started to be made in the development and validation of non-animal methods. However, recent advances in the biosciences provide exciting opportunities to accelerate this process and to ensure that the alternative paradigms for hazard identification and risk assessment deliver lasting 3Rs benefits, whilst improving the quality and relevance of safety assessment. The NC3Rs, a UK-based scientific organisation which supports the development and application of novel 3Rs techniques and approaches, held a workshop recently which brought together over 20 international experts in the field of chemical safety assessment. The aim of this workshop was to review the current scientific, technical and regulatory landscapes, and to identify key opportunities towards reaching these goals. Here, we consider areas where further strategic investment will need to be focused if significant impact on 3Rs is to be matched with improved safety science, and why the timing is right for the field to work together towards an environment where we no longer rely on whole animal data for the accurate safety assessment of chemicals. PMID- 25932489 TI - Progesterone in traumatic brain injury. PMID- 25932490 TI - Public health: Behind a vaccine. PMID- 25932491 TI - Measurement of photosynthesis using PAM technology in a purple sulfur bacterium Thermochromatium tepidum (Chromatiaceae). AB - We demonstrate that Blue-diode-based pulse amplitude modulation (PAM) technology can be used to measure the photosynthetic electron transport rate (ETR) of purple sulfur bacteria (Thermochromatium tepidum, Chromatiaceae). Previous studies showed that PAM technology could be used to estimate photosynthesis in purple nonsulfur bacteria and so PAM technology can be used to estimate photosynthesis of both kinds of purple photosynthetic bacteria. The absorptance of Thermochromatium films on glass fiber disks was measured and used to calculate actual ETR. ETR vs Irradiance (P vs E) curves fitted the waiting-in-line model (ETR = (ETRmax * E/Eopt) * exp (1-E/Eopt)). Yield (Y) was only ~ 0.3-0.4. Thermochromatium saturates at 325 +/- 13.8 MUmol photons m(-2) s(-1) or ~15% sunlight and shows photoinhibition at high irradiances. A pond of Thermochromatium would exhibit classic surface inhibition. Photosynthesis is extremely low in the absence of an electron source: ETR increases in the presence of acetate (5 mol m(-3)) provided as an organic carbon source and also increases in the presence of sulfite (3 mol m(-3)) but not sulfide and is only marginally increased by the presence of Fe(2+). Nonphotochemical quenching does occur in Thermochromatium but at very low levels compared to oxygenic photo-organisms or Rhodopseudomonads. PMID- 25932492 TI - Future has tradition in JAFC, but tradition, too, has a future! PMID- 25932495 TI - Early data suggest new protocol to risk-stratify chest pain patients, potentially preserving resources without compromising safety. AB - Early data from the study of a new protocol suggest there may be a more efficient way to risk-stratify patients presenting to the ED with chest pain so that lower risk patients can be safely discharged rather face longer hospital stays and expensive tests. The approach, dubbed the HEART Pathway, involves using the HEART score, a clinical decision tool developed in the Netherlands, along with slight modifications including a second blood test for troponin levels. Experts say that the United States spends $10 to $13 billion per year for workups on chest pain patients when fewer than 10% are actually having an acute coronary syndrome. In a single-center randomized controlled trial, investigators found that when compared to usual care, use of the HEART Pathway resulted in 12% fewer cardiac tests, shorter lengths-of-stay, and 21% more early discharges. No patients in either group experienced a major cardiac complication within 30 days of their ED visit. Larger studies of the HEART Pathway approach are being implemented with more robust findings expected within a year. PMID- 25932496 TI - Mount Sinai leverages smartphone technology, aiming to boost care, coordination of ED patients while also trimming costs. AB - Mount Sinai Hospital in New York, NY, is using smartphone technology to enhance follow-up calls to senior patients who have visited the ED, and to help provide acute-level care to select patients in their own homes. Investigators are hoping to show that these approaches can improve care and coordination while trimming costs, and they expect that patients will approve of these new approaches as well. While senior patients are still in the ED, nurse coordinators will work with them to load a HIPAA-compliant application to their smartphones so they can conduct face-to-face follow-up calls that meet HIPAA standards. Nurses say the face-to-face communications enhance their ability to assess how patients are doing following their ED visit. The hospital is also testing a program that enables some ED patients who meet inpatient criteria to receive this care in the home setting through the use of a mobile acute care team (MACT). In the case of emergencies, the MACT team relies on community paramedics who will visit the patients' homes and provide care under the direction of MACT physicians who are linked in to these visits via smartphone technology. PMID- 25932497 TI - Patient passports aim to speed appropriate care for medically complex children presenting to ED. AB - Mattel Children's Hospital at Ronald Reagan UCLA Medical Center in Los Angeles, CA, has developed a "patient passport" to improve the timely and appropriate care of medically complex children who present to the ED. The one-page form, which parents can keep in their wallets, highlights any special indications or sensitivities that the child has as well as contact information for the patient's primary care provider. The form also includes special instructions for the triage nurse. Creation of the tool was prompted by the parents who complained that their medically complex children were receiving different care in the ED than on the pediatric floor of the hospital. The tool was developed by a group comprised of parents, pediatric providers, and ED representatives. Physicians must create and sign the passports, either in the hospital or in their outpatient clinics, although parents may request a passport for their children. PMID- 25932498 TI - Response of Flour Beetles to Multiple Stressors of Parasitic (Hymenolepis diminuta), Environmental (Diatomaceous Earth), and Host (Reproduction) Origin. AB - Organisms face a multitude of potential stressors, and the way these stressors interact can provide insights into underlying biological processes. This study examined the flour beetle Tribolium confusum and its survival, net fecundity, and surface-seeking behavior in response to combinations of stressors from 3 categories. Infection by the cestode Hymenolepis diminuta provided a stress of parasitic origin. Exposure to diatomaceous earth (DE) provided a stress of environmental origin. Use of virgin and mated beetles evaluated reproduction as a stress of host origin. Single and multiple exposure of beetles to parasite eggs achieved a maximum mean abundance of 21 parasites/beetle and a maximum intensity of 90 parasites in an individual beetle. DE reduced initial parasite establishment, but did not directly affect survival of parasites after their establishment in the host. A rehydration technique was used to recover parasites from dead beetles, enabling this to be the first study to correlate H. diminuta intensity at time of death directly to mortality of T. confusum. A dichotomous intensity-mortality relationship was observed in 8% DE, whereby lightly infected (<20 parasites) hosts were killed by DE in an intensity-independent manner, but more heavily infected hosts were killed in an intensity-dependent manner. Host mating status did not affect host survival, but there were interactions among mating status, parasitism, and DE on net fecundity and surface-seeking behavior. However, these effects were minor compared to the host mortality that occurred when parasite abundance and DE concentration were both high. The aggregated distribution of T. confusum in beetles, the difficulty of achieving high mean abundances, and an apparent need for the stressors to have strong effects individually if they are to have enhanced effects when in combination, suggests that exposure to multiple stressors would seriously impact only a small proportion of the host population. PMID- 25932499 TI - The requisite electronic structure theory to describe photoexcited nonadiabatic dynamics: nonadiabatic derivative couplings and diabatic electronic couplings. AB - Electronically photoexcited dynamics are complicated because there are so many different relaxation pathways: fluorescence, phosphorescence, radiationless decay, electon transfer, etc. In practice, to model photoexcited systems is a very difficult enterprise, requiring accurate and very efficient tools in both electronic structure theory and nonadiabatic chemical dynamics. Moreover, these theoretical tools are not traditional tools. On the one hand, the electronic structure tools involve couplings between electonic states (rather than typical single state energies and gradients). On the other hand, the dynamics tools involve propagating nuclei on multiple potential energy surfaces (rather than the usual ground state dynamics). In this Account, we review recent developments in electronic structure theory as directly applicable for modeling photoexcited systems. In particular, we focus on how one may evaluate the couplings between two different electronic states. These couplings come in two flavors. If we order states energetically, the resulting adiabatic states are coupled via derivative couplings. Derivative couplings capture how electronic wave functions change as a function of nuclear geometry and can usually be calculated with straightforward tools from analytic gradient theory. One nuance arises, however, in the context of time-dependent density functional theory (TD-DFT): how do we evaluate derivative couplings between TD-DFT excited states (which are tricky, because no wave function is available)? This conundrum was recently solved, and we review the solution below. We also discuss the solution to a second, pesky problem of origin dependence, whereby the derivative couplings do not (strictly) satisfy translation variance, which can lead to a lack of momentum conservation. Apart from adiabatic states, if we order states according to their electronic character, the resulting diabatic states are coupled via electronic or diabatic couplings. The couplings between diabatic states |XiA? and |XiB? are just the simple matrix elements, ?XiA|H|XiB?. A difficulty arises, however, because constructing exactly diabatic states is formally impossible and constructing quasi-diabatic states is not unique. To that end, we review recent advances in localized diabatization, which is one approach for generating adiabatic-to diabatic (ATD) transformations. We also highlight outstanding questions in the arena of diabatization, especially how to generate multiple globally stable diabatic surfaces. PMID- 25932500 TI - Effect of alkane chain length and counterion on the freezing transition of cationic surfactant adsorbed film at alkane mixture - water interfaces. AB - Penetration of alkane molecules into the adsorbed film gives rise to a surface freezing transition of cationic surfactant at the alkane-water interface. To examine the effect of the alkane chain length and counterion on the surface freezing, we employed interfacial tensiometry and ellipsometry to study the interface of cetyltrimethylammonium bromide and cetyltrimethylammonium chloride aqueous solutions against dodecane, tetradecane, hexadecane, and their mixtures. Applying theoretical equations to the experimental results obtained, we found that the alkane molecules that have the same chain length as the surfactant adsorb preferentially into the surface freezing film. Furthermore, we demonstrated that the freezing transition temperature of cationic surfactant adsorbed film was independent of the kind of counterion. PMID- 25932501 TI - Synthesis of amphiphilic resveratrol lipoconjugates and evaluation of their anticancer activity towards neuroblastoma SH-SY5Y cell line. AB - Resveratrol, a polyphenol present in grapes and other edible plants, possesses several important pharmacological activities, including anticancer activity. Nevertheless, its therapeutic use is still limited because of some unfavourable physicochemical and pharmacokinetic properties, mainly, poor cellular uptake and too rapid metabolism resulting in elimination from the body. To meet these drawbacks, some resveratrol conjugates would be useful, which would possess improved stability, uptake and bioavailability than the lead compound, and the ability to release it once it is internalized into the cell. In this paper we report a synthetic strategy which allowed us to obtain new amphiphilic resveratrol derivatives starting from different selectively protected resveratrol phosphoramidites or even from the resveratrol triphosphoramidite. Specifically, resveratrol was conjugated through phosphate bridge(s) to different lipophilic groups related to membrane lipids, such as cholesteryl or diacylglycero moieties. All the new lipoconjugates were tested towards human neuroblastoma SH-SY5Y cells and proved to be significantly more active than resveratrol, with a concentration dependent activity. PMID- 25932502 TI - Ptaquiloside, the major carcinogen of bracken fern, in the pooled raw milk of healthy sheep and goats: an underestimated, global concern of food safety. AB - Bracken fern (Pteridium aquilinum) is a worldwide plant containing toxic substances, which represent an important chemical hazard for animals, including humans. Ptaquiloside, 1, a norsesquiterpenoid glucoside, is the major carcinogen of bracken detected in the food chain, particularly in the milk from farm animals. To date, ptaquiloside has been shown in the milk of cows feeding on a diet containing bracken fern. This is the first study that shows the systematic detection of ptaquiloside, 1, and reports its direct quantitation in pooled raw milk of healthy sheep and goats grazing on bracken. Ptaquiloside, 1, was detected by a sensitive method based on the chemical conversion of ptaquiloside, 1, into bromopterosine, 4, following gas chromatography-mass spectrometry (GC-MS) analysis. The presence of ptaquiloside, 1, possibly carcinogenic to humans, in the milk of healthy animals is an unknown potential health risk, thus representing a harmful and potential global concern of food safety. PMID- 25932503 TI - CuInP2S6 Room Temperature Layered Ferroelectric. AB - We explore ferroelectric properties of cleaved 2-D flakes of copper indium thiophosphate, CuInP2S6 (CITP), and probe size effects along with limits of ferroelectric phase stability, by ambient and ultra high vacuum scanning probe microscopy. CITP belongs to the only material family known to display ferroelectric polarization in a van der Waals, layered crystal at room temperature and above. Our measurements directly reveal stable, ferroelectric polarization as evidenced by domain structures, switchable polarization, and hysteresis loops. We found that at room temperature the domain structure of flakes thicker than 100 nm is similar to the cleaved bulk surfaces, whereas below 50 nm polarization disappears. We ascribe this behavior to a well-known instability of polarization due to depolarization field. Furthermore, polarization switching at high bias is also associated with ionic mobility, as evidenced both by macroscopic measurements and by formation of surface damage under the tip at a bias of 4 V-likely due to copper reduction. Mobile Cu ions may therefore also contribute to internal screening mechanisms. The existence of stable polarization in a van-der-Waals crystal naturally points toward new strategies for ultimate scaling of polar materials, quasi-2D, and single-layer materials with advanced and nonlinear dielectric properties that are presently not found in any members of the growing "graphene family". PMID- 25932511 TI - Method transfer between bioanalytical laboratories. PMID- 25932505 TI - The Abbreviated Dimensions of Temperament Survey: Factor Structure and Construct Validity Across Three Racial/Ethnic Groups. AB - The factor structure, reliability, and construct validity of an abbreviated version of the Revised Dimensions of Temperament Survey (DOTS-R) were evaluated across Black, Hispanic, and White early adolescents. Primary caregivers reported on 5 dimensions of temperament for 4,701 children. Five temperament dimensions were identified via maximum likelihood exploratory factor analysis and were labeled flexibility, general activity level, positive mood, task orientation, and sleep rhythmicity. Multigroup mean and covariance structures analysis provided partial support for strong factorial invariance across these racial/ethnic groups. Mean level comparisons indicated that relative to Hispanics and Blacks, Whites had higher flexibility, greater sleep regularity, and lower activity. They also reported higher positive mood than Blacks. Blacks, relative to Hispanics, had higher flexibility and lower sleep regularity. Construct validity was supported as the 5 temperament dimensions were significantly correlated with externalizing problems and socioemotional competence. This abbreviated version of the DOTS-R could be used across racial/ethnic groups of early adolescents to assess significant dimensions of temperament risk that are associated with mental health and competent (healthy) functioning. PMID- 25932512 TI - Ask the experts: method transfer. AB - As part of this themed issue, Bioanalysis invited a selection of researchers to express their views on method transfer in the bioanalytical field. The topics discussed include the main challenges in method transfer, the importance of communication and approaches for assessing the acceptability of transfers. Their responses provide a valuable insight into the considerations that need to be taken into account for successful method transfer. PMID- 25932513 TI - Method transfer: giant leap of faith or well-trodden path? PMID- 25932514 TI - The potential impact of laboratory informatics on technology transfer. PMID- 25932515 TI - Robust, fit-for-purpose method transfer: why we should apply equivalence testing. AB - Efficient method transfer is the key in advancing drug candidates through development and requires careful planning and communication between the two laboratories. Successful transfers require robust bioanalytical methods that allow for some small deviations from the method in sender laboratory; however, by keeping the fundamentals of the sender method intact. The equivalence of data produced at both sides should be tested by mutually prepared and analyzed QCs and by analyzing incurred samples at both sides and assessed by a statistical equivalence testing. Current regulatory bodies' guidances provide very limited direction for experimental setup and evaluation of transfer. This perspective paper gives an overview of the available approaches and proposes a way forward for the bioanalytical community. PMID- 25932516 TI - The quest for assay robustness across the life cycle of a bioanalytical method. AB - White has been an analytical chemist for 28 years, with a range of knowledge and experience across multiple disciplines including pharmaceuticals, foodstuffs, environmental and forensic analysis. Steve works within the regulated bioanalytical group at GSK supporting both preclinical and clinical bioanalysis. His responsibilities have included leadership of bioanalytical, dose formulation and sample management teams as well as assisting with the set up of the Anti Doping Testing Laboratory for the London 2012 Olympics. In his current role, Steve is part of the UK bioanalytical leadership team with a focus on regulatory & compliance issues. Steve is the small molecule rep for GSK within the European Bioanalysis Forum (EBF), a member of the EBF Steering Committee and also contributed to the Global Bioanalysis Consortium S2 team. The successful validation or qualification of an assay plus incurred sample reproducibility gives the bioanalyst confidence of assay suitability. However, these elements alone do not give the full picture of how reliable an assay may be during routine production use for analysis of unknown study samples. The robustness of an assay can be understood by applying key performance indicators to monitor assay performance pre- and post-transfer between laboratories, plus a cross-validation step during assay transfer. The measurement of assay robustness (beyond the context of cross-validation) should not be considered as yet another regulatory layer, but more as a means for the bioanalyst to better understand an individual assay within a large portfolio, when used for its intended purpose. PMID- 25932517 TI - An interlaboratory transfer of a multi-analyte assay between continents. AB - Alex has worked at GlaxoSmithKline for the past 15 years and currently works within the bioanalytical and toxicokinetic group in the United Kingdom. Alex's role in previous years has been the in-house support of preclinical and clinical bioanalysis, from method development through to sample analysis activities as well as acting as PI for GLP bioanalysis and toxicokinetics. For the past two years, Alex has applied this analytical and regulatory experience to focus on the outsourcing of preclinical bioanalysis, toxicokinetics and clinical bioanalysis, working closely with multiple bioanalytical and in-life CRO partners worldwide. Alex works to support DMPK and Safety Assessment outsourcing activities for GSK across multiple therapeutic areas, from the first GLP study through to late stage clinical PK studies. Transfer and cross-validation of an existing analytical assay between a laboratory providing current analytical support, and a laboratory needed for new or additional support, can present the bioanalyst with numerous challenges. These challenges can be technical or logistical in nature and may prove to be significant when transferring an assay between laboratories in different continents. Part of GlaxoSmithKline's strategy to improve confidence in providing quality data, is to cross-validate between laboratories. If the cross validation fails predefined acceptance criteria, then a subsequent investigation would follow. This may also prove to be challenging. The importance of thorough planning and good communication throughout assay transfer, cross-validation and any subsequent investigations is illustrated in this case study. PMID- 25932518 TI - Making methods rugged for regulated bioanalysis. AB - Methods started in discovery are optimized as they progress through preclinical and clinical development. Making a robust assay includes testing individual steps for consistency and points of failure. Assays may be transferred, optimized and revalidated several times. A rugged assay will not only meet regulatory requirements, but will execute with a low failure rate and confirm results under repeat analysis. Challenging aspects such as differential recovery, sample stabilization, resolution of isomers or conjugate analysis must be tackled and made routine. The proper selection of the IS can overcome limitations. It is best to know the potential points of failure before a study has started, but lessons learned from each study also provide invaluable insights to improve assay ruggedness. PMID- 25932519 TI - Differential mobility spectrometry: a valuable technology for analyzing challenging biological samples. PMID- 25932520 TI - Practical applications of integrated microfluidics for peptide quantification. AB - BACKGROUND: Increased pressure to obtain more, higher sensitivity data from less sample is especially critical for large peptides, whose already optimized LC-MS methods are heavily challenged by traditional ligand-binding assays. RESULTS: Critical bioanalytical assays were adapted to integrated microscale LC to reduce sample volumes while increasing sensitivity. Assays for teriparatide, glucagon and human insulin and five analogs were transferred from 2.1 mm analytical scale LC to a 150 um scale system. This resulted in a 15-30 fold overall improvement in sensitivity derived from increased signal to noise, three to six fold reduction in injection volumes, and a two to five fold reduction in sample consumption. CONCLUSION: Integrated microscale LC reduces sample consumption while enabling single picomolar quantification for therapeutic and endogenous peptides. PMID- 25932521 TI - Dried blood spot analysis for rat and dog studies: validation, hematocrit, toxicokinetics and incurred sample reanalysis. AB - BACKGROUND: Execution of experiments to introduce dried blood spot (DBS) sampling for preclinical GLP studies and subsequent clinical studies. RESULTS: Bridging data showed high concordance with DBS:plasma ratios of 0.9 in rats and 1.1 in dogs, demonstrating no preferential uptake or association with cellular components of the blood. The DBS methodology was fully validated incorporating additional experiments pertinent to DBS sampling, storage and analysis. Individual hematocrit (Hct) values in the test animals (rats and dogs) were within the validated Hct range. DBS concentration data and the resulting TK profiles were not impacted by an Hct bias. Incurred sample reanalysis showed high correlation in dogs (97%) and rats (100%) meeting acceptance criteria. CONCLUSION: Successfully validated and adopted DBS for preclinical GLP studies. PMID- 25932522 TI - PK study of octreotide based on LC-MS/MS combining protein precipitation and impurity extraction technique. AB - AIM: To establish a robust methodology for quantitative analysis of therapeutic peptide in biological samples. MATERIALS & METHODS: Octreotide was chosen as a model therapeutic peptide, and oxidized-octreotide was synthesized as internal standard. Protein precipitation combining liquid-liquid extraction technique was adopted to enhance the recovery and reduce the endogenous interferences effectively. A LC-MS/MS method for the quantification of octreotide in plasma has been optimized and validated according to FDA guidelines. RESULTS: Linearity, selectivity, accuracy, precision, stability, matrix effect and recovery were within bioanalytical method validation acceptance criteria as FDA guidelines. The methodology was then successfully applied into the studies for octreotide. CONCLUSION: This robust methodology would be useful for the PK studies for octreotide and other therapeutic peptides. PMID- 25932523 TI - Quantification of iodiconazole by LC-MS/MS, a new topical transdermal cream, in dermatophytosis patients' plasma. AB - BACKGROUND: A rapid and sensitive LC-MS/MS method was established to measure iodiconazole (ADKZ) in dermatophytosis patients treated topically with 2% ADKZ cream. METHODOLOGY: ADKZ was extracted by liquid-liquid extraction (LLE) and separated by an Agilent Zorbax SB-C18 column (2.1 * 150 mm, 3.5 MUm) using methanol - 0.01% formic acid (70:30, v/v) as the mobile phase. All the validation assays met the acceptable criteria and the linearity ranged from 10 to 1000 pg/ml. CONCLUSION: The method has been validated to be simple, sensitive and successfully applied to the study. The average amount of ADKZ absorbed into blood was approximately 0.51 MUg daily, and ADKZ blood concentrations were consistent during the four-week treatment course. The cumulation of ADKZ in vivo was almost negligible. PMID- 25932524 TI - Microfluidic chip-capillary electrophoresis device for the determination of urinary metabolites and proteins. AB - Microfluidic chip-CE (MC-CE) devices have caught recent attention for diagnostic applications in urine. This is due to the successes reported in handling real urine samples by integrating microfluidic chips (MC) with analyte enrichment and sample cleanup to CE with high separation efficiency and sensitive analyte detection. Here, we review the determination of urinary metabolites and proteins by MC-CE devices within the past 7 years. The application scope for MC-CE integrated devices was found to exceed the use of either technique alone, showing comparable performance to laser-induced fluorescence detection using less sensitive UV detectors, offering the flexibility to handle difficult urine samples with on-chip dilution and online standard addition and delivering enhanced performance as compared with commercial microfluidic chip electrophoresis chips. PMID- 25932525 TI - Intramedullary Nailing and Adjunct Permanent Plate Fixation in Complex Tibia Fractures. AB - The use of adjunct plate fixation is known to be a useful reduction aid during intramedullary nailing of the proximal tibia. We have expanded the indications beyond aiding the reduction and now use these plates as an adjunct to intramedullary nailing during the healing period. Specific indications include diaphyseal tibial fractures with severe bone loss/comminution and segmental tibial fractures with or without intraarticular extension. We believe the adjunctive permanent plate fixation technique may offer a treatment solution in these selected situations with the added benefit of immediate weight bearing. PMID- 25932526 TI - Training Distal Locking Screw Insertion Skills to Novice Trainees: A Comparison Between Fluoroscopic- and Electromagnetic-Guided Techniques. AB - OBJECTIVES: To compare the effect fluoroscopy or electromagnetic (EM) guidance has on the learning of locking screw insertion in tibial nails in surgical novices. METHODS: A randomized, prospective, controlled trial was conducted involving 18 surgical trainees with no prior experience inserting locking screws in intramedullary nails. After a training session using fluoroscopy, participants underwent a pretest using fluoroscopic guidance. Participants were then randomized into either the fluoroscopy or EM group and were further trained using their respective technique. Post, retention, and transfer tests were conducted. Outcomes included task completion, drill attempts, screw changes, and radiation time. RESULTS: Intragroup comparisons revealed that the EM group used significantly less drill attempts during the post and retention tests compared with the pretest (P = 0.016 and P = 0.016, respectively). Intergroup comparisons revealed that the EM group was (1) more likely to complete the task during the retention test (P = 0.043) and (2) had significantly less radiation time during the post and retention tests (P = 0.002 and P = 0.003, respectively). Radiation time in the EM group during the transfer test increased to a level equal to what the fluoroscopy group used during the post and retention tests (P = 0.71 and P = 0.92, respectively). No other significant between-group differences occurred. CONCLUSIONS: EM guidance may be safely used to assist in the training of surgical novices in the skill of distal locking screw insertion. Not only does this technology significantly improve the ability to complete the task and decrease radiation use but also it does so without compromising skill acquisition. LEVEL OF EVIDENCE: Therapeutic Level II. See Instructions for Authors for a complete description of levels of evidence. PMID- 25932527 TI - Influence of Femoral Component Design on Retrograde Femoral Nail Starting Point. AB - PURPOSE: Our experience with retrograde femoral nailing after periprosthetic distal femur fractures was that femoral components with deep trochlear grooves posteriorly displace the nail entry point resulting in recurvatum deformity. This study evaluated the influence of distal femoral prosthetic design on the starting point. METHODS: One hundred lateral knee images were examined. The distal edge of Blumensaat's line was used to create a ratio of its location compared with the maximum anteroposterior condylar width called the starting point ratio (SPR). Femoral trials from 6 manufacturers were analyzed to determine the location of simulated nail position in the sagittal plane compared with the maximum anteroposterior prosthetic width. These measurements were used to create a ratio, the femoral component ratio (FCR). The FCR was compared with the SPR to determine if a femoral component would be at risk for retrograde nail starting point posterior to the Blumensaat's line. RESULTS: The mean SPR was 0.392 +/- 0.03, and the mean FCR was 0.416 +/- 0.05, which was significantly greater (P = 0.003). The mean FCR was 0.444 +/- 0.06 for the cruciate retaining (CR) trials and was 0.393 +/- 0.04 for the posterior stabilized trials; this difference was significant (P < 0.001). CONCLUSIONS: The FCR for the femoral trials studied was significantly greater than the SPR for native knees and was significantly greater for CR femoral components compared with posterior stabilized components. These findings demonstrate that many total knee prostheses, particularly CR designs, are at risk for a starting point posterior to Blumensaat's line. PMID- 25932528 TI - Complex Osteotomies of Tibial Plateau Malunions Using Computer-Assisted Planning and Patient-Specific Surgical Guides. AB - The accurate reduction of tibial plateau malunions can be challenging without guidance. In this work, we report on a novel technique that combines 3 dimensional computer-assisted planning with patient-specific surgical guides for improving reliability and accuracy of complex intraarticular corrective osteotomies. Preoperative planning based on 3-dimensional bone models was performed to simulate fragment mobilization and reduction in 3 cases. Surgical implementation of the preoperative plan using patient-specific cutting and reduction guides was evaluated; benefits and limitations of the approach were identified and discussed. The preliminary results are encouraging and show that complex, intraarticular corrective osteotomies can be accurately performed with this technique. For selective patients with complex malunions around the tibia plateau, this method might be an attractive option, with the potential to facilitate achieving the most accurate correction possible. PMID- 25932529 TI - Osteotomy of the Anterior Superior Iliac Spine as an Adjunct to Improve Access and Visualization Through the Lateral Window. AB - The lateral "window" has previously been described as part of the ilioinguinal and anterior intrapelvic approaches for gaining access to the anterior aspect of the sacroiliac joint, the internal iliac fossa, and upper portion of the anterior column for reduction and placement of fixation. Surgical exposure of this window typically involves release of the external oblique muscle from the iliac crest and elevation of the iliacus muscle from the internal iliac fossa. This exposure is limited by the residual attachment of the external oblique muscle and inguinal ligament to the anterior superior iliac spine, particularly in patients with a large abdomen or in fractures that involve the anterior wall of the acetabulum and pubic root region. Herein, we describe the addition of an osteotomy of the anterior superior iliac spine for improved medial mobilization of the abdominal wall musculature to allow better visualization and access to the internal iliac fossa and anterior aspect of the sacroiliac joint. PMID- 25932530 TI - Autosterilization of Contaminated and Devascularized Bone Fragments Through a Subcutaneous Bone Pouch. AB - OBJECTIVES: The purpose of this article was to present results of cases using a subcutaneous bone pouch technique and to assess the potential "autosterilization" effect that occurs when these contaminated free bone fragments are placed in nontraumatized tissue. DESIGN: Retrospective review of prospectively collected data. SETTING: Community-Based Level 1 Trauma Center. PATIENTS/PARTICIPANTS: Eight patients were consented for the described technique, and data were collected over an 8-year period. INTERVENTION: Placement of fragments into a surgically created subcutaneous pouch in a nontraumatized tissue zone, followed by delayed, cultured, and attempted reimplantation at the initial injury site. MAIN OUTCOME MEASUREMENTS: Culture results after extraction of bone fragments from subcutaneous bone pouch and clinical outcomes after reimplantation into initial open fracture site. RESULTS: All 8 cases undergoing this technique resulted in healing of the subcutaneous bone pouch without signs or symptoms of infection at the time of attempted reimplantation or fragment removal. Four of the 8 cases had successful reimplantation and union at the open fracture site. CONCLUSIONS: Preserving devascularized bone fragments in a subcutaneous pouch in a region of nontraumatized tissue appears to be a safe procedure that allows for an "autosterilization" type of process to occur. LEVEL OF EVIDENCE: Therapeutic Level IV. See Instructions for Authors for a complete description of levels of evidence. PMID- 25932531 TI - Haloviruses of archaea, bacteria, and eukaryotes. AB - Hypersaline environments up to near saturation are rich reservoirs of extremophilic viruses. One milliliter of salt water may contain up to 10(9) viruses which can also be trapped inside salt crystals. To date, most of the ~100 known halovirus isolates infect extremely halophilic archaea, although a few bacterial and eukaryotic viruses have also been described. These isolates comprise tailed and tailless icosahedral, pleomorphic, and lemon-shaped viruses which have been classified according to features such as host range, genome type, and replication. Recent studies have revealed that viruses can be grouped into a few structure-based viral lineages derived from a common ancestor based on conserved virion architectural principles and the major capsid protein fold. PMID- 25932532 TI - Donor Heart Treatment With COMP-Ang1 Limits Ischemia-Reperfusion Injury and Rejection of Cardiac Allografts. AB - The major cause of death during the first year after heart transplantation is primary graft dysfunction due to preservation and ischemia-reperfusion injury (IRI). Angiopoietin-1 is a Tie2 receptor-binding paracrine growth factor with anti-inflammatory properties and indispensable roles in vascular development and stability. We used a stable variant of angiopoietin-1 (COMP-Ang1) to test whether ex vivo intracoronary treatment with a single dose of COMP-Ang1 in donor Dark Agouti rat heart subjected to 4-h cold ischemia would prevent microvascular dysfunction and inflammatory responses in the fully allogeneic recipient Wistar Furth rat. COMP-Ang1 reduced endothelial cell-cell junction disruption of the donor heart in transmission electron microscopy during 4-h cold ischemia, improved myocardial reflow, and reduced microvascular leakage and cardiomyocyte injury of transplanted allografts during IRI. Concurrently, the treatment reduced expression of danger signals, dendritic cell maturation markers, endothelial cell adhesion molecule VCAM-1 and RhoA/Rho-associated protein kinase activation and the influx of macrophages and neutrophils. Furthermore, COMP-Ang1 treatment provided sustained anti-inflammatory effects during acute rejection and prevented the development of cardiac fibrosis and allograft vasculopathy. These results suggest donor heart treatment with COMP-Ang1 having important clinical implications in the prevention of primary and subsequent long-term injury and dysfunction in cardiac allografts. PMID- 25932533 TI - An indigenous single-vial kit formulation of human serum albumin nanocolloid for use in sentinel lymph node detection. AB - OBJECTIVE: In-situ sentinel lymph node (SLN) detection is an important component in staging cancers of various origins. At present, technetium-99m (Tc)-labeled nanoparticle formulations like sulfur colloid and human serum albumin (HSA) nanocolloid are used in the clinic as SLN tracers. In India, HSA nanocolloid cold kits have so far been imported. This study aims to develop and evaluate an indigenous alternative to imported HSA nanocolloid cold kits for SLN detection/imaging. MATERIALS AND METHODS: Production of cold kits was standardized and the product was characterized for its suitability in terms of particle size. Tc-labeling of an in-house HSA nanocolloid was optimized, and the yield and stability of the product were assessed. Animal studies were performed in Wistar rats using the footpad model. Clinical evaluation was performed in 54 patients using a combination of scintigraphic imaging and a hand-held gamma probe. RESULTS AND CONCLUSION: With the optimized protocol, HSA nanocolloids with particle sizes ranging from 50 to 200 nm were obtained. Greater than 90% Tc labeling yield was obtained in 15 min reactions, and the radiopharmaceutical was stable for up to 24 h after preparation. The animal studies showed similar SLN uptake and improved retention pattern compared with those of the imported Nanocoll radiopharmaceutical. Clinical studies showed detectable 'hot' nodes in 53 of 54 patients, demonstrating sensitivity of the product for clinical utility. In conclusion, this indigenous HSA nanocolloid cold kit is proposed as a logistically favorable alternative to imported kits for SLN detection in the Indian clinical scenario. PMID- 25932534 TI - Systematic evaluation of salivary gland damage following I-131 therapy in differentiated thyroid cancer patients by quantitative scintigraphy and clinical follow-up. AB - OBJECTIVES: Radioiodine therapy is a common adjunct to thyroidectomy in papillary thyroid cancer treatment. However, a variety of associated adverse effects have been reported. In this study, we assessed radioiodine-induced salivary gland dysfunction using quantitative scintigraphy, and evaluated the associated complications. METHODS: Patients were divided into five groups on the basis of the cumulative I-131 dosage received. Scintigraphic dynamic images of the salivary glands were obtained and converted into clinically relevant parameters: uptake index (UI), maximum secretion rate (%SR), and combined gland function scores. Patients were followed up for 3-66 months and interviewed for side effects including xerostomia, taste alteration, bitter taste, dental caries, xerophthalmia, and pain/swelling. RESULTS: An increase in I-131 doses resulted in a reduction in the UI and %SR and an increase in the combined scintigraphy score. Parotid glands were more affected than submandibular glands. A cumulative dosage of greater than 600 mCi resulted in complete loss of %SR in the parotid glands. No significant difference in either the UI or the %SR was observed between nontreated patients and patients receiving an I-131 dosage of up to 150 mCi. The occurrence of xerostomia was significantly correlated with the gland scintigraphic score, the number of treatment cycles, and I-131 dosage. The occurrence of pain and swelling was extremely low and only lasted for a short time. CONCLUSION: Although the side effects associated with radioiodine treatment were apparent, they were usually small and temporary. Nevertheless, more consideration should be placed on careful dosing of I-131. PMID- 25932535 TI - The clinical significance of standardized uptake value in breast cancer measured using 18F-fluorodeoxyglucose positron emission tomography/computed tomography. AB - OBJECTIVE: The objective of this study was to investigate the clinical and biological significance of F-fluorodeoxyglucose (F-FDG) uptake levels in breast cancer patients. PATIENTS AND METHODS: F-FDG PET/computed tomography was performed in 206 women with breast cancer, and the standardized uptake value (SUV) in breast cancer was analyzed to test associations with prognostic parameters. RESULTS: PET/computed tomography sensitivity for primary tumor detection was 90.4% (206/228) and sensitivity and specificity for metastatic axillary lymph node were 72.6% (45/62) and 84.7% (122/144), respectively. A high SUV was significantly associated with large tumor size (>2 cm, P<0.001), positive axillary lymph node metastasis (P<0.001), distant metastasis (P=0.016), higher tumor node metastasis stage (P<0.001), higher histologic grade (P<0.001), higher nuclear grade (P<0.001), estrogen receptor negativity (P<0.001), progesterone receptor negativity (P<0.001), triple negativity (P=0.006), B-cell lymphoma/leukemia-2 negativity (P=0.031), cytokeratin 5/6 positivity (P=0.001), epidermal growth factor receptor positivity (P=0.005), and Ki67 positivity (P=0.003). Multivariate analysis showed that tumor size (>2 cm, P=0.001), positive axillary lymph node metastasis (P=0.028), and estrogen receptor negativity (P<0.001) were significantly associated with the SUV. CONCLUSION: High levels of F-FDG uptake in primary breast cancer were correlated with poor prognostic factors and aggressive biologic markers such as triple negativity, markers of basal-type cancer, and Ki67. The SUV might be predictive of biologic markers and assist therapeutic decision making. PMID- 25932536 TI - Early prediction of pathological complete response in luminal B type neoadjuvant chemotherapy-treated breast cancer patients: comparison between interim 18F-FDG PET/CT and MRI. AB - PURPOSE: The aim of this study is to justify the effectiveness of interim PET/computed tomography (CT) for predicting pathological complete response (pCR) in luminal B type breast cancer patients and to compare the diagnostic performance of interim PET/CT and MRI. MATERIALS AND METHODS: Twenty-one patients with neoadjuvant chemotherapy (NAC)-treated luminal B type breast cancer were included. All patients underwent PET/CT and MRI at baseline and interim (mid point). Breast surgery was performed after completion of NAC. Maximum standardized uptake values (SUV(max)) of breast malignant lesions in each PET/CT scan were acquired in each patient. The metabolic response was calculated as follows: DeltaSUV (%) = (baseline SUV(max)-interim SUV(max))/baseline SUV(max) * 100 (%). In MRI, the relative size change was calculated as follows: Size change (%) = longest diameter interim MRI-longest diameter baseline MRI/longest diameter baseline MRI * 100 (%). pCR was concluded through the final pathologic specimen after breast surgery. The receiver-operating characteristic analysis was used as a statistical method. RESULTS: Of 21 patients, seven achieved a pCR after surgery. In PET/CT, an optimal cut-off DeltaSUV (%) of 69.0% was proposed with a sensitivity of 85.7% and a specificity of 100% (P < 0.0001). In MRI, an optimal cut-off size change (%) was 38.2% with a sensitivity of 64.3% and a specificity of 71.4% (P = 0.29). The area under the curve was 0.92 and 0.65, respectively. PET/CT presented better predictability of the pCR than MRI (P = 0.04). CONCLUSION: In luminal B type NAC-treated breast cancer patients, it is possible to use PET/CT as an early surrogate marker for predicting pCR and it is significantly more predictable for pCR than MRI. PMID- 25932537 TI - Comparative assessment of gastric emptying in obese patients before and after laparoscopic sleeve gastrectomy using radionuclide scintigraphy. AB - Radionuclide scintigraphy provides a standard physiologic evaluation of gastric emptying (GE) after laparoscopic sleeve gastrectomy (LSG). This operation can be associated with motor gastric dysfunction and abnormal GE. The aim of this study was to evaluate the short-term effect of LSG on GE quantitative indices for liquids and solids compared with preoperative results. Forty obese patients were divided into two equal groups, the liquid and solid groups. Tc-sulfur colloid GE scintigraphy was performed on all patients submitted to LSG before and after surgery (1-4 weeks for liquids and 4-6 weeks for solids). The quantitative indices included half emptying time (T1/2) and percentage gastric retention at 15, 30, and 60 min for liquids and at 30, 60, 90, and 120 min for solids. A modified technique was used to label a boiled egg in order to be tolerated by the patients. T1/2 was significantly enhanced after LSG compared with baseline (25.3+/-4.4 vs. 11.8+/-3.0 min for liquids and 74.9+/-7.1 vs. 28.4+/-8.3 min for solids, respectively, P<0.001). The percentage of gastric retention in operated patients was significantly less than that at baseline for liquids at 15, 30, and 60 min (33.9+/-5.6, 17.7+/-3.9, and 7.5+/-2.8% vs. 69.4+/-10.5, 55.6+/-14.95, and 26.1+/-4.7%, respectively, P<0.001), as well as for solids at 30, 60, 90, and 120 min (42.0+/-11.1, 20.8+/-6.1, 11.0+/-5.9, and 3.8+/-2.7% vs. 79.9+/-8.7, 67.4+/ 12.2, 37.0+/-10.9%, and 13.8+/-4.4%, respectively, P<0.001). The significant acceleration of GE of liquids and solids after LSG may have contributed to weight loss in the immediate postoperative period (4-6 weeks). It remains to be determined whether the weight loss will continue beyond that period. PMID- 25932538 TI - Delayed renal tissue tracer transit in Tc-99m-DTPA renography correlates with postoperative renal function improvement in UPJO patients. AB - OBJECTIVE: The aim of the study was to explore the potential parameters for evaluating the improvement in relative renal function (RRF) in patients with unilateral ureteropelvic junction obstruction (UPJO) who underwent surgery. In this regard we observed the RRF expressed as the obstructed kidney's percentage contribution to overall renal function in technetium-99m diethylenetriaminepentaacetic acid (Tc-99m-DTPA) diuretic renography. MATERIALS AND METHODS: Data on 47 patients, who underwent Anderson-Hynes pyeloplasty for diagnosed unilateral UPJO during the period of February 2003 to October 2014, were retrospectively collected. Tc-99m-DTPA diuretic renography was performed on all patients before and after surgery, and no morphological or functional abnormalities were detected on the contralateral kidney. Several parameters, especially renal tissue tracer transit (TTT), the response to furosemide stimulation, and RRF, were evaluated. All data were analyzed with the statistical software SPSS, 17.0, and a value of P less than 0.05 was considered statistically significant. RESULTS: Data on 42 patients were eventually retained for further analysis; five patients were excluded because of indeterminate TTT. All patients showed obstructive response to furosemide stimulation with a preoperative RRF of 41+/-12%. Postoperative RRF of the obstructed kidneys was 47+/-11%, significantly higher than the preoperative RRF (P<0.05). Postoperative RRF improvement (absolute increment>=5%) was seen in 18/42 (43%) patients, and 24/42 (57%) of them manifested with postoperative drainage improvement. After surgery, both the RRF increment and the percentage of patients with postoperative RRF improvement in the preoperative delayed TTT group were significantly higher than those in the normal TTT group (12+/-7 vs. 2+/-4%, and 81 vs. 19%, respectively; P<0.05), but no significant difference in postoperative drainage improvement was detected between the two groups (56 vs. 54%, P>0.05). None of the other factors, including the preoperative RRF, obstructed kidney location, surgical method, sex, and age, had a significant influence on postoperative RRF improvement (P>0.05). CONCLUSION: Preoperatively delayed TTT of Tc-99m-DTPA diuretic renography was an independent factor that correlated with RRF improvement of unilaterally hydronephrotic kidneys, and might provide valuable information for surgical decisions pertaining to UPJO patients. PMID- 25932539 TI - Relevance of a thyroid phantom in estimating thyroid radioiodine uptake values using a gamma camera. AB - The objective of this work was to evaluate the necessity of a thyroid phantom in counting a standard capsule during estimation of iodine-131 thyroid uptake using gamma camera methods. For this, camera-based uptake was calculated taking a standard capsule within a thyroid phantom, as well as a standard capsule (without phantom) placed at 5, 10, and 15 cm from the face of the collimator. The values obtained in each setting were compared with the traditional standard thyroid probe-based method. Among these four sets of values, that with the phantom was the closest to the reference probe-based uptake values. Among those without the phantom, the camera-based uptake with the standard at 15 cm from the face of the collimator was closer to the standard probe method. However, as the image at 15 cm would give poor resolution, it would not be feasible to adopt this method for clinical routine. Thus, to conclude, for calculating camera-based uptake, a standard capsule in the phantom gives the best comparable values to the standard probe-based method, indicating the need for the phantom when adopting the gamma camera-based methodology. PMID- 25932540 TI - Utility of 18F-FDG PET/CT in the diagnosis and staging of extramammary Paget's disease. AB - PURPOSE: Extramammary Paget's disease (EMPD) is rare, and limited data have been reported on the utilization of fluorine-18 fluorodeoxyglucose PET/computed tomography ((18)F-FDG PET/CT) in this disease. The aim of this study is to evaluate the role of (18)F-FDG PET/CT in the diagnosis and staging of EMPD. MATERIALS AND METHODS: Whole-body (18)F-FDG PET/CT images of 10 patients with newly diagnosed or recurrent EMPD were retrospectively analyzed. The lesion with increased (18)F-FDG uptake was considered positive and was measured using the maximum standardized uptake value (SUV(max)). The results of PET/CT were compared by conventional staging examinations. RESULTS: All malignant lesions showed increased (18)F-FDG uptake, except for some small lung metastases. Whole-body (18)F-FDG PET/CT detected all primary lesions in four newly diagnosed patients and recurrences in the primary sites in two patients. Two thick lesions showed intense uptake of (18)F-FDG (SUV(max): 14.9 and 7.5) whereas four thin lesions had only mild (18)F-FDG uptake (mean SUV(max): 3.25 +/- 0.24). A false-positive result was found in one patient with suspected primary recurrence. (18)F-FDG PET/CT also detected lymph node metastases in six patients, bone metastases in five patients, liver metastases in two patients, lung metastases in one patient, and an adrenal gland metastasis in one patient. Compared with conventional staging examinations, three of 10 patients were upstaged by PET/CT. CONCLUSION: (18)F-FDG PET/CT diagnosis of primary lesions in EMPD is mainly dependent on the thickness of the lesions, whereas it is more sensitive for the diagnosis of metastases. PMID- 25932541 TI - Both a visual and a semiquantitative analysis for differentiating benign from malignant chondrogenic bone tumors using Tc-99m (V) DMSA scintigraphy: a prospective study. AB - OBJECTIVE: The aims of this prospective study were to assess the relationship between tumor aggressiveness and Tc-99m (V) dimercaptosuccinic acid (DMSA) uptake in chondrogenic bone tumors and the value of Tc-99m (V) DMSA scintigraphy for differentiating benign from malignant tumors. METHODS: Twenty-four patients with chondrogenic tumors (19 benign and five malignant) underwent Tc-99m DMSA (V) scintigraphy. Radiopharmaceutical uptake was classified using a three-point scale to allow a visual-only analysis, and a tumor-to-background contrast (TBC) was computed using regions of interest to provide a semiquantitative analysis. Spearman's correlation coefficient was used to assess the correlation between tumor aggressiveness and TBC. The difference in TBC between benign and malignant tumors was analyzed with the Mann-Whitney U-test. An appropriate cutoff value of TBC was chosen for the diagnosis of malignancy of a tumor using receiver operating characteristic analysis. RESULTS: Six benign tumors showed negative uptake (uptake score 0), whereas 13 benign tumors showed positive uptake (n=10 uptake score 1; n=3 uptake score 2). All chondrosarcomas showed positive uptake (n=2 uptake score 1; n=3 uptake score 2). A significant correlation was found between tumor aggressiveness and TBC. A significant difference was seen in TBC between benign and malignant tumors. With the chosen cutoff value of TBC equal to 0.611, the sensitivity was 80.0%, specificity was 78.9%, the positive predictive value was 50.0%, and the negative predictive value was 93.8%. CONCLUSION: Tc-99m (V) DMSA scintigraphy may have the potential to improve diagnostic methods for detecting chondrosarcomas using visual and/or semiquantitative analyses. PMID- 25932542 TI - Evaluation of the diagnostic and prognostic use of gated myocardial perfusion single-photon emission computed tomography in patients with acute chest pain: comparison with the SYNTAX score. AB - OBJECTIVE: The aim of this study was to evaluate the diagnostic and prognostic efficacy of gated single-photon emission computed tomography (GSPECT) in patients with acute chest pain and to compare quantitative GSPECT parameters and the coronary angiographic SYNTAX score. MATERIALS AND METHODS: A total of 168 patients who presented with clinical symptoms of acute chest pain were enrolled in the study. Study participants were divided into two groups according to the risk of acute coronary syndrome (ACS): low-intermediate and high risk. All participants underwent rest or stress-GSPECT (R/S-GSPECT). Coronary angiography was performed in all high-risk patients and the SYNTAX score was determined. All patients were followed for 24 +/- 3 months and monitored for the occurrence of major adverse coronary events (MACE). RESULTS: Among patients with low intermediate ACS risk, R-GSPECT and S-GSPECT were associated with 100 and 86% sensitivity, 99 and 98% specificity, 100 and 98% negative predictive value, 80 and 86% positive predictive value, and 98 and 97% accuracy, respectively. At follow-up, MACE occurred in 16 patients. Among high-risk patients, GSPECT quantitative parameters were the most significant predictors of MACE in Cox regression analysis. CONCLUSION: R/S-GSPECT, a noninvasive diagnostic method, is associated with an excellent safety profile and exceptional diagnostic and prognostic accuracy in cases of ACS. PMID- 25932543 TI - 18F-FDG-avid plantar nodules on true whole-body 18F-FDG PET/CT in cancer patients. AB - Plantar pain is a common problem endured by most adults at some point in their life that may result in considerable disability. Plantar fibromatosis is a locally invasive neoplasm, with the development of fibrous nodules on the plantar aspect of the feet, which can remain asymptomatic for years. (18)F Fluorodeoxyglucose ((18)F-FDG) PET/CT has been more prevalent as the imaging modality of choice for cancer patients, but the imaged field of view is often from the base of the skull to the upper thighs. Therefore, the feet are typically not included in the field. However, true whole-body imaging from the top of the skull to the bottom of the feet is performed at some institutions and can provide clinically useful findings. One such finding is the presence of (18)F-FDG-avid plantar nodules. This review is intended to help clinicians become aware of these potential false-positive nodules that can affect a patient's staging and management. PMID- 25932544 TI - Lacosamide cardiac safety: a thorough QT/QTc trial in healthy volunteers. AB - OBJECTIVE: To determine whether lacosamide prolongs the corrected QT interval (QTc). MATERIALS AND METHODS: In this randomized, double-blind, positive- and placebo-controlled, parallel-design trial, healthy volunteers were randomized to lacosamide 400 mg/day (maximum-recommended daily dose, 6 days), lacosamide 800 mg/day (supratherapeutic dose, 6 days), placebo (6 days), or moxifloxacin 400 mg/day (3 days). Variables included maximum time-matched change from baseline in QT interval individually corrected for heart rate ([HR] QTcI), other ECG parameters, pharmacokinetics (PK), and safety/tolerability. RESULTS: The QTcI mean maximum difference from placebo was -4.3 ms and -6.3 ms for lacosamide 400 and 800 mg/day; upper limits of the 2-sided 90% confidence interval were below the 10 ms non-inferiority margin (-0.5 and -2.5 ms, respectively). Placebo corrected QTcI for moxifloxacin was +10.4 ms (lower 90% confidence bound >0 [6.6 ms]), which established assay sensitivity for this trial. As lacosamide did not increase QTcI, the trial is considered a negative QTc trial. There was no dose related or clinically relevant effect on QRS duration. HR increased from baseline by ~5 bpm with lacosamide 800 mg/day versus placebo. Placebo-subtracted mean increases in PR interval at tmax were 7.3 ms (400 mg/day) and 11.9 ms (800 mg/day). There were no findings of second-degree or higher atrioventricular block. Adverse events (AEs) were dose related and most commonly involved the nervous and gastrointestinal systems. CONCLUSIONS: Lacosamide (<= 800 mg/day) did not prolong the QTc interval. Lacosamide caused a small, dose-related increase in mean PR interval that was not associated with AEs. Cardiac, overall safety, and PK profiles for lacosamide in healthy volunteers were consistent with those observed in patients with partial-onset seizures. PMID- 25932545 TI - OBSERVED COMPLICATIONS FROM DEXAMETHASONE INTRAVITREAL IMPLANT FOR THE TREATMENT OF MACULAR EDEMA IN RETINAL VEIN OCCLUSION OVER 3 TREATMENT ROUNDS. AB - PURPOSE: To report adverse events after treatment of macular edema secondary to retinal vein occlusion with intravitreal dexamethasone implant (IDI) in a UK center across three treatment rounds. METHODS: A review of 61 eyes receiving IDI treatment (1 implant [n = 61], 2 implants [n = 17], 3 implants [n = 6]). Data were collected at initiation and 2 and 6 months. Outcomes were intraocular pressure (IOP) (mean IOP, IOP >25 mmHg and IOP rise >10 mmHg) and cataract surgery. Other adverse events were recorded as they occurred. An adverse event incidence in central retinal vein occlusion versus branch retinal vein occlusion and glaucoma/ocular hypertension versus nonglaucoma/ocular hypertension subgroups was analyzed. RESULTS: Ten eyes (12%) had IOP >25 mmHg, whereas 11% required medical and 1.2% required surgical IOP management. No significant IOP change was observed during the second/third implant rounds. The IOP was higher in the glaucoma/ocular hypertension and central retinal vein occlusion subgroups. Twenty four percent of treated phakic eyes required cataract surgery, and the incidence increased with repeated implants. The mean time to cataract surgery from IDI initiation was 377 days. CONCLUSION: Intraocular pressure rise is greatest 2 months after implant. In the absence of IOP complications after initial IDI exposure, repeated treatments do not represent an increased IOP risk profile. Central retinal vein occlusion and glaucoma/ocular hypertension subgroups are more likely to experience IOP-related side effects. The incidence of cataract surgery significantly increases with repeated IDI treatments. PMID- 25932546 TI - Multimodal Imaging of a Tuberculous Granuloma. PMID- 25932547 TI - CHOROIDAL THICKNESS AFTER FULL-FLUENCE AND HALF-FLUENCE PHOTODYNAMIC THERAPY IN CHRONIC CENTRAL SEROUS CHORIORETINOPATHY. AB - PURPOSE: To compare clinical outcomes after full-fluence and half-fluence photodynamic therapy (PDT) in chronic central serous chorioretinopathy, focusing on changes in subfoveal choroidal thickness (SFCT) using enhanced depth imaging optical coherence tomography. METHODS: Retrospective, comparative interventional case series. RESULTS: In the full-fluence (n = 25) and half-fluence groups (n = 43), SFCT decreased from 351 +/- 70 MUm and 362 +/- 63 MUm at baseline to 276 +/- 65 MUm and 322 +/- 70 MUm at 3 months and remained at 267 +/- 66 MUm and 318 +/- 76 MUm at 12 months, respectively (all P < 0.001, for each comparison with baseline). The change in SFCT was greater in the full-fluence group than in the half-fluence group (P = 0.001). In the half-fluence group, SFCT was thicker in the treated eye than in the fellow eye (P = 0.045), whereas in the full-fluence group, the difference in SFCT was not significant (P = 0.209). Best-corrected visual acuity and central retinal thickness improved after PDT in both groups (all P < 0.001). However, the differences between the groups were not significant (P = 0.873 and P = 0.124, respectively). CONCLUSION: The results at 1 year show that full-fluence PDT reduces SFCT more than half-fluence PDT, and that SFCT after half-fluence PDT was still thicker than that in the fellow eye. The clinical implications of this finding for long-term outcomes including recurrence rate remain to be elucidated. PMID- 25932548 TI - PARS PLANA VITRECTOMY COMBINED WITH CATARACT EXTRACTION: A Comparison of Surgical Outcomes Using Single-Piece and Multipiece Foldable Intraocular Lenses. AB - PURPOSE: To assess whether complication rates are comparable between phacovitrectomy using multipiece lenses versus single-piece foldable intraocular lenses. METHODS: Single-center, multisurgeon retrospective comparative consecutive interventional case series. Two hundred and seventy-one patients undergoing combined phacovitrectomy performed during a single session at a university-based ophthalmology practice from 2004 to 2013 were identified, of whom 184 met study inclusion criteria; 56.4% patients had diabetes mellitus. RESULTS: There was no difference in the total incidences of postoperative complications between combined surgery using single-piece and multipiece intraocular lenses (P = 0.80) or among individual complications between the 2 groups, including synechiae (2.7 vs. 5.3%; P = 0.61), pupillary capture (0.7 and 2.6%; P = 0.36), and lens subluxation (1.4 and 0%; P > 0.99). There was no difference in the incidences of complications in patients with diabetes mellitus compared with nondiabetic patients undergoing phacovitrectomy (P = 0.13). Complication rates did not differ between single-piece and multipiece lenses with the use of postoperative intravitreal tamponade (P = 0.67). CONCLUSION: Single piece, acrylic intraocular lenses are associated with a low rate of surgical complications after combined phacovitrectomy and represent an acceptable alternative to multipiece foldable intraocular lenses under the circumstances and using the surgical techniques implemented in this study. PMID- 25932549 TI - RANDOMIZED CONTROLLED STUDY OF INTRAVITREAL BEVACIZUMAB 0.16 MG INJECTED ONE DAY BEFORE SURGERY FOR PROLIFERATIVE DIABETIC RETINOPATHY. AB - PURPOSE: To investigate the usefulness of 0.16 mg/0.05 mL intravitreal bevacizumab (IVB) injection 1 day before vitrectomy for proliferative diabetic retinopathy. METHODS: Sixty-two patients with proliferative diabetic retinopathy (66 eyes) with an indication for primary vitrectomy were randomized to IVB group (34 eyes) or sham control group (32 eyes). Intravitreal bevacizumab group received intravitreal injection of 0.16 mg/0.05 mL bevacizumab, and sham control group received sham injection 1 day before vitrectomy. Vitreous fluid was sampled before vitrectomy was started. RESULTS: Frequency of reoperation due to recurrent vitreous hemorrhage within 4 weeks after surgery was significantly lower (P = 0.033) in IVB group (3.1%, 1/32) than in sham control group (20.6%, 7/34). The number of intraoperative endodiathermy spots (0.63 +/- 1.0 vs. 1.3 +/- 1.4, P = 0.025) and frequency of postoperative recurrent vitreous hemorrhage (3.1%, 1/32 vs. 23.5%, 8/34, P = 0.017) were significantly lower in IVB group than in sham control group. Vitreous vascular endothelial growth factor concentrations were 1315.3 +/- 1153.4 pg/mL in sham control group and 25.0 +/- 13.6 pg/mL in IVB group (P < 0.0001). CONCLUSION: Intravitreal injection of 0.16 mg/0.05 mL bevacizumab 1 day before vitrectomy blocked vascular endothelial growth factor production in vitreous and significantly reduced the incidence of reoperation due to early postoperative recurrent vitreous hemorrhage. PMID- 25932550 TI - FUNCTIONAL OUTCOMES OF YOUNG INFANTS WITH AND WITHOUT MACULAR EDEMA. AB - PURPOSE: The authors relate posterior segment microanatomy from perinatal spectral domain optical coherence tomography to visual acuity, brain abnormalities, and neurodevelopment. METHODS: Thirteen infants (11 preterm and 2 term birth), imaged in the nursery with portable spectral domain optical coherence tomography, had visual acuity and sensorimotor testing at age 9 months to 15 months (grating acuity) or 4 years to 5 years (optotype), and medical records reviewed for brain magnetic resonance imaging reports and Bayley scales testing at age 18 months to 24 months. RESULTS: Eight children with age appropriate macular microanatomy without edema on perinatal spectral domain optical coherence tomography had optimal (>= 20/40) or within normal limits (grating acuity) visual acuity. Five children with perinatal macular edema had suboptimal visual acuity (in 9/10 eyes) and sensorimotor deficits, magnetic resonance imaging abnormalities, or poor neurodevelopment. Macular edema persisted in 1 infant through 9-month corrected age. CONCLUSION: Maturation of the visual system and evolution of retinal anomalies can be monitored with posterior segment spectral domain optical coherence tomography. Retinal microanatomy observed in infancy might relate to subsequent vision and other central nervous system events, but additional studies are needed to determine the range of normal microanatomy in infants and how this relates to vision and neurodevelopment. PMID- 25932551 TI - Subretinal Surgery Ab Externo: A Novel Approach to Access the Subretinal Space Without the Need for Retinotomy. PMID- 25932552 TI - CORRELATION OF CHOROIDAL THICKNESS AND BODY MASS INDEX. AB - PURPOSE: To evaluate the possible changes in the microvascular structure of the choroid by measuring choroidal thickness (CT) in four different body mass index (BMI) groups of healthy individuals. METHODS: One hundred and sixty eyes of 160 healthy individuals (70 females and 90 males) were included in this cross sectional study. Healthy individuals were divided into 4 groups according to their BMIs. Cases with BMI <= 18.50 formed Group 1, cases with BMI between 18.50 and 24.99 formed Group 2, cases with BMI between 25.00 and 29.99 formed Group 3, and cases with BMI between 30.00 and 34.99 formed Group 4. The CT was measured by the enhanced depth imaging technique of the spectral domain optical coherence tomography. The CT was measured at subfoveal area and at 500-MUm intervals to the nasal and temporal to the fovea up to 2,000 MUm. The measurements were then statistically compared among the four groups. RESULTS: The mean ages were 26.5 +/ 6.9 years (range: 18-39 years) in Group 1, 27.2 +/- 5.0 (range: 21-38 years) in Group 2, 28.5 +/- 5.9 (range: 20-40 years) in Group 3, and 29.25 +/- 5.6 (range: 20-40 years) in Group 4. The mean subfoveal CT (in micrometers) was 378 +/- 86 (range: 189-563) in Group 1, 384 +/- 102 (range: 225-643) in Group 2, 314 +/- 66 (range: 160-455) in Group 3, and 317 +/- 63 (range: 220-411) in Group 4. There was a statistically significant difference among the 4 groups in regard to CT in all locations (P < 0.05). CONCLUSION: We have demonstrated that BMI may have an influence on the CT of healthy persons. Individuals in both Group 3 and Group 4 have thinner choroids than the individuals in both Group 1 and Group 2. PMID- 25932553 TI - Phase ii, randomized, placebo-controlled, 90-day study of emixustat hydrochloride in geographic atrophy associated with dry age-related macular degeneration. AB - PURPOSE: This study assessed the safety, tolerability, and pharmacodynamics of emixustat hydrochloride (ACU-4429), a novel visual cycle modulator, in subjects with geographic atrophy associated with dry age-related macular degeneration. METHODS: Subjects were randomly assigned to oral emixustat (2, 5, 7, or 10 mg once daily) or placebo (3:1 ratio) for 90 days. Recovery of rod photoreceptor sensitivity after a photobleach was measured by electroretinography. Safety evaluations included analysis of adverse events and ophthalmic examinations. RESULTS: Seventy-two subjects (54 emixustat and 18 placebo) were evaluated. Emixustat suppressed rod photoreceptor sensitivity in a dose-dependent manner. Suppression plateaued by Day 14 and was reversible within 7 days to 14 days after drug cessation. Most systemic adverse events were not considered treatment related. Dose-related ocular adverse events (chromatopsia, 57% emixustat vs. 17% placebo and delayed dark adaptation, 48% emixustat vs. 6% placebo) were mild to moderate in severity, and the majority resolved on study or within 7 days to 14 days after study drug cessation. Reversibility of these adverse events with long term administration, however, is undetermined. CONCLUSION: In this Phase II study, emixustat produced a dose-dependent reversible effect on rod function that is consistent with the proposed mechanism of action. These results support further testing of emixustat for the treatment of geographic atrophy associated with dry age-related macular degeneration. PMID- 25932554 TI - MACULAR PIGMENT OPTICAL DENSITY IS LOWER IN TYPE 2 DIABETES, COMPARED WITH TYPE 1 DIABETES AND NORMAL CONTROLS. AB - PURPOSE: This study was designed to investigate the optical density of macular pigment in Type 1 and Type 2 diabetes subjects relative to normal controls. METHODS: One hundred and fifty subjects were recruited to the study and divided into one of the three study groups on the basis of their health status, as follows: Group 1: Healthy controls; Group 2: Type 1 diabetes; Group 3: Type 2 diabetes. Macular Pigment Optical Density, at 0.5 degrees of retinal eccentricity, was measured using customized heterochromatic flicker photometry. Dietary intake of macular carotenoids was quantified using a lutein and zeaxanthin food frequency questionnaire. Diabetes type, duration, medication, smoking habits, glycosylated hemoglobin (HbA1C), and serum lipid levels were recorded, whereas visual acuity, body mass index, and diabetic retinopathy grade were measured for each participant. RESULTS: One-way analysis of variance revealed a statistically significant difference in body mass index, age, high density lipoprotein cholesterol and HbA1C between the three groups (P < 0.01 for all). Chi-square analysis revealed a statistically significant difference in diabetic retinopathy distribution (P < 0.01). None of these variables exhibited a statistically significant correlation with macular pigment optical density for any study group (P > 0.05 for all). There was no difference in dietary carotenoid intake between groups. Macular pigment optical density was lower among Type 2 diabetes subjects (0.33 +/- 0.21) compared with Type 1 diabetes (0.49 +/- 0.23) and controls (0.48 +/- 0.35). General linear model analysis, including age, body mass index, diabetes duration, diabetic retinopathy status, high-density lipoprotein cholesterol, and HbA1C as covariates, revealed a statistically significant effect of diabetes type on macular pigment optical density (F = 2.62; P = 0.04). CONCLUSION: Macular pigment optical density was statistically significantly lower in Type 2 diabetes compared with Type 1 diabetes and normal controls. Although body mass index was higher in the Type 2 diabetes group, the lower macular pigment optical density levels observed among Type 2 diabetes seem not to be attributable to differences in dietary carotenoid intake or to the specific presence of diabetes, diabetic control, duration, or diabetic retinopathy. PMID- 25932555 TI - RETINAL BLOOD FLOW CORRELATES TO AQUEOUS VASCULAR ENDOTHELIAL GROWTH FACTOR IN CENTRAL RETINAL VEIN OCCLUSION. AB - PURPOSE: As laser speckle flowgraphy can measure blood flow distribution in the ocular fundus, the authors analyzed the relationship between retinal blood flow and aqueous vascular endothelial growth factor (VEGF) concentration in central retinal vein occlusion. METHODS: This prospective observational study examined 45 eyes of 45 patients with central retinal vein occlusion before treatment. Blood flow in large vessels around and at the optic disk, aqueous VEGF concentration, and arteriovenous passage time were examined. Blood flow was evaluated as mean blur rate by laser speckle flowgraphy. RESULTS: Fluorescein angiography found 20 ischemic and 25 nonischemic type eyes. Aqueous VEGF concentration in the ischemic type was significantly higher than that in the nonischemic type (P = 0.01). Arteriovenous passage time was significantly correlated to the logarithm of the aqueous VEGF concentration (P = 0.0001). Mean blur rate of the affected eye/mean blur rate of the unaffected eye of the ischemic type was significantly lower than the nonischemic type (P = 0.039). Additionally, mean blur rate was significantly correlated both to the logarithm of the aqueous VEGF concentration (P < 0.0001) and to the arteriovenous passage time (P = 0.0001). CONCLUSION: Laser speckle flowgraphy may be useful for predicting aqueous VEGF concentration and severity of central retinal vein occlusion. PMID- 25932556 TI - DYNAMIC AND STATIC RETINAL VESSEL ANALYSES IN PATIENTS WITH MACULAR EDEMA SECONDARY TO RETINAL VEIN OCCLUSION. AB - PURPOSE: To investigate the vasomotor responses and diameter of retinal vessels in patients with macular edema secondary to retinal vein occlusion (RVO). METHODS: A total of 18 eyes of 18 RVO patients were consecutively included and compared with age- and sex-matched controls. Participants underwent an examination with optical coherence tomography and dynamic and static retinal vessel analyses using the Dynamic Vessel Analyzer. RESULTS: Dynamic vessel analysis in RVO showed mean maximum venous and arterial dilation of 2.22 +/- 1.23% and 1.87 +/- 1.41%, respectively, as compared with 5.05 +/- 2.75% (P = 0.001) and 3.95 +/- 1.44% (P = 0.0004), respectively, in controls. Static retinal vessel analysis in RVO revealed a mean arteriovenous ratio (AVR) of 0.74 +/- 0.09 versus 0.90 +/- 0.04 (P < 0.0001) in controls. Mean AVRs of occluded and nonoccluded quadrants in RVO were 0.71 +/- 0.13 and 0.85 +/- 0.19, respectively; in the corresponding quadrants of controls, mean AVRs were 0.90 +/- 0.19 (P < 0.0001) and 0.86 +/- 0.17 (P = 0.89), respectively. In branch RVO patients, mean AVRs of occluded versus nonoccluded quadrants were 0.70 +/- 0.06 and 0.90 +/- 0.22 (P = 0.002), respectively. CONCLUSION: In patients with macular edema secondary to RVO, dynamic vessel analysis showed an impairment of both venous and arterial motility and/or reactivity and static vessel analysis showed a reduced AVR indicating a general enlargement of the retinal venous network. Moreover, in branch RVO patients, static analysis demonstrated that retinal vessels could actually be uninvolved by the occlusive process in areas spared by disease. PMID- 25932557 TI - MULTIMODAL VISUAL FUNCTION TESTING IN EYES WITH NONEXUDATIVE AGE-RELATED MACULAR DEGENERATION. AB - PURPOSE: To investigate the interactions among drusen type and multimodal vision testing in eyes with nonexudative age-related macular degeneration. METHODS: Fifty-one eyes of 39 patients with nonexudative age-related macular degeneration underwent fundus imaging including spectral domain optical coherence tomography, color fundus photograph, and autofluorescence imaging, each of which was graded by 2 masked readers. Multimodal vision testing included visual acuity using the Early Treatment Diabetic Retinopathy Study protocol refraction, contrast sensitivity, and microperimetry. RESULTS: Generalized estimating equation modeling showed that the significant predictors of contrast sensitivity was the presence of pseudodrusen (P = 0.012) and refractive error (P = 0.028). The presence of pseudodrusen inversely correlated with contrast sensitivity. The significant predictors of parafoveal microperimetry score were area of confluent hypoautofluorescence (P = 0.026) and the presence of pseudodrusen (P = 0.027). Both of them showed an inverse correlation with microperimetry score. The only significant predictor of macular microperimetry score was the presence of pseudodrusen (P = 0.004), which showed an inverse correlation with microperimetry score. CONCLUSION: The analysis of predictors of the visual function highlights the importance of pseudodrusen. Pseudodrusen are not only the risk factor of late age-related macular degeneration but also affect visual function. Recognition of this problem is important for low-vision rehabilitation and therapeutic strategies for late age-related macular degeneration. PMID- 25932558 TI - IN VIVO CHARACTERIZATION OF RETINAL VASCULARIZATION MORPHOLOGY USING OPTICAL COHERENCE TOMOGRAPHY ANGIOGRAPHY. AB - PURPOSE: To evaluate retinal vessel morphology using split-spectrum amplitude decorrelation angiography with optical coherence tomography in healthy eyes. METHODS: Fifty-two eyes of 26 healthy volunteers (age range from 35 to 48 years; mean age 41.94 years; SD: +/-4.13) were evaluated by optical coherence tomography angiography in the macular region. The protocol acquisition consisted of a 216 * 216 A-scan that was repeated 5 times in the same position, in 3 * 3 mm centered into the fovea. RESULTS: All 52 eyes showed 2 separate vascular networks in the inner retina: the superficial network, located in the nerve fiber layer and in the ganglion cell layer, and the deep network, detected in the outer plexiform layer. The superficial and deep networks showed interconnections of vertical vessels. The reference planes to observe the 2 networks were defined at 60 MUm, with an inner limiting membrane reference (6 MUm offset), and 30 MUm, with an inner plexiform layer reference (60 MUm offset), respectively. CONCLUSION: Optical coherence tomography angiography can separately detect the superficial vascular and the deep vascular networks. These networks are overlaid and seem to be fused when seen with standard angiographies. Furthermore, optical coherence tomography angiography technology allows for the visualization of abnormal blood column and vessel wall details. PMID- 25932559 TI - GENETIC ASSOCIATION BETWEEN ARTERIAL STIFFNESS-RELATED GENE POLYMORPHISMS IN BRVO AND CRVO PATIENTS IN A TURKISH POPULATION. AB - PURPOSE: To investigate possible associations between five different single nucleotide polymorphisms, from genes associated with arterial stiffness and branch retinal vein occlusion (BRVO), or central retinal vein occlusion. METHODS: A total of 187 patients with retinal vein occlusion (133 with BRVO and 54 with central retinal vein occlusion), and 167 controls, were enrolled in this study. All subjects were screened for hypertension, diabetes, smoking status, body mass index, high-density lipoprotein cholesterol, low-density lipoprotein cholesterol, triglycerides, total cholesterol, and very low-density lipoprotein. The genotyping of adiponectin +276 G/T, ACE I/D, AGTR1 A1166C, eNOS E298D, and p22phox -242 C/T polymorphisms was performed using real-time polymerase chain reaction. RESULTS: The percentage of the adiponectin +275 T allele carriers was significantly higher in the BRVO patients (37%) than in the controls (23%, P < 0.001). Similarly, the percentage of AGTR1 1166 C allele carriers was significantly higher in the BRVO patients (38%) than in the controls (24%, P < 0.001). At the multiple logistic regression analysis, the adiponectin +275 T allele carrier and AGTR1 1166 C allele carrier status were found to be associated with an increased risk of BRVO (TT vs. GG and TG: odds ratio = 2.278, P = 0.002, 95% confidence interval: 1.370-3.789; CC vs. AA and AC: odds ratio = 1.804, P = 0.025, 95% confidence interval: 1.079-3.017). The genotype distributions or allelic frequencies of ACE I/D, eNOS E298D, and p22phox -242 C/T did not significantly differ between the patients with BRVO and the control subjects. There was no significant difference between the central retinal vein occlusion patients and controls for the genotype or the allele frequency distributions of all evaluated single-nucleotide polymorphisms. CONCLUSION: Adiponectin +276 G/T and AGTR1 A1166C single-nucleotide polymorphism are likely to be risk factors for BRVO. PMID- 25932560 TI - FELLOW EYE CHANGES IN PATIENTS WITH NONISCHEMIC CENTRAL RETINAL VEIN OCCLUSION: Assessment of Perfused Foveal Microvascular Density and Identification of Nonperfused Capillaries. AB - PURPOSE: Eyes fellow to nonischemic central retinal vein occlusion (CRVO) were examined for abnormalities, which might explain their increased risk for future occlusion, using adaptive optics scanning light ophthalmoscope fluorescein angiography. METHODS: Adaptive optics scanning light ophthalmoscope fluorescein angiography foveal microvascular densities were calculated. Nonperfused capillaries adjacent to the foveal avascular zone were identified. Spectral domain optical coherence tomography, ultrawide field fluorescein angiographies, and microperimetry were also performed. RESULTS: Ten fellow eyes of nine nonischemic CRVO and 1 nonischemic hemi-CRVO subjects and four affected eyes of three nonischemic CRVO and one nonischemic hemi-CRVO subjects were imaged. Ninety percent of fellow eyes and 100% of affected eyes demonstrated at least 1 nonperfused capillary compared with 31% of healthy eyes. Fellow eye microvascular density (35 +/- 3.6 mm(-1)) was significantly higher than that of affected eyes (25 +/- 5.2 mm(-1)) and significantly lower than that of healthy eyes (42 +/- 4.2 mm(-1)). Compared with healthy controls, spectral domain optical coherence tomography thicknesses showed no significant difference, whereas microperimetry and 2/9 ultrawide field fluorescein angiography revealed abnormalities in fellow eyes. CONCLUSION: Fellow eye changes detectable on adaptive optics scanning light ophthalmoscope fluorescein angiography reflect subclinical pathology difficult to detect using conventional imaging technologies. These changes may help elucidate the pathogenesis of nonischemic CRVO and help identify eyes at increased risk of future occlusion. PMID- 25932561 TI - THE INFLUENCE OF VITREOMACULAR ADHESION ON OUTCOMES AFTER AFLIBERCEPT THERAPY FOR NEOVASCULAR AGE-RELATED MACULAR DEGENERATION. AB - PURPOSE: To evaluate the influence of vitreomacular attachment on outcomes after intravitreal aflibercept for neovascular age-related macular degeneration. METHODS: In a prospective case series, eyes with neovascular age-related macular degeneration were treated with intravitreal aflibercept, given as 3 consecutive monthly injections, followed by further injection every 2 months. Spectral domain optical coherence tomography images were reviewed at each visit to determine the attachment of the posterior hyaloid. Best-corrected visual acuity and retinal thickness were also recorded. Outcomes at Months 2 and 6 were compared between the eyes with persistent vitreomacular attachment (Stage 1) and those with posterior vitreous detachment (Stages 2 or 3 PVD) at baseline. RESULTS: At baseline, 30 eyes had Stage 1 PVD and 63 eyes had either Stage 2 or 3 PVD. Although there was a trend for both greater visual acuity gains and reductions in retinal thickness for the eyes with Stages 2 or 3 PVD, this failed to reach significance. Baseline visual acuity and age were negatively associated with visual acuity change, and baseline retinal thickness alone was associated with retinal thickness change. CONCLUSION: Visual acuity, retinal thickness, and age at the baseline examination, but not PVD status, are associated with functional and anatomical outcomes after intravitreal aflibercept for neovascular age related macular degeneration. PMID- 25932562 TI - Catalytic hydrodechlorination of trichloroethylene in a novel NaOH/2 propanol/methanol/water system on ceria-supported Pd and Rh catalysts. AB - The catalytic hydrodechlorination (HDC) of high concentrations of trichloroethylene (TCE) (4.9 mol%, 11.6 vol%) was studied over 1%Pd, 1%Rh and 0.5%Pd-0.5%Rh catalysts supported on CeO2 under conditions of room temperature and pressure. For this, a one-phase system of NaOH/2-propanol/methanol/water was designed with molar percentages of 13.2/17.5/36.9/27.6, respectively. In this system, the alcohols delivered the hydrogen required for the reaction through in situ dehydrogenation reactions. PdRh/CeO2 was the most active catalyst for the degradation of TCE among the evaluated materials, degrading 85% of the trichloroethylene, with alcohol dehydrogenation rates of 89% for 2-propanol and 83% for methanol after 1 h of reaction. Fresh and used catalysts were characterized by Transmission Electron Microscopy (TEM), X-ray Photoelectron Spectroscopy (XPS), and Thermogravimetric analysis (TGA). These results showed important differences of the active phase in each catalyst sample. Rh/CeO2 had particle sizes smaller than 1 nm and the active metal was partially oxidized (Rh(0)/Rh(+delta) ratio of 0.43). This configuration showed to be suitable for alcohols dehydrogenation. On the contrary, Pd/CeO2 showed a Pd completed oxidized and with a mean particle size of 1.7 nm, which seemed to be unfavorable for both, alcohols dehydrogenation and TCE HDC. On PdRh/CeO2, active metals presented a mean particle size of 2.7 nm and more reduced metallic species, with ratios of Rh(0)/Rh(+delta) = 0.67 and Pd(0)/Pd(+delta) = 0.28, which showed to be suitable features for the TCE HDC. On the other hand, TGA results suggested some deposition of NaCl residues over the catalyst surfaces. Thus, the new reaction system using PdRh/CeO2 allowed for the degradation of high concentrations of the chlorinated compound by using in situ hydrogen liquid donors in a reaction at room temperature and pressure. PMID- 25932563 TI - Ultrafast Intramolecular Electron and Proton Transfer in Bis(imino)isoindole Derivatives. AB - Concerted motion of electrons and protons in the excited state is pertinent to a wide range of chemical phenomena, including those relevant for solar-to-fuel light harvesting. The excited state dynamics of small proton-bearing molecules are expected to serve as models for better understanding such phenomena. In particular, for designing the next generation of multielectron and multiproton redox catalysts, understanding the dynamics of more than one proton in the excited state is important. Toward this goal, we have measured the ultrafast dynamics of intramolecular excited state proton transfer in a recently synthesized dye with two equivalent transferable protons. We have used a visible ultrafast pump to initiate the proton transfer in the excited state, and have probed the transient absorption of the molecule over a wide bandwidth in the visible range. The measurement shows that the signal which is characteristic of proton transfer emerges within ~710 fs. To identify whether both protons were transferred in the excited state, we have measured the ultrafast dynamics of a related derivative, where only a single proton was available for transfer. The measured proton transfer time in that molecule was ~427 fs. The observed dynamics in both cases were reasonably fit with single exponentials. Supported by the ultrafast observations, steady-state fluorescence, and preliminary computations of the relaxed excited states, we argue that the doubly protonated derivative most likely transfers only one of its two protons in the excited state. We have performed calculations of the frontier molecular orbitals in the Franck-Condon region. The calculations show that in both derivatives, the excitation is primarily from the HOMO to LUMO causing a large rearrangement of the electronic charge density immediately after photoexcitation. In particular, charge density is shifted away from the phenolic protons and toward the proton acceptor nitrogens. The proton transfer is hypothesized to occur both due to enhanced acidity of the phenolic proton and enhanced basicity of the nitrogen in the excited state. We hope this study can provide insight for better understanding of the general class of excited state concerted electron-proton dynamics. PMID- 25932564 TI - Knowledge, attitudes, and decision making in hospital glycemic management: are faculty up to speed? AB - OBJECTIVE: Knowledge and confidence deficits in the management of hospital glucose abnormalities are prevalent among resident physicians. However, it is unclear whether such gaps prevail among faculty within different professional fields. In this study, we examined faculty knowledge and explored perceptions of challenges related to the management of inpatient hyperglycemia and diabetes. METHODS: We conducted a survey that examined management decisions about inpatient hyperglycemia and diabetes among Medicine, Medicine/Pediatrics, Family and Community Medicine, Surgery, and Neurology faculty clinicians. All participating faculty had teaching and patient care responsibilities. RESULTS: Responses from 69 faculty participants revealed gaps in several areas, including biomedical and contextual knowledge, familiarity with resources, clinical decision making, and self-efficacy. We identified important factors perceived as barriers to optimal glycemic management in the inpatient settings. CONCLUSION: The results of this study enhance our insight about the limitations existing among faculty related to the management of hyperglycemia and diabetes in hospitalized patients. We suggest that these barriers may impede optimization of patient care. Faculty play a crucial role in the clinical decision-making process and quality of care delivered by trainees. Therefore, attending physicians are likely to impact trainees' clinical performance and competency in the management of inpatient diabetes during training and beyond. Education in this subject should be a priority among trainees and faculty alike. PMID- 25932565 TI - Clinical features and retroperitoneal laparoscopic resection of adrenal schwannoma in 19 patients. AB - OBJECTIVE: To explore the diagnostic and therapeutic principles of the rare adrenal schwannoma. METHODS: We objectively analyzed the detailed clinical data of 19 patients with adrenal schwannoma treated in a large comprehensive medical center in China between January 2009 and March 2014, including general information, clinical manifestations, imaging, adrenal-related endocrine tests, treatment, pathology, and follow-up records. RESULTS: Patients included 16 females and 3 males ranging from 23 to 66 years of age (mean, 48.3 +/- 12.6 years), of whom 15 were discovered incidentally. Four patients reported mild abdominal discomfort. Each patient had one unilateral lesion, ranging in diameter from 4.0 to 8.8 cm (mean, 6.2 +/- 1.2 cm). Lesions were hypoechoic in 16 patients and cystic-solid in 3 patients. Computed tomography (CT) scanning revealed soft tissue density, mostly with calcifications and clear boundaries. Average values in normal and enhanced CT were 28.7 +/- 7.2 Hounsfield units (HU) and 59.7 +/- 5.4 HU, respectively. Indicators of adrenal-related endocrine tests were normal, except that catecholamines levels were slightly low in 2 patients with excessively large lesions. All patients underwent uncomplicated retroperitoneal laparoscopic surgery, with subsequent pathology confirmation of adrenal schwannoma. The patients have been followed for 6 months to 4 years, with no recurrence. CONCLUSION: Our results demonstrate that the onset of adrenal schwannoma is always occult, without typical clinical manifestations and adrenal related endocrine abnormalities, and the pre-operative diagnosis depends primarily on imaging features of hypoechoic calcifications and mild enhancement. Diagnosis can be confirmed by postoperative pathology. Even with large diameter lesions, retroperitoneal laparoscopic surgery is still the preferred approach, with good prognosis. PMID- 25932566 TI - LONG-TERM, SUSTAINED, LIFESTYLE-INDUCED WEIGHT LOSS IN SEVERE OBESITY: THE GET ReAL PROGRAM. AB - OBJECTIVE: To study the long-term effectiveness of a patient-centered, multidisciplinary lifestyle intervention treatment in patients medically eligible for bariatric surgery. METHODS: Using a case-control study design, we compared treatment results for 98 adults (mean body mass index [BMI], 44.2 kg/m(2)) with the outcomes of 148 controls (mean BMI, 43.0 kg/m(2)) receiving standard care. The approach included a phased triage for inclusion, followed by 12 lifestyle intervention group sessions alternating with individual visits for behavior, diet, and exercise instructions. RESULTS: At 2 years, weight loss averaged 15.3 +/- 1.4 kg (P<.0010) (12 +/- 1% of initial body weight [IBW], P<.001; 21 +/- 2% of excess body weight [EBW], P<.001) in an intention-to-treat (ITT) analysis; in completers, weight loss was 18.8 +/- 1.5 kg (P<.001) (15 +/- 1% IBW, P<.001; 26 +/- 3% EBW, P<.001). A total of 42 patients lost >=10% IBW. Controls remained weight stable (P = .35); 3% lost >=10% IBW. Patients achieving weight loss that would be considered satisfactory for bariatric surgery included 20% who achieved >=35% EBW loss, 29% who achieved a BMI <35 kg/m(2) (if starting BMI <50 kg/m(2)) or BMI <40 kg/m(2) (if starting BMI >=50 kg/m(2)), and 37% who achieved EBW loss <=50%. These values for completers were 31, 39, and 48%, respectively. In the 55 patients starting the program >=4 years ago, weight loss maintenance of 12 +/- 1% IBW (ITT, 16 +/- 1% in completers) was observed. CONCLUSION: Substantial nonsurgical weight loss, maintained at 2 to 4 years, is achievable in severely obese patients using comprehensive lifestyle approaches; the efficacy/safety trade-off in obesity treatment is an important consideration in interpreting these results. PMID- 25932567 TI - Endocrine dysfunction and follow-up outcomes in patients with pituitary abscess. AB - OBJECTIVE: Endocrine dysfunction caused by pituitary abscess (PA) and its outcomes have not been fully studied. This study aims to investigate endocrine dysfunction and outcomes in patients with PA. METHODS: Eight patients (3 males and 5 females) with PA were identified for collecting clinical, hormone, and therapeutic data before and after long-term follow-up lasting 12 to 116 months (median, 25 months) since the first hospitalization, which was regarded as the baseline time. All patients' pituitary and respective target gland functions were evaluated. Six patients had acute onset (less than 1 month), and the other 2 patients had chronic onset (more than 6 months). Five patients underwent surgical therapy, and the other 3 patients underwent conservative therapy. The factors associated with endocrine outcome were analyzed as well. RESULTS: At baseline, the release of 91.7% (22 of 24 total) of pituitary tropic hormones was impaired, but 59.1% (13 of 22) had normalized by the last follow-up. Male gender, acute onset mode, and normal baseline prolactin level seemed to be the factors that favored tropic hormone normalization, whereas surgical operation was not. Two patients received provocative test suggesting decreased reserves of both somatotrophin and prolactin or only somatotrophin. Only 1 patient suffered from permanent diabetes insipidus. CONCLUSION: The production of almost all pituitary tropic hormones was impaired with PA in the present study, but production of nearly 60% percent of the hormones normalized during follow-up of >1 year. A chronic abscess state may be the most important factor associated with permanent hormone deficiency. PMID- 25932569 TI - Electron ionization mass spectrum of tellurium hexafluoride. AB - The electron ionization mass spectrum of tellurium hexafluoride (TeF6) is reported for the first time. The starting material was produced by direct fluorination of Te metal or TeO2 with nitrogen trifluoride. Formation of TeF6 was confirmed through cryogenic capture of the tellurium fluorination product and analysis through Raman spectroscopy. The eight natural abundance isotopes were observed for each of the set of fragment ions: TeF5(+), TeF4(+) TeF3(+), TeF2(+), TeF1(+), and Te(+), Te2(+). A trend in increasing abundance was observed for the odd fluoride bearing ions, TeF1(+) < TeF3(+) < TeF5(+), and a decreasing abundance was observed for the even fragment series, Te(F0)(+) > TeF2(+) > TeF4(+) > TeF6(+), with the molecular ion TeF6(+) not observed at all. Density functional theory based electronic structure calculations were used to calculate optimized ground state geometries of these gas phase species, and their relative stabilities explain the trends in the data and the lack of observed signal for TeF6(+). PMID- 25932570 TI - No need for bad blood over bad blood. PMID- 25932571 TI - Sepsis: a need for new solutions. PMID- 25932568 TI - Capitalizing on knowledge of hepatitis C virus neutralizing epitopes for rational vaccine design. AB - Hepatitis C virus infects nearly 3% of the world's population and is often referred as a silent epidemic. It is a leading cause of liver cirrhosis and hepatocellular carcinoma in endemic countries. Although antiviral drugs are now available, they are not readily accessible to marginalized social groups and developing nations that are disproportionally impacted by HCV. To stop the HCV pandemic, a vaccine is needed. Recent advances in HCV research have provided new opportunities for studying HCV neutralizing antibodies and their subsequent use for rational vaccine design. It is now recognized that neutralizing antibodies to conserved antigenic sites of the virus can cross-neutralize diverse HCV genotypes and protect against infection in vivo. Structural characterization of the neutralizing epitopes has provided valuable information for design of candidate immunogens. PMID- 25932572 TI - What next for sepsis? PMID- 25932573 TI - Sepsis research and the poorest of the poor. PMID- 25932574 TI - Neonatal sepsis: an old issue needing new answers. PMID- 25932575 TI - Corrections. AB - Worldwide Antimalarial Resistance Network (WWARN) AL Dose Impact Study Group. The effect of dose on the antimalarial efficacy of artemetherlumefantrine: a systematic review and pooled analysis of individual patient data. Lancet Infect Dis 2015; published online March 13. http://dx.doi. org/10.1016/S1473 3099(15)70024-1- In the WWARN Dose Impact Study Group, the affiliation for S Borrmann was incorrect and has been corrected to Institute for Tropical Medicine, University of Tubingen, Tubingen. The correction has been made to the online version as of April 20. PMID- 25932576 TI - Corrections. AB - Ravimohan S, Tamuhla N, Steenhoff AP, et al. Immunological profiling of tuberculosis-associated immune reconstitution inflammatory syndrome and non immune reconstitution inflammatory syndrome death in HIV-infected adults with pulmonary tuberculosis starting antiretroviral therapy: a prospective observational cohort study. Lancet Infect Dis 2015; published online Feb 9. http://dx.doi.org/10.1016/S1473-3099(15)70008-3- In figure 1B of this Article, the marker and line for MCP-1 had been moved up and were consequently missing from the MCP-1 row, and the square for eotaxin was not in line with the marker. This figure has been corrected as of Feb 11, 2015, and the printed Article will be correct. PMID- 25932577 TI - Ebola: the real lessons from HIV scale-up. PMID- 25932578 TI - Long-term vaccine strategies for Ebola. PMID- 25932579 TI - Ebola superspreading. PMID- 25932580 TI - Norovirus in patients with gastroenteritis. PMID- 25932581 TI - Bacterial meningitis in the USA. PMID- 25932582 TI - Bacterial meningitis in the USA. PMID- 25932583 TI - Chikungunya, the emerging migratory rheumatism. PMID- 25932584 TI - Chikungunya, the emerging migratory rheumatism. PMID- 25932585 TI - Treating infestations of the human botfly, Dermatobia hominis. PMID- 25932586 TI - HIV rumbles on in the south of the USA. AB - Poverty within the USA seems to be the defining characteristic for regional HIV risk, and entrenched political positions are hampering progress. Talha Burki reports. PMID- 25932587 TI - The virtual classroom and Ebola preparedness. AB - A hospital in Sierra Leone has collaborated in the development of computer-based training for Ebola management. Clare Sansom reports. PMID- 25932591 TI - Sepsis: a roadmap for future research. AB - Sepsis is a common and lethal syndrome: although outcomes have improved, mortality remains high. No specific anti-sepsis treatments exist; as such, management of patients relies mainly on early recognition allowing correct therapeutic measures to be started rapidly, including administration of appropriate antibiotics, source control measures when necessary, and resuscitation with intravenous fluids and vasoactive drugs when needed. Although substantial developments have been made in the understanding of the basic pathogenesis of sepsis and the complex interplay of host, pathogen, and environment that affect the incidence and course of the disease, sepsis has stubbornly resisted all efforts to successfully develop and then deploy new and improved treatments. Existing models of clinical research seem increasingly unlikely to produce new therapies that will result in a step change in clinical outcomes. In this Commission, we set out our understanding of the clinical epidemiology and management of sepsis and then ask how the present approaches might be challenged to develop a new roadmap for future research. PMID- 25932592 TI - Stability of root coverage outcomes at single maxillary gingival recession with loss of interdental attachment: 3-year extension results from a randomized, controlled, clinical trial. AB - BACKGROUND: The aim of this study was to assess the stability of root coverage outcomes 3 years after Connective Tissue Graft (CTG) plus Coronally Advanced Flap (CAF) or CAF alone at single maxillary gingival recession with minimal inter dental clinical attachment loss. MATERIAL AND METHODS: Twenty-four of the original 29 patients, 13 treated with CAF + CTG and 11 with CAF, were available for the 3-year follow-up. Measurements were performed by a blind and calibrated examiner. Outcome measures included complete root coverage (CRC), recession reduction (RecRed), Root coverage Esthetic Score (RES) and Keratinized Tissue (KT) Gain. Visual Analogue Scale (VAS) was used to evaluate patient satisfaction. RESULTS: After 3 years, CAF + CTG resulted in better outcomes in terms of CRC (p = 0.0054) than CAF alone. No difference was detected in terms of RecRed, RES score and VAS values. Furthermore, CAF + CTG was associated with higher KT gain than CAF at the last follow-up (p < 0.0001). CONCLUSION: Root coverage outcomes in single gingival recession with inter-dental CAL loss are stable after 3 years. The application of CTG under CAF was associated with increased probability to obtain CRC than CAF alone at the final follow-up. PMID- 25932593 TI - Anthropometrics of Italian Senior Male Rugby Union Players: From Elite to Second Division. AB - Anthropometric evaluation of athletes is necessary to optimize talent identification and player development. OBJECTIVES: To provide a specific anthropometric reference database of senior male rugby players competing at different levels in the southern European region. DESIGN: Cross-sectional. METHODS: In 362 professional players (25 +/- 4 y; 138 Italian national team, 97 first-division, and 127 second-division national championships) the authors measured mass, stature, and percentage body fat (plicometry). Mean, SD, and coefficient of variation were calculated for forwards and backs and for positional subgroups. Binomial logistic regression and receiver-operating characteristic curve were performed to assess which variables best predicted level assignment (international vs national level). RESULTS: For all competitive levels forwards were significantly heavier and taller and had a larger percentage body fat and fat-free mass than backs. The lower the competitive level, the higher the within-role variability observed; furthermore, players in a specific positional subgroup were lighter, shorter, and fatter and had less fat-free mass. Fatfree mass is the variable that best predicts the likelihood of being classified as an international or national player (cutoff value 79.54 kg). CONCLUSIONS: The data confirm the specificity in the physical requirements of rugby in individual playing positions at all competitive levels and document significant differences among elite and 1st- and 2nd-division players in the same positional role. These differences may reflect the variable technical abilities, selection, training practices, and requirements of the game among these categories. PMID- 25932595 TI - Novel mechanisms of intracellular cholesterol transport: oxysterol-binding proteins and membrane contact sites. AB - Cholesterol is an essential membrane constituent, and also plays a key role in cell signalling. Within a cell, how cholesterol is transported and how its heterogeneous distribution is maintained are poorly understood. Recent advances have identified novel pathways and regulators of cholesterol trafficking. Sterol transfer by lipid-binding proteins, such as OSBP (oxysterol-binding protein), coupled with phosphatidylinositol 4-phosphate exchange at membrane contact sites (MCSs) has emerged as a new theme of cholesterol transport between organellar membranes. Moreover, a previously unappreciated role of peroxisomes in cholesterol trafficking has been revealed recently. These discoveries highlight the crucial role of MCSs, or junctions, in facilitating lipid movement, and provide mechanistic insights into how cholesterol is sorted in cells. PMID- 25932594 TI - Tributyltin engages multiple nuclear receptor pathways and suppresses osteogenesis in bone marrow multipotent stromal cells. AB - Organotins are members of the environmental obesogen class of contaminants because they activate peroxisome proliferator-activated receptor gamma (PPARgamma), the essential regulator of adipogenesis. Exposure to thiazolidinediones (PPARgamma ligands used to treat type 2 diabetes) is associated with increased fractures. Diminished bone quality likely results from PPARgamma's role in promoting adipogenesis while suppressing osteogenesis of bone marrow multipotent mesenchymal stromal cells (BM-MSC). We hypothesized that tributyltin (TBT) would be a potent modifier of BM-MSC differentiation and a negative regulator of bone formation. Organotins interact with both PPARgamma and retinoid X receptors (RXR), suggesting that they activate multiple nuclear receptor pathways. To investigate the role of RXR in the actions of TBT, the effects of PPARgamma (rosiglitazone) and RXR (bexarotene, LG100268) agonists were compared to the effects of TBT in BMS2 cells and primary mouse BM-MSC cultures. In BMS2 cells, TBT induced the expression of Fabp4, Abca1, and Tgm2 in an RXR dependent manner. All agonists suppressed osteogenesis in primary mouse BM-MSC cultures, based on decreased alkaline phosphatase activity, mineralization, and expression of osteoblast-related genes. While rosiglitazone and TBT strongly activated adipogenesis, based on lipid accumulation and expression of adipocyte related genes, the RXR agonists did not. Extending these analyses to other RXR heterodimers showed that TBT and the RXR agonists activated the liver X receptor pathway, whereas rosiglitazone did not. Application of either a PPARgamma antagonist (T0070907) or an RXR antagonist (HX531) significantly reduced rosiglitazone-induced suppression of bone nodule formation. Only the RXR antagonist significantly reduced LG100268- and TBT-induced bone suppression. The RXR antagonist also inhibited LG100268- and TBT-induced expression of Abca1, an LXR target gene, in primary BM-MSC cultures. These results provide novel evidence that TBT activates multiple nuclear receptor pathways in BM-MSCs, activation of RXR is sufficient to suppress osteogenesis, and TBT suppresses osteogenesis largely through its direct interaction with RXR. PMID- 25932596 TI - Efficacy of treatments for anxiety disorders: a meta-analysis. AB - To our knowledge, no previous meta-analysis has attempted to compare the efficacy of pharmacological, psychological and combined treatments for the three main anxiety disorders (panic disorder, generalized anxiety disorder and social phobia). Pre-post and treated versus control effect sizes (ES) were calculated for all evaluable randomized-controlled studies (n = 234), involving 37,333 patients. Medications were associated with a significantly higher average pre post ES [Cohen's d = 2.02 (1.90-2.15); 28,051 patients] than psychotherapies [1.22 (1.14-1.30); 6992 patients; P < 0.0001]. ES were 2.25 for serotonin noradrenaline reuptake inhibitors (n = 23 study arms), 2.15 for benzodiazepines (n = 42), 2.09 for selective serotonin reuptake inhibitors (n = 62) and 1.83 for tricyclic antidepressants (n = 15). ES for psychotherapies were mindfulness therapies, 1.56 (n = 4); relaxation, 1.36 (n = 17); individual cognitive behavioural/exposure therapy (CBT), 1.30 (n = 93); group CBT, 1.22 (n = 18); psychodynamic therapy 1.17 (n = 5); therapies without face-to-face contact (e.g. Internet therapies), 1.11 (n = 34); eye movement desensitization reprocessing, 1.03 (n = 3); and interpersonal therapy 0.78 (n = 4). The ES was 2.12 (n = 16) for CBT/drug combinations. Exercise had an ES of 1.23 (n = 3). For control groups, ES were 1.29 for placebo pills (n = 111), 0.83 for psychological placebos (n = 16) and 0.20 for waitlists (n = 50). In direct comparisons with control groups, all investigated drugs, except for citalopram, opipramol and moclobemide, were significantly more effective than placebo. Individual CBT was more effective than waiting list, psychological placebo and pill placebo. When looking at the average pre-post ES, medications were more effective than psychotherapies. Pre post ES for psychotherapies did not differ from pill placebos; this finding cannot be explained by heterogeneity, publication bias or allegiance effects. However, the decision on whether to choose psychotherapy, medications or a combination of the two should be left to the patient as drugs may have side effects, interactions and contraindications. PMID- 25932597 TI - Synergistic effects from graphene and carbon nanotubes endow ordered hierarchical structure foams with a combination of compressibility, super-elasticity and stability and potential application as pressure sensors. AB - Nanostructured carbon material based three-dimensional porous architectures have been increasingly developed for various applications, e.g. sensors, elastomer conductors, and energy storage devices. Maintaining architectures with good mechanical performance, including elasticity, load-bearing capacity, fatigue resistance and mechanical stability, is prerequisite for realizing these functions. Though graphene and CNT offer opportunities as nanoscale building blocks, it still remains a great challenge to achieve good mechanical performance in their microarchitectures because of the need to precisely control the structure at different scales. Herein, we fabricate a hierarchical honeycomb-like structured hybrid foam based on both graphene and CNT. The resulting materials possess excellent properties of combined high specific strength, elasticity and mechanical stability, which cannot be achieved in neat CNT and graphene foams. The improved mechanical properties are attributed to the synergistic-effect induced highly organized, multi-scaled hierarchical architectures. Moreover, with their excellent electrical conductivity, we demonstrated that the hybrid foams could be used as pressure sensors in the fields related to artificial skin. PMID- 25932598 TI - Reduction in adjacent-segment degeneration after multilevel posterior lumbar interbody fusion with proximal DIAM implantation. AB - OBJECT Multilevel long-segment lumbar fusion poses a high risk for future development of adjacent-segment degeneration (ASD). Creating a dynamic transition zone with an interspinous process device (IPD) proximal to the fusion has recently been applied as a method to reduce the occurrence of ASD. The authors report their experience with the Device for Intervertebral Assisted Motion (DIAM) implanted proximal to multilevel posterior lumbar interbody fusion (PLIF) in reducing the development of proximal ASD. METHODS This retrospective study reviewed 91 cases involving patients who underwent 2-level (L4-S1), 3-level (L3 S1), or 4-level (L2-S1) PLIF. In Group A (42 cases), the patients received PLIF only, while in Group B (49 cases), an interspinous process device, a DIAM implant, was put at the adjacent level proximal to the PLIF construct. Bone resection at the uppermost segment of the PLIF was equally limited in the 2 groups, with preservation of the upper portion of the spinous process/lamina and the attached supraspinous ligament. Outcome measures included a visual analog scale (VAS) for low-back pain and leg pain and the Oswestry Disability Index (ODI) for functional impairment. Anteroposterior and lateral flexion/extension radiographs were used to evaluate the fusion status, presence and patterns of ASD, and mobility of the DIAM-implanted segment. RESULTS Solid interbody fusion without implant failure was observed in all cases. Radiographic ASD occurred in 20 (48%) of Group A cases and 3 (6%) of Group B cases (p < 0.001). Among the patients in whom ASD was identified, 9 in Group A and 3 in Group B were symptomatic; of these patients, 3 in Group A and 1 in Group B underwent a second surgery for severe symptomatic ASD. At 24 months after surgery, Group A patients fared worse than Group B, showing higher mean VAS and ODI scores due to symptoms related to ASD. At the final follow-up evaluations, as reoperations had been performed to treat symptomatic ASD in some patients, significant differences no longer existed between the 2 groups. In Group B, flexion/extension mobility at the DIAM-implanted segment was maintained in 35 patients and restricted or lost in 14 patients, 5 of whom had already lost segmental flexion/extension mobility before surgery. No patient in Group B developed ASD at the segment proximal to the DIAM implant. CONCLUSIONS Providing a dynamic transition zone with a DIAM implant placed immediately proximal to a multilevel PLIF construct was associated with a significant reduction in the occurrence of radiographic ASD, compared with PLIF alone. Given the relatively old age and more advanced degeneration in patients undergoing multilevel PLIF, this strategy appears to be effective in lowering the risk of clinical ASD and a second surgery subsequent to PLIF. PMID- 25932599 TI - Posterior thoracic corpectomy with cage reconstruction for metastatic spinal tumors: comparing the mini-open approach to the open approach. AB - OBJECT Spinal metastases most commonly affect the vertebral bodies of the spinal column, and spinal cord compression is an indication for surgery. Commonly, an open posterior approach is employed to perform a transpedicular costotransversectomy or lateral extracavitary corpectomy. Because of the short life expectancies in patients with metastatic spinal disease, decreasing the morbidity of surgical treatment and recovery time is critical. One potential approach to decreasing morbidity is utilizing minimally invasive surgery (MIS). Although significant advances have been made in MIS of the spine, data supporting the utility of MIS are still emerging. This study compared outcomes of patients who underwent mini-open versus traditional open transpedicular corpectomy for spinal metastases in the thoracic spine. METHODS A consecutive cohort from 2006 to 2013 of 49 adult patients who underwent thoracic transpedicular corpectomies for spinal metastases was retrospectively identified. Patients were categorized into one of 2 groups: open surgery and mini-open surgery. Mini-open transpedicular corpectomy was performed with a midline facial incision over only the corpectomy level of interest and percutaneous instrumentation above and below that level. The open procedure consisted of a traditional posterior transpedicular corpectomy. Chi-square test, 2-tailed t-test, and ANOVA models were employed to compare perioperative and follow-up outcomes between the 2 groups. RESULTS In the analysis, there were 21 patients who had mini-open surgery and 28 patients who had open surgery. The mean age was 57.9 years, and 59.2% were male. The tumor types encountered were lung (18.3%), renal/bladder (16.3%), breast (14.3%), hematological (14.3%), gastrointestinal tract (10.2%), prostate (8.2%), melanoma (4.1%), and other/unknown (14.3%). There were no significant intergroup differences in demographics, comorbidities, neurological status (American Spinal Injury Association [ASIA] grade), number of corpectomies performed, and number of levels instrumented. The open group had a mean operative time of 413.6 minutes, and the mini-open group had a mean operative time of 452.4 minutes (p = 0.329). Compared with the open group, the mini-open group had significantly less blood loss (917.7 ml vs. 1697.3 ml, p = 0.019) and a significantly shorter hospital stay (7.4 days vs. 11.4 days, p = 0.001). There was a trend toward a lower perioperative complication rate in the mini-open group (9.5%) compared with the open group (21.4%), but this was not statistically significant (p = 0.265). At follow-up, there were no significant differences in ASIA grade (p = 0.342), complication rate after the 30-day postoperative period (p = 0.999), or need for surgical revision (p = 0.803). The open approach had a higher overall infection rate of 17.9% compared with that in the mini-open approach of 9.5%, but this was not statistically significant (p = 0.409). CONCLUSIONS The mini-open transpedicular corpectomy is associated with less blood loss and shorter hospital stay compared with open transpedicular corpectomy. The mini-open corpectomy also trended toward lower infection and complication rates, but these did not reach statistical significance. PMID- 25932600 TI - Effect of steroid use in anterior cervical discectomy and fusion: a randomized controlled trial. AB - OBJECT Anterior cervical discectomy and fusion (ACDF) is an effective procedure for the treatment of cervical radiculopathy and/or myelopathy; however, postoperative dysphagia is a significant concern. Dexamethasone, although potentially protective against perioperative dysphagia and airway compromise, could inhibit fusion, a generally proinflammatory process. The authors conducted a prospective, randomized, double-blinded, controlled study of the effects of steroids on swallowing, the airway, and arthrodesis related to multilevel anterior cervical reconstruction in patients who were undergoing ACDF at Albany Medical Center between 2008 and 2012. The objective of this study was to determine if perioperative steroid use improves perioperative dysphagia and airway edema. METHODS A total of 112 patients were enrolled and randomly assigned to receive saline or dexamethasone. Data gathered included demographics, functional status (including modified Japanese Orthopaedic Association myelopathy score, neck disability index, 12-Item Short-Form Health Survey score, and patient reported visual analog scale score of axial and radiating pain), functional outcome swallowing scale score, interval postoperative imaging, fusion status, and complications/reoperations. Follow-up was performed at 1, 3, 6, 12, and 24 months, and CT was performed 6, 12, and 24 months after surgery for fusion assessment. RESULTS Baseline demographics were not significantly different between the 2 groups, indicating adequate randomization. In terms of patient reported functional and pain-related outcomes, there were no differences in the steroid and placebo groups. However, the severity of dysphagia in the postoperative period up to 1 month proved to be significantly lower in the steroid group than in the placebo group (p = 0.027). Furthermore, airway difficulty and a need for intubation trended toward significance in the placebo group (p = 0.057). Last, fusion rates at 6 months proved to be significantly lower in the steroid group but lost significance at 12 months (p = 0.048 and 0.57, respectively). CONCLUSIONS Dexamethasone administered perioperatively significantly improved swallowing function and airway edema and shortened length of stay. It did not affect pain, functional outcomes, or long-term swallowing status. However, it significantly delayed fusion, but the long-term fusion rates remained unaffected. Clinical trial registration no.: NCT01065961 (clinicaltrials.gov). PMID- 25932601 TI - Determination of the biomechanical effect of an interspinous process device on implanted and adjacent lumbar spinal segments using a hybrid testing protocol: a finite-element study. AB - OBJECT The authors evaluated the biomechanical effects of an interspinous process (ISP) device on kinematics and load sharing at the implanted and adjacent segments. METHODS A 3D finite-element (FE) model of the lumbar spine (L1-5) was developed and validated through comparison with published in vitro study data. Specifically, validation was achieved by a flexible (load-control) approach in 3 main planes under a pure moment of 10 Nm and a compressive follower load of 400 N. The ISP device was inserted between the L-3 and L-4 processes. Intact and implanted cases were simulated using the hybrid protocol in all motion directions. The resultant motion, facet load, and intradiscal pressure after implantation were investigated at the index and adjacent levels. In addition, stress at the bone-implant interface was predicted. RESULTS The hybrid approach, shown to be appropriate for adjacent-level investigations, predicted that the ISP device would decrease the range of motion, facet load, and intradiscal pressure at the index level relative to the corresponding values for the intact spine in extension. Specifically, the intradiscal pressure induced after implantation at adjacent segments increased by 39.7% and by 6.6% at L2-3 and L4-5, respectively. Similarly, facet loads at adjacent segments after implantation increased up to 60% relative to the loads in the intact case. Further, the stress at the bone implant interface increased significantly. The influence of the ISP device on load sharing parameters in motion directions other than extension was negligible. CONCLUSIONS Although ISP devices apply a distraction force on the processes and prevent further extension of the index segment, their implantation may cause changes in biomechanical parameters such as facet load, intradiscal pressure, and range of motion at adjacent levels in extension. PMID- 25932602 TI - Wake-up stroke in a young woman with rotational vertebral artery occlusion due to far-lateral cervical disc herniation. AB - Wake-up stroke is most likely to be caused by small-vessel disease, and is related to snoring. The authors present a rare case of far-lateral cervical disc herniation with neck rotation, resulting in wake-up stroke in a young woman. The patient, a 31-year-old woman, was admitted to the hospital because of dysarthria and confusion when she awoke in the morning. Brain MRI showed acute infarction in the posterior fossa. Cerebral angiography showed thrombus in the distal top of the basilar artery and the bilateral posterior cerebral arteries. During angiography, the thrombus size decreased with heparinization. There was severe stenosis of the right vertebral artery (VA) at C5-6, and head rotation to the right resulted in complete occlusion of the right VA. Neck MRI showed far-lateral intervertebral disc herniation. Surgical decompression of the VA was performed via the anterior cervical approach. Histological examination showed a degenerative intervertebral disc. Postoperative angiography confirmed successful decompression of the VA. PMID- 25932603 TI - Editorial: Biomechanical effects of interspinous process devices using a hybrid testing protocol. PMID- 25932604 TI - An involvement of SR-B1 mediated p38 MAPK signaling pathway in serum amyloid A induced angiogenesis in rheumatoid arthritis. AB - Serum amyloid A (SAA) has been reported high expression in autoimmune diseases, such as rheumatoid arthritis (RA). However, detailed molecular mechanisms induced by SAA in the pathogenesis of RA are still unclear. Herein, we focused on the role of SAA-SR-B1 mediated p38 MAPK signaling pathway in the process of RA angiogenesis. Our results showed that both SAA and SR-B1 predominantly localized to vascular endothelial cells, lining and sublining layers in RA synovium. In a series of in vitro experiments with human umbilical vein endothelial cells (HUVECs), SAA induced the endothelial cells (ECs) proliferation, migration and tube formation. However, blockage of SR-B1 and p38 MAPK inhibited SAA-induced cells proliferation, migration and tube formation. In conclusion, our data showed a possible molecular mechanism for SAA-SR-B1 induced angiogenesis events via p38 MAPK signaling pathway. PMID- 25932605 TI - Continuous intraputamenal convection-enhanced delivery in adult rhesus macaques. AB - OBJECT: Assessing the safety and feasibility of chronic delivery of compounds to the brain using convection-enhanced delivery (CED) is important for the further development of this important therapeutic technology. The objective of this study was to follow and model the distribution of a compound delivered by CED into the putamen of rhesus monkeys. METHODS: The authors sequentially implanted catheters into 4 sites spanning the left and right putamen in each of 6 rhesus monkeys. The catheters were connected to implanted pumps, which were programmed to deliver a 5 mM solution of the MRI contrast agent Gd-DTPA at 0.1 MUl/minute for 7 days and 0.3 MUl/minute for an additional 7 days. The animals were followed for 28 days per implant cycle during which they were periodically examined with MRI. RESULTS: All animals survived the 4 surgeries with no deficits in behavior. Compared with acute infusion, the volume of distribution (Vd) increased 2-fold with 7 days of chronic infusion. Increasing the flow rate 3-fold over the next week increased the Vd an additional 3-fold. Following withdrawal of the compound, the half-life of Gd-DTPA in the brain was estimated as 3.1 days based on first-order pharmacokinetics. Histological assessment of the brain showed minimal tissue damage limited to the insertion site. CONCLUSIONS: These results demonstrate several important features in the development of a chronically implanted pump and catheter system: 1) the ability to place catheters accurately in a predetermined target; 2) the ability to deliver compounds in a chronic fashion to the putamen; and 3) the use of MRI and MR visible tracers to follow the evolution of the infusion volume over time. PMID- 25932606 TI - Changes in glutamate receptors in dyskinetic parkinsonian monkeys after unilateral subthalamotomy. AB - OBJECT: Unilateral subthalamotomy is a surgical procedure that may be used to alleviate disabling levodopa-induced dyskinesias (LIDs) in patients with Parkinson disease (PD). However, the mechanisms involved in LID remain largely unknown. The subthalamic nucleus (STN) is the sole glutamatergic nucleus within the basal ganglia, and its lesion may produce changes in glutamate receptors in various areas of the basal ganglia. The authors aimed to investigate the biochemical changes in glutamate receptors in striatal and pallidal regions of the basal ganglia after lesion of the STN in parkinsonian macaque monkeys. METHODS: The authors treated 12 female ovariectomized monkeys with 1-methyl-4 phenyl-1,2,3,6-tetrahydropyridine (MPTP) to induce PD-like symptoms, treated 8 of these animals with 3,4-dihydroxy-l-phenylalanine (L-DOPA; levodopa) to induce LID, and performed unilateral subthalamotomy in 4 of these 8 monkeys. Four additional monkeys were treated with saline only and were used as controls. The MPTP monkeys had previously been shown to respond behaviorally to lower doses of levodopa after the STN lesion. Autoradiography of slices from postmortem brain tissues was used to visualize changes in the specific binding of striatal and pallidal ionotropic glutamate receptors (that is, of the alpha-amino-3-hydroxy 5 methyl-4-isoxazole propionate [AMPA] and N-methyl-d-aspartate [NMDA] NR1/NR2B subunit receptors) and of metabotropic glutamate (mGlu) receptors (that is, mGlu2/3 and mGlu5 receptors). The specific binding and distribution of glutamate receptors in the basal ganglia of the levodopa-treated, STN-lesioned MPTP monkeys were compared with those in the saline-treated control monkeys and in the saline treated and levodopa-treated MPTP monkeys. RESULTS: The autoradiographic results indicated that none of the pharmacological and surgical treatments produced changes in the specific binding of AMPA receptors in the basal ganglia. Levodopa treatment increased the specific binding of NMDA receptors in the basal ganglia. Subthalamotomy reversed these increases in the striatum, but in the globus pallidus (GP), the subthalamotomy reversed these increases only contralaterally. Levodopa treatment reversed MPTP-induced increases in mGlu2/3 receptors only in the GP. mGlu2/3 receptor-specific binding in the striatum and GP decreased bilaterally in the levodopa-treated, STN-lesioned MPTP monkeys compared with the other 3 groups. Compared with mGlu5 receptor-specific binding in the control monkeys, that of the levodopa-treated MPTP monkeys increased in the dorsal putamen and remained unchanged in the caudate nucleus and in the GP. CONCLUSIONS: These results implicate glutamate receptors in the previously observed benefits of unilateral subthalamotomy to improve motor control. PMID- 25932607 TI - Pineal cyst resection. PMID- 25932608 TI - Posterior interhemispheric transfalcine transprecuneus approach for microsurgical resection of periatrial lesions: indications, technique, and outcomes. AB - OBJECT: Surgical exposure of the peritrigonal or periatrial region has been challenging due to the depth of the region and overlying important functional cortices and white matter tracts. The authors demonstrate the operative feasibility of a contralateral posterior interhemispheric transfalcine transprecuneus approach (PITTA) to this region and present a series of patients treated via this operative route. METHODS: Fourteen consecutive patients underwent the PITTA and were included in this study. Pre- and postoperative clinical and radiological data points were retrospectively collected. Complications and extent of resection were reviewed. RESULTS: The mean age of patients at the time of surgery was 39 years (range 11-64 years). Six of the 14 patients were female. The mean duration of follow-up was 4.6 months (range 0.5 19.6 months). Pathology included 6 arteriovenous malformations, 4 gliomas, 2 meningiomas, 1 metastatic lesion, and 1 gray matter heterotopia. Based on the results shown on postoperative MRI, 1 lesion (7%) was intentionally subtotally resected, but >= 95% resection was achieved in all others (93%) and gross-total resection was accomplished in 7 (54%) of 13. One patient (7%) experienced a temporary approach-related complication. At last follow-up, 1 patient (7%) had died due to complications of his underlying malignancy unrelated to his cranial surgery, 2 (14%) demonstrated a Glasgow Outcome Scale (GOS) score of 4, and 11 (79%) manifested a GOS score of 5. CONCLUSIONS: Based on this patient series, the contralateral PITTA potentially offers numerous advantages, including a wider, safer operative corridor, minimal need for ipsilateral brain manipulation, and better intraoperative navigation and working angles. PMID- 25932609 TI - Preoperative identification of neurosurgery patients with a high risk of in hospital complications: a prospective cohort of 418 consecutive elective craniotomy patients. AB - OBJECT: Patients undergoing craniotomy are routinely assessed preoperatively, yet the role of these assessments in predicting outcome is poorly studied. This study aimed to identify preoperative factors predicting in-hospital outcome after cranial neurosurgery. METHODS: The study cohort consisted of 418 consecutive adults undergoing elective craniotomy for any intracranial lesion. Apart from the age criteria (>= 18 years), almost all patients were considered eligible for the study to increase external validity of the results. The studied preoperative assessments included various patient-related data, routine blood tests, American Society of Anesthesiologists (ASA) Physical Status Classification system, and a local modification of the ASA classification (Helsinki ASA classification). Adverse outcomes were in-hospital mortality, in-hospital systemic or infectious complications, and in-hospital CNS deficits. Resource use was defined as length of stay (LOS) in the intensive care unit and overall LOS in the hospital. RESULTS: The in-hospital mortality rate was 1.0%. In-hospital systemic or infectious complications and permanent or transient CNS deficits occurred in 6.7% and 11.2% of the patients, respectively. Advanced age (>= 60-65 years), elevated C-reactive protein level (> 3 mg/L), and high Helsinki ASA score (Class 4) were associated with in-hospital systemic and infectious complications, and a combination of these could identify one-fourth of the patients with postoperative complications. Moreover, this combination of preoperative assessment parameters was significantly associated with increased resource use. CONCLUSIONS: In this first prospective and unselected cohort study of outcome after elective craniotomy, simple preoperative assessments identified patients with a high risk of in-hospital systemic or infectious complications as well as extended resource use. Presented risk assessment methods may be widely applicable, also in low volume centers, as they are based on composite predictors and outcome events. PMID- 25932610 TI - Pineal cyst resection in the absence of ventriculomegaly or Parinaud's syndrome: clinical outcomes and implications for patient selection. AB - OBJECT: Surgical indications for patients with pineal cysts are controversial. While the majority of patients harboring a pineal cyst require no treatment, surgery is a well-accepted option for a subset of those patients with secondary hydrocephalus or Parinaud's syndrome. The majority of pineal cysts are identified incidentally during workup for other potential conditions, which may or may not be related to the presence of the cyst. In the absence of clear obstruction of CSF pathways, the treatment of presumed symptomatic pineal cysts is debatable. To clarify the role of surgery in these borderline cases, the authors reviewed their experience with resection of pineal cysts in the absence of ventriculomegaly or Parinaud's syndrome. METHODS: The authors retrospectively reviewed medical records and imaging of all patients surgically treated between 2001 and 2014 with a pineal cyst in the absence of ventriculomegaly and Parinaud's syndrome. The presenting symptoms, preoperative cyst size, preoperative radiographic aqueductal compression, extent of resection, and radiographic and clinical follow-up were documented. RESULTS: Eighteen patients (14 female and 4 male; mean age 24 years, range 4-47 years) underwent cyst resection in the absence of ventriculomegaly or Parinaud's syndrome. Presenting symptoms included headache (17 patients), visual disturbances (10 patients), gait instability (5 patients), dizziness (5 patients), episodic loss of consciousness (2 patients), and hypersomnolence (1 patient). The mean preoperative cyst diameter was 1.5 cm (range 0.9-2.2 cm). All patients had a complete resection. At a mean clinical follow-up of 19.1 months (range postoperative to 71 months), 17 (94%) patients had resolution or improvement of their presenting symptoms. CONCLUSIONS: The authors' results suggest that ventriculomegaly and Parinaud's syndrome are not absolute requisites for a pineal cyst to be symptomatic. Analogous to colloid cysts of the third ventricle, intermittent occlusion of cerebrospinal fluid pathways may cause small pineal cysts to become intermittently symptomatic. A select cohort of patients with pineal cysts may benefit from surgery despite a lack of hydrocephalus or other obvious compressive pathology. PMID- 25932611 TI - Contralateral transfalcine approach for peritrigonal lesions. PMID- 25932612 TI - The incidence of high-frequency hearing loss after microvascular decompression for trigeminal neuralgia, glossopharyngeal neuralgia, or geniculate neuralgia. AB - OBJECT: The primary aim of this study was to evaluate the incidence and discuss the pathogenesis of high-frequency hearing loss (HFHL) after microvascular decompression (MVD) for trigeminal neuralgia (TGN), glossopharyngeal neuralgia (GPN), or geniculate neuralgia (GN). METHODS: The authors analyzed preoperative and postoperative audiogram data and brainstem auditory evoked potentials (BAEPs) from 93 patients with TGN, 6 patients with GPN, and 8 patients with GN who underwent MVD. Differences in pure tone audiometry > 10 dB at frequencies of 0.25, 0.5, 1, 2, 4, and 8 kHz were calculated preoperatively and postoperatively for both the ipsilateral and the contralateral sides. Intraoperative monitoring records were analyzed and compared with the incidence of HFHL, which was defined as a change in pure tone audiometry > 10 dB at frequencies of 4 and 8 kHz. RESULTS: The incidence of HFHL was 30.84% on the side ipsilateral to the surgery and 20.56% on the contralateral side. Of the 47 patients with HFHL, 20 had conductive hearing loss, and 2 experienced nonserviceable hearing loss after the surgery. The incidences of HFHL on the ipsilateral side at 4 and 8 kHz were 17.76% and 25.23%, respectively, and 8.41% and 15.89%, respectively, on the contralateral side. As the audiometric frequency increased, the number of patients with hearing loss increased. No significant postoperative difference was found between patients with and without HFHL in intraoperative BAEP waveforms. Sex, age, and affected side were not associated with an increase in the incidence of hearing loss. CONCLUSIONS: High-frequency hearing loss occurred after MVD for TGN, GPN, or GN, and the greatest incidence occurred on the ipsilateral side. This hearing loss may be a result of drill-induced noise and/or transient loss of cerebrospinal fluid during the course of the procedure. Changes in intraoperative BAEP waveforms were not useful in predicting HFHL after MVD. Repeated postoperative audiological examinations may be useful in assessing the prognosis of HFHL. PMID- 25932613 TI - First application of quantum annealing to IMRT beamlet intensity optimization. AB - Optimization methods are critical to radiation therapy. A new technology, quantum annealing (QA), employs novel hardware and software techniques to address various discrete optimization problems in many fields. We report on the first application of quantum annealing to the process of beamlet intensity optimization for IMRT. We apply recently-developed hardware which natively exploits quantum mechanical effects for improved optimization. The new algorithm, called QA, is most similar to simulated annealing, but relies on natural processes to directly minimize a system's free energy. A simple quantum system is slowly evolved into a classical system representing the objective function. If the evolution is sufficiently slow, there are probabilistic guarantees that a global minimum will be located. To apply QA to IMRT-type optimization, two prostate cases were considered. A reduced number of beamlets were employed, due to the current QA hardware limitations. The beamlet dose matrices were computed using CERR and an objective function was defined based on typical clinical constraints, including dose-volume objectives, which result in a complex non-convex search space. The objective function was discretized and the QA method was compared to two standard optimization methods, simulated annealing and Tabu search, run on a conventional computing cluster. Based on several runs, the average final objective function value achieved by the QA was 16.9 for the first patient, compared with 10.0 for Tabu and 6.7 for the simulated annealing (SA) method. For the second patient, the values were 70.7 for the QA, 120.0 for Tabu and 22.9 for the SA. The QA algorithm required 27-38% of the time required by the other two methods. In this first application of hardware-enabled QA to IMRT optimization, its performance is comparable to Tabu search, but less effective than the SA in terms of final objective function values. However, its speed was 3-4 times faster than the other two methods. This initial experiment suggests that more research into QA-based heuristics may offer significant speedup over conventional clinical optimization methods, as quantum annealing hardware scales to larger sizes. PMID- 25932614 TI - The Madrid Statement on Poly- and Perfluoroalkyl Substances (PFASs). PMID- 25932615 TI - Electrochemical behavior of thin-film Sm-doped ceria: insights from the point contact configuration. AB - The electrochemical behavior of chemical vapor deposition (CVD) grown porous films of Sm-doped ceria (SDC) for hydrogen oxidation has been evaluated by impedance spectroscopy using a point contact geometry at a temperature of 650 degrees C. Porous SDC films, 950 nm in thickness, were deposited on both sides of single-crystal YSZ(100). Pt paste was applied over the surface of one SDC layer to create a high-activity counter electrode. Ni wire was contacted to the surface of the other SDC layer to create a limited contact-area working electrode. The active area of contact at the working electrode was determined using the Newman equation and the electrolyte constriction impedance. The radius of this area varied from 5 to 18 MUm, depending on gas composition and bias. The area normalized electrode impedance (where the area was that determined as described above) varied from 0.03 to 0.17 Omega cm(2) and generally decreased with cathodic bias and decreasing oxygen partial pressure. From an analysis of the dimensions of the active area with bias, it was found that the majority of the overpotential occurred at the SDC|gas interface rather than the SDC|YSZ interface. Overall, the anode overpotential is found to be extremely small, competitive with the best oxide anodes reported in the literature. Nevertheless, the impedance falls in line with expected values based on extrapolations of the properties of dense, flat SDC model electrodes grown by pulsed laser deposition (Chueh et al., Nat. Mater., 2012). The results demonstrate that, with suitable fabrication approaches, exceptional activity can be achieved with SDC for hydrogen electrooxidation even in the absence of metal-oxide-gas triple phase boundaries. PMID- 25932616 TI - Soil-foraging animals alter the composition and co-occurrence of microbial communities in a desert shrubland. AB - Animals that modify their physical environment by foraging in the soil can have dramatic effects on ecosystem functions and processes. We compared bacterial and fungal communities in the foraging pits created by bilbies and burrowing bettongs with undisturbed surface soils dominated by biocrusts. Bacterial communities were characterized by Actinobacteria and Alphaproteobacteria, and fungal communities by Lecanoromycetes and Archaeosporomycetes. The composition of bacterial or fungal communities was not observed to vary between loamy or sandy soils. There were no differences in richness of either bacterial or fungal operational taxonomic units (OTUs) in the soil of young or old foraging pits, or undisturbed soils. Although the bacterial assemblage did not vary among the three microsites, the composition of fungi in undisturbed soils was significantly different from that in old or young foraging pits. Network analysis indicated that a greater number of correlations between bacterial OTUs occurred in undisturbed soils and old pits, whereas a greater number of correlations between fungal OTUs occurred in undisturbed soils. Our study suggests that digging by soil-disturbing animals is likely to create successional shifts in soil microbial and fungal communities, leading to functional shifts associated with the decomposition of organic matter and the fixation of nitrogen. Given the primacy of organic matter decomposition in arid and semi-arid environments, the loss of native soil-foraging animals is likely to impair the ability of these systems to maintain key ecosystem processes such as the mineralization of nitrogen and the breakdown of organic matter, and to recover from disturbance. PMID- 25932617 TI - Contrasting taxonomic stratification of microbial communities in two hypersaline meromictic lakes. AB - Hypersaline meromictic lakes are extreme environments in which water stratification is associated with powerful physicochemical gradients and high salt concentrations. Furthermore, their physical stability coupled with vertical water column partitioning makes them important research model systems in microbial niche differentiation and biogeochemical cycling. Here, we compare the prokaryotic assemblages from Ursu and Fara Fund hypersaline meromictic lakes (Transylvanian Basin, Romania) in relation to their limnological factors and infer their role in elemental cycling by matching taxa to known taxon-specific biogeochemical functions. To assess the composition and structure of prokaryotic communities and the environmental factors that structure them, deep-coverage small subunit (SSU) ribosomal RNA (rDNA) amplicon sequencing, community domain specific quantitative PCR and physicochemical analyses were performed on samples collected along depth profiles. The analyses showed that the lakes harbored multiple and diverse prokaryotic communities whose distribution mirrored the water stratification patterns. Ursu Lake was found to be dominated by Bacteria and to have a greater prokaryotic diversity than Fara Fund Lake that harbored an increased cell density and was populated mostly by Archaea within oxic strata. In spite of their contrasting diversity, the microbial populations indigenous to each lake pointed to similar physiological functions within carbon degradation and sulfate reduction. Furthermore, the taxonomy results coupled with methane detection and its stable C isotope composition indicated the presence of a yet undescribed methanogenic group in the lakes' hypersaline monimolimnion. In addition, ultrasmall uncultivated archaeal lineages were detected in the chemocline of Fara Fund Lake, where the recently proposed Nanohaloarchaeota phylum was found to thrive. PMID- 25932618 TI - Bilateral brain reorganization with memantine and constraint-induced aphasia therapy in chronic post-stroke aphasia: An ERP study. AB - Changes in ERP (P100 and N400) and root mean square (RMS) were obtained during a silent reading task in 28 patients with chronic post-stroke aphasia in a randomized, double-blind, placebo-controlled trial of both memantine and constraint-induced aphasia therapy (CIAT). Participants received memantine/placebo alone (weeks 0-16), followed by drug treatment combined with CIAT (weeks 16-18), and then memantine/placebo alone (weeks 18-20). ERP/RMS values (week 16) decreased more in the memantine group than in the placebo group. During CIAT application (weeks 16-18), improvements in aphasia severity and ERP/RMS values were amplified by memantine and changes remained stable thereafter (weeks 18-20). Changes in ERP/RMS occurred in left and right hemispheres and correlated with gains in language performance. No changes in ERP/RMS were found in a healthy group in two separated evaluations. Our results show that aphasia recovery induced by both memantine alone and in combination with CIAT is indexed by bilateral cortical potentials. PMID- 25932620 TI - 11th International Conference on Conservative Management of Spinal Deformities - SOSORT. PMID- 25932619 TI - Skeletal rearrangement of O-propargylic formaldoximes by a gold-catalyzed cyclization/intermolecular methylene transfer sequence. AB - Skeletal rearrangement of O-propargylic formaldoximes, in the presence of gold catalysts, afforded 4-methylene-2-isoxazolines in good to excellent yields by an intermolecular methylene transfer. In addition, the cascade reaction with maleimide in the presence of a gold catalyst afforded isoxazole derivatives by cyclization/methylene transfer and a subsequent ene reaction, whereas that using a copper catalyst gave oxazepines through a 2,3-rearrangement. PMID- 25932621 TI - 3rd WAO International Scientific Conference (WISC) 2014. PMID- 25932622 TI - Bicyclic Guanidine Catalyzed Asymmetric Tandem Isomerization Intramolecular-Diels Alder Reaction: The First Catalytic Enantioselective Total Synthesis of (+)-alpha Yohimbine. AB - Hydroisoquinoline derivatives were prepared in moderate to good enantioselectivities via a bicyclic guanidine-catalyzed tandem isomerization intramolecular-Diels-Alder (IMDA) reaction of alkynes. With this synthetic method, the first enantioselective synthesis of (+)-alpha-yohimbine was completed in 9 steps from the IMDA products. PMID- 25932623 TI - One-Step, Facile and Ultrafast Synthesis of Phase- and Size-Controlled Pt-Bi Intermetallic Nanocatalysts through Continuous-Flow Microfluidics. AB - Ordered intermetallic nanomaterials are of considerable interest for fuel cell applications because of their unique electronic and structural properties. The synthesis of intermetallic compounds generally requires the use of high temperatures and multiple-step processes. The development of techniques for rapid phase- and size-controlled synthesis remains a formidable challenge. The intermetallic compound Pt1Bi2 is a promising candidate catalyst for direct methanol fuel cells because of its high catalytic activity and excellent methanol tolerance. In this work, we explored a one-step, facile and ultrafast phase- and size-controlled process for synthesizing ordered Pt-Bi intermetallic nanoparticles (NPs) within seconds in microfluidic reactors. Single-phase Pt1Bi1 and Pt1Bi2 intermetallic NPs were prepared by tuning the reaction temperature, and size control was achieved by modifying the solvents and the length of the reaction channel. The as-prepared Pt-Bi intermetallic NPs exhibited excellent methanol tolerance capacity and high electrocatalytic activity. Other intermetallic nanomaterials, such as Pt3Fe intermetallic nanowires with a diameter of 8.6 nm and Pt1Sn1 intermetallic nanowires with a diameter of 6.3 nm, were also successfully synthesized using this method, thus demonstrating its feasibility and generality. PMID- 25932624 TI - Tracking organophosphates: new method for assessing long-term dietary exposures. PMID- 25932625 TI - Does pelvic floor muscle training augment the effect of surgery in women with pelvic organ prolapse? A systematic review of randomized controlled trials. AB - BACKGROUND: Pelvic floor muscle training (PFMT) is often used as a treatment for pelvic organ prolapse (POP) and can improve function. However, the effectiveness of this modality as an adjunct to prolapse surgery for women with POP is unknown. AIMS: To evaluate whether the use of pelvic floor muscle training as an adjunct to prolapse surgery is superior to surgery alone for women with pelvic organ prolapse. METHODS: We searched PubMed, Embase, the Cochrane Library, and the Web of Science from their inception dates to June 30, 2014 for data describing randomized controlled trials (RCTs) that compare the efficacy of PFMT with or without lifestyle modification plus surgery versus surgery alone for women with POP. Additional relevant studies were identified by searching the references of retrieved articles and using Google Scholar. Two investigators independently reviewed and selected relevant studies that met the pre-specified inclusion criteria, extracted the data, and assessed the risk of bias in the included studies according to the Cochrane Handbook, version 5.1.0. Due to great heterogeneity in the choice and reporting of outcome measures and the different durations of follow-up among the studies, this analysis is confined to a qualitative systematic review. RESULTS: Five RCTs involving 591 women were reviewed (treatment group [TG], 292 cases; control group [CG], 299 cases). Generally, the five RCTs exhibited low risk of bias. This study indicated no significant improvement in prolapse symptoms, in quality of life, or in the degree of prolapse for women with POP in the TG compared to those in the CG. CONCLUSIONS: Insufficient evidence was found to support adding perioperative PFMT to surgery over the use of surgery alone in women undergoing surgery for POP. Adequately, powered RCTs with longer follow-up periods are required to evaluate the long-term effect of perioperative PFMT. Neurourol. Urodynam. 35:666-674, 2016. (c) 2015 Wiley Periodicals, Inc. PMID- 25932626 TI - Co-medication of statins with contraindicated drugs. AB - BACKGROUND: The concomitant use of cytochrome P450 3A4 (CYP3A4) metabolized statins (simvastatin, lovastatin, and atorvastatin) with CYP3A4 inhibitors has been shown to increase the rate of adverse events. OBJECTIVE: This study was performed to describe the co-medication prevalence of CYP3A4-metabolized statins with contraindicated drugs. METHODS: The patients aged 40 or older receiving CYP3A4-metabolized statin prescriptions in 2009 were identified using the national patient sample from a Korea Health Insurance Review and Assessment Service database. Contraindicated co-medication was defined as prescription periods of statins and contraindicated drugs overlapping by at least one day. Co medication patterns were classified into 3 categories as follows: co-medication in the same prescription, co-medication by the same medical institution, and co medication by different medical institutions. The proportion of co-medication was analyzed by age, gender, co-morbidities, and the statin's generic name. RESULTS: A total of 2,119,401 patients received CYP3A4-metabolized statins and 60,254 (2.84%) patients were co-medicated with contraindicated drugs. The proportion of co-medication was 4.6%, 2.2%, and 1.8% in simvastatin, lovastatin, and atorvastatin users, respectively. The most frequent combination was atorvastatin itraconazole, followed by simvastatin-clarithromycin and simvastatin itraconazole. Among the co-medicated patients, 85.3% were prescribed two drugs by different medical institutions. CONCLUSION: The proportion of co-medication of statins with contraindicated drugs was relatively lower than that of previous studies; however, the co-medication occurring by different medical institutions was not managed appropriately. There is a need to develop an effective system and to conduct outcomes research confirming the association between co-medication and the risk of unfavorable clinical outcomes. PMID- 25932627 TI - Validation of a P-Glycoprotein (P-gp) Humanized Mouse Model by Integrating Selective Absolute Quantification of Human MDR1, Mouse Mdr1a and Mdr1b Protein Expressions with In Vivo Functional Analysis for Blood-Brain Barrier Transport. AB - It is essential to establish a useful validation method for newly generated humanized mouse models. The novel approach of combining our established species specific protein quantification method combined with in vivo functional studies is evaluated to validate a humanized mouse model of P-gp/MDR1 efflux transporter. The P-gp substrates digoxin, verapamil and docetaxel were administered to male FVB Mdr1a/1b(+/+) (FVB WT), FVB Mdr1a/1b(-/-) (Mdr1a/1b(-/-)), C57BL/6 Mdr1a/1b(+/+) (C57BL/6 WT) and humanized C57BL (hMDR1) mice. Brain-to-plasma total concentration ratios (Kp) were measured. Quantitative targeted absolute proteomic (QTAP) analysis was used to selectively quantify the protein expression levels of hMDR1, Mdr1a and Mdr1b in the isolated brain capillaries. The protein expressions of other transporters, receptors and claudin-5 were also quantified. The Kp for digoxin, verapamil, and docetaxel were 20, 30 and 4 times higher in the Mdr1a/1b(-/-) mice than in the FVB WT controls, as expected. The Kp for digoxin, verapamil and docetaxel were 2, 16 and 2-times higher in the hMDR1 compared to the C57BL/6 WT mice. The hMDR1 mice had 63- and 9.1-fold lower expressions of the hMDR1 and Mdr1a proteins than the corresponding expression of Mdr1a in C57BL/6 WT mice, respectively. The protein expression levels of other molecules were almost consistent between C57BL/6 WT and hMDR1 mice. The P-gp function at the BBB in the hMDR1 mice was smaller than that in WT mice due to lower protein expression levels of hMDR1 and Mdr1a. The combination of QTAP and in vivo functional analyses was successfully applied to validate the humanized animal model and evaluates its suitability for further studies. PMID- 25932628 TI - Plant fertilization interacts with life history: variation in stoichiometry and performance in nettle-feeding butterflies. AB - Variation in food stoichiometry affects individual performance and population dynamics, but it is also likely that species with different life histories should differ in their sensitivity to food stoichiometry. To address this question, we investigated the ability of the three nettle-feeding butterflies (Aglais urticae, Polygonia c-album, and Aglais io) to respond adaptively to induced variation in plant stoichiometry in terms of larval performance. We hypothesized that variation in larval performance between plant fertilization treatments should be functionally linked to species differences in host plant specificity. We found species-specific differences in larval performance between plant fertilization treatments that could not be explained by nutrient limitation. We showed a clear evidence of a positive correlation between food stoichiometry and development time to pupal stage and pupal mass in A. urticae. The other two species showed a more complex response. Our results partly supported our prediction that host plant specificity affects larval sensitivity to food stoichiometry. However, we suggest that most of the differences observed may instead be explained by differences in voltinism (number of generations per year). We believe that the potential of some species to respond adaptively to variation in plant nutrient content needs further attention in the face of increased eutrophication due to nutrient leakage from human activities. PMID- 25932629 TI - Toward Probabilistic Diagnosis and Understanding of Depression Based on Functional MRI Data Analysis with Logistic Group LASSO. AB - Diagnosis of psychiatric disorders based on brain imaging data is highly desirable in clinical applications. However, a common problem in applying machine learning algorithms is that the number of imaging data dimensions often greatly exceeds the number of available training samples. Furthermore, interpretability of the learned classifier with respect to brain function and anatomy is an important, but non-trivial issue. We propose the use of logistic regression with a least absolute shrinkage and selection operator (LASSO) to capture the most critical input features. In particular, we consider application of group LASSO to select brain areas relevant to diagnosis. An additional advantage of LASSO is its probabilistic output, which allows evaluation of diagnosis certainty. To verify our approach, we obtained semantic and phonological verbal fluency fMRI data from 31 depression patients and 31 control subjects, and compared the performances of group LASSO (gLASSO), and sparse group LASSO (sgLASSO) to those of standard LASSO (sLASSO), Support Vector Machine (SVM), and Random Forest. Over 90% classification accuracy was achieved with gLASSO, sgLASSO, as well as SVM; however, in contrast to SVM, LASSO approaches allow for identification of the most discriminative weights and estimation of prediction reliability. Semantic task data revealed contributions to the classification from left precuneus, left precentral gyrus, left inferior frontal cortex (pars triangularis), and left cerebellum (c rus1). Weights for the phonological task indicated contributions from left inferior frontal operculum, left post central gyrus, left insula, left middle frontal cortex, bilateral middle temporal cortices, bilateral precuneus, left inferior frontal cortex (pars triangularis), and left precentral gyrus. The distribution of normalized odds ratios further showed, that predictions with absolute odds ratios higher than 0.2 could be regarded as certain. PMID- 25932630 TI - Prohibitin Is Involved in Patients with IgG4 Related Disease. AB - OBJECTIVE: IgG4-related disease (IgG4-RD) is a chronic systemic disease involved in many organs and tissues. As only limited autoantigens have been found since the beginning of this century, the aim of this study was to reveal new candidate autoantigens of IgG4-RD. METHODS: Multiple cell lines including HT-29, EA.hy926, HEK 293 and HepG2 were used to test the binding ability of circulating autoantibodies from IgG4-RD sera. The amino-acid sequence was then analyzed by matrix-assisted laser desorption/ionization time-of-flight tandem (MALDI-TOF/TOF) mass spectrometry. After the cloning and expression of recombinant putative autoantigen in a bacterial expression system, the corresponding immuno assay was set up and utilized to observe the prevalence of serum autoantibodies in a large set of confirmed clinical samples. RESULTS: One positive autoantigen was identified as prohibitin. ELISA analysis showed that a majority of patients with IgG4-RD have antibodies against prohibitin. Anti-prohibitin antibodies were present in the sera of patients with definite autoimmune pancreatitis (25/34; 73.5%), Mikulicz's disease (8/15; 53.3%), retroperitoneal fibrosis (6/11; 54.5%), other probable IgG4-RD (26/29; 89.7%) and Sjogren's syndrome (4/30; 13.3%) but not in apparently healthy donors (1/70; 1.4%). CONCLUSIONS: An association between prohibitin and patients with some IgG4-RD was observed, although the results were quite heterogeneous among different individuals within autoimmune pancreatitis, Mikulicz's disease and retroperitoneal fibrosis. PMID- 25932631 TI - The Structure of the T190M Mutant of Murine alpha-Dystroglycan at High Resolution: Insight into the Molecular Basis of a Primary Dystroglycanopathy. AB - The severe dystroglycanopathy known as a form of limb-girdle muscular dystrophy (LGMD2P) is an autosomal recessive disease caused by the point mutation T192M in alpha-dystroglycan. Functional expression analysis in vitro and in vivo indicated that the mutation was responsible for a decrease in posttranslational glycosylation of dystroglycan, eventually interfering with its extracellular matrix receptor function and laminin binding in skeletal muscle and brain. The X ray crystal structure of the missense variant T190M of the murine N-terminal domain of alpha-dystroglycan (50-313) has been determined, and showed an overall topology (Ig-like domain followed by a basket-shaped domain reminiscent of the small subunit ribosomal protein S6) very similar to that of the wild-type structure. The crystallographic analysis revealed a change of the conformation assumed by the highly flexible loop encompassing residues 159-180. Moreover, a solvent shell reorganization around Met190 affects the interaction between the B1 B5 anti-parallel strands forming part of the floor of the basket-shaped domain, with likely repercussions on the folding stability of the protein domain(s) and on the overall molecular flexibility. Chemical denaturation and limited proteolysis experiments point to a decreased stability of the T190M variant with respect to its wild-type counterpart. This mutation may render the entire L shaped protein architecture less flexible. The overall reduced flexibility and stability may affect the functional properties of alpha-dystroglycan via negatively influencing its binding behavior to factors needed for dystroglycan maturation, and may lay the molecular basis of the T190M-driven primary dystroglycanopathy. PMID- 25932632 TI - An Atomic Force Microscope Study Revealed Two Mechanisms in the Effect of Anticancer Drugs on Rate-Dependent Young's Modulus of Human Prostate Cancer Cells. AB - Mechanical properties of cells have been recognized as a biomarker for cellular cytoskeletal organization. As chemical treatments lead to cell cytoskeletal rearrangements, thereby, modifications of cellular mechanical properties, investigating cellular mechanical property variations provides insightful knowledge to effects of chemical treatments on cancer cells. In this study, the effects of eight different anticancer drugs on the mechanical properties of human prostate cancer cell (PC-3) are investigated using a recently developed control based nanoindentation measurement (CNM) protocol on atomic force microscope (AFM). The CNM protocol overcomes the limits of other existing methods to in liquid nanoindentation measurement of live cells on AFM, particularly for measuring mechanical properties of live cells. The Young's modulus of PC-3 cells treated by the eight drugs was measured by varying force loading rates over three orders of magnitude, and compared to the values of the control. The results showed that the Young's modulus of the PC-3 cells increased substantially by the eight drugs tested, and became much more pronounced as the force load rate increased. Moreover, two distinct trends were clearly expressed, where under the treatment of Disulfiram, paclitaxel, and MK-2206, the exponent coefficient of the frequency- modulus function remained almost unchanged, while with Celebrex, BAY, Totamine, TPA, and Vaproic acid, the exponential rate was significantly increased. PMID- 25932633 TI - Salt Tolerant and Sensitive Rice Varieties Display Differential Methylome Flexibility under Salt Stress. AB - DNA methylation has been referred as an important player in plant genomic responses to environmental stresses but correlations between the methylome plasticity and specific traits of interest are still far from being understood. In this study, we inspected global DNA methylation levels in salt tolerant and sensitive rice varieties upon salt stress imposition. Global DNA methylation was quantified using the 5-methylcytosine (5mC) antibody and an ELISA-based technique, which is an affordable and quite pioneer assay in plants, and in situ imaging of methylation sites in interphase nuclei of tissue sections. Variations of global DNA methylation levels in response to salt stress were tissue- and genotype-dependent. We show a connection between a higher ability of DNA methylation adjustment levels and salt stress tolerance. The salt-tolerant rice variety Pokkali was remarkable in its ability to quickly relax DNA methylation in response to salt stress. In spite of the same tendency for reduction of global methylation under salinity, in the salt-sensitive rice variety IR29 such reduction was not statistically supported. In 'Pokkali', the salt stress-induced demethylation may be linked to active demethylation due to increased expression of DNA demethylases under salt stress. In 'IR29', the induction of both DNA demethylases and methyltransferases may explain the lower plasticity of DNA methylation. We further show that mutations for epigenetic regulators affected specific phenotypic parameters related to salinity tolerance, such as the root length and biomass. This work emphasizes the role of differential methylome flexibility between salt tolerant and salt sensitive rice varieties as an important player in salt stress tolerance, reinforcing the need to better understand the connection between epigenetic networks and plant responses to environmental stresses. PMID- 25932634 TI - Is 'self-medication' a useful term to retrieve related publications in the literature? A systematic exploration of related terms. AB - BACKGROUND: Self-Medication (SM), i.e. using medications to treat oneself, is a major concern for health researchers and policy makers. The terms "self medication" or "self-medication" (SM terms) have been used to explain various concepts while several terms have also been employed to define this practice. Hence, retrieving relevant publications would require exhaustive literature screening. So, we assessed the current situation of SM terms in the literature to improve the relevancy of search outcomes. METHODS: In this Systematic exploration, SM terms were searched in the 6 following databases and publisher's portals till April 2012: Web of Science, Scopus, PubMed, Google scholar, ScienceDirect, and Wiley. A simple search query was used to include only publications with SM terms. We used Relative-Risk (RR) to estimate the probability of SM terms use in related compared to unrelated publications. Sensitivity and specificity of SM terms as keywords in search query were also calculated. Relevant terms to SM practice were extracted and their Likelihood Ratio positive and negative (LR+/-) were calculated to assess their effect on the probability of search outcomes relevancy in addition to previous search queries. We also evaluated the content of unrelated publications. All mentioned steps were performed in title (TI) and title or abstract (TIAB) of publications. RESULTS: 1999 related and 1917 unrelated publications were found. SM terms RR was 4.5 in TI and 2.1 in TIAB. SM terms sensitivity and specificity respectively were 55.4% and 87.7% in TI and 84.0% and 59.5% in TIAB. "OTC" and "Over-The-Counter Medication", with LR+ 16.78 and 16.30 respectively, provided the most conclusive increase in the probability of the relevancy of publications. The most common unrelated SM themes were self-medication hypothesis, drug abuse and Zoopharmacognosy. CONCLUSIONS: Due to relatively low specificity or sensitivity of SM terms, relevant terms should be employed in search queries and clear definitions of SM applications should be applied to improve the relevancy of publications. PMID- 25932635 TI - Node Survival in Networks under Correlated Attacks. AB - We study the interplay between correlations, dynamics, and networks for repeated attacks on a socio-economic network. As a model system we consider an insurance scheme against disasters that randomly hit nodes, where a node in need receives support from its network neighbors. The model is motivated by gift giving among the Maasai called Osotua. Survival of nodes under different disaster scenarios (uncorrelated, spatially, temporally and spatio-temporally correlated) and for different network architectures are studied with agent-based numerical simulations. We find that the survival rate of a node depends dramatically on the type of correlation of the disasters: Spatially and spatio-temporally correlated disasters increase the survival rate; purely temporally correlated disasters decrease it. The type of correlation also leads to strong inequality among the surviving nodes. We introduce the concept of disaster masking to explain some of the results of our simulations. We also analyze the subsets of the networks that were activated to provide support after fifty years of random disasters. They show qualitative differences for the different disaster scenarios measured by path length, degree, clustering coefficient, and number of cycles. PMID- 25932636 TI - The Induction of IL-33 in the Sinus Epithelium and Its Influence on T-Helper Cell Responses. AB - BACKGROUND: Chronic rhinosinusitis (CRS) is characterized by epithelial activation and chronic T-cell infiltration in sinonasal mucosa and nasal polyps. IL-33 is a new cytokine of the IL-1 cytokine family that has a pro-inflammatory and Th2 type cytokine induction property. The role of IL-33 in the pathomechanisms of CRS and its interaction with other T cell subsets remain to be fully understood. METHODS: The main trigger for IL-33 mRNA expression in primary human sinonasal epithelial cells was determined in multiple cytokine and T-cell stimulated cultures. The effects of IL-33 on naive, Th0 and memory T-cells was studied by PCR, ELISA and flow cytometry. Biopsies from sinus tissue were analyzed by PCR and immunofluorescence for the presence of different cytokines and receptors with a special focus on IL-33. RESULTS: IL-33 was mainly induced by IFN-gamma in primary sinonasal epithelial cells, and induced a typical CRSwNP Th2 favoring cytokine profile upon co-culture with T-helper cell subsets. IL-33 and its receptor ST2 were highly expressed in the inflamed epithelial tissue of CRS patients. While IL-33 was significantly up-regulated in the epithelium for CRSsNP, its receptor was higher expressed in sinus tissue from CRSwNP. CONCLUSIONS: The present study delineates the influence of IL-33 in upper airway epithelium and a potential role of IL-33 in chronic inflammation of CRSwNP by enhancing Th2 type cytokine production, which could both contribute to a further increase of an established Th2 profile in CRSwNP. PMID- 25932637 TI - Strategic lesions in the anterior thalamic radiation and apathy in early Alzheimer's disease. AB - BACKGROUND: Behavioural disorders and psychological symptoms of Dementia (BPSD) are commonly observed in Alzheimer's disease (AD), and strongly contribute to increasing patients' disability. Using voxel-lesion-symptom mapping (VLSM), we investigated the impact of white matter lesions (WMLs) on the severity of BPSD in patients with amnestic mild cognitive impairment (a-MCI). METHODS: Thirty-one a MCI patients (with a conversion rate to AD of 32% at 2 year follow-up) and 26 healthy controls underwent magnetic resonance imaging (MRI) examination at 3T, including T2-weighted and fluid-attenuated-inversion-recovery images, and T1 weighted volumes. In the patient group, BPSD was assessed using the Neuropsychiatric Inventory-12. After quantitative definition of WMLs, their distribution was investigated, without an a priori anatomical hypothesis, against patients' behavioural symptoms. Unbiased regional grey matter volumetrics was also used to assess the contribution of grey matter atrophy to BPSD. RESULTS: Apathy, irritability, depression/dysphoria, anxiety and agitation were shown to be the most common symptoms in the patient sample. Despite a more widespread anatomical distribution, a-MCI patients did not differ from controls in WML volumes. VLSM revealed a strict association between the presence of lesions in the anterior thalamic radiations (ATRs) and the severity of apathy. Regional grey matter atrophy did not account for any BPSD. CONCLUSIONS: This study indicates that damage to the ATRs is strategic for the occurrence of apathy in patients with a-MCI. Disconnection between the prefrontal cortex and the mediodorsal and anterior thalamic nuclei might represent the pathophysiological substrate for apathy, which is one of the most common psychopathological symptoms observed in dementia. PMID- 25932638 TI - Acute heat stress induces differential gene expressions in the testes of a broiler-type strain of Taiwan country chickens. AB - The expression of testicular genes following acute heat stress has been reported in layer-type roosters, but few similar studies have been conducted on broilers. This study investigated the effect of acute heat stress on the gene expression in the testes of a broiler-type strain of Taiwan country chickens. Roosters were subjected to acute heat stress (38 degrees C) for 4 h, and then exposed to 25 degrees C, with testes collected 0, 2, and 6 h after the cessation of heat stress, using non-heat-stressed roosters as controls (n = 3 roosters per group). The body temperature and respiratory rate increased significantly (p<0.05) during the heat stress. The numbers of apoptotic cells increased 2 h after the acute heat stress (79 +/- 7 vs. 322 +/- 192, control vs. heat stress; p<0.05), which was earlier than the time of increase in layer-type roosters. Based on a chicken 44 K oligo microarray, 163 genes were found to be expressed significantly different in the testes of the heat-stressed chickens from those of the controls, including genes involved in the response to stimulus, protein metabolism, signal transduction, cell adhesion, transcription, and apoptosis. The mRNA expressions of upregulated genes, including HSP25, HSP90AA1, HSPA2, and LPAR2, and of downregulated genes, including CDH5, CTNNA3, EHF, CIRBP, SLA, and NTF3, were confirmed through quantitative real-time polymerase chain reaction (qRT-PCR). Moreover, numerous transcripts in the testes exhibited distinct expressions between the heat-stressed broiler-type and layer-type chickens. We concluded that the transcriptional responses of testes to acute heat stress may differ between the broiler-type and layer-type roosters. Whether the differential expression patterns associate with the heat-tolerance in the strains require a further exploration. PMID- 25932639 TI - Adsorption of cationic peptides to solid surfaces of glass and plastic. AB - Cationic membrane-active peptides have been studied for years in the hope of developing them into novel types of therapeutics. In this article, we investigate an effect that might have significant experimental implications for investigators who wish to study these peptides, namely, that the peptides adsorb to solid surfaces of glass and plastic. Specifically, we use analytical HPLC to systematically quantify the adsorption of the three cationic membrane-active peptides mastoparan X, melittin, and magainin 2 to the walls of commonly used glass and plastic sample containers. Our results show that, at typical experimental peptide concentrations, 90% or more of the peptides might be lost from solution due to rapid adsorption to the walls of the sample containers. Thus, our results emphasize that investigators should always keep these adsorption effects in mind when designing and interpreting experiments on cationic membrane-active peptides. We conclude the article by discussing different strategies for reducing the experimental impact of these adsorption effects. PMID- 25932640 TI - Use of medications and lifestyles of hypertensive patients with high risk of cardiovascular disease in rural China. AB - BACKGROUND: Hypertension, with a global prevalence of 40%, is a risk factor for cardiovascular diseases (CVD). We conducted an exploratory study in Zhejiang China to understand the prevention of CVD among hypertensive patients with a 10 year CVD risk of 20% or higher. We assessed current practices in a rural 'township hospital' (a primary care facility), and compared them with international evidence-based practice. METHODS: A questionnaire survey was conducted to examine the use of modern drugs (antihypertensive drugs, statins and aspirin) and traditional drugs, compliance to medications and lifestyle among 274 hypertensive patients aged 40-74, with a CVD risk of 20% or higher (using the Asian Equation). RESULTS: The majority (72%) were diagnosed with hypertension at township hospitals. Only 15% of study participants used two anti-hypertensive drugs, 0.7% took statin and 2.9% aspirin. Only 2.9% combined two types of modern drugs, while 0.4% combined three types (antihypertensives, statins and aspirin). Herbal compounds, sometimes with internationally rarely recommended drugs such as Reserpine were taken by 44%. Analysis of drug adherence showed that 9.8% had discontinued their drug therapy by themselves. 16% had missed doses and these were on less anti-hypertensive drugs than those who did not (t=-5.217, P=0.003). Of all participants, 28% currently smoked, 39% drank regularly and only 21% exercised frequently. The average salt intake per day was 7.1 (+/-3.8) g, while the national recommended level is 6g. CONCLUSION: The study revealed outdated and inadequate treatment and health education for hypertensive patients, especially for those who have high risk scores for CVD. There is a need to review the community-based guidelines for hypertension management. Health providers and patients should make a transition from solely treating hypertension, towards prevention of CVD. Health system issues need addressing including improving rural health insurance cover and primary care doctors' capacity to manage chronic disease patients. PMID- 25932641 TI - Association of MMP-9 Haplotypes and TIMP-1 Polymorphism with Spontaneous Deep Intracerebral Hemorrhage in the Taiwan Population. AB - BACKGROUND: Spontaneous deep intracerebral hemorrhage (SDICH) is a devastating stroke subtype. The causes of SDICH are heterogeneous. Matrix metalloproteinase-9 (MMP-9, Gelantinase B) has been shown to relate to stroke and the development of aneurysm and may increase risks of intracerebral hemorrhage. MMP activities are modulated by their endogenous inhibitors, tissue inhibitors of metalloproteinases (TIMPs). We analyzed the genetic variants of MMP-9 and TIMP-1 and SDICH susceptibility. METHODS: Associations were tested by logistic regression or general linear models with adjusting for multiple covariables. Multiplicative terms between genes were applied to detect the interaction effects on SDICH. Permutation testing of 1,000 replicates was performed for empirical estimates. RESULTS: In the group of >=65 years old (y/o), we found associations of SDICH with rs3787268 (Odds ratio [OR] = 0.48, 95% confidence interval [CI] 0.27 to 0.86, P = 0.01) and haplotype1 (Hap1) (OR = 0.48, 95% CI 0.26 to 0.86, P = 0.014). For TIMP1 gene, rs4898 was associated with SDICH in the elder male group (OR = 0.35, 95% CI 0.15 to 0.81, P = 0.015). In contrast, in the younger male group, there were associations of SDICH with rs2250889 (OR = 0.48, 95% CI 0.27 to 0.84, P = 0.01) and Hap3 (OR = 0.61, 95% CI 0.38 to 0.97, P = 0.04). We found significant genetic interaction between TIMP-1 and MMP-9 in SDICH susceptibility among younger male subjects (P = 0.004). In subjects carrying rs4898 minor allele, carriers with Hap3 had lower SDICH risk than non-carriers (OR = 0.19, 95% CI 0.07 to 0.51, P = 0.001). In addition, this study showed that when young males were exposed to alcohol, Hap3 was a protective factor of SDICH (OR = 0.06, 95% CI 0.01 to 0.27, P = 0.0002). In contrast, when they were exposed to smoke, Hap2 carriers had increased risk of SDICH (OR = 2.45, 95% CI 1.05 to 5.73, P = 0.04). CONCLUSIONS: This study showed modest to moderate effects of MMP-9 and TIMP-1 polymorphisms on SDICH risks with significant age differences. MMP-9 may interact with alcohol to play a role in the SDICH risk in young men. PMID- 25932643 TI - Erratum: Association between lung function in adults and plasma DDT and DDE levels: results from the Canadian Health Measures Survey. PMID- 25932642 TI - Effects of cordycepin on the microglia-overactivation-induced impairments of growth and development of hippocampal cultured neurons. AB - Microglial cells are normally activated in response to brain injury or immunological stimuli to protect central nervous system (CNS). However, over activation of microglia conversely amplifies the inflammatory effects and mediates cellular degeneration, leading to the death of neurons. Recently, cordycepin, an active component found in Cordyceps militarisa known as a rare Chinese caterpillar fungus, has been reported as an effective drug for treating inflammatory diseases and cancer via unclear mechanisms. In this study, we attempted to identify the anti-inflammatory role of cordycepin and its protective effects on the impairments of neural growth and development induced by microglial over-activation. The results indicate that cordycepin could attenuate the lipopolysaccharide (LPS)-induced microglial activation, evidenced by the dramatically reduced release of TNF-alpha and IL-1beta, as well as the down regulation of mRNA levels of iNOS and COX-2 after cordycepin treatment. Besides, cordycepin reversed the LPS-induced activation of NF-kappaB pathway, resulting in anti-inflammatory effects. Furthermore, by employing the conditioned medium (CM), we found cordycepin was able to recover the impairments of neural growth and development in the primary hippocampal neurons cultured in LPS-CM, including cell viability, growth cone extension, neurite sprouting and outgrowth as well as spinogenesis. This study expands our knowledge of the anti-inflammatory function of cordycepin and paves the way for the biomedical applications of cordycepin in the therapies of neural injuries. PMID- 25932644 TI - Comparative evaluation of MRSA nasal colonization epidemiology in the urban and rural secondary school community of Kurdistan, Iraq. AB - BACKGROUND: To study the nasal carriage rate of Staphylococcus aureus (S. aureus) (including methicillin-resistant strains) in secondary school community of the urban and rural districts of the Kurdistan region of Iraq, a cross-sectional population based survey was carried out in the city Duhok and rural areas of Amedya, Akre and Zakho. METHODS: Nasal swabs were obtained from nostrils of 509 students aged 14-23 years. Resistance to methicillin was assessed by Kirby-Bauer disk diffusion and agar dilution assay. Vancomycin sensitivity was also tested on Muller-Hinton agar. RESULTS: It was found that the frequency of overall S. aureus nasal carriage (SANC) was 17.75% (90/509, CI95, 14.58-21.42%). In urban areas, the carriage rate was 20.59% (49/239, CI95, 15.64-26.29%), whereas it was 15.24% (41/270, CI95, 11.17-20.10%) in rural districts. The frequency of methicillin resistant S. aureus (MRSA) among the isolated strains was found to be 2.04% (1/49) and 21.95% (9/41) in urban and rural areas respectively. It was found that in urban residents, the odd ratio (OR) of acquiring SANC was 1.44 (CI95, 0.91 2.27%) and risk ratio (RR) was at least 1.35 (CI95, 0.92-1.96%) while OR decreased to 0.12 (CI95, 0.01-0.96%) for MRSA carriage. Hence, the S. aureus carriage rate was higher in urban districts compared to rural areas while more MRSA were found in rural areas compared to urban districts. All studied strains were sensitive to vancomycin. CONCLUSION: This study provided baseline information for S. aureus nasal colonization in the region. Also, it showed that living in rural areas increased the odds of MRSA colonization. More attention should be paid to control MRSA colonization in rural communities. PMID- 25932645 TI - Correction: Trolox and Ascorbic Acid Reduce Direct and Indirect Oxidative Stress in the IPEC-J2 Cells, an In Vitro Model for the Porcine Gastrointestinal Tract. PMID- 25932646 TI - Multi-objective community detection based on memetic algorithm. AB - Community detection has drawn a lot of attention as it can provide invaluable help in understanding the function and visualizing the structure of networks. Since single objective optimization methods have intrinsic drawbacks to identifying multiple significant community structures, some methods formulate the community detection as multi-objective problems and adopt population-based evolutionary algorithms to obtain multiple community structures. Evolutionary algorithms have strong global search ability, but have difficulty in locating local optima efficiently. In this study, in order to identify multiple significant community structures more effectively, a multi-objective memetic algorithm for community detection is proposed by combining multi-objective evolutionary algorithm with a local search procedure. The local search procedure is designed by addressing three issues. Firstly, nondominated solutions generated by evolutionary operations and solutions in dominant population are set as initial individuals for local search procedure. Then, a new direction vector named as pseudonormal vector is proposed to integrate two objective functions together to form a fitness function. Finally, a network specific local search strategy based on label propagation rule is expanded to search the local optimal solutions efficiently. The extensive experiments on both artificial and real world networks evaluate the proposed method from three aspects. Firstly, experiments on influence of local search procedure demonstrate that the local search procedure can speed up the convergence to better partitions and make the algorithm more stable. Secondly, comparisons with a set of classic community detection methods illustrate the proposed method can find single partitions effectively. Finally, the method is applied to identify hierarchical structures of networks which are beneficial for analyzing networks in multi-resolution levels. PMID- 25932647 TI - MARK/Par1 Kinase Is Activated Downstream of NMDA Receptors through a PKA Dependent Mechanism. AB - The Par1 kinases, also known as microtubule affinity-regulating kinases (MARKs), are important for the establishment of cell polarity from worms to mammals. Dysregulation of these kinases has been implicated in autism, Alzheimer's disease and cancer. Despite their important function in health and disease, it has been unclear how the activity of MARK/Par1 is regulated by signals from cell surface receptors. Here we show that MARK/Par1 is activated downstream of NMDA receptors in primary hippocampal neurons. Further, we show that this activation is dependent on protein kinase A (PKA), through the phosphorylation of Ser431 of Par4/LKB1, the major upstream kinase of MARK/Par1. Together, our data reveal a novel mechanism by which MARK/Par1 is activated at the neuronal synapse. PMID- 25932648 TI - Measurement of inositol 1,4,5-trisphosphate in living cells using an improved set of resonance energy transfer-based biosensors. AB - Improved versions of inositol-1,4,5-trisphosphate (InsP3) sensors were created to follow intracellular InsP3 changes in single living cells and in cell populations. Similar to previous InsP3 sensors the new sensors are based on the ligand binding domain of the human type-I InsP3 receptor (InsP3R-LBD), but contain a mutation of either R265K or R269K to lower their InsP3 binding affinity. Tagging the InsP3R-LBD with N-terminal Cerulean and C-terminal Venus allowed measurement of InsP3 in single-cell FRET experiments. Replacing Cerulean with a Luciferase enzyme allowed experiments in multi-cell format by measuring the change in the BRET signal upon stimulation. These sensors faithfully followed the agonist-induced increase in InsP3 concentration in HEK 293T cells expressing the Gq-coupled AT1 angiotensin receptor detecting a response to agonist concentration as low as 10 pmol/L. Compared to the wild type InsP3 sensor, the mutant sensors showed an improved off-rate, enabling a more rapid and complete return of the signal to the resting value of InsP3 after termination of M3 muscarinic receptor stimulation by atropine. For parallel measurements of intracellular InsP3 and Ca2+ levels in BRET experiments, the Cameleon D3 Ca2+ sensor was modified by replacing its CFP with luciferase. In these experiments depletion of plasma membrane PtdIns(4,5)P2 resulted in the fall of InsP3 level, followed by the decrease of the Ca2+-signal evoked by the stimulation of the AT1 receptor. In contrast, when type-III PI 4-kinases were inhibited with a high concentration of wortmannin or a more specific inhibitor, A1, the decrease of the Ca2+-signal preceded the fall of InsP3 level indicating an InsP3-, independent, direct regulation of capacitative Ca2+ influx by plasma membrane inositol lipids. Taken together, our results indicate that the improved InsP3 sensor can be used to monitor both the increase and decrease of InsP3 levels in live cells suitable for high-throughput BRET applications. PMID- 25932649 TI - Microsatellite Variations of Elite Setaria Varieties Released during Last Six Decades in China. AB - Crop improvement is a multifaceted micro-evolutionary process, involving changes in breeding approaches, planting configurations and consumption preferences of human beings. Recent research has started to identify the specific genes or genomic regions correlate to improved agronomic traits, however, an apparent blank between the genetic structure of crop elite varieties and their improving histories in diverse modern breeding programs is still in existence. Foxtail millet (Setaria italica) was one of the earliest cereal crops to be domesticated and served as a staple crop for early civilizations in China, where it is still widely grown today. In the present trial, a panel of foxtail millet elite varieties, which were released in the last sixty years in different geographical regions of China, was characterized using microsatellite markers (SSRs). A clear separation of two subpopulations corresponding to the two eco-geographical regions of foxtail millet production in China was identified by the dataset, which also indicated that in more recently released elite varieties, large quantities of accessions have been transferred from spring-sowing to summer sowing ecotypes, likely as a result of breeding response to planting configurations. An association mapping study was conducted to identify loci controlling traits of major agronomic interest. Furthermore, selective sweeps involved in improvement of foxtail millet were identified as multi-diverse minor effect loci controlling different agronomic traits during the long-term improvement of elite varieties. Our results highlight the effect of transition of planting configuration and breeding preference on genetic evolvement of crop species. PMID- 25932650 TI - TMREC: A Database of Transcription Factor and MiRNA Regulatory Cascades in Human Diseases. AB - Over the past decades, studies have reported that the combinatorial regulation of transcription factors (TFs) and microRNAs (miRNAs) is essential for the appropriate execution of biological events and developmental processes. Dysregulations of these regulators often cause diseases. However, there are no available resources on the regulatory cascades of TFs and miRNAs in the context of human diseases. To fulfill this vacancy, we established the TMREC database in this study. First, we integrated curated transcriptional and post-transcriptional regulations to construct the TF and miRNA regulatory network. Next, we identified all linear paths using the Breadth First Search traversal method. Finally, we used known disease-related genes and miRNAs to measure the strength of association between cascades and diseases. Currently, TMREC consists of 74,248 cascades and 25,194 cascade clusters, involving in 412 TFs, 266 miRNAs and 545 diseases. With the expanding of experimental support regulation data, we will regularly update the database. TMREC aims to help experimental biologists to comprehensively analyse gene expression regulation, to understand the aetiology and to predict novel therapeutic targets. TMREC is freely available at http://bioinfo.hrbmu.edu.cn/TMREC/. PMID- 25932651 TI - Fluorescence resonance energy transfer-based ratiometric fluorescent probe for detection of Zn(2+) using a dual-emission silica-coated quantum dots mixture. AB - In this work, we report the design and application of a new ratiometric fluorescent probe, which contains different-colored quantum dots (QDs) as dual fluorophores, ultrathin silica shell as spacer, and meso-tetra(4 sulfonatophenyl)porphine dihydrochloride (TSPP) as receptor, for Zn(2+) detection in aqueous solution and living cells. In the architecture of our designed probe, the silica shell plays the key roles in controlling the locations of QDs, TSPP, and Zn(2+), preventing the direct contact between QDs and Zn(2+) but affording fluorescence resonance energy transfer (FRET) from dual-color QDs to TSPP. In the presence of Zn(2+), the analyte-receptor reaction changes the absorption in the range of the Q-band of TSPP and accordingly the efficiencies of two independent FRET processes from the dual-colored QDs to the acceptor, respectively, leading to fluorescence enhancement of green-emission QDs whereas fluorescence quenching of yellow-emission QDs. Benefiting from the well-resolved dual emissions from different-colored QDs and the large range of emission ratios, the probe solution displays continuous color changes from yellow to green, which can be clearly observed by the naked eye. Under physiological conditions, the probe exhibits a stable response for Zn(2+) from 0.3 to 6 MUM, with a detection limit of 60 nM in aqueous solutions. With respect to single-emission probes, this ratiometric probe has demonstrated to feature excellent selectivity for Zn(2+) over other physiologically important cations such as Fe(3+) and Cu(2+). It has been preliminarily used for ratiometric imaging of Zn(2+) in living cells with satisfying resolution. PMID- 25932652 TI - Molecular Mechanism of Photozipper, a Light-Regulated Dimerizing Module Consisting of the bZIP and LOV Domains of Aureochrome-1. AB - Aureochrome-1 (AUREO1) is a blue light (BL) receptor responsible for the BL induced blanching of a stramenopile alga, Vaucheria frigida. The AUREO1 protein contains a central basic region/leucine zipper (bZIP) domain, and a C-terminal light-oxygen-voltage-sensing (LOV) domain. BL induces the dimerization of monomeric AUREO1, which subsequently increases the affinity of this transcription factor for its target DNA [Hisatomi, O., et al. (2014) J. Biol. Chem. 289, 17379 17391]. We constructed a synthetic gene encoding N-terminally truncated monomeric AUREO1 (designated Photozipper) to elucidate the molecular mechanism of this BL regulated transcription factor and to develop it as an optogenetic tool. In this study, four different Photozipper (PZ) protein constructs were prepared comprising different N-terminal truncations. The monomer-dimer equilibria of the PZ constructs were investigated in the dark and light states. Dynamic light scattering and size-exclusion chromatography analyses revealed that the apparent dissociation constants of PZ dimers with and without the ZIP region were ~100 and 30 MUM, respectively, indicating that the ZIP region stabilized the monomeric form in the dark state. In the light state, fluorescence resonance energy transfer analyses demonstrated that deletion of the ZIP region increased the dissociation constant from ~0.15 to 0.6 MUM, suggesting that intermolecular LOV LOV and ZIP-ZIP interactions stabilized the dimeric forms. Our results suggest that synergistic interactions between the LOV and bZIP domains stabilize the monomeric form in the dark state and the dimeric form in the light state, which possibly contributes to the function of PZ as a BL-regulated molecular switch. PMID- 25932653 TI - In situ formation and gelation mechanism of thermoresponsive stereocomplexed hydrogels upon mixing diblock and triblock poly(lactic acid)/poly(ethylene glycol) copolymers. AB - A novel in situ formed gel system with potential biodegradability and biocompatibility is developed by mixing the diblock and triblock poly(lactic acid)/poly(ethylene glycol) (PLA/PEG) copolymers with opposite configurations of PLA blocks. In situ gelation of such system is extremely fast, which happens within 10 s after mixing. In situ gelation, gel-to-sol transition, crystalline structure, microstructures, and mechanical properties of PLA-PEG/PLA-PEG-PLA enantiomerically mixed gels are significantly influenced by the mixing ratio, degree of polymerization for PEG block in triblock (DPPEG,tri) and diblock copolymers (DPPEG,di). It is found that in situ gelation of PLA-PEG/PLA-PEG-PLA enantiomeric mixture just happen at relatively smaller PLA-PEG/PLA-PEG-PLA mass ratio and larger DPPEG,tri. Hydrodynamic diameters of PLA-PEG and PLA-PEG-PLA copolymers in dilute solution increase remarkably upon mixing, indicating the formation of bridging networks. Stereocomplexed crystallites are formed for the PLA hydrophobic domains in PLA-PEG/PLA-PEG-PLA enantiomeric mixtures. As indicated by synchrotron-radiation SAXS analysis, the enantiomeric mixture changes from a compactly to loosely aggregated structure and the intermicellar distance enhances with increasing DPPEG,tri, DPPEG,di, or PLA-PEG-PLA fraction. Gelation mechanism of PLA-PEG/PLA-PEG-PLA enantiomeric mixture is proposed, in which part of PLA-PEG-PLA chains act as the connecting bridges between star and flower-like micelles and the stereocomplexed crystallites in micelle cores act as physically cross-linked points. PMID- 25932654 TI - Sodium-Ion Intercalated Transparent Conductors with Printed Reduced Graphene Oxide Networks. AB - In this work, we report for the first time that Na-ion intercalation of reduced graphene oxide (RGO) can significantly improve its printed network's performance as a transparent conductor. Unlike pristine graphene that inhibits Na-ion intercalation, the larger layer-layer distance of RGO allows Na-ion intercalation, leading to simultaneously much higher DC conductivity and higher optical transmittance. The typical increase of transmittance from 36% to 79% and decrease of sheet resistance from 83k to 311 Ohms/sq in the printed network was observed after Na-ion intercalation. Compared with Li-intercalated graphene, Na ion intercalated RGO shows much better environmental stability, which is likely due to the self-terminating oxidation of Na ions on the RGO edges. This study demonstrated the great potential of metal-ion intercalation to improve the performance of printed RGO network for transparent conductor applications. PMID- 25932655 TI - A Modulated Hydrothermal (MHT) Approach for the Facile Synthesis of UiO-66-Type MOFs. AB - Developing a general and economically viable approach for the large-scale synthesis of water-stable metal-organic frameworks (MOFs) with repeatable quality remains the key step for their massive production and commercialization. We herein report a green (aqueous solutions), mild (100 degrees C, 1 atm), and scalable (can be up to kilograms) modulated hydrothermal (MHT) synthesis of UiO 66, an iconic MOF that has been widely studied recently for its high water stability. More importantly, the MHT synthetic approach can be applied to synthesize other water-stable MOFs with structures identical to UiO-66, such as UiO-66-(F)4, UiO-66-(OCH2CH3)2, and UiO-66-(COOH)4, which cannot be obtained via the traditional solvothermal method. Their performance in postcombustion CO2 capture has also been evaluated. Our MHT approach has clearly depicted a roadmap for the facile synthesis of zirconium-based water stable MOFs to facilitate their massive production and commercialization. PMID- 25932656 TI - Rheological profiling of organogels prepared at critical gelling concentrations of natural waxes in a triacylglycerol solvent. AB - The aim of this study was to use a detailed rheological characterization to gain new insights into the gelation behavior of natural waxes. To make a comprehensive case, six natural waxes (differing in the relative proportion of chemical components: hydrocarbons, fatty alcohols, fatty acids, and wax esters) were selected as organogelators to gel high-oleic sunflower oil. Flow and dynamic rheological properties of organogels prepared at critical gelling concentrations (Cg) of waxes were studied and compared using drag (stress ramp and steady flow) and oscillatory shear (stress and frequency sweeps) tests. Although, none of the organogels satisfied the rheological definition of a "strong gel" (G"/G' (omega) <= 0.1), on comparing the samples, the strongest gel (highest critical stress and dynamic, apparent, and static yield stresses) was obtained not with wax containing the highest proportion of wax esters alone (sunflower wax, SFW) but with wax containing wax esters along with a higher proportion of fatty alcohols (carnauba wax, CRW) although at a comparatively higher Cg (4%wt for latter compared to 0.5%wt for former). As expected, gel formation by waxes containing a high proportion of lower melting fatty acids (berry, BW, and fruit wax, FW) required a comparatively higher Cg (6 and 7%wt, respectively), and in addition, these gels showed the lowest values for plateau elastic modulus (G'LVR) and a prominent crossover point at higher frequency. The gelation temperatures (TG'=G") for all the studied gels were lower than room temperature, except for SFW and CRW. The yielding-type behavior of gels was evident, with most gels showing strong shear sensitivity and a weak thixotropic recovery. The rheological behavior was combined with the results of thermal analysis and microstructure studies (optical, polarized, and cryo-scanning electron microscopy) to explain the gelation properties of these waxes. PMID- 25932657 TI - The Internal and External Responses to a Forward-Specific Rugby League Simulation Protocol Performed With and Without Physical Contact. AB - It is important to understand the extent to which physical contact changes the internal and external load during rugby simulations that aim to replicate the demands of match play. Accordingly, this study examined the role of physical contact on the physiological and perceptual demands during and immediately after a simulated rugby league match. Nineteen male rugby players completed a contact (CON) and a noncontact (NCON) version of the rugby league match-simulation protocol in a randomized crossover design with 1 wk between trials. Relative distance covered (ES = 1.27; +/- 0.29), low-intensity activity (ES = 1.13; +/- 0.31), high-intensity running (ES = 0.49; +/- 0.34), heart rate (ES = 0.52; +/- 0.35), blood lactate concentration (ES = 0.78; +/- 0.34), rating of perceived exertion (RPE) (ES = 0.72; +/- 0.38), and session RPE (ES = 1.45; +/- 0.51) were all higher in the CON than in the NCON trial. However, peak speeds were lower in the CON trial (ES = -0.99; +/- 0.40) despite unclear reductions in knee-extensor (ES = 0.19; +/- 0.40) and -flexor (ES = 0.07; +/- 0.43) torque. Muscle soreness was also greater after CON than in the NCON trial (ES = 0.97; +/- 0.55). The addition of physical contact to the movement demands of a simulated rugby league match increases many of the external and internal demands but also results in players' slowing their peak running speed during sprints. These findings highlight the importance of including contacts in simulation protocols and training practices designed to replicate the demands of real match play. PMID- 25932658 TI - Evaluating a prototype device designed to alleviate night vision goggle induced neck strain among military personnel. AB - The purpose of this study was verify the design of a novel Helmet System Support Device (HSSD) that can be used by military aircrew to help intervene on and reduce the high prevalence of neck trouble. Twelve healthy participants repeated simulated helicopter aircrew tasks on 3 separate days. On each day they wore a different helmet configuration, where measures of performance, perceived demand/preference and muscular demand were recorded. The results showed that vigilance tasks were performed over 10% faster with the HSSD configuration compared to wearing the normal helmet configuration. Participants were able to maintain static (endurance) postures for 28% longer, and use of the HSSD helped to prevent neck muscle fatigue in the most demanding task. The results of this design verification study indicate that the HSSD may be a realistic, feasible near-term solution to intervene on the high prevalence of neck trouble among rotary-wing aircrew. Practitioner Summary: This paper verifies the effectiveness of the Helmet System Support Device (HSSD) as an on-body personal protective device to help control exposures associated with aircrew neck trouble. The HSSD reduced perceived demand, reduced cumulative muscle activity in select muscles and provided improved fatigue resistance, meeting its desired design objectives. PMID- 25932659 TI - Role of aflatoxin toxicity on transmissibility and pathogenicity of H9N2 avian influenza virus in turkeys. AB - The study was conducted to investigate the role of aflatoxin on the infectivity and transmissibility of H9N2 AI virus. The experiment was performed on 80 non vaccinated turkeys, divided into 4 groups of 20 birds each. Group A was kept as non-infected and a non-treated negative control; Group B was inoculated intratracheally with H9N2 AI virus (1 * 10(7) EID50) at 4 weeks of age; Group C was fed on a diet containing 0.5 ppm aflatoxin from Day 1 through the entire experiment period and Group D was fed on diet containing 0.5 ppm aflatoxin as for Group C but inoculated intratracheally with H9N2 AI virus (1 * 10(7) EID50) at the fourth week of age and then mixed with naive birds. Infected and contact birds showed clinical signs of different severity, showing the most prominent disease signs in birds of the aflatoxin + H9N2 group. All infected birds showed virus shedding, however, the pattern of virus shedding was different for birds of the aflatoxin + H9N2 group showing pronounced virus secretion. Similarly, efficient transmission of virus was observed between infected and contact birds, but more prominent virus transmission was seen in those birds inoculated and fed aflatoxin-treated diet. Moreover, significantly lower antibody titres against H9N2 AIV were observed in birds fed aflatoxin-treated diet, indicating an immunotoxic nature of aflatoxin as the reason for poor seroconversion. Similarly, decreased IFNgamma mRNA expression and higher mortality (35%) suggest an immunotoxic and immunosuppressive effect of aflatoxin leading to enhanced pathogenesis of H9N2 viruses in aflatoxin-fed birds. The immunosuppressive nature of aflatoxin might delay influenza virus clearance and this may be one of the reasons for increased pathogenicity of H9N2 LPAI viruses in turkeys under field conditions. PMID- 25932660 TI - Soluble Receptor for Advanced Glycation End-Products Predicts Impaired Alveolar Fluid Clearance in Acute Respiratory Distress Syndrome. AB - RATIONALE: Levels of the soluble form of the receptor for advanced glycation end products (sRAGE) are elevated during acute respiratory distress syndrome (ARDS) and correlate with severity and prognosis. Alveolar fluid clearance (AFC) is necessary for the resolution of lung edema but is impaired in most patients with ARDS. No reliable marker of this process has been investigated to date. OBJECTIVES: To verify whether sRAGE could predict AFC during ARDS. METHODS: Anesthetized CD-1 mice underwent orotracheal instillation of hydrochloric acid. At specified time points, lung injury was assessed by analysis of blood gases, alveolar permeability, lung histology, AFC, and plasma/bronchoalveolar fluid measurements of proinflammatory cytokines and sRAGE. Plasma sRAGE and AFC rates were also prospectively assessed in 30 patients with ARDS. MEASUREMENTS AND MAIN RESULTS: The rate of AFC was inversely correlated with sRAGE levels in the plasma and the bronchoalveolar fluid of acid-injured mice (Spearman's rho = -0.73 and 0.69, respectively; P < 10(-3)), and plasma sRAGE correlated with AFC in patients with ARDS (Spearman's rho = -0.59; P < 10(-3)). Similarly, sRAGE levels were significantly associated with lung injury severity, and decreased over time in mice, whereas AFC was restored and lung injury resolved. CONCLUSIONS: Our results indicate that sRAGE levels could be a reliable predictor of impaired AFC during ARDS, and should stimulate further studies on the pathophysiologic implications of RAGE axis in the mechanisms leading to edema resolution. Clinical trial registered with www.clinicaltrials.gov (NCT 00811629). PMID- 25932661 TI - Barley Ant17, encoding flavanone 3-hydroxylase (F3H), is a promising target locus for attaining anthocyanin/proanthocyanidin-free plants without pleiotropic reduction of grain dormancy. AB - Preharvest sprouting is a serious problem in grain crop production because it causes quality deterioration and economic losses. It is well known that grain colour is closely associated with grain dormancy in wheat; white-grained lines without accumulating proanthocyanidins in testa tend to be more susceptible to preharvest sprouting than red ones. All available white-grained wheat lines are restricted to triple recessive mutations at the R loci (R-A1, R-B1, and R-D1), but barley is known to have 11 independent loci conferring the proanthocyanidin free grain phenotype. In this study, we evaluated the dormancy levels of anthocyanin/proanthocyanidin-free ant17 mutants. Three ant17 mutants showed the same levels of dormancy as their respective wild types. Sequencing of three independent ant17 alleles detected a point mutation within the coding regions of flavanone-3-hydroxylase (F3H), which are predicted to cause a premature stop codon at different sites. The F3H locus completely cosegregated with the Ant17 position on the chromosome arm 2HL. Expression of the barley F3H gene was observed in pigmented tissues, but not in nonpigmented roots and stems. This result indicates that wheat F3H may be a promising new target locus for breeding white-grained lines with a practical level of preharvest sprouting resistance. PMID- 25932663 TI - Anterior cingulate cortex and intuitive bias detection during number conservation. AB - Children's number conservation is often biased by misleading intuitions but the precise nature of these conservation errors is not clear. A key question is whether children detect that their erroneous conservation judgment is unwarranted. The present study reanalyzed available fMRI data to test the implication of the anterior cingulate cortex (ACC) in this detection process. We extracted mean BOLD (Blood Oxygen Level Dependent) signal values in an independently defined ACC region of interest (ROI) during presentation of classic and control number conservation problems. In classic trials, an intuitively cued visuospatial response conflicted with the correct conservation response, whereas this conflict was not present in the control trials. Results showed that ACC activation increased when solving the classic conservation problems. Critically, this increase did not differ between participants who solved the classic problems correctly (i.e., so-called conservers) and incorrectly (i.e., so-called non conservers). Additional control analyses of inferior and lateral prefrontal ROIs showed that the group of conservers did show stronger activation in the right inferior frontal gyrus and right lateral middle frontal gyrus. In line with recent behavioral findings, these data lend credence to the hypothesis that even non-conserving children detect the biased nature of their judgment. The key difference between conservers and non-conservers seems to lie in a differential recruitment of inferior and lateral prefrontal regions associated with inhibitory control. PMID- 25932664 TI - Testing the Factor Structure and Measurement Invariance Across Gender of the Big Five Inventory Through Exploratory Structural Equation Modeling. AB - Confirmatory factor analyses (CFAs) typically fail to support the a priori 5 factor structure of Big Five self-report instruments, due in part to the overly restrictive CFA assumptions. We show that exploratory structural equation modeling (ESEM), an integration of CFA and exploratory factor analysis, overcomes these problems in relation to responses to the 44-item Big Five Inventory (BFI) administered to a large Italian community sample. ESEM fitted the data better and resulted in less correlated factors than CFA, although ESEM and CFA factor scores correlated at near unity with observed raw scores. Tests of gender invariance with a 13-model taxonomy of full measurement invariance showed that the factor structure of the BFI is gender-invariant and that women score higher on Neuroticism, Agreeableness, Extraversion, and Conscientiousness. Through ESEM one could address substantively important issues about BFI psychometric properties that could not be appropriately addressed through traditional approaches. PMID- 25932665 TI - Collection and Utilization of Animal Carcasses Associated with zoonotic Disease in Tshuapa District, the Democratic Republic of the Congo, 2012. AB - The collection and consumption of animal carcasses is a common activity in forested areas of the Congo River basin and creates sustainability, conservation, and health concerns. Residents of the Tshuapa District reported collecting the remains of 5,878 animals from >30 species when surveyed about their wildlife consumption habits. Carcasses were discovered in varying degrees of decomposition and were often consumed at home or sold in local markets. The most commonly collected animals were Cricetomys gambianus (Northern giant pouched rat), Cercopithecus ascanius (red-tailed monkey), and Heliosciurus rufobrachium (red legged sun squirrel). Many of the species recorded may be hosts of zoonotic pathogens, creating concern for spillover events. PMID- 25932666 TI - Is the Oriental House Rat (Rattus tanezumi) a Potential Reservoir for Trypanosoma evansi in Thailand? AB - Trypanosoma evansi is a protozoan blood parasite and etiologic agent of "surra," a disease affecting a wide range of domestic and wild mammals, some identified as potential reservoirs. Although T. evansi has been detected in several small wild rodent species, their role in the epidemiology of surra is unclear. There is molecular evidence of T. evansi in wild rodents in Asia, but it is not known whether they can carry the parasite for sufficient time to significantly contribute to the epidemiology of surra. We assessed the susceptibility of the Oriental house rat (OHR; Rattus tanezumi) to T. evansi infection. Five adult male OHRs trapped in Bangkhen district, Bangkok, Thailand, and five laboratory Wistar rats (Rattus norvegicus) as positive controls, were experimentally infected with a local strain of T. evansi. The five controls and three of the five OHRs were highly susceptible and rapidly exhibited the high levels of parasitemia usually observed in Wistar rats. They died or were euthanized just prior to expected death. Two OHRs presented fluctuating levels of parasitemia, without obvious clinical signs, throughout 40 d of monitoring. These results highlight the moderate susceptibility of some OHRs and their ability to carry the infection over time. Along with the molecular evidence of T. evansi in captured OHRs (demonstrated elsewhere), our results bring new information on the potential role of OHRs in the complex epidemiology of surra. PMID- 25932667 TI - Natural Infection of the Wild Canid Lycalopex gymnocercus by the Protozoan Rangelia vitalii, the Agent of Canine Rangeliosis. AB - Rangelia vitalii is a piroplasmid that causes canine rangeliosis, a severe hemorrhagic disease of domestic dogs in South America. We report about R. vitalii infecting a pampas fox (Lycalopex gymnocercus). The fox, which developed a fatal illness, was also infected by Hepatozoon canis and Capillaria hepatica. PMID- 25932668 TI - Granuloma Coinfection with Mycobacterium bovis, Mycobacterium avium subsp. paratuberculosis, and Corynebacterium pseudotuberculosis in Five Hunted Red deer (Cervus elaphus) in Portugal. AB - We report granulomatous lymphadenitis in red deer (Cervus elaphus) in Portugal caused by coinfection with Corynebacterium pseudotuberculosis, Mycobacterium bovis, and Mycobacterium avium subsp. paratuberculosis, as demonstrated by molecular methods. PMID- 25932669 TI - PREVALENCE AND CHARACTERISTICS OF ESCHERICHIA COLI AND SALMONELLA SPP. IN THE FECES OF WILD URBAN NORWAY AND BLACK RATS (RATTUS NORVEGICUS AND RATTUS RATTUS) FROM AN INNER-CITY NEIGHBORHOOD OF VANCOUVER, CANADA. AB - Although rat feces are widely suspected to be a source of pathogenic bacteria, few investigators have studied fecal pathogens in rats. We investigated the prevalence and characteristics of Escherichia coli and Salmonella spp. in Norway and black rats (Rattus norvegicus and Rattus rattus, respectively) from an urban neighborhood of Vancouver, Canada, collected September 2011-August 2012. Colon content was cultured for E. coli and Salmonella spp. and screened for the seven most-common enteropathogenic Shiga toxin-producing E. coli (STEC) serotypes by PCR. Isolates were tested for antimicrobial resistance and Salmonella isolates were serotyped. We detected E. coli in 397/633 (62.7%) urban rats. Forty-one of 397 (6.5%) E. coli isolates were resistant to >= 1 antimicrobial while 17 (4.3%) were multidrug resistant (including two isolates demonstrating extended-spectrum beta-lactamase resistance). Ten of 633 (1.6%) urban rats were carrying STEC serotypes including O145, O103, O26, and O45. Norway rats were more likely to be carrying E. coli compared to black rats, and there was geographic clustering of specific resistance patterns and STEC serotypes. Salmonella spp. were detected in 3/633 (0.5%) rats including serotypes Derby, Indiana, and Enteritidis. In contrast to zoonotic pathogens for which rats are the natural reservoir (e.g., Leptospira interrogans, Rickettsia typhi, Seoul virus), rats likely acquired E. coli and Salmonella spp. from their environment. The ability of rats to be a 'sponge' for environmental pathogens has received little consideration, and the ecology and public health significance of these organisms in rats requires further investigation. PMID- 25932670 TI - Alternatives to PFASs: perspectives on the science. PMID- 25932671 TI - Cytotoxic Bryostatin Derivatives from the South China Sea Bryozoan Bugula neritina. AB - Four new macrocyclic lactones, bryostatin 21 (1) and 9-O-methylbryostatins 4, 16, and 17 (2-4), together with three known related compounds, bryostatins 4, 16, and 17 (5-7), have been isolated from an extract of the South China Sea bryozoan Bugula neritina. The structures of all compounds were unambiguously elucidated using detailed spectroscopic analysis. Structurally, the presence of a single methyl group at C-18 in compound 1 has not been observed before for known bryostatins. The isolated macrolides exhibited inhibitory effects against a small panel of human cancer cell lines. PMID- 25932672 TI - Tuning the Magnetic Properties of Carbon by Nitrogen Doping of Its Graphene Domains. AB - Here we present the formation of predominantly sp(2)-coordinate carbon with magnetic- and heteroatom-induced structural defects in a graphene lattice by a stoichiometric dehalogenation of perchlorinated (hetero)aromatic precursors [hexachlorobenzene, C6Cl6 (HCB), and pentachloropyridine, NC5Cl5 (PCP)] with transition metals such as copper in a combustion synthesis. This route allows the build-up of a carbon lattice by a chemistry free of hydrogen and oxygen compared to other pyrolytic approaches and yields either nitrogen-doped or -undoped graphene domains depending on the precursor. The resulting carbon was characterized by scanning electron microscopy (SEM), transmission electron microscopy (TEM), Raman spectroscopy, photoelectron spectroscopy (XPS), and SQUID magnetometry to gain information on its morphological, chemical, and electronic structure and on the location of the nitrogen atoms within the carbon lattice. A significant lowering of the magnetization was observed for the nitrogen-doped carbon obtained by this method, which exhibits less ordered graphene domains in the range of approximately 10-30 nm as per TEM analysis compared to the nondoped carbon resulting from the reaction of HCB with larger graphene domains as per TEM and the presence of a 2D mode in the Raman spectra. The decrease of the magnetization by nitrogen doping within the sp(2)-coordinate carbon lattice can be attributed to an increase in pyrrole-type defects along with a reduction in radical defects originating from five-membered carbon ring structures as well as changes in the pi-electron density of edge states. PMID- 25932673 TI - Abstracts of the 2nd European symposium on focused ultrasound therapy. PMID- 25932674 TI - Emerging mechanisms of molecular pathology in ALS. AB - Amyotrophic lateral sclerosis (ALS) is a devastating degenerative disease characterized by progressive loss of motor neurons in the motor cortex, brainstem, and spinal cord. Although defined as a motor disorder, ALS can arise concurrently with frontotemporal lobal dementia (FTLD). ALS begins focally but disseminates to cause paralysis and death. About 10% of ALS cases are caused by gene mutations, and more than 40 ALS-associated genes have been identified. While important questions about the biology of this disease remain unanswered, investigations of ALS genes have delineated pathogenic roles for (a) perturbations in protein stability and degradation, (b) altered homeostasis of critical RNA- and DNA-binding proteins, (c) impaired cytoskeleton function, and (d) non-neuronal cells as modifiers of the ALS phenotype. The rapidity of progress in ALS genetics and the subsequent acquisition of insights into the molecular biology of these genes provide grounds for optimism that meaningful therapies for ALS are attainable. PMID- 25932676 TI - Abdominal obesity: a marker of ectopic fat accumulation. AB - In the early 1980s, we analyzed the metabolic profile of 930 men and women and concluded that an abdominal distribution of fat for a given BMI is associated with increased insulin resistance and risk of developing type 2 diabetes and cardiovascular disease. The correlation between abdominal fat and metabolic dysfunction has since been validated in many studies, and waist circumference is now a criterion for the diagnosis of metabolic syndrome. Several mechanisms for this relationship have been postulated; however, we now know that visceral fat is only one of many ectopic fat depots used when the subcutaneous adipose tissue cannot accommodate excess fat because of its limited expandability. PMID- 25932677 TI - CGRP induction in cystic fibrosis airways alters the submucosal gland progenitor cell niche in mice. PMID- 25932678 TI - Retraction. FOXO3 programs tumor-associated DCs to become tolerogenic in human and murine prostate cancer. PMID- 25932675 TI - Targeting cancer with kinase inhibitors. AB - Kinase inhibitors have played an increasingly prominent role in the treatment of cancer and other diseases. Currently, more than 25 oncology drugs that target kinases have been approved, and numerous additional therapeutics are in various stages of clinical evaluation. In this Review, we provide an in-depth analysis of activation mechanisms for kinases in cancer, highlight recent successes in drug discovery, and demonstrate the clinical impact of selective kinase inhibitors. We also describe the substantial progress that has been made in designing next generation inhibitors to circumvent on-target resistance mechanisms, as well as ongoing strategies for combining kinase inhibitors in the clinic. Last, there are numerous prospects for the discovery of novel kinase targets, and we explore cancer immunotherapy as a new and promising research area for studying kinase biology. PMID- 25932679 TI - Sumoylated HSP90 is a dominantly inherited plasma cell dyscrasias risk factor. PMID- 25932680 TI - Osteocalcin regulates murine and human fertility through a pancreas-bone-testis axis. PMID- 25932681 TI - Profiles in cytotoxicity: a first step toward chemical-specific adjustment factors. PMID- 25932682 TI - Your guide to Medicare value-based care. AB - What is value-based care? What are the various Medicare quality reporting programs? How are those programs tied to quality? This guide breaks down the what, when, why, and how behind what has become an ever-more confusing web of requirements. PMID- 25932683 TI - Seeing the light. AB - TMA's Committee on Physician Distribution and Health Care Access raised concerns that medical schools and residency programs may become overly restrictive of the practice of moonlighting since the Accreditation Council for Graduate Medical Education recently required moonlighting to count toward a resident's total work hour cap of 80 hours per week. In response, TMA's Council on Medical Education adopted a policy put forth by the physician distribution committee that encourages medical schools and residency programs in Texas to reconsider broad limitations or even prohibitions on resident moonlighting. The policy goes before the TMA House of Delegates at its annual meeting in May. PMID- 25932684 TI - Medical board wages war over telephone treatment. AB - In a case working its way through Texas courts, Teladoc argues that a face-to face meeting is unnecessary for new patients. Teladoc provides telephone patient consultations, claiming that a phone call with a licensed physician can serve as a convenient supplement when patients don't have the time or money to see their primary care doctors. Some physicians say a phone conversation is not enough to properly diagnose and treat a patient with whom the physician is unfamiliar. PMID- 25932685 TI - HIEs and the gateway to better care. AB - Health information exchanges (HIEs) are becoming a more widely used method for physicians to share valuable patient information. A proposed health service enterprise gateway would connect to local health information exchanges and give physicians a single place to exchange data with all state health agencies. PMID- 25932686 TI - End-of-life care: the long conversation. AB - California palliative care specialist, author, and consultant Ira Byock, MD, calls the issues surrounding end-of-life care "a public health crisis." But he says many of the same solutions to improving the health care system overall - shared decisionmaking, advancements in medical education, better payment and delivery structures - apply equally to this area of medical care. Dr. Byock is the General Session keynote speaker at TexMed 2015 in May. PMID- 25932687 TI - The lidocaine metabolite N-ethylglycine has antinociceptive effects in experimental inflammatory and neuropathic pain. AB - Glycine transporter 1 (GlyT1) plays a crucial role in regulating extracellular glycine concentrations and might thereby constitute a new drug target for the modulation of glycinergic inhibition in pain signaling. Consistent with this view, inhibition of GlyT1 has been found to induce antinociceptive effects in various animal pain models. We have shown previously that the lidocaine metabolite N-ethylglycine (EG) reduces GlyT1-dependent glycine uptake by functioning as an artificial substrate for this transporter. Here, we show that EG is specific for GlyT1 and that in rodent models of inflammatory and neuropathic pain, systemic treatment with EG results in an efficient amelioration of hyperalgesia and allodynia without affecting acute pain. There was no effect on motor coordination or the development of inflammatory edema. No adverse neurological effects were observed after repeated high-dose application of EG. EG concentrations both in blood and spinal fluid correlated with an increase of glycine concentration in spinal fluid. The time courses of the EG and glycine concentrations corresponded well with the antinociceptive effect. Additionally, we found that EG reduced the increase in neuronal firing of wide-dynamic-range neurons caused by inflammatory pain induction. These findings suggest that systemically applied lidocaine exerts antihyperalgesic effects through its metabolite EG in vivo, by enhancing spinal inhibition of pain processing through GlyT1 modulation and subsequent increase of glycine concentrations at glycinergic inhibitory synapses. EG and other substrates of GlyT1, therefore, may be a useful therapeutic agent in chronic pain states involving spinal disinhibition. PMID- 25932689 TI - Cav3.2-expressing low-threshold C fibres in human hairy skin contribute to cold allodynia--a non-TRPV1- and non-TRPM8-dependent phenomenon. AB - It is generally agreed that cold allodynia is a consequence of impaired (Adelta fibre-mediated) central inhibition of C-nociceptive inputs. However, it is also known that C polymodal nociceptors are not activated at innocuous low temperatures. Recently, we demonstrated the contribution of C-tactile fibres to tactile allodynia. In this study, we investigated whether this, or a related, C fibre class contributes to cold allodynia. In 30 healthy and 3 chronic pain subjects, a series of normally innocuous localised thermal stimuli were applied to the skin overlying a painful tibialis anterior muscle (induced by infusion of hypertonic saline). The effects of thermal stimulation on muscle pain were observed before and after compression blockade of myelinated fibres. Furthermore, intradermal capsaicin, menthol and TTA-A2 were used for desensitisation of TRPV1, TRPM8, and T-type calcium (Cav3.2) channels, respectively. Before muscle pain, all thermal stimuli were reported as nonpainful regardless of whether myelinated fibres were conducting or not. During muscle pain, dynamic skin cooling (32 degrees C -> 20 degrees C) evoked significant and reproducible increases in the overall pain intensity (allodynia). This increase was short lived and locked to the dynamic phase of cooling with pain levels returning to baseline during sustained cooling. Dynamic warming (32 degrees C -> 39 degrees C) had no effect on pain levels. Cold allodynia persisted after nerve compression and TRPV1 and TRPM8 desensitisation but was abolished by localised Cav3.2 blockade. In clinical subjects, C-fibre-mediated allodynia was observed without the need for experimental pain-producing manipulations. In conclusion, cold allodynia represents a non-TRPV1- and non-TRPM8-dependent phenomenon, which is mediated by low-threshold Cav3.2-expressing C fibres. PMID- 25932688 TI - GABA acting on GABAB receptors located in a medullary pain facilitatory area enhances nociceptive behaviors evoked by intraplantar formalin injection. AB - The dorsal reticular nucleus (DRt) plays a key role in facilitation of nociceptive transmission at the spinal cord. In this study, we evaluated the mechanisms involved in GABA-mediated control of the DRt focusing on the role of local GABAB receptors. First, we used in vivo microdialysis to study the release of GABA in the DRt during the course of the formalin test. An increase of GABA levels in comparison with baseline values was detected in the second phase of the test. Because we previously showed that GABAB receptors are expressed by opioidergic DRt neurons, which respond to nociceptive stimuli and inhibit spinally projecting DRt neurons involved in descending pronociception, we then interfered with local GABAB receptors using gene transfer and pharmacological approaches. Lentiviral-mediated knockdown of GABAB1a expression decreased nociceptive responses during the second phase of the test. Local administration of the GABAB receptor antagonist CGP 35348 also decreased nociceptive responses in the second phase of the test, whereas the opposite was detected after injection of the GABAB agonist baclofen. Finally, we determined the GABAergic afferents of the DRt, namely those arising from its main brain afferents, which are located at the telencephalon and diencephalon. For that purpose, we combined retrograde tract-tracing from the DRt with immunodetection of glutamate decarboxylase, the GABA-synthesizing enzyme. The higher numbers of retrogradely labelled glutamate decarboxylase-immunoreactive neurons were located at insular, somatosensory, and motor cortices. Collectively, the results suggest that GABA acting on GABAB receptors may enhance pain facilitation from the DRt during inflammatory pain. PMID- 25932691 TI - Behavioral and electrophysiological abnormalities in two rat models of antiretroviral drug-induced neuropathy. AB - Painful peripheral neuropathy due to the antiretroviral therapy used to treat HIV is one of the most prevalent side effects occurring in at least 30% of patients living with this infection. We have evaluated the electrophysiological and behavioral effects of d4T and ddC on peripheral large and small nerve fibers in male rats treated with d4T (Sprague-Dawley, 50 mg/kg, twice within 1 week), ddC (Wistar, 50 mg/kg, 3 times per week for 3 weeks), or vehicle. The effect of the interventions was assessed using behavioral measures of mechanical sensitivity, conventional nerve conduction studies, and microneurographic single nerve C-fiber recordings. To mimic as much as possible the human clinical condition, all treated animals were included in the study. No statistically significant differences were observed in behavioral parameters of mechanical sensitivity. Nerve conduction studies did not reveal any significant change in the ddC-treated group. In contrast, we observed electrophysiological evidence of significant demyelinating neuropathy 1 week after the start of d4T treatment. Additionally, spontaneous activity in mechanoinsensitive C-nociceptors was observed in both drug-treated groups. No relationship could be established between measures of spontaneous activity in C-nociceptors and the results of the behavioral tests. Our results show that both models of antiretroviral-induced neuropathy differ in their effects on peripheral nerves. However, both groups present abnormal spontaneous activity in mechanoinsensitive C-nociceptors that can be used as a model for pharmacological intervention. PMID- 25932690 TI - Facilitated spinal neuropeptide signaling and upregulated inflammatory mediator expression contribute to postfracture nociceptive sensitization. AB - Tibia fracture induces exaggerated substance P (SP) and calcitonin gene-related peptide (CGRP) signaling and neuropeptide-dependent nociceptive and inflammatory changes in the hind limbs of rats similar to those seen in complex regional pain syndrome. Inflammatory changes in the spinal cord contribute to nociceptive sensitization in a variety of animal pain models. This study tested the hypothesis that fracture-induced exaggerated neuropeptide signaling upregulates spinal inflammatory mediator expression, leading to postfracture hind limb nociceptive sensitization. At 4 weeks after performing tibia fracture and casting in rats, we measured hind limb allodynia, unweighting, warmth, edema, and spinal cord neuropeptide and inflammatory mediator content. The antinociceptive effects of intrathecally injected neuropeptide and inflammatory mediator receptor antagonists were evaluated in fracture rats. Transgenic fracture mice lacking SP or the CGRP RAMP1 receptor were used to determine the effects of neuropeptide signaling on postfracture pain behavior and spinal inflammatory mediator expression. Hind limb allodynia, unweighting, warmth, edema, increased spinal SP and CGRP, and increased spinal inflammatory mediator expression (TNF, IL-1, IL-6, CCL2, and nerve growth factor) were observed at 4 weeks after fracture in rats. Fracture-induced increases in spinal inflammatory mediators were not observed in fracture mice lacking SP or the CGRP receptor, and these mice had attenuated postfracture nociceptive sensitization. Intrathecal injection of selective receptor antagonists for SP, CGRP, TNF, IL-1, IL-6, CCL2, or nerve growth factor each reduced pain behaviors in the fracture rats. Collectively, these data support the hypothesis that facilitated spinal neuropeptide signaling upregulates the expression of spinal inflammatory mediators contributing to nociceptive sensitization in a rodent fracture model of complex regional pain syndrome. PMID- 25932693 TI - Brain aging in female migraineurs: differences in the insula. PMID- 25932692 TI - CXCR3 chemokine receptor signaling mediates itch in experimental allergic contact dermatitis. AB - Persistent itch is a common symptom of allergic contact dermatitis (ACD) and represents a significant health burden. The chemokine CXCL10 is predominantly produced by epithelial cells during ACD. Although the chemokine CXCL10 and its receptor CXCR3 are implicated in the pathophysiology of ACD, it is largely unexplored for itch and pain accompanying this disorder. Here, we showed that CXCL10 and CXCR3 mRNA, protein, and signaling activity were upregulated in the dorsal root ganglion after contact hypersensitivity (CHS), a murine model of ACD, induced by squaric acid dibutylester. CXCL10 directly activated a subset of cutaneous dorsal root ganglion neurons innervating the area of CHS through neuronal CXCR3. In behavioral tests, a CXCR3 antagonist attenuated spontaneous itch- but not pain-like behaviors directed to the site of CHS. Injection of CXCL10 into the site of CHS elicited site-directed itch- but not pain-like behaviors, but neither type of CXCL10-evoked behaviors was observed in control mice. These results suggest that CXCL10/CXCR3 signaling mediates allergic itch but not inflammatory pain in the context of skin inflammation. Thus, upregulation of CXCL10/CXCR3 signaling in sensory neurons may contribute to itch associated with ACD. Targeting the CXCL10/CXCR3 signaling might be beneficial for the treatment of allergic itch. PMID- 25932694 TI - Erratum: Estimated exposure to arsenic in breastfed and formula-fed infants in a United States cohort. PMID- 25932695 TI - The Promise and Ambiguity of eHealth Research. PMID- 25932696 TI - Factors associated with feeding progression in extremely preterm infants. AB - BACKGROUND: Among infants born prematurely, competence at oral feeding is necessary for growth and hospital discharge. Extremely preterm (EP) infants (28 weeks of gestational age [GA]) are at risk for a variety of medical complications, which can limit the infant's capacity to develop oral feeding competence. OBJECTIVE: This study examined feeding progression by assessing timing of acquisition of five early feeding milestones among EP infants and the impact of immaturity and medical complications. DESIGN: A chart review was conducted for 94 EP infants who participated in a larger longitudinal randomized study. Feeding progression was defined as infants' postmenstrual age (PMA) at five milestones: first enteral feeding, full enteral feeding, first oral feeding, half oral feeding, and full oral feeding. GA at birth and five medical complications (neurological risk, bronchopulmonary dysplasia, necrotizing enterocolitis, patent ductus arteriosus, and gastroesophageal reflux disease) were used as potential factors influencing the feeding progression. Linear mixed models were used to examine feeding progression across the milestones and contributions of GA at birth and five medical complications on the progression, after controlling for milk type as a covariate. RESULT: EP infants gradually achieved feeding milestones; however, the attainment of the feeding milestones slowed significantly for infants with younger GA at birth and the presence of medical complications, including neurological risk, bronchopulmonary dysplasia, necrotizing enterocolitis, and patent ductus arteriosus but not gastroesophageal reflux disease. Milk type was a significant covariate for all analyses, suggesting that infants fed with breast milk achieved each of five milestones earlier than formula-fed infants. DISCUSSION: Improved understanding of the timing of essential feeding milestones among EP infants and the contribution of specific medical conditions to the acquisition of these milestones may allow for more targeted care to support feeding skill development. PMID- 25932698 TI - Psychosocial determinants of physical activity in children attending afterschool programs: a path analysis. AB - BACKGROUND: Physical activity (PA) is important for controlling childhood obesity, but a comprehensive PA model for school-aged children is lacking. OBJECTIVES: Guided by the youth PA promotion (YPAP) model, this study estimated the direct and indirect effects of self-efficacy, enjoyment, parental influence, and environment on self-reported PA and pedometer steps. A secondary purpose was to explore the association between self-reported PA and pedometer steps. METHODS: An observational and prospective study was conducted among 133 children, aged 8 11 years old, from 10 elementary schools with afterschool programs in a Midwestern U.S. school district from August through October 2013. PA was assessed by a 7-day recall scale and pedometers. Other variables were assessed by validated questionnaires. RESULTS: Approximately 65 (49%) children were overweight or obese-only 17 (13%) met national PA recommendations-and body mass index z-score was negatively correlated with pedometer steps (r = -.18 p = .04). A path analysis showed that self-efficacy had a direct effect on self-reported PA and pedometer steps, enjoyment had only a direct effect on self-reported PA, and parental influence had a direct effect on pedometer steps and an indirect effect on self-reported PA through self-efficacy and enjoyment. The association between self-reported PA and pedometer steps was not significant. DISCUSSION: Because this study only partially supports the YPAP model, studies with a larger sample size and longitudinal design are essential to further examine this model. The nonsignificant relationship of self-reported PA with pedometer steps may be due to the systematic error resulting from a common method artifact of self-report. Given the importance of parental influence, enjoyment, and self-efficacy, targeting these three determinants in future interventions to increase PA among children is recommended. PMID- 25932697 TI - Nursing case management, peer coaching, and hepatitis a and B vaccine completion among homeless men recently released on parole: randomized clinical trial. AB - BACKGROUND: Although hepatitis A virus (HAV) and hepatitis B virus (HBV) infections are vaccine-preventable diseases, few homeless parolees coming out of prisons and jails have received the hepatitis A and B vaccination series. OBJECTIVES: The study focused on completion of the HAV and HBV vaccine series among homeless men on parole. The efficacy of three levels of peer coaching (PC) and nurse-delivered interventions was compared at 12-month follow-up: (a) intensive peer coaching and nurse case management (PC-NCM); (b) intensive PC intervention condition, with minimal nurse involvement; and (c) usual care (UC) intervention condition, which included minimal PC and nurse involvement. Furthermore, we assessed predictors of vaccine completion among this targeted sample. METHODS: A randomized control trial was conducted with 600 recently paroled men to assess the impact of the three intervention conditions (PC-NCM vs. PC vs. UC) on reducing drug use and recidivism; of these, 345 seronegative, vaccine-eligible subjects were included in this analysis of completion of the Twinrix HAV/HBV vaccine. Logistic regression was added to assess predictors of completion of the HAV/HBV vaccine series and chi-square analysis to compare completion rates across the three levels of intervention. RESULTS: Vaccine completion rate for the intervention conditions were 75.4% (PC-NCM), 71.8% (PC), and 71.9% (UC; p = .78). Predictors of vaccine noncompletion included being Asian and Pacific Islander, experiencing high levels of hostility, positive social support, reporting a history of injection drug use, being released early from California prisons, and being admitted for psychiatric illness. Predictors of vaccine series completion included reporting having six or more friends, recent cocaine use, and staying in drug treatment for at least 90 days. DISCUSSION: Findings allow greater understanding of factors affecting vaccination completion in order to design more effective programs among the high-risk population of men recently released from prison and on parole. PMID- 25932700 TI - The effect of patient migration in bed on torso elevation. AB - BACKGROUND: Elevating the hospital head of bed (HOB) to at least 30 degrees is recommended practice to reduce the risk of ventilator-associated pneumonia (VAP) in mechanically ventilated patients. However, this common practice prescribes the position of the bed and not of the patient, which could be significantly different. OBJECTIVE: The aim of this research was to determine the relationship between patient migration in bed and anatomic torso angle. METHODS: Ten healthy participants were positioned in a hospital bed that was raised from flat to 30 degrees and 45 degrees HOB elevations. Prior to bed movement, participants were aligned to different locations along the length of the bed to represent different amounts of migration. A motion capture system was used to measure torso angle and migration toward the foot of the bed. The relationship between torso angle and migration was estimated by linear regression. RESULTS: Patient migration resulted in lower torso angles for both 30 degrees and 45 degrees HOB articulations. A migration of 10 cm resulted in a loss of 9.1 degrees and 13.0 degrees of torso angle for HOB articulations of 30 degrees and 45 degrees , respectively (for 30 degrees articulations: (Equation is included in full-text article.)= -0.91, R = .96; for 45 degrees articulations: (Equation is included in full-text article.)= -1.30, R = .98). DISCUSSION: Migration toward the foot of the bed flattens the torso. To maintain a torso angle that is likely to protect against VAP, healthcare providers need to manage both HOB angle and migration. Protocols and equipment that minimize patient migration will help support effective clinical practice. Future research on patient migration, as it relates to VAP or other outcomes, should measure patient torso angle to allow accurate translation of the results to care practice. PMID- 25932699 TI - Neighborhood socioeconomic status during childhood versus puberty in relation to endogenous sex hormone levels in adult women. AB - BACKGROUND: Socioeconomic adversity in early life is related to cardiovascular risk in adulthood; however, no studies have examined whether such adversity may be related to endogenous sex hormones, which are themselves associated with cardiovascular outcomes, or whether the timing of adversity exposures (childhood vs. puberty) matters. OBJECTIVE: The goal of the current study was to separately examine neighborhood socioeconomic status (SES) during periods of childhood and puberty in relation to adulthood levels of endogenous sex hormones (estradiol [E2], testosterone), sex hormone binding globulin (SHBG), and a derived index of bioavailable testosterone (free androgen index). METHODS: In a sample of 143 premenopausal women (mean age = 36.8 [SD = 5.5]; 51.7% White, 32.2% African American, 5.6% Latina, 7.0% Chinese, and 3.5% Filipina), retrospective reports of residential address information in designated periods of childhood and puberty were used to derive U.S. census-based neighborhood SES composite scores characterizing the socioeconomic environments of women during these periods. RESULTS: In covariate-adjusted analyses, higher neighborhood SES in puberty predicted higher levels of SHBG in adulthood, but neighborhood SES during childhood did not (standardized regression coefficient = .24, p = .01 vs. standardized regression coefficient = .04, p = .75, respectively). Neighborhood SES was not predictive of other hormones (E2, testosterone, and free androgen index). DISCUSSION: The current findings suggest that puberty may be a time of particular vulnerability to the effects of neighborhood SES on SHBG levels, which have been linked to cardiovascular risk factor profiles and atherosclerotic disease progression. PMID- 25932701 TI - Electronic alerts for triage protocol compliance among emergency department triage nurses: a randomized controlled trial. AB - BACKGROUND: Alerts embedded in electronic health records (EHRs) are designed to improve processes at the point of care. OBJECTIVE: The aim of this study was to determine if an EHR alert-at emergency department (ED) triage-increases the ED triage nurse's utilization of triage protocols. METHODS: ED triage nurses were randomized to receive either a passive EHR alert or no intervention for patients with the following complaints: minor trauma with extremity injuries or female patients with abdominal pain. The EHR alert notified the nurse that the patient was eligible for diagnostic testing: radiographs for patients with injured extremities or urinalysis for female patients with abdominal pain. RESULTS: Twenty-eight nurses triaged 20,410 patients in the 6 months before the intervention and 19,157 in the 6 months after the intervention. Before the intervention, the urinalysis protocol was implemented in 101/624 (16.2%) patients triaged by the intervention group and 116/711 (16.3%) triaged by the control group. After the intervention, the urinalysis protocol was implemented in 146/530 (27.6%) patients triaged by the intervention group and 174/679 (25.6%) triaged by the control group. Before the intervention, the radiograph protocol was implemented in 58/774 (7.5%) patients triaged by the intervention group and 45/684 (6.6%) triaged by the control group. After the intervention, the radiograph protocol was implemented in 78/614 (12.7%) patients triaged by the intervention group and 79/609 (13.0%) triaged by the control group. CONCLUSION: The use of a passive EHR alert to promote ED triage protocols showed little benefit. Before the widespread implementation of EHR alerts for patient care, rigorous studies are required to determine the best alert methods and the impacts of such interventions. PMID- 25932702 TI - Synthesis and biological evaluation of pharbinilic acid and derivatives as NF kappaB pathway inhibitors. AB - A 7-step synthesis of pharbinilic acid, a member of the gibberellin family of natural products and the first naturally occurring allogibberic acid, is reported. An efficient decarboxylative aromatization reaction enables the synthesis of pharbinilic acid and related analogs for evaluation as modulators of NF-kappaB activity. Remarkably, one analog displays a 2 MUM IC50 in an NF-kappaB activity assay and inhibits an endogenous NF-kappaB-regulated pathway. PMID- 25932704 TI - Luminescence studies on SnO2 and SnO2:Eu nanocrystals grown by laser assisted flow deposition. AB - Transparent conductive tin oxide materials have been a research topic extensively studied in recent years due to the great interest for many applications. However, in most of them, the pure form is rarely used, being usually modified by the incorporation of dopants. Selecting the most appropriate technique to develop nanocrystals of doped tin oxide and understanding the influence of dopant on the optical properties are the challenges that need to be addressed when envisaging devices. To fulfill this objective, the recently developed laser assisted flow deposition (LAFD) method is explored to grow SnO2 and SnO2:Eu nanocrystals. The morphology of these nanocrystals was investigated by scanning electron microscopy and well defined prismatic nanocrystals with sizes of ~60 nm were identified. The crystalline quality assessed by X-ray diffraction measurements and Raman spectroscopy indicates that the produced nanocrystals are monophasic and crystallize in the tetragonal rutile structure. Steady state luminescence studies provide the information on the optical active centres in the SnO2 and SnO2:Eu nanocrystals. For the undoped samples only broad emission bands were observed by pumping the samples in the ultraviolet region. The broad emission was found to be an overlap of green and red optical centres as identified by temperature and excitation intensity dependent luminescence. The latter was found to exhibit an excitonic-related behaviour and the green emission was found to be of utmost importance to discuss the intraionic luminescence in the doped samples. For the SnO2:Eu nanocrystals the luminescence is dominated by the magnetic allowed (5)D0 > (7)F1 transition with the ions in almost undistorted centrosymmetric sites. The ion luminescence integrated intensity is found to increase with increasing temperatures being well accounted for a thermal population provided by the thermal quenching of the green band. PMID- 25932703 TI - Hearing and Patient Satisfaction Among 19 Patients Who Received Implants Intended for Hybrid Hearing: A Two-Year Follow-Up. AB - OBJECTIVES: To measure patient satisfaction and correlate to hearing results in partially deaf patients, after hearing preservation cochlear implant surgery with hybrid hearing strategy, and to evaluate the stability of residual low-frequency hearing (LFH) over time. DESIGN: A patient satisfaction survey and a retrospective, 2-year follow-up journal study. Nineteen partially deaf patients intended for hybrid hearing responded to a questionnaire when they had used their cochlear implants for at least a year. The questionnaire consisted of the International Outcome Inventory for Hearing Aids, EuroQol Group visual analogue scale and nine questions about hybrid hearing. Pure-tone audiometry, monosyllables, and hearing in noise test results from the patients' medical records were evaluated and compared with the results from the patient satisfaction survey. RESULTS: All of the patients were satisfied with their CIs. The mean International Outcome Inventory for Hearing Aids score was 29. The CIs provided a major contribution to the speech comprehension of these partially deaf patients. Two years after surgery, the patients' mean binaural score on tests of monosyllables was 58%, and the mean signal to noise ratio was 4.6 dB. We observed ongoing deteriorations in the residual hearing of the operated ears that surpassed the deteriorations observed in the contralateral ears. One month after surgery, the LFH loss (125-500 Hz) was 17 dB, and after 2 years, this loss was 24 dB compared with 5 dB in the nonoperated ear. There were no significant correlations between preserved LFH and patient satisfaction or speech perception results. CONCLUSIONS: Electric stimulation provided a major contribution to speech comprehension of partially deaf patients. The gain reached in speech understanding widely exceeded the downside in losing some residual hearing. All the patients showed a high degree of satisfaction with their CIs regardless of varying hearing preservation. PMID- 25932705 TI - Introducing Teamwork Challenges in Simulation Using Game Cards. AB - STATEMENT: Poor teamwork and communication during resuscitations are linked to patient safety problems and poorer outcomes. We present a novel simulation-based educational intervention using game cards to introduce challenges in teamwork. This intervention uses sets of game cards that designate roles, limitations, or communication challenges designed to introduce common communication or teamwork problems. Game cards are designed to be applicable for any simulation-based scenario and are independent from patient physiology. In our example, participants were pediatric emergency medicine fellows undergoing simulation training for orientation. We describe the use of card sets in different scenarios with increasing teamwork challenge and difficulty. Both postscenario and summative debriefings were facilitated to allow participants to reflect on their performance and discover ways to apply their strategies to real resuscitations. In this article, we present our experience with the novel use of game cards to modify simulation scenarios to improve communication and teamwork skills. PMID- 25932706 TI - Simulation With PARTS (Phase-Augmented Research and Training Scenarios): A Structure Facilitating Research and Assessment in Simulation. AB - INTRODUCTION: Assessment in simulation is gaining importance, as are scenario design methods increasing opportunity for assessment. We present our approach to improving measurement in complex scenarios using PARTS [Phase-Augmented Research and Training Scenarios], essentially separating cases into clearly delineated phases. METHODS: We created 7 PARTS with real-time rating instruments and tested these in 63 cases during 4 weeks of simulation. Reliability was tested by comparing real-time rating with postsimulation video-based rating using the same instrument. Validity was tested by comparing preintervention and postintervention total results, by examining the difference in improvement when focusing on the phase-specific results addressed by the intervention, and further explored by trying to demonstrate the discrete improvement expected from proficiency in the rare occurrence of leader inclusive behavior. RESULTS: Intraclass correlations [3,1] between real-time and postsimulation ratings were 0.951 (95% confidence interval [CI], 0.794-0.990), 1.00 (95% CI, --to--), 0.948 (95% CI, 0.783-0.989), and 0.995 (95% CI, 0.977-0.999) for 3 phase-specific scores and total scenario score, respectively. Paired t tests of prelecture-postlecture performance showed an improvement of 14.26% (bias-corrected and accelerated bootstrap [BCa] 95% CI, 4.71-23.82; P = 0.009) for total performance but of 28.57% (BCa 95% CI, 13.84 43.30; P = 0.002) for performance in the respective phase. The correlation of total scenario performance with leader inclusiveness was not significant (rs = 0.228; BCa 95% CI. -0.082 to 0.520; P = 0.119) but significant for specific phase performance (rs = 0.392; BCa 95% CI, 0.118-0.632; P = 0.006). CONCLUSIONS: The PARTS allowed for improved reliability and validity of measurements in complex scenarios. PMID- 25932707 TI - Goal-Directed Transthoracic Echocardiography During Advanced Cardiac Life Support: A Pilot Study Using Simulation to Assess Ability. AB - INTRODUCTION: Goal-directed echocardiography (GDE) is used to answer specific clinical questions that provide invaluable information to physicians managing a hemodynamically unstable patient. We studied perception and ability of house staff previously trained in GDE to accurately diagnose common causes of cardiac arrest during simulated advanced cardiac life support (ACLS); we compared their results with those of expert echocardiographers. METHODS: Eleven pulmonary and critical care medicine fellows, 7 emergency medicine residents, and 5 cardiologists board certified in echocardiography were enrolled. Baseline ability to acquire 4 transthoracic echocardiography views was assessed, and participants were exposed to 6 simulated cardiac arrests and were asked to perform a GDE during ACLS. House staff performance was compared with the performance of 5 expert echocardiographers. RESULTS: Average baseline and scenario views by house staff were of good or excellent quality 89% and 83% of the time, respectively. Expert average baseline and scenario views were always of good or excellent quality. House staff and experts made the correct diagnosis in 68% and 77% of cases, respectively. On average, participants required 1.5 pulse checks to make the correct diagnosis. Of house staff, 94% perceived this study as an accurate assessment of ability. CONCLUSIONS: In an ACLS-compliant manner, house staff are capable of diagnosing management-altering pathologies the majority of the time, and they reach similar diagnostic conclusions in the same amount of time as expert echocardiographers in a simulated cardiac arrest scenario. PMID- 25932708 TI - In situ simulated cardiac arrest exercises to detect system vulnerabilities. AB - INTRODUCTION: Sudden cardiac arrest is the leading cause of death in the United States. Despite new therapies, progress in this area has been slow, and outcomes remain poor even in the hospital setting, where providers, drugs, and devices are readily available. This is partly attributed to the quality of resuscitation, which is an important determinant of survival for patients who experience cardiac arrest. Systems problems, such as deficiencies in the physical space or equipment design, hospital-level policies, work culture, and poor leadership and teamwork, are now known to contribute significantly to the quality of resuscitation provided. METHODS: We describe an in situ simulation-based quality improvement program that was designed to continuously monitor the cardiac arrest response process for hazards and defects and to detect opportunities for system optimization. RESULTS: A total of 72 simulated unannounced cardiac arrest exercises were conducted between October 2010 and September 2013 at various locations throughout our medical center and at different times of the day. We detected several environmental, human-machine interface, culture, and policy hazards and defects. We used the Systems Engineering Initiative for Patient Safety (SEIPS) model to understand the structure, processes, and outcomes related to the hospital's emergency response system. Multidisciplinary solutions were crafted for each of the hazards detected, and the simulation program was used to iteratively test the redesigned processes before implementation in real clinical settings. CONCLUSIONS: We describe an ongoing program that uses in situ simulation to identify and mitigate latent hazards and defects in the hospital emergency response system. The SEIPS model provides a framework for describing and analyzing the structure, processes, and outcomes related to these events. PMID- 25932709 TI - Learning outcomes associated with patient simulation method in pharmacotherapy education: an integrative review. AB - STATEMENT: The aims of this systematic integrative review were to identify evidence for the use of patient simulation teaching methods in pharmacotherapy education and to explore related learning outcomes. A systematic literature search was conducted using 6 databases as follows: CINAHL, PubMed, SCOPUS, ERIC, MEDIC, and the Cochrane Library, using the key words relating to patient simulation and pharmacotherapy. The methodological quality of each study was evaluated. Eighteen articles met the inclusion criteria. The earliest article was published in 2005. The selected research articles were subjected to qualitative content analysis. Patient simulation has been used in pharmacotherapy education for preregistration nursing, dental, medical, and pharmacy students and for the continuing education of nurses. Learning outcomes reported were summarized as follows: (1) commitment to pharmacotherapy learning, (2) development of pharmacotherapy evaluation skills, (3) improvement in pharmacotherapy application skills, and (4) knowledge and understanding of pharmacotherapy. To develop effective teaching methods and ensure health care professionals' competence in medication management, further research is needed to determine the educational and clinical effectiveness of simulation teaching methods. PMID- 25932710 TI - Deception and simulation education: issues, concepts, and commentary. AB - STATEMENT: The use of deceptive methodology in simulation education is an emerging ethical controversy. At the 2014 International Meeting on Simulation in Healthcare, arguments for and against its use were debated by simulation experts. What emerged from this discussion was an apparent disconnect between current practice and existing empiric research on this subject. At present, no framework exists to guide the simulation community's exploration of this issue of deception.After reviewing the relevant psychological literature, we propose a framework delineating discrete elements and important relationships, which enables a comprehensive view of the factors germane to simulations that use deception. We further comment on key pedagogical and psychological issues in the context of this framework and define an agenda for further research. Educators are encouraged to use this framework when determining whether, when, and how deception might be used and, if used, how it can be ethically justified and carefully implemented. PMID- 25932711 TI - Enhancing the patient and family experience. PMID- 25932712 TI - Can online PA programs reduce the cost of PA education? PMID- 25932713 TI - Understanding Brugada syndrome. AB - Brugada syndrome is an established cause of sudden cardiac arrest in patients without structural cardiac abnormalities. Recognition and diagnosis of this syndrome has been slowly increasing. Syncope, ventricular dysrhythmia, or sudden cardiac arrest may be the presenting symptom, although detection of the characteristic right precordial ST-segment elevation on ECG can be a potentially lifesaving intervention. This article reviews the clinical presentation, pathophysiology, genetics, and current management of Brugada syndrome. PMID- 25932714 TI - Recognizing and managing infections in total joint arthroplasty. AB - Periprosthetic joint infections are a devastating complication of joint arthroplasty procedures, affecting 1% to 4% of patients. With the increasing demand for joint replacement, the clinical and financial burden of periprosthetic joint infections is challenging. This article reviews the diagnosis and treatment of periprosthetic joint infections. PMID- 25932715 TI - Transfer of HLA-Specific Allosensitization From a Highly Sensitized Deceased Organ Donor to the Recipients of Each Kidney. AB - We report for the first time the adoptive transfer of donor HLA-specific allosensitization in two recipients following kidney transplantation from a highly sensitized donor. Kidneys from a donation after circulatory death donor were transplanted into two nontransfused, HLA-specific antibody negative males receiving their first transplant. Antibody screening 7 days after transplant showed high level de novo IgG HLA class I- and class II-specific antibodies in both recipients, with largely overlapping antibody profiles but no antibodies to donor HLA. The unusually rapid appearance of de novo alloantibodies in immunosuppressed nonsensitized recipients and absence of donor HLA-specific antibody prompted testing of stored donor serum that revealed high antibody levels with specificities very similar to those seen in both recipients, but in addition the presence of strong antibodies to each recipient HLA. Alloantibody levels gradually declined but were still detectable at 3 months. These findings suggest that alloreactive passenger B cells/plasma cells within the kidneys of highly sensitized donors may give rise to rapid development of posttransplant de novo HLA-specific alloantibodies. While the clinical significance of this phenomenon is uncertain it provides one explanation for the appearance of de novo HLA-specific antibodies directed against third party but not donor HLA. PMID- 25932716 TI - Antidepressant-like and anxiolytic-like effects of hydrogen sulfide in streptozotocin-induced diabetic rats through inhibition of hippocampal oxidative stress. AB - Depression is highly prevalent in individuals with diabetes, and depressive symptoms are less responsive to current antidepressant therapies. Oxidative stress plays a major role both in the pathogenesis of diabetes and in major depression and anxiety disorders. Hydrogen sulfide (H2S), the third gaseous mediator, is a novel signaling molecule in the brain that has both antioxidative activity and antidepressant-like and anxiolytic-like effects. We hypothesized that H2S could produce antidepressant-like and anxiolytic-like effects in diabetic patients through its antioxidative effect. To test this hypothesis, we generated streptozotocin (STZ)-induced diabetic rats. We found that H2S alleviated depressive-like behaviors of STZ-induced diabetic rats in the forced swimming and tail suspension tests and reduced their anxiety-like behaviors in the elevated plus maze test. We also found that H2S significantly reduced levels of malondialdehyde and 4-hydroxynonenal and elevated levels of superoxide dismutase and reduced glutathione in the hippocampus of STZ-induced diabetic rats. The results provide evidence for antidepressant-like and anxiolytic-like effects of H2S in STZ-induced diabetic rats and suggest that the therapeutic effects may result from inhibition of hippocampal oxidative stress. These findings suggest that elevating H2S signaling is a potential target for treatment of depressive and anxiety disorders related to diabetes. PMID- 25932717 TI - Chronic treatment with a selective 5-HT6 receptor antagonist alters the behavioral and neurochemical effects of ethanol in young adult rats. AB - Experimental evidence indicates a potential role of 5-HT6 receptors in the regulation of addictive behavior. We studied the effects of a potent and selective 5-HT6 receptor antagonist (compound A) on voluntary ethanol intake and behavioral/neurochemical changes induced by ethanol. The pharmacokinetic interaction of compound A and ethanol was assessed. The effect of compound A on schedule-induced ethanol polydipsia was studied to determine its effect on voluntary ethanol intake. Open-field and ethanol-induced loss of righting reflex assays were carried out to determine the effect of compound A on the ataxic and sedative effects of ethanol. The effect on motor learning was evaluated using rotarod and brain microdialysis was carried out to study the effect on monoaminergic neurotransmission. No significant changes were observed in the pharmacokinetic parameters of compound A when cotreated with ethanol. Compound A significantly decreased voluntary ethanol consumption and attenuated the effects of ethanol on motor learning. Compound A also antagonized the sedative and ataxic effects of ethanol. The effect of ethanol on the dopaminergic and noradrenergic neurotransmission was blocked by compound A. The effects of compound A were evident only after chronic treatment. Compound A may have attenuated the behavioral effects of ethanol by blocking the ethanol-induced efflux of dopamine and norepinephrine in the motor cortex. PMID- 25932718 TI - The effects of a shared history of drug exposure on social choice. AB - Selection theories of drug use propose that individuals choose or self-select into peer groups on the basis of perceived similarities with other group members with regard to their beliefs, attitudes, and histories of drug use. The purpose of the present study was to determine whether a shared history of drug exposure would influence choice of a social partner. Adolescent male rats were treated with either cocaine (3.0 mg/kg, intraperitoneally) or saline and their preference for a cocaine-treated rat or a saline-treated rat was measured in a partner preference test. Next, a series of conditioning trials were conducted in which rats were paired with a cocaine-treated and a saline-treated partner on alternating days for 10 days. Finally, a second partner preference test was conducted, in which preference for cocaine-treated and saline-treated partners was reassessed. Relative to baseline, rats showed an increase in the amount of time they spent with their similarly treated partner, and this effect was driven by cocaine-treated rats increasing the amount of time spent in proximity to their cocaine-treated partner after conditioning. These findings support a selection model of drug use by showing that a shared history of drug exposure is sufficient to establish a social preference for one individual over another. PMID- 25932719 TI - Pharmacological profile of encounter-induced hyperactivity in isolation-reared mice. AB - We have recently found that isolation-reared mice show hyperactivity during an encounter with an intruder. However, it is not known whether encounter-induced hyperactivity may model some aspects of psychiatric disorders. The present study examined the pharmacological profile of encounter-induced hyperactivity in isolation-reared mice. Encounter-induced hyperactivity was reduced by acute administration of various antidepressants including the tricyclic antidepressant desipramine (10 mg/kg), the selective serotonin (5-HT) reuptake inhibitors fluvoxamine (10 mg/kg) and paroxetine (10 mg/kg), the 5-HT/noradrenaline reuptake inhibitors venlafaxine (10 mg/kg) and duloxetine (10 mg/kg), the antipsychotic drug risperidone (0.01 mg/kg), the 5-HT2 antagonist ritanserin (1 mg/kg), and the glucocorticoid receptor antagonist RU-43044 (30 mg/kg). The alpha2 adrenoceptor agonist clonidine (0.03 mg/kg) and the 5-HT4 receptor agonist BIMU8 (30 mg/kg) also reduced encounter-induced hyperactivity. The effect of desipramine was blocked by the alpha2 adrenoceptor antagonist idazoxan (0.3 mg/kg). The effect of fluvoxamine was blocked by the 5-HT4 receptor antagonist GR125487 (3 mg/kg), but not the 5-HT1A receptor antagonist WAY100635 (1 mg/kg), the 5-HT3 receptor antagonist azasetron (3 mg/kg), or the 5-HT6 receptor antagonist SB399885 (3 mg/kg). The effect of venlafaxine was blocked by the simultaneous administration of idazoxan (0.3 mg/kg) and GR125487 (3 mg/kg), but not by either compound alone. These findings suggest that encounter-induced hyperactivity in isolation-reared mice is a robust model for testing the pharmacological profile of antidepressants, although the range of antidepressants tested is limited and some non-antidepressants are also effective. The present study also shows a key role of alpha2 and 5-HT4 receptors in the antidepressant effect in this model. PMID- 25932720 TI - The effects of systemic administration and local microinjection into the central nervous system of the selective serotonin 5-HT2C receptor agonist RO-600175 on sleep and wakefulness in the rat. AB - The effects of RO-600175, a selective 5-HT2C receptor agonist, were studied in adult rats implanted for chronic sleep recordings. Intraperitoneal administration of RO-600175 (4 mg/kg) during the light phase of the light-dark cycle significantly increased wakefulness and reduced slow wave sleep and rapid-eye movement sleep during the first 2 h of the recording period. Direct infusion of RO-600175 into the dorsal raphe nucleus (4 mmol/l), laterodorsal tegmental nucleus (4 mmol/l), or horizontal limb of the diagonal band of Broca (4 mmol/l) also decreased rapid-eye-movement sleep. It is proposed that the activation of gamma-aminobutyric acid-ergic cells located in the dorsal raphe nucleus, laterodorsal tegmental nucleus, and horizontal limb of the diagonal band of Broca is responsible, at least in part, for the effects of RO-600175 on rapid-eye movement sleep. It is suggested that the increased wakefulness observed after systemic injection of the 5-HT2C receptor ligand could be partly related to the increased release of acetylcholine in the frontal cortex and hippocampus. However, additional studies are required to characterize the neurotransmitter systems responsible for the increase in wakefulness. PMID- 25932721 TI - Common experience modifies the reinforcing properties of methamphetamine-injected cage mates but not morphine-injected cage mates in C57 mice. AB - The aim of this study was to determine whether previous exposure to a drug affects the social facilitation of conditioned place preference (CPP) for a drug injected cage mate. Twenty-two male C57/BL6J mice received drug injections (methamphetamine or morphine) and 22 male C57/BL6J mice received saline injections. All 44 mice then received CPP training, during which one compartment of a conventional CPP apparatus was associated with a drug-injected cage mate (stimulus mouse) and the other compartment was associated with a saline-injected cage mate (stimulus mouse). The subject mice did not receive any drug injection during this CPP training. Time spent in the compartment associated with the drug injected cage mate was measured before and after training. Subject mice that had previously received methamphetamine injections showed an increase in the time spent in the compartment associated with the methamphetamine-injected cage mate after CPP training. This effect was not observed in subject mice that had previously received saline injections. Subject mice did not show an increase in the time spent in the compartment associated with the morphine-injected cage mate irrespective of whether they had previously received morphine or saline injections. Therefore, in agreement with previous reports, common experience with methamphetamine induced reinforcing properties, but that with morphine did not. PMID- 25932722 TI - Temperature and pressure dependence of methane correlations and osmotic second virial coefficients in water. AB - We report methane's osmotic virial coefficient over the temperatures 275 to 370 K and pressures from 1 bar up to 5000 bar evaluated using molecular simulations of a united-atom description of methane in TIP4P/2005 water. In the first half of this work, we describe an approach for calculating the water-mediated contribution to the methane-methane potential-of-mean force over all separations down to complete overlap. The enthalpic, entropic, heat capacity, volumetric, compressibility, and thermal expansivity contributions to the water-mediated interaction free energy are subsequently extracted from these simulations by fitting to a thermodynamic expansion over all the simulated state points. In the second half of this work, methane's correlation functions are used to evaluate its osmotic second virial coefficient in the temperature-pressure plane. The virial coefficients evaluated from the McMillan-Mayer correlation function integral are shown to be in excellent agreement with those determined from the concentration dependence of methane's excess chemical potential, providing an independent thermodynamic consistency check on the accuracy of the procedures used here. At atmospheric pressure the osmotic virial coefficient decreases with increasing temperature, indicative of increasing hydrophobic interactions. At low temperature, the virial coefficient decreases with increasing pressure while at high temperature the virial coefficient increases with increasing pressure, reflecting the underlying hyperbolic dependence of the virial coefficient on temperature and pressure. The transition between a decreasing to increasing pressure response of the osmotic virial coefficient is shown to follow the response of the methane-methane contact peak to changes in pressure as a function of temperature, though a universal correlation is not observed. PMID- 25932723 TI - Preoperative and intraoperative prognostic factors of epiretinal membranes using chromovitrectomy and internal limiting membrane peeling. AB - BACKGROUND AND OBJECTIVE: To evaluate the preoperative and intraoperative findings as prognostic indicators of functional and anatomic results of idiopathic epiretinal membrane (ERM) surgery. PATIENTS AND METHODS: Vitrectomies included ERM and internal limiting membrane (ILM) removal with vital dyes. Best corrected visual acuity (BCVA), optical coherence tomography (OCT), fluorescein angiography, and autofluorescence were performed at baseline and postoperatively. Intraoperative ILM status after ERM removal was also evaluated. RESULTS: Thirty one eyes were monitored for a mean of 16.78 months. BCVA and central foveal thickness (CFT) improved significantly (P < .001) from baseline at 3 and 12 months. Preoperative hyperautofluorescence was associated with greater CFT reduction (P < .005). ILM status after ERM peeling did not influence visual recovery but was associated with anatomical results as measured by OCT. CONCLUSION: Preoperative poor initial BCVA and RPE defects by FAF may not be bad prognostic factors. Preoperative hyperautofluorescence was associated with greater CFT reduction. Intraoperative classification of ILM status after ERM and ILM staining/peeling was reported and may be useful for future studies, though it was not associated neither with preoperative nor postoperative BCVA. PMID- 25932724 TI - Adverse vitreoretinal outcomes of glaucoma drainage devices based on verified and unverified financial claims data. AB - BACKGROUND AND OBJECTIVE: To determine adverse vitreoretinal outcome rates after glaucoma drainage device (GDD) surgery. PATIENTS AND METHODS: Medical records from the Anne Bates Leach Eye Hospital with financial claims from 1991 to 2005 for GDD surgery coded for endophthalmitis, choroidal hemorrhage, or retinal detachment were reviewed. Cumulative incidences were calculated before and after verifying claims with chart review. RESULTS: GDD surgery was performed in 2,661 eyes. Thirty-three cases of endophthalmitis were identified, with 10 attributable to GDD (1-, 5-, and 10-year cumulative incidences: 0.22%, 0.43%, and 0.83%, respectively). Forty cases of choroidal hemorrhage were identified, with 20 attributable to GDD (1-, 5-, and 10-year incidences: 0.81% for all time points). Rhegmatogenous retinal detachments developed in 148 eyes, with 42 attributable to GDD (1-, 5-, and 10-year incidences: 1.25%, 2.02%, and 2.67%, respectively). CONCLUSION: This study's complication rates compare favorably with those previously reported. The use of claims data without chart review verification may result in overestimated event rates. PMID- 25932725 TI - Vitreous incarceration after ranibizumab injection: an ultrasound biomicroscopy study. AB - BACKGROUND AND OBJECTIVE: The aim of the study was to evaluate vitreous incarceration at the injection site using ultrasound biomicroscopy (UBM) after intravitreal injection of ranibizumab. PATIENTS AND METHODS: The study included 39 eyes of 34 patients who underwent intravitreal injection of 0.05 mL of ranibizumab. UBM (HiScan; Optikon, Rome, Italy) with a 50 MHz probe was performed 1 day after surgery to determine the existence of vitreous incarceration at the injection site. RESULTS: The mean patient age was 59.7 (+/- 10.1) years, and 58.9% were female. Vitreous incarceration into the pars plana site was detected in six eyes (15.3%) the day after intravitreal injection. CONCLUSION: Vitreous incarceration at the injection site after intravitreal injection is thought to lead to a higher risk for complications such as infection, retinal breaks, retinal detachment, vitreous hemorrhage, and fibrovascular proliferation at the injection site. To understand the clinical importance of vitreous incarceration, further long-term prospective studies are necessary. PMID- 25932726 TI - Intravenous catheter-assisted scleral fixation of an intraocular lens in eyes without adequate capsular support. AB - BACKGROUND AND OBJECTIVE: Sutureless scleral fixation is an effective technique for placement of a secondary intraocular lens. The authors propose a modification that may simplify intraoperative technical challenges. STUDY DESIGN: Description of surgical technique. RESULTS: Successful placement of stable secondary intraocular lens. CONCLUSION: This modified technique has the potential to reduce intraoperative complications. Studies including more patients with longer follow up are needed to test the viability. PMID- 25932727 TI - Retinoschisis and outer retinal hole formation in a patient with papillorenal syndrome. AB - This report describes a 19-year-old patient with the rare association of macular retinoschisis and outer retinal hole formation with papillorenal syndrome. Initially diagnosed with transplant-related central serous chorioretinopathy, she presented several years later with worsening vision and distortion in her right eye. On examination, she was found to have bilateral optic nerve dysplasia, bilateral macular and extramacular retinoschisis, and a serous retinal detachment with outer hole formation in the right eye. A history of prior renal transplantation due to poor kidney development led to the diagnosis of papillorenal syndrome. PMID- 25932728 TI - Evolution of septated cavitary subretinal fluid after treatment of choroidal metastasis. AB - An 83-year-old man presented with a 10-day history of decreased vision in the left eye. He was found to have choroidal metastases from lung adenocarcinoma that exhibited unilateral septated cavitary subretinal fluid on spectral-domain optical coherence tomography (OCT). This fluid evolved into atypical lamellar sheets after treatment with systemic chemotherapy and orbital radiation prior to resolution. This is the first description demonstrating cavitary subretinal fluid pockets on spectral-domain OCT from lung cancer; attention is given to its unusual course and proposed pathogenesis. PMID- 25932729 TI - Self-induced laser maculopathy in an adolescent boy utilizing a mirror. AB - Laser maculopathy is a rare complication that can occur when a beam of laser light is focused directly on the macula. This report describes the first published case of self-induced laser pointer maculopathy that was secondary to laser beam reflection from a mirror. The patient demonstrated both visual and anatomic recovery during the follow-up period. In addition, the issue of discrepancy between the labeled and actual power of laser pointers is addressed. PMID- 25932730 TI - An unusual and spontaneous resolution of a total rhegmatogenous retinal detachment. AB - Spontaneous reattachment of rhegmatogenous retinal detachment is a rare event that involves the relief of vitreoretinal traction, closure of the retinal breaks, and reabsorption of subretinal fluid. Diffuse retinal pigmentary alterations within a sharply demarcated and convex margin are the most common findings within the areas corresponding to the reattached retina in all the cases described in the literature. The authors report the case of a 60-year-old man who experienced spontaneous reattachment of a total rhegmatogenous retinal detachment with gradual recovery of visual function and a completely restored retina. This is the first case reported that does not exhibit the ophthalmoscopic findings commonly described in the literature. PMID- 25932731 TI - Microstructural retinal findings by spectral-domain optical coherence tomography after vitrectomy repair of rhegmatogenous retinal detachments. AB - BACKGROUND AND OBJECTIVE: To evaluate macular microstructural changes after macula-involving rhegmatogenous retinal detachment repair and correlate with visual recovery. PATIENTS AND METHODS: A prospective, observational study was performed of select patients presenting with macula-involving rhegmatogenous retinal detachments (RRD). Spectral-domain optical coherence tomography (SD-OCT) imaging was performed at postoperative visits over the course of the first year after operative repair of the RRD. RESULTS: The maculas of seven patients were evaluated. Postoperative best corrected visual acuity (BCVA) at the final follow up ranged from 20/20 to 20/70 for all patients. Eyes with final BCVA greater than 20/40 had intact external limiting membrane and outer photoreceptor structures, while those with BCVA of less than 20/70 had poorer definition to those structures. Serial images showed resolution of irregularities in both the external limiting membrane and outer photoreceptor structures. CONCLUSION: Macular structure and function can progressively improve in the first year after successful RRD repair, including in the external limiting membrane, damage to which has previously been thought to be irreversible. SD-OCT serves as a useful tool to monitor postoperative retinal recovery. PMID- 25932732 TI - Acute retinal necrosis secondary to herpes simplex virus type 2 in neonates. AB - Acute retinal necrosis (ARN) should be in the differential diagnosis of a neonate who presents with vitritis. This report includes three cases of neonatal ARN at the Bascom Palmer Eye Institute from 2004 to 2009. Medical treatment with acyclovir helped reduce sequelae of herpes simplex virus (HSV) 2 infection. Patients with ARN are at risk for retinal detachment and blindness. Although mothers are screened during pregnancy, they are at risk of reactivation or primary contraction of HSV. A neonate presenting with vitritis should raise suspicion of ARN. PMID- 25932733 TI - Outcome measures need context. PMID- 25932734 TI - To the Editor: Diabetes therapy and cardiac risk. PMID- 25932735 TI - In Reply: Diabetes therapy and cardiac risk. PMID- 25932736 TI - Should we be concerned about thyroid cancer in patients taking glucagon-like peptide 1 receptor agonists? PMID- 25932737 TI - But how many people died? Health outcomes in perspective. PMID- 25932738 TI - Pneumatosis cystoides intestinalis: Is surgery always indicated? PMID- 25932739 TI - Does the patient need ultrasonography of the leg to evaluate for deep vein thrombosis? PMID- 25932740 TI - When the dissociation curve shifts to the left. PMID- 25932741 TI - Is triglyceride therapy worth the effort? AB - A scientific statement from the American Heart Association notes that triglyceride levels are an important biomarker of cardiovascular disease risk. Although as yet there is no evidence that lowering elevated triglyceride levels reduces cardiovascular risk, the statement recommends that patients undertake weight loss and dietary changes if fasting levels exceed 150 mg/dL, and that the intensity of these lifestyle measures be increased with higher triglyceride levels. Aerobic activity at least twice a week is also encouraged. Drug therapy is indicated for levels exceeding 500 mg/dL because of an association with pancreatitis. PMID- 25932742 TI - Left atrial appendage closure: An emerging option in atrial fibrillation when oral anticoagulants are not tolerated. AB - Atrial fibrillation is associated with a risk of stroke, primarily from embolization of clots that form in the left atrial appendage. This structure has been targeted to reduce stroke risk in patients who have contraindications to oral anticoagulation. This article appraises the current literature describing surgical and percutaneous isolation of the left atrial appendage. PMID- 25932743 TI - Managing aneurysmal subarachnoid hemorrhage: It takes a team. AB - Patients with aneurysmal subarachnoid hemorrhage are at high risk of complications, including rebleeding, delayed cerebral ischemia, cerebral infarction, and death. This review presents a practical approach for managing this condition and its complications. PMID- 25932744 TI - Cerebrospinal fluid diversion in patients with enlarged Virchow-Robin spaces without ventriculomegaly. AB - OBJECTIVE: Enlarged Virchow-Robin spaces (eVRS) are an MRI biomarker in several neurological diseases of inflammatory, neurodegenerative, vascular, metabolic, or genetic origin. We report on a further condition in which eVRS were observed in patients with an ongoing chronic hydrocephalus-like clinical picture without ventriculomegaly who improved after CSF diversion, and we discuss the possible mechanisms underlying this finding. MATERIALS AND METHODS: A retrospective study of seven patients presenting progressive gait, cognitive, and urinary disturbances in association with eVRS was undertaken. RESULTS: All patients presented an Evans ratio <0.30 and >20 eVRS at the level of basal ganglia and periventricular parenchyma as assessed by T2-weighted MRI. All patients underwent prolonged external lumbar drainage (PELD) with good response. Six patients received ventriculoperitoneal shunt with improvement of their clinical status compared to that before PELD (follow-up: 8-58 months, mean 24.6). The seventh patient did not undergo ventriculoperitoneal shunt and received a second PELD with persistent improvement (follow-up: 14 months). CONCLUSIONS: Our results indicate that a mechanism involving CSF accumulation and stasis in the subarachnoid space was at least a concurrent factor of this clinical picture. This study should stimulate new perspectives on the role of CSF disturbances in the pathogenesis of diseases associated with VRS enlargement. PMID- 25932745 TI - Lycopene inhibits cyclic strain-induced endothelin-1 expression through the suppression of reactive oxygen species generation and induction of heme oxygenase 1 in human umbilical vein endothelial cells. AB - Lycopene is the most potent active antioxidant among the major carotenoids, and its use has been associated with a reduced risk for cardiovascular disease (CVD). Endothelin-1 (ET-1) is a powerful vasopressor synthesized by endothelial cells and plays a crucial role in the pathophysiology of CVD. However, the direct effects of lycopene on vascular endothelial cells have not been fully described. This study investigated the effects of lycopene on cyclic strain-induced ET-1 gene expression in human umbilical vein endothelial cells (HUVECs) and identified the signal transduction pathways that are involved in this process. Cultured HUVECs were exposed to cyclic strain (20% in length, 1 Hz) in the presence or absence of lycopene. Lycopene inhibited strain-induced ET-1 expression through the suppression of reactive oxygen species (ROS) generation through attenuation of p22(phox) mRNA expression and NAD(P)H oxidase activity. Furthermore, lycopene inhibited strain-induced ET-1 secretion by reducing ROS-mediated extrace-llular signal-regulated kinase (ERK) phosphorylation. Conversely, lycopene treatment enhanced heme oxygenase-1 (HO-1) gene expression through the activation of phosphoinositide 3-kinase (PI3K)/Akt pathway, followed by induction of the nuclear factor erythroid 2-related factor 2 (Nrf2) nuclear translocation; in addition, HO-1 silencing partially inhibited the repressive effects of lycopene on strain-induced ET-1 expression. In summary, our study showed, for the first time, that lycopene inhibits cyclic strain-induced ET-1 gene expression through the suppression of ROS generation and induction of HO-1 in HUVECs. Therefore, this study provides new valuable insight into the molecular pathways that may contribute to the proposed beneficial effects of lycopene on the cardiovascular system. PMID- 25932747 TI - Formation of a Cationic Calcium Hydride Cluster with a "Naked" Triphenylsilyl Anion by Hydrogenolysis of Bis(triphenylsilyl)calcium. AB - Protonolysis of bis(triphenylsilyl)calcium [Ca(SiPh3)2(THF)4] (1; THF = tetrahydrofuran) with the NNNN-type macrocyclic amido triamine (Me3TACD)H (TACD = 1,4,7-triazacyclododecane) gave the heteroleptic calcium complex [Ca(Me3TACD)SiPh3] (2) in quantitative yield. Hydrogenolysis of 2 gave the cationic tricalcium dihydride cluster [Ca3H2(Me3TACD)3](+)(SiPh3)(-).2THF (4a) in high yield with concomitant formation of HSiPh3. In the crystal, 4a consists of a cluster cation and a free triphenylsilyl anion. (1)H NMR spectroscopy and deuterium labeling experiments confirmed the selective cleavage of dihydrogen by the highly polar Ca-Si bond in 1. PMID- 25932746 TI - Phage amplification and immunomagnetic separation combined with targeted mass spectrometry for sensitive detection of viable bacteria in complex food matrices. AB - We have developed and describe here for the first time a highly sensitive method for the fast and unambiguous detection of viable Escherichia coli in food matrices. The new approach is based on using label-free phages (T4), obligate parasites of bacteria, which are attractive for pathogen detection because of their inherent natural specificity and ease of use. A specific immunomagnetic separation was used to capture the progeny phages produced. Subsequently, T4 phage markers were detected by liquid chromatography coupled to targeted mass spectrometry. Combining the specificity of these three methodologies is of great interest in developing an alternative to conventional time-consuming culture based technologies for the detection of viable bacteria for industrial applications. First, optimization experiments with phage T4 spiked in complex matrices (without a phage amplification event) were performed and demonstrated specific, sensitive, and reproducible phage capture and detection in complex matrices including Luria-Bertani broth, orange juice, and skimmed milk. The method developed was then applied to the detection of E. coli spiked in foodstuffs (with a phage amplification event). After having evaluated the impact of infection duration on assay sensitivity, we showed that our assay specifically detects viable E. coli in milk at an initial count of >=1 colony-forming unit (cfu)/mL after an 8-h infection. This excellent detection limit makes our new approach an alternative to PCR-based assays for rapid bacterial detection. PMID- 25932748 TI - Chemoselective intramolecular functionalization of methyl groups in nonconstrained molecules promoted by N-iodosulfonamides. AB - Mechanistic evidence observed in Hofmann-Loffler-Freytag-type reactions has been crucial to achieve the chemoselective functionalization of methyl groups under mild conditions. Radical-mediated methyl iodination and subsequent oxidative deiodination are the key steps in this functionalization, where iodine chemistry has a pivotal role on the formation of the C-N bond. The concepts of single hydrogen atom transfer (SHAT) and multiple hydrogen atom transfer (MHAT) are introduced to describe the observed chemoselectivity. PMID- 25932749 TI - Template-Assisted Hydrothermal Synthesis of Li2MnSiO4 as a Cathode Material for Lithium Ion Batteries. AB - Lithium manganese silicate (Li2MnSiO4) is an attractive cathode material with a potential capacity above 300 mA h g(-1) if both lithium ions can be extracted reversibly. Two drawbacks of low electronic conductivity and structural collapse could be overcome by a conductive surface coating and a porous structure. Porous morphology with inner mesopores offers larger surface area and shorter ions diffusion pathways and also buffers the volume changes during lithium insertion and extraction. In this paper, mesoporous Li2MnSiO4 (M-Li2MnSiO4) prepared using MCM-41 as template through a hydrothermal route is compared to a sample of bulk Li2MnSiO4 (B-Li2MnSiO4) using silica as template under the same conditions. Also, in situ carbon coating technique was used to improve the electronic conductivity of M-Li2MnSiO4. The physical properties of these cathode materials were further characterized by SEM, XRD, FTIR, and N2 adsorption-desorption. It is shown that M Li2MnSiO4 exhibits porous structure with pore sizes distributed in the range 9-12 nm, and when used as cathode electrode material, M-Li2MnSiO4 exhibits enhanced specific discharge capacity of 193 mA h g(-1) at a constant current of 20 mA g( 1) compared with 120.1 mA h g(-1) of B-Li2MnSiO4. This is attributed to the porous structure which allows the electrolyte to penetrate into the particles easily. And carbon-coated M-Li2MnSiO4 shows smaller charge transfer resistance and higher capacity of 217 mA h g(-1) because carbon coating retains the porous structure and enhances the electrical conductivity. PMID- 25932750 TI - Jump Shrug Height and Landing Forces Across Various Loads. AB - The purpose of this study was to examine the effect that load has on the mechanics of the jump shrug. Fifteen track and field and club/intramural athletes (age 21.7 +/- 1.3 y, height 180.9 +/- 6.6 cm, body mass 84.7 +/- 13.2 kg, 1 repetition-maximum (1RM) hang power clean 109.1 +/- 17.2 kg) performed repetitions of the jump shrug at 30%, 45%, 65%, and 80% of their 1RM hang power clean. Jump height, peak landing force, and potential energy of the system at jump-shrug apex were compared between loads using a series of 1-way repeated measures ANOVAs. Statistical differences in jump height (P < .001), peak landing force (P = .012), and potential energy of the system (P < .001) existed; however, there were no statistically significant pairwise comparisons in peak landing force between loads (P > .05). The greatest magnitudes of jump height, peak landing force, and potential energy of the system at the apex of the jump shrug occurred at 30% 1RM hang power clean and decreased as the external load increased from 45% to 80% 1RM hang power clean. Relationships between peak landing force and potential energy of the system at jump-shrug apex indicate that the landing forces produced during the jump shrug may be due to the landing strategy used by the athletes, especially at lighter loads. Practitioners may prescribe heavier loads during the jump-shrug exercise without viewing landing force as a potential limitation. PMID- 25932751 TI - Isolation and Characterization of a Novel Imidacloprid-Degrading Mycobacterium sp. Strain MK6 from an Egyptian Soil. AB - Thus far, only a small number and types of bacteria with limited ability in degrading imidacloprid have been reported. Also, genes regulating imidacloprid (IMDA) degradation have yet to be discovered. To study this in more detail, an enrichment technique was used to isolate consortia and pure cultures of IMDA degrading bacteria. Through this approach, we successfully isolated a novel bacterium capable of completely degrading IMDA as a sole nitrogen source. The bacterium was subsequently identified as Mycobacterium sp. strain MK6 by sequence analysis of its 16S rRNA gene (Genbank accession number KR052814 ). BLASTn searches indicated that 16S rRNA gene from Mycobacterium sp. strain MK6 was 99% identical to several Mycobacterium spp. Mycobacterium sp. strain MK6 transformed 99.7% added IMDA (150 MUg mL(-1)) in <2 weeks (t1/2 = 1.6 days) to 6 chloronicotinic acid (6-CNA) as its major metabolite. Although the isolated strain and mixed bacterial consortia were able to degrade IMDA, they failed to grow further on 6-CNA, indicating a lack of IMDA mineralization to carbon dioxide. Small amounts of the desnitro-olefin and desnitro-degradates of IMDA were observed during the incubation but did not accumulate in culture medium. PMID- 25932752 TI - Judgment of Nasolabial Esthetics in Cleft Lip and Palate Is Not Influenced by Overall Facial Attractiveness. AB - OBJECTIVE: To determine whether judgment of nasolabial esthetics in cleft lip and palate (CLP) is influenced by overall facial attractiveness. DESIGN: Experimental study. SETTING: University of Bern, Switzerland. SUBJECTS AND METHODS: Seventy two fused images (36 of boys, 36 of girls) were constructed. Each image comprised (1) the nasolabial region of a treated child with complete unilateral CLP (UCLP) and (2) the external facial features, i.e., the face with masked nasolabial region, of a noncleft child. Photographs of the nasolabial region of six boys and six girls with UCLP representing a wide range of esthetic outcomes, i.e., from very good to very poor appearance, were randomly chosen from a sample of 60 consecutively treated patients in whom nasolabial esthetics had been rated in a previous study. Photographs of external facial features of six boys and six girls without UCLP with various esthetics were randomly selected from patients' files. Eight lay raters evaluated the fused images using a 100-mm visual analogue scale. Method reliability was assessed by reevaluation of fused images after >1 month. A regression model was used to analyze which elements of facial esthetics influenced the perception of nasolabial appearance. RESULTS: Method reliability was good. A regression analysis demonstrated that only the appearance of the nasolabial area affected the esthetic scores of fused images (coefficient = 11.44; P < .001; R(2) = 0.464). The appearance of the external facial features did not influence perceptions of fused images. CONCLUSION: Cropping facial images for assessment of nasolabial appearance in CLP seems unnecessary. Instead, esthetic evaluation can be performed on images of full faces. PMID- 25932756 TI - Correction to: Effects of caregiver-implemented aggression reduction procedure on problem behavior of dogs. PMID- 25932757 TI - Revisiting "Good" and "Bad" Cholesterol. The Battle over Flow through Arteries Now Shifts to Flow through Airways. PMID- 25932758 TI - Walking a tightrope: targeting neutrophils to treat chronic obstructive pulmonary disease. PMID- 25932759 TI - Finding the key to dialysis catheter lock. PMID- 25932760 TI - Nighttime in the intensive care unit. A lens into the value of critical care delivery. PMID- 25932761 TI - Addressing a challenge with a challenge. Investigating respiratory syncytial virus immunity with the human challenge model. PMID- 25932762 TI - Finishing what they started: when do researchers' responsibilities end? PMID- 25932763 TI - Official American Thoracic Society technical standards: flexible airway endoscopy in children. AB - BACKGROUND: Flexible airway endoscopy (FAE) is an accepted and frequently performed procedure in the evaluation of children with known or suspected airway and lung parenchymal disorders. However, published technical standards on how to perform FAE in children are lacking. METHODS: The American Thoracic Society (ATS) approved the formation of a multidisciplinary committee to delineate technical standards for performing FAE in children. The committee completed a pragmatic synthesis of the evidence and used the evidence synthesis to answer clinically relevant questions. RESULTS: There is a paucity of randomized controlled trials in pediatric FAE. The committee developed recommendations based predominantly on the collective clinical experience of our committee members highlighting the importance of FAE-specific airway management techniques and anesthesia, establishing suggested competencies for the bronchoscopist in training, and defining areas deserving further investigation. CONCLUSIONS: These ATS-sponsored technical standards describe the equipment, personnel, competencies, and special procedures associated with FAE in children. PMID- 25932764 TI - New insights in chronic obstructive pulmonary disease and comorbidity. PMID- 25932765 TI - Left pulmonary agenesis showing extraordinary chest x-ray findings. PMID- 25932766 TI - Parametric response mapping adds value to current computed tomography biomarkers in diagnosing chronic obstructive pulmonary disease. PMID- 25932767 TI - Electronic nose identifies bronchoalveolar lavage fluid eosinophils in asthma. PMID- 25932768 TI - Imaging neutrophil extracellular traps in the alveolar space and pulmonary capillaries of a murine sepsis model by multiphoton microscopy. PMID- 25932769 TI - Reply: neutrophil extracellular traps in primary graft dysfunction after lung transplantation. PMID- 25932770 TI - Mistaken step-up units. PMID- 25932771 TI - Flexible bronchoscopy. PMID- 25932772 TI - Risk-Based High-Throughput Chemical Screening and Prioritization using Exposure Models and in Vitro Bioactivity Assays. AB - We present a risk-based high-throughput screening (HTS) method to identify chemicals for potential health concerns or for which additional information is needed. The method is applied to 180 organic chemicals as a case study. We first obtain information on how the chemical is used and identify relevant use scenarios (e.g., dermal application, indoor emissions). For each chemical and use scenario, exposure models are then used to calculate a chemical intake fraction, or a product intake fraction, accounting for chemical properties and the exposed population. We then combine these intake fractions with use scenario-specific estimates of chemical quantity to calculate daily intake rates (iR; mg/kg/day). These intake rates are compared to oral equivalent doses (OED; mg/kg/day), calculated from a suite of ToxCast in vitro bioactivity assays using in vitro-to in vivo extrapolation and reverse dosimetry. Bioactivity quotients (BQs) are calculated as iR/OED to obtain estimates of potential impact associated with each relevant use scenario. Of the 180 chemicals considered, 38 had maximum iRs exceeding minimum OEDs (i.e., BQs > 1). For most of these compounds, exposures are associated with direct intake, food/oral contact, or dermal exposure. The method provides high-throughput estimates of exposure and important input for decision makers to identify chemicals of concern for further evaluation with additional information or more refined models. PMID- 25932774 TI - In vitro and in silico antifungal efficacy of nitrogen-doped carbon nanohorn (NCNH) against Rhizoctonia solani. AB - We have investigated in vitro antifungal efficiency of nitrogen-doped carbon nanohorn (NCNH) against Rhizoctonia solani (R. solani) plant pathogenic fungi. NCNH with size of 50-60 nm and concentrations of 10, 50, 100, and 150 MUg mL(-1) were used. The results showed that growth of fungi in the presence of NCNH was significantly (p > .05) inhibited at 150 MUg mL(-1) (85.13 +/- .97) after 72 h. The results were validated through computational approaches. Molecular docking analysis of NCNH with endochitinase protein of R. solani was performed to validate the potential of antifungal activity of NCNH. Docking results showed different conformations of interaction of NCNH with endochitinase enzyme. The conformation with least binding energy -13.54 kcal/mol was considered further. It is likely that NCNH interacts with the pathogens by mechanically wrapping, which may be one of the major toxicity actions of NCNH against R. solani. The analysis showed that NCNH might interwinds to endochitinase of R. solani leading to the deactivation of the enzyme. To best of our knowledge, this is the first report of antifungal efficacy of NCNH against R. solani and provides useful information about the application of NCNH in resisting crop disease. PMID- 25932775 TI - A thermostable archaeal S-adenosylmethionine synthetase: a promising tool to improve the synthesis of adenosylmethionine analogs of biotechnological interest. AB - The naturally and widely occurring sulfonium compound, S-adenosylmethionine (AdoMet), one of nature's most versatile molecules, is biosynthesized from methionine and ATP by AdoMet synthetase or methionine adenosyltransferase (MAT) in a 2-step reaction in which the energy-rich sulfonium compound is formed by dephosphorylation of ATP. All living cells, with the only exception of some parasites and infectious agents, express MAT. PMID- 25932776 TI - A prospective natural history study of nonoperatively managed Chiari I malformation: does follow-up MRI surveillance alter surgical decision making? AB - OBJECT Chiari malformation Type I (CM-I) in children is a common incidental finding. Resolution of cerebellar tonsil ectopia has been reported, but no studies have followed tonsil position over regular intervals throughout childhood. To better elucidate the clinical and radiological natural history of CM-I in children, the authors prospectively followed up children with nonoperatively managed CM-I for up to 7 years. METHODS The study included all children evaluated for CM-I over a period of 12 years for whom surgery was not initially recommended. The study excluded patients with associated conditions, including syringomyelia and hydrocephalus. For all patients, initial management was nonoperative, and follow-up management consisted of annual cervical spine or brain MRI and clinical examination. At each follow-up examination, the neurological examination findings, subjective symptoms, and the position of the cerebellar tonsils on MR images were recorded. An alteration in tonsillar descent of 2 mm or greater was considered a change. RESULTS Neurological examination findings did not change over the course of the study in the 52 children who met the inclusion criteria. Although radiological changes were common, no surgeries were performed solely because of radiological change. Overall, tonsil position on radiological images remained stable in 50% of patients, was reduced in 38%, and increased in 12%. Resolution was seen in 12% of patients. Radiological changes in tonsil position were seen during every year of follow-up. On average, in any given year, 24% of images showed some form of change in tonsil position. A total of 3 patients, for whom no changes were seen on MR images, ultimately underwent surgery for subjective clinical reasons. CONCLUSIONS CM-I in children is not a radiologically static entity but rather is a dynamic one. Radiological changes were seen throughout the 7 years of follow-up. A reduction in tonsillar descent was substantially more common than an increase. Radiological changes did not correlate with neurological examination finding changes, symptom development, or the need for future surgery. Follow-up imaging of asymptomatic children with CM-I did not alter treatment for any patient. It would be reasonable to follow these children with clinical examinations but without regular surveillance MRI. PMID- 25932777 TI - Neoadjuvant chemotherapy reduces blood loss during the resection of pediatric choroid plexus carcinomas. AB - OBJECT Choroid plexus carcinomas (CPCs) are rare brain tumors originating from the ventricular choroid plexus. They account for 2%-4% of all pediatric brain tumors and are most frequently seen in very young children. This pediatric proclivity, in combination with a marked vascularity, renders an aggressive resection a difficult and often dangerous endeavor. Blood losses of several total blood volumes in small children are not uncommon, sometimes forcing the neurosurgeon to abort the procedure, often leaving residual tumor. Great extent of tumor resection is an accepted beneficial factor for overall survival. Therefore, a second resection usually follows the administration of adjuvant chemotherapy. Second-look surgery appears to be associated with markedly decreased blood loss. Histological examination of specimens obtained at a second intervention shows decreased vascularity and fibrotic changes in tumor tissue. At the Hospital for Sick Children in Toronto, this empirical finding led to the strategy of neoadjuvant chemotherapy to minimize blood loss and maximize cytoreduction. The authors undertook this study to assess the potentially beneficial effect of neoadjuvant chemotherapy on blood loss during surgery for CPCs. METHODS In this retrospective cohort review, the demographic, clinical, and treatment parameters of 22 consecutive patients diagnosed with CPC are presented. All underwent surgical treatment at the Hospital for Sick Children from 1982 to 2013. Special attention was given to the impact of neoadjuvant chemotherapy on extent of resection and intraoperative blood loss. Extent of resection was calculated based on perioperative neuroimaging, and amount of blood loss was estimated based on transfusion parameters and perioperative changes in hematocrit. RESULTS Ten patients did not receive neoadjuvant chemotherapy, and 12 were treated with 2-5 cycles of ICE (ifosfamide, carboplatin, etoposide) chemotherapy in a neoadjuvant fashion. The 22 patients included in the study underwent a total of 37 tumor resection surgeries. In all of the cases in which neoadjuvant chemotherapy was used, at least a near-total resection (> 95% of tumor volume) was achieved. Patients who underwent gross-total resection had prolonged overall survival. Of the 37 resections, 18 were performed after chemotherapy. Mean blood loss in the neoadjuvant chemotherapy group was 22% of total estimated blood volume as opposed to 96% in patients without preoperative chemotherapy. CONCLUSIONS In children with CPC, the administration of neoadjuvant chemotherapy decreases intraoperative blood loss and increases extent of resection with a significant positive effect on overall survival. PMID- 25932778 TI - Case report of an epidural cervical Onchocerca lupi infection in a 13-year-old boy. AB - A 13-year-old boy presented with fever and neck pain and stiffness, which was initially misdiagnosed as culture-negative meningitis. Magnetic resonance images of the brain and cervical spine demonstrated what appeared to be an intradural extramedullary mass at the C1-3 level, resulting in moderate cord compression, and a Chiari Type I malformation. The patient underwent a suboccipital craniectomy and a C1-3 laminectomy with intradural exploration for excisional biopsy and resection. The lesion containing the parasite was extradural, extending laterally through the C2-3 foramina. Inflammatory tissue secondary to Onchocerca lupi infection was identified, and treatment with steroids and doxycycline was initiated. At the 6-month follow-up, the patient remained asymptomatic, with MR images demonstrating a significant reduction in lesional size. However, 10 weeks postoperatively, the infection recurred, necessitating a second operation. The patient was treated with an additional course of doxycycline and is currently maintained on ivermectin therapy. This is the second reported case of cervical O. lupi infection in a human. In the authors' experience, oral doxycycline alone was insufficient in controlling the disease, and the addition of ivermectin therapy was necessary. PMID- 25932780 TI - Initial clinical presentation of children with acute and chronic versus acute subdural hemorrhage resulting from abusive head trauma. AB - OBJECT At presentation, children who have experienced abusive head trauma (AHT) often have subdural hemorrhage (SDH) that is acute, chronic, or both. Controversy exists whether the acute SDH associated with chronic SDH results from trauma or from spontaneous rebleeding. The authors compared the clinical presentations of children with AHT and acute SDH with those having acute and chronic SDH (acute/chronic SDH). METHODS The study was a multicenter retrospective review of children who had experienced AHT during 2004-2009. The authors compared the clinical and radiological characteristics of children with acute SDH to those of children with acute/chronic SDH. RESULTS The study included 383 children with AHT and either acute SDH (n = 291) or acute/chronic SDH (n = 92). The children with acute/chronic SDH were younger, had higher initial Glasgow Coma Scale scores, fewer deaths, fewer skull fractures, less parenchymal brain injury, and fewer acute noncranial fractures than did children with acute SDH. No between-group differences were found for the proportion with retinal hemorrhages, healing noncranial fractures, or acute abusive bruises. A similar proportion (approximately 80%) of children with acute/chronic SDH and with acute SDH had retinal hemorrhages or acute or healing extracranial injures. Of children with acute/chronic SDH, 20% were neurologically asymptomatic at presentation; almost half of these children were seen for macrocephaly, and for all of them, the acute SDH was completely within the area of the chronic SDH. CONCLUSIONS Overall, the presenting clinical and radiological characteristics of children with acute SDH and acute/chronic SDH caused by AHT did not differ, suggesting that repeated abuse, rather than spontaneous rebleeding, is the etiology of most acute SDH in children with chronic SDH. However, more severe neurological symptoms were more common among children with acute SDH. Children with acute/chronic SDH and asymptomatic macrocephaly have unique risks and distinct radiological and clinical characteristics. PMID- 25932779 TI - Outcomes after suboccipital decompression without dural opening in children with Chiari malformation Type I. AB - OBJECT Symptomatic pediatric Chiari malformation Type I (CM-I) is most often treated with posterior fossa decompression (PFD), but controversy exists over whether the dura needs to be opened during PFD. While dural opening as a part of PFD has been suggested to result in a higher rate of resolution of CM symptoms, it has also been shown to lead to more frequent complications. In this paper, the authors present the largest reported series of outcomes after PFD without dural opening surgery, as well as identify risk factors for recurrence. METHODS The authors performed a retrospective review of 156 consecutive pediatric patients in whom the senior authors performed PFD without dural opening from 2003 to 2013. Patient demographics, clinical symptoms and signs, radiographic findings, intraoperative ultrasound results, and neuromonitoring findings were reviewed. Univariate and multivariate regression analyses were performed to determine risk factors for recurrence of symptoms and the need for reoperation. RESULTS Over 90% of patients had a good clinical outcome, with improvement or resolution of their symptoms at last follow-up (mean 32 months). There were no major complications. The mean length of hospital stay was 2.0 days. In a multivariate regression model, partial C-2 laminectomy was an independent risk factor associated with reoperation (p = 0.037). Motor weakness on presentation was also associated with reoperation but only with trend-level significance (p = 0.075). No patient with < 8 mm of tonsillar herniation required reoperation. CONCLUSIONS The vast majority (> 90%) of children with symptomatic CM-I will have improvement or resolution of symptoms after a PFD without dural opening. A non-dural opening approach avoids major complications. While no patient with tonsillar herniation < 8 mm required reoperation, children with tonsillar herniation at or below C-2 have a higher risk for failure when this approach is used. PMID- 25932781 TI - The value of head circumference measurements after 36 months of age: a clinical report and review of practice patterns. AB - OBJECT The cranium is documented to grow from birth through adolescence. The standard of practice in primary care is measuring head circumference and plotting growth using curves that stop at 36 months. The authors report the importance of their experience with measuring head circumference in the child and same-sex parent beyond 36 months. METHODS In the University of Florida genetics and pediatric neurosurgery clinics, head circumference is measured and plotted on growth charts through 18 years of age. Circumference and rate of growth over time are compared with those of the same-sex parent. A diagnostic workup is initiated if there is a discrepancy with the patient's head circumference or if there is significant change in the growth rate of the cranium. RESULTS Between January 2004 and December 2007, the lead author examined 190 patients referred by pediatricians and/or pediatric subspecialists because of the concerns regarding head size of the child. Neuroimaging was performed in 70% of the patients prior to referral. None of the patients had their head size compared with that of their same-sex parent prior to referral. On assessing referring physician responses as to why the same-sex parents, head measurements were not pursued prior to imaging or referral to the specialists, the results were: 1) only have head circumference sheets to 36 months of age (n = 28); 2) the American Academy of Pediatrics does not recommend it (n = 3); and 3) the head stops growing at 36 months of age (n = 2). CONCLUSIONS Pediatricians and pediatric subspecialists need instruction on head circumference measurement in children from infancy through adolescence, and when indicated, in comparison with the head size of the same-sex parent. This measurement may be an effective and inexpensive assessment tool. PMID- 25932783 TI - Canadian Society of Allergy and Clinical Immunology and AllerGen Abstracts 2014. PMID- 25932782 TI - Enhanced aphid detoxification when confronted by a host with elevated ROS production. AB - Reactive oxygen species (ROS) plays an important role in plant defense responses against bacteria, fungi and insect pests. Most recently, we have demonstrated that loss of Arabidopsis thaliana BOTRYTIS-INDUCED KINASE1 (BIK1) function releases its suppression of aphid-induced H2O2 production and cell death, rendering the bik1 mutant more resistant to green peach aphid (Myzus persicae) than wild-type plants. However, little is known regarding how ROS-related gene expression is correlated with bik1-mediated resistance to aphids, or whether these aphids biochemically respond to the oxidative stress. Here, we show that the bik1 mutant exhibited elevated basal expression of ROS-generating and responsive genes, but not ROS-metabolizing genes. Conversely, we detected enhanced detoxification enzymatic activities in aphids reared on bik1 plants compared to those on wild-type plants, suggesting that aphids counter the oxidative stress associated with bik1 through elevated metabolic resistance. PMID- 25932784 TI - Live Cell MicroRNA Imaging Using Cascade Hybridization Reaction. AB - Recent advances in RNA research have posed new directives in biology and chemistry to uncover the complex roles of ribonucleic acids in cellular processes. Innovative techniques to visualize native RNAs, particularly, short, low-abundance RNAs in live cells, can dramatically impact current research on the roles of RNAs in biology. Herein, we report a novel method for real-time, microRNA imaging inside live cells based on programmable oligonucleotide probes, which self-assemble through the Cascade Hybridization Reaction (CHR). PMID- 25932785 TI - Occurrence and sources of selected organochlorine pesticides in the soil of seven major Indian cities: Assessment of air-soil exchange. AB - India is an agricultural country and organochlorine pesticides (OCPs) accounts for nearly three fourth of the annual pesticide consumption. Selected OCPs were therefore quantified in 81 soil samples along urban-suburban-rural transect from New Delhi and Agra in the north, Kolkata in the east, Mumbai and Goa in the west and Chennai and Bangalore in the southern part of India. SigmaOCPs ranges from 2 to 410 ng/g dry weight (Mean, 35) with dominance of endosulfan sulfate in the rural sites. Urban centers and suburbs reflects OCP usage for vector control. Lower winter temperature in New Delhi favored site-specific deposition of most OCPs in soil. Volatilization of OCPs from soil occurred in the Indian cities having higher ambient temperature. Due to the compounded impact of past and ongoing usage of selected OCPs like DDT, a sporadic cycle of emission and re emission from Indian soil is expected to continue for many more years to come. PMID- 25932786 TI - Arsenic exposure in infancy: estimating the contributions of well water and human milk. PMID- 25932787 TI - Analysis of oxidative DNA damage and its repair in Polish patients with diabetes mellitus type 2: Role in pathogenesis of diabetic neuropathy. AB - PURPOSE: Distal symmetric polyneuropathy (DSPN) is common complication of type 2 diabetes (T2DM). In this work we investigated the role of oxidative damage in connection with particular polymorphisms of DNA repair genes and their repair capacity. MATERIAL/METHODS: Materials constitute the peripheral blood of patients with T2DM with and without DSPN and control subjects without disturbance of the carbohydrate fraction. The study of gene polymorphisms which products take part in base excision repair (BER) pathway: 726 Val/Ala adenosine diphosphate ribosyl transferase (ADPRT), 324 His/Glu MutYhomolog (MUTYH) and 148 Asp/Glu human apurinic/apyrimidinic endonuclease (APE) was carried out using restriction fragment length polymorphism polymerase chain reaction (PCR-RFLP) method. The study of DNA damage induced by hydrogen peroxide and the efficiency of their repair was carried out using comet assay. RESULTS: None of the 3 polymorphisms were associated with the risk of DSPN. However, in group of patients together with T2DM and T2DM/DSPN 726 Ala ADPRT allele was significantly susceptible to increased risk of T2DM (OR=1.59; 95% CI: 1.08-2.36). Investigation of DNA damage and repair revealed that T2DM patients have decreased ability to DNA repair. This capacity even drops down in the group of T2DM/DSPN patients compared to subjects with diabetes alone. ADPRT and APE polymorphisms were significantly associated with higher DNA damages (P<0.05) in heterozygous and mutant homozygous in correlation to homozygous wild type, but for MUTYH polymorphism relation was not confirmed. CONCLUSIONS: Pathogenesis of T2DM and development of DSPN may be related to oxidative stress connected with BER gene polymorphisms. PMID- 25932788 TI - Prevalence of alcohol and drugs among motorcycle riders killed in road crashes in Norway during 2001-2010. AB - The aim of the study was to examine the prevalence of alcohol and drugs in blood samples from motorcycle riders who died in road crashes in Norway from 2001 to 2010. An additional aim was to compare the prevalence of alcohol and drugs in blood samples from fatally injured motorcycle riders and car drivers who died during the same time period. Blood samples from motorcycle riders who died within 24h after the accident (n=207, 63% of all killed riders), were analysed for alcohol, psychoactive drugs (medicinal and illicit drugs). The cut-off concentrations for alcohol and drugs findings in blood samples (i.e., the drug concentrations above which a finding was regarded as positive) were set according to the legislative limits under the Norwegian Road Traffic Act. Results were assessed in relation to age, sex, time of the day and week, and single versus multiple-vehicle accidents. Alcohol or drugs were found in 27.1 percent of all investigated riders. For riders killed in single or multiple-vehicle accidents, alcohol or drugs were found in 44.6 and 15.3 percent, respectively. Alcohol was the most frequently found substance for all age groups and most prevalent in samples from riders below 25 years who died in single-vehicle accidents (45.8 percent). Drugs were most often found among riders between 25 and 34 years (19.6 percent in total and 25.9% for those killed in single-vehicle crashes). The prevalence of alcohol or drugs was highest among riders killed in single-vehicle accidents during weekend days and nights (60.9 and 65.2 percent). Alcohol and drugs were less often found in samples from killed motorcycles riders than in samples from car and van drivers (40.2 percent). For single-vehicle accidents, the total prevalence of alcohol or drugs among killed motorcycles riders and car drivers was 44.6 percent and 63.8 percent, respectively. The same pattern of alcohol and drugs was found among the two groups, except that the prevalence among motorcycle riders was lower compared to car drivers in all age groups and time periods, which may be related to the fact that they are more vulnerable for fatal injury compared to car drivers in similar accidents. PMID- 25932789 TI - In vitro detection of small molecule metabolites excreted from cancer cells using a Tenax TA thin-film microextraction device. AB - We developed a new device for the in vitro extraction of small molecule metabolites excreted from cancer cells. The extraction device, which was biocompatible and incubated with cancer cells, consists of a thin Tenax TA film deposited on the surface of a cylindrical aluminum rod. The Tenax TA solid phase was utilized for the direct extraction and preconcentration of the small molecule metabolites from a cell culture sample. The device fabrication and the metabolite extraction were optimized, tested, and validated using HeLa cell cultures. Comparison of metabolic profiles with the control measurement from the culture medium enabled detection of metabolites that were consumed or produced by the cell culture. Tentative identification and semi-quantitative investigation of the excreted metabolites were performed by GC-MS analysis. The proposed approach can be a valuable tool for the characterization of low-volatile cancer cell metabolites that are not covered by use of conventional methods based on headspace solid phase microextraction. PMID- 25932790 TI - Simultaneous determination of seven coumarins by UPLC-MS/MS: Application to a comparative pharmacokinetic study in normal and arthritic rats after oral administration of Huo Luo Xiao Ling Dan or single-herb extract. AB - A simple, sensitive and reliable ultra performance liquid chromatography-tandem mass spectrometry (UPLC-MS/MS) method has been developed and validated for simultaneous quantitation of seven coumarins, the bio-active ingredients of Huo Luo Xiao Ling Dan (HLXLD), in rat plasma. The liquid-liquid extraction method with ether-dichloromethane (2:1, v/v) was used to prepare the plasma samples. Analytes and internal standard (IS) of bifendate were separated on a Shim-pack XR ODS column (75mm*3.0mm, 2.2MUm particles) using gradient elution with the mobile phase consisting of methanol and 0.05% formic acid in water at a flow rate of 0.4mL/min. Detection was performed on a triple quadrupole (TQ) tandem mass spectrometry equipped with an electrospray ionization source in the positive ionization and multiple reaction monitoring (MRM) mode. The lower limits of quantitation (LLOQ) were 0.03-0.25ng/mL for all the analytes. Intra- and inter day precision and accuracy of the seven analytes were well within acceptance criteria (15%). The matrix effect and the mean extraction recoveries of the analytes and IS from rat plasma were all within satisfaction. The validated method has been successfully applied to compare pharmacokinetic profiles of the seven active ingredients in rat plasma between normal and arthritic rats after oral administration of HLXLD, Angelica pubescens extract and Notopterygium incisum extract, respectively. Results showed that there were remarkable differences in pharmacokinetic properties of the analytes among the different groups. PMID- 25932791 TI - Accurate and reproducible reconstruction of coronary arteries and endothelial shear stress calculation using 3D OCT: comparative study to 3D IVUS and 3D QCA. AB - BACKGROUND: Geometrically-correct 3D OCT is a new imaging modality with the potential to investigate the association of local hemodynamic microenvironment with OCT-derived high-risk features. We aimed to describe the methodology of 3D OCT and investigate the accuracy, inter- and intra-observer agreement of 3D OCT in reconstructing coronary arteries and calculating ESS, using 3D IVUS and 3D QCA as references. METHODS-RESULTS: 35 coronary artery segments derived from 30 patients were reconstructed in 3D space using 3D OCT. 3D OCT was validated against 3D IVUS and 3D QCA. The agreement in artery reconstruction among 3D OCT, 3D IVUS and 3D QCA was assessed in 3-mm-long subsegments using lumen morphometry and ESS parameters. The inter- and intra-observer agreement of 3D OCT, 3D IVUS and 3D QCA were assessed in a representative sample of 61 subsegments (n = 5 arteries). The data processing times for each reconstruction methodology were also calculated. There was a very high agreement between 3D OCT vs. 3D IVUS and 3D OCT vs. 3D QCA in terms of total reconstructed artery length and volume, as well as in terms of segmental morphometric and ESS metrics with mean differences close to zero and narrow limits of agreement (Bland-Altman analysis). 3D OCT exhibited excellent inter- and intra-observer agreement. The analysis time with 3D OCT was significantly lower compared to 3D IVUS. CONCLUSIONS: Geometrically correct 3D OCT is a feasible, accurate and reproducible 3D reconstruction technique that can perform reliable ESS calculations in coronary arteries. PMID- 25932792 TI - Effects of niacin and omega-3 fatty acids on the apolipoproteins in overweight patients with elevated triglycerides and reduced HDL cholesterol. AB - OBJECTIVE: Prescription omega-3 acid ethyl esters (P-OM3) and extended release niacin (ERN) both have beneficial effects on plasma lipids and lipoproteins. The purpose of this study was to describe the effects of mono- and combination (Combo) therapy of these agents in patients with the metabolic syndrome. METHODS: Very low density (VLDL), intermediate/low density (IDL/LDL, hereafter LDL), and high density lipoproteins (HDL) were isolated from 56 overweight patients with elevated triglyceride/HDL-C ratios at baseline and after 16 weeks of treatment with placebo, ERN (2g/day), P-OM3 (4g/day), or Combo and then analyzed by quantitative electrophoresis for apolipoproteins (apo) A1, A2, B, C2, C3 and E. Total plasma concentrations and the ratios of each apo with apoB (in VLDL and LDL) and with apoA1 (in HDL) were calculated. An apoC3 glycosylation index (a ratio between di- and mono-sialylated isoforms) was also determined in plasma and in each lipoprotein fraction. RESULTS: ERN reduced plasma apoB (-11%, p < 0.05). Combo increased LDL apoE/apoB ratio (64%, p < 0.01) and LDL apoA1/apoB (91%, p < 0.05). ERN increased the apoC3 glycosylation index only in HDL (37%, p < 0.05), whereas P-OM3 and Combo increased the index in whole plasma (48% and 49%, respectively, p < 0.05 for both) and in every lipoprotein class (VLDL: 26%, p < 0.01 and 26%, p < 0.05; LDL: 55%, p < 0.01 and 61%, p < 0.01; HDL: 43%, p < 0.001 and 44%, p < 0.001, respectively). All findings were significant after adjustment for age, sex, body mass index (BMI), smoking, medications, and baseline apo value. CONCLUSIONS: ERN produced a beneficial reduction in plasma apoB. The enrichment of LDL with apoE and apoA1 was unique to the Combo group and might be beneficial owing to the atheroprotective properties of apoE and HDL2 (a likely source of apoA1 in LDL fraction). The effect of therapies on the apoC3 glycosylation index is a novel finding, the implications of which will require further study. PMID- 25932793 TI - Colorimetric assay for protein detection based on "nano-pumpkin" induced aggregation of peptide-decorated gold nanoparticles. AB - Small peptide can be used as an effective biological recognition element and provide an alternative tool for protein detection. However, the development of peptide-based detecting strategy still remains elusive due to the difficulty of signal transduction. Herein, we report a peptide-based colorimetric strategy for the detection of disease biomarker by using vascular endothelial growth factor receptor 1 (Flt-1) as an example. In this strategy, N-terminal aromatic residue containing peptide modified gold nanoparticles (GNPs) can form bulky aggregate by the introduction of cucurbit[8]uril (CB[8]) that can selectively accommodate two N-terminal aromatic residue of peptides simultaneously regardless of their sequences. However, in the presence of Flt-1, the peptide can specifically bind to the protein molecule and the N-terminal aromatic residue will be occupied, resulting in little aggregation of GNPs. By taking advantage of the highly affinitive peptide and efficiency cross-linking effect of CB[8] to GNPs, colorimetric assay for protein detection can be achieved with a detection limit of 0.2 nM, which is comparable with traditional methods. The feasibility of our method has also been demonstrated in spiked serum sample, indicating potential application in the future. PMID- 25932794 TI - Enzymatically catalytic deposition of gold nanoparticles by glucose oxidase functionalized gold nanoprobe for ultrasensitive electrochemical immunoassay. AB - A novel ultrasensitive immunoassay method was developed by combination of the enzymatically catalytic gold deposition with the prepared gold nanoprobe and the gold stripping analysis at an electrochemical chip based immunosensor. The immunosensor was constructed through covalently immobilizing capture antibody at a carbon nanotube (CNT) modified screen-printed carbon electrode. The gold nanoprobe was prepared by loading signal antibody and high-content glucose oxidase (GOD) on the nanocarrier of gold nanorod (Au NR). After sandwich immunoreaction, the GOD-Au NR nanoprobe could be quantitatively captured onto the immunosensor surface and then induce the deposition of gold nanoparticles (Au NPs) via the enzymatically catalytic reaction. Based on the electrochemical stripping analysis of the Au NR nanocarriers and the enzymatically produced Au NPs, sensitive electrochemical signal was obtained for the immunoassay. Both the GOD-induced deposition of Au NPs by the nanoprobe and the sensitive electrochemical stripping analysis on the CNTs based sensing surface greatly amplified the signal response, leading to the ultrahigh sensitivity of this method. Using carcinoembryonic antigen as a model analyte, excellent analytical performance including a wide linear range from 0.01 to 100 ng/mL and a detection limit down to 4.2 pg/mL was obtained. In addition, this immunosensor showed high specificity and satisfactory reproducibility, stability and reliability. The relatively positive detection potential excluded the conventional interference from dissolved oxygen. Thus this electrochemical chip based immunosensing method provided great potentials for practical applications. PMID- 25932795 TI - An organic electronic biomimetic neuron enables auto-regulated neuromodulation. AB - Current therapies for neurological disorders are based on traditional medication and electric stimulation. Here, we present an organic electronic biomimetic neuron, with the capacity to precisely intervene with the underlying malfunctioning signalling pathway using endogenous substances. The fundamental function of neurons, defined as chemical-to-electrical-to-chemical signal transduction, is achieved by connecting enzyme-based amperometric biosensors and organic electronic ion pumps. Selective biosensors transduce chemical signals into an electric current, which regulates electrophoretic delivery of chemical substances without necessitating liquid flow. Biosensors detected neurotransmitters in physiologically relevant ranges of 5-80 uM, showing linear response above 20 um with approx. 0.1 nA/uM slope. When exceeding defined threshold concentrations, biosensor output signals, connected via custom hardware/software, activated local or distant neurotransmitter delivery from the organic electronic ion pump. Changes of 20 uM glutamate or acetylcholine triggered diffusive delivery of acetylcholine, which activated cells via receptor mediated signalling. This was observed in real-time by single-cell ratiometric Ca(2+) imaging. The results demonstrate the potential of the organic electronic biomimetic neuron in therapies involving long-range neuronal signalling by mimicking the function of projection neurons. Alternatively, conversion of glutamate-induced descending neuromuscular signals into acetylcholine-mediated muscular activation signals may be obtained, applicable for bridging injured sites and active prosthetics. PMID- 25932796 TI - The importance of vasodilator therapy before or during angiography, is ICD necessary or not?: A response to Michal Chyrchel et al. PMID- 25932797 TI - Vascular response to 1 week of sleep restriction in healthy subjects. A metabolic response? AB - BACKGROUND: Sleep loss may induce endothelial dysfunction, a key factor in cardiovascular risk. We examined the endothelial function during one week of sleep restriction and a recovery period (from 3-to-13 days) in healthy subjects, and its link to autonomic, inflammatory and/or endocrine responses. METHODS: 12 men were followed at baseline (B1, 8-h sleep), after 2 (SR2) and 6 (SR6) days of SR (4-h sleep: 02:00-06:00) and after 1 (R1) and 12 (R12) recovery nights (8h sleep). At 10:00, we assessed changes in: arm cutaneous vascular conductance (CVC) induced by local application of methacholine (MCh), cathodal current (CIV) and heat (44 degrees C), finger CVC and skin temperature (Tfi) during local cold exposure (5 degrees C, 20-min) and passive recovery (22 degrees C, 20-min). Blood samples were collected at 08:00. RESULTS: Compared with baseline (B1), MCh and heat-induced maximal CVC values (CVC peak) were decreased at SR6 and R1. No effect of SR was observed for Tfi and CVC during immersion whereas these values were lower during passive recovery on SR6 and R1. From SR2 to R12, plasma concentrations of insulin, IGF-1 (total and free) and MCP-1 were significantly increased while those of testosterone and prolactin were decreased. Whole-blood blood mRNA concentrations of TNF-alpha and IL-1beta were higher than B1. No changes in noradrenaline concentrations, heart rate and blood pressure were observed. CONCLUSIONS: These results demonstrate that SR reduces endothelial dependent vasodilatation and local tolerance to cold. This endothelial dysfunction is independent of blood pressure and sympathetic activity but associated with inflammatory and metabolic pathway responses (ClinicalTrials NCT01989741). PMID- 25932798 TI - Repetitive, incessant supraventricular tachycardia: Noninvasive determination of the electrophysiologic mechanism. PMID- 25932799 TI - Extreme prolongation of sinus node recovery time in a coronary artery disease patient. PMID- 25932800 TI - On the binaural brain entrainment indicating lower heart rate variability. PMID- 25932801 TI - C-reactive protein and ischemic stroke risk in general population: A dose response meta-analysis of prospective studies. PMID- 25932802 TI - Relation of C-reactive protein and new-onset atrial fibrillation in patients with acute myocardial infarction: A systematic review and meta-analysis. PMID- 25932803 TI - Coronary artery calcification is not related to coronary heart disease isolated family history. PMID- 25932804 TI - Ligands involved in conditioning may enhance the protection afforded by remote ischemia and reperfusion. PMID- 25932805 TI - Cardiac manifestations of Sneddon's syndrome. PMID- 25932806 TI - Influence of baseline ejection fraction on the prognostic value of paravalvular leak after transcatheter aortic valve implantation. AB - BACKGROUND: Moderate or severe paravalvular leak (PVL >= moderate) after transcatheter aortic valve implantation (TAVI) is associated with poor outcomes. The aim of this study was to assess whether the baseline ejection fraction (EF) affects the impact of PVL on mortality after TAVI. METHODS: We analyzed 514 consecutive patients with native severe aortic stenosis who underwent TAVI. Patients were divided into two groups: EF < 40% group (n = 84) and EF >= 40% group (n = 430) according to baseline EF. RESULTS: The mean age was 79.5 years and 49% were male. Patients in the EF < 40% group were younger and with higher logistic EuroSCORE compared to patients in the EF >= 40% group. Diabetes, coronary artery disease, atrial fibrillation and renal insufficiency were more prevalent in the EF < 40% group. Patients in the EF <40% group had more mitral regurgitation. In-hospital mortality was significantly higher in the EF < 40% group (8.3% vs. 0.9%, p < 0.0001). PVL >= moderate was significantly associated with increased 2-year estimated mortality only in the EF <40% group (65% vs. 20%, log-rank p < 0.0001) whereas no difference was seen in the EF >=40% group (24% vs. 19%, log-rank p = 0.509). Interaction between PVL >= moderate and EF < 40% was statistically significant. CONCLUSIONS: The impact of PVL >= moderate on mortality after TAVI was significant in the EF <40% group but not in the EF >= 40% group in our study. Even though operators should aim to minimize PVL in all TAVI patients, special attention is required for patients with reduced baseline EF. PMID- 25932807 TI - Tumor necrosis factor-alpha inhibitor: A promising therapeutic approach for attenuating myocardial ischemia-reperfusion by antioxidant stress. PMID- 25932808 TI - Endomyocardial biopsy in Anderson-Fabry disease: The key in uncertain cases. PMID- 25932809 TI - Serum cystatin C level is associated with left atrial enlargement, left ventricular hypertrophy and impaired left ventricular relaxation in patients with stage 2 or 3 chronic kidney disease. AB - BACKGROUND: Cystatin C is an endogenous marker of kidney function that overcomes the limitations of serum creatinine. High serum cystatin C levels have been associated with increased cardiovascular mortality and morbidity. In this cross sectional study, we aimed to determine the associations between serum cystatin C levels and structural and functional cardiac changes in patients with stage 2 or 3 chronic kidney disease (CKD). METHODS AND RESULTS: We enrolled 429 consecutive patients (aged 24-97 years) with CKD stage 2 or 3 and left ventricular (LV) ejection fraction (LVEF)>40%. Echocardiographic parameters, including LV mass index (LVMI), early diastolic mitral annulus velocity (e' velocity), left atrial volume index (LAVI), and N-terminal of the prohormone brain natriuretic peptide (NT-proBNP) were measured. Patients were categorized into quartiles according to serum cystatin C levels. Cystatin C was associated with LAVI (p=0.0055), LVEF (p=0.0432), LVMI (p=0.0409), e' (p=0.0051), E/e' (p=0.0027), and log-transformed NT-proBNP (p<0.0001) according to multivariate linear regression analysis, after adjustment for confounding factors including creatinine-based estimated glomerular filtration rate (eGFRcreat) and urinary albumin to creatinine ratio. Incidence of eccentric and concentric hypertrophy increased with increasing cystatin C (Q1, 38%; Q2 49%; Q3, 51%; Q4, 66%, p=0.0008), mainly because of increasing concentric hypertrophy (Q1, 30%; Q2, 39%; Q3, 39%; Q4, 51%, p=0.0187). CONCLUSION: A high serum cystatin C is strongly associated with structural cardiac abnormalities such as LVH and left atrial enlargement, impaired LV relaxation, and an increased NT-proBNP, independently of eGFRcreat in patients with stage 2 or 3 CKD. PMID- 25932810 TI - Rosuvastatin and risk of acute pancreatitis. PMID- 25932811 TI - Successful repair of mitral valve with acute infective endocarditis located in anterior mitral leaflet: The evidence of Three-dimensional echocardiography. PMID- 25932812 TI - Different responses of arterial blood pressure to electrical stimulation of the renal artery in patients with resistant hypertension. PMID- 25932813 TI - From the editor. The Value of Classic Literature in Shaping the Future. PMID- 25932814 TI - Guest editorial. Nursing models for the future: acknowledging the political nature of nursing. PMID- 25932815 TI - Letter to the editor. PMID- 25932816 TI - An interview with Dr Barbara A. Carper. AB - In 1978, Dr Barbara A. Carper's foundational work, "Fundamental Patterns of Knowing in Nursing," arguably created a paradigm shift in nursing. However, her voice has been absent from the nursing literature in recent years. I was privileged to conduct a personal interview with Dr Carper in 2014. The edited interview includes a synopsis of her background, career trajectory, sources of inspiration, and her perspective on the current state of nursing. She reaffirmed her passion for reflective nursing practice, the importance incorporating the arts and humanities into nursing education, and using an integrated approach with the patterns of knowing in nursing. PMID- 25932817 TI - A practice theory approach to understanding the interdependency of nursing practice and the environment: implications for nurse-led care delivery models. AB - Nursing has a rich knowledge base with which to develop care models that can transform the ways health is promoted and valued. However, theory linking the environment domain of the nursing metaparadigm with the real-world environments where nurses practice and patients experience their health care is tenuous. Practice theory is used to foreground the generative role of nursing practice in producing environments of care, providing the basis for a metaparadigm relational proposition explicitly linking nursing practice and environment metaparadigm domains. A theoretical and empirical focus on the significance of nursing practice dynamics in producing environments of care that promote health and healing will strengthen present and future nursing care models. PMID- 25932818 TI - Cues-to-Action in Initiating Lesbian, Gay, Bisexual, and Transgender-Related Policies Among Magnet Hospital Chief Nursing Officers: A Demographic Assessment. AB - This study explored Magnet Chief Nursing Officers' cues-to-action initiating lesbian, gay, bisexual, or transgender (LGBT)-specific policies. Homonegativity has a negative effect on employee recruitment and retention and patient satisfaction. Little has been known about what cues-to-action might initiate LGBT inclusive training. Surveys were mailed to 343 Chief Nursing Officers. Cues-to action survey was used to assess what inspires initiation of LGBT training. Demographic surveys were used to assess what impact variables might have on cues to-action. Age, sex, religiosity, location, and region had significant effect on cues-to-action. Developing demographically informed training and policies for LGBT equality in health care is suggestive of greater employee and patient satisfaction. PMID- 25932819 TI - Toward cultural safety: nurse and patient perceptions of illicit substance use in a hospitalized setting. AB - As a group, people who use illicit drugs and are affected by social disadvantages often experience health inequities and encounter barriers such as stigma and discrimination when accessing health care services. Cultural safety has been proposed as one approach to address health inequities and mitigate stigma in health care. Drawing on a qualitative ethnographic approach within an overarching collaborative framework, we sought to gain an understanding of what constitutes culturally safe care for people who use(d) illicit drugs. The findings illustrate that illicit substance use in hospitals is often negatively constructed as (1) an individual failing, (2) a criminal activity, and (3) a disease of "addiction" with negative impacts on access to care, management of pain, and provision of harm-reduction supplies and services. These constructions of illicit substance use impact patients' feelings of safety in hospital and nurses' capacity to provide culturally safe care. On the basis of these findings, we provide recommendations and guidance for the development of culturally safe nursing practice. PMID- 25932820 TI - Influences on and outcomes of enacted scope of nursing practice: a new model. AB - Enacted scope of practice is a major issue for nursing administrators, given the potentially negative effect on accessibility, continuity, safety and quality of care, job satisfaction, and organizational costs of nurses working at reduced scope. Optimal deployment of nurses to a fuller enacted scope of nursing practice holds much promise for addressing all of these larger challenges. In this sense, new model of the Enacted Scope of Nursing Practice presented in this article provides a number of directions for interventions that could improve health system functioning. PMID- 25932822 TI - Erratum: Climate change, crop yields, and undernutrition: development of a model to quantify the impact of climate scenarios on child undernutrition. PMID- 25932821 TI - Development and testing of an instrument to measure holistic nursing values in nurse practitioner care. AB - As primary care delivery evolves in the United States with nurse practitioners (NPs) as key providers, exploring the patient's perception of the nature and quality of NPs' care is of critical importance to healthcare consumers, providers, educators, policy makers, and underwriters. The aim of this study was to describe the development and testing of the Nurse Practitioner Holistic Caring Instrument, a new, investigator-developed measure of the preservation of holistic nursing values in NP care. Results suggest that NPs provide patient-centered, comprehensive, and clinically competent care, rendering them ideally suited to leading primary health care delivery. However, further testing in more diverse populations and settings is needed to strengthen preliminary findings. PMID- 25932823 TI - Osteonecrosis of the distal tibial metaphysis after Salter-Harris type-2 injury: a case report. AB - Osteonecrosis of the distal tibial metaphysis following a Salter-Harris type-2 injury is a rare complication with no previous reports in the literature. We report a case of osteonecrosis of the metaphysis in distal tibia, confirmed radiologically and histologically. The natural history was followed with serial MRI scans and we comment on the possible pathophysiology. PMID- 25932824 TI - The need for Achilles tenotomy in the Ponseti method: Is it predictable at the initiation or during the treatment? AB - The aim of this study was to determine whether the need for tenotomy can be predicted at the initiation or during the treatment of the clubfoot treatment according to the Ponseti method. One hundred and eight feet of 77 babies who required tenotomy and who did not were compared statistically according to the parameters of sex, side, bilaterality, presentation day, number of casts, Pirani scores, and the percentage change in Pirani scores, respectively. The mean number of casts required, the initial Pirani scores, and the percentage change in Pirani scores were significantly different between the groups that required tenotomy and the groups that did not (P=0.0001). Pirani scores at the beginning and the percentage change in Pirani scores during the treatment can be used to estimate the need for Achilles tenotomy. PMID- 25932825 TI - Congenital tibial pseudarthrosis, changes in treatment protocol. AB - Ten children with congenital pseudarthrosis of the tibia were treated with resection of pathologic bone, bone grafting, intramedullary rodding, compression with circular frame, simultaneous proximal tibia lengthening, and bone morphologic proteins. Thirteen operations were performed to achieve union. Four patients underwent simultaneous lengthening and four patients received recombinant human bone morphologic protein. Six children required complementary operations for residual ankle and knee valgus, and shortening. Union of the pseudarthrosis was achieved in all cases with lengthening up to 5 cm. This protocol is effective in achieving union of congenital pseudarthrosis of tibia; attention should be paid to the ankle joint to achieve functionality of the limb. PMID- 25932826 TI - Stiffness of various pin configurations for pediatric supracondylar humeral fracture: a systematic review on biomechanical studies. AB - To compare the biomechanical stability of various pin configurations for pediatric supracondylar humeral fractures under varus, internal rotation, and extension conditions. After electronic retrieval, 11 biomechanical studies were included. Stiffness values of pin configurations under different loading conditions were extracted and pooled. There were no statistically significant differences between two cross pins and two divergent lateral pins on the basis of the 'Hamdi method' (P=0.249-0.737). An additional pin did not strengthen two-pin construct (P=0.124-0.367), but better stabilized fractures with medial comminution (P<0.01). Isolated lateral pins are preferable because of a better balance of a lower risk of nerve injury and comparable fixation strength. Limitations such as differences in experimental setup among recruited studies and small sample size may compromise the methodologic power of this study. PMID- 25932827 TI - Internal fixation after fracture or osteotomy of the femur in young children with polyostotic fibrous dysplasia. AB - Children from 4 to 7 years of age with polyostotic fibrous dysplasia (PFD) may need internal fixation of the femur for either fracture or osteotomy. At that age, the small size of the femur allows only the use of small intramedullary nails. However, titanium elastic nails and rigid intramedullary pediatric interlocking femoral nails - good for fracture or osteotomy fixation in the normal femur - are not indicated in PFD. From 2009 to 2011, we treated eight cases of PFD femoral fracture and deformity by internal fixation with a custom modified adult humeral nail to which a spiral blade was connected. The 7-mm thick nail fit properly into the small femoral shaft and the spiral blade conferred ideal mechanical support to the femoral neck. Three cases had replacement of the humeral nail with a more appropriate adult femoral nail 3 years after the index procedure when the femur had reached an adequate size. In the maximum follow-up period of 4 years, few complications were observed. PMID- 25932828 TI - Anticipating the next arrival: Ebola in the pregnant woman. PMID- 25932829 TI - Pyometra in childhood. AB - BACKGROUND: Pyometra, an accumulation of pus in the uterine cavity, occurs rarely in children but should be considered in the differential diagnosis of an intra abdominal or pelvic abscess. CASE: A 10-month-old infant presented with an increasing abdominal mass. She had previous respiratory and diarrheal illnesses. She was underweight, febrile, and tachycardic with an 8*6-cm mobile tender mass in her lower abdomen. Investigations demonstrated leukocytosis and ultrasonogram confirmed a cystic mass. At laparotomy a pyometra was found. Needle aspiration and washout of the uterine cavity were performed but a second procedure was required to place a drain into the cavity. CONCLUSION: Pyometra occurs rarely in childhood. A review of cases associates a hypoestrogenized endometrium exposed to transient bacteremia with obstruction to uterine drainage. Treatment should include continuous drainage of the uterus. PMID- 25932830 TI - Abdominal pregnancy in a low-resource setting. AB - BACKGROUND: Abdominal pregnancies are rare types of ectopic pregnancies with high rates of maternal mortality and morbidity when encountered anywhere in the world. Combining such high-risk pregnancy with the limitations found in a low-resource setting can lead to increased complications, which can be more difficult to manage. CASE: A 21-year-old woman, gravida 2 para 1001, at 36 weeks of gestation presented with a complicated abdominal pregnancy in Cameroon. The patient was followed through multiple complicated surgeries and medical treatments, including chemotherapy, until final resolution and complete recovery. CONCLUSION: This case highlights known complications of advanced abdominal pregnancy, including blood loss and infection. It also emphasizes limitations within the low-resource setting, which can independently add to the patient's morbidity and complicate management, and demonstrates examples of approaches that can be used aid management decisions within low-resource areas. PMID- 25932831 TI - Treating spontaneous and induced septic abortions. AB - Worldwide, abortion accounts for approximately 14% of pregnancy-related deaths, and septic abortion is a major cause of the deaths from abortion. Today, septic abortion is an uncommon event in the United States. The most critical treatment of septic abortion remains the prompt removal of infected tissue. Antibiotic administration and fluid resuscitation provide necessary secondary levels of treatment. Most young physicians have never treated septic abortion. Many obstetrician-gynecologists experience, or plan to experience, global health activities and will likely care for women with septic abortion. Thus, updated knowledge of the pathophysiology, clinical presentation, microbes, and proper treatment is needed to optimally treat this emergency condition when it exists. The pathophysiology of septic abortion involves infection of the placenta, especially the maternal villous space that leads to a high frequency of bacteremia. Symptoms and signs range from mild to severe. The microbes involved are usually common vaginal bacteria, including anaerobes, but occasionally potentially very serious and lethal infection is caused by bacteria that produce toxins. The primary treatment is early curettage to remove infected and devitalized tissue even in the face of continued fetal heart tones. Important secondary treatments are the administration of fluids and antibiotics. Updated references of sepsis and septic shock are reviewed. PMID- 25932832 TI - Transforming communication and safety culture in intrapartum care: a multi organization blueprint. AB - Effective, patient-centered communication facilitates interception and correction of potentially harmful conditions and errors. All team members, including women, their families, physicians, midwives, nurses, and support staff, have a role in identifying the potential for harm during labor and birth. However, the results of collaborative research studies conducted by organizations that represent professionals who care for women during labor and birth indicate that health care providers may frequently witness, but may not always report, problems with safety or clinical performance. Some of these health care providers felt resigned to the continuation of such problems and fearful of retribution if they tried to address them. Speaking up to address safety and quality concerns is a dynamic social process. Every team member must feel empowered to speak up about concerns without fear of put-downs, retribution, or receiving poor-quality care. Patient safety requires mutual accountability: individuals, teams, health care facilities, and professional associations have a shared responsibility for creating and sustaining environments of mutual respect and engaging in highly reliable perinatal care. Defects in human factors, communication, and leadership have been the leading contributors to sentinel events in perinatal care for more than a decade. Organizational commitment and executive leadership are essential to creating an environment that proactively supports safety and quality. The problem is well-known; the time for action is now. PMID- 25932833 TI - Standard compared with mnemonic counseling for fecal incontinence: a randomized controlled trial. AB - OBJECTIVE: To estimate whether women who underwent mnemonic counseling had better recall of fecal incontinence therapies at 2 months and if mnemonic counseling resulted in greater satisfaction with physician counseling and improvement in quality of life when compared with a group who underwent standard counseling. METHODS: Counseling-naive women with fecal incontinence were recruited from an academic urogynecology clinic. Women underwent physical examinations, completed the Quality of the Physician-Patient Interaction, recorded fecal incontinence treatment options they recalled, and completed the Fecal Incontinence Severity Index and Manchester Health Questionnaire immediately after counseling and again at 2 months. RESULTS: Ninety women consented to participate, were randomized, and completed baseline questionnaires. At baseline, women did not differ in age, ethnicity, education, Fecal Incontinence Severity Index, or Manchester Health Questionnaire scores. After counseling, the mnemonic group reported higher satisfaction on Quality of the Physician-Patient Interaction (66.4+/-6.5 compared with 62.2+/-10.7, P=.03). Ninety percent (81/90) of women followed up at 2 months. Our primary endpoint, 2-month recall of fecal incontinence treatments, was not different between groups (2.3+/-1.6 mnemonic counseling compared with 1.8+/-1.0 standard counseling; P=.08). Secondary endpoints for the mnemonic group reported greater improvement on total Manchester Health Questionnaire (P=.02), emotional (P=.03), sleep (0.045), role limitations (P<.01), and physical limitations (P=.04) when compared with the standard group. CONCLUSION: Fecal incontinence counseling with a mnemonic aid did not improve recall at 2 months but improved patient satisfaction and quality of life at 2 months. PMID- 25932834 TI - Factors associated with seeking treatment for urinary incontinence during the menopausal transition. AB - OBJECTIVE: To examine whether longitudinal urinary incontinence (UI) characteristics, race or ethnicity, socioeconomic status, and education were associated with UI treatment-seeking in a prospective cohort of community dwelling midlife women. METHODS: We analyzed data from 9 years of the Study of Women's Health Across the Nation. The study asked participants reporting at least monthly UI about seeking treatment for their UI at baseline and in visit years 7, 8, and 9. Our main covariates included self-reported race or ethnicity, income, level of difficulty paying for basics, and education level. We used multiple logistic regression to examine associations between demographic, psychosocial, and longitudinal UI characteristics and whether women sought UI treatment. We explored interactions by race or ethnicity, socioeconomic status measures, and education level. RESULTS: A total of 1,550 women (68% of women with UI) reported seeking treatment for UI over the 9 years of this study. In multivariable analyses, women had higher odds of seeking treatment when UI in the year before seeking treatment was more frequent (adjusted odds ratio [OR] 3.16, 95% confidence interval [CI] 1.15-8.67) and more bothersome (adjusted OR 1.09, 95% CI 1.01-1.18), with longer symptom duration, and with worsening UI symptoms (adjusted OR 1.75, 95% CI 1.01-3.04). Women who saw physicians regularly, had more preventive women's health visits, or both were more likely to seek UI treatment (adjusted OR 1.18, 95% CI 1.07, 1.30). Race or ethnicity, socioeconomic measures, and education were not significantly related to seeking treatment for UI. CONCLUSION: We found no evidence of racial or ethnic, socioeconomic, or education level disparities in UI treatment-seeking. Rather, longitudinal UI characteristics were most strongly associated with treatment-seeking behavior in midlife women. LEVEL OF EVIDENCE: II. PMID- 25932835 TI - Comparison of levator ani muscle avulsion injury after forceps-assisted and vacuum-assisted vaginal childbirth. AB - OBJECTIVE: Using three-dimensional transperineal ultrasonography, we compared the prevalence of levator ani muscle injury after forceps with vacuum-assisted vaginal delivery. METHODS: This was a retrospective cohort study. Women who experienced at least one forceps delivery (across all deliveries) were compared with women who had at least one vacuum birth. On average, participants were 10 years from the index delivery. Three-dimensional transperineal ultrasound volumes were captured as cine loops at rest with Valsalva and with pelvic floor muscle contraction. The primary outcome was levator ani muscle avulsion. Secondary outcomes included hiatal diameter and area. Prevalence of pelvic floor disorders was also compared between the two delivery groups. RESULTS: Among 45 participants in the forceps group and 28 participants in the vacuum group, there were no differences between groups in maternal age at first delivery, parity, body mass index, birth weight, episiotomy, or duration of second stage. History of anal sphincter laceration was more common in the forceps group. The prevalence of levator ani muscle avulsion was significantly higher after forceps compared with vacuum delivery (22/45 [49%] compared with 5/28 [18%], P=.012, prevalence ratio 2.74, 95% confidence interval [CI] 1.17-6.40, odds ratio 4.40 [95% CI 1.42 13.62]). Controlling for delivery type, levator ani muscle avulsion was associated with symptoms of prolapse (P=.036), although objective evidence of prolapse was not significantly different between groups (P=.20). CONCLUSION: Ten years after delivery, the prevalence of levator avulsion is almost tripled after forceps compared with vacuum-assisted vaginal delivery. LEVEL OF EVIDENCE: II. PMID- 25932836 TI - Wound complications after obstetric anal sphincter injuries. AB - OBJECTIVE: To estimate the incidence of and risk factors for wound complications in women who sustain obstetric anal sphincter injuries. METHODS: This was a prospective cohort study of women who sustained obstetric anal sphincter injuries during delivery of a full-term neonate between September 2011 and August 2013. Women were seen in the urogynecology clinic within 1 week of delivery and at 2, 6, and 12 weeks postpartum for perineal wound assessment. A visual analog scale for pain was administered at each visit. RESULTS: Five hundred two women met inclusion criteria for the study, and, ultimately, 268 women (54%) were enrolled. Eighty-seven percent of the cohort was nulliparous and 81% had a third-degree laceration. The majority (n=194) underwent an operative vaginal delivery (66.0% forceps and 6.0% vacuum). The overall risk was 19.8% (95% confidence interval [CI] 15.2-25.1%) for wound infection (n=53) and 24.6% (95% CI 19.6-30.2%) for wound breakdown (n=66). Operative vaginal delivery was associated with wound complications (infection, breakdown, or both) (adjusted odds ratio [OR] 2.54, 95% CI 1.32-4.87, P=.008). Intrapartum antibiotic therapy for obstetric indications was associated with a decreased risk of wound complications (adjusted OR 0.50, 95% CI 0.27-0.94, P=.03). Women with a wound complication reported significantly more pain within 1 week of delivery than women with a normally healing perineum (visual analog scale: 40.1+/-25.6 compared with 31.0+/-23, P=.002); this persisted at 12 weeks postpartum (6.6+/-7.5 compared with 3.4+/-7.1, P=.005). CONCLUSION: Women who sustain obstetric anal sphincter injuries are at high risk for the development of wound complications in the early postpartum period, warranting immediate and consistent follow-up. LEVEL OF EVIDENCE: II. PMID- 25932837 TI - Uterine rupture risk after periviable cesarean delivery. AB - OBJECTIVE: To investigate the risk of uterine rupture in women with prior periviable cesarean delivery and prior term cesarean delivery independent of initial incision type. METHODS: We conducted a retrospective longitudinal cohort study using Washington state birth certificate data and hospital discharge records, identifying primary cesarean deliveries performed at 20-26 weeks and 37 41 weeks of gestation with subsequent delivery between 1989 and 2008. We compared subsequent uterine rupture risk in the two groups considering both primary incision type and subsequent labor induction and augmentation. RESULTS: We identified 456 women with index periviable cesarean delivery and 10,505 women with index term cesarean delivery. Women with index periviable cesarean delivery were younger, more frequently of nonwhite race, more likely to smoke, and more likely to have hypertension. Women in the periviable group had more index classical incisions (42% compared with 1%, P<.001) and fewer subsequent inductions and augmentations (8% compared with 16%, P<.001). Uterine rupture in the subsequent pregnancy occurred more frequently among women in the index periviable group than those in the index term group (8/456 [1.8%] compared with 38/10,505 [0.4%], odds ratio [OR] 4.9, 95% confidence interval [CI] 2.3-10.6). This relationship persisted among women with a low transverse incision (4/228 [1.8%] compared with 36/9,558 [0.4%], OR 4.7, 95% CI 1.7-13.4). CONCLUSION: Cesarean delivery at periviability compared with term is associated with an increased risk for uterine rupture in a subsequent pregnancy, even after low transverse incision. These data support judicious use of cesarean delivery at periviable gestational ages and inform subsequent counseling. LEVEL OF EVIDENCE: II. PMID- 25932838 TI - Comparison of human papillomavirus infection and cervical cytology in women using copper-containing and levonorgestrel-containing intrauterine devices. AB - OBJECTIVE: To investigate whether there is a difference in cervical cytology and high-risk human papillomavirus (HPV) infection clearance between levonorgestrel- and copper-containing intrauterine device (IUD) users. METHODS: The electronic medical record system was searched by the appropriate procedural code for IUD insertion for all patients undergoing IUD placement during the study period (January 31, 2005 to January 31, 2012). Patients who received treatment for cervical dysplasia, had their IUDs removed, or conceived during the study period were excluded. High-risk HPV and cervical cytology results immediately preceding and after IUD placement were obtained. RESULTS: One hundred fifty patients had a copper-containing and 152 patients a levonorgestrel-containing IUD placed. The groups were comparable in terms of age, body mass index, duration of follow-up, and percentage of smokers. Sixty-six patients were high-risk HPV-positive before IUD insertion (30 in copper compared with 36 in the levonorgestrel IUD group, P=.4), and the groups had similar follow-up times (364.1+/-26.3 compared with 357.2+/-29.7 days, respectively, between the IUD placement and a repeat Pap test with high-risk HPV cotesting, P=.2). Of those, 21 (70%; 95% confidence interval [CI] 53.6-86.4%) cleared the infection after copper-containing IUD placement compared with 15 (42%; 95% CI 25.6-57.8%) in the levonorgestrel group (P=.04). There were only two (1.7%) new high-risk HPV infections in the copper compared with eight (6.9%) in the levonorgestrel group (P=.056). CONCLUSION: Our data suggest that levonorgestrel-containing IUD could be associated with decreased high-risk HPV infection clearance and possibly increased acquisition compared with the copper-containing IUD. LEVEL OF EVIDENCE: II. PMID- 25932839 TI - Manual compared with electric vacuum aspiration for abortion at less than 6 weeks of gestation: a randomized controlled trial. AB - OBJECTIVE: To evaluate whether manual or electric vacuum aspiration results in greater immediate confirmation of completed abortion at less than 6 weeks of gestation. METHODS: Five hundred pregnant women presenting for surgical abortion with mean gestational sac diameter of less than 12 mm or no visible sac on ultrasonography were randomized to manual or electric vacuum aspiration. Tissue examination was performed by operating physicians, not blinded to group assignment, and by trained medical assistants, blinded to group assignment. Patients with no products of conception on gross inspection underwent repeat aspiration as necessary and serial human chorionic gonadotropin monitoring. All patients were scheduled for follow-up visits. The primary outcome was detection of products of conception in patients with subsequently confirmed completed abortion. RESULTS: From April 2010 to October 2011, 252 patients were randomized to manual vacuum aspiration and 248 to electric vacuum aspiration. One hundred eighty-two (82%) patients in the manual vacuum aspiration group had products of conception identified and subsequently confirmed completed abortion compared with 164 (76%) patients undergoing electric vacuum patients (P=.13, relative risk 0.83, 95% confidence interval [CI] 0.64-1.07). In pregnancies of sac size 3 mm or less, including no visible sac, five of 29 (17%) patients undergoing manual vacuum aspiration had accurate identification of products of conception compared with four of 31 (13%) patients undergoing electric vacuum aspiration (P=.64, relative risk 0.85, 95% CI 0.44-1.63). Tissue reports of physicians and medical assistants had 90% concordance. Seventy-nine (16%) patients required human chorionic gonadotropin monitoring to confirm completed abortion. There were seven (1.4%) ongoing pregnancies, including four false-positive products of conception results and, among the latter, one presumed ectopic pregnancy. CONCLUSION: Our study supports providing abortions to women who request them before 6 weeks of gestation using either manual or electric vacuum aspiration. Early aspiration is highly effective, although human chorionic gonadotropin monitoring may be necessary to confirm complete abortion. LEVEL OF EVIDENCE: I. PMID- 25932840 TI - Device-guided slow-paced respiration for menopausal hot flushes: a randomized controlled trial. AB - OBJECTIVE: To evaluate the efficacy of device-guided slow-paced respiration for reducing the frequency and severity of menopausal hot flushes. METHODS: Perimenopausal or postmenopausal women reporting four or more hot flushes per day were recruited into a parallel-group, randomized trial of slow-paced respiration using a portable guided-breathing device. Women were randomly assigned to use a standard device to practice slowing their resting breathing rate to less than 10 breaths per minute for at least 15 minutes everyday or use an identical-appearing control device programmed to play relaxing nonrhythmic music while monitoring spontaneous breathing. The primary outcome, change in hot flush frequency over 12 weeks, was assessed using data from validated 7-day diaries abstracted by blinded analysts. RESULTS: Among the 123 participants, mean age was 53.4 (+/-3.4) years. Women reported an average of 8.5 (+/-3.5) hot flushes per day at baseline. After 12 weeks, women randomized to paced respiration (n=61) reported an average reduction of 1.8 (95% confidence interval [CI] 0.9-2.6) hot flushes per day ( 21%) compared with 3.0 (95% CI 2.1-3.8) hot flushes per day (-35%) in the music listening group (n=62) (P=.048). Paced respiration was associated with a 19% decrease in frequency of moderate-to-severe hot flushes compared with a 44% decrease with music listening (P=.02). CONCLUSION: In this randomized trial, women assigned to device-guided slow-paced respiration reported modest improvements in the frequency and severity of their hot flushes, but the paced respiration intervention was significantly less effective than a music-listening intervention in decreasing the frequency and severity of these symptoms. LEVEL OF EVIDENCE: I. PMID- 25932841 TI - Risk factors for venous thromboembolism after hysterectomy. AB - OBJECTIVE: To assess the prevalence of and risk factors for venous thromboembolism after hysterectomy. METHODS: This is a retrospective analysis of data from a voluntary, statewide surgical quality improvement collaborative. Demographics and perioperative data were obtained for hysterectomies performed from January 1, 2008, to April 4, 2014. Postoperative venous thromboembolism was defined as a deep vein thrombosis, pulmonary embolism, or both diagnosed within 30 days of hysterectomy. Significant variables related to postoperative venous thromboembolism were identified using bivariate analyses, and then logistic mixed modeling was used to develop a final model for venous thromboembolism. RESULTS: The rate of postoperative venous thromboembolism was 0.5% (110/20,496). Women who had a postoperative venous thromboembolism more frequently had a body mass index 35 or greater (40.0% compared with 25.2%, odds ratio [OR] 1.96, 95% confidence interval [CI] 1.08-3.56, P=.03), abdominal hysterectomy (referent nonabdominal hysterectomy; 61.8% compared with 29.9%, OR 2.67, 95% CI 1.46-4.86, P=.001), and gynecologic cancer as the indication for surgery (16.4% compared with 9.6%, OR 2.49, 95% CI 1.22-5.07, P=.01). Increasing surgical time (hours; referent 1 hour; OR 1.55, 95% CI 1.31-1.84, P<.001) was also an associated factor. In bivariate analyses, women with, compared with without, venous thromboembolism more frequently received both preoperative and postoperative heparin (31.9% compared with 15.2%, P<.001 and 55.9% compared with 33.5%, P<.001, respectively), but this did not remain significant in the final model. CONCLUSION: Body mass index 35 or greater, abdominal hysterectomy, increasing surgical time, and cancer as the indication for surgery are risk factors for venous thromboembolism after hysterectomy. LEVEL OF EVIDENCE: III. PMID- 25932842 TI - Innovative technique for enclosed morcellation using a surgical glove. AB - OBJECTIVE: To describe an innovative approach for enclosed morcellation using a surgical glove in multiport laparoscopic surgery. METHODS: Power morcellation was performed within an insufflated surgical glove in a completely enclosed manner between January and May 2014. The specimen was placed into the glove within the abdomen. The glove opening and thumb were exteriorized through the umbilical and left lower abdominal trocar incisions, respectively. The optical trocar and optic were inserted into the glove, which was then insufflated. The thumb tip was cut, and a power morcellator was inserted through this finger. The morcellation was accomplished within the completely enclosed glove. The thumb tip was closed, and the glove, containing residual specimens and bloody fluid, was removed from the abdomen through the umbilical incision. Thus, the risks of bag piercing and leakage during contained power morcellation were eliminated. Demographic and operative data were collected and analyzed for all cases. RESULTS: Thirty multiport laparoscopic myomectomy and morcellation procedures were performed during the study period. The median operative time was 85 minutes (range 60-140 minutes). The median morcellation preparation time, total morcellation time, and withdrawal time were 6 (range 4.5-14), 32 (range 15-55), and 1.2 (range 1-1.5) minutes, respectively. No intraoperative complications or bag ruptures were recorded. CONCLUSION: With our innovative technique, a disposable latex glove can be used for an enclosed morcellation that avoids piercing the enclosure container within the abdominal cavity, thereby offering decreased risks related to bag perforation and leakage compared with previous contained power morcellation techniques. LEVEL OF EVIDENCE: III. PMID- 25932843 TI - Delivery of breech presentation at term gestation in Canada, 2003-2011. AB - OBJECTIVE: To examine neonatal mortality and morbidity rates by mode of delivery among women with breech presentation at term gestation. METHODS: We carried out a population-based cohort study examining neonatal outcomes among term, nonanomalous singletons in breech presentation among all hospital deliveries in Canada (excluding Quebec) between 2003 and 2011. Mode of delivery was categorized into vaginal delivery, cesarean delivery in labor, and cesarean delivery without labor. Composite neonatal mortality and morbidity (death, assisted ventilation, convulsions, or specific birth injury) was the primary outcome. Logistic regression was used to estimate the independent effects of mode of delivery. RESULTS: The study population included 52,671 breech deliveries; vaginal deliveries increased from 2.7% in 2003 to 3.9% in 2011, and cesarean deliveries in labor increased from 8.7% to 9.8%. Composite neonatal mortality and morbidity rates at 37 weeks of gestation or greater after vaginal delivery were significantly higher than those after cesarean without labor (adjusted rate ratio 3.60, 95% confidence interval [CI] 2.50-5.15; adjusted rate difference 15.8/1,000 deliveries, 95% CI 9.2-25.2). Among women at 40 weeks of gestation or greater, neonatal mortality and morbidity rates after vaginal delivery were significantly higher than those after cesarean delivery without labor (adjusted rate ratio 5.39, 95% CI 2.68-10.8; adjusted rate difference 24.1/1,000 deliveries, 95% CI 9.2-53.8). Neonatal mortality and morbidity rates were also higher after caesarean delivery in labor. CONCLUSION: Among term, nonanomalous singletons in breech presentation at term, composite neonatal mortality and morbidity rates were significantly higher after vaginal delivery and cesarean delivery in labor compared with cesarean delivery without labor. LEVEL OF EVIDENCE: II. PMID- 25932844 TI - Once more unto the breech: planned vaginal delivery compared with planned cesarean delivery. AB - This article provides a knowledge-based assessment of planned cesarean delivery compared with planned vaginal delivery for breech presentation at term gestation. The most critical evidence on this issue is the intention-to-treat analysis from the Term Breech Trial, which showed that planned cesarean delivery reduced composite perinatal death and serious neonatal morbidity. Although there was no difference in composite death or neurodevelopmental delay at 2 years of age, this finding was based on only 44% of randomized patients and was not an analysis by intention to treat. On the other hand, the design of the nonexperimental Presentation et Mode d'Accouchement: presentation and mode of delivery (PREMODA) study (which showed no difference in composite perinatal mortality or morbidity after planned cesarean delivery compared with planned vaginal delivery), likely favored the planned vaginal delivery group; lack of exclusion criteria led to higher risk women (with contraindications to vaginal delivery) being included in the planned cesarean delivery group. Such selection bias notwithstanding, both the Term Breech Trial and the PREMODA study showed significantly higher rates of 5-minute Apgar score less than 4, 5-minute Apgar score less than 7, intubation, and birth trauma in the planned vaginal delivery group. Finally, studies from the Netherlands, Denmark, and Canada have shown that increases in planned cesarean delivery after the Term Breech Trial led to improved neonatal outcomes. Nevertheless, planned vaginal delivery continues to be associated with higher rates of adverse perinatal outcomes in these countries. The totality of the evidence therefore unequivocally shows the relatively greater safety of planned cesarean delivery for breech presentation at term gestation. PMID- 25932845 TI - Quantitative fetal fibronectin to predict preterm birth in asymptomatic women at high risk. AB - OBJECTIVE: To evaluate the diagnostic accuracy of cervicovaginal fluid quantitative fetal fibronectin, measured by a bedside analyzer, to predict spontaneous preterm birth before 34 weeks of gestation. METHODS: We conducted a prospective masked observational cohort study of cervicovaginal fluid quantitative fetal fibronectin concentration in asymptomatic women at high risk of spontaneous preterm birth (n=1,448; 22-27 6/7 weeks of gestation) measured using a rapid bedside analyzer. The routine qualitative result (positive negative) was made available to clinicians at the time of testing, but the quantitative result remained blinded until after delivery. RESULTS: Spontaneous preterm birth (less than 34 weeks of gestation) increased from 2.7%, 11.0%, 14.9%, 33.9%, and 47.6% with increasing concentration of fetal fibronectin (less than 10, 10-49, 50-199, 200-499, and 500 ng/mL or greater, respectively). A threshold of 200 ng/mL had a positive predictive value of 37.7 (95% confidence interval [CI] 26.9-49.4) with specificity 96% (95% CI 95.3-97.3). Women with a fetal fibronectin concentration of less than 10 ng/mL had a very low risk of spontaneous preterm birth at less than 34 weeks of gestation (2.7%), no higher than the background spontaneous preterm birth rate of the general hospital population (3.3%). The quantitative fetal fibronectin test predicted birth at less than 34 weeks of gestation with an area under the curve (AUC) of 0.78 (95% CI 0.73-0.84) compared with the qualitative test AUC 0.68 (95% CI 0.63-0.73). Quantitative fetal fibronectin discriminated risk of spontaneous preterm birth at less than 34 weeks of gestation among women with a short cervix (less than 25 mm); 9.5% delivered prematurely less than 10 ng/mL compared with 55.1% greater than 200 ng/mL (P<.001). DISCUSSION: Alternative risk thresholds (less than 10 ng/mL and greater than 200 ng/mL) improve accuracy when using quantitative fetal fibronectin measurements to define risk of spontaneous preterm birth. This is particularly relevant for asymptomatic women with a short cervix. LEVEL OF EVIDENCE: II. PMID- 25932846 TI - Risk for preterm and very preterm delivery in women who were born preterm. AB - OBJECTIVE: To evaluate whether women who themselves were born preterm are at increased risk of preterm delivery and, if so, whether known maternal complications of preterm birth such as hypertension or diabetes explain this risk. METHODS: We conducted a population-based cohort study of all women born preterm (51,148) and term (823,991) in Quebec, Canada, between 1976 and 1995; after frequency matching 1:2 preterm to term, we examined the relationship of preterm birth between women and their offspring. RESULTS: The study included 7,405 women who were born preterm (554 before 32 weeks of gestation and 6,851 at 32-36 weeks of gestation) and 16,714 women born term, who delivered 12,248 and 27,879 newborns, respectively. Overall, 14.2% of women born before 32 weeks of gestation, 13.0% of 32-36 weeks of gestation, and 9.8% of those born term delivered prematurely at least once during the study period, including 2.4%, 1.8%, and 1.2%, respectively, who delivered very preterm (both P<.001 for trend). After adjustment for factors including own birth weight for gestational age and pregnancy complications, the overall odds of preterm first live delivery associated with being born preterm was elevated by 1.63-fold (95% confidence interval [CI] 1.22-2.19) for women born before 32 weeks of gestation and 1.41 fold (95% CI 1.27-1.57) for those born at 32-36 weeks of gestation relative to women born term. CONCLUSION: Women who themselves were born preterm are at increased risk of delivering their neonates prematurely. This is independent of prematurity risks associated with hypertension and diabetes. LEVEL OF EVIDENCE: II. PMID- 25932847 TI - The effect of supervised prenatal exercise on fetal growth: a meta-analysis. AB - OBJECTIVE: To estimate the influence of structured prenatal exercise on newborn birth weight, macrosomia, and growth restriction. DATA SOURCES: A structured search of MEDLINE, EMBASE, CINAHL, Sport Discus, Ovid's All EBM Reviews, and ClinicalTrials.gov databases up to January 13, 2015. The search combined keywords and MeSH-like terms including, but not limited, to "physical activity," "exercise," "pregnancy," "gestation," "neonatal," and "randomized controlled trial." METHODS OF STUDY SELECTION: Articles reporting randomized controlled trials comparing standard care with standard care plus supervised prenatal exercise for which birth size was available were included. Supervision was defined as at least one exercise session performed with study personnel every 2 weeks throughout the program. Interventions consisting solely of pelvic floor exercises, stretching, or relaxation were excluded. Our search yielded 1,036 publications of which 79 were assessed for eligibility. Twenty-eight studies reporting on 5,322 pregnancies were subsequently included in the analysis. TABULATION, INTEGRATION, AND RESULTS: Our meta-analysis demonstrated that prenatal exercise reduced the odds of having a large newborn (birth weight greater than 4,000 g or greater than the 90th percentile for gestational age and sex) by 31% (odds ratio [OR] 0.69, 95% confidence interval [CI] 0.55-0.86; I 25%) without altering the risk of having a small newborn (birth weight less than 2,500 g or less than the 10th percentile for gestational age and sex) (OR 1.02, 95% CI 0.72-1.46; I 0%) or gestational age at delivery (weighted mean difference -0.00 weeks, 95% CI -0.09 to 0.09; I 0%). Newborns of mothers assigned to exercise were lighter than those of nonexercising controls (weighted mean difference -31 g, 95% CI -57 to -4; I 0%). Maternal gestational weight gain (weighted mean difference 1.1 kg, 95% CI -1.5 to -0.6; I 53%) and odds of cesarean delivery (OR 0.80, 95% CI 0.69-0.94; I 0%) were also reduced. CONCLUSION: These data demonstrate that structured prenatal exercise reduces the risk of having a large newborn without a change in the risk of having a small newborn. PMID- 25932849 TI - Cefazolin prophylaxis in obese women undergoing cesarean delivery: a randomized controlled trial. AB - OBJECTIVE: To compare adipose tissue concentration among obese women receiving 2 g compared with 3 g of precesarean cefazolin prophylaxis. METHODS: This was a double-blind randomized controlled trial of women with singleton gestations and body mass indexes (BMIs) of 30 or greater at their first prenatal visit undergoing cesarean delivery at term. Women were randomly allocated, stratified by BMI, to receive 2 g or 3 g of cefazolin. Subcutaneous adipose tissue was harvested twice: before (opening) fascial incision and after (closing) fascial closure. The primary outcome was opening adipose tissue cefazolin concentration, measured by high-pressure liquid chromatography. RESULTS: From April 2013 to July 2014, 58 women were enrolled, 57 included in the analysis: 28 in the 2-g group and 29 in the 3-g group. Baseline characteristics were similar between groups. Median opening adipose tissue concentration was similar between the 2-g and 3-g groups (9.4 [interquartile range 5.1-13.4] compared with 11.7 [interquartile range 7-18.3] micrograms/g, P=.12). The percentage of women with opening concentrations above 8 micrograms/g, the minimally inhibitory concentration of cefazolin for Staphylococcus species, was similar (61% compared with 72%, P=.35). All samples were above 2 micrograms/g, the minimally inhibitory concentration for Enterobacteriaceae. Closing adipose tissue concentrations and stratified analyses were consistent with the overall analysis. CONCLUSION: In obese women undergoing cesarean delivery, prophylaxis with 3 g of cefazolin did not significantly increase adipose tissue concentration. Thus, our data do not support recommendations for 3-g dosing. LEVEL OF EVIDENCE: I. PMID- 25932848 TI - Effect of an exercise intervention on gestational diabetes mellitus: a randomized controlled trial. AB - OBJECTIVE: To examine the effect of an individually tailored, motivationally matched prenatal exercise intervention on gestational diabetes mellitus (GDM) and other measures of glucose intolerance among ethnically diverse prenatal care patients at increased risk for GDM. METHODS: The Behaviors Affecting Baby and You study randomized eligible women at a mean (standard deviation) of 18.2 (4.1) weeks of gestation to a 12-week individually tailored, motivationally matched exercise intervention or a comparison health and wellness intervention. The goal of the exercise intervention was to achieve the American College of Obstetricians and Gynecologists' guidelines for physical activity during pregnancy. Diagnosis of GDM, impaired glucose tolerance, abnormal glucose screen, and screening glucose values (mg/dL) were abstracted from medical records. A sample size of 352 women (176 per group) was planned to have 80% power to detect reductions in risk of 35% or larger. RESULTS: From July 2007 to December 2012, a total of 251 (86.5%) women completed the intervention; n=124 and 127 in the exercise and comparison interventions, respectively. Based on an intention-to-treat analysis, no statistically significant differences between the intervention groups were observed; the relative odds of GDM in the exercise group was 0.61 (95% confidence interval [CI] 0.28-1.32) as compared with the health and wellness comparison group. Odds ratios for impaired glucose tolerance and abnormal glucose screen were 0.68 (95% CI 0.35-1.34) and 0.86 (95% CI 0.51-1.47), respectively. The intervention had no effect on birth outcomes. CONCLUSION: In this randomized trial among ethnically diverse pregnant women at increased risk for GDM, we found that a prenatal exercise intervention implemented in the second trimester did not result in a statistically significant reduction in relative odds for GDM, impaired glucose tolerance, or abnormal glucose screen. LEVEL OF EVIDENCE: I. PMID- 25932850 TI - Screening for human immunodeficiency virus and other sexually transmitted diseases among U.S. women with prenatal care. AB - OBJECTIVE: To estimate prenatal sexually transmitted disease-human immunodeficiency virus (HIV) screening rates among insured women with prenatal care and the association of chlamydia and gonorrhea screening with Pap testing. METHODS: We estimated prenatal screening rates for syphilis, hepatitis B, HIV, chlamydia, and gonorrhea among women aged 15-44 years using a 2009-2010 U.S. administrative claims database that captures information for health services provided for both Medicaid- and commercially insured persons. Procedural and diagnostic codes were used to identify pregnant women with a live birth in 2010 with continuous insurance coverage at least 210 days before delivery and at least one typical prenatal blood test. Strengths of association between chlamydia and gonorrhea screening and Pap testing were measured using a chi test of independence. RESULTS: Among 98,709 Medicaid-insured pregnant women, 95,064 (96.3%) were screened for syphilis, 95,082 (96.3%) for hepatitis B, 81,339 (82.4%) for HIV, 82,047 (83.1%) for chlamydia, and 73,799 (74.8%) for gonorrhea. Among 266,012 commercially insured women, 260,079 (97.8%) were screened for syphilis, 257,675 (96.8%) for hepatitis B, 227,276 (85.4%) for HIV, 187,071 (70.3%) for chlamydia, and 182,400 (68.6%) for gonorrhea. Prenatal screening for chlamydia and gonorrhea among both groups of women was more likely to be performed if a Pap test was also done (P<.001). CONCLUSION: Prenatal screening for syphilis and hepatitis B was nearly universal among Medicaid- and commercially insured women; HIV screening rates were much lower and varied by insurance type and demographic characteristics. Chlamydia screening was suboptimal and most often occurred with Pap testing. LEVEL OF EVIDENCE: III. PMID- 25932851 TI - Assessing White's classification of pregestational diabetes in a contemporary diabetic population. AB - OBJECTIVE: To assess the validity of White's classification, including the role of chronic hypertension, in a contemporary diabetic population. METHODS: We performed a retrospective cohort study of all singleton pregnancies with pre existing diabetes mellitus from 2008 to 2013. Adverse outcomes were compared across classes B, C, D, and vascular disease (R, F, H) and further stratified by the presence or absence of chronic hypertension. Outcomes examined were a composite perinatal outcome (stillbirth, neonatal death, shoulder dystocia, birth injury, seizures, requiring chest compressions or intubation at delivery, blood pressure support), small for gestational age (SGA), large for gestational age (LGA), macrosomia, shoulder dystocia, preterm delivery at less than 37 weeks of gestation, preeclampsia, and cesarean delivery. RESULTS: Of the 475 patients, the 1980 White's classification was significantly associated with SGA, LGA, macrosomia, preterm delivery, preeclampsia, and cesarean delivery (P<=.01). Within each White's class based on age or time since diagnosis alone, hypertension was significantly associated with a higher incidence of preeclampsia in class B (16% without hypertension compared with 32% with hypertension, P<.01) and C (22% compared with 40%, P=.04), SGA in C (4.7% compared with 21%, P<.01), preterm delivery in B (25% compared with 46%, P<.01) and C (35% compared with 58%, P=.01), and the composite neonatal outcome in B (7.9% compared with 17%, P=.03). The incidence of adverse outcomes in classes B and C with hypertension resembles the incidence of adverse outcomes in those with diabetes one class higher. CONCLUSION: The 1980 White's classification system, taking into consideration the presence of chronic hypertension, remains a useful system for counseling pregestational diabetic women regarding adverse pregnancy outcomes. LEVEL OF EVIDENCE: II. PMID- 25932853 TI - The North American Fetal Therapy Network Consensus Statement: prenatal management of uncomplicated monochorionic gestations. AB - Owing to vascular connections within a single placenta, monochorionic gestations present distinctive prenatal management challenges. Complications that can arise as a result of unbalanced hemodynamic exchange (twin-twin transfusion syndrome and twin anemia polycythemia sequence) and unequal placental sharing (selective fetal growth restriction) should be kept in mind while prenatal management is being planned. Because of unique monochorionic angioarchitecture, what happens to one twin can directly affect the other. Death of one twin can result in death or permanent disability of the co-twin. Early detection of these unique disease processes through frequent ultrasonographic surveillance may allow the opportunity for earlier referral, intervention, or both and potentially better outcomes. Therefore, monochorionic gestations should be managed differently than dichorionic gestations or singletons. The purpose of this document is to present in detail methods for monitoring and management of uncomplicated monochorionic gestations and to review the evidence for the roles of these methods for detection of complications in clinical practice. Finally, we present evidence based and expert opinion-supported recommendations developed by the North American Fetal Therapy Network for the diagnosis, surveillance, and delivery of uncomplicated monochorionic gestations. PMID- 25932852 TI - Obstetric and neonatal outcomes after antipsychotic medication exposure in pregnancy. AB - OBJECTIVE: Antipsychotic medications are used by increasing numbers of women of reproductive age. The safety of these medications during pregnancy has not been well described. We undertook a systematic review and meta-analysis of the adverse obstetric and neonatal outcomes associated with exposure to antipsychotics during pregnancy. DATA SOURCES: PubMed, Reprotox, and ClinicalTrials.gov were searched to identify potential studies for inclusion. METHODS OF STUDY SELECTION: Case control or cohort studies estimating adverse birth outcomes associated with antipsychotic exposure during pregnancy were included. Pooled odds ratios (ORs) were used for dichotomous outcomes and weighted mean differences were used for neonatal birth weight and gestational age. Thirteen cohort studies, including 6,289 antipsychotic-exposed and 1,618,039 unexposed pregnancies, were included. TABULATION, INTEGRATION, AND RESULTS: Antipsychotic exposure was associated with an increased risk of major malformations (absolute risk difference [ARD] 0.03, 95% confidence interval [CI] 0.00-0.05, P=.04, Z=2.06), heart defects (ARD 0.01, 95% CI 0.00-0.01, P<.001, Z=3.44), preterm delivery (ARD 0.05, 95% CI 0.03-0.08, P<.001, Z=4.10), small-for-gestational-age births (ARD 0.05, 95% CI 0.02-0.09, P=.006, Z=2.74), elective termination (ARD 0.09, 95% CI 0.05-0.13, P<.001, Z=4.69), and decreased birth weight (weighted mean difference -57.89 g, 95% CI 103.69 to -12.10 g, P=.01). There was no significant difference in the risk of major malformations (test for subgroup differences: chi2=0.07, degrees of freedom=1, P=.79) between typical (OR 1.55, 95% CI 1.21-1.99, P=.006) and atypical (OR 1.39, 95% CI 0.66-2.93, P=.38) antipsychotic medications. Antipsychotic exposure was not associated with risk of large-for-gestational-age births, stillbirth, and spontaneous abortion. Although antipsychotic exposure during pregnancy was associated with increased risk of adverse obstetric and neonatal outcomes, this association does not necessarily imply causation. This analysis was limited by the small number of included studies and limited adjustment in studies for possible confounders. CONCLUSION: Women requiring antipsychotic treatment during pregnancy appear at higher risk of adverse birth outcomes, regardless of causation, and may benefit from close monitoring and minimization of other potential risk factors during pregnancy. PMID- 25932854 TI - What is new in interpregnancy interval and pregnancy outcome? Best articles from the past year. AB - This month we focus on current research in pregnancy spacing. Dr. Campbell discusses five recent publications, and each is concluded with a "bottom line" that is the take-home message. The complete reference for each can be found in on this page, along with direct links to the abstracts. PMID- 25932855 TI - When you need me. PMID- 25932856 TI - In reply. PMID- 25932857 TI - Association of prelabor cesarean delivery with reduced mortality in twins born near term. PMID- 25932858 TI - Association of prelabor cesarean delivery with reduced mortality in twins born near term. PMID- 25932859 TI - In reply. PMID- 25932865 TI - The American College of Obstetricians and Gynecologists Practice Bulletin no. 150. Early pregnancy loss. AB - Early pregnancy loss, or loss of an intrauterine pregnancy within the first trimester, is encountered commonly in clinical practice. Obstetricians and gynecologists should understand the use of various diagnostic tools to differentiate between viable and nonviable pregnancies and offer the full range of therapeutic options to patients, including expectant, medical, and surgical management. The purpose of this Practice Bulletin is to review diagnostic approaches and describe options for the management of early pregnancy loss. PMID- 25932866 TI - The American College of Obstetricians and Gynecologists Committee Opinion no. 630. Screening for perinatal depression. AB - Perinatal depression, which includes major and minor depressive episodes that occur during pregnancy or in the first 12 months after delivery, is one of the most common medical complications during pregnancy and the postpartum period, affecting one in seven women. It is important to identify pregnant and postpartum women with depression because untreated perinatal depression and other mood disorders can have devastating effects on women, infants, and families. Several screening instruments have been validated for use during pregnancy and the postpartum period. Although definitive evidence of benefit is limited, the American College of Obstetricians and Gynecologists recommends that clinicians screen patients at least once during the perinatal period for depression and anxiety symptoms using a standardized, validated tool. Although screening is important for detecting perinatal depression, screening by itself is insufficient to improve clinical outcomes and must be coupled with appropriate follow-up and treatment when indicated; clinical staff in obstetrics and gynecology practices should be prepared to initiate medical therapy, refer patients to appropriate behavioral health resources when indicated, or both. PMID- 25932867 TI - The American College of Obstetricians and Gynecologists Committee Opinion no. 631. Endometrial intraepithelial neoplasia. AB - Endometrial hyperplasia is of clinical significance because it is often a precursor lesion to adenocarcinoma of the endometrium. Making the distinction between hyperplasia and true precancerous lesions or true neoplasia has significant clinical effect because their differing cancer risks must be matched with an appropriate intervention to avoid undertreatment or overtreatment. Pathologic diagnosis of premalignant lesions should use criteria and terminology that clearly distinguish between clinicopathologic entities that are managed differently. At present, the endometrial intraepithelial neoplasia schema is tailored most closely to this objective, incorporating modified pathologic criteria based upon evidence that has become available since the creation of the more widely used 1994 four-class World Health Organization schema (in which atypical hyperplasia is equated with precancerous behavior). The accuracy of dilation and curettage compared with endometrial suction curette in diagnosing precancer and excluding concurrent carcinoma is unclear. Hysteroscopy with directed biopsy is more sensitive than dilation and curettage in the diagnosis of uterine lesions. When clinically appropriate, total hysterectomy for endometrial intraepithelial neoplasia provides definitive assessment of a possible concurrent carcinoma and effectively treats premalignant lesions. Systemic or local progestin therapy is an unproven but commonly used alternative to hysterectomy that may be appropriate for women who are poor surgical candidates or who desire to retain fertility. PMID- 25932868 TI - Simultaneous binding of a cyclophane and classical intercalators to DNA: observation of FRET-mediated white light emission. AB - DNA-assisted Forster resonance energy transfer (FRET) between an anthracene-based cyclophane (CP) and mono- and bis-intercalators such as propidium iodide (PI) and ethidium homodimer-1 (EHD), respectively, has been studied using various photophysical and biophysical techniques. The cyclophane and PI exhibited simultaneous binding to DNA at all concentrations studied and showed DNA-assisted FRET from the excimer of cyclophane with a FRET efficiency of ca. 71%. On the other hand, the bis-intercalator EHD, only at lower concentrations (<3 MUM), can act as an acceptor for the energy transfer process with a lower efficiency of ca. 44%. At higher concentrations (>15 MUM), EHD, on account of its higher binding affinity, displaces cyclophane from the DNA scaffold. Employing the ternary system comprising of the cyclophane, DNA and PI and fine-tuning the concentrations of the components in a molar ratio of 1 : 0.75 : 0.05 (CP : DNA : PI) we have demonstrated white light emission with CIE coordinates (0.35, 0.37). PMID- 25932869 TI - The association between BMI and cervical cancer risk: a meta-analysis. AB - The association between BMI and cervical cancer risk is not clear. This meta analysis was carried out to estimate the association between overweight and obesity and cervical cancer risk. We searched PubMed, Web of Science, Scopus, ScienceDirect, LILACS, and SciELO for observational studies addressing the association between BMI and cervical cancer until February 2015. Data were independently extracted and analyzed using odds ratios and 95% confidence intervals (CIs), on the basis of random-effects models. We identified a total of 3543 references and included nine studies with 128 233 participants. On the basis of the results of case-control and cohort studies, the association between cervical cancer and overweight was estimated to be 1.03 (95% CI: 0.81, 1.25) and 1.10 (95% CI: 1.03, 1.17), respectively. According to the results of case-control and cohort studies, the association between cervical cancer and obesity was estimated to be 1.40 (95% CI: 1.08, 1.71) and 1.08 (95% CI: 0.60, 1.52), respectively. No evidence of heterogeneity and publication bias was observed. The findings from this meta-analysis indicate that overweight is not associated with an increased risk of cervical cancer, but obesity is weakly associated with an increased risk of cervical cancer. However, more evidence, based on large prospective cohort studies, is required to provide conclusive evidence on whether or not BMI is associated with an increased risk of cervical cancer. PMID- 25932870 TI - Diagnostic radiography exposure increases the risk for thyroid microcarcinoma: a population-based case-control study. AB - Thyroid cancer incidence and diagnostic radiography exposures, particularly computed tomography (CT) scanning and nuclear medicine examinations, have increased substantially in the USA. However, very few epidemiologic studies have directly investigated their associations. A population-based case-control study was conducted in Connecticut in 2010-2011, including 462 histologically confirmed incident thyroid cancer cases and 498 population-based controls. Multivariate unconditional logistic regression models were used to estimate the associations between diagnostic radiography and the risk of thyroid cancer, controlling for potential confounding factors. Exposure to any form of diagnostic radiography was associated with an increased risk of well-differentiated thyroid microcarcinoma [tumor size<=10 mm, odds ratio (OR)=2.76, 95% confidence interval (CI): 1.31 5.81]. The highest risk increase occurred with nuclear medicine examinations (excluding cardiology tests and thyroid uptake studies; OR=5.47, 95% CI: 2.10 14.23), followed by chest CT scanning (OR=4.30, 95% CI: 1.66-11.14), head and neck CT scanning (OR=3.88, 95% CI: 1.75-8.63), upper gastrointestinal series (OR=3.56, 95% CI: 1.54-8.21), lower gastrointestinal series (OR=3.29, 95% CI: 1.41-7.66), kidney radiography involving dye injection into a vein or artery (OR=3.21, 95% CI: 1.20-8.54), mammography (OR=2.95, 95% CI: 1.14-7.61), chest radiography (OR=2.93, 95% CI: 1.37-6.29), and abdomen CT scanning (OR=2.54, 95% CI: 1.02-6.30). No significant associations were found between these imaging modalities and thyroid tumors larger than 10 mm. This study provides the first direct evidence that CT scanning and nuclear medicine examinations are associated with an increased risk of thyroid cancer. The novel finding that an array of diagnostic radiography procedures are associated with thyroid microcarcinomas warrants further investigation. PMID- 25932871 TI - AMP-activated protein kinase activators, cancer regression, and survival. PMID- 25932872 TI - Identification of drug-specific pathways based on gene expression data: application to drug induced lung injury. AB - Identification of signaling pathways that are functional in a specific biological context is a major challenge in systems biology, and could be instrumental to the study of complex diseases and various aspects of drug discovery. Recent approaches have attempted to combine gene expression data with prior knowledge of protein connectivity in the form of a PPI network, and employ computational methods to identify subsets of the protein-protein-interaction (PPI) network that are functional, based on the data at hand. However, the use of undirected networks limits the mechanistic insight that can be drawn, since it does not allow for following mechanistically signal transduction from one node to the next. To address this important issue, we used a directed, signaling network as a scaffold to represent protein connectivity, and implemented an Integer Linear Programming (ILP) formulation to model the rules of signal transduction from one node to the next in the network. We then optimized the structure of the network to best fit the gene expression data at hand. We illustrated the utility of ILP modeling with a case study of drug induced lung injury. We identified the modes of action of 200 lung toxic drugs based on their gene expression profiles and, subsequently, merged the drug specific pathways to construct a signaling network that captured the mechanisms underlying Drug Induced Lung Disease (DILD). We further demonstrated the predictive power and biological relevance of the DILD network by applying it to identify drugs with relevant pharmacological mechanisms for treating lung injury. PMID- 25932873 TI - Evaluation and treatment of medial instability of the knee. PMID- 25932874 TI - Anatomy and biomechanics of the medial side of the knee and their surgical implications. AB - In order to reconstruct the medial knee to restore the original biomechanical function of its ligamentous structures, a thorough understanding of its anatomic placement and relationship with surrounding structures is required. To restore the knee to normal kinematics, the diagnosis and surgical approach have to be aligned, to successfully reconstruct the area of injury. Three important ligaments maintain primary medial knee stability: the superficial medial collateral ligament, posterior oblique ligament, and deep medial collateral ligament. It is important not to exclude the assistance that other ligaments of the medial knee provide, including support of patellar stability by the medial patellofemoral ligament and multiligamentous hamstring tendon attachments. Valgus gapping and medial knee stability is accounted for collectively by every primary medial knee stabilizing structure. The following will review the principal medial knee anatomic and biomechanical properties. PMID- 25932875 TI - Management of acute isolated medial and posteromedial instability of the knee. AB - Medial-sided knee injuries are very common, the medial collateral ligament being the most commonly injured ligament of the knee. Injuries to the medial side of the knee can occur in isolation or concomitant with other knee ligament injuries. Isolated grade I and II injuries have been typically treated nonoperatively with excellent results. Isolated grade III injuries, however, are less common and more controversial. Although some recent literature has shown acceptable results with nonoperative treatment of isolated grade III injuries, most authors recommend surgical treatment. A variety of operative techniques have been described, including repair, augmentation, and reconstruction, all with favorable outcomes. Choice of treatment method should be based on injury pattern with the goal of regaining valgus and anteromedial rotatory stability of the knee. PMID- 25932876 TI - Surgical treatment of medial instability of the knee. AB - Medial collateral ligament (MCL) injuries are commonly seen in orthopedic practice. Most MCL injuries are isolated and can be treated nonsurgically with focus on brace protection of the ligament, range of motion, gait training, and relatively quick return to full activity. A subset of MCL injuries, however, requires operative treatment. It is critical to identify patients with medial instability and develop an operative plan that will restore stability and function to the injured knee. Many MCL reconstruction and repair techniques have been described, and improvement in outcomes with improvement of technique remains an area of great interest. This review discusses several MCL reconstruction options and outlines the authors' preferred MCL reconstruction technique. PMID- 25932877 TI - Management of Chronic Combined ACL Medial Posteromedial Instability of the Knee. AB - The medial collateral ligament is the most commonly injured ligament in the knee. High-grade medial collateral injuries are associated with injuries to the posteromedial structures of the knee. Chronic medial-sided instability is rare due to the intrinsic capacity of the medial ligamentous structures to heal. However, when combined with anterior cruciate ligament deficiency, significant anterior, valgus, and rotatory laxity of the knee occurs. In this review, we discuss the important biomechanical, clinical, and surgical considerations in the management of chronic combined anterior cruciate ligament, medial, and posteromedial instability of the knee. PMID- 25932878 TI - Evaluation and treatment of medial instability of the knee. AB - Medial knee ligament injury and instability has frequently been treated by bracing and physical therapy. That has worked well in many instances and patients have been able to resume preinjury activities. However, there is a subset of patients that remain unstable when treated with conservative measures. A critical question we face is why these knees fail when the majority heal well and regain function? What are the differences that lead to failure and how can surgeons recognize these differences and determine which patients will benefit from primary surgical repair or reconstruction? PMID- 25932879 TI - Management of Chronic Combined PCL Medial Posteromedial Instability of the Knee. AB - Currently, there is no collective consensus on the most effective treatment method for medial collateral ligament injuries with or without associated structural deficiencies. An in-depth understanding of relevant anatomic structures and diagnostic tools is critical to determining an appropriate treatment strategy. This article presents an overview for management of chronic combined posterior cruciate ligament (PCL) and posteromedial instability of the knee, and the results of treatment within the context of the PCL-based multiple ligament injured knee. Recognition and correction of the varying types of posteromedial instability is the key to successful PCL reconstruction in combined PCL posteromedial instability. Reasons for failure of PCL reconstruction include failure to address associated collateral ligament instability, associated limb malalignment, and improper tunnel position. The principles of reconstruction in the combined PCL posteromedial injured knee are to identify and treat all pathology, accurately place tunnels to approximate ligament anatomic insertion sites, utilize strong graft material, employ mechanical graft tensioning, provide secure graft fixation, and perform a deliberate postoperative rehabilitation program. Results of treatment indicate that multiple techniques of posterior ligament reconstruction and posteromedial reconstruction are successful and return patients functional activity with long-term follow-up. PMID- 25932880 TI - Nonsurgical management and postoperative rehabilitation of medial instability of the knee. AB - The medial ligaments of the knee are the most frequently injured structures of the knee joint. The decisions regarding the treatment of medial knee injuries must take into account the severity of injury to the entire knee, the chronicity of the injury, and the patient goals and activity level. The treatment and rehabilitation of the medial structures of the knee is largely reliant on the healing potential of these structures. Studies have shown that these medial, extra-articular ligaments may possess the ability to heal by both intrinsic and extrinsic properties. The goals of nonoperative treatment should include healing of the injured medial structures while controlling edema, restoring full knee motion, and preserving muscle strength. In cases of continued medial instability after an isolated grade III injury or in cases of combined multiligamentous knee injuries, the medial structures of the knee may be treated operatively with repair or reconstruction. The goals of rehabilitation following surgical intervention are the same as for nonoperative treatment; however, the progression of activity is more gradual to allow for repaired or reconstructed tissue to heal. If the objectives of early edema control, restoration of knee motion, gradual resumption of weight bearing, and return of muscle strength are followed, patients should return to full activity following medial injuries to the knee. PMID- 25932881 TI - Physical examination and imaging of medial collateral ligament and posteromedial corner of the knee. AB - The medial collateral ligament (MCL) is the most commonly injured knee ligament. Most will heal well with nonoperative treatment. However, not all medial knee injuries are the same. A detailed physical examination can help determine the severity of the medial-sided injury. When combined with advanced imaging, the examination will delineate damage to associated medial knee structures, including the location of MCL damage, posteromedial capsule injuries, and combined cruciate injuries. Failure to recognize MCL injuries that may be prone to chronic laxity can lead to significant disability, joint damage, and failure of concomitant cruciate ligament reconstructions. Magnetic resonance imaging is the mainstay of diagnostic imaging, with coronal sequences allowing full assessment of the MCL complex. Tangential views aid in the diagnosis of concomitant injuries. Stress radiography can play a role in evaluating MCL healing and subtle chronic laxity. Ultrasonography is also gaining acceptance as a means to assess MCL injuries. Use of a detailed examination and advanced imaging will allow optimal treatment of medial knee injuries and improve clinical outcomes. PMID- 25932882 TI - A review of surgical and nonsurgical outcomes of medial knee injuries. AB - Medial-sided knee injuries can result in pain, instability, and loss of function. Many clinical studies have been written on the treatment of medial-sided knee injuries; however, the vast majority are isolated case series of surgical or nonoperative treatment regimens, and only a few randomized prospective clinical trials can be found in the literature that compare different treatment modalities. Comparison of these treatments is challenging due to the variety of medial-sided structures that can be involved, the multiple different approaches to treatment, and the variability of how objective and subjective clinical outcomes are reported. In this paper we report on the injuries by extent and type of anatomic structures damaged including partial medial-sided injuries, completed isolated medial-sided knee injuries, and combined injuries. In general, most authors concur that isolated partial or complete medial collateral ligament (MCL) injuries can be treated nonoperatively with a brace and early motion with good clinical outcomes. Prospective, randomized trials support nonoperative treatment of the MCL in combined anterior cruciate ligament-MCL injuries. Knee dislocations and posterior medial corner injuries appear to have better results with surgical management including reconstruction. Multiple reconstructive techniques have been described for chronic injuries but it is difficult to compare their results. PMID- 25932883 TI - Management of Acute Combined ACL-Medial and Posteromedial Instability of the Knee. AB - Medial collateral ligament (MCL) injuries are the most common ligamentous injury of the knee. The extent of injury can range from a minor first-degree (1-degree) sprain to an extensive third-degree (3-degree) sprain that can propagate across the knee, rupturing one or both cruciate ligaments, and result in a knee subluxation or dislocation. A common pattern involves the combined anterior cruciate ligament (ACL) and MCL injury that is the focus of this chapter. The vast majority of these combined medial-sided injuries are treated nonoperatively with delayed reconstruction of the ACL injury in athletically active individuals. The MCL and associated medial structures are carefully assessed on physical examination, and classification of injury is based upon abnormal limits of joint motion. In vitro cadaveric biomechanical testing has given us a better understanding of ligament deficiency and altered joint motion. Consistency in terminology is necessary for proper classification of injury and reproducible categorization of injury patterns to be able to compare both nonoperative and operative treatment of various injury patterns. PMID- 25932884 TI - Effect of Cumulating Exposure to Abacavir on the Risk of Cardiovascular Disease Events in Patients From the Swiss HIV Cohort Study. AB - BACKGROUND: Patients with HIV exposed to the antiretroviral drug abacavir may have an increased risk of cardiovascular disease (CVD). There is concern that this association arises because of a channeling bias. Even if exposure is a risk, it is not clear how that risk changes as exposure cumulates. METHODS: We assess the effect of exposure to abacavir on the risk of CVD events in the Swiss HIV Cohort Study. We use a new marginal structural Cox model to estimate the effect of abacavir as a flexible function of past exposures while accounting for risk factors that potentially lie on a causal pathway between exposure to abacavir and CVD. RESULTS: A total of 11,856 patients were followed for a median of 6.6 years; 365 patients had a CVD event (4.6 events per 1000 patient-years). In a conventional Cox model, recent--but not cumulative--exposure to abacavir increased the risk of a CVD event. In the new marginal structural Cox model, continued exposure to abacavir during the past 4 years increased the risk of a CVD event (hazard ratio = 2.06; 95% confidence interval: 1.43 to 2.98). The estimated function for the effect of past exposures suggests that exposure during the past 6-36 months caused the greatest increase in risk. CONCLUSIONS: Abacavir increases the risk of a CVD event: the effect of exposure is not immediate, rather the risk increases as exposure cumulates over the past few years. This gradual increase in risk is not consistent with a rapidly acting mechanism, such as acute inflammation. PMID- 25932885 TI - Validation of the Somnotouch-NIBP noninvasive continuous blood pressure monitor according to the European Society of Hypertension International Protocol revision 2010. AB - OBJECTIVE: The present study aimed to evaluate the accuracy of the Somnotouch NIBP noninvasive continuous blood pressure monitor according to the European Society of Hypertension International Protocol revision 2010. MATERIALS AND METHODS: Systolic and diastolic blood pressures were sequentially measured in 33 adults (11 women, mean age 63.5+/-11.9 years) using a mercury sphygmomanometer (two observers) and the Somnotouch-NIBP device (one supervisor). A total of 99 pairs of comparisons were obtained from 33 participants for judgments in two parts with three grading phases. RESULTS: All the validation requirements were fulfilled. The Somnotouch-NIBP device fulfilled the requirements of the part 1 of the validation study. The number of absolute differences between device and observers within 5, 10, and 15 mmHg was 75/99, 90/99, and 96/99, respectively, for systolic blood pressure and 90/99, 99/99, and 99/99, respectively, for diastolic blood pressure. The device also fulfilled the criteria in part 2 of the validation study. Twenty-seven and 31 participants had at least two of the three device-observers differences less than or equal to 5 mmHg for systolic and diastolic blood pressure, respectively. All three device-observer differences were greater than 5 mmHg in two participants for systolic and in one participant for diastolic blood pressure. CONCLUSION: The Somnotouch-NIBP noninvasive continuous blood pressure monitor has passed the requirements of the International Protocol revision 2010, and hence can be recommended for blood pressure monitoring in adults, at least under conditions corresponding to those investigated in our study. PMID- 25932886 TI - The effect of pretest rest time on automated measures of toe systolic blood pressure and the toe brachial index. AB - OBJECTIVES: Evaluation of peripheral blood supply is fundamental to risk categorization and subsequent ongoing monitoring of patients with lower extremity peripheral arterial disease. Toe systolic blood pressure (TSBP) and the toe brachial index (TBI) are both valid and reliable vascular screening techniques that are commonly used in clinical practice. However, the effect of pretest rest duration on the magnitude of these measurements is unclear. METHODS: Eighty individuals meeting current guidelines for lower extremity peripheral arterial disease screening volunteered to participate. The Systoe and MicroLife automated devices were used to measure toe and brachial systolic blood pressures, respectively, following 5, 10 and 15 min of rest in a horizontal supine position. A ratio of TSBP to brachial pressure was used to calculate the TBI and change in TBI at each time interval was investigated. RESULTS: A significant increase in TSBP [3.66 mmHg; 95% confidence interval (CI): 1.44-5.89; P<=0.001] and the TBI (0.03; 95% CI: 0.01-0.05; P<=0.001) occurred between 5 and 10 min. Between 10 and 15 min, there was a nonsignificant decrease in TSBP (-0.73 mmHg; 95% CI: -1.48 to 2.93; P=1.000) and the TBI (0.00; 95% CI: -0.02 to 0.02; P=1.000). CONCLUSION: Ten minutes of pretest rest is recommended for measurement of TSBP and for both pressure measurements used in the calculation of a TBI to ensure that stable pressures are measured. PMID- 25932887 TI - Validation of two automatic devices: Omron HEM-7252G-HP and Omron HEM-7251G for self-measurement of blood pressure according to the European Society of Hypertension International Protocol revision 2010. AB - OBJECTIVE: The aim of this study was to validate the performance of Omron HEM 7252G-HP and Omron HEM-7251G for monitoring upper arm blood pressure (BP) in accordance with the European Society of Hypertension International Protocol revision 2010 (ESH-IP revision 2010). METHODS: Three trained medical doctors validated the performance of these devices by comparing data obtained from these devices with those obtained using a standard mercury sphygmomanometer. We included 33 participants (19 men and 14 women for the experiment using HEM-7252G HP; 16 men and 17 women for the experiment using HEM-7251G). The mean age of the participants was 50+/-12 and 53+/-10 years in the respective studies. RESULTS: The percentages of test device-observer mercury sphygmomanometer BP differences within 5, 10, and 15 mmHg were 76, 92, and 97% for systolic BP (SBP) and 83, 97, and 99% for diastolic BP (DBP), respectively, in the Omron HEM-7252G-HP and 77, 92, and 99% for SBP and 85, 94, and 98% for DBP, respectively, in the Omron HEM 7251G in the part 1 analysis; both SBP and DBP passed the part 1 and part 2 criteria.The mean differences between the device and mercury readings for SBP and DBP were as follows: HEM-7252G-HP, -1.5+/-5.1 and -1.2+/-3.9 mmHg, respectively; HEM-7351G, -0.6+/-4.7 and -0.2+/-4.4 mmHg, respectively. CONCLUSION: The Omron HEM-7252G-HP and HEM-7251G passed all the requirements of the ESH-IP 2010 revision. PMID- 25932888 TI - Evaluation of the ambulatory arterial stiffness index in patients with rheumatoid arthritis. AB - OBJECTIVE: Patients with rheumatoid arthritis (RA) are at a higher risk of arterial disease, endothelial dysfunction, and vascular inflammation than the general population. Therefore, these patients are prone to decreased arterial compliance and increased arterial stiffness. Ambulatory arterial stiffness index (AASI) was introduced as an index that predicts cardiovascular risk. In this study, the AASI was evaluated in RA patients. METHOD: Thirty-three RA patients and 33 healthy age-matched and sex-matched individuals were evaluated according to the 24 h blood pressure (BP) profiles. The regression slope of diastolic over systolic BP was computed for each participant. AASI was defined as 1- regression slope. RESULTS: There was no significant difference in terms of the basic demographic characteristics, and average day, average night, and total average BP profiles as well as dipper status among the two groups. AASI was 0.45+/-0.12 and 0.38+/-0.10 in the RA patients and the healthy controls, respectively (P=0.019). AASI was not significantly different in women and men in both the groups. AASI was significantly higher in nondippers compared with dippers in the entire group and the RA group, but not in the control group. Independent predictors that were found to affect AASI in RA patients were age, nondipper status, VAS score, DAS28 score, and rheumatoid factor positivity. CONCLUSION: AASI is higher in RA patients compared with healthy individuals. When the prognostic significance of AASI is considered, RA patients with higher AASI should be followed closely for future adverse cardiovascular outcomes. PMID- 25932889 TI - Characterization of the bridged proton structure in HTFSI acid ionic liquid solutions. AB - Acidic ionic liquid (AIL) solutions were prepared by dissolving bis(trifluoromethanesulfonyl)imide (HTFSI) acid in the ionic liquid (IL) 1-butyl 3-methylpyrrolidinium bis(trifloromethanesulfonyl)imide (PyrrTFSI). The HTFSI/PyrrTFSI solutions were investigated by conductivity measurements, optical spectroscopy, and DFT calculations in order to understand the ionization/solvation mechanism of HTFSI in the solutions. The HTFSI/PyrrTFSI solution conductivities first increased at lower concentrations and then decreased when the concentration of HTFSI is higher than ~1.5 M. The spectroscopic results indicate that the solvation structure may evolve from lower to higher concentrations to make protonated TFSI(-) motifs. Both spectroscopic and DFT simulation results support the observation of proton-sharing [H(TFSI)2]( ) dimers, which may form through a bridged hydrogen in the format of either a N-H N connection or a N-H-O connection. Both configurations may exist in the AIL solution. The proton-sharing mechanism implied by these structures confirms that the TFSI(-) ion can be a proton acceptor and a Bronsted base as well in IL solutions. However, the IL molecular cations such as imidazolium and (in this work) pyrrolidinium do not contribute significantly to the proton solvation and transportation in the solutions. PMID- 25932890 TI - Drug-poisoning deaths involving heroin: United States, 2000-2013. AB - Drug poisoning (overdose) is the number one cause of injury-related death in the United States, with 43,982 deaths occurring in 2013. While much attention has been given to deaths involving opioid analgesics, in recent years there has been a steady increase in the number of drug-poisoning deaths involving heroin. A recent study using data from 28 states reported that the death rate for heroin overdose doubled from 2010 through 2012. Using data from the National Vital Statistics System, this data brief provides a description of trends and demographics for heroin-related drug-poisoning deaths in the United States from 2000 through 2013. PMID- 25932891 TI - Dental caries and sealant prevalence in children and adolescents in the United States, 2011-2012. AB - Although dental caries has been declining in permanent teeth for many children since the 1960s, previous findings showed caries in primary teeth for preschool children increasing from 24% to 28% between 1988 and 2004. Disparities in caries continue to persist for some race and ethnic groups in the United States. Prevalence of dental sealants--applied to the tooth chewing surfaces to help prevent caries--has also varied among sociodemographic groups. This report describes U.S. youth dental caries and sealant prevalence by race and Hispanic origin for 2011-2012. PMID- 25932892 TI - Emergency department visits and proximity to patients' residences, 2009-2010. AB - The number of emergency department (ED) visits rose 44% from 1991 through 2010, even as the number of hospital EDs declined 10% over the same period. As a result, EDs have increasingly experienced overcrowding and longer waiting times. However, little is known about which ED patients visit, how often patients go to the ED closest to their home, and how differences in geography, patient demographics, and hospital characteristics are associated with ED selection patterns. PMID- 25932893 TI - Hypertension-related Mortality in the United States, 2000-2013. AB - Hypertension is a chronic condition that can lead to heart disease, stroke, and other diseases that can result in premature death. Reducing the number of persons in the population with hypertension is one of the objectives of Healthy People 2020. Using national multiple cause-of-death data files from the National Vital Statistics System, this report presents trends in hypertension-related mortality for 2000-2013 by selected demographic characteristics and the underlying causes of hypertension-related death. Hypertension-related mortality is defined by any mention of hypertension on the death certificate. Because about 2% of all decedents with hypertension reported on the death certificate were under age 45, only decedents aged 45 and over were included in this analysis. PMID- 25932894 TI - Trends in emergency department visits for ischemic stroke and transient ischemic attack: United States, 2001-2011. AB - Stroke is the fifth leading cause of death in the United States. About 87% of all strokes are ischemic strokes. Transient ischemic attacks (TIAs) cause similar symptoms, but the blockage of blood flow to the brain is temporary. However, about one-third of people who have a TIA will have a stroke within 1 year (3). Emergency departments play a critical role in the diagnosis and management of ischemic stroke and TIA. The evaluation of these conditions in the emergency department is similar, so they are combined for this analysis. This report presents recent trends in visits to emergency departments for ischemic stroke or TIA. PMID- 25932895 TI - Acceptance of new patients with public and private insurance by office-based physicians: United States, 2013. AB - Physician acceptance of new Medicaid patients has shown to be lower than acceptance of new Medicare patients or new privately insured patients. Acceptance of new Medicaid patients also has shown to be lower in states with lower Medicaid payment rates to physicians. Using the 2013 National Electronic Health Records Survey (NEHRS), this report summarizes physician acceptance of new patients with Medicaid, Medicare, and private insurance. It also summarizes information on how these acceptance rates vary by select physician characteristics and by state. PMID- 25932896 TI - Emergency department visits for drug poisoning: United States, 2008-2011. AB - Poisoning is the leading cause of injury-related mortality in the United States, with more than 40,000 deaths annually. Drugs account for 90% of poisoning deaths, and the number of deaths from drug poisoning has increased substantially in recent years. The emergency department (ED) plays an important role in the treatment of poisoning. This report describes nationally representative data on ED visits for drug poisoning during 2008-2011. PMID- 25932898 TI - Thermal-Responsive Behavior of a Cell Compatible Chitosan/Pectin Hydrogel. AB - Biopolymer hydrogels are important materials for wound healing and cell culture applications. While current synthetic polymer hydrogels have excellent biocompatibility and are nontoxic, they typically function as a passive matrix that does not supply any additional bioactivity. Chitosan (CS) and pectin (Pec) are natural polymers with active properties that are desirable for wound healing. Unfortunately, the synthesis of CS/Pec materials have previously been limited by harsh acidic synthesis conditions, which further restricted their use in biomedical applications. In this study, a zero-acid hydrogel has been synthesized from a mixture of chitosan and pectin at biologically compatible conditions. For the first time, we demonstrated that salt could be used to suppress long-range electrostatic interactions to generate a thermoreversible biopolymer hydrogel that has temperature-sensitive gelation. Both the hydrogel and the solution phases are highly elastic, with a power law index of close to -1. When dried hydrogels were placed into phosphate buffered saline solution, they rapidly rehydrated and swelled to incorporate 2.7* their weight. As a proof of concept, we removed the salt from our CS/Pec hydrogels, thus, creating thick and easy to cast polyelectrolyte complex hydrogels, which proved to be compatible with human marrow-derived stem cells. We suggest that our development of an acid-free CS/Pec hydrogel system that has excellent exudate uptake, holds potential for wound healing bandages. PMID- 25932897 TI - Selectivity optimization of substituted 1,2,3-triazoles as alpha7 nicotinic acetylcholine receptor agonists. AB - Three series of substituted anti-1,2,3-triazoles (IND, PPRD, and QND), synthesized by cycloaddition from azide and alkyne building blocks, were designed to enhance selectivity and potency profiles of a lead alpha7 nicotinic acetylcholine receptor (alpha7-nAChR) agonist, TTIn-1. Designed compounds were synthesized and screened for affinity by a radioligand binding assay. Their functional characterization as agonists and antagonists was performed by fluorescence resonance energy transfer assay using cell lines expressing transfected cDNAs, alpha7-nAChRs, alpha4beta2-nAChRs, and 5HT3A receptors, and a fluorescence cell reporter. In the IND series, a tropane ring of TTIn-1, substituted at N1, was replaced by mono- and bicyclic amines to vary length and conformational flexibility of a carbon linker between nitrogen atom and N1 of the triazole. Compounds with a two-carbon atom linker optimized binding with Kd's at the submicromolar level. Further modification at the hydrophobic indole of TTIn-1 was made in PPRD and QND series by fixing the amine center with the highest affinity building blocks in the IND series. Compounds from IND and PPRD series are selective as agonists for the alpha7-nAChRs over alpha4beta2-nAChRs and 5HT3A receptors. Lead compounds in the three series have EC50's between 28 and 260 nM. Based on the EC50, affinity, and selectivity determined from the binding and cellular responses, two of the leads have been advanced to behavioral studies described in the companion article (DOI: 10.1021/acschemneuro.5b00059). PMID- 25932899 TI - Effects of electroacupuncture on endothelial function and circulating endothelial progenitor cells in patients with cerebral infarction. AB - This study evaluated the effects of electroacupuncture (EA) on endothelial function and endothelial progenitor cells (EPC) in patients with cerebral infarction. In a randomized, placebo-controlled, crossover study, 20 patients with cerebral infarction were randomized into two treatment groups: EA or placebo. Before and after each intervention, pulse amplitude tonometry (PAT) was used to assess endothelial function and peripheral blood was analyzed for the number of EPCs. Circulating EPCs were quantified by flow cytometry as CD45(low) CD34(+) KDR2(+) cells. Plasma vascular endothelial growth factor (VEGF) and interleukin (IL)-10 levels were measured. Seven days later, crossover was performed on each group, with each group receiving the other treatment using the same protocol. The PAT hyperemia ratio ranged from 1.57 +/- 0.41 to 2.04 +/- 0.51 after EA, representing a significant improvement (P = 0.002); however, there was no improvement in the placebo group (P = 0.48). Circulating EPCs, as measured by flow cytometry, increased to 110.6 +/- 74.3/100 MUL in the EA group (P = 0.001) but did not change in the placebo group (45.9 +/- 35.3/100 MUL, P = 0.08). The increases in the number of EPCs and the PAT ratio after treatment were correlated (r = 0.78, P < 0.001). Plasma VEGF levels increased with EA compared to baseline (261.2 +/- 34.0 vs 334.9 +/- 80.5 pg/mL, P = 0.003). The number of circulating EPCs was positively correlated with plasma levels of VEGF (r = 0.50, P = 0.02). In conclusion, EA induced improvement of EPC levels and the PAT ratio in patients with cerebral infarction. PMID- 25932900 TI - (13)C NMR Metabolomics: INADEQUATE Network Analysis. AB - The many advantages of (13)C NMR are often overshadowed by its intrinsically low sensitivity. Given that carbon makes up the backbone of most biologically relevant molecules, (13)C NMR offers a straightforward measurement of these compounds. Two-dimensional (13)C-(13)C correlation experiments like INADEQUATE (incredible natural abundance double quantum transfer experiment) are ideal for the structural elucidation of natural products and have great but untapped potential for metabolomics analysis. We demonstrate a new and semiautomated approach called INETA (INADEQUATE network analysis) for the untargeted analysis of INADEQUATE data sets using an in silico INADEQUATE database. We demonstrate this approach using isotopically labeled Caenorhabditis elegans mixtures. PMID- 25932901 TI - [Polish legal terms of animal-based research - selected aspects]. AB - Animal-based models used in biomedical sciences allow to perform research that, conducted on humans, would be highly problematic because of bioethical and technical issues. Contemporary researchers race can lead to abuse, hence the need for special law regulations regarding this subject. This necessity reflected both in the EU and Polish legislation, and is rooted in the philosophical and moral achievements of Europe. EU legislation in this case takes the form of directives implemented in the legal systems of the member states. Polish tradition of legislative approach to animal-based research is long. In 1959 the wide attempt to regulate this matter was undertaken. Until 2005, the nature of the matter had been regulated by the Polish animal protection law. Currently, details concerning animal-based-research are regulated by the animal experiments law (2005). The elapsed time since enactment allowed doctrine and judicature to reveal capabilities and vulnerabilities of the law. PMID- 25932902 TI - The effect of processing variables on the mechanical and release properties of tramadol matrix tablets incorporating Cissus populnea gum as controlled release excipient. AB - BACKGROUND: Natural gums are polymers widely used as excipients in drug formulation. Polymer extraction and formulation processing methods could significantly affect formulation characteristics. OBJECTIVES: To evaluate different methods of gum extraction and the effect of different compression methods on the mechanical and release properties of tramadol hydrochloride matrix tablets incorporating cissus gum as controlled release polymer. MATERIAL AND METHODS: Water (CW) and acetone (CA) extracts of cissus gum were obtained from Cissus populea stem and two methods - wet granulation and direct compression - were used to compress the tablet and compare it with xanthan gum (X) formulations. Crushing strength and friability were used to assess mechanical properties while dissolution rate were used to assess release properties. Data were analysed using t-test and ANOVA at p < 0.05. RESULTS: The crushing strength of tramadol tablets has increased together with the increase in polymer concentration in all formulations, while friability has decreased for both methods. Tablets made by wet granulation had higher crushing strength than those made by direct compression method. The release mechanism for both direct compression and wet granulation methods was Fickian and non-Fickian respectively. The rank order for t25, t50 and t75 for all formulations was X > CA > CW. Generally, wet granulation method decreased the rate of tramadol release more than direct compression method, indicating a higher drug retarding ability. CONCLUSIONS: Incorporation of cissus gum controlled the release of tramadol hydrochloride from the matrix tablets. Extraction method and formulation variables influenced mechanical and release properties of the tablets. Cissus gum acetone extract had comparable release properties with xanthan gum and could serve as a cheaper alternative in controlled release tablet formulations. PMID- 25932903 TI - In situ cross-linked matrix tablets for sustained salbutamol sulfate release - formulation development by statistical optimization. AB - BACKGROUND: The use of natural polymers in designing of matrix tablets for sustained-release drug delivery systems has received much attention. OBJECTIVES: The study involves the development and optimization of in situ cross-linked matrix tablets for sustained salbutamol sulfate release. MATERIAL AND METHODS: In situ cross-linked matrix tablets of salbutamol sulfate were prepared by direct compression and optimized by response surface methodology based on 32 factorial design. The influence on sodium alginate and a calcium salt (calcium carbonate) amounts in salbutamol sulfate matrix tablets on the properties like drug release and hardness of salbutamol sulfate sustained release matrix tablets were analyzed by response surface plots and corresponding contour plots. Drug contents, weight variations, hardness, and in vitro drug release with release kinetic analysis of these newly developed matrix tablets were also investigated. RESULTS: All these in situ cross-linked salbutamol sulfate matrix tablets showed satisfactory drug contents, weight variations, hardness and prolonged sustained release of salbutamol sulfate over 6 h. CONCLUSIONS: The developed salbutamol sulfate matrix tablets might be beneficial over the conventional tablets to decrease the dosing frequency and enhanced patient compliance. PMID- 25932904 TI - [Application of beta-cyclodextrin in the formulation of ODT tablets containing ibuprofen]. AB - BACKGROUND: Oral disintegrating tablet (ODT) dissolves or disintegrates in saliva and then it is swallowed. Diluent in direct compression formulation has a dual role: it increases bulk of the dosage form and it promotes binding of the constituent particles of the formulation. Hence, selection of diluent is important in tablets produced by direct compression method. OBJECTIVES: The aim of this work was to exame feasibility of preparing and optimizing oral disintegrating tablet formulation using beta-cyclodextrin as a diluent. MATERIAL AND METHODS: 400 mg round tablets were prepared by direct compression method on single punch tablet press using flat plain-face. 60% beta-CD and MCC (microcrystalline cellulose - MCC-Vivapur 102) were used at different proportions for all the formulations. 5% of Kollidon CL was added as superdisintegrant. The eight formulations prepared were assessed for weight variation, thickness, disintegration time, hardness and dissolution rate according to FP IX. A dissolution test was performed at 37oC using the paddle method at 50 rpm with 900 mL phosphate buffer (pH 6.8) as a dissolution medium. RESULTS: The content of ibuprofen sodium was found inside the +/- 5% of the theoretical value. Hardness values of presented tablets were in the range 0.11-0.15 kG/mm2. Friability of the tablets lower than 1% indicates that the developed formulations can be processed and handled without excessive care. Disintegration time was in the range of 86 to 161 s. CONCLUSIONS: The results confirm the good mechanical properties of tablets containing beta-CD. A composition with 20% beta-CD and 40% MCC fulfilled a maximum requisite of an optimum formulation. These properties were similar to Ludiflash, the formulation used for comparison purposes. In the present study, higher concentration of beta cyclodextrin was found to improve the hardness of tablets without increasing the disintegration time. PMID- 25932905 TI - [The use of semi-synthetic polymers in the formulation of sucking and chewable tablets containing sage extract and zinc gluconate]. AB - BACKGROUND: Halitosis and gingivitis are most common pathologies (15-60% of population) which, if left untreated, lead to periodontal diseases and tooth loss. OBJECTIVES: The aim of this study was to develop, based on polymers of dry sage extract and zinc gluconate, tablets intended for sucking and chewing that can be applied in the treatment of halitosis and gingivitis. MATERIAL AND METHODS: Dried aqueous sage extract, zinc gluconate, Pharmagum M, Prosolv SMCC90 and SMCCHD90, Vivapur 102, sorbitol, mannitol, ludipress. Direct tableting. Testing pharmacopeial parameters and pharmaceutical availability (using basket and rotating disk methods) of tablets intended for sucking and chewing. Approximation of the obtained results. RESULTS: Grey and green color tablets were obtained with smooth and uniform surface, without stains, spalls or mechanical damage. The determined average mass (weight) of a tablet complied with the standard. The friability and crushing strength test revealed that tablets containing Prosolv SMCCHD90, Vivapur 102 and mannitol demonstrated the highest mechanical strength. Tablets containing these substances and intended for sucking had prolonged disintegration and release time. Tablets intended for chewing had a hardness at the level of 124 N.They demonstrated compressibility, low friability and prolonged release. The release profiles of tablets intended for sucking (v2) and those for chewing, obtained by basket and rotating disk methods, were similar. CONCLUSIONS: The addition of Prosolv SMCCHD90, Vivapur 102 and mannitol increased significantly the mechanical strength (higher hardness, lower friability), prolonged the disintegration time and slowed the release from the obtained tablets intended for sucking and chewing. The application of Prosolv SMCCHD90 in the formulation of tablets for chewing carries the risk for sorption of active components to the polymer structure. This process takes place in the early stage of the release. Rotating disk method used in pharmaceutical availability testing gives better results while analyzing the phenomenon than the standard basket method. The suggested and tested formulations of tablets intended for sucking and chewing may be used as an alternative to formulations containing dried titrated extracts from plants of antimicrobial activity (sage - Salvia officinalis) in combination with substances binding volatile sulfur compounds (zinc gluconate). PMID- 25932906 TI - [Production and assessing release of imipramine and magnesium from tablets]. AB - BACKGROUND: In the pharmaceutical technology there is a trend to produce tablets composed of several medicinal substances to increase therapeutic effect and reduce the frequency of drug administration. In the literature there are reports concerning pharmacological studies in which a potentiation of the effects has been observed after a co-administration of antidepressant imipramine and magnesium. Currently, there is no formulation on the market comprising imipramine and magnesium, therefore, it was decided to produce uncoated tablets. In order to prepare the tablets by direct compression, it was necessary to select suitable excipients. OBJECTIVES: The aim of the study was to elaborate the composition and to prepare the tablets with imipramine and magnesium, as well as to assess the quality of the tablets by physical characteristics and by the release study of the active substances. MATERIAL AND METHODS: In order to prepare the tablets, compositions of different polymers and other excipients were added. The tablets were produced by direct compression method in a tablet press. Physical properties of the obtained tablets and the release of the active substances into an acidic medium in a paddle apparatus were tested. The contents of imipramine and magnesium were determined by different methods: spectrophotometrically and atomic absorption spectrometry, respectively. RESULTS: The composition of excipients necessary to produce tablets comprising imipramine and magnesium was established. All of prepared tablets were in compliance with the pharmacopoeial requirements. The release tests showed that above 80% of imipramine was released within 20-35 min and 80-76% of magnesium up to 45 min from the composed tablets and one ingredient tablets, respectively. CONCLUSIONS: The compositions of excipients for tablets consisting of imipramine and magnesium were presented. The active substances were released within 45 min in the acidic medium, and the administration of these substances in the composed tablets did not affect pharmaceutical availability. PMID- 25932907 TI - Study of free volumes of polymer hydrogel and -silicone-hydrogel contact lenses by means of the positron annihilation lifetime spectroscopy method. AB - BACKGROUND: Polymer materials based on hydrogel and silicone-hydrogel materials are commonly used in ophthalmology. It is important to research the structure of these materials, mainly the prevalence of free volumes. OBJECTIVES: The study has been conducted in order to determine the presence of free volume gaps in the structure of polymer hydrogel and silicone-hydrogel contact lenses. In addition, to demonstrate differences in the occurrence of free volumes between types of represented contact lenses. MATERIAL AND METHODS: Three different hydrogel and three different silicone-hydrogel polymer contact lenses were used as research material. The study was done by means of positron annihilation lifetime spectroscopy (PALS). RESULTS: As a result of the performed measurements, a graphical curve resulted which describes the relationship between the number of the annihilation acts in the time function. The study revealed the existence of three tau1, tau2 and tau3 components. Significant changes were observed in the ortho-positronium long life component tau3 and their intensities between the examined polymer contact lenses. CONCLUSIONS: The conducted study using the Tao Eldrup model indicates the presence of free volume holes in all research materials. The results lead to the following connection: contact lenses of higher oxygen permeability coefficient (silicone-hydrogel contact lenses) have more and larger free volumes than contact lenses of less oxygen permeability coefficient (hydrogel contact lenses). PMID- 25932908 TI - The role of RNA conformation in RNA-protein recognition. AB - Interactions between protein and RNA play a key role in many biological processes in the gene expression pathway. Those interactions are mediated through a variety of RNA-binding protein domains, among them the highly abundant RNA recognition motif (RRM). Here we studied protein-RNA complexes from different RNA binding domain families solved by NMR and x-ray crystallography. Characterizing the structural properties of the RNA at the binding interfaces revealed an unexpected number of nucleotides with unusual RNA conformations, specifically found in RNA RRM complexes. Moreover, we observed that the RNA nucleotides that are directly involved in interactions with the RRM domains, via hydrogen bonds and hydrophobic contacts, are significantly enriched with unique RNA conformations. Further examination of the sequences binding the RRM domain showed a preference for G nucleotides in syn conformation to precede or to follow U nucleotides in the anti conformation, and U nucleotides in C2' endo conformation to precede U and G nucleotides possessing the more common C3' endo conformation. These findings imply a possible mode of RNA recognition by the RRM domains which enables the recognition of a wide variety of different RNA sequences and shapes. Overall, this study suggests an additional way by which the RRM domain recognizes its RNA target, involving a conformational readout. PMID- 25932909 TI - Guard cell SLAC1-type anion channels mediate flagellin-induced stomatal closure. AB - During infection plants recognize microbe-associated molecular patterns (MAMPs), and this leads to stomatal closure. This study analyzes the molecular mechanisms underlying this MAMP response and its interrelation with ABA signaling. Stomata in intact Arabidopsis thaliana plants were stimulated with the bacterial MAMP flg22, or the stress hormone ABA, by using the noninvasive nanoinfusion technique. Intracellular double-barreled microelectrodes were applied to measure the activity of plasma membrane ion channels. Flg22 induced rapid stomatal closure and stimulated the SLAC1 and SLAH3 anion channels in guard cells. Loss of both channels resulted in cells that lacked flg22-induced anion channel activity and stomata that did not close in response to flg22 or ABA. Rapid flg22-dependent stomatal closure was impaired in plants that were flagellin receptor (FLS2) deficient, as well as in the ost1-2 (Open Stomata 1) mutant, which lacks a key ABA-signaling protein kinase. By contrast, stomata of the ABA protein phosphatase mutant abi1-1 (ABscisic acid Insensitive 1) remained flg22-responsive. These data suggest that the initial steps in flg22 and ABA signaling are different, but that the pathways merge at the level of OST1 and lead to activation of SLAC1 and SLAH3 anion channels. PMID- 25932910 TI - Remodeling of the Nuclear Envelope and Lamina during Bovine Preimplantation Development and Its Functional Implications. AB - The present study demonstrates a major remodeling of the nuclear envelope and its underlying lamina during bovine preimplantation development. Up to the onset of major embryonic genome activation (MGA) at the 8-cell stage nuclei showed a non uniform distribution of nuclear pore complexes (NPCs). NPCs were exclusively present at sites where DNA contacted the nuclear lamina. Extended regions of the lamina, which were not contacted by DNA, lacked NPCs. In post-MGA nuclei the whole lamina was contacted rather uniformly by DNA. Accordingly, NPCs became uniformly distributed throughout the entire nuclear envelope. These findings shed new light on the conditions which control the integration of NPCs into the nuclear envelope. The switch from maternal to embryonic production of mRNAs was accompanied by multiple invaginations covered with NPCs, which may serve the increased demands of mRNA export and protein import. Other invaginations, as well as interior nuclear segments and vesicles without contact to the nuclear envelope, were exclusively positive for lamin B. Since the abundance of these invaginations and vesicles increased in concert with a massive nuclear volume reduction, we suggest that they reflect a mechanism for fitting the nuclear envelope and its lamina to a shrinking nuclear size during bovine preimplantation development. In addition, a deposit of extranuclear clusters of NUP153 (a marker for NPCs) without associated lamin B was frequently observed from the zygote stage up to MGA. Corresponding RNA-Seq data revealed deposits of spliced, maternally provided NUP153 mRNA and little unspliced, newly synthesized RNA prior to MGA, which increased strongly at the initiation of embryonic expression of NUP153 at MGA. PMID- 25932911 TI - Longitudinal changes in self-reported walking ability in multiple sclerosis. AB - BACKGROUND: Patient-reported outcomes are increasingly used to understand the clinical meaningfulness of multiple sclerosis disability and its treatments. For example, the 12-item Multiple Sclerosis Walking Scale (MSWS-12) measures the patient-reported impact of the disease on walking ability. OBJECTIVE: We studied longitudinal changes in walking ability using the MSWS-12 in a cohort of 108 patients with relapsing-remitting multiple sclerosis and moderate-to-severe disability from a single US center cohort study investigating multiple sclerosis symptoms and physical activity. METHODS: The MSWS-12 was completed every 6 months over 2 years together with self-reported measures of disease impact on daily life (Multiple Sclerosis Impact Scale) and walking disability (Patient Determined Disease Steps scale). RESULTS: The results revealed a high frequency of self reported changes in walking ability at the individual level, affecting approximately 80% of patients for all four time periods. MSWS-12 scores remained stable at the group level for all four time periods. The magnitude of observed changes at the individual level was higher than the proposed minimal clinically important differences of 4 or 6 points and correlated better with Multiple Sclerosis Impact Scale physical scores than psychological scores, but little with self-reported Patient Determined Disease Steps Scale scores. CONCLUSIONS: This novel finding of frequent fluctuations in self-reported walking ability is new and requires further investigation. PMID- 25932912 TI - Computational chemical imaging for cardiovascular pathology: chemical microscopic imaging accurately determines cardiac transplant rejection. AB - Rejection is a common problem after cardiac transplants leading to significant number of adverse events and deaths, particularly in the first year of transplantation. The gold standard to identify rejection is endomyocardial biopsy. This technique is complex, cumbersome and requires a lot of expertise in the correct interpretation of stained biopsy sections. Traditional histopathology cannot be used actively or quickly during cardiac interventions or surgery. Our objective was to develop a stain-less approach using an emerging technology, Fourier transform infrared (FT-IR) spectroscopic imaging to identify different components of cardiac tissue by their chemical and molecular basis aided by computer recognition, rather than by visual examination using optical microscopy. We studied this technique in assessment of cardiac transplant rejection to evaluate efficacy in an example of complex cardiovascular pathology. We recorded data from human cardiac transplant patients' biopsies, used a Bayesian classification protocol and developed a visualization scheme to observe chemical differences without the need of stains or human supervision. Using receiver operating characteristic curves, we observed probabilities of detection greater than 95% for four out of five histological classes at 10% probability of false alarm at the cellular level while correctly identifying samples with the hallmarks of the immune response in all cases. The efficacy of manual examination can be significantly increased by observing the inherent biochemical changes in tissues, which enables us to achieve greater diagnostic confidence in an automated, label-free manner. We developed a computational pathology system that gives high contrast images and seems superior to traditional staining procedures. This study is a prelude to the development of real time in situ imaging systems, which can assist interventionists and surgeons actively during procedures. PMID- 25932913 TI - Robertsonian translocations: an overview of 872 Robertsonian translocations identified in a diagnostic laboratory in China. AB - Robertsonian translocations (ROBs) have an estimated incidence rate of 1/1000 births, making this type of rearrangement the most common structural chromosomal abnormalities seen in the general population. In this study, we reports 872 cases of ROBs from 205,001 specimens karyotyped postnatally in a single accredited laboratory in China, including 583 balanced ROBs, 264 unbalanced ROBs, 9 mosaic ROBs, and 18 complex ROBs. Ninety-three percent of the balanced ROBs observed were adults with infertility, miscarriage, or offspring(s) with known chromosomal abnormalities. Significant excess of females were found to be carriers of balanced ROBs with an adjusted male/female ratio of 0.77. Ninety-eight percent of the unbalanced ROBs observed were children with variable referral reasons. Almost all of the unbalanced ROBs involved chromosome 21 except a single ROB with [46,XX,der(13;14),+13] identified in a newborn girl with multiple congenital anomalies. Multiple novel ROB karyotypes were reported in this report. This study represents the largest collections of ROBs in Chinese population. PMID- 25932914 TI - Patterns and drivers of scattered tree loss in agricultural landscapes: orchard meadows in Germany (1968-2009). AB - Scattered trees support high levels of farmland biodiversity and ecosystem services in agricultural landscapes, but they are threatened by agricultural intensification, urbanization, and land abandonment. This study aimed to map and quantify the decline of orchard meadows (scattered fruit trees of high nature conservation value) for a region in Southwestern Germany for the 1968 2009 period and to identify the driving forces of this decline. We derived orchard meadow loss from 1968 and 2009 aerial images and used a boosted regression trees modelling framework to assess the relative importance of 18 environmental, demographic, and socio-economic variables to test five alternative hypothesis explaining orchard meadow loss. We found that orchard meadow loss occurred in flatter areas, in areas where smaller plot sizes and fragmented orchard meadows prevailed, and in areas near settlements and infrastructure. The analysis did not confirm that orchard meadow loss was higher in areas where agricultural intensification was stronger and in areas of lower implementation levels of conservation policies. Our results demonstrated that the influential drivers of orchard meadow loss were those that reduce economic profitability and increase opportunity costs for orchards, providing incentives for converting orchard meadows to other, more profitable land uses. These insights could be taken up by local- and regional-level conservation policies to identify the sites of persistent orchard meadows in agricultural landscapes that would be prioritized in conservation efforts. PMID- 25932915 TI - High Prevalence and Genotype Diversity of Anal HPV Infection among MSM in Northern Thailand. AB - BACKGROUND: HPV infection is common and may cause cancer among men who have sex with men (MSM). Anal HPV infection (HPV+) was found in 85% of HIV-positive (HIV+) and 59% of HIV-negative (HIV-) MSM in Bangkok, central Thailand. As little is known about HPV in this group in northern Thailand, we studied MSM subgroups comprised of gay men (GM), bisexual men (BM), and transgender women (TGW). METHODS: From July 2012 through January 2013, 85 (42.5% of 200) GM, 30 (15%) BM, and 85 (42.5%) TGW who practiced receptive anal intercourse were recruited after informed consent, followed by self-assisted computer interview, HIV testing, and anal swabs for HPV genotyping. RESULTS: Of 197 adequate specimens, the overall prevalence of any HPV was 157 (80%). Prevalence was 89% (76/85) in GM, 48% (14/29) in BM, and 81% (67/83) in TGW. The most common high-risk types were HPV16 (27% of 197), HPV58 (23%), and HPV51 (18%). Prevalence of high-risk types was 74% in 85 GM, 35% in 29 BM, and 71% in 83 TGW. Prevalence of any HPV type, or high risk type, was 100% and 94%, respectively, among 48 HIV+ MSM, 70% and 54% among 120 HIV- MSM. Of the 197 specimens, 36% (70) had HPV types 16 and/or 18 in the bivalent vaccine, compared to 48% (95) with >=1 of types 16/18/06/11 in the quadrivalent, 56% (111) for 16/18/31/33/45/52/58 in the 7-valent, and 64% (126) for 16/18/31/33/45/52/58/06/11 in the 9-valent. HIV+, GM, and TGW were independently associated with HPV infection. CONCLUSIONS: We found higher rates of both any HPV and high-risk types than previous studies. Among the heretofore unstudied TGW, their equivalent HPV rates were comparable to GM. Current and investigational HPV vaccines could substantially protect GM, BM, and TGW from the serious consequences of HPV infection especially among HIV + MSM. PMID- 25932916 TI - Owned and unowned dog population estimation, dog management and dog bites to inform rabies prevention and response on Lombok Island, Indonesia. AB - Although Indonesia has been rabies-infected since at least the 1880s, some islands remain rabies-free, such as Lombok. However, due to its adjacency to rabies-infected islands such as Bali and Flores, there is considerable risk of a rabies incursion. As part of a rabies risk assessment project, surveys were conducted to estimate the size of the dog population and to describe dog management practices of households belonging to different ethnic groups. A photographic-recapture method was employed and the number of unowned dogs was estimated. A total of 400 dog owning households were interviewed, 300 at an urban site and 100 at a rural site. The majority of the interviewed households belonged to the Balinese ethnic group. Owned dogs were more likely male, and non-pedigree or local breed. These households kept their dogs either fully restricted, semi free roaming or free-roaming but full restriction was reported only at the urban site. Dog bite cases were reported to be higher at the urban site, and commonly affected children/young adults to 20 years old and males. A higher number of unowned dogs was observed at the urban site than at the rural site. Data generated within these surveys can inform rabies risk assessment models to quantify the probability of rabies being released into Lombok and resulting in the infection of the local dog population. The information gained is critical for efforts to educate dog owners about rabies, as a component of preparedness to prevent the establishment of rabies should an incursion occur. PMID- 25932917 TI - Associated factors for tuberculosis recurrence in Taiwan: a nationwide nested case-control study from 1998 to 2010. AB - BACKGROUND: The contribution of human immunodeficiency virus (HIV) co-infection to tuberculosis (TB) recurrence is well established worldwide. We conducted this study to investigate associated factors for recurrent TB in Taiwan, which has a relatively low prevalence of HIV. METHODS: A case-control study nested within a nationwide population-based cohort was performed using the Taiwan National Health Insurance (NHI) database from 1998 to 2010. Patients with notified TB were identified according to diagnosis codes and prescriptions of anti-TB drugs for more than 60 days. Recurrent TB was defined as cases being retreated for more than 60 days and 6 months after the end of previous TB episode. Four controls were randomly selected from cohort and matched to each case by observational period within a calendar year. Socio-demographic variables and comorbidities were evaluated as factors associated with TB recurrence. RESULTS: There were totally 760 patients being investigated (608 controls and 152 cases). During an average 5.12 years of follow-up, 3.76% of all developed recurrent TB and the incidence of TB recurrence was 734 per 100,000 person-years. About half of recurrence (55%) was notified within three years of follow-up, and most (86%) recurrences were intrapulmonary. Independent associated factors for TB recurrence included: male (odds ratio, OR: 2.23, 95% confidence interval, CI: 1.40-3.53), diabetes mellitus (DM) (OR: 1.51, 95% CI: 1.02-2.13), chronic obstructive pulmonary disease (COPD) (OR: 1.59, 95% CI: 1.08-2.36) and lower socio-economic status (p=0.001 between groups). CONCLUSIONS: Despite low prevalence of HIV in the Taiwanese population, the incidence of recurrent TB among Taiwanese was not less than that of other countries. Identification of subgroups such as male gender, low economic status, DM and COPD should be a high priority in TB control programs. PMID- 25932918 TI - Metabolic Response of Escherichia coli upon Treatment with Hypochlorite at Sub Lethal Concentrations. AB - Hypochlorite is a reactive oxygen species that is worldwide as an antibacterial disinfectant. Hypochlorite exposure is known to cause oxidative damage to DNA and proteins. As a response to these effects, the metabolite profiles of organisms treated with sub-lethal doses of hypochlorite are assumed to be severely modified; however, the nature of these changes is hardly understood. Therefore, using nuclear magnetic resonance spectroscopy and gas chromatography-coupled mass spectrometry, we analyzed the time-dependent impact of hypochlorite exposure with a sub-lethal concentration (50 uM) on the metabolite profile of the Escherichia coli strain MG1655. Principle component analysis clearly distinguished between the metabolite profiles of bacteria treated for 0, 5, 10, 20, 40, or 60 min. Major changes in the relative amounts of fatty acids, acetic acid, and formic acid occurred within the first 5 min. Comparative gas chromatography-coupled mass spectrometry analyses revealed that the amounts of free methionine and alanine were significantly decreased in the treated cells, demonstrating their susceptibility to hypochlorite exposure. The concentrations of succinate, urea, orotic acid, 2-aminobutyric acid, and 2-hydroxybutyric acid were also severely affected, indicating general changes in the metabolic network by hypochlorite. However, most metabolite levels relaxed to the reference values of untreated cells after 40-60 min, reflecting the capability of E. coli to rapidly adapt to environmental stress factors such as the presence of sub-lethal oxidant levels. PMID- 25932919 TI - Regional differences in the psychological recovery of Christchurch residents following the 2010/2011 earthquakes: a longitudinal study. AB - We examined changes in psychological distress experienced by residents of Christchurch following two catastrophic earthquakes in late 2010 and early 2011, using data from the New Zealand Attitudes and Values Study (NZAVS), a national probability panel study of New Zealand adults. Analyses focused on the 267 participants (172 women, 95 men) who were living in central Christchurch in 2009 (i.e., before the Christchurch earthquakes), and who also provided complete responses to our yearly panel questionnaire conducted in late 2010 (largely between the two major earthquakes), late 2011, and late 2012. Levels of psychological distress were similar across the different regions of central Christchurch immediately following the September 2010 earthquake, and remained comparable across regions in 2011. By late 2012, however, average levels of psychological distress in the regions had diverged as a function of the amount of property damage experienced within each given region. Specifically, participants in the least damaged region (i.e., the Fendalton-Waimairi and Riccarton-Wigram wards) experienced greater drops in psychological distress than did those in the moderately damaged region (i.e., across the Spreydon-Heathcote and Hagley Ferrymead wards). However, the level of psychological distress reported by participants in the most damaged region (i.e., across Shirley-Papanui and Burwood Pegasus) were not significantly different to those in the least damaged region of central Christchurch. These findings suggest that different patterns of psychological recovery emerged across the different regions of Christchurch, with the moderately damaged region faring the worst, but only after the initial shock of the destruction had passed. PMID- 25932920 TI - A clinical perspective on the analysis and presentation of the number of incontinence episodes following treatment for OAB. AB - AIMS: To provide a clinical view and interpretation on the methods for analysis of incontinence in patients with overactive bladder. METHODS: Results are analyzed using the total number of incontinence episodes in a 3-day diary period, using fixed and random effect Poisson regression models to calculate ratio of event rates and 95% confidence interval (CI) together with P-values and are compared with the analysis of the mean number of incontinence episodes/24 hr using analysis of covariance models to calculate P-values and 95% CI for the difference between treatments. RESULTS: Using random effects Poisson regression models demonstrated that the number of incontinence episodes was reduced by 26% more with mirabegron 50 mg than with placebo. For solifenacin 5 and 10 mg, treatment resulted in a 43% (41%) greater decrease in the number of incontinence episodes compared with placebo. CONCLUSION: Instead of providing a fixed number of incontinence episodes/24 hr that reflects the mean effect, the estimate using Poisson methodology provides an efficacy estimate that can be interpreted in the context of, and relative to, the patient's baseline (severity). Using the total number of incontinence episodes in the diary period, and expressing this as percent decrease in the number of episodes, may be easier to interpret; for example, because this results in a relative measure of effect that provides an alternative understanding of a patient's improvement at end of treatment compared with the comparator arm. Also, it is based on statistical methods that are more suitable for the analysis of count data. Neurourol. Urodynam. 35:728-732, 2016. (c) 2015 Wiley Periodicals, Inc. PMID- 25932921 TI - An interobserver reproducibility analysis of Ki67 visual assessment in breast cancer. AB - BACKGROUND: Ki67 labeling index (LI) is used as a predictive marker and is associated with prognosis in breast cancer. However, standardised methodologies for measurement are lacking which has limited its application in clinical practice. In this study, we evaluated the interobserver concordance of visual assessment of Ki67 LI in breast cancer. METHODS: Ki67-immunostained slides of 160 cases of primary invasive breast cancer were visual assessed by five breast pathologists with two different methods to choose the scoring fields: (1) hot spot score, (2) average score. Proportions of positive invasive tumor cells at 10 % intervals were scored. The intra-class correlation coefficient (ICC) was used to assess the interobserver reproducibility. RESULTS: (1) A perfect concordance of Ki67 LI was demonstrated according to both score methods (P<0.0001). Average score method (ICC, 0.904) demonstrated a better correlation than hot-spot score method (ICC, 0.894). (2) By respective means according to two score methods, all cases were classified into three groups (<=10%, 11%-30% and >30% Ki-67 LI). The concordance was relatively low in intermediate Ki67 LI group compared with low and high Ki67 LI groups. (3) All cases were classified into three groups by paired-difference (d) between means of hot-spot score and average score (d<5, 5<=d<10, d>=10). The consistency was observed to decrease with increasing paired difference according to both methods. CONCLUSIONS: Visual assessment of Ki67 LI at 10 % intervals is a candidate for a standard method in breast cancer clinical practice. Average score and hot-spot score of visual assessment both demonstrated a perfect concordance, and an overall average assessment across the whole section including hot spots may be a better method. Interobserver concordance of intermediate Ki67 LI in which most cutoffs are located for making clinical decisions was relatively low. PMID- 25932922 TI - Plasminogen activator inhibitor-1 in cigarette smoke exposure and influenza A virus infection-induced lung injury. AB - Parenchymal lung inflammation and airway and alveolar epithelial cell apoptosis are associated with cigarette smoke exposure (CSE), which contributes to chronic obstructive pulmonary disease (COPD). Epidemiological studies indicate that people exposed to chronic cigarette smoke with or without COPD are more susceptible to influenza A virus (IAV) infection. We found increased p53, PAI-1 and apoptosis in AECs, with accumulation of macrophages and neutrophils in the lungs of patients with COPD. In Wild-type (WT) mice with passive CSE (PCSE), p53 and PAI-1 expression and apoptosis were increased in AECs as was lung inflammation, while those lacking p53 or PAI-1 resisted AEC apoptosis and lung inflammation. Further, inhibition of p53-mediated induction of PAI-1 by treatment of WT mice with caveolin-1 scaffolding domain peptide (CSP) reduced PCSE-induced lung inflammation and reversed PCSE-induced suppression of eosinophil-associated RNase1 (EAR1). Competitive inhibition of the p53-PAI-1 mRNA interaction by expressing p53-binding 3'UTR sequences of PAI-1 mRNA likewise suppressed CS induced PAI-1 and AEC apoptosis and restored EAR1 expression. Consistent with PCSE-induced lung injury, IAV infection increased p53, PAI-1 and apoptosis in AECs in association with pulmonary inflammation. Lung inflammation induced by PCSE was worsened by subsequent exposure to IAV. Mice lacking PAI-1 that were exposed to IAV showed minimal viral burden based on M2 antigen and hemagglutination analyses, whereas transgenic mice that overexpress PAI-1 without PCSE showed increased M2 antigen and inflammation after IAV infection. These observations indicate that increased PAI-1 expression promotes AEC apoptosis and exacerbates lung inflammation induced by IAV following PCSE. PMID- 25932924 TI - Zoo Playgrounds: A Source of Enrichment or Stress for a Group of Nearby Cockatoos? A Case Study. AB - There is increasing evidence that in some circumstances, zoo visitors may be aversive stimuli to nonhuman animals housed in zoos. Yet, most previous research has focused on primates with little attention given to numerous other species who are housed in zoos. The focus animal of this project was the cockatoo, a species who has received minimal attention in zoo-based research. Furthermore, although the influence of the zoo setting has become increasingly important in visitor effect studies, this is the 1st study to quantify the effect of activity at a children's playground on zoo animals. There was an investigation on the effect of a zoo playground on the behavior of citron-crested and Moluccan cockatoos (Cacatua sulphurea citrinocristata and Cacatua moluccensis), as well as the effect of children standing in front of the birds' aviaries. The results showed that in some circumstances, the Moluccan cockatoos retreated from visitors, while the citron-crested cockatoos did not retreat from visitors and became more social in the presence of visitors. These findings highlight the importance of careful selection of species and individual animals to be housed near zoo playgrounds. PMID- 25932925 TI - Correction: phylogenetic properties of 50 nuclear Loci in medicago (leguminosae) generated using multiplexed sequence capture and next-generation sequencing. PMID- 25932923 TI - Hydroxymethylcytosine and demethylation of the gamma-globin gene promoter during erythroid differentiation. AB - The mechanism responsible for developmental stage-specific regulation of gamma globin gene expression involves DNA methylation. Previous results have shown that the gamma-globin promoter is nearly fully demethylated during fetal liver erythroid differentiation and partially demethylated during adult bone marrow erythroid differentiation. The hypothesis that 5-hydroxymethylcytosine (5 hmC), a known intermediate in DNA demethylation pathways, is involved in demethylation of the gamma-globin gene promoter during erythroid differentiation was investigated by analyzing levels of 5-methylcytosine (5 mC) and 5 hmC at a CCGG site within the 5' gamma-globin gene promoter region in FACS-purified cells from baboon bone marrow and fetal liver enriched for different stages of erythroid differentiation. Our results show that 5 mC and 5 hmC levels at the gamma-globin promoter are dynamically modulated during erythroid differentiation with peak levels of 5 hmC preceding and/or coinciding with demethylation. The Tet2 and Tet3 dioxygenases that catalyze formation of 5 hmC are expressed during early stages of erythroid differentiation and Tet3 expression increases as differentiation proceeds. In baboon CD34+ bone marrow-derived erythroid progenitor cell cultures, gamma-globin expression was positively correlated with 5 hmC and negatively correlated with 5 mC at the gamma-globin promoter. Supplementation of culture media with Vitamin C, a cofactor of the Tet dioxygenases, reduced gamma-globin promoter DNA methylation and increased gamma-globin expression when added alone and in an additive manner in combination with either DNA methyltransferase or LSD1 inhibitors. These results strongly support the hypothesis that the Tet mediated 5 hmC pathway is involved in developmental stage-specific regulation of gamma-globin expression by mediating demethylation of the gamma-globin promoter. PMID- 25932928 TI - What's in pet food? PMID- 25932926 TI - Enhanced Polysaccharide Binding and Activity on Linear beta-Glucans through Addition of Carbohydrate-Binding Modules to Either Terminus of a Glucooligosaccharide Oxidase. AB - The gluco-oligosaccharide oxidase from Sarocladium strictum CBS 346.70 (GOOX) is a single domain flavoenzyme that favourably oxidizes gluco- and xylo- oligosaccharides. In the present study, GOOX was shown to also oxidize plant polysaccharides, including cellulose, glucomannan, beta-(1->3,1->4)-glucan, and xyloglucan, albeit to a lesser extent than oligomeric substrates. To improve GOOX activity on polymeric substrates, three carbohydrate binding modules (CBMs) from Clostridium thermocellum, namely CtCBM3 (type A), CtCBM11 (type B), and CtCBM44 (type B), were separately appended to the amino and carboxy termini of the enzyme, generating six fusion proteins. With the exception of GOOX-CtCBM3 and GOOX-CtCBM44, fusion of the selected CBMs increased the catalytic activity of the enzyme (kcat) on cellotetraose by up to 50%. All CBM fusions selectively enhanced GOOX binding to soluble and insoluble polysaccharides, and the immobilized enzyme on a solid cellulose surface remained stable and active. In addition, the CBM fusions increased the activity of GOOX on soluble glucomannan by up to 30% and on insoluble crystalline as well as amorphous cellulose by over 50%. PMID- 25932929 TI - Predicting development of subaortic stenosis in dogs. PMID- 25932930 TI - What is your diagnosis? Gastrointestinal perforation. PMID- 25932931 TI - Pathology in Practice. Ependymoma of the right lateral ventricle with internal hydrocephalus in a horse. PMID- 25932932 TI - Pathology in Practice. Metastatic osteosarcoma with vascular invasion and moderate, acute, diffuse, suppurative peritonitis. Jejunal metastasis of skeletal osteosarcoma in a dog. PMID- 25932933 TI - Management of incidentally detected heart murmurs in dogs and cats. PMID- 25932934 TI - Effect of cardiac and respiratory cycles on vertebral heart score measured on fluoroscopic images of healthy dogs. AB - OBJECTIVE: To assess the variability in vertebral heart score (VHS) measurement induced by cardiac and respiratory cycles in dogs. DESIGN: Prospective observational study. ANIMALS: 14 healthy Beagles. PROCEDURES: Dogs underwent fluoroscopic examination by 4 observers, and VHS was measured at end-tidal inspiration and end-tidal expiration during end systole and end diastole in left and right lateral recumbency. Mean VHS was compared within and among cardiac and respiratory phases and recumbency type, and correlation between VHS and heart rate was investigated. Interobserver variability was assessed. RESULTS: Mean VHS for each combination of respiratory and cardiac cycle was larger on images obtained in right lateral versus left lateral recumbency. The greatest differences were observed between VHS measured in the diastolic inspiratory phase (mean +/- SD, 10.59 +/- 0.49 vertebral units [VU] and 10.35 +/- 0.50 VU for right and left lateral recumbency, respectively) and the systolic expiratory phase (10.11 +/- 0.37 VU and 9.92 +/- 0.50 VU for right and left lateral recumbency, respectively). The combination of respiratory and cardiac cycles induced a maximal difference in VHS of up to 0.97 VU and 1.11 VU in the inspiratory and expiratory phases, respectively. Heart rate was not correlated with the difference between VHS in systolic and diastolic phases. CONCLUSIONS AND CLINICAL RELEVANCE: Clinicians should be aware of the potential influence of these factors when assessing VHS in dogs; in addition to allowing optimal pulmonary assessment, consistently taking radiographs at end-inspiratory tidal volume may help to limit VHS variability attributable to the respiratory cycle. Further research is needed to assess the effects of cardiac and respiratory phases on VHS in dogs with cardiac or respiratory disease. PMID- 25932935 TI - Associations of diet and breed with recurrence of calcium oxalate cystic calculi in dogs. AB - OBJECTIVE: To evaluate the long-term risk of recurrence of calcium oxalate (CaOx) cystic calculi in dogs of various breeds fed 1 of 2 therapeutic diets. DESIGN: Retrospective cohort study. Animals-135 dogs with a history of CaOx cystic calculi. PROCEDURES: Medical records for 4 referral hospitals were searched to identify dogs that had had CaOx cystic calculi removed. Owners were contacted and medical records evaluated to obtain information on postoperative diet, recurrence of signs of lower urinary tract disease, and recurrence of cystic calculi. Dogs were grouped on the basis of breed (high-risk breeds, low-risk breeds, and Miniature Schnauzers) and diet fed after removal of cystic calculi (diet A, diet B, and any other diet [diet C], with diets A and B being therapeutic diets formulated to prevent recurrence of CaOx calculi). RESULTS: Breed group was a significant predictor of calculi recurrence (as determined by abdominal radiography or ultrasonography), with Miniature Schnauzers having 3 times the risk of recurrence as did dogs of other breeds. Dogs in diet group A had a lower prevalence of recurrence than did dogs in diet group C, but this difference was not significant in multivariable analysis. CONCLUSIONS AND CLINICAL RELEVANCE: Results indicated that Miniature Schnauzers had a higher risk of CaOx cystic calculi recurrence than did dogs of other breeds. In addition, findings suggested that diet may play a role in decreasing recurrence, but future prospective studies are needed to validate these observations. PMID- 25932936 TI - Effects of preoperative administration of hypertonic saline or pentastarch solution on hematologic variables and long-term survival of surgically managed horses with colic. AB - OBJECTIVE: To compare the effects of preoperatively administered pentastarch (10% concentration in isotonic saline [0.9% NaCl] solution) and hypertonic saline (7.2% NaCl) solutions on PCV and circulating total protein (TP) concentration in horses with colic undergoing emergency exploratory laparotomy and to assess survival rates of horses that received each treatment. DESIGN: Prospective, randomized study. ANIMALS: 100 horses with signs of abdominal pain and PCV >= 0.46 L/L. Procedures-Horses received a 4 mL/kg (1.8 mL/lb) dose of pentastarch solution (n = 50) or hypertonic saline solution (50) over a 10- to 20-minute period before anesthetic induction. Blood samples were collected at the time of evaluation and <= 5 minutes after fluid resuscitation; changes in PCV and TP concentration were compared. Survival was evaluated by Kaplan-Meier and Cox proportional hazards analyses. RESULTS: Age, weight, sex, PCV, and heart rate on initial examination were similar between treatment groups. Hypertonic saline solution treatment resulted in a significantly greater reduction in PCV (median change, -0.14 L/L) than did pentastarch treatment (median change, -0.07 L/L). Reduction in TP concentration was also significantly greater after hypertonic saline solution treatment (median change, -16 g/L) than after pentastarch treatment (median change, -2 g/L). Long-term survival was not significantly different between groups. CONCLUSIONS AND CLINICAL RELEVANCE: Despite a greater reduction in preanesthetic hemoconcentration following administration of hypertonic saline solution (4 mL/kg infusion, once), no difference in overall long-term survival was found between horses that received this treatment and those that received an equal volume of pentastarch solution. Findings suggested that, in a clinical setting, either of these fluids would be appropriate for preoperative fluid resuscitation in horses with colic. PMID- 25932937 TI - Evaluation of a handheld device for measurement of beta-hydroxybutyrate concentration to identify prepartum dairy cattle at risk of developing postpartum hyperketonemia. AB - OBJECTIVE: To evaluate the use of a handheld device for measurement of beta hydroxybutyrate (BHBA) concentration to identify prepartum dairy cattle at risk of developing hyperketonemia during the first week after parturition. DESIGN: Cross-sectional study. Animals-210 prepartum dairy cows from 6 herds. PROCEDURES: A blood sample was collected from each cow 3 to 9 days before its expected calving date. beta-Hydroxybutyrate concentration was immediately measured with a handheld device. Serum was harvested from the remaining sample and submitted to a laboratory for measurement of BHBA and nonesterified fatty acid (NEFA) concentrations. beta-Hydroxybutyrate concentration determined with the handheld device was compared with that determined by laboratory methods. The association between prepartum BHBA concentration and the development of hyperketonemia (BHBA concentration, >= 1.2 mmol/L) during the first week after parturition was determined. The agreement between prepartum BHBA and NEFA concentrations for identification of cows at risk of developing postpartum hyperketonemia was evaluated. RESULTS: beta-Hydroxybutyrate concentration determined by the handheld device was moderately correlated with that determined by laboratory methods. Cows with a prepartum BHBA concentration >= 0.6 mmol/L were 2.2 times as likely to develop hyperketonemia within 1 week after parturition as were cows with a prepartum BHBA concentration < 0.6 mmol/L. There was substantial agreement between prepartum BHBA and NEFA concentrations for identification of cows at risk of developing postpartum hyperketonemia. CONCLUSIONS AND CLINICAL RELEVANCE: Results indicated the handheld device was a valid tool for measurement of BHBA concentration in prepartum dairy cattle, and measurement of prepartum BHBA concentration may be helpful for identifying cows at risk of developing postpartum hyperketonemia. PMID- 25932938 TI - Laparoscopic inguinal hernioplasty in a ram. AB - CASE DESCRIPTION: A 4-month-old Hampshire ram underwent open right inguinal herniorrhaphy and unilateral castration following herniation that developed after a kick injury. Seven months later, the ram was reevaluated because of scrotal swelling of 1 month's duration as well as suspected left inguinal hernia. CLINICAL FINDINGS: The ram had marked scrotal swelling. Palpation of the left testicle revealed no abnormalities. Ultrasonographic examination revealed heterogenous tissue within the cranial and medial portions of the scrotum with pronounced accumulation of hypoechoic fluid at the scrotal apex. Examination findings indicated left-sided indirect inguinal herniation of omentum. TREATMENT AND OUTCOME: To preserve fertility, left inguinal hernioplasty without castration was performed. The ram was anesthetized and placed in dorsal recumbency, and laparoscopic abdominal evaluation revealed omental entrapment within the left inguinal ring. The omentum was removed, and a polypropylene mesh was secured over the internal inguinal ring with an articulating hernia stapler. Following mesh placement, a dorsally based peritoneal flap was elevated and secured over the mesh repair. The ram recovered well from surgery; there was no repeated herniation following the surgical correction, and the ram was able to breed successfully without complication. CLINICAL RELEVANCE: Laparoscopic mesh hernioplasty can be successful in rams with inguinal hernias when preservation of fertility is preferred. PMID- 25932939 TI - Dorsal laminectomy for treatment of cervical vertebral stenotic myelopathy in an alpaca. AB - CASE DESCRIPTION: An 11-year-old male breeding alpaca was evaluated for a 2-day history of lowered head carriage and lethargy. CLINICAL FINDINGS: On initial examination, the alpaca had signs of lethargy and lowered carriage of the head and neck, but no specific neurologic deficits. Medical management improved the clinical signs, but 8 months later, the alpaca developed acute, progressive general proprioceptive ataxia affecting all 4 limbs and was referred for further evaluation and treatment. Magnetic resonance imaging and CT identified disruption of the normal osseous architecture of C7 and T1. Medical management was attempted, but because of a lack of improvement, the patient underwent surgery 14 months after initial examination. TREATMENT AND OUTCOME: A dorsal laminectomy of C7 and T1 via a dorsal midline approach was performed, and the spinous processes of both vertebrae were removed prior to removal of the overlying lamina. Free dorsal expansion of the spinal cord was ensured by resection of the ligamentum flavum. Six months after surgery, the alpaca had returned to successful breeding with 7 hembra bred in the first year after surgery, producing 6 crias, and 4 crias in the second year. The patient was eventually euthanized 28 months after surgery because of neurologic deterioration but was still ambulatory at that time. CONCLUSIONS AND CLINICAL RELEVANCE: A good outcome with adequate alleviation of clinical signs and breeding soundness for > 2 years following dorsal laminectomy was achieved in this camelid patient. The surgical approach was similar to that in other species and was associated with mild postoperative morbidity. Veterinarians treating camelids should be aware of the initial clinical signs and treatment options for cervical vertebral stenotic myelopathy. In acute cases, the signs of reduced cervical mobility and pain on manipulation should prompt investigation including appropriate diagnostic imaging. Timely surgical intervention should be considered in patients that respond poorly to medical treatment to avoid irreversible spinal cord injury and optimize outcome. PMID- 25932940 TI - Electronic Transport Properties of Epitaxial Si/SiGe Heterostructures Grown on Single-Crystal SiGe Nanomembranes. AB - To assess possible improvements in the electronic performance of two-dimensional electron gases (2DEGs) in silicon, SiGe/Si/SiGe heterostructures are grown on fully elastically relaxed single-crystal SiGe nanomembranes produced through a strain engineering approach. This procedure eliminates the formation of dislocations in the heterostructure. Top-gated Hall bar devices are fabricated to enable magnetoresistivity and Hall effect measurements. Both Shubnikov-de Haas oscillations and the quantum Hall effect are observed at low temperatures, demonstrating the formation of high-quality 2DEGs. Values of charge carrier mobility as a function of carrier density extracted from these measurements are at least as high or higher than those obtained from companion measurements made on heterostructures grown on conventional strain graded substrates. In all samples, impurity scattering appears to limit the mobility. PMID- 25932942 TI - Effects of government spending on research workforce development: evidence from biomedical postdoctoral researchers. AB - We examine effects of government spending on postdoctoral researchers' (postdocs) productivity in biomedical sciences, the largest population of postdocs in the US. We analyze changes in the productivity of postdocs before and after the US government's 1997 decision to increase NIH funding. In the first round of analysis, we find that more government spending has resulted in longer postdoc careers. We see no significant changes in researchers' productivity in terms of publication and conference presentations. However, when the population is segmented by citizenship, we find that the effects are heterogeneous; US citizens stay longer in postdoc positions with no change in publications and, in contrast, international permanent residents (green card holders) produce more conference papers and publications without significant changes in postdoc duration. Possible explanations and policy implications of the analysis are discussed. PMID- 25932943 TI - Experimental and Computational (77)Se NMR Investigations of the Cyclic Eight Membered Selenium Imides 1,3,5,7-Se4(NR)4 (R = Me, (t)Bu) and 1,5-Se6(NMe)2. AB - The cyclocondensation reaction of equimolar amounts of SeCl2 and (Me3Si)2NMe in THF affords 1,3,5,7-Se4(NMe)4 (5b) [delta((77)Se) = 1585 ppm] in excellent yield. An X-ray structural determination showed that 5b consists of cyclic, puckered crown-shaped molecules with a mean Se-N bond length of 1.841 A typical of single bonds. A minor product of this reaction was isolated as unstable orange-red crystals, which were identified by X-ray analysis as the adduct 1,5 Se6(NMe)2.(1)/2Se8 (1b.(1)/2Se8), composed of cyclic 1,5-Se6(NMe)2 and disordered cyclo-Se8 molecules. A detailed reinvestigation of the cyclocondensation reaction of SeCl2 and (t)BuNH2 as a function of molar ratio and time by multinuclear ((1)H, (13)C, and (77)Se) NMR spectroscopy revealed that the final product exhibits one (77)Se resonance at 1486 ppm and equivalent N(t)Bu groups. The shielding tensors of 28 selenium-containing molecules, for which the (77)Se chemical shifts are unambiguously known, were calculated at the PBE0/def2-TZVPP level of theory to assist the spectral assignment of new cyclic selenium imides. The good agreement between the observed and calculated chemical shifts enabled the assignment of the resonance at 1486 ppm to 1,3,5,7-Se4(N(t)Bu)4 (5a). Those at 1028 and 399 ppm (intensity ratio 2:1) could be attributed to 1,5-Se6(NMe)2 (1b). PMID- 25932941 TI - Genetic Variability of Hepatitis C Virus (HCV) 5' Untranslated Region in HIV/HCV Coinfected Patients Treated with Pegylated Interferon and Ribavirin. AB - Association between hepatitis C virus (HCV) quasispecies and treatment outcome among patients with chronic hepatitis C has been the subject of many studies. However, these studies focused mainly on viral variable regions (E1 and E2) and usually did not include human immunodeficiency virus (HIV)-positive patients. The aim of the present study was to analyze heterogeneity of the 5' untranslated region (5'UTR) in HCV/HIV coinfected patients treated with interferon and ribavirin. The HCV 5'UTR was amplified from serum and peripheral blood mononuclear cells (PBMC) samples in 37 HCV/HIV coinfected patients treated for chronic hepatitis C. Samples were collected right before treatment, and at 2, 4, 6, 8, 12, 20, 24, 36, 44, 48, 60, and 72 weeks. Heterogeneity of the 5'UTR was analyzed by single strand conformational polymorphism (SSCP), cloning and sequencing. Sustained virological response (SVR) was achieved in 46% of analyzed HCV/HIV co-infected patients. Stable SSCP band pattern was observed in 22 patients (62.9%) and SVR rate among these patients was 23%. Decline in the number of bands and/or shift in band positions were found in 6 patients (17.1%), 5 (83%) of whom achieved SVR (p=0.009). A novel viral genotype was identified in all but one of these patients. In 5 of these 6 patients a new genotype was dominant. 5'UTR heterogeneity may correlate with interferon and ribavirin treatment outcome. In the analyzed group of HCV/HIV coinfected patients, viral quasispecies stability during treatment favored viral persistence, whereas decrease in the number of variants and/or emergence of new variants was associated with SVR. Among injection drug users (IDU) patients, a new genotype may become dominant during treatment, probably due to the presence of mixed infections with various strains, which have different susceptibility to treatment. PMID- 25932944 TI - Internal- and External-Rotation Peak Toque in Little League Baseball Players With Subacromial Impingement Syndrome: Improved by Closed Kinetic Chain Shoulder Training. AB - CONTEXT: Many studies have explored closed kinetic chain (CKC) shoulder exercises (SEs) with a sling because they are safer and more effective than open-chain exercises, especially in early stages of treatment. However, the application of CKC SE in youth baseball players has rarely been attempted, although teenage baseball players also experience shoulder pain. OBJECTIVE: To investigate the effects of CKC SE on the peak torque of shoulder internal rotation (IR) and external rotation (ER) in youth baseball players. DESIGN: Single-group pretest, posttest. SETTING: Biomechanics laboratory. PARTICIPANTS: 23 Little League Baseball players with subacromial impingement syndrome. INTERVENTIONS: The CKC SE with a sling was CKC shoulder-flexion exercise, extension exercise, IR exercise, and ER exercise. This exercise regimen was conducted 2 or 3 times/wk for 8 wk. MAIN OUTCOME MEASURES: The peak torque of shoulder IR and ER was measured using an isokinetic dynamometer. Concentric shoulder rotation was performed, with 5 repetitions at an angular velocity of 60 degrees /s and 15 at 180 degrees /s. RESULTS: The IR and ER peak torque significantly increased at each angular velocity after the exercise program. In particular, the increase in IR and ER peak torque values was statistically significant at an angular velocity of 180 degrees /s. CONCLUSIONS: CKC SE was effective in increasing shoulder IR and ER strength, demonstrating its potential benefits in the prevention and treatment of shoulder injury. In addition, increased IR peak torque appears to improve throwing velocity in baseball players. PMID- 25932945 TI - DEVELOPING AND INSTRUCTING PRE-PERFORMANCE ROUTINES FOR TENPIN BOWLING COMPETITIONS (1). AB - This preliminary study developed pre-performance routines for tenpin bowlers and instructed them. To develop the routine, the situations before throwing the ball were divided into four phases; participants were examined through interviews and observations. This study used an A-B design; the A stage included the development of the routines for 3 wk., while the B stage included the instruction and two evaluations of the routine consistency. Practice was implemented for 4 hr. per day for 9 wk. The participants noted they understood the developed routine easily and experienced an atmosphere similar to that of a competition during training through the routines. They found it difficult to practice the relaxation phase, but emphasized that the relaxation phase was helpful. Consistent routines were associated with an improved mental state and performance in a competition. This study suggests that pre-performance routines stabilize the mental state of the athletes, apparently giving them a competitive advantage. PMID- 25932946 TI - Synthesis of Cinnolin-3(2H)-one Derivatives from Rh-Catalyzed Reaction of Azobenzenes with Diazotized Meldrum's Acid. AB - A synthetic method of a wide range of cinnolin-3(2H)-one derivatives is developed from the reaction of symmetrical as well as unsymmetrical azobenzenes with diazotized Meldrum's acid via Rh-catalyzed C-H alkylation followed by cyclization. PMID- 25932947 TI - EEG Single-Trial Detection of Gait Speed Changes during Treadmill Walk. AB - In this study, we analyse the electroencephalography (EEG) signal associated with gait speed changes (i.e. acceleration or deceleration). For data acquisition, healthy subjects were asked to perform volitional speed changes between 0, 1, and 2 Km/h, during treadmill walk. Simultaneously, the treadmill controller modified the speed of the belt according to the subject's linear speed. A classifier is trained to distinguish between the EEG signal associated with constant speed gait and with gait speed changes, respectively. Results indicate that the classification performance is fair to good for the majority of the subjects, with accuracies always above chance level, in both batch and pseudo-online approaches. Feature visualisation and equivalent dipole localisation suggest that the information used by the classifier is associated with increased activity in parietal areas, where mu and beta rhythms are suppressed during gait speed changes. Specifically, the parietal cortex may be involved in motor planning and visuomotor transformations throughout the online gait adaptation, which is in agreement with previous research. The findings of this study may help to shed light on the cortical involvement in human gait control, and represent a step towards a BMI for applications in post-stroke gait rehabilitation. PMID- 25932948 TI - Ascaris and Escherichia coli Inactivation in an Ecological Sanitation System in Port-au-Prince, Haiti. AB - The goal of this study was to evaluate the microbial die-off in a latrine waste composting system in Port-au-Prince, Haiti. Temperature data and samples were collected from compost aged 0-12+ months. Samples collected from compost bin centers and corners at two depths were assessed for moisture content, E. coli concentration, and Ascaris spp. viability. Center temperatures in compost bins were all above 58 degrees C, while corner temperatures were 10 - 20 degrees C lower. Moisture content was 67 +/- 10% in all except the oldest compost. A 4-log reduction in E. coli was observed over the first sixteen weeks of composting at both locations and depths, after which E. coli was undetectable (LOD: 142 MPN g( 1) dry weight). In new compost, 10.4% and 8.3% of Ascaris eggs were viable and fully embryonated, respectively. Percent viability dropped to zero in samples older than six weeks. These findings indicate that the Haitian EcoSan composting process was effective in inactivating E. coli and Ascaris spp. in latrine waste within sixteen weeks. This study is one of the first to document efficacy of an ecological sanitation system under field conditions and provides insight into composting methods and monitoring for other international settings. PMID- 25932949 TI - Jose Luis Mascarenas. PMID- 25932950 TI - Correction: The Role of alpha7 Nicotinic Acetylcholine Receptor in Modulation of Heart Rate Dynamics in Endotoxemic Rats. PMID- 25932951 TI - Comprehensive analysis of glycolytic enzymes as therapeutic targets in the treatment of glioblastoma. AB - Major efforts have been put in anti-angiogenic treatment for glioblastoma (GBM), an aggressive and highly vascularized brain tumor with dismal prognosis. However clinical outcome with anti-angiogenic agents has been disappointing and tumors quickly develop escape mechanisms. In preclinical GBM models we have recently shown that bevacizumab, a blocking antibody against vascular endothelial growth factor, induces hypoxia in treated tumors, which is accompanied by increased glycolytic activity and tumor invasiveness. Genome-wide transcriptomic analysis of patient derived GBM cells including stem cell lines revealed a strong up regulation of glycolysis-related genes in response to severe hypoxia. We therefore investigated the importance of glycolytic enzymes in GBM adaptation and survival under hypoxia, both in vitro and in vivo. We found that shRNA-mediated attenuation of glycolytic enzyme expression interfered with GBM growth under normoxic and hypoxic conditions in all cellular models. Using intracranial GBM xenografts we identified seven glycolytic genes whose knockdown led to a dramatic survival benefit in mice. The most drastic effect was observed for PFKP (PFK1, +21.8%) and PDK1 (+20.9%), followed by PGAM1 and ENO1 (+14.5% each), HK2 (+11.8%), ALDOA (+10.9%) and ENO2 (+7.2%). The increase in mouse survival after genetic interference was confirmed using chemical inhibition of PFK1 with clotrimazole. We thus provide a comprehensive analysis on the importance of the glycolytic pathway for GBM growth in vivo and propose PFK1 and PDK1 as the most promising therapeutic targets to address the metabolic escape mechanisms of GBM. PMID- 25932952 TI - Vasoactive intestinal polypeptide promotes intestinal barrier homeostasis and protection against colitis in mice. AB - Inflammatory bowel disease is a chronic gastrointestinal inflammatory disorder associated with changes in neuropeptide expression and function, including vasoactive intestinal peptide (VIP). VIP regulates intestinal vasomotor and secretomotor function and motility; however, VIP's role in development and maintenance of colonic epithelial barrier homeostasis is unclear. Using VIP deficient (VIPKO) mice, we investigated VIP's role in epithelial barrier homeostasis, and susceptibility to colitis. Colonic crypt morphology and epithelial barrier homeostasis were assessed in wildtype (WT) and VIPKO mice, at baseline. Colitic responses were evaluated following dinitrobenzene sulfonic acid (DNBS) or dextran-sodium sulfate (DSS) exposure. Mice were also treated with exogenous VIP. At baseline, VIPKO mice exhibited distorted colonic crypts, defects in epithelial cell proliferation and migration, increased apoptosis, and altered permeability. VIPKO mice also displayed reduced goblet cell numbers, and reduced expression of secreted goblet cell factors mucin 2 and trefoil factor 3. These changes were associated with reduced expression of caudal type homeobox 2 (Cdx2), a master regulator of intestinal function and homeostasis. DNBS and DSS induced colitis were more severe in VIPKO than WT mice. VIP treatment rescued the phenotype, protecting VIPKO mice against DSS colitis, with results comparable to WT mice. In conclusion, VIP plays a crucial role in the development and maintenance of colonic epithelial barrier integrity under physiological conditions and promotes epithelial repair and homeostasis during colitis. PMID- 25932954 TI - Relationships among Trait Resilience, Virtues, Post-traumatic Stress Disorder, and Post-traumatic Growth. AB - The present study aims to examine the relationship between trait resilience and virtues in the context of trauma. A total of 537 participants who attended the preliminary investigation and completed the Life Events Checklist were screened. Of these participants, 142 suffered from personal traumatic experiences in the past year; these individuals were qualified and invited to respond to online questionnaires to assess trait resilience, virtues (i.e., Conscientiousness, Vitality, and Relationship), post-traumatic stress disorder (PTSD) symptoms, and post-traumatic growth (PTG). The following questionnaires were used: Connor Davidson Resilience Scale-Revised, Chinese Virtues Questionnaire, PTSD Checklist Specific, and Post-traumatic Growth Inventory-Chinese. Only 95 participants who manifested self-reported PTSD symptoms and PTG were involved in the current analyses. Trauma was positively and significantly correlated with PTSD in the current sample. Results indicated that trait resilience was positively associated with virtues and PTG; by contrast, PTSD scores were negatively but not significantly related to most of these factors. The three virtues contributed to PTG to a greater extent than trait resilience in non-PTSD and PTSD groups. However, trait resilience remained a significant predictor in the PTSD group even when the three virtues were controlled. The relationship between trait resilience and PTG was moderated by PTSD type (non-PTSD group vs. PTSD group). Our results further suggested that trait resilience and virtues were conceptually related but functionally different constructs. Trait resilience and virtues are positively related; thus, these factors contributed variances to PTG in the context of trauma; however, trait resilience is only manifested when virtues are controlled and when individuals are diagnosed as PTSD. Furthermore, implications and limitations of this study are discussed. PMID- 25932953 TI - Characterisation of mesothelioma-initiating cells and their susceptibility to anti-cancer agents. AB - Malignant mesothelioma (MM) is an aggressive type of tumour causing high mortality. One reason for this paradigm may be the existence of a subpopulation of tumour-initiating cells (TICs) that endow MM with drug resistance and recurrence. The objective of this study was to identify and characterise a TIC subpopulation in MM cells, using spheroid cultures, mesospheres, as a model of MM TICs. Mesospheres, typified by the stemness markers CD24, ABCG2 and OCT4, initiated tumours in immunodeficient mice more efficiently than adherent cells. CD24 knock-down cells lost the sphere-forming capacity and featured lower tumorigenicity. Upon serial transplantation, mesospheres were gradually more efficiently tumrigenic with increased level of stem cell markers. We also show that mesospheres feature mitochondrial and metabolic properties similar to those of normal and cancer stem cells. Finally, we show that mesothelioma-initiating cells are highly susceptible to mitochondrially targeted vitamin E succinate. This study documents that mesospheres can be used as a plausible model of mesothelioma-initiating cells and that they can be utilised in the search for efficient agents against MM. PMID- 25932955 TI - Million-Fold Electrical Conductivity Enhancement in Fe2(DEBDC) versus Mn2(DEBDC) (E = S, O). AB - Reaction of FeCl2 and H4DSBDC (2,5-disulfhydrylbenzene-1,4-dicarboxylic acid) leads to the formation of Fe2(DSBDC), an analogue of M2(DOBDC) (MOF-74, DOBDC(4-) = 2,5-dihydroxybenzene-1,4-dicarboxylate). The bulk electrical conductivity values of both Fe2(DSBDC) and Fe2(DOBDC) are ~6 orders of magnitude higher than those of the Mn(2+) analogues, Mn2(DEBDC) (E = O, S). Because the metals are of the same formal oxidation state, the increase in conductivity is attributed to the loosely bound Fe(2+) beta-spin electron. These results provide important insight for the rational design of conductive metal-organic frameworks, highlighting in particular the advantages of iron for synthesizing such materials. PMID- 25932957 TI - Proceedings of the 2nd People that Deliver (2nd PtD) Global Conference on Human Resources in Supply Chain Management. PMID- 25932956 TI - Effect of Galactose Ingestion Before and During Exercise on Substrate Oxidation, Postexercise Satiety, and Subsequent Energy Intake in Females. AB - OBJECTIVE: To examine the effects of consuming a galactose carbohydrate (CHO) drink on substrate oxidation, postexercise satiety, and subsequent energy intake. METHODS: Nine recreationally active eumenorrheic females undertook 3 trials, each consisting of running for 60 minutes at 65% VO(2peak) followed immediately by a 90-minute rest period. Prior to (300 ml) and at 15-minute intervals during exercise (150 ml), participants consumed either a glucose (GLU: GI 89) or galactose (GAL: GI 20) drink, each of which contained 45 g of CHO, or an artificially sweetened placebo (PLA). Following the rest period, participants were provided with an ad libitum test lunch and asked to record food intake for the remainder of the day. RESULTS: Plasma glucose was significantly greater throughout exercise and rest following the GLU trial compared with the GAL and PLA trials (P < 0.05); however there were no differences in CHO oxidation. Hunger was significantly lower (P < 0.05) throughout the GAL compared to the GLU and PLA trials. There were no significant differences between trials for energy intake during the postexercise meal. Overall net energy balance for the 24 hours was negative in both the GAL (-162 +/- 115 kcal; P < 0.05 vs GLU) and PLA trials (-49 +/- 160 kcal). CONCLUSIONS: Results demonstrate that ingesting a solution containing GAL before and during exercise can positively impact postexercise satiety and energy balance throughout the day, compared to a more readily available and widely consumed form of CHO. Despite this, there appears to be no apparent benefit in consuming a CHO beverage on fuel utilization for this moderate exercise intensity and duration. PMID- 25932958 TI - A narrative review of schemas and schema therapy outcomes in the eating disorders. AB - Whilst cognitive-behavioural therapy has demonstrated efficacy in the treatment of eating disorders, therapy outcomes and current conceptualizations still remain inadequate. In light of these shortcomings there has been growing interest in the utility of schema therapy applied to eating pathology. The present article first provides a narrative review of empirical literature exploring schemas and schema processes in eating disorders. Secondly, it critically evaluates outcome studies assessing schema therapy applied to eating disorders. Current evidence lends support to schema-focused conceptualizations of eating pathology and confirms that eating disorders are characterised by pronounced maladaptive schemas. Treatment outcomes also indicate that schema therapy, the schema-mode approach, and associated techniques are promising interventions for complex eating disorders. Implications for clinical practice and future directions for research are discussed. PMID- 25932959 TI - Alveolar development and disease. AB - Gas exchange after birth is entirely dependent on the remarkable architecture of the alveolus, its formation and function being mediated by the interactions of numerous cell types whose precise positions and activities are controlled by a diversity of signaling and transcriptional networks. In the later stages of gestation, alveolar epithelial cells lining the peripheral lung saccules produce increasing amounts of surfactant lipids and proteins that are secreted into the airspaces at birth. The lack of lung maturation and the associated lack of pulmonary surfactant in preterm infants causes respiratory distress syndrome, a common cause of morbidity and mortality associated with premature birth. At the time of birth, surfactant homeostasis begins to be established by balanced processes involved in surfactant production, storage, secretion, recycling, and catabolism. Insights from physiology and engineering made in the 20th century enabled survival of newborn infants requiring mechanical ventilation for the first time. Thereafter, advances in biochemistry, biophysics, and molecular biology led to an understanding of the pulmonary surfactant system that made possible exogenous surfactant replacement for the treatment of preterm infants. Identification of surfactant proteins, cloning of the genes encoding them, and elucidation of their roles in the regulation of surfactant synthesis, structure, and function have provided increasing understanding of alveolar homeostasis in health and disease. This Perspective seeks to consider developmental aspects of the pulmonary surfactant system and its importance in the pathogenesis of acute and chronic lung diseases related to alveolar homeostasis. PMID- 25932960 TI - How many tautomerization pathways connect Watson-Crick-like G*.T DNA base mispair and wobble mismatches? AB - In this study, we have theoretically demonstrated the intrinsic ability of the wobble G.T(w)/G*.T*(w)/G.T(w1)/G.T(w2) and Watson-Crick-like G*.T(WC) DNA base mispairs to interconvert into each other via the DPT tautomerization. We have established that among all these transitions, only one single G.T(w) <-> G*.T(WC) pathway is eligible from a biological perspective. It involves short-lived intermediate - the G.T*(WC) base mispair - and is governed by the planar, highly stable, and zwitterionic [Formula: see text] transition state stabilized by the participation of the unique pattern of the five intermolecular O6(+)H?O4(-), O6(+)H?N3(-), N1(+)H?N3(-), N1(+)H?O2(-), and N2(+)H?O2(-) H-bonds. This non dissociative G.T(w) <-> G*.T(WC) tautomerization occurs without opening of the pair: Bases within mispair remain connected by 14 different patterns of the specific intermolecular interactions that successively change each other along the IRC. Novel kinetically controlled mechanism of the thermodynamically non equilibrium spontaneous point GT/TG incorporation errors has been suggested. The mutagenic effect of the analogues of the nucleotide bases, in particular 5 bromouracil, can be attributed to the decreasing of the barrier of the acquisition by the wobble pair containing these compounds of the enzymatically competent Watson-Crick's geometry via the intrapair mutagenic tautomerization directly in the essentially hydrophobic recognition pocket of the replication DNA polymerase machinery. Proposed approaches are able to explain experimental data, namely growth of the rate of the spontaneous point incorporation errors during DNA biosynthesis with increasing temperature. PMID- 25932961 TI - Uterine smooth muscle tumor analysis by comparative genomic hybridization: a useful diagnostic tool in challenging lesions. AB - The diagnosis and management of uterine smooth muscle tumors with uncertain malignant potential (STUMP) is often challenging, and genomic data on these lesions as well as on uterine smooth muscle lesions are limited. We tested the hypothesis that genomic profile determination by array-CGH could split STUMP into a benign group with scarce chromosomal alterations akin to leiomyoma and a malignant group with high chromosomal instability akin to leiomyosarcoma. Array CGH genomic profile analysis was conducted for a series of 29 cases of uterine STUMP. A group of ten uterine leiomyomas and ten uterine leiomyosarcomas served as controls. The mean age was 50 years (range, 24-85) and the follow-up ranged from 12 to 156 months (average 70 months). Since STUMP is a heterogenous group of tumors with genomic profiles that can harbor few to many chromosomal alterations, we compared genomic indices in leiomyomas and leiomyosarcomas and set a genomic index=10 threshold. Tumors with a genomic index <10 were classified as nonrecurring STUMPs and those with a genomic index >10 represented STUMPs with recurrences and unfavorable outcomes. Hence, the genomic index threshold splits the STUMP category into two groups of tumors with different outcomes: a group comparable to leiomyomas and another similar to leiomyosarcomas, but more indolent. In our STUMP series, genomic analysis by array-CGH is an innovative diagnostic tool for problematic smooth muscle uterine lesions, complementary to the morphological evaluation approach. We provide an improved classification method for distinguishing truly malignant tumors from benign lesions within the category of STUMP, especially those with equivocal morphological features. PMID- 25932962 TI - Use of modified Magee equations and histologic criteria to predict the Oncotype DX recurrence score. AB - Oncotype DX (Genomic Health, Redwood City, CA, USA, current list price $4,350.00) is a multigene quantitative reverse transcription-polymerase chain reaction-based assay that estimates the risk of distant recurrence and predicts chemotherapy benefit for patients with estrogen receptor (ER)-positive breast cancers. Studies have suggested that standard histologic variables can provide similar information. Klein and Dabbs et al have shown that Oncotype DX recurrence scores can be estimated by incorporating standard histologic variables into equations (Magee equations). Using a simple modification of the Magee equation, we predict the Oncotype DX recurrence score in an independent set of 283 cases. The Pearson correlation coefficient (r) for the Oncotype DX and average modified Magee recurrence scores was 0.6644 (n=283; P<0.0001). 100% of cases with an average modified Magee recurrence score>30 (n=8) or an average modified Magee recurrence score<9 (with an available Ki-67, n=5) would have been correctly predicted to have a high or low Oncotype DX recurrence score, respectively. 86% (38/44) of cases with an average modified Magee recurrence score<=12, and 89% (34/38) of low grade tumors (NS<6) with an ER and PR>=150, and a Ki-67<10%, would have been correctly predicted to have a low Oncotype DX recurrence score. Using an algorithmic approach to eliminate high and low risk cases, between 5% and 23% of cases would potentially not have been sent by our institution for Oncotype DX testing, creating a potential cost savings between $56,550.00 and $282,750.00. The modified Magee recurrence score along with histologic criteria may be a cost effective alternative to the Oncotype DX in risk stratifying certain breast cancer patients. The information needed is already generated by many pathology laboratories during the initial assessment of primary breast cancer, and the equations are free. PMID- 25932963 TI - Reproducibility of residual cancer burden for prognostic assessment of breast cancer after neoadjuvant chemotherapy. AB - The residual cancer burden index was developed as a method to quantify residual disease ranging from pathological complete response to extensive residual disease. The aim of this study was to evaluate the inter-Pathologist reproducibility in the residual cancer burden index score and category, and in their long-term prognostic utility. Pathology slides and pathology reports of 100 cases from patients treated in a randomized neoadjuvant trial were reviewed independently by five pathologists. The size of tumor bed, average percent overall tumor cellularity, average percent of the in situ cancer within the tumor bed, size of largest axillary metastasis, and number of involved nodes were assessed separately by each pathologist and residual cancer burden categories were assigned to each case following calculation of the numerical residual cancer burden index score. Inter-Pathologist agreement in the assessment of the continuous residual cancer burden score and its components and agreement in the residual cancer burden category assignments were analyzed. The overall concordance correlation coefficient for the agreement in residual cancer burden score among pathologists was 0.931 (95% confidence interval (CI) 0.908-0.949). Overall accuracy of the residual cancer burden score determination was 0.989. The kappa coefficient for overall agreement in the residual cancer burden category assignments was 0.583 (95% CI 0.539-0.626). The metastatic component of the residual cancer burden index showed stronger concordance between pathologists (overall concordance correlation coefficient=0.980; 95% CI 0.954-0.992), than the primary component (overall concordance correlation coefficient=0.795; 95% CI 0.716-0.853). At a median follow-up of 12 years residual cancer burden determined by each of the pathologists had the same prognostic accuracy for distant recurrence-free and survival (overall concordance correlation coefficient=0.995; 95% CI 0.989-0.998). Residual cancer burden assessment is highly reproducible, with reproducible long-term prognostic significance. PMID- 25932964 TI - Real-time driver drowsiness feedback improves driver alertness and self-reported driving performance. AB - Driver drowsiness has been implicated as a major causal factor in road accidents. Tools that allow remote monitoring and management of driver fatigue are used in the mining and road transport industries. Increasing drivers' own awareness of their drowsiness levels using such tools may also reduce risk of accidents. The study examined the effects of real-time blink-velocity-derived drowsiness feedback on driver performance and levels of alertness in a military setting. A sample of 15 Army Reserve personnel (1 female) aged 21-59 (M=41.3, SD=11.1) volunteered to being monitored by an infra-red oculography-based Optalert Alertness Monitoring System (OAMS) while they performed their regular driving tasks, including on-duty tasks and commuting to and from duty, for a continuous period of 4-8 weeks. For approximately half that period, blink-velocity-derived Johns Drowsiness Scale (JDS) scores were fed back to the driver in a counterbalanced repeated-measures design, resulting in a total of 419 driving periods under "feedback" and 385 periods under "no-feedback" condition. Overall, the provision of real-time feedback resulted in reduced drowsiness (lower JDS scores) and improved alertness and driving performance ratings. The effect was small and varied across the 24-h circadian cycle but it remained robust after controlling for time of day and driving task duration. Both the number of JDS peaks counted for each trip and their duration declined in the presence of drowsiness feedback, indicating a dynamic pattern that is consistent with a genuine, entropy-reducing feedback mechanism (as distinct from random re alerting) behind the observed effect. Its mechanisms and practical utility have yet to be fully explored. Direct examination of the alternative, random re alerting explanation of this feedback effect is an important step for future research. PMID- 25932966 TI - Quantification of waterborne pathogens and associated health risks in urban water. AB - Citizens are exposed to microbial hazards in urban waters. To quantify health risks associated with this exposure, pathogen concentrations in an urban river, lake, rainwater sedimentation pond, a pond in a park, and a wadi, were assessed. E. coli concentrations were variable in all locations, with mean values ranging between 1.2 * 10(2) (lake) and 1.7 * 10(4) (sedimentation pond) cfu (colony forming units)/100 mL. High concentrations of Campylobacter were found, being the lowest in the lake (4.2 * 10(1) gc (genomic copies)/L) and the highest in the wadi (1.7 * 10(4) gc/L). Cryptosporidium was not found in any sample. Low levels of adenovirus 40/41 were found in some samples in the river (1.8 * 10(1) gc/L) and lake (7.2 * 10 degrees gc/L), indicating human fecal contamination. Legionella pneumophila was found in the sedimentation pond, with higher concentrations after rain events (1.3 * 10(2) gc/L). Cyanochlorophyll-a was found in the lake (7.0 * 10(-1) MUg/L), the sedimentation pond (1.1 * 10 degrees MUg/L), and the pond in the park (2.9 * 10(1) MUg/L), where low levels of microcystin were found (2.1 * 10 degrees MUg/L). Campylobacter data were used to estimate gastrointestinal risks from recreational exposure. This revealed risks above the annual disease incidence of campylobacteriosis in The Netherlands, being highest in the wadi and river. Measures are proposed to reduce the health risks. PMID- 25932965 TI - Extra-Nuclear Signaling Pathway Involved in Progesterone-Induced Up-Regulations of p21cip1 and p27kip1 in Male Rat Aortic Smooth Muscle Cells. AB - Previously, we demonstrated that progesterone (P4) at physiologic levels (5-500 nM) inhibited proliferation in cultured rat aortic smooth muscle cells (RASMCs) through a P4 receptor (PR)-dependent pathway. We also showed that P4-induced cell cycle arrest in RASMCs occurs when the cyclin-CDK2 system is inhibited just as p21cip1 and p27kip1 protein levels are augmented. In the present study, we further investigated the molecular mechanism underlying P4-induced up-regulations of p21cip1 and p27kip1 in RASMCs. We used pharmacological inhibitors as well as dominant negative constructs and conducted Western blot analyses to delineate the signaling pathway involved. Our data suggest that P4 up-regulated the expression of p21cip1 and p27kip1 in RASMCs through increasing the level of p53 protein mediated by activating the cSrc/Kras/Raf-1/AKT/ERK/p38/IkappaBalpha/NFkappaB pathway. The findings of the present study highlight the molecular mechanism underlying P4-induced up-regulations in p21cip1 and p27kip1 in RASMCs. PMID- 25932967 TI - Applicability of Donnan equilibrium theory at nanochannel-reservoir interfaces. AB - Understanding ionic transport in nanochannels has attracted broad attention from various areas in energy and environmental fields. In most pervious research, Donnan equilibrium has been applied widely to nanofluidic systems to obtain ionic concentration and electrical potential at channel-reservoir interfaces; however, as well known that Donnan equilibrium is derived from classical thermodynamic theories with equilibrium assumptions. Therefore the applicability of the Donnan equilibrium may be questionable when the transport at nanochannel-reservoir interface is strongly non-equilibrium. In this work, the Poisson-Nernst-Planck model for ion transport is numerically solved to obtain the exact distributions of ionic concentration and electrical potential. The numerical results are quantitatively compared with the Donnan equilibrium predictions. The applicability of Donnan equilibrium is therefore justified by changing channel length, reservoir ionic concentration, surface charge density and channel height. The results indicate that the Donnan equilibrium is not applicable for short nanochannels, large concentration difference and wide openings. A non-dimensional parameter, Q factor, is proposed to measure the non-equilibrium extent and the relation between Q and the working conditions is studied in detail. PMID- 25932968 TI - Palliative interventions for controlling vaginal bleeding in advanced cervical cancer. AB - BACKGROUND: Cervical cancer is the second most common cancer among women worldwide, with around 500,000 new diagnoses and 273,000 deaths per year. However, incidence and stage at diagnosis vary greatly between geographic areas and are largely dependent on the availability of a robust population screening programme. For example, in Nigeria, advanced-stage disease at presentation is common (86% to 89.3% of new cases), whereas in the UK, only 21.9% of women present with International Federation of Gynaecology and Obstetrics (FIGO) stage II+ disease. Women with advanced cancer of the cervix often need palliation for distressing symptoms, such as vaginal bleeding. Vaginal bleeding can be life threatening in advanced disease, with an incidence ranging from 0.7% to 100%. Bleeding is the immediate cause of death in 6% of women with cervical cancer and its management often poses a challenge.Thus, vaginal bleeding remains a common consequence of advanced cervical cancer. Currently, there is no systematic review that addresses palliative interventions for controlling vaginal bleeding caused by advanced cervical cancer. A systematic evaluation of the available palliative interventions is needed, to inform decision-making. OBJECTIVES: To evaluate the efficacy and safety of tranexamic acid, vaginal packing (with or without formalin soaked packs), interventional radiology or other interventions compared with radiotherapy for palliative treatment of vaginal bleeding in women with advanced cervical cancer. SEARCH METHODS: We searched the Cochrane Central Register of Controlled Trials (CENTRAL), Issue 2, 2015; the Cochrane Gynaecological Cancer Group Trials Register; MEDLINE from 1980 to March week 3, 2015 and EMBASE from 1980 to February week 12, 2015. We also searched registers of clinical trials, abstracts of scientific meetings and reference lists of review articles and contacted experts in the field. We handsearched citation lists of relevant studies. SELECTION CRITERIA: We searched for randomised and non-randomised comparative studies that evaluated the efficacy and safety of tranexamic acid, vaginal packing (with or without formalin-soaked packs), interventional radiology or other interventions compared with radiotherapy techniques for palliative treatment of vaginal bleeding in women with advanced cervical cancer (with or without metastasis), irrespective of publication status, year of publication or language in the review. DATA COLLECTION AND ANALYSIS: Two review authors independently assessed whether potentially relevant studies met the inclusion criteria. We found no studies were identified for inclusion and, therefore, we analysed no data. MAIN RESULTS: The search strategy identified 1335 unique references of which 1160 were excluded on the basis of title and abstract. We retrieved the remaining 22 articles in full, but none satisfied the inclusion criteria. We identified only observational data from single-arm studies of women treated with formalin-soaked packs, interventional radiology or radiotherapy techniques for palliative control of vaginal bleeding in women with cervical cancer. AUTHORS' CONCLUSIONS: There is no evidence from controlled trials to support or refute the use of any of the proposed interventions compared with radiotherapy. Therefore, the choice of intervention will be based on local resources. Radiotherapy techniques for managing vaginal bleeding are not readily available in resource-poor settings, where advanced cases of cervical cancer are predominant. Thus, this systematic review identified the need for a randomised controlled trial assessing the benefits and risks of palliative treatments for vaginal bleeding in women with advanced cervical cancer. PMID- 25932969 TI - A computer-aided automated methodology for the detection and classification of occlusal caries from photographic color images. AB - The aim of this work is to present a computer-aided automated methodology for the assessment of carious lesions, according to the International Caries Detection and Assessment System (ICDAS II), which are located on the occlusal surfaces of posterior permanent teeth from photographic color tooth images. The proposed methodology consists of two stages: (a) the detection of regions of interest and (b) the classification of the detected regions according to ICDAS IotaIota. In the first stage, pre-processing, segmentation and post-processing mechanisms were employed. For each pixel of the detected regions, a 15*15 neighborhood is used and a set of intensity-based and texture-based features were extracted. A correlation based technique was applied to select a subset of 36 features which were given as input into the classification stage, where five classifiers (J48, Random Tree, Random Forests, Support Vector Machines and Naive Bayes) were compared to conclude to the best one, in our case, to Random Forests. The methodology was evaluated on a set of 103 digital color images where 425 regions of interest from occlusal surfaces of extracted permanent teeth were manually segmented and classified, based on visual assessments by two experts. The methodology correctly detected 337 out of 340 regions in the detection stage with accuracy of detection 80%. For the classification stage an overall accuracy 83% is achieved. The proposed methodology provides an objective and fully automated caries diagnostic system for occlusal carious lesions with similar or better performance of a trained dentist taking into consideration the available medical knowledge. PMID- 25932970 TI - Continuous Positive Airway Pressure treatment of premature infants; application of a computerized decision support system. AB - The predictions of a computerized decision-support system (CDSS) are compared to clinical data obtained from a group of premature infants. The infants were suffering from respiratory distress syndrome (RDS) and were treated by the Continuous Positive Airway Pressure (CPAP) therapy. The predictions of the CDSS are found to be in general agreement with clinical measurements. The CDSS is also used to determine the effect of low level oxygen treatment on arterial oxygen pressure if the infant's oxygenation is low despite CPAP therapy. Based on the computational results, application of low levels of supplemental inspired fraction of oxygen ( [Formula: see text] ) would result in significant improvement in oxygenation of premature infants provided such treatment is carefully controlled to avoid hyperoxemia. PMID- 25932971 TI - Sparsity-constrained three-dimensional image reconstruction for C-arm angiography. AB - X-ray C-arm is an important imaging tool in interventional radiology, road mapping and radiation therapy because it provides accurate descriptions of vascular anatomy and therapeutic end point. In common interventional radiology, the C-arm scanner produces a set of two-dimensional (2D) X-ray projection data obtained with a detector by rotating the scanner gantry around the patient. Unlike conventional fluoroscopic imaging, three-dimensional (3D) C-arm computed tomography (CT) provides more accurate cross-sectional images, which are helpful for therapy planning, guidance and evaluation in interventional radiology. However, 3D vascular imaging using the conventional C-arm fluoroscopy encounters some geometry challenges. Inspired by the theory of compressed sensing, we developed an image reconstruction algorithm for conventional angiography C-arm scanners. The main challenge in this image reconstruction problem is the projection data limitations. We consider a small number of views acquired from a short rotation orbit with offset scan geometry. The proposed method, called sparsity-constrained angiography (SCAN), is developed using the alternating direction method of multipliers, and the results obtained from simulated and real data are encouraging. SCAN algorithm provides a framework to generate 3D vascular images using the conventional C-arm scanners in lower cost than conventional 3D imaging scanners. PMID- 25932972 TI - Acute acalculous cholecystitis (AAC) in the pediatric population associated with Epstein-Barr Virus (EBV) infection. Case report and review of the literature. AB - BACKGROUND: Epstein Barr Virus (EBV) is a ubiquitous herpes virus that persists lifelong in normal humans by colonizing memory B cells. Infection during childhood is usually asymptomatic. Isolated gallbladder wall thickening or hydrops have been reported in patients with EBV infectious mononucleosis. However, acute acalculous cholecystitis is an atypical clinical presentation of primary EBV infection. We present a teenager with acute cholecystitis associated with EBV acute infection. Acute acalculous cholecystitis accounts for 2-15% of all cases of acute cholecystitis. Few cases of acute cholecystitis have been reported during the course of primary EBV infection. PRESENTATION OF CASE: A 15 year-old female who came to the JDCH ER complaining of 3 days history of mild diffuse abdominal pain associated with two episodes of emesis. She also reports headache as well as a mild cough and low grade subjective fever. Blood test results showed mild leukocytosis with significant elevation in the lymphocytes (59%), High alkaline phosphatase (221 U/I), AST (191 U/I), ALT(221 U/I) and bilirubin (Total 1.8 and direct 1.5). Abdominal US showed a contracted gallbladder with wall thickness and pericholecystic fluid. During hospital stay number 2-3 laboratory work up show a trending up in the bilirubin levels. MRCP was ordered and no abdnormalities were found. At this point Hospital stay number 3 EBV acute infection was suspected. Serum serological studies were subsequently diagnostic for this viral disease. Management was conservative and the patient was discharged asymptomatic on hospital day number six. PMID- 25932973 TI - Herlyn-Werner-Wunderlich syndrome: An "early" onset case report and review of Literature. AB - Herlyn-Werner-Wunderlich syndrome (HWWS) is a rare congenital mullerian anomaly consisting of uterus didelphys, hemivaginal septum, and unilateral renal agenesis [1,2]. Most authors reported cases of Herlyn-Werner-Wunderlich syndrome with prepuberal or postpuberal onset with cyclical abdominal pain and a vaginal mass (3-8). Only six cases are reported in Literature with early onset of this syndrome under 5 years (9-14). Our case is about 3 years old girl, with all the features of this syndrome who came to our attention for lower abdominal mass. The aim of this article is to share our experience and focus the attention on the importance of high level of suspicion of HWWS in neonatal period to early diagnosis and treatment. The possible early presentation of this syndrome should be suspected in all neonates (females) with renal agenesia confirmed postnatally or with prenatal diagnosis. It is common, in fact, an error of evaluation with planning of removal of mass, that can damage patients in term of chance for a successful reproductive outcome. For all these reasons, our team consider HWWS as differential diagnosis in newborn with prenatal ultrasonography of a cystic mass behind the urinary bladder in the absence of a kidney and plan a pelvic ultrasound (with aim to identify an uterus, normal or dydhelfus, and presence or absence of pelvic mass), an examination under anesthesia and cystoscopy and vaginoscopy, if it is necessary. A high level of suspicion, indeed, is the key to early diagnosis. PMID- 25932974 TI - Body satisfaction, thin-ideal internalization, and perceived pressure to be thin among Canadian women: The role of acculturation and religiosity. AB - In an online study, 143 Canadian women of various religious backgrounds completed measures of acculturation, religiosity, body satisfaction, internalization of the thin ideal, perceived pressure from media, and manner of dress. Heritage acculturation correlated with appearance satisfaction, but not weight satisfaction. After accounting for BMI and social desirability, higher heritage acculturation and lower mainstream acculturation were associated with lower perceived pressure from media. Thus, heritage acculturation across religious denominations may serve as a buffer against appearance dissatisfaction and perceived media pressure. Manner of dress among the Muslim subgroup and its relation to religiosity and acculturation were also assessed. Muslim women who dressed in greater accordance with Islamic principles reported lower heritage acculturation and greater religiosity. Thus, Muslim women's manner of dress was related to their religiosity and the extent to which they embraced cultural values. These findings are discussed in terms of the possible distinctions between heritage acculturation and religiosity. PMID- 25932975 TI - Dynamics of melanin-concentrating hormone (MCH) serum levels in major depressive disorder during antidepressant treatment. AB - BACKGROUND: In preclinical studies, the hypothalamic polypeptide melanin concentrating hormone (MCH) has been shown to be involved in depression-like behavior and modulations of MCH and MCH-receptors were proposed as potential new antidepressant drug targets. METHODS: For the first time, MCH serum levels were explored in 30 patients with major depressive disorder (MDD) prior to (T1) and after 2 (T2) and 4 weeks (T3) of antidepressant treatment and in 30 age- and sex matched healthy controls by applying a fluorescence immunoassay. RESULTS: Levels of MCH did not differ significantly between un-medicated patients (444.11+/ 174.63pg/mL SD) and controls (450.68+/-210.03pg/mL SD). In MDD patients, MCH levels significantly decreased from T1 to T3 (F=4.663; p=0.013). Post-hoc analyses showed that these changes were limited to patients treated with mirtazapine but not escitalopram and female but not male patients. MCH-levels showed high correlations from T1 to T3 (r>=0.964, p<0.001) and were found to correlate significantly with parameters of sleep within the controls. LIMITATIONS: Small sample size. No follow-up measures were performed within the control group. CONCLUSIONS: Our findings suggest peripheral MCH-levels not to be altered in depression but possibly reflecting depression-related state properties that can be modulated by sleep, medication and sex. PMID- 25932976 TI - Doubly end-on azido bridged mixed-valence cobalt trinuclear complex: Spectral study, VTM, inhibitory effect and antimycobacterial activity on human carcinoma and tuberculosis cells. AB - Doubly end-on azido-bridged mixed-valence trinuclear cobalt complex, [Co3(L)2(N3)6(CH3OH)2] (1) is afforded by employing a potential monoanionic tetradentate-N2O2 Schiff base precursor (2-[{[2 (dimethylamino)ethyl]imino}methyl]-6-methoxyphenol; HL). Single crystal X-ray structure reveals that in 1, the adjacent Co(II) and Co(III) ions are linked by double end-on azido bridges and thus the full molecule is generated by the site symmetry of a crystallographic twofold rotation axis. Complex 1 is subjected on different spectral analysis such as IR, UV-vis, emission and EPR spectroscopy. On variable temperature magnetic study, we observe that during cooling, the chiMT values decrease smoothly until 15K and then reaches to the value 1.56 cm(3) K mol(-1) at 2 K. Complex 1 inhibits the cell growth on human lung carcinoma (A549 cells), human colorectal (COLO 205 and HT-29 cells), and human heptacellular (PLC5 cells) carcinoma cells. Complex 1 exhibits anti-mycobacterial activity and considerable efficacy on Mycobacterium tuberculosis H37Rv ATCC 27294 and H37Ra ATCC 25177 strains. PMID- 25932977 TI - Protein synthesis in artificial cells: using compartmentalisation for spatial organisation in vesicle bioreactors. AB - Whereas spatial organisation of function is ubiquitous in biology, it has been lacking in artificial cells. We rectify this by using multi-compartment vesicles as chassis for artificial cells, allowing distinct biological processes to be isolated in space. This is demonstrated by in vitro synthesis of two proteins in predefined vesicle regions. PMID- 25932978 TI - On simplicity and complexity in the brave new world of large-scale neuroscience. AB - Technological advances have dramatically expanded our ability to probe multi neuronal dynamics and connectivity in the brain. However, our ability to extract a simple conceptual understanding from complex data is increasingly hampered by the lack of theoretically principled data analytic procedures, as well as theoretical frameworks for how circuit connectivity and dynamics can conspire to generate emergent behavioral and cognitive functions. We review and outline potential avenues for progress, including new theories of high dimensional data analysis, the need to analyze complex artificial networks, and methods for analyzing entire spaces of circuit models, rather than one model at a time. Such interplay between experiments, data analysis and theory will be indispensable in catalyzing conceptual advances in the age of large-scale neuroscience. PMID- 25932979 TI - Location of Instability During a Bench Press Alters Movement Patterns and Electromyographical Activity. AB - Instability training devices with the bench press exercise are becoming increasingly popular. Typically, the instability device is placed at the trunk/upper body (e.g., lying on a Swiss ball); however, a recent product called the Attitube has been developed, which places the location of instability at the hands by users lifting a water-filled tube. Therefore, the purpose of this study was to analyze the effects of different instability devices (location of instability) on kinematic and electromyographical patterns during the bench press exercise. Ten healthy males were recruited and performed 1 set of 3 repetitions for 3 different bench press conditions: Olympic bar on a stable bench (BENCH), Olympic bar on a stability ball (BALL), and Attitube on a stable bench (TUBE). The eccentric and concentric phases were analyzed in 10% intervals while electromyography was recorded from 24 electrode sites, and motion capture was used to track elbow flexion angle and 3-dimensional movement trajectories and vertical velocity of the Bar/Attitube. The prime movers tended to show a reduction in muscle activity during the TUBE trials; however, pectoralis major initially showed increased activation during the eccentric phase of the TUBE condition. The trunk muscle activations were greatest during the TUBE and smallest during the BAR. In addition, the TUBE showed decreased range of elbow flexion and increased medial-lateral movement of the Attitube itself. The results further support the notion that instability devices may be more beneficial for trunk muscles rather than prime movers. PMID- 25932980 TI - Physiological Demands of Flat Horse Racing Jockeys. AB - The physiological demands of jockeys during competition remain largely unknown, thereby creating challenges when attempting to prescribe sport-specific nutrition and training guidelines. The purpose of this study was to evaluate the physiological demands and energy requirements of jockeys during flat racing. Oxygen uptake (V[Combining Dot Above]O2) and heart rate (HR) were assessed in 18 male trainee jockeys during a race simulation trial on a mechanical horse racing simulator for the typical time duration to cover a common flat race distance of 1,400 m. In addition, 8 male apprentice jockeys participated in a competitive race, over distances ranging from 1,200 to 1,600 m, during which HR and respiratory rate (RR) were assessed. All participants performed a maximal incremental cycle ergometer test. During the simulated race, peak V[Combining Dot Above]O2 was 42.74 +/- 5.6 ml.kg.min (75 +/- 11% of V[Combining Dot Above]O2peak) and below the mean ventilatory threshold (81 +/- 5% of V[Combining Dot Above]O2peak) reported in the maximal incremental cycle test. Peak HR was 161 +/- 16 b.min (86 +/- 7% of HRpeak). Energy expenditure was estimated as 92.5 +/- 18.8 kJ with an associated value of 9.4 metabolic equivalents. During the competitive race trial, peak HR reached 189 +/- 5 b.min (103 +/- 4% of HRpeak) and peak RR was 50 +/- 7 breaths per minute. Results suggest that horse racing is a physically demanding sport, requiring jockeys to perform close to their physiological limit to be successful. These findings may provide a useful insight when developing sport-specific nutrition and training strategies to optimally equip and prepare jockeys physically for the physiological demands of horse racing. PMID- 25932981 TI - Influence of Resistance Training Frequency on Muscular Adaptations in Well Trained Men. AB - The purpose of this study was to investigate the effects of training muscle groups 1 day per week using a split-body routine (SPLIT) vs. 3 days per week using a total-body routine (TOTAL) on muscular adaptations in well-trained men. Subjects were 20 male volunteers (height = 1.76 +/- 0.05 m; body mass = 78.0 +/- 10.7 kg; age = 23.5 +/- 2.9 years) recruited from a university population. Participants were pair matched according to baseline strength and then randomly assigned to 1 of the 2 experimental groups: a SPLIT, where multiple exercises were performed for a specific muscle group in a session with 2-3 muscle groups trained per session (n = 10) or a TOTAL, where 1 exercise was performed per muscle group in a session with all muscle groups trained in each session (n = 10). Subjects were tested pre- and poststudy for 1 repetition maximum strength in the bench press and squat, and muscle thickness (MT) of forearm flexors, forearm extensors, and vastus lateralis. Results showed significantly greater increases in forearm flexor MT for TOTAL compared with SPLIT. No significant differences were noted in maximal strength measures. The findings suggest a potentially superior hypertrophic benefit to higher weekly resistance training frequencies. PMID- 25932982 TI - Pattern of Weight Loss of Young Female and Male Wrestlers. AB - The aim of this study was to investigate the magnitude of rapid weight loss (RWL) of female and male young wrestlers at the Brazilian high-school games. High school wrestlers (females: n = 16, 13 +/- 2 years; males: n = 15, 13 +/- 2 years) participated in this study. The official weigh-in was conducted 24 hours before competition. Immediately after the official weigh-in, wrestlers completed a hydration habits and a standardized weight loss questionnaires. Twenty-four hours later, wrestlers took part in an unofficial prematch weigh-in. Sodium, potassium, chloride, hematocrit, and hemoglobin were measured immediately before the first competitive match by iSTAT Blood Gas Analyzer. A significant body mass increase was observed from the official weigh-in to the prematch weigh-in (females: 2.7 +/ 1.4 kg and males: 1.5 +/- 0.9 kg; p <= 0.05) with significantly greater body mass increase in females (6.3%) vs. males (3.1%) (p <= 0.05). Rapid weight loss practices were exercised by 42.0% of the wrestlers. Furthermore, 46.2% of those who performed RWL practices reported side effects, which they perceived negatively altered past performance. Despite RWL and subsequent body mass increase, all biomarkers (sodium, potassium, chloride, hematocrit, and hemoglobin) were in the normal range at the prematch weigh-in. The majority (82.0%) of the athletes agreed that hydration habits are important to health and performance. It seems that although wrestlers acknowledge negative performance effects due to RWL, the practice is still exercised among both female and male wrestlers. Therefore, educational programs should be implemented in high-school athletes to discourage RWL and provide information for exercise and nutritional strategies to maintain a healthy body mass and avoid chronic health issues. PMID- 25932983 TI - Fluctuations in Activity Demands Across Game Quarters in Professional and Semiprofessional Male Basketball. AB - Examination of activity demands and stoppage durations across game periods provides useful insight concerning fatigue, tactical strategies, and playing pace in team sports such as basketball. Therefore, the aims of this study were to quantify and compare game activity fluctuations across quarters in professional and semiprofessional basketball players. Video-based time-motion analyses were conducted across multiple games. Frequencies, total durations (in seconds), total distances (in meters), and mean velocities (in meters per second) were calculated for low-intensity movement (<=3 m.s), high-intensity movement (>3 m.s), shuffling, and dribbling activity. Frequencies were determined for jumping and upper-body activity; stoppage durations were also calculated. Separate repeated measures analysis of variance and Cohen's d were used to identify significant differences and quantify the effect sizes between game quarters for all outcome measures, respectively. Pearson correlation analyses were performed to determine the relationship between stoppage duration and all activity measures. The results showed significantly (p <= 0.05) reduced dribbling (3.09 +/- 0.03 m.s vs. 2.81 +/ 0.01 m.s) and total (2.22 +/- 0.04 m.s vs. 2.09 +/- 0.03 m.s) activity velocities during the third compared with the first quarter in professional players. Furthermore, effect size analyses showed greater decreases in high intensity (professional: d = 1.7-5.4; semiprofessional: d = 0.3-1.7), shuffling (professional: d = 2.3-3.2; semiprofessional: d = 1.4-2.1), and total (professional: d = 1.0-4.9; semiprofessional: d = 0.3-0.8) activity and increases in dribbling (professional: d = 1.4-4.7; semiprofessional: d = 2.5-2.8) with game progression in professional players. In semiprofessional players, stoppage duration was significantly (p <= 0.05) related to various low-intensity (R = 0.64 0.72), high-intensity (R = 0.65-0.72), and total (R = 0.63-0.73) activity measures. Although not directly measured, the observed game activity fluctuations were likely because of a combination of physiological (e.g., muscle glycogen depletion, dehydration), tactical (e.g., ball control, game pace), and game related (e.g., time-outs, player fouls) factors. Basketball coaches can use the provided data to (a) develop more precise training plans and management strategies, (b) elevate semiprofessional player performance closer to the professional level, and (c) incorporate tactical strategies to maximize the benefits of stoppages. PMID- 25932984 TI - Acute Effect of Dynamic Stretching on Endurance Running Performance in Well Trained Male Runners. AB - The purpose of this study was to clarify the acute effect of dynamic stretching (DS) on relative high-intensity endurance running performance. The endurance running performances of 7 well-trained middle- or long-distance male runners were assessed on a treadmill after 2 types of pretreatment. The pretreatments were nonstretching (NS) and DS treatment. In the DS treatment, DS was performed as 1 set of 10 repetitions as quickly as possible for the 5 muscle groups in lower extremities. The endurance running performances were evaluated by time to exhaustion (TTE) and total running distance (TRD) during running at a velocity equivalent to 90% maximal oxygen uptake (VO2max) in each subject. The oxygen uptake (VO2) during running was measured as an index of running economy (RE). The TTE (928.6 +/- 215.0 seconds) after DS treatment was significantly (p < 0.01) more prolonged compared with that (785.3 +/- 206.2 seconds) after NS. The TRD (4,301.2 +/- 893.8 m) after DS treatment was also significantly (p < 0.01) longer than that (3,616.9 +/- 783.3 m) after NS. The changes in the VO2 during running, however, did not significantly (p > 0.05) differ between the pretreatments. The results demonstrated that the DS treatment improved the endurance performance of running at a velocity equivalent to 90% VO2max in well-trained male runners, although it did not change the RE. This running velocity is equivalent to that for a 3,000- or 5,000-m race. Our finding suggests that performing DS during warm up before a race is effective for improving performance. PMID- 25932985 TI - Effect of Swim Cap Surface Roughness on Passive Drag. AB - In the last decade, great attention has been given to the improvements in swimming performance that can be obtained by wearing "technical swimsuits"; the technological evolution of these materials only marginally involved swim caps production, even if several studies have pointed out the important role of the head (as main impact point with the fluid) on hydrodynamics. The aim of this study was to compare the effects on passive drag (Dp) of 3 swim cap models: a smooth silicon helmet cap (usually used during swimming competitions), a silicon helmet cap with "dimples," and a silicon helmet cap with "wrinkles." Experiments were performed on 10 swimmers who were towed underwater (at a depth of 60 cm) at 3 speeds (1.5, 1.7, and 1.9 m.s) and in 2 body positions: LA (arms above the swimmer's head) and SA (arms alongside the body). The Dp values obtained in each trial were divided by the square of the corresponding speed to obtain the speed specific drag (the k coefficient = Dp/v). No differences in k were observed among swim caps in the LA position. No differences in k were observed between the smooth and dimpled helmets also in the SA position; however, the wrinkled swim cap helmet showed a significant larger k (4.4%) in comparison with the model with dimples, when the swimmers kept their arms alongside the body (in the SA position). These data suggest that wearing a wrinkled swim cap helmet can be detrimental to performance at least in this specific position. PMID- 25932986 TI - Cross-Validation of Age-Predicted Maximal Heart Rate Equations Among Female Collegiate Athletes. AB - The purpose of this study was to determine the accuracy of 3 general and 2 female specific age-predicted maximal heart rate (HRmax) prediction equations in female collegiate athletes. Thirty female collegiate athletes (age = 21.5 +/- 1.9 years, height = 164.7 +/- 6.6 cm, weight = 61.3 +/- 8.2 kg) participated. HRmax was determined with a maximal graded exercise test and predicted with 3 general equations (Fox et al., Astrand, and Tanaka et al.) and 2 female-specific equations (Fairbarn et al. and Gulati et al.). There was no significant difference between observed HRmax (185.9 +/- 5.0 b.min) and the Fairbarn (187.5 +/- 1.2 b.min) and Gulati (187.1 +/- 1.7 b.min) equations (p = 0.11 and 0.23, respectively). The Fox (198.5 +/- 1.9 b.min), Astrand (198.1 +/- 1.6 b.min), and Tanaka (193.0 +/- 1.4 b.min) equations provided significantly higher estimates compared with observed HRmax (p < 0.001 for each). The standard error of the estimate was similar for all the prediction equations (between 5.0 and 5.4 b.min), but the total error was smallest for Fairbarn and Gulati (5.3 b.min for each) and largest for Fox and Astrand (13.9 and 13.3 b.min, respectively). The 95% limits of agreement of the mean error were similar for all of the prediction equations, with values varying between 9.9 and 10.5 b.min. Because of the wide limits of agreement displayed by each equation, the use of age-predicted methods for estimating HRmax in collegiate female athletes should be performed only with caution. PMID- 25932987 TI - Absence of Respiratory Muscle Fatigue in High-Intensity Continuous or Interval Cycling Exercise. AB - Respiratory muscle fatigue (RMF) occurs during prolonged exercise (~15-20 minutes) at >85% V[Combining Dot Above]O2max. However, RMF has been reported to occur in ~3-6 minutes in various modes of exercise at a high intensity. It is not known if continuous cycling exercise vs. repeated bouts of high-intensity interval training (HIT) at >85% V[Combining Dot Above]O2max will lead to RMF. We hypothesized that RMF would occur after a constant load test and would be present before end exercise in an HIT protocol. Eight moderately active healthy men (21.7 +/- 1.7 years; 181.3 +/- 5.2 cm; 81.3 +/- 2.3 kg) completed a V[Combining Dot Above]O2max test on a cycle ergometer. Subjects then completed 2 bouts of HIT (7 * 1 minute, 2-minute recovery between intervals) and 3 bouts of continuous exercise (CE) tests at 90% of peak power (determined from an incremental exercise test to exhaustion). Maximal inspiratory pressure (PIMAX) and expiratory pressure (PEMAX) were measured pre- and post-exercise for both HIT and CE and after each interval during HIT. Decreases in postexercise PIMAX and PEMAX compared with baseline were used to determine RMF. There were no differences (p > 0.05) in PIMAX or PEMAX pre- to post-exercise for HIT (PIMAX pre: 134 +/- 51, post: 135 +/ 50 cmH2O; PEMAX pre: 143 +/- 41, post: 148 +/- 46 cmH2O) or CE (PIMAX pre: 135 +/- 54, post: 133 +/- 52 cmH2O; PEMAX pre: 146 +/- 46, post: 148 +/- 46 cmH2O) indicating RMF was not present following CE and HIT. These data suggest that repeated high-intensity cycling exercise at 90% peak power in a CE or HIT protocol does not lead to RMF. PMID- 25932988 TI - Maximal Sprint Power in Road Cyclists After Variable and Nonvariable High Intensity Exercise. AB - This study compared the sprint performance of professional cyclists after 10 minutes of variable (VAR) or nonvariable (N-VAR) high-intensity cycling with sprint performance in a rested state. Ten internationally competitive male cyclists (mean +/- SD: age, 20.1 +/- 1.3 years; stature, 1.81 +/- 0.07 m; body weight, 69.5 +/- 4.9 kg; and V[Combining Dot Above]O2peak, 72.5 +/- 4.4 ml.kg.min) performed a 12-second maximal sprint in 3 conditions: (a) a rested state, (b) after 10 minutes of N-VAR cycling, and (c) after 10 minutes of VAR cycling. The intensity during the 10-minute efforts gradually increased to replicate power output observed in the final section of cycling road races. During the VAR cycling, participants performed short (2 seconds) accelerations at 80% of their sprint peak power, every 30 seconds. Average power output, cadence, and maximal heart rate (HR) during the 10-minute efforts were similar between conditions (5.3 +/- 0.2 W.kg, 102 +/- 1 rpm, and 93 +/- 3% HRmax). Postexercise blood lactate concentration and sessional perceived exertion were also similar (8.3 +/- 1.6 mmol.L, 15.4 +/- 1.3 [6-20 scale]). Peak and average power output and cadence during the subsequent maximal sprint were not different between the 3 experimental conditions (p > 0.05). In conclusion, this study showed that neither the VAR nor the N-VAR 10-minute efforts ridden in this study impaired sprint performance in elite competitive cyclists. PMID- 25932989 TI - The Limiting Joint During a Failed Squat: A Biomechanics Case Series. AB - This investigation examined the characteristics of a failed back squat. Subjects were instructed to perform 3 repetitions of a barbell squat with a 3 repetition maximum load while instrumented for biomechanical analyses and standing atop force platforms. Inverse dynamics calculations were used to determine the net joint moment (NJM) power, work, and energy of the hip, knee, and ankle. Five subjects failed to complete all 3 repetitions, allowing for comparisons between a successful and the failed repetition. Although the NJM power and work were lower at all 3 joints during the failed attempt, the only statistically significant differences were at the hip. These findings suggest that the energy generated by the hip joint NJM limited performance of the task. However, examination of the NJM energy generation over time on an individual basis uncovered some features that were masked by the aggregated group mean data. For some subjects, the knee NJM limited the movement. Additionally, negligible to modest compensations occurred between the hip and knee NJM: a decreased energy generated by one NJM was often accompanied by an increase in energy generated at the other. A limiting joint, or "weak link," may explain the failure to complete a lift. Interventions should address the limiting joint on an individual-specific basis and incorporate assistive exercises that target these deficiencies. PMID- 25932990 TI - Effect of Ankle Joint Contact Angle and Ground Contact Time on Depth Jump Performance. AB - Athletes often need to both jump high and get off the ground quickly, but getting off the ground quickly can decrease the vertical ground reaction force (VGRF) impulse, impeding jump height. Energy stored in the muscle-tendon complex during the stretch-shortening cycle (SSC) may mitigate the effects of short ground contact times (GCTs). To take advantage of the SSC, several coaches recommend "attacking" the ground with the foot in a dorsiflexed (DF) position at contact. However, the efficacy of this technique has not been tested. This investigation tested the hypotheses that shorter GCTs would lead to smaller vertical depth jump heights (VDJH), and that this difference could be mitigated by instructing the athletes to land in a DF as opposed to a plantar flexed (PF) foot position. Eighteen healthy junior college athletes performed depth jumps from a 45-cm box onto force platforms under instruction to achieve one of the 2 objectives (maximum jump height [hmax] or minimal GCT [tmin]), with one of the 2 foot conditions (DF or PF). These variations created 4 distinct jump conditions: DF hmax, DF-tmin, PF-hmax, and PF-tmin. For all variables examined, there were no significant interactions. For all 4 conditions, the ankle was PF during landing, but the DF condition was 28.87% less PF than the PF condition. The tmin conditions had a 23.48% shorter GCT than hmax. There were no significant main effects for jump height. The peak impact force for tmin was 22.14% greater than hmax and 19.11% greater for DF compared with PF conditions. A shorter GCT did not necessitate a smaller jump height, and a less PF foot did not lead to improvements in jump height or contact time during a depth jump from a 45-cm box. The same jump height was attained in less PF and shorter GCT conditions by larger impact forces. To decrease contact time while maintaining jump height, athletes should be instructed to "get off the ground as fast as possible." This cue seems to be more important than foot position. However, it should be acknowledged that this technique leads to larger impact forces, which should be considered when prescribing the number of foot contacts in a plyometrics program. The ability of athletes to truly land in a DF position during depth jumps is questioned and needs further investigation. PMID- 25932991 TI - Abstracts of the 63rd Annual Clinical and Scientific Meeting of the American College of Obstetricians and Gynecologists, May 2-6, 2015, San Francisco, CA. PMID- 25932993 TI - Negative pressure wound therapy for seroma prevention and surgical incision treatment in spinal fracture care. AB - To evaluate the clinical use and economic aspects of negative pressure wound therapy (NPWT) after dorsal stabilisation of spinal fractures. This study is a prospective randomised evaluation of NPWT in patients with large surgical wounds after surgical stabilisation of spinal fractures by internal fixation. Patients were randomised to either standard wound dressing treatment (group A) or NPWT (group B). The wound area was examined by ultrasound to measure seroma volumes in both groups on the 5th and 10th day after surgery. Furthermore, data on economic aspects such as nursing time for wound care and material used for wound dressing were evaluated. A total of 20 patients (10 in each group) were enrolled. Throughout the whole study, mean seroma volume was significantly higher in group A than that in group B (day 5: 1.9 ml versus 0 ml; P = 0.0007; day 10: 1.6 ml versus 0.5 ml; P <0.024). Furthermore, patients of group A required more wound care time (group A: 31 +/- 10 minutes; group B 13.8 +/- 6 minutes; P = 0.0005) and more number of compresses (total number; group A 35 +/- 15; group B 11 +/- 3; P = 0.0376). NPWT reduced the development of postoperative seroma, reduced nursing time and reduced material required for wound care. PMID- 25932992 TI - Telomere length and telomerase in a well-characterized sample of individuals with major depressive disorder compared to controls. AB - BACKGROUND: Leukocyte telomere length (LTL) is a marker of cellular turnover and oxidative stress. Studies suggest major depressive disorder (MDD) is associated with oxidative stress, but examinations of MDD and LTL have yielded mixed results, likely because of differences in measurement methods and unmeasured confounding. This study examined LTL and telomerase activity in 166 individuals with MDD compared to 166 age- and gender-matched matched controls free of any psychiatric disorder, using well-validated assays and clinical assessment methods, and controlling for a range of potential confounders. METHODS: Subjects aged 18 to 70 were evaluated by trained raters and provided blood for LTL and telomerase activity measurement. LTL was assayed using Southern blot and replicated with qPCR, and telomerase activity was assayed with a repeat amplification protocol using a commercial kit. RESULTS: There was no significant difference in telomere length for individuals with MDD [mean (SD)=9.1 (3.0)kbp] compared to controls [mean(SD)=8.9(2.5)kbp] measured by Southern blot (p=0.65) or by confirmatory qPCR (p=0.91) assays. Controlling for potential confounders did not alter the results. Telomerase activity did not differ by MDD diagnosis overall (p=0.40), but the effect of MDD was significantly modified by gender (t(299)=2.67, p=0.0079) even after controlling for potential confounders, with telomerase activity significantly greater only in males with MDD versus controls. CONCLUSION: Our well-characterized, well-powered examination of concurrently assessed telomere length and telomerase activity in individuals with clinically significant, chronic MDD and matched controls failed to provide strong evidence of an association of MDD with shorter LTL, while telomerase activity was higher in men with MDD [corrected]. PMID- 25932995 TI - A new schematic for poly(3-alkylthiophene) in an amorphous film studied using a novel structural index in infrared spectroscopy. AB - The molecular structure of poly(3-alkylthiophene-2,5-diyl) in an amorphous film reveals that the short axis of the thiophene ring is kept highly oriented parallel to the substrate, whereas the long axis along the polymer chain is largely disordered. This is unveiled by infrared p-polarized multiple-angle incidence resolution spectroscopy (pMAIRS), achieved by analyzing the orientation angles of three mutually orthogonal vibrational modes localized on the thiophene ring with the aid of a newly developed structural index. This new analytical technique is useful irrespective of the crystallinity of the thin film. As a result, the intrinsic chemical parameters controlling the molecular orientation are understood in a unified manner, and the reason that the hexyl group gives the best results for a photovoltaic cell is also revealed. PMID- 25932994 TI - One-Pot Parallel Synthesis of Alkyl Sulfides, Sulfoxides, and Sulfones. AB - A simple and cost-effective one-pot parallel synthesis approach to sulfides, sulfoxides, and sulfones from thiourea was elaborated. The method combines two procedures optimized to the parallel synthesis conditions: alkylation of thiourea with alkyl chlorides and mono or full oxidation of in situ generated sulfides with H2O2 or H2O2-(NH4)2MoO4. The experimental set up required commonly used lab equipment: conventional oven and ultrasonic bath; the work up includes filtration or extraction with chloroform. The method was evaluated on an 81 member library of drug-like sulfides, sulfoxides, and sulfones yielding the compounds on a 30 300 mg scale. A small-scale synthesis of 2-(benzhydrylsulfinyl)acetamide (modafinil) utilizing our approach resulted in similar efficiency to the published procedures. PMID- 25932996 TI - Coalescent-based species delimitation approach uncovers high cryptic diversity in the cosmopolitan lichen-forming fungal genus Protoparmelia (Lecanorales, Ascomycota). AB - Species recognition in lichen-forming fungi has been a challenge because of unsettled species concepts, few taxonomically relevant traits, and limitations of traditionally used morphological and chemical characters for identifying closely related species. Here we analyze species diversity in the cosmopolitan genus Protoparmelia s.l. The ~25 described species in this group occur across diverse habitats from the boreal-arctic/alpine to the tropics, but their relationship to each other remains unexplored. In this study, we inferred the phylogeny of 18 species currently assigned to this genus based on 160 specimens and six markers: mtSSU, nuLSU, ITS, RPB1, MCM7, and TSR1. We assessed the circumscription of species-level lineages in Protoparmelia s. str. using two coalescent-based species delimitation methods--BP&P and spedeSTEM. Our results suggest the presence of a tropical and an extra-tropical lineage, and eleven previously unrecognized distinct species-level lineages in Protoparmelia s. str. Several cryptic lineages were discovered as compared to phenotype-based species delimitation. Many of the putative species are supported by geographic evidence. PMID- 25932998 TI - A general method for computing the Homfly polynomial of DNA double crossover 3 regular links. AB - In the last 20 years or so, chemists and molecular biologists have synthesized some novel DNA polyhedra. Polyhedral links were introduced to model DNA polyhedra and study topological properties of DNA polyhedra. As a very powerful invariant of oriented links, the Homfly polynomial of some of such polyhedral links with small number of crossings has been obtained. However, it is a challenge to compute Homfly polynomials of polyhedral links with large number of crossings such as double crossover 3-regular links considered here. In this paper, a general method is given for computing the chain polynomial of the truncated cubic graph with two different labels from the chain polynomial of the original labeled cubic graph by substitutions. As a result, we can obtain the Homfly polynomial of the double crossover 3-regular link which has relatively large number of crossings. PMID- 25932997 TI - Phenotyping asthma, rhinitis and eczema in MeDALL population-based birth cohorts: an allergic comorbidity cluster. AB - BACKGROUND: Asthma, rhinitis and eczema often co-occur in children, but their interrelationships at the population level have been poorly addressed. We assessed co-occurrence of childhood asthma, rhinitis and eczema using unsupervised statistical techniques. METHODS: We included 17 209 children at 4 years and 14 585 at 8 years from seven European population-based birth cohorts (MeDALL project). At each age period, children were grouped, using partitioning cluster analysis, according to the distribution of 23 variables covering symptoms 'ever' and 'in the last 12 months', doctor diagnosis, age of onset and treatments of asthma, rhinitis and eczema; immunoglobulin E sensitization; weight; and height. We tested the sensitivity of our estimates to subject and variable selections, and to different statistical approaches, including latent class analysis and self-organizing maps. RESULTS: Two groups were identified as the optimal way to cluster the data at both age periods and in all sensitivity analyses. The first (reference) group at 4 and 8 years (including 70% and 79% of children, respectively) was characterized by a low prevalence of symptoms and sensitization, whereas the second (symptomatic) group exhibited more frequent symptoms and sensitization. Ninety-nine percentage of children with comorbidities (co-occurrence of asthma, rhinitis and/or eczema) were included in the symptomatic group at both ages. The children's characteristics in both groups were consistent in all sensitivity analyses. CONCLUSION: At 4 and 8 years, at the population level, asthma, rhinitis and eczema can be classified together as an allergic comorbidity cluster. Future research including time-repeated assessments and biological data will help understanding the interrelationships between these diseases. PMID- 25933000 TI - Correction: Dynamic adjustment of stimuli in real time functional magnetic resonance imaging. PMID- 25932999 TI - Plasma free hemoglobin and microcirculatory response to fresh or old blood transfusions in sepsis. AB - BACKGROUND: Free hemoglobin (fHb) may induce vasoconstriction by scavenging nitric oxide. It may increase in older blood units due to storage lesions. This study evaluated whether old red blood cell transfusion increases plasma fHb in sepsis and how the microvascular response may be affected. METHODS: This is a secondary analysis of a randomized study. Twenty adult septic patients received either fresh or old (<10 or >15 days storage, respectively) RBC transfusions. fHb was measured in RBC units and in the plasma before and 1 hour after transfusion. Simultaneously, the sublingual microcirculation was assessed with sidestream-dark field imaging. The perfused boundary region was calculated as an index of glycocalyx damage. Tissue oxygen saturation (StO2) and Hb index (THI) were measured with near-infrared spectroscopy and a vascular occlusion test was performed. RESULTS: Similar fHb levels were found in the supernatant of fresh and old RBC units. Despite this, plasma fHb increased in the old RBC group after transfusion (from 0.125 [0.098-0.219] mg/mL to 0.238 [0.163-0.369] mg/mL, p = 0.006). The sublingual microcirculation was unaltered in both groups, while THI increased. The change in plasma fHb was inversely correlated with the changes in total vessel density (r = -0.57 [95% confidence interval -0.82, -0.16], p = 0.008), De Backer score (r = -0.63 [95% confidence interval -0.84, -0.25], p = 0.003) and THI (r = -0.72 [95% confidence interval -0.88, -0.39], p = 0.0003). CONCLUSIONS: Old RBC transfusion was associated with an increase in plasma fHb in septic patients. Increasing plasma fHb levels were associated with decreased microvascular density. TRIAL REGISTRATION: ClinicalTrials.gov NCT01584999. PMID- 25933001 TI - P. falciparum and P. vivax Epitope-Focused VLPs Elicit Sterile Immunity to Blood Stage Infections. AB - In order to design P. falciparum preerythrocytic vaccine candidates, a library of circumsporozoite (CS) T and B cell epitopes displayed on the woodchuck hepatitis virus core antigen (WHcAg) VLP platform was produced. To test the protective efficacy of the WHcAg-CS VLPs, hybrid CS P. berghei/P. falciparum (Pb/Pf) sporozoites were used to challenge immunized mice. VLPs carrying 1 or 2 different CS repeat B cell epitopes and 3 VLPs carrying different CS non-repeat B cell epitopes elicited high levels of anti-insert antibodies (Abs). Whereas, VLPs carrying CS repeat B cell epitopes conferred 98% protection of the liver against a 10,000 Pb/Pf sporozoite challenge, VLPs carrying the CS non-repeat B cell eptiopes were minimally-to-non-protective. One-to-three CS-specific CD4/CD8 T cell sites were also fused to VLPs, which primed CS-specific as well as WHcAg specific T cells. However, a VLP carrying only the 3 T cell domains failed to protect against a sporozoite challenge, indicating a requirement for anti-CS repeat Abs. A VLP carrying 2 CS repeat B cell epitopes and 3 CS T cell sites in alum adjuvant elicited high titer anti-CS Abs (endpoint dilution titer >1x10(6)) and provided 80-100% protection against blood stage malaria. Using a similar strategy, VLPs were constructed carrying P. vivax CS repeat B cell epitopes (WHc Pv-78), which elicited high levels of anti-CS Abs and conferred 99% protection of the liver against a 10,000 Pb/Pv sporozoite challenge and elicited sterile immunity to blood stage infection. These results indicate that immunization with epitope-focused VLPs carrying selected B and T cell epitopes from the P. falciparum and P. vivax CS proteins can elicit sterile immunity against blood stage malaria. Hybrid WHcAg-CS VLPs could provide the basis for a bivalent P. falciparum/P. vivax malaria vaccine. PMID- 25933002 TI - Patients covertly recording clinical encounters: threat or opportunity? A qualitative analysis of online texts. AB - BACKGROUND: The phenomenon of patients covertly recording clinical encounters has generated controversial media reports. This study aims to examine the phenomenon and analyze the underlying issues. METHODS AND FINDINGS: We conducted a qualitative analysis of online posts, articles, blogs, and forums (texts) discussing patients covertly recording clinical encounters. Using Google and Google Blog search engines, we identified and analyzed 62 eligible texts published in multiple countries between 2006 and 2013. Thematic analysis revealed four key themes: 1) a new behavior that elicits strong reactions, both positive and negative, 2) an erosion of trust, 3) shifting patient-clinician roles and relationships, and 4) the existence of confused and conflicting responses. When patients covertly record clinical encounters - a behavior made possible by various digital recording technologies - strong reactions are evoked among a range of stakeholders. The behavior represents one consequence of an erosion of trust between patients and clinicians, and when discovered, leads to further deterioration of trust. Confused and conflicting responses to the phenomenon by patients and clinicians highlight the need for policy guidance. CONCLUSIONS: This study describes strong reactions, both positive and negative, to the phenomenon of patients covertly recording clinical encounters. The availability of smartphones capable of digital recording, and shifting attitudes to patient clinician relationships, seems to have led to this behavior, mostly viewed as a threat by clinicians but as a welcome and helpful innovation by some patients, possibly indicating a perception of subordination and a lack of empowerment. Further examination of this tension and its implications is needed. PMID- 25933003 TI - Digital Microfluidic Dynamic Culture of Mammalian Embryos on an Electrowetting on Dielectric (EWOD) Chip. AB - Current human fertilization in vitro (IVF) bypasses the female oviduct and manually inseminates, fertilizes and cultivates embryos in a static microdrop containing appropriate chemical compounds. A microfluidic microchannel system for IVF is considered to provide an improved in-vivo-mimicking environment to enhance the development in a culture system for an embryo before implantation. We demonstrate a novel digitalized microfluidic device powered with electrowetting on a dielectric (EWOD) to culture an embryo in vitro in a single droplet in a microfluidic environment to mimic the environment in vivo for development of the embryo and to culture the embryos with good development and live births. Our results show that the dynamic culture powered with EWOD can manipulate a single droplet containing one mouse embryo and culture to the blastocyst stage. The rate of embryo cleavage to a hatching blastocyst with a dynamic culture is significantly greater than that with a traditional static culture (p<0.05). The EWOD chip enhances the culture of mouse embryos in a dynamic environment. To test the reproductive outcome of the embryos collected from an EWOD chip as a culture system, we transferred embryos to pseudo-pregnant female mice and produced live births. These results demonstrate that an EWOD-based microfluidic device is capable of culturing mammalian embryos in a microfluidic biological manner, presaging future clinical application. PMID- 25933004 TI - Efavirenz-Based Regimens in Antiretroviral-Naive HIV-Infected Patients: A Systematic Review and Meta-Analysis of Randomized Controlled Trials. AB - Efavirenz, a non-nucleoside reverse-transcriptase inhibitor (NNRTI) is one of the most commonly prescribed antiretroviral drugs. The present article provides a systematic overview and meta-analysis of clinical trials comparing efavirenz and other active drugs currently recommended for treatment of HIV-infected, antiretroviral-naive patients. Electronic databases (Pubmed, Embase, the Cochrane Library, Trip Database) were searched up till 23 December 2013 for randomized controlled clinical trials published as a peer-reviewed papers, and concerning efavirenz-based regimens used as initial treatment for HIV infection. Thirty-four studies were included in the systematic review, while twenty-six trials were suitable for the meta-analysis. Efavirenz was compared with drugs from four different classes: NNRTIs other than efavirenz (nevirapine or rilpivirine), integrase strand transfer inhibitors (InSTIs), ritonavir-boosted protease inhibitors (bPI) and chemokine (C-C motif) receptor 5 (CCR5) antagonists (maraviroc), all of them were added to the background regimen. Results of the current meta-analysis showed that efavirenz-based regimens were equally effective as other recommended regimens based on NNRTI, ritonavir-boosted PI or CCR5 antagonist in terms of efficacy outcomes (disease progression and/or death, plasma viral HIV RNA <50 copies/ml) while statistically significant more patients treated with InSTI achieved plasma viral load <50 copies/ml at week 48. In comparison with both InSTI-based and CCR5-based therapy, efavirenz-based treatment was associated with a higher risk of therapy discontinuation due to adverse events. However, comparisons of efevirenz-based treatment with InSTI based and CCR5-based therapy were based on a limited number of trials, therefore, conclusions from these two comparisons must be confirmed in further reliable randomized controlled studies. Results of our meta-analysis support the present clinical guidelines for antiretroviral-naive, HIV-infected patients, in which efavirenz is one of the most preferred regimens in the analyzed population. Beneficial safety profile of InSTI-based and CCR5-based therapy over efavirenz based treatment needs further studies. PMID- 25933005 TI - An Unexpected Mode Of Binding Defines BMS948 as A Full Retinoic Acid Receptor beta (RARbeta, NR1B2) Selective Agonist. AB - Retinoic acid is an important regulator of cell differentiation which plays major roles in embryonic development and tissue remodeling. The biological action of retinoic acid is mediated by three nuclear receptors denoted RARalpha, beta and gamma. Multiple studies support that RARbeta possesses functional characteristics of a tumor suppressor and indeed, its expression is frequently lost in neoplastic tissues. However, it has been recently reported that RARbeta could also play a role in mammary gland tumorigenesis, thus demonstrating the important but yet incompletely understood function of this receptor in cancer development. As a consequence, there is a great need for RARbeta-selective agonists and antagonists as tools to facilitate the pharmacological analysis of this protein in vitro and in vivo as well as for potential therapeutic interventions. Here we provide experimental evidences that the novel synthetic retinoid BMS948 is an RARbeta selective ligand exhibiting a full transcriptional agonistic activity and activating RARbeta as efficiently as the reference agonist TTNPB. In addition, we solved the crystal structures of the RARbeta ligand-binding domain in complex with BMS948 and two related compounds, BMS641 and BMS411. These structures provided a rationale to explain how a single retinoid can be at the same time an RARalpha antagonist and an RARbeta full agonist, and revealed the structural basis of partial agonism. Finally, in addition to revealing that a flip by 180 degrees of the amide linker, that usually confers RARalpha selectivity, accounts for the RARbeta selectivity of BMS948, the structural analysis uncovers guidelines for the rational design of RARbeta-selective antagonists. PMID- 25933006 TI - Copy Number Variation at the APOL1 Locus. AB - Two coding variants in the APOL1 gene (G1 and G2) explain most of the high rate of kidney disease in African Americans. APOL1-associated kidney disease risk inheritance follows an autosomal recessive pattern: The relative risk of kidney disease associated with inheritance of two high-risk variants is 7-30 fold, depending on the specific kidney phenotype. We wished to determine if the variability in phenotype might in part reflect structural differences in APOL1 gene. We analyzed sequence coverage from 1000 Genomes Project Phase 3 samples as well as exome sequencing data from African American kidney disease cases for copy number variation. 8 samples sequenced in the 1000 Genomes Project showed increased coverage over a ~100kb region that includes APOL2, APOL1 and part of MYH9, suggesting the presence of APOL1 copy number greater than 2. We reasoned that such duplications should be enriched in apparent G1 heterozygotes with kidney disease. Using a PCR-based assay, we observed the presence of this duplication in additional samples from apparent G0G1 or G0G2 individuals. The frequency of this APOL1 duplication was compared among cases (n = 123) and controls (n = 255) with apparent G0G1 heterozygosity. The presence of APOL1 duplication was observed in 4.06% of cases and 0.78% controls, preliminary evidence that this APOL1 duplication may alter susceptibility to kidney disease (p = 0.03). Taqman-based copy number assays confirmed the presence of 3 APOL1 copies in individuals positive for this specific duplication by PCR assay, but also identified a small number of individuals with additional APOL1 copies of presumably different structure. These observations motivate further studies to better assess the contribution of APOL1 copy number on kidney disease risk and on APOL1 function. Investigators and clinicians genotyping APOL1 should also consider whether the particular genotyping platform used is subject to technical errors when more than two copies of APOL1 are present. PMID- 25933007 TI - Ambient air pollution and depressive symptoms in older adults. PMID- 25933008 TI - Interpregnancy intervals in the United States: data from the birth certificate and the national survey of family growth. AB - To describe data on interpregnancy intervals (IPI), defined as the timing between a live birth and conception of a subsequent live birth, from a subset of jurisdictions that adopted the 2003 revised birth certificate. Because this information is available among revised jurisdictions only, the national representativeness of IPI and related patterns to the entire United States were assessed using the 2006-2010 National Survey of Family Growth (NSFG). PMID- 25933009 TI - More than cosmetic changes: taking stock of personal care product safety. PMID- 25933010 TI - Correction: multicolor whole-cell bacterial sensing using a synchronous fluorescence spectroscopy-based approach. PMID- 25933011 TI - Sharing our lessons learned. PMID- 25933012 TI - Adoption of oral health curriculum by physician assistant education programs in 2014. AB - PURPOSE: The purpose of the study was to describe inclusion of didactic and clinical instruction in oral health in physician assistant (PA) education programs in 2014. A previous study in 2008 found that PA education program directors generally understood the importance of teaching about the linkage of oral health with systemic health; yet, few programs had actually integrated oral health instruction into the PA curriculum. This study was undertaken to ascertain the number of PA programs teaching oral health topics and to evaluate the content of instruction and implementation strategies. METHODS: The study used a Web-based survey using a skip logic design that branched respondents based on inclusion or the absence of an oral health curriculum in the PA education program. The questions included predefined response options with the opportunity for narrative responses and comments. Analysis of survey data was completed using SPSS (IBM) and SAS (SAS Institute, Inc) and consisted mainly of frequencies and cross tabulations. RESULTS: There was greater inclusion of oral health curriculum in 2014 than in 2008 with most PA programs now providing didactic and clinical training in oral health. Stakeholders' efforts to engage PA program faculty with integration of oral health subject matter into core curriculum have resulted in wider availability of training for PA students in oral health promotion and prevention services. CONCLUSIONS: Efforts to equip PA faculty to teach oral health topics and clinical skills should continue as past efforts have resulted in wider integration of oral health subject matter into core PA curriculum. PMID- 25933013 TI - A multi-institutional study using simulation to teach cardiopulmonary physical examination and diagnosis skills to physician assistant students. AB - PURPOSE: Research demonstrates limitations in the ability of health care trainees/practitioners, including physician assistants (PAs), to identify important cardiopulmonary examination findings and diagnose corresponding conditions. Studies also show that simulation-based training leads to improved performance and that these skills can transfer to real patients. This study evaluated the effectiveness of a newly developed curriculum incorporating simulation with deliberate practice for teaching cardiopulmonary physical examination/bedside diagnosis skills in the PA population. METHODS: This multi institutional study used a pretest/posttest design. Participants, PA students from 4 different programs, received a standardized curriculum including instructor-led activities interspersed among small-group/independent self-study time. Didactic sessions and independent study featured practice with the "Harvey" simulator and use of specially developed computer-based multimedia tutorials. Preintervention: participants completed demographic questionnaires, rated self confidence, and underwent baseline evaluation of knowledge and cardiopulmonary physical examination skills. Students logged self-study time using various learning resources. Postintervention: students again rated self-confidence and underwent repeat cognitive/performance testing using equivalent written/simulator based assessments. RESULTS: Physician assistant students (N = 56) demonstrated significant gains in knowledge, cardiac examination technique, recognition of total cardiac findings, identification of key auscultatory findings (extra heart sounds, systolic/diastolic murmurs), and the ability to make correct diagnoses. Learner self-confidence also improved significantly. CONCLUSIONS: This study demonstrated the effectiveness of a simulation-based curriculum for teaching essential physical examination/bedside diagnosis skills to PA students. Its results reinforce those of similar/previous research, which suggest that simulation-based training is most effective under certain educational conditions. Future research will include subgroup analyses/correlation of other variables to explore best features/uses of simulation technology for training PAs. PMID- 25933014 TI - Education of military veterans in physician assistant programs. AB - PURPOSE: To assess the admission policies, experiences, and attitudes of physician assistant (PA) program directors regarding recruiting, admitting, and training military veterans after the announcement of the "Helping Veterans Become Physician Assistants" initiative. METHODS: A descriptive survey of 22 questions was distributed to all 173 PA program directors in the United States in April 2013. The survey covered years 2011 to 2013, although it was completed in June of 2013. The results of the survey were compared with the results of a similar survey that covered years 2008 through 2010. RESULTS: One hundred and five (60.7%) program directors participated in this survey. Veterans were admitted into 88.1% of responding programs and accounted for an average of 4.0% of all students. One-third of programs (33%) accepted transfer credits for veterans' military training, and 20% accepted credits for off-duty education. One-third (33%) of programs participated in the Yellow Ribbon Program. Almost 60% of programs had military veteran faculty members. Active recruitment of military veteran students occurred in 31.2% of programs. Program directors described multiple benefits of, and barriers to, admitting and educating veterans. CONCLUSIONS: For the years 2011 through 2013, as compared to 2008 through 2010, there was an increase in the percentage of PA programs that actively recruited veterans, considered veteran status in the admission process, admitted veterans, and contributed to their financial support. There was also an increased percentage of students with military experience matriculating into PA programs. However, barriers still exist for veterans seeking admission into PA programs, the most significant of which is academic preparedness for a graduate-level PA program. PMID- 25933015 TI - What the IOM Report on Graduate Medical Education Means for Physician Assistants. AB - Graduate medical education (GME) is funded by taxpayers through Medicare subsidies that pay for physician residency training, primarily to teaching hospitals. The Institute of Medicine (IOM) recently conducted a study of US GME and issued a series of recommendations for future policy reform. This commentary examines the major elements of proposed reforms for GME and offers analysis of those that may pertain specifically to physician assistant education now and in the future. PMID- 25933016 TI - The looking glass: using reflective writing in medical education. PMID- 25933017 TI - A call for transformation in physician assistant education. PMID- 25933018 TI - Of professionals and potted plants: the case of Marlise Munoz. PMID- 25933019 TI - From clinical practice to academia. PMID- 25933021 TI - Acidosis Mediates the Switching of Gs-PKA and Gi-PKCepsilon Dependence in Prolonged Hyperalgesia Induced by Inflammation. AB - Chronic inflammatory pain, when not effectively treated, is a costly health problem and has a harmful effect on all aspects of health-related quality of life. Previous studies suggested that in male Sprague Dawley rats, prostaglandin E2 (PGE2)-induced short-term hyperalgesia depends on protein kinase A (PKA) activity, whereas long-lasting hyperalgesia induced by PGE2 with carrageenan pre injection, requires protein kinase Cepsilon (PKCepsilon). However, the mechanism underlying the kinase switch with short- to long-term hyperalgesia remains unclear. In this study, we used the inflammatory agents carrageenan or complete Freund's adjuvant (CFA) to induce long-term hyperalgesia, and examined PKA and PKCepsilon dependence and switching time. Hyperalgesia induced by both agents depended on PKA/PKCepsilon and Gs/Gi-proteins, and the switching time from PKA to PKCepsilon and from Gs to Gi was about 3 to 4 h after inflammation induction. Among the single inflammatory mediators tested, PGE2 and 5-HT induced transient hyperalgesia, which depended on PKA and PKCepsilon, respectively. Only acidic solution-induced hyperalgesia required Gs-PKA and Gi-PKCepsilon, and the switch time for kinase dependency matched inflammatory hyperalgesia, in approximately 2 to 4 h. Thus, acidosis in inflamed tissues may be a decisive factor to regulate switching of PKA and PKCepsilon dependence via proton-sensing G-protein-coupled receptors. PMID- 25933020 TI - Passive immunization with phospho-tau antibodies reduces tau pathology and functional deficits in two distinct mouse tauopathy models. AB - In Alzheimer's disease (AD), an extensive accumulation of extracellular amyloid plaques and intraneuronal tau tangles, along with neuronal loss, is evident in distinct brain regions. Staging of tau pathology by postmortem analysis of AD subjects suggests a sequence of initiation and subsequent spread of neurofibrillary tau tangles along defined brain anatomical pathways. Further, the severity of cognitive deficits correlates with the degree and extent of tau pathology. In this study, we demonstrate that phospho-tau (p-tau) antibodies, PHF6 and PHF13, can prevent the induction of tau pathology in primary neuron cultures. The impact of passive immunotherapy on the formation and spread of tau pathology, as well as functional deficits, was subsequently evaluated with these antibodies in two distinct transgenic mouse tauopathy models. The rTg4510 transgenic mouse is characterized by inducible over-expression of P301L mutant tau, and exhibits robust age-dependent brain tau pathology. Systemic treatment with PHF6 and PHF13 from 3 to 6 months of age led to a significant decline in brain and CSF p-tau levels. In a second model, injection of preformed tau fibrils (PFFs) comprised of recombinant tau protein encompassing the microtubule-repeat domains into the cortex and hippocampus of young P301S mutant tau over-expressing mice (PS19) led to robust tau pathology on the ipsilateral side with evidence of spread to distant sites, including the contralateral hippocampus and bilateral entorhinal cortex 4 weeks post-injection. Systemic treatment with PHF13 led to a significant decline in the spread of tau pathology in this model. The reduction in tau species after p-tau antibody treatment was associated with an improvement in novel-object recognition memory test in both models. These studies provide evidence supporting the use of tau immunotherapy as a potential treatment option for AD and other tauopathies. PMID- 25933022 TI - The Mycobacterium tuberculosis ClpP1P2 Protease Interacts Asymmetrically with Its ATPase Partners ClpX and ClpC1. AB - Clp chaperone-proteases are cylindrical complexes built from ATP-dependent chaperonerings that stack onto a proteolytic ClpP double-ring core to carry out substrate protein degradation.Interaction of the ClpP particle with the chaperone is mediated by an N-terminal loop and a hydrophobic surface patch on the ClpP ring surface. In contrast to E. coli, Myco bacterium tuberculosis harbors not only one but two ClpP protease subunits, ClpP1 and ClpP2,and a homo-heptameric ring of each assembles to form the ClpP1P2 double-ring core. Consequently,this hetero double-ring presents two different potential binding surfaces for the interaction with the chaperones ClpX and ClpC1. To investigate whether ClpX or ClpC1 might preferentially interact with one or the other double-ring face, we mutated the hydrophobicchaperone-interaction patch on either ClpP1 or ClpP2, generating ClpP1P2 particles that are defective in one of the two binding patches and thereby in their ability to interact with their chaperone partners. Using chaperone-mediated degradation of ssrA-tagged model substrates, we show that both Mycobacterium tuberculosis Clp chaperones require the intact interaction face of ClpP2 to support degradation, resulting in an asymmetric complex where chaperones only bind to the ClpP2 side of the proteolytic core. This sets the Clpproteases of Mycobacterium tuberculosis, and probably other Actinobacteria, apart from the well-studied E. coli system, where chaperones bind to both sides of the protease core,and it frees the ClpP1 interaction interface for putative new binding partners [corrected]. PMID- 25933023 TI - Systematic Review: Representativeness of Participants in RCTs of Acetylcholinesterase Inhibitors. AB - OBJECTIVE: To determine whether there are differences in age and sex distribution and presence of comorbidities between participants included in randomized controlled trials of acetylcholinesterase inhibitors and nationwide cohort of persons with Alzheimer's disease. METHODS: PubMed, Scopus and Cochrane Library databases were searched for original articles from their inception to January 4, 2015. Double-blind randomized controlled trials with donepezil, rivastigmine or galantamine compared to placebo in participants with Alzheimer's disease were included. Data from a nationwide cohort of persons with clinically verified diagnoses of Alzheimer's disease was defined as a reference population. RESULTS: 128 full-text articles were assessed for eligibility, 31 of them fulfilled criteria. Mean age of participants in randomized controlled trials (n = 15,032) was 5.8 years lower (95% CI 5.7 to 5.9, P < 0.001), compared to the mean age of 79.7 years in the reference population with Alzheimer's disease (n = 28,093). Most of the articles did not report age distribution of participants. The proportion of women was 63.2% (9,475/14,991) in randomized controlled trials and 67.8% (19,043/28,093) (P < 0.001) in the reference population. Information on comorbidities and use of concomitant drugs were lacking or poorly reported in most articles. CONCLUSIONS: There is a discrepancy between participants in randomized controlled trials of acetylcholinesterase inhibitors and real-life population with Alzheimer's disease. Participants in randomized controlled trials were significantly younger. Further, more detailed reporting of age distribution, comorbidities and concomitant drugs would be important information for clinicians when evaluating conclusions from randomized controlled trials to real-life practice. The existing recommendations of inclusion of older people should be followed to ensure safe pharmacotherapy for older people. PMID- 25933024 TI - Correction: bubble-induced cave collapse. PMID- 25933025 TI - Network-based Phenome-Genome Association Prediction by Bi-Random Walk. AB - MOTIVATION: The availability of ontologies and systematic documentations of phenotypes and their genetic associations has enabled large-scale network-based global analyses of the association between the complete collection of phenotypes (phenome) and genes. To provide a fundamental understanding of how the network information is relevant to phenotype-gene associations, we analyze the circular bigraphs (CBGs) in OMIM human disease phenotype-gene association network and MGI mouse phentoype-gene association network, and introduce a bi-random walk (BiRW) algorithm to capture the CBG patterns in the networks for unveiling human and mouse phenome-genome association. BiRW performs separate random walk simultaneously on gene interaction network and phenotype similarity network to explore gene paths and phenotype paths in CBGs of different sizes to summarize their associations as predictions. RESULTS: The analysis of both OMIM and MGI associations revealed that majority of the phenotype-gene associations are covered by CBG patterns of small path lengths, and there is a clear correlation between the CBG coverage and the predictability of the phenotype-gene associations. In the experiments on recovering known associations in cross validations on human disease phenotypes and mouse phenotypes, BiRW effectively improved prediction performance over the compared methods. The constructed global human disease phenome-genome association map also revealed interesting new predictions and phenotype-gene modules by disease classes. PMID- 25933026 TI - Exposure to organic solvents used in dry cleaning reduces low and high level visual function. AB - PURPOSE: To investigate whether exposure to occupational levels of organic solvents in the dry cleaning industry is associated with neurotoxic symptoms and visual deficits in the perception of basic visual features such as luminance contrast and colour, higher level processing of global motion and form (Experiment 1), and cognitive function as measured in a visual search task (Experiment 2). METHODS: The Q16 neurotoxic questionnaire, a commonly used measure of neurotoxicity (by the World Health Organization), was administered to assess the neurotoxic status of a group of 33 dry cleaners exposed to occupational levels of organic solvents (OS) and 35 age-matched non dry-cleaners who had never worked in the dry cleaning industry. In Experiment 1, to assess visual function, contrast sensitivity, colour/hue discrimination (Munsell Hue 100 test), global motion and form thresholds were assessed using computerised psychophysical tests. Sensitivity to global motion or form structure was quantified by varying the pattern coherence of global dot motion (GDM) and Glass pattern (oriented dot pairs) respectively (i.e., the percentage of dots/dot pairs that contribute to the perception of global structure). In Experiment 2, a letter visual-search task was used to measure reaction times (as a function of the number of elements: 4, 8, 16, 32, 64 and 100) in both parallel and serial search conditions. RESULTS: Dry cleaners exposed to organic solvents had significantly higher scores on the Q16 compared to non dry-cleaners indicating that dry cleaners experienced more neurotoxic symptoms on average. The contrast sensitivity function for dry cleaners was significantly lower at all spatial frequencies relative to non dry-cleaners, which is consistent with previous studies. Poorer colour discrimination performance was also noted in dry cleaners than non dry-cleaners, particularly along the blue/yellow axis. In a new finding, we report that global form and motion thresholds for dry cleaners were also significantly higher and almost double than that obtained from non dry-cleaners. However, reaction time performance on both parallel and serial visual search was not different between dry cleaners and non dry-cleaners. CONCLUSIONS: Exposure to occupational levels of organic solvents is associated with neurotoxicity which is in turn associated with both low level deficits (such as the perception of contrast and discrimination of colour) and high level visual deficits such as the perception of global form and motion, but not visual search performance. The latter finding indicates that the deficits in visual function are unlikely to be due to changes in general cognitive performance. PMID- 25933027 TI - Inhibition of Ovarian Epithelial Carcinoma Tumorigenesis and Progression by microRNA 106b Mediated through the RhoC Pathway. AB - Epithelial ovarian cancer (EOC) is the most lethal of the gynecological malignancies. Exploring the molecular mechanisms and major factors of invasion and metastasis could have great significance for the treatment and prognosis of EOC. Studies have demonstrated that microRNA 106b (miR-106b) may be a promising therapeutic target for inhibiting breast cancer bone metastasis, but the role of miR-106b in EOC is largely unknown. In this work, miRNA-106b expression was quantified in various ovarian tissues and tumors. Ovarian carcinoma cell lines were transfected with miR-106b, after which, cell phenotype and expression of relevant molecules was assayed. Dual-luciferase reporter assays and xenograft mouse models were also used to investigate miR-106b and its target gene. MiR-106b mRNA expression was found to be significantly higher in normal ovarian tissues and benign tumors than in ovarian carcinomas and borderline tumors (p < 0.01), and was negatively associated with differentiation (Well vs. Por & Mod) and the International Federation of Gynecology and Obstetrics (FIGO) staging (stage I/II vs. stage III/IV) in ovarian carcinoma (p < 0.05). MiR-106b transfection reduced cell proliferation; promoted G1 or S arrest and apoptosis (p < 0.05); suppressed cell migration and invasion (p < 0.05); reduced Ras homolog gene family member C (RhoC), P70 ribosomal S6 kinase (P70S6K), Bcl-xL, Matrix metallopeptidase 2 (MMP2), MMP9 mRNA and protein expression; and induced p53 expression (p < 0.05). Dual-luciferase reporter assays indicated that miR-106b directly targets RhoC by binding its 3'UTR. MiR-106b transfection also suppressed tumor development and RhoC expression in vivo in xenograft mouse models. This is the first demonstration that miR-106b may inhibit tumorigenesis and progression of EOC by targeting RhoC. The involvement of miR-106b-mediated RhoC downregulation in EOC aggression may give extended insights into molecular mechanisms underlying cancer aggression. Approaches aimed at overexpressing miR-106b may serve as promising therapeutic strategies for treating EOC patients. PMID- 25933028 TI - Clinical influence of early follow-up glycosylated hemoglobin levels on cardiovascular outcomes in diabetic patients with ST-segment elevation myocardial infarction after coronary reperfusion. AB - OBJECTIVE: Recent studies have shown continuous control of diabetes is important for favorable outcomes in patients with ST-segment elevation myocardial infarction (STEMI). This study aimed to evaluate the clinical influence of postprocedural glycosylated hemoglobin A1c (HbA1c) levels on major adverse cardiac events (MACE) in diabetic patients with STEMI after coronary reperfusion. PATIENTS AND METHODS: A total of 303 patients with diabetes and STEMI undergoing a primary percutaneous coronary intervention were enrolled in this study. All eligible patients were divided into the following three groups on the basis of follow-up HbA1c (FU-HbA1c) levels, which were measured at a median of 85 days after the procedure: optimal, FU-HbA1c<7%; suboptimal, 7%<=FU-HbA1c<9%; and poor, FU-HbA1c>=9%. We analyzed the 12-month cumulative MACE, defined as mortality, nonfatal myocardial infarction, and revascularization. In addition, we investigated FU-HbA1c levels as a predictor of MACE. RESULTS: The incidence rates of MACE differed significantly between groups (6.4 vs. 13.6 vs. 19.6%; P=0.048). Moreover, the risk was increased in each successive group (hazard ratio: 1.00 vs. 2.19 vs. 3.68; P=0.046). Each 1% increase in the FU-HbA1c level posed a 26.6% relative increased risk of MACE (P=0.031). The optimal cutoff value for FU-HbA1c in predicting MACE was 7.45%. CONCLUSION: This study showed that higher levels of early FU-HbA1c after reperfusion in diabetic patients with STEMI were associated with increased 12-month MACE, suggesting continuous serum glucose level control even after reperfusion is important for a better outcome. FU-HbA1c seems to be a useful marker for predicting clinical outcome. PMID- 25933029 TI - Inhibition of microglial activity alters spinal wide dynamic range neuron discharge and reduces microglial Toll-like receptor 4 expression in neuropathic rats. AB - It is believed that neuropathic pain results from aberrant neuronal discharges although some evidence suggests that the activation of glia cells contributes to pain after an injury to the nervous system. This study aimed to evaluate the role of microglial activation on the hyper-responsiveness of wide dynamic range neurons (WDR) and Toll-like receptor 4 (TLR4) expressions in a chronic constriction injury (CCI) model of neuropathic pain in rats. Adult male Wistar rats (230 +/- 30 g) underwent surgery for induction of CCI neuropathy. Six days after surgery, administration of minocycline (10, 20, and 40 mg/kg, i.p.) was initiated and continued until day 14. After administration of the last dose of minocycline or saline, a behavioral test was conducted, then animals were sacrificed and lumbar segments of the spinal cord were collected for Western blot analysis of TLR4 expression. The electrophysiological properties of WDR neurons were investigated by single unit recordings in separate groups. The findings showed that after CCI, in parallel with thermal hyperalgesia, the expression of TLR4 in the spinal cord and the evoked response of the WDR neurons to electrical, mechanical, and thermal stimulation significantly increased. Post-injury administration of minocycline effectively decreased thermal hyperalgesia, TLR4 expression, and hyper-responsiveness of WDR neurons in CCI rats. The results of this study indicate that post-injury, repeated administration of minocycline attenuated neuropathic pain by suppressing microglia activation and reducing WDR neuron hyper-responsiveness. This study confirms that post-injury modulation of microglial activity is a new strategy for treating neuropathic pain. PMID- 25933030 TI - Serum Chemerin Concentrations Associate with Beta-Cell Function, but Not with Insulin Resistance in Individuals with Non-Alcoholic Fatty Liver Disease (NAFLD). AB - The novel adipokine chemerin has been related to insulin-resistant states such as obesity and non alcoholic fatty liver disease (NAFLD). However, its association with insulin resistance and beta cell function remains controversial. The main objective was to examine whether serum chemerin levels associate with insulin sensitivity and beta cell function independently of body mass index (BMI), by studying consecutive outpatients of the hepatology clinics of a European university hospital. Individuals (n=196) with NAFLD were stratified into persons with normal glucose tolerance (NGT; n=110), impaired glucose tolerance (IGT; n=51) and type 2 diabetes (T2D; n=35) and the association between serum chemerin and measures of insulin sensitivity and beta cell function as assessed during fasting and during oral glucose tolerance test (OGTT) was measured. Our results showed that serum chemerin positively associated with BMI (P=0.0007) and C peptide during OGTT (P<0.004), but not with circulating glucose, insulin, lipids or liver enzymes (all P>0.18). No BMI independent relationships of chemerin with fasting and OGTT derived measures of insulin sensitivity were found (P>0.5). Chemerin associated positively with fasting beta cell function as well as the OGTT derived insulinogenic index IGI_cp and the adaptation index after adjustment for age, sex and BMI (P=0.002-0.007), and inversely with the insulin/C peptide ratio (P=0.007). Serum chemerin neither related to the insulinogenic index IGI_ins nor the disposition index. In conclusion, circulating chemerin is likely linked to enhanced beta cell function but not to insulin sensitivity in patients with NAFLD. PMID- 25933031 TI - Comparative Resistance to Teriparatide-Induced Bone Resorption With Denosumab or Alendronate. AB - CONTEXT: In postmenopausal osteoporotic women, denosumab fully inhibits teriparatide-induced bone resorption at approved doses. This property of denosumab is distinct from that of alendronate and likely contributes to the efficacy of combination denosumab and teriparatide therapy. Whether denosumab fully inhibits bone resorption when challenged by a higher dose of teriparatide is unknown. OBJECTIVE: We aimed to define the comparative ability of denosumab and alendronate to block the acute proresorptive effects of high-dose teriparatide. DESIGN, SETTING, AND PARTICIPANTS: In this randomized controlled trial, bone resorption (serum C-telopeptide [CTX]) was measured in 25 postmenopausal women prior to and 4 hours after a single 40-MUg sc teriparatide injection. Subjects then received either a single injection of denosumab 60 mg or oral alendronate 70 mg weekly for 8 weeks. After 8 weeks, serum CTX was again measured before and 4 hours after a teriparatide a 40-MUg injection. OUTCOMES: The primary outcome was the between-group difference in the teriparatide-induced change in CTX from baseline to week 8. RESULTS: At baseline, 40 MUg of teriparatide induced similar 4-hour increases in mean CTX in both groups (alendronate 47% +/- 14%, denosumab 46% +/- 16%). After 8 weeks, teriparatide was still able to stimulate bone resorption in women treated with alendronate (mean CTX increase of 43% +/- 29%) but not in women treated with denosumab (-7% +/- 11%; P < .001 for between group comparison). CONCLUSIONS: Denosumab, but not alendronate, fully inhibits the ability of high-dose teriparatide to increase bone resorption acutely. These results suggest that combining denosumab with a more potent anabolic stimulus may result in greater separation between bone resorption and formation and hence greater increases in bone mass. PMID- 25933032 TI - Enzyme-instructed self-assembly: a multistep process for potential cancer therapy. AB - The central dogma of the action of current anticancer drugs is that the drug tightly binds to its molecular target for inhibition. The reliance on tight ligand-receptor binding, however, is also the major root of drug resistance in cancer therapy. In this article, we highlight enzyme-instructed self-assembly (EISA)-the integration of enzymatic transformation and molecular self-assembly-as a multistep process for the development of cancer therapy. Using apoptosis as an example, we illustrate that the combination of enzymatic transformation and self assembly, in fact, is an inherent feature of apoptosis. After the introduction of EISA of small molecules in the context of supramolecular hydrogelation, we describe several key studies to underscore the promises of EISA for developing cancer therapy. Particularly, we will highlight that EISA allows one to develop approaches to target "undruggable" targets or "untargetable" features of cancer cells and provides the opportunity for simultaneously interacting with multiple targets. We envision that EISA, used separately or in combination with current anticancer therapeutics, will ultimately lead to a paradigm shift for developing anticancer medicine that inhibit multiple hallmark capabilities of cancer. PMID- 25933033 TI - Actin as deathly switch? How auxin can suppress cell-death related defence. AB - Plant innate immunity is composed of two layers--a basal immunity, and a specific effector-triggered immunity, which is often accompanied by hypersensitive cell death. Initiation of cell death depends on a complex network of signalling pathways. The phytohormone auxin as central regulator of plant growth and development represents an important component for the modulation of plant defence. In our previous work, we showed that cell death is heralded by detachment of actin from the membrane. Both, actin response and cell death, are triggered by the bacterial elicitor harpin in grapevine cells. In this study we investigated, whether harpin-triggered actin bundling is necessary for harpin triggered cell death. Since actin organisation is dependent upon auxin, we used different auxins to suppress actin bundling. Extracellular alkalinisation and transcription of defence genes as the basal immunity were examined as well as cell death. Furthermore, organisation of actin was observed in response to pharmacological manipulation of reactive oxygen species and phospholipase D. We find that induction of defence genes is independent of auxin. However, auxin can suppress harpin-induced cell death and also counteract actin bundling. We integrate our findings into a model, where harpin interferes with an auxin dependent pathway that sustains dynamic cortical actin through the activity of phospholipase D. The antagonism between growth and defence is explained by mutual competition for signal molecules such as superoxide and phosphatidic acid. Perturbations of the auxin-actin pathway might be used to detect disturbed integrity of the plasma membrane and channel defence signalling towards programmed cell death. PMID- 25933035 TI - Airway management techniques in a restricted-access situation: a manikin study. AB - BACKGROUND: Access to patients can be restricted in emergency situations. A variety of techniques and devices are available for use in patients who require oxygenation in a restricted-access situation. OBJECTIVES: The aim of this study was to investigate whether there is one ventilation technique that is superior to others. MATERIALS AND METHODS: Fifty-four emergency medical services providers including emergency medical technicians, paramedics and physicians were asked to use a bag-valve mask (BVM), a laryngeal mask airway (LMA), and a laryngeal tube (LT) to ventilate a full-scale manikin sitting upright in the driver's seat of a motor vehicle. Access to the manikin was gained through the side window and from the backseat. RESULTS: There were significant differences in time to first successful ventilation between the two approaches for access to the airway. The fastest median time to ventilation was obtained with the BVM (7 and 8 s), followed by the LT (13 and 14 s) and the LMA (15 s for both types of access). Overall success rates were 97.2% for the BVM, 96.3% for the LMA, and 100% for the LT. Most participants needed two attempts for each device. There were no significant differences between participants depending on the level of qualification or professional experience. The BVM was rated the lowest and the LT was rated the highest for ease of use. CONCLUSION: Supraglottic airway devices appear to offer advantages in restricted-access situations. PMID- 25933034 TI - Dendritic cell interactions with Histoplasma and Paracoccidioides. AB - Fungi are among the most common microbes encountered by humans. More than 100, 000 fungal species have been described in the environment to date, however only a few species cause disease in humans. Fungal infections are of particular importance to immunocompromised hosts in whom disease is often more severe, especially in those with impaired cell-mediated immunity such as individuals with HIV infection, hematologic malignancies, or those receiving TNF-alpha inhibitors. Nevertheless, environmental disturbances through natural processes or as a consequence of deforestation or construction can expose immunologically competent people to a large number of fungal spores resulting in asymptomatic acquisition to life-threatening disease. In recent decades, the significance of the innate immune system and more importantly the role of dendritic cells (DC) have been found to play a fundamental role in the resolution of fungal infections, such as in dimorphic fungi like Histoplasma and Paracoccidioides. In this review article the general role of DCs will be illustrated as the bridge between the innate and adaptive immune systems, as well as their specific interactions with these 2 dimorphic fungi. PMID- 25933036 TI - NSC666715 and Its Analogs Inhibit Strand-Displacement Activity of DNA Polymerase beta and Potentiate Temozolomide-Induced DNA Damage, Senescence and Apoptosis in Colorectal Cancer Cells. AB - Recently approved chemotherapeutic agents to treat colorectal cancer (CRC) have made some impact; however, there is an urgent need for newer targeted agents and strategies to circumvent CRC growth and metastasis. CRC frequently exhibits natural resistance to chemotherapy and those who do respond initially later acquire drug resistance. A mechanism to potentially sensitize CRC cells is by blocking the DNA polymerase beta (Pol-beta) activity. Temozolomide (TMZ), an alkylating agent, and other DNA-interacting agents exert DNA damage primarily repaired by a Pol-beta-directed base excision repair (BER) pathway. In previous studies, we used structure-based molecular docking of Pol-beta and identified a potent small molecule inhibitor (NSC666715). In the present study, we have determined the mechanism by which NSC666715 and its analogs block Fen1-induced strand-displacement activity of Pol-beta-directed LP-BER, cause apurinic/apyrimidinic (AP) site accumulation and induce S-phase cell cycle arrest. Induction of S-phase cell cycle arrest leads to senescence and apoptosis of CRC cells through the p53/p21 pathway. Our initial findings also show a 10 fold reduction of the IC50 of TMZ when combined with NSC666715. These results provide a guide for the development of a target-defined strategy for CRC chemotherapy that will be based on the mechanisms of action of NSC666715 and TMZ. This combination strategy can be used as a framework to further reduce the TMZ dosages and resistance in CRC patients. PMID- 25933037 TI - Innate responses induced by whole inactivated virus or subunit influenza vaccines in cultured dendritic cells correlate with immune responses in vivo. AB - Vaccine development involves time-consuming and expensive evaluation of candidate vaccines in animal models. As mediators of both innate and adaptive immune responses dendritic cells (DCs) are considered to be highly important for vaccine performance. Here we evaluated how far the response of DCs to a vaccine in vitro is in line with the immune response the vaccine evokes in vivo. To this end, we investigated the response of murine bone marrow-derived DCs to whole inactivated virus (WIV) and subunit (SU) influenza vaccine preparations. These vaccine preparations were chosen because they differ in the immune response they evoke in mice with WIV being superior to SU vaccine through induction of higher virus neutralizing antibody titers and a more favorable Th1-skewed response phenotype. Stimulation of DCs with WIV, but not SU vaccine, resulted in a cytokine response that was comparable to that of DCs stimulated with live virus. Similarly, the gene expression profiles of DCs treated with WIV or live virus were similar and differed from that of SU vaccine-treated DCs. More specifically, exposure of DCs to WIV resulted in differential expression of genes in known antiviral pathways, whereas SU vaccine did not. The stronger antiviral and more Th1-related response of DCs to WIV as compared to SU vaccine correlates well with the superior immune response found in mice. These results indicate that in vitro stimulation of DCs with novel vaccine candidates combined with the assessment of multiple parameters, including gene signatures, may be a valuable tool for the selection of vaccine candidates. PMID- 25933038 TI - Cerebrovascular Diseases in Workers at Mayak PA: The Difference in Radiation Risk between Incidence and Mortality. AB - A detailed analysis of cerebrovascular diseases (CeVD) for the cohort of workers at Mayak Production Association (PA) is presented. This cohort is especially suitable for the analysis of radiation induced circulatory diseases, due to the detailed medical surveillance and information on several risk factors. The risk after external, typically protracted, gamma exposure is analysed, accounting for potential additional internal alpha exposure. Three different endpoints have been investigated: incidence and mortality from all cerebrovascular diseases and incidence of stroke. Particular emphasis was given to the form of the dose response relationship and the time dependence of the radiation induced risk. Young attained age was observed to be an important, aggravating modifier of radiation risk for incidence of CeVD and stroke. For incidence of CeVD, our analysis supports a dose response sub-linear for low doses. Finally, the excess relative risk per dose was confirmed to be significantly higher for incidence of CeVD compared to CeVD mortality and incidence of stroke. Arguments are presented for this difference to be based on a true biological effect. PMID- 25933039 TI - Estimating the In Vivo Killing Efficacy of Cytotoxic T Lymphocytes across Different Peptide-MHC Complex Densities. AB - Cytotoxic T lymphocytes (CTLs) are important agents in the control of intracellular pathogens, which specifically recognize and kill infected cells. Recently developed experimental methods allow the estimation of the CTL's efficacy in detecting and clearing infected host cells. One method, the in vivo killing assay, utilizes the adoptive transfer of antigen displaying target cells into the bloodstream of mice. Surprisingly, killing efficacies measured by this method are often much higher than estimates obtained by other methods based on, for instance, the dynamics of escape mutations. In this study, we investigated what fraction of this variation can be explained by differences in peptide loads employed in in vivo killing assays. We addressed this question in mice immunized with lymphocytic choriomeningitis virus (LCMV). We conducted in vivo killing assays varying the loads of the immunodominant epitope GP33 on target cells. Using a mathematical model, we determined the efficacy of effector and memory CTL, as well as CTL in chronically infected mice. We found that the killing efficacy is substantially reduced at lower peptide loads. For physiological peptide loads, our analysis predicts more than a factor 10 lower CTL efficacies than at maximum peptide loads. Assuming that the efficacy scales linearly with the frequency of CTL, a clear hierarchy emerges among the groups across all peptide antigen concentrations. The group of mice with chronic LCMV infections shows a consistently higher killing efficacy per CTL than the acutely infected mouse group, which in turn has a consistently larger efficacy than the memory mouse group. We conclude that CTL killing efficacy dependence on surface epitope frequencies can only partially explain the variation in in vivo killing efficacy estimates across experimental methods and viral systems, which vary about four orders of magnitude. In contrast, peptide load differences can explain at most two orders of magnitude. PMID- 25933040 TI - The Mechanism for Stopping Chain and Total-Molecule Growth in Complex Branched Polymers, Exemplified by Glycogen. PMID- 25933041 TI - Ultrastable Polymolybdate-Based Metal-Organic Frameworks as Highly Active Electrocatalysts for Hydrogen Generation from Water. AB - Two novel polyoxometalate (POM)-based metal-organic frameworks (MOFs), [TBA]3[epsilon-PMo(V)8Mo(VI)4O36(OH)4Zn4][BTB]4/3.xGuest (NENU-500, BTB = benzene tribenzoate, TBA(+) = tetrabutylammonium ion) and [TBA]3[epsilon PMo(V)8Mo(VI)4O37(OH)3Zn4][BPT] (NENU-501, BPT = [1,1'-biphenyl]-3,4',5 tricarboxylate), were isolated. In these compounds, the POM fragments serving as nodes were directly connected with organic ligands giving rise to three dimensional (3D) open frameworks. The two anionic frameworks were balanced by TBA(+) ions residing inside the open channels. They exhibit not only good stability in air but also tolerance to acidic and basic media. Furthermore, they were employed as electrocatalysts for the hydrogen evolution reaction (HER) owing to the combination of the redox activity of a POM unit and the porosity of a MOF. Meanwhile, the HER activities of epsilon(trim)(4/3), NENU-5, and HKUST-1 were also studied for comparison. Remarkably, as a 3D hydrogen-evolving cathode operating in acidic electrolytes, NENU-500 exhibits the highest activity among all MOF materials. It shows an onset overpotential of 180 mV and a Tafel slope of 96 mV.dec(-1), and the catalytic current density can approach 10 mA.cm(-2) at an overpotential of 237 mV. Moreover, NENU-500 and NENU-501 maintain their electrocatalytic activities after 2000 cycles. PMID- 25933042 TI - FACTORIAL VALIDITY OF THE SHORT FORM OF THE CHILDHOOD TRAUMA QUESTIONNAIRE (CTQ SF) IN GERMAN PSYCHIATRIC PATIENTS, INMATES, AND UNIVERSITY STUDENTS. AB - For the purpose of retrospective assessment and characterization of childhood trauma in adults, the factorial validity of the short form of the Childhood Trauma Questionnaire (CTQ-SF) in Germany was evaluated by conducting confirmatory factor analyses for three samples including 1,524 adult psychiatric patients, 224 inmates, and 295 university students. In addition, sex-specific confirmatory factor analyses were performed within each sample. Because several authors have suggested a different factor structure than that originally proposed in the manual, two competing models focusing on the Physical neglect subscale were examined. In psychiatric patients and inmates, the fit indices were reasonable to good. Among the students, factor loadings were markedly lower, and fit indices were poor. Sex-specific analyses did not indicate sex differences. Comparing the original and the alternative models revealed better fit indices of the original factor structure. The present findings indicate that the German version of the CTQ-SF has factorial validity in psychiatric patients and inmates, but not in students. PMID- 25933043 TI - RELATIONSHIP BETWEEN TYPE D PERSONALITY AND ANHEDONIA: A DIMENSIONAL STUDY OF UNIVERSITY STUDENTS. AB - Type D personality-characterized by negative affectivity and social inhibition and anhedonia have independently been found to be significantly associated with depression or suicidal ideation in the general population or in psychiatric subjects. The aim of the study was to evaluate the association between Type D personality and anhedonia in a population of 204 university students (102 men, 102 women) after controlling for depression as a confounding variable. Type D personality was evaluated using the Type D scale, anhedonia with the Snaith Hamilton Pleasure Scale, and depression with the Beck Depression Inventory-II. Significant correlations were found between social inhibition and anhedonia before and after adjustment for depression. In women, a Sobel test indicated significant mediation by social inhibition of the relationship between anhedonia and depression. Results suggested that the social inhibition component of Type D personality could constitute a poor prognosis factor. PMID- 25933044 TI - PSYCHOLOGICAL FACTORS THAT FOSTER OR DETER THE DISCLOSURE OF DISABILITY BY UNIVERSITY STUDENTS. AB - Despite the increased number of students with disabilities attending university compared to a few decades ago, many students do not declare that they have a disability, reducing their chances to receive support when it is needed. Here, some of the studies investigating the factors that influence disclosure of disability are reviewed. Psychological factors related to identity, stigma, self worth, and self-awareness are identified as the most important factors in supporting the decision to disclose a disability. Early support for these dimensions is important and should be provided as early as possible in order to facilitate the disclosure and help-seeking of university students with disabilities. PMID- 25933045 TI - STRUCTURE OF THE UNIVERSITY PERSONALITY INVENTORY FOR CHINESE COLLEGE STUDENTS. AB - The University Personality Inventory, a mental health instrument for college students, is frequently used for screening in China. However, its unidimensionality has been questioned. This study examined its dimensions to provide more information about the specific mental problems for students at risk. Four subsamples were randomly created from a sample (N = 6,110; M age = 19.1 yr.) of students at a university in China. Principal component analysis with Promax rotation was applied on the first two subsamples to explore dimension of the inventory. Confirmatory factor analysis was conducted on the third subsample to verify the exploratory dimensions. Finally, the identified factors were compared to the Symptom Checklist-90 (SCL-90) to support validity, and sex differences were examined, based on the fourth subsample. Five factors were identified: Physical Symptoms, Cognitive Symptoms, Emotional Vulnerability, Social Avoidance, and Interpersonal Sensitivity, accounting for 60.3% of the variance. All the five factors were significantly correlated with the SCL-90. Women scored significantly higher than men on Cognitive Symptoms and Interpersonal Sensitivity. PMID- 25933046 TI - IS THE SUICIDE RATE A RANDOM WALK? AB - The yearly suicide rates for the period 1933-2010 and the daily suicide numbers for 1990 and 1991 were examined for whether the distribution of difference scores (from year to year and from day to day) fitted a normal distribution, a characteristic of stochastic processes that follow a random walk. If the suicide rate were a random walk, then any disturbance to the suicide rate would have a permanent effect and national suicide prevention efforts would likely fail. The distribution of difference scores from day to day (but not the difference scores from year to year) fitted a normal distribution and, therefore, were consistent with a random walk. PMID- 25933047 TI - SPOUSAL INTRUSION AS A PREDICTOR OF WIVES' MARITAL SATISFACTION IN THEIR SPOUSES' RETIREMENT. AB - Retirement of men changes their roles and participation and affects their spouses' daily routines, roles, and participation. This study assessed the effects of spousal intrusion on marital satisfaction in retirement. Questionnaires assessing demographics, spousal intrusion, shared couple activities, feelings, and marital satisfaction were administered to a group of 151 volunteer women whose husbands were retired in two cities in Turkey. The women were recruited among those who were willing to share their feelings and thoughts about their husbands' retirement process as a result of one-on-one interviews. Hierarchical regression analysis indicated that the perception of spousal intrusion, education status, frequency of shared activities, and dyadic adjustment predicted women's marital satisfaction in retirement. However, spousal intrusion did not significantly predict women's marital satisfaction when dyadic adjustment was entered in the second model. In the third model, final variables together predicted 19% of women's marital satisfaction in their spouse's retirement. These findings are important as they underline the factors affecting women's marital satisfaction in their spouses' retirement period. PMID- 25933048 TI - THE USE OF SELF-MANAGED TREATMENT STRATEGIES IN A PREDOMINANTLY LOW-INCOME, AFRICAN-AMERICAN SAMPLE OF WOMEN LIVING WITH HIV. AB - While low-income and ethnic minority women represent a growing proportion of new HIV cases in the United States, little is known about how they manage their antiretroviral medication regimens. Using a predominantly low-income, African American sample (N = 85), this study examined medication self-management strategies among HIV seropositive women undergoing antiretroviral therapy in a major metropolitan area. Most study participants (95%; n = 81) reported employing a specific medication management strategy during the previous week. Pillboxes, use of daily activities, and receiving reminders from another person were the most common strategies. Most participants (80.2%) employed two or more strategies. Age, education, and motivation were associated with alarm, pillbox, and visual aid usage. PMID- 25933049 TI - Burn injury induces skeletal muscle degeneration, inflammatory host response, and oxidative stress in wistar rats. AB - Burn injuries (BIs) result in both local and systemic responses distant from the site of thermal injury, such as skeletal muscle. The purpose of this study was to investigate the expression of cyclooxygenase-2 (COX-2) and hydroxy-2' deoxyguanosine (8-OHdG) as a result of inflammation and reactive oxygen species production, respectively. A total of 16 male rats were distributed into two groups: control (C) and submitted to BI. The medial part of gastrocnemius muscle formed the specimens, which were stained with hematoxylin and eosin and were evaluated. COX-2 and 8-OHdG expressions were assessed by immunohistochemistry, and cell profile area and density of muscle fibers (number of fibers per square millimeter) were evaluated by morphometric methods. The results revealed inflammatory infiltrate associated with COX-2 immunoexpression in BI gastrocnemius muscle. Furthermore, a substantial decrease in the muscle cell profile area of BI group was noticed when compared with the control group, whereas the density of muscle fibers was higher in the BI group. 8-OHdG expression in numerous skeletal muscle nuclei was detected in the BI group. In conclusion, the BI group is able to induce skeletal muscle degeneration as a result of systemic host response closely related to reactive oxygen species production and inflammatory process. PMID- 25933050 TI - Sedation and analgesia for critically ill pediatric burn patients: the current state of practice. AB - The objective of this study was to assess current practice patterns and attitudes toward pediatric sedation and analgesia in United States (US) burn centers for critically ill patients. Survey-based questionnaire was sent to 119 Directors at US burn centers that care for pediatric patients. Forty-one surveys (34%) were analyzed. 48.8% of responding centers mandate pediatric consultation for pediatric burn patients based on factors such as age and burn size. The most common sedation and analgesic agents used were midazolam, fentanyl, morphine, ketamine, and diphenhydramine. Written sedation policies exist at 63.4% of centers. 90.2% of centers employ scoring systems to guide agent titration. 60.9% of respondents practice sedation holidays "always" or "usually." 90.2% of centers perceive the medications they routinely use are "always" or "often" efficacious in pediatric sedation and analgesia. 53.7% of respondents reported the presence of withdrawal signs and symptoms in their patient population. The lack of consensus guidelines for sedation and analgesia delivery to pediatric intensive care unit patients results in practice variation. The majority of centers perceive their sedation and analgesia strategies to be efficacious despite the heavy reliance on propofol and midazolam, both of which have questionable safety profiles in critically ill children. PMID- 25933051 TI - Switching closed-shell to open-shell phenalenyl: toward designing electroactive materials. AB - Open-shell phenalenyl chemistry started more than half a century back, and the first solid-state phenalenyl radical was realized only 15 years ago highlighting the synthetic challenges associated in stabilizing carbon-based radical chemistry, though it has great promise as building blocks for molecular electronics and multifunctional materials. Alternatively, stable closed-shell phenalenyl has tremendous potential as it can be utilized to create an in situ open-shell state by external spin injection. In the present study, we have designed a closed-shell phenalenyl-based iron(III) complex, Fe(III)(PLY)3 (PLY-H = 9-hydroxyphenalenone) displaying an excellent electrocatalytic property as cathode material for one compartment membraneless H2O2 fuel cell. The power density output of Fe(III)(PLY)3 is nearly 15-fold higher than the structurally related model compound Fe(III)(acac)3 (acac = acetylacetonate) and nearly 140 fold higher than an earlier reported mononuclear Fe(III) complex, Fe(III)(Pc)Cl (Pc = pthalocyaninate), highlighting the role of switchable closed-shell phenalenyl moiety for electron-transfer process in designing electroactive materials. PMID- 25933052 TI - Reed-Sternberg cells form by abscission failure in the presence of functional Aurora B kinase. AB - Large multinucleated Reed-Sternberg cells (RS) and large mononucleated Hodgkin cells (H) are traditionally considered to be the neoplastic population in classical Hodgkin lymphoma, (cHL) and postulated to promote the disease. However, the contribution of these larger cells to the progression of cHL remains debatable. We used established cHL cell lines and cHL cellular fractions composed of small mononucleated cells only or enriched in large RS/H cells to investigate RS/H cell origin and to characterize the cells which they derive from. We confirm that the small mononucleated cells give rise to RS/H cells, and we show that the latter proliferate significantly more slowly than the small cells. By using live cell imaging, we demonstrate that binucleated RS cells are generated by failure of abscission when a few small cells attempt to divide. Finally, our results reveal that the small mononucleated cells are chromosomally unstable, but this is unlikely to be related to a malfunctioning chromosomal passenger protein complex. We propose that the small mononucleated cells, rather than the RS/H cells, are the main drivers of cHL. PMID- 25933054 TI - Accumulation of clinically relevant antibiotic-resistance genes, bacterial load, and metals in freshwater lake sediments in Central Europe. AB - Wastewater treatment plants (WWTP) receive the effluents from various sources (communities, industrial, and hospital effluents) and are recognized as reservoir for antibiotic-resistance genes (ARGs) that are associated with clinical pathogens. The aquatic environment is considered a hot-spot for horizontal gene transfer, and lake sediments offer the opportunity for reconstructing the pollution history and evaluating the impacts. In this context, variation with depth and time of the total bacterial load, the abundance of faecal indicator bacteria (FIB; E. coli and Enterococcus spp. (ENT)), Pseudomonas spp., and ARGs (blaTEM, blaSHV, blaCTX-M, blaNDM, and aadA) were quantified in sediment profiles of different parts of Lake Geneva using quantitative PCR. The abundance of bacterial marker genes was identified in sediments contaminated by WWTP following eutrophication of the lake. Additionally, ARGs, including the extended-spectrum beta-lactam- and aminoglycoside-resistance genes, were identified in the surface sediments. The ARG and FIB abundance strongly correlated (r >= 0.403, p < 0.05, n = 34) with organic matter and metal concentrations in the sediments, indicating a common and contemporary source of contamination. The contamination of sediments by untreated or partially treated effluent water can affect the quality of ecosystem. Therefore, the reduction of contaminants from the source is recommended for further improvement of water quality. PMID- 25933055 TI - An Observational Study of the Effects of Therapeutic Hoof Blocks on the Locomotion, Behavior, and Production of Healthy Dairy Cattle. AB - Therapeutic hoof blocks have been recommended for treatment of sole ulcers in dairy cattle; however, they are underutilized in the industry. Twenty Holstein cows were randomly assigned to receive a wooden hoof block applied to the left hind leg (n = 5), to the right hind leg (n = 5), or no hoof blocks (n = 10). Accelerometers were affixed to both hind legs of 10 blocked cows and 5 control cows. Cows were observed for locomotion scores, and milk production was recorded. Mixed models were constructed to determine effects of block application on behavior, milk production, and locomotion. Activity was altered by day, with cows being most active on Day - 1. The mean number of daily lying bouts and lying bout duration did not differ by treatment. Locomotion scores were higher for blocked cows on Days 1, 2, and 3 compared with baseline; however, milk production did not differ between treatments. In conclusion, although block application affected the appearance of locomotion, it did not appear to adversely affect the behavior or milk production of sound dairy cows. PMID- 25933057 TI - Correction: bacterial viability and physical properties of antibacterially modified experimental dental resin composites. PMID- 25933056 TI - Poly-Victimisation among Vietnamese High School Students: Prevalence and Demographic Correlates. AB - BACKGROUND: Exposure to multiple forms of violence, including abuse and crime is termed poly-victimisation. There has been increasing research interest in poly victimisation among children and adolescents in high income countries. However, experiences among adolescents living in low- and lower-middle-income countries are yet to be examined. AIMS: To establish the prevalence of lifetime exposure to poly-victimisation and demographic characteristics of victims among high school students in Vietnam. METHODS: A cross-sectional survey with a self-report, anonymous questionnaire was conducted in ten high schools in Hanoi, Vietnam between October 2013 and January 2014. Poly-victimisation was assessed using the Juvenile Victimisation Questionnaire Revised 2 (JVQ R2). RESULTS: A total of 1,606/1,745 (92.0%) eligible students provided data and were included in the analyses. Lifetime exposure to at least one form of victimisation was reported by 94.3% (95%CI: 92.5-95.4%) of participants and lifetime exposure to more than 10 forms by 31.1% (95%CI: 27.8-33.5%). Poly-victimisation was associated with experiencing more adverse life events, having a chronic disease or disability, living with a step-parent, experiencing family life as unhappy, being disciplined at school, and living in a rural area. Poly-victimisation experiences differed among students from the three types of high schools in Vietnam. CONCLUSIONS: These data reveal the prevalence and multi-factorial risks of exposure to poly victimisation among adolescents in Vietnam. Prevalence rates of different forms of victimisation among Vietnamese students, including those previously un investigated, were higher than those reported in other settings. Poly victimisation was also common among them. There were certain subgroups who were more vulnerable to poly-victimisation. Further research to understand the broader aspects of adolescence in Vietnam, including poly-victimisation, is thus recommended. Special attention should be paid to specific subgroups in the prevention of violence against children and adolescents in this setting. Education to raise awareness about poly-victimisation among the community is needed. PMID- 25933058 TI - International Conference for Healthcare and Medical Students (ICHAMS) 2013. PMID- 25933059 TI - PyBidine-NiCl2-Catalyzed Asymmetric Addition of Alcohols and Peroxides to Isatin Derived Ketimines. AB - An (S,S)-diphenyldiamine-derived bis(imidazolidine)pyridine (PyBidine)-NiCl2 complex catalyzed the asymmetric addition of methanol and peroxides to isatin derived N-Boc-imines to form chiral quaternary N,O-acetals at the C3 position of the resulting oxiindoles in up to 99% yield with 94% ee. PMID- 25933060 TI - Effects of Static and Dynamic Stretching on Injury Prevention in High School Soccer Athletes: A Randomized Trial. AB - OBJECTIVE: To determine if there is any benefit to static stretching after performing a dynamic warm-up in the prevention of injury in high school soccer athletes. DESIGN: Prospective cluster randomized nonblinded study. SETTING: 12 high schools with varsity and junior varsity boys' soccer teams (24 soccer teams) across the state of Michigan. PARTICIPANTS: Four hundred ninety-nine student athletes were enrolled, and 465 completed the study. One high school dropped out of the study in the first week, leaving a total of 22 teams. INTERVENTIONS: Dynamic stretching protocol vs dynamic + static (D+S) stretching protocol. MAIN OUTCOME MEASURES: Lower-extremity, core, or lower-back injuries per team. RESULTS: Twelve teams performed the dynamic stretching protocol and 10 teams performed the D+S stretching protocol. There were 17 injuries (1.42 +/- 1.49 injuries/ team) among the teams that performed the dynamic stretching protocol and 20 injuries (2.0 +/- 1.24 injuries/ team) among the teams that performed the D+S protocol. There was no statistically significant difference in injuries between the 2 groups (P = .33). CONCLUSIONS: There is no difference between dynamic stretching and D+S stretching in the prevention of lower-extremity, core, and back injuries in high school male soccer athletes. Static stretching does not provide any added benefit to dynamic stretching in the prevention of injury in this population before exercise. PMID- 25933061 TI - The binding mechanism of a novel nicotinamide isostere inhibiting with TNKSs: a molecular dynamic simulation and binding free energy calculation. AB - Tankyrases (TNKSs), a member of human poly (ADP-ribose) polymerase (PARP) protein superfamily, plays a key role in regulation of cell proliferation. Among the representative proteins of the PARPs family, it is found that the inhibitors have high selectivity for Tankyrase1 (TNKS1). The specific binding modes are investigated between the TNKS1 protein and nicotinamide isostere (ISX) which functions as an inhibitor of TNKS1. The stabilities of ISX-TNKS1 and AVA939-TNKS1 complexes are estimated by molecular dynamics (MD) simulations and free energy calculations; a good agreement with experimental results is reached. On the basis of the calculated results of MD simulations, we found that the inhibitors influence the conformational flexibility of TNKS1 and the XAV939 binding drive the peptide Ile1228-Gly1229-Gly1230 to form a helical structure while the ISX binding drive the peptide to form a turn structure. Moreover, the formed important hydrogen bonds of Tyr1203 residue with XVA939 and WAT1551 with ISX enhance stabilities of the complexes, and the electrostatic interactions in XAV939-TNKS1 and van der Waals interactions in ISX-TNKS1 system are main driving forces for affinity. According to the results of the decomposition of binding free energy, it is obvious that the residues Try1224 and Lys1220 make the most favorable contributions to the binding in, respectively, ISX and XAV939 complexes. Taken together, the obtained results are useful for studying the binding mechanisms of TNKSs and inhibitors and for designing potent inhibitors. PMID- 25933062 TI - Combined epigenetic and intraspecific variation of the DRD4 and SERT genes influence novelty seeking behavior in great tit Parus major. AB - DNA methylation is one of the main epigenetic mechanisms that can regulate gene expression and is an important means for creating phenotypic variation. In the present study, we performed methylation profiling of 2 candidate genes for personality traits, namely DRD4 and SERT, in the great tit Parus major to ascertain whether personality traits and behavior within different habitats have evolved with the aid of epigenetic variation. We applied bisulphite PCR and strand-specific sequencing to determine the methylation profile of the CpG dinucleotides in the DRD4 and SERT promoters and also in the CpG island overlapping DRD4 exon 3. Furthermore, we performed pyrosequencing to quantify the total methylation levels at each CpG location. Our results indicated that methylation was ~1-4% higher in urban than in forest birds, for all loci and tissues analyzed, suggesting that this epigenetic modification is influenced by environmental conditions. Screening of genomic DNA sequence revealed that the SERT promoter is CpG poor region. The methylation at a single CpG dinucleotide located 288 bp from the transcription start site was related to exploration score in urban birds. In addition, the genotypes of the SERT polymorphism SNP234 located within the minimal promoter were significantly correlated with novelty seeking behavior in captivity, with the allele increasing this behavior being more frequent in urban birds. As a conclusion, it seems that both genetic and methylation variability of the SERT gene have an important role in shaping personality traits in great tits, whereas genetic and methylation variation at the DRD4 gene is not strongly involved in behavior and personality traits. PMID- 25933063 TI - Controlled surface topography regulates collective 3D migration by epithelial mesenchymal composite embryonic tissues. AB - Cells in tissues encounter a range of physical cues as they migrate. Probing single cell and collective migratory responses to physically defined three dimensional (3D) microenvironments and the factors that modulate those responses are critical to understanding how tissue migration is regulated during development, regeneration, and cancer. One key physical factor that regulates cell migration is topography. Most studies on surface topography and cell mechanics have been carried out with single migratory cells, yet little is known about the spreading and motility response of 3D complex multi-cellular tissues to topographical cues. Here, we examine the response to complex topographical cues of microsurgically isolated tissue explants composed of epithelial and mesenchymal cell layers from naturally 3D organized embryos of the aquatic frog Xenopus laevis. We control topography using fabricated micropost arrays (MPAs) and investigate the collective 3D migration of these multi-cellular systems in these MPAs. We find that the topography regulates both collective and individual cell migration and that dense MPAs reduce but do not eliminate tissue spreading. By modulating cell size through the cell cycle inhibitor Mitomycin C or the spacing of the MPAs we uncover how 3D topographical cues disrupt collective cell migration. We find surface topography can direct both single cell motility and tissue spreading, altering tissue-scale processes that enable efficient conversion of single cell motility into collective movement. PMID- 25933064 TI - Metallothionein-3 Increases Triple-Negative Breast Cancer Cell Invasiveness via Induction of Metalloproteinase Expression. AB - It has been recently found that metallothionein-3 (MT3) enhances the invasiveness and tumorigenesis of prostate cancer cells. This finding is in contrast to those of earlier studies, which indicated that overexpression of MT3 in breast cancer and prostate cancer cell lines inhibits their growth in vitro. Therefore, to clarify the role of MT3 in breast cancer progression, we analyzed the effect of MT3-overexpression on proliferation, invasiveness, migration, and tumorigenesis of breast cancer MDA-MB-231/BO2 cells. It was found that MDA-MB-231/BO2 cells overexpressing MT3 were characterized by increased invasiveness in vitro, compared to the control cells. Interestingly, this increased invasiveness correlated with a highly increased concentration of MMP3 in the culture supernatants (p<0.0001). Our data suggest that MT3 may regulate breast cancer cell invasiveness by modulating the expression of MMP3. These experimental results, obtained using triple-negative MDA-MB-231/BO2 cells, were further supported by clinical data. It was found that, in triple-negative breast cancer (TNBC), nuclear MT3 immunoreactivity in cancer cells tended to be associated with patients' shorter disease-specific survival, suggesting that nuclear MT3 expression may be a potential marker of poor prognosis of triple-negative TNBC cases. PMID- 25933066 TI - G-jitter induced magnetohydrodynamics flow of nanofluid with constant convective thermal and solutal boundary conditions. AB - Taking into account the effect of constant convective thermal and mass boundary conditions, we present numerical solution of the 2-D laminar g-jitter mixed convective boundary layer flow of water-based nanofluids. The governing transport equations are converted into non-similar equations using suitable transformations, before being solved numerically by an implicit finite difference method with quasi-linearization technique. The skin friction decreases with time, buoyancy ratio, and thermophoresis parameters while it increases with frequency, mixed convection and Brownian motion parameters. Heat transfer rate decreases with time, Brownian motion, thermophoresis and diffusion-convection parameters while it increases with the Reynolds number, frequency, mixed convection, buoyancy ratio and conduction-convection parameters. Mass transfer rate decreases with time, frequency, thermophoresis, conduction-convection parameters while it increases with mixed convection, buoyancy ratio, diffusion-convection and Brownian motion parameters. To the best of our knowledge, this is the first paper on this topic and hence the results are new. We believe that the results will be useful in designing and operating thermal fluids systems for space materials processing. Special cases of the results have been compared with published results and an excellent agreement is found. PMID- 25933065 TI - Long term non-invasive ventilation in children: impact on survival and transition to adult care. AB - BACKGROUND: The number of children receiving domiciliary ventilatory support has grown over the last few decades driven largely by the introduction and widening applications of non-invasive ventilation. Ventilatory support may be used with the intention of increasing survival, or to facilitate discharge home and/or to palliate symptoms. However, the outcome of this intervention and the number of children transitioning to adult care as a consequence of longer survival is not yet clear. METHODS: In this retrospective cohort study, we analysed the outcome in children (<17 years) started on home NIV at Royal Brompton Hospital over an 18 year period 1993-2011. The aim was to establish for different diagnostic groups: survival rate, likelihood of early death depending on diagnosis or discontinuation of ventilation, and the proportion transitioning to adult care. RESULTS: 496 children were commenced on home non invasive ventilation; follow-up data were available in 449 (91%). Fifty six per cent (n=254) had neuromuscular disease. Ventilation was started at a median age (IQR) 10 (3-15) years. Thirteen percent (n=59) were less than 1 year old. Forty percent (n=181) have transitioned to adult care. Twenty four percent (n=109) of patients have died, and nine percent (n=42) were able to discontinue ventilatory support. CONCLUSION: Long term ventilation is associated with an increase in survival in a range of conditions leading to ventilatory failure in children, resulting in increasing numbers surviving to adulthood. This has significant implications for planning transition and adult care facilities. PMID- 25933067 TI - The expansion of thymopoiesis in neonatal mice is dependent on expression of high mobility group a 2 protein (Hmga2). AB - Cell number in the mouse thymus increases steadily during the first two weeks after birth. It then plateaus and begins to decline by seven weeks after birth. The factors governing these dramatic changes in cell production are not well understood. The data herein correlate levels of High mobility group A 2 protein (Hmga2) expression with these temporal changes in thymopoiesis. Hmga2 is expressed at high levels in murine fetal and neonatal early T cell progenitors (ETP), which are the most immature intrathymic precursors, and becomes almost undetectable in these progenitors after 5 weeks of age. Hmga2 expression is critical for the initial, exponential expansion of thymopoiesis, as Hmga2 deficient mice have a deficit of ETPs within days after birth, and total thymocyte number is repressed compared to wild type littermates. Finally, our data raise the possibility that similar events occur in humans, because Hmga2 expression is high in human fetal thymic progenitors and falls in these cells during early infancy. PMID- 25933069 TI - Correction: development of a high-throughput resequencing array for the detection of pathogenic mutations in osteogenesis imperfecta. PMID- 25933068 TI - Volumetric Response beyond Six Months of Cardiac Resynchronization Therapy and Clinical Outcome. AB - AIMS: Response to cardiac resynchronization therapy (CRT) is often assessed six months after implantation. Our objective was to assess the number of patients changing from responder to non-responder between six and 14 months, so-called late non-responders, and compare them to patients who were responder both at six and 14 months, so-called stable responders. Furthermore, we assessed predictive values of six and 14-month response concerning clinical outcome. METHODS: 105 patients eligible for CRT were enrolled. Clinical, laboratory, ECG, and echocardiographic parameters and patient-reported health status (Kansas City Cardiomyopathy Questionnaire [KCCQ]) were assessed before, and six and 14 months after implantation. Response was defined as >=15% LVESV decrease as compared to baseline. Major adverse cardiac events (MACE) were registered until 24 months after implantation. Predictive values of six and 14-month response for MACE were examined. RESULTS: In total, 75 (71%) patients were six-month responders of which 12 (16%) patients became late non-responder. At baseline, late non-responders more often had ischemic cardiomyopathy and atrial fibrillation, higher BNP and less dyssynchrony compared to stable responders. At six months, late non responders showed significantly less LVESV decrease, and higher creatinine levels. Mean KCCQ scores of late non-responders were lower than those of stable responders at every time point, with the difference being significant at 14 months. The 14 months response was a better predictor of MACE than six months response. CONCLUSIONS: The assessment of treatment outcomes after six months of CRT could be premature and response rates beyond might better correlate to long term clinical outcome. PMID- 25933070 TI - The use of an imagery mnemonic to teach the porphyrin biochemical pathway. AB - We designed an imagery mnemonic to help medical students and residents learn the porphyrin pathway and associated diseases. Fourth year medical students at the Icahn School of Medicine at Mount Sinai in the spring of 2014 participated. One group (n=11) received the porphyrin pathway in a lecture explaining a mnemonic, whereas a second group (n=11) was simply taught the steps of the pathway. A pre intervention assessment before the lectures was given to assess baseline differences in knowledge of the porphyrin pathway between the groups. Immediately following the lecture, 1 week after the lecture, and 3 weeks after the lecture, the students were given quizzes to assess their knowledge. Students were aware of the week 1 quiz and were asked not to study for it. The week 3 quiz was a surprise. There were no statistically significant differences in knowledge of the pathway at baseline (p=.45), at the immediate post-intervention (p=.22), or one week post-intervention (p=.40). Three weeks after the lecture, students in the mnemonic group scored 20% higher than controls (p=.02). Students who had learned the mnemonic demonstrated better long-term retention of information than students learning by the control method. This mnemonic minimizes study time while improving long-term retention. PMID- 25933071 TI - An usual elastophagocytic granuloma with involvement of the back: a possible variant of an annular elastolytic giant cell granuloma. AB - Annular elastolytic giant cell granuloma (AEGCG) is a very infrequent granulomatous dermatitis characterized by elastolysis and elastophagocytosis. It usually appears in middle-aged Caucasian women and is normally located in sun exposed areas.We present a case of a 73-year-old woman with hypertension and type II diabetes, who was admitted to the hospital for an ischemic cerebrovascular accident. She presented with annular and serpiginous skin lesions on her back and arms that had appeared seven months earlier; a clinical and histological diagnosis of elastophagocytic granuloma was made. Our patient exhibited a florid presentation and a self-limiting course. PMID- 25933072 TI - Cutaneous sarcoidosis masquerading as psoriatic plaques. AB - Sarcoidosis is a multisystem disease characterized by non-caseating granulomas present in the involved organ systems. The disease is believed to result from an interaction among genetic factors, antigens, and the immune response. Environmental exposures and infectious agents have been implicated as potential causes. Cutaneous sarcoidosis presents clinically in many forms and the lesions are classified as either specific or non-specific. Non-specific lesions show a nondescript inflammatory process whereas specific lesions display typical, non caseating granulomas. There are many different forms of specific lesions with some being more common than others. Psoriasiform lesions are uncommon. The literature suggests that as few as 0.9% of patients display this type of cutaneous sarcoidosis. Some of these patients present solely with cutaneous sarcoidosis, but others have systemic involvement with pulmonary involvement being the most common concomitant presentation. Plaques appear as round or oval, brownish, red infiltrated lesions, frequently involving the extensor surface of the extremities, face, scalp, back, and buttocks. Multiple configurations, including discrete, confluent, annular, and polycyclic, have been reported. Despite the clinical resemblance to psoriasis, on histological examination, only non-caseating granulomas are seen in the dermis. In rare cases both psoriasiform sarcoidosis and psoriasis were present. PMID- 25933073 TI - A misdiagnosed melanoma: a case of cutaneous epithelioid malignant peripheral nerve sheath tumor. AB - Malignant Peripheral Nerve Sheath Tumor (MPNST) is a rare soft tissue sarcoma that can occur in superficial locations. Histologically it is categorized into two variants: a conventional/spindled and an epithelioid variant. The latter one is very rare and can be confused histologically with malignant melanoma as it is diffusely positive for S100-protein. Herein we present a case that was initially misdiagnosed as malignant melanoma and discuss morphological and immunohistochemical clues to reach a correct diagnosis. PMID- 25933074 TI - Morphea-like complications to illicit gluteal silicone injections. AB - We present a case of a 39-year-old Hispanic woman who was referred to our clinic for treatment of several indurated plaques on her buttocks that developed one year prior to presentation, after she received injections of an unknown substance for augmentation. Biopsy of one nodule revealed silicone in the dermis. PMID- 25933075 TI - Bullous acrodermatitis enteropathica: case report of a unique clinical presentation and review of the literature. AB - Acrodermatitis enteropathica is a rare autosomal recessive disease characterized by pink scaly plaques and erosions in the periorificial and acral regions. A mutation in a gene responsible for zinc transport results in significant zinc deficiency in individuals lacking oral supplementation. We present a female infant with acrodermatitis enteropathica with crusting of the periorificial regions along with perineal plaques. A delay in diagnosis and treatment led to the development of pronounced painful acral bullae. Although plaques and erosions in the periorificial and acral regions are most commonly observed, bullae should also be considered in the spectrum of clinical manifestations of acrodermatitis enteropathica. The rare bullous variant of acrodermatitis enteropathica can be distinguished histologically. PMID- 25933076 TI - Erythema multiforme like allergic contact dermatitis associated with laurel oil: a rare presentation. AB - Allergic contact dermatitis is a common skin disease, which affects approximately 20% of the population. This reaction may present with several clinical manifestations. Erythema multiforme-like allergic contact dermatitis is a rare type of non-eczematous contact dermatitis, which may lead to difficulty in diagnosis.Essential oil of Laurus nobilis is widely used in massage therapy for antiinflammatory and analgesic effects. Laurus nobilis induced contact dermatitis has been reported in the literature but an erythema multiforme-like presentation is rare. PMID- 25933077 TI - Coral contact dermatitis. AB - Corals can elicit both toxic and allergic reactions upon contact with the skin. Clinical presentations vary depending on whether the reaction is acute, delayed, or chronic. Literature concerning cutaneous reactions to corals and other Cnidarians is scarce. Herein we report a case of delayed contact hypersensitivity reaction to coral and review the clinical and histopathological features of coral contact dermatitis. PMID- 25933078 TI - Harlequin syndrome: a mask of rare dysautonomic syndromes. AB - Harlequin syndrome (HS) is a rare disorder of the sympathetic nervous system which presents with unilateral decreased sweating and flushing of the face, neck, and chest in response to heat, exercise, or emotional factors. The contralateral side displays a compensatory overreaction to provide normal heat regulation of the face as a whole. In the literature, most of the cases are primary in nature and no underlying cause could be identified. Harlequin sign is used to denote these symptoms in patients who also exhibit associated oculosympathetic paresis, such as Horner syndrome, Adie syndrome, and Ross syndrome.We report a rare case of a 13-year-old boy who presented with complaints of flushing and sweating of the left side of the face after exertion, while the right side remained dry and maintained its normal color. No structural abnormality was identified on detailed work up. Thus, diagnosis of classic idiopathic HS was made. Despite the rarity of this syndrome, dermatologists should be acquainted with this distinctive entity and should refer the patient for complete ophthalmological and neurological examination. PMID- 25933079 TI - Pedunculated polypoid melanoma. A case report of a rare spindle-cell variant of melanoma. AB - We report an 89-year-old man who presented with a slowly growing pigmented pedunculated tumor. The nodule was diagnosed as a spindle cell pedunculated malignant melanoma (PMM), a rare variant of spindle-cell malignant melanoma. The clinical presentation of this tumor and its histological and immunohistological features are discussed. PMID- 25933080 TI - [Utility of skin ultrasound in the differential diagnosis of blue lesions, hydrocysts]. AB - Many skin diseases may present as blue papules and nodules; the differential diagnosis includes such different entities such as metastatic melanoma, angioma, lipoma, epidermoid cyst, pilomatrixoma, blue nevus, glomus tumor, or hidrocystoma. Cutaneous ultrasound can be a complementary diagnostic technique of great value in these cases. PMID- 25933081 TI - Squamous cell carcinoma in the setting of chronic hidradenitis suppurativa; report of a patient and update of the literature. AB - Squamous cell carcinoma (SCC) developing in chronic hidradenitis suppurativa (HS) is rare, but failing to recognize the condition may have significant consequences. Dermatologists must be aware of the potential for malignant transformation and should have a low threshold for biopsy when clinical presentation is atypical. Herein we describe a 64-year-old woman with metastatic vulvar SCC that developed within an area of chronic HS. Like SCC associated with other chronic inflammatory disorders (Marjolin's ulcers), mortality is significant. Past reviews have reported death rates above 40% and our most recent update continues to support poor prognoses for these patients. PMID- 25933082 TI - Patient use of social media to evaluate cosmetic treatments and procedures. AB - BACKGROUND: With a growing sphere of influence in the modern world, online social media serves as a readily accessible interface for communication of information. Aesthetic medicine is one of many industries increasingly influenced by social media, as evidenced by the popular website, "RealSelf," an online community founded in 2006 that compiles ratings, reviews, photographs, and expert physician commentary for nearly 300 cosmetic treatments. OBJECTIVE: To investigate the current preferences of patients regarding cosmetic non-surgical, surgical, and dental treatments on RealSelf and in the documented medical literature. METHODS: On a single day of data collection, all cosmetic treatments or procedures reviewed on the RealSelf website were tabulated, including name, percent "worth it" rating, total number of reviews, and average cost. Patient satisfaction rates documented in the current medical literature for each cosmetic treatment or procedure were also recorded. Statistical t-testingcomparing RealSelf ratings and satisfaction rates in the literature was performed for each category-non surgical, surgical, and dental. RESULTS: The top ten most-commonly reviewed non surgical treatments, top ten most-commonly reviewed surgical procedures, and top 5 most-commonly reviewed dental treatments, along with documented satisfaction rates in the medical literature for each treatment or procedure were recorded in table format and ranked by RealSelf "worth it" rating. Paired t-testing revealed that satisfaction rates documented in the literature were significantly higher than RealSelf "worth it" ratings for both non-surgical cosmetic treatments (p=0.00076) and surgical cosmetic procedures (p=0.00056), with no statistically significant difference for dental treatments. CONCLUSIONS: For prospective patients interested in cosmetic treatments or procedures, social media sites such as RealSelf may offer information helpful to decision-making as well enable cosmetic treatment providers to build reputations and expand practices. "Worth it" ratings on RealSelf may, in fact, represent a more transparent view of cosmetic treatment or procedural outcomes relative to the high satisfaction rates documented in medical literature. Massive online communication of patient experiences made possible through social media will continue to influence the practice of medicine, both aesthetic and otherwise. PMID- 25933083 TI - Nd:YAG laser offers promising treatment option for familial glomuvenous malformation. AB - Although an uncommon entity, familial glomangiomatosis is often a source of significant discomfort to affected patients and impacts quality of life. Patients develop numerous painful vascular lesions, beginning in childhood. Because management strategies for this entity are sparsely reported in the literature, additional study is needed to establish best practice. We report positive results with the use of Nd:YAG laser in treating symptomatic lesions of familial glomuvenous malformation. PMID- 25933084 TI - European trends in the frequency of original research in acne vulgaris, rosacea, dermatitis, psoriasis, skin cancer, and skin infections, 1970-2010. AB - We analyzed trends in the frequency of original publications into common dermatologic topics in two premier European journals, the British Journal of Dermatology and the Journal of the European Academy of Dermatology and Venereology. Most notably, we found that psoriasis publications peaked around the mid-to-late 1980's as well as demonstrated an upward trend since the 21st century. Skin cancer research witnessed a gradual increase in the frequency of publications since 1970. These findings were consistent with a prior study analyzing trends in two American dermatology journals. We attempted to analyze these results from a historical perspective as well as provide an outlook on the future of research into these common dermatologic topics. PMID- 25933085 TI - Tonsillar chancre as unusual manifestation of primary syphilis. AB - Primary syphilis with oropharyngeal manifestations should be kept in mind, though. Lips and tongue ulcers are the most frequently reported lesions and tonsillar ulcers are much more rare. We report the case of a 24-year-old woman with a syphilitic ulcer localized in her left tonsil. PMID- 25933086 TI - Skin cancer screening and melanoma detection: a life saved. AB - Rural America spans about two-thirds of the land that composes the United States. There are major health disparities in this population including a lack of screening, a shortage in education, and limited access to health care providers. These health disparities combined with a lack of health insurance led our patient to ignore the asymptomatic melanoma on her right foot for 10 years. Although the most recent update from the US Preventive Service Task Force found insufficient evidence to recommend for or against routine melanoma and non-melanoma skin cancer screening, our patient insists that the screening she attended that day saved her life. PMID- 25933087 TI - Biopsy rates vary with patient profile across different physicians in an academic dermatology practice. AB - Current healthcare trends promote data-driven "benchmarking" to decrease cost and increase quality. Dermatologists perform 79% of skin biopsies and biopsy rate is an easily measured benchmark. To reduce the risk of a misguided "one size fits all" benchmark for biopsies, it will help to document the factors driving divergent biopsy rates.This letter compares biopsy rates and high-risk patient ratios for 1000 sequential patients from two academic dermatologists. Elevated biopsy rates (0.55 vs 0.42, p < 0.001) were associated with elevated ratios of high-risk patients (.52 versus .30, p< 0.001). Although limited by small sample size, this research takes a first step toward future efforts to improve accuracy of biopsy benchmarking. PMID- 25933088 TI - Topical AC-11 abates actinic keratoses and early squamous cell cancers in hairless mice exposed to Ultraviolet A (UVA) radiation. AB - AC-11 is an aqueous extract of the botanical, Uncaria tomentosa, which has a variety of effects that enhance DNA repair and down regulate inflammation. AC-11 is essentially free of oxindole alkaloids (< 0.05%, w/w) but contains more than 8% carboxy alkyl esters (CAEs) as their active ingredients. Three groups of 10 outbred SK-1 hairless or SK-II hairless strains of mice each were treated with AC 11 at 0.5%, 1.5%, and 3.0% in a non-irritating, dye-free, perfume-free, and fragrance-free vanishing cream vehicle. Ten mice used vehicle only and 10 were untreated. Each concentration of AC-11 and was applied daily to the backs of the mice prior to exposure to a 1,600-watt solar simulator used in this work (Solar Light Co. Philadelphia, PA) emitting (mainly Ultraviolet A (UVA) and B (UVB) radiation) duration of the experimental period with UVB wavelengths was filtered out with a 1.0 cm Schott WG 345 filter. AC-11 with a peak absorption at 200nm does act as a sun block. We tested for and focused on clinical appearance of mice and histological appearance of tumors in mice rather than metrics of radiation generated inflammation. Tumor progression scores were assigned as follows: 4+ = extensive tumor development; 3+ = early malignancies (raised palpable plaques)(early squamous cell cancers) 2+ = firm scaling, palpable keratosis (actinic keratoses); 1+ = light scaling with erythema. Following a total cumulative dose of 738 J/cm2, 85.7% all of the irradiated control animals, which did not receive AC-11 had precancerous actinic keratosis (AK)-type lesions (2+) (64.3% versus 42.9%) or early squamous cell carcinoma (SCC) (3+) (21.4% vs. 4.8%), in comparison with 47.7 % of AC-11-treated animals. There were no significant differences between the AC-11 groups. Three months after cessation of exposure to UVA radiation, the lesions in all but three of the 14 animals which were treated with AC-11 that were still evaluable irradiated with UVA radiation progressed to papillomas and frank squamous cell carcinomas (+4 responses). AC-11 retarded, but did not stop, carcinogenesis progression. It is possible that if AC 11 was continuously applied tumors would not have in mice treated with AC-11 for a limited period. While we do not know how AC-11 exerts its DNA repair and anti inflammatory effects, AC-11 is therapeutic for the treatment at the time of development of actinic keratoses and squamous cell carcinomas in mice and by extension humans. Without the constant presence of AC-11 these protective effects do not occur. PMID- 25933089 TI - Influential role of black carbon in the soil-air partitioning of polychlorinated biphenyls (PCBs) in the Indus River Basin, Pakistan. AB - Levels of polychlorinated biphenyls (PCBs) were assessed in surface soils and passive air samples from the Indus River Basin, and the influential role of black carbon (BC) in the soil-air partitioning process was examined. ?26-PCBs ranged between 0.002-3.03 pg m(-3) and 0.26-1.89 ng g(-1) for passive air and soil samples, respectively. Lower chlorinated (tri- and tetra-) PCBs were abundant in both air (83.9%) and soil (92.1%) samples. Soil-air partitioning of PCBs was investigated through octanol-air partition coefficients (KOA) and black carbon air partition coefficients (KBC-A). The results of the paired-t test revealed that both models showed statistically significant agreement between measured and predicted model values for the PCB congeners. Ratios of fBCKBC-AdeltaOCT/fOMKOA>5 explicitly suggested the influential role of black carbon in the retention and soil-air partitioning of PCBs. Lower chlorinated PCBs were strongly adsorbed and retained by black carbon during soil-air partitioning because of their dominance at the sampling sites and planarity effect. PMID- 25933090 TI - Safety and effectiveness of mycophenolate in systemic sclerosis. A systematic review. AB - BACKGROUND: Mycophenolate is increasingly being used in the rheumatic diseases. Its main adverse effects are gastrointestinal, myelosuppression, and infection. These may limit use in systemic sclerosis (SSc) since gastrointestinal involvement is common. The objective of this study is to evaluate gastrointestinal adverse events of mycophenolate in SSc. Secondarily we evaluated other adverse events, and the effectiveness of mycophenolate in skin and lung disease. METHODS: A literature search of Medline, Embase, Cochrane Central Register of Controlled Trials, and CINAHL (inception-2013) was performed. Studies reporting use of mycophenolate in SSc patients, adverse events, modified Rodnan skin score (MRSS), forced vital capacity (FVC), or diffusing capacity of carbon monoxide (DLCO) were included. The primary outcome was gastrointestinal events occurring after the initiation of mycophenolate. Secondary safety outcomes included myelosuppression, infection, malignancy, and death after the initiation of mycophenolate. RESULTS: 617 citations were identified and 21 studies were included. 487 patients were exposed to mycophenolate. The mean disease duration ranged between 0.8-14.1 years. There were 18 deaths and 90 non-lethal adverse events. The non-lethal adverse events included 43 (47.7%) gastrointestinal events, 34 (26%) infections, 6 (5%) cytopenias and 2 (2%) malignancies. The most common gastrointestinal events included diarrhea (n=18 (14%)), nausea (n=12 (9%)), and abdominal pain (n=3 (2%)). The rate of discontinuation ranged between 8%-40%. Seven observational studies reported improvement or stabilization in FVC, and 5 studies report stabilization or improvement in MRSS. CONCLUSION: Mycophenolate-associated gastrointestinal adverse events are common in SSc, but not severe enough to preclude its use. Observational data suggests mycophenolate may be effective in improving or stabilizing interstitial lung disease, and skin involvement. PMID- 25933091 TI - The Association of Alcohol Use Disorders with Suicidal Ideation and Suicide Attempts in a Population-Based Sample with Mood Symptoms. AB - Using population-based data, we examined associations between alcohol use disorders (AUD) and suicidality, assessing effect modification by mood disorders, and mediation by drinking level. Suicidality was assessed among current drinkers with 2-weeks of low mood (n = 9,173) in the National Epidemiologic Survey on Alcohol and Related Conditions. Independent of mood disorder, alcohol dependence, was associated with suicidal ideation (adjusted odds ratio [AOR] = 1.64; 95% confidence interval [CI] = 1.25-2.14), and suicide attempts (AOR = 2.02; CI = 1.43-2.85) relative to those without AUD. Findings indicate partial mediation by consumption. Associations between AUD and suicidality among those with low mood are not explained by comorbid mood disorder, but are partially mediated by drinking level. Future studies should evaluate transitions in suicidality with change in consumption. PMID- 25933093 TI - Ataxia and Its Association with Hearing Impairment in Childhood Bacterial Meningitis. AB - INTRODUCTION: Ataxia, deemed usually a minor sequela, follows childhood bacterial meningitis (BM) in up to 18% of cases. Although mostly transient and benign, it can predict permanent hearing loss and vestibular dysfunction. We explored the clinical meaning of ataxia by following its course in a large number of BM patients and examining its relation with hearing loss. METHODS: The presence, degree (no, mild, moderate and severe) and course (transient, prolonged and late) of ataxia in BM were registered prospectively by predefined criteria. These data were compared with several patient, disease, and outcome variables including hearing loss (none, moderate, severe and profound) on day 7 of treatment and at a follow-up visit 1 month after discharge. RESULTS: Ataxia was present in 243 of 361 (67%) patients on day 7, being slight in 21%, moderate in 38% and severe in 41%. Its course was transient in 41%, prolonged in 24% and late in 5%, whereas 30% of the patients did not present ataxia at any time. Ataxia associated most significantly not only with several measures of BM severity and suboptimal outcome (P < 0.0001), but also specifically, albeit not consistently, with hearing loss (P = 0.001). The degree of ataxia correlated with the extent of hearing loss (rho, 0.37; P < 0.0001). CONCLUSIONS: Ataxia is more frequent and lasts longer after BM than learned from previous studies. The presence and intensity of ataxia associate with hearing loss and its magnitude. PMID- 25933092 TI - Overlapping DNA methylation dynamics in mouse intestinal cell differentiation and early stages of malignant progression. AB - Mouse models of intestinal crypt cell differentiation and tumorigenesis have been used to characterize the molecular mechanisms underlying both processes. DNA methylation is a key epigenetic mark and plays an important role in cell identity and differentiation programs and cancer. To get insights into the dynamics of cell differentiation and malignant transformation we have compared the DNA methylation profiles along the mouse small intestine crypt and early stages of tumorigenesis. Genome-scale analysis of DNA methylation together with microarray gene expression have been applied to compare intestinal crypt stem cells (EphB2high), differentiated cells (EphB2negative), ApcMin/+ adenomas and the corresponding non-tumor adjacent tissue, together with small and large intestine samples and the colon cancer cell line CT26. Compared with late stages, small intestine crypt differentiation and early stages of tumorigenesis display few and relatively small changes in DNA methylation. Hypermethylated loci are largely shared by the two processes and affect the proximities of promoter and enhancer regions, with enrichment in genes associated with the intestinal stem cell signature and the PRC2 complex. The hypermethylation is progressive, with minute levels in differentiated cells, as compared with intestinal stem cells, and reaching full methylation in advanced stages. Hypomethylation shows different signatures in differentiation and cancer and is already present in the non-tumor tissue adjacent to the adenomas in ApcMin/+ mice, but at lower levels than advanced cancers. This study provides a reference framework to decipher the mechanisms driving mouse intestinal tumorigenesis and also the human counterpart. PMID- 25933094 TI - Fungal Endocarditis in Neonates: A Review of Seventy-one Cases (1971-2013). AB - BACKGROUND: Fungal endocarditis (FE) remains an uncommon but life-threatening complication of invasive fungal infections. As data on neonatal FE are scant, we aimed to review all published experience regarding this serious infection. METHODS: Neonatal FE cases published in PubMed (1971-2013) as single cases, or case series were identified using the terms "fungal endocarditis, neonates and cardiac vegetation." Data on predefined criteria including demographics, predisposing factors, mycology, sites of cardiac involvement, therapy and outcome were collected and analyzed. RESULTS: The dataset comprised 71 neonates with FE. Median birth weight was 940 g [interquartile range (IQR): 609], median gestational age 27 weeks (IQR: 6) and median postnatal age at diagnosis 20 days (IQR: 20). Ninety-two percent of the patients were premature. Right atrium was the most common vegetation site (63%). Seventy-one percent of the cases reported were associated with previous central venous catheters. Candida albicans was the most predominant fungal species (59%). Amphotericin B monotherapy was used in 42.2% and fluconazole in 2.8%. Amphotericin B with flucytosine (25.3%) was the most frequent combined regimen. Surgical treatment was conducted in 28%. Overall mortality was 42.2%. Initiation with combined antifungal treatment was associated with lower mortality than monotherapy (24.2% vs. 51.7%, respectively, P = 0.036). CONCLUSIONS: Neonatal FE most frequently occurs in very premature infants and is associated with central venous catheters. C. albicans is the predominant fungus. Although outcome has been dismal, it may be improved with combined antifungal therapy. PMID- 25933095 TI - Chronic Candida albicans Meningitis in a 4-Year-Old Girl with a Homozygous Mutation in the CARD9 Gene (Q295X). AB - A 4-year-old Turkish girl of consanguineous parents was hospitalized for the evaluation of headaches and recurrent febrile episodes of unknown origin. Her medical history was unremarkable except for a few episodes of uncomplicated oral thrush. Meningitis was diagnosed, and Candida albicans was the only pathogen identified by polymerase chain reaction and culture. Despite systemic antifungal multidrug therapy, a prolonged course of 16 months of therapy was necessary to clear C. albicans from the cerebrospinal fluid. Molecular genetic analysis revealed a homozygous caspase recruitment domain 9 (CARD9) mutation (Q295X), which was reported to predispose to chronic mucocutaneous candidiasis. Immunologic workup excluded predisposing B-cell and T-cell defects. In addition, T cells producing interleukin-17 were repeatedly measured within the normal range. Analyses of neutrophils demonstrated normal nicotinamide adenine dinucleotide phosphate oxidase activity in response to various stimuli including Staphylococcus aureus and C. albicans. Additional neutrophilic functional testing, however, showed a decreased cytotoxicity to nonopsonized C. albicans, indicating an impaired killing mechanism against Candida spp. independent from the production of reactive oxygen species by the nicotinamide adenine dinucleotide phosphate oxidase system. Because this defect was only demonstrated in the absence of opsonins, it might especially predispose to chronic C. albicans infections in the central nervous system where opsonin concentrations are usually low. We, therefore, suggest that due to an additional neutrophil dependent defect CARD9 deficiency predisposes not only to chronic mucocutaneous candidiasis, but also to invasive chronic Candida infections, especially of the central nervous system. PMID- 25933097 TI - Light-Harvesting Nanoparticle Core-Shell Clusters with Controllable Optical Output. AB - We used DNA self-assembly methods to fabricate a series of core-shell gold nanoparticle-DNA-colloidal quantum dot (AuNP-DNA-Qdot) nanoclusters with satellite-like architecture to modulate optical (photoluminescence) response. By varying the intercomponent distance through the DNA linker length designs, we demonstrate precise tuning of the plasmon-exciton interaction and the optical behavior of the nanoclusters from regimes characterized by photoluminescence quenching to photoluminescence enhancement. The combination of detailed X-ray scattering probing with photoluminescence intensity and lifetime studies revealed the relation between the cluster structure and its optical output. Compared to conventional light-harvesting systems like conjugated polymers and multichromophoric dendrimers, the proposed nanoclusters bring enhanced flexibility in controlling the optical behavior toward a desired application, and they can be regarded as controllable optical switches via the optically pumped color. PMID- 25933096 TI - OXPHOS-Mediated Induction of NAD+ Promotes Complete Oxidation of Fatty Acids and Interdicts Non-Alcoholic Fatty Liver Disease. AB - OXPHOS is believed to play an important role in non-alcoholic fatty liver disease (NAFLD), however, precise mechanisms whereby OXPHOS influences lipid homeostasis are incompletely understood. We previously reported that ectopic expression of LRPPRC, a protein that increases cristae density and OXPHOS, promoted fatty acid oxidation in cultured primary hepatocytes. To determine the biological significance of that observation and define underlying mechanisms, we have ectopically expressed LRPPRC in mouse liver in the setting of NAFLD. Interestingly, ectopic expression of LRPPRC in mouse liver completely interdicted NAFLD, including inflammation. Consistent with mitigation of NAFLD, two markers of hepatic insulin resistance--ROS and PKCepsilon activity--were both modestly reduced. As reported by others, improvement of NAFLD was associated with improved whole-body insulin sensitivity. Regarding hepatic lipid homeostasis, the ratio of NAD+ to NADH was dramatically increased in mouse liver replete with LRPPRC. Pharmacological activators and inhibitors of the cellular respiration respectively increased and decreased the [NAD+]/[NADH] ratio, indicating respiration-mediated control of the [NAD+]/[NADH] ratio. Supporting a prominent role for NAD+, increasing the concentration of NAD+ stimulated complete oxidation of fatty acids. Importantly, NAD+ rescued impaired fatty acid oxidation in hepatocytes deficient for either OXPHOS or SIRT3. These data are consistent with a model whereby augmented hepatic OXPHOS increases NAD+, which in turn promotes complete oxidation of fatty acids and protects against NAFLD. PMID- 25933098 TI - The epidemiology of major depressive disorder and subthreshold depression in Izmir, Turkey: Prevalence, socioeconomic differences, impairment and help seeking. AB - BACKGROUND: Subclinical and clinical depression is common, widely distributed in the general population, and usually associated with role impairment and help seeking. Reliable information at the population level is needed to estimate the disease burden of depression and associated care needs in Turkey. METHOD: The cross-sectional study aimed to assess the prevalence of subthreshold (SubD) and clinical major depressive disorder (MDD) in Izmir, Turkey. In the 5242 eligible households, a total of 4011 individuals were successfully interviewed, yielding a response rate of 76.5%. Prevalence estimates of MDD and SubD depression were formed by using the responses to the questions of the CIDI section E. Short Form 36 (SF-36) to assess health status and functional impairments in eight scaled scores during the last four weeks. All respondents were questioned about receiving 12-month treatment for any psychological complaints, the route of help seeking, as well as prescribed medicines and any hospitalization. RESULTS: The one year prevalence estimate for CIDI/DSM IV MDD was 8.2% (95% CI, 7.4-9.1). Less educated, low income, uninsured, low SES, unemployed/disabled and housewives, slum area residents had higher one year MDD prevalence. Determined prevalence of help seeking from mental health services of SubD and MDD cases were 23.6%, 30.6% respectively. Only 24.8% of clinically depressive patients received minimally adequate treatment. LIMITATIONS: Cross sectional design. CONCLUSION: Higher MDD prevalence correlates with younger ages, female gender, unemployment, less education, lower monthly income, lower SES and uninsurance. Help seeking from mental health services were low. There are treatment gap and impairment in depressive group. PMID- 25933099 TI - Adjunctive armodafinil for major depressive episodes associated with bipolar I disorder. AB - BACKGROUND: In a previous study, adjunctive armodafinil 150 mg/day significantly improved depressive symptoms associated with bipolar I disorder. METHODS: Multicenter, double-blind study of patients with a major depressive episode despite bipolar I disorder maintenance therapy randomized to adjunctive placebo or adjunctive armodafinil 150 or 200mg/day for 8 weeks; for logistical reasons, assignment to armodafinil 200mg/day was discontinued early. Primary efficacy was measured by change from baseline to week 8 in 30-Item Inventory of Depressive Symptomatology-Clinician-Rated (IDS-C30) total score. RESULTS: Patients were randomized to adjunctive placebo (n=230), adjunctive armodafinil 150 mg/day (n=232), or adjunctive armodafinil 200mg/day (n=30; analyzed for safety only). Least-square mean change in IDS-C30 total score was numerically superior for adjunctive armodafinil 150 mg/day vs adjunctive placebo, but was not statistically significant (p=0.13). Armodafinil was well-tolerated. Adverse events (AEs) observed in >5% with adjunctive armodafinil 150 mg/day and more frequently than with adjunctive placebo were headache (16% [38/231] vs 13% [30/229]) and nausea (7% [17/231] vs 2% [5/229]). The most common AEs with adjunctive armodafinil 200mg/day were diarrhea and dry mouth (17% [5/30] each vs 6% [13/229] and 1% [3/229], respectively, with adjunctive placebo). LIMITATIONS: Early study discontinuation for logistical reasons by the sponsor limited adjunctive armodafinil 200-mg/day assessment. CONCLUSIONS: FDA-approved bipolar I depression treatments are limited. Adjunctive armodafinil 150 mg/day reduced depressive symptoms associated with bipolar I disorder to a greater extent than adjunctive placebo, although the difference failed to reach statistical significance. Safety data indicate treatment with adjunctive armodafinil was well tolerated. PMID- 25933100 TI - Reversible Changes of Left Atrial Function during Pregnancy Assessed by Two Dimensional Speckle Tracking Echocardiography. AB - BACKGROUND: Left ventricular diastolic function is impaired during pregnancy. However, changes in left atrial (LA) function remain unclear. We aimed to evaluate changes in LA function during pregnancy using two-dimensional speckle tracking echocardiography (2DSTE). METHODS AND RESULTS: 50 pregnant and 50 healthy nulliparous (control group) women were enrolled in this study. All pregnant women were followed up postpartum in sixth-month. The LA maximum volume, LA minimal volume and LA preatrial contraction volume were obtained using biplane modified Simpson's method. LA filling volume, LA expansion index, LA ejection fraction, passive volume, passive emptying index, active volume, and active emptying index were calculated. LA longitudinal systolic strain (SS), systolic strain rate (s-SR), early diastolic strain rate (e-SR), and late diastolic strain rate (a-SR) were obtained by 2DSTE. Compared to the control group, the reservoir function was increased in pregnant patients (P<0.05); conduit function was decreased in pregnant patients (P<0.05); booster pump function was increased in pregnant patients (P<0.05). There was no statistically significant difference between the control group and postpartum group. CONCLUSIONS: LA reservoir and booster pump function were increased, while conduit function was decreased during pregnancy using 2DSTE. The changes were reversible. 2DSTE can easily assess LA function during pregnancy with good repeatability. PMID- 25933101 TI - A neural network-based optimal spatial filter design method for motor imagery classification. AB - In this study, a novel spatial filter design method is introduced. Spatial filtering is an important processing step for feature extraction in motor imagery based brain-computer interfaces. This paper introduces a new motor imagery signal classification method combined with spatial filter optimization. We simultaneously train the spatial filter and the classifier using a neural network approach. The proposed spatial filter network (SFN) is composed of two layers: a spatial filtering layer and a classifier layer. These two layers are linked to each other with non-linear mapping functions. The proposed method addresses two shortcomings of the common spatial patterns (CSP) algorithm. First, CSP aims to maximize the between-classes variance while ignoring the minimization of within classes variances. Consequently, the features obtained using the CSP method may have large within-classes variances. Second, the maximizing optimization function of CSP increases the classification accuracy indirectly because an independent classifier is used after the CSP method. With SFN, we aimed to maximize the between-classes variance while minimizing within-classes variances and simultaneously optimizing the spatial filter and the classifier. To classify motor imagery EEG signals, we modified the well-known feed-forward structure and derived forward and backward equations that correspond to the proposed structure. We tested our algorithm on simple toy data. Then, we compared the SFN with conventional CSP and its multi-class version, called one-versus-rest CSP, on two data sets from BCI competition III. The evaluation results demonstrate that SFN is a good alternative for classifying motor imagery EEG signals with increased classification accuracy. PMID- 25933102 TI - Regiodivergent addition of phenols to allylic oxides. AB - The regiodivergent addition of substituted phenols to allylic oxides has been demonstrated using C2-symmetric palladium complexes. Complex phenol donors tyrosine, estradiol, and griseofulvin follow the predictive model. PMID- 25933103 TI - Metabolomic Profiling of the Nectars of Aquilegia pubescens and A. Canadensis. AB - To date, variation in nectar chemistry of flowering plants has not been studied in detail. Such variation exerts considerable influence on pollinator-plant interactions, as well as on flower traits that play important roles in the selection of a plant for visitation by specific pollinators. Over the past 60 years the Aquilegia genus has been used as a key model for speciation studies. In this study, we defined the metabolomic profiles of flower samples of two Aquilegia species, A. Canadensis and A. pubescens. We identified a total of 75 metabolites that were classified into six main categories: organic acids, fatty acids, amino acids, esters, sugars, and unknowns. The mean abundances of 25 of these metabolites were significantly different between the two species, providing insights into interspecies variation in floral chemistry. Using the PlantSEED biochemistry database, we found that the majority of these metabolites are involved in biosynthetic pathways. Finally, we explored the annotated genome of A. coerulea, using the PlantSEED pipeline and reconstructed the metabolic network of Aquilegia. This network, which contains the metabolic pathways involved in generating the observed chemical variation, is now publicly available from the DOE Systems Biology Knowledge Base (KBase; http://kbase.us). PMID- 25933104 TI - Mechanism of Arctigenin-Induced Specific Cytotoxicity against Human Hepatocellular Carcinoma Cell Lines: Hep G2 and SMMC7721. AB - Arctigenin (ARG) has been previously reported to exert high biological activities including anti-inflammatory, antiviral and anticancer. In this study, the anti tumor mechanism of ARG towards human hepatocellular carcinoma (HCC) was firstly investigated. We demonstrated that ARG could induce apoptosis in Hep G2 and SMMC7721 cells but not in normal hepatic cells, and its apoptotic effect on Hep G2 was stronger than that on SMMC7721. Furthermore, the following study showed that ARG treatment led to a loss in the mitochondrial out membrane potential, up regulation of Bax, down-regulation of Bcl-2, a release of cytochrome c, caspase-9 and caspase-3 activation and a cleavage of poly (ADP-ribose) polymerase in both Hep G2 and SMMC7721 cells, suggesting ARG-induced apoptosis was associated with the mitochondria mediated pathway. Moreover, the activation of caspase-8 and the increased expression levels of Fas/FasL and TNF-alpha revealed that the Fas/FasL related pathway was also involved in this process. Additionally, ARG induced apoptosis was accompanied by a deactivation of PI3K/p-Akt pathway, an accumulation of p53 protein and an inhibition of NF-kappaB nuclear translocation especially in Hep G2 cells, which might be the reason that Hep G2 was more sensitive than SMMC7721 cells to ARG treatment. PMID- 25933106 TI - Ambient air pollution and depressive symptoms in older adults: Wellenius et al. respond. PMID- 25933105 TI - Adrenal Development in Mice Requires GATA4 and GATA6 Transcription Factors. AB - The adrenal glands consist of an outer cortex and an inner medulla, and their primary purposes include hormone synthesis and secretion. The adrenal cortex produces a complex array of steroid hormones, whereas the medulla is part of the sympathetic nervous system and produces the catecholamines epinephrine and norepinephrine. In the mouse, GATA binding protein (GATA) 4 and GATA6 transcription factors are coexpressed in several embryonic tissues, including the adrenal cortex. To explore the roles of GATA4 and GATA6 in mouse adrenal development, we conditionally deleted these genes in adrenocortical cells using the Sf1Cre strain of animals. We report here that mice with Sf1Cre-mediated double deletion of Gata4 and Gata6 genes lack identifiable adrenal glands, steroidogenic factor 1-positive cortical cells and steroidogenic gene expression in the adrenal location. The inactivation of the Gata6 gene alone (Sf1Cre;Gata6(flox/flox)) drastically reduced the adrenal size and corticosterone production in the adult animals. Adrenocortical aplasia is expected to result in the demise of the animal within 2 weeks after birth unless glucocorticoids are provided. In accordance, Sf1Cre;Gata4(flox/flox)Gata6(flox/flox) females depend on steroid supplementation to survive after weaning. Surprisingly, Sf1Cre;Gata4(flox/flox)Gata6(flox/flox) males appear to live normal lifespans as vital steroidogenic synthesis shifts to their testes. Our results reveal a requirement for GATA factors in adrenal development and provide a novel tool to characterize the transcriptional network controlling adrenocortical cell fates. PMID- 25933107 TI - NOD1 and NOD2 Genetic Variants in Association with Risk of Gastric Cancer and Its Precursors in a Chinese Population. AB - BACKGROUND: Genetic variants of nucleotide-binding oligomerization domain containing protein (NOD) may influence the outcome of Helicobacter pylori (H. pylori) infection and gastric carcinogenesis. To explore genetic variants of NOD1 and NOD2 in association with gastric cancer (GC) and its precursors, a population based study was conducted in Linqu County, China. METHODS: TagSNPs of NOD1 and NOD2 were genotyped by Sequenom MASS array in 132 GCs, and 1,198 subjects with precancerous gastric lesions, and were correlated with evolution of gastric lesions in 766 subjects with follow-up data. RESULTS: Among seven tagSNPs, NOD1 rs2709800 and NOD2 rs718226 were associated with gastric lesions. NOD1 rs2709800 TG genotype carriers had a decreased risk of intestinal metaplasia (IM, OR: 0.53; 95% CI: 0.31-0.92), while NOD2 rs718226 G allele (AG/GG) showed increased risks of dysplasia (DYS, OR: 2.96; 95% CI: 1.86-4.71) and GC (OR: 2.35; 95% CI: 1.24 4.46). Moreover, an additive interaction between rs718226 and H. pylori was found in DYS or GC with synergy index of 3.08 (95% CI: 1.38-6.87) or 3.99 (95% CI: 1.55 10.22), respectively. The follow-up data indicated that NOD2 rs2111235 C allele (OR: 0.52; 95% CI: 0.32-0.83) and rs7205423 G allele (OR: 0.56; 95% CI: 0.35 0.89) were associated with decreased risk of progression in H. pylori-infected subjects. CONCLUSIONS: NOD1 rs2709800, NOD2 rs718226, rs2111235, rs7205423 and interaction between rs718226 and H. pylori infection may be related to risk of gastric lesions. PMID- 25933108 TI - Incremental learning for nu-Support Vector Regression. AB - The nu-Support Vector Regression (nu-SVR) is an effective regression learning algorithm, which has the advantage of using a parameter nu on controlling the number of support vectors and adjusting the width of the tube automatically. However, compared to nu-Support Vector Classification (nu-SVC) (Scholkopf et al., 2000), nu-SVR introduces an additional linear term into its objective function. Thus, directly applying the accurate on-line nu-SVC algorithm (AONSVM) to nu-SVR will not generate an effective initial solution. It is the main challenge to design an incremental nu-SVR learning algorithm. To overcome this challenge, we propose a special procedure called initial adjustments in this paper. This procedure adjusts the weights of nu-SVC based on the Karush-Kuhn-Tucker (KKT) conditions to prepare an initial solution for the incremental learning. Combining the initial adjustments with the two steps of AONSVM produces an exact and effective incremental nu-SVR learning algorithm (INSVR). Theoretical analysis has proven the existence of the three key inverse matrices, which are the cornerstones of the three steps of INSVR (including the initial adjustments), respectively. The experiments on benchmark datasets demonstrate that INSVR can avoid the infeasible updating paths as far as possible, and successfully converges to the optimal solution. The results also show that INSVR is faster than batch nu-SVR algorithms with both cold and warm starts. PMID- 25933109 TI - Optimization of cascade-resilient electrical infrastructures and its validation by power flow modeling. AB - Large-scale outages on real-world critical infrastructures, although infrequent, are increasingly disastrous to our society. In this article, we are primarily concerned with power transmission networks and we consider the problem of allocation of generation to distributors by rewiring links under the objectives of maximizing network resilience to cascading failure and minimizing investment costs. The combinatorial multiobjective optimization is carried out by a nondominated sorting binary differential evolution (NSBDE) algorithm. For each generators-distributors connection pattern considered in the NSBDE search, a computationally cheap, topological model of failure cascading in a complex network (named the Motter-Lai [ML] model) is used to simulate and quantify network resilience to cascading failures initiated by targeted attacks. The results on the 400 kV French power transmission network case study show that the proposed method allows us to identify optimal patterns of generators-distributors connection that improve cascading resilience at an acceptable cost. To verify the realistic character of the results obtained by the NSBDE with the embedded ML topological model, a more realistic but also more computationally expensive model of cascading failures is adopted, based on optimal power flow (namely, the ORNL Pserc-Alaska) model). The consistent results between the two models provide impetus for the use of topological, complex network theory models for analysis and optimization of large infrastructures against cascading failure with the advantages of simplicity, scalability, and low computational cost. PMID- 25933110 TI - Development and initial validation of the Drunkorexia Motives and Behaviors scales. AB - Drunkorexia, or restricting calorie intake on days when alcohol consumption is planned, is a trend among college students. The purpose of the present study is to develop a measure of motivations for drunkorexia before, during, and after alcohol consumption. College students (n=349, Mage=20.71years) completed an online survey including the Drinking Motives Questionnaire-Revised, the Eating Attitudes Test-26, and various drunkorexia items. A multidimensional measure of drunkorexia motives was developed through an iterative measurement development process. The first scale assesses drunkorexia motivations and behaviors through two subscales: Drunkorexia Motives and Drunkorexia Behaviors. The second scale assesses behaviors when drunkorexia is planned, but for various reasons, the individual did not restrict calories prior to alcohol consumption. The third measure examines restrictive drinking behaviors during an alcohol consumption event. The final scale measures compensatory behaviors after an alcohol consumption event. The newly developed measures relate to other established eating disorder and alcohol measures. Specifically, drunkorexia motives seem to be derived from conformity drinking motives. Male students report higher levels of drunkorexia motives and consuming alcohol when drunkorexia fails. The newly developed measures provide an additional perspective on the drunkorexia literature. PMID- 25933111 TI - Symptom and Quality of Life Improvement in LUX-Lung 6: An Open-Label Phase III Study of Afatinib Versus Cisplatin/Gemcitabine in Asian Patients With EGFR Mutation-Positive Advanced Non-small-cell Lung Cancer. AB - INTRODUCTION: In the phase III, LUX-Lung 6 trial, afatinib prolonged progression free survival (PFS) versus cisplatin/gemcitabine in Asian patients with epidermal growth factor receptor (EGFR) mutation-positive non-small-cell lung cancer (NSCLC). This article provides detailed assessments of patient-reported outcomes (PROs), a LUX-Lung 6 secondary end point, and explores the relationship between PFS and health-related quality of life (QoL) in these patients. METHODS: Patients (n = 364) were randomized (2:1) to oral afatinib (40 mg/day) or up to six cycles of cisplatin/gemcitabine (21-day cycle; cisplatin 75 mg/m(2) [d1]; gemcitabine 1000 mg/m(2) [d1,8]). QoL was assessed using the European Organization for Research and Treatment of Cancer Quality of Life Questionnaire and its lung cancer-specific module. The relationship between PFS (investigator assessment and independent review) and QoL was evaluated using analysis of covariance and a longitudinal model. RESULTS: More patients treated with afatinib versus cisplatin/gemcitabine showed improvements in global health status/QoL (p < 0.0001) and physical (p < 0.0001), role (p = 0.013), and social (p < 0.001) functioning scales. Delayed symptom deterioration and better QoL over time was also observed with afatinib. QoL measured before tumor assessment was considerably poorer for patients with progression than those without progression, with significant differences in mean scores at multiple assessment time points. Results from the longitudinal analysis consistently demonstrated a significant negative impact of progression on QoL (p < 0.0001). CONCLUSION: Afatinib improved PFS and PROs versus chemotherapy in EGFR mutation-positive NSCLC patients. Progression was associated with statistically significant worsening in QoL measured before tumor assessment, underscoring the value of PFS as a clinically relevant end point. PMID- 25933112 TI - Capsaicin Enhances the Drug Sensitivity of Cholangiocarcinoma through the Inhibition of Chemotherapeutic-Induced Autophagy. AB - Cholangiocarcinoma (CCA), a devastating cancer with a poor prognosis, is resistant to the currently available chemotherapeutic agents. Capsaicin, the major pungent ingredient found in hot red chili peppers of the genus Capsicum, suppresses the growth of several malignant cell lines. Our aims were to investigate the role and mechanism of capsaicin with respect to the sensitivity of CCA cells to chemotherapeutic agents. The effect of capsaicin on CCA tumor sensitivity to 5-fluorouracil (5-FU) was assessed in vitro in CCA cells and in vivo in a xenograft model. The drug sensitivity of QBC939 to 5-FU was significantly enhanced by capsaicin compared with either agent alone. In addition, the combination of capsaicin with 5-FU was synergistic, with a combination index (CI) < 1, and the combined treatment also suppressed tumor growth in the CCA xenograft to a greater extent than 5-FU alone. Further investigation revealed that the autophagy induced by 5-FU was inhibited by capsaicin. Moreover, the decrease in AKT and S6 phosphorylation induced by 5-FU was effectively reversed by capsaicin, indicating that capsaicin inhibits 5-FU induced autophagy by activating the phosphoinositide 3-kinase (PI3K)/protein kinase B (AKT)/mammalian target of rapamycin (mTOR) pathway in CCA cells. Taken together, these results demonstrate that capsaicin may be a useful adjunct therapy to improve chemosensitivity in CCA. This effect likely occurs via PI3K/AKT/mTOR pathway activation, suggesting a promising strategy for the development of combination drugs for CCA. PMID- 25933114 TI - Correction: Multimodal Holographic Microscopy: Distinction between Apoptosis and Oncosis. PMID- 25933113 TI - Effect of pre-fixation delay and freezing on mink testicular endpoints for environmental research. AB - There is growing interest in using wild animals to monitor the real-life cocktail effect of environmental chemicals on male reproduction. However, practical difficulties, such as long distances to the laboratory, generally prolong the time between euthanisation and specimen handling. For instance, tissue fixation is often performed on frozen material or on material where deterioration has started, which may affect tissue morphology. This study examined the effect of pre-fixation delay and freezing on mink testicular endpoints in order to determine robust endpoints in suboptimally handled specimens. Sexually mature farmed mink (n=30) selected at culling were divided into six groups and subjected to different time intervals between euthanisation and fixation or freezing: 0 hours (fixed immediately post mortem), 6 hours, 18 hours, 30 hours, 42 hours, or frozen 6 hours post mortem and thawed overnight. Unaffected endpoints when pre fixation storage was extended to 30 hours included: area and diameter of the seminiferous tubules, length and weight of the testes, and acrosomes marked with Gata-4. Epithelial height, Sertoli cells marked with Gata-4 and cell morphology were affected endpoints after 6 hours of storage. Freezing the tissue prior to fixation severely altered cell morphology and reduced testicular weight, tubular diameter and area. Morphological changes seen after 6 hours included shredded germ cells and excess cytoplasm in seminiferous tubular lumen, chromatin rearrangements and increased germ cell death. Extended delay before fixation and freezing affected many endpoints in the mink testicular tissue. Some of these endpoints may mimic chemically induced effects, which is important to consider when evaluating specimens from wild animals for environmental toxicity. PMID- 25933115 TI - TreeSeq, a Fast and Intuitive Tool for Analysis of Whole Genome and Metagenomic Sequence Data. AB - Next-generation sequencing is not yet commonly used in clinical laboratories because of a lack of simple and intuitive tools. We developed a software tool (TreeSeq) with a quaternary tree search structure for the analysis of sequence data. This permits rapid searches for sequences of interest in large datasets. We used TreeSeq to screen a gut microbiota metagenomic dataset and a whole genome sequencing (WGS) dataset of a strain of Klebsiella pneumoniae for antibiotic resistance genes and compared the results with BLAST and phenotypic resistance determination. TreeSeq was more than thirty times faster than BLAST and accurately detected resistance gene sequences in complex metagenomic data and resistance genes corresponding with the phenotypic resistance pattern of the Klebsiella strain. Resistance genes found by TreeSeq were visualized as a gene coverage heat map, aiding in the interpretation of results. TreeSeq brings analysis of metagenomic and WGS data within reach of clinical diagnostics. PMID- 25933116 TI - Quantification of Interactions between Dynamic Cellular Network Functionalities by Cascaded Layering. AB - Large, naturally evolved biomolecular networks typically fulfil multiple functions. When modelling or redesigning such systems, functional subsystems are often analysed independently first, before subsequent integration into larger scale computational models. In the design and analysis process, it is therefore important to quantitatively analyse and predict the dynamics of the interactions between integrated subsystems; in particular, how the incremental effect of integrating a subsystem into a network depends on the existing dynamics of that network. In this paper we present a framework for simulating the contribution of any given functional subsystem when integrated together with one or more other subsystems. This is achieved through a cascaded layering of a network into functional subsystems, where each layer is defined by an appropriate subset of the reactions. We exploit symmetries in our formulation to exhaustively quantify each subsystem's incremental effects with minimal computational effort. When combining subsystems, their isolated behaviour may be amplified, attenuated, or be subject to more complicated effects. We propose the concept of mutual dynamics to quantify such nonlinear phenomena, thereby defining the incompatibility and cooperativity between all pairs of subsystems when integrated into any larger network. We exemplify our theoretical framework by analysing diverse behaviours in three dynamic models of signalling and metabolic pathways: the effect of crosstalk mechanisms on the dynamics of parallel signal transduction pathways; reciprocal side-effects between several integral feedback mechanisms and the subsystems they stabilise; and consequences of nonlinear interactions between elementary flux modes in glycolysis for metabolic engineering strategies. Our analysis shows that it is not sufficient to just specify subsystems and analyse their pairwise interactions; the environment in which the interaction takes place must also be explicitly defined. Our framework provides a natural representation of nonlinear interaction phenomena, and will therefore be an important tool for modelling large-scale evolved or synthetic biomolecular networks. PMID- 25933117 TI - Ion hydration dynamics in conjunction with a hydrophobic gating mechanism regulates ion permeation in p7 viroporin from hepatitis C virus. AB - The selectivity of the p7 channel from hepatitis C virus (HCV) toward K(+) over Ca(2+) has made the channel an intriguing system for investigating ion permeation. The present study employs umbrella sampling free energy calculations to investigate the atomistic details of cation conduction through the channel. The free energy profiles suggest that the energy barrier for Ca(2+) conduction is higher than that for K(+) conduction by about 4.5 kcal/mol, thus explaining the selectivity exhibited by the channel toward K(+). A hydrophobic stretch in the channel is proposed to be the primary factor that discriminates K(+) from Ca(2+), and the ion solvation dynamics in this stretch reveals interesting insights into the atomistic mechanisms involved. Two-dimensional free energy landscapes for the ion permeation reveal differences in the lateral motions of K(+) and Ca(2+) with respect to the pore axis, and provide additional details of ion-protein interactions that govern selectivity. PMID- 25933118 TI - HIV Protease Inhibitors Sensitize Human Head and Neck Squamous Carcinoma Cells to Radiation by Activating Endoplasmic Reticulum Stress. AB - BACKGROUND: Human head and neck squamous cell carcinoma (HNSCC) is the sixth most malignant cancer worldwide. Despite significant advances in the delivery of treatment and surgical reconstruction, there is no significant improvement of mortality rates for this disease in the past decades. Radiotherapy is the core component of the clinical combinational therapies for HNSCC. However, the tumor cells have a tendency to develop radiation resistance, which is a major barrier to effective treatment. HIV protease inhibitors (HIV PIs) have been reported with radiosensitizing activities in HNSCC cells, but the underlying cellular/molecular mechanisms remain unclear. Our previous study has shown that HIV PIs induce cell apoptosis via activation of endoplasmic reticulum (ER) stress. The aim of this study was to examine the role of ER stress in HIV PI-induced radiosensitivity in human HNSCC. METHODOLOGY AND PRINCIPAL FINDINGS: HNSCC cell lines, SQ20B and FaDu, and the most commonly used HIV PIs, lopinavir and ritonavir (L/R), were used in this study. Clonogenic assay was used to assess the radiosensitivity. Cell viability, apoptosis and cell cycle were analyzed using Cellometer Vision CBA. The mRNA and protein levels of ER stress-related genes (eIF2alpha, CHOP, ATF 4, and XBP-1), as well as cell cycle related protein, cyclin D1, were detected by real time RT-PCR and Western blot analysis, respectively. The results demonstrated that L/R dose-dependently sensitized HNSCC cells to irradiation and inhibited cell growth. L/R-induced activation of ER stress was correlated to down regulation of cyclin D1 expression and cell cycle arrest under G0/G1 phase. CONCLUSION AND SIGNIFICANCE: HIV PIs sensitize HNSCC cells to radiotherapy by activation of ER stress and induction of cell cycle arrest. Our results provided evidence that HIV PIs can be potentially used in combination with radiation in the treatment of HNSCC. PMID- 25933119 TI - SIV Infection of Lung Macrophages. AB - HIV-1 depletes CD4+ T cells in the blood, lymphatic tissues, gut and lungs. Here we investigated the relationship between depletion and infection of CD4+ T cells in the lung parenchyma. The lungs of 38 Indian rhesus macaques in early to later stages of SIVmac251 infection were examined, and the numbers of CD4+ T cells and macrophages plus the frequency of SIV RNA+ cells were quantified. We showed that SIV infected macrophages in the lung parenchyma, but only in small numbers except in the setting of interstitial inflammation where large numbers of SIV RNA+ macrophages were detected. However, even in this setting, the number of macrophages was not decreased. By contrast, there were few infected CD4+ T cells in lung parenchyma, but CD4+ T cells were nonetheless depleted by unknown mechanisms. The CD4+ T cells in lung parenchyma were depleted even though they were not productively infected, whereas SIV can infect large numbers of macrophages in the setting of interstitial inflammation without depleting them. These observations point to the need for future investigations into mechanisms of CD4+ T cell depletion at this mucosal site, and into mechanisms by which macrophage populations are maintained despite high levels of infection. The large numbers of SIV RNA+ macrophages in lungs in the setting of interstitial inflammation indicates that lung macrophages can be an important source for SIV persistent infection. PMID- 25933120 TI - Antineoplastic Effects of siRNA against TMPRSS2-ERG Junction Oncogene in Prostate Cancer. AB - TMPRSS2-ERG junction oncogene is present in more than 50% of patients with prostate cancer and its expression is frequently associated with poor prognosis. Our aim is to achieve gene knockdown by siRNA TMPRSS2-ERG and then to assess the biological consequences of this inhibition. First, we designed siRNAs against the two TMPRSS2-ERG fusion variants (III and IV), most frequently identified in patients' biopsies. Two of the five siRNAs tested were found to efficiently inhibit mRNA of both TMPRSS2-ERG variants and to decrease ERG protein expression. Microarray analysis further confirmed ERG inhibition by both siRNAs TMPRSS2-ERG and revealed one common down-regulated gene, ADRA2A, involved in cell proliferation and migration. The siRNA against TMPRSS2-ERG fusion variant IV showed the highest anti-proliferative effects: Significantly decreased cell viability, increased cleaved caspase-3 and inhibited a cluster of anti-apoptotic proteins. To propose a concrete therapeutic approach, siRNA TMPRSS2-ERG IV was conjugated to squalene, which can self-organize as nanoparticles in water. The nanoparticles of siRNA TMPRSS2-ERG-squalene injected intravenously in SCID mice reduced growth of VCaP xenografted tumours, inhibited oncoprotein expression and partially restored differentiation (decrease in Ki67). In conclusion, this study offers a new prospect of treatment for prostate cancer based on siRNA-squalene nanoparticles targeting TMPRSS2-ERG junction oncogene. PMID- 25933121 TI - Chemical footprinting: identifying hidden liabilities in manufacturing consumer products. PMID- 25933122 TI - Direct inhibition, but indirect sensitization of pacemaker activity to sympathetic tone by the interaction of endotoxin with HCN-channels. AB - In critically ill patients regulation of heart-rate is often severely disturbed. Interaction of bacterial endotoxin (lipopolysaccharide, LPS) with hyperpolarization-activated cyclic nucleotide-gated cation-(HCN)-channels may interfere with heart-rate regulation. This study analyzes the effect of LPS, the HCN-channel blocker ivabradine or Ca(2+) -channel blockers (nifedipine, verapamil) on pacemaking in spontaneously beating neonatal rat cardiomyocytes (CM) in vitro. In vivo, the effect of LPS on the heart-rate of adult CD1-mice with and without autonomic blockade is analyzed telemetrically. LPS (100 ng/mL) and ivabradine (5 MUg/mL) reduced the beating-rate of CM by 20.1% and 24.6%, respectively. Coincubation of CM with both, LPS and ivabradine, did not further reduce the beating-rate, indicating interaction of both compounds with HCN channels, while coincubation with Ca(2+) -channel blockers and LPS caused additive beating-rate reduction. In CD1-mice (containing an active autonomic nervous-system), injection of LPS (0.4 mg/kg) expectedly resulted in increased heart-rate. However, if the autonomic nervous system was blocked by propranolol and atropine, in line with the in vitro data, LPS induced a significant reduction of heart-rate, which was not additive to ivabradine. The in vivo and in vitro results indicate that LPS interacts with HCN-channels of cardiomyocytes. Thus, LPS indirectly sensitizes HCN-channels for sympathetic activation (tachycardic effect), and in parallel directly inhibits channel activity (bradycardic-effect). Both effects may contribute to the detrimental effects of septic cardiomyopathy and septic autonomic dysfunction. PMID- 25933123 TI - A Comparison of Pressure Mapping Between Two Pressure-Reducing Methods for the Sacral Region. AB - PURPOSE: The objective of this study was to quantify tissue interface pressures that occurred in the sacrum, shoulder, and buttock/thigh regions while using (1) pillows or (2) a wedge system for off-loading of sacral pressures. SUBJECTS AND SETTING: Twenty-one volunteers (11 females and 10 males) residing near a Midwestern, university community consented to participate in the study. Testing was conducted in a hospital bed with pillows and a commercially available wedge system. METHODS: Pressures were measured under 3 test conditions: (1) bed alone, (2) pillows positioned above and below the sacral region, and (3) wedges positioned above and below the sacral region. Each condition was tested with the elevation of the head of the bed at 3 different angles with respect to the foot of the bed (0 degrees , 20 degrees , and 30 degrees ). Two pressure mats were used to capture data; one was located in the shoulder region and the other in the sacral/buttocks/thigh region. RESULTS: Between the pillows and the wedge, the wedge system was the most effective in reducing pressures on the sacral area. In comparison to the bed condition, both the pillow and wedge conditions produced significantly lower mean sacral pressures than the bed alone (P < .05). Because the pillow and wedge systems tilted the body onto one side, higher pressures were identified on the buttock/thigh when compared to the bed alone (P < .05). CONCLUSIONS: Pressure reduction occurred in the sacral region with the pillow and wedge systems; however, this reduction resulted in increased pressures in the posterior-lateral regions of the buttocks and thighs. When using off-loading devices, consideration should be given to all factors, including tissue interface pressures on the sacrum, increased pressures on other body locations, and the likelihood that these increased pressures will result in tissue damage. PMID- 25933124 TI - Factors Influencing Adoption of Hospital-Acquired Pressure Ulcer Prevention Programs in US Academic Medical Centers. AB - PURPOSE: Recent data show a decrease in hospital-acquired pressure ulcers (PUs) throughout US hospitals; these changes may be associated with increased success in implementing evidence-based practices for PU prevention. The purpose of this study was to identify wound care nurse perceptions of the primary factors that influenced the overall reduction of PUs. DESIGN: Cross-sectional descriptive survey. SUBJECTS AND SETTING: Surveys were sent to wound care nurses at 98 University HealthSystem Consortium (UHC) hospitals. The UHC consists of more than 120 academic medical centers and affiliated facilities across the United States. Responses solicited from this survey represented a geographically diverse set of hospitals from less than 200 beds to more than 1000 beds. INSTRUMENT: The survey questionnaire used a framework of 7 internal and 5 external influential factors for implementing evidence-based practices for PU prevention. Internal influential factors queried included availability of nurse specialists, high nursing job turnover, high PU rates, and prevention campaigns. External influential factors included data sharing, Medicare nonpayment policy, and applications for Magnet recognition. METHODS: Hospital-acquired PU prevention experts at UHC hospitals were contacted through the Wound, Ostomy and Continence Nurses Society membership directory to complete the questionnaire. Consenting participants were e-mailed a disclosure and online questionnaire; they were also sent monthly reminders until they either responded to the survey or declined participation. RESULTS: Fifty five respondents (59% response rate) indicated several internal factors that influenced evidence-based practice: hospital prevention campaigns; the availability of nursing specialists; and the level of preventive knowledge among hospital staff. External influential factors included financial concerns; application for Magnet recognition; data sharing among peer institutions; and regulatory issues. CONCLUSIONS: These findings suggest that the Centers for Medicare & Medicaid Services nonpayment policy influenced a large majority of hospital's changes in practice. The availability of nursing specialists for wound consult influenced hospitals internally. These factors are informative of the impact policy has on changes in hospital prioritization of adopting evidence based practices for PU prevention. PMID- 25933126 TI - Characterizing unmet medical need and the potential role of new biologic treatment options in patients with ulcerative colitis and Crohn's disease: a systematic review and clinician surveys. AB - OBJECTIVES: Comparative outcomes of patients with ulcerative colitis (UC) and Crohn's disease (CD) prescribed a biologic therapy are inconclusive. The aim of this research was to characterize the degree of unmet medical need in patients with UC or CD and to identify the potential role for new therapies. METHODS: A systematic literature review was undertaken of studies reporting outcomes associated with the use of existing biologic therapies in patients with UC or CD, focusing on the nature and rate of treatment failure. To complement the systematic review, contemporaneous data were obtained from a survey of practising gastroenterologists in the UK and France. Data were qualitatively combined in a narrative framework to evaluate the degree of unmet medical need among patients with UC or CD. RESULTS: Studies identified in the systematic review (n = 120) were heterogeneous, particularly with respect to the definitions of treatment failure; estimates of treatment failure were high but uncertain. On the basis of standardized definitions, estimates of treatment failure provided by clinicians (n = 102) were high, and they were higher for second-line treatment failure (primary: <= 37%; secondary: <= 41%) compared with first-line treatment failure (primary: <= 26%; secondary: <= 28%). The majority of the systematic review and survey data were reflective of outcomes with infliximab and adalimumab. CONCLUSION: High treatment failure rates associated with existing biologics, identified by the review and clinician surveys, indicate a need for other biologic treatment options to improve the management and outcomes for people with UC and CD. Outcomes associated with existing and new biologic treatments should be investigated in head-to-head randomized trials in the context of their likely uses in clinical practice. PMID- 25933127 TI - Appropriate treatment strategies for intrahepatic recurrence after curative resection of hepatocellular carcinoma initially within the Milan criteria: according to the recurrence pattern. AB - OBJECTIVE: The aim of this study was to investigate appropriate treatment strategies for recurrent intrahepatic hepatocellular carcinoma (HCC) in patients who fulfilled the Milan criteria at primary hepatectomy. PATIENTS AND METHODS: A total of 124 patients who underwent curative-intent resection of HCC at our center between January 2007 and March 2014 were retrospectively enrolled; patients had initially fulfilled the Milan criteria, but developed intrahepatic recurrence. Seventy-four patients underwent transarterial chemoembolization (TACE) and another 50 patients underwent repeat resection (RR) or radiofrequency ablation (RFA). The recurrent HCCs were classified into intrahepatic metastasis and multicentric occurrence by pathologic analysis. Demographic and clinical data and overall survival rates were compared between the RR/RFA and the TACE groups. Subgroup analysis on the basis of the recurrence pattern (early recurrence or late recurrence) was carried out, and prognostic factors for survival were investigated. RESULTS: The 1-, 3-, and 5-year overall survival rates for the 124 patients after retreatment were 88.3, 55.4, and 44.3%, respectively. The 1-, 3-, and 5-year overall survival rates after retreatment were not significantly different between the RR/RFA and the TACE groups (P=0.140). Subgroup analysis showed that for late recurrence, survival in the RR/RFA group was better than those of patients in the TACE group (P=0.045). CONCLUSION: TACE may be as effective as RR or RFA for early intrahepatic recurrence, whereas RR/RFA is the preferred option for patients with late recurrence after curative resection of HCC who initially fulfilled the Milan criteria. Prognosis was determined by the number of recurrent tumors and the Child-Pugh class at the time of recurrence. PMID- 25933125 TI - Ribosomal Synthesis of Macrocyclic Peptides in Vitro and in Vivo Mediated by Genetically Encoded Aminothiol Unnatural Amino Acids. AB - A versatile method for orchestrating the formation of side chain-to-tail cyclic peptides from ribosomally derived polypeptide precursors is reported. Upon ribosomal incorporation into intein-containing precursor proteins, designer unnatural amino acids bearing side chain 1,3- or 1,2-aminothiol functionalities are able to promote the cyclization of a downstream target peptide sequence via a C-terminal ligation/ring contraction mechanism. Using this approach, peptide macrocycles of variable size and composition could be generated in a pH-triggered manner in vitro or directly in living bacterial cells. This methodology furnishes a new platform for the creation and screening of genetically encoded libraries of conformationally constrained peptides. This strategy was applied to identify and isolate a low-micromolar streptavidin binder (KD = 1.1 MUM) from a library of cyclic peptides produced in Escherichia coli, thereby illustrating its potential toward aiding the discovery of functional peptide macrocycles. PMID- 25933128 TI - The utility of monetary contingency contracts for weight loss: a systematic review and meta-analysis. AB - Financial incentives to improve health have received increasing attention, but are subject to ethical concerns. Monetary Contingency Contracts (MCCs), which require individuals to deposit money that is refunded contingent on reaching a goal, are a potential alternative strategy. This review evaluates systematically the evidence for weight loss-related MCCs. Randomised controlled trials testing the effect of weight loss-related MCCs were identified in online databases. Random-effects meta-analyses were used to calculate overall effect sizes for weight loss and participant retention. The association between MCC characteristics and weight loss/participant retention effects was calculated using meta-regression. There was a significant small-to-medium effect of MCCs on weight loss during treatment when one outlier study was removed. Group refunds, deposit not paid as lump sum, participants setting their own deposit size and additional behaviour change techniques were associated with greater weight loss during treatment. Post-treatment, there was no significant effect of MCCs on weight loss. There was a significant small-to-medium effect of MCCs on participant retention during treatment. Researcher-set deposits paid as one lump sum, refunds delivered on an all-or-nothing basis and refunds contingent on attendance at classes were associated with greater retention during treatment. Post-treatment, there was no significant effect of MCCs on participant retention. The results support the use of MCCs to promote weight loss and participant retention up to the point that the incentive is removed and identifies the conditions under which MCCs work best. PMID- 25933129 TI - Did you know? PMID- 25933130 TI - Organic-inorganic hybrid nanocomposite-based gas sensors for environmental monitoring. PMID- 25933131 TI - Navigating changes in obstetrics and gynecology. PMID- 25933135 TI - Current management of surgical oncologic emergencies. AB - OBJECTIVES: For some oncologic emergencies, surgical interventions are necessary for dissolution or temporary relieve. In the absence of guidelines, the most optimal method for decision making would be in a multidisciplinary cancer conference (MCC). In an acute setting, the opportunity for multidisciplinary discussion is often not available. In this study, the management and short term outcome of patients after surgical oncologic emergency consultation was analyzed. METHOD: A prospective registration and follow up of adult patients with surgical oncologic emergencies between 01-11-2013 and 30-04-2014. The follow up period was 30 days. RESULTS: In total, 207 patients with surgical oncologic emergencies were included. Postoperative wound infections, malignant obstruction, and clinical deterioration due to progressive disease were the most frequent conditions for surgical oncologic emergency consultation. During the follow up period, 40% of patients underwent surgery. The median number of involved medical specialties was two. Only 30% of all patients were discussed in a MCC within 30 days after emergency consultation, and only 41% of the patients who underwent surgery were discussed in a MCC. For 79% of these patients, the surgical procedure was performed before the MCC. Mortality within 30 days was 13%. CONCLUSION: In most cases, surgery occurred without discussing the patient in a MCC, regardless of the fact that multiple medical specialties were involved in the treatment process. There is a need for prognostic aids and acute oncology pathways with structural multidisciplinary management. These will provide in faster institution of the most appropriate personalized cancer care, and prevent unnecessary investigations or invasive therapy. PMID- 25933136 TI - Viscosity minima in binary mixtures of ionic liquids + molecular solvents. AB - The viscosity (eta) of four binary mixtures (ionic liquids plus molecular solvents, ILs+MSs) was measured in the 283.15 < T/K < 363.15 temperature range. Different IL/MS combinations were selected in such a way that the corresponding eta(T) functions exhibit crossover temperatures at which both pure components present identical viscosity values. Consequently, most of the obtained mixture isotherms, eta(x), exhibit clear viscosity minima in the studied T-x range. The results are interpreted using auxiliary molecular dynamics (MD) simulation data in order to correlate the observed eta(T,x) trends with the interactions in each mixture, including the balance between electrostatic forces and hydrogen bonding. PMID- 25933138 TI - Environmental Sampling for Avian Influenza A(H7N9) in Live-Poultry Markets in Guangdong, China. AB - BACKGROUND: To provide an increased understanding of avian influenza A(H7N9) activity in live-poultry market in space and time and hence improve H7N9 epidemic control, an ongoing environmental sampling program in multiple live-poultry markets across Guangdong, China was conducted during March 2013-June 2014. METHODS: A total of 625 live-poultry markets throughout 21 prefecture areas took part in the study. A total of 10 environmental sites in markets for sampling were identified to represent 4 different poultry-related activity areas. At least 10 environmental samples were collected from each market every month. The real time RT-PCR was performed to detect the avian influenza A(H7N9) virus. Field survey was conducted to investigate the sanitation status of live-poultry markets. RESULTS: There were 109 human infections with H7N9 avian influenza in Guangdong, of which 37 (34%) died. A total of 18741 environmental swabs were collected and subjected to real-time RT-PCR test, of which 905(4.83%) were found positive for H7N9 virus. There were 201 (32.16%) markets affected by H7N9 in 16 prefecture areas. The detection of H7N9 virus in markets spiked in winter months. 63.33% markets (38/60) had no physical segregation for poultry holding, slaughter or sale zones. Closing live-poultry market significantly decreased the H7N9 detection rate from 14.83% (112/755) to 1.67% (5/300). CONCLUSIONS: This study indicates the importance of live-poultry market surveillance based on environmental sampling for H7N9 Avian Influenza control. Improving live-poultry market management and sanitation and changing consumer practices are critical to reduce the risk of H7N9 infection. PMID- 25933137 TI - Articular Joint Lubricants during Osteoarthritis and Rheumatoid Arthritis Display Altered Levels and Molecular Species. AB - BACKGROUND: Hyaluronic acid (HA), lubricin, and phospholipid species (PLs) contribute independently or together to the boundary lubrication of articular joints that is provided by synovial fluid (SF). Our study is the first reporting quantitative data about the molecular weight (MW) forms of HA, lubricin, and PLs in SF from cohorts of healthy donors, patients with early (eOA)- or late (lOA) stage osteoarthritis (OA), and patients with active rheumatoid arthritis (RA). METHODS: We used human SF from unaffected controls, eOA, lOA, and RA. HA and lubricin levels were measured by enzyme-linked immunosorbent assay. PLs was quantified by electrospray ionization tandem mass spectrometry. Fatty acids (FAs) were analyzed by gas chromatography, coupled with mass spectrometry. The MW distribution of HA was determined by agarose gel electrophoresis. RESULTS: Compared with control SF, the concentrations of HA and lubricin were lower in OA and RA SF, whereas those of PLs were higher in OA and RA SF. Moreover, the MW distribution of HA shifted toward the lower ranges in OA and RA SF. We noted distinct alterations between cohorts in the relative distribution of PLs and the degree of FA saturation and chain lengths of FAs. CONCLUSIONS: The levels, composition, and MW distribution of all currently known lubricants in SF--HA, lubricin, PLs--vary with joint disease and stage of OA. Our study is the first delivering a comprehensive view about all joint lubricants during health and widespread joint diseases. Thus, we provide the framework to develop new optimal compounded lubricants to reduce joint destruction. PMID- 25933139 TI - First Week HCV RNA Level Under the Pegylated Interferon and Ribavirin Treatment Predicts Sustained Virological Response. AB - This study was planned to investigate whether the decrease in the hepatitis C virus (HCV) RNA levels at the first week of combined pegylated interferon and ribavirin treatment of naive genotype 1 patients with HCV was predicting sustained virologic response (SVR). Fifty-two patients were enrolled into the study. HCV RNA levels were measured at the baseline, first, fourth, and 12th weeks of treatment. Thirty-four patients achieved SVR, which basal, first week, and fourth week HCV RNA levels were log 5.57, log 3.65, and log 1.92, respectively. Eighteen patients could not achieve SVR, which basal, first week, and fourth week HCV RNA levels were log 6.22, log 5.45, and log 3.84, respectively (P < 0.05). Patients were distributed in 2 groups according to the amount of decrease in HCV RNA levels at the first week as less or more than 1.5 log. There were 20 patients with >=1.5 log decrease in the HCV RNA levels at the first week. They were named as patients with very rapid virologic response (VRVR). All patients (100%) with VRVR were achieved SVR. In only 14 (44%) of the 32 patients without VRVR, SVR was achieved. In 16 (84%) of the 19 patients with rapid virologic response and 33 (79%) of the 42 patients with early virologic response, SVR was achieved. A >=1.5 log decrease (VRVR) in HCV RNA levels of patients with HCV at the first week of combined pegylated interferon and ribavirin treatment predicts SVR very strongly. PMID- 25933140 TI - Ipilimumab-Induced Granulomatous Disease Occurring Simultaneously With Disease Progression in a Patient With Metastatic Melanoma. AB - Malignant melanoma is the most aggressive cutaneous malignancy with dismal prognosis in the advanced setting. The food and drug administration approval of ipilimumab, the monoclonal antibody against cytotoxic T-lymphocyte antigen 4, has significantly changed treatment strategies for this disease. However, the spectrum of immune-related adverse events secondary to ipilimumab therapy is a growing area of research, and clinical observations of rare immune events as a result of such therapies continue to be reported since the approval. The co occurrence of disease progression along with an immune-related adverse event is extremely rare. We here present the first case, to our knowledge, of diffuse nonnecrotizing granulomatous lymphadenopathy occurring simultaneously with disease progression in a patient with metastatic melanoma after receiving the second dose of ipilimumab. PMID- 25933141 TI - Mycophenolate-Induced Posterior Reversible Encephalopathy Syndrome. AB - A 29-year-old woman presented with diffuse anasarca and shortness of breath. Workup revealed a creatinine of 3.3 and a glomerular filtration rate of 17. The patient was also found to be pancytopenic with evidence of hemolytic anemia. A renal biopsy showed evidence of stage IV lupus nephritis with rapidly progressive glomerulonephritis. Her lupus was further classified as ANA negative and anti dsDNA positive. Mycophenolate and triweekly hemodialysis were started along with a steroid burst of methylprednisolone 1 g for 3 days followed by prednisone 60 mg daily. Four days after discharge, the patient represented with a witnessed 3 minute seizure involving bowel incontinence, altered mental status, and tongue biting. She was given 2 mg intravenous lorazepam and loaded with 1000 mg levetiracetam for seizure prophylaxis. Magnetic resonance imaging of the head revealed bilateral posterior hemispheric subcortical edema, and the diagnosis of posterior reversible encephalopathy syndrome was made. Mycophenolate was immediately discontinued and replaced with cyclophosphamide. Strict blood pressure control below 140/90 mm Hg was maintained initially with intravenous nicardipine drip and then transitioned to oral nifedipine, clonidine, losartan, and minoxidil. A repeat head magnetic resonance imaging 8 days later showed resolved subcortical edema consistent with the patient's improved mental status. No permanent neurologic sequelae were recorded as a result of this hospital episode. PMID- 25933142 TI - Increased Vagal Tone and Sleep Apnea Syndrome. AB - It has been observed that atrial overdrive pacing abolishes sleep apnea syndrome, but how it does so has not been explained. There is a possibility that it sends a retrograde inhibitory impulse to the vagal center in the brainstem, which in turn reduces the vagal tone, and thus prevents sleep apnea. Therefore, medical vagolytics such as atropine type of drugs should have the same effect. This is a case report of such an attempt. PMID- 25933143 TI - The Government Does Not Take an Oath of Privacy. PMID- 25933144 TI - The effect of methylprednisolone on facial nerve paralysis with different etiologies. AB - OBJECTIVES: The objective of this study was to evaluate the effectiveness of methylprednisolone (MP) in models of facial nerve paralysis obtained by nerve section, compression, or inoculation with herpes simplex virus (HSV). STUDY DESIGN: Experimental controlled animal study. SETTING: Tertiary referral center. METHODS: A total of 30 female New Zealand rabbits weighing 1200-3000 g were used for the study. They were randomly assigned to one of 6 groups of 5 animals each. A nerve section injury was realized in Groups 1a (section and MP) and 1b (section, control) rabbits. A compression-type injury was inflicted to rabbits in Groups 2a (compression and MP) and 2b (compression, control). As for animals in Groups 3a (Type 1 HSV and MP) and 3b (Type 1 HSV, controls), facial nerve paralysis resulting from viral infection was obtained. Animals in the 3 treatment groups, designated with the letter "a", were administered MP, 1 mg/kg/d, whereas those in control groups "b" received 1 mL normal saline, both during 3 weeks. All subjects were followed up for 2 months. At the end of this period, all animals had the buccal branch of the facial nerve excised on the operated side. Semi-thin sections of these specimens were evaluated under light microscopy for the following: perineural fibrosis, increase in collagen fibers, myelin degeneration, axonal degeneration, Schwann cell proliferation, and edema. RESULTS: No significant difference was observed (P > 0.05) between the MP treatment group and the control group with regard to perineural fibrosis, increase in collagen fibers, myelin degeneration, axonal degeneration, edema, or Schwann cell proliferation. In the group with a compressive lesion (Group 2), controls were no different from MP-treated animals as to perineural fibrosis, increase in collagen fibers, or Schwann cell proliferation, whereas axonal degeneration, myelin degeneration, and edema were significantly higher (P < 0.05) in the control group. When comparing the treatment and control groups among the animals inoculated with Type 1 HSV, no significant difference was found with regard to perineural fibrosis, axonal degeneration, myelin degeneration, or Schwann cell proliferation. The only statistically significant advantage of the treatment group was in edema formation (P < 0.05). CONCLUSIONS: As a result of the evaluation of MP efficacy in different models of facial nerve palsy, we may say that this drug was without effect on nerve healing in paralysis due to nerve section and that it only reduced nervous edema in paralysis induced by Type 1 HSV, whereas it had positive effects on healing in the type of paralysis caused by nerve compression. PMID- 25933145 TI - The effects of aminoguanidine, methylprednisolone, and melatonin on nerve recovery in peripheral facial nerve neurorrhaphy. AB - BACKGROUND: The medications may enhance the recovery after nerve paralysis. We aimed to evaluate the effects of aminoguanidine (AG), melatonin, and methylprednisolone on peripheral facial nerve neurorrhaphy. METHODS: The buccal branch of the facial nerve was transected and autografted in 32 New Zealand rabbits. Subjects were divided into 4 groups equally (AG, melatonin, methylprednisolone, and control). After the medical treatment latency and amplitude were measured with nerve conduction study at 3, 6, and 10 weeks. Then, coapted segments of nerve were examined microscopically. The groups were compared with each other. RESULTS: The latent period was shortened, and the amplitudes were increased in the AG group; the latent period was shortened, and the amplitudes did not show significant change in the melatonin group with the time. There were no significant differences between the amplitudes at 3 to 6 and 3 to 10 weeks in the methylprednisolone group, and the latent period was shortened. There was no significant difference between the amplitude values at 3, 6, and 10 weeks in the control group. In the histological examination, AG had the best influence on preventing myelin degeneration and reducing the accumulation of myelin debris. Considering the increase in collagen fibers, the best results were achieved in the melatonin group. The degree of myelin-axonal degeneration was higher in the methylprednisolone group. The degree of collagen fiber increase, axonal degeneration, myelin degeneration, and the accumulation of myelin debris were detected quite high in the control group. CONCLUSIONS: Aminoguanidine and melatonin alone achieved an increase in regeneration after peripheral facial nerve neurorrhaphy, but methylprednisolone did not. The best healing was determined in the AG group. PMID- 25933146 TI - Blood parameters as indicators of upper airway obstruction in children with adenoid or adenotonsillar hypertrophy. AB - Adenotonsillar hypertrophy (ATH) is the most common cause of obstructive sleep apnea in children. This study aimed to evaluate the blood parameters of children with ATH who underwent surgery. METHODS: The study included a review of the medical records of 130 children who underwent adenoidectomy or adenotonsillectomy with a diagnosis of adenoid hypertrophy and/or chronic tonsillitis. Patients were classified into 3 groups: group 1 (n=69) underwent adenoidectomy, group 2 (n=61) underwent adenotonsillectomy, and group 3 consisted of 82 healthy children. White blood cell count, platelet count, hemoglobin levels, mean platelet volume, and platelet distribution width values were the primary outcome measures. RESULTS: Mean platelet volume, platelet distribution width and hemoglobin values decreased in the groups that underwent surgery. Whereas the decrease in group 1 was insignificant, it was significant in group 2. White blood cell count values increased in both group 1 (adenoidectomy) and group 2 (adenotonsillectomy), but the increase in group 2 was significant. No significant difference in platelet count was detected before versus after the operation. CONCLUSIONS: Upper airway obstruction caused by ATH remarkably changes the blood parameters related to chronic hypoxia. Significant improvement can be achieved after adenotonsillectomy rather than adenoidectomy alone. PMID- 25933148 TI - Alveolar rhabdomyosarcoma in the maxillary alveolar ridge of an adult patient. PMID- 25933147 TI - Calculation of the mastoid cell volume of infants from computed tomography imaging. AB - OBJECTIVE: The objective of this study was to calculate the mastoid cell volume of infants using computed tomography imaging. METHODS: We calculated the mastoid cell volumes of 87 infants younger than 1 year classified into 4 age groups. RESULTS: There were significant (P = 0.0001) differences in the ear mastoid cell volumes (cm(3)) among the 0- to 3-, 4- to 6-, 7- to 9-, and 10- to 12-month age groups. Generally, the mastoid cell volume increased with age. CONCLUSIONS: Mastoid cell volume correlates with the age of infants up to 1 year. We plan to expand this study and determine cutoff values for the mastoid cell volumes of infants. PMID- 25933149 TI - Mandibular distraction osteogenesis for the treatment of neonatal tongue-based airway obstruction. AB - Early postnatal tracheostomy for airway compromise is associated with high morbidity and cost. In certain patients with tongue-base airway obstruction (TBAO), mandibular distraction osteogenesis may be preferred. We present a comprehensive analysis of surgical, airway, and cephalometric outcomes in a large series of neonatal patients with TBAO. A retrospective review was performed of patients with laryngoscopically proven TBAO who underwent mandibular distraction osteogenesis before 1 year of age at our institution. Demographic, operative, postoperative, polysomnographic, and radiographic data were analyzed with the appropriate statistical test. Between 2010 and 2013, 28 patients younger than 1 year underwent mandibular distraction for TBAO. Distraction was performed for documented TBAO and failure to thrive at an average age of 58 days (range, 11 312) days with distractor removal after an average of 90 days. Preoperative polysomnograms were obtained on 20 patients with an average apnea-hypopnea index of 39.3 +/- 22.0/h; the apnea-hypopnea index on postoperative polysomnograms obtained after distraction completion was significantly reduced in all 14 patients in whom it was measured (mean, 3.0 +/- 1.5/h; P < 0.0001). Twenty patients transitioned to oral feeding, and cephalometric and airway diameters were improved (P < 0.0001). Distraction was successful in all but 4 patients including all patients with GILLS scores of 2 or less and 66% of patients with GILLS scores of 3 or greater. Neonatal mandibular distraction is a powerful tool to treat critical obstructive apnea in patients with TBAO. Appropriate patient selection remains a challenge; however, mandibular distraction represents a compelling treatment modality. PMID- 25933150 TI - Effect of periosteum attached to autogenous iliac block bone graft on bone resorption in rabbits. AB - The purpose of this study was to evaluate the effect of the periosteum attached to an iliac block bone graft on resorption of the grafted bone. Twenty-one rabbits were used. Iliac bone was harvested with (experimental group) or without a periosteum (control group) and grafted on the rabbit calvarium and fixed with miniscrews. The animals were killed, and specimens were harvested at 1, 4, and 8 weeks after the surgery. Histologic examination and histomorphometry were done. Grafted bones were severely resorbed, and the overall shapes were changed in the control group. On the contrary, the overall shape of the grafted bone was maintained, although the grafted bone was resorbed in the experimental group. Moreover, there were no osteoclasts adjacent to the periosteum of the graft. These results suggest that the periosteum attached to grafted bone can help establish early revascularization and prevent the resorption of grafted bone. PMID- 25933151 TI - Relief of pain at rest and during swallowing after modified cautery-assisted uvulopalatopharyngoplasty: bupivacaine versus lidocaine. AB - OBJECTIVES: We investigated the efficacy of bupivacaine, lidocaine, and saline infiltrations to peritonsillar region and uvula and soft palate regions for pain relief after tonsillectomy and modified cautery-assisted uvulopalatopharyngoplasty (MCAUP) in patients with obstructive sleep apnea. METHODS: In this prospective study, 91 patients (32-65 years old) with obstructive sleep apnea underwent tonsillectomy and MCAUP and were divided into 3 groups. In group 1 patients (n = 31), 0.25% bupivacaine HCl + 1/200,000 epinephrine (10 mL); in group 2 patients (n = 31), 1% lidocaine HCl + 1/200,000 epinephrine (10 mL); and in group 3 patients (n = 29), 0.9% saline (10 mL) were injected to peritonsillar region and uvula and soft palate regions. Operation duration, amount of bleeding, and analgesic requirement and visual analog scale for pain at rest and at swallowing were evaluated in all groups. RESULTS: Mean body mass index values were between 27.0 and 27.3 kg/m in all groups. Their apnea-hypopnea index values were between 15.3 and 16.9 per hour, and there were no significant differences between their body mass index and apnea-hypopnea index values. Duration of operation of patients in the bupivacaine group was significantly lower than that of patients in the lidocaine and saline groups. In addition, in the lidocaine group, operation duration was significantly lower than that in the saline group. Bleeding amount and postoperative analgesic requirement of the saline group were significantly higher than those of the bupivacaine and lidocaine groups. Although both these measures (operation duration and amount of bleeding) were statistically significant, a mean operating time of 44.3 versus 46.0 minutes and 64.4-mL versus 68.4-mL blood loss for the bupivacaine and lidocaine groups were clinically irrelevant and not too important. In terms of visual analog scale for pain at rest and/or swallowing, Bupivacaine provided more relief than lidocaine and saline injections. The lidocaine provides pain relief less than bupivacaine and more than saline at rest and/or swallowing. CONCLUSION: We recommend the use of bupivacaine injections in peritonsillar, uvular, and soft palate regions during tonsillectomy + MCAUP operations. It reduces operation duration and provides more pain relief postoperatively. When patients had cardiac problems, lidocaine may also be recommended because of its cardiac depressant and antiarrhythmic effects and positive effects for pain relief compared with saline injections. PMID- 25933152 TI - Anatomy of the tenth costal cartilage for a columella strut in an Asian rhinoplasty. AB - The aim of this study was to elucidate the precise radiological and surface anatomy of the 10th costal cartilage for the usage of a columella strut in an Asian rhinoplasty.Three hundred abdominal computed tomography scans were reviewed and measured (166 males, 134 females), and the location of the 10th costochondral junction (CCJ) was measured in reference to the anterior superior iliac spine (ASIS) and umbilicus. Sixteen 10th costal cartilages were harvested from 10 Korean adult cadavers (7 males, 3 females), and the length, width, and thickness of each cartilage were measured.Distance from the anterior ASIS to the umbilicus was 155.4 +/- 15.1 mm (male: 157.9 +/- 15.5 mm, female: 152.2 +/- 14.1 mm). Distance from the umbilicus to the 10th CCJ was 170.7 +/- 23.0 mm (male: 179.2 +/ 22.8 mm, female: 160.3 +/- 18.7 mm). Distance from the ASIS to the 10th CSJ angle was 181.8 +/- 21.8 mm (male: 184.7 +/- 21.3 mm, female: 178.2 +/- 22.1 mm). The ASIS-umbilicus-10th CSJ angle was 56.3 +/- 5.6 degrees (male: 55.1 +/- 5.5 degrees, female: 57.8 +/- 5.3 degrees). The average length of the cartilage was 64.1 +/- 19.7 mm. The average curved length of the cartilage was 69.6 +/- 21.0 mm. The average greatest width was 11.0 +/- 2.1 mm, and the width at its mid length was 8.3 +/- 1.7 mm. The average thickness of the cartilage was 5.7 +/- 0.9 mm. In a 33-year-old woman, the 10th costal cartilage was used for columella strut.It is thought that the 10th costal cartilage can provide a sufficient amount and shape for a columella strut and tip in an onlay graft. PMID- 25933153 TI - Recurrent cherubism in an adult patient. AB - Cherubism is an uncommon, nonneoplastic, fibro-osseous disorder of the jaws in childhood and adolescence. It affects the jaw bones by deforming the cortical shell. Clinical features include progressive painless and mostly bilateral expansion of the mandible and/or maxilla. Because fibrous connective tissue replaces osseous tissue, radiographic features generally include expansile osteolytic lesions and a ground-glass appearance. Several treatment protocols for cherubism have been recommended in the literature; however, despite surgical curettage treatment, recurrences may occur. Our aim was to emphasize the high recurrence rate of cherubic lesions. In this article, we present cherubism in a young girl that relapsed after 5 surgical operations before her appearance to our clinic. PMID- 25933154 TI - Low-grade fibromyxoid sarcoma of superior turbinate in a pediatric patient. PMID- 25933155 TI - A patient with pott puffy tumor with pansinusitis and orbital involvement in an immunocompromised patient. PMID- 25933156 TI - Submandibular ossifying lipoma. PMID- 25933157 TI - The contact of third molar and mandibular nerve: health related quality of life differentials. PMID- 25933158 TI - Comparison among three different fixation techniques in temporal brow lift surgery. AB - INTRODUCTION: The eyebrow lifting with temporal approach is an increasing widespread technique. Many surgical procedures are described, but the long-term stability is dependent on the effectiveness in the fixation of elevated tissues. The authors compared 3 different fixation techniques in temporal brow lift. METHODS: Forty-five consecutive patients aged between 33 and 70 underwent brow lift surgery with temporal approach. Patients were divided into 3 groups; in group 1, anchorage was performed with Endotine Ribbon, group 2 with a Mersilene mesh, and group 3 with a Prolene suture. The amount of brow elevation was assessed comparing the distance between interpupillar line and superior eyebrow hairline, measured at the midpupil and at the lateral and medial canthal angle. The follow-up was 1 year. RESULTS: All patients had a pleasant improvement in brow shape. The average initial brow position was 19.84 mm near the head of the eyebrow area, 20.74 mm at the body, and 19.57 mm in the region of the tail. A progressive recovery and a partial relapse regarding the eyebrow body (23.88 mm at 6 months and 23.02 mm at 1 year) occurred, but overall for the lateral region, it passed from 27.53 mm at 6 months to 25.80 mm after a 12-month follow-up. Final brow position was dependent upon surgical technique used in fixation. DISCUSSION: Different options in brow elevation and stabilization affect the final shape and position of the brows. From the statistical analysis, mesh suspension provided the best results in terms of long-lasting stability. LEVEL OF EVIDENCE: Therapeutic III. PMID- 25933159 TI - A novel micelle-forming material used for preparing a theranostic vehicle exhibiting enhanced in vivo therapeutic efficacy. AB - A new micelle-forming material, folic acid-conjugated carboxymethyl lauryl chitosan (FA-CLC), and superparamagnetic iron oxide (SPIO) nanoparticles were used for preparing an imaging-guided drug vehicle (the FA-CLC/SPIO hybrid micelle) that demonstrates targeted delivery, imaging, and controlled release of hydrophobic agents. We found that the ratio of viable normal cells to tumor cells was increased prominently after delivery of camptothecin (CPT)-loaded FA-CLC/SPIO micelles and therapeutic sonication. In addition, a magnetic field could enhance the tumor-targeting effect of FA-CLC/SPIO micelles. Therefore, after sequential administration of magnetic attraction to CPT-loaded FA-CLC/SPIO micelles, and therapeutic sonication, the in vivo therapeutic efficacy of CPT was markedly enhanced. However, a nonfocused magnetic field could enhance the undesirable accumulation of iron-containing vehicles in the liver if the tumor (i.e., magnetic attraction site) is near the liver. We propose that magnetic attraction must be carefully applied, far from the liver. PMID- 25933160 TI - Incorporation of porcine adenovirus 4 fiber protein enhances infectivity of adenovirus vector on dendritic cells: implications for immune-mediated cancer therapy. AB - One strategy in cancer immunotherapy is to capitalize on the key immunoregulatory and antigen presenting capabilities of dendritic cells (DCs). This approach is dependent on efficient delivery of tumor specific antigens to DCs, which subsequently induce an anti-tumor T-cell mediated immune response. Human adenovirus serotype 5 (HAdV5) has been used in human studies for gene delivery, but has limited infection in DCs, which lack the proper receptors. Addition of the porcine fiber knob (PK) from porcine adenovirus type 4 to HAdV5 allows the virus to deliver genetic material via binding to glycosylated surface proteins and bypasses the coxsackie-and-adenovirus receptor required by wild-type HAdV5. In this study we explored the potential therapeutic applications of an adenovirus with PK-based tropism against cancers expressing mesothelin. Infectivity and gene transfer assays were used to compare Ad5-PK to wild-type HAdV5. Mouse models were used to demonstrate peptide specificity and T-cell responses. We show that the PK modification highly augmented infection of DCs, including the CD141+ DC subset, a key subset for activation of naive CD8+ T-cells. We also show that Ad5-PK increases DC infectivity and tumor specific antigen expression. Finally, vaccination of mice with the Ad5-PK vector resulted in enhanced T-cell-mediated interferon gamma (IFN-gamma) release in response to both mesothelin peptide and a tumor line expressing mesothelin. Ad5-PK is a promising tool for cancer immunotherapy as it improves infectivity, gene transfer, protein expression, and subsequent T-cell activation in DCs compared to wild-type HAdV5 viruses. PMID- 25933161 TI - Effects of beam interruption time on tumor control probability in single fractionated carbon-ion radiotherapy for non-small cell lung cancer. AB - Carbon-ion radiotherapy treatment plans are designed on the assumption that the beams are delivered instantaneously, irrespective of actual dose-delivery time structure in a treatment session. As the beam lines are fixed in the vertical and horizontal directions at our facility, beam delivery is interrupted in multi field treatment due to the necessity of patient repositioning within the fields. Single-fractionated treatment for non-small cell lung cancer (NSCLC) is such a case, in which four treatment fields in multiple directions are delivered in one session with patient repositioning during the session. The purpose of this study was to investigate the effects of the period of dose delivery, including interruptions due to patient repositioning, on tumor control probability (TCP) of NSCLC. All clinical doses were weighted by relative biological effectiveness (RBE) evaluated for instantaneous irradiation. The rate equations defined in the microdosimetric kinetic model (MKM) for primary lesions induced in DNA were applied to the single-fractionated treatment of NSCLC. Treatment plans were made for an NSCLC case for various prescribed doses ranging from 25 to 50 Gy (RBE), on the assumption of instantaneous beam delivery. These plans were recalculated by varying the interruption time tau ranging from 0 to 120 min between the second and third fields for continuous irradiations of 3 min per field based on the MKM. The curative doses that would result in a TCP of 90% were deduced for the respective interruption times. The curative dose was 34.5 Gy (RBE) for instantaneous irradiation and 36.6 Gy (RBE), 39.2 Gy (RBE), 41.2 Gy (RBE), 43.3 Gy (RBE) and 44.4 Gy (RBE) for tau = 0 min, 15 min, 30 min, 60 min and 120 min, respectively. The realistic biological effectiveness of therapeutic carbon-ion beam decreased with increasing interruption time. These data suggest that the curative dose can increase by 20% or more compared to the planned dose if the interruption time extends to 30 min or longer. These effects should be considered in carbon-ion radiotherapy treatment planning if a longer dose-delivery procedure time is anticipated. PMID- 25933162 TI - Short LOV Proteins in Methylocystis Reveal Insight into LOV Domain Photocycle Mechanisms. AB - Light Oxygen Voltage (LOV) proteins are widely used in optogenetic devices, however universal signal transduction pathways and photocycle mechanisms remain elusive. In particular, short-LOV (sLOV) proteins have been discovered in bacteria and fungi, containing only the photoresponsive LOV element without any obvious signal transduction domains. These sLOV proteins may be ideal models for LOV domain function due to their ease of study as full-length proteins. Unfortunately, characterization of such proteins remains limited to select systems. Herein, we identify a family of bacterial sLOV proteins present in Methylocystis. Sequence analysis of Methylocystis LOV proteins (McLOV) demonstrates conservation with sLOV proteins from fungal systems that employ competitive dimerization as a signaling mechanism. Cloning and characterization of McLOV proteins confirms functional dimer formation and reveal unexpected photocycle mechanisms. Specifically, some McLOV photocycles are insensitive to external bases such as imidazole, in contrast to previously characterized LOV proteins. Mutational analysis identifies a key residue that imparts insensitivity to imidazole in two McLOV homologs and affects adduct decay by two orders of magnitude. The resultant data identifies a new family of LOV proteins that indicate a universal photocycle mechanism may not be present in LOV proteins. PMID- 25933163 TI - Cholesterol-lowering properties of oat beta-glucan and the promotion of cardiovascular health: did Health Canada make the right call? AB - In 2010, Health Canada approved a heath claim acknowledging the link between increased oats (Avena sativa)-soluble fibre consumption and a reduction in total serum cholesterol levels. The approval also recognized the relationship between decreased total blood cholesterol concentration and a reduced risk of coronary heart disease. The functional food ingredient believed to be responsible for the hypocholesterolemic property of oats is beta-glucan, a highly viscous, soluble fibre composed of d-glucose monomers linked by a combination of beta-(1->4) and beta-(1->3) glycosidic bonds. Found mainly in the endosperm cell wall of oats, beta-glucan is thought to reduce total serum and low-density lipoprotein cholesterol by forming a viscous mass in the small intestine thus limiting intestinal absorption of dietary cholesterol as well as the re-absorption of bile acids. Given the evolution of research information with time as a result of the continual, rapid generation of new research data by laboratories around the world, it became imperative to examine the compatibility of the conclusion reached by Health Canada on the basis of the body of evidence contained in the initial petition submitted in January 2007, with newer post-2006 data. After careful evaluation, this work concludes on the basis of new research information that a dose of 3 g/day oat beta-glucan consumed as part of a diet "free of saturated fatty acids" or "low in saturated fatty acids" could help to promote cardiovascular health. PMID- 25933164 TI - What Health Service Provider Factors Are Associated with Low Delivery of HIV Testing to Children with Acute Malnutrition in Dowa District of Malawi? AB - BACKGROUND: The Community-based Management of Acute Malnutrition is the national program for treating acute malnutrition in Malawi. Under this program's guidelines all children enrolled should undergo an HIV test, so that those infected can receive appropriate treatment and care. However, the national data of 2012 shows a low delivery of testing. Prior studies have investigated client related factors affecting uptake of HIV testing in Community-based Management of Acute Malnutrition program. Lacking is the information on the service provider factors that are associated with the delivery of testing. This study investigated service provider factors that affect delivery of HIV testing among children enrolled in the program and explored ways in which this could be improved. METHODS: A descriptive study that used qualitative methods of data collection. Client registers were reviewed to obtain the number of children enrolled in Community-based Management of Acute Malnutrition and the number of children who were tested for HIV over a 12-month period. In-depth interviews were conducted with Community-based Management of Acute Malnutrition and HIV Testing and Counselling focal persons to investigate factors affecting HIV test delivery. Descriptive statistics were used to analyze data from client registers. Information from interviews was analyzed using a thematic approach. RESULTS: Quantitative data revealed that 1738 (58%) of 2981 children enrolled in Community based Management of Acute Malnutrition were tested for HIV. From in-depth interviews four themes emerged, that is, lack of resources for HIV tests; shortage of staff skilled in HIV testing and counseling; lack of commitment among staff in referring children for HIV testing; and inadequately trained staff. CONCLUSION: There is a need for a functioning health system to help reduce child mortality resulting from HIV related conditions. PMID- 25933167 TI - Correction: bone cells in birds show exceptional surface area, a characteristic tracing back to Saurischian dinosaurs of the late triassic. PMID- 25933165 TI - Epstein-Barr virus genetic variation in lymphoblastoid cell lines derived from Kenyan pediatric population. AB - Epstein-Barr virus (EBV) is associated with Burkitt's lymphoma (BL), and in regions of sub-Saharan Africa where endemic BL is common, both the EBV Type 1 (EBV-1) and EBV Type 2 strains (EBV-2) are found. Little is known about genetic variation of EBV strains in areas of sub-Saharan Africa. In the present study, spontaneous lymphoblastoid cell lines (LCLs) were generated from samples obtained from Kenya. Polymerase chain reaction (PCR) amplification of the EBV genome was done using multiple primers and sequenced by next-generation sequencing (NGS). Phylogenetic analyses against the published EBV-1 and EBV-2 strains indicated that one sample, LCL10 was closely related to EBV-2, while the remaining 3 LCL samples were more closely related to EBV-1. Moreover, single nucleotide polymorphism (SNP) analyses showed clustering of LCL variants. We further show by analysis of EBNA-1, BLLF1, BPLF1, and BRRF2 that latent genes are less conserved than lytic genes in these LCLs from a single geographic region. In this study we have shown that NGS is highly useful for deciphering detailed inter and intra variations in EBV genomes and that within a geographic region different EBV genetic variations can co-exist, the implications of which warrant further investigation. The findings will enhance our understanding of potential pathogenic variants critical to the development and maintenance of EBV-associated malignancies. PMID- 25933166 TI - Increased B Cell ADAM10 in Allergic Patients and Th2 Prone Mice. AB - ADAM10, as the sheddase of the low affinity IgE receptor (CD23), promotes IgE production and thus is a unique target for attenuating allergic disease. Herein, we describe that B cell levels of ADAM10, specifically, are increased in allergic patients and Th2 prone WT mouse strains (Balb/c and A/J). While T cell help augments ADAM10 expression, Balb WT B cells exhibit increased ADAM10 in the naive state and even more dramatically increased ADAM10 after anti-CD40/IL4 stimulation compared C57 (Th1 prone) WT B cells. Furthermore, ADAM17 and TNF are reduced in allergic patients and Th2 prone mouse strains (Balb/c and A/J) compared to Th1 prone controls. To further understand this regulation, ADAM17 and TNF were studied in C57Bl/6 and Balb/c mice deficient in ADAM10. C57-ADAM10B-/- were more adept at increasing ADAM17 levels and thus TNF cleavage resulting in excess follicular TNF levels and abnormal secondary lymphoid tissue architecture not noted in Balb-ADAM10B-/-. Moreover, the level of B cell ADAM10 as well as Th context is critical for determining IgE production potential. Using a murine house dust mite airway hypersensitivity model, we describe that high B cell ADAM10 level in a Th2 context (Balb/c WT) is optimal for disease induction including bronchoconstriction, goblet cell metaplasia, mucus, inflammatory cellular infiltration, and IgE production. Balb/c mice deficient in B cell ADAM10 have attenuated lung and airway symptoms compared to Balb WT and are actually most similar to C57 WT (Th1 prone). C57-ADAM10B-/- have even further reduced symptomology. Taken together, it is critical to consider both innate B cell levels of ADAM10 and ADAM17 as well as Th context when determining host susceptibility to allergic disease. High B cell ADAM10 and low ADAM17 levels would help diagnostically in predicting Th2 disease susceptibility; and, we provide support for the use ADAM10 inhibitors in treating Th2 disease. PMID- 25933168 TI - Heterologous Protection against Malaria after Immunization with Plasmodium falciparum Sporozoites. AB - BACKGROUND: Sterile protection in >90% of volunteers against homologous Plasmodium falciparum infection has been achieved only using the controlled human malaria infection (CHMI) model. This efficient model involves whole parasite immunizations under chloroquine prophylaxis (CPS-immunization), requiring only 30 45 mosquitoes bites infected with P. falciparum-sporozoites. Given the large diversity of P. falciparum parasites, it is essential to assess protection against heterologous parasite strains. METHODS: In an open-label follow-up study, 16 volunteers previously CPS-immunized and challenged with P. falciparum NF54 (West-Africa) in a dose de-escalation and challenge trial were re-challenged with clone NF135.C10 (Cambodia) at 14 months after the last immunization (NCT01660854). RESULTS: Two out of thirteen NF54 protected volunteers previously fully protected against NF54 were also fully protected against NF135.C10, while 11/13 showed a delayed patency (median prepatent period of 10.5 days (range 9.0 15.5) versus 8.5 days in 5 malaria-naive controls (p = 0.0005). Analysis of patency by qPCR indicated a 91 to >99% estimated reduction of liver parasite load in 7/11 partially protected subjects. Three volunteers previously not protected against NF54, were also not protected against NF135.C10. CONCLUSION: This study shows that CPS-immunization can induce heterologous protection for a period of more than one year, which is a further impetus for clinical development of whole parasite vaccines. TRIAL REGISTRATION: Clinicaltrials.gov NCT01660854. PMID- 25933169 TI - Effect of random/aligned nylon-6/MWCNT fibers on dental resin composite reinforcement. AB - The aims of this study were (1) to synthesize and characterize random and aligned nanocomposite fibers of multi-walled carbon nanotubes (MWCNT)/nylon-6 and (2) to determine their reinforcing effects on the flexural strength of a dental resin composite. Nylon-6 was dissolved in hexafluoropropanol (10 wt%), followed by the addition of MWCNT (hereafter referred to as nanotubes) at two distinct concentrations (i.e., 0.5 or 1.5 wt%). Neat nylon-6 fibers (without nanotubes) were also prepared. The solutions were electrospun using parameters under low- (120 rpm) or high-speed (6000 rpm) mandrel rotation to collect random and aligned fibers, respectively. The processed fiber mats were characterized by scanning (SEM) and transmission (TEM) electron microscopies, as well as by uni-axial tensile testing. To determine the reinforcing effects on the flexural strength of a dental resin composite, bar-shaped (20*2*2 mm(3)) resin composite specimens were prepared by first placing one increment of the composite, followed by one strip of the mat, and one last increment of composite. Non-reinforced composite specimens were used as the control. The specimens were then evaluated using flexural strength testing. SEM was done on the fractured surfaces. The data were analyzed using ANOVA and the Tukey's test (alpha=5%). Nanotubes were successfully incorporated into the nylon-6 fibers. Aligned and random fibers were obtained using high- and low-speed electrospinning, respectively, where the former were significantly (p<0.001) stronger than the latter, regardless of the nanotubes' presence. Indeed, the dental resin composite tested was significantly reinforced when combined with nylon-6 fibrous mats composed of aligned fibers (with or without nanotubes) or random fibers incorporated with nanotubes at 0.5 wt%. PMID- 25933170 TI - Effect of phytic acid etchant on the structural stability of demineralized dentine and dentine bonding. AB - OBJECTIVE: This study examined the effect of phytic acid (IP6) in stabilizing the morphology of dentine collagen network and resin-dentine bonding. METHODS: Dentine beams were fully demineralized with 10% phosphoric acid (PA) or 1% IP6 (pH 1.2). PA-demineralized beams were divided into three groups: (a) no further treatment (control), (b) treatment with 5% glutaraldehyde (GA) for 1 h and (c) treatment with 1% IP6 (pH 7) for 1 h. IP6-demineralized beams received no further treatment. The beams were then subjected to ultimate tensile strength (UTS) testing. Dentine micromorphology evaluation was performed using a field-emission scanning electron microscope (FE-SEM). Dentine disks were etched with 35% PA for 15 s or 1% IP6 for 30s. PA-etched dentine disks were divided into three groups as (a), (b) and (c) as for UTS testing, but the treatment with GA or IP6 was done in 1min. For microtensile bond strength (uTBS) testing, flat dentine surfaces etched with PA or IP6 were blot-dried (wet dentine) or air-dried for 10s (dry dentine) and bonded with an etch-and-rinse adhesive followed by composite build-up. RESULTS: IP6-demineralized dentine showed significantly higher UTS, when compared to PA-demineralized dentine. GA and IP6 significantly improved UTS of PA demineralized dentine. FE-SEM observation revealed that dentine collagen network was preserved by GA and IP6. No significant difference in uTBS was found between the wet and dry IP6-etched dentine groups. CONCLUSION: IP6 etching showed a structural stabilizing effect on demineralized dentine matrix and produced good resin-dentine bonding, regardless of dentine moistness or dryness. PMID- 25933171 TI - Supramolecular structure, phase behavior and thermo-rheological properties of a poly (L-lactide-co-epsilon-caprolactone) statistical copolymer. AB - PLAcoCL samples, both unaged, termed PLAcoCLu, and aged over time, PLAcoCLa, were prepared and analyzed to study the phase structure, morphology, and their evolution under non-quiescent conditions. X- ray diffraction, Differential Scanning Calorimetry and Atomic Force Microscopy were complemented with thermo rheological measurements to reveal that PLAcoCL evolves over time from a single amorphous metastable state to a 3 phase system, made up of two compositionally different amorphous phases and a crystalline phase. The supramolecular arrangements developed during aging lead to a rheological complex behavior in the PLAcoCLa copolymer: Around Tt=131 degrees C thermo-rheological complexity and a peculiar chain mobility reduction were observed, but at T>Tt the thermo rheological response of a homogeneous system was recorded. In comparison with the latter, the PLLA/PCL 70:30 physical blend counterpart showed double amorphous phase behavior at all temperatures, supporting the hypothesis that phase separation in the PLAcoCLa copolymer is caused by the crystallization of polylactide segment blocks during aging. PMID- 25933172 TI - Protonation studies of a mono-dinitrogen complex of chromium supported by a 12 membered phosphorus macrocycle containing pendant amines. AB - The reduction of fac-[CrCl3(P(Ph)3N(Bn)3)], (1(Cl3)), (P(Ph)3N(Bn)3 = 1,5,9 tribenzyl-3,7,11-triphenyl-1,5,9-triaza-3,7,11-triphosphacyclododecane) with Mg in the presence of dmpe (dmpe = 1,2-bis(dimethylphosphino)ethane) affords the first example of a monodinitrogen Cr(0) complex, Cr(N2)(dmpe)(P(Ph)3N(Bn)3), (2(N2)), containing a pentaphosphine coordination environment. 2(N2) is supported by a unique facially coordinating 12-membered phosphorus macrocycle containing pendant amine groups in the second coordination sphere. Treatment of 2(N2) at -78 degrees C with 1 equiv of [H(OEt2)2][B(C6F5)4] results in protonation of the metal center, generating the seven-coordinate Cr(II)-N2 hydride complex, [Cr(H)(N2)(dmpe)(P(Ph)3N(Bn)3)][B(C6F5)4], [2(H)(N2)](+). Treatment of 2((15)N2) with excess triflic acid at -50 degrees C afforded a trace amount of (15)NH4(+) from the reduction of the coordinated (15)N2 ligand (electrons originate from Cr). Electronic structure calculations were employed to evaluate the pKa values of three protonated sites of 2(N2) (metal center, pendant amine, and N2 ligand) and were used to predict the thermodynamically preferred Cr-NxHy intermediates in the N2 reduction pathway for 2(N2) and the recently published complex trans [Cr(N2)2(P(Ph)4N(Bn)4)] upon the addition of protons and electrons. PMID- 25933174 TI - Physical-chemical properties and evaluative fate modelling of 'emerging' and 'novel' brominated and organophosphorus flame retardants in the indoor and outdoor environment. AB - Several groups of flame retardants (FRs) have entered the market in recent years as replacements for polybrominated diphenyl ethers (PBDEs), but little is known about their physical-chemical properties or their environmental transport and fate. Here we make best estimates of the physical-chemical properties and undertake evaluative modelling assessments (indoors and outdoors) for 35 so called 'novel' and 'emerging' brominated flame retardants (BFRs) and 22 organophosphorus flame retardants (OPFRs). A QSPR (Quantitative Structure Property Relationship) based technique is used to reduce uncertainty in physical chemical properties and to aid property selection for modelling, but it is evident that more, high quality property data are required for improving future assessments. Evaluative modelling results show that many of the alternative FRs, mainly alternative BFRs and some of the halogenated OPFRs, behave similarly to the PBDEs both indoors and outdoors. These alternative FRs exhibit high overall persistence (Pov), long-range transport potential (LRTP) and POP-like behaviour and on that basis cannot be regarded as suitable replacements to PBDEs. A group of low molecular weight alternative BFRs and non-halogenated OPFRs show a potentially better environmental performance based on Pov and LRTP metrics. Results must be interpreted with caution though since there are significant uncertainties and limited data to allow for thorough model evaluation. Additional environmental parameters such as toxicity and bioaccumulative potential as well as functionality issues should be considered in an industrial substitution strategy. PMID- 25933173 TI - Programs for the Prevention of Youth Depression: Evaluation of Efficacy, Effectiveness, and Readiness for Dissemination. AB - The objective of this study was to evaluate the current state of evidence of the effectiveness of depression prevention programs for youth, assess the degree to which current evidence supports broad implementation, and outline additional steps needed to close the gap between effectiveness and dissemination. We used the Society for Prevention Research's Standards of Evidence (Flay et al., 2005 ) to evaluate the degree to which existing depression prevention programs have established intervention efficacy, effectiveness, and readiness for dissemination. We reviewed all depression prevention programs for youth that have been evaluated in at least two published, randomized controlled trials in which the intervention was compared to a no-intervention control group. A total of 37 studies evaluating 11 different programs were reviewed with regard to depressive symptoms and diagnoses at postintervention and follow-up (at least 6 months). Eight programs demonstrated significant main effects on depressive symptoms relative to controls in multiple randomized controlled trials; 5 programs had at least 1 trial with significant main effects present at least 1 year postintervention. Two programs demonstrated efficacy for both depressive symptoms and depressive episodes across multiple independent trials. Regarding effectiveness, 6 programs had at least 1 study showing significant effects when delivered by endogenous service providers; 4 programs had significant effects in studies conducted independently of the program developers. Several programs have demonstrated promise in terms of efficacy, but no depression prevention program for children or adolescents as yet has garnered sufficient evidence of effectiveness under real-world conditions to warrant widespread dissemination at this time. PMID- 25933175 TI - The first application of wastewater-based drug epidemiology in five South Korean cities. AB - Illicit drug consumption in five cities in South Korea was estimated by analyzing 17 drug residues in untreated wastewater samples collected during the Christmas and New Year period of 2012-13. Only methamphetamine, amphetamine, and codeine were detected at concentrations of tens of nanograms per liter or even lower concentrations in more than 90% of the samples. Other illicit drug residues (including cocaine, methadone, and benzoylecgonine) that have been detected frequently in wastewater from other countries were not found in this study. Methamphetamine was found to be the most widely used illicit drug in South Korea, and the estimated average consumption rate was 22 mg d(-1) (1000 people)(-1). This rate is, for example, 2-5 times lower than the estimated average consumption rates in Hong Kong and other parts of China and 4-80 times lower than the estimated average consumption rates in cities in Western countries. It should be noted that the wastewater samples analyzed in this study were collected during a holiday season, when daily consumption of illicit drugs is often higher than on an average day. The methamphetamine usage rates were calculated for different cities in South Korea, and the usage rates in smaller cities was higher (2-4 times) than the average. PMID- 25933177 TI - Enantioselective Synthesis of 3-Methyleneindan-1-ols via a One-Pot Allylboration Heck Reaction of 2-Bromobenzaldehydes. AB - A novel, one-pot allylboration-Heck reaction of 2-bromobenzaldehydes has been developed for the general and efficient synthesis of 3-methyleneindan-1-ols. Modification of the one-pot procedure to include chiral Bronsted acid catalyzed allylation has allowed the preparation of these building blocks in high enantioselectivity and excellent yields. PMID- 25933178 TI - Abstracts from the EAACI Skin Allergy Meeting 2014. PMID- 25933176 TI - Association of HMOX1 and NQO1 Polymorphisms with Metabolic Syndrome Components. AB - Metabolic syndrome (MetS) is among the most important public health problems worldwide, and is recognized as a major risk factor for various illnesses, including type 2 diabetes mellitus, obesity, and cardiovascular diseases. Recently, oxidative stress has been suggested as part of MetS aetiology. The heme oxygenase 1 (HMOX1) and NADH:quinone oxidoreductase 1 (NQO1) genes are crucial mediators of cellular defence against oxidative stress. In the present study, we analysed the associations of HMOX1 (GT)n and NQO1 C609T polymorphisms with MetS and its components. Our study population comprised 735 Mexican Mestizos unrelated volunteers recruited from different tertiary health institutions from Mexico City. In order to know the HMOX1 (GT)n and NQO1 C609T allele frequencies in Amerindians, we included a population of 241 Amerindian native speakers. Their clinical and demographic data were recorded. The HMOX1 (GT)n polymorphism was genotyped using PCR and fluorescence technology. NQO1 C609T polymorphism genotyping was performed using TaqMan probes. Short allele (<25 GT repeats) of the HMOX1 polymorphism was associated with high systolic and diastolic blood pressure, and the T allele of the NQO1 C609T polymorphism was associated with increased triglyceride levels and decreased HDL-c levels, but only in individuals with MetS. This is the first study to analyse the association between MetS and genes involved in oxidative stress among Mexican Mestizos. Our data suggest that polymorphisms of HMOX1 and NQO1 genes are associated with a high risk of metabolic disorders, including high systolic and diastolic blood pressure, hypertriglyceridemia, and low HDL-c levels in Mexican Mestizo individuals. PMID- 25933179 TI - Letter from the editor. PMID- 25933180 TI - A review of economic evaluations of 13-valent pneumococcal conjugate vaccine (PCV13) in adults and the elderly. AB - The 13-valent pneumococcal conjugated vaccine (PCV13) is already recommended for some adult groups and is being considered for wider use in many countries. In order to identify the strengths and limitations of the existing economic evaluation studies of PCV13 in adults and the elderly a literature review was conducted. The majority of the studies identified (9 out of 10) found that PCV13 was cost-effective in adults and/or the elderly. However, these results were based on assumptions that could not always be informed by robust evidence. Key uncertainties included the efficacy of PCV13 against non-invasive pneumonia and the herd immunity effect of childhood vaccination programs. Emerging trial evidence on PCV13 in adults from the Netherlands offers the ability to parameterize future economic evaluations with empirical efficacy data. However, it is important that these estimates are used thoughtfully when they are transferred to other settings. PMID- 25933182 TI - Cost-effectiveness analysis of a vaccination program for the prevention of herpes zoster and post-herpetic neuralgia in adults aged 50 and over in Germany. AB - Herpes zoster (HZ; shingles) is a common viral disease that affects the nerves and surrounding skin causing a painful dermatomal rash and leading to debilitating complications such as, mainly, post-herpetic neuralgia (PHN). Currently, there is no effective treatment for HZ and PHN. The objective of this study was to assess the cost-effectiveness of a HZ vaccination program in Germany. An existing Markov Model was adapted to the German healthcare setting to compare a vaccination policy to no vaccination on a lifetime time-horizon, considering 2 scenarios: vaccinating people starting at the age of 50 or at the age of 60 years, from the perspective of the statutory health insurance (SHI) and the societal perspective. According to the perspective, vaccinating 20% of the 60+ German population resulted in 162,713 to 186,732 HZ and 31,657 to 35,793 PHN cases avoided. Corresponding incremental cost-effectiveness ratios (ICER) were 39,306 ?/QALY from the SHI perspective and 37,417 ?/QALY from a societal perspective. Results for the 50+ German population ranged from 336,468 to 394,575 HZ and from 48,637 to 56,087 PHN cases avoided from the societal perspective. Corresponding ICER were 39,782 ?/QALY from a SHI perspective and 32,848 ?/QALY from a societal perspective. Sensitivity analyses showed that results are mainly impacted by discount rates, utility values and use of alternative epidemiological data.The model indicated that a HZ vaccination policy in Germany leads to significant public health benefits and could be a cost-effective intervention. The results were robust and consistent with local and international existing literature. PMID- 25933181 TI - Clinically feasible approaches to potentiating cancer cell-based immunotherapies. AB - The immune system exerts both tumor-destructive and tumor-protective functions. Mature dendritic cells (DCs), classically activated macrophages (M1), granulocytes, B lymphocytes, abeta and gammadelta T lymphocytes, natural killer T (NKT) cells, and natural killer (NK) cells may be implicated in antitumor immunoprotection. Conversely, tolerogenic DCs, alternatively activated macrophages (M2), myeloid-derived suppressor cells (MDSCs), and regulatory T (Tregs) and B cells (Bregs) are capable of suppressing antitumor immune responses. Anti-cancer vaccination is a useful strategy to elicit antitumor immune responses, while overcoming immunosuppressive mechanisms. Whole tumor cells or lysates derived thereof hold more promise as cancer vaccines than individual tumor-associated antigens (TAAs), because vaccinal cells can elicit immune responses to multiple TAAs. Cancer cell-based vaccines can be autologous, allogeneic or xenogeneic. Clinical use of xenogeneic vaccines is advantageous in that they can be most effective in breaking the preexisting immune tolerance to TAAs. To potentiate immunotherapy, vaccinations can be combined with other modalities that target different immune pathways. These modalities include 1) genetic or chemical modification of cell-based vaccines; 2) cross-priming TAAs to T cells by engaging dendritic cells; 3) T-cell adoptive therapy; 4) stimulation of cytotoxic inflammation by non-specific immunomodulators, toll-like receptor (TLR) agonists, cytokines, chemokines or hormones; 5) reduction of immunosuppression and/or stimulation of antitumor effector cells using antibodies, small molecules; and 6) various cytoreductive modalities. The authors envisage that combined immunotherapeutic strategies will allow for substantial improvements in clinical outcomes in the near future. PMID- 25933183 TI - A comparative clinical study to assess safety and reactogenicity of a DTwP HepB+Hib vaccine. AB - Hepatitis B and Haemophilus influenzae type b (Hib) infections are major public health problems in developing countries, including India. Hence, combination vaccines containing DTwP, recombinant hepatitis B and Hib conjugate vaccines have been developed. Here, we report a Phase IV study which assessed safety and reactogenicity of a new DTwP-HepB+Hib vaccine. Three doses of DTwP-HepB+Hib vaccine (Pentavac, Serum Institute of India Ltd) or Tritanrix-HB+Hib (GlaxoSmithKline Beecham) were administered to infants at 6, 10 and 14 weeks of age in 2:1 ratio. The subjects were followed till one month after the third dose for safety assessment. Adverse events were captured in structured diaries and physical examinations were performed on each visit. The study was conducted in 1510 infants. Both vaccines caused injection site local and systemic reactions and the incidence was similar in both the groups. The incidence of local solicited reactions was: tenderness 35.9 %-33.6 %; redness 18.1 %-17.2 %; swelling 23.7 %-22.4 %; induration 12.8 % -13.7 %. The percentage of systemic solicited reactions were: diarrhea 2.2 %-2.2 %; drowsiness 3.3 %-3.4 %; fever 14.0 %-11.2 %; irritability 28.1 %-25.4 %; loss of appetite 6.6 %-5.6 %; persistent crying 17.7 %-15.7 %; vomiting 3.5 %-3.0 %. No serious adverse event was caused by the vaccines. The new DTwP-HepB+Hib combination vaccine showed similar safety profile to that of an imported vaccine in Indian infants. PMID- 25933184 TI - Effects of local nasal immunotherapy in allergic airway inflammation: Using urea denatured Dermatophagoides pteronyssinus. AB - Despite improvements in anti-allergy medication, the prevalence of allergic airway inflammation remains high, affecting up to 40% of the population worldwide. Allergen immunotherapy is effective for inducing tolerance but has the adverse effect of severe allergic reaction. This can be avoided by denaturing with urea. In this study, we demonstrated that the serum level of allergen specific IgE in mice sensitized with native Dermatophagoides pteronyssinus (Der p) crude extract after receiving local nasal immunotherapy (LNIT) with urea denatured Der p crude extract (DN-Dp) significantly decreased compared to that in the normal saline (NS) treatment group. Expressions of IL-4 were significantly reduced in lung tissues after treatment. Inflammation around the bronchial epithelium improved and airway hypersensitivity was down-regulated. LNIT with DN Dp can down-regulate IL-1b, IL-6 and TNF-a expression and then decrease Der p induced allergic airway inflammation. This therapeutic modality may be used as an alternative treatment for airway allergic diseases. PMID- 25933185 TI - Pancreatic cancer, treatment options, and GI-4000. AB - Although pancreatic cancer is but the eleventh most prevalent cancer in the US, it is predicted that of all the patients newly diagnosed with this disease in 2014, only 27% will still be alive at the end of the first year, which is reduced to 6% after 5 years. The choice of chemotherapy in the treatment of pancreatic cancer is dependent on disease stage and patient performance status but, in general, the most widely used approved regimens include 5-fluorouracil (5-FU) combinations and gemcitabine combinations. Recent therapeutic strategies have resulted in an improvement in survival of patients with pancreatic cancer but the magnitude of change is disappointing and vast improvements are still needed. The goal of immunotherapy is to enhance and guide the body's immune system to recognize tumor-specific antigens and mount an attack against the disease. Among newer immune therapies, GI-4000 consists of 4 different targeted molecular immunogens, each containing a different Ras protein (antigen) encoded by the most commonly found mutant RAS genes in solid tumors-RAS mutations exist in over 90% of pancreatic ductal adenocarcinomas. We will review pancreatic cancer epidemiology and its current treatment options, and consider the prospects of immunotherapy, focusing on GI-4000. We discuss the potential mechanism of action of GI-4000, and the performance of this vaccination series thus far in early phase clinical trials. PMID- 25933186 TI - Incidence of Epstein-Barr virus in Syrian women with breast cancer: A tissue microarray study. AB - Epstein-Barr virus (EBV) has been recently shown to be present in human breast cancer worldwide, which could play an important role in the initiation and progression of this cancer. In this regard, we aimed to explore the prevalence of EBV in 108 breast cancer tissues from Syrian women using polymerase chain reaction (PCR) and tissue microarray (TMA) analysis. We found that EBV is present in 56 (51.85%) of breast cancers samples. Additionally, we report that the expression of LMP1 gene of EBV is associated with a cancer invasive phenotype in the majority of the cancer samples. These data imply that EBV is present in breast cancer worldwide including Syria and its presence is associated with more aggressive cancer phenotype. Thus, future investigations are needed to elucidate the exact role of EBV in breast carcinogenesis and metastasis. PMID- 25933187 TI - Protection conferred by virus-like particle vaccines against respiratory syncytial virus infection in mice by intranasal vaccination. AB - Respiratory syncytial virus (RSV) is a major pathogen in infants and the elderly, causing pneumonia and bronchiolitis. Despite decades of research, to date there is still no approved RSV vaccine available. In this study, we developed RSV virus like particle (VLP) vaccines containing an RSV fusion (F) and/or attachment (G) protein with Newcastle disease virus (NDV) as the platform. The VLPs were expressed in a baculovirus system and purified by sucrose gradient centrifugation. BALB/c mice immunized intranasally (i.n.) with rNDV/RSV/F plus rNDV/RSV/G developed robust humoral, mucosal RSV-specific antibodies and cellular immune responses. Furthermore, rNDV/RSV/F plus rNDV/RSV/G provided better protection than did rNDV/RSV/F or rNDV/RSV/G alone, as shown by an obvious decrease in viral replication together with alleviation of histopathological changes in the lungs of the challenged mice. Our data demonstrate that the intranasal vaccination of combined RSV virus-like particle vaccine candidates has great potential for protection against RSV infection. PMID- 25933188 TI - IL17 Mediates Pelvic Pain in Experimental Autoimmune Prostatitis (EAP). AB - Chronic pelvic pain syndrome (CPPS) is the most common form of prostatitis, accounting for 90-95% of all diagnoses. It is a complex multi-symptom syndrome with unknown etiology and limited effective treatments. Previous investigations highlight roles for inflammatory mediators in disease progression by correlating levels of cytokines and chemokines with patient reported symptom scores. It is hypothesized that alteration of adaptive immune mechanisms results in autoimmunity and subsequent development of pain. Mouse models of CPPS have been developed to delineate these immune mechanisms driving pain in humans. Using the experimental autoimmune prostatitis (EAP) in C57BL/6 mice model of CPPS we examined the role of CD4+T-cell subsets in the development and maintenance of prostate pain, by tactile allodynia behavioral testing and flow cytometry. In tandem with increased CD4+IL17A+ T-cells upon EAP induction, prophylactic treatment with an anti-IL17 antibody one-day prior to EAP induction prevented the onset of pelvic pain. Therapeutic blockade of IL17 did not reverse pain symptoms indicating that IL17 is essential for development but not maintenance of chronic pain in EAP. Furthermore we identified a cytokine, IL7, to be associated with increased symptom severity in CPPS patients and is increased in patient prostatic secretions and the prostates of EAP mice. IL7 is fundamental to development of IL17 producing cells and plays a role in maturation of auto-reactive T-cells, it is also associated with autoimmune disorders including multiple sclerosis and type-1 diabetes. More recently a growing body of research has pointed to IL17's role in development of neuropathic and chronic pain. This report presents novel data on the role of CD4+IL17+ T-cells in development and maintenance of pain in EAP and CPPS. PMID- 25933190 TI - Analysis of Lid Contour Change with Aging in Asians by Measuring Midpupil Lid Distance. PMID- 25933189 TI - Protection against T1DM-Induced Bone Loss by Zinc Supplementation: Biomechanical, Histomorphometric, and Molecular Analyses in STZ-Induced Diabetic Rats. AB - Several studies have established an association between diabetes and alterations in bone metabolism; however, the underlying mechanism is not well established. Although zinc is recognized as a potential preventive agent against diabetes induced bone loss, there is no evidence demonstrating its effect in chronic diabetic conditions. This study evaluated the effects of zinc supplementation in a chronic (90 days) type 1 diabetes-induced bone-loss model. Male Wistar rats were distributed in three groups: control, type 1 diabetes mellitus (T1DM), and T1DM plus zinc supplementation (T1DMS). Serum biochemical analysis; tibia histomorphometric, biomechanical, and collagen-content analyses; and femur mRNA expression were evaluated. Relative to T1DM, the zinc-supplemented group showed increased histomorphometric parameters such as TbWi and BAr and decreased TbSp, increased biomechanical parameters (maximum load, stiffness, ultimate strain, and Young's modulus), and increased type I collagen content. Interestingly, similar values for these parameters were observed between the T1DMS and control groups. These results demonstrate the protective effect of zinc on the maintenance of bone strength and flexibility. In addition, downregulation of OPG, COL1A, and MMP 9 genes was observed in T1DMS, and the anabolic effects of zinc were evidenced by increased OC expression and serum ALP activity, both related to osteoblastogenesis, demonstrating a positive effect on bone formation. In contrast, T1DM showed excessive bone loss, observed through reduced histomorphometric and biomechanical parameters, characterizing diabetes associated bone loss. The bone loss was also observed through upregulation of OPG, COL1A, and MMP-9 genes. In conclusion, zinc showed a positive effect on the maintenance of bone architecture and biomechanical parameters. Indeed, OC upregulation and control of expression of OPG, COL1A, and MMP-9 mRNAs, even in chronic hyperglycemia, support an anabolic and protective effect of zinc under chronic diabetic conditions. Furthermore, these results indicate that zinc supplementation could act as a complementary therapy in chronic T1DM. PMID- 25933191 TI - Clinicians Performing Cosmetic Surgery in the Community: A Nationwide Analysis of Physician Certification. PMID- 25933192 TI - Reply: Clinicians Performing Cosmetic Surgery in the Community: A Nationwide Analysis of Physician Certification. PMID- 25933193 TI - Reply: Emerging Paradigms in Perioperative Management for Microsurgical Free Tissue Transfer: Review of the Literature and Evidence-Based Guidelines. PMID- 25933194 TI - Reply: Analysis of Lid Contour Change with Aging in Asians by Measuring Midpupil Distance. PMID- 25933195 TI - Computational Characterization of Transient Strain-Transcending Immunity against Influenza A. AB - The enigmatic observation that the rapidly evolving influenza A (H3N2) virus exhibits, at any given time, a limited standing genetic diversity has been an impetus for much research. One of the first generative computational models to successfully recapitulate this pattern of consistently constrained diversity posits the existence of a strong and short-lived strain-transcending immunity. Building on that model, we explored a much broader set of scenarios (parameterizations) of a transient strain-transcending immunity, ran long-term simulations of each such scenario, and assessed its plausibility with respect to a set of known or estimated influenza empirical measures. We evaluated simulated outcomes using a variety of measures, both epidemiological (annual attack rate, epidemic duration, reproductive number, and peak weekly incidence), and evolutionary (pairwise antigenic diversity, fixation rate, most recent common ancestor, and kappa, which quantifies the potential for antigenic evolution). Taking cumulative support from all these measures, we show which parameterizations of strain-transcending immunity are plausible with respect to the set of empirically derived target values. We conclude that strain transcending immunity which is milder and longer lasting than previously suggested is more congruent with the observed short- and long-term behavior of influenza. PMID- 25933197 TI - Dietary Supplementation with Olive Oil or Fish Oil and Vascular Effects of Concentrated Ambient Particulate Matter Exposure in Human Volunteers. AB - BACKGROUND: Exposure to ambient particulate matter (PM) induces endothelial dysfunction, a risk factor for cardiovascular disease. Olive oil (OO) and fish oil (FO) supplements have beneficial effects on endothelial function. OBJECTIVE: In this study we evaluated the potential efficacy of OO and FO in mitigating endothelial dysfunction and disruption of hemostasis caused by exposure to particulate matter (PM). METHODS AND RESULTS: Forty-two participants (58 +/- 1 years of age) received either 3 g/day of OO or FO, or no supplements (naive) for 4 weeks prior to undergoing 2-hr exposures to filtered air and concentrated ambient particulate matter (CAP; mean, 253 +/- 16 MUg/m3). Endothelial function was assessed by flow-mediated dilation (FMD) of the brachial artery preexposure, immediately postexposure, and 20 hr postexposure. Levels of endothelin-1 and markers of fibrinolysis and inflammation were also measured. The FMD was significantly lower after CAP exposure in the naive (-19.4%; 95% CI: -36.4, -2.3 per 100 MUg/m3 CAP relative to baseline; p = 0.03) and FO groups (-13.7%; 95% CI: -24.5, -2.9; p = 0.01), but not in the OO group (-7.6%; 95% CI: -21.5, 6.3; p = 0.27). Tissue plasminogen activator levels were significantly increased immediately after (11.6%; 95% CI: 0.8, 22.2; p = 0.04) and 20 hr after CAP exposure in the OO group. Endothelin-1 levels were significantly increased 20 hr after CAP exposure in the naive group only (17.1%; 95% CI: 2.2, 32.0; p = 0.03). CONCLUSIONS: Short-term exposure to CAP induced vascular endothelial dysfunction. OO supplementation attenuated CAP-induced reduction of FMD and changes in blood markers associated with vasoconstriction and fibrinolysis, suggesting that OO supplementation may be an efficacious intervention to protect against vascular effects of exposure to PM. CITATION: Tong H, Rappold AG, Caughey M, Hinderliter AL, Bassett M, Montilla T, Case MW, Berntsen J, Bromberg PA, Cascio WE, Diaz Sanchez D, Devlin RB, Samet JM. 2015. Dietary supplementation with olive oil or fish oil and vascular effects of concentrated ambient particulate matter exposure in human volunteers. Environ Health Perspect 123:1173-1179; http://dx.doi.org/10.1289/ehp.1408988. PMID- 25933198 TI - Synthesis of amine functionalized cellulose nanocrystals: optimization and characterization. AB - A simple protocol was used to prepare amine functionalized cellulose nanocrystals (CNC-NH2). In the first step, epichlorohydrin (EPH) was reacted with ammonium hydroxide to produce 2-hydroxy-3-chloro propylamine (HCPA). In the next step, HCPA was grafted to CNC using the etherification reaction in an organic solution media. Various reaction parameters, such as time, temperature, and reactant molar ratio were performed to determine the optimal reaction conditions. The final product (CNC-NH2(T)) was dialyzed for a week. Further purification via centrifugation yielded the sediment (CNC-NH2(P)) and supernatant (POLY-NH2). The presence of amine groups on the surface of modified CNC was confirmed by FTIR and the amine content was determined by potentiometric titration and elemental analysis. A high amine content of 2.2 and 0.6 mmol amine/g was achieved for CNC NH2(T) and CNC-NH2(P), respectively. Zeta potential measurements confirmed the charge reversal of amine CNC from positive to negative when the pH was increased from 3 to 10. The flocculation of amine functionalized CNC due to its interactions with a negatively charged surfactant namely, sodium dodecyl sulfate (SDS) was investigated at pH 4. It showed promising results for applications, such as in flocculation of fine dispersions in water treatment. This simple and versatile synthetic method to produce high amine content CNC can be used for further conjugation as required for various applications. PMID- 25933199 TI - Deterministic Two-Dimensional Polymorphism Growth of Hexagonal n-Type SnS2 and Orthorhombic p-Type SnS Crystals. AB - van der Waals layered materials have large crystal anisotropy and crystallize spontaneously into two-dimensional (2D) morphologies. Two-dimensional materials with hexagonal lattices are emerging 2D confined electronic systems at the limit of one or three atom thickness. Often these 2D lattices also form orthorhombic symmetries, but these materials have not been extensively investigated, mainly due to thermodynamic instability during crystal growth. Here, we show controlled polymorphic growth of 2D tin-sulfide crystals of either hexagonal SnS2 or orthorhombic SnS. Addition of H2 during the growth reaction enables selective determination of either n-type SnS2 or p-type SnS 2D crystal of dissimilar energy band gap of 2.77 eV (SnS2) or 1.26 eV (SnS) as a final product. Based on this synthetic 2D polymorphism of p-n crystals, we also demonstrate p-n heterojunctions for rectifiers and photovoltaic cells, and complementary inverters. PMID- 25933200 TI - Fluorotechnology is critical to modern life: the FluoroCouncil counterpoint to the Madrid Statement. PMID- 25933201 TI - Human intrabony defect regeneration with rhFGF-2 and hyaluronic acid - a randomized controlled clinical trial. AB - AIM: The goal of this study was to evaluate if a biological hydrogel of recombinant human Fibroblast Growth Factor type 2 (rhFGF-2) in a hyaluronic acid (HA) carrier applied in periodontal intrabony defects would enhance the clinical parameters of regeneration of the periodontal attachment apparatus MATERIALS AND METHODS: Thirty adult patients were evaluated. Two intrabony defects present in contra-lateral quadrants in each patient were randomly allocated for each of the treatment methods employed. Control group (n = 30) were treated by open debridement with the papilla preservation flaps, while the test group (n = 30) also received a topical application of rhFGF-2/HA in the intrabony defect. The parameters evaluated, at baseline and after one year, were, were probing depth (PD), gingival recession (REC), probing attachment level (PAL) and probing bone level (PBL). The primary outcome measures was PAL gain RESULTS: Test sites exhibited significantly more PD reduction (5.5 versus 2.9 mm), PAL gains (4.8 versus 2.2 mm) and shallower residual PD (4.2 versus 6.6 mm) than controls. Moreover, residual PD smaller than 5 mm (100 versus 0%) and PAL gain > 4 mm (60 versus 20%) was significantly more frequent in the test group CONCLUSION: Application of rhFGF-2/HA significantly improved clinical parameters of periodontal wound healing one year after treatment. PMID- 25933202 TI - Designed Regular Tetragon-Shaped RNA-Protein Complexes with Ribosomal Protein L1 for Bionanotechnology and Synthetic Biology. AB - RNA nanotechnology has been established by employing the molecular architecture of RNA structural motifs. Here, we report two designed RNA-protein complexes (RNPs) composed of ribosomal protein L1 (RPL1) and its RNA-binding motif that are square-shaped nano-objects. The formation and the shape of the objects were confirmed by gel electrophoresis analysis and atomic force microscopy, respectively. Any protein can be attached to the RNA via a fusion protein with RPL1, indicating that it can be used as a scaffold for loading a variety of functional proteins or for building higher-order structures. In summary, the RNP object will serve as a useful tool in the fields of bionanotechnology and synthetic biology. Moreover, the RNP interaction enhances the RNA stability against nucleases, rendering these complexes stable in cells. PMID- 25933203 TI - New Short Tandem Repeat-Based Molecular Typing Method for Pneumocystis jirovecii Reveals Intrahospital Transmission between Patients from Different Wards. AB - Pneumocystis pneumonia is a severe opportunistic infection in immunocompromised patients caused by the unusual fungus Pneumocystis jirovecii. Transmission is airborne, with both immunocompromised and immunocompetent individuals acting as a reservoir for the fungus. Numerous reports of outbreaks in renal transplant units demonstrate the need for valid genotyping methods to detect transmission of a given genotype. Here, we developed a short tandem repeat (STR)-based molecular typing method for P. jirovecii. We analyzed the P. jirovecii genome and selected six genomic STR markers located on different contigs of the genome. We then tested these markers in 106 P. jirovecii PCR-positive respiratory samples collected between October 2010 and November 2013 from 91 patients with various underlying medical conditions. Unique (one allele per marker) and multiple (more than one allele per marker) genotypes were observed in 34 (32%) and 72 (68%) samples, respectively. A genotype could be assigned to 55 samples (54 patients) and 61 different genotypes were identified in total with a discriminatory power of 0.992. Analysis of the allelic distribution of the six markers and minimum spanning tree analysis of the 61 genotypes identified a specific genotype (Gt21) in our hospital, which may have been transmitted between 10 patients including six renal transplant recipients. Our STR-based molecular typing method is a quick, cheap and reliable approach to genotype Pneumocystis jirovecii in hospital settings and is sensitive enough to detect minor genotypes, thus enabling the study of the transmission and pathophysiology of Pneumocystis pneumonia. PMID- 25933204 TI - Anodal tDCS over the Motor Cortex on Prepared and Unprepared Responses in Young Adults. AB - Anodal transcranial direct current stimulation (tDCS) over the primary motor cortex (M1) has been proposed as a possible therapeutic rehabilitation technique for motor impairment. However, despite extensive investigation into the effects of anodal tDCS on motor output, there is little information on how anodal tDCS affects response processes. In this study, we used a cued go/nogo task with both directional and non-directional cues to assess the effects of anodal tDCS over the dominant (left) primary motor cortex on prepared and unprepared motor responses. Three experiments explored whether the effectiveness of tDCS varied with timing between stimulation and test. Healthy, right-handed young adults participated in a double-blind randomised controlled design with crossover of anodal tDCS and sham stimulation. In Experiment 1, twenty-four healthy young adults received anodal tDCS over dominant M1 at least 40 mins before task performance. In Experiment 2, eight participants received anodal tDCS directly before task performance. In Experiment 3, twenty participants received anodal tDCS during task performance. In all three experiments, participants responded faster to directional compared to non-directional cues and with their right hand. However, anodal tDCS had no effect on go/nogo task performance at any stimulation test interval. Bayesian analysis confirmed that anodal stimulation had no effect on response speed. We conclude that anodal tDCS over M1 does not improve response speed of prepared or unprepared responses of young adults in a go/nogo task. PMID- 25933205 TI - AICAR-Induced Activation of AMPK Inhibits TSH/SREBP-2/HMGCR Pathway in Liver. AB - Our previous study found that thyroid-stimulating hormone promoted sterol regulatory element-binding protein-2 (SREBP-2) expression and suppressed AMP activated protein kinase (AMPK) activity in the liver, but it was unclear whether there was a direct link between TSH, AMPK and SREBP-2. Here, we demonstrate that the 5-aminoimidazole-4-carboxyamide ribonucleoside (AICAR)-induced activation of AMPK directly inhibited the expression of SREBP-2 and its target genes HMGCR and HMGCS, which are key enzymes in cholesterol biosynthesis, and suppressed the TSH stimulated up-regulation of SREBP-2 in HepG2 cells; similar results were obtained in TSH receptor knockout mice. Furthermore, AMPK, an evolutionally conserved serine/threonine kinase, phosphorylated threonine residues in the precursor and nuclear forms of SREBP-2, and TSH interacted with AMPK to influence SREBP-2 phosphorylation. These findings may represent a molecular mechanism by which AMPK ameliorates the hepatic steatosis and hypercholesterolemia associated with high TSH levels in patients with subclinical hypothyroidism (SCH). PMID- 25933206 TI - Spitzoid tumors in children and adults: a comparative clinical, pathological, and cytogenetic analysis. AB - Spitzoid neoplasms may represent a difficult diagnosis in the practice of dermatopathology. We evaluated the concordance of the fluorescence in-situ hybridization (FISH) assay, histopathology, and dermoscopy in a group of adults and in a group of children with spitzoid neoplasms. The FISH assay, designed to detect the copy number of the RREB1 (6p25), MYB (6q23), and CCND1 (11q13) genes and of centromere 6 (Cep 6), was performed in a group of children and in a group of adults with a histopathologic diagnosis of spitzoid neoplasms. FISH data were compared with dermoscopy and histopathology. Fifteen spitzoid neoplasms were collected from 13 patients (five children and eight adults): nine lesions were histologically diagnosed as typical Spitz nevi; three lesions were melanomas and three were atypical Spitz nevi. The conventional FISH criteria were concordant with the clinical and histopathologic diagnosis of Spitz nevi in four adults and in three children. FISH criteria of the other neoplasms showed a concordance with the histopathologic diagnosis in three cases. Discordant results were obtained in five cases (two children, three adults). The FISH melanoma assay proved more reliable in spitzoid lesions found in adults than in children. This assay should be interpreted carefully in pediatric patients with Spitz nevi in the context of histological features as melanomas in the pediatric population may show distinct chromosomal aberrations. PMID- 25933207 TI - Ipilimumab-induced colitis in patients with metastatic melanoma. AB - Ipilimumab is used for the treatment of metastatic melanoma and is associated with serious immune-related colitis. We aimed to report the clinical features, treatment, and outcomes of patients with ipilimumab-induced colitis. In this retrospective observational study, we identified patients with unresectable melanoma treated with ipilimumab between March 2011 and September 2013. Diarrhea was assessed using the Common Terminology Criteria for Adverse Events, v3.0. Colitis was defined by diarrhea (grade>=2) requiring steroids with or without endoscopic/histologic/radiologic evidence of colitis. A total of 103 patients with metastatic melanoma treated with ipilimumab were identified. Of these, 30 patients (29%) developed diarrhea (all grades), and 23 patients (22%) developed colitis requiring systemic corticosteroid therapy. The median number of ipilimumab doses before onset of diarrhea was 2 (range, 1-4). Six of 23 patients responded to less than 1 mg/kg daily prednisone alone. Fifteen patients required high-dose oral and/or intravenous prednisone (1-2 mg/kg body weight). Six patients had diarrhea refractory to prednisone; five required rescue therapy with budesonide (9-12 mg daily) and one was treated with infliximab (5 mg/kg, three doses). There was one case of severe diarrhea (grade 3) treated successfully with high-dose budesonide (12 mg) monotherapy. Ipilimumab-induced colitis requires early and aggressive medical therapy. Most patients can be successfully managed with systemic corticosteroids. High-dose budesonide is an attractive steroid sparing agent, however further studies of its efficacy in this setting are needed. Infliximab should be used in refractory cases to avoid colectomy. PMID- 25933208 TI - Tumor-infiltrating lymphocytes predict cutaneous melanoma survival. AB - Understanding differences in survival across distinct subgroups of melanoma patients may help with the choice of types of therapy. Tumor-infiltrating lymphocytes (TILs) are considered a manifestation of the host immune response to tumor, but the role of TILs in melanoma mortality is controversial. The aim of this study was to investigate independent prognostic factors for melanoma mortality. We carried out a 10-year cohort study on 4133 melanoma patients from the same geographic area (Lazio) with primary cutaneous melanoma diagnosed between January 1998 and December 2008. The probability of survival was estimated using Kaplan-Meier methods and prognostic factors were evaluated by multivariate analysis (Cox proportional hazards model). The 10-year survival rate for melanoma decreased with increasing Breslow thickness (Pfor trend<0.0001) and with age (Pfor trend<0.0001) whereas survival increased with increasing levels of TILs (Pfor trend=0.0001). The 10-year survival rate for melanoma divided into TILs intensity as scanty, moderate, and marked was 88.0, 92.2, and 97.0%, respectively. In the multivariate Cox model, the presence of high levels of TILs in primary invasive melanomas was associated with a lower risk of melanoma death (hazard ratio 0.32; 95% confidence interval 0.13-0.82) after controlling for sex, age, Breslow thickness, histological type, mitotic rate, and ulceration. After including lymph node status in the multivariate analysis, the protective effect of marked TILs on melanoma mortality remained (hazard ratio 0.37; 95% confidence interval 0.15-0.94). The results of this study suggest that the immune microenvironment affects melanoma survival. PMID- 25933209 TI - Intermediate-grade meningeal melanocytoma associated with nevus of Ota: a case report and review of the literature. AB - Meningeal melanocytomas are rare melanin-producing tumors that are often found to be benign. However, a small subset of these tumors can present as intermediate grade melanocytomas (IGMs) that have histopathological features that are between those of benign melanocytomas and malignant melanomas. IGMs have the potential to recur and metastasize or progress to a more histologically high grade melanoma. Melanocytomas appear to differ from primary and metastatic melanoma by their prolonged clinical course and they appear to have different driver mutations (i.e. mutation of GNAQ gene). The association of a meningeal melanocytoma with nevus of Ota is extremely rare. To our knowledge, there have been only 10 reported cases of synchronous occurrence and only one of the cases involved an IGM. We report the second case of intermediate-grade meningeal melanocytoma that is associated with congenital nevus of Ota. Histopathological work-up confirmed the intermediate grade of the lesion and a driver GNAQ mutation was identified consistent with previous reports. PMID- 25933210 TI - Ultrasound-guided core needle biopsy of superficial lymph nodes: an alternative to fine-needle aspiration cytology for the diagnosis of lymph node metastasis in cutaneous melanoma. AB - To investigate the diagnostic value of ultrasound-guided core needle biopsy (US CNB) in suspected cases of lymph node metastasis from cutaneous melanoma. All patients with cutaneous melanoma followed in Saint-Louis Hospital between 2006 and 2010 who underwent US-CNB for suspicion of melanoma lymph node metastasis were reviewed retrospectively. Histopathological results of US-CNB samples were classified as melanoma, other malignancy, suspicious, inadequate, or benign. The diagnostic accuracy of US-CNB was assessed by comparison with two reference standards: histopathological examination of the radical lymph node dissection or, when this was not available, clinical and radiological follow-up. The data from 72 US-CNB were analyzed. Forty-four melanomas, 22 benign, three other malignancies, three inadequate samples, and no inconclusive specimens were diagnosed. Seventy-one US-CNB results were confirmed (98.6%). US-CNB achieved high sensitivity, specificity, and positive predictive value (respectively, 97.9, 100, and 100%). No adverse events were reported after the procedure. US-CNB provided a mean tissue volume of 16.7 mm per lymphadenopathy. US-CNB has diagnostic value similar to that of fine-needle aspiration cytology. It represents a reliable alternative method in melanoma lymph node metastasis to avoid surgery in patients who will not benefit from it. US-CNB provides relatively large samples of tissue suitable for comprehensive genomic analyses currently needed for research and personalized care of melanoma patients. PMID- 25933211 TI - Cerebrospinal fluid concentrations of vemurafenib in patients treated for brain metastatic BRAF-V600 mutated melanoma. AB - Anti-BRAF agents, including vemurafenib, have modified the prognosis for patients with melanoma. However, a difference can still be observed between extracerebral and cerebral responses. The aim of this study was to investigate the diffusion of vemurafenib in cerebrospinal fluid (CSF) from patients treated for brain metastatic BRAF-V600 mutated melanoma. Six patients treated with vemurafenib 960 mg twice daily were included. These patients had undergone a lumbar puncture because of suspicions of leptomeningeal metastasis, along with simultaneous blood sampling to measure vemurafenib level. The concentrations of vemurafenib in the CSF and the plasma were measured by high-performance liquid chromatography. The mean plasma and CSF concentrations of vemurafenib were 53.4+/-26.2 and 0.47+/ 0.37 mg/l, respectively. The mean ratio of the CSF : plasma concentration was 0.98+/-0.84%. No relationship was found between plasma and CSF concentrations (P=0.8). In conclusion, our preliminary results highlight for the first time a low CSF vemurafenib penetration rate associated with a large interindividual variability in patients treated for metastatic BRAF-V600 mutated melanoma and brain metastases. Further investigations with larger cohorts are required to study the relationship between CSF vemurafenib concentrations and cerebral response. PMID- 25933212 TI - Treatment of supraventricular tachycardia in infants: Analysis of a large multicenter database. AB - OBJECTIVE: Supraventricular tachycardia (SVT) is the most common arrhythmia in infants. Infants are typically treated with antiarrhythmic medications, but there is a lack of evidence guiding management, thus exposing infants to risks of both inadequate therapy and medication adverse events. We used data from a large clinical database to better understand current practices in SVT management, safety of commonly used medications, and outcomes of hospitalized infants treated for SVT. METHODS: This retrospective data analysis included all infants discharged from Pediatrix Medical Group neonatal intensive care units between 1998 and 2012 with a diagnosis of SVT who were treated with antiarrhythmic medications. We categorized infants by the presence of congenital heart disease other than patent ductus arteriosus. Medications were categorized as abortive, acute, or secondary prevention therapies. We used descriptive statistics to describe medication use, adverse events, and outcomes including SVT recurrence and mortality. RESULTS: A total of 2848 infants with SVT were identified, of whom 367 (13%) had congenital heart disease. Overall, SVT in-hospital recurrence was high (13%), and almost one fifth of our cohort (18%) experienced an adverse event. Mortality was 2% in the overall cohort and 6% in the congenital heart disease group (p<0.001). Adenosine was the most commonly used abortive therapy, but there was significant practice variation in therapies used for acute treatment and secondary prevention of SVT. CONCLUSION AND PRACTICE IMPLICATION: Significant variation in SVT treatment and suboptimal outcomes warrant future clinical trials to determine best practices in treating SVT in infants. PMID- 25933214 TI - Correction: energy and cost associated with ventilating office buildings in a tropical climate. PMID- 25933213 TI - Effects of tramadol on substantia gelatinosa neurons in the rat spinal cord: an in vivo patch-clamp analysis. AB - Tramadol is thought to modulate synaptic transmissions in the spinal dorsal horn mainly by activating u-opioid receptors and by inhibiting the reuptake of monoamines in the CNS. However, the precise mode of modulation remains unclear. We used an in vivo patch clamp technique in urethane-anesthetized rats to determine the antinociceptive mechanism of tramadol. In vivo whole-cell recordings of spontaneous inhibitory postsynaptic currents (sIPSCs) and spontaneous excitatory postsynaptic currents (sEPSCs) were made from substantia gelatinosa (SG) neurons (lamina II) at holding potentials of 0 mV and -70 mV, respectively. The effects of intravenous administration (0.5, 5, 15 mg/kg) of tramadol were evaluated. The effects of superfusion of tramadol on the surface of the spinal cord and of a tramadol metabolite (M1) were further analyzed. Intravenous administration of tramadol at doses >5 mg/kg decreased the sEPSCs and increased the sIPSCs in SG neurons. These effects were not observed following naloxone pretreatment. Tramadol superfusion at a clinically relevant concentration (10 uM) had no effect, but when administered at a very high concentration (100 uM), tramadol decreased sEPSCs, produced outward currents, and enhanced sIPSCs. The effects of M1 (1, 5 mg/kg intravenously) on sEPSCs and sIPSCs were similar to those of tramadol at a corresponding dose (5, 15 mg/kg). The present study demonstrated that systemically administered tramadol indirectly inhibited glutamatergic transmission, and enhanced GABAergic and glycinergic transmissions in SG neurons. These effects were mediated primarily by the activation of MU-opioid receptors. M1 may play a key role in the antinociceptive mechanisms of tramadol. PMID- 25933215 TI - Automatic Recognition of Fetal Facial Standard Plane in Ultrasound Image via Fisher Vector. AB - Acquisition of the standard plane is the prerequisite of biometric measurement and diagnosis during the ultrasound (US) examination. In this paper, a new algorithm is developed for the automatic recognition of the fetal facial standard planes (FFSPs) such as the axial, coronal, and sagittal planes. Specifically, densely sampled root scale invariant feature transform (RootSIFT) features are extracted and then encoded by Fisher vector (FV). The Fisher network with multi layer design is also developed to extract spatial information to boost the classification performance. Finally, automatic recognition of the FFSPs is implemented by support vector machine (SVM) classifier based on the stochastic dual coordinate ascent (SDCA) algorithm. Experimental results using our dataset demonstrate that the proposed method achieves an accuracy of 93.27% and a mean average precision (mAP) of 99.19% in recognizing different FFSPs. Furthermore, the comparative analyses reveal the superiority of the proposed method based on FV over the traditional methods. PMID- 25933217 TI - Correction: A Systems Genetics Approach Identifies CXCL14, ITGAX, and LPCAT2 as Novel Aggressive Prostate Cancer Susceptibility Genes. PMID- 25933216 TI - Effective Treatment of Established GL261 Murine Gliomas through Picornavirus Vaccination-Enhanced Tumor Antigen-Specific CD8+ T Cell Responses. AB - Glioblastoma (GBM) is among the most invasive and lethal of cancers, frequently infiltrating surrounding healthy tissue and giving rise to rapid recurrence. It is therefore critical to establish experimental model systems and develop therapeutic approaches that enhance anti-tumor immunity. In the current study, we have employed a newly developed murine glioma model to assess the efficacy of a novel picornavirus vaccination approach for the treatment of established tumors. The GL261-Quad system is a variation of the GL261 syngeneic glioma that has been engineered to expresses model T cell epitopes including OVA257-264. MRI revealed that both GL261 and GL261-Quad tumors display characteristic features of human gliomas such as heterogeneous gadolinium leakage and larger T2 weighted volumes. Analysis of brain-infiltrating immune cells demonstrated that GL261-Quad gliomas generate detectable CD8+ T cell responses toward the tumor-specific Kb:OVA257-264 antigen. Enhancing this response via a single intracranial or peripheral vaccination with picornavirus expressing the OVA257-264 antigen increased anti tumor CD8+ T cells infiltrating the brain, attenuated progression of established tumors, and extended survival of treated mice. Importantly, the efficacy of the picornavirus vaccination is dependent on functional cytotoxic activity of CD8+ T cells, as the beneficial response was completely abrogated in mice lacking perforin expression. Therefore, we have developed a novel system for evaluating mechanisms of anti-tumor immunity in vivo, incorporating the GL261-Quad model, 3D volumetric MRI, and picornavirus vaccination to enhance tumor-specific cytotoxic CD8+ T cell responses and track their effectiveness at eradicating established gliomas in vivo. PMID- 25933219 TI - Butyrylcholinesterase predicts cardiac mortality in young patients with acute coronary syndrome. AB - BACKGROUND: The incidence of acute coronary syndrome (ACS) in young people (<=65 years) is continuously rising. While prognostic factors in ACS are well investigated less attention has been paid to their age-dependent prognostic value and their particular relevance in younger patients. The aim of our study was to assess the age-dependent prognostic impact of butyrylcholinesterase (BChE). METHODS: Retrospective cohort study including 624 patients with ACS. Patients were stratified by age into equal groups (n = 208) corresponding to "young patients" (45-64 years), "middle-aged patients" (65-84 years) and "old patients" (85-100 years). Cox regression hazard analysis was used to assess the influence of BChE on survival. RESULTS: After a mean follow-up time of 4.0 (interquartile range [IQR] 2.0-6.4) years, 154 patients (24.7%) died due to a cardiac cause. In the overall cohort, BChE was indirectly associated with cardiac mortality-free survival (adjusted hazard ratio (HR): 0.70 (95% confidence interval [CI] 0.53 0.93, p = 0.01). The primary-analysis of BChE by age strata showed the strongest effect in the age group 45-64 years with an adjusted HR per 1-SD of 0.28 (95% CI 0.12-0.64, p = 0.003), a weaker association with mortality in middle aged (65-84 years: adjusted HR per 1-SD 0.66 [95% CI: 0.41-1.06], p = 0.087), and no association in older patients (85-100 years: adjusted HR per 1-SD 0.89 [95% CI: 0.58-1.38], p = 0.613). CONCLUSION: BChE is a strong predictor for cardiac mortality specifically in younger patients with ACS aged between 45 and 64 years. No significant association of BChE with cardiac-mortality was detected in other age classes. PMID- 25933218 TI - Overexpression of BIRC6 Is a Predictor of Prognosis for Colorectal Cancer. AB - BACKGROUND AND OBJECTIVE: Inhibitors of apoptosis proteins (IAPs) have been well investigated in human cancers, where they are frequently overexpressed and associated with poor prognosis. Here we explored the role of baculoviral IAP repeat containing 6 (BIRC6), a member of IAPs, in human colorectal cancer (CRC). METHODS: We used Western blotting and immunohistochemistry to examine BIRC6 expression in 7 CRC cell lines and 126 CRC clinical samples. We determined the biological significance of BIRC6 in CRC cell lines by a lentivirus-mediated silencing method. RESULTS: We reported that BIRC6 was overexpressed in CRC cell lines and clinical CRC tissues. BIRC6 overexpression was correlated with tumor size and invasion depth of CRC. BIRC6 overexpression is associated with worse overall survival (OS) (P = 0.001) and shorter disease-free survival (DFS) (P = 0.010). BIRC6 knockdown inhibited cell proliferation, arrested cell cycle at S phase, downregulated cyclin A2, B1, D1 and E1 levels, and sensitized CRC cells to chemotherapy in vitro and in vivo. CONCLUSIONS: Taken together, these data suggests that BIRC6 overexpression is a predictor of poor prognosis in colorectal cancer and BIRC6 could be a potential target of CRC therapy. PMID- 25933220 TI - Citreoviridin Enhances Atherogenesis in Hypercholesterolemic ApoE-Deficient Mice via Upregulating Inflammation and Endothelial Dysfunction. AB - Vascular endothelial dysfunction and inflammatory response are early events during initiation and progression of atherosclerosis. In vitro studies have described that CIT markedly upregulates expressions of ICAM-1 and VCAM-1 of endothelial cells, which result from NF-kappaB activation induced by CIT. In order to determine whether it plays a role in atherogenesis in vivo, we conducted the study to investigate the effects of CIT on atherosclerotic plaque development and inflammatory response in apolipoprotein E deficient (apoE-/-) mice. Five-week old apoE-/- mice were fed high-fat diets and treated with CIT for 15 weeks, followed by assay of atherosclerotic lesions. Nitric oxide (NO), vascular endothelial growth factor (VEGF) and endothelin-1 (ET-1) were detected in serum. Levels of intercellular adhesion molecule-1 (ICAM-1), vascular cell adhesion molecule-1 (VCAM-1), VEGF, and ET-1 in plaque areas of artery walls were examined. NF-kappaB p65 expression and NF-kappaB activation in aorta also were assessed. CIT treatment significantly augmented atherosclerotic plaques and increased expressions of ICAM-1, VCAM-1, VEGF and ET-1 in aorta. Mechanistic studies showed that activation of NF-kappaB was significantly elevated by CIT treatment, indicating the effect of CIT on atherosclerosis may be regulated by activation of NF-kappaB. PMID- 25933221 TI - Understanding the role of temperature change and the presence of NaCl salts on caffeine aggregation in aqueous solution: from structural and thermodynamics point of view. AB - To examine the molecular level understanding of temperature induced self association of caffeine molecules in aqueous solution both in the presence and absence of salt NaCl, we have performed long MD simulations at a regime of temperatures ranging from 275 to 350 K with a temperature difference of 25 K. The calculations of different site-site radial distribution functions followed by coordination number analyses, the calculations of preferential interaction parameters, solvent accessible surface area, and cluster structure analyses show a depletion in the caffeine association propensity with increasing temperature. We have also observed the salting out effect of caffeine molecules in salt solution. The simultaneous presence of polar and nonpolar groups in a caffeine molecule leads to anisotropic hydration. Specifically, the hydration tendency of caffeine hydrophobic sites increases with increasing temperature, while hydrophilic sites tend to be less hydrated. This leads to a decrease in caffeine association. In accordance with some experimental studies on thermodynamics of caffeine association, we have also observed enthalpy driven association in pure water. But the presence of salt leads to entropy driven association specifically at higher temperature. This is due to the relatively stronger interactions of salt ions with caffeine at higher temperature. PMID- 25933222 TI - Air pollution and diabetes risk: assessing the evidence to date. PMID- 25933223 TI - Parametric body shape model of standing children aged 3-11 years. AB - A statistical body shape model (SBSM) for children was developed for generating a child body shape with desired anthropometric parameters. A standardised template mesh was fit to whole-body laser scan data from 137 children aged 3-11 years. The mesh coordinates along with a set of surface landmarks and 27 manually measured anthropometric variables were analysed using principal component (PC) analysis. PC scores were associated with anthropometric predictors such as stature, body mass index (BMI) and ratio of erect sitting height to stature (SHS) using a regression model. When the original scan data were compared with the predictions of the SBSM using each subject's stature, BMI and SHS, the mean absolute error was 10.4 +/- 5.8 mm, and 95th percentile error was 24.0 +/- 18.5 mm. The model, publicly available online, will have utility for a wide range of applications. Practitioner Summary: A statistical body shape model for children helps to account for inter-individual variability in body shapes as well as anthropometric dimensions. This parametric modelling approach is useful for reliable prediction of the body shape of a specific child with a few given predictors such as stature, body mass index and age. PMID- 25933224 TI - The Beneficial Effects of P2X7 Antagonism in Rats with Bile Duct Ligation-induced Cirrhosis. AB - Splanchnic angiogenesis in liver cirrhosis often leads to complications as gastroesophageal variceal hemorrhage and the treatment efficacy is adversely affected by poor portal-systemic collateral vasoresponsiveness related to nitric oxide (NO). Purinergic receptor subtype P2X7 participates in the modulation of inflammation, angiogenesis, fibrogenesis and vasoresponsiveness, but the relevant influence in cirrhosis is unknown. Common bile duct-ligated (CBDL) or sham operated Spraque-Dawley rats received brilliant blue G (BBG, a P2X7 antagonist and food additive) or vehicle from the 15th to 28th day after operations, then hemodynamics, mesenteric angiogenesis, portal-systemic shunting, liver fibrosis, and protein expressions of angiogenic and fibrogenic factors were evaluated. The influence of oxidized ATP (oATP, another P2X7 receptor antagonist) on the collateral vasoresponsiveness to arginine vasopressin (AVP) was also surveyed. BBG decreased superior mesenteric artery (SMA) flow, portal-systemic shunting, mesenteric vascular density, and mesenteric protein expressions of vascular endothelial growth factor (VEGF), VEGF receptor 2 (VEGFR2), phospho (p)-VEGFR2, platelet-derived growth factor (PDGF), PDGF receptor beta (PDGFRbeta), cyclooxygenase (COX)-1, COX-2, and endothelial NO synthase (eNOS) in CBDL rats. BBG also ameliorated liver fibrosis and down-regulated hepatic interleukin-6 (IL 6), tumor necrosis factor-alpha (TNF-alpha), PDGF, IL-1beta, transforming growth factor-beta (TGF-beta), p-extracellular-signal-regulated kinases (ERK), and alpha smooth muscle actin (alpha-SMA) expressions in CBDL rats. The collateral vasocontractility to AVP was enhanced by oATP. oATP down-regulated eNOS, inducible NOS (iNOS), VEGF, Akt, p-Akt, and nuclear factor-kappa B (NF-kappaB) expressions in splenorenal shunt, the most prominent intra-abdominal collateral vessel in rodents. P2X7 antagonism alleviates splanchnic hyperemia, severity of portal-systemic shunting, mesenteric angiogenesis, liver fibrosis, and enhances portal-systemic collateral vasoresponsiveness in cirrhotic rats. P2X7 blockade may be a feasible strategy to control cirrhosis and complications. PMID- 25933226 TI - Bias in spontaneous reporting of adverse drug reactions in Japan. AB - BACKGROUND: Attitudes of healthcare professionals regarding spontaneous reporting of adverse drug reactions (ADRs) in Japan are not well known, and Japan's unique system of surveillance, called early post-marketing phase vigilance (EPPV), may affect these reporting attitudes. Our objectives were to describe potential effects of EPPV and to test whether ADR seriousness, prominence, and frequency are related to changes in reporting over time. METHODS: A manufacturer's database of spontaneous ADR reports was used to extract data from individual case safety reports for 5 drugs subject to EPPV. The trend of reporting and the time lag between ADR onset and reporting to the manufacturer were examined. The following indices for ADRs occurring with each drug were calculated and analyzed to assess reporting trends: Serious:Non-serious ratio, High prominence:Low prominence ratio, and High frequency:Low frequency ratio. RESULTS: For all 5 drugs, the time lag between ADR onset and reporting to the manufacturer was shorter in the EPPV period than in the post-EPPV period. All drugs showed higher Serious:Non-serious ratios in the post-EPPV period. No specific patterns were observed for the High prominence:Low prominence ratio. The High frequency:Low frequency ratio for peginterferon alpha-2a and sevelamer hydrochloride decreased steadily throughout the study period. CONCLUSIONS: Healthcare professionals may be more likely to report serious ADRs than to report non-serious ADRs, but the effect of event prominence on reporting trends is still unclear. Factors associated with ADR reporting attitude in Japan might be different from those in other countries because of EPPV and the involvement of medical representatives in the spontaneous reporting process. Pharmacovigilance specialists should therefore be cautious when comparing data between different time periods or different countries. Further studies are needed to elucidate the underlying mechanism of spontaneous ADR reporting in Japan. PMID- 25933227 TI - Health and Functioning of Families of Children With Special Health Care Needs Cared for in Home Care, Long-term Care, and Medical Day Care Settings. AB - OBJECTIVES: To examine and compare child and parent or guardian physical and mental health outcomes in families with children with special health care needs who have medically complex technology-dependent needs in home care, long-term care (LTC), and medical day care (MDC) settings. The number of children requiring medically complex technology-dependent care has grown exponentially. In this study, options for their care are home care, LTC, or MDC. Comparison of child and parent/guardian health outcomes is unknown. METHODS: Using repeated measures data were collected from 84 dyads (parent/guardian, medically complex technology dependent child) for 5 months using Pediatric Quality of Life Inventory Generic Core Module 4.0 and Family Impact Module Data analysis: chi(2), RM-ANCOVA. RESULTS: There were no significant differences in overall physical health, mental health, and functioning of children by care setting. Most severely disabled children were in home care; moderately disabled in MDC; children in vegetative state LTC; however, parents perceived children's health across care setting as good to excellent. Parents/guardians from home care reported the poorest physical health including being tired during the day, too tired to do the things they like to do, feeling physically weak, or feeling sick and had cognitive difficulties, difficulties with worry, communication, and daily activities. Parents/guardians from LTC reported the best physical health with time and energy for a social life and employment. CONCLUSIONS: Trends in health care policy indicate a movement away from LTC care to care in the family home where data indicate these parents/guardians are already mentally and functionally challenged. PMID- 25933229 TI - Taming the lion: the challenge of immunity in regenerative medicine. PMID- 25933228 TI - Serotonin Transporter Genotype (5HTTLPR) Moderates the Longitudinal Impact of Atypical Attachment on Externalizing Behavior. AB - OBJECTIVE: To test whether genotype of the serotonin transporter-linked polymorphic region (5HTTLPR) and atypical attachment interact to predict externalizing psychopathology prospectively in a sample of children with a history of early institutional care. METHODS: Caregiver report of externalizing behavior at 54 months was examined in 105 children initially reared in institutional care and enrolled in the Bucharest Early Intervention Project, a randomized controlled trial of high quality foster care. 5HTTLPR genotype, attachment status at 42 months of age (typical [secure, avoidant, or ambivalent] or atypical [disorganized-controlling, insecure-other]), and their interaction were examined as predictors of externalizing behavior at age 54 months. RESULTS: 5HTTLPR genotype and atypical attachment at age 42 months interacted to predict externalizing behavior at age 54 months. Specifically, children with the s/s genotype with an atypical attachment had the highest externalizing scores. However, s/s children with a typical attachment demonstrated the lowest externalizing scores, even after controlling for intervention group status. There was no association between attachment status and externalizing behavior among children carrying at least 1 copy of the l allele. CONCLUSION: These findings indicate that genetic variation in the serotonergic system moderates the association between atypical attachment status and externalizing in young children. Our findings suggest that children, as a result of genetic variability in the serotonergic system, demonstrate differential sensitivity to the attachment relationship. PMID- 25933230 TI - The issue of immunology in stem cell therapies: a pharmaceutical perspective. AB - Cautious approaches in the clinic are currently proposed, supported by relevant in vitro, in vivo and published data. Key to developing our understanding of the risks of immune rejection of stem cell based therapies will be the inclusion of immunological endpoints in clinical trials and the sharing of data. There is likely not a one-size-fits all strategy but one dependent on cell therapy, mode of action and disease indication. PMID- 25933231 TI - Development of a global network of induced pluripotent stem cell haplobanks. PMID- 25933232 TI - Exercising 'veto' power to make haploidentical hematopoietic stem cell transplantation a safe modality for induction of immune tolerance. PMID- 25933234 TI - The UKRMP Immunomodulation hub. PMID- 25933235 TI - Organizational profile: UK regenerative medicine platform immunomodulation hub. AB - The UK Regenerative Medicine Platform was launched in 2013 as a jointly funded venture by the Biotechnology and Biological Sciences Research Council (BBSRC), Biotechnology and Biological Sciences Research Council, Engineering and Physical Sciences Research Council (EPSRC) and Medical Research Council (MRC) to address the technical and scientific challenges associated with translating promising scientific discoveries into the clinical setting. The first stage of the Platform involved the establishment of five interdisciplinary and cross-institutional research Hubs and the final Hub, the Immunomodulation Hub, was formed in 2014. The Immunomodulation Hub comprises scientists from diverse clinical and nonclinical research backgrounds. Collectively, they provide expertise in tissues for which there is an unmet clinical need for regenerative treatments, in innate and adaptive immunity and in whole organ transplantation. Their vision is that by working together to determine how regenerative medicine cell therapies in a laboratory setting are affected by the immune system, they will make a substantial contribution to long-term clinical deliverables that include improved efficacy of photoreceptor cell therapy to treat blindness; improved repair of damaged heart tissue; and improved survival and functionality of transplanted hepatocytes as an alternative to liver transplantation. PMID- 25933236 TI - Neonatal desensitization for the study of regenerative medicine. AB - Cell replacement is a therapeutic option for numerous diseases of the CNS. Current research has identified a number of potential human donor cell types, for which preclinical testing through xenotransplantation in animal models is imperative. Immune modulation is necessary to promote donor cell survival for sufficient time to assess safety and efficacy. Neonatal desensitization can promote survival of human donor cells in adult rat hosts with little impact on the health of the host and for substantially longer than conventional methods, and has subsequently been applied in a range of studies with variable outcomes. Reviewing these findings may provide insight into the method and its potential for use in preclinical studies in regenerative medicine. PMID- 25933237 TI - Dendritic cells and pluripotency: unlikely allies in the pursuit of immunotherapy. AB - As the fulcrum on which the balance between the opposing forces of tolerance and immunity has been shown to pivot, dendritic cells (DC) hold significant promise for immune intervention in a variety of disease states. Here we discuss how the directed differentiation of human pluripotent stem cells may address many of the current obstacles to the use of monocyte-derived DC in immunotherapy, providing a novel source of previously inaccessible DC subsets and opportunities for their scale-up, quality control and genetic modification. Indeed, given that it is the immunological legacy DC leave behind that is of therapeutic value, rather than their persistence per se, we propose that immunotherapy should serve as an early target for the clinical application of pluripotent stem cells. PMID- 25933238 TI - Avoiding immunological rejection in regenerative medicine. AB - One of the major goals of regenerative medicine is repair or replacement of diseased and damaged tissues by transfer of differentiated stem cells or stem cell-derived tissues. The possibility that these tissues will be destroyed by immunological rejection remains a challenge that can only be overcome through a better understanding of the nature and expression of potentially immunogenic molecules associated with cell replacement therapy and the mechanisms and pathways resulting in their immunologic rejection. This review draws on clinical experience of organ and tissue transplantation, and on transplantation immunology research to consider practical approaches for avoiding and overcoming the possibility of rejection of stem cell-derived tissues. PMID- 25933239 TI - Immunogenicity of allogeneic mesenchymal stromal cells: what has been seen in vitro and in vivo? AB - Mesenchymal stromal cells (MSC) are promising candidates for supporting regeneration and suppressing undesired immune reactivity. Although autologous MSC have been most commonly used for clinical trials, data on application of allogeneic MHC-unmatched MSC were reported. The usage of MSC as an 'off-the shelf' product would have several advantages; however, it is an immunological challenge. The preclinical studies on the (non)immunogenicity of MSC are contradictory and, unfortunately, solid data from clinical trials are missing. Induction of an alloresponse would be a major limitation for the application of allogeneic MSC. Here we discuss the key elements for the induction of an alloresponse and targets of immunomodulation by MSC as well as preclinical and clinical hints on allo(non)response to MSC. PMID- 25933240 TI - Construction of a functional thymic microenvironment from pluripotent stem cells for the induction of central tolerance. AB - The thymus is required for generation of a self-tolerant, self-restricted T-cell repertoire. The capacity to manipulate or replace thymus function therapeutically would be beneficial in a variety of clinical settings, including for improving recovery following bone marrow transplantation, restoring immune system function in the elderly and promoting tolerance to transplanted organs or cells. An attractive strategy would be transplantation of thymus organoids generated from cells produced in vitro, for instance from pluripotent stem cells. Here, we review recent progress toward this goal, focusing on advances in directing differentiation of pluripotent stem cells to thymic epithelial cells, a key cell type of the thymic stroma, and related direct reprogramming strategies. PMID- 25933241 TI - The potential of cytotherapeutics in hematologic reconstitution and in the treatment and prophylaxis of graft-versus-host disease. Chapter I: current practice and remaining unmet medical needs. AB - Hematopoietic stem cell transplantation is a life-saving treatment for inherited anemias, immunodeficiencies or hematologic malignancies. When using partially HLA matched allografts, a major complication is graft-versus-host disease (GvHD). The ideal attributes of a transformational new GvHD treatment include improved survival, decreased corticosteroids, decreased antifungals, improved quality of life through decreased infections, reduced number of hospital stay days, reduced risks of developing chronic GvHD impact on lower GI tract and liver, prophylactic benefits and decreased GvHD relapses, but, in the case of cancer, without negatively impacting beneficial graft-versus-tumor effects. The current practice of hematopoietic stem cell transplantation, its incidence and its unmet medical needs are reviewed here and discussed. PMID- 25933242 TI - The potential of cytotherapeutics in hematologic reconstitution and in the treatment and prophylaxis of graft-versus-host disease. Chapter II: emerging transformational cytotherapies. AB - Hematopoietic stem cell transplantation (HSCT) is a life-saving treatment for inherited anemias, immunodeficiencies or hematologic malignancies. A major complication of allo-HSCT associated with high transplant-related mortality rates is graft-versus-host disease (GvHD). Current and future clinical benefits in HSCT enabled by advances in hematopoietic stem cells, mesenchymal stem cells, Tregs and natural killer cells technologies are reviewed here and discussed. Among these evolutions, based on the need for mesenchymal stem cells to be recruited by an inflammatory environment, the development and use of novel GvHD biomarkers could be explored further to deliver the right pharmaceutical to the right patient at the right time. The successful commercialization of cytotherapeutics to efficiently manage GvHD will create a virtuous 'halo' effect for regenerative medicine. PMID- 25933243 TI - Neuroprotective effect of sulforaphane against methylglyoxal cytotoxicity. AB - Glycation, an endogenous process that leads to the production of advanced glycation end products (AGEs), plays a role in the etiopathogenesis of different neurodegenerative diseases, such as Alzheimer's disease (AD). Methylglyoxal is the most potent precursor of AGEs, and high levels of methylglyoxal have been found in the cerebrospinal fluid of AD patients. Methylglyoxal may contribute to AD both inducing extensive protein cross-linking and mediating oxidative stress. The aim of this study was to investigate the role of sulforaphane, an isothiocyanate found in cruciferous vegetables, in counteracting methylglyoxal induced damage in SH-SY5Y neuroblastoma cells. The data demonstrated that sulforaphane protects cells against glycative damage by inhibiting activation of the caspase-3 enzyme, reducing the phosphorylation of MAPK signaling pathways (ERK1/2, JNK, and p38), reducing oxidative stress, and increasing intracellular glutathione levels. For the first time, we demonstrate that sulforaphane enhances the methylglyoxal detoxifying system, increasing the expression and activity of glyoxalase 1. Sulforaphane modulated brain-derived neurotrophic factor and its pathway, whose dysregulation is related to AD development. Moreover, sulforaphane was able to revert the reduction of glucose uptake caused by methylglyoxal. In conclusion, sulforaphane demonstrates pleiotropic behavior thanks to its ability to act on different cellular targets, suggesting a potential role in preventing/counteracting multifactorial neurodegenerative diseases such as Alzheimer's. PMID- 25933244 TI - Administration of chemotherapy in patients on dialysis. AB - The prevalence of patients on dialysis has increased and these patients present a challenge for chemotherapy administration when diagnosed with cancer. A consensus on the dosage and timing of different chemotherapeutic agents in relation to dialysis has not been established. We describe the pattern of care and treatment outcome for cancer patients on dialysis in our institution. The dataset from the Australia and New Zealand Dialysis and Transplant Registry of patients on dialysis who had a diagnosis of cancer was obtained and matched to the pharmacy records in our institution to identify patients who had received chemotherapy while on dialysis. Relevant clinical information including details of the dialysis regimen, chemotherapy administration and adverse events was extracted for analysis. Between July 1999 and July 2014, 21 patients on dialysis were included for analysis. Five (23.8%) received chemotherapy, most of which was administered before dialysis sessions. As a result of adverse events, one patient discontinued treatment; two other patients required dose reduction or treatment delay. Chemotherapy administration was feasible in cancer patients on dialysis, but chemotherapy usage was low. Better understanding of the altered pharmacokinetics in patients on dialysis may improve chemotherapy access and practice. PMID- 25933245 TI - Discovery of novel androgen receptor antagonists: a hybrid approach of pharmacophore-based and docking-based virtual screening. AB - Androgen receptor (AR) is an attractive target for the treatment of prostate cancer. An integrated pharmacophore-based and docking-based virtual screening approach was applied to identify novel AR antagonists with a distinct scaffold. The candidate compounds were evaluated for their abilities to inhibit prostate cancer cell proliferation and AR target gene prostate-specific antigen gene expression as well as the binding affinity to AR. A potent lead compound, T3, was discovered with the ability to inhibit prostate-specific antigen expression, with a similar binding affinity to AR, and with antiproliferative effects on AR positive prostate cancer cells similar to that of MDV3100. PMID- 25933246 TI - S-1 combined with cisplatin versus cisplatin alone for the treatment of advanced gastric cancer: a pilot randomized-controlled trial. AB - We aimed to assess the efficacy and safety of S-1 combined with cisplatin (SC) over cisplatin alone (C) for the treatment of advanced gastric cancer in China. Between July 2009 and June 2011, 72 eligible patients with advanced gastric cancer were selected and divided randomly into two groups. Thirty-six patients received SC, with S-1 on days 1 through 14 of a 21-day cycle and cisplatin (60 mg/m on day 1) every 4 weeks for two cycles. The other 36 patients were administered only cisplatin (in the same manner as SC). The primary outcome was overall survival. The secondary outcomes were progression-free survival and adverse events. The 2-year overall response rate was 51.5 and 42.3% for the SC and C groups, respectively, and the difference was statistically significant, whereas the median overall survival was 9.4 months (range, 1.9-24.4 months) and 7.6 months (range, 1.7-21.4 months), respectively (P=0.039). The median progression-free survival was 7.7 months for SC (range, 1.8-19.4 months), whereas it was 6.5 months (range, 1.5-16.4 months) for C (P=0.047). The toxicity profile was similar in both groups. In summary, we have shown that S-1 combined with cisplatin is more effective, with acceptable toxicity in comparison with cisplatin alone in Chinese patients with advanced gastric cancer. Chinese Clinical Trials Register: ChiCTR-TRC-13003993. PMID- 25933247 TI - Prolonged remission of recurrent cervical carcinoma following paclitaxel and carboplatin chemotherapy with paclitaxel maintenance chemotherapy. AB - Cervical cancer recurs in ~30% of cases, for which a favorable prognosis is often unattainable. We describe a cervical cancer patient who developed metastatic disease ~5 years after her initial diagnosis. She was subsequently treated with six cycles of paclitaxel (175 mg/m) and carboplatin area under the curve (AUC) 5 chemotherapy every 21 days, and paclitaxel (135 mg/m) maintenance therapy every 21 days; the patient has remained in clinical remission after more than 5 years of follow-up. Chemotherapy has not historically been effective in managing recurrent, persistent, or metastatic cervical cancer. However, our case study involving paclitaxel and carboplatin chemotherapy with maintenance chemotherapy represents one of the longest documented remission rates in association with the management of recurrent cervical cancer. PMID- 25933248 TI - Correction: Orbital entanglement and CASSCF analysis of the Ru-NO bond in a Ruthenium nitrosyl complex. PMID- 25933250 TI - Vacancy-Mediated Processes in the Oxidation of CO on PdO(101). AB - Metal oxide films can form on late transition-metal catalysts under sufficiently oxygen-rich conditions, and typically cause significant changes in the catalytic performance of these materials. Several investigations using sensitive in situ surface characterization techniques reveal that the CO oxidation activity of Pd and other late transition-metal catalysts increases abruptly under conditions at which metal oxide structures begin to develop. Findings such as these provide strong motivation for developing atomic-scale descriptions of oxidation catalysis over oxide films of the late transition-metals. Surface oxygen vacancies can play a central role in mediating oxidation catalysis promoted by metal oxides. In general, adsorbed reactants abstract oxygen atoms from the lattice of the oxide surface, thereby creating oxygen vacancies, while gaseous O2 replenishes the reactive surface oxygen atoms and eliminates oxygen vacancies. Oxygen vacancies also represent a distinct type of surface site on which the binding and reactivity of adsorbed species can differ compared with sites on the pristine oxide surface. Detailed characterization of vacancy-mediated rate processes is thus essential for developing reliable mechanistic descriptions of oxidation catalysis over reducible metal oxide films. Careful measurements performed in ultrahigh vacuum (UHV) using well-defined oxide surfaces in combination with molecular simulations afford the capability to isolate and characterize such reaction steps, and thus provide information that is needed for developing mechanistic models of oxidation catalysis over metal oxides. In this Account, we discuss vacancy-mediated processes that are involved in the oxidation of CO on the PdO(101) surface as determined from UHV surface science experiments and density functional theory (DFT) calculations. These studies show that CO binds strongly on Pd atoms that are located next to surface oxygen vacancies, and diffuses rapidly to these sites during reduction of the oxide surface by CO. The enhanced binding also raises the energy barriers for desorption and oxidation of CO, but the difference in these barriers remains nearly identical to that for CO adsorbed on the pristine PdO(101) surface. These recent studies also show that oxygen from the subsurface efficiently eliminates surface oxygen vacancies during CO oxidation at temperatures as low as 400 K, and thereby reveal a facile pathway by which PdO(101) surface domains can be maintained during oxide reduction. PMID- 25933249 TI - Acromiohumeral Distance During Neuromuscular Electrical Stimulation of the Lower Trapezius and Serratus Anterior Muscles in Healthy Participants. AB - CONTEXT: Compromise to the acromiohumeral distance has been reported in participants with subacromial impingement syndrome compared with healthy participants. In clinical practice, patients with subacromial shoulder impingement are given strengthening programs targeting the lower trapezius (LT) and serratus anterior (SA) muscles to increase scapular posterior tilt and upward rotation. We are the first to use neuromuscular electrical stimulation to stimulate these muscle groups and evaluate how the muscle contraction affects the acromiohumeral distance. OBJECTIVE: To investigate if electrical muscle stimulation of the LT and SA muscles, both separately and simultaneously, increases the acromiohumeral distance and to identify which muscle-group contraction or combination most influences the acromiohumeral distance. DESIGN: Controlled laboratory study. SETTING: Human performance laboratory. PATIENTS OR OTHER PARTICIPANTS: Twenty participants (10 men and 10 women, age = 26.9 +/- 8.0 years, body mass index = 23.8) were screened. INTERVENTION(S): Neuromuscular electrical stimulation of the LT and SA. MAIN OUTCOME MEASURE(S): Ultrasound measurement of the acromiohumeral distance. RESULTS: Acromiohumeral distance increased during contraction via neuromuscular electrical stimulation of the LT muscle (t(19) = -3.89, P = .004), SA muscle (t(19) = -7.67, P = .001), and combined LT and SA muscles (t(19) = -5.09, P = .001). We observed no differences in the increased acromiohumeral distance among the 3 procedures (F(2,57) = 3.109, P = .08). CONCLUSIONS: Our results supported the hypothesis that the muscle force couple around the scapula is important in rehabilitation and scapular control and influences acromiohumeral distance. PMID- 25933251 TI - Polyomaviruses and disease: is there more to know than viremia and viruria? AB - PURPOSE OF REVIEW: Polyomavirus nephropathy (PVN) mainly caused by BK virus (BKV) remains the most common productive viral infection of the kidney. Over the past decade, clinical interest often focused on BK viremia and viruria as the diagnostic mainstays of patient management. The purpose of this review is to discuss viral nephropathy in the context of BK viremia and viruria and new strategies to optimize diagnostic accuracy and patient management. The emerging roles of polyomaviruses in oncogenesis, salivary gland disease, and post-bone marrow transplantation as well as novel Polyomavirus strains are highlighted. RECENT FINDINGS: Areas of investigation include proposals by the Banff working group on the classification of PVN and studies on PVN progression and resolution, including the role cellular immune responses may play during reconstitution injury. New noninvasive strategies to optimize the diagnosis of PVN, that is, the urinary 'polyomavirus-haufen' test and mRNA expression levels for BKV in the urine, hold great promise to accurately identify patients with viral nephropathy. Tools are now available to separate 'presumptive' from 'definitive' disease in various patient cohorts including individuals post-bone marrow transplantation. Recent observations also point to a currently underrecognized role of polyomaviruses in oncogenesis post-transplantation and salivary gland disease in patients with HIV-AIDS. SUMMARY: This review summarizes recent studies on PVN and the significance of the BKV strain in disease. Current paradigms for patient management post-(renal) transplantation are discussed in the setting of new observations. Issues that still require clarification and further validation are highlighted. PMID- 25933252 TI - Chemical and Biological Reduction of the Radical SAM Enzyme 7-Carboxy-7 deazaguanine [corrected] Synthase. AB - The radical S-adenosyl-L-methionine (SAM) superfamily is a large and growing group of enzymes that conduct complex radical-mediated transformations. A one electron reduction of SAM via the +1 state of the cubane [4Fe-4S] cluster generates a 5'-deoxyadenosyl radical, which initiates turnover. The [4Fe-4S] cluster must be reduced from its resting +2 state to the catalytically active +1 oxidation state by an electron. In practice, dithionite or the Escherichia coli flavodoxin (EcFldA)/ferredoxin (flavodoxin):NADP(+) oxidoreductase (Fpr)/NADPH system is used. Herein, we present a systematic investigation of the reductive activation of the radical SAM enzyme CDG synthase (BsQueE) from Bacillus subtilis comparing biological and chemical reductants. These data show that either of the flavodoxin homologues encoded by the B. subtilis genome, BsYkuN or BsYkuP, as well as a series of small molecule redox mediators, supports BsQueE activity. With dithionite as a reductant, the activity of BsQueE is ~75-fold greater in the presence of BsYkuN and BsYkuP compared to that in the presence of dithionite alone. By contrast, EcFldA supports turnover to ~10-fold greater levels than dithionite alone under the same conditions. Comparing the ratio of the rate of turnover to the apparent binding constant for the flavodoxin homologues reveals 10- and 240-fold preferences for BsYkuN over BsYkuP and EcFldA, respectively. The differential activation of the enzyme cannot be explained by the abortive cleavage of SAM. We conclude from these observations that the differential activation of BsQueE by Fld homologues may reside in the details of the interaction between the flavodoxin and the radical SAM enzyme. PMID- 25933253 TI - Nitrification at full-scale municipal wastewater treatment plants: Evaluation of inhibition and bioaugmentation of nitrifiers. AB - Batch nitrification tests were conducted with sludge and wastewater streams obtained from field implementations to evaluate nitrification inhibition and efficiency of a nitrifiers bioaugmentation technology at full-scale municipal wastewater treatment plants (WWTPs). The results showed that the substrate organic carbon and pH of wastewater streams were inhibitory factors to nitrification and the low pH was the cause of the WWTP experiencing poor nitrification. An ammonia-nitrogen removal rate of 0.21mg-N/gMLVSS-h was observed at pH 6.5, while the rate increased to 0.54mg-N/gMLVSS-h with an introduction of 6% bioaugmented nitrifiers, indicating that the integrated side-stream nitrifiers bioaugmentation process was beneficial in improving nitrification efficiency, even under low pH conditions not conducive to nitrification. The study provides new insights into effective upgrading of municipal WWTPs exposed to poor nitrification. PMID- 25933255 TI - Correction to Structure-Guided Design of a Series of MCL-1 Inhibitors with High Affinity and Selectivity. PMID- 25933256 TI - The quest of the human proteome and the missing proteins: digging deeper. AB - Given the diverse range of transcriptional and post-transcriptional mechanisms of gene regulation, the estimates of the human proteome is likely subject to scientific surprises as the field of proteomics has gained momentum worldwide. In this regard, the establishment of the "Human Proteome Draft" using high resolution mass spectrometry (MS), tissue microarrays, and immunohistochemistry by three independent research groups (laboratories of Pandey, Kuster, and Uhlen) accelerated the pace of proteomics research. The Chromosome Centric Human Proteome Project (C-HPP) has taken initiative towards the completion of the Human Proteome Project (HPP) so as to understand the proteomics correlates of common complex human diseases and biological diversity, not to mention person-to-person and population differences in response to drugs, nutrition, vaccines, and other health interventions and host-environment interactions. Although high-resolution MS-based and antibody microarray approaches have shown enormous promises, we are still unable to map the whole human proteome due to the presence of numerous "missing proteins." In December 2014, at the Indian Institute of Technology Bombay, Mumbai the 6(th) Annual Meeting of the Proteomics Society, India (PSI) and the International Proteomics Conference was held. As part of this interdisciplinary summit, a panel discussion session on "The Quest of the Human Proteome and Missing Proteins" was organized. Eminent scientists in the field of proteomics and systems biology, including Akhilesh Pandey, Gilbert S. Omenn, Mark S. Baker, and Robert L. Mortiz, shed light on different aspects of the human proteome drafts and missing proteins. Importantly, the possible reasons for the "missing proteins" in shotgun MS workflow were identified and debated by experts as low tissue expression, lack of enzymatic digestion site, or protein lost during extraction, among other contributing factors. To capture the missing proteins, the experts' collective view was to study the wider tissue range with multiple digesting enzymes and follow targeted proteomics workflow in particular. On the innovation trajectory from the proteomics laboratory to novel proteomics diagnostics and therapeutics in society, we will also need new conceptual frames for translation science and innovation strategy in proteomics. These will embody both technical as well as rigorous social science and humanities considerations to understand the correlates of the proteome from cell to society. PMID- 25933254 TI - Serum malondialdehyde levels in patients with malignant middle cerebral artery infarction are associated with mortality. AB - OBJECTIVE: Malondialdehyde (MDA) is an end-product formed during lipid peroxidation, due to degradation of cellular membrane phospholipids. MDA is released into extracellular space and finally into the blood; it has been used as an effective biomarker of lipid oxidation. High circulating levels of MDA have been previously described in patients with ischemic stoke than in controls, and an association between circulating MDA levels and neurological functional outcome in patients with ischemic stoke. However, an association between serum MDA levels and mortality in patients with ischemic stroke has not been previously reported, and that was the objective of this study. METHODS: Observational, prospective and multicenter study performed in six Intensive Care Units. We included patients with severe malignant middle cerebral artery infarction (MMCAI) defined as Glasgow Coma Scale (GCS) lower than 9. We measured serum MDA levels in 50 patients with severe MMCAI at the time of diagnosis and in 100 healthy subjects. Mortality at 30 days was the end point of the study. RESULTS: We found that patients with severe MMCAI showed higher serum MDA levels than healthy subjects (p<0.001). We found higher serum MDA levels (p<0.001) in non-surviving MMCAI patients (n=26) than in survivors (n=24). The area under the curve for prediction of 30-day mortality for serum MDA levels was 0.77 (95% CI = 0.63-0.88; p<0.001). Serum MDA levels >2.27 nmol/mL were associated with 30-day mortality (OR=7.23; 95% CI=1.84-28.73; p=0.005) controlling for GCS and age on multiple binomial logistic regression analysis. CONCLUSIONS: To our knowledge, this is the first study showing that serum malondialdehyde levels in patients with MMCAI are associated with early mortality. PMID- 25933257 TI - Proteomics of human aqueous humor. AB - The aqueous humor is a colorless, transparent fluid that fills the anterior chamber of the eye. It plays an important role in maintaining the intraocular pressure and providing nourishment to the lens and cornea. The constitution of the aqueous humor is controlled by the blood-aqueous barrier. Though this ocular fluid has been extensively studied, its role in ocular physiology is still not completely understood. In this study, aqueous humor samples were collected from 250 patients undergoing cataract surgery, subjected to multiple fractionation strategies and analyzed on a Fourier transform LTQ-Orbitrap Velos mass spectrometer. In all, we identified 763 proteins, of which 386 have been identified for the first time in this study. Sorbitol dehydrogenase (SORD), filensin (BFSP1), and phakinin (BFSP2) are some of the proteins that have not been previously reported in the aqueous humor. Gene Ontology analysis revealed 35% of the identified proteins to be extracellular, with a majority of them involved in cell communication and signal transduction. This study comprehensively reports 386 novel proteins that have important potential as biomarker candidates for future research into personalized medicine and diagnostics aimed towards improving visual health. PMID- 25933258 TI - Quantitative volumetric breast density estimation using phase contrast mammography. AB - Phase contrast mammography using a grating interferometer is an emerging technology for breast imaging. It provides complementary information to the conventional absorption-based methods. Additional diagnostic values could be further obtained by retrieving quantitative information from the three physical signals (absorption, differential phase and small-angle scattering) yielded simultaneously. We report a non-parametric quantitative volumetric breast density estimation method by exploiting the ratio (dubbed the R value) of the absorption signal to the small-angle scattering signal. The R value is used to determine breast composition and the volumetric breast density (VBD) of the whole breast is obtained analytically by deducing the relationship between the R value and the pixel-wise breast density. The proposed method is tested by a phantom study and a group of 27 mastectomy samples. In the clinical evaluation, the estimated VBD values from both cranio-caudal (CC) and anterior-posterior (AP) views are compared with the ACR scores given by radiologists to the pre-surgical mammograms. The results show that the estimated VBD results using the proposed method are consistent with the pre-surgical ACR scores, indicating the effectiveness of this method in breast density estimation. A positive correlation is found between the estimated VBD and the diagnostic ACR score for both the CC view (p = 0.033) and AP view (p = 0.001). A linear regression between the results of the CC view and AP view showed a correlation coefficient gamma = 0.77, which indicates the robustness of the proposed method and the quantitative character of the additional information obtained with our approach. PMID- 25933260 TI - All in for alcohol awareness. PMID- 25933261 TI - Ending LGBT conversion therapies. PMID- 25933259 TI - Edible fungus degrade bisphenol A with no harmful effect on its fatty acid composition. AB - Bisphenol A (BPA) is an endocrine-disrupting chemical that is ubiquitous in the environment because of its broad industrial use. The authors report that the most widely cultivated mushroom in the world (i.e., white-rot fungus, Pleurotus ostreatus) efficiently degraded 10mg/L of BPA in 7 days. Extracellular laccase was identified as the enzyme responsible for this activity. LC-MS analysis of the metabolites revealed the presence of both low- and high-molecular-weight products obtained via oxidative cleavage and coupling reactions, respectively. In particular, an analysis of the fatty acid composition and chemical structure of the fungal mycelium demonstrated that exposure to BPA resulted in no harmful effects on this edible fungus. The results provide a better understanding of the environmental fate of BPA and its potential impact on food crops. PMID- 25933262 TI - A call for equity in the delivery of UK palliative care. PMID- 25933263 TI - Coalition: the way forward for medical education. PMID- 25933264 TI - Pre-exposure prophylaxis works--it's time to deliver. PMID- 25933266 TI - Tackling teenage pregnancy in Colombia. PMID- 25933267 TI - New global centre launched to address chronic diseases. PMID- 25933268 TI - Profile: Australia's George Institute for Global Health. PMID- 25933270 TI - The history and fate of the gold standard. PMID- 25933271 TI - Dan Tunstall Pedoe. PMID- 25933272 TI - Violence against women: do not forget their children! PMID- 25933273 TI - Improving paediatric care in the community. PMID- 25933274 TI - Prostate cancer screening in Europe. PMID- 25933275 TI - Prostate cancer screening in Europe. PMID- 25933276 TI - Prostate cancer screening in Europe - Authors' reply. PMID- 25933277 TI - Prostate cancer screening in Europe. PMID- 25933278 TI - Opioid substitution therapy-time to replace the term. PMID- 25933279 TI - T-DM1-related carotenoderma and hand-foot syndrome. PMID- 25933280 TI - Parents in Pakistan arrested for polio vaccine refusal: a necessary step? PMID- 25933281 TI - HIV incidence and mortality in China. PMID- 25933282 TI - Department of error. PMID- 25933284 TI - Department of error. PMID- 25933283 TI - Department of error. PMID- 25933285 TI - IgLON5 autoimmunity and abnormal behaviours during sleep. PMID- 25933286 TI - A new family of Ni4 and Ni6 aggregates from the self-assembly of [Ni2] building units: role of carboxylate and carbonate bridges. AB - Carboxylato (R = (t)Bu and Et) and carbonato bridges have been utilized for nickel(II)-based aggregates [Ni4(MU-H2L)2(MU3-OH)2(MU1,3 O2CBu(t))2](NO3)2.H2O.2DMF (1.H2O.2DMF), Ni4(MU-(hy)HL)2(MU3-OMe)2(MU1,1 N3)2(MU1,3-O2CEt)2].4H2O (2.4H2O), and Ni6(MU4-L)(MU3-L)2(MU6 CO3)(H2O)8](ClO4).9H2O (3.9H2O). Building blocks [Ni2(MU-H2L)](3+), [Ni2(MU (hy)HL)](3+), and [Ni2(MU-L)](+) originating from [Ni2(MU-H2L)](3+) have been trapped in these complexes. The complexes have been characterized by X-ray crystallography, magnetic measurements, and density functional theory (DFT) analysis. In 1, the magnetic interactions are transmitted through the MU3 phenoxido/MU3-hydroxido/syn-syn-(t)BuCO2(-), MU3-phenoxido/MU3- hydroxido, and double MU3-phenoxido/double MU3-hydroxido bridges with J = +11.4 cm(-1), J1 = 2.1 cm(-1), and J2 = -2.8 cm(-1), respectively. In 2, the interactions are ferromagnetic, with J1 = +27.5 cm(-1), J2 = +20.62 cm(-1), and J3 = +1.52 cm(-1) describing the magnetic couplings through the MU-phenoxidoo/MU3-methoxido, MU azido/MU3-methoxido, and MU3-methoxido/MU3-methoxido exchange pathways, respectively. Complex 3 gives J1 = -3.30 cm(-1), J2 = +1.7 cm(-1), and J3 = -12.8 cm(-1) for exchange pathways mediated by MU-phenoxido/MU-carbonato, MU alkoxido/MU-alkooxido/MU-syn-syn-carbonato, and the MU-phenoxido/MU-carbonato, respectively. Interestingly, 1 and 3 below 20 K and 35 K, respectively, show an abrupt increase of the chiMT product to reach a magnetic-field-dependent maximum, which is associated with a slightly frequency-dependent out-of-phase alternating current peak. DFT calculations have also been performed on 1-3 to explain the exchange interaction mechanisms and to support the magnitude and sign of the magnetic coupling constants between the Ni(II) ions. PMID- 25933287 TI - The PGE2/IL-10 Axis Determines Susceptibility of B-1 Cell-Derived Phagocytes (B 1CDP) to Leishmania major Infection. AB - B-1 cells can be differentiated from B-2 cells because they are predominantly located in the peritoneal and pleural cavities and have distinct phenotypic patterns and activation properties. A mononuclear phagocyte derived from B-1 cells (B-1CDP) has been described. As the B-1CDP cells migrate to inflammatory/infectious sites and exhibit phagocytic capacity, the microbicidal ability of these cells was investigated using the Leishmania major infection model in vitro. The data obtained in this study demonstrate that B-1CDP cells are more susceptible to infection than peritoneal macrophages, since B-1CDP cells have a higher number of intracellular amastigotes forms and consequently release a larger number of promastigotes. Exacerbated infection by L. major required lipid bodies/PGE2 and IL-10 by B-1CDP cells. Both infection and the production of IL-10 were decreased when PGE2 production was blocked by NSAIDs. The involvement of IL-10 in this mechanism was confirmed, since B-1CDP cells from IL-10 KO mice are more competent to control L. major infection than cells from wild type mice. These findings further characterize the B-1CDP cells as an important mononuclear phagocyte that plays a previously unrecognized role in host responses to L. major infection, most likely via PGE2-driven production of IL-10. PMID- 25933288 TI - Differentiation of IncL and IncM Plasmids Associated with the Spread of Clinically Relevant Antimicrobial Resistance. AB - INTRODUCTION: blaOXA-48, blaNDM-1 and blaCTX-M-3 are clinically relevant resistance genes, frequently associated with the broad-host range plasmids of the IncL/M group. The L and M plasmids belong to two compatible groups, which were incorrectly classified together by molecular methods. In order to understand their evolution, we fully sequenced four IncL/M plasmids, including the reference plasmids R471 and R69, the recently described blaOXA-48-carrying plasmid pKPN El.Nr7 from a Klebsiella pneumoniae isolated in Bern (Switzerland), and the blaSHV-5 carrying plasmid p202c from a Salmonella enterica from Tirana (Albania). METHODS: Sequencing was performed using 454 Junior Genome Sequencer (Roche). Annotation was performed using Sequin and Artemis software. Plasmid sequences were compared with 13 fully sequenced plasmids belonging to the IncL/M group available in GenBank. RESULTS: Comparative analysis of plasmid genomes revealed two distinct genetic lineages, each containing one of the R471 (IncL) and R69 (IncM) reference plasmids. Conjugation experiments demonstrated that plasmids representative of the IncL and IncM groups were compatible with each other. The IncL group is constituted by the blaOXA-48-carrying plasmids and R471. The IncM group contains two sub-types of plasmids named IncM1 and IncM2 that are each incompatible. CONCLUSION: This work re-defines the structure of the IncL and IncM families and ascribes a definitive designation to the fully sequenced IncL/M plasmids available in GenBank. PMID- 25933290 TI - Comparative assessment of button cells using a normalized index for potential pollution by heavy metals. AB - Many household batteries worldwide still end up in landfills or are incinerated due to inefficient collection and recycling schemes. Toxic heavy metals from improperly discarded button cells pose a serious risk to human health and the environment, as they can pollute air, soil and water. This paper analyses a series of button cells selected from batteries available on the retail market, and compares their polluting potential. A total of 64 batteries were subjected to chemical analyses of 19 elements - including metals and metalloids - , and energy density measurements. The samples were from four different brands of each of the four most common button cell technologies (alkaline, zinc-air, silver oxide and lithium). An energy-normalized index - the Weighted Potential Pollution Index (WPPI) - was proposed to compare the polluting potential of the different batteries. The higher the battery WPPI score, the greater the content in toxic elements and the lower the energy output. The results of the chemical composition and energy density varied depending on the construction technology of the button cells. However, significant differences in both variables were also found when comparing different brands within the same technology. The differences in WPPI values confirmed the existence of a significant margin to reduce the environmental impact of discarded button cells simply by avoiding the most polluting options. The choice of the battery with the most favourable WPPI produced a reduction in potential pollution of 3-53% for silver oxide batteries, 4-39% for alkaline, 20-28% for zinc-air and 12-26% for lithium. Comparative potential pollution could be assessed when selecting batteries using an energy normalized index such as WPPI to reduce the environmental impact of improperly disposed button cells. PMID- 25933289 TI - Plasma miR-122 and miR-3149 Potentially Novel Biomarkers for Acute Coronary Syndrome. AB - OBJECTIVE: We evaluated the potentiality of plasma microRNAs (miRNAs, or miRs) that were considered as novel biomarkers for acute coronary syndrome (ACS), including acute myocardial infarction (AMI) and unstable angina (UA). METHODS AND RESULTS: We initially identified plasma miR-122, -140-3p, -144, -720, -1225-3p, 2861, and -3149 as candidate miRNAs associated with AMI (>=2 fold and P < 0.05) by comparing expression differences of miRNAs among AMI, non-coronary heart disease (non-CHD) and stable angina (SA) groups, using miRNA microarrays (n = 8 independent arrays in each group). Those seven plasma miRNAs were further examined with qRT-PCR analyses in two replications including 111 and 428 patients separately, and the results demonstrated that plasma miR-122, -140-3p, -720, 2861, and -3149 were elevated in the ACS group vs. the non-ACS (non-CHD + SA) group (P < 0.01). The area under the receiver operating characteristic curve (AUC) of the five miRNAs for ACS classification was 0.838, 0.818, 0.865, 0.852, and 0.670, respectively (all P < 0.001), while the values reached 0.843 and 0.925 when simultaneously with miR-122 and -3149 or with miR-122, -2861, and -3149 together (all P < 0.001). In plasma of pigs after coronary ligation, miR-122 was increased from 180 min to 240 min and miR-3149 was augmented from 30 min to 240 min compared with the sham pigs (all P < 0.05). CONCLUSION: Plasma miR-122, -140 3p, -720, -2861, and -3149 were associated with and potentially novel biomarkers for ACS. PMID- 25933291 TI - Impact of mitigation strategies on acid sulfate soil chemistry and microbial community. AB - Potential acid sulfate soils contain reduced iron sulfides that if oxidized, can cause significant environmental damage by releasing large amounts of acid and metals. This study examines metal and acid release as well as the microbial community capable of catalyzing metal sulfide oxidation after treating acid sulfate soil with calcium carbonate (CaCO3) or calcium hydroxide (Ca(OH)2). Leaching tests of acid sulfate soil samples were carried out in the laboratory. The pH of the leachate during the initial flushing with water lay between 3.8 and 4.4 suggesting that the jarosite/schwertmannite equilibrium controls the solution chemistry. However, the pH increased to circa 6 after treatment with CaCO3 suspension and circa 12 after introducing Ca(OH)2 solution. 16S rRNA gene sequences amplified from community DNA extracted from the untreated and both CaCO3 and Ca(OH)2 treated acid sulfate soils were most similar to bacteria (69.1% to 85.7%) and archaea (95.4% to 100%) previously identified from acid and metal contaminated environments. These species included a Thiomonas cuprina-like and an Acidocella-like bacteria as well as a Ferroplasma acidiphilum-like archeon. Although the CaCO3 and Ca(OH)2 treatments did not decrease the proportion of microorganisms capable of accelerating acid and metal release, the chemical effects of the treatments suggested their reduced activity. PMID- 25933292 TI - Ecotoxicological characterization of sugarcane vinasses when applied to tropical soils. AB - The impact of sugarcane vinasse on soil invertebrates was assessed through ecotoxicological assays. Increasing concentrations of two vinasses from different distillery plants (VA and VB), and a vinasse from a laboratory production (VC), were amended on two natural tropical Oxisols (LV and LVA) and a tropical artificial soil (TAS) to characterize the effects of the vinasses on earthworms (Eisenia andrei), enchytraeids (Enchytraeus crypticus), mites (Hypoaspis aculeifer) and collembolans (Folsomia candida). The highest concentrations of VA and VB were avoided by earthworms in all soils and by collembolans especially in the natural soils. The presence of VC in all of the tested soils did not cause avoidance behavior in these species. The reproduction of earthworms, enchytraeids and collembolans was decreased in the highest concentrations of VA and VB in the natural soils. In TAS, VB reduced the reproduction of all test species, whereas VA was toxic exclusively to E. andrei and E. crypticus. The vinasse VC only reduced the number of earthworms in TAS and enchytraeids in LVA. The reproduction of mites was reduced by VB in TAS. Vinasses from distillery plants were more toxic than the vinasse produced in laboratory. The vinasse toxicities were influenced by soil type, although this result was most likely because of the way the organisms are exposed to the contaminants in the soils. Toxicity was attributed to the vinasses' high salt content and especially the high potassium concentrations. Data obtained in this study highlights the potential risk of vinasse disposal on tropical soils to soil biota. The toxic values estimated are even more relevant when considering the usual continuous use of vinasses in crop productions. PMID- 25933293 TI - Aquatic acute species sensitivity distributions of ZnO and CuO nanoparticles. AB - Metal oxide nanoparticles are increasingly being produced and will inevitably end up in the aquatic environment. Up till now, most papers have studied individual nanoparticle effects. However, the implementation of these data into a risk assessment tool, needed to characterise their risk to the aquatic environment, is still largely lacking. Therefore, aquatic species sensitivity distributions (SSDs) were constructed for ZnO and CuO nanoparticles and 5% hazard concentrations (HC5) were calculated in this study. The effect of individual nanoparticles on these SSDs was estimated by comparison with bulk SSDs. Additionally, the effect of nanoparticle dynamics (aggregation and dissolution) was considered by evaluating the effect of aggregate size on the toxicity, by estimation of the dissolved fraction and comparison with SSDs for ZnCl2 and CuCl2 inorganic salt. Bacteria, protozoa, yeast, rotifera, algae, nematoda, crustacea, hexapoda, fish and amphibia species were included in the analysis. The results show that algae (Zn) and crustacea (Zn, Cu) are the most sensitive species when exposed to the chemicals. Similar acute sensitivity distributions were obtained for ZnO nanoparticles (HC5: 0.06 with 90% confidence interval: 0.03-0.15 mg Zn/l; 43 data points), bulk ZnO (HC5: 0.06 with CI: 0.03-0.20 mg Zn/l; 23 dps) and ZnCl2 (HC5: 0.03 with CI: 0.02-0.05 mg Zn/l; 261 dps). CuO nanoparticles (HC5: 0.15 with CI: 0.05-0.47 mg Cu/l; 43 dps) are more toxic than the bulk materials (HC5: 6.19 with CI: 2.15-38.11 mg Cu/l; 12 dps) but less toxic than CuCl2 (HC5: 0.009 with CI: 0.007-0.012 mg Cu/l; 594 dps) to aquatic species. However, the combined dissolution and SSD results indicate that the toxicity of these nanoparticles is mainly caused by dissolved metal ions. Based on the available information, no current risk of these nanoparticles to the aquatic environment is expected. PMID- 25933294 TI - Bioavailability and release of nonextractable (bound) residues of chiral cycloxaprid using geophagous earthworm Metaphire guillelmi in rice paddy soil. AB - The widespread adoption of neonicotinoids has led to a move away from integrated pest management (IPM) and caused adverse effects on non-target invertebrate species. Due to their living in close contact with and consuming large amounts of soil, earthworms are a model organism used to study bioaccumulation. We investigated the bioaccumulation and release of bound, or non-extractable, residues (BRs) of (14)C labeled racemic cycloxaprid (CYC) and its individual enantiomers by the geophagous earthworm Metaphire guillelmi. In a previous work, the fraction of BRs of (14)C-CYC individual enantiomers reached up to 70-85% of the initially spiked radioactivity after 100 d of treatment. The bulk volume of the soil was then diluted by a factor of 15 with fresh soil. Here we showed that after earthworms lived in the soil-bound residues for 28 d, 11-25% of the previously bound radioactivity in soil was extractable by solvent, mineralized to CO2, and accumulated in earthworm tissues. While earthworms were exposed to (14)C CYC a two-compartment accumulation model could explain the bio-accumulation as individual enantiomers. At the end of the experiment, the biota-sediment accumulation factors were between 0.59 and 0.82, which suggested CYC immobilization in the soil resulted in its bioavailability being reduced which enhanced its degradation. Additionally, the elimination of CYC individual enantiomers from M. guillelmi was fitted to an availability-adjusted decay model with a half-life of 9 d. Stereoselective release or bioavailability between CYC enantiomers was not observed. These results provide the important data about the release of BRs of CYC and potential transfer in the food chain to support the long-term environmental risk assessment of neonicotinoids. PMID- 25933295 TI - HGF Gene Modification in Mesenchymal Stem Cells Reduces Radiation-Induced Intestinal Injury by Modulating Immunity. AB - BACKGROUND: Effective therapeutic strategies to address intestinal complications after radiation exposure are currently lacking. Mesenchymal stem cells (MSCs), which display the ability to repair the injured intestine, have been considered as delivery vehicles for repair genes. In this study, we evaluated the therapeutic effect of hepatocyte growth factor (HGF)-gene-modified MSCs on radiation-induced intestinal injury (RIII). METHODS: Female 6- to 8-week-old mice were radiated locally at the abdomen with a single 13-Gy dose of radiation and then treated with saline control, Ad-HGF or Ad-Null-modified MSCs therapy. The transient engraftment of human MSCs was detected via real-time PCR and immunostaining. The therapeutic effects of non- and HGF-modified MSCs were evaluated via FACS to determine the lymphocyte immunophenotypes; via ELISA to measure cytokine expression; via immunostaining to determine tight junction protein expression; via PCNA staining to examine intestinal epithelial cell proliferation; and via TUNEL staining to detect intestinal epithelial cell apoptosis. RESULTS: The histopathological recovery of the radiation-injured intestine was significantly enhanced following non- or HGF-modified MSCs treatment. Importantly, the radiation-induced immunophenotypic disorders of the mesenteric lymph nodes and Peyer's patches were attenuated in both MSCs-treated groups. Treatment with HGF-modified MSCs reduced the expression and secretion of inflammatory cytokines, including tumor necrosis factor alpha (TNF-alpha) and interferon-gamma (IFN-gamma), increased the expression of the anti-inflammatory cytokine IL-10 and the tight junction protein ZO-1, and promoted the proliferation and reduced the apoptosis of intestinal epithelial cells. CONCLUSIONS: Treatment of RIII with HGF-gene-modified MSCs reduces local inflammation and promotes the recovery of small intestinal histopathology in a mouse model. These findings might provide an effective therapeutic strategy for RIII. PMID- 25933296 TI - Correction: pathological impact of hepatitis B virus surface proteins on the liver is associated with the host genetic background. PMID- 25933297 TI - Self-testing quantum random number generator. AB - The generation of random numbers is a task of paramount importance in modern science. A central problem for both classical and quantum randomness generation is to estimate the entropy of the data generated by a given device. Here we present a protocol for self-testing quantum random number generation, in which the user can monitor the entropy in real time. Based on a few general assumptions, our protocol guarantees continuous generation of high quality randomness, without the need for a detailed characterization of the devices. Using a fully optical setup, we implement our protocol and illustrate its self testing capacity. Our work thus provides a practical approach to quantum randomness generation in a scenario of trusted but error-prone devices. PMID- 25933298 TI - Energy-tunable sources of entangled photons: a viable concept for solid-state based quantum relays. AB - We propose a new method of generating triggered entangled photon pairs with wavelength on demand. The method uses a microstructured semiconductor piezoelectric device capable of dynamically reshaping the electronic properties of self-assembled quantum dots (QDs) via anisotropic strain engineering. Theoretical models based on k.p theory in combination with finite-element calculations show that the energy of the polarization-entangled photons emitted by QDs can be tuned in a range larger than 100 meV without affecting the degree of entanglement of the quantum source. These results pave the way towards the deterministic implementation of QD entanglement resources in all-electrically controlled solid-state-based quantum relays. PMID- 25933299 TI - Jarzynski Equality in PT-Symmetric Quantum Mechanics. AB - We show that the quantum Jarzynski equality generalizes to PT-symmetric quantum mechanics with unbroken PT symmetry. In the regime of broken PT symmetry, the Jarzynski equality does not hold as also the CPT norm is not preserved during the dynamics. These findings are illustrated for an experimentally relevant system two coupled optical waveguides. It turns out that for these systems the phase transition between the regimes of unbroken and broken PT symmetry is thermodynamically inhibited as the irreversible work diverges at the critical point. PMID- 25933300 TI - Identification of the predicted 5s-4f level crossing optical lines with applications to metrology and searches for the variation of fundamental constants. AB - We measure optical spectra of Nd-like W, Re, Os, Ir, and Pt ions of particular interest for studies of a possibly varying fine-structure constant. Exploiting characteristic energy scalings we identify the strongest lines, confirm the predicted 5s-4f level crossing, and benchmark advanced calculations. We infer two possible values for optical M2/E3 and E1 transitions in Ir^{17+} that have the highest predicted sensitivity to a variation of the fine-structure constant among stable atomic systems. Furthermore, we determine the energies of proposed frequency standards in Hf^{12+} and W^{14+}. PMID- 25933301 TI - Linear mode stability of the Kerr-Newman black hole and its quasinormal modes. AB - We provide strong evidence that, up to 99.999% of extremality, Kerr-Newman black holes (KNBHs) are linear mode stable within Einstein-Maxwell theory. We derive and solve, numerically, a coupled system of two partial differential equations for two gauge invariant fields that describe the most general linear perturbations of a KNBH. We determine the quasinormal mode (QNM) spectrum of the KNBH as a function of its three parameters and find no unstable modes. In addition, we find that the lowest radial overtone QNMs that are connected continuously to the gravitational l=m=2 Schwarzschild QNM dominate the spectrum for all values of the parameter space (m is the azimuthal number of the wave function and l measures the number of nodes along the polar direction). Furthermore, the (lowest radial overtone) QNMs with l=m approach Reomega=mOmegaH(ext) and Imomega=0 at extremality; this is a universal property for any field of arbitrary spin |s|<=2 propagating on a KNBH background (omega is the wave frequency and OmegaH(ext) the black hole angular velocity at extremality). We compare our results with available perturbative results in the small charge or small rotation regimes and find good agreement. PMID- 25933302 TI - No-hair theorem for black holes in astrophysical environments. AB - According to the no-hair theorem, static black holes are described by a Schwarzschild spacetime provided there are no other sources of the gravitational field. This requirement, however, is in astrophysical realistic scenarios often violated, e.g., if the black hole is part of a binary system or if it is surrounded by an accretion disk. In these cases, the black hole is distorted due to tidal forces. Nonetheless, the subsequent formulation of the no-hair theorem holds: The contribution of the distorted black hole to the multipole moments that describe the gravitational field close to infinity and, thus, all sources is that of a Schwarzschild black hole. It still has no hair. This implies that there is no multipole moment induced in the black hole and that its second Love numbers, which measure some aspects of the distortion, vanish as was already shown in approximations to general relativity. But here we prove this property for astrophysical relevant black holes in full general relativity. PMID- 25933303 TI - Muon-Induced Neutrons Do Not Explain the DAMA Data. AB - We present an accurate model of the muon-induced background in the DAMA/LIBRA experiment. Our work challenges proposed mechanisms which seek to explain the observed DAMA signal modulation with muon-induced backgrounds. Muon generation and transport are performed using the MUSIC/MUSUN code, and subsequent interactions in the vicinity of the DAMA detector cavern are simulated with Geant4. We estimate the total muon-induced neutron flux in the detector cavern to be Phi(n)(nu)=1.0 * 10(-9) cm(-2) s(-1). We predict 3.49 * 10(-5) counts/day/kg/keV, which accounts for less than 0.3% of the DAMA signal modulation amplitude. PMID- 25933304 TI - Evidence of lensing of the cosmic microwave background by dark matter halos. AB - We present evidence of the gravitational lensing of the cosmic microwave background by 10(13) solar mass dark matter halos. Lensing convergence maps from the Atacama Cosmology Telescope Polarimeter (ACTPol) are stacked at the positions of around 12 000 optically selected CMASS galaxies from the SDSS-III/BOSS survey. The mean lensing signal is consistent with simulated dark matter halo profiles and is favored over a null signal at 3.2sigma significance. This result demonstrates the potential of microwave background lensing to probe the dark matter distribution in galaxy group and galaxy cluster halos. PMID- 25933305 TI - Natural inflation and quantum gravity. AB - Cosmic inflation provides an attractive framework for understanding the early Universe and the cosmic microwave background. It can readily involve energies close to the scale at which quantum gravity effects become important. General considerations of black hole quantum mechanics suggest nontrivial constraints on any effective field theory model of inflation that emerges as a low-energy limit of quantum gravity, in particular, the constraint of the weak gravity conjecture. We show that higher-dimensional gauge and gravitational dynamics can elegantly satisfy these constraints and lead to a viable, theoretically controlled and predictive class of natural inflation models. PMID- 25933307 TI - Entanglement entropy of dispersive media from thermodynamic entropy in one higher dimension. AB - A dispersive medium becomes entangled with zero-point fluctuations in the vacuum. We consider an arbitrary array of material bodies weakly interacting with a quantum field and compute the quantum mutual information between them. It is shown that the mutual information in D dimensions can be mapped to classical thermodynamic entropy in D+1 dimensions. As a specific example, we compute the mutual information both analytically and numerically for a range of separation distances between two bodies in D=2 dimensions and find a logarithmic correction to the area law at short separations. A key advantage of our method is that it allows the strong subadditivity property to be easily verified. PMID- 25933308 TI - Explaining h->MU(+/-)tau(?), B->K*MU(+)MU(-), and B->KMU(+)MU(-)/B->Ke(+)e(-) in a Two-Higgs-Doublet Model with Gauged L(MU)-L(tau). AB - The LHC has observed, so far, 3 deviations from the Standard Model (SM) predictions in flavor observables: LHCb reported anomalies in B->K*MU(+)MU(-) and R(K)=B->KMU(+)MU(-)/B->Ke(+)e(-), while CMS found an excess in h->MUtau. We show, for the first time, how these deviations from the SM can be explained within a single well-motivated model: a two-Higgs-doublet model with gauged L(MU)-L(tau) symmetry. We find that, despite the constraints from tau->MUMUMU and B(s)-B-(s) mixing, one can explain h->MUtau, B->K*MU(+)MU(-) and R(K) simultaneously, obtaining interesting correlations among the observables. PMID- 25933310 TI - Principal Component Analysis of Event-by-Event Fluctuations. AB - We apply principal component analysis to the study of event-by-event fluctuations in relativistic heavy-ion collisions. This method brings out all the information contained in two-particle correlations in a physically transparent way. We present a guide to the method, and apply it to multiplicity fluctuations and anisotropic flow, using ALICE data and simulated events. In particular, we study elliptic and triangular flow fluctuations as a function of transverse momentum and rapidity. This method reveals previously unknown subleading modes in both rapidity and transverse momentum for the momentum distribution as well as elliptic and triangular flows. PMID- 25933311 TI - Cavity-enhanced field-free molecular alignment at a high repetition rate. AB - Extreme ultraviolet frequency combs are a versatile tool with applications including precision measurement, strong-field physics, and solid-state physics. Here we report on an application of extreme ultraviolet frequency combs and their driving lasers for studying strong-field effects in molecular systems. We perform field-free molecular alignment and high-order harmonic generation with aligned molecules in a gas jet at a repetition rate of 154 MHz using a high-powered optical frequency comb inside a femtosecond enhancement cavity. The cavity enhanced system provides a means to reach suitable intensities to study field free molecular alignment and enhance the observable effects of the molecule-field interaction. We observe modulations of the driving field, arising from the nature of impulsive stimulated Raman scattering responsible for coherent molecular rotations. We foresee the impact of this work on the study of molecule-based strong-field physics, with improved precision and a more fundamental understanding of the interaction effects on both the field and molecules. PMID- 25933306 TI - Measurement of the Direct CP Asymmetry in B-->X(s+dgamma) Decays with a Lepton Tag. AB - We report the measurement of the direct CP asymmetry in the radiative B- >X(s+dgamma) decay using a data sample of (772 +/- 11)*10(6) BB[over -] pairs collected at the Upsilon(4S) resonance with the Belle detector at the KEKB asymmetric-energy e(+)e(-) collider. The CP asymmetry is measured as a function of the photon energy threshold. For Egamma*>=2.1 GeV, where Egamma* is the photon energy in the center-of-mass frame, we obtain A(CP)(B- >X(s+dgamma))=(2.2+/-3.9+/-0.9)%, consistent with the standard model prediction. PMID- 25933312 TI - Monoenergetic positronium emission from metal-organic framework crystals. AB - Recently it has been discovered that positronium (Ps), after forming in metal organic framework (MOF) crystals, is emitted into vacuum with a high efficiency and low energy that can only be explained by its propagating as delocalized Bloch states. We show that the Ps atoms are emitted from MOFs in a series of narrow energy peaks consistent with Ps at Bloch-state energy minima being emitted adiabatically into the vacuum. This implies that the Ps emission energy spectra can be directly compared with calculations to obtain detailed information about the Ps band structure in the MOF crystal. The narrow energy width of the lowest energy Ps peak from one MOF sample (2-Methylimidazole zinc salt ZIF-8) suggests it originates from a polaronic Ps surface state. Other peaks can be assigned to Ps with an effective mass of about twice that of bare Ps. Given the immense catalog of available MOF crystals, it should be possible to tune the Ps properties to make vastly improved sources with high production efficiency and a narrow energy spread, for use in fundamental physics experiments. PMID- 25933313 TI - Orientation and alignment echoes. AB - We present one of the simplest classical systems featuring the echo phenomenon-a collection of randomly oriented free rotors with dispersed rotational velocities. Following excitation by a pair of time-delayed impulsive kicks, the mean orientation or alignment of the ensemble exhibits multiple echoes and fractional echoes. We elucidate the mechanism of the echo formation by the kick-induced filamentation of phase space, and provide the first experimental demonstration of classical alignment echoes in a thermal gas of CO_{2} molecules excited by a pair of femtosecond laser pulses. PMID- 25933315 TI - Resolving multiple molecular orbitals using two-dimensional high-harmonic spectroscopy. AB - High-harmonic radiation emitted from molecules in a strong laser field contains information on molecular structure and dynamics. When multiple molecular orbitals participate in high-harmonic generation, resolving the contribution of each orbital is crucial for understanding molecular dynamics and for extending high harmonic spectroscopy to more complicated molecules. We show that two-dimensional high-harmonic spectroscopy can resolve high-harmonic radiation emitted from the two highest-occupied molecular orbitals, HOMO and HOMO-1, of aligned molecules. By the application of an orthogonally polarized two-color laser field that consists of the fundamental and its second-harmonic fields to aligned CO2 molecules, the characteristics attributed to the two orbitals are found to be separately imprinted in odd and even harmonics. Two-dimensional high-harmonic spectroscopy may open a new route to investigate ultrafast molecular dynamics during chemical processes. PMID- 25933314 TI - Experimental implementation of optimal linear-optical controlled-unitary gates. AB - We show that it is possible to reduce the number of two-qubit gates needed for the construction of an arbitrary controlled-unitary transformation by up to 2 times using a tunable controlled-phase gate. On the platform of linear optics, where two-qubit gates can only be achieved probabilistically, our method significantly reduces the amount of components and increases success probability of a two-qubit gate. The experimental implementation of our technique presented in this Letter for a controlled single-qubit unitary gate demonstrates that only one tunable controlled-phase gate is needed instead of two standard controlled not gates. Thus, not only do we increase the success probability by about 1 order of magnitude (with the same resources), but also avoid the need for conducting quantum nondemolition measurement otherwise required to join two probabilistic gates. Subsequently, we generalize our method to a higher order, showing that n times controlled gates can be optimized by replacing blocks of controlled-not gates with tunable controlled-phase gates. PMID- 25933316 TI - Theory of two threshold fields for relativistic runaway electrons. AB - This Letter presents a rigorous kinetic theory for relativistic runaway electrons in the near critical electric field in tokamaks. The theory provides a distribution function of the runaway electrons, reveals the presence of two different threshold electric fields, and describes a mechanism for hysteresis in the runaway electron avalanche. Two different threshold electric fields characterize a minimal field required for sustainment of the existing runaway population and a higher field required for the avalanche onset. The near threshold regime for runaway electrons determines the time scale of toroidal current decay during runaway mitigation in tokamaks. PMID- 25933317 TI - Measurements of the Conduction-Zone Length and Mass Ablation Rate in Cryogenic Direct-Drive Implosions on OMEGA. AB - Measurements of the conduction-zone length (110+/-20 MUm at t=2.8 ns), the averaged mass ablation rate of the deuterated plastic (7.95+/-0.3 MUg/ns), shell trajectory, and laser absorption are made in direct-drive cryogenic implosions and are used to quantify the electron thermal transport through the conduction zone. Hydrodynamic simulations that use nonlocal thermal transport and cross-beam energy transfer models reproduce these experimental observables. Hydrodynamic simulations that use a time-dependent flux-limited model reproduce the measured shell trajectory and the laser absorption but underestimate the mass ablation rate by ~10% and the length of the conduction zone by nearly a factor of 2. PMID- 25933318 TI - Resistive interchange modes destabilized by helically trapped energetic ions in a helical plasma. AB - A new bursting m=1/n=1 instability (m,n: poloidal and toroidal mode numbers) with rapid frequency chirping down has been observed for the first time in a helical plasma with intense perpendicular neutral beam injection. This is destabilized in the plasma peripheral region by resonant interaction between helically trapped energetic ions and the resistive interchange mode. A large radial electric field is induced near the edge due to enhanced radial transport of the trapped energetic ions by the mode, and leads to clear change in toroidal plasma flow, suppression of microturbulence, and triggering an improvement of bulk plasma confinement. PMID- 25933319 TI - Critical properties of the superfluid-bose-glass transition in two dimensions. AB - We investigate the superfluid (SF) to Bose-glass (BG) quantum phase transition using extensive quantum Monte Carlo simulations of two-dimensional hard-core bosons in a random box potential. T=0 critical properties are studied by thorough finite-size scaling of condensate and SF densities, both vanishing at the same critical disorder Wc=4.80(5). Our results give the following estimates for the critical exponents: z=1.85(15), nu=1.20(12), eta=-0.40(15). Furthermore, the probability distribution of the SF response P(lnrhoSF) displays striking differences across the transition: while it narrows with increasing system sizes L in the SF phase, it broadens in the BG regime, indicating an absence of self averaging, and at the critical point P(lnrhoSF+zlnL) is scale invariant. Finally, high-precision measurements of the local density rule out a percolation picture for the SF-BG transition. PMID- 25933320 TI - Identifying a Superfluid Reynolds Number via Dynamical Similarity. AB - The Reynolds number provides a characterization of the transition to turbulent flow, with wide application in classical fluid dynamics. Identifying such a parameter in superfluid systems is challenging due to their fundamentally inviscid nature. Performing a systematic study of superfluid cylinder wakes in two dimensions, we observe dynamical similarity of the frequency of vortex shedding by a cylindrical obstacle. The universality of the turbulent wake dynamics is revealed by expressing shedding frequencies in terms of an appropriately defined superfluid Reynolds number, Re(s), that accounts for the breakdown of superfluid flow through quantum vortex shedding. For large obstacles, the dimensionless shedding frequency exhibits a universal form that is well-fitted by a classical empirical relation. In this regime the transition to turbulence occurs at Re(s)~0.7, irrespective of obstacle width. PMID- 25933321 TI - New density functional approach for solid-liquid-vapor transitions in pure materials. AB - A new phase field crystal (PFC) type theory is presented, which accounts for the full spectrum of solid-liquid-vapor phase transitions within the framework of a single density order parameter. Its equilibrium properties show the most quantitative features to date in PFC modeling of pure substances, and full consistency with thermodynamics in pressure-volume-temperature space is demonstrated. A method to control either the volume or the pressure of the system is also introduced. Nonequilibrium simulations show that 2- and 3-phase growth of solid, vapor, and liquid can be achieved, while our formalism also allows for a full range of pressure-induced transformations. This model opens up a new window for the study of pressure driven interactions of condensed phases with vapor, an experimentally relevant paradigm previously missing from phase field crystal theories. PMID- 25933323 TI - Coulomb blockade with neutral modes. AB - We study transport through a quantum dot in the fractional quantum Hall regime with filling factors nu=2/3 and nu=5/2, weakly coupled to the leads. We account for both injection of electrons to or from the leads, and quasiparticle rearrangement processes between the edge and the bulk of the quantum dot. The presence of neutral modes introduces topological constraints that modify qualitatively the features of the Coulomb blockade (CB). The periodicity of CB peak spacings doubles and the ratio of spacing between adjacent peaks approaches (in the low temperature and large dot limit) a universal value: 2?1 for nu=2/3 and 3?1 for nu=5/2. The corresponding CB diamonds alternate their width in the direction of the bias voltage and allow for the determination of the neutral mode velocity, and of the topological numbers associated with it. PMID- 25933322 TI - Strong Influence of Coadsorbate Interaction on CO Desorption Dynamics on Ru(0001) Probed by Ultrafast X-Ray Spectroscopy and Ab Initio Simulations. AB - We show that coadsorbed oxygen atoms have a dramatic influence on the CO desorption dynamics from Ru(0001). In contrast to the precursor-mediated desorption mechanism on Ru(0001), the presence of surface oxygen modifies the electronic structure of Ru atoms such that CO desorption occurs predominantly via the direct pathway. This phenomenon is directly observed in an ultrafast pump probe experiment using a soft x-ray free-electron laser to monitor the dynamic evolution of the valence electronic structure of the surface species. This is supported with the potential of mean force along the CO desorption path obtained from density-functional theory calculations. Charge density distribution and frozen-orbital analysis suggest that the oxygen-induced reduction of the Pauli repulsion, and consequent increase of the dative interaction between the CO 5sigma and the charged Ru atom, is the electronic origin of the distinct desorption dynamics. Ab initio molecular dynamics simulations of CO desorption from Ru(0001) and oxygen-coadsorbed Ru(0001) provide further insights into the surface bond-breaking process. PMID- 25933324 TI - Nonexistence of the Luttinger-Ward functional and misleading convergence of skeleton diagrammatic series for hubbard-like models. AB - The Luttinger-Ward functional Phi[G], which expresses the thermodynamic grand potential in terms of the interacting single-particle Green's function G, is found to be ill defined for fermionic models with the Hubbard on-site interaction. In particular, we show that the self-energy Sigma[G]?deltaPhi[G]/deltaG is not a single-valued functional of G: in addition to the physical solution for Sigma[G], there exists at least one qualitatively distinct unphysical branch. This result is demonstrated for several models: the Hubbard atom, the Anderson impurity model, and the full two-dimensional Hubbard model. Despite this pathology, the skeleton Feynman diagrammatic series for Sigma in terms of G is found to converge at least for moderately low temperatures. However, at strong interactions, its convergence is to the unphysical branch. This reveals a new scenario of breaking down of diagrammatic expansions. In contrast, the bare series in terms of the noninteracting Green's function G0 converges to the correct physical branch of Sigma in all cases currently accessible by diagrammatic Monte Carlo calculations. In addition to their conceptual importance, these observations have important implications for techniques based on the explicit summation of the diagrammatic series. PMID- 25933325 TI - Origin of Transitions between Metallic and Insulating States in Simple Metals. AB - Unifying principles that underlie recently discovered transitions between metallic and insulating states in elemental solids under pressure are developed. Using group theory arguments and first-principles calculations, we show that the electronic properties of the phases involved in these transitions are controlled by symmetry principles. The valence bands in these systems are described by simple and composite band representations constructed from localized Wannier functions centered on points unoccupied by atoms, and which are not necessarily all symmetrical. The character of the Wannier functions is closely related to the degree of s-p(-d) hybridization and reflects multicenter chemical bonding in these insulating states. The conditions under which an insulating state is allowed for structures having an integer number of atoms per primitive unit cell as well as reentrant (i.e., metal-insulator-metal) transition sequences are detailed, resulting in predictions of behavior such as phases having band-contact lines. The general principles developed are tested and applied to the alkali and alkaline earth metals, including elements where high-pressure insulating phases have been reported (e.g., Li, Na, and Ca). PMID- 25933326 TI - Magnetoresistance in two-component systems. AB - Two-component systems with equal concentrations of electrons and holes exhibit nonsaturating, linear magnetoresistance in classically strong magnetic fields. The effect is predicted to occur in finite-size samples at charge neutrality due to recombination. The phenomenon originates in the excess quasiparticle density developing near the edges of the sample due to the compensated Hall effect. The size of the boundary region is of the order of the electron-hole recombination length that is inversely proportional to the magnetic field. In narrow samples and at strong enough magnetic fields, the boundary region dominates over the bulk leading to linear magnetoresistance. Our results are relevant for two-and three dimensional semimetals and narrow band semiconductors including most of the topological insulators. PMID- 25933327 TI - Spectral Weight Redistribution in (LaNiO3)n/(LaMnO3)2 Superlattices from Optical Spectroscopy. AB - We have studied the optical properties of four (LaNiO3)n/(LaMnO3)2 superlattices (SL) (n=2,3,4,5) on SrTiO3 substrates. We have measured the reflectivity at temperatures from 20 to 400 K, and extracted the optical conductivity through a fitting procedure based on a Kramers-Kronig consistent Lorentz-Drude model. With increasing LaNiO3 thickness, the SLs undergo an insulator-to-metal transition (IMT) that is accompanied by the transfer of spectral weight from high to low frequency. The presence of a broad midinfrared band, however, shows that the optical conductivity of the (LaNiO3)n/(LaMnO3)2 SLs is not a linear combination of the LaMnO_{3} and LaNiO3 conductivities. Our observations suggest that interfacial charge transfer leads to an IMT due to a change in valence at the Mn and Ni sites. PMID- 25933328 TI - Anomalously low magnetoroton energies of the unconventional fractional quantum Hall States of composite fermions. AB - We show a generic formation of the primary magnetorotons in the collective modes of the observed "unconventional" fractional quantum Hall effect states of the composite fermions at the filling factors 4/11, 4/13, 5/13, 5/17, and 3/8 at very low wave vectors with anomalously low energies which do not have any analog to the conventional fractional quantum Hall states. Rather slow decay of the oscillations of the pair-correlation functions in these states is responsible for the low-energy magnetorotons. This is a manifestation of the distinct topology predicted previously for these fractional quantum Hall effect states. Experimental consequences of our theory are also discussed. PMID- 25933329 TI - Intrinsic damping of collective spin modes in a two-dimensional fermi liquid with spin-orbit coupling. AB - A Fermi liquid with spin-orbit coupling (SOC) is expected to support a new set of collective modes: oscillations of magnetization in the absence of the magnetic field. We show that these modes are damped by the electron-electron interaction even in the limit of an infinitely long wavelength (q=0). The linewidth of the collective mode is on the order of Delta-2/E(F), where Delta- is a characteristic spin-orbit energy splitting and E(F) is the Fermi energy. Such damping is in stark contrast to known damping mechanisms of both charge and spin collective modes in the absence of SOC, all of which disappear at q=0, and arises because none of the components of total spin is conserved in the presence of SOC. PMID- 25933330 TI - Signature of anomalous exciton localization in the optical response of self assembled organic nanotubes. AB - We show that the disorder scaling of the low-temperature optical absorption linewidth of tubular molecular assemblies sharply contrasts with that known for one-dimensional aggregates. The difference can be explained by an anomalous localization of excitons, which arises from the combination of long-range intermolecular interactions and the tube's higher-dimensional geometry. As a result, the exciton density of states near the band bottom drops to zero, leading to a strong suppression of exciton localization. Our results explain the strong linear dichroism and weak exciton-exciton scattering in tubular J aggregates observed in experiments and suggest that for nanoscale wirelike applications a tubular shape is to be preferred over a truly one-dimensional chain. PMID- 25933331 TI - Experimental demonstration of a two-band superconducting state for lead using scanning tunneling spectroscopy. AB - The type I superconductor lead (Pb) has been theoretically predicted to be a two band superconductor. We use scanning tunneling spectroscopy (STS) to resolve two superconducting gaps with an energy difference of 150 MUeV. Tunneling into Pb(111), Pb(110), and Pb(100) crystals reveals a strong dependence of the two coherence peak intensities on the crystal orientation. We show that this is the result of a selective tunneling into the two bands at the energy of the two coherence peaks. This is further sustained by the observation of signatures of the Fermi sheets in differential conductance maps around subsurface defects. A modification of the density of states of the two bands by adatoms on the surface confirms the different orbital character of each of the two subbands. PMID- 25933332 TI - Structural and Magnetic Phase Transitions near Optimal Superconductivity in BaFe2(As(1-x)Px)2. AB - We use nuclear magnetic resonance (NMR), high-resolution x-ray, and neutron scattering studies to study structural and magnetic phase transitions in phosphorus-doped BaFe2(As(1-x)P(x)2. Previous transport, NMR, specific heat, and magnetic penetration depth measurements have provided compelling evidence for the presence of a quantum critical point (QCP) near optimal superconductivity at x=0.3. However, we show that the tetragonal-to-orthorhombic structural (T{s}) and paramagnetic to antiferromagnetic (AF, TN) transitions in BaFe2(As(1-x)Px)2 are always coupled and approach T{N}~T{s}>=T{c} (~29 K) for x=0.29 before vanishing abruptly for x>=0.3. These results suggest that AF order in BaFe_{2}(As(1-x)Px)2 disappears in a weakly first-order fashion near optimal superconductivity, much like the electron-doped iron pnictides with an avoided QCP. PMID- 25933333 TI - Reversibility of superconducting nb weak links driven by the proximity effect in a quantum interference device. AB - We demonstrate the role of the proximity effect in the thermal hysteresis of superconducting constrictions. From the analysis of successive thermal instabilities in the transport characteristics of micron-size superconducting quantum interference devices with a well-controlled geometry, we obtain a complete picture of the different thermal regimes. These determine whether or not the junctions are hysteretic. Below the superconductor critical temperature, the critical current switches from a classical weak-link behavior to one driven by the proximity effect. The associated small amplitude of the critical current makes it robust with respect to the heat generation by phase slips, leading to a nonhysteretic behavior. PMID- 25933334 TI - High-pressure hydrogen sulfide from first principles: a strongly anharmonic phonon-mediated superconductor. AB - We use first-principles calculations to study structural, vibrational, and superconducting properties of H_{2}S at pressures P>=200 GPa. The inclusion of zero-point energy leads to two different possible dissociations of H2S, namely 3H2S->2H3S+S and 5H2S->3H3S+HS2, where both H3S and HS2 are metallic. For H3S, we perform nonperturbative calculations of anharmonic effects within the self consistent harmonic approximation and show that the harmonic approximation strongly overestimates the electron-phonon interaction (lambda~2.64 at 200 GPa) and Tc. Anharmonicity hardens H?S bond-stretching modes and softens H?S bond bending modes. As a result, the electron-phonon coupling is suppressed by 30% (lambda~1.84 at 200 GPa). Moreover, while at the harmonic level Tc decreases with increasing pressure, the inclusion of anharmonicity leads to a Tc that is almost independent of pressure. High-pressure hydrogen sulfide is a strongly anharmonic superconductor. PMID- 25933335 TI - Nearly linear light cones in long-range interacting quantum systems. AB - In nonrelativistic quantum theories with short-range Hamiltonians, a velocity v can be chosen such that the influence of any local perturbation is approximately confined to within a distance r until a time t~r/v, thereby defining a linear light cone and giving rise to an emergent notion of locality. In systems with power-law (1/r^{alpha}) interactions, when alpha exceeds the dimension D, an analogous bound confines influences to within a distance r only until a time t~(alpha/v)logr, suggesting that the velocity, as calculated from the slope of the light cone, may grow exponentially in time. We rule out this possibility; light cones of power-law interacting systems are bounded by a polynomial for alpha>2D and become linear as alpha->infinity. Our results impose strong new constraints on the growth of correlations and the production of entangled states in a variety of rapidly emerging, long-range interacting atomic, molecular, and optical systems. PMID- 25933336 TI - Weyl spin liquids. AB - The fractionalization of quantum numbers in interacting quantum many-body systems is a central motif in condensed-matter physics with prominent examples including the fractionalization of the electron in quantum Hall liquids or the emergence of magnetic monopoles in spin-ice materials. Here, we discuss the fractionalization of magnetic moments in three-dimensional Kitaev models into Majorana fermions (and a Z_{2} gauge field) and their emergent collective behavior. We analytically demonstrate that the Majorana fermions form a Weyl superconductor for the Kitaev model on the recently synthesized hyperhoneycomb structure of beta-Li_{2}IrO_{3} when applying a magnetic field. We characterize the topologically protected bulk and surface features of this state, which we dub a Weyl spin liquid, including thermodynamic and transport signatures. PMID- 25933337 TI - Dissipationless multiferroic magnonics. AB - We propose that the magnetoelectric effect in multiferroic insulators with a coplanar antiferromagnetic spiral order, such as BiFeO_{3}, enables electrically controlled magnonics without the need of a magnetic field. Applying an oscillating electric field in these materials with a frequency as low as household frequency can activate Goldstone modes that manifest fast planar rotations of spin, whose motion is essentially unaffected by crystalline anisotropy. Combining with spin ejection mechanisms, such a fast planar rotation can deliver electricity at room temperature over a distance of the magnetic domain, which is free from energy loss due to Gilbert damping in an impurity-free sample. PMID- 25933225 TI - Demographic History, Population Structure, and Local Adaptation in Alpine Populations of Cardamine impatiens and Cardamine resedifolia. AB - Species evolution depends on numerous and distinct forces, including demography and natural selection. For example, local adaptation and population structure affect the evolutionary history of species living along environmental clines. This is particularly relevant in plants, which are often characterized by limited dispersal ability and the need to respond to abiotic and biotic stress factors specific to the local environment. Here we study the demographic history and the possible existence of local adaptation in two related species of Brassicaceae, Cardamine impatiens and Cardamine resedifolia, which occupy separate habitats along the elevation gradient. Previous genome-wide analyses revealed the occurrence of distinct selective pressures in the two species, with genes involved in cold response evolving particularly fast in C. resedifolia. In this study we surveyed patterns of molecular evolution and genetic variability in a set of 19 genes, including neutral and candidate genes involved in cold response, across 10 populations each of C. resedifolia and C. impatiens from the Italian Alps (Trentino). We inferred the population structure and demographic history of the two species, and tested the occurrence of signatures of local adaptation in these genes. The results indicate that, despite a slightly higher population differentiation in C. resedifolia than in C. impatiens, both species are only weakly structured and that populations sampled at high altitude experience less gene flow than low-altitude ones. None of the genes showed signatures of positive selection, suggesting that they do not seem to play relevant roles in the current evolutionary processes of adaptation to alpine environments of these species. PMID- 25933338 TI - Realizing Strong Light-Matter Interactions between Single-Nanoparticle Plasmons and Molecular Excitons at Ambient Conditions. AB - Realizing strong light-matter interactions between individual two-level systems and resonating cavities in atomic and solid state systems opens up possibilities to study optical nonlinearities on a single-photon level, which can be useful for future quantum information processing networks. However, these efforts have been hampered by unfavorable experimental conditions, such as cryogenic temperatures and ultrahigh vacuum, required to study such systems and phenomena. Although several attempts to realize strong light-matter interactions at room temperature using plasmon resonances have been made, successful realizations on the single nanoparticle level are still lacking. Here, we demonstrate the strong coupling between plasmons confined within a single silver nanoprism and excitons in molecular J aggregates at ambient conditions. Our findings show that deep subwavelength mode volumes V together with quality factors Q that are reasonably high for plasmonic nanostructures result in a strong-coupling figure of merit Q/sqrt[V] as high as ~6*10^{3} MUm^{-3/2}, a value comparable to state-of-the art photonic crystal and microring resonator cavities. This suggests that plasmonic nanocavities, and specifically silver nanoprisms, can be used for room temperature quantum optics. PMID- 25933339 TI - Intermediate band solar cell with extreme broadband spectrum quantum efficiency. AB - We report, for the first time, about an intermediate band solar cell implemented with InAs/AlGaAs quantum dots whose photoresponse expands from 250 to ~6000 nm. To our knowledge, this is the broadest quantum efficiency reported to date for a solar cell and demonstrates that the intermediate band solar cell is capable of producing photocurrent when illuminated with photons whose energy equals the energy of the lowest band gap. We show experimental evidence indicating that this result is in agreement with the theory of the intermediate band solar cell, according to which the generation recombination between the intermediate band and the valence band makes this photocurrent detectable. PMID- 25933340 TI - Local origin of global contact numbers in frictional ellipsoid packings. AB - In particulate soft matter systems the average number of contacts Z of a particle is an important predictor of the mechanical properties of the system. Using x-ray tomography, we analyze packings of frictional, oblate ellipsoids of various aspect ratios alpha, prepared at different global volume fractions phig. We find that Z is a monotonically increasing function of phig for all alpha. We demonstrate that this functional dependence can be explained by a local analysis where each particle is described by its local volume fraction phil computed from a Voronoi tessellation. Z can be expressed as an integral over all values of phil: Z(phig,alpha,X)=?Zl(phil,alpha,X)P(phil|phig)dphil. The local contact number function Zl(phil,alpha,X) describes the relevant physics in term of locally defined variables only, including possible higher order terms X. The conditional probability P(phil|phig) to find a specific value of phil given a global packing fraction phig is found to be independent of alpha and X. Our results demonstrate that for frictional particles a local approach is not only a theoretical requirement but also feasible. PMID- 25933341 TI - Thermodynamic uncertainty relation for biomolecular processes. AB - Biomolecular systems like molecular motors or pumps, transcription and translation machinery, and other enzymatic reactions, can be described as Markov processes on a suitable network. We show quite generally that, in a steady state, the dispersion of observables, like the number of consumed or produced molecules or the number of steps of a motor, is constrained by the thermodynamic cost of generating it. An uncertainty epsilon requires at least a cost of 2k(B)T/epsilon2 independent of the time required to generate the output. PMID- 25933342 TI - Fast-moving bacteria self-organize into active two-dimensional crystals of rotating cells. AB - We investigate a new form of collective dynamics displayed by Thiovulum majus, one of the fastest-swimming bacteria known. Cells spontaneously organize on a surface into a visually striking two-dimensional hexagonal lattice of rotating cells. As each constituent cell rotates its flagella, it creates a tornadolike flow that pulls neighboring cells towards and around it. As cells rotate against their neighbors, they exert forces on one another, causing the crystal to rotate and cells to reorganize. We show how these dynamics arise from hydrodynamic and steric interactions between cells. We derive the equations of motion for a crystal, show that this model explains several aspects of the observed dynamics, and discuss the stability of these active crystals. PMID- 25933343 TI - Age-dependent modes of extensional necking instability in soft glassy materials. AB - We study the instability to necking of an initially cylindrical filament of soft glassy material subject to extensional stretching. By numerical simulation of the soft glassy rheology model and a simplified fluidity model, and by analytical predictions within a highly generic toy description, we show that the mode of instability is set by the age of the sample relative to the inverse of the applied extensional strain rate. Young samples neck gradually via a liquidlike mode, the onset of which is determined by both the elastic loading and plastic relaxation terms in the stress constitutive equation. Older samples fail at smaller draw ratios via a more rapid mode, the onset of which is determined only by the solidlike elastic loading terms (though plastic effects arise later, once appreciable necking develops). We show this solidlike mode to be the counterpart, for elastoplastic materials, of the Considere mode of necking in strain-rate independent solids. PMID- 25933309 TI - Tevatron constraints on models of the Higgs boson with exotic spin and parity using decays to bottom-antibottom quark pairs. AB - Combined constraints from the CDF and D0 Collaborations on models of the Higgs boson with exotic spin J and parity P are presented and compared with results obtained assuming the standard model value JP=0+. Both collaborations analyzed approximately 10 fb(-) of proton-antiproton collisions with a center-of-mass energy of 1.96 TeV collected at the Fermilab Tevatron. Two models predicting exotic Higgs bosons with JP=0- and JP=2+ are tested. The kinematic properties of exotic Higgs boson production in association with a vector boson differ from those predicted for the standard model Higgs boson. Upper limits at the 95% credibility level on the production rates of the exotic Higgs bosons, expressed as fractions of the standard model Higgs boson production rate, are set at 0.36 for both the JP=0- hypothesis and the JP=2+ hypothesis. If the production rate times the branching ratio to a bottom-antibottom pair is the same as that predicted for the standard model Higgs boson, then the exotic bosons are excluded with significances of 5.0 standard deviations and 4.9 standard deviations for the JP=0- and JP=2+ hypotheses, respectively. PMID- 25933345 TI - Reducing degeneracy in maximum entropy models of networks. AB - Based on Jaynes's maximum entropy principle, exponential random graphs provide a family of principled models that allow the prediction of network properties as constrained by empirical data (observables). However, their use is often hindered by the degeneracy problem characterized by spontaneous symmetry breaking, where predictions fail. Here we show that degeneracy appears when the corresponding density of states function is not log-concave, which is typically the consequence of nonlinear relationships between the constraining observables. Exploiting these nonlinear relationships here we propose a solution to the degeneracy problem for a large class of systems via transformations that render the density of states function log-concave. The effectiveness of the method is demonstrated on examples. PMID- 25933344 TI - Dynamics and scission of rodlike cationic surfactant micelles in shear flow. AB - Flow-induced configuration dynamics and scission of rodlike micelles are studied for the first time using molecular dynamics simulations in the presence of an explicit solvent and salt. Predicted dependence of tumbling frequency and orientation distribution on shear rate S agrees with mesoscopic theories. However, micelle stretching increases the distance between the cationic head groups and adsorbed counterions, which reduces electrostatic screening and increases the overall energy Phi linearly with micelle length. Micelle scission occurs when Phi exceeds a threshold value, independent of S. PMID- 25933348 TI - 10th WINFOCUS World Congress on Ultrasound in Emergency and Critical Care. PMID- 25933347 TI - Polyethylene Oxide (PEO) and Polyethylene Glycol (PEG) Polymer Sieving Matrix for RNA Capillary Electrophoresis. AB - The selection of sieving polymer for RNA fragments separation by capillary electrophoresis is imperative. We investigated the separation of RNA fragments ranged from 100 to 10,000 nt in polyethylene glycol (PEG) and polyethylene oxide (PEO) solutions with different molecular weight and different concentration. We found that the separation performance of the small RNA fragments (<1000 nt) was improved with the increase of polymer concentration, whereas the separation performance for the large ones (>4000 nt) deteriorated in PEG/PEO solutions when the concentration was above 1.0%/0.6%, respectively. By double logarithmic plot of mobility and RNA fragment size, we revealed three migration regimes for RNA in PEG (300-500k) and PEO (4,000k). Moreover, we calculated the smallest resolvable nucleotide length (Nmin) from the resolution length analysis. PMID- 25933349 TI - An Fc engineering approach that modulates antibody-dependent cytokine release without altering cell-killing functions. AB - Cytotoxic therapeutic monoclonal antibodies (mAbs) often mediate target cell killing by eliciting immune effector functions via Fc region interactions with cellular and humoral components of the immune system. Key functions include antibody-dependent cell-mediated cytotoxicity (ADCC), antibody-dependent cellular phagocytosis (ADCP), and complement-dependent cytotoxicity (CDC). However, there has been increased appreciation that along with cell-killing functions, the induction of antibody-dependent cytokine release (ADCR) can also influence disease microenvironments and therapeutic outcomes. Historically, most Fc engineering approaches have been aimed toward modulating ADCC, ADCP, or CDC. In the present study, we describe an Fc engineering approach that, while not resulting in impaired ADCC or ADCP, profoundly affects ADCR. As such, when peripheral blood mononuclear cells are used as effector cells against mAb opsonized tumor cells, the described mAb variants elicit a similar profile and quantity of cytokines as IgG1. In contrast, although the variants elicit similar levels of tumor cell-killing as IgG1 with macrophage effector cells, the variants do not elicit macrophage-mediated ADCR against mAb-opsonized tumor cells. This study demonstrates that Fc engineering approaches can be employed to uncouple macrophage-mediated phagocytic and subsequent cell-killing functions from cytokine release. PMID- 25933351 TI - Editorial retraction. PMID- 25933346 TI - Evaluation of the Prognostic Value of Impaired Renal Function on Clinical Progression in a Large Cohort of HIV-Infected People Seen for Care in Italy. AB - Whilst renal dysfunction, especially mild impairment (6090, 60 89, <60 ml/min, was 2.91 (95% CI 2.30-3.67), 4.63 (95% CI 3.51-6.11) and 11.9 (95% CI 6.19-22.85) per 1,000 PYFU respectively, with an unadjusted hazard ratio (HR) of 4.14 (95%CI 2.07-8.29) for patients with eGFR <60 ml/min and 1.58 (95%CI 1.10-2.27) for eGFR 60-89 compared to those with eGFR >=90. Of note, these estimates are adjusted for traditional cardio-vascular risk factors (e.g. smoking, diabetes, hypertension, dyslipidemia). Incidence of AIDS-related events was 9.51 (95%CI 8.35-10.83), 6.04 (95%CI 4.74-7.71) and 25.0 (95%CI 15.96-39.22) per 1,000 PYFU, among patients with eGFR >90, 60-89, <60 ml/min, respectively, with an unadjusted HR of 2.49 (95%CI 1.56-3.97) for patients with eGFR <60 ml/min and 0.68 (95%CI 0.52-0.90) for eGFR 60-89. The risk of AIDS events was significantly lower in mild renal dysfunction group even after adjustment for HIV related characteristics. Our data confirm that impaired renal function is an important risk marker for CCVD events in the HIV-population; importantly, even those with mild renal impairment (90=500 cells/ul, 48.4% had WHO HIV Stage 1 disease and 34.3% were lost to follow up. In a cohort of 180 participants followed up for >=3 months, participants with CD4+ of 351-500 cells/ul and stage 2 disease were more likely to start ART earlier than those with CD4+ > 500 cells/ul (Hazard ratio [HR]-1.7, 95% confidence interval [CI] of 1.0-2.9) and stage 1 disease (HR-2.3 (95% CI-1.3-4.2) respectively. HIV-infected adults with faster CD4+ decay required earlier ART initiation, especially in the first year of follow up. CONCLUSION: ART-ineligible HIV-infected adults on follow up in South-South Nigeria are more likely to require earlier initiation of ART if they have stage 2 HIV disease or CD4+ <=500 cells/ul at presentation. Our findings suggest faster progression of HIV-disease in these groups of individuals and corroborate the growing evidence in support for earlier initiation of ART. PMID- 25933357 TI - A weighted polygenic risk score using 14 known susceptibility variants to estimate risk and age onset of psoriasis in Han Chinese. AB - With numbers of common variants identified mainly through genome-wide association studies (GWASs), there is great interest in incorporating the findings into screening individuals at high risk of psoriasis. The purpose of this study is to establish genetic prediction models and evaluate its discriminatory ability in psoriasis in Han Chinese population. We built the genetic prediction models through weighted polygenic risk score (PRS) using 14 susceptibility variants in 8,819 samples. We found the risk of psoriasis among individuals in the top quartile of PRS was significantly larger than those in the lowest quartile of PRS (OR = 28.20, P < 2.0*10(-16)). We also observed statistically significant associations between the PRS, family history and early age onset of psoriasis. We also built a predictive model with all 14 known susceptibility variants and alcohol consumption, which achieved an area under the curve statistic of ~ 0.88. Our study suggests that 14 psoriasis known susceptibility loci have the discriminating potential, as is also associated with family history and age of onset. This is the genetic predictive model in psoriasis with the largest accuracy to date. PMID- 25933358 TI - Lacosamide cardiac safety: clinical trials in patients with partial-onset seizures. AB - OBJECTIVE: To evaluate the cardiac safety of adjunctive lacosamide in a large pool of adults with partial-onset seizures (POS). METHODS: Post-randomization changes from baseline for electrocardiographic (ECG) measurements, diagnostic findings, and relevant adverse events (AEs) were compared for pooled data from three randomized, placebo-controlled trials of adjunctive lacosamide for the treatment of POS. RESULTS: Lacosamide did not prolong the QTc interval or affect heart rate as determined by an analysis of data from patients randomized to lacosamide 200, 400, or 600 mg/day (n = 944) compared with placebo (n = 364). After 12-week maintenance treatment, mean changes from baseline for QRS duration were similar between the placebo and lacosamide 200 and 400 mg/day groups (0.0, 0.2, and 0.4 ms), but slightly increased for lacosamide 600 mg/day (2.3 ms). A small, dose-related mean increase in PR interval was observed (-0.3, 1.4, 4.4, and 6.6 ms for the placebo and lacosamide 200, 400, and 600 mg/day groups, respectively). First-degree atrioventricular (AV) block was reported as a non serious AE in 0.0%, 0.7%, 0.2%, and 0.5% of patients in the same respective groups. Second- or higher degree AV block was not observed. There was no evidence of a PR-interval-related pharmacodynamic interaction of lacosamide with either carbamazepine or lamotrigine. CONCLUSIONS: Evaluation of the pooled cardiac safety data from patients with POS showed that adjunctive lacosamide at the maximum recommended dose (400 mg/day) was not clearly associated with any cardiac effect other than a small, dose-related increase in PR interval that had no evident symptomatic consequence. PMID- 25933359 TI - Temporal Variation in Heat-Mortality Associations: A Multicountry Study. AB - BACKGROUND: Recent investigations have reported a decline in the heat-related mortality risk during the last decades. However, these studies are frequently based on modeling approaches that do not fully characterize the complex temperature-mortality relationship, and are limited to single cities or countries. OBJECTIVES: We assessed the temporal variation in heat-mortality associations in a multi-country data set using flexible modelling techniques. METHODS: We collected data for 272 locations in Australia, Canada, Japan, South Korea, Spain, the United Kingdom, and the United States, with a total 20,203,690 deaths occurring in summer months between 1985 and 2012. The analysis was based on two-stage time-series models. The temporal variation in heat-mortality relationships was estimated in each location with time-varying distributed lag nonlinear models, expressed through an interaction between the transformed temperature variables and time. The estimates were pooled by country through multivariate meta-analysis. RESULTS: Mortality risk due to heat appeared to decrease over time in several countries, with relative risks associated to high temperatures significantly lower in 2006 compared with 1993 in the United States, Japan, and Spain, and a nonsignificant decrease in Canada. Temporal changes are difficult to assess in Australia and South Korea due to low statistical power, and we found little evidence of variation in the United Kingdom. In the United States, the risk seems to be completely abated in 2006 for summer temperatures below their 99th percentile, but some significant excess persists for higher temperatures in all the countries. CONCLUSIONS: We estimated a statistically significant decrease in the relative risk for heat-related mortality in 2006 compared with 1993 in the majority of countries included in the analysis. CITATION: Gasparrini A, Guo Y, Hashizume M, Kinney PL, Petkova EP, Lavigne E, Zanobetti A, Schwartz JD, Tobias A, Leone M, Tong S, Honda Y, Kim H, Armstrong BG. 2015. Temporal variation in heat-mortality associations: a multicountry study. Environ Health Perspect 123:1200-1207; http://dx.doi.org/10.1289/ehp.1409070. PMID- 25933360 TI - Enantioselective N-heterocyclic carbene-catalyzed synthesis of trifluoromethyldihydropyridinones. AB - The enantioselective N-heterocyclic carbene-catalyzed [4 + 2] cyclocondensation of alpha-chloroaldehydes and trifluoromethyl N-Boc azadienes was developed, giving the corresponding 3,4-disubstituted-6-trifluoromethyldihydropyridin-2(1H) ones in good yields with exclusive cis-selectivities and excellent enantioselectivities. PMID- 25933361 TI - Determinants of health-related quality of life in school-aged children: a general population study in the Netherlands. AB - BACKGROUND: Health related quality of life is the functional effect of a medical condition and/or its therapy upon a patient, and as such is particularly suitable for describing the general health of children. The objective of this study was to identify and confirm potential determinants of health-related quality of life in children aged 4-11 years in the general population in the Netherlands. Understanding such determinants may provide insights into more targeted public health policy. METHODS: As part of a population based cross sectional study, the Child Health Questionnaire (CHQ) Parental Form 28 was used to measure health related quality of life in school-aged children in a general population sample. Parents of 10,651 children aged 4-11 years were interviewed from January 2001 to December 2009. RESULTS: Multivariate and regression analyses demonstrated a declined CHQ Physical Summary score for children who had >1 conditions, disorders or acute health complaints and who were greater consumers of healthcare; children with a non-western immigrant background; and children whose parents did not work. Lower CHQ Psychosocial Summary score was reported for children who had >1 conditions, disorders or acute health complaints, boys, children of single parents and obese children. CONCLUSION: The best predictors of health-related quality of life are variables that describe use of health care and the number of disorders and health complaints. Nonetheless, a number of demographic, socio economic and family/environmental determinants contribute to a child's health related quality of life as well. PMID- 25933362 TI - Synthesis and antimicrobial activity of 6-triazolo-6-deoxy eugenol glucosides. AB - A new series of 1,2,3-triazole eugenol glucosides were synthesized. The new compound structures were confirmed by MS, (1)H NMR and (13)C NMR. All of the synthesized compounds were screened for antimicrobial and cytotoxic activity. Five compounds exerted significant activity against the Gram-negative bacteria Salmonella typhimurium with low IC50 values (49.73-68.53 MUMU), and seven compounds were active against the Gram-positive bacteria Micrococcus luteus (42.89-210.94 MUM). In vitro cytotoxicity on mouse spleen cells was also evaluated. One compound bearing a phenyl substituent at the triazole ring showed good activity against Salmonella typhimurium (49.73 MUM) and low toxicity to normal cells (CC50=157.83 MUM). Thus, the compounds herein can be considered for further modification for improving their antibacterial activity or obtaining novel antibacterial drug candidates. PMID- 25933363 TI - Solid state structure of p-bromo phenyl 4,5,7-tri-O-benzyl-beta-D-glycero-D-talo septanoside and an analysis of non-covalent interactions. AB - The solid state structure of a new seven-membered sugar oxepane derivative, namely, p-bromo phenyl 4,5,7-tri-O-benzyl-beta-D-glycero-D-talo-septanoside is discussed, as determined through single crystal X-ray structural determination and in relation to their conformational features. The molecule adopts twist-chair as the preferred conformation, with conformational descriptor (O,1)TC(2,3). The solid state packing of molecules is governed by a rich network of non-covalent bonding originating from O-H?O, C-H?pi, C-H?Br and aromatic pi?pi interactions that stabilize the packing of molecules in the crystal. PMID- 25933368 TI - Prognostic Factors Influencing the Outcome of 64 Consecutive Patients Undergoing Surgery for Metastatic Melanoma of the Spine. AB - BACKGROUND: Melanoma metastases to the spine remain a challenge for neurosurgeons. OBJECTIVE: To identify factors associated with survival in a series of patients who underwent spinal surgery for metastatic melanoma. METHODS: We retrospectively reviewed all patients (n = 64) who received surgical intervention for melanoma metastases to the spine at the University of Texas MD Anderson Cancer Center between July 1993 and March 2012. RESULTS: No patients were excluded from the study, and vital status data were available for all patients. Median overall survival was 5.7 months (95% confidence interval, 2.7 28.7). On univariate survival analysis, diagnosis of spinal metastasis after prior diagnosis of systemic metastasis, higher total spinal disease burden (including but not exclusive to the operative site), presence of progressive systemic disease at the moment of spine surgery, and postoperative complications were associated with poorer overall survival, whereas the presence of only bone metastasis at the moment of surgery was associated with improved overall survival. On multivariate survival analysis, both progressive systemic disease at the moment of spine surgery and total spinal disease burden of >=3 vertebral levels were significantly associated with worse overall survival (hazard ratio, 6.00; 95% confidence interval, 3.19-11.28; P < .001; and hazard ratio, 2.87; 95% confidence interval, 1.62-5.07; P < .001, respectively). CONCLUSION: On multivariate analysis, involvement of >=3 vertebral bodies and progressive systemic disease were associated with worse overall survival. Consideration of these factors should influence surgical decision making in this patient population. PMID- 25933364 TI - The clinical response and systemic effects of non-surgical periodontal therapy in end-stage renal disease patients: a 6-month randomized controlled clinical trial. AB - AIMS: Scientific evidence on the effects of chronic periodontitis on end-stage renal disease (ESRD) remains inadequate and inconclusive. This intervention study was designed to evaluate the effects of non-surgical periodontal therapy on the clinical response and systemic status of ESRD patients. MATERIALS AND METHODS: Patients in the intervention group (n = 48) received non-surgical periodontal therapy and then a supragingival prophylaxis at the 3-month follow up, and those in the control group (n = 49) received no intervention throughout the study. At 6 weeks, 3 months, and 6 months after therapy, clinical periodontal examinations were conducted and blood samples were taken to evaluate inflammatory, nutritional and lipid profiles. RESULTS: The results showed a significant improvement in clinical periodontal parameters (p < 0.05) in the intervention group. Compared to the control group, the intervention group had significantly lower high sensitivity C-reactive protein at 3 months and 6 months. Significant improvements were found (p < 0.05) in interleukin-6, ferritin, albumin, creatinine, blood urea nitrogen, and transferrin after therapy. CONCLUSIONS: Non-surgical periodontal therapy can effectively improve periodontal, circulating inflammatory and nutritional status in ESRD patients. Non-surgical periodontal therapy, as a relatively simple intervention, has beneficial systemic effects in ESRD patients. PMID- 25933369 TI - Expression and properties of the mitochondrial and cytosolic forms of aconitase in maize scutellum. AB - Aconitase (EC 4.2.1.3) catalyzes the reversible interconversion of citrate, cis aconitate, and D-isocitrate. It operates in mitochondria and cytosol. We investigated the expression of two aconitase genes (Aco1 and Aco4) and activities of the mitochondrial and cytosolic forms in maize (Zea mays L.) scutellum during germination. Both forms were isolated and purified. The cytosolic form had a higher pH optimum (8.0), twice higher affinity to citrate (K(m) 9.5 mM), and slightly lower affinity to D,L-isocitrate (K(m) 1.7 mM) as compared to the mitochondrial form (optimum pH 7.5, K(m) with citrate 21 mM, and K(m) with isocitrate 1.5 mM). The highest activity of both forms of aconitase was observed on the 4th day of germination; then the activity and expression of the cytosolic form sharply decreased, while the mitochondrial form decreased more slowly. The mitochondrial aconitase was more strongly inhibited by H2O2 (half-inhibition at 35 MUM) than the cytosolic form (60 MUM). Aconitase activity was not detected in the glyoxysomal fraction beyond the cross-contamination level. It is suggested that the mitochondrial form operates in the tricarboxylic acid cycle, whereas the cytosolic form participates in the reactions of the glyoxylate cycle taking place outside the glyoxysome. PMID- 25933370 TI - Nonplanar Nanoscale Fin Field Effect Transistors on Textile, Paper, Wood, Stone, and Vinyl via Soft Material-Enabled Double-Transfer Printing. AB - The ability to incorporate rigid but high-performance nanoscale nonplanar complementary metal-oxide semiconductor (CMOS) electronics with curvilinear, irregular, or asymmetric shapes and surfaces is an arduous but timely challenge in enabling the production of wearable electronics with an in situ information processing ability in the digital world. Therefore, we are demonstrating a soft material enabled double-transfer-based process to integrate flexible, silicon based, nanoscale, nonplanar, fin-shaped field effect transistors (FinFETs) and planar metal-oxide-semiconductor field effect transistors (MOSFETs) on various asymmetric surfaces to study their compatibility and enhanced applicability in various emerging fields. FinFET devices feature sub-20 nm dimensions and state-of the-art, high-kappa/metal gate stacks, showing no performance alteration after the transfer process. A further analysis of the transferred MOSFET devices, featuring 1 MUm gate length, exhibits an ION value of nearly 70 MUA/MUm (VDS = 2 V, VGS = 2 V) and a low subthreshold swing of around 90 mV/dec, proving that a soft interfacial material can act both as a strong adhesion/interposing layer between devices and final substrate as well as a means to reduce strain, which ultimately helps maintain the device's performance with insignificant deterioration even at a high bending state. PMID- 25933371 TI - Endoparasite infection has both short- and long-term negative effects on reproductive success of female house sparrows, as revealed by faecal parasitic egg counts. AB - Parasites have the potential to severely reduce host reproductive success. However, the effects of endoparasites on reproductive success have not received the same amount of attention as the effects of parasites on host survival. We investigated the relationship between an avian endoparasite (gapeworm, Syngamus trachea) and both current and future reproductive success of female house sparrows (Passer domesticus) in a population on the coast of Helgeland, northern Norway. We found that the proportion of eggs in a nest that failed to develop into fledglings increased as the faecal parasitic egg count of the mothers increased. We also found that juvenile females with high numbers of parasitic eggs in their faeces had lower lifetime reproductive success as adults. However, we did not find a relationship between maternal parasite infection and clutch size or recruitment rate of offspring. To our knowledge this is the first study to find a relationship between reproductive success of an avian host and faecal egg count of an endoparasite. The present study indicates that infection by an endoparasite may be associated with lower individual reproductive success in both the short-term and long-term in a wild population of hosts. PMID- 25933372 TI - Role of Mechanical Cues in Cell Differentiation and Proliferation: A 3D Numerical Model. AB - Cell differentiation, proliferation and migration are essential processes in tissue regeneration. Experimental evidence confirms that cell differentiation or proliferation can be regulated according to the extracellular matrix stiffness. For instance, mesenchymal stem cells (MSCs) can differentiate to neuroblast, chondrocyte or osteoblast within matrices mimicking the stiffness of their native substrate. However, the precise mechanisms by which the substrate stiffness governs cell differentiation or proliferation are not well known. Therefore, a mechano-sensing computational model is here developed to elucidate how substrate stiffness regulates cell differentiation and/or proliferation during cell migration. In agreement with experimental observations, it is assumed that internal deformation of the cell (a mechanical signal) together with the cell maturation state directly coordinates cell differentiation and/or proliferation. Our findings indicate that MSC differentiation to neurogenic, chondrogenic or osteogenic lineage specifications occurs within soft (0.1-1 kPa), intermediate (20-25 kPa) or hard (30-45 kPa) substrates, respectively. These results are consistent with well-known experimental observations. Remarkably, when a MSC differentiate to a compatible phenotype, the average net traction force depends on the substrate stiffness in such a way that it might increase in intermediate and hard substrates but it would reduce in a soft matrix. However, in all cases the average net traction force considerably increases at the instant of cell proliferation because of cell-cell interaction. Moreover cell differentiation and proliferation accelerate with increasing substrate stiffness due to the decrease in the cell maturation time. Thus, the model provides insights to explain the hypothesis that substrate stiffness plays a key role in regulating cell fate during mechanotaxis. PMID- 25933373 TI - Novel drug candidates for blast phase chronic myeloid leukemia from high throughput drug sensitivity and resistance testing. AB - Chronic myeloid leukemia in blast crisis (CML BC) remains a challenging disease to treat despite the introduction and advances in tyrosine kinase inhibitor (TKI) therapy. In this study we set out to identify novel candidate drugs for CML BC by using an unbiased high-throughput drug testing platform. We used three CML cell lines representing different types of CML blast phases (K562, EM-2 and MOLM-1) and primary leukemic cells from three CML BC patients. Profiling of drug responses was performed with a drug sensitivity and resistance testing platform comprising 295 anticancer agents. Overall, drug sensitivity scores and the drug response profiles of cell line and primary cell samples correlated well and were distinct from other types of leukemia samples. The cell lines were highly sensitive to TKIs and the clinically TKI-resistant patient samples were also resistant ex vivo. Comparison of cell line and patient sample data identified new candidate drugs for CML BC, such as vascular endothelial growth factor receptor and nicotinamide phosphoribosyltransferase inhibitors. Our results indicate that these drugs in particular warrant further evaluation by analyzing a larger set of primary patient samples. The results also pave way for designing rational combination therapies. PMID- 25933374 TI - Abnormal FISH in patients with immunoglobulin light chain amyloidosis is a risk factor for cardiac involvement and for death. AB - Importance of interphase fluorescent in situ hybridization (FISH) with cytoplasmic staining of immunoglobulin FISH (cIg-FISH) on bone marrow is not well understood in light chain amyloidosis (AL). This is in contrast with multiple myeloma where prognostic and treatment related decisions are dependent on cytogenetic testing. This retrospective study reviewed 401 AL patients with cIg FISH testing performed at our institution between 2004 and 2012. Eighty-one percent of patients had an abnormal cIg-FISH. Common abnormalities involved translocations of chromosome 14q32 (52%), specifically: t(11;14) (43%), t(14;16) (3%) and t(4;14) (2%). Other common abnormalities include monosomy 13/deletion 13q (30%), trisomies 9 (20%), 15 (14%), 11 (10%) and 3 (10%). Median overall survival for this cohort of patients is 3.5 years. When plasma cell burden was greater than 10% trisomies predicted for worse survival (44 vs 19 months), and when it was ?10% t(11;14) predicted for worse survival (53 months vs not reached). Abnormal cIg-FISH was significantly associated with advanced cardiac involvement, and remained a prognostic factor on multivariate analysis. This large AL cohort demonstrates that abnormal FISH at diagnosis is prognostic for survival and advanced cardiac disease. Particularly, trisomies and t(11;14) affect survival when degree of plasma cell burden is considered. PMID- 25933375 TI - Vitamin D and the risk of atrial fibrillation--the Rotterdam Study. AB - Atrial fibrillation (AF) is the most common chronic arrhythmia and it increases the risk of cardiovascular morbidity and mortality. Still there is not a complete understanding of its etiology and underlying pathways. Vitamin D might regulate renin-angiotensin-aldosterone system and might be involved in inflammation, both implicated in the pathophysiology of AF. The objective of this work was to investigate the association between vitamin D status with the risk of AF in the elderly. This study was conducted within the Rotterdam Study, a community-based cohort of middle-aged and elderly participants in Rotterdam, The Netherlands. We had 3,395 participants who were free of AF diagnosis at the start of our study and who had vitamin D data available. We analyzed the association between serum 25-hydroxivitamin D (25(OH)D) and incidence of AF using Cox regression models. Vitamin D deficiency was defined as serum 25(OH)D concentrations <50 nmol/l, insufficiency between 50 nmol/l and 75 nmol/l, while serum 25(OH)D concentrations equal to and above 75 nmol/l were considered as adequate. After mean follow-up of 12.0 years 263 (7.7%) participants were diagnosed with incident AF. Vitamin D status was not associated with AF in any of the 3 multivariate models tested (model adjusted for socio-demographic factors and life-style factors: HR per 10 unit increment in serum 25(OH)D 0.96, 95% CI: 0.91-1.02; HR for insufficiency: 0.82, 95%CI: 0.60-1.11,and HR for adequate status: 0.76, 95%CI: 0.52-1.12 compared to deficiency). This prospective cohort study does not support the hypothesis that vitamin D status is associated with AF. PMID- 25933376 TI - Recovery of Recombinant Crimean Congo Hemorrhagic Fever Virus Reveals a Function for Non-structural Glycoproteins Cleavage by Furin. AB - Crimean Congo hemorrhagic fever virus (CCHFV) is a negative-strand RNA virus of the family Bunyaviridae (genus: Nairovirus). In humans, CCHFV causes fever, hemorrhage, severe thrombocytopenia, and high fatality. A major impediment in precisely determining the basis of CCHFV's high pathogenicity has been the lack of methodology to produce recombinant CCHFV. We developed a reverse genetics system based on transfecting plasmids into BSR-T7/5 and Huh7 cells. In our system, bacteriophage T7 RNA polymerase produced complementary RNA copies of the viral S, M, and L segments that were encapsidated with the support, in trans, of CCHFV nucleoprotein and L polymerase. The system was optimized to systematically recover high yields of infectious CCHFV. Additionally, we tested the ability of the system to produce specifically designed CCHFV mutants. The M segment encodes a polyprotein that is processed by host proprotein convertases (PCs), including the site-1 protease (S1P) and furin-like PCs. S1P and furin cleavages are necessary for producing the non-structural glycoprotein GP38, while S1P cleavage yields structural Gn. We studied the role of furin cleavage by rescuing a recombinant CCHFV encoding a virus glycoprotein precursor lacking a functional furin cleavage motif (RSKR mutated to ASKA). The ASKA mutation blocked glycoprotein precursor's maturation to GP38, and Gn precursor's maturation to Gn was slightly diminished. Furin cleavage was not essential for replication, as blocking furin cleavage resulted only in transient reduction of CCHFV titers, suggesting that either GP38 and/or decreased Gn maturation accounted for the reduced virion production. Our data demonstrate that nairoviruses can be produced by reverse genetics, and the utility of our system uncovered a function for furin cleavage. This viral rescue system could be further used to study the CCHFV replication cycle and facilitate the development of efficacious vaccines to counter this biological and public health threat. PMID- 25933377 TI - Effect of active case finding on prevalence and transmission of pulmonary tuberculosis in Dhaka Central Jail, Bangladesh. AB - BACKGROUND: Understanding tuberculosis (TB) transmission dynamics is essential for establishing effective TB control strategies in settings where the burden and risk of transmission are high. The objectives of this study were to evaluate the effect of active screening on controlling TB transmission and also to characterize Mycobacterium tuberculosis strains for investigating transmission dynamics in a correctional setting. METHODS: The study was carried out in Dhaka Central Jail (DCJ), from October 2005 to February 2010. An active case finding strategy for pulmonary TB was established both at the entry point to the prison and inside the prison. Three sputum specimens were collected from all pulmonary TB suspects and subjected to smear microscopy, culture, and drug susceptibility testing as well as genotyping which included deletion analysis, spoligotyping and analysis of mycobacterial interspersed repetitive units (MIRU). RESULTS: A total of 60,585 inmates were screened during the study period. We found 466 inmates with pulmonary TB of whom 357 (77%) had positive smear microscopy results and 109 (23%) had negative smear microscopy results but had positive results on culture. The number of pulmonary TB cases declined significantly, from 49 cases during the first quarter to 8 cases in the final quarter of the study period (p=0.001). Deletion analysis identified all isolates as M. tuberculosis and further identified 229 (70%) strains as 'modern' and 100 (30%) strains as 'ancestral'. Analysis of MIRU showed that 347 strains (85%) exhibited unique patterns, whereas 61 strains (15%) clustered into 22 groups. The largest cluster comprised eight strains of the Beijing M. tuberculosis type. The rate of recent transmission was estimated to be 9.6%. CONCLUSIONS: Implementation of active screening for TB was associated with a decline in TB cases in DCJ. Implementation of active screening in prison settings might substantially reduce the national burden of TB in Bangladesh. PMID- 25933378 TI - A hybrid approach of gene sets and single genes for the prediction of survival risks with gene expression data. AB - Accumulated biological knowledge is often encoded as gene sets, collections of genes associated with similar biological functions or pathways. The use of gene sets in the analyses of high-throughput gene expression data has been intensively studied and applied in clinical research. However, the main interest remains in finding modules of biological knowledge, or corresponding gene sets, significantly associated with disease conditions. Risk prediction from censored survival times using gene sets hasn't been well studied. In this work, we propose a hybrid method that uses both single gene and gene set information together to predict patient survival risks from gene expression profiles. In the proposed method, gene sets provide context-level information that is poorly reflected by single genes. Complementarily, single genes help to supplement incomplete information of gene sets due to our imperfect biomedical knowledge. Through the tests over multiple data sets of cancer and trauma injury, the proposed method showed robust and improved performance compared with the conventional approaches with only single genes or gene sets solely. Additionally, we examined the prediction result in the trauma injury data, and showed that the modules of biological knowledge used in the prediction by the proposed method were highly interpretable in biology. A wide range of survival prediction problems in clinical genomics is expected to benefit from the use of biological knowledge. PMID- 25933379 TI - Abnormal red cell structure and function in neuroacanthocytosis. AB - BACKGROUND: Panthothenate kinase-associated neurodegeneration (PKAN) belongs to a group of hereditary neurodegenerative disorders known as neuroacanthocytosis (NA). This genetically heterogeneous group of diseases is characterized by degeneration of neurons in the basal ganglia and by the presence of deformed red blood cells with thorny protrusions, acanthocytes, in the circulation. OBJECTIVE: The goal of our study is to elucidate the molecular mechanisms underlying this aberrant red cell morphology and the corresponding functional consequences. This could shed light on the etiology of the neurodegeneration. METHODS: We performed a qualitative and semi-quantitative morphological, immunofluorescent, biochemical and functional analysis of the red cells of several patients with PKAN and, for the first time, of the red cells of their family members. RESULTS: We show that the blood of patients with PKAN contains not only variable numbers of acanthocytes, but also a wide range of other misshapen red cells. Immunofluorescent and immunoblot analyses suggest an altered membrane organization, rather than quantitative changes in protein expression. Strikingly, these changes are not limited to the red blood cells of PKAN patients, but are also present in the red cells of heterozygous carriers without neurological problems. Furthermore, changes are not only present in acanthocytes, but also in other red cells, including discocytes. The patients' cells, however, are more fragile, as observed in a spleen-mimicking device. CONCLUSION: These morphological, molecular and functional characteristics of red cells in patients with PKAN and their family members offer new tools for diagnosis and present a window into the pathophysiology of neuroacanthocytosis. PMID- 25933381 TI - Genetic Architecture of Abdominal Pigmentation in Drosophila melanogaster. AB - Pigmentation varies within and between species and is often adaptive. The amount of pigmentation on the abdomen of Drosophila melanogaster is a relatively simple morphological trait, which serves as a model for mapping the genetic basis of variation in complex phenotypes. Here, we assessed natural variation in female abdominal pigmentation in 175 sequenced inbred lines of the Drosophila melanogaster Genetic Reference Panel, derived from the Raleigh, NC population. We quantified the proportion of melanization on the two most posterior abdominal segments, tergites 5 and 6 (T5, T6). We found significant genetic variation in the proportion of melanization and high broad-sense heritabilities for each tergite. Genome-wide association studies identified over 150 DNA variants associated with the proportion of melanization on T5 (84), T6 (34), and the difference between T5 and T6 (35). Several of the top variants associated with variation in pigmentation are in tan, ebony, and bric-a-brac1, genes known to affect D. melanogaster abdominal pigmentation. Mutational analyses and targeted RNAi-knockdown showed that 17 out of 28 (61%) novel candidate genes implicated by the genome-wide association study affected abdominal pigmentation. Several of these genes are involved in developmental and regulatory pathways, chitin production, cuticle structure, and vesicle formation and transport. These findings show that genetic variation may affect multiple steps in pathways involved in tergite development and melanization. Variation in these novel candidates may serve as targets for adaptive evolution and sexual selection in D. melanogaster. PMID- 25933380 TI - Prognostic impact of reduced connexin43 expression and gap junction coupling of neoplastic stromal cells in giant cell tumor of bone. AB - Missense mutations of the GJA1 gene encoding the gap junction channel protein connexin43 (Cx43) cause bone malformations resulting in oculodentodigital dysplasia (ODDD), while GJA1 null and ODDD mutant mice develop osteopenia. In this study we investigated Cx43 expression and channel functions in giant cell tumor of bone (GCTB), a locally aggressive osteolytic lesion with uncertain progression. Cx43 protein levels assessed by immunohistochemistry were correlated with GCTB cell types, clinico-radiological stages and progression free survival in tissue microarrays of 89 primary and 34 recurrent GCTB cases. Cx43 expression, phosphorylation, subcellular distribution and gap junction coupling was also investigated and compared between cultured neoplastic GCTB stromal cells and bone marow stromal cells or HDFa fibroblasts as a control. In GCTB tissues, most Cx43 was produced by CD163 negative neoplastic stromal cells and less by CD163 positive reactive monocytes/macrophages or by giant cells. Significantly less Cx43 was detected in alpha-smooth muscle actin positive than alpha-smooth muscle actin negative stromal cells and in osteoclast-rich tumor nests than in the adjacent reactive stroma. Progressively reduced Cx43 production in GCTB was significantly linked to advanced clinico-radiological stages and worse progression free survival. In neoplastic GCTB stromal cell cultures most Cx43 protein was localized in the paranuclear-Golgi region, while it was concentrated in the cell membranes both in bone marrow stromal cells and HDFa fibroblasts. In Western blots, alkaline phosphatase sensitive bands, linked to serine residues (Ser369, Ser372 or Ser373) detected in control cells, were missing in GCTB stromal cells. Defective cell membrane localization of Cx43 channels was in line with the significantly reduced transfer of the 622 Da fluorescing calcein dye between GCTB stromal cells. Our results show that significant downregulation of Cx43 expression and gap junction coupling in neoplastic stromal cells are associated with the clinical progression and worse prognosis in GCTB. PMID- 25933382 TI - Caffeine Modulates Vesicle Release and Recovery at Cerebellar Parallel Fibre Terminals, Independently of Calcium and Cyclic AMP Signalling. AB - BACKGROUND: Cerebellar parallel fibres release glutamate at both the synaptic active zone and at extrasynaptic sites-a process known as ectopic release. These sites exhibit different short-term and long-term plasticity, the basis of which is incompletely understood but depends on the efficiency of vesicle release and recycling. To investigate whether release of calcium from internal stores contributes to these differences in plasticity, we tested the effects of the ryanodine receptor agonist caffeine on both synaptic and ectopic transmission. METHODS: Whole cell patch clamp recordings from Purkinje neurons and Bergmann glia were carried out in transverse cerebellar slices from juvenile (P16-20) Wistar rats. KEY RESULTS: Caffeine caused complex changes in transmission at both synaptic and ectopic sites. The amplitude of postsynaptic currents in Purkinje neurons and extrasynaptic currents in Bergmann glia were increased 2-fold and 4 fold respectively, but paired pulse ratio was substantially reduced, reversing the short-term facilitation observed under control conditions. Caffeine treatment also caused synaptic sites to depress during 1 Hz stimulation, consistent with inhibition of the usual mechanisms for replenishing vesicles at the active zone. Unexpectedly, pharmacological intervention at known targets for caffeine- intracellular calcium release, and cAMP signalling--had no impact on these effects. CONCLUSIONS: We conclude that caffeine increases release probability and inhibits vesicle recovery at parallel fibre synapses, independently of known pharmacological targets. This complex effect would lead to potentiation of transmission at fibres firing at low frequencies, but depression of transmission at high frequency connections. PMID- 25933383 TI - Costly Inheritance and the Persistence of Insecticide Resistance in Aedes aegypti Populations. AB - Global emergence of arboviruses is a growing public health concern, since most of these diseases have no vaccine or prevention treatment available. In this scenario, vector control through the use of chemical insecticides is one of the most important prevention tools. Nevertheless, their effectiveness has been increasingly compromised by the development of strong resistance observed in field populations, even in spite of fitness costs usually associated to resistance. Using a stage-structured deterministic model parametrised for the Aedes aegypti--the main vector for dengue--we investigated the persistence of resistance by studying the time for a population which displays resistance to insecticide to revert to a susceptible population. By means of a comprehensive series of in-silico experiments, we studied this reversal time as a function of fitness costs and the initial presence of the resistance allele in the population. The resulting map provides both a guiding and a surveillance tool for public health officers to address the resistance situation of field populations. Application to field data from Brazil indicates that reversal can take, in some cases, decades even if fitness costs are not small. As by-products of this investigation, we were able to fit very simple formulas to the reversal times as a function of either cost or initial presence of the resistance allele. In addition, the in-silico experiments also showed that density dependent regulation plays an important role in the dynamics, slowing down the reversal process. PMID- 25933384 TI - Spinal Glia Division Contributes to Conditioning Lesion-Induced Axon Regeneration Into the Injured Spinal Cord: Potential Role of Cyclic AMP-Induced Tissue Inhibitor of Metalloproteinase-1. AB - Regeneration of sensory neurons after spinal cord injury depends on the function of dividing neuronal-glial antigen 2 (NG2)-expressing cells. We have shown that increases in the number of dividing NG2-positive cells through short-term pharmacologic inhibition of matrix metalloproteinases contributes to recovery after spinal cord injury. A conditioning sciatic nerve crush (SNC) preceding spinal cord injury stimulates central sensory axon regeneration via the intraganglionic action of cyclic adenosine monophosphate. Here, using bromodeoxyuridine, mitomycin (mitosis inhibitor), and cholera toxin B tracer, we demonstrate that SNC-induced division of spinal glia is related to the spinal induction of tissue inhibitor of metalloproteinase-1 and contributes to central sensory axon growth into the damaged spinal cord. Dividing cells were mainly NG2 positive and Iba1-positive and included myeloid NG2-positive populations. The cells dividing in response to SNC mainly matured into oligodendrocytes and microglia within the injured spinal cord. Some postmitotic cells remained NG2 reactive and were associated with regenerating fibers. Moreover, intraganglionic tissue inhibitor of metalloproteinase-1 expression was induced after administration of SNC or cyclic adenosine monophosphate analog (dbcAMP) to dorsal root ganglia in vivo and in primary adult dorsal root ganglia cultures. Collectively, these findings support a novel model whereby a cyclic adenosine monophosphate-activated regeneration program induced in sensory neurons by a conditioning peripheral nerve lesion uses tissue inhibitor of metalloproteinase-1 to protect against short-term proteolysis, enabling glial cell division and promoting axon growth into the damaged CNS. PMID- 25933385 TI - Chronic effects of mild neurotrauma: putting the cart before the horse? AB - Accumulation of phosphorylated tau (p-tau) is accepted by many as a long-term consequence of repetitive mild neurotrauma based largely on brain findings in boxers (dementia pugilistica) and, more recently, former professional athletes, military service members, and others exposed to repetitive head trauma. The pathogenic construct is also largely accepted and suggests that repetitive head trauma (typically concussions or subconcussive forces) acts on brain parenchyma to produce a deleterious neuroinflammatory cascade, encompassing p-tau templating, transsynaptic neurotoxicity, progressive neurodegenerative disease, and associated clinical features. Some caution before accepting these concepts and assumptions is warranted, however. The association between the history of concussion and findings of p-tau at autopsy is unclear. Concussions and subconcussive head trauma exposure are poorly defined in available cases, and the clinical features reported in chronic traumatic encephalopathy are not at present distinguishable from other disorders. Because control groups are limited, the idea that p-tau drives the disease process via protein templating or some other mechanism is preliminary. Much additional research in chronic traumatic encephalopathy is needed to determine if it has unique neuropathology and clinical features, the extent to which the neuropathologic alterations cause the clinical features, and whether it can be identified accurately in a living person. PMID- 25933386 TI - Temporal pattern of neurodegeneration, programmed cell death, and neuroplastic responses in the thalamus after lateral fluid percussion brain injury in the rat. AB - The effects of traumatic brain injury (TBI) on the thalamus are not well characterized. We analyzed neuronal degeneration and loss, apoptosis, programmed cell death-executing pathways, and neuroplastic responses in the rat thalamus during the first week after lateral fluid percussion injury (LFPI). The most prominent neurodegenerative and neuroplastic changes were observed in the region containing the posterior thalamic nuclear group and ventral posteromedial and posterolateral thalamic nuclei ipsilateral to the LFPI. There was progressive neurodegeneration in these regions, with maximal neuronal loss on Day 7. Increases in numbers of apoptotic cells were detected on Day 1 and were enhanced on Days 3 and 7 after TBI. There was unchanged expression of active caspase-3 at all postinjury time points, but there was increased expression of apoptosis inducing factor (AIF) on Day 7. The AIF nuclear translocation was detected on Day 1 and was maximal on Day 7. Total thalamic synaptophysin expression was unchanged, but immunostaining intensities were increased at all time points after TBI. Decreased growth-associated protein-43 expression and signal intensity were observed on Day 1. Our results suggest that progressive neuronal damage and loss, AIF signaling pathway-dependent programmed cell death, and limited neuroplastic changes occur in the rat thalamus during the first week after LFPI induction. PMID- 25933387 TI - TDP-43 Pathology Progression Along the Olfactory Pathway as a Possible Substrate for Olfactory Impairment in Amyotrophic Lateral Sclerosis. AB - Odor impairment and its relationship with TAR DNA-binding protein 43 (TDP-43) pathology in patients with amyotrophic lateral sclerosis (ALS) have not been fully elucidated. We performed the odor stick identification test for Japanese (OSIT-J) in 18 ALS patients and in 18 controls. The score was significantly decreased (6.6 +/- 2.7) in the patients versus the controls (9.2 +/- 2.4) (U = 77.0, p = 0.007). This decrement of the OSIT-J score paralleled the cognitive decline. We then studied samples from a series of 42 postmortem ALS cases. Quantitative analyses demonstrated that TDP-43-positive inclusions were most frequent in the hippocampus and least abundant in the olfactory bulb and were of intermediate density in the primary olfactory cortex. This centrifugal gradient suggests that TDP-43 pathology starts in the hippocampus, spreads into the primary olfactory center, and finally reaches the olfactory bulb. TDP-43, tau, and alpha-synuclein accumulations appeared to be independent. These observations suggest that impaired odor discrimination in ALS patients may be related to TDP 43-positive lesions affecting predominantly secondary olfactory centers (especially the hippocampus) in contrast to decreased odor sensitivity in Parkinson disease in which alpha-synuclein pathology mainly involves the peripheral region (i.e., olfactory bulb). We suggest that detectable odor impairments in ALS patients are useful for predicting the presence of TDP-43 pathology in the extramotor system. PMID- 25933389 TI - Placebo Responses to Original vs. Generic ASA Brands During Exposure to Noxious Heat: A Pilot fMRI Study of Neurofunctional Correlates. AB - OBJECTIVE: We studied the expectation effects associated with brands by labeling placebo interventions (original and generic analgesic) and investigating the potential differences in efficacy between the two placebos in dealing with noxious heat pain, as well as exploring the neurometabolic correlates of the placebo response. DESIGN: We applied a two by two design with two identical placebo interventions that differed only in their labeling. One group was told that they received 500 mg of "Aspirin" (original brand) while the other group was told that they received a popular ASA generic (1A Pharma). After establishing the individual pain level of each subject, we measured pain intensities behaviorally before and after the intervention and looked for corresponding brain areas with increased hemodynamic response using functional magnetic resonance imaging. RESULTS: At the behavioral level, we found decreases in pain intensity from baseline to the intervention condition with the original brand only. At the neuronal level, we specifically observed activations of the anterior insulae under the baseline conditions, complemented by activations of the dorsomedial prefrontal cortex after the interventions. A direct comparison of the two placebo conditions revealed higher values of activation for the bilateral dorsolateral (as well as dorsomedial) prefrontal cortex for the original brand. CONCLUSION: Our data indicate a behavioral placebo response for the original brand only. Expectations by subjects appear to be triggered not only by the placebo treatment itself but also by the trusted brand, which thus serves as an enhanced placebo. Both processes appear to be based on fronto-cortical neural networks, as these areas showed significantly stronger activations with the original brand. PMID- 25933388 TI - The Small-Molecule TrkB Agonist 7, 8-Dihydroxyflavone Decreases Hippocampal Newborn Neuron Death After Traumatic Brain Injury. AB - Previous studies in rodents have shown that after a moderate traumatic brain injury (TBI) with a controlled cortical impact (CCI) device, the adult-born immature granular neurons in the dentate gyrus are the most vulnerable cell type in the hippocampus. There is no effective approach for preventing immature neuron death after TBI. We found that tyrosine-related kinase B (TrkB), a receptor of brain-derived neurotrophic factor (BDNF), is highly expressed in adult-born immature neurons. We determined that the small molecule imitating BDNF, 7, 8 dihydroxyflavone (DHF), increased phosphorylation of TrkB in immature neurons both in vitro and in vivo. Pretreatment with DHF protected immature neurons from excitotoxicity-mediated death in vitro, and systemic administration of DHF before moderate CCI injury reduced the death of adult-born immature neurons in the hippocampus 24 hours after injury. By contrast, inhibiting BDNF signaling using the TrkB antagonist ANA12 attenuated the neuroprotective effects of DHF. These data indicate that DHF may be a promising chemical compound that promotes immature neuron survival after TBI through activation of the BDNF signaling pathway. PMID- 25933390 TI - Thioredoxin priming prolongs lung allograft survival by promoting immune tolerance. AB - Tolerance to allograft antigen is the major challenge and final goal of transplant medicine. Our previous study demonstrated that thioredoxin-1 (Trx) priming of donor lung significantly protected allogeneic lung graft. To determine whether Trx priming of donor lung inhibits allograft rejection, extends allograft survival and induces immune tolerance, orthotopic left lung transplantation was performed from Lewis to Sprague-Dawley rats without immunosuppression. Donor lungs were primed with Trx at 4 degrees C for 4 hr prior to transplantation. After up to 37 days post-transplantation, allograft lung morphology, recipient T cell and humoral alloantigen-specific immune responses were examined. We found that Trx-primed lungs exhibited much reduced acute rejection and associated lung injuries resulting in loss of graft functional area at 5-37 days post-transplant in contrast to the control groups. CD4+ T cells from the recipients with Trx primed grafts responded to the stimulation of dendritic cells (DCs) of donor origin, in contrast to DCs from the third party, with significantly reduced proliferation. Consistent with above findings, we observed that CD4+Foxp3+ regulatory T cells in spleen cells from the recipients with Trx-primed grafts were significantly increased compared to controls, and CD4+ T cells from the recipients with Trx-primed grafts produced much higher levels of immunosuppressive cytokine, IL-10 when stimulated with allogeneic donor DCs. In addition, humoral immune tolerance was also induced as there was no significant increase levels of serum antibodies against donor antigens in Trx-lung recipients when re-challenged with allogeneic donor antigens. Our results demonstrate that one-time Trx-priming of donor lung grafts prior to transplantation significantly prolongs the survival of the grafts through inducing or promoting cellular and humoral alloantigen-specific immune tolerance, which might be associated with the induction of immunosuppressive regulatory T cells. PMID- 25933392 TI - Infliximab Does Not Worsen Outcomes During Flare-ups Associated with Cytomegalovirus Infection in Patients with Ulcerative Colitis. AB - BACKGROUND: Immunosuppressive therapies used for treating ulcerative colitis are known to favor chronic and latent viral diseases. This study aimed at evaluating prospectively the association between colonic cytomegalovirus (CMV) reactivation and anti-tumor necrosis factor (TNF) monoclonal antibodies (mabs) by comparison to azathioprine (AZA) in a series of flare-ups occurring in consecutive ulcerative colitis patients. METHODS: A total of 109 flare-ups were recorded in 73 patients receiving a maintenance therapy by anti-TNF mabs (n = 69) or AZA (n = 40). The CMV DNA load in colonic tissue was determined by reverse transcription polymerase chain reaction on a pair of biopsies. RESULTS: The number of CMV reactivation was of 35% and 38% in patients receiving anti-TNF mabs and AZA, respectively. The median of CMV DNA load was 378 [10-29,800] and 8300 [10 3,25,000] copies/mg of tissue in patients treated by anti-TNF mabs and AZA, respectively (P = 0.11 by Mann-Whitney U test). In a subgroup of 45 patients under anti-TNF mabs requiring an optimized treatment by infliximab, clinical remission (partial Mayo score <3) was not significantly impacted by the presence of CMV reactivation at the time of flare-up (P = 0.52). Twenty of these patients underwent a second colonic biopsy 8 weeks after the initiation of flare-up therapy; except for 3 patients, the colonic CMV DNA load was stable or decreased. CONCLUSIONS: Patients under anti-TNF maintenance therapy are not at higher risk of CMV reactivation in case of flare-up. No reciprocal adverse influence was observed between anti-TNF mabs and CMV infection, suggesting that these drugs must be considered for treating flare-ups associated to CMV reactivation. PMID- 25933391 TI - Gene-wise association of variants in four lysosomal storage disorder genes in neuropathologically confirmed Lewy body disease. AB - OBJECTIVE: Variants in GBA are associated with Lewy Body (LB) pathology. We investigated whether variants in other lysosomal storage disorder (LSD) genes also contribute to disease pathogenesis. METHODS: We performed a genetic analysis of four LSD genes including GBA, HEXA, SMPD1, and MCOLN1 in 231 brain autopsies. Brain autopsies included neuropathologically defined LBD without Alzheimer Disease (AD) changes (n = 59), AD without significant LB pathology (n = 71), Alzheimer disease and lewy body variant (ADLBV) (n = 68), and control brains without LB or AD neuropathology (n = 33). Sequencing of HEXA, SMPD1, MCOLN1 and GBA followed by 'gene wise' genetic association analysis was performed. To determine the functional effect, a biochemical analysis of GBA in a subset of brains was also performed. GCase activity was measured in a subset of brain samples (n = 64) that included LBD brains, with or without GBA mutations, and control brains. A lipidomic analysis was also performed in brain autopsies (n = 67) which included LBD (n = 34), ADLBV (n = 3), AD (n = 4), PD (n = 9) and control brains (n = 17), comparing GBA mutation carriers to non-carriers. RESULTS: In a 'gene-wise' analysis, variants in GBA, SMPD1 and MCOLN1 were significantly associated with LB pathology (p range: 0.03-4.14 x10(-5)). Overall, the mean levels of GCase activity were significantly lower in GBA mutation carriers compared to non-carriers (p<0.001). A significant increase and accumulation of several species for the lipid classes, ceramides and sphingolipids, was observed in LBD brains carrying GBA mutations compared to controls (p range: p<0.05-p<0.01). INTERPRETATION: Our study indicates that variants in GBA, SMPD1 and MCOLN1 are associated with LB pathology. Biochemical data comparing GBA mutation carrier to non-carriers support these findings, which have important implications for biomarker development and therapeutic strategies. PMID- 25933393 TI - The Influence of Anti-tumor Necrosis Factor Agents on Hemoglobin Levels of Patients with Inflammatory Bowel Disease. AB - BACKGROUND: Anti-tumor necrosis factor (TNF) agents are an important component of inflammatory bowel disease (IBD) treatment, but data on their influence on anemia, a frequent complication of IBD, are limited. The aim of this study was to evaluate the effect of anti-TNF agents on hemoglobin (Hb) levels in a large IBD cohort. METHODS: Prospectively collected demographic, clinical, laboratory, and treatment data from IBD patients who started anti-TNF treatment at a tertiary referral center during the years 2010 to 2012 were analyzed. Follow-up data including disease activity scores (Harvey-Bradshaw index or ulcerative colitis activity index), quality of life scores (short IBD questionnaire) completed at each visit, and laboratory data were analyzed. Data from the year of anti-TNF initiation (yr 0) to the following year (yr 1) were compared. RESULTS: A total of 430 IBD patients (324 with Crohn's disease, 51.6% females) started anti-TNF treatment. The prevalence of anemia and median Hb levels did not change between years 0 and 1. Median short IBD questionnaire was significantly improved at year 1 (P = 0.002). IBD patients with anemia had significantly higher median Hb levels at year 1 compared with year 0 (P = 0.0009). Hematopoietic response (increase of Hb >=2 g/dL) was observed in only 33.6% of the 134 anemic IBD patients, despite iron replacement being administered in 126 anemic patients (oral, 77%). Improvement in Hb levels was independently significantly correlated with change of C-reactive protein levels (P = 0.04) and immunomodulator use (P = 0.03). CONCLUSIONS: Anemia remains a significant manifestation of IBD 1 year after treatment with anti-TNF agents. PMID- 25933394 TI - Can fecal microbial transplant effectively treat Crohn's disease? PMID- 25933395 TI - What is the Role of Diffusion-weighted Imaging in Ileocolonic Crohn's Disease? PMID- 25933398 TI - Do Unilateral Herpetic Stromal Keratitis and Neurotrophic Ulcers Cause Bilateral Dry Eye? AB - PURPOSE: To evaluate and compare the ocular surface condition in herpetic interstitial stromal keratitis and neurotrophic ulcer groups and their normal fellow eyes. METHODS: In this observational, cross-sectional case-control study, 85 consecutive patients were included, including 56 cases of treated herpetic interstitial keratitis and 29 patients with neurotrophic ulcers. Fifty-six age- and sex-matched participants were also recruited from a normal population as the control group. We evaluated and scored the subjective and objective measures of dry eye for both eyes of all patients. Then, we compared the score of the groups with one another and also with the control group. The main outcome measures were the discomfort level, visual symptoms of dry eye, conjunctival injection, conjunctival staining, corneal staining, corneal tear signs of dry eye, meibomian gland dysfunction, tear break-up time, Schirmer test score with anesthesia, and tear osmolarity. RESULTS: The normal fellow eye of the herpetic keratitis group had significantly higher discomfort levels (1.4 +/- 0.9 vs. 1.3 +/- 0.5, P = 0.003), visual symptoms (1.7 +/- 0.8 vs. 1.3 +/- 0.7, P = 0.002), tear break-up time (8.3 +/- 3.2 vs. 12.1 +/- 3.3 seconds, P = 0.003), Schirmer test scores (9.2 +/- 3.9 vs. 12.9 +/- 3 mm, P = 0.04), and tear osmolarity (9.2 +/- 3.9 vs. 12.9 +/- 3 mm, P = 0.003) in comparison with normal controls. The normal fellow eyes of the neurotrophic ulcer group had significantly worse values for discomfort level (1.9 +/- 0.9 vs. 1.3 +/- 0.5, P < 0.001), tear break-up time (7.9 +/- 4 vs. 12.1 +/- 3.3, P = 0.004), Schirmer test score (8.1 +/- 3.9 vs. 12.9 +/- 3, P = 0.005), and tear osmolarity (295 +/- 9.2 vs. 292.7 +/- 5.9, P = 0.02) compared with normal controls. CONCLUSIONS: Both eyes of patients with neurotrophic ulcer and interstitial herpetic keratitis have a significantly poorer ocular surface condition compared with that of normal controls. PMID- 25933397 TI - Diagnostic intervals and its association with breast, prostate, lung and colorectal cancer survival in England: historical cohort study using the Clinical Practice Research Datalink. AB - Rapid diagnostic pathways for cancer have been implemented, but evidence whether shorter diagnostic intervals (time from primary care presentation to diagnosis) improves survival is lacking. Using the Clinical Practice Research Datalink, we identified patients diagnosed with female breast (8,639), colorectal (5,912), lung (5,737) and prostate (1,763) cancers between 1998 and 2009, and aged >15 years. Presenting symptoms were classified as alert or non-alert, according to National Institute for Health and Care Excellence guidance. We used relative survival and excess risk modeling to determine associations between diagnostic intervals and five-year survival. The survival of patients with colorectal, lung and prostate cancer was greater in those with alert, compared with non-alert, symptoms, but findings were opposite for breast cancer. Longer diagnostic intervals were associated with lower mortality for colorectal and lung cancer patients with non-alert symptoms, (colorectal cancer: Excess Hazards Ratio, EHR >6 months vs <1 month: 0.85; 95% CI: 0.72-1.00; Lung cancer: EHR 3-6 months vs <1 month: 0.87; 95% CI: 0.80-0.95; EHR >6 months vs <1 month: 0.81; 95% CI: 0.74 0.89). Prostate cancer mortality was lower in patients with longer diagnostic intervals, regardless of type of presenting symptom. The association between diagnostic intervals and cancer survival is complex, and should take into account cancer site, tumour biology and clinical practice. Nevertheless, unnecessary delay causes patient anxiety and general practitioners should continue to refer patients with alert symptoms via the cancer pathways, and actively follow-up patients with non-alert symptoms in the community. PMID- 25933399 TI - Lid Margin Sensitivity and Staining in Contact Lens Wear Versus No Lens Wear. AB - PURPOSE: To map the sensitivity and staining of the marginal conjunctiva in soft contact lens (SCL) wearers and nonwearers and to investigate diurnal changes. METHODS: Thirty-five nonwearers and 35 SCL wearers were recruited. Mechanical sensitivity was measured at 8 locations on the ocular surface and adnexa (cornea, marginal, bulbar, and tarsal conjunctivae) using the Cochet-Bonnet aesthesiometer. Lid margin staining (lissamine green) was assessed through image analysis. Measurements were repeated at 12 hours in 11 nonwearers and 10 symptomatic SCL wearers. RESULTS: The marginal conjunctiva was the most sensitive conjunctival region (all P < 0.001). There was no significant difference in sensitivity at 12 hours (all P > 0.05). There was a significant difference in sensitivity between the 2 groups in the morning for the lower lid tarsal conjunctiva (P = 0.003). After 12 hours, the sensitivity of the lower lid marginal conjunctiva was found to be reduced in SCL wearers compared with nonwearers (all P < 0.05). Lower lid margin staining was greater than upper lid margin staining in both groups (all P < 0.05). In the SCL wearers, a significant increase in lower lid margin staining was found at 12 hours compared with the morning (P = 0.04). After 12 hours, lower lid margin staining was significantly greater in SCL wearers compared with nonwearers (P = 0.03). CONCLUSIONS: This work has demonstrated that the marginal conjunctiva is the most sensitive conjunctival region. After 12 hours, symptomatic lens wearers showed decreased sensitivity of the lower marginal conjunctiva and increased lower lid margin lissamine green staining compared with those of the nonwearers. PMID- 25933400 TI - Eyelid Tattooing Induces Meibomian Gland Loss and Tear Film Instability. AB - PURPOSE: To investigate the changes of meibomian gland (MG) and tear film stability in subjects with eyelid tattoos. METHODS: Forty female subjects were recruited. Ten subjects had eyelid tattoos and 30 subjects did not (control group). Tear film break-up time (TBUT) measurement and fluorescein staining were performed to evaluate the tear film. Distances between the eyelid tattoo and the MGs were measured and used to assign a tattoo score. The overall tattoo score, defined as the sum of upper and lower lid tattoo scores, was determined for each eye. MG loss was scored for each eyelid and added together to obtain the total "meiboscore" for each eye using meibography. Values between the tattoo and control groups were examined and compared. RESULTS: The TBUT in the tattoo group (4.3 +/- 0.9 seconds) was shorter than that in the control group (11.0 +/- 4.3 seconds; P < 0.001). Corneal erosion, measured with fluorescein staining, was more severe in the tattoo group (1.6 +/- 0.5) than that in the control group (0.2 +/- 0.2; P < 0.001). MG loss was also more severe in the tattoo group (3.4 +/- 1.5) than that in the control group (0.9 +/- 0.6; P < 0.001). The total tattoo score was correlated with the total meiboscore (r = 0.852, P < 0.001, Spearman correlation coefficient). CONCLUSIONS: Eyelid tattooing shortened TBUT, increased fluorescein staining, and induced MG loss. Therefore, eyelid tattooing increases tear film instability through MG disturbance, and patients could have exacerbated signs and symptoms of ocular surface disease. PMID- 25933401 TI - Eye Bank-Prepared Femtosecond Laser-Assisted Automated Descemet Membrane Endothelial Grafts. AB - PURPOSE: The aim of this study was to investigate the use of a femtosecond laser (FL) in the eye bank preparation of corneas for Descemet membrane (DM) automated endothelial keratoplasty (fDMAEK) and to compare endothelial cell death in graft preparations between fDMAEK, Descemet stripping endothelial keratoplasty (DSEK), and DM endothelial keratoplasty (DMEK). METHODS: Twenty cadaveric tissues were used to test the fDMAEK method. A 9.0-mm-diameter lamellar incision was made using the FL with a 6.0-mm perpendicular anterior ring cut that enabled a stromal rim by acting as a venting incision for bubble expansion. DM was pneumodissected off the central 6.0 mm of the tissue. The fDMAEK grafts were trephined and stained with a viability dye, calcein AM. The entire stained endothelial surface was digitally captured and the endothelial cell loss (ECL) was calculated using trainable segmentation software. For comparison, a series of 6 DSEK grafts and 8 DMEK grafts were created and analyzed. RESULTS: Six of 20 tissues (30%) were lost during fDMAEK preparation. In the 14 successful tissues, the average ECL was 30.4% [95% confidence interval (CI), 25.3-35.6] compared with 21.1% (95% CI, 13.2 28.9, P = 0.09) in the 6 DSEK grafts and 22.5% (95% CI, 18.0-27.0, P = 0.04) in the 8 DMEK grafts. CONCLUSIONS: FLs are useful in preparing DMAEK tissue at the eye bank and may promote predictable and precise big bubbles and stromal rims. The fDMAEK preparation success improved with experience and laser adjustments. In fDMAEK, the ECL is higher than was previously reported in DMEK and DSEK, likely due to greater tissue manipulation, although not significantly higher than DSEK controls. PMID- 25933402 TI - Comparison of Descemet-On Versus Descemet-Off Deep Anterior Lamellar Keratoplasty in Keratoconus Patients: A Randomized Trial. AB - PURPOSE: To compare the visual outcomes of Descemet membrane (DM)-on and DM-off after deep anterior lamellar keratoplasty (DALK) using the big-bubble (BB) technique in keratoconus patients. METHODS: In this prospective trial, keratoconic eyes undergoing DALK procedures with the BB technique were randomized into 2 groups: a donor cornea without DM (group 1; 29 eyes) or with DM (group 2; 30 eyes). These groups were compared with respect to best-corrected visual acuity and contrast sensitivity while wearing gas permeable contact lenses and also endothelial cell counts. RESULTS: There were no statistically significant differences between the 2 groups with regard to best-corrected visual acuity and contrast sensitivity using gas permeable contact lenses as well as endothelial cell counts at 3, 6, and 12 months. After 1 year, the mean (+/-SD) postoperative visual acuity CL (with contact lenses) was 0.05 (+/-0.01) in the DM-off group and 0.05 (+/-0.01) in the DM-on group (P = 0.956). Mean postoperative endothelial cell counts were 2425.0 (+/-123.7) and 2306.7 (79.9), respectively (P = 0.443), and corneal thicknesses were 527.9 (58.3) and 556.6 (47.3), respectively (P = 0.150). During the follow-up period, very few complications occurred and neither group had a predominance of adverse events at 3, 6, 12, or 24 months. CONCLUSIONS: In conclusion, DALK procedures using the BB technique for keratoconus with DM-on or DM-off presented no significant differences regarding the visual outcomes or endothelial cell counts. PMID- 25933403 TI - Characteristics of Pre-Descemet Membrane Corneal Dystrophy by Three Different Imaging Modalities-In Vivo Confocal Microscopy, Anterior Segment Optical Coherence Tomography, and Scheimpflug Corneal Densitometry Analysis. AB - PURPOSE: To evaluate the characteristics of pre-Descemet membrane corneal dystrophy by 3 different imaging modalities: in vivo confocal microscopy (IVCM), anterior segment optical coherence tomography (ASOCT), and Scheimpflug corneal densitometry analysis. METHODS: A 32-year-old male patient with pre-Descemet membrane corneal dystrophy was subjected to imaging by IVCM, ASOCT, and Scheimpflug tomography. RESULTS: Slit-lamp biomicroscopy showed the presence of tiny pleomorphic opacities in the posterior stroma, immediately anterior to Descemet membrane bilaterally. On IVCM, pleomorphic, hyperreflective punctate particles were seen both intracellularly and extracellularly in the anterior and mid stroma with increased reflectivity of some keratocytes that, however, were of normal size. These changes increased in severity from the anterior to mid stroma. The posterior stroma had grossly enlarged hyperreflective keratocytes with prominent processes. The hyperreflective particles were also seen scattered on the endothelium. ASOCT revealed a well-delineated homogenous band of increased reflectivity of approximately 70 MUm width in the posterior stroma of both eyes with a normal-appearing anterior and mid stroma. Corneal densitometry measured by Scheimpflug optical analysis revealed a higher amount of backscattered light from the posterior stroma with a posterior to anterior ratio of 0.8. CONCLUSIONS: In pre-Descemet membrane corneal dystrophy, although the structural changes seem to be limited to the posterior stroma as seen clinically and on ASOCT, IVCM demonstrates that the pathology is more extensive involving the entire corneal stroma and endothelium. PMID- 25933404 TI - Reliability of the Effect of Artificial Anterior Chamber Pressure and Corneal Drying on Corneal Graft Thickness. AB - PURPOSE: To investigate the effect of artificial anterior chamber (AAC) pressure and corneal drying on the graft thickness in preparation for Descemet stripping automated endothelial keratoplasty. METHODS: Twenty-seven corneoscleral discs were placed in an AAC. The AAC pressure (15, 45, 92, 109, and 198 mm Hg) was controlled using the height of an infusion bottle and a roller clamp. The endothelium was removed in 1 subgroup. Corneas were exposed to room air or repeatedly dried using cellulose spears. Central corneal thickness was measured every 90 seconds for the first 15 minutes and again at 20 minutes using an ultrasound pachymeter (SP-100, Tomey). RESULTS: There was a significant linear relationship between the corneal thickness and both AAC pressure and corneal drying. Very high coefficients of determination and narrow 95% confidence intervals were present, in particular for high pressures and drying. The rate of thinning increased with increasing pressure and drying to 1.6% per minute. At the maximum rate of thinning, a 10% reduction in corneal thickness occurred in 6 minutes or 100 MUm in 8.8 minutes. Removal of the corneal endothelium reduced the rate of thinning to 0.3% per minute (R = 0.72). CONCLUSIONS: Increasing AAC pressure and corneal drying reduced the graft thickness at a very predictable rate. Adequate corneal thinning can be achieved by increasing the pressure in the AAC by closing the clamp followed by removal of the residual corneal epithelium and repeated drying with a cellulose spear for 5 to 10 minutes, depending on the initial corneal thickness. This method is simple and is both suitable for use in the eye bank and by the surgeon. PMID- 25933405 TI - Thermoluminescence response of dysprosium doped strontium tetraborate glasses subjected to electron irradiations. AB - The paper presents the thermoluminescence (TL) response of strontium tetraborate glass subjected to electron irradiations at various Dy2O3 concentrations ranging from 0.00 to 1.00mol%. All glass samples exhibited single broad peak with maximum peak temperature positioned at 170-215 degrees C. The optimum TL response was found at Dy2O3 concentration 0.75mol%. This glass showed good linearity and higher sensitivity for 7MeV compared to 6MeV electrons. Analysis of kinetic parameters showed that the glasses demonstrate second order kinetic. PMID- 25933406 TI - Precise measurements of the absolute gamma-ray emission probabilities of (223)Ra and decay progeny in equilibrium. AB - Precise measurements of the absolute gamma-ray emission probabilities have been made of radiochemically pure solutions of (223)Ra in equilibrium with its decay progeny, which had been previously standardised by 4pi(liquid scintillation) gamma digital coincidence counting techniques. Two high-purity germanium gamma ray spectrometers were used which had been accurately calibrated using a suite of primary and secondary radioactive standards. Comparison of the activity concentration determined by the primary technique against gamma-ray spectrometry measurements using the nuclear data evaluations of the Decay Data Evaluation Project exhibited a range of ~18% in the most intense gamma-ray emissions (>1% probability) of the (223)Ra decay series. Absolute gamma-ray emission probabilities and standard uncertainties have been determined for the decay of (223)Ra, (219)Rn, (215)Po, (211)Pb, (211)Bi and (207)Tl in equilibrium. The standard uncertainties of the measured gamma-ray emission probabilities quoted in this work show a significant improvement over previously reported gamma-ray emission probabilities. Correlation coefficients for pairs of the measured gamma ray emission probabilities from the decays of the radionuclides (223)Ra, (219)Rn and (211)Pb have been determined and are presented. The alpha-transition probabilities of the (223)Ra have been deduced from P(gamma+ce) balance using the gamma-ray emission probabilities determined in this work with some agreement observed with the published experimental values of the alpha-emission probabilities. PMID- 25933407 TI - The behavior of fixed and switching oxide traps of RADFETs during irradiation up to high absorbed doses. AB - The behavior of radiation-induced fixed traps (FTs) in gate oxide and radiation induced switching traps (STs) near and at the gate oxide/substrate interface during irradiation up to high absorbed doses has been considered. The zero-bias voltage regime, the simplest and most popular solution in practice, was chosen. Indeed, it is very difficult to predict the creation of radiation defects in the case of low electric fields, because there is a compromise between the external low electric fields induced by work function differences and the internal electrical fields induced by radiation-induced charged defects in the oxide. It was shown that the density of FTs is higher than the density of STs for lower absorbed doses, though the trend is reversed for doses greater than 700Gy. Although the number of FTs is much higher than the number of STs, many FTs are located in the bulk, far from the oxide/semiconductor interface and their influence on channel carriers is much smaller than the influence of STs that are located closer to the channel. The equation for fitting the threshold voltage components induced by FTs (DeltaVft) and by STs (DeltaVst) is proposed and very good fittings are obtained. It is shown that five experimental irradiation points are sufficient to draw a good conclusion about the values of the fitting parameters, i.e., the voltage saturation values and the degree of linearity. PMID- 25933408 TI - A theory-based evaluation of a community-based funding scheme in a disadvantaged suburban city area. AB - Community-driven development (CDD) initiatives frequently involve funding schemes which are aimed at channelling financial investment into local need and fostering community participation and engagement. This exploratory study examined, through a program theory approach, the design and implementation of a small-scale, community-based fund in Ireland. Observations, documentary analysis, interviews and group discussions with 19 participants were utilized to develop a detailed understanding of the program mechanisms, activities and processes, as well as the experiences of key stakeholders engaged with the funding scheme and its implementation. The findings showed that there were positive perceptions of the scheme and its function within the community. Overall, the availability of funding was perceived by key stakeholders as being beneficial. However, there were concerns over the accessibility of the scheme for more marginalized members of the community, as well as dissatisfaction with the openness and transparency surrounding funding eligibility. Lessons for the implementation of small-scale CDD funds are elaborated and the utility of program theory approaches for evaluators and planners working with programs that fund community-based initiatives is outlined. PMID- 25933409 TI - DBA/2J genetic background exacerbates spontaneous lethal seizures but lessens amyloid deposition in a mouse model of Alzheimer's disease. AB - Alzheimer's disease (AD) is a leading cause of dementia in the elderly and is characterized by amyloid plaques, neurofibrillary tangles (NFTs) and neuronal dysfunction. Early onset AD (EOAD) is commonly caused by mutations in amyloid precursor protein (APP) or genes involved in the processing of APP including the presenilins (e.g. PSEN1 or PSEN2). In general, mouse models relevant to EOAD recapitulate amyloidosis, show only limited amounts of NFTs and neuronal cell dysfunction and low but significant levels of seizure susceptibility. To investigate the effect of genetic background on these phenotypes, we generated APPswe and PSEN1de9 transgenic mice on the seizure prone inbred strain background, DBA/2J. Previous studies show that the DBA/2J genetic background modifies plaque deposition in the presence of mutant APP but the impact of PSEN1de9 has not been tested. Our study shows that DBA/2J.APPswePSEN1de9 mice are significantly more prone to premature lethality, likely to due to lethal seizures, compared to B6.APPswePSEN1de9 mice-70% of DBA/2J.APPswePSEN1de9 mice die between 2-3 months of age. Of the DBA/2J.APPswePSEN1de9 mice that survived to 6 months of age, plaque deposition was greatly reduced compared to age-matched B6.APPswePSEN1de9 mice. The reduction in plaque deposition appears to be independent of microglia numbers, reactive astrocytosis and complement C5 activity. PMID- 25933410 TI - Forgetting the best when predicting the worst: Preliminary observations on neural circuit function in adolescent social anxiety. AB - Social anxiety disorder typically begins in adolescence, a sensitive period for brain development, when increased complexity and salience of peer relationships requires novel forms of social learning. Disordered social learning in adolescence may explain how brain dysfunction promotes social anxiety. Socially anxious adolescents (n = 15) and adults (n = 19) and non-anxious adolescents (n = 24) and adults (n = 32) predicted, then received, social feedback from high and low-value peers while undergoing functional magnetic resonance imaging (fMRI). A surprise recall task assessed memory biases for feedback. Neural correlates of social evaluation prediction errors (PEs) were assessed by comparing engagement to expected and unexpected positive and negative feedback. For socially anxious adolescents, but not adults or healthy participants of either age group, PEs elicited heightened striatal activity and negative fronto-striatal functional connectivity. This occurred selectively to unexpected positive feedback from high value peers and corresponded with impaired memory for social feedback. While impaired memory also occurred in socially-anxious adults, this impairment was unrelated to brain-based PE activity. Thus, social anxiety in adolescence may relate to altered neural correlates of PEs that contribute to impaired learning about social feedback. Small samples necessitate replication. Nevertheless, results suggest that the relationship between learning and fronto-striatal function may attenuate as development progresses. PMID- 25933411 TI - Effect of cardiac arrest on cognitive impairment and hippocampal plasticity in middle-aged rats. AB - Cardiopulmonary arrest is a leading cause of death and disability in the United States that usually occurs in the aged population. Cardiac arrest (CA) induces global ischemia, disrupting global cerebral circulation that results in ischemic brain injury and leads to cognitive impairments in survivors. Ischemia-induced neuronal damage in the hippocampus following CA can result in the impairment of cognitive function including spatial memory. In the present study, we used a model of asphyxial CA (ACA) in nine month old male Fischer 344 rats to investigate cognitive and synaptic deficits following mild global cerebral ischemia. These experiments were performed with the goals of 1) establishing a model of CA in nine month old middle-aged rats; and 2) to test the hypothesis that learning and memory deficits develop following mild global cerebral ischemia in middle-aged rats. To test this hypothesis, spatial memory assays (Barnes circular platform maze and contextual fear conditioning) and field recordings (long-term potentiation and paired-pulse facilitation) were performed. We show that following ACA in nine month old middle-aged rats, there is significant impairment in spatial memory formation, paired-pulse facilitation n dysfunction, and a reduction in the number of non-compromised hippocampal Cornu Ammonis 1 and subiculum neurons. In conclusion, nine month old animals undergoing cardiac arrest have impaired survival, deficits in spatial memory formation, and synaptic dysfunction. PMID- 25933412 TI - Single-point but not tonic cuff pressure pain sensitivity is associated with level of physical fitness--a study of non-athletic healthy subjects. AB - Exercise is often used for pain rehabilitation but the link between physical activity level and pain sensitivity is still not fully understood. Pressure pain sensitivity to cuff algometry and conditioned pain modulation (CPM) were evaluated in highly active men (n=22), normally active men (n=26), highly active women (n=27) and normally active women (n=23) based on the Godin Leisure-Time Exercise Questionnaire. Cuff pressure pain sensitivity was assessed at the arm and lower leg. The subjects scored the pain intensity on an electronic Visual Analogue Scale (VAS) during ten minutes with 25 kPa constant cuff pressure and two minutes with zero pressure. The maximal VAS score and area under the VAS curve were extracted. Pressure pain thresholds (PPT) were recorded by manual pressure algometry on the ipsilateral tibialis anterior muscle before, during and after the tonic arm stimulation. Tonic cuff stimulation of the arm and leg resulted in higher VAS peak scores in women compared with men (p<0.04). In all groups the PPTs were reduced during and after the cuff stimulation compared with baseline (p=0.001). PPT were higher in men compared with women (p=0.03) and higher in highly physical active compared with normal active (p=0.048). Besides the well-known gender difference in pressure pain sensitivity this study demonstrates that a high physical fitness degree in non-athletic subjects is associated with increased pressure pain thresholds but does not affect cuff pressure pain sensitivity in healthy people. PMID- 25933413 TI - Bank-firm credit network in Japan: an analysis of a bipartite network. AB - We investigate the networked nature of the Japanese credit market. Our investigation is performed with tools of network science. In our investigation we perform community detection with an algorithm which is identifying communities composed of both banks and firms. We show that the communities obtained by directly working on the bipartite network carry information about the networked nature of the Japanese credit market. Our analysis is performed for each calendar year during the time period from 1980 to 2011. To investigate the time evolution of the networked structure of the credit market we introduce a new statistical method to track the time evolution of detected communities. We then characterize the time evolution of communities by detecting for each time evolving set of communities the over-expression of attributes of firms and banks. Specifically, we consider as attributes the economic sector and the geographical location of firms and the type of banks. In our 32-year-long analysis we detect a persistence of the over-expression of attributes of communities of banks and firms together with a slow dynamic of changes from some specific attributes to new ones. Our empirical observations show that the credit market in Japan is a networked market where the type of banks, geographical location of firms and banks, and economic sector of the firm play a role in shaping the credit relationships between banks and firms. PMID- 25933415 TI - Correction: cerebral hemodynamic changes of mild traumatic brain injury at the acute stage. PMID- 25933414 TI - The Costs of Delivering Integrated HIV and Sexual Reproductive Health Services in Limited Resource Settings. AB - OBJECTIVE: To present evidence on the total costs and unit costs of delivering six integrated sexual reproductive health and HIV services in a high and medium HIV prevalence setting, in order to support policy makers and planners scaling up these essential services. DESIGN: A retrospective facility based costing study conducted in 40 non-government organization and public health facilities in Kenya and Swaziland. METHODS: Economic and financial costs were collected retrospectively for the year 2010/11, from each study site with an aim to estimate the cost per visit of six integrated HIV and SRH services. A full cost analysis using a combination of bottom-up and step-down costing methods was conducted from the health provider's perspective. The main unit of analysis is the economic unit cost per visit for each service. Costs are converted to 2013 International dollars. RESULTS: The mean cost per visit for the HIV/SRH services ranged from $Int 14.23 (PNC visit) to $Int 74.21 (HIV treatment visit). We found considerable variation in the unit costs per visit across settings with family planning services exhibiting the least variation ($Int 6.71-52.24) and STI treatment and HIV treatment visits exhibiting the highest variation in unit cost ranging from ($Int 5.44-281.85) and ($Int 0.83-314.95), respectively. Unit costs of visits were driven by fixed costs while variability in visit costs across facilities was explained mainly by technology used and service maturity. CONCLUSION: For all services, variability in unit costs and cost components suggest that potential exists to reduce costs through better use of both human and capital resources, despite the high proportion of expenditure on drugs and medical supplies. Further work is required to explore the key drivers of efficiency and interventions that may facilitate efficiency improvements. PMID- 25933417 TI - Self-assembled architectures with segregated donor and acceptor units of a dyad based on a monopyrrolo-annulated TTF-PTM radical. AB - An electron donor-acceptor dyad based on a polychlorotriphenylmethyl (PTM) radical subunit linked to a tetrathiafulvalene (TTF) unit through a pi-conjugated N-phenyl-pyrrole-vinylene bridge has been synthesized and characterized. The intramolecular electron transfer process and magnetic properties of the radical dyad have been evaluated by cyclic voltammetry, UV/Vis spectroscopy, vibrational spectroscopy, and ESR spectroscopy in solution and in the solid state. The self assembling abilities of the radical dyad and of its protonated non-radical analogue have been investigated by X-ray crystallographic analysis, which revealed that the radical dyad produced a supramolecular architecture with segregated donor and acceptor units in which the TTF subunits were arranged in 1D herringbone-type stacks. Analysis of the X-ray data at different temperatures suggests that the two inequivalent molecules that form the asymmetric unit of the crystal of the radical dyad evolve into an opposite degree of electronic delocalization as the temperature decreases. PMID- 25933416 TI - Ethanolic Echinacea purpurea Extracts Contain a Mixture of Cytokine-Suppressive and Cytokine-Inducing Compounds, Including Some That Originate from Endophytic Bacteria. AB - Echinacea preparations, which are used for the prevention and treatment of upper respiratory infections, account for 10% of the dietary supplement market in the U.S., with sales totaling more than $100 million annually. In an attempt to shed light on Echinacea's mechanism of action, we evaluated the effects of a 75% ethanolic root extract of Echinacea purpurea, prepared in accord with industry methods, on cytokine and chemokine production from RAW 264.7 macrophage-like cells. We found that the extract displayed dual activities; the extract could itself stimulate production of the cytokine TNF-alpha, and also suppress production of TNF-alpha in response to stimulation with exogenous LPS. Liquid:liquid partitioning followed by normal-phase flash chromatography resulted in separation of the stimulatory and inhibitory activities into different fractions, confirming the complex nature of this extract. We also studied the role of alkylamides in the suppressive activity of this E. purpurea extract. Our fractionation method concentrated the alkylamides into a single fraction, which suppressed production of TNF-alpha, CCL3, and CCL5; however fractions that did not contain detectable alkylamides also displayed similar suppressive effects. Alkylamides, therefore, likely contribute to the suppressive activity of the extract but are not solely responsible for that activity. From the fractions without detectable alkylamides, we purified xanthienopyran, a compound not previously known to be a constituent of the Echinacea genus. Xanthienopyran suppressed production of TNF-alpha suggesting that it may contribute to the suppressive activity of the crude ethanolic extract. Finally, we show that ethanolic extracts prepared from E. purpurea plants grown under sterile conditions and from sterilized seeds, do not contain LPS and do not stimulate macrophage production of TNF-alpha, supporting the hypothesis that the macrophage stimulating activity in E. purpurea extracts can originate from endophytic bacteria. Together, our findings indicate that ethanolic E. purpurea extracts contain multiple constituents that differentially regulate cytokine production by macrophages. PMID- 25933418 TI - Correlates of self-reported sleep duration in middle-aged and elderly Koreans: from the Health Examinees Study. AB - Though various factors related to fluctuations in sleep duration have been identified, information remains limited regarding the correlates of short and long sleep duration among the Korean population. Thus, we investigated characteristics that could be associated with short and/or long sleep duration among middle-aged and elderly Koreans. A total of 84,094 subjects (27,717 men and 56,377 women) who participated in the Health Examinees Study were analyzed by using multinomial logistic regression models. To evaluate whether sociodemographic factors, lifestyle factors, psychological conditions, anthropometry results, and health conditions were associated with short and/or long sleep duration, odds ratios (ORs) and 95% confidence intervals (CIs) were estimated with sleep duration of 6-7 hours as the reference group, accounting for putative covariates. Regardless of sexual differences, we found that adverse behaviors and lifestyle factors including low educational attainment, unemployment, being unmarried, current smoking status, lack of exercise, having irregular meals, poor psychosocial well-being, frequent stress events, and poor self-rated health were significantly associated with abnormal sleep duration. Similarly, diabetes mellitus and depression showed positive associations with abnormal sleep duration in both men and women. Our findings suggest that low sociodemographic characteristics, adverse lifestyle factors, poor psychological conditions, and certain disease morbidities could be associated with abnormal sleep duration in middle-aged and elderly Koreans. PMID- 25933419 TI - Effects of Low-Dose Bisphenol A on DNA Damage and Proliferation of Breast Cells: The Role of c-Myc. AB - BACKGROUND: Humans are exposed to low-dose bisphenol A (BPA) through plastic consumer products and dental sealants containing BPA. Although a number of studies have investigated the mammary gland effects after high-dose BPA exposure, the study findings differ. Furthermore, there has been a lack of mechanistic studies. OBJECTIVE: The objective of this study was to investigate the effect and the mechanism of low-dose BPA in mammary gland cells. METHODS: We evaluated DNA damage following BPA exposure using the comet assay and immunofluorescence staining, and used cell counting and three-dimensional cultures to evaluate effects on proliferation. We examined the expressions of markers of DNA damage and cell-cycle regulators by immunoblotting and performed siRNA-mediated gene silencing to determine the role of c-Myc in regulating BPA's effects. RESULTS: Low-dose BPA significantly promoted DNA damage, up-regulated c-Myc and other cell cycle regulatory proteins, and induced proliferation in parallel in estrogen receptor-alpha (ERalpha)-negative mammary cells. Silencing c-Myc diminished these BPA-induced cellular events, suggesting that c-Myc is essential for regulating effects of BPA on DNA damage and proliferation in mammary cells. CONCLUSIONS: Low dose BPA exerted c-Myc-dependent genotoxic and mitogenic effects on ERalpha negative mammary cells. These findings provide significant evidence of adverse effects of low-dose BPA on mammary cells. PMID- 25933420 TI - Identification of Arabidopsis candidate genes in response to biotic and abiotic stresses using comparative microarrays. AB - Plants have evolved with intricate mechanisms to cope with multiple environmental stresses. To adapt with biotic and abiotic stresses, plant responses involve changes at the cellular and molecular levels. The current study was designed to investigate the effects of combinations of different environmental stresses on the transcriptome level of Arabidopsis genome using public microarray databases. We investigated the role of cyclopentenones in mediating plant responses to environmental stress through TGA (TGACG motif-binding factor) transcription factor, independently from jasmonic acid. Candidate genes were identified by comparing plants inoculated with Botrytis cinerea or treated with heat, salt or osmotic stress with non-inoculated or non-treated tissues. About 2.5% heat-, 19% salinity- and 41% osmotic stress-induced genes were commonly upregulated by B. cinerea-treatment; and 7.6%, 19% and 48% of genes were commonly downregulated by B. cinerea-treatment, respectively. Our results indicate that plant responses to biotic and abiotic stresses are mediated by several common regulatory genes. Comparisons between transcriptome data from Arabidopsis stressed-plants support our hypothesis that some molecular and biological processes involved in biotic and abiotic stress response are conserved. Thirteen of the common regulated genes to abiotic and biotic stresses were studied in detail to determine their role in plant resistance to B. cinerea. Moreover, a T-DNA insertion mutant of the Responsive to Dehydration gene (rd20), encoding for a member of the caleosin (lipid surface protein) family, showed an enhanced sensitivity to B. cinerea infection and drought. Overall, the overlapping of plant responses to abiotic and biotic stresses, coupled with the sensitivity of the rd20 mutant, may provide new interesting programs for increased plant resistance to multiple environmental stresses, and ultimately increases its chances to survive. Future research directions towards a better dissection of the potential crosstalk between B. cinerea, abiotic stress, and oxylipin signaling are of our particular interest. PMID- 25933421 TI - Age-Related Macular Degeneration Is Associated with Less Physical Activity among US Adults: Cross-Sectional Study. AB - BACKGROUND: We have a limited understanding of the effects of age-related macular degeneration (AMD) on physical activity (PA), and we have no prevalence estimates of the daily movement patterns among Americans with AMD. Therefore, we examined the association between AMD and PA and provided estimates of the daily movement patterns of Americans with AMD. METHODS: Data from the 2005-2006 National Health and Nutrition Examination Survey were used, including 1,656 adults (40-85 yrs). Retinal imaging was performed to classify individuals as no AMD, early AMD, or late AMD. Participants wore an ActiGraph 7164 accelerometer for 7 days to measure PA behavior. RESULTS: 93.2% of participants with late AMD were in the least desirable group (not sufficiently active and having a negative light intensity sedentary behavior balance). After adjustments (including age), participants with late AMD, as compared to those with no AMD, engaged in 50% less moderate-to vigorous physical activity (MVPA) (RR = 0.50; 95% CI: 0.28-0.90). When visual acuity was entered into the model along with the other covariates, the association between late AMD and MVPA was no longer significant (RR = 0.54; 95% CI: 0.29-1.01), suggesting that visual acuity may partially mediate this relationship. CONCLUSIONS: Individuals with late AMD engage in very little moderate-to-vigorous physical activity. Visually acuity, in part, explains the relationship between late AMD and PA. PMID- 25933422 TI - Understanding the Impact of Hazardous and Harmful Use of Alcohol and/or Other Drugs on ARV Adherence and Disease Progression. AB - The objective of this study was to understand the impact of hazardous and harmful use of alcohol and/or other drugs on ARV adherence and disease progression among HIV patients. A cross-sectional study design was used. A total of 1503 patients attending HIV clinics in Cape Town, South Africa were screened for problematic substance use. A sub-sample of 607 patients (303 patients who screened positive for problematic substance use and 304 who did not) participated in this study. Hazardous or harmful alcohol use and problematic drug use predicted missing and stopping ARVs which, in turn, was associated with a decrease in CD4 counts and more rapid HIV-disease progression and poorer health outcomes in people living with HIV/AIDS (PLWHA). The findings of this study underscore the need for an integrated approach to managing substance-use disorders in PLWHA. PMID- 25933423 TI - Long-term study of pig carrion entomofauna. AB - Long-term changes of carrion entomofauna are poorly understood. No single carrion study lasted longer than one year. We studied entomofauna of large pig carcasses in the second and the third year postmortem. Ten carcasses were exposed in xerothermic grasslands of Western Poland in spring, early and late summer of 2012. Entomofauna was monitored until September of 2014. 72 species were found in the second year, and six in the third year. In the second or the third year carcasses from the late summer block revealed larger number of taxa compared to carcasses from the spring or the early summer block. Taxa differed in pattern of multiple larval colonizations. Only necrophagous taxa breeding in long-lasting carrion parts as well as predators feeding on arthropods present in these parts were found to recolonize. Recolonizations were always recorded in the second or the third year after death. Patterns of multiple colonization depended on the time of carcass exposure in the first year. Residencies of larvae were unexpectedly long in the second year. Several forensically important flies overwintered on carcasses in the larval stage. Current results support the view that insect fauna of cadavers with long post-mortem interval (PMI) may be used for PMI estimation. PMID- 25933424 TI - Forensic analysis of explosions: Inverse calculation of the charge mass. AB - Forensic analysis of explosions consists of determining the point of origin, the explosive substance involved, and the charge mass. Within the EU FP7 project Hyperion, TNO developed the Inverse Explosion Analysis (TNO-IEA) tool to estimate the charge mass and point of origin based on observed damage around an explosion. In this paper, inverse models are presented based on two frequently occurring and reliable sources of information: window breakage and building damage. The models have been verified by applying them to the Enschede firework disaster and the Khobar tower attack. Furthermore, a statistical method has been developed to combine the various types of data, in order to determine an overall charge mass distribution. In relatively open environments, like for the Enschede firework disaster, the models generate realistic charge masses that are consistent with values found in forensic literature. The spread predicted by the IEA tool is however larger than presented in the literature for these specific cases. This is also realistic due to the large inherent uncertainties in a forensic analysis. The IEA-models give a reasonable first order estimate of the charge mass in a densely built urban environment, such as for the Khobar tower attack. Due to blast shielding effects which are not taken into account in the IEA tool, this is usually an under prediction. To obtain more accurate predictions, the application of Computational Fluid Dynamics (CFD) simulations is advised. The TNO IEA tool gives unique possibilities to inversely calculate the TNT equivalent charge mass based on a large variety of explosion effects and observations. The IEA tool enables forensic analysts, also those who are not experts on explosion effects, to perform an analysis with a largely reduced effort. PMID- 25933425 TI - Forces transmission to the skull in case of mandibular impact. AB - BACKGROUND: Forensic investigations have been reported regarding the loss of consciousness and cardiac arrests resulting from direct mandible impact. However, the mechanisms by which the forces are transferred to the skull through direct mandible impact remain unclear. We conducted a study regarding direct mandible impact on the level of energy required to create a mandible fracture and on the energy dispersion phenomenon to the skull and to the brain. MATERIALS AND METHODS: This study combines an experimental and numerical approach. Mandible strike was studied using experimental trials performed on post-mortem human subjects. A finite element model of the head and face of a male was also developed based on tomodensitometry scans. The model was validated with literature data and experimental trials. A parametric study was then performed to study the effect of diverse variables such as the dentition integrity, cortical bone thickness, etc. RESULTS: The forces measured on our reference model were 3000 N on the chin, 1800 N at the condyles, and 970 N in the occiput. Of all the results, we observed a decrease of approximately one-third of the efforts from the chin to the base of the skull and a lower half of the still forces at the occiput, except in the edentulous and for the lateral and frontal impact where the force is transmitted directly to the skull base area. CONCLUSION: This study allowed us to create a 3D model of the mandible and face bones to better understand the force transfer mechanisms into and from the mandible. The parameters of the model may be modified to suit the individual characteristics for forensic investigations and legal matters. PMID- 25933426 TI - New developmental data for Cynomya mortuorum (L., 1761) in Belgium (Diptera: Calliphoridae). AB - The calliphorid Cynomya mortuorum (L., 1761) is a forensically important species mainly found in the Palearctic region. Knowledge about its biology and ecology is scarce. Thermal constants as well as developmental time were studied at constant and variable regimes of 5 average temperatures: 14, 16, 18, 20 and 22 degrees C, respectively. Total developmental time varied between 15.82+/-0.40 days at 22 degrees C and 28.67+/-2.38 days at 14 degrees C, for the constant regime, and between 16.05+/-0.67 days at 22 degrees C and 32.79+/-1.77 days at 14 degrees C, for the variable regime. No significant differences were observed between ADD, and threshold at the constant (ADD: 277.39+/-14.78 DD; lower threshold: 4.72 degrees C) and variable regimes (275.99+/-14.16 DD; lower threshold: 5.05 degrees C). PMID- 25933427 TI - An investigation into the enhancement of sea-spray exposed fingerprints on glass. AB - Fingerprints are considered one of the best forms of personal identification. While numerous enhancement techniques exist to develop fingerprints under various conditions, the enhancement of fingerprints exposed to sea spray aerosol (SSA) still remains problematic. 1056 fingerprints from four donors, using a depletion series and triplicate repeats, were deposited onto glass panels and exposed to SSA for 1 week and 1 month. Control prints were deposited in the same manner and left under laboratory conditions. All prints were enhanced using fingerprint enhancement techniques available to Forensic Police Officers and subsequently examined for identifiability by a Fingerprint Expert. Significantly fewer identifiable prints (p<0.01) were developed after exposure to SSA for 1 month (11%) compared to exposure for 1 week (69%) (compared to the control prints 99%) for all enhancement techniques. After 1 week's exposure, all techniques enhanced over 50% of prints, except SPR white (12%), with iron (III) oxide and WetwopTM white producing over 90% identifiable prints. Only iron (III) oxide, WetwopTM white and SPR black returned any identifiable prints following 1 month's SSA exposure. Iron (III) oxide being significantly better (p<0.01, 67%) than the other techniques. Iron (III) oxide suspension and WetwopTM white were found to be superior at enhancing prints at both SSA exposure times. PMID- 25933428 TI - Predicting human genetic interactions from cancer genome evolution. AB - Synthetic Lethal (SL) genetic interactions play a key role in various types of biological research, ranging from understanding genotype-phenotype relationships to identifying drug-targets against cancer. Despite recent advances in empirical measuring SL interactions in human cells, the human genetic interaction map is far from complete. Here, we present a novel approach to predict this map by exploiting patterns in cancer genome evolution. First, we show that empirically determined SL interactions are reflected in various gene presence, absence, and duplication patterns in hundreds of cancer genomes. The most evident pattern that we discovered is that when one member of an SL interaction gene pair is lost, the other gene tends not to be lost, i.e. the absence of co-loss. This observation is in line with expectation, because the loss of an SL interacting pair will be lethal to the cancer cell. SL interactions are also reflected in gene expression profiles, such as an under representation of cases where the genes in an SL pair are both under expressed, and an over representation of cases where one gene of an SL pair is under expressed, while the other one is over expressed. We integrated the various previously unknown cancer genome patterns and the gene expression patterns into a computational model to identify SL pairs. This simple, genome-wide model achieves a high prediction power (AUC = 0.75) for known genetic interactions. It allows us to present for the first time a comprehensive genome wide list of SL interactions with a high estimated prediction precision, covering up to 591,000 gene pairs. This unique list can potentially be used in various application areas ranging from biotechnology to medical genetics. PMID- 25933429 TI - Health providers' perceptions of clinical trials: lessons from Ghana, Kenya and Burkina Faso. AB - BACKGROUND: Clinical trials conducted in Africa often require substantial investments to support trial centres and public health facilities. Trial resources could potentially generate benefits for routine health service delivery but may have unintended consequences. Strengthening ethical practice requires understanding the potential effects of trial inputs on the perceptions and practices of routine health care providers. This study explores the influence of malaria vaccine trials on health service delivery in Ghana, Kenya and Burkina Faso. METHODS: We conducted: audits of trial inputs in 10 trial facilities and among 144 health workers; individual interviews with frontline providers (n=99) and health managers (n=14); and group discussions with fieldworkers (n=9 discussions). Descriptive summaries were generated from audit data. Qualitative data were analysed using a framework approach. RESULTS: Facilities involved in trials benefited from infrastructure and equipment upgrades, support with essential drugs, access to trial vehicles, and placement of additional qualified trial staff. Qualified trial staff in facilities were often seen as role models by their colleagues; assisting with supportive supervision and reducing facility workload. Some facility staff in place before the trial also received formal training and salary top-ups from the trials. However, differential access to support caused dissatisfaction, and some interviewees expressed concerns about what would happen at the end of the trial once financial and supervisory support was removed. CONCLUSION: Clinical trials function as short-term complex health service delivery interventions in the facilities in which they are based. They have the potential to both benefit facilities, staff and communities through providing the supportive environment required for improvements in routine care, but they can also generate dissatisfaction, relationship challenges and demoralisation among staff. Minimising trial related harm and maximising benefits requires careful planning and engagement of key actors at the outset of trials, throughout the trial and on its' completion. PMID- 25933430 TI - Immunization against the Spread of Rumors in Homogenous Networks. AB - Since most rumors are harmful, how to control the spread of such rumors is important. In this paper, we studied the process of "immunization" against rumors by modeling the process of rumor spreading and changing the termination mechanism for the spread of rumors to make the model more realistic. We derived mean-field equations to describe the dynamics of the rumor spread. By carrying out steady state analysis, we derived the spreading threshold value that must be exceeded for the rumor to spread. We further discuss a possible strategy for immunization against rumors and obtain an immunization threshold value that represents the minimum level required to stop the rumor from spreading. Numerical simulations revealed that the average degree of the network and parameters of transformation probability significantly influence the spread of rumors. More importantly, the simulations revealed that immunizing a higher proportion of individuals is not necessarily better because of the waste of resources and the generation of unnecessary information. So the optimal immunization rate should be the immunization threshold. PMID- 25933431 TI - Integrative Analysis of Normal Long Intergenic Non-Coding RNAs in Prostate Cancer. AB - Recently, large numbers of normal human tissues have been profiled for non-coding RNAs and more than fourteen thousand long intergenic non-coding RNAs (lincRNAs) are found expressed in normal human tissues. The functional roles of these normal lincRNAs (nlincRNAs) in the regulation of protein coding genes in normal and disease biology are yet to be established. Here, we have profiled two RNA-seq datasets including cancer and matched non-neoplastic tissues from 12 individuals from diverse demography for both coding genes and nlincRNAs. We find 130 nlincRNAs significantly regulated in cancer, with 127 regulated in the same direction in the two datasets. Interestingly, according to Illumina Body Map, significant numbers of these nlincRNAs display baseline null expression in normal prostate tissues but are specific to other tissues such as thyroid, kidney, liver and testis. A number of the regulated nlincRNAs share loci with coding genes, which are either co-regulated or oppositely regulated in all cancer samples studied here. For example, in all cancer samples i) the nlincRNA, TCONS_00029157, and a neighboring tumor suppressor factor, SIK1, are both down regulated; ii) several thyroid-specific nlincRNAs in the neighborhood of the thyroid-specific gene TPO, are both up-regulated; and iii) the TCONS_00010581, an isoform of HEIH, is down-regulated while the neighboring EZH2 gene is up-regulated in cancer. Several nlincRNAs from a prostate cancer associated chromosomal locus, 8q24, are up-regulated in cancer along with other known prostate cancer associated genes including PCAT-1, PVT1, and PCAT-92. We observe that there is significant bias towards up-regulation of nlincRNAs with as high as 118 out of 127 up-regulated in cancer, even though regulation of coding genes is skewed towards down-regulation. Considering that all reported cancer associated lincRNAs (clincRNAs) are biased towards up-regulation, we conclude that this bias may be functionally relevant. PMID- 25933432 TI - A 1-Cys Peroxiredoxin from a Thermophilic Archaeon Moonlights as a Molecular Chaperone to Protect Protein and DNA against Stress-Induced Damage. AB - Peroxiredoxins (Prxs) act against hydrogen peroxide (H2O2), organic peroxides, and peroxynitrite. Thermococcus kodakaraensis KOD1, an anaerobic archaeon, contains many antioxidant proteins, including three Prxs (Tk0537, Tk0815, and Tk1055). Only Tk0537 has been found to be induced in response to heat, osmotic, and oxidative stress. Tk0537 was found to belong to a 1-Cys Prx6 subfamily based on sequence analysis and was named 1-Cys TkPrx. Using gel filtration chromatography, electron microscopy, and blue-native polyacrylamide gel electrophoresis, we observed that 1-Cys TkPrx exhibits oligomeric forms with reduced peroxide reductase activity as well as decameric and dodecameric forms that can act as molecular chaperones by protecting both proteins and DNA from oxidative stress. Mutational analysis showed that a cysteine residue at the N terminus (Cys46) was responsible for the peroxide reductase activity, and cysteine residues at the C-terminus (Cys205 and Cys211) were important for oligomerization. Based on our results, we propose that interconversion between different oligomers is important for regulating the different functions of 1-Cys TkPrx. PMID- 25933433 TI - Protein Degradation of RNA Polymerase II-Association Factor 1(PAF1) Is Controlled by CNOT4 and 26S Proteasome. AB - The PAF complex (PAFc) participates in various steps of the transcriptional process, from initiation to termination, by interacting with and recruiting various proteins to the proper locus for each step. PAFc is an evolutionarily conserved, multi-protein complex comprising PAF1, CDC73, CTR9, LEO1, yRTF1 and, in humans, hSKI8. These components of PAFc work together, and their protein levels are closely interrelated. In the present study, we investigated the mechanism of PAF1 protein degradation. We found that PAF1 protein levels are negatively regulated by the expression of CNOT4, an ortholog of yNOT4 and a member of the CCR4-NOT complex. CNOT4 specifically controls PAF1 but not other components of PAFc at the protein level by regulating the polyubiquitination of PAF1 and its subsequent degradation by the 26S proteasome. The degradation of PAF1 was found to require nuclear localization, as no PAF1 degradation by CNOT4 and the 26S proteasome was observed with NLS (nucleus localization signal) deficient PAF1 mutants. However, chromatin binding by PAF1 was not necessary for 26S proteasome- or CNOT4-mediated degradation. Our results suggest that CNOT4 controls the degradation of chromatin-unbound PAF1 via the 26S proteasome. PMID- 25933434 TI - Regulation of Active DNA Demethylation by a Methyl-CpG-Binding Domain Protein in Arabidopsis thaliana. AB - Active DNA demethylation plays crucial roles in the regulation of gene expression in both plants and animals. In Arabidopsis thaliana, active DNA demethylation is initiated by the ROS1 subfamily of 5-methylcytosine-specific DNA glycosylases via a base excision repair mechanism. Recently, IDM1 and IDM2 were shown to be required for the recruitment of ROS1 to some of its target loci. However, the mechanism(s) by which IDM1 is targeted to specific genomic loci remains to be determined. Affinity purification of IDM1- and IDM2- associating proteins demonstrated that IDM1 and IDM2 copurify together with two novel components, methyl-CpG-binding domain protein 7 (MBD7) and IDM2-like protein 1 (IDL1). IDL1 encodes an alpha-crystallin domain protein that shows high sequence similarity with IDM2. MBD7 interacts with IDM2 and IDL1 in vitro and in vivo and they form a protein complex associating with IDM1 in vivo. MBD7 directly binds to the target loci and is required for the H3K18 and H3K23 acetylation in planta. MBD7 dysfunction causes DNA hypermethylation and silencing of reporter genes and a subset of endogenous genes. Our results suggest that a histone acetyltransferase complex functions in active DNA demethylation and in suppression of gene silencing at some loci in Arabidopsis. PMID- 25933435 TI - Aging of TiO2 Nanoparticles Transiently Increases Their Toxicity to the Pelagic Microcrustacean Daphnia magna. AB - During their aquatic life cycle, nanoparticles are subject to environmentally driven surface modifications (e.g. agglomeration or coating) associated with aging. Although the ecotoxicological potential of nanoparticles might be affected by these processes, only limited information about the potential impact of aging is available. In this context, the present study investigated acute (96 h) and chronic (21 d) implications of systematically aged titanium dioxide nanoparticles (nTiO2; ~90 nm) on the standard test species Daphnia magna by following the respective test guidelines. The nTiO2 were aged for 0, 1, 3 and 6 d in media with varying ionic strengths (Milli-Q water: approx. 0.00 mmol/L and ASTM: 9.25 mmol/L) in the presence or absence of natural organic matter (NOM). Irrespective of the other parameters, aging in Milli-Q did not change the acute toxicity relative to an unaged control. In contrast, 6 d aged nTiO2 in ASTM without NOM caused a fourfold decreased acute toxicity. Relative to the 0 d aged particles, nTiO2 aged for 1 and 3 d in ASTM with NOM, which is the most environmentally relevant setup used here, significantly increased acute toxicity (by approximately 30%), while a toxicity reduction (60%) was observed for 6 d aged nTiO2. Comparable patterns were observed during the chronic experiments. A likely explanation for this phenomenon is that the aging of nTiO2 increases the particle size at the start of the experiment or the time of the water exchange from <100 nm to approximately 500 nm, which is the optimal size range to be taken up by filter feeding D. magna. If subjected to further agglomeration, larger nTiO2 particles, however, cannot be retained by the daphnids' filter apparatus ultimately reducing their ecotoxicological potential. This non-linear pattern of increasing and decreasing nTiO2 related toxicity over the aging duration, highlights the knowledge gap regarding the underlying mechanisms and processes. This understanding seems, however, fundamental to predict the risks of nanoparticles in the field. PMID- 25933437 TI - Wurtzite Cu2GeS3 Nanocrystals: Phase- and Shape-Controlled Colloidal Synthesis. AB - The first colloidal synthesis of Cu2 GeS3 (CGS) nanocrystals with a thermodynamically metastable wurtzite crystal phase is reported. As a benefit of the sulfur precursors used in the synthesis, the shape of the as-synthesized wurtzite CGS nanocrystals can be controlled in the form of spherical nanoparticles, nanorectangles, and hollow nanorectangles. A detailed investigation into the effects of reaction conditions necessary to obtain phase pure wurtzite CGS nanocrystals is presented. The choice of sulfur precursor and precursor injection temperature play a significant role in determining the crystal phase of the CGS nanocrystals. The band gap of the new wurtzite phase CGS was measured to be 1.76 eV and the CGS nanocrystals exhibited a good electrochemical photoresponse, which was indicative of their potential application as an active layer in the field of solar cells. PMID- 25933436 TI - Novel Non-Peptide Inhibitors against SmCL1 of Schistosoma mansoni: In Silico Elucidation, Implications and Evaluation via Knowledge Based Drug Discovery. AB - Schistosomiasis is a major endemic disease known for excessive mortality and morbidity in developing countries. Because praziquantel is the only drug available for its treatment, the risk of drug resistance emphasizes the need to discover new drugs for this disease. Cathepsin SmCL1 is the critical target for drug design due to its essential role in the digestion of host proteins for growth and development of Schistosoma mansoni. Inhibiting the function of SmCL1 could control the wide spread of infections caused by S. mansoni in humans. With this objective, a homology modeling approach was used to obtain theoretical three dimensional (3D) structure of SmCL1. In order to find the potential inhibitors of SmCL1, a plethora of in silico techniques were employed to screen non-peptide inhibitors against SmCL1 via structure-based drug discovery protocol. Receiver operating characteristic (ROC) curve analysis and molecular dynamics (MD) simulation were performed on the results of docked protein-ligand complexes to identify top ranking molecules against the modelled 3D structure of SmCL1. MD simulation results suggest the phytochemical Simalikalactone-D as a potential lead against SmCL1, whose pharmacophore model may be useful for future screening of potential drug molecules. To conclude, this is the first report to discuss the virtual screening of non-peptide inhibitors against SmCL1 of S. mansoni, with significant therapeutic potential. Results presented herein provide a valuable contribution to identify the significant leads and further derivatize them to suitable drug candidates for antischistosomal therapy. PMID- 25933438 TI - Hypercondensation of an amino acid: synthesis and characterization of a black glycine polymer. AB - A granular material was obtained by thermal polymerization of glycine at 200 degrees C. It has been named "thermomelanoid" because of its strikingly deep black color. The polymerization process is mainly a dehydration condensation leading to conventional amide bonds, and also C?C double bonds that are formed from C?O and CH2 groups ("hypercondensation"). Spectroscopic data, in particular from (13) C and (15) N solid-state cross-polarization magic angle spinning (CP MAS) NMR spectra, suggest that the black color is due to (cross-)conjugated C?C, C?O, and NH groups. Small glycine peptides, especially triglycine, appear to be key intermediates in the formation of the thermomelanoid. This has been concluded by comparing the thermal behavior of glyn homopeptides (n=2-6) and glycine. The glycine polymerization was accompanied by the formation of small amounts of byproducts. Notably, a few percent of alanine and aspartic acid could be detected in the polymer. By using (13) C-labeled glycine, it was shown that these two amino acids formed through a common pathway, namely Calpha?Calpha bond formation between glycine molecules. The thermomelanoid is hydrolyzed by strong acids and bases at room temperature, forming brown solutions. PMID- 25933439 TI - 11th Annual Conference of the International Society for the Prevention of Tobacco Induced Diseases (ISPTID). PMID- 25933440 TI - Transverse false tendons in the left ventricular cavity are associated with early repolarization. AB - BACKGROUND: Left ventricular false tendons (LVFTs) are related to precordial murmurs, ventricular arrhythmias and some repolarization abnormalities. Early repolarization (ER) is a specific type of repolarization abnormality. OBJECTIVE: The aim of the present study was to investigate the relationship between LVFTs and ER. METHODS: This study retrospectively included 99 consecutive healthy subjects and 33 patients with ER. Early repolarization was defined as an elevation of the QRS-ST junction of >0.1 mV from baseline in at least 2 inferior or lateral leads, manifested as QRS slurring or notching. Each participant was examined using echocardiography with second harmonic imaging, and the attachments of the LVFTs were recorded. RESULTS: A total of 93 LVFTs were present in 82 (83%) of the 99 healthy subjects. Of these 93 LVFTs, the majority (79/93, or 84.9%) were longitudinal-type LVFTs, which originated from the basal interventricular septum (IVS) and progressed toward the apical segment of the left ventricular free wall. There were significant differences in the positioning of the LVFTs between the ER patients and control (P < 0.0001). LVFTs between mid-IVS to the middle of the LV free wall were found more common in patients with ER compared with control subjects (47.5% vs. 6.5%, P < 0.0001). In the ER group, LVFTs between the basal IVS to the apical segment of LV free wall were only identified in 21% of the LVFTs, compared to a value of 84.9% for the control group (P < 0.0001). The distribution of LVFT trends in the ER group was also significantly different from that in the control group (P < 0.05). CONCLUSIONS: LVFTs are commonly visualized using echocardiography. An LVFT from the basal IVS to the apical segment of the left ventricular free wall may be a normal anatomical structure in the left ventricular cavity. On the contrary, transverse false tendons in the left ventricular cavity may be associated with ER. PMID- 25933441 TI - Performance Analysis of Elite Female Amateur Boxers and Comparison With Their Male Counterparts. AB - Female boxing debuted at the 2012 London Olympic Games. To better understand the performance aspects of the sport, video footage of eighteen 4 * 2-min bouts were analyzed. The boxers involved in the competition were of an elite level (mean +/- SD), age 26.4 +/- 4.6 y, height 169.3 +/- 6.2 cm, and weight 60.3 +/- 10.0 kg. Analysis revealed an activity rate of ~1.6 actions/s, including ~16 punches, ~3.3 defensive movements, and ~63 vertical hip movements, all per minute, over the 4 * ~132-s rounds (R). A 2 * 4 (outcome * round) ANOVA with repeated measures over the rounds was used to analyze the data. Winners maintained a higher activity rate in round 1 (R1) and R2; a higher movement rate in R2, R3, and R4; and an increased punch accuracy including the ratio of total punches to punches landed in R3 and air punches as a percentage of punches missed in R1 and R3. Specific techniques that discriminate between successful and unsuccessful female amateur boxers include the straight rear-hand and body punches, higher for winners in R1, as well as uppercut punches and defensive foot movements, higher for winners in R4. Findings highlight the current demands of elite amateur female boxing. These data will be useful for those designing training programs and may also be useful for guiding sport-specific fitness testing. PMID- 25933442 TI - Maternal intake of fat in pregnancy and offspring metabolic health - A prospective study with 20 years of follow-up. AB - BACKGROUND: Maternal fat intake during pregnancy in relation to offspring metabolic outcomes has been studied primarily in animal models, yet little is known about the association in humans. The aim of this study was to examine the association of total and subtype of fat consumption in pregnancy with anthropometric measures and biomarkers of adiposity and glucose metabolism in the offspring. METHODS: A source population was 965 Danish pregnant women recruited in 1988-1989 with offspring follow-up at 20 years. Information on fat intake was collected in the 30(th) week of gestation, and we subdivided fat according to saturated (SFA), monounsaturated (MUFA), and polyunsaturated (PUFA) fat. Offspring body mass index (BMI) and waist circumference (WC) were recorded at follow-up (n = 670-678), and biomarkers were quantified in a subset (n = 443) of participants. Multivariable linear and log-binomial regression were used to calculate effect estimates and 95% CI for a 1:1%energy substitution of carbohydrates for fat. RESULTS: The mean (standard deviation) BMI was 22.1 (3.3) and 22.8 (2.9) kg/m(2) in female and male offspring, respectively. The median (10th to 90th percentile) of maternal fat intake was 31% of energy [23,39]. We found no overall associations for maternal fat intake with female offspring anthropometry. However, for male offspring higher intake of MUFA during pregnancy was associated with higher insulin levels at 20 years (Q4 vs. Q1: %Delta: 37, 95% CI: 1, 86) accompanied by a non-significant 3.6 (95% CI: -1.1, 8.2) cm increase in WC. High maternal total fat intake (>=35% energy) was also associated with higher BMI (0.9, 95% CI: 0.2, 1.6) and WC (4.0, 95% CI: 1.6, 2.3) among male offspring. CONCLUSIONS: A high fat diet during pregnancy may increase adiposity in adult male offspring. We surmise that maternal MUFA intake during this time included both MUFA and trans fat misclassified as MUFA, and that the associations observed may be more reflective of the latter exposure. PMID- 25933443 TI - Parenteral nutrition admixtures for pediatric patients compounded with highly refined fish oil-based emulsion: Assessment of physicochemical stability - Letter to Editor. PMID- 25933444 TI - Enhancement of endocannabinoid signaling protects against cocaine-induced neurotoxicity. AB - Cocaine is an addictive substance with a potential to cause deleterious effects in the brain. The strategies for treating its neurotoxicity, however, are limited. Evidence suggests that the endocannabinoid system exerts neuroprotective functions against various stimuli. Thus, we hypothesized that inhibition of fatty acid amide hydrolase (FAAH), the main enzyme responsible for terminating the actions of the endocannabinoid anandamide, reduces seizures and cell death in the hippocampus in a model of cocaine intoxication. Male Swiss mice received injections of endocannabinoid-related compounds followed by the lowest dose of cocaine that induces seizures, electroencephalographic activity and cell death in the hippocampus. The molecular mechanisms were studied in primary cell culture of this structure. The FAAH inhibitor, URB597, reduced cocaine-induced seizures and epileptiform electroencephalographic activity. The cannabinoid CB1 receptor selective agonist, ACEA, mimicked these effects, whereas the antagonist, AM251, prevented them. URB597 also inhibited cocaine-induced activation and death of hippocampal neurons, both in animals and in primary cell culture. Finally, we investigated if the PI3K/Akt/ERK intracellular pathway, a cell surviving mechanism coupled to CB1 receptor, mediated these neuroprotective effects. Accordingly, URB597 injection increased ERK and Akt phosphorylation in the hippocampus. Moreover, the neuroprotective effect of this compound was reversed by the PI3K inhibitor, LY294002. In conclusion, the pharmacological facilitation of the anandamide/CB1/PI3K signaling protects the brain against cocaine intoxication in experimental models. This strategy may be further explored in the development of treatments for drug-induced neurotoxicity. PMID- 25933445 TI - Integrative analyses of miRNA and proteomics identify potential biological pathways associated with onset of pulmonary fibrosis in the bleomycin rat model. AB - To determine miRNAs and their predicted target proteins regulatory networks which are potentially involved in onset of pulmonary fibrosis in the bleomycin rat model, we conducted integrative miRNA microarray and iTRAQ-coupled LC-MS/MS proteomic analyses, and evaluated the significance of altered biological functions and pathways. We observed that alterations of miRNAs and proteins are associated with the early phase of bleomycin-induced pulmonary fibrosis, and identified potential target pairs by using ingenuity pathway analysis. Using the data set of these alterations, it was demonstrated that those miRNAs, in association with their predicted target proteins, are potentially involved in canonical pathways reflective of initial epithelial injury and fibrogenic processes, and biofunctions related to induction of cellular development, movement, growth, and proliferation. Prediction of activated functions suggested that lung cells acquire proliferative, migratory, and invasive capabilities, and resistance to cell death especially in the very early phase of bleomycin-induced pulmonary fibrosis. The present study will provide new insights for understanding the molecular pathogenesis of idiopathic pulmonary fibrosis. PMID- 25933447 TI - Transient Diabetes Insipidus Following Cardiopulmonary Bypass. AB - Diabetes insipidus (DI) results from inadequate output of Antidiuretic Hormone (ADH) from the pituitary gland (central DI) or the inability of the kidney tubules to respond to ADH (nephrogenic DI). ADH is an octapeptide produced in the supraoptic and paraventricular nuclei of the hypothalamus and stored in the posterior lobe of the pituitary gland. Cardiopulmonary Bypass (CPB) has been shown to cause a six-fold increased circulating ADH levels 12 hours after surgery. However, in some cases, ADH release may be transiently suppressed due to cardioplegia (cardiac standstill) or CPB leading to DI. We present the postoperative course of a 60-year-old man who developed transient DI after CPB. He was successfully treated by applying nasal desmopressin therapy. Relevant biochemical parameters should be monitored closely in patients who produce excessive urine after open heart surgery. PMID- 25933448 TI - A Giant Gastric Adenoma Embedded in the Duodenum. AB - Gastric adenomas are usually located in the antrum, or occasionally in the fundus of the stomach. Most adenomas are solitary, pedunculated mass. The report describes a 17-year girl who visited the emergency room with complaints of stabbing pain of upper abdomen, nausea, vomiting and melena for last one week. Emergency endoscopic examination revealed a giant polyp with a long about 15 cm pedicle embedded in the duodenum. The polyp was completely removed by surgery, about 15 x 3 x 4 cm in size. At 5-year follow-up by endoscopy and ultrasonography, the patient remained in good general condition. It emphasizes that giant gastric adenomas must be removed by endoscopy or surgery due to its potential of malignancy. It is necessary to follow-up for detecting early gastric neoplasm. PMID- 25933449 TI - Early, non-refractory celiac disease associated with microscopic colitis and splenomegaly. AB - Celiac Disease (CD), also known as non-Tropical sprue, and Celiac sprue is an immune-mediated disorder, triggered by gluten containing grains in genetically susceptible people. The disease may be diagnosed at any age and can affect many organ systems. Its diagnosis and management can often be challenging. A high index of suspicion is required to diagnose this disease at an early stage in patients presenting with atypical symptomatology and delayed onset. Although serological tests are widely used, duodenal biopsy remains the gold standard for diagnosis of CD. Even though CD affects various body systems, Microscopic Colitis (MC) and refractory sprue are among the main gastrointestinal complications of CD, which are resistant to Gluten-Free Diet (GFD). A thorough and appropriate evaluation is mandatory for an early and accurate diagnosis of these complications. Herein, we report a case of a young female with CD in early phase in concordance with MC and splenomegaly. PMID- 25933450 TI - Acute appendicitis after a prior appendicectomy: an unorthodox surgical paradox. AB - Acute appendicitis after prior appendicectomy is highly difficult to diagnose, especially in face of definite history of appendicectomy and presence of appendicectomy scar in the right iliac fossa. We are highlighting a case report of a 40 year old woman who despite having had appendicectomy 2 years back presented with severe abdominal pain in the right iliac fossa in association with anorexia, nausea, vomiting and low-grade pyrexia of one day duration. On the basis of clinical evaluation and haematological and radiological investigations, diagnosis of perforated appendicitis was made. After thorough counselling of the patient and relatives, re-exploration of the patient was performed after excision of previous appendicectomy scar. The appendix was found to be perforated with an extraluminal faecolith and purulent exudate in the right iliac fossa. Appendicectomy and local peritoneal lavage resulted in uneventful recovery of the patient. Histopathology of the specimen revealed acutely inflamed appendicitis. PMID- 25933451 TI - Anaesthetic consideration in a cannabis addict. AB - This case report describes the anaesthetic management of a patient addicted to Bhang(cannabis) for 20 years. Cannabis use has implication in the anaesthetic management of a patient because of its effects on the cardiovascular system, respiratory system, and central nervous system and its interaction with anaesthetic drugs. PMID- 25933452 TI - Jejunal diverticulosis presenting as an acute emergency. AB - Diverticulosis of jejunum is a relatively rare disease of bowel. Jejunal diverticula are false diverticula with projections of mucosa and serosa without the muscular layer. These manifest as diverticulitis, bleeding, perforation or intestinal obstruction. There should be a high index of suspicion when patients present with chronic central abdominal pain, malabsorption and anaemia. Sometimes they are just incidentally picked up on investigations. Laparoscopy can be valuable in diagnosis and treatment as most of the times jejunal diverticulosis can be treated conservatively with surgery required for generalized peritonitis and massive gastrointestinal bleeding. A 33-year man repeatedly presented to emergency with abdominal pain which resolved with analgesics until he developed constipation, vomiting, fever and severe abdominal pain. He had to undergo laparotomy which revealed multiple jejunal diverticula. Resection of the involved gut portion was done. The patient did fine postoperatively. PMID- 25933453 TI - Laparoscopic cholecystectomy for left sided gallbladder in situs inversus totalis. AB - Situs inversus totalis is a rare condition affecting intra abdominal and intra thoracic organs. Situs inversus usually remains asymptomatic. Life expectancy is normal in the absence of rare cardiac abnormalities. Left sided gallbladder can occur even without situs inversus totalis. Cholelithiasis is not more common in patients with situs inversus than the general population. However, these patients may pose a diagnostic difficulty. An ultrasound scan can confirm the presence of gallstones and the left-sided gallbladder. Here we present the case of a 40-year female with this diagnosis who was diagnosed on abdominal scanning and underwent laparoscopic cholecystectomy for left sided cholelithiasis. PMID- 25933454 TI - Spontaneous Idiopathic Unilateral Adrenal Haemorrhage (SIAH). AB - Spontaneous Idiopathic Adrenal Haemorrhage (SIAH) is an unusual surgical emergency which can present with life threatening massive retroperitoneal bleeding. Most of the cases reported in the literature are associated with use of anticoagulation or underlying adrenal pathology such as tumors or cysts. Since this clinical entity is uncommon and clinical presentation is very indistinct, the diagnosis can be easily missed and can be challenging for the treating physicians. Nevertheless a raised clinical suspicion coupled with advances in radiological imaging have considerably improved the detection of SIAH in recent times. We report an unusual case of a 20 years old healthy female student who presented to our hospital with sudden onset of abdominal pain and shock. She was diagnosed as a case of massive spontaneous idiopathic unilateral adrenal haemorrhage, unaccompanied by any hematologic disorder, trauma or underlying pathology. Although patient was hemodynamically unstable at presentation, she was resuscitated promptly, investigated appropriately, hence recovered uneventfully with conservative management alone. PMID- 25933455 TI - Rhinoscleroma of nose extruding into oral cavity. AB - Rhinoscleroma (RS) is a rare chronic granulomatous disease of the upper airways affecting nasal cavity, nasopharynx, and paranasal sinuses. Klebsiella rhinoscleromatis is the causative agent of this infection and Mikulicz cells are specific to this lesion. RS is commonly seen in poorer regions such as Central Africa, South America, Middle East, India and Indonesia. It is predominantly found in rural areas and people with poor socio-economic conditions. Most patients present with chronic rhinitis, sneezing, headache and deviated nasal septum similar to current case. An association with oral cavity has not been reported previously, as per authors' knowledge. This report describes a rare case of RS of nasal cavity extending into the oral cavity. PMID- 25933456 TI - Kikuchi's Disease: A Rare Cause of Fever of Unknown Origin. AB - Kikuchi Fujimoto Disease (KFD) or histiocytic necrotizing lymphadenitis can present with unexplained fever and lymphadenopathy. It is often mistaken for more serious conditions like malignant lymphoma or tuberculosis. First case was described by Kikuchi in Japan, very few cases have been reported in Pakistan. A middle aged female presented with fever and body aches for one month. She was investigated extensively for pyrexia of unknown origin, all of which came out to be normal except a raised ESR. Anti-tuberculous drugs were started on clinical suspicion, with no improvement after a month. Later, a detailed physical examination revealed cervical lymphadenopathy. One of the lymph nodes was excised and biopsied. The histopathology suggested Kikuchi's disease. Oral Prednisolone was started showing improvement. Her fever subsided and lymph nodes disappeared at the follow-up visit. No relapse was encountered in the subsequent visits. PMID- 25933457 TI - A Young Lady with Hypertension - Rare Presentation of a Common Disease. AB - Hypertension is a common finding in patients with renal impairment but it is frequently difficult to establish if one feature is the cause or the effect of the other. Even rarer is the identification of an underlying cause for hypertension or renal failure in such patients. We present a case of hypertension in a young lady as part of nephritic syndrome due to HCV associated essential mixed cryoglobulinemia. She presented with difficult to control hypertension and deranged renal functions. On detailed evaluation, she was found to have nephritic syndrome as part of essential mixed cryoglobulinemia. She tested positive for HCV RNA and underwent treatment with combination of standard interferon and ribavirin. All her symptoms were relieved with this treatment, HTN subsided and renal function tests returned to normal values. Her HCV RNA was negative at the end of treatment as well as 6 months later; confirming a sustained virological response. PMID- 25933458 TI - Recurrent Hypokalemic Periodic Paralysis Unmasks Sjogren Syndrome without Sicca Symptoms. AB - Hypokalemic Periodic Paralysis (HPP) may occur as a rare complication of Sjogren Syndrome (SS) and Renal Tubular Acidosis (RTA). A 64-year male patient came with HPP, and was later diagnosed with distal RTA. The patient, who had no xerostomia and xerophthalmia, was diagnosed with primary SS from serologic and histologic findings of minor salivary gland biopsy. The patient recovered after potassium replacement therapy. Renal biopsy was also performed and revealed evidence of tubulointerstitial nephritis. Corticosteroids were administered and there was no recurrence of HPP during a 4-year follow-up period. The case highlights the significance of acute hypokalemia management in emergency department as it can unmask SS even if the SS is not associated with sicca symptoms. Hypokalemic paralysis associated with normal anion gap metabolic acidosis should prompt toward the diagnosis of SS. PMID- 25933459 TI - Proptosis of eye: an atypical presentation of prostatic malignancy. AB - Orbital metastasis is a rare occurrence found only in about 3 - 10% of all prostate cancers. A 72 years male presented with proptosis of the left eye associated with pain, blurred vision and frequent headaches for the past 8 months. Past medical history had symptoms of bladder outflow obstruction for 3 years. MRI brain and orbit with contrast was consistent with a large soft tissue mass in the left frontal region. The mass was surgically excised in order to achieve palliation. Histopathology revealed poorly differentiated malignant neoplasm with immunohistochemistry favoring metastatic prostate carcinoma. Postoperative radiotherapy was administered with a palliative intent. CT scan identified an enlarged prostate with a nodular lesion, abdominal lymphadenopathy and soft tissue density lesion in the apical segment of left lung. Serum PSA level was 149 ug/L. Bone scan was also consistent with metastatic disease. PMID- 25933460 TI - Prevention of awareness by using bispectral index monitoring in a patient with history of awareness. AB - We describe a case in which risk of awareness was minimized by using bispectral index monitoring. The patient had a history of awareness in two previous surgeries. She was a 50-year obese female, known case of hypertension and acid peptic disease, with a history of hysterectomy and cholecystectomy performed 3 years and 2 years ago respectively, and gave a history of awareness in both operations. No details were available regarding the previous anaesthetic technique. PMID- 25933461 TI - Intrarenal neuroblastoma: a diagnostic challenge. AB - Abdominal masses in children are usually retroperitoneal in location and 50% are renal in origin. In infants less than 2 months, majority of renal masses are benign; frequency of malignancy increases with age. Wilms'tumor is the commonest solid intrarenal tumors. However, occasionally neuroblastoma occurs in the kidney. Neuroblastoma in 50% of cases presents before 2 years of age, and 75% before 4 years. Neuroblastomas can occur anywhere along the neuroectodermal sympathetic chain, although adrenal medulla is the commonest site (50 - 70%). Intrarenal neuroblastoma is a rare clinical diagnosis. It clinically and radiologically mimics Wilms'tumor and it is difficult to differentiate between the two preoperatively. Lung metastasis and vascular invasion are also rare in neuroblastoma but rather common in Wilms'tumor. We present case of a patient who had extensive renal involvement with neuroblastoma and pulmonary metastasis, clinically and radiologically it was difficult to differentiate between the Wilms'tumor and neuroblastoma. PMID- 25933462 TI - Partial Oculocutaneous Albinism: Two Siblings with Features of both Hermansky Pudlak and Waardenburg's Syndrome. AB - Albinism is an inherited abnormality of melanin synthesis with incidence of one per 20,000 births. Its clinical manifestations are related to the reduction or absence of pigmentation in the visual system and/or the skin and teguments. The clinical spectrum of Oculocutaneous Albinism (OCA) has four types ranging from OCA 1 - 4, of which OCA 1, A-1 is the most severe form. Partial cutaneous albinism which is a subtype of OCA is associated with systemic immunodeficiency disorders like Chediak Higashi (CHS), Griscelli (GS) and Hermansky-Pudlak (HPS) syndromes. A7 years boy was labeled initially as a case of Hermansky Pudlak syndrome at the age of 01 year. He as well as his 4 years old younger brother when examined in detail along with audiological investigations were diagnosed as a rare presentation of both Hermansky Pudlak and Waardenburg's syndrome. PMID- 25933463 TI - Bilateral choroidal neovascularization after pegylated interferon therapy. AB - A 30-year-old male presented with gradual decrease in vision in his both eyes after the use of interferon alpha for his hepatitis-C. Ocular examination of patient included, Best Corrected Visual Acuity (BCVA), fundus photographs, Fundus Fluorescein Angiography (FFA) and Optical Coherence Tomography (OCT). His BCVA was recorded as 6/18 in the right eye and 6/12 in the left eye. The anterior segments were unremarkable, with normal intraocular Pressure (IOP) in his both eyes. Both fundi revealed the presence of bilateral Choroidal Neovascularization (CNV), confirmed on FFA and OCT. To the best of authors' knowledge, simultaneous presence of CNV in both eyes is not reported in the literature. PMID- 25933464 TI - Ocular ischemic syndrome and ischemic optic neuropathy in Takayasu arteritis. AB - Ocular Ischemic Syndrome (OIS) is a disorder, which consists of constellation of signs and symptoms secondary to chronic ocular hypoperfusion. We report a case of 35 years old Pakistani female who presented to us with gradual fall of vision in both eyes. On examination, she had bilateral OIS and ischemic optic neuropathy. The patient had past history of transient ischemic attack and facial palsy almost 20 years back. We referred her to physician for the diagnosis of Takayasu arteritis associated with relapsing polychondritis. She was given 60 mg of dexamethasone per day as initial treatment. At her last follow-up after approximately 3 months, she was quite comfortable systemically and her general condition was improved. Unfortunately, her vision did not improve. These two autoimmune diseases are rarely reported together in the same patient in Pakistan. Whether this association is rare or is underdiagnosed still remains to be answered. PMID- 25933465 TI - Preservation of speech and swallowing after excision of a pharyngeal pouch tumour. AB - A pharyngeal pouch is not an uncommon cause of dysphagia in older population. However, finding a tumour in a pharyngeal pouch is very rare. A 79-year-old gentleman presented with dysphagia and a neck lump. Videofluoroscopy showed a pharyngeal pouch. Rigid endoscopy confirmed a tumour arising from the pharyngeal pouch. The histology showed it to be squamous cell carcinoma. The MRI scan based staging was T3N1M0. The patient underwent modified right radical neck dissection, partial pharyngectomy with primary repair and tracheostomy. He completed postoperative radiotherapy and remained disease-free at 4 years follow-up. PMID- 25933466 TI - Simultaneous giant hydatid cysts of brain and liver. AB - While hepatic hydatid cysts are most common in occurrence, intracranial hydatid cyst is less common. Simultaneous presence of both varieties is quite rare and poses a challenge for management in terms of involvement of multidisciplinary team and multiple interventions. An 8-year boy presented with neurological symptoms of a space occupying lesion. There was also hepatomegaly. Radiological investigations revealed giant hydatid cysts involving left cerebral hemisphere and left lobe of liver. Cerebral hydatid cyst was operated first by pediatric neurosurgeons. After 10 days of stabilization period, hepatic lesion was removed by pediatric surgeons. Patient showed uneventful recovery and discharged on oral albendazole for 6 months. There was no recurrence at follow-up. PMID- 25933467 TI - Meckel-Gruber Syndrome with unilateral renal agenesis. AB - Meckel-Gruber Syndrome (MKS) is an autosomal recessive disorder, characterized by a combination of central nervous system malformation (occipital encephalocele), post-axial polydactyly, and enlarged polycystic kidney dysplasia. With a recurrence risk of 25% this lethal syndrome can be detected in early screening by ultrasound. However, to the authors' knowledge, association of MKS with unilateral renal agenesis was reported only once until now. Here, we describe a case of 26-year primigravida with 23 weeks pregnancy whose detailed sonographical examination of the fetus revealed large encephalocele through the posterior fontanelle microcephaly, anhydramnios, unilateral left enlarged polycystic kidney and right sided renal agenesis. The pregnancy was wilfully terminated on medical grounds. Risk for subsequent pregnancies was explained to the parents. PMID- 25933468 TI - A Rare Disorder with Common Clinical Presentation: Neonatal Bartter Syndrome. AB - Bartter syndrome is an autosomal recessive renal tubulopathy that presents with hypokalemic, hypochloremic metabolic alkalosis associated with increased urinary loss of sodium, potassium, calcium and chloride. There is hyperreninemia and hyperaldosteronemia but normotension. A full term male neonate was referred at 20 day of age with features of sepsis and respiratory distress. He was evaluated and managed as case of septicemia with all supportive paraphernalia including mechanical ventilation. Investigations revealed electrolytes imbalance and metabolic alkalosis suggestive of Neonatal Bartter Syndrome (NBS). Raised aldosterone and renin levels confirmed the diagnosis. Electrolyte imbalance was corrected with fluids and indomethacin, treated successfully, discharged and parents counseled. He was thriving well at 9 months of age. Another 2 months old male baby presented with recurrent episodes of lethargy with dehydration and failure to gain weight. Investigations confirmed the diagnosis of NBS. He was also successfully treated with same medication. We report these 2 cases because of the rarity of NBS, presentation of which may mimic common illnesses like sepsis and gastroenteritis. PMID- 25933469 TI - Brugada Syndrome: An Electrical Storm without Warning. AB - Brugada Syndrome (BrS) is an inherited channelopathy causing sodium channel dysfunction in cardiac myocyte. These patients are prone to develop Ventricular Fibrillation (VF) or polymorphic Ventricular Tachycardia (VT). Next to coronary artery disease and cardiomyopathies, BrS is an important cause of sudden cardiac death. We report here a case of 22 year unmarried female with "unexplained" cardiac arrest without prior history of syncope and family history of sudden cardiac death. She was resuscitated out of hospital in some local dispensary in rural settings and after prolonged hypoxia with its neurological sequelae, she eventually died. BrS should be considered in differentials of unexplained cardiac arrest even in patients without family history of sudden cardiac death. First episode of VT/VF in BrS patients can be life threatening. Only prompt cardioversion / defibrillation can save life. We have suggested some measures to identify patients of BrS. PMID- 25933470 TI - An Integrated Approach for Cosmetic Rehabilitation of a Patient with Atrophia bulbi. AB - Atrophia bulbiis a small, shrunken, non-functional eye, most commonly due to trauma. It represents an ocular end-stage disease characterized by atrophy, shrinkage, and disorganization of the eyeball and intraocular contents, demonstrating the result of failed previous ocular therapy in which restoration of the morphologic and functional integrity of the eye is not possible. Majority of the patients with Atrophia bulbi eventually become blind and cosmetically unacceptable. The rehabilitation of such patients presents a challenging clinical situation, as the patient has already been clouded by the psychological distress. This paper demonstrates a case of 35-year male with Atrophia bulbi, who was successfully rehabilitated with precisely fabricated ocular prosthesis fitted over the atrophic eye. PMID- 25933471 TI - Pedicled on-top plasty for thumb reconstruction: utilization of proximal phalanx of an injured ring finger. AB - Thumb has a critical role in the hand function. It is the most important digit for pinching and grasping. Therefore, thumb amputation demands its replantation or reconstruction to restore the hand functions. A case of hand injury which involved multiple digits along with amputation of thumb is reported. The thumb had amputation level just distal to Metacarpophalangeal joint (MPj) along with amputation of other 3 fingers at different levels. Proximal phalanx of ring finger based on palmar vessels was utilized for on-top plasty to build thumb post and restore hand function. On-top plasty for thumb is quite useful, dependable, easier, time saving option which does not increase the morbidity associated with other options of thumb reconstruction. It may especially be a very useful option for the centres lacking the facility and equipment for micro-vascular surgeries and expertise of the trained micro-vascular surgeons. PMID- 25933472 TI - Protective Role of G6PD Deficiency in Aluminium Phosphide Poisoning. AB - A 15-year-old boy was referred to the hospital from the periphery with a history of ingestion of 5 wheat pills (aluminium phosphide) 5 days back. He had been given a stomach wash in his village hospital prior to referral. On arrival, he was jaundiced and had developed haematuria too, but otherwise appeared well in himself. Four days after admission, his haemoglobin showed a marked drop and he was shifted to intensive care, keeping in mind the high mortality rate associated with aluminium phosphide intoxication. His G6PD levels were checked, and he turned out to be G6PD deficient. The patient was given intravenous magnesium sulphate and supportive care and he improved subsequently. Wheat pill poisoning carries a high mortality of 98% in some cases; despite the high mortality, this patient survived. This may mean that G6PD deficiency has a protective role in poisoning due to aluminium phosphide. PMID- 25933473 TI - Successful tricuspid valvectomy in a septic patient with tricuspid valve endocarditis. AB - Endocarditis is characterized by vegetations, which is a mass of platelets, fibrin, micro-colonies of micro-organisms, and inflammatory cells, in the endocardium. Over the past three decades, the incidence of right-sided endocarditis has risen dramatically in Pakistan. We report a 36-year woman with a history of repeated intravenous analgesic injections for low back pain, presenting with high grade fever, sepsis and a white cell count of 44,000 with 90% neutrophils. Echocardiography showed large mobile vegetations on Tricuspid Valve (TV). Tricuspid Valve Endocarditis (TVE) is generally responsive to medical treatment; however, about 25% of TVE patients require surgical intervention. Long term survival of a patient is possible without a prosthetic TV replacement, particularly if the pulmonary artery pressure is normal. PMID- 25933474 TI - Association between direct measurement of active serum calcium and risk of type 2 diabetes mellitus: A prospective study. AB - BACKGROUND AND AIMS: Previous prospective studies showing a positive association between serum calcium and incidence of type 2 diabetes mellitus (T2DM) have relied on total calcium or an indirect estimate of active, ionized calcium (iCa). We aimed to assess this relationship using a direct measurement of iCa. METHODS AND RESULTS: iCa and cardiometabolic risk factors were measured in a population based sample of 2350 men without a known history of T2DM at baseline. Associations between iCa levels and incident cases of T2DM (self-reported, ascertained with a glucose tolerance test, or determined by record linkage to national registers) were estimated using Cox regression analyses adjusted for potential confounders. At baseline, mean (standard deviation) age was 53 (5) years and mean iCa 1.18 (0.05) mmol/L. During a median follow-up of 23.1 years, 140 new cases of T2DM were recorded. In a multivariable analysis adjusted for age, body mass index, systolic blood pressure, serum HDL-cholesterol, and family history of T2DM, there was no association comparing second (hazard ratio 0.84; 95% confidence interval 0.59-1.18), third (0.77; 0.52-1.14), or fourth (0.98; 0.69-1.39) vs first quartile of iCa (p for trend 0.538); further adjustment for C reactive protein, physical activity level, and triglycerides did not change the estimates (p for trend 0.389). CONCLUSION: In this study, we did not find evidence of an association between direct measurement of active calcium and risk of T2DM. Further studies are needed to confirm our findings and define the relationship between factors influencing indirect calcium estimation and incident T2DM. PMID- 25933475 TI - Effects of Carotid Endarterectomy on Cerebral Reperfusion and Cognitive Function in Patients with High Grade Carotid Stenosis: A Perfusion Weighted Magnetic Resonance Imaging Study. AB - OBJECTIVE: To investigate the influence of carotid endarterectomy (CEA) on cerebral perfusion and cognitive function in patients with internal carotid artery stenosis (ICA). METHODS: Patients were prospectively enrolled in this study. Shunted patients were excluded. Cerebral perfusion was measured by magnetic resonance (MR) perfusion weighted imaging (PWI) and diffusion weighted imaging (DWI) in 46 patients with >65% ICA (31 males, 64.5 +/- 6.7 years) 1 week before and 6 weeks after CEA. Cognitive function was assessed using the Mini Mental State Examination (MMSE) and the Montreal Cognitive Assessment (MoCA) 1 week before and 6 weeks after CEA. RESULTS: After CEA, perfusion parameters from PWI decreased, including mean transit time (MTT) (21.07 +/- 7.36 vs. 14.27 +/- 6.22, p < .0001), time to peak (TTP) (28.69 +/- 8.54 vs. 23.45 +/- 4.25, p = .001), arrive time (T0) (19.89 +/- 7.32 vs. 15.20 +/- 3.51, p = .001), and relative cerebral blood volume (rCBV) (11.48 +/- 3.50 vs. 7.53 +/- 3.17, p < .0001). A significant improvement was observed in MoCA (20.48 +/- 1.70 vs. 22.04 +/- 1.48, p = .001). Spearman's rank correlation analysis between TTP and MoCA scores demonstrated a linear relationship with an excellent correlation coefficient (R = -.893, p < .001). Linear regression indicated that diabetes was a risk factor for cognitive improvement in patients with ICA (p = .014). Further analysis showed that patients with DM performed worse in MoCA after the procedure (with-DM 21.15 +/- 1.28 vs. non-DM 22.4 +/- 1.46, p = .010) while the baselines were similar (non-DM: 20.3 +/- 1.8 vs. with-DM: 20.9 +/- 1.4, p = .362). CONCLUSION: CEA could improve the cerebral perfusion and the cognitive function in un-shunted ICA patients. Cerebral reperfusion was an important factor for cognitive improvement. Diabetes had a negative effect on cognitive improvement after CEA. PMID- 25933476 TI - Re: 'Efficacy and Safety of the New Oral Anticoagulants Dabigatran, Rivaroxaban, Apixaban, and Edoxaban in the Treatment and Secondary Prevention of Venous Thromboembolism: A Systematic Review and Meta-analysis of Phase III Trials'- Key Learning Points for Surgeons. PMID- 25933477 TI - Benefits of using culturally unfamiliar stimuli in ambiguous emotion identification: A cross-cultural study. AB - A novel emotion recognition task that employs photos of a Japanese mask representing a highly ambiguous stimulus was evaluated. As non-Asians perceive and/or label emotions differently from Asians, we aimed to identify patterns of task-performance in non-Asian healthy volunteers with a view to future patient studies. The Noh mask test was presented to 42 adult German participants. Reaction times and emotion attribution patterns were recorded. To control for emotion identification abilities, a standard emotion recognition task was used among others. Questionnaires assessed personality traits. Finally, results were compared to age- and gender-matched Japanese volunteers. Compared to other tasks, German participants displayed slowest reaction times on the Noh mask test, indicating higher demands of ambiguous emotion recognition. They assigned more positive emotions to the mask than Japanese volunteers, demonstrating culture dependent emotion identification patterns. As alexithymic and anxious traits were associated with slower reaction times, personality dimensions impacted on performance, as well. We showed an advantage of ambiguous over conventional emotion recognition tasks. Moreover, we determined emotion identification patterns in Western individuals impacted by personality dimensions, suggesting performance differences in clinical samples. Due to its properties, the Noh mask test represents a promising tool in the differential diagnosis of psychiatric disorders, e.g. schizophrenia. PMID- 25933478 TI - Which unmet needs contribute to behavior problems in persons with advanced dementia? AB - The Unmet Needs Model states that problem behaviors of people with dementia result from unmet needs stemming from a decreased ability to communicate those needs and to provide for oneself. The purpose of this study is to describe the unmet needs of persons with dementia exhibiting behavior problems. Eighty-nine residents with dementia from six Maryland nursing homes were assessed by research assistants and nursing assistants for their unmet needs using multiple assessment tools. Three unmet needs per resident were identified on average, with informants rating boredom/sensory deprivation, loneliness/need for social interaction, and need for meaningful activity as the most prevalent needs. Discomfort was associated with higher levels of verbally agitated behaviors (e.g., complaining). Based on results and independent ratings of pain, the authors estimate notable under-detection of discomfort and pain by both types of informants. The study demonstrates methodologies for uncovering unmet needs among persons with dementia and highlights the importance of developing programs that address those unmet needs, especially social and activity needs of nursing home residents. The detection of pain, and possibly that of discomfort, may require a different methodology. PMID- 25933479 TI - Human emotion in the brain and the body: Why language matters: Comment on "The quartet theory of human emotions: An integrative and neurofunctional model" by S. Koelsch et al. PMID- 25933480 TI - Dynamic fluctuations in single-molecule biophysics experiments: Comment on "Extracting physics of life at the molecular level: A review of single-molecule data analyses" by W. Colomb and S.K. Sarkar. PMID- 25933481 TI - On the role of language from basic to cultural modulation of affect: Comment on "The quartet theory of human emotions: An integrative and neurofunctional model" by S. Koelsch et al. PMID- 25933482 TI - Disentangling complex emotions with structured neurophysiological models: Comment on "The quartet theory of human emotions: An integrative and neurofunctional model" by S. Koelsch et al. PMID- 25933483 TI - Phosphatidylserine and the human brain. AB - OBJECTIVE: The aim of this study was to assess the roles and importance of phosphatidylserine (PS), an endogenous phospholipid and dietary nutrient, in human brain biochemistry, physiology, and function. METHODS: A scientific literature search was conducted on MEDLINE for relevant articles regarding PS and the human brain published before June 2014. Additional publications were identified from references provided in original papers; 127 articles were selected for inclusion in this review. RESULTS: A large body of scientific evidence describes the interactions among PS, cognitive activity, cognitive aging, and retention of cognitive functioning ability. CONCLUSION: Phosphatidylserine is required for healthy nerve cell membranes and myelin. Aging of the human brain is associated with biochemical alterations and structural deterioration that impair neurotransmission. Exogenous PS (300-800 mg/d) is absorbed efficiently in humans, crosses the blood-brain barrier, and safely slows, halts, or reverses biochemical alterations and structural deterioration in nerve cells. It supports human cognitive functions, including the formation of short-term memory, the consolidation of long-term memory, the ability to create new memories, the ability to retrieve memories, the ability to learn and recall information, the ability to focus attention and concentrate, the ability to reason and solve problems, language skills, and the ability to communicate. It also supports locomotor functions, especially rapid reactions and reflexes. PMID- 25933484 TI - Healthy food subsidies and unhealthy food taxation: A systematic review of the evidence. AB - The Global Burden of Disease Study and related studies report unhealthy diet is the leading risk for death and disability globally. Given the evidence associating diet and non-communicable diseases (NCDs), international and national health bodies including the World Health Organization and United Nations have called for population health interventions to improve diet as a means to target NCDs. One of the proposed interventions is to ensure healthy foods/beverages are more accessible to purchasers and unhealthy ones less accessible via fiscal policy, namely taxation and subsidies. The objective of this systematic review was to evaluate the evidence base to assess the effect of healthy food/beverage subsidies and unhealthy food/beverage taxation. A comprehensive review was conducted by searching PubMed, Medline, and Google Scholar for peer-reviewed publications and seventy-eight studies were identified for inclusion in this review. This review was performed in keeping with Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidance. Although moderate in quality, there was consistent evidence that taxation and subsidy intervention influenced dietary behaviors. The quality, level and strength of evidence along with identified gaps in research support the need for further policies and ongoing evaluation of population-wide food/beverage subsidies and taxation. To maximize success and effect, this review suggests that food taxes and subsidies should be a minimum of 10 to 15% and preferably used in tandem. Implementation of population-wide polices for taxation and subsides with ongoing evaluation of intended and unintended effects are supported by this review. PMID- 25933485 TI - Yogurt for treating antibiotic-associated diarrhea: Systematic review and meta analysis. AB - OBJECTIVE: Antibiotic-associated diarrhea (AAD) is a common complication in individuals treated with antibiotics. The aim of this review was to systematically evaluate the efficacy of yogurt consumption for the prevention of AAD. METHODS: In this systematic review, a number of databases including MEDLINE, EMBASE, and the Cochrane Library, with no language restrictions, were searched up to September 2014 for randomized controlled trials (RCTs) evaluating the effect of yogurt consumption in adults and children who were receiving antibiotics. The risk for bias was assessed using the Cochrane risk of bias tool. RESULTS: Two RCTs, both low in methodological quality, were included. Compared with no intervention, yogurt consumption reduced the risk for diarrhea in the fixed effect model (two RCTs, n = 314, relative risk [RR], 0.56; 95% confidence interval [CI], 0.31-1.00). Significant heterogeneity between the trials was detected (I(2) = 67%). The significant reduction in the risk for diarrhea was lost in the random effects model (RR, 0.45; 95% CI, 0.11-1.75). CONCLUSIONS: Given the simple nature of the intervention, the scarcity of data is noteworthy. No consistent effect of yogurt consumption for preventing AAD was shown. However, the data are limited and the included trials had methodological limitations. Results from large, rigorously designed RCTs are needed to assess the effect of yogurt consumption on AAD prevention. PMID- 25933486 TI - Vitamin D status is a determinant of skeletal muscle mass in obesity according to body fat percentage. AB - OBJECTIVES: Vitamin D deficiency is now being recognized as an emerging problem worldwide. Obesity has been found to be associated with lower serum 25 hydroxyvitamin D [25(OH)D] concentrations due to various mechanisms. There is increasing evidence showing the extraskeletal health benefit of vitamin D. Previous studies demonstrated the relationship between vitamin D and adiposity. However, the association between vitamin D status and skeletal muscle mass has not been established in healthy obese individuals in tropical countries. The aim of this cross-sectional study was to assess vitamin D status and its relationship to serum 25(OH)D concentrations and body composition, including skeletal muscle mass (SMM) and adiposity in healthy obese individuals without diabetes who live in Thailand, which is located near the equator. METHODS: We enrolled 163 obese Thai individuals (59.5% women) from the obesity clinic at the Ramathibodi Hospital, Mahidol University, in Bangkok, Thailand. RESULTS: The prevalence of vitamin D deficiency (<20 ng/mL) and vitamin D inadequacy (<30 ng/mL) were 49 (30.1%) and 148 (90.8%), respectively. In all, 98% of the individuals with body mass index >35 kg/m(2) had vitamin D inadequacy. Serum 25(OH)D concentrations were negatively associated with percent body fat (%BF) (r = -0.23; P = 0.003). Moreover, vitamin D status was positively associated with SMM (r = 0.18; P = 0.03) and the association remained after controlling for body fat mass and age (P = 0.003). Interestingly, in the individuals with lowest tertile of %BF, multiple linear regression analysis revealed that the significant positive predictors of %SMM were vitamin D status and male sex; the negative predictor was the body mass index after adjusting for age and exercise duration. CONCLUSIONS: Our study demonstrated the high prevalence of vitamin D deficiency in obese, Thai populations without diabetes. Vitamin D status was an independent predictor of %SMM of patients with lowest tertile of %BF. We speculated that adiposity might play a role in the relationship of vitamin D and SMM. PMID- 25933487 TI - Disrupted fatty acid distribution in HDL and LDL according to apolipoprotein E allele. AB - OBJECTIVES: Omega-3 polyunsaturated fatty acid (omega-3 PUFA) metabolism seems to be disrupted in carriers of the epsilon 4 allele of apolipoprotein E (E4+). The objective of this study was to investigate whether the omega-3 PUFA distribution in the high and low density lipoproteins is APOE-genotype dependant before and after supplementation with omega-3 PUFAs. METHODS: Eighty participants, aged between 20 and 35 y old were recruited and supplemented with 900 mg of eicosapentaenoic acid plus 680 mg of docosahexaenoic acid for 4 wk. Over the 4-wk intervention, blood samples were collected and HDL and LDL particles were obtained using sucrose gradient ultracentifugation. Fatty acid profiles of the HDL and LDL fractions were performed by gas chromatography. RESULTS: Baseline anthropometric characteristics of participants were not significantly different between the two APOE-groups (E4+, N = 10; E4-, N = 70). At baseline, in the LDL of E4+ subjects, the omega-6/omega-3 PUFA ratio was 17% higher than E4- subjects. At week 4, the omega-6/omega-3 PUFA ratio was significantly higher in the LDL of E4+ than E4- subjects. There was a significant genotype * time interaction for 16:0 in HDL and LDL and for 18:2 omega-6 in HDL. DHA in the HDL was positively correlated to HDL-C levels pre- and postsupplementation in E4- only. CONCLUSIONS: Contrary to what we anticipated, omega-3 PUFAs content? in HDL and LDL were not APOE isoform-dependant in young participants. However, young E4+ participants already had a tendency toward lower baseline-DHA levels in LDL particles as well as a more atherogenic omega-6/omega-3 PUFA ratio in LDL pre- and post supplementation. PMID- 25933488 TI - Maternal vitamin A supplementation increases natural antibody concentrations of preadolescent offspring in rural Nepal. AB - OBJECTIVE: B1a lymphocytes-which constitutively produce most natural antibodies (NAb)-arise from an early wave of progenitors unique to fetal life. Vitamin A regulates early lymphopoiesis. In animals, deficiency during this critical period compromises B1 cell populations. The aim of this study was to investigate the effect of maternal supplementation with vitamin A or beta-carotene from preconception through lactation on NAb concentrations of offspring. METHODS: Participants (N = 290) were born to participants of a cluster-randomized, placebo controlled trial of weekly maternal vitamin A or beta-carotene supplementation (7000 MUg retinol equivalents) conducted in Sarlahi, Nepal (1994-1997) and assessed at ages 9 to 13 y (2006-2008). Serum retinol was measured by reversed phase high-performance liquid chromatography at mid-pregnancy and 3 mo of age. Enzyme-linked immunosorbent assay (ELISA) was used to measure children's plasma NAb concentrations at 9 to 13 y. RESULTS: Unadjusted geometric mean concentrations were 20.08 U/mL (95% confidence interval [CI], 17.82-22.64) in the vitamin A group compared with 17.64 U/mL (95% CI, 15.70-19.81) and 15.96 U/mL (95% CI, 13.43-18.96) in the beta-carotene and placebo groups (P = 0.07), respectively. After adjustment, maternal vitamin A supplementation was associated with a 0.39 SD increase in NAb concentrations (P = 0.02). The effect was mediated by infant serum retinol in our statistical models. Although girls had 1.4-fold higher NAb concentrations (P < 0.001), sex did not modify the vitamin A effect. CONCLUSIONS: In an undernourished population, maternal vitamin A supplementation enhanced NAb concentrations of preadolescent children. We posit that this was due to a greater allotment of B1a precursors during fetal life and a sustained higher count of NAb-secreting B1a cells. PMID- 25933489 TI - Characterization of metabolically healthy obese Brazilians and cardiovascular risk prediction. AB - OBJECTIVE: The aim of this study was to identify metabolically healthy obese individuals (MHOs) and their characteristics, as well as to estimate cardiovascular risk using the Framingham score. METHOD: In all, 258 adult individuals, with body mass index >=30 kg/m(2), and no report of diabetes mellitus or cardiovascular disease, were classified according to their metabolic state considering two criteria: rhe National Cholesterol Education Program-Adult Treatment Panel III (NCEP-ATP III) and the homeostasis model assessment (HOMA). Biochemical, anthropometric, and body composition characteristics were compared between MHOs and metabolically unhealthy obese (MUO) individuals according to each criterion. Cardiovascular risk was estimated using the Framingham score. RESULTS: MHOs exhibited smaller waist circumference and lower body fat percentage, as well as lower blood glucose, triacylglycerols, and insulin levels, in addition to higher high-density lipoprotein cholesterol concentration, when HOMA criterion (P < 0.05) and associated criteria were adopted. The estimated cardiovascular risk was similar between the two groups according to the HOMA index; however, the risk was significantly lower according to the ATP III guidelines. Obese individuals at intermediate and high risk showed higher body fat percentage compared with those individuals at low risk. CONCLUSIONS: MHOs had biochemical and anthropometric characteristics, such as lower body mass index, waist circumference, percent fat mass, glucose, triacylglycerols, and increased high-density lipoprotein, that made them different from those individuals classified as MUO. The latter exhibited increased risk for cardiovascular disease according to the Framingham score, when using the ATP III criterion alone or in conjunction with the HOMA index. PMID- 25933490 TI - Effects of extra virgin olive oil and fish oil on lipid profile and oxidative stress in patients with metabolic syndrome. AB - OBJECTIVE: The aim of this study was to verify if extra virgin olive oil and fish oil have a synergistic effect on lipid and oxidative stress parameters in patients with metabolic syndrome (MetS). METHODS: This intervention study included 102 patients (81 women and 21 men) with MetS (mean age 51.45 +/- 8.27 y) from the ambulatory center of the University Hospital of Londrina, Parana, Brazil. Patients were randomly assigned to one of four groups: Patients in the control group (CG) were instructed to maintain their usual diet; the second group (fish oil group [FO]) received 3 g/d of fish oil omega-3 fatty acids (10 capsules); the third group (extra virgin olive oil group [OO]) received 10 mL/d of extra virgin olive oil at lunch and dinner; and the fourth group (fish oil and extra virgin olive oil group [FOO]) received 3 g/d of fish oil omega-3 fatty acids and 10 mL/d of extra virgin olive oil. MetS related markers and oxidative stress were measured at baseline and after 90 d. RESULTS: Differences across treatment groups showed a statistically significant decrease (P < 0.05) in total cholesterol (TC) and low-density lipoprotein cholesterol (LDL-C) when FOO was compared with CG and OO, respectively. Hydroperoxides showed a significant decrease (P < 0.05) when FOO was compared with CG, whereas there was an increase in total peroxyl radical-trapping antioxidant potential/advanced oxidation protein products (TRAP/AOPP; P < 0.05) in FOO when compared with FO. In relation to baseline values, there was a significant decrease (P < 0.05) in LDL-C values, and TC/high-density lipoprotein cholesterol (HDL-C) and LDL-C/HDL-C indexes in FOO. There was also a decrease (P < 0.05) in hydroperoxides, in AOPP and in AOPP/TRAP index in FOO, and an increase (P < 0.05) in TRAP/AOPP index in FOO and in TRAP/uric acid ratio in OO. CONCLUSION: The present study provides evidence that increased dietary omega-3 polyunsaturated fatty acids and extra virgin olive oil have beneficial synergistic effects on lipid metabolism and oxidative stress in patients with MetS. PMID- 25933491 TI - Low intake of calcium and vitamin D, but not zinc, iron or vitamin A, is associated with stunting in 2- to 5-year-old children. AB - OBJECTIVES: This cross-sectional study examined the nutritional factors associated with the high levels of stunting in 2- to 5-y-old children in an impoverished South African setting where liver is frequently eaten and vitamin A deficiency known to be absent. METHODS: Children's dietary intake was assessed by a single 24-h recall. Heights and weights were measured and information was obtained on breast-feeding history, the child's habitual milk intake, as well as substance use by the mother during pregnancy (n = 150). RESULTS: The overall prevalence of stunting was 36.9% (CI 29.2, 44.6) and increased with age, being 49% in the 4- to 5-y-old age category. Birth weight correlated significantly with height-for-age z-scores (HAZ; r = 0.250, P = 0.003), and was lower in children whose mothers smoked and used alcohol during pregnancy than in children whose mothers abstained (P < 0.0001). Median intake of energy, carbohydrate and protein was adequate. Median intake for all micronutrients was at least 90% of the estimated average requirement, except for calcium, vitamin D and vitamin E, which was 21%, 15%, and 32%, respectively. Intake of fat, calcium, phosphorous, vitamin D, riboflavin, and vitamin B12 (nutrients that typically occur in milk) was significantly lower in stunted than in non-stunted children (P < 0.05). When excluding children with low birth weight, intake of calcium, vitamin D, and riboflavin were still significantly lower (P < 0.05). HAZ was higher in children who habitually drank milk compared to those who did not (P = 0.003). CONCLUSIONS: Inadequate calcium and vitamin D intake, presumably because of low intake of milk after weaning, may have contributed to stunting in this population. PMID- 25933492 TI - Habitual high intake of fatty fish is related to lower levels of F2-isoprostane in healthy women. AB - OBJECTIVE: The aim of this study was to determine whether habitual dietary intake of fatty fish, whole grains, fruits and vegetables, or a combination of them all, is associated with oxidative stress levels, measured as urine concentration of 8 iso-prostaglandin F2alpha (8-iso-PGF2alpha) in healthy women. METHODS: Eighty-one participants were included in this cross-sectional study. Mean age of the women was 26.1 +/- 6.2 (mean +/- SD) years and mean body mass index (BMI) was 22.4 +/- 3.0 kg/m(2). The concentration of 8-iso-PGF2alpha was determined in urine, and eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) levels were determined in blood. Participants' habitual fish, whole grain, fruit, and vegetable intake was estimated from a food frequency questionnaire. RESULTS: In the multivariate analysis, there was a significant inverse association between 8-iso-PGF2alpha and high fatty fish intake (P < 0.001). Fatty fish intake was positively correlated to serum phospholipid concentrations of EPA (P = 0.001) and DHA (P = 0.002). A borderline effect of DHA was seen on 8-iso-PGF2alpha, but higher serum phospholipid concentrations of fatty acids were generally not related to lower F2 isoprostane levels. No overall effect from whole grains or fruits and vegetables was seen. CONCLUSIONS: The results indicate that high intake of fatty fish is related to lower levels of oxidative stress, but high levels of omega-3 fatty acids in intake may not alone explain the effect. High habitual intake of whole grains or fruits and vegetables did not seem to affect the F2-isoprostane level. PMID- 25933494 TI - Nutrient intake in neurofibromatosis type 1: A cross-sectional study. AB - OBJECTIVES: To evaluate nutrient intake among adult neurofibromatosis type 1 (NF1) patients. METHODS: A cross-sectional study of 60 NF1 patients (29 men, 31 women) who were >=18 y old and were evaluated from September 2012 to September 2013 in a neurofibromatosis outpatient reference center. Patients underwent nutritional assessment, including anthropometric and dietary data collection. Food intake was evaluated using three, non-consecutive, self-reported 24-h dietary recall surveys, and nutrient intake was analyzed according to the recommendations of the dietary reference intake document. RESULTS: Forty-three patients (72%) recorded energy consumption lower than the estimated daily energy requirement (EER). Men (25/29, 86.2%) were more likely to fail to meet their target EER, compared to women (18/31, 58.1%) (P = 0.016). Inadequate intake of vitamin D, magnesium, calcium, and pyridoxine was noted between men and women, and all patients consumed excess sodium. NF1 patients did not consume adequate amounts of fiber or vitamins A and C. Excessive consumption of saturated fatty acids and lipids was also observed in both male and female patients. CONCLUSIONS: In this study, NF1 patients consumed an unhealthy diet that was rich in fats and sodium and lacking in fiber, vitamins, and minerals. Further studies are needed to investigate the role of these dietary and nutritional patterns in the severity of the clinical manifestations of NF1. PMID- 25933493 TI - Supplementation of alpha-linolenic acid improves serum adiponectin levels and insulin sensitivity in patients with type 2 diabetes. AB - OBJECTIVE: omega-3 Polyunsaturated alpha-linolenic acid (ALA) supplementation has not been studied in the setting of adiponectin levels and insulin sensitivity (IS) improvements in patients with type 2 diabetes mellitus (T2DM) by hyperinsulinemic-euglycemic clamp (HEC). The aim of this study was to examine the influence of omega-3 ALA on IS and adiponectin. METHODS: We conducted a randomized study in patients with T2DM and assessed IS using HEC. Twenty patients with T2DM were included and randomly assigned to receive 3 g/d of ALA or placebo for 60 d, in a double-blind design. The assessment of IS by HEC was performed at baseline and after 60 d in all patients; blood samples were taken for the measurement of serum lipids, glucose, insulin, adiponectin, and cytokines. The primary outcome variables were an increase of both glucose infusion rate (GIR) in steady state and glucose metabolization (M) by HEC. The secondary outcomes were an increase in adiponectin levels and a decrease in fasting plasma glucose, glycated hemoglobin, homeostasis model assessment-estimated insulin resistance (HOMA-IR) index, lipids and cytokines. The study was conducted at an academic medical center. RESULTS: The ALA group improved IS corrected for fat-free mass (M/FFM; P = 0.04). Both groups showed increased adiponectin after 60 d (P = 0.01), however, the increase for the ALA group was greater (P = 0.04). In the ALA group, adiponectin was positively correlated with GIR (r = 0.76; P = 0.01) and M/FFM (r = 0.62; P = 0.06), and negatively correlated with HOMA-IR (r = -0.61; P = 0.03). CONCLUSION: omega-3 ALA supplementation improved glucose homeostasis and was associated with an increase in adiponectin. Improvement in the overall metabolic profile with omega-3 ALA suggests a potential clinical utility for this agent and requires further investigation. PMID- 25933495 TI - Postprandial adiponectin and gelatinase response to a high-fat versus an isoenergetic low-fat meal in lean, healthy men. AB - OBJECTIVE: Evidence suggests that an acute systemic inflammatory response is invoked after consumption of a high-energy meal. Postprandial regulation of adiponectin, an adipose tissue-derived, anti-inflammatory hormone, and the gelatinases, matrix metalloproteinase (MMP)-2 and MMP-9, endopeptidases implicated in a diverse range of inflammatory processes, remain inconclusive. The aim of this study was to assess the postprandial effect of a high-energy (1212 kcal) meal on plasma adiponectin, MMP-2 and MMP-9 activity, glucose, insulin, triacylglycerols, total cholesterol, high-density lipoprotein cholesterol, and the differential effects on these parameters depending on whether the test meal was high fat (HF; 46 g fat, 1210 kcal) or isoenergetic and low fat (LF; 15 g fat, 1214 kcal energy). METHODS: Test meals were consumed by 17 lean, healthy men on two separate occasions with blood samples collected by venipuncture at baseline (0 h) and 1 and 3 h after consumption of each test meal. RESULTS: At baseline, no significant difference was seen in the parameters between the two groups, except for MMP-2, MMP-9, and total cholesterol. Over the 3-h postprandial period, no significant differential effect of the HF versus the LF test meal was observed on adiponectin, MMP-2, MMP-9, or on metabolic markers other than triacylglycerol, which increased significantly in response to the HF test meal (time * treatment, P = 0.002). When analyzed independent of time, MMP-2 (treatment, P = 0.006), MMP 9 (treatment, P = 0.022), and glucose (treatment, P = 0.026) were lower after consumption of the HF meal compared with the LF test meal. When analyzed independent of treatment, adiponectin increased over the 3-h postprandial period (time, P = 0.031), but there was no change in MMP-2 or MMP-9 (time, P = 0.503 and P = 0.525, respectively). Over the 3-h postprandial period, insulin (time, P < 0.001) and total cholesterol (time, P = 0.002) increased, whereas glucose (time, P < 0.001) and high-density lipoprotein cholesterol (time, P < 0.001) decreased. CONCLUSION: No differential effects of a HF versus a LF isoenergetic meal were seen on postprandial adiponectin or the gelatinases. Adiponectin increased in response to a high-energy meal independent of treatment, and the gelatinases were lower in response to the HF versus the LF isoenergetic meal, independent of time point. Given the considerable amount of time that humans spend in the postprandial state, additional research is necessary to further understand inflammatory changes in this state. PMID- 25933496 TI - Fructose-induced metabolic syndrome decreases protein expression and activity of intestinal P-glycoprotein. AB - OBJECTVES: Metabolic syndrome (MetS) is a health disorder that increases the risk for cardiovascular complications such as heart disease and type 2 diabetes. Some drugs used in patients with MetS are substrates of intestinal P-glycoprotein (P gp), one of the most important efflux pumps that limit the absorption of xenobiotics. Thus, their bioavailability could be affected by changes in this transporter. Because one of the major causes of MetS in humans is excessive sugar intake, the aim of this study was to evaluate the effect of a fructose-rich diet on intestinal P-gp activity and protein expression in male Sprague-Dawley rats. METHODS: Fructose-drinking animals received standard chow and 15% (w/v) fructose in the drinking water over 8 wk; control rats were fed on standard chow and tap water. RESULTS: Ileal protein expression of P-gp was 50% lower in fructose drinking rats than in control animals. This reduction was confirmed by immunofluorescence microscopy. These results correlated well with the decrease of about 50% in the transport rate of the substrate rhodamine 123 in everted intestinal sacs. Finally, an increase of 62% in the intestinal absorption of digoxin, a P-gp substrate used as therapeutic drug, was observed in vivo, in fructose-drinking animals. CONCLUSION: The present study demonstrated that MetS like conditions generated by enhanced fructose intake in rats decreased the protein expression and activity of ileal P-gp, thus increasing the bioavailability of P-gp substrates. PMID- 25933497 TI - ChREBP binding and histone modifications modulate hepatic expression of the Fasn gene in a metabolic syndrome rat model. AB - OBJECTIVE: Although the expression of hepatic lipogenic genes is enhanced in insulin resistance, the underlying mechanism is unclear. To reveal the details, the aim of this study was to investigate whether the expression of hepatic lipogenic genes are mediated by epigenetic regulation and specific transcription factors in an insulin resistance model of rats. METHODS: Using a rat model of insulin resistance (SHR/NDmc-cp), we investigated the relationship between hepatic expression of the lipogenic gene fatty-acid synthase (Fasn), binding of the transcription factor carbohydrate-responsive element-binding protein (ChREBP) to the Fasn gene, and histone modifications in the region of the Fasn gene by real-time reverse transcriptase polymerase chain reaction, immunoblotting, and chromatin immunoprecipitation assay. RESULTS: Compared with control rats, Fasn mRNA expression and protein levels were higher in the livers of SHR/NDmc-cp rats, as were protein expression levels and Fasn binding of ChREBP and RNA polymerase II. Moreover, compared with the livers of control rats, levels of mono-methylated histone H3 lysine (K) 4 and acetylated histone H4 were higher in the promoter/enhancer region of the Fasn gene in the livers of SHR/NDmc-cp rats. Levels of trimethylated histone H3K4 and acetylated histone H3 were higher in the transcribed region. CONCLUSION: The results of this study indicate that expression of the Fasn gene in the livers of insulin-resistant rats is associated with increased H3K4 methylation, increased histone H3 acetylation, and increased H4 acetylation, and also, binding levels of ChREBP to promoter/enhancer region of Fasn gene is involved in the Fasn gene expression caused by hyperglycemia. PMID- 25933498 TI - Oral supplementation with L-glutamine alters gut microbiota of obese and overweight adults: A pilot study. AB - OBJECTIVE: The aim of this study was to determine whether oral supplementation with L-glutamine (GLN) modifies the gut microbiota composition in overweight and obese adults. METHODS: Thirty-three overweight and obese adults, ages between 23 and 59 y and body mass index between 25.03 and 47.12 kg/m(2), were randomly assigned to receive either oral supplementation with 30 g of L-alanine (ALA group control) or 30 g of GLN (GLN group) daily for 14 d. We analyzed the gut microbiota composition with new-generation sequencing techniques and bioinformatics analysis. RESULTS: After 14 d of supplementation, adults in the GLN group exhibited statistically significant differences in the Firmicutes and Actinobacteria phyla compared with those in the ALA group. The ratio of Firmicutes to Bacteroidetes, a good biomarker for obesity, decreased in the GLN group from 0.85 to 0.57, whereas it increased from 0.91 to 1.12 in the ALA group. At the genus level, Dialister, Dorea, Pseudobutyrivibrio, and Veillonella, belonging to the Firmicutes phylum, had statistically significant reduction. CONCLUSION: Oral supplementation with GLN, for a short time, altered the composition of the gut microbiota in overweight and obese humans reducing the Firmicutes to Bacteroidetes ratio, which resembled weight loss programs already seen in the literature. PMID- 25933499 TI - Niacin metabolism and indoleamine 2,3-dioxygenase activation in malnourished patients with flaky paint dermatosis. AB - Flaky paint dermatosis, characterized by extensive, often bilateral areas of flaking and pigmentation, mostly in sun unexposed areas is considered a feature of kwashiorkor in both children and adults, and must be differentiated from other dermatosis, including chapped and xerotica skin, and pellagra. In this case series we provide evidence that malnourished patients with flaky paint dermatosis and infection/inflammation shown laboratory data suggestive of indoleamine 2,3 dioxygenase (IDO) activation, besides decreased urinary excretion of N1 methylnicotinamide (N1 MN), a marker of pellagra. We study nine adult patients showing flaky paint dermatosis and clinical features of infection or inflammation, and increased serum C-reactive protein, characteristic of the presence of acute phase response syndrome. As a group, they had low or deficient urinary N1 MN excretion (0.52 +/- 0.39 mg/g creatinine) compatible with pellagra. They also showed low serum tryptophan levels (<29 MUmol/L) and a serum kynurenine/tryptophan ratio higher than 0.04, suggesting increased IDO expression and increase in the tryptophan oxidation. Findings suggest that some patients with flaky paint dermatosis showed laboratory data suggestive of IDO activation, besides decreased N1 MN urinary excretion. Taken together, the data support the idea that flaky paint dermatosis could be a skin manifestation of niacin deficiency. PMID- 25933500 TI - A glance at ... exercise and glucose uptake. PMID- 25933502 TI - Vitamin E therapy on aminotransferase levels in NAFLD/NASH patients. PMID- 25933501 TI - Vitamin E therapy for NAFLD/NASH. PMID- 25933503 TI - Time course of appropriate implantable cardioverter-defibrillator therapy and implications for guideline-based driving restrictions. AB - BACKGROUND: American Heart Association/Heart Rhythm Society recommendations restrict driving in implantable cardioverter-defibrillator patients for 6 months after implant for secondary prevention or primary prevention with an appropriate therapy (antitachycardia pacing or shock) for ventricular arrhythmias (VA). OBJECTIVE: The purpose of this study was to analyze implantable cardioverter defibrillator therapy data to inform guideline recommendations on driving. METHODS: The OMNI Registry was queried for VA and assessed for the time course of appropriate therapies. A blind events committee adjudicated events. The Kaplan Meier method was used to estimate event rates. A 7-day blanking period was used for each event of interest. RESULTS: A total of 2262 patients (mean age 67 +/- 12 years; mean left ventricular ejection fraction 28%) were enrolled; 1659 (73%) were men, and 1666 (74%) were implanted for primary prevention. Overall, 628 of 2255 patients (28%) received >=1 appropriate therapy. The probability of receiving a subsequent appropriate therapy increased and occurred in a shorter time interval with each appropriate therapy. At 6 months, the likelihood of receiving a shock when the first VA was terminated by shock (30.0%) was 3 times the risk when the first VA was terminated by antitachycardia pacing (9.9%). CONCLUSION: Each appropriate VA therapy is associated with an increased risk of a subsequent event that occurs, on average, in a time frame shorter than current guideline-based restrictions. A differential risk of shock is noted in those receiving antitachycardia pacing vs shock for the first appropriate VA. These findings may help to inform future clinical guideline and practice decisions related to driving. PMID- 25933504 TI - Hemodynamically significant atrial septal defect after atrial fibrillation ablation: A hole to remember. PMID- 25933505 TI - Generation of multi-innervated dendritic spines as a novel mechanism of long-term memory formation. AB - NMDA receptor-dependent long-term potentiation (LTP) at hippocampal CA1 synapses is a well-accepted mechanism underlying long-term memory (LTM) formation. However, studies with mice that lack threonine-286 autophosphorylation of alphaCaMKII have shown that hippocampal LTM can be formed despite absence of NMDA receptor-dependent CA1 LTP. After multiple training trials, LTM formation in these mutants is linked to the generation of multi-innervated dendritic spines (MIS), a spine that receives typically two presynaptic inputs. PSD-95 overexpression is sufficient for MIS generation and depends on mTOR signaling. LTM that involves MIS generation appears less modifiable upon retrieval in comparison to LTM without MIS generation. Taken together, MIS generation appears to be a novel LTM mechanism after multiple training trials, which may occur in diseases with impaired LTP or conditions affecting negative feedback CaMKII signaling at the synapse. PMID- 25933506 TI - Replay of conditioned stimuli during late REM and stage N2 sleep influences affective tone rather than emotional memory strength. AB - Emotional memories are reprocessed during sleep, and it is widely assumed that this reprocessing occurs mainly during rapid eye movement (REM) sleep. In support for this notion, vivid emotional dreams occur mainly during REM sleep, and several studies have reported emotional memory enhancement to be associated with REM sleep or REM sleep-related parameters. However, it is still unknown whether reactivation of emotional memories during REM sleep strengthens emotional memories. Here, we tested whether re-presentation of emotionally learned stimuli during REM sleep enhances emotional memory. In a split-night design, participants underwent Pavlovian conditioning after the first half of the night. Neutral sounds served as conditioned stimuli (CS) and were either paired with a negative odor (CS+) or an odorless vehicle (CS-). During sound replay in subsequent late REM or N2 sleep, half of the CS+ and half of the CS- were presented again. In contrast to our hypothesis, replay during sleep did not affect emotional memory as measured by the differentiation between CS+ and CS- in expectancy, arousal and valence ratings. However, replay unspecifically decreased subjective arousal ratings of both emotional and neutral sounds and increased positive valence ratings also for both CS+ and CS- sounds, respectively. These effects were slightly more pronounced for replay during REM sleep. Our results suggest that re exposure to previously conditioned stimuli during late sleep does not affect emotional memory strength, but rather influences the affective tone of both emotional and neutral memories. PMID- 25933507 TI - Differential effects of BDNF val(66)met in repetitive associative learning paradigms. AB - In healthy young subjects, the brain derived neurotropic factor (BDNF) val(66)met polymorphism negatively affects behavioural outcome in short-term motor cortex or hippocampus-based learning paradigms. In repetitive training paradigms over several days this effect can be overcome, in tests involving other brain areas even positive effects were found. To further specify the role of this polymorphism in cognitive processes, we used an associative vocabulary learning paradigm over four consecutive days and tested 38 young healthy subjects and 29 healthy elderly subjects. As a control paradigm, we designed a nonverbal haptic Braille letter-learning paradigm based on the same principles. Behavioural outcome was then associated with the BDNF-genotype. In the vocabulary learning task, met carrier (met/val and met/met) benefitted more from the repetitive training than val/val subjects. This was paralleled by a higher reduction of delayed answers during the course of the study, an effect that was also present in the haptic paradigm. However, in a group of healthy elderly subjects, no similar tendency was found. We conclude that the BDNF val(66)met polymorphism alters highly circumscribed answer behaviours in young healthy subjects. This might partly explain the high variability of previously published results. PMID- 25933508 TI - Lithium pinacolone enolate solvated by hexamethylphosphoramide. AB - We report the crystal structure of a substoichiometric, HMPA-trisolvated lithium pinacolone enolate tetramer (LiOPin)4.HMPA3 abbreviated as T3. In this tetramer one HMPA binds to lithium more strongly than the other two causing a reduction in spatial symmetry with corresponding loss of C3 symmetry. A variety of NMR experiments, including HMPA titration, diffusion coefficient-formula weight (D FW) analysis, and other multinuclear one- and two-dimensional NMR techniques reveal that T3 is the major species in hydrocarbon solution when more than 0.6 equiv of HMPA is present. Due to a small amount of moisture from HMPA or air leaking into the solution, a minor complex was identified and confirmed by X-ray diffraction analysis as a mixed aggregate containing enolate, lithium hydroxide, and HMPA in a 4:2:4 ratio, [(LiOPin)4.(LiOH)2.HMPA4], that we refer to as pseudo T4. A tetra-HMPA-solvated lithium cyclopentanone enolate tetramer was also prepared and characterized by X-ray diffraction, leading to the conclusion that steric effects dominate the formation and solvation of the pinacolone aggregates. An unusual mixed aggregate consisting of pinacolone enolate, lithium diisopropyl amide, lithium oxide, and HMPA in the ratio 5:1:1:2 is also described. PMID- 25933509 TI - Sonography of placental abnormalities: a pictorial review. AB - Often overlooked during routine ultrasound evaluation of a normal pregnancy, the placenta forms the biologic interface between the mother and fetus and is critical to fetal growth and development. Malformations in development, positioning, and vascularity can have profound implications for both maternal and fetal well-being. As such, a judicious inspection of the placenta is warranted as an integral part of every screening or emergent prenatal ultrasound. Herein, we present a pictorial review of a variety of placental pathologic conditions including abnormalities in positioning, adherence, vascularity, and hemorrhage as well as potential peri-placental masses and gestational trophoblastic disease, all of which are readily encountered in a busy emergency radiology practice. PMID- 25933510 TI - BWH emergency radiology--surgical correlation: traumatic spigelian hernia with right colonic injury. AB - We present a case of a young man who fell off his motorbike 2 days before presentation to the hospital with a complaint of gastrointestinal upset and abdominal pain. Contrast-enhanced CT of the abdomen and pelvis demonstrated a right-sided traumatic spigelian hernia and an ascending colon injury necessitating operative repair of both. PMID- 25933511 TI - Pre-shock chest compression pause effects on termination of ventricular fibrillation/tachycardia and return of organized rhythm within mechanical and manual cardiopulmonary resuscitation. AB - BACKGROUND: Shorter manual chest compression pauses prior to defibrillation attempts is reported to improve the defibrillation success rate. Mechanical load distributing band (LDB-) CPR enables shocks without compression pause. We studied pre-shock pause and termination of ventricular fibrillation/pulseless ventricular tachycardia 5s post-shock (TOF) and return of organized rhythm (ROOR) with LDB and manual (M-) CPR. METHODS: In a secondary analysis from the Circulation Improving Resuscitation Care trial, patients with initial shockable rhythm and interpretable post-shock rhythms were included. Pre-shock rhythm, pause duration (if any), and post-shock rhythm were obtained for each shock. Associations between TOF/ROOR and pre-shock pause duration, including no pause shocks with LDB CPR, were analyzed with Chi-square test. A p-value <0.05 was considered statistically significant. RESULTS: For TOF and ROOR analyses we included 417 LDB CPR patients with 1476 and 1438 shocks, and 495 M-CPR patients with 1839 and 1796 shocks, respectively. For first shocks with LDB-CPR, pre-shock pause was associated with TOF (p=0.049) with lowest TOF (77%) for shocks given without pre shock compression pause. This association was not significant when all shocks were included (p=0.07) and not for ROOR. With M-CPR there were no significant associations between shock-related chest compression pause duration and TOF or ROOR. CONCLUSION: For first shocks with LDB-CPR, termination of fibrillation was associated with pre-shock pause duration. There was no association for the rate of return of organized rhythm. For M-CPR, where no shocks were given during continuous chest compressions, there were no associations between pre-shock pause duration and TOF or ROOR. PMID- 25933513 TI - Murine hematopoietic stem cell dormancy controlled by induction of a novel short form of PSF1 by histone deacetylase inhibitors. AB - Hematopoietic stem cells (HSCs) can survive long-term in a state of dormancy. Little is known about how histone deacetylase inhibitors (HDACi) affect HSC kinetics. Here, we use trichostatin A (TSA), a histone deacetylase inhibitor, to enforce histone acetylation and show that this suppresses cell cycle entry by dormant HSCs. Previously, we found that haploinsufficiency of PSF1, a DNA replication factor, led to attenuation of the bone marrow (BM) HSC pool size and lack of acute proliferation after 5-FU ablation. Because PSF1 protein is present in CD34(+) transiently amplifying HSCs but not in CD34(-) long-term reconstituting-HSCs which are resting in a dormant state, we analyzed the relationship between dormancy and PSF1 expression, and how a histone deacetylase inhibitor affects this. We found that CD34(+) HSCs produce long functional PSF1 (PSF1a) but CD34(-) HSCs produce a shorter possibly non-functional PSF1 (PSF1b, c, dominantly PSF1c). Using PSF1a-overexpressing NIH-3T3 cells in which the endogenous PSF1 promoter is suppressed, we found that TSA treatment promotes production of the shorter form of PSF1 possibly by inducing recruitment of E2F family factors upstream of the PSF1 transcription start site. Our data document one mechanism by which histone deacetylase inhibitors affect the dormancy of HSCs by regulating the DNA replication factor PSF1. PMID- 25933515 TI - Application of image processing to assess emulsion stability and emulsification properties of Arabic gum. AB - This paper focuses on the development of an effective methodology to determine the optimum levels of independent variables leading to maximize stability of O/W emulsions containing Arabic gum, as a natural emulsifier and stabilizer. Response surface methodology (RSM) was employed to determine the effect of Arabic gum content (2%, 5%, and 8% (w/w)), homogenization time (5, 12.5, and 20 min) and storage temperature (4, 22, and 40 degrees C). Image processing was used to determine emulsion stability based on responses including creaming index, centrifugal stability, viscosity, color parameters, and D32 and D43 indices. For each response, a second-order polynomial model with high coefficient of determination (R(2)) values ranging from 0.95 to 0.989 was developed using multiple linear regression analysis. The optimization results showed that the overall optimum region with the highest stability was found to be at the combined levels of 5.81% (w/w) Arabic gum content, 5 min homogenization time, and 22 degrees C for storage temperature. PMID- 25933516 TI - Cassava starch films containing acetylated starch nanoparticles as reinforcement: Physical and mechanical characterization. AB - This paper reports the use of acetylated starch nanoparticles (NPAac) as reinforcement in thermoplastic starch films. NPAac with an average size of approximately 500 nm were obtained by nanoprecipitation. Fourier transform infrared (FTIR) and thermogravimetric analysis (TGA) indicated that NPAac are more thermally stable and essentially amorphous when compared with acetylated starch. Thermoplastic starch films with different proportions of NPAac (0.5, 1.0, 1.5, 10.0%, w/w) were obtained and characterized by scanning electron microscopy (SEM), water vapor permeability (WVP), adsorption isotherms, TGA and mechanical tests. The inclusion of reinforcement caused changes in film properties: WVP was lowered by 41% for film with 1.5% (w/w) of NPAac and moisture adsorption by 33% for film with 10% (w/w) of NPAac; and the Young's modulus and thermal stability were increased by 162% and 15%, respectively, for film with 0.5% (w/w) of NPAac compared to the starch film without the addition of NPAac. PMID- 25933518 TI - Manipulation of cellulose nanocrystal surface sulfate groups toward biomimetic nanostructures in aqueous media. AB - We report a facile aqueous procedure to create multivalent displays of sulfonated ligands on CNCs for future applications as viral inhibitors. CNCs were decorated with model compounds containing sulfonate groups via reactions of epoxides and isothiocyanates with amines under alkaline conditions. At first, surface sulfate groups of CNCs were hydrolytically cleaved by alkaline hydrolysis to increase the number of available surface hydroxyls. Success of desulfation was confirmed via dynamic light scattering (DLS), zeta potential measurements and thermogravimetric analysis (TGA). CNC surface hydroxyl groups were then activated with epichlorohydrin before subsequent reactions. As proof of concept toward aqueous pathways for functionalizing nanoparticles with sulfonated ligands, 3-chloro-2 hydroxy-1-propanesulfonic acid sodium salt hydrate (CPSA) and 4-sulfophenyl isothiocyanate sodium salt monohydrate (4-SPITC) were chosen as model compounds to react with homobifunctional 2,2'-(ethylenedioxy)bis(ethylamine) (EBEA) molecular spacer. The approaches presented are not only applicable to polysaccharide nanocrystals, but also other classes of polymeric and inorganic substrates presenting surface hydroxyl groups, as in the case of poly(2 hydroxyethyl methacrylate) (PHEMA), silica or glass. CNCs carrying sulfonated ligands were characterized by ATR-FTIR and UV-vis spectroscopy. Surface chemical compositions of desired elements were determined via X-ray photoelectron spectroscopy (XPS). We anticipate that with these facile aqueous procedures as the proof of concept, a diverse library of target-specific functionalities can be conjugated to CNCs for applications in nanomedicine, especially related to viral inhibition. PMID- 25933512 TI - [Hemorrhagic congenital diseases: What can be the future of plasma-derived products against recombinants?]. AB - Until 1990, congenital hemorrhagic disorders were treated by plasma-derived concentrates. The first recombinant drug, recombinant factor VIII was available after this date and few years later recombinant factor IX could also be proposed to patients. The evolution of market share in France was different between these two drugs: while recombinant factor VIII took a large place in hemophilia A treatment (85%), plasma-derived factor IX represent 50% of the French market. In the next years, the arrival of long-acting antihemophilic factors may lead to the dramatically reduce the amount of plasma-derived antihemophilic factors used to treat hemophilia. For rare bleeding coagulation disorders, plasma-derived concentrates are still widely used, while they are the only concentrates available in most diseases. This situation is unlikely to evolve significantly in the next years. PMID- 25933517 TI - Characterization and antioxidant activity in vitro and in vivo of polysaccharide purified from Rana chensinensis skin. AB - Preliminary characterization and antioxidant activity in vitro and in vivo investigation of the polysaccharide fraction named as RCSP II, which was extracted from Rana chensinensis skin, were performed. Results indicated that RCSP II comprised glucose, galactose, and mannose in a molar ratio of 87.82:2.77:1.54 with a molecular weight of 12.8 kDa. Antioxidant activity assay in vitro showed that RCSP II exhibited 75.2% scavenging activity against 2,2' azino-bis(3-ethylbenz-thiazoline-6-sulfonic acid) radicals at the concentration of 2500 mg/L and 85.1% against chelated ferrous ion at 4000 mg/L. Antioxidant activity assay in vivo further showed that RCSP II increased the activities of antioxidant enzymes, decreased the levels of malondialodehyde, and enhanced total antioxidant capabilities in livers and sera of d-galactose induced mice. These results suggested that RCSP II could have potential antioxidant applications as medicine or functional food. PMID- 25933514 TI - Human DNA helicase B interacts with the replication initiation protein Cdc45 and facilitates Cdc45 binding onto chromatin. AB - The chromosomal DNA replication in eukaryotic cells begins at replication initation sites, which are marked by the assembly of the pre-replication complexes in early G1. At the G1/S transition, recruitment of additional replication initiation proteins enables origin DNA unwinding and loading of DNA polymerases. We found that depletion of the human DNA helicase B (HDHB) inhibits the initiation of DNA replication, suggesting a role of HDHB in the beginning of the DNA synthesis. To gain insight into the function of HDHB during replication initiation, we examined the physical interactions of purified recombinant HDHB with key initiation proteins. HDHB interacts directly with two initiation factors TopBP1 and Cdc45. In addition we found that both, the N-terminus and helicase domain of HDHB bind to the N-terminus of Cdc45. Furthermore depletion of HDHB from human cells diminishes Cdc45 association with chromatin, suggesting that HDHB may facilitate Cdc45 recruitment at G1/S in human cells. PMID- 25933519 TI - In-situ glyoxalization during biosynthesis of bacterial cellulose. AB - A novel method to synthesize highly crosslinked bacterial cellulose (BC) is reported. The glyoxalization is started in-situ, in the culture medium during biosynthesis of cellulose by Gluconacetobacter medellensis bacteria. Strong crosslinked networks were formed in the contact areas between extruded cellulose ribbons by reaction with the glyoxal precursors. The crystalline structure of cellulose was preserved while the acidic component of the surface energy was reduced. As a consequence, its predominant acidic character and the relative contribution of the dispersive component increased, endowing the BC network with a higher hydrophobicity. This route for in-situ crosslinking is expected to facilitate other modifications upon biosynthesis of cellulose ribbons by microorganisms and to engineer the strength and surface energy of their networks. PMID- 25933520 TI - Optical and mechanical properties of nanofibrillated cellulose: Toward a robust platform for next-generation green technologies. AB - Nanofibrillated cellulose, a polymer that can be obtained from one of the most abundant biopolymers in nature, is being increasingly explored due to its outstanding properties for packaging and device applications. Still, open challenges in engineering its intrinsic properties remain to address. To elucidate the optical and mechanical stability of nanofibrillated cellulose as a standalone platform, herein we report on three main findings: (i) for the first time an experimental determination of the optical bandgap of nanofibrillated cellulose, important for future modeling purposes, based on the onset of the optical bandgap of the nanofibrillated cellulose film at Eg~275 nm (4.5 eV), obtained using absorption and cathodoluminescence measurements. In addition, comparing this result with ab-initio calculations of the electronic structure the exciton binding energy is estimated to be Eex~800 meV; (ii) hydrostatic pressure experiments revealed that nanofibrillated cellulose is structurally stable at least up to 1.2 GPa; and (iii) surface elastic properties with repeatability better than 5% were observed under moisture cycles with changes of the Young modulus as large as 65%. The results obtained show the precise determination of significant properties as elastic properties and interactions that are compared with similar works and, moreover, demonstrate that nanofibrillated cellulose properties can be reversibly controlled, supporting the extended potential of nanofibrillated cellulose as a robust platform for green-technology applications. PMID- 25933521 TI - Dual production of biopolymers from bacteria. AB - Rapid depletion of natural resources with continued demands of an increasing population and high consumption rates of today's world will cause serious problems in the future. This, along with environmental concerns, has directed research towards finding alternatives in variety of sectors including sustainable and environmentally friendly consumer goods. Biopolymers of bacterial origin, with their vast range of applications, biodegradability and eco-friendly manufacturing processes, are one of the alternatives for a more sustainable future. However, the cost of their production is a drawback. Simultaneous production processes have always been an option for researchers in order to reduce cost, but the variable requirements of microorganisms to produce both different and valuable products are a hindering factor. This review will look at some examples and identify ideas towards developing a successful strategy for simultaneous production of bio-products. PMID- 25933522 TI - Collagen synthesis promoting pullulan-PEI-ascorbic acid conjugate as an efficient anti-cancer gene delivery vector. AB - Cationized pullulan (pullulan-PEI; PP) was synthesized and further modified with an anti-oxidant molecule, ascorbic acid (PPAA) at various ratios. The nanoplexes formed at an optimum ratio of 4:1 was within a size of 150nm and had a zeta potential of 9-14mV. The nanoplexes at this ratio was used for further investigations. The cell internalization and transfection efficiency of these nanoplexes were determined in presence of serum. The internalization and transfection efficiency were found to be unaffected by the presence of fetal bovine serum. Another interesting observation was that this polymer was found to have collagen synthesis promoting property. The collagen synthesis effect of these polymers was quantified and observed that PPAA3 promoted the highest. Transfection efficiency was evaluated by assessing the p53 gene expression in C6 rat glioma cells and cell death was quantified to be 96% by flow cytometry, thus establishing the high efficacy of this polymer. PMID- 25933523 TI - Effect of chitooligosaccharides with different degrees of acetylation on wheat seedlings under salt stress. AB - In this study, chitooligosaccharides (COSs) with varying degrees of acetylation (DAs) were applied to wheat seedlings in order to investigate their effect on the plants' defence response under salt stress. The results showed that treatment with exogenous COSs that had different DAs could promote the growth of plants, decrease the concentration of malondialdehyde (MDA), improve the photosynthetic efficiency and enhance the activities of antioxidant enzymes. The mRNA expression level examination of several salt stress response genes suggested that COS could protect plants from the damage of salt stress by adjusting intracellular ion concentration and enhancing the activities of antioxidant enzymes. Furthermore, COS with DA 50% was the most effective in alleviating salt stress to wheat seedlings, which indicated that the activity of COS was closely related with its DAs. PMID- 25933524 TI - Cationization of kappa- and iota-carrageenan--Characterization and properties of amphoteric polysaccharides. AB - Commercial kappa- and iota carrageenans were cationized with 3-chloro-2 hydroxypropyltrimethylammonium chloride in aqueous sodium hydroxide solution. For kappa-carrageenan three derivatives with different degrees of substitution were obtained. Native and amphoteric kappa-carrageenans were characterized by NMR and infrared spectroscopy, scanning electron and atomic force microscopy; methanolysis products were studied by electrospray ionization mass spectrometry. Young moduli and the strain at break of films, differential scanning calorimetry, rheological and flocculation behavior were also evaluated; the native and the amphoteric derivatives showed different and interesting properties. Cationization of iota-carrageenan was more difficult, indicating as it was previously observed for agarose, that substitution starts preferentially on the 2-position of 3,6 anhydrogalactose residues; in iota-carrageenan this latter unit is sulfated. PMID- 25933525 TI - Effect of interfibrillar PVA bridging on water stability and mechanical properties of TEMPO/NaClO2 oxidized cellulosic nanofibril films. AB - TEMPO/NaClO2 oxidized cellulosic nanofibrils (TCNF) were covalently bonded with poly(vinyl alcohol) (PVA) to render water stable films. Pure TCNF films and TCNF PVA films in dry state showed similar humidity dependent behavior in the elastic region. However, in wet films PVA had a significant effect on stability and mechanical characteristics of the films. When soaked in water, pure TCNF films exhibited strong swelling behavior and poor wet strength, whereas covalently bridged TCNF-PVA composite films remained intact and could easily be handled even after 24h of soaking. Wet tensile strength of the films was considerably enhanced with only 10 wt% PVA addition. At 25% PVA concentration wet tensile strengths were decreased and films were more yielding. This behavior is attributed to the ability of PVA to reinforce and plasticize TCNF-based films. The developed approach is a simple and straightforward method to produce TCNF films that are stable in wet conditions. PMID- 25933526 TI - Thermoplastic starch plasticized with alginate-glycerol mixtures: Melt-processing evaluation and film properties. AB - Corn starch melt-processing in the presence of a commonly used plasticizer mixture (water/glycerol) and a non-conventional alternative (alginate/glycerol) was evaluated. All assayed formulations were successfully processed by melt mixing and injected in circular probes. It was determined that all samples presented a typical viscoelastic behavior, observing a decrease in storage and loss modulus with water and alginate concentration, which facilitated samples processability. Concerning to thermal stability, it was not affected neither for water nor alginate presence. From injected probes, flexible films were obtained by thermo-compression. Films with the highest assayed water content presented a sticky appearance, whereas those containing alginate were non-tacky. Plasticizing action of water and alginate was evidenced by the occurrence of homogeneous fracture surfaces, without the presence of unmelted starch granules. Besides, the shift of glass transition temperature to lower values also corroborated the plasticizing effect of both additives. In conclusion, obtained results demonstrated the well-plasticizing action of sodium alginate on starch matrix, turning this additive into a promissory alternative to replace water during melt processing of thermoplastic corn-starch. PMID- 25933527 TI - Immune-enhancing activity of polysaccharides isolated from Atractylodis macrocephalae Koidz. AB - This study evaluated the immune-enhancing activity of polysaccharides from the rhizoma of Atractylodis macrocephalae Koidz (RAMPS) in vitro. Lymphocyte proliferation, cell cycle distribution, and percentages of CD4(+) and CD8(+) cells were determined. Different concentrations of RAMPS were added to peripheral blood T lymphocytes. Results showed that RAMPStp and RAMPS60c could significantly enhance T lymphocyte proliferation individually or synergistically with phytohemagglutinin at most concentrations. The active sites of RAMPStp and RAMPS60c were then selected. Lymphocyte cell cycle distribution and percentages of CD4(+) and CD8(+) cells were determined by flow cytometry. At most time points, RAMPS60c and RAMPStp could promote lymphocytes enter into S and G2/M phases. RAMPStp and RAMPS60c effectively improved the percentages of CD4(+) and CD8(+) T cells. RAMPStp produced optimal effects. Therefore, RAMPStp could be used as a component of novel immunopotentiators. PMID- 25933528 TI - Preparation of fucoidan-shelled and genipin-crosslinked chitosan beads for antibacterial application. AB - In this study, a fucoidan-shelled chitosan bead was developed with the purpose of oral delivery of berberine to inhibit the growth of bacteria. The cross-linking level and swelling property of the beads were affected by the pH value and the composition of the genipin/fucoidan combined gelling agent. The drug release of the berberine-loaded beads was faster in simulated gastric fluid (pH 1.2) than those in simulated intestinal fluid (pH 7.4). Furthermore, a nanoparticles/beads complex system was developed by incorporation of berberine-loaded chitosan/fucoidan nanoparticles in the fucoidan-shelled chitosan beads. The nanoparticles/beads complex served as a drug carrier to delay the berberine release in simulated gastric fluid, with an estimated lag time of 2 h. Our results showed that the berberine-loaded beads and nanoparticles/beads complex could effectively inhibit the growth inhibition of common clinical pathogens, such as Staphylococcus aureus and Escherichia coli, and have the advantage of continually releasing berberine to inhibit the growth of the bacteria over 24 h. PMID- 25933529 TI - Binding of arabinan or galactan during cellulose synthesis is extensive and reversible. AB - Arabinans and galactans are major components of the side-chains of pectin in plant cell walls. In order to understand how pectin side-chains interact with cellulose, in this work we studied the interaction of de-branched arabinan (from sugar beet) and linear galactan (from potato) during the synthesis of cellulose by Gluconacetobacter xylinus (ATCC 53524) to mimic in muro assembly. The binding studies reveal that arabinan and galactan are able to bind extensively (>200mg/g of cellulose) during cellulose deposition, and more than pectin (from apple) in the absence of calcium. (13)C NMR revealed that associated arabinan, galactan or apple pectin molecules were neither rigid nor affected cellulose crystallinity, and there was no apparent change in cellulose architecture as reflected in scanning electron micrographs. De-binding of arabinan, galactan or apple pectin occurred as a result of washing, indicating a reversible binding to cellulose, which was modelled in terms of a surface-controlled process. Implications for structural models of primary plant cell walls and possible roles for cellulose binding of arabinan- and galactan-rich pectins in biological processes are discussed. PMID- 25933530 TI - The role of cellulosic chains of cotton in biosynthesis of ZnO nanorods producing multifunctional properties: Mechanism, characterizations and features. AB - In situ synthesis of ZnO nanorods on cellulosic chains of cotton fabric was accomplished using natural plant source namely Keliab and zinc acetate. Hierarchical mechanism of nano ZnO generation and deposition on cellulosic chains of cotton fabric was discussed in details and several analytical techniques were used to characterize the formation of nano ZnO wurtzite structure. The morphology, crystal phase, and chemical structure of the fabric were characterized by scanning electron microscope, X-ray diffraction and energy dispersive X-ray spectroscopy. Further, interaction between ZnO and functional groups of cellulosic chains of cotton fabric was studied by Fourier transforms infrared spectroscopy. The influence of zinc acetate and Keliab solution on the self-cleaning activity of the treated cellulosic fabric was investigated with a central composite design based on surface response methodology. The treated fabrics showed self-cleaning activity toward methylene blue degradation under day light irradiation. The optimized treated sample showed high antibacterial efficiency against Staphylococcus aureus and Escherichia coli with enhanced tensile strength and higher crease recovery angle. PMID- 25933531 TI - Biomineralized biomimetic organic/inorganic hybrid hydrogels based on hyaluronic acid and poloxamer. AB - A biomineralized hydrogel system containing hyaluronic acid (HA) and poloxamer composed of a poly(ethylene oxide)/poly(propylene oxide)/poly(ethylene oxide) (PEO-PPO-PEO) block copolymer was developed as a biomimetic thermo-responsive injectable hydrogel system for bone regeneration. Using HA and poloxamer macromers with polymerizable residues, organic/inorganic HA/poloxamer hydrogels with various compositions were prepared and subjected to a biomineralization process to mimic the bone extracellular matrix. An increase in HA content within the hydrogels enhanced intermolecular chelation with calcium ions, leading to an increase in nucleation and growth of calcium phosphate in the hydrogels. After the biomineralization procedure, a crystalline formation was observed within and on the surface of the hydrogel. All of the HA/poloxamer hydrogel samples exhibited relatively high water content of greater than 90% at 25 degrees C, and the water content was influenced by the HA/poloxamer composition, biomineralization, and temperature. In particular, the HA/poloxamer hydrogel was injectable through a syringe without demonstrating appreciable macroscopic fracture at room temperature, whereas it was more opaque and adopted a more rigid structure as the temperature increased because of the increasing hydrophobicity of poloxamer. The enzymatic degradation behavior of the hydrogels depended on the concentration of hyaluronidase, HA/poloxamer composition, and biomineralization. The release kinetics of model drugs from HA/poloxamer hydrogels was primarily dependent on the drug loading content, water content, biomineralization of the hydrogels, and ionic properties of the drug. These results indicate that biomineralized HA/poloxamer hydrogel is a promising candidate material for a biomimetic hydrogel system that promotes bone tissue repair and regeneration via local delivery of drugs. PMID- 25933532 TI - Release mechanism of omega-3 fatty acid in kappa-carrageenan/polydextrose undergoing glass transition. AB - A high-solid matrix of kappa-carrageenan with polydextrose was developed to entrap alpha-linolenic acid, which is an omega-3 bioactive compound. Physicochemical analysis of this system utilised modulated DSC, dynamic oscillation in shear, ESEM, FTIR and WAX diffraction. The carbohydrate matrix was conditioned through an extensive temperature range to induce changes in molecular morphology and identify the network glass transition temperature. Thermally induced variation in phase morphology was employed to rationalise transportation patterns of the bioactive compound within the high-solid preparation. Thus, experimental observations using UV-vis spectroscopy modelled diffusion kinetics to document the mobility arresting effect of the vitrifying matrix on the micro constituent. Within the glass transition region, results argue that free volume theory is the molecular process governing structural relaxation. Further, Less Fickian diffusion follows well the rate of molecular transport of alpha-linolenic acid as a function of time and temperature of observation in the condensed matrix. PMID- 25933533 TI - Preparation and characterization of cross-linked carboxymethyl chitin porous membrane scaffold for biomedical applications. AB - Porous dermal scaffold membrane (PDSM) was successfully prepared by using a so called sol-gel freeze-drying method. In this method, the carboxymethyl chitin (CMC) hydrosol was first cross-linked by 1-ethyl-3-[3-dimethylaminopropyl] carbodiimide hydrochloride (EDC) and N-hydroxysuccinimide (NHS), and then lyophilized to form the PDSM. For the first time, this research focused on the cross-linked CMC as the only component for three-dimensional PDSM. The effects of cross-linking conditions on the performance of the PDSM were investigated. And PDSM with optimal performance was obtained through 4-h cross-linking at 4 wt% of CMC concentration in the hydrosol, where the mass ratio of EDC to NHS to CMC was 5:3:10. The porosity of the optimized PDSM was more than 90% and the water swelling rate was above 4000%. The pore size was well distributed and was between 100 MUm and 200 MUm. And the tensile strength was above 0.09 MPa. The as-made PDSM could be degraded above 80% in 12 days in the presence of a 0.2mg/mL lysozyme solution. Very importantly, the PDSM had no cytotoxicity and good biocompatibility from MTT assays. Our results showed the application possibility of the as-prepared PDSM as dermal scaffold for skin tissue engineering. PMID- 25933535 TI - New product development: Cellulose/egg white protein blend fibers. AB - The aim of the research was to form mixed cellulose/egg white isolate (EWI) fibers. Cellulose was dissolved in the Schweitzer's reagent. The blend fibers were obtained by simultaneous cellulose fiber formation and acid-induced gelation of EWI in 33% sulphuric acid solution. Increased storage modulus was noted for the blend fibers in comparison to the cellulose fibers. EWI alone formed fibers which were composed of microfibers with the average diameter of about 80 nm. Cellulose fibers had a loose microstructure with about 10 MUm gaps and rough surface. The addition of EWI caused that the surface of the fiber was even more rough with a tendency to form microfibers, which were not observed for cellulose alone. EWI protein molecules had the tendency to bridge the voids between cellulose microfibers. Protein in the blend fibrils formed more branched aggregates than in the EWI fibrils, which was probably caused by interactions with copper ions. Both in cellulose and cellulose/EWI fibrils, the cellulose crystallized in cellulose II monoclinic system. Reduction in COH groups was noted, which was probably caused by interactions between the cellulose and proteins molecules. EWI/cellulose interactions caused formation of beta-sheet type structures. PMID- 25933534 TI - Cationic beta-cyclodextrin polymer applied to a dual cyclodextrin polyelectrolyte multilayer system. AB - A polyelectrolyte multilayer film (PEM) based on cationic and anionic beta cyclodextrin polyelectrolytes was coated onto a textile substrate for future drug delivery purposes. We firstly synthesized a novel cationic beta-cyclodextrin polymer (polyEPG-CD) by crosslinking beta-cyclodextrin (betaCD) with epichlorohydrin (EP) under basic conditions, in the presence of glycidyltrimetrylammonium chloride (GTMAC) as cationizing group. The influence of preparation conditions has been investigated in order to preferably obtain a water soluble fraction whose charge density and molecular weights were optimal for the layer-by-layer (LbL) deposition process. The different cationic cyclodextrin polymers obtained were characterized by FTIR, NMR, colloidal titration, conductimetry, thermogravimetric analysis and size exclusion chromatography. Besides, the counterpart polyelectrolyte was a beta-cyclodextrin polymer crosslinked with citric acid, polyCTR-CD, whose synthesis and characterization have been previously reported. Finally we realized the Layer by Layer (LbL) build-up of the PEM coating onto the textile support, using the dip coating method, by alternatively soaking it in cationic polyEPG-CD and anionic polyCTR-CD solutions. This multilayer self-assembly was monitored by SEM, gravimetry and OWLS in function of both polyelectrolytes concentrations and ratios. Solutions parameters such as pH, ionic strenght were also discussed. PMID- 25933536 TI - Preparation of CNC-dispersed Fe3O4 nanoparticles and their application in conductive paper. AB - Well-dispersed Fe3O4 nanoparticles (NPs) were synthesized by a co-precipitation method in the presence of cellulose nano-crystals (CNC) as the template. The thus prepared Fe3O4 NPs were then used as a coating agent for the preparation of conductive paper. Fourier transform infrared spectroscopy (FTIR) results revealed that the Fe3O4 NPs were immobilized on the CNC through interactions between the hydroxyl groups of CNC and Fe3O4. Scanning transmission electron microscopy (STEM) images showed that the Fe3O4 NPs prepared in the presence of CNC can be dispersed in the CNC network, while the Fe3O4 NPs prepared in the absence of CNC tended to aggregate in aqueous solutions. The conductivity of the Fe3O4 NPs coated paper can reach to 0.0269 S/m at the coating amount of 14.75 g/m(2) Fe3O4/CNC nanocomposites. Therefore, the thus obtained coated paper can be potentially used as anti-static packaging material in the packaging field. PMID- 25933537 TI - Structural characterization of a broccoli polysaccharide and evaluation of anti cancer cell proliferation effects. AB - Broccoli is a widely consumed vegetable with abundant amount of nutrients, which bring numerous beneficial effects on human health. The structural information of water-soluble polysaccharides in broccoli was eludicated for the first time in this work. A purified polysaccharide fraction (BPCa) was obtained by column chromatography. It comprised of arabinose (Ara), galactose (Gal), rhamnose (Rha) with a molar ratio of 5.3:0.8:1.0. Nuclear magnetic resonnance spectra data revealed that alpha-L-1,5-Araf and alpha-L-1,3,5-Araf are present in the backbone, while alpha-L-Araf terminal was attended in side chain. alpha-L-1,2 Rhap was found to be linked to alpha-L-1,5-Araf in heteronuclear multiple bond correlation spectra. The presences of beta-D-1,4-Galp and alpha-D-1,4-GalpA were also detected. Furthermore, BPCa showed significant anti-cancer cell proliferation activities against HepG2, Siha and MDA-MB-231 carcinoma cell lines. The results indicated that BPCa had a good potential to be applied as functional food additives. PMID- 25933538 TI - Fractionation and characterization of saccharides and lignin components in wood prehydrolysis liquor from dissolving pulp production. AB - Saccharides and lignin components in prehydrolysis liquor (PHL) from kraft-based dissolving pulp production was characterized after being fractionated using membrane filtration. The results showed that the membrane filtration provided a method for organics fractionation with considerable recovery rate, but exhibited some disadvantages. Besides the limited ability in purifying oligosaccharides (OS) due to the overlaps of molecular weight distribution with lignin components, the membrane filtration could not improve the homogeneity of OS as indicated by the analysis of chemical compositions and the degree of polymerization (DP), which may be ascribed to the linear conformation of OS. The characterization of lignin components indicated a great potential for polymer industry because of the remarkable content of phenolic hydroxyl groups (PhOH), especially for low molecular weight (LMW) fraction. It was concluded the organics in PHL provided streams of value-added chemicals. However, the practical significance thereof can be realized and maximized only when they are successfully and completely fractionated. PMID- 25933539 TI - Hyaluronic acid hydrogel scaffolds with a triple degradation behavior for bone tissue engineering. AB - In this study, in order to better mimick the nature of bone extracellular matrix, hyaluronic acid (HA) hydrogels having a triple degradation behavior were synthesized from 3,3'-dithiodipropionate hydrazide-modified HA (DTPH-HA) and polyethylene glycol dilevulinate (LEV-PEG-LEV) via the reaction of the ketone carbonyl groups of LEV-PEG-LEV with the hydrazide groups of DTPH-HA. The HA hydrogels were characterized by solid state (13)C NMR, FT-IR, SEM, and rheological, swelling and degradation tests. The results showed that the HA hydrogels exhibited a highly porous morphology and had pore diameters ranging from 20 to 200 MUm. The equilibrium swelling ratio of the HA hydrogels was no less than 37.5. The HA hydrogels could be degraded by hyaluronidase and reducing substances or at acidic pH values. The biocompatibility of the HA hydrogels was evaluated using osteoblast-like MC3T3-E1 cells by live/dead staining and MTT assays. The results revealed that the HA hydrogels had good biocompatibility and could support the attachment and proliferation of MC3T3-E1 cells. All the results indicated that the HA hydrogels synthesized by hydrazone bond crosslinking might have great potential to be used in bone tissue engineering. PMID- 25933540 TI - Poly(methacylic acid-co-maleic acid) grafted nanofibrillated cellulose as a reusable novel heavy metal ions adsorbent. AB - A poly(methacrylic acid-co-maleic acid) grafted nanofibrillated cellulose (NFC MAA-MA) aerogel was prepared via radical polymerization in an aqueous solution using Fenton's reagent. The ensuing aerogel, in the form of a rigid porous material, was characterized by FTIR and NMR and used as an adsorbent for the removal of heavy metals from aqueous solutions. It showed an efficient adsorption, exceeding 95% toward Pb(2+), Cd(2+), Zn(2+) and Ni(2+) when their concentration was lower than 10 ppm and ranged from 90% to 60% for a metal concentration higher than 10 ppm. Over 98% of the adsorbed metal ion was recovered using EDTA as a desorbing solution, and the subsequent washing allowed the aerogel to be reused repeatedly without noticeable loss of adsorption capacity. It was concluded that the (NFC-MAA-MA) aerogel may be used as a high capacity and reusable sorbent material in heavy-metal removing processes. PMID- 25933541 TI - New biodegradable dextran-based hydrogels for protein delivery: Synthesis and characterization. AB - A new derivative of dextran grafted with polyethylene glycol methacrylate through a carbonate bond (DEX-PEG-MA) has been synthesized and characterized. The photo crosslinking reaction of DEX-PEG-MA allowed the obtainment of biodegradable networks tested for their mechanical and release properties. The new hydrogels were compared with those made of dextran methacrylate (DEX-MA), often employed as drug delivery systems of small molecules. The inclusion of PEG as a spacer created additional interactions among the polymeric chains improving the extreme fragility and lack of hardness typical of gels made of DEX-MA. Moreover, the different behavior in terms of swelling and degradability of the networks was able to affect the release of a model macromolecule over time, making DEX-PEG-MA matrices suitable candidates for the delivery of high molecular weight peptides. Interestingly, the combination of the two dextran derivatives showed intermediate ability to modulate the release of high molecular weight macromolecules. PMID- 25933542 TI - Versatile properties of an exopolysaccharide R-PS18 produced by Rhizobium sp. PRIM-18. AB - Exopolysaccharides (EPS) produced by bacteria have attracted scientific and industrial attention due to their multifunctional properties and relatively easier production. In this study, an EPS viz., R-PS18 produced by Rhizobium sp. PRIM-18 was characterized and its functional properties were assessed. Cell proliferative and in vitro wound healing activities of the EPS were established using human dermal fibroblast (HDF) cells. The isolate produced 2.1 g L(-1) purified EPS (molecular weight 9.33*10(6) Da) comprising of glucose, galactose, and mannose (6.1:1.8:1). Viscosity of 0.25% solution was 23.4 mPa s (shear rate 75 s(-1)) and it showed pseudoplastic and thixotropic behavior. High emulsification, iron chelation, and superoxide scavenging abilities were also observed. Significant increase in HDF cell proliferation and wound healing in vitro was achieved by R-PS18 treatment. Sulfation of R-PS18 significantly enhanced the cell proliferative and wound healing activities. In conclusion, these findings indicate potential applications of R-PS18. PMID- 25933543 TI - Enhanced anti-tumor effect of pH-responsive dextrin nanogels delivering doxorubicin on colorectal cancer. AB - Efficacy of doxorubicin (DOX) in colorectal cancer treatment is limited by undesirable side-effects, which are partially due to nonspecific delivery DOX to the tumor target site. This study aimed to develop pH-responsive dextrin nanogels (DNGs) as anticancer drug carriers with pH-controlled drug release. DNGs prepared with formaldehyde as a cross-linker (FDNGs) exhibited smaller size, compared to that using glyoxal (GDNGs). Both DNGs showed pH-dependent drug release properties; drug release was slow at neutral pH but increased significantly in acidic medium. The cytotoxicity of empty and DOX-loaded FDNGs was lower than free DOX and GDNGs, against two commonly used colorectal cancer cells. Intracellular uptake studies indicated that the DOX-loaded FDNGs could efficiently deliver DOX into the nuclei. In vivo, DOX-loaded FDNGs substantially enhanced anti-tumor efficacy, compared to free DOX, exhibiting much higher effects on inhibiting proliferation and inducing apoptosis, as confirmed by mice weight shifts, tumor weight, tumor volume and histological assessment. Therefore, FDNGs are promising as a potential drug delivery vehicle for colorectal cancer therapy. PMID- 25933544 TI - Hyaluronic acid-grafted polyamidoamine dendrimers enable long circulation and active tumor targeting simultaneously. AB - Herein, we developed dualfunctional hyaluronic acid (HA)-grafted polyamidoamine (PAMAM) dendrimers for simultaneous systemic long circulation and active tumor targeting and delivery of topotecan hydrochloride (TPT). The possibility of these modified dendrimers as nanocarriers for promoting tissue distribution and antitumor efficiency, as well as a drug release profile, cytotoxicity and cellular uptake, was investigated. The fine targeting efficiency of HA-PAMAM/TPT was confirmed by the CD44 receptor-mediated high cellular uptake efficiency and low cytotoxicity in HCT-116 cells, and the in vivo higher tumor distribution percentage than in other tissues in mice bearing an S-180 tumor. Pharmacokinetic studies showed that the t1/2 and MRT of TPT were significantly extended after intravenous administration of HA-PAMAM/TPT in normal rats. Moreover, TPT-loaded nanovehicles demonstrated higher antitumor activity compared with free drug and PAMAM/TPT. Overall, HA-PAMAM may be an alternative vector for the effective targeted delivery of and tumor therapy with antitumor drugs. PMID- 25933545 TI - Rheological behavior of cellulose nanowhisker suspension under magnetic field. AB - We investigated the influence of a magnetic field on the rheology of cellulose nanowhisker (CNW) suspension. The morphology of CNWs was analyzed by using polarized optical microscopy (POM) and transmission electron microscopy (TEM). The findings show that the application of the magnetic field leads to an increase in shear viscosity and viscoelastic properties such as the storage and loss moduli. A mesoscale constitutive model was adopted to provide better understanding of the effect of particle concentration on the orientation of CNWs. As the concentration increases, the steric interaction between particles becomes significant and the effect of the applied magnetic field on the internal structure of the CNW suspension was reduced. In addition, the size distribution of CNWs was characterized using a light scattering method. PMID- 25933546 TI - Diminished Disease-Free Survival After Lobectomy: Screening Implications. AB - BACKGROUND: The aim of this study was to estimate the effect of lobectomy on life expectancy in healthy smokers and consider the implications for lung cancer screening. MATERIALS AND METHODS: In a retrospective cohort study that provided a minimum of 15 years of follow-up, we analyzed lung cancer survival, all-cause survival, and fatality (1-survival) of 261 persons with stage I non-small-cell lung cancer who underwent lobectomy at Portland Providence Medical Center between 1978 and 1994. We: (1) compared 5-year disease-free fatality (non-lung-cancer fatality) with lung cancer fatality; and (2) based on actuarial data that demonstrated life expectancy equivalence of the healthiest smokers (whom we assumed would be comparable with subjects judged eligible for lobectomy) in the US population, we compared their long-term, disease-free survival (our primary end point) with actuarial expectations by computing the Kaplan-Meier survival function of the differences between lifetimes since surgery in disease-free persons versus matched, expected remaining lifetimes in the US population. RESULTS: (1) Five-year disease-free fatality (16.1%) was 58% as high as 5-year lung cancer fatality (27.6%); (2) disease-free survival was reduced by 6.9-years (95% confidence interval, 5.5-8.3), 41% of actuarial life expectancy (17 years). The divergence from expected survival took place largely after 6 years of follow up. CONCLUSION: Lobectomy materially diminishes long-term disease-free survival in the healthiest smokers--persons judged healthy enough to tolerate major surgery and to have sufficient pulmonary reserve to sustain loss of one-fifth of their lung tissue. In screened populations, diminished survival in overdiagnosed persons will offset, to an undetermined extent, the mortality benefit imparted by preemption of advanced lung cancer. PMID- 25933547 TI - Factors Influencing the Diagnostic Accuracy of Identifying the Histologic Type of Non--Small-Lung Cancer With Small Samples. AB - BACKGROUND: The pathologic diagnosis has become a greater consideration in decision-making regarding the treatment options for lung cancer. Therefore, the accurate diagnosis of the tumor histologic type is essential, even when only small biopsy or cytology samples are available. However, the risk of a misdiagnosis with smaller biopsy samples is greater. The factors underlying the increased risk of a misdiagnosis in small samples are unknown. The aim of the present study was to identify the clinical and pathologic factors (other than immunohistochemical staining) that influence the pathologic diagnostic accuracy in small biopsy and cytological lung samples obtained by bronchoscopy. PATIENTS AND METHODS: We performed transbronchial lung biopsy or brushing and lavage to determine the preoperative diagnosis of 126 of 299 surgically resected lung cancer specimens. We assessed the diagnostic accuracy of the preoperative transbronchoscopic examination findings against that of the surgically resected lung specimens. RESULTS: On univariate analysis, the mean pathologic tumor size in the noncorresponding cases was larger than that in corresponding cases. Vascular invasion was also more prevalent in the noncorresponding cases. The tumor differentiation grade in the noncorresponding cases was poorer than in the corresponding cases. The noncorresponding cases were at a more progressed stage. On multivariate analysis, the pathologic tumor size and tumor differentiation grade were associated with the noncorresponding cases. CONCLUSION: We found a larger tumor size and poor differentiation grade were indicative of lung cancer tissue with a greater content of heterogeneous cells. Therefore, a possibility exists of a false diagnosis using only these factors. Thus, treatment decisions should be made considering the pathologic diagnosis and other relevant factors. PMID- 25933550 TI - Hypothalamic paraventricular nucleus stimulation enhances c-Fos expression in spinal and supraspinal structures related to pain modulation. AB - The hypothalamic paraventricular nuclei (PVN) inhibits spinal nociception. Furthermore, projections from the PVN to other structures related to pain modulation exist, but a functional interaction has not yet been fully demonstrated. As an initial approach, we show here that PVN electric stimulation with the same parameters used to induce analgesia in rats enhances c-Fos expression not only in the dorsal horn of the spinal cord but also in the nucleus raphe magnus, locus coeruleus and the periaqueductal gray area. These results suggest that a functional interaction between these structures could occur, possibly to assure a mechanism of endogenous analgesia. PMID- 25933548 TI - Role of the macrophage in HIV-associated neurocognitive disorders and other comorbidities in patients on effective antiretroviral treatment. AB - Combination antiretroviral therapy (ART) has altered the outcomes of HIV infection in treated populations by greatly reducing the incidence of opportunistic infections, cancer, and HIV-associated dementia. Despite these benefits, treated patients remain at high risk of chronic diseases affecting the peripheral organs and brain. Generally, these morbidities are attributed to persistence of latent HIV in resting T cells, chronic inflammation, and metabolic effects of ART. This review makes the case that monocytes/macrophages warrant attention as persistent reservoirs of HIV under ART, source of systemic and brain inflammation, and important targets for HIV eradication to control chronic HIV diseases. PMID- 25933549 TI - Only extra-high dose of ketamine affects l-glutamate-induced intracellular Ca(2+) elevation and neurotoxicity. AB - The neurotoxic effects of anesthetics on the developing brain are a concern. Although most of the anesthetics are GABAA agonists or NMDA antagonists, the differences in these effects on prospective glutamate-neurotoxicity in the brain is not fully understood. We examined the degree of L-glutamate-induced intracellular calcium ([Ca(2+)]i) elevation and neurotoxicity in neurons exposed to anesthetics. Primary cortical neurons from E17 rats were preincubated with 1 100 MUM of ketamine or thiopental sodium (TPS) for the first 72 h of culturing. Two weeks later, the neurons were exposed to L-glutamate. The extent of glutamate toxicity was evaluated using Ca(2+)-imaging and morphological experiments. Preincubation with 100 MUM ketamine but not with other concentrations of ketamine and TPS for the first 72 h in culture significantly enhanced L-glutamate-induced [Ca(2+)]i elevation 2 weeks later. Morphology experiments showed that vulnerability to L-glutamate-mediated neurotoxicity was only altered in neurons preincubated with 100 MUM ketamine but not with TPS. Although preincubation with high concentration of ketamine showed enhancement of L-glutamate-induced [Ca(2+)]i elevation 2 weeks later, long-term exposure to TPS or ketamine at clinical doses during developmental periods may not result in a dose-related potentiation of exogenous glutamate-induced neurotoxicity, once the intravenous anesthetics are discontinued. PMID- 25933551 TI - Ebola Virus Disease: Readiness for the looming threat. PMID- 25933552 TI - Evaluation of oxidative stress tests in patients diagnosed with renal colic in the emergency department of Ankara Ataturk Training and Research Hospital, Turkey. AB - OBJECTIVE: To investigated oxidative stress changes in renal colic patients, and to determine its role in differential diagnosis of renal colic. METHODS: The cross-sectional study was conducted at Ankara Ataturk Training and Research Hospital, Turkey, from June 2012 to December 2012 and comprised patients with complaints suggesting of renal colic and diagnosed with urinary stone. Healthy individuals were enrolled to form the control group. The patients and the control group were evaluated in terms of oxidative stress parameters. SPSS 17 was used for statistical analysis. RESULTS: Of the 83 subjects, 50(60%) were patients with renal colic, while 33(40%) were healthy controls. Among the patients, 25(50%) were men and 25(50%) were women. Among the controls, there were 17(51.5%) men and 16(48.5%) women. No statistically significant difference was found between the two groups in terms of age and gender (p>0.05). Likewise, no statistically significant difference was found between the oxidative stress indexes of the two groups (p>0.05). CONCLUSIONS: There was no significant increase in oxidative stress in patients with renal colic. The result may help in the differential diagnosis of patients with abdominal pain. PMID- 25933553 TI - Who presents to our electroneurophysiology laboratory? AB - OBJECTIVE: To determine the distribution rate of Electroneuromyography diagnosis and correspondence between the preliminary diagnosis and final outcome. METHODS: The retrospective study was conducted at the Department of Neurology, Harran University, Sanliurfa, Turkey, and comprised record of patients diagnosed with Electroneuromyography during a 24-month period from April 2011 to April 2013. SPSS 11.5 was used for data analysis. RESULTS: Of the 4,230 cases reviewed, 1,946 (46%) showed normal Electroneuromyography findings despite pathological Electroneuromyography findings in 2,284(54%) cases. The most common diagnosis was carpal tunnel syndrome in 721(17%) patients, followed by polyneuropathy 312(7.4%), peripheral nerve injury 238(5.6%), brachial plexus lesion 180(4.3%), myopathy 114(2.7%), lumbar radiculopathy 108(2.6%), poliomyelitis 62(1.5%) and injection neuropathy 62(1.5%). CONCLUSIONS: Off-label use of Electroneuromyography may be reduced by using electroneurophysiological laboratory rotation as well as adequate and comprehensive clinical evaluation of patients. PMID- 25933554 TI - Postpartum sexual function in women and infant feeding methods. AB - OBJECTIVE: To assess postpartum sexual function in mothers using different infant feeding methods. METHODS: The comparative cross-sectional study comprising women referred to health centres in Mashhad, Iran, was conducted from July 7 to December 11, 2011. Sexual function and infant-feeding method of the subjects were assessed four months after childbirth. Data was collected using the standard Female Sexual Function Index and baby's feeding method questionnaire. SPSS 11.5 was used for statistical analysis. RESULTS: There were 366 women in the study with a mean age of 26.70+/-4.70 years who were using four methods of infant feeding: exclusive breastfeeding, breastfeeding plus complementary feeding, formula milk, and breastfeeding plus formula. There was a significant difference between women's sexual function score and infant-feeding method (p=0.04). The highest score 6.23+/-3.5 belonged to women who had exclusive breastfeeding. CONCLUSIONS: There was a difference in women's sexual function between different groups of infant feeding methods. The highest score of sexual function was found in breastfeeding women. Women need to be educated about exclusive breastfeeding and its positive effects on sexual function. PMID- 25933555 TI - Flexible cystoscopy a valuable diagnostic tool for lower urinary tract pathology. AB - OBJECTIVE: To assess the role of flexible cystoscopy in the diagnosis of lower urinary tract pathologies and its suitability as a routine diagnostic protocol in outdoor patients. METHODS: The quasi-experimental study was conducted at the Urology Department, Pakistan Ordinance Factory Hospital, Wah Cantt., from June 2009 to June 2010. All adult patients presenting with lower urinary tract symptoms to outdoor department were included on the basis of universal non probability sampling technique. Cystoscopy was performed as a clinic-based procedure without sedation. SPSS 17 was used for data analysis. RESULTS: Of the 1500 patients in the study, 810(54%) were females and 690(46%) were male. Lower urinary tract pathologies were found in 480(32%) patients. The most common pathology among males was enlarged prostate in 127(8.4%) patients. Among females, urethral stenosis was the most common pathology in 57(3.8%) patients. Transitional cell carcinoma was seen in 57(3.8%) patients having haematuria with inconclusive ultrasound and intravenous urography. All patients tolerated the procedure well. CONCLUSIONS: Flexible cystoscopy is an effective, well-tolerated and easy way of detecting lower urinary tract pathologies among outpatients. PMID- 25933556 TI - Economic burden of dengue in four major cities of Pakistan during 2011. AB - OBJECTIVE: To assess the economic burden of dengue infection by calculating cost per patient and disability adjusted life years lost. METHODS: The cross-sectional study was conducted in Islamabad, Lahore, Faisalabad and Karachi from July 2012 to March 2013. Residential addresses and telephonic numbers of dengue patients were taken from the records of Pakistan Institute of Medical Sciences, Islamabad, Mayo and Ganga Ram Hospital, Lahore, Civil Hospital, Karachi, and Allied Hospital, Faisalabad. A total of 250 dengue confirmed cases - 50 from each hospital - were randomly selected. Information regarding duration of illness and out-of-pocket expenses were collected to estimate the direct cost, while indirect cost (number of work days missed by the patient) was calculated from disability adjusted life years using Murray's formula. RESULTS: Overall, there were 162(65%) men and 88(35%) with a mean age of 30.4+/-13.5years. More than half 138(55%) were below 30 years of age. Socio-economically, 145(58%) belonged to low, 70(28%) middle and 35(14%) to high socioeconomic groups. Of the total, 210(84%) cases had dengue fever followed by 32(12.8%) dengue haemorrhagic fever and 8(3.2%) dengue shock syndrome cases. Average duration of illness was 32+/-7.1 days. Overall direct cost per patient was Rs.35,823 (US$358) and average pre-hospitalisation, hospitalisation and post-hospitalisation was Rs.6154, Rs.21,242 and Rs.8,427 respectively. The overall disability adjusted life years per million population was 133.76. CONCLUSIONS: Although the government had provided free treatment for dengue in public-sector hospitals, still patients had to pay Rs.21,242 during hospital stay, resulting in substantial burden which needs to be addressed. PMID- 25933557 TI - Impact of facebook addiction on narcissistic behavior and self-esteem among students. AB - OBJECTIVE: To investigate the relationship between Facebook addiction, narcissism and self-esteem and to see if gender played any role in this equation. METHODS: The correlational study was conducted from February to March 2013 at the Department of Psychology, University of Sargodha, Punjab, Pakistan. Using convenient sampling, two equal groups of male and female students were enrolled from different departments of the university. Bergen Facebook Addiction Scale, Hypersensitive Narcissism Scale and Rosenberg's Self-esteem Scale were used for evaluation. SPSS 17 was used for statistical analysis. RESULTS: Of the 200 subjects in the study, 100(50%) each were males and females. Facebook addiction was positively correlated with narcissism(r=0.20; p<0.05) and negatively with self-esteem(r=-0.18; p<0.05). Relationship between narcissism and self-esteem was non-significant(r=0.05; p>0.05). Facebook addiction was a significant predictor of narcissistic behaviour (b=0.202; p<0.001) and low self-esteem (b=-0.18; p<0.001). There were no significant gender differences in the three variables (p>0.05 each). CONCLUSIONS: Facebook addiction was a significant predictor of narcissistic behaviour and low levels of self-esteem among students. PMID- 25933558 TI - Sleep quality and depression in hospitalized congestive heart failure patients. AB - OBJECTIVE: To assess the sleep pattern and depression in patients hospitalised with congestive heart failure, and to study the correlation of poor-quality sleep and depression. METHODS: The cross-sectional, descriptive, co-relational study was conducted from October 2011 to March 2012 and comprised New York Heart Association Class III or IV congestive heart failure patients aged >18 years, admitted at teaching hospitals of Rawalpindi, Pakistan. A standardised questionnaire designed in collaboration with cardiologists and psychiatrists of Rawalpindi Medical College and allied teaching hospitals was administered to the patients while they were hospitalised. Pittsburgh Sleep Quality Index and Beck Depression Inventory questionnaire were also used. Statistical analysis was done using SPSS 20. RESULTS: Of the 40 patients recruited, 26(65%) were males and 14(35%) were females. The overall mean age was 60+/-13 years. The mean Pittsburgh Sleep Quality Index score was 15.6+/-3, with 37(92.5%) patients having poor sleep quality. The mean depression score was 27.65+/-7.5, with all 40(100%) patients affected. Among them, 14(35.7%) patients had severe clinical depression. Class IV congestive heart failure patients suffered from greater daytime dysfunction (p<0.008) and poor sleep efficiency (p<0.009) compared to Class III. No association of poor sleep quality and depression was found with previous history of smoking, diabetes and hypertension. The study revealed a significant relationship between sleep quality and depression (p<0.005). CONCLUSIONS: Hospitalised congestive heart failure patients suffered from poor sleep and depressive symptoms with overall female predominance. The two symptoms were highly co-related and were more severe in Class IV patients than in Class III. A regular screening of such patients is thus essential for prognosis. PMID- 25933559 TI - Mesh fixation vs. non-fixation in total extra peritoneal mesh hernioplasty. AB - OBJECTIVE: To compare mesh fixation with non-fixation and its effect on outcome. METHODS: The interventional prospective study was conducted at the National Hospital & Medical Centre, Lahore from January 2007 to December 2008. After the two-year intervention period, the patients were followed up for 5 years. The selected patients were divided into two groups. In group 1, mesh fixation was performed with metal non-absorbable tackers and in group II no fixation of mesh was performed. Patients were followed up at 6, 12, 24 and 60 months. RESULTS: Of the 63 patients in the study, 32(50.7%) were in group I and 31(49.2% in group II. The Mean pain score in group I was 4.7+/-0.683 and 4.1+/-0.860 in group II (p< 0.001). Urinary retention was more common in group 1 (p>0.05), while recurrence was more common in group II (p>0.05). CONCLUSIONS: Pain was significantly less in the non-fixation group, while urinary retention and recurrence were not significantly increased. Non-fixation is a viable option for total extraperitoneal mesh hernioplasty and should be preferred over mesh fixation. PMID- 25933560 TI - Clinical and laboratory features of adult measles cases detected in Van, Turkey. AB - OBJECTIVE: To evaluate adult measles patients with respect to their clinical and laboratory findings as well as complications. METHODS: The retrospective study was conducted at YuzuncuYil University, Van, Turkey, between December 2012 and June 2013, and comprised cases diagnosed with measles. The diagnosis was based on clinical findings and all were serologically confirmed with the presence of Anti measles Immunoglobulin M antibodies. RESULTS: Of the 50 records studied, 41(84%) related to women. Overall mean age was 25.52+/-4.07 years. The most common symptoms were fever and rash 50(100%), malaise 49(98%), cough 48(96%), headache 44(88%) and sore throat 36(72%). The presence of Koplik spots, lymphadenopathy and hepatomegaly were observed in 3(6%), 6(12%) and 2(4%) patients respectively. Thrombocytopenia and elevated liver enzymes were detected in 26(52%) and 22(44%)patients. Pneumonia was the most common complication in 9(18%) patients. Other respiratory complications were bronchitis 5(10%) and laryngotracheitis 6(12%). Of the cases, 9(18%) exhibited otitis media. Premature delivery and spontaneous abortus occurred in 2(4%) and 3(6%) patients of the 15(30%) pregnant women. CONCLUSIONS: Measles continues to be an important health problem in Turkey and needs an effective elimination programme. PMID- 25933561 TI - A retrospective analysis of the treatment results of 1557 patients with acute cholecystitis. AB - OBJECTIVE: To analyse outcomes of variable management strategies for the treatment of Acute Cholecystitis in relation to morbidity, mortality and conversion to open surgery. METHODS: The retrospective study was conducted at Firat University Hospital, Turkey and comprised records of Acute Cholecystitis patients admitted between 2005 and 2011. Patients were divided into subgroups according to admission time as well as American Society of Anaesthesiologists score. The outcomes of early cholecystectomy, interval cholecystectomy, delayed cholecystectomy, 'cooling-off' therapy and percutaneous cholecystostomy were evaluated. Mortality, morbidity, and conversion to open surgery were calculated as measures of success. Data was analysed using SPSS. RESULTS: Of the 1557 patients, 1052(67.6%) were female. The overall mean age was 42.4+/-14.7 years. Success rates of 'cooling-off' therapy and percutaneous cholecystostomy were 89.3% and 96.3%, respectively. The conversion rate following delayed cholecystectomy was 30%, which was higher than that of both early and interval cholecystectomy (0.2% and 0%, respectively; p<0.001 each). Mortality and morbidity rates of delayed cholecystectomy (57.1% and 7.1%, respectively) were also significantly higher than early and interval cholecystectomy (5% and 0.1%; 5.6 and 0%, respectively). CONCLUSIONS: Early laparoscopic cholecystectomy and interval cholecystectomy shared similar outcomes and rates of efficacy. Percutaneous cholecystostomy was a successful treatment option for high-risk patients, while delayed cholecystostomy correlated to the highest rates of conversion to open surgery, mortality and morbidity. PMID- 25933562 TI - Coagulase negative staphylococci - a fast emerging threat. AB - OBJECTIVE: To determine the frequency of isolation of coagulase-negative staphylococci and their resistance to methicillin over a period of time. METHODS: The descriptive cross-sectional study was carried out at Army Medical College, Rawalpindi, from June 2009 to May 2012, and comprised clinical samples mostly from patients admitted to the intensive care unit. They were inoculated onto appropriate culture media depending upon the specimen. After 24-hour incubation at 35 degrees C, coagulase-negative staphylococci were identified on the basis of colony morphology, gram staining, a positive catalase and a negative tube coagulase test.Methicillin resistance among the isolated staphylococci was determined using a 30ug Cefoxitin disc as per the Clinical and Laboratory Standards Institute protocol. Number of coagulase-negative staphylococci for each year and their methicillin resistance rates were calculated. A comparison was made with methicillin resistant staphylococcus aureus) isolated during the same period. RESULTS: Of the total 1331 specimens studies over three years, 581(43.65%) were coagulase-negative staphylococci. The rate of coagulase-negative staphylococci and methicillin resistance was higher each year; 110(26.6%) in May 2009-Jun 2010, 134(36.5%) in 2011, and 337(61%) in 2012. Methicillin resistance rates also increased from 25(22.7%) to 46(34.3%) and then to 201(59.6%) in 2012.Maximum isolated specimens came from blood 311(53.5%), followed by pus/swabs 204(35.1%). CONCLUSIONS: The frequency of isolation of coagulase-negative staphylococci and its methicillin resistance among hospitalised patients is on the rise. PMID- 25933563 TI - Vulnerable road users are at greater risk during Ramadan -- results from road traffic surveillance data. AB - OBJECTIVE: To assess how the frequency, nature and outcome of road traffic crashes differ during the fasting month of Ramadan. METHODS: The retrospective study was conducted in Karachi and comprised data from the Road Traffic Injury Surveillance Project which entailed information on all road traffic injury victims presenting to Emergency Departments in the city between September 2006 and September 2011. Data was analysed to find the frequency of road traffic crashes according to time of incident, road user group and survival. Ramadan and Non-Ramadan groups were compared with respect to time and frequency of incidents, road user group and mortality. SPSS 16 was used for statistical analysis. RESULTS: There were 163,022 subjects from whom 13,640(8.36%) came during Ramadan and 149,382 (91.6%) during the non-Ramadan months. Frequency of road traffic crashes did not change significantly during Ramadan, but was clustered around the breaking of Fast and the Taravih prayers. The most commonly affected road user group was motorbike riders followed by pedestrians. Overall survival of the RTI victims was 96.1% with a mortality rate of 4.1% which was higher than the figure of 3.5% in the non-Ramadan period. CONCLUSIONS: Vulnerable road users were more frequently involved in road traffic injuries during Ramadan. Moreover, the frequency of crashes increased around evening which requires more careful planning of traffic controls, especially for the vulnerable road users. PMID- 25933564 TI - Major depression in Jalal Pur Jattan, district Gujrat, Pakistan: Prevalence and gender differences. AB - OBJECTIVE: To assess the prevalence of depression along gender lines in the general population. METHODS: Using multistage stratified proportionate sampling, the cross-sectional study was conducted in four Union Councils of Jalal Pur Jattan in Gujrat, Pakistan from November 2011 to November 2012. From each stratum, two samples were taken: adults and adolescents. Then each sample was divided into adult males and adult females (20-45 years); adolescent boys and adolescent girls (13-19 years). The questionnaire was developed on the basis of diagnostic criteria given in the revised version of the fourth edition of the Diagnostic and Statistical Manual of Mental Disorders. RESULTS: Of the total population of 28,259, 1117(3.6%) were approached for the study. Of them, 1110(99.3%) people participated. Overall, 173(15%) were found to be vulnerable to psychological problems whereas 59 (5.31%) were found as vulnerable cases to depression. However, the diagnosis of major depression was handed to 38(3.4%) respondents. Of these 38 subjects, 7(18.42%) persons were suffering from mild; 22(57.89%) from moderate, and 9(23.68%) from severe symptoms. Further, 30(78.9%) of these subjects were women. CONCLUSIONS: Major depression was prevailing in the community of Jalal Pur Jattan in almost the same ratio as in other places around the globe, and, therefore, the inhabitants need psychiatric services. PMID- 25933565 TI - Atrial and ventricular septal changes in ethanol vapour exposed chick embryos. AB - OBJECTIVE: To study the effects of ethanol vapour exposure on development of atrial and ventricular septa of chick embryo. METHODS: The experimental study was conducted at the College of Physicians and Surgeons, Islamabad, from 2006 to 2007. The experimental and control groups were further divided into three subgroups based on the day of sacrifice. The experimental group was exposed to ethanol vapours produced in a specially-designed vapour chamber and then compared with age-matched controls. RESULTS: There were 90 eggs in each of the two groups. The development of inter-ventricular septum completed at day 7 of development in chick embryo. Ethanol vapour exposure produced a small discontinuity at day 10 of development in a chick embryo which may be labelled as ventricular septal defect since ventricular development is completed by day 7. Interatrial septum formed till day 7 with small perforations which persisted till hatching. CONCLUSIONS: Ethanol vapour exposure may lead to ventricular septal defect. PMID- 25933566 TI - Effects of testosterone treatment on recovery of rat spermatogenesis after irradiation. AB - OBJECTIVE: To determine the effects of two different radiation doses on sperm parameters and the role of testosterone treatment on rat spermatogenesis. METHODS: The experimental animal study was conducted at Marmara University, Istanbul, Turkey, from September 2012 to January 2013. Male Sprague Dawley 4-6 months old rats weighing 300-350g were randomely divided into 5 equal groups as control, low dose irradiation, testosterone administration following low dose irradiation, high dose irradiation, and testosterone administration following high dose irradiation. The animals were kept at a constant temperature in a room with 12h light and dark cycles. After the group-wise intervention, sperm concentration, testicular size, and histopathological examination of seminiferous tubules were noted. SPSS 10 was used for statistical analysis. RESULTS: The 40 rats in the study were divided in 5 groups of 8(20%) each. In low dose radiation, adverse effects were only temporarily observed with the return of almost normal testicular function at the end of two months with or without testosterone supplementation. In contrast, in high dose radiation, hormonal treatment effect was controversial. CONCLUSIONS: Testosterone treatment had no significant effect upon recovery after irradiation. In order to prevent the untoward effects of radiation, shielding of the remaining testis in a proper manner is crucial to avoid the harmful effects of the scattered radiation. PMID- 25933568 TI - The emerging threat of MERS. PMID- 25933567 TI - Primary debulking surgery versus neo-adjuvant chemotherapy in stage III/IV ovarian cancer: Comparison of perioperative morbidity and survival data in Pakistani women. AB - OBJECTIVE: To compare the peri-operative morbidity and survival rates between ovarian cancer patients treated with two different approaches. METHODS: The retrospective study was conducted at Aga Khan University Hospital, Karachi, and comprised data related to patients with advanced stage ovarian carcinoma treated between 1999 and 2008. Medical records were reviewed and relevant demographic, clinical, surgical, pathologic and follow-up information was acquired. Progression-free survival and overall survival rates were compared between patients who underwent primary debulking surgery and those who had received neo adjuvant chemotherapy before surgery. SPSS 19 was used for statistical analysis. RESULTS: Of the total 118 patients, 78(66%) had undergone primary debulking surgery and 40(34%) had received neo-adjuvant chemotherapy. The mean age and pre operative carcinoma antigen-125 level were similar. The debulking group had 74(94.8%) patients with stage 3, and 4(5.1%) patients with stage 4 disease, while the other group had 32(80%) and 8(20%) with stage 3and 4 respectively. The frequency of optimal debulking was 42(56.8%) in the former group against 27(79.4%) in the latter (p=0.01). Duration of surgery, estimated blood loss >1500ml and stay at the intensive care unit were not statistically different (p>0.05). Rate of Urinary tract, bowel injury and bowel resections were also similar. There was no difference in the progression-free survival in both groups (p>0.05). CONCLUSIONS: Neo-adjuvant chemotherapy followed by interval debulking produced comparable survival rates and peri-operative complications. PMID- 25933569 TI - Opinions on age of marriage -- perspective from university students in Islamabad and Rawalpindi. AB - Child marriages are more common in developing countries, including Pakistan. This study was conducted to determine the perspective of university students on marriageable age in Islamabad and Rawalpindi. Cumulatively, 1039 students participated in this cross-sectional survey based on convenience sampling. There were statistically significant differences between male and female students pertaining to opinions about what should be the legal age for women and men. Male respondents were more likely to accept 16 years of legal age at marriage for both males as well as females. Female respondents rejected 16 years as the legal age of marriage for girls on physical and emotional health grounds as well as on having negative impact on girl's education. Results stress the need for better understanding of socio-cultural norms in the country to more effectively address and discourage the practice of child marriage in the country. PMID- 25933570 TI - Nail as a foreign body in a neonate, an unusual presentation at an unusual age. AB - Children are prone to ingest substances due to their exploratory nature and tendency to put everything in the mouth. Commonly ingested foreign bodies are coins, batteries and buttons. Foreign body ingestion in neonates is a very rare presentation and always needs important consideration as it can be a part of child abuse and can lead to serious life threatening consequences. PMID- 25933571 TI - Endovascular treatment of a post catheterization pseudoaneurysm: A stitch in time saves nine. AB - External iliac artery (EIA) pseudoaneurysms are a well-known complication after arterial catheterization procedures. Most develop as a result of high femoral puncture. Small asymptomatic pseudoaneurysms are usually of no consequence but large symptomatic pseudoaneurysm carries a significant risk of rupture with serious life-threatening consequences and needs to be treated. We report here a case of EIA pseudoaneurysm in a 60 year old male patient after a cardiac catheterization procedure. CT angiography demonstrated a large pseudoaneurysm arising from the EIA and compressing the urinary bladder. Patient complained of abdominal pain and felt dizzy and required transfusions due to rapidly developing anaemia secondary to blood loss. Conventional angiography revealed free extravasation of contrast from the EIA. Percutaneous intervention through femoral access was performed by deploying a covered stent which effectively sealed off the perforation site with no evidence of contrast extravasation. PMID- 25933572 TI - A case of nicotine withdrawal delirium. AB - Nicotine withdrawal is not a well recognized cause of delirium. A few published cases are on post-operative, terminally ill cancer or neuro-intensive care unit patients. Because of the high incidence of morbidity and mortality of delirium it is important to identify and treat delirium promptly and effectively. We report a case of delirium after sudden cessation of smoking in a heavy smoker, with schizophrenia, hospitalized for stabilization of psychiatric illness. PMID- 25933573 TI - Intra-intestinal mesh migration presenting with faecal fistula after incisional hernia repair. AB - Ventral hernias are a frequent problem in our society. Incisional hernia is not an infrequent sequel of ventral abdominal hernia repair. Incisional hernias are characterized by breakdown of the scar in the abdominal wall from an incision for any previous operation. This differentiates them from recurrent hernias where a previously done hernia repair operation breaks down. Such repairs are globally done by applying meshes of different sizes and types. Despite all the documented benefits of its use, a number of complications associated with mesh are reported in many studies. This study reports the case of a man operated for an incisional hernia, repaired by a proline mesh. He developed a complication of migrating mesh after 5 years of surgery at LUMHS, Jamshoro. There are very few such mesh complications reported in the literature. PMID- 25933574 TI - Re-recurrent Dermatofibrosarcomaprotuberans of the chest wall. AB - Dermatofibrosarcomaprotuberans is a rare, soft tissue tumour with high rate of recurrence. It is locally aggressive, with a low rate of metastasis. We describe the case of a 42 year old man who presented with a re-recurrent, large tumour situated on the anterior chest wall in the sternal region. We did a wide local excision and covered the resulting defect by using bilateral, pectoralis major myocutaneous flaps. Histopathology and immunohistochemical staining findings were consistent with the diagnosis of Dermatofibrosarcoma Protuberance. Post operatively the patient was treated with chemotherapy and radiotherapy. PMID- 25933575 TI - Post poliomyelitis syndrome: A rare sequel of acute poliomyelitis. AB - Post poliomyelitis syndrome (PPS) is a rare sequel of acute poliomyelitis, usually seen 30-40 years after an acute episode. It is characterized by new muscle weakness seen in survivors of acute poliomyelitis. We describe a rare case of a 50 year old man; with a previous history of poliomyelitis in right lower limb who now presented with complaints of progressive left lower limb weakness for past two years. The diagnosis was made on the basis of clinical suspicion and EMG findings. PPS is not a well recognized disease in Pakistan and due to the lack of documentation; its true prevalence is not known. Though, over the years, cases of Poliomyelitis have decreased worldwide, however, PPS still remains a constant challenge for the physicians. This report highlights the impact of the disease on the quality of life of patients suffering from PPS and emphasis on the need for new therapeutic approach. PMID- 25933576 TI - Mamun-TKC parathyroid retractor: Parathyroid glands squashed or scooped! AB - Parathyroid gland by its physiologic and anatomic diversity has interestingly been dealt by multiple specialties, including Urology. Besides primary hyperparathyroidism, urologists in close working relationship with nephrologists, tend to get referrals for tertiary hyperparathyroidism. Data from 1999 to 2012 was retrieved for all parathyroidectomies. Medical record of only cases undergoing parathyroidectomy utilising the instrument Mamun-TKC Parathyroid Retractor were reviewed. It is a metal body surgical instrument resembling Gil Vernet retractor having functional flat metal head attached to solid long handle, designed in two forms; one 'Straight' and other 'Angled' at 30 degrees . During the period, 28 cases of parathyroidectomies were performed. The instrument was used in two cases. It was found to facilitate dissection, retraction and pedicle ligation of parathyroid gland by a-traumatic handling. PMID- 25933577 TI - Consenting process in clinical trials. PMID- 25933578 TI - Instant gas geyser induced irreversible hypoxic ischaemic brain injury. PMID- 25933579 TI - An early tracheo-innominate fistula: lessons learnt from a clinical encounter. PMID- 25933580 TI - Background to the Discussion Paper: Proposed Recommendations for Myocardial Revascularisation. PMID- 25933581 TI - Effect of the Duration of Chronic Pancreatitis on Pancreas Islet Yield and Metabolic Outcome Following Islet Autotransplantation. AB - BACKGROUND: Total pancreatectomy (TP) with islet autotransplantation (IAT) is a highly selected treatment for severe pain associated with chronic pancreatitis (CP) after exhausting medical and endoscopic therapies. The effect of duration of CP on TP-IAT has not been clarified. METHODS: Retrospective review of a consecutive cohort undergoing TP-IAT was performed. Patients were classified according to islet dose of <2500 IEQ/kg, 2500 to 5000 IEQ/kg, and >5000 IEQ/kg. Islet yield and metabolic outcomes were compared to disease duration of CP. RESULTS: A total of 76 CP patients underwent TP-IAT. Longer disease duration was associated with lower islet yield transplanted (Spearman's correlation = -0.24; p = 0.04) for total cohort. Highest absolute value of the coefficient was found in patients with hereditary CP when study subjects were classified by the etiology of CP (correlation = -0.72; p = 0.02). Higher islet yields were significantly associated with better metabolic outcomes (7.6 +/- 1.1 vs 6.6 +/- 1.1% of HbA1c post-TPIAT in patients with <2500 and >5000 IEQ/kg transplanted, respectively; p = 0.04). CONCLUSIONS: The duration of CP could affect islet yield and metabolic outcomes. The time since the diagnosis of CP should be considered when selecting patients for islet autotransplantation. PMID- 25933582 TI - Variations in Metastasis Site by Primary Location in Colon Cancer. AB - OBJECTIVE: The purpose of this paper is to determine whether sites of distant recurrence are associated with specific locations of primary disease in colon cancer. METHODS: A cohort including all patients (n = 947) undergoing a segmental colonic resection for colon cancer at our center (2004-2011) comparing site specific metastatic presentation and recurrence rates, as well as their respective multivariable American Joint Committee on Cancer (AJCC) stage-adjusted hazard ratios (mHR). RESULTS: Right-sided colectomies (n = 557) had a lower overall metastasis rate (24.8% vs. 31.8%; P = 0.017; mHR = 1.24 [95% CI: 0.96 1.60]; P = 0.011) due to significantly lower pulmonary metastasis in follow-up (2.7% vs. 9%; P < 0.001; mHR = 0.32 [95% CI: 0.17-0.58]; P = 0.001) and lower overall liver metastasis rate (15.6 vs. 22.1%; P = 0.012; mHR = 0.74 [95% CI: 0.55-0.99];P = 0.050). Left colectomies (n = 127) had higher rates of liver metastasis during follow-up (9.4% vs. 4.8%; P = 0.029; mHR = 1.64 [95% CI: 0.86 3.15]; P = 0.134). Sigmoid resections (n = 238) had higher baseline rates of liver metastasis (17.1% vs. 11.3%; P = 0.015) and higher cumulative rates of lung (12.2% vs. 5.4%; P < 0.001; mHR = 2.26 [95% CI: 1.41-3.63]; P = 0.001) and brain metastases (2.3% vs. 0.6%; P = 0.033; mHR = 4.03 [95% CI: 1.14-14.3]; P = 0.031). Other sites of metastasis, including the (retro) peritoneum, omentum, ovary, and bone, did not yield significant differences. CONCLUSIONS: Important variations in site-specific rates of metastatic disease exist within major resection regions of colon cancer. These variations may be important to consider when evaluating options for adjuvant treatment and surveillance after resection of the primary disease. PMID- 25933583 TI - Factors associated with the differential in actual gestational age and gestational age predicted from transrectal ultrasonography in pregnant dairy cows. AB - The objective of the study was to determine (1) how gestational age predicted using transrectal ultrasonography related to actual gestational age derived as the number of days from the most recent artificial insemination date, (2) what factors, if any, were associated with the differential between the two measures, and (3) the association between this differential in gestational age and the likelihood of subsequent pregnancy loss, stillbirth, or calving dystocia. The data set contained 7340 ultrasound records from 6805 Holstein Friesian dairy cows in 175 herds. Ultrasonography assessment underestimated gestational age relative to days since last service by 0.51 days (standard error [SE]: 0.040), although the differential was less during embryonic development phase (i.e., <=42 days of gestation; mean overestimation of 0.31 days) versus fetal development phase (i.e., >42 days of gestation; mean underestimation of 0.81 days). Predicted calving date calculated from ultrasonography was 1.41 days (SE: 0.040) later than the actual subsequent calving date and was, on average, 0.52 days later than predicted calving date, assuming a gestation length of 282 days. Parity of the dam (P < 0.05), stage of pregnancy (P < 0.001), and sex of the calf born (P < 0.001) were all associated with the differential in gestational age based on ultrasonography versus days since last service. No obvious trend among parities was evident in the difference between the methods in predicting gestational age. Ultrasonography underestimated gestational age by 0.83 (SE: 0.15) days in parity 5+ cows and underestimated gestational age by 0.41 (SE: 0.14) days in the first parity cows. Relative to gestational age predicted from the most recent service, ultrasonography underestimated gestational age by 0.75 (SE: 0.13) days for heifer fetuses and underestimated gestational age by 0.36 (SE: 0.13) days for bull fetuses. The heritability of the differential in gestational age between the methods of prediction was low 0.05 (SE: 0.022), corroborating heritability estimates for most cow reproductive traits. Overestimation of gestational age using ultrasonography was associated with an increased likelihood of pregnancy loss (P < 0.001). Gender of calf born (P < 0.001), sire breed of calf (P < 0.001), and parity (P < 0.001) were all associated with gestation length. Gestation length was 1.27 days longer (SE: 0.01) for bull calves compared to heifer calves. Calves from beef sires had a longer gestation length than calves from dairy sires, and older parity cows had a longer gestation length than younger cows. The results highlight factors associated with differences in gestational age obtained from ultrasonography and insemination data and illustrate the value of ultrasonography for the prediction of calving date and pregnancy loss. PMID- 25933584 TI - Pharyngocutaneous fistula after total laryngectomy: A systematic review and meta analysis of risk factors. AB - OBJECTIVE: The pharyngocutaneous fistula (PCF) is the troublesome complication after total laryngectomy. Despite a large number of investigations having been performed, there is still controversy about which factors are most significant for PCF. The objective of the present meta-analysis was to analyze the potential risk factors for PCF after total laryngectomy. DATA SOURCES: Published English language literature. REVIEW METHODS: PubMed, Ovid, Cochrane, and Web of Science databases were systematically searched using multiple search terms. Twenty-one studies with 3832 patients were identified. The quality of evidence was assessed by The National Institute for Health and Clinical Excellence. RESULTS: Sixteen studies involving 2598 patients were included for the meta-analysis. The results showed that, tumor subsite (RR=0.64, 95% CI 0.47-0.88, P<0.01), T stage (RR=0.70, 95% CI 0.51-0.96, P=0.03), previous radiotherapy (RR=0.62, 95% CI 0.46-0.84, P<0.01), postoperative hemoglobin <12.5g/L (RR=0.46, 95% CI 0.27-0.76, P<0.01), and surgical margin (RR=0.41, 95% CI 0.22-0.74, P<0.01) were the risk factors associated with the development of PCF. CONCLUSIONS: From the results of our study, several significant risk factors for PCF are identified. Methodologically high-quality comparative studies are needed for further evaluation. PMID- 25933585 TI - Indications for superselective intra-arterial cisplatin infusion and concomitant radiotherapy in cases of hypopharyngeal cancer. AB - OBJECTIVE: We retrospectively assessed the indications for superselective intra arterial infusion of cisplatin with concomitant radiotherapy (RADPLAT) in patients with hypopharyngeal cancer (HPC). METHODS: Between April 2000 and March 2013, 41 previously untreated patients received superselective intra-arterial infusion of cisplatin (100-120mg/m(2) per week) with simultaneous intravenous infusions of thiosulfate to neutralize cisplatin toxicity and conventional radiotherapy (65-70Gy). RESULTS: During the median follow-up period of 5.5 years, a statistically significant difference in the 5-year overall survival was noted between patients with N0-1 (n=14) and N2b-3 disease (n=27). One-half of deaths were observed to be the result of distant metastasis. The 5-year local control and overall survival were significantly better in patients with unilateral than in those with bilateral primary tumors. All the patients with T4b disease (n=3) died of disease within 2 years. CONCLUSION: Indications for RADPLAT in patients with HPC were defined as patients with unilateral tumors staged as T3-4a and N0 1. PMID- 25933586 TI - Accuracy of high-resolution computed tomography in revealing fallopian canal fracture of patients with traumatic facial paralysis. AB - OBJECTIVES: To investigate accuracy of high-resolution computed tomography (HRCT) of temporal bone in revealing fallopian canal fracture among the patients with traumatic facial paralysis. METHODS: HRCT of temporal bone with cross-sectional scanning and multi-planar reformation (MPR) was performed on 31 patients with traumatic facial paralysis, and fracture sites of fallopian canal revealed by HRCT were retrospectively analyzed and compared with surgical findings. RESULTS: HRCT of temporal bone showed fracture of fallopian canal at geniculate ganglion in 25 cases, at tympanic segment in 15 cases, at labyrinthine segment in 5 cases, at pyramid segment in 2 cases, and at mastoid segment in one case, while surgical findings revealed that fracture involved geniculate ganglion in 27 cases, labyrinthine segment in 5, tympanic segment in 19, pyramid segment in 12, and mastoid segment in 9; the sensitivity of HRCT of temporal bone to detect fracture at such sites was 88.9%, 100%, 52.6%, 16.7% and 11.1%, respectively, and the specificity was 96.0%, 100%, 66.7%, 100% and 100%, respectively. CONCLUSION: HRCT of temporal bone was able to accurately reveal fracture of fallopian canal at geniculate ganglion and labyrinthine segment in the vast majority cases, but severely underestimated fracture at pyramid segment and mastoid segment of fallopian canal. PMID- 25933587 TI - Comparison of vocal outcomes after angiolytic laser surgery and microflap surgery for vocal polyps. AB - OBJECTIVE: The microflap technique is a standard procedure for the treatment of vocal fold polyps. Angiolytic laser surgery carried out under topical anesthesia is an alternative method for vocal polyp removal. However, it is not clear whether angiolytic laser surgery has the same effects on vocal outcomes as the microflap technique because of a lack of studies comparing both procedures. In the current study, vocal outcomes after both procedures were compared to clarify the effects of angiolytic laser surgery for vocal polyp removal. METHODS: Vocal outcomes were reviewed for patients who underwent angiolytic laser surgery (n=20, laser group) or microflap surgery (n=34, microflap group) for vocal polyp removal. The data analyzed included patient and lesion characteristics, number of surgeries required for complete resolution, and aerodynamic and acoustic examinations before and after surgery. RESULTS: In the laser surgery group, complete resolution of the lesion was achieved with a single procedure in 17 cases (85%) and with two procedures in 3 cases (15%). Postoperative aerodynamic and acoustic parameters demonstrated significant improvement compared to preoperative parameters in both the laser surgery group and the microflap surgery group. There were no significant differences in any postoperative aerodynamic and acoustic parameters between the two groups. CONCLUSION: The current retrospective study demonstrated that angiolytic laser surgery achieved complete resolution of vocal polyps within two procedures. Postoperative effects on aerodynamic and acoustic functions were similar to those after microflap surgery. PMID- 25933588 TI - Red blood cell washing, nitrite therapy, and antiheme therapies prevent stored red blood cell toxicity after trauma-hemorrhage. AB - Transfusion of stored red blood cells (RBCs) is associated with increased morbidity and mortality in trauma patients. Pro-oxidant, pro-inflammatory, and nitric oxide (NO) scavenging properties of stored RBCs are thought to underlie this association. In this study we determined the effects of RBC washing and nitrite and antiheme therapy on stored RBC-dependent toxicity in the setting of trauma-induced hemorrhage. A murine (C57BL/6) model of trauma-hemorrhage and resuscitation with 1 or 3 units of RBCs stored for 0-10 days was used. Tested variables included washing RBCs to remove lower MW components that scavenge NO, NO-repletion therapy using nitrite, or mitigation of free heme toxicity by heme scavenging or preventing TLR4 activation. Stored RBC toxicity was determined by assessment of acute lung injury indices (airway edema and inflammation) and survival. Transfusion with 5 day RBCs increased acute lung injury indexed by BAL protein and neutrophil accumulation. Washing 5 day RBCs prior to transfusion did not decrease this injury, whereas nitrite therapy did. Transfusion with 10 day RBCs elicited a more severe injury resulting in ~90% lethality, compared to <15% with 5 day RBCs. Both washing and nitrite therapy significantly protected against 10 day RBC-induced lethality, suggesting that washing may be protective when the injury stimulus is more severe. Finally, a spectral deconvolution assay was developed to simultaneously measure free heme and hemoglobin in stored RBC supernatants, which demonstrated significant increases of both in stored human and mouse RBCs. Transfusion with free heme partially recapitulated the toxicity mediated by stored RBCs. Furthermore, inhibition of TLR4 signaling, which is stimulated by heme, using TAK-242, or hemopexin-dependent sequestration of free heme significantly protected against both 5 day and 10 day mouse RBC-dependent toxicity. These data suggest that RBC washing, nitrite therapy, and/or antiheme and TLR4 strategies may prevent stored RBC toxicities. PMID- 25933589 TI - Cis-regulatory elements involved in species-specific transcriptional regulation of the SVCT1 gene in rat and human hepatoma cells. AB - Ascorbic acid is transported into cells by the sodium-coupled vitamin C transporters (SVCTs). Recently, we obtained evidence of differential regulation of SVCT expression in response to acute oxidative stress in cells from species that differ in their capacity to synthesize vitamin C, with a marked decrease in SVCT1 mRNA and protein levels in rat hepatoma cells that was not observed in human hepatoma cells. To better understand the regulatory aspects involved, we performed a structural and functional analysis of the proximal promoter of the SVCT1 rat gene. We cloned a 1476-bp segment containing the proximal promoter of the rat SVCT1 gene and generated deletion-derived truncated promoters of decreasing sizes and mutant promoters by modification of consensus binding sites for transcription factors by site-directed mutagenesis. We next analyzed their capacity to direct the transcription of a reporter gene after transfection into rat H4IIE and human HepG2 hepatoma cells, in experiments involving the coexpression of transcription factors whose consensus binding sequences are present in the SVCT1 promoter. This analysis revealed the presence of two critical cis-regulatory elements of the transcriptional activity of the rat SVCT1 gene promoter, sites containing consensus sequences for the binding of the transcription factors Bach1 and HNF4 that are not present in equivalent locations in the human SVCT1 gene promoter. Moreover, a consensus site for HNF1 that is crucial for the regulation of the human SVCT1 promoter is present in the SVCT1 rat promoter but has no effect on its transcriptional activity. These findings imply that regulation of vitamin C metabolism in the rat, a species with the capacity to synthesize large amounts of ascorbic acid, may differ from that of humans, a species that must obtain ascorbic acid from the diet through a transport mechanism that depends on proper SVCT1 expression. PMID- 25933590 TI - Spin trapping combined with quantitative mass spectrometry defines free radical redistribution within the oxidized hemoglobin:haptoglobin complex. AB - Extracellular or free hemoglobin (Hb) accumulates during hemolysis, tissue damage, and inflammation. Heme-triggered oxidative reactions can lead to diverse structural modifications of lipids and proteins, which contribute to the propagation of tissue damage. One important target of Hb's peroxidase reactivity is its own globin structure. Amino acid oxidation and crosslinking events destabilize the protein and ultimately cause accumulation of proinflammatory and cytotoxic Hb degradation products. The Hb scavenger haptoglobin (Hp) attenuates oxidation-induced Hb degradation. In this study we show that in the presence of hydrogen peroxide (H2O2), Hb and the Hb:Hp complex share comparable peroxidative reactivity and free radical generation. While oxidation of both free Hb and Hb:Hp complex generates a common tyrosine-based free radical, the spin-trapping reaction with 5,5-dimethyl-1-pyrroline N-oxide (DMPO) yields dissimilar paramagnetic products in Hb and Hb:Hp, suggesting that radicals are differently redistributed within the complex before reacting with the spin trap. With LC MS(2) mass spectrometry we assigned multiple known and novel DMPO adduct sites. Quantification of these adducts suggested that the Hb:Hp complex formation causes extensive delocalization of accessible free radicals with drastic reduction of the major tryptophan and cysteine modifications in the beta-globin chain of the Hb:Hp complex, including decreased betaCys93 DMPO adduction. In contrast, the quantitative changes in DMPO adduct formation on Hb:Hp complex formation were less pronounced in the Hb alpha-globin chain. In contrast to earlier speculations, we found no evidence that free Hb radicals are delocalized to the Hp chain of the complex. The observation that Hb:Hp complex formation alters free radical distribution in Hb may help to better understand the structural basis for Hp as an antioxidant protein. PMID- 25933591 TI - The Epidemiology of Imported Malaria and Transfusion Policy in 5 Nonendemic Countries. AB - Addressing risk of imported malaria is complicated by 5 human species of Plasmodium, semi-immunity in donors with long-term exposure, increasing travel and immigration, changing risk in endemic areas, and limitations of screening assays. To gain insight into policy formulation, we have compiled epidemiologic data from 5 countries with different policies involving either deferral (the United States and Canada) or selective testing (France, England, and Australia). The greatest risk is from semi-immune former residents of endemic areas, but the greatest impact on sufficiency (donor loss) is from low-risk short-term travel. France and the UK have the highest rates of travel to Africa where most malaria cases originate. The UK has substantial travel to the Indian subcontinent where Plasmodium vivax cases are more common, and Australia, to Southeast Asia and Papua New Guinea. In the United States and Canada, malaria risk travel is more often to lower risk areas such as Mexico and the Caribbean. Each country has imported cases, predominantly Plasmodium falciparum and P. vivax, although data are incomplete. Transfusion-transmitted malaria has been rare over the last 10 years, generally involving P. falciparum, but there were 2 US cases of Plasmodium malariae. Uncertainty due to limitations of epidemiologic data and reliance on donors' answers underpins much of the complexity of policy formulation. Variability in policies between countries reflects not only epidemiologic differences but also operational considerations, donor demographics, regulatory approaches, and public pressure to react to rare transfusion-transmitted malaria cases. Testing reduces the operational impact of addressing the very small risk from travelers and offers improvement over deferral by testing all former residents of endemic areas. Notwithstanding current international regulatory requirements, policies have "evolved" through a series of additions and revisions as concerns and issues arose, with resultant variability in donor selection criteria. PMID- 25933592 TI - Discovery of a potent microtubule-targeting agent: Synthesis and biological evaluation of water-soluble amino acid prodrug of combretastatin A-4 derivatives. AB - Amino acid prodrugs are known to be very useful for improving the aqueous solubility of sparingly water soluble drugs (Drug Discovery Today 2013, 18, 93). Therefore, we synthesized eleven novel combretastatin A-4 amino acid derivatives and evaluated their anti-tumor activities in vitro and in vivo. Among them, compound 15 (valine attached to compound 3, which was shown to be a potent tubulin polymerization inhibitor in our previous study) exhibited high efficacy in tumor-bearing mice, and pharmacokinetic analysis in rats indicated that compound 15 was an effective prodrug as well. Besides, compound 15 significantly inhibited tubulin polymerization in vitro and in vivo by binding to the colchicine binding site. In addition, compound 15 induced cell cycle arrest in the G2/M phase and triggered apoptosis in a caspase-dependent manner. In conclusion, our study showed that compound 15 could have significant anti-tumor activity as a novel microtubule polymerization disrupting agent with improved aqueous solubility. PMID- 25933593 TI - PMA-SiO2 catalyzed synthesis of indolo[2,3-c]quinolines as potent anti cancer agents. AB - PMA-SiO2 catalyzed Pictet-Spengler reaction of aryl amine linked to C-3 of the indole and the aryl aldehydes was achieved. In the series of the synthesized compounds, 6b, 10b and 12b were found to be cytotoxic against prostate, lung, breast and cervical cancer cell lines selectively with no significant effect on the growth of the control fibroblast cell line NIH3T3. Further determining their cytotoxic potential we found that 10b and 12b show cell cycle arrest in DU145 prostate cancer cells indicating a role in cell cycle progression. Both the molecules showed effect on decreased phosphorylation of NF-kappaB on serine 536 residue which is strongly implicated in many different types of cancers. Taken together, the series of indoloquinolines elicit potent anti-cancer potential providing a mean for developing novel indoloquinoline based anti-cancer agents. PMID- 25933595 TI - Chemical constituents from Sonneratia ovata Backer and their in vitro cytotoxicity and acetylcholinesterase inhibitory activities. AB - Sonneratia ovata Backer, Sonneratiaceae, is a widespread plant in mangrove forests in Vietnam, Cambodia, Thailand, Indonesia. Sonneratia ovata's chemical composition remains mostly unknown. Therefore, we now report on the structural elucidation of three new phenolics, sonnerphenolic A (1), sonnerphenolic B (2), and sonnerphenolic C (23), a new cerebroside, sonnercerebroside (3) together with nineteen known compounds, including nine lignans (5-13), two steroids (14, 15), two triterpenoids (16, 17), three gallic acid derivatives (18-20), two phenolic derivatives (4, 22) and a 1-O-benzyl-beta-d-glucopyranose (21) isolated from the leaves of Sonneratia ovata. Their chemical structures were established by spectroscopic data, as well as high resolution mass spectra and comparison with literature data. The in vitro acetylcholinesterase (AChE) inhibition and cytotoxic activities against HeLa (human epithelial carcinoma), NCI-H460 (human lung cancer), MCF-7 (human breast cancer) cancer cell lines and PHF (primary human fibroblast) cell were evaluated on some extracts and purified compounds at a concentration of 100 MUg/mL. Compounds (5, 6, 23) exhibited cytotoxicity against the MCF-7 cell line with the IC50 values of 146.9+/-9.0, 114.5+/-7.2, and 112.8+/-9.4 MUM, respectively, while they showed nontoxic with the normal cell (PHF) with IC50s >277 MUM. Among 15 tested compounds, (S)-rhodolatouchol (22) showed inhibition against AChE with an IC50 value of 96.1+/-14.5 MUM. PMID- 25933594 TI - Boronic acid-containing CXCR1/2 antagonists: Optimization of metabolic stability, in vivo evaluation, and a proposed receptor binding model. AB - Blockade of undesired neutrophil migration to sites of inflammation remains an area of substantial pharmaceutical interest. To effect this blockade, a validated therapeutic target is antagonism of the chemokine receptor CXCR2. Herein we report the discovery of 6-(2-boronic acid-5-trifluoromethoxy-benzylsulfanyl)-N-(4 fluoro-phenyl)-nicotinamide 6, an antagonist with activity at both CXCR1 and CXCR2 receptors (IC50 values 31 and 21 nM, respectively). Compound 6 exhibited potent inhibition of neutrophil influx in a rat model of pulmonary inflammation, and is hypothesized to interact with a unique intracellular binding site on CXCR2. Compound 6 (SX-576) is undergoing further investigation as a potential therapy for pulmonary inflammation. PMID- 25933596 TI - The Impact of Endoscopic Third Ventriculostomy on Shunt Revision Rate: A 14-Year Experience at a Single Institution. AB - BACKGROUND: Shunt-related procedures in the treatment of hydrocephalus are often associated with malfunction and revision resulting in significant patient morbidity and financial impact on the health care system. The increased utilization of endoscopic third ventriculostomy (ETV) as an alternative treatment paradigm for obstructive hydrocephalus carries the theoretical expectation of concomitant decreased numbers of shunt procedures. The objective of the present study was to determine the impact of ETV on shunt-related procedures within a 14 year interval (1998-2011), during which ETV has gained wider acceptance and greater utilization. METHODS: This retrospective chart review describes the annual rate of pediatric patients who underwent either ETV or shunt-related procedures at New York Presbyterian Hospital Weill-Cornell Medical Center. Statistical analyses were done to analyze possible correlation between relative rates of these cases. RESULTS: During the 14-year study period, 954 procedures were performed for the treatment of hydrocephalus (159 ETVs and 795 shunt-related procedures). Of the shunts, 356 were initial insertions and 439 were revisions. The number of ETVs increased from 8 procedures in 1998/1999 to 34 in 2010/2011, whereas the total number of annual shunt-related procedures decreased from 146 to 99. The relative ratios of ETVs and shunt-related procedures to the total number of cases demonstrate an inverse relationship over time (Spearman correlation coefficient rs = -1.0; P = 0.0004). CONCLUSIONS: Based on prior cost effectiveness analyses, the observed trend of the inverse correlation between ETVs and shunt-related procedures may contribute to financial savings and improvement in patient outcomes. Further study is required to define the impact on morbidity and associated success rates. PMID- 25933597 TI - Oncologic Surgery to the Ciliary Region. AB - Dermatologic surgery for tumors affecting only the ciliary region is not very common and it can sometimes be difficult to find published descriptions that deal specifically with surgery to this area. However, reconstruction of the ciliary region is very important, not only because this region is necessary to protect the eye, but also because its position and continuity are of great importance in facial expression, aesthetic appearance, and harmony. We present the cases of patients who have undergone oncologic surgery to the eyebrow region in our department in recent years and review the different techniques proposed for reconstruction of this region. PMID- 25933598 TI - Food Effect in Humans: Predicting the Risk Through In Vitro Dissolution and In Vivo Pharmacokinetic Models. AB - In vitro and in vivo experimental models are frequently used to assess a new chemical entity's (NCE) biopharmaceutical performance risk for food effect (FE) in humans. Their ability to predict human FE hinges on replicating key features of clinical FE studies and building an in vitro-in vivo relationship (IVIVR). In this study, 22 compounds that span a wide range of physicochemical properties, Biopharmaceutics Classification System (BCS) classes, and food sensitivity were evaluated for biorelevant dissolution in fasted- and fed-state intestinal media and the dog fed/fasted-state pharmacokinetic model. Using the area under the curve (AUC) as a performance measure, the ratio of the fed-to-fasted AUC (FE ratio) was used to correlate each experimental model to FE ratio in humans. A linear correlation was observed for the in vitro dissolution-human IVIVR (R (2) = 0.66, % mean square error 20.7%). Similarly, the dog FE ratio correlated linearly with the FE ratio in humans (R (2) = 0.74, % mean square error 16.25%) for 15 compounds. Data points near the correlation line indicate dissolution-driven mechanism for food effect, while deviations from the correlation line shed light on unique mechanisms that can come into play such as GI physiology or unusual physicochemical properties. In summary, fed/fasted dissolution studies and dog PK studies show a reasonable correlation to human FE, hence are useful tools to flag high-risk NCEs entering clinical development. Combining kinetic dissolution, dog FE model and in silico modeling one can study FE mechanism and formulation strategies to mitigate the FE risk. PMID- 25933599 TI - Antibody Drug Conjugates: Application of Quantitative Pharmacology in Modality Design and Target Selection. AB - Antibody drug conjugates (ADCs) are a multi-component modality comprising of an antibody targeting a cell-specific antigen, a potent drug/payload, and a linker that can be processed within cellular compartments to release payload upon internalization. Numerous ADCs are being evaluated in both research and clinical settings within the academic and pharmaceutical industry due to their ability to selectively deliver potent payloads. Hence, there is a clear need to incorporate quantitative approaches during early stages of drug development for effective modality design and target selection. In this review, we describe a quantitative approach and framework for evaluation of the interplay between drug- and systems dependent properties (i.e., target expression, density, localization, turnover, and affinity) in order to deliver a sufficient amount of a potent payload into the relevant target cells. As discussed, theoretical approaches with particular considerations given to various key properties for the target and modality suggest that delivery of the payload into particular effect cells to be more sensitive to antigen concentrations for targets with slow turnover rates as compared to those with faster internalization rates. Further assessments also suggest that increasing doses beyond the threshold of the target capacity (a function of target internalization and expression) may not impact the maximum amount of payload delivered to the intended effect cells. This article will explore the important application of quantitative sciences in selection of the target and design of ADC modalities. PMID- 25933600 TI - A Systematic Analysis of the Sensitivity of Plasma Pharmacokinetics to Detect Differences in the Pulmonary Performance of Inhaled Fluticasone Propionate Products Using a Model-Based Simulation Approach. AB - The role of plasma pharmacokinetics (PK) for assessing bioequivalence at the target site, the lung, for orally inhaled drugs remains unclear. A validated semi mechanistic model, considering the presence of mucociliary clearance in central lung regions, was expanded for quantifying the sensitivity of PK studies in detecting differences in the pulmonary performance (total lung deposition, central-to-peripheral lung deposition ratio, and pulmonary dissolution characteristics) between test (T) and reference (R) inhaled fluticasone propionate (FP) products. PK bioequivalence trials for inhaled FP were simulated based on this PK model for a varying number of subjects and T products. The statistical power to conclude bioequivalence when T and R products are identical was demonstrated to be 90% for approximately 50 subjects. Furthermore, the simulations demonstrated that PK metrics (area under the concentration time curve (AUC) and C max) are capable of detecting differences between T and R formulations of inhaled FP products when the products differ by more than 20%, 30%, and 25% for total lung deposition, central-to-peripheral lung deposition ratio, and pulmonary dissolution characteristics, respectively. These results were derived using a rather conservative risk assessment approach with an error rate of <10%. The simulations thus indicated that PK studies might be a viable alternative to clinical studies comparing pulmonary efficacy biomarkers for slowly dissolving inhaled drugs. PK trials for pulmonary efficacy equivalence testing should be complemented by in vitro studies to avoid false positive bioequivalence assessments that are theoretically possible for some specific scenarios. Moreover, a user-friendly web application for simulating such PK equivalence trials with inhaled FP is provided. PMID- 25933601 TI - Endoscopic intracranial surgery enhanced by electromagnetic-guided neuronavigation in children. AB - PURPOSE: Navigated intracranial endoscopy with conventional technique usually requires sharp head fixation. In children, especially in those younger than 1 year of age and in older children with thin skulls due to chronic hydrocephalus, sharp head fixation is not possible. Here, we studied the feasibility, safety, and accuracy of electromagnetic (EM)-navigated endoscopy in a series of children, obviating the need of sharp head fixation. METHODS: Seventeen children (ten boys, seven girls) between 12 days and 16.8 years (mean age 4.3 years; median 14 months) underwent EM-navigated intracranial endoscopic surgery based on 3D MR imaging of the head. Inclusion criteria for the study were intraventricular cysts, arachnoid cysts, aqueduct stenosis for endoscopic third ventriculostomy (ETV) with distorted ventricular anatomy, the need of biopsy in intraventricular tumors, and multiloculated hydrocephalus. A total of 22 endoscopic procedures were performed. Patients were registered for navigation by surface rendering in the supine position. After confirming accuracy, they were repositioned for endoscopic surgery with the head fixed slightly on a horseshoe headholder. EM navigation was performed using a flexible stylet introduced into the working channel of a rigid endoscope. Neuronavigation accuracy was checked for deviations measured in millimeters on screenshots after the referencing procedure and during surgery in the coronal (z = vertical), axial (x = mediolateral), and sagittal (y = anteroposterior) planes. RESULTS: EM-navigated endoscopy was feasible and safe. In all 17 patients, the aim of endoscopic surgery was achieved, except in one case in which a hemorrhage occurred, blurring visibility, and we proceeded with open surgery without complications for the patient. Navigation accuracy for extracranial markers such as the tragus, bregma, and nasion ranged between 1 and 2.5 mm. Accuracy for fixed anatomical structures like the optic nerve or the carotid artery varied between 2 and 4 mm, while there was a broader variance of accuracy at the target point of the cyst itself ranging between 2 and 9 mm. CONCLUSIONS: EM-navigated endoscopy in children is a safe and useful technique enhancing endoscopic intracranial surgery and obviating the need of sharp head fixation. It is a good alternative to the common opto-electric navigation system in this age group. PMID- 25933602 TI - Evaluation of cardiac masses by real-time perfusion imaging echocardiography. AB - BACKGROUND: Diagnosis of cardiac masses is still challenging by echocardiography and distinguishing tumors from thrombi has important therapeutical implications. We sought to determine the diagnostic value of real-time perfusion echocardiography (RTPE) for cardiac masses characterization. METHODS: We prospectively studied 86 patients, 23 with malignant tumors (MT), 26 with benign tumors (BT), 33 with thrombi and 6 with pseudotumors who underwent RTPE. Mass perfusion was analyzed qualitatively and blood flow volume (A), blood flow velocity (beta), and microvascular blood flow (A x beta) were determined by quantitative RTPE. RESULTS: Logistic regression models showed that the probability of having a tumor increased by 15.8 times with a peripheral qualitative perfusion pattern, and 34.5 times with a central perfusion pattern, in comparison with the absence of perfusion. Using quantitative RTPE analysis, thrombi group had parameters of blood flow lower than tumor group. A values for thrombi, MT, and BT were 0.1 dB (0.01-0.22), 2.78 dB (1-7) and 2.58 dB (1.44-5), respectively; p < 0.05, while A x beta values were 0.0 dB/s(-1) (0.01-0.14), 2.00 dB/s(-1) (1-6), and 1.18 dB/s(-1) (0.52-3), respectively; p < 0.05. At peak dipyridamole stress, MT had greater microvascular blood volume than BT [A = 4.18 dB (2.14-7.93) versus A = 2.04 dB (1.09-3.55); p < 0.05], but no difference in blood flow [Axbeta = 2.46 dB/s(-1) (1.42-4.59) versus Axbeta = 1.55 dB/s [1] (0.51-4.08); p = NS]. An A value >3.28 dB at peak dipyridamole stress predicted MT (AUC = 0.75) and conferred 5.8-times higher chance of being MT rather than BT. CONCLUSION: RTPE demonstrated that cardiac tumors have greater microvascular blood volume and regional blood flow when compared with thrombi. Dipyridamole stress was useful in differentiating MT from BT. PMID- 25933603 TI - Plasmablastic lymphoma of the oral cavity with breast recurrence: a case report. AB - BACKGROUND: Plasmablastic lymphoma is an aggressive variant of diffuse large B cell lymphoma, mostly found in the oral cavity and associated with human immunodeficiency virus. There are no clear guidelines for its treatment. Therapies more intensive than cyclophosphamide, doxorubicin, vincristine, and prednisone are not associated with a prolonged survival. Lymphomas of the breast are rare, in one series representing 0.14% of all female breast malignancies, with diffuse large B cell lymphoma comprising up to 55% of all cases. Only one case of plasmablastic lymphoma involving the breast has been reported in the literature. CASE PRESENTATION: A 30 year old Pakistani woman, presented with a small nodule in the floor of the mouth. An excisional biopsy revealed CD20, CD3, and CD117 negative and CD138, CD79a, CD56, MUM1/IFR4 and CD30 positive lesion with Ki-67 of 60% with cells which were plasmablastic in appearance. The morphological and immunohistochemistry features were consistent with plasmablastic lymphoma. The staging scans did not reveal any lymphadenopathy and the bone marrow biopsy and human immunodeficiency virus test were both negative. After treatment with four courses of CHOP and later radiation to the floor of the mouth, her disease was in complete remission. Two months later, she presented with velvety red lesions in both breasts and its trucut biopsy was consistent with plasmablastic lymphoma. Her CT scans revealed multiple nodules involving both breasts with no lymphadenopathy. The bone marrow was now positive for disease. Her disease continued to progress despite second and third line chemotherapy with DHAP (dexamethasone, cisplatin and cytarabine) and ICE (ifosfamide, carboplatin and etoposide) respectively. Her last CT scans revealed progressive disease with new lung lesions. The patient decided to opt for best supportive care. CONCLUSION: To our knowledge this is the second report of plasmablastic lymphoma involving the breast. The patient who was human immunodeficiency virus negative and immune competent had progressive disease despite three lines of chemotherapies with an overall survival (to date) of 15 months. PMID- 25933604 TI - Psychological antecedents of excess gestational weight gain: a systematic review. AB - BACKGROUND: Excess gestational weight gain (GWG), which has reached epidemic proportions, is associated with adverse outcomes during pregnancy and postpartum obesity in women and children. Psychological variables represent potentially modifiable factors. Moreover, previous systematic reviews on GWG interventions have called for the need for a clearer understanding of psychological factors affecting GWG. Hence, a systematic review was conducted to summarize the relation between psychological factors and GWG. METHODS: Eight databases were searched, and the guidelines on Preferred Reporting Items for Systematic Reviews and Meta Analyses were followed. Methodological quality of the included studies was assessed using a modified Newcastle-Ottawa scale. Two assessors independently reviewed titles, abstracts and full articles, extracted data and assessed quality. RESULTS: A total of 6198 titles and abstracts were reviewed of which 90 full text articles were retrieved. Thirty-five studies (25 cohort, eight cross sectional and two case-control) met the inclusion criteria, assessing 26 different psychological constructs in affect, cognitions and personality. Negative affective states such as depression, anxiety and stress were not related to excess GWG. Among weight-related and dietary-related cognitions, risk factors for excess GWG included concern about weight gain, negative body image and attitude towards weight gain, inaccurate perceptions regarding weight, higher than recommended target weight gain, less knowledge about weight gain, higher levels of cognitive dietary restraint, and perceived barriers to healthy eating. Protective factors included an internal locus of control for weight gain, lower than recommended target weight gain and higher self-efficacy for healthy eating. Only one study examined the relation between personality and excess GWG. CONCLUSION: In this systematic review, a number of cognitive factors were identified that were associated with excess GWG. To address excess GWG, more high quality, adequately powered studies are required examining cognitions, motivation and personality factors. PMID- 25933605 TI - Minocycline does not affect long-term potentiation in the anterior cingulate cortex of normal adult mice. AB - It has been reported that activated microglia plays important roles in chronic pain-related sensory signaling at the spinal cord dorsal horn. Less is known about the possible contribution of microglia to cortical plasticity that has been found to be important for chronic pain. In the present study, we used a 64 channel multi-electrode array recording system to investigate the role of microglia in cortical plasticity of the anterior cingulate cortex (ACC) in normal adult mice. We found that bath application of minocycline, an inhibitor of microglial activation, had no effect on postsynaptic LTP (post-LTP) induced by theta burst stimulation in the ACC. Furthermore, presynaptic LTP (pre-LTP) induced by the combination of low-frequency stimulation with a GluK1-containing kainate receptor agonist was also not affected. The spatial distribution of post LTP or pre-LTP among the cingulate network is also unaltered by minocycline. Our results suggest that minocycline does not affect cingulate plasticity and neurons are the major player in pain-related cortical plasticity. PMID- 25933606 TI - Pydna: a simulation and documentation tool for DNA assembly strategies using python. AB - BACKGROUND: Recent advances in synthetic biology have provided tools to efficiently construct complex DNA molecules which are an important part of many molecular biology and biotechnology projects. The planning of such constructs has traditionally been done manually using a DNA sequence editor which becomes error prone as scale and complexity of the construction increase. A human-readable formal description of cloning and assembly strategies, which also allows for automatic computer simulation and verification, would therefore be a valuable tool. RESULTS: We have developed pydna, an extensible, free and open source Python library for simulating basic molecular biology DNA unit operations such as restriction digestion, ligation, PCR, primer design, Gibson assembly and homologous recombination. A cloning strategy expressed as a pydna script provides a description that is complete, unambiguous and stable. Execution of the script automatically yields the sequence of the final molecule(s) and that of any intermediate constructs. Pydna has been designed to be understandable for biologists with limited programming skills by providing interfaces that are semantically similar to the description of molecular biology unit operations found in literature. CONCLUSIONS: Pydna simplifies both the planning and sharing of cloning strategies and is especially useful for complex or combinatorial DNA molecule construction. An important difference compared to existing tools with similar goals is the use of Python instead of a specifically constructed language, providing a simulation environment that is more flexible and extensible by the user. PMID- 25933607 TI - Current state and trends of access to sanitation in Ethiopia and the need to revise indicators to monitor progress in the Post-2015 era. AB - BACKGROUND: Investigating the current level and trends of access and identifying the underlying challenges to sanitation system development will be useful in determining directions developing countries are heading as they plan to promote sustainable development goals (post 2015 agenda). This research investigates the status and trends of access to improved sanitation coverage (ISC) in relation to the MDG target in Ethiopia with the aim of identifying prevailing constraints and suggesting the way forward in the post-MDG era. METHOD: We examined data from a nationwide inventory conducted in accordance with the sanitation ladder at the national level and from a household survey in randomly selected urban slums in Addis Ababa. The inventory data were analyzed and interpreted using the conceptual model of the sanitation ladder. We used administrative reports and survey results to plot the time trend of the ISC. RESULTS: The data from the nationwide inventory of sanitation facilities, which are presented along the sanitation ladder reveal that more than half of the Ethiopian population (52.1%) still used unimproved sanitation facilities in 2014. The majority (35.6%) practiced open defecation, implying that the country is far from the MDG target for access to improved sanitation (56%). Most people in urban slums (88.6%) used unimproved sanitation facilities, indicating that the urban poor did not receive adequate sanitation services. Trend analysis shows that access to ISC has increased, but Central Statistical Authority (CSA) data reveal a decline. This discrepancy is due to differences in data collection methods and tools. Dry pit latrines are the most widely used toilet facilities in Ethiopia, accounting for about 97.5% of the ISC. CONCLUSION: The sanitation coverage is far from the MDG target and the majority of the population, mainly the urban poor, are living in a polluted environment, exposed to water and sanitation-related diseases. The sanitation coverage estimates might be even lower if proper utilization, regular emptying, and fecal sludge management (FSM) of dry pit latrines were considered as indicators. In order to enhance sanitation services for all in the post-MDG era, urgent action is required that will establish proper monitoring and evaluation systems that can measure real access to ISC. PMID- 25933608 TI - Genomic features separating ten strains of Neorhizobium galegae with different symbiotic phenotypes. AB - BACKGROUND: The symbiotic phenotype of Neorhizobium galegae, with strains specifically fixing nitrogen with either Galega orientalis or G. officinalis, has made it a target in research on determinants of host specificity in nitrogen fixation. The genomic differences between representative strains of the two symbiovars are, however, relatively small. This introduced a need for a dataset representing a larger bacterial population in order to make better conclusions on characteristics typical for a subset of the species. In this study, we produced draft genomes of eight strains of N. galegae having different symbiotic phenotypes, both with regard to host specificity and nitrogen fixation efficiency. These genomes were analysed together with the previously published complete genomes of N. galegae strains HAMBI 540T and HAMBI 1141. RESULTS: The results showed that the presence of an additional rpoN sigma factor gene in the symbiosis gene region is a characteristic specific to symbiovar orientalis, required for nitrogen fixation. Also the nifQ gene was shown to be crucial for functional symbiosis in both symbiovars. Genome-wide analyses identified additional genes characteristic of strains of the same symbiovar and of strains having similar plant growth promoting properties on Galega orientalis. Many of these genes are involved in transcriptional regulation or in metabolic functions. CONCLUSIONS: The results of this study confirm that the only symbiosis-related gene that is present in one symbiovar of N. galegae but not in the other is an rpoN gene. The specific function of this gene remains to be determined, however. New genes that were identified as specific for strains of one symbiovar may be involved in determining host specificity, while others are defined as potential determinant genes for differences in efficiency of nitrogen fixation. PMID- 25933609 TI - A validation study of a clinical prediction rule for screening asymptomatic chlamydia and gonorrhoea infections among heterosexuals in British Columbia. AB - BACKGROUND: One component of effective sexually transmitted infections (STIs) control is ensuring those at highest risk of STIs have access to clinical services because terminating transmission in this group will prevent most future cases. Here, we describe the results of a validation study of a clinical prediction rule for identifying individuals at increased risk for chlamydia and gonorrhoea infection derived in Vancouver, British Columbia (BC), against a population of asymptomatic patients attending sexual health clinics in other geographical settings in BC. METHODS: We examined electronic records (2000-2012) from clinic visits at seven sexual health clinics in geographical locations outside Vancouver. The model's calibration and discrimination were examined by the area under the receiver operating characteristic curve (AUC) and the Hosmer Lemeshow (H-L) statistic, respectively. We also examined the sensitivity and proportion of patients that would need to be screened at different cut-offs of the risk score. RESULTS: The prevalence of infection was 5.3% (n=10 425) in the geographical validation population. The prediction rule showed good performance in this population (AUC, 0.69; H-L p=0.26). Possible risk scores ranged from -2 to 27. We identified a risk score cut-off point of >=8 that detected cases with a sensitivity of 86% by screening 63% of the geographical validation population. CONCLUSIONS: The prediction rule showed good generalisability in STI clinics outside of Vancouver with improved discriminative performance compared with temporal validation. The prediction rule has the potential for augmenting triaging services in STI clinics and enhancing targeted testing in population based screening programmes. PMID- 25933610 TI - Women, children, and global public health: beyond the millennium development goals. PMID- 25933611 TI - Amiodarone and metabolite MDEA inhibit Ebola virus infection by interfering with the viral entry process. AB - Ebola virus disease (EVD) is one of the most lethal transmissible infections characterized by a high fatality rate, and a treatment has not been developed yet. Recently, it has been shown that cationic amphiphiles, among them the antiarrhythmic drug amiodarone, inhibit filovirus infection. In the present work, we investigated how amiodarone interferes with Ebola virus infection. Wild-type Sudan ebolavirus and recombinant vesicular stomatitis virus, pseudotyped with the Zaire ebolavirus glycoprotein, were used to gain further insight into the ability of amiodarone to affect Ebola virus infection. We show that amiodarone decreases Ebola virus infection at concentrations close to those found in the sera of patients treated for arrhythmias. The drug acts by interfering with the fusion of the viral envelope with the endosomal membrane. We also show that MDEA, the main amiodarone metabolite, contributes to the antiviral activity. Finally, studies with amiodarone analogues indicate that the antiviral activity is correlated with drug ability to accumulate into and interfere with the endocytic pathway. Considering that it is well tolerated, especially in the acute setting, amiodarone appears to deserve consideration for clinical use in EVD. PMID- 25933612 TI - Role of vitamin B6 status on antioxidant defenses, glutathione, and related enzyme activities in mice with homocysteine-induced oxidative stress. AB - BACKGROUND: Vitamin B6 may directly or indirectly play a role in oxidative stress and the antioxidant defense system. OBJECTIVE: The purpose of this study was to examine the associations of vitamin B6 status with cysteine, glutathione, and its related enzyme activities in mice with homocysteine-induced oxidative stress. DESIGN: Four-week-old male BALB/c mice were weighed and divided into one of four dietary treatment groups fed either a normal diet (as a control group and a homocysteine group), a vitamin B6-deficient diet (as a B6-deficient group), or a B6-supplemented diet (a pyridoxine-HCl-free diet supplemented with 14 mg/kg of pyridoxine-HCl, as a B6 supplement group) for 28 days. Homocysteine thiolactone was then added to drinking water in three groups for 21 days to induce oxidative stress. At the end of the study, mice were sacrificed by decapitation and blood and liver samples were obtained. RESULTS: Mice with vitamin B6-deficient diet had the highest homocysteine concentration in plasma and liver among groups. Significantly increased hepatic malondialdehyde levels were observed in the vitamin B6-deficient group. Among homocysteine-treated groups, mice with vitamin B6-deficient diet had the highest plasma glutathione concentration and relatively lower hepatic glutathione concentration. The glutathione peroxidase activities remained relatively stable in plasma and liver whether vitamin B6 was adequate, deficient, or supplemented. CONCLUSIONS: Mice with deficient vitamin B6 intakes had an aggravate effect under homocysteine-induced oxidative stress. The vitamin B6-deficient status seems to mediate the oxidative stress in connection with the redistribution of glutathione from liver to plasma, but not further affect glutathione-related enzyme activities in mice with homocysteine-induced oxidative stress. PMID- 25933613 TI - Effects of dietary tryptophan and phenylalanine-tyrosine depletion on phasic alertness in healthy adults - A pilot study. AB - BACKGROUND: The synthesis of the neurotransmitters serotonin (5-HT) and dopamine (DA) in the brain can be directly altered by dietary manipulation of their relevant precursor amino acids (AA). There is evidence that altered serotonergic and dopaminergic neurotransmission are both associated with impaired attentional control. Specifically, phasic alertness is one specific aspect of attention that has been linked to changes in 5-HT and DA availability in different neurocircuitries related to attentional processes. The present study investigated the impact of short-term reductions in central nervous system 5-HT and DA synthesis, which was achieved by dietary depletion of the relevant precursor AA, on phasic alertness in healthy adult volunteers; body weight-adapted dietary tryptophan and phenylalanine-tyrosine depletion (PTD) techniques were used. METHODS: The study employed a double-blind between-subject design. Fifty healthy male and female subjects were allocated to three groups in a randomized and counterbalanced manner and received three different dietary challenge conditions: acute tryptophan depletion (ATD, for the depletion of 5-HT; N=16), PTD (for the depletion of DA; N=17), and a balanced AA load (BAL; N=17), which served as a control condition. Three hours after challenge intake (ATD/PTD/BAL), phasic alertness was assessed using a standardized test battery for attentional performance (TAP). Blood samples for AA level analyses were obtained at baseline and 360 min after the challenge intake. RESULTS: Overall, there were no significant differences in phasic alertness for the different challenge conditions. Regarding PTD administration, a positive correlation between the reaction times and the DA-related depletion magnitude was detected via the lower plasma tyrosine levels and the slow reaction times of the first run of the task. In contrast, higher tryptophan concentrations were associated with slower reaction times in the fourth run of the task in the same challenge group. CONCLUSION: The present study is the first to demonstrate preliminary data that support an association between decreased central nervous system DA synthesis, which was achieved by dietary depletion strategies, and slower reaction times in specific runs of a task designed to assess phasic alertness in healthy adult volunteers; these findings are consistent with previous evidence that links phasic alertness with dopaminergic neurotransmission. A lack of significant differences between the three groups could be due to compensatory mechanisms and the limited sample size, as well as the dietary challenge procedures administered to healthy participants and the strict exclusion criteria used. The potential underlying neurochemical processes related to phasic alertness should be the subject of further investigations. PMID- 25933614 TI - Mispricing in the medicare advantage risk adjustment model. AB - The Centers for Medicare and Medicaid Services (CMS) implemented hierarchical condition category (HCC) models in 2004 to adjust payments to Medicare Advantage (MA) plans to reflect enrollees' expected health care costs. We use Verisk Health's diagnostic cost group (DxCG) Medicare models, refined "descendants" of the same HCC framework with 189 comprehensive clinical categories available to CMS in 2004, to reveal 2 mispricing errors resulting from CMS' implementation. One comes from ignoring all diagnostic information for "new enrollees" (those with less than 12 months of prior claims). Another comes from continuing to use the simplified models that were originally adopted in response to assertions from some capitated health plans that submitting the claims-like data that facilitate richer models was too burdensome. Even the main CMS model being used in 2014 recognizes only 79 condition categories, excluding many diagnoses and merging conditions with somewhat heterogeneous costs. Omitted conditions are typically lower cost or "vague" and not easily audited from simplified data submissions. In contrast, DxCG Medicare models use a comprehensive, 394-HCC classification system. Applying both models to Medicare's 2010-2011 fee-for-service 5% sample, we find mispricing and lower predictive accuracy for the CMS implementation. For example, in 2010, 13% of beneficiaries had at least 1 higher cost DxCG-recognized condition but no CMS-recognized condition; their 2011 actual costs averaged US$6628, almost one-third more than the CMS model prediction. As MA plans must now supply encounter data, CMS should consider using more refined and comprehensive (DxCG-like) models. PMID- 25933615 TI - The opportunity cost of capital: development of new pharmaceuticals. AB - The opportunity cost of the capital invested in pharmaceutical research and development (R&D) to bring a new drug to market makes up as much as half the total cost. However, the literature on the cost of pharmaceutical R&D is mixed on how, exactly, one should calculate this "hidden" cost. Some authors attempt to adopt models from the field of finance, whereas other prominent authors dismiss this practice as biased, arguing that it artificially inflates the R&D cost to justify higher prices for pharmaceuticals. In this article, we examine the arguments made by both sides of the debate and then explain the cost of capital concept and describe in detail how this value is calculated. Given the significant contribution of the cost of capital to the overall cost of new drug R&D, a clear understanding of the concept is critical for policy makers, investors, and those involved directly in the R&D. PMID- 25933616 TI - Diagnostic Criteria and Accuracy of Categorizing Malignant Thyroid Nodules by Ultrasonography and Ultrasound Elastography with Pathologic Correlation. AB - Thyroid nodules are a common medical and surgical concern. Thyroid ultrasound (US) is the primary imaging modality used for initial evaluation and assortment of nodules for fine needle aspiration (FNA) cytology/biopsy. Ultrasound elastography (USE) is believed to improve the diagnostic accuracy of US in distinguishing benign from malignant nodules. The aim of the work described here is to evaluate the diagnostic criteria and accuracy of US and USE in the diagnosis of malignant thyroid nodules. A prospective study of 88 patients who have thyroid nodules was performed. US, color Doppler, and USE were evaluated using a Philips iU22 equipped with a 5 to 12 MHz, linear transducer, followed by FNA of the each scanned nodule. The most sensitive US criteria for malignant nodules were a height-to-width ratio greater than one and the absence of a halo sign (sensitivity 0.875% and 1.000%, respectively). The most specific criteria for malignancy were a spiculated/blurred margin and the presence of microcalcifications (specificity 0.968% and 0.888%, respectively). The receiver operating characteristic curve showed that the cutoff diagnostic criteria of malignancy are two US characteristics and an elastography score of 4. The diagnostic accuracy of US for malignant thyroid nodules increases by combining US and USE. PMID- 25933618 TI - Overexpression of cutaneous mitochondrial superoxide dismutase in recent-onset type 2 diabetes. AB - AIMS/HYPOTHESIS: Oxidative stress and microvascular damage have been implicated in the pathogenesis of diabetic neuropathy, with manganese superoxide dismutase 2 (SOD2) responsible for superoxide detoxification in mitochondria. We hypothesised that patients with recently diagnosed type 2 diabetes would show an altered cutaneous expression of SOD2 and endothelial cell area. METHODS: In this cross sectional study, we assessed skin biopsies using immunohistochemistry, peripheral nerve function and heart rate variability in 69 participants of the German Diabetes Study with recently diagnosed type 2 diabetes and 51 control individuals. RESULTS: Subepidermal SOD2 area in the distal leg was increased by ~60% in the diabetic group vs the controls (0.24 +/- 0.02% vs 0.15 +/- 0.02%; p = 0.0005) and was correlated with an increasing duration of diabetes (r = 0.271; p = 0.024) and with the low frequency/high frequency ratio (beta = 0.381; p = 0.002) as an indicator of sympathovagal balance. The area of the subepidermal endothelial cells (measured by CD31 staining) did not differ between the groups. CONCLUSIONS/INTERPRETATION: Cutaneous antioxidative defence is enhanced in relation to the duration of diabetes and is linked to a cardiac sympathovagal imbalance towards a sympathetic predominance in individuals with recently diagnosed type 2 diabetes without evidence of endothelial cell damage. Whether cutaneous SOD2 levels can predict the development of diabetic neuropathy remains to be determined in prospective studies. PMID- 25933619 TI - Pythium kandovanense sp. nov., a fungus-like eukaryotic micro-organism (Stramenopila, Pythiales) isolated from snow-covered ryegrass leaves. AB - Pythiumkandovanense sp. nov. (ex-type culture CCTU 1813T = OPU 1626T = CBS 139567T) is a novel oomycete species isolated from Lolium perenne with snow rot symptoms in a natural grassland in East-Azarbaijan province, Iran. Phylogenetic analyses based on sequence data from internal transcribed spacer (ITS)-rDNA, coxI and coxII mitochondrial genes clustered our isolates in Pythium group E as a unique, well supported clade. Pythium kandovanense sp. nov. is phylogenetically and morphologically distinct from the other closely related species in this clade, namely Pythium rostratifingens and Pythium rostratum. Pythium kandovanense sp. nov. can be distinguished from these two species by its cylindrical sporangia and lower temperatures for optimum and maximum growth rate. The development of zoospores released through a shorter discharge tube is an additional morphological feature which can be used to differentiate Pythium kandovanense sp. nov. from Pythium rostratifingens. Laboratory inoculation tests demonstrated the pathogenicity of Pythium kandovanense sp. nov. to L. perenne under wet cold (0-3 degrees C) conditions. PMID- 25933617 TI - Multiscale Functional and Molecular Photoacoustic Tomography. AB - Photoacoustic tomography (PAT) combines rich optical absorption contrast with the high spatial resolution of ultrasound at depths in tissue. The high scalability of PAT has enabled anatomical imaging of biological structures ranging from organelles to organs. The inherent functional and molecular imaging capabilities of PAT have further allowed it to measure important physiological parameters and track critical cellular activities. Integration of PAT with other imaging technologies provides complementary capabilities and can potentially accelerate the clinical translation of PAT. PMID- 25933620 TI - Emticicia sediminis sp. nov. isolated from sediment of a shallow stream. AB - A novel bacterial strain, designated JBR12T, was isolated from sediment of a shallow stream in Cheonan, Korea. Phylogenetic analysis based on 16S rRNA gene sequences showed that strain JBR12T belongs to the genus Emticicia, and indicated that its closest relatives are Emticicia oligotrophica DSM 17448T (97.8 % sequence similarity) and E. ginsengisoli Gsoil 085T (94.3%). A DNA-DNA hybridization experiment revealed < 70 % genomic relatedness between strain JBR12T and E. oligotrophica DSM 17448T. The major fatty acids (>5% of the total) were iso-C15 : 0, summed feature 3 (C16 : 1omega7c and/or C16 : 1omega6c), iso C15 : 0 3-OH, anteiso-C15 : 0 and iso-C15 : 0 3-OH. The DNA G+C content of strain JBR12T was 37.7 mol%. According to data from the present polyphasic taxonomic study, strain JBR12T represents a novel species of the genus Emticicia, for which the name Emticicia sediminis sp. nov. is proposed. The type strain is JBR12T ( = KACC 17466T = JCM 19321T). PMID- 25933621 TI - Porphyromonas pasteri sp. nov., isolated from human saliva. AB - A bacterial strain, designated KUFDS01T, isolated from human saliva was characterized using a polyphasic taxonomic approach that included analysis of physiological and biochemical features, cellular fatty acid profiles and phylogenetic position based on 16S rRNA gene sequence analysis. Cells of the strain were obligately anaerobic, non-pigmented, non-spore-forming, non-motile, Gram-stain-negative rods. Growth of the strain was inhibited on medium containing 20% bile. The 16S rRNA gene sequence analysis showed that the strain was a member of the genus Porphyromonas. Strain KUFDS01T was closely related to Porphyromonas catoniae JCM 13863T (96.6% sequence similarity). An hsp60 gene sequence analysis indicated that strain KUFDS01T was different from P. catoniae JCM 13863T, with a sequence similarity value of 87.8%. The major cellular fatty acids of strain KUFDS01T were C16 : 0, iso-C15 : 0, anteiso-C15 : 0, C18 : 2omega6, 9c and C18 : 1omega9c. The DNA G+C content of strain KUFDS01T was 57.7 +/- 0.66 mol%. On the basis of these data, strain KUFDS01T represents a novel species of the genus Porphyromonas, for which the name Porphyromonas pasteri sp. nov. is proposed. The type strain of P. pasteri is KUFDS01T ( = JCM 30531T = CCUG 66735T). PMID- 25933622 TI - Thermoproteus thermophilus sp. nov., a hyperthermophilic crenarchaeon isolated from solfataric soil. AB - A hyperthermophilic crenarchaeon, designated strain CBA1502T, was isolated from volcanic soil in the Mayon volcano in the Philippines. The 16S rRNA gene sequence of strain CBA1502T was most closely related to that of Thermoproteus uzoniensis DSM 5263T (99.2% similarity) and Thermoproteus tenax Kra 1T (99.0%). The organism grew at 75-90 degrees C and pH 4.0-6.0 and in the presence of 0-0.5% (w/v) NaCl, with optimal growth at 85 degrees C and pH 5.0. Strain CBA1502T utilized d arabinose, beef extract, Casamino acids, formate, fumarate, peptone, pyruvate, trimethylamine and yeast extract as energy substrates, and d-arabinose, formate, pyruvate and yeast extract as carbon sources. Fumarate, sulfate, sulfur and thiosulfate functioned as electron acceptors, but not ferric chloride, nitrate, malate or oxidized glutathione. DNA-DNA hybridization studies showed that there was less than 46.1% relatedness between strain CBA1502T and other members of the genus Thermoproteus. The DNA G+C content of strain CBA1502T was 62.0 mol%. We conclude that, according to its phylogenetic, phenotypic and genotypic characteristics, strain CBA1502T represents a novel species of the genus Thermoproteus, and propose the name Thermoproteus thermophilus sp. nov., with the type strain CBA1502T ( = ATCC BAA-2416T = JCM 17229T). PMID- 25933623 TI - Telephone calls to patients after discharge from the hospital: an important part of transitions of care. AB - BACKGROUND: Teaching interns patient-centered communication skills, including making structured telephone calls to patients following discharge, may improve transitions of care. OBJECTIVE: To explore associations between a patient centered care (PCC) curriculum and patients' perspectives of the quality of transitional care. METHODS: We implemented a novel PCC curriculum on one of four inpatient general medicine resident teaching teams in which interns make post discharge telephone calls to patients, contact outpatient providers, perform medication adherence reviews, and engage in patient-centered discharge planning. Between July and November of 2011, we conducted telephone surveys of patients from all four teaching teams within 30 days of discharge. In addition to asking if patients received a call from their hospital physician (intern), we administered the 3-Item Care Transitions Measure (CTM-3), which assesses patients' perceptions of preparedness for the transition from hospital to home (possible score range 0-100). RESULTS: The CTM-3 scores (mean+/-SD) of PCC team patients and standard team patients were not significantly different (82.4+/-17.3 vs. 79.6+/-17.6, p=0.53). However, regardless of team assignment, patients who reported receiving a post-discharge telephone call had significantly higher CTM-3 scores than those who did not (84.7+/-16.0 vs. 78.2+/-17.4, p=0.03). Interns exposed to the PCC curriculum called their patients after discharge more often than interns never exposed (OR=2.78, 95% CI [1.25, 6.18], p=0.013). CONCLUSIONS: The post-discharge telephone call, one element of PCC, was associated with higher CTM-3 scores--which, in turn, have been shown to lessen patients' risk of emergency department visits within 30 days of discharge. PMID- 25933624 TI - From Public to Social Reporting of Hospital Quality. PMID- 25933625 TI - A Look at Person- and Family-Centered Care Among Older Adults: Results from a National Survey [corrected]. AB - BACKGROUND: Person-centered and family-centered care represents the pinnacle of health care quality, but delivering it is challenging, as is assessing whether it has occurred. Prior studies portray older adults as passive in health decisions and burdened by care-but emphasize age-based differences or focus on vulnerable subgroups. OBJECTIVES: We aimed to examine domains of person-centered and family centered care among older adults and whether the social context in which older adults manage their health relates to preferences for participating in health decisions and experiences with care. DESIGN AND PARTICIPANTS: This was an observational study of a nationally representative survey of adults aged 65+ years, conducted in concert with the 2012 National Health and Aging Trends Study (n = 2040). MAIN MEASURES: Approach to managing health (self-manage, co-manage, delegate); preferences for making health care decisions with: (1) doctors, (2) family/close friends; and experiences with care pertaining to treatment burden were measured. KEY RESULTS: Approximately two-thirds of older adults self-manage (69.4 %) and one-third co-manage (19.6 %) or delegate (11.0 %) health care activities. The majority prefer an independent or shared role when making health decisions with doctors (84.7 %) and family/close friends (95.9 %). Nearly four in ten older adults (37.9 %) experience treatment burden-that managing health care activities are sometimes or often hard for either them or their family/close friends, that health care activities get delayed or don't get done, or that they are cumulatively too much to do. Relative to older adults who self-manage, those who delegate health care activities are more likely to prefer to share or leave health decisions to doctors (aOR = 1.79 (95 % CI, 1.37-2.33) and family/close friends (aOR = 3.12 (95 % CI, 2.23-4.36), and are more likely to experience treatment burden (aOR = 2.37 (95 % CI, 1.61-3.47). CONCLUSIONS: Attaining person centered and family-centered care will require strategies that respect diverse decision-making preferences, minimize treatment burden, and support the broader social context in which older adults manage their health. PMID- 25933626 TI - Influence of Hydroxypropyl Methylcellulose on Metronidazole Crystallinity in Spray-Congealed Polyethylene Glycol Microparticles and Its Impact with Various Additives on Metronidazole Release. AB - The purpose of this study was to investigate the effect of a hydrophilic polymer, hydroxypropyl methylcellulose (HPMC), on the crystallinity and drug release of metronidazole (MNZ) in spray-congealed polyethylene glycol (PEG) microparticles and to further modify the drug release using other additives in the formulation. HPMC has been used in many pharmaceutical formulations and processes but to date, it has not been employed as an additive in spray congealing. Crystallinity of a drug is especially important to the development of pharmaceutical products as active pharmaceutical ingredients (APIs) are mostly crystalline in nature. A combination of X-ray diffractometry, differential scanning calorimetry, Raman spectroscopy and Fourier transform-infrared spectroscopy (FT-IR) spectroscopy was employed to investigate the degree of crystallinity and possible solid-state structure of MNZ in the microparticles. The microparticles with HPMC were generally spherical. Spray congealing decreased MNZ crystallinity, and the presence of HPMC reduced the drug crystallinity further. The reduction in MNZ crystallinity was dependent on the concentration of HPMC. Smaller HPMC particles also resulted in a greater percentage reduction in MNZ crystallinity. Appreciable modification to MNZ release could be obtained with HPMC. However, this was largely attributed to the role of HPMC in forming a diffusion barrier. Further modification of drug release from spray-congealed PEG-HPMC microparticles was achieved with the addition of 5% w/w dicalcium phosphate but not with magnesium stearate, methyl cellulose, polyvinylpyrrolidone, silicon dioxide and sodium oleate/citric acid. Dicalcium phosphate facilitated formation of the diffusion barrier. PMID- 25933627 TI - Three regularities of recognition memory: the role of bias. AB - A basic assumption of Signal Detection Theory is that decisions are made on the basis of likelihood ratios. In a preceding paper, Glanzer, Hilford, and Maloney (Psychonomic Bulletin & Review, 16, 431-455, 2009) showed that the likelihood ratio assumption implies that three regularities will occur in recognition memory: (1) the Mirror Effect, (2) the Variance Effect, (3) the normalized Receiver Operating Characteristic (z-ROC) Length Effect. The paper offered formal proofs and computational demonstrations that decisions based on likelihood ratios produce the three regularities. A survey of data based on group ROCs from 36 studies validated the likelihood ratio assumption by showing that its three implied regularities are ubiquitous. The study noted, however, that bias, another basic factor in Signal Detection Theory, can obscure the Mirror Effect. In this paper we examine how bias affects the regularities at the theoretical level. The theoretical analysis shows: (1) how bias obscures the Mirror Effect, not the other two regularities, and (2) four ways to counter that obscuring. We then report the results of five experiments that support the theoretical analysis. The analyses and the experimental results also demonstrate: (1) that the three regularities govern individual, as well as group, performance, (2) alternative explanations of the regularities are ruled out, and (3) that Signal Detection Theory, correctly applied, gives a simple and unified explanation of recognition memory data. PMID- 25933628 TI - Attentional focus, perceived target size, and movement kinematics under performance pressure. AB - The present study examined the relationship between attentional focus, perceived hole size, and radial putting error in a golf task. Twenty-five experienced golfers were asked to produce size estimates immediately after completing a putt. To assess their attentional focus, one of two secondary tasks (chosen randomly) was performed next. In the Hole task, participants were asked to indicate whether a sound played during their putting stroke was presented to the left or right of the hole. In the Club task, they were asked to indicate whether the sound occurred closer to the beginning or end of their backswing. Participants completed three phases: a no pressure pretest, a pressure phase, and a no pressure posttest. There were substantial individual differences in the effects of pressure on putting kinematics: 11 golfers (designated the Choke group) showed significant changes in kinematic variables and heart rate, and 14 golfers (designated the Clutch group) showed no significant change in these variables. For the Choke group, putting error and the accuracy on the Club task significantly increased during the pressure phase while size estimates and accuracy on the Hole task significantly decreased. There were no significant changes in any of these variables for the Clutch group. These findings provide further evidence for the attentional accentuation hypothesis of action-specific effects. PMID- 25933629 TI - Case of human Dirofilaria repens infection manifested by cutaneous larva migrans syndrome. AB - Dirofilaria repens, parasite of subcutaneous tissues of dogs and other carnivores, represents high infection risk for animals and humans in Europe. In men, infection usually presents as nodule in subcutaneous tissues or, less often, the lesions are localised around the eyes. The work presents first confirmed clinical case of human D. repens infection connected with cutaneous larva migrans syndrome. In patient, the migration of the worm caused true signs of creeping eruption, elevated sinuous track under the skin. It was connected with severe pain, burning and erythema of adjacent skin. Symptoms appeared at least three times, approximately once a month, always in the evening or night and lasted from several minutes to several days. In December 2014, during the scratching of residual pruritic lesion, patient removed 6-cm long, whitish worm from the wound. Morphological features (longitudinal ridges) and PCR amplification of cytochrome oxidase subunit 1 (CO1) confirmed Dirofilaria repens as etiological agent of infection. Herein, presented case confirmed that D. repens infection in humans can be associated with real creeping eruption, clinical sign of cutaneous larva migrans and should be included in its differential diagnosis. PMID- 25933631 TI - Allosteric communication pathways and thermal rectification in PDZ-2 protein: a computational study. AB - Allosteric communication in proteins is a fundamental and yet unresolved problem of structural biochemistry. Previous findings, from computational biology ( Ota, N.; Agard, D. A. J. Mol. Biol. 2005 , 351 , 345 - 354 ), have proposed that heat diffuses in a protein through cognate protein allosteric pathways. This work studied heat diffusion in the well-known PDZ-2 protein, and confirmed that this protein has two cognate allosteric pathways and that heat flows preferentially through these. Also, a new property was also observed for protein structures: heat diffuses asymmetrically through the structures. The underling structure of this asymmetrical heat flow was a normal length hydrogen bond (~2.85 A) that acted as a thermal rectifier. In contrast, thermal rectification was compromised in short hydrogen bonds (~2.60 A), giving rise to symmetrical thermal diffusion. Asymmetrical heat diffusion was due, on a higher scale, to the local, structural organization of residues that, in turn, was also mediated by hydrogen bonds. This asymmetrical/symmetrical energy flow may be relevant for allosteric signal communication directionality in proteins and for the control of heat flow in materials science. PMID- 25933632 TI - Diabetes Associated Markers After Bariatric Surgery: Fetuin-A, but Not Matrix Metalloproteinase-7, Is Reduced. AB - BACKGROUND: Recent studies showed that fetuin-A and matrix metalloproteinase-7 (MMP-7) are type 2 diabetes mellitus (T2DM)-associated markers. Bariatric surgery not only reduces body weight but also improves T2DM. This study aimed to investigate the changes of fetuin-A and MMP-7 in obese subjects with and without T2DM after bariatric surgery. METHODS: We enrolled 130 obese subjects that received bariatric surgery, including 41 Roux-en-Y gastric bypass (RYGB), 67 mini gastric bypass (MGB), and 22 sleeve gastrectomy (SG) patients. Forty-three patients suffered from T2DM prior to surgery. The fasting serum fetuin-A and MMP 7 levels were measured before and 1 year after surgery. RESULTS: Only five of 43 patients remained diabetic after surgery. Preoperative T2DM patients had higher fetuin-A and MMP-7 levels than non-T2DM subjects. RYGB, MGB, and SG all decreased the fetuin-A levels 1 year after the operation. The MMP-7 levels were not changed after RYGB, MGB, or SG. In multivariate analyses, the preoperative fetuin-A was significantly related to the diastolic blood pressure (DBP) and glycosylated hemoglobin (HbA1c), while the postoperative fetuin-A was independently related to the waist-to-hip ratio and HbA1c. Moreover, the preoperative MMP-7 level was significantly related to age, DBP, aspartate transaminase, alanine transaminase, and gamma-glutamyl transferase (rGT), while the postoperative MMP-7 level was independently related to age and rGT. CONCLUSIONS: The fetuin-A and MMP-7 levels are both higher in obese T2DM than non-T2DM subjects. The level of fetuin-A is reduced after RYGB, MGB, and SG, but the level of MMP-7 remains unchanged. PMID- 25933633 TI - Outcome of Leaks After Sleeve Gastrectomy Based on a New Algorithm Addressing Leak Size and Gastric Stenosis. PMID- 25933634 TI - Positive effects of the progestin desogestrel 75 MUg on migraine frequency and use of acute medication are sustained over a treatment period of 180 days. AB - BACKGROUND: Premenopausal migraines frequently are associated with fluctuations of estrogen levels. Both, migraine and combined hormonal contraceptives (CHC) increase the risk of vascular events. Therefore progestagen-only contraceptives (POC) are a safer alternative. A previous short-term study demonstrated a positive impact of the oral POC desogestrel on migraine frequency. To study the effect of the POC desogestrel 75 MUg on migraine frequency, intensity, use of acute medication and quality of life in a clinical setting over the period of 180 days. METHODS: Patients' charts were screened for women with migraine, who had decided to use desogestrel for contraception. Charts were included, if routinely conducted headache diaries were complete for 90 days before treatment (baseline) and over a treatment period of 180 days. We also report about starters who stopped treatment early, because of adverse events. Baseline data (day 1-90 before treatment) were compared with first and second treatment period (treatment days 1-90 and days 91-180). Quality of life was evaluated using MIDAS questionnaires. RESULTS: Days with migraine (5.8 vs 3.6), with any kind of headache (9.4 vs 6.6), headache intensity (15.7 vs 10.7), days with severe headache (5.4 vs 2.4) and use of triptans (12.3 vs7.8) were significantly reduced after 180 days. MIDAS score and grade improved significantly. CONCLUSION: Contraception with desogestrel 75 MUg resulted in a significantly improved quality of life and a reduction of migraine days over the observation period of 180 days. A clinically meaningful 30% reduction in pain was observed in 25/42 (60%) participants. For counselling reasons it is of importance, that the major reduction in migraine frequency occured during the initial 90 days, however further improvement occurs with longer duration of use. Prospective studies are needed to confirm these results. PMID- 25933635 TI - Comparison of the Diversity of Basidiomycetes from Dead Wood of the Manchurian fir (Abies holophylla) as Evaluated by Fruiting Body Collection, Mycelial Isolation, and 454 Sequencing. AB - In this study, three different methods (fruiting body collection, mycelial isolation, and 454 sequencing) were implemented to determine the diversity of wood-inhabiting basidiomycetes from dead Manchurian fir (Abies holophylla). The three methods recovered similar species richness (26 species from fruiting bodies, 32 species from mycelia, and 32 species from 454 sequencing), but Fisher's alpha, Shannon-Wiener, Simpson's diversity indices of fungal communities indicated fruiting body collection and mycelial isolation displayed higher diversity compared with 454 sequencing. In total, 75 wood-inhabiting basidiomycetes were detected. The most frequently observed species were Heterobasidion orientale (fruiting body collection), Bjerkandera adusta (mycelial isolation), and Trichaptum fusco-violaceum (454 sequencing). Only two species, Hymenochaete yasudae and Hypochnicium karstenii, were detected by all three methods. This result indicated that Manchurian fir harbors a diverse basidiomycetous fungal community and for complete estimation of fungal diversity, multiple methods should be used. Further studies are required to understand their ecology in the context of forest ecosystems. PMID- 25933636 TI - Sub-Ice Microalgal and Bacterial Communities in Freshwater Lake Baikal, Russia. AB - The sub-ice environment of Lake Baikal represents a special ecotope where strongly increasing microbial biomass causes an "ice-bloom" contributing therefore to the ecosystem functioning and global element turnover under low temperature in the world's largest freshwater lake. In this work, we analyzed bacterial and microalgal communities and their succession in the sub-ice environment in March-April 2010-2012. It was found out that two dinoflagellate species (Gymnodinium baicalense var. minor and Peridinium baicalense Kisselew et Zwetkow) and four diatom species (Aulacoseira islandica, A. baicalensis, Synedra acus subsp. radians, and Synedra ulna) predominated in the microalgal communities. Interestingly, among all microalgae, the diatom A. islandica showed the highest number of physically attached bacterial cells (up to 67 +/- 16 bacteria per alga). Bacterial communities analyzed with pyrosequencing of 16S rRNA gene fragments were diverse and represented by 161 genera. Phyla Proteobacteria, Verrucomicrobia, Actinobacteria, Acidobacteria, Bacteroidetes, and Cyanobacteria represented a core community independently on microalgal composition, although the relative abundance of these bacterial phyla strongly varied across sampling sites and time points; unique OTUs from other groups were rare. PMID- 25933637 TI - Diversity of Fungi on Decomposing Leaf Litter in a Sugarcane Plantation and Their Response to Tillage Practice and Bagasse Mulching: Implications for Management Effects on Litter Decomposition. AB - To minimize the degradation of soil organic matter (SOM) content in conventional sugarcane cropping, it is important to understand how the fungal community contributes to SOM dynamics during the decomposition of sugarcane leaf litter. However, our knowledge of fungal diversity in tropical agroecosystems is currently limited. Thus, we determined the fungal community structure on decomposing sugarcane leaf litter and their response to different soil management systems using the internal transcribed spacer region 1 (ITS1) amplicon sequencing method afforded by Ion Torrent Personal Genome Machine (PGM). The results indicate that no-tillage had positive effects on the relative abundance of Zygomycota and of some taxa that may prefer a moist environment over conventional tillage, whereas bagasse mulching decreased the richness of operational taxonomic units (OTUs) and had positive effect on the relative abundance of slow-growing taxa, which may prefer poor nutrient substrates. Furthermore, a combination of no tillage and bagasse mulching increased the abundance of unique OTUs. We suggest that the alteration of fungal communities through the changes in soil management practices produces an effect on litter decomposition. PMID- 25933638 TI - Parental Spending on School-Age Children: Structural Stratification and Parental Expectation. AB - As consumption expenditures are increasingly recognized as direct measures of children's material well-being, they provide new insights into the process of intergenerational transfers from parents to children. Little is known, however, about how parents allocate financial resources to individual children. To fill this gap, we develop a conceptual framework based on stratification theory, human capital theory, and the child-development perspective; exploit unique child-level expenditure data from Child Supplements of the PSID; and employ quantile regression to model the distribution of parental spending on children. Overall, we find strong evidence supporting our hypotheses regarding the effects of socioeconomic status (SES), race, and parental expectation. Our nuanced estimates suggest that (1) parental education, occupation, and family income have differential effects on parental spending, with education being the most influential determinant; (2) net of SES, race continues to be a significant predictor of parental spending on children; and (3) parental expectation plays a crucial role in determining whether parents place a premium on child development in spending and how parents prioritize different categories of spending. PMID- 25933639 TI - Coexistence of sympatric carnivores in relatively homogeneous Mediterranean landscapes: functional importance of habitat segregation at the fine-scale level. AB - One of the main objectives of community ecology is to understand the conditions allowing species to coexist. However, few studies have investigated the role of fine-scale habitat use segregation in the functioning of guild communities in relatively homogeneous landscapes where opportunities for coexistence are likely to be the most restrictive. We investigate how the process of habitat use differentiation at the home range level according to the degree of specialism/generalism of species can lead to coexistence between guild species. We examine differences in fine-scale habitat use and niche separation as potential mechanisms explaining the coexistence of five sympatric carnivore species that differ in life history traits (Iberian lynx, Eurasian badger, Egyptian mongoose, common genet and red fox) by collecting data from systematic track censuses in a relatively homogeneous Mediterranean landscape. We found that a higher degree of specialism determines the segregation of species among the fine-scale ecological niche dimensions defined using quantitative elements associated with vegetation, landscape, prey availability and human disturbance. The species with the lowest total performance over the set of variables did not exhibit segregation in the use of habitat at this level. Our study indicates that in relatively homogeneous landscapes, there exist subtle patterns of habitat partitioning over small-scale gradients of habitat determinants as a function of the degree of specialism of carnivore species within a guild. Our results also suggest that coexistence between generalist species may be permitted by fine scale spatial-temporal segregation of activity patterns or trophic resource consumption, but not fine-scale habitat use differentiation. PMID- 25933641 TI - Enantiospecific Adsorption of Amino Acids on Naturally Chiral Cu{3,1,17}R&S Surfaces. AB - Gas-phase equilibrium adsorption of D- and L-serine (Ser) mixtures and D- and L phenylalanine (Phe) mixtures has been studied on the naturally chiral Cu{3,1,17}(R&S) surfaces. (13)C labeling of the l enantiomers (*L-Ser and *L-Phe) has enabled mass spectrometric enantiodiscrimination of the species desorbing from the surface following equilibrium adsorption. On the Cu{3,1,17}(R&S) surfaces, both equilibrium adsorption and the thermal decomposition kinetics of the D and *L enantiomers exhibit diastereomerism. Following exposure of the surfaces to D/*L mixtures, the relative equilibrium coverages of the two enantiomers are equal to their relative partial pressures in the gas phase, theta(D)/theta(*L) = P(D)/P(*L). This implies that adsorption is not measurably enantiospecific. The decomposition kinetics of Ser are enantiospecific whereas those of Phe are not. Comparison of these results with those for aspartic acid, alanine, and lysine suggests that enantiospecific adsorption on the naturally chiral Cu surfaces occurs for those amino acids that have side chains with functional groups that allow strong interactions with the surface. There is no apparent correlation between amino acids that exhibit enantiospecific adsorption and those that exhibit enantiospecific decomposition kinetics. PMID- 25933640 TI - Decreased Interferon gamma Production in CD3+ and CD3- CD56+ Lymphocyte Subsets in Metastatic Regional Lymph Nodes of Melanoma Patients. AB - As lymphogenic dissemination is very common in melanoma, regional lymph nodes (LN)s represent first immunological barriers to tumor invasion and play a complex role in antitumor immune defense. In this sense, their most prominent role is the presentation of tumor-derived antigens to naive T cells and generation of cell mediated adaptive immune response. Since tumor micro-environment affects immune cell function in this study we have evaluated the ability of T cells and NK cells in metastatic (involved) and non-metastatic regional LNs to produce interferon gamma (IFNgamma), a pleiotropic cytokine that regulates adaptive antitumor immune response. Our results show reduced IFNgamma production in both T and NK lymphocyte subsets and decreased prevalence of T cells in metastatic regional LNs of melanoma patients. The decrease of IFNgamma production in T cells was more pronounced with increased number of involved regional LNs indicating tumor induced functional impairment of both T and NK cell lymphocyte subsets in involved regional LNs. Therefore, shown low IFNgamma production in metastatic LNs may represent an obstacle in adaptive cell-mediated antitumor immune response and hence may enable tumor progression. PMID- 25933643 TI - Successful Minimally Invasive Treatment of Intractable, Postoperative Chylous Ascites Via Percutaneous Lymph Vessel Embolization. PMID- 25933642 TI - Sex differences in the pathophysiology, treatment, and outcomes in IHD. AB - Heart disease is the number one killer of women. Although there are many similarities between men and women, the evolving understanding of ischemic heart disease in women allow us to emphasize the important differences that need to be recognized. These differences, including symptoms at presentation, importance of particular risk factors, pathophysiology of disease, and treatments/outcomes, will be discussed in this review. PMID- 25933644 TI - The CIRSE Retrievable IVC Filter Registry: Retrieval Success Rates in Practice. AB - CIRSE established a registry of retrievable filter use with the primary aim of determining the success of IVC Filter retrieval and associated complications. Secondary endpoints included filter indications, imaging strategies before retrieval, filter dwell times, and anticoagulation status. A web-based electronic registry was hosted between 01/12/2010 and 30/06/2012. Data entry occurred at the date of IVC filter retrieval and included items such as filter type, indication for filter insertion, access route, dwell time, retrieval success, complications, reasons for failed retrieval, and anticoagulation status. 671 filter retrievals were entered (male:female 333:295, mean age 55, median 57). Retrieval data were not entered in 43/671 leaving 628 patients for analysis. The 4 commonest retrievable filters used were the Celect in 182 patients, the OPTEASE in 161, ALN in 120, and Gunther Tulip in 98. Filters were inserted for absolute indications 40%, relative indications in 31%, and prophylactic in 24%, with 5% missing. Mean filter dwell time was 90 days. Filters were successfully retrieved in 576/628 patients (92%). The mean dwell time for successful retrievals was 85 days versus 145 days for unsuccessful retrievals (p = 0.001). Major complications occurred in 2 patients (0.03%). In summary, the CIRSE retrievable filter registry demonstrates a retrieval rate of 92% across a range of filter types, with a low major complication rate, reflecting current practice. There is an increase in trend of retrievable filter use for relative and prophylactic indications. PMID- 25933645 TI - Teaching Psychopathology in a Galaxy Far, Far Away: The Light Side of the Force. AB - Star Wars films are among the top box office hits of all time. The films have been popular internationally for almost 40 years. As such, both trainees and attending psychiatrists are likely to be aware of them. This article highlights a vast array of psychopathology in Star Wars films which can be useful in teaching, even when the characters are considered the "good guys". Included are as follows: histrionic, obsessive-compulsive, and dependent personality traits, perinatal psychiatric disorders, prodromal schizophrenia, pseudo-dementia, frontal lobe lesions, pathological gambling, and even malingering. As such, Star Wars has tremendous potential to teach psychiatric trainees about mental health issues. PMID- 25933646 TI - Finding Time for Fiction. AB - With growing advances in psychiatric care come growing amounts of knowledge to be read by psychiatry trainees. This essay presents one resident's experience putting aside some of the official psychiatric literature during residency in favor of more fiction, and his self-perceived growth because of that. Fiction, in the author's perspective, can make us all better psychiatrists. PMID- 25933647 TI - What Is the Efficacy of Teaching Psychotherapy to Psychiatry Residents and Medical Students? AB - OBJECTIVE: Because there are no formal reviews, the authors set out to identify and evaluate studies on teaching psychotherapy to psychiatry residents and medical students. METHOD: PubMed, Embase, and PsycINFO were searched for papers with outcomes on teaching psychotherapy. Search terms included psychotherapy, teaching, residents, medical students, supportive, psychodynamic, cognitive, behavioral, learning, training, skills, competency, and mentalization. RESULTS: Nine studies were found that met inclusion criteria. There were seven studies of psychiatry residents and two of medical students. Only two of the research designs had comparison groups, and these were both randomized controlled trials, while seven of the other designs were pretest and posttest. Teaching methods, course content, and outcome measures varied widely across studies. Common methodological problems included a lack of control, low numbers of subjects as learners, and a lack of validity of the outcome measures. Only one of the studies was judged to be methodologically rigorous. CONCLUSIONS: These findings establish a priority for undertaking additional rigorously designed studies in evaluating the teaching of psychotherapy to psychiatry residents and medical students. PMID- 25933649 TI - Intrinsic noise induced coherence resonance in a glow discharge plasma. AB - Experimental evidence of intrinsic noise induced coherence resonance in a glow discharge plasma is being reported. Initially the system is started at a discharge voltage (DV) where it exhibited fixed point dynamics, and then with the subsequent increase in the DV spikes were excited which were few in number and with further increase of DV the number of spikes as well as their regularity increased. The regularity in the interspike interval of the spikes is estimated using normalized variance. Coherence resonance was determined using normalized variance curve and also corroborated by Hurst exponent and power spectrum plots. We show that the regularity of the excitable spikes in the floating potential fluctuation increases with the increase in the DV, up to a particular value of DV. Using a Wiener filter, we separated the noise component which was observed to increase with DV and hence conjectured that noise can play an important role in the generation of the coherence resonance. From an anharmonic oscillator equation describing ion acoustic oscillations, we have been able to obtain a FitzHugh Nagumo like model which has been used to understand the excitable dynamics of glow discharge plasma in the presence of noise. The numerical results agree quite well with the experimental results. PMID- 25933648 TI - Effects of Ethanol on the Cerebellum: Advances and Prospects. AB - Alcohol abuse causes cerebellar dysfunction and cerebellar ataxia is a common feature in alcoholics. Alcohol exposure during development also impacts the cerebellum. Children with fetal alcohol spectrum disorder (FASD) show many symptoms associated specifically with cerebellar deficits. However, the cellular and molecular mechanisms are unclear. This special issue discusses the most recent advances in the study of mechanisms underlying alcoholinduced cerebellar deficits. The alteration in GABAA receptor-dependent neurotransmission is a potential mechanism for ethanol-induced cerebellar dysfunction. Recent advances indicate ethanol-induced increases in GABA release are not only in Purkinje cells (PCs), but also in molecular layer interneurons and granule cells. Ethanol is shown to disrupt the molecular events at the mossy fiber - granule cell - Golgi cell (MGG) synaptic site and granule cell parallel fibers - PCs (GPP) synaptic site, which may be responsible for ethanol-induced cerebellar ataxia. Aging and ethanol may affect the smooth endoplasmic reticulum (SER) of PC dendrites and cause dendritic regression. Ethanol withdrawal causes mitochondrial damage and aberrant gene modifications in the cerebellum. The interaction between these events may result in neuronal degeneration, thereby contributing to motoric deficit. Ethanol activates doublestranded RNA (dsRNA)-activated protein kinase (PKR) and PKR activation is involved ethanolinduced neuroinflammation and neurotoxicity in the developing cerebellum. Ethanol alters the development of cerebellar circuitry following the loss of PCs, which could result in modifications of the structure and function of other brain regions that receive cerebellar inputs. Lastly, choline, an essential nutrient is evaluated for its potential protection against ethanol-induced cerebellar damages. Choline is shown to ameliorate ethanol-induced cerebellar dysfunction when given before ethanol exposure. PMID- 25933650 TI - Recovering network topologies via Taylor expansion and compressive sensing. AB - Gaining knowledge of the intrinsic topology of a complex dynamical network is the precondition to understand its evolutionary mechanisms and to control its dynamical and functional behaviors. In this article, a general framework is developed to recover topologies of complex networks with completely unknown node dynamics based on Taylor expansion and compressive sensing. Numerical simulations illustrate the feasibility and effectiveness of the proposed method. Moreover, this method is found to have good robustness to weak stochastic perturbations. Finally, the impact of two major factors on the topology identification performance is evaluated. This method provides a natural and direct point to reconstruct network topologies from measurable data, which is likely to have potential applicability in a wide range of fields. PMID- 25933651 TI - On quantifying the climate of the nonautonomous Lorenz-63 model. AB - The Lorenz-63 model has been frequently used to inform our understanding of the Earth's climate and provide insight for numerical weather and climate prediction. Most studies have focused on the autonomous (time invariant) model behaviour in which the model's parameters are constants. Here, we investigate the properties of the model under time-varying parameters, providing a closer parallel to the challenges of climate prediction, in which climate forcing varies with time. Initial condition (IC) ensembles are used to construct frequency distributions of model variables, and we interpret these distributions as the time-dependent climate of the model. Results are presented that demonstrate the impact of ICs on the transient behaviour of the model climate. The location in state space from which an IC ensemble is initiated is shown to significantly impact the time it takes for ensembles to converge. The implication for climate prediction is that the climate may-in parallel with weather forecasting-have states from which its future behaviour is more, or less, predictable in distribution. Evidence of resonant behaviour and path dependence is found in model distributions under time varying parameters, demonstrating that prediction in nonautonomous nonlinear systems can be sensitive to the details of time-dependent forcing/parameter variations. Single model realisations are shown to be unable to reliably represent the model's climate; a result which has implications for how real-world climatic timeseries from observation are interpreted. The results have significant implications for the design and interpretation of Global Climate Model experiments. PMID- 25933652 TI - Reliability of unstable periodic orbit based control strategies in biological systems. AB - Presence of recurrent and statistically significant unstable periodic orbits (UPOs) in time series obtained from biological systems is now routinely used as evidence for low dimensional chaos. Extracting accurate dynamical information from the detected UPO trajectories is vital for successful control strategies that either aim to stabilize the system near the fixed point or steer the system away from the periodic orbits. A hybrid UPO detection method from return maps that combines topological recurrence criterion, matrix fit algorithm, and stringent criterion for fixed point location gives accurate and statistically significant UPOs even in the presence of significant noise. Geometry of the return map, frequency of UPOs visiting the same trajectory, length of the data set, strength of the noise, and degree of nonstationarity affect the efficacy of the proposed method. Results suggest that establishing determinism from unambiguous UPO detection is often possible in short data sets with significant noise, but derived dynamical properties are rarely accurate and adequate for controlling the dynamics around these UPOs. A repeat chaos control experiment on epileptic hippocampal slices through more stringent control strategy and adaptive UPO tracking is reinterpreted in this context through simulation of similar control experiments on an analogous but stochastic computer model of epileptic brain slices. Reproduction of equivalent results suggests that far more stringent criteria are needed for linking apparent success of control in such experiments with possible determinism in the underlying dynamics. PMID- 25933653 TI - Complexity extraction of electroencephalograms in Alzheimer's disease with weighted-permutation entropy. AB - In this paper, weighted-permutation entropy (WPE) is applied to investigating the complexity abnormalities of Alzheimer's disease (AD) by analyzing 16-channel electroencephalograph (EEG) signals from 14 severe AD patients and 14 age-matched normal subjects. The WPE values are estimated in the delta, the theta, the alpha, and the beta sub-bands for each channel with an overlapped sliding window. WPE is modified from the permutation entropy (PE), which has been recently suggested as a measurement to extract the complexity of the EEG signals. The advantage of WPE over PE is verified by both the model simulated and the experimental EEG signals. Although the results show that both the average PE and WPE of AD patients are decreased in contrast with the normal group in these four sub-bands, especially in the theta band, WPE can exhibit a better performance in distinguishing the AD patients from the normal controls by the more significant differences in the four sub-bands, which may be attributed to the brain dysfunction. Thus, it suggests that WPE may become a probable useful tool to detect brain dysfunction in AD and it seems to be promising to disclose the abnormalities of brain activity for other neural disease. PMID- 25933654 TI - Causation entropy from symbolic representations of dynamical systems. AB - Identification of causal structures and quantification of direct information flows in complex systems is a challenging yet important task, with practical applications in many fields. Data generated by dynamical processes or large-scale systems are often symbolized, either because of the finite resolution of the measurement apparatus, or because of the need of statistical estimation. By algorithmic application of causation entropy, we investigated the effects of symbolization on important concepts such as Markov order and causal structure of the tent map. We uncovered that these quantities depend nonmonotonically and, most of all, sensitively on the choice of symbolization. Indeed, we show that Markov order and causal structure do not necessarily converge to their original analog counterparts as the resolution of the partitioning becomes finer. PMID- 25933655 TI - Dynamics of self-excited thermoacoustic instability in a combustion system: Pseudo-periodic and high-dimensional nature. AB - We have examined the dynamics of self-excited thermoacoustic instability in a fundamentally and practically important gas-turbine model combustion system on the basis of complex network approaches. We have incorporated sophisticated complex networks consisting of cycle networks and phase space networks, neither of which has been considered in the areas of combustion physics and science. Pseudo-periodicity and high-dimensionality exist in the dynamics of thermoacoustic instability, including the possible presence of a clear power-law distribution and small-world-like nature. PMID- 25933656 TI - Intrinsic excitability state of local neuronal population modulates signal propagation in feed-forward neural networks. AB - Reliable signal propagation across distributed brain areas is an essential requirement for cognitive function, and it has been investigated extensively in computational studies where feed-forward network (FFN) is taken as a generic model. But it is still unclear how distinct local network states, which are intrinsically generated by synaptic interactions within each layer, would affect the ability of FFN to transmit information. Here we investigate the impact of such network states on propagating transient synchrony (synfire) and firing rate by a combination of numerical simulations and analytical approach. Specifically, local network dynamics is attributed to the competition between excitatory and inhibitory neurons within each layer. Our results show that concomitant with different local network states, the performance of signal propagation differs dramatically. For both synfire propagation and firing rate propagation, there exists an optimal local excitability state, respectively, that optimizes the performance of signal propagation. Furthermore, we find that long-range connections strongly change the dependence of spiking activity propagation on local network state and propose that these two factors work jointly to determine information transmission across distributed networks. Finally, a simple mean field approach that bridges response properties of long-range connectivity and local subnetworks is utilized to reveal the underlying mechanism. PMID- 25933657 TI - A mechanical analog of the two-bounce resonance of solitary waves: Modeling and experiment. AB - We describe a simple mechanical system, a ball rolling along a specially-designed landscape, which mimics the well-known two-bounce resonance in solitary wave collisions, a phenomenon that has been seen in countless numerical simulations but never in the laboratory. We provide a brief history of the solitary wave problem, stressing the fundamental role collective-coordinate models played in understanding this phenomenon. We derive the equations governing the motion of a point particle confined to such a surface and then design a surface on which to roll the ball, such that its motion will evolve under the same equations that approximately govern solitary wave collisions. We report on physical experiments, carried out in an undergraduate applied mathematics course, that seem to exhibit the two-bounce resonance. PMID- 25933658 TI - Origin and implications of zero degeneracy in networks spectra. AB - The spectra of many real world networks exhibit properties which are different from those of random networks generated using various models. One such property is the existence of a very high degeneracy at the zero eigenvalue. In this work, we provide all the possible reasons behind the occurrence of the zero degeneracy in the network spectra, namely, the complete and partial duplications, as well as their implications. The power-law degree sequence and the preferential attachment are the properties which enhances the occurrence of such duplications and hence leading to the zero degeneracy. A comparison of the zero degeneracy in protein protein interaction networks of six different species and in their corresponding model networks indicates importance of the degree sequences and the power-law exponent for the occurrence of zero degeneracy. PMID- 25933659 TI - Numerical analysis for finite-range multitype stochastic contact financial market dynamic systems. AB - In an attempt to reproduce and study the dynamics of financial markets, a random agent-based financial price model is developed and investigated by the finite range multitype contact dynamic system, in which the interaction and dispersal of different types of investment attitudes in a stock market are imitated by viruses spreading. With different parameters of birth rates and finite-range, the normalized return series are simulated by Monte Carlo simulation method and numerical studied by power-law distribution analysis and autocorrelation analysis. To better understand the nonlinear dynamics of the return series, a q order autocorrelation function and a multi-autocorrelation function are also defined in this work. The comparisons of statistical behaviors of return series from the agent-based model and the daily historical market returns of Shanghai Composite Index and Shenzhen Component Index indicate that the proposed model is a reasonable qualitative explanation for the price formation process of stock market systems. PMID- 25933660 TI - Organization and identification of solutions in the time-delayed Mackey-Glass model. AB - Multistability in the long term dynamics of the Mackey-Glass (MG) delayed model is analyzed by using an electronic circuit capable of controlling the initial conditions. The system's phase-space is explored by varying the parameter values of two families of initial functions. The evolution equation of the electronic circuit is derived and it is shown that, in the continuous limit, it exactly corresponds to the MG model. In practice, when using a finite set of capacitors, an excellent agreement between the experimental observations and the numerical simulations is manifested. As the delay is increased, different periodic or aperiodic solutions appear. We observe abundant periodic solutions that have the same period but a different alternation of peaks of dissimilar amplitudes and propose a novel symbolic method to classify these solutions. PMID- 25933661 TI - Autaptic activity-induced synchronization transitions in Newman-Watts network of Hodgkin-Huxley neurons. AB - In this paper, we numerically study the effect of autapse on the synchronization of Newman-Watts small-world Hodgkin-Huxley neuron network. It is found that the neurons exhibit synchronization transitions as autaptic self-feedback delay is varied, and the phenomenon becomes strongest when autaptic self-feedback strength is optimal. This phenomenon also changes with the change of coupling strength and network randomness and become strongest when they are optimal. There are similar synchronization transitions for electrical and chemical autapse, but the synchronization transitions for chemical autapse occur more frequently and are stronger than those for electrical synapse. The underlying mechanisms are briefly discussed in quality. These results show that autaptic activity plays a subtle role in the synchronization of the neuronal network. These findings may find potential implications of autapse for the information processing and transmission in neural systems. PMID- 25933662 TI - Onset of chaos in a single-phase power electronic inverter. AB - Supported by experiments on a power electronic DC/AC converter, this paper considers an unusual transition from the domain of stable periodic dynamics (corresponding to the desired mode of operation) to chaotic dynamics. The behavior of the converter is studied by means of a 1D stroboscopic map derived from a non-autonomous ordinary differential equation with discontinuous right hand side. By construction, this stroboscopic map has a high number of border points. It is shown that the onset of chaos occurs stepwise, via irregular cascades of different border collisions, some of which lead to bifurcations while others do not. PMID- 25933663 TI - The expansion of neighborhood and pattern formation on spatial prisoner's dilemma. AB - The prisoner's dilemma (PD), in which players can either cooperate or defect, is considered a paradigm for studying the evolution of cooperation in spatially structured populations. There the compact cooperator cluster is identified as a characteristic pattern and the probability of forming such pattern in turn depends on the features of the networks. In this paper, we investigate the influence of expansion of neighborhood on pattern formation by taking a weak PD game with one free parameter T, the temptation to defect. Two different expansion methods of neighborhood are considered. One is based on a square lattice and expanses along four directions generating networks with degree increasing with K=4m. The other is based on a lattice with Moore neighborhood and expanses along eight directions, generating networks with degree of K=8m. Individuals are placed on the nodes of the networks, interact with their neighbors and learn from the better one. We find that cooperator can survive for a broad degree 4<=K<=70 by taking a loose type of cooperator clusters. The former simple corresponding relationship between macroscopic patterns and the microscopic PD interactions is broken. Under a condition that is unfavorable for cooperators such as large T and K, systems prefer to evolve to a loose type of cooperator clusters to support cooperation. However, compared to the well-known compact pattern, it is a suboptimal strategy because it cannot help cooperators dominating the population and always corresponding to a low cooperation level. PMID- 25933664 TI - The impact of vaccine failure rate on epidemic dynamics in responsive networks. AB - An SIS model based on the microscopic Markov-chain approximation is considered in this paper. It is assumed that the individual vaccination behavior depends on the contact awareness, local and global information of an epidemic. To better simulate the real situation, the vaccine failure rate is also taken into consideration. Our main conclusions are given in the following. First, we show that if the vaccine failure rate alpha is zero, then the epidemic eventually dies out regardless of what the network structure is or how large the effective spreading rate and the immunization response rates of an epidemic are. Second, we show that for any positive alpha, there exists a positive epidemic threshold depending on an adjusted network structure, which is only determined by the structure of the original network, the positive vaccine failure rate and the immunization response rate for contact awareness. Moreover, the epidemic threshold increases with respect to the strength of the immunization response rate for contact awareness. Finally, if the vaccine failure rate and the immunization response rate for contact awareness are positive, then there exists a critical vaccine failure rate alphac > 0 so that the disease free equilibrium (DFE) is stable (resp., unstable) if alpha < alphac (resp., alpha > alphac). Numerical simulations to see the effectiveness of our theoretical results are also provided. PMID- 25933665 TI - Nonlinear effects of electric fields in the Belousov-Zhabotinsky reaction dissolved in a microemulsion. AB - Labyrinth-like Turing patterns are investigated under the influence of an electric field. The patterns form in the ferroin-catalyzed Belousov-Zhabotinsky reaction embedded in the sodium-bis (2-ethylhexyl) sulfosuccinate (AOT) water-in oil microemulsion. For two different values of the droplet fraction above and below the percolation transition of the system, the electric field induced drift of the patterns is different. Above the percolation transition, a linear increase of the drift velocity with increasing electric field strength is found. However, below the percolation transition, this increase shows an exponential behavior. The patterns are also observed to reorient under high electrical field strength, such that they are arranged perpendicular with respect to the field lines. PMID- 25933666 TI - Discrete impulses in ephaptically coupled nerve fibers. AB - We exclusively analyze the condition for modulated waves to emerge in two ephaptically coupled nerve fibers. Through the multiple scale expansion, it is shown that a set of coupled cable-like Hodgkin-Huxley equations can be reduced to a single differential-difference nonlinear equation. The standard approach of linear stability analysis of a plane wave is used to predict regions of parameters where nonlinear structures can be observed. Instability features are shown to be importantly controlled not only by the ephaptic coupling parameter, but also by the discreteness parameter. Numerical simulations, to verify our analytical predictions, are performed, and we explore the longtime dynamics of slightly perturbed plane waves in the coupled nerve fibers. On initially exciting only one fiber, quasi-perfect interneuronal communication is discussed along with the possibility of recruiting damaged or non-myelinated nerve fibers, by myelinated ones, into conduction. PMID- 25933667 TI - Partial synchronization in networks of non-linearly coupled oscillators: The Deserter Hubs Model. AB - We study the Deserter Hubs Model: a Kuramoto-like model of coupled identical phase oscillators on a network, where attractive and repulsive couplings are balanced dynamically due to nonlinearity of interactions. Under weak force, an oscillator tends to follow the phase of its neighbors, but if an oscillator is compelled to follow its peers by a sufficient large number of cohesive neighbors, then it actually starts to act in the opposite manner, i.e., in anti-phase with the majority. Analytic results yield that if the repulsion parameter is small enough in comparison with the degree of the maximum hub, then the full synchronization state is locally stable. Numerical experiments are performed to explore the model beyond this threshold, where the overall cohesion is lost. We report in detail partially synchronous dynamical regimes, like stationary phase locking, multistability, periodic and chaotic states. Via statistical analysis of different network organizations like tree, scale-free, and random ones, we found a measure allowing one to predict relative abundance of partially synchronous stationary states in comparison to time-dependent ones. PMID- 25933668 TI - Five years of phenological monitoring in a mountain grassland: inter-annual patterns and evaluation of the sampling protocol. AB - The increasingly important effect of climate change and extremes on alpine phenology highlights the need to establish accurate monitoring methods to track inter-annual variation (IAV) and long-term trends in plant phenology. We evaluated four different indices of phenological development (two for plant productivity, i.e., green biomass and leaf area index; two for plant greenness, i.e., greenness from visual inspection and from digital images) from a 5-year monitoring of ecosystem phenology, here defined as the seasonal development of the grassland canopy, in a subalpine grassland site (NW Alps). Our aim was to establish an effective observation strategy that enables the detection of shifts in grassland phenology in response to climate trends and meteorological extremes. The seasonal development of the vegetation at this site appears strongly controlled by snowmelt mostly in its first stages and to a lesser extent in the overall development trajectory. All indices were able to detect an anomalous beginning of the growing season in 2011 due to an exceptionally early snowmelt, whereas only some of them revealed a later beginning of the growing season in 2013 due to a late snowmelt. A method is developed to derive the number of samples that maximise the trade-off between sampling effort and accuracy in IAV detection in the context of long-term phenology monitoring programmes. Results show that spring phenology requires a smaller number of samples than autumn phenology to track a given target of IAV. Additionally, productivity indices (leaf area index and green biomass) have a higher sampling requirement than greenness derived from visual estimation and from the analysis of digital images. Of the latter two, the analysis of digital images stands out as the more effective, rapid and objective method to detect IAV in vegetation development. PMID- 25933669 TI - Stigma-Related Stress and Its Correlates Among Men with Pedophilic Sexual Interests. AB - Despite decades of research on the adverse consequences of stereotyping and discrimination for many stigmatized groups, little is known about how people with pedophilia perceive and react to stigma. In this article, we present a framework that outlines how stigma-related stress might negatively affect emotional and social areas of functioning, cognitive distortions, and the motivation to pursue therapy, all of which may contribute to an increased risk of sexual offending. We tested our hypotheses in an online survey among self-identified German-speaking people with pedophilia (N = 104) using a wide range of validated indicators of social and emotional functioning (Brief Symptom Inventory-53, UCLA Loneliness Scale, Emotion Subscale of the Coping Inventory for Stressful Situations, Fear of Negative Evaluation-5, Rosenberg Self-Esteem Scale). Specific risk factors such as self-efficacy, cognitive distortions, and the motivation to seek treatment were also assessed. In line with our hypotheses, fear of discovery generally predicted reduced social and emotional functioning. Contrary to our predictions, perceived social distance and fear of discovery were not linked to self-efficacy, cognitive distortions, or treatment motivation. Results were controlled for the effects of confounding variables (e.g., age, educational level, social desirability, relationship status). We critically evaluate the empirical contribution of this study to research on stigma and child sex offenses, including a discussion of the results in light of the potential indirect effects that public stigma may have on the overall risk for sexual offenses. PMID- 25933670 TI - Models and better evidence needed to clarify causality: a response to Bailey, Ellingson, and Bailey (2014). PMID- 25933671 TI - Between DSM and ICD: Paraphilias and the Transformation of Sexual Norms. AB - The simultaneous revision of the two major international classifications of disease, the Diagnostic and Statistical Manual of Mental Disorders and the International Classification of Diseases, serves as an opportunity to observe the dynamic processes through which social norms of sexuality are constructed and are subject to change in relation to social, political, and historical context. This article argues that the classifications of sexual disorders, which define pathological aspects of "sexually arousing fantasies, sexual urges or behaviors" are representations of contemporary sexual norms, gender identifications, and gender relations. It aims to demonstrate how changes in the medical treatment of sexual perversions/paraphilias passed, over the course of the 20th century, from a model of pathologization (and sometimes criminalization) of non-reproductive sexual behaviors to a model that reflects and privileges sexual well-being and responsibility, and pathologizes the absence or the limitation of consent in sexual relations. PMID- 25933672 TI - Sustained statin use is associated with lower risk of death in lung cancer patients, study shows. PMID- 25933673 TI - Pathways to help: adolescent sexual assault victims' disclosure and help-seeking experiences. AB - In this study, we conducted semistructured interviews with N = 20 adolescent sexual assault victims who sought postassault help from the medical and legal system to understand young survivors' disclosure and help-seeking processes. Results revealed three distinct disclosure patterns and pathways to help-seeking. First, in the voluntary disclosure group, victims told their friends, who encouraged them to tell an adult, who then encouraged--and assisted--the survivors in seeking help. Throughout this process, the survivors' disclosures at each step were within their control and reflected their choices for how to proceed. Second, in the involuntary disclosure pattern, victims also first disclosed to friends, but then those friends told adults about the assault, against the survivors' wishes; the adults made the victims seek help, which was also against the survivors' preferences. Third, in situational disclosures, the survivors were unconscious at the time of the assault, and their friends disclosed and sought help on their behalf. We also examined how these initial disclosure patterns related to victims' continued engagement with these systems. PMID- 25933674 TI - The Impact of Mental Aerobics Training on Older Adults. AB - Mental Aerobics (MA) is a cognitively oriented intervention designed to improve older adults' perceptions of their cognitive ability as well as positively impact their performance. Forty-seven community-residing older adults (M age = 67.39, SD = 5.75) were randomly assigned to either a treatment (n = 24) or a waiting list control (n = 23) group. Participants in both treatment and control conditions completed measures of depression, self-rated health, cognitive functioning, and cognitive self-efficacy. Findings support the conclusion that MA can be an effective intervention in improving older adults' affectivity, everyday task self efficacy, and self-rated health. The impact of MA on measures of generalized fluid ability (Gf) and generalized crystallized ability (Gc) skills was moderated by level of education. The subsequent provision of MA training to controls minimized the performance differences between the treatment and control conditions, as well as the moderating effect of level of education. These findings suggest that MA can be effectively used to enhance older adults' views of their skills, critical to efforts to maintain cognitive functioning into later life, although some older persons may benefit to a greater extent than others. PMID- 25933675 TI - Next-generation sequencing-based panel testing for myeloid neoplasms. AB - Our ability to interrogate a broad array of genetic alterations in myeloid neoplasm has increased significantly with the advance in next-generation sequencing (NGS). In addition to morphologic examination, flow cytometry, and cytogenetics, NGS-based testing can add additional information to the diagnostic workup. More than a dozen myeloid-focused NGS-based panels are now available from commercial and academic laboratories. In this review, we examine the content of these panels in the context of our current understanding of driver alterations in myeloid neoplasms. With improved turnaround time, decreasing costs, and an expanding knowledge of the therapeutic and prognostic significance of the detected variants, NGS-based panel testing is likely to play a major role in the management of patients with myeloid neoplasm in the coming decade. PMID- 25933676 TI - Desmopressin improves platelet function in uremic patients taking antiplatelet agents who require emergent invasive procedures. AB - Uremia is associated with platelet dysfunction and can cause a bleeding tendency resulting in a major bleeding event after an invasive procedure or surgery that may be aggravated by antiplatelet agents. We prospectively investigated the potential of desmopressin to improve platelet dysfunction and to lower bleeding risk after emergent invasive procedures in uremic patients taking antiplatelet drugs. Twenty-three patients were enrolled with a mean age of 60.2 +/- 11.7 years. Baseline blood urea nitrogen and creatinine were 70.5 +/- 29.4 and 10.02 +/- 4.52 mg/dL, respectively. Twenty-one patients took aspirin. All patients were infused with desmopressin before their invasive procedures, which were a central catheter insertion for emergent hemodialysis in 13 patients, percutaneous nephrostomy in 7 patients, and angiography through arm or leg vessels in 3 patients. After desmopressin infusion, both the hematocrit and platelet count were slightly decreased without changes in prothrombin time or activated partial thrombin time. Collagen/epinephrine-closure time was significantly shortened from 252.7 +/- 40.7 to 144.6 +/- 51.0 s (p < 0.001). There were minimal bleeding in 20 patients and mild bleeding in 3 patients. None experienced severe bleeding event or required additional intervention for bleeding control. There were no adverse events including the decrease of serum sodium concentration. In conclusion, a single infusion of desmopressin before invasive procedures in uremic patients on antiplatelet drugs appeared to be well tolerated and improved platelet dysfunction measured by collagen/epinephrine-closure time. PMID- 25933677 TI - Prediction of central venous catheter-related bloodstream infections (CRBSIs) in patients with haematologic malignancies using a modified Infection Probability Score (mIPS). AB - The aim of this study was to predict the probability of central venous catheter related bloodstream infections (CRBSIs) in patients with haematologic malignancies using a modified version of the Infection Probability Score (mIPS). In order to perform a prospective, mono-centric surveillance of complications in clinical routine due to short-term central venous catheters (CVCs) in consecutive patients receiving chemotherapy from March 2013 to September 2014, IPS was calculated at CVC insertion and removal (mIPSin and mIPSex, respectively). We used the 2012 Infectious Diseases Working Party of the German Society of Haematology and Medical Oncology (AGIHO/DGHO) criteria to define CRBSI. In total, 143 patients (mean 59.5 years, 61.4 % male) with 267 triple-lumen CVCs (4044 CVC days; mean 15.1 days, range 1-60 days) were analysed. CVCs were inserted for therapy of acute leukaemia (53.2 %), multiple myeloma (24.3 %) or lymphoma (11.2 %), and 93.6 % were inserted in the jugular vein. A total of 66 CRBSI cases (24.7 %) were documented (12 definite/13 probable/41 possible). The incidence was 16.3/1000 CVC days (2.9/3.1/10.1 per 1000 CVC days for definite/probable/possible CRBSI, respectively). In CRBSI cases, the mIPSex was higher as compared to cases without CRBSI (13.1 vs. 7.1; p < 0.001). The best mIPSex cutoff for CRBSI prediction was 8 points (area under the curve (AUC) = 0.77; sensitivity = 84.9 %, specificity = 60.7 %, negative predictive value = 92.4 %). For patients with an mIPSex >=8, the risk for a CRBSI was high (odds ratio [OR] = 5.9; p < 0.001) and even increased if, additionally, CVC had been in use for about 10 days (OR = 9.8; p < 0.001). In case other causes of infection are excluded, a mIPSex >=8 and duration of CVC use of about 10 days predict a very high risk of CRBSI. Patients with a mIPSex <8 have a low risk of CRBSI of 8 %. PMID- 25933678 TI - Identification of a fusion gene composed of a Hippo pathway gene MST2 and a common translocation partner ETV6 in a recurrent translocation t(8;12)(q22;p13) in acute myeloid leukemia. PMID- 25933679 TI - Interpolated average CT for cardiac PET/CT attenuation correction. AB - BACKGROUND: Previously, we proposed interpolated averaged CT (IACT) for improved attenuation correction (AC) in thoracic PET/CT. This study aims to evaluate its feasibility and effectiveness on cardiac PET/CT. METHODS: We simulated (18)F-FDG distribution using the XCAT phantom with normal and abnormal cardiac uptake. Average activity and attenuation maps represented static PET and respiration average CT (ACT), respectively, while the attenuation maps of end inspiration/expiration represented 2 helical CTs (HCT). IACT was obtained by averaging the 2 extreme phases and the interpolated phases generated between them. Later, we recruited 4 patients who were scanned 1 hr post 315-428 MBq (18)F FDG injection. Simulated and clinical PET sinograms were reconstructed with AC using (1) HCT, (2) IACT, and (3) ACT. Polar plots and the 17-segment plots were analyzed. Two regions-of-interest were drawn on lesion and background area to obtain the intensity ratio (IR). RESULTS: Polar plots of PETIACT-AC were more similar to PETACT-AC in both simulation and clinical data. Artifacts were observed in various segments in PETHCT-AC. IR differences of HCT as compared to the phantom were up to ~20%. CONCLUSIONS: IACT-AC reduced respiratory artifacts and improved PET/CT matching similarly to ACT-AC. It is a promising low-dose alternate of ACT for cardiac PET/CT. PMID- 25933680 TI - The centralization of robotic surgery in high-volume centers for endometrial cancer patients--a study of 6560 cases in the U.S. AB - OBJECTIVE: To evaluate the hospital and patient factors associated with robotic surgery for endometrial cancer in the United States. METHODS: Data was obtained from the Nationwide Inpatient Sample from the year 2010. Chi-squared and multivariate analyses were used for statistical analysis. RESULTS: Of the 6560 endometrial cancer patients who underwent surgery, the median age was 62 (range: 22 to 99). 1647 (25%) underwent robotic surgery, 820 (13%) laparoscopic, and 4093 (62%) had open surgery. The majority was White (65%). Hospitals with 76 or more hysterectomy cases for endometrial cancer patients per year (4% of hospitals in the study) performed 31% of all hysterectomies and 40% of all robotic hysterectomies (p<0.01). 29% of Whites had robotic surgery compared to 15% of Hispanics, 12% of Blacks, and 11% of Asians (p<0.01). Patients with upper-middle and high incomes underwent robotic surgery more than patients with low or middle incomes (p<0.01). 27% of Medicare patients and 26% of patients with private insurance had robotic surgery compared to only 14% of Medicaid patients and 12% of uninsured patients (p<0.01). CONCLUSIONS: The majority of robotic surgeries for endometrial cancer were performed at a small number of high-volume hospitals in the United States. Socioeconomic status, insurance type, and race were also important predictors for the use of RS. Further studies are warranted to better understand the barriers to receiving minimally invasive surgery. PMID- 25933681 TI - Relationship between race and clinical characteristics, extent of disease, and response to chemotherapy in patients with low-risk gestational trophoblastic neoplasia. AB - OBJECTIVE: To evaluate the potential effects of race on clinical characteristics, extent of disease, and response to chemotherapy in women with postmolar low-risk gestational trophoblastic neoplasia (GTN). METHODS: This non-concurrent cohort study was undertaken including patients with FIGO-defined postmolar low-risk GTN treated with comparable doses and schedules of chemotherapy at the New England Trophoblastic Disease Center (NETDC) between 1973 and 2012. Racial groups investigated included whites, African American and Asians. Information on patient characteristics and response to chemotherapy (need for second line chemotherapy, reason for changing to an alternative chemotherapy, number of cycles/regimens, need for combination chemotherapy, and time to hCG remission) was obtained. RESULTS: Of 316 women, 274 (86.7%) were white, 19 (6%) African American, and 23 (7.3%) Asian. African Americans were significantly younger than white and Asian women (p=0.008). Disease presentation, and extent of disease, including antecedent molar histology, median time to persistence, median hCG level at persistence, rate of D&C at persistence, presence of metastatic disease, and FIGO stage and risk score were similar among races. Need for second line chemotherapy (p=0.023), and median number of regimens (p=0.035) were greater in Asian women than in other races. CONCLUSIONS: Low-risk GTN was more aggressive in Asian women, who were significantly more likely to need second line chemotherapy and a higher number of chemotherapy regimens to achieve complete remission than women of African American and Asian descent. Further studies involving racial differences related to clinical, biological and environmental characteristics are needed. PMID- 25933682 TI - Adherence patterns to National Comprehensive Cancer Network (NCCN) guidelines for referral to cancer genetic professionals. AB - OBJECTIVE: Genetic predisposition is responsible for 5-10% of breast cancer, 10% of ovarian cancer and 2-5% of uterine cancer. The study objective was to compare genetic counseling and testing referral rates among women with breast cancer that met NCCN referral guidelines to the referral rates among women with gynecologic cancers and determine predictors of referral. METHODS: Utilizing an institutional tumor registry database, patients from an academic women's oncology program were identified who met a subset of NCCN guidelines for genetic referral between 2004 and 2010. Patients diagnosed with ovarian cancer, breast cancer <=50years of age, or uterine cancer <50years of age were included. A retrospective electronic chart review was conducted to evaluate for a genetic referral and uptake of genetic testing. RESULTS: 820 women were included (216 uterine, 314 breast, and 290 ovarian cancer). The overall genetic referral rate was 21.7%. 34% of eligible breast cancer patients were referred compared to 13.4% of uterine cancer and 14.5% of ovarian cancer patients (p<0.0001). Younger age, breast cancer diagnosis, family history and earlier stage were all significant referral predictors. The odds of being referred increased with the number of affected family members. 70.8% of referred patients, consulted with genetics. Among those who consulted with genetics, 95.2% underwent testing. CONCLUSIONS: Although increasing, genetic counseling remains underutilized across cancer diagnosis. Women with breast cancer are more likely to be referred than women with gynecologic cancers. Younger age, earlier stage and positive family history appear to be predictive of referral for genetic evaluation. PMID- 25933683 TI - Dual blockade of PI3K/AKT/mTOR (NVP-BEZ235) and Ras/Raf/MEK (AZD6244) pathways synergistically inhibit growth of primary endometrioid endometrial carcinoma cultures, whereas NVP-BEZ235 reduces tumor growth in the corresponding xenograft models. AB - OBJECTIVES: Endometrial carcinoma (EC) is the most common gynecological cancer in the Western World. Treatment options are limited for advanced and recurrent disease. Therefore, new treatment options are necessary. Inhibition of the PI3K/AKT/mTOR and/or the Ras/Raf/MEK pathways is suggested to be clinically relevant. However, the knowledge about the effect of combination targeted therapy in EC is limited. The aim of this study was to investigate the effect of these therapies on primary endometrioid EC cell cultures in vitro and in vivo. METHODS: Primary endometrioid EC cell cultures were incubated with Temsirolimus (mTORC1 inhibitor), NVP-BKM120 (pan-PI3K inhibitor), NVP-BEZ235 (pan-PI3K/mTOR inhibitor), or AZD6244 (MEK1/2 inhibitor) as single treatment. In vitro, the effect of NVP-BEZ235 with or without AZD6244 was determined for cell viability, cell cycle arrest, apoptosis induction, and cell signaling. In vivo, the effect of NVP-BEZ35 was investigated for 2 subcutaneous xenograft models of the corresponding primary cultures. RESULTS: NVP-BEZ235 was the most potent PI3K/AKT/mTOR pathway inhibitor. NVP-BEZ235 and AZD6244 reduced cell viability and induced cell cycle arrest and apoptosis, by reduction of p-AKT, p-S6, and p ERK levels. Combination treatment showed a synergistic effect. In vivo, NVP BEZ235 reduced tumor growth and inhibited p-S6 expression. The effects of the compounds were independent of the mutation profile of the cell cultures used. CONCLUSIONS: A synergistic antitumor effect was shown for NVP-BEZ235 and AZD6244 in primary endometrioid EC cells in vitro. In addition, NVP-BEZ235 induced reduction of tumor growth in vivo. Therefore, targeted therapies seem an interesting strategy to further evaluate in clinical trials. PMID- 25933685 TI - [Severe inferior retinal folding after retinectomy: An uncommon form of proliferative vitreoretinopathy]. PMID- 25933686 TI - Synchronization of chaotic systems and identification of nonlinear systems by using recurrent hierarchical type-2 fuzzy neural networks. AB - This paper proposes a novel approach for training of proposed recurrent hierarchical interval type-2 fuzzy neural networks (RHT2FNN) based on the square root cubature Kalman filters (SCKF). The SCKF algorithm is used to adjust the premise part of the type-2 FNN and the weights of defuzzification and the feedback weights. The recurrence property in the proposed network is the output feeding of each membership function to itself. The proposed RHT2FNN is employed in the sliding mode control scheme for the synchronization of chaotic systems. Unknown functions in the sliding mode control approach are estimated by RHT2FNN. Another application of the proposed RHT2FNN is the identification of dynamic nonlinear systems. The effectiveness of the proposed network and its learning algorithm is verified by several simulation examples. Furthermore, the universal approximation of RHT2FNNs is also shown. PMID- 25933684 TI - Topical antifungals for seborrhoeic dermatitis. AB - BACKGROUND: Seborrhoeic dermatitis is a chronic inflammatory skin condition that is distributed worldwide. It commonly affects the scalp, face and flexures of the body. Treatment options include antifungal drugs, steroids, calcineurin inhibitors, keratolytic agents and phototherapy. OBJECTIVES: To assess the effects of antifungal agents for seborrhoeic dermatitis of the face and scalp in adolescents and adults.A secondary objective is to assess whether the same interventions are effective in the management of seborrhoeic dermatitis in patients with HIV/AIDS. SEARCH METHODS: We searched the following databases up to December 2014: the Cochrane Skin Group Specialised Register, the Cochrane Central Register of Controlled Trials (CENTRAL) (2014, Issue 11), MEDLINE (from 1946), EMBASE (from 1974) and Latin American Caribbean Health Sciences Literature (LILACS) (from 1982). We also searched trials registries and checked the bibliographies of published studies for further trials. SELECTION CRITERIA: Randomised controlled trials of topical antifungals used for treatment of seborrhoeic dermatitis in adolescents and adults, with primary outcome measures of complete clearance of symptoms and improved quality of life. DATA COLLECTION AND ANALYSIS: Review author pairs independently assessed eligibility for inclusion, extracted study data and assessed risk of bias of included studies. We performed fixed-effect meta-analysis for studies with low statistical heterogeneity and used a random-effects model when heterogeneity was high. MAIN RESULTS: We included 51 studies with 9052 participants. Of these, 45 trials assessed treatment outcomes at five weeks or less after commencement of treatment, and six trials assessed outcomes over a longer time frame. We believe that 24 trials had some form of conflict of interest, such as funding by pharmaceutical companies.Among the included studies were 12 ketoconazole trials (N = 3253), 11 ciclopirox trials (N = 3029), two lithium trials (N = 141), two bifonazole trials (N = 136) and one clotrimazole trial (N = 126) that compared the effectiveness of these treatments versus placebo or vehicle. Nine ketoconazole trials (N = 632) and one miconazole trial (N = 47) compared these treatments versus steroids. Fourteen studies (N = 1541) compared one antifungal versus another or compared different doses or schedules of administration of the same agent versus one another. KetoconazoleTopical ketoconazole 2% treatment showed a 31% lower risk of failed clearance of rashes compared with placebo (risk ratio (RR) 0.69, 95% confidence interval (CI) 0.59 to 0.81, eight studies, low quality evidence) at four weeks of follow-up, but the effect on side effects was uncertain because evidence was of very low quality (RR 0.97, 95% CI 0.58 to 1.64, six studies); heterogeneity between studies was substantial (I2 = 74%). The median proportion of those who did not have clearance in the placebo groups was 69%.Ketoconazole treatment resulted in a remission rate similar to that of steroids (RR 1.17, 95% CI 0.95 to 1.44, six studies, low-quality evidence), but occurrence of side effects was 44% lower in the ketoconazole group than in the steroid group (RR 0.56, 95% CI 0.32 to 0.96, eight studies, moderate-quality evidence).Ketoconozale yielded a similar remission failure rate as ciclopirox (RR 1.09, 95% CI 0.95 to 1.26, three studies, low-quality evidence). Most comparisons between ketoconazole and other antifungals were based on single studies that showed comparability of treatment effects. CiclopiroxCiclopirox 1% led to a lower failed remission rate than placebo at four weeks of follow-up (RR 0.79, 95% CI 0.67 to 0.94, eight studies, moderate-quality evidence) with similar rates of side effects (RR 0.9, 95% CI 0.72 to 1.11, four studies, moderate-quality evidence). Other antifungalsClotrimazole and miconazole efficacies were comparable with those of steroids on short-term assessment in single studies.Treatment effects on individual symptoms were less clear and were inconsistent, possibly because of difficulties encountered in measuring these symptoms.Evidence was insufficient to conclude that dose or mode of delivery influenced treatment outcome. Only one study reported on treatment compliance. No study assessed quality of life. One study assessed the maximum rash-free period but provided insufficient data for analysis. One small study in patients with HIV compared the effect of lithium versus placebo on seborrhoeic dermatitis of the face, but treatment outcomes were similar. AUTHORS' CONCLUSIONS: Ketoconazole and ciclopirox are more effective than placebo, but limited evidence suggests that either of these agents is more effective than any other agent within the same class. Very few studies have assessed symptom clearance for longer periods than four weeks. Ketoconazole produced findings similar to those of steroids, but side effects were fewer. Treatment effect on overall quality of life remains unknown. Better outcome measures, studies of better quality and better reporting are all needed to improve the evidence base for antifungals for seborrhoeic dermatitis. PMID- 25933687 TI - Natural product (-)-gossypol inhibits colon cancer cell growth by targeting RNA binding protein Musashi-1. AB - Musashi-1 (MSI1) is an RNA-binding protein that acts as a translation activator or repressor of target mRNAs. The best-characterized MSI1 target is Numb mRNA, whose encoded protein negatively regulates Notch signaling. Additional MSI1 targets include the mRNAs for the tumor suppressor protein APC that regulates Wnt signaling and the cyclin-dependent kinase inhibitor P21(WAF-1). We hypothesized that increased expression of NUMB, P21 and APC, through inhibition of MSI1 RNA binding activity might be an effective way to simultaneously downregulate Wnt and Notch signaling, thus blocking the growth of a broad range of cancer cells. We used a fluorescence polarization assay to screen for small molecules that disrupt the binding of MSI1 to its consensus RNA binding site. One of the top hits was ( )-gossypol (Ki = 476 +/- 273 nM), a natural product from cottonseed, known to have potent anti-tumor activity and which has recently completed Phase IIb clinical trials for prostate cancer. Surface plasmon resonance and nuclear magnetic resonance studies demonstrate a direct interaction of (-)-gossypol with the RNA binding pocket of MSI1. We further showed that (-)-gossypol reduces Notch/Wnt signaling in several colon cancer cell lines having high levels of MSI1, with reduced SURVIVIN expression and increased apoptosis/autophagy. Finally, we showed that orally administered (-)-gossypol inhibits colon cancer growth in a mouse xenograft model. Our study identifies (-)-gossypol as a potential small molecule inhibitor of MSI1-RNA interaction, and suggests that inhibition of MSI1's RNA binding activity may be an effective anti-cancer strategy. PMID- 25933689 TI - Aciduric microbial taxa including Scardovia wiggsiae and Bifidobacterium spp. in caries and caries free subjects. AB - Actinobacteria came into focus of being potential caries-associated pathogens and could, together with the established Streptococcus mutans and lactobacilli thus function as caries indicator species. Here we analyzed the role and diagnostic predictive value of the acidogenic-aciduric species Scardovia wiggsiae and Bifidobacterium dentium together with S. mutans, lactobacilli and bifidobacteria in biofilm of non-cavitated (n = 20) and cavitated (n = 6) caries lesions versus controls (n = 30). For the genus Bifidobacterium and for B. dentium new sets of primers were designed. Based on real-time quantitative PCR and confirmed by DNA sequencing we found a higher prevalence (61.5%) of S. wiggsiae in caries lesions than in controls (40%). However, among the controls we found three individuals with both the highest absolute and relative S. wiggsiae numbers. Testing for S. mutans revealed the same prevalence as S. wiggsiae in caries lesions (61.5%) but in controls its prevalence was only 10%. B. dentium was never found in healthy plaque but in 30.8% of clinical cases, with the highest numbers in cavitated lesions. The Bifidobacterium-genus specific PCR had less discriminative power as more control samples were positive. We calculated the relative abundances and applied receiver operating characteristic analyses. The top results of specificity (93% and 87%) and sensitivity (100% and 88%) were found when the constraint set was "Lactobacillus relative abundance >=0.02%" and "two aciduric species with a relative abundance of each >=0.007%". Combinatory measurement of several aciduric taxa may be useful to reveal caries activity or even to predict caries progression. PMID- 25933688 TI - KRAS and HRAS mutations confer resistance to MET targeting in preclinical models of MET-expressing tumor cells. AB - The MET receptor tyrosine kinase is often deregulated in human cancers and several MET inhibitors are evaluated in clinical trials. Similarly to EGFR, MET signals through the RAS-RAF-ERK/MAPK pathway which plays key roles in cell proliferation and survival. Mutations of genes encoding for RAS proteins, particularly in KRAS, are commonly found in various tumors and are associated with constitutive activation of the MAPK pathway. It was shown for EGFR, that KRAS mutations render upstream EGFR inhibition ineffective in EGFR-positive colorectal cancers. Currently, there are no clinical studies evaluating MET inhibition impairment due to RAS mutations. To test the impact of RAS mutations on MET targeting, we generated tumor cells responsive to the MET inhibitor EMD1214063 that express KRAS G12V, G12D, G13D and HRAS G12V variants. We demonstrate that these MAPK-activating RAS mutations differentially interfere with MET-mediated biological effects of MET inhibition. We report increased residual ERK1/2 phosphorylation indicating that the downstream pathway remains active in presence of MET inhibition. Consequently, RAS variants counteracted MET inhibition-induced morphological changes as well as anti-proliferative and anchorage-independent growth effects. The effect of RAS mutants was reversed when MET inhibition was combined with MEK inhibitors AZD6244 and UO126. In an in vivo mouse xenograft model, MET-driven tumors harboring mutated RAS displayed resistance to MET inhibition. Taken together, our results demonstrate for the first time in details the role of KRAS and HRAS mutations in resistance to MET inhibition and suggest targeting both MET and MEK as an effective strategy when both oncogenic drivers are expressed. PMID- 25933690 TI - Enhanced osteogenic differentiation of stem cells via microfluidics synthesized nanoparticles. AB - Advancement of bone tissue engineering as an alternative for bone regeneration has attracted significant interest due to its potential in reducing the costs and surgical trauma affiliated with the effective treatment of bone defects. We have improved the conventional approach of producing polymeric nanoparticles, as one of the most promising choices for drug delivery systems, using a microfluidics platform, thus further improving our control over osteogenic differentiation of mesenchymal stem cells. Molecular dynamics simulations were carried out for theoretical understanding of our experiments in order to get a more detailed molecular-scale insight into the drug-carrier interactions. In this work, with the sustained intracellular delivery of dexamethasone from microfluidics synthesized nanoparticles, we explored the effects of particle design on controlling stem cell fates. We believe that the insights learned from this work will lead to the discovery of new strategies to tune differentiation for in situ differentiation or stem cell therapeutics. FROM THE CLINICAL EDITOR: The use of mesenchymal stem cells has been described by many researchers as a novel therapy for bone regeneration. One major hurdle in this approach is the control of osteogenic differentiation. In this article, the authors described elegantly their microfluidic system in which dexamethasone loaded nanoparticles were produced. This system would allow precise fabrication of nanoparticles and consequently higher efficiency in cellular differentiation. PMID- 25933691 TI - Chemo-spectroscopic sensor for carboxyl terminus overexpressed in carcinoma cell membrane. AB - Certain carboxyl groups of the plasma membrane are involved in tumorgenesis processes. A gold core-hydroxyapatite shell (AuHA) nanocomposite is introduced as chemo-spectroscopic sensor to monitor these carboxyl groups of the cell membrane. Hydroxyapatite (HA) plays the role both of a chemical detector and of a biocompatible Raman marker. The principle of detection is based on chemical interaction between the hydroxyl groups of the HA and the carboxyl terminus of the proteins. The AuHA exhibits a surface enhanced Raman scattering (SERS) signal at 954 cm(-1) which can be used for its localization. The bio-sensing capacity of AuHA towards human skin epidermoid carcinoma (A431) and Chinese hamster ovary (CHO) cell lines is investigated using Raman microspectroscopic imaging. The localization of AuHA on cells is correlated with scanning electron microscopy, transmission electron microscopy and structured illumination fluorescence microscopy. This qualitative approach is a step towards a quantitative study of the proteins terminus. FROM THE CLINICAL EDITOR: This method would enable further studies on the molecular profiling of the plasma membrane, in an attempt to provide accurate cell identification. Using a gold core-hydroxyapatite shell (AuHA) nanocomposite, the authors in this paper showed the feasibility of detecting and differentiating cell surface molecules by surface enhanced Raman scattering. PMID- 25933692 TI - Cyclic-RGDfK peptide conjugated succinoyl-TPGS nanomicelles for targeted delivery of docetaxel to integrin receptor over-expressing angiogenic tumours. AB - Docetaxel (DTX) is an anticancer drug that is used alone and in combination with other drugs to treat tumours. However, it suffers from the drawback of non specific cytotoxicity. To improve the therapeutic potential of DTX, we report the synthesis of cRGDfK peptide-conjugated succinoyl-TPGS (tocopheryl polyethylene glycol succinate) nanomicelles for targeted delivery of DTX. Among RGD (Arg-Gly Asp) peptides, cRGDfK peptide shows specificity towards alphavbeta3 integrin receptors that are most commonly over-expressed in tumour cells. To cRGDfK peptide, succinoylated TPGS was synthesised and conjugated to cRGDfK peptide using a carbodiimide reaction. Peptide-conjugated DTX loaded nanomicelles (PDNM) displayed small particle size with a narrow distribution, controlled drug release and high physicochemical stability. Cytotoxicity, cellular uptake, apoptosis and anti-angiogenic comparisons of unconjugated nanomicelles to PDNM in DU145 human prostate cancer cells and HUVECs (Human Umblical Vein Endothelial Cells) clearly revealed the importance of the cRGDfK peptide in enhancing the drug delivery performance of nanomicelles. FROM THE CLINICAL EDITOR: Common to many chemotherapeutic agents for cancer, systemic toxicity remains a big concern. In this article, the authors attempted to address this issue by conjugating RGD based peptides to Docetaxel, which would target integrins expressed on tumor cell surface. The experimental data revealed enhanced drug delivery. PMID- 25933693 TI - Synchrotron radiation techniques for nanotoxicology. AB - Nanotoxicology studies the interactions of engineered nanomaterials with biological systems. Traditional in vitro and in vivo toxicological assays have been successfully employed. However, the toxicological mechanisms of nanoparticles might not be the same as those incurred in traditional molecular toxicology. Furthermore, how to realize in situ and real time measurements especially in the biological microenvironment is still a challenge. Synchrotron radiation, which is highly polarized and tunable, has been proved to play an indispensible role for nanotoxicology studies. In this review, the role of synchrotron radiation techniques is summarized in screening physicochemical characteristics, in vitro and in vivo behaviors, and ecotoxicological effects of engineered nanomaterials. FROM THE CLINICAL EDITOR: The rapid gain in popularity of nanomaterials has also raised the concern of nanotoxicity, which needs to be assessed and addressed. In this comprehensive review, the authors outlined the underlying principles of using synchrotron radiation techniques for nanotoxicology studies and also in other scientific fields. PMID- 25933694 TI - Nanosized TiO2 is internalized by dorsal root ganglion cells and causes damage via apoptosis. AB - Titanium dioxide (TiO2) is widely used as ingredient in several products in the nanoform. TiO2-nanoparticles (NPs) are also currently studied for different medical applications. A large debate exists on possible adverse health effects related to their exposure. While there is some evidence of TiO2-NP central nervous system toxicity, their effects on peripheral neurons have been poorly explored. In this study we investigated the effects of TiO2-NPs on dorsal root ganglion (DRG) sensory neurons and satellite glial cells that may be reached by nanoparticles from the bloodstream. We found that TiO2-NPs are internalized in DRG cells and induce apoptosis in a dose dependent manner in both types of cells, ROS production and changes in expression of proinflammatory cytokine IL-1beta. Furthermore, we found that the axonal retrograde transport is altered in neurons upon exposure to TiO2-NPs. Overall, the results indicate a potential neurotoxic effect of TiO2-NPs on DRG cells. FROM THE CLINICAL EDITOR: Exposure to titanium dioxide nanoparticles is increasing in medical practice. Little is known about their potential toxic effects on the peripheral nervous system. The authors studied this aspect and showed that titanium nanoparticles might potentially cause toxicity over long term. PMID- 25933695 TI - Tumor regression following intravenous administration of lactoferrin- and lactoferricin-bearing dendriplexes. AB - The possibility of using gene therapy for the treatment of cancer is limited by the lack of safe, intravenously administered delivery systems able to selectively deliver therapeutic genes to tumors. In this study, we investigated if the conjugation of the polypropylenimine dendrimer to lactoferrin and lactoferricin, whose receptors are overexpressed on cancer cells, could result in a selective gene delivery to tumors and a subsequently enhanced therapeutic efficacy. The conjugation of lactoferrin and lactoferricin to the dendrimer significantly increased the gene expression in the tumor while decreasing the non-specific gene expression in the liver. Consequently, the intravenous administration of the targeted dendriplexes encoding TNFalpha led to the complete suppression of 60% of A431 tumors and up to 50% of B16-F10 tumors over one month. The treatment was well tolerated by the animals. These results suggest that these novel lactoferrin and lactoferricin-bearing dendrimers are promising gene delivery systems for cancer therapy. FROM THE CLINICAL EDITOR: Specific targeting of cancer cells should enhance the delivery of chemotherapeutic agents. This is especially true for gene delivery. In this article, the authors utilized a dendrimer-based system and conjugated this with lactoferrin and lactoferricin to deliver anti-tumor genes. The positive findings in animal studies should provide the basis for further clinical studies. PMID- 25933696 TI - Anti-PDGF receptor beta antibody-conjugated squarticles loaded with minoxidil for alopecia treatment by targeting hair follicles and dermal papilla cells. AB - This study developed lipid nanocarriers, called squarticles, conjugated with anti platelet-derived growth factor (PDGF)-receptor beta antibody to determine whether targeted Minoxidil (MXD) delivery to the follicles and dermal papilla cells (DPCs) could be achieved. Squalene and hexadecyl palmitate (HP) were used as the matrix of the squarticles. The PDGF-squarticles showed a mean diameter and zeta potential of 195 nm and -46 mV, respectively. Nanoparticle encapsulation enhanced MXD porcine skin deposition from 0.11 to 0.23 MUg/mg. The antibody-conjugated nanoparticles ameliorated follicular uptake of MXD by 3-fold compared to that of the control solution in the in vivo mouse model. Both vertical and horizontal skin sections exhibited a wide distribution of nanoparticles in the follicles, epidermis, and deeper skin strata. The encapsulated MXD moderately elicited proliferation of DPCs and vascular endothelial growth factor (VEGF) expression. The active targeting of PDGF-squarticles may be advantageous to improving the limited success of alopecia therapy. FROM THE CLINICAL EDITOR: Topical use of minoxidil is only one of the very few treatment options for alopecia. Nonetheless, the current delivery method is far from ideal. In this article, the authors developed lipid nanocarriers with anti-platelet-derived growth factor receptor ? antibody to target dermal papilla cells, and showed enhanced uptake of minoxidil. PMID- 25933697 TI - Imaging-guided high-efficient photoacoustic tumor therapy with targeting gold nanorods. AB - Photoacoustic therapy using the large photoacoustic effect of agents for selectively killing cancer cells is demonstrated. Herein, a highly efficient photoacoustic treatment using gold nanorods (AuNRs) and its antitumor effect are reported. Folic acid conjugated AuNRs are designed to specifically target folate receptor-expressing cancer cells. Following photoacoustic treatment, most of the cancer cells with intracellular AuNRs die within 20s. Compared with single-walled carbon nanotubes and indocyanine green containing nanoparticles, AuNRs can produce much stronger shock waves by absorbing the optical energy and thus induced the more efficient cell death at equal molar concentrations. In addition, the laser-induced shock waves can be detected for photoacoustic imaging. Our in vivo experiments demonstrated that the AuNR-mediated photoacoustic treatment resulted in efficient tumor suppression in mice. Thus, both efficient cancer cell diagnostics and selective photoacoustic treatment can be realized with a single particle formulation. FROM THE CLINICAL EDITOR: Nanotechnology has enabled the development of many novel methods for the treatment of cancer. One of these is photoacoustic therapy. In this article, the authors demonstrated the efficacy of Folic acid conjugated gold nanorods in killing cancer cells after photoacoustic treatment. The findings should provide impetus for future clinical studies. PMID- 25933698 TI - Effects of adenoidectomy/adenotonsillectomy on ADHD symptoms and behavioral problems in children. AB - OBJECTIVES: In children, the most common reason of upper airway obstruction (UAO) is adenotonsillar hypertrophy. In literature, the adverse effects of UAO and obstructive sleep apnea syndrome on behavior and attention in children have been reported in several articles. However, the methods used for the evaluation of behavioral disorders have not been standardized in those studies. The aim of this study was to investigate the behavioral and attention characteristics of children before and after adenoidectomy/adenotonsillectomy using an internationally valid method. METHODS: A total of 41 patients, between 6 and 11 years of age and having a medical history of UAO for at least one year for which adenotonsillectomy procedure was indicated, were enrolled in the study. The patients were evaluated for signs of attention/behavioral disorders by a child-adolescent psychiatrist and Kiddie-Schedule for Affective Disorders and Schizophrenia for School-Age Children: Present and Lifetime Version (K-SADS-PL) and The Turgay DSM-IV-Based Child and Adolescent Disruptive Behavioral Disorders Screening and Rating Scale (T-DSM-IV-S), before and at the 6th month following the operation. RESULTS: In the preoperative period, a psychiatric disorder was identified by K-SADS-PL in 41.4% (n =1 7) of patients. Of these, 11 patients had attention deficit hyperactivity disorder (ADHD), 6 had enuresis nocturna, and 2 had separation anxiety disorder. Pre- and postoperative mean scores in T-DSM-IV-S parent scale were 31.3 +/- 8.5 and 20.2 +/- 10.3, respectively, and this difference was statistically significant (p < 0.001). CONCLUSION: The relationship of UAO and attention/behavioral disorders should be taken into consideration by child adolescent psychiatrists together with ENT specialists and a multidisciplinary approach is important for the treatment team. PMID- 25933699 TI - Which nanny--the state or industry? Wowsers, teetotallers and the fun police in public health advocacy. AB - There is no option for avoiding the 'Nanny'. The only option for communities is to make sensible choices about which 'Nanny' will dominate their lives and at what time, which 'Nanny' will make us healthy and which 'Nanny' will undermine our health and our freedoms. Those political ideologues who use 'nanny statism' largely do so to further their own agenda and are invariably inconsistent in how they apply their concept of non-interference. Who's afraid of the 'Nanny State' is not the question should be asking. Rather the question ought to be--which Nanny should cause the greatest concern? The prime reason that the 'Nanny State' conjures fear is that it is a threat to the freedoms that are a key element of democratic societies. The tenet understood by the concept of the 'Nanny State' is that the more regulation that is made by the State, the more freedoms are whittled away and it is the intention of the wowsers, the teetotallers and the fun police to do so. It is time to rethink the 'nanny' concept, from the narrow sense of loss of individual freedoms (and one which favours 'free enterprise' and money making interests of big industry) to that which enables individuals and populations freedom from domination. Such a change particularly pertains to our understandings of the role of government. Pettit's work in framing the notion of freedom in terms of 'dominance' rather than 'interference' is pertinent. It provides a more realistic way in which to understand why industry uses the 'Nanny State' argument. It is to maintain its own dominance (i.e. in matters of public health) rather than allowing governments to interfere with that dominance. Public health advocacy work is regularly undermined by the 'Nanny State' phrase. This paper explores a series of examples which illustrate how public health is being undermined by the 'Nanny Industry' and how industry uses fear of government regulation to maintain its own dominance, to maintain its profits and to do so at a significant financial and social cost to the community and to public health. PMID- 25933700 TI - Optimisation of steroid prophylaxis schedules in breast cancer patients receiving docetaxel chemotherapy-a survey of health care providers and patients. AB - PURPOSE: Despite the widespread use of steroid prophylaxis schedules for breast cancer patients receiving docetaxel chemotherapy, questions still exist regarding their optimal use. We surveyed health care providers and patients about their experiences with steroid prophylaxis. METHODS: Two questionnaires were developed and circulated. One was presented to health care providers (chemotherapy nurses, pharmacists and medical oncologists) involved in the treatment of breast cancer and the second to patients who had received docetaxel chemotherapy for early stage breast cancer. RESULTS: The health care providers' questionnaire was completed by 184 of 698 invitees: 92/171 (53.8 %) chemotherapy nurses, 56/284 (19.7 %) pharmacists and 36/243 (14.8 %) medical oncologists (overall response rate 26.4 %). Two steroid schedules were found to be the most commonly used: dexamethasone 8 mg BID for 6 doses, with either 3 (79 %) or 2 (11 %) doses taken before docetaxel administration. Suboptimal adherence to steroid premedication had been experienced by 98 % (177/181) of practitioners. Despite the presence of local treatment protocols in 65 % (119/183) of practitioners' institutions, 10 different strategies were commonly used when steroid premedication was taken incorrectly. The patients' questionnaire was completed by 72/87 (82.3 %) invitees. Respondents reported correctly taking their premedication 99 % (70/71) of the time. Patients felt steroids frequently caused side effects, the most common being sleep disturbance (35/72 = 49 %) and skin toxicity (16/72 = 22 %). CONCLUSION: Suboptimal adherence to steroid premedication prior to docetaxel administration is a common clinical challenge. There appears to be discordance between the practitioner and the patient experience. A single, universally accepted and used protocol for both pre- and post-medication and management when premedication is not taken as prescribed could improve adherence. PMID- 25933701 TI - Prevalence of severe depressive symptoms increases as death approaches and is associated with disease burden, tangible social support, and high self-perceived burden to others. AB - PURPOSE: Terminally ill cancer patients experience progressive functional decline, accelerating symptom severity, deteriorating social support, and self perceived burden to others (SPB), predisposing them to depressive symptoms. However, changes in the prevalence of severe depressive symptoms as death approaches and the unique roles of these four variables have not been adequately studied. This study explored longitudinal changes in and associations of symptom distress, functional dependence, social support, and SPB with prevalence of severe depressive symptoms in the last year of life. METHODS: A convenience sample of 325 cancer patients was longitudinally followed until death. Prevalence of severe depressive symptoms (score >=11 on the depression subscale of the Hospital Anxiety and Depression Scale) was examined by multivariate logistic regression modeling with the generalized estimating equation. RESULTS: The prevalence of severe depressive symptoms increased as death approached. The likelihood of severe depressive symptoms was significantly higher in patients who had higher levels of symptom distress and functional dependence, received greater tangible support, and reported high SPB, but lower for patients reporting a higher level of affectionate support and positive social interactions with their supportive network. CONCLUSION: Prevalence of severe depressive symptoms increased as death approached and was associated with several modifiable factors. Healthcare professionals should become familiar with these factors to identify vulnerable patients. To decrease the likelihood of terminally ill cancer patients' severe depressive symptoms, they should receive effective interventions to manage their symptoms, appropriately foster social support to restore their fragile self-esteem due to depending on others, and lighten their SPB. PMID- 25933702 TI - Hospital preparedness for knowledge-based response to Ebola and other emerging infectious diseases: A continuous challenge. PMID- 25933703 TI - Fluorimetric screening assay for protein carbonyl evaluation in biological samples. AB - Many assays are available for the detection of protein carbonyls (PCs). Currently, the measurement of PC groups after their derivatization with 2,4 dinitrophenol hydrazine (DNPH) is widely used for measuring protein oxidation in biological samples. However, this method includes several washing steps. In this context, we have developed a rapid, sensitive, and accurate fluorimetric method adapted to 96-well microplates for the convenient assessment of protein carbonyl level in biological samples. The method reported here is based on the reaction of carbonyl content in proteins with 7-hydrazino-4-nitrobenzo-2,1,3-oxadiazole (NBDH) to form highly fluorescent derivatives via hydrazone formation. PCs were determined using the DNPH and NBDH assays in fully reduced bovine serum albumin (BSA) and plasma and liver homogenates obtained from healthy control rats up the addition of various amounts of HOCl-oxidized BSA (OxBSA). Using the NBDH assay, PC concentrations as low as 0.2 nmol/mg were detected with precision as low as 5%. Matrix-assisted laser desorption/ionization time-of-flight (MALDI-TOF) mass spectroscopy was used to successfully identify the formation of the NBDH adducts after derivatization with standard oxidized peptides. Finally, the two methods were further used for PC determination in plasma and liver samples from diabetic and normal rats, showing that the NBDH assay can be reliably used in biological experiments. PMID- 25933704 TI - PACAP system evolution and its role in melanophore function in teleost fish skin. AB - Pituitary adenylate cyclase-activating polypeptide (PACAP) administered to tilapia melanophores ex-vivo causes significant pigment aggregation and this is a newly identified function for this peptide in fish. The G-protein coupled receptors (GPCRs), adcyap1r1a (encoding Pac1a) and vipr2a (encoding Vpac2a), are the only receptors in melanophores with appreciable levels of expression and are significantly (p < 0.05) down-regulated in the absence of light. Vpac2a is activated exclusively by peptide histidine isoleucine (PHI), which suggests that Pac1a mediates the melanin aggregating effect of PACAP on melanophores. Paradoxically activation of Pac1a with PACAP caused a rise in cAMP, which in fish melanophores is associated with melanin dispersion. We hypothesise that the duplicate adcyap1ra and vipr2a genes in teleosts have acquired a specific role in skin and that the melanin aggregating effect of PACAP results from the interaction of Pac1a with Ramp that attenuates cAMP-dependent PKA activity and favours the Ca(2+)/Calmodulin dependent pathway. PMID- 25933705 TI - The effect of laminae lesion on thoraco-lumbar fracture reduction. AB - INTRODUCTION: The treatment of fractures involving the lumbar spine has been controversial. Laminae lesion may be complete or of the greenstick type (incomplete). Dural tears and nerve root entrapment may accompany these laminae fractures. The aim of this study is twofold, to assess the effect of different types of laminae fractures on the anteriorvertebral height restoration in upper lumbar burst fractures and to determine the incidences of the intraoperatively detected dural tear and neural entrapment in complete and incomplete laminae fractures to choose the optimal treatment. MATERIALS AND METHODS: A retrospective review was conducted on 112 patients with 114 lumbar burst fractures treated operatively, age ranged from 17 to 55 years (mean age 32). Male to female ratio was (93%/7%), 8 females. Patients were divided into three groups, group 1 patients without lamina fracture, group 2 patients with complete type lamina fracture and group 3 patients with (percutaneous) incomplete type lamina fractures. All clinical charts and radiologic data of these groups were analyzed for their association with dural tears, neural entrapment and the impact of lamina fracture (complete and incomplete types) on the efficacy of anterior vertebral height restoration. The severity of injury was determined using the ASIA (Modified Frankel scale). RESULTS: Out of 114 upper lumbar burst fractures, lamina fracture occurred in 34 patients (29.8%), complete lamina fracture occurred in 21 patients (61.7%), whereas incomplete lamina fracture occurred in 13 patients (38.3%). Dural tear was detected in 16 patients (47%) and was predominantly higher in complete type lamina fracture 12 patients (57%) when compared to 4 dural tears (30%) in incomplete lamina fractures. Analysis of the data revealed no significant difference in the preoperative anterior vertebral height loss and local kyphotic angle between the three groups. However the anterior vertebral height and local kyhpotic angle restoration were found to be affected by the presence of complete lamina fracture when compared to other groups with incomplete lamina fracture and without lamina fracture (P=0.001). CONCLUSION: In upper lumbar burst fractures, complete lamina fracture is an indicator of injury severity. When detected preoperatively on CT or MRI scanning, it should be operated by open book laminectomy even if the patient is neurologically intact since it carries a high risk of neural entrapment, and its presence affects the intraoperative postural and instrumental trials for anterior vertebral height restoration. PMID- 25933706 TI - Sulcus deepening trochleoplasty for patellofemoral instability: A series of 34 cases after 15 years postoperative follow-up. AB - INTRODUCTION: Trochlear dysplasia is one of the main elements of patellofemoral instability. Although correction by trochleoplasty seems logical, the long-term outcome of this procedure is unknown and the progression to osteoarthritis has not been clarified. Thus, we performed a retrospective study of a series of sulcus deepening trochleoplasties with a 15-year follow-up whose goal was to (1) evaluate the long-term clinical outcome and radiological rate of osteoarthritis, and (2) define the results in relation to the type of instability and the grade of dysplasia. HYPOTHESIS: Sulcus deepening trochleoplasty is an effective procedure to stabilize the patellofemoral joint that does not increase the risk of osteoarthritis. PATIENTS AND METHODS: This retrospective study analyzed 34 sulcus deepening trochleoplasties based on clinical scores (IKS, Lille, Kujala and Oxford scores) and radiological results (stage of osteoarthritis according to the Iwano score) after a mean follow-up of 15 years (12-19 years). An Insall procedure was systematically associated with an anterior tibial tubercle transfer in 17 cases (7 prior tibial transfers). RESULTS: No recurrent objective instability was observed. Seven knees had additional surgery after a mean follow up of 7 years (2-16): 7 underwent conversion to total knee arthroplasty because of progression of osteoarthritis and one knee had tibial tubercle transfer for pain and episodes of the knee giving way. The mean Lille, Kujala and IKS scores increased from 53.3 (30-92), 55 (13-75) and 127 (54-184) to 61.5 (25-93), 76 (51 94) and 152.4 (66-200) respectively between preoperative and follow-up assessment (P<0.05) (revisions included). Functional outcome was significantly better for dysplasia with supratrochlear spurs (IKS score 168 [127-200] versus 153 [98-198] and Kujula score 81.5 [51-98] versus 76 [51-94] [P<0.05]). Patients were satisfied in 65% of the cases and the total mean Oxford score was 24.1/60 (12-45 points). Occasional pain was present in 53% of the cases. The trochlear prominence decreased from 4.9 mm (3-9 mm) to -1.2mm (-7-4mm). Ten cases of preoperative patellofemoral osteoarthritis were identified, but none with>Iwano 2, while osteoarthritis was present in 33/34 cases at the final follow-up with 20 cases>Iwano 2 (65%). DISCUSSION: Sulcus deepening trochleoplasty corrects patellofemoral stability even in patients with severe dysplasia and the long-term functional outcome is better in this group. It does not prevent patellofemoral osteoarthritis. It should be limited to severe dysplasia with supratrochlear spurs and associated with procedures to realign the extensor apparatus. PMID- 25933707 TI - A Randomized Controlled Study of the Use of ProRoot Mineral Trioxide Aggregate and Endocem as Direct Pulp Capping Materials: 3-month versus 1-year Outcomes. AB - INTRODUCTION: The purpose of this study was to assess the long-term clinical outcomes of direct pulp capping (DPC) with ProRoot MTA (Dentsply, Tulsa, OK) and Endocem (Maruchi, Wonju, Korea) as pulp capping materials. To this end, the 1 year cumulative successes of both materials were evaluated and compared with those of the 3-month outcomes in a prospective, randomized controlled trial. METHODS: Patients were recruited from the Department of Conservative Dentistry of the Yonsei University Dental Hospital, Seoul, South Korea, from January to May 2013. Of the 48 teeth that met the inclusion criteria, 46 teeth were randomly allocated to either ProRoot MTA or Endocem groups (n = 23). Direct pulp capping was performed, and clinical and radiographic examinations were conducted over 1 year after the treatment. Survival analyses were conducted to compare the cumulative successes between ProRoot MTA and Endocem and to evaluate other clinical variables. RESULTS: Forty-one teeth were recalled 1 year after the treatments (recall rate = 89.13%). There were no significant differences between the cumulative successes of ProRoot MTA and Endocem in either log-rank or Cox proportional hazard regression analyses (P > .05). Among the other clinical variables, cavity type (class I, II, III vs class V) was determined to be significant in both the log-rank test (P = .001) and Cox regression analysis (P = .006). CONCLUSIONS: Both ProRoot MTA and Endocem exhibited similar cumulative successes as direct pulp capping materials up to 1 year. The teeth restored with class V cavities exhibited significantly lower cumulative success rates after direct pulp capping compared with the teeth restored with other types of cavities. PMID- 25933708 TI - Exploring the nature of situational goal-based coping in early-stage breast cancer patients: A contextual approach. AB - PURPOSE: The psychosocial impact of breast cancer varies widely across patients and over time. Greater insight into goal-based coping processes theorised to underpin psychological resilience may inform efforts to support the maintenance and recovery of psychological wellbeing in the context of breast cancer treatment and recovery. This prospective study adopted a qualitative descriptive design to better understand the nature of situational goal-based coping in response to personal goal interference encountered across the six months following surgery for early-stage breast cancer. METHOD: Responses to specific instances of goal interference were derived from semi-structured interviews conducted at three time points following surgery (i.e., approximately two, four, and six months post surgery). Thematic and cross-case analytic techniques were utilised to identify broad patterns across the goal-specific response trajectories. RESULTS: Three broad response patterns were identified - goal-based coping only, combined goal based coping and other (i.e., informed waiting and/or passive) responses, and informed waiting and/or passive responses only. Specific response patterns were further identified within each category. The majority of response trajectories incorporated the utilisation of assimilative and/or accommodative goal-based coping. CONCLUSIONS: Early-stage breast cancer patients utilised goal-based coping in response to many instances of goal-specific interference encountered during the study period. While the initial or delayed activation of these processes appeared generally adaptive, there was also evidence of maladaptive coping and blocked goal pursuit. Further insight into the nature of adaptive and maladaptive goal-based coping in this context could help oncology nurses facilitate ongoing personal goal pursuit and psychological resilience across the cancer continuum. PMID- 25933709 TI - Normal saline versus heparin solution to lock totally implanted venous access devices: Results from a multicenter randomized trial. AB - PURPOSE: Our aim was to determine the non-inferiority of normal saline flushing compared to heparin flushing in maintaining the patency of totally implanted venous access devices (TIVADs). METHOD: Four hundred and thirty patients were recruited from 14 Italian centres. Patients were randomized to heparin group or to normal saline group. The primary outcome of the study was TIVAD occlusion. RESULTS: After randomisation, 203 patients were assigned to normal saline group and 212 to heparin group. Median follow up time was 204 days in normal saline group and 294 in the heparin group. We observed 24 withdrawal occlusions (5.78%): 10 in the heparin group and 14 in the normal saline group. One total occlusion was observed in the normal saline group. Taking as reference the arm treated with heparin, the absolute risk difference was 2.67 with the 90% CI including the non inferiority margin of 4%. No significant difference between hazards of occlusion was found. CONCLUSIONS: This study failed to demonstrate that normal saline flushing is not inferior to heparin flushing, even if a significant difference between the two treatments was not found. The use of heparin is controversial and other prospective trials are necessary in this field. TRIAL REGISTRATION: EudraCT number: 2009-013620-22. PMID- 25933710 TI - Pulmonary Capillary Hemorrhage Induced by Fixed-Beam Pulsed Ultrasound. AB - The induction of pulmonary capillary hemorrhage (PCH) by pulsed ultrasound was discovered 25 y ago, but early research used fixed-beam systems rather than actual diagnostic ultrasound machines. In this study, results of exposure of rats to fixed-beam focused ultrasound for 5 min at 1.5 and 7.5 MHz were compared with recent research on diagnostic ultrasound. One exposure condition at each frequency used 10-MUs pulses delivered at 25-ms intervals. Three conditions involved Gaussian modulation of the pulse amplitudes at 25-ms intervals to simulate diagnostic scanning: 7.5 MHz with 0.3- and 1.5-MUs pulses at 100- and 500-MUs pulse repetition periods, respectively, and 1.5 MHz with 1.7-MUs pulses at 500-MUs repetition periods. Four groups were tested for each condition to assess PCH areas at different exposure levels and to determine occurrence thresholds. The conditions with identical pulse timing resulted in smaller PCH areas for the smaller 7.5-MHz beam, but both had thresholds of 0.69-0.75 MPa in situ peak rarefactional pressure amplitude. The Gaussian modulation conditions for both 7.5 MHz with 0.3-MUs pulses and 1.5 MHz with 1.7-MUs pulses had thresholds of 1.12-1.20 MPa peak rarefactional pressure amplitude, although the relatively long 1.5-MUs pulses at 7.5 MHz yielded a threshold of 0.75 MPa. The fixed-beam pulsed ultrasound exposures produced lower thresholds than diagnostic ultrasound. There was no clear tendency for thresholds to increase with increasing ultrasonic frequency when pulse timing conditions were similar. PMID- 25933711 TI - Ultrasound Backscattering Is Anisotropic in Bovine Articular Cartilage. AB - Collagen, proteoglycans and chondrocytes can contribute to ultrasound scattering in articular cartilage. However, anisotropy of ultrasound scattering in cartilage is not fully characterized. We investigate this using a clinical intravascular ultrasound device with ultrasound frequencies of 9 and 40 MHz. Osteochondral samples were obtained from intact bovine patellas, and cartilage was imaged in two perpendicular directions: through articular and lateral surfaces. At both frequencies, ultrasound backscattering was higher (p < 0.05) when measured through the lateral surface of cartilage. In addition, the composition and structure of articular cartilage were investigated with multiple reference methods involving light microscopy, digital densitometry, polarized light microscopy and Fourier infrared imaging. Reference methods indicated that acoustic anisotropy of ultrasound scattering arises mainly from non-uniform distribution of chondrocytes and anisotropic orientation of collagen fibers. To conclude, ultrasound backscattering in articular cartilage was found to be anisotropic and dependent on the frequency in use. PMID- 25933712 TI - Sensitivity, Specificity and Accuracy of Ultrasound in Diagnosis of Breast Cancer Metastasis to the Axillary Lymph Nodes in Chinese Patients. AB - The use of ultrasound in the diagnosis of axillary lymph node metastases from breast cancer in a Chinese population was investigated. Data for 1,049 with breast cancer were retrospectively collected. All patients had undergone pre operative axillary ultrasound and then axillary lymph node dissection. The sensitivity, specificity and accuracy of axillary ultrasound in this cohort were 69.4%, 81.8% and 77.0%, respectively. The overall false-negative rate of ultrasound images was 30.6% (123/402). False-negative ultrasound rates for pathologic N1, N2 and N3 patients were 46.2%, 21.8% and 9.3%, respectively. In patients with stage T1 disease and fewer than three metastatic lymph nodes, the false-negative ultrasound rate was 52.2% (47/90). Moreover, breast cancer patients with a false-negative axillary ultrasound were more likely to have a large tumor (p < 0.001) and high tumor grade (p = 0.009). However, there were no statistically significant differences between accuracy of axillary ultrasound and age of patients or experiences of ultrasound practitioners. In conclusion, the sensitivity, specificity and accuracy of ultrasound in the diagnosis of breast cancer metastasis to the axillary lymph nodes in Chinese patients were assessed. These data could help us to carefully use axillary ultrasound to diagnose and predict breast cancer axillary lymph node metastasis. PMID- 25933714 TI - Non-continuous measurement of intraocular pressure in laboratory animals. AB - Glaucoma is a leading cause of blindness, which is treatable but currently incurable. Numerous animal models therefore have both been and continue to be utilized in the study of numerous aspects of this condition. One important facet associated with the use of such models is the ability to accurately and reproducibly measure (by cannulation) or estimate (by tonometry) intraocular pressure (IOP). At this juncture there are several different approaches to IOP measurement in different experimental animal species, and the list continues to grow. We feel therefore that a review of this subject matter is timely and should prove useful to others who wish to perform similar measurements. The general principles underlying various types of tonometric and non-tonometric techniques for non-continuous determination of IOP are considered. There follows discussion of specific details as to how these techniques are applied to experimental animal species involved in the research of this disease. Specific comments regarding anesthesia, circadian rhythm, and animal handling are also included, especially in the case of rodents. Brief consideration is also given to possible future developments. PMID- 25933713 TI - Ex vivo and in vivo capture and deactivation of circulating tumor cells by dual antibody-coated nanomaterials. AB - Circulating tumor cells (CTCs) have been detected by us and others in cancer patient blood. However, little is known about how to specifically capture and deactivate CTCs in vivo, which may lead to successful metastasis prevention in asymptomatic cancer survivors after surgery. We hypothesize that the dual antibody conjugates may have the advantage of capturing CTCs specifically over their single antibody counterparts. Here we show that the surface-functionalized dendrimers can be sequentially coated with two antibodies directed to surface biomarkers (EpCAM and Slex) of human colorectal CTCs. The dual antibody-coated dendrimers exhibit a significantly enhanced specificity in capturing CTCs in the presence of interfering blood cells, and in both eight-patient bloods and nude mice administered with the labeled CTCs in comparison to their single antibody coated counterparts. The dual antibody-coated conjugates down-regulate the captured CTCs. This study provides the first conceptual evidence that two antibodies can be biocompatibly conjugated to a nanomaterial to capture and down regulate CTCs in vivo with the enhanced specificity. PMID- 25933715 TI - TRPV4 activation triggers the release of melatonin from human non-pigmented ciliary epithelial cells. AB - Melatonin is a neurohormone mainly produced in the pineal gland; nevertheless, various ocular structures such as the ciliary body, lens and the retina produce it. One of the roles of melatonin in the eye is the modulation of intraocular pressure, although little is known about the mechanisms that causes its presence in the aqueous humour. TRPV4 is a membrane channel which is activated by both physical and chemical stimuli. Therefore, this channel is sensitive to osmotic and hydrostatic pressure. As a consequence, TRPV4 results as an interesting candidate to study the relation between the activation of the TRPV4 channel and the production of melatonin. In this sense we have studied the role of the TRPV4 agonist GSK1016790A to modulate the production of melatonin in a cell line derived from human non-pigmented ciliary epithelial cells. The stimulation of the TRPV4 produced an increase in the extracellular melatonin levels changing from 8.5 +/- 0.6 nM/well/30 min (control) to 23.3 +/- 2.1 nM/well/30 min after 10 nM GSK1016790A application, this action being blocked by the selective antagonist RN 1734. The activation of the TRPV4 by GSK1016790A permitted to observe a melatonin increase which was concentration-dependent, and provided a pD2 value of -8.5 +/- 0.1 (EC50 of 3.0 nM). In conclusion, the activation of the TRPV4 present in human non-pigmented ciliary epithelial cells can modulate the presence of extracellular melatonin, this being of relevance since this substance controls the dynamics of the aqueous humour. PMID- 25933716 TI - Formulation and evaluation of biodegradable nanoparticles for the oral delivery of fenretinide. AB - Fenretinide is an anticancer drug with low water solubility and poor bioavailability. The goal of this study was to develop biodegradable polymeric nanoparticles of fenretinide with the intent of increasing its apparent aqueous solubility and intestinal permeability. Three biodegradable polymers were investigated for this purpose: two different poly lactide-co-glycolide (PLGA) polymers, one acid terminated and one ester terminated, and one poly lactide-co glycolide/polyethylene glycol (PLGA/PEG) diblock copolymer. Nanoparticles were obtained by using an emulsification solvent evaporation technique. The formulations were characterized by differential scanning calorimetry (DSC), scanning electron microscopy (SEM), and particle size analysis. Dissolution studies and Caco-2 cell permeation studies were also carried out for all formulations. Ultra high performance liquid chromatography coupled with mass spectrometry (UPLC/MS) and ultraviolet detection was used for the quantitative determination of fenretinide. Drug loading and the type of polymer affected the nanoparticles' physical properties, drug release rate, and cell permeability. While the acid terminated PLGA nanoparticles performed the best in drug release, the ester terminated PLGA nanoparticles performed the best in the Caco-2 cell permeability assays. The PLGA/PEG copolymer nanoparticles performed better than the formulations with ester terminated PLGA in terms of drug release but had the poorest performance in terms of cell permeation. All three categories of formulations performed better than the drug alone in both drug release and cell permeation studies. PMID- 25933717 TI - Anticancer activity and toxicity profiles of 2-benzylidene indanone lead molecule. AB - 3-(3',4',5'-Trimethoxyphenyl)-4,5,6-trimethoxy,2-(3",4" methylenedioxybenzylidene)-indan-1-one (1) is an optimized anti-cancer lead molecule obtained on modification of gallic acid, a plant phenolic acid. It exhibited potent cytotoxicities (IC50=0.010-14.76MUM) against various human carcinoma cells. In cell cycle analysis, benzylidene indanone 1 induced G2/M phase arrest in both MCF-7 and MDA-MB-231 cells. It also induced apoptosis in DU145 cells which was evident by cleavage of PARP. In Ehrlich ascites carcinoma, benzylidene indanone 1 showed 45.48% inhibition of tumour growth at 20mg/kg dose in Swiss albino mice. Further, in sub-acute toxicity experiment in Swiss-albino mice, it was found to be non-toxic up to 100mg/kg dose for 28days. The lead compound benzylidene indanone 1 can further be optimized for better anti-cancer activity. PMID- 25933718 TI - A study on the applicability of in-line measurements in the monitoring of the pellet coating process. AB - Special populations including paediatric and elderly patients often need advanced approaches in treatment, such as one-a-day dosing, which is achieved with modified release formulations or alternative routes of applications such as nasogastric route. Pellets are a dosage form that is frequently used in such formulations. The aim of the present work was to study the applicability of two in-line techniques, namely, Near Infrared Spectroscopy (NIR) and Spatial Filtering Technique (SFT) in the pellet coating process. The first objective of our work was to develop a prediction model for moisture content determination with the in-line NIR and to test its robustness in terms of sensitivity to changes in composition of the pellets and performance in wide range of moisture content. Secondly, the in-line SFT measurement was correlated with different off line particle size methods. The third objective was to evaluate the ability of both in-line techniques for the detection of undesired deviations during the process, such as pellet attrition and agglomeration. Finally, the ability to predict coating thickness with the in-line NIR probe was evaluated. Results suggested that NIR prediction model for moisture content was less robust outside the calibration range and was also sensitive to changes in composition of the film coating. Nevertheless, satisfactory prediction was achieved in the case when coating composition was partially altered and adequate calibration range was used. The SFT probe results were in good correlation with off-line particle size measurement methods and proved to be an effective tool for coating thickness determination during the coating, however, the probe failed to accurately show the actual amount of the agglomerates formed during the process. In experiment when pellet attrition was initiated, both probes successfully detected abrasion of the pellet surface in real time. Furthermore, a predictive NIR model for coating thickness was made and showed a good potential to measure coating thickness in-line, suggesting that the NIR probe can be used as a single tool to monitor water content, coating thickness, and deviations in the coating process. PMID- 25933719 TI - Gadobutrol for contrast-enhanced magnetic resonance imaging in elderly patients: review of the safety profile from clinical trial, post-marketing surveillance, and pharmacovigilance data. AB - AIM: To assess the safety of gadobutrol administration in elderly patients (>=65 years) by comparing the incidence of adverse drug reactions (ADRs) following gadobutrol-enhanced magnetic resonance imaging (MRI) procedures in elderly patients with that in adults aged 18-64 years. MATERIALS AND METHODS: Safety data on gadobutrol administration from clinical trials, post-marketing surveillance (PMS) studies, and pharmacovigilance reports were collected in three databases. In each dataset, absolute and relative frequencies of ADRs between age groups were analysed, along with odds ratios and 95% confidence intervals. Logistic regression was used to identify significant influencing factors on ADRs in the PMS and pharmacovigilance data. RESULTS: Rates of reported ADRs were lower in elderly patients versus adults aged <65 years due to a reduced incidence of non serious ADRs; this was statistically significant for the clinical trials and pharmacovigilance populations, with a trend in the PMS database. Serious ADRs occurred infrequently in the clinical trials and PMS populations (too low for statistical comparison), and pharmacovigilance data demonstrated a low incidence (<0.005%) in both age groups. CONCLUSIONS: This evaluation involving three large databases demonstrated no greater incidence of ADRs following gadobutrol-enhanced MRI in elderly patients (>=65 years) compared with younger adults, with gadobutrol having a favourable safety profile in both age groups. PMID- 25933720 TI - Imaging submandibular pathology in the paediatric patient. AB - A wide range of pathologies may arise from the submandibular space (SMS) or submandibular gland (SMG) in children. We review herein the normal anatomy of the SMS and describe the role of imaging in the evaluation of SMS lesions. A schematic approach for the categorisation of SMS pathology based on imaging characteristics is provided. PMID- 25933721 TI - Maximum Power During Vertical Jump and Isometric Knee Extension Torque Alter Mobility Performance: A Cross-Sectional Study of Healthy Individuals. AB - OBJECTIVE: To provide reference values of muscle function (MF) and mobility performance (MP) and to clarify the effects of MF on MP. DESIGN: A normative cross-sectional study. SETTING: An urban area of Niigata, Japan. PARTICIPANTS: A total of 401 individuals (210 men and 191 women) with a mean age of 41.8 years (range, 7-79 years) who lived in the community and did not have impairments in activities of daily living. METHODS: Grip strength, isometric knee extension torque (IKET), and maximum ground reaction force (Fmax) and maximum power (Pmax) during a vertical jump were used as measurements of MF. The chair-rise test (CRT) and the timed "Up and Go" test (TUG) were used to assess MP. MAIN OUTCOME MEASUREMENTS: Mean values of GS, IKET, CRT, TUG, Fmax, and Pmax were calculated according to age and gender. A stepwise multiple regression analysis was used to identify MF factors with an effect on CRT and TUG in participants >=20 years of age. RESULTS: Our results showed that all MF parameters were decreased in individuals >=20 years of age compared to those <20 years old. Moreover, all of the MP parameters increasingly deteriorated with increasing age. CRT and TUG were affected by Pmax and IKET in men and by IKET in women according to logistic regression analysis. CONCLUSION: The study findings suggest that muscle power affects MP more than the muscle strength in persons aged >=20 years. PMID- 25933722 TI - Screening for impaired renal function in outpatients before iodinated contrast injection: Comparing the Choyke questionnaire with a rapid point-of-care-test. AB - RATIONALE AND PURPOSE: To determine the usefulness of the Choyke questionnaire with a creatinine point-of-care test (POCT) to detect impaired renal function amongst outpatients receiving intravenous iodinated contrast in a tertiary centre. MATERIALS AND METHODS: Between July and December 2012, 1361 outpatients had their serum creatinine determined by POCT and answered the Chokye questionnaire just before their examination. RESULTS: Four hundred and eighty (35.2%) patients had at least one 'Yes' response. Forty-four patients (3.2%) had estimated glomerular filtration rate (eGFR) <60 mL/min/1.73 m(2) and 14 patients (1.0%) have eGFR <45 mL/min/1.73 m(2). Sensitivity, specificity, positive predictive value and negative predictive value of the Choyke criteria in detecting patients with eGFR <60 mL/min/1.73 m(2) are respectively: 65.9%, 65.8%, 6.0% and 98.3% and to detect eGFR <45 mL/min/1.73 m(2): 92.9%, 65.3%, 2.7% and 99.9%. Only 'Yes' responses to 'Have you ever been told you have renal problems?' and 'Do you have diabetes mellitus?' were statistically significant in predicting eGFR <45 mL/min/1.73 m(2), with odds ratio 98.7 and 4.4 respectively. CONCLUSION: The Choyke questionnaire has excellent sensitivity and moderate-to-good specificity in detecting patients with <45 mL/min/1.73 m(2), below this level it has been shown that risk of contrast induced nephropathy increases significantly, making it an effective screening tool. Also the use of POCT can potentially reduce waiting time. PMID- 25933723 TI - Application of clinical bioinformatics in lung cancer-specific biomarkers. AB - The fact that lung cancer is a heterogeneous disease suggests that there is a high likelihood that effective lung cancer biomarkers will need to address patient-specific molecular defects, clinical characters, and aspects of the tumor microenvironment. In this transition, clinical bioinformatics tools and resources are the most appropriate means to improve the analysis, as major biological databases are now containing clinical data alongside genomics, proteomics, and other biological data. Clinical bioinformatics comprises a series of concepts and approaches that have been used successfully both to delineate novel biological mechanisms and to drive translational advances in individualized healthcare. In this article, we outline several of emerging clinical bioinformatics-based strategies as they apply specifically to lung cancer. PMID- 25933724 TI - The Mortality Risk of Conventional Antipsychotics in Elderly Patients: A Systematic Review and Meta-analysis of Randomized Placebo-Controlled Trials. AB - BACKGROUND: Numerous observational studies have reported an increased risk of mortality for conventional antipsychotics in elderly patients, and for haloperidol in particular. Subsequently, health authorities have warned against use of conventional antipsychotics in dementia. Experimental evidence is lacking. OBJECTIVE: To assess the mortality risk of conventional antipsychotics in elderly patients with a meta-analysis of trials. METHODS: Original studies were identified in electronic databases, online trial registers, and hand-searched references of published reviews. Two investigators found 28 potentially eligible studies, and they selected 17 randomized placebo-controlled trials in elderly patients with dementia, delirium, or a high risk of delirium. Two investigators independently abstracted trial characteristics and deaths, and 3 investigators assessed the risk of bias. Deaths were pooled with RevMan to obtain risk differences and risk ratios. RESULTS: Data of 17 trials with a total of 2387 participants were available. Thirty-two deaths occurred. The pooled risk difference of 0.1% was not statistically significant (95% confidence interval (CI) -1.0%-1.2%). The risk ratio was 1.07 (95% CI 0.54-2.13). Eleven of 17 trials tested haloperidol (n = 1799). The risk difference was 0.4% (95% CI -0.9%-1.6%), the risk ratio was 1.25 (95% CI 0.59-2.65). CONCLUSIONS: This meta-analysis of placebo-controlled randomized trials does not show that conventional antipsychotics in general or haloperidol in particular increase the risk of mortality in elderly patients. It questions the observational findings and the warning based on these findings. PMID- 25933725 TI - White matter lesions (leukoaraiosis): a major cause of falls. PMID- 25933726 TI - Unplanned Transfer to Emergency Departments for Frail Elderly Residents of Aged Care Facilities: A Review of Patient and Organizational Factors. AB - BACKGROUND: With an aging population, a growing number of older adults experience physical or cognitive decline that necessitates admission to residential aged care facilities (RACF). Each year a considerable proportion of these residents has at least 1 emergency transfer to hospital, which may result in a number of adverse outcomes. Rates of transfer from RACF to hospital can vary considerably between different RACFs suggesting the presence of potentially modifiable risk factors for emergency department (ED) transfer. METHODS: A systematic and comprehensive search of the peer-reviewed literature using 4 electronic databases was conducted. Included papers were those reporting on determinants of unplanned transfer to hospital for elderly people (aged 65 years and above) living in RACFs. Studies were assessed for quality and key concepts and themes extracted. RESULTS: There are both individual patient factors and health system factors, which influence rates of transfer to hospital for elderly RACF residents. For individuals, increased risk of ED transfer has been associated with presence of particular comorbidities such as chronic airways disease, congestive cardiac failure, and diabetes; presence of indwelling devices; absence of an advance care plan; and reduced functional ability. For organizations, "for profit" facilities and those with poorer staff to patient ratios also have higher rates of transfer to hospital, compared with those owned by not-for-profit organizations and those with improved registered nurse and medical practitioner staffing. CONCLUSIONS: This review has identified a number of potentially modifiable patient and organizational factors that should reduce the need for burdensome transfer to the ED and improve the quality of both acute care and end-of-life care for this population of frail, elderly individuals. A number of these determinants, including facility staffing, the role of specialist geriatricians, and advance directives, should be further examined, ideally through interventional trials to evaluate their impact on the pre-hospital and emergency management of these patients. PMID- 25933727 TI - Dysphagia in Dementia: Influence of Dementia Severity and Food Texture on the Prevalence of Aspiration and Latency to Swallow in Hospitalized Geriatric Patients. AB - OBJECTIVES: To evaluate influences of disease severity and food texture on prevalence and type of dysphagia in hospitalized geriatric patients. DESIGN: We screened for dysphagia in 161 geriatric inpatients with different forms of dementia and 30 control patients. MEASUREMENTS: Signs of aspiration were registered with 3 different food consistencies (water, apple puree, and slice of an apple) and the latency until the first swallow was documented. SETTING: Geriatric department of an academic teaching hospital in Hamburg, Germany. RESULTS: Compared with the controls, patients with dementia more often showed signs of aspiration. In the patients with dementia, signs of aspiration occurred more frequently with water (35.6%) than with a slice of an apple (15.1%) or apple puree (6.3%). We observed an inverse relationship between Mini-Mental State Examination score level and the suspected rate of aspiration, as well as with the length of latency until the first swallow of puree. CONCLUSIONS: The prevalence of dysphagia is high in patients with dementia, especially in patients with moderate to severe cognitive impairment. The relationships observed in this study encourage screening for dysphagia and adapting meal consistencies to prevent aspiration in patients with dementia. PMID- 25933728 TI - Blood transfusion and overall quality of life after hip fracture in frail elderly patients--the transfusion requirements in frail elderly randomized controlled trial. AB - BACKGROUND: We examined possible associations between different red blood cell (RBC) transfusion strategies, overall quality of life (OQoL), and recovery of activities of daily living (ADL) in operated frail elderly hip fracture patients, and the possibility that OQoL was related to ADL recovery. METHODS: A prospective, assessor-blinded, randomized controlled trial was carried out among 157 elderly residents (>=65 years) from nursing homes and sheltered housing facilities with Mini-Mental State Examination scores >=5 points. Patients were assigned to either a restrictive RBC transfusion strategy [hemoglobin (Hb) < 9.7 g/dL, 6 mmol/L] or a liberal strategy (Hb < 11.3 g/dL, 7 mmol/L) during the first 30 days after surgery. An interview-based questionnaire, the depression list (DL) assessing OQoL, and the modified Barthel Index (MBI) assessing ADL performance, were conducted on day 30 and 1 year after hip fracture surgery. Sum-scores of DL, MBI, and their changes from day 30 until 1 year (expressing recovery) were compared between RBC transfusion groups. Possible associations between changes of DL and MBI sum-scores were tested for across total patient population. RESULTS: There was no association between OQoL and RBC transfusion strategies on day 30 or at 1 year. The DL sum-score changes were similar for both groups, (ie, 1.06 points) [95% confidence interval (CI) -0.62, 2.76)] P = .21. The MBI sum-scores increased at 1 year following the liberal transfusion strategy (ie, by 6.86 points) (95% CI 0.41, 13.3) P = .03. Recoveries of OQoL and ADL were associated: beta = -0.06 (95% CI -0.11, -0.01) P = .02. CONCLUSIONS: According to our Hb threshold criteria, OQoL and RBC transfusion strategies for frail elderly hip fracture patients are not associated. However, for survivors with less severe dementia, ADL recovery after 1 year is greater following a liberal transfusion strategy than a restrictive strategy. OQoL progress and ADL recovery were associated. PMID- 25933729 TI - Factors influencing time between surgery and radiotherapy: A population based study of breast cancer patients. AB - This study describes variation in the time interval between surgery and radiotherapy in breast cancer (BC) patients and assesses factors at patient, hospital and radiotherapy centre (RTC) level influencing this variation. To do so, the factors were investigated in BC patients using multilevel logistic regression. The study sample consisted of 15,961 patients from the Netherlands Cancer Registry at 79 hospitals and 19 (RTCs) with breast-conserving surgery or mastectomy directly followed by radiotherapy. The percentage of patients starting radiotherapy <=42 days varied from 14% to 94%. Early year of incidence, higher age, higher stage, mastectomy, higher ASA category and no availability of radiotherapy facilities were significantly associated with a longer time interval between radiotherapy and surgery. More patients received radiotherapy <=42 days in hospitals with on-site radiotherapy facilities (OR 1.36, p = 0.024). Among the remainder, significant variation was found at the RTC level (11.1%, sigma(2) = 0.254, SE 0.054), and at the hospital level (6.4% sigma2 = 0.443, SE 0.163) (ICC 0.064). The significant delay and unexplained variance remaining at the RCT and hospital level suggests delays caused by the patient referral pathway from hospital to RCT, and indicates potential for improvement at both levels. PMID- 25933730 TI - Dual Antiplatelet Therapy After Coronary Artery Bypass Grafting in the Setting of Acute Coronary Syndrome. AB - After acute coronary syndrome (ACS), dual antiplatelet therapy (DAPT) is the standard of care for both invasive management with percutaneous intervention and noninvasive (medical) management. Conversely, studies using dual antiplatelet in the population of patients presenting with ACS who undergo coronary artery bypass grafting (CABG) are conflicting. The appropriate antiplatelet regimen after CABG remains an area of controversy. Plaque stability, prevention of graft closure, and secondary thrombosis form the basis for using a second antiplatelet drug, whereas the additional risk of bleeding and lack of conclusive evidence should also be considered. After an extensive literature search, 12 clinical trials with efficacy outcomes were identified. Most of the studies are retrospective, nonrandomized single-center trials. A few large patient populations have been examined using database information. To date, there is only 1 prospective, multicenter, randomized trial published. Recommendations from national guidelines differ, proposing single antiplatelet therapy with aspirin or DAPT with the combination of aspirin and clopidogrel. The purpose of this report is to review the available clinical trial data and provide guidance to practitioners when caring for this patient population. In conclusion, there is no clear consensus regarding the use of DAPT in patients after CABG. If not contraindicated, it is reasonable to use DAPT, starting in the postoperative period, in patients presenting with ACS. Large, multicenter, randomized clinical trials are needed to definitively investigate the role of DAPT in patients with ACS after CABG. PMID- 25933731 TI - Effect of Surgical Atrial Fibrillation Ablation at the Time of Cardiac Surgery on Risk of Postoperative Pacemaker Implantation. AB - The aim of this study was to retrospectively investigate whether performing surgical atrial fibrillation (AF) ablation in conjunction with cardiac surgery (CS) increases the risk for postoperative permanent pacemaker (PPM) requirement. The 30-day risk for PPM requirement was analyzed in consecutive patients who underwent CS from January 2007 to August 27, 2013. Patients were divided into 3 groups: (1) those who underwent AF ablation concomitant with CS (AF ABL), (2) patients with any history of AF who underwent surgery who did not undergo ablation (AF NO ABL), and (3) those with no histories of AF who underwent surgery (NO AF). Logistic regression analysis was performed adjusting for age, gender, and surgery type. Of 13,453 CS patients, 353 (3%) were in the AF ABL group, 1,701 (12%) in the AF NO ABL group, and 11,399 (85%) in the NO AF group. A total of 7,651 patients (57%) underwent coronary artery bypass grafting, 4,384 (33%) underwent valve surgery, and 1,418 (10%) underwent coronary artery bypass grafting and valve surgery. The overall PPM risk was 1.6% (212 of 13,453); risk was 5.7% (20 of 353) in the AF ABL group, 3.1% (53 of 1,701) in the AF NO ABL group, and 1.2% (139 of 11,399) in the NO AF group. The unadjusted and adjusted odds of PPM were higher in the AF ABL and AF NO ABL groups than in the NO AF group (adjusted odds ratio [OR] 2.7, 95% confidence interval [CI] 1.7 to 4.4, and adjusted OR 1.7, 95% CI 1.2 to 2.4, respectively). The unadjusted OR comparing the AF ABL group and the AF NO ABL group was significant (unadjusted OR 1.9, 95% CI 1.9 to 3.2); however, the OR adjusted for surgery type, age, and gender showed a trend toward significance (adjusted OR 1.6, 95% CI 0.9 to 2.7). In conclusion, in this large cohort of patients who underwent CS, surgical AF ablation appeared to carry an increased risk for postoperative PPM implantation. PMID- 25933732 TI - Effect of Smaller Left Ventricular Capture Threshold Safety Margins to Improve Device Longevity in Recipients of Cardiac Resynchronization-Defibrillation Therapy. AB - Device longevity in cardiac resynchronization therapy (CRT) is affected by the pacing capture threshold (PCT) and programmed pacing amplitude of the left ventricular (LV) pacing lead. The aims of this study were to evaluate the stability of LV pacing thresholds in a nationwide sample of CRT defibrillator recipients and to determine potential longevity improvements associated with a decrease in the LV safety margin while maintaining effective delivery of CRT. CRT defibrillator patients in the Medtronic CareLink database were eligible for inclusion. LV PCT stability was evaluated using >=2 measurements over a 14-day period. Separately, a random sample of 7,250 patients with programmed right atrial and right ventricular amplitudes <=2.5 V, LV thresholds <= 2.5 V, and LV pacing >=90% were evaluated to estimate theoretical battery longevity improvement using LV safety margins of 0.5 and 1.5 V. Threshold stability analysis in 43,256 patients demonstrated LV PCT stability of <0.5 V in 77% of patients and <1 V in 95%. Device longevity analysis showed that the use of a 0.5-V safety margin increased average battery longevity by 0.62 years (95% confidence interval 0.61 to 0.63) compared with a safety margin of 1.5 V. Patients with LV PCTs >1 V had the greatest increases in battery life (mean increase 0.86 years, 95% confidence interval 0.85 to 0.87). In conclusion, nearly all CRT defibrillator patients had LV PCT stability <1.0 V. Decreasing the LV safety margin from 1.5 to 0.5 V provided consistent delivery of CRT for most patients and significantly improved battery longevity. PMID- 25933733 TI - Gastroparesis as a Complication of Atrial Fibrillation Ablation. AB - Percutaneous catheter ablation is a safe and effective treatment for symptomatic drug-resistant atrial fibrillation (AF). Gastroparesis is a little known complication of AF ablation. We aimed to evaluate the frequency of gastroparesis in the patients who underwent catheter ablation for AF by cryoballoon (CB) or radiofrequency (RF) and to define risk factors for gastroparesis. In all, 104 patients were treated with pulmonary vein (PV) isolation with 2 different technologies: CB in 58 patients (group 1) and open-irrigated tip RF catheter in 46 patients (group 2). Gastroparesis was seen in 7 cases (6 cases in group 1 and 1 case in group 2, respectively). The complaints related with gastroparesis began during the procedure in 4 of 6 patients of group 1. The other 3 patients admitted to our outpatient clinic with similar complaints within 72 to 96 hours after the procedure. For gastroparesis cases of group 1, mean minimal CB temperature on inferior PVs was lower and left atrium diameter was smaller. Management was conservative, and the patients have no residual symptoms at 6-month follow-up. The only patient still demonstrating residual symptoms during follow-up was in group 2. Although, clinically manifest gastroparesis is quite common with CB ablation, the process is generally reversible. However, damage may not be as reversible with RF ablation. In conclusion, during cryoablation, lower temperatures on inferior PVs and small left atrium size may be associated with increased risk of gastroparesis, and fluoroscopic guidance may be useful to avoid this complication. PMID- 25933734 TI - A 35-Year Perspective (1975 to 2009) into the Long-Term Prognosis and Hospital Management of Patients Discharged from the Hospital After a First Acute Myocardial Infarction. AB - There are limited population-based data available describing trends in the long term prognosis of patients discharged from the hospital after an initial acute myocardial infarction (AMI). Our objectives were to describe multidecade trends in post-discharge mortality and their association with hospital management practices in patients discharged from all medical centers in Central Massachusetts after a first AMI. Residents of the Worcester, Massachusetts, metropolitan area discharged from all hospitals in Central Massachusetts after a first AMI from 1975 to 2009 comprised the study population (n = 8,728). Multivariable-adjusted logistic regression analyses were used to examine the association between year of hospitalization and 1-year post-discharge mortality. The average age of this population was 66 years, and 40% were women. Patients hospitalized in 1999 to 2009, compared with those discharged in 1975 to 1984, were older, more likely to be women, and have multiple previously diagnosed co morbidities. Hospital use of invasive cardiac interventions and medications increased markedly over time. Unadjusted 1-year mortality rates were 12.9%, 12.5%, and 15.8% for patients discharged during 1975 to 1984, 1986 to 1997, and 1999 to 2009, respectively. After adjusting for several demographic characteristics, clinical factors, and inhospital complications, there were no significant differences in the odds of dying at 1-year post-discharge during the years under study. After further adjustment for hospital treatment practices, the odds of dying at 1 year post-discharge was 2.43 (95% confidence interval = 1.83 to 3.23) times higher in patients hospitalized in 1999 to 2009 than in 1975 to 1984. In conclusion, the increased use of invasive cardiac interventions and pharmacotherapies was associated with enhanced long-term survival in patients hospitalized for a first AMI. PMID- 25933735 TI - Meta-Analysis on Risk Stratification of Asymptomatic Individuals With the Brugada Phenotype. AB - The prognosis of asymptomatic subjects remains the most controversial issue in Brugada syndrome (BS). A meta-analysis on the prognostic role of spontaneous type 1 electrocardiographic (ECG) pattern and programmed ventricular stimulation (PVS) in asymptomatic subjects with Brugada electrocardiogram was performed. Current databases were searched until March 2014. Fourteen prospective observational studies were included in the present meta-analysis, accumulating data on 3,536 asymptomatic subjects (2,820 men) with BS phenotype. The mean follow-up period varied from 20 and 77 months. Data regarding 1,398 asymptomatic subjects with spontaneous type 1 ECG pattern of BS were retrieved from 6 studies. During follow up, arrhythmic events (sustained ventricular tachycardia/fibrillation, appropriate device therapies, or arrhythmic death) occurred in 42 patients (3%). The meta-analysis of these studies demonstrated that asymptomatic subjects with spontaneous type 1 ECG pattern of BS exhibit an increased risk of future arrhythmic events (odds ratio = 3.56, 95% confidence interval 1.70 to 7.47, Z = 3.37, p = 0.0008); 1,104 asymptomatic subjects with BS ECG pattern from 12 studies underwent PVS and were available for analysis. During follow-up, arrhythmic events occurred in 36 subjects (3.3%). Inducible ventricular arrhythmias at PVS were predictive of future arrhythmic events (odds ratio = 3.51, 95% confidence interval 1.60 to 7.67, Z = 3.14, p = 0.002). In conclusion, this meta-analysis showed that asymptomatic subjects with either spontaneous diagnostic ECG pattern or inducible ventricular arrhythmias at PVS are at increased risk. PMID- 25933736 TI - Comparative Effectiveness of Cardiac Resynchronization Therapy Defibrillators Versus Standard Implantable Defibrillators in Medicare Patients. AB - Previous analyses have shown that there is lower mortality with cardiac resynchronization therapy defibrillators (CRT-D) in patients with left bundle branch block (LBBB) but demonstrated mixed results in patients without LBBB. We evaluated the comparative effectiveness of CRT-D versus standard implantable defibrillators (ICDs) separately in patients with LBBB and right bundle branch block (RBBB) using Medicare claims data. Medicare records from CRT-D and ICD recipients from 2002 to 2009 that were followed up for up to 48 months were analyzed. We used propensity scores to match patients with ICD to those with CRT D. In LBBB, 1:1 matching with replacement resulted in 54,218 patients with CRT-D and 20,763 with ICD, and in RBBB, 1:1 matching resulted in 7,298 patients with CRT-D and 7,298 with ICD. In LBBB, CRT-D had a 12% lower risk of heart failure hospitalization or death (hazard ratio [HR] 0.88, 95% confidence interval 0.86 to 0.90) and 5% lower death risk (HR 0.95, 0.92 to 0.97) compared with ICD. In RBBB, CRT-D had a 15% higher risk of heart failure hospitalization or death (HR 1.15, 1.10 to 1.20) and 13% higher death risk (HR 1.13, 1.07 to 1.18). Sensitivity analysis revealed that accounting for covariates not captured in the Medicare database may lead to increased benefit with CRT-D in LBBB and no difference in RBBB. In conclusion, in a large Medicare population, CRT-D was associated with lower mortality in LBBB but higher mortality in RBBB. The absence of certain covariates, in particular those that determine treatment selection, may affect the results of comparative effectiveness studies using claims data. PMID- 25933737 TI - Diagnostic and Therapeutic Usefulness of Coronary Computed Tomography Angiography in Out-Clinic Patients Referred for Chest Pain. AB - Coronary computed tomography angiography (CCTA) is widely used to exclude coronary artery disease (CAD) in patients with low-to-intermediate pretest probability (PTP) of obstructive CAD. The aim of our study was to investigate the reclassification by CCTA and the implications of CCTA results on management because limited studies exist on these subjects; 1,560 patients with chest pain without a history of CAD and with low or intermediate PTP of CAD referred for CCTA from the out-patient clinic were prospectively included. PTP was defined by the Duke Clinical Score as either low (<15%), low-intermediate (15% to 50%), or high-intermediate (50% to 85%). Distribution of CCTA results among the categories of PTP of CAD and the influence of CCTA results on management were analyzed. CCTA revealed obstructive CAD in 7%, 15%, and 23% of cases, in patients with low, low intermediate, and high-intermediate PTP, respectively; 855 of 1,031 patients (83%) with intermediate PTP of CAD showed no obstructive CAD on CCTA and were consequently reclassified. Management changes after CCTA occurred in 689 patients (44%). In 633 patients (41%), medication was altered and 135 (9%) were referred for invasive coronary angiography. Treatment with statin was initiated in 442 (28%) and stopped in 71 patients (5%). Aspirin was initiated in 192 (12%) and stopped in 139 patients (9%). In conclusion, in a routine clinical cohort, CCTA resulted in reclassification in most patients. Furthermore, our study suggests that the Duke Clinical Score overestimates the probability of obstructive CAD compared with CCTA findings. Finally, CCTA results have implications on patient management, with medication changes in 41% of patients. PMID- 25933738 TI - Suboptimal choice of methodology for meta-analysis and publication bias assessment. PMID- 25933741 TI - The evolution of evaluation and management of urinary or fecal incontinence and pelvic organ prolapse. PMID- 25933742 TI - Enhancement patterns and pseudo-washout of hepatic haemangiomas on gadoxetate disodium-enhanced liver MRI. AB - OBJECTIVES: To compare the enhancement patterns and prevalence of pseudo-washout between rapidly and slowly enhancing hepatic haemangiomas on gadoxetate disodium enhanced MRI in patients with chronic liver disease (CLD) and healthy liver (HL). METHODS: On gadoxetate disodium-enhanced MRI, the extent of intralesional arterial enhancement >50 % and <= 50 % of lesions was defined as rapid and slow enhancement, respectively. The enhancement patterns and presence of pseudo washout during the portal venous phase (PVP) and transitional phase (TP) of 74 hepatic haemangiomas were retrospectively evaluated in the CLD and HL groups. Sequential changes of signal-to-noise ratio (SNR) were measured in unenhanced phase, PVP and TP. RESULTS: Irrespective of hepatic health status, pseudo-washout in TP was significantly more common in the rapidly enhancing haemangiomas (p <= 0.026). In both groups, rapidly enhancing haemangiomas showed complete or progressive incomplete enhancement in PVP, which either lasted or transformed to pseudo-washout in TP, whereas slowly enhancing haemangiomas showed progressive incomplete enhancement in PVP and TP. SNR of hepatic parenchyma continued to rise until TP, whereas that of portal vein and haemangioma falls in TP. CONCLUSIONS: Regardless of CLD, pseudo-washout in TP was more common in rapidly than in slowly enhancing haemangiomas, with enhancement patterns differing in the two subgroups. KEY POINTS: On gadoxetate disodium-enhanced MRI, some hepatic haemangiomas show pseudo-washout in transitional phase. Regardless of chronic liver disease, pseudo washout is significantly more common in rapidly enhancing haemangiomas. Rapidly enhancing haemangiomas show complete or progressive incomplete enhancement or pseudo-washout in TP. Slowly enhancing haemangiomas show progressive incomplete enhancement in portal venous phase and TP. PMID- 25933744 TI - Communication: Microsecond dynamics of the protein and water affect electron transfer in a bacterial bc(1) complex. AB - Cross-membrane electron transport between cofactors localized in proteins of mitochondrial respiration and bacterial photosynthesis is the source of all biological energy. The statistics and dynamics of nuclear fluctuations in these protein/membrane/water heterogeneous systems are critical for their energetic efficiency. The results of 13 MUs of atomistic molecular dynamics simulations of the membrane-bound bc1 bacterial complex are analyzed here. The reaction is affected by a broad spectrum of nuclear modes, with the slowest dynamics in the range of time-scales ~0.1-1.6 MUs contributing half of the reaction reorganization energy. Two reorganization energies are required to describe protein electron transfer due to dynamical arrest of protein conformations on the observation window. This mechanistic distinction allows significant lowering of activation barriers for reactions in proteins. PMID- 25933743 TI - Assessment of the residual tumour of colorectal liver metastases after chemotherapy: diffusion-weighted MR magnetic resonance imaging in the peripheral and entire tumour. AB - OBJECTIVES: To evaluate the value of diffusion-weighted imaging (DWI) in detecting residual tumours (RTs) in colorectal liver metastases (CLMs) following chemotherapy, with a focus on tumour periphery. METHODS: From January 2009 January 2012, 57 patients who underwent liver resection for CLMs with preoperative MRI (<3 months) including DWI were retrospectively included. CLMs were classified into three response groups on pathology: (1) major histological (MHR, RTs <= 10 %), (2) partial histological (PHR, RT = 10-49 %), and (3) no histological (NHR, RT >= 50 %). On DWI, regions of interest (ROIs) were drawn around the entire tumour and tumour periphery. Apparent diffusion (ADC) and pure diffusion (D) coefficients were calculated using a monoexponential fit, and compared using Kruskal-Wallis test on a lesion-per-lesion analysis. RESULTS: 111 CLMs were included. Fourteen (12.5 %), 42 (38 %) and 55 (49.5 %) CLMs presented a MHR, PHR and NHR, respectively. ADC and D of the peripheral ROIs were significantly higher in the MHR group (P = 0.013/P = 0.013). ADC and D from the entire tumour were not significantly different among the groups (P = 0.220/P = 0.103). CONCLUSION: In CLM treated with chemotherapy, ADC and D values from the entire tumour are not related to the degree of RT, while peripheral zone diffusion parameters could help identify metastases with MHR. KEY POINTS: Peripheral ADC and D of CLMs were higher with major pathological responses. Global ADC and D of CLMs were not different according to residual tumour. Diffusion-weighted images of CLM periphery could be an interesting biomarker of MHR. Diffusion-weighted images could be used to help tailor treatment. PMID- 25933745 TI - Communication: Local structure-mobility relationships of confined fluids reverse upon supercooling. AB - We examine the structural and dynamic properties of confined binary hard-sphere mixtures designed to mimic realizable colloidal thin films. Using computer simulations, governed by either Newtonian or overdamped Langevin dynamics, together with other techniques including a Fokker-Planck equation-based method, we measure the position-dependent and average diffusivities of particles along structurally isotropic and inhomogeneous dimensions of the fluids. At moderate packing fractions, local single-particle diffusivities normal to the direction of confinement are higher in regions of high total packing fraction; however, these trends are reversed as the film is supercooled at denser average packings. Auxiliary short-time measurements of particle displacements mirror data obtained for experimental supercooled colloidal systems. We find that average dynamics can be approximately predicted based on the distribution of available space for particle insertion across orders of magnitude in diffusivity regardless of the governing microscopic dynamics. PMID- 25933746 TI - Dissipative time-dependent quantum transport theory: Quantum interference and phonon induced decoherence dynamics. AB - A time-dependent inelastic electron transport theory for strong electron-phonon interaction is established via the equations of motion method combined with the small polaron transformation. In this work, the dissipation via electron-phonon coupling is taken into account in the strong coupling regime, which validates the small polaron transformation. The corresponding equations of motion are developed, which are used to study the quantum interference effect and phonon induced decoherence dynamics in molecular junctions. Numerical studies show clearly quantum interference effect of the transport electrons through two quasi degenerate states with different couplings to the leads. We also found that the quantum interference can be suppressed by the electron-phonon interaction where the phase coherence is destroyed by phonon scattering. This indicates the importance of electron-phonon interaction in systems with prominent quantum interference effect. PMID- 25933747 TI - Polarisabilities of long conjugated chain molecules with density functional response methods: The role of coupled and uncoupled response. AB - The longitudinal component of the dipole-dipole polarisability of polyacetylene molecules containing 4 to 20 carbon atoms has been calculated with density functional theory (DFT) response methods. In order to analyse the effect of the uncoupled and coupled contributions to the response matrix, a number of different sets of orbitals were combined with different approximations for the Hessian matrix. This revealed a surprising result: a qualitatively correct increase of the polarisability with the chain length can already be reproduced on the uncoupled level if the response matrix is constructed from Hartree-Fock (HF) or exact-exchange (EXX) DFT orbitals. The nonlocal HF and the local EXX exchange potentials both produce a displacement of charge from the chain ends to the centre of the polyacetylene molecule compared to DFT methods using standard exchange-correlation potentials. In this way, the reduced increase of the transition dipole moments along the molecular axis counteracts the decrease of the occupied-virtual orbital energy gaps and leads to a linear dependence of the polarisabilities (normalised by the number of carbon atoms) on the chain length. A new DFT response approach is tested which utilises unitary transformed Hartree Fock orbitals as input and which resolves the failure of standard DFT response methods. PMID- 25933748 TI - Coherent quantum transport in disordered systems: A unified polaron treatment of hopping and band-like transport. AB - Quantum transport in disordered systems is studied using a polaron-based master equation. The polaron approach is capable of bridging the results from the coherent band-like transport regime governed by the Redfield equation to incoherent hopping transport in the classical regime. A non-monotonic dependence of the diffusion coefficient is observed both as a function of temperature and system-phonon coupling strength. In the band-like transport regime, the diffusion coefficient is shown to be linearly proportional to the system-phonon coupling strength and vanishes at zero coupling due to Anderson localization. In the opposite classical hopping regime, we correctly recover the dynamics described by the Fermi's Golden Rule and establish that the scaling of the diffusion coefficient depends on the phonon bath relaxation time. In both the hopping and band-like transport regimes, it is demonstrated that at low temperature, the zero point fluctuations of the bath lead to non-zero transport rates and hence a finite diffusion constant. Application to rubrene and other organic semiconductor materials shows a good agreement with experimental mobility data. PMID- 25933749 TI - On the equivalence of LIST and DIIS methods for convergence acceleration. AB - Self-consistent field extrapolation methods play a pivotal role in quantum chemistry and electronic structure theory. We, here, demonstrate the mathematical equivalence between the recently proposed family of LIST methods [Wang et al., J. Chem. Phys. 134, 241103 (2011); Y. K. Chen and Y. A. Wang, J. Chem. Theory Comput. 7, 3045 (2011)] and the general form of Pulay's DIIS [Chem. Phys. Lett. 73, 393 (1980); J. Comput. Chem. 3, 556 (1982)] with specific error vectors. Our results also explain the differences in performance among the various LIST methods. PMID- 25933750 TI - Discontinuous non-equilibrium phase transition in a threshold Schloegl model for autocatalysis: Generic two-phase coexistence and metastability. AB - Threshold versions of Schloegl's model on a lattice, which involve autocatalytic creation and spontaneous annihilation of particles, can provide a simple prototype for discontinuous non-equilibrium phase transitions. These models are equivalent to so-called threshold contact processes. A discontinuous transition between populated and vacuum states can occur selecting a threshold of N >= 2 for the minimum number, N, of neighboring particles enabling autocatalytic creation at an empty site. Fundamental open questions remain given the lack of a thermodynamic framework for analysis. For a square lattice with N = 2, we show that phase coexistence occurs not at a unique value but for a finite range of particle annihilation rate (the natural control parameter). This generic two phase coexistence also persists when perturbing the model to allow spontaneous particle creation. Such behavior contrasts both the Gibbs phase rule for thermodynamic systems and also previous analysis for this model. We find metastability near the transition corresponding to a non-zero effective line tension, also contrasting previously suggested critical behavior. Mean-field type analysis, extended to treat spatially heterogeneous states, further elucidates model behavior. PMID- 25933751 TI - Theory of femtosecond coherent double-pump single-molecule spectroscopy: Application to light harvesting complexes. AB - We develop a first principles theoretical description of femtosecond double-pump single-molecule signals of molecular aggregates. We incorporate all singly excited electronic states and vibrational modes with significant exciton-phonon coupling into a system Hamiltonian and treat the ensuing system dynamics within the Davydov D1 Ansatz. The remaining intra- and inter-molecular vibrational modes are treated as a heat bath and their effect is accounted for through lineshape functions. We apply our theory to simulate single-molecule signals of the light harvesting complex II. The calculated signals exhibit pronounced oscillations of mixed electron-vibrational (vibronic) origin. Their periods decrease with decreasing exciton-phonon coupling. PMID- 25933752 TI - Excitonic couplings between molecular crystal pairs by a multistate approximation. AB - In this paper, we present a diabatization scheme to compute the excitonic couplings between an arbitrary number of states in molecular pairs. The method is based on an algebraic procedure to find the diabatic states with a desired property as close as possible to that of some reference states. In common with other diabatization schemes, this method captures the physics of the important short-range contributions (exchange, overlap, and charge-transfer mediated terms) but it becomes particularly suitable in presence of more than two states of interest. The method is formulated to be usable with any level of electronic structure calculations and to diabatize different types of states by selecting different molecular properties. These features make the diabatization scheme presented here especially appropriate in the context of organic crystals, where several excitons localized on the same molecular pair may be found close in energy. In this paper, the method is validated on the tetracene crystal dimer, a well characterized case where the charge transfer (CT) states are closer in energy to the Frenkel excitons (FE). The test system was studied as a function of an external electric field (to explore the effect of changing the relative energy of the CT excited state) and as a function of different intermolecular distances (to probe the strength of the coupling between FE and CT states). Additionally, we illustrate how the approximation can be used to include the environment polarization effect. PMID- 25933753 TI - On the use of Abelian point group symmetry in density-fitted local MP2 using various types of virtual orbitals. AB - Electron correlation methods based on symmetry-adapted canonical Hartree-Fock orbitals can be speeded up significantly in the well known group theoretical manner, using the fact that integrals vanish unless the integrand is totally symmetric. In contrast to this, local electron correlation methods cannot benefit from such simplifications, since the localized molecular orbitals (LMOs) generally do not transform according to irreducible representations of the underlying point group symmetry. Instead, groups of LMOs become symmetry equivalent and this can be exploited to accelerate local calculations. We describe an implementation of such a symmetry treatment for density-fitted local Moller-Plesset perturbation theory, using various types of virtual orbitals: Projected atomic orbitals, orbital specific virtuals, and pair natural orbitals. The savings by the symmetry treatment are demonstrated by calculations for several large molecules having different point group symmetries. Benchmarks for the parallel execution efficiency of our method are also presented. PMID- 25933754 TI - Exchange repulsive potential adaptable for electronic structure changes during chemical reactions. AB - Hybrid methods combining quantum mechanical (QM) and classical calculations are becoming important tools in chemistry. The popular approach to calculate the interaction between QM and classical calculations employs interatomic potentials. In most cases, the interatomic potential is constructed of an electrostatic (ES) potential and a non-ES potential. Because QM treatment is employed in the calculation of the ES potential, the electronic change can be considered in this ES potential. However, QM treatment of the non-ES potential is difficult because of high computational cost. To overcome this difficulty of evaluating the non-ES potential, we proposed an exchange repulsive potential as the main part of the non-ES potential on the basis of a QM approach. This potential is independent of empirical parameters and adaptable for electronic structure. We combined this potential with the reference interaction site model self-consistent field explicitly including spatial electron density distribution and successfully applied it to the chemical reactions in aqueous phase. PMID- 25933755 TI - Stochastic rotation dynamics for nematic liquid crystals. AB - We introduce a new mesoscopic model for nematic liquid crystals (LCs). We extend the particle-based stochastic rotation dynamics method, which reproduces the Navier-Stokes equation, to anisotropic fluids by including a simplified Ericksen Leslie formulation of nematodynamics. We verify the applicability of this hybrid model by studying the equilibrium isotropic-nematic phase transition and nonequilibrium problems, such as the dynamics of topological defects and the rheology of sheared LCs. Our simulation results show that this hybrid model captures many essential aspects of LC physics at the mesoscopic scale, while preserving microscopic thermal fluctuations. PMID- 25933756 TI - Synchrotron-based double imaging photoelectron/photoion coincidence spectroscopy of radicals produced in a flow tube: OH and OD. AB - We present a microwave discharge flow tube coupled with a double imaging electron/ion coincidence device and vacuum ultraviolet (VUV) synchrotron radiation. The system has been applied to the study of the photoelectron spectroscopy of the well-known radicals OH and OD. The coincidence imaging scheme provides a high selectivity and yields the spectra of the pure radicals, removing the ever-present contributions from excess reactants, background, or secondary products, and therefore obviating the need for a prior knowledge of all possible byproducts. The photoelectron spectra encompassing the X(3)Sigma(-) ground state of the OH(+) and OD(+) cations have been extracted and the vibrational constants compared satisfactorily to existing literature values. Future advantages of this approach include measurement of high resolution VUV spectroscopy of radicals, their absolute photoionization cross section, and species/isomer identification in chemical reactions as a function of time. PMID- 25933757 TI - Accurate and absolute diffusion measurements of Rhodamine 6G in low-concentration aqueous solutions by the PGSE-WATERGATE sequence. AB - A pulsed field gradient spin-echo nuclear magnetic resonance (NMR) sequence with solvent suppression (PGSE-WATERGATE) was applied to accurately measure the diffusion coefficients of Rhodamine 6G (Rh6G) in low-concentration aqueous solutions. Three samples with Rh6G concentrations of CRh6G = 1, 4.5, and 25 MUM were investigated. The precise determination of the diffusion coefficients in this low-concentration range was made possible by using a cryogenically cooled NMR probe and by the effective solvent suppression of the PGSE-WATERGATE sequence. The present results bridge the gap between diffusion data measured by fluorescence correlation spectroscopy in the single molecule limit and diffusivities obtained by pulsed field gradient NMR (PFG-NMR) without solvent suppression at higher concentrations. To further extend the concentration range, the diffusion coefficient of Rh6G was also measured on a sample with CRh6G = 410 MUM by PFG-NMR. The overall concentration dependence of the Rh6G diffusion at 25 degrees C is discussed in terms of dimerization of the Rh6G molecules. The concentration-dependent monomer/dimer proportion is deduced from the diffusion data. PMID- 25933758 TI - Photoelectron imaging spectroscopy of MoC(-) and NbN(-) diatomic anions: A comparative study. AB - The isoeletronic diatomic MoC(-) and NbN(-) anions have been prepared by laser ablation and studied by photoelectron imaging spectroscopy combined with quantum chemistry calculations. The photoelectron spectra of NbN(-) can be very well assigned on the basis of literature reported optical spectroscopy of NbN. In contrast, the photoelectron spectra of MoC(-) are rather complex and the assignments suffered from the presence of many electronically hot bands and limited information from the reported optical spectroscopy of MoC. The electron affinities of NbN and MoC have been determined to be 1.450 +/- 0.003 eV and 1.360 +/- 0.003 eV, respectively. The good resolution of the imaging spectroscopy provided a chance to resolve the Omega splittings of the X(3)Sigma(-) (Omega = 0 and 1) state of MoC and the X(4)Sigma(-) (Omega = 1/2 and 3/2) state of MoC(-) for the first time. The spin-orbit splittings of the X(2)Delta state of NbN(-) and the a(2)Delta state of MoC(-) were also determined. The similarities and differences between the electronic structures of the NbN and MoC systems were discussed. PMID- 25933759 TI - Dynamical screening of van der Waals interactions in nanostructured solids: Sublimation of fullerenes. AB - Sublimation energy is one of the most important properties of molecular crystals, but it is difficult to study, because the attractive long-range van der Waals (vdW) interaction plays an important role. Here, we apply efficient semilocal density functional theory (DFT), corrected with the dynamically screened vdW interaction (DFT + vdW), the Rutgers-Chalmers nonlocal vdW-DF, and the pairwise based dispersion-corrected DFT-D2 developed by Grimme and co-workers, to study the sublimation of fullerenes. We find that the short-range part, which accounts for the interaction due to the orbital overlap between fullerenes, is negligibly small. Our calculation shows that there exists a strong screening effect on the vdW interaction arising from the valence electrons of fullerenes. On the other hand, higher-order contributions can be as important as the leading-order term. The reasons are that (i) the surface of fullerene molecules is metallic and thus highly polarizable, (ii) the band gap of fullerene solids is small (less than 2 eV), and (iii) fullerene molecules in the solid phase are so densely packed, yielding the high valence electron density and small equilibrium intermolecular distances (the first nearest neighbor distance is only about 10 A for C60). However, these two effects make opposite contributions, leading to significant error cancellation between these two contributions. We demonstrate that, by considering higher-order contributions and the dynamical screening, the DFT + vdW method can yield sublimation energies of fullerenes in good agreement with reference values, followed by vdW-DF and DFT-D2. The insights from this study are important for a better understanding of the long-range nature of vdW interactions in nanostructured solids. PMID- 25933760 TI - A seven-degree-of-freedom, time-dependent quantum dynamics study on the energy efficiency in surmounting the central energy barrier of the OH + CH3 -> O + CH4 reaction. AB - A time-dependent, quantum reaction dynamics calculation with seven degrees of freedom was carried out to study the energy efficiency in surmounting the approximate center energy barrier of OH + CH3. The calculation shows the OH vibration excitations greatly enhance the reactivity, whereas the vibrational excitations of CH3 and the rotational excitations hinder the reactivity. On the basis of equal amount of total energy, although this reaction has a slight early barrier, it is the OH vibrational energy that is the dominate force in promoting the reactivity, not the translational energy. The studies on both the forward O + CH4 and reverse OH + CH3 reactions demonstrate, for these central barrier reactions, a small change of the barrier location can significantly change the energy efficacy roles on the reactivity. The calculated rate constants agree with the experimental data. PMID- 25933761 TI - Reactive scattering calculations for (87)Rb+(87)RbHe->Rb2((3)Sigma(u)(+),v)+He from ultralow to intermediate energies. AB - We investigate atom-diatom reactive collisions, as a preliminary step,in order to assess the possibility of forming Rb(2) molecules in their lowest triplet electronic state by cold collisions of rubidium atoms on the surface of helium nanodroplets [corrected]. A simple model related to the well-known Rosen treatment of linear triatomic molecules [N. Rosen, J. Chem. Phys. 1, 319 (1933)] in relative coordinates is used, allowing to estimate reactive probabilities for different values of the total angular momentum. The best available full dimensional potential energy surface [Guillon et al., J. Chem. Phys. 136, 174307 (2012)] is employed through the calculations. Noticeable values of the probabilities in the ultracold regime, which numerically fulfill the Wigner threshold law, support the feasibility of the process. The rubidium dimer is mainly produced at high vibrational states, and the reactivity is more efficient for a bosonic helium partner than when the fermion species is considered. PMID- 25933762 TI - Observation of orbiting resonances in He((3)S(1)) + NH3 Penning ionization. AB - Resonances are among the clearest quantum mechanical signatures of scattering processes. Previously, shape resonances and Feshbach resonances have been observed in inelastic and reactive collisions involving atoms or diatomic molecules. Structure in the integral cross section has been observed in a handful of elastic collisions involving polyatomic molecules. The present paper presents the observation of shape resonances in the reactive scattering of a polyatomic molecule, NH3. A merged-beam study of the gas phase He((3)S1) + NH3 Penning ionization reaction dynamics is described in the collision energy range 3.3 MUeV < Ecoll < 10 meV. In this energy range, the reaction rate is governed by long range attraction. Peaks in the integral cross section are observed at collision energies of 1.8 meV and 7.3 meV and are assigned to l = 15,16 and l = 20,21 partial wave resonances, respectively. The experimental results are well reproduced by theoretical calculations with the short-range reaction probability Psr = 0.035. No clear signature of the orbiting resonances is visible in the branching ratio between NH3 (+) and NH2 (+) formation. PMID- 25933763 TI - Isotopic dependence of the predissociations of the E(1)Pi state of CO. AB - The predissociations of the E(1)Pi state of CO are again studied. They include both the background predissociation attributed to the continuum of the A(1)Pi state and the accidental predissociation due to the k(3)Pi state. They are calculated using a coupled equations method. The three components of the k state are introduced. These predissociations are studied for different isotopologues and are shown to decrease with increasing reduced mass, in agreement with the experimental results of Ubachs et al. [J. Chem. Phys. 113, 547 (2000)]. PMID- 25933764 TI - On the effect of pressure and carrier gas on homogeneous water nucleation. AB - Homogeneous nucleation rates of water droplets were measured at a nucleation temperature close to 240 K in a Pulse-Expansion Wave Tube (PEWT). Several measures were taken to improve the data obtained with the PEWT. For instance, the molar water vapor fraction was determined with three independent techniques. The resulting standard uncertainty of the supersaturation was within 1.8%. Results are given for water nucleation in helium at 100 kPa and at 1000 kPa and in nitrogen at 1000 kPa. Two trends were observed: (i) the values of the nucleation rate of water in helium at 1000 kPa are slightly but significantly higher (factor 3) than its values at 100 kPa and (ii) nucleation rates of water in nitrogen at 1000 kPa are clearly higher (factor 10) than in helium at the same pressure. It is argued that the explanation of the two observed trends is different. For case (i), it is the insufficient thermalization of the growing water clusters in helium at the lowest pressure that has a reducing effect on the nucleation rate, although a full quantitative agreement has not yet been reached. For case (ii), thermal effects being negligible, it is the pressure dependency of the surface tension, much stronger for nitrogen than for helium, that explains the trends observed, although also here a full quantitative agreement has not yet been achieved. PMID- 25933765 TI - From photoelectron detachment spectra of BrHBr(-), BrDBr(-) and IHI(-), IDI(-) to vibrational bonding of BrMuBr and IMuI. AB - Photoelectron detachment XLX(-)(00(0)0) + hnu -> XLX(vib) + e(-) + KER (X = Br or I, L = H or D) at sufficiently low temperatures photoionizes linear dihalogen anions XLX(-) in the vibrational ground state (v1v2 (l)v3 = 00(0)0) and prepares the neutral radicals XLX(vib) in vibrational states (vib). At the same time, part of the photon energy (hnu) is converted into kinetic energy release (KER) of the electron [R. B. Metz, S. E. Bradforth, and D. M. Neumark, Adv. Chem. Phys. 81, 1 (1992)]. The process may be described approximately in terms of a Franck-Condon type transfer of the vibrational wavefunction representing XLX(-)(00(0)0) from the domain close to the minimum of its potential energy surface (PES) to the domain close to the linear transition state of the PES of the neutral XLX. As a consequence, prominent peaks of the photoelectron detachment spectra (pds) correlate with the vibrational energies EXLX,vib of states XLX(vib) which are centered at linear transition state. The corresponding vibrational quantum numbers may be labeled vib = (v1v2 (l)v3) = (00(0)v3). Accordingly, the related most prominent peaks in the pds are labeled v3. We construct a model PES which mimics the "true" PES in the domain of transition state such that it supports vibrational states with energies EXLX,pds,00(0)v3 close to the peaks of the pds labeled v3 = 0, 2, and 4. Subsequently, the same model PES is also used to calculate approximate values of the energies EXMuX,00(0)0 of the isotopomers XMuX(00(0)0). For the heavy isotopomers XHX and XDX, it turns out that all energies EXLX,00(0)v3 are above the threshold for dissociation, which means that all heavy XLX(00(0)v3) with wavefunctions centered at the transition state are unstable resonances with finite lifetimes. Turning the table, bound states of the heavy XLX are van der Waals (vdW) bonded. In contrast, the energies EXMuX,00(0)0 of the light isotopomers XMuX(00(0)0) are below the threshold for dissociation, with wavefunctions centered at the transition state. This means that XMuX(00(0)0) are vibrationally bonded. This implies a fundamental change of the nature of chemical bonding, from vdW bonding of the heavy XHX, XDX to vibrational bonding of XMuX. For BrMuBr, the present results derived from experimental pds of BrHBr( ) and BrDBr(-) confirm the recent discovery of vibrational bonding based on quantum chemical ab initio calculations [D. G. Fleming, J. Manz, K. Sato, and T. Takayanagi, Angew. Chem., Int. Ed. 53, 13706 (2014)]. The extension from BrLBr to ILI means the discovery of a new example of vibrational bonding. These empirical results for the vibrational bonding of IMuI, derived from the photoelectron spectra of IHI(-) and IDI(-), are supported by ab initio simulations of the spectra and of the wavefunction representing vibrational bonding of IMuI. PMID- 25933766 TI - Quantum mechanical differential and integral cross sections for the C((1)D) + H2(nu = 0, j = 0) -> CH(nu', j') + H reaction. AB - Accurate quantum dynamics calculations for the C((1)D) + H2 reaction are performed using a real wave packet approach with full Coriolis coupling. The newly constructed ZMB-a ab initio potential energy surface [Zhang et al., J. Chem. Phys. 140, 234301 (2014)] is used. The integral cross sections (ICSs), differential cross sections (DCSs), and product state distributions are obtained over a wide range of collision energies. In contrast to previous accurate quantum dynamics calculations on the reproducing kernel Hilbert space potential energy surface, the present total ICS is much larger at low collision energies, yielding larger rate coefficients in better agreement with experiment and with slight inverse temperature dependence. Meanwhile, interesting nonstatistical behaviors in the DCSs are revealed. In particular, the DCSs display strong oscillations with the collision energy; forward biased product angular distribution appears when only small J partial wave contributions are included; alternate forward and backward biases emerge with very small increments of collision energy; and the rotational state-resolved DCSs show strong oscillations with the scattering angle. Nevertheless, the total DCSs can be roughly regarded as backward-forward symmetric over the whole energy range and are in reasonably good agreement with the available experimental measurements. PMID- 25933767 TI - Further insight into the tunneling contribution to the vibrational relaxation of NO in Ar. AB - Tunneling corrections to Landau-Zener rate coefficients for the vibrational relaxation NO(X(2)Pi, v = 1) + Ar -> NO(X(2)Pi, v = 0) + Ar between 300 and 2000 K are determined employing ab initio potential energy surfaces calculated by the code provided by Alexander [J. Chem. Phys. 111, 7426 (1999)]. The calculations use a reaction coordinate approach and lead to vibronically nonadiabatic transition probabilities within the generalized Airy approximation as extended to the WKB underbarrier Landau-Lifshitz limit. The calculations confirm experimental evidence for an onset of major tunneling contributions to the relaxation rate at temperatures below about 900 K and rationalize large tunneling contributions at 300 K. These effects increase the rate coefficients by several orders of magnitude over the uncorrected Landau-Zener values and remove the large gap between the latter and experimental results. PMID- 25933768 TI - Rigidity and soft percolation in the glass transition of an atomistic model of ionic liquid, 1-ethyl-3-methyl imidazolium nitrate, from molecular dynamics simulations--Existence of infinite overlapping networks in a fragile ionic liquid. AB - The typical ionic liquid, 1-ethyl-3-methyl imidazolium nitrate (EMIM-NO3), was examined by molecular dynamics simulations of an all-atomistic model to show the characteristics of networks of cages and/or bonds in the course of vitrification of this fragile glass-former. The system shows changes of dynamics at two characteristic temperatures, TB (or Tc) and the glass transition temperature Tg, found in other fragile glass forming liquids [K. L. Ngai and J. Habasaki, J. Chem. Phys. 141, 114502 (2014)]. On decreasing temperature, the number of neighboring cation-anion pairs, NB, within the first minimum of the pair correlation function, g(r)min, increases. On crossing TB (>Tg), the system volume and diffusion coefficient both show changes in temperature dependence, and as usual at Tg. The glass transition temperature, Tg, is characterized by the saturation of the total number of "bonds," NB and the corresponding decrease in degree of freedom, F = [(3N - 6) - NB], of the system consisting of N particles. Similar behavior holds for the other ion-ion pairs. Therefore, as an alternative, the dynamics of glass transition can be interpreted conceptually by rigidity percolation. Before saturation occurring at Tg, the number of bonds shows a remarkable change at around TB. This temperature is associated with the disappearance of the loosely packed coordination polyhedra of anions around cation (or vice versa), related to the loss of geometrical freedom of the polyhedra, fg, of each coordination polyhedron, which can be defined by fg = [(3NV - 6) - Nb]. Here, 3Nv is the degree of freedom of NV vertices of the polyhedron, and Nb is number of fictive bonds. The packing of polyhedra is characterized by the soft percolation of cages, which allows further changes with decreasing temperature. The power spectrum of displacement of the central ion in the cage is found to be correlated with the fluctuation of Nb of cation-cation (or anion-anion) pairs in the polyhedron, although the effect from the coordination shells beyond the neighboring ions is not negligible. PMID- 25933769 TI - High-precision gigahertz-to-terahertz spectroscopy of aqueous salt solutions as a probe of the femtosecond-to-picosecond dynamics of liquid water. AB - Because it is sensitive to fluctuations occurring over femtoseconds to picoseconds, gigahertz-to-terahertz dielectric relaxation spectroscopy can provide a valuable window into water's most rapid intermolecular motions. In response, we have built a vector network analyzer dielectric spectrometer capable of measuring absorbance and index of refraction in this frequency regime with unprecedented precision. Using this to determine the complex dielectric response of water and aqueous salt solutions from 5.9 GHz to 1.12 THz (which we provide in the supplementary material), we have obtained strong new constraints on theories of water's collective dynamics. For example, while the salt-dependencies we observe for water's two slower relaxations (8 and 1 ps) are easily reconciled with suggestions that they arise due to rotations of fully and partially hydrogen bonded molecules, respectively, the salt-dependence of the fastest relaxation (180 fs) appears difficult to reconcile with its prior assignment to liberations of single hydrogen bonds. PMID- 25933770 TI - Theory of the jamming transition at finite temperature. AB - A theory for the microscopic structure and the vibrational properties of soft sphere glass at finite temperature is presented. With an effective potential, derived here, the phase diagram and vibrational properties are worked out around the Maxwell critical point at zero temperature T and pressure p. Variational arguments and effective medium theory identically predict a non-trivial temperature scale T(*) ~ p((2-a)/(1-a)) with a ~ 0.17 such that low-energy vibrational properties are hard-sphere like for T ? T(*) and zero-temperature soft-sphere like otherwise. However, due to crossovers in the equation of state relating T, p, and the packing fraction phi, these two regimes lead to four regions where scaling behaviors differ when expressed in terms of T and phi. Scaling predictions are presented for the mean-squared displacement, characteristic frequency, shear modulus, and characteristic elastic length in all regions of the phase diagram. PMID- 25933771 TI - P-rho-T measurements of H2O up to 260 GPa under laser-driven shock loading. AB - Pressure, density, and temperature data for H2O were obtained up to 260 GPa by using laser-driven shock compression technique. The shock compression technique combined with the diamond anvil cell was used to assess the equation of state models for the P-rho-T conditions for both the principal Hugoniot and the off Hugoniot states. The contrast between the models allowed for a clear assessment of the equation of state models. Our P-rho-T data totally agree with those of the model based on quantum molecular dynamics calculations. These facts indicate that this model is adopted as the standard for modeling interior structures of Neptune, Uranus, and exoplanets in the liquid phase in the multi-Mbar range. PMID- 25933772 TI - Ab initio molecular dynamics studies of hydrogen bonded structure, molecular motion, and frequency fluctuations of water in the vicinity of azide ions. AB - First principles theoretical studies of vibrational spectral diffusion of the stretch modes of water and azide (N3(-)) ions are presented by means of ab initio molecular dynamics simulations for two different concentrations of the ions. The vibrational spectral diffusion of hydration shell water in a dilute solution containing a single azide ion is found to occur with three time scales while two time scales are found for the spectral diffusion in the solution of higher ion concentration. The frequency time correlation of the stretching vibration of azide ion is also found to have two time scales. The vibrational spectral diffusion of the stretching mode of azide ions in the concentrated solution is found to occur at a slightly faster rate while that of the water OD modes becomes slower with increase of ion concentration. The effects of dispersion interactions are also investigated by using a dispersion corrected density functional. The time constants of frequency correlations and dynamical spectral shifts are analyzed in terms of the relaxation of azide ion-water and water-water hydrogen bonds. The results of present theoretical calculations are compared with the available experimental and other theoretical results. PMID- 25933773 TI - Role of string-like collective atomic motion on diffusion and structural relaxation in glass forming Cu-Zr alloys. AB - We investigate Cu-Zr liquid alloys using molecular dynamics simulation and well accepted embedded atom method potentials over a wide range of chemical composition and temperature as model metallic glass-forming (GF) liquids. As with other types of GF materials, the dynamics of these complex liquids are characterized by "dynamic heterogeneity" in the form of transient polymeric clusters of highly mobile atoms that are composed in turn of atomic clusters exhibiting string-like cooperative motion. In accordance with the string model of relaxation, an extension of the Adam-Gibbs (AG) model, changes in the activation free energy DeltaGa with temperature of both the Cu and Zr diffusion coefficients D, and the alpha structural relaxation time taualpha can be described to a good approximation by changes in the average string length, L. In particular, we confirm that the strings are a concrete realization of the abstract "cooperatively rearranging regions" of AG. We also find coexisting clusters of relatively "immobile" atoms that exhibit predominantly icosahedral local packing rather than the low symmetry packing of "mobile" atoms. These two distinct types of dynamic heterogeneity are then associated with different fluid structural states. Glass-forming liquids are thus analogous to polycrystalline materials where the icosahedrally packed regions correspond to crystal grains, and the strings reside in the relatively disordered grain boundary-like regions exterior to these locally well-ordered regions. A dynamic equilibrium between localized ("immobile") and wandering ("mobile") particles exists in the liquid so that the dynamic heterogeneity can be considered to be type of self-assembly process. We also characterize changes in the local atomic free volume in the course of string like atomic motion to better understand the initiation and propagation of these fluid excitations. PMID- 25933774 TI - A theoretical approach to La L(1)-edge XANES spectra of La complex oxides and their local configuration. AB - The characteristic peaks (pre-edge peaks) in the La L1-edge X-ray absorption near edge structure (XANES) of various La complex oxides were analyzed by both experimental and theoretical approaches. The pre-edge peak areas are correlated with the bond angle analysis (BAA) parameter, which we proposed as an indicator of the centrosymmetry or disorder of the local configuration of the La site. The origin of the pre-edge peak and the parameterization criteria of the BAA parameter were evaluated using theoretical calculations based on molecular orbital theory and multiple scattering theory. The theoretical calculations showed that the origin of the pre-edge peak at the La L1-edge is electric dipole transition from 2s to unoccupied states generated by p-d hybridization. Medium scale theoretical simulations of the La L1-edge XANES spectra of thousands of virtual La aqueous complex models verified that the parameterization criteria of the BAA parameter are applicable to local configuration analysis of La. PMID- 25933775 TI - A multi-scale approach to characterize pure CH4, CF4, and CH4/CF4 mixtures. AB - In this study, we develop three intermolecular potentials for methane (CH4), tetrafluoromethane (CF4), and CH4/CF4 dimers using a novel ab initio method. The ultimate goal is to understand microscopically the phase-separation in CH4/CF4 systems, which takes place in the liquid states near their freezing points. Monte Carlo (MC) simulations of the pure CH4 system are performed using the ab initio energies to verify the potential. The simulations reproduce quite well the experimentally known liquid densities, the internal energies, the second virial coefficients, and the radial distribution function. The essentially six dimensional (6D) ab initio potential is then reduced to a one-dimensional (1D) effective potential using the inverse Monte-Carlo technique. This potential, too, successfully reproduces the experimental results. Interestingly, the MC study cannot be extended to the pure CF4 system and the CH4/CF4 mixed system because the two respective ab initio potentials present very rough potential landscapes. This renders the interpolation of energies for the MC simulations and thus the multi-scale approach unreliable. It suggests, however, a possible driving force for the experimentally observed phase separation of the CH4/CF4 system at low temperatures. Furthermore, we carefully study the determination of 1D effective potentials via inverse MC techniques. We argue that to a good approximation the temperature dependence of the 1D potentials can be estimated via reweighting techniques for a fixed temperature. PMID- 25933776 TI - Effects of molecular structure on microscopic heat transport in chain polymer liquids. AB - In this paper, we discuss the molecular mechanism of the heat conduction in a liquid, based on nonequilibrium molecular dynamics simulations of a systematic series of linear- and branched alkane liquids, as a continuation of our previous study on linear alkane [T. Ohara et al., J. Chem. Phys. 135, 034507 (2011)]. The thermal conductivities for these alkanes in a saturated liquid state at the same reduced temperature (0.7Tc) obtained from the simulations are compared in relation to the structural difference of the liquids. In order to connect the thermal energy transport characteristics with molecular structures, we introduce the new concept of the interatomic path of heat transfer (atomistic heat path, AHP), which is defined for each type of inter- and intramolecular interaction. It is found that the efficiency of intermolecular AHP is sensitive to the structure of the first neighbor shell, whereas that of intramolecular AHP is similar for different alkane species. The dependence of thermal conductivity on different lengths of the main and side chain can be understood from the natures of these inter- and intramolecular AHPs. PMID- 25933777 TI - Vapor-deposited non-crystalline phase vs ordinary glasses and supercooled liquids: Subtle thermodynamic and kinetic differences. AB - Vapor deposition of molecules on a substrate often results in glassy materials of high kinetic stability and low enthalpy. The extraordinary properties of such glasses are attributed to high rates of surface diffusion during sample deposition, which makes it possible for constituents to find a configuration of much lower energy on a typical laboratory time scale. However, the exact nature of the resulting phase and the mechanism of its formation are not completely understood. Using fast scanning calorimetry technique, we show that out-of equilibrium relaxation kinetics and possibly the enthalpy of vapor-deposited films of toluene and ethylbenzene, archetypical fragile glass formers, are distinct from those of ordinary supercooled phase even when the deposition takes place at temperatures above the ordinary glass softening transition temperatures. These observations along with the absolute enthalpy dependences on deposition temperatures support the conjecture that the vapor-deposition may result in formation of non-crystalline phase of unique structural, thermodynamic, and kinetic properties. PMID- 25933778 TI - First-principles investigation on the electronic efficiency and binding energy of the contacts formed by graphene and poly-aromatic hydrocarbon anchoring groups. AB - The electronic efficiency and binding energy of contacts formed between graphene electrodes and poly-aromatic hydrocarbon (PAH) anchoring groups have been investigated by the non-equilibrium Green's function formalism combined with density functional theory. Our calculations show that PAH molecules always bind in the interior and at the edge of graphene in the AB stacking manner, and that the binding energy increases following the increase of the number of carbon and hydrogen atoms constituting the PAH molecule. When we move to analyzing the electronic transport properties of molecular junctions with a six-carbon alkyne chain as the central molecule, the electronic efficiency of the graphene-PAH contacts is found to depend on the energy gap between the highest occupied molecular orbital (HOMO) and the lowest unoccupied molecular orbital (LUMO) of the corresponding PAH anchoring group, rather than its size. To be specific, the smaller is the HOMO-LUMO gap of the PAH anchoring group, the higher is the electronic efficiency of the graphene-PAH contact. Although the HOMO-LUMO gap of a PAH molecule depends on its specific configuration, PAH molecules with similar atomic structures show a decreasing trend for their HOMO-LUMO gap as the number of fused benzene rings increases. Therefore, graphene-conjugated molecule graphene junctions with high-binding and high-conducting graphene-PAH contacts can be realized by choosing appropriate PAH anchor groups with a large area and a small HOMO-LUMO gap. PMID- 25933779 TI - Hybrid-state emission in a polythienylenevinylene derivative with an electron deficient moiety. AB - The photoluminescence (PL) of a novel imide-substituted poly(3 thienylenevinylene) derivative (imidePTV) was studied in film and solution. PL quantum efficiency was measured to be more than two orders of magnitude larger than its nonluminescent counterpart, namely, alkyl-substituted PTV and was interpreted as evidence for a near degeneracy of optically allowed 1(1)Bu and optically forbidden 2(1)Ag excitonic states. As a result, coexistence of 2(1)Ag and 1(1)Bu emissions was observed, and the predominance was found to be sensitive to temperature and morphological environment. PL of solutions in solvents of higher polarity and polarizability and from low-temperature films was dominated by the transition from the dipole allowed 1(1)Bu state. On the other hand, the PL spectra of films at high temperature and solutions in solvents of low polarity and polarizability were primarily from the 2(1)Ag state that obtains a finite transmission moment from an asymmetric perturbation mixing with the 1(1)Bu. PMID- 25933780 TI - Mixtures of ions and amphiphilic molecules in slit-like pores: A density functional approach. AB - We investigate microscopic structure and thermodynamic properties of a mixture that contains amphiphilic molecules and charged hard spheres confined in slit like pores with uncharged hard walls. The model and the density functional approach are the same as described in details in our previous work [Pizio et al., J. Chem. Phys. 140, 174706 (2014)]. Our principal focus is in exploring the effects brought by the presence of ions on the structure of confined amphiphilic particles. We have found that for some cases of anisotropic interactions, the change of the structure of confined fluids occurs via the first-order transitions. Moreover, if anions and cations are attracted by different hemispheres of amphiphiles, a charge at the walls appears at the zero value of the wall electrostatic potential. For a given thermodynamic state, this charge is an oscillating function of the pore width. PMID- 25933781 TI - The cluster model of a hot dense vapor. AB - We explore thermodynamic properties of a vapor in the range of state parameters where the contribution to thermodynamic functions from bound states of atoms (clusters) dominates over the interaction between the components of the vapor in free states. The clusters are assumed to be light and sufficiently "hot" for the number of bonds to be minimized. We use the technique of calculation of the cluster partition function for the cluster with a minimum number of interatomic bonds to calculate the caloric properties (heat capacity and velocity of sound) for an ideal mixture of the lightest clusters. The problem proves to be exactly solvable and resulting formulas are functions solely of the equilibrium constant of the dimer formation. These formulas ensure a satisfactory correlation with the reference data for the vapors of cesium, mercury, and argon up to moderate densities in both the sub- and supercritical regions. For cesium, we extend the model to the densities close to the critical one by inclusion of the clusters of arbitrary size. Knowledge of the cluster composition of the cesium vapor makes it possible to treat nonequilibrium phenomena such as nucleation of the supersaturated vapor, for which the effect of the cluster structural transition is likely to be significant. PMID- 25933782 TI - Structural stability and defect energetics of ZnO from diffusion quantum Monte Carlo. AB - We have applied the many-body ab initio diffusion quantum Monte Carlo (DMC) method to study Zn and ZnO crystals under pressure and the energetics of the oxygen vacancy, zinc interstitial, and hydrogen impurities in ZnO. We show that DMC is an accurate and practical method that can be used to characterize multiple properties of materials that are challenging for density functional theory (DFT) approximations. DMC agrees with experimental measurements to within 0.3 eV, including the band-gap of ZnO, the ionization potential of O and Zn, and the atomization energy of O2, ZnO dimer, and wurtzite ZnO. DMC predicts the oxygen vacancy as a deep donor with a formation energy of 5.0(2) eV under O-rich conditions and thermodynamic transition levels located between 1.8 and 2.5 eV from the valence band maximum. Our DMC results indicate that the concentration of zinc interstitial and hydrogen impurities in ZnO should be low under n-type and Zn- and H-rich conditions because these defects have formation energies above 1.4 eV under these conditions. Comparison of DMC and hybrid functionals shows that these DFT approximations can be parameterized to yield a general correct qualitative description of ZnO. However, the formation energy of defects in ZnO evaluated with DMC and hybrid functionals can differ by more than 0.5 eV. PMID- 25933783 TI - Calorimetric measurements on Li4C60 and Na4C60. AB - We show specific heat data for Na4C60 and Li4C60 in the range 0.4-350 K for samples characterized by Raman spectroscopy and X-ray diffraction. At high temperatures, the two different polymer structures have very similar specific heats both in absolute values and in general trend. The specific heat data are compared with data for undoped polymeric and pristine C60. At high temperatures, a difference in specific heat between the intercalated and undoped C60 polymers of 100 J K(-1) mol(-1) is observed, in agreement with the Dulong-Petit law. At low temperatures, the specific heat data for Li4C60 and Na4C60 are modified by the stiffening of vibrational and librational molecular motion induced by the polymer bonds. The covalent twin bonds in Li4C60 affect these motions to a somewhat higher degree than the single intermolecular bonds in Na4C60. Below 1 K, the specific heats of both materials become linear in temperature, as expected from the effective dimensionality of the structure. The contribution to the total specific heat from the inserted metal ions can be well described by Einstein functions with TE = 386 K for Li4C60 and TE = 120 K for Na4C60, but for both materials we also observe a Schottky-type contribution corresponding to a first approximation to a two-level system with DeltaE = 9.3 meV for Li4C60 and 3.1 meV for Na4C60, probably associated with jumps between closely spaced energy levels inside "octahedral-type" ionic sites. Static magnetic fields up to 9 T had very small effects on the specific heat below 10 K. PMID- 25933784 TI - Solid-liquid interfaces of ionic liquid solutions--Interfacial layering and bulk correlations. AB - The influence of the polar, aprotic solvent propylene carbonate on the interfacial structure of the ionic liquid (IL) 1-butyl-1-methylpyrrolidinium tris(pentafluoroethyl)trifluorophosphate on sapphire was investigated by high energy x-ray reflectivity. Experiments at solvent concentrations between 17 mol. % and 83 mol. % bridge the gap between diluted electrolytes described by the classical Gouy-Chapman theory and pure ionic liquids. Analysis of our experimental data revealed interfacial profiles comprised of alternating anion and cation enriched regions decaying gradually into the bulk liquid. With increasing solvent concentration, we observed a decrease in correlation length of the interfacial layering structure. At high ion concentrations, solvent molecules were found to accumulate laterally within the layers. By separating like-charged ions, they reduce their Coulomb repulsion. The results are compared with the bulk structure of IL/solvent blends probed by x-ray scattering and predictions from fundamental fluid theory. PMID- 25933785 TI - Computational study of trimer self-assembly and fluid phase behavior. AB - The fluid phase diagram of trimer particles composed of one central attractive bead and two repulsive beads was determined as a function of simple geometric parameters using flat-histogram Monte Carlo methods. A variety of self-assembled structures were obtained including spherical micelle-like clusters, elongated clusters, and densely packed cylinders, depending on both the state conditions and shape of the trimer. Advanced simulation techniques were employed to determine transitions between self-assembled structures and macroscopic phases using thermodynamic and structural definitions. Simple changes in particle geometry yield dramatic changes in phase behavior, ranging from macroscopic fluid phase separation to molecular-scale self-assembly. In special cases, both self assembled, elongated clusters and bulk fluid phase separation occur simultaneously. Our work suggests that tuning particle shape and interactions can yield superstructures with controlled architecture. PMID- 25933786 TI - Generalized mapping of multi-body dissipative particle dynamics onto fluid compressibility and the Flory-Huggins theory. AB - In this work, a generalized relation between the fluid compressibility, the Flory Huggins interaction parameter (chi), and the simulation parameters in multi-body dissipative particle dynamics (MDPD) is established. This required revisiting the MDPD equation of state previously reported in the literature and developing general relationships between the parameters used in the MDPD model. We derive a relationship to the Flory-Huggins chi parameter for incompressible fluids similar to the work previously done in dissipative particle dynamics by Groot and Warren. The accuracy of this relationship is evaluated using phase separation in small molecules and the solubility of polymers in dilute solvent solutions via monitoring the scaling of the radius of gyration (Rg) for different solvent qualities. Finally, the dynamics of the MDPD fluid is studied with respect to the diffusion coefficient and the zero shear viscosity. PMID- 25933787 TI - Structure factor of a Gaussian chain confined between two parallel plates. AB - We study the structure factor of a single Gaussian chain confined between two macroscopic parallel plates theoretically. The chain propagator is constructed in terms of the eigen-spectrum of the Laplace operator under the Dirichlet boundary condition enforced at the two plates, by which the confinement effect enters the treatment through size-dependent eigen-spectrum. In terms of the series expansion solution for the chain propagator, we first calculate the confinement free energy and the confinement force for an arbitrary confinement strength. It is found that the confinement force scales to the distance between the two confining surfaces with a power of -3 for strong confinements and of -2 for weak confinements. Based on the ground state dominance approximation for strong confinements and the Euler Maclaurin formula for weak confinements, we develop approximation theories for the two limit situations, which agree with the numerical results well. We further calculate the structure factor of the confined Gaussian chain in this slit geometry. While the scattering function of the transverse chain fluctuations perpendicular to the confinement direction is still a Debye function form, the structure factor for the longitudinal fluctuations along the confinement dimension starts with the monotonic Debye function behavior for weak confinements and develops a decaying oscillation behavior with the increase of confinements. The numerical results for the structure factor are also interpreted by developing approximation theories in different confinement regimes. Finally, the orientational average of the anisotropic structure factor is performed and an analytic expression for the averaged structure factor is derived under the ground state dominance approximation for strong confinements. PMID- 25933788 TI - Taming Levy flights in confined crowded geometries. AB - We study two-dimensional diffusive motion of a tracer particle in restricted, crowded anisotropic geometries. The underlying medium is formed from a monolayer of elongated molecules [Ciesla J. Chem. Phys. 140, 044706 (2014)] of known concentration. Within this mesh structure, a tracer molecule is allowed to perform a Cauchy random walk with uncorrelated steps. Our analysis shows that the presence of obstacles significantly influences the motion, which in an obstacle free space would be of a superdiffusive type. At the same time, the selfdiffusive process reveals different anomalous properties, both at the level of a single trajectory realization and after the ensemble averaging. In particular, due to obstacles, the sample mean squared displacement asymptotically grows sublinearly in time, suggesting a non-Markov character of motion. Closer inspection of survival probabilities indicates, however, that the underlying diffusion is memoryless over long time scales despite a strong inhomogeneity of the motion induced by the orientational ordering. PMID- 25933789 TI - Force-extension curves for broken-rod macromolecules: Dramatic effects of different probing methods for two and three rods. AB - We study force-extension curves of a single semiflexible chain consisting of several rigid rods connected by flexible spacers. The atomic force microscopy and laser optical or magnetic tweezers apparatus stretching these rod-coil macromolecules are discussed. In addition, the stretching by external isotropic force is analyzed. The main attention is focused on computer simulation and analytical results. We demonstrate that the force-extension curves for rod-coil chains composed of two or three rods of equal length differ not only quantitatively but also qualitatively in different probe methods. These curves have an anomalous shape for a chain of two rods. End-to-end distributions of rod coil chains are calculated by Monte Carlo method and compared with analytical equations. The influence of the spacer's length on the force-extension curves in different probe methods is analyzed. The results can be useful for interpreting experiments on the stretching of rod-coil block-copolymers. PMID- 25933790 TI - Characterizing the bending and flexibility induced by bulges in DNA duplexes. AB - Advances in DNA nanotechnology have stimulated the search for simple motifs that can be used to control the properties of DNA nanostructures. One such motif, which has been used extensively in structures such as polyhedral cages, two dimensional arrays, and ribbons, is a bulged duplex, that is, two helical segments that connect at a bulge loop. We use a coarse-grained model of DNA to characterize such bulged duplexes. We find that this motif can adopt structures belonging to two main classes: one where the stacking of the helices at the center of the system is preserved, the geometry is roughly straight, and the bulge is on one side of the duplex and the other where the stacking at the center is broken, thus allowing this junction to act as a hinge and increasing flexibility. Small loops favor states where stacking at the center of the duplex is preserved, with loop bases either flipped out or incorporated into the duplex. Duplexes with longer loops show more of a tendency to unstack at the bulge and adopt an open structure. The unstacking probability, however, is highest for loops of intermediate lengths, when the rigidity of single-stranded DNA is significant and the loop resists compression. The properties of this basic structural motif clearly correlate with the structural behavior of certain nano scale objects, where the enhanced flexibility associated with larger bulges has been used to tune the self-assembly product as well as the detailed geometry of the resulting nanostructures. We further demonstrate the role of bulges in determining the structure of a "Z-tile," a basic building block for nanostructures. PMID- 25933791 TI - On the ambiguity of conformational states: A B&S-LEUS simulation study of the helical conformations of decaalanine in water. AB - Estimating the relative stabilities of different conformational states of a (bio )molecule using molecular dynamics simulations involves two challenging problems: the conceptual problem of how to define the states of interest and the technical problem of how to properly sample these states, along with achieving a sufficient number of interconversion transitions. In this study, the two issues are addressed in the context of a decaalanine peptide in water, by considering the 310-, alpha-, and pi-helical states. The simulations rely on the ball-and-stick local-elevation umbrella-sampling (B&S-LEUS) method. In this scheme, the states are defined as hyperspheres (balls) in a (possibly high dimensional) collective coordinate space and connected by hypercylinders (sticks) to ensure transitions. A new object, the pipe, is also introduced here to handle curvilinear pathways. Optimal sampling within the so-defined space is ensured by confinement and (one dimensional) memory-based biasing potentials associated with the three different kinds of objects. The simulation results are then analysed in terms of free energies using reweighting, possibly relying on two distinct sets of collective coordinates for the state definition and analysis. The four possible choices considered for these sets are Cartesian coordinates, hydrogen-bond distances, backbone dihedral angles, or pairwise sums of successive backbone dihedral angles. The results concerning decaalanine underline that the concept of conformational state may be extremely ambiguous, and that its tentative absolute definition as a free-energy basin remains subordinated to the choice of a specific analysis space. For example, within the force-field employed and depending on the analysis coordinates selected, the 310-helical state may refer to weakly overlapping collections of conformations, differing by as much as 25 kJ mol(-1) in terms of free energy. As another example, the pi-helical state appears to correspond to a free-energy basin for three choices of analysis coordinates, but to be unstable with the fourth one. The problem of conformational-state definition may become even more intricate when comparison with experiment is involved, where the state definition relies on spectroscopic or functional observables. PMID- 25933792 TI - Publisher's Note: "Solvation thermodynamics of amino acid side chains on a short peptide backbone" [J. Chem. Phys. 142, 144502 (2015)]. PMID- 25933793 TI - Publisher's Note: "Vibrational coherence and energy transfer in two-dimensional spectra with the optimized mean-trajectory approximation" [J. Chem. Phys. 142, 212417 (2015)]. PMID- 25933794 TI - Perinatal malnutrition stimulates motivation through reward and enhances drd(1a) receptor expression in the ventral striatum of adult mice. AB - AIM: The aim of this study was to analyze the effects of protein perinatal malnutrition on the function of dopamine DRD1 and DRD2 receptors in regards to motivation and food consumption in adult mice. The study also analyzed the effect of protein perinatal malnutrition on the gene expression of these receptors in the ventral striatum. METHODS: Wistar lineage mice were divided into two groups according to maternal diet: control (17% casein), n=30 and low protein (8% casein), n=30. Between 30 and 120days of life, the following factors were measured: body weight; the effect of dopamine D1 and D2 agonists on the ingestion of palatable food; the motivational aspect under the action of the D1 (SKF 38393) and D2 Quinpirole dopaminergic agonists; and the gene expression of DRD1 and DRD2 receptors in the ventral striatum. RESULTS: The body weights of the malnourished animals remained significantly lower than those of the control group from 30 to 120days of life. Malnourished animals ingested a greater quantity of palatable food. There was a decrease in palatable diet consumption in both the control and malnourished groups after the application of D1 and D2 agonists; however, the anorexic effect of the D1 agonist was understated in malnourished animals. Perinatal malnutrition increases the motivational behavior of the animal when food reward is used. There was an increase in gene expression of the DRD1a receptor in the ventral striatum of malnourished animals, and there were no significant changes concerning the DRD2 receptor. CONCLUSIONS: Perinatal protein malnutrition stimulates hedonic control of eating behavior by promoting increased intake of palatable foods, possibly due to increased expression of dopamine receptor DRD1a in the ventral striatum. PMID- 25933795 TI - Combined varenicline and naltrexone treatment reduces smoking topography intensity in heavy-drinking smokers. AB - Heavy drinking smokers constitute a distinct sub-population of smokers for whom traditional smoking cessation therapies may not be effective. Recent evidence suggested that combined varenicline (VAR) and naltrexone (NTX) therapy may be more efficacious than either monotherapy alone in reducing smoking and drinking related behavior in this population. The manner in which individuals smoke a cigarette (i.e., smoking topography) may be predictive of smoking cessation outcomes, yet the effects of smoking pharmacotherapies on puffing behavior have not been thoroughly examined. Therefore, the current double-blind medication study examined the effects of VAR alone (1mg BID), low dose NTX alone (25mg QD), the combination of VAR+NTX, and placebo on smoking topography measures in heavy drinking, non-treatment seeking daily smokers (n=120). After a 9-day titration period, participants completed a laboratory session in which they smoked their first cigarette of the day using a smoking topography device following 12h of nicotine abstinence and consumption of an alcoholic beverage (BrAC=0.06g/dl). The primary measures were puff count, volume, duration, and velocity and inter-puff interval (IPI). Independent of medication group, puff velocity and IPI increased, while puff volume and duration decreased, over the course of the cigarette. The active medication groups, vs. the placebo group, had significantly blunted puff duration and velocity slopes over the course of the cigarette, and this effect was particularly evident in the VAR+NTX group. Additionally, the VAR+NTX group demonstrated lower average IPI than the monotherapy groups and lower average puff volume than all other groups. These results suggest that smoking pharmacotherapies, particularly the combination of VAR+NTX, alter smoking topography in heavy drinking smokers, producing a pattern of less intense puffing behavior. As smoking topography has been predictive of the ability to quit smoking, future studies should examine how smoking pharmacotherapies' effects on puffing behavior relate to smoking cessation outcomes. PMID- 25933796 TI - Development of translational preclinical models in substance abuse: Effects of cocaine administration on cocaine choice in humans and non-human primates. AB - Human drug use involves repeated choices to take drugs or to engage in alternative behaviors. The purpose of this study was to examine how response cost for cocaine and the value of an alternative reinforcer (opportunity to play a game of chance) and how 'free' doses (with minimal response cost) affected cocaine choice. Two laboratory studies of cocaine self-administration were conducted in a group of humans who were habitual cocaine smokers and in a group of rhesus monkeys that intravenously self-administered cocaine. Nine human cocaine smokers who were not seeking treatment for their cocaine were repeatedly presented with the choice to smoke 25mg cocaine base or play a game of chance for a monetary bonus paid at study completion. The response cost for choosing cocaine varied (up to 4000 responses/dose) and the number of game plays varied (up to 8). In this sample of humans, increasing either the response cost for cocaine or increasing the value of the alternative reinforcer did not significantly affect cocaine choice, while increasing both simultaneously slightly decreased cocaine choice and increased choice of the alternative. In monkeys, the dose-response function for cocaine self-administration (10 choices of 0.0125-0.1mg/kg/infusion vs. candy coated chocolate) was steep and we failed to achieve a 50/50 cocaine/candy choice even after substantially manipulating cost and number of candies available. Providing a large 'free' self-administered cocaine dose to humans did not significantly affect cocaine choice, whereas in monkeys, a large free dose of cocaine decreased cocaine choice when higher doses of cocaine were available for self-administration. The present results demonstrate that in the laboratory, it is difficult to modify on-going cocaine self-administration behavior in both humans and non-human primates. PMID- 25933797 TI - Traveling by Private Motorized Vehicle and Physical Fitness in Taiwanese Adults. AB - BACKGROUND: Although the time spent sitting in motorized vehicles has been determined to be adversely associated with cardiometabolic health, its association with other health indicators remains unclear. PURPOSE: This study examined associations between traveling by private motorized vehicle and 4 indicators of physical fitness in adults. METHOD: Data from 52,114 Taiwanese adults aged 20 to 65 years who participated in the 2013 National Adults Fitness Survey were used. The examined variables were height, body mass, and performance in modified sit-and-reach (flexibility), bent-leg sit-up (abdominal muscular strength and endurance), and a 3-min step test (cardiorespiratory endurance). Participants were asked on how many days they had used a private car or motorcycle for traveling from place to place and categorized as non-, occasional, and daily private motorized vehicle travelers. Logistic and linear regression models were used to examine associations between the categories of using private motorized vehicles to travel and physical fitness performance. RESULTS: After an adjustment for potential demographic and behavioral confounders, daily traveling by private motorized vehicle was associated with a higher probability of overweight (odds ratio = 1.18), lower performance of abdominal muscular strength and endurance (-0.37 times/min), and lower cardiorespiratory fitness (-0.60 physical fitness index) than was traveling that did not involve private motorized vehicles. CONCLUSION: The results suggest that in addition to unfavorable cardiorespiratory fitness and a risk of overweight, daily traveling by private motorized vehicle is associated with poor performance in abdominal muscular strength and endurance. PMID- 25933798 TI - Development and preliminary testing of a web-based, self-help application for disaster-affected families. AB - Technology-based self-help interventions have the potential to increase access to evidence-based mental healthcare, especially for families affected by natural disasters. However, development of these interventions is a complex process and poses unique challenges. Usability testing, which assesses the ability of individuals to use an application successfully, can have a significant impact on the quality of a self-help intervention. This article describes (a) the development of a novel web-based multi-module self-help intervention for disaster affected adolescents and their parents and (b) a mixed-methods formal usability study to evaluate user response. A total of 24 adolescents were observed, videotaped, and interviewed as they used the depressed mood component of the self help intervention. Quantitative results indicated an above-average user experience, and qualitative analysis identified 120 unique usability issues. We discuss the challenges of developing self-help applications, including design considerations and the value of usability testing in technology-based interventions, as well as our plan for widespread dissemination. PMID- 25933799 TI - Serum-Mediated Inhibition of Enzyme Replacement Therapy in Fabry Disease. AB - Fabry disease (FD) is a progressive multisystemic disorder, treatable with recombinant enzyme replacement therapy (agalsidase). However, recent studies suggest an endogenous inhibition of agalsidase in patients with FD, as reported for other lysosomal storage diseases. To assess the clinical consequences of serum-mediated agalsidase inhibition in affected patients, we determined the agalsidase inhibition status of 168 patients (68 male) with FD and compared outcomes of inhibition-positive patients with those of inhibition-negative patients. The assessment included clinical events during time on agalsidase, determination of renal and cardiac function, and evaluation of FD-related symptoms. The frequency of serum-mediated agalsidase inhibition was 40% in agalsidase-treated males. Inhibition did not depend on the compound initially used (agalsidase-alpha or -beta). Agalsidase inhibition was associated with higher lyso-globotriaosylceramide levels and worse disease severity scores in patients. Compared with agalsidase inhibition-negative men, agalsidase inhibition positive men showed greater left ventricular mass (P=0.02) and substantially lower renal function (difference in eGFR of about -30 ml/min per 1.73 m(2); P=0.04), which was confirmed by a longitudinal 5-year retrospective analysis. Additionally, affected patients presented more often with FD-typical symptoms, such as diarrhea, fatigue, and neuropathic pain, among others. Therefore, patients with poor clinical outcome on agalsidase should be tested for agalsidase inhibition. Future studies are warranted to determine if affected patients with FD benefit from acute reduction of anti-agalsidase antibodies or long-term immune modulation therapies to suppress agalsidase inhibition and to identify mechanisms that minimize antibody generation against agalsidase. PMID- 25933800 TI - An unusual case of a well-differentiated neuroendocrine tumour of the ileum with peritoneal carcinomatosis: a case report. AB - Neuroendocrine tumours (NETs) are a family of neoplasms that come from neuroendocrine cells and express neural markers, such as synaptophysin or chromogranin A.The current classifications of these tumours are presented by the WHO 2000 classification, based on histological parameters, and the WHO 2010 classification, based on the proliferative index, that divides the NETs into a neuroendocrine tumour of a low grade, neuroendocrine tumour of a intermediate grade and neuroendocrine carcinoma (NEC) of a high grade.We are reporting a very rare case of a G1 low-grade neuroendocrine tumour (NET) of the ileum with a peritoneal carcinomatosis.This case is challenging because the tumour expresses low proliferative index as G1 tumours, but it has an aggressive clinical behaviour such as node metastasis and peritoneal carcinomatosis.The peritoneal carcinomatosis is not actually considered by the current classifications of NETs, so it is difficult to predict the prognosis of this patient. PMID- 25933801 TI - Considerations for practice-based research: a cross-sectional survey of chiropractic, acupuncture and massage practices. AB - BACKGROUND: Complementary and alternative medicine (CAM) use has steadily increased globally over the past two decades and is increasingly playing a role in the healthcare system in the United States. CAM practice-based effectiveness research requires an understanding of the settings in which CAM practitioners provide services. This paper describes and quantifies practice environment characteristics for a cross-sectional sample of doctors of chiropractic (DCs), licensed acupuncturists (LAcs), and licensed massage therapists (LMTs) in the United States. METHODS: Using a cross-sectional telephone survey of DCs (n = 32), LAcs (n = 70), and LMTs (n = 184) in the Tucson, AZ metropolitan area, we collected data about each location where practitioners work, as well as measures on practitioner and practice characteristics including: patient volume, number of locations where practitioners worked, CAM practitioner types working at each location, and business models of practice. RESULTS: The majority of practitioners reported having one practice location (93.8% of DCs, 80% of LAcs and 59.8% of LMTs) where they treat patients. Patient volume/week was related to practitioner type; DCs saw 83.13 (SD = 49.29) patients/week, LAcs saw 22.29 (SD = 16.88) patients/week, and LMTs saw 14.21 (SD =10.25) patients per week. Practitioners completed surveys for N = 388 practice locations. Many CAM practices were found to be multidisciplinary and/or have more than one practitioner: 9/35 (25.7%) chiropractic practices, 24/87 (27.6%) acupuncture practices, and 141/266 (53.0%) massage practices. Practice business models across CAM practitioner types were heterogeneous, e.g. sole proprietor, employee, partner, and independent contractor. CONCLUSIONS: CAM practices vary across and within disciplines in ways that can significantly impact design and implementation of practice-based research. CAM research and intervention programs need to be mindful of the heterogeneity of CAM practices in order to create appropriate interventions, study designs, and implementation plans. PMID- 25933802 TI - Acute systemic embolism due to an idiopathic floating thrombus of the thoracic aorta: success of medical management: a case report. AB - BACKGROUND: Idiopathic thoracic aortic mural thrombi are rare. They can be responsible for dramatic systemic embolization. Early treatment is imperative because of their high morbidity and mortality rate. CASE PRESENTATION: A 55-year old previously healthy Moroccan male came in an array of acute right lower limbs pain and abdominal sensibility. Severe systemic embolism involving the lower extremities, spleen, kidney, and digestive tract, due to an idiopathic mural thrombus of the thoracic aorta was diagnosed. He received medical treatment leading to the complete disappearance of the thrombus and the effects caused by the latter. CONCLUSIONS: When faced unexplained peripheral embolization, research for a thrombus of the thoracic aorta should be performed. Medical treatment should be considered for its management, especially in patients with high surgical risk. PMID- 25933803 TI - Prevalence, infectivity and correlates of hepatitis B virus infection among pregnant women in a rural district of the Far North Region of Cameroon. AB - BACKGROUND: Epidemiological data on hepatitis B virus (HBV) infection among pregnant women in Cameroon are very scarce, especially in the rural milieu. The purpose of this study was to determine the prevalence and factors associated with HBV infection, and the infectivity of rural pregnant women in the Far North Region of Cameroon. METHODS: A cross-sectional study was conducted in three rural health facilities of the Guidiguis health district between December 2013 and March 2014. We consecutively recruited 325 pregnant women attending antenatal consultations. A pretested questionnaire was used to collect socio-demographic data and factors associated with HBV infection. The presence of hepatitis B surface antigen (HBsAg), hepatitis B e antigen (HBeAg) and human immunodeficiency virus (HIV) were determined using commercial test strips. Regression analyses were used to assess correlates of HBV infection. RESULTS: The mean age was 24.4 (SD5.6) years. Most women were married (97.2%) and housewives (96.4%), with less than secondary education level (80%). Only 4 women (1.2%) had been vaccinated against HBV. Thirty-three women (10.2%) were HBsAg-positive, of whom 4 (12.1%) were positive to HBeAg. The prevalence of HIV infection was 2.5% (8/325). Overall, 5 (1.5%) women were co-infected with HIV and HBV. Independent correlates of HBV infection included history of blood transfusion (adjusted odd ratio 12.59, 95% CI 1.46-108.89; p = 0.021) and concurrent infection by HIV (adjusted odd ratio 22.53, 95% CI 4.76-106.71; p < 0.0001). CONCLUSION: The prevalence of HBV infection among pregnant women in this rural milieu is high. History of blood transfusion and HIV infection are highly associated with HBV infection. The relative low rate of women positive to both HBsAg and HBeAg suggests that perinatal transmission of HBV might not be the prevailing mode of HBV transmission in this area. PMID- 25933804 TI - A review of the physical and metabolic effects of cross-sex hormonal therapy in the treatment of gender dysphoria. AB - This review focuses on the effect that cross-gender sex steroid therapy has on metabolic and hormonal parameters. There is an emphasis on those changes that result in significant clinical effects such as the positive effects of the development of secondary sexual characteristics and negative effects such as haemostatic effects and thromboembolism in transwomen or dyslipidaemia in transmen. There is also a description of the current hormonal regimens used at the largest UK gender identity clinic. The overall safety of these treatments in the context of long-term outcome data is reviewed. PMID- 25933806 TI - Factors influencing the uptake of Voluntary HIV Counseling and Testing among secondary school students in Arusha City, Tanzania: a cross sectional study. AB - BACKGROUND: Voluntary HIV counseling and testing (VCT) is a key strategy towards HIV prevention yet, the uptake of VCT services among young people remains low. This study determined the factors that influence the uptake of VCT among secondary school students in Arusha City, Tanzania. METHODS: A cross sectional study using quantitative methods was conducted. A multi-stage sampling method was applied to randomly select the secondary schools. Stratification, random and systematic sampling techniques were used to identify the study participants. Interviews were conducted using structured questionnaires. Data analysis was done using statistical package for social sciences version 16. Analytical statistics were done using odds ratio to measure strength of association between VCT uptake and independent variables. Association with p-value < 0.05 was considered significant. Binary logistic regression was used to identify predictors of VCT uptake. RESULTS: Of 400 study participants, 50.5% were male and 49.5% were female. 93.5% of the respondents were aware of the VCT services, 79.1% had high knowledge on VCT services and 75.9% had positive attitude towards VCT services. On VCT uptake, only 29.3% had ever tested. VCT uptake was found to be significantly predicted by age (p = 0.003), sex (p < 0.001), religion (p < 0.001), exposure to VCT information from a VCT centre (p < 0.001) and type of school ownership (p < 0.013). CONCLUSION: Despite high knowledge on VCT services, the uptake of VCT among secondary school students was found to be low. The uptake of VCT was mainly found to be influenced by fear of HIV test results, knowledge and attitude on VCT services, age, education, engagement in sexual relationships, stigma and distance to the VCT centre. Integration of youth friendly VCT services in secondary schools would increase VCT uptake among secondary school students. Support and care received after knowing the test results should be clearly communicated as it helps motivate more young people towards VCT uptake and reduce stigma among them. PMID- 25933805 TI - Cytotoxicity and infiltration of human NK cells in in vivo-like tumor spheroids. AB - BACKGROUND: The complex cellular networks within tumors, the cytokine milieu, and tumor immune escape mechanisms affecting infiltration and anti-tumor activity of immune cells are of great interest to understand tumor formation and to decipher novel access points for cancer therapy. However, cellular in vitro assays, which rely on monolayer cultures of mammalian cell lines, neglect the three-dimensional architecture of a tumor, thus limiting their validity for the in vivo situation. METHODS: Three-dimensional in vivo-like tumor spheroid were established from human cervical carcinoma cell lines as proof of concept to investigate infiltration and cytotoxicity of NK cells in a 96-well plate format, which is applicable for high-throughput screening. Tumor spheroids were monitored for NK cell infiltration and cytotoxicity by flow cytometry. Infiltrated NK cells, could be recovered by magnetic cell separation. RESULTS: The tumor spheroids were stable over several days with minor alterations in phenotypic appearance. The tumor spheroids expressed high levels of cellular ligands for the natural killer (NK) group 2D receptor (NKG2D), mediating spheroid destruction by primary human NK cells. Interestingly, destruction of a three-dimensional tumor spheroid took much longer when compared to the parental monolayer cultures. Moreover, destruction of tumor spheroids was accompanied by infiltration of a fraction of NK cells, which could be recovered at high purity. CONCLUSION: Tumor spheroids represent a versatile in vivo-like model system to study cytotoxicity and infiltration of immune cells in high-throughput screening. This system might proof useful for the investigation of the modulatory potential of soluble factors and cells of the tumor microenvironment on immune cell activity as well as profiling of patient-/donor-derived immune cells to personalize cellular immunotherapy. PMID- 25933807 TI - Diagnostic performance of the Bernese versus Ottawa ankle rules: Results of a randomised controlled trial. AB - PURPOSE: The Ottawa ankle rules (OAR) brought about a reduction of radiographs on the Emergency Department (ED). However, still 50% of patients with ankle injuries undergo unnecessary radiography. Compared to the OAR, the Bernese ankle rule (BAR) has an acclaimed 84% reduction in radiography without loss of sensitivity. The primary aim of this study was to compare the diagnostic accuracy and reproducibility of both rules. Furthermore, the ability of triage nurses to accurately interpret the BAR was assessed. METHODS: Participants were assessed by both the ED resident and the triage nurse, applying the OAR and the BAR. After standardised data collection, ankle and foot radiographs were performed in all patients. Sensitivity and specificity of both tests applied by both observers were obtained and compared by McNemar's test. Reproducibility was calculated with Cohen's kappa. RESULTS: A total of 203 patients with ankle trauma were included. For the OAR obtained by the ED residents, the sensitivity and specificity were 0.97 and 0.29, respectively. For the BAR, the sensitivity and specificity of the ED residents were 0.69 and 0.45, respectively. For the triage nurses, the OAR sensitivity and specificity were 0.86 and 0.25, respectively. The BAR sensitivity and specificity for the nurses were 0.86 and 0.40, respectively. The reproducibility of the OAR was 0.45, and for the BAR, it was 0.48. CONCLUSION: Both rules showed comparable reproducibility. Although the BAR showed a superior specificity compared to the OAR, its sensitivity was too low to promote clinical use. The triage nurses demonstrated too low sensitivity on both rules to allow safe application. Therefore, the OAR remain the decision rules of choice for ankle injuries despite its modest 'ruling out' capacity. PMID- 25933808 TI - Can we achieve bone healing using the diamond concept without bone grafting for recalcitrant tibial nonunions? AB - The purpose of this study was to evaluate the efficacy and safety of a combination of recombinant human bone morphogenetic protein 7 (rhBMP-7) and resorbable calcium phosphate bone substitute (rCPBS) as a salvage solution for recalcitrant tibial fracture nonunions. Twenty consecutive patients, 16 male and four female, with a mean age of 46.8+/-15.7 years (21-78) and a mean body mass index (BMI) of 24.2+/-5.3kgm(-2) (21.5-28.5), suffering from 20 recalcitrant tibial fracture nonunions were included. The mean number of operations performed prior to the procedure was 3.3, with homolateral iliac crest bone grafts being used for all of the patients. All patients were treated with a procedure including debridement and decortications of the bone ends, nonunion fixation with a locking plate, and filling of the bony defect with a combined graft of rhBMP-7 (as osteoinductor) with an rCPBS (as scaffold). The mean follow-up was 14+/-2.7 months. Both clinical and radiological union occurred in 18 cases, within a mean time of 4.7+/-3.2 months. A recurrence of deep infection was diagnosed for one of the non-consolidated patients. No specific complication of rCPBS or rhBMP-7 was encountered. This study supports the view that the application of rCPBS combined with rhBMP-7, without any bone grafting, is safe and efficient in the treatment of recalcitrant bone union. PMID- 25933809 TI - Effect of 5 years of imaging and CEA follow-up to detect recurrence of colorectal cancer: The FFCD PRODIGE 13 randomised phase III trial. PMID- 25933810 TI - 3D-manufactured patient-specific models of congenital heart defects for communication in clinical practice: feasibility and acceptability. AB - OBJECTIVES: To assess the communication potential of three-dimensional (3D) patient-specific models of congenital heart defects and their acceptability in clinical practice for cardiology consultations. DESIGN: This was a questionnaire based study in which participants were randomised into two groups: the 'model group' received a 3D model of the cardiac lesion(s) being discussed during their appointment, while the 'control group' had a routine visit. SETTING: Outpatient clinic, cardiology follow-up visits. PARTICIPANTS: 103 parents of children with congenital heart disease were recruited (parental age: 43+/-8 years; patient age: 12+/-6 years). In order to have a 3D model made, patients needed to have a recent cardiac MRI examination; this was the crucial inclusion criterion. INTERVENTIONS: Questionnaires were administered to the participants before and after the visits and an additional questionnaire was administered to the attending cardiologist. MAIN OUTCOME MEASURES: Rating (1-10) for the liking of the 3D model, its usefulness and the clarity of the explanation received were recorded, as well as rating (1-10) of the parental understanding and their engagement according to the cardiologist. Furthermore, parental knowledge was assessed by asking them to mark diagrams, tick keywords and provide free text answers. The duration of consultations was recorded and parent feedback collected. RESULTS: Parents and cardiologists both found the models to be very useful and helpful in engaging the parents in discussing congenital heart defects. Parental knowledge was not associated with their level of education (p=0.2) and did not improve following their visit. Consultations involving 3D models lasted on average 5 min longer (p=0.02). CONCLUSIONS: Patient-specific models can enhance engagement with parents and improve communication between cardiologists and parents, potentially impacting on parent and patient psychological adjustment following treatment. However, in the short-term, parental understanding of their child's condition did not improve. PMID- 25933811 TI - Why do smokers try to quit without medication or counselling? A qualitative study with ex-smokers. AB - OBJECTIVE: When tobacco smokers quit, between half and two-thirds quit unassisted: that is, they do not consult their general practitioner (GP), use pharmacotherapy (nicotine-replacement therapy, bupropion or varenicline), or phone a quitline. We sought to understand why smokers quit unassisted. DESIGN: Qualitative grounded theory study (in-depth interviews, theoretical sampling, concurrent data collection and data analysis). PARTICIPANTS: 21 Australian adult ex-smokers (aged 28-68 years; 9 males and 12 females) who quit unassisted within the past 6 months to 2 years. 12 participants had previous experience of using assistance to quit; 9 had never previously used assistance. SETTING: Community, Australia. RESULTS: Along with previously identified barriers to use of cessation assistance (cost, access, lack of awareness or knowledge of assistance, including misperceptions about effectiveness or safety), our study produced new explanations of why smokers quit unassisted: (1) they prioritise lay knowledge gained directly from personal experiences and indirectly from others over professional or theoretical knowledge; (2) their evaluation of the costs and benefits of quitting unassisted versus those of using assistance favours quitting unassisted; (3) they believe quitting is their personal responsibility; and (4) they perceive quitting unassisted to be the 'right' or 'better' choice in terms of how this relates to their own self-identity or self-image. Deep-rooted personal and societal values such as independence, strength, autonomy and self control appear to be influencing smokers' beliefs and decisions about quitting. CONCLUSIONS: The reasons for smokers' rejection of the conventional medical model for smoking cessation are complex and go beyond modifiable or correctable problems relating to misperceptions or treatment barriers. These findings suggest that GPs could recognise and respect smokers' reasons for rejecting assistance, validate and approve their choices, and modify brief interventions to support their preference for quitting unassisted, where preferred. Further research and translation may assist in developing such strategies for use in practice. PMID- 25933812 TI - Computer keyboarding biomechanics and acute changes in median nerve indicative of carpal tunnel syndrome. AB - BACKGROUND: Carpal tunnel syndrome is a common and costly peripheral neuropathy. Occupations requiring repetitive, forceful motions of the hand and wrist may play a role in the development of carpal tunnel syndrome. Computer keyboarding is one such task, and has been associated with upper-extremity musculoskeletal disorder development. The purpose of this study was to determine whether continuous keyboarding can cause acute changes in the median nerve and whether these changes correlate with wrist biomechanics during keyboarding. METHODS: A convenience sample of 37 healthy individuals performed a 60-minute typing task. Ultrasound images were collected at baseline, after 30 and 60 min of typing, then after 30 min of rest. Kinematic data were collected during the typing task. Variables of interest were median nerve cross-sectional area, flattening ratio, and swelling ratio at the pisiform; subject characteristics (age, gender, BMI, wrist circumference, typing speed) and wrist joint angles. FINDINGS: Cross-sectional area and swelling ratio increased after 30 and 60 min of typing, and then decreased to baseline after 30 min of rest. Peak ulnar deviation contributed to changes in cross-sectional area after 30 min of typing. INTERPRETATION: Results from this study confirmed a typing task causes changes in the median nerve, and changes are influenced by level of ulnar deviation. Furthermore, changes in the median nerve are present until cessation of the activity. While it is unclear if these changes lead to long-term symptoms or nerve injury, their existence adds to the evidence of a possible link between carpal tunnel syndrome and keyboarding. PMID- 25933813 TI - Fracture of the index sesamoid. A case report. PMID- 25933814 TI - An Homage to Understanding How Animals Function: The Knut Schmidt-Nielsen Lecture at IUPS 2017 in Rio de Janeiro. PMID- 25933815 TI - Living together in society. PMID- 25933816 TI - Understanding renal physiology leads to therapeutic advances in renal disease. PMID- 25933817 TI - Transforming medicine through physiology. PMID- 25933818 TI - Chronic renal ischemia in humans: can cell therapy repair the kidney in occlusive renovascular disease? AB - Occlusive renovascular disease caused by atherosclerotic renal artery stenosis (ARAS) elicits complex biological responses that eventually lead to loss of kidney function. Recent studies indicate a complex interplay of oxidative stress, endothelial dysfunction, and activation of fibrogenic and inflammatory cytokines as a result of atherosclerosis, hypoxia, and renal hypoperfusion in this disorder. Human studies emphasize the limits of the kidney adaptation to reduced blood flow, eventually leading to renal hypoxia with activation of inflammatory and fibrogenic pathways. Several randomized prospective clinical trials show that stent revascularization alone in patients with atherosclerotic renal artery stenosis provides little additional benefit to medical therapy once these processes have developed and solidified. Experimental data now support developing adjunctive cell-based measures to support angiogenesis and anti-inflammatory renal repair mechanisms. These data encourage the study of endothelial progenitor cells and/or mesenchymal stem/stromal cells for the repair of damaged kidney tissue. PMID- 25933819 TI - Macrophages in kidney injury, inflammation, and fibrosis. AB - Macrophages are found in normal kidney and in increased numbers in diseased kidney, where they act as key players in renal injury, inflammation, and fibrosis. Macrophages are highly heterogeneous cells and exhibit distinct phenotypic and functional characteristics in response to various stimuli in the local microenvironment in different types of kidney disease. In kidney tissue necrosis and/or infection, damage- and/or pathogen-associated molecular patterns induce pro-inflammatory macrophages, which contribute to further tissue injury, inflammation, and subsequent fibrosis. Apoptotic cells and anti-inflammatory factors in post-inflammatory tissues induced anti-inflammatory macrophages, which can mediate kidney repair and regeneration. This review summarizes the role of macrophages with different phenotypes in kidney injury, inflammation, and fibrosis in various acute and chronic kidney diseases. Understanding alterations of kidney microenvironment and the factors that control the phenotype and functions of macrophages may offer an avenue for the development of new cellular and cytokine/growth factor-based therapies as alternative treatment options for patients with kidney disease. PMID- 25933821 TI - Mitochondria, muscle health, and exercise with advancing age. AB - Skeletal muscle health is dependent on the optimal function of its mitochondria. With advancing age, decrements in numerous mitochondrial variables are evident in muscle. Part of this decline is due to reduced physical activity, whereas the remainder appears to be attributed to age-related alterations in mitochondrial synthesis and degradation. Exercise is an important strategy to stimulate mitochondrial adaptations in older individuals to foster improvements in muscle function and quality of life. PMID- 25933820 TI - Molecular pathways and therapies in autosomal-dominant polycystic kidney disease. AB - Autosomal-dominant polycystic kidney disease (ADPKD) is the most prevalent inherited renal disease, characterized by multiple cysts that can eventually lead to kidney failure. Studies investigating the role of primary cilia and polycystins have significantly advanced our understanding of the pathogenesis of PKD. This review will present clinical and basic aspects of ADPKD, review current concepts of PKD pathogenesis, evaluate potential therapeutic targets, and highlight challenges for future clinical studies. PMID- 25933823 TI - Ecophysiology of omega Fatty acids: a lid for every jar. AB - Omega fatty acids affect various physiological functions, such as locomotion, cardiac function, and thermogenesis. We highlight evidence from animal models that points to pathways by which specific omega fatty acids exert differential effects. We suggest that optimizing the omega fatty acid composition of tissues involves trade-offs between costs and benefits of specific fatty acids. PMID- 25933822 TI - Impact of maternal obesity on fetal programming of cardiovascular disease. AB - The in utero environment is a key determinant of long-term health outcomes; poor maternal metabolic state and placental insufficiency are strongly associated with these long-term health risks. Human epidemiological studies link maternal obesity and offspring cardiovascular disease in later life, but mechanistic studies in animal models are limited. Here, we review the literature pertaining to maternal consequences of obesity during pregnancy and the subsequent impact on fetal cardiovascular development. PMID- 25933824 TI - NOD-Like Receptors: Guardians of Intestinal Mucosal Barriers. AB - The NOD-like receptors (NLRs) are cytosolic pattern-recognition receptors, which are critically involved in mucosal immune defense. The association of the NLR, NOD2, with inflammatory bowel disease first pointed to the NLRs potential function as guardians of the intestinal barrier. Since then, several studies have emphasized the importance of NLRs in maintaining gut homeostasis and intestinal infections, and in shaping the microbiota. In this review, we will highlight the function of NLRs in intestinal inflammation. PMID- 25933825 TI - Haematological and biochemical reference intervals for three species of hydrophiine sea snakes (Hydrophis curtus, H. elegans and H. peronii) in Australia. AB - This study presents the first set of comprehensive reference intervals (RIs) for plasma biochemistry and haematology for three species of sea snakes common to the Indo-Pacific waters of Australia. In total 98 snakes, composed of Hydrophis curtus (n= 60), H. elegans (n = 27) and H. peronii (n = 11), were captured, clinically examined and had venous blood samples collected. All snakes were deemed healthy and in good to excellent body condition with snout to vent lengths of 40.7-73.9 cm (H. curtus), 68.9-131.4 cm (H. elegans) and 55.0-83.0 cm (H. peronii), respectively. Lymphocyte numbers, alkaline phosphatase, alanine aminotransferase, creatine kinase and lactate dehydrogenase levels were species dependent. All other parameters are presented as a single range for the three species. Gender ratio was evenly distributed for H. curtus and H. elegans, but 8/11 (73%) of H. peronii were males. No significant differences were detected between males and females for any of the measured blood parameters. Lymph contamination was considered and accounted for. Although only three species of sea snakes are represented in this study, the RIs generated may be useful in the clinical assessment of other sea snake species. PMID- 25933826 TI - Somatic cell count and milk neutrophil viability of dairy heifers with specific CXCR1 genotypes following experimental intramammary infection with Staphylococcus chromogenes originating from milk. AB - Previous observational studies suggest an association between polymorphism c.980A>G in the CXCR1 gene, encoding the chemokine (C-X-C motif) receptor 1, and the innate immunity and infection status of the mammary gland. Mammary glands of eight Holstein heifers were experimentally infected with a Staphylococcus chromogenes isolate originating from a chronic intramammary infection (IMI) to study differences between CXCR1 genotypes c.980AG and c.980GG. Quarters from heifers with genotypes c.980AG and c.980GG developed subclinical mastitis but showed differences in the early response at 6-18 h post challenge. Bacterial count at 18 h post challenge tended to be higher in quarters from c.980AG heifers compared to c.980GG heifers. Somatic cell count (SCC) was higher at 6 h post challenge and tended to be higher at 9 h post challenge in c.980AG heifers compared to c.980GG heifers. Milk production decreased similarly. Milk neutrophils of c.980AG heifers showed more apoptosis at 9 h post challenge and tended to show more necrosis at 6, 9 and 12 h post challenge than c.980GG heifers. Differences were less pronounced in the later stage (>18 h) of infection. The results demonstrate that CXCR1 polymorphism can influence SCC and milk neutrophil viability following experimental IMI. PMID- 25933827 TI - Llamas and alpacas in Europe: Endoparasites of the digestive tract and their pharmacotherapeutic control. AB - There are distinctive specifications for veterinary medical care of South American camelids (SACs), namely, llamas, alpacas, vicunas and guanacos. Camelids are classified as food-producing animals, but as veterinary medicinal products are often only licensed for domestic food-producing species such as horses, goats, sheep and cattle, treatment of SACs generally requires off-label use of drugs. Endoparasitism is a major health concern in camelids and can result in severe clinical diseases and economic losses. There is still a lack of work on the pharmacokinetics, safety and efficacy for most antiparasitic drugs used in SACs. Even when choosing an appropriate route of administration, several aspects must be considered such as the fact that pour-on formulations are largely ineffective in camelids due to the unique features of llama and alpaca skin and hair that result in extremely low drug bioavailability. This review focuses on the main endoparasites of the digestive tract in llamas and alpacas in Europe and pharmacotherapeutic options based on current knowledge. PMID- 25933828 TI - Advances in the understanding of the clinically relevant genetic pathways and molecular aspects of canine mammary tumours. Part 2: invasion, angiogenesis, metastasis and therapy. AB - Significant advances have been made recently in the understanding of the molecular events and critical pathways associated with and driving cancer of the mammary gland in humans and dogs. The study of canine mammary tumour biology, particularly the interactions of neoplastic cells with stromal and immune cells, is crucial for the development of novel effective therapeutic agents and strategies. This second part of a two-part review discusses some of the latest advances in the understanding of the clinically relevant genetic and molecular pathways involved in metastasis and in the interactions between tumour and stromal cells, including inflammatory and immune cells, cancer-associated fibroblasts, and endothelial cells. Recent experimental data on the role of matrix-degrading proteases and angiogenic factors are also discussed. Finally, the clinical utility of different non-surgical therapeutic modalities is reviewed. PMID- 25933829 TI - Novel treatment strategies for feline chronic kidney disease: A critical look at the potential of mesenchymal stem cell therapy. AB - Stem cell therapy is an innovative field of scientific investigation with tremendous potential for clinical application that holds promise for the treatment of a variety of diseases in veterinary medicine. Based on the known desirable properties of mesenchymal stem cells, the therapy has potential for treatment of both acute kidney injury and chronic kidney disease in cats. This review details terminology commonly used in this field of study, sources of mesenchymal stem cells and their proposed mechanism of action particularly as it relates to renal repair. Studies performed in rodent models of chronic kidney disease and feline clinical trial results are also summarized with the aim of providing an overview of the current status of this treatment modality and its potential for the future. PMID- 25933830 TI - Cell-specific uptake of mantle cell lymphoma-derived exosomes by malignant and non-malignant B-lymphocytes. AB - Mantle cell lymphoma (MCL) is an aggressive and incurable mature B cell neoplasm. The current treatments are based on chemotherapeutics and new class of drugs (e.g. Ibrutinib((r))), which in most cases ends with tumor resistance and relapse. Therefore, further development of novel therapeutic modalities is needed. Exosomes are natural extracellular vesicles, which play an important role in intercellular communication. The specificity of exosome uptake by different target cells remains unknown. In this study, we observed that MCL exosomes are taken up rapidly and preferentially by MCL cells. Only a minor fraction of exosomes was internalized into T-cell leukemia and bone marrow stroma cell lines, when these cells were co-cultured with MCL cells. Moreover, MCL patients' exosomes were taken up by both healthy and patients' B-lymphocytes with no apparent internalization to T lymphocytes and NK cells. Exosome internalization was not inhibited by specific siRNA against caveolin1 and clathrin but was found to be mediated by a cholesterol-dependent pathway. These findings demonstrate natural specificity of exosomes to B-lymphocytes and ultimately might be used for therapeutic intervention in B cells malignancies. PMID- 25933831 TI - How to discuss goals of care with patients. AB - Effective communication with patients and their caregivers continues to form the basis of a constructive clinician-patient relationship and is critical to provide patient-centered care. Engaging patients in meaningful, empathic communication not only fulfills an ethical imperative for our work as clinicians but also leads to increased patient satisfaction with their own care and improved clinical outcomes. While these same imperatives and benefits exist for discussing goals of care and end-of-life, communicating with patients about these topics can be particularly daunting. While clinicians receive extensive training on how to identify and treat illness, communication techniques, especially those centering around emotion-laden topics such as end-of-life care, receive short shrift medical education. Fortunately, communication techniques can be taught and learned through deliberate practice, and in this article, we seek to discuss a framework, drawn from published literature and our own experience, for approaching goals-of-care discussions in patients with cardiovascular disease. PMID- 25933832 TI - Plant phospholipase C family: Regulation and functional role in lipid signaling. AB - Phospholipase C (PLC), a major membrane phospholipid hydrolyzing enzyme generates signaling messengers such as diacylglycerol (DAG) and inositol 1,4,5 trisphosphate (IP3) in animals, and their phosphorylated forms such as phosphatidic acid (PA) and inositol hexakisphosphate (IP6) are thought to regulate various cellular processes in plants. Based on substrate specificity, plant PLC family is sub-divided into phosphatidylinositol-PLC (PI-PLC) and phosphatidylcholine-PLC (PC-PLC) groups. The activity of plant PLCs is regulated by various factors and the major ones include, Ca(2+) concentration, phospholipid substrate, post-translational modifications and interacting proteins. Most of the PLC members have been localized at the plasma membrane, suited for their function of membrane lipid hydrolysis. Several PLC members have been implicated in various cellular processes and signaling networks, triggered in response to a number of environmental cues and developmental events in different plant species, which makes them potential candidates for genetically engineering the crop plants for stress tolerance and enhancing the crop productivity. In this review article, we are focusing mainly on the plant PLC signaling and regulation, potential cellular and physiological role in different abiotic and biotic stresses, nutrient deficiency, growth and development. PMID- 25933834 TI - Invited Review Article: Error and uncertainty in Raman thermal conductivity measurements. AB - Error and uncertainty in Raman thermal conductivity measurements are investigated via finite element based numerical simulation of two geometries often employed Joule-heating of a wire and laser-heating of a suspended wafer. Using this methodology, the accuracy and precision of the Raman-derived thermal conductivity are shown to depend on (1) assumptions within the analytical model used in the deduction of thermal conductivity, (2) uncertainty in the quantification of heat flux and temperature, and (3) the evolution of thermomechanical stress during testing. Apart from the influence of stress, errors of 5% coupled with uncertainties of +/-15% are achievable for most materials under conditions typical of Raman thermometry experiments. Error can increase to >20%, however, for materials having highly temperature dependent thermal conductivities or, in some materials, when thermomechanical stress develops concurrent with the heating. A dimensionless parameter-termed the Raman stress factor-is derived to identify when stress effects will induce large levels of error. Taken together, the results compare the utility of Raman based conductivity measurements relative to more established techniques while at the same time identifying situations where its use is most efficacious. PMID- 25933835 TI - Continuous refractive index dispersion measurement based on derivative total reflection method. AB - Traditionally, continuous refractive index dispersion (CRID) measurement of materials with scattering is hard to realize. In this paper, CRID measurement based on the derivative total reflection method (CRIDM-DTRM) is proposed to measure the CRID of both absorption and scattering materials. It effectively determined the CRID of K9 glass, concentrated milk, and 0.5% methyl red solution in the 400-750 nm range with the spectral resolution of about 0.259 nm. For the first time, CRID of a scattering material is measured. CRIDM-DTRM is a useful technique in the field of RID measurement, especially for biotissues and anomalous dispersion materials. PMID- 25933833 TI - Phase 1 dose escalation trial of ilorasertib, a dual Aurora/VEGF receptor kinase inhibitor, in patients with hematologic malignancies. AB - BACKGROUND: Ilorasertib (ABT-348) is a novel inhibitor of Aurora kinase, vascular endothelial growth factor (VEGF) and platelet-derived growth factor receptors, and the Src families of tyrosine kinases. Ilorasertib alone or in combination with azacitidine demonstrated activity in preclinical models in various hematological malignancies, indicating that pan-Aurora kinase and multiple kinase inhibition may have preferential antileukemic activity. This phase 1 trial determined the safety, pharmacokinetics, and preliminary antitumor activity of ilorasertib alone or combined with azacitidine in advanced hematologic malignancies. PATIENTS AND METHODS: Fifty-two patients (median age, 67 years; 35 % with >4 prior regimens) with acute myelogenous leukaemia (AML; n = 38), myelodysplastic syndrome (n = 12), or chronic myelomonocytic leukaemia (n = 2) received 3 or 6 doses of ilorasertib per 28-day cycle and were assigned to arm A (once-weekly oral), B (twice-weekly oral), C (once-weekly oral plus azacitidine), or D (once-weekly intravenous) treatment. RESULTS: Maximum tolerated doses were not determined; the recommended phase 2 oral monotherapy doses were 540 mg once weekly and 480 mg twice weekly. The most common grade 3/4 adverse events were hypertension (28.8 %), hypokalemia (15.4 %), anemia (13.5 %), and hypophosphatemia (11.5 %). Oral ilorasertib pharmacokinetics appeared dose proportional, with a 15-hour half-life and no interaction with azacitidine. Ilorasertib inhibited biomarkers for Aurora kinase and VEGF receptors, and demonstrated clinical responses in 3 AML patients. CONCLUSIONS: Ilorasertib exhibited acceptable safety and pharmacokinetics at or below the recommended phase 2 dose, displayed evidence of dual Aurora kinase and VEGF receptor kinase inhibition, and activity in AML. PMID- 25933836 TI - Hard X-ray nanofocusing using adaptive focusing optics based on piezoelectric deformable mirrors. AB - An adaptive Kirkpatrick-Baez mirror focusing optics based on piezoelectric deformable mirrors was constructed at SPring-8 and its focusing performance characteristics were demonstrated. By adjusting the voltages applied to the deformable mirrors, the shape errors (compared to a target elliptical shape) were finely corrected on the basis of the mirror shape determined using the pencil beam method, which is a type of at-wavelength figure metrology in the X-ray region. The mirror shapes were controlled with a peak-to-valley height accuracy of 2.5 nm. A focused beam with an intensity profile having a full width at half maximum of 110 * 65 nm (V * H) was achieved at an X-ray energy of 10 keV. PMID- 25933837 TI - Fast wavelength calibration method for spectrometers based on waveguide comb optical filter. AB - A novel fast wavelength calibration method for spectrometers based on a standard spectrometer and a double metal-cladding waveguide comb optical filter (WCOF) is proposed and demonstrated. By using the WCOF device, a wide-spectrum beam is comb filtered, which is very suitable for spectrometer wavelength calibration. The influence of waveguide filter's structural parameters and the beam incident angle on the comb absorption peaks' wavelength and its bandwidth are also discussed. The verification experiments were carried out in the wavelength range of 200-1100 nm with satisfactory results. Comparing with the traditional wavelength calibration method based on discrete sparse atomic emission or absorption lines, the new method has some advantages: sufficient calibration data, high accuracy, short calibration time, fit for produce process, stability, etc. PMID- 25933838 TI - A fast determination method for transverse relaxation of spin-exchange-relaxation free magnetometer. AB - We propose a fast and accurate determination method for transverse relaxation of the spin-exchange-relaxation-free (SERF) magnetometer. This method is based on the measurement of magnetic resonance linewidth via a chirped magnetic field excitation and the amplitude spectrum analysis. Compared with the frequency sweeping via separate sinusoidal excitation, our method can realize linewidth determination within only few seconds and meanwhile obtain good frequency resolution. Therefore, it can avoid the drift error in long term measurement and improve the accuracy of the determination. As the magnetic resonance frequency of the SERF magnetometer is very low, we include the effect of the negative resonance frequency caused by the chirp and achieve the coefficient of determination of the fitting results better than 0.998 with 95% confidence bounds to the theoretical equation. The experimental results are in good agreement with our theoretical analysis. PMID- 25933839 TI - A recoil ion momentum spectrometer for molecular and atomic fragmentation studies. AB - We report the development and performance studies of a newly built recoil ion momentum spectrometer for the study of atomic and molecular fragmentation dynamics in gas phase upon the impact of charged particles and photons. The present design is a two-stage Wiley-McLaren type spectrometer which satisfies both time and velocity focusing conditions and is capable of measuring singly charged ionic fragments up-to 13 eV in all directions. An electrostatic lens has been introduced in order to achieve velocity imaging. Effects of the lens on time of-flight as well as on the position have been investigated in detail, both, by simulation and in experiment. We have used 120 keV proton beam on molecular nitrogen gas target. Complete momentum distributions and kinetic energy release distributions have been derived from the measured position and time-of-flight spectra. Along with this, the kinetic energy release spectra of fragmentation of doubly ionized nitrogen molecule upon various projectile impacts are presented. PMID- 25933840 TI - The discrete Fourier transform algorithm for determining decay constants Implementation using a field programmable gate array. AB - Cavity ringdown spectroscopy (CRDS) uses the exponential decay constant of light exiting a high-finesse resonance cavity to determine analyte concentration, typically via absorption. We present a high-throughput data acquisition system that determines the decay constant in near real time using the discrete Fourier transform algorithm on a field programmable gate array (FPGA). A commercially available, high-speed, high-resolution, analog-to-digital converter evaluation board system is used as the platform for the system, after minor hardware and software modifications. The system outputs decay constants at maximum rate of 4.4 kHz using an 8192-point fast Fourier transform by processing the intensity decay signal between ringdown events. We present the details of the system, including the modifications required to adapt the evaluation board to accurately process the exponential waveform. We also demonstrate the performance of the system, both stand-alone and incorporated into our existing CRDS system. Details of FPGA, microcontroller, and circuitry modifications are provided in the Appendix and computer code is available upon request from the authors. PMID- 25933841 TI - Laboratory-based X-ray reflectometer for multilayer characterization in the 15 150 keV energy band. AB - A laboratory-based X-ray reflectometer has been developed to measure the performance of hard X-ray multilayer coatings at their operational X-ray energies and incidence angles. The instrument uses a sealed-tube X-ray source with a tungsten anode that can operate up to 160 kV to provide usable radiation in the 15-150 keV energy band. Two sets of adjustable tungsten carbide slit assemblies, spaced 4.1 m apart, are used to produce a low-divergence white beam, typically set to 40 MUm * 800 MUm in size at the sample. Multilayer coatings under test are held flat using a vacuum chuck and are mounted at the center of a high-resolution goniometer used for precise angular positioning of the sample and detector; additionally, motorized linear stages provide both vertical and horizontal adjustments of the sample position relative to the incident beam. A CdTe energy sensitive detector, located behind a third adjustable slit, is used in conjunction with pulse-shaping electronics and a multi-channel analyzer to capture both the incident and reflected spectra; the absolute reflectance of the coating under test is computed as the ratio of the two spectra. The instrument's design, construction, and operation are described in detail, and example results are presented obtained with both periodic, narrow-band and depth-graded, wide band hard X-ray multilayer coatings. PMID- 25933842 TI - Pressure optimization of high harmonic generation in a differentially pumped Ar or H2 gas jet. AB - We experimentally studied the dependence of high harmonic generation in argon and molecular hydrogen on pressure changes in a gas jet that cause variations of the phase matching conditions and absorption. The study was performed at a peak laser intensity of ~1.5 * 10(14) W/cm(2). To enable measurements over a wide range of pressures, we employed differential pumping with an additional cell (~20 cm(3) volume) enclosing the gas jet. By increasing the pressure in the gas jet up to a maximum of 1.5 bars with argon or 0.5 bars with hydrogen, we observed an increase in the high harmonic (HH) yield until an optimum pressure of 0.2 bars was reached for Ar, beyond which the output began decreasing. For H2, we observed an increase of the HH output up to the maximum pressure of 0.5 bars. This pressure-dependence study allowed us to achieve a tenfold enhancement in the high harmonic yield at the optimum pressure. PMID- 25933843 TI - Study of non-contact measurement of the thermal expansion coefficients of materials based on laser feedback interferometry. AB - The noncooperative and ultrahigh sensitive length measurement approach is of great significance to the study of a high-precision thermal expansion coefficient (TEC) determination of materials at a wide temperature range. The novel approach is presented in this paper based on the Nd:YAG microchip laser feedback interferometry with 1064 nm wavelength, the beam frequency of which is shifted by a pair of acousto-optic modulators and then the heterodyne phase measurement technique is used. The sample is placed in a muffle furnace with two coaxial holes opened on the opposite furnace walls. The measurement beams are perpendicular and coaxial on each surface of the sample, the configuration which can not only achieve the length measurement of sample but also eliminate the influence of the distortion of the sample supporter. The reference beams inject on the reference mirrors which are put as possible as near the holes, respectively, to eliminate the air disturbances and the influence of thermal lens effect out of the furnace chamber. For validation, the thermal expansion coefficients of aluminum and steel 45 samples are measured from room temperature to 748 K, which proved measurement repeatability of TECs is better than 0.6 * 10( 6)(K(-1)) at the range of 298 K-598 K and the high-sensitive non-contact measurement of the low reflectivity surface induced by the oxidization of the samples at the range of 598 K-748 K. PMID- 25933844 TI - Photon-counting 1.0 GHz-phase-modulation fluorometer. AB - We have constructed an improved version of a photon-counting phase-modulation fluorometer (PC-PMF) with a maximum modulation frequency of 1.0 GHz, where a phase domain measurement is conducted with a time-correlated single-photon counting electronics. While the basic concept of the PC-PMF has been reported previously by one of the authors, little attention has been paid to its significance, other than its weak fluorescence measurement capability. Recently, we have recognized the importance of the PC-PMF and its potential for fluorescence lifetime measurements. One important aspect of the PC-PMF is that it enables us to perform high-speed measurements that exceed the frequency bandwidths of the photomultiplier tubes that are commonly used as fluorescence detectors. We describe the advantages of the PC-PMF and demonstrate its usefulness based on fundamental performance tests. In our new version of the PC PMF, we have used a laser diode (LD) as an excitation light source rather than the light-emitting diode that was used in the primary version. We have also designed a simple and stable LD driver to modulate the device. Additionally, we have obtained a sinusoidal histogram waveform that has multiple cycles within a time span to be measured, which is indispensable for precise phase measurements. With focus on the fluorescence intensity and the resolution time, we have compared the performance of the PC-PMF with that of a conventional PMF using the analogue light detection method. PMID- 25933845 TI - Determination of the solid angle and response function of a hemispherical spectrograph with injection lens for Auger electrons emitted from long lived projectile states. AB - We present SIMION 8.1 Monte Carlo type simulations of the response function and detection solid angle for long lived Auger states (lifetime tau ~ 10(-9) - 10(-5) s) recorded by a hemispherical spectrograph with injection lens and position sensitive detector used for high resolution Auger spectroscopy of ion beams. Also included in these simulations for the first time are kinematic effects particular to Auger emission from fast moving projectile ions such as line broadening and solid angle limitations allowing for a more accurate and realistic line shape modeling. Our results are found to be in excellent agreement with measured electron line shapes of both long lived 1s2s2p(4)P and prompt Auger projectile states formed by electron capture in collisions of 25.3 MeV F(7+) with H2 and 12.0 MeV C(4+) with Ne recorded at 0 degrees to the beam direction. These results are important for the accurate evaluation of the 1s2s2p (4)P/(2)P ratio of K-Auger cross sections whose observed non-statistical production by electron capture into He-like ions, recently a field of interesting interpretations, awaits further resolution. PMID- 25933846 TI - Development of a broadband reflectivity diagnostic for laser driven shock compression experiments. AB - A normal-incidence visible and near-infrared shock wave optical reflectivity diagnostic was constructed to investigate changes in the optical properties of materials under dynamic laser compression. Documenting wavelength- and time dependent changes in the optical properties of laser-shock compressed samples has been difficult, primarily due to the small sample sizes and short time scales involved, but we succeeded in doing so by broadening a series of time delayed 800 nm pulses from an ultrafast Ti:sapphire laser to generate high-intensity broadband light at nanosecond time scales. This diagnostic was demonstrated over the wavelength range 450-1150 nm with up to 16 time displaced spectra during a single shock experiment. Simultaneous off-normal incidence velocity interferometry (velocity interferometer system for any reflector) characterized the sample under laser-compression and also provided an independent reflectivity measurement at 532 nm wavelength. The shock-driven semiconductor-to-metallic transition in germanium was documented by the way of reflectivity measurements with 0.5 ns time resolution and a wavelength resolution of 10 nm. PMID- 25933847 TI - A self-injected, diode-pumped, solid-state ring laser for laser cooling of Li atoms. AB - We have constructed a solid-state light source for experiments with laser cooled lithium atoms based on a Nd:YVO4 ring laser with second-harmonic generation. Unidirectional lasing, an improved mode selection, and a high output power of the ring laser were achieved by weak coupling to an external cavity which contained the lossy elements required for single frequency operation. Continuous frequency tuning is accomplished by controlling two piezoelectric transducers (PZTs) in the internal and the external cavities simultaneously. The light source has been utilized to trap and cool fermionic lithium atoms into the quantum degenerate regime. PMID- 25933848 TI - Frequency chirped light at large detuning with an injection-locked diode laser. AB - We have developed a laser system to generate frequency-chirped light at rapid modulation speeds (~100 MHz) with a large frequency offset. Light from an external cavity diode laser with its frequency locked to an atomic resonance is passed through a lithium niobate electro-optical phase modulator. The phase modulator is driven by a ~6 GHz signal whose frequency is itself modulated with a RF MHz signal (<200 MHz). A second injection locked diode laser is used to filter out all of the light except the frequency-chirped +/-1 order by more than 30 dB. Using this system, it is possible to generate a 1 GHz frequency chirp in 5 ns. PMID- 25933849 TI - The development of a room temperature electron cyclotron resonance ion source (Lanzhou electron cyclotron resonance ion source No. 4) with evaporative cooling technology at Institute of Modern Physics. AB - LECR4 (Lanzhou electron cyclotron resonance ion source No. 4) has been successfully constructed at IMP and has also been connected with the Low Energy Beam Transport (LEBT) and Radio Frequency Quadrupole (RFQ) systems. These source magnet coils are cooled through evaporative cooling technology, which is the first attempt with an ECR ion source in the world. The maximum mirror field is 2.5 T (with iron plug) and the effective plasma chamber volume is 1.2 l. It was designed to be operated at 18 GHz and aimed to produce intense multiple charge state heavy ion beams for the linear injector project SSC-Linac at IMP. In February 2014, the first analyzed beam at 18 GHz was extracted. During about three months' commissioning, some outstanding results have been achieved, such as 1.97 emA of O(6+), 1.7 emA of Ar(8+), 1.07 emA of Ar(9+), and 118 euA of Bi(28+). The source has also successfully delivered O(5+) and Ar(8+) ion beams for RFQ commissioning in April 2014. This paper will give a brief overview of the design of LECR4. Then, the latest results of this source at 18 GHz will be presented. PMID- 25933850 TI - A multi-functional high voltage experiment apparatus for vacuum surface flashover switch research. AB - A multifunctional high voltage apparatus for experimental researches on surface flashover switch and high voltage insulation in vacuum has been developed. The apparatus is composed of five parts: pulse generating unit, axial field unit, radial field unit, and two switch units. Microsecond damped ringing pulse with peak-to-peak voltage 800 kV or unipolar pulse with maximum voltage 830 kV is generated, forming transient axial or radial electrical field. Different pulse waveforms and field distributions make up six experimental configurations in all. Based on this apparatus, preliminary experiments on vacuum surface flashover switch with different flashover dielectric materials have been conducted in the axial field unit, and nanosecond pulse is generated in the radial field unit which makes a pulse transmission line in the experiment. Basic work parameters of this kind of switch such as lifetime, breakdown voltage are obtained. PMID- 25933851 TI - Demonstration of the stabilization technique for nonplanar optical resonant cavities utilizing polarization. AB - Based on our previously developed scheme to stabilize nonplanar optical resonant cavities utilizing polarization caused by a geometric phase in electromagnetic waves traveling along a twisted path, we report an application of the technique for a cavity installed in the Accelerator Test Facility, a 1.3-GeV electron beam accelerator at KEK, in which photons are generated by laser-Compton scattering. We successfully achieved a power enhancement of 1200 with 1.4% fluctuation, which means that the optical path length of the cavity has been controlled with a precision of 14 pm under an accelerator environment. In addition, polarization switching utilizing a geometric phase of the nonplanar cavity was demonstrated. PMID- 25933852 TI - Design and testing of miniaturized plasma sensor for measuring hypervelocity impact plasmas. AB - An increasingly notable component of the space environment pertains to the impact of meteoroids and orbital debris on spacecraft and the resulting mechanical and electrical damages. Traveling at speeds of tens of km/s, when these particles, collectively referred to as hypervelocity particles, impact a satellite, they vaporize, ionize, and produce a radially expanding plasma that can generate electrically harmful radio frequency emission or serve as a trigger for electrostatic discharge. In order to measure the flux, composition, energy distribution, and temperature of ions and electrons in this plasma, a miniaturized plasma sensor has been developed for carrying out in-situ measurements in space. The sensor comprises an array of electrostatic analyzer wells split into 16 different channels, catering to different species and energy ranges in the plasma. We present results from numerical simulation based optimization of sensor geometry. A novel approach of fabricating the sensor using printed circuit boards is implemented. We also describe the test setup used for calibrating the sensor and show results demonstrating the energy band pass characteristics of the sensor. In addition to the hypervelocity impact plasmas, the plasma sensor developed can also be used to carry out measurements of ionospheric plasma, diagnostics of plasma propulsion systems, and in other space physics experiments. PMID- 25933853 TI - Practical method using superposition of individual magnetic fields for initial arrangement of undulator magnets. AB - We have developed a practical method for determining an excellent initial arrangement of magnetic arrays for a pure-magnet Halbach-type undulator. In this method, the longitudinal magnetic field distribution of each magnet is measured using a moving Hall probe system along the beam axis with a high positional resolution. The initial arrangement of magnetic arrays is optimized and selected by analyzing the superposition of all distribution data in order to achieve adequate spectral quality for the undulator. We applied this method to two elliptically polarizing undulators (EPUs), called U#16-2 and U#02-2, at the Photon Factory storage ring (PF ring) in the High Energy Accelerator Research Organization (KEK). The measured field distribution of the undulator was demonstrated to be excellent for the initial arrangement of the magnet array, and this method saved a great deal of effort in adjusting the magnetic fields of EPUs. PMID- 25933854 TI - A new Stark decelerator based surface scattering instrument for studying energy transfer at the gas-surface interface. AB - We report on the design and characterization of a new apparatus for performing quantum-state resolved surface scattering experiments. The apparatus combines optical state-specific molecule preparation with a compact hexapole and a Stark decelerator to prepare carrier gas-free pulses of quantum-state pure CO molecules with velocities controllable between 33 and 1000 m/s with extremely narrow velocity distributions. The ultrahigh vacuum surface scattering chamber includes homebuilt ion and electron detectors, a closed-cycle helium cooled single crystal sample mount capable of tuning surface temperature between 19 and 1337 K, a Kelvin probe for non-destructive work function measurements, a precision leak valve manifold for targeted adsorbate deposition, an inexpensive quadrupole mass spectrometer modified to perform high resolution temperature programmed desorption experiments and facilities to clean and characterize the surface. PMID- 25933855 TI - Sensitive fast electron spectrometer in adjustable triode configuration with pulsed tunable laser for research on photo-induced field emission cathodes. AB - We have completed an ultra-high vacuum system for sensitive fast electron spectroscopy from cold cathodes in triode configuration under high electric fields E (<100 MV/m) and pulsed tunable laser illumination (3.5 ns, 10 Hz, hnu = 0.5-5.9 eV, and 0.3-17 mJ). The cathodes are prepared and inserted under clean room conditions and can be precisely 3D-positioned, cooled or heated (77-400 K). Commissioning results with the upgraded system are presented. Field emission measurements with a W tip yielded an energy resolution of 14 meV at 4 eV pass energy and a precise determination of the emitter work function, size, and temperature. Photoemission spectroscopy of short electron bunches from a virgin and laser-ablated S-GaP crystal and quantum efficiency measurements revealed surface states, energy relaxation, and band structure effects. In conclusion, this novel system is ready now for the development and characterization of photo induced field emission cathodes. PMID- 25933856 TI - The design of a correlation electron cyclotron emission system on J-TEXT. AB - To study the anomalous transport, a correlation electron cyclotron emission (CECE) was planned to be developed on J-TEXT for electron temperature fluctuation measurement. The spectral decorrelation method was employed for the CECE system. It was developed based on the previous 16-channel electron cyclotron emission system. They shared the optical transmission line and mixer. The CECE part consists of 4 channels. Two fixed frequency narrow band filters were used for two channels and two yttrium iron garnet (YIG) filters for the other two channels. To meet the measuring requirement, some tests have been taken for the YIG filters. The results show good performance of the filters. Gaussian optics is used to produce a good poloidal resolution. Wavenumbers resolved by the CECE diagnostic are k(theta) <= 1.5 rad/cm and k(r) <= 12 rad/cm. Some preliminary experiment results are also presented in this paper. PMID- 25933857 TI - A compact broadband ion beam focusing device based on laser-driven megagauss thermoelectric magnetic fields. AB - Ultra-intense lasers can nowadays routinely accelerate kiloampere ion beams. These unique sources of particle beams could impact many societal (e.g., proton therapy or fuel recycling) and fundamental (e.g., neutron probing) domains. However, this requires overcoming the beam angular divergence at the source. This has been attempted, either with large-scale conventional setups or with compact plasma techniques that however have the restriction of short (<1 mm) focusing distances or a chromatic behavior. Here, we show that exploiting laser-triggered, long-lasting (>50 ps), thermoelectric multi-megagauss surface magnetic (B) fields, compact capturing, and focusing of a diverging laser-driven multi-MeV ion beam can be achieved over a wide range of ion energies in the limit of a 5 degrees acceptance angle. PMID- 25933858 TI - Simultaneous neutron and x-ray imaging of inertial confinement fusion experiments along a single line of sight at Omega. AB - Neutron and x-ray imaging provide critical information about the geometry and hydrodynamics of inertial confinement fusion implosions. However, existing diagnostics at Omega and the National Ignition Facility (NIF) cannot produce images in both neutrons and x-rays along the same line of sight. This leads to difficulty comparing these images, which capture different parts of the plasma geometry, for the asymmetric implosions seen in present experiments. Further, even when opposing port neutron and x-ray images are available, they use different detectors and cannot provide positive information about the relative positions of the neutron and x-ray sources. A technique has been demonstrated on implosions at Omega that can capture x-ray images along the same line of sight as the neutron images. The technique is described, and data from a set of experiments are presented, along with a discussion of techniques for coregistration of the various images. It is concluded that the technique is viable and could provide valuable information if implemented on NIF in the near future. PMID- 25933859 TI - Analysis and implementation of a space resolving spherical crystal spectrometer for x-ray Thomson scattering experiments. AB - The application of a space-resolving spectrometer to X-ray Thomson Scattering (XRTS) experiments has the potential to advance the study of warm dense matter. This has motivated the design of a spherical crystal spectrometer, which is a doubly focusing geometry with an overall high sensitivity and the capability of providing high-resolution, space-resolved spectra. A detailed analysis of the image fluence and crystal throughput in this geometry is carried out and analytical estimates of these quantities are presented. This analysis informed the design of a new spectrometer intended for future XRTS experiments on the Z machine. The new spectrometer collects 6 keV x-rays with a spherically bent Ge (422) crystal and focuses the collected x-rays onto the Rowland circle. The spectrometer was built and then tested with a foam target. The resulting high quality spectra prove that a spherical spectrometer is a viable diagnostic for XRTS experiments. PMID- 25933860 TI - Imaging polychromator for density measurements of polystyrene pellet cloud on the Large Helical Device. AB - Experimental data on spatial distributions of a pellet cloud electron density are necessary for the development of many applications of pellet injection, namely, plasma fuelling, discharge control, and plasma diagnostics. An improved approach of electron density measurements inside the cloud of a polystyrene pellet ablating in hot plasma of the large helical device is described. Density values of (1-30) * 10(16) cm(-3) depending on the background plasma parameters and distance from the solid pellet were measured. PMID- 25933861 TI - 1D fast coded aperture camera. AB - A fast (100 MHz) 1D coded aperture visible light camera has been developed as a prototype for imaging plasma experiments in the EUV/X-ray bands. The system uses printed patterns on transparency sheets as the masked aperture and an 80 channel photodiode array (9 V reverse bias) as the detector. In the low signal limit, the system has demonstrated 40-fold increase in throughput and a signal-to-noise gain of ~7 over that of a pinhole camera of equivalent parameters. In its present iteration, the camera can only image visible light; however, the only modifications needed to make the system EUV/X-ray sensitive are to acquire appropriate EUV/X-ray photodiodes and to machine a metal masked aperture. PMID- 25933862 TI - Interaction between periodic structures of object and X-ray standing wave generated by wavefront-division interferometer. AB - An x-ray imaging method that utilizes interaction between standing wave and periodic structure of object is proposed. When a periodic object is placed in a standing wave field, the interaction is modulated by relation between the periodic structure of object and the standing wave period. Then, the structure of object can be observed as a modulation of transmission image, and the existence of fine periodic structures can be detected with an imaging detector of low spatial resolution. Feasibility studies have been performed using a standing wave generated by a wavefront-division x-ray interferometer with refractive prism optics. PMID- 25933863 TI - A dedicated compression device for high resolution X-ray tomography of compressed gas diffusion layers. AB - We present an experimental approach to study the three-dimensional microstructure of gas diffusion layer (GDL) materials under realistic compression conditions. A dedicated compression device was designed that allows for synchrotron-tomographic investigation of circular samples under well-defined compression conditions. The tomographic data provide the experimental basis for stochastic modeling of nonwoven GDL materials. A plain compression tool is used to study the fiber courses in the material at different compression stages. Transport relevant geometrical parameters, such as porosity, pore size, and tortuosity distributions, are exemplarily evaluated for a GDL sample in the uncompressed state and for a compression of 30 vol.%. To mimic the geometry of the flow-field, we employed a compression punch with an integrated channel-rib-profile. It turned out that the GDL material is homogeneously compressed under the ribs, however, much less compressed underneath the channel. GDL fibers extend far into the channel volume where they might interfere with the convective gas transport and the removal of liquid water from the cell. PMID- 25933864 TI - Model based control of dynamic atomic force microscope. AB - A model-based robust control approach is proposed that significantly improves imaging bandwidth for the dynamic mode atomic force microscopy. A model for cantilever oscillation amplitude and phase dynamics is derived and used for the control design. In particular, the control design is based on a linearized model and robust H(infinity) control theory. This design yields a significant improvement when compared to the conventional proportional-integral designs and verified by experiments. PMID- 25933865 TI - An ultra-compact, high-throughput molecular beam epitaxy growth system. AB - We present a miniaturized molecular beam epitaxy (miniMBE) system with an outer diameter of 206 mm, optimized for flexible and high-throughput operation. The three-chamber system, used here for oxide growth, consists of a sample loading chamber, a storage chamber, and a growth chamber. The growth chamber is equipped with eight identical effusion cell ports with linear shutters, one larger port for either a multi-pocket electron beam evaporator or an oxygen plasma source, an integrated cryoshroud, retractable beam-flux monitor or quartz-crystal microbalance, reflection high energy electron diffraction, substrate manipulator, main shutter, and quadrupole mass spectrometer. The system can be combined with ultrahigh vacuum (UHV) end stations on synchrotron and neutron beamlines, or equivalently with other complex surface analysis systems, including low temperature scanning probe microscopy systems. Substrate handling is compatible with most UHV surface characterization systems, as the miniMBE can accommodate standard surface science sample holders. We introduce the design of the system, and its specific capabilities and operational parameters, and we demonstrate the epitaxial thin film growth of magnetoelectric Cr2O3 on c-plane sapphire and ferrimagnetic Fe3O4 on MgO (001). PMID- 25933866 TI - Novel experimental design for high pressure-high temperature electrical resistance measurements in a "Paris-Edinburgh" large volume press. AB - We present a novel experimental design for high sensitivity measurements of the electrical resistance of samples at high pressures (0-6 GPa) and high temperatures (300-1000 K) in a "Paris-Edinburgh" type large volume press. Uniquely, the electrical measurements are carried out directly on a small sample, thus greatly increasing the sensitivity of the measurement. The sensitivity to even minor changes in electrical resistance can be used to clearly identify phase transitions in material samples. Electrical resistance measurements are relatively simple and rapid to execute and the efficacy of the present experimental design is demonstrated by measuring the electrical resistance of Pb, Sn, and Bi across a wide domain of temperature-pressure phase space and employing it to identify the loci of phase transitions. Based on these results, the phase diagrams of these elements are reconstructed to high accuracy and found to be in excellent agreement with previous studies. In particular, by mapping the locations of several well-studied reference points in the phase diagram of Sn and Bi, it is demonstrated that a standard calibration exists for the temperature and pressure, thus eliminating the need for direct or indirect temperature and pressure measurements. The present technique will allow simple and accurate mapping of phase diagrams under extreme conditions and may be of particular importance in advancing studies of liquid state anomalies. PMID- 25933867 TI - Practical uncertainty reduction and quantification in shock physics measurements. AB - We report the development of a simple error analysis sampling method for identifying intersections and inflection points to reduce total uncertainty in experimental data. This technique was used to reduce uncertainties in sound speed measurements by 80% over conventional methods. Here, we focused on its impact on a previously published set of Mo sound speed data and possible implications for phase transition and geophysical studies. However, this technique's application can be extended to a wide range of experimental data. PMID- 25933868 TI - Automatized and desktop AC-susceptometer for the in situ and real time monitoring of magnetic nanoparticles' synthesis by coprecipitation. AB - The main purpose of this work was to design, develop, and construct a simple desktop AC susceptometer to monitor in situ and in real time the coprecipitation synthesis of magnetic nanoparticles. The design incorporates one pair of identical pick-up sensing coils and one pair of Helmholtz coils. The picked up signal is detected by a lock-in SR850 amplifier that measures the in- and out-of phase signals. The apparatus also includes a stirrer with 45 degrees -angle blades to promote the fast homogenization of the reaction mixture. Our susceptometer has been successfully used to monitor the coprecipitation reaction for the synthesis of iron oxide nanoparticles. PMID- 25933869 TI - Space charge distributions in insulating polymers: A new non-contacting way of measurement. AB - A new technique for the determination of space charge profiles in insulating polymers is proposed. Based on the evolution of an existing thermal wave technique called Focused Laser Intensity Modulation Method ((F)LIMM), it allows non-contact measurements on thin films exhibiting an internal charge to be studied. An electrostatic model taking into account the new sample-cell geometry proposed was first developed. It has been shown, in particular, that it was theoretically possible to calculate the internal charge from experimental measurements while allowing an evaluation of the air layer appearing between the sample and the electrode when non-contact measurements are performed. These predictions were confirmed by an experimental implementation for two thin polymer samples (25 MUm-polyvinylidenefluoride and 50 MUm-polytetrafluoroethylene (PTFE)) used as tests. In these cases, minimum air-layer thickness was determined with an accuracy of 3% and 20%, respectively, depending on the signal-to-noise ratio during the experimental procedure. In order to illustrate the reachable possibilities of this technique, 2D and 3D cartographies of a negative space charge implanted by electron beam within the PTFE test sample were depicted: like in conventional (F)LIMM, a multidimensional representation of a selectively implanted charge remains possible at a few microns depth, but using a non contacting way of measurement. PMID- 25933870 TI - A high pressure x-ray photoelectron spectroscopy experimental method for characterization of solid-liquid interfaces demonstrated with a Li-ion battery system. AB - We report a methodology for a direct investigation of the solid/liquid interface using high pressure x-ray photoelectron spectroscopy (HPXPS). The technique was demonstrated with an electrochemical system represented by a Li-ion battery using a silicon electrode and a liquid electrolyte of LiClO4 in propylene carbonate (PC) cycled versus metallic lithium. For the first time the presence of a liquid electrolyte was realized using a transfer procedure where the sample was introduced into a 2 mbar N2 environment in the analysis chamber without an intermediate ultrahigh vacuum (UHV) step in the load lock. The procedure was characterized in detail concerning lateral drop gradients as well as stability of measurement conditions over time. The X-ray photoelectron spectroscopy (XPS) measurements demonstrate that the solid substrate and the liquid electrolyte can be observed simultaneously. The results show that the solid electrolyte interphase (SEI) composition for the wet electrode is stable within the probing time and generally agrees well with traditional UHV studies. Since the methodology can easily be adjusted to various high pressure photoelectron spectroscopy systems, extending the approach towards operando solid/liquid interface studies using liquid electrolytes seems now feasible. PMID- 25933871 TI - Development of nanosecond time-resolved infrared detection at the LEAF pulse radiolysis facility. AB - When coupled with transient absorption spectroscopy, pulse radiolysis, which utilizes high-energy electron pulses from an accelerator, is a powerful tool for investigating the kinetics and thermodynamics of a wide range of radiation induced redox and electron transfer processes. The majority of these investigations detect transient species in the UV, visible, or near-IR spectral regions. Unfortunately, the often-broad and featureless absorption bands in these regions can make the definitive identification of intermediates difficult. Time resolved vibrational spectroscopy would offer much improved structural characterization, but has received only limited application in pulse radiolysis. In this paper, we describe in detail the development of a unique nanosecond time resolved infrared (TRIR) detection capability for condensed-phase pulse radiolysis on a new beam line at the LEAF facility of Brookhaven National Laboratory. The system makes use of a suite of high-power, continuous wave external-cavity quantum cascade lasers as the IR probe source, with coverage from 2330 to 1051 cm(-1). The response time of the TRIR detection setup is ~40 ns, with a typical sensitivity of ~100 MUOD after 4-8 signal averages using a dual beam probe/reference normalization detection scheme. This new detection method has enabled mechanistic investigations of a range of radiation-induced chemical processes, some of which are highlighted here. PMID- 25933872 TI - Proposed linear energy transfer areal detector for protons using radiochromic film. AB - Radiation therapy depends on predictably and reliably delivering dose to tumors and sparing normal tissues. Protons with kinetic energy of a few hundred MeV can selectively deposit dose to deep seated tumors without an exit dose, unlike x rays. The better dose distribution is attributed to a phenomenon known as the Bragg peak. The Bragg peak is due to relatively high energy deposition within a given distance or high Linear Energy Transfer (LET). In addition, biological response to radiation depends on the dose, dose rate, and localized energy deposition patterns or LET. At present, the LET can only be measured at a given fixed point and the LET spatial distribution can only be inferred from calculations. The goal of this study is to develop and test a method to measure LET over extended areas. Traditionally, radiochromic films are used to measure dose distribution but not for LET distribution. We report the first use of these films for measuring the spatial distribution of the LET deposited by protons. The radiochromic film sensitivity diminishes for large LET. A mathematical model correlating the film sensitivity and LET is presented to justify relating LET and radiochromic film relative sensitivity. Protons were directed parallel to radiochromic film sandwiched between solid water slabs. This study proposes the scaled-normalized difference (SND) between the Treatment Planning system (TPS) and measured dose as the metric describing the LET. The SND is correlated with a Monte Carlo (MC) calculation of the LET spatial distribution for a large range of SNDs. A polynomial fit between the SND and MC LET is generated for protons having a single range of 20 cm with narrow Bragg peak. Coefficients from these fitted polynomial fits were applied to measured proton dose distributions with a variety of ranges. An identical procedure was applied to the protons deposited from Spread Out Bragg Peak and modulated by 5 cm. Gamma analysis is a method for comparing the calculated LET with the LET measured using radiochromic film at the pixel level over extended areas. Failure rates using gamma analysis are calculated for areas in the dose distribution using parameters of 25% of MC LET and 3 mm. The processed dose distributions find 5%-10% failure rates for the narrow 12.5 and 15 cm proton ranges and 10%-15% for proton ranges of 15, 17.5, and 20 cm and modulated by 5 cm. It is found through gamma analysis that the measured proton energy deposition in radiochromic film and TPS can be used to determine LET. This modified film dosimetry provides an experimental areal LET measurement that can verify MC calculations, support LET point measurements, possibly enhance biologically based proton treatment planning, and determine the polymerization process within the radiochromic film. PMID- 25933873 TI - A self-analyzing double-loop digital controller in laser frequency stabilization for inter-satellite laser ranging. AB - We present a digital controller specially designed for laser frequency stabilization in the application of inter-satellite laser ranging. The prototype of controller is developed using field programmable gate arrays programmed with National Instruments LabVIEW software. The controller is flexible, self analyzing, and easily optimized with build-in system analysis. Application and performance of the controller to a laser frequency stabilization system designed for spaceborne scientific missions are demonstrated. PMID- 25933874 TI - Magnetic tweezers with high permeability electromagnets for fast actuation of magnetic beads. AB - As a powerful and versatile scientific instrument, magnetic tweezers have been widely used in biophysical research areas, such as mechanical cell properties and single molecule manipulation. If one wants to steer bead position, the nonlinearity of magnetic properties and the strong position dependence of the magnetic field in most magnetic tweezers lead to quite a challenge in their control. In this article, we report multi-pole electromagnetic tweezers with high permeability cores yielding high force output, good maneuverability, and flexible design. For modeling, we adopted a piece-wise linear dependence of magnetization on field to characterize the magnetic beads. We implemented a bi-linear interpolation of magnetic field in the work space, based on a lookup table obtained from finite element simulation. The electronics and software were custom made to achieve high performance. In addition, the effects of dimension and defect on structure of magnetic tips also were inspected. In a workspace with size of 0.1 * 0.1 mm(2), a force of up to 400 pN can be applied on a 2.8 MUm superparamagnetic bead in any direction within the plane. Because the magnetic particle is always pulled towards a tip, the pulling forces from the pole tips have to be well balanced in order to achieve control of the particle's position. Active video tracking based feedback control is implemented, which is able to work at a speed of up to 1 kHz, yielding good maneuverability of the magnetic beads. PMID- 25933875 TI - Simultaneous and accurate measurement of the dielectric constant at many frequencies spanning a wide range. AB - We present an innovative technique which allows the simultaneous measurement of the dielectric constant of a material at many frequencies, spanning a four orders of magnitude range chosen between 10(-2) Hz and 10(4) Hz. The sensitivity and accuracy are comparable to those obtained using standard single frequency techniques. The technique is based on three new and simple features: (a) the precise real time correction of the amplification of a current amplifier, (b) the specific shape of the excitation signal and its frequency spectrum, and (c) the precise synchronization between the generation of the excitation signal and the acquisition of the dielectric response signal. This technique is useful in the case of relatively fast dynamical measurements when the knowledge of the time evolution of the dielectric constant is needed. PMID- 25933876 TI - A broadband single-chip transceiver for multi-nuclear NMR probes. AB - In this article, we present an integrated broadband complementary metal-oxide semiconductor single-chip transceiver suitable for the realization of multi nuclear pulsed nuclear magnetic resonance (NMR) probes. The realized single-chip transceiver can be interfaced with on-chip integrated microcoils or external LC resonators operating in the range from 1 MHz to 1 GHz. The dimension of the chip is about 1 mm(2). It consists of a radio-frequency (RF) power amplifier, a low noise RF preamplifier, a frequency mixer, an audio-frequency amplifier, and fully integrated transmit-receive switches. As specific example, we show its use for multi-nuclear NMR spectroscopy. With an integrated coil of about 150 MUm external diameter, a (1)H spin sensitivity of about 1.5 * 10(13) spins/Hz(1/2) is achieved at 7 T. PMID- 25933877 TI - Research of 100 MHz ultra-low-jitter clock generating circuit. AB - Jitter which quantifies the quality of a clock is an important specification. It is of great significance for an electronic system. To obtain a good signal-to noise ratio for sampling systems, there must be clocks with low jitter performances. By using the relationship between jitter and phase noise, the 100 MHz clock generating circuit with ultra-low jitter and phase noise characteristics are studied in this paper. Bipolar junction transistor with low noise figure and low corner frequency should be selected. Inductance and capacitance in the feedback circuit are obviously the main contributions to the jitter. Impacts of the loaded quality factor (Q(L)) of the circuit on the jitter are analyzed, and the explicit expression for the jitter based on circuit components is derived as well. The simulation and experiment results are proved to show that the jitter and phase noise characteristics can be improved by increasing Q(L) of the circuit. PMID- 25933878 TI - Using time-frequency analysis to determine time-resolved detonation velocity with microwave interferometry. AB - Two time-frequency analysis methods based on the short-time Fourier transform (STFT) and continuous wavelet transform (CWT) were used to determine time resolved detonation velocities with microwave interferometry (MI). The results were directly compared to well-established analysis techniques consisting of a peak-picking routine as well as a phase unwrapping method (i.e., quadrature analysis). The comparison is conducted on experimental data consisting of transient detonation phenomena observed in triaminotrinitrobenzene and ammonium nitrate-urea explosives, representing high and low quality MI signals, respectively. Time-frequency analysis proved much more capable of extracting useful and highly resolved velocity information from low quality signals than the phase unwrapping and peak-picking methods. Additionally, control of the time frequency methods is mainly constrained to a single parameter which allows for a highly unbiased analysis method to extract velocity information. In contrast, the phase unwrapping technique introduces user based variability while the peak picking technique does not achieve a highly resolved velocity result. Both STFT and CWT methods are proposed as improved additions to the analysis methods applied to MI detonation experiments, and may be useful in similar applications. PMID- 25933879 TI - Pulse-forming-line based on-chip short pulse generator. AB - A traditional pulse generation circuit based on the pulse-forming-line (PFL) is implemented in a commercial 0.13 MUm digital CMOS technology. A meandered on-chip coplanar waveguide is used as the PFL, and CMOS transistor is used as switch in the Cadence Spectre simulation. The circuit sample is fabricated and tested. Pulses of ~170 ps durations and 120-200 mV amplitudes are obtained when the power supply is tuned from 1.2 V to 2 V. The results show that the traditional PFL based circuit can be implemented in standard CMOS technology for on-chip short pulse generation. Furthermore, the PFL circuits significantly extend the short pulse generation capabilities of CMOS technology. PMID- 25933880 TI - Modular high-voltage bias generator powered by dual-looped self-adaptive wireless power transmission. AB - We proposed a modular high-voltage (HV) bias generator powered by a novel transmitter-sharing inductive coupled wireless power transmission technology, aimed to extend the generator's flexibility and configurability. To solve the problems caused through an uncertain number of modules, a dual-looped self adaptive control method is proposed that is capable of tracking resonance frequency while maintaining a relatively stable induction voltage for each HV module. The method combines a phase-locked loop and a current feedback loop, which ensures an accurate resonance state and a relatively constant boost ratio for each module, simplifying the architecture of the boost stage and improving the total efficiency. The prototype was built and tested. The input voltage drop of each module is less than 14% if the module number varies from 3 to 10; resonance tracking is completed within 60 ms. The efficiency of the coupling structure reaches up to 95%, whereas the total efficiency approaches 73% for a rated output. Furthermore, this technology can be used in various multi-load wireless power supply applications. PMID- 25933881 TI - Super-resolution spectral estimation in short-time non-contact vital sign measurement. AB - Non-contact techniques for measuring vital signs attract great interest due to the benefits shown in medical monitoring, military application, etc. However, the presence of respiration harmonics caused by nonlinear phase modulation will result in performance degradation. Suffering from smearing and leakage problems, conventional discrete Fourier transform (DFT) based methods cannot distinguish the heartbeat component from closely located respiration harmonics in frequency domain, especially in short-time processing. In this paper, the theory of sparse reconstruction is merged with an extended harmonic model of vital signals, aiming at achieving a super-resolution spectral estimation of vital signals by additionally exploiting the inherent sparse prior information. Both simulated and experimental results show that the proposed algorithm has superior performance to DFT-based methods and the recently applied multiple signal classification algorithm, and the required processing window length has been shortened to 5.12 s. PMID- 25933882 TI - Automated setup for magnetic hysteresis characterization based on a voltage controlled current source with 500 kHz full power bandwidth and 10 A peak-to-peak current. AB - This paper describes the design of a system for the characterization of magnetic hysteresis behavior in soft ferrite magnetic cores. The proposed setup can test magnetic materials exciting them with controlled arbitrary magnetic field waveforms, including the capability of providing a DC bias, in a frequency bandwidth up to 500 kHz, with voltages up to 32 V peak-to-peak, and currents up to 10 A peak-to-peak. In order to have an accurate control of the magnetic field waveform, the system is based on a voltage controlled current source. The electronic design is described focusing on closed loop feedback stabilization and passive components choice. The system has real-time hysteretic loop acquisition and visualization. The comparisons between measured hysteresis loops of sample magnetic materials and datasheet available ones are shown. Results showing frequency and thermal behavior of the hysteresis of a test sample prove the system capabilities. Moreover, the B-H loops obtained with a multiple waveforms excitation signal, including DC bias, are reported. The proposal is a low-cost and replicable solution for hysteresis characterization of magnetic materials used in power electronics. PMID- 25933883 TI - A four-probe thermal transport measurement method for nanostructures. AB - Several experimental techniques reported in recent years have enabled the measurement of thermal transport properties of nanostructures. However, eliminating the contact thermal resistance error from the measurement results has remained a critical challenge. Here, we report a different four-probe measurement method that can separately obtain both the intrinsic thermal conductance and the contact thermal resistance of individual nanostructures. The measurement device consists of four microfabricated, suspended metal lines that act as resistive heaters and thermometers, across which the nanostructure sample is assembled. The method takes advantage of the variation in the heat flow along the suspended nanostructure and across its contacts to the four suspended heater and thermometer lines, and uses sixteen sets of temperature and heat flow measurements to obtain nine of the thermal resistances in the measurement device and the nanostructure sample, including the intrinsic thermal resistance and the two contact thermal resistances to the middle suspended segment of the nanostructure. Two single crystalline Si nanowires with different cross sections are measured in this work to demonstrate the effectiveness of the method. This four-probe thermal transport measurement method can lead to future discoveries of unique size-dependent thermal transport phenomena in nanostructures and low dimensional materials, in addition to providing reliable experimental data for calibrating theoretical models. PMID- 25933884 TI - Non-intrusive, high-resolution, real-time, two-dimensional imaging of multiphase materials using acoustic array sensors. AB - Two parallel multi-element ultrasonic acoustic arrays combined with sets of focal laws for acoustic signal generation and a classical tomographic inversion algorithm are used to generate real-time two-dimensional micro seismic acoustic images of multiphase materials. Proof of concept and calibration measurements were performed for single phase and two phase liquids, uniform polyvinyl chloride (PVC) plates, and aluminum cylinders imbedded in PVC plates. Measurement artefacts, arising from the limited range of viewing angles, and the compromise between data acquisition rate and image quality are discussed. The angle range of scanning and the image resolution were varied, and the effects on the quality of the reproduction of the speed of sound profiles of model solids and liquids with known geometries and compositions were analysed in detail. The best image quality results were obtained for a scanning angle range of [-35 degrees , 35 degrees ] at a step size of 2.5 degrees post processed to generate images on a 40 MUm square grid. The data acquisition time for high quality images with a 30 mm * 40 mm view field is 10 min. Representation of two-phase solids with large differences in speed of sound between phases and where one phase is dispersed in the form of macroscopic objects (greater than 1 mm in diameter) proved to be the most difficult to image accurately. Liquid-liquid and liquid-vapor phase boundaries, in micro porous solids by contrast, were more readily defined. Displacement of air by water and water by heptane in natural porous limestone provides illustrative kinetic examples. Measurement results with these realistic cases demonstrate the feasibility of the technique to monitor in real time and on the micrometer length scale local composition and flow of organic liquids in inorganic porous media, one of many envisioned engineering applications. Improvement of data acquisition rate is an area for future collaborative study. PMID- 25933885 TI - Compact sound-speed sensor for quartz enhanced photoacoustic spectroscopy based applications. AB - A compact sound-speed sensor based on a phase difference method was developed. The sensor employs a U-shaped stainless steel tube with two holes located on its front and back ends, which serves as a sound wave guide. The phase difference between the two holes was measured using two mini-microphones by means of a phase sensitive detection technique. This method offers the advantage of eliminating the influence of signal fluctuations. The frequency of a sound source offered by a loudspeaker can be scanned between 1 kHz and 50 kHz. The slope of the phase difference as a function of frequency was obtained by scanning the frequency of the sound source. The speed of sound was retrieved from the rate of change of the phase difference. The performance of the sensor was evaluated over a wide range of speeds of sound from 260 m/s to 1010 m/s in different gas mixtures. The measured speed of sound was found to be in good agreement with the theoretical value for the sound-speed sensor. PMID- 25933886 TI - Rapid and noncontact photoacoustic tomography imaging system using an interferometer with high-speed phase modulation technique. AB - We designed, fabricated, and tested a rapid and noncontact photoacoustic tomography (PAT) imaging system using a low-coherence interferometer with high speed phase modulation technique. Such a rapid and noncontact probing system can greatly decrease the time of imaging. The proposed PAT imaging system is experimentally verified by capturing images of a simulated tissue sample and the blood vessels within the ear flap of a mouse (pinna) in vivo. The axial and lateral resolutions of the system are evaluated at 45 and ~15 MUm, respectively. The imaging depth of the system is 1 mm in a special phantom. Our results show that the proposed system opens a promising way to realize noncontact, real-time PAT. PMID- 25933887 TI - Thermal reactive ion etching technique involving use of self-heated cathode. AB - In this work, the thermal reactive ion etching (TRIE) technique for etching hard to-etch materials is presented. The TRIE technique employs a self-heated cathode and a thermally insulated aluminum plate is placed on the cathode of a regular reactive ion etching (RIE) system. By optimizing the beam size to support the sample stage, the temperature of the stage can be increased to a desired temperature without a cathode heater. The technique was used to etch a bulk titanium plate. An etch rate of 0.6 MUm/min and an etch selectivity to nickel of 100 were achieved with SF6 plasma. The proposed technique makes a regular RIE system a more powerful etcher without the use of chlorine gas, a cathode heater, and an inductively coupled plasma source. PMID- 25933888 TI - Design and experimental tests of a dual-servo piezoelectric nanopositioning stage for rotary motion. AB - A dual-servo nanopositioning stage for high-accuracy rotary motion is presented in this article. A piezoelectric actuator is employed to achieve both the coarse motion and fine motion. By the coarse motion and fine motion, the designed dual servo nanopositioning stage can obtain large-range rotary motion and high resolution simultaneously. The configuration and motion principle of the dual servo nanopositioning stage were illustrated and discussed. A prototype was fabricated to test the working performance and the results demonstrate that the maximum speed of the presented dual-servo nanopositioning stage is 32,000 MUrad/s and the rotary resolution is about 1.54 MUrad. The working performance confirms the feasibility of the dual-servo nanopositioning stage. PMID- 25933889 TI - Pd/Ag coated fiber Bragg grating sensor for hydrogen monitoring in power transformers. AB - Compared with conventional DGA (dissolved gas analysis) method for on-line monitoring of power transformers, FBG (fiber Bragg grating) hydrogen sensor represents marked advantages over immunity to electromagnetic field, time-saving, and convenience to defect location. Thus, a novel FBG hydrogen sensor based on Pd/Ag (Palladium/Silver) along with polyimide composite film to measure dissolved hydrogen concentration in large power transformers is proposed in this article. With the help of Pd/Ag composite coating, the enhanced performance on mechanical strength and sensitivity is demonstrated, moreover, the response time and sensitivity influenced by oil temperature are solved by correction lines. Sensitivity measurement and temperature calibration of the specific hydrogen sensor have been done respectively in the lab. And experiment results show a high sensitivity of 0.055 pm/(MUl/l) with instant response time about 0.4 h under the typical operating temperature of power transformers, which proves a potential utilization inside power transformers to monitor the health status by detecting the dissolved hydrogen concentration. PMID- 25933890 TI - A beam-membrane structure micromachined differential pressure flow sensor. AB - A beam-membrane structure micromachined flow sensor is designed, depending on the principle of differential pressure caused by the mass flow, which is directly proportional to the square flow rate. The FSI (fluid structure interaction) characteristics of the differential pressure flow sensor are investigated via numerical analysis and analog simulation. The working mechanism of the flow sensor is analyzed depending on the FSI results. Then, the flow sensor is fabricated and calibrated. The calibration results show that the beam-membrane structure differential pressure flow sensor achieves ideal static characteristics and works well in the practical applications. PMID- 25933891 TI - A phase match based frequency estimation method for sinusoidal signals. AB - Accurate frequency estimation affects the ranging precision of linear frequency modulated continuous wave (LFMCW) radars significantly. To improve the ranging precision of LFMCW radars, a phase match based frequency estimation method is proposed. To obtain frequency estimation, linear prediction property, autocorrelation, and cross correlation of sinusoidal signals are utilized. The analysis of computational complex shows that the computational load of the proposed method is smaller than those of two-stage autocorrelation (TSA) and maximum likelihood. Simulations and field experiments are performed to validate the proposed method, and the results demonstrate the proposed method has better performance in terms of frequency estimation precision than methods of Pisarenko harmonic decomposition, modified covariance, and TSA, which contribute to improving the precision of LFMCW radars effectively. PMID- 25933892 TI - The experimental setup of the Interaction in Crystals for Emission of RADiation collaboration at Mainzer Mikrotron: Design, commissioning, and tests. AB - Silicon/germanium flat/bent crystals are thin devices able to efficiently deflect charged particle GeV-energy beams up to a few hundreds of MUrad; moreover, high intensity photons can be efficiently produced in the so-called Multi-Volume Reflection (MVR) and Multiple Volume Reflections in One Crystal (MVROC) conditions. In the last years, the research interest in this field has moved to the dynamic studies of light negative leptons in the low energy range: the possibility to deflect negative particles and to produce high intensity gamma sources via the coherent interactions with crystals in the sub-GeV energy range has been proved by the ICE-RAD (Interaction in Crystals for Emission of RADiation) Collaboration at the MAinzer MIkrotron (MAMI, Germany). This paper describes the setup used by the ICE-RAD experiment for the crystals characterization (both in terms of deflection and radiation emission properties): a high precision goniometer is used to align the crystals with the incoming beam, while a silicon based profilometer and an inorganic scintillator reconstruct, respectively, the particle position and the photon spectra after the samples. The crystals manufacturing process and their characterization, the silicon profilometer commissioning at the CERN PS T9 beamline, and the commissioning of the whole setup installed at MAMI are presented. PMID- 25933893 TI - Measurement and simulation of thermoelectric efficiency for single leg. AB - Thermoelectric efficiency measurements were carried out on n-type bismuth telluride legs with the hot-side temperature at 100 and 150 degrees C. The electric power and heat flow were measured individually. Water coolant was utilized to maintain the cold-side temperature and to measure heat flow out of the cold side. Leg length and vacuum pressure were studied in terms of temperature difference across the leg, open-circuit voltage, internal resistance, and heat flow. Finite-element simulation on thermoelectric generation was performed in COMSOL Multiphysics, by inputting two-side temperatures and thermoelectric material properties. The open-circuit voltage and resistance were in good agreement between the measurement and simulation. Much larger heat flows were found in measurements, since they were comprised of conductive, convective, and radiative contributions. Parasitic heat flow was measured in the absence of bismuth telluride leg, and the conductive heat flow was then available. Finally, the maximum thermoelectric efficiency was derived in accordance with the electric power and the conductive heat flow. PMID- 25933894 TI - Design and verification of a novel hollow vibrating module for laser machining. AB - If a vibration module is added on laser machining system, the quality of surface finish and aspect ratio on metals can be significantly enhanced. In this study, a single mobility model of vibrating laser along the path of laser beam was put forward. In order to realize the desired unidirectional motion, a resonance type vibration module with optical lens was designed and manufactured. This cylindrical module was composed of curved-beam flexure elements. The cylindrical coordinate system was established to describe the relationship of a curved-beam flexure element's motion and deformation. In addition, the stiffness matrix of the curved-beam element was obtained. Finite element method and dynamical modeling were provided to analyze the resonance frequency and the displacement of the motion. The feasibility of the design was demonstrated with the help of experiments on frequency response. Experimental results show good agreement with theoretical analysis and simulation predictions. PMID- 25933895 TI - Influence of mechanical noise inside a scanning electron microscope. AB - The scanning electron microscope is becoming a popular tool to perform tasks that require positioning, manipulation, characterization, and assembly of micro components. However, some of these applications require a higher level of performance with respect to dynamics and precision of positioning. One limiting factor is the presence of unidentified noises and disturbances. This work aims to study the influence of mechanical disturbances generated by the environment and by the microscope, identifying how these can affect elements in the vacuum chamber. To achieve this objective, a dedicated setup, including a high resolution vibrometer, was built inside the microscope. This work led to the identification and quantification of main disturbances and noise sources acting on a scanning electron microscope. Furthermore, the effects of external acoustic excitations were analysed. Potential applications of these results include noise compensation and real-time control for high accuracy tasks. PMID- 25933896 TI - A novel monolithic piezoelectric actuated flexure-mechanism based wire clamp for microelectronic device packaging. AB - A novel monolithic piezoelectric actuated wire clamp is presented in this paper to achieve fast, accurate, and robust microelectronic device packaging. The wire clamp has compact, flexure-based mechanical structure and light weight. To obtain large and robust jaw displacements and ensure parallel jaw grasping, a two-stage amplification composed of a homothetic bridge type mechanism and a parallelogram leverage mechanism was designed. Pseudo-rigid-body model and Lagrange approaches were employed to conduct the kinematic, static, and dynamic modeling of the wire clamp and optimization design was carried out. The displacement amplification ratio, maximum allowable stress, and natural frequency were calculated. Finite element analysis (FEA) was conducted to evaluate the characteristics of the wire clamp and wire electro discharge machining technique was utilized to fabricate the monolithic structure. Experimental tests were carried out to investigate the performance and the experimental results match well with the theoretical calculation and FEA. The amplification ratio of the clamp is 20.96 and the working mode frequency is 895 Hz. Step response test shows that the wire clamp has fast response and high accuracy and the motion resolution is 0.2 MUm. High speed precision grasping operations of gold and copper wires were realized using the wire clamper. PMID- 25933897 TI - Compliance and control characteristics of an additive manufactured-flexure stage. AB - This paper presents a compliance and positioning control characteristics of additive manufactured-nanopositioning system consisted of the flexure mechanism and voice coil motor (VCM). The double compound notch type flexure stage was designed to utilize the elastic deformation of two symmetrical four-bar mechanisms to provide a millimeter-level working range. Additive manufacturing (AM) process, stereolithography, was used to fabricate the flexure stage. The AM stage was inspected by using 3D X-ray computerized tomography scanner: air-voids and shape irregularity. The compliance, open-loop resonance peak, and damping ratio of the AM stage were measured 0.317 mm/N, 80 Hz, and 0.19, respectively. The AM stage was proportional-integral-derivative positioning feedback-controlled and the capacitive type sensor was used to measure the displacement. As a result, the AM flexure mechanism was successfully 25 nm positioning controlled within 500 MUm range. The resonance peak was found approximately at 280 Hz in closed-loop. This research showed that the AM flexure mechanism and the VCM can provide millimeter range with high precision and can be a good alternative to an expensive metal-based flexure mechanism and piezoelectric transducer. PMID- 25933899 TI - Note: A simple vibrating orifice monodisperse droplet generator using a hard drive actuator arm. AB - We propose that the rotary voice coil actuators found in magnetic hard drives are fit to supercede loudspeakers as expedient vibration sources in the laboratory setting. A specific use case is the excitation of a liquid jet to induce controlled breakup into monodisperse droplets. Like loudspeakers, which are typically used for prototyping such devices, hard drive actuators are cheap and ubiquitous, but they are less unwieldy and supply greater amplitudes without producing noise. Frequencies between 0 and 17 kHz, and likely beyond, can be reproduced reliably. No machining tools or amplifying electronics are needed for the construction and operation of the presented droplet generator. PMID- 25933898 TI - Development of a pulsed uniform supersonic gas expansion system based on an aerodynamic chopper for gas phase reaction kinetic studies at ultra-low temperatures. AB - A detailed description of a new pulsed supersonic uniform gas expansion system is presented together with the experimental validation of the setup by applying the CRESU (French acronym for Cinetique de Reaction en Ecoulement Supersonique Uniforme or Reaction Kinetics in a Uniform Supersonic Flow) technique to the gas phase reaction of OH radicals with 1-butene at ca. 23 K and 0.63 millibars of helium (carrier gas). The carrier gas flow, containing negligible mixing ratios of OH-precursor and 1-butene, is expanded from a high pressure reservoir (337 millibars) to a low pressure region (0.63 millibars) through a convergent divergent nozzle (Laval type). The novelty of this experimental setup is that the uniform supersonic flow is pulsed by means of a Teflon-coated aerodynamic chopper provided with two symmetrical apertures. Under these operational conditions, the designed Laval nozzle achieves a temperature of (22.4 +/- 1.4) K in the gas jet. The spatial characterization of the temperature and the total gas density within the pulsed uniform supersonic flow has also been performed by both aerodynamical and spectroscopic methods. The gas consumption with this technique is considerably reduced with respect to a continuous CRESU system. The kinetics of the OH+1-butene reaction was investigated by the pulsed laser photolysis/laser induced fluorescence technique. The rotation speed of the disk is temporally synchronized with the exit of the photolysis and the probe lasers. The rate coefficient (k(OH)) for the reaction under investigation was then obtained and compared with the only available data at this temperature. PMID- 25933900 TI - Note: A simple method to suppress the artificial noise for velocity map imaging spectroscopy. AB - A simple method has been proposed to suppress artificial noise from the counts with respect to the central line (or point) for the reconstructed 3D images with cylindrical symmetry in the velocity-map imaging spectroscopy. A raw 2D projection around the z-axis (usually referred to as central line) for photodetachment, photoionization, or photodissociation experiments is pre processed via angular tailored method to avoid the signal counts distributed near the central line (or point). Two types of photoelectron velocity-map imaging (O( ) and Au(-)?NH3) are demonstrated to give rise to the 3D images with significantly reduced central line noise after pre-processing operation. The major advantages of the pre-operation are the ability of suppression of central line noise to resolve weak structures or vibrational excitation in atoms or molecules near photon threshold. PMID- 25933901 TI - Note: Determining the detection efficiency of excited neutral atoms by a microchannel plate detector. AB - We present a method for determining the detection efficiency of neutral atoms relative to keV ions. Excited D* atoms are produced by D2 fragmentation in a strong laser field. The fragments are detected by a micro-channel plate detector either directly as neutrals or as keV ions following field ionization and acceleration by a static electric field. Moreover, we propose a new mechanism by which neutrals are detected. We show that the ratio of the yield of neutrals and ions can be related to the relative detection efficiency of these species. PMID- 25933902 TI - Note: Optical and electronic design of an amplitude-modulated continuous-wave laser scanner for high-accuracy distance measurement. AB - To utilize a time-of-flight-based laser scanner as a distance measurement sensor, the measurable distance and accuracy are the most important performance parameters to consider. For these purposes, the optical system and electronic signal processing of the laser scanner should be optimally designed in order to reduce a distance error caused by the optical crosstalk and wide dynamic range input. Optical system design for removing optical crosstalk problem is proposed in this work. Intensity control is also considered to solve the problem of a phase-shift variation in the signal processing circuit caused by object reflectivity. The experimental results for optical system and signal processing design are performed using 3D measurements. PMID- 25933903 TI - Note: Establishing alpha-particle radiation damage experiments using the Dalton Cumbrian Facility's 5 MV tandem pelletron. AB - Evaluating the radiation stability of mineral phases is a vital research challenge when assessing the performance of the materials employed in a Geological Disposal Facility for radioactive waste. This report outlines the setup and methodology for efficiently allowing the determination of the dose dependence of damage to a mineral from a single ion irradiated sample. The technique has been deployed using the Dalton Cumbrian Facility's 5 MV tandem pelletron to irradiate a suite of minerals with a controlled alpha-particle ((4)He(2+)) beam. Such minerals are proxies for near-field clay based buffer material surrounding radioactive canisters, as well as the sorbent components of the host rock. PMID- 25933904 TI - Note: Rotational Raman scattering on CO2 plasma using a volume Bragg grating as a notch filter. AB - We present a novel approach for filtering Rayleigh scattering and stray light from Raman scattering in a gas discharge, using a volume Bragg grating as a notch filter. For low frequency rotational Raman contributions, it is essential to filter out Rayleigh scattering and stray light at the laser wavelength to be able to measure an undisturbed Raman spectrum. Using the Bragg grating, having an optical density of 3.1 at the central wavelength of 532 nm and a full width at half maximum of 7 cm(-1), we were able to measure a nearly full rotational CO2 spectrum (1.56 cm(-1) peak-to-peak separation). The rotational temperature in a CO2 discharge was determined with an accuracy of 2%. PMID- 25933905 TI - Note: A silicon-on-insulator microelectromechanical systems probe scanner for on chip atomic force microscopy. AB - A new microelectromechanical systems-based 2-degree-of-freedom (DoF) scanner with an integrated cantilever for on-chip atomic force microscopy (AFM) is presented. The silicon cantilever features a layer of piezoelectric material to facilitate its use for tapping mode AFM and enable simultaneous deflection sensing. Electrostatic actuators and electrothermal sensors are used to accurately position the cantilever within the x-y plane. Experimental testing shows that the cantilever is able to be scanned over a 10 MUm * 10 MUm window and that the cantilever achieves a peak-to-peak deflection greater than 400 nm when excited at its resonance frequency of approximately 62 kHz. PMID- 25933906 TI - Note: A three-dimension active vibration isolator for precision atom gravimeters. AB - An ultra-low frequency active vibration isolator, simultaneously suppressing three-dimensional vibration noise, is demonstrated experimentally. The equivalent natural period of the isolator is 100 s and 12 s for the vertical and horizontal direction, respectively. The vibration noise in the vertical direction is about 50 times reduced during 0.2 and 2 Hz, and 5 times reduced in the other two orthogonal directions in the same frequency range. This isolator is designed for atom gravimeters, especially suitable for the gravimeter whose sensitivity is limited by vibration couplings. PMID- 25933907 TI - Note: Vectorial-magneto optical Kerr effect technique combined with variable temperature and full angular range all in a single setup. AB - Here, we report on a versatile full angular resolved/broad temperature range/vectorial magneto optical Kerr effect (MOKE) magnetometer, named TRISTAN. Its versatility relies on its capacity to probe temperature and angular dependencies of magnetization reversal processes without the need to do any intervention on the apparatus during measurements. The setup is a combination of a vectorial MOKE bench and a cryostat with optical access. The cryostat has a motorized rotatable sample holder with azimuthal correction. It allows for simultaneous and quantitative acquisition of the two in-plane magnetization components during the hysteresis loop at different temperatures from 4 K up to 500 K and in the whole angular range, without neither changing magnet orientation nor opening the cryostat. Measurements performed in a model system with competing collinear biaxial and uniaxial contributions are presented to illustrate its capabilities. PMID- 25933909 TI - Publisher's Note: "Monte-Carlo simulation of noise in hard X-ray Transmission Crystal Spectrometers: Identification of contributors to the background noise and shielding optimization" [Rev. Sci. Instrum. 85, 11D615 (2014)]. PMID- 25933910 TI - Erratum: "Physical apparatus parameters and model for vibrating tube densimeters at pressures to 140 MPa and temperatures to 473 K" [Rev. Sci. Instrum. 85, 095111 (2014)]. PMID- 25933912 TI - Presence of tracheal bronchus in children undergoing flexible bronchoscopy. AB - BACKGROUND AND OBJECTIVES: Tracheal bronchus (TB) is a rare congenital malformation of the lung tree with a bronchus originating from the trachea. Only a small number of publications have analyzed the frequency and diagnostic procedure of TB in children, based on a restricted sample of patients. In the present study, we analyze and discuss new aspects of prevalence, clinical presentation and associated malformations of TB based on a large pediatric cohort. METHODS: Data from 5970 children having a flexible bronchoscopy for investigation of respiratory symptoms were selected. We analyzed the anaesthesic management, the presence of associated malformations, and all tracheobronchial anomalies observed during the endoscopic procedure. RESULTS: Fifty-seven cases of tracheal bronchus were identified (0.9%). In the majority of them, tracheal bronchus was a fortuitous discovery without clear clinical relevance. Statistical analysis revealed that the majority of TB originated from the middle and lower one third of the trachea (56%). 61.5% of patients had associated anomalies such as syndromic association (21%), cardiac malformations (19.2%) or tracheal stenosis (14%). Only 38.5% of children had no associated anomalies. CONCLUSIONS: Tracheal bronchus is a rare morphological anomaly of the tracheobronchial tree. Most often TB is associated with other birth defects such as another tracheo bronchial tree malformation, vascular abnormality, congenital heart malformation or in the context of a syndromic pattern. A relationship between respiratory symptoms and the presence of TB is very rare and selective treatment is infrequent. PMID- 25933911 TI - Efficacy of perioperative synbiotics treatment for the prevention of surgical site infection after laparoscopic colorectal surgery: a randomized controlled trial. AB - PURPOSE: The aim of this study was to assess the effect of perioperative oral administration of synbiotics on the surgical outcome in patients undergoing laparoscopic colorectal resection. METHODS: In this single-center randomized, controlled trial, patients scheduled to undergo elective laparoscopic colorectal surgery were eligible to participate and randomly assigned to a synbiotics group or a control group. The primary study outcome was the development of infectious complications, particularly surgical site infection (SSI), within 30 days of surgery. RESULTS: In this study, 379 patients were enrolled and randomly assigned (173 to the synbiotics group and 206 to the control group), of whom 362 patients (168 to the synbiotics group and 194 to the control group) were eligible for this study. SSI occurred in 29 (17.3%) patients in the synbiotics group and 44 (22.7%) patients in the control group (OR: 0.761, 95% CI 0.50-1.16; p = 0.20). Overall, the rate of postoperative complications, including anastomotic leakage, did not differ significantly between the two groups. Synbiotics treatment reversed the changes in fecal bacteria and organic acids after surgery and suppressed the increases in potentially pathogenic species, such as Clostridium difficile. CONCLUSION: The efficacy of perioperative administration of synbiotics was not validated as a treatment for reducing the incidence of infectious complications after laparoscopic colorectal resection. However, the microbial imbalance, in addition to the reduction in organic acids, could be improved by perioperative synbiotics treatment. PMID- 25933913 TI - The impact of changing people with sleep apnea using CPAP less than 4 h per night to a Bi-level device. AB - Pressure intolerance is a reason for poor acceptance and subsequent compliance in some patients starting treatment with continuous positive airway pressure (CPAP). In unselected populations initiating CPAP; different types of pressure generating device have not been found to improve compliance. We hypothesized that using Bi level PAP for patients who reported pressure related discomfort as a cause for poor compliance with CPAP might increase their hours of treatment use. Patients using CPAP <4 h/night with symptoms to suggest pressure intolerance were randomized to receive either a Bi-level PAP device or a new CPAP for 4 weeks. Following a washout period of 2 weeks, they were crossed over to the other device for 4 weeks. Twenty eight volunteers completed the protocol. Compared to the baseline (mean 1.49 h per night), improvement in compliance was noticed when changed to a new CPAP (2.23 h, p = 0.006) or Bi-level PAP (2.73 h, p < 0.001). The trend suggesting superior compliance with a Bi-level PAP device compared to new CPAP was not significant (p = 0.059) and there were no differences in subjective or objective measures of sleepiness. The results of this study suggest that routine intervention with Bi-level PAP in this group of sub-optimally compliant individuals was not very effective in improving PAP usage. There is however a subgroup of patients who complains of difficulty with exhalation; where favorable trends towards improved compliance were observed on Bi-level PAP. PMID- 25933914 TI - Association between rotation-related impairments and activity type in people with and without low back pain. AB - OBJECTIVE: To determine whether people with low back pain (LBP) who regularly participated in a rotation-related activity displayed more rotation-related impairments than people without LBP who did and did not participate in the activity. DESIGN: Secondary analysis of data from a case-control study. SETTING: Musculoskeletal analysis laboratory at an academic medical center. PARTICIPANTS: A convenience sample of participants with LBP (n=55) who participated in a rotation-related sport, back-healthy controls (n=26) who participated in a rotation-related sport, and back-healthy controls (n=42) who did not participate in a rotation-related sport. Participants were matched based on age, sex, and activity level. INTERVENTIONS: Not applicable. MAIN OUTCOME MEASURES: The total number of rotation-related impairments and asymmetrical rotation-related impairments identified during a standardized clinical examination. RESULTS: Compared with the back-healthy controls who do not play a rotation-related sport group, both the LBP and back-healthy controls who play a rotation-related sport groups displayed significantly more (1) rotation-related impairments (LBP, P<.001; back-healthy controls who play a rotation-related sport, P=.015), (2) asymmetrical rotation-related impairments (LBP, P=.006; back-healthy controls who play a rotation-related sport, P=.020), and (3) rotation-related impairments with trunk movement tests (LBP, P=.002; back-healthy controls who play a rotation related sport, P<.001). The LBP group had significantly more rotation-related impairments with extremity movement tests than both of the back-healthy groups (back-healthy controls who play a rotation-related sport, P=.011; back-healthy controls who do not play a rotation-related sport, P<.001). CONCLUSIONS: The LBP and back-healthy controls who play a rotation-related sport groups demonstrated a similar number of total rotation-related impairments and asymmetrical rotation related impairments, and these numbers were greater than those of the back healthy controls who do not play a rotation-related sport group. Compared with people without LBP, people with LBP displayed more rotation-related impairments when moving an extremity. These findings suggest that impairments associated with extremity movements may be associated with having an LBP condition. PMID- 25933915 TI - Delayed initial recovery and long lie after a fall among middle-aged and older people with multiple sclerosis. AB - OBJECTIVES: To determine (1) the prevalence of lying on the floor or ground for >=10 minutes (delayed initial recovery [IR]) and for >1 hour (long lie) after a fall; and (2) the factors associated with delayed IR among people with multiple sclerosis (PwMS). DESIGN: A secondary analysis of data available from a national, cross-sectional descriptive study of PwMS. Information regarding postfall experiences was extracted from open-ended questions about participants' most recent fall. SETTING: Community. PARTICIPANTS: PwMS (N=700) aged >=55 years were recruited from the North America Committee on Multiple Sclerosis Registry; 354 of them completed the interview, and 322 provided a fall story that included information regarding postfall experiences. INTERVENTION: Not applicable. MAIN OUTCOME MEASURES: Participants' self-reports regarding time lying on the floor or ground after their most recent fall were used to determine delayed IR and long lie. RESULTS: A total of 89 (27.6%) of 322 fallers reported delayed IR; 15 (4.7%) of them reported a long lie. Logistic regression analysis revealed 5 factors associated with delayed IR: longer disease duration (odds ratio [OR]=1.03; 95% confidence interval [CI], 1.00-1.05), fall leading to a fracture (OR=2.73; 95% CI, 1.11-6.72), received help to get up (OR=3.94; 95% CI, 2.07-7.50), depression (OR=1.96; 95% CI, 1.10-3.49), and leg weakness (OR=2.14; 95% CI, 1.13-4.03). No significant differences were found between fallers who reported a long lie and those who reported a delayed IR. CONCLUSIONS: The findings suggest that while delayed IR is common, long lies are not prevalent among PwMS. The high prevalence of delayed IR highlights the importance of including fall management strategies in fall prevention programs for PwMS. PMID- 25933916 TI - Executive functioning and suicidal behavior among veterans with and without a history of traumatic brain injury. AB - OBJECTIVE: To examine the relationship between executive dysfunction, as a multidimensional construct (ie, decision-making, impulsivity, aggression, concept formation), and suicide attempt (SA) history in a high-risk sample of veterans with moderate to severe traumatic brain injury (TBI). DESIGN: Observational, 2*2 factorial design. To estimate group differences, linear regression was used to model the primary and secondary outcomes of interest as a function of history of SA, TBI, and the interaction between the 2 variables. Additionally, to determine the pattern of performance over the course of the Iowa Gambling Test (IGT), scores were modeled across the 5 IGT blocks by using a varying-coefficient model. SETTING: Veterans Health Administration. PARTICIPANTS: Veterans (N=133; no SA/no TBI, n=48; no SA/yes TBI, n=51; yes SA/no TBI, n=12; yes SA/yes TBI, n=22) completed the study measures. INTERVENTIONS: Not applicable. MAIN OUTCOME MEASURES: IGT, Immediate and Delayed Memory Test, State-Trait Anger Expression Inventory-2, Wisconsin Card Sorting Test. RESULTS: All groups demonstrated learning over the course of the IGT, except for veterans with a history of both SA and TBI. No group differences were identified on other measures of executive functioning. CONCLUSIONS: These findings highlight the potential, unique decision making challenges faced by veterans with a history of TBI and SA. Specialized interventions focused on overall distress reduction and means restriction may be required to prevent future self-directed violence. PMID- 25933917 TI - Ebola virus disease: awareness among junior doctors in England. AB - The current Ebola virus epidemic continues to pose a threat to the UK. Junior clinicians are often at the frontline of medical care in hospitals and their awareness of the clinical features and management of the Ebola virus disease (EVD) may significantly influence the timely implementation of infection control measures. In view of this, we carried out a cross-sectional survey of 119 junior doctors across four different hospitals in England in order to assess their level of knowledge of EVD. We demonstrate that there is currently a deficiency of knowledge about critical aspects of EVD in this population. PMID- 25933918 TI - Risk factors for healthcare-associated infection in light of two years of experience with the ECDC point prevalence survey of healthcare-associated infection and antimicrobial use in Poland. AB - BACKGROUND: Healthcare-associated infection (HAI) and antimicrobial resistance are two of the most important threats in contemporary medicine. The aim of this study was to evaluate independent risk factors associated with higher prevalence of HAI in a population of patients hospitalized in acute care hospitals in Poland. METHODS: This study was conducted in accordance with the protocol of the European Centre for Disease Prevention and Control (ECDC) point prevalence survey of HAI and antimicrobial use. Data for 16,598 patients were collected from 50 hospitals. Independent risk factors assessed included: hospital size and type; consumption of alcohol hand rub; isolation capacity; number of beds per full-time equivalent (FTE) infection control doctor/nurse; sex; age; hospitalization specialty; exposure to invasive procedures; and McCabe score. FINDINGS: The highest prevalence of HAI was observed in large and teaching hospitals (6.7% and 7.4%, respectively), in children aged less than one (13.3%) and among males (7.2%). With regard to invasive procedures, the strongest association was observed for central venous catheterization (30.2%), intubation (41.6%) and urinary catheterization (17.5%). The highest prevalence of HAI was observed among patients in intensive care units (adult 39.8%, paediatric 30.8%). The lowest prevalence of HAI was observed in hospitals with one FTE infection control nurse per <200 beds (4.1%). CONCLUSION: A high prevalence of HAI combined with high exposure to risk factors among patients in paediatric and adult ICUs should result in the introduction of an HAI prevention programme across Poland. PMID- 25933919 TI - Maximizing the utility of a single site randomized controlled psychotherapy trial. AB - PURPOSE OF THE RESEARCH: There is increasing interest in including measures of biological mechanisms as mediators and moderators of treatment outcome in randomized controlled trials (RCT's) of psychotherapy efficacy. However, examining biological mechanisms is often expensive and budget caps of most major funding agencies have remained stable in recent years. The goal of this manuscript is to describe how a psychotherapy efficacy trial is using a model of collaborative, affiliated grants to maximize resources and the potential knowledge to be gained from a single site RCT. Principal results and conclusions: The trial is an ongoing RCT comparing two psychotherapies for the treatment of concurrent posttraumatic stress disorder (PTSD) and alcohol use disorder (AUD) with a sample of treatment seeking veterans. Through collaboration with a team of investigators with independently-funded but affiliated grants, measures of select sleep, neurobiological, and genetic biomarkers were integrated into this single site RCT. This model has allowed us to pose research questions regarding the role of biological mechanisms, maximize the utility of recruitment, and be efficient in maximizing knowledge to be gained in a way that would not be possible solely on the funding of a single site RCT. Challenges of this model include high participant burden in regard to assessment and complicated coordinating procedures among studies. Strategies to address these challenges are described. PMID- 25933920 TI - Presentation of the Julius M. Friedenwald Medal to Robert S. Sandler, MD, MPH. PMID- 25933921 TI - Clinical trialist perspectives on the ethics of adaptive clinical trials: a mixed methods analysis. AB - BACKGROUND: In an adaptive clinical trial (ACT), key trial characteristics may be altered during the course of the trial according to predefined rules in response to information that accumulates within the trial itself. In addition to having distinguishing scientific features, adaptive trials also may involve ethical considerations that differ from more traditional randomized trials. Better understanding of clinical trial experts' views about the ethical aspects of adaptive designs could assist those planning ACTs. Our aim was to elucidate the opinions of clinical trial experts regarding their beliefs about ethical aspects of ACTs. METHODS: We used a convergent, mixed-methods design employing a 22-item ACTs beliefs survey with visual analog scales and open-ended questions and mini focus groups. We developed a coding scheme to conduct thematic searches of textual data, depicted responses to visual analog scales on box-plot diagrams, and integrated findings thematically. Fifty-three clinical trial experts from four constituent groups participated: academic biostatisticians (n = 5); consultant biostatisticians (n = 6); academic clinicians (n = 22); and other stakeholders including patient advocacy, National Institutes of Health, and U.S. Food and Drug Administration representatives (n = 20). RESULTS: The respondents recognized potential ethical benefits of ACTs, including a higher probability of receiving an effective intervention for participants, optimizing resource utilization, and accelerating treatment discovery. Ethical challenges voiced include developing procedures so trial participants can make informed decisions about taking part in ACTs and plausible, though unlikely risks of research personnel altering enrollment patterns. CONCLUSIONS: Clinical trial experts recognize ethical advantages but also pose potential ethical challenges of ACTs. The four constituencies differ in their weighing of ACT ethical considerations based on their professional vantage points. These data suggest further discussion about the ethics of ACTs is needed to facilitate ACT planning, design and conduct, and ultimately better allow planners to weigh ethical implications of competing trial designs. PMID- 25933922 TI - Prevalence and characterization of hepatitis B and C virus infections in a needle sharing population in Northern China. AB - BACKGROUND: The epidemiologies of hepatitis C virus (HCV) and hepatitis B virus (HBV) infections in specific populations in certain areas of China are poorly understood. A pilot survey of HCV/HBV infections was carried out in villages in Kuancheng County, Heben Province, where injection of sodium benzoate or amphetamines using shared needles has been a common practice. The aims of this study were to analyze the endemicity and characterize HCV/HBV infections in this population. METHODS: Data on demographic characteristics and drug abuse were collected from individuals who signed informed consent forms. Serum HCV antibody (anti-HCV), hepatitis B surface antigen (HBsAg), and hepatitis B core antibody (anti-HBc) were measured in all participants. HCV RNA was measured in samples positive for anti-HCV using real-time polymerase chain reaction. RESULTS: Among 852 participants from 11 villages, 49.9% had used sodium benzoate or amphetamine at least once, by intravenous injection. The overall prevalence of anti-HCV, HCV RNA, anti-HBc, HBsAg, and HCV/HBV co-infection was 37.1%, 26.6%, 67.7%, 10.7%, and 30.0%, respectively. Two-hundred-twenty-three of 227 (98.2%) participants positive for HCV RNA were aged >40 years. Co-infection was related to sex, age, number of injections, and time from first injection. The rate of spontaneous HCV RNA clearance was 28.2% (89/316), and was related to the number of injections, time from first injection, and HBsAg positivity. However, HBsAg was related to the anti-HBc signal/cut-off ratio rather than to the above parameters. Trend tests demonstrated that the prevalence of anti-HCV, HCV RNA, and anti-HBc was related to the number of injections (P < 0.001), while HBsAg prevalence was not (P = 0.347). CONCLUSIONS: The prevalence of HCV and HBV infection is likely to be high among individuals older than 40 years in areas of needle sharing, and one time screening for HCV infection should be offered to these populations. PMID- 25933923 TI - Outcomes in the physiologically most severe congenital diaphragmatic hernia (CDH) patients: Whom should we treat? AB - PURPOSE: Centers that care for newborns with congenital diaphragmatic hernia (CDH) may impose selection criteria for offering or limiting aggressive support in those patients most severely affected. The purpose of this study was to analyze outcomes in newborns with highly severe CDH uniformly treated for survival. METHODS: We reviewed 172 consecutive inborn patients without associated lethal anomalies treated at a single institution with a dedicated CDH program. Survival, respiratory outcome, and time to discharge in the most severe 10% (or fewer) of patients based on the physiologic measures of 5-minute Apgar, CDH Study Group (CDHSG) predicted survival, need for ECMO in the first 6 hours, and need for ECMO in the first 3 hours of life were studied. We also identified patients with best PaCO2 greater than 100 and best pH less than 7.0. A multivariate model (AUC-0.92) predicting mortality was also used to define the most severe 10%. RESULTS: Of 172 consecutive inborn patients, 18 had a 5-minute Apgar of 3 or less, and 11 survived (61%), 10 had a 5-minute Apgar of 2 or less, and 6 survived (60%), and 6 had a 5-minute Apgar of 1 or less, and 4 survived (67%). Seventeen had a CDHSG predicted survival less than 25%, and 9 survived (53%). Thirteen of 172 required ECMO for rescue in the first 6 hours of life, and 9 survived (69%), including 7 in the first 3 hours, and 5 survived (71%). Despite focused resuscitation in the delivery room and high levels of ventilatory support, 22 patients had a best PCO2 greater than 100 and best pH less than 7.0 for 1 hour or longer. Twelve of these 22 survived to discharge (55%). Of 17 defined by multivariate predictive modeling as the most severe, 8 survived (47%) with zero of the 3 ECMO ineligible prematures surviving. Of the 16 (10%) most severe ECMO eligible patients, 10 of 16 survived (63%). All survivors were discharged home on no ventilatory support greater than nasal cannula oxygen. CONCLUSION: In newborn CDH patients without lethal associated anomalies, accepted measures of physiologic severity failed to predict mortality. Survival met or exceeded 50% even in the most severe 10% as defined by these measures. These data support the practice of treating each patient for survival regardless of the physiologic severity in the first hours of life, and selection criteria for not offering ECMO should be reevaluated where practiced. PMID- 25933924 TI - Cerebral, renal and mesenteric regional oxygen saturation of term infants during transition. AB - OBJECTIVE: To measure cerebral regional oxygen saturation (CrSO2), renal regional oxygenation saturation (RrSO2) and mesenteric tissue regional oxygen saturation (MrSO2) during immediate transition and continuously for the first 9 hours of age. Fractional tissue oxygen extraction of the brain (CtFOE), kidneys (RtFOE), splanchnic tissue (MtFOE) were also assessed. STUDY DESIGN: Prospective, observational study of 61 term infants, delivered by elective caesarean section. Using near-infrared spectroscopy, changes in CrSO2, RrSO2, MrSO2 and changes in CtFOE, RtFOE and MtFOE were measured all through the first 9 hours of life. All the episodes of feeding during this period were recorded. RESULTS: Mean CrSO2 increased quickly to 7 minutes, with no further changes. On the other hand, mean RrSO2 and mean MrSO2 increased for 10 minutes and thereafter they remained on their newly reached level. RrSO2 and MrSO2 were significantly lower at 3-4-5-6-7 minutes of life compared to the CrSO2 (p<0.05). RtFOE and MtFOE were significantly higher at 3-4-5-6-7 minutes of life compared to the CtFOE (p<0.05). During feeding, CrSO2, RrSO2 and MrSO2 did not significantly change. CONCLUSIONS: During early adaptive period, oxygen delivery is preserved to 'vital' organs, like brain, at the expense of kidneys and splanchnic tissue. Term infants can provide for the increasing metabolic activity of the intestinal tract during feeding periods without compromising oxygenation. PMID- 25933925 TI - Validation of a pediatric single-port laparoscopic surgery simulator. AB - BACKGROUND: This study aims to adapt an existing multiport pediatric laparoscopic surgery simulator to be suitable for pediatric single-port laparoscopy and to investigate construct validity for its use as a resource for skills training and assessment. METHODS: An existing pediatric-sized box trainer was modified to accommodate a commercially available port. A total of 41 participants (18 novices, 16 intermediates and 7 experts) were recruited to complete four curriculum tasks via a single-port access approach. Objective task performance scores were evaluated. RESULTS: Task completion times and performance scores were significantly different between novices and experts for the peg transfer (P = 0.02, P = 0.008 respectively), pattern cut (P < 0.001, P < 0.001 respectively) and ligating loop (P = 0.038, P = 0.035 respectively). There were significant differences in outcomes between novices and intermediates for all tasks, including the intracorporeal suture task (P <= 0.001). There were no significant differences in outcomes between intermediates and experts for all tasks. CONCLUSIONS: The Pediatric Laparoscopic Surgery (PLS) simulator can be easily adapted for single-port laparoscopic surgery to be construct valid for the peg transfer, ligating loop and pattern cut tasks. There is scope for additional tasks to be developed that focus on the unique technical challenges and skills associated with single-port techniques. PMID- 25933926 TI - Knocking down schistosomes - promise for lentiviral transduction in parasites. AB - Underpinned by major advances in our understanding of the genomes of schistosomes, progress in the development of functional genomic tools is providing unique prospects to gain insights into the intricacies of the biology of these blood flukes, their host relationships, and the diseases that they cause. This article reviews some key applications of double-stranded RNA interference (RNAi) in Schistosoma mansoni, appraises delivery systems for transgenesis and stable gene silencing, considers ways of increasing efficiency and specificity of gene silencing, and discusses the prospects of using a lentivirus delivery system for future functional genomic-phenomic explorations of schistosomes and other parasites. The ability to achieve effective and stable gene perturbation in parasites has major biological implications and could facilitate the development of new interventions. PMID- 25933927 TI - Proteotyping: Proteomic characterization, classification and identification of microorganisms--A prospectus. AB - Modern microbial systematics requires a range of methodologies for the comprehensive characterization, classification and identification of microorganisms. While whole-genome sequences provide the ultimate reference for defining microbial phylogeny and taxonomy, selected biomarker-based strategies continue to provide the means for the bulk of microbial systematic studies. Proteomics, the study of the expression of genes, as well as the structure and function of the resulting proteins, offers indirect measures of genome sequence data. Recent developments in applications of proteomics for analyzing microorganisms have paralleled the growing microbial genome sequence database, as well as the evolution of mass spectrometry (MS) instrumentation and bioinformatics. MALDI-TOF MS, which generates proteomic mass patterns for 'fingerprint'-based characterizations, has provided a marked breakthrough for microbial identification. However, MALDI-TOF MS is limited in the number of targets that can be detected for strain characterization. Advanced methods of tandem mass spectrometry, in which proteins and peptides generated from proteins, are characterized and identified, using LC-MS/MS, provide the ability to detect hundreds or thousands of expressed microbial strain markers for high-resolution characterizations and identifications. Model studies demonstrate the application of proteomics-based analyses for bacterial species- and strain-level detection and identification and for characterization of environmentally relevant, metabolically diverse bacteria. Proteomics-based approaches represent an emerging complement to traditional methods of characterizing microorganisms, enabling the elucidation of the expressed biomarkers of genome sequence information, which can be applied to 'proteotyping' applications of microorganisms at all taxonomic levels. PMID- 25933928 TI - Prevalence and genetic diversity of endosymbiotic bacteria infecting cassava whiteflies in Africa. AB - BACKGROUND: Cassava provides over half of the dietary requirement for more than 200 million poor in Africa. In recent years, cassava has been affected by an epidemic of a virus disease called cassava brown streak disease (CBSD) that is spreading in much of eastern and central Africa, affecting food security and the economic development of the poor. The viruses that cause CBSD are transmitted by the insect vector whitefly (Bemisia tabaci), which have increased to very high numbers in some African countries. Strains of endosymbiotic bacteria infecting whiteflies have been reported to interact specifically with different whitefly populations with varied effects on its host biology and efficiency of virus transmission. The main aim of this study was therefore to investigate the prevalence and diversity of the secondary endosymbiotic bacteria infecting cassava whiteflies with a view to better understand their role on insect population dynamics and virus disease epidemics. RESULTS: The genetic diversity of field-collected whitefly from Tanzania, Malawi, Uganda and Nigeria was determined by mitochondrial DNA based phylogeny and restriction fragment length polymorphism. Cassava in these countries was infected with five whitefly populations, and each one was infected with different endosymbiotic bacteria. Incidences of Arsenophonus, Rickettsia, Wolbachia and Cardinium varied amongst the populations. Wolbachia was the most predominant symbiont with infection levels varying from 21 to 97%. Infection levels of Arsenophonus varied from 17 to 64% and that of Rickettsia was 0 to 53%. Hamiltonella and Fritschea were absent in all the samples. Multiple locus sequence typing identified four different strains of Wolbachia infecting cassava whiteflies. A common strain of Wolbachia infected the whitefly population Sub-Saharan Africa 1-subgroup 1 (SSA1-SG1) and SSA1-SG2, while others were infected with different strains. Phylogeny based on 16S rDNA of Rickettsia and 23S rDNA of Arsenophonus also identified distinct strains. CONCLUSIONS: Genetically diverse bacteria infect cassava whiteflies in Africa with varied prevalence across different host populations, which may affect their whitefly biology. Further studies are required to investigate the role of endosymbionts to better understand the whitefly population dynamics. PMID- 25933929 TI - Frequency, Predictors, and Medical Record Documentation of Chemical Coping Among Advanced Cancer Patients. AB - BACKGROUND: In this prospective study, we determined the frequency of opioid related chemical coping among advanced cancer patients, as diagnosed by palliative medicine specialists. We also determined predictors for chemical coping and the concordance between the physician's diagnosis and documentation in the medical records. PATIENTS AND METHODS: Palliative medicine specialists evaluated and diagnosed consecutive patients seen for chemical coping. The proportion of patients identified as chemically coping was compared with the proportion documented in the medical records. Demographic data; cancer diagnosis; history of smoking; substance abuse; psychiatric disease; morphine equivalent daily dosage; Cut-down, Annoyed, Guilty, and Eye-opener (CAGE) questionnaire scores; and Edmonton Symptom Assessment System scores were also collected. RESULTS: A total of 432 patients were evaluated. Overall, 76 patients (18%; 95% confidence interval [CI]: 14%-21%) were diagnosed as chemically coping. Documentation of chemical coping in the medical records was reported for only 15 patients (4%; 95% CI: 2%-6%). CAGE positivity (odds ratio [OR]: 2.89), younger age (OR: 0.97 per year), better performance status (OR: 0.68 per point), pain (OR: 1.20 per point), and well-being (OR: 1.28 per point) were found to be significant predictors of chemical coping by protocol definition. After recursive partitioning, 21 of 50 patients (42%) who were CAGE positive and had an Eastern Cooperative Oncology Group performance status <=2 were diagnosed as chemically coping. CONCLUSION: Approximately 18% of palliative care patients seen were diagnosed as chemically coping by palliative medicine specialists. The frequency of documentation in the medical records was significantly lower. Better and safer ways for physicians to assess and report chemical coping are needed. IMPLICATIONS FOR PRACTICE: Cancer pain is a multidimensional symptom for which opioids are the mainstay of treatment. However, opioids can have a double effect resulting in drug-seeking behaviors. Chemical coping occurs when a patient uses opioids in a nonprescribed way to cope with various stressful events. This can lead to misuse of opioids and complications including neurotoxicities, respiratory depression, and death. Proper diagnosis and documentation is needed to ensure proper management of pain and to avoid unnecessary harm. The findings of this study suggest that ~18% of advanced cancer patients seen by a palliative care service were diagnosed as chemical coping, but only 4% were documented in the medical records. PMID- 25933930 TI - Symptoms and Symptom Attribution Among Women on Endocrine Therapy for Breast Cancer. AB - BACKGROUND: Adherence to adjuvant endocrine therapy (ET) influences breast cancer survival. Because ET side effects are frequently cited as reasons for nonadherence, understanding how perceptions and motivations in relation to ET are associated with symptom attribution can help promote timely symptom management. MATERIALS AND METHODS: Participants were 2,086 breast cancer survivors recruited through the Army of Women registry who were current tamoxifen or aromatase inhibitor (AI) users. Participants reported whether they were bothered by each of 47 symptoms during the past month and whether they thought each symptom was related to taking ET. Frequencies of overall symptoms and symptoms attributed and misattributed to ET were calculated, and linear regression was used to assess sociodemographics, emotions, and illness perceptions as predictors of symptoms attributed to ET. RESULTS: Women attributed a mean of 8.9 symptoms and misattributed a mean of 1.5 symptoms to ET. In the multivariable analysis, younger age, a more recent diagnosis, AI use (vs. tamoxifen), anxiety, depressive symptoms, more ET-related negative emotions, more concern about long-term ET use, and greater perceived ET necessity were independently associated with attribution of more symptoms to ET. More perceived ET necessity was associated with correctly attributing symptoms to ET, whereas higher depressive symptoms and more concern about ET use were associated with misattribution of symptoms to ET. CONCLUSION: Given that many women perceive a range of symptoms as a consequence of ET, attention to these symptoms may reduce symptom burden and improve quality of life, potentially improving ET adherence and optimizing survival. IMPLICATIONS FOR PRACTICE: Many breast cancer survivors on endocrine therapy (ET) experience a range of side effects while taking ET. Targeting potentially modifiable factors associated with attributing a greater number of symptoms to ET, including perceived need for ET, concerns about long-term ET use, negative emotions toward ET, and symptoms of anxiety and depression, may reduce symptom burden and improve quality of life. PMID- 25933931 TI - Diastolic Dysfunction Occurs Early in HER2-Positive Breast Cancer Patients Treated Concurrently With Radiation Therapy and Trastuzumab. AB - BACKGROUND: Left ventricular ejection fraction (LVEF) is used routinely to monitor cardiac dysfunction associated with breast cancer treatment. In this study the prevalence of early left ventricular diastolic dysfunction (LVDD) and its relationship to the dose-volume of the heart irradiated were evaluated in HER2-positive breast cancer patients undergoing concurrent trastuzumab and adjuvant radiotherapy (RT). MATERIALS AND METHODS: Data from 40 breast cancer patients treated with concurrent trastuzumab and left-sided adjuvant RT between September 2011 and October 2012 were collected prospectively. For comparison, 32 patients treated with concurrent trastuzumab and right-sided adjuvant RT and 71 patients treated with left-sided RT alone were collected retrospectively. Echocardiography was obtained before RT, immediately following RT, and 3 and 6 months after RT. Doses to the heart and left ventricle (LV) were quantified. RESULTS: Prior to RT with concurrent trastuzumab, 11 of 29 (left) and 8 of 25 (right) patients with normal baseline left ventricular diastolic function (LVDF) developed LVDD. In patients receiving left-sided RT alone, 12 of 61 patients with normal baseline LVDF developed LVDD. Dmean, D15-D40, D60-D70, and V3-V10 of the LV were significantly higher in patients who developed LVDD after concurrent trastuzumab and left-sided RT. In contrast, only two patients developed grade 1 LVEF decrease after both concurrent treatment and left-sided RT alone. CONCLUSION: Changes in LVDF compared with LVEF are more sensitive for early detection of cardiotoxicity. The dose-volume of the heart contributes significantly to the risk of LVDD in patients with left-sided breast cancer treated concurrently with trastuzumab. IMPLICATIONS FOR PRACTICE: Abnormalities in diastolic function are more sensitive than changes in the left ventricular ejection fraction for detecting acute cardiotoxicity and are related to the dose volume of the heart irradiated in patients with left-sided breast cancer receiving radiotherapy concurrently with trastuzumab. This result highlights the importance of decreasing the dose-volume of heart irradiated as a protective strategy in the treatment setting of concurrent trastuzumab and radiotherapy. Diastolic dysfunction may serve as a more sensitive tool for the early detection of cardiac damage and should be incorporated as a routine parameter in the functional monitoring of cardiotoxicity. PMID- 25933932 TI - Transdermal fentanyl and its use in ovine surgery. AB - Fentanyl delivered via a transdermal patch has the potential to decrease the need for post-operative handling of sheep undergoing surgical procedures. Two studies were performed to test: (1) the ideal timing for the application of pre-emptive analgesic patches and (2) the efficacy of a 2 ug/kg/h dose, as extrapolated from other species. The first study had sheep divided into two groups. Group 1 had a fentanyl patch applied for 24 h prior to a patch change and group 2 had a fentanyl patch applied 72 h prior to a change. The second study applied the results obtained in the first and tested the efficacy of 2 ug/kg/h as an effective dose in an orthopaedic surgical environment. Results indicated that the ideal time for pre-emptive fentanyl patch administration is 24-36 h prior to surgery and that 2 ug/kg/h is an effective minimum therapeutic dose rate for the use of fentanyl as an analgesic in an orthopaedic surgical environment. PMID- 25933933 TI - Post-exercise dynamics of serum amyloid A blood concentration in thoroughbred horses classified as injured and non-injured after the race. AB - The aim of this study was to evaluate serum amyloid A (SAA) concentration in horses with orthopedic injuries acquired during racing and in healthy ones after completing the race. Injuries of bone and tendon did not cause radical increase in SAA concentration observed in other inflammatory conditions. SAA concentration correlated positively with white blood cell count (WBC) on the 3rd-4th days after race being significantly higher in the injured horses than in the control group in that time. It was suggested that racing effort may cause increase in SAA level, more pronounced in horses manifesting clinical signs of orthopedic injury after the race. PMID- 25933934 TI - Phase II Study With Epirubicin, Cisplatin, and Infusional Fluorouracil Followed by Weekly Paclitaxel With Metronomic Cyclophosphamide as a Preoperative Treatment of Triple-Negative Breast Cancer. AB - BACKGROUND: The aggressive biological behavior and the lack of target therapy prompts the search for new therapeutic approaches for triple-negative breast cancers. PATIENTS AND METHODS: We evaluated the efficacy in terms of Ki-67 variation and clinical response but also the toxicity of a neoadjuvant regimen based on metronomic principles including ECF (epidoxorubicin with cisplatin on day 1 with low-dose 5-fluorouracil in continuous infusion every 21 days for 4 courses) followed by paclitaxel (90 mg/m(2)) on day 1, 8, and 15 every 28 days for 3 courses in combination with metronomic oral cyclophosphamide 50 mg/d for 12 weeks in patients with HER2-negative breast cancer (T2-T4a-d, N0-3, M0) with estrogen receptor and progesterone receptor < 10%. RESULTS: We enrolled 34 patients from June 2009 to May 2013. All were considered evaluable on an intention-to treat basis. The mean difference between the percentage of Ki-67 positive cells evaluated in surgical resection specimens and in pretreatment tumor core biopsy was 41% (95% confidence interval [CI], 30-51; P < .0001) for the entire population, and 22% (95% CI, 7-38; P = .0097) in patients who did not achieve pathological complete response (pCR). Responses to the treatment were obtained in 31 patients [91%] of the patients, and 19 patients (56%; 95% CI, 35 70) had a pCR. Stable disease was observed in 3 patients and none had progressive disease. Grade >= 3 hematologic adverse events included leukopenia in 9% (3 of 34), neutropenia in 38% (13 of 34), and anemia in 3% (1 of 34) of patients. Nonhematologic Grade >= 3 toxicities included only stomatitis in 1 patient. CONCLUSION: A neoadjuvant program with an ECF regimen followed by weekly paclitaxel with metronomic cyclophosphamide proved to be very effective, with high pCR rates, reduction of Ki-67, and it was associated with a low toxicity profile. PMID- 25933935 TI - Acute heat stress up-regulates neuropeptide Y precursor mRNA expression and alters brain and plasma concentrations of free amino acids in chicks. AB - Heat stress causes an increase in body temperature and reduced food intake in chickens. Several neuropeptides and amino acids play a vital role in the regulation of food intake. However, the responses of neuropeptides and amino acids to heat-stress-induced food-intake regulation are poorly understood. In the current study, the hypothalamic mRNA expression of some neuropeptides related to food intake and the content of free amino acids in the brain and plasma was examined in 14-day-old chicks exposed to a high ambient temperature (HT; 40+/-1 degrees C for 2 or 5 h) or to a control thermoneutral temperature (CT; 30+/-1 degrees C). HT significantly increased rectal temperature and plasma corticosterone level and suppressed food intake. HT also increased the expression of neuropeptide Y (NPY) and agouti-signaling protein (ASIP) precursor mRNA, while no change was observed in pro-opiomelanocortin, cholecystokinin, ghrelin, or corticotropin-releasing hormone precursor mRNA. It was further found that the diencephalic content of free amino acids - namely, tryptophan, leucine, isoleucine, valine and serine - was significantly higher in HT chicks with some alterations in their plasma amino acids in comparison with CT chicks. The induction of NPY and ASIP expression and the alteration of some free amino acids during HT suggest that these changes can be the results or causes the suppression of food intake. PMID- 25933936 TI - Effect of salinity changes on olfactory memory-related genes and hormones in adult chum salmon Oncorhynchus keta. AB - Studies of memory formation have recently concentrated on the possible role of N methyl-d-aspartate receptors (NRs). We examined changes in the expression of three NRs (NR1, NR2B, and NR2C), olfactory receptor (OR), and adrenocorticotropic hormone (ACTH) in chum salmon Oncorhynchus keta using quantitative polymerase chain reaction (QPCR) during salinity change (seawater->50% seawater >freshwater). NRs were significantly detected in the diencephalon and telencephalon and OR was significantly detected in the olfactory epithelium. The expression of NRs, OR, and ACTH increased after the transition to freshwater. We also determined that treatment with MK-801, an antagonist of NRs, decreased NRs in telencephalon cells. In addition, a reduction in salinity was associated with increased levels of dopamine, ACTH, and cortisol (in vivo). Reductions in salinity evidently caused NRs and OR to increase the expression of cortisol and dopamine. We concluded that memory capacity and olfactory imprinting of salmon is related to the salinity of the environment during the migration to spawning sites. Furthermore, salinity affects the memory/imprinting and olfactory abilities, and cortisol and dopamine is also related with olfactory-related memories during migration. PMID- 25933937 TI - The Italian version of the Depression Anxiety Stress Scales-21: Factor structure and psychometric properties on community and clinical samples. AB - OBJECTIVE: The Depression Anxiety Stress Scales-21 (DASS-21) is the short version of a self-report measure that was originally developed to provide maximum differentiation between depressive and anxious symptoms. Despite encouraging evidence, the factor structure and other features of the DASS-21 are yet to be firmly established. METHOD: A community sample of 417 participants and two clinical groups (32 depressive patients and 25 anxious patients) completed the Italian version of the DASS-21 along with several measures of psychopathology. RESULTS: Confirmatory factor analyses suggested that the DASS-21 is a measure of general distress plus three additional orthogonal dimensions (anxiety, depression, and stress). The internal consistency and temporal stability of the measure were good; each DASS-21 scale correlated more strongly with a measure of a similar construct, demonstrating good convergent and divergent validity. Lastly, the DASS-21 demonstrated good criterion-oriented validity. CONCLUSION: The validity of the Italian DASS-21 and its utility, both for community and clinical individuals, are supported. PMID- 25933938 TI - Vaginal drug distribution modeling. AB - This review presents and applies fundamental mass transport theory describing the diffusion and convection driven mass transport of drugs to the vaginal environment. It considers sources of variability in the predictions of the models. It illustrates use of model predictions of microbicide drug concentration distribution (pharmacokinetics) to gain insights about drug effectiveness in preventing HIV infection (pharmacodynamics). The modeling compares vaginal drug distributions after different gel dosage regimens, and it evaluates consequences of changes in gel viscosity due to aging. It compares vaginal mucosal concentration distributions of drugs delivered by gels vs. intravaginal rings. Finally, the modeling approach is used to compare vaginal drug distributions across species with differing vaginal dimensions. Deterministic models of drug mass transport into and throughout the vaginal environment can provide critical insights about the mechanisms and determinants of such transport. This knowledge, and the methodology that obtains it, can be applied and translated to multiple applications, involving the scientific underpinnings of vaginal drug distribution and the performance evaluation and design of products, and their dosage regimens, that achieve it. PMID- 25933940 TI - Effective incorporation of insulin in mucus permeating self-nanoemulsifying drug delivery systems. AB - The development of a novel, mucus permeating SNEDDS formulation for oral insulin delivery containing a hydrophobic ion pair of insulin/dimyristoyl phosphatidylglycerol (INS/DMPG) is presented. Three oil/surfactant/cosurfactant combinations and 27 weight ratios of oil, surfactant and cosurfactant for each combination were evaluated with the aid of ternary phase diagrams, for the incorporation of the protein/phospholipid complex. The developed formulation was characterized by an average droplet diameter of 30-45 nm. Depending on the initial protein concentration, the loading of insulin in SNEDDS varied between 0.27 and 1.13 wt%. The therapeutic protein was found to be efficiently protected from enzymatic degradation by intestinal enzymes (i.e., trypsin, alpha chymotrypsin). The SNEDDS formulation exhibited increased mucus permeability and did not appear to be affected by ionic strength. The incorporation of INS/DMPG in SNEDDS prevented an initial burst release of insulin. INS/DMPG loaded SNEDDS were found to be non-cytotoxic up to a concentration of 2mg/ml. According to the reported results, the incorporation of the hydrophobic ion pair of INS/DMPG in SNEDDS could be regarded as a promising strategy for the oral delivery of insulin. PMID- 25933941 TI - Understanding the etiology of the posteromedial tibial stress fracture. AB - Previous human in vivo tibial strain measurements from surface strain gauges during vigorous activities were found to be below the threshold value of repetitive cyclical loading at 2500 microstrain in tension necessary to reduce the fatigue life of bone, based on ex vivo studies. Therefore it has been hypothesized that an intermediate bone remodeling response might play a role in the development of tibial stress fractures. In young adults tibial stress fractures are usually oblique, suggesting that they are the result of failure under shear strain. Strains were measured using surface mounted unstacked 45 degrees rosette strain gauges on the posterior aspect of the flat medial cortex just below the tibial midshaft, in a 48year old male subject while performing vertical jumps, staircase jumps and running up and down stadium stairs. Shear strains approaching 5000 microstrain were recorded during stair jumping and vertical standing jumps. Shear strains above 1250 microstrain were recorded during runs up and down stadium steps. Based on predictions from ex vivo studies, stair and vertical jumping tibial shear strain in the test subject was high enough to potentially produce tibial stress fracture subsequent to repetitive cyclic loading without necessarily requiring an intermediate remodeling response to microdamage. PMID- 25933939 TI - Intratumoral injection of IFN-alpha dendritic cells after dacarbazine activates anti-tumor immunity: results from a phase I trial in advanced melanoma. AB - BACKGROUND: Advanced melanoma patients have an extremely poor long term prognosis and are in strong need of new therapies. The recently developed targeted therapies have resulted in a marked antitumor effect, but most responses are partial and some degree of toxicity remain the major concerns. Dendritic cells play a key role in the activation of the immune system and have been typically used as ex vivo antigen-loaded cell drugs for cancer immunotherapy. Another approach consists in intratumoral injection of unloaded DCs that can exploit the uptake of a wider array of tumor-specific and individual unique antigens. However, intratumoral immunization requires DCs endowed at the same time with properties typically belonging to both immature and mature DCs (i.e. antigen uptake and T cell priming). DCs generated in presence of interferon-alpha (IFN DCs), due to their features of partially mature DCs, capable of efficiently up taking, processing and cross-presenting antigens to T cells, could successfully carry out this task. Combining intratumoral immunization with tumor-destructing therapies can induce antigen release in situ, facilitating the injected DCs in triggering an antitumor immune response. METHODS: We tested in a phase I clinical study in advanced melanoma a chemo-immunotherapy approach based on unloaded IFN DCs injected intratumorally one day after administration of dacarbazine. Primary endpoint of the study was treatment safety and tolerability. Secondary endpoints were immune and clinical responses of patients. RESULTS: Six patients were enrolled, and only three completed the treatment. The chemo-immunotherapy was well tolerated with no major side effects. Three patients showed temporary disease stabilization and two of them showed induction of T cells specific for tyrosinase, NY-ESO-1 and gp100. Of interest, one patient showing a remarkable long-term disease stabilization kept showing presence of tyrosinase specific T cells in PBMC and high infiltration of memory T cells in the tumor lesion at 21 months. CONCLUSION: We tested a chemo-immunotherapeutic approach based on IFN-DCs injected intratumorally one day after DTIC in advanced melanoma. The treatment was well tolerated, and clinical and immunological responses, including development of vitiligo, were observed, therefore warranting additional clinical studies aimed at evaluating efficacy of this approach. TRIAL REGISTRATION: Trial Registration Number not publicly available due to EudraCT regulations: https://www.clinicaltrialsregister.eu/doc/EU_CTR_FAQ.pdf. PMID- 25933942 TI - Porous gelatin/tricalcium phosphate/genipin composites containing lumbrokinase for bone repair. AB - Bone cell activities are very important in bone remodeling. This study investigates the effects of lumbrokinase on bone cell activities in cultures. Moreover, a biodegradable composite (GGT) containing genipin-crosslinked gelatin and beta-tricalcium phosphate was prepared to carry lumbrokinase (GGTLK). Rat calvarial bone defects were filled with GGT and GGTLK composites. Bone healing was monitored in vivo by bioluminescence imaging and micro-CT. Lumbrokinase was found to have a dose-dependent effect on bone cell activities. Low concentrations (<1MUg/ml) of lumbrokinase increased the viability, total alkaline phosphatase activity and mobility of osteoblasts, the number of total calcified nodules and the expression of osteopontin and osteocalcin; however, they considerably reduced the total tartrate-resistant acid phosphatase activity of osteoclasts. IVIS images revealed a stronger fluorescent signal in GGTLK-treated animals than in GGT-treated animals. Micro-CT analysis revealed that GGTLK induced more new bone formation than did GGT. These observations suggest that lumbrokinase released from GGTLK composite can enhance bone tissue regeneration. PMID- 25933943 TI - Activation of AMP-activated protein kinase protects against homocysteine-induced apoptosis of osteocytic MLO-Y4 cells by regulating the expressions of NADPH oxidase 1 (Nox1) and Nox2. AB - BACKGROUND: Elevated plasma homocysteine (Hcy) level is associated with the risk of osteoporotic fracture. While Hcy increases oxidative stress, AMP-activated protein kinase (AMPK) activation ameliorates it. This study aimed to investigate whether Hcy induces apoptosis of osteocytic MLO-Y4 cells through regulating expressions of oxidant and anti-oxidant enzymes and determine the effects of AMPK activation by 5-aminoimidazole-4-carboxamide-1-beta-D-ribofuranoside (AICAR) and metformin on the Hcy-induced apoptosis of the cells. RESULTS: DNA fragment ELISA and TUNEL staining assays showed that Hcy treatments (0.1-5.0 mM) induced apoptosis of MLO-Y4 cells in a dose-dependent manner. The detrimental effect of Hcy was partly but significantly reversed by an antioxidant (N-acetylcysteine) and NADPH oxidase (Nox) inhibitors (apocynin and diphenyleneiodonium). In addition, treatment with AICAR (0.05-0.1 mM) and metformin (10-100 MUM) ameliorated Hcy-induced apoptosis of the cells. The favorable effect of metformin on Hcy-induced apoptosis was completely canceled by an AMPK inhibitor Ara-A. Hcy increased the expression levels of Nox1 and Nox2, while it had no effects on the expressions of Nox4 or the anti-oxidant enzymes, superoxide dismutase 1 and 2. Hcy-induced increases in the expressions of Nox1 and Nox2 decreased significantly by treatments with AICAR. CONCLUSION: These findings suggest that Hcy induces apoptosis of osteocytes by increasing the expressions of Nox1 and Nox2, and AMPK activation by AICAR and metformin effectively prevents the detrimental reactions. Thus, AMPK activation may be a potent therapeutic candidate for preventing Hcy induced osteocyte apoptosis and the resulting bone fragility. PMID- 25933944 TI - Declining incidence trends for hip fractures have not been accompanied by improvements in lifetime risk or post-fracture survival--A nationwide study of the Swedish population 60 years and older. AB - BACKGROUND: Hip fracture is a common cause of disability and mortality among the elderly. Declining incidence trends have been observed in Sweden. Still, this condition remains a significant public health problem since Sweden has one of the highest incidences worldwide. Yet, no Swedish lifetime risk or survival trends have been presented. By examining how hip fracture incidence, post-fracture survival, as well as lifetime risk have developed between 1995 and 2010 in Sweden, this study aims to establish how the burden hip fractures pose on the elderly changed over time, in order to inform initiatives for improvements of their health. MATERIAL AND METHODS: The entire Swedish population 60 years-old and above was followed between 1987 and 2010 in the National Patient Register and the Cause of Death Register. Annual age-specific hip fracture cumulative incidence was estimated using hospital admissions for hip fractures. Three-month and one-year survival after the first hip fracture were also estimated. Period life table was used to assess lifetime risk of hip fractures occurring from age 60 and above, and the expected mean age of the first hip fracture. RESULTS: The age-specific hip fracture incidence decreased between 1995 and 2010 in all ages up to 94 years, on average by 1% per year. The lifetime risk remained almost stable, between 9% and 11% for men, and between 18% and 20% for women. The expected mean age of a first hip fracture increased by 2.5 years for men and by 2.2 years for women. No improvements over time were observed for the 3-month survival for men, while for women a 1% decrease per year was observed. The 1-year survival slightly increased over time for men (0.4% per year) while no improvement was observed for women. CONCLUSIONS: The age-specific hip fracture incidence has decreased over time. Yet the lifetime risk of a hip fracture has not decreased because life expectancy in the population has increased in parallel. Overall, survival after hip fracture has not improved. PMID- 25933945 TI - The influence of the route of administration of gold nanoparticles on their tissue distribution and basic biochemical parameters: In vivo studies. AB - BACKGROUND: The gold nanoparticles (AuNP's) exhibit interesting chemical and physical properties and for this reason are intensively tested in medicine. However there is a lack of information about toxicity of those nanoparticles as well as their excretion from the body. Thus, the aim of the present study was to investigate the influence of the route of administration of gold nanoparticles to rats on their distribution in tissues and excretion rate. METHODS: The experiment was carried out on male Wistar rats. The colloidal gold suspension containing 0.3619 mg of particles per milliliter, was administered per 1 kg of body weight. Serum levels of alanine aminotransferase, aspartate aminotransferase, total cholesterol, triglycerides, glucose and ferric reducing ability of plasma were measured in all investigated animals. RESULTS: It was shown that after oral administration only a small amount of AuNPs was absorbed. In addition, excretion of the metal during consecutive days after po or iv administration was examined. Moreover, the impact of AuNPs on some biochemical parameters 3 days after intravenous administration was studied. It was shown that the AuNPs are mainly cumulated in the liver, lungs and in spleen after iv administration and only slightly removed from the body in urine and feces. CONCLUSION: Accumulation of those nanoparticles effect in increases of FRAP and glucose level up to 27% and 73%, respectively. This in turn suggests that iv administration of AuNPs may effect in serious medical complications. On the other site, the accumulation in the liver of about 50% of introduced particles to the rats body is promising for phototherapy and it opens "door" for drug transport to this organ. PMID- 25933946 TI - The protective effect of curcumin administration on carbon tetrachloride (CCl4) induced nephrotoxicity in rats. AB - BACKGROUND: The aim of the present study was to examine the protective effect of curcumin (CUR) on carbon tetrachloride (CCl4)-induced nephrotoxicity to evaluate the detailed mechanisms by which CUR exerts its protective action. METHODS: Thirty male Wistar-Albino rats weighing 250-300 g were randomly divided into three groups: administrations of olive oil (control, po), CCl4 (0.5mg/kg in olive oil sc) every other day for 3 weeks, and CCl4 (0.5mg/kg in olive oil sc) plus CUR (200mg/kg) every day for 3 weeks. RESULTS: Administration of CCl4 significantly (p<0.001) increased the levels of renal function test such as creatinine and blood urea nitrogen (BUN). Furthermore, treatment of CCl4 significantly elevated the oxidant status of renal tissues while decreasing its anti-oxidant status (p<0.001). CUR displayed a renal protective effect as evident by significant decrease in inflammation and apoptosis during histopathological examination. The administration of CCl4 resulted in an increase in malondialdehyde (MDA) production due to an increase in membrane lipid peroxidation; however, the administration of CUR attenuated this, probably via its antioxidant and free radical scavenging properties. CONCLUSION: The finding of our study indicates that CUR may have an important role to play in protecting the kidney from oxidative insult. PMID- 25933947 TI - Seizure susceptibility to electroconvulsions or pentylenetetrazol after complete cerebral ischemia in rats due to cardiac arrest. AB - BACKGROUND: Experimental data provide evidence on the induction of a susceptibility to audiogenic seizures in rats surviving cardiac arrest and subsequent global brain ischemia. The aim of this study was to find out whether cardiac arrest in rats could affect seizure susceptibility in the long-term period of one and two months, following this event. Seizure susceptibility was evaluated against electroconvulsions and pentylenetetrazol-induced seizures. METHODS: Experiments were conducted on 34 rats surviving cardiac arrest and 34 sham-operated animals which also had surgery but their hearts were not stopped. The threshold for electroconvulsions and pentylenetetrazol was calculated in 3 groups of 5-6 rats. The endpoint for electroconvulsions was the tonic hindlimb extension and for pentylenetetrazol-generalized clonic seizure. RESULTS: The results indicate that cardiac arrest did not modify the threshold for electroconvulsions either one or two months, following the surgery. On the other hand, a significant reduction in the seizure threshold for pentylenetetrazol was noted one month after cardiac arrest. The median convulsive dose of pentylenetetrazol was decreased from 52.47 mg/kg (sham-operated rats) to 34.03 mg/kg of the convulsant for the induction of clonic seizure activity. This effect was not observed at two months after cardiac arrest. CONCLUSIONS: It is evident that global brain ischemia is associated with a transient reduction in the convulsive threshold for pentylenetetrazol whilst the threshold for electroconvulsions remains unchanged. PMID- 25933948 TI - Cocaine exposure alters H2S tissue concentrations in peripheral mouse organs. AB - BACKGROUND: Hydrogen sulfide (H2S) is well-known as a physiological mediator in the mammalian brain and peripheral tissues. Among several factors that change the concentration of H2S, oxidative stress and generation of reactive oxygen species, which accompany neurochemical actions of drugs of abuse, are of recent interest. OBJECTIVE: Limited data on the connection of cocaine and H2S levels prompted us to investigate the effect of this psychostimulant on the H2S concentration in the mouse brain and peripheral organs. METHODS: Male BALB/C mice were given several cocaine dosage and treatment regimens, and the free and acid-labile H2S tissue concentrations were determined with a modified spectrophotometric method of Siegel. RESULTS: We demonstrated the dose- and treatment-dependent decreases in the H2S level in the heart (83% of control level), and in the liver and kidney (17-34% of control levels) homogenates, but no changes were seen in the mouse brain. The strongest effect occurred after repeated administration of cocaine (20mg/kg) in all peripheral tissues. CONCLUSION: A reduction in the peripheral tissue H2S level in the heart, liver and kidney homogenates after repeated injections of cocaine may be the result of a strong toxic effect of the drug. PMID- 25933949 TI - Antiepileptic drugs and adverse skin reactions: An update. AB - This paper summarizes current views on clinical manifestation, pathogenesis, prognosis and management of antiepileptic drug (AED)-induced adverse skin reactions. Cochrane Central Register of Controlled Trials, MEDLINE (PubMed) and ISI Web of Knowledge were searched. The recent classification, among drug-induced skin injuries, points to Stevens-Johnson syndrome/toxic epidermal necrolysis (SJS/TEN), acute generalized exanthematous pustulosis and hypersensitivity syndrome (HSS), which may be also recognized as a drug reaction with eosinophilia and systemic symptoms (DRESS) or drug-induced hypersensitivity syndrome (DIHS). The use of aromatic AEDs, e.g. phenytoin, carbamazepine, oxcarbazepine, phenobarbital, primidone, zonisamide, and lamotrigine is more frequently associated with cutaneous eruption and other signs or symptoms of drug hypersensitivity. There is a high degree of cross-reactivity (40-80%) in patients with hypersensitivity or allergic reactions to AEDs. Pharmacogenetic variations in drug biotransformation may also play a role in inducing these undesired effects. It is suggested that avoidance of specific AEDs in populations at special risk, cautious dose titration and careful monitoring of clinical response and, if applicable, laboratory parameters can minimize the serious consequences of idiosyncratic reactions. PMID- 25933950 TI - Apomorphine enhances harmaline-induced tremor in rats. AB - BACKGROUND: Harmaline-induced tremor is a well-known model of essential tremor in humans. The aim of the present study was to examine the influence of apomorphine, a non-selective dopamine receptor agonist, on the tremor induced by harmaline in rats. Propranolol (a first-line drug in essential tremor) was used as a reference compound. METHODS: Tremor, locomotor activity and focused stereotypy were measured objectively using force plate actimeters. Tremor was analyzed using a Fourier transform to generate power spectra for rhythmic behavior. RESULTS: The tremor induced by harmaline administered at a dose of 15 mg/kg ip was associated with an increase in power in the 9-15 Hz band (AP2) and in the tremor index, calculated as a difference between AP2 and power in the 0-8 Hz band (AP1). Propranolol injected at a dose of 20mg/kg ip reversed both of these effects of harmaline. Apomorphine administered at the doses of 0.5 and 1mg/kg sc further enhanced AP2 and at the lower dose also the tremor index elevated by harmaline. This increase in AP2 was stronger than enhancement of locomotor activity induced by apomorphine in the harmaline-treated animals. CONCLUSIONS: The present study suggests that the dopamine agonist apomorphine enhances the tremor induced by harmaline, and this effect is at least partly independent of hyperactivity. PMID- 25933951 TI - Functional polymorphism of matrix metalloproteinase-9 (MMP9) gene is not associated with schizophrenia and with its deficit subtype. AB - BACKGROUND: The deficit subtype of schizophrenia is hypothesized to constitute a pathophysiologically distinct subgroup of schizophrenia patients suffering from enduring, idiopathic negative symptoms and various neuropsychological deficits. Matrix metalloproteinases (MMPs) are extracellularly acting endopeptidases the substrates of which are matrix and adhesion molecules. Recently, MMP9 has been shown to be involved in various forms of synaptic plasticity, learning and memory consolidation. The primary aim of the present study was to evaluate associations between the functional MMP-9 -1562C/T gene polymorphism and the deficit and non deficit subtypes of schizophrenia. METHODS: The study was conducted between 2009 and 2012. Deficit schizophrenia was diagnosed using the SDS. The sample consisted of 468 patients, Caucasians, of Polish descent with ICD 10 diagnosis of schizophrenia: 189 [51% males] were included in a non-deficit subgroup, 279 patients [53% males] were included in a deficit subgroup. The control group consisted of 532 subjects, Caucasians, of Polish descent [51% males]. MMP-9 1562C/T gene polymorphism was genotyped using the fluorescence resonance energy transfer (FRET) method and the Light Cycler System 2.0. RESULTS: The frequencies of genotypes and alleles did not differ between the schizophrenia patients and control group. The deficit and non-deficit patients did not differ in terms of the genotype and allele frequencies. No differences were found in genotype and allele frequencies between the deficit patients and the controls and between the non-deficit patients and the controls. CONCLUSION: We found no evidence for the association between the functional MMP-9 -1562C/T gene polymorphism and deficit/non-deficit subtypes of schizophrenia. PMID- 25933952 TI - Effect of sodium selenite on chosen anti- and pro-oxidative parameters in rats treated with lithium: A pilot study. AB - BACKGROUND: Selenium is an essential element of antioxidant properties. Lithium is widely used in medicine but its administration can cause numerous side effects including oxidative stress. The present study aimed at evaluating if sodium selenite could influence chosen anti- and pro-oxidant parameters in rats treated with lithium. METHODS: The experiment was performed on four groups of Wistar rats: I (control) - treated with saline; II (Li) - treated with lithium (2.7 mgLi/kg b.w. as Li2CO3), III (Se) - treated with selenium (0.5 mgSe/kg b.w. as Na2SeO3), IV (Li+Se) - treated with Li2CO3 and Na2SeO3 together at the same doses as in group II and III, respectively. All treatments were performed by stomach tube for three weeks in form of water solutions. The following anti- and pro oxidant parameters: total antioxidant status (TAS) value, catalase (CAT) activity, concentrations of ascorbic acid (AA) and malonyldialdehyde (MDA) in plasma as well as whole blood superoxide dismutase (SOD) and glutathione peroxidase (GPx) activities were measured. RESULTS: Selenium given alone markedly enhanced whole blood GPx and diminished plasma CAT vs. CONTROL: Lithium significantly decreased plasma CAT and slightly increased AA vs. CONTROL: Selenium co-administration restored these parameters to the values observed in control animals. Furthermore, selenium co-administration significantly increased GPx in Li-treated rats. All other parameters (TAS, SOD and MDA) were not affected by lithium and/or selenium. CONCLUSION: Further research seems to be warranted to decide if application of selenium as an adjuvant in lithium therapy is worth considering. PMID- 25933953 TI - Context-controlled nicotine-induced changes in the labeling of serotonin (5-HT)2A and 5-HT2C receptors in the rat brain. AB - BACKGROUND: We have previously demonstrated that serotonin (5-HT)2A and 5-HT2C receptor ligands modulate the sensitizing effects of nicotine. In the present study we used male rats to verify the hypothesis that the binding pattern of 5 HT2A and 5-HT2C receptors in the brain is altered by chronic nicotine treatment in different environments. METHODS: Rats were given repeatedly vehicle or nicotine in different sensitizing regimens (home or experimental cages). On day 10, animals were challenged with nicotine (expression of nicotine sensitization) or vehicle in either home or experimental cages, and were sacrificed immediately after the experiment. RESULTS: Repeated treatment with nicotine in home cages evoked significant increases in [(3)H]ketanserin binding to 5-HT2A receptors in the prefrontal cortex, striatal subregions and ventral tegmental area as well as reductions in [(3)H]mesulergine binding to 5-HT2C receptors in subregions of the prefrontal cortex. In contrast, nicotine paired with environmental context produced robust increases in 5-HT2A receptor labeling in the infralimbic cortex and decreased [(3)H]ketanserin binding in striatal subregions and ventral tegmental area; 5-HT2C receptor labeling in the prefrontal cortex fell. CONCLUSIONS: The present data indicate that chronic nicotine administration in home cages induces bi-directional neuroplastic changes within 5-HT2A and 5-HT2C receptors in the prefrontal cortex. Pairing the nicotine with environmental context potentiates the neuroplastic response in the latter region and evokes opposite changes in 5-HT2A receptor binding in striatal and tegmental regions compared with nicotine administered in the absence of the context, indicating a modulatory role of environmental context in the expression of nicotine-induced sensitization. PMID- 25933954 TI - Increased prevalence of functional minor allele variants of drug metabolizing CYP2B6 and CYP2D6 genes in Roma population samples. AB - BACKGROUND: Cytochrome P450 2B6 and 2D6 are important enzymes in human drug metabolism. These phase I enzymes are known to contribute the biotransformation of clinically important pharmaceuticals, including antidepressants, anticancer and anxiolytic drugs. The aim of this work was to determine the pharmacogenetic profile of CYP2B6 and CYP2D6 in Roma and Hungarian population samples. METHODS: A study population of 426 healthy Roma and 431 healthy Hungarian subjects were characterized for CYP2B6 c.516G>T, CYP2D6 c.100C>T and c.1846G>A polymorphisms using predesigned TaqMan Drug Metabolism Genotyping Real Time-PCR assays. RESULTS: We found significant differences in the presence of CYP2B6 c.516G>T (p<0.001), CYP2D6 c.100C>T (p=0.003) and c.1846G>A (p=0.022) between Hungarian and Roma population. The 516T allele frequency was 33.6% in the Roma group, 21.4% in Hungarians, whereas the minor CYP2D6 100T allele was present in 26.6% in Romas and 20.5% in Hungarians. The 1864A allele frequency was 22.5% in Roma and 18.1% in Hungarian samples. A significant increase was found in genotype frequencies for homozygous minor allele carrier Roma participants compared to Hungarians for CYP2B6 516TT and CYP2D6 100TT. The following CYP2D6 genotypes were identified in Roma samples: *1/*1 (55.4%), *1/*4 (2.1%), *1/*10 (3.1%), *4/*10 (38.7%), *10/*10 (0.7%). CONCLUSION: Our results demonstrate an increased minor allele frequency for CYP2B6 and CYP2D6 polymorphisms in Roma samples that implies clinical significance in this ethnic group. PMID- 25933955 TI - Anticonvulsant active inhibitor of GABA transporter subtype 1, tiagabine, with activity in mouse models of anxiety, pain and depression. AB - BACKGROUND: Tiagabine, a selective inhibitor of GABA transporter subtype 1 is used as an add-on therapy of partial seizures in humans but its mechanism of action suggests other potential medical indications for this drug. In this research we assess its pharmacological activity in several screening models of seizures, pain, anxiety and depression in mice. METHODS: For pharmacological tests tiagabine was administered intraperitoneally 60 min before the assay. Behavioral tests were performed using models of chemically and electrically induced seizures, thermal acute pain and formalin-induced tonic pain. Anxiolytic like properties were evaluated using the four plate test and the elevated plus maze test. Antidepressant-like activity was assessed in the forced swim test. In addition, to exclude false positive results in these assays, the influence of tiagabine on animals' locomotor activity and motor coordination was investigated, too. RESULTS: Tiagabine demonstrated anticonvulsant properties in chemically induced seizures (pentylenetetrazole and pilocarpine seizures). At the dose of 100mg/kg it also elevated the seizure threshold for electrically induced seizures by 31.6% (p<0.01), but it had no activity in the maximal electroshock seizure test. Tiagabine showed anxiolytic-like and antidepressant-like effects. Although it apparently reduced animals' nociceptive responses in pain tests, these activities rather resulted from its sedative and motor-impairing properties demonstrated in the locomotor activity and the rotarod tests, respectively. CONCLUSIONS: The results obtained in the present study suggest that tiagabine, apart its anticonvulsant effect, has anxiolytic-like, sedative and antidepressant like properties. In view of this, it can be potentially used in the treatment of anxiety and mood disorders. PMID- 25933956 TI - Ellagic acid enhances the antinociceptive action of venlafaxine in mouse acetic acid-induced pain: An isobolographic analysis. AB - BACKGROUND: Several antidepressants have been used to treat severe pain in clinics. Recently, it has been shown that ellagic acid (EA), a major constituent of pomegranate juice, produced antinociceptive and anti-inflammatory effect through the central and peripheral sites of action. MATERIALS AND METHODS: In this study, we examined the interaction between EA and venlafaxine (VLF) on pain induced by intraperitoneal acetic acid in mice using isobolographic analysis. RESULTS: EA (0.3-10mg/kg, ip) and VLF (3-60 mg/kg, ip) produced a dose-dependent inhibition of the writhing response evoked by acetic acid. Fifty percent effective dose (ED50) values against writhing behaviors were 1.02 (0.86 1.19)mg/kg and 12.37 (9.74-15.37)mg/kg for EA and VLF, respectively, and also with higher potency than that of VLF. Co-administration of increasing fractional increments of ED50 doses of EA and VLF produced synergistic interaction against writhing behaviors, as revealed by isobolographic analysis. CONCLUSION: The synergistic action of EA and VLF provides valuable tool referring to the management of visceral pain. PMID- 25933957 TI - Antidepressant-like effect of modafinil in mice: Evidence for the involvement of the dopaminergic neurotransmission. AB - BACKGROUND: Modafinil is a wake-promoting agent that provides wide ranges of neurological effects. There is evidence that it can produce antidepressant effects. This study investigated the antidepressant effect of modafinil in the tail suspension (TST) in mice. METHODS: Different doses of modafinil was intraperitoneally (ip) administrated and then animals were subjected to TST and/or open field test (OFT). Moreover, the implication of the dopaminergic neurotransmission in modafinil's antidepressant effect was studied. For this purpose, animals were pretreated with haloperidol (non-selective dopamine receptor antagonist), or SCH23390 and sulpiride (the dopamine D1 and D2 receptor antagonist, respectively), then were assessed by TST. The possible effect of sub effective dose of modafinil in combination with sub-therapeutic doses of standard antidepressants was also evaluated in separate groups. RESULTS: Modafinil (75 mg/kg, ip) produced antidepressant effect in TST, as compared to a control group, without any alterations in ambulation in OFT. Pretreatment of mice with haloperidol (0.2mg/kg, ip) and sulpride (50mg/kg, ip) blocked the anti-immobility effect of modafinil (75 mg/kg, ip). We also found that the administration of SCH23390 (0.05 mg/kg, sc) couldn't antagonize the antidepressant effects of modafinil. In addition, a sub-effective dose of modafinil (50mg/kg, ip) potentiated the sub-effective doses of standard antidepressants including of bupropion (1mg/kg, ip), fluoxetine (1mg/kg, ip) and imipramine (0.1mg/kg, ip) and reduced immobility time in TST. CONCLUSION: Results show that modafinil induced an antidepressant property in TST and this effect apparently was mediated through interaction with the dopaminergic (D2 receptors) system. PMID- 25933958 TI - Clonidine intensifies memantine cutaneous analgesia in response to local skin noxious pinprick in the rat. AB - BACKGROUND: The purposes of this study were to evaluate the co-administration of clonidine with memantine and to determine whether it has a peripheral action in intensifying cutaneous analgesia. METHODS: Cutaneous analgesia was examined through inhibition of the cutaneous trunci muscle reflex in response to the local noxious pinprick in rats. Effect of the added subcutaneous clonidine to memantine on infiltrative cutaneous analgesia was assessed and compared with the local anesthetic lidocaine. RESULTS: On the 50% effective dose (ED50) basis, the rank of drug potency was memantine [4.05 (3.95-4.18) MUmol]>lidocaine [5.81 (5.70 5.98) MUmol] (p<0.01). Clonidine at a dose of 0.12 MUmol did not elicit cutaneous analgesia. Mixtures of clonidine (0.12 MUmol) with drug (memantine or lidocaine) at ED50 or ED95 prolonged the duration of action and enhanced the potency as infiltrative cutaneous analgesia. Clonidine enhanced the lidocaine cutaneous analgesia in which had a better effect than added to memantine. CONCLUSIONS: Our resulting data showed that memantine displayed more potent cutaneous analgesia than lidocaine. Co-administration of memantine or lidocaine with clonidine increased the potency and duration of the cutaneous analgesia. Clonidine intensified the effects of lidocaine promoting cutaneous analgesia than added to memantine. PMID- 25933959 TI - Evaluation of the role of NMDA receptor function in antidepressant-like activity. A new study with citalopram and fluoxetine in the forced swim test in mice. AB - BACKGROUND: The NMDA/glutamate receptors are involved in the mechanism of antidepressant activity. METHODS: The present study was designed to investigate the effect of NMDA receptor ligands (agonists and antagonists of glutamate sites) on the antidepressant-like activity of selective serotonin reuptake inhibitors (SSRIs), citalopram and fluoxetine, in the forced swim test in mice. RESULTS: The antidepressant activity (reduction in immobility time) of citalopram but not of fluoxetine was antagonized by N-methyl-D-aspartate acid and enhanced by CGP37849 (antagonist of the NMDA receptor). CONCLUSIONS: The present literature data indicate that the antidepressant-like activity of conventional antidepressants is generally affected by the NMDA receptor, although by modulation from different sites of the complex. Thus, it supports the issue of the ability of NMDA receptor antagonists to enhance the antidepressant action in human depression. PMID- 25933960 TI - Pharmacokinetics of cotinine in rats: a potential therapeutic agent for disorders of cognitive function. AB - BACKGROUND: Attention has been paid to cotinine (COT), one of the major metabolites of nicotine (NIC), for its pro-cognitive effects and potential therapeutic activities against Alzheimer's disease (AD) and other types of cognitive impairment. In order to facilitate pharmacological and toxicological studies on COT for its pro-cognitive activities, we conducted a pharmacokinetic (PK) study of COT in rats, providing important oral and intravenously (iv) PK information. METHODS: In this study, plasma samples were obtained up to 48 h after COT was dosed to rats orally and iv at a dose of 3mg/kg. Plasma samples were prepared and analyzed using a sensitive liquid chromatography tandem mass spectrometry (LC-MS/MS) bioanalytical method, providing concentration profiles of COT and metabolites after oral and iv administrations. RESULTS: The data were fitted into a one-compartment model and a two-compartment model for the oral and iv groups, respectively, providing important PK information for COT including PK profiles, half-life, clearance and bioavailability. The results suggested fast absorption, slow elimination and high bioavailability of COT in rats. CONCLUSIONS: Several important facts about the PK properties in rats suggested COT could be a potential pro-cognitive agent. Information about the pharmacokinetics of COT in rats revealed in this study is of great importance for the future studies on COT or potential COT analogs as agents for improving cognition. PMID- 25933961 TI - Long-term disease-modifying effect of the endocannabinoid agonist WIN55,212-2 in a rat model of audiogenic epilepsy. AB - BACKGROUND: Modulation of the endocannabinoid (eCB) transmission is a promising approach to treating epilepsy. Animal models can be used to investigate this approach. Krushinsky-Molodkina (KM) rats have, genetically, audiogenic epilepsy. Moreover, in these animals, repeated induction of audiogenic seizures results in a progressive prolongation of the seizures, known as audiogenic kindling. METHODS: The present study evaluated, in these KM rats, acute and long-term effects of a single dose of 4 mg/kg of the cannabinoid-receptor agonist WIN55,212 2. RESULTS: Administration of the single dose of WIN55,212-2 one hour before the 4th seizure delayed the kindling process by two weeks, without any acute effect on the audiogenic seizures. CONCLUSIONS: This result suggests that short-term potentiation of the eCB system might modify the epileptogenic disease process in patients with a progressive course of epilepsy. PMID- 25933962 TI - Binge eating in pre-clinical models. AB - Obesity is a globally widespread disease. Approximately 35% of world population has the problem of inappropriate body weight due to sedentary lifestyle, excessive food consumption and the lack of physical activity. In the course of many years, several pharmacological anti-obesity drugs have been discovered. Most of them, however, possess severe side effects. Recent findings suggest that disturbed functioning of the reward system can be involved in the development of obesity. The data coming from clinical and animal studies provide new evidence that links excessive food consumption with compulsive behavior that can lead to binge eating disease occurrence. In this review we discuss most commonly used animal models of binge eating such as restriction/refeeding, limited access and stress schedule model, and related to them neurobiological findings as well. We also present new, anti-obesity drugs, which are characterized by central mechanism of action. PMID- 25933963 TI - Effect of atorvastatin, a HMG-CoA reductase inhibitor in monosodium iodoacetate induced osteoarthritic pain: implication for osteoarthritis therapy. AB - BACKGROUND: Oxidative stress is one of the main causes of pain and cartilage degradation in osteoarthritis. This study on atorvastatin, a HMG-CoA reductase inhibitor used in the treatment of hypercholesterolemia and prevention of coronary heart disease aimed to investigate its effect on hyperalgesia and cartilage damage in monosodium iodoacetate (MIA)-induced osteoarthritis model in rats. METHODS: Osteoarthritis was induced by a single intra-articular injection of 3mg MIA. After daily administration of atorvastatin (3, 10 and 30 mg/kg) for 20 days by oral gavage, pain was assessed on days 0, 1, 3, 7, 14 and 21. Histopathology of ipsilateral knee joint; oxidative markers and antioxidants in plasma were assessed on day 21. RESULTS: Atorvastatin attenuated hyperalgesia. The increased level of lipid peroxidation, superoxide, protein carbonyl; decreased activity of catalase, glutathione-S-transferase, reduced glutathione and total thiol levels in MIA rats were restored to the normal levels, however, superoxide dismutase and nitric oxide levels remained unaltered by atorvastatin. Further, atorvastatin reduced the MIA-induced histopathological alteration in the knee joint. CONCLUSION: Our study demonstrated that atorvastatin attenuates MIA induced osteoarthritic pain and protect cartilage degradation through inhibition of oxidative stress suggesting its importance in osteoarthritic pain management. PMID- 25933964 TI - Telmisartan decreases inflammation by modulating TNF-alpha, IL-10, and RANK/RANKL in a rat model of ulcerative colitis. AB - BACKGROUND: Telmisartan is an antihypertensive angiotensin II receptor blocker. This antihypertensive shows antiinflammatory activity. PURPOSE: In this study, the antiinflammatory activity of telmisartan was tested in an acetic acid (10%) model of ulcerative colitis (UC) in rats. METHODS: Rats were given 1, 3, and 5mg/kg/day of telmisartan orally for 3 days before induction of UC. The same doses were also administered 2 and 24h after induction. Rats from the non-colitis and non-treated colitis groups were administered vehicle (saline, 5 ml/kg) orally and another group received sulfasalazine (50mg/kg/day). Colons tissue was analyzed by macroscopic, by histopathology, by the immunohistochemical examination of RANKL/RANK pathway; by ELISA analysis of the levels of IL-10, TNF alpha, myeloperoxidase (MPO) and malonaldehyde (MDA). RESULTS: Telmisartan at 5mg/kg reduced levels of MPO, MDA, TNF-alpha and increased of IL-10 (p<0.05). Additionally, telmisartan reduced macroscopic damage, number of ulcers, and inflammatory and histopathological processes such as neutrophil infiltration, changes in cytoarchitecture, and necrosis. Immunohistochemistry revealed down regulation of nuclear factor-kappaB receptor/nuclear factor-kappaB ligand (RANK/RANKL) in groups treated with sulfasalazine or telmisartan. CONCLUSION: Telmisartan exerts beneficial effects in an acetic acid model of colitis in rats. These effects may be due to accelerated termination of the acute inflammatory phase, indicated by decreased TNF-alpha and increased production of IL-10 and low expression of RANKL and RANK. PMID- 25933965 TI - Anti-tumor potential of nitroxyl derivative Pirolin in the DMBA-induced rat mammary carcinoma model: A comparison with quercetin. AB - BACKGROUND: Considering the role of oxidative stress in carcinogenesis, we investigated the effect of synthetic antioxidant Pirolin (3-carbamoyl-2,2,5,5 tetramethylpyrroline-1-oxyl) on breast cancer progression. Since the anticancer drugs may cause cardiotoxicity due to oxidative stress in the heart muscle, we also evaluated Pirolin performance in heart tissue and compared its effect with that of the natural dietary flavonoid quercetin. METHODS: Sprague-Dawley rats were administered with 7,12-dimethylbenz(a)anthracene (DMBA) and then treated ip with an antioxidant (each at a dose of 10mg/kg b.w.) for 14 days. The histopathology of tumors, their size and multiplicity were assesed. The effect of antioxidants on heart tissue was evaluated by the oxidative stress markers and poly (ADP-ribose) polymerase 1 (PARP 1) cleavage. RESULTS: The median number of tumors and their volume, at the end of the study, were considerably smaller in both antioxidant-treated groups. We found a better antioxidative performance of quercetin in the heart, since a restoration of the GSH pool and decreased amount of hydroperoxides were observed. Antioxidants did not prevent cardiomyocytes from apoptosis. CONCLUSION: The attenuation of tumor progression by Pirolin was comparable with the action of quercetin. No negative changes were observed in the heart of animals after Pirolin treatment. Thus, its use in targeting deregulated redox pathways should be further studied. PMID- 25933966 TI - Subacute poisoning of mice with deltamethrin produces memory impairment, reduced locomotor activity, liver damage and changes in blood morphology in the mechanism of oxidative stress. AB - BACKGROUND: Deltamethrin (DEL) is a synthetic pyrethroid (PYR) insecticide, potent neurotoxicant. The current investigation was envisaged to explore behavioral, biochemical and morphologic effects of subacute poisoning with DEL in mice and to find one common mechanism of these changes. METHODS: Mice were daily injected ip with different doses of DEL: 8.3, 20.75 or 41.5mg/kg bw for 28 days. Their memory retention in passive avoidance task (PA), fresh spatial memory in a Y-maze and locomotor activity were measured once weekly. On day 29, blood morphology, alanine transaminase (ALT) activity and creatinine concentration in the blood sera, superoxide dismutase (SOD) and glutathione peroxidase (GPx) activities were measured in the livers and kidneys. Livers were examined with light microscopy. RESULTS: Significant impairment of memory retention was recorded on day 2, 7 and 28 after exposure to DEL. Fresh spatial memory was significantly impaired by the highest dose of DEL on day 1, 14 and 28. Locomotor activity was reduced at every stage of experiment in all the groups exposed to DEL. In the animals exposed to the highest dose of DEL activities of alanine transaminase (ALT) and SOD were elevated, GPx was reduced, lymphocyte infiltrates were detected in the livers and there were changes in blood morphology. CONCLUSION: The results obtained indicate that liver and bone marrow, apart from the central nervous system (CNS) are damaged in the course of subacute poisoning with DEL. The possible common mechanism of the damage is oxidative stress. PMID- 25933967 TI - The pharmacokinetic interaction between levofloxacin and sunitinib. AB - BACKGROUND: The aim of this study was to evaluate the impact of sunitinib on pharmacokinetics of levofloxacin. The previous study proved that levofloxacin co administered with sunitib changes the following pharmacokinetic parameters i.e. Cmax and AUC for both sunitinib and SU012662 (sunitinib metabolite). We will also investigate if the limited sample strategy can be applied for levofloxacin. METHODS: Rabbits were divided into two groups. In both groups there were six animals. In the control group levofloxacin was administered and in investigated group levofloxacin and sunitinib were co-administered. The dose of levofloxacin was 20mg/kg and the dose of sunitinib was 25mg. The concentration in plasma was determined by HPLC-FLD. The pharmacokinetic parameters were evaluated by WinNonLin software. The results were evaluated by the following statistical tests: Shapiro-Wilk, t-Student and Mann-Whitney test. RESULTS: Pharmacokinetics of levofloxacin obeys the two-compartment model. Sunitinib influences the following pharmacokinetic parameters of levofloxacin: half-life, elimination constant and volume of distribution. Statistical analysis proved that there is a correlation between AUC and the following five time-points: 0.25 h, 4h, 6h, 10h and 12h. CONCLUSIONS: The study proved that there is a potential pharmacokinetic interaction between sunitinib and levofloxacin. The statistical analysis proved that the limited sample strategy can be applied for levofloxacin. PMID- 25933968 TI - Celecoxib reduces hyperalgesia and tactile allodynia in diabetic rats. AB - BACKGROUND: In the present study we determined the antihyperalgesic and antiallodynic effect of celecoxib in diabetic rats as well as the possible participation of opioid receptors in the mechanism of action of celecoxib in these rats. METHODS: Experimental diabetes was induced by streptozotocin. Formalin (0.5%) was used to produce hyperalgesia in non-diabetic and diabetic rats. von Frey filaments were used to determine the 50% withdrawal threshold in diabetic rats. RESULTS: Oral administration of celecoxib (0.3-30 mg/kg) reduced formalin-induced nociceptive behavior during phase 2. Systemic pre-treatment (-10 min) with naltrexone (3mg/kg) prevented celecoxib-induced antihyperalgesia in formalin-treated diabetic rats. Furthermore, naltrexone as well as the delta and kappa opioid receptor antagonists naltrindole (3mg/kg) and 5'-guanidino naltrindole (1mg/kg), respectively, fully prevented celecoxib-induced antihyperalgesia (10mg/kg) in formalin-treated non-diabetic and diabetic rats. Furthermore, celecoxib (0.3-30 mg/kg) produced an antiallodynic effect in diabetic rats. Pre-treatment with naltrexone (3mg/kg) fully prevented the antiallodynic effect of celecoxib at 0.3, 3 and 10mg/kg. In contrast, this dose of naltrexone only partially prevented the antiallodynic effect of celecoxib 30 mg/kg. Naltrexone and naltrindole (3mg/kg), but not 5'-guanidino naltrindole (1mg/kg), fully prevented the antiallodynic effect of celecoxib in diabetic rats. CONCLUSIONS: Data suggest that celecoxib produces an antihyperalgesic and antiallodynic effect in diabetic rats. These effects seem to result from activation of MU, delta and kappa opioid receptors for antinociception and MU and delta for antiallodynia. Celecoxib could be useful to treat neuropathic pain in diabetic patients. PMID- 25933969 TI - Hypocholesterolemic and choleretic effects of three dimethoxycinnamic acids in relation to 2,4,5-trimethoxycinnamic acid in rats fed with a high cholesterol/cholate diet. AB - BACKGROUND: 2,4,5-Trimethoxycinnamic acid (2,4,5-TMC) is the major and non-toxic metabolite of alpha-asarone, which retains hypocholesterolemic and choleretic activities. We compared the activities of 2,4,5-TMC with those of 2,4 dimethoxycinnamic acid (2,4-DMC), 3,4-DMC and 3,5-DMC, to understand the role of the methoxyls on carbons 2, 4 and 5 on the pharmacologic properties of these compounds. METHODS: The methoxycinnamic acids were administered to high cholesterol/cholate-fed rats. We measured bile flow, and quantified bile acids, phospholipids and cholesterol in bile, and cholesterol and cholesterol lipoproteins in serum. The inhibition of HMG-CoA reductase by the methoxycinnamic acids was evaluated in vitro. RESULTS: The four methoxycinnamic acids decreased serum cholesterol, without affecting the concentration of HDL-cholesterol. 2,4,5 TMC produced the highest decrease in LDL-cholesterol, 73.5%, which exceeds the range of statins (20-40%), and produced the highest inhibition of the activity of HMG-CoA reductase. 3,4-DMC produced the highest increase in bile flow, bile acids and phospholipids concentrations, and reduction in bile cholesterol, which led to a decrease in the biliary cholesterol saturation index. CONCLUSIONS: 2,4,5-TMC (which has three methoxyls) had the highest hypocholesterolemic activity, while 3,4-DMC, which lacks the methoxyl in carbon 2 but conserves the two other methoxyls in an adjacent position, had the highest choleretic activity and a probable cholelitholytic activity. In methoxycinnamic acids with two methoxyls in non-adjacent positions (2,4-DMC and 3,5-DMC), the hypocholesterolemic and choleretic activities were not as evident. 2,4,5-TMC and 3,4-DMC, which did not cause liver damage during the treatment period, should be further explored as a hypocholesterolemic and choleretic compounds in humans. PMID- 25933970 TI - Oxidative stress as an etiological factor and a potential treatment target of psychiatric disorders. Part 1. Chemical aspects and biological sources of oxidative stress in the brain. AB - Oxidative stress is a dysfunctional state of living cells, caused by the disturbance of the pro-/antioxidative equilibrium. This dynamic equilibrium, constitutive for all aerobic organisms, is an inevitable necessity of maintaining the level of oxidative factors on non-destructive value to the cell. Among these factors reactive oxygen species (ROS) and reactive nitrogen species (RNS) are the best known molecules. This review article shows the current state of knowledge on the chemical specificity, relative reactivity and main sources of ROS and RNS in biological systems. As a Part 1 to the report about the role of oxidative stress in psychiatric disorders (see Smaga et al., Pharmacological Reports, this issue), special emphasis is placed on biochemical determinants in nervous tissue, which predisposed it to oxidative damage. Oxidative stress can be identified based on the analysis of various biochemical indicators showing the status of antioxidant barrier or size of the damage. In our article, we have compiled the most commonly used biomarkers of oxidative stress described in the literature with special regard to potentially effective in the early diagnosis of neurodegenerative processes. PMID- 25933971 TI - Oxidative stress as an etiological factor and a potential treatment target of psychiatric disorders. Part 2. Depression, anxiety, schizophrenia and autism. AB - The pathophysiology of psychiatric diseases, including depression, anxiety, schizophrenia and autism, is far from being fully elucidated. In recent years, a potential role of the oxidative stress has been highlighted in the pathogenesis of neuropsychiatric disorders. A body of clinical and preclinical evidence indicates that psychiatric diseases are characterized by higher levels of oxidative biomarkers and with lower levels of antioxidant defense biomarkers in the brain and peripheral tissues. In this article, we review current knowledge on the role of the oxidative stress in psychiatric diseases, based on clinical trials and animal studies, in addition, we analyze the effects of drug-induced modulation of oxidative balance and explore pharmacotherapeutic strategies for oxidative stress reduction. PMID- 25933972 TI - Luteolin 8-C-beta-fucopyranoside downregulates IL-6 expression by inhibiting MAPKs and the NF-kappaB signaling pathway in human monocytic cells. AB - Numerous studies have been suggested that derivatives can improve the effects of original substances. Therefore, we made luteolin derivative luteolin 8-C-beta fucopyranoside (LU8C-FP) for better anti-inflammatory and anti-cancer effects. In a previous study, we demonstrated that LU8C-FP inhibits invasion of human breast cancer cells via suppression of matrix metalloproteinase 9 and IL-8, which play major roles in tumor progression and cancer cell invasion. Various stimuli trigger inflammatory responses by inducing pro-inflammatory cytokines and chemokines in THP-1 cells. IL-6 induces inflammation via inducing various cytokines and appears to be a potential mediator of inflammatory diseases. Here, we investigated the precise mechanism by which LU8C-FP inhibited phorbol 12 myristate 13-acetate-induced IL-6 mRNA and protein expression. We showed LU8C-FP downregulated IL-6 expression by inhibiting mitogen-activated protein kinases and the nuclear factor-kappaB signaling pathway in human monocytic cells. Furthermore, LU8C-FP exerts less cytotoxicity than luteolin and also it has specific inhibitory effect on IL-6 expression. However, luteolin has a variety of inhibitory effects on pro-inflammatory cytokines and chemokines. Our in vitro studies may provide valuable information leading to the use of LU8C-FP to treat inflammatory diseases caused by IL-6. PMID- 25933973 TI - Characterization and preliminary anticonvulsant assessment of some 1,3,4 thiadiazole derivatives. AB - BACKGROUND: The aim of this study was to perform the anticonvulsant screening test to select some 1,3,4-thiadiazole derivatives that could offer a distinct protection against maximal electroshock (MES)-induced seizures in mice. METHODS: The screening test was performed for 13 tested compounds administered intraperitoneally (ip) in a constant dose of 300 mg/kg at various pretreatment times (i.e., 15, 30, 60 and 120 min) before the MES test. Additionally, the active compounds in the screening test were subsequently subjected to the MES test that allowed determination of their median effective doses (ED50 values). RESULTS: Only 2 out of 13 tested 1,3,4-thiadiazole derivatives i.e., 5-butyl-; and 5-heptyl-substituted in the heterocyclic ring 1,3,4-thiadiazoles produced a distinct protection against MES-induced tonic seizures in mice. Time-course and dose-response effects revealed that 5-butyl-2-(2,4-dihydroxyphenyl)-1,3,4 thiadiazole produced its maximum anticonvulsant action at 15 min after its ip administration to mice. In contrast, 5-heptyl-2-(2,4-dihydroxyphenyl)-1,3,4 thiadiazole exerted the maximum anticonvulsant action at 60 min after its ip administration to mice. The ED50 values for 5-butyl-2-(2,4-dihydroxyphenyl)-1,3,4 thiadiazole ranged between 247 and >500 mg/kg, whereas those for 5-heptyl-2-(2,4 dihydroxyphenyl)-1,3,4-thiadiazole ranged between 233 and >500 mg/kg. CONCLUSIONS: 5-Butyl-2-(2,4-dihydroxyphenyl)-1,3,4-thiadiazole and 5-heptyl-2 (2,4-dihydroxyphenyl)-1,3,4-thiadiazole could become potentially favorable antiepileptic drugs, if the results from this study were to be extrapolated into clinical settings. PMID- 25933974 TI - Effects of microinjection of histamine into the anterior cingulate cortex on pain related behaviors induced by formalin in rats. AB - BACKGROUND: The present study was aimed to investigate the effects of microinjection of histamine and its H1, H2 and H3 receptor antagonists, mepyramine, ranitidine and thioperamide, respectively, into the anterior cingulate cortex (ACC) on pain-related behaviors induced by formalin in rats. METHODS: Two stainless steel guide canulas were bilaterally implanted into the ACC of anaesthetized rats. For induction of pain, intraplantar (ipl) injection of a 2.5% formalin solution was performed. The duration of paw licking/biting and the number of paw flinching were recorded in 5 min blocks for 60 min. Locomotor activity was assessed using an open-field test. RESULTS: Formalin produced a marked biphasic pattern of pain. Histamine reduced the second phases of paw licking/biting and flinching. Mepyramine (2 MUg/side) prevented the suppressive effect of histamine (1 MUg/side) on second phase of pain, but at a dose of 8 MUg/side it did not inhibit the suppressive effects of 4 MUg/side of histamine. Ranitidine at doses of 2 and 8 MUg/side prevented histamine (1 and 4 MUg/side) induced antinociception. Thioperamide not only suppressed the second phases of pain, but also increased the suppressive effect of histamine. Naloxone prevented suppressive effects of histamine and thioperamide on pain. Mepyramine (8 MUg/side) suppressed locomotor activity. CONCLUSION: The results of the present study showed pain suppressing effects for histamine. Histamine H2 and H3, and to a lesser extent, H1 receptors might be involved in histamine-induced antinociception. Opioid receptors might be involved in suppressive effects of histamine and thioperamide. PMID- 25933975 TI - Dawn of antioxidants and immune modulators to stop HIV-progression and boost the immune system in HIV/AIDS patients: An updated comprehensive and critical review. AB - In the last two decades, human immunodeficiency virus (HIV), the retrovirus responsible for the acquired immunodeficiency syndrome (AIDS), is one of the leading causes of morbidity and mortality, worldwide. Providing the optimum management of HIV/AIDS is a major challenge in the 21st century. Since, HIV infected persons have an extended lifespan due to the development of effective antiretroviral therapies, malnutrition is becoming central factors of long-term survivors. The nutrition status of AIDS patients has a significant influence on the maintenance and optimal effectiveness of the immune system. Micronutrient therapy in combination with allopathic treatments can extend and improve the quality and quantity of life in individuals infected with HIV/AIDS. HIV infection is thought to lead to augmented oxidative stress which may in turn lead to faster development of HIV disease. Hence, antioxidants might have a significant role in the treatment of HIV/AIDS. An additional approach to treating HIV infection is fortifying the immune response of infected people. Immune modulators help to activate and boost the normal immune function. The present review first describes the boon of antioxidants (especially Vitamin A) and immune modulators (cytolin, resveratrol, murabutide, setarud, tucaresol, AVR118, Immunitin (HE2000), reticulose, and interleukin-7) in the treatment of HIV/AIDS. Then, providing a comparatively succinct outline on updated patents study on antioxidants and immune modulators to treat HIV/AIDS will be discussed. PMID- 25933976 TI - Zinc sulphate: A reasonable choice for depression management in patients with multiple sclerosis: A randomized, double-blind, placebo-controlled clinical trial. AB - INTRODUCTION: Major Depressive Disorder (MDD) is known as one of the most common psychiatric disorders in patients with multiple sclerosis (MS). In recent years, zinc has been found to have beneficial effects on psychopathology and the therapy of depression. The aim of the present study was to examine the effect of zinc supplement on depression and neurological signs in patients with MS. METHODS: The present randomized, double-blind, placebo-controlled clinical trial was performed on 43 patients with MS and who also demonstrated MDD based on the Beck questionnaire. These patients were randomly selected and were divided into two groups: the placebo group (n=22) and the intervention group (n=21). The patients received either zinc sulphate (220 mg containing 50mg zinc element) or a placebo for 12 weeks. Clinical examinations were obtained in terms of abnormal ocular movement, muscle power, and gait disorder. RESULTS: The results indicated that in the patients who received the zinc supplement, the mean score of depression was reduced compared to those in the placebo group, whereas the neurological examinations revealed that there were no differences between the treatment and control groups. CONCLUSION: Therefore, the zinc supplementation is an appropriate choice for the depression management in patients with MS. PMID- 25933977 TI - n-3 Fatty acids as resolvents of inflammation in the A549 cells. AB - BACKGROUND: Fatty acids and their derivatives are one of the most crucial inflammation mediators. The aim of our study was to evaluate the impact of polyunsaturated fatty acids as eicosanoids precursors on the A549 cell line. METHODS: Cells were incubated with 40 MUM of arachidonic, eicosapentaenoic or docosahexaenoic acid for 24h, then activated with LPS. Fatty acids content in the cell membranes were determined using gas chromatography. COX-2, cPGES and FP receptor quantities were determined by Western blot. 8-Isoprostane F2alpha concentrations were determined by EIA. Maresin and protectin D1 contents were analyzed by UHPLC/MS-TOF method. RESULTS: Significant differences in membrane fatty acids and levels of 8-isoPGF2alpha in the activated cells were detected. Elevated expression of COX-2 and FP-receptor was observed in cells treated with AA and activated with LPS. Moreover, compared to AA and AA+LPS groups, cells incubated with EPA, DHA, EPA+LPS and DHA+LPS showed decreased expression of COX 2, cPGES and FP-receptor. In cells incubated with EPA or DHA and activated with LPS maresin and protectin D1 were detected. CONCLUSIONS: The results of the study have revealed the pro-inflammatory properties of AA, while the EPA and DHA had the opposite, resolving effect. Interestingly, FP-receptor inhibition by EPA and DHA demonstrated the unique role of the FP-receptor as a potential target for antagonists, in the diseases of inflammatory character. This study provides new information about n-3 fatty acids and their pro-resolving mediators, which can be used in the process of developing new anti-inflammatory drugs. PMID- 25933978 TI - Effect of chenodeoxycholic acid and sodium hydrogen sulfide in dinitro benzene sulfonic acid (DNBS)--Induced ulcerative colitis in rats. AB - BACKGROUND: Ulcerative colitis is a chronic inflammatory condition in which the inflammatory response confined to the colon. There is a need to explore the new targets for UC such as Farnesoid X receptor and hydrogen sulfide pathway. METHODS: Wistar rats of either sex (200-250 g) were used. 2,4-Dinitrobenzene sulfonic acid (DNBS) (25mg/rat) given by rectal route into the colon to induced symptoms of ulcerative colitis. Chenodeoxycholic acid (CDCA) (10 and 20mg/kg) and sodium hydrogen sulfide (NaHS) (10 and 30 MUmol/kg) and a inhibitor of cystathionine-gamma-lyase enzyme (CSE) i.e. dl-propargylglycine (10mg/kg) treatment given along with 2,4-dinitrobenzene sulfonic acid. The disease activity index was assessed by daily change in body weight and rectal bleed score and change in length of colon. Oxidative stress markers (reduced glutathione, malondialdehyde (MDA), nitrite, and catalase and myeloperoxidase enzyme activity), serum glutamic-oxaloacetic transaminase (SGOT) and serum glutamic pyruvic transaminase (SGPT) levels in blood serum, and cardiac hemodynamic were performed on last day. RESULTS: The administration of DNBS intra-rectally in rats produced loss of body weight and bloody diarrhea with significant increase in oxidative stress markers in the colon. CDCA (10 and 20mg/kg) and NaHS (10 and 30 MUmol/kg) significantly attenuated DNBS-induced UC in rats. The combination of CDCA (10mg/kg) and NaHS (10 MUmol/kg) showed synergetic effect whereas; dl propargylglycine reversed the protective effect of CDCA. CONCLUSION: The observed beneficial effects following CDCA may be due to its action through activation of CSE enzyme which leads to hydrogen sulfide generation. PMID- 25933979 TI - Brain concentrations of mGluR5 negative allosteric modulator MTEP in relation to receptor occupancy--Comparison to MPEP. AB - BACKGROUND: To verify relation between brain free levels, receptor occupancy in vivo and in vitro affinity at the target for mGluR5 negative allosteric modulator (NAM) MTEP. METHODS: We evaluated plasma and brain extra-cellular fluid (ECF) concentration of MTEP at behaviourally active dose (5mg/kg) using in vivo microdialysis. These values were compared it to the affinity in vitro (receptor binding and FLIPR) and to receptor occupancy in vivo. Another, related substance, MPEP was used for comparison. RESULTS: MTEP and MPEP respectively inhibited mGluR5 receptors function in vitro with an affinity of 25.4 and 12.3 nM respectively. Accordingly peak ECF (extracellular fluid) levels were 1.3 and 0.14 MUM, and peak total plasma levels were 7-11 and 2.6 MUM. The ED50 for in vivo receptor occupancy was for both agents in the range of 0.8-0.7 mg/kg. CONCLUSIONS: At behaviourally active dose MTEP produced complete mGluR5 receptor occupancy but over 50 times higher ECF concentrations than affinity for mGluR5 receptor in vitro. This difference is seems lower for other mGluR5 NAM compounds such as MPEP. A possibly explanation could be different distribution in body compartments of both agents leading to errors of estimation with the microdialysis technique or different pharmacological activity at the receptor. PMID- 25933980 TI - beta-Resorcylidene aminoguanidine (RAG) dilates coronary arteries in an endothelium-independent manner. AB - BACKGROUND: beta-Resorcylidene aminoguanidine (RAG), a highly reactive derivative of aminoguanidine, possesses antithrombotic activity which involves the activation of the vascular COX-2/PGI2 pathway. This endothelium-dependent effect suggests that RAG may demonstrate vasomotor activity in arterial vessels. The aim of the present study was to investigate a possible vasoactive action of RAG in coronary arteries of rat heart. METHODS: Isolated rat hearts were perfused in the Langendorff model. To investigate the dose dependency of the effect of RAG on coronary flow, the hearts were perfused with RAG at increasing concentrations. Mechanisms of RAG-mediated vasodilation were subsequently tested using selective inhibitors of the endothelium-dependent and endothelium-independent mechanisms responsible for regulation of vascular tone. RESULTS: RAG dilated coronary arteries at concentrations above 10(-5)mol/l. Inhibition of the endothelium dependent mechanism of vasodilation by NG-nitro-L-arginine methyl ester, indomethacin and aminobenzotriazole did not affect RAG-mediated vasodilation. Other compounds also had no impact on the vasodilating effect of RAG: the NO dependent guanylate cyclase inhibitor - 1H-[1,2,4]oxadiazolo[4,3]quinoxalin-1 one, the cAMP-dependent protein kinase inhibitor - PKAi, and the K(+) channel blockers - glibenclamide, tetraethylammonium, charybdotoxin, and apamin. CONCLUSIONS: RAG is a strong vasodilator that exerts its effect via endothelium independent mechanisms. PMID- 25933981 TI - Role of mTOR inhibitors in epilepsy treatment. AB - In spite of the fact, that subsequent new antiepileptic drugs (AEDs) are being introduced into clinical practice, the percentage of drug-resistant epilepsy cases remains stable. Although a substantial progress has been made in safety profile of antiepileptic drugs, currently available substances have not been unambiguously proven to display disease-modifying effect in epilepsy and their mechanisms of action influence mainly on the end-stage phase of epileptogenesis, namely seizures. Prevention of epileptogenesis requires new generation of drugs modulating molecular pathways engaged in epileptogenesis processes. The mammalian target of rapamycin (mTOR) pathway is involved in highly epileptogenic conditions, such as tuberous sclerosis complex (TSC) and represents a reasonable target for antiepileptogenic interventions. In animal models of TSC mTOR inhibitors turned out to prevent the development of epilepsy and reduce underlying brain abnormalities. Accumulating evidence from animal studies suggest the role of mTOR pathway in acquired forms of epilepsy. Preliminary clinical studies with patients affected by TSC demonstrated seizure reduction and potential disease-modifying effect of mTOR inhibitors. Further studies will determine the place for mTOR inhibitors in the treatment of patients with TSC as well as its potential antiepileptogenic effect in other types of genetic and acquired epilepsies. This review presents current knowledge of mTOR pathway physiology and pathology in the brain, as well as potential clinical use of its inhibitors. PMID- 25933982 TI - Hydrogen sulfide in pharmacology and medicine--An update. AB - Hydrogen sulfide (H2S) is the endogenously produced gasotransmitter involved in the regulation of nervous system, cardiovascular functions, inflammatory response, gastrointestinal system and renal function. Together with nitric oxide and carbon monoxide, H2S belongs to a family of gasotransmitters. H2S is synthesized from L-cysteine and/or L-homocysteine by cystathionine beta-synthase, cystathionine gamma-lyase and cysteine aminotransferase together with 3 mercaptopyruvate sulfurtransferase. Significant progress has been made in recent years in our understanding of H2S biochemistry, signaling mechanisms and physiological role. H2S-mediated signaling may be accounted for not only by the intact compound but also by its oxidized form, polysulfides. The most important signaling mechanisms include reaction with protein thiol groups to form persulfides (protein S-sulfhydration), reaction with nitric oxide and related species such as nitrosothiols to form thionitrous acid (HSNO), nitrosopersulfide (SSNO(-)) and nitroxyl (HNO), as well as reaction with hemoproteins. H2S is enzymatically oxidized in mitochondria to thiosulfate and sulfate by specific enzymes, sulfide:quinone oxidoreductase, persulfide dioxygenase, rhodanese and sulfite oxidase. H2S donors have therapeutic potential for diseases such as arterial and pulmonary hypertension, atherosclerosis, ischemia-reperfusion injury, heart failure, peptic ulcer disease, acute and chronic inflammatory diseases, Parkinson's and Alzheimer's disease and erectile dysfunction. The group of currently available H2S donors includes inorganic sulfide salts, synthetic organic slow-releasing H2S donors, H2S-releasing non-steroidal antiinflammatory drugs, cysteine analogs, nucleoside phosphorothioates and plant-derived polysulfides contained in garlic. H2S is also regulated by many currently used drugs but the mechanism of these effects and their clinical implications are only started to be understood. PMID- 25933983 TI - Zinc, future mono/adjunctive therapy for depression: Mechanisms of antidepressant action. AB - Affective disorders (depression) are considered as chronic illnesses leading to substantial disability, morbidity and mortality. While the etiology and pathophysiology of these diseases are still poorly recognized, the most important problems concerning them are low treatment response, treatment resistance and/or tolerance and risk of relapse. Recently published review articles have already demonstrated the important role of zinc in the pathophysiology and treatment of affective disorders, plus discussed the potential value of zinc as a marker of these diseases. This present concise review will update the experimental and clinical data on the antidepressant activity of zinc and focus on the mechanisms of its action. The mechanisms involving NMDA and AMPA glutamate, 5-HT1A serotonin and the GPR39 zinc-sensing receptor and intracellular pathways will be discussed. PMID- 25933984 TI - Prospects of epileptogenesis prevention. AB - Epilepsy is a common neurologic disease, affecting about 1-2% of the population. In around 30% of patients with epilepsy, their seizures are not satisfactorily controlled and drug-resistant epilepsy constitutes a real therapeutic challenge. Consequently, there are efforts aimed at the inhibition of epileptogenesis, a process of converting a normal into an epileptic brain. Data on this problem have been mainly obtained in post-status epilepticus rodent models in which spontaneous seizure activity and behavioral disturbances develop over time. Among antiepileptic drugs, diazepam at high dose of 20mg/kg given during status epilepticus, significantly inhibited the development of spontaneous seizures and also, a strong neuroprotective effect was evident. Also gabapentin and valproate (over a period of 40 days) proved effective in the inhibition of spontaneous seizure activity and reduction of behavioral deficit. However, there are also data that valproate (over 28 days) significantly improved the behavioral performance without affecting the occurrence of spontaneous seizures. A number of antiepileptic drugs, carbamazepine, lamotrigine, levetiracetam, phenobarbital, and topiramate were completely ineffective. Among non-antiepileptic drugs, some promise show rapamycin, losartan and combinations of anti-inflammatory drugs, targeting different inflammatory pathways. Inhibition of epileptogenesis may become a valuable therapeutic approach provided that there are reliable markers of this process. Actually, such markers begin to emerge. PMID- 25933985 TI - Comparative Distribution, Correlation, and Chemometric Analyses of Selected Metals in Scalp Hair of Angina Patients and Healthy Subjects. AB - Numerous epidemiological studies are preponderance of evidences intimating development of coronary artery disease caused by metal imbalance. The present study was aimed to analyze Ca, Cd, Cr, Cu, Fe, K, Mg, Mn, Na, Pb, Sr, and Zn in the scalp hair of angina patients and healthy subjects/controls employing HNO3 HCLO4-based wet digestion followed by quantification with atomic absorption spectrophotometry. The average concentrations of Cd, Cu, Cr, Fe, Mn, Pb, and Sr revealed significantly higher levels in scalp hair of patients than controls; however, Na and Zn were appreciably higher in healthy subjects. Dissimilarity in the trace metal distribution was also observed with gender, residence, dietary habits, and smoking habits of both donor groups. The correlation study and multivariate analyses revealed diverse mutual relationships and apportionment of the trace metals in the scalp hair of patients and controls. PMID- 25933986 TI - Sobering realizations in cancer prevention and screening and their lessons. PMID- 25933987 TI - The contribution of lifestyle, environment, genetics and chance to cancer risk in individuals and populations. PMID- 25933989 TI - Pulmonary Nodules as Presentation of Pulmonary Artery Aneurysm. PMID- 25933988 TI - Correcting for Brain Swelling's Effects on Infarct Volume Calculation After Middle Cerebral Artery Occlusion in Rats. AB - Evaluating infarct volume is the primary outcome for experimental ischemic stroke studies and is a major factor in determining translation of a drug into clinical trials. Numerous algorithms are available for evaluating this critical value, but a major limitation of current algorithms is that brain swelling is not appropriately considered. The model by Lin et al. is widely used, but overestimates swelling within the infarction, yielding infarct volumes which do not reflect the true infarct size. Herein, a new infarct volume algorithm is developed to minimize the effects of both peri-infarct and infarct core swelling on infarct volume measurement. 2,3,5-Triphenyl-2H-tetrazolium chloride-stained brain tissue of adult rats subjected to middle cerebral artery occlusion was used for infarct volume analysis. When both peri-infarct swelling and infarction core swelling are removed from infarct volume calculations, such as accomplished by our algorithm, larger infarct volumes are estimated than those of Lin et al.'s algorithm. Furthermore, the infarct volume difference between the two algorithms is the greatest for small infarcts (<10% of brain volume) when peri-infarct swelling is the greatest. Finally, using data from four published studies, our algorithm is compared to Lin et al.'s algorithm. Our algorithm offers a more reliable estimation of the infarct volume after ischemic brain injury, and thus may provide the foundation for comparing infarct volumes between experimental studies and standardizing infarct volume quantification to aid in the selection of the best candidates for clinical trials. PMID- 25933990 TI - Infective Endocarditis in a Patient With a Transcatheter LOTUS Valve. PMID- 25933991 TI - Tracking progress in teenage driver crash risk in the United States since the advent of graduated driver licensing programs. AB - INTRODUCTION: This study examined U.S. teenagers' crash rates since 1996, when the first graduated driver licensing (GDL) program in the United State was implemented. METHODS: Passenger vehicle driver crash involvement rates for 16-19 and 30-59 (middle-aged) year-olds were examined, using data from the Fatality Analysis Reporting System, National Automotive Sampling System General Estimates System, Census Bureau, and National Household Travel Surveys. RESULTS: Per capita fatal and police-reported crash rates in 2012 were lower for 16year-olds than for middle-aged drivers but older teenagers' rates were higher. Mileage-based fatal and police-reported crash rates in 2008 were higher for teenagers than for middle aged drivers and higher for 16-17year-olds than for older teenagers. In 1996 2012, teenagers' per capita fatal and police-reported crash rates declined sharply, especially for 16-17year-olds, and more so than for middle-aged drivers. Substantial declines also occurred in teenagers' mileage-based fatal and police reported crash rates from 1995-96 to 2008, generally more so than for middle-aged drivers. Regarding factors in fatal crashes in 1996 and 2012, proportions of young teenagers' crashes occurring at night and with multiple teenage passengers declined, more so than among older teenagers and middle-aged drivers. The proportion of fatally injured drivers who had been drinking declined for teenagers but changed little for middle-aged drivers. Improvements were not apparent in rates of driver errors or speeding among teenage drivers in fatal crashes. CONCLUSIONS: Teenage drivers' crash risk dropped during the period of implementation of GDL laws, especially fatal crash types targeted by GDL. However, teenagers' crash risk remains high, and important crash factors remain unaddressed by GDL. PRACTICAL APPLICATIONS: Although this study was not designed to examine the role of GDL, the results are consistent with the increased presence of such laws. More gains are achievable if states strengthen their laws. PMID- 25933992 TI - Geospatial distribution of fall-related hospitalization incidence in Texas. AB - INTRODUCTION: With the rapid growth of the aging U.S. population, the incidence of falls and fall-related injuries is expected to rise. We examined incidence and characteristics of fall-related hospitalizations (falls) among Texans aged 50 and older, by geography and across time. METHOD: We calculated fall-related hospitalization incidence rates (65 and older), identified fall 'hot spots,' and examined availability of fall-prevention programming. RESULTS: The incidence of fall-related hospitalizations for older adults increased by nearly 20% from 2007 to 2011. There were clusters of 'hot spot' counties throughout the state, many of which lack fall prevention programs. CONCLUSIONS: Increased efforts are needed to identify older adults at elevated risk for falling and develop referral systems for promoting evidence-based fall prevention programs at multiple levels accounting for geographic settings. PRACTICAL APPLICATIONS: Geospatial investigations can inform strategic planning efforts to develop clinical community partnerships to offer fall prevention programming in high risk areas. PMID- 25933993 TI - What affects annual changes in traffic safety? A macroscopic perspective in Virginia. AB - INTRODUCTION: Virginia saw a 20% reduction in traffic fatalities in 2008, an unprecedented annual reduction since 1950, and safety stakeholders in Virginia were intrigued about what caused such large a reduction and more generally what affects traffic safety from a macroscopic perspective. METHOD: This study attempted to find factors associated with such a reduction using historical data of Virginia. Specifically, the study related 18 factors to seven traffic safety measures. RESULTS: In terms of annual changes, the study found that typical crash exposures were not generally associated with the seven measures, while two economic indicators (unemployment rate and U.S. Consumer Price Index [CPI]) were strongly associated with most of them. CONCLUSIONS: Annual changes in the CPI and unemployment rate account for about half of the annual changes in total and fatal crash counts, respectively. On average, a 1 point increase in CPI and a 1% increase in the unemployment rate are associated with about 2,500 fewer traffic crashes and about 40 fewer fatal crashes annually in Virginia, respectively. PMID- 25933994 TI - Contributing factors of crash injury severity at public highway-railroad grade crossings in the U.S. AB - INTRODUCTION: The Moving Ahead for Progress in the 21st Century (MAP-21) includes a separate program that supports safety improvements to reduce the number of fatalities and injuries at public highway-railroad grade crossings (HRGCs). This study identifies the significant factors affecting crash injury severity at public HRGCs in the United States. METHOD: Crashes from 2009 through 2013 on 5,528 public HRGCs, extracted from the Federal Railroad Administration database, were used in the analysis. A comprehensive list of risk factors was explored. Examples include predictors related to geographic region of crash, geometry (e.g., area type and pavement marking type), railroad (e.g., warning device type and railroad class), traffic (e.g., train speed and vehicles annual average daily traffic "AADT"), highway user (e.g., driver age and gender), and environment (e.g., lighting and weather conditions). The study used the mixed logit model to better capture the complex highway user behavior at HRGCs. RESULTS: Female highway users were at higher risk of involvement in injuries and fatalities compared to males. Higher train speeds, very old drivers, open areas, concrete road surface types, and railroad equipment striking highway users before crash, were all found to increase the injury likelihood. On the other hand, young and middle-age drivers, non-passing of standing vehicles at HRGCs, industrial areas, and presence of warning bells were found to reduce injuries and fatalities. CONCLUSIONS: The mixed logit model succeeded in identifying contributing factors of crash severity at public HRGCs and potential countermeasures to reduce both fatalities and injuries are suggested. PRACTICAL APPLICATIONS: It is important to install warning bells at public HRGCs, especially at those with high number of injury and fatality crashes. Enforcement of traffic nearby HRGCs is necessary to prevent vehicles from overtaking of standing vehicles. PMID- 25933995 TI - Drivers' judgments of the effect of headlight glare on their ability to see pedestrians at night. AB - INTRODUCTION: Several studies have concluded that pedestrians typically overestimate their own conspicuity to approaching drivers at night. The present experiments extended this research by exploring the accuracy of drivers' judgments of pedestrian conspicuity while facing varying degrees of headlight glare. METHOD: In Experiment 1, participants on an open road estimated their ability to see a roadside pedestrian in each of two clothing configurations and with each of three different glare intensities present. In Experiment 2, participants responded to a roadside pedestrian under the same open road conditions; the participants were naive with regard to both the position of the pedestrian and to the clothing and glare manipulations. RESULTS: Consistent with earlier research, estimates of response distance were, on the average, over three times greater than actual recognition distance. The extent to which participants overestimated conspicuity was greater when the pedestrian wore a retroreflective vest, and participants incorrectly judged that headlight glare would not degrade drivers' ability to see a pedestrian wearing a retroreflective vest. CONCLUSIONS AND PRACTICAL APPLICATIONS: These results confirm that road users' understanding of issues involving drivers' night vision is limited. These misunderstandings may result in road users behaving in ways that increase the risk of nighttime collisions with pedestrians. PMID- 25933997 TI - Emergency department visits vs. fatalities among substance-impaired underage youths involved in motor vehicle crashes. AB - INTRODUCTION: Emergency department (ED) visits resulting from motor vehicle crashes (MVCs) among individuals younger than 21 impaired by alcohol and/or drugs have been less studied than MVC fatalities. METHOD: Using data from 2004 to 2011, we compare the magnitude and pattern of national ED visit and mortality data for alcohol- and drug-impaired youths involved in MVCs. RESULTS: Temporal patterns of ED visits are similar to those of fatalities, but the two differ in magnitude. The ratio of ED visits to fatalities is 3.5:1; alcohol related events involvement dominates other drugs in both categories. DISCUSSION: The volume of injuries serious enough to warrant ED visits imposes significant health, social, and financial burdens. In ED visits, alcohol is the prime source of MVC morbidity burden; other drugs consistently contribute less. PRACTICAL APPLICATIONS: These incidents are persistent and require interventions aimed at multiple levels of prevention, including stricter corrective steps earlier in the impaired driving career to reduce subsequent incidents. ED visits for MVC injuries can be important "teachable moments." Limitations of the study indicate the need for improved surveillance of underage substance-involved crashes. PMID- 25933996 TI - Prevalence and demographic differences in microaccidents and safety behaviors among young workers in Canada. AB - INTRODUCTION: The present study examines the self-reported frequency of non-lost work time workplace injuries ("microaccidents") and the frequency of three types of work-related safety behaviors (i.e., safety voice, safety compliance, and safety neglect) recalled over a four-week period. METHOD: We analyzed data on microaccidents and safety behaviors from 19,547 young workers (aged 15-25years, Mdn=18years; 55% male) from multiple Canadian provinces. RESULTS: Approximately one-third of all young workers recalled experiencing at least one microaccident at work in the last four weeks. Comparisons across three age groups revealed that younger workers, particularly between the ages of 15-18, reported more frequent microaccidents, less safety voice, less safety compliance, and more safety neglect than workers aged 19-22. This pattern of results also held for comparisons between workers in 19-22 and 23-25 age groups, except for safety voice which did not differ between these two older age groups. In terms of gender, males and females reported the same frequency of microaccidents, but males reported more safety voice, more safety compliance, and more safety neglect than females did. The results and limitations of the present study are discussed. CONCLUSION: Frequency of microaccidents and safety behavior vary among young worker age sub-groups. PMID- 25933998 TI - Leader communication approaches and patient safety: An integrated model. AB - INTRODUCTION: Leader communication is known to influence a number of employee behaviors. When it comes to the relationship between leader communication and safety, the evidence is more scarce and ambiguous. The aim of the present study is to investigate whether and in what way leader communication relates to safety outcomes. The study examines two leader communication approaches: leader safety priority communication and feedback to subordinates. These approaches were assumed to affect safety outcomes via different employee behaviors. METHOD: Questionnaire data, collected from 221 employees at two hospital wards, were analyzed using structural equation modeling. RESULTS: The two examined communication approaches were both positively related to safety outcomes, although leader safety priority communication was mediated by employee compliance and feedback communication by organizational citizenship behaviors. CONCLUSION: The findings suggest that leader communication plays a vital role in improving organizational and patient safety and that different communication approaches seem to positively affect different but equally essential employee safety behaviors. PRACTICAL APPLICATIONS: The results highlights the necessity for leaders to engage in one-way communication of safety values as well as in more relational feedback communication with their subordinates in order to enhance patient safety. PMID- 25933999 TI - The impact of airport characteristics on airport surface accidents and incidents. AB - INTRODUCTION: Airport surface safety and in particular runway and taxiway safety is acknowledged globally as one of aviation's greatest challenges. To improve this key area of aviation safety, it is necessary to identify and understand the causal and contributing factors on safety occurrences. While the contribution of human factors, operations, and procedures has been researched extensively, the impact of the airport and its associated characteristics itself has received little or no attention. METHOD: This paper introduces a novel methodology for risk and hazard assessment of airport surface operations, and models the relationships between airport characteristics, and (a) the rate of occurrences, (b) the severity of occurrences, and (c) the causal factors underlying occurrences. RESULTS: The results show for the first time how the characteristics of airports, and in particular its infrastructure and operations, influence the safety of surface operations. PMID- 25934000 TI - Vehicle characteristics associated with LATCH use and correct use in real-world child restraint installations. AB - INTRODUCTION: The objective of this study was to determine if vehicle features associated with LATCH ease-of-use in laboratory studies with volunteers predict LATCH use and misuse in real-world child restraint installations. METHOD: Vehicle characteristics were extracted from prior surveys of more than 100 top-selling 2010-13 vehicles. Use and correct use of LATCH was determined from records of more than 14,000 child restraint installations in these vehicles that were inspected by child passenger safety technicians at Safe Kids car seat checkup events during 2010-12. Logistic regression was used to examine the association between vehicle features and use and correct use of lower anchors and top tethers, controlling for other relevant installation features. RESULTS: Lower anchors were more likely to be used and correctly used when the clearance angle around them was greater than 54 degrees , the force required to attach them to the lower anchors was less than 178N, and their depth within the seat bight was less than 4cm. Restraints were more likely to be attached correctly when installed with the lower anchors than with the seat belt. After controlling for lower anchor use and other installation features, the likelihood of tether use and correct use in installations of forward-facing restraints was significantly higher when there was no hardware present that could potentially be confused with the tether anchor or when the tether anchor was located on the rear deck, which is typical in sedans. CONCLUSIONS: There is converging evidence from laboratory studies with volunteers and real-world child restraint installations that vehicle features are associated with correct LATCH use. PRACTICAL APPLICATIONS: Vehicle designs that improve the ease of installing child restraints with LATCH could improve LATCH use rates and reduce child restraint misuse. PMID- 25934001 TI - Driving context influences drivers' decision to engage in visual-manual phone tasks: Evidence from a naturalistic driving study. AB - INTRODUCTION: Visual-manual (VM) phone tasks (i.e., texting, dialing, reading) are associated with an increased crash/near-crash risk. This study investigated how the driving context influences drivers' decisions to engage in VM phone tasks in naturalistic driving. METHOD: Video-recordings of 1,432 car trips were viewed to identify VM phone tasks and passenger presence. Video, vehicle signals, and map data were used to classify driving context (i.e., curvature, other vehicles) before and during the VM phone tasks (N=374). Vehicle signals (i.e., speed, yaw rate, forward radar) were available for all driving. RESULTS: VM phone tasks were more likely to be initiated while standing still, and less likely while driving at high speeds, or when a passenger was present. Lead vehicle presence did not influence how likely it was that a VM phone task was initiated, but the drivers adjusted their task timing to situations when the lead vehicle was increasing speed, resulting in increasing time headway. The drivers adjusted task timing until after making sharp turns and lane change maneuvers. In contrast to previous driving simulator studies, there was no evidence of drivers reducing speed as a consequence of VM phone task engagement. CONCLUSIONS: The results show that experienced drivers use information about current and upcoming driving context to decide when to engage in VM phone tasks. However, drivers may fail to sufficiently increase safety margins to allow time to respond to possible unpredictable events (e.g., lead vehicle braking). PRACTICAL APPLICATIONS: Advanced driver assistance systems should facilitate and possibly boost drivers' self-regulating behavior. For instance, they might recognize when appropriate adaptive behavior is missing and advise or alert accordingly. The results from this study could also inspire training programs for novice drivers, or locally classify roads in terms of the risk associated with secondary task engagement while driving. PMID- 25934002 TI - Nonfatal tractor-related injuries presenting to a state trauma system. AB - PURPOSE: To identify tractor-related injuries using data from a statewide trauma system, to characterize the mechanisms of nonfatal tractor-related injury, and to determine which injuries are associated with higher severity injury. METHODS: A retrospective observational study was conducted using the Iowa State Trauma Registry to identify cases of nonfatal tractor-related injuries over an 11-year period from 2002 to 2012. Frequency of injury was reported by age, sex, severity, and nature. Injuries were classified by mechanism and a polytomous regression model was used to predict injury severity adjusting for sex and age. RESULTS: Five-hundred thirteen nonfatal tractor-related injuries were identified with 18% classified as severe. Injuries were most frequent among males and among those >=45years of age. Rollovers were the most frequent mechanism of both total (25%) and severe injury (38%), although the frequency of injury mechanism varied by age. Falls were the next most frequent mechanism of injury (20%) but resulted in fewer high-severity injuries. Collision (adjOR=1.89, 95% CI=1.01-3.51), rollover (adjOR=2.03, 95% CI=1.21-3.40), and run over/rolled on (adjOR=2.06, 95% CI=1.17 3.62) injuries were significantly associated with higher injury severity. Advanced age was also a significant predictor of higher severity injury (adjOR=1.82, 95% CI=1.06-3.12). SUMMARY: Mechanisms of nonfatal tractor-related injuries are heterogeneous, differ by age, and are associated with varying level of severity. PRACTICAL APPLICATIONS: This work shows the burden of nonfatal tractor injuries on a rural state trauma system. These findings also demonstrate the heterogeneous nature of nonfatal tractor injuries and underscore the need for a multi-level approaches to injury prevention. PMID- 25934003 TI - Predictors of rear seat belt use among U.S. adults, 2012. AB - INTRODUCTION: Seat belt use reduces the risk of injuries and fatalities among motor vehicle occupants in a crash, but belt use in rear seating positions is consistently lower than front seating positions. Knowledge is limited concerning factors associated with seat belt use among adult rear seat passengers. METHODS: Data from the 2012 ConsumerStyles survey were used to calculate weighted percentages of self-reported rear seat belt use by demographic characteristics and type of rear seat belt use enforcement. Multivariable regression was used to calculate prevalence ratios for rear seat belt use, adjusting for person-, household- and geographic-level demographic variables as well as for type of seat belt law in place in the state. RESULTS: Rear seat belt use varied by age, race, geographic region, metropolitan status, and type of enforcement. Multivariable regression showed that respondents living in states with primary (Adjusted Prevalence Ratio (APR): 1.23) and secondary (APR: 1.11) rear seat belt use enforcement laws were significantly more likely to report always wearing a seat belt in the rear seat compared with those living in a state with no rear seat belt use enforcement law. CONCLUSIONS AND PRACTICAL APPLICATIONS: Several factors were associated with self-reported seat belt use in rear seating positions. Evidence suggests that primary enforcement covering all seating positions is an effective intervention that can be employed to increase seat belt use and in turn prevent motor vehicle injuries to rear-seated occupants. PMID- 25934004 TI - [Gender inequalities in science: Gaceta Sanitaria takes a step forward]. PMID- 25934005 TI - [Factors associated with empowerment in people with a spinal cord injury due to traffic accidents]. AB - OBJETIVO: Analizar la capacidad de empoderamiento de un grupo de personas con lesion medular en funcion de la edad, el sexo, la condicion funcional y la edaden la cual adquirieron la lesion. METHODS: Ninety-four participants with a spinal cord injury (42 tetraplegics and 52 paraplegics) completed the Spanish version of the Rogers, Chamberlin, Ellison and Crean Scale (1997), designed to measure empowerment. RESULTS: The analyses indicated higher levels of empowerment among women. Persons with tetraplegia whose injury was more longstanding also showed greater empowerment. CONCLUSION: This study suggests that the capacity to become empowered can vary and evolve and should therefore be promoted in intervention programs. PMID- 25934006 TI - The emerging outcome of postoperative radiotherapy for stage IIIA(N2) non-small cell lung cancer patients: based on the three-dimensional conformal radiotherapy technique and institutional standard clinical target volume. AB - BACKGROUND: The aim of this study was to evaluate the clinical efficacy of postoperative radiotherapy (PORT), administered using three-dimensional conformal radiotherapy (3D-CRT) and our institutional standard clinical target volume (CTV) delineation, for completely resected stage IIIA(N2) non-small cell lung cancer (NSCLC). METHODS: From 2005 to 2012, consecutive patients with pT1-3N2 NSCLC who were treated with PORT employing our institutional CTV delineation after complete surgery or who underwent complete resection in our hospital but without PORT were identified. We excluded patients who had received neoadjuvant chemotherapy or radiation therapy (RT). Kaplan-Meier estimates for locoregional recurrence-free survival (LRFS), distant metastasis-free survival (DMFS) and overall survival (OS) were performed. In the OS estimation, patients who received epidermal growth factor receptor tyrosine kinase inhibitor (EGFR-TKI) during follow-up were censored at the time of TKI initiation. RESULTS: Data from 70 patients in the PORT group and 287 in the non-PORT group were analysed. All 70 cases received 3D CRT following our institutional CTV guideline, with a median total dose of 50.4 Gy at 1.8 Gy/fraction. At a median follow-up of 34.3 months for the PORT group and 31.2 months for the non-PORT group, PORT significantly improved local control (5-yr LRFS 91.9% for PORT vs 66.4% for non-PORT, P < 0.001) and OS (5-yr OS 57.5% for PORT vs 35.1% for non-PORT, P = 0.003), whereas no differences in DMFS were noted (P = 0.18). In multivariable analyses, PORT was independently associated with an improved LRFS (HR 0.2, P = 0.001) and OS (HR 0.4, P = 0.001). All patients completed the planned RT dose without interruption of RT due to treatment-related complications. CONCLUSIONS: Our data suggested that PORT administered using the 3D-CRT technique following our institutional CTV delineation guideline resulted in a promising outcome with favourable survival for completely resected IIIA(N2) NSCLC, after controlling for subsequent EGFR-TKI confounding in the OS analysis. Prospective trials are needed to further corroborate these results. PMID- 25934007 TI - Thresholds of Central Systolic Blood Pressure in a Normotensive Chinese Middle Aged Population. AB - An increasing body of evidence has emerged showing that the central systolic blood pressure (CSBP) is more relevant to the risk of cardiovascular (CV) diseases than brachial blood pressure. However, there are no agreed CSBP threshold values above which the risk of CV disease is increased. The aim of our study was to define the threshold values of the CSBP in a normotensive Chinese population; 10 012 adults 35 to 65 years of age were eligible for analysis. We excluded 3765 participants with hypertension, and the final normotensive reference sample consisted of 6247 participants. We defined abnormally high CSBP as exceeding the 90th percentile age- and sex-specific values in the normotensive population. The 90th percentile cutoff value for CSBP in the reference sample was 125 mm Hg in men and 126 mm Hg in women. The CSBP was significantly higher in participants with diabetes, history of CV disease, and hyperlipidemia (P < .001). The CSBP values increased with age (P < .001). We established that the 90th percentile of the CSBP threshold value in normotensive Chinese middle-aged population is 125 mm Hg for men and 126 mm Hg for women. PMID- 25934008 TI - Prefrontal dysfunction in pediatric Tourette's disorder as measured by near infrared spectroscopy. AB - BACKGROUND: Tourette's disorder (TD) is a chronic childhood-onset disorder characterized by the presence of multiple motor and vocal tics. Despite strong evidence that the pathophysiology of TD involves structural and functional disturbances of the basal ganglia and cortical frontal areas, in vivo imaging studies have produced conflicting results. Recent developments in near-infrared spectroscopy (NIRS) technology have enabled noninvasive assessment of brain function in people with psychiatric disorders. METHODS: We asked 10 individuals with pediatric TD and 10 healthy controls who were age- and sex- matched to perform the Stroop color-word task during NIRS. We used prefrontal probes and a 24-channel NIRS machine to measure the relative concentrations of oxyhemoglobin (oxy-Hb) every 0.1 s during the task. RESULTS: We found that oxy-Hb changes in the prefrontal cortex were significantly smaller in the TD group compared with the control group, especially in the left dorsolateral prefrontal cortex. CONCLUSIONS: Our data suggest that individuals with pediatric TD have a reduced prefrontal hemodynamic response as measured by NIRS. PMID- 25934009 TI - From evidence to clinical practice in blood and marrow transplantation. AB - Clinical practice in the field of blood and marrow transplantation (BMT) has evolved over time, as a result of thousands of basic and clinical research studies. While it appears that scientific discovery and adaptive clinical research may be well integrated in case of BMT, there is lack of sufficient literature to definitively understand the process of translation of evidence to practice and if it may be selective . In this review, examples from BMT and other areas of medicine are used to highlight the state of and potential barriers to evidence uptake. Strategies to help improve knowledge transfer are discussed and the role of existing framework provided by the Center for International Blood and Marrow Transplant Registry (CIBMTR) to monitor uptake and BMT Clinical Trials Network (BMT CTN) to enhance translation of evidence into practice is highlighted. PMID- 25934010 TI - Initiation of meiotic homologous recombination: flexibility, impact of histone modifications, and chromatin remodeling. AB - Meiotic recombination is initiated by the formation of DNA double-strand breaks (DSBs) catalyzed by the evolutionary conserved Spo11 protein and accessory factors. DSBs are nonrandomly distributed along the chromosomes displaying a significant (~400-fold) variation of frequencies, which ultimately establishes local and long-range "hot" and "cold" domains for recombination initiation. This remarkable patterning is set up within the chromatin context, involving multiple layers of biochemical activity. Predisposed chromatin accessibility, but also a range of transcription factors, chromatin remodelers, and histone modifiers likely promote local recruitment of DSB proteins, as well as mobilization, sliding, and eviction of nucleosomes before and after the occurrence of meiotic DSBs. Here, we assess our understanding of meiotic DSB formation and methods to change its patterning. We also synthesize current heterogeneous knowledge on how histone modifications and chromatin remodeling may impact this decisive step in meiotic recombination. PMID- 25934011 TI - Reproductive parasitism: maternally inherited symbionts in a biparental world. AB - Most species of insect, and many other plants and animals, carry maternally heritable microorganisms-viruses, bacteria, unicellular eukaryotes, and fungi that pass from a female host to her progeny. Maternal inheritance establishes a correlation between the fitness of symbiont and host female, which can select for the symbiont to contribute to host fitness. Nevertheless, its lack of transmission through male hosts places the symbiont in conflict with biparentally inherited nuclear genes. In this review, we first examine how this conflict is manifest in selection to promote the production and survival of infected female hosts and gametes. We then examine how the distorted population sex ratios that they produce may affect host reproductive ecology, and thus the intensity of other conflicts associated with sexual reproduction. Finally, we examine evolved host responses to symbiont manipulation. We argue that the unusual intensity of symbiont-host conflict generates extreme selection pressures that can drive changes in sex-determination systems, the basic pathway through which males and females are constructed. PMID- 25934012 TI - A phyletic perspective on cell growth. AB - Commonalities, as well as lineage-specific differences among bacteria, fungi, plants, and animals, are reviewed in the context of (1) the coordination of cell growth, (2) the flow of mass and energy affecting the physiological status of cells, (3) cytoskeletal dynamics during cell division, and (4) the coordination of cell size in multicellular organs and organisms. A comparative approach reveals that similar mechanisms are used to gauge and regulate cell size and proliferation, and shows that these mechanisms share similar modules to measure cell size, cycle status, competence, and number, as well as ploidy levels, nutrient availability, and other variables affecting cell growth. However, this approach also reveals that these modules often use nonhomologous subsystems when viewed at modular or genomic levels; that is, different lineages have evolved functionally analogous, but not genomically homologous, ways of either sensing or regulating cell size and growth, in much the same way that multicellularity has evolved in different lineages using analogous developmental modules. PMID- 25934013 TI - Dosage compensation in Drosophila. AB - Dosage compensation in Drosophila increases the transcription of genes on the single X chromosome in males to equal that of both X chromosomes in females. Site specific histone acetylation by the male-specific lethal (MSL) complex is thought to play a fundamental role in the increased transcriptional output of the male X. Nucleation and sequence-independent spreading of the complex to active genes serves as a model for understanding the targeting and function of epigenetic chromatin-modifying complexes. Interestingly, two noncoding RNAs are key for MSL assembly and spreading to active genes along the length of the X chromosome. PMID- 25934014 TI - Adult hippocampal neurogenesis in natural populations of mammals. AB - This review will discuss adult hippocampal neurogenesis in wild mammals of different taxa and outline similarities with and differences from laboratory animals. It begins with a review of evidence for hippocampal neurogenesis in various mammals, and shows the similar patterns of age-dependent decline in cell proliferation in wild and domesticated mammals. In contrast, the pool of immature neurons that originate from proliferative activity varies between species, implying a selective advantage for mammals that can make use of a large number of these functionally special neurons. Furthermore, rapid adaptation of hippocampal neurogenesis to experimental challenges appears to be a characteristic of laboratory rodents. Wild mammals show species-specific, rather stable hippocampal neurogenesis, which appears related to demands that characterize the niche exploited by a species rather than to acute events in the life of its members. Studies that investigate adult neurogenesis in wild mammals are not numerous, but the findings of neurogenesis under natural conditions can provide new insights, and thereby also address the question to which cognitive demands neurogenesis may respond during selection. PMID- 25934015 TI - Enhancing cerebral perfusion with external counterpulsation after ischaemic stroke: how long does it last? AB - OBJECTIVE: External counterpulsation (ECP) is a non-invasive method used to augment cerebral perfusion in ischaemic stroke. We aimed to investigate time course effects on blood pressure elevation and cerebral blood flow augmentation induced by ECP in ischaemic stroke. METHODS: Patients with acute unilateral ischaemic stroke and large artery occlusive disease were recruited to receive 35 daily 1 h ECP treatment sessions. Serial transcranial Doppler monitoring of bilateral middle cerebral arteries was performed on days 3, 5, 7, 10, 14, 21, 28 and 35 after stroke onset. Flow velocity changes before, during and after ECP and continuous beat-to-beat blood pressure data were recorded. The cerebral augmentation index (CAI) is the increase in the percentage of the middle cerebral artery mean flow velocity during ECP compared with baseline. RESULTS: The CAI in patients with stroke was significantly higher on the ipsilateral side and on the contralateral side on day 3 (ipsilateral CAI, 9.3%; contralateral CAI, 7.2%), day 5 (7.0%; 6.7%), day 7 (6.8%; 6.0%), day 10 (6.0%; 5.1%), day 14 (4.7%; 2.6%) and day 21 (4.1%; 2.2%) after stroke onset than that in controls (-2.0%) (all p<0.05). There was a significant trend of decreasing CAI on the ipsilateral and contralateral sides over time after a stroke. Differences in the percentage increase in the mean blood pressure did not change significantly over time in patients with stroke. CONCLUSIONS: Blood pressure elevation persists throughout ECP treatment, which consists of 35 sessions. However, cerebral blood flow augmentation may last at least 3 weeks and then appears to return to baseline 1 month after acute stroke onset. PMID- 25934016 TI - Postoperative apathy can neutralise benefits in quality of life after subthalamic stimulation for Parkinson's disease. AB - BACKGROUND: Subthalamic nucleus deep brain stimulation (STN-DBS) improves motor symptoms of Parkinson's disease, leading to improvement in health-related quality of life (HRQoL). However, an excessive decrease in dopaminergic medication can lead to a withdrawal syndrome with apathy as the predominant feature. The present study aims to assess the impact of postoperative apathy on HRQoL. METHODS: A cohort of 88 patients who underwent STN-DBS was divided into two groups, those who were apathetic at 1 year and those who were not, as measured by the Starkstein scale. HRQoL was assessed using the Parkinson's disease questionnaire 39 (PDQ-39) and was compared between the two groups. We also compared activities of daily living, motor improvement and motor complications (Unified Parkinson's Disease Rating Scale, UPDRS), depression and anxiety, as well as cognition and drug dosages. Baseline characteristics and postoperative complications were recorded. RESULTS: One year after surgery, 27.1% of patients suffered from apathy. While motor improvement was significant and equivalent in both the apathy (-40.4% of UPDRS motor score) and non-apathy groups (-48.6%), the PDQ-39 score did not improve in the apathy group (-5.5%; p=0.464), whereas it improved significantly (-36.7%; p<=0.001) in the non-apathy group. Change in apathy scores correlated significantly with change in HRQoL scores (r=0.278, p=0.009). Depression and anxiety scores remained unchanged from baseline in the apathy group (p=0.409, p=0.075), while they improved significantly in patients without apathy (p=0.006, p<=0.001). A significant correlation was found between changes in apathy and depression (r=0.594, p<=0.001). CONCLUSIONS: The development of apathy after STN-DBS can cancel out the benefits of motor improvement in terms of HRQoL. Systematic evaluation and management of apathy occurring after subthalamic stimulation appears mandatory. PMID- 25934017 TI - Applicability of Demirjian's four methods and Willems method for age estimation in a sample of Turkish children. AB - The aim of this study was to evaluate applicability of five dental methods including Demirjian's original, revised, four teeth, and alternate four teeth methods and Willems method for age estimation in a sample of Turkish children. Panoramic radiographs of 799 children (412 females, 387 males) aged between 2.20 and 15.99years were examined by two observers. A repeated measures ANOVA was performed to compare dental methods among gender and age groups. All of the five methods overestimated the chronological age on the average. Among these, Willems method was found to be the most accurate method, which showed 0.07 and 0.15years overestimation for males and females, respectively. It was followed by Demirjian's four teeth methods, revised and original methods. According to the results, Willems method can be recommended for dental age estimation of Turkish children in forensic applications. PMID- 25934018 TI - Lancet Commission. Editor's note. PMID- 25934019 TI - The Lancet Commission on Global Surgery Global surgery 2030: Evidence and solutions for achieving health, welfare and economic development. PMID- 25934020 TI - Assessing cesarean section and inguinal hernia repair as proxy indicators of the total number of surgeries performed in Sierra Leone in 2012. AB - BACKGROUND: The traditional tools to assess surgical capacity in low-income countries require significant amounts of time and resources, and have thus not been utilized systematically in this context. Proxy indicators have been suggested as a simpler tool to estimate surgical volume. The aim of this study was to assess caesarean section and inguinal hernia repair as proxy indicators of the total number of surgeries performed per capita in a given region of sub Saharan Africa. METHODS: Surgical data was compiled from 58 health institutions (96.7%) that performed major surgery in Sierra Leone in 2012. In total, 24,152 operative procedures were included in the study. Validity of proxy indicators was tested by logistic regression analyses with the rate of caesarean sections compared with total operations (%CS), hernia repairs (%HR) or both (%CS&HR) as dependent variables and the operations per 100,000 capita as the covariate. RESULTS: There was significant correlation for each of the proxy indicators, with the estimated odds ratio for %CS being 0.675 (95% CI, 0.520-0.876; P < .01), the estimated odds ratio for %HR being 0.822 (95% CI, 0.688-0.983; P < .05), and the estimated odds ratio for %CS&HR being 0.838 (95% CI, 0.731-0.962; P < .05). CONCLUSION: The unmet need for surgical services in a region of sub-Saharan Africa can be estimated by using any of the 3 proxy indicators. However, it seems that %CS is more sensitive for small changes in operations per 100,000 capita, compared with the %HR. There is no obvious added benefit for using the combined proxy indicator. PMID- 25934021 TI - Injury prevalence and causality in developing nations: Results from a countrywide population-based survey in Nepal. AB - BACKGROUND: Traumatic injury affects nearly 5.8 million people annually and causes 10% of the world's deaths. In this study we aimed to estimate injury prevalence, to describe risk-factors and mechanisms of injury, and to estimate the number of injury-related deaths in Nepal, a low-income South Asian country. METHODS: A cluster randomized, cross-sectional nationwide survey using the Surgeons OverSeas Assessment of Surgical Need tool was conducted in Nepal in 2014. Questions were structured anatomically and designed around a representative spectrum of operative conditions. Two-stage cluster sampling was performed: 15 of 75 districts were chosen randomly proportional to population; within each district, after stratification for urban and rural populations, 3 clusters were randomly chosen. Injury-related results were analyzed. RESULTS: A total of 1,350 households and 2,695 individuals were surveyed verbally, with a response rate of 97%. A total of 379 injuries were reported in 354 individuals (13.1%, 95% confidence interval 11.9-14.5%), mean age of 32.6. The most common mechanism of injury was falls (37.5%), road traffic injuries (19.8%), and burns (14.2%). The most commonly affected anatomic site was the upper extremity (42.0%). Of the deaths reported in the previous year, 16.3% were injury-related; 10% of total deaths may have been averted with access to operative care. CONCLUSION: This study provides baseline data on the epidemiology of traumatic injuries in Nepal and is the first household-based countrywide assessment of injuries in Nepal. These data provide valuable information to help advise policymakers and government officials for allocation of resources toward trauma care. PMID- 25934022 TI - Operative trauma in low-resource settings: The experience of Medecins Sans Frontieres in environments of conflict, postconflict, and disaster. AB - BACKGROUND: Conflicts and disasters remain prevalent in low- and middle-income countries, and injury remains a leading cause of death worldwide. The objective of this study was to describe the operative procedures performed for injury related pathologies at facilities supported by Medecins Sans Frontieres (MSF) to guide the planning of future responses. METHODS: A retrospective review of a prospectively collected database of all MSF procedures performed between July 2008 and June 2014 for injury-related indications was completed. Individual data points included country of project and date of procedure; age, patient sex, and the American Society of Anesthesiologists' score of each patient; indication for surgery, including mechanism of injury; operative procedure; operative urgency; operative order; type of anesthesia; and intraoperative mortality. Injury severity was stratified according to operative order and urgency. RESULTS: A total of 79,715 procedures were performed in MSF projects that met the inclusion criteria. Of these, 35,756 (44.9%) were performed specifically for traumatic indications across 17 countries. Even after excluding trauma centers, 29.4% (18,329/62,288) of operative cases were for injuries. Operative trauma procedures were performed most commonly for road traffic injuries (29.9%; 10,686/35,756). The most common procedure for acute trauma was extensive wound debridement (31.6%; 3,165/10,022) whereas burn dressings were the most frequent planned reoperation (27.1%; 4,361/16,078). CONCLUSION: Trauma remains an important component of the operative care provided in humanitarian assistance. This review of procedures performed by MSF in a variety of settings provides valuable insight into demographics of trauma patients, mechanisms of injury, and surgical capabilities required in planning resource allocation for future humanitarian missions in low- and middle-income countries. PMID- 25934023 TI - Surgical need in an aging population: A cluster-based household survey in Nepal. AB - BACKGROUND: With an aging global population comes an obligate and substantial burden of noncommunicable disease, especially in low- and middle-income countries. An unknown proportion of this burden is treatable with surgical expertise. For health system planning, this study aimed to estimate the operative needs of individuals older than 50 of age years in Nepal. METHODS: A 2-stage, cluster randomized, community-based survey was performed in Nepal using the validated Surgeons OverSeas Surgical Assessment Survey (SOSAS). SOSAS collects household demographics and selects household members randomly for verbal, head-to toe examinations for surgical conditions; moreover, SOSAS also completes a verbal autopsy for deaths in the preceding year. Only respondents older than 50 years were included in the analysis. RESULTS: The survey sampled 1,350 households, totaling 2,695 individuals (97% response rate). Of these, 273 surgical conditions were reported by 507 persons ages >= 50 years. Extrapolating, there are potentially 2.1 million people older than 50 years of age with surgically treatable conditions who need care in Nepal (95% confidence interval 1.8-2.4 million; 46,000-62,600 per 100,000 persons). One in 5 deaths was potentially treatable or palliated by surgical care. Although growths or masses (including hernias and goiters) were the surgical condition reported most commonly (25%), injuries and fractures also were common and associated with the greatest disability. Literacy and distance to secondary and tertiary health facilities were associated with lack of care for operative conditions (P < .05). CONCLUSION: There is a large, unmet surgical need among the elderly in Nepal. Low literacy and distance from a capable health facility are the greatest barriers to care. As the global population ages, there is an increasing need to improve surgical services and strengthen health systems to care for this group. PMID- 25934024 TI - Use of major surgery in south India: A retrospective audit of hospital claim data from a large, community health insurance program. AB - BACKGROUND: Information on the use of major surgery in India is scarce. In this study we aimed to bridge this gap by auditing hospital claims from Rajiv Aarogyasri Community Health Insurance Scheme, which provides access to free hospital care through state-funded insurance to 68 million beneficiaries, an estimated 81% of population in the states of Telangana and Andhra Pradesh. METHODS: Publicly available deidentified hospital claim data for all surgery procedures conducted between mid-2008 and mid-2012 were compiled across all 23 districts in Telangana and Andhra Pradesh. RESULTS: A total of 677,332 operative admissions (80% at private hospitals) were recorded at an annual rate of 259 per 100,000 beneficiaries, with male subjects accounting for 56% of admissions. Injury was the most common cause for operative admission (27%) with operative correction of long bone fractures being the most common procedure (20%) identified in the audit. Diseases of the digestive (16%), genitourinary (12%), and musculoskeletal (10%) systems were other leading causes for operative admissions. Most hospital bed-days were used by admissions for injuries (31%) and diseases of the digestive (17%) and musculoskeletal system (11%) costing 19%, 13%, and 11% of reimbursement. Operations on the circulatory system (8%) accounted for 21% of reimbursements. Annual per capita cost of operative claims was US$1.48. CONCLUSION: The use of surgery by an insured population in India continued to be low despite access to financing comparable with greater spending countries, highlighting need for strategies, beyond traditional health financing, that prioritize improvement in access, delivery, and use of operative care. PMID- 25934025 TI - Intrahepatic and intraperitoneal splenosis mimicking hepatocellular carcinoma with abdominal wall metastasis in a patient with hepatitis C cirrhotic liver. PMID- 25934026 TI - Volvulus of the splenic flexure of colon: The coffee bean and whirl signs. PMID- 25934027 TI - Pigmented lymphadenopathy secondary to tattoo ink: A potential masquerader. PMID- 25934028 TI - Measurements in Mandibular Pantomographic X-rays and Relation to Skeletal Mineral Densitometric Values. AB - The gold standard diagnostic modality for osteoporosis is dual-energy X-ray absorptiometry (DXA). But it is expensive and often unavailable. Studies have demonstrated that decreased bone mineral density (BMD) may affect mandibular bone morphometrically on radiographs. Such studies are rare in the Indian population. This study was conducted to evaluate correlation between radiomorphometric markers on digital orthopantomograms (OPGs) and BMD measurements done by DXA in an Indian population. A total of 344 subjects aged 45 years or above, who visited a dental outpatient department over a period of 6 years were included in the study after obtaining ethical committee approval and informed consent. Digital OPG and DXA BMD measurements were obtained. Subjects' T-scores were obtained, on the basis of which they were divided into osteoporotic, osteopenic, and normal. OPGs were evaluated to obtain the mandibular cortical index (MCI) and the panoramic mandibular index (PMI). Correlations of MCI and PMI with BMD were analyzed statistically with SPSS (version 16.0; SPSS, Chicago, IL). In the osteoporotic group, there was no subject with MCI finding of C1, and 77.42% prevalence of C3 finding was found. C2 finding was in highest proportion in the osteopenic group (p<0.05). Normal BMD group was associated with the C1 finding of 76.47%. Almost 48% of the osteoporotic group had a PMI score of <0.40, whereas 50% of osteopenic subjects had a PMI score of 0.4-0.44. Normal subjects having a PMI score of >0.44 constituted 49.1% of the population. Mean BMD scores decreased significantly with increasing MCI stage and increased significantly with increasing PMI (p<0.05). Significant correlations between PMI and MCI were obtained with DXA BMD. Digital OPGs may provide an economical and reliable diagnostic tool to rule out osteoporosis or osteopenia in undiagnosed patients, where DXA screening may not be available or is financially nonviable. PMID- 25934029 TI - Should Dual-Energy X-ray Absorptiometry Technologists Estimate Dietary Calcium Intake at the Time of DXA? AB - Adequate calcium intake is essential for bone health. Calcium is obtained from dietary sources and supplementation. Knowing the daily dietary calcium intake is helpful in deciding on the need for supplementation. Dietary calcium intake can be estimated quickly and accurately using an approach recommended by the National Osteoporosis Foundation. We sought to evaluate the usefulness of estimating dietary calcium intake by a technologist at the time of attendance for dual energy X-ray absorptiometry (DXA) scanning. We conducted a retrospective survey of results on estimated dietary calcium intake in adults attending our DXA unit over 2 years (n=5569). We assessed intake with reference to the specifications of the Institute of Medicine according to sex and age. The average intake was 736 mg daily: Young adults had higher intakes than older adults (p<0.001), and men had higher intakes than women (p=0.017). According to Institute of Medicine's specification, we estimate that nearly 45% of Irish women need supplemental intake of 500 mg daily but <4% need supplemental intake of 1000 mg daily. Younger adults are apt to have intakes within, or higher than, the requirement. Having DXA technologists estimate dietary calcium intake at the time of DXA scanning may provide helpful information to the referring clinicians about the need for supplementation. PMID- 25934030 TI - Hippocampal neuroplasticity in major depressive disorder. AB - One of the most replicated findings has been that hippocampus volume is decreased in patients with major depressive disorder (MDD). Recent volumetric magnetic resonance imaging (MRI) studies suggest that localized differences in hippocampal volume may be more prominent than global differences. Preclinical and post-mortem studies in MDD indicated that different subfields of the hippocampus may respond differently to stress and may also have differential levels of plasticity in response to antidepressant treatment. Advances in high-field MRI allowed researchers to visualize and measure hippocampal subfield volumes in MDD patients in vivo. The results of these studies provide the first in vivo evidence that hippocampal volume reductions in MDD are specific to the cornu ammonis and dentate gyrus hippocampal subfields, findings that appear, on the surface, consistent with preclinical evidence for localized mechanisms of hippocampal neuroplasticity. In this review we discuss how recent advances in neuroimaging allow researchers to further understand hippocampal neuroplasticity in MDD and how it is related to antidepressant treatment, memory function, and disease progression. PMID- 25934031 TI - Potentiation of tonic GABAergic inhibition by activation of postsynaptic kainate receptors. AB - Presynaptic kainate-type glutamate ionotropic receptors (KARs) that mediate either the depression or the facilitation of GABA release have been intensively studied. Little attention has been given to the modulation of GABAA receptors (GABAARs) by postsynaptic KARs. Recent studies suggest that two GABAAR populations, synaptic (sGABAAR) and extrasynaptic (eGABAAR) GABAARs, mediate phasic and tonic forms of inhibition, respectively. Tonic inhibition plays an important role in the excitability of neuronal circuits and the occurrence of epileptic seizures. For this study, we are the first to report that the activation of postsynaptic KARs by the KAR agonist, Kainic acid (KA, 5 MUM), enhanced tonic inhibition by potentiating eGABAARs. KA enhanced THIP-induced eGABAAR currents and prolonged the rise and decay time of muscimol-induced sGABAAR/eGABAAR currents, but also depressed the amplitude of evoked inhibitory postsynaptic currents (IPSCs), unitary IPSCs (uIPSCs), and muscimol-induced sGABAAR/eGABAAR currents. The PKC inhibitor, staurosporine (1 MUM), in the patch pipette solution fully blocked the KA-induced potentiation of tonic inhibition, suggesting the involvement of an intracellular PKC pathway. Our study suggests that the activation of postsynaptic KARs potentiates eGABAARs but depresses sGABAARs. By activating postsynaptic KARs, synaptically released glutamate depresses phasic inhibition to facilitate neuronal plasticity, but potentiates tonic inhibition to protect neurons from over-excitation. PMID- 25934032 TI - Imaging microstructural damage and plasticity in the hippocampus during epileptogenesis. AB - Epileptogenesis refers to the development and extension of tissue capable of generating spontaneous seizures, resulting in the development of an epileptic condition and/or progression of epilepsy after the condition is established. The hippocampus is the seizure-initiating zone in many epilepsy patients as well as in animal models of epilepsy. During epileptogenesis, the hippocampus undergoes structural changes, including mossy fiber sprouting; alterations in dendritic branching, spine density, and shape; and neurogenesis. In vivo magnetic resonance imaging (MRI) techniques provide insights into the microstructural organization of the hippocampus. An assessment of the structural plasticity of the hippocampus may provide parameters that could be used as biomarkers for epileptogenesis. Here we review conventional and more advanced MRI methods for detecting hippocampal tissue changes related to epileptogenesis. In addition, we summarize how diffusion tensor imaging can reveal cellular damage and plasticity, even at the level of hippocampal subfields. Finally, we discuss challenges and future directions for using novel MRI techniques in the search of biomarkers associated with epileptogenesis after brain injury. PMID- 25934033 TI - Hindbrain lactate regulates preoptic gonadotropin-releasing hormone (GnRH) neuron GnRH-I protein but not AMPK responses to hypoglycemia in the steroid-primed ovariectomized female rat. AB - Steroid positive-feedback activation of the gonadotropin-releasing hormone (GnRH) pituitary luteinizing hormone (LH) neuroendocrine axis propagates the pre ovulatory LH surge, a crucial component of female reproduction. Our work shows that this key event is restrained by inhibitory metabolic input from hindbrain A2 noradrenergic neurons. GnRH neurons express the ultra-sensitive energy sensor adenosine 5'-monophosphate-activated protein kinase (AMPK); here, we investigated the hypothesis that GnRH nerve cell AMPK and peptide neurotransmitter responses to insulin-induced hypoglycemia are controlled by hindbrain lack of the oxidizable glycolytic end-product L-lactate. Data show that hypoglycemic inhibition of LH release in steroid-primed ovariectomized female rats was reversed by coincident caudal hindbrain lactate infusion. Western blot analyses of laser-microdissected A2 neurons demonstrate hypoglycemic augmentation [Fos, estrogen receptor-beta (ER-beta), phosphoAMPK (pAMPK)] and inhibition (dopamine beta-hydroxylase, GLUT3, MCT2) of protein expression in these cells, responses that were normalized by insulin plus lactate treatment. Hypoglycemia diminished rostral preoptic GnRH nerve cell GnRH-I protein and pAMPK content; the former, but not the latter response was reversed by lactate. Results implicate caudal hindbrain lactoprivic signaling in hypoglycemia-induced suppression of the LH surge, demonstrating that lactate repletion of that site reverses decrements in A2 catecholamine biosynthetic enzyme and GnRH neuropeptide precursor protein expression. Lack of effect of lactate on hypoglycemic patterns of GnRH AMPK activity suggests that this sensor is uninvolved in metabolic-inhibition of positive-feedback-stimulated hypophysiotropic signaling to pituitary gonadotropes. PMID- 25934034 TI - Sex-specific restoration of MK-801-induced sensorimotor gating deficit by environmental enrichment. AB - Despite ample evidence of N-methyl-D-aspartate (NMDA) receptor dysfunction in schizophrenia, no study has addressed the effects of enriched environment (EE) on sensorimotor gating deficits induced by postnatal NMDA receptor blockade. We evaluated the effect of EE on sensorimotor gating (measured by prepulse inhibition, PPI), or on sensorimotor gating deficit induced by the NMDA receptor antagonist (+)-5-methyl-10,11-dihydro-5H-dibenzo[a,d]cyclohepten-5,10-imine maleate (MK-801) in both sexes of Wistar rats. Rats were injected with MK-801 (1 mg/kg) on postnatal days (P) 6-10. EE was provided from birth up to the time of experiments on P28-30 or P58-60. PPI data were collected at three prepulse intensities and then averaged to yield global PPI. MK-801 treatment reduced PPI significantly in both sexes. While EE per se had no significant effect on PPI, it restored MK-801-induced PPI deficit only in male rats. An extended period of EE did not influence PPI deficit in female rats. Our results indicate that postnatal exposure to MK-801 may exert long-lasting effects on neuronal circuits underlying sensorimotor gating. Sex-specific modulation of such effects by EE suggests sexually dimorphic mechanisms are involved. PMID- 25934035 TI - The 3-second auditory conditioned stimulus is a more effective stressor than the 20-second auditory conditioned stimulus in male rats. AB - Using fear-conditioning model, we have used a 3-s auditory conditioned stimulus (CS) as a stressor and observed fear and stress responses during a specific experimental period regardless of the presence or absence of the CS. Because the CS was extremely short compared with the experimental period, we observed responses primarily in the absence of the CS. In contrast, most studies in the literature have analyzed responses in the presence of the CS. Therefore, the characteristics of fear and stress responses in the absence of the CS remain to be clarified. To clarify this, we compared the characteristics of fear and stress responses elicited by a 3-s auditory CS with those observed during a 20-s auditory CS. The basolateral complex of the amygdala (BLA), but not the bed nucleus of the stria terminalis (BNST), participated in the fear response elicited by the 3-s CS, whereas both the BLA and BNST were involved in the response observed during the 20-s CS. Additional analyses revealed that the BNST participated in the fear response during the 20-s CS when the CS was paired with a 0.75-mA, but not with a 0.9-mA, foot shock, and to the contextual CS. In addition, the fear response elicited by the 3-s CS was more resistant to extinction than that during the 20-s CS. Finally, the 3-s CS produced more intense freezing and corticosterone secretion than the 20-s CS. On the basis of these characteristics, we conclude that the 3-s auditory CS is a more effective stressor than the 20-s auditory CS. Our findings also suggest that foot shock intensity is an additional determinant in the type of fear response induced by the CS. PMID- 25934037 TI - Deconstructing 5-HT6 receptor effects on striatal circuit function. AB - Medium spiny neurons (MSNs) constitute 95% of neurons in the dorsal striatum subdivided into direct (striatonigral) and indirect (striatopallidal) pathways. Whereas D1 and D2 receptors and several neuropeptides, including dynorphin and enkephalin, are differentially expressed in these neurons, 5-hydroxytryptamine 6 receptors (5-HT6) are expressed in both pathways. Previous results demonstrate that concurrent 5-HT6 receptor overexpression in MSNs of both pathways in the dorsomedial striatum (DMS) interferes with instrumental learning and that 5-HT6 overexpression in the dorsolateral striatum (DLS) relieves rats from inflexible habitual behaviors. We hypothesized that 5-HT6 receptor-mediated co-activation of both pathways interferes with the differential activation/inhibition of direct/indirect pathways by dopamine. To test this idea, we cloned novel viral vectors to selectively overexpress 5-HT6 receptors in direct or indirect pathway MSNs to deconstruct their role in modulating instrumental learning and habitual responding. We found that increasing 5-HT6 receptor expression in either direct or indirect pathway MSNs of the posterior DMS selectively enhanced or impaired initial acquisition of a discrete instrumental learning task respectively, though all rats were ultimately able to learn the task. In a separate set of experiments, 5-HT6 receptor overexpression in indirect pathway MSNs of the DLS facilitated behavioral flexibility in rats overtrained on a repetitive pressing task using a variable interval schedule of reinforcement, during an omission contingency training session and subsequent probe testing. Together these findings further the notion that 5-HT6 signaling causes balanced activation of opposing MSN pathways by serotonin in sub-regions of the dorsal striatum allowing for more reflective modalities of behavior. PMID- 25934036 TI - Models and mechanisms for hippocampal dysfunction in obesity and diabetes. AB - Clinical studies suggest that obesity and Type 2 (insulin-resistant) diabetes impair the structural integrity of medial temporal lobe regions involved in memory and confer greater vulnerability to neurological insults. While eliminating obesity and its endocrine comorbidities would be the most straightforward way to minimize cognitive risk, structural barriers to physical activity and the widespread availability of calorically dense, highly palatable foods will likely necessitate additional strategies to maintain brain health over the lifespan. Research in rodents has identified numerous correlates of hippocampal functional impairment in obesity and diabetes, with several studies demonstrating causality in subsequent mechanistic studies. This review highlights recent work on pathways and cell-cell interactions underlying the synaptic consequences of obesity, diabetes, or in models with both pathological conditions. Although the mechanisms vary across different animal models, immune activation has emerged as a shared feature of obesity and diabetes, with synergistic exacerbation of neuroinflammation in model systems with both conditions. This review discusses these findings with reference to the benefits of incorporating existing models from the fields of obesity and metabolic disease. Many transgenic lines with basal metabolic alterations or differential susceptibility to diet-induced obesity have yet to be characterized with respect to their cognitive and synaptic phenotype. Adopting these models, and building on the extensive knowledge base used to generate them, is a promising avenue for understanding interactions between peripheral disease states and neurodegenerative disorders. PMID- 25934038 TI - Tracing the trajectory of behavioral impairments and oxidative stress in an animal model of neonatal inflammation. AB - Exposure to early-life inflammation results in time-of-challenge-dependent changes in both brain and behavior. The consequences of this neural and behavioral reprogramming are most often reported in adulthood. However, the trajectory for the expression of these various changes is not well delineated, particularly between the juvenile and adult phases of development. Moreover, interventions to protect against these neurodevelopmental disruptions are rarely evaluated. Here, female Sprague-Dawley rats were housed in either environmental enrichment (EE) or standard care (SC) and their male and female offspring were administered 50 MUg/kg i.p. of lipopolysaccharide (LPS) or pyrogen-free saline in a dual-administration neonatal protocol. All animals maintained their respective housing assignments from breeding until the end of the study. LPS exposure on postnatal days (P) 3 and 5 of life resulted in differential expression of emotional and cognitive disruptions and evidence of oxidative stress across development. Specifically, social behavior was reduced in neonatal-treated (n)LPS animals at adolescence (P40), but not adulthood (P70). In contrast, male nLPS rats exhibited intact spatial memory as adolescents which was impaired in later life. Moreover, these males had decreased prefrontal cortex levels of glutathione at P40, which was normalized in adult animals. Notably, EE appeared to offer some protection against the consequences of inflammation on juvenile social behavior and fully prevented reduced glutathione levels in the juvenile prefrontal cortex. Combined, these time-dependent effects provide evidence that early-life inflammation interacts with other developmental variables, specifically puberty and EE, in the expression (and prevention) of select behavioral and molecular programs. PMID- 25934040 TI - Local group I mGluR antagonists reduce TMJ-evoked activity of trigeminal subnucleus caudalis neurons in female rats. AB - Group I metabotropic glutamate receptors (mGluR1 and mGluR5) are functionally linked to estrogen receptors and play a key role in the plasticity of central neurons. Estrogen status strongly influences sensory input from the temporomandibular joint (TMJ) to neurons at the spinomedullary (Vc/C1-2) region. This study tested the hypothesis that TMJ input to trigeminal subnucleus caudalis/upper cervical cord (Vc/C1-2) neurons involved group I mGluR activation and depended on estrogen status. TMJ-responsive neurons were recorded in superficial laminae at the Vc/C1-2 region in ovariectomized (OvX) female rats treated with low-dose estradiol (2 MUg/day, LE) or high-dose estradiol (20 MUg/day, HE) for 2 days. TMJ-responsive units were activated by adenosine triphosphate (ATP, 1mM) injected into the joint space. Receptor antagonists selective for mGluR1 (CPCCOEt) or mGluR5 (MPEP) were applied topically to the Vc/C1-2 surface at the site of recording 10 min prior to the intra-TMJ ATP stimulus. In HE rats, CPCCOEt (50 and 500 MUM) markedly reduced ATP-evoked unit activity. By contrast, in LE rats, a small but significant increase in neural activity was seen after 50 MUM CPCCOEt, while 500 MUM caused a large reduction in activity that was similar in magnitude as that seen in HE rats. Local application of MPEP produced a significant inhibition of TMJ-evoked unit activity independent of estrogen status. Neither mGluR1 nor mGluR5 antagonism altered the spontaneous activity of TMJ units in HE or LE rats. High-dose MPEP caused a small reduction in the size of the convergent cutaneous receptive field in HE rats, while CPCCOEt had no effect. These data suggest that group I mGluRs play a key role in sensory integration of TMJ nociceptive input to the Vc/C1-2 region and are largely independent of estrogen status. PMID- 25934039 TI - Altered expression of neuroplasticity-related genes in the brain of depressed suicides. AB - BACKGROUND: Expression of the neuronal membrane glycoprotein M6a (GPM6A), the proteolipid protein (PLP/DM20) family member, is downregulated in the hippocampus of chronically stressed animals. Its neuroplastic function involves a role in neurite formation, filopodium outgrowth and synaptogenesis through an unknown mechanism. Disruptions in neuroplasticity mechanisms have been shown to play a significant part in the etiology of depression. Thus, the current investigation examined whether GPM6A expression is also altered in human depressed brain. METHODS: Expression levels and coexpression patterns of GPM6A, GPM6B, and PLP1 (two other members of PLP/DM20 family) as well as of the neuroplasticity-related genes identified to associate with GPM6A were determined using quantitative polymerase chain reaction (qPCR) in postmortem samples from the hippocampus (n = 18) and the prefrontal cortex (PFC) (n = 25) of depressed suicide victims and compared with control subjects (hippocampus n = 18; PFC n = 25). Neuroplasticity related proteins that form complexes with GPM6A were identified by coimmunoprecipitation technique followed by mass spectrometry. RESULTS: Results indicated transcriptional downregulation of GPM6A and GPM6B in the hippocampus of depressed suicides. The expression level of calcium/calmodulin-dependent protein kinase II alpha (CAMK2A) and coronin1A (CORO1A) was also significantly decreased. Subsequent analysis of coexpression patterns demonstrated coordinated gene expression in the hippocampus and in the PFC indicating that the function of these genes might be coregulated in the human brain. However, in the brain of depressed suicides this coordinated response was disrupted. CONCLUSIONS: Disruption of coordinated gene expression as well as abnormalities in GPM6A and GPM6B expression and expression of the components of GPM6A complexes were detected in the brain of depressed suicides. PMID- 25934041 TI - Effects of long-term methylphenidate treatment in adolescent and adult rats on hippocampal shape, functional connectivity and adult neurogenesis. AB - Methylphenidate (MPH) is a widely prescribed stimulant drug for the treatment of attention deficit hyperactivity disorder (ADHD) in children and adolescents. Its use in this age group raises concerns regarding the potential interference with ongoing neurodevelopmental processes. Particularly the hippocampus is a highly plastic brain region that continues to develop postnatally and is involved in cognition and emotional behavior, functions known to be affected by MPH. In this study, we assessed whether hippocampal structure and function were affected by chronic oral MPH treatment and whether its effects were different in adolescent or adult rats. Using behavioral testing, resting-state functional MRI, post mortem structural magnetic resonance imaging (MRI), and immunohistochemistry, we assessed MPH's effects on recognition memory, depressive-like behavior, topological features of functional connectivity networks, hippocampal shape and markers for hippocampal neurogenesis and proliferation. Object recognition memory was transiently impaired in adolescent treated rats, while in animals treated during adulthood, increased depressive-like behavior was observed. Neurogenesis was increased in adolescent treated rats, whereas cell proliferation was decreased following adult treatment. Adolescent treated rats showed inward shape deformations adjacent to ventral parahippocampal regions known to be involved in recognition memory, whereas such deformations were not observed in adult treated animals. Irrespective of the age of treatment, MPH affected topological features of ventral hippocampal functional networks. Thus, chronic oral treatment with a therapeutically relevant dose of MPH preferentially affected the ventral part of the hippocampus and induced contrasting effects in adolescent and adult rats. The differences in behavior were paralleled by opposite effects on adult neurogenesis and granule cell proliferation. PMID- 25934042 TI - Ras does not contribute to the facilitation of hippocampal synaptic plasticity enabled by environmental enrichment. AB - Environmental enrichment (EE), which mimics the wealth of sensory, motor and cognitive stimuli that arise through intense interactions with the ambient environment, results in enhanced hippocampal long-term potentiation (LTP) and spatial learning. A key molecular factor in the mediation of these changes is the brain-derived neurotrophic factor (BDNF). One of the downstream cascades that is activated by BDNF is the cascade linked to the small GTPase, Ras, that triggers mitogen-activated protein kinase (MAPK) activity and is part of the cAMP response element-binding protein (CREB) pathway that can lead to synaptic restructuring to support LTP. Here, we explored whether persistent activation of Ras in neurons further enhances LTP following EE of rodents. Immediately following weaning, transgenic mice that expressed constitutively activated neuronal Ras, or their wildtype (Wt) littermates, underwent 3weeks of constant EE. In the absence of EE, theta burst stimulation (TBS) evoked LTP in the CA1 region of transgenic mice that was not significantly different from LTP in Wts. After 3weeks of EE, hippocampal LTP was improved in Wt mice. Enriched transgenic mice showed an equivalent level of LTP to enriched Wts, but it was not significantly different from non-enriched synRas controls. Western blot analysis performed after a pull down assay showed that non-enriched transgenic mice expressed higher Ras activity compared to non-enriched Wts. Following EE, Ras activity was reduced in transgenics to levels detected in Wts. These results show that constitutive activation of Ras does not mimic the effects of EE on LTP. In addition, EE results in an equivalent enhancement of LTP transgenics and Wts, coupled with a decrease in Ras activity to Wt levels. This suggests that permanent activation of Ras in neurons of synRas animals following EE results in an altered feedback regulation of endogenous Ras activity that is not a key factor in LTP enhancements. The maintenance of Ras within a physiological range may thus be required for the optimization of LTP in the hippocampus. PMID- 25934043 TI - Fatigue accumulation and twitch potentiation during complex MVC-relative profiles. AB - Fatigue accumulation can be significantly influenced by post-activation potentiation (PAP). This phenomenon leads to increased force generating capacity after a series of conditioning efforts. The purpose of our study was to examine how the order of force demands impacted muscle fatigue accumulation, and how fatigue was affected by potentiation. We had 33 participants complete one of four different force orders, consisting of 5 cycles of 12-s submaximal isometric "task plateaus". Every order consisted of 8 force plateaus of the different intensity, arranged in a different ways. A subset of 18 participants then received a stimulated muscle twitch, and all participants performed a brief MVC. Each task plateau was followed by a 12s long 10% MVC "reference plateau" also followed by twitch and MVC. Overall, the order of the force presentation only had an impact on fatigue levels and twitch potentiation during the first cycle. Maximum voluntary forces decreased, and twitch forces increased, at different rates between orders during the first cycle. At the end of each cycle, there was no difference between any of the orders in terms of twitch potentiation or decrease in MVC force. In a task that features identical force patterns, arranged in different orders, the order did not affect the final fatigue accumulation or potentiation level. PMID- 25934044 TI - Procalcitonin and pyuria-based algorithm reduces antibiotic use in urinary tract infections: a randomized controlled trial. AB - BACKGROUND: Urinary tract infections (UTIs) are common drivers of antibiotic use. The minimal effective duration of antibiotic therapy for UTIs is unknown, but any reduction is important to diminish selection pressure for antibiotic resistance, costs, and drug-related side-effects. The aim of this study was to investigate whether an algorithm based on procalcitonin (PCT) and quantitative pyuria reduces antibiotic exposure. METHODS: From April 2012 to March 2014, we conducted a factorial design randomized controlled open-label trial. Immunocompetent adults with community-acquired non-catheter-related UTI were enrolled in the emergency department of a tertiary-care 600-bed hospital in northwestern Switzerland. Clinical presentation was used to guide initiation and duration of antibiotic therapy according to current guidelines (control group) or with a PCT-pyuria based algorithm (PCT-pyuria group). The primary endpoint was overall antibiotic exposure within 90 days. Secondary endpoints included duration of the initial antibiotic therapy, persistent infection 7 days after end of therapy and 30 days after enrollment, recurrence and rehospitalizations within 90 days. RESULTS: Overall, 394 patients were screened, 228 met predefined exclusion criteria, 30 declined to participate, and 11 were not eligible. Of these, 125 (76% women) were enrolled in the intention-to-treat (ITT) analysis and 96 patients with microbiologically confirmed UTI constituted the per protocol group; 84 of 125 (67%) patients had a febrile UTI, 28 (22%) had bacteremia, 5 (4%) died, and 3 (2%) were lost to follow-up. Overall antibiotic exposure within 90 days was shorter in the PCT-pyuria group than in the control group (median 7.0 [IQR, 5.0 14.0] vs. 10.0 [IQR, 7.0-16.0] days, P = 0.011) in the ITT analysis. Mortality, rates of persistent infections, recurrences, and rehospitalizations were not different. CONCLUSIONS: A PCT-pyuria-based algorithm reduced antibiotic exposure by 30% when compared to current guidelines without apparent negative effects on clinical outcomes. PMID- 25934046 TI - Intestinal Microbiota Signatures Associated With Histological Liver Steatosis in Pediatric-Onset Intestinal Failure. AB - BACKGROUND: Intestinal failure (IF)-associated liver disease (IFALD) is the major cause of mortality in IF. The link between intestinal microbiota and IFALD is unclear. METHODS: We compared intestinal microbiota of patients with IF (n = 23) with healthy controls (n = 58) using culture-independent phylogenetic microarray analysis. The microbiota was related to histological liver injury, fecal markers of intestinal inflammation, matrix metalloproteinase 9 and calprotectin, and disease characteristics. RESULTS: Overabundance of Lactobacilli, Proteobacteria, and Actinobacteria was observed in IF, whereas bacteria related to Clostridium clusters III, IV, and XIVa along with overall diversity and richness were reduced. Patients were segregated into 3 subgroups based on dominating bacteria: Clostridium cluster XIVa, Proteobacteria, and bacteria related to Lactobacillus plantarum. In addition to liver steatosis and fibrosis, Proteobacteria were associated with prolonged current parenteral nutrition (PN) as well as liver and intestinal inflammation. Lactobacilli were related to advanced steatosis and fibrosis mostly after weaning off PN without associated inflammation. In multivariate permutational analysis of variance, liver steatosis, bowel length, PN calories, and antibiotic treatment best explained the microbiota variation among patients with IF. CONCLUSIONS: Intestinal microbiota composition was associated with liver steatosis in IF and better predicted steatosis than duration of PN or length of the remaining intestine. Our results may be explained by a model in which steatosis is initiated during PN in response to proinflammatory lipopolysaccharides produced by Proteobacteria and progresses after weaning off PN, as the L plantarum group Lactobacilli becomes dominant and affects lipid metabolism by altering bile acid signaling. PMID- 25934045 TI - Bombesin Preserves Goblet Cell Resistin-Like Molecule beta During Parenteral Nutrition but Not Other Goblet Cell Products. AB - INTRODUCTION: Parenteral nutrition (PN) increases the risk of infection in critically ill patients and is associated with defects in gastrointestinal innate immunity. Goblet cells produce mucosal defense compounds, including mucin (principally MUC2), trefoil factor 3 (TFF3), and resistin-like molecule beta (RELMbeta). Bombesin (BBS), a gastrin-releasing peptide analogue, experimentally reverses PN-induced defects in Paneth cell innate immunity. We hypothesized that PN reduces goblet cell product expression and PN+BBS would reverse these PN induced defects. METHODS: Two days after intravenous cannulation, male Institute of Cancer Research mice were randomized to chow (n = 15), PN (n = 13), or PN+BBS (15 ug tid) (n = 12) diets for 5 days. Defined segments of ileum and luminal fluid were analyzed for MUC2, TFF3, and RELMbeta by quantitative reverse transcriptase polymerase chain reaction and Western blot. Th2 cytokines interleukin (IL)-4 and IL-13 were measured by enzyme-linked immunosorbent assay. RESULTS: Compared with chow, PN significantly reduced MUC2 in ileum (P < .01) and luminal fluid (P = .01). BBS supplementation did not improve ileal or luminal MUC2 compared with PN (P > .3). Compared with chow, PN significantly reduced TFF3 in ileum (P < .02) and luminal fluid (P < .01). BBS addition did not improve ileal or luminal TFF3 compared with PN (P > .3). Compared with chow, PN significantly reduced ileal RELMbeta (P < .01). BBS supplementation significantly increased ileal RELMbeta to levels similar to chow (P < .03 vs PN; P > .6 vs chow). Th2 cytokines were decreased with PN and returned to chow levels with BBS. CONCLUSION: PN significantly impairs the goblet cell component of innate mucosal immunity. BBS only preserves goblet cell RELMbeta during PN but not other goblet cell products measured. PMID- 25934047 TI - Whole genome and transcriptome analysis of a novel AML cell line with a normal karyotype. AB - Acute myeloid leukemia (AML) occurs when hematopoietic progenitor cells acquire genetic defects blocking the regulation of normal growth and differentiation. Although recurrent translocations have been identified in AML, almost half of adult AML patients present with a normal karyotype (NK-AML). While cell line models exist to study AML, they frequently have abnormal/unstable karyotypes, while primary cells from NK-AML patients are difficult to maintain in vitro. Here we provide a thorough molecular characterization of a recently established cell line, CG-SH, which has normal cytogenetics, representing a useful new model for NK-AML. Using high-throughput DNA sequencing, we first defined the genetic background of this cell line. In addition to identifying potentially deleterious SNVs in genes relevant to AML, we also found insertions in both GATA2 and EZH2, two genes previously linked to AML. We further characterized the growth of this model system in vitro with a cytokine mix that promotes faster cell growth. We assessed gene expression changes after the addition of cytokines to the culture media and found differential expression in genes implicated in proliferation, apoptosis and differentiation. Our results provide a detailed molecular characterization of genetic defects in this cell line derived from an NK-AML patient. PMID- 25934048 TI - Impact of tobacco usage on disease outcome in myelodysplastic syndromes. AB - We hypothesized that tobacco usage is an independent prognostic factor in patients with myelodysplastic syndromes (MDS). To evaluate the impact of tobacco usage in this population, we identified patients diagnosed with MDS in our Center's MDS database and reviewed individual charts retrospectively. Of the 767 MDS patients identified, 743 patients (97%) had a known tobacco usage history. Given that the majority of tobacco users were smokers, we stratified patients as having never smoked (never-smoker group) versus current or former smokers (ever smoker group). Greater than 60% of ever-smokers were risk stratified as having low or intermediate-1 (int-1) risk at diagnosis based on the International Prognostic Scoring System for MDS. In patients with lower-risk MDS, we found that ever-smokers had an increased proportion of poor-risk karyotypes (8.8%) compared with never-smokers (2.4%) (P=0.003). The adverse effect of smoking was greatest in the low-risk and int-1-risk groups, where median overall survival was 69 months (95% CI 42-96) in never-smokers versus 48 months (95% CI 41-55) in ever smokers (P=0.006). The median overall survival for never-smokers, former smokers, and current smokers was 69 months (95% CI 42-96), 50 months (95% CI 43-57), and 38 months (95% CI 23-53), respectively, in patients risk stratified as lower-risk MDS (P=0.01). Our findings suggest that tobacco usage negatively impacts overall survival in patients with lower-risk MDS. PMID- 25934049 TI - Potentiating the activity of rituximab against mantle cell lymphoma in mice by targeting interleukin-2 to the neovasculature. AB - There is increasing interest in the site-directed pharmacodelivery of therapeutic payloads to the tumor site using antibodies as transport vehicles. Here, we investigated the efficacy of L19-IL2, an antibody-cytokine fusion protein that specifically delivers IL-2 to the tumor site by homing to the extra-domain B of fibronectin (EDB-Fn) expressed on tumor-associated blood vessels, against mantle cell lymphoma (MCL) in mice. L19-IL2 was shown to selectively localize at lymphoma lesions in vivo and to mediate significant lymphoma growth retardation, which was potentiated by co-administration of the anti-CD20 antibody rituximab. When co-injected with rituximab, L19-IL2 induced complete remissions of localized MCL xenografts in 6/8 mice (75%), whereas the combination of rituximab and equivalent doses of non-targeted IL-2 only slightly delayed tumor growth. In disseminated MCL, combination therapy with L19-IL2 and rituximab exhibited a significant survival benefit over treatment with IL-2 and rituximab and completely eradicated the disease in 2/7 cases (28.6%). Mechanistically, histological analyses of post-therapeutic lymphoma tissues revealed a strong intratumoral accumulation of macrophages and natural killer cells after a single dose of the immunocytokine, whereas L19-IL2 had no significant impact on microvessel density or on tissue penetration of co-injected rituximab. Collectively, these results provide the scientific rationale for the clinical evaluation of L19-IL2 in combination with anti-CD20 immunotherapy in patients with MCL. PMID- 25934050 TI - Evaluation of rural areas in terms of landscape quality: Salacik Village (Trabzon/Turkey) example. AB - As a result of the increasing urbanization and fast pace of work life, people started to turn to rural areas so as to regenerate both socially and psychologically. Increasing interest in the rural areas made the importance of landscape quality of these areas more significant. This improvement gave way to the idea of the necessity of preserving the resourceful landscape areas in terms of visual characteristics and bringing them under the spotlight, and it became the driving power in reconciling the planners and administrators. From this point of view, a study was conducted in Salacik Village of Akcaabat district of Trabzon (Turkey) in order to identify the visually resourceful landscape areas and maintain the sustainability of the resource values by preserving them. In this respect, the area was divided into seven individual landscape types, visual landscape evaluation including the opinions of the experts, and a survey that is used in planning of the rural areas was implemented. It is thought that the results attained with the evaluations made taking the principles of Gestalt theory into consideration will constitute an essential fundamental for urban and regional planners, natural resource administrators, and other planning parties in their planning decisions relating the specific area. Apart from that, among the goals of this study are contributing in the preservation of visually resourceful landscapes, maintaining their sustainability, and integration of these areas into the development strategies. PMID- 25934051 TI - Metals bioavailability in surface sediments off Nile delta, Egypt: Application of acid leachable metals and sequential extraction techniques. AB - Surface sediments from Nile Delta coast were analyzed for texture, CaCO3, organic matter, fractionation, and acid leachable metals (Cr, Fe, Mn, Ni, Pb, and Zn). The distribution pattern of acid leachable heavy metals in the sediment follows the sequence: Fe>Mn>Pb>Zn>Ni>Cr. All the acid leachable metals didn't exceed the sediment quality guidelines values (effects range low (ERL) and effects range medium (ERM)) and therefore doesn't represent a danger to marine organisms. The correlation of acid leachable Fe, Ni, and Mn indicates a similarity in the association of metals of similar origin. The negative correlation of sand with acid leachable Cr, Fe, Ni, Pb, and Zn indicates that these elements can be easily released by ion exchange processes due to the electrostatic interaction of trace metals as they are weakly bound and is bioavailable to the liquid phase. The acid leachable Cr, Pb, and Zn indicate their association with the CaCO3, while acid leachable Fe, Mn, and Ni are hardly combined with carbonates. All the contents of acid leachable metals are negatively correlated or uncorrelated with OM, which indicates that the studied heavy metals are hardly combined with OM. The results of the partitioning study showed that the residual form was the dominant fraction of the Cr, Fe, and Ni among most of the studied locations. Among the non lithogenic fractions, the Fe-Mn oxy-hydroxide is the main scavenger for all metals. In terms of risk assessment code (RAC) value, a decrease order in environmental risk by heavy metals was Pb>Mn>Zn>Ni>Cr>Fe. Although the results of the two techniques were not consistent with each other in terms of predicting the metals bioavailability, a combination of total metal concentrations, acid leachable metals, and sequential extraction analysis is necessary to acquire the comprehensive information on the baseline, anthropogenic input, and bioavailability of heavy metals. PMID- 25934052 TI - Differential effects of cadmium and chromium on growth, photosynthetic activity, and metal uptake of Linum usitatissimum in association with Glomus intraradices. AB - The current study was aimed at analyzing the differential effects of heavy metals (cadmium and chromium) and mycorrhizal fungus; Glomus intraradices on growth, chlorophyll content, proline production, and metal accumulation in flax plant (Linum usitatissimum L.). Heavy metal accumulation rate in flax varied from 90 to 95 % for Cd and 61-84 % for Cr at a concentration range of 250 to 500 ppm for both metals in 24 days of experiment. Growth and photosynthetic activity of flax reduced to an average of 21 and 45 %, respectively. However, inoculation of G. intraradices significantly increased the plant biomass even under metal stressed conditions. Additionally, mycorrhizal association also assists the Cd and Cr increased uptake by 23 and 33 %, respectively. Due to metal stress, chlorophyll contents were decreased by 27 and 45 %, while 84 and 71 % increased proline content was observed under Cd and Cr stress, respectively. The present results clearly signify the differential response and potential of flax plant towards heavy metal tolerance and accumulation that can further increase with mycorrhizal fungus. PMID- 25934053 TI - Influence of municipal solid waste compost application on heavy metal content in soil. AB - Municipal solid waste composts (MSWC) are widely used over agricultural lands as organic soil amendment and fertilizer. However, MSWC use may result in various adverse impacts over agricultural lands. Especially, heavy metal contents of MSWC should always be taken into consideration while using in agricultural practices. The present study was conducted to find out heavy metal contents of municipal solid waste compost (MSWC) and to investigate their effects on soils. Experiments were carried out in three replications as field experiments for 2 years. Dry based MSWC was applied to each plot at the ratios of 0, 40, 80, 120, 160, 200 t ha(-1). Results revealed that heavy metal content of MSWC was within the allowable legal limits. Compost treatments significantly increased Cu, Zn, Ni, Cr, Cd, and Pb content of soils (p < 0.01). Increasing soil heavy metal contents were observed with increasing applied compost doses. Although compost treatments significantly increased soil heavy metal contents, the final contents were still within the allowable legal limits. Results showed that MSWC doses over 10 t ha( 1) may create a heavy metal risk in long term for soils with pH >= 7. Therefore, in MSWC use over agricultural lands, heavy metal contents should always be taken into consideration and excessive uses should be avoided. PMID- 25934054 TI - Diversion of opioid maintenance treatment medications and predictors for diversion among Finnish maintenance treatment patients. AB - BACKGROUND: Diversion (i.e. selling or giving away) of opioid maintenance treatment (OMT) medications is a challenge that concerns many units providing OMT worldwide and tools for prevention are needed. The object of this study was to examine the prevalence and predictors for diversion of the OMT medications buprenorphine-naloxone (BNX) and methadone (MET) among Finnish OMT patients. METHODS: A cross-sectional study was conducted among all Finnish OMT patients of whom 60% (n=1508) participated. The data were collected by anonymous questionnaires distributed through all OMT units in Finland. To evaluate predictors for diversion, we used binominal regression analysis with unadjusted and adjusted ORs. Selling and/or giving away of OMT medication was used as a dependent variable and explanatory variables were gender, age, duration of OMT, type of OMT medication and dose, dispensation method of OMT medication, place of residence and intravenous use of any intoxicating drugs during the past six months. RESULTS: Of all 1508 respondents, 7% (n=100) had sold and 12% (n=169) had given their OMT medication to others, 57% for money and 23% in exchange for other drugs. In multivariate analysis, predictors associated with diversion were BNX as OMT medication (OR 2.76, 95% CI 1.76-4.33), low (<9.0mg/day) BNX dose (OR 1.74, 95% CI 1.01-2.98), intravenous use of intoxicating drugs during the past six months (OR 4.48, 95% CI 3.13-6.43) and increasing length of OMT (OR 1.01, 95% CI 1.01-1.02). Age, place of residence or unsupervised pharmacy distribution of BNX were not associated with diversion. CONCLUSIONS: In order to reduce diversion, more interventions are needed to support patients to stop concurrent substance abuse. Increasing control measures, for example, increased supervision, are unlikely to prevent diversion. Given that sub-optimal dosing of BNX increases the risk of diversion, more attention should be paid to providing patients with an optimal medical dose. PMID- 25934055 TI - Structural variations of the cell wall precursor lipid II in Gram-positive bacteria - Impact on binding and efficacy of antimicrobial peptides. AB - Antimicrobial peptides (AMPs) are natural antibiotics produced by virtually all living organisms. Typically, AMPs are cationic and amphiphilic and first contacts with target microbes involve interactions with negatively charged components of the cell envelope such as lipopolysaccharide (LPS), and wall- or lipoteichoic acids (WTA, LTA). The importance of charge-mediated interactions of AMPs with the cell envelope is reflected by effective microbial resistance mechanisms which are based on reduction of the overall charge of these polymers. The anionic polymers are linked in various ways to the stress-bearing polymer of the cell envelope, the peptidoglycan, which is made of a highly conserved building block, a disaccharide-pentapeptide moiety that also contains charged residues. This structural element, in spite of its conservation throughout the bacterial world, can undergo genus- and species-specific modifications that also impact significantly on the overall charge of the cell envelope and on the binding affinity of AMPs. The modification reactions involved largely occur on the membrane-bound peptidoglycan building block, the so-called lipid II, which is a most prominent target for AMPs. In this review, we focus on modifications of lipid II and peptidoglycan and discuss their consequences for the interactions with various classes of AMPs, such as defensins, lantibiotics and glyco-(lipo) peptide antibiotics. This article is part of a Special Issue entitled: Bacterial Resistance to Antimicrobial Peptides. PMID- 25934056 TI - Transabdominal Cervical Cerclage: Laparoscopy Versus Laparotomy. AB - STUDY OBJECTIVE: To evaluate the obstetric outcome, surgical morbidity, and pre abdominal cerclage characteristics of women undergoing transabdominal cerclage (TAC) via laparotomy or laparoscopy. DESIGN: Prospective cohort study (Canadian Task Force classification II-2). SETTING: University hospital. PATIENTS AND INTERVENTION: Between 2007 and 2014, 51 patients underwent laparoscopic abdominal cervical cerclage to treat cervical incompetence. These women were compared with a historical cohort of 18 patients who underwent the same procedure via laparotomy between 1995 and 2011. All of the women had a diagnosis of cervical incompetence based on previous obstetric history and/or a short or absent cervix. MEASUREMENTS AND MAIN RESULTS: The fetal survival rate postcerclage was 100% in the laparotomy group (n = 30 pregnancies) and 98% in the laparoscopy group (n = 54 pregnancies). There were no perioperative pregnancy losses in either group. The median gestation age was 36.9 weeks (range: 35.0-37.3) in the laparotomy group and 37.0 weeks (range: 34.7-38.0) in the laparoscopy group. Complications were recorded in 4 (22%) cases from the laparotomy group and 1 (2%) of the laparoscopies; however, the types of complications might not be comparable between groups. There were no conversions to laparotomy in the laparoscopy group. Pre-TAC median gestational age in the laparotomy group was 24.0 weeks (range: 20.0-25.1) with 19 (57.6%) previous pregnancies occurring after transvaginal cervical cerclage placement. The corresponding laparoscopy pre-TAC median gestational age was 22.0 weeks (range 19.0-34.0) with 40 (40%) previous pregnancies having a transvaginal cerclage. Before the TAC, women in the laparotomy group had lost 25 babies, and 63 babies were lost in the laparoscopy group. After TAC, these numbers were 0 and 1. CONCLUSIONS: Our findings show that transabdominal cervical cerclage placed laparoscopically appears to be as effective as TAC placed via laparotomy. Neither approach was associated with serious or long-term complications. Because of this finding, the approach depends on the surgical experience and expertise of the unit in conjunction with discussion with the patient. PMID- 25934058 TI - An update on sexual function and dysfunction in women. AB - Sexual function of women can be affected by many factors resulting in female sexual dysfunction (FSD). Sexual dysfunction is a common problem among women of all ages and has negative effects not only on their quality of lives but also on the sexual function and quality of life of their partners. It can also affect mental health of the entire family and society. Regarding the multidimensional nature of female sexual dysfunction and considering its consequences, this condition needs to be recognised in its early stages in order to prevent future consequences and impacts. This article discusses biopsychosocial aspect of female sexual function, classifications and risk factors of female sexual dysfunction and investigates current approaches to identify and treat this problem. PMID- 25934057 TI - Do marmosets care to share? Oxytocin treatment reduces prosocial behavior toward strangers. AB - Cooperatively-breeding and socially-monogamous primates, like marmosets and humans, exhibit high levels of social tolerance and prosociality toward others. Oxytocin (OXT) generally facilitates prosocial behavior, but there is growing recognition that OXT modulation of prosocial behavior is shaped by the context of social interactions and by other motivational states such as arousal or anxiety. To determine whether prosociality varies based on social context, we evaluated whether marmoset donors (Callithrix penicillata) preferentially rewarded pairmates versus opposite-sex strangers in a prosocial food-sharing task. To examine potential links among OXT, stress systems, and prosociality, we evaluated whether pretrial cortisol levels in marmosets altered the impact of OXT on prosocial responses. Marmosets exhibited spontaneous prosociality toward others, but they did so preferentially toward strangers compared to their pairmates. When donor marmosets were treated with marmoset-specific Pro(8)-OXT, they exhibited reduced prosociality toward strangers compared to marmosets treated with saline or consensus-mammalian Leu(8)-OXT. When pretrial cortisol levels were lower, marmosets exhibited higher prosociality toward strangers. These findings demonstrate that while marmosets show spontaneous prosocial responses toward others, they do so preferentially toward opposite-sex strangers. Cooperative breeding may be associated with the expression of prosociality, but the existence of a pair-bond between marmoset partners appears to be neither necessary nor sufficient for the expression of spontaneous prosocial responses. Furthermore, high prosociality toward strangers is significantly reduced in marmosets treated with Pro(8)-OXT, suggesting that OXT does not universally enhance prosociality, but, rather OXT modulation of prosocial behavior varies depending on social context. PMID- 25934059 TI - Difference in compliance with Standard Precautions by nursing staff in Brazil versus Hong Kong. AB - The Standard Precautions (SP) are measures to reduce the risk of transmission of bloodborne and other pathogens, and should be used by health professionals in the care of all patients regardless of their condition of infection. However, suboptimal compliance with SP has been consistently reported in the nursing literature. This study evaluated the differences of compliance with SP among nurses from Brazil and Hong Kong. This cross-sectional study was conducted in 2 countries-Hong Kong and Brazil-with nurses working in hospitals who responded to a self-administered questionnaire with demographic data and responses to a 20 item Compliance with Standard Precautions Scale. The compliance rate of 560 nurses was 69.4% for the Brazilian sample and 57.4% for the Hong Kong sample. The additional clinical experience of the Brazilian nurses versus those in Hong Kong may be related to differences in compliance with SP between nurses. PMID- 25934060 TI - Frequency-risk and duration-risk relations between occupational livestock contact and methicillin-resistant Staphylococcus aureus carriage among workers in Guangdong, China. AB - BACKGROUND: Increasing evidence indicates a strong association between occupational livestock contact and methicillin-resistant Staphylococcus aureus (MRSA) carriage. However, it remains unclear whether there are frequency-risk and duration-risk relations between occupational livestock contact and human MRSA carriage. METHODS: A cross-sectional survey was conducted in Guangdong, China, using a multistage sampling method. Participants were interviewed and provided a nasal swab for S aureus analysis. All MRSA isolates were genotyped by multilocus sequence typing. The dose-response relation was examined using logistic regression models. RESULTS: Among the 1,860 participants, 1.4% of controls tested positive for MRSA (characterized as sequence type [ST] 59 and ST7), and 7% of workers with livestock contact tested positive for MRSA (characterized as ST9, ST59, and ST7). There was a 5.31 times increased risk of MRSA carriage corresponding to occupational livestock contact (odds ratio = 6.31; 95% confidence interval, 3.44-11.57) using no contact as reference. We found frequency and short-term duration of occupational livestock contact were associated with increased risk of MRSA carriage in a dose-response manner. These significant trends were observed consistently among workers with occupational pig contact. However, no long-term duration-risk increasing trend was observed for occupational livestock or pig contact. CONCLUSION: Our findings suggest that there may be dose-response relations between occupational livestock contact and human MRSA carriage. Nasal MRSA clonal complex 9 is not found in controls, but it is found in workers with livestock contact. PMID- 25934061 TI - Prescribing errors in antibiotic prophylaxis by dentists in a large Brazilian city. AB - Prescribing errors may contribute to antibiotic resistance and other drug-related problems. To investigate the quality of prescriptions involving antibiotic prophylaxis by dentists in a large Brazilian city, 366 dental prescriptions were randomly selected from 31,105. A prophylaxis indication represented 24.9% of the prescriptions, and only 12 (13.2%; 95% confidence interval, 7.7%-21.7%) were correct regarding the generic name, dose, and length of antibiotic use. Prescriptions for antibiotic prophylaxis by dentists are mostly inadequate in this city. PMID- 25934062 TI - Adherence to tuberculosis infection control guidelines by nurses in Lesotho. AB - BACKGROUND: Lesotho has a high prevalence rate of tuberculosis (TB) that has been exacerbated by high prevalence of HIV. Adherence to the TB infection control guidelines recommended by the World Health Organization is pivotal in TB infection control. OBJECTIVES: We assessed the level of adherence to the TB infection control guidelines by nurses in TB wards and outpatient departments and the factors associated with nonadherence to the guidelines in Lesotho. METHODS: This was an analytical study based on a semistructured questionnaire administered on 55 purposively sampled nurses working in TB wards and outpatient departments at Motebang and Mafeteng Hospitals. Logistic regression analysis was used to determine the variables associated with nonadherence to TB infection control guidelines. RESULTS: Fear of occupational exposure (P = .026), female gender (P = .03), lack of equipment (P = .02), inadequate staff (P = .005), and the keeping of guidelines by certain nurses (P = .02) were significantly associated with nonadherence. Overall, 43.6% of the respondents had poor adherence to the guidelines. Adherence to the guidelines was not influenced significantly by age, TB ward work experience, and qualifications of nursing staff. CONCLUSIONS: There is poor adherence to World Health Organization TB infection control guidelines by nurses in Lesotho. There is need to improve access to equipment, increase accessibility of guidelines, and ensure adequate staff to increase adherence to TB infection control guidelines. PMID- 25934063 TI - Measuring hand hygiene compliance rates at hospital entrances. AB - BACKGROUND: Despite the importance of hand hygiene in the health care setting, there are no studies evaluating hand hygiene compliance at hospital entrances. METHODS: The study was prospectively performed over a 33-week period from March 30, 2014-November 15, 2014, to evaluate hand hygiene compliance in 2 hospital reception areas. We compared electronic handwash counters with the application of radiofrequency identification (GOJO SMARTLINK) (electronic observer) that counts each activation of alcohol gel dispensers to direct observation (human observer) via remote review of video surveillance. RESULTS: We found low hand hygiene compliance rates of 2.2% (99/4,412) and 1.7% (140/8,277), respectively, at reception areas A and D, detected by direct observation. Using the electronic observer, we measured rates of 17% (15,624/91,724) and 7.1% (51,605/730,357) at reception areas A and D, respectively. For the overall time period of simultaneous electronic and human observation, the human observer captured 1% of the hand hygiene episodes detected by the electronic observer. CONCLUSIONS: Our study showed very low hand hygiene compliance in hospital reception areas, and we found an electronic hand hygiene system to be a useful method to monitor hand hygiene compliance. PMID- 25934064 TI - Impact of antibiotic- and silver-impregnated external ventricular drains on the risk of infections: A systematic review and meta-analysis. AB - BACKGROUND AND PURPOSE: External ventricular drainage (EVD) is one of the most common and effective procedures in neurosurgery practice. However, catheter related infection (CRI), which is associated with significant mortality and morbidity, plagues this procedure. We evaluated the efficacy of antibiotic impregnated EVD (AI-EVD) and silver-impregnated EVD (SI-EVD) catheters compared with plain EVD catheters for the prevention of CRI. METHODS: The authors performed an independent search of Medline, Embase, and the Cochrane Library to identify eligible studies published between January 2002 and August 2014. We searched all relevant literature using an exhaustive search strategy. Randomized controlled trials or observational studies that compared AI-EVD catheters with plain EVD catheters for the prevention of CRI were included. The quality of each included study was assessed using a risk of bias assessment tool and the Newcastle-Ottawa Scale. RevMan5.3 software (The Cochrane Collaboration, Oxford, UK) was used to perform this meta-analysis, and publication bias was investigated using funnel plot constructions and Egger test. RESULTS: A total of 4 randomized and 10 observational studies involving 4,399 patients were included in this meta analysis. Pooled results comparing AI-EVD catheters with plain EVD catheters in the management of patients with acute high intracranial pressure demonstrated the superiority of antimicrobial EVDs for the prevention of CRI with a risk induction of 62% (95% confidence interval [CI], 0.25-0.58; P < .00001). Subgroup analyses of pooled data from separate analyses of AI-EVDs and SI-EVDs showed the efficacy of both measures for CRI prevention, with a risk ratio (RR) of 0.31 (95% CI, 0.18 0.55; P < .0001) and an RR of 0.59 (95% CI, 0.40-0.88; P = .010), respectively. The protective effects of these AI-EVD catheters remained significant in the subgroup of randomized controlled trials with an RR of 0.48 (95% CI, 0.25-0.90; P = .02). A similar result was also seen after a pooled analysis of observational studies with an RR of 0.35 (95% CI, 0.21-0.60; P = .0001). The heterogeneity among studies was moderate (I(2) = 49%) and was primarily attributed to the inclusion of 1 large, positive cohort study. Publication bias was unlikely in the current meta-analysis. CONCLUSIONS: Our restults indicate that both AI-EVDs and SI-EVDs are more effective than plain EVDs for the prevention of CRI. There is no conclusive evidence on the preference of AI-EVDs vs SI-EVDs because of insufficient data. Further well-designed, multicenter randomized controlled trials are required to confirm the findings of this meta-analysis. PMID- 25934065 TI - Efficiency of chlorhexidine-silver sulfadiazine-impregnated venous catheters at subclavian sites. AB - BACKGROUND: Cost-effectiveness analyses show that chlorhexidine-silver sulfadiazine (CHSS)-impregnated catheters reduce catheter-related bloodstream infection (CRBSI) and central venous catheter (CVC)-related costs. However, no studies have reported the efficiency of CHSS-impregnated catheters for venous access when the risk of CRBSI is low; for example, at the subclavian site. This study determined the cost of a CVC, diagnosis of CRBSI, and antimicrobial agents to treat CRBSI; we did not consider the cost of increased hospital stay. METHODS: This retrospective study included patients admitted to the intensive care unit at Hospital Universitario de Canarias (Tenerife, Spain) who had a subclavian venous catheter. RESULTS: Patients with CHSS catheters (n = 353) had a lower incidence density of CRBSI (2.12 vs 0 out of 1,000 catheter-days; P = .02) and lower CVC related cost per catheter-day (3.35 +/- 3.75 vs 3.94 +/- 9.95; P = .002) than those with standard catheters (n = 518). CHSS-impregnated catheters were associated with a lower risk of CRBSI (exact logistic regression) (odds ratio, 0.10; 95% confidence interval, -infinity to 0.667; P = .008) than standard catheters when controlling for catheter duration. CHSS-impregnated catheters were also associated with a lower CVC-related cost per catheter day than standard catheters (Poisson regression) (odds ratio, 0.85; 95% confidence interval, 0.001 0.873; P < .001). CONCLUSIONS: CHSS-impregnated catheters may be efficient in preventing CRBSI in patients with subclavian venous access. PMID- 25934066 TI - Health care-associated infection outbreaks in pediatric long-term care facilities. AB - Children in pediatric long-term care facilities (pLTCFs) have complex medical conditions and increased risk for health care-associated infections (HAIs). We performed a retrospective study from January 2010-December 2013 at 3 pLTCFs to describe HAI outbreaks and associated infection control interventions. There were 62 outbreaks involving 700 cases in residents and 250 cases in staff. The most common interventions were isolation precautions and education and in-services. Further research should examine interventions to limit transmission of infections in pLTCFs. PMID- 25934067 TI - Environmental infection control considerations for Ebola. PMID- 25934068 TI - Risk factors for bloodstream infection caused by extended-spectrum beta-lactamase producing Escherichia coli and Klebsiella pneumoniae: A focus on antimicrobials including cefepime. AB - BACKGROUND: Extended-spectrum beta-lactamase (ESBL)-producing pathogens represent increasing challenges to physicians because of rising prevalence, high mortality, and challenging treatment. Identifying high risks and early appropriate therapy is critical to favorable outcomes. METHODS: This is a 5-year retrospective case case-control study performed at the Detroit Medical Center on adult patients with bloodstream infection (BSI) caused by ESBL-producing and non-ESBL-producing Escherichia coli or Klebsiella pneumoniae, each compared with uninfected controls. Data were collected from December 2004-August 2009. Multivariate analysis was performed using logistic regression. RESULTS: Participants included 103 patients with BSI caused by ESBL-producing pathogens and 79 patients with BSI caused by pathogens that did not produce ESBLs. The mean age of patients in the ESBL group was 67 years; of the patients, 51% were men, 77% were black, and 38% (n = 39) died in hospital. The mean age of patients in the non-ESBL group was 58 years; of the patients, 51% were men, 92% were black, and 22% (n = 17) died in hospital. On multivariate analysis, predictors of BSI caused by ESBL-producing pathogens included central venous catheter (odds ratio [OR], 29.4; 95% confidence interval [CI], 3.0-288.3), prior beta-lactam-/beta-lactamase-inhibitor therapy (OR, 28.1; 95% CI, 1.99-396.5), and prior cefepime therapy (OR, 22.7; 95% CI, 2.7 192.4). The only risk factor for BSI caused by non-ESBL-producing pathogens was urinary catheter insertion (OR, 18.2; 95% CI, 3.3-100.3). CONCLUSION: Prior antimicrobial therapy, particularly with beta-lactam, was the strongest unique risk factor for BSI caused by ESBL-producing E coli or K pneumoniae. PMID- 25934069 TI - A Shining Scrotal Fountain. PMID- 25934070 TI - Developing Indigenous Therapeutic Calcium Supplementation for Treating Nutritional Rickets. PMID- 25934071 TI - Harnessing the Early-Life Microbiota to Protect Children with Cystic Fibrosis. PMID- 25934072 TI - Pediatric asthma readmission: A marker of disease severity leading to increased parental knowledge. PMID- 25934073 TI - Molecular dynamics simulations of anchored viral peptide interactions. AB - The authors use molecular dynamics simulations to investigate viral peptide interactions as the cause of pH-dependent fusion in liposomal drug delivery. Viral peptides (LEFN) are composed of a linker peptide (LELELELE) connected to a synthetic viral peptide (DRGWGNGCGLFGKGSI). Rather than being anchored in a lipid bilayer, the viral peptides are anchored to a neutral surface by the amino termini of the linker peptide (anchor atoms are mobile in the xy-plane). Atomistic-level peptide pair arrangement on a surface depends on pH; however, the overall propensity to cluster is independent of pH, indicating that pH-sensitive liposome fusion is not due to peptide clustering. To further investigate a molecular cause of pH-sensitive fusion, the authors treat the linker peptides as ectodomains, with the assumption that the viral peptides are already inserted into a target membrane. In these simulations, the linker peptides are elongated to encourage them to bundle. At both high and low pH, the peptides readily bundle. At high pH, however, bundling was constrained by long-range order induced by sodium ions bridging negatively charged glutamic acid residues on neighboring peptides. The authors hypothesize that this constraint hinders the ability of the linker peptides to support viral peptide insertion, resulting in decreased levels of fusion observed experimentally. PMID- 25934074 TI - Effect of discharge polarity on the propagation of atmospheric-pressure helium plasma jets and the densities of OH, NO, and O radicals. AB - The atmospheric-pressure helium plasma jet is an emerging technology for plasma biomedical applications. In this paper, the authors focus on the effect of discharge polarity on propagation of the discharge and the densities of OH, NO, and O radicals. The plasma jet is applied to a glass surface placed on a grounded metal plate. Positive or negative voltage pulses with 25 MUs duration, 8 kV amplitude, and 10 kpps repetition rate are used for the plasma jet. The plasma propagation is measured using a short-gated ICCD camera. The light emission intensity of the discharge generated at the rising phase of the voltage pulse is approximately equivalent for both polarities, while that generated during the falling phase is much higher for the negative discharge than the positive one. The shape of the discharge changes with the discharge polarity. The OH, NO, and O densities in the plasma jet are also measured for both polarities. It is found that the OH density is almost the same regardless the discharge polarity. Conversely, the negative discharge produces more O atoms and the positive discharge produces more NO molecules. These results indicate that the polarity of the discharge affects the densities of some reactive species produced in the plasma jet. PMID- 25934075 TI - What factors within the peri-operative environment influence the training of scrub nurses? AB - The aim of this study was to extrapolate factors within the peri-operative environment which influence the acclimatisation of novice scrub nurses by exploring the lived experience of learning from both a novice and expert perspective. Insights to the cultural perioperative environment which have not previously been explored can be identified. Comparing how novices view their environment with how expert mentors see it is useful in order to plan targeted learning goals. Two groups were considered; one group consisting of 6 novice scrub nurses and the other consisting of 7 senior scrub nurses teaching novices in a large tertiary teaching public hospital in South Australia. Individual interviews and a focus group interview were digitally recorded and field notes were taken. A Heideggerian structural approach with a vanManen immersive aspect was taken for the data collection and Ricoeur's hermeneutic theory of interpretation was utilised for data analysis. Five emergent themes were isolated from the data: Challenges to proficiency, Fear, Expectations, Support and Adaptation. The study revealed that novice scrub learning is externally modulated by their perioperative cultural surroundings and the support of the senior staff. Senior scrub staff investment in educating novices was dictated by their perception of novice attitude. PMID- 25934076 TI - Targeting Translation Initiation Bypasses Signaling Crosstalk Mechanisms That Maintain High MYC Levels in Colorectal Cancer. AB - Deregulated expression of MYC is a driver of colorectal carcinogenesis, suggesting that inhibiting MYC may have significant therapeutic value. The PI3K and mTOR pathways control MYC turnover and translation, respectively, providing a rationale to target both pathways to inhibit MYC. Surprisingly, inhibition of PI3K does not promote MYC turnover in colon carcinoma cells, but enhances MYC expression because it promotes FOXO-dependent expression of growth factor receptors and MAPK-dependent transcription of MYC. Inhibition of mTOR fails to inhibit translation of MYC, because levels of 4EBPs are insufficient to fully sequester eIF4E and because an internal ribosomal entry site element in the 5' untranslated region of the MYC mRNA permits translation independent of eIF4E. A small-molecule inhibitor of the translation factor eIF4A, silvestrol, bypasses the signaling feedbacks, reduces MYC translation, and inhibits tumor growth in a mouse model of colorectal tumorigenesis. We propose that targeting translation initiation is a promising strategy to limit MYC expression in colorectal tumors. SIGNIFICANCE: Inhibiting MYC function is likely to have a significant therapeutic impact in colorectal cancers. Here, we explore several strategies to target translation initiation in order to block MYC expression. We show that a small molecule inhibitor of eIF4A inhibits MYC expression and suppresses tumor growth in vivo. PMID- 25934077 TI - Heterogeneity Underlies the Emergence of EGFRT790 Wild-Type Clones Following Treatment of T790M-Positive Cancers with a Third-Generation EGFR Inhibitor. AB - Rociletinib is a third-generation EGFR inhibitor active in lung cancers with T790M, the gatekeeper mutation underlying most first-generation EGFR drug resistance. We biopsied patients at rociletinib progression to explore resistance mechanisms. Among 12 patients with T790M-positive cancers at rociletinib initiation, six had T790-wild-type rociletinib-resistant biopsies. Two T790-wild type cancers underwent small cell lung cancer transformation; three T790M positive cancers acquired EGFR amplification. We documented T790-wild-type and T790M-positive clones coexisting within a single pre-rociletinib biopsy. The pretreatment fraction of T790M-positive cells affected response to rociletinib. Longitudinal circulating tumor DNA (ctDNA) analysis revealed an increase in plasma EGFR-activating mutation, and T790M heralded rociletinib resistance in some patients, whereas in others the activating mutation increased but T790M remained suppressed. Together, these findings demonstrate the role of tumor heterogeneity when therapies targeting a singular resistance mechanism are used. To further improve outcomes, combination regimens that also target T790-wild-type clones are required. SIGNIFICANCE: This report documents that half of T790M positive EGFR-mutant lung cancers treated with rociletinib are T790-wild-type upon progression, suggesting that T790-wild-type clones can emerge as the dominant source of resistance. We show that tumor heterogeneity has important clinical implications and that plasma ctDNA analyses can sometimes predict emerging resistance mechanisms. PMID- 25934078 TI - Half a billion surgical cases: Aligning surgical delivery with best-performing health systems. AB - BACKGROUND: Surgical delivery varies 200-fold across countries. No direct correlation exists, however, between surgical delivery and health outcomes, making it difficult to pinpoint a goal for surgical scale-up. This report determines the amount of surgery that would be delivered worldwide if the world aligned itself with countries providing the best health outcomes. METHODS: Annual rates of surgical delivery have been published previously for 129 countries. Five health outcomes were plotted against reported surgical delivery. Univariate and multivariate polynomial regression curves were fit, and the optimal point on each regression curve was determined by solving for first-order conditions. The country closest to the optimum for each health outcome was taken as representative of the best-performing health system. Monetary inputs to and surgical procedures provided by these systems were scaled to the global population. RESULTS: For 3 of the 5 health outcomes, optima could be found. Globally, 315 million procedures currently are provided annually. If global delivery mirrored the 3 best-performing countries, between 360 million and 460 million cases would be provided annually. With population growth, this will increase to approximately half a billion cases by 2030. Health systems delivering these outcomes spend approximately 10% of their GDP on health. CONCLUSION: This is the first study to provide empirical evidence for the surgical output that an ideal health system would provide. Our results project ideal delivery worldwide of approximately 550 million annual surgical cases by 2030. PMID- 25934079 TI - An integrated approach to surgery and primary care systems strengthening in low- and middle-income countries: building a platform to deliver across the spectrum of disease. AB - BACKGROUND: Surgical services in low- and middle income countries (LMICs) must be considered within the context of a coordinated strategy for building primary care systems. Weak front-line primary care systems lead to delayed presentation and poor follow-up of patients with surgical illness, increasing the risk of poor outcomes. METHODS: Here we propose a framework to integrating surgery and primary care, organized around basic primary care principles of access, longitudinal care, coordination, integration and equity. RESULTS: Making surgical care accessible will require frontline provider capacity to screen for and recognize common surgical conditions, as well as to deliver certain basic surgical services themselves. Making this care effective will require strengthening the capacity of interdisciplinary teams to provide longitudinal care, involving coordinated networks for referral, communication with and mentorship by more specialized providers, and postoperative follow-up. Innovative approaches to information and communication technology can help to overcome the transportation and infrastructure barriers that jeopardize both access and effectiveness. Explicit integration of surgical and primary care programs at the managerial and administrative levels, as well as at the point-of-care, will also be critical. Taking a pro-equity approach can ensure that populations with the greatest unmet needs are effectively reached. CONCLUSION: Utilizing the pillars of effective primary care as a guiding framework to design, implement, and scale surgical programs in LMICs offers an opportunity for strengthening and enhancing the quality of health systems as a whole. PMID- 25934080 TI - Cost of surgery in a low-income setting in eastern Uganda. AB - BACKGROUND: Operative interventions have traditionally been seen as expensive; therefore, surgery has been given low priority in global health care planning in low-income countries. A growing body of evidence indicates that surgery can also be highly cost effective in low-income settings, but our current knowledge of the actual cost of surgery in such settings is limited. This study was carried out to obtain data on the costs of commonly performed operative procedures in a rural/semiurban setting in eastern Uganda. METHODS: A prospective, facility-based study carried out at a general district hospital (public) and a mission hospital (private, not-for-profit) in the Iganga and Mayuge districts in eastern Uganda. Items included in the cost calculations were staff time, materials and medicines, overhead costs, and capital costs. RESULTS: The cost of surgery was higher at the mission hospital, with higher expenditure and lower productivity than the public hospital. The most commonly performed major procedures were caesarean section, uterine evacuation, and herniorrhaphy for groin hernia. The costs for these interventions varied between $68.4 and $74.4, $25.0 and $32.6, and $58.6 and $66.0, respectively. The most commonly performed minor procedures were circumcision, suture of cuts and lacerations, and incision and drainage of abscess. The costs for these interventions varied between $16.2 and $24.6, $15.8 and $24.3, and $10.1 and $18.6, respectively. CONCLUSION: The cost of surgery in the study setting compares favorably with other prioritized health care interventions, such as treatment for tuberculosis, human immunodeficiency virus/AIDS, and childhood immunization. Surgery in low-income settings can be made more cost effective, leading to increased quantity and improved quality of surgical services. PMID- 25934081 TI - Met and unmet needs for surgery in Sierra Leone: A comprehensive, retrospective, countrywide survey from all health care facilities performing operations in 2012. AB - BACKGROUND: Understanding a country's baseline operative actors and capacity is critical to improving the quality of services and outcomes. The aim of this study was to describe all operative providers and national operative production, to evaluate district and nationwide population rates for operations, and to estimate unmet operative need in Sierra Leone. METHODS: A nationwide, exhaustive, retrospective, facility-based study of operative actors and surgical procedures was performed in Sierra Leone. Between January and May 2013, 4 teams of 12 medical students collected data on the characteristics of the institutions and of the operations performed in 2012. Data were retrieved from the log books of operations, anesthesia, and delivery. RESULTS: A total of 24,152 operative procedures were identified, equal to a national rate of 400 operative procedures per 100,000 inhabitants (district range 32-909/100,000, interquartile range 95 502/100,000). Hernia repair was the most common operative procedure at 86.1 per 100,000 inhabitants (22.4% of the total national volume) followed by cesarean delivery at 80.6 per 100,000 (21.0% of the total). Private, nonprofit facilities performed 54.0% of the operations, compared with 39.6% by governmental and 6.4% by private for-profit facilities. More than 90% of the estimated operative need in Sierra Leone was unmet in 2012. CONCLUSION: The unmet operative need in Sierra Leone is very high. The 30-fold difference in operative output between districts also is very high. As the main training institution, operative services within the governmental sector need to be strengthened. An understanding of the existing operative platform is a good start for expanding operative services. PMID- 25934083 TI - Gill-specific (Na(+), K(+))-ATPase activity and alpha-subunit mRNA expression during low-salinity acclimation of the ornate blue crab Callinectes ornatus (Decapoda, Brachyura). AB - We evaluate (Na(+), K(+))-ATPase activity, and protein and gene expression of the alpha-subunit in posterior gills 6 and 7 of Callinectes ornatus, a euryhaline crab, during a 10-day acclimation period from seawater (330/00 S) to low salinity (210/00 S). (Na(+), K(+))-ATPase activity decreased within 1h after transfer to 210/00 S, values recovering by 24h and attaining a maximum of ~180 nmol Pi min( 1) mg(-1) after 10 days (~2.5-fold increase). (Na(+), K(+))-ATPase activity is ~1.5-fold greater in gill 6 than in gill 7, independently of salinity. Relative expression of (Na(+), K(+))-ATPase alpha-subunit mRNA increased in both gills within 1- to 2-h exposure to low salinity, reaching an ~8-fold maximum after 24-h exposure, decreasing slightly by 10 days acclimation to low salinity. This increase in alpha-subunit mRNA expression may underpin the increased (Na(+), K(+))-ATPase activity seen after 10 days acclimation to low salinity. Enzyme affinity for ATP was greater in gill 6 than in gill 7, in contrast to ouabain affinity that was greater in gill 7. Western blotting analysis identified a single immunoreactive band against the (Na(+), K(+))-ATPase alpha-subunit with an Mr of ~105 kDa, independently of gill number and low salinity acclimation. Despite these differences, gills 6 and 7 appear to perform similar functions in salt uptake from the dilute medium. The partial cDNA sequence obtained for the gill (Na(+), K(+))-ATPase of C. ornatus (GenBank deposit KF056804) showed 97 to 91% identities with similar sequences from other portunid crab gills. The regulation of gill (Na(+), K(+))-ATPase activity during acclimation to low salinity is discussed. PMID- 25934082 TI - Financial catastrophe, treatment discontinuation and death associated with surgically operable cancer in South-East Asia: Results from the ACTION Study. AB - BACKGROUND: This study assessed the extent to which individuals with surgically operable cancer in Southeast Asia experience financially catastrophic out-of pocket costs, discontinuation of treatment, or death. METHODS: The ACTION study is a prospective, 8-country, cohort study of adult patients recruited consecutively with an initial diagnosis of cancer from public and private hospitals. Participants were interviewed at baseline and 3 months. In this paper, we identified 4,584 participants in whom surgery was indicated in initial treatment plans and assessed the following competing outcomes: death, financial catastrophe (out-of-pocket costs of >30% of annual household income), treatment discontinuation, and hospitalization without financial catastrophe incurred. We then analyzed a range of predictors using a multinomial regression model. RESULTS: Of the participants, 72% were female and 44% had health insurance at baseline. At 3 months, 31% of participants incurred financial catastrophe, 8% had died, 23% had discontinued treatment, and 38% were hospitalized but avoided financial catastrophe. Health insurance status was found to be associated with lower odds of treatment discontinuation (odds ratio [OR], 0.60; 95% CI, 0.47 0.77) relative to hospitalization without financial catastrophe. Women had greater odds of financial catastrophe than men (OR, 1.35; 95% CI, 1.05-1.74), whereas lower socioeconomic status (range of indicators) was generally found to be associated with higher odds of death, treatment discontinuation, and financial catastrophe. CONCLUSION: Priority should be given to measures such as programs to extend social health insurance to offset the out-of-pocket costs associated with surgery for cancer faced in particular by women, the uninsured, and individuals of low socioeconomic status in Southeast Asia. PMID- 25934084 TI - A potential antioxidant enzyme belonging to the atypical 2-Cys peroxiredoxin subfamily characterized from rock bream, Oplegnathus fasciatus. AB - Peroxiredoxins (Prxs), a diverse family of antioxidant enzymes, exert their antioxidant function through which different peroxide species are detoxified. This study describes both structural and functional characterization of a mitochondrial Prx identified in rock bream, Oplegnathus fasciatus (RbPrx5). The ORF (573 bp) of RbPrx5 encoded a protein of 190 amino acids (20 kDa) containing a putative mitochondrial targeting sequence (residues 1-20) and a thioredoxin-2 motif (residues 31-190) and three conserved Cys residues. Homology assessment and phylogenetic analysis clearly disclosed relatively higher amino acid sequence similarities and a closer evolutionary position of RbPrx5 with those of other teleost homologs. The ORF of RbPrx5 was distributed among six exons as found in other vertebrates, but it possessed an additional exon in its 5'-UTR. In silico examination of RbPrx5 gene's putative promoter region revealed the presence of several cis-elements which may be important in its transcriptional regulation. Constitutive expression of RbPrx5 was detected in eleven tissues with the highest level in the heart. Modulation of RbPrx5 transcription was evidenced from varying mRNA levels in head kidney post in vivo LPS-, poly I:C-, Edwardsiella tarda bacterial- and rock bream iridoviral-challenges. The antioxidant function of RbPrx5 was investigated using recombinant RbPrx5 protein. Results of an in vitro mixed-function oxidase assay demonstrated a dose-dependent inhibition of DNA damage by rRbPrx5. A H2O2 tolerance assay showed that in vivo overexpression of rRbPrx5 increased the bacterial survival under H2O2-mediated oxidative stress condition. These findings provide an overall insight into the structural, expressional and functional aspects of RbPrx5. PMID- 25934085 TI - Phylogenetic analysis of receptor FgfrL1 shows divergence of the C-terminal end in rodents. AB - FGFRL1 is a member of the fibroblast growth factor receptor (FGFR) family. Similar to the classical receptors FGFR1-FGFR4, it contains three extracellular Ig-like domains and a single transmembrane domain. However, it lacks the intracellular tyrosine kinase domain that would be required for signal transduction, but instead contains a short intracellular tail with a peculiar histidine-rich motif. This motif has been conserved during evolution from mollusks to echinoderms and vertebrates. Only the sequences of FgfrL1 from a few rodents diverge at the C-terminal region from the canonical sequence, as they appear to have suffered a frameshift mutation within the histidine-rich motif. This mutation is observed in mouse, rat and hamster, but not in the closely related rodents mole rat (Nannospalax) and jerboa (Jaculus), suggesting that it has occurred after branching of the Muridae and Cricetidae from the Dipodidae and Spalacidae. The consequence of the frameshift is a deletion of a few histidine residues and an extension of the C-terminus by about 40 unrelated amino acids. A similar frameshift mutation has also been observed in a human patient with a craniosynostosis syndrome as well as in several patients with colorectal cancer and bladder tumors, suggesting that the histidine-rich motif is prone to mutation. The reason why this motif was conserved during evolution in most species, but not in mice, is not clear. PMID- 25934086 TI - The role of magnetic assisted capsule endoscopy (MACE) to aid visualisation in the upper GI tract. AB - Examination of the upper gastrointestinal tract by a standard endoscope is often thought as a daunting experience to many who have undertaken or are about to undergo the procedure. The overall perceived size of the gastroscope, unpleasantness of stimulation of the gag reflex and the need often for sedation is discouraging to many. A method to visualise the upper gastrointestinal mucosa which negates the need for sedation, the associated expensive decontamination costs and the possibility of having a community based examination would be particularly welcoming to this endoscopy field. Since the first swallow of a capsule endoscope by a human volunteer in 1999, their usage for examining the small bowel has exponentially grown to that of over a million patients worldwide. More recently, innovation in this field have shown plausibility for its use to visualise the upper gastrointestinal tract, with the integration of magnets within the capsule the most promising method. PMID- 25934087 TI - Prevalence of picky eating behaviour in Chinese school-age children and associations with anthropometric parameters and intelligence quotient. A cross sectional study. AB - Previous studies have demonstrated the importance of eating behaviour regarding dietary variety and nutrient intake of children. However, the association between picky eating and growth of children is still a topic of debate. This study sought to estimate the prevalence of picky eating and to identify possible associations with the growth of school-age children in China. In this survey, 793 healthy children aged 7-12 years were recruited from nine cities and rural areas in China using a multi-stage cluster sampling method. Data collected included socio demographic information and parents' perceptions of picky eating using a structured questionnaire, nutrient intake using 24-hour dietary recall, weight and height using body measurements, and intelligence using the Wechsler Intelligence Scale for Children. Blood samples were collected and analysed for minerals. The prevalence of picky eating reported by parents was 59.3% in children. Compared with non-picky eaters, picky eaters had a lower dietary intake of energy, protein, carbohydrates, most vitamins and minerals, and lower levels of magnesium, iron, and copper in the blood (p < 0.05), and also had a 0.184 z score lower in height for age (95% CI: -0.332, 0.036; p = 0.015), a 0.385 z-score lower in weight for age (95% CI: -0.533, -0.237; p < 0.001), a 0.383 z-score lower in BMI for age (95% CI: -0.563, -0.203; p < 0.001), and scored 2.726 points higher on the intelligence test (95% CI: 0.809, 4.643; p = 0.006) when adjusted for children's birth weight and food allergy, mothers' education, and family income. Picky eating behaviour towards meat, eggs and vegetables showed negative associations with growth. Picky eating behaviour is prevalent in school-age children in China and may have a negative effect on growth. PMID- 25934088 TI - A taste of ethical consumption at a slow food festival. AB - This paper examines the motives and experiences of attendees at a Slow Food festival to gain an understanding of how people engage with ethical consumer projects. Slow Food is a global social movement aimed at promoting food that is regionally, ethically, and sustainably produced, and convivially consumed. The movement uses culinary tourist events, such as food festivals and farmers' markets, to promote its philosophy and attract new members. There have been no empirical studies of ethical consumption using a Slow Food event as a case study. This study uses an ethnographic approach and a framework of virtue ethics to explore the views of people attending a major Slow Food festival in the city of Melbourne, Australia. Semi-structured interviews were conducted in situ with 33 participants (19 consumers and 14 stallholders) to discover their rationales for attending the festival, and their perspectives on ethical consumption. Transcripts were coded and thematically analysed, resulting in three themes reflecting varying degrees of public virtues (altruistic motivations) and private virtues (personal wellbeing): the quest for virtuous lifestyles through ethical consumption, the importance of co-production, and the challenges of putting ethical consumer projects like Slow Food into daily practice. The findings reveal the manner in which virtue ethics affects foodways and highlights the contingent and challenging nature of practising ethical eating. PMID- 25934089 TI - Ingredients of gender-based stereotypes about food. Indirect influence of food type, portion size and presentation on gendered intentions to eat. AB - The association between certain foods and masculinity or femininity has been widely discussed in different disciplines. However, extant research has yet to clarify which are the critical dimensions lending these gender connotations to food and thus impacting on the willingness to eat it. We present a study on the role of food type, portion size, and dish presentation as potential factors constituting the gender-based stereotype about food, and their indirect or mediated effect on the intention of men and women to eat certain feminine/masculine stereotyped foods. We manipulated the three features cited above in a 2 (food type: Caprese vs. hamburger) * 2 (portion size: small vs. big) * 2 (presentation: elegant vs. rough) full factorial design. Results confirmed a model of moderated mediation: the Caprese salad, the small portion and the elegantly presented dish (in respect to the hamburger, the big portion and the roughly presented dish) tend to be considered "feminine food", and thus women expressed a more pronounced intention to eat it than men. The implications of the findings for both theory and practice are discussed. PMID- 25934090 TI - Primary atypical teratoid/rhabdoid tumor of the optic nerve: a rare entity in an exceptional location. AB - Atypical teratoid/rhabdoid tumors are rare and highly malignant central nervous system tumors. They have no specific radiological features and often present several histological components that make a problem in differential diagnosis with medulloblastoma and primitive neuroectodermal tumors. We present the case of a newborn girl complained of a gradual proptosis of the left eye secondary to an expansive lesional process of the optic nerve. The location at the optic nerve, reported only twice in the literature, and an exclusive rhabdoid appearance on biopsy added additional differential diagnosis problems. The proptosis worsened and the infant died few days after two cycles of chemotherapy. VIRTUAL SLIDES: The virtual slides for this article can be found here: http://www.diagnosticpathology.diagnomx.eu/vs/2037718783145212 . PMID- 25934091 TI - Anatomical relationship between the sublingual fossa and the lateral lingual foramen. AB - This study investigated the locational relationship between the sublingual fossa (SF) and the lateral lingual foramen (LLF) in order to gain useful knowledge so that perforation of the lingual cortical bone and damage to the adjacent blood vessels can be avoided when placing an endosseous implant (implant) in the mandibular interforaminal region. The deepest point of the SF (SFP) and the LLF were identified in 38 Japanese cadaver mandibles (20 edentulous and 18 dentate) by computed tomography (CT) and physical measurement. Their locations were measured. In the edentulous cases, the SFP was located approximately 15 mm vertically from the alveolar crest in the direction of the mandibular lower margin in the canine and premolar regions, and the LLF was located within a 5mm radius from the SFP. Thus, significant attention to the locational relationship between the SFP and the LLF, as seen on preoperative CT, is required when placing an implant >=3.75 mm in diameter and >=15 mm in length in this region. PMID- 25934092 TI - Wedelolactone induces growth of breast cancer cells by stimulation of estrogen receptor signalling. AB - Wedelolactone, a plant coumestan, was shown to act as anti-cancer agent for breast and prostate carcinomas in vitro and in vivo targeting multiple cellular proteins including androgen receptors, 5-lipoxygenase and topoisomerase IIalpha. It is cytotoxic to breast, prostate, pituitary and myeloma cancer cell lines in vitro at MUM concentrations. In this study, however, a novel biological activity of nM dose of wedelolactone was demonstrated. Wedelolactone acts as agonist of estrogen receptors (ER) alpha and beta as demonstrated by transactivation of estrogen response element (ERE) in cells transiently expressing either ERalpha or ERbeta and by molecular docking of this coumestan into ligand binding pocket of both ERalpha and ERbeta. In breast cancer cells, wedelolactone stimulates growth of estrogen receptor-positive cells, expression of estrogen-responsive genes and activates rapid non-genomic estrogen signalling. All these effects can be inhibited by pretreatment with pure ER antagonist ICI 182,780 and they are not observed in ER-negative breast cancer cells. We conclude that wedelolactone acts as phytoestrogen in breast cancer cells by stimulating ER genomic and non-genomic signalling pathways. PMID- 25934093 TI - Local temperature-sensitive mechanisms are important mediators of limb tissue hyperemia in the heat-stressed human at rest and during small muscle mass exercise. AB - Limb tissue and systemic blood flow increases with heat stress, but the underlying mechanisms remain poorly understood. Here, we tested the hypothesis that heat stress-induced increases in limb tissue perfusion are primarily mediated by local temperature-sensitive mechanisms. Leg and systemic temperatures and hemodynamics were measured at rest and during incremental single-legged knee extensor exercise in 15 males exposed to 1 h of either systemic passive heat stress with simultaneous cooling of a single leg (n = 8) or isolated leg heating or cooling (n = 7). Systemic heat stress increased core, skin and heated leg blood temperatures (Tb), cardiac output, and heated leg blood flow (LBF; 0.6 +/- 0.1 l/min; P < 0.05). In the cooled leg, however, LBF remained unchanged throughout (P > 0.05). Increased heated leg deep tissue blood flow was closely related to Tb (R(2) = 0.50; P < 0.01), which is partly attributed to increases in tissue VO2 (R(2) = 0.55; P < 0.01) accompanying elevations in total leg glucose uptake (P < 0.05). During isolated limb heating and cooling, LBFs were equivalent to those found during systemic heat stress (P > 0.05), despite unchanged systemic temperatures and hemodynamics. During incremental exercise, heated LBF was consistently maintained ~ 0.6 l/min higher than that in the cooled leg (P < 0.01), with LBF and vascular conductance in both legs showing a strong correlation with their respective local Tb (R(2) = 0.85 and 0.95, P < 0.05). We conclude that local temperature-sensitive mechanisms are important mediators in limb tissue perfusion regulation both at rest and during small-muscle mass exercise in hyperthermic humans. PMID- 25934094 TI - Cystathionine gamma-lyase, a H2S-generating enzyme, is a GPBAR1-regulated gene and contributes to vasodilation caused by secondary bile acids. AB - GPBAR1 is a bile acid-activated receptor (BAR) for secondary bile acids, lithocholic (LCA) and deoxycholic acid (DCA), expressed in the enterohepatic tissues and in the vasculature by endothelial and smooth muscle cells. Despite that bile acids cause vasodilation, it is unclear why these effects involve GPBAR1, and the vascular phenotype of GPBAR1 deficient mice remains poorly defined. Previous studies have suggested a role for nitric oxide (NO) in regulatory activity exerted by GPBAR1 in liver endothelial cells. Hydrogen sulfide (H2S) is a vasodilatory agent generated in endothelial cells by cystathionine-gamma-lyase (CSE). Here we demonstrate that GPBAR1 null mice had increased levels of primary and secondary bile acids and impaired vasoconstriction to phenylephrine. In aortic ring preparations, vasodilation caused by chenodeoxycholic acid (CDCA), a weak GPBAR1 ligand and farnesoid-x receptor agonist (FXR), was iberiotoxin-dependent and GPBAR1-independent. In contrast, vasodilation caused by LCA was GPBAR1 dependent and abrogated by propargyl-glycine, a CSE inhibitor, and by 5beta-cholanic acid, a GPBAR1 antagonist, but not by N(5)-(1-iminoethyl)-l-ornithine (l-NIO), an endothelial NO synthase inhibitor, or iberiotoxin, a large-conductance calcium-activated potassium (BKCa) channels antagonist. In venular and aortic endothelial (HUVEC and HAEC) cells GPBAR1 activation increases CSE expression/activity and H2S production. Two cAMP response element binding protein (CREB) sites (CREs) were identified in the CSE promoter. In addition, TLCA stimulates CSE phosphorylation on serine residues. In conclusion we demonstrate that GPBAR1 mediates the vasodilatory activity of LCA and regulates the expression/activity of CSE. Vasodilation caused by CDCA involves BKCa channels. The GPBAR1/CSE pathway might contribute to endothelial dysfunction and hyperdynamic circulation in liver cirrhosis. PMID- 25934095 TI - Right ventricular nitric oxide signaling in an ovine model of congenital heart disease: a preserved fetal phenotype. AB - We recently reported superior right ventricle (RV) performance in response to acute afterload challenge in lambs with a model of congenital heart disease with chronic left-to-right cardiac shunts. Compared with control animals, shunt lambs demonstrated increased contractility because of an enhanced Anrep effect (the slow increase in contractility following myocyte stretch). This advantageous physiological response may reflect preservation of a fetal phenotype, since the RV of shunt lambs remains exposed to increased pressure postnatally. Nitric oxide (NO) production by NO synthase (NOS) is activated by myocyte stretch and is a necessary intermediary of the Anrep response. The purpose of this study was to test the hypothesis that NO signaling is increased in the RV of fetal lambs compared with controls and shunt lambs have persistence of this fetal pattern. An 8-mm graft was placed between the pulmonary artery and aorta in fetal lambs (shunt). NOS isoform expression, activity, and association with activating cofactors were determined in fetal tissue obtained during late-gestation and in 4 wk-old juvenile shunt and control lambs. We demonstrated increased RNA and protein expression of NOS isoforms and increased total NOS activity in the RV of both shunt and fetal lambs compared with control. We also found increased NOS activation and association with cofactors in shunt and fetal RV compared with control. These data demonstrate preserved fetal NOS phenotype and NO signaling in shunt RV, which may partially explain the mechanism underlying the adaptive response to increased afterload seen in the RV of shunt lambs. PMID- 25934096 TI - Modulation of endothelial cell phenotype by physical activity: impact on obesity related endothelial dysfunction. AB - Increased levels of physical activity are associated with reduced cardiovascular disease (CVD) risk and mortality in obesity and diabetes. Available evidence suggests that local factors, including local hemodynamics, account for a significant portion of this CVD protection, and numerous studies have interrogated the therapeutic benefit of physical activity/exercise training in CVD. Less well established is whether basal differences in endothelial cell phenotype between/among vasculatures related to muscle recruitment patterns during activity may account for reports of nonuniform development of endothelial dysfunction in obesity. This is the focus of this review. We highlight recent work exploring the vulnerability of two distinct vasculatures with established differences in endothelial cell phenotype. Specifically, based largely on dramatic differences in underlying hemodynamics, arteries perfusing soleus muscle (slow-twitch muscle fibers) and those perfusing gastrocnemius muscle (fast-twitch muscle fibers) in the rat exhibit an exercise training-like versus an untrained endothelial cell phenotype, respectively. In the context of obesity, therefore, arteries to soleus muscle exhibit protection from endothelial dysfunction compared with vulnerable arteries to gastrocnemius muscle. This disparate vulnerability is consistent with numerous animal and human studies, demonstrating increased skeletal muscle blood flow heterogeneity in obesity coincident with reduced muscle function and exercise intolerance. Mechanistically, we highlight emerging areas of inquiry exploring novel aspects of hemodynamic-sensitive signaling in endothelial cells and the time course of physical activity associated endothelial adaptations. Lastly, further exploration needs to consider the impact of endothelial heterogeneity on the development of endothelial dysfunction because endothelial dysfunction independently predicts CVD events. PMID- 25934098 TI - Cardiac autonomic regulation during hypoxic exercise. PMID- 25934097 TI - Differences in genetic signaling, and not mechanical properties of the wall, are linked to ascending aortic aneurysms in fibulin-4 knockout mice. AB - Fibulin-4 is an extracellular matrix protein that is essential for proper assembly of arterial elastic fibers. Mutations in fibulin-4 cause cutis laxa with thoracic aortic aneurysms (TAAs). Sixty percent of TAAs occur in the ascending aorta (AA). Newborn mice lacking fibulin-4 (Fbln4(-/-)) have aneurysms in the AA, but narrowing in the descending aorta (DA), and are a unique model to investigate locational differences in aneurysm susceptibility. We measured mechanical behavior and gene expression of AA and DA segments in newborn Fbln4(-/-) and Fbln4(+/+) mice. Fbln4(-/-) AA has increased diameters compared with Fbln4(+/+) AA and Fbln4(-/-) DA at most applied pressures, confirming genotypic and locational specificity of the aneurysm phenotype. When diameter compliance and tangent modulus were calculated from the mechanical data, we found few significant differences between genotypes, suggesting that the mechanical response to incremental diameter changes is similar, despite the fragmented elastic fibers in Fbln4(-/-) aortas. Fbln4(-/-) aortas showed a trend toward increased circumferential stretch, which may be transmitted to smooth muscle cells (SMCs) in the wall. Gene expression data suggest activation of pathways for SMC proliferation and inflammation in Fbln4(-/-) aortas compared with Fbln4(+/+). Additional genes in both pathways, as well as matrix metalloprotease-8 (Mmp8), are upregulated specifically in Fbln4(-/-) AA compared with Fbln4(+/+) AA and Fbln4(-/-) DA. Mmp8 is a neutrophil collagenase that targets type 1 collagen, and upregulation may be necessary to allow diameter expansion in Fbln4(-/-) AA. Our results provide molecular and mechanical targets for further investigation in aneurysm pathogenesis. PMID- 25934099 TI - Angiotensin II blockade: how its molecular targets may signal to mitochondria and slow aging. Coincidences with calorie restriction and mTOR inhibition. AB - Caloric restriction (CR), renin angiotensin system blockade (RAS-bl), and rapamycin-mediated mechanistic target of rapamycin (mTOR) inhibition increase survival and retard aging across species. Previously, we have summarized CR and RAS-bl's converging effects, and the mitochondrial function changes associated with their physiological benefits. mTOR inhibition and enhanced sirtuin and KLOTHO signaling contribute to the benefits of CR in aging. mTORC1/mTORC2 complexes contribute to cell growth and metabolic regulation. Prolonged mTORC1 activation may lead to age-related disease progression; thus, rapamycin-mediated mTOR inhibition and CR may extend lifespan and retard aging through mTORC1 interference. Sirtuins by deacetylating histone and transcription-related proteins modulate signaling and survival pathways and mitochondrial functioning. CR regulates several mammalian sirtuins favoring their role in aging regulation. KLOTHO/fibroblast growth factor 23 (FGF23) contribute to control Ca(2+), phosphate, and vitamin D metabolism, and their dysregulation may participate in age-related disease. Here we review how mTOR inhibition extends lifespan, how KLOTHO functions as an aging suppressor, how sirtuins mediate longevity, how vitamin D loss may contribute to age-related disease, and how they relate to mitochondrial function. Also, we discuss how RAS-bl downregulates mTOR and upregulates KLOTHO, sirtuin, and vitamin D receptor expression, suggesting that at least some of RAS-bl benefits in aging are mediated through the modulation of mTOR, KLOTHO, and sirtuin expression and vitamin D signaling, paralleling CR actions in age retardation. Concluding, the available evidence endorses the idea that RAS-bl is among the interventions that may turn out to provide relief to the spreading issue of age-associated chronic disease. PMID- 25934100 TI - Sources of traffic and visitors' preferences regarding online public reports of quality: web analytics and online survey results. AB - BACKGROUND: In the context of the Affordable Care Act, there is extensive emphasis on making provider quality transparent and publicly available. Online public reports of quality exist, but little is known about how visitors find reports or about their purpose in visiting. OBJECTIVE: To address this gap, we gathered website analytics data from a national group of online public reports of hospital or physician quality and surveyed real-time visitors to those websites. METHODS: Websites were recruited from a national group of online public reports of hospital or physician quality. Analytics data were gathered from each website: number of unique visitors, method of arrival for each unique visitor, and search terms resulting in visits. Depending on the website, a survey invitation was launched for unique visitors on landing pages or on pages with quality information. Survey topics included type of respondent (eg, consumer, health care professional), purpose of visit, areas of interest, website experience, and demographics. RESULTS: There were 116,657 unique visitors to the 18 participating websites (1440 unique visitors/month per website), with most unique visitors arriving through search (63.95%, 74,606/116,657). Websites with a higher percent of traffic from search engines garnered more unique visitors (P=.001). The most common search terms were for individual hospitals (23.25%, 27,122/74,606) and website names (19.43%, 22,672/74,606); medical condition terms were uncommon (0.81%, 605/74,606). Survey view rate was 42.48% (49,560/116,657 invited) resulting in 1755 respondents (participation rate=3.6%). There were substantial proportions of consumer (48.43%, 850/1755) and health care professional respondents (31.39%, 551/1755). Across websites, proportions of consumer (21% 71%) and health care professional respondents (16%-48%) varied. Consumers were frequently interested in using the information to choose providers or assess the quality of their provider (52.7%, 225/427); the majority of those choosing a provider reported that they had used the information to do so (78%, 40/51). Health care professional (26.6%, 115/443) and consumer (20.8%, 92/442) respondents wanted cost information and consumers wanted patient narrative comments (31.5%, 139/442) on the public reports. Health care professional respondents rated the experience on the reports higher than consumers did (mean 7.2, SD 2.2 vs mean 6.2, SD 2.7; scale 0-10; P<.001). CONCLUSIONS: Report sponsors interested in increasing the influence of their reports could consider using techniques to improve search engine traffic, providing cost information and patient comments, and improving the website experience for both consumers and health care professionals. PMID- 25934101 TI - Neurobeachin Regulates Glutamate- and GABA-Receptor Targeting to Synapses via Distinct Pathways. AB - Neurotransmission and synaptic strength depend on expression of post-synaptic receptors on the cell surface. Post-translational modification of receptors, trafficking to the synapse through the secretory pathway, and subsequent insertion into the synapse involves interaction of the receptor with A-kinase anchor proteins (AKAPs) and scaffolding proteins. Neurobeachin (Nbea), a brain specific AKAP, is required for synaptic surface expression of both glutamate and GABA receptors. Here, we investigated the role of Nbea-dependent targeting of postsynaptic receptors by studying Nbea interaction with synapse-associated protein 102 (SAP102/Dlg3) and protein kinase A subunit II (PKA II). A Nbea mutant lacking the PKA binding domain showed a similar distribution as wild-type Nbea in Nbea null neurons and partially restored GABA receptor surface expression. To understand the relevance of Nbea interaction with SAP102, we analysed SAP102 null mutant mice. Nbea levels were reduced by ~80% in SAP102 null mice, but glutamatergic receptor expression was normal. A single-point mutation in the pleckstrin homology domain of Nbea (E2218R) resulted in loss of binding with SAP102. When expressed in Nbea null neurons, this mutant fully restored GABA receptor surface expression, but not glutamate receptor expression. Our results suggest that the PKA-binding domain is not essential for Nbea's role in receptor targeting and that Nbea targets glutamate and GABA receptors to the synapse via distinct molecular pathways by interacting with specific effector proteins. PMID- 25934102 TI - Experimental Advances Towards Neural Regeneration from Induced Stem Cells to Direct In Vivo Reprogramming. AB - Neuronal loss is a common substrate of many neurological diseases that still lack effective treatments and highly burden lives of affected individuals. The discovery of self-renewing stem cells within the central nervous system (CNS) has opened the doors to the possibility of using the plasticity of CNS as a potential strategy for the development of regenerative therapies after injuries. The role of neural progenitor cells appears to be crucial, but insufficient in reparative processes after damage. In addition, the mechanisms that regulate these events are still largely unknown. Stem cell-based therapeutic approaches have primarily focused on the use of either induced pluripotent stem cells or induced neural stem cells as sources for cell transplantation. More recently, in vivo direct reprogramming of endogenous CNS cells into multipotent neural stem/progenitor cells has been proposed as an alternative strategy that could overcome the limits connected with both the invasiveness of exogenous cell transplantation and the technical issues of in vitro reprogramming (i.e., the time requested and the limited available amount of directly induced neuronal cells). In this review, we aim to highlight the recent studies on in vivo direct reprogramming, focusing on astrocytes conversion to neurons or to neural stem/precursors cells, in the perspective of future therapeutic purposes for neurological disorders. PMID- 25934104 TI - Improvement of crocin stability by biodegradeble nanoparticles of chitosan alginate. AB - This study aimed to improve the stability of crocin, a saffron carotenoid, encapsulating into chitosan (Cs)-sodium alginate (Alg) nanoparticles prepared by a modified ionic gelation method were investigated as a new carrier to improve the stability of crocin. Response surface methodology was used to optimize the important variables, namely the concentrations of Cs and Alg, and pH influencing the particle size, zeta-potential, and encapsulation efficiency to find the optimum formulation for production of crocin nanoparticles (CNPs). Microscopic analysis and dynamic light scattering examination indicated non-smooth and spherical nanoparticles with the size range of 165-230 nm in weight ratio of Cs:Alg (1:1.25) and pH 4.7. Fourier transform-infrared spectroscopy displayed an extensive hydrogen bonding interaction between the crocin and biopolymers. Encapsulation efficiency, loading capacity and yield of CNPs were 38.16, 30.96 and 48.33%, respectively. The zeta-potential of NPs was about -33.52 mV which resulted in the better stability of NPs during manipulation and storage. Stability studies showed that nanoencapsulation provided enhanced crocin stability with biopolymers compared to the standard crocin under unfavorable environmental conditions. PMID- 25934105 TI - A novel glucose oxidase biosensor based on poly([2,2';5',2"]-terthiophene-3' carbaldehyde) modified electrode. AB - In the study, the electrochemical behavior of glucose oxidase (GOx) immobilized on poly([2,2';5',2"]-terthiophene-3'-carbaldehyde) (poly(TTP)) modified glassy carbon electrode (GCE) was investigated. The biosensor (poly(TTP)/GOx/GCE) showed a pair of redox peaks in 0.1 M phosphate buffer (pH 7.4) solution in the absence of oxygen the co-substrate of GOx. In here, Poly(TTP)/GOx/GCE biosensor acts as the co-substrate instead of oxygen. Upon the addition of glucose, the reduction and oxidation peak currents increased until the active site of GOx was fully saturated with glucose. The apparent m was estimated 26.13 mM from Lineweaver Burk graph. The biosensor displayed a good stability and bioactivity. The biosensor showed a high sensitivity (56.1 nA/mM), a linear range (from 0.5 to 20.15 mM), and a good reproducibility with 3.6% of relative standard deviation. In addition, the interference currents of glycin, ascorbic acid, histidine, uric acid, dopamine, arginine, and fructose on GOx biosensor were investigated. All that substances exhibited an interference current under 10%. It was not shown a marked difference between GOx biosensor and spectrophotometric measurement of glucose in serum examples. UV-visible spectroscopy and scanning electron microscopy (SEM) experiments of the biosensor were also performed. PMID- 25934106 TI - Structural identification and immunostimulating activity of a Laminaria japonica polysaccharide. AB - In the present study, a new water-soluble polysaccharide (LJP-11) was obtained from Laminaria japonica by anion exchange DEAE-cellulose chromatography and Sephacryl S-500 chromatography. The average molecular weight of this polysaccharide was estimated to be about 2.89*10(6) Da by high performance liquid chromatography system. Gas chromatography showed that LJP-11 was composed of arabinose, mannose and glucose in a molar ratio of 1.0:1.16:6.33. LJP-11 contains a long backbone consisting of (1->4)-beta-D-GlcpAc, (1->4)-alpha-D-Glcp, (1->6) beta-D-Glcp and (1->3,6)-alpha-D-Manp. The 1-linked beta-L-Araf was linked to the C-6 of (1->3)-alpha-D-Manp and the sulfate group was attached to the C-4 of (1 >6)-beta-D-Glcp. Pharmacological tests displayed that LJP-11 can stimulate macrophages to release NO, IL-6, TNF-alpha and IL-10 as well as the up-regulation of their gene expressions, indicating LJP-11 has beneficial effects on immunostimulation. Moreover, LJP-11 exhibited positive effects on the translocation of NF-kappaB p65 from cytoplasm to nucleus and the phosphorylation of IkappaBalpha, ERK1/2, JNK1/2 and P38 in macrophages. These results suggested that the activation of MAPK and NF-kappaB signaling pathways is one of the mechanisms responsible for the immunostimulating activity of LJP-11. PMID- 25934103 TI - Toward Omics-Based, Systems Biomedicine, and Path and Drug Discovery Methodologies for Depression-Inflammation Research. AB - Meta-analyses confirm that depression is accompanied by signs of inflammation including increased levels of acute phase proteins, e.g., C-reactive protein, and pro-inflammatory cytokines, e.g., interleukin-6. Supporting the translational significance of this, a meta-analysis showed that anti-inflammatory drugs may have antidepressant effects. Here, we argue that inflammation and depression research needs to get onto a new track. Firstly, the choice of inflammatory biomarkers in depression research was often too selective and did not consider the broader pathways. Secondly, although mild inflammatory responses are present in depression, other immune-related pathways cannot be disregarded as new drug targets, e.g., activation of cell-mediated immunity, oxidative and nitrosative stress (O&NS) pathways, autoimmune responses, bacterial translocation, and activation of the toll-like receptor and neuroprogressive pathways. Thirdly, anti inflammatory treatments are sometimes used without full understanding of their effects on the broader pathways underpinning depression. Since many of the activated immune-inflammatory pathways in depression actually confer protection against an overzealous inflammatory response, targeting these pathways may result in unpredictable and unwanted results. Furthermore, this paper discusses the required improvements in research strategy, i.e., path and drug discovery processes, omics-based techniques, and systems biomedicine methodologies. Firstly, novel methods should be employed to examine the intracellular networks that control and modulate the immune, O&NS and neuroprogressive pathways using omics-based assays, including genomics, transcriptomics, proteomics, metabolomics, epigenomics, immunoproteomics and metagenomics. Secondly, systems biomedicine analyses are essential to unravel the complex interactions between these cellular networks, pathways, and the multifactorial trigger factors and to delineate new drug targets in the cellular networks or pathways. Drug discovery processes should delineate new drugs targeting the intracellular networks and immune-related pathways. PMID- 25934107 TI - Effective removal of cationic dyes from aqueous solution using gum ghatti-based biodegradable hydrogel. AB - Biodegradable hydrogels of gum ghatti (Gg) with a co-polymer mixture of acrylamide (AAm) and methacrylic acid (MAA) (termed as Gg-cl-P(AAm-co-MAA)) were synthesised by microwave-assisted free radical graft co-polymerisation technique. The hydrogel polymer was characterized by FTIR, SEM, and Brunauer-Emmett-Teller techniques. The Gg-cl-P(AAm-co-MAA) hydrogel was studied as an adsorbent for the removal of methylene blue (MB) and methyl violet (MV) from aqueous solutions. Adsorption of both the dyes followed pseudo-second-order kinetics and Langmuir adsorption isotherm models. The hydrogel polymer adsorbed 98% of MB and 95% of MV from aqueous solution. The Gg-cl-P(AAm-co-MAA) maintained its original sorption capacity for three cycles of adsorption-desorption. Furthermore, the hydrogel polymer degraded fully within 50 days in soil compost. In summary, the Gg-cl P(AAm-co-MAA) hydrogel could be a potential adsorbent for the remediation of dyes from industrial wastewater. PMID- 25934108 TI - Chuanminshen violaceum polysaccharides improve the immune responses of foot-and mouth disease vaccine in mice. AB - Water-soluble polysaccharides from Chuanminshen violaceum (CVPS) were evaluated for their physicochemical properties, monosaccharide composition, and adjuvant potential to specific cellular and humoral immune responses in a mouse model of foot-and-mouth disease virus (FMDV) vaccination. The average molecular weight (Mw) of the CVPS was 968.31 kDa. The monosaccharide components of the CVPS was rhamnose, arabinose, fucose, mannose, glucose, and galactose with a relative mass of 6.29%, 21.87%, 16.59%, 12.54%, 13.07%, and 28.05%, respectively. Administering CVPS as an adjuvant significantly enhanced the phagocytic capacity of peritoneal macrophages, splenocyte proliferation, and the activity of NK cells and CTL as well as increased FMDV-specific IgG and IgG subclass antibody titers. Moreover, CVPS increased the expression of IL-2, IFN-gamma, and IL-4 in CD4(+) T cells and IFN-gamma expression in CD8(+) T cells. Additionally, CVPS enhanced CD40(+), CD80(+), and CD86(+) expression on DCs. Moreover, CVPS upregulated MHC-I/II, TLR 2/4 mRNA levels. In contrast, CVPS downregulated TGF-beta mRNA expression and the frequency of CD4(+)CD25(+)Foxp3(+) Treg cells. Taken together, these results indicate that administering CVPS as an adjuvant enhances both cellular and humoral immune responses via the TLR-2 and TLR-4 signalling pathways, thereby promoting DC maturation and suppressing TGF-beta expression and Treg frequency. PMID- 25934109 TI - DNA template-assisted inhibition of tyrosinase activity. AB - Enzyme-mediated polymerization reactions have been widely studied in the context of DNA template-assisted reactions. We have recently highlighted the ability of DNA templates to modulate enzyme-catalyzed single-step transformations. In this work, we focus on the intramolecular transformation of L-dopa catalyzed by enzyme tyrosinase and report a novel role of DNA templates in inhibition of the enzyme. The kinetics of mushroom tyrosinase monitored by UV-visible spectroscopy reveals significant decrease in the enzyme's efficiency in the presence of short double stranded DNA molecules. KM of tyrosinase is found to increase by nearly 1.8-fold, implying a lower affinity of the enzyme for L-dopa, whereas Vmax is only marginally affected. The mode of inhibition is assessed to be a mixed mode with kinetic constants of inhibition in the micromolar range. Further, in the presence of cinnamic acid and DNA duplexes, the KM of tyrosinase increases nearly 3.5 fold, whereas Ki and Ki' are lowered by an order of magnitude. These results are a corollary of the known influence of substrate-template interactions and greater local substrate concentrations on enzyme activity and expand the paradigm with respect to use of DNA templates in enzyme-catalyzed reactions. PMID- 25934110 TI - The effects of ginsenosides to amyloid fibril formation by RCMkappa-casein. AB - When not incorporated into the casein micelle, isolated kappa-casein spontaneously forms amyloid fibrils under physiological conditions, and is a convenient model for researching generic aspects of fibril formation. Ginsenosides have recently attracted much research interest because of the effects on aging diseases, which are always associated with amyloid fibril formation, for example, Alzheimer's, Parkinson's, and Huntington's diseases. In addition, the mechanism remains unclear that ginsenosides exert the effects against aging diseases. To address these aspects, we have investigated the ability of ginsenoside Rb1, Rc, Rg1, and Re influencing fibril formation by RCMkappa-casein (reduced and carboxymethylated kappa-casein), with the methods of Thioflavin T fluorescence assay, transmission electron microscopy (TEM), and intrinsic fluorescence spectroscopy. The results showed that ginsenoside Rb1 and Rg1 inhibited obviously RCMkappa-CN fibrillation in both the initial rate and final level of ThT fluorescence. On the contrary, ginsenoside Re had a few effect on promoting RCMkappa-CN fibril formation, proved by thick and larger fibrils observed frequently in TEM. While Rc did not influence RCMkappa-CN fibrillation. It is demonstrated that Rg1 prevent RCMkappa-CN fibril formation by stabilising RCMkappa-CN in its native like state. Additional chemical structure difference of ginsenosides and the effects on fibril formation are also implicated. PMID- 25934111 TI - Acetyl Fentanyl, a Novel Fentanyl Analog, Causes 14 Overdose Deaths in Rhode Island, March-May 2013. PMID- 25934112 TI - Anaplastic pleomorphic xanthoastrocytoma with spinal leptomeningeal spread at the time of diagnosis in an adult. AB - We describe the first patient, to our knowledge, with anaplastic pleomorphic xanthoastrocytoma (PXA) with spinal leptomeningeal spread at the time of diagnosis and present a review of the literature. PXA is a tumor that typically has an indolent course but occasionally, when anaplastic features are present, behaves in a more aggressive manner. We found that PXA with spinal leptomeningeal spread at the time of diagnosis confers a worse prognosis. Craniospinal imaging should be obtained at time of diagnosis of PXA and the presence of leptomeningeal spread may be indicative of a more aggressive disease process. PMID- 25934113 TI - Quantitative assessment of hemodynamic changes during spinal dural arteriovenous fistula surgery. AB - We aimed to evaluate the efficacy of FLOW 800 (Carl Zeiss Meditec, Jena, Thuringia, Germany) with indocyanine green (ICG) videoangiography for the quantitative assessment of flow dynamics in spinal dural arteriovenous fistula (dAVF) surgeries. We prospectively enrolled nine patients with spinal dAVF diagnosed within the past year and performed FLOW 800 analyses using ICG videoangiography before and after surgical obliteration of the fistula. A color coded map was semi-automatically generated by FLOW 800 and used for high resolution visualization of the vasculature and instant interpretation of the dynamic flow changes. The FLOW 800-specific hemodynamic parameters were employed for real-time measurements of parenchymal perfusion alterations. Overall, 18 intraoperative FLOW 800 analyses using ICG videoangiography were performed in nine patients. The color-coded map aided the detection and complete obliteration of the fistulas in all patients and the results were verified by postoperative spinal digital subtraction angiography. The transit time parameter was significantly shorter in the preobliteration phase than in the postobliteration phase (p < 0.01), the rise time parameter exhibited the same pattern (p = 0.08) and maximum intensity and blood flow index were not significantly different between these phases. FLOW 800 with ICG videoangiography provided an intuitive and objective understanding of blood flow dynamics intraoperatively and enabled easy and confident identification and treatment of this pathology. The FLOW 800 specific hemodynamic analyses provided additional perfusion information that enabled real-time measurements of parenchymal perfusion alterations. FLOW 800 with ICG videoangiography is useful for intraoperative quantitative assessment of flow dynamics, facilitating safety and confidence in the treatment of spinal dAVF. PMID- 25934115 TI - Europe aspires to set the record straight on familial hypercholesterolaemia. PMID- 25934114 TI - Lowering the dietary omega-6: omega-3 does not hinder nonalcoholic fatty-liver disease development in a murine model. AB - It is hypothesized that a high dietary n-6:n-3 (eg, 10-20:1) is partly responsible for the rise in obesity and related health ailments. However, no tightly controlled studies using high-fat diets differing in the n-6:n-3 have tested this hypothesis. The aim of the study was to determine the role that the dietary n-6:n-3 plays in non-alcoholic fatty-liver disease (NAFLD) and colitis development. We hypothesized that reducing the dietary n-6:n-3 would hinder the development of NAFLD and colitis. Male C57BL/6 J mice were fed high-fat diets, differing in the n-6:n-3 (1:1, 5:1, 10:1, 20:1), for 20 weeks. Gas chromatography mass spectrometry was used to analyze the hepatic phospholipid arachidonic acid (AA):eicosapentaenoic acid and AA:docosahexaenoic acid. Hepatic metabolism, inflammatory signaling, macrophage polarization, gene expression of inflammatory mediators, oxidative and endoplasmic reticulum stress, and oxidative capacity were assessed as well as colonic inflammatory signaling, and gene expression of inflammatory mediators and tight-junction proteins. Although reducing the dietary n-6:n-3 lowered the hepatic phospholipid AA:eicosapentaenoic acid and AA:docosahexaenoic acid in a dose-dependent manner and mildly influenced inflammatory signaling, it did not significantly attenuate NAFLD development. Furthermore, the onset of NAFLD was not paired to colitis development or changes in tight-junction protein gene expression. In conclusion, reducing the dietary n 6:n-3 did not attenuate NAFLD progression; nor is it likely that colitis, or gut permeability, plays a role in NAFLD initiation in this model. PMID- 25934116 TI - Near-infrared spectroscopy: applications in neonates. AB - Near-infrared spectroscopy (NIRS) offers non-invasive, in-vivo, real-time monitoring of tissue oxygenation. Changes in regional tissue oxygenation as detected by NIRS may reflect the delicate balance between oxygen delivery and consumption. Originally used predominantly to assess cerebral oxygenation and perfusion perioperatively during cardiac and neurosurgery, and following head trauma, NIRS has gained widespread popularity in many clinical settings in all age groups including neonates. However, more studies are required to establish the ability of NIRS monitoring to improve patient outcomes, especially in neonates. This review provides a comprehensive description of the use of NIRS in neonates. PMID- 25934117 TI - The innate immune response to Aspergillus fumigatus at the alveolar surface. AB - Aspergillus fumigatus is an ubiquitous, saprophytic mould that forms and releases airborne conidia which are inhaled by humans on a daily basis. When the immune system is compromised (e.g. immunosuppressive therapy prior to organ transplantation) or there is pre-existing pulmonary malfunction (e.g. asthma, cystic fibrosis, TB lesions), A. fumigatus exploits weaknesses in the host defenses which can result in the development of saphrophytic, allergic or invasive aspergillosis. If not effectively eliminated by the innate immune response, conidia germinate and form invasive hyphae which can penetrate pulmonary tissues. The innate immune response to A. fumigatus is stage-specific and various components of the host's defenses are recruited to challenge the different cellular forms of the pathogen. In immunocompetent hosts, anatomical barriers (e.g. the mucociliary elevator) and professional phagocytes such as alveolar macrophages (AM) and neutrophils prevent the development of aspergillosis by inhibiting the growth of conidia and hyphae. The recognition of inhaled conidia by AM leads to the intracellular degradation of the spores and the secretion of proinflammatory mediators which recruit neutrophils to assist in fungal clearance. During the later stages of infection, dendritic cells activate a protective A. fumigatus-specific adaptive immune response which is driven by Th1 CD4(+) T cells. PMID- 25934118 TI - sRNA and mRNA turnover in Gram-positive bacteria. AB - It is widely recognized that RNA degradation plays a critical role in gene regulation when fast adaptation of cell growth is required to respond to stress and changing environmental conditions. Bacterial ribonucleases acting alone or in concert with various trans-acting regulatory factors are important mediators of RNA degradation. Here, we will give an overview of what is known about ribonucleases in several Gram-positive bacteria, their specificities and mechanisms of action. In addition, we will illustrate how sRNAs act in a coordinated manner with ribonucleases to regulate the turnover of particular mRNA targets, and the complex interplay existing between the ribosome, the ribonucleases and RNAs. PMID- 25934121 TI - Microbial regulation of terrestrial nitrous oxide formation: understanding the biological pathways for prediction of emission rates. AB - The continuous increase of the greenhouse gas nitrous oxide (N2O) in the atmosphere due to increasing anthropogenic nitrogen input in agriculture has become a global concern. In recent years, identification of the microbial assemblages responsible for soil N2O production has substantially advanced with the development of molecular technologies and the discoveries of novel functional guilds and new types of metabolism. However, few practical tools are available to effectively reduce in situ soil N2O flux. Combating the negative impacts of increasing N2O fluxes poses considerable challenges and will be ineffective without successfully incorporating microbially regulated N2O processes into ecosystem modeling and mitigation strategies. Here, we synthesize the latest knowledge of (i) the key microbial pathways regulating N2O production and consumption processes in terrestrial ecosystems and the critical environmental factors influencing their occurrence, and (ii) the relative contributions of major biological pathways to soil N2O emissions by analyzing available natural isotopic signatures of N2O and by using stable isotope enrichment and inhibition techniques. We argue that it is urgently necessary to incorporate microbial traits into biogeochemical ecosystem modeling in order to increase the estimation reliability of N2O emissions. We further propose a molecular methodology oriented framework from gene to ecosystem scales for more robust prediction and mitigation of future N2O emissions. PMID- 25934119 TI - DNA and RNA interference mechanisms by CRISPR-Cas surveillance complexes. AB - The CRISPR (clustered regularly interspaced short palindromic repeats)-Cas (CRISPR-associated) adaptive immune systems use small guide RNAs, the CRISPR RNAs (crRNAs), to mark foreign genetic material, e.g. viral nucleic acids, for degradation. Archaea and bacteria encode a large variety of Cas proteins that bind crRNA molecules and build active ribonucleoprotein surveillance complexes. The evolution of CRISPR-Cas systems has resulted in a diversification of cas genes and a classification of the systems into three types and additional subtypes characterized by distinct surveillance and interfering complexes. Recent crystallographic and biochemical advances have revealed detailed insights into the assembly and DNA/RNA targeting mechanisms of the various complexes. Here, we review our knowledge on the molecular mechanism involved in the DNA and RNA interference stages of type I (Cascade: CRISPR-associated complex for antiviral defense), type II (Cas9) and type III (Csm, Cmr) CRISPR-Cas systems. We further highlight recently reported structural and mechanistic themes shared among these systems. PMID- 25934120 TI - How do base-pairing small RNAs evolve? AB - The increasing numbers of characterized base-pairing small RNAs (sRNAs) and the identification of these regulators in a broad range of bacteria are allowing comparisons between species and explorations of sRNA evolution. In this review, we describe some examples of trans-encoded base-pairing sRNAs that are species specific and others that are more broadly distributed. We also describe examples of sRNA orthologs where different features are conserved. These examples provide the background for a discussion of mechanisms of sRNA evolution and selective pressures on the sRNAs and their mRNA target(s). PMID- 25934122 TI - Regulatory RNAs in photosynthetic cyanobacteria. AB - Regulatory RNAs play versatile roles in bacteria in the coordination of gene expression during various physiological processes, especially during stress adaptation. Photosynthetic bacteria use sunlight as their major energy source. Therefore, they are particularly vulnerable to the damaging effects of excess light or UV irradiation. In addition, like all bacteria, photosynthetic bacteria must adapt to limiting nutrient concentrations and abiotic and biotic stress factors. Transcriptome analyses have identified hundreds of potential regulatory small RNAs (sRNAs) in model cyanobacteria such as Synechocystis sp. PCC 6803 or Anabaena sp. PCC 7120, and in environmentally relevant genera such as Trichodesmium, Synechococcus and Prochlorococcus. Some sRNAs have been shown to actually contain MUORFs and encode short proteins. Examples include the 40-amino acid product of the sml0013 gene, which encodes the NdhP subunit of the NDH1 complex. In contrast, the functional characterization of the non-coding sRNA PsrR1 revealed that the 131 nt long sRNA controls photosynthetic functions by targeting multiple mRNAs, providing a paradigm for sRNA functions in photosynthetic bacteria. We suggest that actuatons comprise a new class of genetic elements in which an sRNA gene is inserted upstream of a coding region to modify or enable transcription of that region. PMID- 25934123 TI - Mechanisms of solvent resistance mediated by interplay of cellular factors in Pseudomonas putida. AB - A number of microorganisms have the ability to thrive in the presence of a range of toxic solvents. Tolerance to these chemicals is a multifactorial process, meaning that bacterial cells use a set of physiological and gene expression changes to overcome the damage imparted by these chemicals. This review focuses mainly on issues related to tolerance to aromatic hydrocarbons and butanol in Pseudomonas, although other microorganisms are also discussed. Pseudomonas putida strains contain a circular chromosome of approximately 6 Mbp which encodes about 5300 genes. A combination of physiological and biochemical assays, a genome-wide collection of mutants and several omics approaches have provided useful information to help identify functions involved in solvent tolerance in P. putida. The solvent response involves fine-tuning of lipid fluidity to adjust membrane functions including impermeabilization, activation of a general stress response system, increased energy generation and induction of specific efflux pumps that extrude solvents to the medium. These responses are modulated at the transcriptional level by local and global regulators as well as by a number of sRNAs whose levels fluctuate with the presence of solvents in the environment. Taken as a whole these regulatory inputs orchestrate the complex network of metabolic responses observed after solvent addition. PMID- 25934125 TI - Ultrasound intensification suppresses the need of methanol excess during the biodiesel production with Lipozyme TL-IM. AB - The synthesis of biodiesel from sunflower oil and methanol based on transesterification using the immobilized lipase from Thermomyces lanuginosus (Lipozyme TL-IM) has been investigated under silent conditions and under an ultrasound field. Ultrasound assisted process led to reduced processing time and requirement of lower enzyme dosage. We found for the first time that oil to methanol ratio of 1:3 was favored for the ultrasound assisted enzymatic process which is lower than that observed for the case of conventional stirring based approach (ratio of 1.4). Our results indicate that intensification provided by ultrasound suppresses the need of the excess of the methanol reactant during the enzymatic biodiesel production. Ultrasound assisted enzymatic biodiesel production is therefore a faster and a cleaner processes. PMID- 25934126 TI - The decomposition of protoporphyrin IX by ultrasound is dependent on the generation of hydroxyl radicals. AB - The ultrasound activation of certain drugs, such as porphyrins, could cause synergistic cytotoxic effects on cells. Both sonomechanical and sonochemical effects occur and the latter play a critical role because antioxidant agents could exert significant protective effects against the cytotoxicity. To investigate the reactive oxygen species involved in the sonochemical effects, aqueous protoporphyrin IX (PpIX) solutions were characterized under ultrasound sonication in this study. Inertial cavitation was indirectly evaluated using terephthalic acid dosimetry. The fluorescence intensity of the PpIX was measured using a fluorescence spectrophotometer. The effects of PpIX concentration, ultrasound parameters and free radical scavengers on the PpIX activation by ultrasound were investigated. Our results showed that the increase in PpIX decomposition was significantly correlated with cavitation activities (R=0.9874, p<0.05), and the decomposing effect increases with ultrasound intensity (0.6-1.5 W/cm(2)), initial PpIX concentration (1-5 MUM), duty cycle (10-100%) and the sonication duration (2-10 min). The fluorescence and absorption spectra of PpIX showed a decrease in the peak intensity without spectral shifts or new peak build up after sonication. The PpIX decomposition was significantly inhibited by hydroxyl radical scavengers, histidine, mannitol, acetone, methanol and ethanol, but the decomposition was not inhibited by sodium azide, catalase or superoxide dismutase. These results suggest that the decomposition of protoporphyrin IX by ultrasound is dependent on the generation of hydroxyl radicals, which sheds some light on the sonochemical effects of the interaction between ultrasound and porphyrins. PMID- 25934127 TI - Synergistic degradation of chitosan by impinging stream and jet cavitation. AB - Chitosan degradation was investigated using a combination of jet cavitation and impinging stream. Different operating parameters such as the initial concentration (1-5 g L(-1)), initial pH (3.2-4.8), solution temperature (30, 40, 50, 60, and 70 degrees C), inlet pressure (0.1-0.45 MPa), and treatment time (0 120 min) were optimized to achieve the maximum degradation of chitosan. After the optimization of jet cavitation parameters, chitosan degradation was carried out using venturi tubes of different structures (the fluidic generator). The efficiency of the jet cavitation degradation was improved significantly by combining with impinging stream. The structures of the degradation products were characterized by Fourier-transform infrared spectroscopy and X-ray diffraction. This study has conclusively established that a combination of jet cavitation and impinging stream can be effectively used for the complete degradation of chitosan. PMID- 25934128 TI - The comparison of sonochemistry, electrochemistry and sonoelectrochemistry techniques on decolorization of C.I Reactive Blue 49. AB - In this paper, the ability of three decolorization techniques including sonochemistry, electrochemistry and sonoelectrochemistry for decolorization of C.I Reactive Blue 49 in aqueous solutions have been compared. Various parameters affecting decolorization efficiency, such as pH, initial concentration of the dye, the decolorization time, H2O2 concentration and effect of applied potential on electrochemistry and sonoelectrochemistry, were evaluated. For further comparison, the methods were evaluated based on their ability in COD removal percentage. The maximum COD removal at the optimum condition of each method were 36.0%, 68.0%, 87.8% and 76.2% for sonochemistry, electrochemistry, sonoelectrochemistry with H2O2 and sonoelectrochemistry without H2O2, respectively. The result was an environment friendly method for removal of C.I Reactive Blue 49 from aqueous solutions. PMID- 25934124 TI - Target activation by regulatory RNAs in bacteria. AB - Bacterial small regulatory RNAs (sRNAs) are commonly known to repress gene expression by base pairing to target mRNAs. In many cases, sRNAs base pair with and sequester mRNA ribosome-binding sites, resulting in translational repression and accelerated transcript decay. In contrast, a growing number of examples of translational activation and mRNA stabilization by sRNAs have now been documented. A given sRNA often employs a conserved region to interact with and regulate both repressed and activated targets. However, the mechanisms underlying activation differ substantially from repression. Base pairing resulting in target activation can involve sRNA interactions with the 5(') untranslated region (UTR), the coding sequence or the 3(') UTR of the target mRNAs. Frequently, the activities of protein factors such as cellular ribonucleases and the RNA chaperone Hfq are required for activation. Bacterial sRNAs, including those that function as activators, frequently control stress response pathways or virulence associated functions required for immediate responses to changing environments. This review aims to summarize recent advances in knowledge regarding target mRNA activation by bacterial sRNAs, highlighting the molecular mechanisms and biological relevance of regulation. PMID- 25934129 TI - Sonocatalytic decolorization of textile wastewater using synthesized gamma-FeOOH nanoparticles. AB - gamma-FeOOH nanoparticles were synthesized and applied for decolorization of a textile wastewater containing reactive orange 29 (RO29) by ultrasonic/gamma FeOOH/H2O2 process. X-ray diffraction, transmittance electron microscope, scanning electron microscope, and nitrogen adsorption/desorption analysis approved synthesis of gamma-FeOOH nanoparticles with the average width of 60-70 nm. The catalyst dosage, H2O2 concentration, pH, and ultrasonic power had significant effect on catalytic performance of gamma-FeOOH nanoparticles. gamma FeOOH nanoparticles can be effectively used as catalyst in successive US/gamma FeOOH/H2O2 processes without significant activity loss. Gas chromatography-mass spectrometry analysis was used to verify the main intermediates produced through the RO29 degradation. Mineralization of the textile wastewater during treatment process was determined by chemical oxygen demand analysis. PMID- 25934130 TI - Effect of ultrasonic waves on the stability of all-trans lutein and its degradation kinetics. AB - Ultrasound treatment has been widely applied in the extraction of biologically active compounds including carotenoids. However, there are few reports on their effects on the stability of these compounds. In the present study, the stability of all-trans lutein, one of the carotenoids, was investigated under the action of ultrasound. Results showed that ultrasound induced the isomerization of all-trans lutein to its isomers, namely to 13-cis lutein, 13'-cis lutein, 9-cis lutein and 9'-cis lutein as analyzed by HPLC coupled with DAD and LC-MS; and the percentage of the isomerization increased with increasing both ultrasonic frequency and power. The stability of all-trans lutein in dichloromethane was worst among multiple kinds of solvents. Interestingly, the retention rate of all-trans lutein improved as the temperature increased, which runs counter to the Arrhenius law. Under ultrasound irradiation, the degradation mechanism might be different with various temperatures, the degradation of all-trans lutein followed first-order kinetics at 20 degrees C, while second-order kinetics was followed at 30-50 degrees C. As the ultrasonic reaction time prolonged, lutein epoxidation nearly occurred. Those results presented here emphasized that UAE techniques should be carefully used in the extraction of all-trans lutein. PMID- 25934132 TI - Prevalence of use of non-prescription analgesics in the Norwegian HUNT3 population: Impact of gender, age, exercise and prescription of opioids. AB - BACKGROUND: There are concerns about potential increasing use of over-the-counter (OTC) analgesics. The aims of this study were to examine 1) the prevalence of self-reported use of OTC analgesics; 2) the prevalence of combining prescription analgesics drugs with OTC analgesics and 3) whether lifestyle factors such as physical activity were associated with prevalence of daily OTC analgesic use. METHODS: Questionnaire data from the Nord-Trondelag health study (HUNT3, 2006 08), which includes data from 40,000 adult respondents. The questionnaire included questions on use of OTC analgesics, socioeconomic conditions, health related behaviour, symptoms and diseases. Data were linked to individual data from the Norwegian Prescription Database. A logistic regression was used to investigate the association between different factors and daily use of paracetamol and/or non-steroid anti-inflammatory drugs (NSAIDs) in patients with and without chronic pain. RESULTS: The prevalence of using OTC analgesics at least once per week in the last month was 47%. Prevalence of paracetamol use was almost 40%, compared to 19% and 8% for NSAIDs and acetylsalicylic acid (ASA), respectively. While the use of NSAIDs decreased and the use of ASA increased with age, paracetamol consumption was unaffected by age. Overall more women used OTC analgesics. About 3-5% of subjects using OTC analgesics appeared to combine these with the same analgesic on prescription. Among subjects reporting chronic pain the prevalence of OTC analgesic use was almost twice as high as among subjects without chronic pain. Subjects with little physical activity had 1.5-4 times greater risk of daily use of OTC compared to physically active subjects. CONCLUSIONS: Use of OTC analgesics is prevalent, related to chronic pain, female gender and physical inactivity. PMID- 25934131 TI - Omega-3 fatty acids in first-episode schizophrenia - a randomized controlled study of efficacy and relapse prevention (OFFER): rationale, design, and methods. AB - BACKGROUND: Polyunsaturated fatty acid (PUFA) metabolism abnormalities have been long implicated in the etiology of schizophrenia. Although several randomized clinical trials have been carried out to assess the efficacy of omega-3 PUFA as add-on therapy in reducing psychopathology in populations of chronic patients with schizophrenia, only a few concern first-episode schizophrenia. The majority of these studies used a 12-week intervention based on ethyl-eicosapentaenoic acid (ethyl-EPA), however, with conflicting results. An intervention based on docosahexaenoic acid plus EPA has not been used in first-episode schizophrenia studies so far. No add-on supplementation studies have been carried out in medicated first-episode schizophrenia patients to assess the efficacy of omega-3 PUFA in preventing relapses. METHODS: A randomized placebo-controlled one-center trial will be used to compare the efficacy of 26-week intervention, composed of either 1320 mg/day of EPA and 880 mg/day of DHA, or olive oil placebo with regard to symptom severity and relapse rate in first-episode schizophrenia patients. Eighty-two patients (aged 16-35) will be recruited for the study. Eligible patients will be randomly allocated to one of two intervention arms: an active arm or a placebo arm (olive oil). The primary outcome measure of the clinical evaluation is schizophrenia symptom severity measured by the Positive and Negative Syndrome Scale (PANSS). Other outcomes include depressive symptoms, patient functioning and the level of insight. Correlates of change measured during the study will include structural brain changes, oxidative stress and defense, as well as neuroplasticity indicators. Metabolic syndrome components will also be assessed throughout the study. DISCUSSION: By comparing 26-week administration of EPA + DHA or (placebo) olive oil as add-on therapy in reducing symptom severity and one-year relapse rate in patients with first episode schizophrenia, it is intended to provide new insights into the efficacy of omega 3 PUFA and correlates of change, and contribute to the improvement of mental health care for individuals suffering from schizophrenia. TRIAL REGISTRATION: This study has been registered at Clinical Trials.gov with the following number: NCT02210962 . PMID- 25934133 TI - Subjective stress reactivity in psoriasis - a cross sectional study of associated psychological traits. AB - BACKGROUND: Stress or psychological distress is often described as a causative or maintaining factor in psoriasis. Psychological traits may influence the appraisal, interpretation and coping ability regarding stressful situations. Detailed investigations of psychological traits in relation to stress reactivity in psoriasis are rare. The aim of this study was to examine whether patients with psoriasis who report an association between psychological distress and exacerbation, "stress reactors" (SRs), differ psychologically from those with no stress reactivity "non-stress reactors" (NSRs). METHODS: This cross-sectional study was conducted among 101 consecutively recruited outpatients with plaque psoriasis. A psychosocial interview was performed including questions concerning stress reactivity in relation to onset and exacerbation. Three validated self rating scales were used: Spielberger State-Trait Anxiety Inventory (STAI, Form Y), Beck Depression Inventory (BDI-II) and Swedish Universities Scales of Personality (SSP). Independent samples t-tests, Chi-square tests and one-way ANOVA analyses were used for group comparisons when appropriate. A logistic regression model was designed with SR as the dependent variable. RESULTS: Sixty four patients (63%) reported a subjective association between disease exacerbation and stress (SRs). Patients defined as SRs reported significantly higher mean scores regarding state and trait anxiety, depression, and also five SSP scale personality traits, i.e. somatic trait anxiety, psychic trait anxiety, stress susceptibility, lack of assertiveness and mistrust, compared with NSRs. In multivariate analysis, SSP-stress susceptibility was the strongest explanatory variable for SR, i.e. OR (95% CI)=1.13 (1.02 - 1.24), p=0.018. CONCLUSION: According to our results, patients who perceive stress as a causal factor in their psoriasis might have a more vulnerable psychological constitution. This finding suggests important opportunities for clinicians to identify patients who may benefit from additional psychological exploration and support. PMID- 25934134 TI - Variations in killer whale food-associated calls produced during different prey behavioural contexts. AB - Killer whales produce herding calls to increase herring school density but previous studies suggested that these calls were made only when feeding upon spawning herring. Herring schools less densely when spawning compared to overwintering; therefore, producing herding calls may be advantageous only when feeding upon less dense spawning schools. To investigate if herding calls were produced across different prey behavioural contexts and whether structural variants occurred and correlated with prey behaviour, this study recorded killer whales when feeding upon spawning and overwintering herring. Herding calls were produced by whales feeding on both spawning and overwintering herring, however, calls recorded during overwintering had significantly different duration and peak frequency to those recorded during spawning. Calls recorded in herring overwintering grounds were more variable and sometimes included nonlinear phenomena. Thus, herding calls were not produced exclusively when feeding upon spawning herring, likely because the call increases feeding efficiency regardless of herring school density or behaviour. Variations in herding call structure were observed between prey behavioural contexts and did not appear to be adapted to prey characteristics. Herding call structural variants may be more likely a result of individual or group variation rather than a reflection of properties of the food source. PMID- 25934135 TI - Biparentally deserted offspring are viable in a species with intense sexual conflict over care. AB - Desertion of clutch (or brood) by both parents often leads to breeding failure, since in vast majority of birds care by at least one parent is required for any young to fledge. Recent works in a highly polygamous passerine bird, the Eurasian penduline tit (Remiz pendulinus), suggest that biparental clutch desertion is due to intense sexual conflict over care. However, an alternative yet untested hypothesis for biparental desertion is low offspring viability so that the parents abandon the offspring that have poor prospect for survival. Here we test the latter hypothesis in a common garden experiment by comparing the viability of deserted and cared for eggs. We show that embryonic development does not differ between deserted and cared for eggs. Therefore, sexual conflict over care remains the best supported hypothesis for biparental clutch desertion in penduline tits. Our work points out that conflict over care is a potential - yet rarely considered - cause of biparental nest desertion, and a strong alternative for the traditional explanations of low offspring viability, human disturbance or deteriorating ambient environment. Apart from a handful of species, the intensity of sexual conflict has not been quantified, and we call for further studies to consider sexual conflict as a cause of nest desertion. PMID- 25934136 TI - Effect of bariatric surgery on asthma control, lung function and bronchial and systemic inflammation in morbidly obese subjects with asthma. AB - BACKGROUND: The pathogenesis of asthma in obese subjects is poorly understood and has been described as a specific phenotype in these patients. Weight loss improves asthma control and lung function. Whether this improvement is the result of better mechanical properties of the airways or decreased systemic and bronchial inflammation remains unclear. METHODS: A longitudinal study in obese patients with asthma (bariatric surgery and asthma group (BS+A), n=27) and obese control (bariatric surgery without asthma group (BS-A), n=39) subjects undergoing bariatric surgery, and obese patients with asthma without intervention (no bariatric surgery and asthma group (NBS+A), n=12). Lung function, asthma control, cellular infiltrates in bronchial biopsies and circulating markers of systemic inflammation were measured during follow up at 3, 6 and 12 months. RESULTS: Bariatric surgery resulted in a profound weight loss at 12 months. In the BS+A group as well as the BS-A group FEV1, functional residual capacity, total lung capacity improved, whereas FEV1/FVC only improved in the BS-A group. In addition, Asthma Control Questionnaire (ACQ), Asthma Quality of Life Questionnaire, inhaled corticosteroid use and PD20 improved in BS+A, whereas in the NBS+A group only ACQ improved. Small airway function R5-R20 improved in both surgery groups, however the change in the BS+A group was greater, resulting in a comparable R5-R20 between BS+A and BS-A at 12-month follow-up. Besides improvement of systemic inflammation (high sensitivity C-reactive protein, adiponectin and leptin) after BS, only a decrease in mast cell numbers was detectable in the BS+A group. CONCLUSIONS: Bariatric surgery improved small airway function, decreased systemic inflammation and number of mast cells in the airways. These effects could explain the improvement of asthma control, quality of life and lung function. Therefore bariatric surgery, in addition to all other positive effects, also improves asthma in subjects with morbid obesity. TRIAL REGISTRATION NUMBER: 3204. PMID- 25934137 TI - Iatrogenic injury to the intercostal artery: aetiology, diagnosis and therapeutic intervention. PMID- 25934138 TI - Dynamic laryngeal narrowing in COPD may have effects on the trachea. PMID- 25934139 TI - Acute resistance exercise stimulates sex-specific dimeric immunoreactive growth hormone responses. AB - PURPOSE: We sought to determine if an acute heavy resistance exercise test (AHRET) would elicit sex-specific responses in circulating growth hormone (GH), with untreated serum and serum treated with a reducing agent to break disulfide bindings between GH dimers. METHODS: 19 untrained participants (nine men and ten women) participated in an acute heavy resistance exercise test using the back squat. Blood samples were drawn before exercise (Pre), immediate post (IP), +15 min (+15), and +30 min (+30) afterwards. Serum samples were chemically reduced using glutathione (GSH). ELISAs were then used to compare immunoreactive GH concentrations in reduced (+GSH) and non-reduced (-GSH) samples. Data were analyzed using a three-way (2 sex * 2 treatment * 4 time) mixed methods ANOVA, with significance set at p <= 0.05. RESULTS: GSH reduction resulted in increased immunoreactive GH concentrations when compared to non-reduced samples at Pre (1.68 +/- 0.33 MUg/L vs 1.25 +/- 0.25 MUg/L), IP (7.69 +/- 1.08 MUg/L vs 5.76 +/- 0.80 MUg/L), +15 min (4.39 +/- 0.58 MUg/L vs 3.24 +/- 0.43 MUg/L), and +30 min (2.35 +/- 0.49 MUg/L vs 1.45 +/- 0.23 MUg/L). Also, women demonstrated greater GH responses compared to men, and this was not affected by reduction. CONCLUSIONS: Heavy resistance exercise increases immunoreactive GH dimer concentrations in men and women, with larger increases in women and more sustained response in men. The physiological significance of a sexually dimorphic GH response adds to the growing literature on aggregate GH and may be explained by differences in sex hormones and the structure of the GH cell network. PMID- 25934140 TI - Clinical Course of Cerebral Venous Thrombosis in Adult Acute Lymphoblastic Leukemia. AB - BACKGROUND: Venous thromboembolism (VTE) is a frequent complication in patients with acute lymphoblastic leukemia (ALL). A significant proportion of patients develop cerebral venous thrombosis (CVT). METHODS: To investigate risk factors for and the clinical course of CVT in ALL patients, we describe all cases of CVT which occurred in a well-defined cohort of 240 adults, treated for newly diagnosed ALL in the HOVON (Dutch-Belgian Hemato-Oncology Cooperative Group)-37 study. We conducted a nested case-control study to explore the relevance of early symptoms and risk factors for CVT in ALL patients. RESULTS: Nine of 240 patients developed CVT (4%). CVT occurred during or shortly after L-asparaginase therapy (in 8 cases) and shortly after intrathecal methotrexate injections (in all cases) during cycle I of remission induction treatment. CVT was associated with prior headache and seizures. In 5 of 9 patients with CVT, headache before the diagnosis of CVT occurred within 3 days after lumbar puncture and initially had a postural character. CONCLUSIONS: CVT is relatively common in adult ALL patients. Our data suggest that CVT in adult ALL patients results from the additive effects of multiple risk factors, with a particular role for asparaginase and the effects of lumbar punctures for intrathecal therapy. PMID- 25934141 TI - The Possible Damaged Mechanism and the Preventive Effect of Monosialotetrahexosylganglioside in a Rat Model of Cerebral Ischemia-Reperfusion Injury. AB - BACKGROUND: The pathogenesis of cerebral ischemia-reperfusion injury (CIRI) is not completely clear and therapies are limited now. Therefore, our study aimed to investigate the possible pathogenesis and preventive approach of CIRI through analyzing changes of aspartate (Asp), glutamate (Glu), mitochondrial calcium (MCa), calmodulin (CaM), and malondialdehyde (MDA) contents and ultramicropathology in hippocampus and cerebral cortex of ischemic susceptible injured regions and the effect of monosialotetrahexosylganglioside (GM1) in the rat model of CIRI. METHODS: Contents of Asp, Glu, MCa, CaM, and MDA in hippocampus and cerebral cortex tissues were measured by a high-performance liquid chromatography, atomic absorption spectrophotometer, and ordinary spectrophotometer, respectively, changes of ultramicrostructure in neurons of the hippocampus CA1 region and frontal cerebral cortex were observed by a transmission electron microscope. RESULTS: Contents of Asp and Glu in hippocampus and cerebral cortex tissues of CIRI groups significantly decreased and contents of MCa, CaM, and MDA significantly increased than those in control groups, and the ultramicrostructure in neurons of the hippocampus CA1 region and frontal cerebral cortex revealed a significant damaged change, and GM1 significantly ameliorated changes of Asp, Glu, MCa, CaM, and MDA contents in hippocampus and ultrastructural changes in neurons of the hippocampus CA1 region and frontal cerebral cortex. CONCLUSIONS: Our findings further support that the abnormal release and/or reuptake of excitatory amino acid neurotransmitters, the disordered calcium homeostasis and the excessive production and/or reduced elimination of reactive oxygen species contribute to the pathogenesis of CIRI, and GM1 can partially prevent these pathogenesises to exert the protective effect on CIRI. PMID- 25934142 TI - High prevalence of sulphadoxine-pyrimethamine resistance-associated mutations in Plasmodium falciparum field isolates from pregnant women in Brazzaville, Republic of Congo. AB - Intermittent preventive treatment during pregnancy with sulfadoxine-pyrimethamine (IPTp-SP) has not been evaluated in the Republic of Congo since its implementation in 2006 and there is no published data on molecular markers of SP resistance among Plasmodium falciparum isolates from pregnant women. This first study in this country aimed to describe the prevalence of dihydrofolate reductase (dhfr) and dihydropteroate synthase (dhps) point mutations and haplotypes in P. falciparum isolates collected from pregnant women with asymptomatic infection. From March 2012 to December 2013, pregnant women attending Madibou health centre (in Southern Brazzaville) for antenatal visits were enrolled in this study after obtaining their written informed consent. Blood samples were collected and P. falciparum infections were characterized using PCR. A total of 363 pregnant women were enrolled. P. falciparum infection was detected in 67 (18.4%) samples as their PCR amplification of dhfr and dhps genes yielded bands and all the PCR products were successfully digested. Out of these 67 isolates, 59 (88%), 57 (85%) and 53 (79.1%) carried 51I, 59R and 108N dhfr mutant alleles, respectively. The prevalence of dhps 436A, 437G and 540E mutations were 67.1% (45/67), 98.5% (66/67) and 55.2% (37/67), respectively. More than one-half of the isolates carried quintuple mutations, with highly resistant haplotype dhfr51I/59R/108N + dhps437G/540E detected in 33% (22/67) whereas 25% (17/67) were found to carry sextuple mutations. We observed significantly higher frequencies of triple dhps mutations 436A/437G/540E and quintuple mutations dhfr51I/59R/108N+dhps437G/540E in isolates from women who received IPTp-SP than those who did not. Overall, this study shows high prevalence rates of SP-associated resistance mutations in P. falciparum isolates collected from pregnant women. The presence of the dhps mutant allele 540E and the high prevalence of isolates carrying quintuple dhfr/dhps mutations are here reported for the first time in the Republic of Congo. The increasing prevalence of multiple mutant alleles observed in this study is alarming and may present a challenge for the future interventions including IPTp-SP in the country. PMID- 25934143 TI - The diverging roles of dendritic cells in kidney allotransplantation. AB - Dendritic cells (DCs) are a family of antigen presenting cells that play a paramount role in bridging innate and adaptive immunity. In murine models several subtypes of DCs have been identified, including classical DCs, monocyte-derived DCs, and plasmacytoid DCs. Quiescent, immature DCs and some subtypes of plasmacytoid cells favor the expression of regulatory T cells, but in an inflammatory milieu DCs become mature and after intercepting the antigen migrate to lymphatic system where they present the antigen to naive T cells. Transplant rejection largely depends on the phenotype and maturation of DCs. The ischemia reperfusion injury causes the release of endogenous molecules that are recognized as danger signals by the pattern recognition receptor of the innate immunity with subsequent activation of inflammatory cells and mediators. In this environment DCs become mature and migrate to lymphonodes where they present the alloantigen to T cells and direct their differentiation towards Th1 and Th17 effector cells. On the other hand, manipulation of DCs may favor T cell differentiation towards tolerant Th2 and T regulators (Treg). Experimental studies in murine models showed the possibility of inducing an operational tolerance by injecting immature tolerogenic DCs. Recently, such a possibility has been also confirmed in primates. Although manipulation of DCs may represent an important step ahead in kidney transplantation, a number of technical and ethical issues should be solved before its clinical application. PMID- 25934144 TI - First molecular evidence of the transplacental transmission of Theileria annulata. AB - Bovine tropical theileriosis (BTT) is a serious hindrance in the cattle upgradation programme using the exotic germplasm. There is a wide range of variations in the pathobiology alongside clinical symptoms of the animals suffering from BTT. The present paper communicates the first report about the transplacental transmission of T. annulata in a cross bred 2-day old calf. T. sergenti, T. lestoquardi and T. equi are known to undergo transplacental transmission, but baring a single citation in literature, there are no records about the transplacental transmission of T. annulata. PMID- 25934145 TI - Productivity and parasitic infections of pigs kept under different management systems by smallholder farmers in Mbeya and Mbozi districts, Tanzania. AB - An on farm experiment was carried out to assess the effects of production systems on the performance of local pigs kept by smallholder farmers. Six villages from Mbeya and Mbozi districts, Tanzania were purposely selected based on the prominent pig production systems: free range, semi-confinement and total confinement. Fifteen pig keeping households were randomly selected from each village to participate in the study. A participatory rural appraisal and structured questionnaire were used for collecting information from the households on pig production and reproduction performance. In addition, a total of 180 weaner pigs, 2-3 months old, were purchased and randomly allocated to the 90 participating households. The pigs were subjected to three production systems: free range (M1), confinement with local diet (M2) and confinement with a compounded diet and anthelmintic treatment (M3). The anthelmintic treatment (piperazine citrate) was administered at 1 g per kg body weight. Faecal and blood samples were collected at month three of the experiment to assess the burden of intestinal helminths and sero-prevalence of Taenia solium cysticercosis, respectively. Sows kept under free range system were reported to have smaller litter size both at farrowing and at weaning compared to those kept under confinement. The experiment showed pigs under M3 had higher (P < 0.05) liveweight gains (136 g/day) compared to pigs in M2 (73 g/day) and M1 (68 g/day). In addition, pigs in M3 had higher body length and heart girth size with the feed to gain ratio of 8.5. Free range pigs tended to have lower faecal egg counts for most worm species compared to permanently confined pigs. Sero-prevalence of Taenia solium cysticercosis was 26%, with village prevalence ranging from 8 to 52%. Although pigs kept in M3 performed better than the rest, the compounded feed was too expensive for the farmers to afford. Locally available feed types combined with vitamin and mineral supplements may be a more sustainable option. PMID- 25934146 TI - Cost-effectiveness of DTG + ABC/3TC versus EFV/TDF/FTC for first-line treatment of HIV-1 in the United States. AB - OBJECTIVE: Data from the SINGLE trial demonstrated that 88% of treatment-naive HIV-1 patients treated with dolutegravir and abacavir/lamivudine (DTG + ABC/3TC) achieved viral suppression at 48 weeks compared with 81% of patients treated with efavirenz/tenofovir disoproxil fumarate/emtricitabine (EFV/TDF/FTC). It is unclear how this difference in short-term efficacy impacts long-term cost effectiveness of these regimens. This study sought to evaluate long-term cost effectiveness of DTG + ABC/3TC vs EFV/TDF/FTC from a US payer perspective. METHODS: This study is an individual discrete-event simulation which tracked the disease status and treatment pathway of HIV-1 patients. The model simulated treatment over a lifetime horizon by tracking change in patients' CD4 count, clinical events occurrence (opportunistic infections, cancer, and cardiovascular events), treatment switch, and death. The model included up to four lines of treatment. Baseline patient characteristics, efficacy, and safety of DTG + ABC/3TC and EFV/TDF/FTC were informed by data from the SINGLE trial. The efficacy of subsequent treatment lines, clinical event risks, mortality, cost, and utility inputs were based on literature and expert opinion. Outcomes were lifetime discounted medical costs, quality-adjusted life-years (QALYs), and incremental cost-effectiveness ratio (ICER). RESULTS: Compared with EFV/TDF/FTC, DTG + ABC/3TC increased lifetime costs by $19,153 and per person survival by 0.12 QALYs, resulting in an ICER of $158,890/QALY. ICERs comparing DTG + ABC/3TC to EFV/TDF/FTC remained above the traditional, US willingness-to-pay threshold of $50,000/QALY gained in all scenarios, and above $100,000 or $150,000/QALY gained in most scenarios. LIMITATIONS: Due to data limitations, the treatment patterns, CD4 count during viral rebound and treatment switch, viral rebound after trial end, and long-term adverse event-related treatment discontinuation were based on assumptions, presented to and approved by clinical experts. CONCLUSIONS: Compared with EFV/TDF/FTC, DTG + ABC/3TC resulted in higher cost and only slightly increased QALYs over a lifetime, with an ICER that exceeded the standard cost effectiveness threshold. This indicates that the incremental benefit in effectiveness associated with DTG + ABC/3TC may not be worth the incremental increase in costs. PMID- 25934147 TI - A network meta-analysis to compare simeprevir with boceprevir and telaprevir in combination with peginterferon-alpha and ribavirin in patients infected with genotype 1 Hepatitis C virus. AB - OBJECTIVE: To conduct a network meta-analysis (NMA) to assess the relative efficacy and safety of simeprevir, a second generation oral protease inhibitor (PI), compared to telaprevir and boceprevir in combination with pegylated interferon-alpha and ribavirin (PR) in patients with chronic hepatitis C. METHODS: A systematic literature review and NMA of randomized controlled trials involving anti-virals added to PR were conducted. Electronic database searches and hand searches were conducted to identify relevant publications. Outcomes of interest included sustained virologic response (SVR), incidence of adverse events (AEs), and discontinuation due to AEs. Networks were based on treatment-, dose-, and duration-specific nodes. Sub-group analyses were conducted to investigate heterogeneity, based on Metavir scores, sub-genotypes 1a/1b, and prior response. RESULTS: A total of 15 publications were considered for the base case of the meta analysis. Simeprevir was associated with higher SVR rates than PR alone. Compared to telaprevir and boceprevir, SVR rates tended to be higher for simeprevir, with odds ratios ranging from 1.27 [0.81-2.00] to 2.61 [1.44-4.74] in treatment-naive and from 1.04 [0.78-1.38] to 1.74 [0.84-3.61] in treatment-experienced patients, respectively. In terms of safety, the risks of anemia and discontinuations due to AEs were lower for simeprevir compared to PR alone, telaprevir, and boceprevir. The risk of rash was lower for simeprevir compared to telaprevir, and similar compared to PR alone and boceprevir. CONCLUSION: This NMA in genotype 1 HCV patients suggests a similar or better efficacy and tolerability profile for simeprevir compared to telaprevir and boceprevir. PMID- 25934148 TI - Observational evaluation of outcomes and resource utilization from hemostatic matrices in spine surgery. AB - OBJECTIVE: Studies have indicated that outcomes may differ by choice of flowable hemostat, but there is limited evidence in spine surgery. The objective of this study was to conduct a comparison of outcomes following use of advanced flowable hemostatic matrices in a large spine surgery population. METHODS: This is an observational retrospective cohort analysis using Premier's US Perspective Hospital Database. Two commonly-used hemostatic matrices (Floseal and Surgiflo kitted with thrombin) were compared in cases categorized as either major or severe spine surgery. Outcomes included complications, blood product administration, hospital length of stay (LOS), surgery time, and amount of matrix used in surgery. RESULTS: Major spine surgery patients treated with Surgiflo were associated with increased risk of blood product transfusion (OR = 2.56, 95% CI = 1.79-3.65, p < 0.001), longer surgery time (+8.84 min, p < 0.0001), and increased product usage (+3.34 mL, p < 0.001), compared to Floseal; however, risk of complications and LOS did not differ by choice of matrix in this patient group. Severe spine surgery patients treated with Surgiflo were associated with longer surgical time (+26.9 min, p < 0.001) and increased product usage (+1.52 mL, p < 0.01), compared to Floseal; however, risk of complications, transfusion and LOS did not differ by choice of matrix in this patient group. LIMITATIONS: Inherent to limitations associated with database analysis, this study did not evaluate potential physician differences such as skill and experience, assess long-term outcomes, nor include cases with missing data. CONCLUSION: The results from this analysis indicated that surgery time, risk of blood transfusion, and amount of matrix used are greater with Surgiflo patients, compared to Floseal patients. Choice of matrix did not appear to impact hospital LOS or risk of surgical complications. Future research should evaluate the cost consequences of increased clinical and resource utilization by choice of hemostatic matrix in spine surgery. PMID- 25934149 TI - Lysine 271 but not lysine 210 of XRCC4 is required for the nuclear localization of XRCC4 and DNA ligase IV. AB - XRCC4 and DNA Ligase IV (LIG4) cooperate to join two DNA ends at the final step of DNA double-strand break (DSB) repair through non-homologous end-joining (NHEJ). However, it is not fully understood how these proteins are localized to the nucleus. Here we created XRCC4(K271R) mutant, as Lys271 lies within the putative nuclear localization signal (NLS), and XRCC4(K210R) mutant, as Lys210 was reported to undergo SUMOylation, implicated in the nuclear localization of XRCC4. Wild-type and mutated XRCC4 with EGFP tag were introduced into HeLa cell, in which endogenous XRCC4 had been knocked down using siRNA directed to 3' untranslated region, and tested for the nuclear localization function by fluorescence microscopy. XRCC4(K271R) was defective in the nuclear localization of itself and LIG4, whereas XRCC4(K210R) was competent for the nuclear localization with LIG4. To examine DSB repair function, wild-type and mutated XRCC4 were introduced into XRCC4-deficient M10. M10-XRCC4(K271R), but not M10 XRCC4(K210R), showed significantly reduced surviving fraction after 2 Gy gamma ray irradiation as compared to M10-XRCC4(WT). The number of gamma-H2AX foci remaining 2 h after 2 Gy gamma-ray irradiation was significantly greater in M10 XRCC4(K271R) than in M10-XRCC4(WT), whereas it was only marginally increased in M10-XRCC4(K210R) as compared to M10-XRCC4(WT). The present results collectively indicated that Lys271, but not Lys210, of XRCC4 is required for the nuclear localization of XRCC4 and LIG4 and that the nuclear localizing ability is essential for DSB repair function of XRCC4. PMID- 25934150 TI - Insulin-induced CARM1 upregulation facilitates hepatocyte proliferation. AB - Previously, we reported that CARM1 undergoes ubiquitination-dependent degradation in renal podocytes. It was also reported that CARM1 is necessary for fasting induced hepatic gluconeogenesis. Based on these reports, we hypothesized that treatment with insulin, a hormone typically present under the 'fed' condition, would inhibit gluconeogenesis via CARM1 degradation. HepG2 cells, AML-12 cells, and rat primary hepatocytes were treated with insulin to confirm CARM1 downregulation. Surprisingly, insulin treatment increased CARM1 expression in all cell types examined. Furthermore, treatment with insulin increased histone 3 methylation at arginine 17 and 26 in HepG2 cells. To elucidate the role of insulin-induced CARM1 upregulation, the HA-CARM1 plasmid was transfected into HepG2 cells. CARM1 overexpression did not increase the expression of lipogenic proteins generally increased by insulin signaling. Moreover, CARM1 knockdown did not influence insulin sensitivity. Insulin is known to facilitate hepatic proliferation. Like insulin, CARM1 overexpression increased CDK2 and CDK4 expression. In addition, CARM1 knockdown reduced the number of insulin-induced G2/M phase cells. Moreover, GFP-CARM1 overexpression increased the number of G2/M phase cells. Based on these results, we concluded that insulin-induced CARM1 upregulation facilitates hepatocyte proliferation. These observations indicate that CARM1 plays an important role in liver pathophysiology. PMID- 25934151 TI - Purification and characterization of four antibacterial peptides from protamex hydrolysate of Atlantic mackerel (Scomber scombrus) by-products. AB - Proteins from fish by-product sources are valuable source of bioactive peptides and show promise as functional foods ingredients. The objective of the present study was to isolate and characterize antibacterial peptides from protamex hydrolysates of Atlantic mackerel (Scomber scombrus) by-products. Four sequences SIFIQRFTT (P4), RKSGDPLGR (P8.1), AKPGDGAGSGPR (P8.2) and GLPGPLGPAGPK (P11) were identified in peptide fractions separated using RP-HPLC. At 200 MUg mL(-1), while peptides P8.1, P8.2 and P11 exhibited partial inhibition, P4 totally inhibited tested Gram-positive (Listeria innocua) and Gram-negative (Escherichia coli) bacterial strains. These results suggest that the protein hydrolysate derived from mackerel by-products could be used as an antimicrobial ingredient in both functional food and nutraceutical applications. PMID- 25934152 TI - Differences in the faecal microbiome of non-diarrhoeic clinically healthy dogs and cats associated with Giardia duodenalis infection: impact of hookworms and coccidia. AB - The protozoan parasite Giardia duodenalis causes a waterborne diarrhoeal disease in animals and humans, yet many Giardia-infected hosts remain asymptomatic. Mixed parasite infections are common in both animals and humans with unknown consequences for Giardia or other parasites. We compared the composition and diversity of bacterial communities from 40 dogs, including free-roaming dogs, and 21 surrendered cats from Australia. The dog cohort included 17 (42.5%) dogs positive for Giardia and 13 (32.5%) dogs positive for dog hookworm (Ancylostoma caninum). The cat samples included eight positive for Giardia and eight positive for Cystoisospora. The V4 region of 16S rRNA was sequenced at an average of 36,383 high quality sequences (>200 bp) per sample using the Ion Torrent PGM platform. In dogs we found significant (P<0.05, AnoSim) difference between the Giardia-positive and -negative groups when evaluating bacterial genera. No such difference was demonstrated between Ancylostoma-positive and -negative dogs. However, there was a modest but not significant separation of the Giardia negative and -positive dogs (P=0.09, UniFrac) using principal coordinate analysis. Removal of dogs with hookworms further separated Giardia-positive and negative groupings (P=0.06, UniFrac). In cats, the presence of Giardia was not associated with a significant difference based on bacterial genera (P>0.05, AnoSim). Cystoisospora-positive cats, however, exhibited significantly different profiles from Cystoisospora-negative cats (P=0.02, AnoSim) and UniFrac showed significant separation of Cystoisospora-positive and -negative samples (P<0.01). The results suggest that in clinically heathy dogs and cats, helminths and protozoa are associated with different microbiomes and possibly variable gut microbiota functions. Understanding the association of parasites and microbiomes has important consequences for the administration of antiparasitic drugs in animals and humans. PMID- 25934153 TI - Neurodegeneration in the elderly - When the blood type matters: An overview of the McLeod syndrome with focus on hematological features. AB - Multisystem deterioration occurs mainly in older individuals and may be related to physiological tissue degeneration. However, genetic predisposition may be unmasked by inappropriate functional and structural system deficiencies. McLeod syndrome (MLS) is a rare, multisystem disease which is X-chromosomal inherited and belongs to the neuroacanthocytosis syndromes (NAS). The main clinical manifestations contain progressive neuro-psychiatric and cognitive deterioration, choreatic movement disorder, as well as myopathy, sensory motor axonal neuropathy and cardiomyopathy. In addition, MLS patients have red blood cell abnormalities including immune-hematological, morphological and functional impairments of red blood cells. In large deletions, contiguous gene syndrome may arise, including Duchenne muscular dystrophia, cellular immunodeficiency or retinitis pigmentosa. Hematological abnormalities such as blood group abnormalities in Kell- and XK blood group system, formation of anti-public red blood cell alloantibodies, acanthocytosis and elevated creatinine phosphokinase may precede clinical disease manifestation for decades and provide tools for early diagnosis. Patients with unexplained neuro-muscular deterioration and/or neuro-psychological pathologies accompanied with hematological abnormalities should be investigated for MLS. PMID- 25934154 TI - Cardiovascular and psychiatric characteristics associated with oxidative stress markers among adolescents with bipolar disorder. AB - INTRODUCTION: In the field of bipolar disorder (BD) research there is an absence of validated biomarkers and limited understanding of the biology underlying excessive and premature cardiovascular disease (CVD). Oxidative stress is a potential biomarker in both BD and CVD. OBJECTIVE: To examine psychiatric and cardiovascular characteristics associated with peripheral oxidative stress markers among adolescents with BD, who are at high risk for CVD. METHODS: Participants were 30 adolescents, 13-19years old, with BD and without CVD. Ultrasonography was used to evaluate vascular function and structure. Traditional CVD risk factors were also measured. Psychiatric assessments were conducted via semi-structured interview. Serum levels of oxidative stress (lipid hydroperoxides (LPH) and protein carbonylation (PC)) were assayed. RESULTS: Compared to published data on adults with BD, adolescents had significantly lower levels of LPH and PC (t52(11.34), p<0.0001; t58(29.68), p<0.0001, respectively). Thicker mean and maximum carotid intima media thickness was associated with greater levels of LPH (r=.455, p=.015; r=.620, p<0.0001, respectively). LPH was associated with diastolic blood pressure (r=-.488, p=0.008) and pulse pressure (r=.543, p=0.003). Mood symptoms and medication were not significantly associated with oxidative stress. CONCLUSION: Adolescents with BD have lower levels of oxidative stress compared to adults with BD, supporting prevailing illness staging theories for BD. Oxidative stress is robustly associated with a proxy measure of atherosclerosis and may explain in part the increased risk of CVD in BD. PMID- 25934155 TI - A distinct alleles and genetic recombination of pmrCAB operon in species of Acinetobacter baumannii complex isolates. AB - To investigate pmrCAB sequence divergence in 5 species of Acinetobacter baumannii complex, a total of 80 isolates from a Korean hospital were explored. We evaluated nucleotide and amino acid polymorphisms of pmrCAB operon, and phylogenetic trees were constructed for each gene of prmCAB operon. Colistin and polymyxin B susceptibility was determined for all isolates, and multilocus sequence typing was also performed for A. baumannii isolates. Our results showed that each species of A. baumannii complex has divergent pmrCAB operon sequences. We identified a distinct pmrCAB allele allied with Acinetobacter nosocomialis in gene trees. Different grouping in each gene tree suggests sporadic recombination or emergence of pmrCAB genes among Acinetobacter species. Sequence polymorphisms among Acinetobacter species might not be associated with colistin resistance. We revealed that a distinct pmrCAB allele may be widespread across the continents such as North America and Asia and that sporadic genetic recombination or emergence of pmrCAB genes might occur. PMID- 25934156 TI - Detection of Mycoplasma genitalium from male primary urine specimens: an epidemiologic dichotomy with Trichomonas vaginalis. AB - A total of 2750 male urines subjected to a transcription-mediated amplification (TMA)-based Mycoplasma genitalium assay yielded 188 positive results (6.84%). This rate was similar to Chlamydia trachomatis (6.87%; P = 0.96) and greater than Neisseria gonorrhoeae (4.0%) and Trichomonas vaginalis (2.3%; P < 0.0002). Mean age of M. genitalium-infected males (30.8) was similar to N. gonorrhoeae (P = 0.78) but less than T. vaginalis (mean, 41.6; P < 0.0001). A total of 266 STI clinic encounters had at least 1 sexually transmitted infection (STI); 36.5% of these encounters had sole detection of M. genitalium (P <= 0.009 versus sole detection of other STI agents). In 209 community encounters with at least 1 STI, 22.0% exhibited sole detection of M. genitalium (P = 0.0007 versus sole M. genitalium detection in STI clinic males), while 18.7% had sole detection of T. vaginalis (P < 0.0002 versus detection in STI clinic males). TMA-based M. genitalium screening identifies additional cases of nongonococcal urethritis. PMID- 25934157 TI - Explore the reaction mechanism of the Maillard reaction: a density functional theory study. AB - The mechanism of Maillard reaction has been investigated by means of density functional theory calculations in the gaseous phase and aqueous solution. The Maillard reaction is a cascade of consecutive and parallel reaction. In the present model system study, glucose and glycine were taken as the initial reactants. On the basis of previous experimental results, the mechanisms of Maillard reaction have been proposed, and the possibility for the formation of different compounds have been evaluated through calculating the relative energy changes for different steps of reaction under different pH conditions. Our calculations reveal that the TS3 in Amadori rearrangement reaction is the rate determining step of Maillard reaction with the activation barriers of about 66.7 and 68.8 kcal mol(-1) in the gaseous phase and aqueous solution, respectively. The calculation results are in good agreement with previous studies and could provide insights into the reaction mechanism of Maillard reaction, since experimental evaluation of the role of intermediates in the Maillard reaction is quite complicated. PMID- 25934159 TI - Incidence and outcome of Staphylococcus aureus endocarditis--a 10-year single centre northern European experience. AB - Staphylococcus aureus is a leading cause of infective endocarditis. Little has been published on the outcome and epidemiology of S. aureus endocarditis (SAE) in the twenty-first century. Our aim was to evaluate the short-term and long-term outcome of SAE in Stockholm, Sweden, and assess its incidence over time. Patients treated for SAE from January 2004 through December 2013 were retrospectively identified at the Karolinska University Hospital. Clinical data were obtained from medical records and the diagnosis was verified according to the modified Duke criteria. Of 245 SAE cases, 152 (62%) were left-sided and 120 (49%) occurred in intravenous drug users. The calculated incidence in Stockholm County was 1.56/100 000 person-years, increasing from 1.28 in 2004-08 to 1.82/100 000 person years in 2009-13 (p 0.002). In-hospital and 1-year mortality rates were 9.0% (22/245) and 19.5% (46/236), respectively. Age (OR 1.06 per year) and female sex (OR 3.0) were independently associated with in-hospital mortality in multivariate analysis. Involvement of the central nervous system (CNS) was observed in 30 (12%) patients, and valvular surgery was performed during hospitalization in 37 (15%). In left-sided endocarditis the strongest predictors for surgery were severe valvular insufficiency (OR 8.9), lower age (OR 1.07 per year) and no intravenous drug use (OR 10.7), and for CNS involvement lower age (OR 1.04 per year). In conclusion we noted low mortality, low CNS complication rate, and low valvular surgery frequency associated with SAE in our setting. The incidence was high and increased over time. The study provides an update on the outcome and epidemiology of SAE in the twenty-first century. PMID- 25934158 TI - Screening of novel inhibitors targeting lactate dehydrogenase A via four molecular docking strategies and dynamics simulations. AB - Lactate dehydrogenase A (LDHA) is a metabolic enzyme which catalyzes the interconversion of lactate and pyruvate in the glycolysis pathway, thus playing key roles in aerobic glycolysis. The inhibition of LDHA by small molecules has become an attractive strategy for anticancer therapy in recent years. However, very few LDHA inhibitors have been reported, even though a great deal of effort has directed into identifying LDHA inhibitors using structure-based approaches. Therefore, high-throughput and high-accuracy screening approaches are still urgently needed in order to target LDHA effectively. In the present work, after establishing that our docking strategies performed well using test datasets, we screened 32791 Specs products for their docking scores with the substrate-binding pocket and, separately, the cofactor-binding pocket of LDHA. We subsequently identified 76 hits (i.e., ligands that show low docking scores) for the cofactor binding pocket and 27 hits for the substrate-binding pocket. Two representative compounds, ZINC20036549 and ZINC19369718, were then chosen for further MD simulation analysis, and we found that these compounds maintained their inhibitory activity during the MD simulations. Meanwhile, we found that ZINC19369718 interacts with a novel binding site close to the active site, and that this interaction may inhibit the catalytic activity of LDHA. Together, these results offer not only a new paradigm for identifying Specs drug-like products for novel therapeutic use but they also provide further opportunity to adopt LDHA inhibition as a strategy for cancer therapy. PMID- 25934160 TI - Validation of the Novaco Anger Scale-Provocation Inventory (Danish) With Nonclinical, Clinical, and Offender Samples. AB - Anger has high prevalence in clinical and forensic settings, and it is associated with aggressive behavior and ward atmosphere on psychiatric units. Dysregulated anger is a clinical problem in Danish mental health care systems, but no anger assessment instruments have been validated in Danish. Because the Novaco Anger Scale and Provocation Inventory (NAS-PI) has been extensively validated with different clinical populations and lends itself to clinical case formulation, it was selected for translation and evaluation in the present multistudy project. Psychometric properties of the NAS-PI were investigated with samples of 477 nonclinical, 250 clinical, 167 male prisoner, and 64 male forensic participants. Anger prevalence and its relationship with other anger measures, anxiety/depression, and aggression were examined. NAS-PI was found to have high reliability, concurrent validity, and discriminant validity, and its scores discriminated the samples. High scores in the offender group demonstrated the feasibility of obtaining self-report assessments of anger with this population. Retrospective and prospective validity of the NAS were tested with the forensic patient sample regarding physically aggressive behavior in hospital. Regression analyses showed that higher scores on NAS increase the risk of having acted aggressively in the past and of acting aggressively in the future. PMID- 25934161 TI - Screening of Cognitive Impairment in Schizophrenia: Reliability, Sensitivity, and Specificity of the Repeatable Battery for the Assessment of Neuropsychological Status in a Spanish Sample. AB - BACKGROUND: In recent years, a number of studies focusing on the evaluation of neuropsychological deficits in individuals with schizophrenia have shown deficits that include several cognitive functions. Attention deficits as well as memory or executive function deficits are common in this kind of disorder together with sustained attention problems, working memory deficiencies, and problem-solving difficulties, among many others. Currently, the Repeatable Battery for the Assessment of Neuropsychological Status (RBANS) is gaining special importance in the evaluation of the cognitive deficits associated with schizophrenia. METHOD: In this article, we describe an RBANS screening in a sample of 88 Spanish patients diagnosed with schizophrenia. We also aimed to check the battery's reliability, sensitivity, and specificity in the studied sample. We performed a comparative study with 88 healthy participants. RESULTS: The results showed a reliability index value of alpha = .795 and an item value of alpha = .762. For total test reliability, we obtained an index value of alpha = .761 and an item value of alpha = .762. Sensitivity score was 87.5% and specificity 86.4%. CONCLUSIONS: RBANS obtained good reliability, sensitivity, and specificity scores and represents a good screening tool in detecting cognitive deficits associated with schizophrenia. PMID- 25934162 TI - Assessing Adolescent Anxiety in General Psychiatric Care: Diagnostic Accuracy of the Swedish Self-Report and Parent Versions of the Spence Children's Anxiety Scale. AB - This study examined the psychometric properties and diagnostic accuracy of the Swedish translations of the Spence Children's Anxiety Scale, self- and parent report versions, in a sample of 104 adolescents presenting at two general psychiatric outpatient units. Results showed high informant agreement and good internal reliability and concurrent and discriminant validity for both versions and demonstrated that this scale can distinguish between adolescents with and without an anxiety disorder in a non-anxiety-specific clinical setting. The relative clinical utility of different cutoff scores was compared by looking at the extent to which dichotomized questionnaire results altered the pretest probability of the presence of a diagnosis as defined by the Schedule for Affective Disorders and Schizophrenia for School-Age Children. Optimized for screening and diagnostic purposes in Sweden, cutoff scores obtained in the current study outperformed a previously identified cutoff score derived from an Australian community sample. The Spence Children's Anxiety Scale is a useful clinical instrument for the assessment of anxiety in adolescents. PMID- 25934163 TI - Regulation of body fat mass by the gut microbiota: Possible mediation by the brain. AB - New insight suggests gut microbiota as a component in energy balance. However, the underlying mechanisms by which gut microbiota can impact metabolic regulation is unclear. A recent study from our lab shows, for the first time, a link between gut microbiota and energy balance circuitries in the hypothalamus and brainstem. In this article we will review this study further. PMID- 25934164 TI - Three-year efficacy and safety of a new 52-mg levonorgestrel-releasing intrauterine system. AB - OBJECTIVE: To assess 3-year data on the efficacy and safety of a new 52-mg levonorgestrel intrauterine contraceptive (LNG20) designed for up to 7 years use. STUDY DESIGN: Nulliparous and parous women aged 16-45 years at enrollment with regular menstrual cycles and requesting contraception were enrolled in an open label, partially randomized trial to evaluate LNG20. The primary outcome was pregnancy rate for women aged 16-35 years calculated as the Pearl Index. Women aged 36-45 years received LNG20 for safety evaluation only. All participants had in-person or phone follow-up approximately every 3 months during the study. RESULTS: A total of 1600 women aged 16-35 years and 151 women aged 36-45 years agreed to LNG20 placement, including 1011 (57.7%) nulliparous and 438 (25.1%) obese women. Successful placement occurred in 1714 (97.9%) women. Six pregnancies occurred, four of which were ectopic. The Pearl Index for LNG20 was 0.15 (95% CI 0.02-0.55) through Year 1, 0.26 (95% CI 0.10-0.57) through Year 2, and 0.22 (95% CI 0.08-0.49) through Year 3. The cumulative life-table pregnancy rate was 0.55 (95% CI 0.24-1.23) through 3 years. Expulsion was reported in 62 (3.5%) participants, most (50 [80.6%]) during the first year of use. Of women who discontinued LNG20 and desired pregnancy, 86.8% conceived spontaneously within 12 months. Pelvic infection was diagnosed in 10 (0.6%) women. Only 26 (1.5%) LNG20 users discontinued due to bleeding complaints. CONCLUSION: The LNG20 intrauterine system is highly effective and safe over 3 years of use in nulliparous and parous women. IMPLICATIONS STATEMENT: A new 52-mg levonorgestrel-releasing intrauterine system is effective and safe for nulliparous and parous women for at least 3 years. PMID- 25934166 TI - Effect of host plant and immune challenge on the levels of chemosensory and odorant-binding proteins in caterpillar salivary glands. AB - More than half of the proteome from mandibular glands in caterpillars is represented by chemosensory proteins. Based on sequence similarity, these proteins are putative transporters of ligands to gustatory receptors in sensory organs of insects. We sought to determine whether these proteins are inducible by comparing, both qualitatively and quantitatively, the salivary (mandibular and labial) proteomes from caterpillars (Vanessa cardui) reared on different plants and artificial diet containing either bacteria or bacterial cell-walls. We included a treatment where the caterpillars were switched from feeding on artificial diet to plant material at some point in their development. Additionally, we evaluated the degree of overlap between the proteomes in the hemolymph-filled coelom and salivary glands of caterpillars reared on plant material. We found that the quality and quantity of the identified proteins differed clearly between hemolymph-filled coelome, labial and mandibular glands. Our results indicated that even after molting and two-day feeding on a new diet, protein production is affected by the previous food source used by the caterpillar. Candidate proteins involved in chemosensory perception by insects were detected: three chemosensory (CSPs) and two odorant-binding proteins (OBPs). Using the relative amounts of these proteins across tissues and treatments as criteria for their classification, we detected hemolymph- and mandibular gland specific CSPs and observed that their levels were affected by caterpillar diet. Moreover, we could compare the protein and transcript levels across tissues and treatment for at least one CSP and one OBP. Therefore, we have identified specific isoforms for testing the role of CSPs and OBPs in plant and pathogen recognition. We detected catalase, immune-related protein and serine proteases and their inhibitors in high relative levels in the mandibular glands in comparison to the labial glands. These findings suggest that the mandibular glands of caterpillars may play an important role protecting the caterpillar from oxidative stress, pathogens and aiding in digestion. Contamination with hemolymph proteins during dissection of salivary glands from caterpillars may occur but it is not substantial since the proteomes from hemolymph, mandibular and labial glands were easily discriminated from each other by principal component analysis of proteomic data. PMID- 25934165 TI - Differential hepatic avoidance radiation therapy: Proof of concept in hepatocellular carcinoma patients. AB - PURPOSE: To evaluate the feasibility of a novel planning concept that differentially redistributes RT dose away from functional liver regions as defined by (99m)Tc-sulphur colloid (SC) uptake on patient SPECT/CT images. MATERIALS AND METHODS: Ten HCC patients with different Child-Turcotte-Pugh scores (A5-B9) underwent SC SPECT/CT scans in treatment position prior to RT that were registered to planning CT scans. Proton pencil beam scanning (PBS) therapy plans were optimized to deliver 37.5-60.0Gy (RBE) over 5-15 fractions using single field uniform dose technique robust to range and setup uncertainty. Photon volumetrically modulated arc therapy (VMAT) plans were optimized to the same prescribed dose and minimum target coverage. For both treatment modalities, differential hepatic avoidance RT (DHART) plans were generated to decrease dose to functional liver volumes (FLV) defined by a range of thresholds relative to maximum SC uptake (43-90%) in the tumor-subtracted liver. Radiation dose was redistributed away from regions of increased SC uptake in each FLV by linearly scaling mean dose objectives during PBS or VMAT optimization. DHART planning feasibility was assessed by a significantly negative Spearman's rank correlation (RS) between dose difference and SC uptake. Patient, tumor, and treatment planning characteristics were tested for association to DHART planning feasibility using non-parametric Kruskal-Wallis ANOVA. RESULTS: Compared to conventional plans, DHART plans achieved a 3% FLV dose reduction for every 10% SC uptake increase. DHART planning was feasible in the majority of patients with 60% of patients having RS<-0.5 (p<0.01, range -1.0 to 0.2) and was particularly effective in 30% of patients (RS<-0.9). Mean dose to FLV was reduced by up to 20% in these patients. Only fractionation regimen was associated with DHART planning feasibility: 15 fraction courses were more feasible than 5-6 fraction courses (RS<-0.93 vs. RS>-0.60, p<0.02). CONCLUSION: Differential avoidance of functional liver regions defined on sulphur colloid SPECT/CT is achievable with either photon VMAT or proton PBS therapy. Further investigation with phantom studies and in a larger cohort of patients may validate the utility of DHART planning for HCC radiotherapy. PMID- 25934167 TI - Clinical significance of auditory target P300 subcomponents in psychosis: Differential diagnosis, symptom profiles, and course. AB - BACKGROUND: Reduced auditory target P300 amplitude is a leading biomarker for psychotic disorders, although its relevance for differential diagnosis and link to specific clinical features (symptom profiles, functional impairment, and course) are unclear. This study aims to clarify the clinical significance of auditory target P300 using concurrent and retrospective clinical data from a longitudinal cohort with psychosis. METHODS: 92 cases from an epidemiological study of first-admission psychosis were assessed using an auditory oddball paradigm at 15-year follow-up along with 44 never-psychotic adults. Subcomponents of auditory target P300 amplitude (i.e., a central positive P3a, a parietal positive P3b, and a frontal negative slow wave) were isolated using temporal spatial principal component analysis. RESULTS: P3a amplitude was blunted across psychotic disorders relative to non-psychotic adults. P3b amplitude was reduced in schizophrenia specifically, including cases initially misclassified at baseline. The frontal negative slow wave did not distinguish among groups. P3b amplitude reduction was associated with several clinical features at the concurrent assessment, as well as previous time points, including recovery from psychosis even 5 years earlier and functioning even 15 years earlier. CONCLUSIONS: Auditory target P300 amplitude yields both a schizophrenia-specific component (i.e., P3b) and a transdiagnostic psychosis component (i.e., P3a). The P3b component may also shed light on prognosis, real-world functioning, and course, as well as help to reduce misdiagnosis of psychotic disorders. Prospective studies are needed to test whether P3b tracks or predicts clinical status. PMID- 25934168 TI - The effect of transcranial direct current stimulation on social cognition in schizophrenia: A preliminary study. AB - In this preliminary study, we examined the effect of transcranial direct current stimulation (tDCS) on social cognition in 36 individuals with schizophrenia. Participants received a baseline assessment and one week later received either anodal, cathodal, or sham tDCS, with 12 participants randomized to each condition. A single 20-minute session tDCS was administered bilaterally over the dorsolateral prefrontal cortex (centered at positions Fp1 and Fp2) at 2 mA. Among the 4 social cognitive tasks, participants showed a significant improvement on one of them, emotion identification, following anodal stimulation. Findings demonstrate the safety of this procedure and suggest potential therapeutic effects on one aspect of social cognition in schizophrenia. PMID- 25934169 TI - Direct costs of radiotherapy for rectal cancer: a microcosting study. AB - BACKGROUND: Radiotherapy provides significant benefits in terms of reducing risk of local recurrence and death from rectal cancer. Despite this, up-to-date cost estimates for radiotherapy are lacking, potentially inhibiting policy and decision-making. Our objective was to generate an up-to-date estimate of the cost of traditional radiotherapy for rectal cancer and model the impact of a range of potential efficiency improvements. METHODS: Microcosting methods were used to estimate total direct radiotherapy costs for long- (assumed at 45-50 Gy in 25 daily fractions over a 5 week period) and short-courses (assumed at 25 Gy in 5 daily fractions over a one week period). Following interviews and on-site visits to radiotherapy departments in two designated cancer centers, a radiotherapy care pathway for a typical rectal cancer patient was developed. Total direct costs were derived by applying fixed and variable unit costs to resource use within each care phase. Costs included labor, capital, consumables and overheads. Sensitivity analyses were performed. RESULTS: Radiotherapy treatment was estimated to cost between ?2,080 (5-fraction course) and ?3,609 (25-fraction course) for an average patient in 2012. Costs were highest in the treatment planning phase for the short-course (?1,217; 58% of total costs), but highest in the radiation treatment phase for the long-course (?1,974: 60% of total costs). By simultaneously varying treatment time, capacity utilization rates and linear accelerator staff numbers, the base cost fell by 20% for 5-fractions: (?1,660) and 35% for 25-fractions: (?2,354). CONCLUSIONS: Traditional radiotherapy for rectal cancer is relatively inexpensive. Moreover, significant savings may be achievable through service organization and provision changes. These results suggest that a strong economic argument can be made for expanding the use of radiotherapy in rectal cancer treatment. PMID- 25934171 TI - Ethnoecology - The best medicine against allergy? AB - This essay, which is the 6(th) in the series "Recollections, Reflections, and Revelations: Ethnobiologists and Their First Time in the Field", is a personal reflection by the researcher on his first field experiences with ethnobiology. Author writes on how Hungarian herders in the Hortobagy salt steppes and Csango people in the Carpathian mountains changed his views on landscape, vegetation, local people, traditional small-scale grassland management and finally, ecology and nature conservation. PMID- 25934170 TI - Cognitive-behavioural therapy has no effect on disease activity but improves quality of life in subgroups of patients with inflammatory bowel disease: a pilot randomised controlled trial. AB - BACKGROUND: Studies have demonstrated usefulness of cognitive-behavioural therapy (CBT) in managing distress in inflammatory bowel disease (IBD); however, few have focused on IBD course. The present trial aimed to investigate whether adding CBT to standard treatment prolongs remission in IBD in comparison to standard therapy alone. METHODS: A 2-arm parallel pragmatic randomised controlled trial (+CBT - standard care plus either face-to-face (F2F) or online CBT over 10 weeks versus standard care alone (SC)) was conducted with adult patients in remission. IBD remission at 12 months since baseline was the primary outcome measure while the secondary outcome measures were mental health status and quality of life (QoL). Linear mixed-effect models were used to compare groups on outcome variables while controlling for baseline. RESULTS: Participants were 174 patients with IBD (90 +CBT, 84 SC). There was no difference in remission rates between groups, with similar numbers flaring at 12 months. Groups did not differ in anxiety, depression or coping at 6 or 12 months (p >0.05). When only participants classified as 'in need' (young, high baseline IBD activity, recently diagnosed; poor mental health) were examined in the post-hoc analysis (n = 74, 34 CBT and 40 controls), CBT significantly improved mental QoL (p = .034, d = .56) at 6 months. Online CBT group had a higher score on Precontemplation than the F2F group, which is consistent with less developed coping with IBD in the cCBT group (p = .045). CONCLUSIONS: Future studies should direct psychological interventions to patients 'in need' and attempt to recruit larger samples to compensate for significant attrition when using online CBT. TRIAL REGISTRATION: The protocol was registered on 21/10/2009 with the Australian New Zealand Clinical Trials Registry (ID: ACTRN12609000913279). PMID- 25934172 TI - A Rapid Embryonic Stem Cell-Based Mouse Model for B-cell Lymphomas Driven by Epstein-Barr Virus Protein LMP1. AB - The Epstein-Barr virus (EBV) latent membrane protein 1 (LMP1) contributes to oncogenic human B-cell transformation. Mouse B cells conditionally expressing LMP1 are not predisposed to B-cell malignancies, as LMP1-expressing B cells are eliminated by T cells. However, mice with conditional B-cell LMP1 expression and genetic elimination of alpha/beta and gamma/delta T cells ("CLT" mice) die early in association with B-cell lymphoproliferation and lymphomagenesis. Generation of CLT mice involves in-breeding multiple independently segregating alleles. Thus, although introduction of additional activating or knockout mutations into the CLT model is desirable for further B-cell expansion and immunosurveillance studies, doing such experiments by germline breeding is time-consuming, expensive, and sometimes unfeasible. To generate a more tractable model, we generated clonal CLT embryonic stem (ES) cells from CLT embryos and injected them into RAG2-deficient blastocysts to generate chimeric mice, which, like germline CLT mice, harbor splenic CLT B cells and lack T cells. CLT chimeric mice generated by this RAG2 deficient blastocyst complementation ("RDBC") approach die rapidly in association with B-cell lymphoproliferation and lymphoma. Because CLT lymphomas routinely express the activation-induced cytidine deaminase (AID) antibody diversifier, we tested potential AID roles by eliminating the AID gene in CLT ES cells and testing them via RDBC. We found that CLT and AID-deficient CLT ES chimeras had indistinguishable phenotypes, showing that AID is not essential for LMP1-induced lymphomagenesis. Beyond expanding accessibility and utility of CLT mice as a cancer immunotherapy model, our studies provide a new approach for facilitating generation of genetically complex mouse cancer models. PMID- 25934173 TI - Use of a Therapeutic, Socially Assistive Pet Robot (PARO) in Improving Mood and Stimulating Social Interaction and Communication for People With Dementia: Study Protocol for a Randomized Controlled Trial. AB - BACKGROUND: Socially assistive robotics is a growing area for geriatric research. OBJECTIVE: This single-blind, randomized controlled trial (RCT) aims to investigate the use of PARO, a therapeutic, socially assistive pet robot, in improving mood, and stimulating social interaction and communication for people with dementia in the community. METHODS: For the study, 40 community-dwelling older Chinese adults (>=60 years) with mild to moderate dementia will be recruited and randomly assigned to the PARO therapy group or the psychosocial activities control group. Both treatments consist of six, 30-minute weekly sessions, which will be conducted in a geriatric day hospital. Subjects in both groups will be assessed by a trained research assistant at baseline (pre-), during, and post-treatment. Mood (assessed with a simplified face scale), social interaction, and communication (ie, facial expressions and reactions towards each treatment, assessed with an observation table) will be the primary outcome measures. Secondary outcome measures will include assessments on cognitive function (Mini-Mental State Examination) and depressive symptoms (Cornell Scale for Depression in Dementia), as well as caregiver burden (Zarit Burden Inventory). Subjective impression towards each treatment and qualitative comments from the caregivers, facilitator, and therapists will also be obtained. RESULTS: Recruitment to the pilot study began in 2014 and the last subject is expected to complete their post-treatment assessment in 2015. CONCLUSIONS: This will be the first RCT using PARO to improve mood, and stimulate social interaction and communication in the care of older people with dementia, as well as provide an evidence basis for the use of PARO in dementia care in Hong Kong. TRIAL REGISTRATION: The Australian New Zealand Clinical Trials Registry (ANZCTR): ACTRN12614000037606; https://www.anzctr.org.au/Trial/Registration/TrialReview.aspx?ACTRN=1261400003760 (Archived by WebCite at http://www.webcitation.org/6Xi7uXdu9). PMID- 25934174 TI - Clusterin transcript variants expression in thyroid tumor: a potential marker of malignancy? AB - BACKGROUND: Clusterin (CLU) is a ubiquitous multifunctional factor involved in neoplastic transformation. The CLU transcript variants and protein forms play a crucial role in balancing cells proliferation and death. METHODS: We investigated the regulation of CLU transcript variants expression in an in vivo model system consisting of both neoplastic tissues and fine needle aspiration biopsy (FNAB) samples isolated from patients undergoing thyroidectomy. RESULTS: The immunohistochemical analyses showed an overall CLU up-regulation in papillary carcinoma. A specific CLU2 transcript variant increase was registered using qPCR in papillary carcinomas while CLU1 decreased. In addition, the analysis of CLU transcripts expression level showed an increase of the CLU2 transcript in the TIR 3 patients with histologically confirmed thyroid cancer. CONCLUSIONS: Our results suggest the existence of a specific alteration of CLU2:CLU1 ratio towards CLU2, thus providing the first circumstantial evidence for the potential use of CLU transcript variants as effective biomarkers for a more accurate assessment of the so called "indeterminate" thyroid nodules. PMID- 25934175 TI - Cost effectiveness of interpersonal community psychiatric treatment for people with long-term severe non-psychotic mental disorders: protocol of a multi-centre randomized controlled trial. AB - BACKGROUND: This study aims for health gain and cost reduction in the care for people with long-term non-psychotic psychiatric disorders. Present care for this population has a limited evidence base, is often open ended, little effective, and expensive. Recent epidemiological data shows that 43.5% of the Dutch are affected by mental illness during their life. About 80% of all patients receiving mental health services (MHS) have one or more non-psychotic disorders. Particularly for this group, long-term treatment and care is poorly developed. Care As Usual (CAU) currently is a form of low-structured treatment/care. Interpersonal Community Psychiatric Treatment (ICPT) is a structured treatment for people with long-term, non-psychotic disorders, developed together with patients, professionals, and experts. ICPT uses a number of evidence-based techniques and was positively evaluated in a controlled pilot study. METHODS/DESIGN: Multi-centre cluster-randomized clinical trial: 36 professionals will be randomly allocated to either ICPT or CAU for an intervention period of 12 months, and a follow-up of 6 months. 180 Patients between 18-65 years of age will be included, who have been diagnosed with a non-psychotic psychiatric disorder (depressive, anxiety, personality or substance abuse disorder), have long-term (>2 years) or high care use (>1 outpatient contact per week or >2 crisis contacts per year or >1 inpatient admission per year), and who receive treatment in a specialized mental health care setting. The primary outcome variable is quality of life; secondary outcomes are costs, recovery, general mental health, therapeutic alliance, professional-perceived difficulty of patient, care needs and social contacts. DISCUSSION: No RCT, nor cost-effectiveness study, has been conducted on ICPT so far. The empirical base for current CAU is weak, if not absent. This study will fill this void, and generate data needed to improve daily mental health care. TRIAL REGISTRATION: Netherlands Trial Register (NTR): 3988 . Registered 13th of May 2013. PMID- 25934176 TI - A functional Rim101 complex is required for proper accumulation of the Ena1 Na+ ATPase protein in response to salt stress in Saccharomyces cerevisiae. AB - The maintenance of ionic homeostasis is essential for cell viability, thus the activity of plasma membrane ion transporters must be tightly controlled. Previous studies in Saccharomyces cerevisiae revealed that the proper trafficking of several nutrient permeases requires the E3 ubiquitin ligase Rsp5 and, in many cases, the presence of specific adaptor proteins needed for Rsp5 substrate recognition. Among these adaptor proteins are nine members of the arrestin related trafficking adaptor (ART) family. We studied the possible role of the ART family in the regulation of monovalent cation transporters. We show here that the salt sensitivity phenotype of the rim8/art9 mutant is due to severe defects in Ena1 protein accumulation, which is not attributable to transcriptional defects. Many components of the Rim pathway are required for correct Ena1 accumulation, but not for the accumulation of other nutrient permeases. Moreover, we observe that strains lacking components of the endosomal sorting complexes required for transport (ESCRT) pathway previously described to play a role in Rim complex formation present similar defects in Ena1 accumulation. Our results show that, in response to salt stress, a functional Rim complex via specific ESCRT interactions is required for the proper accumulation of the Ena1 protein, but not induction of the ENA1 gene. PMID- 25934177 TI - Achievement of individualized treatment targets in patients with comorbid type-2 diabetes and hypertension: 6 months results of the DIALOGUE registry. AB - BACKGROUND: Patients with type-2 diabetes mellitus (T2DM) and hypertension have increased risk of cardiovascular disease (CVD). We studied individualized treatment targets and their achievement in clinical practice. METHODS: DIALOGUE is a prospective, multi-center registry in patients with both T2DM and hypertension. RESULTS: Patients (n = 6,586) had a baseline fasting glucose (8.5 +/- 2.8 mmol/l), postprandial glucose (10.9 +/- 3.4 mmol/l), and HbA1c (7.8 +/- 2.1%) levels indicated poor glycemic control. Baseline systolic and diastolic BP were 140.3 +/- 15.7 and 82.6 +/- 9.5, respectively. Patients were categorized by HbA1c treatment goals: <=6.5% (strict), >6.5 to <=7.0% (medium), and >7.0 to <=7.5% (loose). When considering systolic BP (SBP) targets (<=130 mmHg [strict], >130 to <=135 mmHg [medium], and >135 to <=140 mmHg [loose]), patients with strict SBP treatment goals displayed similar characteristics to those with strict HbA1c targets. Although approximately 70% of patients received both strict HbA1c and SBP targeting, overall treatment goals remained unmet in all HbA1c target groups at the 6-month follow-up. SBP targets were not reached in the strict and medium groups, but were achieved in the loose treatment group. Specific predictors for choosing loose SBP or HbA1c treatment goals were identified, including SBP/HbA1c levels and various comorbidities. CONCLUSIONS: Individualized glucose and BP targets were selected by treating physicians based on patient characteristics and overall comorbidity. While treatment goals were not consistently met using various antidiabetic and antihypertensive therapies, our analyses indicated that the strictly targeted patient populations maintained lower overall HbA1c and SBP levels at 6 months. PMID- 25934178 TI - Characteristics and outcomes of adult Ethiopian patients enrolled in HIV care and treatment: a multi-clinic observational study. AB - BACKGROUND: We describe trends in characteristics and outcomes among adults initiating HIV care and treatment in Ethiopia from 2006-2011. METHODS: We conducted a retrospective longitudinal analysis of HIV-positive adults (>= 15 years) enrolling at 56 Ethiopian health facilities from 2006-2011. We investigated trends over time in the proportion enrolling through provider initiated counseling and testing (PITC), baseline CD4+ cell counts and WHO stage. Additionally, we assessed outcomes (recorded death, loss to follow-up (LTF), transfer, and total attrition (recorded death plus LTF)) before and after ART initiation. Kaplan-Meier techniques estimated cumulative incidence of these outcomes through 36 months after ART initiation. Factors associated with LTF and death after ART initiation were estimated using Hazard Ratios accounting for within-clinic correlation. RESULTS: 93,418 adults enrolled into HIV care; 53,300 (57%) initiated ART. The proportion enrolled through PITC increased from 27.6% (2006-2007) to 44.8% (2010-2011) (p < .0001). Concurrently, median enrollment CD4+ cell count increased from 158 to 208 cells/mm(3) (p < .0001), and patients initiating ART with advanced WHO stage decreased from 56.6% (stage III) and 15.0% (IV) in 2006-2007 to 47.6% (stage III) and 8.5% (IV) in 2010-2011. Median CD4+ cell count at ART initiation remained stable over time. 24% of patients were LTF before ART initiation. Among those initiating ART, attrition was 30% after 36 months, with most occurring within the first 6 months. Recorded death after ART initiation was 6.4% and 9.2% at 6 and 36 months, respectively, and decreased over time. Younger age, male gender, never being married, no formal education, low CD4+ cell count, and advanced WHO stage were associated with increased LTF. Recorded death was lower among younger adults, females, married individuals, those with higher CD4+ cell counts and lower WHO stage at ART initiation. CONCLUSIONS: Over time, enrollment in HIV care through outpatient PITC increased and patients enrolled into HIV care at earlier disease stages across all HIV testing points. However, median CD4+ cell count at ART initiation remained steady. Pre- and post-ART attrition (particularly in the first 6 months) have remained major challenges in ensuring prompt ART initiation and retention on ART. PMID- 25934179 TI - Dynamic structures in DNA damage responses & cancer. PMID- 25934180 TI - MRI versus histological methods for time course monitoring of steatosis amount in a murine model of NAFLD. AB - PURPOSE: Hepatic steatosis is an increasingly frequent disease with potentially severe complications. A simple quantification method is required for pretherapeutic studies to allow steatosis monitoring. This study aimed at evaluating steatosis quantification via a standard 1.5T MRI machine in a murine model. MATERIALS AND METHODS: Eleven groups of two rats received a choline methionine deficient diet. MRI was performed at days 0, 2, 4, 5, 6, 7 and 8, and weeks 2, 3, 4 and 5. A phased array surface coil system was used to acquire a GE T1 in- and out-of-phase multi-echo sequence, with neither cardiac nor respiratory synchronization. Steatosis was calculated with the 3-echoes method. Histological quantifications were performed both by optical analysis (percentage of fatty hepatocytes) and by automated measurement of the area of steatosis (AOS). The reference was total intrahepatic triglycerides (TIT). Protocol was approved by the ethic committee. RESULTS: Steatosis without inflammation, increasing with diet duration, was obtained. MRI provided better agreement (intraclass correlation coefficient) with TIT (0.889, p<0.001) than did AOS (0.629, p=0.001) or optical analysis (0.280, p=0.098). MRI permitted closer monitoring of TIT over time than did AOS or optical analysis. By multivariate analysis, MRI was an independent predictor of TIT on first step and ALT on second step. A model combining these 2 variables provided excellent agreement with TIT (0.953, p<0.001) and permitted excellent monitoring of steatosis over time. CONCLUSION: MRI is reliable, easy, fast and superior to histological techniques for the assessment of hepatic steatosis in a murine model. PMID- 25934181 TI - Pseudotumoral vertebral body enhancement. PMID- 25934182 TI - Characteristics of undetected prostate cancer on diffusion-weighted MR Imaging at 3-Tesla with a b-value of 2000s/mm(2): Imaging-pathologic correlation. AB - OBJECTIVE: To assess the accuracy of Diffusion-Weighted MR Imaging (DW-MRI) at 3 Teslas (3T) with a b-value of 2000s/mm(2) (b-2000 DW-MRI) to detect prostate cancer (PCa) and to describe the histological features of missed tumors. METHODS: Prior to radical prostatectomy, 35 patients with a mean age of 64+/-6.2years old [51-77years old] had a b-2000 DW-MRI at 3-T, without rectal coil (acquisition time: 2min, 15s), and were analysed on an eight-sector basis by two independent readers blinded to the rest of the multiparametric-MRI protocol. Pathological tumor foci were matched with high intensity focal areas on MRI and correlated for Gleason score, sector location and largest axial diameter. RESULTS: Of the 280 sectors analysed, histology showed PCa in 113 (113/280, 40%). Overall DW-MRI sensitivity, specificity and accuracy for tumor detection were 79-81%, 99-95% and 92-82% for readers 1 and 2, respectively (kappa test: 0.78). Of all, 28 (28/113, 25%) and 22 (22/113, 20%) tumor foci were not detected by reader 1 and 2 respectively. These undetected tumor foci had a mean pathological axial axis of 5mm (range: 3-15mm) and a Gleason score of 6, 7 (3+4), 7 (4+3) and>7 in 15/28 (54%), 9/28 (32%), 3/28 (10%) and 1/28 (4%) of cases for reader 1, and in 11 (50%), 5 (23%), 5 (23%) and 1 (4%) of cases for reader 2. CONCLUSION: A normal b 2000 DW-MRI at 3-T may miss small tumors without or with a minor Gleason 4 component. PMID- 25934183 TI - C9orf72 hexanucleotide expansion analysis in Chinese patients with multiple system atrophy. PMID- 25934184 TI - Clinical evolution, neuroimaging, and volumetric analysis of a patient with a CSF1R mutation who presented with progressive nonfluent aphasia. PMID- 25934185 TI - First molecular characterisation and expression analysis of a teleost thioredoxin interacting protein (TXNIP) gene from rock bream (Oplegnathus fasciatus). AB - Thioredoxin-interacting protein (TXNIP) is an important regulator of glucose metabolism that functions by inhibiting cellular glucose uptake. The full-length rock bream (Oplegnathus fasciatus) TXNIP (RbTXNIP) cDNA (2499 bp) contains an open reading frame of 1188 bp encoding 396 amino acids. Furthermore, multiple alignments showed that the arrestin domain was well conserved among the other TXNIP sequences tested. RbTXNIP was predicted to contain a PxxP and PPxY motif. Phylogenetic analysis indicated that RbTXNIP is most closely related to Fugu rubripes TXNIP. RbTXNIP was expressed significantly in the RBC, intestine, and spleen. RbTXNIP mRNA expression was also examined in several tissues under conditions of bacterial and viral challenge. Generally, all tissues examined from fish infected with Streptococcus iniae, Edwardsiella tarda and red sea bream iridovirus (RSIV) showed significant downregulation in RbTXNIP expression compared to controls. However, RbTXNIP expression showed significant upregulation in the spleen and kidney after injection of recombinant rock bream TRx1 protein. These findings provide a molecular foundation for functional studies and applications in teleosts. PMID- 25934186 TI - Mapping kinematic functional abilities of the hand to three dimensional shapes for inclusive design. AB - Loss of hand function can have adverse effects on an individual's ability to maintain independence. The ability to perform daily activities, such as food preparation and medication delivery, is dependent on the hand's ability to grasp and manipulate objects. Therefore, the goal of this research was to demonstrate that three dimensional (3D) modeling of hand function can be used to improve the accessibility of handheld objects for individuals with reduced functionality through informed design. Individual models of hand functionality were created for 43 participants and group models were developed for groups of individuals without (Healthy) and with reduced functionality due to arthritis (RFA) of the hand. Cylindrical models representative of auto-injectors of varying diameters were analyzed in 3D space relative to hand function. The individual model mappings showed the cylinder diameter with the highest mapped functional values varied depending on the type of functional weighting chosen: kinematic redundancy of fingertip pad positional placement, fingertip pad orientation, or finger force directionality. The group mappings showed that for a cylinder to be grasped in a power grasp by at least 75% of the Healthy or RFA groups, a diameter of 40mm was required. This research utilizes a new hand model to objectively compare design parameters across three different kinematic factors of hand function and across groups with different functional abilities. The ability to conduct these comparisons enables the creation of designs that are universal to all - including accommodation of individuals with limits in their functional abilities. PMID- 25934187 TI - Increased prevalence of two mitochondrial DNA polymorphisms in functional disease: Are we describing different parts of an energy-depleted elephant? AB - About 20% of the population suffers from "functional syndromes". Since these syndromes overlap greatly in terms of co-morbidity, pathophysiology (including aberrant autonomic activity) and treatment responses, common predisposing genetic factors have been postulated. We had previously showed that two common mitochondrial DNA (mtDNA) polymorphisms at positions 16519 and 3010 are statistically associated with the functional syndromes of migraine, cyclic vomiting syndrome and non-specific abdominal pain. Herein, among individuals with mtDNA haplogroup H (HgH), the presence of these two mtDNA polymorphisms were ascertained in additional functional syndromes: chronic fatigue syndrome, complex regional pain syndrome, sudden infant death syndrome, and major depressive disorder. Polymorphic prevalence rates were compared between disease and control groups, and within each disease group in participants with and without specific clinical findings. In all four conditions, one or both of the polymorphisms was significantly associated with the respective condition and/or co-morbid functional symptomatology. Thus, we conclude that these two mtDNA polymorphisms likely modify risk for the development of multiple functional syndromes, likely constituting a proportion of the postulated common genetic factor, at least among individuals with HgH. Pathophysiology likely involves broad effects on the autonomic nervous system. PMID- 25934189 TI - Haplotype analysis and LD detection at DM1 locus. AB - Myotonic dystrophy type 1 (DM1) is the most common form of muscular dystrophy affecting adults and is due to trinucleotide sequence (CTG) in the 3' UTR region of DMPK gene located at 19q13.3 chromosome. Several neighboring genes (markers) located on the same chromosomes that are statistically associated and transmitted together (haplotype), influence the disease pathogenesis as caused by mutated DMPK. The intention of the study was to investigate the population genetic characteristics and to identify founder haplotypes from Northern India. Clinically diagnosed and molecularly confirmed DM1 patients (=27) and their family members (=76) were included in the study. PCR-RFLP analysis was performed for intron 5 (C/T)/HhaI, DMPK (G/T) intron 9/HinfI, Bpm1 and CKMM genetic polymorphism. The SNP Stat Online Software was used to construct haplotype group and for linkage-disequilibrium analysis. In all DM chromosomes: allele 2 had higher frequency in HhaI and HinfI while allele 1 had higher frequency in BpmI and CKMM. Total 11, 7, 10 and 11 haplotype groups had been formed in proband (patients), proband's father, proband's mother and in combined group respectively. Haplotype combination 2 (HhaI)/2 (HinfI)/1 (BpmI)/1 (CKMM TaqI)/1 (CKMM Nco1) had higher frequency, 0.4096 and 0.2867 in patients and combined group respectively. The haplotype combination 1/1/1/1/1 and 2/1/1/1/1 was most common for patient's father and mother respectively. The polymorphic markers HhaI & HinfI; HinfI & BpmI; and HinfI & CKMM TaqI showed significant LD. In comparison to other population, HhaI and HinfI have common origin of mutation. PMID- 25934188 TI - The nicotinic acetylcholine receptor alpha 4 subunit contains a functionally relevant SNP Haplotype. AB - BACKGROUND: Non-coding single nucleotide polymorphisms within the nicotinic acetylcholine receptor alpha 4 subunit gene (CHRNA4) are robustly associated with various neurological and behavioral phenotypes including schizophrenia, cognition and smoking. The most commonly associated polymorphisms are located in exon 5 and segregate as part of a haplotype. So far it is unknown if this haplotype is indeed functional, or if the observed associations are an indirect effect caused by linkage disequilibrium with not yet identified adjacent functional variants. We therefore analyzed the functional relevance of the exon 5 haplotype alleles. RESULTS: Using voltage clamp experiments we were able to show that the CHRNA4 haplotype alleles differ with respect to their functional effects on receptor sensitivity including reversal of receptor sensitivity between low and high acetylcholine concentrations. The results indicate that underlying mechanisms might include differences in codon usage bias and changes in mRNA stability. CONCLUSIONS: Our data demonstrate that the complementary alleles of the CHRNA4 exon 5 haplotype are functionally relevant, and might therefore be causative for the above mentioned associations. PMID- 25934190 TI - Examination of the brain natriuretic peptide rs198389 single-nucleotide polymorphism on type 2 diabetes mellitus and related phenotypes in an Algerian population. AB - BACKGROUND: In European populations, the NPPB rs198389 single nucleotide polymorphism (SNP) is associated with a reduced risk of type 2 diabetes mellitus (T2DM). We investigated the putative associations between NPPB rs198389, the T2DM risk and quantitative metabolic traits in an Algerian population. METHODS: The association analysis was performed as a T2DM case-control study (with 78 cases and 645 controls) nested into the ISOR population-based study. RESULTS: The NPPB rs198389 SNP was not associated with T2DM (odds ratio (OR) [95% confidence interval (CI)]=0.73 [0.51-1.04], p=0.08). However, the C allele was associated with lower fasting plasma insulin levels (p=0.05) and a lower homeostatic model assessment insulin resistance index (p=0.05) in non-diabetic individuals. CONCLUSION: The NPPB rs198389 SNP might modulate fasting insulin levels in an Algerian population. PMID- 25934191 TI - CD81 and CLDN1 polymorphisms and hepatitis C virus infection susceptibility: a case control study. AB - CD81 and CLDN1 interact to form a CD81-CLDN1 co-receptor complex that is crucial in hepatitis C virus (HCV) entry. Variations in the two genes were shown to influence immunological functions; therefore, we hypothesized that polymorphisms in these genes may contribute to HCV susceptibility. A case-control study consisting of 461 patients and 461 controls was conducted to explore the associations between CD81 rs708564 and CLDN1 rs893051 and HCV susceptibility in a Chinese population. We found a decreased HCV risk associated with the CD81 rs708564 TT (odds ratio (OR) = 0.66, 95% CI = 0.44-0.98) genotype. The gene-gene interaction between CD81 and CLDN1 polymorphisms also decreased HCV risk in a joint multiplicative manner (OR for the presence of both CD81 rs708564 TT and CLDN1 rs893051 GG genotypes = 0.59, 95% CI = 0.36-0.97). Furthermore, the CD81 rs708564 TT genotype conferred a more pronounced decrease in HCV susceptibility in combination with lower levels of high-density lipoprotein cholesterol (HDL-C; OR = 0.71, 95% CI = 0.52-0.96), and higher levels of low-density lipoprotein cholesterol (OR = 0.24, 95% CI = 0.09-0.65). We also observed a decreased HCV susceptibility in individuals with higher HDL-C levels who carried the CLDN1 rs893051 G/C genotype. These findings suggest that homozygous CD81 rs708564 TT may be a genetic modifier for avoiding HCV infection whether as a sole single nucleotide polymorphism or combined with the CLDN1 rs893051 GG genotype, and this effect is associated with serum levels of lipoprotein. PMID- 25934193 TI - Management and complications of traumatic peripheral nerve injuries. AB - This article provides an overview of the management of traumatic peripheral nerve injuries. It examines the basic pathophysiology of peripheral nerve injuries, along with the clinical presentation, diagnostic work-up, and treatment options and outcomes for the various classifications of traumatic peripheral nerve injuries. PMID- 25934192 TI - Complications of compressive neuropathy: prevention and management strategies. AB - Compressive neuropathies of the upper extremity are common and can result in profound disability if left untreated. Nerve releases are frequently performed, but can be complicated by both iatrogenic events and progression of neuropathy. In this review, we examine the management of postoperative complications after 2 common nerve compression release procedures: carpal tunnel release and cubital tunnel release. PMID- 25934194 TI - Management of complications with hand fractures. AB - Both operative and nonoperative treatment of hand fractures can result in numerous complications, including stiffness, malunion, nonunion, arthritis, infection, and complex regional pain syndrome. These complications are frequently encountered and are often challenging to treat. This article systematically outlines the diagnosis and treatment of each of these complications to achieve the best possible outcome for the patient's overall hand function. PMID- 25934195 TI - Management of complications of periarticular fractures of the distal interphalangeal, proximal interphalangeal, metacarpophalangeal, and carpometacarpal joints. AB - Fractures involving the bones of the hand are among the most common injuries in the United States. A significant portion of these fractures are periarticular. Although the great majority of these fractures are treated successfully by nonoperative means, complications arise. We present a comprehensive review of prevention and management of complications of periarticular fractures of the distal interphalangeal, proximal interphalangeal, metacarpophalangeal, and carpometacarpal joints. PMID- 25934196 TI - Management of complications of wrist fractures. AB - This article reviews the most common complications associated with the management of carpal fractures. Discussion focuses on the recognition of commonly "missed" fractures and fracture patterns and the negative sequelae that can result from these delayed diagnoses. The pitfalls of conservative treatment of specific carpal fractures are reviewed, and the most common complications resulting from the operative management of carpal injuries are described. PMID- 25934198 TI - Management of complications of forearm fractures. AB - Forearm fractures may be complicated by the disruption of the distal radioulnar, proximal radioulnar, or radiocapitellar joints. The key principles in treating this unique subset of fractures include early recognition and management of the injury and restoration and maintenance of the anatomic alignment. This articles addresses radial diaphyseal fractures with distal radioulnar joint disruption, proximal ulnar fractures with radiocapitellar disruption, and disruption of the forearm longitudinal axis and how to properly recognize and manage these forearm fracture-dislocations. PMID- 25934199 TI - Management of complications of distal radioulnar joint. AB - The distal radioulnar joint (DRUJ) is a complex structure that participates in forearm rotation and weight-bearing. Myriad disorders affect the DRUJ and present diagnostic and management challenges. Degenerative and posttraumatic arthritis and pain at the DRUJ have been traditionally treated with resection of 1 of the 2 arthritic surfaces. Although the procedure often relieves pain associated with incongruence, it creates a different problem by changing the overall dynamics of the forearm rotation and weight-bearing, resulting in radioulnar convergence and ulnar translation of the carpus. This article focuses on the management of painful radioulnar convergence after distal ulnar resections. PMID- 25934197 TI - Management of complications of distal radius fractures. AB - Treating a fracture of the distal radius may require the surgeon to make a difficult decision between surgical treatment and nonsurgical management. The use of surgical fixation has recently increased because of complications associated with conservative treatment. However, conservative action may be necessary depending on certain patient factors. The treating surgeon must be aware of the possible complications associated with distal radius fracture treatments to prevent their occurrence. Prevention can be achieved with a proper understanding of the mechanism of these complications. This article discusses the most recent evidence on how to manage and prevent complications following a fracture of the distal radius. PMID- 25934200 TI - The management of complications of small joint arthrodesis and arthroplasty. AB - Arthrodesis and arthroplasty are surgical options used for the management of pain, stiffness, deformity, and instability related to arthritis and traumatic injury of the small joints of the hand. Arthrodesis and arthroplasty come with a risk of postoperative infection. Superficial soft tissue infections can often be managed with oral antibiotics alone. Deep infections and osteomyelitis frequently require removal of hardware in addition to antibiotics and may require surgical revision once the infection is cleared. Selection of the most appropriate revision technique depends on the underlying cause of the initial failure, patients' functional and outcome needs, and surgeon preference. PMID- 25934201 TI - Management of complications of ligament injuries of the wrist. AB - Despite advances in understanding the anatomy and biomechanics of wrist motion, intrinsic carpal ligament injuries are difficult to diagnose and treat. Even when an accurate diagnosis is made, there is no consensus on the most appropriate and reliable treatment. Injury predisposes to a progressive decline in wrist function and a predictable pattern of degenerative arthritis. To prevent inadequate outcomes, many treatment options exist, all having inherent benefits and complications. This article reviews the complications of intrinsic carpal ligament injuries and complications of their treatment. Methods to prevent and principles to manage the complications are discussed. PMID- 25934202 TI - Management of complications of wrist arthroplasty and wrist fusion. AB - The human wrist joint is unique from functional and anatomic standpoints. Numerous articulations exist within the wrist that allow for many options for partial wrist fusion and arthroplasty. In cases of pancarpal disease, fusion or arthroplasty of the entire wrist joint can be performed. Because of the high functional demand of the wrist, many of these surgical options can fail, leading to devastating complications. This article addresses the types of fusions and arthroplasties available for the wrist and discusses the potential complications associated with each. Methods to prevent these complications are presented and those to treat them once they have occurred are discussed. PMID- 25934203 TI - Management of complications of flexor tendon injuries. AB - Innovations in operative techniques, biomaterials, and rehabilitation protocols have improved outcomes after treatment of flexor tendon injuries. However, despite these advances, treatment of flexor tendon injuries remains challenging. The purpose of this review is to highlight the complications of flexor tendon injuries and review the management of these complications. PMID- 25934204 TI - Management of complications of extensor tendon injuries. AB - Treatment goals for the management of extensor tendon injuries include restoration of function, minimizing disability, and decreasing the risk of complications. These goals can be achieved with an accurate understanding of the zone-specific concerns for extensor tendon injuries, early referral to hand therapy, and active communication between hand surgeons and therapists. This article reviews extensor tendon injuries by zone, outlines optimal management strategies that help prevent complications, and describes the treatment of these complications. PMID- 25934205 TI - Management of complications relating to complex traumatic hand injuries. AB - Complex hand injuries result in local trauma to osseous, neurovascular, and soft tissue structures. The large amount of energy imparted to these tissues may result in complex regional pain syndrome, stiffness, or infection. Unfortunately, a good outcome may not only depend on the technical aspects of the procedure but on the expectations, occupation, age, and other factors that are out of the surgeon's control. The best treatment for these complications is prevention; however, this review offers strategies to combat the complications once they arise. PMID- 25934206 TI - Management of complications relating to finger amputation and replantation. AB - There are many options in the management of fingertip or finger amputations. Injudicious revision amputation may cause complications. These complications can be prevented by tension-free closure of the amputation stump or primary coverage with appropriate flap. Replantation is the best way to keep the original length and maintain digital function. Patent vein repair or venous drainage with bleeding until neovascularization to the replanted part is the key to successful replantation. Prevention and management of complications in replantation and revision amputation increase patients' satisfaction and decrease costs. Research is needed to define new indications of replantation for digital amputation. PMID- 25934207 TI - Management of complications with flap procedures and replantation. AB - Replantation and flap procedures employ microvascular techniques to salvage or reconstruct a severely damaged limb or digit. The most devastating complications include complete or partial flap loss, or replantation failure due to vascular complications. Often, these complications can be prevented by appropriate patient selection, careful surgical planning, meticulous technique, and proper postoperative management. This article discusses complications related to replantation and flap procedures in the upper limb, focusing on preventing and managing these complications. PMID- 25934208 TI - Management of complications of Dupuytren contracture. AB - This evidence-based article discusses the current management options of Dupuytren disease and strategies to avoid and manage any potential complications. Treatment options include fasciectomy, needle fasciotomy/aponeurotomy, and collagenase injection. Complications include digital nerve and artery injury, flexor tendon injury, skin fissures and wound healing complications, hematoma, infection, flare reaction/complex regional pain syndrome, and recurrence. Complication rates, prevention, and management differ with each treatment modality. A detailed understanding of each of these options allows hand surgeons to select the most appropriate treatment for each patient. PMID- 25934209 TI - Infection after hand surgery. AB - Postoperative infections are uncommon after hand surgery. Infection can delay recovery and contribute to scarring and stiffness. Measures intended to reduce the risk of infection after hand surgery include hand washing, skin preparation, sterile technique, and prophylactic antibiotics. The role of prophylactic antibiotics for small, clean, elective hand surgery procedures lasting less than 2 hours is debated. PMID- 25934210 TI - Management of complications of congenital hand disorders. AB - This article reviews treatment and presents complications seen in the treatment of 7 common congenital hand differences, including syndactyly, camptodactyly, ulnar and radial polydactyly, thumb hypoplasia, radial longitudinal deficiency, and epidermolysis bullosa. The management of these conditions is challenging but has evolved over the last several decades with refined understanding of the disease processes and treatments. The goal of this article is to synthesize prior knowledge and provide further insights into these conditions that will help the surgeon avoid treatment complications. PMID- 25934211 TI - The word complication strikes fear in all of us. Introduction. PMID- 25934212 TI - [Highlight on clinical research in pediatrics]. PMID- 25934213 TI - [Contribution of reflectance confocal microscopy for the diagnosis of junctional naevus]. PMID- 25934214 TI - [High-definition optical coherence tomography: Presentation of the technique and applications in dermatology]. PMID- 25934215 TI - The mouse brain metabolome: region-specific signatures and response to excitotoxic neuronal injury. AB - Neurodegeneration is a multistep process characterized by a multitude of molecular entities and their interactions. Systems analyses, or omics approaches, have become an important tool in characterizing this process. Although RNA and protein profiling made their entry into this field a couple of decades ago, metabolite profiling is a more recent addition. The metabolome represents a large part or all metabolites in a tissue, and gives a snapshot of its physiology. By using gas chromatography coupled to mass spectrometry, we analyzed the metabolic profile of brain regions of the mouse, and found that each region is characterized by its own metabolic signature. We then analyzed the metabolic profile of the mouse brain after excitotoxic injury, a mechanism of neurodegeneration implicated in numerous neurological diseases. More important, we validated our findings by measuring, histologically and molecularly, actual neurodegeneration and glial response. We found that a specific global metabolic signature, best revealed by machine learning algorithms, rather than individual metabolites, was the most robust correlate of neuronal injury and the accompanying gliosis, and this signature could serve as a global biomarker for neurodegeneration. We also observed that brain lesioning induced several metabolites with neuroprotective properties. Our results deepen the understanding of metabolic changes accompanying neurodegeneration in disease models, and could help rapidly evaluate these changes in preclinical drug studies. PMID- 25934216 TI - The felt presence of other minds: Predictive processing, counterfactual predictions, and mentalising in autism. AB - The mental states of other people are components of the external world that modulate the activity of our sensory epithelia. Recent probabilistic frameworks that cast perception as unconscious inference on the external causes of sensory input can thus be expanded to enfold the brain's representation of others' mental states. This paper examines this subject in the context of the debate concerning the extent to which we have perceptual awareness of other minds. In particular, we suggest that the notion of perceptual presence helps to refine this debate: are others' mental states experienced as veridical qualities of the perceptual world around us? This experiential aspect of social cognition may be central to conditions such as autism spectrum disorder, where representations of others' mental states seem to be selectively compromised. Importantly, recent work ties perceptual presence to the counterfactual predictions of hierarchical generative models that are suggested to perform unconscious inference in the brain. This enables a characterisation of mental state representations in terms of their associated counterfactual predictions, allowing a distinction between spontaneous and explicit forms of mentalising within the framework of predictive processing. This leads to a hypothesis that social cognition in autism spectrum disorder is characterised by a diminished set of counterfactual predictions and the reduced perceptual presence of others' mental states. PMID- 25934217 TI - Nitric oxide augments single Ca(2+) channel currents via cGMP-dependent protein kinase in Kenyon cells isolated from the mushroom body of the cricket brain. AB - Behavioral and pharmacological studies in insects have suggested that the nitric oxide (NO)/cyclic GMP (cGMP) signaling pathway is involved in the formation of long-term memory (LTM) associated with olfactory learning. However, the target molecules of NO and the downstream signaling pathway are still not known. In this study, we investigated the action of NO on single voltage-dependent Ca(2+) channels in the intrinsic neurons known as Kenyon cells within the mushroom body of the cricket brain, using the cell-attached configuration of the patch-clamp technique. Application of the NO donor S-nitrosoglutathione (GSNO) increased the open probability (NPO) of single Ca(2+) channel currents. This GSNO-induced increase was blocked by ODQ, a soluble guanylate cyclase (sGC) inhibitor, suggesting that the NO generated by GSNO acts via sGC to raise cGMP levels. The membrane-permeable cGMP analog 8-Bro-cGMP also increased the NPO of single Ca(2+) channel currents. Pretreatment of cells with KT5823, a protein kinase G blocker, abolished the excitatory effect of GSNO. These results suggest that NO augments the activity of single Ca(2+) channels via the cGMP/PKG signaling pathway. To gain insight into the physiological role of NO, we examined the effect of GSNO on action potentials of Kenyon cells under current-clamp conditions. Application of GSNO increased the frequency of action potentials elicited by depolarizing current injections, indicating that NO acts as a modulator resulting in a stimulatory signal in Kenyon cells. We discuss the increased Ca(2+) influx through these Ca(2+) channels via the NO/cGMP signaling cascade in relation to the formation of olfactory LTM. PMID- 25934218 TI - Leaching characteristics of calcium-based compounds in MSWI Residues: From the viewpoint of clogging risk. AB - Leachate collection system (LCS) clogging caused by calcium precipitation would be disadvantageous to landfill stability and operation. Meanwhile, calcium-based compounds are the main constituents in both municipal solid waste incineration bottom ash (MSWIBA) and stabilized air pollution control residues (SAPCR), which would increase the risk of LCS clogging once these calcium-rich residues were disposed in landfills. The leaching behaviors of calcium from the four compounds and municipal solid waste incineration (MSWI) residues were studied, and the influencing factors on leaching were discussed. The results showed that pH was the crucial factor in the calcium leaching process. CaCO3 and CaSiO3 began leaching when the leachate pH decreased to less than 7 and 10, respectively, while Ca3(PO4)2 leached at pH<12. CaSO4 could hardly dissolve in the experimental conditions. Moreover, the sequence of the leaching rate for the different calcium based compounds is as follows: CaSiO3>Ca3(PO4)2>CaCO3. The calcium leaching from the MSWIBA and SAPCR separately started from pH<7 and pH<12, resulting from CaCO3 and Ca3(PO4)2 leaching respectively, which was proven by the X-ray diffraction results. Based on the leaching characteristics of the different calcium compounds and the mineral phase of calcium in the incineration residues, simulated computation of their clogging potential was conducted, providing the theoretical basis for the risk assessment pertaining to LCS clogging in landfills. PMID- 25934219 TI - Windrow co-composting of natural casings waste with sheep manure and dead leaves. AB - After studying the waste management opportunities in small and medium companies of natural casings, composting has proved more viable and cost effective solution for the valorization of these types of waste, but its feasibility depends on the final product value. This paper investigated a pilot scale program for the windrow co-composting of natural casings waste with sheep manure and dead leaves incorporation. Processing, characterization and application of the final compost were described and the final compost was analyzed for pathogens, metals, nutrients, maturity, and agronomic parameters. The results showed that all test result levels were below the limits specified in the EPA regulations published in Title 40, Section 503, of the Code of Federal Regulations (40 CFR 503). Moreover, the agronomic value tests which include nutrients, organic matter, pH, electrical conductivity, etc. showed that the compost had high organic-matter content and low salt content, all of which indicate good compost characteristics. The ratio of nitrogen (N), phosphorus (P), and potassium (K), or NPK ratio, was measured at 1.6-0.9-0.7. Reported units are consistent with those found on fertilizer formulations. PMID- 25934220 TI - Assessment of municipal solid waste settlement models based on field-scale data analysis. AB - An evaluation of municipal solid waste (MSW) settlement model performance and applicability was conducted based on analysis of two field-scale datasets: (1) Yolo and (2) Deer Track Bioreactor Experiment (DTBE). Twelve MSW settlement models were considered that included a range of compression behavior (i.e., immediate compression, mechanical creep, and biocompression) and range of total (2-22) and optimized (2-7) model parameters. A multi-layer immediate settlement analysis developed for Yolo provides a framework to estimate initial waste thickness and waste thickness at the end-of-immediate compression. Model application to the Yolo test cells (conventional and bioreactor landfills) via least squares optimization yielded high coefficient of determinations for all settlement models (R(2)>0.83). However, empirical models (i.e., power creep, logarithmic, and hyperbolic models) are not recommended for use in MSW settlement modeling due to potential non-representative long-term MSW behavior, limited physical significance of model parameters, and required settlement data for model parameterization. Settlement models that combine mechanical creep and biocompression into a single mathematical function constrain time-dependent settlement to a single process with finite magnitude, which limits model applicability. Overall, all models evaluated that couple multiple compression processes (immediate, creep, and biocompression) provided accurate representations of both Yolo and DTBE datasets. A model presented in Gourc et al. (2010) included the lowest number of total and optimized model parameters and yielded high statistical performance for all model applications (R(2)?0.97). PMID- 25934221 TI - Assessment of co-composting of sludge and woodchips in the perspective of environmental impacts (EASETECH). AB - To reveal potential impacts to environment and human health quantitatively, co composting and utilization of sludge and woodchips were investigated using a life cycle-based model, EASETECH. Three scenarios were assessed through experiments using different material ratios. Emission amounts during co-composting were determined by monitoring data and mass balance. With 100t sludge treatment, co composting showed impacts to acidification (29.9 PE) and terrestrial eutrophication (57.7 PE) mainly for ammonia emission. Compost utilization presented savings on freshwater eutrophication (-1.5 PE) because of phosphorus substitution. With the application of fewer woodchips, impacts to acidification and terrestrial eutrophication decreased because more ammonium was reserved rather than released. All impacts to human toxicity were not significant (8.2+/ 0.6 PE) because the compost was used for urban landscaping rather than farming. Trace gaseous compounds showed marginal impacts to global warming and toxicity categories. The results provide a new perspective and offer evidence for appropriate sludge treatment selection. PMID- 25934222 TI - Celecoxib inhibits Ewing sarcoma cell migration via actin modulation. AB - BACKGROUND: Ewing sarcoma (ES) is an aggressive childhood solid tumor in which 30% of cases are metastatic at presentation, and subsequently carry a poor prognosis. We have previously shown that treatment with celecoxib significantly reduces invasion and metastasis of ES cells in a cyclooxygenase-2-independent fashion. Celecoxib is known to downregulate beta-catenin independently of cyclooxygenase-2. Additionally, the actin cytoskeleton is known to play an important role in tumor micrometastasis. We hypothesized that celecoxib's antimetastatic effect in ES acts via modulation of one of these two targets. METHODS: ES cells were treated with celecoxib, and the levels of beta-catenin and total actin were examined by Western blot and quantitative polymerase chain reaction. Cells were transfected with small interfering RNA targeting beta catenin, and invasion assays were performed. Immunofluorescence staining for beta catenin and F-actin was performed on treated and untreated cells. Additionally, cells were subjected to a wound healing assay to assess migration. RESULTS: Celecoxib had no effect on the messenger RNA or protein levels of beta-catenin but did significantly decrease the amount of total actin within ES cells. Reduction of beta-catenin by small interfering RNA had no effect on invasion, and celecoxib treatment of the beta-catenin depleted cells continued to inhibit invasion. Immunofluorescence staining demonstrated no change in beta-catenin with treatment but did show a significant reduction in the amount of F-actin, as well as morphologic changes of the cells. Wound healing assays demonstrated that celecoxib significantly inhibited migration. CONCLUSIONS: Celecoxib does not exert its antimetastatic effects in ES through alteration of beta-catenin but does significantly modulate the actin cytoskeleton. PMID- 25934223 TI - Patient-Physician Communication and Knowledge Regarding Fertility Issues from German Oncologists' Perspective-a Quantitative Survey. AB - Many people diagnosed with haematologic malignancies are of child-bearing age. Typical treatment courses pose a high risk of infertility, and a lot of people affected by this are in the midst of starting or growing their families. Thus, it is crucial that they are well informed about fertility preservation options and can discuss these with an oncologist early on in the development of their treatment plans. Unfortunately, however, this does not always happen. One hundred twenty oncologists from 37 German adult clinical facilities were surveyed regarding their discussions with young patients about fertility, family planning, and fertility preservation. Almost all of them said that they consider fertility preservation to be an important issue. They also reported several factors as having an influence on the likelihood and practicability of discussing these subjects. Most knew about the existence of cryoconservation of germ cells and the use of GnRH analogues (95 %), but only half of them claimed to have a thorough understanding of these options. Many said they would like to learn more about this and that informational brochures could be helpful. Even though many oncologists do have good working knowledge of the subject, patients of reproductive age are not yet consistently given comprehensive information about the options available to them. To improve oncologists' knowledge of reproductive medicine, cooperation with fertility specialists should be facilitated, and informational leaflets should be made available both to patients and their medical care providers. PMID- 25934224 TI - Promiscuity and selectivity of bitter molecules and their receptors. AB - Bitter taste is essential for survival, as it protects against consuming poisonous compounds, which are often bitter. Bitter taste perception is mediated by bitter taste receptors (TAS2Rs), a subfamily of G-protein coupled receptors (GPCRs). The number of TAS2R subtypes is species-dependent, and varies from 3 in chicken to 50 in frog. TAS2Rs present an intriguing case for studying promiscuity: some of the receptors are still orphan, or have few known agonists, while others can be activated by numerous, structurally dissimilar compounds. The ligands also vary in the repertoire of TAS2Rs that they activate: some bitter compounds are selective toward a single TAS2R, while others activate multiple TAS2Rs. Selectivity/promiscuity profile of bitter taste receptors and their compounds was explored by a chemoinformatic approach. TAS2R-promiscuous and TAS2R selective bitter molecules were found to differ in chemical features, such as AlogP, E-state, total charge, number of rings, globularity, and heavy atom count. This allowed the prediction of bitter ligand selectivity toward TAS2Rs. Interestingly, while promiscuous TAS2Rs are activated by both TAS2R-promiscuous and TAS2R-selective compounds, almost all selective TAS2Rs in human are activated by promiscuous compounds, which are recognized by other TAS2Rs anyway. Thus, unique ligands, that may have been the evolutionary driving force for development of selective TAS2Rs, still need to be unraveled. PMID- 25934225 TI - Anti-dormant mycobacterial activity and target analysis of nybomycin produced by a marine-derived Streptomyces sp. AB - In the course of our search for anti-dormant Mycobacterial substances, nybomycin (1) was re-discovered from the culture broth of a marine-derived Streptomyces sp. on the bioassay-guided separation. Compound 1 showed anti-microbial activity against Mycobacterium smegmatis and Mycobacterium bovis BCG with the MIC of 1.0MUg/mL under both actively growing aerobic conditions and dormancy inducing hypoxic conditions. Compound 1 is also effective to Mycobacterium tuberculosis including the clinically isolated strains. The mechanistic analysis indicated that 1 bound to DNA and induces a unique morphological change to mycobacterial bacilli leading the bacterial cell death. PMID- 25934227 TI - Fragmentation of GW4064 led to a highly potent partial farnesoid X receptor agonist with improved drug-like properties. AB - The ligand activated transcription factor farnesoid X receptor (FXR) is a crucial regulator of several metabolic and inflammatory pathways and its activation by agonistic ligands seems a valuable therapeutic approach for many disorders. Most known non-steroidal FXR agonists however, have limitations that hinder their clinical development and novel FXR ligands are required. Evaluation of the co crystal structures of the widely used FXR agonist GW4064 and related compounds in complex with the FXR ligand binding domain indicated that their disubstituted isoxazole moiety is especially relevant for FXR activation. By investigation of GW4064-fragments missing the aromatic tail, we discovered a highly potent and soluble partial FXR agonist (14, ST-1892) as well as a fluorescent FXR ligand (15) as potential pharmacological tool. PMID- 25934226 TI - Synthesis and molecular docking of 1,2,3-triazole-based sulfonamides as aromatase inhibitors. AB - A series of 1,4-disubstituted-1,2,3-triazoles (13-35) containing sulfonamide moiety were synthesized and evaluated for their aromatase inhibitory effects. Most triazoles with open-chain sulfonamide showed significant aromatase inhibitory activity (IC50=1.3-9.4MUM). Interestingly, the meta analog of triazole benzene-sulfonamide (34) bearing 6,7-dimethoxy substituents on the isoquinoline ring displayed the most potent aromatase inhibitory activity (IC50=0.2MUM) without affecting normal cell. Molecular docking of these triazoles against aromatase revealed that the compounds could snugly occupy the active site of the enzyme through hydrophobic, pi-pi stacking, and hydrogen bonding interactions. The potent compound 34 was able to form hydrogen bonds with Met374 and Ser478 which were suggested to be the essential residues for the promising inhibition. The study provides compound 34 as a potential lead molecule of anti-aromatase agent for further development. PMID- 25934228 TI - Studies of binding interactions between Dufulin and southern rice black-streaked dwarf virus P9-1. AB - Southern rice black-streaked dwarf virus (SRBSDV) is an important rice virus that can cause considerable crop losses. During infection, SRBSDV P9-1 accumulates viroplasms in SRBSDV-infected plant and insect cells, which may facilitate the formation of SRBSDV particles. Our field trial results showed that Dufulin inhibited infection activity in SRBSDV-infected rice. However it is not clear how Dufulin inhibits the infection activity. Therefore we studied the interactions between Dufulin and SRBSDV using P9-1 as a potential target, and found that Dufulin inhibited SRBSDV P9-1 gene expression and had a micromole affinity for the arginine 175 residue. Substituting arginine with glycine resulted in a mutant that was significantly less sensitive to Dufulin. Based on these results, we speculate that Dufulin inhibits the virulence of SRBSDV by binding with arginine 175 in the internal pore of P9-1 octameric protein. PMID- 25934229 TI - Synthesis and evaluation of selegiline derivatives as monoamine oxidase inhibitor, antioxidant and metal chelator against Alzheimer's disease. AB - A series of compounds with monoamine oxidase inhibition and biometal chelation activities were designed, synthesised and evaluated as agents against Alzheimer's disease. The in vitro assay shows that most target compounds exhibit good MAO-B activities with submicromolar IC50 values and antioxidant activity (1.49-5.67 ORAC-FL values). The selected compounds were used to determine the biometal chelating ability using UV-vis spectrometry and high-resolution mass spectrometry, which confirm that they can effectively interact with copper(II), iron(II) and zinc(II). The ThT fluorescence binding assay indicates that the synthetic compounds can inhibit Cu(II)-induced Abeta1-42 aggregation. The parallel artificial membrane permeation assay shows that most target compounds can cross the BBB. Based on these results, compound 8a was selected as a potential multifunctional agent for the treatment of AD. PMID- 25934231 TI - Golden Retriever dogs with neuronal ceroid lipofuscinosis have a two-base-pair deletion and frameshift in CLN5. AB - We studied a recessive, progressive neurodegenerative disease occurring in Golden Retriever siblings with an onset of signs at 15 months of age. As the disease progressed these signs included ataxia, anxiety, pacing and circling, tremors, aggression, visual impairment and localized and generalized seizures. A whole genome sequence, generated with DNA from one affected dog, contained a plausibly causal homozygous mutation: CLN5:c.934_935delAG. This mutation was predicted to produce a frameshift and premature termination codon and encode a protein variant, CLN5:p.E312Vfs*6, which would lack 39 C-terminal amino acids. Eighteen DNA samples from the Golden Retriever family members were genotyped at CLN5:c.934_935delAG. Three clinically affected dogs were homozygous for the deletion allele; whereas, the clinically normal family members were either heterozygotes (n = 11) or homozygous for the reference allele (n = 4). Among archived Golden Retrievers DNA samples with incomplete clinical records that were also genotyped at the CLN5:c.934_935delAG variant, 1053 of 1062 were homozygous for the reference allele, 8 were heterozygotes and one was a deletion-allele homozygote. When contacted, the owner of this homozygote indicated that their dog had been euthanized because of a neurologic disease that progressed similarly to that of the affected Golden Retriever siblings. We have collected and stored semen from a heterozygous Golden Retriever, thereby preserving an opportunity for us or others to establish a colony of CLN5-deficient dogs. PMID- 25934230 TI - Diversity of active microbial communities subjected to long-term exposure to chemical contaminants along a 40-year-old sediment core. AB - In estuarine ecosystems, metallic and organic contaminants are mainly associated with fine grain sediments which settle on mudflats. Over time, the layers of sediment accumulate and are then transformed by diagenetic processes mainly controlled by microbial activity, recording the history of the estuary's chemical contamination. In an environment of this specific type, we investigated the evolution of the chemical contamination and the structure of both total and active microbial communities, based on PhyloChip analysis of a 4.6-m core corresponding to a 40-year sedimentary record. While the archaeal abundance remained constant along the core, a decrease by one order of magnitude in the bacterial abundance was observed with depth. Both total and active microbial communities were dominated by Proteobacteria, Actinobacteria, and Firmicutes in all sediment samples. Among Proteobacteria, alpha-Proteobacteria dominated both total (from 37 to 60 %) and metabolically active (from 19.7 to 34.6 %) communities, including the Rhizobiales, Rhodobacter, Caulobacterales, and Sphingomonadales orders. Co-inertia analysis revealed a relationship between polycyclic aromatic hydrocarbons, zinc and some polychlorobiphenyls concentrations, and the structure of total and active microbial communities in the oldest and most contaminated sediments (from 1970 to 1975), suggesting that long-term exposure to chemicals shaped the structure of the microbial community. PMID- 25934232 TI - Cholesterol homeostasis and autophagic flux in perifosine-treated human hepatoblastoma HepG2 and glioblastoma U-87 MG cell lines. AB - Perifosine exerts an antiproliferative effect on HepG2 and U-87 MG cells and also interferes with the transport of cholesterol from the plasma membrane to the endoplasmic reticulum (ER). Recently we demonstrated that exposure of U-87 MG cells to perifosine causes an accumulation of autophagosomes. We have now expanded the study to establish the molecular mechanism by which perifosine interferes with the autophagic process. Using transmission electron microscopy, we report that the treatment of HepG2 and U-87 MG cells with perifosine causes an intense cytoplasmic vacuolization identified as autophagic vesicles. The accumulation of autophagosomes induced by perifosine is due to a blockage of the autophagic flux, thereby affecting cell proliferation. Perifosine also provokes a differential ER stress response in the HepG2 and U-87 MG cell lines. We have also demonstrated a relationship between the deregulation of cholesterol transport and the inhibition of the autophagic flux prompted by perifosine. Thus our findings clearly demonstrate that perifosine impairs the autophagic flux in HepG2 and U-87 MG cells, which is related to defects in intracellular cholesterol transport. Our study is relevant for anticancer therapy because tumour cells exhibit autophagy as a pro-survival mechanism. Further research to identify the precise mechanisms of autophagy maturation and the role of cholesterol may provide new insights into the antiproliferative action of perifosine. PMID- 25934233 TI - Bilateral false-positive tube thoracostomy in helicopter emergency medical service: letter in reply. PMID- 25934235 TI - Targeted temperature management: part 1. PMID- 25934234 TI - A 66-year-old woman with high-risk pulmonary embolism. PMID- 25934236 TI - A little sex in the workplace. PMID- 25934237 TI - Articles that may change your practice: the benefits of helicopter emergency medical services in trauma. PMID- 25934238 TI - Prevalence of intubation rescue by air medical personnel during transfers from rural emergency departments. AB - OBJECTIVE: Non-emergency-trained providers in rural emergency departments (ED) often lack the skills required for emergency resuscitations and rely on air medical transport teams to provide the initial airway stabilization of these patients. In this study, we determined the prevalence with which endotracheal intubations are required of air medical personnel upon arrival to rural EDs including intubations that were first attempted by the local provider. METHODS: A retrospective database review was conducted of all air medical transfers from rural hospitals for a 28-month period. Those patients requiring an airway were categorized according to which provider initiated the intubation procedure. The prevalence of intubations performed by air medical and local providers was recorded as the percent of the total number of intubations. RESULTS: There were a total of 217 patients from 11 rural EDs requiring airway support. Air medical personnel were responsible for 85% of the intubations. Alternative airway support was necessary in 5% of the patients after unsuccessful intubation attempts. The failed intubations tended to be slightly older and female. CONCLUSION: Our study suggests that the vast majority of the intubations for patients requiring a helicopter evacuation from these rural settings are performed by the air medical personnel. PMID- 25934239 TI - Medical Emergency Workload of a Regional UK HEMS Service. AB - OBJECTIVE: Regionalized trauma networks have been established in England to centralize specialist care at dedicated centers of excellence throughout the country. Helicopter emergency medical services (HEMS) in the West Midlands region have been redesigned to form an integrated component of such systems. The continued use of such valuable and scarce resources for medical emergencies requires evaluation. METHODS: A retrospective review of mission data for a regional Air Ambulance Service in England over a two year period. RESULTS: Medical emergencies continue to contribute a large proportion of the overall workload of the service. Requirement for advanced interventions at the scene was rare, with less than 10% of patients attended by HEMS teams having care needs that fall beyond the scope of standard paramedic practice. CONCLUSION: Dynamic solutions are needed to ensure that HEMS support for cases of medical emergency are appropriately targeted to incidents in which clinical benefit is conferred to the patient. Intelligent tasking of appropriate resources has the potential to improve the HEMS response to medical emergencies while optimizing the availability of resources to respond to other incidents, most notably cases of major trauma. PMID- 25934240 TI - An 8-year-old boy with altered mental status. AB - Management of an acutely ill pediatric patient with undifferentiated altered mental status is a common challenge facing air medical crewmembers. The transport team is often the vital link between the referring agency and a tertiary care center; it is incumbent upon the team to be able to meet the challenges of patient management including airway management, providing hemodynamic support, and addressing presenting symptoms. This case presents a child with altered mental status and seizure activity requiring advanced interventions and support. His hospital course is described and reveals an encephalopathy caused by the Bartonella henselae bacterium also known as cat-scratch disease. This case shows the pathology, symptomology, and management along with the importance of proper management and interventions by air medical crewmembers to maximize outcomes. PMID- 25934241 TI - A 29-year-old with gunshot wound to the spine. AB - A mobile intensive care unit (MICU) was dispatched to transport a critically injured patient with a gunshot wound to the spine from a community hospital to a level I trauma center. The patient transported suffered from a gunshot wound to the left posterior midthoracic region. The patient experienced transient traumatic cardiac arrest before transfer. The MICU crew arrived at the emergency department and found the patient intubated and with a chest tube. Fluid resuscitation was continued, and the patient was transported. At the level I trauma center, the patient was admitted in critical condition. The patient was declared brain-dead on postinjury day 8. Spinal immobilization in penetrating trauma is a controversial topic. This patient met the historic clinical indication for spinal immobilization. The patient's injuries included multiple cervical vertebrae fractures and spinal cord disruption from the penetrating projectile, with the bullet remaining in the patient. Interfacility management by the MICU crew was focused on adequate ventilations and immobilization while continuing to address the patient's shock state. Penetrating injuries to the spinal cord can be devastating. Being aware of the pathophysiology of penetrating spinal injuries, along with current evidence-based practice, will assist providers in making sound clinical decisions for their patients. PMID- 25934242 TI - Lumboperitoneal shunt surgery for idiopathic normal pressure hydrocephalus (SINPHONI-2): an open-label randomised trial. AB - BACKGROUND: Lumboperitoneal shunt surgery has the potential to alleviate symptoms of normal pressure hydrocephalus but the benefits of such surgery have not been tested in a randomised trial. The aim of this trial was to determine the safety and efficacy of the lumboperitoneal shunt surgery for this disorder. METHODS: For the open-label randomised SINPHONI-2 trial, eligible participants (60-85 years of age) with idiopathic normal pressure hydrocephalus, with ventriculomegaly, and tightness of the high-convexity and medial subarachnoid spaces on MRI, were recruited from 20 neurological and neurosurgical centres in Japan. Enrolled participants were randomly assigned in a 1:1 ratio according to a random code generated by the trial statistician, with a permuted block design (using a block size of 4 or 6) within each centre, to receive lumboperitoneal shunt surgery within 1 month after randomisation, or to surgery postponed for 3 months. Patients and assessors were not masked to treatment assignment. The primary endpoint was favourable outcome, defined as an improvement of one point or more on the modified Rankin scale (mRS) at 3 months after randomisation, analysed by intention to treat, and the main secondary endpoint was the same outcome 12 months after surgery, analysed per protocol. This trial is registered with the University Hospital Medical Information Network Clinical Trials Registry (UMIN CTR), number UMIN000002730. FINDINGS: Between March 1, 2010, and Oct 19, 2011, 93 patients with idiopathic normal pressure hydrocephalus were enrolled and randomly assigned to the immediate treatment group (n=49) or the postponed treatment group (n=44). More patients in the immediate treatment group than in the postponed treatment group had an improvement of one point or more on the mRS at 3 months: 32 (65%) of 49 in the immediate group vs 2 (5%) of 44 in the postponed group (difference 61% [95% CI 42-68]; p<0.0001). The number of patients who had an improvement of one point or more on the mRS at 12 months after surgery was similar between the two groups: 30 (67%) of 45 patients in the immediate group vs 22 (58%) of 38 in the postponed group (difference 9% [95% CI -14 to 31]; p=0.496). The proportions of patients with serious adverse events did not differ significantly between the groups during the 3 months post-randomisation (7 [15%] of 46 in the immediate group vs 1 [2%] of 42 in the postponed group; p=0.060). During the 12 months after surgery, 19 (22%) of 87 patients had serious adverse events, the most common of which was cerebral infarction (six patients [7%]). INTERPRETATION: Our results suggest that lumboperitoneal shunt surgery might be beneficial for patients with idiopathic normal pressure hydrocephalus and, if these findings are confirmed in larger studies, could be a first-line treatment option for this disease. FUNDING: Johnson & Johnson and Nihon Medi-Physics. PMID- 25934243 TI - Improving research and care for patients with idiopathic NPH. PMID- 25934244 TI - Autologous blood injection for treatment of chronic recurrent TMJ dislocation: is it successful? Is it safe enough? A systematic review. AB - PURPOSE: The purpose of this article is to review the English literature about the efficacy and safety of autologous blood injection in treating patients suffering from chronic recurrent temporomandibular joint dislocation. In this article, we highlight the key trials and recent directions about this modality and discuss about the mechanism, advantages, and disadvantages of this approach. MATERIALS AND METHODS: A literature search was performed using PubMed, Medline, and Ovid Medline databases to identify articles reporting on the injection of autologous blood for treatment of chronic recurrent dislocation of temporomandibular joint. Other references cited in the retrieved reports, as well as the "related articles" tool in PubMed Medline, were also checked to improve the search and, if relevant, were included in the study. The search was restricted to articles published in the English language. RESULTS: Seven studies meeting the inclusion criteria were reviewed. The selected articles included four prospective clinical trials and three case report articles. CONCLUSION: There are a few articles about the clinical use of autologous blood for treating patients with chronic recurrent temporomandibular joint dislocation. Reviewing of the literature shows that there are successful results about this modality, but there are still some concerns about it in terms of the effect of the injected blood on the articular cartilage and formation of fibrous or bony ankylosis. PMID- 25934245 TI - Primary amelanotic mucosal melanoma of the oronasal region: report of two new cases and literature review. AB - Primary amelanotic mucosal melanoma is a rare entity with challenging histopathological features. Because these tumors are thought to be biologically more aggressive, they have a poorer prognosis than that of pigmented melanomas. In this work, we present a literature review about the clinical, histopathological, and immunohistochemical features of primary amelanotic mucosal melanoma of the oronasal region and report two new cases. Amelanotic mucosal melanoma commonly affects men in the seventh decade of life and tend to have a poor prognosis, as seen by the high incidence of metastasis, recurrences, and, ultimately, death. There is a similar pattern in the clinic-pathological predilections (such as age, gender, primary site, and metastatic potential) of amelanotic mucosal melanoma when comparing with data reported for pigmented lesions. This work reinforces knowledge about amelanotic mucosal melanomas and epidemiologic predilections. The optimal management of this lesion remains controversial. PMID- 25934247 TI - Electromyography assessment in zygomaticomaxillary complex fractures. AB - OBJECTIVE: The aim of this study was to assess the activity of the masseter and temporalis muscles using surface electromyography (EMG) in patients with zygomaticomaxillary complex (ZMC) fractures. PATIENTS AND METHODS: This prospective study was carried out on 25 patients who had ZMC fractures. Fifteen patients were managed by open reduction and rigid fixation (ORIF) using titanium miniplates. This study, using surface electromyography, analyzed the activity of the masseter and temporalis muscles of 25 patients with ZMC fractures; 15 of them were surgically treated under general anesthesia (GA). Evaluations were made before surgery and 6 weeks after surgery by recording the mean of muscle contraction of 20 motor unit action potential (MUAP) against resistance, and statistical analyses were performed. RESULTS: A significant EMG difference between the normal and ZMC fracture sides was found (P < 0.0001) for both masseter and temporalis muscles and was significantly improved after ORIF. However, postoperative EMV values of the repaired side was significantly less than measured postoperatively in the normal side (P < 0.0001) for both muscles. CONCLUSION: ZMC fractures significantly diminish muscular activity of the masseter and temporalis and even though significant recovery of muscle activity was revealed after 6 weeks, it is still less than normal activity, highlighting the importance of postoperative rehabilitation. PMID- 25934246 TI - Predictors of blood loss during orthognathic surgery: outcomes from a teaching institution. AB - PURPOSE: The objective of the study was to correlate different orthognathic surgical procedures with operating time and blood loss, reported from an accredited resident training institution. METHODS: Ninety-five patient records were evaluated retrospectively. Individual blood volume, percent blood volume lost (BVL), and estimated blood loss (EBL) for each patient were recorded and correlated with operating time (OT). Statistics included independent t tests, one way analysis of variance, and linear regression. RESULTS: The mean OT for all procedures was 203 min with mean blood loss 556 ml. Mean EBL for males was 676 ml versus 468 ml for females. Overall BVL was 12.4 %, while for males, BVL was 13.3 % compared to 11.8 % for females. For a single orthognathic procedure (n = 45), mean OT 145 min., EBL 414 ml, and BVL 9.0 %; two procedures (n = 41), mean OT was 239 min., EBL 659 ml, and BVL 15 %; three procedures (n = 9), mean OT 328 min, EBL 793 ml, and BVL was 17 %. CONCLUSION: Examination of individual procedures suggests a shorter OT for Le Fort I procedures with slightly greater EBL. Concomitant orthognathic procedures are associated with greater OT and EBL. Blood volume should be calculated for male and female patients separately. Percent BVL can be predicted based on OT using a basic equation. PMID- 25934248 TI - Gauze vs XSTAT in wound packing for hemorrhage control. PMID- 25934249 TI - Suprasellar chordoid neoplasm with expression of thyroid transcription factor 1: evidence that chordoid glioma of the third ventricle and pituicytoma may form part of a spectrum of lineage-related tumors of the basal forebrain. AB - Chordoid glioma of the third ventricle is a rare neuroepithelial tumor characterized by a unique histomorphology and exclusive association with the suprasellar/third ventricular compartment. Variously interpreted as either astrocytic- or ependymal-like, and speculatively ascribed to the lamina terminalis/subcommissural organ, its histogenesis remains, nevertheless, unsettled. Here, we report on a suprasellar chordoid glioma occurring in a 52 year-old man. Although displaying otherwise typical morphological features, the tumor was notable for expression of thyroid transcription factor 1, a marker of tumors of pituicytic origin in the context of the sellar region. We furthermore found overlapping immunoprofiles of this example of chordoid glioma and pituicytic tumors (pituicytoma and spindle cell oncocytoma), respectively. Specifically, phosphorylated ribosomal protein S6, a marker of mTOR pathway activation, was expressed in both groups. Based on these findings, we suggest that chordoid glioma and pituicytic tumors may form part of a spectrum of lineage related neoplasms of the basal forebrain. PMID- 25934250 TI - Molecular alterations of appendiceal serrated lesions. PMID- 25934251 TI - Overexpressed GRP78 affects EMT and cell-matrix adhesion via autocrine TGF beta/Smad2/3 signaling. AB - Glucose-regulated protein of 78kD (GRP78) is a multifunctional protein belonging to the heat shock protein 70 family. Overexpression of GRP78 triggered by environmental and physiological stresses is positively correlated with the occurrence and progression of various tumors, but the molecular mechanisms have not been well established. The present study indicated that overexpression of GRP78 in colon cancer cells could promote cell-matrix adhesion through the upregulation of fibronectin, integrin-beta1 and phosphorylated FAK. Meanwhile, it resulted in a visible epithelial-mesenchymal transition in DLD1 cells, and the Snail-2 played the key role during the process. More importantly, the data indicated that GRP78 overexpression facilitated the expression and secretion of TGF-beta1, which further activated the downstream Smad2/3 signaling module to effectuate the cell-matrix adhesion and epithelial-mesenchymal transition. Taken together, this study provides a novel molecular mechanism involving in the effects of GRP78 on colon cancer metastasis. PMID- 25934252 TI - Trichinella britovi in a red fox (Vulpes vulpes) from Portugal. AB - Trichinellosis is one of the most important foodborne parasitic zoonoses, caused by nematodes of the genus Trichinella. Pigs and other domestic and wild animals, including red foxes (Vulpes vulpes), are sources of Trichinella infection for human beings. Trichinella britovi is the major agent of infection in sylvatic animals and the most important species circulating in the European wildlife. The present study aimed at assessing Trichinella spp. infection in red foxes from the North of Portugal. Forty-seven carcasses of wild red foxes shot during the official hunting season or killed in road accidents were obtained between November 2008 and March 2010. In order to identify the presence of Trichinella spp. larvae in red foxes, an individual artificial digestion was performed using approximately 30 g of muscle samples. Larvae of Trichinella spp. were detected in one (2.1%) out of the 47 assessed foxes. After a multiplex polymerase chain reaction analysis, T. britovi was molecularly identified as the infecting species. The recognition of T. britovi in a red fox confirms that a sylvatic cycle is present in the North of Portugal and that the local prevalence of Trichinella infection in wildlife must not be ignored due to its underlying zoonotic risks. PMID- 25934253 TI - Maintenance of Certification. PMID- 25934254 TI - A Solution Is Worth 1,000 Criticisms. PMID- 25934255 TI - Extension of the Dermal Sensitisation Threshold (DST) approach to incorporate chemicals classified as reactive. AB - The evaluation of chemicals for their skin sensitising potential is an essential step in ensuring the safety of ingredients in consumer products. Similar to the Threshold of Toxicological Concern, the Dermal Sensitisation Threshold (DST) has been demonstrated to provide effective risk assessments for skin sensitisation in cases where human exposure is low. The DST was originally developed based on a Local Lymph Node Assay (LLNA) dataset and applied to chemicals that were not considered to be directly reactive to skin proteins, and unlikely to initiate the first mechanistic steps leading to the induction of sensitisation. Here we have extended the DST concept to protein reactive chemicals. A probabilistic assessment of the original DST dataset was conducted and a threshold of 64 MUg/cm(2) was derived. In our accompanying publication, a set of structural chemistry based rules was developed to proactively identify highly reactive and potentially highly potent materials which should be excluded from the DST approach. The DST and rule set were benchmarked against a test set of chemicals with LLNA/human data. It is concluded that by combining the reactive DST with knowledge of chemistry a threshold can be established below which there is no appreciable risk of sensitisation for protein-reactive chemicals. PMID- 25934257 TI - Subject-specific finite element model with an optical tracking system in total hip replacement surgery. AB - Intra-operative peri-prosthetic femoral fractures are a significant concern in total hip arthroplasty and can occur at any time during surgery, with the highest incidence during implant insertion. This study combines subject-specific finite element analysis modeling with an optical tracking system to characterize the resultant strain in the bone and results of impaction during total hip replacement surgery. The use of ABG II femoral stem (Stryker Orthopaedics, Mahwah, NJ, USA) in the model yielded the following results. Hammer velocity was measured experimentally using a three-dimensional optical tracking system and these data were input into the finite element analysis model so that intra operative loading scenario could be simulated. A quasi-static explicit simulation and a dynamic loading step using two implant-bone interface friction (0.1 and 0.4 friction coefficients) states were simulated. The maximum swing velocity of a mallet was experimentally measured at 1.5 m/s and occurred just before impaction of the hammer with implant introducer. Two friction states resulted in different results with the lower friction coefficient generating higher strains in the anterior regions of the model and higher displacement of the implant with respect to the femur when compared to the high friction state. PMID- 25934256 TI - Method for the determination of ammonium in cigarette tobacco using ion chromatography. AB - Ammonia and other alkaline substances have been postulated to be important in cigarette design. The most significant potential contribution of ammonia is a possible interaction with the native, protonated nicotine in the smoke. Ammonia is more alkaline than nicotine and could facilitate a shift in the acid/base equilibrium where a fraction of the total nicotine converts to the more lipophilic, non-protonated form. This non-protonated, or free-base, form of nicotine absorbs more efficiently across membranes, resulting in more rapid delivery to the smoker's bloodstream. Ammonia and other potential ammonia sources, such as additives like diammonium phosphate, could influence the acid base dynamics in cigarette smoke and ultimately the rate of nicotine delivery. To examine and characterize the ammonia content in modern cigarettes, we developed a fast, simple and reliable ion chromatography based method to measure extractable ammonia levels in cigarette filler. This approach has minimal sample preparation and short run times to achieve high sample throughput. We quantified ammonia levels in tobacco filler from 34 non-mentholated cigarette brands from 3 manufacturers to examine the ranges found across a convenience sampling of popular, commercially available domestic brands and present figures of analytical merit here. Ammonia levels ranged from approximately 0.9 to 2.4mg per gram of cigarette filler between brands and statistically significance differences were observed between brands and manufacturers. Our findings suggest that ammonia levels vary by brand and manufacturer; thus in domestic cigarettes ammonia could be considered a significant design feature because of the potential influence on smoke chemistry. PMID- 25934258 TI - Physiological outflow boundary conditions methodology for small arteries with multiple outlets: a patient-specific hepatic artery haemodynamics case study. AB - Physiological outflow boundary conditions are necessary to carry out computational fluid dynamics simulations that reliably represent the blood flow through arteries. When dealing with complex three-dimensional trees of small arteries, and therefore with multiple outlets, the robustness and speed of convergence are also important. This study derives physiological outflow boundary conditions for cases in which the physiological values at those outlets are not known (neither in vivo measurements nor literature-based values are available) and in which the tree exhibits symmetry to some extent. The inputs of the methodology are the three-dimensional domain and the flow rate waveform and the systolic and diastolic pressures at the inlet. The derived physiological outflow boundary conditions, which are a physiological pressure waveform for each outlet, are based on the results of a zero-dimensional model simulation. The methodology assumes symmetrical branching and is able to tackle the flow distribution problem when the domain outlets are at branches with a different number of upstream bifurcations. The methodology is applied to a group of patient-specific arteries in the liver. The methodology is considered to be valid because the pulsatile computational fluid dynamics simulation with the inflow flow rate waveform (input of the methodology) and the derived outflow boundary conditions lead to physiological results, that is, the resulting systolic and diastolic pressures at the inlet match the inputs of the methodology, and the flow split is also physiological. PMID- 25934259 TI - Effect of SiC interlayer between Ti6Al4V alloy and hydroxyapatite films. AB - Bioactive coatings are frequently used to improve the osseointegration of the metallic implants used in dentistry or orthopaedics. Among different types of bioactive coatings, hydroxyapatite (Ca10(PO4)6(OH)2) is one of the most extensively used due to its chemical similarities to the components of bones and teeth. In this article, production and characterization of hydroxyapatite films deposited on Ti6Al4V alloy prepared by magnetron sputtering were reported. Besides, SiC was deposited on substrate surface to study the interlayer effect. Obtained coatings were annealed at 600 degrees C for 30 and 120 min in a mixed atmosphere of N2 + H2O vapours with the heating rate of 12 degrees C min(-1). The effects of SiC interlayer and heat treatment parameters on the structural, mechanical and corrosion properties were investigated. After heat treatment process, the crystalline hydroxyapatite was obtained. Additionally, cell viability tests were performed. The results show that the presence of the SiC interlayer contributes a decrease in surface roughness and improves the mechanical properties and corrosion performance of the hydroxyapatite coatings. Biological properties were not affected by the presence of the SiC interlayer. PMID- 25934260 TI - Automated hand thermal image segmentation and feature extraction in the evaluation of rheumatoid arthritis. AB - The aim of the study was (1) to perform an automated segmentation of hot spot regions of the hand from thermograph using the k-means algorithm and (2) to test the potential of features extracted from the hand thermograph and its measured skin temperature indices in the evaluation of rheumatoid arthritis. Thermal image analysis based on skin temperature measurement, heat distribution index and thermographic index was analyzed in rheumatoid arthritis patients and controls. The k-means algorithm was used for image segmentation, and features were extracted from the segmented output image using the gray-level co-occurrence matrix method. In metacarpo-phalangeal, proximal inter-phalangeal and distal inter-phalangeal regions, the calculated percentage difference in the mean values of skin temperatures was found to be higher in rheumatoid arthritis patients (5.3%, 4.9% and 4.8% in MCP3, PIP3 and DIP3 joints, respectively) as compared to the normal group. k-Means algorithm applied in the thermal imaging provided better segmentation results in evaluating the disease. In the total population studied, the measured mean average skin temperature of the MCP3 joint was highly correlated with most of the extracted features of the hand. In the total population studied, the statistical feature extracted parameters correlated significantly with skin surface temperature measurements and measured temperature indices. Hence, the developed computer-aided diagnostic tool using MATLAB could be used as a reliable method in diagnosing and analyzing the arthritis in hand thermal images. PMID- 25934261 TI - Epidemiological survey of Angiostrongylus vasorum in dogs and slugs around a new endemic focus in Scotland. AB - The nematode parasite Angiostrongylus vasorum is an increasingly important cause of respiratory and other diseases in dogs. Geographical spread from previously limited endemic foci has occurred rapidly. This paper investigates parasite epidemiology around the location of the first reported case in Scotland in 2009: by detection of A vasorum-specific DNA in gastropod intermediate hosts, and in dogs circulating DNA and specific antibodies, and first stage larvae in faeces. Overall prevalence in gastropods was 6.7 per cent (16/240), with parasite DNA found in slugs in the Arion ater and Arion hortensis species aggregates and the snail Helix aspersa (syn. Cornu aspersum). Of 60 dogs presenting with clinical signs compatible with angiostrongylosis, none tested positive using PCR on peripheral blood or Baermann test on faeces, and none of 35 tested for circulating anti-A vasorum antibodies were positive. PCR prevalence in gastropods was highest (11 per cent) in the park frequented by the canine angiostrongylosis index case. Molecular survey for infection in gastropods is a potentially informative and efficient method for characterising the distribution of A vasorum and therefore local risk of canine infection. However, there appears to be a complex relationship between prevalence in gastropods and emergence of canine clinical disease, which requires further work to advance understanding of parasite transmission and geographical disease spread. PMID- 25934262 TI - Visual weight estimation and the risk of underdosing dairy cattle. PMID- 25934263 TI - CAST: An automated segmentation and tracking tool for the analysis of transcriptional kinetics from single-cell time-lapse recordings. AB - Fluorescence and bioluminescence time-lapse imaging allows to investigate a vast range of cellular processes at single-cell or even subcellular resolution. In particular, time-lapse imaging can provide uniquely detailed information on the fine kinetics of transcription, as well as on biological oscillations such as the circadian and cell cycles. However, we face a paucity of automated methods to quantify time-lapse imaging data with single-cell precision, notably throughout multiple cell cycles. We developed CAST (Cell Automated Segmentation and Tracking platform) to automatically and robustly detect the position and size of cells or nuclei, quantify the corresponding light signals, while taking into account both cell divisions (lineage tracking) and migration events. We present here how CAST analyzes bioluminescence data from a short-lived transcriptional luciferase reporter. However, our flexible and modular implementation makes it easily adaptable to a wide variety of time-lapse recordings. We exemplify how CAST efficiently quantifies single-cell gene expression over multiple cell cycles using mouse NIH3T3 culture cells with a luminescence expression driven by the Bmal1 promoter, a central gene of the circadian oscillator. We further illustrate how such data can be used to quantify transcriptional bursting in conditions of lengthened circadian period, revealing thereby remarkably similar bursting signature compared to the endogenous circadian condition despite marked period lengthening. In summary, we establish CAST as novel tool for the efficient segmentation, signal quantification, and tracking of time-lapse images from mammalian cell culture. PMID- 25934264 TI - FEATnotator: A tool for integrated annotation of sequence features and variation, facilitating interpretation in genomics experiments. AB - As approaches are sought for more efficient and democratized uses of non-model and expanded model genomics references, ease of integration of genomic feature datasets is especially desirable in multidisciplinary research communities. Valuable conclusions are often missed or slowed when researchers refer experimental results to a single reference sequence that lacks integrated pan genomic and multi-experiment data in accessible formats. Association of genomic positional information, such as results from an expansive variety of next generation sequencing experiments, with annotated reference features such as genes or predicted protein binding sites, provides the context essential for conclusions and ongoing research. When the experimental system includes polymorphic genomic inputs, rapid calculation of gene structural and protein translational effects of sequence variation from the reference can be invaluable. Here we present FEATnotator, a lightweight, fast and easy to use open source software program that integrates and reports overlap and proximity in genomic information from any user-defined datasets including those from next generation sequencing applications. We illustrate use of the tool by summarizing whole genome sequence variation of a widely used natural isolate of Arabidopsis thaliana in the context of gene models of the reference accession. Previous discovery of a protein coding deletion influencing root development is replicated rapidly. Appropriate even in investigations of a single gene or genic regions such as QTL, comprehensive reports provided by FEATnotator better prepare researchers for interpretation of their experimental results. The tool is available for download at http://featnotator.sourceforge.net. PMID- 25934265 TI - In vitro effects of new artemisinin derivatives in Neospora caninum-infected human fibroblasts. AB - From a panel of 34 artemisinin derivatives tested in vitro, artemisone, GC007 and GC012 were most efficacious at inhibiting Neospora caninum replication (IC50 values of 3-54nM), did not notably impair the invasiveness of tachyzoites and were non-toxic for human foreskin fibroblasts (HFFs). Transmission electron microscopy of drug-treated N. caninum-infected HFFs demonstrated severe alterations in the parasite cytoplasm, changes in the composition of the matrix of the parasitophorous vacuole (PV) and diminished integrity of the PV membrane. To exert parasiticidal activity, parasites had to be cultured continuously in the presence of 5MUM artemisone or GC007 for 3 weeks. N. caninum tachyzoites readily adapted to a stepwise increase in concentrations (0.5-10MUM) of GC012, but not to artemisone or GC007. Drugs induced the expression of elevated levels of NcBAG1 and NcSAG4 mRNA, but only NcBAG1 could be detected by immunofluorescence. Thus, artemisinin derivatives represent interesting leads that should be investigated further. PMID- 25934266 TI - Evaluation of the capability of the PCV2 genome to encode miRNAs: lack of viral miRNA expression in an experimental infection. AB - Porcine circovirus type 2 (PCV2) is a ssDNA virus causing PCV2-systemic disease (PCV2-SD), one of the most important diseases in swine. MicroRNAs (miRNAs) are a new class of small non-coding RNAs that regulate gene expression post transcriptionally. Viral miRNAs have recently been described and the number of viral miRNAs has been increasing in the past few years. In this study, small RNA libraries were constructed from two tissues of subclinically PCV2 infected pigs to explore if PCV2 can encode viral miRNAs. The deep sequencing data revealed that PCV2 does not express miRNAs in an in vivo subclinical infection. PMID- 25934267 TI - Genetic transformation of extremophilic fungi Acidea extrema and Acidothrix acidophila. AB - Intact, growing cells of strongly acidophilic fungi Acidea extrema and Acidothrix acidophila have been successfully transformed by introduction of heterologous DNA fragment (composed of the glyceraldehyde-phosphate-dehydrogenase gene promoter from Emericella nidulans, a metallothionein-coding gene AsMt1 from Amanita strobiliformis and glyceraldehyde-phosphate-dehydrogenase gene terminator from Colletotrichum gloeosporioides) with the length of 1690 bp. The transformation procedure was based on the DNA transfer mediated by Agrobacterium tumefaciens bearing disarmed helper plasmid pMP90 and binary vector pCambia1300 with inserted DNA fragment of interest. The transformants proved to be mitotically stable, and the introduced gene was expressed at least at the level of transcription. Our work confirms that metabolic adaptations of strongly acidophilic fungi do not represent an obstacle for genetic transformation using conventional methods and can be potentially used for production of heterologous proteins. A promising role of the fast growing A. acidophila as active biomass in biotechnological processes is suggested not only by the low susceptibility of the culture grown at low pH to contaminations but also by reduced risk of accidental leaks of genetically modified microorganisms into the environment because highly specialized extremophilic fungi can poorly compete with common microflora under moderate conditions. PMID- 25934269 TI - [30 Congreso Nacional SENPE]. PMID- 25934268 TI - Black lives matter: Differential mortality and the racial composition of the U.S. electorate, 1970-2004. AB - Excess mortality in marginalized populations could be both a cause and an effect of political processes. We estimate the impact of mortality differentials between blacks and whites from 1970 to 2004 on the racial composition of the electorate in the US general election of 2004 and in close statewide elections during the study period. We analyze 73 million US deaths from the Multiple Cause of Death files to calculate: (1) Total excess deaths among blacks between 1970 and 2004, (2) total hypothetical survivors to 2004, (3) the probability that survivors would have turned out to vote in 2004, (4) total black votes lost in 2004, and (5) total black votes lost by each presidential candidate. We estimate 2.7 million excess black deaths between 1970 and 2004. Of those, 1.9 million would have survived until 2004, of which over 1.7 million would have been of voting age. We estimate that 1 million black votes were lost in 2004; of these, 900,000 votes were lost by the defeated Democratic presidential nominee. We find that many close state-level elections over the study period would likely have had different outcomes if voting age blacks had the mortality profiles of whites. US black voting rights are also eroded through felony disenfranchisement laws and other measures that dampen the voice of the US black electorate. Systematic disenfranchisement by population group yields an electorate that is unrepresentative of the full interests of the citizenry and affects the chance that elected officials have mandates to eliminate health inequality. PMID- 25934270 TI - An in vitro study of different material properties of Biodentine compared to ProRoot MTA. AB - INTRODUCTION: The aim of this study was to compare solubility, microhardness, radiopacity, and setting time of Biodentine with ProRoot MTA. METHODS: Solubility in distilled water, radioopacity, and setting time were evaluated in accordance with International Standard ISO 6876:2001. In addition, the solubility in Phosphate Buffered Saline (PBS) buffer was determined. For microhardness-testing, ten samples of each cement were produced. All samples were loaded with a diamond indenter point with a weight of 100 g for 30s. All data were analysed using the Student-t-test. RESULTS: Both materials fulfilled the requirements of the International Standard ISO 6876:2001 and showed a solubility of <3% after 24 h. At all exposure times Biodentine was significantly more soluble than ProRoot MTA (p < 0.0001). After immersion in PBS-buffer a precipitation of hydroxyapatite was visible. The Vickers microhardness for Biodentine was significantly higher (62.35 +/- 11.55HV) compared with ProRoot MTA (26.93 +/- 4.66HV) (p < 0.0001). ProRoot MTA was significantly more radiopaque (6.40 +/- 0.06 mm Al) than Biodentine (1.50 +/- 0.10 mm Al) (p < 0.0001). The setting time for Biodentine (85.66 +/- 6.03 min) was significantly lower than for ProRoot MTA (228.33 +/- 2.88 min) (p < 0.0001). CONCLUSIONS: Biodentine and ProRoot MTA displayed different material properties. The solubility of both cements was in accordance with the International Standard ISO 6876:2001, whereas ProRoot MTA showed a significantly lower solubility. With regard to microhardness, Biodentine may be used to replace dentine. The radioopacity of Biodentine did not fulfil the requirements laid down in the International Standard ISO 6876:2001. The setting time for ProRoot MTA is significantly higher. Both materials can be used in different indications where specific material properties may be favourable. Hence, the here tested material properties are of clinical relevance. PMID- 25934271 TI - Factors impacting physicians' decisions to prevent variceal hemorrhage. AB - BACKGROUND: Reasons underlying the variability of physicians' preferences for non selective beta-blockers (BBs) and endoscopic variceal ligation (EVL) to prevent a first variceal bleed have not been empirically studied. Our aims were to examine whether 1) gastroenterologists can be classified into distinct subgroups based on how they prioritize specific treatment attributes and 2) physician characteristics are associated with treatment preference. METHODS: We surveyed physicians to determine their preferred treatment for a standardized patient with large varices and examined the influence of treatment characteristics on physicians' decision making using best-worst scaling. Latent class analysis was used to examine whether physicians could be classified into groups with similar decision-making styles. RESULTS: 110 physicians were interviewed (participation rate 39%). The majority spent two or more days a week performing endoscopies and had practices comprising less than 25% of patients with liver disease. Latent class analysis demonstrated that physicians could be classified into at least two distinct groups. Most (n = 80, Group 1) were influenced solely by the ability to visually confirm eradication of varices. In contrast, members of Group 2 (n = 30) were influenced by the side effects and mechanism of action of BBs. Group 1 members were more likely to have practices that included fewer patients with liver disease and more likely to choose options including EVL (p = 0.01 for both). CONCLUSIONS: Among physicians, where the majority performs endoscopy on two or more days per week, most prefer prevention strategies which include EVL. This may be due to the strong appeal of being able to visualize eradication of varices. PMID- 25934272 TI - Are measurements of patient safety culture and adverse events valid and reliable? Results from a cross sectional study. AB - BACKGROUND: The association between measurements of the patient safety culture and the "true" patient safety has been insufficiently documented, and the validity of the tools used for the measurements has been questioned. This study explored associations between the patient safety culture and adverse events, and evaluated the validity of the tools. METHODS: In 2008/2009, a survey on patient safety culture was performed with Hospital Survey on Patient Safety Culture (HSOPSC) in two medical departments in two geographically separated hospitals of Innlandet Hospital Trust. Later, a retrospective analysis of adverse events during the same period was performed with the Global Trigger Tool (GTT). The safety culture and adverse events were compared between the departments. RESULTS: 185 employees participated in the study, and 272 patient records were analysed. The HSOPSC scores were lower and adverse events less prevalent in department 1 than in department 2. In departments 1 and 2 the mean HSOPSC scores (SD) were at the unit level 3.62 (0.42) and 3.90 (0.37) (p < 0.001), and at the hospital level 3.35 (1.53) and 3.67 (0.53) (ns, p = 0.19) respectively. The proportion of records with adverse events were 10/135 (7%) and 28/137 (20%) (p = 0.003) respectively. CONCLUSIONS: There was an inverse association between the patient safety culture and adverse events. Until the criterion validity of the tools for measuring patient safety culture and tracking of adverse events have been further evaluated, measurement of patient safety culture could not be used as a proxy for the "true" safety. PMID- 25934273 TI - A mitochondria-targeted ratiometric fluorescent probe to monitor endogenously generated sulfur dioxide derivatives in living cells. AB - Sulfur dioxide (SO2) can be endogenously produced by enzymes in mitochondria during oxidation of H2S or sulphur-containing amino acids, and plays important roles in several physiological processes. However, the design and synthesis of fluorescent probes which can detect mitochondrial SO2 and its derivatives in living cells still remain unresolved. Herein, we report the preparation of a lipophilic cationic dye 1 (Mito-Ratio-SO2), which targets the mitochondria in living cells and is sensitive to the presence of SO2 derivatives. The ratiometric probe Mito-Ratio-SO2 displays a 170 nm blue-shift in emission with two well resolved emission bands upon addition of sulfite. Mechanistic studies indicate that three probe-SO2 adducts coexist after reaction, as supported by liquid chromatography and density function theory investigations. Importantly, the ratiometric probe is highly selective for sulfite over other bio-species including H2S. Fluorescence co-localization studies indicate that the probe localizes solely in the mitochondria of HeLa cells. Last but not least, fluorescent imaging of HeLa cells successfully demonstrates the detection of intrinsically generated intracellular SO2 derivatives in living cells. PMID- 25934274 TI - Tumor-specific delivery of BSH-3R for boron neutron capture therapy and positron emission tomography imaging in a mouse brain tumor model. AB - Glioblastoma, a malignant brain tumor with poor disease outcomes, is managed in modern medicine by multimodality therapy. Boron neutron capture therapy (BNCT) is an encouraging treatment under clinical investigation. In malignant cells, BNCT consists of two major factors: neutron radiation and boron uptake. To increase boron uptake in cells, we created a mercapto-closo-undecahydrododecaborate ([B12HnSH](2-)2Na(+), BSH) fused with a short arginine peptide (1R, 2R, 3R) and checked cellular uptake in vitro and in vivo. In a mouse brain tumor model, only BSH with at least three arginine domains could penetrate cell membranes of glioma cells in vitro and in vivo. Furthermore, to monitor the pharmacokinetic properties of these agents in vivo, we fused BSH and BSH-3R with 1,4,7,10 tetraazacyclododecane-1,4,7,10-tetraacetic acid (DOTA); DOTA is a metal chelating agent for labeling positron emission tomography (PET) probe with (64)Cu. We administered BSH-DOTA-(64)Cu and BSH-3R-DOTA-(64)Cu to the tumor model through a mouse tail vein and determined the drugs' pharmacokinetics by PET imaging. BSH-3R showed a high uptake in the tumor area on PET imaging. We concluded that BSH-3R is the ideal boron compound for clinical use during BNCT and that in developing this compound for clinical use, the BSH-3R PET probe is essential for pharmacokinetic imaging. PMID- 25934275 TI - Combination of BMP-2-releasing gelatin/beta-TCP sponges with autologous bone marrow for bone regeneration of X-ray-irradiated rabbit ulnar defects. AB - The objective of this study is to evaluate the feasibility of gelatin sponges incorporating beta-tricalcium phosphate (beta-TCP) granules (gelatin/beta-TCP sponges) to enhance bone regeneration at a segmental ulnar defect of rabbits with X-ray irradiation. After X-ray irradiation of the ulnar bone, segmental critical sized defects of 20-mm length were created, and bone morphogenetic protein-2 (BMP 2)-releasing gelatin/beta-TCP sponges with or without autologous bone marrow were applied to the defects to evaluate bone regeneration. Both gelatin/beta-TCP sponges containing autologous bone marrow and BMP-2-releasing sponges enhanced bone regeneration at the ulna defect to a significantly greater extent than the empty sponges (control). However, in the X-ray-irradiated bone, the bone regeneration either by autologous bone marrow or BMP-2 was inhibited. When combined with autologous bone marrow, the BMP-2 exhibited significantly high osteoinductivity, irrespective of the X-ray irradiation. The bone mineral content at the ulna defect was similar to that of the intact bone. It is concluded that the combination of bone marrow with the BMP-2-releasing gelatin/beta-TCP sponge is a promising technique to induce bone regeneration at segmental bone defects after X-ray irradiation. PMID- 25934276 TI - Photothermal tumor ablation in mice with repeated therapy sessions using NIR absorbing micellar hydrogels formed in situ. AB - Repeated cancer treatments are common, owing to the aggressive and resistant nature of tumors. This work presents a chitosan (CS) derivative that contains self-doped polyaniline (PANI) side chains, capable of self-assembling to form micelles and then transforming into hydrogels driven by a local change in pH. Analysis results of small-angle X-ray scattering indicate that the sol-gel transition of this CS derivative may provide the mechanical integrity to maintain its spatial stability in the microenvironment of solid tumors. The micelles formed in the CS hydrogel function as nanoscaled heating sources upon exposure to near-infrared light, thereby enabling the selective killing of cancer cells in a light-treated area. Additionally, photothermal efficacy of the micellar hydrogel is evaluated using a tumor-bearing mouse model; hollow gold nanospheres (HGNs) are used for comparison. Given the ability of the micellar hydrogel to provide spatial stability within a solid tumor, which prevents its leakage from the injection site, the therapeutic efficacy of this hydrogel, as a photothermal therapeutic agent for repeated treatments, exceeds that of nanosized HGNs. Results of this study demonstrate that this in situ-formed micellar hydrogel is a highly promising modality for repeated cancer treatments, providing a clinically viable, minimally invasive phototherapeutic option for therapeutic treatment. PMID- 25934277 TI - Dissecting stromal-epithelial interactions in a 3D in vitro cellularized intestinal model for permeability studies. AB - Absorption evaluation plays an increasingly important role at the early stage of drug discovery due to its potential to scan the ADME (absorption, distribution, metabolism and excretion) properties of new drug candidates. Therefore, a new three-dimensional (3D) in vitro model replicating the intestinal functioning is herein proposed aiming to dissect the stromal-epithelial interactions and evaluate the permeation of a model drug, insulin. Inspired on the intestinal mucosal architecture, the present model comprises intestinal myofibroblasts (CCD18-Co cells) embedded in Matrigel, onto which epithelial enterocytes (Caco-2 cells) and mucus-producing cells (HT29-MTX cells) were seeded. CCD18-Co myofibroblasts showed to have a central role in the remodeling of the surrounding matrix confirmed by the production of fibronectin. Subsequently, this matrix revealed to be essential to the maintenance of the model architecture by supporting the overlying epithelial cells. In terms of functionality, this model allowed the efficient prediction of insulin permeability in which the presence of mucus, the less tight character between Caco-2 and HT29-MTX epithelial cells and the 3D assembly were critical factors. Concluding, this model constitutes a robust tool in the drug development field with potential to bridge the traditional 2D cell culture models and in vivo animal models. PMID- 25934278 TI - Multifunctional and stable bone mimic proteinaceous matrix for bone tissue engineering. AB - Biomaterial surface design with biomimetic proteins holds great promise for successful regeneration of tissues including bone. Here we report a novel proteinaceous hybrid matrix mimicking bone extracellular matrix that has multifunctional capacity to promote stem cell adhesion and osteogenesis with excellent stability. Osteocalcin-fibronectin fusion protein holding collagen binding domain was networked with fibrillar collagen, featuring bone extracellular matrix mimic, to provide multifunctional and structurally-stable biomatrices. The hybrid protein, integrated homogeneously with collagen fibrillar networks, preserved structural stability over a month. Biological efficacy of the hybrid matrix was proven onto tethered surface of biopolymer porous scaffolds. Mesenchymal stem cells quickly anchored to the hybrid matrix, forming focal adhesions, and substantially conformed to cytoskeletal extensions, benefited from the fibronectin adhesive domains. Cells achieved high proliferative capacity to reach confluence rapidly and switched to a mature and osteogenic phenotype more effectively, resulting in greater osteogenic matrix syntheses and mineralization, driven by the engineered osteocalcin. The hybrid biomimetic matrix significantly improved in vivo bone formation in calvarial defects over 6 weeks. Based on the series of stimulated biological responses in vitro and in vivo the novel hybrid proteinaceous composition will be potentially useful as stem cell interfacing matrices for osteogenesis and bone regeneration. PMID- 25934279 TI - A complementary density gradient of zwitterionic polymer brushes and NCAM peptides for selectively controlling directional migration of Schwann cells. AB - Selective enhancement of directional migration of Schwann cells (SCs) over fibroblasts (FIBs) plays a significant role in peripheral nerve regeneration, because this behavior facilitates neuron repair and avoids fibrosis. Herein a complementary density gradient of poly(3-dimethyl-methacryloyloxyethyl ammonium propane sulfonate) (PDMAPS, a zwitterionic polymer with antifouling property) and KHIFSDDSSE peptide (KHI, derived from neural cell adhesion molecule NCAM which mediates cell-cell adhesion) was fabricated. The gradient was visualized by fluorescent labeling, and further characterized by X-ray photoelectron spectrometry (XPS) and quartz crystal microbalance with dissipation (QCM-d). The SCs exhibited preferential orientation and enhanced directional migration on the gradient surface toward the region of lower PDMAPS density and higher KHI peptide density, while FIBs showed random migration. Moreover, the migration rate of the SCs was significantly enhanced to 2 folds, whereas that of the FIBs was reduced to 60% compared to their natural state on glass, leading to a faster migration rate of SCs than FIBs. The success of the complementary gradient relies on the appropriate interplay between the PDMAPS brushes and the cell-specific ligands, enabling the selective guidance of SCs migration. PMID- 25934280 TI - Vascularization of hollow channel-modified porous silk scaffolds with endothelial cells for tissue regeneration. AB - Despite the promise for stem cell-based tissue engineering for regenerative therapy, slow and insufficient vascularization of large tissue constructs negatively impacts the survival and function of these transplanted cells. A combination of channeled porous silk scaffolds and prevascularization with endothelial cells was investigated to test the ability of this tissue engineering strategy to support rapid and extensive vascularization process. We report that hollow channels promote in vitro prevascularization by facilitating endothelial cell growth, VEGF secretion, and capillary-like tube formation. When implanted in vivo, the pre-established vascular networks in the hollow channel scaffolds anastomose with host vessels and exhibit accelerated vascular infiltration throughout the whole tissue construct, which provides timely and sufficient nutrients to ensure the survival of the transplanted stem cells. This tissue engineering strategy can promote the effective application of stem cell-based regeneration to improve future clinical applications. PMID- 25934281 TI - Myelin repair in vivo is increased by targeting oligodendrocyte precursor cells with nanoparticles encapsulating leukaemia inhibitory factor (LIF). AB - Multiple sclerosis (MS) is a progressive demyelinating disease of the central nervous system (CNS). Many nerve axons are insulated by a myelin sheath and their demyelination not only prevents saltatory electrical signal conduction along the axons but also removes their metabolic support leading to irreversible neurodegeneration, which currently is untreatable. There is much interest in potential therapeutics that promote remyelination and here we explore use of leukaemia inhibitory factor (LIF), a cytokine known to play a key regulatory role in self-tolerant immunity and recently identified as a pro-myelination factor. In this study, we tested a nanoparticle-based strategy for targeted delivery of LIF to oligodendrocyte precursor cells (OPC) to promote their differentiation into mature oligodendrocytes able to repair myelin. Poly(lactic-co-glycolic acid) based nanoparticles of ~120 nm diameter were constructed with LIF as cargo (LIF NP) with surface antibodies against NG-2 chondroitin sulfate proteoglycan, expressed on OPC. In vitro, NG2-targeted LIF-NP bound to OPCs, activated pSTAT-3 signalling and induced OPC differentiation into mature oligodendrocytes. In vivo, using a model of focal CNS demyelination, we show that NG2-targeted LIF-NP increased myelin repair, both at the level of increased number of myelinated axons, and increased thickness of myelin per axon. Potency was high: a single NP dose delivering picomolar quantities of LIF is sufficient to increase remyelination. Impact statement Nanotherapy-based delivery of leukaemia inhibitory factor (LIF) directly to OPCs proved to be highly potent in promoting myelin repair in vivo: this delivery strategy introduces a novel approach to delivering drugs or biologics targeted to myelin repair in diseases such as MS. PMID- 25934282 TI - Efficient differentiation of stem cells encapsulated in a cytocompatible phospholipid polymer hydrogel with tunable physical properties. AB - A large number of lineage-committed progenitor cells are required for advanced regenerative medicine based on cell engineering. Due to their ability to differentiate into multiple cells lines, multipotent stem cells have emerged as a vital source for generating transplantable cells for use in regenerative medicine. Increment in differentiation efficiency of the mesenchymal stem cell was obtained by using hydrogel to adjust the proliferation cycle of encapsulated cells to signal sensitive phase. Three dimensional (3-D) polymer networks composed of poly(2-methacyloyloxyethyl phosphorylcholine (MPC)-co-n-butyl methacrylate (BMA)-co-p-vinylphenylboronic acid (VPBA)) (PMBV) and poly(vinyl alcohol) (PVA) were prepared as a hydrogel. The proliferation of cells encapsulated in the PMBV/PVA hydrogel was highly sensitive to the storage modulus (G') of the hydrogel. That is, when the G' value of the hydrogel was higher than 1.0 kPa, the cell proliferation was ceased and the proliferation cycle of cells was converged to G1 phase, whereas when the G' value was below 1.0 kPa, cell proliferation proceeded. By changing the G' value of hydrogels under encapsulation the cells, proliferation cycle of encapsulated mesenchymal stem cells was regulated to G1 phase and thus signal sensitivity were increased. 3-D polymer networks as hydrogels with tunable physical properties can be effectively used to control proliferation and lineage-restricted differentiation of stem cells. PMID- 25934283 TI - Variants of self-assembling peptide, KLD-12 that show both rapid fracture healing and antimicrobial properties. AB - KLD-12 (KLD) is a 12-residue self-assembling peptide that can adopt nano structures and is known for its tissue-engineering properties. Our objective was to introduce antimicrobial attribute to KLD which would help in preventing secondary infection associated with external application of such tissue engineering materials. Considering the net charge of KLD-12, varying number of cationic arginine residues were added to its N-terminus. KLD variants showed appreciable bactericidal properties without any significant increase in cytotoxicity against tested mammalian cells. Further, these variants adopted beta sheet structures and self-assembled into nano-structures comparable to that of KLD. Interestingly, the KLD variants with two (KLD-2R) and three (KLD-3R) arginine residues added to its N-terminus showed significant osteogenic effect which was comparable or better than the original peptide as evident from the alkaline phosphatase activity assay, mineralized nodule formation and expression of different osteogenic genes. Particularly, application of KLD-2R in rats to the site of a drill-hole (0.8 mm diameter) that was created in the femur metaphysis displayed significantly higher bone regeneration compared to that of KLD. The results demonstrate a simple way to improve biological property of a self assembling peptide with tissue engineering property. PMID- 25934284 TI - Ultrasound molecular imaging of tumor angiogenesis with a neuropilin-1-targeted microbubble. AB - Ultrasound molecular imaging has great potential to impact early disease diagnosis, evaluation of disease progression and the development of target specific therapy. In this paper, two neuropilin-1 (NRP) targeted peptides, CRPPR and ATWLPPR, were conjugated onto the surface of lipid microbubbles (MBs) to evaluate molecular imaging of tumor angiogenesis in a breast cancer model. Development of a molecular imaging agent using CRPPR has particular importance due to the previously demonstrated internalizing capability of this and similar ligands. In vitro, CRPPR MBs bound to an NRP-expressing cell line 2.6 and 15.6 times more than ATWLPPR MBs and non-targeted (NT) MBs, respectively, and the binding was inhibited by pretreating the cells with an NRP antibody. In vivo, the backscattered intensity within the tumor, relative to nearby vasculature, increased over time during the ~6 min circulation of the CRPPR-targeted contrast agents providing high contrast images of angiogenic tumors. Approximately 67% of the initial signal from CRPPR MBs remained bound after the majority of circulating MBs had cleared (8 min), 8 and 4.5 times greater than ATWLPPR and NT MBs, respectively. Finally, at 7-21 days after the first injection, we found that CRPPR MBs cleared faster from circulation and tumor accumulation was reduced likely due to a complement-mediated recognition of the targeted microbubble and a decrease in angiogenic vasculature, respectively. In summary, we find that CRPPR MBs specifically bind to NRP-expressing cells and provide an effective new agent for molecular imaging of angiogenesis. PMID- 25934285 TI - Activation of the Nrf2-regulated antioxidant cell response inhibits HEMA-induced oxidative stress and supports cell viability. AB - Oxidative stress due to increased formation of reactive oxygen species (ROS) in target cells of dental resin monomers like 2-hydroxyethyl methacrylate (HEMA) is a major mechanism underlying the disturbance of vital cell functions including mineralization and differentiation, responses of the innate immune system, and the induction of cell death via apoptosis. Although a shift in the equilibrium between cell viability and apoptosis is related to the non-enzymatic antioxidant glutathione (GSH) in HEMA-exposed cells, the major mechanisms of adaptive antioxidant cell responses to maintain cellular redox homeostasis are still unknown. The present study provides insight into the induction of a communicating network of pathways under the control of the redox-sensitive transcription factor Nrf2, a major transcriptional activator of genes coding for enzymatic antioxidants. Here, oxidative stress was indicated by DCF fluorescence in cells after a short exposure (1 h) to HEMA, while DHR123 fluorescence significantly increased about 1.8-fold after a long exposure period (24 h) showing the formation of hydrogen peroxide (H2O2). The corresponding expression of Nrf2 was activated immediately after HEMA exposure (1 h) and remained constant up to 24 h. Nrf2-regulated expression of enzymes of the glutathione metabolism (glutathione peroxidase 1/2, glutathione reductase) decreased in HEMA-exposed cells as a result of GSH depletion, and superoxide dismutase expression was downregulated after H2O2 overproduction. However, the expression of Nrf2-controlled enzymatic antioxidants (catalase, peroxiredoxin, thioredoxin 1, thioredoxin reductase, heme oxygenase-1) and the NADPH-regenerating system (glucose 6-phosphate dehydrogenase, transaldolase) was increased. Phenolic tert-butylhydroquinone (tBHQ), a classic inducer of the Nrf2 pathway, reduced oxidative stress and protected cells from HEMA-induced cell death through a shift in the number of cells in necrosis to apoptosis. The expression of Nrf2 and related enzymatic antioxidants downstream was enhanced by tBHQ in parallel. In conclusion, this investigation expanded the detailed understanding of the underlying mechanisms of HEMA-induced oxidative stress, and highlighted the cross-talk and interdependence between various Nrf2-regulated antioxidant pathways as a major adaptive cell response. The current results demonstrate that modulation of the Nrf2-mediated cellular defense response is an effective means for manipulating the sensitivity of cells to dental resin monomers. PMID- 25934286 TI - Deconstructing the role of the ECM microenvironment on drug efficacy targeting MAPK signaling in a pre-clinical platform for cutaneous melanoma. AB - Therapeutics targeting the BRAF kinase in cutaneous melanoma have significantly improved patient survival. However, durable responses in the face of metastatic disease are rarely realized where the problem of brain metastases is generally growing in magnitude. Tumor and stromal cells dynamically remodel the extracellular matrix (ECM) during the establishment of a metastatic lesion. We reasoned that ECM composition strongly determines drug efficacy on cell motility, adhesion and viability rendering one drug more potent and another less so. To test this hypothesis, we constructed platforms recreating the ECM composition due to the stroma and tumor cells, mimicking the brain's perivascular niche and hyaluronic acid (HA) rich parenchyma. Using human melanoma cell lines, we observed that cell adhesion was minimally affected by BRAF inhibition but ablated by ERK inhibition. Cell motility was impaired for both drugs. We determined that the composition and architecture of the ECM niche modulated drug efficacy. In one series, potency of BRAF inhibition was blunted in 3D Fibronectin-HA hydrogels whereas Laminin-HA hydrogels protected against ERK inhibition. In the other series, Laminin blunted drug efficacy, despite both series sharing the same BRAF mutation. These data reinforce the importance of contextual drug assessment in designing future therapeutics. PMID- 25934287 TI - Ruthenium(II) polypyridyl complexes as mitochondria-targeted two-photon photodynamic anticancer agents. AB - Clinical acceptance of photodynamic therapy is currently hindered by poor depth efficacy and inefficient activation of the cell death machinery in cancer cells during treatment. To address these issues, photoactivation using two-photon absorption (TPA) is currently being examined. Mitochondria-targeted therapy represents a promising approach to target tumors selectively and may overcome the resistance in current anticancer therapies. Herein, four ruthenium(II) polypyridyl complexes (RuL1-RuL4) have been designed and developed to act as mitochondria-targeted two-photon photodynamic anticancer agents. These complexes exhibit very high singlet oxygen quantum yields in methanol (0.74-0.81), significant TPA cross sections (124-198 GM), remarkable mitochondrial accumulation, and deep penetration depth. Thus, RuL1-RuL4 were utilized as one photon and two-photon absorbing photosensitizers in both monolayer cells and 3D multicellular spheroids (MCSs). These Ru(II) complexes were almost nontoxic towards cells and 3D MCSs in the dark and generate sufficient singlet oxygen under one- and two-photon irradiation to trigger cell death. Remarkably, RuL4 exhibited an IC50 value as low as 9.6 MUM in one-photon PDT (lambdairr = 450 nm, 12 J cm(-2)) and 1.9 MUM in two-photon PDT (lambdairr = 830 nm, 800 J cm(-2)) of 3D MCSs; moreover, RuL4 is an order of magnitude more toxic than cisplatin in the latter test system. The combination of mitochondria-targeting and two-photon activation provides a valuable paradigm to develop ruthenium(II) complexes for PDT applications. PMID- 25934288 TI - Deoxycholate bile acid directed synthesis of branched Au nanostructures for near infrared photothermal ablation. AB - We report an approach for simple, reproducible and high-yield synthesis of branched GNPs directed by deoxycholate bile acid supramolecular aggregates in Au solution. A growth process involving stepwise trapping of the GNP seeds and Au ions in the deoxycholate bile acid solution yields multiple-branched GNPs. Upon NIR laser irradiation strong NIR absorption for branched GNPs induced photothermal-heating to destroy tumor cells. Subsequently, these branched GNPs were biofunctionalized with cRGD cell penetrating-targeting peptides for photothermal cancer treatment applications. Branched GNPs conjugated with cRGD peptides enhanced internalization of the branched GNPs in BxPC3 human pancreatic adenocarcinoma cells and effectively ablated BxPC3 cells when irradiated with a NIR laser (808 nm). Their potential use as photothermal transducing agents was demonstrated in in vivo settings using a pancreatic cancer xenograft model. The tumors were effectively ablated with cRGD-branched GNPs injection and laser exposure without any observation of tumor recurrence. This firstly reported method for deoxycholate bile acid directed synthesis of branched GNPs opens new possibilities for the production of strong NIR absorbing nanostructures for selective nano-photothermolysis of cancer cells and the further design of novel materials with customized spectral and structural properties for broader applications. PMID- 25934289 TI - The transducible TAT-RIZ1-PR protein exerts histone methyltransferase activity and tumor-suppressive functions in human malignant meningiomas. AB - Malignant meningiomas are a rare meningioma subtype and tend to have post surgical recurrence. Significant endeavors have been taken to identify functional therapeutic targets to halt the growth of this aggressive cancer. We have recently discovered that RIZ1 is downregulated in high-grade meningiomas, and RIZ1 overexpression inhibits proliferation while promoting cell apoptosis of the IOMM-Lee malignant meningioma cell line. In this report, we show that the N terminal PR domain of RIZ1 alone possessed growth-inhibitory activity and anticancer activity in primary human meningioma cells. Interestingly, the effects seem to be dependent on differential RIZ1 protein levels. Transducible TAT-RIZ1 PR protein could also inhibit meningioma tumor growth in nude mice models. We further demonstrate that PR protein exerts histone methyltransferase activity. A microarray analysis of TAT-RIZ1-PR-treated human malignant meningioma cells reveals 969 differentially expressed genes and 848 alternative splicing exons. Moreover, c-Myc and TXNIP, two putative downstream targets of H3K9 methylation, may be involved in regulating RIZ1 tumor-suppressive effects. The reciprocal relationship between RIZ1 and c-Myc was then validated in primary meningioma cells and human tumor samples. These findings provide insights into RIZ1 tumor suppression mechanisms and suggest that TAT-RIZ1-PR protein is a potential new epigenetic therapeutic agent for advanced meningiomas. PMID- 25934290 TI - Surfactant functionalization induces robust, differential adhesion of tumor cells and blood cells to charged nanotube-coated biomaterials under flow. AB - The metastatic spread of cancer cells from the primary tumor to distant sites leads to a poor prognosis in cancers originating from multiple organs. Increasing evidence has linked selectin-based adhesion between circulating tumor cells (CTCs) and endothelial cells of the microvasculature to metastatic dissemination, in a manner similar to leukocyte adhesion during inflammation. Functionalized biomaterial surfaces hold promise as a diagnostic tool to separate CTCs and potentially treat metastasis, utilizing antibody and selectin-mediated interactions for cell capture under flow. However, capture at high purity levels is challenged by the fact that CTCs and leukocytes both possess selectin ligands. Here, a straightforward technique to functionalize and alter the charge of naturally occurring halloysite nanotubes using surfactants is reported to induce robust, differential adhesion of tumor cells and blood cells to nanotube-coated surfaces under flow. Negatively charged sodium dodecanoate-functionalized nanotubes simultaneously enhanced tumor cell capture while negating leukocyte adhesion, both in the presence and absence of adhesion proteins, and can be utilized to isolate circulating tumor cells regardless of biomarker expression. Conversely, diminishing nanotube charge via functionalization with decyltrimethylammonium bromide both abolished tumor cell capture while promoting leukocyte adhesion. PMID- 25934291 TI - Altering in vivo macrophage responses with modified polymer properties. AB - Macrophage reprogramming has long been the focus of research in disease therapeutics and biomaterial implantation. With different chemical and physical properties of materials playing a role in macrophage polarization, it is important to investigate and categorize the activation effects of material parameters both in vitro and in vivo. In this study, we have investigated the effects of material surface chemistry on in vivo polarization of macrophages. The library of materials used here include poly(N-isopropylacrylamide-co-acrylic acid) (p(NIPAm-co-AAc)) nanoparticles (~600 nm) modified with various functional groups. This study also focuses on the development of a quantitative structure activity relationship method (QSAR) as a predictive tool for determining the macrophage polarization in response to particular biomaterial surface chemistries. Here, we successfully use in vivo imaging and histological analysis to identify the macrophage response and activation. We demonstrate the ability to induce a spectrum of macrophage phenotypes with a change in material functionality as well as identify certain material parameters that seem to correlate with each phenotype. This suggests the potential to develop materials for a variety of applications and predict the outcome of macrophage activation in response to new surface chemistries. PMID- 25934292 TI - Multilayer hydrogel coatings to combine hemocompatibility and antimicrobial activity. AB - While silver-loaded catheters are widely used to prevent early-onset catheter related infections [1], long term antimicrobial protection of indwelling catheters remains to be achieved [2] and antiseptic functionalization of coatings often impairs their hemocompatibility characteristics. Therefore, this work aimed to capitalize on the antimicrobial properties of silver nanoparticles, incorporated in anticoagulant poly(ethylene glycol) (PEG)-heparin hydrogel coatings [3] on thermoplastic polyurethane materials. For prolonged antimicrobial activity, the silver-containing starPEG-heparin hydrogel layers were shielded with silver-free hydrogel layers of otherwise similar composition. The resulting multi-layered gel coatings showed long term antiseptic efficacy against Escherichia coli and Staphylococcus epidermidis strains in vitro, and similarly performed well when incubated with freshly drawn human whole blood with respect to hemolysis, platelet activation and plasmatic coagulation. The introduced hydrogel multilayer system thus offers a promising combination of hemocompatibility and long-term antiseptic capacity to meet an important clinical need. PMID- 25934293 TI - An efficient nano-based theranostic system for multi-modal imaging-guided photothermal sterilization in gastrointestinal tract. AB - Since understanding the healthy status of gastrointestinal tract (GI tract) is of vital importance, clinical implementation for GI tract-related disease have attracted much more attention along with the rapid development of modern medicine. Here, a multifunctional theranostic system combining X rays/CT/photothermal/photoacoustic mapping of GI tract and imaging-guided photothermal anti-bacterial treatment is designed and constructed. PEGylated W18O49 nanosheets (PEG-W18O49) are created via a facile solvothermal method and an in situ probe-sonication approach. In terms of excellent colloidal stability, low cytotoxicity, and neglectable hemolysis of PEG-W18O49, we demonstrate the first example of high-performance four-modal imaging of GI tract by using these nanosheets as contrast agents. More importantly, due to their intrinsic absorption of NIR light, glutaraldehyde-modified PEG-W18O49 are successfully applied as fault-free targeted photothermal agents for imaging-guided killing of bacteria on a mouse infection model. Critical to pre-clinical and clinical prospects, long-term toxicity is further investigated after oral administration of these theranostic agents. These kinds of tungsten-based nanomaterials exhibit great potential as multi-modal contrast agents for directed visualization of GI tract and anti-bacterial agents for phothothermal sterilization. PMID- 25934294 TI - Epsilon-caprolactone modified polyethylenimine for highly efficient antigen delivery and chemical exchange saturation transfer functional MR imaging. AB - Serious challenges remain in immunotherapy, such as to effectively deliver antigens and non-invasively monitor biological processes. Therefore, we aim to design a useful nanocarrier for enhancing antigen-specific immune response and performing functional molecular imaging guided immunotherapy. To achieve this goal, epsilon-caprolactone modified polyethylenimine (PEI-CL) was prepared based on the ring-opening reaction. This novel macromolecule served as an optimal vehicle that efficiently bound ovalbumin (OVA) antigen forming a controlled nanostructure through electronic self-assembly and resulted in a substantially increased cellular uptake. In vivo, PEI-CL/OVA nanovaccine stimulated inflammatory cytokine production and promoted proliferation of OVA-specific T cells. Moreover, due to the unique chemical and physical properties, PEI-CL was demonstrated as a chemical exchange saturation transfer contrast agent for magnetic resonance imaging. In conclusion, the PEI-CL has synergistic advantages in the effective delivery of antigen and non-invasive imaging for tracking immunotherapeutic cells. PMID- 25934295 TI - Targeted polymeric therapeutic nanoparticles: Design and interactions with hepatocellular carcinoma. AB - Nanoparticles (NPs) have great potential as drug delivery systems or as drugs for treating certain diseases. We designed three NPs with different charges and modifications with PEG to treat tumors. PDLA-CS, PEG-PLGA-PLL, and PEG-PS/CaP NPs were designed and evaluated to assess NPs fate in vivo and efficacy for treating tumors. Comparison between PEG-modified and non-PEG-modified NPs showed that PEG modified NPs increased K(+) efflux, easily escaped from lysosomes, affected the mitochondria, induced mitochondrial apoptosis, had longer circulation time, and easily targeted tumors. Non-PEG-modified NPs induce the endoplasmic reticulum apoptosis pathway. Comparison between positively and negatively charged NPs showed that negatively charged NPs have less effect on the K(+) efflux of normal cells and more effect on the mitochondrial apoptosis of tumor cells. Positively charged NPs accumulated within the tumors and the liver and lungs. These results provide a theoretical basis for future clinical applications. PMID- 25934296 TI - Nonsense and missense mutation of mitochondrial ND6 gene promotes cell migration and invasion in human lung adenocarcinoma. AB - BACKGROUND: Previous study showed that mitochondrial ND6 (mitND6) gene missense mutation resulted in NADH dehydrogenase deficiency and was associated with tumor metastasis in several mouse tumor cell lines. In the present study, we investigated the possible role of mitND6 gene nonsense and missense mutations in the metastasis of human lung adenocarcinoma. METHODS: The presence of mitND6 gene mutations was screened by DNA sequencing of tumor tissues from 87 primary lung adenocarcinoma patients and the correlation of the mutations with the clinical features was analyzed. In addition, we constructed cytoplasmic hybrid cells with denucleared primary lung adenocarcinoma cell as the mitochondria donor and mitochondria depleted lung adenocarcinoma A549 cell as the nuclear donor. Using these cells, we studied the effects of mitND6 gene nonsense and missense mutations on cell migration and invasion through wounding healing and matrigel coated transwell assay. The effects of mitND6 gene mutations on NADH dehydrogenase activity and ROS production were analyzed by spectrophotometry and flow cytometry. RESULTS: mitND6 gene nonsense and missense mutations were detected in 11 of 87 lung adenocarcinoma specimens and was correlated with the clinical features including age, pathological grade, tumor stage, lymph node metastasis and survival rate. Moreover, A549 cell containing mitND6 gene nonsense and missense mutation exhibited significantly lower activity of NADH dehydrogenase, higher level of ROS, higher capacity of cell migration and invasion, and higher pAKT and pERK1/ERK2 expression level than cells with the wild type mitND6 gene. In addition, NADH dehydrogenase inhibitor rotenone was found to significantly promote the migration and invasion of A549 cells. CONCLUSIONS: Our data suggest that mitND6 gene nonsense and missense mutation might promote cell migration and invasion in lung adenocarcinoma, probably by NADH dehydrogenase deficiency induced over-production of ROS. PMID- 25934297 TI - Overcoming barriers to recruiting ethnic minorities to mental health research: a typology of recruitment strategies. AB - BACKGROUND: The ethnic minority population in developed countries is increasing over time. These groups are at higher risk of mental illness and demonstrate lower participation in research. Published evidence suggests that multiple factors like stigma, lack of trust, differences in explanatory models, logistical issues and lack of culturally aware researchers act as barriers to ethnic minority recruitment into mental health research. To reduce inequalities in participation, there is a need to devise innovative and culturally sensitive recruitment strategies. It is important that researchers share their experience of employing these strategies so that ethnic minority participation can be facilitated. METHODS: We previously published a systematic review of barriers to recruiting ethnic minority participants into mental health research. The nine papers included in our prior review formed the basis for developing a typology of barriers to recruiting ethnic minorities into mental health research. This typology identified 33 barriers, described under five themes. We further extracted data on the strategies used to overcome these recruitment barriers, as described in the included studies. RESULTS: The strategies employed by the authors could be matched to all but two barriers (psychopathology/substance misuse and limited resource availability). There was evidence that multiple strategies were employed, and that these depended upon the population, clinical set-up and resources available. CONCLUSIONS: This typology of strategies to overcome barriers to recruiting ethnic minorities provides guidance on achieving higher rates of recruitment. It is important that researchers plan to deploy these strategies well in advance of initiating recruitment. Whilst adopting these strategies, the authors have not been able to quantify the positive impact of these strategies on recruitment. The typology should encourage researchers to employ these strategies in future research, refine them further and quantitatively evaluate their impact. PMID- 25934298 TI - Diagnostic neglect: the potential impact of losing a separate axis for personality disorder. AB - Both major classifications in psychiatry have now moved away from the multi-axial nosological model. This is clinically understandable as the specific categorical diagnoses, other than borderline personality disorder and personality disorder 'NOS' (not otherwise specified) were so seldom used and empirical evidence would not support the polythetic categorical system. As a consequence, those with personality disorders, frequently referred to as Axis II disorders, now have to compete with all other mental disorders for clinical attention. PMID- 25934299 TI - NICE CG178 Psychosis and Schizophrenia in Adults: Treatment and Management - an evidence-based guideline? AB - National Institute for Health and Care Excellence (NICE) clinical guideline (CG)178 was published in 2014. NICE guidelines occupy an important international position. We argue that CG178 overemphasises the use of cognitive-behavioural therapy for schizophrenia and those 'at risk' of psychosis, with recommendations that do not always reflect the evidence base. The CG178 recommendations on medications are limited. PMID- 25934300 TI - Quetiapine immediate release v. placebo for schizophrenia: systematic review, meta-analysis and reappraisal. AB - BACKGROUND: Immediate-release (IR) quetiapine has been used to treat schizophrenia since 1997, although all the principal placebo-controlled trials have >50% missing outcome data. New studies with relatively lower rates of participant withdrawal have since been published. AIMS: To assess the efficacy and adverse effects of quetiapine IR for schizophrenia, with consideration of outcome quality and clinical meaningfulness of results, and to examine the potential impact of missing data on the main efficacy findings. METHOD: We conducted a systematic review and meta-analysis of randomised controlled trials comparing quetiapine IR and placebo (or subtherapeutic dose in relapse prevention trials) for the treatment of schizophrenia (PROSPERO registration CRD4201100165). Primary outcomes were change in overall symptoms and response rates. We also examined whether high rates of participant withdrawal (>=50%) attenuated effect sizes, and assessed the impact of making different assumptions about these people's outcomes. RESULTS: We identified 15 relevant trials (including 2 unpublished), providing the first 12-week data for this drug and the first data on self-reported quality of life. We found quetiapine IR to have a weighted mean difference (WMD) of 6.5 points (95% CI -8.9 to -4) on Positive and Negative Syndrome Scale (PANSS) total scores, which corresponds to a standardised mean difference (SMD) of -0.33 (95% CI -0.46 to -0.21). Longer trials reported larger mean differences favouring quetiapine IR, but the overall estimate was smaller if more conservative assumptions about the outcomes of people who left the trial early were made. Approximately 21 people needed to take quetiapine IR for 1 person to experience at least a 50% improvement in PANSS score. No difference in quality of life was observed (two RCTs), although small to moderate improvements in social functioning were found (three RCTs). Quetiapine IR caused sedation and increased rates of clinically significant weight gain, but no extrapyramidal effects were observed. CONCLUSIONS: Quetiapine IR has a small beneficial effect on overall psychotic symptoms over 2-12 weeks, but also leads to weight gain and sedation. PMID- 25934301 TI - I, me, my cell phone - extra. PMID- 25934302 TI - Something nasty in the woodshed - psychiatry in literature. PMID- 25934304 TI - Good grief - in 100 words. PMID- 25934305 TI - Therapeutic potential of psychedelic agents. PMID- 25934306 TI - Therapeutic potential of psychedelic agents. PMID- 25934307 TI - Author's reply: To PMID 25561484. PMID- 25934308 TI - Are conclusions overstated for placebo response? PMID- 25934309 TI - Author's reply: To PMID 25213159. PMID- 25934310 TI - Improving assessment and treatment of physical health problems in people with severe mental illness: the case for a shared IT system. PMID- 25934316 TI - Reversible alterations of the neuronal activity in spontaneous intracranial hypotension. AB - AIM: The aim of this article is to investigate the pathophysiology underlying the alternation of the cognitive function and neuronal activity in spontaneous intracranial hypotension (SIH). METHODS: Fifteen patients with SIH underwent resting-state functional magnetic resonance imaging and working-memory (WM) test one day before and one month after a surgical operation. Alternation of the cognitive function and spontaneous neuronal activity measured as amplitude of the low-frequency fluctuations (ALFF) and the functional connectivity of the default mode network (DMN) and frontoparietal networks (FPNs) were evaluated. RESULTS: WM performance significantly improved post-operatively. Whole-brain linear regression analysis of the ALFF revealed a positive correlation between cognitive performance change and ALFF change in the precuneus while a negative correlation was found in the bilateral orbitofrontal cortices (OFCs) and right medial frontal cortex (MFC). The ALFF changes normalised with the WM performance improvement post-operatively. The FPN activity in the right OFC was also increased pre operatively. Partial correlation analysis revealed a significant correlation between WM performance and right OFC activity controlled for right FPN activity. CONCLUSIONS: The abnormal activity of the OFCs and MFC that is not originating from the synchronous intrinsic network activity, together with the decreased activity of the central node of the DMN, could lead to cognitive impairment in SIH that is reversible through restoration of the cerebrospinal fluid. PMID- 25934314 TI - Genetic polymorphisms of the sortase A gene and social-behavioural factors associated with caries in children: a case-control study. AB - BACKGROUND: Streptococcus mutans (S. mutans) is the primary etiological agent of dental caries. Sortase is a transpeptidase that anchors several surface proteins to the S. mutans cell wall and has been shown to play a major role in cariogenicity. The purpose of this study was to explore the genetic polymorphisms of the sortase gene (srtA) and the social-behavioural factors associated with dental caries in children with S. mutans. METHODS: In this case-control study, 121 S. mutans strains were separately selected from caries-free children and high severity caries children for sequencing of the srtA gene. Social and behavioural data were collected by self-administered questionnaires. Genomic DNA was extracted from S. mutans strains and amplified by PCR to obtain the srtA gene. The purified PCR products were sequenced and analysed for mutations with ABI Variant Reporter software. The distribution of missense mutations and the mean of social-behavioural factors were compared between the groups. A multiple logistic regression model was used to control for confounding factors. RESULTS: The mutation frequencies at loci 168 (P = 0.023) and 470 (P = 0.032) were significantly different between the groups. The best-fitting model showed that greater age, high frequencies of solid sugar consumption, prolonged breastfeeding, a high proportion of visible plaque, and S. mutans with a T at locus 168 of the srtA gene were associated with high-severity caries in children (P < 0.05). Children carrying a G at locus 168 of S. mutans had a decreased risk for high-severity caries (OR = 0.32, 95% CI = 0.12-0.86) compared with those carrying a T. CONCLUSIONS: The present study suggested that the locus 168 missense mutation of the srtA gene may correlate with caries susceptibility in children with S. mutans. In addition, age, duration of breastfeeding, solid sugar consumption, and poor oral hygiene contributed to this complex disease. PMID- 25934317 TI - Toward a pragmatic migraine model for drug testing: I. Cilostazol in healthy volunteers. AB - BACKGROUND: A model for the testing of novel antimigraine drugs should ideally use healthy volunteers for ease of recruiting. Cilostazol provokes headache in healthy volunteers with some migraine features such as pulsating pain quality and aggravation by physical activity. Therefore, this headache might respond to sumatriptan, a requirement for validation. The hypothesis of the present study was that sumatriptan but not placebo is effective in cilostazol-induced headache in healthy individuals. METHODS: In a double-blind, randomized, cross-over design, 30 healthy volunteers of both sexes received cilostazol 200 mg on two separate days, each day followed by oral self-administered placebo or sumatriptan 50 mg. Headache response and accompanying symptoms were registered in a questionnaire by the participants themselves. RESULTS: Cilostazol induced a reproducible headache in 90% of the participants. The headache had several migraine-like features in most individuals. Median peak headache score was 2 on the sumatriptan day and 3 on the placebo day (p = 0.17). There was no reduction in headache intensity two hours after sumatriptan (p = 0.97) and difference in AUC 0 to four hours between two experimental days was not significant (p = 0.18). On the placebo day eight participants took rescue medication compared to 3 on the sumatriptan day (p = 0.13). CONCLUSION: Despite similarities with migraine headache, cilostazol-induced headache in healthy volunteers does not respond to sumatriptan. PMID- 25934315 TI - Factors associated with appropriate home management of uncomplicated malaria in children in Kassena-Nankana district of Ghana and implications for community case management of childhood illness: a cross-sectional study. AB - BACKGROUND: Home management of uncomplicated malaria (HMM) is now integrated into the community case management of childhood illness (CCM), an approach that requires parasitological diagnosis before treatment. The success of CCM in resource-constrained settings without access to parasitological testing significantly depends on the caregiver's ability to recognise malaria in children under five years (U5), assess its severity, and initiate early treatment with the use of effective antimalarial drugs in the appropriate regimen at home. Little is known about factors that influence effective presumptive treatment of malaria in U5 by caregivers in resource-constrained malaria endemic areas. This study examined the factors associated with appropriate HMM in U5 by caregivers in rural Kassena-Nankana district, northern Ghana. METHODS: A cross-sectional household survey was conducted among 811 caregivers recruited through multistage sampling. A caregiver was reported to have practiced appropriate HMM if an antimalarial drug was administered to a febrile child in the recommended regimen (correct dose and duration for the child's age). Binary logistic regression was used to determine factors associated with appropriate HMM. RESULTS: Of the 811 caregivers, 87% recognised the symptoms of uncomplicated malaria in U5, and 49% (n = 395) used antimalarial drugs for the HMM. Fifty percent (n = 197) of caregivers who administered antimalarial drugs used the appropriate regimen. In the multivariate logistic regression, caregivers with secondary (OR = 1.71, 95% CI: 1.03, 2.83) and tertiary (OR = 3.58, 95% CI: 1.08, 11.87) education had increased odds of practicing appropriate HMM compared with those with no formal education. Those who sought treatment in the hospital for previous febrile illness in U5 had increased odds of practicing appropriate HMM (OR = 2.24, 95% CI: 1.12, 4.60) compared with those who visited the health centres. CONCLUSIONS: Half of caregivers who used antimalarial drugs practiced appropriate HMM. Educational status and utilisation of hospitals in previous illness were associated with appropriate HMM. Health education programmes that promote the use of the current first line antimalarial drugs in the appropriate regimen should be targeted at caregivers with no education in order to improve HMM in communities where parasitological diagnosis of malaria may not be feasible. PMID- 25934318 TI - Saviour siblings: no avoiding the hard questions. PMID- 25934319 TI - Adab and its significance for an Islamic medical ethics. AB - Discussions of Islamic medical ethics tend to focus on Shari'ah-based, or obligation-based, ethics. However, limiting Islamic medical ethics discourse to the derivation of religious duties ignores discussions about moulding an inner disposition that inclines towards adherence to the Shari'ah. In classical Islamic intellectual thought, such writings are the concern of adab literature. In this paper, we call for a renewal of adabi discourse as part of Islamic medical ethics. We argue that adab complements Shari'ah-based writings to generate a more holistic vision of Islamic medical ethics by supplementing an obligation-based approach with a virtue-based approach. While Shari'ah-based medical ethics focuses primarily on the moral status of actions, adab literature adds to this genre by addressing the moral formation of the agent. By complementing Shari'ah based approaches with adab-focused writings, Islamic medical ethics discourse can describe the relationship between the agent and the action, within a moral universe informed by the Islamic intellectual tradition. PMID- 25934320 TI - DIAGEOTROPICA: news from the auxin swamp. AB - Recently established links between the tomato cyclophilin A-type protein DIAGEOTROPICA and the regulation of polar auxin transport provide first mechanistic insights into the function of this enigmatic locus. PMID- 25934321 TI - Enhancing repair of full-thickness excisional wounds in a murine model: Impact of tissue-engineered biological dressings featuring human differentiated adipocytes. AB - Promotion of skin repair for acute or chronic wounds through the use of tissue engineered products is an active field of research. This study evaluates the effects mediated by tissue-engineered biological dressings containing human in vitro-differentiated adipocytes and adipose-derived stromal cells (ASCs). Re epithelialization, granulation tissue formation and neovascularization of full thickness cutaneous wounds were specifically assessed using a murine model featuring a fluorescent epidermis. In comparison with wounds that did not receive an adipocyte-containing biological dressing, treated wounds displayed a slight but significantly faster wound closure based on macroscopic observations over 18 days. Non-invasive imaging of GFP-expressing keratinocytes determined that the kinetics of re-epithelialization were similar for both groups. Treated wounds featured thicker granulation tissues (1.7-fold, P < 0.0001) enriched in collagens (1.3-fold, P < 0.0104). In addition, wound cryosections labeled for detection of CD31-expressing cells indicated a 2.2-fold (P < 0.0002) increased neovascularization for the treated wounds at the time of terminal biopsy. This is in accordance with the secretion of pro-angiogenic factors detected in media conditioned by the dressings. Taken together, these results establish that a new type of engineered substitutes featuring a mixture of adipocytes and ASCs can promote cutaneous healing when applied as temporary dressings, suggesting their potential relevance for chronic wound management studies. PMID- 25934323 TI - Nutritional considerations for patients with interstitial cystitis/bladder pain syndrome. PMID- 25934322 TI - Micromechanical poroelastic finite element and shear-lag models of tendon predict large strain dependent Poisson's ratios and fluid expulsion under tensile loading. AB - As tendons are loaded, they reduce in volume and exude fluid to the surrounding medium. Experimental studies have shown that tendon stretching results in a Poisson's ratio greater than 0.5, with a maximum value at small strains followed by a nonlinear decay. Here we present a computational model that attributes this macroscopic observation to the microscopic mechanism of the load transfer between fibrils under stretch. We develop a finite element model based on the mechanical role of the interfibrillar-linking elements, such as thin fibrils that bridge the aligned fibrils or macromolecules such as glycosaminoglycans (GAGs) in the interfibrillar sliding and verify it with a theoretical shear-lag model. We showed the existence of a previously unappreciated structure-function mechanism whereby the Poisson's ratio in tendon is affected by the strain applied and interfibrillar-linker properties, and together these features predict tendon volume shrinkage under tensile loading. During loading, the interfibrillar linkers pulled fibrils toward each other and squeezed the matrix, leading to the Poisson's ratio larger than 0.5 and fluid expulsion. In addition, the rotation of the interfibrillar-linkers with respect to the fibrils at large strains caused a reduction in the volume shrinkage and eventual nonlinear decay in Poisson's ratio at large strains. Our model also predicts a fluid flow that has a radial pattern toward the surrounding medium, with the larger fluid velocities in proportion to the interfibrillar sliding. PMID- 25934324 TI - [Crystalluria]. AB - Crystalluria is the presence of crystals in urine. It results from excessive supersaturation and may induce kidney problems such as nephrolithiasis, nephrocalcinosis and sometimes acute or chronic kidney impairment able to result in end stage renal failure. Crystalluria is not, per se, a marker of a pathologic condition. For distinguishing between physiologic and pathologic crystalluria, various criteria may be considered (1) either related to the sample such as urine pH, crystal identity, crystal habit, abundance of the crystals, aggregation and also the occurrence of crystalluria judged on serial samples, (2) or related to the clinical context such as nephrolithiasis, nephrocalcinosis or renal failure. The choice of the sample and the pre-analytical conditions are critical to validate the results from a clinical point of view. In our experience, the first morning urine sample is often the best one to assess, through the crystalluria analysis, the main metabolic factors involved in the crystal and stone formation. The storage of urine sample should be less than two hours at room temperature following the voiding. Crystalluria examination allows identifying simply monogenic crystallogenetic pathologies, providing explanation for acute renal failure related to drug intake, helping the physician for identifying the main metabolic disorders involved in stone formation and assessing the efficacy of preventive measures proposed to avoid stone recurrence in stone former patients. Crystalluria study is by far the best marker for predicting stone recurrence during the follow-up of stone formers, offering the opportunity to adjust dietary advices or drug management and thus to prevent stone formation. In conclusion, crystalluria examination is a major tool for the diagnosis and the management of most lithogenetic diseases and pathologic conditions responsible for intratubular crystal formation and renal impairment. PMID- 25934326 TI - The prevention, diagnosis and management of central venous line infections in children. AB - With advancing paediatric healthcare, the use of central venous lines has become a fundamental part of management of neonates and children. Uses include haemodynamic monitoring and the delivery of lifesaving treatments such as intravenous fluids, blood products, antibiotics, chemotherapy, haemodialysis and total parenteral nutrition (TPN). Despite preventative measures, central venous catheter-related infections are common, with rates of 0.5-2.8/1000 catheter days in children and 0.6-2.5/1000 catheter days in neonates. Central line infections in children are associated with increased mortality, increased length of hospital and intensive care unit stay, treatment interruptions, and increased complications. Prevention is paramount, using a variety of measures including tunnelling of long-term devices, chlorhexidine antisepsis, maximum sterile barriers, aseptic non-touch technique, minimal line accessing, and evidence-based care bundles. Diagnosis of central line infections in children is challenging. Available samples are often limited to a single central line blood culture, as clinicians are reluctant to perform painful venepuncture on children with a central, pain-free, access device. With the advancing evidence basis for antibiotic lock therapy for treatment, paediatricians are pushing the boundaries of line retention if safe to do so, due to among other reasons, often limited venous access sites. This review evaluates the available paediatric studies on management of central venous line infections and refers to consensus guidelines such as those of the Infectious Diseases Society of America (IDSA). PMID- 25934325 TI - Development of immunity in early life. AB - The immune system in early life goes through rapid and radical changes. Early life is also the period with the highest risk of infections. The foetal immune system is programmed to coexist with foreign antigenic influences in utero, and postnatally to rapidly develop a functional system capable of distinguishing helpful microbes from harmful pathogens. Both host genetics and environmental influences shape this dramatic transition and direct the trajectory of the developing immune system into early childhood and beyond. Given the malleability of the immune system in early life, interventions aimed at modulating this trajectory thus have the potential to translate into considerable reductions in infectious disease burden with immediate as well as long-lasting benefit. However, an improved understanding of the underlying molecular drivers of early life immunity is prerequisite to optimise such interventions and transform the window of early life vulnerability into one of opportunity. PMID- 25934327 TI - Genetic diversity and drug susceptibility profile of Mycobacterium tuberculosis isolated from different regions of India. AB - OBJECTIVES: Molecular genotyping profiles of Mycobacterium tuberculosis (MTB) provide a valuable insight into the evolution and transmission of the bacilli. Due to the lack of comprehensive national level data from India on this subject, we performed this study to determine the recent trends and distribution of various MTB lineages circulating in India. METHODS: A total of 628 MTB isolates were obtained from North, West, South, Central and Eastern India. Spoligotyping and drug susceptibility testing was performed by using manufacturer's instructions. RESULTS: Spoligotyping detected 102 distinct spoligo-patterns. A total of 536 (85.3%) isolates were distributed into 85 SITs which matched the pre existing database, whereas 17 SITs were newly created for 34 (5.4%) isolates. Overall, CAS family genotype was predominant, comprising 222 (35.4%) isolates, followed by EAI in 152 (24.2%), Beijing in 108 (17.2%), Manu in 41 (6.5%), T in 30 (4.8%), H in 6 (0.9%), X in 3 (0.5%) and one (0.2%) each in Ural and AFRI. Drug susceptibility testing identified 134 (21.3%) isolates as multi drug resistant (MDR). CONCLUSIONS: The CAS lineage had a pan India presence but EAI lineage was confined to southern parts of India. Beijing genotype of MTB was significantly associated (p-value <0.0001) with MDR. PMID- 25934328 TI - MicroResearch--Finding sustainable solutions to local health challenges in East Africa. AB - The urgent need in Africa for research capacity building has been recognized by African leaders and governments for many years. However, lack of large research funding opportunities has been seen as a major obstacle to improving research capacity in precisely those countries that need it the most. Microfinance has shown that a small infusion of capital can "prime the pump" to creative local economic productivity. In a similar way, MicroResearch has proven effective in promoting a similar bottom-up strategy to find sustainable solutions to local health challenges through local community focused research. Specifically, MicroResearch through hands-on didactic courses, mentoring and small-scale research funding promotes small research projects that improve research skills across the entire health-care provider spectrum to unleash a culture of inquiry. This in turn stimulates health care providers to identify the locally most relevant obstacles that need to be overcome and implement locally feasible and sustainable solutions. MicroResearch is a bottom-up strategy proven effective at finding sustainable solutions to local health challenges. PMID- 25934330 TI - Multiparametric assay using HepaRG cells for predicting drug-induced liver injury. AB - The utility of HepaRG cells as an in vitro cell-based assay system for assessing drug-induced liver injury (DILI) risk was investigated. Seventeen DILI-positive and 15 DILI-negative drugs were selected for the assay. HepaRG cells were treated with each drug for 24h at concentrations that were 1.6-, 6.3-, 25-, and 100-fold the therapeutic maximum plasma concentration (Cmax). After treatment, the cell viability, glutathione content, caspase 3/7 activity, lipid accumulation, leakage of lactate dehydrogenase, and albumin secretion were measured. The sensitivity and specificity were calculated to assess the ability of the assay to predict DILI. Our multiparametric assay using HepaRG cells exhibited a 67% sensitivity and 73% specificity at a 100-fold concentration of Cmax and a 41% sensitivity and 87% specificity at a 25-fold concentration of Cmax. When a 25-fold Cmax cut-off was applied, approximately 70% of drugs exhibiting positive responses were classified into the high DILI risk category. HepaRG cells distinguished relatively safe drugs from their high-risk analogs. Our study indicates that HepaRG cells may be of use to (1) prioritize drug analogs, (2) analyze the mechanism of DILI, and (3) assess the risk for DILI in the early drug discovery stage. PMID- 25934331 TI - Doping reversed-phase media for improved peptide purification. AB - The purification of therapeutic peptides is most often performed using one or more reversed phase chromatography steps. This ensures high purities while keeping the costs of purification under control. In this paper, a doped reversed phase chromatographic material is tested and compared to traditional reversed phase materials. The doping consists of adding limited amounts of ion exchange ligands to the surface of the material to achieve orthogonal separation and increase the non-hydrophobic interactions with the surface. These ionic groups can either be attractive (opposite charge), or repulsive (same charge) to the peptide. The benefit of this new doped reversed phase material is shown through increases in selectivity in diluted conditions and yield and productivity in overloaded (i.e. industrial) conditions. It is the conjectured that all performance characteristics should increase using repulsive doping groups, whereas these characteristics should decrease when using attractive doping groups. This conjecture is shown to be true through several examples, including purifications of industrially relevant peptide crudes, in industrially relevant conditions. Moreover, the effect of ionic strength and organic modifier concentration was explored and shown to be in line with the expected behavior. PMID- 25934332 TI - The auditory dynamic attending theory revisited: A closer look at the pitch comparison task. AB - The dynamic attending theory as originally proposed by Jones, 1976. Psychol. Rev. 83(5), 323-355 posits that tone sequences presented at a regular rhythm entrain attentional oscillations and thereby facilitate the processing of sounds presented in phase with this rhythm. The increased interest in neural correlates of dynamic attending requires robust behavioral indicators of the phenomenon. Here we aimed to replicate and complement the most prominent experimental implementation of dynamic attending (Jones et al., 2002. Psychol. Sci. 13(4), 313 319). The paradigm uses a pitch comparison task in which two tones, the initial and the last of a longer series, have to be compared. In-between the two, distractor tones with variable pitch are presented, at a regular pace. A comparison tone presented in phase with the entrained rhythm is hypothesized to lead to better behavioral performance. Aiming for a conceptual replication, four different variations of the original paradigm were created which were followed by an exact replication attempt. Across all five experiments, only 40 of the 140 tested participants showed the hypothesized pattern of an inverted U-shaped profile in task accuracy, and the group average effects did not replicate the pattern reported by Jones et al., 2002. Psychol. Sci. 13(4), 313-319 in any of the five experiments. However, clear evidence for a relationship between musicality and overall behavioral performance was found. This study casts doubt on the suitability of the pitch comparison task for demonstrating auditory dynamic attending. We discuss alternative tasks that have been shown to support dynamic attending theory, thus lending themselves more readily to studying its neural correlates. This article is part of a Special Issue entitled SI: Prediction and Attention. PMID- 25934333 TI - Overexpression of ANCCA/ATAD2 in endometrial carcinoma and its correlation with tumor progression and poor prognosis. AB - This study aimed to explore the clinical significance of AAA+ (ATPases associated with various cellular activities) nuclear coregulator cancer-associated (ANCCA) protein expression in endometrial carcinoma (EC). Correlations of ANCCA expression with clinicopathological factors and prognosis of EC patients were analyzed. Expression of ANCCA was detected in EC from 207 patients along with corresponding normal endometrium specimens by immunohistochemistry. ANCCA immunoreactivity was overexpressed in EC cases compared with that in normal endometrium (P < 0.001). High ANCCA expression was positively correlated with the International Federation of Gynecology and Obstetrics (FIGO) stage, histological grade, depth of myometrial invasion, lymph node metastasis, lymph vascular space involvement, and recurrence but not with age and histological type. Patients with high ANCCA expression exhibited significantly poorer overall survival (OS) and disease-free survival (DFS) than patients with low ANCCA expression (P = 0.001 and 0.002, respectively). Cox multivariate analysis showed that high ANCCA expression was an independent prognostic factor for both OS (hazard ratio (HR) = 4.954, 95 % confidence interval (CI) = 1.537-15.966; P = 0.007) and DFS of patients with EC (HR = 4.237, 95 % CI = 1.295-13.859; P = 0.017). We identified ANCCA protein expression as a novel independent poor prognostic indicator in EC. PMID- 25934334 TI - HAS3 underexpression as an indicator of poor prognosis in patients with urothelial carcinoma of the upper urinary tract and urinary bladder. AB - Via data mining a published transcriptomic database of UBUC (GSE31684), we discovered hyaluronan synthase-3 (HAS3) as the most significant gene stepwise downregulated from early tumorigenesis to progression among those associated with hyaluronan synthase activity (GO:0050501). We consequently analyzed HAS3 protein expression and their association with clinicopathological factors and survival in our well-characterized cohort of urothelial carcinoma of upper urinary tract (UTUC) and urinary bladder (UBUC). HAS3 expression was assessed by immunohistochemistry and evaluated by using H score method in 295 UBUCs and 340 UTUCs, respectively. HAS3 protein expression statuses were further correlated with clinicopathological parameters and evaluated the prognostic significance for disease-specific survival (DSS) and metastasis-free survival (MeFS). HAS3 protein underexpression was significantly associated with advanced pT status, nodal metastasis, high histological grade, vascular invasion, and frequent mitoses in both groups of UCs. HAS3 underexpression not only predicted poorer DSS and MeFS with univariate analysis, but also indicated dismal DSS and MeFS in multivariate analysis. HAS3 underexpression is associated with advanced tumor stage and adverse pathological features, as well as implies inferior clinical outcomes for both groups of patients with UTUCs and UBUCs, suggesting its critical role in tumor progression in UCs and may serve as a prospective prognostic biomarker and a novel therapeutic target in UCs. PMID- 25934335 TI - In vitro expansion of U87-MG human glioblastoma cells under hypoxic conditions affects glucose metabolism and subsequent in vivo growth. AB - Hypoxia is a characteristic feature of solid tumors leading to the over expression of hypoxia-inducible factor (HIF)-1alpha protein and therefore to a specific cellular behavior. However, even though the oxygen tension in tumors is low (<5 %), most of the cell lines used in cancer studies are grown under 21 % oxygen tension. This work focuses on the impact of oxygen conditions during in vitro cell culture on glucose metabolism using 1-(13)C-glucose. Growing U87-MG glioma cells under hypoxic conditions leads to a two- to threefold reduction of labeled glutamine and an accumulation of fructose. However, under both hypoxic and normoxic conditions, glucose is used for de novo synthesis of pyrimidine since the (13)C label is found both in the uracil and ribose moieties. Labeling of the ribose ring demonstrates that U87-MG glioma cells use the reversible branch of the non-oxidative pentose phosphate pathway. Interestingly, stereotactic implantation of U87-MG cells grown under normoxia or mild hypoxia within the striatum of nude mice led to differential growth; the cells grown under hypoxia retaining an imprint of the oxygen adaptation as their development is then slowed down. PMID- 25934336 TI - Transforming growth factor beta receptor signaling restrains growth of pancreatic carcinoma cells. AB - Pancreatic ductal adenocarcinoma (PDAC) is extremely malignant. Efficient control of cancer growth may substantially improve the survival of PDAC patients. However, no efficient treatments are so far available. Here, we inhibited transforming growth factor beta (TGFbeta) receptor signaling by overexpression of a key inhibitor of this pathway, SMAD7, in the mouse pancreas, using a recently developed intraductal infusion method. Overexpression of SMAD7 significantly increased growth of both implanted PDAC and PDAC by K-ras modification. Our data thus suggest that TGFbeta receptor signaling restrains growth of PDAC, and modulation of TGFbeta receptor signaling may be an effective treatment for PDAC. PMID- 25934337 TI - Inducing cell growth arrest and apoptosis by silencing long non-coding RNA PCAT-1 in human bladder cancer. AB - Long non-coding RNAs (lncRNAs) are a class of non-coding RNAs that play important roles in cancer development and progression. Prostate cancer-associated transcript 1 (PCAT-1) is a novel lncRNA that promotes cell proliferation in prostate cancer. We hypothesized that PCAT-1 also have roles in bladder cancer. In this study, we found that PCAT-1 was up-regulated in bladder cancer compared to paired normal urothelium. Cell proliferation inhibition and apoptosis induction were also observed in PCAT-1 small hairpin RNA (shRNA)-transfected bladder cancer T24 and 5637 cells. Our data suggest that PCAT-1 plays oncogenic roles and can be used as a therapeutic target for treating human bladder cancer. PMID- 25934338 TI - New approaches for cancer immunotherapy. AB - Immunotherapy is a promising field that offers alternative methods for treatment of cancer. The current strategy consists of cancer vaccines, monoclonal antibodies, and cellular therapies. Cancer vaccines aim to eradicate cancer cells via immune system. Thus, they may attack these cells derived from any type of cancer, besides their role in preventing cancer. Lymphocytes and dendritic cells are often used in cellular therapy. In addition, monoclonal antibodies are designed to target specific antigens found in cancer cells. Currently, at least 12 clinically approved monoclonal antibodies are being used and many cancer vaccines are being developed with ongoing phase studies for cancer therapy. Relevant studies are focused on glioma and several other cancer types. Correspondingly, the combination of effective methods may enhance the efficacy of immunotherapy. It is thought that particularly immune checkpoint inhibitors will play a crucial role in immunotherapeutic approaches. PMID- 25934340 TI - Possible associations between ascites and vascular invasion in patients with hepatocellular carcinoma. PMID- 25934339 TI - Genetic polymorphisms in cytochrome P450 and clinical outcomes of FOLFIRI chemotherapy in patients with metastatic colorectal cancer. AB - The purpose of this study is to evaluate the influence of germline polymorphisms of cytochrome P450 (CYP450) on objective response, progression-free survival (PFS) and overall suruvival (OS) in metastatic colorectal cancer (mCRC) receiving the combination chemotherapy of irinotecan, 5-fluorouracil, and leucovorin (FOLFIRI). All SNPs in CYP450, whose minor allele frequency were more than 10 %, were genotyped in 82 patients with mCRC who received first-line FOLFIRI regimen. chi (2) test or Fisher's exact test was used to assess the correlation between SNPs and objective response as appropriate and log-rank test between SNPs and PFS or OS. Cox proportional hazards models were used to analyze the association of CYP450 gene polymorphisms and clinical factors for PFS and OS. No SNP showed predictive or prognostic value for clinical outcomes, except for CYP3A5 rs776746 A>G, which was significantly associated with PFS (P = 0.0002). Multivariate analysis confirmed its prognostic value for PFS (P = 0.002). CYP3A5 rs776746 A>G polymorphisms have a prognostic contribution toward FOLFIRI regimen in mCRC. This could represent a further step toward personalized therapy. PMID- 25934341 TI - Anti-N-methyl-D-aspartate receptor encephalitis: Should psychiatrists shoulder the responsibility for a non-psychiatric disorder? PMID- 25934342 TI - Adult brainstem gliomas: Correlation of clinical and molecular features. AB - BACKGROUND: Brainstem gliomas are rare in adults and overall have superior survival outcomes compared to pediatric brainstem gliomas. PATIENTS AND METHODS: We conducted a retrospective data and tissue analysis of all adult patients (>= 18 years old) with World Health Organization (WHO) Grade II, III, and IV brainstem gliomas in the University of Texas MD Anderson Cancer Center institutional database from 1990 to 2012. RESULTS: We identified 143 cases in adults ages 18 and over. There were 28 glioblastomas, 43 anaplastic astrocytomas, 15 diffuse astrocytomas, and 11 gliomas not otherwise specified, and in 46 cases the diagnosis was made radiographically. 128 (89.5%) cases were classified radiographically as diffuse and of the focal tumors, 9 of the 15 were WHO Grade III or IV tumors. Increasing tumor grade and contrast enhancement were associated with significantly reduced overall survival. The median overall survival for the entire cohort was 32.1 months similar to previously published studies. Two of 25 grade II and III tumors, and 1 of 17 glioblastomas had IDH1 mutations on immunohistochemical testing. Nine cases had sufficient tissue for mutation profiling, 1 case had a BRAF V600E mutation and 2 had 2 PIK3CA mutations. CONCLUSIONS: Survival outcomes for adult WHO Grade II to IV brainstem gliomas were similar to supratentorial IDH1 wild-type tumors of similar grade and histology. Potentially actionable mutations can be identified from small biopsy samples in a subset of adult brainstem gliomas. PMID- 25934344 TI - A practical method of modeling a treatment couch using cone-beam computed tomography for intensity-modulated radiation therapy and RapidArc treatment delivery. AB - The effect of a treatment couch on dose perturbation is not always fully considered in intensity-modulated radiation therapy (IMRT) and volumetric modulated arc therapy (VMAT). In the course of inverse planning radiotherapy techniques, beam parameter optimization may change in the absence of the couch, causing errors in the calculated dose distributions. Although modern treatment planning systems (TPS) include data for the treatment couch components, they are not manufactured identically. Thus, variations in their Hounsfield unit (HU) values may exist. Moreover, a radiotherapy facility may wish to have a third party custom tabletop installed that is not included by the TPS vendor. This study demonstrates a practical and simple method of acquiring reliable computed tomography (CT) data for the treatment couch and shows how the absorbed dose calculated with the modeled treatment couch can differ from that with the default treatment couch found in the TPS. We also experimentally verified that neglecting to incorporate the treatment couch completely in the treatment planning process might result in dose differences of up to 9.5% and 7.3% for 4-MV and 10-MV photon beams, respectively. Furthermore, 20 RapidArc and IMRT cases were used to quantify the change in calculated dose distributions caused by using either the default or modeled couch. From 2-dimensional (2D) ionization chamber array measurements, we observed large dose distribution differences between the measurements and calculations when the couch was omitted that varied according to the planning technique and anatomic site. Thus, incorporating the treatment couch in the dose calculation phase of treatment planning significantly decreases dose calculation errors. PMID- 25934343 TI - Neuromyelitis optica overlapping systemic sclerosis with anti-centromere antibodies. PMID- 25934345 TI - Scientists talking to politicians: Could you please save the environment? (Correspondence on Diamond et al. 2015. Exploring the planetary boundary for chemical pollution. Environment International 78, 8-15). PMID- 25934346 TI - [The Moodle platform: A useful tool for training in life support. Analysis of satisfaction questionnaires from students and instructors of the semFYC advanced life support courses]. AB - OBJECTIVE: The aim of this study is to assess the validity and use of a mixed method of training in life support. The use of Moodle to implement an online pre sessional phase prior to a "classic" classroom phase of teaching in this type of course is the main novelty. DESIGN: Analysis of satisfaction questionnaires of students and instructors of a mixed course in the advanced life support program of SemFYC (ESVAP). SETTING: Moodle platform. semFYC Virtual Classroom. PARTICIPANTS AND/OR CONTEXTS: Students and instructors participating in the semFYC advanced life support program, ESVAP. METHOD: Qualitative analysis. RESULTS: The majority of students rate as very useful (50%) or useful (45.37%) the existence of an online pre-sessional phase, and consider that it has helped them very much (42.20%) or quite a lot (48.62%) to make the most of the face-to face sessions. For instructors, they considered that the existence of an online pre-sessional phase was very useful (89%) or useful (11%) for the development of the face-to-face sessions. DISCUSSION: The analysis of the results concluded that: 1) the students considered a prior non-face to face phase as very useful, and it helped them much/very much in the face to face phase, and 2) the instructors believe that the non-face to face phase had helped them a lot in the presentations and efficiency of the workshops in the face-to-face phase. PMID- 25934347 TI - Preliminary evaluation of beta3-adrenoceptor agonist-induced 18F-FDG metabolic activity of brown adipose tissue in obese Zucker rat. AB - BACKGROUND: We have investigated beta3-adrenoceptor agonist mediated brown adipose tissue (BAT) activation using (18)F-FDG PET/CT in Zucker lean (ZL) and obese (ZF) rats. METHODS: (18)F-FDG was injected into ZL and ZF rats pretreated with saline or agonist CL316,243 for scans. (18)F-FDG metabolic activity was computed as standard uptake values. RESULTS: CL316,243 in ZL activated BAT up to 4-fold compared to saline, while ZF BAT was only up by 2 fold. The decreased activation was consistent with lower beta3-adrenoceptor levels in ZF rats. CONCLUSIONS: The genetically modified ZL and ZF rats may provide a useful rat model to evaluate the significance of beta3-adrenoceptor agonist-induced BAT activation in obesity. PMID- 25934348 TI - Synthesis of [11C]palmitic acid for PET imaging using a single molecular sieve 13X cartridge for reagent trapping, radiolabeling and selective purification. AB - INTRODUCTION: Radiolabeled fatty acids are valuable metabolic tracers for PET imaging. Carbon-11 is widely used in clinical PET studies due to the prevalence of facile techniques enabling the incorporation of [(11)C]CO2 and [(11)C]CH3 into molecules and a short half-life (20.4 min) that translates into low patient dose. However, the short half-life considerably limits the time for radiosynthesis. Furthermore, the majority of the syntheses of [(11)C]palmitic acid in common use employ high starting [(11)C]CO2 activities and/or expensive equipment. METHODS: [(11)C]CO2 was trapped with greater than 99.99% efficiency by a three stage cartridge packed with molecular sieve 13X, 100-120 mesh. The labeling of n pentadecylmagnesium bromide took place in 5 min in the cartridge, and the [(11)C]palmitic acid product was selectively eluted in ethanol following alkaline and acidic washes of the column. RESULTS: The system reliably produced more than 925 MBq (25 mCi) of [(11)C]palmitic acid suitable for human use from 7.4 GBq (200 mCi) of [(11)C]CO2 in 8 min from end-of-bombardment. CONCLUSIONS: We have exploited the properties of the inexpensive molecular sieve 13X to develop a miniature, disposable and leak tight "gas capture" system for the rapid labeling and purification of [(11)C]fatty acids in good yield and >99% radiochemical purity. The rapidity of the synthesis and purification allows small [(11)C]CO2 starting activities to be used, and with no requirement for expensive synthesis equipment or facilities, the system can be implemented in any radiopharmaceutical center. PMID- 25934349 TI - PCD-GED: Protein complex detection considering PPI dynamics based on time series gene expression data. AB - Detection of protein complexes from protein-protein interaction (PPI) networks is essential to understand the function of cell machinery. However, available PPIs are static, and cannot reflect the dynamics inherent in real networks. Our method uses time series gene expression data in addition to PPI networks to detect protein complexes. The proposed method generates a series of time-sequenced subnetworks (TSN) according to the time that the interactions are activated. It finds, from each TSN, the protein complexes by employing the weighted clustering coefficient and maximal weighted density concepts. The final set of detected protein complexes are obtained from union of all complexes from different subnetworks. Our findings suggest that by employing these considerations can produce far better results in protein complex detection problem. PMID- 25934350 TI - Global contraction or local growth, bleb shape depends on more than just cell structure. AB - When the plasma membrane of a cell locally delaminates from its actin cortex the membrane is pushed outwards due to the cell's internal fluid pressure. The resulting spherical protrusion is known as a bleb. A cell's ability to function correctly is highly dependent on the production of such protrusions with the correct size and shape. Here, we investigate the nucleation of large blebs from small, local neck regions. A mathematical model of a cell's membrane, cortex and interconnecting adhesions demonstrates that these three components are unable to capture experimentally observed bleb shapes without the addition of further assumptions. We have identified that combinations of global cortex contraction and localised membrane growth are the most promising methods for generating prototypical blebs. Currently, neither proposed mechanism has been fully tested experimentally and, thus, we propose experiments that will distinguish between the two methods of bleb production. PMID- 25934351 TI - Fusion leads to effective segregation of damage during cell division: An analytical treatment. AB - High levels of cellular damage are associated with impairment of cellular function and cell death. Partitioning the damage into a fraction of cells in the population improves population fitness and survival. We have previously shown that protein aggregates, resulting from misfolded, damaged proteins, fuse with each other leading to damage partitioning during cell division. Here, using an analytical treatment of aggregate fusion in dividing cells we present analytical expressions for two measures of damage partition: aggregate mass partition asymmetry between two dividing cells and standard deviation of total aggregate mass across the population. The scaling laws obtained demonstrate how damage partition may generally depend on characteristics of the cellular processes, facilitating better understanding of damage segregation in biological cells. PMID- 25934352 TI - The maximal C(3) self-complementary trinucleotide circular code X in genes of bacteria, eukaryotes, plasmids and viruses. AB - In 1996, a set X of 20 trinucleotides is identified in genes of both prokaryotes and eukaryotes which has in average the highest occurrence in reading frame compared to the two shifted frames (Arques and Michel, 1996). Furthermore, this set X has an interesting mathematical property as X is a maximal C(3) self complementary trinucleotide circular code (Arques and Michel, 1996). In 2014, the number of trinucleotides in prokaryotic genes has been multiplied by a factor of 527. Furthermore, two new gene kingdoms of plasmids and viruses contain enough trinucleotide data to be analysed. The approach used in 1996 for identifying a preferential frame for a trinucleotide is quantified here with a new definition analysing the occurrence probability of a complementary/permutation (CP) trinucleotide set in a gene kingdom. Furthermore, in order to increase the statistical significance of results compared to those of 1996, the circular code X is studied on several gene taxonomic groups in a kingdom. Based on this new statistical approach, the circular code X is strengthened in genes of prokaryotes and eukaryotes, and now also identified in genes of plasmids. A subset of X with 18 or 16 trinucleotides is identified in genes of viruses. Furthermore, a simple probabilistic model based on the independent occurrence of trinucleotides in reading frame of genes explains the circular code frequencies and asymmetries observed in the shifted frames in all studied gene kingdoms. Finally, the developed approach allows to identify variant X codes in genes, i.e. trinucleotide codes which differ from X. In genes of bacteria, eukaryotes and plasmids, 14 among the 47 studied gene taxonomic groups (about 30%) have variant X codes. Seven variant X codes are identified with at least 16 trinucleotides of X. Two variant X codes XA in cyanobacteria and plasmids of cyanobacteria, and XD in birds are self-complementary, without permuted trinucleotides but non circular. Five variant X codes XB in deinococcus, plasmids of chloroflexi and deinococcus, mammals and kinetoplasts, XC in elusimicrobia and apicomplexans, XE in fishes, XF in insects, and XG in basidiomycetes and plasmids of spirochaetes are C(3) self-complementary circular. In genes of viruses, no variant X code is found. PMID- 25934353 TI - Management of simple renal cyst in children: French multicenter experience of 36 cases and review of the literature. AB - OBJECTIVE: The widespread use of renal ultrasonography has resulted in simple renal cysts (SRC) being discovered with increasing frequency in routine pediatric urological practice. Management of SRC, however, remains controversial. Most SRC are asymptomatic, are diagnosed incidentally, and have no clinical consequence. Our goal was to focus on management strategies for SRC in children with the support of our experience and a review of the literature. MATERIALS AND METHODS: A literature review was made of SRC in children since 1950, analyzing epidemiologic data, diagnosis, and management. In addition, a retrospective multicenter study was conducted from 1998 to 2009. Patients included presented with a unique SRC. Data recorded were patient characteristics (age, gender), symptoms, imaging features of the cyst (size, side, pole, and location), type of management, and long-term outcomes. To focus on management, two groups of patients were defined: primary surgical management and primary conservative management consisting of clinical and US follow-up. Our results were compared with the literature. RESULTS: Thirty-six cases were included. Fifteen patients were symptomatic. Comparing the two groups, long-term outcomes were similar. The only significant factors were preoperative (age of the patient, diameter and location of the cyst): the bigger the cyst, the more likely it was to be exorenal, and the greater the likelihood that surgery would be performed (p = 0.006). Symptoms were not a significant indicator for surgery. CONCLUSION: According to the literature and our experience, and considering the benign natural history of SRC and the similar outcomes whatever the treatment, primary conservative management is recommended for all cases. Surgery should be restricted to symptomatic large compressive cysts, increase in cyst size on follow-up, and uncertain diagnosis. Percutaneous cyst aspiration with sclerotherapy has not yet been used enough to ascertain its safety, and requires prospective evaluation. PMID- 25934354 TI - Provider Perspectives on Principle-Adherent Practice in Empirically Supported Interventions for Emerging Adults with Serious Mental Health Conditions. AB - In recognition of the need to create new treatment approaches that will be appealing to and effective for emerging adults with serious mental health conditions, researchers have begun to create and evaluate programs and interventions that are specifically tailored to reflect the preferences and needs of the population. The literature that describes these new approaches-including both descriptions of interventions and guidelines based on expert consensus expresses a high degree of agreement regarding practice principles that should guide intervention. However, beyond naming these principles, the literature provides little information about what the principles mean, or how principle adherent practice can be recognized. This article describes a qualitative investigation of providers' understanding of principle-driven practice in the context of programs and interventions for emerging adults with serious mental health conditions. The goal was to learn about how providers conceptualize the principles that drive their practice, and how they describe principle-adherent practice. PMID- 25934355 TI - Implementation of Network for the Improvement of Addiction Treatment (NIATx) Processes in Substance Use Disorder Treatment Centers. AB - Internal process improvements embedded within the Network for Improvement of Addiction Treatment (NIATx) program are promising innovations for improving substance use disorder (SUD) treatment performance, such as engagement and retention. To date, few studies have examined the variables that may increase diffusion and implementation of NIATx innovations. This study investigates organizational characteristics associated with SUD treatment center utilization of NIATx process improvements in a sample of 458 treatment programs. Overall, 19% had utilized NIATx process improvements. After statistically controlling environmental factors, five organizational variables were associated with the likelihood that treatment centers used NIATx processes. Organization size, administrative intensity, membership in a provider association, and participation in National Institute on Drug Abuse's Clinical Trials Network were positively associated with the odds of utilizing NIATx processes, while the association for the level of slack resources was negative. The findings suggest that policies and related supportive efforts may be required to facilitate diffusion and implementation of NIATx processes to affect SUD treatment center performance and capacity. PMID- 25934356 TI - The history of Distilbene(r) (Diethylstilbestrol) told to grandchildren--the transgenerational effect. AB - The Distilbene(r) story is a dramatic episode which belongs to the history of medicine. It provided several useful lessons such as the importance of evidence based medicine and the hazard to develop treatments during pregnancy without careful animal verifications. However, this experience has also provided unexpected progress by suggesting new pathophysiological concepts: fetal programming of adult diseases and/or transgenerational transmission of environmental effects through epigenetic modifications. PMID- 25934357 TI - Neurocognitive outcomes of children secondary to mild iodine deficiency in pregnant women. AB - Iodine deficiency is the most important preventable cause of brain damage worldwide. During pregnancy, severe iodine deficiency causes endemic cretinism, whereas mild-to-moderate iodine deficiency impairs neurocognitive function of the offspring. Numerous reports demonstrate the impact of iodine supplementation on prevention of cretinism, and recent studies evaluate the effects of iodine prophylaxis on neurocognitive development in children of women with mild-to moderate iodine deficiency. Iodine prophylaxis is generally well tolerated without side effects for the pregnant women and the offspring. In France, the iodine status was recently considered as satisfactory in children and adult population, but regional studies conducted during the last two decades have shown that healthy women are mild-to-moderately iodine deficient during pregnancy. According to recent World Heath Organization guidelines, systematic iodine prophylaxis is recommended in women planning a pregnancy, during gestation and lactation in order to prevent maternal, neonatal and infantile consequences of mild-to-moderate iodine deficiency. PMID- 25934358 TI - D-dimer: An Overview of Hemostasis and Fibrinolysis, Assays, and Clinical Applications. AB - D-dimer is the smallest fibrinolysis-specific degradation product found in the circulation. The origins, assays, and clinical use of D-dimer will be addressed. Hemostasis (platelet and vascular function, coagulation, fibrinolysis, hemostasis) is briefly reviewed. D-dimer assays are reviewed. The D-dimer is very sensitive to intravascular thrombus and may be markedly elevated in disseminated intravascular coagulation, acute aortic dissection, and pulmonary embolus. Because of its exquisite sensitivity, negative tests are useful in the exclusion venous thromboembolism. Elevations occur in normal pregnancy, rising two- to fourfold by delivery. D-dimer also rises with age, limiting its use in those >80 years old. There is a variable rise in D-dimer in active malignancy and indicates increased thrombosis risk in active disease. Elevated D-dimer following anticoagulation for a thrombotic event indicates increased risk of recurrent thrombosis. These and other issues are addressed. PMID- 25934360 TI - Cancer therapy and replication stress: forks on the road to perdition. AB - Deregulated DNA replication occurs in cancer where it contributes to genomic instability. This process is a target of cytotoxic therapies. Chemotherapies exploit high DNA replication in cancer cells by modifying the DNA template or by inhibiting vital enzymatic activities that lead to slowing or stalling replication fork progression. Stalled replication forks can be converted into toxic DNA double-strand breaks resulting in cell death, i.e., replication stress. While likely crucial for many cancer treatments, replication stress is poorly understood due to its complexity. While we still know relatively little about the role of replication stress in cancer therapy, technical advances in recent years have shed new light on the effect that cancer therapeutics have on replication forks and the molecular mechanisms that lead from obstructed fork progression to cell death. This chapter will give an overview of our current understanding of replication stress in the context of cancer therapy. PMID- 25934359 TI - Circulating biomarkers in malignant melanoma. AB - Melanoma is an aggressive tumor with increasing incidence worldwide. Biomarkers are valuable tools to minimize the cost and improve efficacy of treatment of this deadly disease. Serological markers have not widely been introduced in routine clinical practice due to their insufficient diagnostic sensitivity and specificity. It is likely that the lack of objective responses with traditional treatment hinder biomarker research and development in melanoma. Recently, new drugs and therapies have, however, emerged in advanced melanoma with noticeable objective response ratio and survival. In this new scenario, serological tumor markers should be revisited. In addition, other potential circulating biomarkers such as cell-free DNA, exosomes, microRNA, and circulating tumor cells have also been identified. In this review, we summarize classical and emerging tumor markers and discuss their possible roles in emerging therapeutics. PMID- 25934362 TI - Biofluid proteases profiling in diabetes mellitus. AB - The investigation of protease relevance in biologic systems beyond catabolism of proteins and peptides to amino acids has stimulated interest as to their role in the pathogenesis of several disorders including diabetes mellitus (DM). Evaluation of proteases and the assessment of their activity in biofluids are fundamental to elucidate these proteolytic systems in DM and its related complications. In contrast to traditional immunoassay or substrate based approaches that targeted specific proteases and their inhibitors, the field of degradomics has provided a comprehensive approach to study these enzymes. Although the degradome contains over 500 proteases, very few have been associated with DM and its micro- and macrovascular complications. In this paper, we review these proteases and their respective inhibitors with emphasis on DM. It is likely that future research will expand these initial studies and look to develop high throughput automated technologies to identify and characterize biofluid proteases of diagnostic and prognostic value in other pathologies. PMID- 25934361 TI - Soluble ST2 in Ventricular Dysfunction. AB - Heart failure is a commonly encountered condition associated with increased morbidity, mortality, and healthcare cost. For years, its management has been strongly influenced by the use of B-type natriuretic peptide and N-terminal pro-B type natriuretic peptide biomarkers. In some cases, this approach does not always identify patients with heart failure accurately and may not provide the best prognostic assessment, particularly in the presence of comorbidities. Biomarkers that help refine diagnosis and risk stratification are needed. Soluble ST2, a peptide belonging to the interleukin-1 receptor family, is secreted when cardiomyocytes and cardiac fibroblasts are subjected to mechanical strain. Although preliminary results on this novel biomarker are encouraging, additional and more comprehensive studies are clearly needed to establish its role in the management of patients with heart failure. The purpose of this chapter is to provide an overview of data currently available. PMID- 25934363 TI - Biomarker Characterization by MALDI-TOF/MS. AB - Mass spectrometric techniques frequently used in clinical diagnosis, such as gas chromatography-mass spectrometry, liquid chromatography-mass spectrometry, ambient ionization mass spectrometry, and matrix-assisted laser desorption ionization/time-of-flight mass spectrometry (MALDI-TOF/MS), are discussed. Due to its ability to rapidly detect large biomolecules in trace amounts, MALDI-TOF/MS is an ideal tool for characterizing disease biomarkers in biologic samples. Clinical applications of MS for the identification and characterization of microorganisms, DNA fragments, tissues, and biofluids are introduced. Approaches for using MALDI-TOF/MS to detect various disease biomarkers including peptides, proteins, and lipids in biological fluids are further discussed. Finally, various sample pretreatment methods which improve the detection efficiency of disease biomarkers are introduced. PMID- 25934364 TI - Antibody arrays in biomarker discovery. AB - All of life is regulated by complex and organized chemical reactions that help dictate when to grow, to move, to reproduce, and to die. When these processes go awry, or are interrupted by pathological agents, diseases such as cancer, autoimmunity, or infections can result. Cytokines, chemokines, growth factors, adipokines, and other chemical moieties make up a vast subset of these chemical reactions that are altered in disease states, and monitoring changes in these molecules could provide for the identification of disease biomarkers. From the first identification of carcinoembryonic antigen, to the discovery of prostate specific antigen, to numerous others described within, biomarkers of disease are detectable in a plethora of sample types. The growing number of biomarkers for infection, autoimmunity, and cancer allow for increasingly early detection, to identification of novel drug targets, to prognostic indicators of disease outcome. However, more and more studies are finding that a single cytokine or growth factor is insufficient as a true disease biomarker and that a more global perspective is needed to understand true disease biology. Such a broad view requires a multiplexed platform for chemical detection, and antibody arrays meet and exceed this need by performing this detection in a high-throughput fashion. Herein, we will discuss how antibody arrays have evolved, and how they have helped direct new drug target design, helped identify therapeutic disease markers, and helped in earlier disease detection. From asthma to renal disease, and neurological dysfunction to immunologic disorders, antibody arrays afford a bright future for new biomarkers discovery. PMID- 25934365 TI - Preface. PMID- 25934367 TI - Hydrogen as a GC/MS carrier and buffer gas for use in forensic laboratories. AB - A custom set of ion volumes was manufactured in order to investigate the gain and byproducts using hydrogen as a buffer gas following electron ionization in a quadrupole ion trap mass spectrometer as compared with helium. Analyses of illicit drugs such as cocaine, codeine, and oxycodone, and explosives such as TNT, RDX, and HMTD with ion volume exit orifices of 1mm, 2mm, 4mm, 6mm, 8mm and 10mm were performed using GC/MS. Strong similarities between hydrogen and helium spectra of illicit drugs and explosives provide evidence that hydrogen can be used effectively as a buffer gas in an ion trap mass spectrometer. PMID- 25934366 TI - The appliance of science to justice.... PMID- 25934368 TI - Fast detection and characterization of organic and inorganic gunshot residues on the hands of suspects by CMV-GC-MS and LIBS. AB - A rapid method for the characterization of both organic and inorganic components of gunshot residues (GSR) is proposed as an alternative tool to facilitate the identification of a suspected shooter. In this study, two fast screening methods were developed and optimized for the detection of organic compounds and inorganic components indicative of GSR presence on the hands of shooters and non-shooters. The proposed methods consist of headspace extraction of volatile organic compounds using a capillary microextraction of volatiles (CMV) device previously reported as a high-efficiency sampler followed by detection by GC-MS. This novel sampling technique has the potential to yield fast results (<2min sampling) and high sensitivity capable of detecting 3ng of diphenylamine (DPA) and 8ng of nitroglycerine (NG). Direct analysis of the headspace of over 50 swabs collected from the hands of suspected shooters (and non-shooters) provides information regarding VOCs present on their hands. In addition, a fast laser induced breakdown spectroscopy (LIBS) screening method for the detection of the inorganic components indicative of the presence of GSR (Sb, Pb and Ba) is described. The sampling method for the inorganics consists of liquid extraction of the target elements from the same cotton swabs (previously analyzed for VOCs) and an additional 30 swab samples followed by spiking 1MUL of the extract solution onto a Teflon disk and then analyzed by LIBS. Advantages of LIBS include fast analysis (~12s per sample) and high selectivity and sensitivity, with expected LODs 0.1 18ng for each of the target elements after sampling. The analytical performance of the LIBS method is also compared to previously reported methods (inductively coupled plasma-optical emission spectroscopy). The combination of fast CMV sampling, unambiguous organic compound identification with GC-MS and fast LIBS analysis provides the basis for a new comprehensive screening method for GSR. PMID- 25934369 TI - Substrate interferences in identifying flammable liquids in food, environmental and biological samples: case studies. AB - The analysis of samples for traces of ignitable liquids is most often connected with suspected arson cases. In such cases, samples taken from the point of origin of the fire are analyzed for the presence of ignitable liquids. However, sometimes, in cases not connected with arson, there is a need to detect and identify traces of ignitable liquids. Three examples of such cases are given in this paper. Aqueous samples (polluted water, juice and blood) were analyzed using a procedure routinely used in the analyses of fire debris. The procedure consists of passive adsorption of volatile organic compounds on Tenax, followed by thermal desorption and chromatographic analysis. Results showed that analysis of such untypical samples may be connected with unusual matrix effects, not frequently encountered in fire debris samples. PMID- 25934370 TI - Estimating temperature exposure of burnt bone - A methodological review. AB - Forensic anthropologists are frequently confronted with the need to interpret burnt bone. Regardless of the context, one of the key factors for the correct interpretation of the remains and a reconstruction of the incidents leading to incineration is the estimation of the maximum exposure temperature. The recent years have seen an influx in experimental research focusing on temperature estimation, spanning from colour assessment, mechanical strength measurements, histology and structural observations, biochemical changes and crystallinity studies, vastly advancing the understanding of heat induced changes in bone, thus facilitating a more accurate interpretation. This paper draws together and evaluates all currently available methodologies for temperature estimation. PMID- 25934371 TI - The effect of elapsed time on the cardiac Troponin-T (cTnT) proteolysis in case of death due to burn: A study to evaluate the potential forensic use of cTnT to determine the postmortem interval. AB - BACKGROUND: After the death of an organism, intracellular enzymes cause protein to degrade into smaller fragments as the time passes, if these fragments can be isolated and visualized, and if the fragmentation is proved to be measurable and quantifiable, it can be a good sign of the post-mortem interval (PMI). The aim of this study is to evaluate the effect of PMI on Troponin-T protein degradation in cardiac tissues of cadavers through quantitative analysis of Troponin-T degradation by easily electrophoretic method and its association with PMI in case of deaths due to burn. METHODS: An efficient extraction protocol to analyze the banding pattern of cTnT in post-mortem tissue was developed. The analysis involves extraction of the protein (at different PMI (~7.30, 18.20, 30.30, 41.20, 41.40, 54.30..................88.40h), from the heart muscles of cadavers (burn cases), separation by denaturing gel electrophoresis (SDS-PAGE) and visualization by Western blot using cTnT specific monoclonal antibodies. RESULTS: The results specify a characteristic banding pattern amongst human cadavers (n=9), a pseudo linear relationship between percent cTnT degraded and the time since death (r=0.87, p=0.0001). The area of the bands within a lane was quantified by scanning and digitizing the image using commonly available scanners. CONCLUSIONS: The present research used a simple, easy, applicable and highly informative electrophoresis method that make it an ideal for the busy forensic laboratory. The post-mortem Troponin-T fragmentation observed in this study reveals a sequential, time-dependent process with the potential for use as a predictor of PMI in cases of burning. This result shows a potential for use as a future applied method of evaluating time since death. PMID- 25934372 TI - Blood creatinine level in postmortem cases. AB - Blood chemical analysis for the diagnosis of diseases in forensic cases should be conducted in the same way as for clinical cases. However, it is sometimes difficult to obtain serum samples in forensic cases because of postmortem changes such as hemolysis and putrefaction. This study aimed to evaluate renal function in postmortem cases by blood creatinine analysis. The blood creatinine level was measured by high performance liquid chromatography (HPLC) using whole blood samples taken from 77 postmortem cases, and the relationships between blood creatinine level, postmortem interval, and cause of death were examined. The median blood creatinine level was found to be 1.15 mg/dL, with no significant differences between blood samples taken from different parts of the body. The blood creatinine level was stable for 3 days after death and gradually increased after that period, in line with a previous study using enzymatic analysis that found the serum creatinine level was stable in the early postmortem period. The blood creatinine level was high in the cases of blunt injury, intoxication, and in deaths caused by fire. This was considered to reflect acute renal dysfunction. However, the postmortem blood creatinine level remained higher than the clinical normal value despite omitting cases with renal dysfunction from the analysis. Therefore, we next investigated the change in postmortem creatinine levels in mice and found that the blood creatinine level increased with the emergence of rigor mortis. Our findings indicate that HPLC is useful in the postmortem evaluation of renal function even in the cases where serum cannot be obtained. However, the presence of rigor mortis should be considered in the evaluation of blood creatinine values. PMID- 25934373 TI - An evaluation of the performance of five extraction methods: Chelex(r) 100, QIAamp(r) DNA Blood Mini Kit, QIAamp(r) DNA Investigator Kit, QIAsymphony(r) DNA Investigator(r) Kit and DNA IQTM. AB - DNA left at a crime scene was often limited in amount and far from pristine. To maximize the chance of recovering as much information as possible from such compromised samples, an appropriate extraction method using the available technologies needs to be devised. In this study, we used human blood, buffy coat and a total of 76 simulated touch DNA samples to test the effectiveness of the following five common DNA extraction methods, namely, Chelex(r) 100, QIAamp(r) DNA Blood Mini Kit, QIAamp(r) DNA Investigator Kit, QIAsymphony(r) DNA Investigator(r) Kit and DNA IQTM system, in the recovery of such DNA. We demonstrated that the QIAamp(r) and QIAsymphony(r) DNA Investigator(r) Kits, and the DNA IQTM system, exhibited a better effectiveness in DNA recovery amongst these methods and yielded extracts with higher success rate in subsequent DNA profiling. These extracts also generated profiles with better intra-colour signal balance. The findings in this work allowed us to propose an extraction approach as follows: 1) casework samples shall be extracted with the QIAamp(r)/QIAsymphony(r) DNA Investigator(r) Kits or the DNA IQTM system, viz., QIAsymphony(r) DNA Investigator(r) Kit and DNA IQTM, due to their higher throughput, are for the touched DNA evidence from the volume crime, while QIAamp(r) DNA Investigator Kit is preferable for challenging bloodstain samples; and 2) control samples, such as buccal swab, with known identity can be extracted with the Chelex, due to their cheaper cost per sample. PMID- 25934374 TI - Modelling crime linkage with Bayesian networks. AB - When two or more crimes show specific similarities, such as a very distinct modus operandi, the probability that they were committed by the same offender becomes of interest. This probability depends on the degree of similarity and distinctiveness. We show how Bayesian networks can be used to model different evidential structures that can occur when linking crimes, and how they assist in understanding the complex underlying dependencies. That is, how evidence that is obtained in one case can be used in another and vice versa. The flip side of this is that the intuitive decision to "unlink" a case in which exculpatory evidence is obtained leads to serious overestimation of the strength of the remaining cases. PMID- 25934375 TI - Blood culture fluorescence rates predict severity and mortality of invasive pneumococcal pneumonia. AB - Invasive pneumococcal pneumonia is associated with high rates of mortality. Clinical assessment tools have poor sensitivity for predicting clinical outcomes. Molecular measurements of bacterial load correlate closely with clinical outcome but require specialist facilities and expertise. This study describes how routine blood culture testing can estimate bacterial load and predict clinical outcome for invasive pneumococcal pneumonia. Between December 2009 to March 2014, clinical and laboratory data were collected for 50 patients with Streptococcus pneumoniae bacteraemia secondary to community-acquired pneumonia. Fluorescence rates (FR) were calculated from growth curves generated by BACTEC blood culture analysers by dividing change in fluorescence units (FU), measured at the first point of detectable fluorescence and at the point of automated BACTEC positivity, by time in hours. The mean age of the patients was 70.6 years (49.6-86.3). Forty patients survived invasive pneumococcal disease and ten patients died. These two groups did not significantly differ by demographic or clinical characteristics. The mean FR for the non-survival group (3.62 * 10(-3) FU/h) was significantly higher (p < 0.001) than that of the survival group (1.73 * 10(-3) FU/h). FR did not vary by serotype. We determined that an FR of 2.59 * 10(-3) FU/h might represent a useful threshold for predicting high mortality risk with a sensitivity of 91 % and a specificity of 97 %. Our FR calculation uses cheap and accessible routine blood culture techniques to predict mortality in a small retrospective cohort study. In patients admitted to hospital with pneumococcal bacteraemia and, potentially, other organisms, this single tool could guide early escalation of clinical care. PMID- 25934377 TI - Erythema Ab Igne. PMID- 25934378 TI - Avoiding Computed Tomography Scans By Using Point-Of-Care Ultrasound When Evaluating Suspected Pediatric Renal Colic. AB - BACKGROUND: Although renal colic in children in the United States remains relatively uncommon compared to in adults, its incidence has nearly doubled from 1999 to 2008. Noncontrast computed tomography (CT) is the current standard for the evaluation of suspected renal colic, given its high sensitivity and specificity. However, the greater lifetime risk of radiation-induced cancer from CT in pediatric patients has led to efforts to minimize radiation exposure. Additionally, pediatric renal colic is often recurrent, which might require multiple imaging studies during their lifetime. Point-of-care ultrasound (POCUS) by emergency physicians avoids radiation, has a low marginal cost, can be performed concurrently with other management, and allows for earlier diagnosis and more rapid treatment of renal colic. Adult randomized controlled trial evidence supports using POCUS as the initial approach to imaging and management of suspected renal colic. However, there remain limited data on POCUS in children for renal colic. CASE REPORT: This is a case series where the sonographic findings of hydronephrosis, ureteral jets, "twinkling artifact," and the identification of urinary tract stones were used to evaluate adolescent and pediatric patients with renal colic. We report five cases of renal colic in adolescent and pediatric patients where urolithiasis was confirmed by using POCUS and irradiation by CT was avoided in all 5 patients. WHY SHOULD AN EMERGENCY PHYSICIAN BE AWARE OF THIS?: POCUS can provide information about the presence or absence of urinary tract stones as well as obstruction of the collecting system without the cost and radiation exposure of CT. PMID- 25934376 TI - The role of probiotics in the inhibition of Campylobacter jejuni colonization and virulence attenuation. AB - Campylobacter jejuni is one of the most common bacterial causes of human gastroenterocolitis worldwide, leading to diarrhea and other serious post infectious complications. Probiotics form an attractive alternative intervention strategy for most of the enteric infections. However, the role of probiotics in C. jejuni infections requires detailed investigations in order to delineate the probiotic strains that are effective against C. jejuni. Although there are several biological mechanisms involved in the inhibition of pathogenic bacterial growth, the strains of probiotics and their mechanisms of actions through which they combat C. jejuni invasion have not been studied in greater detail. This mini review details the factors that are involved in the colonization and establishment of C. jejuni infection, with special reference to chickens, the natural host of C. jejuni, and the studies that have investigated the effect of different probiotic strains against C. jejuni colonization and growth. This review has collated the studies conducted using probiotics to inhibit C. jejuni colonization and growth to date to provide a collective knowledge about the role of probiotics as an alternative intervention strategy for campylobacteriosis. PMID- 25934379 TI - Sensitivity and Specificity of Emergency Physicians and Trainees for Identifying Internally Concealed Drug Packages on Abdominal Computed Tomography Scan: Do Lung Windows Improve Accuracy? AB - BACKGROUND: Suspected body packers may be brought to emergency departments (EDs) close to international airports for abdominal computed tomography (CT) scanning. Senior emergency clinicians may be asked to interpret these CT scans. Missing concealed drug packages have important clinical and forensic implications. The accuracy of emergency clinician interpretation of abdominal CT scans for concealed drugs is not known. Limited evidence suggests that accuracy for identification of concealed packages can be increased by viewing CT images on "lung window" settings. OBJECTIVES: To determine the accuracy of senior emergency clinicians in interpreting abdominal CT scans for concealed drugs, and to determine if this accuracy was improved by viewing scans on both abdominal and lung window settings. METHODS: Emergency clinicians blinded to all patient identifiers and the radiology report interpreted CT scans of suspected body packers using standard abdominal window settings and then with the addition of lung window settings. The reference standard was the radiologist's report. RESULTS: Fifty-five emergency clinicians reported 235 CT scans. The sensitivity, specificity, and accuracy of interpretation using abdominal windows was 89.9% (95% confidence interval [CI] 83.0-94.7), 81.9% (95% CI 73.7-88.4), and 86.0% (95% CI 81.5-90.4), respectively, and with both window settings was 94.1% (95% CI 88.3-97.6), 76.7% (95% CI 68.0-84.1), 85.5% (95% CI 81.0-90.0), respectively. Diagnostic accuracy was similar regardless of the clinician's experience. Interrater reliability was moderate (kappa 0.46). CONCLUSION: The accuracy of interpretation of abdominal CT scans performed for the purpose of detecting concealed drug packages by emergency clinicians is not high enough to safely discharge these patients from the ED. The use of lung windows improved sensitivity, but at the expense of specificity. PMID- 25934380 TI - Hypovolemic Shock Caused by a Ruptured Hemorrhagic Hepatic Cyst. PMID- 25934381 TI - American Academy of Emergency Medicine Position Statement: Ultrasound Should Be Integrated into Undergraduate Medical Education Curriculum. PMID- 25934382 TI - Unraveling the sources of ground level ozone in the Intermountain Western United States using Pb isotopes. AB - Ozone as an atmospheric pollutant is largely produced by anthropogenic precursors and can significantly impact human and ecosystem health, and climate. The U.S. Environmental Protection Agency has recently proposed lowering the ozone standard from 75 ppbv (MDA8 = Maximum Daily 8-Hour Average) to between 65 and 70 ppbv. This will result in remote areas of the Intermountain West that includes many U.S. National Parks being out of compliance, despite a lack of significant local sources. We used Pb isotope fingerprinting and back-trajectory analysis to distinguish sources of imported ozone to Great Basin National Park in eastern Nevada. During discrete Chinese Pb events (> 1.1 ng/m(3) & > 80% Asian Pb) trans Pacific transported ozone was 5 +/- 5.5 ppbv above 19 year averages for those dates. In contrast, concentrations during regional transport from the Los Angeles and Las Vegas areas were 15 +/- 2 ppbv above the long-term averages, and those characterized by high-altitude transport 3 days prior to sampling were 19 +/- 4ppbv above. However, over the study period the contribution of trans-Pacific transported ozone increased at a rate of 0.8 +/- 0.3 ppbv/year, suggesting that Asian inputs will exceed regional and high altitude sources by 2015-2020. All of these sources will impact regulatory compliance with a new ozone standard, given increasing global background. PMID- 25934383 TI - [Unexpected out-of-hospital deliveries: Management and risk factors]. AB - OBJECTIVES: To estimate the frequency of accidental out-of-hospital deliveries (OHDs), to describe the home care and the complications occurred, and to identify risk factors. MATERIALS AND METHODS: A retrospective case-control study from 1st January 2012 to 31 December 2012 in Lyon urban area. Cases were identified from the Emergency Medical Aid Service 69 (SAMU 69) registry and control from the birth registry of the maternity corresponding to the case, recruiting two controls per case. RESULTS: The frequency of the OHDs was 0.3% [0.2-0.4]. At home, the prophylactic administration of oxytocin was performed in 18.3% [9.31 27.3] of cases and prevention of neonatal hypothermia was performed in 45.7% [34.1%-57.3%] of cases. Multiparity [OR: 3.43 (1.65-7.23)], a precarious situation [OR: 37.63 (5.02-7.81)], and lack of antenatal care [OR: 3.36 (2.72 4.15)] were OHDs' risk factors. CONCLUSION: The practical prevention of postpartum hemorrhage, and that of the home neonatal hypothermia could be improved. Points of vigilance for the medical teams to look for during the pregnancy monitoring are precariousness and less than 3 consultations scheduled. PMID- 25934384 TI - [Second twin delivery in cephalic presentation. Apropos of a series of 127 patients]. AB - INTRODUCTION: In 2009, the French National College of Obstetricians and Gynaecologists (CNGOF) clinical practice guidelines encouraged the active management of the second twin (T2) in high and mobile cephalic presentation (CP) by performing systematic internal maneuvers. In our department, this type of management is less frequent as whenever T2 is not delivered spontaneously after a short time interval, an instrumental extraction is realized. MATERIALS AND METHODS: We analyzed our practice for 5 years upon 127 twin pregnancies with a trial of vaginal delivery for T2 in CP. We compared the results following different modes of delivery which are: spontaneous delivery, instrumental extraction, and total breech extraction after manual internal version. RESULTS: No significant difference was found among the 3 groups in terms of maternal, fetal and neonatal well-being. Moreover, instrumental delivery was feasible, with a mean time interval for delivery between the 2 twins<15 minutes, even when performed by an obstetrician on training. CONCLUSION: The aim of our study was to evaluate our practice on T2 in CP, because this event can be quite tricky, thus discouraging less experienced obstetricians towards this practice and resulting in an increase in caesarean sections for T2. Instrumental delivery should be considered a possible option for any T2 in CP so as to ensure the continued existence of vaginal births for twin pregnancies. PMID- 25934385 TI - Biomarkers for rheumatoid and psoriatic arthritis. AB - Rheumatic diseases, such as rheumatoid and psoriatic arthritis are systemic inflammatory conditions characterized by a chronic form of arthritis, often leading to irreversible joint damage. Early treatment for patients with rheumatic diseases is required to reduce or prevent joint injury. However, early diagnosis can be difficult and currently it is not possible to predict which individual patient will develop progressive erosive disease or who may benefit from a specific treatment according to their clinical features at presentation. Biomarkers are therefore required to enable earlier diagnosis and predict prognosis in both rheumatoid arthritis and psoriatic arthritis. In this review we will examine the evidence and current status of established and experimental biomarkers in rheumatoid and psoriatic arthritis for three important purposes; disease diagnosis, prognosis and prediction of response to therapy. PMID- 25934386 TI - Stratified medicine in inflammatory disorders: From theory to practice. AB - Chronic inflammatory disorders are complex and characterized by significant heterogeneity in molecular, pathological, and clinical features. This heterogeneity poses challenges for the development of targeted molecular interventions for these disorders, as not all patients with a given clinical diagnosis have disease driven by a single dominant molecular pathway, hence not all patients will benefit equally from a given intervention. Biomarkers related to molecular manifestations of disease are increasingly being applied to enable stratified approaches to drug development. Biomarkers may be used to identify which patients are most likely to benefit from an intervention (predictive), identify patients at increased risk of disease progression (prognostic), and monitor biological responsiveness to an intervention (pharmacodynamic). Here we consider how biomarker-guided stratification of patients may increase benefit from targeted therapies for asthma, rheumatoid arthritis and inflammatory bowel diseases. PMID- 25934387 TI - Involvement of high mobility group box 1 in the activation of C5a-primed neutrophils induced by ANCA. AB - C5a plays a central role in antineutrophil cytoplasmic antibody (ANCA)-mediated neutrophil recruitment and activation. A previous study showed that C5a played a crucial role in the regulation of high mobility group box 1 (HMGB1) release from human neutrophils. The current study further investigated the interaction between C5a and HMGB1 in ANCA-induced neutrophil activation. The effects of HMGB1 inhibitors on the translocation of ANCA antigens, ANCA-induced respiratory burst and degranulation of C5a-primed neutrophils were tested. We found that blocking HMGB1 decreased C5a-mediated translocation of ANCA antigens, as well as ANCA induced respiratory burst and degranulation of C5a-primed neutrophils. Further study showed that supernatant of C5a-primed neutrophils, which contained HMGB1, also caused translocation of ANCA antigens of primary neutrophils, whereas blocking HMGB1 decreased the translocation. In conclusion, blocking HMGB1 may attenuate ANCA-induced activation of C5a-primed neutrophils. The interaction between HMGB1 and C5a might play an important role in ANCA-induced neutrophil activation. PMID- 25934388 TI - Revisiting visual dysfunctions in schizophrenia from the retina to the cortical cells: A manifestation of defective neurodevelopment. AB - This review highlights morphological and functional anomalies found along the entire visual pathway in schizophrenia, from the retina to the cortex. Based on the evidence of widespread anatomical and functional visual abnormalities, we posited that a neurodevelopmental anomaly occurring early in life was likely to explain those. Incidentally, support to the neurodevelopmental theory of schizophrenia is strongly emerging from many neurobiological domains. In vertebrates, the first visual structures migrate toward the orbit position at the end of the fourth week of gestation. A neurodevelopmental defect around that time on these embryonic structures could account for the visual anomalies in schizophrenia. Retinol activity might be involved in the process. Future research in schizophrenia should focus on early visual testing, on trials combining multiple visual anomaly assessments and a closer look to retinol activity during the pregnancy. PMID- 25934389 TI - Combined Crystal Structure of a Type I Cohesin: MUTATION AND AFFINITY BINDING STUDIES REVEAL STRUCTURAL DETERMINANTS OF COHESIN-DOCKERIN SPECIFICITIES. AB - Cohesin-dockerin interactions orchestrate the assembly of one of nature's most elaborate multienzyme complexes, the cellulosome. Cellulosomes are produced exclusively by anaerobic microbes and mediate highly efficient hydrolysis of plant structural polysaccharides, such as cellulose and hemicellulose. In the canonical model of cellulosome assembly, type I dockerin modules of the enzymes bind to reiterated type I cohesin modules of a primary scaffoldin. Each type I dockerin contains two highly conserved cohesin-binding sites, which confer quaternary flexibility to the multienzyme complex. The scaffoldin also bears a type II dockerin that anchors the entire complex to the cell surface by binding type II cohesins of anchoring scaffoldins. In Bacteroides cellulosolvens, however, the organization of the cohesin-dockerin types is reversed, whereby type II cohesin-dockerin pairs integrate the enzymes into the primary scaffoldin, and type I modules mediate cellulosome attachment to an anchoring scaffoldin. Here, we report the crystal structure of a type I cohesin from B. cellulosolvens anchoring scaffoldin ScaB to 1.84-A resolution. The structure resembles other type I cohesins, and the putative dockerin-binding site, centered at beta-strands 3, 5, and 6, is likely to be conserved in other B. cellulosolvens type I cohesins. Combined computational modeling, mutagenesis, and affinity-based binding studies revealed similar hydrogen-bonding networks between putative Ser/Asp recognition residues in the dockerin at positions 11/12 and 45/46, suggesting that a dual-binding mode is not exclusive to the integration of enzymes into primary cellulosomes but can also characterize polycellulosome assembly and cell-surface attachment. This general approach may provide valuable structural information of the cohesin-dockerin interface, in lieu of a definitive crystal structure. PMID- 25934390 TI - Yeast Tolerance to Various Stresses Relies on the Trehalose-6P Synthase (Tps1) Protein, Not on Trehalose. AB - Trehalose is a stable disaccharide commonly found in nature, from bacteria to fungi and plants. For the model yeast Saccharomyces cerevisiae, claims that trehalose is a stress protectant were based indirectly either on correlation between accumulation of trehalose and high resistance to various stresses or on stress hypersensitivity of mutants deleted for TPS1, which encodes the first enzyme in trehalose biosynthetic pathway. Our goal was to investigate more directly which one, between trehalose and/or the Tps1 protein, may serve yeast cells to withstand exposure to stress. By employing an original strategy that combined the use of mutant strains expressing catalytically inactive variants of Tps1, with MAL(+) yeast strains able to accumulate trehalose from an exogenous supply, we bring for the first time unbiased proof that trehalose does not protect yeast cells from dying and that the stress-protecting role of trehalose in this eukaryotic model was largely overestimated. Conversely, we identified the Tps1 protein as a key player for yeast survival in response to temperature, oxidative, and desiccation stress. We also showed by robust RT-quantitative PCR and genetic interaction analysis that the role of Tps1 in thermotolerance is not dependent upon Hsf1-dependent transcription activity. Finally, our results revealed that the Tps1 protein is essential to maintain ATP levels during heat shock. Altogether, these findings supported the idea that Tps1 is endowed with a regulatory function in energy homeostasis, which is essential to withstand adverse conditions and maintain cellular integrity. PMID- 25934391 TI - Allosteric Activation of a G Protein-coupled Receptor with Cell-penetrating Receptor Mimetics. AB - G protein-coupled receptors (GPCRs) are remarkably versatile signaling systems that are activated by a large number of different agonists on the outside of the cell. However, the inside surface of the receptors that couple to G proteins has not yet been effectively modulated for activity or treatment of diseases. Pepducins are cell-penetrating lipopeptides that have enabled chemical and physical access to the intracellular face of GPCRs. The structure of a third intracellular (i3) loop agonist, pepducin, based on protease-activated receptor-1 (PAR1) was solved by NMR and found to closely resemble the i3 loop structure predicted for the intact receptor in the on-state. Mechanistic studies revealed that the pepducin directly interacts with the intracellular H8 helix region of PAR1 and allosterically activates the receptor through the adjacent (D/N)PXXYYY motif through a dimer-like mechanism. The i3 pepducin enhances PAR1/Galpha subunit interactions and induces a conformational change in fluorescently labeled PAR1 in a very similar manner to that induced by thrombin. As pepducins can potentially be made to target any GPCR, these data provide insight into the identification of allosteric modulators to this major drug target class. PMID- 25934392 TI - Chronic Exposure to Excess Nutrients Left-shifts the Concentration Dependence of Glucose-stimulated Insulin Secretion in Pancreatic beta-Cells. AB - Hyperinsulinemia (HI) is elevated plasma insulin at basal glucose. Impaired glucose tolerance is associated with HI, although the exact cause and effect relationship remains poorly defined. We tested the hypothesis that HI can result from an intrinsic response of the beta-cell to chronic exposure to excess nutrients, involving a shift in the concentration dependence of glucose stimulated insulin secretion. INS-1 (832/13) cells were cultured in either a physiological (4 mm) or high (11 mm) glucose concentration with or without concomitant exposure to oleate. Isolated rat islets were also cultured with or without oleate. A clear hypersensitivity to submaximal glucose concentrations was evident in INS-1 cells cultured in excess nutrients such that the 25% of maximal (S0.25) glucose-stimulated insulin secretion was significantly reduced in cells cultured in 11 mm glucose (S0.25 = 3.5 mm) and 4 mm glucose with oleate (S0.25 = 4.5 mm) compared with 4 mm glucose alone (S0.25 = 5.7 mm). The magnitude of the left shift was linearly correlated with intracellular lipid stores in INS-1 cells (r(2) = 0.97). We observed no significant differences in the dose responses for glucose stimulation of respiration, NAD(P)H autofluorescence, or Ca(2+) responses between left- and right-shifted beta-cells. However, a left shift in the sensitivity of exocytosis to Ca(2+) was documented in permeabilized INS-1 cells cultured in 11 versus 4 mm glucose (S0.25 = 1.1 and 1.7 MUm, respectively). Our results suggest that the sensitivity of exocytosis to triggering is modulated by a lipid component, the levels of which are influenced by the culture nutrient environment. PMID- 25934393 TI - A Conserved Residue Cluster That Governs Kinetics of ATP-dependent Gating of Kir6.2 Potassium Channels. AB - ATP-sensitive potassium (KATP) channels are heteromultimeric complexes of an inwardly rectifying Kir channel (Kir6.x) and sulfonylurea receptors. Their regulation by intracellular ATP and ADP generates electrical signals in response to changes in cellular metabolism. We investigated channel elements that control the kinetics of ATP-dependent regulation of KATP (Kir6.2 + SUR1) channels using rapid concentration jumps. WT Kir6.2 channels re-open after rapid washout of ATP with a time constant of ~60 ms. Extending similar kinetic measurements to numerous mutants revealed fairly modest effects on gating kinetics despite significant changes in ATP sensitivity and open probability. However, we identified a pair of highly conserved neighboring amino acids (Trp-68 and Lys 170) that control the rate of channel opening and inhibition in response to ATP. Paradoxically, mutations of Trp-68 or Lys-170 markedly slow the kinetics of channel opening (500 and 700 ms for W68L and K170N, respectively), while increasing channel open probability. Examining the functional effects of these residues using phi value analysis revealed a steep negative slope. This finding implies that these residues play a role in lowering the transition state energy barrier between open and closed channel states. Using unnatural amino acid incorporation, we demonstrate the requirement for a planar amino acid at Kir6.2 position 68 for normal channel gating, which is potentially necessary to localize the epsilon-amine of Lys-170 in the phosphatidylinositol 4,5-bisphosphate-binding site. Overall, our findings identify a discrete pair of highly conserved residues with an essential role for controlling gating kinetics of Kir channels. PMID- 25934395 TI - Amorphous calcium carbonate controls avian eggshell mineralization: A new paradigm for understanding rapid eggshell calcification. AB - Avian eggshell mineralization is the fastest biogenic calcification process known in nature. How this is achieved while producing a highly crystalline material composed of large calcite columnar single crystals remains largely unknown. Here we report that eggshell mineral originates from the accumulation of flat disk shaped amorphous calcium carbonate (ACC) particles on specific organic sites on the eggshell membrane, which are rich in proteins and sulfated proteoglycans. These structures known as mammillary cores promote the nucleation and stabilization of a amorphous calcium carbonate with calcitic short range order which predetermine the calcite composition of the mature eggshell. The amorphous nature of the precursor phase was confirmed by the diffuse scattering of X-rays and electrons. The nascent calcitic short-range order of this transient mineral phase was revealed by infrared spectroscopy and HRTEM. The ACC mineral deposited around the mammillary core sites progressively transforms directly into calcite crystals without the occurrence of any intermediate phase. Ionic speciation data suggest that the uterine fluid is equilibrated with amorphous calcium carbonate, throughout the duration of eggshell mineralization process, supporting that this mineral phase is constantly forming at the shell mineralization front. On the other hand, the transient amorphous calcium carbonate mineral deposits, as well as the calcite crystals into which they are converted, form by the ordered aggregation of nanoparticles that support the rapid mineralization of the eggshell. The results of this study alter our current understanding of avian eggshell calcification and provide new insights into the genesis and formation of calcium carbonate biominerals in vertebrates. PMID- 25934394 TI - Identification of Distinct Conformations of the Angiotensin-II Type 1 Receptor Associated with the Gq/11 Protein Pathway and the beta-Arrestin Pathway Using Molecular Dynamics Simulations. AB - Biased signaling represents the ability of G protein-coupled receptors to engage distinct pathways with various efficacies depending on the ligand used or on mutations in the receptor. The angiotensin-II type 1 (AT1) receptor, a prototypical class A G protein-coupled receptor, can activate various effectors upon stimulation with the endogenous ligand angiotensin-II (AngII), including the Gq/11 protein and beta-arrestins. It is believed that the activation of those two pathways can be associated with distinct conformations of the AT1 receptor. To verify this hypothesis, microseconds of molecular dynamics simulations were computed to explore the conformational landscape sampled by the WT-AT1 receptor, the N111G-AT1 receptor (constitutively active and biased for the Gq/11 pathway), and the D74N-AT1 receptor (biased for the beta-arrestin1 and -2 pathways) in their apo-forms and in complex with AngII. The molecular dynamics simulations of the AngII-WT-AT1, N111G-AT1, and AngII-N111G-AT1 receptors revealed specific structural rearrangements compared with the initial and ground state of the receptor. Simulations of the D74N-AT1 receptor revealed that the mutation stabilizes the receptor in the initial ground state. The presence of AngII further stabilized the ground state of the D74N-AT1 receptor. The biased agonist [Sar(1),Ile(8)]AngII also showed a preference for the ground state of the WT-AT1 receptor compared with AngII. These results suggest that activation of the Gq/11 pathway is associated with a specific conformational transition stabilized by the agonist, whereas the activation of the beta-arrestin pathway is linked to the stabilization of the ground state of the receptor. PMID- 25934396 TI - Grey matter volumes in treatment naive vs. chronically treated children with attention deficit/hyperactivity disorder: a combined approach. AB - Psychostimulants are the first-line treatment in attention deficit/hyperactivity disorder (ADHD), but their effects on brain development remain poorly understood. In particular, previous structural magnetic resonance imaging (sMRI) studies only investigated treatment effects on grey matter (GM) volumes in selected regions of interest (ROIs). In this study, voxel-based morphometry (VBM) was used to assess medication-related GM volume differences across the entire brain. Automated tracing measurements of selected ROIs were also obtained. Three groups (77 participants aged 7-to-13 year old) underwent MRI scans and were compared: never medicated children with ADHD (n=33), medicated (methylphenidate) children with ADHD (n=20) and typically developing children (TD; n=24). Optimised VBM was used to investigate regional GM volumes, controlling for age and gender. Automated tracing procedures were also used to assess the average volume of the caudate nucleus, the amygdala and the nucleus accumbens. When compared to both medicated children with ADHD and TD children, never-medicated children with ADHD exhibited decreased GM volume in the insula and in the middle temporal gyrus. When compared to TD children, medicated children with ADHD had decreased GM volume in the middle frontal gyrus and in the precentral gyrus. Finally, ROI analyses revealed a significant association between duration of treatment and GM volume of the left nucleus accumbens in medicated children with ADHD. In conclusion, this study documents potential methylphenidate-related GM volume normalization and deviation in previously unexplored brain structures, and reports a positive association between treatment history and GM volume in the nucleus accumbens, a key region for reward-processing. PMID- 25934397 TI - Anti-depressant therapy and cancer risk: a nested case-control study. AB - Previous studies demonstrated a possible association between anti-depressant therapy with selective serotonin reuptake inhibitors (SSRI) and tricyclic anti depressants (TCA), several genetic and hormonal pathways and cancer risk, with inconsistent results. Exposure to serotonin-norepinephrine reuptake inhibitors (SNRI) was not studied extensively. We sought to evaluate the association between exposure to SSRIs, TCAs and SNRIs and the five most common solid tumors. We conducted nested case-control studies using a large UK population-representative database. Cases were those with any medical code for the specific malignancy. For every case, four controls matched on age, sex, practice site, and duration of follow-up before index date were selected using incidence-density sampling. Exposure of interest was SSRI, SNRI or TCA therapy before index date. Odds ratios (ORs) and 95% CIs were estimated for each anti-depressant class using conditional logistic-regression analysis, adjusted for potential confounders, such as obesity, smoking history and alcohol consumption. RESULTS: 109,096 cancer patients and 426,402 matched controls were included. Current SSRI users with treatment initiation>one year before index date had modestly higher risk for lung and breast cancers with ORs of 1.27 (95% CI 1.16-1.38) and 1.12 (95% CI 1.06 1.18), respectively. Among current TCA users, there was a higher risk only for lung cancers with OR of 1.45 (95% CI 1.31-1.6). There was no statistically significant association between current SNRI therapy and cancer risk. DISCUSSION: Treatment with SSRI and TCA might be associated with increased lung cancer risk. SSRI therapy might be associated with modest increase in breast cancer risk. PMID- 25934398 TI - [Feedback on the French national authority for health report about breast autologous fat grafting]. PMID- 25934399 TI - Etiological classification of presbycusis in Turkish population according to audiogram configuration. AB - OBJECTIVES: This study aims to classify age related hearing loss in Turkish population according to Schuknecht audiometric configurations for presbycusis and investigate the most common etiologies. PATIENTS AND METHODS: A total of 1,134 patients (568 males, 566 females; mean age 70.5+/-7.7 years; range 55 to 80 years) with age related hearing loss were included in the study. Audiograms of patients were classified into three categories: high frequency steeply sloping (HFSS), flat, and high frequency gently sloping (HFGS). Speech discrimination scores were evaluated and compared. RESULTS: In the study population, HFSS audiogram configuration was the most frequently observed (48.5%), followed by HFGS configuration (26.9%), and flat configuration (24.5%), respectively. While HFSS audiogram configuration was statistically significantly more common in males, flat audiogram configuration was statistically significantly more common in females (p=0.0001). HFSS group mean air conduction threshold were statistically significantly higher than flat and HFGS groups (p=0.0001). No statistically significantly difference was detected in terms of speech discrimination scores between three groups (p=0.796). CONCLUSION: Results of this study suggest that, in Turkish population, while sensory presbycusis is more common in males, strial presbycusis is more common in females. No difference was detected in terms of the prevalence of cochlear presbycusis in males and females (p=0.0001). PMID- 25934400 TI - Positron emission tomography evaluation of sinonasal inverted papilloma and related conditions: a prospective clinical study. AB - OBJECTIVES: This study aims to determine whether there is a difference between inverted papilloma (IP) and nasal polyp, and squamous cell carcinoma (SCC) with regard to fluorodeoxyglucose uptake. PATIENTS AND METHODS: Between September 2007 and May 2014, positron emission tomography computed tomography (PET/CT) images of 27 patients (20 males, 7 females; mean age 53.4 years; range 18 to 74 years), with unilateral polyposis diagnosed on examination and tomographic scans of paranasal sinus were obtained. Nasal polyps in eight of the patients (group 1), IP in 10 patients (group 2), and SCC in nine patients (group 3) were found. The data were compared with Kruskal-Wallis and Mann-Whitney U tests. RESULTS: The mean maximum standardized uptake (SUVmax) values were found to be 2.9 in the group 1; 7.8 in the group 2, and 17.8 in the group 3. There was significant difference in the SUVmax values between the group 1 and the group 2 (p=0.016), the group 1 and the group 3 (p=0.001), and the group 2 and the group 3 (p=0.01). CONCLUSION: According to the results of this study, PET/CT scan in the patients with unilateral polyposis is invaluable to distinguish nasal polyp from IP and SCC. It is also useful to recognize the distinctions between IP and SCC. In our study of 27 patients, a SUVmax of 6 or higher ruled out the presence of nasal polyp [95% CI (5.93 to 13.39), specificity 100%] might also be clinically useful. PMID- 25934401 TI - Evaluation of mean platelet volume and its ratio over platelet count in children with obstructive sleep apnea syndrome. AB - OBJECTIVES: This study aims to determine the association between obstructive sleep apnea syndrome (OSAS) caused by adenotonsillar hypertrophy and mean platelet volume (MPV) and MPV/platelet count ratio in children, and to evaluate the impact of adenotonsillectomy on these two parameters. PATIENTS AND METHODS: This prospective study consisted of 73 child patients (38 boys, 35 girls; mean age 8.6+/-3.3 years, range 2 to 17 years) with chronic adenotonsillar hypertrophy who applied to Gaziosmanpasa University Faculty of Medicine, Ear, Nose and Throat policlinics due to witnessed apnea and snoring in January 2011 and January 2013. Also, 56 age and sex matched pediatric patients (28 boys, 26 girls; mean age 8.0+/-3.2 years; range 3 to 13 years) who admitted to our clinic due to reasons besides OSAS were included in the study as control group. Preoperative and postoperative third month hemoglobin, white blood cell, thrombocyte count, and MPV values of the patients were recorded. RESULTS: Although ratio of MPV/platelet count was higher in patient group than in control group, the difference was not statistically significant. Mean platelet volume level was 7.68+/-1.07 fL in patient group and 7.21+/-0.84 fL in control group. Preoperative MPV level in patient group was significantly higher than that in control group (p<0.05). A statistically significant decrease was detected in postoperative third month MPV level and platelet count compared with preoperative MPV and platelet count (7.68+/-1.07 fL and 7.17+/-0.97 fL, respectively; p<0.05). CONCLUSION: High MPV and MPV/platelet count in children with adenotonsillar hypertrophy may be an important risk factor for cardiopulmonary and cerebrovascular morbidities which may develop both in childhood and in adulthood. Adenotonsillectomy may reduce this risk significantly. PMID- 25934402 TI - Clinical evaluation of inner ear changes as result of chronic otitis media and its surgery. AB - OBJECTIVES: This study aims to evaluate whether chronic otitis media (COM) may cause inner ear damages or middle ear surgery may improve this damage with regard to sensorineural hearing loss (SNHL) and tinnitus and dizziness-related disability. PATIENTS AND METHODS: An observational prospective study was performed on a series of 65 patients (41 males, 24 females; mean age 26.4+/-12.6; range 11 to 62 years) who were diagnosed with COM and were scheduled for surgical intervention at the Department of Otorhinolaryngology of the Haydarpasa Numune Education and Research Hospital. Patients were divided into two subgroups as tympanoplasty and mastoidectomy group according to the surgical procedure. Standard patient work-up included otomicroscopy, pure tone audiometry and completion of the Turkish translation of Dizziness Handicap Inventory (DHI) and Tinnitus Handicap Inventory (THI) before surgery and eight weeks after surgery. RESULTS: We found higher bone conduction thresholds in the group of patients with mastoidectomy preoperatively. There was a statistically significant difference in the mean preoperative and postoperative THI and DHI scores between the groups (p<0.05). CONCLUSION: Our study results suggest that a successful surgery results in improved tinnitus and vertigo symptoms in patients with COM. PMID- 25934403 TI - [Is it possible to predict postoperative facial nerve function by monitorization during parotidectomy]. AB - OBJECTIVES: This study aims to assess the value of facial nerve monitorization and minimum facial nerve stimulation thresholds during superficial parotidectomy in the prediction of postoperative facial nerve function. PATIENTS AND METHODS: Twenty superficial parotidectomy patients (9 males, 11 females; mean age 52 years; range 23 to 80 years), who treated in our clinic between January 2013 and May 2013 were recruited in this study. Intraoperative facial nerve monitorization was applied and minimum facial nerve stimulation thresholds were recorded in the main trunk at the end of the operation. Postoperative facial nerve functions were evaluated by House Brackmann (HB) grading system. RESULTS: In early postoperative evaluation, minimum stimulation thresholds of 12 patients with facial nerve function HB grade 1 (normal) and of eight patients with HB grade 2 facial paresis in marginal mandibular branch were 0.20+/-0.14 mA and 0.22+/-0.05 mA respectively (p>0.05). At the end of the first day, minimum stimulation thresholds in 17 HB grade 1 patients and three HB grade 2 patients were 0.20+/-0.12 mA and 0.25+/ 0.07 mA, respectively (p>0.05). No significant difference was detected in terms of stimulation thresholds between patients who developed or did not develop postoperative facial paresis. All patients were HB grade 1 at the end of third month. No correlation was found between tumor size and postoperative facial nerve function (p>0.05). CONCLUSION: Minimum facial nerve stimulation thresholds during superficial parotidectomy were not effective in the prediction of postoperative mild facial nerve paresis. PMID- 25934404 TI - [Examination of relationship between level of hearing and written language skills in 10-14-year-old hearing impaired children]. AB - OBJECTIVES: This study aims to review the relationship between written language skills and factors which are thought to affect this skill such as mean hearing loss, duration of auditory deprivation, speech discrimination score, and pre school education attendance and socioeconomic status of hearing impaired children who attend 4th-7th grades in primary school in inclusive environment. PATIENTS AND METHODS: The study included 25 hearing impaired children (14 males, 11 females; mean age 11.4+/-1.4 years; range 10 to 14 years) (study group) and 20 children (9 males, 11 females; mean age 11.5+/-1.3 years; range 10 to 14 years) (control group) with normal hearing in the same age group and studying in the same class. Study group was separated into two subgroups as group 1a and group 1b since some of the children with hearing disability used hearing aid while some used cochlear implant. Intragroup comparisons and relational screening were performed for those who use hearing aids and cochlear implants. Intergroup comparisons were performed to evaluate the effect of the parameters on written language skills. RESULTS: Written expression skill level of children with hearing disability was significantly lower than their normal hearing peers (p=0.001). A significant relationship was detected between written language skills and mean hearing loss (p=0.048), duration of auditory deprivation (p=0.021), speech discrimination score (p=0.014), and preschool attendance (p=0.005), when it comes to socioeconomic status we were not able to find any significant relationship (p=0.636). CONCLUSION: It can be said that hearing loss affects written language skills negatively and hearing impaired individuals develop low-level written language skills compared to their normal hearing peers. PMID- 25934405 TI - [Repair of incus long arm defects by hydroxyapatite bone cement]. AB - OBJECTIVES: This study aims to evaluate our ossiculoplasty results using hydroxyapatite bone cement. PATIENTS AND METHODS: Data of 29 patients (16 males, 13 females; mean age 28 years; range 17 to 57 years) who were performed ossiculoplasty using hydroxyapatite bone cement in Izmir Katip Celebi University Ataturk Training and Research Hospital Department of Otorhinolaryngology between January 2010 and December 2013 were retrospectively evaluated. Of the 29 operated patients, bone cement was administered in 23 patients during tympanoplasty, in two patients during open technique tympanomastoidectomy, and in four patients during exploratory tympanotomy. Hydroxyapatite bone cement was only used to repair defects between incus and stapes no longer than one third of incus long arm length. Mean follow-up time was 6.5 months (range 2-32 months). RESULTS: Success of ossiculoplasty was evaluated by Belfast 15/30 dB rule of thumb. Preoperative air-bone gap was 45.1 dB (range 35-55) and postoperative air-bone gap was 17.7 dB (range 6-40). Air-bone gap was below 10 dB in six patients, between 10-20 dB in 14 patients, between 20-30 dB in seven patients, and between 30-40 dB in two patients. CONCLUSION: Ossiculoplasty using hydroxyapatite bone cement is a safe and effective method for the repair of particularly small incus long arm defects. PMID- 25934406 TI - A case of sinonasal paraganglioma with a different morphology: nine-year follow up. AB - Paragangliomas are very occasionally located in the nasal cavity. In this article, we present a 32-year-old female case with a sinonasal paraganglioma with atypical histopathological morphology. In our case, sinonasal paraganglioma consisted of lipoblast-like vacuolated cells instead of the typical Zellballan histological pattern. The prognosis of a nasal paraganglioma is not very clear. The present article is important, as it describes the first case report of a sinonasal paraganglioma with atypical lipoblast-like vacuolated cells with a nine year follow-up. PMID- 25934407 TI - [Atypical presentation in Kimura's disease]. AB - Kimura's disease is a rare chronic inflammatory disorder with an unknown etiology which presents with the involvements of salivary glands and subdermal tissue in the head or neck region, in particular. Besides the most common manifestations of the disease; as the involvements of preauricular region, submandibular region, cervical lymph nodes and major salivary glands, nephrotic syndrome, as an additional systemic pathology, may be also seen due to glomerulonephritis. The differential diagnosis is made with the identification of characteristic histological features as follicular hyperplasia, eosinophil infiltration, and proliferation of the postcapillary venules. Although Kimura's disease may occasionally resemble angiolymphoid hyperplasia with eosinophilia, both have different clinical and histological features. In this case report, we discuss the clinical, histopathological features and treatment of a 57-year-old male patient admitted with a slowly progressing mass in his right buccal region for almost two years, which was approximately 3x3 cm in diameter and soft to palpation, and was excised completely by an intraoral approach and reported histopathologically as Kimura's disease in the light of literature. PMID- 25934408 TI - [Giant osteoma with intracranial extension filling sinonasal cavity: a rare case]. AB - Osteomas are the most frequently observed benign bone tumors of paranasal sinuses. Although they are generally detected by chance during radiological analyses, they may create severe complications after intracranial extension. While computed tomography findings play a key role to differentiate osteoma from other osseous lesions of paranasal sinus, magnetic resonance imaging identifies extension to surrounding structures and possible complications. Osteoma was detected in a 28-year-old female patient who admitted with complaints of headache and difficulty in breathing. Patient was operated after diagnosis; however, we were unable to remove the mass totally due to its location and size. In this article, we report, to our knowledge, the largest defined osteoma case in the literature to date, with ethmoid sinus origin, orbital, nasal cavity and intracranial extension, accompanied with distinctive computed tomography and magnetic resonance imaging findings. PMID- 25934409 TI - Unusually large submandibular gland stone. AB - Submandibular gland calculi is the most common disease of the gland. In this article, we report a case with unusually large stone located at the hilum of the gland causing necrosis of the overlying duct and the oral mucosa (floor of mouth). PMID- 25934410 TI - [Subjective assessment of olfactory function]. AB - Of the five senses, the sense of smell is the most complex and unique in structure and organization. As diagnostic and therapeutic modalities are often underdeveloped, the sense of smell has been inadequately studied. Olfactory disorders may result from benign pathologies such as sinusitis as well as several diseases including Parkinson's disease, temporal lobe epilepsy, schizophrenia and Alzheimer disease. In this article, we aim to instruct the otorhinolaryngology specialists and residents regarding the tests which measure odor subjectively. PMID- 25934411 TI - Adolescents leaving mental health or social care services: predictors of mental health and psychosocial outcomes one year later. AB - BACKGROUND: UK service structure necessitates a transition out of youth services at a time of increased risk for the development and onset of mental disorders. Little is currently known about the mental health and psychosocial outcomes of leaving services at this time. The aim of this study was to determine predictors of mental health and social adjustment in adolescents leaving mental health or social care services. METHODS: A cohort (n = 53) of 17 year olds were interviewed and assessed when preparing to leave adolescent services and again 12 months later. Their mental health and psychosocial characteristics were compared to a same-age community sample group (n = 1074). RESULTS: At discharge 34 (64%) met DSM IV criteria for a current psychiatric diagnosis and only 3 (6%) participants met operational criteria for successful outcomes at follow-up. Impairments in mental health, lack of employment, education or training and low preparedness were associated with poor outcomes. CONCLUSIONS: The findings suggest the current organisation of mental health and care services may not be fit for purpose and even unwittingly contribute to persistent mental illness and poor psychosocial outcomes. A redesign of services should consider a model where the timing of transition does not fall at the most hazardous time for young people, but is sufficiently flexible to allow young people to move on when they are personally, socially and psychologically most able to succeed. Assessment of a young person's readiness to transition might also be useful. A youth focused service across the adolescent and early adult years may be better placed to avoid young people falling through the service gap created by poor transitional management. PMID- 25934412 TI - MicroRNA-10a is reduced in breast cancer and regulated in part through retinoic acid. AB - BACKGROUND: MicroRNAs (miRNAs) are short non-coding RNA molecules that play a critical role in mRNA cleavage and translational repression, and are known to be altered in many diseases including breast cancer. MicroRNA-10a (miR-10a) has been shown to be deregulated in various cancer types. The aim of this study was to investigate miR-10a expression in breast cancer and to further delineate the role of retinoids and thyroxine in regulation of miR-10a. METHODS: Following informed patient consent and ethical approval, tissue samples were obtained during surgery. miR-10a was quantified in malignant (n = 103), normal (n = 30) and fibroadenoma (n = 35) tissues by RQ-PCR. Gene expression of Retinoic Acid Receptor beta (RARbeta) and Thyroid Hormone receptor alpha (THRalpha) was also quantified in the same patient samples (n = 168). The in vitro effects of all trans Retinoic acid (ATRA) and L-Thyroxine (T4) both individually and in combination, on miR-10a expression was investigated in breast cancer cell lines, T47D and SK-BR-3. RESULTS: The level of miR-10a expression was significantly decreased in tissues harvested from breast cancer patients (Mean (SEM) 2.1(0.07)) Log10 Relative Quantity (RQ)) compared to both normal (3.0(0.16) Log10 RQ, p < 0.001) and benign tissues (2.6(0.17) Log10 RQ, p < 0.05). The levels of both RARbeta and THRalpha gene expression were also found to be decreased in breast cancer patients compared to controls (p < 0.001). A significant positive correlation was determined between miR-10a and RARbeta (r = 0.31, p < 0.001) and also with THRalpha (r = 0.32, p < 0.001). In vitro stimulation assays revealed miR-10a expression was increased in both T47D and SK-BR-3 cells following addition of ATRA (2 fold (0.7)). While T4 alone did not stimulate miR-10a expression, the combination of T4 and ATRA was found to have a positive synergistic effect. CONCLUSION: The data presented supports a potential tumour suppressor role for miR-10a in breast cancer, and highlights retinoic acid as a positive regulator of the microRNA. PMID- 25934413 TI - Evaluation of a community awareness programme to reduce delays in referrals to early intervention services and enhance early detection of psychosis. AB - BACKGROUND: Reducing treatment delay and coercive pathways to care are accepted aims for Early Intervention Services (EIS) for people experiencing first episode psychosis but how to achieve this is unclear. A one-year community awareness programme was implemented in a London EIS team, targeting staff in non-health service community organisations. The programme comprised psycho-educational workshops and EIS link workers, and offering direct referral routes to EIS. Its feasibility and its impact on duration of untreated psychosis and pathways to EIS were evaluated. METHODS: Evaluation comprised: pre and post questionnaires with workshop participants assessing knowledge and attitudes to psychosis and mental health services; and a comparison of new service users' "service DUP"(time from first psychotic symptom to first contact with EIS) and pathways to care in the intervention year and preceding year. Focus groups sought stakeholders' views regarding the benefits and limitations of the programme and what else might promote help-seeking. RESULTS: 41 workshops at 36 community organisations were attended by 367 staff. 19 follow up workshops were conducted and 16 services were allocated an EIS link worker. Participants' knowledge and attitudes to psychosis and attitudes to mental health services improved significantly following workshops. In the year of the intervention, only 6 of 110 new service users reached EIS directly via community organisations. For all new referrals accepted by EIS, in the intervention year compared to the previous year, there was no difference in mean or median service DUP. A clear impact on pathways to care could not be discerned. Stakeholders suggested that barriers to referral remained. These included: uncertainty about the signs of early psychosis, disengagement by young people when becoming unwell, and worries about stigma or coercive treatment from mental health services. More general, youth focused, mental health services were proposed. CONCLUSIONS: The community awareness programme did not reduce treatment delays for people experiencing first episode psychosis. Further research is needed regarding effective means to reduce duration of untreated psychosis. Although EIS services are guided to promote access through community engagement, this may not be an effective use of their limited resources. TRIAL REGISTRATION: Current Controlled Trial ISRCTN98260910 Registered 19th May 2010. PMID- 25934414 TI - World Workshop on Oral Medicine VI: a systematic review of the treatment of mucocutaneous pemphigus vulgaris. AB - OBJECTIVE: To determine the efficacy and safety of interventions for pemphigus vulgaris (PV). STUDY DESIGN: We conducted a systematic review from 2003 to 2013 according to the Cochrane Collaboration methodology. Randomized controlled trials (RCTs) or controlled clinical trials (CCTs) and observational studies were conducted along with diagnosis confirmed by clinical, histopathologic, and immunofluorescence criteria. Primary outcomes were disease remission and mortality; several relevant secondary outcomes were also included. RESULTS: Fourteen RCTs or CCTs and 110 observational studies were included in the final analyses. RCTs or CCTs demonstrated considerable heterogeneity in outcome measures, and all had a high risk of bias for at least 1 of 8 domains. Of the studies, 96.8% (120) described the use of oral corticosteroids. Azathioprine and mycophenolate-mofetil were the most commonly cited treatments. An increasing number of studies described biologic therapies (rituximab, intravenous immunoglobulin [IVIg]). Evidence supporting recent comprehensive treatment guidelines was reviewed. CONCLUSIONS: We found persisting wide variations in treatment practice and inadequate quality of research supporting optimal PV treatment. PMID- 25934415 TI - World Workshop on Oral Medicine VI: Patient-reported outcome measures and oral mucosal disease: current status and future direction. AB - OBJECTIVE: This systematic review aimed to (1) explore the patient-reported outcome measures (PROMs) currently used in the oral mucosal disease literature and report on the type and context of the use of these instruments and (2) provide a future direction for PROMs in Oral Medicine practice and research. STUDY DESIGN: A systematic review of published English-language articles relating to the use of PROMs in the oral mucosal diseases literature was performed in November 2013. RESULTS: In total, 131 articles met the inclusion criteria; these articles addressed the following oral mucosal conditions: lichen planus (75); recurrent aphthous stomatitis (30); mucous membrane pemphigoid/pemphigus vulgaris (14); orofacial granulomatosis (1); and multiple oral mucosal diseases (11). The most commonly used instruments were visual analog scales (VAS) and the oral health impact profile (OHIP). CONCLUSIONS: Limited progress has been achieved with use of PROMs in Oral Medicine in the last few decades in both clinical practice and a research setting. With the engagement of allied medical disciplines in PROM usage and the promotion of PROMs by national health care bodies globally, advancement of PROMs is imperative for Oral Medicine. Exposure through the World Workshop on Oral Medicine (WWOM), along with potential involvement in the Core Outcome Measures in Effectiveness Trials (COMET) or other such initiatives, will enable worldwide collaboration to promote the development and utilization of valid and reliable PROMs in oral medicine, and improve patient care. PMID- 25934416 TI - Evidence-based surgery: The obstacles and solutions. AB - Surgeons are often accused of lagging behind their medical colleagues in embracing evidence based medicine and utilizing new research tools to conducting high quality randomized controlled trials. Although there has been a noticeable improvement in the quantity and quality of high quality studies in surgical journals, the widespread practice of evidence based surgery is still poor. Unlike evidence based medicine, the practice of evidence based surgery is hampered by inherent problems and obstacles. This article reviews these difficulties and the limitations of randomized controlled trials in surgical practice. It also outlines some solutions that may help remedy this ongoing problem. PMID- 25934417 TI - Validation of intra-operative parathyroid hormone and its decline as early predictors of hypoparathyroidism after total thyroidectomy: A prospective cohort study. AB - INTRODUCTION: Total thyroidectomy is a preferred surgical technique for benign as well as malignant thyroid pathologies, but many a times can cause hypoparathyroidism. The aim of this study is to evaluate the intra-operative parathyroid hormone (ioPTH) level and its decline as predictors for post operative hypoparathyroidism after total thyroidectomy. METHODS: In this single centre prospective cohort study, 90 patients who underwent total thyroidectomy for benign as well as malignant pathologies of thyroid gland were studied. Intra operative parathyroid levels and at different time intervals parathyroid hormone and serum calcium levels were measured to predict hypoparathyroidism. The data was analysed using independent sample t test and p value < .05 was considered to be significant. RESULTS: There were 14 male and 76 female patients with a mean age of 41 years. Most common thyroid pathology for which total thyroidectomy was done was colloid goitre (62). Twenty four patients (26.66%) developed hypoparathyroidism. Intra-operative PTH was found to be most accurate predictor for diagnosing post-operative hypoparathyroidism (cut off was (11.3 pg/ml, calculated using ROC curves) and has maximum sum of sensitivity (91.7%) and specificity (97%). On taking cut off values of intra-operative PTH and PTH decline together, they were found to be most accurate predictor for permanent hypoparathyroidism. DISCUSSION: Early and accurate predictor of hypoparathyroidism is very important and always sought. Very early prediction during intra-operative periods can be used for auto transplantation of parathyroid gland. CONCLUSION: Intra-operative parathyroid hormone and its decline are accurate, reliable, and early predictor of hypoparathyroidism after total thyroidectomy. PMID- 25934418 TI - Parotid gland tumors: a retrospective study of 154 patients. AB - INTRODUCTION: Benign tumors of the parotid gland comprise the majority of salivary gland tumors. OBJECTIVE: To review the clinical characteristics of parotid gland tumors submitted to surgical treatment by the same surgeon. METHODS: Retrospective study with 154 patients who had parotid gland tumors. Clinical and histological data, type of surgery, and complications were assessed and described. RESULTS: The main manifestation was a mass with a median evolution of 12 months for benign tumors and five months for malignant tumors. Ultrasonography was the most frequent complementary exam. Pleomorphic adenoma was the most common of the benign tumors, and mucoepidermoid carcinoma was the most frequent malignant tumor. Superficial parotidectomy with preservation of the facial nerve was the most common surgical procedure and reversible paresis of branches of the facial nerve was the most common complication. CONCLUSIONS: Pleomorphic adenoma is the most common parotid gland tumor and superficial parotidectomy with preservation of the facial nerve is the most common and appropriate treatment for most low-morbidity tumors. PMID- 25934419 TI - The C-terminal end of the capsid protein of Avian Nephritis Virus is antigenic and induces broadly cross-reactive antibodies. AB - Avian nephritis virus (ANV) has been isolated frequently from commercial broilers in many countries. The prevalence and economic impact of ANV however has been difficult to ascertain due to the lack of convenient serological techniques. In this study the full-length and fragments of the ANV capsid protein were expressed in Baculovirus and affinity purified recombinant proteins used for the detection of ANV antibodies in ELISA. The crystal structure of Human Astrovirus (HAstV) was used as a model to determine potential homologous C-terminal antigenic regions in ANV. The rp37 fragment from three ANV strains NSW_3, ANV-1 and ANV-2, and a shorter NSW_3 fragment (rp33) were compared for their ability to detect ANV antibodies in seven reference chicken sera. The ANV-1 rp37 antigen was the most strain specific whereas the NSW_3 rp37 and rp33 antigens detected antibodies in all heterologous sera, including ANV-1 serum. Irrespective of the strain used, the two NSW_3 protein fragments rp37 and rp33 were found to be superior as antigens for ELISA when compared to the full-length capsid protein rp75. An ELISA designed using the NSW_3 rp33 could reliably differentiate between uninfected and infected commercial broiler flocks, as demonstrated by statistically significant differences between the OD values. This study identified an ANV immunogenic region and successfully used recombinant protein expression of this region to detect cross-reactive ANV antibodies. The results of this study facilitate future studies into the epidemiology and importance of ANV infections in commercial poultry. PMID- 25934421 TI - Biomechanical effects of sensorimotor orthoses in adults with Charcot-Marie-Tooth disease. AB - BACKGROUND: Charcot-Marie-Tooth disease is an inherited neuropathy causing progressive weakness, foot deformity and difficulty walking. Clinical anecdotes suggest orthoses designed on the 'sensorimotor' paradigm are beneficial for improving gait in Charcot-Marie-Tooth disease. OBJECTIVES: Investigate the effect of sensorimotor orthoses on in-shoe and lower limb biomechanics in adults with Charcot-Marie-Tooth disease. STUDY DESIGN: Randomised, repeated-measures, exploratory study. METHODS: Eight males and two females with Charcot-Marie-Tooth disease aged 31-68 years fitted with pedorthic shoes and custom-made sensorimotor orthoses were randomly tested at baseline and after 4 weeks of adaptation. In shoe three-dimensional multi-segment foot and lower limb kinematics and kinetics were collected as were plantar pressures, electromyography and self-reported comfort, stability, cushioning and preference. RESULTS: Compared to the shoe only condition, sensorimotor orthoses increased midfoot eversion and plantarflexion, increased ankle eversion and produced small but significant changes at the knee and hip indicating increased internal rotation. The orthoses increased medial ground reaction forces and increased pressure at the heel, midfoot and toes. There were minimal effects on electromyography. The sensorimotor orthoses were rated higher for comfort, cushioning, stability and preference. CONCLUSION: Sensorimotor orthoses produced changes in kinematic, kinetic and pressure variables in adults with Charcot-Marie-Tooth disease and were regarded as more comfortable, cushioned and stable during walking. CLINICAL RELEVANCE: In this study, the walking ability of patients with Charcot-Marie-Tooth disease improved with the use of foot orthoses designed according to the sensorimotor paradigm. However, the mechanism of action appears to be primarily mechanical in origin. Randomised controlled trials are necessary to evaluate the long-term patient reported outcomes of sensorimotor orthoses. PMID- 25934420 TI - Shear bond strength between alumina substrate and prosthodontic resin composites with various adhesive resin systems. AB - BACKGROUND: With the increase in demand for cosmetics and esthetics, resin composite restorations and all-ceramic restorations have become an important treatment alternative. Taking into consideration the large number of prosthodontic and adhesive resins currently available, the strength and durability of these materials needs to be evaluated. This laboratory study presents the shear bond strengths of a range of veneering resin composites bonded to all-ceramic core material using different adhesive resins. METHODS: Alumina ceramic specimens (Techceram Ltd, Shipley, UK) were assigned to three groups. Three types of commercially available prosthodontic resin composites [BelleGlass(r), (BG, Kerr, CA, USA), Sinfony(r) (SF, 3 M ESPE, Dental Products, Germany), and GC Gradia(r) (GCG, GC Corp, Tokyo, Japan)] were bonded to the alumina substrate using four different adhesive resins. Half the specimens per group (N = 40) were stored dry for 24 hours, the remaining were stored for 30 days in water. The bonding strength, so-called shear bond strengths between composite resin and alumina substrate were measured. Data were analysed statistically and variations in bond strength within each group were additionally evaluated by calculating the Weibull modulus. RESULTS: Bond strengths were influenced by the brand of prosthodontic resin composites. Shear bond strengths of material combinations varied from 24.17 +/- 3.72-10.15 +/- 3.69 MPa and 21.20 +/- 4.64-7.50 +/- 4.22 at 24 h and 30 days, respectively. BG resin composite compared with the other resin composites provided the strongest bond with alumina substrate (p < 0.01). SF resin composite was found to have a lower bond strength than the other composites. The Weibull moduli were highest for BG, which was bonded by using Optibond Solo Plus adhesive resin at 24 h and 30 days. There was no effect of storage time and adhesive brand on bond strength. CONCLUSION: Within the limitations of this study, the shear bond strengths of composite resins to alumina substrate are related to the composite resins. PMID- 25934422 TI - Development of novel 3D-printed robotic prosthetic for transradial amputees. AB - BACKGROUND AND AIM: Upper extremity myoelectric prostheses are expensive. The Robohand demonstrated that three-dimensional printing reduces the cost of a prosthetic extremity. The goal of this project was to develop a novel, inexpensive three-dimensional printed prosthesis to address limitations of the Robohand. TECHNIQUE: The prosthesis was designed for patients with transradial limb amputation. It is shoulder-controlled and externally powered with an anthropomorphic terminal device. The user can open and close all five fingers, and move the thumb independently. The estimated cost is US$300. DISCUSSION: After testing on a patient with a traumatic transradial amputation, several advantages were noted. The independent thumb movement facilitated object grasp, the device weighed less than most externally powered prostheses, and the size was easily scalable. Limitations of the new prosthetic include low grip strength and decreased durability compared to passive prosthetics. CLINICAL RELEVANCE: Most children with a transradial congenital or traumatic amputation do not use a prosthetic. A three-dimensional printed shoulder-controlled robotic prosthesis provides a cost effective, easily sized and highly functional option which has been previously unavailable. PMID- 25934423 TI - Potential impact of a nonavalent HPV vaccine on the occurrence of HPV-related diseases in France. AB - BACKGROUND: Human Papillomavirus (HPV) infection is known to be associated with a number of conditions including cervical, vaginal, vulvar, penile, anal neoplasias and cancers, oropharynx cancers and genitals warts (GW). Two prophylactic vaccines are currently available: a bivalent vaccine designed to prevent HPV type 16 and 18 infection and a quadrivalent vaccine targeting HPV 6, 11, 16, and 18. In France, HPV vaccination is recommended in 11-14 year-old girls with a catch-up for girls aged 15-19. The objective of this study was to assess the potential impact of an HPV 6/11/16/18/31/33/45/52/58 nonavalent vaccine on anogenital and oropharyngeal HPV-related diseases in France. METHODS: HPV genotype distributions from 6 multicentric retrospective studies (EDiTH I to VI) were analyzed including 516 cases of invasive cervical cancers (ICC), 493 high-grade cervical neoplasias (CIN2/3), 397 low-grade squamous intraepithelial lesions (LSIL), 423 GW, 366 anal cancer and 314 oropharyngeal carcinomas. Low and high estimates of HPV vaccine impact were calculated as follows: low estimate: prevalence of HPV 6/11/16/18/31/33/45/52/58 genotypes alone or in association but excluding presence of another HPV type; high estimate: prevalence of HPV 6/11/16/18/31/33/45/52/58 genotypes alone or in association, possibly in presence of another HPV type. RESULTS: Estimates of potential impact varied from 85% (low estimate) to 92% (high estimate) for ICC, 77% to 90% for CIN2/3, 26% to 56% for LSIL, 69% to 90% for GW, 81% to 93% for anal cancer, and 41% to 44% for oropharyngeal carcinomas. Compared to the quadrivalent vaccine, the proportion of additional cases potentially prevented by the nonavalent vaccine was 9.9%-15.3% for ICC, 24.7%-33.3% for CIN2/3, 12.3%-22.7% for LSIL, 2.1%-5.4% for GW, 8.5% 10.4% for anal cancer, and 0.0%-1.6% for oropharyngeal carcinoma. CONCLUSIONS: The nonavalent HPV vaccine showed significant increased potential impact compared to the HPV 6/11/16/18 quadrivalent vaccine for ICC, CIN2/3 and LSIL. Considering a 100% vaccine efficacy and high vaccine coverage, about 90% of ICC, CIN2/3, GW or anal cancer cases could be prevented by a nonavalent HPV vaccine in France. PMID- 25934425 TI - Estimation of Young's modulus of pharmaceutical tablet obtained by terahertz time delay measurement. AB - In this paper, it is suggested that Young's modulus of pharmaceutical tablets with different porosity can be estimated from terahertz (THz) pulse time delay. We demonstrate such a possibility using a training set of tablets compressed from starch acetate. Once the mechanical properties are taught to the THz measurement system, using an ideal tablet as a reference, it is possible to get information about the Young's modulus of the tablet. Here, we show that there are optical counterparts of classical mechanical laws that couple the Young's modulus and porosity of the tablet. PMID- 25934424 TI - Volubility, consonant, and syllable characteristics in infants and toddlers later diagnosed with childhood apraxia of speech: A pilot study. AB - PURPOSE: This pilot study explored the volubility, consonant singleton acquisition, and syllable structure development between infants and toddlers (birth-24 months) with typical speech sound production (TYP) and those later diagnosed with childhood apraxia of speech (CAS). METHOD: A retrospective longitudinal between- and within-subjects research design was utilized (TYP N=2; CAS N=4). Vocalizations from participants were analyzed between birth-24 months from home videotapes, volunteered by the children's parents, according to type (nonresonant vs. resonant), volubility, place and manner of consonant singletons, and syllable shape (V, CV, VC, CVC, VCV, CVCV, VCVC, and "Other"). RESULTS: Volubility between groups was not significant but statistically significant differences were found in the number of: resonant and non-resonant productions; different consonant singletons; different place features; different manner classes; and proportional use of fricative, glottal, and voiceless phones. Infants and toddlers in the CAS group also demonstrated difficulty with CVCs, had limited syllable shapes, and possible regression of vowel syllable structure. CONCLUSIONS: Data corroborate parent reports that infants and toddlers later diagnosed with CAS present differently than do those with typical speech sound skills. Additional study with infants and toddlers later diagnosed with non-CAS speech sound disorder is needed. LEARNING OUTCOMES: Readers will: (1) describe current perspectives on volubility of infants and toddlers later diagnosed with CAS; (2) describe current perspectives of the consonant singleton and syllable shape inventories of infants and toddlers later diagnosed with CAS; and (3) discuss the potential differences between the speech sound development of infants and toddlers later diagnosed with CAS and those with typical speech sound skill. PMID- 25934426 TI - Development and evaluation in vitro and in vivo of injectable hydrolipidic gels with sustained-release properties for the management of articular pathologies such as osteoarthritis. AB - This study aimed to evaluate glycerol monooleate (GMO) as a carrier to develop viscoelastic and injectable sustained-release drug delivery systems. The potential pro- and antioxidant activity of the developed hydrolipidic gels were evaluated by measuring the production of ROS by polymorphonuclear leukocytes (PMNs). In addition, the biocompatibility and effectiveness of two selected gel candidates were evaluated in vivo by evaluating the benefit of a single intraarticular injection of these new treatments in a model of osteoarthritis in rabbits. The in vitro study demonstrated that the carrier F1 did not have a pro oxidative effect and even protected PMNs against natural auto-activation, regardless of the incorporation of either clonidine chlorhydrate or betamethasone dipropionate. The in vivo study demonstrated that F1 and F1-BDP induced a loss of cartilage quality in comparison to the control and reference groups but that the lesions of cartilage observed were generally mild, with not much full-depth erosion. Moreover, no exacerbating inflammation was observed when considering the synovial membranes and the PGE2 and CRP levels. These results seemed to demonstrate that the sustained-release formulation based on GMO could be well tolerated after intraarticular injection. Moreover, it could have the potential to prevent inflammatory conditions while sustaining drug activity locally over weeks. PMID- 25934427 TI - Polymorphic solidification of Linezolid confined in electrospun PCL fibers for controlled release in topical applications. AB - Poly(epsilon-caprolactone) (PCL) membranes loaded with Linezolid, chemically N [[(5S)-3-[3-fluoro-4-(4-morpholinyl)phenyl]-2-oxo-5-oxazolidinyl]methyl]acetamide (empirical formula C16H20FN3O4) have been prepared by electrospinning technique, at different Linezolid concentrations (0.5, 1, 2.5 and 5%, w/w). Structural characterization, morphological analysis and the study of the mechanical properties have been performed on loaded membranes and compared with neat PCL membranes. Linezolid embedded in the membranes is prevalently amorphous, with a low crystallinity showing a different polymorphic form respect to the usual Form I and Form II. The release kinetics of the drug were studied by spectrophotometric analysis (UV-vis). It allowed to discriminate between Linezolid molecules on the surface and encapsulated into the fibers. The antibacterial activity of the electrospun membranes was effective to inhibit Staphylococcus aureus. The properties of the loaded membranes and their capability for local delivery of the antibiotic make them good candidates as drug release devices for topical use. PMID- 25934428 TI - Effect of geometry on drug release from 3D printed tablets. AB - The aim of this work was to explore the feasibility of combining hot melt extrusion (HME) with 3D printing (3DP) technology, with a view to producing different shaped tablets which would be otherwise difficult to produce using traditional methods. A filament extruder was used to obtain approx. 4% paracetamol loaded filaments of polyvinyl alcohol with characteristics suitable for use in fused-deposition modelling 3DP. Five different tablet geometries were successfully 3D-printed-cube, pyramid, cylinder, sphere and torus. The printing process did not affect the stability of the drug. Drug release from the tablets was not dependent on the surface area but instead on surface area to volume ratio, indicating the influence that geometrical shape has on drug release. An erosion-mediated process controlled drug release. This work has demonstrated the potential of 3DP to manufacture tablet shapes of different geometries, many of which would be challenging to manufacture by powder compaction. PMID- 25934429 TI - Asymmetric lipid-polymer particles (LIPOMER) by modified nanoprecipitation: role of non-solvent composition. AB - Asymmetric lipid polymer nanostructures (LIPOMER) comprising glyceryl monostearate (GMS) as lipid and Gantrez AN 119 (Gantrez) as polymer, revealed enhanced splenic accumulation. In the present paper, we attempt to explain the formation of asymmetric GMS LIPOMER using real time imaging. Particles were prepared by precipitation under static conditions using different non-solvent phase compositions. The process was video recorded and the videos converted to time elapsed images using the FFmpeg 0.10.2 software at 25 frames/sec. Non solvent compositions comprising >30% of IPA/Acetone revealed significant stranding of the solvent phase and slower onset of precipitation(2-6s). At lower concentrations of IPA and acetone, and in non-solvent compositions comprising ethanol/water the stranding phenomenon was not evident. Further, rapid precipitation(<1 s) was evident. Nanoprecipitation based on the Marangoni effect is a result of diffusion stranding, interfacial turbulence, and mass transfer of solvent and non-solvent resulting in solute precipitation. Enhanced diffusion stranding favored by high interaction of GMS and Gantrez(low DeltaPol), and the low solubility parameter(Deltadeltatotal) and high mixing enthalpy(DeltaHM) of GMS in IPA resulted in droplets with random shapes analogous to an amoeba with pseudopodia, which on precipitation formed asymmetric particles. Asymmetric particles could be readily designed through appropriate selection of solutes and non-solvent phase by modified nanoprecipitation. PMID- 25934430 TI - On the selection of an opioid for local skin analgesia: Structure-skin permeability relationships. AB - Recent studies demonstrated that post-herpetical and inflammatory pain can be locally managed by morphine gels, empirically chosen. Aiming to rationalize the selection of the most suitable opioid for the cutaneous delivery, we studied the in vitro penetration through human epidermis of eight opioids, evidencing the critical modifications of the morphinan core. Log P, log D, solid-state features and solubility were determined. Docking simulations were performed using supramolecular assembly made of ceramide VI. The modifications on position 3 of the morphinan core resulted the most relevant in determining both physicochemical characteristics and diffusion pattern. The 3-methoxy group weakened the cohesiveness of the crystal lattice structure and increased the permeation flux (J). Computational studies emphasized that, while permeation is essentially controlled by molecule apolarity, skin retention depends on a fine balance of polar and apolar molecular features. Moreover, ChemPLP scoring the interactions between the opioids and ceramide, correlated with both the amount retained into the epidermis (Qret) and J. The balance of the skin penetration properties and the affinity potency for MU-receptors evidenced hydromorphone as the most suitable compound for the induction of local analgesia. PMID- 25934431 TI - Disruption of erythrocyte antioxidant defense system, hematological parameters, induction of pro-inflammatory cytokines and DNA damage in liver of co-exposed rats to aluminium and acrylamide. AB - The individual toxic effects of aluminium and acrylamide are well known but there are no data on their combined effects. The present study was undertaken to determine (i) hematological parameters during individual and combined chronic exposure to aluminium and acrylamide (ii) correlation of oxidative stress in erythrocytes with pro-inflammatory cytokines expression, DNA damage and histopathological changes in the liver. Rats were exposed to aluminium (50 mg/kg body weight) in drinking water and acrylamide (20 mg/kg body weight) by gavage, either individually or in combination for 3 weeks. Exposure rats to AlCl3 or/and ACR provoked an increase in MDA, AOPP, H2O2 and a decrease in GSH and NPSH levels in erythrocytes. Activities of catalase, glutathione peroxidase and superoxide dismutase were decreased in all treated rats. Our results showed that all treatments induced an increase in WBC, erythrocyte osmotic fragility and a decrease in RBC, Hb and Ht. While MCV, MCH, MCHC remained unchanged. Hepatic pro inflammatory cytokines expression including tumor necrosis factor-alpha, interleukin-6, interleukin-1beta was increased suggesting leucocytes infiltration in the liver. A random DNA degradation was observed on agarose gel only in the liver of co-exposed rats to AlCl3 and ACR treatment. Interestingly, co-exposure to these toxicants exhibited synergism based on physical and biochemical variables in erythrocytes, pro-inflammatory cytokines and DNA damage in liver. PMID- 25934432 TI - Bathing water profile in the coastal belt of the province of Pescara (Italy, Central Adriatic Sea). AB - The quality of bathing water is fundamental, not only from an environmental point of view but also due to the economic importance of tourism. This paper examines the water profile in the coastal belt of the province of Pescara (Italy, Central Adriatic Sea) with reference to the microbiological parameters Escherichia coli and intestinal enterococci required by Directive 2006/07 of European Commission. The water quality of 15 coastal beaches was surveyed; data were produced from monitoring and controls made available by the Abruzzo Regional Environmental Prevention and Protection Agency (ARTA) and extracted and elaborated for the period of interest (2010-2013). Statistical analysis was used to confirm the aspects deduced from mean values of monitoring and control data for each stretch. The data highlight critical situations in various parts of the coast; these problems can be attributed to river pollution, mainly due to the malfunctioning of the treatment plants for urban wastewater. PMID- 25934433 TI - Influence of river discharge on abundance and dissemination of heterotrophic, indicator and pathogenic bacteria along the East Coast of India. AB - In order to examine the influence of discharge from different rivers from peninsular India and urban sewage on intensity and dissemination of heterotrophic, indicator and pathogenic bacteria, a study was carried out during peak discharge period along coastal Bay of Bengal. The coastal Bay received freshwater inputs from the river Ganges while Godavari and Krishna contributed to the south. Contrasting difference in salinity, temperature, nutrients and organic matter was observed between north and south east coast of India. The highest heterotrophic, indicator and pathogenic bacterial abundance was observed in the central coastal Bay that received urban sewage from the major city. Intensity and dissemination of heterotrophic, indicator and pathogenic bacteria displayed linear relation with magnitude of discharge. The coliform load was observed up to 100km from the coast suggesting that marine waters were polluted during the monsoon season and its impact on the ecosystem needs further studies. PMID- 25934434 TI - Preface. 15th European Meeting on Complement in Human Disease 2015, Uppsala, Sweden. PMID- 25934436 TI - [Sepsis-like syndrome and acute meningoencephalitis due to parechovirus type 3]. PMID- 25934437 TI - Meaning of illness and quality of life in patients with type 2 diabetes. AB - BACKGROUND: Investigations into personal factors influencing quality of life are important for those developing strategies to support patients with diabetes. This study aimed to investigate the influence of meaning of illness on quality of life in patients with type 2 diabetes. METHODS: Veterans from primary care clinics in the southeastern United States completed a questionnaire including questions from the validated 5-scale Meaning of Illness Questionnaire (MIQ). Unadjusted and adjusted linear regression models investigated the physical and mental components of quality of life with the 5 MIQ factors. RESULTS: The sample comprised 302 Black and White veterans. The physical component of quality of life (PCS) was positively associated with type of stress/attitude of harm (beta = 2.43, CI: 0.94 to 3.93) and challenge/motivation/hope (beta = 3.02, CI: 0.40 to 5.64) after adjustment, whereas the mental component of quality of life (MCS) was positively associated with the degree of stress/change in commitment (beta = 2.58, CI: 0.78 to 4.38), and negatively associated with challenge/motivation/hope (beta = -2.55, CI: -4.99 to -0.11). CONCLUSION: Attitudes of challenge, motivation and hope had opposite effects on mental and physical components of quality of life in this sample of veterans. Additionally, whereas, the type of stress and attitude towards harm or loss was associated with the physical component, the degree of stress and change in commitments was associated with the mental component. This suggests addressing the meaning of an illness may be complex but is an important consideration in improving both physical and mental components of quality of life in patients with type 2 diabetes. PMID- 25934435 TI - In vivo imaging with antibodies and engineered fragments. AB - Antibodies have clearly demonstrated their utility as therapeutics, providing highly selective and effective drugs to treat diseases in oncology, hematology, cardiology, immunology and autoimmunity, and infectious diseases. More recently, a pressing need for equally specific and targeted imaging agents for assessing disease in vivo, in preclinical models and patients, has emerged. This review summarizes strategies for developing and optimizing antibodies as targeted probes for use in non-invasive imaging using radioactive, optical, magnetic resonance, and ultrasound approaches. Recent advances in engineered antibody fragments and scaffolds, conjugation and labeling methods, and multimodality probes are highlighted. Importantly, antibody-based imaging probes are seeing new applications in detection and quantitation of cell surface biomarkers, imaging specific responses to targeted therapies, and monitoring immune responses in oncology and other diseases. Antibody-based imaging will provide essential tools to facilitate the transition to truly precision medicine. PMID- 25934438 TI - Development and external validation of nomograms predictive of response to radiation therapy and overall survival in nasopharyngeal cancer patients. AB - INTRODUCTION: Large variability in the clinical outcomes has been observed among the nasopharyngeal cancer (NPC) patients with the same stage receiving similar treatment. This suggests that the current Tumour-Node-Metastasis staging systems need to be refined. The nomogram is a useful predictive tool that integrates individual variables into a statistical model to predict outcome of interest. This study was to design predictive nomograms based on the clinical and pathological features of patients with NPC. MATERIALS AND METHODS: Clinical data of 270 NPC patients who underwent definitive radiation therapy (RT) alone or concurrent with chemotherapy were collected. Factors predictive of response to RT and overall survival (OS) were determined by univariate and multivariate analyses, and predictive nomograms were created. Nomograms were validated externally by assessing discrimination and calibration using an independent data set (N=122). RESULTS: Three variables predictive of response to RT (age, histology classification and N classification) and four predictive of OS (age, performance status, smoking status and N classification), in addition to T classification, were extracted to generate the nomograms. The nomograms were validated externally, which showed perfect correlation with each other. CONCLUSION: The designed nomograms proved highly predictive of response to RT and OS in individual patients, and could facilitate individualised and personalised patients' counselling and care. PMID- 25934439 TI - EUROCOURSE recipe for cancer surveillance by visible population-based cancer RegisTrees in Europe: From roots to fruits. AB - Currently about 160 population-based cancer registries (CRs) in Europe have extensive experience in generating valid information on variation in cancer risk and survival with time and place. Most CRs cover all cancers, but some are confined to specific cancers or to children. They cover 15-55% of the populations in all of the larger member states of the European Union (EU), except the United Kingdom (UK), and 100% coverage in 80% of those with populations below 20 million. The EU FP 7 EUROCOURSE project, which operated in 2009-2013, explored the essential role of CRs in cancer research and public health, and also focused attention on their programme owners (POs) and stakeholders (e.g. cancer societies, oncological professionals, cancer patient groups, and planners, providers and evaluators of cancer care and mass screening). Generally, all CRs depended on their regional and/or national oncological context and were increasingly involved in population-based studies of quality of cancer care, long term prognosis and quality of life, one third being very active. Within the public health domain, CRs, in addition to describing the variety of environmental and lifestyle-related cancer epidemics, have also contributed actively to aetiologic research by a European databases that showed wide discrepancies in cancer risk and survival across the EU, and in more depth by follow-up of cohorts and recruitment for case-control studies. CRs were also actively contributing to independent evaluation of mass screening as an intervention which affects quality of care and cancer mortality. The potential of CRs for clinical evaluation has grown substantially through interaction with clinical stakeholders and more incidentally biobanks, also with greater involvement of patient groups - with a special focus on elderly patients who generally do not take part in clinical trials. Whereas 25-35% of CRs are active in a range of cancer research areas, the rest have a low profile and usually provide only incidence and survival data. If they are unable to do so because POs and stakeholders do not demand it, they might also be inhibited by data protection restrictions, especially in German and French speaking countries. The value of population-based studies of quality of oncologic care and mass screening and the flawless reputation with regard to data protection of intensively used CRs in the northwest of Europe offered a sharp contrast, although they also follow the 1995 EU guideline on data protection. CRs thus offer a perfect example of what can be done with sensitive and minimal data, also when enriched by linkages to other databases. Intensive use of the data has allowed CR research departments to take on a visible expertise-based profile but a neutral in many public controversies in preventive oncology. Their management and fundability also appeared to benefit from externally classifying the wide array of tumour- or tract-specific intelligence and research activities for the various users in oncology and public health and also patients - who are the source of the data - are better informed. Transparency on what CRs enable may also improve through programmes of research have been deemed essential to our funding POs (ministries, cancer charities, cancer centres or public health institutes) who might benefit from some guidance to - often suboptimal governance. Therefore, a metaphoric RegisTree has been developed for self assessment and to clarify CR working methods and domain-specific performance to stakeholders and funding agencies, showing much room for development in many CRs. All in all, CRs are likely to remain unique sources of independent expert information on the burden of cancer, indispensable for cancer surveillance, with increased attention to cancer survivors, up to 4% of the population. Investments in the expanding CR network across Europe offer an excellent way forward for comparative future cancer surveillance with so many epidemiologic and clinical changes ahead. PMID- 25934440 TI - Patient-specific reconstruction plates are the missing link in computer-assisted mandibular reconstruction: A showcase for technical description. AB - INTRODUCTION: Preoperative planning of mandibular reconstruction has moved from mechanical simulation by dental model casts or stereolithographic models into an almost completely virtual environment. CAD/CAM applications allow a high level of accuracy by providing a custom template-assisted contouring approach for bone flaps. However, the clinical accuracy of CAD reconstruction is limited by the use of prebent reconstruction plates, an analogue step in an otherwise digital workstream. TECHNICAL REPORT: In this paper the integration of computerized, numerically-controlled (CNC) milled, patient-specific mandibular plates (PSMP) within the virtual workflow of computer-assisted mandibular free fibula flap reconstruction is illustrated in a clinical case. Intraoperatively, the bone segments as well as the plate arms showed a very good fit. Postoperative CT imaging demonstrated close approximation of the PSMP and fibular segments, and good alignment of native mandible and fibular segments and intersegmentally. Over a follow-up period of 12 months, there was an uneventful course of healing with good bony consolidation. CONCLUSION: The virtual design and automated fabrication of patient-specific mandibular reconstruction plates provide the missing link in the virtual workflow of computer-assisted mandibular free fibula flap reconstruction. PMID- 25934441 TI - A Murine Model of K-RAS and beta-Catenin Induced Renal Tumors Expresses High Levels of E2F1 and Resembles Human Wilms Tumor. AB - PURPOSE: Wilms tumor is the most common renal neoplasm of childhood. We previously found that restricted activation of the WNT/beta-catenin pathway in renal epithelium late in kidney development is sufficient to induce small primitive neoplasms with features of epithelial Wilms tumor. Metastatic disease progression required simultaneous addition of an activating mutation of the oncogene K-RAS. We sought to define the molecular pathways activated in this process and their relationship to human renal malignancies. MATERIALS AND METHODS: Affymetrix(r) expression microarray data from murine kidneys with activation of K-ras and/or Ctnnb1 (beta-catenin) restricted to renal epithelium were analyzed and compared to publicly available expression data on normal and neoplastic human renal tissue. Target genes were verified by immunoblot and immunohistochemistry. RESULTS: Mouse kidney tumors with activation of K-ras and Ctnnb1, and human renal malignancies had similar mRNA expression signatures and were associated with activation of networks centered on beta-catenin and TP53. Up regulation of WNT/beta-catenin targets (MYC, Survivin, FOXA2, Axin2 and Cyclin D1) was confirmed by immunoblot. K-RAS/beta-catenin murine kidney tumors were more similar to human Wilms tumor than to other renal malignancies and demonstrated activation of a TP53 dependent network of genes, including the transcription factor E2F1. Up-regulation of E2F1 was confirmed in murine and human Wilms tumor samples. CONCLUSIONS: Simultaneous activation of K-RAS and beta catenin in embryonic renal epithelium leads to neoplasms similar to human Wilms tumor and associated with activation of TP53 and up-regulation of E2F1. Further studies are warranted to evaluate the role of TP53 and E2F1 in human Wilms tumor. PMID- 25934442 TI - Urinary Biomarkers for Screening for Renal Scarring in Children with Febrile Urinary Tract Infection: Pilot Study. AB - PURPOSE: Recurrent febrile urinary tract infections during infancy cause renal scarring, which is characterized by progressive focal interstitial fibrosis and may lead to renal failure. Renal scarring can be diagnosed through scintigraphy, although it seems impractical to perform renal scintigraphy for all infants with febrile urinary tract infections. Therefore, it is important to search for a biomarker to identify the presence of renal scarring. We hypothesized that urinary biomarkers of nephropathy may increase in infants with renal scarring following febrile urinary tract infections. MATERIALS AND METHODS: A total of 49 infants who underwent renal scintigraphy for febrile urinary tract infections were enrolled in the study. Several measurements were performed using urine samples, including total proteins, beta2-microglobulins, N-acetyl-beta-D glucosaminidase, neutrophil gelatinase associated lipocalin, liver-type fatty acid binding protein and angiotensinogen. Values were corrected by creatinine and compared between patients with and without renal scarring. RESULTS: Among urinary biomarkers only angiotensinogen in patients with scarring (median 14.6 MUg/gm creatinine) demonstrated significantly higher levels than in patients without scarring (3.6 MUg/gm creatinine, p <0.001). CONCLUSIONS: Urinary angiotensinogen may be useful for diagnosing the presence of renal scarring. PMID- 25934443 TI - Use of the Conceptual Change Teaching Method to Address Food Safety Among Native American and Hispanic Food Preparers. PMID- 25934444 TI - Non small cell carcinoma of lung with metachronous breast metastasis and cardiac tamponade: Unusual presentation of a common cancer. AB - INTRODUCTION: Lung cancer is the most common cause of cancer related death worldwide. Mostly these tumors present with cough, chest pain weight loss. However, presentation as breast mass and cardiac tamponade is very rare. RESULTS: We are presenting a rare case of breast metastasis from primary lung cancer. This case presented as cardiac tamponade adding to the diagnostic dilemma. CONCLUSION: The importance of this case is to highlight molecular profiling as an applicable tool to distinguish extra-mammary metastasis that masquerade as mammary neoplasm thereby preventing unnecessary need of surgery and radiation therapy. PMID- 25934445 TI - Bilateral clear cell sarcoma of the kidney. AB - Clear cell sarcoma of the kidney (CCSK) accounts for 2-5% of all pediatric renal malignancies, and is known for its propensity to metastasize to bone and other sites. We are reporting two cases with bilateral CCSK that were diagnosed at our institution. One patient initially presented with bilateral renal masses, as well as pulmonary, hepatic and bone metastasis; while other present only with bilateral masses with no evident distant metastasis. Both patients received aggressive neo-adjuvant chemotherapy to decrease tumor size. One patient completed his designated treatment and initially showed complete remission (CR); eventually suffering from relapse. The other patient's tumor progressed during the course of chemotherapy. Both cases manifested brain dissemination at the time of relapse or progression. This emphasizes the importance of staging stratification in CCSK. This also illustrates CCSK's ability to metastasize to bone and other sites including the brain (a primary relapse site in our cases). PMID- 25934446 TI - Effects of sage extract on memory performance in mice and acetylcholinesterase activity. AB - INTRODUCTION: Salvia officinalis L. (sage) has been widely used in the Tunisian traditional medicine for the treatment of digestive system and memory disorders. OBJECTIVES: This work aims to investigate the anti-amnesiac and antioxidant activity of aqueous extract of S. officinalis (ASOE) in mice. MATERIALS AND METHODS: Evaluation of memory functions in rodents was assessed by Y-maze active test after an initial acquisition phase. RESULTS: Results showed that the S. officinalis aqueous extract had high total phenolic contents (6.2mg gallic E/g extract) and flavonoids (2.44mg catechin E/g extract). It exhibited an interesting scavenging activity (IC50=14.5MUg/ml). The mice treated with 300mg/kg body weight for 7 days exhibited a significant decrease in avoidance and discrimination errors during a retention trial compared to control group (P<0.05). Acetylcholinesterase (AChE) activity significantly decreased in mice treated with the extract of sage. CONCLUSION: These findings suggested that aqueous extract of sage leaves possess a mnemonic effect on adult male mice, confirming their use in traditional medicine. PMID- 25934447 TI - Human urine-derived stem cells can be induced into osteogenic lineage by silicate bioceramics via activation of the Wnt/beta-catenin signaling pathway. AB - Human urine-derived stem cells (USCs) have great application potential for cytotherapy as they can be obtained by non-invasive and simple methods. Silicate bioceramics, including calcium silicate (CS), can stimulate osteogenic differentiation of stem cells. However, the effects of silicate bioceramics on osteogenic differentiation of USCs have not been reported. In this study, at first, we investigated the effects of CS ion extracts on proliferation and osteogenic differentiation of USCs, as well as the related mechanism. CS particles were incorporated into poly (lactic-co-glycolic acid) (PLGA) to obtain PLGA/CS composite scaffolds. USCs were then seeded onto these scaffolds, which were subsequently transplanted into nude mice to analyze the osteogenic differentiation of USCs and mineralization of extracellular matrix formed by USCs in vivo. The results showed that CS ion extracts significantly enhanced cell proliferation, alkaline phosphatase (ALP) activity, calcium deposition, and expression of certain osteoblast-related genes and proteins. In addition, cardamonin, a Wnt/beta-catenin signaling inhibitor, reduced the stimulatory effects of CS ion extracts on osteogenic differentiation of USCs, indicating that the observed osteogenic differentiation of USCs induced by CS ion extracts involves Wnt/beta-catenin signaling pathway. Furthermore, histological analysis showed that PLGA/CS composite scaffolds significantly enhanced the osteogenic differentiation of USCs in vivo. Taken together, these results suggest the therapeutic potential of combining USCs and PLGA/CS scaffolds in bone tissue regeneration. PMID- 25934448 TI - Co-delivery of doxorubicin and tumor-suppressing p53 gene using a POSS-based star shaped polymer for cancer therapy. AB - In this work, a star-shaped polymer consisting of a cationic poly[2 (dimethylamino) ethyl methacrylate] (PDMAEMA) shell and a zwitterionic poly[N-(3 (methacryloylamino) propyl)-N,N-dimethyl-N-(3-sulfopropyl) ammonium hydroxide] (PMPD) corona was grafted from a polyhedral oligomeric silsesquioxanes (POSS) based initiator via atomic transfer radical polymerization (ATRP). The reported star-shaped polymer could form stable micelles in aqueous solutions even in the presence of serum. In addition, anti-cancer drug doxorubicin and tumor suppressing p53 gene were loaded in the process of micelle formation. The formed polyplex was biocompatible and highly efficient for both drug and gene delivery. Furthermore, the polyplex was able to cause a high apoptotic rate of tumor cells both in vitro and in vivo. This combination delivery strategy offers a promising method for cancer therapy and can be used for further clinical applications. PMID- 25934449 TI - An investigation of the carbon nanotube--Lipid interface and its impact upon pulmonary surfactant lipid function. AB - Multiwalled carbon nanotubes (MWCNTs) are now synthesized on a large scale, increasing the risk of occupational inhalation. However, little is known of the MWCNT-pulmonary surfactant (PS) interface and its effect on PS functionality. The Langmuir-Blodgett trough was used to evaluate the impact of MWCNTs on fundamental properties of PS lipids which influence PS function, i.e. compression resistance and maximum obtainable pressure. Changes were found to be MWCNT length-dependent. 'Short' MWCNTs (1.1 MUm, SD = 0.61) penetrated the lipid film, reducing the maximum interfacial film pressure by 10 mN/m (14%) in dipalmitoylphosphatidylcholine (DPPC) and PS, at an interfacial MWCNT-PS lipid mass ratio range of 50:1 to 1:1. 'Long' commercial MWCNTs (2.1 MUm, SD = 1.2) caused compression resistance at the same mass loadings. 'Very long' MWCNTs (35 MUm, SD = 19) sequestered DPPC and were squeezed out of the DPPC film. High resolution transmission electron microscopy revealed that all MWCNT morphologies formed DPPC coronas with ordered arrangements. These results provide insight into how nanoparticle aspect ratio affects the interaction mechanisms with PS, in its near-native state at the air-water interface. PMID- 25934450 TI - pH-triggered release of manganese from MnAu nanoparticles that enables cellular neuronal differentiation without cellular toxicity. AB - At high concentrations, manganese (Mn) promotes cellular neurodevelopment but causes toxicity. Here, we report that Mn ion at high concentrations can be delivered to pheochromocytoma 12 (PC12) cells using gold nanoparticles (AuNPs) to enhance cellular neurodevelopment without toxicity. Mn(2+) release from AuNPs was designed to be pH-responsive so that low pH condition of the cell endosomes can trigger in situ release of Mn(2+) from AuNPs after cellular uptake of Mn incorporated AuNPs (MnAuNPs). Due to the differences in reduction potentials of Mn and Au, only Mn ionized and released while Au remained intact when MnAuNPs were uptaken by cells. Compared to PC12 cells treated with a high concentration of free Mn(2+), PC12 cells treated with an equal concentration of MnAuNPs resulted in significantly enhanced cellular neurodevelopment with decreased apoptosis and necrosis. Treatment with a high concentration of free Mn(2+) led to an abrupt consumption of a large amount of ATP for the intracellular transport of Mn(2+) through the ion channel of the cell membrane and to mitochondrial damage caused by the high intracellular concentration of Mn(2+), both of which resulted in cell necrosis and apoptosis. In contrast, MnAuNP-treated cells consumed much smaller amount of ATP for the intracellular transport of MnAuNPs by endocytosis and showed pH-triggered in situ release of Mn(2+) from the MnAuNPs in the endosomes of the cells, both of which prevented the cell death caused by ATP depletion and mitochondrial damage. To our knowledge, this is the first report on the use of AuNPs as a vehicle for pH-responsive, intracellular delivery of metal ion, which may open a new window for drug delivery and clinical therapy. PMID- 25934451 TI - PRGD/PDLLA conduit potentiates rat sciatic nerve regeneration and the underlying molecular mechanism. AB - Peripheral nerve injury requires optimal conditions in both macro-environment and micro-environment for reestablishment. Though various strategies have been carried out to improve the macro-environment, the underlying molecular mechanism of axon regeneration in the micro-environment provided by nerve conduit remains unclear. In this study, the rat sciatic nerve of 10 mm defect was made and bridged by PRGD/PDLLA nerve conduit. We investigated the process of nerve regeneration using histological, functional and real time PCR analyses after implantation from 7 to 35 days. Our data demonstrated that the ciliary neurotrophic factor highly expressed and up-regulated the downstream signaling pathways, in the case of activated signals, the expressions of axon sprout relative proteins, such as tubulin and growth-associated protein-43, were strongly augmented. Taken together, these data suggest a possible mechanism of axon regeneration promoted by PRGD/PDLLA conduit, which created a micro environment for enhancement of diffusion of neurotrophic factors secreted by the injured nerve stumps, and activation of molecular signal transduction involved in growth cone, to potentiate the nerve recovery. PMID- 25934452 TI - Development of an oral nanotherapeutics using redox nanoparticles for treatment of colitis-associated colon cancer. AB - Oral chemotherapy is the preferred treatment for colon cancer. However, this strategy faces many challenges, including instability in the gastrointestinal (GI) tract, insufficient bioavailability, low tumor targeting, and severe adverse effects. In this study, we designed a novel redox nanoparticle (RNP(O)) that is an ideal oral therapeutics for colitis-associated colon cancer treatment. RNP(O) possesses nitroxide radicals in the core, which act as reactive oxygen species (ROS) scavengers. Orally administered RNP(O) highly accumulated in colonic mucosa, and specifically internalized in cancer tissues, but less in normal tissues. Despite of long-term oral administration of RNP(O), no noticeable toxicities were observed in major organs of mice. Because RNP(O) effectively scavenged ROS, it significantly suppressed tumor growth after accumulation at tumor sites. Combination of RNP(O) with the conventional chemotherapy, irinotecan, led to remarkably improved therapeutic efficacy and effectively suppressed its adverse effects on GI tract. Therefore, RNP(O) is promising oral nanotherapeutics for cancer therapies. PMID- 25934453 TI - Glucosamine loaded injectable silk-in-silk integrated system modulate mechanical properties in bovine ex-vivo degenerated intervertebral disc model. AB - Injectable hydrogels offer a tremendous potential for treatment of degenerated intervertebral disc due to their ability to withstand complex loading, conforming precisely to the defect spaces and eliminating the need for invasive surgical procedures. We have developed an injectable hydrogel platform of N-acetyl glucosamine (GlcNAc) loaded silk hollow spheres embedded in silk hydrogel for in situ therapeutic release and enhanced mechanical strength. The assembled silk hydrogel provided adequate structural support to the ex vivo degenerated disc model in a cyclic compression test at par with the native tissue. Spatiotemporal release of GlcNAc in a controlled manner from the silk hollow microspheres trigger enhanced proteoglycan production from ADSCs embedded in the composite system. Role of MAPK and SMAD pathways in increasing proteoglycan production have been explored by immunohistological analysis as a result of the action of GlcNAc on the cells, elucidating the potential of injectable silk microsphere-in-silk hydrogel for the regeneration of degenerated disc tissue. PMID- 25934454 TI - Carbon nanotubes enhance intercalated disc assembly in cardiac myocytes via the beta1-integrin-mediated signaling pathway. AB - Carbon nanotubes (CNTs) offer a new paradigm for constructing functional cardiac patches and repairing myocardial infarction (MI). However, little is known about how CNTs enhance the mechanical integrity and electrophysiological function of cardiac myocytes. To address this issue, we investigated the regularity and precise mechanism of the influence of CNTs on the assembly of intercalated disc (IDs). Here, single walled CNTs incorporated into collagen substrates were utilized as growth supports for neonatal cardiomyocytes, which enhanced cardiomyocyte adhesion and maturation. Furthermore, through the use of immunohistochemical staining, western blotting, transmission electron microscopy, and intracellular calcium transient measurement, we discovered that the addition of CNTs remarkably increased ID-related protein expression and enhanced ID assembly and functionality. On that basis, we further explored the underlying mechanism for how CNTs enhanced ID assembly through the use of immunohistochemical staining and western blotting. We found that the beta1 integrin-mediated signaling pathway mediated CNT-induced upregulation of electrical and mechanical junction proteins. Notably, CNTs remarkably accelerated gap junction formation via activation of the beta1-integrin-mediated FAK/ERK/GATA4 pathway. These findings provide valuable insight into the mechanistic effects that CNTs have on neonatal cardiomyocyte performance and will have a significant impact on the future of nanomedical research. PMID- 25934455 TI - Stem cell behavior on tailored porous oxide surface coatings. AB - Nanoscale surface topographies are known to have a profound influence on cell behavior, including cell guidance, migration, morphology, proliferation, and differentiation. In this study, we have observed the behavior of human mesenchymal stem cells cultured on a range of tailored porous SiO2 and TiO2 nanostructured surface coatings fabricated via glancing angle electron-beam deposition. By controlling the physical vapor deposition angle during fabrication, we could control systematically the deposited coating porosity, along with associated topographic features. Immunocytochemistry and image analysis quantitatively revealed the number of adherent cells, as well as their basic cellular morphology, on these surfaces. Signaling pathway studies showed that even with subtle changes in nanoscale surface structures, the behavior of mesenchymal stem cells was strongly influenced by the precise surface structures of these porous coatings. PMID- 25934456 TI - 3D culture broadly regulates tumor cell hypoxia response and angiogenesis via pro inflammatory pathways. AB - Oxygen status and tissue dimensionality are critical determinants of tumor angiogenesis, a hallmark of cancer and an enduring target for therapeutic intervention. However, it is unclear how these microenvironmental conditions interact to promote neovascularization, due in part to a lack of comprehensive, unbiased data sets describing tumor cell gene expression as a function of oxygen levels within three-dimensional (3D) culture. Here, we utilized alginate-based, oxygen-controlled 3D tumor models to study the interdependence of culture context and the hypoxia response. Microarray gene expression analysis of tumor cells cultured in 2D versus 3D under ambient or hypoxic conditions revealed striking interdependence between culture dimensionality and hypoxia response, which was mediated in part by pro-inflammatory signaling pathways. In particular, interleukin-8 (IL-8) emerged as a major player in the microenvironmental regulation of the hypoxia program. Notably, this interaction between dimensionality and oxygen status via IL-8 increased angiogenic sprouting in a 3D endothelial invasion assay. Taken together, our data suggest that pro inflammatory pathways are critical regulators of tumor hypoxia response within 3D environments that ultimately impact tumor angiogenesis, potentially providing important therapeutic targets. Furthermore, these results highlight the importance of pathologically relevant tissue culture models to study the complex physical and chemical processes by which the cancer microenvironment mediates new vessel formation. PMID- 25934457 TI - Engineered heart slices for electrophysiological and contractile studies. AB - A major consideration in the design of engineered cardiac tissues for the faithful representation of physiological behavior is the recapitulation of the complex topography and biochemistry of native tissue. In this study we present engineered heart slices (EHS), which consist of neonatal rat ventricular cells (NRVCs) seeded onto thin slices of decellularized cardiac tissue that retain important aspects of native extracellular matrix (ECM). To form EHS, rat or pig ventricular tissue was sectioned into 300 MUm-thick, 5 to 16 mm-diameter disks, which were subsequently decellularized using detergents, spread on coverslips, and seeded with NRVCs. The organized fiber structure of the ECM remained after decellularization and promoted cell elongation and alignment, resulting in an anisotropic, functional tissue that could be electrically paced. Contraction decreased at higher pacing rates, and optical mapping revealed electrical conduction that was anisotropic with a ratio of approximately 2.0, rate-dependent shortening of the action potential and slowing of conduction, and slowing of conduction by the sodium channel blocker lidocaine. Reentrant arrhythmias could also be pace-induced and terminated. EHS constitute an attractive in vitro cardiac tissue in which cardiac cells are cultured on thin slices of decellularized cardiac ECM that provide important biochemical, structural, and mechanical cues absent in traditional cell cultures. PMID- 25934458 TI - The Impact of Exercise On Depression and Anxiety Symptoms Among Abstinent Methamphetamine-Dependent Individuals in A Residential Treatment Setting. AB - BACKGROUND: This paper reports data from a study designed to determine the impact of an 8-week exercise program on depression and anxiety symptoms among newly abstinent methamphetamine (MA)-dependent individuals in residential treatment. METHODS: One hundred thirty-five MA-dependent individuals, newly enrolled in residential treatment, were randomly assigned to receive either a 3-times-per week, 60-minute structured exercise program for 8 weeks (24 sessions) or an equivalent number of health education sessions. Using mixed-modeling repeated measures regression, we examined changes in weekly total depression and anxiety scores as measured by the Beck Depression Inventory and Beck Anxiety Inventory over the 8-week study period. RESULTS: Mean age of participants was 31.7 (SD = 6.9); 70.4% were male and 48% Latino. Analyses indicate a significant effect of exercise on reducing depression (beta = -0.63, P = 0.001) and anxiety (beta = 0.95, P=0.001) symptoms (total scores) over the 8-week period compared to a health education control group. A significant dose interaction effect between session attendance and exercise was found as well on reducing depression (beta = 0.61, P < 0.001) and anxiety symptoms (beta = -0.22, P=0.009) over time compared to the control group. CONCLUSIONS: Results support the role of a structured exercise program as an effective intervention for improving symptoms of depression and anxiety associated with MA abstinence. PMID- 25934459 TI - Provision of onsite HIV Services in Substance Use Disorder Treatment Programs: A Longitudinal Analysis. AB - The provision of HIV education and testing in substance use disorder (SUD) treatment programs is an important public health strategy for reducing HIV incidence. For many at-risk individuals, SUD treatment represents the primary point of access for testing and receiving HIV-related services. This study uses two waves of nationally representative data of 265 privately-funded SUD treatment programs in the U.S. to examine organizational and patient characteristics associated with offering a dedicated HIV/AIDS treatment track, onsite HIV/AIDS support groups, and onsite HIV testing. Our longitudinal analysis indicated that the majority of treatment programs reported providing education and prevention services, but there was a small, yet significant, decline in the number of programs providing these services. Programs placed more of an emphasis on providing information on the transmission of HIV rather than on acquiring risk reduction skills. There was a notable and significant increase (from 26.0% to 31.7%) in programs that offered onsite HIV testing, including rapid HIV testing, and an increase in the percentage of patients who received testing in the programs. Larger programs were more likely to offer a dedicated HIV/AIDS treatment track and to offer onsite HIV/AIDS support groups, while accredited programs and programs with a medical infrastructure were more likely to provide HIV testing. The percentage of injection drug users was positively linked to the availability of specialized HIV/AIDS tracks and HIV/AIDS support groups, and the percentage of female clients was associated with the availability of onsite support groups. The odds of offering HIV/AIDS support groups were also greater in programs that had a dedicated LGBT track. The findings suggest that access to hospitals and medical care services is an effective way to facilitate adoption of HIV services and that programs are providing a needed service among a group of patients who have a heightened risk of HIV transmission. Nonetheless, the fact that fewer than one third of programs offered onsite testing, and, of the ones that did, fewer than one third of their patients received testing, raises concern in light of federal guidelines. PMID- 25934460 TI - Modeling the Innovation-Decision Process: Dissemination and Adoption of a Motivational Interviewing Preparatory Procedure In Addiction Outpatient Clinics. AB - Widespread adoption of empirically-supported treatment innovations has the potential to improve effectiveness of treatment received by individuals with substance use disorders. However, the process of disseminating such innovations has been complex, slow, and difficult. We empirically describe the dissemination and adoption of a treatment innovation--an alcohol-treatment preparatory therapeutic procedure based on motivational interviewing (MI)--in the context of Rogers' (2003) five stages of innovation-decision process (knowledge, persuasion, decision, implementation and confirmation). To this end, 145 randomly-chosen outpatient addiction treatment clinics in New York State received an onsite visit from a project trainer delivering one of three randomly-assigned dissemination intensities: a 15-minute, a half-day or a full-day presentation. Across these clinics, 141 primary administrators and 837 clinicians completed questionnaires assessing aspects of five innovation-decision stages. At each clinic, questionnaire administration occurred immediately pre- and post-dissemination, as well as 1 and 6 months after dissemination. Consistent with Rogers' theory, earlier stages of the innovation-decision process predicted later stages. As hypothesized, dissemination intensity predicted clinicians' post-dissemination knowledge. Clinician baseline characteristics (including gender, pre dissemination knowledge regarding the MI preparatory technique, education, case load, beliefs regarding the nature of alcohol problems, and beliefs and behavior with regard to therapeutic style) predicted knowledge and persuasion stage variables. One baseline clinic characteristic (i.e., clinic mean beliefs and behavior regarding an MI-consistent therapeutic style) predicted implementation stage variables. Findings suggest that dissemination strategies should accommodate clinician and clinic characteristics. PMID- 25934461 TI - Hepatitis B virus epidemiology. AB - The epidemiology of hepatitis B virus (HBV) infection is geographically diverse, with population prevalence, age and mode of acquisition, and likelihood of progression to chronic infection mutually interdependent. The burden of chronic HBV infection is increasingly being recognized, with cirrhosis and liver cancer attributable to HBV continuing to increase. The outcomes of chronic HBV infection are affected by a range of factors, including viral genotype, the presence of coinfections with other blood-borne viruses, and the impact of other causes of liver disease. The increased recognition of HBV infection as a leading cause of death globally has resulted in the development of new structures and policies at the international level; immediate attention to implementing these strategies is now required. PMID- 25934464 TI - Recombinant human thrombomodulin in the treatment of acute myeloid leukemia patients complicated by disseminated intravascular coagulation: retrospective analysis of outcomes between patients treated with heparin and recombinant human thrombomodulin therapy. AB - BACKGROUND: Recombinant thrombomodulin (rTM) is a promising anticoagulant. Improvements in disseminated intravascular coagulation (DIC) and the amelioration of bleeding complications in DIC patients were reported to be greater with rTM therapy than with unfractionated heparin therapy. However, it remains unknown whether rTM therapy affects the outcomes of patients with acute myeloblastic leukemia (AML). DESIGN AND METHOD: We retrospectively analyzed 103 patients with AML and compared outcomes between patients treated with low molecular weight heparin therapy and rTM. The diagnostic criteria for DIC were previously proposed by the Japanese Ministry of Health and Welfare. Comparisons between qualitative variables were carried out using the chi(2) test. Survival probabilities were estimated by the Kaplan-Meier method, and differences in survival distributions were evaluated using the log-rank test. RESULTS: Forty-seven patients developed DIC due to chemotherapy or their disease status. Fourteen patients were treated with rTM, while 33 patients were treated with low-molecular-weight heparin (LMWH). The log-rank test revealed that overall survival was significantly worse in the DIC group than in the non-DIC group (P=0.003), and was signfiacntly better in the rTM group than the LMWH group (P=0.016). CONCLUSION: rTM was more efficient than LMWH because of the improvements it induced in overall survival. PMID- 25934462 TI - Hepatitis B virus genotypes and variants. AB - At least 10 hepatitis B virus (HBV) genotypes (A to J) with distinct geographic distributions and several HBV mutants, including precore/core promoter mutations and pre-S/S deletion mutations, have been recognized to be not only predictive of liver disease progression but also associated with response to antiviral therapy. HBV genotype-specific pathogenesis may contribute to heterogeneous clinical outcomes in chronic hepatitis B patients across the world. For example, patients with HBV genotypes C and D infection have a lower rate of spontaneous HBeAg seroconversion. In addition, HBV genotypes C and D have a higher frequency of core promoter and pre-S mutations than genotypes A and B. Genotypes C and D also carry a higher lifetime risk of cirrhosis and HCC development than genotypes A and B. Core promoter and pre-S mutations also correlate with an increased risk of hepatocellular carcinoma (HCC). Therapeutically, genotypes A and B patients have a better response to interferon-based therapy than genotypes C and D patients, but the response to nucleos(t)ide analogs is comparable across different HBV genotypes. In conclusion, HBV genotypes and variants may serve as viral genetic markers to predict disease progression as well as help practicing physicians optimize individualized antiviral therapy in clinical practice. PMID- 25934465 TI - Suppression of plasminogen activator inhibitor-1 by inhaled nitric oxide attenuates the adverse effects of hyperoxia in a rat model of acute lung injury. AB - INTRODUCTION: Locally increased expression of plasminogen activator inhibitor-1 (PAI-1) in acute lung injury (ALI) is largely responsible for fibrin deposition in the alveolae and lung microvasculature. In vitro, nitric oxide (NO) effectively suppresses the ischemic induction of PAI-1. We aimed to investigate the effects of inhaled NO on PAI-1 expression in ALI in a rat model with and without hyperoxia. MATERIALS AND METHODS: Healthy adult rats were primed with lipopolysaccharide (LPS) via an intraperitoneal challenge followed by a second dose of LPS given intratracheally to induce ALI (LPS group), whereas the control groups were given sterile saline. All groups were allocated to subgroups according to gas exposure: NO (20 parts per million, NO), 95% oxygen (O), both (ONO), or room air (A). At 4h, 24h, 48h (after 4h or 24h exposure to the various gases, 24h gas intervention and then observation until 48h), the rat lungs were processed and PAI-1 protein and mRNA expression, histopathological lung injury scores and fibrin deposition were evaluated. RESULTS: At 4 and 24h, inhaled NO caused the PAI-1 mRNA levels in the LPS-NO and LPS-ONO subgroups to decrease compared with the untreated LPS subgroups. At 48h, higher PAI-1 mRNA levels than those of the corresponding control subgroup were only observed in the LPS-O subgroup, and these values were lower in the LPS-ONO subgroup than in the LPS-O subgroup. The trends of the PAI-1 protein levels mirrored those of PAI-1 mRNA. At 48h, PAI-1 protein levels in the LPS-NO and LPS-ONO subgroups were decreased compared with those in the untreated LPS subgroups. The histopathological lung injury scores and fibrin deposition in LPS subgroups that inhaled NO showed a decreasing trend compared with the untreated LPS subgroups. CONCLUSIONS: Inhaled NO can suppress elevated PAI-1 expression in rats with ALI induced by endotoxin. Although exposure to high-concentration oxygen prolongs the duration of PAI-1 mRNA overexpression in ALI, inhaled NO can reduce this effect and alleviate both fibrin deposition and lung injury. PMID- 25934466 TI - Development, implementation and evaluation of an information model for archetype based user responsive medical data visualization. AB - BACKGROUND: When medical data have been successfully recorded or exchanged between systems there appear a need to present the data consistently to ensure that it is clearly understood and interpreted. A standard based user interface can provide interoperability on the visual level. OBJECTIVES: The goal of this research was to develop, implement and evaluate an information model for building user interfaces for archetype based medical data. METHODS: The following types of knowledge were identified as important elements and were included in the information model: medical content related attributes, data type related attributes, user-related attributes, device-related attributes. In order to support flexible and efficient user interfaces an approach that represents different types of knowledge with different models separating the medical concept from a visual concept and interface realization was chosen. We evaluated the developed approach using Guideline for Good Evaluation Practice in Health Informatics (GEP-HI). RESULTS: We developed a higher level information model to complement the ISO 13606 archetype model. This enabled the specification of the presentation properties at the moment of the archetypes' definition. The model allows realizing different users' perspectives on the data. The approach was implemented and evaluated within a functioning EHR system. The evaluation involved 30 patients of different age and IT experience and 5 doctors. One month of testing showed that the time required reading electronic health records decreased for both doctors (from average 310 to 220s) and patients (from average 95 to 39s). Users reported a high level of satisfaction and motivation to use the presented data visualization approach especially in comparison with their previous experience. CONCLUSION: The introduced information model allows separating medical knowledge and presentation knowledge. The additional presentation layer will enrich the graphical user interface's flexibility and will allow an optimal presentation of medical data considering the different users' perspectives and different media used for data presentation. PMID- 25934463 TI - Malformations of cortical development and epilepsy. AB - Malformations of cortical development (MCDs) are an important cause of epilepsy and an extremely interesting group of disorders from the perspective of brain development and its perturbations. Many new MCDs have been described in recent years as a result of improvements in imaging, genetic testing, and understanding of the effects of mutations on the ability of their protein products to correctly function within the molecular pathways by which the brain functions. In this review, most of the major MCDs are reviewed from a clinical, embryological, and genetic perspective. The most recent literature regarding clinical diagnosis, mechanisms of development, and future paths of research are discussed. PMID- 25934467 TI - One-year stability for a glucose/oxygen biofuel cell combined with pH reactivation of the laccase/carbon nanotube biocathode. AB - This study reports a mixed operational/storage stability of a MWCNT-based glucose biofuel cell (GBFC) over one year. The latter was examined by performing a one hour discharge every day during one month followed by several discharges over a period of 11 months. Under continuous discharge in physiological conditions (5 mM glucose, 37 degrees , pH7), the GBFC exhibits a 25% power decrease after 1 h of operation. This decrease is mainly due to the deactivation of laccase biocathodes at neutral pH. Nevertheless, the biocathodes can be reversibly reactivated via storage in phosphate buffer (pH 5). Under these conditions, the GBFC finally exhibits 22% of its initial maximum power density after one year at intermittent reactivation/discharge cycles. Although both GBFC electrodes can exhibit one year stability, short-term experiments show that biocathodes are limited by hydroxide inhibition while long-term experiments indicate that bioanodes are likely limited by the stability of the GOx itself. While most of the GBFCs in the literature present stability in the range of several weeks, these results demonstrate the viability of a GBFC for industrial applications in a long period of time. PMID- 25934468 TI - Comprehensive chemical characterization of Rape tobacco products: Nicotine, un ionized nicotine, tobacco-specific N'-nitrosamines, polycyclic aromatic hydrocarbons, and flavor constituents. AB - Rape, a diverse group of smokeless tobacco products indigenous to South America, is generally used as a nasal snuff and contains substantial amount of plant material with or without tobacco. Previously uncharacterized, rape contains addictive and harmful chemicals that may have public health implications for users. Here we report % moisture, pH, and the levels of total nicotine, un ionized nicotine, flavor-related compounds, tobacco-specific N-nitrosamines (TSNAs) and polycyclic aromatic hydrocarbons (PAHs) for manufactured and hand made rape. Most rape products were mildly acidic (pH 5.17-6.23) with total nicotine ranging from 6.32 to 47.6 milligram per gram of sample (mg/g). Calculated un-ionized nicotine ranged from 0.03 to 18.5 mg/g with the highest values associated with hand-made rapes (pH 9.75-10.2), which contain alkaline ashes. In tobacco-containing rapes, minor alkaloid levels and Fourier transform infrared spectra were used to confirm the presence of Nicotiana rustica, a high nicotine tobacco species. There was a wide concentration range of TSNAs and PAHs among the rapes analyzed. Several TSNAs and PAHs identified in the products are known or probable carcinogens according to the International Agency for Research on Cancer. Milligram quantities of some non-tobacco constituents, such as camphor, coumarin, and eugenol, warrant additional evaluation. PMID- 25934469 TI - Morphology and morphometry of the human embryonic brain: A three-dimensional analysis. AB - The three-dimensional dynamics and morphology of the human embryonic brain have not been previously analyzed using modern imaging techniques. The morphogenesis of the cerebral vesicles and ventricles was analyzed using images derived from human embryo specimens from the Kyoto Collection, which were acquired with a magnetic resonance microscope equipped with a 2.35-T superconducting magnet. A total of 101 embryos between Carnegie stages (CS) 13 and 23, without apparent morphological damage or torsion in the brain ventricles and axes, were studied. To estimate the uneven development of the cerebral vesicles, the volumes of the whole embryo and brain, prosencephalon, mesencephalon, and rhombencephalon with their respective ventricles were measured using image analyzing AmiraTM software. The brain volume, excluding the ventricles (brain tissue), was 1.15 +/- 0.43 mm(3) (mean +/- SD) at CS13 and increased exponentially to 189.10 +/- 36.91 mm(3) at CS23, a 164.4-fold increase, which is consistent with the observed morphological changes. The mean volume of the prosencephalon was 0.26 +/- 0.15 mm(3) at CS13. The volume increased exponentially until CS23, when it reached 110.99 +/- 27.58 mm(3). The mean volumes of the mesencephalon and rhombencephalon were 0.20 +/- 0.07 mm(3) and 0.69 +/- 0.23 mm(3) at CS13, respectively; the volumes reached 21.86 +/- 3.30 mm(3) and 56.45 +/- 7.64 mm(3) at CS23, respectively. The ratio of the cerebellum to the rhombencephalon was approximately 7.2% at CS20, and increased to 12.8% at CS23. The ratio of the volume of the cerebral vesicles to that of the whole embryo remained nearly constant between CS15 and CS23 (11.6-15.5%). The non-uniform thickness of the brain tissue during development, which may indicate the differentiation of the brain, was visualized with surface color mapping by thickness. At CS23, the basal regions of the prosencephalon and rhombencephalon were thicker than the corresponding dorsal regions. The brain was further studied by the serial digital subtraction of layers of tissue from both the external and internal surfaces to visualize the core region (COR) of the thickening brain tissue. The COR, associated with the development of nuclei, became apparent after CS16; this was particularly visible in the prosencephalon. The anatomical positions of the COR were mostly consistent with the formation of the basal ganglia, thalamus, and pyramidal tract. This was confirmed through comparisons with serial histological sections of the human embryonic brain. The approach used in this study may be suitable as a convenient alternative method for estimating the development and differentiation of the neural ganglia and tracts. These findings contribute to a better understanding of brain and cerebral ventricle development. PMID- 25934470 TI - ConnectomeDB--Sharing human brain connectivity data. AB - ConnectomeDB is a database for housing and disseminating data about human brain structure, function, and connectivity, along with associated behavioral and demographic data. It is the main archive and dissemination platform for data collected under the WU-Minn consortium Human Connectome Project. Additional connectome-style study data is and will be made available in the database under current and future projects, including the Connectome Coordination Facility. The database currently includes multiple modalities of magnetic resonance imaging (MRI) and magnetoencephalograpy (MEG) data along with associated behavioral data. MRI modalities include structural, task, resting state and diffusion. MEG modalities include resting state and task. Imaging data includes unprocessed, minimally preprocessed and analysis data. Imaging data and much of the behavioral data are publicly available, subject to acceptance of data use terms, while access to some sensitive behavioral data is restricted to qualified investigators under a more stringent set of terms. ConnectomeDB is the public side of the WU Minn HCP database platform. As such, it is geared towards public distribution, with a web-based user interface designed to guide users to the optimal set of data for their needs and a robust backend mechanism based on the commercial Aspera fasp service to enable high speed downloads. HCP data is also available via direct shipment of hard drives and Amazon S3. PMID- 25934471 TI - Sparse, reliable, and long-term stable representation of periodic whisker deflections in the mouse barrel cortex. AB - The rodent whisker system is a preferred model for studying plasticity in the somatosensory cortex (barrel cortex). Contrarily, only a small amount of research has been conducted to characterize the stability of neuronal population activity in the barrel cortex. We used the mouse whisker system to address the neuronal basis of stable perception in the somatosensory cortex. Cortical representation of periodic whisker deflections was studied in populations of neurons in supragranular layers over extended time periods (up to 3 months) with long-term two-photon Ca(2+) imaging in anesthetized mice. We found that in most of the neurons (87%), Ca(2+) responses increased sublinearly with increasing number of contralateral whisker deflections. The imaged population of neurons was activated in a stereotypic way over days and for different deflection rates (pulse frequencies). Thus, pulse frequencies are coded by response strength rather than by distinct neuronal sub-populations. A small population of highly responsive neurons (~3%) was sufficient to decode the whisker stimulus. This conserved functional map, led by a small set of highly responsive neurons, might form the foundation of stable sensory percepts. PMID- 25934472 TI - Postsurgical Intercostal Lung Herniation. PMID- 25934473 TI - Transbronchial cryobiopsy in interstitial lung disease: advantageous costs to benefits ratio. PMID- 25934475 TI - Effects of deferasirox-deferoxamine on myocardial and liver iron in patients with severe transfusional iron overload. AB - Deferasirox (DFX) monotherapy is effective for reducing myocardial and liver iron concentrations (LIC), although some patients may require intensive chelation for a limited duration. HYPERION, an open-label single-arm prospective phase 2 study, evaluated combination DFX-deferoxamine (DFO) in patients with severe transfusional myocardial siderosis (myocardial [m] T2* 5-<10 ms; left ventricular ejection fraction [LVEF] >=56%) followed by optional switch to DFX monotherapy when achieving mT2* >10 ms. Mean dose was 30.5 mg/kg per day DFX and 36.3 mg/kg per day DFO on a 5-day regimen. Geometric mean mT2* ratios (Gmeanmonth12/24/Gmeanbaseline) were 1.09 and 1.30, respectively, increasing from 7.2 ms at baseline (n = 60) to 7.7 ms at 12 (n = 52) and 9.5 ms at 24 months (n = 36). Patients (17 of 60; 28.3%) achieved mT2* >=10 ms and >=10% increase from baseline at month 24; 15 switched to monotherapy during the study based on favorable mT2*. LIC decreased substantially from a baseline of 33.4 to 12.8 mg Fe/g dry weight at month 24 (-52%). LVEF remained stable with no new arrhythmias/cardiac failure. Five patients discontinued with mT2* <5 ms and 1 died (suspected central nervous system infection). Safety was consistent with established monotherapies. Results show clinically meaningful improvements in mT2* in about one-third of patients remaining on treatment at month 24, alongside rapid decreases in LIC in this heavily iron-overloaded, difficult-to-treat population. Combination therapy may be useful when rapid LIC reduction is required, regardless of myocardial iron overload. This trial was registered at www.clinicaltrials.gov as #NCT01254227. PMID- 25934476 TI - Genetic variants in the ADAMTS13 and SUPT3H genes are associated with ADAMTS13 activity. AB - A disintegrin and metalloproteinase with thrombospondin motifs 13 (ADAMTS13) cleaves von Willebrand factor, reducing its prothrombotic activity. The genetic determinants of ADAMTS13 activity remain unclear. We performed a genome-wide association study of ADAMTS13 activity in the Rotterdam Study, a population-based cohort study. We used imputed genotypes of common variants in a discovery sample of 3443 individuals and replication sample of 2025 individuals. We examined rare exonic variant associations in ADAMTS13 in 1609 individuals using an exome array. rs41314453 in ADAMTS13 was associated with ADAMTS13 activity in both our discovery (beta, -20.2%; P = 1.3 * 10(-33)) and replication sample (P = 3.3 * 10( 34)), and explained 3.6% to 6.5% of the variance. In the combined analysis of our discovery and replication samples, there were 2 further independent associations at the ADAMTS13 locus: rs3118667 (beta, 3.0; P = 9.6 * 10(-21)) and rs139911703 (beta, -11.6; P = 3.6 * 10(-8)). In addition, rs10456544 in SUPT3H was associated with a 4.2 increase in ADAMTS13 activity (P = 1.13.6 * 10(-8)). Finally, we found 3 independent associations with rare coding variants in ADAMTS13: rs148312697 (beta, -32.2%; P = 3.7 * 10(-6)), rs142572218 (beta, -46.0%; P = 3.9 * 10(-5)), and rs36222275 (beta, -13.9%; P = 2.9 * 10(-3)). In conclusion, we identified rs41314453 as the main genetic determinant of ADAMTS13 activity, and we present preliminary findings for further associations at the ADAMTS13 and SUPT3H loci. PMID- 25934477 TI - Leukemia stem cells in T-ALL require active Hif1alpha and Wnt signaling. AB - The Wnt signaling pathway has been shown to play important roles in normal hematopoietic stem cell biology and in the development of both acute and chronic myelogenous leukemia. Its role in maintaining established leukemia stem cells, which are more directly relevant to patients with disease, however, is less clear. To address what role Wnt signaling may play in T-cell acute lymphoblastic leukemia (T-ALL), we used a stably integrated fluorescent Wnt reporter construct to interrogate endogenous Wnt signaling activity in vivo. In this study, we report that active Wnt signaling is restricted to minor subpopulations within bulk tumors, that these Wnt-active subsets are highly enriched for leukemia initiating cells (LICs), and that genetic inactivation of beta-catenin severely reduces LIC frequency. We show further that beta-catenin transcription is upregulated by hypoxia through hypoxia-inducible factor 1alpha (Hif1alpha) stabilization, and that deletion of Hif1alpha also severely reduces LIC frequency. Of note, the deletion of beta-catenin or Hif1alpha did not impair the growth or viability of bulk tumor cells, suggesting that elements of the Wnt and Hif pathways specifically support leukemia stem cells. We also confirm the relevance of these findings to human disease using cell lines and patient-derived xenografts, suggesting that targeting these pathways could benefit patients with T-ALL. PMID- 25934478 TI - Correlation of cardiovascular magnetic resonance imaging findings and endomyocardial biopsy results in patients undergoing screening for heart transplant rejection. AB - BACKGROUND: Endomyocardial biopsy (EMB) is the current gold standard to screen for heart transplant rejection but has important risks and limitations. Cardiovascular magnetic resonance imaging (CMRI) is increasingly used to characterize cardiac function and myocardial tissue. We evaluated the diagnostic accuracy of CMRI compared with EMB and clinically diagnosed heart transplant rejection. METHODS: Comprehensive CMRI scans were performed on adult heart transplant recipients within 24 hours of EMB (routine or clinically indicated), before initiation of any anti-rejection therapy, and blinded to EMB results. Multivariable analysis was used to create CMRI diagnostic criteria for comparison with a positive EMB (Grade >= 2R or antibody-mediated rejection) and clinical rejection (change in medical therapy to treat rejection). RESULTS: Sixty participants (75% male; mean age, 51 +/- 14 years) were recruited, providing 73 comparisons between CMRI and EMB for the diagnosis of rejection. Multivariable logistic regression identified myocardial edema (T2 relaxation time) and right ventricular end-diastolic volume index as independent predictors of a positive EMB. Combining threshold right ventricular end-diastolic volume index and edema values predicted a positive EMB with very good accuracy: sensitivity, 93%; specificity, 78%; positive predictive value, 52%; and negative predictive valve, 98%. CMRI was more sensitive than EMB at predicting clinical rejection (sensitivity of 67% vs 58%). CONCLUSIONS: CMRI has high sensitivity and high negative predictive value in predicting biopsy-positive heart transplant rejection and may be useful as a screening test before routine EMB. CMRI also has better sensitivity for clinically diagnosed heart transplant rejection and could be helpful in cases of negative rejection on the biopsy specimen. PMID- 25934479 TI - Autophagy protects against ischemia/reperfusion-induced lung injury through alleviating blood-air barrier damage. AB - BACKGROUND: Understanding the role and underlying regulation mechanism of autophagy in ischemia/reperfusion (I/R)-induced lung injury may provide potentially new pharmacologic targets for treatment of acute lung injury. The aim of this study was to adjust autophagy with pharmacologic agents to determine its functional significance in I/R-induced lung injury. METHODS: Human pulmonary microvascular endothelial cells (HPMVECs) and mice were pre-conditioned with autophagy inhibitor chloroquine or promoter rapamycin before they were challenged with oxygen-glucose deprivation/oxygen-glucose restoration (OGD) and lung I/R, respectively. Extracellular signal-regulated kinase (ERK)1/2 inhibitor U0126 was pre-injected into I/R-induced mice to test the role of ERK1/2 in regulating autophagy. RESULTS: OGD caused tight conjunction damage and cell death in HPMVECs, which was further aggravated by blocking autophagy, yet ameliorated through promoting autophagy. On a consistent basis, inhibiting autophagy aggravated I/R-induced lung edema and tissue inflammation, which was significantly alleviated by promoting autophagy with rapamycin. In addition, inhibition of ERK1/2 increased expression of active mammalian target-of-rapamycin and thus decreased I/R-induced autophagy. CONCLUSIONS: It appears that autophagy plays a protective role in I/R-induced lung injury and this effect may be enhanced by moderately improving autophagy level. Meanwhile, the ERK1/2 signal pathway has a positively regulating role in lung I/R-induced autophagy. PMID- 25934480 TI - Non-neuronal and neuronal BACE1 elevation in association with angiopathic and leptomeningeal beta-amyloid deposition in the human brain. AB - BACKGROUND: Cerebral amyloid angiopathy (CAA) refers to the deposition of beta amyloid (Abeta) peptides in the wall of brain vasculature, commonly involving capillaries and arterioles. Also being considered a part of CAA is the Abeta deposition in leptomeninge. The cellular origin of angiopathic Abeta and the pathogenic course of CAA remain incompletely understood. METHODS: The present study was aimed to explore the pathogenic course of CAA in the human cerebrum via examination of changes in beta-secretase-1 (BACE1), the obligatory Abeta producing enzyme, relative to Abeta and other cellular markers, by neuroanatomical and biochemical characterizations with postmortem brain samples and primary cell cultures. RESULTS: Immunoreactivity (IR) for BACE1 was essentially not visible at vasculature in cases without cerebral amyloidosis (control group, n = 15, age = 86.1 +/- 10.3 year). In cases with brain amyloid pathology (n = 15, age = 78.7 +/- 12.7 year), increased BACE1 IR was identified locally at capillaries, arterioles and along the pia, localizing to endothelia, perivascular dystrophic neurites and meningeal cells, and often coexisting with vascular iron deposition. Double immunofluorescence with densitometric analysis confirmed a site-specific BACE1 elevation at cerebral arterioles in the development of vascular Abeta deposition. Levels of BACE1 protein, activity and its immediate product (C99) were elevated in leptomeningeal lysates from cases with CAA relative to controls. The expression of BACE1 and other amyloidogenic proteins in the endothelial and meningeal cells was confirmed in primary cultures prepared from human leptomeningeal and arteriolar biopsies. CONCLUSION: These results suggest that BACE1 elevation in the endothelia and perivascular neurites may be involved in angiopathic Abeta deposition, while BACE1 elevation in meningeal cells might contribute Abeta to leptomeningeal amyloidosis. PMID- 25934481 TI - Interrater variability of EEG interpretation in comatose cardiac arrest patients. AB - OBJECTIVE: EEG is widely used to predict outcome in comatose cardiac arrest patients, but its value has been limited by lack of a uniform classification. We used the EEG terminology proposed by the American Clinical Neurophysiology Society (ACNS) to assess interrater variability in a cohort of cardiac arrest patients included in the Target Temperature Management trial. The main objective was to evaluate if malignant EEG-patterns could reliably be identified. METHODS: Full-length EEGs from 103 comatose cardiac arrest patients were interpreted by four EEG-specialists with different nationalities who were blinded for patient outcome. Percent agreement and kappa (kappa) for the categories in the ACNS EEG terminology and for prespecified malignant EEG-patterns were calculated. RESULTS: There was substantial interrater agreement (kappa 0.71) for highly malignant patterns and moderate agreement (kappa 0.42) for malignant patterns. Substantial agreement was found for malignant periodic or rhythmic patterns (kappa 0.72) while agreement for identifying an unreactive EEG was fair (kappa 0.26). CONCLUSIONS: The ACNS EEG terminology can be used to identify highly malignant EEG-patterns in post cardiac arrest patients in an international context with high reliability. SIGNIFICANCE: The establishment of strict criteria with high transferability between interpreters will increase the usefulness of routine EEG to assess neurological prognosis after cardiac arrest. PMID- 25934482 TI - The prevalence of 'Clinical Neurophysiology' and related terms in the English literature: A specialty in transition. PMID- 25934483 TI - Oxidative stress and nitric oxide signaling related biomarkers in patients with pulmonary hypertension: a case control study. AB - BACKGROUND: Oxidative stress (OS) and reduced nitric oxide (NO) bioavailability contribute to the pathogenesis of pulmonary hypertension (PH). Whether there are associations between OS and NO signaling biomarkers and whether these biomarkers are associated with the severity of PH remain unclear. METHODS: Blood samples were collected from 35 healthy controls and 35 patients with pulmonary arterial hypertension (PAH, n = 12) or chronic thromboembolic pulmonary hypertension (CTEPH, n = 23). The mean pulmonary artery pressure (mPAP) and pulmonary vascular resistance index (PVRI) were measured by right heart catheterization. We measured the derivative of reactive oxygen molecules (d-ROMs), biological antioxidant potential (BAP) and superoxide dismutase (SOD) by automatic biochemical analyzer, malondialdehyde (MDA) and asymmetric dimethylarginine (ADMA) by enzyme-linked immunosorbent assay. The relationship between oxidative-antioxidative biomarkers and ADMA, as well as their association with pulmonary hemodynamics, were analyzed. RESULTS: Compared with age- and gender-matched controls, there was no significant difference of d-ROMs in PAH and CTEPH patients; MDA was increased in CTEPH patients (P = 0.034); BAP and SOD were decreased in PAH (P = 0.014, P < 0.001) and CTEPH patients (P = 0.015, P < 0.001); ADMA level was significantly higher in PAH (P = 0.007) and CTEPH patients (P < 0.001). No association between oxidative-antioxidative biomarkers and ADMA was found. Serum ADMA concentration was correlated with mPAP (r = 0.762, P = 0.006) and PVRI (r = 0.603, P = 0.038) in PAH patients. CONCLUSIONS: The antioxidative potential and NO signaling are impaired in PAH and CTEPH. Increased serum ADMA level is associated with unfavorable pulmonary hemodynamics in PAH patients. Thus, ADMA may be useful in the severity evaluation and risk stratification of PAH. PMID- 25934484 TI - Identical by descent L1CAM mutation in two apparently unrelated families with intellectual disability without L1 syndrome. AB - Mutations in the L1 Cell Adhesion Molecule (L1CAM) gene (MIM#308840) cause a variety of X-linked recessive neurological disorders collectively called L1 syndrome. Using massively parallel sequencing (MPS) of the X-chromosome exome, we identified a novel missense variant in L1CAM in two Caucasian families with mild moderate intellectual disability without obvious L1 syndrome features. These families were not known to be related. SNP data extracted from MPS identified a 5.6 cM tract of identity by descent (IBD), encompassing the L1CAM gene, between the DNA of the two probands. This cannot be explained by chance alone and strongly implies that the two families are related. It also suggests that the L1CAM (NM_000425.3, c.604G > A, p.D202N) variant is pathogenic. This report also demonstrates the usefulness of additional information, which can be extracted from exome sequencing data. PMID- 25934485 TI - Brain-derived neurotrophic factor (BDNF) and its precursor (proBDNF) in genetically defined fear-induced aggression. AB - The brain-derived neurotrophic factor (BDNF), its precursor (proBDNF) and BDNF mRNA levels were studied in the brain of wild rats selectively bred for more than 70 generations for either high level or for the lack of affective aggressiveness towards man. Significant increase of BDNF mRNA level in the frontal cortex and increase of BDNF level in the hippocampus of aggressive rats was revealed. In the midbrain and hippocampus of aggressive rats proBDNF level was increased, whereas BDNF/proBDNF ratio was reduced suggesting the prevalence and increased influence of proBDNF in highly aggressive rats. In the frontal cortex, proBDNF level in aggressive rats was decreased. Thus, considerable structure-specific differences in BDNF and proBDNF levels as well as in BDNF gene expression between highly aggressive and nonaggressive rats were shown. The data suggested the implication of BDNF and its precursor proBDNF in the mechanism of aggressiveness and in the creation of either aggressive or nonaggressive phenotype. PMID- 25934486 TI - Involvement of the rostral agranular insular cortex in nicotine self administration in rats. AB - Our prior work demonstrated the involvement of the caudal granular subregion of the insular cortex in a rat model of nicotine self-administration. Recent studies in various animal models of addiction for nicotine and other drugs have identified a role for the rostral agranular subregion (RAIC). The current research was undertaken to examine the involvement of the RAIC in a rat model of nicotine self-administration. We investigated the inactivating effects of local infusions of a gamma-aminobutyric acid agonist mixture (baclofen/muscimol) into the RAIC on nicotine self-administration under a fixed-ratio 5 (FR-5) schedule and on reinstatement of nicotine seeking induced by nicotine-associated cues in rats. We also evaluated the effects of RAIC inactivation on food self administration under an FR5 schedule as a control. Inactivation of the RAIC decreased nicotine, but not food, self-administration. RAIC inactivation also prevented the reinstatement, after extinction, of nicotine seeking induced by nicotine-associated cues. Our study indicates that the RAIC is involved in nicotine-taking and nicotine-seeking in rats. Modulating insular cortex function appears to be a promising approach for nicotine dependence treatment. PMID- 25934487 TI - Canonical correlation between LFP network and spike network during working memory task in rat. AB - Working memory refers to a system to temporary holding and manipulation of information. Previous studies suggested that local field potentials (LFPs) and spikes as well as their coordination provide potential mechanism of working memory. Popular methods for LFP-spike coordination only focus on the two modality signals, isolating each channel from multi-channel data, ignoring the entirety of the networked brain. Therefore, we investigated the coordination between the LFP network and spike network to achieve a better understanding of working memory. Multi-channel LFPs and spikes were simultaneously recorded in rat prefrontal cortex via microelectrode array during a Y-maze working memory task. Functional connectivity in the LFP network and spike network was respectively estimated by the directed transfer function (DTF) and maximum likelihood estimation (MLE). Then the coordination between the two networks was quantified via canonical correlation analysis (CCA). The results show that the canonical correlation (CC) varied during the working memory task. The CC-curve peaked before the choice point, describing the coordination between LFP network and spike network enhanced greatly. The CC value in working memory showed a significant higher level than inter-trial interval. Our results indicate that the enhanced canonical correlation between the LFP network and spike network may provide a potential network integration mechanism for working memory. PMID- 25934488 TI - Characterization of long-term motor deficits in the 6-OHDA model of Parkinson's disease in the common marmoset. AB - Research aimed at developing new therapies for Parkinson's disease (PD) critically depend on valid animal models of the disease that allows for repeated testing of motor disabilities over extended time periods. We here present an extensive characterization of a wide range of motor symptoms in the 6-OHDA marmoset model of PD when tested over several months. The severity of motor deficits was quantified in two ways: (i) through manual scoring protocols appropriately adapted to include species specific motor behavior and (ii) using automated quantitative motion tracking based on image processing of the digital video recordings. We show that the automated methods allow for rapid and reliable characterization of motor dysfunctions, thus complementing the manual scoring procedures, and that robust motor symptoms lasting for several months could be induced when using a two-stage neurotoxic lesioning procedure involving one hemisphere at a time. This non-human primate model of PD should therefore be well suited for long-term evaluation of novel therapies for treatment of PD. PMID- 25934489 TI - The long-term impact of oxaliplatin chemotherapy on rodent cognition and peripheral neuropathy. AB - Chemotherapy treatment is associated with cognitive dysfunction in cancer survivors after treatment completion. The duration of these impairments is unclear. Therefore this paper aims to evaluate the lasting impact of varying doses of the chemotherapy oxaliplatin (OX) on cognition and peripheral neuropathy. In Experiment 1 rats were treated once a week for 3 weeks with either physiological saline (control) or 6 mg/kg OX i.p. and were assessed for peripheral neuropathy, using von Frey filaments, and cognitive function, using novel object and location recognition, up to 2 weeks after treatment completion. For Experiment 2 rats received 3 weekly i.p. injections of either physiological saline (control), 0.6 mg/kg, 2mg/kg or 6 mg/kg OX and assessed for peripheral neuropathy and cognitive function up to 11 months after treatment completion. Systemic OX treatment induced lasting effects on cognitive function at 11 months after treatment, and peripheral neuropathy at 1 month after treatment and these were dose dependent; higher doses of OX resulted in worse cognitive outcomes and more severe peripheral neuropathy. PMID- 25934491 TI - Learning by observation in the macaque monkey under high experimental constraints. AB - While neuroscience research has tremendously advanced our knowledge about the neural mechanisms of individual learning, i.e. through trial-and-error, it is only recently that neuroscientists have begun to study observational learning, and thus little is known about its neural mechanisms. One limitation is that observational learning has been addressed under unconstrained experimental conditions, not compatible with neuronal recordings. This study examined observational learning in macaque monkeys under the constraining conditions of behavioral neurophysiology. Two animals sat in primate chairs facing each other, with their head fixed. A touch screen was placed face up between the chairs at arm's reach, and the monkeys were trained on an abstract visuomotor associative task. In one experiment, the monkeys alternated the roles of "actor" and "observer". The actor learned to associate visual cues with reaching targets, while the observer "watched" freely. Then, the observer was given the same cue target associations just performed by the actor, or had to learn new, not previously observed ones. The results show that learning performance is better after observation. In experiment 2, one monkey learned from a human actor who performed the task with errors only, or with successes only in separate blocks. The monkey's gain in performance was higher after observation of errors than after successes. The findings suggest that observational learning can occur even under highly constraining conditions, and open the way for investigating the neuronal correlates of social learning using the methods of behavioral neurophysiology. PMID- 25934490 TI - Transcranial direct current stimulation (tDCS) of frontal cortex decreases performance on the WAIS-IV intelligence test. AB - Transcranial direct current stimulation (tDCS) modulates excitability of motor cortex. However, there is conflicting evidence about the efficacy of this non invasive brain stimulation modality to modulate performance on cognitive tasks. Previous work has tested the effect of tDCS on specific facets of cognition and executive processing. However, no randomized, double-blind, sham-controlled study has looked at the effects of tDCS on a comprehensive battery of cognitive processes. The objective of this study was to test if tDCS had an effect on performance on a comprehensive assay of cognitive processes, a standardized intelligence quotient (IQ) test. The study consisted of two substudies and followed a double-blind, between-subjects, sham-controlled design. In total, 41 healthy adult participants were included in the final analysis. These participants completed the Wechsler Adult Intelligence Scale, Fourth Edition (WAIS-IV) as a baseline measure. At least one week later, participants in substudy 1 received either bilateral tDCS (anodes over both F4 and F3, cathode over Cz, 2 mA at each anode for 20 min) or active sham tDCS (2 mA for 40 s), and participants in substudy 2 received either right or left tDCS (anode over either F4 or F3, cathode over Cz, 2 mA for 20 min). In both studies, the WAIS-IV was immediately administered following stimulation to assess for performance differences induced by bilateral and unilateral tDCS. Compared to sham stimulation, right, left, and bilateral tDCS reduced improvement between sessions on Full Scale IQ and the Perceptual Reasoning Index. This demonstration that frontal tDCS selectively degraded improvement on specific metrics of the WAIS-IV raises important questions about the often proposed role of tDCS in cognitive enhancement. PMID- 25934492 TI - Tumor necrosis factor alpha and its receptors in behaviour and neurobiology of adult mice, in the absence of an immune challenge. AB - Tumor necrosis factor alpha (TNF-alpha) is a vital component of the immune system and CNS. We previously showed that 3-month-old TNF-alpha and TNF-alpha receptor knockout mice had impaired cognition, whilst at 12-months-old mice had better cognition. To extend these findings on possible age-dependent TNF-alpha effects in the brain, we investigated the behaviour of 6-month-old TNF-alpha knockout mice and their neurobiological correlates. 6-month-old TNF(-/-), TNF-R1(-/-) and TNF-R2(-/-) mice were compared to age-matched WT mice and tested for various behaviours. ELISA hippocampal levels of nerve growth factor (NGF) and brain derived neurotrophic factor (BDNF) and qPCR mRNA levels of Tnfa, Tnfr1, Tnfr2, Il10 and Il1beta were measured. TNF-R1(-/-) and TNF(-/-) mice were found to have lesser exploratory behaviour than WT mice, while TNF-R1(-/-) mice displayed better memory than WT and TNF-R2(-/-) mice. Both TNF(-/-) and TNF-R2(-/-) mice exhibited significantly lower immobility on the depression test than WT mice. Additionally, TNF(-/-) mice expressed significantly lower levels of BDNF than WT mice in the hippocampus while TNF-R1(-/-) mice displayed significantly lower BDNF levels compared to both WT and TNF-R2(-/-) mice. TNF-R2(-/-) mice also displayed significantly higher levels of NGF compared to TNF-R1(-/-) mice. These results illustrate that TNF-alpha and its receptors mediate several behavioural phenotypes. Finally, BDNF and NGF levels appear to be regulated by TNF-alpha and its receptors even under immunologically unchallenged conditions. PMID- 25934494 TI - The pretreatment albumin to globulin ratio predicts chemotherapeutic outcomes in patients with unresectable metastatic colorectal cancer. AB - BACKGROUND: The pretreatment albumin to globulin ratio (AGR) has been reported to correlate with the long-term survival in patients with various cancers. However, there are no reports regarding the correlation between the pretreatment AGR and chemotherapeutic outcomes in patients with unresectable metastatic colorectal cancer. The aim of this study was to evaluate the prognostic significance of the pretreatment AGR in patients with unresectable metastatic colorectal cancer. METHODS: A total of 66 patients with unresectable metastatic colorectal cancer who underwent palliative chemotherapy for metastatic tumors were enrolled. The AGR was calculated as follows: Albumin/(Total protein - Albumin). RESULTS: The median pretreatment AGR was 1.254 (range: 0.849-1.840). We set 1.25 as the cut off value based on the receiver operating characteristic curve. Based on the cut off value of 1.25, 34 patients were classified into the high-AGR group and 32 patients were classified into the low-AGR group. The high-AGR group had a significantly higher chemotherapeutic disease control rate (p = 0.040) and better progression-free survival (p = 0.0171) and overall survival (p = 0.0360) rates than the low-AGR group. According to a multivariate analysis of survival, the AGR was identified to be an independent prognostic factor for progression-free survival (Hazard Ratio: 2.662, 95% Confidence Interval: 1.085-6.631, p = 0.033) and overall survival (Hazard Ratio: 2.247, 95% Confidence Interval: 1.069-4.722, p = 0.033). CONCLUSIONS: The pretreatment AGR is a useful prognostic marker in patients with unresectable metastatic colorectal cancer who receive palliative chemotherapy. PMID- 25934493 TI - No evidence of locus heterogeneity in familial microcephaly with or without chorioretinopathy, lymphedema, or mental retardation syndrome. AB - BACKGROUND: Microcephaly with or without chorioretinopathy, lymphedema, or mental retardation syndrome (MCLMR) is a rare autosomal dominant disorder with variable expressivity. It is characterized by mild-to-severe microcephaly, often associated with intellectual disability, ocular defects and lymphedema. It can be sporadic or inherited. Eighty-seven patients have been described to carry a mutation in KIF11, which encodes a homotetrameric motor kinesin, EG5. METHODS: We tested 23 unreported MCLMR index patients for KIF11. We also reviewed the clinical phenotypes of all our patients as well as of those described in previously published studies. RESULTS: We identified 14 mutations, 12 of which are novel. We detected mutations in 12 affected individuals, from 6 out of 6 familial cases, and in 8 out of 17 sporadic patients. Phenotypic evaluation of patients (our 26 + 61 earlier published = 87) revealed microcephaly in 91%, eye anomalies in 72%, intellectual disability in 67% and lymphedema in 47% of the patients. Unaffected carriers were rare (4 out of 87: 5%). Family history is not a requisite for diagnosis; 31% (16 out of 52) were de novo cases. CONCLUSIONS: All inherited cases, and 50% of sporadic cases of MCLMR are due to germline KIF11 mutations. It is possible that mosaic KIF11 mutations cause the remainder of sporadic cases, which the methods employed here were not designed to detect. On the other hand, some of them might have another mimicking disorder and genetic defect, as microcephaly is highly heterogeneous. In aggregate, KIF11 mutations likely cause the majority, if not all, of MCLMR. PMID- 25934495 TI - A MRS study of metabolic alterations in the frontal white matter of major depressive disorder patients with the treatment of SSRIs. AB - BACKGROUND: Proton magnetic resonance spectroscopy provides a non-invasive technology to study brain metabolite levels in vivo, which can be used to measure biochemical compounds or metabolite concentrations in circumscribed brain regions. Previous research has highlighted the role of glial cells in brain white matter. It has been assumed that antidepressant treatment with SSRIs not only affects neurons, but also activates glial cells. This study focused on the observation of any potential changes in the metabolite levels of the ventral prefrontal white matter in major depressive disorder (MDD) patients who have received antidepressant treatment. METHODS: 17 female patients diagnosed as MDD according to Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition (DSM-IV) criteria with the scores of 18 and above on the 24-item Hamilton Depression Rating Scale (HDRS) were recruited. MRS studies were performed on a 3.0 T MR system, single voxel PRESS spectroscopy with chemical-shift selective saturation water suppression. The volume of interest was localized at the bilateral ventral prefrontal white matter regions (voxel size: 2 * 2 * 2 mm(3)). The spectral data analysis was performed by using the instrument manufacturer supplied software. RESULTS: The bilateral ventral prefrontal white matter of MDD patients showed significantly lower Cho/Cr (p < 0.05) before receiving treatment. The HDRS, as the indicator of treatment response, showed a significant decrease in patients who had gone through 12 weeks treatment (p < 0.01). The bilateral Cho/Cr values of post-treatment patients were increased significantly compared to that of pre-treatment (p < 0.05). CONCLUSION: The alteration of ventral prefrontal white matter metabolite levels are likely involved in MDD pathophysiology and imply a crucial role of white matter in MDD. PMID- 25934497 TI - A comparison of methods to calculate a total merit index using stochastic simulation. AB - BACKGROUND: Modern dairy cattle breeding goals include several production and more and more functional traits. Estimated breeding values (EBV) that are combined in the total merit index usually come from single-trait models or from multivariate models for groups of traits. In most cases, a multivariate animal model based on phenotypic data for all traits is not feasible and approximate methods based on selection index theory are applied to derive the total merit index. Therefore, the objective of this study was to compare a full multitrait animal model with two approximate multitrait models and a selection index approach based on simulated data. METHODS: Three production and two functional traits were simulated to mimic the national Austrian Brown Swiss population. The reference method for derivation of the total merit index was a multitrait evaluation based on all phenotypic data. Two of the approximate methods were variations of an approximate multitrait model that used either yield deviations or de-regressed breeding values. The final method was an adaptation of the selection index method that is used in routine evaluations in Austria and Germany. Three scenarios with respect to residual covariances were set up: residual covariances were equal to zero, or half of or equal to the genetic covariances. RESULTS: Results of both approximate multitrait models were very close to those of the reference method, with rank correlations of 1. Both methods were nearly unbiased. Rank correlations for the selection index method showed good results when residual covariances were zero but correlations with the reference method decreased when residual covariances were large. Furthermore, EBV were biased when residual covariances were high. CONCLUSIONS: We applied an approximate multitrait two-step procedure to yield deviations and de-regressed breeding values, which led to nearly unbiased results. De-regressed breeding values gave even slightly better results. Our results confirmed that ignoring residual covariances when a selection index approach is applied leads to remarkable bias. This could be relevant in terms of selection accuracy. Our findings suggest that the approximate multitrait approach applied to de-regressed breeding values can be used in routine genetic evaluation. PMID- 25934496 TI - Are interventions to promote healthy eating equally effective for all? Systematic review of socioeconomic inequalities in impact. AB - BACKGROUND: Interventions to promote healthy eating make a potentially powerful contribution to the primary prevention of non communicable diseases. It is not known whether healthy eating interventions are equally effective among all sections of the population, nor whether they narrow or widen the health gap between rich and poor. We undertook a systematic review of interventions to promote healthy eating to identify whether impacts differ by socioeconomic position (SEP). METHODS: We searched five bibliographic databases using a pre piloted search strategy. Retrieved articles were screened independently by two reviewers. Healthier diets were defined as the reduced intake of salt, sugar, trans-fats, saturated fat, total fat, or total calories, or increased consumption of fruit, vegetables and wholegrain. Studies were only included if quantitative results were presented by a measure of SEP. Extracted data were categorised with a modified version of the "4Ps" marketing mix, expanded to 6 "Ps": "Price, Place, Product, Prescriptive, Promotion, and Person". RESULTS: Our search identified 31,887 articles. Following screening, 36 studies were included: 18 "Price" interventions, 6 "Place" interventions, 1 "Product" intervention, zero "Prescriptive" interventions, 4 "Promotion" interventions, and 18 "Person" interventions. "Price" interventions were most effective in groups with lower SEP, and may therefore appear likely to reduce inequalities. All interventions that combined taxes and subsidies consistently decreased inequalities. Conversely, interventions categorised as "Person" had a greater impact with increasing SEP, and may therefore appear likely to reduce inequalities. All four dietary counselling interventions appear likely to widen inequalities. We did not find any "Prescriptive" interventions and only one "Product" intervention that presented differential results and had no impact by SEP. More "Place" interventions were identified and none of these interventions were judged as likely to widen inequalities. CONCLUSIONS: Interventions categorised by a "6 Ps" framework show differential effects on healthy eating outcomes by SEP. "Upstream" interventions categorised as "Price" appeared to decrease inequalities, and "downstream" "Person" interventions, especially dietary counselling seemed to increase inequalities. However the vast majority of studies identified did not explore differential effects by SEP. Interventions aimed at improving population health should be routinely evaluated for differential socioeconomic impact. PMID- 25934498 TI - Bivalirudin as an adjunctive anticoagulant to heparin in the treatment of heparin resistance during cardiopulmonary bypass-assisted cardiac surgery. AB - Heparin resistance (unresponsiveness to heparin) is characterized by the inability to reach acceptable activated clotting time values following a calculated dose of heparin. Up to 20% of the patients undergoing cardiothoracic surgery with cardiopulmonary bypass using unfractionated heparin (UFH) for anticoagulation experience heparin resistance. Although UFH has been the "gold standard" for anticoagulation, it is not without its limitations. It is contraindicated in patients with confirmed heparin-induced thrombocytopenia (HIT) and heparin or protamine allergy. The safety and efficacy of the use of the direct thrombin inhibitor bivalirudin for anticoagulation during cardiac surgery has been reported. However, there have been no reports on the treatment of heparin resistance with bivalirudin during CPB. In this review, we report the favorable outcome of our single-center experience with the alternative use of bivalirudin in the management of anticoagulation of heparin unresponsive patients undergoing coronary artery bypass graft surgery. PMID- 25934499 TI - The methyl binding domain 3/nucleosome remodelling and deacetylase complex regulates neural cell fate determination and terminal differentiation in the cerebral cortex. AB - BACKGROUND: Chromatin-modifying complexes have key roles in regulating various aspects of neural stem cell biology, including self-renewal and neurogenesis. The methyl binding domain 3/nucleosome remodelling and deacetylation (MBD3/NuRD) co repressor complex facilitates lineage commitment of pluripotent cells in early mouse embryos and is important for stem cell homeostasis in blood and skin, but its function in neurogenesis had not been described. Here, we show for the first time that MBD3/NuRD function is essential for normal neurogenesis in mice. RESULTS: Deletion of MBD3, a structural component of the NuRD complex, in the developing mouse central nervous system resulted in reduced cortical thickness, defects in the proper specification of cortical projection neuron subtypes and neonatal lethality. These phenotypes are due to alterations in PAX6+ apical progenitor cell outputs, as well as aberrant terminal neuronal differentiation programmes of cortical plate neurons. Normal numbers of PAX6+ apical neural progenitor cells were generated in the MBD3/NuRD-mutant cortex; however, the PAX6+ apical progenitor cells generate EOMES+ basal progenitor cells in reduced numbers. Cortical progenitor cells lacking MBD3/NuRD activity generate neurons that express both deep- and upper-layer markers. Using laser capture microdissection, gene expression profiling and chromatin immunoprecipitation, we provide evidence that MBD3/NuRD functions to control gene expression patterns during neural development. CONCLUSIONS: Our data suggest that although MBD3/NuRD is not required for neural stem cell lineage commitment, it is required to repress inappropriate transcription in both progenitor cells and neurons to facilitate appropriate cell lineage choice and differentiation programmes. PMID- 25934500 TI - "Taking your place at the table": an autoethnographic study of chaplains' participation on an interdisciplinary research team. AB - BACKGROUND: There are many potential benefits to chaplaincy in transforming into a "research-informed" profession. However little is known or has been documented about the roles of chaplains on research teams and as researchers or about the effects of research engagement on chaplains themselves. This report describes the experience and impact of three chaplains, as well as tensions and challenges that arose, on one particular interdisciplinary team researching a spiritual assessment model in palliative care. Transcripts of our research team meetings, which included the three active chaplain researchers, as well as reflections of all the members of the research team provide the data for this descriptive, qualitative, autoethnographic analysis. METHODS: This autoethnographic project evolved from the parent study, entitled "Spiritual Assessment Intervention Model (AIM) in Outpatient Palliative Care Patients with Advanced Cancer." This project focused on the use of a well-developed model of spiritual care, the Spiritual Assessment and Intervention Model (Spiritual AIM). Transcripts of nine weekly team meetings for the parent study were reviewed. These parent study team meetings were attended by various disciplines and included open dialogue and intensive questions from non-chaplain team members to chaplains about their practices and Spiritual AIM. Individual notes (from reflexive memoing) and other reflections of team members were also reviewed for this report. The primary methodological framework for this paper, autoethnography, was not only used to describe the work of chaplains as researchers, but also to reflect on the process of researcher identity formation and offer personal insights regarding the challenges accompanying this process. RESULTS: Three major themes emerged from the autoethnographic analytic process: 1) chaplains' unique contributions to the research team; 2) the interplay between the chaplains' active research role and their work identities; and 3) tensions and challenges in being part of an interdisciplinary research team. CONCLUSIONS: Describing the contributions and challenges of one interdisciplinary research team that included chaplains may help inform chaplains about the experience of participating in research. As an autoethnographic study, this work is not meant to offer generalizable results about all chaplains' experiences on research teams. Research teams that are interdisciplinary may mirror the richness and efficacy of clinical interdisciplinary teams. Further work is needed to better characterize both the promise and pitfalls of chaplains' participation on research teams. PMID- 25934501 TI - The end of the message: multiple protein-RNA interactions define the mRNA polyadenylation site. AB - The key RNA sequence elements and protein factors necessary for 3' processing of polyadenylated mRNA precursors are well known. Recent studies, however, have significantly reshaped current models for the protein-RNA interactions involved in poly(A) site recognition, painting a picture more complex than previously envisioned and also providing new insights into regulation of this important step in gene expression. Here we review the recent advances in this area and provide a perspective for future studies. PMID- 25934502 TI - Aneuploid proliferation defects in yeast are not driven by copy number changes of a few dosage-sensitive genes. AB - Aneuploidy-the gain or loss of one or more whole chromosome-typically has an adverse impact on organismal fitness, manifest in conditions such as Down syndrome. A central question is whether aneuploid phenotypes are the consequence of copy number changes of a few especially harmful genes that may be present on the extra chromosome or are caused by copy number alterations of many genes that confer no observable phenotype when varied individually. We used the proliferation defect exhibited by budding yeast strains carrying single additional chromosomes (disomes) to distinguish between the "few critical genes" hypothesis and the "mass action of genes" hypothesis. Our results indicate that subtle changes in gene dosage across a chromosome can have significant phenotypic consequences. We conclude that phenotypic thresholds can be crossed by mass action of copy number changes that, on their own, are benign. PMID- 25934503 TI - A genetic screen reveals Foxa3 and TNFR1 as key regulators of liver repopulation. AB - The fundamental question of which genes are most important in controlling liver regeneration remains unanswered. We employed a parallel screen to test the impact of 43 selected genes on liver repopulation in the Fah(-/-) mouse model of hereditary tyrosinemia. We discovered that the transcription factor Foxa3 was a strong promoter of liver regeneration, while tumor necrosis factor receptor 1 (TNFR1) was the most significant suppressor of repopulation among all of the genes tested. Our approach enabled the identification of these factors as important regulators of liver repopulation and potential drug targets for the promotion of liver repopulation. PMID- 25934504 TI - Gender-specific postnatal demethylation and establishment of epigenetic memory. AB - DNA methylation patterns are set up in a relatively fixed programmed manner during normal embryonic development and are then stably maintained. Using genome wide analysis, we discovered a postnatal pathway involving gender-specific demethylation that occurs exclusively in the male liver. This demodification is programmed to take place at tissue-specific enhancer sequences, and our data show that the methylation state at these loci is associated with and appears to play a role in the transcriptional regulation of nearby genes. This process is mediated by the secretion of testosterone at the time of sexual maturity, but the resulting methylation profile is stable and therefore can serve as an epigenetic memory even in the absence of this inducer. These findings add a new dimension to our understanding of the role of DNA methylation in vivo and provide the foundations for deciphering how environment can impact on the epigenetic regulation of genes in general. PMID- 25934505 TI - Loss of the RNA polymerase III repressor MAF1 confers obesity resistance. AB - MAF1 is a global repressor of RNA polymerase III transcription that regulates the expression of highly abundant noncoding RNAs in response to nutrient availability and cellular stress. Thus, MAF1 function is thought to be important for metabolic economy. Here we show that a whole-body knockout of Maf1 in mice confers resistance to diet-induced obesity and nonalcoholic fatty liver disease by reducing food intake and increasing metabolic inefficiency. Energy expenditure in Maf1(-/-) mice is increased by several mechanisms. Precursor tRNA synthesis was increased in multiple tissues without significant effects on mature tRNA levels, implying increased turnover in a futile tRNA cycle. Elevated futile cycling of hepatic lipids was also observed. Metabolite profiling of the liver and skeletal muscle revealed elevated levels of many amino acids and spermidine, which links the induction of autophagy in Maf1(-/-) mice with their extended life span. The increase in spermidine was accompanied by reduced levels of nicotinamide N methyltransferase, which promotes polyamine synthesis, enables nicotinamide salvage to regenerate NAD(+), and is associated with obesity resistance. Consistent with this, NAD(+) levels were increased in muscle. The importance of MAF1 for metabolic economy reveals the potential for MAF1 modulators to protect against obesity and its harmful consequences. PMID- 25934506 TI - Genome-wide analysis of human global and transcription-coupled excision repair of UV damage at single-nucleotide resolution. AB - We developed a method for genome-wide mapping of DNA excision repair named XR-seq (excision repair sequencing). Human nucleotide excision repair generates two incisions surrounding the site of damage, creating an ~30-mer. In XR-seq, this fragment is isolated and subjected to high-throughput sequencing. We used XR-seq to produce stranded, nucleotide-resolution maps of repair of two UV-induced DNA damages in human cells: cyclobutane pyrimidine dimers (CPDs) and (6-4) pyrimidine pyrimidone photoproducts [(6-4)PPs]. In wild-type cells, CPD repair was highly associated with transcription, specifically with the template strand. Experiments in cells defective in either transcription-coupled excision repair or general excision repair isolated the contribution of each pathway to the overall repair pattern and showed that transcription-coupled repair of both photoproducts occurs exclusively on the template strand. XR-seq maps capture transcription-coupled repair at sites of divergent gene promoters and bidirectional enhancer RNA (eRNA) production at enhancers. XR-seq data also uncovered the repair characteristics and novel sequence preferences of CPDs and (6-4)PPs. XR-seq and the resulting repair maps will facilitate studies of the effects of genomic location, chromatin context, transcription, and replication on DNA repair in human cells. PMID- 25934507 TI - Arabidopsis TOE proteins convey a photoperiodic signal to antagonize CONSTANS and regulate flowering time. AB - Plants flower in an appropriate season to allow sufficient vegetative development and position flower development in favorable environments. In Arabidopsis, CONSTANS (CO) and FLAVIN-BINDING KELCH REPEAT F-BOX1 (FKF1) promote flowering by inducing FLOWER LOCUS T (FT) expression in the long-day afternoon. The CO protein is present in the morning but could not activate FT expression due to unknown negative mechanisms, which prevent premature flowering before the day length reaches a threshold. Here, we report that TARGET OF EAT1 (TOE1) and related proteins interact with the activation domain of CO and CO-like (COL) proteins and inhibit CO activity. TOE1 binds to the FT promoter near the CO-binding site, and reducing TOE function results in a morning peak of the FT mRNA. In addition, TOE1 interacts with the LOV domain of FKF1 and likely interferes with the FKF1-CO interaction, resulting in partial degradation of the CO protein in the afternoon to prevent premature flowering. PMID- 25934508 TI - Recent applications of 1,3-thiazole core structure in the identification of new lead compounds and drug discovery. AB - 1,3-Thiazole is one of the most important scaffolds in heterocyclic chemistry and drug design and discovery. It is widely found in diverse pharmacologically active substances and in some naturally-occurring compounds. Thiazole is a versatile building-block for lead generation, and is easily access of diverse derivatives for subsequent lead optimization. In the recent years, many thiazole derivatives have been synthesized and subjected to varied biological activities. In this article we intended to review the most important biological effects of thiazole based compounds and highlight their roles in new leads identification and drug discovery. This article is also intended to help researches for finding potential future directions on the development of more potent and specific analogs of thiazole-based compounds for various biological targets. PMID- 25934509 TI - Potential misinterpretations related to artificial pacemaker signals generated by electrocardiographs. PMID- 25934510 TI - Boston Keratoprosthesis: Outcomes and Complications: A Report by the American Academy of Ophthalmology. AB - OBJECTIVE: To review the published literature on safety and outcomes of the Boston type I keratoprosthesis (BI-KPro) for the surgical treatment of corneal opacification not amenable to human cadaveric corneal transplantation. METHODS: Searches of peer-reviewed literature were conducted in PubMed and the Cochrane Library in December 2012, July 2013, and January 2014 without date restrictions. The searches were limited to studies published in English and yielded 587 citations. The abstracts of these articles were reviewed, 48 articles were selected for possible clinical relevance, and 22 were determined to be relevant for the assessment objectives. Nine studies were rated as level II evidence and 13 studies were rated as level III evidence. Excluded were level III evidence, case reports, review articles, letters, editorials, and case series with fewer than 25 eyes. RESULTS: In 9 articles, a best-corrected Snellen visual acuity (BCSVA) of 20/200 or better occurred in 45% to 89% of eyes. Five articles described a BCSVA of 20/50 or better in 43% to 69% of eyes, and 4 articles found a BCSVA of 20/40 or better in 11% to 39% of eyes. Retention rates of the BI-KPro ranged from 65% to 100%. Reasons for loss of vision after BI-KPro implantation most commonly included corneal melts resulting from exposure keratopathy, endophthalmitis, and infectious keratitis or corneal ulceration. The 2 most common complications after surgery were retroprosthetic membrane formation (range, 1.0%-65.0%; mean +/- standard deviation [SD], 30.0+/-19.0%) and elevated intraocular pressure (range, 2.4%-64.0%; mean +/- SD, 27.5+/-18.1%). The 2 most common posterior segment complications were endophthalmitis (range, 0%-12.5%; mean +/- SD, 4.6+/-4.6%) and vitritis (range, 0%-14.5%; mean +/- SD, 5.6+/-4.7%). CONCLUSIONS: The reviewed articles on BI-KPro use suggest that the device improves vision in cases of severe corneal opacification that were not amenable to corneal transplantation using human cadaveric keratoplasty techniques. A number of severe anterior and posterior segment complications can develop as follow-up continues, making ongoing close observation paramount for patients undergoing this surgery. These complications include infection, device extrusion, and permanent vision loss. PMID- 25934511 TI - Changes in plasma levels of asymmetric dimethylarginine, symmetric dimethylarginine, and arginine after a single dose of vardenafil in patients with pulmonary hypertension. AB - OBJECTIVE: We investigated whether vardenafil, a phosphodiesterase-5 inhibitor, alters plasma levels of asymmetric dimethylarginine (ADMA), symmetric dimethylarginine (SDMA), and arginine. PATIENTS AND METHODS: ADMA, SDMA, and arginine were measured (0-540 min) in 12 patients with pulmonary hypertension after a single oral dose of vardenafil. Invasive hemodynamic data were collected at baseline and after 60 min. RESULTS: A reduction in ADMA was observed at 30 and 45 min with a median change of -11.1% (P=0.021) and -12.5% (P=0.002). SDMA decreased with a median -5.3% change (P=0.032) at 45 min. An increase in arginine, median 40.3% (P=0.002), 45.0% (P=0.010), and 77.1% (P=0.008) was observed at 120, 300, and 540 min respectively. An increase in the arginine/ADMA ratio, median 11.7% (P=0.012), 32.5% (P=0.003), 26.5% (P=0.021), 33% (P=0.007), 48.5% (P=0.007), and 63.1% (P=0.008) was observed at 15, 45, 60, 120, 300, and 540 min respectively. There was a positive correlation between vardenafil exposure and the percent change in the arginine/ADMA ratio from baseline to 540 min (r=0.80; P=0.01). A correlation between baseline mean right atrial pressure (mRAP) and baseline ADMA (r=0.65; P=0.023), and baseline SDMA (r=0.61; P=0.035) was observed. A correlation between the baseline arginine/ADMA ratio and baseline cardiac output (CO) (r=0.59; P=0.045) and baseline cardiac index (CI) (r=0.61; P=0.036) was observed. Baseline arginine/ADMA ratio correlated with baseline mRAP (r=-0.79; P=0.002). A correlation between change (0-60 min) in CI and change in arginine (r=0.77; P=0.003) as well as change in the arginine/ADMA ratio (r=0.61; P=0.037) was observed. CONCLUSIONS: Vardenafil induced changes in ADMA, SDMA, arginine, and the arginine/ADMA ratio in patients with PH. An increase in arginine and the arginine/ADMA ratio was associated with improvement in CI. PMID- 25934512 TI - Relationship between plasma phospholipase A2 concentrations and lipoprotein subfractions in patients with stable coronary artery disease. AB - BACKGROUND: Both increased lipoprotein-associated phospholipase A2 (Lp-PLA2) concentrations and atherogenic lipoprotein subfractions have been shown to reflect unfavourable cardiovascular risk. However, the correlation between Lp PLA2 and lipoprotein subfractions in patients with coronary artery disease (CAD) has not been assessed yet. METHODS: A total of 324 consecutive subjects who were not treated with lipid-lowering drugs were enrolled (angiographically proven CAD: n = 253; non-CAD: n = 71). Plasma Lp-PLA2 concentrations were measured using ELISA. The low-density lipoprotein (LDL) and high-density lipoprotein (HDL) subfractions were determined by Lipoprint System. RESULTS: Plasma Lp-PLA2 concentrations were higher in patients with CAD compared with those without CAD (153.61 +/- 78.73 vs. 131.41 +/- 65.49 ng/ml, p = 0.028). The univariable correlation analysis revealed that Lp-PLA2 concentrations were positively correlated with the cholesterol concentrations of each LDL subfractions and the intermediate as well as small HDL subfractions, while negatively linked with the LDL particle size and large HDL-cholesterol (HDL-C) concentrations in CAD group. However, no similar results were observed in the non-CAD group. Furthermore, multivariable regression analysis was performed in patients with CAD and showed that plasma Lp-PLA2 concentrations were independently correlated with the cholesterol concentrations of each LDL subfractions [large LDL-cholesterol (LDL C): beta = 0.263, p < 0.001; intermediate LDL-C: beta = 0.327, p < 0.001; small LDL-C: beta = 0.135, p = 0.033] and small HDL-C (beta = 0.133, p = 0.034). CONCLUSION: Lp-PLA2 concentrations were positively associated with all LDL subfractions and small HDL subfraction, suggesting an interaction between Lp-PLA2 and lipoprotein subfraction phenotypes in the status of CAD. PMID- 25934513 TI - Compound Astragalus and Salvia miltiorrhiza extracts modulate MAPK-regulated TGF beta/Smad signaling in hepatocellular carcinoma by multi-target mechanism. AB - ETHNOPHARMACOLOGICAL RELEVANCE: Astragalus membranaceus Bunge (Leguminosae) and Salvia miltiorrhiza Bunge (Lamiaceae) are two important Chinese herbs with a long history of extensive ethnobotanical usage in the treatment of liver-related diseases over many centuries. Presently, these two herbs are being used either as a single herbal formulation or a composite formula for the treatment of liver related conditions. In response, recent studies on these two herbs have focused on elucidating their mechanisms of action, particularly with regards to their anti-hepatocarcinogenic effects. Previously, we have reported that Compound Astragalus and Salvia miltiorrhiza extract (CASE), a synergized composite extract from Astragalus membranaceus and Salvia miltiorrhiza ameliorates liver fibrosis and hepatocellular carcinoma (HCC) by modulating the TGF-beta/Smad pathway. Meanwhile, MAPK activation and MAPK-dependent linker phosphorylation of Smad2/3 and their preferential nuclear import are crucial for overall oncogenic role of TGF-beta/Smad signaling in HCC. To elucidate further, we studied the effect of CASE on the MAPK pathway and how it affects MAPK-dependent regulation of TGF beta/Smad signaling using both cell and animal models of HCC. MATERIALS AND METHODS: We used immunofluorescence and western blot techniques to monitor effect of CASE on the activation of the MAPKs (pERK, pJNK and pp38) in TGF-beta1 stimulated hepatic stellate cells (HSCs), HepG2 cells and also diethylnitrosamine (DEN)-induced HCC in rats. Also phosphorylation and subcellular distribution of pSmad2/3, Smad4 and Imp7/8 in TGF-beta1-stimulated HSC and HepG2 cells were monitored. The expression of pERK, pJNK, pp38 and PAI-1 gene were monitored by using western blot technique. The effect of CASE on domain-specific phosphorylation of Smad2/3 and their subcellular distribution, and the expression of Smad4 and its subcellular distribution in TGF-beta1-stimulated HSCs and HepG2 cells were evaluated by using immunofluorescence technique. And the expression of Imp7/8 and their subcellular distribution were assessed by both immunofluorescence and western blot techniques, while PAI-1 gene expression was assessed by western blot RESULTS: In vitro, CASE in a concentration-dependent manner increased the expression of pp38 but decreased the expression of pERK and pJNK; however, in vivo, CASE in a dose dependent manner decreased the expression of pERK, pJNK as well as pp38. Also, CASE concentration dependently inhibited pSmad2C/L, pSmad3L, Smad4, Imp7/8 and their nuclear import; it had no effect on pSmad3C in HepG2 cells; significantly decreased PAI-1 gene expression in both in vitro and in vivo. CONCLUSIONS: CASE blocked MAPK activation, MAPK-dependent linker phosphorylation of Smad2/3, Smad4 expression, Imp7 expression and their nuclear import leading to significant down-regulation of PAI-1 gene expression; further highlighting the multi-target anti-HCC effect of CASE and its potential drug candidature. PMID- 25934514 TI - Schisantherin A protects against 6-OHDA-induced dopaminergic neuron damage in zebrafish and cytotoxicity in SH-SY5Y cells through the ROS/NO and AKT/GSK3beta pathways. AB - ETHNOPHARMACOLOGICAL RELEVANCE: The fruit of Schisandra chinensis (Turcz.) Baill, has been traditionally used in management of liver diseases and ageing associated neurodegeneration. The bioactive compound from this medicinal plant would be valuable for its potential use in prevention and treatment of Parkinson's disease. AIM OF THE STUDY: The overall objective of the present study was to understand the neuroprotective effect of schisantherin A, a dibenzocyclooctadiene lignan from the fruit of S. chinensis (Turcz.) Baill, and to elucidate its underlying mechanism of action. MATERIAL AND METHODS: This study investigated the protective effect of schisantherin A against selective dopaminergic neurotoxin 6 hydroxydopamine (6-OHDA)-induced neural damage in human neuroblastoma SH-SY5Y cells and zebrafish models. Oxidative stress and related signaling pathways underlying the neuroprotective effect were determined by multiple biochemical assays and Western blot. RESULTS: Pretreatment with schisantherin A offered neuroprotection against 6-OHDA-induced SH-SY5Y cytotoxicity. Moreover, schisantherin A could prevent 6-OHDA-stimulated dopaminergic neuron loss in zebrafish. Our mechanistic study showed that schisantherin A can regulate intracellular ROS accumulation, and inhibit NO overproduction by down-regulating the over-expression of iNOS in 6-OHDA treated SH-SY5Y cells. Schisantherin A also protects against 6-OHDA-mediated activation of MAPKs, PI3K/Akt and GSK3beta. CONCLUSION: These findings demonstrate that schisantherin A may have potential therapeutic value for neurodegenerative diseases associated with abnormal oxidative stress such as Parkinson's disease. PMID- 25934515 TI - Detection of a negative correlation between prescription of Chinese herbal products containing coumestrol, genistein or daidzein and risk of subsequent endometrial cancer among tamoxifen-treated female breast cancer survivors in Taiwan between 1998 and 2008: A population-based study. AB - ETHNOPHARMACOLOGICAL RELEVANCE: Tamoxifen users sometimes seek complementary and alternative medicine advice for treatment of a variety of illness and co administer with phytoestrogen-containing herbs, resulting in an increasing concern of its influence in subsequent endometrial cancer risk. Our study aims to determine the prevalence of Chinese herbal products containing coumestrol, genistein, or daidzein and their association with subsequent endometrial cancer risk among tamoxifen-treated breast cancer survivors in Taiwan. METHODS: We selected all patients who were newly diagnosed with invasive breast cancer and received tamoxifen treatment between January 1, 1998, and December 31, 2008, from the National Health Insurance Research Database. Among the 26,656 tamoxifen treated breast cancer survivors, we evaluated the usage, frequency of service, and prescription of Chinese herbal products containing coumestrol, genistein, or daidzein. The logistic regression method was employed to calculate the odds ratios for utilization of those herbal products. Cox proportional hazard regression was set to calculate the hazard ratios of endometrial cancer associated with such usage. RESULTS: Of the patients surveyed, 36.2% (n=9652) of the tamoxifen-treated breast cancer survivors examined in the study had consumed Chinese herbal products containing coumestrol, genistein, or daidzein during the study period. Exposure to Ge Gen(Puerariae Radix) specifically was the most extensive. For it, the population consumed an average cumulative dose of above 180g. Compared to those who had never used Chinese herbal products, breast cancer survivors who had taken Chinese herbal products containing coumestrol, genistein, or daidzein concurrently with tamoxifen treatment did not have a higher hazard ratio for subsequent development of endometrial cancer. CONCLUSION: Among those tamoxifen-treated female breast cancer survivors in Taiwan, consumption of Chinese herbal products containing coumestrol, genistein, or daidzein is negatively correlated with subsequent endometrial cancer risk. PMID- 25934516 TI - Effects of Cydonia oblonga Miller leaf and fruit flavonoids on blood lipids and anti-oxydant potential in hyperlipidemia rats. AB - OBJECTIVE: To study the effects of Cydonia oblonga Miller (COM) total flavonoids (TF) from leaves and fruit on the blood lipid and antioxidant potentials using hyperlipidaemic rat models. METHODS: Hyperlipidaemic rat models were created with high-lipid emulsion. Rats were distributed into normal controls, hyperlipidaemic models, and daily high (160mg/kg), medium (80mg/kg) and low (40mg/kg) TF from leaves and fruit and simvastatin (5mg/kg) groups. After four weeks, serum total cholesterol (TC), triglyceride (TG), high-density lipoprotein cholesterol (HDL), low-density lipoprotein cholesterol (LDL), alanine aminotransferase (ALT), aspartate aminotransferase (AST), as well as hepatic superoxide dismutase (SOD), glutathione peroxidase (GSH-Px) and malondialdehyde (MDA) were measured. RESULTS: Compared with the hyperlipidaemic model group, TF significantly reduced serum TC, TG, LDL-C (P<0.01), ALT and AST (P<0.01 or P<0.05) and increased HDL-C (P<0.05 or P<0.01). TF also reduced MDA (P<0.01 or P<0.01). CONCLUSION: COM total flavonoids can effectively regulate the metabolism of lipids, and remove oxygen free radicals. This confirms its potential value in the prevention and treatment of hyperlipidaemia. PMID- 25934517 TI - A Taxonomic Integrative Review of Short Message Service (SMS) Methodology: A Framework for Improved Diabetic Outcomes. AB - BACKGROUND: To acquire self-management skills that affect clinical outcomes, collaboration and communication with one's health care team is essential, yet many health care systems are not designed adequately to be responsive to a patient's efforts to self-manage. This review synthesizes the intervention methodology of current studies facilitating the efforts of health care providers who wish to design, develop, and implement evidence-based SMS programs for patients with diabetes, focusing on clinical outcomes of A1C values, medication adherence rates, and participant satisfaction. METHODS: This integrative review was conducted using an integrative taxonomic analysis approach. This approach involves creating a classification system with domains or characteristics, defining the relationships between those domains, and creating a foundation for new theories or constructs. RESULTS: Synthesis of the evidence included in this integrated review suggests the best design for a SMS diabetes management program aimed at improving A1C levels, medication adherence rates, and participant satisfaction is an intervention providing weekly SMS education, with 2-way message direction, that is 3 months in length. CONCLUSIONS: The studies in this review have demonstrated that SMS interventions can be an important part of a viable and effective program in the effort to better manage adults with type 2 diabetes. PMID- 25934518 TI - Quantitative analysis of eicosanoids in biological samples by LC-MS/MS: Mission accomplished? PMID- 25934519 TI - High-throughput sequencing in mutation detection: A new generation of genotoxicity tests? AB - The advent of next generation sequencing (NGS) technology has provided the means to directly analyze the genetic material in primary cells or tissues of any species in a high throughput manner for mutagenic effects of potential genotoxic agents. In principle, direct, genome-wide sequencing of human primary cells and/or tissue biopsies would open up opportunities to identify individuals possibly exposed to mutagenic agents, thereby replacing current risk assessment procedures based on surrogate markers and extrapolations from animal studies. NGS based tests can also precisely characterize the mutation spectra induced by genotoxic agents, improving our knowledge of their mechanism of action. Thus far, NGS has not been widely employed in genetic toxicology due to the difficulties in measuring low-abundant somatic mutations. Here, we review different strategies to employ NGS for the detection of somatic mutations in a cost-effective manner and discuss the potential applicability of these methods in testing the mutagenicity of genotoxic agents. PMID- 25934520 TI - Insulin therapy normalizes reduced myocardial beta-adrenoceptors at both the onset and after sustained hyperglycemia in diabetic rats. AB - AIMS: Reduced cardiac beta-adrenoceptors (beta-AR) and cardiovascular (CV) dysfunction occur in diabetes mellitus (DM) and can be normalized by insulin. It is unclear how the duration of untreated hyperglycemia prior to intervention impacts insulin's effects. This study assesses insulin's effect on reduced myocardial beta-AR and CV function, comparing insulin therapy at the onset of hyperglycemia and after a sustained period of hyperglycemia in streptozotocin (STZ) rats. MAIN METHODS: Ex vivo biodistribution experiments with [(3)H]CGP12177 were performed in high-fat fed STZ rats after 8 weeks of hyperglycemia evaluating cardiac beta-AR expression. Western blotting of beta-AR subtypes was completed in parallel. Serial echocardiography at 0, 6, and 8 weeks post-STZ investigated CV function. Sub-groups of hyperglycemic rats were treated with insulin early, at 1 week post-STZ (InsE) for 7 weeks, or late at 6 weeks post-STZ (InsL) for 2 weeks to observe how the duration of hyperglycemia prior to insulin impacts its effects. KEY FINDINGS: Reduced myocardial [(3)H]CGP12177 binding occurred 8 weeks post-STZ in hyperglycemics, but was normal in both insulin treatments. Western blotting supported reduced beta1-AR in hyperglycemics, but not in either treatment. InsE and InsL treatments improved prolonged mitral valve deceleration (MVD) observed in hyperglycemic animals, but hyperglycemic and InsL still displayed reduced heart rates (HR). SIGNIFICANCE: This work supports that glycemic control with insulin normalizes cardiac beta-AR effectively regardless of prior hyperglycemia but HR may not recover as readily, indirectly supporting the utility of [(11)C]CGP12177 positron emission tomography (PET) in assessing cardiac beta-AR and their modulation with glycemic therapy. PMID- 25934521 TI - Radical cystectomy versus organ-sparing trimodality treatment in muscle-invasive bladder cancer: A systematic review of clinical trials. AB - BACKGROUND: Radical cystectomy (RC) represents the mainstay of treatment in patients with muscle-invasive urinary bladder cancer but how it compares with the best organ preservation approach is not known. MATERIALS AND METHODS: The objective of our review is to compare the 5-year overall survival (OS) rates from retrospective and prospective studies of RC and trimodality treatment (TMT), i.e. concurrent delivery of chemotherapy and radiotherapy after a transurethral resection of bladder tumor (TURBT), involving a total of 10,265 and 3131 patients, respectively. We used random-effect models to pool outcomes across studies and compared event rates of combined outcomes for TMT and RC using an interaction test. RESULTS: The median 5-year OS rate was 57% in the TMT group, when compared with 52% (P=0.04), 51% (P=0.02) and 53% (P=0.38) in the whole group receiving RC or the group treated with RC alone or RC+chemotherapy, respectively. The hazard risk (HR) of mortality of patients treated with TMT or RC was 1.22 (95% CI=1.13-1.32) with an absolute benefit of 5% in favor of the former. The HR of mortality from TMT persisted significantly better not only versus the group treated with RC alone (HR=1.22; 95% CI=1.12-1.32), but also versus the group receiving RC+chemotherapy (HR=1.22; 95% CI=1.09-1.36). Multivariate analysis confirmed TMT as a significant prognostic variable for both RC alone and RC+chemotherapy. CONCLUSION: Compared with RC, TMT seems to be associated with a better outcome for patients with muscle-invasive bladder cancer (MIBC). The addition of chemotherapy may improve the RC outcome in some subgroups of patients with a higher probability of micrometastases. Prospective randomized trials are urged to verify these findings and better define the role of organ preservation and radical treatment strategy in the management of patients with MIBC. PMID- 25934523 TI - Geometric and dosimetric accuracy and imaging dose of the real-time tumour tracking system of a gimbal mounted linac. AB - PURPOSE: To suggest a comprehensive testing scheme to evaluate the geometric and dosimetric accuracy and the imaging dose of the VERO dynamic tumour tracking (DTT) for its clinical implementation. METHODS: Geometric accuracy was evaluated for gantry 0 degrees and 90 degrees in terms of prediction (EP), mechanical (EM) and tracking (ET) errors for sinusoidal patterns with 10 and 20 mm amplitudes, 2-6 s periods and phase shift up to 1 s and for 3 patient patterns. The automatic 4D model update was investigated simulating changes in the breathing pattern during treatment. Dosimetric accuracy was evaluated with gafchromic films irradiated in static and moving phantom with and without DTT. The entrance skin dose (ESD) was assessed using a solid state detector and gafchromic films. RESULTS: The RMS of EP, EM, and ET were up to 0.8, 0.5 and 0.9 mm for all non phased-shifted motion patterns while for the phased-shifted ones, EP and ET increased to 2.2 and 2.6 mm. Up to 4 updates are necessary to restore a good correlation model, according to type of change. For 100 kVp and 1 mA s X-ray beam, the ESD per portal due to 20 s fluoroscopy was 16.6 mGy, while treatment verification at a frequency of 1 Hz contributed with 4.2 mGy/min. CONCLUSIONS: The proposed testing scheme highlighted that the VERO DTT system tracks a moving target with high accuracy. The automatic update of the 4D model is a powerful tool to guarantee the accuracy of tracking without increasing the imaging dose. PMID- 25934522 TI - Molecular staging of gynecological cancer: What is the future? AB - The purpose of cancer staging is to classify cancers into prognostic groups and to allow for comparison of treatment results and survival between patients and institutions. Staging for gynecologic cancers is based on extent of disease and metastasis, which was historically determined by physical examination and is now based on surgical and histologic examination of tumor specimens. Although the extent of disease is currently considered the most important predictor of recurrence and survival, current staging does not include molecular features that are associated with tumor aggressiveness, response to therapy, and prognosis. This review focuses on genomic and proteomic features of gynecologic cancers and the future of biomarkers in staging classification. PMID- 25934524 TI - Synchrotron X-ray microbeams: A promising tool for drug-resistant epilepsy treatment. AB - Epilepsy is one of the most important neurological diseases. It concerns about 1% of the population worldwide. Despite the discovery of new molecules, one third of epileptic patients are resistant to anti-epileptic drugs and among them only a few can benefit from resective surgery. In this context, radiotherapy is an interesting alternative to the other treatments and several clinical devices exist (e.g., Gamma Knife((r))). The European Synchrotron Radiation Facility offers the possibility to develop new methods of radiosurgery and to study their antiepileptic effects. Here, we discuss several studies that we performed recently to test and try to understand the antiepileptic effects of X-ray synchrotron microbeams in different animal models of epilepsy. We showed a decrease of seizures after Interlaced Microbeam Radiotherapy (IntMRT) of the somatosensory cortex, known as the seizure generator, in a genetic model of absence epilepsy. These antiepileptic effects were stable over 4 months and with low tissular and functional side-effects. The irradiated pyramidal neurons still displayed their physiological activity but did not synchronize anymore. We also obtained a lasting suppression of seizures after IntMRT of the dorsal hippocampus in a mouse model of mesiotemporal lobe epilepsy. However, an important variability of antiepileptic efficiency was observed probably due to the small size of the targeted structure. Despite these encouraging proofs-of-concepts, there is now a need to adapt IntMRT to other models of epilepsy in rodents which are close to refractory forms of epilepsy in human patients and to implement this approach to non-human primates, before moving to clinical trials. PMID- 25934525 TI - Effect of sitagliptin on intrahepatic lipid content and body fat in patients with type 2 diabetes. AB - AIMS: To evaluate the effect of the DPP-4 inhibitor sitagliptin on intrahepatic lipid (IHL) content and body fat in overweight Japanese patients with type 2 diabetes. METHODS: A prospective, 24-week, single-center, open-label comparative study enrolled 20 Japanese patients with type 2 diabetes (male: 11, female: 9) with a BMI>=25 kg/m(2) or fatty liver. Subjects were randomly assigned to receive treatment with sitagliptin (25 mg titrated up to 50 mg: S) or glimepiride (0.5 mg titrated up to 1 mg: G). After starting each treatment, IHL and total fat mass were evaluated by (1)H-magnetic resonance spectroscopy ((1)H-MRS) and dual energy X-ray absorptiometry (DEXA), respectively at baseline and at 12 weeks and 24 weeks. RESULTS: After 24 weeks, HbA1c levels showed a similar significant decrease in both groups from 7.2 (7.0, 7.5) to 6.6 (6.4, 6.8)%, (54 (53, 56) to 48(47, 49) mmol/mol) with S and 7.3(6.8, 7.4) to 6.6 (6.3, 6.7)%, (55 (51, 56) to 48 (46, 49) mmol/mol) with G, median (interquartile range), p<0.05 vs. baseline, with no significant differences between the two groups. The IHL and total body fat mass were decreased in S group from 24.5(18.9, 36.6) to 20.5 (14.6, 28.5)% (p=0.009) and 22.5 (20.6, 33.7) to 21.6 (19.7, 32.4)kg (p=0.028), respectively, but not in G group. CONCLUSIONS: Our findings indicate that sitagliptin and glimepiride achieved similar glycemic control, but only sitagliptin reduced IHL and total body fat (UMIN: 000013356). PMID- 25934526 TI - The relationship between the oxidative stress and the cardiac hypertrophy in infants of diabetic mothers. AB - Recently, oxidative stress was suggested to play a role in maternal and fetal complications of diabetic pregnancies. The aim of this study is to evaluate the global oxidant and antioxidant status in infants of diabetic mothers (IDM) via measurement of total antioxidant capacity (TAC) and total oxidant status (TOS) and to determine their association with the clinical and cardiac manifestations of gestational diabetes on infants. Forty five infants constituted the IDM group, 51 infants born to non diabetic mothers served as the control group. Umbilical cord blood was drawn from IDM and controls for TAC and TOS measurement. Echocardiographic measurements were performed in the first three days of life. Infants of diabetic mother had significantly higher TAC (p=0.024), TOS (p=0.03) and oxidative stress index (OSI, p=0.04) levels compared to controls. Hemoglobin values were correlated to TOS (r=0.310, p=0.03) and OSI (r=0.310, p=0.03). Maternal HbA1c values were also correlated to TOS (r=0.576, p=0.001) and OSI (r=0.606, p<0.001). Systolic and diastolic interventicular septum measurements, and left ventricular mass were also correlated with TOS (r=0.330, p=0.02; r=0.453, p=0.002; r=0.404, p=0.006, respectively) and OSI (r=0.330, p=0.02; r=0.300, p=0.04, r=0.300; p=0.04, respectively). Oxidant-antioxidant balance is disturbed in favor of oxidants in IDM despite compensatory increase in TAC. The degree of oxidative stress is related to the severity of myocardial and hematological involvement in IDM in the first days of life and maternal glycemic control. PMID- 25934527 TI - Effects of sleep duration and sleep quality on prevalence of type 2 diabetes mellitus: A 5-year follow-up study in China. AB - OBJECTIVE: To explore the interactions of sleep quality and sleep duration on the development of type 2 diabetes mellitus (DM2) in Chinese adults. RESEARCH DESIGN AND METHODS: We randomly selected 11,842 Chinese subjects from the Xuzhou community of China and obtained self-reported quality and duration of sleep by questionnaire. DM2 was assessed by fasting blood glucose. Sleep quality was categorized as good, common, or poor. Sleep duration was measured by average hours of sleep per night. We evaluated interaction, relative excess risk of interaction (RERI), the attributable proportion (AP), and the synergy index (S) using a logistic regression model. RESULTS: The relative risk for the development of DM2 was higher in subjects with short sleep duration (1.67 [1.34-2.16]) or poor sleep quality (1.91 [1.31-2.74]) or long sleep duration (1.45 [1.02-1.77]). DM2 occurred more frequently with poor sleep quality combined with short sleep duration (odds ratio: 6.21; 95% confidence interval (CI): 2.78-11.81). RERI, AP, and S values (and their 95% CI) were 3.99 (1.41-7.76), 0.64 (0.45-0.76), and 5.15 (3.74-7.89) for the interaction between poor sleep quality and short sleep duration. In subjects with poor sleep quality combined with long sleep duration, the RERI, AP, and S values (and 95% CI) were 0.13 (-0.19 to 0.66), 0.07 (-0.35 to 0.18), and 1.19 (0.85-2.11). CONCLUSIONS: Interactions between poor sleep quality and short sleep duration were additive. Preventive measures should focus on short sleep duration and poor sleep quality. PMID- 25934528 TI - Polymorphism in the transcription factor 7-like 2 (TCF7L2) gene is associated with impaired proinsulin conversion--A meta-analysis. AB - AIMS: Available evidence supports the emerging hypothesis that the T-Allele of the transcription factor 7-like 2 (TCF7L2) rs7903146 may be associated with the risk of impaired proinsulin conversion, but no consensus was available up to now. METHODS: A computer-based search of electronic databases (PubMed, EMBASE, Cochrane Library) and reference lists of relevant articles was carried out, and then 19 studies involving 15830 subjects were identified. The combined weighted mean difference (WMD) and their corresponding 95% confidence interval (CI) were calculated by a fixed or random effect. RESULTS: In the overall analysis, the T Allele was observed to be significantly associated with the risk of impaired proinsulin conversion (up-regulate fasting proinsulin concentration WMD -0.40 pM/L (95% CI -0.57 to -0.23); down-regulate fasting insulin concentration 3.86 pM/L (95% CI 1.91 to 5.81)). Subgroup analyse stratified by subjects population characteristics and ethnicity were performed. The results indicated the TCF7L2 rs7903146 polymorphism was associated with the risk of impaired proinsulin conversion in various population characteristics study. With only a few of subjects in Asians and Africans were available, we failed to detect significant ethnic difference about TCF7L2 rs7903146 polymorphism and the risk of impaired proinsulin conversion. CONCLUSIONS: Our results indicated that the T-Allele of the TCF7L2 rs7903146 is a significantly risk factor for impaired proinsulin conversion. Future research should gather more data about the effect of TCF7L2 rs7903146 polymorphism on Asians and Africans. PMID- 25934529 TI - A multilocus phylogenetic analysis reveals the monophyly of a recircumscribed papilionoid legume tribe Diocleae with well-supported generic relationships. AB - Deciphering the phylogenetic relationships within the species-rich Millettioid clade has persisted as one of the major challenges in the systematics and evolutionary history of papilionoid legumes (Leguminosae, Papilionoideae). Historically, the predominantly neotropical lianas of subtribe Diocleinae in the Millettioid legumes have been taxonomically tangled together with the largely heterogeneous tribe Phaseoleae. This work presents a comprehensive molecular phylogenetic analysis based on nuclear and chloroplast markers and includes all genera ever referred to Diocleae except for the monospecific Philippine Luzonia, resolving several key generic relationships within the Millettioid legumes. The first of two separate analyses includes 310 matK accessions and strongly supports the reestablishment of tribe Diocleae as a branch of the Millettioid clade. This work sheds greater light on the higher-level phylogeny of Diocleae and allows the recognition of three major lineages: the Canavalia, Dioclea, and Galactia clades. The second set of phylogenetic analyses utilized nuclear (ITS/5.8S and ETS) and plastid (matK and trnT-Y) DNA sequences to reveal (i) the monophyly of Canavalia and Cleobulia; (ii) the monophyly of Bionia with the exclusion of Bionia bella; (iii) the paraphyly of Dioclea with respect to Cleobulia, Cymbosema, and Macropsychanthus; (iv) the paraphyly of Cratylia with respect to the broadly polyphyletic Camptosema; and (v) the polyphyly of Galactia with species scattered widely across the tree. PMID- 25934530 TI - [Study impacto: Descriptive analyzis of pharmacist's clinical practice in onco hematology]. AB - Pharmaceutical analyses of chemotherapy prescriptions by hospital pharmacists are activities codified by regulation and rules (bon usage). The involvement of the pharmacists in clinical pharmacy activities in the oncology setting is not clearly identified, justifying the development of a mapping of these activities from a questionnaire addressed to the professionals. One hundred and seven centers have participated to this study at the national level (overall participation rate of 32.4%). More than 95% of them used a computerized ordering system and three quarter of them submit the introduction of new compounds to an analysis by the drug therapeutic committee. Prescription analysis allowed detecting around 2% of errors from the current prescription. Clinical pharmacist participates to tumor boards of onco-hematology (RCP) at a level of 46% for senior pharmacist and 42% for junior pharmacist. This involvement in the RCP allowed anticipating protocol's modification and temporary used authorization. Ninety-two percent of the senior pharmacists estimate that they highlight the risk of no reimbursement for prescription out of the guideline during RCP, resulting to a modification of the prescription for 40% of them. This level of intervention is lower with respectively 64% and 10% for the juniors. This study underlines the expert value of the clinical pharmacist dedicated to oncology setting in pre and post analysis prescriptions. It could be targeted by a prospective analysis of both clinical and pharmacoeconomics impact of these interventions. PMID- 25934531 TI - [Review and analysis of the evidence on the role and the impact of pharmacists' activities: Development of an online tool]. AB - BACKGROUND: Considering the increase in healthcare expenses, stakeholders need to make choices, including healthcare program funding, and professional activities to prioritise. PURPOSE: The main objective was to list evidences about the role and impact of pharmacists. METHODS: Themes were chosen according to three dimensions of the pharmacist profession: (1) activities, (2) healthcare programs and (3) disorders. A literature search was conducted for each theme. A bibliographic data sheet was completed for each article. An analytic data sheet, consisting of descriptive and impact outcomes, was also completed for the most relevant articles. For each theme, a synthesis was elaborated. The website Impact Pharmacie (http://impactpharmacie.org) was developed. RESULTS: A total of 70 synthesis were written. A total of 1442 articles were included with a bibliographic data sheet, and 914 with an analytic data sheet. Six hundred and fifty articles had positive outcomes on the role of the pharmacist, representing 803 different positive outcome markers. Pharmacists had positive outcomes on morbidity (n=212), adherence (n=92), costs (n=36), adverse effects (n=26), drug errors (n=31) and mortality (n=13). CONCLUSION: This descriptive study presents the review of the evidence on the role and the impact of pharmacists activities, which led to the Impact Pharmacie website. This francophone website can contribute to support clinical pharmacy development, and to a better use of pharmacists in healthcare. PMID- 25934532 TI - [Comparison between implantation costs of peripherally inserted central catheter and implanted subcutaneous ports]. AB - INTRODUCTION: Peripherally Inserted Central Catheter or PICC Line and implanted subcutaneous ports are two types of central catheters allowing drug administration and blood samplings. These two devices are very controversial (because of infectious and thrombotic complications), it seemed interesting to estimate their cost of implantation and to correlate them with the reimbursement by the Health Insurance. MATERIALS AND METHODS: Direct (material and drugs) and indirect (use of the room and staff) costs were prospectively evaluated for PICC Lines and implanted subcutaneous ports. RESULTS: The global costs of the implantation of a PICC Line and of an implanted subcutaneous port in the interventional radiology room and in the operating room were respectively evaluated at 220.2 ?, 286.6 ? and 666.3 ?. DISCUSSION-CONCLUSION: Only a PICC Line in outpatients can be reimbursed by the health insurance; which amounts to 110.4 ?. The establishment therefore loses money with every implantation. However, PICC Lines offer to the patients a fast access to a central venous way and thus an optimal therapeutic care, fulfilling one of the main missions of the public health institutions. Implanted subcutaneous ports are economically worth being implanted only in ambulatory inpatients. Its implantation in radiology seemed more profitable because the indirect costs were much more moderate. PMID- 25934533 TI - Identification and characterization of a novel antigenic epitope in the hemagglutinin of the escape mutants of H9N2 avian influenza viruses. AB - H9N2 avian influenza virus (AIV) evolves rapidly in both genovariation and antigenicity. It is essential to monitor the change of antigenicity, in particular in the hemagglutinin (HA) protein. Here we reported the selection of antigenic variants from A/Chicken/Shanghai/F/98 (H9N2) and A/chicken/Taixing/10/2010 (H9N2) viruses using HA-specific monoclonal antibodies (MAbs). Based on the reactivity of these variant and wild-type strains with the MAbs, we identified 6 critical amino acid positions (92, 145, 166, 167, 168, and 197) in the H9 antigenic sites, including the position 92 that has never been reported. Among AIVs originated from chicken in mainland China, the rates of Gly and Arg at position 92 within BJ/94-like (A/chicken/Beijing/1/1994) lineage viruses were 62.2% (28/45) and 37.8% (17/45), respectively; whereas the rates of Gly and Arg at position 92 within Y280-like (A/duck/Hong Kong/Y280/97) lineage viruses were 0.3% (2/670) and 99.1% (673/679), respectively. Our study suggests that G92R mutation together with other identified antigenic sites may serve as molecular markers for H9N2 virus evolution, and may aid improving AIV vaccine effectiveness. PMID- 25934534 TI - Generation of hepatitis E virus-like particles of two new genotypes G5 and G6 and comparison of antigenic properties with those of known genotypes. AB - In addition to the four major genotypes (G1 through G4) known for human hepatitis E virus (HEV), two new genotypes (G5 and G6) were suggested, based on unique viral nucleotide sequences derived from wild boars in Japan. It has been unknown whether the virus of these new genotypes can cause hepatitis in humans; neither G5 nor G6 HEV has been found in patients to date. To study the antigenic properties of G5 and G6 HEV, we expressed N-terminus-truncated HEV ORF2 protein by a recombinant baculovirus system, and we obtained virus-like particles (VLPs) for both G5 and G6. The VLPs showed antigenic cross-reactivity against G1, G3 and G4 HEV more strongly than against ferret or rat HEV. Moreover, both anti-G5 and anti-G6 VLPs antibodies could neutralize G3 HEV's ability to infect PLC/PRF/5 cells, suggesting that G5 and G6 HEV have the same serotype as human HEV. PMID- 25934535 TI - Reprint of: Outcomes in patients with metastatic renal cell cancer treated with individualized sunitinib therapy: Correlation with dynamic microbubble ultrasound data and review of the literature. AB - BACKGROUND: Increased sunitinib exposure (area under the curve) is associated with better outcome in metastatic renal cell cancer. Recommendations for dose modification do not take this into account. A treatment strategy, based on individual patient toxicity, was developed to maximize dose and minimize time without therapy for patients who could not tolerate the standard sunitinib schedule of 50mg given for 28 days with a 14-day break (50mg, 28/14). METHODS: A single-center retrospective review was conducted on patients with metastatic renal cell cancer treated from October 2005 to March 2010. Dose/schedule modifications (DSM) were done to keep toxicity (hematological, fatigue, skin, and gastrointestinal) at <= grade 2. DSM-1 was 50mg, 14 days on/7 days off with individualized increases in days on treatment. DSM-2 was 50mg, 7 days on/7 days off with individualized increase in days on treatment. DSM-3 was 37.5mg with individualized 7-day breaks. DSM-4 was 25mg with individualized 7-day breaks. Multivariable analysis was performed for outcome as a function of patient and treatment variables. RESULTS: Overall, 172 patients were included in the analysis. Most patients had clear cell histology (79.1%) with sunitinib given as a first-line therapy in 59%. The DSM-1 and 2 and DSM-3 and 4 groups had a progression-free survival (PFS) (10.9-11.9 mo) and overall survival (OS) (23.4 24.5 mo) that was significantly better than the PFS (5.3 mo; P<0.001) and OS (14.4 mo; P = 0.03 and 0.003) for the standard schedule (50mg, 28/14). DCE-US in a subset of patients showed that maximum antiangiogenic activity was achieved after 14 days on therapy. CONCLUSIONS: Individualized sunitinib scheduling based on toxicity may improve PFS and OS. This hypothesis is supported by several other respective data that are reviewed. A confirmatory prospective trial is ongoing. PMID- 25934536 TI - Nocturnal agitation in Huntington disease is caused by arousal-related abnormal movements rather than by rapid eye movement sleep behavior disorder. AB - BACKGROUND: Patients with Huntington disease (HD) and their spouses often complain of agitation during sleep, but the causes are mostly unknown. OBJECTIVE: To evaluate sleep and nocturnal movements in patients with various HD stages and CAG repeats length. METHODS: The clinical features and sleep studies of 29 patients with HD were retrospectively collected (11 referred for genotype phenotype correlations and 18 for agitation during sleep) and compared with those of 29 age- and sex-matched healthy controls. All patients had videopolysomnography, but the movements during arousals were re-analyzed in six patients with HD with stored video. RESULTS: The patients had a longer total sleep period and REM sleep onset latency, but no other differences in sleep than controls. There was no correlation between CAG repeat length and sleep measures, but total sleep time and sleep efficiency were lower in the subgroup with moderate than milder form of HD. Periodic limb movements and REM sleep behavior disorders were excluded, although 2/29 patients had abnormal REM sleep without atonia. In contrast, they had clumsy and opisthotonos-like movements during arousals from non-REM or REM sleep. Some movements were violent and harmful. They might consist of voluntary movements inappropriately involving the proximal part of the limbs on a background of exaggerated hypotonia. Giant (>65 mcV) sleep spindles were observed in seven (24%) patients with HD and one control. CONCLUSION: The nocturnal agitation in patients with HD seems related to anosognostic voluntary movements on arousals, rather than to REM sleep behavior disorder and other sleep problems. PMID- 25934537 TI - Sternberg working memory performance following treatment with pramipexole in patients with moderate-to-severe restless legs syndrome. AB - OBJECTIVES: We recently reported that the P300 amplitude related to the Sternberg working memory (WM) task was significantly lower in drug-naive severe restless legs syndrome (RLS) patients than controls. Here, we evaluated the effects of pramipexole on the Sternberg WM task performance by event-related potential (ERP) study. METHODS: Thirteen drug-naive RLS patients (52.0 +/- 9.48 years) were enrolled in the study. Pramipexole was administered over a period of 12 weeks every night 1 h before bedtime. Two ERP studies were carried out: the first was performed just before giving the first dose of pramipexole and the second was conducted at 12-16 weeks after commencement of pramipexole administration. P300 amplitudes and reaction times were compared before and after treatment considering brain regions and memory load as within-subject factors. Clinical and sleep-related variables were correlated with P300 amplitude. RESULTS: After treatment with pramipexole, the International RLS Severity Scale (IRLS) score was significantly decreased. Sleep quality and depression were also significantly improved. Omission error was significantly reduced without significant change of commission error. Reaction time was significantly shortened, regardless of memory load size, following treatment with pramipexole. Parietal P300 amplitude was significantly increased after treatment with pramipexole for all memory load sizes. Increase of frontal P300 amplitude was significantly correlated with improvement of sleep duration, IRLS, Insomnia Severity Index, and Pittsburgh Sleep Quality Index score. CONCLUSION: Our study suggested that pramipexole improves WM performance in patients with RLS in addition to improving RLS symptoms, sleep disturbance, and depression. PMID- 25934539 TI - Rapid maxillary expansion outcomes in treatment of obstructive sleep apnea in children. AB - OBJECTIVES: The objectives of this study were to confirm the efficacy of rapid maxillary expansion in children with moderate adenotonsillar hypertrophy in a larger sample and to evaluate retrospectively its long-term benefits in a group of children who underwent orthodontic treatment 10 years ago. METHODS: After general clinical examination and overnight polysomnography, all eligible children underwent cephalometric evaluation and started 12 months of therapy with rapid maxillary expansion. A new polysomnography was performed at the end of treatment (T1). Fourteen children underwent clinical evaluation and Brouilette questionnaire, 10 years after the end of treatment (T2). RESULTS: Forty patients were eligible for recruitment. At T1, 34/40 (85%) patients showed a decrease of apnea-hypopnea index (AHI) greater than 20% (DeltaAHI 67.45% +/- 25.73%) and were defined responders. Only 6/40 (15%) showed a decrease <20% of AHI at T1 and were defined as non-responders (DeltaAHI -53.47% +/- 61.57%). Moreover, 57.5% of patients presented residual OSA (AHI > 1 ev/h) after treatment. Disease duration was significantly lower (2.5 +/- 1.4 years vs 4.8 +/- 1.9 years, p <0.005) and age at disease onset was higher in responder patients compared to non-responders (3.8 +/- 1.5 years vs 2.3 +/- 1.9 years, p <0.05). Cephalometric variables showed an increase of cranial base angle in non-responder patients (p <0.05). Fourteen children (mean age 17.0 +/- 1.9 years) who ended orthodontic treatment 10 years previously showed improvement of Brouilette score. CONCLUSION: Starting an orthodontic treatment as early as symptoms appear is important in order to increase the efficacy of treatment. An integrated therapy is needed. PMID- 25934538 TI - Sleep and future cardiovascular risk: prospective analysis from the English Longitudinal Study of Ageing. AB - STUDY OBJECTIVES: Hypertension and inflammation may contribute to the increased risk of cardiovascular disease in individuals with suboptimal sleep, but large prospective studies are lacking. This study tested whether sleep duration and disturbance were predictive of incident hypertension and inflammation four years later. METHODS: Participants were men and women aged 50 years and older from the English Longitudinal Study of Ageing. Sleep was assessed by self-report, incident hypertension (N = 3068) was defined by clinical examination and C-reactive protein and fibrinogen (N = 3768) were measures of inflammation. RESULTS: Both men (odds ratio, OR:1.73, confidence interval, C.I. 1.08-2.76) and women (OR: 1.44, C.I. 1.00-2.07) reporting short sleep at baseline had increased odds of incident hypertension 4 years later, after adjustment for covariates. Age stratified analyses revealed that short sleep was predictive of incident hypertension in men (OR: 2.27, C.I. 1.01-5.11) and women (OR: 2.10, C.I. 1.08 4.09) younger than 60 years but not in older people. Disturbed sleep also predicted incident hypertension in men (OR: 1.20, C.I. 1.02-1.41). In women, disturbed sleep was associated with elevated C-reactive protein (B = 0.030, C.I. 0.00-0.06) and fibrinogen (B = 0.030, C.I. 0.01-0.05) at follow-up controlling for baseline inflammation and other covariates. Sleep duration was unrelated to inflammatory markers in either sex. CONCLUSIONS: This study of older men and women adds to growing evidence that aberrant sleep patterns may increase the risk of cardiovascular outcomes through its adverse impact on blood pressure and inflammation. PMID- 25934540 TI - New data on psychological traits and sleep profiles of patients affected by nocturnal eating. AB - OBJECTIVE: Nocturnal eating behavior is shared by patients affected by a parasomnia, sleep-related eating disorder (SRED), and several eating disorders such as night eating syndrome (NES) and binge-eating disorder (BED); however, the differential clinical features of these patients have been poorly studied, with persisting difficulties in defining the borders between these pathologies. The aim of this study was to evaluate polysomnographic and personality characteristics of nocturnal eaters to further differentiate the syndromes. METHODS: During a period of six months, consecutive patients complaining of nocturnal eating were asked to participate to the study. Twenty-four patients who were found to eat during the polysomnographic recording (PSG) study, and gender matched control subjects were included. All subjects underwent a full-night video PSG study and a psychometric assessment including the Eating Disorder Inventory (EDI-2), the self-rating Bulimic Investigatory Test-Edinburgh (BITE), the Temperament and Character Inventory (TCI), and the Barratt Impulsivity Scale (BIS). RESULTS: Nocturnal eaters showed a mild reduction in sleep efficiency and duration due to a moderate sleep fragmentation, whereas the percentage of each sleep stage was not significantly affected. Nocturnal eaters scored higher at many subscales of the EDI-2, at the BITE symptoms subscale, and at the BIS attentional impulsivity subscale. CONCLUSION: The psychological characteristics found in our patients with NES seem to be typical for patients affected by eating disorders, and support the hypothesis that the nocturnal behavior of these individuals is due to an eating disorder; however, specific traits also allow differentiation of NES from BED. PMID- 25934541 TI - Prevalence and clinical characteristics of patients with restless legs syndrome with painful symptoms. AB - BACKGROUND: The complaint of pain has largely been ignored in the diagnostic criteria for restless legs syndrome (RLS). The purpose of this study was to investigate the prevalence of painful symptoms in RLS, and to compare sleep related characteristics between the patients who experienced the painful symptoms and those who did not. METHODS: The patients with RLS were retrospectively screened from July 2011 to December 2013 at a tertiary-care sleep center. For classifying those with pain and those without pain, more than three specialists separately observed the patients' reports and complaints of symptoms, and the final decision was made through consensus. The demographics and clinical characteristics, including sleep, psychiatric-related scales, and polysomnographic data were reviewed for the study. RESULTS: One hundred and sixty patients with RLS were selected, and 23.8% of them reported painful symptoms of RLS. Patients with RLS who experienced painful sensations were found to have lower ferritin levels, more severe RLS symptoms, anxiety and depressive symptoms, and a lower quality of life. The polysomnography data found that patients with RLS who experienced painful sensations had a longer latency to sleep onset and a lower periodic limb movement index (PLMI) (p <0.05). CONCLUSIONS: Patients who experienced painful sensations had more severe RLS symptoms and a trend toward lower PLMI during sleep. According to these results, an inference can be made that painful sensations may be one important point in determining the severity of RLS. PMID- 25934542 TI - Increase of a group of PTC(+) transcripts by curcumin through inhibition of the NMD pathway. AB - Nonsense-mediated mRNA decay (NMD), an mRNA surveillance mechanism, eliminates premature termination codon-containing (PTC+) transcripts. For instance, it maintains the homeostasis of splicing factors and degrades aberrant transcripts of human genetic disease genes. Here we examine the inhibitory effect on the NMD pathway and consequent increase of PTC+ transcripts by the dietary compound curcumin. We have found that several PTC+ transcripts including that of serine/arginine-rich splicing factor 1 (SRSF1) were specifically increased in cells by curcumin. We also observed a similar curcumin effect on the PTC+ mutant transcript from a Tay-Sachs-causing HEXA allele or from a beta-globin reporter gene. The curcumin effect was accompanied by significantly reduced expression of the NMD factors UPF1, 2, 3A and 3B. Consistently, in chromatin immunoprecipitation assays, curcumin specifically reduced the occupancy of acetyl histone H3 and RNA polymerase II at the promoter region (-376 to -247nt) of human UPF1, in a time- and dosage-dependent way. Importantly, knocking down UPF1 abolished or substantially reduced the difference of PTC(+) transcript levels between control and curcumin-treated cells. The disrupted curcumin effect was efficiently rescued by expression of exogenous Myc-UPF1 in the knockdown cells. Together, our data demonstrate that a group of PTC+ transcripts are stabilized by a dietary compound curcumin through the inhibition of UPF factor expression and the NMD pathway. PMID- 25934543 TI - The core promoter: At the heart of gene expression. AB - The identities of different cells and tissues in multicellular organisms are determined by tightly controlled transcriptional programs that enable accurate gene expression. The mechanisms that regulate gene expression comprise diverse multiplayer molecular circuits of multiple dedicated components. The RNA polymerase II (Pol II) core promoter establishes the center of this spatiotemporally orchestrated molecular machine. Here, we discuss transcription initiation, diversity in core promoter composition, interactions of the basal transcription machinery with the core promoter, enhancer-promoter specificity, core promoter-preferential activation, enhancer RNAs, Pol II pausing, transcription termination, Pol II recycling and translation. We further discuss recent findings indicating that promoters and enhancers share similar features and may not substantially differ from each other, as previously assumed. Taken together, we review a broad spectrum of studies that highlight the importance of the core promoter and its pivotal role in the regulation of metazoan gene expression and suggest future research directions and challenges. PMID- 25934544 TI - Forensic typing of short tandem repeat markers on the X and Y chromosomes. AB - Short tandem repeat (STR) markers are the cornerstone of forensic identity and kinship testing. Markers located on the X and the Y chromosome can complement those found on the autosomes, which are commonly used in laboratories today. The distinctive inheritance pattern of the sex chromosomes affords advantages to the investigation of family pedigrees required by mass disaster victim identification or missing persons cases, as well as mixed samples typically recovered in sexual assault crimes. This review aims to provide an overview of how X and Y STR markers are currently being used in forensic laboratories, including the applications which target their use, the markers and multiplexes facilitating recovery of this genetic information, and the tools available to interpret the resulting data. Emerging research topics are considered as well as issues requiring further study for both marker systems. PMID- 25934545 TI - Orthopaedic surgeon who botched four operations while working as a locum is struck off. PMID- 25934546 TI - Combination of selective enrichment and MALDI-TOF MS for rapid detection of Streptococcus agalactiae colonisation of pregnant women. AB - Sample preparation was optimized for MALDI-TOF MS directly from selective enrichment broth to detect Streptococcus agalactiae. The method was tested on 100 vaginal samples of pregnant women; positive and negative predictive values were 100 and 91%, respectively. If it indicates positivity, colonisation can be reported 18-24h after sample collection. PMID- 25934547 TI - Detection of Helicobacter pylori DNA sequences in gastric biopsy samples to refine the diagnosis and therapy. PMID- 25934548 TI - Development of a novel molecular detection method for clustered regularly interspaced short palindromic repeats (CRISPRs) in Taylorella organisms. AB - Contagious equine metritis is a bacterial infectious disease of horses caused by Taylorella equigenitalis, a Gram-negative eubacterium. The disease has been described in several continents, including Europe, North America and Asia. A novel molecular method was developed to detect clustered regularly interspaced short palindromic repeats (CRISPRs), which were separated by non-repetitive unique spacer regions (NRUSRs) of similar length, in the Taylorella equigenitalis EQ59 strain using a primer pair, f-/r-TeCRISPR-ladder, by PCR amplification. In total, 31 Taylorella isolates (17 T. equigenitalis and 14 Taylorella asinigenitalis) were examined. The T. equigenitalis isolates came from thoroughbred and cold-blooded horses from nine countries during 1980-1996, whilst the T. asinigenitalis isolates all originated from donkey jacks in France and the USA during 1997-2006. PAGE fractionated all of the 13 CRISPRs separated by 12 NRUSRs in T. equigenitalis EQ59. Permutation examples of CRISPRs, which were separated by NRUSRs for small-sized ladders, consisting of two doublet bands were shown. Putative CRISPRs separated by NRUSRs were amplified with 14/17 (82.4 %) geographically disparate T. equigenitalis isolates using the newly designed primer pair. Approximately 82.4 % of the T. equigenitalis isolates had CRISPRs separated by NRUSRs. The CRISPR locus was also found in the French T. asinigenitalis strain MCE3. Putative CRISPRs separated by NRUSRs were detected similarly in 4/14 (28.6 %) T. asinigenitalis isolates. Overall, a more detailed understanding of the molecular biology of CRISPRs within Taylorella organisms may help elucidate the pathogenic virulence and transmission mechanisms associated with this important equine pathogen. PMID- 25934549 TI - Monitoring antibiotic-resistant enterobacteria faecal levels is helpful in predicting antibiotic susceptibility of bacteraemia isolates in patients with haematological malignancies. AB - Delay of active antimicrobial therapy in haematological patients with Gram negative bacilli bacteraemia during profound neutropenia exposes them to increased morbidity and mortality. The digestive tract is the main source of enterobacteria causing bacteraemia in these patients. We thus evaluated the usefulness of broad-spectrum beta-lactam resistant enterobacteria (BSBL-RE) faecal shedding assessment in forecasting the susceptibility to BSBLs of the strains isolated from blood cultures. From 2002 to 2011, neutropenic haematological patients with bacteraemia caused by enterobacteria who had a stool culture during the previous 7 days were retrospectively included. BSBL-RE intestinal carriers were compared with non-carriers in terms of clinical and microbiological criteria. One hundred and four patients were included and 16 of them (15.4 %) were BSBL-RE carriers. Multivariate analysis showed that BSBL-RE carriage was independently associated with BSBL-RE identified in blood cultures (P < 0.001) and the use of carbapenems as empirical treatment of the bacteraemia (P = 0.008). Sensitivity, specificity, and the positive and negative predictive values of the test were 80 %, 91 %, 50 % and 98 %, respectively. Among the carriers, those with the highest level of BSBL-RE carriage were also those with the highest risk of bacteraemia due to BSBL-RE (P < 0.001). Close monitoring of BSBL-RE intestinal carriage may help to choose the most appropriate initial antimicrobial treatment for neutropenic haematological patients with bacteraemia. PMID- 25934550 TI - Increase in SCCmec type IV strains affects trends in antibiograms of meticillin resistant Staphylococcus aureus at a tertiary-care hospital. AB - The prevalence of community-acquired meticillin-resistant Staphylococcus aureus (CA-MRSA) strains has become a serious problem worldwide. The aim of this study was to investigate the annual transitions of MRSA strains with the CA-MRSA feature, which were identified as SCCmec type IV or V, in a hospital setting in Japan. Between 2005 and 2012, MRSA strains were collected from a tertiary-care hospital in Tokyo, Japan, and SCCmec typing, detection of the virulence factors and antimicrobial susceptibility testing were conducted. The rate of detection of type II SCCmec, which is found mainly in healthcare-associated MRSA, significantly decreased from 90.0 (2005-2006) to 74.3 % (2011-2012) (P < 0.01). In contrast, the rate of detection of type IV SCCmec, which is mainly found in CA MRSA, significantly increased from 5.8 (2005-2006) to 16.3 % (2011-2012) (P < 0.01). The rate of detection of the toxic shock syndrome toxin-1 gene significantly decreased from 66.7 (2005-2006) to 51.6 % (2011-2012) (P < 0.01), whilst that of the Panton-Valentine leukocidin gene significantly increased from 0.1 (2005-2006) to 2.1 % (2011-2012) (P < 0.01). The resistance rates of cefotaxime, levofloxacin, clarithromycin and minocycline decreased every year. The resistance rates of these antimicrobial agents for the SCCmec type IV or V strains were significantly lower than those for the SCCmec type I or II strains (P < 0.01, respectively). Therefore, these results suggest that the annual transitions of the virulence factors and antibiograms in MRSA are closely related to the increase of SCCmec type IV/V strains. PMID- 25934551 TI - Prevalence and molecular analysis of macrolide-resistant Moraxella catarrhalis clinical isolates in Japan, following emergence of the highly macrolide-resistant strain NSH1 in 2011. AB - Although Moraxella catarrhalis is known to be susceptible to macrolides, highly macrolide-resistant M. catarrhalis isolates have recently been reported in Japan and China. In this study, we investigated the prevalence of macrolide-resistant M. catarrhalis isolates in Tokyo and Chiba, Japan, and studied the mechanisms underlying their resistance. Specifically, we determined the susceptibility of 593 clinical isolates (collected between December 2011 and May 2014) to erythromycin, using the disk diffusion method. For isolates with erythromycin resistance, we identified the MICs of seven antimicrobial agents, including macrolides, and used PFGE to analyse the clonal spread. We also performed sequencing analysis to investigate macrolide-resistance targets. Thirteen isolates (2.2 %) were found to be resistant to erythromycin, showing a high MIC90 to erythromycin, clarithromycin, clindamycin and azithromycin. However, those isolates, in addition to 156 randomly selected erythromycin-susceptible strains, were susceptible to amoxicillin-clavulanate, cefixime and levofloxacin. The 13 highly macrolide-resistant isolates were classified into 10 clades and harboured three or four A2058T-mutated 23S rRNA alleles. Three highly macrolide-resistant isolates also exhibited mutations in ribosomal proteins L4 (V27A and R161C) and L22 (K68T). To the best of our knowledge, we have demonstrated for the first time that, whilst the prevalence of macrolide-resistant M. catarrhalis isolates is low in clinical settings in Japan, genetically diverse isolates with high-level macrolide resistance due to the acquisition of an A2058T mutation in the 23S rRNA have already spread. Our study therefore lays the basis for epidemiological studies of macrolide-resistant M. catarrhalis clinical isolates. PMID- 25934552 TI - Modified Hodge test using Mueller-Hinton agar supplemented with cloxacillin improves screening for carbapenemase-producing clinical isolates of Enterobacteriaceae. AB - Increasing numbers of clinical isolates of Enterobacteriaceae that produce carbapenemase are now being detected, with the most common carbapenemase found among Enterobacteriaceae in Japan being IMP-1-type metallo-beta-lactamase. Clinical isolates of Enterobacteriaceae harbouring carbapenemases may be resistant to carbapenem antimicrobial agents, despite apparent in vitro susceptibility when tested according to Clinical and Laboratory Standards Institute criteria. We evaluated the prevalence of carbapenemase producers among isolates of Enterobacteriaceae at our hospital and assessed the performance of the modified Hodge test (MHT) for correctly identifying the phenotype. We studied 47 clinical isolates obtained between 2006 and 2010 for which the MIC of imipenem was 2 or 4 MUg imipenem ml- 1. Antibacterial susceptibility testing was done for cephalosporins and carbapenems, the MHT was performed with meropenem and detection of the genes encoding IMP-1, VIM-2, KPC-2 and NDM-1-type metallo-beta lactamases was performed by PCR. Twelve isolates showed a positive result in the MHT with meropenem and were classified as carbapenemase producers. Of these 12 isolates, seven carried the gene for IMP-1 type, but not for VIM-2, KPC-2 or NDM 1 types. None of the carbapenemase genes tested were detected in the other five isolates. All five isolates were Enterobacter cloacae showing high resistance to ceftazidime and aztreonam. False-positive results were inhibited when Mueller Hinton agar supplemented with 200 mg cloxacillin ml- 1 was used for the MHT. Five of 12 MHT-positive isolates were shown to have no carbapenemase genes and these isolates were high AmpC producers. Adding cloxacillin when performing the MHT prevented such false-positive results. The MHT with cloxacillin can overcome most problems related to detection of carbapenemases. PMID- 25934553 TI - Spread of OXA-23-producing Acinetobacter baumannii ST2 and ST246 in a hospital in Japan. AB - A total of 1085 strains of Acinetobacter sp. obtained from 280 medical institutions in the Chugoku and Shikoku areas of Japan were investigated between 2011 and 2013. Among these strains, 20 (1.84 %) showing meropenem or imipenem resistance with a MIC of >4 MUg ml- 1 were detected. Of these 20 strains, the bla(OXA-23) gene was detected in 17 strains isolated from the same institution. The PFGE patterns of the 17 strains were separated into two clusters, and multi locus sequence typing showed the sequence types (STs) to be ST2 and ST246. This investigation demonstrated that A. baumannii ST2 of international clone II, which has rarely been isolated in Japan, has not yet spread nationwide. PMID- 25934554 TI - Effectiveness of Montelukast on asthma control in infants: methodology of a French claims data study. AB - BACKGROUND: This pilot study, conducted on a 1/97th representative sample of French claims data, prepared a project to assess the effectiveness of Montelukast (MTL-4) as add-on therapy for asthma in infants (6-24 months) compared to inhaled corticosteroids (ICS), based on real-world data. Due to the very recent opening of French claims data for effectiveness research, and the complex structure of this data source, we first tested the feasibility of identifying infants with asthma and outcome criteria, and the ability to perform relevant comparisons. METHODS: We identified a cohort of infants with uncontrolled asthma and receiving >=2 consecutive dispensations of any respiratory drug (R03 ATC classification) during a 6-month period. Uncontrolled asthma was identified either from exacerbations or from markers of acute loss of asthma control; date of occurrence of an event (exacerbation and/or acute loss of asthma control) was defined as index date. The study groups comprised infants receiving MTL-4 +/- ICS (MTL-4 group) or ICS without MTL-4 (ICS group) at index date. These two groups were matched on gender, age, quarter of index date, therapy before index date, past asthma-related hospitalization (ever), and were followed for 6 months. The outcome was the rate of infants with uncontrolled asthma, defined as above. RESULTS: This pilot cohort study included 1,149 infants with asthma (mean age 14.1 months, 64% boys). Of these, 51 and 768 were assigned to the MTL-4 and ICS groups, respectively. Uncontrolled asthma occurred in 78.8% and 78.4% of infants in these groups, respectively (oral corticosteroids were dispensed to 49% and 61%, respectively). Assessment of uncontrolled asthma, exposure to MTL-4 and ICS, and occurrence of outcomes were achieved. For the development of matching criteria, we defined a new marker of severity (therapeutic typologies). CONCLUSION: These data support the feasibility of the final project, to be conducted on claims data from the whole French population. We also showed that, with appropriate methodology and by using valid criteria, French claims data are an adequate resource for conducting comparative effectiveness studies in pediatric asthma. Finally, the algorithm used to identify infants with asthma could be applied to other studies using claims data. PMID- 25934555 TI - Effects of cytarabine on activation of human T cells - cytarabine has concentration-dependent effects that are modulated both by valproic acid and all trans retinoic acid. AB - BACKGROUND: Cytarabine is used in the treatment of acute myeloid leukemia (AML). Low-dose cytarabine can be combined with valproic acid and all-trans retinoic acid (ATRA) as AML-stabilizing treatment. We have investigated the possible risk of immunotoxicity by this combination. We examined the effects of cytarabine combined with valproic acid and ATRA on in vitro activated human T cells, and we tested cytarabine at concentrations reached during in vivo treatment with high doses, conventional doses and low doses. METHODS: T cells derived from blood donors were activated in vitro in cell culture medium alone or supplemented with ATRA (1 MUM), valproic acid (500 or 1000 MUM) or cytarabine (0.01-44 MUM). Cell characteristics were assessed by flow cytometry. Supernatants were analyzed for cytokines by ELISA or Luminex. Effects on primary human AML cell viability and proliferation of low-dose cytarabine (0.01-0.5 MUM) were also assessed. Statistical tests include ANOVA and Cluster analyses. RESULTS: Only cytarabine 44 MUM had both antiproliferative and proapoptotic effects. Additionally, this concentration increased the CD4:CD8 T cell ratio, prolonged the expression of the CD69 activation marker, inhibited CD95L and heat shock protein (HSP) 90 release, and decreased the release of several cytokines. In contrast, the lowest concentrations (0.35 and 0.01 MUM) did not have or showed minor antiproliferative or cytotoxic effects, did not alter activation marker expression (CD38, CD69) or the release of CD95L and HSP90, but inhibited the release of certain T cell cytokines. Even when these lower cytarabine concentrations were combined with ATRA and/or valproic acid there was still no or minor effects on T cell viability. However, these combinations had strong antiproliferative effects, the expression of both CD38 and CD69 was altered and there was a stronger inhibition of the release of FasL, HSP90 as well as several cytokines. Cytarabine (0.01-0.05 MUM) showed a dose-dependent antiproliferative effect on AML cells, and in contrast to the T cells this effect reached statistical significance even at 0.01 MUM. CONCLUSIONS: Even low levels of cytarabine, and especially when combined with ATRA and valproic acid, can decrease T cell viability, alter activation induced membrane-molecule expression and decrease the cytokine release. PMID- 25934556 TI - Risk factors and clinical outcomes of acute myeloid leukaemia with central nervous system involvement in adults. AB - BACKGROUND: Acute myeloid leukaemia (AML) with central nervous system (CNS) involvement in adults is uncommon, and studies of this subject are scant. METHODS: We conducted a retrospective study to investigate the clinical aspects, cytogenetic abnormalities, molecular gene mutations and outcomes of adult AML patients with CNS involvement. Three hundred and ninety-five patients with newly diagnosed AML were reviewed. RESULTS: Twenty (5.1%) patients had CNS involvement, including 7 (1.8%) with initial CNS disease and 4 (1%) who suffered an isolated CNS relapse. The patients with CNS involvement were younger, had higher leukocyte, platelet, and peripheral blast cell counts, FAB M4 morphology, and chromosome translocations involving 11q23 (11q23 abnormalities) more frequently than did the patients without CNS involvement. No differences in sex, haemoglobin levels, serum LDH levels, immunophenotype of leukaemia cells, or molecular gene mutations were observed between the two groups. Multivariate analyses showed that age <= 45 years (OR, 5.933; 95% CI, 1.82 to 19.343), leukocyte counts >= 50,000/MUl (OR, 3.136; 95% CI, 1.083 to 9.078), and the presence of 11q23 abnormalities (OR, 5.548; 95% CI, 1.208 to 25.489) were significant predictors of CNS involvement. Patients with initial CNS disease had 5-year overall survival and relapse-free survival rates that were similar to those without initial CNS disease. However, three of four patients who suffered an isolated CNS relapse died, and their prognosis was as poor as that of patients who suffered a bone marrow relapse. CONCLUSION: CNS involvement in adult patients with AML is rare. Three significant risk factors for CNS involvement including age <= 45 years, leukocyte counts >= 50,000/MUl and the presence of 11q23 abnormalities were identified in this study. Future investigations to determine whether adult AML patients having these specific risk factors would benefit from CNS prophylactic therapy are necessary. PMID- 25934557 TI - Understanding attitudes, barriers and challenges in a small island nation to disease and partner notification for HIV and other sexually transmitted infections: a qualitative study. AB - BACKGROUND: In Barbados sexually transmitted infections (STIs) including HIV are not notifiable diseases and there is not a formal partner notification (PN) programme. Objectives were to understand likely attitudes, barriers, and challenges to introducing mandatory disease notification (DN) and partner notification (PN) for HIV and other STIs in a small island state. METHODS: Six key informants identified study participants. Interviews were conducted, recorded, transcribed and analysed for content using standard methods. RESULTS: Participants (16 males, 13 females, median age 59 years) included physicians, nurses, and representatives from governmental, youth, HIV, men's, women's, church, and private sector organisations. The median estimated acceptability by society of HIV/STI DN on a scale of 1 (unacceptable) to 5 (completely acceptable) was 3. Challenges included; maintaining confidentiality in a small island; public perception that confidentiality was poorly maintained; fear and stigma; testing might be deterred; reporting may not occur; enacting legislation would be difficult; and opposition by some opinion leaders. For PN, contract referral was the most acceptable method and provider referral the least. Contract referral unlike provider referral was not "a total suspension of rights" while taking into account that "people need a little gentle pressure sometimes". Extra counselling would be needed to elicit contacts or to get patients to notify partners. Shame, stigma and discrimination in a small society may make PN unacceptable and deter testing. With patient referral procrastination may occur, and partners may react violently and not come in for care. With provider referral patients may have concerns about confidentiality including neighbours becoming suspicious if a home visit is used as the contact method. Successful contact tracing required time and effort. With contract referral people may neither inform contacts nor say that they did not. Strategies to overcome barriers to DN and PN included public education, enacting appropriate legislation to allow DN and PN, good patient counselling and maintaining confidentiality. CONCLUSIONS: There was both concern that mandatory DN and PN would deter testing and recognition of the benefits. Public and practitioner education and enabling legislation would be necessary, and the public needed to be convinced that confidentiality would be maintained. PMID- 25934558 TI - Nursing students' assessment of pain and decision of triage for different ethnic groups: An experimental study. AB - BACKGROUND: Pain management is a priority in nursing care but little is known about the factors that affect nursing students' assessment of pain expressed by patients of different ethnic backgrounds. OBJECTIVES: This study examined undergraduate nursing students' assessment of pain and decision of triage when pain was expressed in different languages and their relation to students' empathy and social identity. Comparison between students with and without clinical experience was also carried out. DESIGN: This is a cross-sectional quantitative design. SETTING: This study took place at a university in Hong Kong. PARTICIPANTS: 74 female undergraduate nursing students. METHODS: Students listened to eight audio recordings in which an individual expressed pain in one of the two dialects of Chinese, either Cantonese or Putonghua. For each dialect, two recordings depicted mild pain and two depicted severe pain. After listening to each recording, students rated the pain level and indicated their decision of triage. Subsequently, students completed a questionnaire that measured their empathy and social identity and reported their demographics. The data were analyzed by descriptive statistics, correlational analyses, and t-tests. RESULTS: Severe pain described in Putonghua was rated as more intense than that described in Cantonese but it was not classified as more urgent. Students with clinical experience tended to perceive mild pain as less painful and less urgent than those without clinical experience. For mild pain described in Cantonese, students with clinical experience evaluated it as more urgent than those without such experience. The empathy level of students with and without clinical experience was comparable. Students with more empathy, especially those without clinical experience, reported heightened perceived intensity of severe pain described in Putonghua. CONCLUSIONS: Nurse educators should note that empathy, social identity, and clinical experience may alter students' pain assessment of patients from different ethnicities. Pain education needs to be reinforced. PMID- 25934559 TI - Echocardiographic Discovery of Doubled Interatrial Septum: An Incidental Finding. AB - A double-walled interatrial septum is a rare congenital cardiac anomaly characterized by a distinct echolucent cavity between the atria formed by 2 separate interatrial septae. It may be a variant of other well-recognized cardiac anomalies such as persistent venous valve of the sinus venosus or cor triatriatum. Although uncommon, it may be associated with thromboembolic disease due to stagnant flow in the septal cavity. Awareness of this rare entity and its clinical significance along with a thorough echocardiographic examination to rule out similarly presenting or coexisting conditions are the key to an accurate diagnosis and appropriate management. PMID- 25934560 TI - End-of-life care research with bereaved informal caregivers--analysis of recruitment strategy and participation rate from a multi-centre validation study. AB - BACKGROUND: One essential element of research is the successful recruitment of participants. However, concerns are obvious regarding the ethical implications of involving terminally ill and even dying patients and their informal caregivers as research participants. This study aims to illustrate central issues encountered when recruiting bereaved informal caregivers for a questionnaire validation study on the quality of dying and death. METHODS: Between July 2012 and November 2013, informal caregivers of deceased inpatients who were treated at two palliative care units in Germany were invited to participate in a questionnaire validation study. Informal caregivers were called by a trained researcher at the end of the fourth week after death at the earliest and by the sixteenth week after death at the latest and asked to participate in a face-to-face interview in their private home. RESULTS: The overall participation rate of all eligible informal caregivers was 76.1% (226/297). The mean burden score was 2.5 (NRS from 0=no burden to 10=maximum burden; n=221). Higher burden scores (>=4) were associated with emotional and burdensome memories (n=34) being invoked throughout the interview. Severe or maximum burden scores (>=7) were stated by 13.2% of participants. The average time between the associated patient's death and the informal caregiver's interview was 57.3 days (range 26-176 days, median 49.5 days). 5.3% of all 226 interviews were not completed due to different reasons. Participants' comments on the way in which the study was conducted gave insight into their motivation to take part in the study and their evaluation of the interview situation. CONCLUSIONS: The recruitment strategy can be recommended to other researchers developing research with bereaved carers. The burden caused by study participation was acceptable to the researchers carrying out this research, although a small group of participants experienced high levels of burden which should be anticipated and appropriate support services offered. Family caregivers are willing to support end-of-life care research, have different motivations for participation and even reported benefits from participation. Nevertheless, study designs have to take into account and ease the potential burden of interviews for caregivers experiencing grief. PMID- 25934561 TI - Synthesis and luminescence properties of salicylaldehyde isonicotinoyl hydrazone derivatives and their europium complexes. AB - Four novel salicylaldehyde isonicotinoyl hydrazone derivatives and their corresponding europium ion complexes were synthesized and characterized, while the luminescence properties and the fluorescence quantum yields of the target complexes were investigated. The results indicated that the ligands favored energy transfers to the emitting energy level of europium ion, and four target europium complexes showed the characteristic luminescence of central europium ion. Besides the luminescence intensity of the complex with methoxy group, which possessed the highest fluorescence quantum yield (0.522), was stronger than that of other complexes. Furthermore, the electrochemical properties of the target complexes were further investigated by cyclic voltammetry, the results indicated that the highest occupied molecular orbital (HOMO), lowest unoccupied molecular orbital (LUMO) energy levels and the oxidation potential of the complexes with electron donating group increased, however, that of the complexes with accepting electron group decreased. PMID- 25934562 TI - Reliability of dynamic sentinel node biopsy combined with ultrasound-guided removal of sonographically suspicious lymph nodes as a diagnostic approach in patients with penile cancer with palpable inguinal lymph nodes. AB - INTRODUCTION AND OBJECTIVES: Dynamic sentinel node biopsy (DSNB) is considered "unsuitable" in patients with penile cancer and palpable inguinal lymph nodes. The aim of this study was to determine the diagnostic reliability of DSNB combined with ultrasound (US)-guided removal of additional suspicious lymph nodes as a minimally invasive diagnostic approach in these patients. MATERIAL AND METHODS: A total of 23 consecutive patients with penile cancer and unilaterally or bilaterally palpable inguinal lymph nodes underwent DSNB according to the 2 day protocol. Before the combined staging procedure, the patients underwent preoperative US of both groins. During surgery, sentinel nodes and additional suspicious lymph nodes as determined by the US examination were removed under US guidance. A complete inguinal lymph node dissection was only performed in patients who had tumor-positive nodes. Follow-up consisted of control visits according to the European Association of Urology guidelines, including US investigation of the groins. RESULTS: The primary tumors were staged as T1, T2, and T3 carcinomas in 12, 8, and 3 patients, respectively. Grading was good, moderate, and poor in 2, 16, and 4 cases, respectively. Tumor grading could not be determined in 1 patient who underwent surgery of the invasive part of the primary tumor elsewhere. Sentinel nodes or nonsentinel nodes or both were positive in 15 of 36 palpatory-positive groins. DSNB alone showed lymphatic spread in 10 inguinal regions. US-guided removal of suspicious nonsentinel nodes revealed 5 further inguinal basins with metastases, which would have been missed by DSNB owing to rerouting or complete blockage of the lymphotropic tracer. So far, no lymph node relapse has been observed in the 12 patients with node negative disease by this combined diagnostic approach with a median follow-up of 42 (16-84) months. The morbidity (postoperative bleeding and prolonged lymphorrhea) associated with this procedure was minor (6%). CONCLUSIONS: The results of this study imply that DSNB combined with US-guided removal of suspicious lymph nodes is a reliable diagnostic approach in patients with penile cancer with palpable inguinal lymph nodes. DSNB alone in these patients leads to a significant false-negative rate. These early and promising results have to be confirmed in larger cohort studies. PMID- 25934563 TI - Unmasking alternative splicing inside protein-coding exons defines exitrons and their role in proteome plasticity. AB - Alternative splicing (AS) diversifies transcriptomes and proteomes and is widely recognized as a key mechanism for regulating gene expression. Previously, in an analysis of intron retention events in Arabidopsis, we found unusual AS events inside annotated protein-coding exons. Here, we also identify such AS events in human and use these two sets to analyse their features, regulation, functional impact, and evolutionary origin. As these events involve introns with features of both introns and protein-coding exons, we name them exitrons (exonic introns). Though exitrons were detected as a subset of retained introns, they are clearly distinguishable, and their splicing results in transcripts with different fates. About half of the 1002 Arabidopsis and 923 human exitrons have sizes of multiples of 3 nucleotides (nt). Splicing of these exitrons results in internally deleted proteins and affects protein domains, disordered regions, and various post translational modification sites, thus broadly impacting protein function. Exitron splicing is regulated across tissues, in response to stress and in carcinogenesis. Intriguingly, annotated intronless genes can be also alternatively spliced via exitron usage. We demonstrate that at least some exitrons originate from ancestral coding exons. Based on our findings, we propose a "splicing memory" hypothesis whereby upon intron loss imprints of former exon borders defined by vestigial splicing regulatory elements could drive the evolution of exitron splicing. Altogether, our studies show that exitron splicing is a conserved strategy for increasing proteome plasticity in plants and animals, complementing the repertoire of AS events. PMID- 25934564 TI - The Art and Science of Diagnosing and Treating Lung and Heart Disease Secondary to Liver Disease. AB - Patients with chronic liver disease are at risk of extrahepatic complications related to cirrhosis and portal hypertension, as well as organ-specific complications of certain liver diseases. These complications can compromise quality of life, while also increasing morbidity and mortality before and after liver transplantation. Patients with chronic liver disease are at risk for pulmonary complications of hepatopulmonary syndrome and portopulmonary syndrome; the cardiac complication fall under the general concept of cirrhotic cardiomyopathy, which can affect systolic and diastolic function, as well as cardiac conduction. In addition, patients with certain diseases are at risk of lung and/or cardiac complications that are specific to the primary disease (ie, emphysema in alpha-1-antitrypsin deficiency) or occur with increased incidence in certain conditions (ie, ischemic heart disease associated with nonalcoholic steatohepatitis). This article focuses on the epidemiology, clinical presentation, pathogenesis, treatment options, and role of transplantation for lung and heart diseases secondary to liver disease, while also highlighting select liver diseases that directly affect the lungs and heart. PMID- 25934565 TI - Atorvastatin protects endothelium by decreasing asymmetric dimethylarginine in dyslipidemia rats. AB - BACKGROUND: Asymmetric Dimethylarginine (ADMA) is an inhibitor of endogenous nitric oxide synthase, which is the key synthase for nitric oxide (NO) production. Whether statins could protect endothelium by reducing ADMA concentration is unclear, and whether this effect is associated with the dose of statins usage is also needed further studied. METHODS: Dyslipidemia rat model was produced by giving high-fat and high-cholesterol diet for 8 weeks. Thereafter, low-dose (5 mg/kg body weight/day) and high-dose (20 mg/kg body weight/day) atorvastatin were orally prescribed for 4 weeks. Parameters of interest including lipid profiles, inflammatory and oxidative markers, NO production and plasma levels of ADMA and ADMA concentration of myocardium were evaluated. Liver enzymes and creatinine kinase (CK) were also detected for safety concern. RESULTS: At baseline, all parameters were comparable between the sham and the dyslipidemia groups. At 8 weeks of dyslipidemia establishment, as compared to the sham group, body weight and lipid profiles were significantly elevated, and plasma levels of C-reactive protein (CRP), malondialdehyde (MDA) and ADMA were concomitantly increased in accompanying with NO reduction in the dyslipidemia groups. With 4 weeks of atorvastatin therapy, as compared to the control group, lipid disorders and NO production were improved, and plasma levels of CRP, MDA and ADMA were significantly decreased in the high-dose atorvastatin group. ADMA concentration of cardiac tissues was also significantly reduced in the high-dose atorvastatin group. Notably, there was a trend to similar effects which did not reach statistical significance in the low-dose atorvastatin group when compared to the control group. Liver enzyme and CK were comparable after 4 weeks of atorvastatin therapy between groups. CONCLUSION: In rats with dyslipidemia, atorvastatin therapy could reduce plasma level of ADMA and ADMA concentration in cardiac tissues, and these effects are associated with the dose of atorvastatin therapy. PMID- 25934566 TI - The anti-inflammatory effects of palmitoylethanolamide (PEA) on endotoxin-induced uveitis in rats. AB - The aim of this study was to investigate the effects of palmitoylethanolamide (PEA), an endogenous fatty acid amide belonging to the family of the N acylethanolamines (NAEs), in rats subjected to endotoxin-induced uveitis (EIU). EIU was induced in male rats by a single footpad injection of 200MUg lipopolysaccharide (LPS). PEA was administered intraperitoneally at 1h before and 7h after injection of LPS. Another group of animals was treated with vehicle. Dexamethasone (DEX) was administered as a positive control. Rats were sacrificed 16h after injection and the eyes tissues were collected for histology, immunohistochemical and western blot analyses. The histological evaluation of the iris-ciliary body showed an increase of neutrophilic infiltration and nuclear modification of vessel of endothelial cells. PEA treatment decreased the inflammatory cell infiltration and improved histological damage of eye tissues. In addition, PEA treatment reduced pro-inflammatory tumor necrosis factor (TNF alpha) levels, protein extravasion and lipid peroxidation. Immunohistochemical analysis for intracellular adhesion molecule (ICAM)-1 and nitrotyrosine showed a positive staining from LPS-injected rats. The degree of staining for ICAM-1 and nitrotyrosine was significantly reduced in eye sections from LPS-injected rats treated with PEA. In addition, an increase of inducible nitric oxide synthase (iNOS) and nuclear factor (NF-kappaB) was also evaluated in inflammed ocular tissues by western blot. PEA strongly inhibited iNOS expression and nuclear NF kappaB translocation. Thus, in this study we demonstrated that PEA reduces the degree of ocular inflammation in a rat model of EIU. PMID- 25934567 TI - Extracellular Ca(2+)-dependent enhancement of cytocidal potency of zoledronic acid in human oral cancer cells. AB - Direct antitumor effects of bisphosphonates (BPs) have been demonstrated in various cancer cells in vitro. However, the effective concentrations of BPs are typically much higher than their clinically relevant concentrations. Oral cancers frequently invade jawbone and may lead to the release of Ca(2+) in primary lesions. We investigated the effects of the combined application of zoledronic acid (ZA) and Ca(2+) on proliferation and apoptosis of oral cancer cells. Human oral cancer cells, breast cancer cells, and colon cancer cells were treated with ZA at a wide range of concentrations in different Ca(2+) concentration environments. Under a standard Ca(2+) concentration (0.6mM), micromolar concentrations of ZA were required to inhibit oral cancer cell proliferation. Increasing extracellular Ca(2+) concentrations greatly enhanced the potency of the ZA cytocidal effect. The ability of Ca(2+) to enhance the cytocidal effects of ZA was negated by the Ca(2+)-selective chelator EGTA. In contrast, the cytocidal effect of ZA was less pronounced in breast and colon cancer cells regardless of whether extracellular Ca(2+) was elevated. In oral cancer cells incubated with 1.6mM Ca(2+), ZA up-regulated mitochondrial Bax expression and increased mitochondrial Ca(2+) uptake. This was associated with decreased mitochondrial membrane potential and increased release of cytochrome c. We suggest that ZA can specifically produce potent cytocidal activity in oral cancer cells in an extracellular Ca(2+)-dependent manner, implying that BPs may be useful for treatment of oral squamous cell carcinoma with jawbone invasion leading to the hypercalcemic state. PMID- 25934568 TI - Angiotensin II increases nerve-evoked contractions in mouse tail artery by a T type Ca(2+) channel-dependent mechanism. AB - Angiotensin II (Ang II) increases sympathetic nerve-evoked contractions of arterial vessels. Here the mechanisms underlying this effect were investigated in mouse tail artery. Isometrically mounted segments of mouse distal tail artery were used to investigate the effects of endothelium denudation, blocking Ca(2+) channels and inhibiting superoxide signalling on Ang II-induced facilitation of nerve-evoked contractions. In addition, in situ amperometry was used to assess effects of Ang II on noradrenaline release. Ang II (0.1-1nM) increased nerve evoked contractions but did not change noradrenaline release. Losartan (Ang II type 1 receptor antagonist), but not PD 123319 (Ang II type 2 receptor antagonist), blocked the facilitatory effect of Ang II on nerve-evoked contractions. Ang II increased vascular muscle reactivity to phenylephrine and UK 14304 (alpha1- and alpha2-adrenoceptor agonists, respectively). Endothelial denudation increased nerve-evoked contractions and reduced the facilitatory effect of Ang II on these responses. Efonidipine (L- and T-type Ca(2+) channel blocker) and NNC 55-0396 (T-type Ca(2+) channel blocker) also attenuated this effect of Ang II, while nifedipine (L-type Ca(2+) channel blocker) did not. Blockers of superoxide generation/signalling did not change the facilitatory effect of Ang II on nerve-evoked contractions. The findings indicate that Ang II increases the contribution of T-type Ca(2+) channels to neural activation of the vascular muscle. In addition, Ang II appears to reduce the inhibitory influence of the endothelium on nerve-evoked contractions. PMID- 25934569 TI - PJ-34 inhibits PARP-1 expression and ERK phosphorylation in glioma-conditioned brain microvascular endothelial cells. AB - Inhibitors of PARP-1(Poly(ADP-ribose) polymerase-1) act by competing with NAD(+), the enzyme physiological substrate, which play a protective role in many pathological conditions characterized by PARP-1 overactivation. It has been shown that PARP-1 also promotes tumor growth and progression through its DNA repair activity. Since angiogenesis is an essential requirement for these activities, we sought to determine whether PARP inhibition might affect rat brain microvascular endothelial cells (GP8.3) migration, stimulated by C6-glioma conditioned medium (CM). Through wound-healing experiments and MTT analysis, we demonstrated that PARP-1 inhibitor PJ-34 [N-(6-Oxo-5,6-dihydrophenanthridin-2-yl)-N,N dimethylacetamide] abolishes the migratory response of GP8.3 cells and reduces their viability. PARP-1 also acts in a DNA independent way within the Extracellular-Regulated-Kinase (ERK) signaling cascade, which regulates cell proliferation and differentiation. By western analysis and confocal laser scanning microscopy (LSM), we analyzed the effects of PJ-34 on PARP-1 expression, phospho-ERK and phospho-Elk-1 activation. The effect of MEK (mitogen-activated protein-kinase-kinase) inhibitor PD98059 (2-(2-Amino-3-methoxyphenyl)-4 H-1 benzopyran-4-one) on PARP-1 expression in unstimulated and in CM-stimulated GP8.3 cells was analyzed by RT-PCR. PARP-1 expression and phospho-ERK activation were significantly reduced by treatment of GP8.3 cells with PJ-34 or PD98059. By LSM, we further demonstrated that PARP-1 and phospho-ERK are coexpressed and share the same subcellular localization in GP8.3 cells, in the cytoplasm as well as in nucleoplasm. Based on these data, we propose that PARP-1 and phospho-ERK interact in the cytosol and then translocate to the nucleus, where they trigger a proliferative response. We also propose that PARP-1 inhibition blocks CM-induced endothelial migration by interfering with ERK signal-transduction pathway. PMID- 25934570 TI - Negative effect of serotonin-norepinephrine reuptake inhibitor therapy on rat bone tissue after orchidectomy. AB - Our goal was to determine if venlafaxine has a negative effect on bone metabolism. Rats were divided into three groups. The sham-operated control group (SHAM), the control group after orchidectomy (ORX), and the experimental group after orchidectomy received venlafaxine (VEN ORX) in standard laboratory diet (SLD) for 12 weeks. Bone mineral content (BMC) was measured by dual energy X-ray absorptiometry (DXA). Bone marker concentrations of carboxy-terminal cross linking telopeptide of type I collagen (CTX-I), osteoprotegerin (OPG), amino terminal propeptide of procollagen type I (P1NP), bone alkaline phosphatase (BALP), sclerostin and bone morphogenetic protein 2 (BMP-2) were examined in bone homogenate. The femurs were used for biomechanical testing. Compared to the ORX group we found lower BMD in the diaphysis area of the femur in the VEN ORX group, suggesting a preferential effect on cortical bone. Of the bone metabolism markers, there was significant decrease (ORX control group versus VEN ORX experimental group) in BALP levels and increase in sclerostin and CTX-I levels, suggesting a decrease in osteoid synthesis and increased bone resorption. The results suggest that the prolonged use of venlafaxine may have a negative effect on bone metabolism. Further studies are warranted to establish whether venlafaxine may have a clinically significant adverse effect on bone. PMID- 25934571 TI - Acute stress blocks the caffeine-induced enhancement of contextual memory retrieval in mice. AB - This study investigated in mice the dose-effect of caffeine on memory retrieval in non-stress and stress conditions. C57 Bl/6 Jico mice learned two consecutive discriminations (D1 and D2) in a four-hole board which involved either distinct contextual (CSD) or similar contextual (SSD) cues. All mice received an i.p. injection of vehicle or caffeine (8, 16 or 32mg/kg) 30min before the test session. Results showed that in non-stress conditions, the 16mg/kg caffeine dose induced a significant enhancement of D1 performance in CSD but not in SSD. Hence, we studied the effect of an acute stress (electric footshocks) administered 15min before the test session on D1 performance in caffeine-treated mice. Results showed that stress significantly decreased D1 performance in vehicle-treated controls and the memory-enhancing effect induced by the 16mg/kg caffeine dose in non-stress condition is no longer observed. Interestingly, whereas caffeine treated mice exhibited weaker concentrations of plasma corticosterone as compared to vehicles in non-stress condition, stress significantly increased plasma corticosterone concentrations in caffeine-treated mice which reached similar level to that of controls. Overall, the acute stress blocked both the endocrinological and memory retrieval enhancing effects of caffeine. PMID- 25934572 TI - Baicalin-induced Akt activation decreases melanogenesis through downregulation of microphthalmia-associated transcription factor and tyrosinase. AB - Scutellaria baicalensis has been used topically to treat inflammatory skin diseases in traditional East Asian medicine. Because post-inflammatory hyperpigmentation of the skin is difficult to manage, we investigated the effects of baicalin, a major component of S. baicalensis, on melanin synthesis in Mel-Ab cells. Our data showed that baicalin significantly inhibited melanin production and tyrosinase activity in a dose-dependent fashion, but it did not directly influence tyrosinase activity. Moreover, baicalin treatment triggered decreases in both mRNA and protein levels of microphthalmia-associated transcription factor (MITF) and tyrosinase. Although AMP-activated protein kinase (AMPK) and extracellular signal-regulated kinase (ERK) activation were induced in baicalin treated Mel-Ab cells, they were not responsible for baicalin-induced hypopigmentation. Because the Akt pathway is also known to be involved in regulation of melanogenic protein expression and melanin synthesis, we examined the effects of baicalin on the Akt pathway. Our results showed that baicalin treatment stimulated Akt activation. Treatment with LY294002, a specific Akt inhibitor, restored baicalin-induced melanogenesis inhibition and abolished MITF and tyrosinase downregulation by baicalin. Taken together, our data suggest that Akt activation by baicalin inhibits melanin production via downregulation of MITF and tyrosinase in Mel-Ab cells. PMID- 25934573 TI - MicroRNA let-7c-5p protects against cerebral ischemia injury via mechanisms involving the inhibition of microglia activation. AB - The present study was designed to reveal the potential role of let-7c-5p, a highly conserved miRNA in stroke. We found that the content of let-7c-5p was significantly decreased in the plasma of patients with ischemic stroke as well as in experimental animals. Moreover, we also observed a significant decrease of let 7c-5p in ipsilateral cortex and striatum in mice that were subjected to middle cerebral artery occlusion (MCAO) at 24h reperfusion. Overexpression of let-7c-5p via ICV injection decreased the infarction volume and attenuated the neurological deficits, and most interestingly, inhibited microglial activation. To further explore the mechanism, we checked let-7c-5p expression in BV2 cells and primary microglia in an OGD condition and in LPS-induced microglial activation. The results indicated that decreased let-7c-5p was evidenced in the activated microglia. Overexpression of let-7c-5p in BV2 cells remarkably inhibited the microglial activation. The inhibition of microglial activation by overexpression of let-7c-5p was also observed in mice with experimental stroke, which is in line with the decreased infarction volume and improved neurological deficits. We identified that let-7c-5p directly targeted to the 3'-untranslated region of the caspase 3 mRNA to reduce caspase 3 levels, which may underline the miRNA - modulated microglial activity. The present study revealed that suppression of microglia activation by let-7c-5p overexpression may be involved in the protection effects of ischemic damage. The mechanism may include the miRNA mediated caspase 3 pathway. PMID- 25934574 TI - Chimeric MicroRNA-1291 Biosynthesized Efficiently in Escherichia coli Is Effective to Reduce Target Gene Expression in Human Carcinoma Cells and Improve Chemosensitivity. AB - In contrast to the growing interests in studying noncoding RNAs (ncRNAs) such as microRNA (miRNA or miR) pharmacoepigenetics, there is a lack of efficient means to cost effectively produce large quantities of natural miRNA agents. Our recent efforts led to a successful production of chimeric pre-miR-27b in bacteria using a transfer RNA (tRNA)-based recombinant RNA technology, but at very low expression levels. Herein, we present a high-yield expression of chimeric pre-miR 1291 in common Escherichia coli strains using the same tRNA scaffold. The tRNA fusion pre-miR-1291 (tRNA/mir-1291) was then purified to high homogeneity using affinity chromatography, whose primary sequence and post-transcriptional modifications were directly characterized by mass spectrometric analyses. Chimeric tRNA/mir-1291 was readily processed to mature miR-1291 in human carcinoma MCF-7 and PANC-1 cells. Consequently, recombinant tRNA/mir-1291 reduced the protein levels of miR-1291 target genes, including ABCC1, FOXA2, and MeCP2, as compared with cells transfected with the same doses of control methionyl-tRNA scaffold with a sephadex aptamer (tRNA/MSA). In addition, tRNA-carried pre-miR 1291 suppressed the growth of MCF-7 and PANC-1 cells in a dose-dependent manner, and significantly enhanced the sensitivity of ABCC1-overexpressing PANC-1 cells to doxorubicin. These results indicate that recombinant miR-1291 agent is effective in the modulation of target gene expression and chemosensitivity, which may provide insights into high-yield bioengineering of new ncRNA agents for pharmacoepigenetics research. PMID- 25934575 TI - Hydroxylation and N-dechloroethylation of Ifosfamide and deuterated Ifosfamide by the human cytochrome p450s and their commonly occurring polymorphisms. AB - The hydroxylation and N-dechloroethylation of deuterated ifosfamide (d4IFO) and ifosfamide (IFO) by several human P450s have been determined and compared. d4IFO was synthesized with deuterium at the alpha and alpha' carbons to decrease the rate of N-dechloroethylation and thereby enhance hydroxylation of the drug at the 4' position. The purpose was to decrease the toxic and increase the efficacious metabolites of IFO. For all of the P450s tested, hydroxylation of d4IFO was improved and dechloroethylation was reduced as compared with nondeuterated IFO. Although the differences were not statistically significant, the trend favoring the 4'-hydroxylation pathway was noteworthy. CYP3A5 and CYP2C19 were the most efficient enzymes for catalyzing IFO hydroxylation. The importance of these enzymes in IFO metabolism has not been reported previously and warrants further investigation. The catalytic ability of the common polymorphisms of CYP2B6 and CYP2C9 for both reactions were tested with IFO and d4IFO. It was determined that the commonly expressed polymorphisms CYP2B6*4 and CYP2B6*6 had reduced catalytic ability for IFO compared with CYP2B6*1, whereas CYP2B6*7 and CYP2B6*9 had enhanced catalytic ability. As with the wild-type enzymes, d4IFO was more readily hydroxylated by the polymorphic variants than IFO, and d4IFO was not dechloroethylated by any of the polymorphic forms. We also assessed the use of specific inhibitors of P450 to favor hydroxylation in human liver microsomes. We were unable to separate the pathways with these experiments, suggesting that multiple P450s are responsible for catalyzing both metabolic pathways for IFO, which is not observed with the closely related drug cyclophosphamide. PMID- 25934577 TI - Pharmacokinetics and Pharmacodynamics of the SGLT2 Inhibitor Remogliflozin Etabonate in Subjects with Mild and Moderate Renal Impairment. AB - Remogliflozin etabonate (RE), the prodrug of remogliflozin, is an inhibitor of the sodium glucose-dependent renal transporter 2 (SGLT2), enabling urinary glucose excretion to reduce hyperglycemia for the treatment of type 2 diabetes. Renal function declines more rapidly in patients with type 2 diabetes, making it difficult or unsafe to continue on some antidiabetic therapeutics. In an initial effort to understand the potential utility of RE in patients with renal impairment, the pharmacodynamics and pharmacokinetics of RE were evaluated in a single oral dose (250 mg) in patients with renal impairment as compared with control subjects. As shown by pharmacodynamic measurements of urinary glucose excretion, there was no clinically significant reduction in the ability of remogliflozin to inhibit SGLT2. In addition, there were no significant changes in area under the curve (from 0 to infinity) or half-life of remogliflozin, suggesting renal impairment does not alter the pharmacokinetics of remogliflozin. In contrast to other SGLT2 inhibitors which accumulate in patients with renal impairment, adjustment of the dosage of RE in subjects with mild or moderate renal impairment is not indicated based on the observations in this study. PMID- 25934576 TI - Activity Suppression Behavior Phenotype in SULT4A1 Frameshift Mutant Zebrafish. AB - Since its identification in 2000, sulfotransferase (SULT) 4A1 has presented an enigma to the field of cytosolic SULT biology. SULT4A1 is exclusively expressed in neural tissue, is highly conserved, and has been identified in every vertebrate studied to date. Despite this singular level of conservation, no substrate or function for SULT4A1 has been identified. Previous studies demonstrated that SULT4A1 does not bind the obligate sulfate donor, 3' phosphoadenosine-5'-phosphosulfate, yet SULT4A1 is classified as a SULT superfamily member based on sequence and structural similarities to the other SULTs. In this study, transcription activator-like effector nucleases were used to generate heritable mutations in the SULT4A1 gene of zebrafish. The mutation (SULT4A1(Delta8)) consists of an 8-nucleotide deletion within the second exon of the gene, resulting in a frameshift mutation and premature stop codon after 132 AA. During early adulthood, casual observations were made that mutant zebrafish were exhibiting excessively sedentary behavior during the day. These observations were inconsistent with published reports on activity in zebrafish that are largely diurnal organisms and are highly active during the day. Thus, a decrease in activity during the day represents an abnormal behavior and warranted further systematic analysis. EthoVision video tracking software was used to monitor activity levels in wild-type (WT) and SULT4A1(Delta8/Delta8) fish over 48 hours of a normal light/dark cycle. SULT4A1(Delta8/Delta8) fish were shown to exhibit increased inactivity bout length and frequency as well as a general decrease in daytime activity levels when compared with their WT counterparts. PMID- 25934578 TI - The feasibility of using combined TiO2 photocatalysis oxidation and MBBR process for advanced treatment of biologically pretreated coal gasification wastewater. AB - The study examined the feasibility of using combined heterogeneous photocatalysis oxidation (HPO) and moving bed biofilm reactor (MBBR) process for advanced treatment of biologically pretreated coal gasification wastewater (CGW). The results indicated that the TOC removal efficiency was significantly improved in HPO. Gas chromatography-mass spectrometry (GC-MS) analysis indicated that the HPO could be employed to eliminate bio-refractory and toxic compounds. Meanwhile, the BOD5/COD of the raw wastewater was increased from 0.08 to 0.49. Furthermore, in the integration of TiO2 photocatalysis oxidation and MBBR process, the effluent of COD, BOD5, TOC, NH4(+)-N and TN were 22.1 mg/L, 1.1 mg/L, 11.8 mg/L, 4.1mg/L and 13.7 mg/L, respectively, which all met class-I criteria of the Integrated Wastewater Discharge Standard (GB18918-2002, China). The total operating cost was 2.8CNY/t. Therefore, there is great potential for the combined system in engineering applications as a final treatment for biologically pretreated CGW. PMID- 25934579 TI - High consistency cellulase treatment of hardwood prehydrolysis kraft based dissolving pulp. AB - For enzymatic treatment of dissolving pulp, there is a need to improve the process to facilitate its commercialization. For this purpose, the high consistency cellulase treatment was conducted based on the hypothesis that a high cellulose concentration would favor the interactions of cellulase and cellulose, thus improves the cellulase efficiency while decreasing the water usage. The results showed that compared with a low consistency of 3%, the high consistency of 20% led to 24% increases of cellulase adsorption ratio. As a result, the viscosity decrease and Fock reactivity increase at consistency of 20% were enhanced from 510 mL/g and 70.3% to 471 mL/g and 77.6%, respectively, compared with low consistency of 3% at 24h. The results on other properties such as alpha cellulose, alkali solubility and molecular weight distribution also supported the conclusion that a high consistency of cellulase treatment was more effective than a low pulp consistency process. PMID- 25934580 TI - Negotiating Care in the Special Care Nursery: Parents' and Nurses' Perceptions of Nurse-Parent Communication. AB - OBJECTIVE: Nursing staff are an important source of support for parents of a hospitalized preterm infant. This study aimed to describe parents' and nurses' perceptions of communicating with each other in the context of the special care nursery. METHOD: A qualitative descriptive design was employed. Thirty two parents with a newborn admitted to one of two special care nurseries in Queensland, Australia participated, and 12 nurses participated in semi-structured interviews. Thematic analysis was used to analyze the interviews. RESULTS: Nurses and parents focused on similar topics, but their perceptions differed. Provision of information and enabling parenting were central to effective communication, supported by an appropriate interpersonal style by nurses. Parents described difficulties accessing or engaging nurses. Managing enforcement of policies was a specific area of difficulty for both parents and nurses. CONCLUSION: The findings indicated a tension between providing family-centered care that is individualized and based on family needs and roles, and adhering to systemic nursery policies. PMID- 25934581 TI - Pharmacogenetics of abacavir hypersensitivity: A systematic review and meta analysis of the association with HLA-B*57:01. PMID- 25934582 TI - Intercellular: local and systemic actions of skeletal muscle PGC-1s. AB - Physical exercise promotes complex adaptations in skeletal muscle that benefit various aspects of human health. Many of these adaptations are coordinated at the gene expression level by the concerted action of transcriptional regulators. Peroxisome proliferator-activated receptor gamma (PPARgamma) coactivator-1 (PGC 1) proteins play a prominent role in skeletal muscle transcriptional reprogramming induced by numerous stimuli. PGC-1s are master coactivators that orchestrate broad gene programs to modulate fuel supply and mitochondrial function, thus improving cellular energy metabolism. Recent studies unveiled novel biological functions for PGC-1s that extend well beyond skeletal muscle bioenergetics. Here we review recent advances in our understanding of PGC-1 actions in skeletal muscle, with special focus on their systemic effects. PMID- 25934583 TI - The effect of medial temporal lobe epilepsy on visual memory encoding. AB - Effective visual memory encoding, a function important for everyday functioning, relies on episodic and semantic memory processes. In patients with medial temporal lobe epilepsy (MTLE), memory deficits are common as the structures typically involved in seizure generation are also involved in acquisition, maintenance, and retrieval of episodic memories. In this study, we used group independent component analysis (GICA) combined with Granger causality analysis to investigate the neuronal networks involved in visual memory encoding during a complex fMRI scene-encoding task in patients with left MTLE (LMTLE; N=28) and in patients with right MTLE (RMTLE; N=18). Additionally, we built models of memory encoding in LMTLE and RMTLE and compared them with a model of healthy memory encoding (Nenert et al., 2014). For those with LMTLE, we identified and retained for further analyses and model generation 7 ICA task-related components that were attributed to four different networks: the frontal and posterior components of the DMN, visual network, auditory-insular network, and an "other" network. For those with RMTLE, ICA produced 9 task-related components that were attributed to the somatosensory and cerebellar networks in addition to the same networks as in patients with LMTLE. Granger causality analysis revealed group differences in causality relations within the visual memory network and MTLE-related deviations from normal network function. Our results demonstrate differences in the networks for visual memory encoding between those with LMTLE and those with RMTLE. Consistent with previous studies, the organization of memory encoding is dependent on laterality of seizure focus and may be mediated by functional reorganization in chronic epilepsy. These differences may underlie the observed differences in memory abilities between patients with LMTLE and patients with RMTLE and highlight the modulating effects of epilepsy on the network for memory encoding. PMID- 25934584 TI - Seizure metaphors in children with epilepsy: A study based on a multiple-choice self-report questionnaire. AB - The advantages of metaphorical representation are pointed out in many fields of clinical research (e.g. cancer, HIV, psychogenic nonepileptic seizures). This study aimed at offering a novel contribution showing how children with epilepsy describe the symptomatology of their seizure experiences by means of particular kinds of cognitive metaphors. Twenty-three children with idiopathic generalized epilepsy and thirty-one healthy children were recruited for this study and interviewed with a multiple-choice questionnaire asking them to describe their epileptic seizures by means of suitable metaphors. A psychologist blinded to medical diagnosis assessed and categorized all metaphors. By considering the 89 metaphors produced by the children with epilepsy and the 147 ones by the healthy controls, Agent/Force was the primary metaphor assessed by children with epilepsy, followed by Event/Situation as the second preference. Moreover, comparing the results of the control group with those of the subjects with epilepsy, it was found that controls were oriented towards selecting exogenous forces, while subjects with epilepsy tended to select endogenous forces. In particular, children with epilepsy showed a peculiar preference for an endogenous force resembling the waggle metaphor, which is similar to the effect of a quake's shaking (earthquake or seaquake). The metaphors identified by this research are a useful resource to better understand the seizure experiences of patients with epilepsy, helping to improve clinical treatment. PMID- 25934585 TI - Ischemic-hypoxic mechanisms leading to hippocampal dysfunction as a consequence of status epilepticus. AB - Status epilepticus (SE) is one of the recognized primary precipitating events that can lead to temporal lobe epilepsy (TLE) associated with hippocampal sclerosis. This type of epilepsy is characterized by poor response to drug treatment, often requiring surgical intervention to remove the mesial temporal regions involved in the seizure onset. However, even neurosurgery may not be completely successful. Thus, the prevention of hippocampal damage and epileptogenesis is currently evaluated as a possible alternative therapeutic approach to prevent the development of pharmacoresistant TLE. Lines of evidence suggest that ischemic-hypoxic lesions might occur in different brain regions, including the hippocampus, during SE. Especially in the hippocampal CA3 region, an ischemic-like lesion develops in the stratum lacunosum-moleculare and is mainly characterized by a loss of astrocytes and neuronal processes and increased immunostaining of pimonidazole which probes areas exposed to hypoxia. Interestingly, these mechanisms can contribute to neuronal cell loss and may be counteracted by drugs that can afford vascular protection, as in the case of ligands of the ghrelin receptor. Notably, some of the ghrelin receptor ligands possess a double edge effect, since they are anticonvulsant and vascular protective, thus, potentially representing new tools to counteract the consequences of SE. This article is part of a Special Issue entitled "Status Epilepticus". PMID- 25934586 TI - Hyperventilation and photic stimulation are useful additions to a placebo-based suggestive seizure induction protocol in patients with psychogenic nonepileptic seizures. AB - The early and definitive diagnosis of psychogenic nonepileptic seizures is a common challenge in epileptology practice. Suggestive seizure induction is a valuable tool to aid the differentiation between epileptic and psychogenic nonepileptic seizures, especially when long-term video-EEG monitoring is inconclusive or unavailable. In this retrospective analysis, we compared the diagnostic yield of a classical, placebo-based induction protocol with that of an extended protocol that includes hyperventilation and photic stimulation as means of suggestion while also implementing more open, standardized patient information. We investigated whether the diversification of suggestive seizure induction has an effect on diagnostic yield and whether it preempts the administration of placebo. Data from 52 patients with confirmed psychogenic nonepileptic seizures were analyzed. While suggestive seizure induction using only placebo-based suggestion provoked a typical event in 13 of 20 patients (65%), the extended protocol was positive in 27 of 34 cases (84%); this improvement was not significant (p=0.11). Noninvasive suggestion techniques accounted for 78% of inductions, avoiding placebo administration in a majority of patients. Still, placebo remains an important part of suggestive seizure induction, responsible for 22% (6 out of 27) of successful inductions using our extended protocol. Our study demonstrates that the diversification of suggestive seizure induction is feasible and beneficial for both patients and diagnosticians. PMID- 25934587 TI - The relationship between epilepsy and religiosity illustrated by the story of the visionary mystic Wise-Knut. AB - The story of Wise-Knut is remarkable. He was born in a poor mountain district in Norway in 1792 and lived for 84years. He had severe and untreated epilepsy with apparent ictal, postictal, and interictal religious symptoms. He heard voices and had religious delusions; a spiritual awakening after a seizure cluster was a turning point in his life. Contemporary biographers have narrated his major life events in detail, but without a precise separation between ictal and postictal spiritual symptoms. Religious and supernatural significance was attributed to his experiences; he himself believed that his extraordinary abilities were a gift from God: "The prophets have had it like myself." His story corroborates the impression that epilepsy may have had a considerable role in the history of religions. However, apart from anecdotes on visionary and healing abilities, his biographies contain nothing that is miraculous or incredible. He falls into the line of various mystics and religious figures of the past that are currently thought to have had epilepsy. Apparently, the advancing understanding of epilepsy and its complications have influenced the dynamic balance between faith, superstition, and rationalism. PMID- 25934588 TI - The demise of Archbishop Wolf Dietrich--A historical note on a fatal status epilepticus documented at Salzburg in 1617. AB - INTRODUCTION: Wolf Dietrich of Raitenau (WD) ruled the archiepiscopal Salzburg from March 2nd 1587 to December 17th 1611. He was condemned by his successor Archbishop Markus Sittikus of Hohenems to spend his last years imprisoned at the Fortress Hohensalzburg, where he died on January 16th 1617. This historical note describes the causes of his death. MATERIALS AND METHODS: The original Latin handwriting, including the detailed medical history and the autopsy of the Archbishop's body performed by his personal physician, was analyzed in conjunction with historical handwritings provided by St. Peter's Abbey, Salzburg handwriting assigned to Markus Sittikus. RESULTS: Wolf Dietrich of Raitenau had his first well-documented left hemispheric stroke in winter 1604/05. He had palsy of his right arm, was unable to write, and, therefore, used a stamp instead of his signature until October 1605. After another stroke, right hemispheric in origin with persisting palsy of his left arm ["leva corporis pars iam pridem simili ex apoplectico assultu in paralysin resoluta"], he developed symptomatic epilepsy with recurring seizures ["epileptico insultu quo etiam alias correptus est"]. On January 15th 1617, he suffered from a secondarily generalized convulsive status epilepticus ["toto corpore convellitur epileptico insultu"] with stertorous breathing and distortion of his face ["spuma stertore insigni faciei perversione"] and was unconscious for 8h. He recovered from coma and showed dysphagia, buccofacial apraxia ["abolitam diglutiendi facultatem"], reversible speech disturbance ["accisa etiam verba loqui"], and left-sided hemiplegia ["leva corporis pars... immobilis prorsus est reddita"]. The following day, he had speech disturbances, and he died at noon. His autopsy showed large but intact liver ["hepar magnum sanum"] and heart ["cor magnum in quo lapsus nullus"]. There was intrapulmonal mucus ["pituita imbutus"], and part of the lungs adhered to its pleura. He had five kidney stones and a partly cirrhotic spleen. The cause of his death was assumed to be intracerebral ["causa mortis in capite requienda fuisset"]. DISCUSSION: The terminal suffering of Wolf Dietrich of Raitenau is the first witnessed case report on a fatal status epilepticus in Salzburg. Most likely, he suffered from vascular epilepsy due to a right hemispheric stroke, leading to status epilepticus with left-sided Todd's palsy and speech disturbances. An acute symptomatic etiology of this disease cannot be ruled out, as for religious reasons, the Archbishop's brain was not autopsied. CONCLUSION: Meticulous medical reporting including autopsy was already available in Salzburg in 1617, and the symptomatic etiology of epilepsy was diagnosed correctly. This article is part of a Special Issue entitled "Status Epilepticus". PMID- 25934590 TI - Web-based intervention improves social acknowledgement and disclosure of trauma, leading to a reduction in posttraumatic stress disorder symptoms. AB - This study aims to investigate the effectiveness of web-based intervention on social acknowledgement and disclosure of trauma and to examine the mediating effect of the improvement in social acknowledgement and disclosure of trauma on the reduction of posttraumatic stress disorder symptoms. A randomized controlled trial was used, with 21 participants in a web-based intervention group and 29 participants in a wait-list control group completing a pre-test and post-test. Results showed that social acknowledgement and disclosure of trauma improved significantly after 1-month intervention, and this improvement mediated the reduction in the posttraumatic stress disorder symptoms. Implications and limitations of this study are discussed. PMID- 25934589 TI - The OB-fold domain 1 of human POT1 recognizes both telomeric and non-telomeric DNA motifs. AB - The POT1 protein plays a critical role in telomere protection and telomerase regulation. POT1 binds single-stranded 5'-TTAGGGTTAG-3' and forms a dimer with the TPP1 protein. The dimer is recruited to telomeres, either directly or as part of the Shelterin complex. Human POT1 contains two Oligonucleotide/Oligosaccharide Binding (OB) fold domains, OB1 and OB2, which make physical contact with the DNA. OB1 recognizes 5'-TTAGGG whereas OB2 binds to the downstream TTAG-3'. Studies of POT1 proteins from other species have shown that some of these proteins are able to recognize a broader variety of DNA ligands than expected. To explore this possibility in humans, we have used SELEX to reexamine the sequence-specificity of the protein. Using human POT1 as a selection matrix, high-affinity DNA ligands were selected from a pool of randomized single-stranded oligonucleotides. After six successive rounds of selection, two classes of high-affinity targets were obtained. The first class was composed of oligonucleotides containing a cognate POT1 binding sites (5'-TTAGGGTTAG-3'). The second and more abundant class was made of molecules that carried a novel non-telomeric consensus: 5' TNCANNAGKKKTTAGG-3' (where K = G/T and N = any base). Binding studies showed that these non-telomeric sites were made of an OB1-binding motif (TTAGG) and a non telomeric motif (NT motif), with the two motifs recognized by distinct regions of the OB1 domain. POT1 interacted with these non-telomeric binding sites with high affinity and specificity, even when bound to its dimerization partner TPP1. This intrinsic ability of POT1 to recognize NT motifs raises the possibility that the protein may fulfill additional functions at certain non-telomeric locations of the genome, in perhaps gene transcription, replication, or repair. PMID- 25934591 TI - [Are the UroLift((r)) implants an alternative for the treatment of benign prostatic hyperplasia? Short-term results and predictive factors of failure]. AB - OBJECTIVE: To report the results of UroLift((r)) implants after a 2-year experience in the technique. PATIENTS AND METHODS: The procedure was proposed between February 2012 and April 2014 in patients with symptomatic benign prostatic hyperplasia, as an alternative to standard endoscopic ablation techniques. Evaluation of BPH related symptoms relied on the IPSS and IPSS-QoL self-questionnaires, as well as on maximum uroflow (Qmax). Evaluation of erectile and ejaculatory functions relied on the IIEF5 and MSHQ-EjD self-questionnaires, respectively. RESULTS: A total of 23 patients were treated during this period. Median age was 66 years [53-78]. Median prostate volume was 38mL [20-80]. Preoperative IPSS and IPSS-QoL were 20 [9-29] and 5 [3-6], respectively. No severe adverse event was observed postoperatively. Median follow-up was 14 [5-31] months. At the end of follow-up, 19 (83%) patients reported sustained symptomatic improvement without any additional treatment. Median IPSS and IPSS-QoL were improved significantly (11 [1-27] and 2 [0-6], P<0.0001), with however no significant improvement in Qmax. Four patients needed additional treatment during the first postoperative year. Among them, 3 had a prostate volume>60mL. No patient reported retrograde ejaculation or worsened erectile function. CONCLUSIONS: UroLift((r)) implants allowed symptomatic improvement in more than 80% of the patients after 1-year follow-up. A high prostate volume may potentially be predictive of symptomatic failure. LEVEL OF PROOF: 5. PMID- 25934592 TI - [Evolution of surgical activity related to the female stress urinary incontinence (SUI) with regard to the ageing of the French female population]. AB - INTRODUCTION AND OBJECTIVE: One of the main factors associated with urinary incontinence of women is aging. The total female French population seems to grow for 10 years, with more and more women over 60 years. The authors wanted to assess the evolution of the surgical activity related to the treatment of the urinary incontinence with regard to the aging of the female French population. MATERIALS AND METHODS: The number of surgical procedures for the treatment of stress urinary incontinence was obtained by querying the database of the Agence Technique de l'Information sur l'Hospitalisation (ATIH) for the period 2002-2013. The Catalogue Des Actes Medicaux (CDAM) and the Classification Commune des Actes Medicaux (CCAM) were used to extract the codes relating to surgery of the female urinary incontinence during this period. Demographics data were obtained from the website of the National Institute of Demographic studies (INED). The results were then compared. RESULTS: On the 2002-2010 period, the total female French population increased by 5%. In the class of age over 60 years, it increased by 12.7%. Support-related surgical activity continued to decrease until 2013 with 17.3% interventions less than in 2002. CONCLUSION: The evolution of surgical activity does not seem to follow the evolution of the ageing of the population, even if age is a risk factor essential for the female urinary incontinence. The improvement of risk factors (gynecological, obstetrical), over the past decade, could explain this evolution. LEVEL OF EVIDENCE: 3. PMID- 25934593 TI - uSIMPK. An Excel for Windows-based simulation program for instruction of basic pharmacokinetics principles to pharmacy students. AB - Pharmacokinetics can be a challenging topic to teach due to the complex relationships inherent between physiological parameters, mathematical descriptors and equations, and their combined impact on shaping the blood fluid concentration vs. time curves of drugs. A computer program was developed within Microsoft Excel for Windows, designed to assist in the instruction of basic pharmacokinetics within an entry-to-practice pharmacy class environment. The program is composed of a series of spreadsheets (modules) linked by Visual Basic for Applications, intended to illustrate the relationships between pharmacokinetic and in some cases physiological parameters, doses and dose rates and the drug blood fluid concentration vs. time curves. Each module is accompanied by a simulation user's guide, prompting the user to change specific independent parameters and then observe the impact of the change(s) on the drug concentration vs. time curve and on other dependent parameters. "Slider" (or "scroll") bars can be selected to readily see the effects of repeated changes on the dependencies. Topics covered include one compartment single dose administration (iv bolus, oral, short infusion), intravenous infusion, repeated doses, renal and hepatic clearance, nonlinear elimination, two compartment model, plasma protein binding and the relationship between pharmacokinetics and drug effect. The program has been used in various forms in the classroom over a number of years, with positive ratings generally being received from students for its use in the classroom. PMID- 25934594 TI - Ovarian volume in normal and hyperandrogenic adolescent women. AB - OBJECTIVE: To study the threshold for increased ovarian size during different periods of adolescence. DESIGN: Cross sectional study with retrospective analysis. SETTING: University center. PATIENT(S): A total of 146 hyperandrogenic adolescent women and 72 healthy adolescent controls. INTERVENTION(S): Intravaginal or transabdominal ovarian sonography. MAIN OUTCOME MEASURE(S): Determination of normal ovarian size during the different phases of adolescence calculated using the ellipsoid formula; calculation of threshold for increased ovarian size during different adolescent gynecologic ages and prevalence of increased ovarian size for hyperandrogenic girls at different gynecologic ages. RESULT(S): In adolescent women, the threshold for increased ovarian size was 11.5 cm(3) during first 2 years from menarche, 10.5 cm(3) during the third year from menarche, and 10 cm(3) during the fourth and fifth years from menarche. The prevalence of increased ovarian size in hyperandrogenic adolescents was around 50% from the third to fifth years from menarche and 35% during the first 2 years from menarche. CONCLUSION(S): After the first 2 years from menarche, the thresholds for increased ovarian size are similar to those used among adults. During first 2 years from menarche, ovarian size is larger, and differentiation between normal or increased ovarian sizes may be more difficult. In hyperandrogenic adolescent patients, the prevalence of increased ovarian size is relatively low (ranging from 35% to 50% during the different periods of adolescence). In these patients, increased ovarian size may have low sensitivity as a criterion for the diagnosis of possible polycystic ovary syndrome. PMID- 25934596 TI - Introduction: Fertility and longevity. AB - The authors of this Views and Reviews outline the current understanding of the association between fertility and longevity. Natural fertility in populations that did not employ any contraception make up the model that attempts to define this relationship. Longevity seems to be increased in women with late-age conceptions and may be the result of genetic or environmental factors or both. A new concept is suggested that demonstrates the potential rejuvenating effect of pregnancy on older pregnant mothers. The link between infertility itself and conceptions at an older age with morbidity and mortality is summarized. PMID- 25934597 TI - Natural fertility and longevity. AB - Much empirical work suggests an association between fertility patterns and longevity. I review this association, focusing on natural fertility populations and emphasizing the role of both the timing and the intensity of fertility. Overall, it appears that although age at last reproduction routinely correlates with post-reproductive longevity, suggesting a slower rate of senescence among late fertile women, the same is not true for age at first reproduction and parity. I discuss some of the conceptual and methodologic issues, as well as the sources of the biases, that have been a persistent feature of this body of research. I conclude by suggesting avenues of research that could be initiated or pursued in the area. PMID- 25934595 TI - Cardiomyopathy in a dish: using human inducible pluripotent stem cells to model inherited cardiomyopathies. AB - Inherited cardiomyopathies, including hypertrophic cardiomyopathy, dilated cardiomyopathies, arrythmogenic right ventricular cardiomyopathy, and other inherited forms of heart failure, represent a unique set of genetically defined cardiovascular disease processes. Unraveling the molecular mechanisms of these deadly forms of human heart disease has been challenging, but recent groundbreaking scientific advances in stem cell technology have allowed for the generation of patient-specific human inducible stem cell (hiPSC)-derived cardiomyocytes (CMs). hiPSC-derived CMs retain the genetic blueprint of the patient, they can be maintained in culture, and they recapitulate the phenotypic characteristics of the disease in vitro, thus serving as a disease in a dish. This review provides an overview of in vitro modeling of inherited cardiomyopathies with the use of patient-specific hiPSC-derived CMs. PMID- 25934598 TI - Effect of fertility and infertility on longevity. AB - Changing demographic trends and projections of the survival and fertility rates of each generation have been a topic of great interest to not only demographers and epidemiologists but also to evolutionary biologists and reproductive endocrinologists. Compelling evolutionary theories suggest that there is an inverse association between fertility and longevity. Multiple historic, demographic, and current studies have since been conducted to test this theory, but the results have been inconclusive. The average number of children born to each woman has been declining progressively in developed countries during recent decades. This is in part due to changes in the behavior of couples but also to environmental factors. While improved accessibility to assisted reproductive technology can relieve some of the burden of infertility on these couples and lessen the problem of low total fertility rates in many developed countries, it is not enough to overcome the overall decrease in total fertility rates that we have witnessed in recent decades. This article critically reviews some important studies and provides an overview of this ongoing debate, while highlighting the relevance of trying to understand the possible mechanisms that may link fertility and infertility to longevity. PMID- 25934599 TI - Reproduction at an advanced maternal age and maternal health. AB - Advanced age is a risk factor for female infertility, pregnancy loss, fetal anomalies, stillbirth, and obstetric complications. These concerns are based on centuries-old observations, yet women are delaying childbearing to pursue educational and career goals in greater numbers than ever before. As a result, reproductive medicine specialists are treating more patients with age-related infertility and recurrent pregnancy loss, while obstetricians are faced with managing pregnancies often complicated by both age and comorbidities. The media portrayal of a youthful but older woman, able to schedule her reproductive needs and balance family and job, has fueled the myth that "you can have it all," rarely characterizing the perils inherent to advanced-age reproduction. Reproductive medicine specialists and obstetrician/gynecologists should promote more realistic views of the evidence-based realities of advanced maternal age pregnancy, including its high-risk nature and often compromised outcomes. Doctors should also actively educate both patients and the public that there is a real danger of childlessness if individuals choose to delay reproduction. PMID- 25934600 TI - Testosterone therapy: many players and much controversy. PMID- 25934601 TI - Can we isolate occupational effects on male fertility? PMID- 25934602 TI - Promoting sex and gender to optimize clinical research and healthcare delivery. PMID- 25934603 TI - [Pediatric infectious diseases: A discipline in transition]. PMID- 25934604 TI - [Publication of pediatric medical dissertations in France]. AB - INTRODUCTION: A medical dissertation is mandatory during medical studies in France. Often these dissertations are only considered an old-fashioned tradition but nonetheless require scientific research. According to recent publications, only 10% are secondarily published; however, there are no specific studies on pediatric medical dissertations. METHOD: For all medical dissertations from students assigned to pediatrics in 2003, a subsequent publication was searched for on Pubmed and Google Scholar. When such a publication was found, data on the student's rank, the impact factor (IF), the language of publication, and the number of citations were retrieved. RESULTS: For students assigned to pediatrics in 2003, 27.9% of the 172 medical theses were published, with a mean delay of 2.21 years. French was the language in 29%, and the mean IF was 2.3. There was no statistical association between student sex, age, university, size of the medical dissertation and publication. DISCUSSION: More than 25% of the pediatric medical dissertations are published. According to available data, this is a good rate but nonetheless still low. We found no clear factor associated with publication. CONCLUSION: Only a small fraction of pediatric medical dissertations are published. PMID- 25934605 TI - [Fishtail deformity after a non-displaced supracondylar humeral fracture in childhood: A case report]. AB - We report the case of a 13-year-old boy presenting with stiffness and pain in the elbow, which had appeared a few years before consultation. He reported a history of a closed, nondisplaced supracondylar fracture of the humerus 7 years before. Progression was good after orthopedic treatment. X-rays and CT showed a distinctive deformation, called a fishtail deformity, associated with severe arthritic injuries. We recall here that supracondylar fractures of the humerus are common in children and that early reduction decreases the complication rate. However, this case shows that fishtail deformity is a late and serious complication, which may occur after a nondisplaced supracondylar fracture of the humerus, with no severity factors and with good early progression. PMID- 25934606 TI - [Kabuki syndrome: Update and review]. AB - Kabuki syndrome (OMIM: 147920) is a rare condition, mainly associating intellectual deficiency, a polymalformative syndrome, and specific morphological changes in the face. It nevertheless has a strong clinical and biological heterogeneity with rarer but very different symptoms (endocrinological anomalies, autoimmune disorders, obesity, etc.). Clinical diagnosis is difficult because it is based on a spectrum of clinical, radiological, and biological factors. Complications are numerous, sometimes interpenetrating, and early diagnosis of the disease is essential for optimal management. The development of genetic testing is therefore essential for the diagnosis of this disease. Recently, exome sequencing has helped identify two genes responsible for the disease: KMT2D (lysine (K)-specific methyltransferase 2D, better known as MLL2 - mixed lineage leukemia), and KDM6A (lysine-specific demethylase 6A). Functional studies of these genes should help clarify their role in the pathogenesis of the disease, in particular to test the hypothesis of epigenetic changes during embryogenesis and development. Finally, understanding the interactions between KMT2D and its target genes could unravel other candidate genes for hitherto unexplained Kabuki syndrome cases. PMID- 25934607 TI - [Management of urinary tract infections in children. Recommendations of the Pediatric Infectious Diseases Group of the French Pediatrics Society and the French-Language Infectious Diseases Society]. AB - Urine dipsticks have to be used more frequently for the screening of urinary tract infections (UTI) in febrile infants and children (grade A). Confirmation of the UTI by urine culture should prefer other methods of sampling than the urine bag: sampling jet, urethral catheterization, or pubic puncture (grade A). The percentage of Escherichia coli producing extended-spectrum beta-lactamases (ESBL) in children accounts for less than 10 % in France and does not justify revising the 2007 recommendations (grade B). An increase in the use of carbapenems in first-line treatment is a major environmental hazard and exposes the patient to the risk of untreatable infections. For febrile UTI, the expert group recommended: (1) recover the results of susceptibility testing as soon as possible to quickly adapt treatment for possible resistant strains; (2) favor initial treatment with aminoglycosides (particularly amikacin) which remain active in the majority of ESBL strains for patients seen in the pediatric emergency department and/or hospital; (3) ceftriaxone (IV or IM) remains an appropriate treatment for patients seen in the emergency department or outpatient clinic because the percentage of ESBL-producing enterobacteria strains remains low; (4) use oral cefixime (grade B) in nonsevere cases and low-risk patients defined as age>3 months, general condition preserved, disease duration of fever<4 days, no associated comorbidity, and no history of urinary tract infection, uropathy, or prior antibiotic therapy in the last 3 months; (5) oral relay for parenteral treatment is guided by in vitro susceptibility testing, in an attempt to reduce the use of oral cephalosporins to limit the selection of resistant bacterial strains. The total duration of treatment recommended is usually 10 days. Except for special circumstances, there is no need to prescribe retrograde cystography or antibiotic prophylaxis after a first febrile urinary tract infection. For cystitis, the panel recommends systematic urinalysis and initial prescription before the results of the urine culture of one of the three following oral antibiotics: amoxicillin-clavulanate, cotrimoxazole, cefixime. The total duration of antibiotic treatment is 5days to tailor treatment based on clinical progression and antibiotic susceptibility. PMID- 25934608 TI - [Smith-Magenis syndrome is an association of behavioral and sleep/wake circadian rhythm disorders]. AB - Smith-Magenis syndrome (SMS) is a genetic disorder characterized by the association of facial dysmorphism, oral speech delay, as well as behavioral and sleep/wake circadian rhythm disorders. Most SMS cases (90%) are due to a 17p11.2 deletion encompassing the RAI1 gene; other cases stem from mutations of the RAI1 gene. Behavioral issues may include frequent outbursts, attention deficit/hyperactivity disorders, self-injuries with onychotillomania and polyembolokoilamania (insertion of objects into bodily orifices), etc. It is noteworthy that the longer the speech delay and the more severe the sleep disorders, the more severe the behavioral issues are. Typical sleep/wake circadian rhythm disorders associate excessive daytime sleepiness with nocturnal agitation. They are related to an inversion of the physiological melatonin secretion cycle. Yet, with an adapted therapeutic strategy, circadian rhythm disorders can radically improve. Usually an association of beta-blockers in the morning (stops daily melatonin secretion) and melatonin in the evening (mimics the evening deficient peak) is used. Once the sleep disorders are controlled, effective treatment of the remaining psychiatric features is needed. Unfortunately, as for many orphan diseases, objective guidelines have not been drawn up. However, efforts should be focused on improving communication skills. In the same vein, attention deficit/hyperactivity disorders, aggressiveness, and anxiety should be identified and specifically treated. This whole appropriate medical management is underpinned by the diagnosis of SMS. Diagnostic strategies include fluorescent in situ hybridization (FISH) or array comparative genomic hybridization (array CGH) when a microdeletion is sought and Sanger sequencing when a point mutation is suspected. Thus, the diagnosis of SMS can be made from a simple blood sample and should be questioned in subjects of any age presenting with an association of facial dysmorphism, speech delay with behavioral and sleep/wake circadian rhythm disorders, and other anomalies including short stature and mild dysmorphic features. PMID- 25934609 TI - [Pediatric eating disorders: Do not forget to protect bones!]. PMID- 25934610 TI - [Vaccine news]. PMID- 25934611 TI - [Unclassifiable B-cell lymphoma: Between diffuse large B-cell lymphoma and Burkitt lymphoma]. PMID- 25934612 TI - [Evaluation of family and community practices in children's home healthcare in Togo]. PMID- 25934614 TI - Biliary Epithelial Cells Are Not the Predominant Source of Hepatic CXCL12. AB - Hepatic expression levels of CXCL12, a chemokine important in inflammatory and stem cell recruitment, and its receptor, C-X-C chemokine receptor 4, are increased during all forms of liver injury. CXCL12 is expressed by both parenchymal and nonparenchymal hepatic cells, and on the basis of immunohistochemistry, biliary epithelial cells (BECs) are thought to be a predominant source of hepatic CXCL12, thereby promoting periportal recruitment of C-X-C chemokine receptor 4-expressing lymphocytes. Our study aims to show that BECs may, in fact, not be the predominant source of hepatic CXCL12. We measured CXCL12 secretion and expression from human and murine BECs using enzyme-linked immunosorbent assay and Western blot analysis from cell culture supernatants and whole cell lysates, respectively, whereas CXCL12 expression in murine livers was analyzed in a Cxcl12-Gfp reporter mouse. Cell culture supernatants and whole cell lysates from BECs failed to demonstrate their expression of CXCL12. Furthermore, we confirmed these results with a Cxcl12-Gfp reporter mouse in which green fluorescent protein expression is notably absent from BECs. Interestingly, on the basis of green fluorescent protein expression, we demonstrate a population of CXCL12-expressing cells within the portal tract that are distinct, yet intimately associated with BECs. These findings indicate that BECs are not a predominant source of CXCL12. PMID- 25934615 TI - Bacteriophages Isolated from Chicken Meat and the Horizontal Transfer of Antimicrobial Resistance Genes. AB - Antimicrobial resistance in microbes poses a global and increasing threat to public health. The horizontal transfer of antimicrobial resistance genes was thought to be due largely to conjugative plasmids or transposons, with only a minor part being played by transduction through bacteriophages. However, whole genome sequencing has recently shown that the latter mechanism could be highly important in the exchange of antimicrobial resistance genes between microorganisms and environments. The transfer of antimicrobial resistance genes by phages could underlie the origin of resistant bacteria found in food. We show that chicken meat carries a number of phages capable of transferring antimicrobial resistance. Of 243 phages randomly isolated from chicken meat, about a quarter (24.7%) were able to transduce resistance to one or more of the five antimicrobials tested into Escherichia coli ATCC 13706 (DSM 12242). Resistance to kanamycin was transduced the most often, followed by that to chloramphenicol, with four phages transducing tetracycline resistance and three transducing ampicillin resistance. Phages able to transduce antimicrobial resistance were isolated from 44% of the samples of chicken meat that we tested. The statistically significant (P = 0.01) relationship between the presence of phages transducing kanamycin resistance and E. coli isolates resistant to this antibiotic suggests that transduction may be an important mechanism for transferring kanamycin resistance to E. coli. It appears that the transduction of resistance to certain antimicrobials, e.g., kanamycin, not only is widely distributed in E. coli isolates found on meat but also could represent a major mechanism for resistance transfer. The result is of high importance for animal and human health. PMID- 25934616 TI - Wolbachia Influences the Production of Octopamine and Affects Drosophila Male Aggression. AB - Wolbachia bacteria are endosymbionts that infect approximately 40% of all insect species and are best known for their ability to manipulate host reproductive systems. Though the effect Wolbachia infection has on somatic tissues is less well understood, when present in cells of the adult Drosophila melanogaster brain, Wolbachia exerts an influence over behaviors related to olfaction. Here, we show that a strain of Wolbachia influences male aggression in flies, which is critically important in mate competition. A specific strain of Wolbachia was observed to reduce the initiation of aggressive encounters in Drosophila males compared to the behavior of their uninfected controls. To determine how Wolbachia was able to alter aggressive behavior, we investigated the role of octopamine, a neurotransmitter known to influence male aggressive behavior in many insect species. Transcriptional analysis of the octopamine biosynthesis pathway revealed that two essential genes, the tyrosine decarboxylase and tyramine beta hydroxylase genes, were significantly downregulated in Wolbachia-infected flies. Quantitative chemical analysis also showed that total octopamine levels were significantly reduced in the adult heads. PMID- 25934617 TI - LA35 Poultry Fecal Marker Persistence Is Correlated with That of Indicators and Pathogens in Environmental Waters. AB - Disposal of fecally contaminated poultry litter by land application can deliver pathogens and fecal indicator bacteria (FIB) into receiving waters via runoff. While water quality is regulated by FIB enumeration, FIB testing provides inadequate information about contamination source and health risk. This microbial source tracking (MST) study compared the persistence of the Brevibacterium sp. strain LA35 16S rRNA gene (marker) for poultry litter with that of pathogens and FIB under outdoor, environmentally relevant conditions in freshwater, marine water, and sediments over 7 days. Salmonella enterica, Campylobacter jejuni, Campylobacter coli, Bacteroidales, and LA35 were enumerated by quantitative PCR (qPCR), and Enterococcus spp. and E. coli were quantified by culture and qPCR. Unlike the other bacteria, C. jejuni was not detectable after 48 h. Bacterial levels in the water column consistently declined over time and were highly correlated among species. Survival in sediments ranged from a slow decrease over time to growth, particularly in marine microcosms and for Bacteroidales. S. enterica also grew in marine sediments. Linear decay rates in water (k) ranged from -0.17 day(-1) for LA35 to -3.12 day(-1) for C. coli. LA35 levels correlated well with those of other bacteria in the water column but not in sediments. These observations suggest that, particularly in the water column, the fate of LA35 in aquatic environments is similar to that of FIB, C. coli, and Salmonella, supporting the hypothesis that the LA35 marker gene can be a useful tool for evaluating the impact of poultry litter on water quality and human health risk. PMID- 25934618 TI - Extracellular Vesicles of the Hyperthermophilic Archaeon "Thermococcus onnurineus" NA1T. AB - Extracellular vesicles (EVs) produced by a sulfur-reducing, hyperthermophilic archaeon, "Thermococcus onnurineus" NA1(T), were purified and characterized. A maximum of four EV bands, showing buoyant densities between 1.1899 and 1.2828 g cm(-3), were observed after CsCl ultracentrifugation. The two major EV bands, B (buoyant density at 25 degrees C [rho(25)] = 1.2434 g cm(-3)) and C (rho(25) = 1.2648 g cm(-3)), were separately purified and counted using a qNano particle analyzer. These EVs, showing different buoyant densities, were identically spherical in shape, and their sizes varied from 80 to 210 nm in diameter, with 120- and 190-nm sizes predominant. The average size of DNA packaged into EVs was about 14 kb. The DNA of the EVs in band C was sequenced and assembled. Mapping of the T. onnurineus NA1(T) EV (ToEV) DNA sequences onto the reference genome of the parent archaeon revealed that most genes of T. onnurineus NA1(T) were packaged into EVs, except for an ~9.4-kb region from TON_0536 to TON_0544. The absence of this specific region of the genome in the EVs was confirmed from band B of the same culture and from bands B and C purified from a different batch culture. The presence of the 3'-terminal sequence and the absence of the 5'-terminal sequence of TON_0536 were repeatedly confirmed. On the basis of these results, we hypothesize that the unpackaged part of the T. onnurineus NA1(T) genome might be related to the process that delivers DNA into ToEVs and/or the mechanism generating the ToEVs themselves. PMID- 25934619 TI - Chlamydiaceae in North Atlantic Seabirds Admitted to a Wildlife Rescue Center in Western France. AB - Birds are the primary hosts of Chlamydia psittaci, a bacterium that can cause avian chlamydiosis in birds and psittacosis in humans. Wild seabirds are frequently admitted to wildlife rescue centers (WRC) at European Atlantic coasts, for example, in connection with oil spills. To investigate the extent of chlamydial shedding by these birds and the resulting risk for animals in care and the medical staff, seabirds from a French WRC were sampled from May 2011 to January 2014. By use of a quantitative PCR (qPCR), 195 seabirds belonging to 4 orders, 5 families and 13 species were examined, of which 18.5% proved to be Chlamydiaceae positive. The highest prevalence of shedders was found in northern gannets (Morus bassanus) (41%), followed by European herring gulls (Larus argentatus) (14%) and common murres (Uria aalge) (7%). Molecular characterization and phylogenetic analysis of qPCR-positive northern gannet samples revealed two variants of a strain closely related to C. psittaci. In European herring gulls and in one common murre, strains showing high sequence similarity to the atypical Chlamydiaceae-like C122 previously found in gulls were detected. Our study shows that seabirds from the northeastern Atlantic Ocean carry several chlamydial organisms, including C. psittaci-related strains. The staff in WRCs should take protective measures, particularly in the case of mass admissions of seabirds. PMID- 25934621 TI - Soil Conditions That Can Alter Natural Suppression of Escherichia coli O157:H7 in Ohio Specialty Crop Soils. AB - Food-borne pathogen persistence in soil fundamentally affects the production of safe vegetables and small fruits. Interventions that reduce pathogen survival in soil would have positive impacts on food safety by minimizing preharvest contamination entering the food chain. Laboratory-controlled studies determined the effects of soil pH, moisture content, and soil organic matter (SOM) on the survivability of this pathogen through the creation of single-parameter gradients. Longitudinal field-based studies were conducted in Ohio to quantify the extent to which field soils suppressed Escherichia coli O157:H7 survival. In all experiments, heat-sensitive microorganisms were responsible for the suppression of E. coli O157 in soil regardless of the chemical composition of the soil. In laboratory-based studies, soil pH and moisture content were primary drivers of E. coli O157 survival, with increases in pH after 48 h (P = 0.02) and decreases in moisture content after 48 h (P = 0.007) significantly increasing the log reduction of E. coli O157 numbers. In field-based experiments, E. coli O157 counts from both heated and unheated samples were sensitive to both season (P = 0.004 for heated samples and P = 0.001 for unheated samples) and region (P = 0.002 for heated samples and P = 0.001 for unheated samples). SOM was observed to be a more significant driver of pathogen suppression than the other two factors after 48 h at both planting and harvest (P = 0.002 at planting and P = 0.058 at harvest). This research reinforces the need for both laboratory-controlled experiments and longitudinal field-based experiments to unravel the complex relationships controlling the survival of introduced organisms in soil. PMID- 25934620 TI - Stable-Isotope Probing Identifies Uncultured Planctomycetes as Primary Degraders of a Complex Heteropolysaccharide in Soil. AB - The exopolysaccharides (EPSs) produced by some bacteria are potential growth substrates for other bacteria in soil. We used stable-isotope probing (SIP) to identify aerobic soil bacteria that assimilated the cellulose produced by Gluconacetobacter xylinus or the EPS produced by Beijerinckia indica. The latter is a heteropolysaccharide comprised primarily of l-guluronic acid, d-glucose, and d-glycero-d-mannoheptose. (13)C-labeled EPS and (13)C-labeled cellulose were purified from bacterial cultures grown on [(13)C]glucose. Two soils were incubated with these substrates, and bacteria actively assimilating them were identified via pyrosequencing of 16S rRNA genes recovered from (13)C-labeled DNA. Cellulose C was assimilated primarily by soil bacteria closely related (93 to 100% 16S rRNA gene sequence identities) to known cellulose-degrading bacteria. However, B. indica EPS was assimilated primarily by bacteria with low identities (80 to 95%) to known species, particularly by different members of the phylum Planctomycetes. In one incubation, members of the Planctomycetes made up >60% of all reads in the labeled DNA and were only distantly related (<85% identity) to any described species. Although it is impossible with SIP to completely distinguish primary polysaccharide hydrolyzers from bacteria growing on produced oligo- or monosaccharides, the predominance of Planctomycetes suggested that they were primary degraders of EPS. Other bacteria assimilating B. indica EPS included members of the Verrucomicrobia, candidate division OD1, and the Armatimonadetes. The results indicate that some uncultured bacteria in soils may be adapted to using complex heteropolysaccharides for growth and suggest that the use of these substrates may provide a means for culturing new species. PMID- 25934622 TI - Mutual Exclusion between Fungal Species of the Fusarium Head Blight Complex in a Wheat Spike. AB - Fusarium head blight (FHB) is one of the most damaging diseases of wheat. FHB is caused by a species complex that includes two genera of Ascomycetes: Microdochium and Fusarium. Fusarium graminearum, Fusarium culmorum, Fusarium poae, and Microdochium nivale are among the most common FHB species in Europe and were chosen for these experiments. Field studies and surveys show that two or more species often coexist within the same field or grain sample. In this study, we investigated the competitiveness of isolates of different species against isolates of F. graminearum at the scale of a single spike. By performing point inoculations of a single floret, we ensured that each species was able to establish independent infections and competed for spike colonization only. The fungal colonization was assessed in each spike by quantitative PCR. After establishing that the spike colonization was mainly downwards, we compared the relative colonization of each species in coinoculations. Classical analysis of variance suggested a competitive interaction but remained partly inconclusive because of a large between-spike variance. Further data exploration revealed a clear exclusion of one of the competing species and the complete absence of coexistence at the spike level. PMID- 25934624 TI - The Intestinal Microbiota Influences Campylobacter jejuni Colonization and Extraintestinal Dissemination in Mice. AB - Campylobacter jejuni is a leading cause of human foodborne gastroenteritis worldwide. The interactions between this pathogen and the intestinal microbiome within a host are of interest as endogenous intestinal microbiota mediates a form of resistance to the pathogen. This resistance, termed colonization resistance, is the ability of commensal microbiota to prevent colonization by exogenous pathogens or opportunistic commensals. Although mice normally demonstrate colonization resistance to C. jejuni, we found that mice treated with ampicillin are colonized by C. jejuni, with recovery of Campylobacter from the colon, mesenteric lymph nodes, and spleen. Furthermore, there was a significant reduction in recovery of C. jejuni from ampicillin-treated mice inoculated with a C. jejuni virulence mutant (DeltaflgL strain) compared to recovery of mice inoculated with the C. jejuni wild-type strain or the C. jejuni complemented isolate (DeltaflgL/flgL). Comparative analysis of the microbiota from nontreated and ampicillin-treated CBA/J mice led to the identification of a lactic acid fermenting isolate of Enterococcus faecalis that prevented C. jejuni growth in vitro and limited C. jejuni colonization of mice. Next-generation sequencing of DNA from fecal pellets that were collected from ampicillin-treated CBA/J mice revealed a significant decrease in diversity of operational taxonomic units (OTUs) compared to that in control (nontreated) mice. Taken together, we have demonstrated that treatment of mice with ampicillin alters the intestinal microbiota and permits C. jejuni colonization. These findings provide valuable insights for researchers using mice to investigate C. jejuni colonization factors, virulence determinants, or the mechanistic basis of probiotics. PMID- 25934625 TI - Identity and Substrate Specificity of Reductive Dehalogenases Expressed in Dehalococcoides-Containing Enrichment Cultures Maintained on Different Chlorinated Ethenes. AB - Many reductive dehalogenases (RDases) have been identified in organohalide respiring microorganisms, and yet their substrates, specific activities, and conditions for expression are not well understood. We tested whether RDase expression varied depending on the substrate-exposure history of reductive dechlorinating communities. For this purpose, we used the enrichment culture KB-1 maintained on trichloroethene (TCE), as well as subcultures maintained on the intermediates cis-dichloroethene (cDCE) and vinyl chloride (VC). KB-1 contains a TCE-to-cDCE dechlorinating Geobacter and several Dehalococcoides strains that together harbor many of the known chloroethene reductases. Expressed RDases were identified using blue native polyacrylamide gel electrophoresis, enzyme assays in gel slices, and peptide sequencing. As anticipated but never previously quantified, the RDase from Geobacter was only detected transiently at the beginning of TCE dechlorination. The Dehalococcoides RDase VcrA and smaller amounts of TceA were expressed in the parent KB-1 culture during complete dechlorination of TCE to ethene regardless of time point or amended substrate. The Dehalococcoides RDase BvcA was only detected in enrichments maintained on cDCE as growth substrates, in roughly equal abundance to VcrA. Only VcrA was detected in subcultures enriched on VC. Enzyme assays revealed that 1,1-DCE, a substrate not used for culture enrichment, afforded the highest specific activity. trans-DCE was substantially dechlorinated only by extracts from cDCE enrichments expressing BvcA. RDase gene distribution indicated enrichment of different strains of Dehalococcoides as a function of electron acceptor TCE, cDCE, or VC. Each chloroethene reductase has distinct substrate preferences leading to strain selection in mixed communities. PMID- 25934626 TI - Meta-Analysis of the Reduction of Norovirus and Male-Specific Coliphage Concentrations in Wastewater Treatment Plants. AB - Human norovirus (NoV) is the leading cause of foodborne illness in the United States and Canada. Wastewater treatment plant (WWTP) effluents impacting bivalve mollusk-growing areas are potential sources of NoV contamination. We have developed a meta-analysis that evaluates WWTP influent concentrations and log10 reductions of NoV genotype I (NoV GI; in numbers of genome copies per liter [gc/liter]), NoV genotype II (NoV GII; in gc/liter), and male-specific coliphage (MSC; in number of PFU per liter), a proposed viral surrogate for NoV. The meta analysis included relevant data (2,943 measurements) reported in the scientific literature through September 2013 and previously unpublished surveillance data from the United States and Canada. Model results indicated that the mean WWTP influent concentration of NoV GII (3.9 log10 gc/liter; 95% credible interval [CI], 3.5, 4.3 log10 gc/liter) is larger than the value for NoV GI (1.5 log10 gc/liter; 95% CI, 0.4, 2.4 log10 gc/liter), with large variations occurring from one WWTP to another. For WWTPs with mechanical systems and chlorine disinfection, mean log10 reductions were -2.4 log10 gc/liter (95% CI, -3.9, -1.1 log10 gc/liter) for NoV GI, -2.7 log10 gc/liter (95% CI, -3.6, -1.9 log10 gc/liter) for NoV GII, and -2.9 log10 PFU per liter (95% CI, -3.4, -2.4 log10 PFU per liter) for MSCs. Comparable values for WWTPs with lagoon systems and chlorine disinfection were -1.4 log10 gc/liter (95% CI, -3.3, 0.5 log10 gc/liter) for NoV GI, -1.7 log10 gc/liter (95% CI, -3.1, -0.3 log10 gc/liter) for NoV GII, and -3.6 log10 PFU per liter (95% CI, -4.8, -2.4 PFU per liter) for MSCs. Within WWTPs, correlations exist between mean NoV GI and NoV GII influent concentrations and between the mean log10 reduction in NoV GII and the mean log10 reduction in MSCs. PMID- 25934627 TI - Acute Limonene Toxicity in Escherichia coli Is Caused by Limonene Hydroperoxide and Alleviated by a Point Mutation in Alkyl Hydroperoxidase AhpC. AB - Limonene, a major component of citrus peel oil, has a number of applications related to microbiology. The antimicrobial properties of limonene make it a popular disinfectant and food preservative, while its potential as a biofuel component has made it the target of renewable production efforts through microbial metabolic engineering. For both applications, an understanding of microbial sensitivity or tolerance to limonene is crucial, but the mechanism of limonene toxicity remains enigmatic. In this study, we characterized a limonene tolerant strain of Escherichia coli and found a mutation in ahpC, encoding alkyl hydroperoxidase, which alleviated limonene toxicity. We show that the acute toxicity previously attributed to limonene is largely due to the common oxidation product limonene hydroperoxide, which forms spontaneously in aerobic environments. The mutant AhpC protein with an L-to-Q change at position 177 (AhpC(L177Q)) was able to alleviate this toxicity by reducing the hydroperoxide to a more benign compound. We show that the degree of limonene toxicity is a function of its oxidation level and that nonoxidized limonene has relatively little toxicity to wild-type E. coli cells. Our results have implications for both the renewable production of limonene and the applications of limonene as an antimicrobial. PMID- 25934623 TI - Aggressive Emerging Pathovars of Xanthomonas arboricola Represent Widespread Epidemic Clones Distinct from Poorly Pathogenic Strains, as Revealed by Multilocus Sequence Typing. AB - Deep and comprehensive knowledge of the genetic structure of pathogenic species is the cornerstone on which the design of precise molecular diagnostic tools is built. Xanthomonas arboricola is divided into pathovars, some of which are classified as quarantine organisms in many countries and are responsible for diseases on nut and stone fruit trees that have emerged worldwide. Recent taxonomic studies of the genus Xanthomonas showed that strains isolated from other hosts should be classified in X. arboricola, extending the host range of the species. To investigate the genetic structure of X. arboricola and the genetic relationships between highly pathogenic strains and strains apparently not relevant to plant health, we conducted multilocus sequence analyses on a collection of strains representative of the known diversity of the species. Most of the pathovars were clustered in separate monophyletic groups. The pathovars pruni, corylina, and juglandis, responsible for pandemics in specific hosts, were highly phylogenetically related and clustered in three distinct clonal complexes. In contrast, strains with no or uncertain pathogenicity were represented by numerous unrelated singletons scattered in the phylogenic tree. Depending on the pathovar, intra- and interspecies recombination played contrasting roles in generating nucleotide polymorphism. This work provides a population genetics framework for molecular epidemiological surveys of emerging plant pathogens within X. arboricola. Based on our results, we propose to reclassify three former pathovars of Xanthomonas campestris as X. arboricola pv. arracaciae comb. nov., X. arboricola pv. guizotiae comb. nov., and X. arboricola pv. zantedeschiae comb. nov. An emended description of X. arboricola Vauterin et al. 1995 is provided. PMID- 25934628 TI - 2,3-Butanediol Metabolism in the Acetogen Acetobacterium woodii. AB - The acetogenic bacterium Acetobacterium woodii is able to reduce CO2 to acetate via the Wood-Ljungdahl pathway. Only recently we demonstrated that degradation of 1,2-propanediol by A. woodii was not dependent on acetogenesis, but that it is disproportionated to propanol and propionate. Here, we analyzed the metabolism of A. woodii on another diol, 2,3-butanediol. Experiments with growing and resting cells, metabolite analysis and enzymatic measurements revealed that 2,3 butanediol is oxidized in an NAD(+)-dependent manner to acetate via the intermediates acetoin, acetaldehyde, and acetyl coenzyme A. Ethanol was not detected as an end product, either in growing cultures or in cell suspensions. Apparently, all reducing equivalents originating from the oxidation of 2,3 butanediol were funneled into the Wood-Ljungdahl pathway to reduce CO2 to another acetate. Thus, the metabolism of 2,3-butanediol requires the Wood-Ljungdahl pathway. PMID- 25934629 TI - Ruminal Bacterial Community Composition in Dairy Cows Is Dynamic over the Course of Two Lactations and Correlates with Feed Efficiency. AB - Fourteen Holstein cows of similar ages were monitored through their first two lactation cycles, during which ruminal solids and liquids, milk samples, production data, and feed consumption data were collected for each cow during early (76 to 82 days in milk [DIM]), middle (151 to 157 DIM), and late (251 to 257 DIM) lactation periods. The bacterial community of each ruminal sample was determined by sequencing the region from V6 to V8 of the 16S rRNA gene using 454 pyrosequencing. Gross feed efficiency (GFE) for each cow was calculated by dividing her energy-corrected milk by dry matter intake (ECM/DMI) for each period of both lactation cycles. Four pairs of cows were identified that differed in milk production efficiency, as defined by residual feed intake (RFI), at the same level of ECM production. The most abundant phyla detected for all cows were Bacteroidetes (49.42%), Firmicutes (39.32%), Proteobacteria (5.67%), and Tenericutes (2.17%), and the most abundant genera included Prevotella (40.15%), Butyrivibrio (2.38%), Ruminococcus (2.35%), Coprococcus (2.29%), and Succiniclasticum (2.28%). The bacterial microbiota between the first and second lactation cycles were highly similar, but with a significant correlation between total community composition by ruminal phase and specific bacteria whose relative sequence abundances displayed significant positive or negative correlation with GFE or RFI. These data suggest that the ruminal bacterial community is dynamic in terms of membership and diversity and that specific members are associated with high and low milk production efficiency over two lactation cycles. PMID- 25934630 TI - Small changes to diet could bring substantial health and environmental benefits, say researchers. PMID- 25934631 TI - A double blind randomized placebo control crossover trial on the effect of dietary nitrate supplementation on exercise tolerance in stable moderate chronic obstructive pulmonary disease. AB - BACKGROUND: Dietary nitrate supplementation has been shown to decrease the oxygen cost of exercise and prolong exercise tolerance, as measured by sub-maximal exercise endurance distance and time at 85% VO2max, in both elite athletes and normal healthy subjects. Patients with chronic obstructive pulmonary disease (COPD) have reduced quality of life and ability to perform activities of daily living attributable to diminished exercise tolerance, and dietary nitrate may be able to ameliorate this. METHODS: We performed a double-blind, computer randomized placebo control crossover trial at a tertiary Australian hospital to investigate whether dietary nitrate supplementation as beetroot juice (BR) would augment submaximal exercise endurance in individuals with spirometrically confirmed stable moderate COPD. Volunteers underwent an incremental shuttle walk test to determine VO2max followed by a test dose of BR to establish safety in the study population. Participants performed an endurance shuttle walk test (ESWT) at 85% VO2max after randomization to either a 3 day wash-in of BR (4.8 mmol twice a day) or placebo (nitrate deplete BR), with a final dose on the morning of testing. They then crossed over after 4 day washout. Repeated measures two sided paired t-tests were employed. RESULTS: 35 participants were recruited with 19 completing the trial. In the initial safety phase, we measured systolic blood pressure over four hours post first dose of BR, and found a mean 10 mmHg decrement maximal at 1 hour. One individual developed symptomatic postural hypotension and was excluded. The primary outcomes of ESWT distance and time to fatigue improved by 11% and 6% respectively; however these differences did not achieve statistical significance (p = 0.494 and 0.693 respectively). CONCLUSIONS: Our study does not support a role for routine dietary nitrate supplementation for enhancement of exercise endurance in COPD. TRIAL REGISTRATION: Australia and New Zealand Clinical Trial Register: ACTRN12611001088932. PMID- 25934632 TI - Diffusion-weighted MR neurography for the assessment of brachial plexopathy in oncological practice. AB - BACKGROUND: To evaluate diffusion-weighted MR neurography (DW-MRN) for visualizing the brachial plexus and for the assessment of brachial plexopathy. METHODS: 40 oncological patients with symptoms of brachial plexopathy underwent 1.5 T MRI using conventional MR sequences and unidirectional DW-MRN. The images were independently reviewed by two radiologists. Anatomic visualization of the brachial plexus was scored using a 5 point scale on conventional MR sequences and then combined with DW-MRN. A brachial plexus abnormality was also scored using a 5 point scale and inter-observer agreement determined by kappa statistics. Diagnostic accuracy for brachial plexopathy assessed by conventional MRI alone versus conventional MRI combined with DW-MRN was compared by ROC analysis using reference standards. RESULTS: DW-MRN significantly improved visualization of the brachial plexus compared with conventional MRI alone (P<0.001). When assessing brachial plexopathy, inter-observer agreement was moderate for conventional MRI (kappa=0.48) but good for conventional MRI with DW-MRN (kappa=0.62). DW-MRN combined with conventional MRI significantly improved diagnostic accuracy in one observer (P<0.05) but was similar in the other observer. CONCLUSION: DW-MRN improved visualization of the brachial plexus. Combining DW-MRN with conventional MRI can improve inter-observer agreement and detection of brachial plexopathy in symptomatic oncological patients. PMID- 25934633 TI - Differential contribution of velocity and distance to time estimation during self initiated time-to-collision judgment. AB - To successfully intercept/avoid a moving object, human brain needs to precisely estimate the time-to-collision (TTC) of the object. In real life, time estimation is determined conjointly by the velocity and the distance of a moving object. However, surprisingly little is known concerning whether and how the velocity and the distance dimensions contribute differentially to time estimation. In this fMRI study, we demonstrated that variations of velocity evoked substantially different behavioral and neural responses than distance during self-initiated TTC judgments. Behaviorally, the velocity dimension induced a stronger time dilation effect than the distance dimension that participants' responses were significantly more delayed by increasing velocity than by decreasing distance, even with the theoretical TTC being equated between the two conditions. Neurally, activity in the dorsal fronto-parietal TTC network was parametrically modulated by variations in TTC irrespective of whether the variations in TTC were caused by velocity or distance. Importantly, even with spatial distance being equated, increasing velocity induced illusory perception of longer spatial trajectory in early visual cortex. Moreover, as velocity increased, the early visual cortex showed enhanced connectivity with the TTC network. Our results thus implied that with increasing velocity, TTC judgments depended increasingly on the velocity induced illusory distance information from early visual cortex and was eventually tampered. PMID- 25934634 TI - Native and non-native speech sound processing and the neural mismatch responses: A longitudinal study on classroom-based foreign language learning. AB - Learning a foreign language in a natural immersion context with high exposure to the new language has been shown to change the way speech sounds of that language are processed at the neural level. It remains unclear, however, to what extent this is also the case for classroom-based foreign language learning, particularly in children. To this end, we presented a mismatch negativity (MMN) experiment during EEG recordings as part of a longitudinal developmental study: 38 monolingual (Swiss-) German speaking children (7.5 years) were tested shortly before they started to learn English at school and followed up one year later. Moreover, 22 (Swiss-) German adults were recorded. Instead of the originally found positive mismatch response in children, an MMN emerged when applying a high pass filter of 3 Hz. The overlap of a slow-wave positivity with the MMN indicates that two concurrent mismatch processes were elicited in children. The children's MMN in response to the non-native speech contrast was smaller compared to the native speech contrast irrespective of foreign language learning, suggesting that no additional neural resources were committed to processing the foreign language speech sound after one year of classroom-based learning. PMID- 25934635 TI - Disorders of representation and control in semantic cognition: Effects of familiarity, typicality, and specificity. AB - We present a case-series comparison of patients with cross-modal semantic impairments consequent on either (a) bilateral anterior temporal lobe atrophy in semantic dementia (SD) or (b) left-hemisphere fronto-parietal and/or posterior temporal stroke in semantic aphasia (SA). Both groups were assessed on a new test battery designed to measure how performance is influenced by concept familiarity, typicality and specificity. In line with previous findings, performance in SD was strongly modulated by all of these factors, with better performance for more familiar items (regardless of typicality), for more typical items (regardless of familiarity) and for tasks that did not require very specific classification, consistent with the gradual degradation of conceptual knowledge in SD. The SA group showed significant impairments on all tasks but their sensitivity to familiarity, typicality and specificity was more variable and governed by task specific effects of these factors on controlled semantic processing. The results are discussed with reference to theories about the complementary roles of representation and manipulation of semantic knowledge. PMID- 25934636 TI - Time, number and attention in very low birth weight children. AB - Premature birth has been associated with damage in many regions of the cerebral cortex, although there is a particularly strong susceptibility for damage within the parieto-occipital lobes (Volpe, 2009). As these areas have been shown to be critical for both visual attention and magnitudes perception (time, space, and number), it is important to investigate the impact of prematurity on both the magnitude and attentional systems, particularly for children without overt white matter injuries, where the lack of obvious injury may cause their difficulties to remain unnoticed. In this study, we investigated the ability to judge time intervals (visual, audio and audio-visual temporal bisection), discriminate between numerical quantities (numerosity comparison), map numbers onto space (numberline task) and to maintain visuo-spatial attention (multiple-object tracking) in school-age preterm children (N29). The results show that various parietal functions may be more or less robust to prematurity-related difficulties, with strong impairments found on time estimation and attentional task, while numerical discrimination or mapping tasks remained relatively unimpaired. Thus while our study generally supports the hypothesis of a dorsal stream vulnerability in children born preterm relative to other cortical locations, it further suggests that particular cognitive processes, as highlighted by performance on different tasks, are far more susceptible than others. PMID- 25934637 TI - Polysulfide evokes acute pain through the activation of nociceptive TRPA1 in mouse sensory neurons. AB - BACKGROUND: Hydrogen sulfide (H2S) is oxidized to polysulfide. Recent reports show that this sulfur compound modulates various biological functions. We have reported that H2S is involved in inflammatory pain in mice. On the other hand, little is known about the functional role of polysulfide in sensory neurons. Here we show that polysulfide selectively stimulates nociceptive TRPA1 and evokes acute pain, using TRPA1-gene deficient mice (TRPA1(-/-)), a heterologous expression system and a TRPA1-expressing cell line. RESULTS: In wild-type mouse sensory neurons, polysulfide elevated the intracellular Ca concentration ([Ca(2+)]i) in a dose-dependent manner. The half maximal effective concentration (EC50) of polysulfide was less than one-tenth that of H2S. The [Ca(2+)]i responses to polysulfide were observed in neurons responsive to TRPA1 agonist and were inhibited by blockers of TRPA1 but not of TRPV1. Polysulfide failed to evoke [Ca(2+)]i increases in neurons from TRPA1(-/-) mice. In RIN-14B cells, constitutively expressing rat TRPA1, polysulfide evoked [Ca(2+)]i increases with the same EC50 value as in sensory neurons. Heterologously expressed mouse TRPA1 was activated by polysulfide and that was suppressed by dithiothreitol. Analyses of the TRPA1 mutant channel revealed that cysteine residues located in the internal domain were related to the sensitivity to polysulfide. Intraplantar injection of polysulfide into the mouse hind paw induced acute pain and edema which were significantly less than in TRPA1(-/-) mice. CONCLUSIONS: The present data suggest that polysulfide functions as pronociceptive substance through the activation of TRPA1 in sensory neurons. Since the potency of polysulfide is higher than parental H2S and this sulfur compound is generated under pathophysiological conditions, it is suggested that polysulfide acts as endogenous ligand for TRPA1. Therefore, TRPA1 may be a promising therapeutic target for endogenous sulfur compound-related algesic action. PMID- 25934638 TI - A chromatin code for alternative splicing involving a putative association between CTCF and HP1alpha proteins. AB - BACKGROUND: Alternative splicing is primarily controlled by the activity of splicing factors and by the elongation of the RNA polymerase II (RNAPII). Recent experiments have suggested a new complex network of splicing regulation involving chromatin, transcription and multiple protein factors. In particular, the CCCTC binding factor (CTCF), the Argonaute protein AGO1, and members of the heterochromatin protein 1 (HP1) family have been implicated in the regulation of splicing associated with chromatin and the elongation of RNAPII. These results raise the question of whether these proteins may associate at the chromatin level to modulate alternative splicing. RESULTS: Using chromatin immunoprecipitation sequencing (ChIP-Seq) data for CTCF, AGO1, HP1alpha, H3K27me3, H3K9me2, H3K36me3, RNAPII, total H3 and 5metC and alternative splicing arrays from two cell lines, we have analyzed the combinatorial code of their binding to chromatin in relation to the alternative splicing patterns between two cell lines, MCF7 and MCF10. Using Machine Learning techniques, we identified the changes in chromatin signals that are most significantly associated with splicing regulation between these two cell lines. Moreover, we have built a map of the chromatin signals on the pre mRNA, that is, a chromatin-based RNA-map, which can explain 606 (68.55%) of the regulated events between MCF7 and MCF10. This chromatin code involves the presence of HP1alpha, CTCF, AGO1, RNAPII and histone marks around regulated exons and can differentiate patterns of skipping and inclusion. Additionally, we found a significant association of HP1alpha and CTCF activities around the regulated exons and a putative DNA binding site for HP1alpha. CONCLUSIONS: Our results show that a considerable number of alternative splicing events could have a chromatin dependent regulation involving the association of HP1alpha and CTCF near regulated exons. Additionally, we find further evidence for the involvement of HP1alpha and AGO1 in chromatin-related splicing regulation. PMID- 25934639 TI - Expansion of brucellosis detection in the country of Georgia by screening household members of cases and neighboring community members. AB - BACKGROUND: Brucellosis is considered as endemic zoonotic disease in the country of Georgia. However, the burden of the disease on a household level is not known. Therefore, this study sought to determine the benefits of active surveillance coupled to serological screening for the early detection of brucellosis among close contacts of brucellosis cases. METHODS: We used an active surveillance approach to estimate the rate of seropositivity among household family members and neighboring community members of brucellosis index cases. All participants were screened using the serum tube agglutination test (SAT). Blood cultures were performed, obtained isolates were identified by a bacteriological algorithm, and confirmed as Brucella spp. using real-time PCR. Further confirmation of Brucella species was done using the AMOS PCR assay. RESULTS: A total of 141 participants enrolled. Of these, 27 were brucellosis index cases, 86 were household family members, and 28 were neighboring community members. The serological evidence of brucellosis in the household member group was 7% and the rate at the household level was 21%. No screened community members were Brucella seropositive. Majority of brucellosis cases were caused by B. melitensis; only one index case was linked to B. abortus. CONCLUSION: We found evidence of brucellosis infection among household family members of brucellosis index cases. B. melitensis was the most common species obtained. Findings of this active surveillance study highlight the importance of screening household family members of brucellosis cases and of the use of culture methods to identify Brucella species in the country of Georgia. PMID- 25934640 TI - A novel inflammation-based prognostic score in esophageal squamous cell carcinoma: the C-reactive protein/albumin ratio. AB - BACKGROUND: Plenty of studies have demonstrated the prognostic value of various inflammation-based indexes in cancer. This study was designed to investigate the prognostic value of the C-reactive protein/albumin (CRP/Alb) ratio in esophageal squamous cell carcinoma. METHODS: A retrospective study of 423 cases with newly diagnosed esophageal squamous cell carcinoma was conducted. We analyzed the association of the CRP/Alb ratio with clinicopathologic characteristics. The prognostic value was explored by univariate and multivariate survival analysis. In addition, we compared the discriminatory ability of the CRP/Alb ratio with other inflammation-based prognostic scores by evaluating the area under the receiver operating characteristics curves (AUC), including the modified Glasgow Prognostic Score (mGPS), neutrophil lymphocyte ratio (NLR) and platelet lymphocyte ratio (PLR). RESULTS: The optimal cut-off value was identified to be 0.095 for the CRP/Alb ratio. A higher level of the CRP/Alb ratio was associated with larger tumor size (P < 0.001), poorer differentiation (P = 0.019), deeper tumor invasion (P = 0.003), more lymph node metastasis (P = 0.015), more distant metastasis (P < .001) and later TNM stage (P < 0.001). The CRP/Alb ratio was identified to be the only inflammation-based prognostic score with independent association with overall survival by multivariate analysis (P = 0.031). The AUC value of the CRP/Alb ratio was higher compared with the NLR and PLR, but not mGPS at 6, 12 and 24 months of follow-up. In addition, the CRP/Alb ratio could identify a group of patients with mGPS score of 0 who had comparable overall survival with those with mGPS score of 1. CONCLUSIONS: The CRP/Alb ratio is a novel but promising inflammation-based prognostic score in esophageal squamous cell carcinoma. It is a valuable coadjutant for the mGPS to further identify patients' survival differences. PMID- 25934641 TI - Physician and patient concordance of report of tobacco cessation intervention in primary care in India. AB - BACKGROUND: Tobacco cessation interventions by physicians hold promise in improving quit rates. The 5As intervention ('Ask', 'Advise', 'Assess', 'Assist' and 'Arrange') is an evidence-based approach for tobacco cessation. However, little is known about adherence with the tobacco cessation interventions in primary care in India. In the present study we assessed physicians' adherence with the 5As intervention and explored physician and patient concordance on the report of 5As intervention for tobacco cessation. METHODS: We used data from two cross-sectional surveys conducted in 12 districts of Andhra Pradesh and Gujarat in India. The surveys were administered simultaneously to both patients attending, and physicians working in health facilities providing primary care. Health facilities were selected by systematic random sampling and patients were recruited by simple random sampling. Common health facilities where both surveys were performed were identified, and individual patients were matched to their physicians through a unique matching code to obtain the two study samples. RESULTS: Slight agreement was observed between the physician and patient responses on 'Ask' and 'Arrange' component of the 5As intervention. The 'Advise', 'Assess' and 'Assist' components showed low agreement. Slightly higher levels of agreement were seen on all components of the 5As, except 'Advise', for those patients who had made an attempt to quit. CONCLUSIONS: Our study suggests an urgent need for revising current strategies in order to strengthen the 'Advise', 'Assess', and 'Assist' interventions in tobacco cessation in primary care settings. Patient surveys should be used routinely in assessing fidelity and provider adherence for large scale behavioral health programs. PMID- 25934643 TI - The performance of inverse probability of treatment weighting and full matching on the propensity score in the presence of model misspecification when estimating the effect of treatment on survival outcomes. AB - There is increasing interest in estimating the causal effects of treatments using observational data. Propensity-score matching methods are frequently used to adjust for differences in observed characteristics between treated and control individuals in observational studies. Survival or time-to-event outcomes occur frequently in the medical literature, but the use of propensity score methods in survival analysis has not been thoroughly investigated. This paper compares two approaches for estimating the Average Treatment Effect (ATE) on survival outcomes: Inverse Probability of Treatment Weighting (IPTW) and full matching. The performance of these methods was compared in an extensive set of simulations that varied the extent of confounding and the amount of misspecification of the propensity score model. We found that both IPTW and full matching resulted in estimation of marginal hazard ratios with negligible bias when the ATE was the target estimand and the treatment-selection process was weak to moderate. However, when the treatment-selection process was strong, both methods resulted in biased estimation of the true marginal hazard ratio, even when the propensity score model was correctly specified. When the propensity score model was correctly specified, bias tended to be lower for full matching than for IPTW. The reasons for these biases and for the differences between the two methods appeared to be due to some extreme weights generated for each method. Both methods tended to produce more extreme weights as the magnitude of the effects of covariates on treatment selection increased. Furthermore, more extreme weights were observed for IPTW than for full matching. However, the poorer performance of both methods in the presence of a strong treatment-selection process was mitigated by the use of IPTW with restriction and full matching with a caliper restriction when the propensity score model was correctly specified. PMID- 25934642 TI - Alternative divalent cations (Zn2+, Co2+, and Mn2+) are not mutagenic at conditions optimal for HIV-1 reverse transcriptase activity. AB - BACKGROUND: Fidelity of DNA polymerases can be influenced by cation co-factors. Physiologically, Mg(2+) is used as a co-factor by HIV reverse transcriptase (RT) to perform catalysis; however, alternative cations including Mn(2+), Co(2+), and Zn(2+) can also support catalysis. Although Zn(2+) supports DNA synthesis, it inhibits HIV RT by significantly modifying RT catalysis. Zn(2+) is currently being investigated as a component of novel treatment options against HIV and we wanted to investigate the fidelity of RT with Zn(2+). METHODS: We used PCR-based and plasmid-based alpha complementation assays as well as steady-state misinsertion and misincorporation assays to examine the fidelity of RT with Mn(2+), Co(2+), and Zn(2+). RESULTS: The fidelity of DNA synthesis by HIV-1 RT was approximately 2.5 fold greater in Zn(2+) when compared to Mg(2+) at cation conditions optimized for nucleotide catalysis. Consistent with this, RT extended primers with mismatched 3' nucleotides poorly and inserted incorrect nucleotides less efficiently using Zn(2+) than Mg(2+). In agreement with previous literature, we observed that Mn(2+) and Co(2+) dramatically decreased the fidelity of RT at highly elevated concentrations (6 mM). However, surprisingly, the fidelity of HIV RT with Mn(2+) and Co(2+) remained similar to Mg(2+) at lower concentrations that are optimal for catalysis. CONCLUSION: This study shows that Zn(2+), at optimal extension conditions, increases the fidelity of HIV-1 RT and challenges the notion that alternative cations capable of supporting polymerase catalysis are inherently mutagenic. PMID- 25934644 TI - Saturated fatty acids in human visceral adipose tissue are associated with increased 11- beta-hydroxysteroid-dehydrogenase type 1 expression. AB - BACKGROUND: Visceral fat accumulation is associated with metabolic disease. It is therefore relevant to study factors that regulate adipose tissue distribution. Recent data shows that overeating saturated fatty acids promotes greater visceral fat storage than overeating unsaturated fatty acids. Visceral adiposity is observed in states of hypercortisolism, and the enzyme 11-beta-hydroxysteroid dehydrogenase type 1 (11beta-hsd1) is a major regulator of cortisol activity by converting inactive cortisone to cortisol in adipose tissue. We hypothesized that tissue fatty acid composition regulates body fat distribution through local effects on the expression of 11beta-hsd1 and its corresponding gene (HSD11B1) resulting in altered cortisol activity. FINDINGS: Visceral- and subcutaneous adipose tissue biopsies were collected during Roux-en-Y gastric bypass surgery from 45 obese women (BMI; 41+/-4 kg/m2). The fatty acid composition of each biopsy was measured and correlated to the mRNA levels of HSD11B1. 11beta-hsd1 protein levels were determined in a subgroup (n=12) by western blot analysis. Our main finding was that tissue saturated fatty acids (e.g. palmitate) were associated with increased 11beta-hsd1 gene- and protein-expression in visceral but not subcutaneous adipose tissue. CONCLUSIONS: The present study proposes a link between HSD11B1 and saturated fatty acids in visceral, but not subcutaneous adipose tissue. Nutritional regulation of visceral fat mass through HSD11B1 is of interest for the modulation of metabolic risk and warrants further investigation. PMID- 25934645 TI - Multistep processing of the secretion leader of the extracellular protein Epx1 in Pichia pastoris and implications for protein localization. AB - Secretion leaders are required to direct nascent proteins to the secretory pathway. They are of interest in the study of intracellular protein transport, and are required for the production of secretory recombinant proteins. Secretion leaders are processed in two steps in the endoplasmic reticulum and Golgi. Although yeast cells typically contain about 150 proteins entering the secretory pathway, only a low number of proteins are actually secreted to the cell supernatant. Analysis of the secretome of the yeast Pichia pastoris revealed that the most abundant secretory protein, which we named Epx1, belongs to the cysteine rich secretory protein family CRISP. Surprisingly, the Epx1 secretion leader undergoes a three-step processing on its way to the cell exterior instead of the usual two-step processing. The Kex2 cleavage site within the P. pastoris Epx1 leader is not conserved in the homologues of most other yeasts. We studied the effect of exchanging the Kex2-cleavage motif on the secretory behaviour of reporter proteins fused to variants of the Epx1 leader sequence, and observed mistargeting for some but not all of the variants using fluorescence microscopy. By targeting several recombinant human proteins for secretion, we revealed that a short variant of the leader sequence, as well as the Epx1 signal sequence alone, resulted in the correct N-termini of the secreted proteins. Both leader variants proved to be very efficient, even exceeding the secretion levels obtained with commonly used secretion leaders. Taken together, the novel Epx1 secretion leader sequences are a valuable tool for recombinant protein production as well as basic research of intracellular transport. PMID- 25934646 TI - Deciphering the mechanisms against oxidative stress in developing and mature akinetes of the cyanobacterium Aphanizomenon ovalisporum. AB - Cells of filamentous cyanobacteria of the orders Nostocales and Stigonematales can differentiate into dormant forms called akinetes. Akinetes play a key role in the survival, abundance and distribution of the species, contributing an inoculum for their perennial blooms. In the cyanobacterium Aphanizomenon ovalisporum, potassium deficiency triggers the formation of akinetes. Here we present experimental evidence for the production of reactive oxygen species (ROS) during akinete development in response to potassium deficiency. The function of ROS as a primer signal for akinete differentiation was negated. Nevertheless, akinetes acquired protective mechanisms against oxidative damage during their differentiation and maintained them as they matured, giving akinetes advantages enabling survival in harsh conditions. PMID- 25934647 TI - Connection of KinC to flotillins and potassium leakage in Bacillus subtilis. PMID- 25934648 TI - Inflammatory cytokines regulate the expression of glycosyltransferases involved in the biosynthesis of tumor-associated sialylated glycans in pancreatic cancer cell lines. AB - BACKGROUND: Pancreatic ductal adenocarcinoma (PDAC) is characterized by an abundant stroma containing several pro-inflammatory cytokines, which are described to modulate the expression of important genes related to tumor promotion and progression. In the present work we have investigated the potential role of these cytokines in the biosynthesis of tumor-associated carbohydrate antigens such as sialyl-Lewis(x) (SLe(x)) through the regulation of specific glycosyltransferase genes. METHODS: Two human PDAC cell lines MDAPanc-3 and MDAPanc-28 were treated with pro-inflammatory cytokines IL-1beta, TNFalpha, IL-6 or IL-8, and the content of tumor-associated carbohydrate antigens at the cell membrane was analyzed by flow cytometry. In addition, variation in the mRNA expression of sialyltransferase (ST) and fucosyltransferase (FUT) genes, which codify for the ST and FucT enzymes involved in the carbohydrate antigens' biosynthesis, was determined. The inflammatory microenvironment of PDAC tissues and the expression of Lewis-type antigens were analyzed by immunohistochemistry to find a possible correlation between inflammation status and the presence of tumor-associated carbohydrate antigens. RESULTS: IL-1beta stimuli increased SLe(x) and alpha2,6-sialic acid levels in MDAPanc-28 cells and enhanced the mRNA levels of ST3GAL3-4 and FUT5-7, which codify for ST and FucT enzymes related to SLe(x) biosynthesis, and of ST6GAL1. IL-6 and TNFalpha treatments increased the levels of SLe(x) and Le(y) antigens in MDPanc-3 cells and, similarly, the mRNA expression of ST3GAL3-4, FUT1-2 and FUT6, related to these Lewis-type antigens' biosynthesis, were increased. Most PDAC tissues stained for SLe(x) and SLe(a) and tended to be expressed in the tumor samples with a higher presence of inflammatory immune cells. CONCLUSIONS: The inflammatory microenvironment can modulate the glycosylation pattern of PDAC cells, increasing the expression of tumor-associated sialylated antigens such as SLe(x), which contributes to pancreatic tumor malignancy. PMID- 25934650 TI - Whistleblowing in the NHS. PMID- 25934649 TI - Long-term sublingual immunotherapy for Japanese cedar pollinosis and the levels of IL-17A and complement components 3a and 5a. AB - Allergen-specific immunotherapy is the only treatment that can alter the natural course of allergic disease. We performed long-term sublingual immunotherapy (SLIT) for patients with seasonal allergic rhinitis caused by Japanese cedar pollen (SAR-JCP), screened molecules as candidate biomarkers, and investigated serum IL-17A and complement components 3a (C3a) and C5a in order to evaluate whether these molecules show changes correlated to symptom scores. In this study, we found that the long-term SLIT reduced the serum levels of IL-17A and C3a and C5a. The levels of C3a in the patients significantly decreased from year 1 compared with those at the baseline, and their levels of IL-17A significantly decreased from year 2 compared with those at baseline. The levels of IL-17A, C3a, and C5a at year 4 of SLIT were significantly lower than not only those at baseline, but also those at year 1. A significant positive correlation was found between the symptom medication scores and the levels of IL-17A at year 4. The symptom medication scores in the group in which IL-17A levels decreased at year 4 were significantly lower than those in the group without such a decrease. The serum level of IL-17A might prove useful as a biological parameter to ascertain the effectiveness of SLIT for patients with SAR-JCP. It is necessary to produce new therapeutics for non-responders in whom serum IL-17A levels are still higher against long-term SLIT. PMID- 25934651 TI - For lack of wanting: Discourses of desire in Ukrainian opiate substitution therapy programs. AB - Available treatments for addiction and substance abuse in Ukraine have been shaped by the economic, political, and social shifts that have followed the country's independence. The introduction of methadone-based opiate substitution therapy (OST) for opiate addicts is especially representative of this. Biomedical paradigms of addiction, its etiology, and its treatment, promoted and paid for by international donors and elite global health entities, are being met by Ukrainian notions of personhood and psychology in both public discourse and clinical settings. Ukrainian physicians who work in OST programs frequently reference desire (zhelanie) as the most significant factor in determining the success or failure of treatment. They refer to a desire to be treated, desire to get better, desire to live. The moralized imperative to possess this desire to get better is, in many ways, a reflection of how addiction and the addicted psyche is constructed and understood in the Ukrainian context. By exploring discourses of desire in narratives of addiction and treatment, I examine how notions of psychology, will, and self-control intersect, shaping the subjectivity, agency, and daily experiences of this vulnerable population. PMID- 25934652 TI - [Organization and long-term follow-up of adults treated for cancer during childhood: A necessity in 2015]. PMID- 25934653 TI - [A childhood and adolescence cancer survivors' association: Les Aguerris]. AB - In France, we can estimate that 50,000 adults are childhood or adolescence cancer survivors. Not all of them will experience late effects but they should be informed about their previous disease and should get a detailed summary of treatment information including a personal plan for late effects screening. They also should have access to appropriate follow-up care including detection and treatment of late effects and provision of support and advice. From a follow-up clinic experience, the need of a survivor association has emerged and "Les Aguerris" has been created with several objectives: to improve the quality of life of survivors providing them information about the possible physical, social and psychological consequences of childhood cancer, to raise awareness of public authorities and other actors on questions regarding the need of long-term follow up of the patients in dedicated clinics, to support researches about late effects of cancer and treatments and to create a network of adult survivors of childhood cancer in relation with other European survivors or parents associations. This paper describes the activities of the association to fulfill its objectives and the annual national meetings they are organizing. PMID- 25934654 TI - Stop the damaging drive towards a health market, former college president demands. PMID- 25934655 TI - Coil herniation following intra-arterial verapamil infusion for the treatment of cerebral vasospasm: Case report and literature review. AB - Complications associated with intra-arterial infusion of vasodilator agents for the treatment of vasospasm associated with a ruptured cerebral aneurysm are extremely rare. We present the case of a patient who developed left lower extremity monoplegia following intra-arterial infusion of verapamil for treatment of diffuse cerebral vasospasm, 6 days after initially undergoing treatment of a ruptured right A1-2 junction aneurysm. A repeat angiogram following this intra arterial vasodilator treatment demonstrated a coil loop which had herniated into the right A2 artery. Herein, we describe a previously unreported complication which occurred following intra-arterial pharmacologic vasospasm treatment, review the existing literature, and suggest potential causes and treatment options. PMID- 25934657 TI - Usefulness of the fusion imaging of 3D-CT and MRA for carotid artery stenting with minimum use of contrast medium in patient with renal dysfunction. AB - Patients with severe internal carotid artery (ICA) stenosis with multiple medical problems generally undergo carotid artery stenting (CAS). However, it is difficult to perform CAS in some patients because iodinated contrast medium is hard to use. We report a patient with asymptomatic ICA stenosis and chronic renal failure, in whom successful treatment was achieved using CAS with minimal use of iodinated contrast medium. A 68-year-old man with severely chronic renal failure was consulted for treatment of left ICA stenosis. Magnetic resonance angiography (MRA) and carotid echography revealed left ICA severe stenosis, and systemic non contrast MRA showed left femoral artery constriction, but right femoral artery to be intact. CAS was therefore performed through the right femoral artery, using non-contrast three-dimensional computed tomography (3D-CT) with MRA fusion imaging, intravascular ultrasonography, and a small amount of iodinated low osmolar contrast medium. Postoperative course was uneventful with no aggravation of renal dysfunction, and he was discharged 7 days postoperatively. These techniques are very useful for patients with chronic renal failure, and this present case represents the first report of CAS treated by using non-contrast 3D CT with MRA fusion image technique. PMID- 25934656 TI - China Angioplasty and Stenting for Symptomatic Intracranial Severe Stenosis (CASSISS): A new, prospective, multicenter, randomized controlled trial in China. AB - BACKGROUND: Patients with symptomatic stenosis of intradural arteries are at high risk for subsequent stroke. Since the SAMMPRIS trial, stenting is no longer recommended as primary treatment; however, the results of this trial, its inclusion criteria and its center selection received significant criticism and did not appear to reflect our experience regarding natural history nor treatment complications rate. As intracranial atherosclerosis (ICAS) is the most common cause for stroke in Asian countries, we are hereby proposing a refined prospective, randomized, multicenter study in an Asian population with strictly defined patient and participating center inclusion criteria. METHODS: The China Angioplasty and Stenting for Symptomatic Intracranial Severe Stenosis (CASSISS) trial is an ongoing, government-funded, prospective, multicenter, randomized trial. It recruits patients with recent TIA or stroke caused by 70%-99% stenosis of a major intracranial artery. Patients with previous stroke related to perforator ischemia will not be included. Only high-volume centers with a proven track record will enroll patients as determined by a lead-in phase. Patients will be randomized (1:1) to best medical therapy alone or medical therapy plus stenting. Primary endpoints are any stroke or death within 30 days after enrollment or after any revascularization procedure of the qualifying lesion during follow-up, or stroke in the territory of the symptomatic intracranial artery beyond 30 days. The CASSISS trial will be conducted in eight sites in China with core imaging lab review at a North American site and aims to have a sample size of 380 participants (stenting, 190; medical therapy, 190). Recruitment is expected to be finished by December 2016. Patients will be followed for at least three years. The trial is scheduled to complete in 2019. CONCLUSION: In the proposed trial, certain shortcomings of SAMMPRIS including patient and participating center selection will be addressed. The present manuscript outlines the rationale and design of the study. We estimate that this trial will allow for a critical reappraisal of the role of intracranial stenting for selected patients in high-volume centers. PMID- 25934658 TI - Ophthalmic artery occlusion immediately following placement of a flow diverter without clinical sequelae. AB - Branch vessel occlusion is a potential consequence following flow diverter placement for intracranial aneurysms, but the frequency and clinical impact has not been completely elucidated. In this case of a 45-year-old woman with a large left internal carotid artery aneurysm, the ophthalmic artery was covered by two flow diverters and was acutely occluded along with the aneurysm. Common carotid injections failed to demonstrate collateral flow to the ophthalmic artery via the external carotid artery. Nonetheless, the patient woke from anesthesia with objectively stable and subjectively improved vision. This case demonstrates that an acute occlusion of the ophthalmic artery without external carotid artery collaterals can be tolerated clinically. PMID- 25934659 TI - A herculean task for the Olympics borough. PMID- 25934660 TI - What are the odds? PMID- 25934661 TI - Serum alpha-Tocopherol Has a Nonlinear Inverse Association with Periodontitis among US Adults. AB - BACKGROUND: Previous experimental models suggest that vitamin E may ameliorate periodontitis. However, epidemiologic studies show inconsistent evidence in supporting this plausible association. OBJECTIVE: We investigated the association between serum alpha-tocopherol (alphaT) and gamma-tocopherol (gammaT) and periodontitis in a large cross-sectional US population. METHODS: This study included 4708 participants in the 1999-2001 NHANES. Serum tocopherols were measured by HPLC and values were adjusted by total cholesterol (TC). Periodontal status was assessed by mean clinical attachment loss (CAL) and probing pocket depth (PPD). Total periodontitis (TPD) was defined as the sum of mild, moderate, and severe periodontitis. All measurements were performed by NHANES. RESULTS: Means +/- SDs of serum alphaT:TC ratio from low to high quartiles were 4.0 +/- 0.4, 4.8 +/- 0.2, 5.7 +/- 0.4, and 9.1 +/- 2.7 MUmol/mmol. In multivariate regression models, alphaT:TC quartiles were inversely associated with mean CAL (P trend = 0.06), mean PPD (P-trend < 0.001), and TPD (P-trend < 0.001) overall. Adjusted mean differences (95% CIs) between the first and fourth quartile of alphaT:TC were 0.12 mm (0.03, 0.20; P-difference = 0.005) for mean CAL and 0.12 mm (0.06, 0.17; P-difference < 0.001) for mean PPD, whereas the corresponding OR for TPD was 1.65 (95% CI: 1.26, 2.16; P-difference = 0.001). In a dose-response analysis, a clear inverse association between alphaT:TC and mean CAL, mean PPD, and TPD was observed among participants with relatively low alphaT:TC. No differences were seen in participants with higher alphaT:TC ratios. Participants with gammaT:TC ratio in the interquartile range showed a significantly lower mean PPD than those in the highest quartile. CONCLUSIONS: A nonlinear inverse association was observed between serum alphaT and severity of periodontitis, which was restricted to adults with normal but relatively low alphaT status. These findings warrant further confirmation in longitudinal or intervention studies. PMID- 25934662 TI - Maternal protein restriction increases respiratory and sympathetic activities and sensitizes peripheral chemoreflex in male rat offspring. AB - BACKGROUND: Maternal protein restriction in rats increases the risk of adult offspring arterial hypertension through unknown mechanisms. OBJECTIVES: The aims of the study were to evaluate the effects of a low-protein (LP) diet during pregnancy and lactation on baseline sympathetic and respiratory activities and peripheral chemoreflex sensitivity in the rat offspring. METHODS: Wistar rat dams were fed a control [normal-protein (NP); 17% protein] or an LP (8% protein) diet during pregnancy and lactation, and their male offspring were studied at 30 d of age. Direct measurements of baseline arterial blood pressure (ABP), heart rate (HR), and respiratory frequency (Rf) as well as peripheral chemoreflex activation (potassium cyanide: 0.04%) were recorded in pups while they were awake. In addition, recordings of the phrenic nerve (PN) and thoracic sympathetic nerve (tSN) activities were obtained from the in situ preparations. Hypoxia-inducible factor 1alpha (HIF-1alpha) expression was also evaluated in carotid bifurcation through a Western blotting assay. RESULTS: At 30 d of age, unanesthetized LP rats exhibited enhanced resting Rf (P = 0.001) and similar ABP and HR compared with the NP rats. Despite their similar baseline ABP values, LP rats exhibited augmented low-frequency variability (~91%; P = 0.01). In addition, the unanesthetized LP rats showed enhanced pressor (P = 0.01) and tachypnoeic (P = 0.03) responses to peripheral chemoreflex activation. The LP rats displayed elevated baseline tSN activity (~86%; P = 0.02) and PN burst frequency (45%; P = 0.01) and amplitude (53%; P = 0.001) as well as augmented sympathetic (P = 0.01) and phrenic (P = 0.04) excitatory responses to peripheral chemoreflex activation compared with the NP group. Furthermore, LP rats showed an increase of ~100% in HIF-1alpha protein density in carotid bifurcation compared with NP rats. CONCLUSION: Sympathetic-respiratory overactivity and amplified peripheral chemoreceptor responses, potentially through HIF-1alpha-dependent mechanisms, precede the onset of hypertension in juvenile rats exposed to protein undernutrition during gestation and lactation. PMID- 25934664 TI - Iron biofortification and revisiting the accuracy of extrinsic labeling in studies of iron absorption. PMID- 25934663 TI - Higher Intake of Fruit, but Not Vegetables or Fiber, at Baseline Is Associated with Lower Risk of Becoming Overweight or Obese in Middle-Aged and Older Women of Normal BMI at Baseline. AB - BACKGROUND: Fruit, vegetable, and dietary fiber intake have been associated with lower risk of cardiovascular disease (CVD); however, little is known about their role in obesity prevention. OBJECTIVE: Our goal was to investigate whether intake of fruits, vegetables, and dietary fiber is associated with weight change and the risk of becoming overweight and obese. METHODS: We studied 18,146 women aged >=45 y from the Women's Health Study free of CVD and cancer with an initial body mass index (BMI) of 18.5 to <25 kg/m2. Fruit, vegetable, and dietary fiber intakes were assessed at baseline through a 131-item food-frequency questionnaire, along with obesity-related risk factors. Women self-reported body weight on annual questionnaires. RESULTS: During a mean follow-up of 15.9 y, 8125 women became overweight or obese (BMI >=25 kg/m2). Intakes of total fruits and vegetables, fruits, and dietary fiber were not associated with the longitudinal changes in body weight, whereas higher vegetable intake was associated with greater weight gain (P-trend: 0.02). In multivariable analyses, controlling for total energy intake and physical activity along with other lifestyle, clinical, and dietary factors, women in the highest vs. lowest quintile of fruit intake had an HR of 0.87 (95% CI: 0.80, 0.94; P-trend: 0.01) of becoming overweight or obese. No association was observed for vegetable or dietary fiber intake. The association between fruit intake and risk of becoming overweight or obese was modified by baseline BMI (P-interaction: <0.0001) where the strongest inverse association was observed among women with a BMI <23 kg/m2 (HR: 0.82; 95% CI: 0.71, 0.94). CONCLUSION: Our results suggest that greater baseline intake of fruit, but not vegetables or fiber, by middle-aged and older women with a normal BMI at baseline is associated with lower risk of becoming overweight or obese. PMID- 25934665 TI - Communication of randomized controlled trial results must match the study focus. PMID- 25934666 TI - Lowering of large bowel butyrate levels in healthy populations is unlikely to be beneficial. PMID- 25934669 TI - Functional impact of diaphragm muscle sarcopenia in both male and female mice. AB - To perform a range of ventilatory and nonventilatory behaviors, the diaphragm muscle (DIAm) must be able to generate sufficient forces throughout the lifespan. We hypothesized that sarcopenia impacts DIAm force generation and thus limits performance of expulsive, higher force, nonventilatory behaviors. Male and female mice (n = 79) at 6 and 24 mo of age (100 vs. 70-75% survival, respectively) were used to examine transdiaphragmatic pressure (Pdi) generation across motor behaviors in vivo and in vitro DIAm specific force. We found a significant effect of age on maximum Pdi (20-41% decline during tracheal occlusion and bilateral phrenic nerve stimulation), maximum DIAm specific force (30% decline), and DIAm fatigue resistance (15% increase). There were no differences between sexes in these age effects on DIAm performance. These results support our hypothesis that sarcopenia primarily impacts higher force, nonventilatory motor behaviors of the DIAm. Such functional limitations may have negative implications in the ability of the DIAm to generate forces needed for airway clearance in old age and thereby contribute to age-related respiratory complications. PMID- 25934670 TI - Increased lung prolyl hydroxylase and decreased glucocorticoid receptor are related to decreased surfactant protein in the growth-restricted sheep fetus. AB - Experimental placental restriction (PR) by carunclectomy in fetal sheep results in intrauterine growth restriction (IUGR), chronic hypoxemia, increased plasma cortisol, and decreased lung surfactant protein (SP) expression. The mechanisms responsible for decreased SP expression are unknown but may involve decreased glucocorticoid (GC) action or changes in hypoxia signaling. Endometrial caruncles were removed from nonpregnant ewes to induce PR. Lungs were collected from control and PR fetuses at 130-135 (n = 19) and 139-145 (n = 28) days of gestation. qRT-PCR and Western blotting were used to quantify lung mRNA and protein expression, respectively, of molecular regulators and downstream targets of the GC and hypoxia-signaling pathways. We confirmed a decrease in SP-A, -B, and -C, but not SP-D, mRNA expression in PR fetuses at both ages. There was a net downregulation of GC signaling with a reduction in GC receptor (GR)-alpha and beta protein expression and a decrease in the cofactor, GATA-6. GC-responsive genes including transforming growth factor-beta1, IL-1beta, and beta2-adrenergic receptor were not stimulated. Prolyl hydroxylase domain (PHD)2 mRNA and protein and PHD3 mRNA expression increased with a concomitant increase in hypoxia inducible factor-1alpha (HIF-1alpha) and HIF-1beta mRNA expression. There was an increase in mRNA expression of several, but not all, hypoxia-responsive genes. Hence, both GC and hypoxia signaling may contribute to reduced SP expression. Although acute hypoxia normally inactivates PHDs, chronic hypoxemia in the PR fetus increased PHD abundance, which normally prevents HIF signaling. This may represent a mechanism by which chronic hypoxemia contributes to the decrease in SP production in the IUGR fetal lung. PMID- 25934672 TI - From prevention to plaque rupture and infarction. PMID- 25934671 TI - Defective parasympathetic innervation is associated with airway branching abnormalities in experimental CDH. AB - Developmental mechanisms leading to lung hypoplasia in congenital diaphragmatic hernia (CDH) remain poorly defined. Pulmonary innervation is defective in the human disease and in the rodent models of CDH. We hypothesize that defective parasympathetic innervation may contribute to airway branching abnormalities and, therefore, lung hypoplasia, during lung development in CDH. The murine nitrofen model of CDH was utilized to study the effect of the cholinergic agonist carbachol on embryonic day 11.5 (E11.5) lung explant cultures. Airway branching and contractions were quantified. In a subset of experiments, verapamil was added to inhibit airway contractions. Sox9 immunostaining and 5-bromo-2-deoxyuridine incorporation were used to identify and quantify the number and proliferation of distal airway epithelial progenitor cells. Intra-amniotic injections were used to determine the in vivo effect of carbachol. Airway branching and airway contractions were significantly decreased in nitrofen-treated lungs compared with controls. Carbachol resulted in increased airway contractions and branching in nitrofen-treated lungs. Nitrofen-treated lungs exhibited an increased number of proliferating Sox9-positive distal epithelial progenitor cells, which were decreased and normalized by treatment with carbachol. Verapamil inhibited the carbachol-induced airway contractions in nitrofen-treated lungs but had no effect on the carbachol-induced increase in airway branching, suggesting a direct carbachol effect independent of airway contractions. In vivo treatment of nitrofen-treated embryos via amniotic injection of carbachol at E10.5 resulted in modest increases in lung size and branching at E17.5. These results suggest that defective parasympathetic innervation may contribute to airway branching abnormalities in CDH. PMID- 25934673 TI - CardioPulse Articles. PMID- 25934674 TI - Erratum. PMID- 25934675 TI - Focus on 68Ga and PRRT: 3rd Theranostics World Congress. PMID- 25934676 TI - FDA updates "Bonn call for action" activities. PMID- 25934677 TI - Walter Wolf, PhD, 1931-2014. PMID- 25934678 TI - Warren K. Sinclair, PhD, 1924-2014. PMID- 25934679 TI - Ismael Mena, MD, 1928-2015. PMID- 25934680 TI - Amyloid Imaging Coverage with Evidence Development and the IDEAS Study. PMID- 25934683 TI - The Era of Evidence-Based Medicine: What Are the Implications for JNM and Other Imaging Journals? PMID- 25934684 TI - A man with rust coloured urine and normocytic anaemia. PMID- 25934685 TI - How to stop making a crisis out of a drama: towards better portrayal of mental ill health in television and film. PMID- 25934686 TI - Third Theranostics World Congress on Gallium-68 and PRRT: Abstracts. PMID- 25934687 TI - Regulation of tumor cell plasticity by the androgen receptor in prostate cancer. AB - Prostate cancer (PCa) has become the most common form of cancer in men in the developed world, and it ranks second in cancer-related deaths. Men that succumb to PCa have a disease that is resistant to hormonal therapies that suppress androgen receptor (AR) signaling, which plays a central role in tumor development and progression. Although AR continues to be a clinically relevant therapeutic target in PCa, selection pressures imposed by androgen-deprivation therapies promote the emergence of heterogeneous cell populations within tumors that dictate the severity of disease. This cellular plasticity, which is induced by androgen deprivation, is the focus of this review. More specifically, we address the emergence of cancer stem-like cells, epithelial-mesenchymal or myeloid plasticity, and neuroendocrine transdifferentiation as well as evidence that demonstrates how each is regulated by the AR. Importantly, because all of these cell phenotypes are associated with aggressive PCa, we examine novel therapeutic approaches for targeting therapy-induced cellular plasticity as a way of preventing PCa progression. PMID- 25934688 TI - Procalcitonin for detecting medullary thyroid carcinoma: a systematic review. AB - The aim of the present study was to perform a systematic review of published studies to provide a robust estimation of the use of procalcitonin (ProCT) as a diagnostic marker of medullary thyroid carcinoma (MTC), with particular focus on its specificity and negative predictive value in excluding MTC. A comprehensive computer literature search was conducted to find relevant published articles on the topic. We used a search algorithm based on a combination of the terms 'medullary,' 'thyroid,' and 'ProCT.' The search was updated until February 2015. To expand our search, references of the retrieved articles were also screened. A total of 39 articles were retrieved, of which nine original papers published from 2003 to 2014 were selected for the review. Some of these studies used ProCT in the preoperative diagnosis of MTC, whereas others measured ProCT during the follow-up of patients who had been previously treated for MTC. Other laboratory measurements were performed in some of the included studies. The results of the majority of the studies indicate that ProCT measurement appears to be a very promising and reliable serum marker for the diagnosis of MTC, and it is not inferior to calcitonin (CT). The sample handling is less laborious, and in the few CT-negative cases reviewed, the assay had even greater sensitivity. It would be worthwhile to establish cutoff levels using larger patient series, because we speculate that this assay could potentially replace CT measurement in the future. PMID- 25934689 TI - Chitinases Are Essential for Cell Separation in Ustilago maydis. AB - Chitin is an essential component of the fungal cell wall, providing rigidity and stability. Its degradation is mediated by chitinases and supposedly ensures the dynamic plasticity of the cell wall during growth and morphogenesis. Hence, chitinases should be particularly important for fungi with dramatic morphological changes, such as Ustilago maydis. This smut fungus switches from yeast to filamentous growth for plant infection, proliferates as a mycelium in planta, and forms teliospores for spreading. Here, we investigate the contribution of its four chitinolytic enzymes to the different morphological changes during the complete life cycle in a comprehensive study of deletion strains combined with biochemical and cell biological approaches. Interestingly, two chitinases act redundantly in cell separation during yeast growth. They mediate the degradation of remnant chitin in the fragmentation zone between mother and daughter cell. In contrast, even the complete lack of chitinolytic activity does not affect formation of the infectious filament, infection, biotrophic growth, or teliospore germination. Thus, unexpectedly we can exclude a major role for chitinolytic enzymes in morphogenesis or pathogenicity of U. maydis. Nevertheless, redundant activity of even two chitinases is essential for cell separation during saprophytic growth, possibly to improve nutrient access or spreading of yeast cells by wind or rain. PMID- 25934690 TI - Unraveling the Function of the Response Regulator BcSkn7 in the Stress Signaling Network of Botrytis cinerea. AB - Important for the lifestyle and survival of every organism is the ability to respond to changing environmental conditions. The necrotrophic plant pathogen Botrytis cinerea triggers an oxidative burst in the course of plant infection and therefore needs efficient signal transduction to cope with this stress. The factors involved in this process and their precise roles are still not well known. Here, we show that the transcription factor Bap1 and the response regulator (RR) B. cinerea Skn7 (BcSkn7) are two key players in the oxidative stress response (OSR) of B. cinerea; both have a major influence on the regulation of classical OSR genes. A yeast-one-hybrid (Y1H) approach proved direct binding to the promoters of gsh1 and grx1 by Bap1 and of glr1 by BcSkn7. While the function of Bap1 is restricted to the regulation of oxidative stress, analyses of Deltabcskn7 mutants revealed functions beyond the OSR. Involvement of BcSkn7 in development and virulence could be demonstrated, indicated by reduced vegetative growth, impaired formation of reproductive structures, and reduced infection cushion-mediated penetration of the host by the mutants. Furthermore, Deltabcskn7 mutants were highly sensitive to oxidative, osmotic, and cell wall stress. Analyses of Deltabap1 bcskn7 double mutants indicated that loss of BcSkn7 uncovers an underlying phenotype of Bap1. In contrast to Saccharomyces cerevisiae, the ortholog of the glutathione peroxidase Gpx3p is not required for nuclear translocation of Bap1. The presented results contribute to the understanding of the OSR in B. cinerea and prove that it differs substantially from that of yeast, demonstrating the complexity and versatility of components involved in signaling pathways. PMID- 25934691 TI - Transglutaminase Is Required for Epidermal Squamous Cell Carcinoma Stem Cell Survival. AB - Cancer stem cells are thought to be responsible for rapid tumor growth, metastasis, and enhanced tumor survival following drug treatment. For this reason, there is a major emphasis on identifying proteins that can be targeted to kill cancer stem cells or control their growth, and transglutaminase type II (TGM2/TG2) is such a target in epidermal squamous cell carcinoma. TG2 was originally described as a transamidase in the extracellular matrix that crosslinks proteins by catalyzing epsilon-(gamma-glutamyl)lysine bonds. However, subsequent studies have shown that TG2 is a GTP-binding protein that plays an important role in cell signaling and survival. In the present study, TG2 shows promise as a target for anticancer stem cell therapy in human squamous cell carcinoma. TG2 was determined to be highly elevated in epidermal cancer stem cells (ECS cells), and TG2 knockdown or suppression of TG2 function with inhibitors reduced ECS cell survival, spheroid formation, Matrigel invasion, and migration. The reduction in survival is associated with activation of apoptosis. Mechanistic studies, using TG2 mutants, revealed that the GTP-binding activity is required for maintenance of ECS cell growth and survival, and that the action of TG2 in ECS cells is not mediated by NF-kappaB signaling. IMPLICATIONS: This study suggests that TG2 has an important role in maintaining cancer stem cell survival, invasive, and metastatic behavior and is an important therapeutic target to reduce survival of cancer stem cells in epidermal squamous cell carcinoma. PMID- 25934692 TI - Therapeutic Targeting of Nuclear gamma-Tubulin in RB1-Negative Tumors. AB - In addition to its cytosolic function, gamma-tubulin is a chromatin-associated protein. Reduced levels of nuclear gamma-tubulin increase the activity of E2 promoter-binding factors (E2F) and raise the levels of retinoblastoma (RB1) tumor suppressor protein. In tumor cells lacking RB1 expression, decreased gamma tubulin levels induce cell death. Consequently, impairment of the nuclear activity of gamma-tubulin has been suggested as a strategy for targeted chemotherapy of RB1-deficient tumors; thus, tubulin inhibitors were tested to identify compounds that interfere with gamma-tubulin. Interestingly, citral increased E2F activity but impaired microtubule dynamics while citral analogues, such citral dimethyl acetal (CDA), increased E2F activity without affecting microtubules. The cytotoxic effect of CDA on tumor cells was attenuated by increased expression of either RB1 or gamma-tubulin, and increased by reduced levels of either RB1 or gamma-tubulin. Mechanistic study, in silico and in vitro, demonstrated that CDA prevents GTP binding to gamma-tubulin and suggested that the FDA-approved drug dimethyl fumarate is also a gamma-tubulin inhibitor. Finally, in vivo growth of xenograft tumors carrying defects in the RB1 signaling pathway were inhibited by CDA treatment. These results demonstrate that inhibition of gamma-tubulin has the potential to specifically target tumor cells and may aid in the design of safer and more efficient chemotherapeutic regimes. IMPLICATIONS: The in vivo antitumorigenic activity of gamma-tubulin inhibitors paves the way for the development of a novel broad range targeted anticancer therapy that causes fewer side effects. PMID- 25934693 TI - miR-19-Mediated Inhibition of Transglutaminase-2 Leads to Enhanced Invasion and Metastasis in Colorectal Cancer. AB - Transglutaminase-2 (TG2) is a critical cross-linking enzyme in the extracellular matrix (ECM) and tumor microenvironment (TME). Although its expression has been linked to colorectal cancer, its functional role in the processes that drive disease appears to be context dependent. There is now considerable evidence of a role for microRNAs (miRNA) in the development and progression of cancer, including metastasis. A cell model of metastatic colon adenocarcinoma was used to investigate the contribution of miRNAs to the differential expression of TG2, and functional effects on inflammatory and invasive behavior. The impact of TG2 in colorectal cancer was analyzed in human colorectal tumor specimens and by manipulations in SW480 and SW620 cells. Effects on invasive behavior were measured using Transwell invasion assays, and cytokine production was assessed by ELISA. TG2 was identified as a target for miR-19 by in silico analysis, which was confirmed experimentally. Functional effects were evaluated by overexpression of pre-miR-19a in SW480 cells. Expression of TG2 correlated inversely with invasive behavior, with knockdown in SW480 cells leading to enhanced invasion, and overexpression in SW620 cells the opposite. TG2 expression was observed in colorectal cancer primary tumors but lost in liver metastases. Finally, miR-19 overexpression and subsequent decreased TG2 expression was linked to chromosome 13 amplification events, leading to altered invasive behavior in colorectal cancer cells. IMPLICATIONS: Chromosome-13 amplification in advanced colorectal cancer contributes to invasion and metastasis by upregulating miR-19, which targets TG2. PMID- 25934694 TI - Defective Myb Function Ablates Cyclin E1 Expression and Perturbs Intestinal Carcinogenesis. AB - Cyclin E1 is essential for the reentry of quiescent cells into the cell cycle. When hypomorphic mutant Myb mice (Myb(Plt4)) were examined, it was noted that Cyclin E1 (Ccne1) expression was reduced. Furthermore, the induction of Ccne1 in recovering intestinal epithelia following radiation-induced damage was ablated in Myb-mutant mice. These data prompted us to investigate whether Myb directly regulated Ccne1 and to examine whether elevated Myb in colorectal cancer is responsible for Cyclin E1-driven tumor growth. Here, it was found that Myb/MYB and Ccne1/CCNE1 expressions were coupled in both mouse and human adenomas. In addition, the low molecular weight Cyclin E1 was the predominant form in intestinal crypts and adenomatous polyposis coli (Apc)-mutant adenomas. Chromatin immunoprecipitation (ChIP) analysis confirmed that Myb bound directly to the Ccne1 promoter and regulated its endogenous expression. In contrast, Myb(Plt4) served as a dominant-negative factor that inhibited wild-type Myb and this was not apparently compensated for by the transcription factor E2F1 in intestinal epithelial cells. Myb(Plt4/Plt4) mice died prematurely on an Apc(Min/) (+) background associated with hematopoietic defects, including a myelodysplasia; nevertheless, Apc(Min/) (+) mice were protected from intestinal tumorigenesis when crossed to Myb(Plt4/) (+) mice. Knockdown of CCNE1 transcript in murine colorectal cancer cells stabilized chromosome ploidy and decreased tumor formation. These data suggest that Cyclin E1 expression is Myb dependent in normal and transformed intestinal epithelial cells, consistent with a cell-cycle progression and chromosome instability role in cancer. IMPLICATIONS: This study demonstrates that Myb regulates Cyclin E1 expression in normal gastrointestinal tract epithelial cells and is required during intestinal tumorigenesis. PMID- 25934695 TI - Colorectal Carcinogenesis: Connecting K-RAS-Induced Transformation and CREB Activity In Vitro and In Vivo. AB - Oncogenic transformation is often associated with an increased expression of the cAMP response element binding (CREB) transcription factor controlling the expression of genes involved in cell proliferation, cell cycle, apoptosis, and tumor development, but a link between K-RAS(V12)-induced transformation and CREB has not yet been determined. Therefore, the constitutive and/or inhibitor regulated mRNA and protein expression of CREB and signal transduction components and growth properties of parental fibroblasts, K-RAS(V12)-transformed counterparts, shCREB K-RAS(V12) transfectants and human colon carcinoma cells were determined. Increased CREB transcript and protein levels accompanied by an enhanced CREB activity was detected in K-RAS(V12)-transformed murine fibroblasts and K-RAS(V12)-mutated human tumor cells, which is dependent on the MAPK/MEK, PI3K, and/or PKC signal transduction. Immunohistochemical (IHC) staining of colorectal carcinoma lesions and murine tumors, with known KRAS gene mutation status, using antibodies specific for CREB and phospho-CREB, revealed a mechanistic link between CREB expression and K-RAS(V12)-mutated colorectal carcinoma lesions when compared with control tissues. Silencing of CREB by shRNA and/or treatment with a CREB inhibitor (KG-501) reverted the neoplastic phenotype of K-RAS(V12) transformants as demonstrated by a more fibroblast-like morphology, enhanced apoptosis sensitivity, increased doubling time, decreased migration, invasion and anchorage-independent growth, reduced tumorigenesis, and enhanced immunogenicity in vivo. The impaired shCREB-mediated invasion of K-RAS(V12) transformants was accompanied by a transcriptional downregulation of different matrix metalloproteinases (MMP) coupled with their reduced enzymatic activity. IMPLICATIONS: CREB plays a key role in the K-RAS(V12)-mediated neoplastic phenotype and represents a suitable therapeutic target for murine and human K RAS(V12)-induced tumors. PMID- 25934696 TI - HIC1 Tumor Suppressor Loss Potentiates TLR2/NF-kappaB Signaling and Promotes Tissue Damage-Associated Tumorigenesis. AB - Hypermethylated in cancer 1 (HIC1) represents a prototypic tumor suppressor gene frequently inactivated by DNA methylation in many types of solid tumors. The gene encodes a sequence-specific transcriptional repressor controlling expression of several genes involved in cell cycle or stress control. In this study, a Hic1 allele was conditionally deleted, using a Cre/loxP system, to identify genes influenced by the loss of Hic1. One of the transcripts upregulated upon Hic1 ablation is the toll-like receptor 2 (TLR2). Tlr2 expression levels increased in Hic1-deficient mouse embryonic fibroblasts (MEF) and cultured intestinal organoids or in human cells upon HIC1 knockdown. In addition, HIC1 associated with the TLR2 gene regulatory elements, as detected by chromatin immunoprecipitation, indicating that Tlr2 indeed represents a direct Hic1 target. The Tlr2 receptor senses "danger" signals of microbial or endogenous origin to trigger multiple signaling pathways, including NF-kappaB signaling. Interestingly, Hic1 deficiency promoted NF-kappaB pathway activity not only in cells stimulated with Tlr2 ligand, but also in cells treated with NF-kappaB activators that stimulate different surface receptors. In the intestine, Hic1 is mainly expressed in differentiated epithelial cells and its ablation leads to increased Tlr2 production. Finally, in a chemical-induced mouse model of carcinogenesis, Hic1 absence resulted in larger Tlr2-positive colonic tumors that showed increased proportion of proliferating cells. IMPLICATIONS: The tumor suppressive function of Hic1 in colon is related to its inhibitory action on proproliferative signaling mediated by the Tlr2 receptor present on tumor cells. PMID- 25934697 TI - Sprouty2 Drives Drug Resistance and Proliferation in Glioblastoma. AB - Glioblastoma multiforme (GBM) is notoriously resistant to therapy, and the development of a durable cure will require the identification of broadly relevant regulators of GBM cell tumorigenicity and survival. Here, we identify Sprouty2 (SPRY2), a known regulator of receptor tyrosine kinases (RTK), as one such regulator. SPRY2 knockdown reduced proliferation and anchorage-independent growth in GBM cells and slowed xenograft tumor growth in mice. SPRY2 knockdown also promoted cell death in response to coinhibition of the epidermal growth factor receptor (EGFR) and the c-MET receptor in GBM cells, an effect that involved regulation of the ability of the p38 mitogen-activated protein kinase (MAPK) to drive cell death in response to inhibitors. Analysis of data from clinical tumor specimens further demonstrated that SPRY2 protein is definitively expressed in GBM tissue, that SPRY2 expression is elevated in GBM tumors expressing EGFR variant III (EGFRvIII), and that elevated SPRY2 mRNA expression portends reduced GBM patient survival. Overall, these results identify SPRY2 and the pathways it regulates as novel candidate biomarkers and therapeutic targets in GBM. IMPLICATIONS: SPRY2, counter to its roles in other cancer settings, promotes glioma cell and tumor growth and cellular resistance to targeted inhibitors of oncogenic RTKs, thus making SPRY2 and the cell signaling processes it regulates potential novel therapeutic targets in glioma. PMID- 25934698 TI - Control of Wnt5b secretion by Wntless modulates chondrogenic cell proliferation through fine-tuning fgf3 expression. AB - Wnts and Fgfs regulate various tissues development in vertebrates. However, how regional Wnt or Fgf activities are established and how they interact in any given developmental event is elusive. Here, we investigated the Wnt-mediated craniofacial cartilage development in zebrafish and found that fgf3 expression in the pharyngeal pouches is differentially reduced along the anteroposterior axis in wnt5b mutants and wntless (wls) morphants, but its expression is normal in wnt9a and wnt11 morphants. Introducing fgf3 mRNAs rescued the cartilage defects in Wnt5b- and Wls-deficient larvae. In wls morphants, endogenous Wls expression is not detectable but maternally deposited Wls is present in eggs, which might account for the lack of axis defects in wls morphants. Secretion of endogenous Wnt5b but not Wnt11 was affected in the pharyngeal tissue of Wls morphants, indicating that Wls is not involved in every Wnt secretion event. Furthermore, cell proliferation but not apoptosis in the developing jaw was affected in Wnt5b- and Wls-deficient embryos. Therefore, Wnt5b requires Wls for its secretion and regulates the proliferation of chondrogenic cells through fine-tuning the expression of fgf3 during jaw cartilage development. PMID- 25934699 TI - Dgcr8 and Dicer are essential for sex chromosome integrity during meiosis in males. AB - Small RNAs play crucial roles in regulating gene expression during mammalian meiosis. To investigate the function of microRNAs (miRNAs) and small interfering RNAs (siRNAs) during meiosis in males, we generated germ-cell-specific conditional deletions of Dgcr8 and Dicer in mice. Analysis of spermatocytes from both conditional knockout lines revealed that there were frequent chromosomal fusions during meiosis, always involving one or both sex chromosomes. RNA sequencing indicates upregulation of Atm in spermatocytes from miRNA-deficient mice, and immunofluorescence imaging demonstrates an increased abundance of activated ATM kinase and mislocalization of phosphorylated MDC1, an ATM phosphorylation substrate. The Atm 3'UTR contains many potential microRNA target sites, and, notably, target sites for several miRNAs depleted in both conditional knockout mice were highly effective at promoting repression. RNF8, a telomere associated protein whose localization is controlled by the MDC1-ATM kinase cascade, normally associates with the sex chromosomes during pachytene, but in both conditional knockouts redistributed to the autosomes. Taken together, these results suggest that Atm dysregulation in microRNA-deficient germ lines contributes to the redistribution of proteins involved in chromosomal stability from the sex chromosomes to the autosomes, resulting in sex chromosome fusions during meiotic prophase I. PMID- 25934701 TI - Human ribosomes from cells with reduced dyskerin levels are intrinsically altered in translation. AB - Dyskerin is a pseudouridine (psi) synthase involved in fundamental cellular processes including uridine modification in rRNA and small nuclear RNA and telomere stabilization. Dyskerin functions are altered in X-linked dyskeratosis congenita (X-DC) and cancer. Dyskerin's role in rRNA pseudouridylation has been suggested to underlie the alterations in mRNA translation described in cells lacking dyskerin function, although relevant direct evidences are currently lacking. Our purpose was to establish definitely whether defective dyskerin function might determine an intrinsic ribosomal defect leading to an altered synthetic activity. Therefore, ribosomes from dyskerin-depleted human cells were purified and 1) added to a controlled reticulocyte cell-free system devoid of ribosomes to study mRNA translation; 2) analyzed for protein contamination and composition by mass spectrometry, 3) analyzed for global pseudouridylation levels. Ribosomes purified from dyskerin-depleted cells showed altered translational fidelity and internal ribosome entry site (IRES)-mediated translation. These ribosomes displayed reduced uridine modification, whereas they were not different in terms of protein contamination or ribosomal protein composition with respect to ribosomes from matched control cells with full dyskerin activity. In conclusion, lack of dyskerin function in human cells induces a defect in rRNA uridine modification, which is sufficient to alter ribosome activity. PMID- 25934702 TI - Soluble receptor for advanced glycation end products inhibits disease progression in autosomal dominant polycystic kidney disease by down-regulating cell proliferation. AB - Autosomal polycystic kidney disease (ADPKD) is a highly prevalent genetic renal disorder in which epithelial-lining fluid-filled cysts appear in kidneys. It is accompanied by hyperactivation of cell proliferation, interstitial inflammation, and fibrosis around the cyst lining cells, finally reaching end-stage renal disease. Previously, we found high expression of ligands stimulating the receptor for advanced glycation end products (RAGE) in ADPKD mice. Furthermore, gene silencing of RAGE was revealed to cause reduction of cystogenesis via down regulation of cell proliferation in vitro, and intravenous administration of anti RAGE adenovirus in vivo also displayed alleviation of the disease. Here, we attempted to identify the role of soluble RAGE (sRAGE) in inhibiting the progression of ADPKD using 2 different ADPKD mouse models. sRAGE is an endogenously expressed form of RAGE that has no membrane-anchoring domain, thereby giving it the ability to neutralize the ligands that stimulate RAGE signals. Both overexpression of sRAGE and sRAGE treatment blocked RAGE-mediated cell proliferation in vitro. In addition, sRAGE-injected ADPKD mice showed reduced cysts accompanied by enhanced renal function, inhibition of cell proliferation, inflammation, and fibrosis. These positive therapeutic effects of sRAGE displayed little liver toxicity, suggesting it as a new potential therapeutic target of ADPKD with low side effects. PMID- 25934700 TI - SEA you later alli-GATOR--a dynamic regulator of the TORC1 stress response pathway. AB - Cells constantly adapt to various environmental changes and stresses. The way in which nutrient and stress levels in a cell feed back to control metabolism and growth are, unsurprisingly, extremely complex, as responding with great sensitivity and speed to the 'feast or famine, slack or stress' status of its environment is a central goal for any organism. The highly conserved target of rapamycin complex 1 (TORC1) controls eukaryotic cell growth and response to a variety of signals, including nutrients, hormones and stresses, and plays the key role in the regulation of autophagy. A lot of attention has been paid recently to the factors in this pathway functioning upstream of TORC1. In this Commentary, we focus on a major, newly discovered upstream regulator of TORC1--the multiprotein SEA complex, also known as GATOR. We describe the structural and functional features of the yeast complex and its mammalian homolog, and their involvement in the regulation of the TORC1 pathway and TORC1-independent processes. We will also provide an overview of the consequences of GATOR deregulation in cancer and other diseases. PMID- 25934703 TI - Determination of single nucleotide variants in Escherichia coli DH5alpha by using short-read sequencing. AB - Escherichia coli DH5alpha is a common laboratory strain that provides an important platform for routine use in cloning and synthetic biology applications. Many synthetic circuits have been constructed and successfully expressed in E. coli DH5alpha; however, its genome sequence has not been determined yet. Here, we determined E. coli DH5alpha genome sequence and identified genetic mutations that affect its phenotypic functions by using short-read sequencing. The sequencing results clearly described the genotypes of E. coli DH5alpha, which aid in further studies using the strain. Additionally, we observed 105 single nucleotide variants (SNVs), 83% of which were detected in protein-coding regions compared to the parental strain E. coli DH1. Interestingly, 23% of the protein-coding regions have mutations in their amino acid residues, whose biological functions were categorized into two-component systems, peptidoglycan biosynthesis and lipopolysaccharide biosynthesis. These results underscore the advantages of E. coli DH5alpha, which tolerates the components of transformation buffer and expresses foreign plasmids efficiently. Moreover, these SNVs were also observed in the commercially available strain. These data provide the genetic information of E. coli DH5alpha for its future application in metabolic engineering and synthetic biology. PMID- 25934704 TI - Inhibition of Sam68 triggers adipose tissue browning. AB - Obesity is associated with insulin resistance and type 2 diabetes; molecular mechanisms that promote energy expenditure can be utilized for effective therapy. Src-associated in mitosis of 68 kDa (Sam68) is potentially significant, because knockout (KO) of Sam68 leads to markedly reduced adiposity. In the present study, we sought to determine the mechanism by which Sam68 regulates adiposity and energy homeostasis. We first found that Sam68 KO mice have a significantly reduced body weight as compared to controls, and the difference is explained entirely by decreased adiposity. Interestingly, these effects were not mediated by a difference in food intake; rather, they were associated with enhanced physical activity. When they were fed a high-fat diet, Sam68 KO mice gained much less body weight and fat mass than their WT littermates did, and they displayed an improved glucose and insulin tolerance. In Sam68 KO mice, the brown adipose tissue (BAT), inguinal, and epididymal depots were smaller, and their adipocytes were less hypertrophied as compared to their WT littermates. The BAT of Sam68 KO mice exhibited reduced lipid stores and expressed higher levels of Ucp1 and key thermogenic and fatty acid oxidation genes. Similarly, depots of inguinal and epididymal white adipose tissue (WAT) in Sam68 KO mice appeared browner, their multilocular Ucp1-positive cells were much more abundant, and the expression of Ucp1, Cidea, Prdm16, and Ppargc1a genes was greater as compared to WT controls, which suggests that the loss of Sam68 also promotes WAT browning. Furthermore, in all of the fat depots of the Sam68 KO mice, the expression of M2 macrophage markers was up-regulated, and that of M1 markers was down-regulated. Thus, Sam68 plays a crucial role in controlling thermogenesis and may be targeted to combat obesity and associated disorders. PMID- 25934705 TI - Contribution of the hypothalamus and gut to weight gain susceptibility and resistance in mice. AB - Obesity susceptibility in humans and in rodent strains varies in response to the consumption of high-energy density (HED) diets. However, the exact mechanism(s) involved in this susceptibility remain(s) unresolved. The aim of the present study was to gain greater insight into this susceptibility by using C57BL/6J (B6) mice that were separated into obesity-prone (diet-induced obese (DIO)) and obesity-resistant (diet-induced resistant (DR)) groups following an HED diet for 6 weeks. Physiological, biochemical and gene expression assessments of energy balance were performed in the DIO and DR mice on an HED diet and chow-fed mice. The increased weight gain of the DIO mice as compared to the DR mice was associated with increased energy intake and higher plasma leptin and adiponectin levels but not with reduced physical activity or resting energy expenditure. Hypothalamic Pomc gene expression was elevated, but there were no changes in Npy or Agrp expression. Adipose tissue leptin and adiponectin gene expression were significantly reduced in the DIO group as compared to the DR group. Interestingly, ileum expression of G protein-coupled receptor (Gpr) 40 (Gpr40) was significantly increased, whereas Gpr120, Gpr119, Gpr41, and glucagon-like peptide 1 (Glp1) were reduced. Contrastingly, the lower weight gain of the DR group was associated with elevated adipose tissue leptin and adiponectin gene expression, but there were no differences in plasma hormone or hypothalamic gene expression levels as compared to chow-fed mice. Therefore, the present data demonstrate that susceptibility and resistance to diet-induced weight gain in B6 mice appears to be predominantly driven by peripheral rather than hypothalamic modifications, and changes in gut-specific receptors are a potentially important contributor to this variation. PMID- 25934707 TI - AGS67E, an Anti-CD37 Monomethyl Auristatin E Antibody-Drug Conjugate as a Potential Therapeutic for B/T-Cell Malignancies and AML: A New Role for CD37 in AML. AB - CD37 is a tetraspanin expressed on malignant B cells. Recently, CD37 has gained interest as a therapeutic target. We developed AGS67E, an antibody-drug conjugate that targets CD37 for the potential treatment of B/T-cell malignancies. It is a fully human monoclonal IgG2 antibody (AGS67C) conjugated, via a protease cleavable linker, to the microtubule-disrupting agent monomethyl auristatin E (MMAE). AGS67E induces potent cytotoxicity, apoptosis, and cell-cycle alterations in many non-Hodgkin lymphoma (NHL) and chronic lymphocytic leukemia (CLL) cell lines and patient-derived samples in vitro. It also shows potent antitumor activity in NHL and CLL xenografts, including Rituxan-refractory models. During profiling studies to confirm the reported expression of CD37 in normal tissues and B-cell malignancies, we made the novel discovery that the CD37 protein was expressed in T-cell lymphomas and in AML. AGS67E bound to >80% of NHL and T-cell lymphomas, 100% of CLL and 100% of AML patient-derived samples, including CD34(+)CD38(-) leukemic stem cells. It also induced cytotoxicity, apoptosis, and cell-cycle alterations in AML cell lines and antitumor efficacy in orthotopic AML xenografts. Taken together, this study shows not only that AGS67E may serve as a potential therapeutic for B/T-cell malignancies, but it also demonstrates, for the first time, that CD37 is well expressed and a potential drug target in AML. PMID- 25934706 TI - 60 YEARS OF NEUROENDOCRINOLOGY: Redefining neuroendocrinology: stress, sex and cognitive and emotional regulation. AB - The discovery of steroid hormone receptors in brain regions that mediate every aspect of brain function has broadened the definition of 'neuroendocrinology' to include the reciprocal communication between the brain and the body via hormonal and neural pathways. The brain is the central organ of stress and adaptation to stress because it perceives and determines what is threatening, as well as the behavioral and physiological responses to the stressor. The adult and developing brain possess remarkable structural and functional plasticity in response to stress, including neuronal replacement, dendritic remodeling, and synapse turnover. Stress causes an imbalance of neural circuitry subserving cognition, decision-making, anxiety and mood that can alter expression of those behaviors and behavioral states. This imbalance, in turn, affects systemic physiology via neuroendocrine, autonomic, immune and metabolic mediators. In the short term, as for increased fearful vigilance and anxiety in a threatening environment, these changes may be adaptive. But, if the danger passes and the behavioral state persists along with the changes in neural circuitry, such maladaptation may need intervention with a combination of pharmacological and behavioral therapies, as is the case for chronic anxiety and depression. There are important sex differences in the brain responses to stressors that are in urgent need of further exploration. Moreover, adverse early-life experience, interacting with alleles of certain genes, produce lasting effects on brain and body over the life course via epigenetic mechanisms. While prevention is most important, the plasticity of the brain gives hope for therapies that take into consideration brain-body interactions. PMID- 25934708 TI - Selective Nuclear Export Inhibitor KPT-330 Enhances the Antitumor Activity of Gemcitabine in Human Pancreatic Cancer. AB - Pancreatic cancer is an aggressive and deadly malignancy responsible for the death of over 37,000 Americans each year. Gemcitabine-based therapy is the standard treatment for pancreatic cancer but has limited efficacy due to chemoresistance. In this study, we evaluated the in vitro and in vivo effects of gemcitabine combined with the selective nuclear export (CRM1) inhibitor KPT-330 on pancreatic cancer growth. Human pancreatic cancer MiaPaCa-2 and metastatic pancreatic cancer L3.6pl cell lines were treated with different concentrations of KPT-330 and gemcitabine alone or in combination, and anchorage dependent/independent growth was recorded. In addition, L3.6pl cells with luciferase were injected orthotopically into the pancreas of athymic nude mice, which were treated with (i) vehicle (PBS 1 mL/kg i.p., 2/week and povidone/pluronic F68 1 mL/kg p.o., 3/week), (ii) KPT-330 (20 mg/kg p.o., 3/week), (iii) gemcitabine (100 mg/kg i.p., 2/week), or (iv) KPT-330 (10 mg/kg) + gemcitabine (50 mg/kg) for 4 weeks. KPT-330 and gemcitabine alone dose dependently inhibited anchorage-dependent growth in vitro and tumor volume in vivo compared with vehicle treatment. However, the combination inhibited growth synergistically. In combination, KPT-330 and gemcitabine acted synergistically to enhance pancreatic cancer cell death greater than each single-agent therapy. Mechanistically, KPT-330 and gemcitabine promoted apoptosis, induced p27, depleted survivin, and inhibited accumulation of DNA repair proteins. Together, our data suggest that KPT-330 potentiates the antitumor activity of gemcitabine in human pancreatic cancer through inhibition of tumor growth, depletion of the antiapoptotic proteins, and induction of apoptosis. PMID- 25934709 TI - Rho Kinase Inhibitor Fasudil Suppresses the Vasculogenic Mimicry of B16 Mouse Melanoma Cells Both In Vitro and In Vivo. AB - The aim of this study was to investigate the biologic role of the Rho kinase inhibitor fasudil in the vasculogenic mimicry (VM) of B16 mouse melanoma cells. It was previously reported that RhoA plays a critical role in angiogenesis by coordinating endothelial cell cytoskeleton remodeling and promoting endothelial cell motility. Although RhoA has been implicated in the regulation of angiogenesis, little has been described regarding its control of these tumor cell lined channels. In this study, we established an in vitro model of VM using 3 dimensional cell culturing of mouse B16 melanoma cells and studied VM in vivo by transplanting B16 cells into C57/BL mice. Next, we explored the effect of RhoA and Rho-associated, coiled-coil containing protein kinase (ROCK) on VM formation using the Rho kinase inhibitor fasudil. We provide direct evidence that fasudil leads to reduced vascular-like channels in Matrigel. Additional experiments suggested that fasudil prevents both initial cellular architecture changes and cell migration in vitro. Finally, we provide in-depth evidence for the underlying mechanisms of fasudil-induced VM destruction using the Rho-GTPase agonist lysophosphatidic acid. In vivo studies revealed that fasudil reduced B16 melanoma cell xenograft tumor growth without causing significant toxicity in mice. Fasudil treated tumors also displayed fewer VM channels. These results suggest that fasudil may be an emerging therapeutic option for targeting cancer VM. PMID- 25934712 TI - Correction: PTEN Loss Contributes to Erlotinib Resistance in EGFR-Mutant Lung Cancer by Activation of Akt and EGFR. PMID- 25934713 TI - Measles 2015: why public health matters to critical care. PMID- 25934710 TI - Inhibition of Mouse Breast Tumor-Initiating Cells by Calcitriol and Dietary Vitamin D. AB - The anticancer actions of vitamin D and its hormonally active form, calcitriol, have been extensively documented in clinical and preclinical studies. However, the mechanisms underlying these actions have not been completely elucidated. Here, we examined the effect of dietary vitamin D and calcitriol on mouse breast tumor-initiating cells (TICs, also known as cancer stem cells). We focused on MMTV-Wnt1 mammary tumors, for which markers for isolating TICs have previously been validated. We confirmed that these tumors expressed functional vitamin D receptors and estrogen receptors (ER) and exhibited calcitriol-induced molecular responses including ER downregulation. Following orthotopic implantation of MMTV Wnt1 mammary tumor cells into mice, calcitriol injections or a vitamin D supplemented diet caused a striking delay in tumor appearance and growth, whereas a vitamin D-deficient diet accelerated tumor appearance and growth. Calcitriol inhibited TIC tumor spheroid formation in a dose-dependent manner in primary cultures and inhibited TIC self-renewal in secondary passages. A combination of calcitriol and ionizing radiation inhibited spheroid formation more than either treatment alone. Further, calcitriol significantly decreased TIC frequency as evaluated by in vivo limiting dilution analyses. Calcitriol inhibition of TIC spheroid formation could be overcome by the overexpression of beta-catenin, suggesting that the inhibition of Wnt/beta-catenin pathway is an important mechanism mediating the TIC inhibitory activity of calcitriol in this tumor model. Our findings indicate that vitamin D compounds target breast TICs reducing tumor-initiating activity. Our data also suggest that combining vitamin D compounds with standard therapies may enhance anticancer activity and improve therapeutic outcomes. PMID- 25934716 TI - Reducing pressure injuries in critically ill patients by using a patient skin integrity care bundle (InSPiRE). AB - PURPOSE: To test an interventional patient skin integrity bundle, the InSPiRE protocol, for reducing pressure injuries in critically ill patients in an Australian adult intensive care unit. METHODS: Before and after design: patients receiving the intervention (InSPiRE protocol) were compared with a similar control group who received standard care. Data collected included demographic and clinical variables, skin assessment, presence and stage of pressure injuries, and score on the Sequential Organ Failure Assessment (SOFA). RESULTS: Overall, 207 patients were enrolled, 105 in the intervention group and 102 in the control group. Most patients were men (mean age, 55 years). The groups were similar on major demographic variables (age, SOFA scores, intensive care unit stay). Cumulative incidence of pressure injuries was significantly lower in the intervention group (18.1%) than in the control group (30.4%) for skin injuries ( [Formula: see text], P = .04) and mucous injuries (t = 3.27, P <= .001). Significantly fewer pressure injuries developed over time in the intervention group (log rank = 11.842, df = 1, P <= .001) and intervention patients had fewer skin injuries (> 3 pressure injuries/patient = 1/105) than did control patients (> 3 pressure injuries/patient = 10/102; P = .02). CONCLUSION: The intervention group, receiving the InSPiRE protocol, had a lower cumulative incidence of pressure injuries, and fewer and less severe pressure injuries that developed over time. Systematic and ongoing assessment of the patient's skin and risk for pressure injuries as well as implementation of tailored prevention measures are central to preventing pressure injuries. PMID- 25934717 TI - Validation of the RightLevelpH Detector for Monitoring Gastric pH. AB - BACKGROUND: The RightLevelpH indicator is a new device designed to measure the pH of gastric aspirate obtained via a nasogastric tube while minimizing exposure of the operator. OBJECTIVE: To validate the RightLevelpH indicator in vivo and in vitro. METHODS: With general anesthesia, 20 patients had placement of a nasogastric tube and a gastric pH electrode catheter after endotracheal intubation. Direct intragastric pH was recorded simultaneously with gastric aspirate pH by using the RightLevelpH indicator and by using an external pH electrode. Measurements were made every 30 minutes until removal of the nasogastric tube as indicated clinically. In vitro validation of the RightLevelpH indicator was performed by using standard buffer solutions. RESULTS: The pH of clear buffer solutions was linearly related to pH determined by the RightLevelpH indicator (R(2) = 0.99; P < .001). The pH of gastric aspirate determined with an external pH electrode was linearly related to the gastric aspirate pH determined by using the RightLevelpH indicator (R(2) = 0.92; P < .001). Intragastric pH determined with the catheter electrode was also linearly related but more loosely correlated with gastric aspirate pH determined by using an external pH electrode (R(2) = 0.52; P < .001) and by the RightLevelpH indicator (R(2) = 0.55; P < .001). CONCLUSIONS: The RightLevelpH indicator provides accurate measurements of the pH of gastric aspirate in patients. PMID- 25934718 TI - Use of a patient hand hygiene protocol to reduce hospital-acquired infections and improve nurses' hand washing. AB - BACKGROUND: Critically ill patients are at marked risk of hospital-acquired infections, which increase patients' morbidity and mortality. Registered nurses are the main health care providers of physical care, including hygiene to reduce and prevent hospital-acquired infections, for hospitalized critically ill patients. OBJECTIVE: To investigate a new patient hand hygiene protocol designed to reduce hospital-acquired infection rates and improve nurses' hand-washing compliance in an intensive care unit. METHODS: A preexperimental study design was used to compare 12-month rates of 2 common hospital-acquired infections, central catheter-associated bloodstream infection and catheter-associated urinary tract infection, and nurses' hand-washing compliance measured before and during use of the protocol. RESULTS: Reductions in 12-month infection rates were reported for both types of infections, but neither reduction was statistically significant. Mean 12-month nurse hand-washing compliance also improved, but not significantly. CONCLUSIONS: A hand hygiene protocol for patients in the intensive care unit was associated with reductions in hospital-acquired infections and improvements in nurses' hand-washing compliance. Prevention of such infections requires continuous quality improvement efforts to monitor lasting effectiveness as well as investigation of strategies to eliminate these infections. PMID- 25934719 TI - Nosocomial infections in patients with spontaneous intracerebral hemorrhage. AB - BACKGROUND: Nosocomial infections are frequent complications in patients with intracerebral hemorrhage. OBJECTIVES: To determine the prevalence, risk factors, and outcomes of nosocomial infections in patients with intracerebral hemorrhage. METHODS: Prospectively collected data on patients with spontaneous intracerebral hemorrhage between January 2009 and June 2012 were retrospectively reviewed. Patients who had nosocomial infection during the hospital stay were compared with patients who did not. Poor outcome was defined as death or discharge to a long term nursing facility. RESULTS: At least 1 nosocomial infection developed in 26% of 202 patients with intracerebral hemorrhage. The most common infections were pneumonia (18%), urinary tract infection (12%), meningitis or ventriculitis (3%), and bacteremia (1%). On univariate analysis, independent predictors of nosocomial infection were intraventricular hemorrhage, hydrocephalus, low score on the Glasgow Coma Scale at admission, hyperglycemia at admission, and treatment with mechanical ventilation. On multivariate regression analysis, the only significant predictor of nosocomial infection was intraventricular hemorrhage (odds ratio, 5.4; 95% CI, 1.2-11.4; P = .02). Patients with nosocomial infection were more likely than those without to require a percutaneous gastrostomy tube (odds ratio, 33.1, 95% CI, 23.3-604.4; P < .001) and to have a longer stay in the intensive care unit or hospital without a significant increase in mortality. Patients with nosocomial pneumonia were also more likely to have a poor outcome (P < .001). CONCLUSION: Pneumonia was the most common infection among patients with intracerebral hemorrhage. PMID- 25934720 TI - Negotiating Transitions: Involvement of Critical Care Outreach Teams in End-of Life Decision Making. AB - BACKGROUND: Little research has examined the involvement of critical care outreach teams in end-of-life decision making. OBJECTIVE: To establish how much time critical care outreach teams spend with patients who are subsequently subject to limitation of medical treatment and end-of-life decisions and how much influence the teams have on those decisions. METHODS: A single-center retrospective review, with qualitative analysis, in a large cancer center. Data from all patients referred emergently for critical care outreach from October 2010 to October 2011 who later had limitation of medical treatment or end-of-life care were retrieved. Findings were analyzed by using SPSS 19 and qualitative free text analysis. RESULTS: Of 890 patients referred for critical care outreach from October 2010 to October 2011, 377 were referred as an emergency; 108 of those had limitation of medical treatment and were included in the review. Thirty-five patients (32.4%) died while hospitalized. As a result of outreach intervention and a decision to limit medical treatment, 56 (51.9%) of the 108 patients received a formal end-of-life care plan (including care pathways, referral to palliative care team, hospice). About a fifth (21.5%) of clinical contact time is being spent on patients who subsequently are subject to limitation of medical treatment. Qualitative document analysis showed 5 emerging themes: difficulty of discussions about not attempting cardiopulmonary resuscitation, complexities in coordinating multiple teams, delays in referral and decision making, decision reversals and opaque decision making, and technical versus ethical imperatives. CONCLUSION: A considerable amount of time is being spent on these emergency referrals, and decisions to limit medical treatment are common. The appropriateness of escalation of levels of care is often not questioned until patients become critically or acutely unwell, and outreach teams subsequently intervene. PMID- 25934721 TI - An analysis of patients transferred to a tertiary oncological intensive care unit for defined procedures. AB - BACKGROUND: Up to 50 000 intensive care unit interhospital transfers occur annually in the United States. OBJECTIVE: To determine the prevalence, characteristics, and outcomes of cancer patients transferred from an intensive care unit in one hospital to another intensive care unit at an oncological center and to evaluate whether interventions planned before transfer were performed. METHODS: Data on transfers for planned interventions from January 2008 through December 2012 were identified retrospectively. Demographic and clinical variables, receipt of planned interventions, and outcome data were analyzed. RESULTS: Of 4625 admissions to an intensive care unit at the oncological center, 143 (3%) were transfers from intensive care units of other hospitals. Of these, 47 (33%) were transfers for planned interventions. Patients' mean age was 57 years, and 68% were men. At the time of intensive care unit transfer, 20 (43%) were receiving mechanical ventilation. Interventions included management of airway (n = 19) or gastrointestinal (n = 2) obstruction, treatment of tumor bleeding (n = 12), chemotherapy (n = 10), and other (n = 4). A total of 37 patients (79%) received the planned interventions within 48 hours of intensive care unit arrival; 10 (21%) did not because their signs and symptoms abated. Median intensive care unit and hospital lengths of stay at the oncological center were 4 and 13 days, respectively. Intensive care unit and hospital mortality rates were 11% and 19%, respectively. Deaths occurred only in patients who received interventions. CONCLUSIONS: Interhospital transfers of cancer patients to an intensive care unit at an oncological center are infrequent but are most commonly done for direct interventional care. Most patients received planned interventions soon after transfer. PMID- 25934722 TI - Screening situations for risk of ethical conflicts: a pilot study. AB - BACKGROUND: Ethical conflicts, often leading to poor teamwork and moral distress, are very challenging to patients, patients' families, and health care providers. A proactive approach to ethical conflicts may improve patient care outcomes. OBJECTIVES: To examine acceptability and feasibility of an ethics screening and early intervention tool for use by nurses caring for critically ill patients. METHODS: Twenty-eight nurses in 2 medical centers applied the ethics screening tool to 55 patient situations. Nurses assessed situations for risk factors and early indicators of ethical conflicts and analyzed level of risk. At study completion, nurses participated in focus group discussions about the tool's benefits and challenges. Frequency counts were performed on risk factors and early indicators of ethical conflicts. Content analysis was used on written explanations regarding high-, medium-, and low-risk situations and on focus group data. RESULTS: Older patients with multiple comorbid conditions and aggressive treatments were frequently assessed to be at risk for ethical conflicts. Nurses who witnessed patients' suffering and deterioration were likely to initiate the screening process. The most prominent family risk factors included unrealistic expectations and adamancy about treatment. The most prominent early indicators were signs of patients' suffering, unrealistic expectations, and providers' own moral distress. High-risk situations averaged a greater number of risk factors and early indicators than did medium- and low-risk situations. Certain risk factors featured prominently in high-risk situations. CONCLUSIONS: A phenomenon of shared suffering emerged from the study and signifies the importance of relational strategies such as routine family conferences and ethics consultation. PMID- 25934724 TI - Caring for patients with enteral feedings. PMID- 25934723 TI - Withholding or continuing enteral feedings during repositioning and the incidence of aspiration. AB - BACKGROUND: Withholding enteral feedings during repositioning is based on tradition, but available evidence does not support this practice. Although research indicates that withholding of enteral feedings during repositioning contributes to undernourishment, the relationship between continuing enteral feedings during repositioning and the incidence of aspiration has not been determined. OBJECTIVE: To determine the feasibility of a study designed to explore differences in the incidence of aspiration when enteral feedings are withheld or continued during repositioning. METHODS: A crossover design with a convenience sample from 3 medical and 3 surgical intensive care units was used. Two sample sets of subglottal secretions were collected from each patient, once when enteral feedings were withheld during repositioning and once when enteral feedings were continued during the change in position. The incidence of aspiration was assessed by testing specimens for the presence of pepsin. RESULTS: Sublgottal secretions were collected from 23 patients (n = 46 with crossover design). Aspiration during repositioning occurred in 2 patients when enteral feedings were withheld and in 2 patients when feedings were continued during repositioning. According to the McNemar test, the incidence of aspiration when enteral feedings were withheld did not differ significantly from the incidence when the feedings were continued during repositioning (P = .88). CONCLUSIONS: A research protocol to directly explore the relationship between the incidence of aspiration and withholding or continuing enteral feedings during repositioning is feasible. PMID- 25934725 TI - A case of thyrotoxic periodic paralysis with respiratory failure in an African American woman. AB - Thyrotoxic periodic paralysis is an acute endocrine emergency characterized by hyperthyroidism, profound muscle weakness and/or paralysis, and hypokalemia that is not due to potassium deficiency. Typically described in young males of Asian descent, it is becoming increasingly recognized outside of this demographic group and is believed to be an underrecognized cause of symptomatic hypokalemia. Thyrotoxic periodic paralysis usually manifests as acute onset of symmetrical distal extremity weakness and is treated with careful potassium replacement and nonselective beta-blockers. In this case, a 43-year-old African American woman with thyrotoxic periodic paralysis had recurrent lower extremity myopathy and acute respiratory failure precipitated by noncompliance with treatment for Graves disease. PMID- 25934726 TI - Post-myocardial infarction arrhythmias. PMID- 25934727 TI - Provider to patient ratios for nurse practitioners and physician assistants in critical care units. AB - BACKGROUND: Nurse practitioners and physician assistants are being increasingly integrated into intensive care unit and hospital-based care teams, yet limited information is available on provider to patient ratios. OBJECTIVE: To determine current provider to patient ratios for nurse practitioners and physician assistants working in intensive and acute care units and to assess factors that affect the ratios. METHODS: A descriptive study design was used with a Web-based survey of members of the American Association of Nurse Practitioners, American Academy of Physician Assistants, and the Society of Critical Care Medicine. RESULTS: Responses were received from 222 nurse practitioners and 211 physician assistants from all but 8 of the 50 United States and from Canada. Mean provider to patient ratios in intensive care were 1 to 5 (range, 1 to 3 - 1 to 8). In pediatric intensive care, the mean ratio of nurse practitioners to patients was 1 to 4 (range, 1 to 3 - 1 to 8). Factors that affected nurse practitioner and physician assistant provider to patient ratios included patients' severity of illness, number of patients in the unit, number of providers in the unit, patient diagnosis, number of physicians in the unit, time of day, and number of fellows and medical residents on service. CONCLUSIONS: Additional information on factors influencing provider to patient ratios and specific components of the roles of nurse practitioners and physician assistants will be important to ensure the best utilization of these providers to enable optimal patient care outcomes. PMID- 25934728 TI - Secondary ventricular fibrillation or pulseless ventricular tachycardia during cardiac arrest and epinephrine dosing. AB - BACKGROUND: Development of ventricular fibrillation or pulseless ventricular tachycardia after an initial rhythm of pulseless electrical activity or asystole is associated with significantly increased cardiac arrest mortality. OBJECTIVE: To examine differences in epinephrine administration during cardiac arrest between patients who had a secondary ventricular fibrillation or ventricular tachycardia develop and patients who did not. METHODS: Data were collected for 2 groups of patients with in-hospital cardiac arrest and an initial rhythm of pulseless electrical activity or asystole: those who had a secondary ventricular fibrillation or ventricular tachycardia develop (cases) and those who did not (controls). Dosing of epinephrine during cardiac arrest and other variables were compared between cases and controls. RESULTS: Of the 215 patients identified with an initial rhythm of pulseless electrical activity or asystole, 51 (23.7%) had a secondary ventricular fibrillation or ventricular tachycardia develop. Throughout the total duration of arrest, including periods of return of spontaneous circulation, the dosing interval for epinephrine in patients who had a secondary ventricular fibrillation or ventricular tachycardia develop was 1 mg every 3.4 minutes compared with 1 mg every 5 minutes in controls (P= .001). For the total duration of pulselessness, excluding periods of return of spontaneous circulation during the arrest, the dosing interval for epinephrine in patients who had a secondary ventricular fibrillation or ventricular tachycardia develop was 1 mg every 3.1 minutes versus 1 mg every 4.3 minutes in controls (P= .001). CONCLUSION: More frequent administration of epinephrine during cardiac arrest is associated with development of secondary ventricular fibrillation or ventricular tachycardia. PMID- 25934730 TI - Characterization of thrombin-bound dabigatran effects on protease-activated receptor-1 expression and signaling in vitro. AB - Thrombin, the key effector protease of the coagulation cascade, drives fibrin deposition and activates human platelets through protease-activated receptor-1 (PAR1). These processes are critical to the progression of thrombotic diseases. Thrombin is the main target of anticoagulant therapy, and major efforts have led to the discovery of new oral direct inhibitors of thrombin. Dabigatran is the first oral anticoagulant licensed for the prevention of thromboembolisms associated with orthopedic surgery and stroke prevention in atrial fibrillation. Dabigatran is a direct thrombin inhibitor that effectively blocks thrombin's catalytic activity but does not preclude thrombin's exosites and binding to fibrinogen. Thus, we hypothesized that catalytically inactive thrombin retains the capacity to bind to PAR1 through exosite-I and may modulate its function independent of receptor cleavage and activation. Here, we report that dabigatran at clinically relevant concentrations is an effective and acute inhibitor of thrombin-induced PAR1 cleavage, activation, internalization, and beta-arrestin recruitment in vitro. Interestingly, prolonged exposure to catalytic inactive thrombin incubated with dabigatran at 20-fold higher therapeutic concentration resulted in increased PAR1 cell-surface expression, which correlated with higher detectable levels of ubiquitinated receptor. These findings are consistent with ubiquitin function as a negative regulator of PAR1 constitutive internalization. Increased PAR1 expression also enhanced agonist-induced phosphoinositide hydrolysis and endothelial barrier permeability. Thus, catalytically inactive thrombin appears to modulate PAR1 function in vitro by stabilizing receptor cell surface expression; but given the high clearance rate of thrombin, the high concentration of dabigatran required to achieve this effect the in vivo physiologic relevance is unknown. PMID- 25934732 TI - TB contracts: BVA and BCVA call for more time. PMID- 25934733 TI - Marking World Veterinary Day. PMID- 25934731 TI - Agonist Binding and Desensitization of the MU-Opioid Receptor Is Modulated by Phosphorylation of the C-Terminal Tail Domain. AB - Sustained activation of G protein-coupled receptors can lead to a rapid decline in signaling through acute receptor desensitization. In the case of the MU-opioid receptor (MOPr), this desensitization may play a role in the development of analgesic tolerance. It is understood that phosphorylation of MOPr promotes association with beta-arrestin proteins, which then facilitates desensitization and receptor internalization. Agonists that induce acute desensitization have been shown to induce a noncanonical high-affinity agonist binding state in MOPr, conferring a persistent memory of prior receptor activation. In the current study, live-cell confocal imaging was used to investigate the role of receptor phosphorylation in agonist binding to MOPr. A phosphorylation cluster in the C terminal tail of MOPr was identified as a mediator of agonist-induced affinity changes in MOPr. This site is unique from the primary phosphorylation cluster responsible for beta-arrestin binding and internalization. Electrophysiologic measurements of receptor function suggest that both phosphorylation clusters may play a parallel role during acute receptor desensitization. Desensitization was unaffected by alanine mutation of either phosphorylation cluster, but was largely eliminated when both clusters were mutated. Overall, this work suggests that there are multiple effects of MOPr phosphorylation that appear to regulate MOPr function: one affecting beta-arrestin binding and a second affecting agonist binding. PMID- 25934734 TI - Ultimate accolade for farriers' past master. PMID- 25934735 TI - BEVA offers advice on employing EU vets. PMID- 25934736 TI - Strengthening collaboration on veterinary education. PMID- 25934737 TI - WSAVA draws attention to risks of raw meat-based diets. PMID- 25934738 TI - Making the transition from veterinary student to practice team member. PMID- 25934739 TI - Thinking differently about pedigree dogs. PMID- 25934741 TI - Rewarding contributions to animal welfare. PMID- 25934740 TI - Veterinary medicines: product update. PMID- 25934742 TI - Changes affecting the equine sector. PMID- 25934743 TI - Building practice-based research in the UK. PMID- 25934744 TI - TB testing. PMID- 25934745 TI - Emerging disease in UK amphibians. PMID- 25934746 TI - Organism of interest for research into CRGV. PMID- 25934747 TI - One swallow makes a runner. PMID- 25934748 TI - Getting ready for compulsory microchipping. PMID- 25934749 TI - VBF board election. PMID- 25934757 TI - Support for graduates taking their first steps in practice. PMID- 25934758 TI - Ten-minute chat. PMID- 25934759 TI - Clinical response to peroral endoscopic myotomy in patients with idiopathic achalasia at a minimum follow-up of 2 years. AB - BACKGROUND: The recently developed technique for peroral endoscopic myotomy (POEM) has been shown to be effective in several short-term studies. Longer term outcome data are largely non-existent. OBJECTIVE: To systematically report clinical outcome with a minimum post-POEM follow-up of 2 years. DESIGN: All patients treated consecutively by POEM for achalasia at three centres were retrospectively analysed, with a minimum follow-up of 2 years. The main outcome was the rate of POEM failures (Eckardt score >3) related to follow-up time. RESULTS: Of 85 patients treated, five (5.9%) cases were excluded due to protocol violation or loss to follow-up; the remaining 80 patients (mean age 44.9 years, 54% men) were followed clinically for 29 months (range 24-41). Initial clinical response was observed in 77 cases (96.3%). Clinical recurrences (later failures) were seen in a further 14 cases (17.7%), accounting for a total failure rate of 21.5%. In a multivariate analysis, age and endoscopic reflux signs were independent predictors of treatment success. Of the 17 failures, eight were among the first 10 cases treated in the participating centres. Reflux-associated sequelae included one case of a severe reflux-associated stricture requiring dilatation, and two patients with minor transient Eckardt score elevations curable by proton pump inhibitor (PPI) treatment. Endoscopic signs of reflux oesophagitis, mostly Los Angeles grade A/B, were seen in 37.5% (37/72) at the 2 year control. CONCLUSIONS: In this multicentre retrospective analysis, a high initial success rate of POEM is followed by a mid-term recurrence rate of 18%. Reflux oesophagitis, albeit mild, is frequent and should probably be treated by regular low-dose PPI therapy. TRIAL REGISTRATION NUMBER: NCT 01405417 (UKE study). PMID- 25934761 TI - Retraction. S-nitrosoglutathione supplementation to ovalbumin-sensitized and challenged mice ameliorates methacholine-induced bronchoconstriction. PMID- 25934762 TI - Correction to "Targeting of VX2 Rabbit Liver Tumor by Selective Delivery of 3 Bromopyruvate: A Biodistribution and Survival Study". PMID- 25934760 TI - The applicability of hepatocellular carcinoma risk prediction scores in a North American patient population with chronic hepatitis B infection. AB - BACKGROUND: Patients with chronic hepatitis B (CHB) infection are at an increased risk of developing hepatocellular carcinoma (HCC). Risk scores have been developed in Asian populations to predict HCC risk over time. AIM: To assess the performance of HCC risk prediction models in a heterogeneous population of patients with CHB. METHODS: Scores were calculated at baseline using CU-HCC, REACH-B, NGM1-HCC, NGM2-HCC and GAG-HCC models and the incidence of HCC was determined. The predictive ability of each score was evaluated using the area under the receiver operating characteristic curve (AUROC), Cox regression and plots of observed versus predicted HCC. The predictive value of the scores was compared between Asian and non-Asian patients and between cirrhotic versus non cirrhotic with and without treatment. RESULTS: Of 2105 patients, 70 developed HCC. Increasing risk score was associated with HCC in all models. The CU-HCC model had the highest AUROC in Asian (0.85) and non-Asian (0.91) patients. Patients identified as low risk by any model had a very low incidence of HCC (0 0.15 per year), with the highest proportion of patients identified as low risk using CU-HCC (67%) or GAG-HCC (78%). The risk of HCC was similar to predicted for low-risk and medium-risk patients but was lower than predicted for high-risk patients. Treated patients had a lower than predicted risk of HCC, particularly in non-cirrhotic high-risk patients with longer follow-up. CONCLUSIONS: Although all models predicted the risk of HCC, models that incorporated parameters of liver function or cirrhosis (CU-HCC/GAG-HCC) were most accurate. Low-risk patients likely require reduced HCC surveillance. PMID- 25934763 TI - Correction to "5-aza-Cytidine Is a Potent Inhibitor of DNA Methyltransferase 3a and Induces Apoptosis in HCT-116 Colon Cancer Cells via Gadd45- and p53-Dependent Mechanisms". PMID- 25934764 TI - Re: Magierowski M, Jasnos K, Pawlik M, Krzysiek-Maczka G, Ptak-Belowska A, Olszanecki R, Kwiecien S, Korbut R, and Brzozowski T (2013) Role of Angiotensin (1-7) in Gastroprotection against Stress-Induced Ulcerogenesis. The Involvement of Mas Receptor, Nitric Oxide, Prostaglandins, and Sensory Neuropeptides. J Pharmacol Exp Ther 347:717-726; doi:10.1124/jpet.113.207233. PMID- 25934765 TI - Dietary omega-3 fatty acids protect against vasculopathy in a transgenic mouse model of sickle cell disease. AB - The anemia of sickle cell disease is associated with a severe inflammatory vasculopathy and endothelial dysfunction, which leads to painful and life threatening clinical complications. Growing evidence supports the anti inflammatory properties of omega-3 fatty acids in clinical models of endothelial dysfunction. Promising but limited studies show potential therapeutic effects of omega-3 fatty acid supplementation in sickle cell disease. Here, we treated humanized healthy and sickle cell mice for 6 weeks with omega-3 fatty acid diet (fish-oil diet). We found that a omega-3 fatty acid diet: (i) normalizes red cell membrane omega-6/omega-3 ratio; (ii) reduces neutrophil count; (iii) decreases endothelial activation by targeting endothelin-1 and (iv) improves left ventricular outflow tract dimensions. In a hypoxia-reoxygenation model of acute vaso-occlusive crisis, a omega-3 fatty acid diet reduced systemic and local inflammation and protected against sickle cell-related end-organ injury. Using isolated aortas from sickle cell mice exposed to hypoxia-reoxygenation, we demonstrated a direct impact of a omega-3 fatty acid diet on vascular activation, inflammation, and anti-oxidant systems. Our data provide the rationale for omega 3 dietary supplementation as a therapeutic intervention to reduce vascular dysfunction in sickle cell disease. PMID- 25934766 TI - Analysis of phenotype and outcome in essential thrombocythemia with CALR or JAK2 mutations. AB - The JAK2 V617F mutation, the thrombopoietin receptor MPL W515K/L mutation and calreticulin (CALR) mutations are mutually exclusive in essential thrombocythemia and support a novel molecular categorization of essential thrombocythemia. CALR mutations account for approximately 30% of cases of essential thrombocythemia. In a retrospective study, we examined the frequency of MPL and CALR mutations in JAK2 V617F-negative cases of essential thrombocythemia (n=103). In addition, we compared the clinical phenotype and outcome of CALR mutant cases of essential thrombocythemia with a cohort of JAK2 V617F-positive essential thrombocythemia (n=57). CALR-positive cases represented 63.7% of double-negative cases of essential thrombocythemia, and most carried CALR type 1 or type 2 indels. However, we also identified one patient who was positive for both the JAK2 V617F and the CALR mutations. This study revealed that CALR mutant essential thrombocythemia is associated with younger age, higher platelet counts, lower erythrocyte counts, leukocyte counts, hemoglobin, and hematocrit, and increased risk of progression to myelofibrosis in comparison with JAK2 V617F-positive essential thrombocythemia. Analysis of the CALR mutant group according to indel type showed that CALR type 1 deletion is strongly associated with male gender. CALR mutant patients had a better overall survival than JAK2 V617F-positive patients, in particular patients of age 60 years or younger. In conclusion, this study in a Belgian cohort of patients supports and extends the growing body of evidence that CALR mutant cases of essential thrombocythemia are phenotypically distinct from JAK2 V617F-positive cases, with regards to clinical and hematologic presentation as well as overall survival. PMID- 25934767 TI - Deficiency in mouse hyaluronidase 2: a new mechanism of chronic thrombotic microangiopathy. AB - Hyaluronan is a major component of the extracellular matrix and glycocalyx. Its main somatic degrading enzymes are hyaluronidases 1 and 2, neither of which is active in the bloodstream. We generated hyaluronidase 2-deficient mice. These animals suffer from chronic, mild anemia and thrombocytopenia, in parallel with a 10-fold increase in plasma hyaluronan concentration. In this study we explored the mechanism of these hematologic anomalies. The decreased erythrocyte and platelet counts were attributed to peripheral consumption. The erythrocyte half life was reduced from 25 to 8 days without signs of premature aging. Hyaluronidase 2-deficient platelets were functional. Major intrinsic defects in erythrocyte membrane or stability, as well as detrimental effects of high hyaluronan levels on erythrocytes, were ruled out in vitro. Normal erythrocytes transfused into hyaluronidase 2-deficient mice were quickly destroyed but neither splenectomy nor anti-C5 administration prevented chronic hemolysis. Schistocytes were present in blood smears from hyaluronidase 2-deficient mice at a level of 1% to 6%, while virtually absent in control mice. Hyaluronidase 2-deficient mice had increased markers of endothelial damage and microvascular fibrin deposition, without renal failure, accumulation of ultra-large multimers of von Willebrand factor, deficiency of A Disintegrin And Metalloproteinase with ThromboSpondin type 1 motifs, member 13 (ADAMTS13), or hypertension. There was no sign of structural damage in hepatic or splenic sinusoids, or in any other microvessels. We conclude that hyaluronidase 2 deficiency induces chronic thrombotic microangiopathy with hemolytic anemia in mice. The link between this uncommon condition and hyaluronidase 2 remains to be explored in humans. PMID- 25934768 TI - Periprocedural safety of Pipeline therapy for unruptured cerebral aneurysms: Analysis of 279 Patients in a multihospital database. AB - The relative safety of unruptured aneurysm treatment with coiling versus flow diversion therapy is unknown. Most data available on flow diversion reflect highly focused patient groups and very experienced operators. We evaluated a national, multihospital patient database to examine periprocedural morbidity and mortality in patients treated with endovascular flow diversion therapy. The Premier Perspective database was used to identify patients hospitalized between May 2011 and March 2013 for unruptured aneurysm who underwent flow diversion therapy with a Pipeline embolization device. The risk of in-hospital mortality and morbidity was determined using ICD 9 codes. A total of 279 unruptured aneurysm patients at 18 medical centers underwent endovascular therapy with a Pipeline device. Adverse outcomes included in-hospital mortality in two cases (0.7%), discharge to long-term care in 22 cases (7.9%), ischemic complications in 14 cases (5.0%), hemorrhagic complications in four cases (1.4%), and postoperative neurological complications in nine cases (3.2%). This study of a large cohort of patient hospitalizations in the United States provides preliminary data on flow diversion in a "real world" scenario and demonstrates that the periprocedural morbidity and mortality is not negligible and must be considered in the context of the natural history of the aneurysms that are being treated. PMID- 25934769 TI - Effect of flow diversion with silk on aneurysm size: A single center experience. AB - Alterations in aneurysm size and mass effect can result in alleviation or aggravation of symptoms. We assessed the effects of flow diversion with SILK stents on aneurysm sac size and associated factors. A retrospective evaluation of 14 aneurysms treated with SILK stents alone with MRI follow-up was performed. Aneurysm sac size was measured using the sequence best demonstrating the sac. Aneurysm characteristics and flow-related enhancement on time of flight images were documented. Clinical histories were reviewed for evolution of symptoms. Complete collapse of the aneurysm sac was demonstrated at three and 18 months in 2/14 aneurysms. Increase in size was observed in 2/14 aneurysms with associated persistent flow on time of flight MRA. Blister formation with aggravation of symptoms was observed in one aneurysm, and subsequent decrease in size occurred after treatment with a second SILK. The other aneurysm which increased in size initially continued to enlarge asymptomatically despite retreatment with a second SILK, however at 24 months thrombosis of the sac and decrease in size was observed. The remaining 10/14 aneurysms decreased in size. Nine had corresponding MRA occlusion and the tenth demonstrated decreased but persistent flow on the time of flight MRA. No aneurysm with MRA occlusion increased in size. Decrease in sac size was associated with MRA occlusion in our study. Persistence of flow and blistering were associated with increased sac size. As previously demonstrated flow diversion may be effective in the treatment of large aneurysms presenting with mass effect, however rates of sac obliteration in this small series were not as high as previously reported. PMID- 25934770 TI - Severe cerebral vasospasm in chronic cocaine users during neurointerventional procedures: A report of two cases. AB - Cocaine is a widespread recreational drug that has the potential to induce neurological vascular diseases, including ischaemic and haemorrhagic stroke. Although arterial vasospasm has been suggested as a pathogenic factor in the development of neurovascular complications, it remains unclear whether cocaine users carry an increased risk to suffer iatrogenic vasospasm during endovascular procedures. We report the case of two patients with a history of cocaine abuse, who developed unusual severe vasospasms during different interventional procedures. The first case occurred in a middle-aged woman with an unruptured left internal carotid artery bifurcation aneurysm who was scheduled for treatment by remodelling assisted coiling. Just after the placement of the remodelling balloon, a severe occlusive vasospasm interrupted the procedure. The second case happened to a 46-year-old man with a non-aneurysmal subarachnoid haemorrhage and a symptomatic vasospasm in the right-sided anterior circulation who developed another occlusive vasospasm after the first attempt at transluminal balloon angioplasty. Further research is needed to establish a relation between cocaine use and increased risk of iatrogenic vasospasm in endovascular procedures, but we suggest practitioners be extremely cautious when treating this subgroup of patients. PMID- 25934771 TI - Flow-diverter stenting of post-traumatic bilateral anterior cerebral artery pseudoaneurysm: A case report. AB - The use of flow-diverter (FD) stents in recent years has positively changed the therapeutic approach to some vascular diseases, especially of certain types of aneurysms. This paper describes the case of a young patient after a major head trauma causing multiple skull fractures. The trauma occasioned two pseudoaneurysms from the A1 segment of the right anterior cerebral artery and from the A2 segment of the left anterior cerebral artery. Both lesions were treated with two Pipeline devices (ev3, Irvine, CA, USA) in two different sessions. The CT study and angiographic investigations performed in the following month showed a complete resolution of the post-traumatic pseudoaneurysmal lesions. Although the use of FD stents is described in the literature, particularly in the treatment of selected aneurysms, this paper shows good technical results in the use of these stents in cases of intracranial post traumatic pseudoaneurysms with clinical improvement. PMID- 25934772 TI - Hybrid, Y-configured, dual stent-assisted coil embolization in the treatment of wide-necked bifurcation aneurysms. AB - In Y-stenting, stabilization of the first stent may be problematic as in some cases it migrates during second stent insertion. This report evaluates the safety and effectiveness of the technique and presents the long-term results of hybrid, Y-configured, dual stent-assisted coil embolization in the treatment of wide necked bifurcation aneurysms. We retrospectively evaluated the patients treated endovascularly due to cerebral aneurysms. Twenty patients treated with hybrid Y stent-assisted coil embolization were enrolled in the study. In hybrid stenting, an open-cell intracranial stent (Neuroform) was used as a first stent to prevent stent migration. A closed-cell stent (Enterprise or Acclino) was used as a second stent and the aneurysm was embolized with coils between the stent struts. In all patients, hybrid Y-stenting and coil embolization were accomplished successfully. No stent migration occurred. Clinically, neither symptomatic neurologic complication nor death was seen. Of 20 wide-necked bifurcation aneurysms, nine were at the basilar tip, while seven were at the middle cerebral artery and three at the anterior communicating artery. In one patient, the aneurysm was at the A2 3 junction of the anterior cerebral artery. One of the patients had a subarachnoid hemorrhage. The mean angiographic follow-up was 25.6 months. No in stent stenosis was seen in any of the patients and recanalization in only one. Hybrid, Y-configured, dual stent-assisted coil embolization is a safe and effective method in the treatment of wide-necked bifurcation aneurysms to prevent stent migration and aneurysm recanalization, and is a viable alternative to microsurgery. PMID- 25934773 TI - Stent-assisted coiling for the treatment of ruptured micro-intracranial wide necked aneurysms. AB - The stent-assisted coil embolization technique has been increasingly used in the clinic, but its efficacy and safety have yet to be assessed. This study aimed to evaluate the efficacy and safety of stent-assisted coiling in the treatment of micro-intracranial wide-necked aneurysms. Between May 2007 and November 2011, a total of 35 micro-intracranial wide-necked ruptured aneurysms were occluded with Enterprise stent-assisted coils. The patients were followed up for two years. Stent-assisted coiling was performed successfully in all cases, and stent placement was satisfactory without any complications. Of 35 aneurysms, 13 (37.1%) were completely occluded, ten (28.5%) had residual necks, and 12 (34.2%) had residual aneurysms. In the two-year follow-up, no aneurysm rupture occurred and no patients had nerve dysfunction. All patients were reviewed by digital subtraction angiography or computed tomography angiography. One patient had a residual neck (2.8%), and no patients experienced stent restenosis or thromboembolic events. In general, stent-assisted coiling is effective and safe for the treatment of micro-intracranial wide-necked aneurysms. PMID- 25934774 TI - Coiling of a recurrent broad-necked posterior communicating aneurysm incorporating a fetal cerebral artery: A technical case report. AB - We describe a case of a right broad-necked posterior communicating artery (PcomA) aneurysm with a fetal posterior cerebral artery (PCA) incorporated in the aneurysm neck. We performed waffle cone stent-assisted coiling and achieved almost complete occlusion of the aneurysm. At 18-month follow-up angiography, the aneurysm was recanalized and further coiling was needed. The same waffle cone method of coiling might be expected to produce the same unsatisfactory results on follow-up, so we decided to use retrograde stent navigation and placement through the anterior communicating artery (AcomA) from the contralateral internal carotid artery (ICA) to the ipsilateral ICA and fetal PCA. The stent delivery microcatheter from the contralateral ICA could not be introduced in the AcomA. So 2 mg nimodipine was infused through the stent delivery microcatheter to the AcomA and the stent delivery microcatheter was passed through the AcomA easily and could be navigated to the ipsilateral A1, ICA, and to the fetal PCA. With this additional stent, the aneurysm was completely separated from the fetal PCA and ICA. Further coiling could be performed safely through the microcatheter in the ipsilateral ICA. The patient had stable aneurysm occlusion at the six-month follow up. PMID- 25934775 TI - Ultra-small diameter coils for treatment of intracranial aneurysms. AB - This study reports our initial clinical experience treating very small intracranial aneurysms using only Target(r) NanoTM coils. Retrospective angiographic and clinical analysis was performed on a non-randomized single arm registry of all intracranial aneurysms treated with only Target(r) NanoTM coils (1 mm and 1.5 mm diameter only) during a 12 month period at two academic hospitals. Fourteen patients with 14 intracranial aneurysms were treated. The maximum diameter of saccular aneurysms treated ranged from 1.5 to 3.5 mm; minimum aneurysm diameter was 1.1 to 2 mm. The immediate complete aneurysm occlusion rate was 86% (12/14), and a small residual within the aneurysm was seen in 14% (2/14) of cases. Packing density from coils ranged between 24% and 83% (mean 51%). The immediate complication rate was 0% (0/14). The angiographic/MR angiography follow up period was 22 to 70 weeks (mean 37 weeks) with an overall complete occlusion rate of 9/11 (81%), recurrence in 18% (2/11), and lack of follow-up in three cases, two due to death during hospitalization and one procedure not yet due for imaging follow-up. Both patients who died presented with brain aneurysm ruptures prior to treatment. Both recurrences were retreated with repeat coiling procedures. Our initial results using only Target(r) NanoTM coils for the endovascular treatment of very small intracranial aneurysms have demonstrated initial good safety and efficacy profiles. PMID- 25934776 TI - Carotid rete mirabile associated with subarachnoid hemorrhage from intracranial aneurysm: A case report and systematic review. AB - Carotid rete mirabile (CRM) is a rare physiological vascular network in humans that is most often found in Eastern populations. This paper describes a CRM associated with an aneurysmal subarachnoid hemorrhage (aSAH) and discusses the details of the patient's treatment. A 28-year-old woman was admitted to our service with clinical signs and symptoms of a spontaneous aSAH. Computed tomography revealed a diffuse and extensive SAH (Fisher group IV), while an angiogram showed an abnormal collateral network in the right carotid system and a hypoplastic aspect to the internal carotid artery (ICA) on the same side. In addition, a saccular aneurysm with a diameter of 9.5 mm was present in the ophthalmic segment of the left ICA. This case is extremely uncommon. To avoid rebleeding in the patient, we successfully treated the patient by clipping the aneurysmal lesion. No procedure was performed for the CRM. PMID- 25934777 TI - Thromboelastography for monitoring platelet function in unruptured intracranial aneurysm patients undergoing stent placement. AB - This study evaluated patients' preoperative platelet function and the relation between acute embolic or hemorrhagic complications in unruptured intracranial aneurysm patients undergoing stent treatment. From September 2013 to December 2013 we prospectively collected clinical data in all unruptured intracranial aneurysm patients undergoing stent-assisted coiling. All patients received a dual antiplatelet therapy (aspirin and clopidogrel) protocol. Diffusion-weighted 3-T MRI was performed for cerebral aneurysm patients within 24 hours after treatment. Platelet function was tested by thromboelastography. Forty-six patients with 50 intracranial aneurysms treated by stent-assisted coiling were included. Fifty three stents were deployed in 46 procedures, including 39 Enterprise stents and 14 Solitaire stents. Acute ischemia was detected in the territory of the stented vessel in 25 of 46 patients (54.3%), but did not cause permanent disability. There was a significant difference between groups with and without thromboembolism in terms of percentage platelet inhibition and ADP-induced clot strength (MAADP) for clopidogrel, but no significant difference with aspirin. MAADP had a predictive value yielding an area under the ROC curve of 0.67 (95% CI: 0.57-0.81, P < 0.05). Anterior circulation aneurysms were also associated with ischemic events (P = 0.034). Silent acute embolism may be frequent in unruptured intracranial aneurysm treated with stent-assisted coiling even when dual antiplatelet therapy is given. The antiplatelet inhibition parameter (MAADP) was a predictor for acute thromboembolism in unruptured intracranial aneurysm patients treated by stent-assisted coiling. PMID- 25934778 TI - Evaluation of CTA, time-resolved 4D CE-MRA and DSA in the follow-up of an intracranial aneurysm treated with a flow diverter stent: Experience from a single case. AB - Endovascular treatment of giant, fusiform and dissecting aneurysms with flow diverter stents is becoming more and more popular. However, very few studies on the follow-up have been published. We describe a patient with a dissecting aneurysm of the right vertebral artery treated with flow diverter stent placement. The patient was followed up with CT angiography (CTA), time-resolved contrast-enhanced MR angiography (CE-MRA) and digital subtraction angiography (DSA). CTA had false negative results in two instances, whereas time-resolved CE MRA and DSA were the most accurate in depicting the residual flow in the aneurysmal sac. However, in the case of DSA the demonstration of residual flow proved quite difficult and required a very thorough examination with oblique projections. Our 2.5-year experience with this patient led us to believe that time-resolved CE-MRA is a valuable tool in the follow-up of flow diverter-treated stents. PMID- 25934779 TI - Rare complication characterized by late-onset transient neurological symptoms without hyperperfusion after carotid artery stenting: A report of three cases. AB - We experienced a rare complication after carotid artery stenting (CAS) characterized by transient neurological symptoms with no evidence of distal emboli or hyperperfusion. Using neuroimaging, we investigated the pathogenesis of the complication that occurred after CAS in three patients who developed neurological symptoms over a period of ten hours after CAS and improved within two days. None of the three patients showed signs of fresh infarctions on diffusion-weighted imaging or hyperperfusion on single-photon emission computed tomography. However, high signal intensity was observed in the leptomeningeal zone of the cerebral hemisphere on the stent side in all three patients and in the leptomeningeal zone of the contralateral anterior cerebral artery territory in one patient. These areas were assessed using fluid-attenuated inversion recovery (FLAIR) magnetic resonance imaging without gadolinium administration. The high signal intensity in the leptomeningeal zone disappeared as the symptoms improved. Based on the transient nature of the neurological disorders and the normalization of FLAIR imaging findings in these patients, the pathogenesis of this complication might have been vasogenic edema due to vasoparalysis of the local vessels caused by the hemodynamic changes occurring after CAS. PMID- 25934780 TI - Targeted embolization reduces hemorrhage complications in partially embolized cerebral AVM combined with gamma knife surgery. AB - This study investigated the effect and safety of targeted embolization in partially embolized cerebral arteriovenous malformation (AVM) followed by gamma knife surgery (GKS). We retrospectively analyzed 86 AVM patients who were targeted embolized by Onyx followed by GKS for residual nidus. Embolization related complications were collected and the clinical effect was evaluated. During targeted embolization, intranidus or hemodynamic aneurysms and AVM-related fistula were evaluated and targeted embolized. Patients with AVM-related aneurysms and fistula were divided into a targeted embolization group and non targeted embolization group based on the retrospectively determined treatment strategy. The effect of targeted embolization on hemorrhage risk was evaluated. The overall annual hemorrhage rate was 1.66% with 2.26% for ruptured AVMs and 1.08% for unruptured lesions. The annual mortality rate was 0.4%. Only one in 16 patients with embolization-related complications had permanent neurologic deficit. Twenty-four of 29 cases with intranidus aneurysms were targeted embolized, four of five cases with hemodynamic aneurysms were targeted embolized and eight of nine cases with arteriovenous fistula were targeted embolized. Chi square results showed the hemorrhage complications in the target embolization group were significantly lower than those in the non-target embolization group (p < 0.01). Targeted embolization combined with GKS treatment decreased the annual hemorrhage rate and improved clinical outcome with low permanent complications in partially embolized AVMs. This method could be proposed for the treatment of large brain AVMs when a single-technique treatment is not feasible. PMID- 25934781 TI - Hypoglossal canal dural arteriovenous fistula embolized under precise anatomical evaluation by selective intra-arterial injection computed tomography angiography. AB - Dural arteriovenous fistula (DAVF) involving the hypoglossal canal is rare but increasingly reported. To achieve complete obliteration without a procedure related complication, understanding of the precise anatomy of this DAVF is essential. Here, we describe a 72-year-old man who underwent selective intra arterial injection computed tomography angiography which allowed us to understand the detailed anatomy of the complex DAVF regarding access routes and the target regions for transvenous embolization (TVE). With the aid of this novel neuroimaging technique successful target TVE was achieved safely and completely. PMID- 25934782 TI - Embolization of a superior sagittal sinus dural arteriovenous fistula under intrasinus balloon protection: A case report. AB - Endovascular embolization has evolved to become the primary therapeutic option for dural arteriovenous fistulas (DAVFs). While guaranteeing complete occlusion of the fistula orifice, the goal of DAVF embolization is also to ensure the patency of normal cerebral venous drainage. This paper describes a case of successful embolization of a complex DAVF in the superior sagittal sinus with a multistaged approach using a combination of transvenous and transarterial tactics. The strategies and techniques are discussed. PMID- 25934783 TI - Assessment of periprocedural hemodynamic changes in arteriovenous malformation vessels by endovascular dual-sensor guidewire. AB - Endovascular embolization is an important modality in the treatment of brain AVMs. Nowadays staged embolization is the method of choice for the prevention of perioperative hemorrhagic complications. Current theory suggests that simultaneous occlusion of more than 60% of AVM volume induces significant redistribution local blood flow. That, in turn, may lead to hemorrhage due to AVM rupture. Aside from angiographic findings, there is still no method that predicts the degree of safe partial embolization. Intraluminal measurement of flow velocity and pressure in the vicinity of the AVM nidus might allow detecting the changes in local hemodynamics. That can provide a valuable data and shed the light on the origin of vascular catastrophes. Ten patients underwent 12 embolization sessions with intraluminal flow velocity and pressure monitoring. The measurements were performed by dual-sensor guidewire. The "Combomap" (Volcano) system with Combowire microguidewires was chosen for measurements, as there is a documented experience of safe use of said guidewires in the cerebral vasculature. The findings observed during the study matched empirical data as well as the current physiological hypothesis of AVM hemorrhage. In conjunction with DSA runs, intraluminal flow velocity and pressure monitoring has the potential to become a valuable tool in AVM treatment. PMID- 25934784 TI - Head and neck neurovascular trauma: Clinical and angiographic correlation. AB - A retrospective review of all angiograms done for craniocervical trauma, over an eight-year period at Groote Schuur Hospital identified 61 patients out of 823 angiographically studied who had extradural vascular injury and required endovascular treatment. Multiple lesions were identified in nine (14,8%) patients and associated injuries were found in 23 patients (37%). The mechanism of injury was blunt in nine (14.8%) patients and penetrating in 52 (85.2%). There was a statistically significant correlation between the presenting clinical feature and the underlying angiographic lesion. Patients with active bleeding were more likely to have a vessel laceration, an expanding hematoma was associated with false aneurysm and a pulsatile mass with arteriovenous fistula. Endovascular treatment with emphasis on vessel occlusion rather than preservation was successful in all cases except one which required surgical vessel ligation. PMID- 25934785 TI - Prospective series of two hours supine rest after 4fr sheath-based diagnostic cerebral angiography: Outcomes, productivity and cost. AB - There is no standard of care for catheter size or post-procedure supine time in cerebral angiography. Catheter sizes range from 4-Fr to 6-Fr with supine times ranging from two to over six hours. The objective of our study was to establish the efficacy, safety, and cost savings of two-hour supine time after 4-Fr elective cerebral angiography. A prospective, single arm study was performed on 107 patients undergoing elective cerebral angiography. All cerebral angiograms were performed with a 4-Fr sheath-based system without closure devices. Ten minutes of manual compression was applied to the femoral access site, with further compression held as clinically indicated. Patients were then monitored in a nursing unit for two hours supine and subsequently mobilized. Nursing discretion was allowed for earlier mobilization. Patients were called the next day to assess delayed hematoma and bleeding. Estimates of cost savings and productivity increases are provided. All patients ambulated in two hours or less. There were no strokes or vessel dissections. Five patients (4.7%) experienced a palpable hematoma, three patients (2.8%) experienced bleeding immediately following the procedure requiring further compression, and one patient (0.9%) experienced minor groin oozing at home. No patient required transfusion, thrombin injection, or endovascular/surgical management of a groin complication. A two hour post-procedure supine time resulted in cost savings of $952 per angiogram and a total of $101,864. 4-Fr sheath based cerebral angiography with two-hour post-procedure supine time is safe and effective, and allows for a considerable increase in patient satisfaction, cost savings and productivity. PMID- 25934786 TI - Endovascular biopsy: Technical feasibility of novel endothelial cell harvesting devices assessed in a rabbit aneurysm model. AB - The lack of safe and reliable methods to sample vascular tissue in situ limits discovery of the underlying genetic and pathophysiological mechanisms of many vascular disorders, including aneurysms. We investigated the feasibility and comparable efficacy of in vivo vascular endothelial cell sampling using a spectrum of endovascular devices. Using the rabbit elastase carotid aneurysm model we evaluated the performance of existing aneurysmal coils, intracranial stents, and stent-like devices to collect vascular endothelial cells. Additionally, we modified a subset of devices to assess the effects of alterations to coil pitch, coil wire contour, and stent surface finishing. Device performance was evaluated by (1) the number of viable endothelial cells harvested, (2) the degree of vascular wall damage analyzed using digital subtraction angiography and histopathological analysis, and (3) the ease of device navigability and retrieval. Isolated cells underwent immunohistochemical analysis to confirm cell type and viability. Coil and stent specifications, technique, and endothelial cell counts were tabulated and statistical analysis performed. Using conventional detachable-type and modified aneurysm coils 11 of 14 (78.6%) harvested endothelial cells with a mean of 7.93 (+/-8.33) cells/coil, while 15 of 15 (100%) conventional stents, stent-like devices and modified stents harvested endothelial cells with a mean of 831.33 (+/-887.73) cells/device. Coil stiffness was significantly associated with endothelial cell count in univariate analysis (p = 0.044). For stents and stent-like devices univariate analysis demonstrated stent-to-aorta diameter ratios (p = 0.001), stent length (p = 0.049), and the use of a pulling retrieval technique (p = 0.019) significantly predictive of endothelial cell counts, though a multivariate model using these variables demonstrated only the stent-to-aorta diameter ratio (p = 0.029) predictive of endothelial cell counts. Modified devices did not significantly impact harvesting. The efficacy and safety of existing aneurysm coils, intracranial stents and stent-like devices in collecting viable endothelial cells was confirmed. The technique is reproducible and the quantity and quality of collected endothelial cells is adequate for targeted genetic analysis. PMID- 25934787 TI - Does preoperative transarterial embolization decrease blood loss during spine tumor surgery? AB - This paper aimed to evaluate the effect of preoperative transarterial embolization (TAE) on estimated blood loss (EBL) during surgical excision of the vertebral tumors. Three hundred and forty-eight patients with spinal tumors were retrospectively analyzed. The preoperative TAE group consisted of 190 patients and the control group consisted of 158 patients. Gelatin sponge particles mixed withy contrast agent were used in the TAE group to embolize the tumor-feeding artery. The factors evaluated included: the time interval between embolism and surgery; the number of vertebrae involved by the tumor; pathological type of tumor; surgical approach; extent of excision and instrumental fixation. The time interval (P = 0.4669)between embolism and surgery had no significant correlation with EBL during surgery. The pathological diagnosis of vertebral tumor such as plasma cell myeloma, giant cell tumor, chondrosarcoma, hemangioma and metastasis had no significant correlation with EBL between the TAE group and control group during surgery, while the EBL of chordoma in the TAE group was significantly higher than that in the control group (p = 0.0254). The number of vertebrae involved (p = 0.4669, 0.6804, 0.6677), posterior approach (p = 0.3015), anterior approach (p = 0.2446), partial excision (p = 0.1911) and instrumental fixation (p = 0.1789) had no significant correlation with EBL during surgery between the TAE group and the control group. This study showed that preoperative TAE of the spinal tumor had no significant effect on intra-operative blood loss during surgical excision of the spinal tumor. In view of the risk of embolism, this method should be carefully considered. PMID- 25934789 TI - Erratum. AB - Stent fracture and occlusion after treatment of symptomatic vertebral artery ostium stenosis with a self-expanding device: A case report by Jun Lu, Jiachun Liu, Daming Wang and Shuo Wang, Interventional Neuroradiology 2014 20: 755-760, DOI: 10.15274/INR-2014-10068. In the above article the author affiliations were listed incorrectly, the correct version is listed below: Jun Lu(1), Jiachun Liu(2), Daming Wang(2) and Shuo Wang(1) (1)Department of Neurosurgery, Beijing Tiantan Hospital, Capital Medical University, Beijing, China (2)Department of Neurosurgery, Beijing Hospital, Beijing, China. PMID- 25934790 TI - Evolution of a G6P[6] rotavirus strain isolated from a child with acute gastroenteritis in Ghana, 2012. AB - Unusual human G6P[6] rotavirus A (RVA) strains have been reported sporadically in Europe and Africa, but how they evolved was not fully understood. The whole genome of a Ghanaian G6P[6] strain designated PML1965 (2012) was analysed to understand how it evolved in Africa and to learn how its G6 VP7 gene was related to that of rotaviruses of human and artiodactyl origin. The genotype constellation of RVA/Human-wt/GHA/PML1965/2012/G6P[6] was G6-P-[6]-I2-R2-C2-M2-A2 N2-T2-E2-H2. It shared sublineages with G6P[6] strains previously detected in Italy and Africa in all genome segments except the VP6 gene of a few Burkinabe and Cameroonian strains and both the VP6 and NSP4 genes of Guinea Bissau strains. The VP7 gene of the G6P[6] strains appeared to derive from those of human G6P[9] strains, and they were distantly related to the VP7 genes of artiodactyl G6 or human G6P[14] strains. The time of the most recent common ancestor of the VP7 sequences of G6P[6] strains was estimated to be the year 1998. The evolutionary rates of the VP7 genes in bovine and human G6 rotaviruses were 6.93 * 10(-4) and 3.42 * 10(-3) nucleotide substitutions site(-1) year(-1), respectively, suggesting an accelerated adaptive process in the new host. The sequences of the remaining 10 genome segments of PML1965 clustered with those of G2 and G8 human rotaviruses detected in Africa possessing the DS-1-like genetic background. In conclusion, PML1965 evolved from G2 or G8 RVA strains with DS-1-like background, acquiring the G6 VP7 gene from a human G6P[9] RVA and not from an artiodactyl G6 RVA strain. PMID- 25934791 TI - Identification and characterization of a novel geminivirus with a monopartite genome infecting apple trees. AB - A novel circular DNA virus sequence has been identified through next-generation sequencing and in silico assembly of small RNAs of 21-24 nt from an apple tree grown in China. The virus genome was cloned using two independent approaches and sequenced. With a size of 2932 nt, it showed the same genomic structure and conserved origin of replication reported for members of the family Geminiviridae. However, the low nucleotide and amino acid sequence identity with known geminiviruses indicated that it was a novel virus, for which the provisional name apple geminivirus (AGV) is proposed. Rolling circle amplification followed by RFLP analyses indicated that AGV was a virus with a monopartite DNA genome. This result was in line with bioassays showing that the cloned viral genome was infectious in several herbaceous plants (Nicotiana bethamiana, Nicotiana glutinosa and Solanum lycopersicum), thus confirming it was complete and biologically active, although no symptoms were observed in these experimental hosts. AGV genome structure and phylogenetic analyses did not support the inclusion of this novel species in any of the established genera in the family Geminiviridae. A survey of 165 apple trees grown in four Chinese provinces showed a prevalence of 7.2% for AGV, confirming its presence in several cultivars and geographical areas in China, although no obvious relationship between virus infection and specific symptoms was found. PMID- 25934792 TI - The C terminus of NS1 protein of influenza A/WSN/1933(H1N1) virus modulates antiviral responses in infected human macrophages and mice. AB - Non-structural protein NS1 of influenza A viruses interacts with cellular factors through its N-terminal RNA-binding, middle effector and C-terminal non-structured domains. NS1 attenuates antiviral responses in infected cells and thereby secures efficient virus replication. Some influenza strains express C-terminally truncated NS1 proteins due to nonsense mutations in the NS1 gene. To understand the role of the NS1 C-terminal region in regulation of antiviral responses, we engineered influenza viruses expressing C-terminally truncated NS1 proteins using A/WSN/33(H1N1) reverse genetics and tested them in human macrophages and in mice. We showed that a WSN virus expressing NS1 with a 28 aa deletion from its C terminus is a more powerful inducer of antiviral responses than the virus expressing full-length NS1, or one with a 10 aa truncation of NS1 in vitro. Thus, our findings suggest that the C-terminal region of NS1 is essential for regulation of antiviral responses. Moreover, viruses expressing truncated NS1 proteins could be good vaccine candidates. PMID- 25934794 TI - Oxygen and viruses: a breathing story. AB - The effect of oxygen on virus replication is complex, and the role of hypoxia inducible factor 1alpha (HIF-1alpha) in the metabolism of virus-infected cells remains uncertain. Solid tumours are hypoxic, and some viruses use this low oxygen tension level to facilitate their replication in tumour cells, thereby causing cell lysis. In addition, the interactions between viruses and HIF-1alpha may stimulate a trained immunity. However, the evolutionary basis for the oxygen regulatory mechanism of virus replication is ill-defined and requires further investigation. PMID- 25934793 TI - Characterization of the Punta Toro species complex (genus Phlebovirus, family Bunyaviridae). AB - Punta Toro virus (PTV), a member of the PTV complex, is a relatively common causative agent of febrile illness in Panama that is often misdiagnosed as 'dengue' or 'influenza'. Currently, only two named members make up this species complex, PTV and Buenaventura virus (BUEV). Genomic and antigenic characterization of 17 members of the PTV complex, nine of which were isolated from human acute febrile illness cases, reveals that this species complex is composed of six distant viruses. We propose to add four additional new viruses, designated Leticia virus, Cocle virus, Campana virus and Capira virus. PMID- 25934795 TI - Colon perforation and Budd-Chiari syndrome in Behcet's disease. AB - BACKGROUND: Behcet's disease is a chronic inflammatory disease involving multiple systems, with vasculitis being the most important pathological feature. Multiple colon perforations are thought to be secondary to vasculitis and they occur in patients with ulcers. These may be encountered within the entire colon but most commonly in the ileocecal region. Intestinal perforation and Budd-Chiari syndrome are infrequent in Behcet's disease, and are associated with high mortality and morbidity. Budd-Chiari syndrome results from occlusion of either hepatic veins or adjacent inferior vena cava, or both. CASE REPORT: We report a patient with Behcet's disease having multiple perforations in the transverse colon, descending colon, and sigmoid colon. The patient also had Budd-Chiari syndrome due to inferior vena cava thrombosis extending into the right and middle hepatic vein. Our observations are presented with a review of the literature. CONCLUSIONS: In Behcet's disease, treatment of colon perforation necessitates urgent surgery, whereas management of Budd-Chiari syndrome is directed towards the underlying cause. Behcet's disease, as a chronic multisystemic disease with various forms of vasculitis, is resistant to medical and surgical treatment. Prognosis is worse in Behcet's disease with colon perforation than that in Budd-Chiari syndrome alone. PMID- 25934796 TI - Expression of cold-inducible RNA-binding protein (CIRP) in pituitary adenoma and its relationships with tumor recurrence. AB - BACKGROUND: The aim of this study was to detect the expression of cold-inducible RNA-binding protein in pituitary adenoma and to determine its effects on tumor recurrence. MATERIAL/METHODS: We collected a total of 60 post-op samples collected from pituitary adenoma patients (including 20 cases of invasive pituitary adenoma, 20 cases of non-invasive adenoma, and 20 cases of non-invasive recurrent adenoma) admitted in our hospital. Both protein and mRNA levels of CIRP in 3 types of pituitary adenoma samples were quantified by Western blotting and real-time PCR, respectively. RESULTS: Western blotting revealed significantly elevated CIRP expression levels in invasive pituitary adenoma compared to non invasive tumors, with statistical significance (p<0.05). Recurrent pituitary adenoma expressed significantly higher CIRP levels compared to non-recurrent tumors (p<0.05). Real-time PCR for CIRP mRNA obtained consistent results: transcript levels were significantly higher in invasive pituitary adenoma compared to non-invasive adenoma (p<0.05); recurrent adenoma also had significantly higher CIRP mRNA levels compared to non-recurrent tumors (p<0.05). Among all 3 types of pituitary adenoma, recurrent tumors had the highest levels of CIRP mRNA and protein. CONCLUSIONS: The expression of CIRP in pituitary adenoma is closely related with tumor proliferation and invasion, and its significantly elevated expression level indicates post-op recurrence. PMID- 25934797 TI - Pathways with PathWhiz. AB - PathWhiz (http://smpdb.ca/pathwhiz) is a web server designed to create colourful, visually pleasing and biologically accurate pathway diagrams that are both machine-readable and interactive. As a web server, PathWhiz is accessible from almost any place and compatible with essentially any operating system. It also houses a public library of pathways and pathway components that can be easily viewed and expanded upon by its users. PathWhiz allows users to readily generate biologically complex pathways by using a specially designed drawing palette to quickly render metabolites (including automated structure generation), proteins (including quaternary structures, covalent modifications and cofactors), nucleic acids, membranes, subcellular structures, cells, tissues and organs. Both small molecule and protein/gene pathways can be constructed by combining multiple pathway processes such as reactions, interactions, binding events and transport activities. PathWhiz's pathway replication and propagation functions allow for existing pathways to be used to create new pathways or for existing pathways to be automatically propagated across species. PathWhiz pathways can be saved in BioPAX, SBGN-ML and SBML data exchange formats, as well as PNG, PWML, HTML image map or SVG images that can be viewed offline or explored using PathWhiz's interactive viewer. PathWhiz has been used to generate over 700 pathway diagrams for a number of popular databases including HMDB, DrugBank and SMPDB. PMID- 25934798 TI - Signal integration by the CYP1A1 promoter--a quantitative study. AB - Genes involved in detoxification of foreign compounds exhibit complex spatiotemporal expression patterns in liver. Cytochrome P450 1A1 (CYP1A1), for example, is restricted to the pericentral region of liver lobules in response to the interplay between aryl hydrocarbon receptor (AhR) and Wnt/beta-catenin signaling pathways. However, the mechanisms by which the two pathways orchestrate gene expression are still poorly understood. With the help of 29 mutant constructs of the human CYP1A1 promoter and a mathematical model that combines Wnt/beta-catenin and AhR signaling with the statistical mechanics of the promoter, we systematically quantified the regulatory influence of different transcription factor binding sites on gene induction within the promoter. The model unveils how different binding sites cooperate and how they establish the promoter logic; it quantitatively predicts two-dimensional stimulus-response curves. Furthermore, it shows that crosstalk between Wnt/beta-catenin and AhR signaling is crucial to understand the complex zonated expression patterns found in liver lobules. This study exemplifies how statistical mechanical modeling together with combinatorial reporter assays has the capacity to disentangle the promoter logic that establishes physiological gene expression patterns. PMID- 25934799 TI - An HDAC2-TET1 switch at distinct chromatin regions significantly promotes the maturation of pre-iPS to iPS cells. AB - The maturation of induced pluripotent stem cells (iPS) is one of the limiting steps of somatic cell reprogramming, but the underlying mechanism is largely unknown. Here, we reported that knockdown of histone deacetylase 2 (HDAC2) specifically promoted the maturation of iPS cells. Further studies showed that HDAC2 knockdown significantly increased histone acetylation, facilitated TET1 binding and DNA demethylation at the promoters of iPS cell maturation-related genes during the transition of pre-iPS cells to a fully reprogrammed state. We also found that HDAC2 competed with TET1 in the binding of the RbAp46 protein at the promoters of maturation genes and knockdown of TET1 markedly prevented the activation of these genes. Collectively, our data not only demonstrated a novel intrinsic mechanism that the HDAC2-TET1 switch critically regulates iPS cell maturation, but also revealed an underlying mechanism of the interplay between histone acetylation and DNA demethylation in gene regulation. PMID- 25934800 TI - Signatures of accelerated somatic evolution in gene promoters in multiple cancer types. AB - Cancer-associated somatic mutations outside protein-coding regions remain largely unexplored. Analyses of the TERT locus have indicated that non-coding regulatory mutations can be more frequent than previously suspected and play important roles in oncogenesis. Using a computational method called SASE-hunter, developed here, we identified a novel signature of accelerated somatic evolution (SASE) marked by a significant excess of somatic mutations localized in a genomic locus, and prioritized those loci that carried the signature in multiple cancer patients. Interestingly, even when an affected locus carried the signature in multiple individuals, the mutations contributing to SASE themselves were rarely recurrent at the base-pair resolution. In a pan-cancer analysis of 906 samples from 12 tumor types, we detected SASE in the promoters of several genes, including known cancer genes such as MYC, BCL2, RBM5 and WWOX. Nucleotide substitution patterns consistent with oxidative DNA damage and local somatic hypermutation appeared to contribute to this signature in selected gene promoters (e.g. MYC). SASEs in selected cancer gene promoters were associated with over-expression, and also correlated with the age of onset of cancer, aggressiveness of the disease and survival. Taken together, our work detects a hitherto under-appreciated and clinically important class of regulatory changes in cancer genomes. PMID- 25934802 TI - Splice junctions are constrained by protein disorder. AB - We have discovered that positions of splice junctions in genes are constrained by the tolerance for disorder-promoting amino acids in the translated protein region. It is known that efficient splicing requires nucleotide bias at the splice junction; the preferred usage produces a distribution of amino acids that is disorder-promoting. We observe that efficiency of splicing, as seen in the amino-acid distribution, is not compromised to accommodate globular structure. Thus we infer that it is the positions of splice junctions in the gene that must be under constraint by the local protein environment. Examining exonic splicing enhancers found near the splice junction in the gene, reveals that these (short DNA motifs) are more prevalent in exons that encode disordered protein regions than exons encoding structured regions. Thus we also conclude that local protein features constrain efficient splicing more in structure than in disorder. PMID- 25934801 TI - MDC1 functionally identified as an androgen receptor co-activator participates in suppression of prostate cancer. AB - Mediator of DNA damage checkpoint protein 1 (MDC1) is essential for DNA damage response. However, the role of MDC1 in modulating gene transcription independently of DNA damage and the underlying mechanisms have not been fully defined. Androgen receptor (AR) is the central signaling pathway in prostate cancer (PCa) and its target genes are involved in both promotion and suppression of PCa. Here, we functionally identified MDC1 as a co-activator of AR. We demonstrate that MDC1 facilitates the association between AR and histone acetyltransferase GCN5, thereby increasing histone H3 acetylation level on cis regulatory elements of AR target genes. MDC1 knockdown promotes PCa cells growth and migration. Moreover, depletion of MDC1 results in decreased expression of a subset of the endogenous androgen-induced target genes, including cell cycle negative regulator p21 and PCa metastasis inhibitor Vinculin, in AR positive PCa cell lines. Finally, the expression of MDC1 and p21 correlates negatively with aggressive phenotype of clinical PCa. These studies suggest that MDC1 as an epigenetic modifier regulates AR transcriptional activity and MDC1 may function as a tumor suppressor of PCa, and provide new insight into co-factor-AR-signaling pathway mechanism and a better understanding of the function of MDC1 on PCa. PMID- 25934803 TI - PUG-SOAP and PUG-REST: web services for programmatic access to chemical information in PubChem. AB - PubChem (http://pubchem.ncbi.nlm.nih.gov) is a public repository for information on chemical substances and their biological activities, developed and maintained by the US National Institutes of Health (NIH). PubChem contains more than 180 million depositor-provided chemical substance descriptions, 60 million unique chemical structures and 225 million bioactivity assay results, covering more than 9000 unique protein target sequences. As an information resource for the chemical biology research community, it routinely receives more than 1 million requests per day from an estimated more than 1 million unique users per month. Programmatic access to this vast amount of data is provided by several different systems, including the US National Center for Biotechnology Information (NCBI)'s Entrez Utilities (E-Utilities or E-Utils) and the PubChem Power User Gateway (PUG)-a common gateway interface (CGI) that exchanges data through eXtended Markup Language (XML). Further simplifying programmatic access, PubChem provides two additional general purpose web services: PUG-SOAP, which uses the simple object access protocol (SOAP) and PUG-REST, which is a Representational State Transfer (REST)-style interface. These interfaces can be harnessed in combination to access the data contained in PubChem, which is integrated with the more than thirty databases available within the NCBI Entrez system. PMID- 25934806 TI - Localize.pytom: a modern webserver for cryo-electron tomography. AB - Localize.pytom, available through http://localize.pytom.org is a webserver for the localize module in the PyTom package. It is a free website and open to all users and there is no login requirement. The server accepts tomograms as they are imaged and reconstructed by Cryo-Electron Tomography (CET) and returns densities and coordinates of candidate-macromolecules in the tomogram. Localization of macromolecules in cryo-electron tomograms is one of the key procedures to unravel structural features of imaged macromolecules. Positions of localized molecules are further used for structural analysis by single particle procedures such as fine alignment, averaging and classification. Accurate localization can be furthermore used to generate molecular atlases of whole cells. Localization uses a cross-correlation-based score and requires a reference volume as input. A reference can either be a previously detected macromolecular structure or extrapolated on the server from a specific PDB chain. Users have the option to use either coarse or fine angular sampling strategies based on uniformly distributed rotations and to accurately compensate for the CET common 'Missing Wedge' artefact during sampling. After completion, all candidate macromolecules cut out from the tomogram are available for download. Their coordinates are stored and available in XML format, which can be easily integrated into successive analysis steps in other software. A pre-computed average of the first one hundred macromolecules is also available for immediate download, and the user has the option to further analyse the average, based on the detected score distribution in a novel web-density viewer. PMID- 25934805 TI - Intermolecular 'cross-torque': the N4-cytosine propargyl residue is rotated to the 'CH'-edge as a result of Watson-Crick interaction. AB - Propargyl groups are attractive functional groups for labeling purposes, as they allow CuAAC-mediated bioconjugation. Their size minimally exceeds that of a methyl group, the latter being frequent in natural nucleotide modifications. To understand under which circumstances propargyl-containing oligodeoxynucleotides preserve base pairing, we focused on the exocyclic amine of cytidine. Residues attached to the exocyclic N4 may orient away from or toward the Watson-Crick face, ensuing dramatic alteration of base pairing properties. ROESY-NMR experiments suggest a uniform orientation toward the Watson-Crick face of N(4) propargyl residues in derivatives of both deoxycytidine and 5-methyl deoxycytidine. In oligodeoxynucleotides, however, UV-melting indicated that N(4) propargyl-deoxycytidine undergoes standard base pairing. This implies a rotation of the propargyl moiety toward the 'CH'-edge as a result of base pairing on the Watson-Crick face. In oligonucleotides containing the corresponding 5-methyl deoxycytidine derivative, dramatically reduced melting temperatures indicate impaired Watson-Crick base pairing. This was attributed to a steric clash of the propargyl moiety with the 5-methyl group, which prevents back rotation to the 'CH'-edge, consequently preventing Watson-Crick geometry. Our results emphasize the tendency of an opposing nucleic acid strand to mechanically rotate single N(4)-substituents to make way for Watson-Crick base pairing, providing no steric hindrance is present on the 'CH'-edge. PMID- 25934807 TI - Postdischarge phone calls after pediatric hospitalization: an observational study. AB - OBJECTIVES: Difficulties with transition from inpatient to outpatient care can lead to suboptimal outcomes for patients. We implemented a protocol for systematic follow-up phone calls to families of pediatric patients after discharge, primarily to improve care transition. We also hypothesized that the phone calls would decrease readmissions and emergency department (ED) visits after discharge and improve patient satisfaction. METHODS: We conducted a quasi experimental study examining the impact of routinely making follow-up phone calls, compared with historical control discharges. We implemented standardized attending physician phone calls to families of all patients discharged from a general pediatric hospitalist service. Calls were made within 72 hours of discharge to assess problems with transition. Charts were reviewed for documentation of difficulty with the care transition, 14-day and 30-day readmissions, ED visits, and Press-Ganey satisfaction scores. All results in the 12 months after the intervention were compared with the preceding12 months. RESULTS: We reached 78% of all patients' families by phone after discharge. Of the families reached, 19.9% needed an issue addressed, half of which were medication related. There were improvements in 14-day and 30-day readmissions and 14-day ED visit rates, as well as improvement in patient satisfaction scores, but none of these results reached statistical significance. CONCLUSIONS: Standardized, physician-performed, postdischarge phone calls identified frequent patient care issues related to difficulties with inpatient to outpatient transition, many of which were medication related. However, our study was underpowered to detect a statistically significant correlation with changes in readmission rates, ED visits, or patient satisfaction. PMID- 25934804 TI - The transcriptional PPARbeta/delta network in human macrophages defines a unique agonist-induced activation state. AB - Peroxisome proliferator-activated receptor beta/delta (PPARbeta/delta) is a lipid ligand-inducible transcription factor with established metabolic functions, whereas its anti-inflammatory function is poorly understood. To address this issue, we determined the global PPARbeta/delta-regulated signaling network in human monocyte-derived macrophages. Besides cell type-independent, canonical target genes with metabolic and immune regulatory functions we identified a large number of inflammation-associated NFkappaB and STAT1 target genes that are repressed by agonists. Accordingly, PPARbeta/delta agonists inhibited the expression of multiple pro-inflammatory mediators and induced an anti inflammatory, IL-4-like morphological phenotype. Surprisingly, bioinformatic analyses also identified immune stimulatory effects. Consistent with this prediction, PPARbeta/delta agonists enhanced macrophage survival under hypoxic stress and stimulated CD8(+) T cell activation, concomitantly with the repression of immune suppressive target genes and their encoded products CD274 (PD-1 ligand), CD32B (inhibitory Fcgamma receptor IIB) and indoleamine 2,3-dioxygenase 1 (IDO-1), as well as a diminished release of the immune suppressive IDO-1 metabolite kynurenine. Comparison with published data revealed a significant overlap of the PPARbeta/delta transcriptome with coexpression modules characteristic of both anti-inflammatory and pro-inflammatory cytokines. Our findings indicate that PPARbeta/delta agonists induce a unique macrophage activation state with strong anti-inflammatory but also specific immune stimulatory components, pointing to a context-dependent function of PPARbeta/delta in immune regulation. PMID- 25934808 TI - Is secondhand smoke exposure associated with increased exacerbation severity among children hospitalized for asthma? AB - OBJECTIVE: To determine the association between secondhand smoke (SHS) exposure and length of stay (LOS) and other exacerbation severity indicators in children hospitalized for asthma. METHODS: We conducted a retrospective chart review at 2 children's hospitals. Patients aged 2 to 18 hospitalized for asthma in 2012 were included. Outcome variables included LOS, PICU, magnesium, and intravenous (IV) steroids. Bivariate analysis determined differences between SHS-exposed and non SHS-exposed groups. Geometric means were used for LOS to account for skewed distribution. Logistic and zero-truncated negative binomial regression models were used to determine the independent association between SHS exposure and hospitalization severity indicators. RESULTS: A total of 623 patients were included; 41% reported SHS exposure. Mean LOS was 47.5 hours. In the SHS-exposed group, LOS was 50.0 (95% confidence interval [CI] 46.7-54.0) and in the nonexposed group it was 45.8 (95% CI 43.4-48.4) (P = .02). In regression analysis, institution modified the effect of SHS exposure on LOS. At Children's Hospital Colorado, SHS exposure was associated with a 20% increase in LOS (incidence rate ratio 1.2, 95% CI 1.1-1.3). At the Medical University of South Carolina, there was no significant association. SHS-exposed patients were more likely to receive IV steroids (odds ratio 1.6, 95% CI 1.1-2.3) CONCLUSIONS: Among children hospitalized for asthma, we identified a significant association at 1 institution between SHS exposure and LOS and found that IV steroid use was significantly associated with LOS at both institutions. Eliminating SHS exposure among children with asthma is important. PMID- 25934809 TI - Association Between Implementation of a Cardiovascular Step-Down Unit and Process of-Care Outcomes in Patients With Congenital Heart Disease. AB - BACKGROUND: The Joint Commission's 2009 National Patient Safety Goals aimed to improve identification of and response to clinical deterioration in hospital-ward patients. Some hospitals implemented intermediate-care units for patients without intensive care-level support needs. No studies have evaluated what effect changes associated with a move to a pediatric cardiovascular step-down unit (CVSDU) has on process-of-care outcomes. METHODS: A retrospective cohort study comparing process-of-care outcomes in units caring for children with congenital heart disease (n=1415) 1 year before (July 1, 2010-June 30, 2011) and 1 year after (August 1, 2011-July 30, 2012) implementation of a CVSDU following the move to a new hospital building. Units caring for noncardiac tracheostomy and/or ventilator dependent patients were used as controls (n=606). Primary outcomes included length of stay (LOS) and transfers to higher levels of care. Secondary outcomes included rapid response team, cardiopulmonary arrest, and code blue rates. Mann Whitney U and z tests were used for all analyses. RESULTS: When compared with a medical-surgical unit, cardiac patients admitted to a CVSDU had a significantly decreased total LOS (median 7.0 vs 5.4 days, P=.03), non-ICU LOS (median 3.5 vs 3.0 days, P=.006), and rapid response team/code blue rate per 1000 non-ICU patient days (11.2 vs 7.0, P=.04). No significant differences in primary or secondary outcomes were seen within the control group. CONCLUSIONS: Changes associated with a new CVSDU were associated with decreased LOS and lower rates of rapid response and code blue events for patients with congenital heart disease. PMID- 25934810 TI - Early weight loss nomograms for formula fed newborns. AB - OBJECTIVES: To develop nomograms depicting percentiles of weight loss by hour of age for both vaginal and cesarean-delivered newborns who are exclusively formula fed. METHODS: Data regarding delivery mode, race/ethnicity, feeding type, and weights were extracted from electronic medical records of the birth hospitalization at 14 Kaiser Permanente Northern California hospitals between 2009 and 2013. Newborns whose first feeding was formula from a cohort of 161 471 healthy, term, singleton neonates born at >=36 weeks' gestation between 2009 and 2013 were identified. Quantile regression was used to create nomograms stratified according to delivery mode; percentiles of weight loss were estimated as a function of time among formula-fed neonates. Weights measured subsequent to any breast milk feeding were excluded. Percentiles were determined through 48 and 72 hours of age for those born vaginally and via cesarean delivery, respectively. RESULTS: A total of 7075 formula-fed newborns had weights recorded; 4525 were delivered vaginally, and 2550 were born via cesarean delivery. The median weight loss was 2.9% at 48 hours after vaginal delivery; weight loss>7% was rare. For cesarean-delivered neonates, median weight losses at 48 and 72 hours were 3.7% and 3.5%, respectively; weight loss>8% was rare. CONCLUSIONS: For newborns who are formula fed, these results provide nomograms depicting percentiles of weight loss according to mode of delivery. These plots can be used to classify early weight loss according to percentile and may enable early identification of feeding difficulties or other neonatal morbidities. PMID- 25934811 TI - Effect of timing of psychiatry consultation on length of pediatric hospitalization and hospital charges. AB - OBJECTIVES: The purpose of this study was to evaluate the impact of timing of a psychiatry consultation during pediatric hospitalization on length of hospital stay and total hospitalization charges. METHODS: The charts of 279 pediatric patients (totaling 308 consultations) referred to the psychiatry consultation liaison service at a freestanding tertiary pediatric hospital between January 1, 2010, and June 30, 2010 were retrospectively analyzed. The variables analyzed included the following: patient demographic characteristics; dates of admission, psychiatric consultation, and discharge; psychiatric diagnoses based on the psychiatric diagnostic evaluation; psychiatric treatment disposition; and illness severity and total charges associated with the medical stay. RESULTS: Earlier psychiatry consultation was associated with shorter length of stay and lower hospitalization charges after adjusting for psychiatric functioning, physical illness severity, and psychiatric disposition. Poorer psychiatric functioning and milder physical illness were associated with shorter referral time. CONCLUSIONS: Timely involvement of psychiatry consultation services during a medical or surgical hospitalization was associated with reductions in length of stay and total hospital charges in pediatric settings. These findings have important effects on quality of care via decreasing burden on the patient and family and on the medical system resources. Educating pediatric health care providers about the importance of early psychiatry consultation regardless of physical illness severity or psychiatric acuity will likely improve resource management for patients and hospitals. PMID- 25934813 TI - Medical evaluation of abandoned infants less than 61 days of age. PMID- 25934812 TI - An evaluation of vancomycin dosing for complicated infections in pediatric patients. AB - OBJECTIVE: To determine the incidence with which a vancomycin dosing regimen of 15 mg/kg per dose every 6 hours achieves steady-state trough concentrations of 15 to 20 mg/L in pediatric patients with complicated infections. METHODS: We performed a retrospective chart review for patients admitted to our children's hospital between July 1, 2009, and June 30, 2011. Patients were included if they were between 1 month and 18 years of age, had at least 1 steady-state vancomycin trough obtained, received an initial vancomycin dose of 15 mg/kg per dose every 6 hours, and were being treated for a diagnosis of meningitis, pneumonia, osteomyelitis, bacteremia/sepsis, or endocarditis. RESULTS: Seventy-four patients were enrolled, mean age of 4.2+/-3.9 years and weight of 17.0+/-11.2 kg. Five (6.8%) patients obtained an initial trough of 15 to 20 mg/L. Patients between 1.0 and 5.9 years of age were significantly less likely to achieve an initial trough of 15 to 20 mg/L compared with other age groups evaluated (P=.041). Thirty-four patients with initial subtherapeutic troughs received a dose adjustment and a follow-up vancomycin trough. Of these patients, 15 (44.1%) achieved a trough between 15 and 20 mg/L. The median dose for patients achieving a therapeutic trough at any point during the study was 80 mg/kg per day. CONCLUSIONS: A vancomycin dosing regimen of 15 mg/kg per dose every 6 hours is not likely to achieve a trough concentration of 15 to 20 mg/L in pediatric patients with complicated infections. An initial regimen of 80 mg/kg per day for these patients may be more likely to result in therapeutic steady-state concentrations of vancomycin. PMID- 25934814 TI - Making every drop count for pediatric kidney transplant patients. PMID- 25934815 TI - Pediatric hospitalists in community hospitals: hospital-based generalists with expanded roles. PMID- 25934817 TI - Patients' Experience of Myositis and Further Validation of a Myositis-specific Patient Reported Outcome Measure - Establishing Core Domains and Expanding Patient Input on Clinical Assessment in Myositis. Report from OMERACT 12. AB - OBJECTIVE: The Outcome Measures in Rheumatology (OMERACT) myositis working group was established to examine patient-reported outcomes (PRO) as well as to validate patient-reported outcome measures (PROM) in myositis. METHODS: Qualitative studies using focus group interviews and cognitive debriefing of the myositis specific Myositis Activities Profile (MAP) were used to explore the experience of adults living with polymyositis (PM) and dermatomyositis (DM). RESULTS: Preliminary results underscore the importance of patient input in the development of PROM to ensure content validity. Results from multicenter focus groups indicate the range of symptoms experienced including pain, fatigue, and impaired cognitive function, which are not currently assessed in myositis. Preliminary cognitive debriefing of the MAP indicated that while content was deemed relevant and important, several activities were not included; and that questionnaire construction and wording may benefit from revision. A research agenda was developed to continue work toward optimizing PRO assessment in myositis with 2 work streams. The first would continue to conduct and analyze focus groups until saturation in the thematic analysis was achieved to develop a framework that encompassed the patient-relevant aspects of myositis. The second would continue cognitive debriefing of the MAP to identify potential areas for revision. There was agreement that further work would be needed for inclusion body myositis and juvenile dermatomyositis, and that the inclusion of additional contributors such as caregivers and individuals from the pharmaceutical/regulatory spheres would be desirable. CONCLUSIONS: The currently used PROM do not assess symptoms or the effects of disease that are most important to patients; this emphasizes the necessity of patient involvement. Our work provides concrete examples for PRO identification. PMID- 25934818 TI - Falls Associated with Muscle Strength in Patients with Knee Osteoarthritis and Self-reported Knee Instability. AB - OBJECTIVE: We aimed to evaluate the associations between knee muscle strength (MS) and falls, controlling for knee joint proprioception, varus-valgus knee joint laxity, and knee pain, among patients with knee osteoarthritis (OA) reporting knee instability. METHODS: A sample of 301 subjects (203 women, 98 men, 35-82 yrs) with established knee OA and self-reported knee instability was studied. The occurrence of at least 1 fall in the previous 3 months was assessed by questionnaire. Maximum knee extension and flexion strength were measured isokinetically. Additionally, proprioception, varus-valgus laxity, and pain were assessed. Student t tests were used to assess differences between subgroups. The association of muscle strength and falls was calculated using univariate and multivariate logistic regression analysis. RESULTS: Over 10% of the subjects (31 out of 301) reported a fall in the previous 3 months. High knee extension muscle strength (crude OR 0.3, 95% CI 0.1-0.8, p = 0.022) and high knee flexion muscle strength (crude OR 0.2, 95% CI 0.0-1.0, p = 0.048) were associated with a lower risk of falls. Proprioception and laxity did not confound this relationship. After adjusting for pain, extensor strength had an adjusted OR of 0.5 (95% CI 0.2 1.4, p = 0.212) for falls and flexor strength had an adjusted OR of 0.4 (95% CI 0.1-2.3, p = 0.312). CONCLUSION: High knee extension and flexion muscle strength decreased the risk of falls in patients with knee OA and self-reported knee instability. After considering the effect of pain, there was insufficient statistical power to detect an association between muscle strength and falls, which might be because of the low number of subjects who fell (n = 31). PMID- 25934816 TI - Toward precision medicine in glioblastoma: the promise and the challenges. AB - Integrated sequencing strategies have provided a broader understanding of the genomic landscape and molecular classifications of multiple cancer types and have identified various therapeutic opportunities across cancer subsets. Despite pivotal advances in the characterization of genomic alterations in glioblastoma, targeted agents have shown minimal efficacy in clinical trials to date, and patient survival remains poor. In this review, we highlight potential reasons why targeting single alterations has yielded limited clinical efficacy in glioblastoma, focusing on issues of tumor heterogeneity and pharmacokinetic failure. We outline strategies to address these challenges in applying precision medicine to glioblastoma and the rationale for applying targeted combination therapy approaches that match genomic alterations with compounds accessible to the central nervous system. PMID- 25934819 TI - Cardiac Involvement in Granulomatosis with Polyangiitis. AB - OBJECTIVE: To determine frequency and outcomes of granulomatosis with polyangiitis (GPA)-related cardiac disease in a North American GPA cohort. METHODS: Analysis was done of all patients in the Vasculitis Clinical Research Consortium Longitudinal Study of GPA. Demographic and clinical characteristics of patients with and without GPA-related cardiac involvement were compared. RESULTS: Of 517 patients with GPA, 3.3% had cardiac involvement. No differences were observed between patients with or without cardiac involvement in terms of demographics, antineutrophil cytoplasmic antibody positivity, or relapse rate. CONCLUSION: Cardiac involvement in GPA is rare and heterogeneous. In this cohort, cardiac involvement was not associated with a higher rate of relapse or premature death. PMID- 25934820 TI - Communication Vulnerabilities in Working-age Australians with Musculoskeletal Conditions: A Cross-sectional Analysis. AB - OBJECTIVE: To estimate the prevalence of communication vulnerability (CV) and its association with various health measures among working-age Australians with musculoskeletal conditions (MSK). The various vulnerability characteristics may lead to inadequate communication between consumers and healthcare professionals. METHODS: Prevalence of CV among 18-64 year olds, with or without MSK, was analyzed using the Australian Bureau of Statistics' National Health Survey 2007 08 data. Associations between CV and measures of health complexity (accumulating multimorbidity and risk factors) and health burden (poorer self-rated health, psychological distress, and pain restricting work) in the MSK population were estimated using logistic regression. Further analyses were conducted for each vulnerability characteristic to determine the degree of association (crude and adjusted) with measures of interest. RESULTS: CV were more prevalent in working age Australians with MSK (65%) than those without (51%). Adjusted for age and sex among working-age Australians with at least 1 MSK, those with 1 or more CV were more likely to have multimorbidity [adjusted OR (aOR) = 1.8, 95% CI 1.5-2.2], lifestyle risk factors (aOR = 2.1, 95% CI 1.5-2.8), poorer self-rated health (aOR = 3.4, 95% CI 2.7-4.2), greater psychological distress (aOR = 2.9, 95% CI 2.3 3.7), and pain restricting employment (aOR = 1.7, 95% CI 1.4-2.1) compared with those without CV. CONCLUSION: For working-age people, there is an association between MSK and CV. For those with MSK, CV were associated with increased likelihood of health complexity and burden. These findings have policy and clinical relevance. Research is needed to determine whether interventions that address these specific CV characteristics reduce the burden of disease within these populations. PMID- 25934821 TI - Near-infrared Fluorescence Optical Imaging in Early Rheumatoid Arthritis: A Comparison to Magnetic Resonance Imaging and Ultrasonography. AB - OBJECTIVE: Near-infrared fluorescence optical imaging (FOI) is a novel imaging technology in the detection and evaluation of different arthritides. FOI was validated in comparison to magnetic resonance imaging (MRI), greyscale ultrasonography (GSUS), and power Doppler ultrasonography (PDUS) in patients with early rheumatoid arthritis (RA). METHODS: Hands of 31 patients with early RA were examined by FOI, MRI, and US. In each modality, synovitis of the wrist, metacarpophalangeal joints (MCP) 2-5, and proximal interphalangeal joints (PIP) 2 5 were scored on a 4-point scale (0-3). Sensitivity and specificity of FOI were analyzed in comparison to MRI and US as reference methods, differentiating between 3 phases of FOI enhancement (P1-3). Intraclass correlation coefficients (ICC) were calculated to evaluate the agreement of FOI with MRI and US. RESULTS: A total of 279 joints (31 wrists, 124 MCP and 124 PIP joints) were evaluated. With MRI as the reference method, overall sensitivity/specificity of FOI was 0.81/0.00, 0.49/0.84, and 0.86/0.38 for wrist, MCP, and PIP joints, respectively. Under application of PDUS as reference, sensitivity was even higher, while specificity turned out to be low, except for MCP joints (0.88/0.15, 0.81/0.76, and 1.00/0.27, respectively). P2 appears to be the most sensitive FOI phase, while P1 showed the highest specificity. The best agreement of FOI was shown for PDUS, especially with regard to MCP and PIP joints (ICC of 0.57 and 0.53, respectively), while correlation with MRI was slightly lower. CONCLUSION: FOI remains an interesting diagnostic tool for patients with early RA, although this study revealed limitations concerning the detection of synovitis. Further research is needed to evaluate its full diagnostic potential in rheumatic diseases. PMID- 25934822 TI - Erectile Dysfunction Is Common among Patients with Gout. AB - OBJECTIVE: To determine whether men with gout may have an increased prevalence of erectile dysfunction (ED) as compared with men without gout. METHODS: In this cross-sectional study, men aged 18-89 presenting to the rheumatology clinic between August 26, 2010, and May 13, 2013, were asked to participate. The presence of ED was determined by the Sexual Health Inventory in Men (SHIM). SHIM classifies ED into 1 of 5 categories: absent (22-25), mild (17-21), mild to moderate (12-16), moderate (8-11), and severe (1-7). Patient's history, physical examination, and recent laboratory studies were reviewed as well. Descriptive statistics and subgroup analyses were used to summarize the data. RESULTS: Of the 201 men surveyed, 83 had gout (control, n = 118). A significantly greater proportion of patients with gout (63, 76%) had ED versus patients without gout (60, 51%, p = 0.0003). A significantly greater proportion of patients with gout (22, 26%) had severe ED versus patients without gout (17, 15%, p = 0.04). Patients with gout had an average SHIM score of 14.4 versus 18.48 in patients without gout (p < 0.0001). There was a statistically significant association between gout and ED. The association remained significant after adjustment for age, hypertension, diabetes, and obesity. CONCLUSION: ED is present in most men with gout and is frequently severe. We propose that patients with gout be routinely screened for ED. PMID- 25934823 TI - Consensus on the Need for a Hierarchical List of Patient-reported Pain Outcomes for Metaanalyses of Knee Osteoarthritis Trials: An OMERACT Objective. AB - OBJECTIVE: Although protocol registration for systematic reviews is still not mandatory, reviewers should be strongly encouraged to register the protocol to identify the methodological approach, including all outcomes of interest. This will minimize the likelihood of biased decisions in reviews, such as selective outcome reporting. A group of international experts convened to address issues regarding the need to develop hierarchical lists of outcome measurement instruments for a particular outcome for metaanalyses. METHODS: Multiple outcome measurement instruments exist to measure the same outcome. Metaanalysis of knee osteoarthritis (OA) trials, and the assessment of pain as an outcome, was used as an exemplar to assess how Outcome Measures in Rheumatology (OMERACT), the Cochrane Collaboration, and other international initiatives might contribute in this area. The meeting began with formal presentations of background topics, empirical evidence from the literature, and a brief introduction to 2 existing hierarchical lists of pain outcome measurement instruments recommended for metaanalyses of knee OA trials. RESULTS: After discussions, most participants agreed that there is a need to develop a methodology for generation of hierarchical lists of outcome measurement instruments to guide metaanalyses. Tools that could be used to steer development of such a prioritized list are the COSMIN checklist (COnsensus-based Standards for the selection of health status Measurement Instruments) and the OMERACT Filter 2.0. CONCLUSION: We list meta epidemiological research agenda items that address the frequency of reported outcomes in trials, as well as methodologies to assess the best measurement properties (i.e., truth, discrimination, and feasibility). PMID- 25934824 TI - Metric Properties of the SPARCC Score of the Sacroiliac Joints - Data from Baseline, 3-month, and 12-month Followup in the SPACE Cohort. AB - OBJECTIVE: To evaluate metric properties of the SpondyloArthritis Research Consortium of Canada (SPARCC) score of the sacroiliac (SI) joints. METHODS: Patients with back pain (>= 3 months, <= 2 years, onset < 45 years) were included in the SPACE cohort (SpondyloArthritis Caught Early). Patients with (possible) axial spondyloarthritis had followup visits after 3 and 12 months and were treated according to clinical practice. Magnetic resonance imaging (MRI) of the SI joints (MRI-SI) was scored in 2 independent campaigns (campaign 1: at baseline and 3 months; campaign 2: at baseline, 3 months, and 12 months) by 2 different blinded reader pairs, applying the Assessment of Spondyloarthritis International Society (ASAS) definition (MRI-SI+ vs MRI-SI-; discordant cases were adjudicated by a third reader) and SPARCC score (mean of 2 agreeing readers). Calculations were made for agreement between SPARCC score cutoff values and a consensus judgment of MRI-SI+ (ASAS definition) as external standard, change in SPARCC score, and smallest detectable changes (SDC) over 3 and 12 months. RESULTS: SPARCC score >= 2 showed best agreement with MRI-SI+ in both campaigns. Regarding observed changes in relation to SDC, SPARCC score changed in 70/151 patients; 26/70 patients changed > SDC (3.4), of whom 20 patients received stable treatment over 3 months in campaign 1. Over 3 months, 20/68 patients showed changes in SPARCC score; 11/20 > SDC (2.1), of whom 8 patients received stable treatment. Over 1 year, 23/74 patients changed their SPARCC score; 14/23 changed > SDC (2.4), of whom 7 received stable treatment in campaign 2. CONCLUSION: SPARCC score >= 2 can be used as surrogate for a consensus judgment of MRI-SI+ (ASAS definition) in clinical trials. The SDC ranged from 2.1-3.4 dependent on reader pair and were close to the proposed minimum important change of 2.5. PMID- 25934825 TI - Rheumatoid Arthritis Does Not Increase Risk of Short-term Adverse Events after Total Knee Arthroplasty: A Retrospective Case-control Study. AB - OBJECTIVE: More adverse events (AE) are reported after total knee arthroplasty (TKA) for patients with rheumatoid arthritis (RA) than for patients with osteoarthritis (OA). This study evaluates 6-month postoperative AE in a high volume center in a contemporary RA cohort. METHODS: Patients with RA in an institutional registry (2007-2010) were studied. AE were identified by self report and review of office and hospital charts. Subjects with RA were matched to 2 with OA by age, sex, and procedure. RA-specific surgical volume was determined. Baseline characteristics and AE were compared and analyzed. RESULTS: There were 159 RA TKA and 318 OA. Of the patients with RA, 88.0% were women, 24.5% received corticosteroids, 41.5% received biologics, and 67% received nonbiologic disease modifying antirheumatic drugs (DMARD). There was no difference in comorbidities. RA-specific surgical volume was high; 64% of cases were performed by surgeons with >= 20 RA cases during the study period. Patients with RA had worse baseline pain and function and lower perceived health status (EQ-5D 0.59 vs 0.65, p < 0.01). There were no deep infections in either group and no difference in superficial infection (9.4% RA vs 10.1% OA, p = 0.82), myocardial infarction (0.7% RA vs 0% OA, p = 0.33), or thromboembolism (1.3% RA vs 0.6% OA, p = 0.60). CONCLUSION: In a high-volume center, with high RA-specific experience, RA does not increase postoperative AE. Despite worse preoperative function and high steroid and DMARD use, complications were not increased. However, further study to determine generalizability is needed. PMID- 25934827 TI - Salivary Gland Ultrasonography as a Diagnostic Tool for Secondary Sjogren Syndrome in Rheumatoid Arthritis. AB - OBJECTIVE: To assess salivary gland ultrasonography (US) as a diagnostic tool for secondary Sjogren syndrome (sSS) in patients with rheumatoid arthritis (RA). METHODS: Salivary gland US images from 30 patients with RA were graded using a validated semiquantitative scoring system. Sicca symptoms, oral health, and RA disease activity were assessed. RESULTS: US changes consistent with SS were found in 40% of patients. Patients with higher US scores had more sicca symptoms as well as higher RA activity and poorer oral health. CONCLUSION: Salivary gland US may aid the diagnosis of sSS in patients with RA. PMID- 25934826 TI - Upregulation of Thrombospondin 1 Expression in Synovial Tissues and Plasma of Rheumatoid Arthritis: Role of Transforming Growth Factor-beta1 toward Fibroblast like Synovial Cells. AB - OBJECTIVE: To investigate the role of thrombospondin 1 (TSP-1) in RA. METHODS: Expression of TSP-1 in synovial tissues was determined by immunohistochemistry. Expression of TSP-1 in rheumatoid fibroblast-like synovial cells (FLS) was investigated by quantitative real-time PCR and ELISA. Correlations among the plasma TSP-1 and other variables in patients with RA were examined. RESULTS: Expression of TSP-1 was increased in rheumatoid synovial tissues. Transforming growth factor-beta1 (TGF-beta1) clearly increased TSP-1 expression in FLS on both mRNA and protein levels. Changes in plasma TSP-1 were associated with those in 28 joint Disease Activity Score-erythrocyte sedimentation rate and plasma TGF-beta1. CONCLUSION: TSP-1 might be critically involved in the disease process of RA through the TGF-beta1/TSP-1 axis. PMID- 25934828 TI - Enhanced Patient Involvement and the Need to Revise the Core Set - Report from the Psoriatic Arthritis Working Group at OMERACT 2014. AB - OBJECTIVE: To discuss the need for revision of the "core set" of domains to be included for assessment in psoriatic arthritis (PsA) randomized controlled trials and longitudinal observational studies, review work undertaken since the 2012 meeting of Outcome Measures for Rheumatology 11 (OMERACT 11) to include patient perspectives in this revision, and reassess proposed composite measures in the context of new research data and the OMERACT Filter 2.0 framework. METHODS: The OMERACT 12 (2014) PsA working group presented work completed over the last 2 years to incorporate patient involvement in PsA outcomes research, review the endorsed PsA core set based on the patient perspective as well as new research findings, and further develop PsA responder indices. Breakout groups then discussed 2 topics: (1) the need to revise the PsA core set, and opportunities to add, move, or merge existing domains to improve existing redundancy; and (2) how to incorporate the core set in a composite index. Breakout groups fed back to the working group before participant voting. RESULTS: Meeting participants endorsed the need to revise the PsA core set according to the OMERACT Filter 2.0 framework (100%), and the inclusion of disease impact (94%) and fatigue (72%) in the inner circle. Breakout group feedback suggested the core set revision was an opportunity to consolidate pathophysiologic aspects such as arthritis, enthesitis, dactylitis, spondylitis as "inflammatory musculoskeletal disease," and nail and skin psoriasis as "psoriasis activity." CONCLUSION: Future work will focus on updating the PsA core set and development of responder indices with ongoing, meaningful involvement of patient research partners. PMID- 25934829 TI - Effectiveness of Rituximab for the Treatment of Rheumatoid Arthritis in Patients with Prior Exposure to Anti-TNF: Results from the CORRONA Registry. AB - OBJECTIVE: To characterize the real-world effectiveness of rituximab (RTX) in patients with rheumatoid arthritis. METHODS: Clinical effectiveness at 12 months was assessed in patients who were prescribed RTX based on the Clinical Disease Activity Index (CDAI). Change in CDAI was calculated (CDAI at 12 mos minus at initiation). Achievement of remission or low disease activity (LDA; CDAI <= 10) among those with moderate/high disease activity at the time of RTX initiation was compared based on prior anti-tumor necrosis factor agent (anti-TNF) use (1 vs >= 2) using logistic regression models. RESULTS: Patients (n = 265) were followed for 12 months with a mean change in CDAI of -8.1 (95% CI -9.8 - -6.4). Of the 218 patients with moderate/high disease activity at baseline, patients with 1 prior anti-TNF (baseline CDAI 25.0) demonstrated a mean change in CDAI of -10.1 (95% CI -13.2 - -7.0); patients with >= 2 prior anti-TNF (baseline CDAI 30.0) demonstrated a mean change of -10.5 (95% CI -12.9 - -8.0). The unadjusted OR for achieving LDA/remission in patients with moderate/high disease activity at baseline exposed to >= 2 versus 1 prior anti-TNF was 0.40 (95% CI 0.22-0.73), which was robust to 4 different adjusted models (OR range 0.38-0.44). CONCLUSION: A good clinical response was observed in all patients; however, patients previously treated with 1 anti-TNF, who had lower baseline CDAI and a greater opportunity for clinical improvement compared with patients previously treated with >= 2 anti-TNF, were more likely to achieve LDA/remission. PMID- 25934831 TI - Statin use and survival from lung cancer: a population-based cohort study. AB - BACKGROUND: Preclinical evidence from lung cancer cell lines and animal models suggest that statins could have anticancer properties. We investigated whether statin users had reduced risk of cancer-specific mortality in a population-based cohort of lung cancer patients. METHODS: Newly diagnosed lung cancer patients, from 1998 to 2009, were identified from English cancer registry data and linked to the UK Clinical Practice Research Datalink, providing prescription records, and to Office of National Statistics mortality data up to 2012. Cox regression models were used to calculate HRs for cancer-specific mortality and 95% confidence intervals (CI) by statin use before and after diagnosis, and to adjust these HRs for potential confounders. RESULTS: In 3,638 lung cancer patients, there was some evidence that statin use after diagnosis was associated with reduced lung cancer-specific mortality (adjusted HR, 0.89; 95% CI, 0.78-1.02; P = 0.09). Associations were more marked after 12 prescriptions (adjusted HR, 0.81; 95% CI, 0.67-0.98; P = 0.03) and when lipophilic statins were investigated (adjusted HR, 0.81; 95% CI, 0.70-0.94; P = 0.01), but were attenuated in some sensitivity analyses. Furthermore, in 11,051 lung cancer patients, statin use before diagnosis was associated with reduced lung cancer-specific mortality (adjusted HR, 0.88; 95% CI, 0.83-0.93; P < 0.001). CONCLUSIONS: There was some evidence that lung cancer patients who used statins, and particularly simvastatin, had reduced rates of cancer-specific mortality. IMPACT: These findings should first be confirmed in observational studies, but provide some support for conducting randomized controlled trials of simvastatin as adjuvant cancer therapy in lung cancer patients. PMID- 25934832 TI - Lifetime physical activity and the risk of non-Hodgkin lymphoma. AB - Research regarding the association between physical activity and the risk of non Hodgkin lymphoma (NHL) is limited and inconsistent, and few studies have investigated whether the intensity and timing of physical activity influence the association. A case-control study of NHL was conducted in British Columbia, Canada, in 2000 to 2004. Data were collected on various NHL risk factors, including moderate-intensity and vigorous-intensity physical activity performed over the lifetime. Logistic regression was used to estimate the association between physical activity and the risk of NHL. This analysis included 818 controls and 749 cases. Lifetime vigorous-intensity physical activity was inversely associated with NHL risk. Participants in the second, third, and fourth quartiles of lifetime vigorous-intensity physical activity had an approximately 25% to 30% lower risk of NHL than those in the lowest quartile [adjusted odds ratios, 0.69 (95% confidence interval [CI], 0.52-0.93); 0.68 (95% CI, 0.50-0.92); and 0.75 (95% CI, 0.55-1.01), respectively]. No consistent associations were observed for total or moderate-intensity physical activity. There were no apparent age periods in which physical activity appeared to confer a greater risk reduction. In this study, we found that lifetime vigorous-intensity physical activity was associated with a significantly reduced risk of NHL. Given this finding, more research on physical activity intensity and timing in relation to NHL risk is warranted. PMID- 25934833 TI - The heritability of prostate cancer-letter. PMID- 25934834 TI - The heritability of prostate cancer-response. PMID- 25934835 TI - Correction: Improved survival outcomes in cancer patients with hereditary hemorrhagic telangiectasia. PMID- 25934836 TI - Correction: Urinary lead exposure and breast cancer risk in a population-based case-control study. PMID- 25934837 TI - Building a funded research program in cancer health disparities: considerations for young investigators. AB - A workshop entitled "Building a funded research program in cancer health disparities" was held at the 38th Annual American Society of Preventive Oncology (ASPO) Meeting. Organized by the Junior Members Interest Group, the session addressed topics relevant to career development for cancer disparities investigators. Such considerations include the development of research programs on a backdrop of existing multi- and transdisciplinary teams, recognizing opportunities for advancing their research, given the growth of consortia-related research, and development of effective community-based partnerships. Key strategies for developing a sustainable career in cancer health disparities in the current environment include the need to effectively engage with communities, appreciate the value of team science and develop cross-discipline collaborations, and navigate the use and utility of consortia for disparities research. Academic considerations related to earning tenure and promotion that may be faced by the junior investigator in cancer health disparities were also discussed. This report may serve to both educate and provide lessons for early-stage investigators who wish to tackle complex scientific questions while developing their careers in cancer health disparities. PMID- 25934839 TI - SMAD3 negatively regulates serum irisin and skeletal muscle FNDC5 and peroxisome proliferator-activated receptor gamma coactivator 1-alpha (PGC-1alpha) during exercise. PMID- 25934840 TI - Synovitis in knee osteoarthritis: a precursor or a concomitant feature? PMID- 25934838 TI - Platelet Extracellular Regulated Protein Kinase 5 Is a Redox Switch and Triggers Maladaptive Platelet Responses and Myocardial Infarct Expansion. AB - BACKGROUND: Platelets have a pathophysiologic role in the ischemic microvascular environment of acute coronary syndromes. In comparison with platelet activation in normal healthy conditions, less attention is given to mechanisms of platelet activation in diseased states. Platelet function and mechanisms of activation in ischemic and reactive oxygen species-rich environments may not be the same as in normal healthy conditions. Extracellular regulated protein kinase 5 (ERK5) is a mitogen-activated protein kinase family member activated in hypoxic, reactive oxygen species-rich environments and in response to receptor-signaling mechanisms. Prior studies suggest a protective effect of ERK5 in endothelial and myocardial cells after ischemia. We present evidence that platelets express ERK5 and that platelet ERK5 has an adverse effect on platelet activation via selective receptor-dependent and receptor-independent reactive oxygen species-mediated mechanisms in ischemic myocardium. METHODS AND RESULTS: Using isolated human platelets and a mouse model of myocardial infarction (MI), we found that platelet ERK5 is activated post-MI and that platelet-specific ERK5(-/-) mice have less platelet activation, reduced MI size, and improved post-MI heart function. Furthermore, the expression of downstream ERK5-regulated proteins is reduced in ERK5(-/-) platelets post-MI. CONCLUSIONS: ERK5 functions as a platelet activator in ischemic conditions, and platelet ERK5 maintains the expression of some platelet proteins after MI, leading to infarct expansion. This demonstrates that platelet function in normal healthy conditions is different from platelet function in chronic ischemic and inflammatory conditions. Platelet ERK5 may be a target for acute therapeutic intervention in the thrombotic and inflammatory post MI environment. PMID- 25934841 TI - Gleaning relapse risk from B cell phenotype: decreased CD5+ B cells portend a shorter time to relapse after B cell depletion in patients with ANCA-associated vasculitis. PMID- 25934842 TI - A novel semi-automated in situ hybridisation protocol for microRNA detection in paraffin embedded tissue sections. AB - MicroRNAs (miRNAs) are small non-coding RNAs that modulate gene expression by binding to complementary sequences on target messenger RNA transcripts. In situ hybridisation (ISH) methods have been applied to the study of miRNA in tissue samples in order to understand which is the source of the miRNA of interest. In this paper, the authors describe a novel semi-automated bright field ISH method to visualise miRNAs in formalin fixed paraffin embedded tissue sections. The relevance of this work resides in the use of 3,3'-diaminobenzidine and peroxidase as the detection method, which provides a good defined deposition within tissues This method, which reveals the cells of origin of specific miRNAs, will enable investigators to further explore the biological role of miRNAs. PMID- 25934843 TI - UK guidance for the pathological reporting of serrated lesions of the colorectum. AB - Bowel cancer screening programmes have highlighted to endoscopists and clinicians the spectrum of serrated colorectal lesions. One of the most significant developments has been the recognition that sessile serrated lesions (SSLs), while bearing histological resemblance to hyperplastic polyps (HPs), may be associated with the enhanced development of epithelial dysplasia and colorectal adenocarcinoma. Different minimum criteria exist for the diagnosis of SSLs and their differentiation from HPs. Furthermore, the spectrum of terminology used to describe the entire range of serrated lesions is wide. This variability has impaired interobserver agreement during their histopathological assessment. Here, we provide guidance for the histopathological reporting of serrated lesions, including a simplified nomenclature system. Essentially, we recommend use of the following terms: HP, SSL, SSL with dysplasia, traditional serrated adenoma (TSA) and mixed polyp. It is hoped that this standardisation of nomenclature will facilitate studies of the biological significance of serrated lesions in terms of the relative risk of disease progression. PMID- 25934844 TI - Blood and lymphatic vessel invasion in pT1 colorectal cancer: an international concordance study. AB - AIM: This study was performed to evaluate the concordance in pathological assessments of blood and lymphatic vessel invasion (BLI) in pT1 colorectal cancers and to assess the effect of diagnostic criterion on consistency in the assessment of BLI. METHODS: Forty consecutive patients undergoing surgical resection of pT1 colorectal cancers were entered into this study. H&E-stained, D2 40-stained and elastica-stained slides from the tumours were examined by 18 pathologists from seven countries. The 40 cases were divided into two cohorts with 20 cases each. In cohort 1, pathologists diagnosed BLI using criteria familiar to them; all Japanese pathologists used a criterion of BLI from the Japanese Society for Cancer of the Colon and Rectum (JSCCR). In cohort 2, all pathologists used the JSCCR diagnostic criterion. RESULTS: In cohort 1, diagnostic concordance was moderate in the US/Canadian and European pathologists. There were no differences in the consistency compared with results for Japanese pathologists, and no improvement in the diagnostic concordance was found for using the JSCCR criterion. However, in cohort 2, the JSCCR criterion decreased the consistency of BLI diagnosis in the US/Canadian and European pathologists. The level of decreased consistency in the assessment of BLI was different between the US/Canadian and European pathologists. CONCLUSIONS: A uniform criterion strongly influences the diagnostic consistency of BLI but may not always improve the concordance. Further study is required to achieve an objective diagnosis of BLI in colorectal cancer. The varying effects of diagnostic criterion on the pathologists from Japan, the USA/Canada and Europe might reflect varied interpretations of the criterion. Internationally accepted criterion should be developed by participants from around the world. PMID- 25934845 TI - Comparison of primary graft survival following penetrating keratoplasty and Descemet's stripping endothelial keratoplasty in eyes with prior trabeculectomy. AB - PURPOSE: To compare corneal graft survival rate after primary Descemet's stripping endothelial keratoplasty (DSEK) and primary penetrating keratoplasty (PK) in patients with prior trabeculectomy or medically managed glaucoma. METHODS: A retrospective chart review was conducted on consecutive patients who underwent DSEK or PK. Inclusion criteria consisted of eyes with a diagnosis of glaucoma prior to corneal transplantation and >= 6 months of follow-up. Graft failure was defined as an oedematous cornea with failure to maintain deturgescence lasting beyond a period of 1 month of intense steroid therapy or vascularisation and scarring resulting in irreversible loss of central graft clarity. Corneal graft survival was calculated using Kaplan-Meier survival analysis. Patients were divided into four groups: trabeculectomy-DSEK, trabeculectomy-PK, medical-DSEK or medical-PK. RESULTS: Fifty eyes (30 DSEK, 20 PK) of 50 patients (mean age 77 +/- 10 years) met the enrollment criteria. Mean follow-up was 17.4 +/- 14.2 months. A significantly higher proportion of the DSEK grafts (50%) compared with PK grafts (10%) failed at last follow-up (p = 0.005). Kaplan-Meier analysis identified a significant difference between the groups with respect to time to graft failure (p = 0.006). Patients with trabeculectomy who underwent DSEK had earlier graft failures than all other groups (p <= 0.035), but there were no differences between the medical-DSEK, medical-PK and trabeculectomy PK groups (all p > 0.35). CONCLUSIONS: Eyes with prior glaucoma showed higher rates of DSEK graft failure compared with PK. Patients with prior trabeculectomy demonstrated higher and earlier corneal graft failure rates with DSEK than with PK. PMID- 25934846 TI - Patient-reported outcomes in randomised controlled trials on age-related macular degeneration. AB - BACKGROUND/AIMS: The purpose of this systematic review was to identify the frequency and type of patient-reported outcome measures (PROMs) used in recent randomised controlled trials (RCTs) for age-related macular degeneration (AMD). METHODS: The authors conducted a systematic search between January 2010 and November 2013 in MEDLINE, EMBASE, Scopus, Cochrane Library (Central) and the clinical trials registries (http://www.controlled-trials.com and http://www.ClinicalTrials.gov) according to defined inclusion criteria (RCTs on AMD in English). Two independent reviewers evaluated studies for inclusion. One reviewer extracted data of included studies, and a second masked reviewer assessed 10% to confirm accuracy in data collection. Reference lists of included papers and appendices of relevant Cochrane systematic reviews were scanned to identify other relevant RCTs. Information collected on extracted outcomes was analysed using descriptive statistics. RESULTS: Literature and registry search yielded 3816 abstracts of journal articles and 493 records from trial registries. A total of 177 RCTs were deemed to have met inclusion criteria. Of the 858 outcomes reported, 38 outcomes were identified as PROMs (4.4%). Of the 177 RCTs examined, PROMs were used in 25 trials (14.1%). The National Eye Institute Visual Function Questionnaire-25 was the most frequently used PROM instrument (64% of RCTs with PROMs included). CONCLUSIONS: This review highlights that a small proportion of AMD RCTs included PROMs as outcome measures and that there was a variety in the instruments used. TRIAL REGISTRATION NUMBER: The systematic review was registered in the PROSPERO database for systematic reviews, registration number CRD42014010040. PMID- 25934847 TI - Threats of dismissal and symptoms of major depression: a study using repeat measures in the Swedish working population. AB - BACKGROUND: Job insecurity is considered a profound work stressor. While previous research has indicated that job insecurity represents a substantial mental health burden, few studies have examined its relationship with symptoms of major depression. The aim of this study was to assess whether episodic and repeated self-reported threats of dismissal increase the risk of subsequent symptoms of major depression and whether symptoms of major depression are related to subsequent experience of threats of dismissal. METHODS: The study is based on the Swedish Longitudinal Occupational Survey of Health (SLOSH) study, a cohort study with multiple repeated measurements. The sample consisted of 6275 participants who were in regular paid employment and who provided data in 2008, 2010 and 2012. Severity of depression was assessed with a brief Symptom Checklist scale and categorised according to symptoms of major depression or not. RESULTS: Results based on generalised estimating equations logit models showed that prior threats of dismissal predicted symptoms of major depression OR 1.37; 95% CI 1.04 to 1.81) after adjustment for prior depression and major confounders. Especially related threats increased the risk of major depression symptoms (OR 1.74 CI 1.09 to 2.78). Major depression symptoms also increased the odds of subsequent threats of dismissal (OR 1.52, CI 1.17 to 1.98). CONCLUSIONS: These findings support a prospective association between threats of dismissal and symptoms of major depression, in particular repeated exposure to threats of dismissal. The results also indicate that threats of dismissal are more likely to be reported by workers with symptoms of major depression. PMID- 25934849 TI - Is it time already to revise the Neurology Milestones? PMID- 25934848 TI - Milestone-compatible neurology resident assessments: A role for observable practice activities. AB - OBJECTIVE: Beginning in 2014, US neurology residency programs were required to report each trainee's educational progression within 29 neurology Milestone competency domains. Trainee assessment systems will need to be adapted to inform these requirements. The primary aims of this study were to validate neurology resident assessment content using observable practice activities (OPAs) and to develop assessment formats easily translated to the Neurology Milestones. METHODS: A modified Delphi technique was used to establish consensus perceptions of importance of 73 neurology OPAs among neurology educators and trainees at 3 neurology residency programs. A content validity score (CVS) was derived for each neurology OPA, with scores >=4.0 determined in advance to indicate sufficient content validity. RESULTS: The mean CVS for all OPAs was 4.4 (range 3.5-5.0). Fifty-seven (78%) OPAs had a CVS >=4.0, leaving 16 (22%) below the pre established threshold for content validity. Trainees assigned a higher importance to individual OPAs (mean CVS 4.6) compared to faculty (mean 4.4, p = 0.016), but the effect size was small (eta(2) = 0.10). There was no demonstrated effect of length of education experience on perceived importance of neurology OPAs (p = 0.23). Two sample resident assessment formats were developed, one using neurology OPAs alone and another using a combination of neurology OPAs and the Neurology Milestones. CONCLUSIONS: This study provides neurology training programs with content validity evidence for items to include in resident assessments, and sample assessment formats that directly translate to the Neurology Milestones. Length of education experience has little effect on perceptions of neurology OPA importance. PMID- 25934850 TI - Health economics of cerebrovascular disease: Can we do better? PMID- 25934851 TI - Absence of alpha- and beta-dystroglycan is associated with Walker-Warburg syndrome. AB - OBJECTIVE: To identify the underlying genetic defect in 5 patients from a consanguineous family with a Walker-Warburg phenotype, together with intracranial calcifications. METHODS: Homozygosity mapping and exome sequencing, followed by Sanger sequencing of the obtained candidate gene, was performed. Expression of the candidate gene was tested by reverse transcription PCR. Patient fibroblasts were converted to myotubes, and the expression and function of dystroglycan was tested by Western blotting. RESULTS: We detected a homozygous loss-of-function frameshift mutation in the DAG1 gene and showed that this mutation results in a complete absence of both alpha- and beta-dystroglycan. CONCLUSIONS: A loss-of function mutation in DAG1 can result in Walker-Warburg syndrome and is not embryonic lethal. PMID- 25934852 TI - Odor identification and Alzheimer disease biomarkers in clinically normal elderly. AB - OBJECTIVES: Our objective was to investigate cross-sectional associations between odor identification ability and imaging biomarkers of neurodegeneration and amyloid deposition in clinically normal (CN) elderly individuals, specifically testing the hypothesis that there may be an interaction between amyloid deposition and neurodegeneration in predicting odor identification dysfunction. METHODS: Data were collected on 215 CN participants from the Harvard Aging Brain Study. Measurements included the 40-item University of Pennsylvania Smell Identification Test and neuropsychological testing, hippocampal volume (HV) and entorhinal cortex (EC) thickness from MRI, and amyloid burden using Pittsburgh compound B (PiB) PET. A linear regression model with backward elimination (p < 0.05 retention) evaluated the cross-sectional association between the University of Pennsylvania Smell Identification Test and amyloid burden, HV, and EC thickness, assessing for effect modification by PiB status. Covariates included age, sex, premorbid intelligence, APOE epsilon4 carrier status, and Boston Naming Test. RESULTS: In unadjusted univariate analyses, worse olfaction was associated with decreased HV (p < 0.001), thinner EC (p = 0.003), worse episodic memory (p = 0.03), and marginally associated with greater amyloid burden (binary PiB status, p = 0.06). In the multivariate model, thinner EC in PiB-positive individuals (interaction term) was associated with worse olfaction (p = 0.02). CONCLUSIONS: In CN elderly, worse odor identification was associated with markers of neurodegeneration. Furthermore, individuals with elevated cortical amyloid and thinner EC exhibited worse odor identification, elucidating the potential contribution of olfactory testing to detect preclinical AD in CN individuals. PMID- 25934854 TI - Comment: Tackling shared genetic underpinnings of migraine and ischemic stroke. PMID- 25934853 TI - Etanercept in Alzheimer disease: A randomized, placebo-controlled, double-blind, phase 2 trial. AB - OBJECTIVES: To determine whether the tumor necrosis factor alpha inhibitor etanercept is well tolerated and obtain preliminary data on its safety in Alzheimer disease dementia. METHODS: In a double-blind study, patients with mild to moderate Alzheimer disease dementia were randomized (1:1) to subcutaneous etanercept (50 mg) once weekly or identical placebo over a 24-week period. Tolerability and safety of this medication was recorded including secondary outcomes of cognition, global function, behavior, and systemic cytokine levels at baseline, 12 weeks, 24 weeks, and following a 4-week washout period. This trial is registered with EudraCT (2009-013400-31) and ClinicalTrials.gov (NCT01068353). RESULTS: Forty-one participants (mean age 72.4 years; 61% men) were randomized to etanercept (n = 20) or placebo (n = 21). Etanercept was well tolerated; 90% of participants (18/20) completed the study compared with 71% (15/21) in the placebo group. Although infections were more common in the etanercept group, there were no serious adverse events or new safety concerns. While there were some interesting trends that favored etanercept, there were no statistically significant changes in cognition, behavior, or global function. CONCLUSIONS: This study showed that subcutaneous etanercept (50 mg/wk) was well tolerated in this small group of patients with Alzheimer disease dementia, but a larger more heterogeneous group needs to be tested before recommending its use for broader groups of patients. CLASSIFICATION OF EVIDENCE: This study shows Class I evidence that weekly subcutaneous etanercept is well tolerated in Alzheimer disease dementia. PMID- 25934855 TI - Neurofilament light chain: A prognostic biomarker in amyotrophic lateral sclerosis. AB - OBJECTIVE: To test blood and CSF neurofilament light chain (NfL) levels in relation to disease progression and survival in amyotrophic lateral sclerosis (ALS). METHODS: Using an electrochemiluminescence immunoassay, NfL levels were measured in samples from 2 cohorts of patients with sporadic ALS and healthy controls, recruited in London (ALS/control, plasma: n = 103/42) and Oxford (ALS/control, serum: n = 64/36; paired CSF: n = 38/20). NfL levels in patients were measured at regular intervals for up to 3 years. Change in ALS Functional Rating Scale-Revised score was used to assess disease progression. Survival was evaluated using Cox regression and Kaplan-Meier analysis. RESULTS: CSF, serum, and plasma NfL discriminated patients with ALS from healthy controls with high sensitivity (97%, 89%, 90%, respectively) and specificity (95%, 75%, 71%, respectively). CSF NfL was highly correlated with serum levels (r = 0.78, p < 0.0001). Blood NfL levels were approximately 4 times as high in patients with ALS compared with controls in both cohorts, and maintained a relatively constant expression during follow-up. Blood NfL levels at recruitment were strong, independent predictors of survival. The highest tertile of blood NfL at baseline had a mortality hazard ratio of 3.91 (95% confidence interval 1.98-7.94, p < 0.001). CONCLUSION: Blood-derived NfL level is an easily accessible biomarker with prognostic value in ALS. The individually relatively stable levels longitudinally offer potential for NfL as a pharmacodynamic biomarker in future therapeutic trials. CLASSIFICATION OF EVIDENCE: This report provides Class III evidence that the NfL electrochemiluminescence immunoassay accurately distinguishes patients with sporadic ALS from healthy controls. PMID- 25934856 TI - A slowly progressive mitochondrial encephalomyopathy widens the spectrum of AIFM1 disorders. PMID- 25934858 TI - Hospital costs of ischemic stroke and TIA in the Netherlands. AB - OBJECTIVES: There have been no ischemic stroke costing studies since major improvements were implemented in stroke care. We therefore determined hospital resource use and costs of ischemic stroke and TIA in the Netherlands for 2012. METHODS: We conducted a retrospective cost analysis using individual patient data from a national diagnosis-related group registry. We analyzed 4 subgroups: inpatient ischemic stroke, inpatient TIA, outpatient ischemic stroke, and outpatient TIA. Costs of carotid endarterectomy and costs of an extra follow-up visit were also estimated. Unit costs were based on reference prices from the Dutch Healthcare Insurance Board and tariffs provided by the Dutch Healthcare Authority. Linear regression analysis was used to examine the association between hospital costs and various patient and hospital characteristics. RESULTS: A total of 35,903 ischemic stroke and 21,653 TIA patients were included. Inpatient costs were ?5,328 ($6,845) for ischemic stroke and ?2,470 ($3,173) for TIA. Outpatient costs were ?495 ($636) for ischemic stroke and ?587 ($754) for TIA. Costs of carotid endarterectomy were ?6,836 ($8,783). Costs of inpatient days were the largest contributor to hospital costs. Age, hospital type, and region were strongly associated with hospital costs. CONCLUSIONS: Hospital costs are higher for inpatients and ischemic strokes compared with outpatients and TIAs, with length of stay (LOS) the most important contributor. LOS and hospital costs have substantially declined over the last 10 years, possibly due to improved hospital stroke care and efficient integrated stroke services. PMID- 25934859 TI - Primary prevention of stroke by a healthy lifestyle in a high-risk group. AB - OBJECTIVE: To examine the impact of a healthy lifestyle on stroke risk in men at higher risk of stroke because of other cardiovascular diseases or conditions. METHODS: Our study population comprised 11,450 men in the Cohort of Swedish Men who had a history of hypertension, high cholesterol levels, diabetes, heart failure, or atrial fibrillation. Participants had completed a questionnaire about diet and lifestyle and were free from stroke and ischemic heart disease at baseline (January 1, 1998). We defined a healthy lifestyle as a low-risk diet (>=5 servings/d of fruits and vegetables and <30 g/d of processed meat), not smoking, >=150 min/wk of physical activity, body mass index of 18.5 to 25 kg/m(2), and low to moderate alcohol consumption (>0 to <=30 g/d). Ascertainment of stroke cases was accomplished through linkage with the National Inpatient Register and the Swedish Cause of Death Register. RESULTS: During a mean follow up of 9.8 years, we ascertained 1,062 incident stroke cases. The risk of total stroke and stroke types decreased with increasing number of healthy lifestyle factors. The multivariable relative risk of total stroke for men who achieved all 5 healthy lifestyle factors compared with men who achieved 0 or 1 factor was 0.28 (95% confidence interval 0.14-0.55). The corresponding relative risks (95% confidence interval) were 0.31 (0.15-0.66) for ischemic stroke and 0.32 (0.04 2.51) for hemorrhagic stroke. CONCLUSIONS: A healthy lifestyle is associated with a substantially reduced risk of stroke in men at higher risk of stroke. PMID- 25934857 TI - Shared genetic basis for migraine and ischemic stroke: A genome-wide analysis of common variants. AB - OBJECTIVE: To quantify genetic overlap between migraine and ischemic stroke (IS) with respect to common genetic variation. METHODS: We applied 4 different approaches to large-scale meta-analyses of genome-wide data on migraine (23,285 cases and 95,425 controls) and IS (12,389 cases and 62,004 controls). First, we queried known genome-wide significant loci for both disorders, looking for potential overlap of signals. We then analyzed the overall shared genetic load using polygenic scores and estimated the genetic correlation between disease subtypes using data derived from these models. We further interrogated genomic regions of shared risk using analysis of covariance patterns between the 2 phenotypes using cross-phenotype spatial mapping. RESULTS: We found substantial genetic overlap between migraine and IS using all 4 approaches. Migraine without aura (MO) showed much stronger overlap with IS and its subtypes than migraine with aura (MA). The strongest overlap existed between MO and large artery stroke (LAS; p = 6.4 * 10(-28) for the LAS polygenic score in MO) and between MO and cardioembolic stroke (CE; p = 2.7 * 10(-20) for the CE score in MO). CONCLUSIONS: Our findings indicate shared genetic susceptibility to migraine and IS, with a particularly strong overlap between MO and both LAS and CE pointing towards shared mechanisms. Our observations on MA are consistent with a limited role of common genetic variants in this subtype. PMID- 25934860 TI - PD-1 upregulated on regulatory T cells during chronic virus infection enhances the suppression of CD8+ T cell immune response via the interaction with PD-L1 expressed on CD8+ T cells. AB - Regulatory T (Treg) cells act as terminators of T cell immuniy during acute phase of viral infection; however, their role and suppressive mechanism in chronic viral infection are not completely understood. In this study, we compared the phenotype and function of Treg cells during acute or chronic infection with lymphocytic choriomeningitis virus. Chronic infection, unlike acute infection, led to a large expansion of Treg cells and their upregulation of programmed death 1 (PD-1). Treg cells from chronically infected mice (chronic Treg cells) displayed greater suppressive capacity for inhibiting both CD8(+) and CD4(+) T cell proliferation and subsequent cytokine production than those from naive or acutely infected mice. A contact between Treg and CD8(+) T cells was necessary for the potent suppression of CD8(+) T cell immune response. More importantly, the suppression required cell-specific expression and interaction of PD-1 on chronic Treg cells and PD-1 ligand on CD8(+) T cells. Our study defines PD-1 upregulated on Treg cells and its interaction with PD-1 ligand on effector T cells as one cause for the potent T cell suppression and proposes the role of PD 1 on Treg cells, in addition to that on exhausted T cells, during chronic viral infection. PMID- 25934861 TI - A novel lung explant model for the ex vivo study of efficacy and mechanisms of anti-influenza drugs. AB - Influenza A virus causes considerable morbidity and mortality largely because of a lack of effective antiviral drugs. Viral neuraminidase inhibitors, which inhibit viral release from the infected cell, are currently the only approved drugs for influenza, but have recently been shown to be less effective than previously thought. Growing resistance to therapies that target viral proteins has led to increased urgency in the search for novel anti-influenza compounds. However, discovery and development of new drugs have been restricted because of differences in susceptibility to influenza between animal models and humans and a lack of translation between cell culture and in vivo measures of efficacy. To circumvent these limitations, we developed an experimental approach based on ex vivo infection of human bronchial tissue explants and optimized a method of flow cytometric analysis to directly quantify infection rates in bronchial epithelial tissues. This allowed testing of the effectiveness of TVB024, a vATPase inhibitor that inhibits viral replication rather than virus release, and to compare efficacy with the current frontline neuraminidase inhibitor, oseltamivir. The study showed that the vATPase inhibitor completely abrogated epithelial cell infection, virus shedding, and the associated induction of proinflammatory mediators, whereas oseltamivir was only partially effective at reducing these mediators and ineffective against innate responses. We propose, therefore, that this explant model could be used to predict the efficacy of novel anti-influenza compounds targeting diverse stages of the viral replication cycle, thereby complementing animal models and facilitating progression of new drugs into clinical trials. PMID- 25934862 TI - Transcription factors STAT6 and KLF4 implement macrophage polarization via the dual catalytic powers of MCPIP. AB - Macrophage polarization plays a critical role in tissue homeostasis, disease pathogenesis, and inflammation and its resolution. IL-4-induced macrophage polarization involves induction of STAT6 and Kruppel-like factor 4 (KLF4), which induce each other and promote M2 polarization. However, how these transcription factors implement M2 polarization is not understood. We report that in murine macrophages MCP-1-induced protein (MCPIP), induced by KLF4, inhibits M1 polarization by inhibiting NF-kappaB activation and implements M2 polarization using both its deubiquitinase and RNase activities that cause sequential induction of reactive oxygen species (ROS), endoplasmic reticulum (ER) stress, and autophagy required for M2 polarization. MCPIP also induces C/EBPbeta and PPARgamma, which promote M2 polarization. Macrophages from mice with myeloid targeted overexpression of MCPIP show elevated expression of M2 markers and reduced response to LPS, whereas macrophages from mice with myeloid-specific deletion of MCPIP manifest elevated M1 polarization with enhanced phagocytic activity. Thus, both in vivo and in vitro experiments demonstrate that the transcription factors STAT6 and KLF4 implement IL-4-induced M2 polarization via the dual catalytic activities of MCPIP. PMID- 25934863 TI - Nanotubes connect CD4+ T cells to airway smooth muscle cells: novel mechanism of T cell survival. AB - Contact between airway smooth muscle (ASM) cells and activated CD4(+) T cells, a key interaction in diseases such as asthma, triggers ASM cell proliferation and enhances T cell survival. We hypothesized that direct contact between ASM and CD4(+) T cells facilitated the transfer of anti-apoptotic proteins via nanotubes, resulting in increased survival of activated CD4(+) T cells. CD4(+) T cells, isolated from PBMCs of healthy subjects, when activated and cocultured with ASM cells for 24 h, formed nanotubes that were visualized by immunofluorescence and atomic force microscopy. Cell-to-cell transfer of the fluorescent dye calcein-AM confirmed cytoplasmic communication via nanotubes. Immunoreactive B cell lymphoma 2 (Bcl-2) and induced myeloid leukemia cell differentiation protein (Mcl-1), two major anti-apoptotic proteins, were present within the nanotubes. Downregulation of Mcl-1 by small interfering RNA in ASM cells significantly increased T cell apoptosis, whereas downregulation of Bcl-2 had no effect. Transfer of GFP-tagged Mcl-1 from ASM cells to CD4(+) T cells via the nanotubes confirmed directionality of transfer. In conclusion, activated T cells communicate with ASM cells via nanotube formation. Direct transfer of Mcl-1 from ASM to CD(+) T cells via nanotubes is involved in T cell survival. This study provides a novel mechanism of survival of CD4(+) T cells that is dependent on interaction with a structural cell. PMID- 25934865 TI - The impact of protein on chronic disease risk should be considered in studies of weight loss. PMID- 25934864 TI - Effects of the pure flavonoids epicatechin and quercetin on vascular function and cardiometabolic health: a randomized, double-blind, placebo-controlled, crossover trial. AB - BACKGROUND: Prospective cohort studies showed inverse associations between the intake of flavonoid-rich foods (cocoa and tea) and cardiovascular disease (CVD). Intervention studies showed protective effects on intermediate markers of CVD. This may be due to the protective effects of the flavonoids epicatechin (in cocoa and tea) and quercetin (in tea). OBJECTIVE: We investigated the effects of supplementation of pure epicatechin and quercetin on vascular function and cardiometabolic health. DESIGN: Thirty-seven apparently healthy men and women aged 40-80 y with a systolic blood pressure (BP) between 125 and 160 mm Hg at screening were enrolled in a randomized, double-blind, placebo-controlled, crossover trial. CVD risk factors were measured before and after 4 wk of daily flavonoid supplementation. Participants received (-)-epicatechin (100 mg/d), quercetin-3-glucoside (160 mg/d), or placebo capsules for 4 wk in random order. The primary outcome was the change in flow-mediated dilation from pre- to postintervention. Secondary outcomes included other markers of CVD risk and vascular function. RESULTS: Epicatechin supplementation did not change flow mediated dilation significantly (1.1% absolute; 95% CI: -0.1%, 2.3%; P = 0.07). Epicatechin supplementation improved fasting plasma insulin (Delta insulin: -1.46 mU/L; 95% CI: -2.74, -0.18 mU/L; P = 0.03) and insulin resistance (Delta homeostasis model assessment of insulin resistance: -0.38; 95% CI: -0.74, -0.01; P = 0.04) and had no effect on fasting plasma glucose. Epicatechin did not change BP (office BP and 24-h ambulatory BP), arterial stiffness, nitric oxide, endothelin 1, or blood lipid profile. Quercetin-3-glucoside supplementation had no effect on flow-mediated dilation, insulin resistance, or other CVD risk factors. CONCLUSIONS: Our results suggest that epicatechin may in part contribute to the cardioprotective effects of cocoa and tea by improving insulin resistance. It is unlikely that quercetin plays an important role in the cardioprotective effects of tea. This study was registered at clinicaltrials.gov as NCT01691404. PMID- 25934866 TI - Acute pancreatitis: watch what you eat! PMID- 25934867 TI - Reply to AM Bernstein et al. PMID- 25934868 TI - Regular physical activity: a little is good, but is it good enough? PMID- 25934869 TI - Biomarkers of dairy fat. PMID- 25934870 TI - Reply to H Pareja-Galeano et al. PMID- 25934871 TI - Concerns about the use of 15:0, 17:0, and trans-16:1n-7 as biomarkers of dairy fat intake in recent observational studies that suggest beneficial effects of dairy food on incidence of diabetes and stroke. PMID- 25934872 TI - Reply to M Lankinen and U Schwab and WMN Ratnayake. PMID- 25934873 TI - Erratum for Silva et al. Impact of a 6-wk olive oil supplementation in healthy adults on urinary proteomic biomarkers of coronary artery disease, chronic kidney disease, and diabetes (types 1 and 2): a randomized, parallel, controlled, double blind study. Am J Clin Nutr 2015;101:44-54. PMID- 25934875 TI - "ACPA" in Rheumatoid Arthritis: From Population-based Data to Personalized Medicine. PMID- 25934876 TI - Screening for psoriatic arthritis in people with psoriasis. PMID- 25934877 TI - Prednisone for cardiac failure in patients with hypertension. PMID- 25934878 TI - Rare Case of Nodular-type Muscle Sarcoidosis with Typical 3-Stripes Sign. PMID- 25934879 TI - An unusual presentation of joint inflammation in pachydermodactyly. PMID- 25934880 TI - Informational continuity is integral for successful transition of adolescents to adult care. PMID- 25934881 TI - Dr. Hersh replies. PMID- 25934882 TI - Dr. Chira replies. PMID- 25934884 TI - Correction. PMID- 25934883 TI - Double trouble: a case of concurrent opportunistic infections. PMID- 25934886 TI - CCR 20th Anniversary Commentary: Setting the Stage for Nanoparticle Albumin-Bound Paclitaxel-How Far Science Has Come. AB - In this phase I pharmacokinetic study of ABI-007, which was published in the May 1, 2002, issue of Clinical Cancer Research, Ibrahim and colleagues provided the framework needed for subsequent studies to confirm the benefits of ABI-007 over solvent-based formulations. Since the study's publication, experiments have highlighted the importance of drug-delivery systems, the immune system in cancer biology, and immunoregulatory properties of taxane compounds. PMID- 25934887 TI - Molecular Pathways: A Novel Approach to Targeting Hypoxia and Improving Radiotherapy Efficacy via Reduction in Oxygen Demand. AB - Tumor hypoxia presents a unique therapeutic challenge in the treatment of solid malignancies. Its presence has been established to be a poor prognostic factor in multiple cancer types, and past hypoxia-directed approaches have yielded generally disappointing results. Previous approaches have centered on either increasing oxygen delivery or administering agents that preferentially radiosensitize or kill hypoxic cells. However, a novel and potentially more effective method may be to increase therapeutic benefit by decreasing tumor oxygen consumption via agents such as metformin or nelfinavir in a patient population that is enriched for tumor hypoxia. This promising approach is currently being investigated in clinical trials and the subject of this article. PMID- 25934888 TI - Targeting Notch signaling with a Notch2/Notch3 antagonist (tarextumab) inhibits tumor growth and decreases tumor-initiating cell frequency. AB - PURPOSE: The Notch pathway plays an important role in both stem cell biology and cancer. Dysregulation of Notch signaling has been reported in several human tumor types. In this report, we describe the development of an antibody, OMP-59R5 (tarextumab), which blocks both Notch2 and Notch3 signaling. EXPERIMENTAL DESIGN: We utilized patient-derived xenograft tumors to evaluate antitumor effect of OMP 59R5. Immunohistochemistry, RNA microarray, real-time PCR, and in vivo serial transplantation assays were employed to investigate the mechanisms of action and pharmacodynamic readouts. RESULTS: We found that anti-Notch2/3, either as a single agent or in combination with chemotherapeutic agents was efficacious in a broad spectrum of epithelial tumors, including breast, lung, ovarian, and pancreatic cancers. Notably, the sensitivity of anti-Notch2/3 in combination with gemcitabine in pancreatic tumors was associated with higher levels of Notch3 gene expression. The antitumor effect of anti-Notch2/3 in combination with gemcitabine plus nab-paclitaxel was greater than the combination effect with gemcitabine alone. OMP-59R5 inhibits both human and mouse Notch2 and Notch3 function and its antitumor activity was characterized by a dual mechanism of action in both tumor and stromal/vascular cells in xenograft experiments. In tumor cells, anti Notch2/3 inhibited expression of Notch target genes and reduced tumor-initiating cell frequency. In the tumor stroma, OMP-59R5 consistently inhibited the expression of Notch3, HeyL, and Rgs5, characteristic of affecting pericyte function in tumor vasculature. CONCLUSIONS: These findings indicate that blockade of Notch2/3 signaling with this cross-reactive antagonist antibody may be an effective strategy for treatment of a variety of tumor types. PMID- 25934890 TI - RAF plus EGFR Inhibition for BRAF-Mutant Metastatic Colorectal Cancer-Letter. PMID- 25934891 TI - RAF plus EGFR Inhibition for BRAF-Mutant Metastatic Colorectal Cancer-Response. PMID- 25934889 TI - IL2 Inducible T-cell Kinase, a Novel Therapeutic Target in Melanoma. AB - PURPOSE: IL2 inducible T-cell kinase (ITK) promoter CpG sites are hypomethylated in melanomas compared with nevi. The expression of ITK in melanomas, however, has not been established and requires elucidation. EXPERIMENTAL DESIGN: An ITK specific monoclonal antibody was used to probe sections from deidentified, formalin-fixed paraffin-embedded tumor blocks or cell line arrays and ITK was visualized by IHC. Levels of ITK protein differed among melanoma cell lines and representative lines were transduced with four different lentiviral constructs that each contained an shRNA designed to knockdown ITK mRNA levels. The effects of the selective ITK inhibitor BI 10N on cell lines and mouse models were also determined. RESULTS: ITK protein expression increased with nevus to metastatic melanoma progression. In melanoma cell lines, genetic or pharmacologic inhibition of ITK decreased proliferation and migration and increased the percentage of cells in the G0-G1 phase. Treatment of melanoma-bearing mice with BI 10N reduced growth of ITK-expressing xenografts or established autochthonous (Tyr Cre/Pten(null)/Braf(V600E)) melanomas. CONCLUSIONS: We conclude that ITK, formerly considered an immune cell-specific protein, is aberrantly expressed in melanoma and promotes tumor development and progression. Our finding that ITK is aberrantly expressed in most metastatic melanomas suggests that inhibitors of ITK may be efficacious for melanoma treatment. The efficacy of a small-molecule ITK inhibitor in the Tyr-Cre/Pten(null)/Braf(V600E) mouse melanoma model supports this possibility. PMID- 25934892 TI - Retraction: Glioma-associated cancer-initiating cells induce immunosuppression. PMID- 25934893 TI - Correction: Associations and Interactions between Ets-1 and Ets-2 and Coregulatory Proteins, SRC-1, AIB1, and NCoR in Breast Cancer. PMID- 25934894 TI - Correction: Phase I Safety, Pharmacokinetic, and Pharmacodynamic Study of SAR245408 (XL147), an Oral Pan-Class I PI3K Inhibitor, in Patients with Advanced Solid Tumors. PMID- 25934895 TI - Policy Statement--Immunization for Streptococcus pneumoniae Infections in High Risk Children. Pediatrics. 2014;134(6):1230-1233. PMID- 25934896 TI - Romitti et al. Prevalence of Duchenne and Becker muscular dystrophies in the United States. Pediatrics. 2015;135(3):513-521. PMID- 25934897 TI - Betancourt et al. HIV and Child Mental Health: A Case-Control Study in Rwanda. Pediatrics. 2014;134(2):e464-e472. PMID- 25934898 TI - Weitzman, Wegner, the Section on Developmental and Behavioral Pediatrics, Committee on Pyschosocial Aspects of Child and Family Health, Council on Early Childhood, and Society for Developmental and Behavioral Pediatrics. Promoting Optimal Development: Screening for Behavioral and Emotional Problems. Pediatrics. 2015;135(2):384-395. PMID- 25934899 TI - Butler et al. Growth Charts for Non-growth Hormone Treated Prader-Willi Syndrome. Pediatrics. 2015;135(1):e126-e135. PMID- 25934901 TI - Puberty is not a disorder. PMID- 25934902 TI - Author's Response. PMID- 25934903 TI - Delivery room research: when does poor quality evidence become an ethical issue? PMID- 25934904 TI - Re: delivery room research: when does poor quality evidence become an ethical issue? PMID- 25934905 TI - Author's Response. PMID- 25934906 TI - Application of deuterium oxide (D2O) to metabolic research: just D2O it? Depends just how you D2O it! PMID- 25934907 TI - The limping child. AB - Limping is a symptom of varied diagnoses in children and adolescents and can present a difficult diagnostic challenge for primary care clinicians. A careful and systematic evaluation can shorten the long list of potential diagnoses to direct appropriate diagnostic tests to determine the cause of the problem. Trauma and infections are the most common causes of limping. Inflammatory conditions, developmental diagnoses,and overuse injuries are other causes. Although rare, malignancies such as osteosarcoma and blood cell cancers must also be considered as potential causes of limping in children and adolescents.* Limping presents a diagnostic challenge due to the number of possible causes.* On the basis of consensus, diagnostic laboratory tests that include complete blood count, erythrocyte sedimentation rate,C-reactive protein, and blood cultures should be ordered if suspicion is high for infectious etiology.* On the basis of consensus, orthopedic emergencies are vascular compromise, compartment syndrome, and open fractures.* On the basis of moderate evidence and consensus, compartment syndrome in children presents with the three "As" analgesia,anxiety, and agitation. (4)* On the basis of strong evidence and consensus, septic arthritis asa diagnosis increases with the number of Kocher criteria present(temperature >38.5 degrees C, white blood cell count >12,000/mL[12109/L], erythrocyte sedimentation rate >40 mm/h, and inability to bear weight). (8)* On the basis of moderate evidence and consensus, laboratory studies are not always definitive for diagnosis of juvenile idiopathic arthritis. (13)* On the basis of consensus, it is always important to examine the joint above and the joint below the area of the chief compliant,specifically when looking at slipped capital femoral epiphysis and Legg Calve-Perthes disease. PMID- 25934908 TI - Correction. PMID- 25934910 TI - Wound management. AB - The care of wounds is common in pediatric practice. Most simple wounds can be handled by clinicians in the office or by trained emergency medicine clinicians. Knowledge of appropriate wound care, wound repair techniques, and judicious use of antibiotics for prophylaxis ensures the best possible long-term outcomes. The following review describes appropriate recommendations for acute and long-term wound care, management, and special circumstances common to pediatric practice. PMID- 25934909 TI - Nonalcoholic fatty liver disease. AB - On the basis of strong research and consensus, nonalcoholic fatty liver disease (NAFLD) is the most common liver disease in children and is soon to be the most common indication for liver transplantation in adults. Although the disease begins as simple steatosis, some patients may progress to nonalcoholic steatohepatitis (NASH) and cirrhosis, making early identification and treatment critical.* The diagnosis of NAFLD can be challenging because patients are typically asymptomatic, with no major clinical symptoms of liver disease. Overweight and obese children are at the highest risk for disease. (1)(2)* On the basis of moderate research and consensus, serum ALT is usually mildly elevated but is an imperfect test with a low sensitivity for detecting NAFLD at commonly used thresholds.(10) Liver biopsy is still considered the gold standard for diagnosis but is too invasive for population-level screening and is often used selectively. Novel, noninvasive diagnostic modalities and serum biomarkers are currently being studied but warrant further validation, especially in children.* On the basis of moderate research and consensus, assessing serum liver tests in any overweight or obese child is reasonable.Liver disease should be suspected if the serum ALT is ?22 U/L(0.37 mkat/L) in girls and ?25 U/L (0.42 mkat/L) in boys. (10)Subspecialist referral should be considered for those with a normal BMI, persistent ALT elevation longer than 6 months,specific symptoms of advanced liver disease such as splenomegaly, or concerning laboratory findings on selected screening tests.* On the basis of strong research evidence, weight loss is the most efficacious treatment for NAFLD.* On the basis of some research and consensus, initiation of vitamin E therapy (400 IU BID) may be started, although its use probably should be restricted to those children with biopsy-proven disease. (12)* On the basis of some research and consensus, novel elastography based imaging modalities are being studied in children and several drugs show promise in treating NAFLD. PMID- 25934911 TI - Case 1: Joint Pain, Weight Loss, Fatigue, and Persistent Pleural Effusions in 17 year-old Boy. PMID- 25934912 TI - Case 2: Poor Weight Gain, Cough, Shortness of Breath, and Chest Pain in an 11 year-old Boy. PMID- 25934913 TI - Case 3: Fever, Vomiting, and Increased Sleepiness in a 4-year-old Girl. PMID- 25934914 TI - Cardiogenic shock. PMID- 25934915 TI - Visual Diagnosis: 7-year-old Girl With Swelling in the Arm. PMID- 25934916 TI - Correction for Zhang et al., Hemoglobin betaCys93 is essential for cardiovascular function and integrated response to hypoxia. PMID- 25934917 TI - Correction for Liu et al., beta-Arrestin-biased signaling mediates memory reconsolidation. PMID- 25934918 TI - Ambiguity and nonidentifiability in the statistical analysis of neural codes. AB - Many experimental studies of neural coding rely on a statistical interpretation of the theoretical notion of the rate at which a neuron fires spikes. For example, neuroscientists often ask, "Does a population of neurons exhibit more synchronous spiking than one would expect from the covariability of their instantaneous firing rates?" For another example, "How much of a neuron's observed spiking variability is caused by the variability of its instantaneous firing rate, and how much is caused by spike timing variability?" However, a neuron's theoretical firing rate is not necessarily well-defined. Consequently, neuroscientific questions involving the theoretical firing rate do not have a meaning in isolation but can only be interpreted in light of additional statistical modeling choices. Ignoring this ambiguity can lead to inconsistent reasoning or wayward conclusions. We illustrate these issues with examples drawn from the neural-coding literature. PMID- 25934919 TI - Snake robot uncovers secrets to sidewinders' maneuverability. PMID- 25934920 TI - Targeted noninvasive imaging of the innate immune response. PMID- 25934921 TI - Correction for Keskin et al., Reply to van de Sandt and Rimmelzwann: Matching epitope display with functional avidity. PMID- 25934923 TI - Cytokines in Graft-versus-Host Disease. AB - Graft-versus-host disease (GVHD) is a complication of allogeneic bone marrow transplantation whereby transplanted naive and marrow-derived T cells damage recipient tissue through similar mechanisms to those that allow destruction of malignant cells, the therapeutic intent of bone marrow transplantation. The manifestations and severity of GVHD are highly variable and are influenced by the proportions of naive cells maturing along regulatory T cell, Th1, Th2, or Th17 phenotypes. This maturation is largely influenced by local cytokines, which, in turn, activate transcription factors and drive development toward a dominant phenotype. In addition, proinflammatory cytokines exert direct effects on GVHD target tissues. Our knowledge of the role that cytokines play in orchestrating GVHD is expanding rapidly and parallels other infective and inflammatory conditions in which a predominant T cell signature is causative of pathology. Because a broad spectrum of cytokine therapies is now routinely used in clinical practice, they are increasingly relevant to transplant medicine. PMID- 25934924 TI - Development of a nondestructive method for sexing live adult Sternoplax souvorowiana (Coleoptera: Tenebrionidae). AB - The darkling beetle, Sternoplax souvorowiana (Reitter) (Coleoptera: Tenebrionidae), is flightless and lives in the Guerbantonggut desert in northwestern China. Its special eggshell structure, day-active habit, large body size, short life cycle, and ease of rearing under laboratory conditions make it an excellent model for advanced studies on desert adaptation. Determining the sex of this beetle is usually complicated by the lack of a discreet, externally visible gender-specific character. To date, dissection has been used for sex identification in this species, whereas a nondestructive means is needed for further studies of sexual dimorphism. Here, a new method based on the difference of the pigmentation pattern on the eighth tergite of each sex is described and illustrated. This method can be quickly learned, is nondestructive, is 100% accurate, and is fast enough for most applications in both the field and the laboratory. Experienced users in our laboratory routinely sex 8-10 beetles per minute. PMID- 25934922 TI - FcRn: The Architect Behind the Immune and Nonimmune Functions of IgG and Albumin. AB - The neonatal FcR (FcRn) belongs to the extensive and functionally divergent family of MHC molecules. Contrary to classical MHC family members, FcRn possesses little diversity and is unable to present Ags. Instead, through its capacity to bind IgG and albumin with high affinity at low pH, it regulates the serum half lives of both of these proteins. In addition, FcRn plays an important role in immunity at mucosal and systemic sites through its ability to affect the lifespan of IgG, as well as its participation in innate and adaptive immune responses. Although the details of its biology are still emerging, the ability of FcRn to rescue albumin and IgG from early degradation represents an attractive approach to alter the plasma half-life of pharmaceuticals. We review some of the most novel aspects of FcRn biology, immune as well as nonimmune, and provide some examples of FcRn-based therapies. PMID- 25934925 TI - Vitamin A induces inhibitory histone methylation modifications and down-regulates trained immunity in human monocytes. AB - Epidemiologic studies suggest that VAS has long-lasting immunomodulatory effects. We hypothesized that ATRA inhibits inflammatory cytokines in a model of trained immunity in monocytes by inducing epigenetic reprogramming through histone modifications. We used an previously described in vitro model of trained immunity, in which adherent monocytes of healthy volunteers were incubated for 24 h with BCG in the presence or absence of ATRA. After washing the cells, they were incubated for an additional 6 d in culture medium and restimulated with microbial ligands, and cytokine production was assessed. ATRA inhibited cytokine responses upon restimulation of monocytes, and this effect was exerted through increased expression of SUV39H2, a histone methyltransferase that induces the inhibitory mark H3K9me3. H3K9me3 at promoter sites of several cytokines was up-regulated by ATRA, and inhibition of SUV39H2 restored cytokine production. In addition to H3K9me3, the stimulatory histone mark H3K4me3 was down-regulated by ATRA at several promoter locations of cytokine genes. Therefore, we can conclude that ATRA inhibits cytokine production in models of direct stimulation or BCG-induced trained immunity and that these effects are mediated by histone modifications. PMID- 25934926 TI - CD13 mediates phagocytosis in human monocytic cells. AB - CD13 is a membrane-bound ectopeptidase, highly expressed on monocytes, macrophages, and dendritic cells. CD13 is involved in diverse functions, including degradation of peptide mediators, cellular adhesion, migration, viral endocytosis, signaling, and positive modulation of phagocytosis mediated by FcgammaRs and other phagocytic receptors. In this work, we explored whether besides acting as an accessory receptor, CD13 by itself is a primary phagocytic receptor. We found that hCD13 mediates efficient phagocytosis of large particles (erythrocytes) modified so as to interact with the cell only through CD13 in human macrophages and THP-1 monocytic cells. The extent of this phagocytosis is comparable with the phagocytosis mediated through the canonical phagocytic receptor FcgammaRI. Furthermore, we demonstrated that hCD13 expression in the nonphagocytic cell line HEK293 is sufficient to enable these cells to internalize particles bound through hCD13. CD13-mediated phagocytosis is independent of other phagocytic receptors, as it occurs in the absence of FcgammaRs, CR3, and most phagocytic receptors. Phagocytosis through CD13 is independent of its enzymatic activity but is dependent on actin rearrangement and activation of PI3K and is partially dependent on Syk activation. Moreover, the cross-linking of CD13 with antibodies rapidly induced pSyk in human macrophages. Finally, we observed that antibody-mediated cross-linking of hCD13, expressed in the murine macrophage-like J774 cell line, induces production of ROS. These results demonstrate that CD13 is a fully competent phagocytic receptor capable of mediating internalization of large particles. PMID- 25934927 TI - CCR2 deficiency leads to increased eosinophils, alternative macrophage activation, and type 2 cytokine expression in adipose tissue. AB - Adipose tissue (AT) inflammation during obesity is mediated by immune cells and closely correlates with systemic insulin resistance. In lean AT, eosinophils are present in low but significant numbers and capable of promoting alternative macrophage activation in an IL-4/IL-13-dependent manner. In WT mice, obesity causes the proportion of AT eosinophils to decline, concomitant with inflammation and classical activation of AT macrophages. In this study, we show that CCR2 deficiency leads to increased eosinophil accumulation in AT. Furthermore, in contrast to WT mice, the increase in eosinophils in CCR2(-/-) AT is sustained and even amplified during obesity. Interestingly, a significant portion of eosinophils is found in CLSs in AT of obese CCR2(-/-) mice, which is the first time eosinophils have been shown to localize to these inflammatory hot spots. CCR2(-/-) bone marrow precursors displayed increased expression of various key eosinophil genes during in vitro differentiation to eosinophils, suggesting a potentially altered eosinophil phenotype in the absence of CCR2. In addition, the proportion of eosinophils in AT positively correlated with local expression of Il5, a potent eosinophil stimulator. The increase in eosinophils in CCR2(-/-) mice was detected in all white fat pads analyzed and in the peritoneal cavity but not in bone marrow, blood, spleen, or liver. In AT of CCR2(-/-) mice, an increased eosinophil number positively correlated with M2-like macrophages, expression of the Treg marker Foxp3, and type 2 cytokines, Il4, Il5, and Il13. This is the first study to link CCR2 function with regulation of AT eosinophil accumulation. PMID- 25934928 TI - Metabolic danger signals, uric acid and ATP, mediate inflammatory cross-talk between hepatocytes and immune cells in alcoholic liver disease. AB - Inflammation defines the progression of ALD from reversible to advanced stages. Translocation of bacterial LPS to the liver from the gut is necessary for alcohol induced liver inflammation. However, it is not known whether endogenous, metabolic danger signals are required for inflammation in ALD. Uric acid and ATP, 2 major proinflammatory danger signals, were evaluated in the serum of human volunteers exposed to a single dose of ethanol or in supernatants of primary human hepatocytes exposed to ethanol. In vitro studies were used to evaluate the role of uric acid and ATP in inflammatory cross-talk between hepatocytes and immune cells. The significance of signaling downstream of uric acid and ATP in the liver was evaluated in NLRP3-deficient mice fed a Lieber-DeCarli ethanol diet. Exposure of healthy human volunteers to a single dose of ethanol resulted in increased serum levels of uric acid and ATP. In vitro, we identified hepatocytes as a significant source of these endogenous inflammatory signals. Uric acid and ATP mediated a paracrine inflammatory cross-talk between damaged hepatocytes and immune cells and significantly increased the expression of LPS inducible cytokines, IL-1beta and TNF-alpha, by immune cells. Deficiency of NLRP3, a ligand-sensing component of the inflammasome recognizing uric acid and ATP, prevented the development of alcohol-induced liver inflammation in mice and significantly ameliorated liver damage and steatosis. Endogenous metabolic danger signals, uric acid, and ATP are involved in inflammatory cross-talk between hepatocytes and immune cells and play a crucial role in alcohol-induced liver inflammation. PMID- 25934929 TI - Identification of RNA cargoes by antibody-positioned RNA amplification. AB - The interactions between various RNA-binding proteins (RBPs) and the RNA transcripts they bind strongly influence posttranscriptional control of gene expression in vertebrates. The hundreds of vertebrate RBPs that have been identified within the genome, often with multiple RNA recognition motifs, are capable of recognizing specific target RNA sequences mediating the maturation, movement, and translational state of their RNA cargoes. To identify the cargoes associated with a specific RBP, we have developed a technique called antibody positioned RNA amplification (APRA), which positions an oligonucleotide with a degenerate priming sequence in proximity to the RNAs sequestered by a specific RBP. The conjugation of the priming oligonucleotide to the antibody by itself does not interfere with the antibody's intrinsic affinity for the target RBP epitope, thus enabling RNA targets to be reverse-transcribed and amplified via a T7 bacteriophage RNA polymerase promoter sequence located upstream of the degenerate priming sequence in the oligonucleotide. By identifying the mRNA transcripts associated with the RBP in situ, we may be able to ascertain the significance of their temporal expression and physiological activities within the vast transcriptional networks regulating functional responses to stimuli. PMID- 25934930 TI - Measuring Ca2+ sparks in cardiac myocytes. AB - This protocol describes the measurement of Ca(2+) sparks in intact myocytes by using a Ca(2+)-sensitive dye and imaging using laser scanning confocal microscopy. It takes advantage of spontaneous Ca(2+)-release events-sparks-using them as a measure of the activity of ryanodine receptors (RyRs). Two methodologies are described: One requires that cardiomyocytes be stimulated, preferably under voltage clamp by depolarizing pulses, until steady-state is reached, and then stimulation is stopped and Ca(2+) sparks are recorded. The second requires that cells be permeabilized and bathed in a solution to load the cell with Ca(2+) sufficient to elicit Ca(2+) sparks, but not Ca(2+) waves. These are then analyzed offline to quantify spark frequency and morphology. The advantages and disadvantages of each approach are discussed. PMID- 25934931 TI - Assessing Ca2+-removal pathways in cardiac myocytes. AB - The decline of an intracellular calcium ([Ca(2+)]i) transient during a single excitation-contraction coupling (ECC) cycle reflects the combined activity of the sarcoplasmic reticulum Ca(2+)-ATPase (SERCA) pump and the sarcolemmal Na(+) Ca(2+) exchanger (NCX), along with minor contributions of the plasma membrane Ca(2+)-ATPase and mitochondrial Ca(2+) uniporter, in removing Ca(2+) from the cytosol. A traditional approach for assessing the individual components is to fit the decline of the [Ca(2+)]i transient evoked during electrical stimulation with an exponential. This reflects mostly the SERCA-dependent rate of uptake, which can be properly deduced after correcting for a component of NCX removal. As NCX function is an important determinant of the membrane potential as well as the Ca(2+) balance, we present here several detailed protocols for assessing NCX function. As the reversal potential and the amplitudes of the current are highly dependent on the prevailing concentrations of Na(+) and Ca(2+), we show how NCX function can be assessed under highly controlled conditions, with Ca(2+) and Na(+) clamped, as well as under more physiological conditions, with freely changing Ca(2+) and Na(+). PMID- 25934932 TI - Creation of primary cell lines from lineage-labeled mouse models of cancer. AB - Frequently, it is necessary to isolate pure populations of cancer cells for downstream assays, such as transcriptional analysis, signaling studies, and the creation of noncontaminated primary cell lines. Genetic lineage labeling with fluorescent reporter alleles allows for the identification of epithelial-derived cells within tumors. This protocol describes a method to isolate lineage-labeled pancreatic epithelial cells for ex vivo analysis, but it can be adapted for any type of lineage-labeled tumor. PMID- 25934933 TI - Organotypic culture of untransformed and tumorigenic primary mammary epithelial cells. AB - Three-dimensional (3D) culture systems represent an important means to study untransformed and neoplastic cells. These cultures can recapitulate organotypic growth by developing a polarized phenotype, forming specialized cell-cell contacts, and attaching to an underlying basement membrane. All of these features are necessary for the proper control of single-cell behavior within a growing structure. By employing 3D cultures, specific aspects of single cells, such as their capacity to proliferate, survive, and differentiate, can be followed in real time. This protocol describes how to generate 3D cultures of primary mammary epithelial cells. PMID- 25934934 TI - Subcellular fractionation of the brain: preparation of synaptosomes and synaptic vesicles. AB - The human brain is estimated to contain trillions of synaptic nerve terminals. These are the connections between neurons that are responsible for transmitting information and are modified as a result of learning. A valuable tool for studying synapses is the isolated nerve terminal, or synaptosome, which is obtained by homogenizing the brain in such a way that individual synapses pinch off to form metabolically active compartments that can recapitulate neurotransmitter release. This protocol describes the stepwise fractionation of rat brain tissue to yield synaptosomes and synaptic vesicles, which can be used in many different experimental approaches to study the structure and protein composition of the synapse and even dissect the molecular mechanisms of neurotransmission. PMID- 25934935 TI - Mapping protein-protein interactions using yeast two-hybrid assays. AB - Yeast two-hybrid (Y2H) screens are an efficient system for mapping protein protein interactions and whole interactomes. The screens can be performed using random libraries or collections of defined open reading frames (ORFs) called ORFeomes. This protocol describes both library and array-based Y2H screening, with an emphasis on array-based assays. Array-based Y2H is commonly used to test a number of "prey" proteins for interactions with a single "bait" (target) protein or pool of proteins. The advantage of this approach is the direct identification of interacting protein pairs without further downstream experiments: The identity of the preys is known and does not require further confirmation. In contrast, constructing and screening a random prey library requires identification of individual prey clones and systematic retesting. Retesting is typically performed in an array format. PMID- 25934936 TI - Investigating Bax subcellular localization and membrane integration. AB - Bax is a pivotal effector of apoptosis responsible for permeabilization of the mitochondrial outer membrane (MOM). A key event in mitochondrial damage is the translocation of Bax from the cytosol to the MOM. A simple and effective method for assessing the cytosol vs. mitochondrial localization of Bax is digitonin fractionation, which uses a low concentration of detergent to permeabilize the plasma membrane without damaging intracellular membranes. This allows separation of the cytosol (light membranes) from the heavy membranes (with mitochondria and nuclei) by centrifugation. Localization of Bax can then be assessed by immunoblotting. To further differentiate membrane-integrated Bax from that which is peripherally associated, carbonate extraction of the membrane fraction can be performed before immunoblotting. Treatment of membranes at high pH disrupts protein-protein interactions, whereas protein-lipid interactions are largely retained, although membrane integrity is lost. PMID- 25934937 TI - Investigating Bak/Bax activating conformation change by immunoprecipitation. AB - Activation of both Bax and Bak during apoptosis involves significant conformation change. Investigation of this phenomenon by immunoprecipitation (IP) requires a detergent such as CHAPS that does not induce significant conformation change. IP with conformation-specific Bax or Bak antibodies is observed in CHAPS only following an apoptotic stimulus, whereas the same antibodies will immunoprecipitate from both nonapoptotic and apoptotic cells in the presence of Triton X-100. Thus, the latter detergent can serve as a positive control for IP, as described here. PMID- 25934938 TI - Detection of Bak/Bax activating conformation change by intracellular flow cytometry. AB - Like the commonly used immunoprecipitation (IP) approach, this procedure for the detection of activated Bak or Bax by intracellular flow cytometry is based on the principle that Bak and Bax, during activation, expose occluded amino-terminal epitopes that can be recognized by conformation-specific antibodies. Flow cytometric analysis requires fewer cells and is less time-consuming than IP. Further, in contrast to IP, flow cytometry produces a quantifiable assessment of the percentage of cells containing activated Bak or Bax, which can be correlated with cell death. PMID- 25934939 TI - Investigating the Oligomerization of Bak and Bax during Apoptosis by Cysteine Linkage. AB - Following conformation change, Bak and Bax self-associate to form the putative apoptotic pore in the mitochondrial outer membrane. The nature of this pore and whether it is purely proteinaceous or lipidic are still unresolved. Induction of disulfide linkage with oxidants such as copper (II)(1,10-phenanthroline)3 (CuPhe) and chemical cross-linking with cell-permeable homobifunctional maleimide reagents are convenient ways to investigate Bak and Bax oligomerization in cells or isolated mitochondria. A limitation of these methods is they are based on the linkage of cysteines, and their success is reliant on the positions of the endogenous cysteines in Bak and Bax. Consequently, the protocols are more efficient and informative for human Bak than that for its murine counterpart. An additional benefit when investigating human Bak is that cysteine-based linkage assays provide information on the conformation change that precedes Bak oligomerization: Endogenous cysteines in the inactive form are in close proximity, and intramolecular linkage after treatment causes inactive Bak to migrate faster during SDS-PAGE. This intramolecular linkage is lost on activation, as the cysteines are distanced by conformation change. During apoptosis, Bak oligomerization induces the proximity of cysteines that favor intermolecular linkage. Trapped Bak oligomers can be detected with nonreducing (following oxidation with CuPhe) or reducing (following chemical cross-linking with homobifunctional maleimide reagents) SDS-PAGE and immunoblotting, as described here. PMID- 25934940 TI - Blue Native PAGE and Antibody Gel Shift to Assess Bak and Bax Conformation Change and Oligomerization. AB - Blue native PAGE (BN-PAGE) uses Coomassie dye rather than denaturing SDS to provide a negative charge to proteins for electrophoresis. As such, it is a useful assay for investigating native supramolecular membrane complexes without the need for cross-linking. As Bak and Bax oligomers form in the mitochondrial outer membrane, and they can be efficiently monitored by BN-PAGE. Furthermore, BN PAGE performed in conjunction with gel-shift using conformation-specific antibodies can provide additional information regarding the activation state of Bak or Bax in specific membrane complexes. PMID- 25934941 TI - A systematic approach for assessing Ca2+ handling in cardiac myocytes. AB - In cardiac myocytes, Ca(2+) release from the sarcoplasmic reticulum (SR) Ca(2+) store through the opening of ryanodine receptors (RyRs) is the major source of Ca(2+) for activation of myofilaments and contraction. Over the past 20 years, tools have become available to study this release process in detail, allowing new insights into the regulation of SR Ca(2+) release and RyR function. To assess these processes, we recommend and here review a systematic approach that evaluates the essential transport mechanisms and Ca(2+) fluxes in isolated single cardiac myocytes by using fluorescent Ca(2+) indicators and whole-cell recording of membrane voltage and ionic currents under voltage clamp. The approach includes an assessment of the L-type Ca(2+) current as a trigger for opening of RyRs and release of SR Ca(2+), of the SR Ca(2+) content, of intrinsic properties of RyRs, and of Ca(2+)-removal systems. PMID- 25934942 TI - The synaptosome as a model system for studying synaptic physiology. AB - Alongside rodent brain slices and primary neuronal cultures, synaptosomes (isolated nerve terminals) have been an important model system for studying the molecular mechanisms of synaptic function in the brain. Synaptosomes were first prepared in the late 1950s by Whittaker and colleagues and were instrumental in studying synaptic structure and defining the functional components of the synapse, including the identity of the major neurotransmitters and their uptake mechanisms. Synaptosomes can also be stimulated to release neurotransmitters and were used to discover a number of regulatory signaling pathways that fine-tune synaptic transmission. In the past decade, landmark proteomic studies of synaptosomes and synaptic vesicle preparations have further dissected the protein composition of the synapse. This introduction briefly describes the history of the synaptosome preparation and highlights how it continues to be relevant as our focus in the neuroscience community centers on synaptic dysfunction in aging and neurological disease. PMID- 25934943 TI - The yeast two-hybrid system: a tool for mapping protein-protein interactions. AB - Virtually all processes in living cells are dependent on protein-protein interactions (PPIs). Understanding PPI networks is thus essential for molecular biology and disease research. One powerful genetic system for mapping PPIs both at a small scale and in a high-throughput manner is the yeast two-hybrid (Y2H) screen. In Y2H screening, PPIs are detected through the activation of reporter genes responding to a reconstituted transcription factor. In this introduction, we describe library- and array-based Y2H methods and explain their basic theory. We also include the rationale behind different Y2H approaches and strategies for optimizing results. PMID- 25934944 TI - New editorial board members in pediatrics and health services research. PMID- 25934945 TI - Endogenous interleukin 18 regulates testicular germ cell apoptosis during endotoxemia. AB - Orchitis (testicular swelling) often occurs during systemic inflammatory conditions, such as sepsis. Interleukin 18 (IL18) is a proinflammatory cytokine and is an apoptotic mediator during endotoxemia, but the role of IL18 in response to inflammation in the testes was unclear. WT and IL18 knockout (KO) mice were injected lipopolysaccharide (LPS) to induce endotoxemia and examined 12 and 48 h after LPS administration to model the acute and recovery phases of endotoxemia. Caspase activation was assessed using immunohistochemistry. Protein and mRNA expression were examined by western blot and quantitative real-time RT-PCR respectively. During the acute phase of endotoxemia, apoptosis (as indicated by caspase-3 cleavage) was increased in WT mice but not in IL18 KO mice. The death receptor-mediated and mitochondrial-mediated apoptotic pathways were both activated in the WT mice but not in the KO mice. During the recovery phase of endotoxemia, apoptosis was observed in the IL18 KO mice but not in the WT mice. Activation of the death-receptor mediated apoptotic pathway could be seen in the IL18 KO mice but not the WT mice. These results suggested that endogenous IL18 induces germ cell apoptosis via death receptor mediated- and mitochondrial mediated pathways during the acute phase of endotoxemia and suppresses germ cell apoptosis via death-receptor mediated pathways during recovery from endotoxemia. Taken together, IL18 could be a new therapeutic target to prevent orchitis during endotoxemia. PMID- 25934946 TI - Phase I trial of repeated intrathecal autologous bone marrow-derived mesenchymal stromal cells in amyotrophic lateral sclerosis. AB - Stem cell therapy is an emerging alternative therapeutic or disease-modifying strategy for amyotrophic lateral sclerosis (ALS). The aim of this open-label phase I clinical trial was to evaluate the safety of two repeated intrathecal injections of autologous bone marrow (BM)-derived mesenchymal stromal cells (MSCs) in ALS patients. Eight patients with definite or probable ALS were enrolled. After a 3-month lead-in period, autologous MSCs were isolated two times from the BM at an interval of 26 days and were then expanded in vitro for 28 days and suspended in autologous cerebrospinal fluid. Of the 8 patients, 7 received 2 intrathecal injections of autologous MSCs (1 * 10(6) cells per kg) 26 days apart. Clinical or laboratory measurements were recorded to evaluate the safety 12 months after the first MSC injection. The ALS Functional Rating Scale-Revised (ALSFRS-R), the Appel ALS score, and forced vital capacity were used to evaluate the patients' disease status. One patient died before treatment and was withdrawn from the study. With the exception of that patient, no serious adverse events were observed during the 12-month follow-up period. Most of the adverse events were self-limited or subsided after supportive treatment within 4 days. Decline in the ALSFRS-R score was not accelerated during the 6-month follow-up period. Two repeated intrathecal injections of autologous MSCs were safe and feasible throughout the duration of the 12-month follow-up period. SIGNIFICANCE: Stem cell therapy is an emerging alternative therapeutic or disease-modifying strategy for amyotrophic lateral sclerosis (ALS). To the authors' best knowledge, there are no clinical trials to evaluate the safety of repeated intrathecal injections of autologous bone marrow mesenchymal stromal cells in ALS. After the clinical trial (phase I/II) was conducted, the stem cell (HYNR-CS, NEURONATA-R) was included in the revision of the regulations on orphan drug designation (number 160; December 31, 2013) and approved as a New Drug Application (Department of Cell and Gene Therapy 233; July 30, 2014) by the Korean Food and Drug Administration. The phase II trial is expected to be reported later. PMID- 25934948 TI - Intelligibility in Context Scale: Normative and Validation Data for English Speaking Preschoolers. AB - PURPOSE: The purpose of this study was to describe normative and validation data on the Intelligibility in Context Scale (ICS; McLeod, Harrison, & McCormack, 2012c) for English-speaking children. METHOD: The ICS is a 7-item, parent-report measure of children's speech intelligibility with a range of communicative partners. Data were collected from the parents of 803 Australian English-speaking children ranging in age from 4;0 (years;months) to 5;5 (37.0% were multilingual). RESULTS: The mean ICS score was 4.4 (SD = 0.7) out of a possible total score of 5. Children's speech was reported to be most intelligible to their parents, followed by their immediate family, friends, and teachers; children's speech was least intelligible to strangers. The ICS had high internal consistency (alpha = .94). Significant differences in scores were identified on the basis of sex and age but not on the basis of socioeconomic status or the number of languages spoken. There were significant differences in scores between children whose parents had concerns about their child's speech (M = 3.9) and those who did not (M = 4.6). A sensitivity of .82 and a specificity of .58 were established as the optimal cutoff. Test-retest reliability and criterion validity were established for 184 children with a speech sound disorder. There was a significant low correlation between the ICS mean score and percentage of phonemes correct (r = .30), percentage of consonants correct (r = .24), and percentage of vowels correct (r = .30) on the Diagnostic Evaluation of Articulation and Phonology (Dodd, Hua, Crosbie, Holm, & Ozanne, 2002). Thirty-one parents completed the ICS related to English and another language spoken by their child with a speech sound disorder. The significant correlations between the scores suggest that the ICS may be robust between languages. CONCLUSIONS: This article provides normative ICS data for English-speaking children and additional validation of the psychometric properties of the ICS. The robustness of the ICS was suggested because mean ICS scores were not affected by socioeconomic status, number of languages spoken, or whether the ICS was completed in relation to English or another language. The ICS is recommended as a screening measure of children's speech intelligibility. PMID- 25934947 TI - Targeting Disease Persistence in Gastrointestinal Stromal Tumors. AB - SummaryGastrointestinal stromal tumors (GISTs) represent 20%-40% of human sarcomas. Although approximately half of GISTs are cured by surgery, prognosis of advanced disease used to be poor due to the high resistance of these tumors to conventional chemo- and radiotherapy. The introduction of molecularly targeted therapy (e.g., with imatinib mesylate) following the discovery of the role of oncogenic mutations in the receptor tyrosine kinases KIT and platelet-derived growth factor alpha (PDGFRA) significantly increased patient survival. However, GIST cells persist in 95%-97% of imatinib-treated patients who eventually progress and die of the disease because of the emergence of clones with drug resistant mutations. Because these secondary mutations are highly heterogeneous, even second- and third-line drugs that are effective against certain genotypes have only moderately increased progression-free survival. Consequently, alternative strategies such as targeting molecular mechanisms underlying disease persistence should be considered. We reviewed recently discovered cell-autonomous and microenvironmental mechanisms that could promote the survival of GIST cells in the presence of tyrosine kinase inhibitor therapy. We particularly focused on the potential role of adult precursors for interstitial cells of Cajal (ICCs), the normal counterpart of GISTs. ICC precursors share phenotypic characteristics with cells that emerge in a subset of patients treated with imatinib and in young patients with GIST characterized by loss of succinate dehydrogenase complex proteins and lack of KIT or PDGFRA mutations. Eradication of residual GIST cells and cure of GIST will likely require individualized combinations of several approaches tailored to tumor genotype and phenotype. SIGNIFICANCE: Gastrointestinal stromal tumors (GISTs) are one of the most common connective tissue cancers. Most GISTs that cannot be cured by surgery respond to molecularly targeted therapy (e.g., with imatinib); however, tumor cells persist in almost all patients and eventually acquire drug-resistant mutations. Several mechanisms contribute to the survival of GIST cells in the presence of imatinib, including the activation of "escape" mechanisms and the selection of stem-like cells that are not dependent on the expression of the drug targets for survival. Eradication of residual GIST cells and cure of GIST will likely require individualized combinations of several approaches tailored to the genetic makeup and other characteristics of the tumors. PMID- 25934949 TI - Making Inferences From Text: It's Vocabulary That Matters. AB - PURPOSE: Many children with communication disorders have reading comprehension difficulties, and in order to target interventions effectively it is important to identify which specific components of comprehension are especially challenging. The current study explored the relationship between text-inferencing skill, autistic symptomatology, and language phenotype. METHOD: Typically developing children (n = 32), children with autism spectrum disorders (ASD) and age appropriate structural language skills (n = 27), children with ASD and language impairment (n = 15), and nonautistic children with language impairment (n = 12) were administered the Neale Analysis of Reading Ability-Revised (Neale, 1997), and responses to literal and inferential questions were analyzed. RESULTS: For the sample as a whole, inferencing competence was predicted by oral language skill, with autistic symptomatology not contributing significant variance. However, although only 12.5% of typically developing children found answering inferential questions disproportionally challenging relative to answering literal questions, one third of children with age-appropriate structural language skills demonstrated inferencing deficits, as did over 50% of children with language impairments, regardless of ASD status. CONCLUSION: These results indicate that children with language impairments are most likely to find inferencing challenging, but practitioners will also need to monitor the inferencing skills of children with ASD and good language and single-word reading skills. PMID- 25934951 TI - When Do Children Understand "Opposite"? AB - PURPOSE: The aims of the present research were to determine (a) the age at which children with typical development understand the concept of opposite, (b) whether this is related to other cognitive abilities or experiences, and (c) whether there is early implicit understanding of the concept. METHOD: Children (N = 204) between 3 and 5 years of age were randomly assigned to 1 of 3 experimental conditions in a novel opposite task. Children's language and working memory skills were assessed, and parents provided information about children's access to learning materials about opposites. RESULTS: In the opposite task, 4- and 5-year olds, but not 3-year-olds, demonstrated acquisition of the concept of opposite. Children demonstrated this understanding only when asked for the "opposite" one, suggesting that antonymy was not made salient by stimulus properties alone. Children's accuracy was not significantly related to their language or working memory skills, to their child care experience, or to whether parents reported having books or games about opposites or playing opposite word games with children. Eye gaze analyses provided no evidence for early implicit understanding of the concept of opposite. CONCLUSION: Children with typical development have a concept of opposite by 4 years of age. PMID- 25934950 TI - Speech, Spatial and Qualities of Hearing Scale (SSQ) and Spatial Hearing Questionnaire (SHQ) Changes Over Time in Adults With Simultaneous Cochlear Implants. AB - PURPOSE: The purpose of the present study is to evaluate the changes over time of the Spatial Hearing Questionnaire (SHQ; Tyler, Perreau, & Ji, 2009) and the Speech, Spatial and Qualities of Hearing Scale (SSQ; Gatehouse & Noble, 2004) in adults with simultaneous bilateral cochlear implants by collecting data for 2 years after implantation. METHOD: Nineteen postlingual subjects participated in this study. Average age at implant was 63 years. The subjects' data were included in this retrospective analysis only if they completed both questionnaires. We compared subjects' SSQ and SHQ scores to word recognition and sound localization performances. RESULTS: The study showed SHQ and SSQ scores continuously improved up to 1 year postimplantation, with the most improvement occurring within the first 6 months of implantation. After 1 year, the scores reached a plateau. This is consistent with laboratory tests from the same 19 subjects, and they showed high correlations (p < .05). The present study also showed a high degree of correlation between SHQ and SSQ scores. CONCLUSIONS: Both the SSQ and SHQ scores improved up to 12 months postimplantation, with the most improvement during the first 6 months of implantation. Both were consistent with laboratory tests. There was a high degree of correlation between SHQ and SSQ scores. PMID- 25934952 TI - Hypercalcemic crisis - a fatal case of primary hyperparathyroidism. AB - The scapula is a flat, triangular bone overlying the posterior chest wall and forming the posterior aspect of the shoulder girdle. To the best of our knowledge, there is no previous description of a notch of the medial aspect of the superior border of the scapula in the literature. The imaging findings of a supero-medial scapula border notch mimicking a bone tumour are presented in this case report. PMID- 25934954 TI - What Do Mothers know about Neonatal Jaundice? Knowledge, Attitude and Practice of Mothers in Malaysia. AB - No abstract available. PMID- 25934953 TI - Clinical presentation, severity and progression of primary angle closure in malay and chinese patients. AB - OBJECTIVE: To compare the clinical presentation, severity and progression of primary angle closure between Chinese and Malays residing in Malaysia. METHODS: A comparative retrospective record review study was conducted involving one hundred (200 eyes) Malay and fifty eight (116 eyes) Chinese patients. They were selected from medical records of Hospital Universiti Sains Malaysia, Kelantan and Hospital Pulau Pinang, Penang, Malaysia. The selected patients were re-diagnosed based on the International Society of Geographical and Epidemiological classification. The clinical data on presentation including the presence of systemic diseases were documented. Progression of the disease was based on available reliable visual fields and optic disc changes of patients who have been on follow-up for at least five years. RESULTS: Malay patients presented at older age (61.4 years SD 8.4) compared to Chinese (60.6 years SD 8.3). There was significant higher baseline Intraocular Pressure (IOP) among Malays (34.7 SD 18.5mmHg) compared to Chinese (30.3 SD 16.7mmHg) (p=0.032). The Chinese patients presented with significantly better visual acuity (p<0.001) and less advanced cup to disc changes (p=0.001) compared to Malays. Malay patients progressed faster than the Chinese. Majority progressed within 1 year of diagnosis. Malays without laser peripheral iridotomy (LPI) have a 4 fold (95% CI 1.4, 10.9) risk of progression. Higher baseline IOP, more advanced visual field defect and absence of LPI was identified as significant predictors associated with progression. CONCLUSION: The Malays presented with more advanced angle closure glaucoma as compared to the Chinese in Malaysia. Aggressive disease progression was observed in Malays with the onset of optic neuropathy. Effective public awareness and aggressive management is important to prevent blindness in the Malaysian population. PMID- 25934955 TI - Urogenital melioidosis: a review of clinical presentations, characteristic and outcomes. AB - INTRODUCTION: Melioidosis is endemic to the tropical regions, in particular Thailand and Northern Australia. Any organ can be affected by melioidosis. Involvement of the urogenital system is common in Northern Australia, but is less common in other regions. This study assesses the characteristics of melioidosis affecting the urogenital system treated in a tertiary referral centre in Brunei Darussalam. MATERIAL AND METHODS: All patients treated for melioidosis of the urogenital system were identified and retrospectively reviewed. RESULTS: There were 9 patients with 11 episodes of urogenital infections treated over 13 years. The median age at diagnosis was 38 years old (range 29 - 63) with men predominantly affected. The major risk factor was underlying diabetes mellitus (n=9), including three patients diagnosed at the time of diagnosis of melioidosis. The median glycosylated haemoglobin (HbA1c) was 12.8% (range 6.4 to 16.6%). One patient's risk factor was only moderate alcohol consumption. Common symptoms included; fever, lethargy, rigor and anorexia. Dysuria was reported by two patients. The median duration of symptoms before presentation was 7 days (range 2 to 21 days) and the median number of sites involved were 3 (range of 2 to 6). Urogenital involvement included prostate (n=6), kidney (n=8), seminal vesicles (n=1) and testis (n=1). Radiological imaging showed that large prostate abscesses (>4.5cm) were common, and in some patients, the kidney abscess had the 'honeycomb' previously described as typical for melioidosis liver abscess. All patients were successfully treated for melioidosis and at a median follow up of 34 months (range 1 - 97), there was one death from complications of diabetes mellitus. CONCLUSION: Urogenital melioidosis only accounted for a small proportion of all melioidosis involvement, with prostate and kidney most commonly affected. Concomitant involvement of other sites were common. The major risk factor was poorly controlled diabetes mellitus. PMID- 25934956 TI - Brain and spinal tumour. AB - This study reviewed the epidemiology of brain and spinal tumours in Sarawak from January 2009 till December 2012. The crude incidence of brain tumour in Sarawak was 4.6 per 100,000 population/year with cumulative rate 0.5%. Meningioma was the most common brain tumour (32.3%) and followed by astrocytoma (19.4%). Only brain metastases showed a rising trend and cases were doubled in 4 years. This accounted for 15.4% and lung carcinoma was the commonest primary. Others tumour load were consistent. Primitive neuroectodermal tumour (PNET) and astrocytoma were common in paediatrics (60%). We encountered more primary spinal tumour rather than spinal metastases. Intradural schwannoma was the commonest and frequently located at thoracic level. The current healthcare system in Sarawak enables a more consolidate data collection to reflect accurate brain tumours incidence. This advantage allows subsequent future survival outcome research and benchmarking for healthcare resource planning. PMID- 25934957 TI - A snapshot of stroke from miri hospital. AB - Our objective was to study the profile of cerebrovascular accidents and proportion of cerebral haemorrhage (CH) among stroke patients. This project was designed after we observed higher incidence of CH in Miri hospital as compared to conventionally reported data. METHODS: This was a prospective observational study conducted from 1st June 2008 to 31st May 2009. All patients admitted in both male and female wards of the Medical Unit with the first incidence of a stroke were recruited for analysis. CT scan brain was done in all patients. RESULTS: Total admissions in one year in the medical department were 3204 patients, both male and female together, out of which 215 were due to a first incidence of stroke; Stroke accounted for 6.7% of admissions and 16.8% of deaths in medical unit. 139 (64.7%) were ischaemic strokes and 76 (35.3%) were cerebral haemorrhages. The incidence of CH (35.3%) was high compared to regional data. 71.7% (154) patients had preexisting hypertension. Higher incidence of hypertension, diabetes mellitus and aspirin intake was noted in the ischaemic group. Also compliance to treatment for hypertension was better in the Ischaemic group with more defaults in CH category (P<0.01). Significantly more deaths were noted in patients with higher systolic blood pressure on presentation, poor Glasgow Coma Scale (GCS) and those with dysphagia. CONCLUSION: Every third stroke was due to cerebral hemorrhage; CH patients were largely unaware of their hypertension or were altogether treatment naive or defaulters while compliance was far better in ischaemic stroke category. PMID- 25934958 TI - Giant lipomatous lesion of the thigh with retroperitoneal extension: case series. AB - Giant lipomatous lesions of the thigh swelling with extension into retroperitoneum are rare. Lesions can be malignant or benign and can have similar clinical presentation. Treatments options differ and their prognosis varies with histology. We present two cases of liposarcoma and lipoma with the same clinical presentations that underwent surgical resection. PMID- 25934959 TI - A Testicular Cancer that was Thought to be an Inguino-Scrotal Hernia. AB - We present a case of a young man with a 5-year history of testicular swelling which was initially thought to be inguinoscrotal hernia. Intra-operatively it was found to be a testicular tumour and histopathological examination confirmed a mixed germ cell tumour. He had an orchidectomy and later underwent chemotherapy. It is interesting to note that the patient had kept the tumour for 5 years with no evidence of distant metastasis at diagnosis. This is probably the longest presentation of a testicular tumour. PMID- 25934960 TI - Congenital mastoid cholesteatoma presenting as a mass obstructing external auditory canal. AB - We describe the clinical presentation, investigation and management of an eventually fatal case of hypercalcemic crisis due to primary hyperparathyridism (PHPT). A 60 year-old lady with history of urolithiasis presented with worsening generalized bone pain, spinal scoliosis and a limp. Laboratory data showed hypercalcemia and raised alkaline phosphatase. Left hip x-ray revealed a subcapital femoral neck fracture. Intact parathyroid hormone was elevated, 187.6 pmol/L (1.6 - 6.9) and ultrasound showed an enlarged right parathyroid gland. Despite initial reduction of serum calcium with saline infusion and multiple doses of intravenous pamidronate, her calcium increased to 4.14 mmol/L a week following application of Buck's traction for persistent left hip pain. She succumbed eventually with serum calcium peaking at 6.28 mmol/L despite multiple therapeutic interventions. PMID- 25934961 TI - Kimura's Disease: Diagnostic Challenge and Treatment Modalities. AB - CASE REPORT: Five cases of Kimura's disease had been treated in our centre from year 2003 to 2010. All cases were presented with head and neck mass with cervical lymphadenopathy. Surgical excision was performed for all cases. Definite diagnosis was made by histopathological examination of the resected specimens. One out of five cases developed tumour recurrence four years after resection. CONCLUSION: Surgical excision is our choice of treatment because the outcome is immediate and definite tissue diagnosis is feasible after resection. Oral corticosteroid could be considered as an option in advanced disease. However, tumour recurrence is common after cessation of steroid therapy. PMID- 25934962 TI - Shewanella dysentery in a patient with underlying malignancy. AB - Shewanella spp is a facultatively anaerobic, motile, gramnegative bacillus and can be found throughout the world mainly in marine environments and soil. It is a rare pathogen in human and infection by it is usually associated with underlying severe morbidities. We report a case of a 69- years old woman who presented with Shewanella putrefaciens dysentery and who was subsequently found to have underlying malignancy. PMID- 25934963 TI - Colon cancer recurrence mimicking renal cell carcinoma. AB - No abstract available. PMID- 25934964 TI - Spontaneous intracranial haemorrhage in children with chronic immune thrombocytopenic purpura. AB - Spontaneous intracranial haemorrhage (ICH) is a rare complication of chronic immune thrombocytopenic purpura (ITP) in children. We report four patients with cITP who developed ICH. The latency between onset of ITP and ICH varied from 1-8 years. All our patients were profoundly thrombocytopenic (platelet count of <10 x 109/l) at the time of their intracranial bleed. The presenting features and management are discussed. All patients survived, three had complete neurological recovery while one had a minimal residual neurological deficit. PMID- 25934965 TI - Abdominal stab wound with inferior vena cava injury: a case report. AB - No abstract available. PMID- 25934966 TI - Ectopic inferior vena cava thrombus secondary to a tubo-ovarian abscess. AB - Inferior vena cava (IVC) thrombosis typically arises distally from a thrombophlebitic extension in the pelvis or the lower extremities. It may also occur from propagation of an ovarian vein thrombosis as a result of gynaecological disorders such as pelvic inflammatory disease, endometritis or from pelvic surgeries. In this report, we present an interesting case of a tubo ovarian abscess with an ectopic IVC thrombus. The approach to management in such cases is also highlighted. PMID- 25934967 TI - Yoga for epilepsy. AB - BACKGROUND: This is an updated version of the original Cochrane review published in The Cochrane Library, Issue 1, 2002.Yoga may induce relaxation and stress reduction, and influence the electroencephalogram and the autonomic nervous system, thereby controlling seizures. Yoga would be an attractive therapeutic option for epilepsy if proved effective. OBJECTIVES: To assess whether people with epilepsy treated with yoga:(a) have a greater probability of becoming seizure free;(b) have a significant reduction in the frequency or duration of seizures, or both; and(c) have a better quality of life. SEARCH METHODS: We searched the Cochrane Epilepsy Group Specialized Register (26 March 2015), the Cochrane Central Register of Controlled Trials (CENTRAL, The Cochrane Library, 26 March 2015), MEDLINE (Ovid, 1946 to 26 March 2015), SCOPUS (1823 to 9 January 2014), ClinicalTrials.gov (26 March 2015), the World Health Organization (WHO) International Clinical Trials Registry Platform ICTRP (26 March 2015), and also registries of the Yoga Biomedical Trust and the Research Council for Complementary Medicine. In addition, we searched the references of all the identified studies. No language restrictions were imposed. SELECTION CRITERIA: The following study designs were eligible for inclusion: randomised controlled trials (RCT) of treatment of epilepsy with yoga. Eligible participants were adults with uncontrolled epilepsy comparing yoga with no treatment or different behavioural treatments. DATA COLLECTION AND ANALYSIS: Three review authors independently selected trials for inclusion and extracted data. The following outcomes were assessed: (a) percentage of people rendered seizure free; (b) seizure frequency and duration; (c) quality of life. Analyses were on an intention-to-treat basis. Odds ratio (OR) with 95% confidence intervals (95% Cl) were estimated for the outcomes. MAIN RESULTS: Two unblinded trials recruited a total of 50 people (18 treated with yoga and 32 to control interventions). Antiepileptic drugs were continued in all the participants. Baseline phase lasted 3 months in both studies and treatment phase from 5 weeks to 6 months in the two trials. Randomisation was by roll of a die in one study and using a computerised randomisation table in the other one but neither study provided details of concealment of allocation and were rated as unclear risk of bias. Overall, the two studies were rated as low risk of bias (all participants were included in the analysis; all expected and pre-expected outcomes were reported; no other sources of bias). The overall OR with 95% confidence interval (CI) was: (i) seizure free for six months - for yoga versus sham yoga ORs of 14.54 (95% CI 0.67 to 316.69) and for yoga versus no treatment group 17.31 (95% CI 0.80 to 373.45); for Acceptance and Commitment Therapy (ACT) versus yoga ORs of 1.00 (95% Cl 0.16 to 6.42; (ii) reduction in seizure frequency - the Mean Difference between yoga versus sham yoga group was -2.10 (95% CI -3.15 to -1.05) and for yoga versus no treatment group -1.10 (95% CI -1.80 to -0.40); (iii) more than 50% reduction in seizure frequency - for yoga versus sham yoga group ORs of 81.00 (95% CI 4.36 to 1504.46) and for the yoga versus no treatment group 158.33 (95% CI 5.78 to 4335.63); ACT versus yoga ORs of 0.78 (95% Cl 0.04 to 14.75); (iv) more than 50% reduction in seizure duration - for yoga versus sham yoga group ORs of 45.00 (95% CI 2.01 to 1006.75) and for yoga versus no treatment group 53.57 (95% CI 2.42 to 1187.26); ACT versus yoga ORs of 0.67 (95% Cl 0.10 to 4.35). In addition in Panjwani 1996 the authors reported that the one-way analysis of variance revealed no statistically significant differences between the three groups. A P-Lambda test taking into account the P values between the three groups also indicated that the duration of epilepsy in the three groups was not comparable. No data were available regarding quality of life. In Lundgren 2008 the authors reported that there was no significant difference between the yoga and ACT groups in seizure free rates, 50% or greater reduction in seizure frequency or seizure duration at one year follow-up. The yoga group showed significant improvement in their quality of life according to the Satisfaction With Life Scale (SWLS) (P < 0.05), while the ACT group had significant improvement in the World Health Organization Quality of Life-BREF (WHOQOL-BREF) scale (P < 0.01). AUTHORS' CONCLUSIONS: Study of 50 subjects with epilepsy from two trials reveals possible beneficial effect in control of seizures. Results of the overall efficacy analysis show that yoga treatment was better when compared with no intervention or interventions other than yoga (postural exercises mimicking yoga). There was no difference between yoga and Acceptance and Commitment Therapy. However no reliable conclusions can be drawn regarding the efficacy of yoga as a treatment for uncontrolled epilepsy, in view of methodological deficiencies such as limited number of studies, limited number of participants randomised to yoga, lack of blinding and limited data on quality-of-life outcome. Physician blinding would normally be taken to be the person delivering the intervention, whereas we think the 'physician' would in fact be the outcome assessor (who could be blinded), so that would be a reduction in detection bias rather than performance bias. In addition, evidence to inform outcomes is limited and of low quality. Further high quality research is needed to fully evaluate the efficacy of yoga for refractory epilepsy. PMID- 25934968 TI - Comparison of Saline-Irrigated Catheter vs. Temperature-Controlled Catheter for Renal Denervation in a Canine Model. AB - BACKGROUND: The effectiveness of catheter-based renal denervation (RDN) remains controversial. Although the reasons for this have not yet been elucidated, ineffective denervation appears to be an important factor. The present study aimed to investigate the difference in RDN between a saline-irrigated catheter (SIC) and a temperature-controlled catheter (TCC). METHODS: Dogs (n = 6) from the Kunming province in Chinese were ablated; the SIC was introduced into the right renal artery, while the TCC was introduced into the left renal artery. After 6 months, histopathology and renal angiography were performed, and the change in neural density was evaluated using morphometric software. The average values of heart rate (HR), blood pressure (BP), and catecholamine metabolites were assessed at baseline and follow-up. RESULTS: Histopathology showed nerve demyelination and denaturation, as well as interstitial hyperplasia, although these changes were more pronounced when the SIC was used. The change in neural density was greater and ablation was deeper when the SIC was used. Intimal hyperplasia was greater when the TCC was used, whereas medial hyperplasia was greater when the SIC was used. A trend toward a decrease in HR, BP, metanephrine, and normetanephrine between baseline and follow-up was observed. CONCLUSIONS: Our findings suggest that SIC ablation results in more extensive neural degeneration, deeper penetration, and less extensive intimal hyperplasia than TCC ablation for RDN. PMID- 25934969 TI - Nicotinic Transmission onto Layer 6 Cortical Neurons Relies on Synaptic Activation of Non-alpha7 Receptors. AB - Nicotinic excitation in neocortex is mediated by low-affinity alpha7 receptors and by high-affinity alpha4beta2 receptors. There is evidence that alpha7 receptors are synaptic, but it is unclear whether high-affinity receptors are activated by volume transmission or synaptic transmission. To address this issue, we characterized responses of excitatory layer 6 (L6) neurons to optogenetic release of acetylcholine (ACh) in cortical slices. L6 responses consisted in a slowly decaying alpha4beta2 current and were devoid of alpha7 component. Evidence that these responses were mediated by synapses was 4-fold. 1) Channelrhodopsin positive cholinergic varicosities made close appositions onto responsive neurons. 2) Inhibition of ACh degradation failed to alter onset kinetics and amplitude of currents. 3) Quasi-saturation of alpha4beta2 receptors occurred upon ACh release. 4) Response kinetics were unchanged in low release probability conditions. Train stimulations increased amplitude and decay time of responses and these effects appeared to involve recruitment of extrasynaptic receptors. Finally, we found that the alpha5 subunit, known to be associated with alpha4beta2 in L6, regulates short-term plasticity at L6 synapses. Our results are consistent with previous anatomical observations of widespread cholinergic synapses and suggest that a significant proportion of these small synapses operate via high-affinity nicotinic receptors. PMID- 25934970 TI - Editorial: "pharmaceutical biotechnology for tissue repair". PMID- 25934971 TI - Hydrogels in tissue engineering: scope and applications. AB - Hydrogels have been employed as an emerging and promising tool in tissue engineering. They find application in the interdisciplinary field that applies the basic principles of biology and engineering and act as a substitute for conventional tissue engineering materials having improved and restored tissue function. This review article discusses the important characteristic properties of polymers used for the synthesis of hydrogels, which find application in tissue engineering. Furthermore, this article also reviews the recent advances and development in hydrogels used for corneal, cartilage, skin, bone and cardiac tissue for tissue engineering applications. This article highlights the future prospects and scope of hydrogels in tissue engineering. PMID- 25934972 TI - Effectiveness and efficiency of platelet rich plasma in the treatment of diabetic ulcers. AB - "There is a growing body of evidence suggesting that wound healing in chronic diabetic foot ulcers is growth factor dependent, and that the therapeutic delivery of these growth factors to wounds topically, has the potential ability to accelerate wound healing in conjunction with conventional wound care". There is, however, confusion about the utility of platelet rich plasma because the studies that have evaluated them use a wide range of products (different platelet and leukocyte concentrations, different techniques and frequencies of application, very heterogeneous simple, and different endpoints) making almost impossible to compare data and draw conclusions. In this study, we have analyzed the different platelet rich plasma products from a new perspective: cost efficiency. According to our data, we observe that platelet rich plasma is a cost effective option that allows faster healing of ulcers, and that should be taken into account in patients with long evolution ulcers. PMID- 25934973 TI - Recent advances in biomaterials for tissue engineering and controlled drug delivery. AB - In this review, recent advances in biomaterials developed to favor tissue repair are presented. The focus is particularly on devices used to promote bone repair, skin wound healing and nerve regeneration. In each case, the specifications for an ideal substitute and the recent advances in the field of these biomaterials are presented. Alternatively, drug delivery systems associated with biomaterials have been developed over the recent decades to stimulate wound healing without any side effects. For this purpose, the overview presents recent advances in medicated dressings for controlled release of antibiotic to prevent infections, growth factors to promote tissue regeneration and gene delivery to modulate cell phenotype. PMID- 25934974 TI - Drug delivery technologies and stem cells for tissue repair and regeneration. AB - In the last few years several technologies are being developed for eventually repairing or replacing damaged or injured tissues and even organs. Some of these emerging technologies include the design and development of new biomaterials, the optimization of nano- and micro-technologies for drug and cell delivery, the use of autologous proteins or the application of stem cells as therapeutics. Thus, several types of stem cells, e.g. ESCs, iPSCs, MSCs, CD133+ stem cells are being evaluated for tissue regeneration purposes. The present review describes some of these emerging technologies and discusses their potential benefits and challenges. PMID- 25934976 TI - Synthesis and characterization of ibandronate-loaded silica nanoparticles and collagen nanocomposites. AB - Non-porous bare silica nanoparticles, amine modified silica nanoparticles and mesoporous particles, were evaluated as carriers for sodium ibandronate. The synthesized nanoparticles were characterized by SEM, TEM, DLS and porosity. Then, their capacity to incorporate a bisphosphonate drug (sodium ibandronate) and the in vitro release behavior was analyzed by capillary electrophoresis. Mesoporous and amine-modified particles showed higher levels of drug incorporation, 44.68 mg g(-1) and 28.90 mg g(-1), respectively. The release kinetics from the two types of particles was similar following a first order kinetics. However, when these particles were included into collagen hydrogels only mesoporous nanoparticles had a sustained release for over 10 days. The biocompatibility of mesoporous particles towards Saos-2 cells was also evaluated by the MTT assay observing an increase in cell viability for concentrations lower than 0.6 mg ml(-1) of particles and a decrease for concentrations over 1.2 mg ml(-1). Furthermore, when these particles were incubated with mesenchymal cells it was observed that they had the capacity to promote the differentiation of the cells with a significant increase in the alkaline phosphatase activity. PMID- 25934975 TI - A Pilot Study Evaluating Combinatorial and Simultaneous Delivery of Polyethylenimine-Plasmid DNA Complexes Encoding for VEGF and PDGF for Bone Regeneration in Calvarial Bone Defects. AB - Gene therapy is a promising strategy to deliver growth factors of interest locally in a sustained fashion and has the potential to overcome barriers to using recombinant protein therapy such as sustainability and cost. Recent studies demonstrate the safety and efficacy of non-viral delivery of plasmid DNA (pDNA) encoding a single growth factor to enhance bone healing. This pilot study is aimed at testing a non-viral gene delivery system that can deliver two different plasmids encoding two different growth factors. Polyethylenimine (PEI), a cationic polymer, was utilized as a gene delivery vector and collagen scaffold was used as a carrier to deliver the PEI-pDNA complexes encoding platelet derived growth factor B (PDGF-B) and/or vascular endothelial growth factor (VEGF). Calvarial defects in rats were implanted with scaffolds containing PEI-pPDGF-B complexes, PEI-pVEGF complexes or containing both PEIpPDGF- B and PEI-pVEGF complexes in a 1:1 ratio of plasmids. The results indicated that bone regeneration as measured using micro-CT and histological assessments was inferior in groups treated with PEI-(pPDGF-B + pVEGF) complexes, compared to defects treated with PEI-pPDGF-B complexes. This pilot study that explores the feasibility and efficacy of combinatorial non-viral gene delivery system for bone regeneration appears to provide a rationale for investigation of sequential delivery of growth factors at specific time points during the healing phases and this will be explored further in future studies. PMID- 25934977 TI - Can different primary care databases produce comparable estimates of burden of disease: results of a study exploring venous leg ulceration. AB - BACKGROUND: Primary care databases from the UK have been widely used to produce evidence on the epidemiology and health service usage of a wide range of conditions. To date there have been few evaluations of the comparability of estimates between different sources of these data. AIM: To estimate the comparability of two widely used primary care databases, the Health Improvement Network Database (THIN) and the General Practice Research Database (GPRD) using venous leg ulceration as an exemplar condition. DESIGN OF STUDY: Cross prospective cohort comparison. SETTING: GPRD and the THIN databases using data from 1998 to 2006. METHOD: A data set was extracted from both databases containing all cases of persons aged 20 years or greater with a database diagnosis of venous leg ulceration recorded in the databases for the period 1998 2006. Annual rates of incidence and prevalence of venous leg ulceration were calculated within each database and standardized to the European standard population and compared using standardized rate ratios. RESULTS: Comparable estimates of venous leg ulcer incidence from the GPRD and THIN databases could be obtained using data from 2000 to 2006 and of prevalence using data from 2001 to 2006. CONCLUSIONS: Recent data collected by these two databases are more likely to produce comparable results of the burden venous leg ulceration. These results require confirmation in other disease areas to enable researchers to have confidence in the comparability of findings from these two widely used primary care research resources. PMID- 25934978 TI - Characterization of Sensory Properties of Flavanols - A Molecular Dynamic Approach. AB - In this work, sensations elicited by catechin and procyanidins in comparison with those elicited by gallocatechin and prodelphinidins were evaluated by means of a sensory panel. To obtain further insights into the mechanisms of action, molecular dynamics (MD) simulations and saturation transfer difference nuclear magnetic resonance (STD NMR) experiments have been performed. Results showed clear differences between the 2 types of flavanols. Dihydroxylated B-ring flavanols were more astringent, bitter, dry, rough, unripe, and persistent than trihydroxylated B-ring ones. Besides, these last compounds were smoother, more velvety, and viscous. MD simulations and STD NMR experiments support results obtained from tasting panel. MD results suggested that catechin binds to a human salivary proline-rich peptide IB714 faster than gallocatechin and this interaction is maintained longer. IB714 can interact with 2 catechin molecules concurrently while only interacts with 1 gallocatechin molecule. Accordingly, STD NMR experiments showed a greater affinity of catechin than gallocatechin for the peptide (K D = 2.7 and 25.7, respectively). Results indicate that the number of hydroxyl substituents present in B-ring of the flavanic nucleus is decisive for the interaction with salivary proteins and the development of astringency perception. PMID- 25934979 TI - The therapeutic potential of rutin for diabetes: an update. AB - Diabetes and its major risk factor, obesity, have become a world-wide epidemic and cause of suffering for millions of people. There is still no drug of cure for diabetes and the currently available drugs suffer from a number of limitations either due to side effects and/or loss of efficacy during prolonged use. Rutin is one of the most abundant polyphenolic compounds belonging to the flavonoid class. In the present communication, its therapeutic potential for diabetes is critically analysed by reviewing its effect on the various targets of diabetes. The multifunctional nature of rutin including action via antioxidant, anti inflammatory, organoprotection, etc., mechanisms is outlined through review of evidences from in vitro and in vivo studies. PMID- 25934980 TI - Nanotoxicity: the toxicity research progress of metal and metal-containing nanoparticles. AB - Along with the exuberant development of nanotechnology, a large number of nanoformulations or non materials are successfully applied in the clinics, biomedicine, cosmetics and industry. Despite some unique advantages of nanoformulations, there exist potentially worrying toxic effects, particularly those related to metal and metal-containing nanoparticles (NPs). Although various researches have been conducted to assess the metallic and metal-containing nanoparticles toxic effects, only little is known about the toxicity expressive types and evaluation, reasons and mechanisms, influencing factors and research methods of metal and metal-containing nanotoxicity. Therefore, it is of importance to acquire a better understanding of metal and metal-containing nanoparticles toxicity for medical application. This review presents a summary on the metal and metal-containing nanoparticles toxicity research progress consulting relevant literature. PMID- 25934981 TI - MLVA-typing on Streptococcus pneumoniae serotype 1 isolated from meningitis cases in Niger before the introduction of PCV-13 revealed a low genetic diversity. AB - BACKGROUND: Serotype 1 was the most prevalent pneumococcal meningitis serotype encountered in Niger over the period 2003-2011 (pre-vaccination era), accounting for 45.3% of infections. METHODS: Multiple locus VNTR analysis (MLVA) was used to create a genotypic snapshot of a representative subset of the pneumococcal population of serotype 1. RESULTS: MLVA using 16 markers revealed a homogeneous genetic background of pneumococci serotype 1 from Niger, which clustered with few serotype 1 pneumococci from some African countries, while other African countries displayed different clonal complexes. DNA from Niger and from other African countries were different from pneumococci serotype 1 from European countries. CONCLUSIONS: MLVA-typing revealed a low genetic diversity among pneumococci serotype 1 from meningitis cases in Niger in the pre-vaccination era. PMID- 25934982 TI - Systematic review: height-adjustable workstations to reduce sedentary behaviour in office-based workers. AB - BACKGROUND: Time spent sitting in the workplace is an important contributor to overall sedentary risk. Installation of height-adjustable workstations has been proposed as a feasible approach for reducing occupational sitting time in office workers. AIMS: To provide an accurate overview of the controlled trials that have evaluated the effects of height-adjustable workstation interventions on workplace sitting time in office-based workers. METHODS: A comprehensive search was conducted up until March 2014 in the following databases: Medline, PsychINFO, CENTRAL, EMBASE and PEDro. To identify unpublished studies and grey literature, the reference lists of relevant official or scientific web pages were also checked. Studies assessing the effectiveness of height-adjustable workstations using a randomized or non-randomized controlled design were included. RESULTS: The initial search yielded a total of 8497 citations. After a thorough selection process, five studies were included with 172 participants. A formal quality assessment indicated that risk of bias was high in all studies and heterogeneity in interventions and outcomes prevented meta-analysis. Nevertheless, all studies reported that height-adjustable workstation interventions reduced occupational sitting time in office workers. There was insufficient evidence to determine effects on other relevant health outcomes (e.g. body composition, musculoskeletal symptoms, mental health). CONCLUSIONS: There is insufficient evidence to make firm conclusions regarding the effects of installing height-adjustable workstations on sedentary behaviour and associated health outcomes in office workers. Larger and longer term controlled studies are needed, which include more representative populations. PMID- 25934983 TI - Editorial: Molecular determinants of bacterial diseases. PMID- 25934984 TI - Continued progress in developing the Pig-a gene mutation assay. AB - The Pig-a assay has shown promise as a regulatory assay for evaluating in vivo gene mutation. A recent International Workshop on Genotoxicity Testing workgroup discussed the state of the assay and identified several knowledge gaps in assay development. This Mutagenesis Special Topic includes a collection of reports that addresses some of these knowledge gaps, including identifying the mutations responsible for the Pig-a mutant phenotype, the effect of sex on the response, probing the robustness of the assay and expanding the number of agents tested in the assay, especially agents expected to yield negative responses. PMID- 25934986 TI - New insights into the role of siderophores as triggers of plant immunity: what can we learn from animals? AB - Microorganisms use siderophores to obtain iron from the environment. In pathogenic interactions, siderophores are involved in iron acquisition from the host and are sometimes necessary for the expression of full virulence. This review summarizes the main data describing the role of these iron scavengers in animal and plant defence systems. To protect themselves against iron theft, mammalian hosts have developed a hypoferremia strategy that includes siderophore binding molecules called siderocalins. In addition to microbial ferri-siderophore sequestration, siderocalins are involved in triggering immunity. In plants, no similar mechanisms have been described and many fewer data are available, although recent advances have shed light on the role of siderophores in plant pathogen interactions. Siderophores can trigger immunity in plants in several contexts. The most frequently described situation involving siderophores is induced systemic resistance (ISR) triggered by plant-growth-promoting rhizobacteria. Although ISR responses have been observed after treating roots with certain siderophores, the underlying mechanisms are poorly understood. Immunity can also be triggered by siderophores in leaves. Siderophore perception in plants appears to be different from the well-known perception mechanisms of other microbial compounds, known as microbe-associated molecular patterns. Scavenging iron per se appears to be a novel mechanism of immunity activation, involving complex disturbance of metal homeostasis. Receptor-specific recognition of siderophores has been described in animals, but not in plants. The review closes with an overview of the possible mechanisms of defence activation, via iron scavenging by siderophores or specific siderophore recognition by the plant host. PMID- 25934985 TI - Integration of Pig-a, micronucleus, chromosome aberration and comet assay endpoints in a 28-day rodent toxicity study with urethane. AB - As part of the international Pig-a validation trials, we examined the induction of Pig-a mutant reticulocytes and red blood cells (RET(CD59-) and RBC(CD59-), respectively) in peripheral blood of male Sprague Dawley((r)) rats treated with urethane (25, 100 and 250mg/kg/day) or saline by oral gavage for 29 days. Additional endpoints integrated into this study were: micronucleated reticulocytes (MN-RET) in peripheral blood; chromosome aberrations (CAb) and DNA damage (%tail intensity via the comet assay) in peripheral blood lymphocytes (PBL); micronucleated polychromatic erythrocytes (MN-PCE) in bone marrow; and DNA damage (comet) in various organs at termination (the 29th dose was added for the comet endpoint at sacrifice). Ethyl methanesulfonate (EMS; 200mg/kg/day on Days 3, 4, 13, 14, 15, 27, 28 and 29) was evaluated as the concurrent positive control (PC). All animals survived to termination and none exhibited overt toxicity, but there were significant differences in body weight and body weight gain in the 250 mg/kg/day urethane group, as compared with the saline control animals. Statistically significant, dose-dependent increases were observed for urethane for: RET(CD59-) and RBC(CD59-) (on Days 15 and 29); MN-RET (on Days 4, 15 and 29); and MN-PCE (on Day 29). The comet assay yielded positive results in PBL (Day 15) and liver (Day 29), but negative results for PBL (Days 4 and 29) and brain, kidney and lung (Day 29). No significant increases in PBL CAb were observed at any sample time. Except for PBL CAb (likely due to excessive cytotoxicity), EMS induced significant increases in all endpoints/tissues. These results compare favorably with earlier in vivo observations and demonstrate the utility and sensitivity of the Pig-a in vivo gene mutation assay, and its ability to be easily integrated, along with other standard genotoxicity endpoints, into 28-day rodent toxicity studies. PMID- 25934987 TI - Expression of functional traits during seedling establishment in two populations of Pinus ponderosa from contrasting climates. AB - First-year tree seedlings represent a particularly vulnerable life stage and successful seedling establishment is crucial for forest regeneration. We investigated the extent to which Pinus ponderosa P. & C. Lawson populations from different climate zones exhibit differential expression of functional traits that may facilitate their establishment. Seeds from two populations from sites with contrasting precipitation and temperature regimes east (PIPO dry) and west (PIPO mesic) of the Oregon Cascade mountains were sown in a common garden experiment and grown under two water availability treatments (control and drought). Aboveground biomass accumulation, vegetative phenology, xylem anatomy, plant hydraulic architecture, foliar stable carbon isotope ratios (delta(13)C), gas exchange and leaf water relations characteristics were measured. No treatment or population-related differences in leaf water potential were detected. At the end of the first growing season, aboveground biomass was 74 and 44% greater in PIPO mesic in the control and drought treatments, respectively. By early October, 73% of PIPO dry seedlings had formed dormant buds compared with only 15% of PIPO mesic seedlings. Stem theoretical specific conductivity, calculated from tracheid dimensions and packing density, declined from June through September and was nearly twice as high in PIPO mesic during most of the growing season, consistent with measured values of specific conductivity. Intrinsic water-use efficiency based on delta(13)C values was higher in PIPO dry seedlings for both treatments across all sampling dates. There was a negative relationship between values of delta(13)C and leaf-specific hydraulic conductivity across populations and treatments, consistent with greater stomatal constraints on gas exchange with declining seedling hydraulic capacity. Integrated growing season assimilation and stomatal conductance estimated from foliar delta(13)C values and photosynthetic CO2-response curves were 6 and 28% lower, respectively, in PIPO dry seedlings. Leaf water potential at the turgor loss point was 0.33 MPa more negative in PIPO dry, independent of treatment. Overall, PIPO dry seedlings exhibited more conservative behavior, suggesting reduced growth is traded off for increased resistance to drought and extreme temperatures. PMID- 25934988 TI - Vulnerability of native savanna trees and exotic Khaya senegalensis to seasonal drought. AB - Seasonally dry ecosystems present a challenge to plants to maintain water relations. While native vegetation in seasonally dry ecosystems have evolved specific adaptations to the long dry season, there are risks to introduced exotic species. African mahogany, Khaya senegalensis Desr. (A. Juss.), is an exotic plantation species that has been introduced widely in Asia and northern Australia, but it is unknown if it has the physiological or phenotypic plasticity to cope with the strongly seasonal patterns of water availability in the tropical savanna climate of northern Australia. We investigated the gas exchange and water relations traits and adjustments to seasonal drought in K. senegalensis and native eucalypts (Eucalyptus tetrodonta F. Muell. and Corymbia latifolia F. Muell.) in a savanna ecosystem in northern Australia. The native eucalypts did not exhibit any signs of drought stress after 3 months of no rainfall and probably had access to deeper soil moisture late into the dry season. Leaf water potential, stomatal conductance, transpiration and photosynthesis all remained high in the dry season but osmotic adjustment was not observed. Overstorey leaf area index (LAI) was 0.6 in the native eucalypt savanna and did not change between wet and dry seasons. In contrast, the K. senegalensis plantation in the wet season was characterized by a high water potential, high stomatal conductance and transpiration and a high LAI of 2.4. In the dry season, K. senegalensis experienced mild drought stress with a predawn water potential -0.6 MPa. Overstorey LAI was halved, and stomatal conductance and transpiration drastically reduced, while minimum leaf water potentials did not change (-2 MPa) and no osmotic adjustment occurred. Khaya senegalensis exhibited an isohydric behaviour and also had a lower hydraulic vulnerability to cavitation in leaves, with a P50 of -2.3 MPa. The native eucalypts had twice the maximum leaf hydraulic conductance but a much higher P50 of -1.5 MPa. Khaya senegalensis has evolved in a wet-dry tropical climate in West Africa (600-800 mm) and appears to be well suited to the seasonal savanna climate of northern Australia. The species exhibited a large phenotypic plasticity through leaf area adjustments and conservative isohydric behaviour in the 6 months dry season while operating well above its critical hydraulic threshold. PMID- 25934989 TI - Extraction and estimation of the quantity of calcium oxalate crystals in the foliage of conifer and hardwood trees. AB - The main goal of this study was to develop a method for the extraction and indirect estimation of the quantity of calcium oxalate (CaOx) in the foliage of trees. Foliar tissue was collected from a single tree of each species (five conifers and five hardwoods) for comparison of extractions in different solvents using 10 replicates per species from the same pool of tissue. For each species, calcium (Ca) and oxalate were extracted sequentially in double deionized water and 2N acetic acid, and finally, five replicate samples were extracted in 5% (0.83N) perchloric acid (PCA) and the other five in 2N hydrochloric acid (HCl); three cycles of freezing and thawing were used for each solvent. Total ions were extracted by microwave digestion. Calcium was quantified with an inductively coupled plasma emission spectrophotometer method and oxalate was eluted and quantified using a high performance liquid chromatography method. This experiment was repeated again with two conifer and two hardwood species using four trees per species, and two analytical replicates for each tree. We report here that, regardless of age of individual trees within a species, time of collection or species type, the third extraction in PCA or HCl resulted in near equimolar quantities of Ca and oxalate (r(2) >= 0.99). This method provides an easy estimate of the quantity of CaOx crystals using a small sample of foliar tissue. An additional benefit of PCA is that it precipitates the nucleic acids and proteins, allowing the quantification of several free/soluble metabolites such as amino acids, polyamines, organic acids and inorganic elements all from a single sample extract. PMID- 25934990 TI - Pregnancy during dialysis: still a challenge to get there, but worth the effort. PMID- 25934991 TI - Encapsulating peritoneal sclerosis is associated with T-cell activation. AB - BACKGROUND: Encapsulating peritoneal sclerosis (EPS) is an excessive fibrotic response of the peritoneum that may occur after long-term peritoneal dialysis (PD). The underlying pathophysiology is poorly understood, but involvement of peritoneal inflammatory T helper 1 cells may be pivotal. METHODS: Soluble interleukin-2 receptor alpha (sCD25) concentration was measured as a marker for T cell activation in serum and ascites from EPS patients and various control patient groups. Peritoneal biopsies were stained for the presence of T cells, and T cells isolated from ascites of EPS patients were characterized in detail for differentiation status and cytokine expression. RESULTS: Serum sCD25 concentrations are significantly and specifically increased in EPS patients compared with haemodialysis, PD and predialysis patients. Peritoneal effluent of stable PD patients contains very low levels of sCD25, while sCD25 levels in ascites of EPS patients are high and indicative of local production. In the years preceding the diagnosis of EPS, the serum sCD25 concentrations increased while remaining at stable levels in control PD patients. The peritoneum and ascites of EPS patients showed a significant influx of T cells with relatively increased numbers of CD4(+) T cells. These T cells were fully differentiated and displayed a T helper 1 cell type with a pro-inflammatory cytokine profile. CONCLUSIONS: Increased serum sCD25 concentrations and peritoneal lymphocytosis in EPS patients indicate the involvement of activated T cells in the pathophysiology of excessive fibrosis. PMID- 25934992 TI - Metabolic acidosis in renal transplantation: neglected but of potential clinical relevance. AB - Chronic metabolic acidosis (CMA) is a common complication of the more advanced stages of chronic kidney diseases (CKD), and is associated with morbidity and mortality of CKD patients and possibly with the progression of renal disease. Nevertheless, there is limited evidence or information on the prevalence, the potential causal factors, the clinical impact and the effects of correction of CMA in kidney transplant recipients. In this review, we briefly look at the more relevant, though scanty, studies which have, over time, addressed the above mentioned points, with the hope that in the future the interest of transplant nephrologists and surgeons will grow towards this unreasonably neglected issue. PMID- 25934993 TI - Polymorphisms Falling Within Putative miRNA Target Sites in the 3'UTR Region of SIRT2 and DRD2 Genes Are Correlated With Human Longevity. AB - Many studies have suggested that individual differences in aging phenotypes may be associated to polymorphisms affecting gene regulation. As single-nucleotide polymorphisms (SNPs) in the 3'-untranslated regions (3'UTR) targeted by microRNAs (miRNAs) can alter the strength of miRNA binding (and, consequently, the regulation of target genes), we wondered whether these SNPs (known as miRSNPs) affect the individual chance to become long-lived. Thus, we estimated the effect of miRSNPs falling in the 3'-untranslated regions of 140 aging-related genes on the DNA/miRNA bond. The 24 miRSNPs with the highest difference of binding energy between the two alleles were then investigated for their association with longevity by case-control analysis. Two SNPs,SIRT2-rs45592833 G/T and DRD2-rs6276 A/G, provided a significant association with human longevity, also after correcting for multiple comparisons. For both SNPs, the minor allele was associated with a significantly decreased chance to became long-lived in an allele dose-dependent manner (p= 1.090 * 10(-6)and 1.964 * 10(-4)forSIRT2 and DRD2, respectively). The results indicate that the individual aging phenotype may be affected by the variability of specific miRNA targeted regions, as shown for SIRT2 and DRD2, and may suggest further studies to analyze the variability of gene expression regulation as a modulator of aging phenotypes. PMID- 25934994 TI - Rate of Cognitive Decline Before and After the Onset of Functional Limitations in Older Persons. AB - BACKGROUND: Loss in physical function is indicative of deterioration in physiological health that may also be associated with deterioration in neurological health. The objective of this study was to examine whether the onset of functional limitations and their severity is associated with increases in cognitive decline among older adults. METHODS: The study sample consists of 3825 (65% African Americans and 53% females) participants over the age of 65 with no functional limitations. Cognitive function was assessed using a standardized global cognitive score, and functional limitations using a summary measure of 8 Rosow-Breslau and Nagi limitations (ROS-B/Nagi). Cognitive decline before and after the onset of limitations were analyzed using a linear piecewise change point model. RESULTS: During follow-up, 2682 (70%) participants reported limitations in ROS-B/Nagi measure. The rate of cognitive decline was 0.053-units per year before any limitations, and increased to 0.069-units per year after one or more limitations in ROS-B/Nagi measure. This was about 30% (95% Confidence Interval [CI]: 18 - 42%) increase in the rate of cognitive decline comparing before and after the onset of limitations in ROS-B/Nagi measure. Also, higher number of limitations in ROS-B/Nagi measure at the time of onset was associated with faster cognitive decline. CONCLUSIONS: The rate of cognitive decline was significantly higher following functional limitations. This study suggests that self-reported measures of functional limitations may serve as an important marker of cognitive decline. PMID- 25934995 TI - Age- and Sex-Specific Bone Structure Patterns Portend Bone Fragility in Radii and Tibiae in Relation to Osteodensitometry: A High-Resolution Peripheral Quantitative Computed Tomography Study in 385 Individuals. AB - BACKGROUND: Age- and sex-specific 3D bone structure patterns in human radii and tibiae were investigated with respect to individuals' osteodensitometric status to unravel associations with site-specific fracture occurrences and underlying loading patterns. METHODS: A sample of 385 patients (121 men and 264 women, age range: 23-91 years) were investigated. The patients were classified according to dual X-ray absorptiometry T-scores in three groups: control (n = 60), osteopenia (n = 160), and osteoporosis (n = 165). Bone architecture and geometry were assessed by high-resolution peripheral quantitative computed tomography of the cortical and trabecular compartments in distal radii and tibiae. RESULTS: We found site-dependent age- and sex-related trends regarding bone architecture and geometry. Females displayed more pronounced age-related changes than males. Specifically, female radii showed both cortical and trabecular structural deterioration with aging, whereas the tibiae demonstrated exclusively cortical deterioration. The mean cortical perimeter revealed a significant age-related increase for both sexes even after adjusting for body height and weight, which suggests that periosteal expansion can be observed in both the tibia and also in the radius. Osteopenia and osteoporosis cases did not reveal higher cortical perimeters in comparison to controls. CONCLUSIONS: The tomographic assessment of bone structure further clarifies the architectural basis for increased bone fragility at distal radii and tibiae with advanced age leading to fracture predilection in females. Our findings may represent a morphological link to epidemiological data on age-dependent fracture incidences. Our data support the presence of periosteal apposition at both skeletal sites despite different loading magnitudes, and challenges the view on periosteal expansion just as a compensatory mechanism to counterbalance bone loss. PMID- 25934996 TI - Can a Body-Fixed Sensor Reduce Heisenberg's Uncertainty When It Comes to the Evaluation of Mobility? Effects of Aging and Fall Risk on Transitions in Daily Living. AB - BACKGROUND: Functional performance-based tests like the Timed Up and Go test (TUG) and its subtasks have been associated with fall risk, future disability, nursing home admission, and other poor outcomes in older adults. However, a single measurement in the laboratory may not fully reflect the subject's condition and everyday performance. To begin to validate an approach based on long-term, continuous monitoring, we investigated the sit-to-walk and walk-to-sit transitions performed spontaneously and naturally during daily living. METHODS: Thirty young adults, 38 older adults, and 33 elderly (idiopathic) fallers were studied. After evaluating mobility and functional performance in the laboratory, participants wore an accelerometer on their lower back for 3 days. We analyzed the sit-to-walk and walk-to-sit transitions using temporal and distribution related features. Machine learning algorithms assessed the feature set's ability to discriminate between the different cohorts. RESULTS: 5,027 transitions were analyzed. Significant differences were observed between the young and older adults (p < .044) and between the fallers and older adults (p < .032). Machine learning algorithms classified the young and older adult with an accuracy of about 98% and the fallers and the older adults at 88%, which was better than the results achieved using traditional laboratory assessments (~72%). CONCLUSIONS: Features extracted from the multiple transitions recorded during daily living apparently reflect changes associated with aging and fall risk. Long-term monitoring of temporal features and their distribution may be helpful to provide a more complete and accurate assessment of the effects of aging and fall risk on daily function and mobility. PMID- 25934997 TI - An astrocyte neuromorphic circuit that influences neuronal phase synchrony. AB - Neuromorphic circuits are designed and simulated to emulate the role of astrocytes in phase synchronization of neuronal activity. We emulate, to a first order, the ability of slow inward currents (SICs) evoked by the astrocyte, acting on extrasynaptic N-methyl-D-aspartate receptors (NMDAR) of adjacent neurons, as a mechanism for phase synchronization. We run a simulation test incorporating two small networks of neurons interacting with astrocytic microdomains. These microdomains are designed using a resistive and capacitive ladder network and their interactions occur through pass transistors. Upon enough synaptic activity, the astrocytic microdomains interact with each other, generating SIC events on synapses of adjacent neurons. Since the amplitude of SICs is several orders of magnitude larger compared to synaptic currents, a SIC event drastically enhances the excitatory postsynaptic potential (EPSP) on adjacent neurons simultaneously. This causes neurons to fire synchronously in phase. Phase synchrony holds for a duration of time proportional to the time constant of the SIC decay. Once the SIC decay has completed, the neurons are able to go back to their natural phase difference, inducing desynchronization of their firing of spikes. This paper incorporates some biological aspects observed by recent experiments showing astrocytic influence on neuronal synchronization, and intends to offer a circuit view on the hypothesis of astrocytic role on synchronous activity that could potentially lead to the binding of neuronal information. PMID- 25934998 TI - Three dimensional data-driven multi scale atomic representation of optical coherence tomography. AB - In this paper, we discuss about applications of different methods for decomposing a signal over elementary waveforms chosen in a family called a dictionary (atomic representations) in optical coherence tomography (OCT). If the representation is learned from the data, a nonparametric dictionary is defined with three fundamental properties of being data-driven, applicability on 3D, and working in multi-scale, which make it appropriate for processing of OCT images. We discuss about application of such representations including complex wavelet based K-SVD, and diffusion wavelets on OCT data. We introduce complex wavelet based K-SVD to take advantage of adaptability in dictionary learning methods to improve the performance of simple dual tree complex wavelets in speckle reduction of OCT datasets in 2D and 3D. The algorithm is evaluated on 144 randomly selected slices from twelve 3D OCTs taken by Topcon 3D OCT-1000 and Cirrus Zeiss Meditec. Improvement of contrast to noise ratio (CNR) (from 0.9 to 11.91 and from 3.09 to 88.9, respectively) is achieved. Furthermore, two approaches are proposed for image segmentation using diffusion. The first method is designing a competition between extended basis functions at each level and the second approach is defining a new distance for each level and clustering based on such distances. A combined algorithm, based on these two methods is then proposed for segmentation of retinal OCTs, which is able to localize 12 boundaries with unsigned border positioning error of 9.22 +/-3.05 MUm, on a test set of 20 slices selected from 13 3D OCTs. PMID- 25934999 TI - Seipin is necessary for normal brain development and spermatogenesis in addition to adipogenesis. AB - Seipin, encoded by BSCL2 gene, is a protein whose physiological functions remain unclear. Mutations of BSCL2 cause the most-severe form of congenital generalized lipodystrophy (CGL). BSCL2 mRNA is highly expressed in the brain and testis in addition to the adipose tissue in human, suggesting physiological roles of seipin in non-adipose tissues. Since we found BSCL2 mRNA expression pattern among organs in rat is similar to human while it is not highly expressed in mouse brain, we generated a Bscl2/seipin knockout (SKO) rat using the method with ENU (N-ethyl-N nitrosourea) mutagenesis. SKO rats showed total lack of white adipose tissues including mechanical fat such as bone marrow and retro-orbital fats, while physiologically functional brown adipose tissue was preserved. Besides the lipodystrophic phenotypes, SKO rats showed impairment of spatial working memory with brain weight reduction and infertility with azoospermia. We confirmed reduction of brain volume and number of sperm in human patients with BSCL2 mutation. This is the first report demonstrating that seipin is necessary for normal brain development and spermatogenesis in addition to white adipose tissue development. PMID- 25935000 TI - How much dystrophin is enough: the physiological consequences of different levels of dystrophin in the mdx mouse. AB - Splice modulation therapy has shown great clinical promise in Duchenne muscular dystrophy, resulting in the production of dystrophin protein. Despite this, the relationship between restoring dystrophin to established dystrophic muscle and its ability to induce clinically relevant changes in muscle function is poorly understood. In order to robustly evaluate functional improvement, we used in situ protocols in the mdx mouse to measure muscle strength and resistance to eccentric contraction-induced damage. Here, we modelled the treatment of muscle with pre existing dystrophic pathology using antisense oligonucleotides conjugated to a cell-penetrating peptide. We reveal that 15% homogeneous dystrophin expression is sufficient to protect against eccentric contraction-induced injury. In addition, we demonstrate a >40% increase in specific isometric force following repeated administrations. Strikingly, we show that changes in muscle strength are proportional to dystrophin expression levels. These data define the dystrophin restoration levels required to slow down or prevent disease progression and improve overall muscle function once a dystrophic environment has been established in the mdx mouse model. PMID- 25935001 TI - Epigenetic regulation of differential HLA-A allelic expression levels. AB - MHC class I expression levels influence the strength of immune responses and represent another variable in determining outcome to disease beyond peptide binding alone. Identification of the HLA loci that vary in allelic expression levels and delineating the mechanism responsible for expression variation may provide the opportunity to modify their expression therapeutically. We have examined the expression levels of allelic lineages at the HLA-A locus in a sample of 216 European Americans using a real-time polymerase chain reaction assay, which amplifies all HLA-A lineages specifically with equal efficiency, and observed a gradient of expression that associates with HLA-A allelic lineage (R = 0.6, P = 5 * 10(-25)). DNA methylation of the HLA-A gene appears to contribute to the variation in HLA-A mRNA expression levels, as a significant inverse correlation was observed between HLA-A mRNA expression levels in untreated cells and the degree to which expression is increased after treatment of the cells with a DNA methyltransferase inhibitor (R = 0.6, P = 2.8 * 10(-6)). Further, deep sequencing and immunoprecipitation assays revealed allelic lineage-specific methylation patterns within the HLA-A promoter region where increased DNA methylation levels correlated significantly with reduced HLA-A expression levels (R = 0.89, P = 3.7 * 10(-9)). These data demonstrate HLA-A allelic lineage specific variation in expression levels, and DNA methylation as a likely factor in contributing to this variation. PMID- 25935002 TI - Second-generation compound for the modulation of utrophin in the therapy of DMD. AB - Duchenne muscular dystrophy (DMD) is a lethal, X-linked muscle-wasting disease caused by lack of the cytoskeletal protein dystrophin. There is currently no cure for DMD although various promising approaches are progressing through human clinical trials. By pharmacologically modulating the expression of the dystrophin related protein utrophin, we have previously demonstrated in dystrophin-deficient mdx studies, daily SMT C1100 treatment significantly reduced muscle degeneration leading to improved muscle function. This manuscript describes the significant disease modifying benefits associated with daily dosing of SMT022357, a second generation compound in this drug series with improved physicochemical properties and a more robust metabolism profile. These studies in the mdx mouse demonstrate that oral administration of SMT022357 leads to increased utrophin expression in skeletal, respiratory and cardiac muscles. Significantly, utrophin expression is localized along the length of the muscle fibre, not just at the synapse, and is fibre-type independent, suggesting that drug treatment is modulating utrophin transcription in extra-synaptic myonuclei. This results in improved sarcolemmal stability and prevents dystrophic pathology through a significant reduction of regeneration, necrosis and fibrosis. All these improvements combine to protect the mdx muscle from contraction induced damage and enhance physiological function. This detailed evaluation of the SMT C1100 drug series strongly endorses the therapeutic potential of utrophin modulation as a disease modifying therapeutic strategy for all DMD patients irrespective of their dystrophin mutation. PMID- 25935005 TI - Variation of atmospheric tritium concentration in three chemical forms at Toki, Japan: 2004-12. AB - Atmospheric tritium concentrations of HTO, HT and CH3T have been measured at Toki, Japan, for the environmental impact assessment of tritium for a fusion test facility. According to the data from 2004 to 2012, the concentrations of HT and HTO in water vapour tend to increase in spring. The seasonal variation in HT concentration at Toki was compared with the H2 concentration between 1990 and 2005 at Tae-ahn Peninsula, Republic of Korea, which is at approximately the same latitude as Toki. The monthly average of HT-specific activity varied from 1.24 * 10(5) to 1.76 * 10(5) TU. The peak of the monthly average H2 concentration did not match that of HT. This indicates that the mechanism of the production or the source of HT might be different from the production mechanism of H2. PMID- 25935003 TI - Improved integrative framework combining association data with gene expression features to prioritize Crohn's disease genes. AB - Genome-wide association studies in Crohn's disease (CD) have identified 140 genome-wide significant loci. However, identification of genes driving association signals remains challenging. Furthermore, genome-wide significant thresholds limit false positives at the expense of decreased sensitivity. In this study, we explored gene features contributing to CD pathogenicity, including gene based association data from CD and autoimmune (AI) diseases, as well as gene expression features (eQTLs, epigenetic markers of expression and intestinal gene expression data). We developed an integrative model based on a CD reference gene set. This integrative approach outperformed gene-based association signals alone in identifying CD-related genes based on statistical validation, gene ontology enrichment, differential expression between M1 and M2 macrophages and a validation using genes causing monogenic forms of inflammatory bowel disease as a reference. Besides gene-level CD association P-values, association with AI diseases was the strongest predictor, highlighting generalized mechanisms of inflammation, and the interferon-gamma pathway particularly. Within the 140 high confidence CD regions, 598 of 1328 genes had low prioritization scores, highlighting genes unlikely to contribute to CD pathogenesis. For select regions, comparably high integrative model scores were observed for multiple genes. This is particularly evident for regions having extensive linkage disequilibrium such as the IBD5 locus. Our analyses provide a standardized reference for prioritizing potential CD-related genes, in regions with both highly significant and nominally significant gene-level association P-values. Our integrative model may be particularly valuable in prioritizing rare, potentially private, missense variants for which genome-wide evidence for association may be unattainable. PMID- 25935006 TI - An experimental method for quantitatively evaluating the elemental processes of indoor radioactive aerosol behavior. AB - An experimental method for quantitatively evaluating the elemental processes governing the indoor behaviour of naturally occurring radioactive aerosols was proposed. This method utilises transient response of aerosol concentrations to an artificial change in aerosol removal rate by turning on and off an air purifier. It was shown that the indoor-outdoor exchange rate and the indoor deposition rate could be estimated by a continuous measurement of outdoor and indoor aerosol number concentration measurements and by the method proposed in this study. Although the scatter of the estimated parameters is relatively large, both the methods gave consistent results. It was also found that the size distribution of radioactive aerosol particles and hence activity median aerodynamic diameter remained not largely affected by the operation of the air purifier, implying the predominance of the exchange and deposition processes over other processes causing change in the size distribution such as the size growth by coagulation and the size dependence of deposition. PMID- 25935004 TI - Epigenome-wide association study (EWAS) of BMI, BMI change and waist circumference in African American adults identifies multiple replicated loci. AB - Obesity is an important component of the pathophysiology of chronic diseases. Identifying epigenetic modifications associated with elevated adiposity, including DNA methylation variation, may point to genomic pathways that are dysregulated in numerous conditions. The Illumina 450K Bead Chip array was used to assay DNA methylation in leukocyte DNA obtained from 2097 African American adults in the Atherosclerosis Risk in Communities (ARIC) study. Mixed-effects regression models were used to test the association of methylation beta value with concurrent body mass index (BMI) and waist circumference (WC), and BMI change, adjusting for batch effects and potential confounders. Replication using whole-blood DNA from 2377 White adults in the Framingham Heart Study and CD4+ T cell DNA from 991 Whites in the Genetics of Lipid Lowering Drugs and Diet Network Study was followed by testing using adipose tissue DNA from 648 women in the Multiple Tissue Human Expression Resource cohort. Seventy-six BMI-related probes, 164 WC-related probes and 8 BMI change-related probes passed the threshold for significance in ARIC (P < 1 * 10(-7); Bonferroni), including probes in the recently reported HIF3A, CPT1A and ABCG1 regions. Replication using blood DNA was achieved for 37 BMI probes and 1 additional WC probe. Sixteen of these also replicated in adipose tissue, including 15 novel methylation findings near genes involved in lipid metabolism, immune response/cytokine signaling and other diverse pathways, including LGALS3BP, KDM2B, PBX1 and BBS2, among others. Adiposity traits are associated with DNA methylation at numerous CpG sites that replicate across studies despite variation in tissue type, ethnicity and analytic approaches. PMID- 25935007 TI - Environmental radioactivity of water samples collected in Higashi-Hiroshima campus, Hiroshima University, Japan. AB - The relation between concentration of elements and microbial activity in the water samples of Higashi-Hiroshima Campus, Hiroshima University was investigated. Energy dispersive X-ray spectroscopy revealed that microbial mat contains iron, aluminium, silicon and phosphorus. Model experiment revealed that the potassium was adsorbed by living microorganism in the microbial mats, while it was not adsorbed by dead microbial mat. Iron was adsorbed by both living and dead microbial mats. The present results explain the increase in the total beta radioactivity of water sample in summer and the decrease in winter. PMID- 25935008 TI - Measurement of radioactivity and heavy metal levels in edible vegetables and their impact on Kuala Selangor communities of Peninsular Malaysia. AB - Vegetable is an essential daily diet item for the people of Malaysia. This work addressed the radiation and heavy metal exposure scenarios through the consumption of vegetables. Kuala Selangor is located in Sungai Selangor estuary in the west coast of Peninsular Malaysia, which is susceptible to pollution load due to the presence of large-scale industrial and human activities. Radioactivity and heavy metals level in human diet is of particular concern for the assessment of possible radiological and chemical hazards to human health. Therefore, a comprehensive study was carried out to determine the radioactivity levels ((226)Ra, (228)Ra and (40)K) and heavy metal concentrations (Cr, As, Cd, Mn, Mg, Al, Sr, Rb, Sb, Ba, Hg, Fe, Ni, Zn, Cu, Bi and Pb) in 10 varieties of vegetable collected from different farmlands in Kuala Selangor region. The committed doses for (226)Ra, (228)Ra and (40)K due to consumption of vegetables were found 16.6+/ 1.3, 23.6+/-1.7 and 58+/-5 uSv y(-1), respectively, with a total of 98+/-8 uSv y( 1). This dose imposes no significant threat to human health. The estimated cancer risk shows that probability of increase in cancer risk from daily intake of vegetables is only a minor fraction of International Commission on Radiological Protection values. The concentrations of heavy metal were below the daily intake recommended by the international organisations. PMID- 25935009 TI - Effect on radioactivity concentration estimation of radon progenies with NaI(Tl) pulse height distribution from considering geometric structure around detector and infiltration of radionuclides. AB - The surface radioactivity concentrations of the radon progenies, (214)Pb and (214)Bi, were estimated from NaI(Tl) pulse height distributions during rain. The improvement in estimation errors caused by considering geometric structures around measuring points and infiltration of radionuclides was discussed. The surface radioactivity concentrations were determined by comparing the count rates at the full-energy peak ranges between observation and calculation with the electron-photon transport code EGS5. It was shown that the concentrations can be underestimated by about 30 % unless the obstacles around the detector or infiltration of radionuclides are considered in gamma ray transfer calculations at measuring points, where there are many tall obstacles, or the ground is covered with unpaved areas. PMID- 25935010 TI - Radiation-induced non-targeted effects: some open questions. AB - The existence of non-targeted effects (NTEs) of radiation (genomic instability and bystander effects) has been generally accepted for >20 y; however, there is research, which was largely ignored going back to 1915 reporting these effects. Despite today's general acceptance of the phenomenon of NTE, there is little agreement about the mechanisms involved and the implications in radiation biology and radiation protection. The aim of this review was to consider some of the odd data, which have been published in the field with a view to obtaining insights or stimulating new ways of thinking about this field. By highlighting some key challenges and controversies, concerning the mechanisms and more importantly, the reason these effects exist, current ideas about the wider implications of NTEs in evolution and biology are also discussed. PMID- 25935011 TI - Concentration of 129I in aquatic biota collected from a lake adjacent to the spent nuclear fuel reprocessing plant in Rokkasho, Japan. AB - The spent nuclear fuel reprocessing plant in Rokkasho, Japan, has been undergoing final testing since March 2006. During April 2006-October 2008, that spent fuel was cut and chemically processed, the plant discharged (129)I into the atmosphere and coastal waters. To study (129)I behaviour in brackish Lake Obuchi, which is adjacent to the plant, (129)I concentrations in aquatic biota were measured by accelerator mass spectrometry. Owing to (129)I discharge from the plant, the (129)I concentration in the biota started to rise from the background concentration in 2006 and was high during 2007-08. The (129)I concentration has been rapidly decreasing after the fuel cutting and chemically processing were finished. The (129)I concentration factors in the biota were higher than those reported by IAEA for marine organisms and similar to those reported for freshwater biota. The estimated annual committed effective dose due to ingestion of foods with the maximum (129)I concentration in the biota samples was 2.8 nSv y(-1). PMID- 25935012 TI - Changes in the chemical form of exogenous iodine in forest soils and their extracts. AB - Information about the chemical form of exogenous iodine in soil is important for predicting the mobility and behaviour of radioiodine in the terrestrial environment. In this study, soil samples collected at various depths in a pine forest in Rokkasho, Japan, were spiked with stable iodine (as iodide or iodate); after incubation of the spiked soils for 1 or 14 d, the chemical forms of iodine were investigated in both the soils and their water extracts. In surface soil and its extracts, inorganic iodine was found to have been transformed to organically bound forms after incubation for 14 d, resulting in a decrease in the amount of water-extractable iodine in the soil. In contrast, in subsurface soil, which had low organic matter content, the predominant chemical form of iodine after incubation did not differ from that in the spiked soil, and the amount of water extractable iodine did not decrease noticeably. PMID- 25935013 TI - Comparative dosimetry for radon and thoron in high background radiation areas in China. AB - The present study focuses on internal exposure caused by the inhalation of radon and thoron progenies because the internal exposures have not yet been clarified. For their dose assessment, radon, thoron and thoron progeny concentrations were measured by passive monitors over a long period (for 6 months). Consequently, radon, thoron and equilibrium equivalent thoron concentrations were given as 124 +/- 78, 1247 +/- 1189 and 7.8 +/- 9.1 Bq m(-3), respectively. Annual effective doses are estimated to be 3.1 +/- 2.0 mSv for radon and 2.2 +/- 2.5 mSv for thoron. Total dose are estimated to be 5.3 +/- 3.5 mSv a(-1). The present study has revealed that the radon dose was comparable with the thoron dose, and the total dose was ~2 times higher than the worldwide average. PMID- 25935014 TI - Analysis of natural radionuclides in soil samples of Purola area of Garhwal Himalaya, India. AB - Naturally occurring radioactive materials are widely spread in the earth's environment, being distributed in soil, rocks, water, air, plants and even within the human body. All of these sources have contributed to an increase in the levels of environmental radioactivity and population radiation doses. This paper presents the activity level due to the presence of (226)Ra, (232)Th and (40)K in soil samples of Purola area in Garhwal Himalaya region. The measured activity of (226)Ra, (232)Th and (40)K in collected soil samples of Purola was found to vary from 13+/-10 to 55+/-10 Bq kg(-1) with an average of 31+/-2 Bq kg(-1), 13+/-10 to 101+/-13 Bq kg(-1) with an average 30+/-3 Bq kg(-1) and 150+/-81 to 1310+/-154 Bq kg(-1) with an average 583+/-30 Bq kg(-1), respectively. The radium equivalent activity in collected soil samples was found to vary from 47 to 221 Bq kg(-1) with an average of 115 Bq kg(-1). The total absorbed gamma dose rate in this area was found to vary from 22 to 93 nGy h(-1) with an average of 55 nGy h(-1). The distribution of these radionuclides in the soil of study area is discussed in details. PMID- 25935015 TI - An overview of radon research in Canada. AB - Based on new scientific information and broad public consultation, the Government of Canada updated the guideline for exposure to indoor radon and launched a multi year radon programme in 2007. Major achievements in radon research accomplished in the past 7 y are highlighted here. PMID- 25935016 TI - Organ and effective dose coefficients for cranial and caudal irradiation geometries: photons. AB - With the introduction of new recommendations of the International Commission on Radiological Protection (ICRP) in Publication 103, the methodology for determining the protection quantity, effective dose, has been modified. The modifications include changes to the defined organs and tissues, the associated tissue weighting factors, radiation weighting factors and the introduction of reference sex-specific computational phantoms. Computations of equivalent doses in organs and tissues are now performed in both the male and female phantoms and the sex-averaged values used to determine the effective dose. Dose coefficients based on the ICRP 103 recommendations were reported in ICRP Publication 116, the revision of ICRP Publication 74 and ICRU Publication 57. The coefficients were determined for the following irradiation geometries: anterior-posterior (AP), posterior-anterior (PA), right and left lateral (RLAT and LLAT), rotational (ROT) and isotropic (ISO). In this work, the methodology of ICRP Publication 116 was used to compute dose coefficients for photon irradiation of the body with parallel beams directed upward from below the feet (caudal) and directed downward from above the head (cranial). These geometries may be encountered in the workplace from personnel standing on contaminated surfaces or volumes and from overhead sources. Calculations of organ and tissue kerma and absorbed doses for caudal and cranial exposures to photons ranging in energy from 10 keV to 10 GeV have been performed using the MCNP6.1 radiation transport code and the adult reference phantoms of ICRP Publication 110. As with calculations reported in ICRP 116, the effects of charged-particle transport are evident when compared with values obtained by using the kerma approximation. At lower energies the effective dose per particle fluence for cranial and caudal exposures is less than AP orientations while above ~30 MeV the cranial and caudal values are greater. PMID- 25935023 TI - Pulsed Transcranial Ultrasound Stimulation Immediately After The Ischemic Brain Injury is Neuroprotective. AB - GOAL: We applied a low-intensity pulsed transcranial ultrasound stimulation (pTUS) to the ischemic cortex after a distal middle cerebral artery occlusion (dMCAO) to study whether pTUS is capable of protecting brain from ischemic injury. METHODS: Rats were randomly assigned to Sham (n = 6), Control (n = 16), and pTUS (n = 16) groups. The pTUS-treated rats were subjected to 60-min ultrasonic stimulation immediately after the ischemia. After 48 h, the sensorimotor-related behavioral outcomes were assessed by a neurological severity score (NSS), and the permanent brain injury was assessed by the histologic analysis of TTC staining of brain slices. RESULTS: pTUS group showed significantly lower NSS (n = 10, 5.5 +/- 2.5) than the Control group ( n = 10, 10.5 +/-1.4) (p < 0.01). Concordantly, the ischemic lesion was significantly reduced after receiving pTUS immediately after dMCAO. The cortical infarct volume in the control group was more than threefold of the pTUS group (43.39% +/- 2.33%, n = 16 versus 13.78% +/- 8.18%, n = 16, p < 0.01). Immunohistochemical staining indicated reduction of neutrophils in the affected area, and laser speckle imaging showed significant increase of a cerebral blood flow after pTUS, which consistently supported the neuroprotection of pTUS in ischemic brain injury. CONCLUSION: Both behavior and histological results suggested that pTUS on ischemic core immediately after ischemic stroke could be neuroprotective. SIGNIFICANCE: The noninvasiveness and high spatiotemporal resolution of pTUS makes it a unique neuromodulation technique in comparison with the current TMS and tDCS. PMID- 25935024 TI - A Computationally Efficient Sound Environment Classifier for Hearing Aids. AB - A computationally efficient system for sound environment classification in digital hearing aids is presented in this paper. The goal is to automatically classify three different listening environments: "speech," "music," and "noise." The system is designed considering the computational limitations found in such devices. The proposed algorithm is based on a novel set of heuristically designed features inspired in the Mel frequency cepstral coefficients. Experiments carried out with real signals demonstrate that the three listening environments can be robustly classified with the proposed system, obtaining low error rates when using a small part of the total computational resources of the DSP of the device. This study demonstrates that the proposed system can be implemented with the available resources in state-of-the-art digital hearing aids. PMID- 25935025 TI - Quantifying Pituitary-Adrenal Dynamics and Deconvolution of Concurrent Cortisol and Adrenocorticotropic Hormone Data by Compressed Sensing. AB - Pulsatile release of cortisol from the adrenal glands is governed by pulsatile release of adrenocorticotropic hormone (ACTH) from the anterior pituitary. In return, cortisol has a negative feedback effect on ACTH release. Simultaneous recording of ACTH and cortisol is not typical, and determining the number, timing, and amplitudes of pulsatile events from simultaneously recorded data is challenging because of several factors: 1) stimulator ACTH pulse activity, 2) kinematics of ACTH and cortisol, 3) the sampling interval, and 4) the measurement error. We model ACTH and cortisol secretion simultaneously using a linear differential equations model with Gaussian errors and sparse pulsatile events as inputs to the model. We propose a novel framework for recovering pulses and parameters underlying the interactions between ACTH and cortisol. We recover the timing and amplitudes of pulses using compressed sensing and employ generalized cross validation for determining the number of pulses. We analyze serum ACTH and cortisol levels sampled at 10-min intervals over 24 h from ten healthy women. We recover physiologically plausible timing and amplitudes for these pulses and model the feedback effect of cortisol. We recover 15 to 18 pulses over 24 h, which is highly consistent with the results of another cortisol data analysis approach. Modeling the interactions between ACTH and cortisol allows for accurate quantification of pulsatile events, and normal and pathological states. This could lay the basis for a more physiologically-based approach for administering cortisol therapeutically. The proposed approach can be adapted to deconvolve other pairs of hormones with similar interactions. PMID- 25935026 TI - In Silico Closed-Loop Control Validation Studies for Optimal Insulin Delivery in Type 1 Diabetes. AB - This study presents a general closed-loop control strategy for optimal insulin delivery in type 1 Diabetes Mellitus (T1DM). The proposed control strategy aims toward an individualized optimal insulin delivery that consists of a patient specific model predictive controller, a state estimator, a personalized scheduling level, and an open-loop optimization problem subjected to patient specific process model and constraints. This control strategy can be also modified to address the case of limited patient data availability resulting in an "approximation" control strategy. Both strategies are validated in silico in the presence of predefined and unknown meal disturbances using both a novel mathematical model of glucose-insulin interactions and the UVa/Padova Simulator model as a virtual patient. The robustness of the control performance is evaluated under several conditions such as skipped meals, variability in the meal time, and metabolic uncertainty. The simulation results of the closed-loop validation studies indicate that the proposed control strategies can potentially achieve improved glycaemic control. PMID- 25935027 TI - Quantitative evaluation of knee subchondral bone mineral density using cone beam computed tomography. AB - Contrast agent enhanced cone beam computed tomography (CE-CBCT), a technique capable of high-resolution in vivo imaging with small radiation dose, has been applied successfully for clinical diagnostics of cartilage degeneration, i.e., osteoarthritis (OA). As an X-ray technique, CE-CBCT may also detect changes in mineral density of subchondral bone (volumetric bone mineral density, vBMD), known to be characteristic for OA. However, its feasibility for density measurements is not clear due to limited signal-to-noise ratio and contrast of CBCT images. In the present study, we created clinically applicable hydroxyapatite phantoms and determined vBMDs of cortical bone, trabecular bone, subchondral trabecular bone and subchondral plate of 10 cadaver (ex vivo) and 10 volunteer (in vivo) distal femora using a clinical CBCT scanner, and for reference, also using a conventional CT scanner. Our results indicated strong linear correlations between the vBMD values measured with the CT and CBCT scanners , however, absolute vBMD values were dependent on the scanner in use. Further, the differences between the vBMDs of cortical bone, trabecular bone and subchondral bone were similar and independent of the scanner. The present results indicate that vBMD values might not be directly comparable between different instruments. However, based on our present and previous results, we propose that, for OA diagnostics, clinical CBCT enables not only quantitative analysis of articular cartilage but also subchondral bone vBMD. Quantitative information on both cartilage and subchondral bone could be beneficial in OA diagnostics. PMID- 25935029 TI - Computer-Aided Prostate Cancer Detection Using Ultrasound RF Time Series: In Vivo Feasibility Study. AB - This paper presents the results of a computer-aided intervention solution to demonstrate the application of RF time series for characterization of prostate cancer, in vivo. METHODS: We pre-process RF time series features extracted from 14 patients using hierarchical clustering to remove possible outliers. Then, we demonstrate that the mean central frequency and wavelet features extracted from a group of patients can be used to build a nonlinear classifier which can be applied successfully to differentiate between cancerous and normal tissue regions of an unseen patient. RESULTS: In a cross-validation strategy, we show an average area under receiver operating characteristic curve (AUC) of 0.93 and classification accuracy of 80%. To validate our results, we present a detailed ultrasound to histology registration framework. CONCLUSION: Ultrasound RF time series results in differentiation of cancerous and normal tissue with high AUC. PMID- 25935028 TI - A majorize-minimize framework for Rician and non-central chi MR images. AB - The statistics of many MR magnitude images are described by the non-central chi (NCC) family of probability distributions, which includes the Rician distribution as a special case. These distributions have complicated negative log-likelihoods that are nontrivial to optimize. This paper describes a novel majorize-minimize framework for NCC data that allows penalized maximum likelihood estimates to be obtained by solving a series of much simpler regularized least-squares surrogate problems. The proposed framework is general and can be useful in a range of applications. We illustrate the potential advantages of the framework with real and simulated data in two contexts: 1) MR image denoising and 2) diffusion profile estimation in high angular resolution diffusion MRI. The proposed approach is shown to yield improved results compared to methods that model the noise statistics inaccurately and faster computation relative to commonly-used nonlinear optimization techniques. PMID- 25935030 TI - Direct Parametric Reconstruction Using Anatomical Regularization for Simultaneous PET/MRI Data. AB - Pharmacokinetic analysis of dynamic positron emission tomography (PET) imaging data maps the measured time activity curves to a set of model-specific pharmacokinetic parameters. Voxel-based parameter estimation via curve fitting is conventionally performed indirectly on a sequence of independently reconstructed PET images, leading to high variance and bias in the parametric images. We propose a direct parametric reconstruction algorithm with raw projection data as input that leverages high-resolution anatomical information simultaneously obtained from magnetic resonance (MR) imaging in a PET/MRI scanner for regularization. The reconstruction problem is formulated in a flexible Bayesian framework with Gaussian Markov Random field modeling of activity, parameters, or both simultaneously. MR information is incorporated through a Bowsher-like prior function. Optimization transfer using an expectation-maximization surrogate and a new Bowsher-like penalty surrogate is applied to obtain a voxel-separable algorithm that interleaves a reconstruction with a fitting step. An analytical input function model is used. The algorithm is evaluated on simulated [(18)F]FDG and clinical [(18)F]FET brain data acquired with a Biograph mMR. The results indicate that direct and simultaneously regularized parametric reconstruction increases image quality. Anatomical regularization leads to higher contrast than conventional distance-weighted regularization. PMID- 25935031 TI - A Digital Preclinical PET/MRI Insert and Initial Results. AB - Combining Positron Emission Tomography (PET) with Magnetic Resonance Imaging (MRI) results in a promising hybrid molecular imaging modality as it unifies the high sensitivity of PET for molecular and cellular processes with the functional and anatomical information from MRI. Digital Silicon Photomultipliers (dSiPMs) are the digital evolution in scintillation light detector technology and promise high PET SNR. DSiPMs from Philips Digital Photon Counting (PDPC) were used to develop a preclinical PET/RF gantry with 1-mm scintillation crystal pitch as an insert for clinical MRI scanners. With three exchangeable RF coils, the hybrid field of view has a maximum size of 160 mm * 96.6 mm (transaxial * axial). 0.1 ppm volume-root-mean-square B 0-homogeneity is kept within a spherical diameter of 96 mm (automatic volume shimming). Depending on the coil, MRI SNR is decreased by 13% or 5% by the PET system. PET count rates, energy resolution of 12.6% FWHM, and spatial resolution of 0.73 mm (3) (isometric volume resolution at isocenter) are not affected by applied MRI sequences. PET time resolution of 565 ps (FWHM) degraded by 6 ps during an EPI sequence. Timing-optimized settings yielded 260 ps time resolution. PET and MR images of a hot-rod phantom show no visible differences when the other modality was in operation and both resolve 0.8-mm rods. Versatility of the insert is shown by successfully combining multi-nuclei MRI ((1)H/(19)F) with simultaneously measured PET ((18)F-FDG). A longitudinal study of a tumor-bearing mouse verifies the operability, stability, and in vivo capabilities of the system. Cardiac- and respiratory-gated PET/MRI motion capturing (CINE) images of the mouse heart demonstrate the advantage of simultaneous acquisition for temporal and spatial image registration. PMID- 25935032 TI - Enhancement of textural differences based on morphological component analysis. AB - This paper proposes a new texture enhancement method which uses an image decomposition that allows different visual characteristics of textures to be represented by separate components in contrast with previous methods which either enhance texture indirectly or represent all texture information using a single image component. Our method is intended to be used as a preprocessing step prior to the use of texture-based image segmentation algorithms. Our method uses a modification of morphological component analysis (MCA) which allows texture to be separated into multiple morphological components each representing a different visual characteristic of texture. We select four such texture characteristics and propose new dictionaries to extract these components using MCA. We then propose procedures for modifying each texture component and recombining them to produce a texture-enhanced image. We applied our method as a preprocessing step prior to a number of texture-based segmentation methods and compared the accuracy of the results, finding that our method produced results superior to comparator methods for all segmentation algorithms tested. We also demonstrate by example the main mechanism by which our method produces superior results, namely that it causes the clusters of local texture features of each distinct image texture to mutually diverge within the multidimensional feature space to a vastly superior degree versus the comparator enhancement methods. PMID- 25935033 TI - Inverse sparse tracker with a locally weighted distance metric. AB - Sparse representation has been recently extensively studied for visual tracking and generally facilitates more accurate tracking results than classic methods. In this paper, we propose a sparsity-based tracking algorithm that is featured with two components: 1) an inverse sparse representation formulation and 2) a locally weighted distance metric. In the inverse sparse representation formulation, the target template is reconstructed with particles, which enables the tracker to compute the weights of all particles by solving only one l1 optimization problem and thereby provides a quite efficient model. This is in direct contrast to most previous sparse trackers that entail solving one optimization problem for each particle. However, we notice that this formulation with normal Euclidean distance metric is sensitive to partial noise like occlusion and illumination changes. To this end, we design a locally weighted distance metric to replace the Euclidean one. Similar ideas of using local features appear in other works, but only being supported by popular assumptions like local models could handle partial noise better than holistic models, without any solid theoretical analysis. In this paper, we attempt to explicitly explain it from a mathematical view. On that basis, we further propose a method to assign local weights by exploiting the temporal and spatial continuity. In the proposed method, appearance changes caused by partial occlusion and shape deformation are carefully considered, thereby facilitating accurate similarity measurement and model update. The experimental validation is conducted from two aspects: 1) self validation on key components and 2) comparison with other state-of-the-art algorithms. Results over 15 challenging sequences show that the proposed tracking algorithm performs favorably against the existing sparsity-based trackers and the other state-of-the art methods. PMID- 25935034 TI - Stacked Multilayer Self-Organizing Map for Background Modeling. AB - In this paper, a new background modeling method called stacked multilayer self organizing map background model (SMSOM-BM) is proposed, which presents several merits such as strong representative ability for complex scenarios, easy to use, and so on. In order to enhance the representative ability of the background model and make the parameters learned automatically, the recently developed idea of representative learning (or deep learning) is elegantly employed to extend the existing single-layer self-organizing map background model to a multilayer one (namely, the proposed SMSOM-BM). As a consequence, the SMSOM-BM gains several merits including strong representative ability to learn background model of challenging scenarios, and automatic determination for most network parameters. More specifically, every pixel is modeled by a SMSOM, and spatial consistency is considered at each layer. By introducing a novel over-layer filtering process, we can train the background model layer by layer in an efficient manner. Furthermore, for real-time performance consideration, we have implemented the proposed method using NVIDIA CUDA platform. Comparative experimental results show superior performance of the proposed approach. PMID- 25935035 TI - Objective quality assessment for multiexposure multifocus image fusion. AB - There has been a growing interest in image fusion technologies, but how to objectively evaluate the quality of fused images has not been fully understood. Here, we propose a method for objective quality assessment of multiexposure multifocus image fusion based on the evaluation of three key factors of fused image quality: 1) contrast preservation; 2) sharpness; and 3) structure preservation. Subjective experiments are conducted to create an image fusion database, based on which, performance evaluation shows that the proposed fusion quality index correlates well with subjective scores, and gives a significant improvement over the existing fusion quality measures. PMID- 25935036 TI - Online kernel slow feature analysis for temporal video segmentation and tracking. AB - Slow feature analysis (SFA) is a dimensionality reduction technique which has been linked to how visual brain cells work. In recent years, the SFA was adopted for computer vision tasks. In this paper, we propose an exact kernel SFA (KSFA) framework for positive definite and indefinite kernels in Krein space. We then formulate an online KSFA which employs a reduced set expansion. Finally, by utilizing a special kind of kernel family, we formulate exact online KSFA for which no reduced set is required. We apply the proposed system to develop a SFA based change detection algorithm for stream data. This framework is employed for temporal video segmentation and tracking. We test our setup on synthetic and real data streams. When combined with an online learning tracking system, the proposed change detection approach improves upon tracking setups that do not utilize change detection. PMID- 25935037 TI - SLED: Semantic Label Embedding Dictionary Representation for Multilabel Image Annotation. AB - Most existing methods on weakly supervised image annotation rely on jointly unsupervised feature representation, the components of which are not directly correlated with specific labels. In practical cases, however, there is a big gap between the training and the testing data, say the label combination of the testing data is not always consistent with that of the training. To bridge the gap, this paper presents a semantic label embedding dictionary representation that not only achieves the discriminative feature representation for each label in the image, but also mines the semantic relevance between co-occurrence labels for context information. More specifically, to enhance the discriminative representation of labels, the training data is first divided into a set of overlapped groups by graph shift based on the exclusive label graph. Afterward, given a group of exclusive labels, we try to learn multiple label-specific dictionaries to explicitly decorrelate the feature representation of each label. A joint optimization approach is proposed according to the Fisher discrimination criterion for seeking its solution. Then, to discover the context information hidden in the co-occurrence labels, we explore the semantic relationship between visual words in dictionaries and labels in a multitask learning way with respect to the reconstruction coefficients of the training data. In the annotation stage, with the discriminative dictionaries and exclusive label groups as well as a group sparsity constraint, the reconstruction coefficients of a test image can be easily obtained. Finally, we introduce a label propagation scheme to compute the score of each label for the test image based on its reconstruction coefficients. Experimental results on three challenging data sets demonstrate that our proposed method leads to significant performance gains over existing methods. PMID- 25935038 TI - Closed-Loop Asynchronous Neuromuscular Electrical Stimulation Prolongs Functional Movements in the Lower Body. AB - Neuromuscular electrical stimulation (NMES) is commonly used in rehabilitative settings and is also used for assistive purposes to create functional movements, where it is termed functional electrical stimulation (FES). One limitation of NMES/FES is early onset of muscle fatigue. NMES-induced fatigue can be reduced by switching between multiple stimulation channels that target different motor units or synergistic muscles (i.e., asynchronous stimulation). However, switching stimulation channels introduces additional complexity due to the need to consider the switching dynamics and differing muscle response to stimulation. The objective of this study was to develop and test a closed-loop controller for asynchronous stimulation. The developed closed-loop controller yields asymptotic tracking of a desired trajectory for a person's knee-shank complex despite switching between stimulation channels. The developed controller was implemented on four able-bodied individuals with four-channel asynchronous stimulation as well as single-channel conventional stimulation. The results indicate that asynchronous stimulation extends the duration that functional movements can be performed during feedback control. This result is promising for the implementation of asynchronous stimulation in closed-loop rehabilitative procedures and in assistive devices as a method to reduce muscle fatigue while maintaining a person's ability to track a desired limb trajectory. PMID- 25935039 TI - A Framework of De Novo Peptide Sequencing for Multiple Tandem Mass Spectra. AB - With tandem mass spectrometry (MS/MS), spectra can be generated by various fragmentation techniques including collision-induced dissociation (CID), higher energy collisional dissociation (HCD), electron capture dissociation (ECD), electron transfer dissociation (ETD) and so on. At the same time, de novo sequencing using multiple spectra from the same peptide generated by different fragmentation techniques is becoming popular in proteomics studies. The focus of this study is the use of paired spectra from CID (or HCD) and ECD (or ETD) fragmentation because of the complementarity between them. We present a de novo peptide sequencing framework for multiple tandem mass spectra, and apply it to paired spectra sequencing problem. The performance of the framework on paired spectra is compared to another successful method named pNovo+. The results show that our proposed method outperforms pNovo+ in terms of full length peptide sequencing accuracy on three pairs of experimental datasets, with the accuracy increasing up to 13.6% compared to pNovo+. PMID- 25935040 TI - Identification Exon Skipping Events From High-Throughput RNA Sequencing Data. AB - The emergence of next-generation high-throughput RNA sequencing (RNA-Seq) provides tremendous opportunities for researchers to analyze alternative splicing on a genome-wide scale. However, accurate identification of alternative splicing events from RNA-Seq data has remained an unresolved challenge in next-generation sequencing (NGS) studies. Identifying exon skipping (ES) events is an essential part in genome-wide alternative splicing event identification. In this paper, we propose a novel method ESFinder, a random forest classifier to identify ES events from RNA-Seq data. ESFinder conducts thorough studies on predicting features and figures out proper features according to their relevance for ES event identification. Experimental results on real human skeletal muscle and brain RNA Seq data show that ESFinder could effectively predict ES events with high predictive accuracy. The codes of ESFinder are available at http://mlg.hit.edu.cn/ybai/ES/ESFinder.html. PMID- 25935042 TI - Rough Based Symmetrical Clustering for Gene Expression Profile Analysis. AB - Identification of coexpressed genes is the central goal in microarray gene expression data analysis. Point symmetry-based clustering is an important unsupervised learning technique for recognizing symmetrical convex or non-convex shaped clusters. To enable fast automatic clustering of large microarray data, in this article, a distributed time-efficient scalable parallel rough set based hybrid approach for point symmetry-based clustering algorithm has been proposed. A natural basis for analyzing gene expression data using the symmetry-based algorithm, is to group together genes with similar symmetrical patterns of expression. Rough-set theory helps in faster convergence and initial automatic optimal classification, thereby solving the problem of unknown knowledge of number of clusters in microarray data. This new parallel implementation with K means algorithm also satisfies the linear speedup in timing on large microarray datasets. This proposed algorithm is compared with another parallel symmetry based K-means and parallel version of existing K-means over four artificial and benchmark microarray datasets. We also have experimented over three skewed cancer gene expression datasets. The statistical analysis are also performed to establish the significance of this new implementation. The biological relevance of the clustering solutions are also analyzed. PMID- 25935041 TI - Signal Quality Assessment Model for Wearable EEG Sensor on Prediction of Mental Stress. AB - Electroencephalogram (EEG) plays an important role in E-healthcare systems, especially in the mental healthcare area, where constant and unobtrusive monitoring is desirable. In the context of OPTIMI project, a novel, low cost, and light weight wearable EEG sensor has been designed and produced. In order to improve the performance and reliability of EEG sensors in real-life settings, we propose a method to evaluate the quality of EEG signals, based on which users can easily adjust the connection between electrodes and their skin. Our method helps to filter invalid EEG data from personal trials in both domestic and office settings. We then apply an algorithm based on Discrete Wavelet Transformation (DWT) and Adaptive Noise Cancellation (ANC) which has been designed to remove ocular artifacts (OA) from the EEG signal. DWT is applied to obtain a reconstructed OA signal as a reference while ANC, based on recursive least squares, is used to remove the OA from the original EEG data. The newly produced sensors were tested and deployed within the OPTIMI framework for chronic stress detection. EEG nonlinear dynamics features and frontal asymmetry of theta, alpha, and beta bands have been selected as biological indicators for chronic stress, showing relative greater right anterior EEG data activity in stressful individuals. Evaluation results demonstrate that our EEG sensor and data processing algorithms have successfully addressed the requirements and challenges of a portable system for patient monitoring, as envisioned by the EU OPTIMI project. PMID- 25935043 TI - Characterizing Energy Landscapes of Peptides Using a Combination of Stochastic Algorithms. AB - Obtaining accurate representations of energy landscapes of biomolecules such as proteins and peptides is central to the study of their physicochemical properties and biological functions. Peptides are particularly interesting, as they exploit structural flexibility to modulate their biological function. Despite their small size, peptide modeling remains challenging due to the complexity of the energy landscape of such highly-flexible dynamic systems. Currently, only stochastic sampling-based methods can efficiently explore the conformational space of a peptide. In this paper, we suggest to combine two such methods to obtain a full characterization of energy landscapes of small yet flexible peptides. First, we propose a simplified version of the classical Basin Hopping algorithm to reveal low-energy regions in the landscape, and thus to identify the corresponding meta stable structural states of a peptide. Then, we present several variants of a robotics-inspired algorithm, the Transition-based Rapidly-exploring Random Tree, to quickly determine transition path ensembles, as well as transition probabilities between meta-stable states. We demonstrate this combined approach on met-enkephalin. PMID- 25935044 TI - Nanoscale Surface Characterization of Human Erythrocytes by Atomic Force Microscopy: A Critical Review. AB - Erythrocytes (red blood cells, RBCs), the most common type of blood cells in humans are well known for their ability in transporting oxygen to the whole body through hemoglobin. Alterations in their membrane skeletal proteins modify shape and mechanical properties resulting in several diseases. Atomic force microscopy (AFM), a new emerging technique allows non-invasive imaging of cell, its membrane and characterization of surface roughness at micrometer/nanometer resolution with minimal sample preparation. AFM imaging provides direct measurement of single cell morphology, its alteration and quantitative data on surface properties. Hence, AFM studies of human RBCs have picked up pace in the last decade. The aim of this paper is to review the various applications of AFM for characterization of human RBCs topology. AFM has been used for studying surface characteristics like nanostructure of membranes, cytoskeleton, microstructure, fluidity, vascular endothelium, etc., of human RBCs. Various modes of AFM imaging has been used to measure surface properties like stiffness, roughness, and elasticity. Topological alterations of erythrocytes in response to different pathological conditions have also been investigated by AFM. Thus, AFM-based studies and application of image processing techniques can effectively provide detailed insights about the morphology and membrane properties of human erythrocytes at nanoscale. PMID- 25935045 TI - A PSO-Based Approach for Pathway Marker Identification From Gene Expression Data. AB - In this article, a new and robust pathway activity inference scheme is proposed from gene expression data using Particle Swarm Optimization (PSO). From microarray gene expression data, the corresponding pathway information of the genes are collected from a public database. For identifying the pathway markers, the expression values of each pathway consisting of genes, termed as pathway activity, are summarized. To measure the goodness of a pathway activity vector, t score is widely used in the existing literature. The weakness of existing techniques for inferring pathway activity is that they intend to consider all the member genes of a pathway. But in reality, all the member genes may not be significant to the corresponding pathway. Therefore, those genes, which are responsible in the corresponding pathway, should be included only. Motivated by this, in the proposed method, using PSO, important genes with respect to each pathway are identified. The objective is to maximize the average t-score. For the pathway activities inferred from different percentage of significant pathways, the average absolute t -scores are plotted. In addition, the top 50% pathway markers are evaluated using 10-fold cross validation and its performance is compared with that of other existing techniques. Biological relevance of the results is also studied. PMID- 25935046 TI - Body Sensor Networks: In the Era of Big Data and Beyond. AB - Body sensor networks (BSN) have emerged as an active field of research to connect and operate sensors within, on or at close proximity to the human body. BSN have unique roles in health applications, particularly to support real-time decision making and therapeutic treatments. Nevertheless, challenges remain in designing BSN nodes with antennas that operate efficiently around, ingested or implanted inside the human body, as well as new methods to process the heterogeneous and growing amount of data on-node and in a distributed system for optimized performance and power consumption. As the battery operating time and sensor size are two important factors in determining the usability of BSN nodes, ultralow power transceivers, energy-aware network protocol, data compression, on-node processing, and energy-harvesting techniques are highly demanded to ultimately achieve a self-powered BSN. PMID- 25935047 TI - The Importance of Visual Experience, Gender, and Emotion in the Assessment of an Assistive Tactile Mouse. AB - Tactile maps are efficient tools to improve spatial understanding and mobility skills of visually impaired people. Their limited adaptability can be compensated with haptic devices which display graphical information, but their assessment is frequently limited to performance-based metrics only which can hide potential spatial abilities in O&M protocols. We assess a low-tech tactile mouse able to deliver three-dimensional content considering how performance, mental workload, behavior, and anxiety status vary with task difficulty and gender in congenitally blind, late blind, and sighted subjects. Results show that task difficulty coherently modulates the efficiency and difficulty to build mental maps, regardless of visual experience. Although exhibiting attitudes that were similar and gender-independent, the females had lower performance and higher cognitive load, especially when congenitally blind. All groups showed a significant decrease in anxiety after using the device. Tactile graphics with our device seems therefore to be applicable with different visual experiences, with no negative emotional consequences of mentally demanding spatial tasks. Going beyond performance-based assessment, our methodology can help with better targeting technological solutions in orientation and mobility protocols. PMID- 25935048 TI - Perception Evolution Network Based on Cognition Deepening Model--Adapting to the Emergence of New Sensory Receptor. AB - The proposed perception evolution network (PEN) is a biologically inspired neural network model for unsupervised learning and online incremental learning. It is able to automatically learn suitable prototypes from learning data in an incremental way, and it does not require the predefined prototype number or the predefined similarity threshold. Meanwhile, being more advanced than the existing unsupervised neural network model, PEN permits the emergence of a new dimension of perception in the perception field of the network. When a new dimension of perception is introduced, PEN is able to integrate the new dimensional sensory inputs with the learned prototypes, i.e., the prototypes are mapped to a high dimensional space, which consists of both the original dimension and the new dimension of the sensory inputs. In the experiment, artificial data and real world data are used to test the proposed PEN, and the results show that PEN can work effectively. PMID- 25935049 TI - The Kernel Adaptive Autoregressive-Moving-Average Algorithm. AB - In this paper, we present a novel kernel adaptive recurrent filtering algorithm based on the autoregressive-moving-average (ARMA) model, which is trained with recurrent stochastic gradient descent in the reproducing kernel Hilbert spaces. This kernelized recurrent system, the kernel adaptive ARMA (KAARMA) algorithm, brings together the theories of adaptive signal processing and recurrent neural networks (RNNs), extending the current theory of kernel adaptive filtering (KAF) using the representer theorem to include feedback. Compared with classical feedforward KAF methods, the KAARMA algorithm provides general nonlinear solutions for complex dynamical systems in a state-space representation, with a deferred teacher signal, by propagating forward the hidden states. We demonstrate its capabilities to provide exact solutions with compact structures by solving a set of benchmark nondeterministic polynomial-complete problems involving grammatical inference. Simulation results show that the KAARMA algorithm outperforms equivalent input-space recurrent architectures using first- and second-order RNNs, demonstrating its potential as an effective learning solution for the identification and synthesis of deterministic finite automata. PMID- 25935050 TI - Smart-Grid Backbone Network Real-Time Delay Reduction via Integer Programming. AB - This research investigates an optimal delay-based virtual topology design using integer linear programming (ILP), which is applied to the current backbone networks such as smart-grid real-time communication systems. A network traffic matrix is applied and the corresponding virtual topology problem is solved using the ILP formulations that include a network delay-dependent objective function and lightpath routing, wavelength assignment, wavelength continuity, flow routing, and traffic loss constraints. The proposed optimization approach provides an efficient deterministic integration of intelligent sensing and decision making, and network learning features for superior smart grid operations by adaptively responding the time-varying network traffic data as well as operational constraints to maintain optimal virtual topologies. A representative optical backbone network has been utilized to demonstrate the proposed optimization framework whose simulation results indicate that superior smart-grid network performance can be achieved using commercial networks and integer programming. PMID- 25935051 TI - Imitation of Dynamic Walking With BSN for Humanoid Robot. AB - Humanoid robots have been used in a wide range of applications including entertainment, healthcare, and assistive living. In these applications, the robots are expected to perform a range of natural body motions, which can be either preprogrammed or learnt from human demonstration. This paper proposes a strategy for imitating dynamic walking gait for a humanoid robot by formulating the problem as an optimization process. The human motion data are recorded with an inertial sensor-based motion tracking system (Biomotion+). Joint angle trajectories are obtained from the transformation of the estimated posture. Key locomotion frames corresponding to gait events are chosen from the trajectories. Due to differences in joint structures of the human and robot, the joint angles at these frames need to be optimized to satisfy the physical constraints of the robot while preserving robot stability. Interpolation among the optimized angles is needed to generate continuous angle trajectories. The method is validated using a NAO humanoid robot, with results demonstrating the effectiveness of the proposed strategy for dynamic walking. PMID- 25935052 TI - A natural walking monitor for pulmonary patients using mobile phones. AB - Mobile devices have the potential to continuously monitor health by collecting movement data including walking speed during natural walking. Natural walking is walking without artificial speed constraints present in both treadmill and nurse assisted walking. Fitness trackers have become popular which record steps taken and distance, typically using a fixed stride length. While useful for everyday purposes, medical monitoring requires precise accuracy and testing on real patients with a scientifically valid measure. Walking speed is closely linked to morbidity in patients and widely used for medical assessment via measured walking. The 6-min walk test (6MWT) is a standard assessment for chronic obstructive pulmonary disease and congestive heart failure. Current generation smartphone hardware contains similar sensor chips as in medical devices and popular fitness devices. We developed a middleware software, MoveSense, which runs on standalone smartphones while providing comparable readings to medical accelerometers. We evaluate six machine learning methods to obtain gait speed during natural walking training models to predict natural walking speed and distance during a 6MWT with 28 pulmonary patients and ten subjects without pulmonary condition. We also compare our model's accuracy to popular fitness devices. Our universally trained support vector machine models produce 6MWT distance with 3.23% error during a controlled 6MWT and 11.2% during natural free walking. Furthermore, our model attains 7.9% error when tested on five subjects for distance estimation compared to the 50-400% error seen in fitness devices during natural walking. PMID- 25935053 TI - Intent Inference for Hand Pointing Gesture-Based Interactions in Vehicles. AB - Using interactive displays, such as a touchscreen, in vehicles typically requires dedicating a considerable amount of visual as well as cognitive capacity and undertaking a hand pointing gesture to select the intended item on the interface. This can act as a distractor from the primary task of driving and consequently can have serious safety implications. Due to road and driving conditions, the user input can also be highly perturbed resulting in erroneous selections compromising the system usability. In this paper, we propose intent-aware displays that utilize a pointing gesture tracker in conjunction with suitable Bayesian destination inference algorithms to determine the item the user intends to select, which can be achieved with high confidence remarkably early in the pointing gesture. This can drastically reduce the time and effort required to successfully complete an in-vehicle selection task. In the proposed probabilistic inference framework, the likelihood of all the nominal destinations is sequentially calculated by modeling the hand pointing gesture movements as a destination-reverting process. This leads to a Kalman filter-type implementation of the prediction routine that requires minimal parameter training and has low computational burden; it is also amenable to parallelization. The substantial gains obtained using an intent-aware display are demonstrated using data collected in an instrumented vehicle driven under various road conditions. PMID- 25935054 TI - Off-Policy Actor-Critic Structure for Optimal Control of Unknown Systems With Disturbances. AB - An optimal control method is developed for unknown continuous-time systems with unknown disturbances in this paper. The integral reinforcement learning (IRL) algorithm is presented to obtain the iterative control. Off-policy learning is used to allow the dynamics to be completely unknown. Neural networks are used to construct critic and action networks. It is shown that if there are unknown disturbances, off-policy IRL may not converge or may be biased. For reducing the influence of unknown disturbances, a disturbances compensation controller is added. It is proven that the weight errors are uniformly ultimately bounded based on Lyapunov techniques. Convergence of the Hamiltonian function is also proven. The simulation study demonstrates the effectiveness of the proposed optimal control method for unknown systems with disturbances. PMID- 25935055 TI - Investigation of myringosclerosis development in different grafting materials after myringo-/tympanoplasty. AB - OBJECTIVES: This study aims to investigate the prevalence of myringosclerosis in tragal perichondrium (TP) and temporalis fascia (TF) grafts after myringo /tympanoplasty. PATIENTS AND METHODS: Thirty patients, who were diagnosed with non-suppurative chronic otitis media and administered myringo-/tympanoplasty under general anesthesia using TP or TF as grafting material in our clinic between January 2012 and May 2013, were recruited in this retrospective case control study. Patients were divided into two groups according to used graft material as group 1 (TP) (9 males, 6 females; median age 35.4 years; range 20 to 62 years) and group 2 (TF) (7 males, 8 females; median age 39.8 years; range 19 to 63 years). Occurrence of myringosclerosis on the intact tympanic membrane grafts was evaluated postoperatively by the same surgeon under surgical microscope. RESULTS: Postoperative myringosclerosis was detected in six patients (40%) in TP group and 13 patients (86.7%) in TF group. CONCLUSION: Prevalence of myringosclerosis on graft materials used in myringo-/tympanoplasty was lower in TP group compared to TF group. We believe that this may be due to different vascular structures of different graft tissues and that the low predisposition of perichondrium towards development of myringosclerosis can be considered as an advantage for this graft. We hope that this study adds a new dimension to etiopathogenesis of myringosclerosis and assists otologists in the prevention and treatment of this lesion. PMID- 25935056 TI - Is the time from the onset to the treatment a prognostic indicator for hearing recovery in idiopathic sudden sensorineural hearing loss? AB - OBJECTIVES: This study aims to investigate whether the time from the onset of symptoms to the start of treatment is a prognostic indicator in patients with idiopathic sudden sensorineural hearing loss (ISSNHL). PATIENTS AND METHODS: In this study, 96 patients (58 males, 38 females; mean age 37.8+/-2.5 years; range 16 to 67 years) who were diagnosed with ISSNHL in our clinic between January 1992 and April 2010 were retrospectively analyzed. All patients were treated with dextran 40 (rheomacrodex), pentoxifyllin, vitamin B complex and vitamin C regimen over 10 days with hospitalization and bed rest. The patients were tested by pure tone audiometry. Audiograms were obtained on alternate days and at the end of the treatment. RESULTS: There was a complete recovery in 45 (60%) of 75 patients whose treatment was started in the first seven days, while a partial recovery was observed in 17 (22.66%) and no recovery was observed in 13 (17.33%). There was a complete recovery in two (9.52%) of 21 patients whose treatment was started after the eighth day, while a partial recovery was observed in seven (33.33%) and no recovery was observed in 12 (57.14%). CONCLUSION: Our study results suggest that treatment outcomes are better in the patients presenting to hospital at an early stage of loss of hearing. PMID- 25935057 TI - Efficacy of multimodality approach to sudden hearing loss. AB - OBJECTIVES: This study aims to investigate whether addition of intratympanic steroid (ITS) to systemic steroid and hyperbaric oxygen (HBO) is effective in the treatment of sudden hearing loss (SHL). PATIENTS AND METHODS: Between January 2008 and October 2011, 58 patients diagnosed with SHL were enrolled in the study. Twenty patients (11 males, 9 females; mean age 45.3+/-21 years; range 24 to 66 years) who received systemic steroid and HBO composed group 1, while 38 patients (19 males, 19 females; mean age 41.6+/-16 years; range 25 to 61 years) who received ITS in addition to systemic steroid and HBO composed group 2. RESULTS: Post-treatment hearing improvement was statistically significant in both groups in terms of the mean pure tone according to the Siegel's criteria (p<0.05). Treatment was successful at 55% of patients in group 1 and 63% in group 2. Despite increased success rate with the addition of ITS, it did not indicate statistical significance (p>0.05). However, there was a strong statistically significant difference in terms of profound hearing loss over 90 dB (p<0.05). None of six patients (0%) with profound hearing loss in group 1 benefited treatment, while addition of ITS to the treatment yielded success in six of 12 patients with profound hearing loss (50%) in group 2 (p<0.05). CONCLUSION: Addition of ITS to systemic steroid and HBO treatment may yield better results in patients with SHL. However, ITS injection seems beneficial for patients with profound SHL. PMID- 25935058 TI - [Does Onodi cell limit the exposure of sella during transsphenoidal pituitary surgery?]. AB - OBJECTIVES: This study aims to evaluate the association between the presence of Onodi cell and sella exposure during endonasal endoscopic transsphenoidal pituitary surgery (EETPS). PATIENTS AND METHODS: Forty-two patients who underwent EETPS for a pituitary adenoma with the collaboration of Neurosurgery and Otorhinolaryngology Departments at Katip Celebi University Ataturk Training and Research Hospital between February 2011 and March 2014 were retrospectively analyzed. Preoperative paranasal sinus tomography and intraoperative findings were evaluated for the presence of Onodi cells. The location of the Onodi cell and its relation with sella exposure during surgery were also assessed. RESULTS: The incidence of Onodi cell was 19%. The Onodi cells were observed in eight of 42 patients on preoperative paranasal sinus computed tomography. The Onodi cells were unilateral in five patients and bilateral in three. Intraoperative findings were correlated with tomographic findings. In seven patients, Onodi cells limited the exposure of sellar floor and the inferior-medial wall of these cells were removed and connected with the sphenoid sinus and the entire sellar floor was exposed. In the remaining one patient, the Onodi cell was smaller and located superolaterally. This cell was not removed, as it did not limited the sellar exposure. CONCLUSION: The Onodi cell may limit the sella exposure during transsphenoidal surgery. Onodi cell should be removed and connected with the sphenoid sinus cavity for the entire sellar floor exposure. PMID- 25935059 TI - [The incidence of facial canal dehiscence in Bell's palsy patients]. AB - OBJECTIVES: In this study, we compared the incidence of facial canal dehiscence in patients with idiopathic peripheral facial paralysis (Bell's palsy) with a healthy population. PATIENTS AND METHODS: Forty-five patients who were defined as idiopathic peripheral facial paralysis between May 2011 and June 2012 were enrolled the study. The clinical and demographic characteristics of the patients were noted. Spiral computed tomography (CT) was used for the study with a slice thickness of 1 mm and slice gap of 0.5 mm. Fifty patients having no middle ear pathology who underwent temporal CT due to other reasons were enrolled in the study as control group. The both groups were compared by means of demographic characteristics and the presence of the facial canal dehiscence. RESULTS: The incidence of facial canal dehiscence was 42% in the control group, while the incidence of the facial canal dehiscence in the study group at the paralyzed side was 46.7%. Although the incidence of the facial canal dehiscence in the study group was higher than the control group, the difference between the groups was not statistically significant (p=0.802). When the incidence of bilateral facial canal dehiscence in the study group (22.2%) and the control group (0%) was compared, the difference between the groups was statistically significant (p<0.001). CONCLUSION: Although the incidence of the facial canal dehiscence in the patients with Bell's palsy was higher than the control group, the difference between the groups was not statistically significant. The incidence of the bilateral facial canal dehiscence of the study group was significantly higher than the healthy population. PMID- 25935060 TI - [Evaluation of smell function changes in pregnancy]. AB - OBJECTIVES: This study aims to compare the olfactory function changes among pregnant women in varying trimesters and non-pregnant women. PATIENTS AND METHODS: Thirty-five healthy pregnant women and 14 non-pregnant women were included in the study. Volunteer pregnant women were divided into three subgroups including the first trimester, second trimester, and third trimester. All volunteers were tested with the smell bottle test battery. The content of the test was consistent with the Sniffin' sticks including three detailed olfactory function tests, namely olfactory threshold (OT), olfactory discrimination (OD), and olfactory identification (OI). Total results of these three tests were defined as TDI scores. RESULTS: TDI score and test scores of the pregnant women in the first trimester statistically significantly decreased compared to pregnant women in other trimesters and non-pregnant women (p<0.05). Pregnant women in the second and third trimesters had similar olfactory function scores to the non pregnant women (p>0.05). CONCLUSION: The olfactory function changes are observed in women during pregnancy. In particular, decreased smell sensitivity in the first trimester returns to normal scores towards the end of pregnancy. PMID- 25935061 TI - [New predictive parameters of nasal polyposis: neutrophil to lymphocyte ratio and platelet to lymphocyte ratio]. AB - OBJECTIVES: This study aims to investigate the correlations between nasal polyposis (NP) and NP density with neutrophil to lymphocyte ratio (NLR) and platelet to lymphocyte ratio (PLR). PATIENTS AND METHODS: The study included 105 patients (72 males, 33 females; mean age 41.33+/-12.85 years; range 16 to 63 years) diagnosed as NP (NP group) and 83 healthy individuals (54 males, 29 females; mean age 44.01+/-8.50 years; range 18 to 62 years) (control group). Nasal polyposis density score was calculated with preoperative Lund-Mackay computed tomography grading system. Neutrophil to lymphocyte and PLR ratio values of NP and control groups were calculated and statistically compared. Neutrophil to lymphocyte and PLR values were statistically compared in terms of NP density in the NP group. RESULTS: Mean NLR value was 2.26 in the NP group and 1.75 in the control group with a statistically significant difference (p=0.001). Mean PLR value was 120.79 in the NP group and 109.84 in the control group with a statistically insignificant difference (p=0.073). CONCLUSION: Neutrophil to lymphocyte ratio value may be used as a novel marker that is easily administered in patients with nasal polyps and obtained with low-cost tests. New studies with larger patient series are needed for the value of PLR. PMID- 25935062 TI - Clinical features of deep neck infection: analysis of 77 patients. AB - OBJECTIVES: This retrospective study aims to detect the prognostic factors which affect the duration of hospital stay and evaluate the complications which develop in patients with deep neck infection. PATIENTS AND METHODS: The study included 77 patients (40 males, 37 females; mean age 42.4+/-20.1 years; range 11 to 88 years) treated with a diagnosis of deep neck infection in our clinic between November 2006 and November 2012. Patients' demographic and clinical features were analyzed to detect their associations with development of complications and hospitalization time. RESULTS: Odontogenic origin and submandibular localization were the most frequently observed clinical appearance. Of eight patients (10.4%) who developed serious complications, two (2.6%) died. Age, comorbidity, presence of anemia alone, Ludwig's angina and retropharyngeal involvement were associated with increased rate of complications (p<0.05); while sex, antibiotic usage prior to admittance and primary location of infection were not related (p>0.05). Submandibular localization and absence of leucopenia reduced the risk of complications (p<0.05). The mean duration of hospital stay was 12.9+/-8.7 days (range 2-59 days). Age, presence of comorbidity and development of complications extended the hospitalization period (p<0.05). CONCLUSION: In spite of the improvements in diagnosis and treatment, deep neck infection may be an important cause of mortality if complications develop. Comorbid anemia, Ludwig's angina and retropharyngeal involvement were identified as the strongest predictors in terms of development of complications. Duration of hospital stay extended in patients who developed complications. PMID- 25935063 TI - [Nasal foreign bodies: an analysis of 130 patients]. AB - OBJECTIVES: This study aims to investigate clinical manifestations and treatment protocols in patients with a diagnosis of nasal foreign bodies. PATIENTS AND METHODS: We retrospectively evaluated 130 patients (72 males, 58 females; mean age 3.65+/-2.31 years; range 15 month to 72 years) who were diagnosed with nasal foreign bodies and received treatment between November 2008 and July 2013. Age and sex of the patients, type of foreign body, side of presentation, signs and symptoms, management practices, and outcomes were recorded. RESULTS: Most of the patients were children between the ages of 2 and 5 (n=113, 86.9%). The most common foreign bodies were small plastic toys (43.8%), nut, walnut, corn, bean and the other seed grains (29.2%). Foreign bodies were detected in the right nasal passage in 74 patients (56.9%), left nasal passage in 54 patients (41.6%) and both nostrils in two patients (1.5%). Of the patients, 92.3% were admitted to our clinic within 24 hours. CONCLUSION: Nasal foreign bodies are frequent encountered in the emergency setting of ear, nose, and throat diseases. Although they are not life-threatening conditions, they require urgent intervention, as they may lead to several complications in the long-term. Parents and caregivers of children should keep objects which can be put into the nose away and be instructed that they should consult a physician in case of nasal foreign bodies. PMID- 25935064 TI - Laryngeal leiomyosarcoma with coexistent tuberculous mediastinal lymphadenopathy. AB - Laryngeal leiomyosarcoma is an extremely rare malignancy originating from the smooth muscles of blood vessels. Herein, we present the first case of leiomyosarcoma arising from the glottic area of the larynx with coexistent tuberculous mediastinal lymphadenopathy. The patient was treated with vertical laryngectomy and anti-tuberculous medication. He has been disease-free for 24 months since initial treatment. PMID- 25935065 TI - Bilateral hypopharyngeal perforations caused by penetrating trauma to the neck. AB - External laryngeal trauma is a relatively rare-encountered and sometimes life threatening emergency condition. Recognition of laryngeal injury related to either blunt or penetrating trauma is important for both initial preservation of life as well as long-term airway and vocal function. Treatment options include medical management with observation and open surgical treatment with or without tracheotomy. We, herein, describe a 23-year-old male case who sustained external penetrating trauma to lateral aspect of neck. The etiology, clinical manifestations, investigation modalities and management of penetrating neck trauma were discussed in the light of the literature data. PMID- 25935066 TI - [Idiopathic spontaneous tonsillar hemorrhage]. AB - Since the advent of antibiotics, major spontaneous tonsillar hemorrhage is extremely rare. The majority of the spontaneous tonsillar hemorrhage events is associated with acute or chronic tonsillitis, coagulopathies, or tonsillar cancer. A 36-year-old female patient was admitted to the otolaryngology department with the complaint of tonsillar hemorrhage. The patient had no history of prior trauma, coagulopathy, malignancy and infection sign. Preoperatively, carotid angiography was performed to detect any arteriovenous malformation of tonsillar vessels. The carotid angiography results were within normal ranges. The patient underwent tonsillectomy and no perioperative complication was occurred. Management of idiopathic spontaneous tonsillar hemorrhage may be challenging for the clinician and may require tonsillectomy. PMID- 25935067 TI - A rare cause of odynophagia: infected tracheal diverticulum. AB - Tracheal diverticulum is a relatively rare lesion. Tracheal diverticula are divided into two subgroups as congenital and acquired with different characteristics and etiologies. The majority of these anomalies is asymptomatic and found as incidental findings on radiological imaging. This article presents a case of an infected tracheal diverticulum presenting with odynophagia. It should be noted that infection may obstruct the air-filled lumen of the diverticulum, causing a diagnostic challenge. Multislice computed tomography with coronal reconstructed images is the modality of choice for diagnosing diverticulum and assessing therapeutic response in associated complications. PMID- 25935069 TI - Mapping allied health evidence-based practice: providing a basis for organisational realignment. AB - OBJECTIVE: Ahead of the convergence of two major paediatric services, we examined evidence-based practice (EBP) self-efficacy, outcome expectance, knowledge and use among allied health (AH) staff in two major Queensland (Qld) paediatric services. This was to determine whether any differences existed based on organisational affiliation, profession and any previous training to inform a strategy to enhance AH EBP within the new organisational setting. METHODS: All AH staff from the two Brisbane (Qld) tertiary paedritic hospitals were invited to participate in the survey. Using a cross-sectional design EBP self-efficacy, outcome expectancy, knowledge and use, as well as previous EBP training, were assessed with an online survey. Background demographic information obtained included professional discipline and hospital. RESULTS: One hundreD and thirty eight health practitioners completed the survey (37% respone rate). Most practioners had accessed EBP training. Mean scores for EBP attitudes (self efficacy and outcome expectancy) and knowledge were higher than for EBP use scores. Greater variation was observed across professional disciplines than organisations. Training impacted positively on EBP measures but explained a small proportion of total variance in regression models. CONCLUSIONS: The results underscore the need to provide organisational supports to AH staff ro EBP implementation. Strategies other than training are requred to maximally enhance EBP attitudes. The new organisational structure provides an oppotunity for this cultural shift to occur. PMID- 25935068 TI - Neural Correlates of Disturbed Emotion Processing in Borderline Personality Disorder: A Multimodal Meta-Analysis. AB - BACKGROUND: Disturbances in the processing and regulation of emotions are core symptoms of borderline personality disorder (BPD). To further elucidate neural underpinnings of BPD, the present meta-analysis summarizes functional neuroimaging findings of emotion processing tasks, as well as structural neuroimaging findings, and investigates multimodally affected brain regions. METHODS: Combined coordinate- and image-based meta-analyses were calculated using anisotropic effect size signed differential mapping. Nineteen functional neuroimaging studies investigating the processing of negative compared with neutral stimuli in a total of 281 patients with BPD and 293 healthy control subjects (HC) were included. In addition, 10 studies investigating gray matter abnormalities in 263 patients with BPD and 278 HC were analyzed. RESULTS: Compared with HC, BPD patients showed relatively increased activation of the left amygdala and posterior cingulate cortex, along with blunted responses of the bilateral dorsolateral prefrontal cortex, during the processing of negative emotional stimuli. The multimodal analysis identified the left amygdala to be characterized by a combination of functional hyperactivity and smaller gray matter volume compared with HC. Hyperresponsivity of the amygdala was moderated by medication status of the patient samples. Medication-free samples were characterized by limbic hyperactivity, whereas no such group differences were found in patients currently taking psychotropic medication. CONCLUSIONS: Results strengthen the assumption that dysfunctional dorsolateral prefrontal and limbic brain regions are a hallmark feature of BPD and therefore are consistent with the conceptualization of BPD as an emotion dysregulation disorder. PMID- 25935070 TI - Severe reversible left ventricular dysfunction in an infant. PMID- 25935071 TI - High left ventricular outflow tract gradient: Aortic stenosis, obstructive hypertrophic cardiomyopathy or both? AB - The authors report the case of a patient diagnosed with both hypertrophic cardiomyopathy and aortic stenosis. Due to clinical deterioration, additional investigation was performed, and a high left ventricular outflow tract gradient was identified. Correct identification of the condition causing the symptoms was challenging, and involved several imaging techniques, the contribution of transesophageal echocardiography being crucial. The final diagnosis of severe aortic stenosis led to successful valve replacement surgery. The presence of these two conditions in the same patient has been documented, although it is uncommon. This association poses particular diagnostic and therapeutic challenges, which are discussed in this paper. PMID- 25935072 TI - Inflammation, systemic lupus erythematosus and the Kounis mast cell activation associated syndrome. PMID- 25935073 TI - APOLLO I: Anticoagulation control in atrial fibrillation. AB - INTRODUCTION AND AIMS: Anticoagulation control as assessed by time in therapeutic range (TTR) correlates positively with the safety and efficacy of thromboprophylaxis in atrial fibrillation. We set out to assess TTR in our unit and to investigate determinants of better control. METHODS: This was a case series study of atrial fibrillation patients anticoagulated with warfarin or acenocoumarol at the Family Health Unit of Fanzeres. Sociodemographic and clinical data were collected and TTR was calculated by the Rosendaal method, based on international normalized ratio tests performed in external laboratories in the preceding six months. SPSS 21.0 was used for the statistical analysis, with descriptive statistics, Spearman's correlation, and the Mann-Whitney U and Kruskal-Wallis tests. RESULTS: Of the 106 eligible patients, 70% participated in the study. Median TTR was 65.3% (P25=48.3%, P75=86.8%). We found a positive association between this variable and duration of atrial fibrillation (rho=0.477, p<0.001, r(2)=0.116) and with duration of anticoagulation (rho=0.5, p<0.001, r(2)=0.087). No association was found with age, gender, educational level or existence of a caregiver (p>0.05). CONCLUSIONS: Median TTR in our unit is similar to that in southern European countries and close to the good control threshold (70%) proposed by the European Society of Cardiology. The duration of atrial fibrillation and of anticoagulation explains only a small part of the measure's variability. Other determinants of anticoagulation control must be investigated in future studies and comparative studies should be carried out in family health units monitoring anticoagulation on the premises. PMID- 25935074 TI - Long QT syndrome with mutations in three genes: A rare case. AB - Congenital long QT syndrome (LQTS) is a rare hereditary disease, with an incidence of 1 in 2000, characterized by prolonged ventricular repolarization and malignant ventricular tachyarrhythmias. We report the case of a 30-year-old woman, previously diagnosed with neurocardiogenic syncope, in whom LQTS was identified. The patient received an implantable cardioverter-defibrillator due to polymorphic ventricular tachycardia under beta-blocker therapy. Molecular genetic testing identified three mutations in heterozygosity in the KCNH2, KCNQ1 and SCN5A genes, which is a rare finding and is associated with worse prognosis. PMID- 25935075 TI - A conservative strategy in non-ST-segment elevation myocardial infarction - constraints and prognosis: The situation in Portugal. AB - INTRODUCTION AND OBJECTIVES: The aim of this study was to assess the impact of a conservative strategy in non-ST-segment elevation myocardial infarction in patients in the Portuguese Registry of Acute Coronary Syndromes. METHODS: The 3780 patients included in the study over a three-year period were divided into three groups: group 1, patients treated by a conservative strategy during hospitalization; group 2, patients who underwent coronary angiography without percutaneous coronary intervention (PCI); and group 3, patients who underwent PCI. Clinical and procedural data and in-hospital complications were compared. The primary endpoint was defined as in-hospital or one-year mortality and the secondary endpoint as the presence of at least one of the following in-hospital complications: major bleeding according to the GUSTO criteria, need for blood transfusion, invasive ventilation, heart failure or reinfarction. RESULTS: Of the patients analyzed, 16.5% were treated by a conservative strategy. Patients in this group were older, more often women, and had more high-risk factors. A conservative strategy was associated with a higher rate of the primary endpoint - in-hospital mortality (10.6% vs. 1.1% vs. 0.6% in groups 1, 2 and 3, respectively, p<0.001, odds ratio (OR) 6.974, 95% confidence interval [CI]: 2.775 17.527) and one-year mortality (26.1% vs. 6.8% vs. 4.1%, p<0.001, hazard ratio (HR) 2.925, 95% CI: 1.433 -5.974) - and of the secondary endpoint - 37.2% vs. 18.9% vs. 14.6%, p<0.001; OR 1.471 95% CI: 1.043 -2.076. CONCLUSIONS: In this patient population, a conservative strategy is an independent predictor of in hospital mortality, in-hospital complications and one-year mortality. PMID- 25935076 TI - Performance of children with social communication disorder on the Happe Strange Stories: Physical and mental state responses and relationship to language ability. AB - This study investigated whether a modified scoring method was useful for examining the ability of children with social communication disorder (CwSCD) to understand non-literal language and use mental state responses on the Happe Strange Stories (HSS) task. CwSCD and a control group of children with typical language development (CwTLD) completed 10 of the original HSS. CwSCD scored significantly lower on the HSS task than did CwTLD and were much less likely to produce mental state responses. There was a high level of inter-rater reliability (Weighted Kappa=0.907) across data from both groups. HSS performance and language ability correlated significantly for CwSCD. A regression model with age, nonverbal intelligence, receptive and expressive language as predictors explained 55.2% of the variance in HSS ability for CwSCD. The results suggest that the HSS have potential to be used as a clinical assessment to investigate high-level language and ability to infer intent in CwSCD. LEARNING OUTCOMES: Readers will be able to describe a modified scoring method for the Happe Strange Stories task. Readers will be able to identify areas of impairment for children with social communication disorder. Readers will identify how these areas of impairment have an effect on ability to understand non-literal language and produce mental state responses on the Happe Strange Stories task. PMID- 25935077 TI - Primary tuberculosis of the eustachian tube causing otitis media with effusion. AB - Eustachian tube (ET) dysfunction may cause pathological changes in the middle ear, including recurrent acute otitis media and otitis media with effusion (OME). Mechanical obstruction of the ET may be caused by primary tumor-like lesions arising from ET or secondary ET infiltration due to nasopharyngeal and parapharyngeal space tumor. Tuberculosis is known to affect almost every organ in the body, and it should be a concern of each and every medical practitioner. However, tuberculosis of the ET has not been reported in the literature previously. This article reports primary tuberculosis arising in the ET that presented as aural fullness and hearing disturbance in a patient with OME. PMID- 25935078 TI - Incorporating digital scans of diagnostic casts into computed tomography for virtual implant treatment planning. AB - The success of implant treatment depends on the accuracy of the diagnosis and planning. Accurate diagnosis can be achieved with clinician experience and proper diagnostic methods. Cone beam computerized tomography (CBCT) helps to develop and implement a comprehensive treatment plan for the surgeon, restorative team, and patient in order to minimize complications. Radiographic stents are used during CBCT scans; however, they are not problem-free. This article describes a technique for incorporating digital scans of diagnostic casts into CBCT scans for virtual treatment planning. PMID- 25935079 TI - Case for implant platform unswitching. AB - Platform switching was introduced to reduce marginal bone loss and therefore maintain the gingival architecture, leading to a more favorable esthetic result. In the patient presented, recession had resulted in the exposure of the implant neck and threads; this was managed with a custom-made additional prosthetic component. The result, although not ideal esthetically, provided an implant abutment interface that was easier for the patient to clean. PMID- 25935080 TI - Morphologic custom shade guide fabricated with feldspathic ceramic. PMID- 25935081 TI - Digital design of a surgical guide for placement of definitive implants before orthodontic treatment. AB - Interdisciplinary treatment planning is an essential part of orthodontic therapy for patients with partial edentulism, especially when dental implants are to serve initially as anchorage and ultimately as prosthetic abutments for the definitive fixed restoration. A technique is presented for designing and fabricating a computed tomography-based surgical guide to place definitive implants before orthodontic therapy. First, the diagnostic cast and the orthodontic tooth arrangement and diagnostic waxing cast are scanned with a 3 dimensional optical scanner. Three-dimensional renderings of these scans are then merged and superimposed onto the cone beam computed tomography (CBCT) image with implant planning software to develop definitive implant positions. A custom surgical guide is fabricated from these data. PMID- 25935082 TI - Influence of recasting on the quality of dental alloys: A systematic review. AB - STATEMENT OF PROBLEM: Dental alloy manufacturers advise against the reuse of previously melted alloy. However, for economic reasons, dental laboratories often reuse the casting surplus (sprue and metal remaining in the crucible former). Such reuse remains a controversial topic in dental practice. PURPOSE: The purpose of this systematic review was to assess the effects of remelting dental alloys by evaluating the following parameters: reasons for recasting and associated processes, feasible number of recastings, treatment of alloys before recasting and its effects on cytotoxicity, color of opaque porcelain, castability of alloys, marginal accuracy, mechanical properties, porcelain-metal interfaces, and corrosion. MATERIAL AND METHODS: The systematic review included all studies on dental alloy recasting. MEDLINE, Dentistry and Oral Science Source, Science Direct, and ISI Web of Science were searched (up to July 2014). Data were extracted and the quality of studies was assessed. RESULTS: Thirty-four studies published between 1983 and 2014 were included. The number of recastings ranged from 1 to 10. The percentage of new alloy ranged from 0 to 100 wt%, although the mean value was 50 wt%. CONCLUSIONS: Evidence for the feasibility of adding 50% new metal at each recasting is limited. The number of recastings should be limited to a maximum of 4. No general test protocol can be deduced from these studies, which limits the comparison and exploitation of data. Furthermore, no consensus protocol exists for the evaluation of recasting. Future studies should work toward establishing a standard protocol. PMID- 25935083 TI - Altered polyurethane cast for a partial removable dental prosthesis. PMID- 25935084 TI - Comparative study of interim materials for direct fixed dental prostheses and their fabrication with CAD/CAM technique. AB - STATEMENT OF PROBLEM: Prosthodontic treatment sometimes requires a long-term interim fixed dental prosthesis (FDP) until the definitive restoration can be cemented. However, some interim materials are weak and do not have an adequate marginal seal. PURPOSE: The purpose of this study was to compare the marginal fit and fracture strengths of interim FDPs fabricated by using a direct technique with different materials (Structur 3, Trim, and DuraLay) with interim prostheses (Telio CAD) made with a computer-aided design and computer-aided manufacturing (CAD/CAM) system. MATERIAL AND METHODS: Seventy interim FDPs were fabricated by using different materials (Structur 3, Trim, DuraLay, and Telio CAD) on a metal master model. Resin-impregnated, light-polymerizing glass fiber (GrandTEC) was used to reinforce 10 interim FDPs per material fabricated with the direct technique. Interim FDPs were stored at 37 degrees C for 24 hours before thermocycling. Marginal fit was analyzed at 6 points in each interim FDP before and after thermocycling with either 2500 or 5000 cycles. After fracturing the interim FDPs with a universal testing machine, fracture strength, fragments separation, and fracture point were recorded. Marginal fit data were analyzed with 2-way repeated measure analysis of variance (ANOVA), fracture strength with 1-way ANOVA, and fragments separation and fracture point with the chi-square test at a 99% confidence interval. RESULTS: All interim materials showed marginal discrepancies over time, but no significant differences were found among groups (P>.001), except in the marginal fit of interim FDPs reinforced with glass fiber (S3F), which showed the smallest marginal gap after 5000 cycles (P<.001). Reinforced interim FDPs (S3F, TMF, and DLF) and CAD/CAM FDPs (TCC) presented a fracture strength ranging between 471.3 +/-62.4 N and 531.1 +/-150.1 N (P>.001). Finally, significant differences were observed in the fracture point and frequency of separation (P<.001). CONCLUSIONS: Bis-acryl reinforced with glass fiber showed the least marginal discrepancy. No differences were found between the fracture strengths of interim FDPs fabricated with CAD/CAM system and interim FDPs reinforced with glass fiber. No significant difference in fracture strength was observed between interim FDPs reinforced with glass fiber and prostheses fabricated with CAD/CAM system. However, unreinforced interim FDPs showed the lowest fracture strength. PMID- 25935085 TI - Clinical performance of two different CAD/CAM-fabricated ceramic crowns: 2-Year results. AB - STATEMENT OF PROBLEM: Recently, technical problems, especially chipping, have been reported for ceramic restorations; as a result, ceramic crowns produced entirely by computer-aided design and computer-aided manufacture (CAD/CAM) have become popular because the incidence of chipping is less. PURPOSE: The purpose of this study was to report on 2-year results for 2 different types of CAD/CAM ceramic crowns placed in adult patients in a dental practice. MATERIAL AND METHODS: Sixty participants who required a crown for a first or second molar were randomly assigned to 1 of 2 groups. Crowns in the veneered zirconia (VZ) group were made of zirconia frameworks veneered with CAD/CAM-produced lithium disilicate ceramic; the other group's crowns were made of monolithic lithium disilicate (MLD) ceramic. Each crown was reviewed after 2 weeks, 1 year, and 2 years by using modified the US Public Health Service (USPHS) criteria. Statistical analysis was performed by using the log-rank test, nonparametric tests, and Kaplan-Meier survival analysis. RESULTS: All 60 participants were recalled after 1 and 2 years. In the VZ group, 2 endodontic complications occurred, and deterioration of periodontal health was observed for 3 participants. In the MLD group, 2 endodontic complications occurred within 2 years. In both of the groups, no caries or marginal discoloration was observed. No technical complications, for example, cracks, chipping, or fractures, were detected after 2 years. The shape and appearance of all crowns were assessed positively by the examining dentist. The log-rank test showed no significant differences in respect to technical or biologic complications (P=.324). CONCLUSION: For both types of single-crown restoration, no technical failures occurred. The number of biological complications did not differ significantly between the types of crowns. PMID- 25935086 TI - Using the "final-on-four" concept to deliver an immediate metal-resin implant fixed complete dental prosthesis. AB - In traditional dental implant therapy, the time between implant placement and delivery of the definitive prosthesis can be long and uncomfortable for a patient wearing a conventional removable denture on an atrophied ridge. New clinical protocols, often with tilted implants, are being used to immediately restore mandibular implants with interim restorations, thus shortening the patient's return to function. However, these conversion type interim restorations do not decrease the time to definitive prosthetic rehabilitation. The Ohio State University (OSU) developed an immediate load surgical and prosthetic protocol to compensate for the disadvantages of previous techniques. With this protocol, a custom, definitive, screw-retained metal-resin fixed prosthesis can be delivered 2 to 4 days postoperatively and has been described using 5 implants. This clinical report presents the OSU immediate loading protocol, combined with a tilted implant technique, for the fabrication of a mandibular metal-resin implant fixed complete dental prosthesis (MRIFCDP) in 3 days postoperatively and with only 4 implants. Replacing the mandibular dentition with an immediate load-fixed metal-resin prosthesis by means of the "final-on-four" technique resulted in a custom, definitive, and functional restorative solution immediately after surgery. PMID- 25935087 TI - Management of accidental swallowing in implant dentistry. AB - This report describes a protocol for managing the accidental swallowing of dental instruments in implant dentistry, illustrated by a patient who accidentally swallowed a hexagonal wrench. The first step was to refer the patient to the medical emergency hospital service for radiographic and clinical evaluation. The hexagonal wrench was located in the stomach and was immediately removed with an endoscopic procedure. The gastric mucosa was sampled via biopsy and the sample submitted to the urease test, which was positive for Helicobacter pylori. Triple treatment was instituted for gastritis caused by H pylori to avoid exposing the patient to unnecessary risk. Removal of a foreign body by means of an endoscopic procedure constitutes a safe and effective treatment. PMID- 25935088 TI - An alternative technique for transferring denture-related soft tissue irritation to the denture. PMID- 25935089 TI - Critical appraisal of implant impression accuracies: A systematic review. AB - STATEMENT OF PROBLEM: Different assessment methods have been used to measure the accuracy of implant impression techniques; therefore, the readers should understand the benefits and limitations of each assessment method used. PURPOSE: The purpose of this systematic review was to classify the implant impression studies by the assessment methods and techniques used and to understand the characteristics of each assessment method. The results of published studies were also analyzed to draw meaningful conclusions about the accuracy of the implant impressions. MATERIAL AND METHODS: An electronic search of the MEDLINE/PubMed database was performed in February 2013 using specific search terms and predetermined criteria to identify and assess laboratory studies of the accuracy of implant impression techniques. A final list of articles deemed to be of interest was comprehensively reviewed by 2 reviewers to ensure that these were suitable for the purpose of this review. The results of the current review were also compared with results from a previous systematic review. RESULTS: A total of 56 studies met the inclusion criteria for this review. Thirty-seven studies measured the amount of linear distortion, and 17 studies compared the angular change to assess the accuracy. Most linear or angular distortions were only measured in 2 dimensions, and 3-dimensional analysis was rare. More than 80% of the studies compared nonsplinting versus splinting, direct versus indirect techniques, and different impression materials. CONCLUSIONS: In recent publications, the direct or splint technique showed more accurate results than the indirect or nonsplinted technique. In contrast to external connection implants, inconsistent results were reported for internal connection implants. PMID- 25935090 TI - Performance of stress resistant variants of Listeria monocytogenes in mixed species biofilms with Lactobacillus plantarum. AB - Population diversity and the ability to adapt to changing environments allow Listeria monocytogenes to grow and survive under a wide range of environmental conditions. In this study, we aimed to evaluate the performance of a set of acid resistant L. monocytogenes variants in mixed-species biofilms with Lactobacillus plantarum as well as their benzalkonium chloride (BAC) resistance in these biofilms. L. monocytogenes LO28 wild type and acid resistant variants were capable of forming mixed biofilms with L. plantarum at 20 degrees C and 30 degrees C in BHI supplemented with manganese and glucose. Homolactic fermentation of glucose by L. plantarum created an acidic environment with pH values below the growth boundary of L. monocytogenes. Some of the variants were able to withstand the low pH in the mixed biofilms for a longer time than the WT and there were clear differences in survival between the variants which could not be correlated to (lactic) acid resistance alone. Adaptation to mild pH of liquid cultures during growth to stationary phase increased the acid resistance of some variants to a greater extent than of others, indicating differences in adaptive behaviour between the variants. Two variants that showed a high level of acid adaptation when grown in liquid cultures, showed also better performance in mixed species biofilms. There were no clear differences in BAC resistance between the wild type and variants in mixed biofilms. It can be concluded that acid resistant variants of L. monocytogenes show diversity in their adaptation to acidic conditions and their capacity to survive in mixed cultures and biofilms with L. plantarum. PMID- 25935091 TI - Maternal diabetes induces changes in the umbilical cord gene expression. AB - INTRODUCTION: Since maternal diabetes may affect fetal development and the umbilical cord provides an extension of the fetal vasculature, we decided to investigate cords' biological responses to maternal diabetic milieu. METHODS: Using microarray analysis, we determined the gene expression profiles in the umbilical cords of six neonates born to type 1 diabetic mothers and in six control cords. Umbilical cord tissue was collected immediately after elective cesarean section. Expression data were confirmed by real-time polymerase chain reaction (11 genes). Additionally, the same umbilical cords were analyzed histologically. RESULTS: Two hundred eighty six genes were differentially expressed in the umbilical cords from diabetic pregnancies compared to the controls (fold change +/-1.5 and P < 0.01). Maternal diabetes had a major effect on the expression of genes involved in vascular development (Bone morphogenetic protein 4, Delta-like 1, and Notch homolog 4), vessel wall integrity (Collagen type VIII alpha 1, Myocyte enhancer factor 2C, and Matrix metalloproteinase 2), and vascular function (Natriuretic peptide precursor B, Endothelin 1, Endothelin receptor B, Cyclooxygenase 1, and Phosphodiesterase 5A). Maternal diabetes was associated with thicker umbilical vein intima-media layers and larger umbilical vein and artery intima-media areas compared to the controls. DISCUSSION: Maternal diabetic environment seems to alter umbilical cord expression of genes involved in the regulation of vascular development and function with simultaneous umbilical vessel muscle layer thickening. These alterations suggest vascular phenotypic modifications, which in turn may lead to long-term vascular consequences in various tissues in infants of diabetic mothers. PMID- 25935092 TI - Lost interest for existing compounds: New boosts. AB - Development of new drugs is typically thought of as a bottom-up endeavor where basic science identifies a target, various strategies are used to generate drugs that stimulate or inhibit the target, the drugs are first tested for safety and efficacy in animals and finally efficacy and safety are evaluated in a well defined clinical development process. However, this is not the only way that new drug products are developed. Many new products come from re-initiating development of discontinued drugs, finding new uses for existing drugs, creating a new product by obtaining marketing approval in expanded territories, obtaining approvals for new formulations or a single isomer of a previously approved racemic drug, converting products from prescription to over-the- counter use or converting folk medicines or vitamins to modern pharmaceuticals. Based on this long and successful history of contributions to modern therapeutics, these alternative sources of new products should not be neglected. PMID- 25935093 TI - Potential roles for Homer1 and Spinophilin in the preventive effect of electroconvulsive seizures on stress-induced CA3c dendritic retraction in the hippocampus. AB - Electroconvulsive therapy (ECT) remains the treatment of choice for patients with severe or drug-resistant depressive disorders, yet the mechanism behind its efficacy remains poorly characterized. In the present study, we used electroconvulsive seizures (ECS), an animal model of ECT, to identify proteins possibly involved in the preventive effect of ECS on stress-induced neuronal atrophy in the hippocampus. Rats were stressed daily using the 21-day 6h daily restraint stress paradigm and subjected to sham seizures, a single ECS on the last day of the restraint period or daily repeated seizures for 10 consecutive days during the end of the restraint period. Consistent with previous findings, dendritic atrophy was observed in the CA3c hippocampal region of chronically stressed rats. In addition, we confirmed our recent findings of increased spine density in the CA1 region following chronic restraint stress. The morphological alterations in the CA3c area were prevented by treatment with ECS. On the molecular level, we showed that the synaptic proteins Homer1 and Spinophilin are targeted by ECS. Repeated ECS blocked stress-induced up-regulation of Spinophilin protein levels and further increased the stress-induced up-regulation of Homer1. Given the roles of Spinophilin in the regulation of AMPA receptors and Homer1 in the regulation of metabotropic glutamate receptors (mGluRs), our data imply the existence of a mechanism where ECS regulate cell excitability by modulating AMPA receptor function and mGluR related calcium homeostasis. These molecular changes could potentially contribute to the mechanism induced by ECS which prevents the stress-induced morphological changes in the CA3c region. PMID- 25935094 TI - Environmental occurrence and biota concentration of phthalate esters in Epe and Lagos Lagoons, Nigeria. AB - The high global occurrence of phthalates in different environmental matrixes has resulted in the detection of their metabolites in human urine, blood, and breast milk, indicating a widespread human exposure. In addition, the notorious endocrine disrupting effects of phthalates have shown that they mimic or antagonize the action of endogenous hormones, consequently producing adverse effects on reproduction, growth and development. Herein, we have studied the occurrence of phthalate esters (PEs) in water, sediment and biota of two lagoons (Epe and Lagos) in Nigeria. Two fish species (Tilapia guineensis, and Chrysichthys nigrodigitatus) and a crustacean (the African river prawn- Macrobrachium vollenhovenii) were analyzed for PEs levels using a HPLC method and the derived values were used for calculating bioconcentration factor (BCF), biota sediment accumulation factor (BSAF) and phthalate pollution index (PPI) in the biota and environment. We observed that the growth and health condition of the fish species were normal with a k-factor of >1. Sediment PE levels were compared with water, at both lagoons showing concentration pattern that is characterized as DEHP = DEP > DBP. We observed that DBP was the predominant compound in T. guineensis, C. nigrodigitatus and African prawn, at both lagoons, showing organ specific differences in bioconcentration (BCF and BSAF) patterns in the fish species. While there were no observed consistency in the pattern of PE concentration in fish organs, elevated DBP levels in different fish organs may be related to fish habitat and degradation level of phthalates. Low concentration of DEHP, compared with DBP and DEP, was measured in fish organs and whole prawn body. The BSAF values for DEHP were lowest, and highest for DBP for all species at both lagoons, and DEHP easily accumulated more in the sediment (sediment PPI = 0.28 and 0.16 for Epe and Lagos lagoon, respectively). Overall, our findings suggest a broader environmental and human health implication of the high PE levels in these lagoons since they represent significant sources of aquatic food resources for the neighboring communities. PMID- 25935095 TI - Disseminated nocardia infection mimicking malignancy on FDG PET/CT. PMID- 25935096 TI - Subsequent Receipt of Interventions for Glaucoma Among a Nationwide Sample of Patients Who Underwent Laser Peripheral Iridotomy. AB - PURPOSE: To evaluate use of medical, laser, or incisional surgical interventions for glaucoma after laser peripheral iridotomy (LPI). DESIGN: Retrospective longitudinal cohort study. METHODS: All enrollees aged >=21 years in a US managed care network who underwent bilateral LPIs in 2001-2011 were identified. The mean numbers of pre- and post-LPI glaucoma medication classes prescribed and the proportion of enrollees requiring cataract or glaucoma surgery within 2 years after the LPIs were determined. Multivariable logistic regression assessed factors associated with enrollees' prescription of >=1 glaucoma medication class after bilateral LPIs. RESULTS: Of the 1660 patients undergoing bilateral LPIs, 1280 (77.1%) had no pre- or post-LPI prescriptions for any glaucoma medication class. Of the remaining patients, 251 (66.1%) required more glaucoma medication classes after than before the procedures, whereas 44 (11.6%) used fewer after the procedures; 85 (22.4%) were prescribed the same number before and after the LPIs. A total of 167 patients (10.1%) underwent cataract surgery and 79 (4.8%) received glaucoma surgery over the 2-year follow-up. Black patients had a 130% increased odds for glaucoma medication-class prescriptions after bilateral LPIs, compared with white patients (P = .02). The odds of post-LPI glaucoma medication use increased by 21% for every additional 5 years of age (P < .0001). CONCLUSION: Most patients undergoing bilateral LPIs received no pre- or post-LPI glaucoma medication-class prescriptions and had no cataract or additional glaucoma surgery within 2 years after LPIs. Clinicians should alert black or older patients and those already taking glaucoma medications before the procedure of their higher odds of requiring medications afterward. PMID- 25935097 TI - Hedgehog Pathway Inhibition for Locally Advanced Periocular Basal Cell Carcinoma and Basal Cell Nevus Syndrome. AB - PURPOSE: To review our experience treating patients with the Hedgehog pathway inhibitor, vismodegib, in patients with orbital or periocular locally advanced or metastatic basal cell carcinoma (BCC) or basal cell nevus syndrome. DESIGN: Retrospective interventional case series. METHODS: We reviewed all patients with locally advanced or metastatic orbital or periocular BCC or basal cell nevus syndrome treated with the Hedgehog pathway inhibitor, vismodegib, at a comprehensive cancer center from 2009 through 2015. Reviewed data included age; sex; American Joint Commission on Cancer tumor, node, metastasis staging system designation; type and grade of drug-related side effects; response to treatment; duration of follow-up, and status at last follow-up. RESULTS: The study included 10 white men and 2 white women; the median age was 64.5 years. Ten patients had locally advanced BCC; 2 had basal cell nevus syndrome. Among the patients with locally advanced BCC, 5 had T3bN0M0 disease at presentation; 1 each had T3aN0M0, T3bN1M0, T2N1M1, T4N1M1, and T4N2cM1 disease. Overall, 3 patients had a complete response, 6 had a partial response, and 3 had stable disease at last follow-up. Two patients developed progressive disease after a complete response for 38 months and stable disease for 16 months, respectively. All patients developed grade I drug-related adverse effects, most commonly muscle spasms (12 patients), weight loss (10), dysgeusia (9), alopecia (9), decreased appetite (5), and fatigue (4). Five patients developed grade II adverse effects. At last follow-up, none of the 5 patients presenting with T3bN0M0, nor the patient with T3bN1M0 disease, had required orbital exenteration. CONCLUSION: Hedgehog pathway inhibition produces a significant clinical response in most patients with locally advanced or metastatic orbital or periocular BCC or basal cell nevus syndrome and can obviate orbital exenteration in some patients. Drug-related adverse effects are manageable in most patients. PMID- 25935098 TI - Polyquaternium-1-Preserved Travoprost 0.003% or Benzalkonium Chloride-Preserved Travoprost 0.004% for Glaucoma and Ocular Hypertension. AB - PURPOSE: To demonstrate equivalence of polyquaternium-1-preserved travoprost 0.003% with benzalkonium chloride-preserved travoprost 0.004% in patients with open-angle glaucoma or ocular hypertension. DESIGN: Double-masked, randomized, 2 treatment, equivalence clinical trial. METHODS: setting: Multicenter clinical trial conducted in 60 centers in the United States and Europe. PATIENT POPULATION: Adult patients with open-angle glaucoma or ocular hypertension. One eye per patient was analyzed. INTERVENTION: Patients were randomized 1:1 to receive polyquaternium-1-preserved travoprost 0.003% (n = 442) or benzalkonium chloride-preserved travoprost 0.004% (n = 422) once daily for 3 months. MAIN OUTCOME MEASURES: Mean intraocular pressure (IOP) was assessed at 8 AM, 10 AM, and 4 PM at week 2, week 6, and month 3. Supportive outcomes were mean and percent IOP change, percentage of patients achieving IOP <18 mm Hg or >=30% IOP reduction, and adverse events. RESULTS: Mean IOP was similar between groups at all study visits (travoprost 0.003% range, 17.5-18.9 mm Hg; travoprost 0.004% range, 17.4-19.0 mm Hg). Mean change (least squares mean differences, -0.1 to 0.3 mm Hg; 95% confidence interval, -0.5 to 0.7 mm Hg) and percentage change (travoprost 0.003%, 28.4%-30.7%; travoprost 0.004%, 28.5%-31.0%) from baseline were comparable. The percentages of patients with IOP <18 mm Hg and >=30% reduction of IOP were also similar. Hyperemia was the most frequent treatment related adverse event with both formulations (travoprost 0.003%, 11.8%; travoprost 0.004%, 14.5%). CONCLUSIONS: In patients with open-angle glaucoma or ocular hypertension, polyquaternium-1-preserved travoprost 0.003% solution provided equivalent IOP-lowering efficacy to that of benzalkonium chloride preserved travoprost 0.004%. PMID- 25935099 TI - Fundus Autofluorescence Changes After Ranibizumab Treatment for Subfoveal Choroidal Neovascularization Secondary to Pathologic Myopia. AB - PURPOSE: To describe fundus autofluorescence (FAF) patterns of myopic choroidal neovascularization (CNV) treated with intravitreal ranibizumab and their correlation with visual acuity. DESIGN: Prospective interventional case series. METHODS: Twenty-seven eyes (27 patients) affected by myopic CNV were enrolled from January 2011 to January 2013. All patients underwent a complete ophthalmologic examination, including best-corrected visual acuity (BCVA) determination and fundus autofluorescence (FAF). The patients underwent ranibizumab injections following a pro re nata treatment regimen. The main outcome measure was the identification of the FAF patterns of myopic CNV over a 12-month follow-up. The secondary outcome was the correlation of the FAF patterns with the BCVA. RESULTS: At baseline 17 eyes (63%) showed a hyperautofluorescent pattern and 10 eyes (37%) a patchy pattern. BCVA changed from 0.48 +/- 0.23 (logMAR) to 0.30 +/- 0.32 at the 12-month examination (P = .027) in the hyper-FAF subgroup. In the subgroup showing the patchy pattern, the BCVA declined slightly from 0.51 +/- 0.27 to 0.56 +/- 0.37 (P = .53). The 14 eyes preserving the hyper FAF pattern during the follow-up had a final BCVA of 0.20 +/- 0.17, whereas the 9 eyes maintaining the patchy pattern showed a final BCVA of 0.60 +/- 0.37 (P = .002). The atrophic area of the retinal pigment epithelium assessed on the basis of FAF increased from 1.27 +/- 2.80 mm(2) to 1.83 +/- 3.74 mm(2) at the 12-month examination (P = .016). The mean atrophic area increased by 0.37 mm(2) in the hyper-FAF subgroup and by 0.90 mm(2) in the patchy FAF subgroup. CONCLUSIONS: Two main patterns were identified on FAF in myopic CNV and were related to the prognostic evolution, the hyperautofluorescent CNV being associated with a greater visual gain and fewer atrophic changes over a 12-month follow-up. PMID- 25935100 TI - Variability in Human Cone Topography Assessed by Adaptive Optics Scanning Laser Ophthalmoscopy. AB - PURPOSE: To assess between- and within-individual variability of macular cone topography in the eyes of young adults. DESIGN: Observational case series. METHODS: Cone photoreceptors in 40 eyes of 20 subjects aged 19-29 years with normal maculae were imaged using a research adaptive optics scanning laser ophthalmoscope. Refractive errors ranged from -3.0 diopters (D) to 0.63 D and differed by <0.50 D in fellow eyes. Cone density was assessed on a 2-dimensional sampling grid over the central 2.4 mm * 2.4 mm. Between-individual variability was evaluated by coefficient of variation (COV). Within-individual variability was quantified by maximum difference and root mean square (RMS). Cones were cumulated over increasing eccentricity. RESULTS: Peak densities of foveal cones are 168 162 +/- 23 529 cones/mm(2) (mean +/- SD) (COV = 0.14). The number of cones within the cone-dominated foveola (0.8-0.9 mm diameter) is 38 311 +/- 2319 (COV = 0.06). The RMS cone density difference between fellow eyes is 6.78%, and the maximum difference is 23.6%. Mixed-model statistical analysis found no difference in the association between eccentricity and cone density in the superior/nasal (P = .8503), superior/temporal (P = .1551), inferior/nasal (P = .8609), and inferior/temporal (P = .6662) quadrants of fellow eyes. CONCLUSIONS: New instrumentation imaged the smallest foveal cones, thus allowing accurate assignment of foveal centers and assessment of variability in macular cone density in a large sample of eyes. Though cone densities vary significantly in the fovea, the total numbers of foveolar cones are very similar both between and within subjects. Thus, the total number of foveolar cones may be an important measure of cone degeneration and loss. PMID- 25935101 TI - Prospective Evaluation of Acupuncture as Treatment for Glaucoma. AB - PURPOSE: To evaluate acupuncture as treatment for glaucoma. DESIGN: Prospective double-masked randomized crossover study. METHODS: setting: Clinical practice. POPULATION: One eye per patient with primary open-angle glaucoma and stable intraocular pressure (IOP). INTERVENTION: Patients were randomized to receive 1 acupuncture series (12 sessions with either eye-related [eye-points] or non-eye related [non-eye-points] acupoints) and then crossed over to receive the other series. OUTCOME MEASURES: IOP, blood pressure (BP), heart rate (HR), best corrected visual acuity (BCVA), visual field (VF), optic disc and peripapillary retinal nerve fiber layer (RNFL) measurements, compliance, and adverse reactions. Probability to detect 3 mm Hg IOP difference between series was 90%. RESULTS: Twenty-two patients volunteered and 11 (50.0%) completed the study; 8 (36.4%) did not complete treatment owing to changes of health, moving away, lack of transportation, or family crisis; and 3(13.6%) were withdrawn owing to needle sensitivity or IOP elevation (8 mm Hg) in the contralateral eye. After an acupuncture session, mean IOP increased slightly with both eye-points (from 12.9 +/- 1.8 mm Hg to 13.6 +/- 2.0 mm Hg, P = .019) and non-eye-points (from 13.0 +/- 1.5 mm Hg to 13.5 +/- 1.7 mm Hg, P = .073) series. HR, diurnal IOP, and BCVA showed no statistically significant changes after 12 sessions of either series. Systolic and diastolic BP were reduced after 12 sessions of non-eye-points series (P = .040, P = .002, respectively). Optic disc, RNFL, and VF showed no statistically significant changes. CONCLUSIONS: Acupuncture has no overall effect on diurnal IOP or BCVA but may temporally increase the IOP immediately after a treatment session. BP is lowered by acupuncture with non-eye-points, but not with eye-points. Compliance and adverse event rates were low. PMID- 25935102 TI - Investigation of toxic effects of imidazolium ionic liquids, [bmim][BF4] and [omim][BF4], on marine mussel Mytilus galloprovincialis with or without the presence of conventional solvents, such as acetone. AB - This study investigated the cytotoxic, oxidative and genotoxic effects of two commonly used imidazolium ionic liquids (ILs), [bmim][BF4] (1-butyl-3 methylimidazolium) and [omim][BF4] (1-methyl-3-octylimidazolium tetrafluoroborate), on the marine mussel Mytilus galloprovincialis, as well as whether acetone could mediate their toxic profile. In this context, mussels were firstly exposed to different concentrations of [bmim][BF4] or [omim][BF4], with or without the presence of acetone (at a final concentration of 0.06% v/v), for a period of 96h, in order to determine the concentration that causes 50% mussel mortality (LC50 values) in each case. Thereafter, mussels were exposed to sub- and non-lethal concentrations of ILs for investigating their ability to cause lysosomal membrane impairment (with the use of neutral red retention assay/NRRT), superoxide anion and lipid peroxidation byproduct (malondialdehyde/MDA) formation, as well as DNA damage and formation of nuclear abnormalities in hemocytes. The results showed that [omim][BF4] was more toxic than [bmim][BF4] in all cases, while the presence of acetone resulted in a slight attenuation of its toxicity. The different toxic behavior of ILs was further revealed by the significantly lower levels of NRRT values observed in [omim][BF4]-treated mussels, compared to those occurring in [bmim][BF4] in all cases. Similarly, [bmim][BF4]-mediated oxidative and genotoxic effects were observed only in the highest concentration tested (10mgL(-1)), while [omim][BF4]-mediated effects were enhanced at lower concentrations (0.01-0.05mgL(-1)). Overall, the present study showed that [bmim][BF4] and [omim][BF4] could induce not only lethal but also nonlethal effects on mussel M. galloprovincialis. The extent of [bmim][BF4] and/or [omim][BF4]-mediated effects could be ascribed to the length of each IL alkyl chain, as well as to their lipophilicity. Moreover, the role of acetone on the obtained toxic effects of the specific ILs was reported for the first time, giving evidence for its interaction with the ILs and the modulation of their toxicity. PMID- 25935103 TI - Biodynamics of copper oxide nanoparticles and copper ions in an oligochaete - Part I: Relative importance of water and sediment as exposure routes. AB - Copper oxide (CuO) nanoparticles (NPs) are widely used, and likely released into the aquatic environment. Both aqueous (i.e., dissolved Cu) and particulate Cu can be taken up by organisms. However, how exposure routes influence the bioavailability and subsequent toxicity of Cu remains largely unknown. Here, we assess the importance of exposure routes (water and sediment) and Cu forms (aqueous and nanoparticulate) on Cu bioavailability and toxicity to the freshwater oligochaete, Lumbriculus variegatus, a head-down deposit-feeder. We characterize the bioaccumulation dynamics of Cu in L. variegatus across a range of exposure concentrations, covering both realistic and worst-case levels of Cu contamination in the environment. Both aqueous Cu (Cu-Aq; administered as Cu(NO3)2) and nanoparticulate Cu (CuO NPs), whether dispersed in artificial moderately hard freshwater or mixed into sediment, were weakly accumulated by L. variegatus. Once incorporated into tissues, Cu elimination was negligible, i.e., elimination rate constants were in general not different from zero for either exposure route or either Cu form. Toxicity was only observed after waterborne exposure to Cu-Aq at very high concentration (305MUgL(-1)), where all worms died. There was no relationship between exposure route, Cu form or Cu exposure concentration on either worm survival or growth. Slow feeding rates and low Cu assimilation efficiency (approximately 30%) characterized the uptake of Cu from the sediment for both Cu forms. In nature, L. variegatus is potentially exposed to Cu via both water and sediment. However, sediment progressively becomes the predominant exposure route for Cu in L. variegatus as Cu partitioning to sediment increases. PMID- 25935104 TI - Evaluation of allergen-microarray-guided dietary intervention as treatment of eosinophilic esophagitis. PMID- 25935105 TI - A novel hypomorphic mutation in STIM1 results in a late-onset immunodeficiency. PMID- 25935107 TI - Atopic dermatitis disease control and age: A cohort study. PMID- 25935106 TI - Genome-wide association study of recalcitrant atopic dermatitis in Korean children. AB - BACKGROUND: Atopic dermatitis (AD) is a heterogeneous chronic inflammatory skin disease. Most AD during infancy resolves during childhood, but moderate-to-severe AD with allergic sensitization is more likely to persist into adulthood and more often occurs with other allergic diseases. OBJECTIVE: We sought to find susceptibility loci by performing the first genome-wide association study (GWAS) of AD in Korean children with recalcitrant AD, which was defined as moderate-to severe AD with allergic sensitization. METHODS: Our study included 246 children with recalcitrant AD and 551 adult control subjects with a negative history of both allergic disease and allergic sensitization. DNA from these subjects was genotyped; sets of common single nucleotide polymorphisms (SNPs) were imputed and used in the GWAS after quality control checks. RESULTS: SNPs at a region on 13q21.31 were associated with recalcitrant AD at a genome-wide threshold of significance (P < 2.0 * 10(-8)). These associated SNPs are more than 1 Mb from the closest gene, protocadherin (PCDH)9. SNPs at 4 additional loci had P values of less than 1 * 10(-6), including SNPs at or near the neuroblastoma amplified sequence (NBAS; 2p24.3), thymus-expressed molecule involved in selection (THEMIS; 6q22.33), GATA3 (10p14), and S-phase cyclin A-associated protein in the ER (SCAPER; 15q24.3) genes. Further analysis of total serum IgE levels suggested 13q21.31 might be primarily an IgE locus, and analyses of published data demonstrated that SNPs at the 15q24.3 region are expression quantitative trait loci for 2 nearby genes, ISL2 and proline-serine-threonine phosphatase interacting protein 1 (PSTPIP1), in immune cells. CONCLUSION: Our GWAS of recalcitrant AD identified new susceptibility regions containing genes involved in epithelial cell function and immune dysregulation, 2 key features of AD, and potentially extend our understanding of their role in pathogenesis. PMID- 25935108 TI - Patterns of IgE responses to multiple allergen components and clinical symptoms at age 11 years. AB - BACKGROUND: The relationship between sensitization to allergens and disease is complex. OBJECTIVE: We sought to identify patterns of response to a broad range of allergen components and investigate associations with asthma, eczema, and hay fever. METHODS: Serum specific IgE levels to 112 allergen components were measured by using a multiplex array (Immuno Solid-phase Allergen Chip) in a population-based birth cohort. Latent variable modeling was used to identify underlying patterns of component-specific IgE responses; these patterns were then related to asthma, eczema, and hay fever. RESULTS: Two hundred twenty-one of 461 children had IgE to 1 or more components. Seventy-one of the 112 components were recognized by 3 or more children. By using latent variable modeling, 61 allergen components clustered into 3 component groups (CG1, CG2, and CG3); protein families within each CG were exclusive to that group. CG1 comprised 27 components from 8 plant protein families. CG2 comprised 7 components of mite allergens from 3 protein families. CG3 included 27 components of plant, animal, and fungal origin from 12 protein families. Each CG included components from different biological sources with structural homology and also nonhomologous proteins arising from the same biological source. Sensitization to CG3 was most strongly associated with asthma (odds ratio [OR], 8.20; 95% CI, 3.49-19.24; P < .001) and lower FEV1 (P < .001). Sensitization to CG1 was associated with hay fever (OR, 12.79; 95% CI, 6.84-23.90; P < .001). Sensitization to CG2 was associated with both asthma (OR, 3.60; 95% CI, 2.05-6.29) and hay fever (OR, 2.52; 95% CI, 1.38 4.61). CONCLUSIONS: Latent variable modeling with a large number of allergen components identified 3 patterns of IgE responses, each including different protein families. In 11-year-old children the pattern of response to components of multiple allergens appeared to be associated with current asthma and hay fever but not eczema. PMID- 25935109 TI - Phase II pilot study of single-agent etirinotecan pegol (NKTR-102) in bevacizumab resistant high grade glioma. AB - Patients with recurrence of high-grade glioma (HGG) after bevacizumab (BEV) have an extremely poor prognosis. Etirinotecan pegol (EP) is the first long-acting topoisomerase-I inhibitor designed to concentrate in and provide continuous tumor exposure throughout the entire chemotherapy cycle. Here we report results of a Phase 2, single arm, open-label trial evaluating EP in HGG patients who progressed after BEV. Patients age >18 with histologically proven anaplastic astrocytoma or glioblastoma (GB) who previously received standard chemo-radiation and recurred after BEV were eligible. A predicted life expectancy >6 weeks and KPS >= 50 were required. The primary endpoint was PFS at 6-weeks. Secondary endpoint was overall survival from first EP infusion. Response was assessed by RANO criteria. Single agent EP was administered IV every 3 weeks at 145 mg/m2. Patients did not receive BEV while on EP. 20 patients (90 % GB) were enrolled with a median age of 50 and median KPS of 70. Three patients with GB (16.7 % of GB) had partial MRI responses. 6-week PFS was 55 %. Median and 6-month PFS were 2.2 months (95 % CI 1.4-3.4 months) and 11.2 % (95 % CI 1.9-28.9 %) respectively. Median overall survival from first EP infusion was 4.5 months (95 % CI 2.4-5.9). Only one patient had grade 3 toxicity (diarrhea with dehydration) attributable to EP. Hematologic toxicity was mild. Three patients had confirmed partial responses according to RANO criteria. These clinical data combined with a favorable safety profile warrant further clinical investigation of this agent in HGG. PMID- 25935110 TI - Combination treatment of TRAIL, DFMO and radiation for malignant glioma cells. AB - Tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) has shown potent and cancer-selective killing activity and drawn considerable attention as a promising therapy for cancer. Another promising cancer therapy is difluoromethylornithine (DFMO), an inhibitor of ornithine decarboxylase, which is oraly administered and well tolerated. Nevertheless, many types of cancer, including gliomas, have exhibited resistance to TRAIL-induced apoptosis and similarly the potency of DFMO should be enhanced to optimize therapeutic efficacy. In this study we sought to determine whether DFMO, in combination with TRAIL and radiation, could result in an enhanced anti-glioma effect in vitro. We investigated the effect of DFMO, TRAIL and radiation in various combinations on a panel of glioblastoma cell lines (A172, T98G, D54, U251MG). Viability and proliferation of the cells were examined with trypan blue exclusion assay, crystal violet and xCELLigence system. Apoptosis (Annexin-PI), cell cycle and activation of caspase-8 were tested with flow cytometry. BAD protein levels were determined by Western blot analysis. DFMO induced BAD overexpression. Combination treatment with DFMO, TRAIL and radiation significantly reduced cell viability in all cell lines tested. Increased induction of cell death and cell cycle arrest was confirmed with flow cytometry in A172 and D54 cell lines, while enhanced activation of annexin and caspase-8 was revealed in U251MG and T98G cells. The treatment of glioblastoma cell lines with combination of DFMO, TRAIL and radiation showed an enhanced effect. This combination treatment may represent a novel strategy for targeting glioblastoma. PMID- 25935111 TI - Impact of Global and Segmental Hypertrophy on Two-Dimensional Strain Derived from Three-Dimensional Echocardiography in Hypertrophic Cardiomyopathy: Comparison with Healthy Subjects. AB - BACKGROUND: Patients with hypertrophic cardiomyopathy (HCM) present unusual myocardial mechanics. The aim of this study was to assess the impact of hypertrophy on global and regional two-dimensional (2D) strain derived from both tomographic images (2D/2D) and volumetric image acquisition (2D/three-dimensional [3D]) in patients with HCM compared with control subjects. METHODS: Comprehensive resting 2D and 3D echocardiography was performed in 40 patients with HCM and in 53 control subjects, with comparable distributions of age, gender, and left ventricular (LV) ejection fraction. LV global and segmental measurements of all 2D/2D and 2D/3D peak strain components (global and segmental longitudinal strain, global and segmental circumferential strain, global and segmental radial strain, and global and segmental area strain) and 3D indexed LV end-diastolic myocardial mass were obtained from all patients. LV wall thickness was assessed in short axis views and classified in four quartiles (<10.5, 10.5-13.0, 13.0-16.5, and >16.5 mm). RESULTS: The reproducibility of 2D/3D strain was similar or greater and more consistent for all components compared with 2D/2D strain analysis. There was a significant correlation between 3D LV end-diastolic mass and all 2D/3D strain components (P < .05). Two-dimensional/3D global circumferential strain had the strongest association with 3D LV ejection fraction (r = 0.50, P = .001). For segmental deformation, patients with HCM had lower longitudinal deformation whatever the LV wall thickness, whereas circumferential function was increased in nonhypertrophied and poorly hypertrophied segments compared with control subjects. CONCLUSIONS: Two-dimensional/3D strain is a reliable technique to assess myocardial deformation. Myocardial mass is related to 2D/3D strain components in patients with HCM. Circumferential deformation, compared with longitudinal deformation, seems to be the main component of the maintenance of systolic function in HCM. PMID- 25935112 TI - Structural determinants of Smad function in TGF-beta signaling. AB - Smad transcription factors are central to the signal transduction pathway that mediates the numerous effects of the transforming growth factor beta (TGF-beta) superfamily of cytokines in metazoan embryo development as well as in adult tissue regeneration and homeostasis. Although Smad proteins are conserved, recent genome-sequencing projects have revealed their sequence variation in metazoan evolution, human polymorphisms, and cancer. Structural studies of Smads bound to partner proteins and target DNA provide a framework for understanding the significance of these evolutionary and pathologic sequence variations. We synthesize the extant mutational and structural data to suggest how genetic variation in Smads may affect the structure, regulation, and function of these proteins. We also present a web application that compares Smad sequences and displays Smad protein structures and their disease-associated variants. PMID- 25935113 TI - Associations between serum cholinesterase and incident hyper-LDL cholesterolemia, hypertriglyceridemia and hypo-HDL cholesterolemia as well as changes in lipid levels in a health screening population. AB - OBJECTIVE: To investigate longitudinal associations between serum cholinesterase (ChE) and lipid status. METHODS: Hazard ratios (HRs) of incident hyper-LDL cholesterolemia, hypertriglyceridemia and hypo-HDL cholesterolemia for baseline ChE and correlation coefficients between baseline ChE and changes in LDL cholesterol, log triglycerides and HDL cholesterol during 5 years were calculated in a health screening population. RESULTS: During the 5-year follow-up period, 337 men (22.9%) and 208 women (26.3%), 330 men (24.3%) and 114 women (12.4%) and 137 men (8.3%) and 117 women (12.7%) developed hyper-LDL cholesterolemia, hypertriglyceridemia and hypo-HDL cholesterolemia, respectively. The HRs of incident hyper-LDL cholesterolemia, hypertriglyceridemia and hypo-HDL cholesterolemia for each 1 SD increase in baseline ChE were 1.15 (p = 0.009) in men and 1.17 (p = 0.017) in women, 1.25 (p < 0.001) in men and 1.37 (p < 0.001) in women and 1.15 (p = 0.113) in men and 1.12 (p = 0.248) in women, respectively adjusted for BMI and other confounders, while the HRs were not significant after further adjusted for each baseline lipid level except for the HR of hypertriglyceridemia in women (HR, 1.22 (p = 0.047)). The baseline ChE was inversely correlated with the changes in LDL cholesterol (r = -0.117, p < 0.001) and log triglycerides (r = -0.114, p < 0.001) in men and the change in LDL cholesterol (r = -0.191, p < 0.001) in women. CONCLUSION: ChE was positively associated with incident hyper-LDL cholesterolemia and hypertriglyceridemia adjusted for BMI, while with only incident hypertriglyceridemia in women after further adjusted for the baseline lipid level. PMID- 25935114 TI - Obstructive sleep apnea and abdominal aortic calcification: Is there an association independent of comorbid risk factors? AB - BACKGROUND: No studies have addressed the relationship between obstructive sleep apnea (OSA) and abdominal aortic calcification (AAC), a marker for subclinical atherosclerosis and future cardiovascular events. OBJECTIVES: To investigate 1) the association between OSA severity and AAC, and 2) whether OSA can impact the extent of AAC independent of comorbid atherogenic risk factors. METHODS: 390 participants aged 40-70 years underwent polysomnography and abdominal computed tomography. AAC was separately quantified in the upper and lower abdominal aorta using the modified Agatston scoring method, and the total AAC score was calculated as a sum of the two scores. OSA was defined as none/mild (apnea hypopnea index [AHI] <15, n = 87), moderate (AHI 15-30, n = 129), and severe (AHI >=30, n = 174). RESULTS: Log-transformed total AAC score adjusted for age and body mass index (BMI) was greater in participants with an elevated AHI (3.4 for none/mild OSA, 3.7 for moderate OSA, and 4.2 for severe OSA, p = 0.04). Multivariate linear regression analysis including age and BMI as covariates showed that severe OSA was associated with higher scores for the lower and total AAC (beta = 0.15 and 0.14, p = 0.01 and 0.01, respectively). The association did not persist after additionally adjusting for traditional atherogenic risk factors including visceral fat, smoking, hypertension, dyslipidemia, and diabetes. CONCLUSIONS: Severe OSA was associated with a greater extent of AAC, which was dependent on coexisting atherogenic risk factors. Comorbid cardiometabolic disorders may largely mediate the association of OSA with subclinical atherosclerosis. PMID- 25935115 TI - Computational Analysis of CRTh2 receptor antagonist: A Ligand-based CoMFA and CoMSIA approach. AB - CRTh2 receptor is an important mediator of inflammatory effects and has attracted much attention as a therapeutic target for the treatment of conditions such as asthma, COPD, allergic rhinitis and atopic dermatitis. In pursuit of better CRTh2 receptor antagonist agents, 3D-QSAR studies were performed on a series of 2-(2 (benzylthio)-1H-benzo[d]imidazol-1-yl) acetic acids. There is no crystal structure information available on this protein; hence in this work, ligand-based comparative molecular field analysis (CoMFA) and comparative molecular similarity indices analysis (CoMSIA) were performed by atom by atom matching alignment using systematic search and simulated annealing methods. The 3D-QSAR models were generated with 10 different combinations of test and training set molecules, since the robustness and predictive ability of the model is very important. We have generated 20 models for CoMFA and 100 models for CoMSIA based on two different alignments. Each model was validated with statistical cut off values such as q(2)>0.4, r(2)>0.5 and r(2)pred>0.5. Based on better q(2) and r(2)pred values, the best predictions were obtained for the CoMFA (model 5 q(2)=0.488, r(2)pred=0.732), and CoMSIA (model 45 q(2)=0.525, r(2)pred=0.883) from systematic search conformation alignment. The high correlation between the cross validated/predicted and experimental activities of a test set revealed that the CoMFA and CoMSIA models were robust. Statistical parameters from the generated QSAR models indicated the data is well fitted and have high predictive ability. The generated models suggest that steric, electrostatic, hydrophobic, H-bond donor and acceptor parameters are important for activity. Our study serves as a guide for further experimental investigations on the synthesis of new CRTh2 antagonist. PMID- 25935116 TI - Genomic distribution and possible functional roles of putative G-quadruplex motifs in two subspecies of Oryza sativa. AB - G-quadruplex is a stable, four-stranded DNA or RNA structure formed from guanine rich regions and implicated in telomere maintenance, replication, gene regulation at transcription level or translation level, etc. Based on bioinformatics methods, we analyzed different putative G-quadruplex motifs (PGQMs) patterns in various genomic regions of two subspecies (indica and japonica) of Oryza sativa and the whole genomes of other 8 species. In total, in the 10 species we discussed, the PGQMs densities in monocots were higher than dicots. 40,483 and 31,795 PGQMs were identified with a density of 108.46 and 84.89 PGQMs/Mb, respectively, in japonica and indica genomes, 10,655 and 5420 loci were found to contain at least one PGQM in their gene bodies (with a percentage of 19% and 14%) indicating a wide distribution of G-quadruplex motifs in O. sativa genome. They preferred to locate in transcription start sites proximal regions and 5'-UTR with relative high enrichment. This phenomenon supports the hypothesis that PGQMs are involved in gene transcription and translation. In addition, we analyzed the distribution of different loop length in G-quadruplex and found the density of long loop PGQMs was less than short loop in indica's intron but it was similar in japonica. Meanwhile, we focused on the loci with PGQMs and conducted gene ontology (GO) analysis of them. As a result, many GO terms were identified and significantly correlated with the loci containing at least one PGQM. The GO analysis in the two subspecies of rice may be helpful for elucidating the functional roles of G-quadruplexes. PMID- 25935118 TI - Gene network coherence based on prior knowledge using direct and indirect relationships. AB - Gene networks (GNs) have become one of the most important approaches for modeling biological processes. They are very useful to understand the different complex biological processes that may occur in living organisms. Currently, one of the biggest challenge in any study related with GN is to assure the quality of these GNs. In this sense, recent works use artificial data sets or a direct comparison with prior biological knowledge. However, these approaches are not entirely accurate as they only take into account direct gene-gene interactions for validation, leaving aside the weak (indirect) relationships. We propose a new measure, named gene network coherence (GNC), to rate the coherence of an input network according to different biological databases. In this sense, the measure considers not only the direct gene-gene relationships but also the indirect ones to perform a complete and fairer evaluation of the input network. Hence, our approach is able to use the whole information stored in the networks. A GNC JAVA based implementation is available at: http://fgomezvela.github.io/GNC/. The results achieved in this work show that GNC outperforms the classical approaches for assessing GNs by means of three different experiments using different biological databases and input networks. According to the results, we can conclude that the proposed measure, which considers the inherent information stored in the direct and indirect gene-gene relationships, offers a new robust solution to the problem of GNs biological validation. PMID- 25935117 TI - Systematic investigation of sequence and structural motifs that recognize ATP. AB - Interaction between ATP, a multifunctional and ubiquitous nucleotide, and proteins initializes phosphorylation, polypeptide synthesis and ATP hydrolysis which supplies energy for metabolism. However, current knowledge concerning the mechanisms through which ATP is recognized by proteins is incomplete, scattered, and inaccurate. We systemically investigate sequence and structural motifs of proteins that recognize ATP. We identified three novel motifs and refined the known p-loop and class II aminoacyl-tRNA synthetase motifs. The five motifs define five distinct ATP-protein interaction modes which concern over 5% of known protein structures. We demonstrate that although these motifs share a common GXG tripeptide they recognize ATP through different functional groups. The p-loop motif recognizes ATP through phosphates, class II aminoacyl-tRNA synthetase motif targets adenosine and the other three motifs recognize both phosphates and adenosine. We show that some motifs are shared by different enzyme types. Statistical tests demonstrate that the five sequence motifs are significantly associated with the nucleotide binding proteins. Large-scale test on PDB reveals that about 98% of proteins that include one of the structural motifs are confirmed to bind ATP. PMID- 25935119 TI - Study on the interaction of artificial and natural food colorants with human serum albumin: A computational point of view. AB - Due to the high amount of artificial food colorants present in infants' diets, their adverse effects have been of major concern among the literature. Artificial food colorants have been suggested to affect children's behavior, being hyperactivity the most common disorder. In this study we compare binding affinities of a group of artificial colorants (sunset yellow, quinoline yellow, carmoisine, allura red and tartrazine) and their natural industrial equivalents (carminic acid, curcumin, peonidin-3-glucoside, cyanidin-3-glucoside) to human serum albumin (HSA) by a docking approach and further refinement through atomistic molecular dynamics simulations. Due to the protein-ligand conformational interface complexity, we used collective variable driven molecular dynamics to refine docking predictions and to score them according to a hydrogen bond criterion. With this protocol, we were able to rank ligand affinities to HSA and to compare between the studied natural and artificial food additives. Our results show that the five artificial colorants studied bind better to HSA than their equivalent natural options, in terms of their H-bonding network, supporting the hypothesis of their potential risk to human health. PMID- 25935120 TI - Recombination between Streptococcus suis ICESsu32457 and Streptococcus agalactiae ICESa2603 yields a hybrid ICE transferable to Streptococcus pyogenes. AB - Integrative conjugative elements (ICEs) are mobile genetic elements that reside in the chromosome but retain the ability to undergo excision and to transfer by conjugation. Genes involved in drug resistance, virulence, or niche adaptation are often found among backbone genes as cargo DNA. We recently characterized in Streptococcus suis an ICE (ICESsu32457) carrying resistance genes [tet(O/W/32/O), tet(40), erm(B), aphA, and aadE] in the 15K unstable genetic element, which is flanked by two ~1.3kb direct repeats. Remarkably, ~1.3-kb sequences are conserved in ICESa2603 of Streptococcus agalactiae 2603V/R, which carry heavy metal resistance genes cadC/cadA and mer. In matings between S. suis 32457 (donor) and S. agalactiae 2603V/R (recipient), transconjugants were obtained. PCR experiments, PFGE, and sequence analysis of transconjugants demonstrated a tandem array between ICESsu32457 and ICESa2603. Matings between tandem array-containing S. agalactiae 2603V/R (donor) and Streptococcus pyogenes RF12 (recipient) yielded a single transconjugant containing a hybrid ICE, here named ICESa2603/ICESsu32457. The hybrid formed by recombination of the left ~1.3-kb sequence of ICESsu32457 and the ~1.3-kb sequence of ICESa2603. Interestingly, the hybrid ICE was transferable between S. pyogenes strains, thus demonstrating that it behaves as a conventional ICE. These findings suggest that both tandem arrays and hybrid ICEs may contribute to the evolution of antibiotic resistance in streptococci, creating novel mobile elements capable of disseminating new combinations of antibiotic resistance genes. PMID- 25935121 TI - The effect of dietary n-3/n-6 polyunsaturated fatty acid ratio on salmonid alphavirus subtype 1 (SAV-1) replication in tissues of experimentally infected rainbow trout (Oncorhynchus mykiss). AB - Salmon pancreas disease (SPD) is one of the most commercially significant viral diseases of farmed Atlantic salmon (Salmo salar) and rainbow trout (Oncorhynchus mykiss) in Europe. In this study, the potential for dietary mitigation of the disease using different polyunsaturated fatty acid (PUFA) profiles was assessed in rainbow trout. We experimentally infected fish with salmonid alphavirus subtype 1 (SAV-1), the causative agent of SPD. These fish were fed two diets with different n-3/n-6 PUFA ratio (high omega 3, 3.08, and high omega 6, 0.87). We assessed the influence of the diets on the fatty acid composition of the heart at 0 days post infection (d.p.i.) (after 4 weeks of feeding the experimental diets prior to SAV-1 infection), and sampled infected and control fish at 5, 15 and 30d.p.i. Viral E1 and E2 glycoprotein genes were quantified by two absolute real time PCRs in all the organs sampled, and significantly lower levels of the virus were evident in the organs of fish fed with high omega 6. Characteristic pathological lesions were identified in infected fish as early as 5d.p.i., with no significant differences in the pathology lesion scores between the two dietary regimes. This study shows that decreasing the n-3/n-6 PUFA ratio in experimental diets of rainbow trout changes the fatty acid content of the fish, and is associated with reduced SAV-1 replication in rainbow trout. PMID- 25935122 TI - Neutrophils exacerbate tuberculosis infection in genetically susceptible mice. AB - Mice of the I/St inbred strain genetically hyper-susceptible to TB infection and prone to form neutrophil-abundant necrotic lung lesions and relatively resistant mice of the C57BL/6 (B6) strain were infected with 100 CFU of M. tuberculosis H37Rv. To verify the role of neutrophils in TB immunity, we selectively depleted neutrophils from infected mice with highly specific 1A8 anti-Ly6G antibodies at day 2 and 6 post-challenge. Depletion of neutrophils resulted in reduced lung tissue pathology, mycobacterial CFU counts and an increase of the survival time in genetically susceptible I/St, but not in B6 mice. Furthermore, we demonstrated that in vivo neutrophil depletion at the onset of TB infection results in a significant increase in numbers of mycobacteria-specific IFN-gamma-producing T cells at the time point when the acquired immunity to mycobacteria is fully developed. These results suggest antagonistic activity of neutrophils and immune T-cells in the course of TB infection and provide further evidence of deleterious rather than protective role of the former. PMID- 25935123 TI - Estimated confidence interval from single blood pressure measurement based on algorithmic fusion. AB - BACKGROUND: Current oscillometric blood pressure measurement devices generally provide only single-point estimates for systolic and diastolic blood pressures and rarely provide confidence ranges for these estimates. A novel methodology to obtain confidence intervals (CIs) for systolic blood pressure (SBP) and diastolic blood pressure (DBP) estimates from a single oscillometric blood pressure measurement is presented. METHODS: The proposed methodology utilizes the multiple regression technique to fuse optimally a set of SBP and DBP estimates obtained through different algorithms. However, the set of SBP and DBP estimates is a small number to determine the CI of each individual subject. To address this issue, the weighted bootstrap approach based on the multiple regression technique was used to generate a pseudo sample set for the SBP and the DBP. In this paper, the multiple regression technique can estimate the best-fitting surface of an efficient function that relates the input sample set as an independent vector to the auscultatory nurse measurement as a dependent vector to estimate regression coefficients. Consequently, the coefficients are assigned to an eight-sample set obtained from the fusion of different algorithms as optimally weighted parameters. CIs are also estimated using the conventional methods on the set of fused SBP and DBP estimates for comparison purposes. RESULTS: The proposed method was applied to an experimental dataset of 85 patients. The results indicated that the proposed approach provides better blood pressure estimates than the existing algorithms and, in addition, is able to provide CIs for a single measurement. CONCLUSIONS: The CIs derived from the proposed scheme are much smaller than those calculated by conventional methods except for the pseudo maximum amplitude envelope algorithm for both the SBP and the DBP, probably because of the decrease in the standard deviation through the increase in the pseudo measurements using the weighted bootstrap method for each subject. The proposed methodology is likely the only one currently available that can provide CIs for single-sample blood pressure measurements. PMID- 25935124 TI - Understanding the effects of pre-processing on extracted signal features from gait accelerometry signals. AB - Gait accelerometry is an important approach for gait assessment. Previous contributions have adopted various pre-processing approaches for gait accelerometry signals, but none have thoroughly investigated the effects of such pre-processing operations on the obtained results. Therefore, this paper investigated the influence of pre-processing operations on signal features extracted from gait accelerometry signals. These signals were collected from 35 participants aged over 65years: 14 of them were healthy controls (HC), 10 had Parkinson's disease (PD) and 11 had peripheral neuropathy (PN). The participants walked on a treadmill at preferred speed. Signal features in time, frequency and time-frequency domains were computed for both raw and pre-processed signals. The pre-processing stage consisted of applying tilt correction and denoising operations to acquired signals. We first examined the effects of these operations separately, followed by the investigation of their joint effects. Several important observations were made based on the obtained results. First, the denoising operation alone had almost no effects in comparison to the trends observed in the raw data. Second, the tilt correction affected the reported results to a certain degree, which could lead to a better discrimination between groups. Third, the combination of the two pre-processing operations yielded similar trends as the tilt correction alone. These results indicated that while gait accelerometry is a valuable approach for the gait assessment, one has to carefully adopt any pre-processing steps as they alter the observed findings. PMID- 25935125 TI - Discrimination of retinal images containing bright lesions using sparse coded features and SVM. AB - Diabetic Retinopathy (DR) is a chronic progressive disease of the retinal microvasculature which is among the major causes of vision loss in the world. The diagnosis of DR is based on the detection of retinal lesions such as microaneurysms, exudates and drusen in retinal images acquired by a fundus camera. However, bright lesions such as exudates and drusen share similar appearances while being signs of different diseases. Therefore, discriminating between different types of lesions is of interest for improving screening performances. In this paper, we propose to use sparse coding techniques for retinal images classification. In particular, we are interested in discriminating between retinal images containing either exudates or drusen, and normal images free of lesions. Extensive experiments show that dictionary learning techniques can capture strong structures of retinal images and produce discriminant descriptors for classification. In particular, using a linear SVM with the obtained sparse coded features, the proposed method achieves superior performance as compared with the popular Bag-of-Visual-Word approach for image classification. Experiments with a dataset of 828 retinal images collected from various sources show that the proposed approach provides excellent discrimination results for normal, drusen and exudates images. It achieves a sensitivity and a specificity of 96.50% and 97.70% for the normal class; 99.10% and 100% for the drusen class; and 97.40% and 98.20% for the exudates class with a medium size dictionary of 100 atoms. PMID- 25935126 TI - Endometrial cancer: redefining the molecular-targeted approach. AB - Endometrial cancer (EC) is the most frequent gynecologic malignancy in the world. Metastatic and recurrent disease confers a worse prognosis, and the side effects of the current cytotoxic agents are the main cause of treatment disruption. Recently, the genetic alterations that facilitate the start, development and progression of EC have been elucidated, reclassifying the disease in distinct subtypes with different mechanisms of carcinogenesis. Targeted therapy aims to interfere specifically these mechanisms causing less toxicity, therefore opening new perspectives for a tailored treatment and improvement of response and survival rates for heavily treated recurrent disease. Treatment with hormone therapy was not addressed in this review because it is an extensively discussed issue and would divert the discussion about molecular-targeted therapy. The purpose of this paper was to review the available literature data regarding the main genetic abnormalities related to the carcinogenesis and evaluate the safety and efficacy of the molecular-targeted agents in the treatment of metastatic and recurrent EC. PMID- 25935127 TI - Technical note: Orbitozygomatic craniotomy using an ultrasonic osteotome for precise osteotomies. AB - BACKGROUND: The orbitozygomatic craniotomy is a fundamental procedure in neurosurgery, allowing access to orbital and skull base pathology. OBJECTIVE: Determine the feasibility of using an ultrasonic osteotome to safely perform orbitozygomatic osteotomies in patients with intracranial pathology. METHODS: The medical records of patients undergoing orbitozygomatic craniotomy using an ultrasonic osteotome (Aesculap BoneScalpelTM) for tumor resection at Johns Hopkins Hospital between November 2009 and March 2013 were retrospectively reviewed. RESULTS: Six patients underwent orbitozygomatic craniotomy for tumor resection using an ultrasonic osteotome at the Johns Hopkins Hospital during the study period. All patients were female and the average age was 53.2 years. Patients were followed for an average of 375 days. There were two cases of transient diplopia. There were no cases of periorbital violation, orbital injury, enophthalmos, or orbital hematoma. Post-operative imaging showed the cuts were well opposed and no cosmetic issues were encountered. CONCLUSION: Use of an ultrasonic osteotome allows for precise cuts under direct visualization with minimal risk to critical adjacent structures in our cohort of patients undergoing a two-piece orbitozygomatic craniotomy. This appears to be a safe instrument for osteotomy creation in skull base approaches. PMID- 25935128 TI - Comparison between anterior approaches and posterior approaches for the treatment of multilevel cervical spondylotic myelopathy: A meta-analysis. AB - OBJECTIVE: We aimed to compare the clinical outcomes of anterior approaches (anterior cervical corpectomy with fusion, cervical discectomy with fusion) and posterior approaches (laminectomy, laminoplasty) in multilevel cervical spondylotic myelopathy (MCSM) patients using a systematic meta-analysis. METHODS: PubMed, Embase, Scopus, and the Cochrane library were searched for literatures up to March 27, 2015 without language restriction. The reference lists of selected articles were also screened. Heterogeneity was identified using Q test and I(2) statistic. A fixed effect model was used for homogeneous data and a random effects model for heterogeneous data. Weighted mean difference (WMD) or odds ratio (OR) with 95% confidence intervals (CIs) were calculated. Subgroup analysis was conducted according to the cause of MCSM. RESULTS: Seventeen articles were selected. Higher post-Japanese Orthopedic Association (JOA, P=0.002) and shorter length of stay (P=0.004) were found in anterior approaches group compared with posterior approaches. Moreover, operation time was shorter (P<0.00001) and neurological recovery rate was higher (P=0.005) in ossification of posterior longitudinal ligament patients underwent posterior approaches. Complication rate of posterior approaches was lower in spinal stenosis subgroup (P<0.0001). CONCLUSIONS: MCSM patients performed anterior approaches showed superior post-JOA and shorten length of stay. However, the outcomes such as operation time and complication rate are associated with the cause of MCSM. Therefore, the favorable surgical strategy for MCSM still needs more studies. PMID- 25935129 TI - Detection of IgG anti-Domain I beta2 Glycoprotein I antibodies by chemiluminescence immunoassay in primary antiphospholipid syndrome. AB - BACKGROUND: IgG anti-Domain I (anti-DI) beta2 Glycoprotein I (beta2GPI) antibodies are associated to thrombotic risk in antiphospholipid syndrome (APS), but their detection is technically difficult. In this study, a chemiluminescent immunoassay (CLIA) was used to evaluate the clinical significance of IgG anti-DI in a large cohort of patients with primary APS (PAPS). METHODS: The study population included 88 patients with PAPS, 63 ELISA-negative subjects and 166 controls. IgG anti-DI, IgG anticardiolipin (aCL) and IgG anti-beta2GPI antibodies were assayed using CLIA (HemosIL AcuStar(r)). RESULTS: The sensitivity and specificity of IgG anti-DI antibodies were comparable to those of IgG aCL and IgG anti-beta2GPI antibodies. There was a significant agreement, association and titre correlation between IgG anti-DI and IgG aCL as well as IgG anti-beta2GPI antibodies (p<0.001 for all). IgG anti-DI antibody showed lesser prevalence and mean titres in the pregnancy morbidity than in thrombotic and PAPS patients with both involvements (p<0.001). Regarding the conventional aPL antibody profiles, the triple positivity group had higher prevalence and mean titres than single and double positivity ones (p<0.001). CONCLUSIONS: This study provides further evidence that anti-DI antibodies can be considered a promising biomarker for risk assessment particularly in patients having vascular thrombosis and triple conventional aPL positivity. PMID- 25935130 TI - Managing a research hospital at the time of a global economics crisis: Cruising between Scylla and Charybdis. PMID- 25935131 TI - Initiation of rivaroxaban in patients with nonvalvular atrial fibrillation at the primary care level: the Swiss Therapy in Atrial Fibrillation for the Regulation of Coagulation (STAR) Study. AB - BACKGROUND: Rivaroxaban has become an alternative to vitamin-K antagonists (VKA) for stroke prevention in non-valvular atrial fibrillation (AF) patients due to its favourable risk-benefit profile in the restrictive setting of a large randomized trial. However in the primary care setting, physician's motivation to begin with rivaroxaban, treatment satisfaction and the clinical event rate after the initiation of rivaroxaban are not known. METHODS: Prospective data collection by 115 primary care physicians in Switzerland on consecutive nonvalvular AF patients with newly established rivaroxaban anticoagulation with 3-month follow up. RESULTS: We enrolled 537 patients (73+/-11years, 57% men) with mean CHADS2 and HAS-BLED-scores of 2.2+/-1.3 and 2.4+/-1.1, respectively: 301(56%) were switched from VKA to rivaroxaban (STR-group) and 236(44%) were VKA-naive (VN group). Absence of routine coagulation monitoring (68%) and fixed-dose once-daily treatment (58%) were the most frequent criteria for physicians to initiate rivaroxaban. In the STR-group, patient's satisfaction increased from 3.6+/-1.4 under VKA to 5.5+/-0.8 points (P<0.001), and overall physician satisfaction from 3.9+/-1.3 to 5.4+/-0.9 points (P<0.001) at 3months of rivaroxaban therapy (score from 1 to 6 with higher scores indicating greater satisfaction). In the VN-group, both patient's (5.4+/-0.9) and physician's satisfaction (5.5+/-0.7) at follow-up were comparable to the STR-group. During follow-up, 1(0.19%; 95%CI, 0.01-1.03%) ischemic stroke, 2(0.37%; 95%CI, 0.05-1.34%) major non-fatal bleeding and 11(2.05%; 95%CI, 1.03-3.64%) minor bleeding complications occurred. Rivaroxaban was stopped in 30(5.6%) patients, with side effects being the most frequent reason. CONCLUSION: Initiation of rivaroxaban for patients with nonvalvular AF by primary care physicians was associated with a low clinical event rate and with high overall patient's and physician's satisfaction. PMID- 25935132 TI - Cast-treated distal radius fractures: a prospective cohort study of radiological outcomes and their association with impaired calcaneal bone mineral density. AB - INTRODUCTION: We hypothesized that treating distal radius fractures with cast only or closed reduction and cast is associated with high malunion risk and that the risk is higher in patients with low bone mineral density (BMD). MATERIALS AND METHODS: We prospectively studied 130 patients aged 40 years or older with distal radius fractures treated with cast only (87 patients) or closed reduction and cast (43 patients). Radiographs were obtained before treatment, after reduction (in the closed reduction group), and at 1 year. We measured calcaneal BMD with DXA scanner and calculated T scores. We calculated radiological changes from baseline (initial radiographs in cast only and post-reduction radiographs in closed reduction patients) to 1 year. We assessed the relationship between BMD status (normal, osteopenia or osteoporosis) and baseline-to-1-year worsening in volar tilt, ulnar variance, and radial inclination with analysis of covariance adjusting for baseline radiological values. We used receiver operating characteristic (ROC) analysis to determine the ability of T scores to distinguish patients with severe malunion (dorsal tilt >25 degrees and/or ulnar variance >=5 mm) from those with less severe or no malunion. RESULTS: In both treatment groups, baseline radiological variables had deteriorated at 1 year, more in the closed reduction group. Compared to patients with normal BMD, those with osteoporosis had significantly greater worsening in volar tilt and radial inclination but did not differ in ulnar variance worsening. Severe malunion was found in 34 fractures (26 %, 15 in cast only group); T scores had a modest ability in distinguishing severe malunion (area under ROC curve 0.67, 95 % CI 0.56-0.78, p = 0.003). CONCLUSIONS: Closed reduction and cast is not an effective treatment for distal radius fractures if radiological graphic outcomes are considered. There is a higher risk of malunion involving dorsal and radial tilt in patients with osteoporosis. Calcaneal BMD measurement may have some benefit in predicting the risk of severe malunion. PMID- 25935133 TI - Retraction Note to: Carpal tunnel syndrome in patients who are receiving long term renal hemodialysis. PMID- 25935134 TI - Ethanol and Isopropyl Alcohol Exposure Increases Biofilm Formation in Staphylococcus aureus and Staphylococcus epidermidis. AB - INTRODUCTION: Alcohols, including ethanol and isopropyl alcohol, are used in clinical practice for disinfection and infection prevention. Recent studies, however, demonstrate that alcohols may enhance biofilm production in Staphylococci. METHODS: We quantified biofilm formation in the presence of ethanol and isopropyl alcohol in six different, well-characterized strains of Staphylococcus epidermidis and Staphylococcus aureus. After 24 h of biofilm development, each strain was exposed to normal saline (NS), ethanol, or isopropyl alcohol (40%, 60%, 80% and 95%) for additional 24 h incubation. Adherent biofilms were stained and optical density was determined. Viability of strains was also determined after alcohol exposure. RESULTS: Ethanol increased biofilm formation in all six strains compared to normal saline (p < 0.05). There was increased biofilm formation with increasing ethanol concentration. Isopropyl alcohol also increased biofilm formation with increasing alcohol concentration in all six strains (p < 0.01 vs NS). The slime-negative, chemical mutant strain of S. epidermidis increased biofilm formation after exposure to both alcohols, likely reverting back its primary phenotype through modulation of the intercellular adhesin repressor. All strains demonstrated viability after exposure to each alcohol concentration, though viability was decreased. CONCLUSION: Ethanol and isopropyl alcohol exposure increases biofilm formation of S. aureus and S. epidermidis at concentrations used in clinical settings. Ethanol and isopropyl alcohol did not eradicate viable Staphylococci from formed biofilm. PMID- 25935135 TI - Implementation of a model of bodily fluids regulation. AB - The classic model of blood pressure regulation by Guyton et al. (Annu Rev Physiol 34:13-46, 1972a; Ann Biomed Eng 1:254-281, 1972b) set a new standard for quantitative exploration of physiological function and led to important new insights, some of which still remain the focus of debate, such as whether the kidney plays the primary role in the genesis of hypertension (Montani et al. in Exp Physiol 24:41-54, 2009a; Exp Physiol 94:382-388, 2009b; Osborn et al. in Exp Physiol 94:389-396, 2009a; Exp Physiol 94:388-389, 2009b). Key to the success of this model was the fact that the authors made the computer code (in FORTRAN) freely available and eventually provided a convivial user interface for exploration of model behavior on early microcomputers (Montani et al. in Int J Bio-med Comput 24:41-54, 1989). Ikeda et al. (Ann Biomed Eng 7:135-166, 1979) developed an offshoot of the Guyton model targeting especially the regulation of body fluids and acid-base balance; their model provides extended renal and respiratory functions and would be a good basis for further extensions. In the interest of providing a simple, useable version of Ikeda et al.'s model and to facilitate further such extensions, we present a practical implementation of the model of Ikeda et al. (Ann Biomed Eng 7:135-166, 1979), using the ODE solver Berkeley Madonna. PMID- 25935136 TI - LH (Trp8Arg/Ile15Thr), LHR (insLQ) and FSHR (Asn680Ser) polymorphisms genotypic prevalence in women with endometriosis and infertility. AB - PURPOSE: To verify if polymorphisms of LH (Trp8Arg/Ile15Thr), LH receptor (insLQ), and FSH receptor (Asn680Ser) are associated with endometriosis and infertility. METHODS: This is a prospective case-control study. Sixty-seven patients with endometriosis and infertility (study group) and 65 healthy fertile patients (control group) were enrolled in the study between July 2010 and July 2013. All patients had their endometriosis diagnosis made or excluded by laparoscopic surgery; study group was submitted to the surgery for infertility investigation and control group for tubal ligation. Day-3 serum hormones were collected from all patients. Analysis of nucleotide mutations for LH polymorphisms (Trp8Arg and Ile15Thr), LHR polymorphism (insLQ), and FSHR polymorphism (Asn680Ser) were performed by PCR. RESULTS: Day-3 FSH, estradiol and LH serum levels were not different between the groups, while CA-125 was higher in patients with endometriosis and infertility. All polymorphisms studied were in Hardy-Weinberg equilibrium. The prevalence of insLQ was significantly higher in patients with endometriosis and infertility (P = 0.005). Allele occurrence in control group was 0.10 versus 0.25 in infertile endometriosis group (P = 0.001). There was no difference regarding Trp8Arg/Ile15Thr (P > 0.05) and Asn680Ser (P > 0.05) prevalence between groups. CONCLUSION: This is the first time that prevalence of insLQ was shown to be higher in patients with endometriosis and infertility than in healthy fertile patients. There was no difference in LH and FSHR polymorphisms' prevalence between groups. PMID- 25935137 TI - Is ABO blood type associated with ovarian stimulation response in patients with diminished ovarian reserve? AB - PURPOSE: Recent studies have explored the relationship between ABO blood type and serum markers of ovarian reserve, specifically follicle-stimulating hormone (FSH) and anti-mullerian hormone (AMH). The primary objective of this study is to investigate whether there is an association between ABO blood type and ovarian stimulation response in patients with serum markers of diminished ovarian reserve (DOR). METHODS: This is a retrospective study of all patients undergoing controlled ovarian stimulation (COS) for in vitro fertilization (IVF) between May 2010 and July 2013. Patients were sub-grouped, a priori, based on serum AMH levels: <=1 ng/mL, <=0.5 ng/mL and <=0.16 ng/mL. Within each sub-group, demographic, baseline IVF characteristics and COS response parameters based on ABO blood types were compared. The number of mature oocytes retrieved was considered the primary outcome. Analysis of variance (ANOVA) and Chi-square tests were used to compare means and percentages between ABO blood types within groups. RESULTS: Complete data was available for 2575 patients. The mean (+/- SD) age and BMI of the study cohort was 38.9 (+/-3.97) years, 23.4 (+/-5.91) kg/m(2), respectively. The distribution of ABO blood types in the cohort was as follows: 36.8 % (A), 6.56 % (AB), 17.3 % (B), and 39.3 % (O). The demographics and baseline IVF characteristics were comparable among patients with blood types A, AB, B, and O within each AMH group. Within each AMH sub-group, no difference was found in the total days of COS, total gonadotropins administered, peak estradiol level, or number of mature oocytes retrieved based on blood type. CONCLUSIONS: Our results suggest no association between ABO blood type and ovarian stimulation response in patients with DOR. The predictive value of ABO blood type in determining ovarian stimulation response in such patients is currently limited. PMID- 25935138 TI - HSP70 inhibits stress-induced cardiomyocyte apoptosis by competitively binding to FAF1. AB - Stress-induced cardiomyocyte apoptosis plays an important role in the pathogenesis of a variety of cardiovascular diseases. Our early studies showed that HSP70 effectively inhibited apoptosis, but the underlying mechanism remained unclear. Fas-associated factor 1 (FAF1) is a member of the Fas death-inducing signaling complex (Fas-DISC) that acts upstream of caspase-8. We investigated the interactions among FAF1, HSP70, and FAS in stressed cardiomyocytes to elucidate the protective mechanism of HSP70. FAS and caspase-3/8 activity was higher in cardiomyocytes undergoing stress-induced apoptosis in restraint-stressed rats compared with cardiomyocytes in non-stressed rats, which indicated that the Fas signaling pathway was activated after restraint stress. Geranylgeranylacetone (GGA) induced an increase in HSP70 expression, which reduced stress-induced apoptosis. Additionally, overexpression of HSP70 via transfection with the pEGFP rHSP70 plasmid attenuated norepinephrine (NE)-induced apoptosis. FAF1 expression increased during stress-induced apoptosis, and overexpression of FAF1 exacerbated NE-induced apoptosis. We also found that HSP70 interacted with FAF1. Overexpression of HSP70 inhibited the binding of FAF1 to FAS in H9C2 cells, which indicated that HSP70 suppressed NE-induced apoptosis by competitively binding to FAF1. An N-terminal deletion mutant of HSP70 (HSP70-?N) was unable to interact with FAF1. After HSP70-?N was transfected into H9C2 cells, the cells were unable to attenuate the NE-induced increases in caspase-8 and apoptosis. These results indicate that the 1-120 sequence of HSP70 binds to FAF1, which alters the interactions between FAS and FAF1 and inhibits the activation of the Fas signaling pathway and apoptosis. PMID- 25935139 TI - An evaluation of Tamm-Horsfall protein glycans in kidney stone formers using novel techniques. AB - Tamm-Horsfall protein (THP) is theorized to play a critical role in preventing kidney stone formation. There is conflicting literature on THP analysis in kidney stone patients; therefore, this study was conducted using sensitive and specific bio-analytical techniques to better understand differences in THP, which play a potential role in nephrolithiasis pathogenesis. THP was isolated from urine samples of 34 male and 19 female kidney stone patients and 30 male and 24 female control subjects using diatomaceous earth. Protein was quantified by Superdex-200 size-exclusion chromatography. Sialic acid was determined by 1,2-diamino-4,5 methylenedioxybenzene high-performance liquid chromatography. Neutral and amino sugars were determined by high pH anion-exchange chromatography (HPAEC) with pulsed amperometric detection. THP N-glycans were derivatized with 2 aminobenzamide (2-AB) and profiled by HPAEC with fluorescence detection. N-glycan structures were confirmed by matrix-assisted laser desorption/ionization time-of flight mass spectrometry (MALDI-TOF MS). Results indicate that kidney stone patients had 32% lower protein content compared to controls, while sialic acid content was lower by 29 and 24% in male and female kidney stone patients, respectively, compared to controls. The neutral and amino sugars were also lower by 18 and 20% for male and female kidney stone patients, respectively, compared to controls. All results were statistically significant (p<0.001). These results are supported by 2-AB profiling of THP N-glycans and by MALDI-TOF MS of highly sialylated N-glycans in the range of m/z 3000-6000. This study demonstrates quantitative and qualitative differences in THP, which can be crucial contributing factors for nephrolithiasis. PMID- 25935140 TI - Effects of tannin-rich host plants on the infection and establishment of the entomopathogenic nematode Heterorhabditis bacteriophora. AB - Parasitized animals can self-medicate. As ingested plant phenolics, mainly tannins, reduce strongyle nematode infections in mammalian herbivores. We investigated the effect of plant extracts known to be anthelmintic in vertebrate herbivores on the recovery of the parasitic entomopathogenic nematode Heterorhabditis bacteriophora infecting African cotton leafworm (Spodoptera littoralis). Nematode infective juveniles (IJs) were exposed to 0, 300, 900, 1200, 2400 ppm of Pistacia lentiscus L. (lentisk), Inula viscosa L. (strong smelling inula), Quercus calliprinos Decne. (common oak) and Ceratonia siliqua L. (carob) extracts on growth medium (in vitro assay). In control treatments, 50-80% of IJs resumed development to J4, young and developed adult hermaphrodites, whereas all extracts, except for C. siliqua at 300 ppm, impaired IJ exsheathment and development. The highest concentration of I. viscosa extract (2400 ppm) had the strongest effect, killing 95% of exposed nematodes. Surviving nematodes did not recover, remaining at the IJ stage. Over the whole cycle, I. viscosa extract inhibited recovery to 25% or less, and did not allow full development to adulthood, whereas 65% of IJs in the control treatment recovered and resumed development, 12% reaching complete maturation within 72 h of incubation. When herbivorous S. littoralis larvae were fed with different plant extracts in vivo, I. viscosa had the strongest effect at concentrations above 300 ppm, with 90% of insect-invading IJs not developing to parasitic stages, whereas in the control treatment, 85% of IJs resumed development. Exposure to C. siliqua extract also inhibited exsheathment and development of 75% of the IJs. Half of those that resumed development reached full maturation. P. lentiscus and Q. calliprinos extracts also inhibited development of 50% IJs. Our results suggest that H. bacteriophora can be used to study herbal medication against parasites in animals. PMID- 25935141 TI - Big data is essential for further development of integrative medicine. AB - To give a short summary on achievements, opportunities and challenges of big data in integrative medicine (IM) and explore the future works on breaking the bottleneck to make IM develop rapidly, this paper presents the growing field of big data from IM, describes the systems of data collection and the techniques of data analytics, introduces the advances, and discusses the future works especially the challenges in this field. Big data is increasing dramatically as the time flies, whatever we face it or not. Big data is evolving into a promising way for deep insight IM, the ancient medicine integrating with modern medicine. We have great achievements in data collection and data analysis, where existing results show it is possible to discover the knowledge and rules behind the clinical records. Transferring from experience-based medicine to evidence-based medicine, IM depends on the big data technology in this great era. PMID- 25935142 TI - Relationships between pathological patterns and vocal qualities estimated by acoustic parameters. AB - OBJECTIVE: To examine whether vocal characteristics estimated by acoustic parameters were associated with phlegm, yin deficiency, or cold-heat patterns. METHODS: A total of 75 college students (males:females = 53:22) aged 19-24 years were enrolled in this study. Each subject was asked to complete the phlegm pattern questionnaire (PPQ), yin deficiency questionnaire (YDQ) and cold-heat questionnaire (CHQ). For the acoustic analysis, each subject was asked to produce a sustained vowel sound (/a/) for 3 s to be used to calculate acoustic parameters. Then, habitual fundamental frequency (F0), jitter, shimmer, F0tremor, mean F0, standard deviation of F0, maximum F0, minimum F0, normalized noise energy, harmonic-to-noise ratio, signal-to-noise ratio, amplitude tremor, and power ratio were calculated using the Dr. Speech software. Finally, four hierarchical regression models with pattern questionnaire scores as dependent variables were formed to examine which factors among acoustic parameters, sex, and age were predictive of those pattern scores. RESULTS: PPQ, YDQ, heat, and cold pattern scores all formed significant regression model equations and the adjusted R2 values were 0.281, 0.164, 0.156, and 0.170, respectively. There were aging effects in the PPQ and YDQ models (standardized beta=0.199, 0.271, respectively). Vocal tremor-related F0 tremor and vocal ringing-related power ratio parameters were associated with PPQ and YDQ scores. Gender was directly predictive of PPQ and indirectly moderated the relationship between power ratio and YDQ score. Vocal pitch-related habitual F0 and mean F0 were associated with heat and cold scores. These results indicate that the vocal qualities of phlegm- and yin deficiency-susceptible subjects tend to be ringing and less tremorous, and those of heat- and cold-susceptible subjects tend to be high-pitched. CONCLUSION: Our study results suggest that vocal characteristics estimated by acoustic parameters are partially predictive of phlegm, yin deficiency, heat, and cold patterns. In terms of phlegm and yin deficiency patterns, there were direct or moderating effects of sex and age. PMID- 25935143 TI - Pulse signal analysis of patients with coronary heart diseases using Hilbert Huang transformation and time-domain method. AB - OBJECTIVE: To explore characteristic of pulse signal to distinguish patients with coronary heart diseases (CHD) from patients without CHD and healthy adults, and accordingly evaluate the potential role of pulse signal to diagnosis CHD. METHODS: Totally 407 patients enrolled from 4 collaborating medical centers were assigned to a CHD group (205 patients) and a non-CHD group (202 patients). The healthy control group (62 adults) enrolled from Shanghai University of Traditional Chinese Medicine. Pulse signals were collected using the synchronous multiplex pulse signal acquisition system. The pulse signals were analyzed and extracted using Hilbert-Huang transformation (HHT) and time-domain, respectively. The time-domain parameters of pulse signal were processed by the analysis of variance (SNK test). RESULTS: Special patterns in the CHD group pulse signal were found in this study: (1) time-domain parameters of pulse signal, h1, h3, h4, h3/h1, ts, t4/t were increased and w was wider; (2) 44% of C2 waves in HHT were chaotic and disordered and 72% of C waves were exhibited irregularly with average amplitude over 10 g-forces, which were all significantly different from controls. CONCLUSION: Characteristic wave and time-domain parameters of pulse signal were extracted using HHT and time-domain which could be served as a non-invasive approach for assessing patients with CHD. PMID- 25935144 TI - Review and analysis on the meridian research of China over the past sixty years. AB - The meridian research situation and various meridian hypotheses of China in the past sixty years between 1950 and 2013 are summarized in the paper; possible existed problems in the process of current meridian research are analyzed. Based on previous research results, we proposed that the essence of meridian can not be explained by the reductive analysis method, meridian research should be carried out under the guidance of overall concept of Chinese medicine theory. In this paper, combined with coherence theory of biophoton, we put forward the quantum interference hypothesis of meridian, which provides a possible research idea for meridian study. PMID- 25935145 TI - Continuous wound infusion of ropivacaine for the control of pain after thoracolumbar spinal surgery: a randomized clinical trial. AB - PURPOSE: A prospective randomized clinical trial was carried out to observe the analgesic efficacy of ropivacaine for postoperative pain following thoracolumbar spinal surgery. METHODS: Seventy-one patients with elective posterior thoracolumbar spinal surgery were randomly divided into two groups. Local group received 0.33 % ropivacaine by pump through the wound, and intravenous group received flurbiprofen axetil, pentazocine and palonosetron via intravenous pump. We evaluated the level of pain, the incidence of adverse reactions at 2, 4, 6, 12, 24, 36 and 48 h after operation, and the occurrence of chronic pain 3 months later. RESULTS: There were no significant differences in the pain level between the two groups. However, the incidence of nausea, vomiting and chronic pain was significantly lower in the local group. CONCLUSIONS: Our results showed that local infusion of ropivacaine achieved similar analgesic effects to intravenous delivery of analgesic drugs, but significantly reduced incidence of nausea, vomiting and chronic pain. PMID- 25935146 TI - F-18 FDG PET/CT findings of metastatic ovarian tumors from gastrointestinal tract origin. AB - PURPOSE: To review the F-18 FDG PET/CT findings of metastatic ovarian tumors and to determine any correlation between FDG uptake by metastatic ovarian tumors and that by the primary tumors. METHODS: PET/CT performed from June 2005 to March 2011 on patients with metastatic ovarian tumors of gastrointestinal tract origin malignancies was analyzed retrospectively. The SUV(max) of metastatic ovarian tumors and primary tumors, when available, was measured. RESULTS: Thirty-two patients were included. Of the 32 cases, 20 had metastatic tumors in bilateral ovaries and 12 had in a single ovary. The mean SUV(max) of the 52 total lesions was 4.1 +/- 3.1 (range 1.2-13.3), and 46 lesions showed a heterogeneous FDG uptake pattern. In 22 cases with available primary tumor SUV(max) values, there was a moderate positive correlation with the SUV(max) of the corresponding metastatic tumors (r = 0.559, p = 0.007). There was no significant correlation between the size and SUV(max) of metastatic ovarian tumors (p = 0.128). The mean SUV(max) of metastatic ovarian tumors from colorectal cancers was significantly higher than that of stomach cancers (p = 0.039). CONCLUSIONS: Metastatic ovarian tumors showed FDG uptake of variable intensity, depending on the primary tumor type. The FDG uptake pattern was heterogeneous by PET imaging in vast majority of the cases. When the primary tumor demonstrates a low FDG uptake, careful evaluation is necessary since the metastatic ovarian tumors may also show low FDG uptake. PMID- 25935147 TI - Readability of Online Patient Education Materials Related to IR. AB - PURPOSE: To assess the readability of online patient education materials (OPEM) related to common diseases treated by and procedures performed by interventional radiology (IR). MATERIALS AND METHODS: The following websites were chosen based on their average Google search return for each IR OPEM content area examined in this study: Society of Interventional Radiology (SIR), Cardiovascular and Interventional Radiological Society of Europe (CIRSE), National Library of Medicine, RadiologyInfo, Mayo Clinic, WebMD, and Wikipedia. IR OPEM content area was assessed for the following: peripheral arterial disease, central venous catheter, varicocele, uterine artery embolization, vertebroplasty, transjugular intrahepatic portosystemic shunt, and deep vein thrombosis. The following algorithms were used to estimate and compare readability levels: Flesch-Kincaid Grade Formula, Flesch Reading Ease Score, Gunning Frequency of Gobbledygook, Simple Measure of Gobbledygook, and Coleman-Liau Index. Data were analyzed using general mixed modeling. RESULTS: On average, online sources that required beyond high school grade-level readability were Wikipedia (15.0), SIR (14.2), and RadiologyInfo (12.4); sources that required high school grade-level readability were CIRSE (11.3), Mayo Clinic (11.0), WebMD (10.6), and National Library of Medicine (9.0). On average, OPEM on uterine artery embolization, vertebroplasty, varicocele, and peripheral arterial disease required the highest level of readability (12.5, 12.3, 12.3, and 12.2, respectively). CONCLUSIONS: The IR OPEM assessed in this study were written above the recommended sixth-grade reading level and the health literacy level of the average American adult. Many patients in the general public may not have the ability to read and understand health information in IR OPEM. PMID- 25935148 TI - Alcohol Ablation in Hypertrophic Cardiomyopathy: Localization and Quantification of Target Septal Artery-dependent Myocardium With 3-Dimensional Echocardiography. PMID- 25935151 TI - Prevention of sexually transmitted infections using mobile devices and ubiquitous computing. AB - BACKGROUND: Advances in the development of information and communication technologies have facilitated social interrelationships, but also sexual contacts without appropriate preventive measures. In this paper, we will focus on situations in which people use applications to meet sexual partners nearby, which could increase their chance of exposure to sexually transmitted infections (STI). How can we encourage users to adopt preventive measures without violating their privacy or infringing on the character of the application? METHODS: To achieve the goal of preventing STI, we have used the design and creation methodology and have developed a prototype software package. This prototype follows the RESTful services principles and has two parts: an Android OS application with emphasis on ubiquitous computing and designed according to General Responsibility Assignment Software Patterns (GRASP), and a server with a web page. To choose the preventive messages, we performed a test in 17 men who have sex with men (MSM). RESULTS: Our software sends preventive notifications to users when it detects situations such as the activation of particular applications on their smartphones, or their proximity to areas with a high probability of intercourse (hot zones). The underlying idea is the same as that for warning messages on cigarette packets, since users read the message just when they are going to smoke. The messages used have been selected from a list that has been rated by the users themselves. The most popular message is "Enjoy sex and enjoy life. Do not expose yourself to HIV". The user is unaware of the software, which runs in the background. CONCLUSIONS: Ubiquitous computing may be useful for alerting users with preventive and educational messages. The proposed application is non-intrusive because: 1) the users themselves decide to install it and, therefore, users' privacy rights are preserved; 2) it sends a message that helps users think about taking appropriate preventive measures; and 3) it works in the background without interfering with users unless a trigger situation is detected. Thus, this type of application could become an important tool in the complex task of STI prevention. PMID- 25935149 TI - Bone microenvironment signals in osteosarcoma development. AB - The bone is a complex connective tissue composed of many different cell types such as osteoblasts, osteoclasts, chondrocytes, mesenchymal stem/progenitor cells, hematopoietic cells and endothelial cells, among others. The interaction between them is finely balanced through the processes of bone formation and bone remodeling, which regulates the production and biological activity of many soluble factors and extracellular matrix components needed to maintain the bone homeostasis in terms of cell proliferation, differentiation and apoptosis. Osteosarcoma (OS) emerges in this complex environment as a result of poorly defined oncogenic events arising in osteogenic lineage precursors. Increasing evidence supports that similar to normal development, the bone microenvironment (BME) underlies OS initiation and progression. Here, we recapitulate the physiological processes that regulate bone homeostasis and review the current knowledge about how OS cells and BME communicate and interact, describing how these interactions affect OS cell growth, metastasis, cancer stem cell fate and therapy outcome. PMID- 25935150 TI - Amyloid beta peptide-induced inhibition of endothelial nitric oxide production involves oxidative stress-mediated constitutive eNOS/HSP90 interaction and disruption of agonist-mediated Akt activation. AB - BACKGROUND: Amyloid beta (Abeta)-induced vascular dysfunction significantly contributes to the pathogenesis of Alzheimer's disease (AD). Abeta is known to impair endothelial nitric oxide synthase (eNOS) activity, thus inhibiting endothelial nitric oxide production (NO). METHOD: In this study, we investigated Abeta-effects on heat shock protein 90 (HSP90) interaction with eNOS and Akt in cultured vascular endothelial cells and also explored the role of oxidative stress in this process. RESULTS: Treatments of endothelial cells (EC) with Abeta promoted the constitutive association of HSP90 with eNOS but abrogated agonist (vascular endothelial growth factor (VEGF))-mediated HSP90 interaction with Akt. This effect resulted in blockade of agonist-mediated phosphorylation of Akt and eNOS at serine 1179. Furthermore, Abeta stimulated the production of reactive oxygen species in endothelial cells and concomitant treatments of the cells with the antioxidant N-acetyl-cysteine (NAC) prevented Abeta effects in promoting HSP90/eNOS interaction and rescued agonist-mediated Akt and eNOS phosphorylation. CONCLUSIONS: The obtained data support the hypothesis that oxidative damage caused by Abeta results in altered interaction of HSP90 with Akt and eNOS, therefore promoting vascular dysfunction. This mechanism, by contributing to Abeta-mediated blockade of nitric oxide production, may significantly contribute to the cognitive impairment seen in AD patients. PMID- 25935152 TI - A comparison between a hinged plate and screw system and a conventional tension band plate and screw system used for correction of an angular deformity of the lower limb: an animal study. AB - BACKGROUND: The purpose of the animal study is to introduce a newly designed hinged plate and screw system for correction of angular deformities of the lower limbs. The technique was compared with the use of a conventional tension-band plate and screw system. METHODS: This is a randomized controlled animal trial. Eight 3-month-old Bama miniature pigs were used to establish animal models. In each animal, one leg was randomly allocated into study group and another leg into control group. Legs of the study group were corrected with a hinged plate and screw system, and legs of the control group were corrected with a conventional tension-band plate and screw system. The corrective rates of medial slope angle, medial proximal tibial angle, and angle of the two arms of the hinged plate were measured. Residual stress on the implants was also evaluated. A P < 0.05 was statistical significant. RESULTS: At the final measurements of 18 weeks, the mean corrective rates of medial slope angle, medial proximal tibial angle, and angle of the two arms of the study group were 0.71 degrees /week, 0.85 degrees /week, and 2.18 degrees /week, respectively; the data in the control group were 0.84 degrees /week, 0.89 degrees /week, and 2.13 degrees /week, respectively. No significant difference was found between the groups regarding the mean corrective rates of the angles (P < 0.05). The mean residual stress in the study group was 643.35 MPa, and measurement in the control group was 1,273.63 MPa, with a significant difference (P < 0.05). CONCLUSIONS: Compared to the conventional tension-band plate and screw system, the hinged plate and screw system may be more reliable for correction of angular deformities of the lower limb. PMID- 25935155 TI - Spider surgical system versus multiport laparoscopic surgery: performance comparison on a surgical simulator. AB - BACKGROUND: The rising interest towards minimally invasive surgery has led to the introduction of laparo-endoscopic single site (LESS) surgery as the natural evolution of conventional multiport laparoscopy. However, this new surgical approach is hampered with peculiar technical difficulties. The SPIDER surgical system has been developed in the attempt to overcome some of these challenges. Our study aimed to compare standard laparoscopy and SPIDER technical performance on a surgical simulator, using standardized tasks from the Fundamentals of Laparoscopic Surgery (FLS). METHODS: Twenty participants were divided into two groups based on their surgical laparoscopic experience: 10 PGY1 residents were included in the inexperienced group and 10 laparoscopists in the experienced group. Participants performed the FLS pegboard transfers task and pattern cutting task on a laparoscopic box trainer. Objective task scores and subjective questionnaire rating scales were used to compare conventional laparoscopy and SPIDER surgical system. RESULTS: Both groups performed significantly better in the FLS scores on the standard laparoscopic simulator compared to the SPIDER. Inexperienced group: Task 1 scores (median 252.5 vs. 228.5; p = 0.007); Task 2 scores (median 270.5 vs. 219.0; p = 0.005). Experienced group: Task 1 scores (median 411.5 vs. 309.5; p = 0.005); Task 2 scores (median 418.0 vs. 331.5; p = 0.007). Same aspects were highlighted for the subjective evaluations, except for the inexperienced surgeons who found both devices equivalent in terms of ease of use only in the peg transfer task. CONCLUSIONS: Even though the SPIDER is an innovative and promising device, our study proved that it is more challenging than conventional laparoscopy in a population with different degrees of surgical experience. We presume that a possible way to overcome such challenges could be the development of tailored training programs through simulation methods. This may represent an effective way to deliver training, achieve mastery and skills and prepare surgeons for their future clinical experience. PMID- 25935154 TI - Factors associated with knowledge of hypertension among adolescents: implications for preventive education programs in primary care. AB - BACKGROUND: Hypertension (HT) amongst adolescents remains a vital issue of both a medical and social nature. There is a lack of data regarding the factors influencing the awareness of the disease among the youth. The aim of this study was to evaluate the knowledge about HT among adolescents and its level corresponding to the selected demographic, environmental and medical factors. METHODS: The study was carried out among 250 adolescents of secondary schools. The authors' questionnaire poll and the psychological tests Personal Values List (PVL) and Personal Competence Scale (PCS) were performed. RESULTS: Only 13.2% of the youth surveyed displayed the "medium" level (defined below) of HT knowledge. Most of them present satisfactory knowledge about the causes of HT. The children from urban areas generally displayed better knowledge about HT than their peers from rural regions. Only the children who had had their blood pressure previously examined displayed good knowledge about HT. The most frequently indicated source of this knowledge was school; however, its level still remains low. There was no significant association between the level of global knowledge about HT and the feeling of one's own competences and considering the category "good health" an important personal value. CONCLUSIONS: Knowledge about HT among adolescents remains unsatisfactory and random, which indicates the necessity for routine education in this field, especially as it applies to HT symptoms. It seems that the consideration of such elements as blood pressure measurement and family history of HT in education programs can improve their efficiency. PMID- 25935156 TI - Determinants of the low uptake of HIV-related intervention services by female sex workers in Shenzhen, China: an observational study (2009-2012). AB - Background Female sex workers (FSWs) are highly vulnerable to HIV but make little use of HIV-related intervention services provided by the Chinese government. Determinants of the low uptake of HIV services by FSWs in Shenzhen, Guangdong province were investigated. METHODS: FSWs were recruited by venue-based sampling; 1656 FSWs were interviewed about sociodemographics, behaviours and uptake of HIV related intervention services. Determinants of no uptake of HIV testing, condom promotion, and peer education were determined through logistic regression. The association between uptake of HIV-related services, condom use and HIV-related knowledge was also assessed. RESULTS: The overall uptake of HIV testing, condom promotion, and peer education by FSWs was 21.5%, 47.8% and 28.0%, respectively. Young age and shorter duration of working in Shenzhen were statistically significantly correlated with no uptake of all three interventions. Uptake of these services was positively associated with consistent condom use and good HIV related knowledge. CONCLUSIONS: The uptake of HIV-related intervention services by FSWs is low in Shenzhen. As their uptake is positively associated with condom use and HIV-related knowledge, it is necessary to intensify promotion of these, focusing on young and recently started FSWs. PMID- 25935153 TI - M-CSF in a new biomarker panel with HE4 and CA 125 in the diagnostics of epithelial ovarian cancer patients. AB - BACKGROUND: We investigated plasma levels of M-CSF and conventional tumor markers (HE4 and CA 125) in epithelial ovarian cancer patients as compared to control groups: benign ovarian tumor patients (cysts) and healthy subjects. METHODS: M CSF levels were determined by ELISA, HE4 and CA 125 levels - by CMIA method. RESULTS: Our results have demonstrated significant differences in the concentration levels of M-CSF, CA 125 and HE4 between the groups of ovarian cancer patients, cysts patients and the healthy controls. In the groups tested M CSF demonstrated equal to or higher values than both CA 125 and HE4 in diagnostic sensitivity (SE), positive and negative predictive values (PPV, NPV), and in the area under the ROC curve (AUC), particularly in the group with the serous epithelial sub-type of OC. Moreover, CA 125 showed better results of the aforementioned diagnostic criteria than HE4. The combined use of the parameters studied resulted in a further, significant increase in the value of the diagnostic indicators and in the value of the diagnostic power (AUC), especially in the early stages of ovarian cancer. CONCLUSIONS: These findings suggest a high usefulness of M-CSF in diagnosing the serous sub-type of epithelial ovarian cancer and in discriminating between cancer and non-carcinoma lesions, particularly in new diagnostic panels in combination with CA 125 and HE4 for the detection of EOC in the early stages. PMID- 25935157 TI - The Impact of Social Work Intervention in Alcohol-Induced Pancreatitis in Ireland: a Single-Center Experience. AB - AIM: To evaluate the effect on recurrent admission for alcohol-induced pancreatitis (that can be up to 48%) of a brief social work intervention for alcohol dependence in a single center in Ireland METHODS: Retrospective cohort study of patients admitted with acute alcohol-induced pancreatitis to a tertiary hospital in Ireland from January 2009 to December 2012. RESULTS: The relapse rate in the cohort of 160 patients with alcohol-induced pancreatitis was 28.1%. There was no difference in the relapse rate of those patients who received a social work intervention compared with those who did not (ANOVA, P = 0.229). The employment status was a significant risk factor for relapse (ANOVA, P = 0.027), but did not differ between those who did, and did not, receive the intervention. CONCLUSION: Although the cohort size did not allow great statistical power, it appears that our hospital's current social work intervention for alcohol-induced pancreatitis is ineffective in preventing relapse. Long-term prospective studies are required to formulate and better implement more efficacious interventions for such patients. PMID- 25935158 TI - HPLC-MS-MS Method Development and Validation of Antileishmanial Agent, S010-0269, in Hamster Serum. AB - A rapid, sensitive and simple high-performance liquid chromatography-tandem mass spectrometry method was developed and validated for the quantification of the antileishmanial agent, S010-0269, in hamster serum. A Discovery HS C-18 column (5 MUm, 50 * 4.6 mm) maintained at 40 degrees C was utilized for chromatographic separation with mobile phase [acetonitrile: aqueous ammonium acetate (0.01 M) buffer (85:15, v/v)] at a flow rate of 0.6 mL/min. The method requires low serum volume (20 uL) with a run time of 3.5 min. Excellent linear relationships (r >= 0.99) were obtained between the measured and added concentration over a range of 1-200 ng/mL. Validation parameters (accuracy, specificity, precision, recovery, matrix effect and stability) were assessed as per FDA guidelines. The precision and accuracy were acceptable as indicated by relative standard deviation ranging from 2.3 to 13.6% and bias values ranging from 1.5 to 6.5%, respectively. Moreover, the compound was found stable in hamster serum even after 30 days of storage at -80 degrees C and being subjected to two freeze-thaw cycles. The validated method was successfully applied to the pharmacokinetic study after 10 mg/kg oral dose of S010-0269 in hamsters. PMID- 25935159 TI - Direct Injection LC-MS-MS Analysis of Opiates, Methamphetamine, Buprenorphine, Methadone and Their Metabolites in Oral Fluid from Substitution Therapy Patients. AB - A rapid and sensitive liquid chromatography-tandem mass spectrometry (LC-MS-MS) method was developed, validated and applied to simultaneous analysis of oral fluid samples for the following 10 analytes: methadone, 2-ethylidene-1,5-dimethyl 3,3-diphenylpyrrolidine (EDDP), buprenorphine, norbuprenorphine, morphine, codeine, 6-acetylmorphine, 6-acetylcodeine, amphetamine, and methamphetamine. The oral fluid sample was briefly centrifuged and the supernatant was directly injected into the LC-MS-MS system operated under reverse-phase chromatography and electrospray ionization (ESI). Deuterated analogs of the analytes were adopted as the internal standards and found to be effective (except for buprenorphine) to compensate for potential matrix effects. Each analytical run took <10 min. Linearity range (r(2) > 0.99) established for buprenorphine and the other nine analytes were 5-100 and 1-100 ng/mL. Intra- and interday precision (% CV) ranges for the 10 analytes were 0.87-12.2% and 1.27-12.8%, while the corresponding accuracy (%) ranges were 91.8-113% and 91.9-111%. Limits of detection and quantitation established for these 10 analytes were in the ranges of 0.1-1.0 and 0.25-1.0 ng/mL (5 ng/mL for buprenorphine). The method was successfully applied to the analysis of 62 oral fluid specimens collected from patients participating in methadone and buprenorphine substitution therapy programs. Analytical results of methadone and buprenorphine were compared with data derived from GC-MS analysis and found to be compatible. Overall, the direct injection LC-MS-MS method performed well, permitting rapid analysis of oral fluid samples for simultaneous quantification of methadone, buprenorphine, opiate and amphetamine drug categories without extensive sample preparation steps. PMID- 25935160 TI - Whole-genome sequencing identifies a homozygous deletion encompassing exons 17 to 23 of the integrin beta 4 gene in a Charolais calf with junctional epidermolysis bullosa. AB - BACKGROUND: Since 2010, four Charolais calves with a congenital mechanobullous skin disorder that were born in the same herd from consanguineous matings were reported to us. Clinical and histopathological examination revealed lesions that are compatible with junctional epidermolysis bullosa (JEB). RESULTS: Fifty-four extended regions of homozygosity (>1 Mb) were identified after analysing the whole-genome sequencing (WGS) data from the only case available for DNA sampling at the beginning of the study. Filtering of variants located in these regions for (i) homozygous polymorphisms observed in the WGS data from eight healthy Charolais animals and (ii) homozygous or heterozygous polymorphisms found in the genomes of 234 animals from different breeds did not reveal any deleterious candidate SNPs (single nucleotide polymorphisms) or small indels. Subsequent screening for structural variants in candidate genes located in the same regions identified a homozygous deletion that includes exons 17 to 23 of the integrin beta 4 (ITGB4), a gene that was previously associated with the same defect in humans. Genotyping of a second case and of six parents of affected calves (two sires and four dams) revealed a perfect association between this mutation and the assumed genotypes of the individuals. Mining of Illumina BovineSNP50 Beadchip genotyping data from 6870 Charolais cattle detected only 44 heterozygous animals for a 5.6-Mb haplotype around ITGB4 that was shared with the carriers of the mutation. Interestingly, none of the 16 animals genotyped for the deletion carried the mutation, which suggests a rather recent origin for the mutation. CONCLUSIONS: In conclusion, we successfully identified the causative mutation for a very rare autosomal recessive mutation with only one case by exploiting the most recent DNA sequencing technologies. PMID- 25935161 TI - A comprehensive comparative review of sequence-based predictors of DNA- and RNA binding residues. AB - Motivated by the pressing need to characterize protein-DNA and protein-RNA interactions on large scale, we review a comprehensive set of 30 computational methods for high-throughput prediction of RNA- or DNA-binding residues from protein sequences. We summarize these predictors from several significant perspectives including their design, outputs and availability. We perform empirical assessment of methods that offer web servers using a new benchmark data set characterized by a more complete annotation that includes binding residues transferred from the same or similar proteins. We show that predictors of DNA binding (RNA-binding) residues offer relatively strong predictive performance but they are unable to properly separate DNA- from RNA-binding residues. We design and empirically assess several types of consensuses and demonstrate that machine learning (ML)-based approaches provide improved predictive performance when compared with the individual predictors of DNA-binding residues or RNA-binding residues. We also formulate and execute first-of-its-kind study that targets combined prediction of DNA- and RNA-binding residues. We design and test three types of consensuses for this prediction and conclude that this novel approach that relies on ML design provides better predictive quality than individual predictors when tested on prediction of DNA- and RNA-binding residues individually. It also substantially improves discrimination between these two types of nucleic acids. Our results suggest that development of a new generation of predictors would benefit from using training data sets that combine both RNA- and DNA-binding proteins, designing new inputs that specifically target either DNA- or RNA-binding residues and pursuing combined prediction of DNA- and RNA binding residues. PMID- 25935162 TI - Community challenges in biomedical text mining over 10 years: success, failure and the future. AB - One effective way to improve the state of the art is through competitions. Following the success of the Critical Assessment of protein Structure Prediction (CASP) in bioinformatics research, a number of challenge evaluations have been organized by the text-mining research community to assess and advance natural language processing (NLP) research for biomedicine. In this article, we review the different community challenge evaluations held from 2002 to 2014 and their respective tasks. Furthermore, we examine these challenge tasks through their targeted problems in NLP research and biomedical applications, respectively. Next, we describe the general workflow of organizing a Biomedical NLP (BioNLP) challenge and involved stakeholders (task organizers, task data producers, task participants and end users). Finally, we summarize the impact and contributions by taking into account different BioNLP challenges as a whole, followed by a discussion of their limitations and difficulties. We conclude with future trends in BioNLP challenge evaluations. PMID- 25935163 TI - Combined catheter ablation and left atrial appendage closure as a hybrid procedure for the treatment of atrial fibrillation. AB - AIMS: Left atrial appendage (LAA) is the source of thrombi in up to 90% of patients with non-valvular atrial fibrillation (AF). Catheter ablation (CA) is an effective treatment for symptomatic AF and, in selected cases, LAA occlusion devices have been introduced as an alternative to oral anticoagulants (OACs). The safety and feasibility of combining CA and percutaneous LAA closure (LAAC) are unknown. METHODS AND RESULTS: Patients with symptomatic drug-refractory AF, CHADS2 score of >=1, and CHA2DS2-VASc score >=2 were included. Catheter ablation consisted in pulmonary vein isolation with or without roof line with radiofrequency and LAA was occluded with the Watchman or Amplatzer Cardiac Plug (ACP) devices guided by angiography and transoesophageal echocardiography. A total of 35 patients were included (71% male; 70 years). Median score was 3 on both CHA2DS2-VASc and HAS-BLED, 9% had prior stroke under OAC, and 48% had bleeding complications. Successful CA and device implantation were achieved in 97% of cases. The Watchman device was used in 29 patients and ACP in 6 patients. Periprocedural complications included three cases of cardiac tamponade. At 3 months, all patients met the criteria for successful sealing of the LAA. After a mean follow-up of 13 months (3-75), 78% of patients were free of arrhythmia recurrences and OAC was withheld in 97% of patients. CONCLUSIONS: The combination of CA and percutaneous LAAC in a single procedure is technically feasible in patients with symptomatic drug-refractory AF, high risk of stroke, and contraindications to OACs, although it is associated with a significant risk of major complications. PMID- 25935164 TI - Incidence and predictors of dormant conduction after cryoballoon ablation incorporating a 30-min waiting period. AB - AIMS: Electrical reconnection after pulmonary vein (PV) isolation is associated with atrial fibrillation (AF) recurrence. Reconnection may already develop within a 30 min waiting period and may only occur as dormant conduction (DC) revealed by adenosine infusion. This study determines incidence and predictors of DC after cryoballoon ablation incorporating a 30 min waiting period and the effect of treating this 'late' DC on 1 year AF-recurrence. METHODS AND RESULTS: Consecutive patients scheduled for a first ablation were prospectively included. Intravenous adenosine was administered 30 min after PV isolation to unmask DC (adenosine+). Additional applications were performed to abolish DC. Atrial fibrillation recurrence was evaluated after 3, 6, and 12 months with ECG and 24 h Holter recordings. Results were compared with a prior group of consecutive patients that underwent cryoablation without DC testing (adenosine-). The adenosine+ group consisted of 36 patients (78% male, 61 +/- 10 years, paroxysmal AF 86%). ***Dormant conduction was found in 42% of patients (15/36) and 14% of PVs (20/143). Multivariate analysis showed that PV isolation during the first freeze independently reduced DC risk (OR = 0.064, P < 0.01). After 12 +/- 1 months, 11 (83%) of adenosine+ patients had no AF-recurrences, compared with 37 (60%) of adenosine- patients (n = 62, 70% male, 59 +/- 11 years, 90% paroxysmal AF, P = 0.02). Ablation with DC treatment independently reduced the risk of AF-recurrence (OR = 0.26, P = 0.02). CONCLUSION: Incorporating a 30-min waiting period after cryoballoon ablation increases the incidence of DC compared with previous results. Absence of PV isolation during the first freeze is associated with an increased risk of late DC. Treatment of this DC seems to improve outcome. PMID- 25935165 TI - Clinical significance of early atrial arrhythmia type and timing after single ring isolation of the pulmonary veins. AB - AIMS: Early atrial arrhythmia following atrial fibrillation (AF) ablation is associated with higher recurrence rates. Few studies explore the impact of early AF (EAF) and atrial tachycardia (EAT) on long-term outcomes. Furthermore, EAF/EAT have not been characterized after wide pulmonary vein isolation. We aimed to characterize EAF and EAT and its impact on late AF (LAF) and AT (LAT) after single ring isolation (SRI). METHODS AND RESULTS: We recruited 119 (females 21, age 58 +/- 10 years) consecutive patients with AF (paroxysmal 76, persistent 43) undergoing SRI. Early atrial fibrillation/ early atrial tachycardia was defined as AF/AT within 3 months post-procedure (blanking period). Patients were followed for median 2.8[2.2-4] years. Early atrial fibrillation occurred in 28% (n = 33) and EAT in 25% (n = 30). At follow-up, 25% (n = 30) had LAF and 28% (n = 33) had LAT. Patients with EAF and EAT had higher rates of LAF (48 vs. 16%, P<0.0001) and LAT (60 vs. 16%, P < 0.0001), respectively. Independent predictors of LAF were EAF (3.53(1.72-7.29) P = 0.001); and of LAT were EAT (5.62(2.88-10.95) P < 0.0001) and procedure time (1.38/ h(1.07-1.78) P = 0.04). Importantly, EAF did not predict LAT and EAT did not predict LAF. Early atrial fibrillation late in the blanking period was associated with higher rates of LAF (73% for month 3 vs. 25% for Months 1-2, P = 0.004). However, EAT timing did not predict LAT. CONCLUSION: Early atrial fibrillation and EAT are predictive of LAF and LAT, respectively. Early atrial fibrillation late in the blanking period has greater predictive significance for LAF. This timing is not relevant for LAT. Early arrhythmia type and timing have important prognostic significance following SRI. CLINICAL TRIAL REGISTRATION: http://www.anzctr.org.au;ACTRN12606000467538. PMID- 25935166 TI - An extra piece of grey. PMID- 25935167 TI - Monitoring asthma in children: what does BATMAN tell us? PMID- 25935168 TI - Severe dyspnoea in a patient with chronic myelogenous leukaemia on a tyrosine kinase inhibitor. PMID- 25935169 TI - 'It's always just there in your face': young people's views on porn. AB - Background Young people's exposure to pornography has increased, as has the violent and sexist nature of mainstream porn. Contemporary content means young people are exposed to violent porn whether they like it or not, and it is no longer a question of whether they will be exposed, but rather when. METHODS: Using purposive sampling, 33 in-depth interviews were conducted with young people aged 15-20 years in 2010-11, to explore the phenomenon of sexting. During initial interviews, participants raised the topic of pornography exposure as a secondary, unexpected finding. Discussions highlighted an important link between sexting and pornography. The inductive nature of the research meant this new and important area of inquiry was able to be explored. RESULTS: Data was thematically coded and analysed using a grounded theory approach. Findings highlight that many young people are exposed to porn both intentionally and unintentionally. Furthermore, they are concerned about gendered norms that reinforce men's power and subordination over women. A link between porn exposure, young men's sexual expectations and young women's pressure to conform to what is being viewed, has been exposed. CONCLUSIONS: Results are significant given this is one of few recent qualitative Australian studies to explore the issue of pornography exposure from the perspective of young people. Important implications for educators, parents and health providers have been revealed, including the need to create opportunities for young people to challenge the messages expressed in porn, and for their views to be heard in academic and public debate. PMID- 25935170 TI - Celebrating the world blood donor day. PMID- 25935171 TI - Predictors of diastolic dysfunction in rheumatoid arthritis. AB - The main objective was to determine the predictors of diastolic dysfunction in rheumatoid arthritis (RA). Articles pertaining to diastolic dysfunction in RA were retrieved from Scopus, EBSCO, PubMed, Web of Science, and Cochrane Library databases. Keywords such as: diastolic, cardiac, left ventricular function, heart failure, rheumatoid arthritis, and cardiac failure were used. Studies, which examined factors, or predictors of diastolic dysfunction in RA, and those with echocardiographic evaluation of diastolic dysfunction, were included. A total of 8 studies met the eligibility criteria. Most studies (6 out of 7 studies) demonstrated a significant inverse relationship between the E (early)/A (late) ratio and disease duration. The pooled analysis using the random effects model revealed a significant but weak inverse relationship between the ratio of the E to A ventricular filling velocities (E/A) ratio and the disease duration (p less than 0.05, r=-0.385). There was a significant relationship between E/A ratio and disease duration in RA. PMID- 25935172 TI - A review of the therapeutic effects of using miswak (Salvadora Persica) on oral health. AB - Miswak is a traditional chewing stick prepared from the roots, twigs, and stem of Salvadora persica and has been used as a natural method for tooth cleaning in many parts of the world for thousands of years. A number of scientific studies have demonstrated that the miswak (Salvadora persica) possesses antibacterial, anti-fungal, anti-viral, anti-cariogenic, and anti-plaque properties. Several studies have also claimed that miswak has anti-oxidant, analgesic, and anti inflammatory effects. The use of a miswak has an immediate effect on the composition of saliva. Several clinical studies have confirmed that the mechanical and chemical cleansing efficacy of miswak chewing sticks are equal and at times greater than that of the toothbrush. The present article provides a review of the various therapeutic effects of Salvadora persica on oral health, which will help to elucidate the significance and importance of this indigenous oral hygiene tool. PMID- 25935173 TI - Genetic polymorphisms in paraoxonase 1 and G protein-coupled receptor 77, and the risk of glucose-6-phosphate dehydrogenase deficiency in a Saudi population. AB - OBJECTIVES: To investigate the role of amino acid substitution variants Q192R and C698T in the development of glucose-6-phosphate dehydrogenase (G6PD) deficiency in a Saudi male population. METHODS: This case-control study was carried out in 200 Saudi male individuals: 100 patients with G6PD deficiency, and 100 control subjects collected between July and August 2011 in the Taif region of Saudi Arabia. A total of 2100 male Saudi individuals were screened by a fluorescence spot test, and 100 with G6PD deficiency were selected. Two common variants PON1 (rs662) and C5L2 (rs149572881) were genotyped using polymerase chain reaction followed by restriction fragment length polymorphism analysis. RESULTS: The results showed that the R allele and QR genotype were associated with the Q192R polymorphism in PON1 (R versus Q odds ratio [OR], 1.72; 95% confidence interval [95% CI], 1.1-2.6; p=0.01; and QR versus QQ: OR, 1.98; 95% CI, 1.1-3.6; p=0.02). All the C698T genotypes and allele frequencies in C5L2 were almost similar in both the cases and controls (CT versus CC: OR, 2.04; 95% CI, 0.3-11.4; p=0.40; and T versus C: OR, 2.02; 95% CI, 0.3-11.1; p=0.41). CONCLUSIONS: These findings suggest the association of PON1 with G6PD deficiency in the Saudi male population studied herein. Future studies, including correlation analyses between the clinical features and genotypes in populations of different ethnicities, are warranted to confirm the disease association with these genetic mutations. PMID- 25935174 TI - Intravascular ultrasound-guided unprotected left main coronary artery stenting in the elderly. AB - OBJECTIVES: To investigate whether intravascular ultrasound (IVUS) guided percutaneous coronary intervention (PCI) could improve clinical outcomes compared with angiography-guided PCI in the treatment of unprotected left main coronary artery stenosis (ULMCA) in the elderly. METHODS: This controlled study was carried out between October 2009 and September 2012, in Qinhuangdao First Hospital, Hebei Province, China. One hundred and twenty-three consecutive patients with ULMCA, aged 70 or older, were randomized to an IVUS-guided group and a control group. The occurrence of major adverse cardiac events (MACE): death, non-fatal myocardial infarction, or target lesion revascularizations) were recorded after 2 years of follow-up. RESULTS: The IVUS-guided group had a lower rate of 2-year MACE than the control group (13.1% versus 29.3%, p=0.031). The incidence of target lesion revascularization was lower in the IVUS-guided group than in the control group (9.1% versus 24%, p=0.045). However, there were no differences in death and myocardial infarction in the 2 groups. On Cox proportional hazard analysis, distal lesion was the independent predictor of MACE (hazard ratio [HR]: 1.99, confidence interval [CI]: 1.129-2.367; p=0.043); IVUS guidance was independent factor of survival free of MACE (HR: 0.414, CI: 0.129 0.867; p=0.033). CONCLUSION: The use of IVUS could reduce MACE in elderly patients undergoing ULMCA intervention. PMID- 25935175 TI - Antibiotic prophylaxis against infective endocarditis in adult and child patients. Knowledge among dentists in Saudi Arabia. AB - OBJECTIVES: To evaluate dentists' knowledge regarding the prevention of infective endocarditis in Saudi Arabia and their implementation of the 2007 American Heart Association guidelines. METHODS: In this cross-sectional study, in March 2014, 801 dentists who practice in different regions of Saudi Arabia completed a questionnaire regarding the need for antibiotic prophylaxis for specific cardiac conditions and specific dental procedures, prophylaxis regimens in adults and children, and recommendations for patients on chronic antibiotics, and in dental emergencies. The data were analyzed using one-way analyses of variance (ANOVAs) and independent t-tests, and a p-value less than 0.05 was considered statistically significant. RESULTS: The total knowledge level regarding antibiotic prophylaxis among all participants was 52.2%, with a significant difference between dentists who graduated before and after 2007. Comparing the level of knowledge among different dental specialists, surgeons and periodontists had the highest level of knowledge regarding the use of antibiotic prophylaxis. Amoxicillin was prescribed as the drug of choice by 63.9% of the participants. CONCLUSION: This study emphasized the need for continuous education and for formal inclusion of the guidelines in the students' curriculum, as well as for strategic placement of the guidelines in locations throughout dental clinics. PMID- 25935176 TI - The role of anti-Mullerian hormone and inhibin B in the assessment of metformin therapy in women with polycystic ovarian syndrome. AB - OBJECTIVES: To evaluate the role of anti-Mullerian hormone (AMH) and inhibin B in the evaluation of the effectiveness of short- (3 months) and long-term (6 months or more) metformin therapy in Iraqi women with polycystic ovarian syndrome (PCOS). METHODS: This cross-sectional study was carried out at the Biochemistry Department, College of Medicine, University of Baghdad, Baghdad, Iraq from June 2010 to May 2011. It included 38 volunteers of women patients with PCOS, aged 18 38 years, who were classified into: Group I (GI, n=20); Group II included women in GI that were followed up after they were treated with metformin hydrochloride tablet 500 mg 3 times daily for 3 months; and GIII included 18 women that were already on metformin hydrochloride treatment 500 mg tablet 3 times daily for 6 months to 3 years. Investigations included serum measurement of insulin, AMH, inhibin B, androgen hormones using enzyme-linked immunosorbent assay, and mini Vidus techniques. RESULTS: The mean +/- standard error of the mean value of serum AMH levels was significantly decreased in post metformin treatment women (3 months; GII) compared with those before treatment (GI), and those women on prolonged treatment (GIII) (p less than 0.01 for both). However, there was no significant difference in serum AMH between GI and GIII. With respect to serum inhibin B, both women of GI and GII had significant decrease compared with GIII, with no significant changes between GI and GII. CONCLUSION: This study showed the efficacy of serum AMH measurement as a prognostic biochemical marker in the follow up of metformin treatment of PCOS women. PMID- 25935177 TI - Visual and neurologic sequelae of methanol poisoning in Saudi Arabia. AB - OBJECTIVES: To present the visual sequelae of methanol poisoning and to emphasize the characteristics of methanol exposure in the Kingdom of Saudi Arabia (KSA). METHODS: A retrospective case series was carried out on 50 sequential patients with methanol poisoning seen at the King Khaled Eye Specialist Hospital and King Saud University Hospitals in Riyadh, KSA between 2008 and 2014. All patients were examined by a neuro-ophthalmologist at least one month after methanol intoxication. RESULTS: All 50 patients were young or middle-aged males. All admitted to drinking unbranded alcohol within 2-3 days before profound or relatively profound, painless, bilateral visual loss. Mean visual acuity in this group was hand motions (logMAR 2.82; range 0.1 - 5.0) with some eye to eye variability within individuals. Worse visual acuity was correlated with advancing age (Pearson correlation: oculus dextrus [right eye] - 0.37, p=0.008; oculus sinister [left eye] - 0.36, p=0.011). All patients had optic atrophy bilaterally, and all tested patients had visual field defects. Tremors with or without rigidity were present in 12 patients, and 11 of 30 patients who had neuroimaging performed had evidence of putaminal necrosis. CONCLUSION: Methanol intoxication causes visual loss within 12-48 hours due to relatively severe, painless, bilateral optic nerve damage that may be somewhat variable between eyes, and is generally worse with advancing age. The coincidence of bilateral optic nerve damage and bilateral putaminal necrosis in a young or middle-aged male is very suspicious for methanol-induced damage. PMID- 25935178 TI - Comprehensive patient care improves quality of life in transfusion dependent patients with beta-thalassemia. AB - OBJECTIVES: To investigate levels of quality of life (QOL) among thalassemia patients at the Hereditary Blood Disorders Center in Al-Madinah Al-Munawarah, Kingdom of Saudi Arabia. METHODS: A cross-sectional study was performed on 43 transfusion dependent thalassemia patients compared with 43 normal subjects, as a control, using the World Health Organization Quality Of Life - Brief questionnaire between May 2012 and September 2012 at the Hereditary Blood Disorders Center, Maternity and Children Hospital in Al-Madinah Al-Munawarah, Kingdom of Saudi Arabia. RESULTS: Forty-three thalassemia patients were examined, 23 males and 20 females, and compared with 43 peers (control group), 24 males and 19 females. There was no statistical difference between patients and controls for psychological domains (53.4 versus 56.9, p=0.059) and environmental domains (56.6 versus 57.0, p=0.884). Patients had better social QOL than the control group (39.3 versus 31.7, p=0.003), while the control group had better physical QOL (55.4 versus 61.9, p=0.047). Among patients, there was no statistical difference in QOL domains for variables of age, desferroxamine use, serum ferritin level, disease severity, presence of complications; splenectomy status, hepatitis C virus status, or family history. CONCLUSION: Quality of life in thalassemia patients is similar to the control group particularly social life, though physical health is less. Improvement of patients care from all aspects will improve their QOL. More studies in this field are needed with a bigger sample size. PMID- 25935179 TI - Effect of energy drink intake before exercise on indices of physical performance in untrained females. AB - OBJECTIVES: To determine the effect of energy drink consumption before exercise on indices of physical performance in untrained females. METHODS: This single blind placebo controlled experimental study was carried out at the Physiology Department, University of Dammam, Dammam, Kingdom of Saudi Arabia from September 2011 to May 2012, on 32 healthy female students, in a crossover design. They were given either a standardized energy drink or the placebo 45 minutes before the exercise. Time to exhaustion and the stages of Bruce protocol achieved were noted. Heart rate, blood pressure, peripheral capillary oxygen saturation, and blood lactate were recorded before and after the exercise. Maximum oxygen consumption (VO2max) was calculated by formula. Paired sample t-test was used for statistics. RESULTS: The mean age was 19.93+/-0.8 years, mean height 156.40+/ 3.83 cm, and the mean weight 51.73+/-3.65 kg. Time to exhaustion in the placebo group was 11.67+/-1.51 minutes and 11.41+/-1.56 in the energy drink group (p less than 0.157). The VO2max in the placebo group was 34.06+/-6.62, while it was 32.89+/-6.83 in the energy drink group (p less than 0.154). There were no significant differences between the placebo and the energy drinks groups in regards to heart rate, blood pressure, and blood lactate levels, before or after the exercise. However, there were significant differences before, immediately, and 30 minutes post exercise for all parameters between each group. CONCLUSION: The effects of energy drinks intake on physical performance during the exercise in our small sample does not significantly differ from placebo. PMID- 25935180 TI - Epidemiology of pediatric hand fractures presenting to a university hospital in Central Saudi Arabia. AB - OBJECTIVES: To investigate the epidemiology of pediatric hand fractures and to provide recommendations regarding prevention. METHODS: Medical records and x-rays were retrospectively reviewed for age at the time of injury, gender, fracture pattern, place where the injury occurred, and mechanism of injury. The study was conducted at King Khalid University Hospital, Riyadh, Saudi Arabia between January 2005 and December 2011. RESULTS: Of 361 cases reviewed, there were 291 (80.6%) male and 70 (19.4%) female patients. Most (46.2%) were in the age group of 13-18 years. For age group 1-4 years, the most common place of occurrence was at home (81.3%) and for the group 13-18 years, outdoors was the place of occurrence (64.7%). Females were mostly injured at home while males had similar distribution of indoor and outdoor injuries. The most common causes of fractures were: door slams in the 1-8 years age group; falls at home, in the 9-12 years age group; and both falls at home and sports in the oldest age group (13-18 years). The little finger ray are the most frequently injured part of the hand followed by the middle finger. CONCLUSION: Our series showed that most hand fractures in children occurred at home, which requires reevaluation of home settings. Implementation of safety measures during sports activities are relevant in the oldest age group. PMID- 25935181 TI - An epidemic analysis of hand, foot, and mouth disease in Zunyi, China between 2012 and 2014. AB - OBJECTIVES: To re-evaluate the epidemiology of hand, foot, and mouth disease (HFMD) in a non-vaccinated population in Zunyi, China. METHODS: We used laboratory-based data from the Third Affiliated Hospital of Zunyi Medical College, Zunyi, China to assess the epidemiology of the HFMD caused by enteroviruses between January 2012 and November 2014. Real-time polymerase chain reaction was used to determine human enteroviruses from a total of 12313 probable cases enrolled in this retrospective study. All analyses were stratified by enterovirus serotype, gender, and age. RESULTS: Virological results were available for 12313 cases of probable HFMD. A total of 5750 cases were positive for viral detection, and the positive rates of infection caused by other enteroviruses was 46.7%, EV71 9%, and CVA16 4.7%. During the study period there was a substantial increase in the occurrence of HFMD. Most of the HFMD patients (87.4%) were aged 0-59 months (median 24; range 0-59). Males showed a higher HFMD prevalence rate (62.4%) than females (37.6%). CONCLUSION: Enterovirus infection remains an important public health problem and other entroviruses are emerging as the major causative agent of the HFMD in Zunyi, China. PMID- 25935182 TI - Asthma control among adults in Saudi Arabia. Study of determinants. AB - OBJECTIVES: To explore the determinants of uncontrolled asthma in Saudi Arabia. METHODS: A consecutive series of adult asthma patients attending 3 pulmonary primary care clinics in Riyadh, Saudi Arabia for a scheduled appointment were interviewed. A multiple logistic regression analysis was used. RESULTS: The proportion of patients with uncontrolled asthma was 68.1% (177/260). Daily tobacco smoking or monthly household income less than 15,000 Saudi Arabian Riyals were associated with a 4.6 (95% confidence interval [CI]=1.3-16.4) and 3.4 (95% CI=1.8-6.6) times increase in the odds of having uncontrolled asthma. Patients with less than a graduate degree (odds ratio [OR]=3.1; 95% CI=1.0-9.5) or patients who were unemployed, disabled, or too ill to work (OR=3.1; 95% CI=1.4 6.9) had poorer asthma control. Having heartburn during the past 4 weeks decreased the odds of asthma control by 2.5 (95% CI=1.3-4.9), and having chronic sinusitis during the past 4 weeks decreased the odds of asthma control by 2.0 (95% CI=1.0-4.0) times. Being female (OR=2.0; 95% CI=1.0-4.0) or >=35 years of age (OR=2.0; 95% CI=1.0-3.9) was also associated with having uncontrolled asthma. CONCLUSION: Our findings suggest that most respondents had uncontrolled asthma. Less modifiable socio-demographic factors (for example, income, education, occupation, gender, and age) significantly increased the odds of having uncontrolled asthma. However, modifiable risk factors such as tobacco smoking and clinical factors such as heartburn and chronic sinusitis could also be targeted for intervention. PMID- 25935183 TI - Prevalence of stress and its determinants among residents in Saudi Arabia. AB - OBJECTIVES: To examine perceived stress among residents in Saudi Arabia and its associated risk factors. METHODS: A cross-sectional study of all residents registered at the Saudi Commission for Health Specialties, Riyadh, Saudi Arabia, was conducted between May and October 2012. We assessed the likelihood of stress using the perceived stress scale (PSS). RESULTS: Out of the 4000 residents contacted, 1035 responded and 938 were included. The mean (+/-standard deviation) PSS score was 22.0+/-5.1 (median 22 and inter-quartile range of 18-25). With the exception of gender and nationality, no significant associations were found between stress and socio-demographic or behavioral factors. Stress was associated with higher workload, sleep deprivation, dissatisfaction with colleagues and the program, and harmful ideations. Stressors included work-related, academic, and homesickness stressors. In multivariate analysis, the following were independently associated with stress: Saudi nationality, facing homesick stressor, facing work-related stressor, dissatisfaction with relationships with colleagues, and frequent thoughts of quitting the medical profession. CONCLUSION: Residents in Saudi Arabia are at comparable or slightly higher risk of perceived stress than that reported among residents worldwide. Unfortunately, most of the participants never received stress management, which highlights the need for stress management programs during residency. PMID- 25935184 TI - Physicians' knowledge, perceptions, and attitudes toward antimicrobial prescribing in Riyadh, Saudi Arabia. AB - OBJECTIVES: To assess knowledge, perceptions, and attitudes toward antimicrobial prescribing among physicians practicing in Riyadh, Saudi Arabia. METHODS: A questionnaire was developed and distributed to physicians working in hospitals in Riyadh, Saudi Arabia between June and August 2013. The results were analyzed using Stata 12 software. RESULTS: Two hundred and twelve (84.8%) full responses were returned. Most respondents perceived antimicrobial resistance as a significant problem in their daily practice (119, 56.1%) and at a national level (148, 69.8%). Inappropriate empirical therapy (101, 47.6%) and excessive use of antimicrobials in healthcare settings (66, 31.1%) were believed to be the main contributors to increasing bacterial resistance. Respondents favor treating infection rather than colonization (98, 46.2%), and physician education (74, 34.9%) as the most effective interventions to reduce antimicrobial resistance. Many respondents (95, 44.8%) do not feel confident in their knowledge of antimicrobial prescribing. Two-thirds of the respondents (135, 63.7%) have local antimicrobial guidelines, of which 90 (66.7%) felt were useful. Most respondents (160, 75.5%) considered their local infectious diseases service to be very helpful. CONCLUSION: There are considerable unmet training and education need for physicians in the area of antimicrobial prescribing. Local antimicrobial guidelines need revision to ensure they are more relevant and helpful for medical practitioners. PMID- 25935185 TI - Mycobacterium riyadhense infections. AB - Mycobacterium riyadhense is a newly described slowly growing, non-tuberculous mycobacterium species. We describe 2 new cases of Mycobacterium riyadhense infections presenting with extra-pulmonary involvement, and reviewed all previously reported cases in the literature. We also describe the spectrum of the disease and explore treatment options based on the experience with the current and previously reported cases. PMID- 25935186 TI - Persistent primitive trigeminal artery associated with monocular blindness and external carotid-vertebral artery anastomosis. AB - In this paper, we present 2 rare cases of persistent embryonic anastomoses. In one case, the patient presented with persistent trigeminal artery along with multiple foci of cerebral infarction as well as central retinal artery thrombosis. In the other case, the patient had direct anastomosis of the vertebral artery with ipsilateral external carotid artery as well as pontine infarction, aneurysm, and unilateral hypoplasia of the vertebral artery. The findings in these cases may shed light on the clinical presentation of such persistent anastomoses and aid their detection in clinical settings. PMID- 25935187 TI - Sigmoid colon endometriotic mass. A rare cause of complete large bowel obstruction. AB - Large bowel obstruction is a rare complication of gastrointestinal endometriosis. A 32-year-old female patient presented to the emergency department with complaints of diffuse abdominal pain and constipation for 10 days with progressive abdominal distention and vomiting. Plain abdominal x-ray showed grossly dilated large bowel up to the sigmoid colon with no gas in the rectum. Abdominal computed tomography revealed hugely dilated large bowel up to the sigmoid colon, with sigmoid soft tissue mass. Flexible sigmoidoscopy showed a non ulcerating sigmoid mass, with complete obstruction of the sigmoid colon, which impeded the further advancement of the scope. She underwent exploratory laparotomy with provisional diagnosis of complete large bowel obstruction due to sigmoid tumor. Sigmiodectomy with end colostomy was performed. Histopathology revealed endometrial glands with stroma in muscularis properia of the sigmoid colon mass. Endometriosis should be considered in women of reproductive age presenting with symptoms of large bowel obstruction. PMID- 25935188 TI - A fatal outcome due to pulmonary hemorrhage following Russell's viper bite. AB - Russell's viper (RV) envenomation causes local effects, coagulopathy, thrombosis, rhabdomyolysis, acute kidney injury, and neurological manifestations. Although coagulopathy and endothelial destruction causing local and mucosal surface bleeding is known, isolated severe pulmonary hemorrhage is not commonly reported. We report a previously healthy 18-year-old male who had bilateral severe pulmonary hemorrhages, which resulted in a fatal outcome following RV bite. This diagnosis was supported by persistent alveolar shadows, with minimum improvement despite hemodialysis without heparin, mixed acidosis and endotracheal tube bleeding. Other bleeding manifestations were absent. Polyvalent antivenom was administered in lieu of prolonged whole blood clotting time. Thrombocytopenia and mildly deranged clotting parameters were noted. Pulmonary hemorrhages were significant enough to require transfusion. This case highlights the importance of suspecting pulmonary hemorrhages in patients with alveolar shadows and desaturation following RV bite despite the absence of other bleeding manifestations in light of failure of optimum therapy including hemodialysis. PMID- 25935189 TI - Rheumatoid arthritis in the Kingdom of Saudi Arabia. PMID- 25935190 TI - The effects of probiotics on the treatment of Helicobacter pylori eradication in children. PMID- 25935191 TI - Destructive Lesions of the Breast. PMID- 25935192 TI - Chondrocutaneous Island Flap for Reconstruction of an Antihelix Defect. PMID- 25935193 TI - Cutaneous Nodules in Multiple Myeloma. Cutaneous plasmacytoma associated with multiple myeloma. PMID- 25935194 TI - Dose Modification in Biologic Therapy for Moderate to Severe Psoriasis: A Descriptive Analysis in a Clinical Practice Setting. AB - INTRODUCTION: In biologic therapy, dose modification in carefully selected patients when psoriasis is in remission could reduce treatment costs and the risks associated with drug exposure. MATERIAL AND METHODS: Observational, descriptive, crosssectional study, performed in January 2014, of 112 patients with moderate to severe psoriasis who had been on biologic therapy for at least 6 months. The therapeutic objective in all cases was to achieve and maintain a 75% reduction in Psoriasis Area and Severity Index (PASI 75). All the patients had started treatment with the standard regimen. During treatment, the dose had been reduced in patients who achieved the therapeutic objective and escalated in those who failed to respond adequately to standard doses. RESULTS: At the time of the study, 42.9% of the patients were receiving the standard dose, 50% were on a reduced dose, and 7.1% were on an escalated regimen. The agent with which the dose was most often reduced was adalimumab (57.7%), and the agents with which therapy was most often escalated were ustekinumab (17.9%) and infliximab (12.5%). Patients who received reduced doses had significantly longer-standing disease (P=.049) and longer treatment duration with the same biologic agent (P=.009). In the group that did not fulfill the criteria for dose reduction, the proportion of patients with psoriatic arthritis was significantly higher (P=.023). Cost savings were as follows: 21.5% with adalimumab, 13.8% with etanercept, .9% with ustekinumab, and .55% with infliximab. CONCLUSIONS: Patients with longer-standing disease and longer treatment duration with the same biologic agent were significantly more likely to be candidates for dose reduction. The proportion of patients with psoriatic arthritis was greater in the group of patients who did not fulfill the conditions for dose reduction. The overall cost saving achieved using the dose modification algorithm described in this study was 13%. Controlled studies are needed to define the profile of the patients best suited for dose reduction strategies without loss of treatment efficacy. PMID- 25935195 TI - Adjuvant therapeutic decisions in elderly breast cancer patients: the role of chemotherapy in a retrospective analysis. AB - PURPOSE: Decisions on the type of adjuvant treatment in older breast cancer patients are challenging. Side effects of chemotherapy have to be weighed against life expectancy, comorbidities, functional status, and frailty on the basis of studies usually excluding patients over 69 years. To aid this decision, we analyzed a database of 6000 unselected patients and of those evaluated elderly primary breast cancer patients with hormone receptor-negative tumors from 1963 until 2003 in respect of survival data depending on adjuvant treatment. METHODS: A total of 131 elderly (i.e., >65 years) patients were observed retrospectively for a median of 72 months. Patients received breast-conserving therapy or mastectomy and adjuvant radiotherapy, chemotherapy, and endocrine therapy. Data were collected from a hospital-intern database. RESULTS: Median age at diagnosis was 72 years. Mostly, tumors were small (81 % T1, 17 % T2) but of unfavorable grading (40 % G2, 35 % G3). Lymph nodes were positive in 42 %. Mastectomy was performed in 65 %. While 42 % of patients received radiotherapy, only 10 % were treated with chemotherapy. Patients with G2 and G3 tumors (p = 0.027), younger women (p = 0.012), and patients with positive lymph node status (p < 0.0001) more likely received chemotherapy. Recurrence-free survival was longer in patients without chemotherapy (37 vs. 29 months, p = 0.234). Overall survival was non significantly shorter in patients who received chemotherapy (59 vs. 81 months, p = 0.131). CONCLUSIONS: In this analysis, adjuvant chemotherapy was not associated with improved survival, presumably caused by an a priori poor prognosis of these patients. For an aging society more data are urgently needed to help selecting and personalizing adjuvant treatment within subgroups of breast cancer in older women. PMID- 25935197 TI - New associate Editor Prof. Dr. med. Christina Fotopoulou. PMID- 25935196 TI - Curettage or operative hysteroscopy in the treatment of cesarean scar pregnancy. AB - OBJECTIVES: To compare the clinical effects of dilatation and curettage (D&C) regimen and operative hysteroscopy coupled with curettage regimen in the treatment of cesarean scar pregnancy (CSP) following preventive uterine artery embolization (UAE). MATERIALS AND METHODS: Thirty-three women were treated with D&C after UAE (group A) and 33 women were treated with operative hysteroscopy coupled with curettage after UAE (group B). The clinical outcomes of the two groups were compared. RESULTS: There was no significant difference between the two groups with respect to the success rate, the intraoperative blood loss, the hysterectomy rate, the hospitalization time, the decline of serum beta-hCG after surgery, the time of serum beta-hCG resolution, the time of vaginal bleeding after surgery, the time to CSP mass disappearance, and the subsequent intrauterine pregnancies. The hospitalization cost in group B was higher than group A. CONCLUSIONS: Both D&C and operative hysteroscopy coupled with curettage were successful in terminating a CSP. Hysteroscopy coupled with curettage regimen did not have significant advantages and good prognosis in dealing with the gestational sac type of CSP following preventive UAE compared with D&C regimen. Treatment should be individualized and several conditions must be considered. PMID- 25935198 TI - Incorporating linked healthcare claims to improve confounding control in a study of in-hospital medication use. AB - INTRODUCTION: The Premier Perspective hospital billing database provides a promising data source for studies of inpatient medication use. However, in hospital recording of confounders is limited, and incorporating linked healthcare claims data available for a subset of the cohort may improve confounding control. We investigated methods capable of adjusting for confounders measured in a subset, including complete case analysis, multiple imputation of missing data, and propensity score (PS) calibration. METHODS: Methods were implemented in an example study of adults in Premier undergoing percutaneous coronary intervention (PCI) in 2004-2008 and exposed to either bivalirudin or heparin. In a subset of patients enrolled in UnitedHealth for at least 90 days before hospitalization, additional confounders were assessed from healthcare claims, including comorbidities, prior medication use, and service use intensity. Diagnostics for each method were evaluated, and methods were compared with respect to the estimates and confidence intervals of treatment effects on repeat PCI, bleeding, and in-hospital death. RESULTS: Of 210,268 patients in the hospital-based cohort, 3240 (1.5 %) had linked healthcare claims. This subset was younger and healthier than the overall study population. The linked subset was too small for complete case evaluation of two of the three outcomes of interest. Multiple imputation and PS calibration did not meaningfully impact treatment effect estimates and associated confidence intervals. CONCLUSIONS: Despite more than 98 % missingness on 24 variables, PS calibration and multiple imputation incorporated confounders from healthcare claims without major increases in estimate uncertainty. Additional research is needed to determine the relative bias of these methods. PMID- 25935199 TI - Upregulation of alpha2delta-1 Calcium Channel Subunit in the Spinal Cord Contributes to Pelvic Organ Cross-Sensitization in a Rat Model of Experimentally Induced Endometriosis. AB - Pelvic organ cross-sensitization, also termed as viscero-visceral referred hyperalgesia, is a major contributor to painful endometriosis. Its underlying mechanism is poorly understood. Clinical and basic studies have shown that gabapentin, a drug that binds to the alpha2delta-1 subunit of voltage-dependent calcium channels (Cavalpha2delta-1), is effective in treating chronic visceral pain. Accordingly, we hypothesized that pelvic organ cross-sensitization in painful endometriosis is mediated by an upregulation of Cavalpha2delta-1 in the spinal cord. We examined if the dysregulation of spinal Cavalpha2delta-1 subunit may play an important role in the development of ectopic growths-to-colon cross sensitization in a rat model of experimentally-induced endometriosis. Our findings suggest that there was an increased Cavalpha2delta-1 expression in the dorsal horn and an ectopic growths-to-colon cross-sensitization in female rats with established endometriosis. Intrathecal administration of gabapentin (300 MUg) remarkably reduced the ectopic growths-to-colon cross-sensitization in rats with established endometriosis. Furthermore, intrathecal injection of Cavalpha2delta-1 antisense oligodeoxynucleotides reversed the ectopic growths-to colon cross-sensitization and also normalized the upregulation of spinal Cavalpha2delta-1 expression in endometriosis rats. The current study suggests that the upregulation of Cavalpha2delta-1 in the spinal cord may contribute to pelvic organ cross-sensitization in painful endometriosis. Our study may provide a biological basis for selectively targeting this pathway to relieve viscero visceral referred hyperalgesia in patients with painful endometriosis. PMID- 25935200 TI - Occurrence of Polychlorodibenzothiophenes in Nanjing Section of the Yangtze River, China. AB - Sediment and water samples collected from 8 sites of the Yangtze River in Nanjing section were characterized with 31 congeners of polychlorodibenzothiophenes (PCDTs). Concentrations and percentage compositions of these PCDTs in water and sediments were analyzed by gas chromatography-mass spectrometry. Results showed that ?PCDT concentrations in sediments were higher (0.86-1.75 MUg/kg) than those in water (0.56-1.30 MUg/L). A linear relationship existed between ?PCDT concentrations and total organic carbon content in sediments, whereas there was a poor linearity between ?PCDTs concentrations and dissolved organic carbon content in water phase. Moreover, percentage compositions showed that penta-chlorinated DTs were the predominant congeners both in sediments and water. Differences existed in the percentage compositions between water and sediments. Highly chlorinated DTs accounted for a larger proportion in sediments than those in water. In conclusion, the present study showed the prevalent contamination by PCDTs in sediments and water from the Nanjing section of the Yangtze River. PMID- 25935201 TI - Clostridium difficile ribotype 078 cultured from post-surgical non-healing wound in a patient carrying ribotype 014 in the intestinal tract. AB - Extra-intestinal infections caused by Clostridium difficile are rare. The risk of extra-intestinal infections associated with C. difficile may be particularly relevant in environments contaminated with C. difficile spores. This paper describes the case of a non-diarrheic patient colonized with C. difficile ribotype 014 in the intestinal tract who developed a post-surgical wound infection by C. difficile ribotype 078. The infection responded to metronidazole administered first intravenously and then orally. This case indicates that C. difficile may not only be related to diarrheic diseases, but also to infections of non-healing wounds, especially in situations when C. difficile is the only isolated pathogen. PMID- 25935202 TI - Characterization and Genomic Analysis of Quinolone-Resistant Delftia sp. 670 Isolated from a Patient Who Died from Severe Pneumonia. AB - Antibiotic-resistant opportunistic pathogens have become a serious concern in recent decades, as they are increasingly responsible for hospital-acquired infections. Here, we describe quinolone-resistant Delftia sp. strain 670, isolated from the sputum of a patient who died from severe pulmonary infection. The draft genome sequence of this strain was obtained by whole-genome shotgun sequencing, and was subjected to comparative genome analysis. Genome analysis revealed that one critical mutation (Ser83Ile in gyrA) might play a decisive role in quinolone resistance. The genome of Delftia sp. strain 670 contains both type II and type VI secretion systems, which were predicted to contribute to the virulence of the strain. Phylogenetic analysis, assimilation tests, and comparative genome analysis indicated that strain 670 differed from the four known Delftia species, suggesting this strain could represent a novel species. Although the study could not determine the strain 670 as the pathogen led to mortality, our findings also presented the pathogenic potential of Delftia species, and the increasing severity of antibiotic resistance among emerging opportunistic pathogens. The whole genome sequencing and comparative analysis improved our understanding of genome evolution in the genus Delftia, and provides the foundation for further study on drug resistance and virulence of Delftia strains. PMID- 25935203 TI - Non-cognitive selected students do not outperform lottery-admitted students in the pre-clinical stage of medical school. AB - Medical schools all over the world select applicants using non-cognitive and cognitive criteria. The predictive value of these different types of selection criteria has however never been investigated within the same curriculum while using a control group. We therefore set up a study that enabled us to compare the academic performance of three different admission groups, all composed of school leaver entry students, and all enrolled in the same Bachelor curriculum: students selected on non-cognitive criteria, students selected on cognitive criteria and students admitted by lottery. First-year GPA and number of course credits (ECTS) at 52 weeks after enrollment of non-cognitive selected students (N = 102), cognitive selected students (N = 92) and lottery-admitted students (N = 356) were analyzed. In addition, chances of dropping out, probability of passing the third year OSCE, and completing the Bachelor program in 3 years were compared. Although there were no significant differences between the admission groups in first-year GPA, cognitive selected students had obtained significantly more ECTS at 52 weeks and dropped out less often than lottery-admitted students. Probabilities of passing the OSCE and completing the bachelor program in 3 years did not significantly differ between the groups. These findings indicate that the use of only non-cognitive selection criteria is not sufficient to select the best academically performing students, most probably because a minimal cognitive basis is needed to succeed in medical school. PMID- 25935204 TI - Trypanosoma cruzi burden, genotypes, and clinical evaluation of Chilean patients with chronic Chagas cardiopathy. AB - There are currently no biomarkers to assess which patients with chronic indeterminate Chagas disease will develop heart disease and which will spend their entire life in this state. We hypothetize that the parasite burden and Trypanosoma cruzi genotypes are related to the presence of heart disease in patients with Chagas disease. This study is aimed to investigate the parasite burden and T. cruzi genotypes in chagasic cardiopaths versus chagasic individuals without cardiac involvement according to the New York Heart Association. Patients with chronic Chagas disease, 50 with and 50 without cardiopathy (controls), groups A and B, respectively, were submitted to anamnesis, physical examination, and electrocardiogram. Echo-Doppler was performed for group A; all important known causes of cardiopathy were discarded. Xenodiagnosis, conventional PCR, and quantitative PCR were performed on patients of both groups. T. cruzi genotyping was done for 25 patients of group A and 20 of group B. The 50 cardiopaths had 80 electrocardiographic alterations, most of them in grade II of the New York Heart Association classification; 49 were classified in grade I by Echo-Doppler, and only one patient was in grade III. The difference in average parasitemia in patients of groups A and B was not significant. The most frequent T. cruzi DTU found was TcV. The parasite burden and genotype of the groups with and without cardiopathy were similar. Graphical abstract Imagen 1 Chronic chagas cardiopathy chest X-ray heart enlargement Figure 2 Chronic Chagas cardiopathy microaneurism of left ventricle. Cineangiography. PMID- 25935205 TI - Current topics in surgery for multiple ventricular septal defects. AB - In this review article, we describe several topics, including the sandwich technique, the transatrial re-endocardialization technique, the limited apical left ventriculotomy approach and device closure. The sandwich technique was introduced for the closure of muscular ventricular septal defects (VSD) by sandwiching the septum between two felt patches placed in the left and right ventricle. This technique requires neither the transection of muscular trabeculae nor ventriculotomy. Although the sandwich technique has resulted in the improvement of surgical outcomes, cases of postoperative cardiac dysfunction have been reported. Multiple smaller VSDs have been closed with transatrial re endocardialization. Septal dysfunction may be avoided through this technique, in which the septal trabeculae are approximated in two layers of superficial, endocardial running sutures. Recently, a number of reports have recommended a limited apical left ventriculotomy approach. With this technique, a much shorter incision of around 1 cm at the apex of the left ventricle may be sufficient for achieving the complete closure of apical muscular VSDs. The transcatheter or perventricular device closure of muscular VSDs has increasingly been performed with good results. Although favorable early and mid-term results of device closure have been reported, this method is not always safer or less invasive than surgical closure. Long-term evaluations should be performed to determine whether the right and left ventricular functions are affected by treatment with relatively large devices in the heart. PMID- 25935206 TI - Perceived Challenges in Dementia Care by Vietnamese Family Caregivers and Care Workers in South Australia. AB - The majority of Vietnamese Australians migrated to Australia as refugees to escape a war and this unique migration background may affect their ability to access and utilize healthcare services in Australia. Inability to utilize dementia services is associated with higher levels of caregiver burden, higher rates of morbidities and mortality and hospitalization. The aim of the study was to explore the perceived challenges of dementia care from Vietnamese family caregivers and Vietnamese care workers. Gadamer's philosophical hermeneutics was used to interpret and describe the experiences of the participants. Data were collected from in-depth interviews with six Vietnamese family caregivers and a focus group with Vietnamese care workers using purposive sampling. Participants were recruited from a Vietnamese community care organization in South Australia. Five themes were identified from the data analysis namely: (1) a need for culturally and linguistically appropriate dementia education programs; (2) a willingness and unwillingness to seek help; (3) poor knowledge of health care service availability related to dementia; (4) the effect of language barrier in accessing services; and (5) the main sources of services utilized. The study revealed that Vietnamese family caregivers and Vietnamese care workers held different views on the association of stigma with dementia. Findings also revealed factors that impacted accessing and utilizing dementia services. These findings facilitate a more comprehensive understanding of Vietnamese family caregivers' needs and have implications for developing individualized support for family caregivers and for consumer-directed dementia services in Australia. PMID- 25935207 TI - Influence of curve magnitude and other variables on operative time, blood loss and transfusion requirements in adolescent idiopathic scoliosis. AB - BACKGROUND: Posterior spinal instrumentation and fusion for correction of adolescent idiopathic scoliosis (AIS) typically requires lengthy operating time and may be associated with significant blood loss and subsequent transfusion. This study aimed to identify factors predictive of duration of surgery, intraoperative blood loss and transfusion requirements in an Irish AIS cohort. METHODS: A retrospective review of 77 consecutive patients with AIS who underwent single-stage posterior spinal instrumentation and fusion over a two-year period at two Dublin tertiary hospitals was performed. Data were collected prospectively and parameters under analysis included pre- and postoperative radiographic measurements, intraoperative blood loss, surgical duration, blood products required, laboratory blood values and perioperative complications. RESULTS: Mean preoperative primary curve Cobb angle was 62.3 degrees ; mean surgical duration was 5.6 h. The perioperative allogeneic red blood cell transfusion rate was 42.8 % with a median requirement of 1 unit. Larger curve magnitudes were positively correlated with longer fusion segments, increased operative time and greater estimated intraoperative blood loss. Preoperative Cobb angles greater than 70 degrees [Relative Risk (RR) 4.42, p = 0.003] and estimated intraoperative blood loss greater than 1400 ml (RR 3.01, p = 0.037) were independent predictors of red blood cell transfusion risk. CONCLUSION: Larger preoperative curve magnitudes in AIS increase operative time and intraoperative blood loss; preoperative Cobb angles greater than 70(o) and intraoperative blood loss greater than 1400 ml are predictive of red blood cell transfusion requirement in this patient group. PMID- 25935208 TI - Whole-blood immunoassay for gammaH2AX as a radiation biodosimetry assay with minimal sample preparation. AB - The current state of the art in high-throughput minimally invasive radiation biodosimetry involves the collection of samples in the field and analysis at a centralized facility. We have developed a simple biological immunoassay for radiation exposure that could extend this analysis out of the laboratory into the field. Such a forward placed assay would facilitate triage of a potentially exposed population. The phosphorylation and localization of the histone H2AX at double-stranded DNA breaks has already been proven to be an adequate surrogate assay for reporting DNA damage proportional to radiation dose. Here, we develop an assay for phosphorylated H2AX directed against minimally processed sample lysates. We conduct preliminary verification of H2AX phosphorylation using irradiated mouse embryo fibroblast cultures. Additional dosimetry is performed using human blood samples irradiated ex vivo. The assay reports H2AX phosphorylation in human blood samples in response to ionizing radiation over a range of 0-5 Gy in a linear fashion, without requiring filtering, enrichment, or purification of the blood sample. PMID- 25935209 TI - Lack of reliability in the disruption of cognitive performance following exposure to protons. AB - A series of three replications were run to determine the reliability with which exposure to protons produces a disruption of cognitive performance, using a novel object recognition task and operant responding on an ascending fixed-ratio task. For the first two replications, rats were exposed to head-only exposures to 1000 MeV/n protons at the NASA Space Radiation Laboratory. For the third replication, subjects were given head-only or whole-body exposures to both 1000 and 150 MeV/n protons. The results were characterized by a lack of consistency in the effects of exposure to protons on the performance of these cognitive tasks, both within and between replications. The factors that might influence the lack of consistency and the implications for exploratory class missions are discussed. PMID- 25935210 TI - Cell-free DNA in the urine of rats exposed to ionizing radiation. AB - Investigation of cell-free DNA (cf-DNA) in body fluids, as a potential biomarker for assessing the effect of ionizing radiation on the organism, is of considerable interest. We investigated changes in the contents of cell-free mitochondrial DNA (cf-mtDNA) and cell-free nuclear DNA (cf-nDNA) in the urine of X-ray-exposed rats. Assays of cf-mtDNA and cf-nDNA were performed by a real-time PCR in rat urine collected before and after irradiation of animals with doses of 3 and 5 Gy. We also determined the presence of mutations in urine cf-mtDNA, as recognized by Surveyor nuclease. A sharp increase in cf-mtDNA and cf-nDNA in the urine of irradiated rats was observed within 24 h after exposure, followed by a decrease to normal levels. In all cases, the contents of cf-mtDNA fragment copies (estimated by gene tRNA) were significantly higher than those of cf-nDNA estimated by gene GAPDH. A certain portion of mutant cf-mtDNA fragments was detected in the urine of exposed rats, whereas they were absent in the urine of the same animals before irradiation. These preliminary data also suggest that the increased levels of urine cf-mtDNA and cf-nDNA may be a potential biomarker for noninvasive assessment of how the organism responds to ionizing radiation influence. PMID- 25935212 TI - Repaired tetralogy of Fallot with coexisting unrepaired partial anomalous pulmonary venous connection is associated with diminished right ventricular ejection fraction and more severe right ventricular dilation. AB - BACKGROUND: There is an established association between tetralogy of Fallot and partial anomalous pulmonary venous connections. This association is important because surgically repaired tetralogy patients have increased risk of right heart failure. We hypothesize that partial anomalous venous connections increase right ventricular volumes and worsen right ventricular failure. MATERIALS AND METHODS: We reviewed cardiac MRI exams performed at a tertiary pediatric hospital from January 2005 to January 2014. We identified patients with repaired tetralogy and unrepaired partial anomalous pulmonary venous connection. We used age- and gender matched repaired tetralogy patients without partial anomalous pulmonary venous connection as controls. We analyzed the MRI results and surgical course and performed comparative statistics to identify group differences. RESULTS: There were eight patients with repaired tetralogy and unrepaired partial anomalous pulmonary venous connection and 16 controls. In all cases, the partial anomalous pulmonary venous connection was not detected on preoperative echocardiography. There were no significant differences in surgical course and body surface area between the two groups. Repaired tetralogy patients with unrepaired partial anomalous pulmonary venous connection showed significantly higher indexed right ventricular end diastolic volume (149 +/- 33 mL/m(2) vs. 118 +/- 30 mL/m(2)), right ventricle to left ventricle size ratios (3.1 +/- 1.3 vs. 1.9 +/- 0.5) and a higher incidence of reduced right ventricular ejection fraction compared to controls (3/8 vs. 0/16). CONCLUSION: Repaired tetralogy of Fallot with unrepaired partial anomalous pulmonary venous connection is associated with reduced right ventricular ejection fraction and more significant right ventricular dilation. PMID- 25935211 TI - The Economic and Humanistic Burden of Severe Sepsis. AB - Sepsis and severe sepsis in particular remain a major health problem worldwide. Their cost to society extends well beyond lives lost, as the impact of survivorship is increasingly felt. A review of the medical literature was completed in MEDLINE using the search phrases "severe sepsis" and "septic shock" and the MeSH terms "epidemiology", "statistics", "mortality", "economics", and "quality of life". Results were limited to human trials that were published in English from 2002 to 2014. Articles were classified by dominant themes to address epidemiology and outcomes, including quality of life of both patient and family caregivers, as well as societal costs. The severity of sepsis is determined by the number of organ failures and the presence of shock. In most developed countries, severe sepsis and septic shock account for disproportionate mortality and resource utilization. Although mortality rates have decreased, overall mortality continues to increase and is projected to accelerate as people live longer with more chronic illness. Among those who do survive, impaired quality of life, increased dependence, and rehospitalization increase healthcare consumption and, along with increased mortality, all contribute to the humanistic burden of severe sepsis. A large part of the economic burden of severe sepsis occurs after discharge. Initial inpatient costs represent only 30 % of the total cost and are related to severity and length of stay, whereas lost productivity and other indirect medical costs following hospitalization account for the majority of the economic burden of sepsis. Timeliness of treatment as well as avoidance of intensive care unit (ICU)-acquired illness/morbidity lead to important differences in both cost and outcome of treatment for severe sepsis and represent areas where improvement in care is possible. The degree of sophistication of a health system from a national perspective results in significant differences in resource use and outcomes for patients with serious infections. Comprehensive understanding of the cost and humanistic burden of severe sepsis provides an initial practical framework for health policy development and resource use. PMID- 25935213 TI - A new lymphocyte proliferation assay for potency determination of bovine tuberculin PPDs. AB - The tuberculin skin test is the method of choice for tuberculosis surveillance in livestock ruminants. The exact definition of the biological activity of bovine tuberculin purified protein derivatives (bovine tuberculin PPDs) is essential for the reliability of a test system. PPDs consist of heterogeneous mixtures of mycobacterial antigens, making it difficult to determine their potency in vitro. The commonly used batch potency test is therefore based on the evaluation of skin reactions in mycobacteria-sensitized guinea pigs. Aim of the present study was to test an alternative in vitro method that reliably quantifies tuberculin PPD potency. This novel approach may prevent animal distress in the future. To this end a flow cytometry-based lymphocyte proliferation assay using peripheral blood mononuclear cells (PBMCs) from sensitized guinea pigs was established. Potency estimates for individual PPD preparations were calculated in comparison to an international standard. The comparison with results obtained from the guinea pig skin test revealed that the lymphocyte proliferation assay is more precise but results in systematically higher potency estimates. However, with a manufacturer specific correction factor a correlation of over 85% was achieved, highlighting the potential of this in vitro method to replace the current guinea pig skin test. PMID- 25935214 TI - Assessment of contamination and misclassification biases in a randomized controlled trial of a social network peer education intervention to reduce HIV risk behaviors among drug users and risk partners in Philadelphia, PA and Chiang Mai, Thailand. AB - Controlled trials of HIV prevention and care interventions are susceptible to contamination. In a randomized controlled trial of a social network peer education intervention among people who inject drugs and their risk partners in Philadelphia, PA and Chiang Mai, Thailand, we tested a contamination measure based on recall of intervention terms. We assessed the recall of test, negative and positive control terms among intervention and control arm participants and compared the relative odds of recall of test versus negative control terms between study arms. The contamination measures showed good discriminant ability among participants in Chiang Mai. In Philadelphia there was no evidence of contamination and little evidence of diffusion. In Chiang Mai there was strong evidence of diffusion and contamination. Network structure and peer education in Chiang Mai likely led to contamination. Recall of intervention materials can be a useful method to detect contamination in experimental interventions. PMID- 25935215 TI - The Association Between Alcohol Consumption and Condom Use: Considering Correlates of HIV Risk Among Black Men Who Have Sex with Men. AB - Epidemiological data indicate Black men who have sex with men (MSM) are the most at-risk group for HIV infection. However, the factors driving this disparity are not fully understood. Condom use remains a significant point of intervention in mitigating sexually transmitted infections. Alcohol consumption is highly prevalent among Black MSM, has a significant role in the culture of sex, and may significantly interfere with condom use. This review will examine the relationship between alcohol consumption and condom use among Black MSM. In this review we, (a) discuss the prevalence of alcohol use among MSM and its association with condom use; (b) consider the role of alcohol in the culture of MSM; (c) review the literature on the relationship between alcohol and condom use; and (d) discuss the role of several empirically-supported moderating variables in strengthening the relationship between alcohol use and noncondom use. This review places the finding and implications for HIV risk among Black MSM in the context of the broader literature on MSM. PMID- 25935216 TI - Past, present, and future of arenavirus taxonomy. AB - Until recently, members of the monogeneric family Arenaviridae (arenaviruses) have been known to infect only muroid rodents and, in one case, possibly phyllostomid bats. The paradigm of arenaviruses exclusively infecting small mammals shifted dramatically when several groups independently published the detection and isolation of a divergent group of arenaviruses in captive alethinophidian snakes. Preliminary phylogenetic analyses suggest that these reptilian arenaviruses constitute a sister clade to mammalian arenaviruses. Here, the members of the International Committee on Taxonomy of Viruses (ICTV) Arenaviridae Study Group, together with other experts, outline the taxonomic reorganization of the family Arenaviridae to accommodate reptilian arenaviruses and other recently discovered mammalian arenaviruses and to improve compliance with the Rules of the International Code of Virus Classification and Nomenclature (ICVCN). PAirwise Sequence Comparison (PASC) of arenavirus genomes and NP amino acid pairwise distances support the modification of the present classification. As a result, the current genus Arenavirus is replaced by two genera, Mammarenavirus and Reptarenavirus, which are established to accommodate mammalian and reptilian arenaviruses, respectively, in the same family. The current species landscape among mammalian arenaviruses is upheld, with two new species added for Lunk and Merino Walk viruses and minor corrections to the spelling of some names. The published snake arenaviruses are distributed among three new separate reptarenavirus species. Finally, a non-Latinized binomial species name scheme is adopted for all arenavirus species. In addition, the current virus abbreviations have been evaluated, and some changes are introduced to unequivocally identify each virus in electronic databases, manuscripts, and oral proceedings. PMID- 25935217 TI - Interactive effects of fire and large herbivores on web-building spiders. AB - Altered disturbance regimes are a major driver of biodiversity loss worldwide. Maintaining or re-creating natural disturbance regimes is therefore the focus of many conservation programmes. A key challenge, however, is to understand how co occurring disturbances interact to affect biodiversity. We experimentally tested for the interactive effects of prescribed fire and large macropod herbivores on the web-building spider assemblage of a eucalypt forest understorey and investigated the role of vegetation in mediating these effects using path analysis. Fire had strong negative effects on the density of web-building spiders, which were partly mediated by effects on vegetation structure, while negative effects of large herbivores on web density were not related to changes in vegetation. Fire amplified the effects of large herbivores on spiders, both via vegetation-mediated pathways and by increasing herbivore activity. The importance of vegetation-mediated pathways and fire-herbivore interactions differed for web density and richness and also differed between web types. Our results demonstrate that for some groups of web-building spiders, the effects of co-occurring disturbance drivers may be mostly additive, whereas for other groups, interactions between drivers can amplify disturbance effects. In our study system, the use of prescribed fire in the presence of high densities of herbivores could lead to reduced densities and altered composition of web building spiders, with potential cascading effects through the arthropod food web. Our study highlights the importance of considering both the independent and interactive effects of disturbances, as well as the mechanisms driving their effects, in the management of disturbance regimes. PMID- 25935218 TI - A New AP2/ERF Transcription Factor from the Oil Plant Jatropha curcas Confers Salt and Drought Tolerance to Transgenic Tobacco. AB - Jatropha curcas L. is a drought and salt-tolerant oil plant widely used for various purposes and has considerable potential as a diesel/kerosene substitute or extender. Understanding the molecular mechanisms underlie that the response to various biotic and abiotic stresses of this plant could be important to crop improvement efforts. Here, a new AP2/ERF-type transcription factor gene, named JcERF2, was isolated from the leaves of J. curcas. Sequence analysis showed that the JcERF2 gene contains a 759-bp open reading frame encoding a polypeptide of 252 amino acids. The predicted JcERF2 protein contained a conserved DNA-binding domain (the AP2/ERF domain) with 58 amino acids. The JcERF2 protein is highly homologous with other ERFs. JcERF2 was localized in the nucleus by analysis with a JcERF2-green fluorescent protein (GFP) fusion protein. Quantitative polymerase chain reaction (qPCR) analysis showed that JcERF2 was induced by drought, salt, abscisic acid, and ethylene. Overexpression of JcERF2 in transgenic tobacco plants enhanced the expression of biotic and abiotic stress-related genes, increased the accumulation of free proline and soluble carbohydrates, and conferred tolerance to drought and salt stresses compared to the wild type (WT). Taken together, the JcERF2 gene is a novel AP2/ERF transcription factor involved in plant response to environmental factors, which can be used as a potential candidate gene for genetic engineering of crops. PMID- 25935219 TI - A Comprehensive Review of Aliphatic Hydrocarbon Biodegradation by Bacteria. AB - Hydrocarbons are relatively recalcitrant compounds and are classified as high priority pollutants. However, these compounds are slowly degraded by a large variety of microorganisms. Bacteria are able to degrade aliphatic saturated and unsaturated hydrocarbons via both aerobic and anaerobic pathways. Branched hydrocarbons and cyclic hydrocarbons are also degraded by bacteria. The aerobic bacteria use different types of oxygenases, including monooxygenase, cytochrome dependent oxygenase and dioxygenase, to insert one or two atoms of oxygen into their targets. Anaerobic bacteria, on the other hand, employ a variety of simple organic and inorganic molecules, including sulphate, nitrate, carbonate and metals, for hydrocarbon oxidation. PMID- 25935220 TI - Modeling the Effect of pH and Temperature for Cellulases Immobilized on Enzymogel Nanoparticles. AB - Production costs of cellulosic biofuels can be lowered if cellulases are recovered and reused using particulate carriers that can be extracted after biomass hydrolysis. Such enzyme recovery was recently demonstrated using enzymogel nanoparticles with grafted polymer brushes loaded with cellulases. In this work, cellulase (NS50013) and beta-glucosidase (Novozyme 188) were immobilized on enzymogels made of poly(acrylic acid) polymer brushes grafted to the surface of silica nanoparticles. Response surface methodology was used to model effects of pH and temperature on hydrolysis and recovery of free and attached enzymes. Hydrolysis yields using both enzymogels and free cellulase and beta-glucosidase were highest at the maximum temperature tested, 50 degrees C. The optimal pH for cellulase enzymogels and free enzyme was 5.0 and 4.4, respectively, while both free beta-glucosidase and enzymogels had an optimal pH near 4.4. Highest hydrolysis sugar concentrations with cellulase and beta glucosidase enzymogels were 69 and 53 % of those with free enzymes, respectively. Enzyme recovery using enzymogels decreased with increasing pH, but cellulase recovery remained greater than 88 % throughout the operating range of pH values less than 5.0 and was greater than 95 % at pH values below 4.3. Recovery of beta glucosidase enzymogels was not affected by temperature and had little impact on cellulase recovery. PMID- 25935221 TI - The Photovoltaic Effect of CdS Quantum Dots Synthesized in Inverse Micelles and R Phycoerythrin Tunnel Cavities. AB - CdS quantum dots (CdS QDs) 4.3 nm in diameter synthesized in an AOT/isooctane/water microemulsion and in R-phycoerythrin tunnel cavities (3.5 * 6.0 nm) were analyzed for photoelectrochemical properties. The CdS QDs preparations were applied onto a platinum electrode to obtain solid films. Experiments were performed in a two-section vessel, with one section filled with ethanol and the other, with 3 M KCl. The sections were connected through an agar stopper. It was found that illumination of the films resulted in a change of the electrode potential. The magnitude of this change and the kinetics of the appearance and disappearance of the photopotential, i.e., the difference between the electrode potential on the light and in dark, depended on the nature of the QD shell. The photovoltaic effect of CdS QDs in R-phycoerythrin, compared to that of CdS QDs in AOT/isooctane micelles, is three to four times greater due to the photosensitizing action of R-phycoerythrin. The photosensitized effect was markedly higher than the photoelectric sensitivity of R-phycoerythrin and had the opposite polarity. Changes in the potential upon turning the light on and off could be observed repeatedly. PMID- 25935222 TI - Chemiluminescence Detection of Serine, Proline, Glycine, Asparagine, Leucine, and Histidine by Using Corresponding Aminoacyl-tRNA Synthetases as Recognition Elements. AB - Analysis of the concentration of free amino acids in biological samples is useful in clinical diagnostics. However, currently available methods are time consuming, potentially delaying diagnosis. Therefore, the development of more rapid analytical tools is needed. In this study, a chemiluminescence detection method for amino acids was developed, and the conditions for the enzyme reaction and assay were examined. For the recognition of each amino acid (here, serine, proline, glycine, asparagine, leucine, and histidine), the corresponding aminoacyl-tRNA synthetase (aaRS) was employed, and multiple enzymatic reactions were combined with a luminol chemiluminescence reaction. This method provided selective quantification from 1 to 20 MUM for serine, proline, glycine, and leucine; 1 to 60 MUM for asparagine; and 1 to 150 MUM for histidine. This assay, which utilized aaRSs for the detection of amino acids, could be useful for simple and rapid analysis of amino acids in clinical diagnostics. PMID- 25935223 TI - Enhancing T-DNA Transfer Efficiency in Barley (Hordeum vulgare L.) Cells Using Extracellular Cellulose and Lectin. AB - A major limitation of transforming barley tissues by Agrobacterium tumefaciens is the low frequency of T-DNA transfer due to recalcitrance of barley as a host. The effect of extracellular cellulose and lectin on Agrobacterium transformation efficiency was investigated in this study. Barley callus cultures were transformed with the AGL1 strain containing the vector pBI121 in the presence of 10 mg mL(-1) cellulose or 0.001, 0.05 and 0.1 mg mL(-1) lectin. Addition of cellulose significantly (P <= 0.05) increased the number of GUS spots by 50 % compared to standard conditions in the presence of only 200 MUM acetosyringone (AS). Frequency of G418-resistant aggregates on the surfaces of callus cultures was 29 and 71.5 %, following AS and AS + cellulose treatments, respectively, after 4 weeks of selection. Presence of 0.05 or 0.1 mg mL(-1) lectin also increased the number of GUS spots and frequency of G418-resistant cells in the selection period, but the increase in blue spots was not significant. We examined the effect of lectin and cellulose on bacterial attachment to callus tissues. Both cellulose and lectin were found to have a significant positive effect on the numbers of bacteria attached to barley callus. Epifluorescence microscopy revealed that Agrobacterium cells had accumulated in the scaffolds of irregular fibrous cellulose with a mean particle size of 200 MUm. Expression of nptII in transformed callus lines confirmed the stable transformation of the gene. Our study showed for the first time the binding of Agrobacterium cells to fibrous cellulose and also demonstrated how polysaccharides and glycoproteins can be used to improve T-DNA transfer in monocotyledon transformation procedures. PMID- 25935224 TI - The Inhibitory Effects of Cu(2+) on Exopalaemon carinicauda Arginine Kinase via Inhibition Kinetics and Molecular Dynamics Simulations. AB - We studied the Cu(2+)-mediated inhibition and aggregation of Exopalaemon carinicauda arginine kinase (ECAK). We found that Cu(2+) significantly inactivated ECAK activity and double-reciprocal kinetics demonstrated that Cu(2+) induced noncompetitive inhibition of arginine and ATP (IC50 = 2.27 +/- 0.16 MUM; K i for arginine = 13.53 +/- 3.76; K i for ATP = 4.02 +/- 0.56). Spectrofluorometry results showed that Cu(2+) induced ECAK tertiary structural changes including the exposure of hydrophobic surfaces that directly induced ECAK aggregation. The addition of osmolytes such as glycine and proline successfully blocked ECAK aggregation induced by Cu(2+) and recovered ECAK activity. We built a 3D structure for ECAK using the ECAK ORF gene sequence. Molecular dynamics (MD) and docking simulations between ECAK and Cu(2+) were conducted to elucidate the binding mechanisms. The results showed that Cu(2+) blocked the entrance to the ATP active site; these results are consistent with the experimental result that Cu(2+) induced ECAK inactivation. Since arginine kinase (AK) plays an important role in cellular energy metabolism in invertebrates, our study can provide new information about the effect of Cu(2+) on ECAK enzymatic function and unfolding, including aggregation, and the protective effects of osmolytes on ECAK folding to better understand the role of the invertebrate ECAK metabolic enzyme in marine environments. PMID- 25935225 TI - Ultrasensitive Impedimetric Biosensor Fabricated by a New Immobilisation Technique for Parathyroid Hormone. AB - This paper presents a novel ultrasensitive and rapid impedimetric biosensor with new immobilisation materials for parathyroid hormone (PTH) with the aim to determine the PTH level in serum for the diagnosis and monitoring of parathyroid diseases such as hyperparathyroidism, adenoma, and thyroid cancer. The interaction between PTH and the biosensor was investigated with an electrochemical method. The biosensor was based on the gold electrode modified by mercaptohexanol (6-MHL). Anti-parathyroid hormone (anti-PTH) was covalently immobilised onto a self-assembled monolayer (SAM) by using epiclorhidrina (EPI) with ethanolamine (EA). The EPI-EA interaction represents the first use of these for the construction of biosensors in published reports. The immobilisation of the anti-PTH was monitored by electrochemical impedance spectroscopy, cyclic voltammetry and scanning electron microscopy (SEM) techniques. After the optimisation studies of immobilisation materials such as 6-MHL, EPI, EA and glutaraldehyde, linearity, repeatability and sensitivity of biosensor were evaluated as the performance of biosensor. PTH was detected within a linear range of 0.1-0.6 pg/ml, and the detection limit was 0.1 fg/ml. The specificity of the biosensor was also investigated. Finally, the described biosensor was used to detect the PTH levels in artificial serum samples. PMID- 25935226 TI - Atrial fibrillation ablation using remote magnetic navigation and the risk of atrial-esophageal fistula: international multicenter experience. AB - PURPOSE: Remote magnetic navigation (RMN) has been used in various electrophysiological procedures, including atrial fibrillation (AF) ablation. Atrial-esophageal fistula (AEF) is one of most disastrous complications of AF ablation. We aimed to evaluate the incidence of AEF during AF ablation using RMN in comparison to manual ablation. METHODS: We conducted the first international survey among RMN operators for assessment of the prevalence of AEF and procedural parameters affecting the risk. Data from parallel survey of AEF among Canadian interventional electrophysiologists (CIE) using only manual catheters served as control. RESULTS: Fifteen RMN operators (who performed 3637 procedures) and 25 manual CIE operators (7016 procedures) responded to the survey. RMN operators were more experienced than CIE operators (16.3 +/- 8.3 vs. 9.2 +/- 5.4 practice years in electrophysiology, p = 0.007). The maximal energy output in the posterior wall was higher in the operator using RMN (33 +/- 5 vs. 28.6 +/- 4.9 W; p = 0.02). Other parameters including use of preprocedural images, irrigated catheter, pump flow rate, esophageal temperature monitoring, intracardiac echocardiography (ICE), and general anesthesia were similar. CIE operators administered proton-pump inhibitors postoperatively significantly more than RMN operators (76 vs. 35%, p = 0.01). AEF was reported in 5 of the 7016 patients in the control group (0.07%) but in none of the RMN group (p = 0.11). CONCLUSIONS: AEF is a rare complication and its evaluation necessitates large-scale studies. Although no AEF case with RMN was reported in this large study or previously on the literature, the rarity of this complication prevents firm conclusion about the risk. PMID- 25935228 TI - Challenges in minimizing the adverse effects of cannabis use after legalization. PMID- 25935227 TI - Detection of left atrial thrombus by intracardiac echocardiography in patients undergoing ablation of atrial fibrillation. AB - BACKGROUND: The role of intracardiac echocardiography (ICE) to detect thrombus within left atrium (LA) before atrial fibrillation (AF) ablation despite a recent transesophageal echocardiogram (TEE) is not well defined. We examined the prevalence of LA/left atrial appendage (LAA) thrombus using ICE immediately prior to AF ablation in patients in whom anticoagulation was not withheld. METHODS: We analyzed 122 consecutive patients (62.6 +/- 10.8 years, 90 males, CHA(2)DS(2) VASc score 2.4 +/- 1.5, persistent AF 29.5 %) who underwent an ICE-guided AF ablation 1 day after a negative (n = 120) or inconclusive (n = 2) TEE for LA thrombus. LA was imaged with ICE from the right atrium, coronary sinus, and right ventricular inflow tract (RVIT). ICE and TEE images were compared for LAA area, thrombus, and spontaneous echo contrast (SEC). RESULTS: LAA was adequately visualized in 99 and 100 % of patients with TEE and ICE, respectively. RVIT was the best ICE view for LAA visualization. The LAA 2-D-area measured by TEE was 4.9 +/- 0.5 vs. 5 +/- 0.5 cm(2) by ICE (P = NS). ICE identified a thrombus in seven patients with a previous negative TEE, leading to cancellation of ablation. It ruled out a thrombus in two patients with an inconclusive TEE. Thrombi were found in the LAA (n = 4), atrial septum (n = 2), and left superior pulmonary vein (n = 1). SEC during TEE was more frequent in patients with thrombus on ICE than those without (85.7 vs. 17.4 %; p = 0.03; positive predictive value 23.1 %, negative predictive value 98.9 %). CONCLUSIONS: The results of our staged imaging approach suggest that ICE has a complimentary value in re-screening the LA/LAA for thrombus after a recent negative or equivocal TEE. The presence of SEC during TEE increases the probability of finding a thrombus with ICE, which could potentially be dislodged during catheter manipulation. PMID- 25935229 TI - Liver resection with thrombectomy as a treatment of hepatocellular carcinoma with major vascular invasion: results from a retrospective multicentric study. AB - BACKGROUND: The role of liver resection (LR) of hepatocellular carcinoma with macroscopic vascular thrombosis (MVT) remains controversial. The aim of this study is to evaluate whether the presence of MVT should still be considered a contraindication for LR. METHODS: Retrospective study was carried out on 62 patients who underwent LR and thrombectomy for hepatocellular carcinoma complicated by MVT. Of the 62 patients, 15 (36.5%) had tumor thrombus (TT) in the peripheral portal vein (Vp1), 5 (12.2%) in second branch (Vp2), and 21 (51.3%) in the first branch/portal vein trunk (Vp3), while on the hepatic/cava vein side, 8 (12.9%) had TT in the main trunk of the hepatic veins (Vv2) and 3 (4.8%) had TT reaching the vena cava/right atrium (Vv3). RESULTS: Perioperative major morbidity was 14.5%, while in-hospital mortality was 4.8%. Overall, 1, 3, and 5-year survival rates were 53.3%, 30.1%, and 20%, and disease-free survival rates were 31.7%, 20.8%, and 15.6%, respectively. There were no differences in survival about the MVT localized in Vp1, Vp2, or Vp3 (P = .77), while we found a statistical trend between patients with Vv2 and Vv3 (P = .06). CONCLUSION: Surgical resection seems to be justified in these patients, and the presence of MVT should no longer be considered an absolute contraindication for LR. PMID- 25935230 TI - D-ribose-L-cysteine supplementation enhances wound healing in a rodent model. AB - BACKGROUND: Wound healing and chronic wounds are serious public health issues. While wounds heal, cellular stores of antioxidants are depleted. d-ribose-l cysteine (DRLC) is a precursor to the antioxidant glutathione. The effect of oral supplementation with DRLC on wound healing was studied in rats. METHODS: A rodent model of calibrated wounding was used. Group A rats were given DLRC for 1 week before wounding and for 3, 7, or 14 days after wounding. Group B rats were given DRLC only after wounding. Control animals were given no supplement. Photographic comparisons were made to study wound edema and inflammation. Wound strength was determined by using a laser-vacuum device. RESULTS: During healing, both Group A and B animals showed less edema and inflammation than Control. Group A animals had the weakest wounds at 3 days after surgery, but the strongest wounds after 14 days. Group B animals had similar wound strength to Control animals at 7 days, but stronger wounds after 14 days. CONCLUSIONS: DRLC supplementation appears to reduce wound inflammation early after wounding and enhance wound strength by 14 days. This suggests that increased intracellular glutathione levels may improve and enhance wound healing. PMID- 25935231 TI - [Chemotherapy-induced cardiotoxicity: Incidence, diagnosis and prevention]. AB - Chemotherapy-induced cardiotoxicity is a major cause of morbidity and mortality in cancer survivor. The most clinically evident and best known cardiotoxicity is the anthracycline adverse effect with heart failure. Many cardiovascular adverse effects appear after cancer therapy: heart congestive failure, myocardial ischemia, hypertension, thromboembolic complications, arrhythmias and conduction disturbances. There are potential strategies to mitigate the risks of cardiac complications for cancer patients with physical examination, echocardiography and electrocardiogram. The management of the cardiotoxicity is variable. PMID- 25935232 TI - [Renal late effects in patients treated for cancer in childhood]. AB - Impaired renal function may occur following multimodal treatment of cancer in childhood. Renal late effects caused by chemotherapy, renal surgery and/or radiotherapy are now well described; but little is known about their prevalence and time of development. Herein, we provide a synthesis of the different renal complications that may occur with their physiopathology in relation with specific treatment exposures. This review summarized the literature that supported the recommendations issued by the long-term follow-up group of the "Societe francaise des cancers de l'enfant (SFCE)" for childhood cancer survivors at risk for nephrotoxicity (www.sfce.org ; www.soc-nephrologie.org/SNP/index.htm). We developed these monitoring elements and the lifestyle recommendations for all asymptomatic survivors. PMID- 25935233 TI - Translation and cultural adaptation of the Mother-Generated Index into Brazilian Portuguese: A postnatal quality of life study. AB - OBJECTIVE: quality of life issues are central to maternal health and well-being. Within the context of a study examining postnatal quality of life, we set out to translate into Brazilian Portuguese the Mother-Generated Index and ensure its cross-cultural adaption for use in a Brazilian context. DESIGN: the Mother Generated Index, a subjective quality of life tool, underwent a validated process of translation and cultural adaptation: synthesis of two independently translated versions, back-translation and review by an expert committee was followed by testing of the preliminary tool with 30 mothers. SETTINGS: community-based study in city in north-eastern Brazil. PARTICIPANTS: 30 postpartum mothers, interviewed approximately 30 days after birth. FINDINGS: while the mothers understood the concept of identifying and scoring quality of life aspects, many did not grasp the concept behind the use of 'spending points' to produce a relative ranking of these aspects. We resolved this by giving the mothers 'spending beans' instead; beans are a regional food staple. This use of a physical 'currency' solved the problem. DISCUSSION: this modified approach was ratified by the committee of experts and used with success on a further sample of 91 mothers. The whole process aimed to ensure semantic equivalence of the translated tool, and following this process we concluded that face validity of the Brazilian Portuguese Mother-Generated Index was good. While considerable resources are required to ensure a robust process of translation and adaptation, this is necessary if valid and reliable tools are to be produced. IMPLICATIONS: We conclude that the Mother-Generated Index is a valid tool to measure quality of life among Brazilian postpartum mothers, as it allows a simple and understandable way of assessing the various dimensions involved in their quality of life. Moreover, the Mother-Generated Index can provide healthcare professionals the opportunity to become aware of all significant aspects of a woman's life after childbirth. PMID- 25935234 TI - Long Term Treatment Results for Deep Infections of Total Knee Arthroplasty. AB - This study aims to identify the long-term outcomes of total knee arthroplasty (TKA) treated for deep infection. 3270 consecutive primary and 175 revision TKAs were followed prospectively. There were 39 deep infections (1.16%): 29 primary (0.9%) and 10 revision (5.7%) cases. Two-stage resection and re-implantation procedure was performed in 13 primary cases with 10/13 (77%) successfully resolved. Early (<1 month) Irrigation and Debridement (I&D) was performed in 16 primary cases with 100% success. Late (>4 months) I&D was performed in 6 cases with 5/6 (83.3%) successful. Infection following revision TKA resulted in poor outcomes with both two-stage (2/4 successful) and I&D (2/6 successful). Deep infection after primary TKA can be successfully resolved with I&D and appropriate antibiotic treatment in the early postoperative course. PMID- 25935235 TI - The Financial Impact of a Multidisciplinary Preoperative Risk Stratification Program for Joint Arthroplasty. AB - This study's purpose was to assess the impact of a preoperative risk stratification program on joint arthroplasty outcomes at a single institution. We hypothesized that by using a standardized preoperative risk stratification center we would see better outcomes and decreased costs. The triage cohort (T) included 1498 patients assessed at a standardized risk stratification center, and the non triage cohort (NT) included 1100 patients who did not utilize the center. The T cohort had significantly higher ASA classification (P<0.0001) and ACCI scores (P=0.028). We found no significant difference in complication rates. The T cohort showed a significant decrease in LOS (P<0.0001) and an increase in average reimbursement (P=0.009). A standardized preoperative risk stratification center can contribute to decreased LOS, increased reimbursement and help prevent complications. PMID- 25935236 TI - Genotype combinations of two IL4 polymorphisms influencing IL-4 plasma levels are associated with different risks of severe malaria in the Malian population. AB - We have previously found that children heterozygous for IL4 variable-number tandem repeat (VNTR) (rs8179190) or IL4-33 (rs2070874) variants were at risk for severe malaria (SM), whereas homozygous children were protected suggesting a complex genetic control. Hence, to dissect this complex genetic control of IL4 VNTR and IL4-33, we performed further investigation by conditional logistic regression analysis and found a strong interaction between both markers (p < 10( 6)). The best-fit model revealed three genotype combinations associated with different levels of SM risk. The highest risk (odds ratio (OR) = 4.8, 95% confidence interval (CI) = 2.0-11.5) was observed for subjects carrying at least one copy of both IL4-33 allele T and IL4 VNTR allele 1, who exhibited higher interleukin (IL)-4 plasma levels (p = 0.007). Children homozygous for IL4 VNTR allele 2 had a lower SM risk as well as lower IL-4 plasma levels. Our findings indicate that the genetic interaction between these two IL-4 variants is a key factor of SM susceptibility, probably because of its direct role in IL-4 regulation. PMID- 25935237 TI - Analysis of 16 autosomal STRs and 17 Y-STRs in an indigenous Maya population from Guatemala. AB - The aim of this study was to contribute new data on autosomal STR and Y-STR markers of the Mayas from Guatemala in order to improve available databases of forensic interest. We analyzed 16 autosomal STR markers in a population sample of 155 indigenous Maya and 17 Y-chromosomal STR markers in the 100 males of the sample. Deviations from Hardy-Weinberg equilibrium and linkage disequilibrium between autosomal STR markers were not observed at any loci. The combined power of exclusion was estimated as 99.9991% and the combined power of discrimination was >99.999999999999%. Haplotype diversity of Y-STRs was calculated as 0.9984 +/- 0.0018 and analysis of pairwise genetic distances (Rst) supported the Native American background of the population. PMID- 25935238 TI - The medico-legal investigation of abandoned fetuses and newborns--a review of cases admitted to the Pretoria Medico-Legal Laboratory, South Africa. AB - There is a dearth of literature on the extent of fetal or newborn abandonment or "dumping" and the medico-legal investigation procedures these cases require. This is despite the fact that these occurrences are a worldwide phenomenon and by definition involve criminal law concerns such as illegal abortion, concealment of birth, murder, or neonaticide, depending on the country concerned. This article contributes to current literature in both respects and provides a retrospective case audit for the period 2004-2008 pertaining to all abandoned newborns and fetuses admitted to the Pretoria Medico-Legal Laboratory (PMLL) in South Africa. Demographic details, scope, and nature of the medico-legal investigation as well as formulation of cause of death were recorded. A total of 289 cases were identified for inclusion in this study, 57% of which were considered to have been non-viable fetuses, while 45 of the viable fetuses were deemed to have been stillborn. These instances involve the crimes of concealment of birth and at times illegal abortion, yet prosecution of these cases are relatively unheard of. Signs of live birth were identified in 38 of the cases in the study. Of these infants, 9 were deemed to have died from injuries they have sustained, and in a further 9 cases, no anatomical cause of death could be identified. Homicidal cases should be brought in cases where death ensued as a result of abandonment; however, it is not known how many cases were prosecuted. A comparatively large number of cases were found to have been admitted to the Pretoria Medico-Legal Laboratory. This is alarming because South African abortion laws are liberal and services are free at point of access in the public health care sector. A substantial percentage of cases of abandoned infants were found to have shown signs of life after birth implying a homicidal manner of death or death by abandonment, but it seems these cases are merely shelved. PMID- 25935239 TI - Effect of adding cofactors to exogenous fibrolytic enzymes on preingestive hydrolysis, in vitro digestibility, and fermentation of bermudagrass haylage. AB - Our objectives were to examine if adding metal ion cofactors (COF) to exogenous fibrolytic enzymes (EFE) would increase the beneficial effects of the EFE on the preingestive hydrolysis and in vitro digestibility and fermentation of bermudagrass haylage. In experiment 1, 5 COF (Mn(2+), Co(2+), Fe(2+), Ca(2+), and Mg(2+)) were screened to select the best candidates for synergistically enhancing release of water-soluble carbohydrates (WSC) from bermudagrass haylage by 5 EFE. The 5 EFE (1A, 2A, 11C, 13D, and 15D) were sourced from Trichoderma reesei and Aspergillus oryzae and they were the most effective of 12 EFE at increasing the neutral detergent fiber digestibility of bermudagrass haylage in a previous trial. Adding 1mM of each of the COF to EFE 2A or 11C synergistically increased release of WSC from bermudagrass haylage, as did adding (1mM) Fe(2+) to 1A, Mn(2+), Co(2+), or Fe(2+) to 13D, or Co(2+)or Fe(2+) to 15D. The greatest release of WSC responses were obtained by adding Mn(2+) to 11C (38%) or by adding Fe(2+) to 2A or 13D (10 and 21.9%, respectively). In experiment 2, the effect of increasing the COF dose on in vitro digestibility and fermentation of bermudagrass haylage was examined using the best EFE-COF combinations from experiment 1. Effects of adding increasing doses of these COF on EFE-mediated changes in vitro digestibility depended on the COF-EFE combination. Adding 10mM Mn(2+) alone to bermudagrass haylage increased DMD and NDFD by 2.7 and 6.3% and adding 11C alone increased these measures by 6.6 and 15.5%, respectively. However, adding 10mM Mn(2+) with 11C resulted in 3.5 and 8.1% increases in DMD and NDFD, respectively, beyond the increases caused by adding 11C alone. Adding Fe(2+) to 2A had no effects on EFE-mediated digestibility responses, but 2A prevented adverse effects of adding Fe(2+) alone on DMD and NDFD. In contrast, adding Fe(2+) to 13D reduced the increases in DMD and NDFD caused by adding the EFE alone. This study shows that adding COF to EFE can synergistically increase, decrease, or not affect the hydrolytic effects of EFE on bermudagrass haylage cell walls. The outcome depends on the specific EFE-COF combination and the COF dose. More research is required to understand the mechanisms resulting in these outcomes to exploit beneficial effects of COF on EFE. PMID- 25935240 TI - Effect of feeding calcareous marine algae to Holstein cows prepartum or postpartum on serum metabolites and performance. AB - Thirty-six multiparous Holstein cows and 12 springing heifers were used in a 9-wk randomized design trial to determine the response of cows fed calcareous marine algae (CMA) beginning 3wk prepartum or after parturition through 6wk postpartum on dry matter intake (DMI), blood and urine metabolites, and milk yield and composition. Within parity and expected calving date, cows were assigned randomly to 1 of 4 treatments with a 2*2 factorial arrangement. Prepartum diets were supplemented with calcium carbonate (CON) or 50g/d of CMA with a resulting dietary cation-anion difference of -5.17 and -3.99mEq/100g, respectively. Postpartum diets were formulated to provide either 317g/d of sodium bicarbonate and calcium carbonate (NBC) or 100g/d of CMA, providing a dietary cation-anion difference of 35.58 and 15.64mEq/100g, based on 25kg/d of DMI, respectively. No differences were observed in prepartum DMI or postpartum DMI, milk yield, percentage of milk fat, protein, lactose, and solids-not fat among treatments. Milk protein yield was higher for cows fed CMA prepartum compared with CON. Interactions of prepartum treatment and week were observed for yield of milk fat and energy-corrected milk because of higher yields for cows fed CMA during wk 2 and 6 compared with CON. Serum Na concentrations were greater for cows fed CON prepartum or NBC postpartum compared with CMA. Postpartum urinary concentrations of Na exhibited an interaction among treatments and were higher for CON-NBC and CMA-NBC compared with CON-CMA and CMA-CMA. Similar interactions of treatments were also observed for serum urea N and creatinine postpartum. Postpartum urinary K concentrations were higher for cows fed CMA postpartum compared with NBC. Results of this trial indicate that feeding cows CMA prepartum does not affect DMI or serum metabolites prepartum, but does support higher milk protein yield. Performance and serum metabolite concentrations of cows fed CMA postpartum were comparable with that of cows fed NBC, except for changes in serum and urinary concentration of Na, which was a function of dietary Na intake. PMID- 25935241 TI - Experienced and inexperienced observers achieved relatively high within-observer agreement on video mobility scoring of dairy cows. AB - Assessment of lameness prevalence and severity requires visual evaluation of thelocomotion of a cow. Welfare schemes including locomotion assessments are increasingly being adopted, and more farmers and their veterinarians might implement a locomotion-scoring routine together. However, high within-observer agreement is a prerequisite for obtaining valid mobility scorings, and within observer agreement cannot be estimated in a barn, because the gait of cows is dynamic and may change between 2 occasions. The objective of this study was to estimate the within-observer agreement according to the observers' educational background and experience with cattle, based on video recordings with very diverse types of gait. Groups of farmers, bovine veterinarians, first- and fourth year veterinary students, researchers, and cattle-inexperienced sensory assessors evaluated mobility using a 5-point mobility score system developed specifically for walking cows (n=102 observers). The evaluation sessions were similar for all groups, lasted 75 min, and were organized as follows: introduction, test A, short training session, break, and test B. In total, video recordings of 22 cows were displayed twice in a random order (11 cows in each test * 2 replicates). Data were analyzed applying kappa coefficient, logistic regression, and testing for random effects of observers. The crude estimates of 95% confidence interval for weighted kappa in test A and B ranged, respectively, from 0.76 to 0.80 and 0.70 to 0.75. When adjusting for the fixed effects of video sample and gait scoring preferences, the probability of assigning the same mobility score twice to the same cow varied from 55% (sensory assessors) to 72% (fourth-year veterinary students). The random effect of the individual observers was negligible. That is, in general observers could categorize the mobility characteristics of cows quite well. Observers who preferred to assess the attributes back arch or the overall mobility score (based on uneven gait) had the highest agreement, respectively, 69 or 68%. The training session seemed insufficient to improve agreement. Nonetheless, even novice observers were able to achieve perfect agreement up to 60% of the 22 scorings with merely the experience obtained during the study (introduction and training session). The relatively small differences between groups, together with a high agreement, demonstrate that the new system is easy to follow compared with previously described scoring systems. The mobility score achieves sufficiently high within-observer repeatability to allow between observer agreement estimates, which are reliable compared with other more-complex scoring systems. Consequently, the new scoring scale seems feasible for on-farm applications as a tool to monitor mobility within and between cows, for communication between farmers and veterinarians with diverse educational background, and for lamenessbenchmarking of herds. PMID- 25935242 TI - Effects of a 6-wk intraduodenal supplementation with quercetin on energy metabolism and indicators of liver damage in periparturient dairy cows. AB - Periparturient dairy cows experience metabolic challenges that result in a negative energy balance (EB) and a range of postpartum health problems. To compensate for the negative EB, cows mobilize fatty acids from adipose tissues, which can lead to fatty liver disease, a periparturient metabolic disorder. Flavonoids, such as quercetin (Q), are polyphenolic substances found in all higher plants and have hepatoprotective potential and the ability to prevent or reduce lipid accumulation in the liver. In ruminants, few studies on the metabolic effects of Q are available, and thus this study was conducted to determine whether Q has beneficial effects on EB, lipid metabolism, and hepatoprotective effects in periparturient dairy cows. Quercetin was supplemented intraduodenally to circumvent Q degradation in the rumen. Cows (n=10) with duodenal fistulas were monitored for 7wk. Beginning 3wk before expected calving, 5 cows were treated with 100mg of quercetin dihydrate per kilogram of body weight daily in a 0.9% sodium chloride solution for a total period of 6wk, whereas the control cows received only the sodium chloride solution. The plasma flavonoid levels were higher in the Q-treated cows than in the control cows. A tendency for higher postpartum (pp) than antepartum (ap) plasma flavonoid levels was observed in the Q-treated cows than in the controls, which was potentially caused by a reduced capacity to metabolize Q. However, the metabolic status of the Q-treated cows did not differ from that of the control cows. The pp increases in plasma aspartate aminotransferase and glutamate dehydrogenase activities were less in the Q-treated cows than in the control cows. The Q had no effect on energy expenditures, but from ap to pp the cows had a slight decline in respiratory quotients. Irrespective of the treatment group, the oxidation of fat peaked after calving, suggesting that the increase occurred because of an increased supply of fatty acids from lipomobilization. In conclusion, supplementation with Q resulted in lower pp plasma aminotransferase and glutamate dehydrogenase, which indicated reduced liver damage. However, the direct effects of Q on the liver and the implications for animal performance remain to be investigated. PMID- 25935243 TI - Effect of colostrum heat treatment and bacterial population on immunoglobulin G absorption and health of neonatal calves. AB - Improved IgG absorption in calves fed heat-treated colostrum has been attributed to the reduced bacteria content in colostrum after heat treatment. However, at least one study reported that colostrum bacteria content did not affect IgG absorption. The main objective of the current study was a more conclusive test of the combined effects of colostrum bacteria content and heat treatment on IgG absorption. Comparison of conclusions from plasma IgG as measured by radial immunodiffusion and ELISA and comparison of health scores in the first week of life were secondary and tertiary objectives. Colostrum from individual cows was pooled, divided, either heat treated or unheated, and allowed to incubate for bacterial growth or not. The 4 treatments were unheated, low bacteria; unheated, high bacteria; heat-treated, low bacteria; and heat-treated, high bacteria. Plasma samples were collected from bull calves (n=25-27 per treatment) before and 48h after colostrum feeding for IgG and total protein analysis. Fecal, respiratory, and general health scores were assigned daily for the first 7 d. Plasma IgG, total protein, apparent efficiency of IgG absorption, and frequency of illness were analyzed using the MIXED and FREQ procedures in SAS (SAS Institute Inc., Cary, NC). Plasma IgG values from ELISA were lower than radial immunodiffusion; however, conclusions were similar. Greater colostrum bacteria content reduced total protein, plasma IgG, and efficiency of IgG absorption. Heat treatment tended to improve 48-h plasma IgG as measured by ELISA. Respiratory scores were not affected by colostrum treatment, but calves fed heat-treated, low bacteria colostrum tended to experience fewer scour days. These results provide conclusive evidence for the benefits of minimizing bacterial contamination in colostrum for feeding calves. PMID- 25935244 TI - Short communication: Reliability of single-step genomic BLUP breeding values by multi-trait test-day model analysis. AB - The purpose of our study was to develop an approximation procedure to estimate reliabilities of single-step genomic BLUP breeding values in a test-day model for routine evaluation of milk yield in a dairy cattle population. Input data consisted of 20,220,047 first-, second-, and third-lactation test-day milk yield records of 1,126,102 Czech Holstein cows (each lactation being considered a separate trait), with 1,844,679 animals in the pedigree file and with genomic data from 2,236 bulls. Evaluation was according to a multi-lactation model. The procedure was based on the effective number of records per animal from milk recording as well as from genomic and pedigree relationships. Traits were analyzed individually, and genetic covariances among traits were subsequently taken into account. The use of genomic information increased average reliability in young bulls from 0.276 to 0.505, but increased reliability in proven bulls only from 0.828 to 0.855. The reliabilities of genomic breeding values in multi trait evaluation for first, second and third lactations, respectively, averaged 0.652, 0.673, and 0.633 for young bulls and 0.907, 0.894, and 0.852 for proven bulls. For an index combining all 3 lactations, the average reliability of a single-step genomic BLUP prediction was 0.712 and 0.925 for younger and proven bulls, respectively. Increased reliability due to genotyping in the population of all genotyped and nongenotyped animals was very small (<0.01) because of the small proportion of genotyped animals in the population. PMID- 25935245 TI - The effects of feeding rations that differ in neutral detergent fiber and starch concentration within a day on rumen digesta nutrient concentration, pH, and fermentation products in dairy cows. AB - There is a daily pattern of feed intake in the dairy cow, and feeding a single total mixed ration results in variation in the amount of fermentable substrate entering the rumen over the day. The object of this study was to determine if feeding multiple rations over the day that complement the pattern of feed intake would stabilize rumen pool sizes and fermentation. Nine ruminally cannulated cows were used in a 3*3 Latin square design with 23-d periods. Diets were a control diet [33.3% neutral detergent fiber (NDF)], a low-fiber diet (LF; 29.6% NDF), and a high-fiber diet (HF; 34.8% NDF). The LF and HF diets were balanced to provide the same nutrient composition as the control diet when cows were fed 3 parts of LF and 7 parts of HF. Cows on the control treatment (CON) were fed at 0900h, cows on the high/low treatment (H/L) were fed HF at 70% of daily offering at 0900h and LF at 30% of daily offering at 2200h, and cows on the low/high (L/H) treatment were fed LF at 30% of daily offering at 0900h and HF at 70% of daily offering at 1300h. All treatments were fed at 110% of daily intake. Preplanned contrasts compared CON with H/L and H/L with L/H. Feeding the LF diet in the evening resulted in a large increase in the amount of feed consumed immediately after feed delivery at that feeding. Rumen digesta starch concentration increased and NDF concentration decreased following feeding of the LF diet in both the L/H and H/L treatments. Starch pool size also increased following feeding of the LF diet in the evening and tended to increase after feeding the LF diet in the morning. Rumen ammonia concentration was increased following feeding of the HF diet in the morning and the LF diet in the evening in the H/L treatment. Additionally, cis-9 C18:1 and cis-9,cis-12 18:2 are higher in concentrate feeds and were increased after feeding the LF diet in both treatments. Trans fatty acid isomers of the normal and alternate biohydrogenation pathways followed a daily pattern, and the H/L treatment increased isomers of the alternate pathway during the overnight period following the evening feeding of the LF diet. Additionally, C17:0 decreased during the overnight period in the H/L treatment. Feeding multiple rations over the day changed feeding behavior, and the combined effect of diet composition and feeding pattern resulted in a change in rumen nutrient pool sizes and fermentation products. Feeding the low-fiber diet in the evening resulted in a large increase in feed intake after feed delivery and did not increase starch intake during the overnight period. The H/L treatment failed to stabilize rumen fermentation because of the shift in the feeding pattern. Feeding strategies that feed multiple diets over the day must integrate diet composition and feeding behavior to achieve the desired effect on rumen nutrient pools and fermentation. PMID- 25935246 TI - Minimum inhibitory concentrations of selected antimicrobials against Escherichia coli and Trueperella pyogenes of bovine uterine origin. AB - Minimum inhibitory concentrations (MIC) of 9 antimicrobials for isolates of 2 common bovine intrauterine bacterial pathogens, Escherichia coli (n=209) and Trueperella pyogenes (n=35), were determined using broth microdilution methodology. The isolates were recovered from dairy cows from 7 herds postpartum using the cytobrush technique. The pathogens were initially identified using phenotypic techniques. Additionally, PCR was used to confirm the identity of T. pyogenes isolates and to categorize the E. coli isolates into phylogenetic groups A, B1, B2, and D. Minimum inhibitory concentrations in excess of published cut points or bimodal distributions of MIC indicated potential antimicrobial resistance to ampicillin, cefuroxime, cephapirin, and oxytetracycline for E. coli, and to oxytetracycline for T. pyogenes. Of the antimicrobials tested, ticarcillin/clavulanic acid, ceftiofur, and enrofloxacin had the lowest MIC for these 2 pathogens. Differences in MIC of some antimicrobials were found between herds, age, breeds, and E. coli phylogenetic groups. Isolation of E. coli with an MIC >=8MUg/mL of oxytetracycline at 23d postpartum was associated with a lower probability of pregnancy within 6wk of commencement of breeding compared with those isolates with an MIC <8MUg/mL (relative risk=0.66). Minimum inhibitory concentrations for uterine pathogens were determined for isolates from New Zealand dairy cows. However, in the absence of either epidemiological or clinical interpretive criteria, the interpretation of these MIC remains unclear. Further studies are required to define interpretative criteria, including determination of pharmacokinetic and pharmacodynamic profiles for antimicrobials. PMID- 25935247 TI - The effects of feeding rations that differ in neutral detergent fiber and starch concentration within a day on production, feeding behavior, total-tract digestibility, and plasma metabolites and hormones in dairy cows. AB - Dairy cows exhibit a daily pattern of feed intake and milk synthesis, and feeding a single total mixed ration over the day may not synchronize ruminal fermentation, nutrient absorption, and milk synthesis. Our hypothesis was that feeding a high-fiber diet during the high-intake period of the day and a low fiber diet during the low-intake overnight period would stabilize rumen fermentation, nutrient absorption, and the availability of nutrients for milk synthesis. Nine ruminally cannulated cows were used in a 3*3 Latin square design with 23-d periods. Diets were a control [CON; 33.3% neutral detergent fiber (NDF)], a low-fiber diet (LF; 29.6% NDF), and a high-fiber diet (HF; 34.8% NDF). The HF and LF diets were balanced to provide the same nutrient composition as the control diet when cows were fed a 7:3 ratio of HF:LF. Control cows were fed once daily at 0900h. Cows in the high/low treatment (H/L) were fed HF at 70% of daily offering at 0900h and LF at 30% of daily offering at 2200h; cows in the low/high (L/H) treatment were fed LF at 30% of daily offering at 0900h and HF at 70% of daily offering at 1300h. Dry matter intake was decreased 1.9kg/d by H/L compared with CON, but intake did not differ between H/L and L/H. The H/L and L/H treatments resulted in a large amount of feed consumed after each feeding, which shifted the daily patterns of starch and fiber intake. Treatments did not differ in total-tract digestibility. We detected no differences between CON and H/L for milk yield and composition. The H/L treatment unexpectedly tended to reduce milk and reduced milk fat yield compared with L/H, although L/H was expected to result in poorer rumen fermentation and decreased milk fat yield. Treatment did not affect milk fat concentrations of trans-10 C18:1, trans-11 C18:1, or de novo synthesized fatty acids, but H/L increased milk fat concentration of preformed fatty acids compared with CON (39.15 vs. 37.38% of FA, respectively). Treatment had no effect on plasma insulin or glucose at individual time points but did modify the phase and amplitude of the daily rhythms. Daily average plasma nonesterified fatty acids (NEFA) were decreased by H/L compared with CON and L/H, and H/L treatments decreased the amplitude of the daily rhythm of NEFA by 3.4 and 6.7MUEq/L compared with CON and L/H, respectively. The amplitude of the daily rhythm of plasma blood urea N was increased by more than 15% by H/L compared with CON and L/H. Feeding multiple rations over the day changed the daily pattern of starch and fiber intake and decreased daily intake without decreasing milk yield or body weight gain over the 23-d observation periods. Feeding a high-fiber diet during the high-intake period of the day and a low-fiber diet during the low intake overnight period failed to show other benefits, likely because of the change in feeding behavior. PMID- 25935248 TI - Definition of prepartum hyperketonemia in dairy goats. AB - A prospective cohort study was conducted on 1,081 dairy goats from 10 commercial herds in Quebec (Canada) to define prepartum hyperketonemia based on optimal blood beta-hydroxybutyrate acid threshold values for the early prediction of pregnancy toxemia (PT) and mortality in late-gestation dairy goats. All pregnant goats had blood sampled weekly during the last 5wk of pregnancy. The blood was analyzed directly on the farm for beta-hydroxybutyrate acid quantification using a Precision Xtra meter (Abbott Diabetes Care, Saint-Laurent, QC, Canada). Body condition scores on the lumbar region and sternum were noted. Each goat was classified as being at low (n=973) or high risk (n=108) of having PT by producers based on a standardized definition. The optimal threshold for predicting a PT diagnosis or mortality for each week before kidding was determined based on the highest sum of sensitivity and specificity. The association between hyperketonemia and subsequent PT was tested using a multivariable logistic regression model considering hyperketonemia at wk 4 prepartum, litter size, and body condition score at wk 4 prepartum as covariates, and herd and parturition cohort as random effects. The association between mortality and hyperketonemia was also tested using a logistic regression model accounting for the presence or absence of treatment during the last month of pregnancy. The hyperketonemia definition based on PT varied between >=0.4 and >=0.9mmol/L during the last 5wk prepartum. Goats affected by hyperketonemia at wk 4 prepartum and with a large litter size (>=3 fetuses) had 2.1 and 40.5 times the odds, respectively, of subsequent PT than other goats. Hyperketonemia definitions based on mortality varied between >=0.6 and >=1.4mmol/L during the last 4wk prepartum, and was >=1.7mmol/L during the first week postpartum. Goats affected by hyperketonemia and treated by producers had 3.4 and 11.8 times the odds, respectively, of subsequent mortality than did other goats. These results showed that prepartum hyperketonemia could be defined in dairy goats using subsequent risks of PT or mortality during the last month of pregnancy. PMID- 25935249 TI - Preferences of lame cows for type of surface and level of social contact in hospital pens. AB - To investigate preferences of lame cows for flooring and level of social contact, 37 lame, lactating dairy cows (diagnosed with sole ulcer or white line disease) were housed individually for 6 d in experimental hospital pens, where they could choose between 2 equally sized areas (6m * 4.5m) with either deep-bedded sand or a rubber surface. On both surfaces, cows could choose between 2 equally sized areas either near or away from heifers in a neighboring group pen. Cows spent more time lying on the deep-bedded sand than on the rubber surface (870 vs. 71min/d), whereas they spent less time upright (standing or walking) on the sand than on the rubber surface (180 vs. 319min/d). In addition, cows spent less time self-grooming on the sand than on the rubber surface (2.2 vs. 4.7% of time spent upright). With regard to level of social contact, cows spent more time near the neighboring heifers than away from them; this was true both while lying (565 vs. 374min/d) and upright (276 vs. 223min/d). Self-grooming was seen significantly more near neighboring heifers than away from them (4.8 vs. 3.3% of time spent upright). When lying, cows more often positioned themselves in areas of the pen where they could maintain visual contact with neighboring heifers. Lame cows with sole ulcers or white line disease preferred deep-bedded sand for lying, and preferred to perform self-grooming while on the rubber surface. Similarly, they preferred to lie and to perform self-grooming while positioned near animals in a neighboring pen. These results suggest that provision of a deep-bedded lying area in hospital pens is important to the welfare of lame cows. We found no evidence of isolation-seeking behavior in animals with these diagnoses (and no systemic symptoms) while they were kept in individual hospital pens. PMID- 25935250 TI - Genomic evaluation of a relatively small dairy cattle population by combination with a larger population. AB - The objectives were to investigate the accuracy of genomic evaluations obtained for a small dairy cattle population (Israeli Holsteins) via joint evaluation with a larger population (Dutch Holsteins), and to evaluate the use of pedigree data from foreign bulls computed by Interbull without daughter records in Israel. The training population included 4,010 Dutch bulls and 713 Israeli bulls. The validation population included 185 Israeli bulls with daughter records for milk production traits and slightly fewer bulls for the nonproduction traits. Milk, fat, and protein yields, somatic cell score, longevity, female fertility, direct and maternal calving ease, direct and maternal stillbirth, and the Israeli breeding index were analyzed. The genomic prediction model was based on the Bayesian multi-QTL model of Meuwissen and Goddard, where the effects of dense single nucleotide polymorphisms across the whole genome are fitted directly, without the use of haplotypes or identical-by-descent probabilities. Correlations of May 2014 estimated breeding values (EBV14) with genomic EBV (GEBV) were higher than the correlations of EBV14 with parent averages (PA) computed from the June 2009 evaluation for all traits. For the Israel selection index, the difference between EBV14 and GEBV correlation on the one hand and EBV14 and PA computed using Interbull data on the other hand was 15 percentage points. For protein, the difference between the corresponding correlations was 14 percentage points. Generally, correlations of EBV14 with PA based on Israeli EBV only were similar to correlations of EBV14 with PA including Interbull evaluations. Relative to EBV14, milk production traits were biased upwards for both GEBV and PA, but the bias was greater for PA. The Y-intercepts of regressions of EBV14 were significantly different from zero for regression on GEBV for all 3 milk production traits and the Israeli selection index. This was not the case for regression of EBV14 on PA. The regression line intersected with the line of unbiased estimation near the EBV of the bulls with highest values. Because only bulls with high evaluations are of interest for selection, GEBV for these bulls were less biased compared with that of bulls with lower evaluations. The difference in mean EBV14 between bulls born during 2007-2008 selected by GEBV and PA was 65 units. If half of all inseminations are by young bulls, then the annual genetic gain obtained by implementation of genomic evaluation will be 8 units per year (65/8). Because annual gain is currently 107 units, this is a gain of 7%. PMID- 25935251 TI - Effect of administration of recombinant bovine somatotropin on health and performance of lactating dairy cows diagnosed with hyperketonemia. AB - The effect of administering recombinant bovine somatotropin (rbST) to cows with hyperketonemia during the early postpartum period on health, metabolic parameters, milk production, and early reproductive performance was evaluated in a double-blinded clinical trial. Cows from 8 dairy herds in New York State were tested weekly between 3 and 16d in milk for elevated serum beta-hydroxybutyrate. Cows were enrolled in the study when blood beta-hydroxybutyrate was >=1.3mmol/L for the first time. Enrolled cows were randomly assigned to a treatment (n=273) or placebo control (n=270) group. Treated cows were given 325mg of rbST subcutaneously on the day of enrollment and again 14d later. Control cows received the same regimen except the syringe contained only the carrier without somatotropin. After enrollment, blood samples were collected weekly for 4wk and submitted to the laboratory to be analyzed for selected metabolites. Risk ratios for clinical diseases subsequent to treatment were calculated using Poisson regression. Continuous data were analyzed using linear mixed models. Time to first insemination was assessed with survival analysis. In the 42d following the first administration of rbST, incidence risks of displaced abomasum, clinical ketosis, metritis, clinical mastitis, and lameness were not different between treatment groups. Cows treated with rbST had a slightly lower body condition score 28d after enrollment compared with control cows. In the 4wk following enrollment, serum nonesterified fatty acids and aspartate amino-transferase were slightly higher for treated than control cows, respectively. Serum glucose, calcium, haptoglobin, and beta-hydroxybutyrate were similar between groups. Treatment had no effect on resolution of hyperketonemia in any of the 4wk after enrollment. Milk production in either of the 2-wk periods after each treatment was not different between treated and control cows. Furthermore, milk production was not different between groups from enrollment to 98d in milk (42.6+/-0.6 and 42.1+/-0.7kg/d for treatment and control groups, respectively). Treatment had no effect on time to first insemination (83 and 74d in milk for treatment and control groups, respectively; hazard ratio=0.72) or first insemination pregnancy risk (27 and 29% for treatment and control groups, respectively; risk ratio=0.92). Based on the current results, it is not recommended to use a low dose of rbST as therapy for cows with hyperketonemia. PMID- 25935252 TI - Evidence of a sex-dependent restrictive epigenome in schizophrenia. AB - When compared to women, men have a higher incidence of schizophrenia, with increases in negative and cognitive symptoms, and an overall poorer disease course. Schizophrenia is conceptualized as a disorder of aberrant gene transcription and regulation. Thus, epigenetics, the study of environmentally induced changes in gene regulation, could advance our understanding of the molecular underpinnings of schizophrenia. Peripheral histone methyltransferase (HMT) mRNA levels have been previously shown to be significantly increased in patients with schizophrenia and correlate with symptomology. In this independent study, peripheral lymphocytes were extracted and clinical symptoms were measured on 74 participants, (40 patients with schizophrenia (19 women, 21 men) and 34 healthy individuals (19 women, 15 men)). HMT (G9alpha, SETDB1 and GLP) mRNA levels and their resulting histone modification H3K9me2 were measured with RT-PCR and ELISA respectively. Plasma estradiol levels were also measured via ELISA and correlated with HMT mRNA. Clinical symptoms were measured utilizing the Positive and Negative Syndrome Scale (PANSS) and the Heinrichs Carpenter Quality of Life Scale (QLS). The results indicate that men with schizophrenia expressed the highest levels of G9alpha, SETDB1 mRNA and H3K9me2 protein levels. Additionally, higher levels of symptom presentation and an overall poorer quality of life were correlated with higher HMT mRNA and H3K9me2 protein levels in a sex-dependent pattern. These data support the hypothesis of a sex-dependent restrictive epigenome contributing towards the etiology of schizophrenia. The histone methyltransferases measured here could be potential future therapeutic targets for small molecule pharmacology. PMID- 25935254 TI - Decision making in child protection: An international comparative study on maltreatment substantiation, risk assessment and interventions recommendations, and the role of professionals' child welfare attitudes. AB - Child welfare professionals regularly make crucial decisions that have a significant impact on children and their families. The present study presents the Judgments and Decision Processes in Context model (JUDPIC) and uses it to examine the relationships between three independent domains: case characteristic (mother's wish with regard to removal), practitioner characteristic (child welfare attitudes), and protective system context (four countries: Israel, the Netherlands, Northern Ireland and Spain); and three dependent factors: substantiation of maltreatment, risk assessment, and intervention recommendation. The sample consisted of 828 practitioners from four countries. Participants were presented with a vignette of a case of alleged child maltreatment and were asked to determine whether maltreatment was substantiated, assess risk and recommend an intervention using structured instruments. Participants' child welfare attitudes were assessed. The case characteristic of mother's wish with regard to removal had no impact on judgments and decisions. In contrast, practitioners' child welfare attitudes were associated with substantiation, risk assessments and recommendations. There were significant country differences on most measures. The findings support most of the predictions derived from the JUDPIC model. The significant differences between practitioners from different countries underscore the importance of context in child protection decision making. Training should enhance practitioners' awareness of the impact that their attitudes and the context in which they are embedded have on their judgments and decisions. PMID- 25935253 TI - Time distortion associated with smartphone addiction: Identifying smartphone addiction via a mobile application (App). AB - BACKGROUND: Global smartphone penetration has brought about unprecedented addictive behaviors. AIMS: We report a proposed diagnostic criteria and the designing of a mobile application (App) to identify smartphone addiction. METHOD: We used a novel empirical mode decomposition (EMD) to delineate the trend in smartphone use over one month. RESULTS: The daily use count and the trend of this frequency are associated with smartphone addiction. We quantify excessive use by daily use duration and frequency, as well as the relationship between the tolerance symptoms and the trend for the median duration of a use epoch. The psychiatrists' assisted self-reporting use time is significant lower than and the recorded total smartphone use time via the App and the degree of underestimation was positively correlated with actual smartphone use. CONCLUSIONS: Our study suggests the identification of smartphone addiction by diagnostic interview and via the App-generated parameters with EMD analysis. PMID- 25935256 TI - In remembrance of Professor Eugenio Muller (1933-2015). PMID- 25935255 TI - TP53 polymorphism may contribute to genetic susceptibility to develop Hashimoto's thyroiditis. AB - PURPOSE: p53, which is encoded by the tumor suppressor gene TP53, plays a crucial role in the regulation of mechanisms of cell cycle arrest and apoptosis. Some SNPs of TP53, involving a different apoptotic ability of p53, have been associated with increased susceptibility to develop autoimmune diseases as well as cancer. We investigated the genotypic distribution of TP53 exon 4 SNPs in a cohort of Caucasian patients affected by Hashimoto's thyroiditis (HT). METHODS: Peripheral blood for DNA extraction was collected from 109 Caucasian unrelated subjects, 79 HT patients and 30 healthy controls. SNPs analysis was carried out by amplification and sequencing of exon 4 TP53. RESULTS: For the Pro72Arg (rs 1042522) SNP we found these rates in HT patients: 11.4% wild-type C/C (Pro72Pro), 24.0% heterozygous G/C (Pro72Arg), 64.6% homozygous G/G (Arg72Arg). The corresponding rates in healthy controls were 10, 46.7 and 43.3%, respectively. Thus, significantly different were G/C heterozygosity (24.0 vs 46.7 %, p = 0.039) and G/G homozygosity (64.6 vs 43.3%, p = 0.042). These differences were also confirmed when comparing our study population to published Caucasian control groups. The other described SNPs (Pro34Pro rs 11575998, Pro36Pro rs1800370, Pro47Ser rs1800371, and Arg110Leu rs 11540654) were absent or very rare in our study population. CONCLUSIONS: Our preliminary data, the first on a Caucasian population, indicate an increased prevalence of the homozygous genotype Arg/Arg and a decreased prevalence of heterozygous genotype Arg/Pro of rs 1042522 in HT patients compared to controls, suggesting that such SNP may contribute to confer susceptibility to HT. PMID- 25935257 TI - [Impact of intensity-modulated radiotherapy on node irradiation for breast cancer]. AB - Irradiation of node areas is still a complex challenge in external radiotherapy for breast cancer. Acceptable target coverage is always balanced by protection of organs at risk and patient morphology. Intensity-modulated radiotherapy increases the quality of dose distribution on the planning target volume, but modifies dramatically the irradiation coverage of critical structures in a different way compared to 3D treatment. In this paper we analyze this new technique in breast treatment with node regions, its expected gain and potential risks. PMID- 25935258 TI - Medical care expenditures associated with chronic kidney disease in adults with diabetes: United States 2011. AB - OBJECTIVE: Approximately 1 in 3 adults with diabetes have CKD. However, there are no recent national estimates of the association of CKD with medical care expenditures in individuals with diabetes. Our aim is to assess the association of CKD with total medical expenditures in US adults with diabetes using a national sample and novel cost estimation methodology. RESEARCH DESIGN AND METHODS: Data on 2,053 adults with diabetes in the 2011 Medical Expenditure Panel Survey (MEPS) was analyzed. Individuals with CKD were identified based on self report. Adjusted mean health services expenditures per person in 2011 were estimated using a two-part model after adjusting for demographic and clinical covariates. RESULTS: Of the 2,053 individuals with diabetes, approximately 9.7% had self-reported CKD. Unadjusted mean expenditures for individuals with CKD were $20,726 relative to $9,689.49 for no CKD. Adjusted mean expenditures from the 2 part model for individuals with CKD were $8473 higher relative to individuals without CKD. Additional significant covariates were Hispanic/other race, uninsured, urban dwellers, CVD, stroke, high cholesterol, arthritis, and asthma. The estimated unadjusted total expenditures for individuals with CKD were estimated to be in excess of $43 billion in 2011. CONCLUSIONS: We showed that CKD is a significant contributor to the financial burden among individuals with diabetes, and that minorities and the uninsured with CKD may experience barriers in access to care. Our study also provides a baseline national estimate of CKD cost in Diabetes by which future studies can be used for comparison. PMID- 25935259 TI - A competitive enzyme-linked immunosorbent assay for quantification of tetrastatin in body fluids and tumor extracts. AB - Basement membrane collagens or derived fragments are measured in biological fluids such as blood and urine of patients and appear to be useful for diagnosis, prognostication, or treatment monitoring as proposed for endostatin, a fragment of collagen XVIII, or tumstatin, a fragment of collagen IV. Tetrastatin, the NC1 alpha 4 collagen IV domain, was previously reported to inhibit tumor growth and angiogenesis. The aim of this study was to develop and validate a method to measure tetrastatin concentrations in human fluids. We developed a competitive enzyme-linked immunosorbent assay (ELISA). It allowed measuring tetrastatin levels in human serum, bronchial aspiration and bronchoalveolar lavage fluids, and lung tissue extracts. The tetrastatin level was significantly higher in tumor tissues than in healthy lung tissues. Tetrastatin competitive ELISA could be useful to quantify tetrastatin in tissues and biological fluids for the diagnosis or prognostication of diseases in which basement membrane metabolism may be altered, especially tumor progression. PMID- 25935260 TI - Sensing pH via p-cyanophenylalanine fluorescence: Application to determine peptide pKa and membrane penetration kinetics. AB - We expand the spectroscopic utility of a well-known infrared and fluorescence probe, p-cyanophenylalanine, by showing that it can also serve as a pH sensor. This new application is based on the notion that the fluorescence quantum yield of this unnatural amino acid, when placed at or near the N-terminal end of a polypeptide, depends on the protonation status of the N-terminal amino group of the peptide. Using this pH sensor, we are able to determine the N-terminal pKa values of nine tripeptides and also the membrane penetration kinetics of a cell penetrating peptide. Taken together, these examples demonstrate the applicability of using this unnatural amino acid fluorophore to study pH-dependent biological processes or events that accompany a pH change. PMID- 25935261 TI - Method for trapping affinity chromatography of transcription factors using aldehyde-hydrazide coupling to agarose. AB - The use of a method of coupling DNA was investigated for trapping and purifying transcription factors. Using the GFP-C/EBP (CAAT/enhancer binding protein) fusion protein as a model, trapping gives higher purity and comparable yield to conventional affinity chromatography. The chemistry used is mild and was shown to have no detrimental effect on GFP fluorescence or GFP-C/EBP DNA binding. The method involves introducing a ribose nucleotide to the 3' end of a DNA sequence. Reaction with mM NaIO4 (sodium metaperiodate) produces a dialdehyde of ribose that couples to hydrazide-agarose. The DNA is combined at nM concentration with a nuclear extract or other protein mixture, and DNA-protein complexes form. The complex is then coupled to hydrazide-agarose for trapping the DNA-protein complex and the protein eluted by increasing NaCl concentration. Using a different oligonucleotide with the proximal E-box sequence from the human telomerase promoter, USF-2 transcription factor was purified by trapping, again with higher purity than results from conventional affinity chromatography and similar yield. Other transcription factors binding E-boxes, including E2A, c-Myc, and Myo-D, were also purified, but myogenin and NFkappaB were not. Therefore, this approach proved to be valuable for both affinity chromatography and the trapping approach. PMID- 25935262 TI - Homeotropic orientation behavior of nematic liquid crystals induced by copper ions. AB - A homeotropic ordering film of nematic liquid crystal (LC) induced by copper ions (Cu(2+)) had been developed. The Cu(ClO4)2 was directly spin-coated on the glass substrate without any other chemical modification. A homeotropic orientation of LC thin-film was generated by the interfacial chemical interaction between nitrile-containing LC and copper ions on the surface. Results showed that an appropriate density of Cu(2+) could shorten the response time of orientation, but a shelf-time was prolonged. The LC film fabrication not only offered a simple process, but also presented a great repeatability to detect organophosphonates (DMMP). This study provided guidance for the design of LC films responding to organic molecules as a biosensor. PMID- 25935263 TI - Enhancement of the photokilling effect of aluminum phthalocyanine in photodynamic therapy by conjugating with nitrogen-doped TiO2 nanoparticles. AB - As a second-generation photodynamic therapy (PDT) photosensitizer, aluminum phthalocyanine chloride tetrasulfonate (Pc) has gained great attention due to its high absorption at the red light region. Yet, its application in PDT is strongly limited by its low cellular uptake efficiency. In this report, nitrogen-doped TiO2 nanoparticles (N-TiO2) conjugated with Pc are synthesized by a two-step surface modification method. The N-TiO2-Pc products are characterized by Zeta potential, transmission electron microscopy and UV-vis absorption spectroscopy. The cellular uptake, intracellular distribution, cytotoxicity and the photokilling effect of the nanoparticles are studied on different cancer cell lines. Compared with Pc, the absorption spectrum of N-TiO2-Pc expands from red to UV region, resulting in a higher production of reactive oxygen species under visible light irradiation. In addition, the cellular uptake of Pc is largely improved by its carrier N-TiO2. The photokilling efficiency of N-TiO2-Pc is over ten times higher than that of Pc. The results suggest that N-TiO2-Pc is an excellent candidate as a photosensitizer in PDT. PMID- 25935264 TI - Self-assembled enzyme-inorganic hybrid nanoflowers and their application to enzyme purification. AB - We report a novel method to synthesize organic-inorganic nanoflowers for crude soybean peroxidase (SBP) purification. A hierarchical flower-like spherical structure with hundreds of nanopetals was self-assembled by using crude SBP as the organic component and Cu3(PO4)2.3H2O as the inorganic component. The structure of the hybrid nanoflowers was confirmed by Fourier-transform infrared spectroscopy, X-ray diffraction, and energy-dispersive X-ray spectroscopy, and the enzymatic activity of SBP embedded in the hybrid nanoflowers was evaluated using guaiacol as substrate. Compared with free crude SBP in solution, SBP embedded in hybrid nanoflowers exhibited enhanced enzymatic activity (~446%). The hybrid nanoflowers also exhibited excellent reusability and reproducibility during cycle analysis. These results demonstrate that synthesis of hybrid nanoflowers is an effective enzyme purification strategy. PMID- 25935265 TI - Stable self-assembled nanostructured hen egg white lysozyme exhibits strong anti proliferative activity against breast cancer cells. AB - Chemotherapy side effects have long been a matter of great concern. Here we describe a structurally stable self-assembled nanostructured lysozyme (snLYZ) synthesized using a simple desolvation technique that exhibited anticancer activity, as well as excellent hemocompatibility. Field emission scanning electron microscopy; atomic force microscopy and dynamic particle size analyzer were used for analyzing the synthesized snLYZ. The analysis revealed spherical shape with an average size of 300 nm. Circular dichroism and tryptophan fluorescence spectroscopic analysis revealed its gross change in secondary as well as the tertiary level of the structure. snLYZ also demonstrated excellent structural as well as the functional stability of LYZ in a wide range of pH and temperature with a fair level of protection against proteinase K digestion. When applied to MCF-7 breast cancer cells, it exhibited approximately 95% cell death within 24h, involving a reactive oxygen species (ROS) based mechanism, and showed excellent hemocompatibility. Fluorescence microscopy imaging revealed distinct cellular internalization of snLYZ and the formation of cytoplasmic granules, which initiated a cell-killing process through membrane damage. In order to mimic targeted therapy, we tagged folic acid with snLYZ, which further enhanced cytotoxicity against MCF-7 cells. Therefore, this is the first report of its kind where we demonstrated the preparation of a highly stable self-assembled nanostructured lysozyme with a strong anti-proliferative activity against breast cancer cells. PMID- 25935266 TI - Ketoprofen-loaded pomegranate seed oil nanoemulsion stabilized by pullulan: Selective antiglioma formulation for intravenous administration. AB - This study aimed to prepare pomegranate seed oil nanoemulsions containing ketoprofen using pullulan as a polymeric stabilizer, and to evaluate antitumor activity against in vitro glioma cells. Formulations were prepared by the spontaneous emulsification method and different concentrations of pullulan were tested. Nanoemulsions presented adequate droplet size, polydispersity index, zeta potential, pH, ketoprofen content and encapsulation efficiency. Nanoemulsions were able to delay the photodegradation profile of ketoprofen under UVC radiation, regardless of the concentration of pullulan. In vitro release study indicates that nanoemulsions were able to release approximately 95.0% of ketoprofen in 5h. Free ketoprofen and formulations were considered hemocompatible at 1 MUg/mL, in a hemolysis study, for intravenous administration. In addition, a formulation containing the highest concentration of pullulan was tested against C6 cell line and demonstrated significant activity, and did not reduce fibroblasts viability. Thus, pullulan can be considered an interesting excipient to prepare nanostructured systems and nanoemulsion formulations can be considered promising alternatives for the treatment of glioma. PMID- 25935267 TI - Initial clinical experience with a new low-profile thoracic endograft. AB - BACKGROUND: The Zenith Alpha thoracic endograft (William Cook Europe, ApS, Bjaeverskov, Denmark) is a new low-profile thoracic endograft that has recently become commercially available in Europe. The reduced profile offers potential benefits and extended applicability, especially in patients with small or diseased iliofemoral vessels. The aim of this study was to evaluate the safety and efficacy of thoracic endovascular aortic repair performed with the new Zenith Alpha thoracic endograft. METHODS: From November 2013 to the present, Zenith Alpha thoracic stent grafts have been employed to treat 42 patients (31 men; median age, 71 years; range, 54-83 years) suffering from descending thoracic aortic disease: 34 degenerative aneurysms, 4 aortic ulcers, 2 false aneurysms following prior thoracic open repair, and 2 traumatic blunt injuries. The mean proximal neck length was 25 mm (range, 17-40 mm), with a mean access vessel diameter of 6.7 mm (range, 6-11 mm). In 11 cases, aortoiliac occlusive disease (TransAtlantic Inter-Society Consensus type B and C lesions) was present. The proximal landing was in zone 1 in 2 cases, in zone 2 in 25 cases, in zone 3 in 11 cases, and in zone 4 in 4 cases. RESULTS: Fifty-one endografts (45 proximal components and 6 distal components) were deployed in 42 patients. The endografts were deployed safely and effectively from one surgical femoral access site in all cases. In patients with associated aortoiliac disease, no adjunctive procedures for device insertion, except for predilation with balloon angioplasty in two cases, were required. No major complications related to the devices were observed in any of the patients during the postoperative course, and there was no perioperative mortality, paraparesis, or paraplegia. At 30 days, morbid events included one case of major stroke, two cases of transient acute renal failure, and one case of postimplantation syndrome. No access-related complications were recorded. Computed tomography performed within 6 months was obtained in 39 patients and confirmed 100% clinical success without device-related complications. No type I endoleaks or bird's beak effects were documented. CONCLUSIONS: Our early experience shows that deployment of the new Zenith Alpha endograft from a surgical femoral access is safe and effective in treating thoracic aortic aneurysms, aortic ulcers, and traumatic blunt injuries, even in patients with small or diseased access vessels. Endograft conformance to the aorta and exclusion of the aneurysm were satisfactory. Long-term durability remains to be evaluated. PMID- 25935268 TI - Nasal methicillin-resistant Staphylococcus aureus colonization is associated with increased wound occurrence after major lower extremity amputation. AB - OBJECTIVE: Wound occurrence (WO) after major lower extremity amputation (MLEA) can be due to wound infection or sterile dehiscence. We sought to determine the association of nasal methicillin-resistant Staphylococcus aureus (MRSA) colonization and other patient factors with overall WO, WO due to wound infection, and WO due to sterile dehiscence. METHODS: The medical records of all patients undergoing MLEA from August 1, 2011, to November 1, 2013, were reviewed. Demographic data, hemoglobin A1c level, albumin concentration, dialysis dependence, peripheral vascular disease (PVD), nasal MRSA colonization, and diabetes mellitus (DM) were examined as variables. The overall WO rate was determined, and the cause of WO was categorized as either a sterile dehiscence or a wound infection. RESULTS: Eighty-three patients underwent 96 MLEAs during a 27 month period. The rates of overall WO, WO due to infection, and WO due to sterile dehiscence were 39%, 19%, and 19%, respectively (1% developed a traumatic wound). On univariate analysis, PVD, MRSA colonization, DM, and dialysis dependence were all associated with higher rates of overall WO (P < .05). On multivariate analysis, MRSA colonization was associated with higher rates of overall WO (P = .03) and WO due to wound infection (11% vs 45%; P < .01). DM and PVD were associated with higher rates of overall WO and WO due to sterile dehiscence on both univariate and multivariate analysis (P < .05). CONCLUSIONS: Nasal MRSA colonization is associated with higher rates of overall WO and WO due to wound infection. DM and PVD are associated with higher rates of overall WO and WO due to sterile dehiscence but are not associated with WO due to wound infection. Further studies addressing the effect of nasal MRSA eradication on postoperative wound outcomes after MLEA are warranted. PMID- 25935269 TI - Discussion. PMID- 25935270 TI - Use of computational fluid dynamics studies in predicting aneurysmal degeneration of acute type B aortic dissections. AB - OBJECTIVE: Whereas uncomplicated acute type B aortic dissections are often medically managed with good outcomes, a subset develop subacute or chronic aneurysmal dilation. We hypothesized that computational fluid dynamics (CFD) simulations may be useful in identifying patients at risk for this complication. METHODS: Patients with acute type B dissection complicated by rapidly expanding aortic aneurysms (N = 7) were compared with patients with stable aortic diameters (N = 7). Three-dimensional patient-specific dissection geometries were generated from computed tomography angiography and used in CFD simulations of pulsatile blood flow. Hemodynamic parameters including false lumen flow and wall shear stress were compared. RESULTS: Patients with rapid aneurysmal degeneration had a growth rate of 5.3 +/- 2.7 mm/mo compared with those with stable aortic diameters, who had rates of 0.2 +/- 0.02 mm/mo. Groups did not differ in initial aortic diameter (36.1 +/- 2.9 vs 34.4 +/- 3.6 mm; P = .122) or false lumen size (22.6 +/- 2.9 vs 20.2 +/- 4.5 mm; P = .224). In patients with rapidly expanding aneurysms, a greater percentage of total flow passed through the false lumen (78.3% +/- 9.3% vs 56.3% +/- 11.8%; P = .016). The time-averaged wall shear stress on the aortic wall was also significantly higher (12.6 +/- 3.7 vs 7.4 +/- 2.8 Pa; P = .028). CONCLUSIONS: Hemodynamic parameters derived from CFD simulations of acute type B aortic dissections were significantly different in dissections complicated by aneurysm formation. Thus, CFD may assist in predicting which patients may benefit from early stent grafting. PMID- 25935271 TI - Endovascular aneurysm repair delivery redesign leads to quality improvement and cost reduction. AB - OBJECTIVE: Endovascular aneurysm repair (EVAR) is now a mainstay of therapy for abdominal aortic aneurysm, although it remains associated with significant expense. We performed a comprehensive analysis of EVAR delivery at an academic medical center to identify targets for quality improvement and cost reduction in light of impending health care reform. METHODS: All infrarenal EVARs performed from April 2011 to March 2012 were identified (N = 127). Procedures were included if they met standard commercial instructions for use guidelines, used a single manufacturer, and were billed to Medicare diagnosis-related group 238 (n = 49). By use of DMAIC (define, measure, analyze, improve, and control) quality improvement methodology (define, measure, analyze, improve, control), targets for EVAR quality improvement were identified and high-yield changes were implemented. Procedure technical costs were calculated before and after process redesign. RESULTS: Perioperative services and clinic visits were identified as targets for quality improvement efforts and cost reduction. Mean technical costs before the intervention were $31,672, with endograft implants accounting for 52%. Pricing redesign in collaboration with hospital purchasing reduced mean EVAR technical costs to $28,607, a 10% reduction in overall cost, with endograft implants now accounting for 46%. Perioperative implementation of instrument tray redesign reduced instrument use by 32% (184 vs 132 instruments), saving $50,000 annually. Unnecessary clinic visits were reduced by 39% (1.6 vs 1.1 clinic visits per patient) through implementation of a preclinic imaging protocol. There was no difference in mean length of stay after the intervention. CONCLUSIONS: Comprehensive EVAR delivery redesign leads to cost reduction and waste elimination while preserving quality. Future efforts to achieve more competitive and transparent device pricing will make EVAR more cost neutral and enhance its financial sustainability for health care systems. PMID- 25935272 TI - Risk factors for cranial nerve injury after carotid endarterectomy. AB - BACKGROUND: Although numerous studies have described the incidence of postoperative cranial nerve injury (CNI) after carotid endarterectomy (CEA), there have been few attempts to identify risk factors for this complication. METHODS: The 2012 CEA-targeted American College of Surgeons National Surgical Quality Improvement Program database was used to determine the incidence of CNI after CEA. Multivariate logistic regression analysis was performed to identify independent predictors of CNI after CEA, using a comprehensive array of patient-, carotid disease-, and procedure-related factors as potential predictor variables. RESULTS: Of the 3762 CEA patients who were included in our analysis, 84 (2.2%) were noted to have sustained CNI in the first 30 days after their operation. Independent predictors of this complication included age >=80 years (reference group, <70 years; adjusted odds ratio [AOR] for CNI, 1.74; 95% confidence interval [CI], 1.00-3.03; P = .05), presence of a preoperative bleeding disorder (including patients in whom preoperative nonaspirin anticoagulation therapy was not stopped before CEA; AOR, 1.66; 95% CI, 1.03-2.68; P = .04), duration of operation (AOR, 1.15 for each 30-minute interval beyond an operative time of 90 minutes; 95% CI, 1.06-1.25; P = .001), and need for reoperation (AOR, 2.65; 95% CI, 1.03-6.80; P = .04). CONCLUSIONS: Our study demonstrates clinically evident CNI to be a relatively uncommon event after CEA at institutions that participate in the CEA-targeted American College of Surgeons National Surgical Quality Improvement Program and identifies four separate factors that are independently associated with an increased risk of CNI. PMID- 25935273 TI - Surgical marking pen dye inhibits saphenous vein cell proliferation and migration in saphenous vein graft tissue. AB - OBJECTIVE: Markers containing dyes such as crystal violet (CAS 548-62-9) are routinely used on the adventitia of vein bypass grafts to avoid twisting during placement. Because little is known about how these dyes affect vein graft healing and function, we determined the effect of crystal violet on cell migration and proliferation, which are responses to injury after grafting. METHODS: Fresh human saphenous veins were obtained as residual specimens from leg bypass surgeries. Portions of the vein that had been surgically marked with crystal violet were analyzed separately from those that had no dye marking. In the laboratory, they were split into easily dissected inner and outer layers after removal of endothelium. This cleavage plane was within the circular muscle layer of the media. Cell migration from explants was measured daily as either (1) percentage of migration-positive explants, which exclusively measures migration, or (2) number of cells on the plastic surrounding each explant, which measures migration plus proliferation. Cell proliferation and apoptosis (Ki67 and TUNEL staining, respectively) were determined in dye-marked and unmarked areas of cultured vein rings. The dose-dependent effects of crystal violet were measured for cell migration from explants as well as for proliferation, migration, and death of cultured outer layer cells. Dye was extracted from explants with ethanol and quantified by spectrophotometry. RESULTS: There was significantly less cell migration from visibly blue compared with unstained outer layer explants by both methods. There was no significant difference in migration from inner layer explants adjacent to blue-stained or unstained sections of vein because dye did not penetrate to the inner layer. Ki67 staining of vein in organ culture, which is a measure of proliferation, progressively increased up to 6 days in nonblue outer layer and was abolished in the blue outer layer. Evidence of apoptosis (TUNEL staining) was present throughout the wall and not different in blue stained and unstained vein wall segments. Blue outer layer explants had 65.9 +/- 8.0 ng dye/explant compared with 2.1 +/- 1.3 for nonblue outer layer explants. Dye applied in vitro to either outer or inner layer explants dose dependently inhibited migration (IC50~10 ng/explant). The IC50s of crystal violet for outer layer cell proliferation and migration were 0.1 and 1.2 MUg/mL, whereas the EC50 for death was between 1 and 10 MUg/mL. CONCLUSIONS: Crystal violet inhibits venous cell migration and proliferation, indicating that alternative methods should be considered for marking vein grafts. PMID- 25935275 TI - Self-reported fitness of American Society of Anesthesiologists class 3 patients undergoing endovascular aneurysm repair predicts patient survival. AB - BACKGROUND: Most patients undergoing elective endovascular aneurysm repair (EVAR) are classified American Society of Anesthesiologists (ASA) 3. However, the severity of systemic disease among these patients can vary, resulting in markedly different levels of fitness. In this study, we explored the hypothesis that ASA 3 patients with good self-reported exercise tolerance have better survival after EVAR. METHODS: Data for EVAR patients classified ASA 3 were extracted retrospectively from a prospectively collected registry database. Patients were split into two groups according to fitness level, based on their self-reported ability to climb stairs or to walk briskly for 1 km. Patient survival for each group was assessed by Cox proportional hazards models. RESULTS: During follow-up of 392 patients for a mean of 1.9 years, there were 64 deaths (16.3%), 13.4% in the more physically able group and 21.6% in the less able group. Self-reported inability to walk or to climb stairs was associated with increased risk of all cause mortality (hazard ratio, 3.55; P < .0001). Following risk adjustment for a number of possible confounding variables, fitness remained significant (hazard ratio, 3.03; P = .0011). CONCLUSIONS: This study has shown that among ASA 3 patients, self-reported exercise capacity is an excellent means of predicting survival. Physicians should consider the physical fitness of their ASA 3 patients when discussing treatment options. PMID- 25935274 TI - Scavenger receptor class A member 5 (SCARA5) and suprabasin (SBSN) are hub genes of coexpression network modules associated with peripheral vein graft patency. AB - OBJECTIVE: Approximately 30% of autogenous vein grafts develop luminal narrowing and fail because of intimal hyperplasia or negative remodeling. We previously found that vein graft cells from patients who later develop stenosis proliferate more in vitro in response to growth factors than cells from patients who maintain patent grafts. To discover novel determinants of vein graft outcome, we have analyzed gene expression profiles of these cells using a systems biology approach to cluster the genes into modules by their coexpression patterns and to correlate the results with growth data from our prior study and with new studies of migration and matrix remodeling. METHODS: RNA from 4-hour serum- or platelet derived growth factor (PDGF)-BB-stimulated human saphenous vein cells obtained from the outer vein wall (20 cell lines) was used for microarray analysis of gene expression, followed by weighted gene coexpression network analysis. Cell migration in microchemotaxis chambers in response to PDGF-BB and cell-mediated collagen gel contraction in response to serum were also determined. Gene function was determined using short-interfering RNA to inhibit gene expression before subjecting cells to growth or collagen gel contraction assays. These cells were derived from samples of the vein grafts obtained at surgery, and the long-term fate of these bypass grafts was known. RESULTS: Neither migration nor cell mediated collagen gel contraction showed a correlation with graft outcome. Although 1188 and 1340 genes were differentially expressed in response to treatment with serum and PDGF, respectively, no single gene was differentially expressed in cells isolated from patients whose grafts stenosed compared with those that remained patent. Network analysis revealed four unique groups of genes, which we term modules, associated with PDGF responses, and 20 unique modules associated with serum responses. The "yellow" and "skyblue" modules, from PDGF and serum analyses, respectively, correlated with later graft stenosis (P = .005 and P = .02, respectively). In response to PDGF, yellow was also associated with increased cell growth. For serum, skyblue was also associated with inhibition of collagen gel contraction. The hub genes for yellow and skyblue (ie, the gene most connected to other genes in the module), scavenger receptor class A member 5 (SCARA5) and suprabasin (SBSN), respectively, were tested for effects on proliferation and collagen contraction. Knockdown of SCARA5 increased proliferation by 29.9% +/- 7.8% (P < .01), whereas knockdown of SBSN had no effect. Knockdown of SBSN increased collagen gel contraction by 24.2% +/- 8.6% (P < .05), whereas knockdown of SCARA5 had no effect. CONCLUSIONS: Using weighted gene coexpression network analysis of cultured vein graft cell gene expression, we have discovered two small gene modules, which comprise 42 genes, that are associated with vein graft failure. Further experiments are needed to delineate the venous cells that express these genes in vivo and the roles these genes play in vein graft healing, starting with the module hub genes SCARA5 and SBSN, which have been shown to have modest effects on cell proliferation or collagen gel contraction. PMID- 25935276 TI - Morbidity and mortality after use of iliac conduits for endovascular aortic aneurysm repair. AB - OBJECTIVE: Although placement of an open iliac conduit for endovascular aortic aneurysm repair (EVAR) is generally felt to result in higher morbidity and mortality, published literature is scarce. Our objective was to assess 30-day outcomes after elective EVAR with an open iliac conduit using a multi institutional database. METHODS: Patients who underwent elective EVAR (n = 14,339) for abdominal aortic aneurysm were identified from the American College of Surgeons National Surgical Quality Improvement Program 2005 to 2011 database. Univariable and multivariable logistic regression analyses were performed. RESULTS: An open iliac conduit was used in 231 patients (1.6%), and the remainder had femoral exposure or percutaneous EVAR. Women comprised 32% of patients with iliac conduits in contrast to 17% of those without iliac conduits. Patients with iliac conduits were older and had a lower body mass index. Univariable analysis showed patients with open iliac conduits had a higher incidence of postoperative pneumonia (3.0% vs 1.1%), ventilator dependence (4.8% vs 1.0%), renal failure (3.0% vs 0.7%), cardiac arrest or myocardial infarction (5.2% vs 1.1%), return to the operating room (9.1% vs 3.7%), major morbidity (16.0 vs 6.6%), and death (3.0% vs 0.9%). On multivariable analysis, the use of open iliac conduits was associated with higher risk of 30-day mortality (odds ratio, 2.7; 95% confidence interval, 1.2-6.0) and 30-day major morbidity (odds ratio, 2.3; 95% confidence interval, 1.6-3.3). CONCLUSIONS: Patients with open iliac conduits for EVAR are more likely to be female and have higher postoperative morbidity and mortality. For patients with complex iliac artery disease, conduits are a viable alternative after EVAR to be performed, albeit at an increased risk. These data do suggest the need for lower-profile grafts and other alternative strategies for navigating complex iliac artery disease. PMID- 25935277 TI - Increased use of brachiocephalic arteriovenous fistulas improves functional primary patency. AB - OBJECTIVE: As vascular surgeons strive to meet the Fistula First Initiative, some authors have observed a decrease in arteriovenous fistula (AVF) maturation rates in association with an increase in AVF creation. In May 2012, we adopted a practice change in an attempt to maintain the same high level of AVF creation while leading to a decrease in fistula failures. METHODS: A retrospective study was conducted of all dialysis access procedures performed by a single vascular surgeon before (period 1; before May 1, 2012) and after (period 2; after May 1, 2012) the change in practice pattern. The adopted change included favoring the brachiocephalic location unless the patient was an ideal anatomic candidate for a radiocephalic AVF, creating a larger and standardized arteriotomy, and using a large venous footplate whenever possible. The main outcome measure was primary functional patency at 1 year. Secondary outcome measures included primary patency at 1 year, time to maturation, type of fistula created, steal syndrome, and tunneled hemodialysis catheter infections. RESULTS: Of 213 vascular access procedures performed, 191 (90%) were AVFs. There was no difference in use of AVFs between period 1 (93% AVFs) and period 2 (88% AVFs; P = .2). Use of brachiocephalic AVFs increased from 38% in period 1 to 56% in period 2 (P = .01), with a corresponding trend toward a decrease in radiocephalic AVFs in period 2 (36% in period 1 to 27% in period 2; P = .2). Primary functional patency at 1 year was 47% in period 1 and 63% in period 2 (P = .03). Primary patency at 1 year was 51% in period 1 and 70% in period 2 (P = .001). Time to reach functional maturation was decreased in period 2 (median, 76 vs 82.5 days; P = .046). There was no difference in steal syndrome (P = 1.0), and the incidence of hemodialysis catheter infections was lower in period 2 (0 vs 7 [7%]; P = .006). CONCLUSIONS: Increasing brachiocephalic AVF creation and reducing our reliance on radiocephalic AVFs resulted in a significant increase in primary functional patency at 1 year. This was achieved while maintaining the same high percentage of fistulas, a lower rate of central catheter infections, and the same low incidence of steal syndrome. PMID- 25935278 TI - Protective effect of apigenin on Freund's complete adjuvant-induced arthritis in rats via inhibiting P2X7/NF-kappaB pathway. AB - To evaluate the effect of apigenin (AP) on arthritis in rats stimulated by Freund's complete adjuvant (FCA) was the main purpose of the investigation. Arthritis model was established by the administration of 0.1 ml FCA in the palmar surface. AP and diclofenac sodium (DS) were administered to explore and evidence the protective effects against adjuvant-induced arthritis (AA). Cytokines tumor necrosis factor-alpha (TNF-alpha), interleukin-1 beta (IL-1beta) and interleukin 6 (IL-6) were detected to assess the anti-inflammatory effect of AP. Besides, pathological conditions were examined in rat paws. Related-proteins of nuclear factor kappa B (NF-kappaB) signal pathway activated by P2X7 were investigated to determine the molecular mechanism of AP and their expressions were measured by western blot. The data showed that AP significantly suppressed the expressions of P2X7/NF-kappaB signal-related proteins and alleviated inflammatory reactions. Therefore, it was assumed that AP might be a potential therapeutic candidate to treat arthritis. PMID- 25935279 TI - The synthesis of CdS/TiO2 hetero-nanofibers with enhanced visible photocatalytic activity. AB - In this paper, CdS/TiO2 heteronanofibers have been prepared for the photocatalysis toward organic dyes under visible irradiation. Firstly, the one dimensional (1D) TiO2 porous nanofibers (50-100) nm in diameter and several micrometers in length were synthesized by electrospinning and then CdS nanopaticles (50-100 nm in size) successfully grown onto TiO2 fibers to form the heterostructure. These CdS/TiO2 heteronanofibers were adopted as photocatalyst and the photocatalsis processes were analyzed in detail, showing the enhanced visible photodecomposition and good recycle ability. Furthermore, the degradation kinetics was further investigated by varying the amount of CdS. The increase of CdS component may enhance the degradation rate under visible light, but the total degradation efficiency also is affected by the adsorption capacity of catalyst toward the dyes. With the improved visible light degradation performance, these CdS/TiO2 heteronanofibers would be expected to be used in water purification. PMID- 25935280 TI - High-performance lubricant additives based on modified graphene oxide by ionic liquids. AB - Graphene oxide (GO) is a layered material bearing a variety of oxygen-containing functional groups on its basal planes and edges, which allow it as a substrate to conduct a variety of chemical transformations. Here modified graphene oxide (MGO) was prepared using alkyl imidazolium ionic liquids (ILs) (1-butyl-3 methylimidazolium tetrafluoroborate (LB104), 1-butyl-3-methyl imidazolium hexafluorophosphate (LP104) and 1-hexyl-3-methylimidazolium bis(trifluoromethylsulfonyl) amide (LF106)) via epoxide ring-opening reaction, cation-pi stacking or van der Waals interactions, with LB104 modified graphene (MG) exfoliated from graphite rod by a moderate electrochemical method as a comparison. The stability and tribological properties of MGO and MG as multialkylated cyclopentanes (MACs) additives were investigated in detail. The results show that GO is converted into graphene through the chemical modification using ILs, and MGO with good dispersion and stability in MACs significantly improves the tribological performance (friction and wear were reduced about 27% and 74% with pure MACs as a comparison, respectively). The excellent tribological properties are attributed to the formation of an ILs-containing graphene-rich tribofilm on the sliding surfaces, which as the third body can prevent the sliding surfaces from straight asperity contact and improve friction reducing and anti-wear behaviors. PMID- 25935281 TI - Novel yolk-shell structure bismuth-rich bismuth molybdate microspheres for enhanced visible light photocatalysis. AB - The yolk-shell structure Bi(4-2x)Mo(x)O6 (x?1) microspheres were successfully synthesized via a simple solvothermal method. The morphology, structure and photocatalytic performances of the samples in the degradation of rhodamine B (RhB) and methyl orange (MO) were characterized by X-ray photoelectron spectroscopy, scanning electron microscopy, transmission electron microscopy, X ray diffraction, UV-vis absorption spectroscopy and electrochemical impedance spectra, respectively. The results show that the yolk-shell structure Bi(2.38)Mo(0.81)O6 microspheres exhibit the best photocatalytic performance for the degradation of RhB and MO with a degradation rate of 99% and 72% under visible light irradiation. PMID- 25935282 TI - Novel approach for synthesis of boehmite nanostructures and their conversion to aluminum oxide nanostructures for remove Congo red. AB - A phase transfer method was developed to prepare boehmite (gamma-AlOOH) nanostructures with various morphologies including nanofragments, nanorods, nanoflakes and multiply stacked nanostructures. The effect of the reaction temperature on the morphology of the as-prepared gamma-AlOOH was investigated systematically. After calcination, the corresponding aluminum oxide (gamma-Al2O3) nanostructures were obtained from the as-prepared gamma-AlOOH products and preserving the same morphology. The obtained samples were characterized by several techniques, such as X-ray diffraction (XRD), field-emission scanning electron microscopy (FESEM), transmission electron microscopy (TEM) and N2 adsorption-desorption technique. The possible formation mechanism of the boehmites has also been proposed. Adsorption experiments indicated that gamma Al2O3 nanorods exhibited better adsorption capacity for Congo red (CR) in contrast to other as-prepared gamma-Al2O3 nanostructures and commercial alumina (Al2O3), and the adsorption obeyed well to Langmuir isotherm model. Besides, the adsorption kinetics followed pseudo-second-order rate equation. PMID- 25935283 TI - ZnO/Ag/CdO nanocomposite for visible light-induced photocatalytic degradation of industrial textile effluents. AB - A ternary ZnO/Ag/CdO nanocomposite was synthesized using thermal decomposition method. The resulting nanocomposite was characterized by X-ray diffraction, field emission scanning electron microscopy, transmission electron microscopy, UV-Vis spectroscopy, and X-ray photoelectron spectroscopy. The ZnO/Ag/CdO nanocomposite exhibited enhanced photocatalytic activity under visible light irradiation for the degradation of methyl orange and methylene blue compared with binary ZnO/Ag and ZnO/CdO nanocomposites. The ZnO/Ag/CdO nanocomposite was also used for the degradation of the industrial textile effluent (real sample analysis) and degraded more than 90% in 210 min under visible light irradiation. The small size, high surface area and synergistic effect in the ZnO/Ag/CdO nanocomposite is responsible for high photocatalytic activity. These results also showed that the Ag nanoparticles induced visible light activity and facilitated efficient charge separation in the ZnO/Ag/CdO nanocomposite, thereby improving the photocatalytic performance. PMID- 25935284 TI - Enhancing adsorption efficiency of dichloroacetic acid onto mesoporous carbons: Procedure optimization, mechanism and characterization. AB - Highly ordered mesoporous carbon may be directly synthesized via supramolecular self-assembly with in situ evaporation-induced crystallization process by controlling thermal reaction temperatures and carbon mass loading. In the present study, the effects of thermal reaction temperatures on the structural characterization and adsorption capacity of mesoporous carbon have been investigated and analyzed with orthogonal test experiments. The results show the carbonization temperature (R=32.1) plays a more important role than the self assembly temperature (R=8.5) and thermal polymerization temperature (R=10.1) in manipulating the pore texture structures. The optimization grouping temperature was 40-110-500 degrees C. The optimum mesoporous carbon sample had the highest BET specific surface area (474 m(2)/g), the largest pore volume (0.46 cm(3)/g), and with reasonable uniform pore size distribution. The adsorption evaluation also shows the adsorption capacity is strongly correlated with the pore structure of mesoporous carbon, the optimized mesoporous carbon sample displayed the largest adsorption capacity (350 mg/g) at an initial concentration of 20.0 mg/L of dichloroacetic acid. The study results indicate optimization of thermal reaction parameters is an effective approach for synthesis of ordered mesoporous carbons. PMID- 25935285 TI - Interface-mediated fabrication of bowl-like and deflated ballon-like hollow carbon nanospheres. AB - In our work, two kinds of hollow carbon nanospheres with controlled morphologies have been successfully prepared from low-cost and nontoxic glucose as the sole carbon precursor under neutral aqueous medium via a simple hydrothermal route. During the process, sodium dodecylbenzene sulfonate (SDBS) and triblock copolymer P123 ((EO)20(PO)70(EO)20) was skillfully selected as the structure-directing agent, respectively. SEM, TEM and AFM results revealed that the two products showed bowl-like and deflated-balloon-like morphology with uniform particle sizes, respectively. Based on the experimental observations, a possible formation mechanism was also discussed, in which the growth of the carbon nanospheres involved an interface-medicated assembly process. The present method was easy, green and mild. Apart from the unique nanostructure, the obtained bowl-like hollow carbon nanospheres exhibited excellent biocompatibility. In particular, it should be mentioned that the open window formed by the bowl-like morphology can facilitate ion transport, thus improving their performances. PMID- 25935286 TI - Probing the role of Proline in the antimicrobial activity and lipopolysaccharide binding of indolicidin. AB - HYPOTHESIS: Indolicidin (ILPWKWPWWPWRR-NH2), an antimicrobial peptide from bovine neutrophils, possesses significant antibacterial activity. An interesting feature of indolicidin is its unusually high content of Tryptophan and Proline residues. While the involvement of Tryptophan has been studied for its hemolytic and antibacterial activity, little is known about the roles played by Proline in these aspects. We herein investigate the structure and biological activities of indolicidin, where Proline at either one or more of the 3rd, 7th, 10th positions has been replaced by Alanine to better understand its structure and biological function. EXPERIMENTS: Structural aspects of Proline residues of indolicidin and its effect on antimicrobial activity were elucidated by replacing Proline residues with Alanine. Minimum inhibitory concentration (MIC) and scanning electron microscopy (SEM) experiments provide substantial evidence for the importance of Proline residues for antimicrobial activity and cell wall disintegration. Binding affinity of the peptides to Lipopolysaccharide (LPS) was investigated using fluorescence spectroscopy and dynamic light scattering (DLS) in conjunction with (31)PNMR spectroscopy and confirmed the disintegration of LPS layer. FINDINGS: Our study reveals that Proline residues are necessary for interaction of indolicidin with LPS and establishes the significance of the third and tenth Proline residues for its antimicrobial activity. We believe that the presence of so many Proline residues provides the molecule a selective advantage of adopting different conformations varying from a globular, closed conformation to an open extended conformation, and even to a wedge-shaped conformation, which account for the diverse mechanisms of action of indolicidin. PMID- 25935287 TI - How hydrophobically modified chitosans are stabilized by biocompatible lipid aggregates. AB - Nanostructured hydrogels composed by biocompatible molecules are formulated and characterized. They are based on a polymer network formed by hydrophobically modified chitosans (HMCHIT or CnCHIT) in which vesicles of monoolein (MO) and oleic acid or sodium oleate (NaO), depending on pH, are embedded. The best conditions for gel formation, in terms of pH, length of the hydrophobic moieties of chitosan, and weight proportion among the three components were estimated by visual inspection of a large number of samples. Among all possible combinations, the system C12CHIT-MO-NaO in the weight proportion (1:1:1) is optimal for the formation of a well-structured gel-like system, which is also confirmed by rheological experiments. Electron paramagnetic resonance (EPR) measurements unambiguously show the presence of lipid bilayers in this mixture, indicating that MO-NaO vesicles are stabilized by C12CHIT even at acid pH. A wide small angle neutron scattering investigation performed on several ternary systems of general formula CnCHIT-MO-NaO shows that the length of the hydrophobic tail Cn is a crucial parameter in stabilizing the polymer network in which lipid vesicles are embedded. Structural parameters for the vesicles are determined by using a multilamellar model that admits the possibility of displacement of the center of each shell. The number of shells tends to be reduced by increasing the polymer content. The thickness and the distance between consecutive lamellae are not influenced by either the polymer or MO-NaO concentration. The hydrogel presented in this work, being fully biocompatible and nanostructured, is well-suited for possible application in drug delivery. PMID- 25935288 TI - Colloidal synthesis and electrical behaviour of n-ZnGdO/p-Si heterojunction diodes. AB - Studies on manoeuvring the optoelectronic characteristics of a semiconducting nanostructure are of recent specific interest for a wide range of photonic applications. In this regard, the optical and electrical characteristics of ZnO nanostructures have been tuned and studied systematically using Gd ions. The structural and morphological characteristics of the solution processed ZnGdO nanostructures were studied in detail using the results of X-ray diffraction and microscopic measurements. The absorption band edge in ZnO was noted to shift towards the lower wavelength values on Gd substitution, suggesting an increase in its energy band gap. The blue emissivity from ZnO complexes was also noted to improve as a function of Gd composition in ZnO. The potential of ZnGdO nanostructures for optoelectronic functions was evaluated by fabricating heterojunction diodes based on n-ZnGdO/p-Si. The diode characteristics revealed an improved electrical conductivity and rectifying behaviour from the fabricated architectures upon Gd substitution and photon illumination. The findings are correlated with the increased charge carrier concentration and defect states existing within ZnGdO species, through appropriate mechanisms. PMID- 25935289 TI - Exploring the structure-activity relationships of ABCC2 modulators using a screening approach. AB - ABCC2 is a transporter with key influence on liver and kidney pharmacokinetics. In order to explore the structure-activity relationships of compounds that modulate ABCC2, and by doing so gain insights into drug-drug interactions, we screened a library of 432 compounds for modulators of radiolabeled beta-estradiol 17-(beta-d-glucuronide) (EG) and fluorescent 5(6)-carboxy-2',7' dichlorofluorescein transport (CDCF) in membrane vesicles. Following the primary screen at 80MUM, dose-response curves were used to investigate in detail 86 compounds, identifying 16 low MUM inhibitors and providing data about the structure-activity relationships in four series containing 19, 24, 10, and eight analogues. Measurements with the CDCF probe were consistently more robust than for the EG probe. Only one compound was clearly probe-selective with a 50-fold difference in the IC50s obtained by the two assays. We built 24 classification models using the SVM and fused-XY Kohonen methods, revealing molecular descriptors related to number of rings, solubility and lipophilicity as important to distinguish inhibitors from inactive compounds. This study is to the best of our knowledge the first to provide details about structure-activity relationships in ABCC2 modulation. PMID- 25935290 TI - Macrocyclic naphthalene diimides as G-quadruplex binders. AB - The synthesis, biological and molecular modeling evaluation of a series of macrocyclic naphthalene diimides is reported. The present investigation expands on the study of structure-activity relationships of prototype compound 2 by constraining the molecule into a macrocyclic structure with the aim of improving its G-quadruplex binding activity and selectivity. The new derivatives, compounds 4-7 carry spermidine- and spermine-like linkers while in compound 8 the inner basic nitrogen atoms of spermine have been replaced with oxygen atoms. The design strategy has led to potent compounds stabilizing both human telomeric (F21T) and c-KIT2 quadruplex sequences, and high selectivity for quadruplex in comparison to duplex DNA. Antiproliferative effects of the new derivatives 4-8 have been evaluated in a panel of cancer cell lines and all the tested compounds showed activity in the low micromolar or sub-micromolar range of concentrations. In order to rationalize the molecular basis of the DNA G-quadruplex versus duplex recognition preference, docking and molecular dynamics studies have been performed. The computational results support the observation that the main driving force in the recognition is due to electrostatic factors. PMID- 25935291 TI - Protection of horses against Culicoides biting midges in different housing systems in Switzerland. AB - Species belonging to the Culicoides complexes (Diptera, Ceratopogonidae), obsoletus and pulicaris, in Switzerland, are potential vectors of both bluetongue virus (BTV) and African horse sickness virus (AHSV). The epidemic of BTV in 2006 and 2007 in Europe has highlighted the risk of introduction and spread of vector borne diseases in previously non-endemic areas. As a measure of prevention, as part of an integrated control programme in the event of an outbreak of African horse sickness (AHS), it is of utmost importance to prevent, or substantially reduce, contact between horses and Culicoides. The aim of the present study was to compare the effect of three protection systems, net, fan, repellent, or combinations thereof, with regard to their potential to reduce contact between horses and Culicoides. Three different equine housing systems, including individual boxes (BX), group housing systems (GR), and individual boxes with permanently accessible paddock (BP) were used. The efficacy of the protection systems were evaluated by comparing the total number counts of collected female Culicoides, of non-blood-fed and blood-fed Culicoides, respectively, with UV black light traps. The study was conducted over 3 summer months during 2012 and 2013 each and focused on the efficacy and practicality of the protection systems. The repellent was tested in 2012 only and not further investigated in 2013, as it showed no significant effect in reducing Culicoides collected in the light traps. Net protection system provided the best overall protection for the total number of female Culicoides, non-blood-fed and blood-fed Culicoides in all tested housing systems. The net, with a pore size of 0.1825 mm(2), reduced the total number of Culicoides collected in the housing systems BP, GR and BX by 98%, 85% and 67%, respectively. However, in the GR housing system, no significant difference between the effectiveness of the fan and the net were determined for any of the three Culicoides categories. The results of the present study demonstrated that horse owners can substantially reduce their horses' exposure to Culicoides, by using net protection in the housing systems BX, BP and GR. In GR housing systems, protection against Culicoides using a fan is also recommended. PMID- 25935292 TI - A real-time assemblage-specific PCR assay for the detection of Giardia duodenalis assemblages A, B and E in fecal samples. AB - Giardiosis is a common gastrointestinal infection caused by the flagellate Giardia duodenalis, and affects both humans and animals, worldwide. Animals are infected with both zoonotic and host-specific G. duodenalis assemblages, and their role in the transmission of the infection to humans has been a subject of intense research and debate. Conventional PCR assays are appropriate to determine G. duodenalis assemblages, but lack sensitivity for the detection of mixed infections. Previous surveys demonstrated the occurrence of mixed infections with G. duodenalis assemblage A and B in humans, and with assemblages A and E in cattle, but are likely to be underestimated. In this study, we designed a set of assemblage-specific primers by exploiting sequence variability in homologous genes from assemblages A, B and E. Primers were designed to amplify fragments of different size that generated different melting curves from each assemblage in real-time PCR (rt-PCR) experiments. The assay has been tested on a large panel of human and farm animal isolates, and shown to possess high specificity (no cross reactions observed) and sensitivity (detection limit close to 20 copies). Therefore, this assay can be useful to detect zoonotic and host-specific G. duodenalis assemblages in fecal samples from farm animals, particularly when a large number of samples is to be tested. PMID- 25935293 TI - Study on the use of toltrazuril to eliminate Neospora caninum in congenitally infected lambs born from experimentally infected ewes. AB - To determine if toltrazuril was effective in eliminating Neospora caninum infection from congenitally infected lambs. Twenty-eight ewes were allocated to 3 groups where animals in Groups A and B were inoculated with 1 * 10(7)N. caninum tachyzoites on Day 120 of gestation and Group C was maintained as a negative control group. Lambs born from ewes in Group A were treated with toltrazuril (20mg/kg) on Days 0, 7, 14 and 21 after birth. Lambs in Groups B and C were untreated. All lambs in Groups A and B were seropositive at 12 weeks of age. At 12 weeks of age, no differences between lambs in Group A and Group B were observed in serological results (ELISA and western blot), presence of N. caninum related brain histopathological lesions or the number of organisms detected by qPCR. Group C remained negative for serology, detection of N. caninum DNA as well as histopathology throughout the study. Results indicate that N. caninum congenitally-infected lambs had a continuing infection with N. caninum despite being treated with toltrazuril. PMID- 25935294 TI - What works to prevent falls in older adults dwelling in long term care facilities and hospitals? An umbrella review of meta-analyses of randomised controlled trials. AB - Preventing falls in long term care facilities (LTCF) and hospitals is an international priority. Many interventions have been investigated and summarised in meta-analyses (MA) and there is a need to synthesise the top of the hierarchy of evidence in one place. Therefore we conducted an umbrella review of MA of randomised controlled trials (RCTs) of falls prevention interventions LTCF and hospitals. Two independent reviewers searched major electronic databases from inception till October 2014 for MA containing >=3 RCTs investigating any intervention to prevent falls in LTCF or hospitals in older adults aged >=60 years. Methodological quality was assessed by the AMSTAR tool and data were narratively synthesised. The methodological quality of the MA was moderate to high across the 10 included MA. Nine MA provided data for LTCF and only two considered hospital settings. Only one MA defined a fall and two reported adverse events (although minor). Consistent evidence suggests that multifactorial interventions reduce falls (including the rate, risk and odds of falling) in LTCF and hospitals. Inconsistent evidence exists for exercise and vitamin D as single interventions in LTCF, whilst no MA has investigated this in hospitals. No evidence exists for hip protectors and medication review on falls in LTCF. In conclusion, multifactorial interventions appear to be the most effective interventions to prevent falls in LTCF and hospital settings. This is not without limitations and more high quality RCTs are needed in hospital settings in particular. Future RCTs and MA should clearly report adverse events. PMID- 25935295 TI - Organizational impact of governmental audit of blood transfusion services in Norway: A qualitative study. AB - Little is known about the organizational impact of supervisory activities in blood banks. We did a study with the aim to explore health professional's experiences with the external audit of blood transfusion services in Norway. The audit and supervision brought attention to deficiencies in systems and practices, and had been a catalyst for quality improvement. We identify facilitators and barriers to change. While audits can bring attention to known deficiencies, and trigger improvement processes which previously have not been prioritized, involvement of senior management is important to secure change across departments. PMID- 25935296 TI - Comparison of the spectroscopic speciation and chemical fractionation of chromium in contaminated paddy soils. AB - Sequential extraction has been widely used to classify metal species in soils and sediments; however, the lack of selectivity in extraction reagents may lead to the misinterpretation of metal speciation. In this study, we used X-ray absorption near edge structure (XANES) spectroscopy to classify Cr species based on its molecular form. These results complement the conventional Cr fractionation derived from the Tessier extraction method. The linear combination fitting (LCF) for the Cr-XANES spectra indicated that the Cr species in the soils could generally be described as Cr(III) sorbed on ferrihydrite (Cr-FH), Cr(III) complexed with humic acid (Cr-HA), and precipitated Cr. While the sum of the adsorbed Cr(III) and Cr(III)/Fe coprecipitates showed a nearly 1:1 relationship with reducible Cr, the total of Cr precipitates and organic Cr also followed the same trend with oxidizable Cr. This result indicated that there might be a underestimation in the reducible fraction as pure Cr(III) precipitates associated with surfaces of Fe minerals would not be extracted in the reducible process. Instead, such pure Cr(III) precipitates were dissolved during the oxidizable process, resulting in a overestimation in the fractionation of organic-related Cr. PMID- 25935297 TI - Evaluation of heavy metals in hazardous automobile shredder residue thermal residue and immobilization with novel nano-size calcium dispersed reagent. AB - This study was conducted to synthesize and apply a nano-size calcium dispersed reagent as an immobilization material for heavy metal-contaminated automobile shredder residues (ASR) dust/thermal residues in dry condition. Simple mixing with a nanometallic Ca/CaO/PO4 dispersion mixture immobilized 95-100% of heavy metals in ASR dust/thermal residues (including bottom ash, cavity ash, boiler and bag filter ash). The quantity of heavy metals leached from thermal residues after treatment by nanometallic Ca/CaO/PO4 was lower than the Korean standard regulatory limit for hazardous waste landfills. The morphology and elemental composition of the nanometallic Ca/CaO-treated ASR residue were characterized by field emission scanning election microscopy combined with electron dispersive spectroscopy (FE-SEM/EDS). The results indicated that the amounts of heavy metals detectable on the ASR thermal residue surface decreased and the Ca/PO4 mass percent increased. X-ray diffraction (XRD) pattern analysis indicated that the main fraction of enclosed/bound materials on ASR residue included Ca/PO4- associated crystalline complexes, and that immobile Ca/PO4 salts remarkably inhibited the desorption of heavy metals from ASR residues. These results support the potential use of nanometallic Ca/CaO/PO4 as a simple, suitable and highly efficient material for the gentle immobilization of heavy metals in hazardous ASR thermal residue in dry condition. PMID- 25935298 TI - Intimate partner violence and postpartum contraceptive use: the role of race/ethnicity and prenatal birth control counseling. AB - OBJECTIVES: Intimate partner violence (IPV) is a major problem that could affect reproductive decision making. The aim of this study is to examine the association between IPV and contraceptive use and assess whether the association varies by receipt of prenatal birth control counseling and race/ethnicity. STUDY DESIGN: This study analyzed the 2004-2008 national Pregnancy Risk Assessment Monitoring System (PRAMS) that included 193,310 women with live births in the United States. IPV was determined by questions that asked about physical abuse by a current or former partner in the 12 months before or during pregnancy. The outcome was postpartum contraceptive use (yes vs. no). Multiple logistic regression analyses were conducted to assess the influence of experiencing IPV at different periods (preconception IPV, prenatal IPV, both preconception and prenatal IPV, preconception and/or prenatal IPV). Data were stratified to assess differential effects by race/ethnicity and receipt of birth control counseling. RESULTS: Approximately 6.2% of women reported IPV, and 15.5% reported no postpartum contraceptive use. Regardless of the timing of abuse, IPV-exposed women were significantly less likely to report contraceptive use after delivery. This was particularly true for Hispanic women who reported no prenatal birth control counseling and women of all other racial/ethnic groups who received prenatal birth control counseling. CONCLUSIONS: IPV victimization adversely affects the use of contraceptive methods following delivery in women with live births. Birth control counseling by health providers may mitigate these effects; however, the quality of counseling needs further investigation. Better integration of violence prevention services and family planning programs is greatly needed. IMPLICATIONS: Consistent with national recommendations by the U.S. Preventive Service Task Force, clinicians and public health workers are strongly encouraged to screen for IPV. Health providers should educate women on effective contraceptive options and discuss long-acting reversible contraceptives that are not partner dependent within the context of abusive relationships. PMID- 25935299 TI - Higher monetary incentives led to a lowered response rate in ambulatory patients: a randomized trial. AB - OBJECTIVES: Monetary incentives can increase response rate in patient surveys, but calibration of the optimal incentive level is required. Our aim was to assess the effect of different monetary incentives on response rates to calibrate the optimal monetary incentive for ambulatory patients. STUDY DESIGN AND SETTING: A patient-randomized trial was performed in which targeted individuals received different gift vouchers (?5.00, ?7.50, ?10.00, and ?12.50) on completion of a survey and interview. Eligible patients (diagnosed type 2 diabetes, over 18 years) were recruited from primary care practices. RESULTS: The response rate for the ?12.50 incentive was lower compared with both the ?7.50 and the ?10.00 incentive [odds ratio (OR) = 0.60 and OR = 0.58]. A nonlinear model yield a better fit than a linear model. Within the observed range of incentive levels, an overall decrease in response rate was found. CONCLUSION: High monetary incentives are not only inefficient but also less effective. PMID- 25935300 TI - Unraveling interactions in microbial communities - from co-cultures to microbiomes. AB - Microorganisms do not exist in isolation in the environment. Instead, they form complex communities among themselves as well as with their hosts. Different forms of interactions not only shape the composition of these communities but also define how these communities are established and maintained. The kinds of interaction a bacterium can employ are largely encoded in its genome. This allows us to deploy a genomescale modeling approach to understand, and ultimately predict, the complex and intertwined relationships in which microorganisms engage. So far, most studies on microbial communities have been focused on synthetic co-cultures and simple communities. However, recent advances in molecular and computational biology now enable bottom up methods to be deployed for complex microbial communities from the environment to provide insight into the intricate and dynamic interactions in which microorganisms are engaged. These methods will be applicable for a wide range of microbial communities involved in industrial processes, as well as understanding, preserving and reconditioning natural microbial communities present in soil, water, and the human microbiome. PMID- 25935301 TI - Two stress sensor proteins for the expression of sigmaE regulon: DegS and RseB. AB - In E. coli, sigmaE-dependent transcription is controlled by regulated-proteolysis of RseA. RseA, which holds sigmaE as an anti-sigma factor, is sequentially digested by DegS, RseP and cytoplasmic proteases to liberate sigmaE in response to dysfunction in outer-membrane biogenesis. Additionally, the sequential proteolysis is regulated by RseB binding to RseA (Fig. 1A). Direct interaction between RseA and RseB inhibits RseA-cleavage by DegS. Both proteolytic activation of DegS and binding disruption of RseB are thus required to initiate sigmaE stress response. For the induction of sigmaEstress response, DegS and RseB recognize the states of OMP and LPS for outer-membrane biogenesis. DegS is activated by binding of unfolded OMPs and RseB binding to RseA is antagonized by LPS accumulated in periplasm. In this regard, DegS and RseB are proposed to be stress sensor proteins for sigmaE signal transduction. Interestingly, biogenesis of OMP and LPS appears to cross-talk with each other, indicating that dysfunction of either OMP or LPS can initiate RseA proteolysis. This review aims to briefly introduce two stress sensor proteins, DegS and RseB, which regulate sigmaEdependent transcription. PMID- 25935302 TI - Communities of ammonia oxidizers at different stages of Spartina alterniflora invasion in salt marshes of Yangtze River estuary. AB - Spartina alterniflora, an aggressive invasive plant species at the estuarine wetlands of China's coasts, has become a major threat to the natural ecosystems. To understand its potential influence on nitrification processes, the community structures and abundance of ammonia-oxidizing archaea (AOA) and ammonia-oxidizing bacteria (AOB) were investigated using 454-pyrosequencing and quantitative real time PCR (qPCR) in S. alterniflora invading salt marsh sediments at the Yangtze River estuary in Chongming island, Shanghai, China. Copy numbers of archaeal and bacterial ammonia monooxygenase subunit A (amoA) genes did not show accordant shifts with S. alterniflora invasion in the two sampling sites. However, the copy numbers of archaeal amoA gene were higher in summer than in spring. Phylogenetic analysis indicated that more than 90% of the archaeal and 92% of the bacterial amoA gene sequences were closely related to marine group I.1a and the clusters 13 and 15 in Nitrosospira lineage, respectively. The effect of different seasons (spring and summer) was important for the abundance variation of AOA, while different stages of S. alterniflora invasion did not show significant effect for both AOA and AOB. Variation of AOA community was significantly related to total carbon (TC) and sulfate concentration (P < 0.05), whereas the AOB community was significantly related to sulfate concentration, total nitrogen (TN), TC and pH (P < 0.05). In conclusion, the abundance and diversity of ammonia oxidizing microbial communities were not strongly affected by S. alterniflora invasion. PMID- 25935303 TI - In vitro effects of N-acetyl cysteine alone and in combination with antibiotics on Prevotella intermedia. AB - N-acetyl cysteine (NAC) is an antioxidant that possesses anti-inflammatory activities in tissues. In the field of dentistry, NAC was demonstrated to prevent the expression of LPS-induced inflammatory mediators in phagocytic cells and gingival fibroblasts during the inflammatory process, but the effect of NAC on oral pathogens has been rarely studied. Here, we examined the effect of NAC against planktonic and biofilm cells of Prevotella intermedia, a major oral pathogen. NAC showed antibacterial activity against the planktonic P. intermedia with MIC value of 3 mg/ml and significantly decreased biofilm formation by the bacterium even at sub MIC. NAC did not affect the antibiotic susceptibility of planktonic P. intermedia, showing indifference (fractional inhibitory concentration index of 0.5-4) results against the bacterium in combination with ampicillin, ciprofloxacin, tetracycline or metronidazole. On the other hand, viability of the pre-established bacterial biofilm exposed to the antibiotics except metronidazole was increased in the presence of NAC. Collectively, NAC may be used for prevention of the biofilm formation by P. intermedia rather than eradication of the pre-established bacterial biofilm. Further studies are required to explore antibacterial and anti-biofilm activity of NAC against mixed population of oral bacteria and its modulatory effect on antibiotics used for oral infectious diseases. PMID- 25935304 TI - Identification of seven novel virulence genes from Xanthomonas citri subsp. citri by Tn5-based random mutagenesis. AB - To identify novel virulence genes, a mutant library of Xanthomonas citri subsp. citri 29-1 was produced using EZ-Tn5 transposon and the mutants were inoculated into susceptible grapefruit. Forty mutants with altered virulence phenotypes were identified. Nine of the mutants showed a complete loss of citrus canker induction, and the other 31 mutants resulted in attenuated canker symptoms. Southern blot analysis revealed that each of the mutants carried a single copy of Tn5. The flanking sequence was identified by plasmid rescue and 18 different ORFs were identified in the genome sequence. Of these 18 ORFs, seven had not been previously associated with the virulence of X. citri subsp. citri and were therefore confirmed by complementation analysis. Real-time PCR analysis showed that the seven genes were upregulated when the bacteria were grown in citrus plants, suggesting that the expression of these genes was essential for canker development. PMID- 25935305 TI - Genome sequence analysis of potential probiotic strain Leuconostoc lactis EFEL005 isolated from kimchi. AB - Leuconostoc lactis EFEL005 (KACC 91922) isolated from kimchi showed promising probiotic attributes; resistance against acid and bile salts, absence of transferable genes for antibiotic resistance, broad utilization of prebiotics, and no hemolytic activity. To expand our understanding of the species, we generated a draft genome sequence of the strain and analyzed its genomic features related to the aforementioned probiotic properties. Genome assembly resulted in 35 contigs, and the draft genome has 1,688,202 base pairs (bp) with a G+C content of 43.43%, containing 1,644 protein-coding genes and 50 RNA genes. The average nucleotide identity analysis showed high homology (>= 96%) to the type strain L. lactis KCTC3528, but low homology (<= 95%) to L. lactis KCTC3773 (formerly L. argentinum). Genomic analysis revealed the presence of various genes for sucrose metabolism (glucansucrases, invertases, sucrose phosphorylases, and mannitol dehydrogenase), acid tolerance (F1F0 ATPases, cation transport ATPase, branched chain amino acid permease, and lysine decarboxylase), vancomycin response regulator, and antibacterial peptide (Lactacin F). No gene for production of biogenic amines (histamine and tyramine) was found. This report will facilitate the understanding of probiotic properties of this strain as a starter for fermented foods. PMID- 25935306 TI - Phosphorylation of the nucleocapsid protein of Hantaan virus by casein kinase II. AB - Hantaanvirus (HTNV) is the prototype of the genus Hantavirus, which belongs to the family Bunyaviridae. Hantaviruses are carried and transmitted by rodents and are known to cause two serious disease syndromes in humans i.e., hemorrhagic fever with renal syndrome (HFRS) and the hantavirus pulmonary syndrome (HPS). HTNV is an enveloped virus that contains a tripartite genome consisting of three negative-sense RNA segments (L, M, S), and the S and M segment of HTNV, respectively, encode the viral nucleocapsid protein (NP) and envelope glycoproteins. Possible phosphorylation motifs of casein kinase II (CKII) and protein kinase C (PKC) were identified in HTNV NP through bioinformatics searches. Sucrose gradient SDS-PAGE analysis indicated that dephosphorylated HTNV NP migrated faster than non-dephosphorylated NP, suggesting that HTNV NP is phosphorylated in infected Vero E6 cells. Immunoblot anaylsis of HTNV particles with anti-phosphoserine antibody and anti-phosphothreonine antibody after immunoprecipitation showed that viral particles are readily phosphorylated at threonine residues. In vitro kinase assay further showed that HTNV NP is phosphorylated by CK II, but not by PKC. Full length or truncated HTNV NPs expressed in E. coli were phosphorylated in vitro by CKII suggesting that phosphorylation may occur in vivo at multiple sites. Site specific mutagenesis studies suggest that HTNV NP phosphorylation might occur at unknown sites excluding the site-directly mutagenized locations. Taken together, HTNV NP can be phosphorylated mainly at threonine residues in vivo by CK II treatment. PMID- 25935307 TI - Identification of Porcine Endogenous Retrovirus (PERV) packaging sequence and development of PERV packaging viral vector system. AB - Studies of the retroviruses have focused on the specific interaction of the nucleocapsid protein with a packaging signal in the viral RNA as important for this selectivity, but the packaging signal in porcine endogenous retrovirus (PERV) has not been defined. Herein, we identified and analyzed this packaging signal in PERV and found hairpin structures with conserved tetranucleotides in their loops and nucleocapsid recognition sequences; both of which are key elements in the viral packaging signal of MLV. We evaluated packaging efficiency of sequence variants isolated from viral and proviral integrated genomes. All viral packaging sequences (Psi) were identical, while five distinct packaging sequences were identified from proviral sources. One proviral sequence (Psi1) was identical to that of the viral Psi and had the highest packaging efficiency. Three variants (Psi2, Psi3, Psi4) maintained key elements of the viral packaging signal, but had nucleotide replacements and consequently demonstrated reduced packaging efficiency. Despite of the same overall hairpin structure, the proviral variant (Psi5) had only one GACG sequence in the hairpin loop and showed the lowest packaging efficiency other than ?Psi, in which the essential packaging sequence was removed. This result, thus, defined the packaging sequences in PERV and emphasized the importance of nucleotide sequence and RNA structure in the determination of packaging efficiency. In addition, we demonstrate efficient infection and gene expression from the PERV based viral vector, which may serve as a novel alternative to current retroviral expression systems. PMID- 25935308 TI - Perinatal protein restriction affects milk free amino acid and fatty acid profile in lactating rats: potential role on pup growth and metabolic status. AB - Perinatal undernutrition affects not only fetal and neonatal growth but also adult health outcome, as suggested by the metabolic imprinting concept. Although maternal milk is the only channel through which nutrients are transferred from mother to offspring during the postnatal period, the impact of maternal undernutrition on milk composition is poorly understood. The present study investigates, in a rat model of nutritional programming, the effects of feeding an isocaloric, low-protein diet throughout gestation and lactation on milk composition and its possible consequences on offspring's growth and metabolic status. We used an integrated methodological approach that combined targeted analyses of macronutrients, free amino acid and fatty acid content throughout lactation, with an untargeted mass-spectrometric-based metabolomic phenotyping. Whereas perinatal dietary protein restriction failed to alter milk protein content, it dramatically decreased the concentration of most free amino acids at the end of lactation. Interestingly, a decrease of several amino acids involved in insulin secretion or gluconeogenesis was observed, suggesting that maternal protein restriction during the perinatal period may impact the insulinotrophic effect of milk, which may, in turn, account for the slower growth of the suckled male offspring. Besides, the decrease in sulfur amino acids may alter redox status in the offspring. Maternal undernutrition was also associated with an increase in milk total fatty acid content, with modifications in their pattern. Altogether, our results show that milk composition is clearly influenced by maternal diet and suggest that alterations in milk composition may play a role in offspring growth and metabolic programming. PMID- 25935309 TI - Deubiquitinating enzyme CYLD mediates pressure overload-induced cardiac maladaptive remodeling and dysfunction via downregulating Nrf2. AB - Ubiquitin proteasome system (UPS) consists of ubiquitin, ubiquitin-activating enzymes (E1s), ubiquitin-conjugating enzymes (E2s), ubiquitin ligases (E3s), proteasomes, and deubiquitinating enzymes (DUBs). Ubiquitin, E1s, several E2s, E3s, and proteasomes play an important role in the regulation of cardiac homeostasis and dysfunction; however, less is known about the role of DUBs in the heart. Here, we uncovered a crucial role of cyclindromatosis (CYLD), a DUB, in mediating cardiac maladaptive remodeling and dysfunction. CYLD expression was dramatically upregulated in the cardiomyocytes of hypertrophic and failing human and murine hearts. Knockout of CYLD improved survival rate and alleviated cardiac hypertrophy, fibrosis, apoptosis, oxidative stress, and dysfunction in mice that were subjected to sustained pressure overload induced by transverse aortic constriction. Deep sequencing and gene array analyses revealed that the most dramatically changed genes are those involving in the free radical scavenging pathway and cardiovascular disease, including fos, jun, myc, and nuclear factor erythroid-2 related factor 2 (Nrf2) in the heart. Moreover, knockdown of CYLD enhanced mitogen-activated protein kinase (MAPK) ERK- and p38-mediated expression of c-jun, c-fos, and c-myc, which govern Nrf2 expression in cardiomyocytes. The CYLD deficiency-induced suppression of reactive oxygen species (ROS) formation, death and hypertrophy in cardiomyocytes was blocked by additional knockdown of Nrf2. Taken together, our findings demonstrate for the first time that CYLD mediates cardiac maladaptive remodeling and dysfunction, most likely via enhancing myocardial oxidative stress in response to pressure overload. At the molecular level, CYLD interrupts the ERK- and p38-/AP-1 and c-Myc pathways to suppress Nrf2-operated antioxidative capacity, thereby enhancing oxidative stress in the heart. PMID- 25935310 TI - Calcineurin B homologous protein 3 negatively regulates cardiomyocyte hypertrophy via inhibition of glycogen synthase kinase 3 phosphorylation. AB - Cardiac hypertrophy is a leading cause of serious heart diseases. Although many signaling molecules are involved in hypertrophy, the functions of some proteins in this process are still unknown. Calcineurin B homologous protein 3 (CHP3)/tescalcin is an EF-hand Ca(2+)-binding protein that is abundantly expressed in the heart; however, the function of CHP3 is unclear. Here, we aimed to identify the cardiac functions of CHP3. CHP3 was expressed in hearts at a wide range of developmental stages and was specifically detected in neonatal rat ventricular myocytes (NRVMs) but not in cardiac fibroblasts in culture. Moreover, knockdown of CHP3 expression using adenoviral-based RNA interference in NRVMs resulted in enlargement of cardiomyocyte size, concomitant with increased expression of a pathological hypertrophy marker ANP. This same treatment elevated glycogen synthase kinase (GSK3alpha/beta) phosphorylation, which is known to inhibit GSK3 function. In contrast, CHP3 overexpression blocked the insulin induced phosphorylation of GSK3alpha/beta without affecting the phosphorylation of Akt, which is an upstream kinase of GSK3alpha/beta, in HEK293 cells, and it inhibited both IGF-1-induced phosphorylation of GSK3beta and cardiomyocyte hypertrophy in NRVMs. Co-immunoprecipitation experiments revealed that GSK3beta interacted with CHP3. However, a Ca(2+)-binding-defective mutation of CHP3 (CHP3 D123A) also interacted with GSK3beta and had the same inhibitory effect on GSK3alpha/beta phosphorylation, suggesting that the action of CHP3 was independent of Ca(2+). These findings suggest that CHP3 functions as a novel negative regulator of cardiomyocyte hypertrophy via inhibition of GSK3alpha/beta phosphorylation and subsequent enzymatic activation of GSK3alpha/beta. PMID- 25935311 TI - Jellyfish Stings: A Practical Approach. AB - Jellyfish have a worldwide distribution. Their stings can cause different reactions, ranging from cutaneous, localized, and self-limited to serious systemic or fatal ones, depending on the envenoming species. Several first aid treatments are used to manage such stings but few have evidence behind their use. This review of the literature describes and discusses the different related first aid and treatment recommendations, ending with a summarized practical approach. Further randomized controlled trials in this field are needed. PMID- 25935313 TI - Atrial Fibrillation and Stroke: It's About Point of View. PMID- 25935312 TI - Hiker Fatality From Severe Hyponatremia in Grand Canyon National Park. AB - We present the case of a hiker who died of severe hyponatremia at Grand Canyon National Park. The woman collapsed on the rim shortly after finishing a 5-hour hike into the Canyon during which she was reported to have consumed large quantities of water. First responders transported her to the nearest hospital. En route, she became unresponsive, and subsequent treatment included intravenous normal saline. Imaging and laboratory data at the hospital confirmed hypervolemic hyponatremia with encephalopathy. She never regained consciousness and died of severe cerebral edema less than 24 hours later. We believe this is the first report of a fatality due to acute hyponatremia associated with hiking in a wilderness setting. This case demonstrates the typical pathophysiology, which includes overconsumption of fluids, and demonstrates the challenges of diagnosis and the importance of appropriate acute management. Current treatment guidelines indicate that symptomatic exercise-associated hyponatremia should be acutely managed with hypertonic saline and can be done so without concern over central pontine myelinolysis, whereas treatment with high volumes of isotonic fluids may delay recovery and has even resulted in deaths. PMID- 25935314 TI - Long-term consequences of severe health anxiety on sick leave in treated and untreated patients: Analysis alongside a randomised controlled trial. AB - Health anxiety (HA) is prevalent and costly for health services. However, little is known about the full societal burden of HA. Based on complete register data, we (1) compared weeks on sickness-related benefits (SB) in untreated patients with severe HA (n=126) with a matched population sample (n=12,600); and (2) tested whether Acceptance & Commitment group Therapy (ACT-G) (n=63) reduced weeks on SB during the first year after randomisation compared to a waitlist (n=63). We found that (1) HA patients showed a six-monthly increment of 2 weeks on SB compared with the general population (p<0.0001), and (2) that ACT-G and the waitlist showed no difference in their ability to reduce SB during the first year (p=0.246). We conclude that HA is associated with a considerable societal burden. A possible beneficial effect of psychotherapy on SB needs further investigation. PMID- 25935315 TI - Posttraumatic stress and other health consequences of catastrophic avalanches: A 16-year follow-up of survivors. AB - To date, no study has investigated the effects of avalanches on survivor's health beyond the first years. The aim of this study was to examine long-term health status 16 years after exposure to avalanches using a matched cohort design. Mental health, sleep quality and somatic symptoms among avalanche survivors (n=286) and non-exposed controls (n=357) were examined. Results showed that 16% of survivors currently experience avalanche-specific PTSD symptoms (PDS score>14). In addition, survivors presented with increased risk of PTSD hyperarousal symptoms (>85th percentile) (aRR=1.83; 98.3% CI [1.23-2.74]); sleep related problems (PSQI score>5) (aRR=1.34; 95% CI [1.05-1.70]); PTSD-related sleep disturbances (PSQI-A score>=4) (aRR=1.86; 95% CI [1.30-2.67]); musculoskeletal and nervous system problems (aRR 1.43; 99% CI 1.06-1.93) and gastrointestinal problems (aRR 2.16; 99% CI 1.21-3.86) compared to the unexposed group. Results highlight the need for treatment for long-term PTSD symptoms and sleep disruption in disaster communities. PMID- 25935316 TI - Predictors of generic substitution: The role of psychological, sociodemographic, and contextual factors. AB - BACKGROUND: Escalating pharmaceutical costs have become a global challenge for both governments and patients. Generic substitution is one way of decreasing these costs. OBJECTIVE: The aim of this study was to investigate factors associated with patients' choice between generic drugs and innovator drugs. METHOD: The survey was conducted in June 2013, 1000 people from across Poland were chosen as a representative population sample. The outcome (a preference for generics/a preference for innovator pharmaceuticals/no preference) was modeled by multinomial logistic regression, adjusted for several variables describing patients' sensitivity to selected generic features (price, brand, and country of origin), to third-party opinions about generics (information on generics in the mass media, opinions of health professionals (i.e. physicians, pharmacists), relatives/friends), as well as patients' personal experiences and income per household. RESULTS: The results supported the predictive capacity of most independent variables (except for patient sensitivity to the country of origin and to the information on generics in the mass media), denoting patients' preferences toward generic substitution. Patient sensitivity to recommendations by physicians, generic brand, and household income were the strongest predictors of the choice between generic and innovator pharmaceuticals (P < 0.001). The probability of choosing generics over innovator drugs was significantly higher among respondents with the lowest income levels, in those who were indifferent to generic brand or their physician's opinion, as well as in respondents who were sensitive to recommendations by pharmacists or attached a greater value to a past experience with generics (their own experience or that of relatives/friends). CONCLUSION: In consideration of the foregoing, awareness-raising campaigns may be recommended, supported by a variety of systemic solutions and tools to encourage generic substitution. PMID- 25935317 TI - A simple derivation of the critical condition for the ultrasonic atomization of polymer solutions. AB - A simple model is proposed for the ultrasonic atomization of polymer solutions. In this model, the atomization process is approximated as an equilibrium process. It is shown that the minimum attainable droplet size is determined by two parameters, the (Rayleigh) acoustic pressure acting on the surface of the liquid, and the surface tension of the liquid. Increasing the viscosity of the liquid suppresses the formation of small-sized droplets because of increased attenuation of the sound wave and thus decreased acoustic pressure. Lowering the surface tension of the liquid (e.g., by spreading a surfactant film on the liquid surface) has the opposite effect of enhancing the formation of smaller droplets. Also, there exists a maximum limit for the droplet size, because when the produced droplet is too large, the aspiration flow is unable to carry the droplet against sedimentation. These predictions are supported by experimental observations. PMID- 25935318 TI - Land use regression models for crustal and traffic-related PM2.5 constituents in four areas of the SAPALDIA study. AB - Many studies have documented adverse health effects of long-term exposure to fine particulate matter (PM2.5), but there is still limited knowledge regarding the causal relationship between specific sources of PM2.5 and such health effects. The spatial variability of PM2.5 constituents and sources, as a exposure assessment strategy for investigating source contributions to health effects, has been little explored so far. Between 2011 and 2012, three measurement campaigns of PM and nitrogen dioxide (NO2) were performed in 80 sites across four areas of the Swiss Study on Air Pollution and Lung and heart Diseases in Adults (SAPALDIA). Reflectance analysis and energy dispersive X-ray fluorescence (XRF) were performed on PM2.5 filter samples to estimate light absorbance and trace element concentrations, respectively. Three air pollution source factors were identified using principal-component factor analysis: vehicular, crustal, and long-range transport. Land use regression (LUR) models were developed for temporally-adjusted scores of each factor, combining the four study areas. Model performance was assessed using two cross-validation methods. Model explained variance was high for the vehicular factor (R(2)=0.76), moderate for the crustal factor (R(2)=0.46), and low for the long-range transport factor (R(2)=0.19). The cross-validation methods suggested that models for the vehicular and crustal factors moderately accounted for both the between and within-area variability, and therefore can be applied to the four study areas to estimate long-term exposures within the SAPALDIA study population. The combination of source apportionment techniques and LUR modelling may help in identifying air pollution sources and disentangling their contribution to observed health effects in epidemiologic studies. PMID- 25935319 TI - Relationships between socioeconomic and lifestyle factors and indoor air quality in French dwellings. AB - BACKGROUND: To date, few studies have analyzed the relationships between socioeconomic status (SES) and indoor air quality (IAQ). OBJECTIVE: The aim of this study was to examine the relationships between socioeconomic and other factors and indoor air pollutant levels in French homes. METHODS: The indoor air concentrations of thirty chemical, biological and physical parameters were measured over one week in a sample of 567 dwellings representative of the French housing stock between September 2003 and December 2005. Information on SES (household structure, educational attainment, income, and occupation), building characteristics, and occupants' habits and activities (smoking, cooking, cleaning, etc.) were collected through administered questionnaires. Separate stepwise linear regression models were fitted to log-transformed concentrations on SES and other factors. Logistic regression was performed on fungal contamination data. RESULTS: Households with lower income were more likely to have higher indoor concentrations of formaldehyde, but lower perchloroethylene indoor concentrations. Formaldehyde indoor concentrations were also associated with newly built buildings. Smoking was associated with increasing acetaldehyde and PM2.5 levels and the risk of a positive fungal contamination index. BTEX levels were also associated with occupant density and having an attached garage. The major predictors for fungal contamination were dampness and absolute humidity. CONCLUSION: These results, obtained from a large sample of dwellings, show for the first time in France the relationships between SES factors and indoor air pollutants, and believe they should be considered alongside occupant activities and building characteristics when study IAQ in homes. PMID- 25935320 TI - Evaluating efficacy and feasibility of transcutaneous electrical nerve stimulation for postoperative pain after video-assisted thoracoscopic surgery: A randomized pilot trial. AB - BACKGROUND: Transcutaneous electrical nerve stimulation (TENS) has been applied for pain relief after surgical procedures. This study evaluated whether TENS after video-assisted thoracoscopic surgery (VATS), in addition to opioid administration, decreased postoperative pain and pain medication use. METHODS: In a controlled trial, 56 patients scheduled to undergo VATS were randomly assigned to TENS plus opioids (Group 1) or opioids alone (Group 2) for 48 h. RESULTS: Forty patients completed the study. Pain scores and use of oral morphine equivalents (OMEs) were not significantly different between the groups during the first and second 24 h. A decreased use of OMEs between the first and second 24 h was significant for Group 1 (P = .005) but not for Group 2 (P = .11); a decreased use of OMEs between groups was not significant (P = .35). CONCLUSIONS: A larger, well-powered clinical trial is indicated to evaluate the effects of TENS for pain control after a VATS procedure. Clinical Trial No.: NCT01046695. PMID- 25935321 TI - The use of the "Objective Structured Assessment of Technical Skills" as an Assessment Tool Among Danish Vascular Surgeons in Training. AB - OBJECTIVE: The concept of the Objective Structured Assessment of Technical Skills (OSATS) is to quantify surgical skills in an objective way and, thereby, produce an additional procedure-specific assessment tool. Since 2005, a 2-day practical course for upcoming specialist registrars in vascular surgery has been obligatory. The aim of this study is to describe the results from a tailored OSATS test as a tool for the evaluation of practical skills during an intensive training session in a simple simulator box for vascular anastomoses. METHOD: Between 2005 and 2013, we registered the OSATS scores of all course participants. The following data were collected from the questionnaires: years as a candidate, months in vascular surgery or in another type of surgery, and the number of vascular anastomoses performed before the course. The assessment of surgical skills was conducted with an OSATS score template specifically made for this purpose. It consists of a 12-item table with a 5-point grading scale. OSATS score (points) and time for the procedure (OSATS time in min) were registered at baseline (OSATS I) and at the end of the course (OSATS II). RESULTS: OSATS scores were given in both OSATS I and OSATS II for the 83 trainees, and the mean difference was 8.1 points (95% CI: 6.7; 9.5, p < 0.001). OSATS time was given for 69 trainees, and the mean difference was 2.8 minutes (95% CI: 1.4; 4.2, p < 0.001). We found no relationship between years since graduation, months in any surgical specialty, or the experience with vascular anastomoses and outcomes. CONCLUSION: OSATS is a valuable tool for evaluating the advancement of technical skills during an intensive practical course in performing vascular anastomoses. PMID- 25935322 TI - Reflection on adverse event disclosure in the postsurgical hospital context. PMID- 25935323 TI - Allergic rhinitis phenotypes based on mono-allergy or poly-allergy. AB - BACKGROUND: Allergic rhinitis (AR) is characterized by typical symptoms that are dependent on inflammation. Poly-allergy is a frequent phenomenon. Phenotyping AR represents an up-to-date issue. OBJECTIVE: The aim of this study was to evaluate whether the number of allergies is able to define different phenotypes in patients with AR. METHODS: 83 patients (43 males, mean age 34.7 years) suffering from AR were evaluated. Sensitization, VAS for nasal symptoms perception, and nasal cytology were evaluated. RESULTS: Poly-allergic patients perceived more severe nasal obstruction than mono-allergic ones (p = 0.0006) as well as they had more frequent sneezing (p < 0.0001). Moreover, poly-allergic patients had a more intense inflammatory infiltrate, concerning both eosinophils (p = 0.0005) and mast cells (p = 0.0001), than mono-allergic patients. CONCLUSIONS: The present study demonstrates that the presence of poly-allergy could define a distinct AR phenotype in comparison with mono-allergy. It could be clinically relevant as poly-allergic patients have more intense inflammation and more severe symptoms than mono-allergic ones. PMID- 25935324 TI - Perturbation of cellular mechanistic system by silver nanoparticle toxicity: Cytotoxic, genotoxic and epigenetic potentials. AB - Currently the applications of silver nanoparticles (Ag NPs) are gaining overwhelming response due to the advancement of nanotechnology. However, only limited information is available with regard to their toxicity mechanism in different species. It is very essential to understand the complete molecular mechanism to explore the functional and long term applications of Ag NPs. Ag NPs could be toxic at cellular, subcellular, biomolecular, and epigenetic levels. Toxicity effects induced by Ag NPs have been evaluated using numerous in vitro and in vivo models, but still there are contradictions in interpretations due to disparity in methodology, test endpoints and several other model parameters which needs to be considered. Thus, this review article focuses on the progressive elucidation of molecular mechanism of toxicity induced by Ag NPs in various in vitro and in vivo models. Apart from these, this review also highlights the various ignored factors which are to be considered during toxicity studies. PMID- 25935325 TI - Genetic evaluation in primary hyperparathyroidism: What investigation? For which patients? PMID- 25935326 TI - Synthesis, Characterization and Properties of Novel Coumarin Derivatives and Their Europium Complexes. AB - Seven novel coumarin derivatives derived from salicylaldehyde and phenol were synthesized and characterized by (1)H NMR and (13)C NMR spectra, mass spectra, infrared spectra and elemental analysis. Their corresponding Eu(III) complexes having general formula EuL(1-7)(NO3)3[Symbol: see text]2H2O were successfully prepared and characterized by elemental analysis, EDTA titrimetric, molar conductivity, UV-Vis, FT-IR and thermal performance studies. The luminescence properties, fluorescence quantum yields and the electrochemical properties of the title complexes were investigated. The results showed that the title complexes exhibited characteristic emissions of europium ions and possessed relatively good fluorescence quantum yields. The luminescence intensity of the complex with bromine-substituted group is the strongest among all the title complexes. The introduction of electron-withdrawing groups can increase the luminescence properties and fluorescence quantum yields, decrease the HOMO and LUMO energy levels of the title europium complexes, but electron-withdrawing group conversely. And these title complexes may possibly be useful for studying in luminescent materials field. Graphical Abstract Synthesis route of the ligands L (1-7). PMID- 25935327 TI - Enzymatic synthesis of isoamyl butyrate catalyzed by immobilized lipase on poly methacrylate particles: optimization, reusability and mass transfer studies. AB - Isoamyl butyrate (banana flavor) was synthesized by esterification reaction of isoamyl alcohol and butyric acid in heptane medium. Immobilized Thermomyces lanuginosus lipase (TLL) prepared via physical adsorption on mesoporous poly methacrylate particles (PMA) was used as biocatalyst. The factors that affect the esterification reaction were optimized by response surface methodology (RSM). Under optimal experimental conditions, maximum ester conversion percentage of 96.1 and 73.6% was reached after 50 and 90 min, respectively, for esterification reaction performed at equimolar ratio alcohol:acid at 500 and 2000 mM of each substrate. Under these experimental conditions, the esterification reaction was not controlled by external and intra-particle mass transfer effects. The product (isoamyl butyrate) was confirmed by proton nuclear magnetic resonance ((1)H NMR) spectroscopy. Reusability tests showed that the biocatalyst retained around 96 and 31% of its initial activity after eight successive esterification cycles performed at 500 and 2000 mM, respectively. The application of the biocatalyst prepared showed to be a promising strategy to catalyze flavor ester synthesis in a non-aqueous medium. PMID- 25935328 TI - Screening of endocrine organ-specific humoral autoimmunity in 47,XXY Klinefelter's syndrome reveals a significant increase in diabetes-specific immunoreactivity in comparison with healthy control men. AB - The aim of this study was to evaluate the frequency of humoral endocrine organ specific autoimmunity in 47,XXY Klinefelter's syndrome (KS) by investigating the autoantibody profile specific to type 1 diabetes (T1DM), Addison's disease (AD), Hashimoto thyroiditis (HT), and autoimmune chronic atrophic gastritis (AG). Sixty one adult Caucasian 47,XXY KS patients were tested for autoantibodies specific to T1DM (Insulin Abs, GAD Abs, IA-2 Abs, Znt8 Abs), HT (TPO Abs), AD (21-OH Abs), and AG (APC Abs). Thirty-five of these patients were not undergoing testosterone replacement therapy TRT (Group 1) and the remaining 26 patients started TRT before the beginning of the study (Group 2). KS autoantibody frequencies were compared to those found in 122 control men. Six of 61 KS patients (9.8 %) were positive for at least one endocrine autoantibody, compared to 6.5 % of controls. Interestingly, KS endocrine immunoreactivity was directed primarily against diabetes-specific autoantigens (8.2 %), with a significantly higher frequency than in controls (p = 0.016). Two KS patients (3.3 %) were TPO Ab positive, whereas no patients were positive for AD- and AG-related autoantigens. The autoantibody endocrine profile of untreated and treated KS patients was not significantly different. Our findings demonstrate for the first time that endocrine humoral immunoreactivity is not rare in KS patients and that it is more frequently directed against type 1 diabetes-related autoantigens, thus suggesting the importance of screening for organ-specific autoimmunity in clinical practice. Follow-up studies are needed to establish if autoantibody-positive KS patients will develop clinical T1DM. PMID- 25935329 TI - Partial nephrectomy driven by cavitron ultrasonic surgical aspirator under zero ischemia: a pilot study. AB - PURPOSE: To investigate the efficacy and technical applicability of cavitron ultrasonic surgical aspirator (CUSA)-driven zero-ischemia open partial nephrectomy in patients with renal tumors. MATERIALS AND METHODS: We prospectively collected data of 13 consecutive patients, who underwent open partial nephrectomy under non-ischemic conditions. Tumor resection was done using an ultrasonic device (CUSA/SONOCA 300). Demographic and laboratory data, tumor characteristics, perioperative, and postoperative variables were evaluated. RESULTS: The median age was 60.0 years (range 40-76); body mass index 28.0 kg/m(2) (range 22.9-43.3); tumor size 37.0 mm (range 11-110 mm). Patient were stratified according to the PADUA score into low- (score 6-7; n - 4), intermediate- (score 8-9; n - 5), and high-risk (score of >10; n - 4) groups, and the median score was 9.0 (range 6-13; SD +2.3). The vast majority of kidney tumors were diagnosed incidentally (n - 11; 84.6 %). Median operative time was 175 min (55-270 min); median time of tumor extirpation was 12 min (6-25 min); and median blood loss was 250 ml. Serum creatinine, glomerular filtration rate, and hemoglobin were nearly unaltered before and after surgery in 11 cases (84.6 %). Three patients received a blood transfusion (Clavien-Dindo Grade II); one had Grade IIIa complication (insertion of double J stent without general anesthesia); and three had Grade IIIb complications (insertion of double J under general anesthesia). CONCLUSIONS: The ultrasonic device demonstrated acceptable hemostatic and resection properties during open partial nephrectomy without ischemia. Our series showed promising perioperative and postoperative outcomes that may help in maximizing preservation of renal function in partial nephrectomy candidates. PMID- 25935330 TI - An antimicrobial prophylaxis protocol using rectal swab cultures for transrectal prostate biopsy. AB - PURPOSE: To evaluate the benefit of an antimicrobial prophylaxis protocol using rectal swab cultures in patients undergoing transrectal ultrasound (TRUS)-guided prostate biopsy in our Veterans Affairs population. METHODS: Between June 1, 2013, and June 1, 2014, we implemented an antimicrobial prophylaxis protocol using rectal swab cultures on selective media containing ciprofloxacin for all men scheduled for TRUS-guided prostate biopsy. Data from 2759 patients from Jan 1, 2006 to May 31, 2013, before protocol implementation served as historical controls. Patients with fluoroquinolone (FQ)-susceptible organisms received FQ monotherapy, while those with FQ-resistant organisms received targeted prophylaxis. Our objective was to compare the rate of infectious complications 30 days after prostate biopsy before and after implementation of our antimicrobial protocol. RESULTS: One hundred and sixty-seven patients received rectal swab cultures using our protocol. Seventeen (14 %) patients had FQ-resistant positive cultures. Patients with positive FQ-resistant culture results were more likely to have had a history of previous prostate biopsy and a positive urine culture in the last 12 months (p = 0.032, p = 0.018, respectively). The average annual infectious complication rate within 30 days of biopsy was reduced from 2.8 to 0.6 % before and after implementation of our antimicrobial prophylaxis protocol using rectal swab cultures, although this difference was not statistically significant (p = 0.13). CONCLUSION: An antimicrobial prophylaxis protocol using rectal culture swabs is a viable option for prevention of TRUS-guided prostate biopsy infectious complications. After implementation of an antimicrobial prophylaxis protocol, we observed a nonsignificant decrease in the rate of post-biopsy infectious complications when compared to historical controls. PMID- 25935331 TI - Comparison of Different Extraction Methods for Analysis of 10 Organochlorine Pesticides: Application of MAE-SPE Method in Soil from Beijing. AB - Four commonly applied extraction techniques for organochlorine pesticides, microwave-assisted extraction (MAE), accelerated solvent extraction (ASE), quick, easy, cheap, effective, rugged, and safe (QuEChERS) extraction and ultrasonic solvent extraction, were applied on soil samples in order to evaluate their performances. The extracts were analyzed by GC-ECD and confirmed by GC-MS/MS. The MAE and QuEChERS extraction methods generally yielded higher results compared to the ultrasonication and ASE methods, while the lowest recovery (56.8 %) for o,p' DDD was obtained using the QuEChERS method. The MAE method was further applied to six different soils from Beijing. In the soil samples only alpha-endosulfan and beta-endosulfan were not detected. The ratios of alpha-HCH/gamma-HCH and alpha HCH/beta-HCH indicated HCH residues likely originated from historical use of HCHs, and that technical HCHs were not likely being currently applied in Beijing. PMID- 25935332 TI - Sediment Profile and Fluxes of Mercury and Methyl Mercury in Weihe Watershed in Henan, China. AB - Sediment core samples were collected from the Weihe River in February and August 2013. Cores were sectioned and analyzed for total Hg (THg) and methyl mercury (MeHg). THg in sediment cores ranged from 156 to 282 ng g(-1) in February, and from 172 to 300 ng g(-1) in August. MeHg concentrations ranged from 0.80 to 3.11 ng g(-1) in both seasons. Results showed that the diffusive fluxes were up to two orders of magnitude lower than the in situ benthic fluxes. Fluxes of MeHg measured in in situ experiments in August were positively correlated with [Formula: see text] (r = 0.930). THg and MeHg release were not strongly correlated with TOC in February. Patterns of MeHg flux differed greatly depending on oxidation-reduction potential (Eh) (r > 0.70) conditions in the two seasons. PMID- 25935333 TI - Degradation of Fluxapyroxad in Soils and Water/Sediment Systems Under Aerobic or Anaerobic Conditions. AB - The persistence and fate of fluxapyroxad were investigated including studies with four soils from Hunan (HN), Shanxi (SX), Jiangsu (JS), and Heilongjiang (HLJ) and two water/sediment systems (water/sediment systems 1 and 2) from Beijing, China. The results demonstrated that the biodegradation efficiency of fluxapyroxad in soils under aerobic conditions was higher than that observed under anaerobic conditions. The order of degradation capability was HLJ soil > JS soil > SX soil > HN soil, and fluxapyroxad dissipated faster in water/sediment system 2 than in system 1. The tested systems (four soils and two water/sediments systems) with rich organic matter content, high oxygen level and neutral pH had a high potential to degrade fluxapyroxad, possibly because rich organic matter and oxygen level stimulated microbial activity and the neutral pH was suitable for microbial growth. These results showed that fluxapyroxad exhibited high persistence in tested systems, with half-lives >=157.6 day. PMID- 25935334 TI - Fungi associated with black mould on baobab trees in southern Africa. AB - There have been numerous reports in the scientific and popular literature suggesting that African baobab (Adansonia digitata) trees are dying, with symptoms including a black mould on their bark. The aim of this study was to determine the identity of the fungi causing this black mould and to consider whether they might be affecting the health of trees. The fungi were identified by sequencing directly from mycelium on the infected tissue as well as from cultures on agar. Sequence data for the ITS region of the rDNA resulted in the identification of four fungi including Aureobasidium pullulans, Toxicocladosporium irritans and a new species of Rachicladosporium described here as Rachicladosporium africanum. A single isolate of an unknown Cladosporium sp. was also found. These fungi, referred to here as black mould, are not true sooty mould fungi and they were shown to penetrate below the bark of infected tissue, causing a distinct host reaction. Although infections can lead to dieback of small twigs on severely infected branches, the mould was not found to kill trees. PMID- 25935335 TI - Mechanisms for the synthesis of conjugated enynes from diphenylacetylene and trimethylsilylacetylene catalyzed by a nickel(0) complex: DFT study of ligand controlled selectivity. AB - Density functional theory (DFT) was utilized to elucidate the reaction mechanisms of and the key factors that influence the Ni(0)-catalyzed cross-dimerization and trimerization of trimethylsilylacetylene (R1) and diphenylacetylene (R2). Calculated results revealed that the electron-donating ability of the ligand plays a crucial role in determining the regionselectivity of this tandem reaction. The use of strongly electron-donating ligands favors the formation of cross-dimer intermediates, whereas cross-trimer products can easily be synthesized using weakly electron-donating ligands. A simple method of estimating the electron-donating abilities of different ligands based on the Mulliken charge distribution of the ligand-ligand pair was employed. The present theoretical results allow us to elucidate the reaction mechanisms for and to identify the factors that exert the greatest influence on the ligand-controlled cross dimerization and -trimerization of trimethylsilylacetylene and diphenylacetylene. Guidelines for the design of novel ligand systems with Ni(0) catalysts are also proposed. PMID- 25935336 TI - Energetic salts from nitroformate ion. AB - Development of new energetic salts is the key factor in replacing low performance compounds in conventional formulations of high explosives as well as propellants. Ten salts based on the nitroformate anion and various nitrogen-rich cations were designed and their geometric optimizations carried out using the density functional method. With reasonable oxygen balance (from -36% to 0%), heats of formation (47-624 kJ mol(-1)) and high densities (1.81-1.89 g cm(-3)), the detonation velocity (D) and pressure (P) values of salts were calculated as 8.62 9.36 km s(-1) and 33.10-40.01 GPa, respectively. Lastly, the nitroformate salts studied in this work are of prospective interest as high performance explosives. PMID- 25935337 TI - Evaluation of uveal and capsule biocompatibility of a single-piece hydrophobic acrylic intraocular lens with ultraviolet-ozone treatment on the posterior surface. AB - PURPOSE: To evaluate a single-piece hydrophobic acrylic intraocular lens (IOL) with ultraviolet-ozone (UV-O3) treatment on the posterior surface and compare it with an identical untreated IOL in a rabbit model. SETTING: John A. Moran Eye Center, University of Utah, Salt Lake City, Utah, USA. DESIGN: Experimental study. METHODS: Study IOLs were implanted in the right eyes and control IOLs in the left eyes of 10 New Zealand rabbits. Slitlamp examinations were performed 1 to 6 weeks postoperatively. Neodymium:YAG (Nd:YAG) posterior capsulotomy was performed in both eyes of 5 rabbits after the 4-week slitlamp examination. At 6 weeks, the rabbits were killed humanely and their globes were enucleated. Capsular bag opacification was scored from the posterior aspect (Miyake-Apple view), and the eyes were processed for histopathology. RESULTS: At 4 weeks, the mean posterior capsule opacification (PCO) scores were 0.88 +/- 0.33 (SD) in the study eyes and 2.55 +/- 1.13 in the control eyes (P=.003, 2-tailed paired t test). Performance of Nd:YAG posterior capsulotomy was similar in both groups. Gross postmortem examination also showed statistically less peripheral PCO in eyes with the study IOLs than in control eyes. There was no difference in histopathologic findings between study eyes and control eyes and no signs of untoward inflammation or toxicity in any eye evaluated. CONCLUSIONS: Treatment of the posterior surface of a single-piece hydrophobic acrylic IOL with UV-O3 appears to prevent PCO, likely by increasing adhesion between the posterior capsule and the IOL while retaining uveal biocompatibility. Performance of Nd:YAG posterior capsulotomy was similar between treated IOLs and untreated IOLs. PMID- 25935338 TI - Evaluation of scleral and corneal thickness in keratoconus patients. AB - PURPOSE: To determine whether the scleral stroma is affected as much as the corneal stroma in keratoconus. SETTING: University Eye Clinic, Bern, Switzerland. DESIGN: Comparative case-control study. METHODS: Eyes with keratoconus (keratoconus group) and eyes of age-, sex-, and axial length-matched controls (control group) were analyzed. Corneal videokeratometry and pachymetry were performed using a Scheimpflug tomographer (Pentacam). For measurements of the peripheral cornea and the anterior sclera, a spectral-domain anterior segment optical coherence tomography device (Spectralis) was used. RESULTS: The study group comprised 51 eyes and the control group, 50 eyes. The mean central corneal thickness in the keratoconus group was statistically significantly lower than in the control group (447.8 MUm +/- 57.8 [SD] versus 550.5 +/- 35.5 MUm) (P < .0001). No significant difference in the mean anterior scleral thickness was found between the keratoconus group and the control group (479.1 +/- 43.7 MUm versus 474.2 +/- 43.0 MUm) (P =.57). CONCLUSION: Although corneal thinning was observed in keratoconus patients, the anterior scleral stroma thickness in these patients seemed to be similar to that in healthy control eyes. PMID- 25935339 TI - Combined astigmatic keratotomy and conductive keratoplasty to correct high corneal astigmatism. AB - PURPOSE: To determine the safety, efficacy, and predictability of combined astigmatic keratotomy (AK) and conductive keratoplasty (CK) for treating high corneal astigmatism. SETTING: University of California-Los Angeles, Los Angeles, California, USA. DESIGN: Retrospective case series. METHODS: From January 1, 2004, to December 31, 2009, AK and CK were performed in eyes with corneal astigmatism of 5.0 diopters (D) or more after keratoplasty or trauma. The uncorrected (UDVA) and corrected (CDVA) distance visual acuities, spherical equivalent (SE), defocus equivalent, mean astigmatism, efficacy index, and complications were evaluated. RESULTS: In 11 eyes of 11 patients, the mean UDVA improved from 1.54 logMAR +/- 0.50 (SD) preoperatively to 0.69 +/- 0.62 logMAR 3 months postoperatively (P < .001) and the mean CDVA from 0.55 +/- 0.62 logMAR to 0.12 +/- 0.11 logMAR (P = .028). The mean SE and mean defocus equivalent decreased from -1.25 +/- 5.06 D to 3.13 +/- 3.06 D (P = .15) and from 7.98 +/- 4.41 D to 6.97 +/- 3.73 D (P = .45), respectively; these changes were not statistically significant. The mean absolute astigmatism decreased from 10.25 +/- 4.71 D to 4.31 +/- 2.34 D (P < .001). The mean absolute orthogonal and mean oblique astigmatism showed a statistically significant decrease. The efficacy index was 0.82. One case of wound gape after AK required suturing. No infectious keratitis, corneal perforation, or graft rejection occurred. CONCLUSIONS: Results indicate that combined AK and CK is safe and effective for correcting high corneal astigmatism after surgery or trauma. PMID- 25935340 TI - Effect of a hyperosmotic agent on epithelial disruptions during laser in situ keratomileusis. AB - PURPOSE: To evaluate the incidence of epithelial disruptions during primary laser in situ keratomileusis (LASIK) with the use of a preoperative hyperosmotic treatment comprising sodium chloride 5% ophthalmic ointment (Muro-128) and to identify the incidence of epithelial disruptions in various demographic populations. SETTING: TLC Laser Eye Center, McLean, Virginia, USA. DESIGN: Comparative case series. METHODS: Using a matched-pair design, hyperosmotic treatment was randomized to 1 eye of patients having bilateral LASIK. The primary outcome measure, epithelial integrity, was assessed in each eye. Epithelial integrity was evaluated in groups defined by characteristics that included age, sex, ethnicity, skin type, presence or absence of rosacea, eye color, and hair color. RESULTS: The study evaluated 496 eyes of 248 patients. The preoperative hyperosmotic treatment was associated with significantly less corneal epithelial disruption, as indicated by an epithelial integrity score. Compared with control eyes, the rate of corneal epithelial disruptions in the population of treated eyes decreased by 40% (relative risk, 0.60; 95% confidence interval [CI], 0.38 0.95). Among the characteristics studied, age was the best predictor of corneal epithelial disruptions; every 1-year increase in age was associated with a 9.0% increase in the risk for corneal epithelial disruptions (odds ratio [OR], 1.09; 95% CI, 1.05-1.13). Eyes of patients older than 34 years had a 4.4 times greater odds of being associated with epithelial disturbances than eyes of patients 34 years or younger. CONCLUSIONS: The preoperative use of hyperosmotic agents can reduce the risk for intraoperative epithelial disruptions during LASIK. An increase in epithelial disruptions was associated with increasing age. PMID- 25935341 TI - Pathologic evidence of pseudoexfoliation in cases of in-the-bag intraocular lens subluxation or dislocation. AB - PURPOSE: To provide complete histopathologic evaluation of explanted capsular bags that spontaneously dislocated in the late postoperative period, with the main objective being to assess the presence of pseudoexfoliation (PXF) material. SETTING: Goethe-University Frankfurt, Frankfurt, Germany, and John A. Moran Eye Center, University of Utah, Salt Lake City, Utah, USA. DESIGN: Retrospective case series. METHODS: Standard gross and light microscopy and complete histopathology were performed on explanted subluxated and dislocated capsular bags containing an intraocular lens (IOL) or a capsular tension ring (CTR) and an IOL. Questionnaires were sent to explanting surgeons, and a patient chart review was performed, when available. RESULTS: The specimens were represented by capsular bags containing an IOL (n = 37) or an IOL-CTR (n = 3). The IOLs included 3-piece hydrophobic acrylic (n = 13), 1-piece hydrophobic acrylic (n = 7), 3-piece silicone (n = 6), 1-piece hydrophilic acrylic (n = 6), 3-piece hydrophilic acrylic (n = 2), and 1-piece poly(methyl methacrylate) (PMMA) (n = 6) designs; all CTRs were PMMA. Soemmering ring formation was mild in 8 specimens, moderate in 18 specimens, and severe in 14 specimens. Excessive contraction of the capsular bag with capsulorhexis phimosis was observed in 24 specimens. Twenty-six specimens had histopathologic evidence of PXF; 13 had a clinical history or evidence of PXF. CONCLUSIONS: Pseudoexfoliation might be implicated in a larger proportion of late in-the-bag IOL subluxations and dislocations than previously thought as a result of significant clinical underdiagnosis. This might indicate a need for new considerations during the preoperative and postoperative cataract surgery assessments and follow-up. PMID- 25935342 TI - Novel cyclohexane monooxygenase from Acidovorax sp. CHX100. AB - Acidovorax sp. CHX100 has a remarkable ability for growth on short cycloalkanes (C5-C8) as a sole source of carbon and energy under aerobic conditions via an uncharacterized mechanism. Transposon mutagenesis of Acidovorax sp. CHX100 revealed a novel cytochrome P450 monooxygenase (CYP450chx) which catalyzed the transformation of cyclohexane to cyclohexanol. Primer walking methods categorized CYP450chx as cytochrome P450 class I taking into account its operon structure: monooxygenase, FAD oxidoreductase, and ferredoxin. CYP450chx was successfully cloned and expressed in Escherichia coli JM109. The activity of CYP450chx was demonstrated by means of the indole co-oxidation. Biotransformation capability of CYP450chx was confirmed through the catalysis of cycloalkanes (C5-C8) to their respective cyclic alcohols. PMID- 25935343 TI - A monoclonal antibody-based VZV glycoprotein E quantitative assay and its application on antigen quantitation in VZV vaccine. AB - Varicella-zoster virus (VZV) is a highly infectious agent that causes varicella and herpes zoster (HZ), which may be associated with severe neuralgia. Vaccination is the most effective way to reduce the burden of the diseases. VZV glycoprotein E (gE) is the major and most immunogenic membrane protein that plays important roles in vaccine efficacy. A quantitative assay for gE content is desirable for the VZV vaccine process monitoring and product analysis. In this study, 70 monoclonal antibodies (mAbs) were obtained after immunizing mice with purified recombinant gE (rgE). The collection of mAbs was well-characterized, and a pair of high-affinity neutralization antibodies (capture mAb 4A2 and detection mAb 4H10) was selected to establish a specific and sensitive sandwich enzyme linked immunosorbent assay (ELISA) to quantify the native and recombinant gE. The detection limit of this assay was found to be 1.95 ng/mL. Furthermore, a reasonably good correlation between the gE content (as measured by the mAb-based quantitative ELISA) and the virus titer (as measured by the "gold standard" plaque assay) was observed when both assays were performed for tracking the kinetics of virus growth during cell culture. A total of 16 batches of lyophilized VZV vaccine were tested using the newly developed quantitative ELISA and classical plaque assay, demonstrating reasonably good correlation between gE content and virus titer. Therefore, this mAb-based gE quantitative assay serves as a rapid, stable, and sensitive method for monitoring viral antigen content, one additional quantitative method for VZV vaccine process and product characterization. This quantitative ELISA may also serve as a complementary method for virus titering. PMID- 25935344 TI - A fungal biofilm reactor based on metal structured packing improves the quality of a Gla::GFP fusion protein produced by Aspergillus oryzae. AB - Fungal biofilm is known to promote the excretion of secondary metabolites in accordance with solid-state-related physiological mechanisms. This work is based on the comparative analysis of classical submerged fermentation with a fungal biofilm reactor for the production of a Gla::green fluorescent protein (GFP) fusion protein by Aspergillus oryzae. The biofilm reactor comprises a metal structured packing allowing the attachment of the fungal biomass. Since the production of the target protein is under the control of the promoter glaB, specifically induced in solid-state fermentation, the biofilm mode of culture is expected to enhance the global productivity. Although production of the target protein was enhanced by using the biofilm mode of culture, we also found that fusion protein production is also significant when the submerged mode of culture is used. This result is related to high shear stress leading to biomass autolysis and leakage of intracellular fusion protein into the extracellular medium. Moreover, 2-D gel electrophoresis highlights the preservation of fusion protein integrity produced in biofilm conditions. Two fungal biofilm reactor designs were then investigated further, i.e. with full immersion of the packing or with medium recirculation on the packing, and the scale-up potentialities were evaluated. In this context, it has been shown that full immersion of the metal packing in the liquid medium during cultivation allows for a uniform colonization of the packing by the fungal biomass and leads to a better quality of the fusion protein. PMID- 25935345 TI - Evolution of a chimeric aspartate kinase for L-lysine production using a synthetic RNA device. AB - Aspartate kinase (AK) is a key enzyme involved in catalyzing the first step of the aspartate-derived amino acid biosynthesis, including L-lysine and L threonine, which is regulated by the end-metabolites through feedback inhibition. In order to accumulate the end-metabolites in the host, the feedback inhibition of AK has to be released. In this study, a chimeric aspartate kinase, which is composed of the N-terminal catalytic region from Bacillus subtilis AKII and the C terminal region from Thermus thermophilus, was evolved through random mutagenesis and then screened using a high-throughput synthetic RNA device which comprises of an L-lysine-sensing riboswitch and a selection module. Of three evolved aspartate kinases, the best mutant BT3 showed 160 % increased in vitro activity compared to the wild-type enzyme. Recombinant Escherichia coli harboring BT3 produced 674 mg/L L-lysine in batch cultivation, similar to that produced by the strain harboring the typical commercial widely used feedback resistant aspartate kinase AKC (fbr) from E. coli. The results suggested that this strategy can be extended for screening of other key enzymes involved in lysine biosynthesis pathways. PMID- 25935346 TI - Adaptive laboratory evolution of ethanologenic Zymomonas mobilis strain tolerant to furfural and acetic acid inhibitors. AB - Furfural and acetic acid from lignocellulosic hydrolysates are the prevalent inhibitors to Zymomonas mobilis during cellulosic ethanol production. Developing a strain tolerant to furfural or acetic acid inhibitors is difficul by using rational engineering strategies due to poor understanding of their underlying molecular mechanisms. In this study, strategy of adaptive laboratory evolution (ALE) was used for development of a furfural and acetic acid-tolerant strain. After three round evolution, four evolved mutants (ZMA7-2, ZMA7-3, ZMF3-2, and ZMF3-3) that showed higher growth capacity were successfully obtained via ALE method. Based on the results of profiling of cell growth, glucose utilization, ethanol yield, and activity of key enzymes, two desired strains, ZMA7-2 and ZMF3 3, were achieved, which showed higher tolerance under 7 g/l acetic acid and 3 g/l furfural stress condition. Especially, it is the first report of Z. mobilis strain that could tolerate higher furfural. The best strain, Z. mobilis ZMF3-3, has showed 94.84% theoretical ethanol yield under 3-g/l furfural stress condition, and the theoretical ethanol yield of ZM4 is only 9.89%. Our study also demonstrated that ALE method might also be used as a powerful metabolic engineering tool for metabolic engineering in Z. mobilis. Furthermore, the two best strains could be used as novel host for further metabolic engineering in cellulosic ethanol or future biorefinery. Importantly, the two strains may also be used as novel-tolerant model organisms for the genetic mechanism on the "omics" level, which will provide some useful information for inverse metabolic engineering. PMID- 25935347 TI - Intraarticular gene transfer of SPRY2 suppresses adjuvant-induced arthritis in rats. AB - AKT and ERK pathways have been implicated as therapeutic targets for human rheumatoid arthritis (RA), fibroblast-like synoviocytes (FLS) inhibition, and thus RA treatment. Sprouty2 (SPRY2) has been known as a tumor suppressor by blocking both ERK and AKT signaling cascades. Whether SPRY2 can function as a suppressor of tumor-like inflammatory FLS and RA through negatively regulating AKT and ERK activation has not been reported. The purpose of this study was to determine whether SPRY2 might have antiarthritic effects in experimental animal model of RA. We first determined that expression of SPRY2 mRNA was decreased in FLS from patients with RA compared with patients with osteoarthritis (OA). Further studies demonstrated that intraarticular gene transfer with AdSPRY2, the recombinant adenovirus containing SPRY2 complementary DNA, resulted in a significant suppression of rat adjuvant-induced arthritis (AIA) compared with the control AdGFP, the adenoviral vector encoding green fluorescent protein, as reflected in both clinical and histological observations. AdSPRY2 suppressed the production of proinflammatory cytokines and matrix metalloproteinases (MMPs), and the activation of ERK and AKT signals in AIA ankle joints. These results suggest that using SPRY2 to block the AKT and ERK pathways effectively reduces the inflammatory responses and arthritic progression in AIA. Thus, the development of an immunoregulatory strategy based on SPRY2 may therefore have therapeutic potential in the treatment of RA. PMID- 25935348 TI - Characterizing the spatial distribution of ambient ultrafine particles in Toronto, Canada: A land use regression model. AB - Exposure models are needed to evaluate the chronic health effects of ambient ultrafine particles (<0.1 MUm) (UFPs). We developed a land use regression model for ambient UFPs in Toronto, Canada using mobile monitoring data collected during summer/winter 2010-2011. In total, 405 road segments were included in the analysis. The final model explained 67% of the spatial variation in mean UFPs and included terms for the logarithm of distances to highways, major roads, the central business district, Pearson airport, and bus routes as well as variables for the number of on-street trees, parks, open space, and the length of bus routes within a 100 m buffer. There was no systematic difference between measured and predicted values when the model was evaluated in an external dataset, although the R(2) value decreased (R(2) = 50%). This model will be used to evaluate the chronic health effects of UFPs using population-based cohorts in the Toronto area. PMID- 25935349 TI - Arrhythmias in a long-term adult survivor with uncorrected tetralogy of Fallot: Case report and review of the literature. AB - We present a case of a middle-aged adult with uncorrected Tetralogy of Fallot (TOF) with pulmonary atresia who developed symptomatic supraventricular and ventricular arrhythmias. The lack of data regarding management of electrical and other complications in adults with uncorrected TOF is highlighted and emphasizes the need for a registry to better understand the medical management of long standing adult survivors. PMID- 25935350 TI - Good reproducibility of heart rate variability after orthostatic challenge in patients with a history of acute coronary syndrome. AB - BACKGROUND: Several parameters of heart rate variability (HRV) have been shown to predict the risk of sudden cardiac death (SCD) in cardiac patients. There is consensus that risk prediction is increased when measuring HRV during specific provocations such as orthostatic challenge. For the first time, we provide data on reproducibility of such a test in patients with a history of acute coronary syndrome. METHODS: Sixty male patients (65 +/- 8 years) with a history of acute coronary syndrome on stable medication were included. HRV was measured in supine (5 min) and standing (5 min) position on 2 occasions separated by two weeks. For risk assessment relevant time-domain [standard deviation of all R-R intervals (SDNN) and root mean squared standard differences between adjacent R-R intervals (RMSSD)], frequency domain [low-frequency power (LF), high-frequency power (HF) and LF/HF power ratio] and short-term fractal scaling component (DF1) were computed. Absolute reproducibility was assessed with the standard errors of the mean (SEM) and 95% limits of random variation, and relative reproducibility by the intraclass correlation coefficient (ICC). RESULTS: We found comparable SEMs and ICCs in supine position and after an orthostatic challenge test. All ICCs were good to excellent (ICCs between 0.636 and 0.869). CONCLUSIONS: Reproducibility of HRV parameters during orthostatic challenge is good and comparable with supine position. PMID- 25935351 TI - Tumour necrosis factor-alpha inhibitor therapy in chronic physical illness: A systematic review and meta-analysis of the effect on depression and anxiety. AB - OBJECTIVE: Depression is more common among individuals with chronic physical illness than in the general population. New treatments for severe and chronic inflammatory conditions which inhibit tumour necrosis factor alpha (TNF-alpha), a pro-inflammatory cytokine, may be able to shed some light on the role of inflammatory mediators in depression. This systematic review and meta-analysis of randomised controlled trials determined the effects of TNF-alpha inhibitor therapy on depression and anxiety in people with chronic physical illness. METHODS: Seven databases were searched from inception to January 2014: AMED, Central, Cochrane Database of Systematic Reviews, CINAHL, Embase, MEDLINE, and PsycINFO. Articles were screened for inclusion independently by two reviewers. Data extraction and appraisal were conducted by one reviewer and checked by a second. Random-effects meta-analyses were performed. RESULTS: Six randomised controlled trials (reported in seven articles) met eligibility criteria and were included in the final review. In total 2540 participants were enrolled across the trials, with participants presenting with rheumatoid arthritis (n=3 trials), psoriasis (n=2) or ankylosing spondylitis (n=1). Meta-analyses, using standardised mean differences, showed evidence of small reductions in depression (-0.24; 95% CI -0.33 to -0.14; p<0.001), and anxiety (-0.17; 95% CI -0.31 to 0.02; p=0.02). CONCLUSION: TNF-alpha inhibitor therapy reduces depression in people with chronic disease though the effects are small. Whilst this is consistent with inflammation contributing to the development of depression, further studies investigating a more detailed timeline of changes in depression, inflammatory biomarkers and disease activity status are required. PMID- 25935352 TI - Position statement: Gender dysphoria in childhood and adolescence. Working Group on Gender Identity and Sexual Development of the Spanish Society of Endocrinology and Nutrition (GIDSEEN). AB - Gender dysphoria (GD) in childhood and adolescence is a complex condition where early detection and comprehensive treatment are essential to improve quality of life, decrease mental comorbidity, and improve GD. In this position statement, the Working Group on Gender Identity and Sexual Development of the Spanish Society of Endocrinology and Nutrition (GIDSEEN), consisting of specialists in Endocrinology, Psychology, Psychiatry, Pediatrics and Sociology, sets out recommendations for evaluation and treatment of GD in children and adolescents. Interdisciplinary management of GD should be carried out at specialized units (UTIGs), considering that any clinical intervention should follow the principles of scientific rigor, experience, ethical and deontological principles, and the necessary caution in front of chronic, aggressive, and irreversible treatments. PMID- 25935354 TI - An update on the use of health information technology in newborn screening. AB - Newborn screening (NBS) has high-stakes health implications and requires rapid and effective communication between many people and organizations. Multiple NBS stakeholders worked together to create national guidance for reporting NBS results with HL7 (Health Level 7) messages that contain LOINC (Logical Observation Identifiers Names and Codes) and SNOMED-CT (Systematized Nomenclature of Medicine-Clinical Terms) codes, report quantitative test results, and use standardized computer-readable UCUM units of measure. This guidance (a LOINC panel and an example annotated HL7 message) enables standard HL7 v2.5.1 laboratory messages to carry the information required for reporting NBS results. Other efforts include HL7 implementation guides for reporting point-of-care (POC) NBS results as well as standardizing follow-up of patients diagnosed with conditions identified through NBS. If the guidance is used nationally, regional and national registries can aggregate results from state programs to facilitate research and quality assurance and help ensure continuity of operations following a disaster situation. PMID- 25935353 TI - Validation of the PROMIS physical function measures in a diverse US population based cohort of cancer patients. AB - PURPOSE: To evaluate the validity of the Patient-Reported Outcomes Measurement Information System (PROMIS) physical function measures in a diverse, population based cancer sample. METHODS: Cancer patients 6-13 months post-diagnosis (n = 4840) were recruited for the Measuring Your Health study. Participants were diagnosed between 2010 and 2013 with non-Hodgkin lymphoma or cancers of the colorectum, lung, breast, uterus, cervix, or prostate. Four PROMIS physical function short forms (4a, 6b, 10a, and 16) were evaluated for validity and reliability across age and race-ethnicity groups. Covariates included gender, marital status, education level, cancer site and stage, comorbidities, and functional status. RESULTS: PROMIS physical function short forms showed high internal consistency (Cronbach's alpha = 0.92-0.96), convergent validity (fatigue, pain interference, FACT physical well-being all r >= 0.68), and discriminant validity (unrelated domains all r <= 0.3) across survey short forms, age, and race-ethnicity. Known-group differences by demographic, clinical, and functional characteristics performed as hypothesized. Ceiling effects for higher functioning individuals were identified on most forms. CONCLUSIONS: This study provides strong evidence that PROMIS physical function measures are valid and reliable in multiple race-ethnicity and age groups. Researchers selecting specific PROMIS short forms should consider the degree of functional disability in their patient population to ensure that length and content are tailored to limit response burden. PMID- 25935355 TI - Characterization of the peripheral artery disease symptom experience. AB - Claudication is the most commonly recognized peripheral artery disease (PAD) symptom, but not the most prevalent. Only 7.5%-33% of patients report claudication as being part of their symptom experience. However, there is little evidence supporting atypical symptom reporting. The study purpose was to describe the full spectrum of symptoms experienced by older and younger individuals with PAD. Semistructured interviews were conducted with a purposive sample of 38 community-dwelling adults aged 49-83 years; transcripts were analyzed using content analysis. Six themes emerged: symptom descriptors (claudication and atypical), maintaining equilibrium, temporal fluctuations, the role of exercise, perceived impact on quality of life, and disease presence and treatment. Results suggest heavy reliance on claudication can result in mis- or under-diagnosis of PAD. Further research is needed to validate the correspondence of atypical symptoms with ischemic changes during exercise to broaden currently accepted symptom locations and descriptors associated with PAD. PMID- 25935356 TI - New CMS focused surveys are coming: Minimum data set compliance and staffing level assessments. PMID- 25935357 TI - Psychometric evaluation of the Korean Version of the Self-Efficacy for Exercise Scale for older adults. AB - We evaluated the psychometric properties of the Korean version of the Self Efficacy for Exercise Scale (SEE-K). The SEE-K consists of nine items and was translated into Korean using the forward-backward translation method. We administered it to 212 community-dwelling older adults along with measures of outcome expectation for exercise, quality of life, and physical activity. The validity was determined using confirmatory factor analysis and Rasch analysis with INFIT and OUTFIT statistics, which showed acceptable model fit. The concurrent validity was confirmed according to positive correlations between the SEE-K, outcome expectation for exercise, and quality of life. Furthermore, the high physical activity group had higher SEE-K scores. Finally, the reliability of the SEE-K was deemed acceptable based on Cronbach's alpha, coefficients of determination, and person and item separation indices with reliability. Thus, the SEE-K appears to have satisfactory validity and reliability among older adults in South Korea. PMID- 25935358 TI - Contemporary demographics and complications of patients treated for open ankle fractures. AB - Open ankle fractures are rare injuries with a high likelihood of wound complications and subsequent infections. There is limited information about the complications and outcomes of these injuries in different age groups. The aim of this study was to assess the contemporary demographics and complications related to this injury. We performed a chart review of all the 3030 patients treated for ankle fractures at a Level 1 trauma centre from 2006 to 2011. 137 (4.5%) patients had an open ankle fracture. The demographic data, injury mechanism, comorbidities, and fracture type were collected. Treatment, complications, length of stay and number of outpatient visits were also recorded. The mean age of the patients was 60 years and 56% were women. Most fractures were Weber type B with a medial sided wound (93%). Only 20% of the fractures were the result of high energy trauma, and 31% were Gustilo grade III injuries. Immediate internal fixation was performed in 82% of patients, and the wound was primarily closed in most cases (80%). The incidence of postoperative wound necrosis and deep infection was 18% and 17%, respectively. There were more deep infections if pulsatile lavage was used during the wound debridement (p=0.029). About 14 (10%) patients required a flap reconstruction to cover the soft-tissue defect. Every other patient (54%) had a complication, and 21 patients (15%) suffered a long term disability related to the injury. The number complications did not differ for nighttime and daytime operations (p=0.083). High-energy injuries were more common in younger patients (p<0.001) and these patients also had more lateral sided open wounds than older patients (p=0.002). Interestingly, younger patients also had significantly more complications (p=0.024), suffered more often from chronic pain (p=0.003), and required more flap reconstructions (p=0.026), reoperations (p=0.026), and outpatient clinic visits (p=0.006). Open ankle fractures have a high complication rate and often require multiple surgical procedures. In young patients these injuries are more likely to be the consequence of high-energy trauma leading to more complications and subsequently increased healthcare resource utilisation. PMID- 25935359 TI - Two kinds of ocular trauma score for paediatric traumatic cataract in penetrating eye injuries. AB - PURPOSE: To compare the ocular trauma score (OTS) and the paediatric penetrating ocular trauma score (POTS) as prognostic model for visual outcome in paediatric traumatic cataract cases after penetrating eye injuries. METHODS: All children younger than 16 years with unilateral traumatic cataract following penetrating trauma between 2007 and 2012 were retrospectively reviewed. Univariate chi-square analysis was conducted to identify the variables associated with profound visual loss. The area under the receiver-operating characteristic curves (AUROC) was used to assess the predictive ability of the two models. RESULTS: The study group comprised 65 boys and 37 girls. The variables associated with profound visual loss were: a relative afferent papillary defect (RAPD) (P<0.001), poor initial vision (P=0.01), vitreous haemorrhage (P<0.001), retinal detachment (P<0.001), posterior penetrating site (P<0.001), hyphema (P<0.001), no intraocular len implantation (P<0.001) and endophthalmitis (P=0.001). OTS could not be calculated in 21 patients (20.6%) without clinical data on initial visual acuity and RAPD. For the patients with complete clinical data, POTS was similar to OTS in predicting poor vision (AUROC 0.904 vs 0.924) and in predicting good vision (AUROC 0.766 vs 0.736). For all the samples, POTS was a robust predictor of poor vision (AUROC 0.910) and had a moderate ability to predict good vision (AUROC 0.764). CONCLUSION: OTS has high ability to predict visual outcome for paediatric traumatic cataract following penetrating ocular trauma. POTS is also a reliable prognostic model for very young child without initial vision or RAPD, but is only for penetrating eye injuries. PMID- 25935360 TI - [Postpartum obturator neuropathy]. PMID- 25935361 TI - Improving communication among nurses and patients. AB - Patients use nurse call systems to signal nurses for medical help. Traditional push button-flashing lamp call systems are not integrated with other hospital automation systems. Therefore, nurse response time becomes a matter of personal discretion. The improvement obtained by integrating a pager system into the nurse call systems does not increase care efficiency, because unnecessary visits are still not eliminated. To obtain an immediate response and a purposeful visit by a nurse; regardless of the location of nurse in hospital, traditional systems have to be improved by intelligent telephone system integration. The results of the developed Nurse Call System Software (NCSS), the Wireless Phone System Software (WPSS), the Location System Software (LSS) and the communication protocol are provided, together with detailed XML message structures. The benefits of the proposed system are also discussed and the direction of future work is presented. PMID- 25935362 TI - Using intervention-oriented evaluation to diagnose and correct students' persistent climate change misconceptions: A Singapore case study. AB - The evaluation of classroom-based educational interventions is fraught with tensions, the most critical of which is choosing between focusing the inquiry on measuring the effects of treatment or in proximately utilizing the data to improve practice. This paper attempted to achieve both goals through the use of intervention-oriented evaluation of a professional development program intended to diagnose and correct students' misconceptions of climate change. Data was gathered, monitored and analyzed in three stages of a time-series design: the baseline, treatment and follow-up stages. The evaluation itself was the 'intervention' such that the data was allowed to 'contaminate' the treatment. This was achieved through giving the teacher unimpeded access to the collected information and to introduce midcourse corrections as she saw fit to her instruction. Results showed a significant development in students' conceptual understanding only after the teacher's decision to use direct and explicit refutation of misconceptions. Due to the accessibility of feedback, it was possible to locate specifically at which point in the process that the intervention was most effective. The efficacy of the intervention was then measured through comparing the scores across the three research stages. The inclusion of a comparison group to the design is recommended for future studies. PMID- 25935363 TI - Policy recommendations for rare disease centres of expertise. AB - AIM: Rare diseases are a serious public health concern and are a priority in the EU. This study aims to develop policy recommendations for rare disease centres of expertise (CoEs) in order to improve standards and quality of care. SUBJECT AND METHODS: A modified 3-round Delphi technique was used. Participants included rare diseases patients, carers, patient representatives and healthcare professionals (HCPs) from CoEs in two countries-Denmark and the UK. RESULTS: The results suggest the need to make improvements within current CoE environments, access to CoEs and the need for coordination and cooperation of services within and outside CoEs. It is recommended that CoEs are not overly 'medicalised', while at the same time they should be established as research facilities. The importance of including patient representatives in CoE performance management was also highlighted. Raising awareness and provision of appropriate training amongst non specialist HCPs is seen as a priority for early and correct diagnosis and ensuring high quality care. Similarly, provision of targeted information about patients' illness and care was considered essential along with access to social assistance within CoEs. CONCLUSIONS: Policy recommendations were developed in areas previously recognised as having gaps. Their implementation is expected to strengthen and improve current care provision for rare disease patients. In member states where national plans and strategies are being developed, it is recommended to replicate the methodological approach used in this study as it has proven to be a helpful tool in rare disease centres of expertise policy development. PMID- 25935365 TI - EGFR negates the proliferative effect of oncogenic HER2 in MDA-MB-231 cells. AB - Members of the EGFR family are potent mediators of normal cell growth and development. HER2 possesses an active tyrosine kinase domain, but no direct ligand has been identified. To investigate the differential effect of HER2 in breast cell lines, HER2 was overexpressed in MCF-10A, MCF7 and MDA-MB-231 cells. HER2 overexpression promoted proliferation, survival and migration in MCF-10A and MCF-7 cells. No significant differences were seen in proliferation, survival or migration between MDA-MB-231 vec and HER2 cells. The activity of downstream HER2 proteins increased in MCF-10A HER2 and MCF-7 HER2 cells but not in MDA-MB-231 HER2 cells. Exogenously expressed HER2 failed to associate with EGFR or HER3 in MDA-MB-231 cells, while overexpression of HER2 enhanced HER family dimerization in MCF-10A and MCF-7 cells. PMID- 25935366 TI - Free nitrous acid serving as a pretreatment method for alkaline fermentation to enhance short-chain fatty acid production from waste activated sludge. AB - Alkaline condition (especially pH 10) has been demonstrated to be a promising method for short-chain fatty acid (SCFA) production from waste activated sludge anaerobic fermentation, because it can effectively inhibit the activities of methanogens. However, due to the limit of sludge solubilization rate, long fermentation time is required but SCFA yield is still limited. This paper reports a new pretreatment method for alkaline fermentation, i.e., using free nitrous acid (FNA) to pretreat sludge for 2 d, by which the fermentation time is remarkably shortened and meanwhile the SCFA production is significantly enhanced. Experimental results showed the highest SCFA production of 370.1 mg COD/g VSS (volatile suspended solids) was achieved at 1.54 mg FNA/L pretreatment integration with 2 d of pH 10 fermentation, which was 4.7- and 1.5-fold of that in the blank (uncontrolled) and sole pH 10 systems, respectively. The total time of this integration system was only 4 d, whereas the corresponding time was 15 d in the blank and 8 d in the sole pH 10 systems. The mechanism study showed that compared with pH 10, FNA pretreatment accelerated disruption of both extracellular polymeric substances and cell envelope. After FNA pretreatment, pH 10 treatment (1 d) caused 38.0% higher substrate solubilization than the sole FNA, which indicated that FNA integration with pH 10 could cause positive synergy on sludge solubilization. It was also observed that this integration method benefited hydrolysis and acidification processes. Therefore, more SCFA was produced, but less fermentation time was required in the integrated system. PMID- 25935364 TI - SR-135, a peroxynitrite decomposing catalyst, enhances beta-cell function and survival in B6D2F1 mice fed a high fat diet. AB - Peroxynitrite has been implicated in beta-cell dysfunction and insulin resistance in obesity. Chemical catalysts that destroy peroxynitrite, therefore, may have therapeutic value for treating type 2 diabetes. To this end, we have recently demonstrated that Mn(III) bis(hydroxyphenyl)-dipyrromethene complexes, SR-135 and its analogs, can effectively catalyze the decomposition of peroxynitrite in vitro and in vivo through a 2-electron mechanism (Rausaria et al., 2011). To study the effects of SR-135 on glucose homeostasis in obesity, B6D2F1 mice were fed with a high fat-diet (HFD) for 12 weeks and treated with vehicle, SR-135 (5mg/kg), or a control drug SRB for 2 weeks. SR-135 significantly reduced fasting blood glucose and insulin levels, and enhanced glucose tolerance as compared to HFD control, vehicle or SRB. SR-135 also enhanced glucose-stimulated insulin secretion based on ex vivo studies. Moreover, SR-135 increased insulin content, restored islet architecture, decreased islet size, and reduced tyrosine nitration and apoptosis. These results suggest that a peroxynitrite decomposing catalyst enhances beta cell function and survival under nutrient overload. PMID- 25935367 TI - Microthrix parvicella abundance associates with activated sludge settling velocity and rheology - Quantifying and modelling filamentous bulking. AB - The objective of this work is to identify relevant settling velocity and rheology model parameters and to assess the underlying filamentous microbial community characteristics that can influence the solids mixing and transport in secondary settling tanks. Parameter values for hindered, transient and compression settling velocity functions were estimated by carrying out biweekly batch settling tests using a novel column setup through a four-month long measurement campaign. To estimate viscosity model parameters, rheological experiments were carried out on the same sludge sample using a rotational viscometer. Quantitative fluorescence in-situ hybridisation (qFISH) analysis, targeting Microthrix parvicella and phylum Chloroflexi, was used. This study finds that M. parvicella - predominantly residing inside the microbial flocs in our samples - can significantly influence secondary settling through altering the hindered settling velocity and yield stress parameter. Strikingly, this is not the case for Chloroflexi, occurring in more than double the abundance of M. parvicella, and forming filaments primarily protruding from the flocs. The transient and compression settling parameters show a comparably high variability, and no significant association with filamentous abundance. A two-dimensional, axi-symmetrical computational fluid dynamics (CFD) model was used to assess calibration scenarios to model filamentous bulking. Our results suggest that model predictions can significantly benefit from explicitly accounting for filamentous bulking by calibrating the hindered settling velocity function. Furthermore, accounting for the transient and compression settling velocity in the computational domain is crucial to improve model accuracy when modelling filamentous bulking. However, the case-specific calibration of transient and compression settling parameters as well as yield stress is not necessary, and an average parameter set - obtained under bulking and good settling conditions - can be used. PMID- 25935368 TI - Characterization of the proton binding sites of extracellular polymeric substances in an anaerobic membrane bioreactor. AB - This paper focuses on the characterization of the chemical compositions and acidic constants of the extracellular polymeric substances (EPSs) in an anaerobic membrane bioreactor treating synthetic brewery wastewater by using chemical analysis, linear programming analysis (LPA) of titration data, and FT-IR analysis. The linear programming analysis of titration data revealed that the EPSs have proton binding sites with pKa values from pKa <= 6, between 6 and 7, and approximately 9.8. The strong acidic sites (pKa <= 6) and some weak acidic sites (7.5 < pKa < 9.0) were found to be readily removed by 0.45-MUm membrane filtration. In addition, the FT-IR analysis confirmed the presence of proteins, carbohydrates, nucleic acids, and lipids in the EPS samples. Based on the FT-IR analysis and the main chemical functional groups at the bacterial cell surfaces, the identified proton binding sites were related to carboxyl, phosphate, and hydroxyl/amine groups with pKa values of 4.6 +/- 0.7, 6.6 +/- 0.01, and 9.7 +/- 0.1, respectively, with the corresponding respective intensities of 0.31 +/- 0.05, 0.96 +/- 0.3, and 1.53 +/- 0.3 mmole/g-EPS. The pKa values and intensities of the proton binding sites are the fundamental molecular properties of EPSs that affect the EPS charge, molecular interactions, and metal complexation characteristics. Determination of such properties can advance Derjaguin-Landau Verwey-Overbeek (DLVO)-based concentration polarization modeling, facilitate the estimation of the osmotic pressure of the EPS concentration polarization layers, and lead to a deeper understanding of the role of metal complexation in membrane fouling. PMID- 25935370 TI - The eating experience after treatment for head and neck cancer: A review of the literature. AB - PURPOSE: Research has identified significant challenges that patients experience following treatment for head and neck cancer (HNC). These include the physical and emotional impacts of the diagnosis and treatment, which compound weight loss and negatively impact eating ability. There is limited research about the lived experience and the changed meaning of food, eating and the eating experience after treatment for patients with HNC. The purpose of this review was to explore available research pertinent to the lived experiences of patients in regards to the changed meaning of food, eating and the eating experience after treatment for HNC. PRINCIPAL RESULTS: The review identified a limited number of studies that focused on the eating experience and/or the changed meaning of food after a HNC diagnosis. However, the findings do highlight that there are physical, psychological/emotional and social losses associated with the changed meaning of food and eating within the HNC population. CONCLUSIONS: The eating experience is impacted after treatment for HNC. Physical, emotional and social losses in regards to the eating experience have been identified. Acknowledging the significance of eating challenges and the changed meaning of food is necessary to ensure patients receive the appropriate management and support to best manage these challenges in a timely manner. PMID- 25935369 TI - Enhanced reductive dechlorination of trichloroethylene by sulfidated nanoscale zerovalent iron. AB - Direct injection of reactive nanoscale zerovalent iron particles (NZVI) is considered to be a promising approach for remediation of aquifers contaminated by chlorinated organic pollutants. In this study we show that the extent of sulfidation of NZVI enhances the rate of dechlorination of trichloroethylene (TCE) compared to that by unamended NZVI, and the enhancement depends on the Fe/S molar ratio. Experiments where TCE was reacted with NZVI sulfidated to different extents (Fe/S molar ratios 0.62-66) showed that the surface-area normalized first order TCE degradation rate constant increased up to 40 folds compared to non sulfidated NZVI. Fe/S ratios in the range of 12-25 provided the highest TCE dechlorination rates, and rates decreased at both higher and lower Fe/S. In contrast, sulfidated NZVI exposed to water in the absence of TCE showed significantly lower hydrogen evolution rate (2.75 MUmol L(-1) h(-1)) compared to that by an unamended NZVI (6.92 MUmol L(-1) h(-1)), indicating that sulfidation of NZVI suppressed corrosion reactions with water. Sulfide (HS(-)) ions reacted rapidly with NZVI and X-ray photoelectron spectroscopy analyses showed formation of a surface layer of FeS and FeS2. We propose that more electrons are preferentially conducted from sulfidated NZVI than from unamended NZVI to TCE, likely because of greater binding of TCE on the reactive sites of the iron sulfide outer layer. Resuspending sulfidated NZVI in sulfide-free or sulfide containing solutions altered the TCE degradation rate constants because of changes in the FeS layer thickness. Sulfidated NZVI maintained its high reactivity in the presence of multiple mono and divalent ions and with polyelectrolyte coatings. Thus, sulfide ions in groundwater can significantly alter NZVI reactivity. PMID- 25935371 TI - Screening for predictors of adverse outcome in onco-geriatric surgical patients: A multicenter prospective cohort study. AB - AIMS: The aim of this study was to investigate the predictive ability of screening tools regarding the occurrence of major postoperative complications in onco-geriatric surgical patients and to propose a scoring system. METHODS: 328 patients >= 70 years undergoing surgery for solid tumors were prospectively recruited. Preoperatively, twelve screening tools were administered. Primary endpoint was the incidence of major complications within 30 days. Odds ratios (OR) and 95% confidence intervals (95% CI) were estimated using logistic regression. A scoring system was derived from multivariate logistic regression analysis. The area under the receiver operating characteristic curve (AUC) was applied to evaluate model performance. RESULTS: At a median age of 76 years, 61 patients (18.6%) experienced major complications. In multivariate analysis, Timed Up and Go (TUG), ASA-classification and Nutritional Risk Screening (NRS) were predictors of major complications (TUG>20 OR 3.1, 95% CI 1.1-8.6; ASA >= 3 OR 2.8, 95% CI 1.2-6.3; NRS impaired OR 3.3, 95% CI 1.6-6.8). The scoring system, including TUG, ASA, NRS, gender and type of surgery, showed good accuracy (AUC: 0.81, 95% CI 0.75-0.86). The negative predictive value with a cut-off point >8 was 93.8% and the positive predictive value was 40.3%. CONCLUSIONS: A substantial number of patients experience major postoperative complications. TUG, ASA and NRS are screening tools predictive of the occurrence of major postoperative complications and, together with gender and type of surgery, compose a good scoring system. PMID- 25935372 TI - A retrospective study on clinical findings of 7300 cases (2007-2014) of barren female dromedaries. AB - The objective of this study was to investigate the clinical findings in barren female dromedaries examined for different complaints. Female camels were examined for repeat breeding with regular heat interval (RB-R, n = 5444), refused mating (RM, n = 1299), repeat breeding with long heat interval (RB-L, n = 489), difficulties or bleeding during mating (DM, n = 53), and for manifestation of male-like behavior (MB, n = 15). The genital tracts of all females were evaluated using transrectal palpation, ultrasonography, and exploration of the vagina. Cervical swabs were obtained for bacteriologic examination. Clinical endometritis, ovarian hydrobursitis, and vaginal adhesions were the main clinical findings in the female camels examined for RB-R, RM, and RB-L, respectively. Parity affected the frequency of occurrence of these findings. The incidences of clinical endometritis, ovarian hydrobursitis, and vaginal adhesions in nullipara and multipara were 28% versus 32.3% (P = 0.004), 37.1% versus 23.7% (P = 0.001), and 5.7% versus 18.3% (P = 0.001), respectively. Vaginal adhesions, persistent hymen, pelvic abscess, and vulvar atresia were the clinical findings in the female camels presented due to bleeding at mating or with a history of an incomplete intromission of the penis. The male-like behavior was associated with an enlargement of the clitoris and narrowing of the vulva and vagina. Trueperella pyogenes, Staphylococcus aureus, Pseudomonas aeruginosa, Klebsiella pneumonia, Streptococcus zooepidemicus, and beta-hemolytic Streptococcus were isolated from females presented for repeat breeding syndrome. In conclusion, clinical endometritis, ovarian hydrobursitis, and vaginal adhesions were the main clinical findings in barren female dromedaries. Parity affected the frequency of the clinical findings. PMID- 25935373 TI - A mosaic small supernumerary marker chromosome 17 in a patient with Tourette syndrome, ADHD and intellectual disability: A case story and review of the literature. PMID- 25935374 TI - Outcomes of cognitive behaviour therapy for obsessive-compulsive disorder in young people with and without autism spectrum disorders: A case controlled study. AB - Obsessive-compulsive disorder (OCD) and autism spectrum disorders (ASD) are highly co-morbid. It is suggested that youth with ASD will respond less well to cognitive behaviour therapy (CBT), as compared to their typically developing counterparts. To date there is no empirical evidence to support this view. The current study sought to compare CBT for OCD outcomes among youth with and without ASD. 22 young people with ICD-10 diagnoses of OCD and ASD (OCD+ASD) were matched with 22 youth with OCD, but no ASD (OCD+NoASD) according to base line OCD symptom severity, age, and gender. Outcomes were assessed for the two groups following a course of individually tailored, but protocol-driven CBT for OCD. While both groups responded to treatment the OCD+ASD group's outcomes were inferior to the OCD+NoASD group, as indicated by a significantly smaller decrease in symptoms over treatment (38.31% vs. 48.20%) and lower remission rates at post-treatment (9% vs. 46%). Overall, young people experiencing OCD in the context of ASD benefitted from CBT, but to a lesser extent than typically developing children. Recent efforts to modifying standard CBT protocols for OCD in ASD should continue in order to optimise outcomes among youth with this particular dual psychopathology. PMID- 25935375 TI - The prevalence of body dysmorphic disorder and its clinical correlates in a VA primary care behavioral health clinic. AB - We examined the prevalence of body dysmorphic disorder (BDD) in a Veterans Affairs (VA) primary care behavioral health clinic. Of 100 Veterans, 11% (95% CI = 6.3-18.6%) had current BDD and 12% (95% CI = 7.0-19.8%) had lifetime BDD. However, only 8.3% of these Veterans had been diagnosed with BDD. BDD was significantly associated with a substantially elevated rate of suicide attempts, major depression, and obsessive-compulsive disorder. This severe disorder appears to be underdiagnosed in VA settings. PMID- 25935376 TI - Optimization of psychopharmacotherapy for schizophrenia in a male, locked, non acute unit serving for persistently ill patients over one year. AB - We describe real-world psychopharmacological treatment in a Japanese, male, closed psychiatric unit where clozapie was still unavailable. Fifty-five persistently-ill patients with schizophrenia (ICD-10), mean +/- S.D. age: 57.5 +/ 13.0 y.o., duration of illness and admissions: 30.9 +/- 15.2 years and 20.7 +/- 14.5 years, respectively) treated longitudinally were evaluated. The rule was to treat with a simplest possible psychotropic regimen without polypharmacy. Compared to the baseline, the number and dose of antipsychotics were reduced from 1.9 to 1.1 and 1012 mg/day to 607 mg/day, respectively. The number of total psychotropics was minimized from 4.7 to 2.1, with a simplified once or twice daily dosing. Overall, the CGI-Severity and FACT-Sz (global functioning) improved slightly from 5.8 to 5.5 and 28.7 to 32.6, respectively. Of note, no patients got worse in comparison with the baseline clinical presentation. Forty-four patients were successfully treated with a single antipsychotic; only seven needed two antipsychotics simultaneously while 36 had been treated with antipsychotic polypharmacy at baseline. Benzodiazepines (mostly lorazepam) and antiparkinsonian drugs were prescribed in 28 and only two, respectively. Nineteen needed adjunctive valproate (average blood levels: 99.3 +/- 21.8 MUg/mL) and nine used lithium (0.61 +/- 0.26 mEq/L). Optimization of psychopharmacotherapy is still possible for difficult-to-treat patients and, while augmentation of an antipsychotic with mood stabilizers is frequently needed, antipsychotic polypharmacy should be exceptional. PMID- 25935377 TI - [International Network for the History of Neuropsychopharmacology, INHN -- Editorial]. PMID- 25935378 TI - [Treatment of bipolar disorder with lamotrigine -- relapse rate and suicidal behaviour during 6 month follow-up]. AB - The present paper describes a 8-month prospective, observational, non intervention multicentric study in 969 bipolar patients, where data were obtained on changes during lamotrigine treatment with special focus rates of relapse, suicidal behaviour and adverse events. 969 patients entered the study and 961 patients (99%) completed the study. Patients received lamotrigine mostly as an add-on treatment in addition to ongoing antidepressant and/or antipsychotic medication. By the end of the six-month treatment period 38% of patients achieved remission and rate of relapse after three months was 24%. Rate of adverse events was very low (1%) and they in no case led o termination of therapy. At baseline 17% of patients had clinically significant suicide risk which gradually decreased to 2.1% during the 6-month study period. No suicide attempt or completed suicide occurred during the study period. Results indicate that lamotrigine is an effective and well-tolerated treatment for the acute and long-term treatment of bipolar patients. PMID- 25935379 TI - [Non-suicidal self-injury in adolescents: current issues]. AB - Although non-suicidal self-injury (NNSI), a behavior with a typical onset during adolescence, is a well-researched topic in the international literature and affects numerous adolescents both in clinical and non-clinical populations, it is rarely studied in Hungary. The aim of our paper is to review the historical and cultural background, terms and definitions used in the international and Hungarian literature, the epidemiology, the psychosocial correlates and the theories for possible predictors and functions of NSSI. Terms and definitions for NSSI evolved in international but not in Hungarian literature. Most frequently found functions for NSSI were affect regulation, self-punishment, anti-suicide, anti-dissociation. NSSI is also used to affirm interpersonal boundaries, for sensation seeking and to influence others. Prevalence of NSSI is 15-46% in community and 40-80% in clinical sample in adolescents. Hungarian results on prevalence of NSSI are relatively low in comparison with international data (7 17% in adolescent community sample). NSSI is often associated with psychiatric disorders: DSM-IV Axis I disorders are present in 88% and Axis II disorders are present in 67% of adolescent self-injurer samples. NSSI and suicidal behavior are two different but not independent phenomena: correlation is approximately 50% in community and 70% in clinical population. In conclusion we would like to highlight that NSSI affects numerous adolescents and it is often comorbid with other psychiatric disorders, thus developing adequate Hungarian terminology, increasing the amount of Hungarian studies and the up-to-date knowledge of the clinicians are necessary. PMID- 25935380 TI - [The problem of small "n" and big "P" in neuropsycho-pharmacology, or how to keep the rate of false discoveries under control]. AB - One of the characteristics of many methods used in neuropsychopharmacology is that a large number of parameters (P) are measured in relatively few subjects (n). Functional magnetic resonance imaging, electroencephalography (EEG) and genomic studies are typical examples. For example one microarray chip can contain thousands of probes. Therefore, in studies using microarray chips, P may be several thousand-fold larger than n. Statistical analysis of such studies is a challenging task and they are refereed to in the statistical literature such as the small "n" big "P" problem. The problem has many facets including the controversies associated with multiple hypothesis testing. A typical scenario in this context is, when two or more groups are compared by the individual attributes. If the increased classification error due to the multiple testing is neglected, then several highly significant differences will be discovered. But in reality, some of these significant differences are coincidental, not reproducible findings. Several methods were proposed to solve this problem. In this review we discuss two of the proposed solutions, algorithms to compare sets and statistical hypothesis tests controlling the false discovery rate. PMID- 25935381 TI - [Association between depression and cognitive decline in sclerosis multiplex patients]. AB - BACKGROUND: Multiple sclerosis (MS) is the most common neuroimmunological disease. In addition to its somatic symptoms, fatigue, mood disorder (depression) and cognitive impairment can be detected. Cognitive impairment significantly affects social relationships, work capacity, quality of life independently of disability. AIM: The aim of our research is to analyse the complex relationship between depression, manifestation of which occurs more often in MS compared to normal population, and cognitive functioning in multiple sclerosis. METHODS: Forty participants (sixteen men, twenty-four women) are MS patients of the Department of Neurology, Semmelweis University. Control group included forty-two age-, gender-, and education-matched subjects (sixteen men, twenty-six women). Patients were screened using MMSE; and verbal learning, visual information processing, attention, short-term and long-term memory were tested. Depression was also assessed. RESULTS: In multiple sclerosis learning, long-term verbal memory and short-term visuospatial memory were impaired compared to control group. Working memory, information processing and attention were found to be intact. Depression scores of MS patients were significantly higher than those of the normal population. Regarding the relationship between depression and cognitive impairment, negative correlation was found between mood and short-term visuospatial memory. CONCLUSION: Results of our research reflect the findings of clinical studies whereas short-term and long-term memory excluding working memory can be impaired in multiple sclerosis. Because of incidence of depression and fatigue and the important role of psychological factors in quality of life, more detailed analysis of the relationship between mood, fatigue and cognitive impairment would be required which is planned in the future. PMID- 25935382 TI - [Most important deficits, contradictions and possibilities in suicide prevention in Hungary]. AB - Suicide is not only a contradictory biological, psychological, sociocultural and spiritual phenomenon, but also a serious public health problem, which is manifold, therefore the fight against it is also complex. The aim of the present publication is to establish the current situation of the fight against suicide in Hungary, which are the most important deficits, contradictions and unexploited possibilities. The author states that although we have accomplished important steps in the prevention of suicide, we did not realise the majority of them in everyday practice. The author defines the most important problems and tasks which should be solved in the next decade. In the near future a great deal more should be done for prevention than what we have accomplished so far in order to significantly reduce the number of suicide victims in Hungary. PMID- 25935383 TI - Discovery of piperidin-4-yl-aminopyrimidine derivatives as potent non-nucleoside HIV-1 reverse transcriptase inhibitors. AB - A novel series of piperidin-4-yl-aminopyrimidine derivatives were designed fusing the pharmacophore templates of etravirine-VRX-480773 hybrids our group previously described and piperidine-linked aminopyrimidines. Most compounds displayed significantly improved activity against wild-type HIV-1 with EC50 values in single-digit nanomolar concentrations compared to etravirine-VRX-480773 hybrids. Selected compounds were also evaluated for activity against reverse transcriptase, and had lower IC50 values than that of nevirapine. The improved potency observed in this in vitro model of HIV RNA replication partly validates the mechanism by which this class of allosteric pyrimidine derivatives inhibits reverse transcriptase, and represents a remarkable step forward in the development of AIDS therapeutics. PMID- 25935384 TI - New quinolone- and 1,8-naphthyridine-3-carboxamides as selective CB2 receptor agonists with anticancer and immuno-modulatory activity. AB - Several recent studies suggest that selective CB2 receptor agonists may represent a valid pharmacological approach in the treatment of various diseases due to the absence of relevant psychoactive side effect. In this study, we synthesized and tested a series of new quinoline-2(1H)-one- and 4-hydroxy-2-oxo-1,2-dihydro-1,8 naphthyridine derivatives characterized by a 4-methylcyclohexylamido substituent in position 3 of the heterocyclic nucleus with high CB2 receptor affinity and selectivity. Two compounds showing the best binding and selectivity profile behaved as a full agonist and a partial agonist at the CB2 receptor and induced a concentration-dependent decrease of cell viability on LNCaP, a prostatic cancer cell line expressing CB2 receptor. Moreover considering that the CB2 receptor is mainly expressed in cells and organs of the immune system, the same compounds were studied for their potential immune-modulatory and anti-inflammatory effects in activated lymphocytes isolated from healthy controls and multiple sclerosis (MS) patients. PMID- 25935385 TI - Design and synthesis of piperidine derivatives as novel human heat shock protein 70 inhibitors for the treatment of drug-resistant tumors. AB - HSP70 is a potential target for tumour treatment. HSP70 plays significant roles in several biological processes, including the regulation of apoptosis. In this study, piperidine derivatives were designed as novel HSP70 inhibitors based on virtual fragment screening performed in Dock 4.0, Discovery Studio 2.5 and SYBYL 6.9. A total of 67 novel piperidine derivatives were synthesized. Cell viability assays were performed in 16 cancer cell lines. The emphasis was placed on lapatinib-resistant breast cancer cells (BT/Lap(R)1.0, MDA-MB-361, SK/Lap(R)1.0, and MDA-MB-453). The compounds HSP70-36/37/40/43/46 significantly inhibited the proliferation of human breast cancer cells. Compound HSP70-36 inhibited the growth of BT474 and BT/Lap(R)1.0 cells with IC50 values of 1.41 MUM and 1.47 MUM, respectively. The binding affinity of HSP70-36/HSP70 was evaluated by surface plasmon resonance and yielded Kd values of 2.46 MUM. The LD50 was 869.0 mgkg(-1). These data suggest that HSP70-36 may be a potential candidate compound for tumour treatment. PMID- 25935386 TI - Radiosynthesis and initial characterization of a PDE10A specific PET tracer [18F]AMG 580 in non-human primates. AB - INTRODUCTION: Phosphodiesterase 10A (PDE10A) is an intracellular enzyme responsible for the breakdown of cyclic nucleotides which are important second messengers for neurotransmission. Inhibition of PDE10A has been identified as a potential target for treatment of various neuropsychiatric disorders. To assist drug development, we have identified a selective PDE10A positron emission tomography (PET) tracer, AMG 580. We describe here the radiosynthesis of [(18)F]AMG 580 and in vitro and in vivo characterization results. METHODS: The potency and selectivity were determined by in vitro assay using [(3)H]AMG 580 and baboon brain tissues. [(18)F]AMG 580 was prepared by a 1-step [(18)F]fluorination procedure. Dynamic brain PET scans were performed in non-human primates. Regions of-interest were defined on individuals' MRIs and transferred to the co registered PET images. Data were analyzed using two tissue compartment analysis (2TC), Logan graphical (Logan) analysis with metabolite-corrected input function and the simplified reference tissue model (SRTM) method. A PDE10A inhibitor and unlabeled AMG 580 were used to demonstrate the PDE10A specificity. KD was estimated by Scatchard analysis of high and low affinity PET scans. RESULTS: AMG 580 has an in vitro KD of 71.9 pM. Autoradiography showed specific uptake in striatum. Mean activity of 121 +/- 18 MBq was used in PET studies. In Rhesus, the baseline BPND for putamen and caudate was 3.38 and 2.34, respectively, via 2TC, and 3.16, 2.34 via Logan, and 2.92, and 2.01 via SRTM. A dose dependent decrease of BPND was observed by the pre-treatment with a PDE10A inhibitor. In baboons, 0.24 mg/kg dose of AMG 580 resulted in about 70% decrease of BPND. The in vivo KD of [(18)F]AMG 580 was estimated to be around 0.44 nM in baboons. CONCLUSION: [(18)F]AMG 580 is a selective and potent PDE10A PET tracer with excellent specific striatal binding in non-human primates. It warrants further evaluation in humans. PMID- 25935387 TI - Application and reactivation of magnetic nanoparticles in Microcystis aeruginosa harvesting. AB - This study developed a magnetic nanoparticles (MNPs) harvesting and reactivation technique for rapid cyanobacteria Microcystis aeruginosa separation. The harvesting of raw MNPs achieved high efficiency of 99.6% with the MNPs dosage of 0.58g MNPs/g dry-biomass, but gradually decreased to 59.1% when directly reused 5 times. With extra ultrasonic chloroform:methanol solvent treatment, the MNPs can be effectively reactivated for M. aeruginosa harvesting with 60% efficiency after 5 times reactivation and the separation efficiency kept above 93% with 0.20g MNPs/g dry-biomass dosage. The cyanobacteria-MNPs complex can be effectively disrupted by ultrasonic chloroform:methanol solvent treatment and the zeta potential was recovered for MNPs electrostatic attraction. The MNPs adsorption followed the Langmuir isotherm, and the maximum adsorption capacity and Langmuir constant was 3.74g dry-biomass/g and 311.64L/g respectively. This MNPs reactivation technique can achieve low energy separation and reduce MNPs consumption by 67%, providing potential engineering implementation for cyanobacterial biomass harvesting. PMID- 25935388 TI - A Comparative study of microwave-induced pyrolysis of lignocellulosic and algal biomass. AB - Microwave (MW) pyrolysis of algal and lignocellulosic biomass samples were studied using a modified domestic oven. The pyrolysis temperature was recorded continuously by inserting a thermocouple into the samples. Temperatures as high as 1170 and 1015 degrees C were achieved for peanut shell and Chlorella vulgaris. The activation energy for MW pyrolysis was calculated by Coats-Redfern method and the values were 221.96 and 214.27kJ/mol for peanut shell and C. vulgaris, respectively. Bio-oil yields reached to 27.7wt.% and 11.0wt.% during pyrolysis of C. vulgaris and peanut shell, respectively. The bio-oil samples from pyrolysis were analyzed by a gas chromatography-mass spectrometry (GC-MS). Bio-oil from lignocellulosic biomass pyrolysis contained more phenolic compounds while that from microalgae pyrolysis contained more nitrogen-containing species. Fourier transform infrared spectroscopy (FTIR) analysis results showed that concentration of OH, CH, CO, OCH3, and CO functional groups in char samples decreased significantly after pyrolysis. PMID- 25935389 TI - Optimization of uncatalyzed steam explosion pretreatment of rapeseed straw for biofuel production. AB - Rapeseed straw constitutes an agricultural residue with great potential as feedstock for ethanol production. In this work, uncatalyzed steam explosion was carried out as a pretreatment to increase the enzymatic digestibility of rapeseed straw. Experimental statistical design and response surface methodology were used to evaluate the influence of the temperature (185-215 degrees C) and the process time (2.5-7.5min). According to the rotatable central composite design applied, 215 degrees C and 7.5min were confirmed to be the optimal conditions, considering the maximization of enzymatic hydrolysis yield as optimization criterion. These conditions led to a maximum yield of 72.3%, equivalent to 81% of potential glucose in pretreated solid. Different configurations for bioethanol production from steam exploded rapeseed straw were investigated using the pretreated solid obtained under optimal conditions as a substrate. As a relevant result, concentrations of ethanol as high as 43.6g/L (5.5% by volume) were obtained as a consequence of using 20% (w/v) solid loading, equivalent to 12.4g ethanol/100g biomass. PMID- 25935390 TI - Biomass hydrolysis inhibition at high hydrogen partial pressure in solid-state anaerobic digestion. AB - In solid-state anaerobic digestion, so-called ss-AD, biogas production is inhibited at high total solids contents. Such inhibition is likely caused by a slow diffusion of dissolved reaction intermediates that locally accumulate. In this study, we investigated the effect of H2 and CO2 partial pressure on ss-AD. Partial pressure of H2 and/or CO2 was artificially fixed, from 0 to 1 557mbars for H2 and from 0 to 427mbars for CO2. High partial pressure of H2 showed a significant effect on methanogenesis, while CO2 had no impact. At high [Formula: see text] , the overall substrate degradation decreased with no accumulation of metabolites from acidogenic bacteria, indicating that the hydrolytic activity was specifically impacted. Interestingly, such inhibition did not occur when CO2 was added with H2. This result suggests that CO2 gas transfer is probably a key factor in ss-AD from biomass. PMID- 25935391 TI - Butanol and hexanol production in Clostridium carboxidivorans syngas fermentation: Medium development and culture techniques. AB - Clostridium carboxidivorans was grown on model syngas (CO:H2:CO2 [70:20:10]) in a defined nutrient medium with concentrations of nitrogen, phosphate and trace metals formulated to enhance production of higher alcohols. C. carboxidivorans was successfully grown in a limited defined medium (no yeast extract, no MES buffer and minimal complex chemical inputs) using an improved fermentation protocol. Low partial pressure of CO in the headspace, coupled with restricted mass transfer for CO and H2, was required for successful fermentation. In the absence of substrate inhibition (particularly from CO), growth limitation increased production of alcohols, especially butanol and hexanol. Concentrations of butanol (over 1.0g/L), hexanol (up to 1.0g/L) and ethanol (over 3.0g/L) were achieved in bottle fermentations. Minimal medium and controlled supply of CO and H2 should be used in characterizing candidate butanol and hexanol producing strains to select for commercial potential. PMID- 25935392 TI - Repeated-batch operation for the synthesis of lactulose with beta-galactosidase immobilized by aggregation and crosslinking. AB - Synthesis of lactulose under repeated-batch operation was done with cross-linked aggregates of Aspergillus oryzae beta-galactosidase (CLAGs). The effect of the crosslinking agent to enzyme mass ratio and cross-linking time were first evaluated. Best results were obtained at 5.5gdeglutaraldehyde/g enzyme at 5h of cross-linking, obtaining a specific activity of 15,000IUg(-1), with 30% immobilization yield. CLAG was more stable than the free enzyme under non reactive conditions with a half-life of 123h at 50 degrees C and when operated in repeated-batch mode, yield and productivity was 3.8 and 4.3 times higher. Maximum number of batches was determined considering biocatalyst replacement at 50% residual activity. 98 and 27 batches could be performed under such criterion at fructose/lactose molar ratio of 4 and 20 respectively, reflecting that enzyme stability is strongly affected by the sugars distribution in the reaction medium. PMID- 25935393 TI - Accelerated methanogenesis from effluents of hydrogen-producing stage in anaerobic digestion by mixed cultures enriched with acetate and nano-sized magnetite particles. AB - Potential for paddy soil enrichments obtained in the presence of nano-sized magnetite particles (named as PSEM) to promote methane production from effluents of hydrogen-producing stage in two-stage anaerobic digestion was investigated. The results showed that the addition of magnetite significantly accelerated methane production from acetate in a dose-independent manner. The results from high-throughput sequencing analysis revealed that Rhodocyclaceae-related species were selectively enriched, which were likely the key players for conversion of acetate to methane in PSEM. Compared to the paddy soil enrichments obtained in the absence of magnetite (named as PSEC), the maximum methane production rate in PSEM was significantly higher (1.5-5.5times higher for the artificial medium and 0.2-1.7times higher for the effluents). The accelerated methane production from the effluents indicated remarkably application potential of PSEM for improving performance of anaerobic digestion. PMID- 25935394 TI - Pilot-scale study of sludge pretreatment by microwave and sludge reduction based on lysis-cryptic growth. AB - To evaluate the performance of microwave (MW)-chemical hybrid sludge treatment system, a pilot scale MW disintegration unit (treatment capacity of 500L/d) was constructed. The results showed that organic matter, nitrogen, and phosphorus were effectively released from the MW-pretreated sludge. The values of COD released were 15.91%, 15.07%, 13.83%, 19.35%, and 15.07% for the MW, MW-acid, MW alkali, MW-H2O2, and MW-H2O2-alkali treatment processes, respectively. Additionally, for a wastewater treatment system with a capacity of 200m(3)/d, when coupled with a MW sludge pretreatment unit, the sludge production and sludge yield were greatly reduced by 38.60% and to 0.35kg VSS/kg CODconsumed, respectively. The total operating cost of the lysis-cryptic growth system was 13.64% lower than that of the CAS system without a MW unit. PMID- 25935395 TI - Impact of several antibiotics and 2-bromoethanesulfonate on the volatile fatty acid degradation, methanogenesis and community structure during thermophilic anaerobic digestion. AB - The main aim of the present study was to gain insight into the stability of an anaerobic digestion process suffering from exposure to antibiotics and the methanogenic inhibitor 2-bromoethanesulfonate (BES). For this purpose, eleven antibiotics and BES were investigated with regard to the degradation of volatile fatty acids (VFAs), methanogenesis, and impact on the microbial community structure. Only neomycin, gentamicin, rifampicin, and BES showed complete inhibitions of VFA degradations. This points to distinct interferences with important trophic degradation cascades. Based upon DGGE and sequencing approaches, Methanosarcina spp. were severely influenced by the treatments while hydrogenotrophic methanogens were less affected. Interestingly, BES and neomycin inhibited the degradation of acetate while only BES inhibited methanogenesis completely. It seems that Methanosarcina spp. were mandatory for the degradation of acetate at high rates. The present results highly emphasize the detrimental effects of antimicrobial compounds with the potential to significantly inhibit the anaerobic digestion. PMID- 25935396 TI - Performance and microbial community dynamics in bioaugmented aerated filter reactor treating with coking wastewater. AB - In this study, zeolite-biological aerated filters (Z-BAFs) bioaugmented by free and magnetically immobilized cells of Arthrobacter sp. W1 were designed to treat coking wastewater containing high concentrations of phenol and naphthalene along with carbazole (CA), dibenzofuran (DBF), and dibenzothiophene (DBT). All treatments were carried out for a period of 100days and the data indicated that bioaugmented Z-BAFs with magnetically immobilized cells was most efficient for treating coking wastewaters. Illumina high-throughput sequencing was used to reveal the microbial community structures of Z-BAFs. Both bioaugmentation treatments could accelerate the shift of the bacterial community structures. The introduced strain W1 remained dominant in the bioaugmented Z-BAFs with magnetically immobilized cells, indicating both strain W1 and the indigenous degrading bacteria played the most significant role in the treatment. Overall, bioaugmented Z-BAF with magnetically immobilized cells can be used to efficiently degrade phenol, naphthalene, CA, DBF, and DBT in coking wastewater. PMID- 25935397 TI - Brain inflammation and hypertension: the chicken or the egg? AB - Inflammation of forebrain and hindbrain nuclei controlling the sympathetic nervous system (SNS) outflow from the brain to the periphery represents an emerging concept of the pathogenesis of neurogenic hypertension. Angiotensin II (Ang-II) and prorenin were shown to increase production of reactive oxygen species and pro-inflammatory cytokines (interleukin-1 beta (IL-1beta), interleukin-6 (IL-6), tumor necrosis factor-alpha (TNF-alpha)) while simultaneously decreasing production of interleukin-10 (IL-10) in the paraventricular nucleus of the hypothalamus and the rostral ventral lateral medulla. Peripheral chronic inflammation and Ang-II activity seem to share a common central mechanism contributing to an increase in sympathetic neurogenic vasomotor tone and entailing neurogenic hypertension. Both hypertension and obesity facilitate the penetration of peripheral immune cells in the brain parenchyma. We suggest that renin-angiotensin-driven hypertension encompasses feedback and feedforward mechanisms in the development of neurogenic hypertension while low-intensity, chronic peripheral inflammation of any origin may serve as a model of a feedforward mechanism in this condition. PMID- 25935398 TI - Dysregulated mechanisms underlying Duchenne muscular dystrophy from co-expression network preservation analysis. AB - BACKGROUND: Duchenne Muscular Dystrophy (DMD) is an X-linked recessive disorder with its primary insult on the skeletal muscle. Severe muscle wasting, chronic inflammation and fibrosis characterize dystrophic muscle. Here we identify dysregulated pathways in DMD utilizing a co-expression network approach as described in Weighted Gene Co-expression Network Analysis (WGCNA). Specifically, we utilize WGCNA's "preservation" statistics to identify gene modules that exhibit a weak conservation of network topology within healthy and dystrophic networks. Preservation statistics rank modules based on their topological metrics such as node density, connectivity and separability between networks. METHODS: Raw data for DMD was downloaded from Gene Expression Omnibus (GSE6011) and suitably preprocessed. Co-expression networks for each condition (healthy and dystrophic) were generated using the WGCNA library in R. Preservation of healthy network edges was evaluated with respect to dystrophic muscle and vice versa using WGCNA. Highly exclusive gene pairs for each of the low preserved modules within both networks were also determined using a specificity measure. RESULTS: A total of 11 and 10 co-expressed modules were identified in the networks generated from 13 healthy and 23 dystrophic samples respectively. 5 out of the 11, and 4 out of the 10 modules were identified as exhibiting none-to-weak preservation. Functional enrichment analysis identified that these weakly preserved modules were highly relevant to the condition under study. For instance, weakly preserved dystrophic module D2 exhibited the highest fraction of genes exclusive to DMD. The highly specific gene pairs identified within these modules were enriched for genes activated in response to wounding and affect the extracellular matrix including several markers such as SPP1, MMP9 and ITGB2. CONCLUSION: The proposed approach allowed us to identify clusters of genes that are non-randomly associated with the disease. Furthermore, highly specific gene pairs pointed to interactions between known markers of disease and identification of putative markers likely associated with disease. The analysis also helped identify putative novel interactions associated with the progression of DMD. PMID- 25935399 TI - Glomerular protein separation as a mechanism for powering renal concentrating processes. AB - Various models have been proposed to explain the urine concentrating mechanism in mammals, however uncertainty remains regarding the origin of the energy required for the production of concentrated urine. We propose a novel mechanism for concentrating urine. We postulate that the energy for the concentrating process is derived from the osmotic potentials generated by the separation of afferent blood into protein-rich efferent blood and protein-deplete filtrate. These two streams run in mutual juxtaposition along the length of the nephron and are thus suitably arranged to provide the osmotic potential to concentrate the urine. The proposed model is able to qualitatively explain the production of various urine concentrations under different clinical conditions. An approach to testing the feasibility of the hypothesis is proposed. PMID- 25935400 TI - A smartphone-based cloud computing tool for managing type 1 diabetes in Ontarians. PMID- 25935401 TI - Prevalence of Painful Diabetic Neuropathy Using the Self-Completed Leeds Assessment of Neuropathic Symptoms and Signs Questionnaire in a Population with Diabetes. AB - OBJECTIVE: This study assessed the feasibility of diagnosing painful diabetic neuropathy (PDN) using a postal self-completed Leeds Assessment of Neuropathic Symptoms and Signs (S-LANSS) questionnaire, and it compared the prevalence of PDN in patients with diabetes attending primary and secondary care. METHODS: This was an observational study in northwest England, United Kingdom (n=204). S-LANSS were used by post to diagnose PDN. Consent for participation and access of blood results were obtained from the subjects with diabetes. Ethical approval was granted to do the work. RESULTS: In this study the prevalence of PDN was 30.3%, comprising 33.1% of patients with type 2 diabetes compared to 14.1% patients with type 1 diabetes. The overall prevalence of PDN was 33% (n=43) in the secondary care group and 25.6% (n=19) in the primary care group; the rates were not statistically significant. There were no gender differences between the primary and secondary care populations. There was a significant association of obesity, smoking and height in males with PDN compared to the non-PDN group (p<0.05). There was a significant trend toward increasing prevalence of PDN with duration of diabetes, increasing glycated hemoglobin and increasing body mass index (p<0.05). CONCLUSION: The overall prevalence of PDN in this study was 30.3%. The results demonstrated the use of self-administered S-LANSS was easy and can be used for epidemiologic surveys of PDN. The results are comparable to and similar to other published series, in both primary and secondary care settings. PMID- 25935402 TI - Harnessing the power of technology to improve the lives of those with diabetes. PMID- 25935403 TI - A case of bilateral pheochromocytoma during pregnancy. AB - BACKGROUND: Pheochromocytoma is a disease where catecholamines are secreted. If pheochromocytoma occurs during pregnancy, it can be difficult to diagnose because it is similar to pregnancy-induced hypertension. Furthermore, bilateral pheochromocytoma during pregnancy is even rarer than unilateral pheochromocytoma. CASE PRESENTATION: A 32-year-old primigravida, who was 12 weeks' pregnant, was aware of right abdominal discomfort. Masses in both adrenal glands were observed by abdominal ultrasonography. She was diagnosed with pheochromocytoma. Bilateral adrenalectomy was undertaken at 15 weeks' gestation and she continued pregnancy. At 39 weeks' gestation, a healthy male neonate was delivered. She was discharged on the 4th postpartum day. CONCLUSIONS: We present a case of bilateral pheochromocytoma during pregnancy that was diagnosed in the first trimester. Differentiating pheochromocytoma from pregnancy-induced hypertension is important. Early diagnosis and appropriate blood pressure management with medical treatment followed by surgical removal of the tumor results in good maternal and fetal outcomes. PMID- 25935405 TI - Enhanced As(III) oxidation and removal by combined use of zero valent iron and hydrogen peroxide in aerated waters at neutral pH values. AB - The oxidation and removal of As(III) by commercially available micro-scale zero valent iron (mZVI) was studied in aerated synthetic groundwater with initially 6.7 MUM As(III) at neutral pH values. Batch experiments were performed to investigate the influence of ZVI and H2O2 concentrations on As(III) oxidation and removal. Oxidation and removal kinetics was significantly increased by increasing ZVI concentration or by adding H2O2 in micromolar concentrations slightly higher than that of initial As(III). Observed half-lifes for arsenic removal without added H2O2 were 81-17 min at ZVI concentrations of 0.15-2.5 g/L, respectively. X ray absorption spectroscopy (XAS) confirmed that almost all As(III) was converted to As(V) after 2 h of reaction in the pH range 5-9. Addition of 9.6 MUM H2O2 to 0.15 g/L ZVI suspensions diminished half-lifes for arsenic removal from 81 to 32 min and for As(III) oxidation from 77 to 8 min, i.e., by approximately a factor of 10. The increased rate of As(III) oxidation is attributable to enhanced formation of oxidants by the Fenton reaction with higher initial concentrations of H2O2. In practice, results of this study suggest that addition of small amounts (<1 mg/L) of H2O2 in various forms (e.g. stable and widely available Na percarbonate) to water prior to treatment could significantly enhance As(III) oxidation and removal with ZVI. PMID- 25935404 TI - Metformin increases survival in hormone receptor-positive, HER2-positive breast cancer patients with diabetes. AB - INTRODUCTION: Metformin use has recently been observed to decrease both the rate and mortality of breast cancer. Our study was aim to determine whether metformin use is associated with survival in diabetic breast cancer patients by breast cancer subtype and systemic treatment. METHODS: Data from the Asan Medical Center Breast Cancer Database from 1997 to 2007 were analyzed. The study cohort comprised 6,967 nondiabetic patients, 202 diabetic patients treated with metformin, and 184 diabetic patients that did not receive metformin. Patients who were divided into three groups by diabetes status and metformin use were also divided into four subgroups by hormone receptor and HER2-neu status. RESULTS: In Kaplan-Meier analysis, the metformin group had a significantly better overall and cancer specific survival outcome compared with non metformin diabetic group (P <0.005 for both). There was no difference in survival between the nondiabetic and metformin groups. In multivariate analysis, Compared with metformin group, patients who did not receive metformin tended to have a higher risk of metastasis with HR 5.37 (95 % CI, 1.88 to 15.28) and breast cancer death with HR 6.51 (95 % CI, 1.88 to 15.28) on the hormone receptor-positive and HER2-negative breast cancer. The significant survival benefit of metformin observed in diabetic patients who received chemotherapy and endocrine therapy (HR for disease free survival 2.14; 95 % CI 1.14 to 4.04) was not seen in diabetic patients who did not receive these treatments. CONCLUSION: Patients receiving metformin treatment when breast cancer diagnosis show a better prognosis only if they have hormone receptor-positive, HER2-positive tumors. Metformin treatment might provide a survival benefit when added to systemic therapy in diabetic patients. PMID- 25935406 TI - Small-scale experimental study of vaporization flux of liquid nitrogen released on water. AB - A small-scale experimental study was conducted using liquid nitrogen to investigate the convective heat transfer behavior of cryogenic liquids released on water. The experiment was performed by spilling five different amounts of liquid nitrogen at different release rates and initial water temperatures. The vaporization mass fluxes of liquid nitrogen were determined directly from the mass loss measured during the experiment. A variation of initial vaporization fluxes and a subsequent shift in heat transfer mechanism were observed with changes in initial water temperature. The initial vaporization fluxes were directly dependent on the liquid nitrogen spill rate. The heat flux from water to liquid nitrogen determined from experimental data was validated with two theoretical correlations for convective boiling. It was also observed from validation with correlations that liquid nitrogen was found to be predominantly in the film boiling regime. The substantial results provide a suitable procedure for predicting the heat flux from water to cryogenic liquids that is required for source term modeling. PMID- 25935407 TI - Maternal exposure to di-(2-ethylhexyl) phthalate disrupts placental growth and development in pregnant mice. AB - Di-(2-ethylhexyl) phthalate (DEHP) is used as a plasticizer and widely dispersed in the environment. DEHP exposure reduces embryo implantations, increases embryonic loss, and decreases fetal body weights. However, no detailed information is available about the effect of DEHP on the placentation during pregnancy. Thus, our aim was to explore the effect of DEHP on the growth and development of placenta in vivo. Mice were administered DEHP by gavages at 125, 250, 500 mg/kg/day from gestational days (GD) 1 until sacrifice. Results showed that DEHP treatment significantly reduced the weight of placenta at GD 13. Histopathologically, in DEHP-treated group, the ectoplacental cones significantly became smaller at GD9, and total area of placenta and area of spongiotrophoblast were significantly reduced at GD 13. Expression levels of Ascl2, Esx1 and Fosl1 mRNA dramatically decreased in DEHP-treated placenta at GD 13. DEHP administration disrupted labyrinth vascularization of placentas, and inhibited proliferation and induced apoptosis of placenta by the activation of caspase-3 and -8, up-regulation of Bax and down-regulation of Bcl-2 mRNA and protein at GD 13. In conclusion, these results suggest that adverse pregnancy outcomes including low birth-weight and pregnancy loss exposed to DEHP are possibly mediated, at least in part, via the suppression of placental growth and development. PMID- 25935408 TI - Complete removal of AHPS synthetic dye from water using new electro-fenton oxidation catalyzed by natural pyrite as heterogeneous catalyst. AB - The mineralization of a new azo dye - the (4-amino-3-hydroxy-2-p-tolylazo naphthalene-1-sulfonic acid) (AHPS) - has been studied by a novel electrochemical advanced oxidation process (EAOP), consisting in electro-Fenton (EF) oxidation, catalyzed by pyrite as the heterogeneous catalyst - the so-called 'pyrite-EF'. This solid pyrite used as heterogeneous catalyst instead of a soluble iron salt, is the catalyst the system needs for production of hydroxyl radicals. Experiments were performed in an undivided cell equipped with a BDD anode and a commercial carbon felt cathode to electrogenerate in situ H2O2 and regenerate ferrous ions as catalyst. The effects on operating parameters, such as applied current, pyrite concentration and initial dye content, were investigated. AHPS decay and mineralization efficiencies were monitored by HPLC analyses and TOC measurements, respectively. Experimental results showed that AHPS was quickly oxidized by hydroxyl radicals (OH) produced simultaneously both on BDD surface by water discharge and in solution bulk from electrochemically assisted Fenton's reaction with a pseudo-first-order reaction. AHPS solutions with 175 mg L(-1) (100 mg L( 1) initial TOC) content were then almost completely mineralized in 8h. Moreover, the results demonstrated that, under the same conditions, AHPS degradation by pyrite electro-Fenton process was more powerful than the conventional electro Fenton process. PMID- 25935409 TI - Application of (13)C and (15)N stable isotope probing to characterize RDX degrading microbial communities under different electron-accepting conditions. AB - This study identified microorganisms capable of using the explosive hexahydro 1,3,5-trinitro-1,3,5-triazine (RDX) or its metabolites as carbon and/or nitrogen sources under different electron-accepting conditions using (13)C and (15)N stable isotope probing (SIP). Mesocosms were constructed using groundwater and aquifer solids from an RDX-contaminated aquifer. The mesocosms received succinate as a carbon source and one of four electron acceptors (nitrate, manganese(IV), iron(III), or sulfate) or no additional electron acceptor (to stimulate methanogenesis). When RDX degradation was observed, subsamples from each mesocosm were removed and amended with (13)C3- or ring-(15)N3-, nitro-(15)N3-, or fully labeled (15)N6-RDX, followed by additional incubation and isolation of labeled nucleic acids. A total of fifteen 16S rRNA sequences, clustering in alpha- and gamma-Proteobacteria, Clostridia, and Actinobacteria, were detected in the (13)C DNA fractions. A total of twenty seven sequences were derived from different (15)N-DNA fractions, with the sequences clustered in alpha- and gamma Proteobacteria, and Clostridia. Interestingly, sequences identified as Desulfosporosinus sp. (in the Clostridia) were not only observed to incorporate the labeled (13)C or (15)N from labeled RDX, but also were detected under each of the different electron-accepting conditions. The data suggest that (13)C- and (15)N-SIP can be used to characterize microbial communities involved in RDX biodegradation, and that the dominant pathway of RDX biodegradation may differ under different electron-accepting conditions. PMID- 25935410 TI - Built environment interventions aimed at improving physical activity levels in rural Ontario health units: a descriptive qualitative study. AB - BACKGROUND: Few studies to date have explored the relationship between the built environment and physical activity specifically in rural settings. The Ontario Public Health Standards policies mandate that health units in Ontario address the built environment; however, it is unclear how public health practitioners are integrating the built environment into public health interventions aimed at improving physical activity in chronic disease prevention programs. METHODS: This descriptive qualitative study explored interventions that have or are being implemented which address the built environment specifically related to physical activity in rural Ontario health units, and the impact of these interventions. Data were collected through twelve in-depth semi-structured interviews with rural public health practitioners and managers representing 12 of 13 health units serving rural communities. Key themes were identified using qualitative content analysis. RESULTS: Themes that emerged regarding the types of interventions that health units are employing included: Engagement with policy work at a municipal level; building and working with community partners, committees and coalitions; gathering and providing evidence; developing and implementing programs; and social marketing and awareness raising. Evaluation of interventions to date has been limited. CONCLUSIONS: Public health interventions, and their evaluations, are complex. Health units who serve large rural populations in Ontario are engaging in numerous activities to address physical activity levels. There is a need to further evaluate the impact of these interventions on population health. PMID- 25935411 TI - Reevaluating Emx gene phylogeny: homopolymeric amino acid tracts as a potential factor obscuring orthology signals in cyclostome genes. AB - BACKGROUND: Vertebrate Emx genes, retained as multiple copies, are expressed in a nested pattern in the early embryonic forebrain and required for its regionalization. This pattern seems to have originated in a vertebrate common ancestor; however, a previous analysis, reporting two lamprey Emx genes, claimed independent Emx gene duplications in both cyclostome (extant jawless fish) and gnathostome (jawed vertebrate) lineages after their divergence. This scenario is neither parsimonious nor consistent with the hypothesis that genome expansion occurred before the cyclostome-gnathostome split, which is supported by recent genome-wide analyses. RESULTS: We isolated and sequenced cDNA of two hagfish Emx genes and performed intensive molecular phylogenetic analyses, including the hagfish and/or lamprey Emx genes. The lamprey genes tended to attract each other in inferred phylogenetic trees, an effect that tended to be relaxed on inclusion of the hagfish genes. The results of these analyses suggest that cyclostome EmxB is orthologous to gnathostome Emx2, which was also supported by conserved synteny. Homopolymeric amino acid (HPAA) tracts represent a remarkable feature of the lamprey Emx sequences, and a comparative genome-wide scan revealed that lamprey proteins exhibit a unique pattern of HPAA tract accumulation. CONCLUSIONS: Our analysis, including hagfish Emx genes, suggests that gene duplications gave rise to Emx1, -2 and -3 before the cyclostome-gnathostome split. We propose that independent HPAA tract accumulations in multiple ancient duplicates, as identified in lamprey Emx gene products, may have led to erroneous identification of gene duplication in the lamprey lineage. Overall, our reanalysis favors the scenario that the nested Emx expression pattern in mouse and lamprey shares a common origin. PMID- 25935412 TI - 'Are smokers less deserving of expensive treatment? A randomised controlled trial that goes beyond official values'. AB - BACKGROUND: To investigate whether Swedish physicians, contrary to Swedish health care policy, employ considerations of patient responsibility for illness when rationing expensive treatments. METHODS: A random sample of oncologists and pulmonologists made up the main study-group (n = 296). A random sample of GPs (n = 289) and participants from the general population (n = 513) was used as contrast group. The participants randomly received one version of a questionnaire containing a case description of a terminally ill lung cancer patient. The two versions differed in only one aspect: in one version the patient was a smoker and in the other a non-smoker. The main questions were whether to offer a novel, expensive and marginally life-prolonging treatment and whether the patient could be held responsible for her illness. The quantitative data was analysed using Chi2-tests and comments were analysed using content analysis. RESULTS: Among oncologists and pulmonologists, 78% (95% CI: 72-85) would offer the treatment to the non-smoker and 66% (95% CI: 58-74) to the smoker (Chi-2 = 5.4, df = 1, p = 0.019). Among the GPs, 69% (95% CI: 61-76) would treat the non-smoker and 56% (95% CI: 48-64) the smoker (Chi-1 = 4.9, df = 1 and p = 0.026). Among the general population the corresponding proportions were 84% (95% CI: 79-88) and 69% (95% CI: 63-74). CONCLUSION: This study indicates that applying an experimental design allowed us to go beyond the official norms and to show that, compared to a smoking patient, both the general population and physicians are more inclined to treat a non-smoking patient. This clearly runs counter to the official Swedish health care norms. It also seems to run counter to the fact that among the physicians studied, there was no association between finding the patient responsible for her disease and the inclination to treat her. We think these paradoxical findings merit further studies. PMID- 25935413 TI - Risk factors and outcome analysis after surgical management of ventricular septal rupture complicating acute myocardial infarction: a retrospective analysis. AB - BACKGROUND: Ventricular septal rupture (VSR) is an uncommon but well-recognized mechanical complication of acute myocardial infarction (AMI). The outcome of VSR remains poor even in the era of reperfusion therapy. We reviewed our experience with surgical repair of post-infarction VSR and analyzed outcomes in an attempt to identify prognostic factors. METHODS: From October 1995 to December 2013, data from 47 consecutive patients (mean age, 68 +/- 9.5 years) with post-infarction VSR who underwent surgical repair at our institute were retrospectively reviewed. The preoperative conditions, morbidity and surgical mortality were analyzed. Multivariate analysis was subsequently carried out by constructing a logistic regression model in order to identify independent predictors of postoperative mortality. Long term survival function were estimated using the Kaplan-Meier method and compared using the log-rank test. RESULTS: Percutaneous coronary intervention was performed in 17 (36.2%) patients, intra-aortic balloon pump (IABP) was used in 34 (72.3%), and six (12.8%) were supported with extracorporeal membrane oxygenation (ECMO) preoperatively. Forty-one (87.2%) patients received emergent surgical treatment. Concomitant coronary artery bypass grafting was performed in 27 (57.4%) patients. Operative mortality was 36.2% (17 of 47). The survival rate was 59.3% with concomitant CABG and 70% without concomitant CABG (p = 14). Multivariate analysis revealed that the survivors had higher preoperative left ventricular ejection fractions (LVEFs) compared with those who died (51 +/- 13.7% vs. 36.6 +/- 6.4% , respectively; p < 0.001) and lower European system for cardiac operative risk evaluation II (EuroSCORE II) (22.9 +/- 14.9 vs. 38.3 +/- 13.9, respectively; p < 0.001). The patients receiving total revascularization has long term survival benefit (p = 0.028). CONCLUSIONS: Post-infarction VSR remains a serious and challenging complication of AMI in the modern surgical era. The EuroSCORE II can be used for an approximate prediction of operative mortality. Preserved LVEF was associated with better prognosis, while the need for postoperative RRT was associated with higher early and late mortality. Besides, the strategy of total revascularization should be applied to ensure long term survival benefit. PMID- 25935414 TI - Contact genomics: scaffolding and phasing (meta)genomes using chromosome 3D physical signatures. AB - High-throughput DNA sequencing technologies are fuelling an accelerating trend to assemble de novo or resequence the genomes of numerous species as well as to complete unfinished assemblies. While current DNA sequencing technologies remain limited to reading stretches of a few hundreds or thousands of base pairs, experimental and computational methods are continuously improving with the goal of assembling entire genomes from large numbers of short DNA sequences. However, the algorithms that piece together DNA strands face important limitations due, notably, to the presence of repeated sequences or of multiple haplotypes within one genome, thus leaving many assemblies incomplete. Recently, the realization that the physical contacts experienced by a portion of a DNA molecule could be used as a robust and quantitative assay to determine its genomic position has led to the emerging field of contact genomics, which promises to revolutionize current genome assembly approaches by exploiting the flexible polymer properties of chromosomes. Here we review the current applications of contact genomics to genome scaffolding, haplotyping and metagenomic assembly, then outline the future developments we envision. PMID- 25935415 TI - Unusual structures of TTTA repeats in icaC gene of Staphylococcus aureus. AB - One and two TTTA repeat expansions have been found in the coding region of icaC gene of Staphylococcus aureus variants which influence the expression of IcaC protein and alter the phenotype. Yet, the mechanism of these small-size TTTA repeat expansions remains unclear. In this study, we performed high-resolution nuclear magnetic resonance spectroscopic studies on TTTA repeats. Our results show that a DNA sequence containing three TTTA repeats can fold into dumbbell structures with a 3' or 5'-overhang. Exchange of these dumbbells makes the sequence behave like a 2-nt TT mini-loop at 25 degrees C. The occurrence of these mini-loop and dumbbell structures in the nascent strand during DNA replication provides possible mechanistic pathways which account for one and two repeat expansions. PMID- 25935416 TI - Biosensor-based affinities and binding kinetics of small molecule antagonists to the adenosine A(2A) receptor reconstituted in HDL like particles. AB - The options for investigating solubilised G protein-coupled receptors (GPCRs) by biophysical techniques have long been hampered by their instability. A thermostabilised adenosine A2A receptor expressed in insect cells, purified in detergent and reconstituted into high-density lipoprotein (HDL) particles was immobilised onto a Surface Plasmon Resonance sensor chip. This allowed measurement of affinities and kinetics for A2A antagonists with affinities ranging from 50 pM to almost 2 MUM. Compared with other formats, reproduction of affinities, and dissociation and association rate constants are good, reasonable and poor respectively, indicating stabilised receptors in HDL particles are useful for investigating specific aspects of GPCR-ligand interactions. PMID- 25935417 TI - Differential regulation of Connexin50 and Connexin46 by PI3K signaling. AB - Gap junction channels can modify their activity in response to cell signaling pathways. Here, we demonstrate that Connexin50 (Cx50) coupling, but not Connexin46 (Cx46), increased when co-expressed with a constitutively active p110alpha subunit of PI3K in Xenopus oocytes. In addition, inhibition of PI3K signaling by blocking p110alpha, or Akt, significantly decreased gap junctional conductance in Cx50 transfected HeLa cells, with no effect on Cx46. Alterations in coupling levels were not a result of reduced Cx50 unitary conductance, suggesting that changes in the number of active channels were responsible. These data indicate that Cx50 is specifically regulated by the PI3K signaling pathway. PMID- 25935418 TI - MS in South Asians in England: early disease onset and novel pattern of myelin autoimmunity. AB - BACKGROUND: Epidemiological studies describe a latitude gradient for increased MS prevalence and a preponderance of disease in Caucasian individuals. However, individuals from other ethnic backgrounds and low-risk regions can acquire a raised risk through migration. Nearly a fifth of the London population is of Asian/Asian-British origin and a significant proportion of referrals are from this group. METHODS: We investigated whether there were differences in timing, presentation, severity, and immunology of disease (with respect to CD4 myelin epitope recognition) between individuals in London with MS who were either of S. Asian or Caucasian origin. Individuals of S. Asian origin with MS were compared with healthy S. Asian controls, individuals with MS and of Caucasian origin and Caucasian controls. RESULTS: Age at MS onset is significantly lower in the S. Asian group, attributable to earlier onset specifically in UK-born individuals, though clinical presentation is similar. Analysis of CD4 autoimmunity to myelin antigens shows disease in S. Asian individuals to encompass recognition of novel epitopes; immunity to MBP116-130 in S. Asian individuals was highly disease specific. CONCLUSIONS: These findings emphasize the need to define disease profiles across ethnicities and identify environmental triggers conferring acquired risk. Such findings must inform choices for immunotherapeutic interventions suitable for all, across ethnicities. PMID- 25935419 TI - A novel water-soluble benzothiazole derivative BD926 inhibits human activated T cell proliferation by down-regulating the STAT5 activation. AB - Immunosuppressants are widely used for treatment of T cell-mediated autoimmune diseases and allogeneic graft rejection. However, because of the toxicity and tolerance of these drugs, novel immunosuppressants are urgently needed. We synthesized a series of novel water-soluble benzothiazole derivatives and found that BD926 [sodium 2-(benzo[d]thiazol-2-yl)-4,5,6,7-tetrahydro-2H-indazol-3 olate] had potent immunosuppressive activity. Treatment with BD926 significantly inhibited anti-CD3/anti-CD28 and alloantigen-induced human T cell proliferation as well as IL2-stimulated activated T cell proliferation in a dose-dependent manner in vitro. BD926 had no obvious cytotoxicity against human resting T cells, IL-4 treated activated T cells and fibroblast-like synoviocytes in our experimental conditions. Furthermore, BD926 induced cell cycle arrest at G0/G1 phase and inhibited the cyclin D3 and CDK 6 expression in activated T cells. BD926 inhibited the STAT5, but not Akt and p70S6K, phosphorylation in a dose dependent manner in the IL-2-treated activated T cells. Interestingly, BD926 inhibited IFN-gamma, IL-6 and IL-17, but not IL-2, IL-4 and IL-10, production in activated T cells. Finally, treatment with BD926 reduced delayed-type hypersensitivity in mice in a dose-dependent manner. Collectively, these data suggest that BD926 may be a lead compound for the design and development of new immunosuppressants for the intervention of allograft rejection and autoimmune diseases. PMID- 25935420 TI - Identification of conserved drought-adaptive genes using a cross-species meta analysis approach. AB - BACKGROUND: Drought is the major environmental stress threatening crop-plant productivity worldwide. Identification of new genes and metabolic pathways involved in plant adaptation to progressive drought stress at the reproductive stage is of great interest for agricultural research. RESULTS: We developed a novel Cross-Species meta-Analysis of progressive Drought stress at the reproductive stage (CSA:Drought) to identify key drought adaptive genes and mechanisms and to test their evolutionary conservation. Empirically defined filtering criteria were used to facilitate a robust integration of 17 deposited microarray experiments (148 arrays) of Arabidopsis, rice, wheat and barley. By prioritizing consistency over intensity, our approach was able to identify 225 differentially expressed genes shared across studies and taxa. Gene ontology enrichment and pathway analyses classified the shared genes into functional categories involved predominantly in metabolic processes (e.g. amino acid and carbohydrate metabolism), regulatory function (e.g. protein degradation and transcription) and response to stimulus. We further investigated drought related cis-acting elements in the shared gene promoters, and the evolutionary conservation of shared genes. The universal nature of the identified drought adaptive genes was further validated in a fifth species, Brachypodium distachyon that was not included in the meta-analysis. qPCR analysis of 27, randomly selected, shared orthologs showed similar expression pattern as was found by the CSA:Drought.In accordance, morpho-physiological characterization of progressive drought stress, in B. distachyon, highlighted the key role of osmotic adjustment as evolutionary conserved drought-adaptive mechanism. CONCLUSIONS: Our CSA:Drought strategy highlights major drought-adaptive genes and metabolic pathways that were only partially, if at all, reported in the original studies included in the meta-analysis. These genes include a group of unclassified genes that could be involved in novel drought adaptation mechanisms. The identified shared genes can provide a useful resource for subsequent research to better understand the mechanisms involved in drought adaptation across-species and can serve as a potential set of molecular biomarkers for progressive drought experiments. PMID- 25935421 TI - Modulation of intestinal L-glutamate transport by luminal leptin. AB - Leptin is secreted into the digestive tract and contributes to the absorption of dietary molecules by regulating transporters activity. Here, we studied the effect of luminal leptin on the intestinal transport of L-glutamate, an important component of human diet. We examined the effect of leptin on L-glutamate uptake in rat intestine in vitro measuring glutamate-induced short-circuit current (Isc) in Ussing chambers and L-[(3)H (U)]-glutamate uptake in jejunal everted rings. Glutamate-induced Isc was only observed in Na(+)-free conditions. This Isc was concentration (1-60 mmol L(-1)) and pH dependent. Luminal leptin increased glutamate Isc (~100 %). Dose-response curve showed a biphasic pattern, with maximal stimulations observed at 10(-13) and 10(-10) mmol L(-1), that were sensitive to leptin receptor antagonist. In everted rings, two glutamate transport mechanisms were distinguished: a Na(+)-dependent, H(+)-independent, that was inhibited by leptin (~20 %), and a Na(+)-independent but H(+)-dependent, that was enhanced by leptin (~20 %), in line with data obtained in Ussing chambers. Altogether, these data reveal original non-monotonic effect of luminal leptin in the intestine and demonstrate a new role for this hormone in the modulation of L-glutamate transport, showing that luminal active gut peptides can influence absorption of amino acids. PMID- 25935422 TI - The effect of co-administration of intravenous calcium chloride and oxytocin on maternal hemodynamics and uterine tone following cesarean delivery: a double blinded, randomized, placebo-controlled trial. AB - BACKGROUND: Oxytocin administration to prevent uterine atony following cesarean delivery is associated with adverse effects including hypotension, tachycardia, and nausea. Calcium chloride increases mean arterial pressure, systemic vascular resistance, and uterine smooth muscle contractility. This study evaluated whether the co-administration of calcium chloride with oxytocin following cesarean delivery could alter maternal hemodynamics. Secondary outcomes included uterine tone and blood loss. METHODS: Sixty healthy parturients with singleton, term, vertex pregnancies undergoing elective cesarean delivery under spinal anesthesia were randomized to one of three study solutions given intravenously immediately after umbilical cord clamping: (1) placebo, oxytocin 5U alone; (2) CA-200, oxytocin 5U+calcium chloride 200mg; or (3) CA-400, oxytocin 5U+calcium chloride 400mg. Blood pressure, heart rate, uterine tone, vasopressor or alternate uterotonic use and the incidence of nausea or vomiting were recorded. Baseline and intraoperative plasma concentration of ionized calcium and hematocrit were measured. RESULTS: Plasma concentration of ionized calcium was elevated in both study groups compared with placebo (P=0.001). Blood pressure decreased and heart rate increased in all groups (P <0.0001), with no differences between groups. No differences were observed between groups in uterine tone, vasopressor use, hematocrit change, estimated blood loss, incision-to-delivery interval, delivery to-skin closure interval, total intravenous fluid administered or incidence of nausea. CONCLUSIONS: The decrease in blood pressure associated with oxytocin administration following cesarean delivery was not attenuated with co administration of calcium chloride at the doses evaluated. Vasopressor use, uterine tone, and blood loss were also unaffected. PMID- 25935423 TI - Re: Admission interview scores are associated with clinical performance in an undergraduate physiotherapy course: an observational study. PMID- 25935424 TI - Using Behavioral Risk Factor Surveillance System Data to Estimate the Percentage of the Population Meeting US Department of Agriculture Food Patterns Fruit and Vegetable Intake Recommendations. AB - Most Americans do not eat enough fruits and vegetables with significant variation by state. State-level self-reported frequency of fruit and vegetable consumption is available from the Centers for Disease Control and Prevention's Behavioral Risk Factor Surveillance System (BRFSS). However, BRFSS cannot be used to directly compare states' progress toward national goals because of incongruence in units used to measure intake and because distributions from frequency data are not reflective of usual intake. To help states track progress, we developed scoring algorithms from external data and applied them to BRFSS 2011 data to estimate the percentage of each state's adult population meeting US Department of Agriculture Food Patterns fruit and vegetable intake recommendations. We used 24 hour dietary recall data from the National Health and Nutrition Examination Survey, 2007-2010, to fit sex- and age-specific models that estimate probabilities of meeting recommendations as functions of reported consumption frequency, race/ethnicity, and poverty-income ratio adjusting for intraindividual variation. Regression parameters derived from these models were applied to BRFSS to estimate the percentage meeting recommendations. We estimate that 7%-18% of state populations met fruit recommendations and 5%-12% met vegetable recommendations. Our method provides a new tool for states to track progress toward meeting dietary recommendations. PMID- 25935425 TI - Traumatic brain injury, driver aggression and motor vehicle collisions in Canadian adults. AB - OBJECTIVE: This study examines the associations between lifetime traumatic brain injury (TBI), driver aggression, and motor vehicle collisions among a population sample of adults who reside in the province of Ontario, Canada. METHOD: A cross sectional sample of 3993 Ontario adults, aged 18-97 were surveyed by telephone in 2011 and 2012 as part of Center for Addiction and Mental Health's ongoing representative survey of adult mental health and substance use in Canada. TBI was defined as trauma to the head that resulted in loss of consciousness for at least five minutes or overnight hospitalization. RESULTS: An estimated 91% (95% CI: 90.0, 91.9) of individuals in this sample held a valid Ontario driver's license at the time of testing. Among those, 16.7% reported a history of lifetime TBI and 83.3% reported no TBI. The prevalence of TBI was higher among men than women. Relative to licensed adults without TBI, adults with a history of TBI had significantly higher odds of engaging in serious driver aggression in the past 12 months, such as making threats to hurt another driver, passenger or their vehicle (AOR=4.39). These individuals also reported significantly higher odds (AOR=1.74) of being involved in a motor vehicle collision that resulted in hurting themselves, their passenger(s) or their vehicle. CONCLUSION: This is the first population-based study to demonstrate a relationship between a history of TBI and higher rates of serious driver aggression and collision involvement. Given the large proportion of adult drivers with a history of TBI, these individuals may account for a disproportion burden of all traffic safety problems. Whether the increased road safety risk of adults with a history of TBI is reflective of neurocognitive deficits or is merely evidence of a cluster of unsafe activities produced by a higher risk lifestyles requires further research attention. PMID- 25935426 TI - Analyzing pedestrian crash injury severity at signalized and non-signalized locations. AB - This study identifies and compares the significant factors affecting pedestrian crash injury severity at signalized and unsignalized intersections. The factors explored include geometric predictors (e.g., presence and type of crosswalk and presence of pedestrian refuge area), traffic predictors (e.g., annual average daily traffic (AADT), speed limit, and percentage of trucks), road user variables (e.g., pedestrian age and pedestrian maneuver before crash), environmental predictors (e.g., weather and lighting conditions), and vehicle-related predictors (e.g., vehicle type). The analysis was conducted using the mixed logit model, which allows the parameter estimates to randomly vary across the observations. The study used three years of pedestrian crash data from Florida. Police reports were reviewed in detail to have a better understanding of how each pedestrian crash occurred. Additionally, information that is unavailable in the crash records, such as at-fault road user and pedestrian maneuver, was collected. At signalized intersections, higher AADT, speed limit, and percentage of trucks; very old pedestrians; at-fault pedestrians; rainy weather; and dark lighting condition were associated with higher pedestrian severity risk. For example, a one-percent higher truck percentage increases the probability of severe injuries by 1.37%. A one-mile-per-hour higher speed limit increases the probability of severe injuries by 1.22%. At unsignalized intersections, pedestrian walking along roadway, middle and very old pedestrians, at-fault pedestrians, vans, dark lighting condition, and higher speed limit were associated with higher pedestrian severity risk. On the other hand, standard crosswalks were associated with 1.36% reduction in pedestrian severe injuries. Several countermeasures to reduce pedestrian injury severity are recommended. PMID- 25935427 TI - Effectiveness of low speed autonomous emergency braking in real-world rear-end crashes. AB - This study set out to evaluate the effectiveness of low speed autonomous emergency braking (AEB) technology in current model passenger vehicles, based on real-world crash experience. The validating vehicle safety through meta-analysis (VVSMA) group comprising a collaboration of government, industry consumer organisations and researchers, pooled data from a number of countries using a standard analysis format and the established MUND approach. Induced exposure methods were adopted to control for any extraneous effects. The findings showed a 38 percent overall reduction in rear-end crashes for vehicles fitted with AEB compared to a comparison sample of similar vehicles. There was no statistical evidence of any difference in effect between urban (<=60 km/h) and rural (>60 km/h) speed zones. Areas requiring further research were identified and widespread fitment through the vehicle fleet is recommended. PMID- 25935428 TI - Demographic profile, clinical features and outcome of peripheral ulcerative keratitis: a prospective study. AB - PURPOSE: To evaluate aetiology, demographic profile, clinical features and outcomes in cases of peripheral ulcerative keratitis (PUK). METHODS: Seventy-six eyes of 65 consecutive patients with PUK were evaluated in this prospective interventional study over an 18 month period, which were followed for 3 years. The main outcome measures were sociodemographic profile, aetiology, clinical features, management strategies and outcome. RESULTS: Sixty per cent (39/65) of cases were men and mean age was 45.5 +/- 17.9 years. Two-thirds (43/65) of the patients were from rural areas with majority (48/65) belonging to low socioeconomic status. Unilateral disease was present in 83% of patients (54/65) with nasal involvement in 60.5% (46/76) cases. The most common aetiology was Mooren's ulcer (31.5% cases (24/76 eyes)) followed by infection and systemic collagen vascular disease. Meibomian gland dysfunction (17/76: 22.3%) was the most common extraocular association and complicated cataract (12/76:15.7%) was the most common intraocular abnormality. In mild and moderate cases, no significant visual improvement was observed (p = 0.085 and p = 0.156) as compared with the pretreatment status. Surgical treatment was successful in maintaining anatomical integrity in 83.3% (30/36) eyes. Recurrence of the disease was seen in one eye in moderate disease and three eyes in severe disease. CONCLUSIONS: Mooren's ulcer followed by collagen vascular diseases and infection are important causes of PUK in developing countries. Surgical intervention in perforated cases had good anatomical success and visual prognosis. PMID- 25935429 TI - Clinical efficacy and immunological changes subjacent to egg oral immunotherapy. AB - BACKGROUND: Evidence of the efficacy of food oral immunotherapy (OIT) is not robust enough to change clinical practice from current standard management. Furthermore, the immunologic changes underlying food desensitization are unknown. OBJECTIVE: To establish the immunologic basal status and differences between an egg-allergic group of children and a population of nonallergic children and to investigate the safety and efficacy of a specific egg OIT protocol to induce clinical desensitization and the associated immune responses. METHODS: Children with or without egg allergy were recruited. Allergic subjects underwent an OIT protocol based on weekly doses of egg protein and a maintenance phase. Immune profile and changes in all subjects were investigated by measuring T-helper cells types 1 and 2 (TH1 and TH2) and T-regulatory cytokines and transcription factors and egg-specific IgE and IgG4 levels. RESULTS: At baseline, a significantly lower production of ovalbumin-specific interleukin (IL)-10 and tumor necrosis factor alpha and a trend toward higher IL-5 and IL-13 were found in allergic children. The egg OIT protocol enabled 60% of them to ingest 32 mL of egg white. Significant increases in egg-specific IgG4 levels and IL-10 production, with a trend toward lower IL-5 and IL-13 and higher tumor necrosis factor-alpha and interferon-gamma levels, and significant decreases in egg-specific IgE concentration were observed. CONCLUSION: Egg-allergic individuals display a bias toward TH2 type cytokine production and decreased TH1 and IL-10 responses compared with nonallergic individuals. The OIT protocol was safe and effective in inducing egg desensitization, leading to a shift in the immune profile of allergic individuals toward a nonallergic phenotype. PMID- 25935430 TI - Anaphylaxis after application of topical bacitracin-neomycin powder. PMID- 25935431 TI - Anaphylaxis induced by Goji berries. PMID- 25935432 TI - Association between asthma self-management knowledge and asthma control in the elderly. AB - BACKGROUND: Considerable evidence points to the importance of patient education in achieving better asthma control. However, little is known about the effect of older adults' asthma knowledge on asthma control. OBJECTIVE: To identify the relation between asthma self-management knowledge and short-term asthma control in older adults. METHODS: The study included 82 patients with asthma undergoing usual asthma care who were interviewed by the same trained allergist. At the same time, the authors conducted an asthma knowledge questionnaire, an Asthma Control Test, skin prick testing, spirometry, and evaluation of inhaler device technique. The Turkish version of the asthma knowledge questionnaire was administered to all participants in face-to-face interviews. The relation between asthma knowledge and asthma control was tested by regression analysis. RESULTS: The education level was below the secondary level in 79% of patients; 59% of patients were obese; and 44% of patients had mild, 41% had moderate, and 5% had severe persistent asthma. The atopy rate was 21%. The most common sensitization was to Dermatophagoides pteronyssinus. Fifty-two percent of patients had uncontrolled asthma; 22 patients showed proper use of the inhaler device. Forty patients (48%) had limited asthma knowledge. The main source of asthma knowledge was from physicians for 81% of patients. There was no significant association between patients' asthma knowledge and asthma control level (P = .991). CONCLUSION: Knowledge of asthma was very low in elderly patients and usual asthma care was largely insufficient. These findings suggest that asthma education programs should be developed for older adults based on their education level and clinical asthma characteristics. PMID- 25935433 TI - Acute exercise is associated with reduced exhaled nitric oxide in physically inactive adults with asthma. AB - BACKGROUND: Although exercise has multiple health benefits, relatively little attention has been paid to its potential therapeutic effects in those with asthma. OBJECTIVE: To examine the effects of acute exercise on inflammation in physically inactive and active adults with asthma. METHODS: Fourteen adults with asthma (n = 6 physically inactive, n = 8 physically active) completed (1) 30 minutes of moderate-intensity exercise on a treadmill and (2) 30 minutes of rest in random order, with 4 weeks between sessions. Exhaled nitric oxide (eNO) was measured before and after the intervention (0, 0.5, 1, 2, 4, and 24 hours). Blood inflammatory mediators were measured before and after the intervention (0, 2, and 24 hours). RESULTS: Physically inactive participants had a significant decrease in eNO 4 hours after exercise (-4.8 ppb, -6.4 to -0.5 ppb, P = .028), which was not observed in physically active participants (P = .362). Interluekin-1 receptor antagonist increased in the physically inactive group 2 hours after exercise, with this increase strongly correlated with the decrease in eNO at 4 hours (R = 0.685, P = .007) and 24 hours (R = -0.659, P = .014) after exercise. Interleukin 6 was increased significantly 2 hours after exercise in physically inactive participants. Blood neutrophils and nuclear factor erythroid 2-like 2 gene expression were increased 2 hours after exercise in the overall cohort. CONCLUSION: This study demonstrates that acute moderate-intensity exercise is associated with decreased eNO in physically inactive adults with asthma and suggests that interluekin-1 receptor antagonist could have a role in mediating this effect. The attenuated response in physically active participants might be due to the sustained anti-inflammatory effects of exercise training. Future studies should investigate the impact of exercise intensity and exercise training on airway inflammation in those with asthma. TRIAL REGISTRATION: Australian New Zealand Clinical Trials Registry (http://www.anzctr.org.au), registration number ACTRN12613001014741. PMID- 25935434 TI - Factors associated with hospital admission in hereditary angioedema attacks: a multicenter prospective study. AB - BACKGROUND: Acute attacks of hereditary angioedema are characterized by recurrent localized edema. These attacks can be life threatening and are associated with substantial morbidity and mortality. OBJECTIVE: To determine factors associated with hospital admission of patients with an acute attack of hereditary angioedema presenting at the emergency department. METHODS: This was a multicenter prospective observational study of consecutive patients (January 2011 through December 2013) experiencing an acute hereditary angioedema attack and presenting at the emergency department at 1 of 4 French reference centers for bradykinin mediated angioedema. Attacks requiring hospital admission were compared with those not requiring admission. RESULTS: Of 57 attacks in 29 patients, 17 (30%) led to hospital admission. In multivariate analysis, laryngeal and facial involvements were associated with hospital admission (odds ratio 18.6, 95% confidence interval 3.9-88; odds ratio 7.7, 95% confidence interval 1.4-43.4, respectively). Self-injection of icatibant at home was associated with non admission (odds ratio 0.06, 95% confidence interval 0.01-0.61). The course was favorable in all 57 cases. No upper airway management was required. CONCLUSION: Most patients attended the emergency department because they were running out of medication and did not know that emergency treatment could be self-administered. Risk factors associated with hospital admission were laryngeal and facial involvement, whereas self-injection of icatibant was associated with a return home. PMID- 25935435 TI - Chronic lung allograft dysfunction and organ donation: Is it a problem? Response to Mohamed. PMID- 25935436 TI - Interleukin-17 receptor polymorphism predisposes to primary graft dysfunction after lung transplantation. AB - BACKGROUND: Primary graft dysfunction (PGD), with an incidence of 11% to 57%, is a major cause of morbidity and mortality within the first 30 days after lung transplantation (LTx). In this study, we postulate that recipient genetic variants in interleukin-17 and -23 receptor genes (IL-17R and IL-23R, respectively) may predispose LTx recipients to an increased risk for developing PGD. METHODS: Seven genetic variants of IL-17R and IL-23R were successfully genotyped in 431 lung transplant recipients. Our primary end-point was PGD and secondary end-points were time to extubation, intensive care unit (ICU) stay, bronchoalveolar lavage neutrophilia and serum C-reactive protein. RESULTS: The AA genotype of the rs882643 genetic variant of IL-17R was associated with higher PGD grades at 0 hour (adjusted p = 0.042), 12 hours (adjusted p = 0.013) and 48 hours (adjusted p = 0.0092) after LTx. The GG genotype of the rs2241049 genetic variant of IL-17R was associated with higher PGD grades at 48 hours (adjusted p = 0.0067) after LTx. For both genetic variants, no association was found with extubation time, ICU stay, post-operative BAL neutrophilia, serum CRP, chronic lung allograft dysfunction (CLAD) or graft loss. CONCLUSION: Both genetic variants of IL-17R (rs882643 and rs2241049) were associated with PGD. This confirms a genetic predisposition toward PGD and suggests a role of IL-17 in driving neutrophilia in PGD. PMID- 25935437 TI - The influence of expected risks on decision making for destination therapy left ventricular assist device: An MTurk survey. PMID- 25935438 TI - Incidence and clinical significance of late right heart failure during continuous flow left ventricular assist device support. AB - BACKGROUND: Right heart failure (RHF) is an unresolved issue during continuous flow left ventricular assist device (LVAD) support. Little is known about the incidence and clinical significance of late RHF during LVAD support. METHODS: Between May 2004 and December 2013, 336 patients underwent continuous-flow LVAD implantation. Of these, 293 patients (87%) discharged with isolated LVAD support were included in this study. Late RHF was defined as HF requiring re-admission and medical or surgical intervention after initial surgery. RESULTS: Late RHF occurred in 33 patients (11%) at a median of 99 days after discharge (range 19 to 1,357 days). Freedom from late RHF rates were 87%, 84% and 79% at 1, 2 and 3 years, respectively. RHF recurred in 15 patients. Three patients required right ventricular assist device insertion. Univariable Cox proportional hazards regression model showed diabetes mellitus (HR 2.05, 95% CI 1.03 to 4.06, p = 0.04), body mass index >29 (HR 2.47, 95% CI 1.24 to 4.94, p = 0.01) and blood urea nitrogen level >41 mg/dl (HR 2.19; 95% CI 1.10 to 4.36; p = 0.025) as significant predictors for late RHF. Estimated on-device survival rates at 2 years were 73% in the RHF group and 82% in the non-RHF group (p = 0.20). However, overall survival at 2 years was significantly worse in patients who developed late RHF (60% vs 85%, p = 0.016). This reduction was mostly attributed to worse overall outcomes in the bridge-to-transplant (BTT) population. CONCLUSIONS: Late RHF is common after continuous-flow LVAD implantation, but does not affect survival during LVAD support. However, it is associated with worse overall outcomes in the BTT population. PMID- 25935439 TI - Defining the impact of intraaortic balloon pump setting on ventricular assist device flow. PMID- 25935440 TI - Superficial branch of radial nerve mistaken for extensor pollicis longus tendon repair. PMID- 25935441 TI - Genomic profile of a Li-Fraumeni-like syndrome patient with a 45,X/46,XX karyotype, presenting neither mutations in TP53 nor clinical stigmata of Turner syndrome. AB - Li-Fraumeni syndrome (LFS) is a hereditary disorder that predisposes patients to several types of cancer and is associated with TP53 germline mutations. Turner syndrome (TS) is one of the most common aneuploidies in women. Patients with TS have a higher risk of developing cancer, although multiple malignant tumors are extremely rare. Herein, we describe a patient with a 45,X/46,XX karyotype with no classic phenotype of TS. She presented with a clinical diagnosis of Li-Fraumeni like syndrome (LFL), showing papillary thyroid carcinoma and fibrosarcoma of the left flank, and had no TP53 germline mutations. Genome-wide analysis of copy number variations (CNVs) was assessed in DNA from peripheral blood cells and saliva. A total of 109 rare CNVs in the blood cells, including mosaic loss of the X chromosome (76% of cells), were identified. In saliva, three rare CNVs were detected, all of them were also detected in the blood cells: loss of 8q24.11 (EXT1), gain of 16q24.3 (PRDM7 and GAS8), and the mosaic loss of the X chromosome (50% of cells). Results of conventional G-banding confirmed the 45,X/46,XX karyotype. Surprisingly, the patient presented with an apparently normal phenotype. The PRDM and GAS8 genes are potential candidates to be associated with the risk of developing cancer in this LFL/TS patient. PMID- 25935442 TI - Reliability, Agreement, and Presentation of a Reference Standard for Assessing Implanted Heart Valve Sizes by Multidetector-Row Computed Tomography. AB - The implanted prosthetic heart valve (PHV) size is vital for the evaluation of suspected PHV dysfunction and in case of reoperation or valve-in-valve transcatheter approaches. The labeled size is not always known, and discrepancies exist between manufacturers' labeled sizes and true sizes. Reproducible methods for noninvasive PHV size assessment are lacking. We determined the reliability and agreement of PHV size measurements using multidetector-row computed tomography (MDCT) and provide reference values of MDCT measurements compared with manufacturer specifications. In vitro, 15 different PHV types in available sizes (total n = 63) were imaged. In vivo, available MDCT acquisitions of patients with PHVs were retrospectively gathered in 2 centers, and 230 patients with 249 PHVs were included. Inner valve area and area-derived diameter were measured in all PHVs. For mechanical PHVs, the inner diameter was also measured. Data were analyzed using the intraclass correlation coefficient and Bland-Altman plots and related to manufacturer specifications. Measurements could be obtained for all PHV types, except the Bjork-Shiley (n = 7) because of severe valve-related artifacts hampering the image quality. Intrarater and interrater reliability was excellent for biological and mechanical PHVs (intraclass correlation coefficients >=0.903). Agreement was good for all measurements with an overall maximal mean difference (95% confidence interval) of -2.61 mm(2) (-37.9 to 32.7), -0.1 mm ( 1.1 to 1.0), and 0 mm (-0.4 to 0.3) for valve area, area-derived diameter, and inner diameter, respectively. MDCT reliably discriminated consecutive PHV sizes as labeled by the manufacturer because the absolute ranges for the measurements never overlapped. In conclusion, MDCT allows assessment of the implanted PHV size with excellent reliability and agreement and can discriminate between PHV sizes for contemporary prostheses. MDCT can be used to noninvasively identify the manufacturer-labeled PHV size. PMID- 25935443 TI - Chagas Disease in a Non-endemic Country: A Multidisciplinary Research, Bologna, Italy. AB - Global processes have brought about a substantial change in the epidemiological landscape of Chagas disease, spreading it to non-endemic areas. Italy is the second country in Europe in terms of Latin American migrants and expected infection rate. Given that scenario, the Bologna University Teaching Hospital undertaken a study aimed at providing preliminary data on the prevalence and investigating the knowledge and the subjective perceptions of Chagas disease, migration pathways and other relevant ill-health experiences. A cross-sectional study was undertaken in association with an ethnographic research. Between November 2010 and May 2013 Chagas disease testing was offered to people who attended the hospital and data were collected to investigate the broader socio demographic and cultural factors. 151 individuals were screened for anti T. cruzi antibodies; 12 of them, 10 Bolivians and 2 Argentinians, were seroreactive, resulting in an overall prevalence of 7.94 %. Both the quantitative and the qualitative analysis revealed a degree of heterogeneity in terms of knowledge and perceptions of the disease as well as of migration pathways. The results are comparable with those reported by previous studies with similar characteristics and highlight the relevance of such public health issue in a non-endemic context. Moreover, the interdisciplinary approach has greatly helped to unveil the complex social and cultural implications of Chagas disease, to explain the subjective ill health experiences, and to understand the ways in which the broader socio economic and cultural context affects an intervention and its potential for success or failure. PMID- 25935444 TI - Comment on "Decreased Tongue Pressure is Associated with Sarcopenia and Sarcopenic Dysphagia in the Elderly". PMID- 25935445 TI - Breast metastasis as the first clinical manifestation of ileal neuroendocrine tumor. A challenging diagnosis with relevant clinical implications. AB - Ileal neuroendocrine tumors are slow-growing grade 1 or, more rarely, grade 2 neuroendocrine tumors which, however, are frequently metastatic to regional lymph nodes and the liver. A few cases of ileal neuroendocrine tumors that are metastatic to the breast have also been reported in the medical literature. The knowledge of this uncommon clinical presentation is of great importance because it needs to be differentiated from primary breast carcinomas with neuroendocrine features, which represent completely different entities with a different therapeutic approach. The diagnosis of a breast metastasis from an ileal neuroendocrine tumor and its distinction from a well-differentiated primary neuroendocrine tumor of the breast is a challenging task for clinicians and pathologists. This workup is particularly difficult when the breast lesion is the first sign of malignancy. In the present paper, we describe the clinicopathological features of an ileal neuroendocrine tumor first presenting with a breast metastasis in a 50-year-old woman and we discuss the key diagnostic features for the differential diagnosis with primary well-differentiated neuroendocrine tumor of the breast. Moreover, we have reviewed the medical literature to give the reader a comprehensive overview on this topic. PMID- 25935446 TI - Epithelioid angiosarcoma of the thyroid: report of a case from an italian non alpine area and review of the literature. AB - Epithelioid angiosarcoma of the thyroid is a rare mesenchymal neoplasm, mainly described in the Alpine area. This lesion was initially considered an anaplastic carcinoma, but immunohistochemical and ultrastructural features have proven the endothelial differentiation of tumor cells. In fact, the peculiarity of this tumor concerns the expression of low-molecular weight cytokeratins by neoplastic cells of endothelial origin. We describe a case of epithelioid angiosarcoma of the thyroid occurred in a 73-year-old woman from an Italian non-Alpine area, and a review of non-Alpine primary thyroid epitheliod angiosarcoma is presented. PMID- 25935447 TI - Diagnostic value of C-reactive protein to rule out infectious complications after major abdominal surgery: a systematic review and meta-analysis. AB - PURPOSE: Infectious complications occur frequently after major abdominal surgery and have a major influence on patient outcome and hospital costs. A marker that can rule out postoperative infectious complications (PICs) could aid patient selection for safe and early hospital discharge. C-reactive protein (CRP) is a widely available, fast, and cheap marker that might be of value in detecting PIC. Present meta-analysis evaluates the diagnostic value of CRP to rule out PIC following major abdominal surgery, aiding patient selection for early discharge. METHODS: A systematic literature search of Medline, PubMed, and Cochrane was performed identifying all prospective studies evaluating the diagnostic value of CRP after abdominal surgery. Meta-analysis was performed according to the PRISMA statement. RESULTS: Twenty-two studies were included for qualitative analysis of which 16 studies were eligible for meta-analysis, representing 2215 patients. Most studies analyzed the value of CRP in colorectal surgery (eight studies). The pooled negative predictive value (NPV) improved each day after surgery up to 90% at postoperative day (POD) 3 for a pooled CRP cutoff of 159 mg/L (range 92-200). Maximum predictive values for PICs were reached on POD 5 for a pooled CRP cutoff of 114 mg/L (range 48-150): a pooled sensitivity of 86% (95% confidence interval (CI) 79-91%), specificity of 86% (95% CI 75-92%), and a positive predictive value of 64% (95% CI 49-77%). The pooled sensitivity and specificity were significantly higher on POD 5 than on other PODs (p < 0.001). CONCLUSION: Infectious complications after major abdominal surgery are very unlikely in patients with a CRP below 159 mg/L on POD 3. This can aid patient selection for safe and early hospital discharge and prevent overuse of imaging. PMID- 25935448 TI - Emergency resection versus bridge to surgery with stenting in patients with acute right-sided colonic obstruction: a systematic review focusing on mortality and morbidity rates. AB - PURPOSE: No consensus exists on the optimal treatment of acute malignant right sided colonic obstruction (RSCO). This systematic review aims to compare procedure-related mortality and morbidity rates between primary resection and stent placement as a bridge to surgery followed by elective resection for patients with acute RSCO. METHODS: PubMed, Embase and Cochrane library were searched for all relevant literature. Primary endpoints were procedure-related mortality and morbidity. Methodological quality of the included studies was assessed using the MINORS criteria. RESULTS: Fourteen cohort studies were eligible for analysis. A total of 2873 patients were included in the acute resection group and 155 patients in the stent group. Mean mortality rate for patients who underwent acute resection with primary anastomosis was 10.8% (8.1 18.5%). Overall mortality for patients initially treated with a colonic stent followed with elective resection was 0%. Major morbidity was 23.9% (9.3-35.6%) and 0.8% (0-4.8%), respectively. Both mortality and major morbidity were significantly different. In addition, stent placement shows lower rates of anastomotic leakages (0 vs 9.1%) and fewer permanent ileostomies (0 vs 1.0%). CONCLUSION: Primary resection for patients with acute RSCO seems to be associated with higher mortality and major morbidity rates than stent placement and elective resection. In addition, stent placement resulted in fewer anastomotic leakages and permanent ileostomies. However, as no high-level studies are available on the optimal treatment of RSCO and proximal stenting is considered technically challenging, future comparative studies are warranted for the development of an evidence-based clinical decision guideline. PMID- 25935449 TI - Prophylactic surgery in familial adenomatous polyposis (FAP)--a single surgeon's short- and long-term experience with hand-assisted proctocolectomy and smaller J pouches. AB - PURPOSE: Prophylactic proctocolectomy with an ileoanal neo-reservoir is the established procedure in non-attenuated familial adenomatous polyposis (FAP). Traditionally, the ileal J-pouch is created by doubling 15 cm of the terminal ileum. Pouch inlet problems are not infrequently encountered in longer pouches. On this rationale, this series reports on the functional outcome and quality of life (QoL) following standardized construction of a shorter J-pouch with a limb of 8-9 cm length. METHODS: All patients of a single-surgeon series with FAP who underwent hand-assisted laparoscopic proctocolectomy and small ileal pouch-anal anastomosis as the primary procedure between 10/2005 and 04/2010 and responded to the questionnaire were included and retrospectively analyzed. RESULTS: A total of 46 patients (78 %) out of the consecutive series who underwent operation in this period were included in the study. After a mean follow-up of 38 months, 40/46 patients (87 %) did not report any incontinence and 3 patients (6.5 %) complained about occasional nocturnal incontinence (3 failed to answer this question). The mean stool frequency per 24 h was 6.25. No significant difference was encountered between the QoL outcome of our patients versus the German normative population. Comparable results were achieved in a study analyzing the long-term results in FAP patients with a 15-cm pouch. CONCLUSIONS: Smaller, 8-9 cm J-pouches show excellent functional results both in short- and in long-term results. The hand assisted procedure was safe and no conversions were required. QoL is equal to a normative population, as it is in a series of patients with larger J-pouches. PMID- 25935451 TI - Intersphincteric infection due to an anal fissure. PMID- 25935450 TI - Prognostic value of CD45RO(+) tumor-infiltrating lymphocytes for locally advanced rectal cancer following 30 Gy/10f neoadjuvant radiotherapy. AB - AIM: This study aims to evaluate the prognostic value of CD45RO(+) tumor infiltrating lymphocytes (TILs) in locally advanced rectal cancer treated with 30 Gy/10 fraction (10 f) neoadjuvant radiotherapy. METHODS: This retrospective study involved 185 patients with locally advanced rectal cancer who underwent 30 Gy/10 f nRT (biologic equivalent dose, 30 Gy) followed by total mesorectal excision (TME) between August 2003 and October 2009. The density of CD45RO(+) TILs was assessed by immunohistochemistry using an image-analysis system and tissue microarray and was evaluated for its association with histopathologic features along with disease-free survival (DFS). RESULTS: Following neoadjuvant radiotherapy, the median density of CD45RO(+) TILs is 654/mm(2). High density of CD45RO(+) TILs was significantly associated with increased T and N downstaging effect (p = 0.006; p = 0.014), lesser-advanced T stage (p = 0.003) and TNM stage (p = 0.022). Prolonged DFS (89.0 vs. 68.1%) was also observed in CD45RO(+Hi) cases. On multivariate regression model, CD45RO(+) TILs (p = 0.026; odds ratio (OR), 0.436 (95% confidence interval (CI), 0.209-0.907)), tumor differentiation (p = 0.057; OR, 1.878 (95% CI, 0.982-3.593)), ypT stage (p = 0.066; OR, 2.383 (95% CI, 0.943-6.025)), and ypN stage (p = 0.009; OR, 2.612 (95% CI, 1.266 5.388)) were independent factors for DFS. CONCLUSION: The density of CD45RO(+) TILs cannot only predict tumor downstaging and ypTNM stage for rectal cancer following 30 Gy/10 f nRT but also promisingly predict long-term outcomes. These findings may be used to stratify patients and make alternative strategy of adjuvant treatment. PMID- 25935452 TI - Hopanoid inventory of Rhodoplanes spp. AB - Hopanoids are pentacyclic triterpenoid lipids and are important for bacterial membrane stability and functioning. These pentacyclic triterpenoids of hopane series are biomarkers for eubacteria and can be used as chemotaxonomic markers. Anoxygenic phototrophic bacteria are good producers of hopanoids, and their inventory to date is restricted to a few members. Rhodoplanes spp. are phototrophic prokaryotes which grow and thrive in subsurface and sediment environments. A study on the diversity of hopanoids of several species of Rhodoplanes revealed a rich diversity of hopanoids with carbon length of C30/C31 and C35. Hop-22(29)-ene (II), diplopterol (V), tetrahymanol (VII), 2 methyldiplopterol (VI), 2-methyltetrahymanol (VIII), bacteriohopanetetrol (IX), bacteriohopaneaminotriol (X) and bacteriohopanepolyols [BHP-492 (XIII), BHP-550 (XIV), BHP-508 (XII)] are the major hopanoids of the genus Rhodoplanes. Tetrahymanol (VII) content is high (38-60 %) among all the members, except for Rhodoplanes elegans. Hopanoid fingerprints allowed differentiation of species of the genus Rhodoplanes. Statistical analyses also indicate hopanoids as good chemotaxonomic markers to distinguish species of the genus Rhodoplanes. PMID- 25935453 TI - Membrane cholesterol plays an important role in enteropathogen adhesion and the activation of innate immunity via flagellin-TLR5 signaling. AB - Lipid rafts are cholesterol- and sphingolipid-rich ordered microdomains distributed in the plasma membrane that participates in mammalian signal transduction pathways. To determine the role of lipid rafts in mediating interactions between enteropathogens and intestinal epithelial cells, membrane cholesterol was depleted from Caco-2 and IPEC-J2 cells using methyl-beta cyclodextrin. Cholesterol depletion significantly reduced Escherichia coli and Salmonella enteritidis adhesion and invasion into intestinal epithelial cells. Complementation with exogenous cholesterol restored bacterial adhesion to basal levels. We also evaluated the role of lipid rafts in the activation of Toll-like receptor 5 signaling by bacterial flagellin. Depleting membrane cholesterol reduced the ability of purified recombinant E. coli flagellin to activate TLR5 signaling in intestinal cells. These data suggest that both membrane cholesterol and lipid rafts play important roles in enteropathogen adhesion and contribute to the activation of innate immunity via flagellin-TLR5 signaling. PMID- 25935454 TI - Dihydroartemisinin induces apoptosis preferentially via a Bim-mediated intrinsic pathway in hepatocarcinoma cells. AB - This report is designed to dissect the detail molecular mechanism by which dihydroartemisinin (DHA), a derivative of artemisinin, induces apoptosis in human hepatocellular carcinoma (HCC) cells. DHA induced a loss of the mitochondrial transmemberane potential (DeltaPsim), release of cytochrome c, activation of caspases, and externalization of phosphatidylserine indicative of apoptosis induction. Compared with the modest inhibitory effects of silencing Bax, silencing Bak largely prevented DHA-induced DeltaPsim collapse and apoptosis though DHA induced a commensurable activation of Bax and Bak, demonstrating a key role of the Bak-mediated intrinsic apoptosis pathway. DHA did not induce Bid cleavage and translocation from cytoplasm to mitochondria and had little effects on the expressions of Puma and Noxa, but did increase Bim and Bak expressions and decrease Mcl-1 expression. Furthermore, the cytotoxicity of DHA was remarkably reduced by silencing Bim, and modestly but significantly reduced by silencing Puma or Noxa. Silencing Bim or Noxa preferentially reduced DHA-induced Bak activation, while silencing Puma preferentially reduced DHA-induced Bax activation, demonstrating that Bim and to a lesser extent Noxa act as upstream mediators to trigger the Bak-mediated intrinsic apoptosis pathway. In addition, silencing Mcl-1 enhanced DHA-induced Bak activation and apoptosis. Taken together, our data demonstrate a crucial role of Bim in preferentially regulating the Bak/Mcl-1 rheostat to mediate DHA-induced apoptosis in HCC cells. PMID- 25935455 TI - Serum resistin levels in patients with rheumatoid arthritis and systemic lupus erythematosus: a meta-analysis. AB - The purpose of this meta-analysis was to investigate whether serum resistin level was associated with rheumatoid arthritis (RA) and systemic lupus erythematosus (SLE) by comparing serum resistin levels between RA or SLE patients and normal controls. PubMed and EMBASE databases (up to May 13, 2014) were used to search all related articles. The weighted mean differences (WMDs) with 95 % confidence interval (CI) were calculated using random-effect model analysis. The Cochrane Q test and I(2) statistic were used to test heterogeneity. To assess publication bias, the Egger's test and visual observation of a funnel plot were used. The Newcastle-Ottawa scale was used to assess the study quality. The STATA statistical software (version 11.0) was applied to deal with statistical data. A total of eight studies of RA including 620 patients and 460 healthy controls, and six studies of SLE including 559 patients and 430 healthy controls were finally included in the meta-analysis. The results revealed that the serum resistin levels in RA were significantly higher than those in normal controls (WMD = 0.767 ng/ml, 95 % CI = 0.114-1.419, P = 0.021), but there was no significant difference between SLE patients and normal controls (WMD = 2.771 ng/ml, 95 % CI = -0.521 6.063, P = 0.099). Publication bias was undetected. In conclusion, this meta analysis indicate that serum resistin level was significantly elevated in RA patients. PMID- 25935456 TI - Ankylosis in ankylosing spondylitis: current concepts. AB - Ankylosing spondylitis (AS) is the most common form of spondyloarthritis and is characterized by both inflammation and new bone formation. Despite many years of arduous efforts, we still do not clearly understand the pathogenesis of AS. The mechanisms behind new bone formation have been especially challenging to decipher due to the difficulty in obtaining tissue from spinal joints. The link between inflammation and bone formation looks obvious, but how inflammation drives spinal fusion is not evident. There are now two genes linked to prostaglandins (PG) that could be involved in AS pathogenesis. The first one is PTGER4 that codes for the EP4 receptor for PGE2 and the other one is PTGS1 that codes for prostaglandin endoperoxide syntase 1 or cyclogenase 1. The bone morphogenic protein and Wnt signaling pathways could be important in signaling increased bone formation in AS. The disease-modifying potential of anti-inflammatories and tumor necrosis factor alpha inhibitors is discussed. PMID- 25935457 TI - A chance to cut is not always a chance to cure- fasciotomy in the treatment of rattlesnake envenomation: A retrospective poison center study. AB - BACKGROUND: Fasciotomy has been described in the treatment of rattlesnake envenomation. We sought to compare the characteristics of patients undergoing fasciotomy with those where fasciotomy was discussed but not performed. METHODS: A retrospective case-series constructed from a single-statewide-poison-system electronic database for cases of fasciotomy discussion or completion in rattlesnake-envenomation between January 2001 and May 2012. Age, gender, bite location, antivenom administered, compartment pressure measurements, Snakebite Severity Score (SSS) and length of hospitalization (LOS) were recorded. Comparisons were made between fasciotomy completed and where fasciotomy was only discussed. RESULTS: One-hundred-five cases of fasciotomy discussion or completion were identified. Fasciotomy was performed in 28 cases (27%). There was no statistically significant difference (p > 0.05) between groups in age, gender, bite site, SSS, and total number of vials of antivenom administered. Only 2 of 28 (7%) had compartment pressure measurements. Patients undergoing fasciotomy spent an additional 2 days in the hospital. CONCLUSIONS: Fasciotomies continue to take place, without compartment pressure measurements, and without repeat dosing of antivenom. In the absence of clear objective evidence that limb-threatening compartment syndrome occurs despite adequate antivenom administration, fasciotomy does not favorably impact morbidity and may be associated with increased costs for care following rattlesnake envenomation. PMID- 25935458 TI - Comparison of total protein and enzyme levels in successive regenerations of venom from individual coralsnakes. AB - Coralsnakes produce highly potent neurotoxic venoms, but little is known about variations in specific enzyme components within a species or from one replenishment of venom to the next within the same animal. Since published studies are often conducted using venom pools from multiple snakes, individual differences are masked and variations among individual snakes and between subsequent venom regenerations from the same snake have rarely been documented. This study involves the analysis and comparison of four successive venom collections from each of nine individual coralsnakes in order to detect these differences. Significant variation was found within the successive re-synthesis of venom components. Even greater differences were observed between the venoms from similar individual snakes. Since studies of variation in enzymatic activity would be significant only if they were above these normal variations, it is important to be aware of these differences. These results suggest the importance of understanding the variations present within and between individuals of the same species when interpreting the potential significance of differences found as the result of genetic, environmental or ecological factors. PMID- 25935459 TI - Incidental imaging finding of chest wall mass. PMID- 25935461 TI - The bidirectional impact of perceived and enacted support on mood in bipolar outpatients: A two-year prospective study. AB - Bipolar disorder (BD) is a chronic illness, and a great need has been expressed to elucidate factors affecting the course of the disease. Social support is one of the psychosocial factors that is assumed to play an important role in the course of BD, but it is largely unknown whether the depressive and/or manic symptoms also affect the patients' support system. Further, the perception of one's social support appears to have stronger effects on disease outcomes than one's enacted or received support, but whether this also applies to BD has not been investigated. The objective of this study is to examine temporal, bidirectional associations between mood states (depression and mania) and both enacted and perceived support in BD patients. The current study was conducted among 173 BD I and II outpatients, with overall light to mild mood symptoms. Severity of mood symptoms and social support (enacted as well as perceived) were assessed every 3months, for 2years (1146 data points). Multilevel regression analyses (linear mixed-models) showed that lower perceived support during 3months was associated with subsequent higher levels of depressive, but not of manic symptoms in the following 3months. Vice versa, depressive symptoms during 3months were associated with less perceived support in the following 3months. Further, manic symptoms during 3months were associated with less enacted support in the subsequent 3 months. The current study suggests that perceived, but not enacted, support is consistently related to depressive symptoms in a bidirectional way, while mania is specifically associated with a subsequent loss of enacted support. Clinical implications of the current findings are discussed. PMID- 25935460 TI - Workplace bullying and sickness presenteeism: cross-sectional and prospective associations in a 2-year follow-up study. AB - PURPOSE: The aim of this study was to investigate exposure to workplace bullying as a potential risk factor for sickness presenteeism (SP), i.e. working while ill. METHODS: This study is based on data collected through self-reported questionnaires in a 2-year prospective study on employees in Denmark. At baseline, 3363 employees (45.7 % response rate) answered to a questionnaire on their psychosocial work environment and health status. After 2 years, 1664 of the respondents also completed a follow-up questionnaire (49.5 % of the total baseline respondents). After excluding participants with missing values, the final samples were composed of 2865 and 1331 participants in the cross-sectional and prospective analyses, respectively. RESULTS: Modified poisson regression analyses showed that frequent (i.e. daily or weekly) exposure to workplace bullying was associated with reporting 8 or more days of SP in the preceding year in both the cross-sectional and the prospective analysis, also when controlling for several confounders including health-related variables. However, the prospective relationship became non-significant after adjustment for baseline SP. CONCLUSION: This study provides indications of a significant relationship between exposure to frequent workplace bullying and SP, although causal connections could not be established. Methodological and theoretical considerations about study findings are provided, which could be of benefit to future studies examining the impact of being a target of workplace bullying on SP. PMID- 25935462 TI - Low self-compassion in patients with bipolar disorder. AB - BACKGROUND: Emerging research suggests that low self-compassion may be linked to psychopathology and in particular depressive symptoms. To further elucidate this topic, the present study investigated self-compassion in patients with Bipolar Disorder (BD). METHOD: Thirty remitted BD patients were compared to thirty age- and sex matched controls on the Self-Compassion Scale (SCS). The BD patients also completed the Altman Self-Rating Mania Scale (ASRM), the Major Depression Inventory (MDI), the Work and Social Adjustment Scale (WSAS), the Satisfaction With Life Scale (SWLS) and the Internalized Stigma of Mental Illness Scale (ISMI 10) and further reported their illness history on a survey sheet. RESULTS: The BD patients were found to have significantly lower self-compassion than controls. In addition, self-compassion correlated positively and significantly with life satisfaction but no significant correlations with functional impairment, internalized stigma or frequency of past affective episodes were found. LIMITATIONS: The small sample size entailed reduced statistical power. CONCLUSIONS: By suggesting that self-compassion is reduced and possibly linked to life-satisfaction in BD, the findings highlight a potential vulnerability meriting further investigations. PMID- 25935463 TI - Experience with headwear influences the other-race effect in 4-year-old children. AB - The other-race effect (ORE) implies the better recognition of faces of one's own race compared with faces of a different race. It demonstrates that face recognition is shaped by daily experience with human faces. Such experience mainly includes structural information of own-race faces and also information on the way faces are usually seen, as a whole or partly covered by scarves or other headwear. In two experiments, we investigated how this mode of presentation is related to the occurrence of the ORE during childhood. In Experiment 1, 4-year old German children (N = 104), accustomed to seeing faces without headwear in daily life, were asked to recognize female Caucasian or African faces, presented either as a whole or wearing a woolen hat, in a forced choice paradigm. In Experiment 2, 4-year-olds from rural Cameroon (N = 70), accustomed to seeing faces with and without headwear in daily life, participated in the same task. In both groups, the ORE was present in the familiar mode of presentation, that is, in whole faces in German children and in whole and partly covered faces in Cameroonian children. The results are discussed in relation to the role of experience for face recognition processes. PMID- 25935464 TI - Management of anticoagulation in patients with acute gastrointestinal bleeding. AB - Acute gastrointestinal bleeding represents the most common adverse event associated with the use of oral anticoagulant therapy. Due to increasing prescription of anticoagulants worldwide, gastroenterologists are more and more called to deal with bleeding patients taking these medications. Their management is challenging because several issues have to be taken into account, such as the severity of bleeding, the intensity of anticoagulation, the patient's thrombotic risk and endoscopy findings. The recent introduction into the marketplace of new direct oral anticoagulants, for whom specific reversal agents are still lacking, further contributes to make the decision-making process even more demanding. Available evidence on this topic is limited and practice guidelines by gastroenterology societies only marginally address key issues for clinicians, including when and how to reverse coagulopathy, the optimal timing of endoscopy and when and how to resume anticoagulation thereafter. The present paper reviews the evidence in the literature and provides practical algorithms to support clinicians in the management of patients on anticoagulants who present with acute gastrointestinal bleeding. PMID- 25935465 TI - Treatment of peritoneal carcinomatosis with intraperitoneal administration of Ad hARF. AB - BACKGROUND: Peritoneal dissemination of cancer is a terminal condition with limited therapeutic options. Because the peritoneal cavity is a single enclosed space, regional treatment approaches for isolated peritoneal cancrinomatosis are appealing. There is a potential role for gene therapy in the management of peritoneal cancrinomatosis. MATERIALS AND METHODS: An adenoviral construct of the human p14ARF gene (a tumor suppressor) and a 22 amino acid sequence of the ARF gene product, which has cell membrane penetrating properties, were assayed for proapoptotic properties in a human colorectal cancer cell line (Clone A) cells in vitro. Peritoneal carcinomatosis derived from Clone A cells was also established in nude mice and then treated with intraperitoneal administration of an adenoviral construct of the human p14ARF gene. RESULTS: Treatment of ARF-negative Clone A cells with Ad-hARF in vitro reestablished ARF function. However, the cell penetrating ARF-related peptide did not restore ARF function in Clone A cells. Treatment of Clone A peritoneal xenografts with a single intraperitoneal dose of Ad-hARF (9 * 10(6) viral particles) suppressed the progression of peritoneal disease. Weekly (six times) administration of the Ad-hARF at a lower dose (3 * 10(6) viral particles) also suppressed tumor progression. CONCLUSIONS: Treatment of peritoneal carcinomatosis by intraperitoneal administration of adenoviral constructs of inactivated tumor suppressor genes may be a feasible clinical approach, and ARF may represent a suitable molecular target for tumors where the ARF gene is inactivated. PMID- 25935466 TI - Revisiting outcomes of right congenital diaphragmatic hernia. AB - BACKGROUND: Studies comparing outcomes of right- and left-sided congenital diaphragmatic hernia (R-CDH and L-CDH) have yielded conflicting results. We hypothesized that R-CDH is associated with higher short-term pulmonary morbidity than L-CDH. METHODS: We reviewed all CDH patients at a tertiary children's hospital over 10 y. In prenatally diagnosed CDH, the observed-to-expected total fetal lung volume and percentage liver herniation (%LH) were calculated using fetal magnetic resonance imaging-based measurements. Outcomes were compared in patients with isolated CDH. Patients were subsequently matched by %LH to compare outcomes. RESULTS: Of 189 CDH patients, 37 (20.1 %) were R-CDH and 147 (79.9%) were L-CDH. Those with R-CDH were prenatally diagnosed at a significantly lower rate (40.5% versus 73.5%; P < 0.001) and later gestational age (26.5 +/- 7.7 versus 22.6 +/- 5.65 wk; P = 0.062). There was no difference in observed-to expected total fetal lung volume between those with R-CDH and L-CDH (30.2 +/- 11.1% versus 33.1 +/- 14.2%; P = 0.471). Fetuses with R-CDH had a higher %LH than those with L-CDH (37.5 +/- 14.1% versus 18.6 +/- 12.2%; P < 0.001). Patients with isolated R-CDH had a higher need for extracorporeal membrane oxygenation than L CDH (48% versus 27%; P = 0.055). There was no difference in duration of tracheal intubation, hospital stay, need for supplemental oxygen at 30-d of life or 6-mo mortality between groups. There was no difference in mortality and pulmonary morbidity when patients were matched by %LH. CONCLUSIONS: Compared to those with L-CDH, fetuses with R-CDH are less likely to be diagnosed prenatally and have a higher need for extracorporeal membrane oxygenation. The sidedness of the hernia defect was not associated with differences in short-term pulmonary morbidity in this large, contemporary single-institution experience of neonates with CDH. PMID- 25935467 TI - Adjuvant chemotherapy for the perineural invasion of colorectal cancer. AB - BACKGROUND: To evaluate the association of perineural invasion (PNI) with outcomes in patients after colorectal resection of colorectal cancer (CRC) and to assess the effect of PNI on the response to adjuvant chemotherapy. PATIENTS AND METHODS: Data were retrospectively reviewed for 178 patients with consecutive stages I-III CRC who underwent curative surgery between January 1999 and December 2004. PNI data were examined, and the overall survival (OS) and disease-free survival rates were analyzed. RESULTS: PNI was detected in 36 of 178 patients (20%) and positively correlated with lymphatic invasion (P = 0.020), venous invasion (P = 0.037), and the incidence of metastasis or recurrence (P = 0.029). Five-year disease-free survival was 46% and 68% (P < 0.001) and the 5-y OS was 64% and 80% (P < 0.001) for patients with and without PNI, respectively. In stage III CRC, multiple regression analysis identified PNI as a strong negative prognostic factor of OS; among PNI-positive patients, median OS with adjuvant chemotherapy was almost twofold higher than that without adjuvant chemotherapy (6 versus 2.8 y; P = 0.017). CONCLUSIONS: PNI was a poor predictor of survival among patients with stage III CRC, and adjuvant chemotherapy may attenuate the adverse effects of PNI on survival. PMID- 25935468 TI - Laparoscopic bowel resection for pediatric inflammatory bowel disease. AB - BACKGROUND: To compare 30-d outcomes between laparoscopic and open intestinal resection performed on pediatric patients with ulcerative colitis and Crohn disease. MATERIALS AND METHODS: We identified all proctocolectomies performed on patients with ulcerative colitis and all intestinal resections with primary anastomosis performed on patients with Crohn disease in the 2012-2013 American College of Surgeons National Surgical Quality Improvement Program Pediatric. We compared demographic, clinical, and 30-d outcome characteristics between patients who underwent an open or laparoscopic resection. RESULTS: Of the 140 patients with ulcerative colitis who underwent proctocolectomy, 103 (74%) were performed laparoscopically. Patients undergoing laparoscopic colectomy had shorter postoperative length of stay (LOS) and fewer incisional complications. On multivariate analysis, open versus laparoscopic proctocolectomy is not an independent predictor of postoperative LOS for patients with ulcerative colitis. Of the 188 patients with Crohn disease who underwent an intestinal resection, 122 (65%) underwent laparoscopic resection. In comparison with patients undergoing open resection, patients undergoing laparoscopic resection had similar rates of complications but a shorter postoperative LOS. CONCLUSIONS: For children with ulcerative colitis, laparoscopic proctocolectomy is not independently associated with a difference in postoperative LOS. In unadjusted analyses, laparoscopic bowel resections for children with Crohn disease may be associated with a shorter postoperative LOS compared with that of open procedures. Additional accrual of cases within the American College of Surgeons National Surgical Quality Improvement Program Pediatric will allow for risk-adjusted analyses of outcomes, including factors independently associated with incisional complications. PMID- 25935469 TI - Evaluating visual perception for assessing reconstructed flap health. AB - BACKGROUND: Detecting failing tissue flaps before they are clinically apparent has the potential to improve postoperative flap management and salvage rates. This study demonstrates a model to quantitatively compare clinical appearance, as recorded via digital camera, with spatial frequency domain imaging (SFDI), a noninvasive imaging technique using patterned illumination to generate images of total hemoglobin and tissue oxygen saturation (stO2). METHODS: Using a swine pedicle model in which blood flow was carefully controlled with occlusion cuffs and monitored with ultrasound probes, throughput was reduced by 25%, 50%, 75%, and 100% of baseline values in either the artery or the vein of each of the flaps. The color changes recorded by a digital camera were quantified to predict which occlusion levels were visible to the human eye. SFDI was also used to quantify the changes in physiological parameters including total hemoglobin and oxygen saturation associated with each occlusion. RESULTS: There were no statistically significant changes in color above the noticeable perception levels associated with human vision during any of the occlusion levels. However, there were statistically significant changes in total hemoglobin and stO2 levels detected at the 50%, 75%, and 100% occlusion levels for arterial and venous occlusions. CONCLUSIONS: As demonstrated by the color imaging data, visual flap changes are difficult to detect until significant occlusion has occurred. SFDI is capable of detecting changes in total hemoglobin and stO2 as a result of partial occlusions before they are perceivable, thereby potentially improving response times and salvage rates. PMID- 25935470 TI - Under fire: gun violence is not just an urban problem. AB - BACKGROUND: Gun violence continues to be a source of trauma patient morbidity and mortality annually in the United States. We sought to characterize gun violence in the combined suburban and rural county of Lancaster, PA, and compare it with gun violence results obtained in urban areas. MATERIALS AND METHODS: All gunshot wound (GSW) admissions from January 2000-December 2013 were queried from trauma registry. Patients sustaining ball bearing/ball bullet (BB) or pellet gun injury were excluded. Data collected included mortality, injury severity score (ISS), number of GSW per patient, and cost data. Linear trend tests assessed the change in mortality, patients with three or more GSWs, and patients with an ISS >=15 and ISS >=25 over the study period. Statistical significance was defined as P < 0.05. RESULTS: A total of 478 patients met our inclusion criteria. Linear trend tests revealed no significant changes in percent mortality (P = 0.973), percent of patients with three or more GSWs (P = 0.692), percent of patients with an ISS >=15 (P = 0.545), and percent of patients with an ISS >=25 (P = 0.343) over the 14-y study period. No significant change in cost per case was observed over the study period (P = 0.246); however, percent reimbursement significantly increased (P = 0.012). CONCLUSIONS: In the relatively affluent suburban and rural community of Lancaster, PA, there is a low-level pattern of gunshot violence and subsequent mortality that has not changed over time. This continuing pattern of gunshot violence speaks to the need for development of innovative preventative measures, as well as continuing efforts against gunshot violence by health care and law enforcement personnel in suburban and urban centers alike. PMID- 25935471 TI - Preliminary findings of arterial embolization with balloon-occluded and flow dependent histoacryl glue embolization in a swine model. AB - PURPOSE: To evaluate the potential usefulness of the balloon-occluded histoacryl glue embolization (B-glue) technique. MATERIALS AND METHODS: Both flow-dependent (no balloon occlusion) and B-glue techniques were used for 24 intercostal arteries of two female swine. N-butyl 2-cyanoacrylate (NBCA) was diluted with lipiodol to a 50 % solution, which was infused after occluding the arteries with microballoon catheters. The embolization range, fragmentation, reflux, adhesion, and glue particle attachment were compared between flow-dependent and B-glue techniques. RESULTS: The B-glue technique was performed in a controlled fashion resulting in successful arterial occlusion without fragmented migration of the injected glue cast. Reflux occurred less frequently with the B-glue technique and was significantly different (p = 0.039) [Corrected] from that for the flow dependent technique. Catheters were safely removed from the arterial walls, although in one instance (8.3 %), large glue particles were found to be attached to the catheter tip on removal. Conversely, the flow-dependent technique was more difficult to control and resulted in several instances of higher rates of fragmentation. CONCLUSION: The B-glue technique can efficiently control NBCA delivery with lower rates of reflux. PMID- 25935472 TI - Health-related quality of life among women in rural Bangladesh after surgical repair of obstetric fistula. AB - OBJECTIVE: To identify factors influencing health-related quality of life (QOL) among women in Bangladesh after successful surgical repair of obstetric fistula. METHODS: In 2012, a cross-sectional study was conducted of women who had undergone a successful surgical repair of an obstetric fistula at a hospital in northwest Bangladesh between June 2005 and May 2012. Sociodemographic, obstetric, and fistula-related information was collected by interview. Health-related QOL was assessed using the 36-item Short Form Health Survey (SF-36). RESULTS: A total of 113 women were included. Linear regression analysis showed that discrimination experiences negatively affected four of the eight scales of SF-36, as well as both the physical and mental component summaries (P<0.05 for all). Married status had a positive effect on four scales and the mental component summary (P<0.05 for all). Age inversely affected two scales and the physical component summary (P<0.01 for all). Internalized stigma negatively influenced two scales (P<0.05 for both). Not having living children and experiencing two or more previous stillbirths negatively influenced one scale (P<0.05 for both). CONCLUSION: Several factors influence health-related QOL after obstetric fistula repair; a comprehensive approach is needed to address these issues. PMID- 25935473 TI - Uterine rupture in Mekelle, northern Ethiopia, between 2009 and 2013. AB - OBJECTIVE: To review cases of uterine rupture at a center in northern Ethiopia. METHODS: In a retrospective chart review, data were assessed for cases of symptomatic uterine rupture treated at Ayder Referral Hospital in Mekelle between January 1, 2009, and December 31, 2013. RESULTS: In the 5-year study period, there were 5185 deliveries and 47 cases of uterine rupture, giving a rate of one case per 110 deliveries. All patients underwent laparotomy for suspected uterine rupture. Mean parity was 3.6 (range 0-8). The most common predisposing factors were cephalopelvic disproportion (35 [74%] patients), previous cesarean delivery (5 [11%)], and fetal malpresentation (4 [9%]). Hysterectomy was undertaken for 35 (74%) patients; the other 12 (26%) were treated conservatively by simple repair of the rupture. There were 44 (95%) stillbirths and 1 (2%) maternal death. CONCLUSION: Uterine rupture remains an important clinical problem in northern Ethiopia. Changes in the cultural preference for home delivery, better transport and referral systems, and improved obstetric training and hospital management of laboring women are needed. PMID- 25935474 TI - Endometriosis and associated symptoms among Nigerian women. AB - OBJECTIVE: To determine the prevalence of endometriosis and identify associated symptoms among Nigerian women. METHODS: A cross-sectional study was conducted at a center in Ibadan, Nigeria, between October 2008 and December 2010. All women aged 18-45 years scheduled for their first diagnostic laparoscopy for gynecologic indications were enrolled. Participants completed a previously validated self administered questionnaire. Endometriosis was diagnosed on the basis of visual evidence. RESULTS: Among 239 women analyzed, 115 (48.1%) had endometriotic lesions. Endometriosis was more common among women reporting dysmenorrhea and pelvic pain than among those not reporting these symptoms (20/28 [71.4%] vs 95/211 [45.0%]; P=0.009). Women who reported dysmenorrhea were significantly more likely to have endometriosis than were those without dysmenorrhea (90/171 [52.6%] vs 25/68 [36.8%]; P=0.027). The risk of endometriosis was not significantly increased in women with one pain symptom (odds ratio [OR]1.69; 95% confidence interval [CI] 0.67-4.27), but was significantly increased in women with two (OR 2.70; 95% CI 1.13-6.52) or three (OR 4.87; 95% CI 1.88-12.82) pain symptoms (chi(2)trend=15.5; P<0.001). In a multivariate logistic regression model, only pain other than dysmenorrhea or dyspareunia independently predicted endometriosis (P=0.017). CONCLUSION: Endometriosis is fairly common among Nigerian women. Efforts to increase the awareness of endometriosis among the public, researchers, and clinicians are needed. PMID- 25935475 TI - The role of obstetrics and gynecology national societies during natural disasters. AB - When a natural disaster occurs, such as an earthquake, floods, or a tsunami, the international response is quick. However, there is no organized strategy in place to address obstetric and gynecological (ob/gyn) emergencies. International organizations and national ob/gyn societies do not have an organized plan and rely on the good will of volunteers. Too often, local specialists are ignored and are not involved in the response. The massive earthquake in Haiti in 2010 exemplifies the lack of coordinated response involving national organizations following the disaster. The Society of Obstetricians and Gynaecologists of Canada (SOGC) engaged rapidly with Haitian colleagues in response to the obstetric and gynecological emergencies. An active strategy is proposed. PMID- 25935476 TI - Pregnancy outcomes after laparoscopic sleeve gastrectomy among obese patients. AB - OBJECTIVE: To analyze pregnancy outcomes after laparoscopic sleeve gastrectomy (LSG) according to body mass index (BMI) at conception and the interval between LSG and pregnancy. METHODS: In a retrospective study, data were obtained for all women who became pregnant after LSG at a center in France between December 2001 and December 2011. Frequencies of perinatal events according to BMI at conception and the interval between LSG and pregnancy were compared. RESULTS: A total of 63 pregnancies occurring in 54 patients were included, among which 52 (83%) occurred after the first postoperative year and 26 (41%) in women who remained obese. Compared with women who were no longer obese at conception, women who were still obese delivered neonates of significantly lower gestational age at birth (P=0.02) and birth weight (P=0.001). Odds of preterm delivery were also increased (odds ratio 4.37, 95% confidence interval 1.17-16.27; P=0.03). Maternal and neonatal outcomes according to the interval between LSG and pregnancy did not differ significantly. CONCLUSION: Women who remain obese following LSG are at increased risk of adverse outcomes, including low gestational age at birth, low birth weight, and preterm delivery, and should be regarded as a risk group. PMID- 25935477 TI - Clinical features of enterococcal bacteremia due to ampicillin-susceptible and ampicillin-resistant enterococci: An eight-year retrospective comparison study. AB - Enterococcus consists human bowel flora, but sometimes behave as an important nosocomial pathogen. In order to identify clinical characteristics that help discriminate between ampicillin-susceptible and ampicillin-resistant enterococcal bacteremia in advance for antimicrobial susceptibility testing, a retrospective eight-year study was carried out in patients with enterococcal bacteremia experienced in Saga University Hospital, Japan. A total of 143 patients were included in the analysis: 85 (59.4%) with bacteremia caused by ampicillin susceptible enterococci and 58 (40.6%) by ampicillin-resistant strains. Hospital acquired bacteremia was present in 79.0% (113/143) of patients. Abdominal infections, urinary tract infections, and unknown source were predominant foci for the two groups. Patients with ampicillin-resistant enterococcal bacteremia was significantly associated with hematological cancer, immunosuppressive therapy, prior use of antibiotics, and mucositis associated with febrile neutropenia. The 28-day mortality was significantly higher in ampicillin resistant enterococcal bacteremia. On multivariate analysis, independent risk factors for ampicillin-resistant enterococci were as follows: prior exposures to penicillins and carbapenems, and bacteremia related to mucositis with febrile neutropenia. These findings would assist physicians in deciding whether glycopeptide antibiotics should be included as an empiric antibiotic therapy in patients with suspected enterococcal infections and also those with persistent neutropenic fever refractory to fourth generation cephalosporin. A few cases of MALDI-TOF MS-identified Enterococcus faecium that turned out ampicillin-sensitive were also described to emphasize the importance of taking epidemiological aspects of patients into considerations when deciding initial antimicrobial treatment. PMID- 25935478 TI - The E3 ligase ube3a is required for learning in Drosophila melanogaster. AB - Angelman syndrome and autism are neurodevelopmental disorders linked to mutations and duplications of an E3 ligase called ube3a respectively. Since cognitive deficits and learning disabilities are hallmark symptoms of both these disorders, we investigated a role for dube3a in the learning ability of flies using the aversive phototaxis suppression assay. We show that down and up-regulation of dube3a are both detrimental to learning in larvae and adults. Using conditional gene expression we found that dube3a is required for normal brain development and during adulthood. Furthermore, we suggest that dube3a could be interacting with other learning and memory genes such as derailed. Along with firmly establishing dube3a as a gene that is required for learning, our work also opens avenues for further understanding the role played by this gene in brain development and behavior. PMID- 25935479 TI - Anti-HCV effect of Lentinula edodes mycelia solid culture extracts and low molecular-weight lignin. AB - Lentinula edodes mycelia solid culture extract (MSCE) contains several bioactive molecules, including some polyphenolic compounds, which exert immunomodulatory, antitumor, and hepatoprotective effects. In this study, we examined the anti hepatitis C virus (HCV) activity of MSCE and low-molecular-weight lignin (LM lignin), which is the active component responsible for the hepatoprotective effect of MSCE. Both MSCE and LM-lignin inhibited the entry of two HCV pseudovirus (HCVpv) types into Huh7.5.1 cells. LM-lignin inhibited HCVpv entry at a lower concentration than MSCE and inhibited the entry of HCV particles in cell culture (HCVcc). MSCE also inhibited HCV subgenome replication. LM-lignin had no effect on HCV replication, suggesting that MSCE contains additional active substances. We demonstrate here for the first time the anti-HCV effects of plant derived LM-lignin and MSCE. The hepatoprotective effect of LM-lignin suggests that lignin derivatives, which can be produced in abundance from existing plant resources, may be effective in the treatment of HCV-related diseases. PMID- 25935480 TI - The natural product peiminine represses colorectal carcinoma tumor growth by inducing autophagic cell death. AB - Autophagy is evolutionarily conservative in eukaryotic cells that engulf cellular long-lived proteins and organelles, and it degrades the contents through fusion with lysosomes, via which the cell acquires recycled building blocks for the synthesis of new molecules. In this study, we revealed that peiminine induces cell death and enhances autophagic flux in colorectal carcinoma HCT-116 cells. We determined that peiminine enhances the autophagic flux by repressing the phosphorylation of mTOR through inhibiting upstream signals. Knocking down ATG5 greatly reduced the peiminine-induced cell death in wild-type HCT-116 cells, while treating Bax/Bak-deficient cells with peiminine resulted in significant cell death. In summary, our discoveries demonstrated that peiminine represses colorectal carcinoma cell proliferation and cell growth by inducing autophagic cell death. PMID- 25935481 TI - Cell proliferation is a key determinant of the outcome of FOXO3a activation. AB - The FOXO family of forkhead transcription factors have a pivotal role in determining cell fate in response to oxidative stress. FOXO activity can either promote cell survival or induce cell death. Increased FOXO-mediated cell death has been implicated in the pathogenesis of degenerative diseases affecting musculoskeletal tissues. The aim of this study was to determine the conditions under which one member of the FOXO family, FOXO3a, promotes cell survival as opposed to cell death. Treatment of primary human tenocytes with 1 pM hydrogen peroxide for 18 h resulted in increased protein levels of FOXO3a. In peroxide treated cells cultured in low serum media, FOXO3a inhibited cell proliferation and protected against apoptosis. However in peroxide treated cells cultured in high serum media, cell proliferation was unchanged but level of apoptosis significantly increased. Similarly, in tenocytes transduced to over-express FOXO3a, cell proliferation was inhibited and level of apoptosis unchanged in cells cultured in low serum. However there was a robust increase in cell death in FOXO3a-expressing cells cultured in high serum. Inhibition of cell proliferation in either peroxide-treated or FOXO3a-expressing cells cultured in high serum protected against apoptosis induction. Conversely, addition of a Chk2 inhibitor to peroxide-treated or FOXO3a-expressing cells overrode the inhibitory effect of FOXO3a on cell proliferation and led to increased apoptosis in cells cultured in low serum. This study demonstrates that proliferating cells may be particularly susceptible to the apoptosis-inducing actions of FOXO3a. Inhibition of cell proliferation by FOXO3a may be a critical event in allowing the pro-survival rather than the pro-apoptotic activity of FOXO3a to prevail. PMID- 25935482 TI - The relationship between glycan structures and expression levels of an endoplasmic reticulum-resident glycoprotein, UDP-glucose: Glycoprotein glucosyltransferase 1. AB - In this article, we report a relationship between glycan structures and expression levels of a recombinant ER-resident glycoprotein, uridine 5' diphosphate-glucose: glycoprotein glucosyltransferase (UGGT1). The function of glycan structures attached to a glycoprotein is actively studied; however, the glycan structures of recombinant, and not endogenous, glycoproteins have not been examined. In this study, we indicate a relationship between the glycan structure and the level of protein expression. Expression levels were controlled utilizing a series of vectors (pFN21K, pFN22K, pFN23K, and pFN24K HaloTag CMV Flexi Vectors). Qualitative and semi-quantitative confirmation of glycan structures was achieved with tandem mass spectrometry. The results of this study indicate that glycan structures are similar to endogenous glycans at low expression levels. PMID- 25935483 TI - Transgenic over-expression of YY1 induces pathologic cardiac hypertrophy in a sex specific manner. AB - YY1 can activate or repress transcription of various genes. In cardiac myocytes in culture YY1 has been shown to regulate expression of several genes involved in myocyte pathology. YY1 can also acutely protect the heart against detrimental changes in gene expression. In this study we show that cardiac over-expression of YY1 induces pathologic cardiac hypertrophy in male mice, measured by changes in gene expression and lower ejection fraction/fractional shortening. In contrast, female animals are protected against pathologic gene expression changes and cardiac dysfunction. Furthermore, we show that YY1 regulates, in a sex-specific manner, the expression of mammalian enable (Mena), a factor that regulates cytoskeletal actin dynamics and whose expression is increased in several models of cardiac pathology, and that Mena expression in humans with heart failure is sex-dependent. Finally, we show that sex differences in YY1 expression are also observed in human heart failure. In summary, this is the first work to show that YY1 has a sex-specific effect in the regulation of cardiac pathology. PMID- 25935484 TI - Pirfenidone enhances the efficacy of combined radiation and sunitinib therapy. AB - Radiotherapy is a widely used treatment for many tumors. Combination therapy using anti-angiogenic agents and radiation has shown promise; however, these combined therapies are reported to have many limitations in clinical trials. Here, we show that radiation transformed tumor endothelial cells (ECs) to fibroblasts, resulting in reduced vascular endothelial growth factor (VEGF) response and increased Snail1, Twist1, Type I collagen, and transforming growth factor (TGF)-beta release. Irradiation of radioresistant Lewis lung carcinoma (LLC) tumors greater than 250 mm3 increased collagen levels, particularly in large tumor vessels. Furthermore, concomitant sunitinib therapy did not show a significant difference in tumor inhibition versus radiation alone. Thus, we evaluated multimodal therapy that combined pirfenidone, an inhibitor of TGF induced collagen production, with radiation and sunitinib treatment. This trimodal therapy significantly reduced tumor growth, as compared to radiation alone. Immunohistochemical analysis revealed that radiation-induced collagen deposition and tumor microvessel density were significantly reduced with trimodal therapy, as compared to radiation alone. These data suggest that combined therapy using pirfenidone may modulate the radiation-altered tumor microenvironment, thereby enhancing the efficacy of radiation therapy and concurrent chemotherapy. PMID- 25935485 TI - The structure and conformational switching of Rap1B. AB - Rap1B is a small GTPase involved in the regulation of numerous cellular processes including synaptic plasticity, one of the bases of memory. Like other members of the Ras family, the active GTP-bound form of Rap1B can bind to a large number of effector proteins and so transmit signals to downstream components of the signaling pathways. The structure of Rap1B bound only to a nucleotide has yet to be solved, but might help reveal an inactive conformation that can be stabilized by a small molecule drug. Unlike other Ras family proteins such as H-Ras and Rap2A, Rap1B crystallizes in an intermediate state when bound to a non hydrolyzable GTP analog. Comparison with H-Ras and Rap2A reveals conservative mutations relative to Rap1B, distant from the bound nucleotide, which control how readily the protein may adopt the fully activated form in the presence of GTP. High resolution crystallographic structures of mutant proteins show how these changes may influence the hydrogen bonding patterns of the key switch residues. PMID- 25935486 TI - Heat shock factor 1 prevents the reduction in thrashing due to heat shock in Caenorhabditis elegans. AB - Heat shock factor 1 (HSF-1) is activated by heat stress and induces the expression of heat shock proteins. However, the role of HSF-1 in thermotolerance remains unclear. We previously reported that heat stress reversibly reduces thrashing movement in Caenorhabditis elegans. In this study, we analyzed the function of HSF-1 on thermotolerance by monitoring thrashing movement. hsf-1 RNAi suppressed the restoration of thrashing reduced by heat stress. In contrast, hsf 1 knockdown cancelled prevention of movement reduction in insulin/IGF-1-like growth factor 1 receptor (daf-2) mutant, but didn't suppress thrashing restoration in daf-2 mutant. In addition, hsf-1 RNAi accelerated the reduction of thrashing in heat-shocked wild-type C. elegans. And, daf-16 KO didn't accelerate the reduction of thrashing by heat stress. Taken together, these results suggest that HSF-1 prevents the reduction of thrashing caused by heat shock. PMID- 25935487 TI - The poplar basic helix-loop-helix transcription factor BEE3 - Like gene affects biomass production by enhancing proliferation of xylem cells in poplar. AB - Brassinosteroids (BRs) play important roles in many aspects of plant growth and development, including regulation of vascular cambium activities and cell elongation. BR-induced BEE3 (brassinosteroid enhanced expression 3) is required for a proper BR response. Here, we identified a poplar (Populus alba * Populus glandulosa) BEE3-like gene, PagBEE3L, encoding a putative basic helix-loop-helix (bHLH)-type transcription factor. Expression of PagBEE3L was induced by brassinolide (BL). Transcripts of PagBEE3L were mainly detected in stems, with the internode having a low level of transcription and the node having a relatively higher level. The function of the PagBEE3L gene was investigated through phenotypic analyses with PagBEE3L-overexpressing (ox) transgenic lines. This work particularly focused on a potential role of PagBEE3L in stem growth and development of polar. The PagBEE3L-ox poplar showed thicker and longer stems than wild-type plants. The xylem cells from the stems of PagBEE3L-ox plants revealed remarkably enhanced proliferation, resulting in an earlier thickening growth than wild-type plants. Therefore, this work suggests that xylem development of poplar is accelerated in PagBEE3L-ox plants and PagBEE3L plays a role in stem growth by increasing the proliferation of xylem cells to promote the initial thickening growth of poplar stems. PMID- 25935488 TI - Anti-arthritis effect of a novel quinazoline derivative through inhibiting production of TNF-alpha mediated by TNF-alpha converting enzyme in murine collagen-induced arthritis model. AB - TNF-alpha is a dominant inflammatory mediator in the pathogenesis of inflammatory diseases including rheumatoid arthritis. In our research, we discovered 2-chloro N-(4-(2-morpholinoethoxy)phenyl)quinazolin-4-amine (9c) exhibited an outstanding anti-inflammatory activity on inhibiting TNF-alpha production with an IC50 of 8.86 MUM in RAW264.7 cells. Interestingly, 9c had no effect on mRNA level of TNF alpha but up-regulated the precursor of TNF-alpha (pro-TNF-alpha). Then, we studied TNF-alpha converting enzyme (TACE), which is the most important proteases responsible for the release of TNF-alpha from pro-TNF-alpha to soluble TNF-alpha. The results showed 9c reduced TACE both on the levels of mRNA and protein in a dose-dependent manner. In vivo study, collagen-induced arthritis (CIA) mice were treated by 9c orally. 9c exhibited significant anti-arthritis effect by ameliorating arthritic score, reducing inflammatory cell infiltration, protecting joints from destruction and decreasing the production of systemic TNF-alpha, IL 6, IL-1beta. The underlying mechanism of 9c on CIA was coincided with the in vitro, which was mediated by TACE. In conclusion, we discovered a novel quinazoline derivative which ameliorates arthritis through inhibiting production of TNF-alpha mediated by TACE for the first time. PMID- 25935489 TI - Drospirenone induces decidualization in human eutopic endometrial stromal cells and reduces DNA synthesis of human endometriotic stromal cells. AB - OBJECTIVE: To investigate the in vitro effect of drospirenone on human eutopic endometrial (EuSC) and ectopic endometriotic stromal cells (EcSC). DESIGN: Comparative and laboratory study. The experimental procedures were approved by the Institutional Review Board of the University of Tokyo (registration no. 0324 4). SETTING: University research laboratory. PATIENTS(S): Eight patients undergoing hysterectomy for benign gynecologic disease and 19 patients undergoing cystectomy or adnectomy for endometriosis. INTERVENTION(S): EuSC and EcSC were treated with drospirenone. MAIN OUTCOME MEASURE(S): For the analysis of decidualization of EuSC, cells were observed using microscopy, and the production of PRL was measured using enzyme immunoassay. For the analysis of DNA synthesis of EcSC, 5-bromo-2'-deoxyuridine incorporation was measured by ELISA. Cells in apoptosis were detected and measured by flow cytometry. RESULT(S): Drospirenone induced decidualization in EuSC, and the induction was negated by RU486. Drospirenone reduced DNA synthesis on EcSC, and this reduction was negated by RU486 or P receptor silencing, but not by aldosterone or mineralocorticoid receptor silencing. Drospirenone did not cause EcSC to undergo apoptosis. CONCLUSION(S): Our study demonstrates the direct effects of drospirenone: decidualization of EuSC and reduced DNA synthesis of EcSC, but it does not cause EsSC apoptosis. PMID- 25935490 TI - Risk of major congenital anomalies after assisted hatching: analysis of three year data from the national assisted reproduction registry in Japan. AB - OBJECTIVE: To assess perinatal risk of major congenital anomalies in children born after embryo transfer with assisted hatching (AH). DESIGN: Retrospective cohort study. SETTING: Not applicable. PATIENT(S): Cycles registered from 2010 to 2012 and conceived via single-embryo transfer were included for the analysis. Live births, still births after 22 weeks of gestation, and selectively terminated cases because of congenital anomalies were included. INTERVENTION(S): None. MAIN OUTCOME MEASURE(S): Major congenital anomaly. RESULT(S): AH was performed in 35,488 cycles among 72,125 included cycles (49.2%). A total of 1,046 major congenital anomalies (1.4%) were identified (1.36% in AH group vs. 1.50% in non AH group). Overall risks for major congenital anomalies were not significantly different between AH and non-AH groups adjusting for maternal age, calendar year, fetal sex, embryo stage at transfer, and status of cryopreservation. There were 1,009 cases of twins (1.5%) and 10 cases of triplets (0.015%) among all included cycles. No specific organ system demonstrated significant association between AH and non-AH groups. Subgroup analysis demonstrated no significant association between AH and non-AH groups in intracytoplasmic sperm injection cycles or in vitro fertilization in fresh cycles. Similar nonsignificant association was observed between early-cleavage or blastocyst stage at transfer in frozen-thawed cycles. CONCLUSION(S): Our results suggest that AH alone does not increase the risk of major congenital anomaly. PMID- 25935491 TI - Endocannabinoid system activation may be associated with insulin resistance in women with polycystic ovary syndrome. AB - OBJECTIVE: To assess the levels of endocannabinoids and cannabinoid receptors (CB) 1 and 2 in women with polycystic ovary syndrome (PCOS). DESIGN: Case-control study. SETTING: University teaching hospital. PATIENT(S): In total, 20 women with PCOS and 20 healthy women in a control group, who were matched for body mass index and age, were enrolled in this study. INTERVENTION(S): The homeostasis model index was used to assess insulin resistance. MAIN OUTCOME MEASURE(S): Omental adipose tissue and human peripheral blood mononuclear cells (PBMCs) from PCOS and the controls were analyzed using real-time polymerase chain reactions for the expressions of CB1 and CB2. The levels of endocannabinoids were analyzed using high-performance liquid chromatography. RESULT(S): The levels of anandamide and 2-arachidonoylglycerol, and the expression of CB1 and CB2 mRNA (messenger ribonucleic acid) in the PBMCs were significantly higher in the women with PCOS than in the women serving as controls. We found that expression of CB1, but not CB2, in adipose tissue was significantly higher in the women with, vs. without, PCOS. The expressions of CB1 mRNA and endocannabinoids showed a significant positive correlation with 2-hour glucose and insulin levels 2 hours after glucose loading in the PBMCs and adipose tissue. CONCLUSION(S): Activation of endocannabinoids and overexpression of cannabinoid receptors, especially CB1, may be associated with insulin resistance in women with PCOS. PMID- 25935492 TI - External validation of the Endometriosis Fertility Index in a French population. AB - OBJECTIVE: To show an external validation of the Endometriosis Fertility Index (EFI) and to observe cumulated pregnancy rates after infertility management combining surgery and assisted reproductive technologies (ART). DESIGN: Observational study from January 2004 to December 2012. SETTING: Tertiary-care university hospital and ART center. PATIENT(S): Four hundred twelve infertile and endometriotic patients after laparoscopic surgery. INTERVENTION(S): Surgical diagnosis and treatment followed by spontaneous fertility or ART management. MAIN OUTCOME MEASURE(S): Spontaneous pregnancy rates and cumulative (spontaneous and ART) pregnancy rates according to the EFI. RESULT(S): A significant relationship between EFI and spontaneous pregnancy rates was observed at 12 months (P=.001). The least function score and complete removal of endometriotic lesions and pelvic adhesions were significantly associated with spontaneous pregnancy (P=.006). Cumulative pregnancy rate at 18 months was 78.8%. ART benefits for pregnancy rates were higher for patients with poor EFI. CONCLUSION(S): External validation of the EFI in a French population was demonstrated. Combining surgery for endometriosis and ART led to a 78.8% pregnancy rate at 18 months after surgery. PMID- 25935493 TI - Day-3 embryo metabolomics in the spent culture media is altered in obese women undergoing in vitro fertilization. AB - OBJECTIVE: To determine whether the global metabolomic profile of the spent culture media (SCM) of day-3 embryos is different in obese and normoweight women undergoing in vitro fertilization (IVF). DESIGN: Prospective cohort analysis. SETTING: IVF clinic. PATIENT(S): Twenty-eight young, nonsmoking women with normoweight, nonsmoking male partners with mild/normal sperm factors undergoing a first IVF attempt for idiopathic infertility, tubal factor infertility, or failed ovulation induction: obese ovulatory women (n = 12); obese women with polycystic ovary syndrome (PCOS; n = 4); normoweight ovulatory women (n = 12). INTERVENTION(S): Fifty MUl of SCM collected from two day-3 embryos of each cohort. MAIN OUTCOME MEASURE(S): Metabolomic profiling via ultrahigh performance liquid chromatography coupled to mass spectrometry of SCM from a total of 56 embryos. RESULT(S): The untargeted metabolomic profile was different in obese and normoweight women. Partial least squares discriminant analysis resulted in a clear separation of samples when a total of 551 differential metabolites were considered. A prediction model was generated using the most consistent metabolites. Most of the metabolites identified were saturated fatty acids, which were detected in lower concentrations in the SCM of embryos from obese women. The metabolomic profile was similar in obese women with or without PCOS. CONCLUSION(S): The metabolomic profile in the SCM of day-3 embryos is different in normoweight and obese women. Saturated fatty acids seem to be reduced when embryos from obese patients are present. CLINICAL TRIAL REGISTRATION NUMBER: NCT01448863. PMID- 25935494 TI - Regulatory T cells, inflammation, and endoplasmic reticulum stress in women with defective endometrial receptivity. AB - OBJECTIVE: To investigate immunologic parameters and endoplasmic reticulum (ER) stress associated with unexplained infertility. DESIGN: Case-control study. SETTING: Academic center. PATIENT(S): Women with no fertility problems (FS) (n = 13), women with recurrent miscarriage (RM) (n = 15) and women with repeated in vitro fertilization failure (RIF) (n = 15). INTERVENTION(S): Endometrial biopsy and collection of peripheral blood during the midsecretory phase of menstrual cycle. MAIN OUTCOME MEASURE(S): Leptin, resistin, soluble tumor necrosis factor receptor (sTNF-R), myeloperoxidase (MPO), soluble intercellular adhesion molecule 1 (sICAM-1), and interleukin 22 (IL-22) concentration in peripheral blood, endometrial CD3(+), CD4(+), CD5(+), CD8(+), and FoxP3(+) T lymphocytes, and endometrial expression of HSPA5, a specific marker of ER stress. RESULT(S): We found an increase of proinflammatory molecules such as resistin, leptin, and IL 22 in both RM and RIF patients; sTNF-R and MPO only in RIF patients when compared with the FS women. We also found in endometria of infertile women a statistically significant increase of CD3(+), CD4(+), CD8(+) in both RM and RIF patients and CD5(+) in RM patients when compared with FS women. This was paralleled by a statistically significant reduction of infiltrating FoxP3(+) regulatory T cells. Finally, endometrial HSPA5 expression levels were statistically significantly up regulated in both RM and RIF patients. CONCLUSION(S): Women with RM and RIF showed an increase of circulating proinflammatory cytokines, altered endometrial T lymphocytes subsets, and signs of endometrial ER stress. PMID- 25935495 TI - Antral follicle count as a predictor of ovarian responsiveness in women with endometriomas or with a history of surgery for endometriomas. AB - OBJECTIVE: To evaluate the accuracy of antral follicular count (AFC) in predicting ovarian responsiveness in ovaries with endometriomas or with a past history of surgical excision of endometriomas. DESIGN: Retrospective review. SETTING: Academic hospital. PATIENT(S): Eighty-three women for a total of 166 gonads. INTERVENTION(S): None. MAIN OUTCOME MEASURE(S): Total number of developing follicles. RESULT(S): The ovaries were characterized as four groups: [1] unoperated gonads without endometriomas (n = 42, control group), [2] unoperated gonads with endometriomas (n = 46), [3] operated gonads without endometriomas (n = 55), and [4] operated gonads with endometriomas (n = 23). The analyses subsequently considered all ovaries with endometriomas (groups 2 + 4, n = 69) and all operated ovaries (groups 3 + 4, n = 78). The capacity of AFC to predict low response (<= 2 follicles) or hyperresponsiveness (>= 7 follicles) was evaluated using receiver operating characteristic curves. We used a linear regression model to calculate the adjusted B coefficients. The adjusted B coefficients in unaffected ovaries, in all ovaries with endometriomas, and in all operated ovaries were 0.55 (95% confidence interval [CI], 0.07-1.03), 0.76 (95% CI, 0.54-0.98), and 0.51 (95% CI, 0.26-0.76), respectively. The area under the curve (AUC) for the prediction of low response was 0.83 (95% CI, 0.68-0.99), 0.83 (95% CI, 0.73-0.93), and 0.74 (95% CI, 0.63-0.85), respectively. The AUC for the prediction of hyperresponse was 0.84 (95% CI, 0.70-0.97), 0.74 (95% CI, 0.63 0.85), and 0.77 (0.60-0.94), respectively. CONCLUSION(S): The accuracy of AFC for predicting ovarian response is similar in unaffected ovaries, ovaries with endometriomas and ovaries with a history of surgery for endometriomas. PMID- 25935496 TI - Impacts of PCB analytical interpretation uncertainties on dechlorination assessment and remedial decisions. AB - Laboratory analyses of polychlorinated biphenyls (PCBs) often do not quantitate the 209 individual PCB congeners, thereby requiring analyst interpretation to determine individual congener concentrations. Error introduced during this interpretation is subsequently propagated to calculated surrogate variables, such as the number of chlorines per biphenyl (CPB), and the molar dechlorination product ratio (MDPR), which are used to assess the extent of dechlorination and inform remedial decisions. The present work applies a Monte Carlo (MC) analysis to assess current methods for quantitating co-eluting congeners and the errors that could occur in individual congeners and derived CPB and MDPR estimates. Synthetic chromatograms, which were created using two alternative methods (random assignment and assignment based on relative proportions in Aroclors) for assigning mass to co-eluting congeners, were compared to their fully-quantitated counterparts. The percent error introduced in total PCB (?PCB) concentration ranges from approximately -60% to +50%. Similarly, the errors associated with CPB and MDPR estimates range from approximately -20% to +20% and -120% to +30%, respectively. Uncertainties introduced during congener analysis and propagated to surrogate variables can thus be substantial, and should be considered in assessments of the extent of dechlorination and associated remedial decisions. PMID- 25935497 TI - Suppression of dioxins in waste incinerator emissions by recirculating SO2. AB - Sulphur is an effective inhibitor of the formation of Polychlorinated dibenzo-p dioxins and polychlorinated dibenzo-furans (PCDD/Fs), as was proven in laboratory and pilot plant studies. In this study, a pilot-scale system with capacity 300 N m(3) h(-1) was situated at the bypass of an actual hazardous waste incinerator (HWI) and tested to reduce the emission of PCDD/Fs. Activated carbon was used as a medium to adsorb SO2 from flue gas and release it again at the higher temperature of filtered ash detoxification to achieve SO2 circulation in the system. Most PCDD/Fs in the filtered ash are decomposed by thermal treatment. Experimental results indicate that the system is capable of stable operation with SO2 accumulation at a high level of concentration and a high reduction efficiency of PCDD/Fs. A reduction of more than 80% was already achieved without addition of other sulphur compounds. When pyrite (FeS2) was added the reduction of PCDD/Fs could reach 94%, with a residual PCDD/Fs concentration in the flue gas as low as 0.13 ng TEQ N m(-3). This SO2 recirculating and suppression technology potentially provides significant progress for dioxin emission control in waste incineration and could be useful for controlling emissions of PCDD/Fs and other chlorinated organic chemicals in China. PMID- 25935498 TI - Polychlorinated dibenzo-p-dioxins and polychlorinated dibenzofurans (PCDD/Fs) in municipal and industrial effluents. AB - Polychlorinated dibenzo-p-dioxins and polychlorinated dibenzofurans (PCDD/Fs) were quantified in 45 effluent samples in the Houston Ship Channel (HSC) system in Texas. Total PCDD/F concentrations ranged from 0.16 to 13.23 pg L(-1) in the dissolved phase and from 0.79 to 682.27 pg L(-1) in the suspended phase. Generally, industrial facilities contained more PCDD/F contamination than municipal wastewater treatment plants or refuse facilities. World Health Organization Toxic Equivalents (WHO-TEQs) ranged from 0.007 to 0.279 pg L(-1) in the dissolved phase and 0.021-1.851 pg L(-1) in the suspended phase. The major TEQ contributor was 2,3,7,8-TCDD and overall, TEQs were greatest in industrial effluents. A correlation between high solids and high PCDD/F concentrations was observed and based on the results obtained in this study, the abundance of suspended solids may have largely contributed to high PCDD/F contamination in the suspended phase. Homolog profiles revealed that PCDD/F contamination increased with increasing chlorination and the highest concentrations were primarily from the octa-chlorinated congeners (OCDD/F) in both the dissolved and suspended phase. PMID- 25935499 TI - Hematinic deficiencies and pernicious anemia in oral mucosal disease patients with macrocytosis. AB - BACKGROUND/PURPOSE: Macrocytosis is defined as having the mean corpuscular volume (MCV) >= 100 fL. This study assessed hematinic deficiencies and pernicious anemia (PA) in oral mucosal disease patients with macrocytosis. METHODS: The blood hemoglobin (Hb), iron, vitamin B12, folic acid, and homocysteine concentrations and MCV in 60 oral mucosal disease patients with macrocytosis were measured and compared with the corresponding data in 120 age- and sex-matched healthy control participants. PA was defined by the World Health Organization (WHO) as having an Hb concentration < 13 g/dL for men and < 12 g/dL for women, an MCV >= 100 fL, a serum vitamin B12 level < 200 pg/mL, and serum gastric parietal cell antibody (GPCA) positivity. RESULTS: We found that 30 (50.0%), 7 (11.7%), 24 (40.0%), and three (5.0%) oral mucosal disease patients with macrocytosis had deficiencies of Hb (men < 13 g/dL, women < 12 g/dL), iron (< 60 MUg/dL), vitamin B12 (< 200 pg/mL), and folic acid (< 4 mg/mL), respectively. Moreover, 38 (63.3%) and 16 (26.7%) macrocytosis patients had abnormally high blood homocysteine level (> 12.3 MUM) and serum GPCA positivity, respectively. Macrocytosis patients had a significantly higher frequency of Hb, iron, or vitamin B12 deficiency, of abnormally elevated blood homocysteine level, and of GPCA positivity than healthy control participants (p < 0.001). However, only 16.7% of 60 macrocytosis patients were diagnosed as having PA by the WHO definition. CONCLUSION: Only 16.7% of oral mucosal disease patients with macrocytosis are discovered to have PA by the WHO definition. PMID- 25935500 TI - Antenatal Bartter syndrome resembling nephrogenic diabetes insipidus in a 5-year old boy. PMID- 25935501 TI - Photosensitizer and polycationic peptide-labeled streptavidin as a nano-carrier for light-controlled protein transduction. AB - Transductions of exogenous proteins into cells enable the precise study of the effect of the transduced proteins on cellular functions. Accordingly, the protein transduction technique, which can control the release of proteins into the cytosol with certainty and high-throughput, is highly desired in various research fields. In this study, streptavidin (SA) labeled with a photosensitizer and cell permeable peptides (CPP) was proposed as a nano-carrier for light-controlled protein transduction. SA was modified with biotinylated oligo-arginine peptides (Rpep), which were functionalized with Alexa Fluor 546 (AF546), to achieve cell penetrating and endosomal escape functionalities. The SA-Rpep complex was efficiently internalized into living HeLa cells corresponding to the length and the modification number of Rpep. SA conjugated with more than three equimolar AF546-modified Rpep consisting of fifteen arginine residues was achieved to diffuse throughout the cytosol without cytotoxicity by irradiation of the excitation light for AF546. The optimized nano-carrier was confirmed to transduce a biotinylated model cargo protein, enhanced green fluorescent protein fused with thioredoxin (tEGFP) into the cytosol at the light-irradiated area. The results provided proof-of-principle that SA possessing multiple AF546-modified Rpep has the potential to be a versatile and facile carrier for light-controlled protein transduction into the cytosol of mammalian cells. PMID- 25935502 TI - Evaluation of recombinant Neospora caninum antigens purified from silkworm larvae for the protection of N. caninum infection in mice. AB - Three antigens (NcSAG1, NcSRS2 and NcMIC3) from Neospora caninum were expressed using the BmNPV bacmid system in silkworm larvae and purified from the hemolymph. From 20 silkworm larvae, 1.5, 1.2 and 1.4 mg of purified recombinant NcSAG1, NcSRS2 and NcMIC3 were obtained, respectively. When each purified recombinant antigen was immunized with Freund's incomplete adjuvant (FIA) to mice, recombinant NcSAG1 induced a Th2 immune response in immunized mice and produced a SAG1-specific antibody. In the experiment where NcSAG1-immunized mice were challenged with N. caninum, the cerebral N. caninum burden was significantly reduced compared with that of either the FIA- or PBS-immunized mice. Recombinant NcSRS2 or NcMIC3 induced both Th1 and Th2 immune responses, but NcMIC3 immunization did not induce significant production of NcMIC3-specific antibodies. These results suggest that the silkworm can produce recombinant antigens of N. caninum, which can be used as a recombinant vaccine against N. caninum. PMID- 25935503 TI - Adolescent and Young Adult Preventive Care: Comparing National Survey Rates. AB - INTRODUCTION: The Affordable Care Act's preventive healthcare provisions have the potential to increase adolescents' and young adults' receipt of recommended preventive services. Assessing whether this potential is realized requires valid monitoring data in several areas, including receipt of an annual preventive visit. The purpose of this study is to describe and compare preventive visit rates across national surveys for adolescents and young adults. METHODS: This study, conducted in 2014: (1) identified national surveys with past-year preventive visit measures; (2) compared survey features, including mode of administration, respondent, response rate, demographic profile (univariate analysis), preventive visit measure wording, and method of construction; and (3) compared preventive visit rates, including rates among sociodemographic subgroups (bivariate analyses). RESULTS: Four 2011 surveys were identified: National Health Interview Survey, National Survey of Children's Health (2011-2012), and Medical Expenditure Panel Survey (MEPS) for adolescents, and MEPS and Behavioral Risk Factor Surveillance System for young adults. Surveys varied by most assessed features; demographic profiles were similar. Preventive visit rates varied significantly across adolescents (43%-81%) and young adults (26%-58%). The largest differences in visit rates were in comparisons of subjective assessments to a more detailed assessment coded from specific records of visits kept by respondents. Sociodemographic differences in visit rates were consistent across surveys. CONCLUSIONS: Further research is needed to assess reasons for the different estimates of preventive visits across national surveys. Those who monitor trends in receipt of recommended care for adolescents and young adults should take survey differences into account. Monitoring content of care is also needed. PMID- 25935504 TI - Correlation between Volume of Apical Periodontitis Determined by Cone-beam Computed Tomography Analysis and Endotoxin Levels Found in Primary Root Canal Infection. AB - INTRODUCTION: This clinical study was conducted to correlate the levels of endotoxins and bacterial counts found in primary endodontic infection with the volume of periapical bone destruction determined by cone-beam computed tomography (CBCT) analysis. Moreover, the levels of bacteria and endotoxins were correlated with the development of clinical features. METHODS: Twenty-four root canals with primary endodontic disease and apical periodontitis were selected. Clinical features such as pain on palpation, pain on percussion, and previous episode of pain were recorded. The volume (cubic millimeters) of periapical bone destruction was determined by CBCT analysis. Endotoxins and bacterial samplings were collected by using sterile/apyrogenic paper points. Endotoxins were quantified by using limulus amebocyte lysate assay (KQCL test), and bacterial count (colony forming units [CFU]/mL) was determined by using anaerobic culture techniques. Data were analyzed by Pearson correlation and multiple logistic regression (P < .05). RESULTS: Endotoxins and bacteria were detected in 100% of the root canal samples (24 of 24), with median values of 10.92 endotoxin units (EU)/mL (1.75-128 EU/mL) and 7.5 * 10(5) CFU/mL (3.20 * 10(5)-8.16 * 10(6) CFU/mL), respectively. The median volume of bone destruction determined by CBCT analysis was 100 mm(3) (10-450 mm(3)). The multiple regression analysis revealed a positive correlation between higher levels of endotoxins present in root canal infection and larger volume of bone destruction (P < .05). Moreover, higher levels of endotoxins were also correlated with the presence of previous pain (P < .05). CONCLUSIONS: Our findings revealed that the levels of endotoxins found in root canal infection are related to the volume of periapical bone destruction determined by CBCT analysis. Moreover, the levels of endotoxin are related to the presence of previous pain. PMID- 25935505 TI - Transfer factors and effective half-lives of (134)Cs and (137)Cs in different environmental sample types obtained from Northern Finland: case Fukushima accident. AB - The Fukushima NPP accident caused a small but detectable cesium fallout in northern Finland, of the order of 1 Bq/m(2). This fallout transferred further to soil, water, flora and fauna. By using modern HPGe detector systems traces of (134)Cs from the Fukushima fallout were observed in various samples of biota. In northern Finland different types of environmental samples such as reindeer meat, berries, fish, lichens and wolf were collected during 2011-2013. The observed (134)Cs concentrations varied from 0.1 Bq/kg to a few Bq/kg. By using the known (134)Cs/(137)Cs ratio observed in Fukushima fallout the increase of the Fukushima accident to the (137)Cs concentrations was found to vary from 0.06 % to 6.9 % depending on the sample type. The aggregated transfer factors (Tag) and effective half-lives (Teff) for (134)Cs and (137)Cs were also determined and then compared with known values found from earlier studies which are calculated based on the fallout from the Chernobyl accident. Generally, the Tag and Teff values determined in this study were found to agree with the values found in the earlier studies. The Teff values were sample-type specific and were found to vary from 0.91 to 2.1 years for (134)Cs and the estimates for (137)Cs ranged between 1.6 and 19 years. Interestingly, the ground lichens had the longest Teff whereas the beard lichen had the shortest. In fauna, highest Tag values were determined for wolf meat ranging between 1.0 and 2.2 m(2)/kg. In flora, the highest Tag values were determined for beard lichens, ranging from 1.9 m(2)/kg to 3.5 m(2)/kg. PMID- 25935506 TI - Perceived sources of stress among Malaysian dental students. AB - OBJECTIVE: The study objectives were to identify the stress levels and to explore the impact of students' year of study and gender on the perceived sources of stress among Malaysian dental students. METHODS: This was a cross-sectional study involving dental students from year one to year five from private and public universities in Malaysia. The study was formally approved by the Research and Ethics Committee, International Medical University Malaysia. Dental Environment Stress (DES) questionnaire was used for data collection and the gathered data were analyzed using SPSS(r) version 18. The Kruskal-Wallis and the Mann-Whitney U tests were used to compare stress items across various academic years and universities. RESULTS: A total of five hundred and twenty nine (529) students participated in this study. Fear of failing the course at the end of year exams (mean stress level=5.57); concerns regarding completion of clinical work (mean=5.30); and examination results and grades (mean=5.27) were found as top stressors among dental students. Female students had higher stress scores than males with respect to personal issues, academic performance, educational environment and learning of clinical skills. Students from public universities had higher stress scores than their counterparts from private universities. CONCLUSIONS: The Malaysian dental students reported higher levels of stress. Present study identified stressors affecting dental students' academic life, and highlights the importance of stress management programs and other measures to minimize the impact of stress on both academic and personal lives of the students. PMID- 25935507 TI - Radiation dose for normal organs by helical tomotherapy for lung cancer. AB - This study derived a simple equation of effective dose (E) versus normal organ of patients with varying body weights undergoing lung cancer treatment of helical tomotherapy (TOMO). Five tissue-equivalent and Rando phantoms were used to simulate lung cancer patients. This study then measured E and equivalent dose of organ or tissues (DT) using thermoluminescent dosimetry (TLD-100H). The TLD-100H was calibrated using TOMO 6MV photons, then inserted into phantom positions that closely corresponded with the position of the represented organs and tissues. Both E and DT were evaluated by ICRP 103. Peripheral doses varied markedly at positions close to the tumor center. The maximum statistical and total errors were 16.7-22.3%. This analytical result indicates that E of Rando and tissue equivalent phantoms was in the ranged of 9.44+/-1.70 (10kg) to 4.58+/-0.83 (90kg)mSv/Gy. Notably, E decreased exponentially as phantom weight increased. Peripheral doses were also evaluated by TLD as a function of distance from the tumor center. Finally, experimental results are compared with those in literature. These findings will prove useful to patients, physicians, radiologists, and the public. PMID- 25935508 TI - Otoscopic and audiological findings in different populations of 5-14 year-old schoolchildren in Colombia. AB - OBJECTIVE: To present the otoscopic and audiological findings of studies carried out in groups of 5-14 year old schoolchildren in diverse indigenous, White, and African descended communities in the Republic of Colombia. MATERIALS AND METHODS: The present study is descriptive and cross-sectional. We obtained a convenience sample for the analysis. We define acute otitis media (AOM), (bulging or redness); tympanic perforation (TP), (disruption of continuity in the tympanic membrane) and sequelea (scarring, myringosclerosis, retractions, secrections). Our results are described as frequencies in percentages. Audiometry was performed in every student. Readings were taken at 250, 500, 1000, 2000, 4000, and 8000 Hz for air-conduction and bone-conduction thresholds. Normal hearing is considered up to 20 dB, mild sensorineural hearing loss between 21 and 39 dB, moderate between 40 and 59 dB, severe between 60 and 89 dB and profound more than 90 dB. For conductive hearing loss the air-bone gap is measured. RESULTS: 3052 otoscopies were conducted in 1526 schoolchildren. Males predominated in each group except in the Wayuu group. Otoscopic abnormalities rates varied between 1.5% in Providencia group, up to 9.6% in the Amazon groups. No perforations were found in the Wayuu Indian schoolchildren and the highest frequency of Tympanic perforations (1.2%) and sequelaes (8.2)% in the Amazon groups. Audiometric findings were normal in 94-98% of cases. Conductive hearing loss (CHL) was found in 5.5% of Amazon groups and the lowest (1.4%) in the Wayuu groups. Slight to moderate Neurosensorial Hearing Loss (NHL) were found in 1.3% in the Arhuaca communities and moderate 0.9% in the Amazon groups. CONCLUSIONS: The present study is the first conducted in Colombia to evaluate the frequency of ear diseases and sequelae in populations of 5-14 year old children. High prevalences of sequelaes were found in the indigenous groups of the Amazon and the lowest in the Black schoolchildren on the island of Providencia. It is recommended that medical anthropological studies be conducted in these areas, and evaluation done on the probable connection between these types of diseases and processes of intercultural interaction. PMID- 25935509 TI - Speech performance in pediatric users of Nurotron (r) VenusTM cochlear implants. AB - OBJECTIVES: The primary purpose of this study was to investigate the longitudinal speech performance over 3 years in pediatric users of the Nurotron((r)) cochlear implant system. The secondary purpose was to compare the speech performances of younger and older children with cochlear implants (CIs). METHODS: The Mandarin Early Speech Perception (MESP), Meaningful Use of Speech Scale (MUSS), and Putonghua Chinese Communicative Development Inventory (PCDI) were used to evaluate speech performance of 22 Mandarin-speaking pediatric CI users throughout the first 36 months post-implantation. The subjects were grouped according to the age at implantation, i.e., younger CI group (<3 years) and older CI group (>3 years). RESULTS: All the subjects demonstrated improvement in speech performance throughout the first 3 years of implant use with mean scores reaching the maximum performance at 36 months post-implantation. The median categories of MESP increased from 0.23 pre-implantation to 5.57 three years post-implantation. Likewise, the median percentage of MUSS was 5.57% to 73.75%; the median performance of PCDI was 55 to 400 for PCDI-comprehension and 32 to 384 for PCDI production at the same interval. At nearly all test intervals, the older group performed better than the younger group except 24 months post-implantation, at which the MUSS score of the younger CI group was higher than that of the older CI group. CONCLUSION: The children with Nurotron((r)) VenusTM CI system showed considerable gains in speech and language development including tone performance which improved with hearing age. Earlier implantations haven't presented significantly positive performances until 24 months post-implantation in all the tests. PMID- 25935510 TI - Distribution of manganese species in an oxidative dimerization reaction of a bis terpyridine mononuclear manganese (II) complex and their heterogeneous water oxidation activities. AB - Heterogeneous water oxidation catalyses were studied as a synthetic model of oxygen evolving complex (OEC) in photosynthesis using mica adsorbing various manganese species. Distribution of manganese species formed in the oxidative dimerization reaction of [Mn(II)(terpy)2](2+) (terpy=2,2':6',2"-terpyridine) (1') with various oxidants in water was revealed. 1' was stoichiometrically oxidized to form di-MU-oxo dinuclear manganese complex, [(OH2)(terpy)Mn(III)(MU O)2Mn(IV)(terpy)(OH2)](3+) (1) by KMnO4 as an oxidant. When Oxone and Ce(IV) oxidants were used, the further oxidation of 1 to [(OH2)(terpy)Mn(IV)(MU O)2Mn(IV)(terpy)(OH2)](4+) (2) was observed after the oxidative dimerization reaction of 1'. The mica adsorbates with various composition of 1', 1 and 2 were prepared by adding mica suspension to the various oxidant-treated solutions followed by filtration. The heterogeneous water oxidation catalysis by the mica adsorbates was examined using a Ce(IV) oxidant. The observed catalytic activity of the mica adsorbates corresponded to a content of 1 (1ads) adsorbed on mica for KMnO4- and Oxone-treated systems, indicating that 1' (1'ads) and 2 (2ads) adsorbed on mica do not work for the catalysis. The kinetic analysis suggested that 1ads works for the catalysis through cooperation with adjacent 1ads or 2ads, meaning that 2ads assists the cooperative catalysis by 1ads though 2ads is not able to work for the catalysis alone. For the Ce(IV)-treated system, O2 evolution was hardly observed although the sufficient amount of 1ads was contained in the mica adsorbates. This was explained by the impeded penetration of Ce(IV) ions (as an oxidant for water oxidation) into mica by Ce(3+) cations (generated in oxidative dimerization of 1') co-adsorbed with 1ads. PMID- 25935511 TI - Perceived efficacy of cannabidiol-enriched cannabis extracts for treatment of pediatric epilepsy: A potential role for infantile spasms and Lennox-Gastaut syndrome. AB - There is a great need for safe and effective therapies for treatment of infantile spasms (IS) and Lennox-Gastaut syndrome (LGS). Based on anecdotal reports and limited experience in an open-label trial, cannabidiol (CBD) has received tremendous attention as a potential treatment for pediatric epilepsy, especially Dravet syndrome. However, there is scant evidence of specific utility for treatment of IS and LGS. We sought to document the experiences of children with IS and/or LGS who have been treated with CBD-enriched cannabis preparations. We conducted a brief online survey of parents who administered CBD-enriched cannabis preparations for the treatment of their children's epilepsy. We specifically recruited parents of children with IS and LGS and focused on perceived efficacy, dosage, and tolerability. Survey respondents included 117 parents of children with epilepsy (including 53 with IS or LGS) who had administered CBD products to their children. Perceived efficacy and tolerability were similar across etiologic subgroups. Eighty-five percent of all parents reported a reduction in seizure frequency, and 14% reported complete seizure freedom. Epilepsy was characterized as highly refractory with median latency from epilepsy onset to CBD initiation of five years, during which the patient's seizures failed to improve after a median of eight antiseizure medication trials. The median duration and the median dosage of CBD exposure were 6.8 months and 4.3mg/kg/day, respectively. Reported side effects were far less common during CBD exposure, with the exception of increased appetite (30%). A high proportion of respondents reported improvement in sleep (53%), alertness (71%), and mood (63%) during CBD therapy. Although this study suggests a potential role for CBD in the treatment of refractory childhood epilepsy including IS and LGS, it does not represent compelling evidence of efficacy or safety. From a methodological standpoint, this study is extraordinarily vulnerable to participation bias and limited by lack of blinded outcome ascertainment. Appropriately controlled clinical trials are essential to establish efficacy and safety. PMID- 25935512 TI - Use of antiepileptic or benzodiazepine medication and suicidal ideation--The Northern Finland Birth Cohort 1966. AB - Both antiepileptic drugs (AEDs) and benzodiazepines (BZDs) have previously been associated with an increased risk of suicidality. Our aim was to study the association between the use of conventional AEDs and BZDs and suicidal ideation in a large population-based cohort. Information on the medications used in the Northern Finland Birth Cohort 1966 was collected from the subjects at the age of 31 years, using a postal questionnaire (N=8211). The presence of suicidal ideation and other symptoms of depression and anxiety was assessed via the Hopkins Symptom Checklist - 25 questionnaire. The associations between medications and suicidal ideation were studied in different diagnostic groups and adjusted for symptoms of depression and anxiety. No difference was observed in suicidal ideation between AED users (n=54) and nonusers (n=8157). Subjects using BZDs (n=147) had greater suicidal ideation compared with nonusers (n=8064). Antiepileptic drug and benzodiazepine users more often exhibited other depression and anxiety symptoms. After adjustment for these symptoms, both AED and BZD users had less suicidal ideation compared with nonusers. In conclusion, in this population-based cohort, neither the use of AEDs nor that of BZDs was found to be associated with increased suicidal ideation when the symptoms of depression and anxiety were taken into account. PMID- 25935513 TI - Duration of focal complex, secondarily generalized tonic-clonic, and primarily generalized tonic-clonic seizures--A video-EEG analysis. AB - INTRODUCTION: Identifying seizures with prolonged duration during video electroencephalographic (EEG) monitoring is of importance to inform clinicians when to start emergency treatment of seizures to prevent status epilepticus. The aims of this study were to assess the clinical and EEG seizure duration (SD) in consecutive patients with epilepsy who underwent prolonged video-EEG monitoring and to identify a seizure type-dependent time point to start emergency treatment based on the likelihood that seizures will not stop spontaneously. Furthermore, we sought to determine predictors of SD and explored the relationship between antiepileptic drug (AED) serum levels and SD. MATERIAL AND METHODS: We retrospectively analyzed 1796 seizures in 200 patients undergoing video-EEG monitoring between January 2006 and March 2008. RESULTS: Focal simple seizures lasted significantly shorter (clinical SD: 28s, EEG SD: 42 s) compared with focal complex seizures (clinical SD: 64 s, EEG SD: 62 s), and both seizure types lasted significantly shorter compared with secondarily generalized tonic-clonic seizures (GTCSs; clinical SD: 90 s, EEG SD: 96 s). There was no difference between the duration of the convulsive phase of primary GTCSs (defined as nonfocal) and that of secondarily GTCSs (each 65 s). Cumulative clinical SD (99%) was 7 min in focal complex seizures and 11 min in focal simple seizures. Mixed linear regression model demonstrated that history of status epilepticus (P = 0.034), temporal lobe seizure onset (P = 0.040), and MRI lesions (P = 0.013) were significantly associated with logarithmic EEG SD in focal epilepsies recorded with scalp electrodes. We found significant negative correlations between the AED serum level and the EEG SD in patients treated with monotherapy: carbamazepine (P < 0.001), levetiracetam (P = 0.001), oxcarbazepine (P = 0.001), and valproic acid (P = 0.038) but not with lamotrigine monotherapy and EEG SD. DISCUSSION: Based on the results of this study, we propose 2 min of convulsive seizure activity (irrespective of focal or generalized onset) as a prolonged seizure, which could serve as a time point to consider treatment to prevent status epilepticus. In focal complex seizures, we suggest an upper limit of 7 min, and in focal simple seizures 11 min, as definition of prolonged seizures. History of status epilepticus, temporal seizure onset, and lesional MRI findings are factors associated with significantly longer SD. Negative correlations of carbamazepine, levetiracetam, oxcarbazepine, and valproic acid serum levels and SD suggest a prolonging effect on seizures during withdrawal of these AEDs during video-EEG monitoring sessions. This article is part of a Special Issue entitled "Status Epilepticus". PMID- 25935514 TI - Altered functional connectivity among default, attention, and control networks in idiopathic generalized epilepsy. AB - Numerous resting-state fMRI studies have demonstrated altered functional connectivity within canonical intrinsic connectivity networks (ICNs) in patients with idiopathic generalized epilepsy (IGE). It is possible that the widespread ICN abnormalities on electroencephalography in IGE derive from abnormal functional interactions between ICNs. To test this possibility, we explored the functional connectivity between the subnetworks of the default mode network (DMN), attention network (ATN), and frontoparietal control network (FPN) using independent component analysis of resting-state fMRI data collected from 27 patients with IGE characterized by generalized tonic-clonic seizures (GTCS) and 29 matched healthy controls. It was observed that the left FPN exhibited increased connectivity with the anterior DMN and ventral ATN, while the right FPN exhibited increased connectivity with the anterior and posterior DMNs in the patients with IGE-GTCS. Furthermore, the functional connectivity between the anterior DMN and ventral ATN was negative in healthy controls but positive in the patients with IGE-GTCS. In addition, the anterior DMN exhibited increased intranetwork functional connectivity in the right frontal pole in IGE-GTCS. These findings suggest that IGE-GTCS is likely associated with a disrupted brain organization probably derived from abnormal functional interactions among ICNs. Furthermore, the alterations in the functional architecture of the ICNs may be related to deficits in mentation and attention in IGE-GTCS, providing informative evidence for the understanding of the pathophysiology of IGE-GTCS. PMID- 25935515 TI - Cross-sensitivity of patient-perceived adverse cognitive effects with antiepileptic drug use. AB - OBJECTIVE: The extent to which adverse cognitive effects (ACEs) to a specific antiepileptic drug (AED) affect the chance of developing ACEs to other AEDs (i.e., cross-sensitivity) is unknown. We investigated the rates of cross sensitivity of ACEs among AEDs and examined the association between clinical characteristics and occurrence of having ACEs to multiple AEDs in adults with epilepsy. METHODS: The rates of cross-sensitivity of intolerable ACEs (IACEs; i.e., ACEs leading to dosage reduction or discontinuation) and the non-AED predictors of IACEs were investigated in 2269 patients who had taken at least two AEDs at a single center. We accounted for AED load and looked for specific cross sensitivities between AEDs as well as cross-sensitivity based on the AED mechanism of action. RESULTS: Among the 2269 patients, the highest rates of IACEs were seen with TPM (26.3%), ZNS (9.8%), PHT (8.8%), and VPA (8.5%). Intolerable ACEs to two or more AEDs occurred in 100 patients (4.4%). History of psychiatric condition(s) and absence seizure type were independent predictors of IACEs to two or more AEDs. High rates of cross-sensitivity of IACEs were seen between phenytoin (PHT) and lamotrigine (LTG), valproate (VPA) and phenytoin, and valproate and zonisamide (ZNS). For example, of patients who had IACEs to VPA and were also prescribed ZNS, 46.2% had IACEs to ZNS (abbreviated as VPA->ZNS: 46.2%); of patients who had IACEs to ZNS and were also prescribed VPA, 37.5% had IACEs to VPA (abbreviated as ZNS->VPA: 37.5%). Other results are as follows: LTG >PHT: 28.6%, PHT->LTG: 20.0%, PHT->VPA: 42.9%, and VPA->PHT: 27.3%. No specific cross-sensitivities were found among AEDs sharing a similar mechanism of action. SIGNIFICANCE: The probability of ACE intolerability to an AED can increase if a patient developed ACE intolerability to another AED. The cross-sensitivity rates for ACE intolerability between LTG and PHT, PHT and VPA, and VPA and ZNS were found to be particularly high. The cross-sensitivity rates provided here may be clinically useful for predicting ACE intolerability in patients taking certain AEDs and for AED selection in individual patients. PMID- 25935516 TI - Impairments of thalamic resting-state functional connectivity in patients with chronic tinnitus. AB - PURPOSE: The phantom sound of tinnitus is believed to arise from abnormal functional coupling between the thalamus and cerebral cortex. To explore this hypothesis, we used resting-state functional magnetic resonance imaging (fMRI) to compare the degree of thalamocortical functional connectivity in chronic tinnitus patients and controls. MATERIALS AND METHODS: Resting-state fMRI scans were obtained from 31 chronic tinnitus patients and 33 well-matched healthy controls. Thalamocortical functional connectivity was characterized using a seed-based whole-brain correlation method. The resulting thalamic functional connectivity measures were correlated with other clinical data. RESULTS: We found decreased functional connectivity between the seed region in left thalamus and right middle temporal gyrus (MTG), right middle orbitofrontal cortex, left middle frontal gyrus, right precentral gyrus, and bilateral calcarine cortex. Decreased functional connectivity was detected between the seed in the right thalamus and the left superior temporal gyrus (STG), left amygdala, right superior frontal gyrus, left precentral gyrus, and left middle occipital gyrus. Tinnitus distress correlated negatively with thalamic functional connectivity in right MTG; tinnitus duration correlated negatively with thalamic functional connectivity in left STG. Increased functional connectivity between the bilateral thalamus and a set of regions were also observed. CONCLUSIONS: Chronic tinnitus patients have disrupted thalamocortical functional connectivity to selected brain regions which is associated with specific tinnitus characteristics. Resting-state thalamic functional connectivity disturbances may play an important role in neuropathological features of tinnitus. PMID- 25935517 TI - Denosumab, a Potential Alternative to the Surgical Treatment of Distal Radius Giant Cell Tumor of Bone: Case Report. AB - Juxta-articular giant cell tumors can pose major surgical challenges. Aggressive distal radius giant cell tumors often require complex reconstructive procedures that are associated with numerous complications. We present a case of a 25-year old man with a Campanacci grade 3 giant cell tumor of the distal radius that was successfully treated with denosumab without complex reconstructive procedures. At 3.5-year follow-up and 1-year drug free period, the patient remained asymptomatic without histologic evidence of recurrent tumor. With denosumab therapy, patients can potentially avoid surgery and achieve a successful outcome. PMID- 25935518 TI - Report of a successful ongoing pregnancy as a result of IMSI with assisted oocyte activation. AB - We report a successful ongoing pregnancy obtained in a case of total globozoospermia after intracytoplasmic morphologically selected sperm injection (IMSI) with oocyte activation. The first semen analysis on investigation showed partial globozoospermia. However, under high magnification assessment at oocyte retrieval only round headed sperm were observed. Considering the high risk of a complete failure to fertilize from IMSI the couple gave written informed consent to the use of oocyte activation media post IMSI. One embryo fertilized, developed to a hatching blastocyst and was transferred resulting in an ongoing pregnancy. This successful outcome shows the use of IMSI is useful in the evaluation of total globozooozpermia and therefore aids in the justification of the use of oocyte activation media. PMID- 25935519 TI - Myocardial signal density levels and beam-hardening artifact attenuation using dual-energy computed tomography. AB - The assessment of myocardial perfusion using single-energy (SE) imaging is influenced by beam-hardening artifacts (BHA). We sought to explore the ability of dual-energy (DE) imaging to attenuate the presence of BHA. Myocardial signal density (SD) was evaluated in 2240 myocardial segments (112 for each energy level) and in 320 American Heart Association segments among the SE group. Compared to DE reconstructions at the best energy level, SE acquisitions showed no significant differences overall regarding myocardial SD or signal-to-noise ratio. The segments most commonly affected by BHA showed significantly lower myocardial SD at the lowest energy levels, progressively normalizing at higher energy levels. PMID- 25935520 TI - Topical treatment with fresh human milk versus emollient on atopic eczema spots in young children: a small, randomized, split body, controlled, blinded pilot study. AB - BACKGROUND: Public health nurses report on effects of fresh human milk as treatment for conjunctivitis, rhinitis and atopic eczema (AE), the latter being highly prevalent in early childhood. Emollients and topical corticosteroids are first line treatment of AE. As many caregivers have steroid phobia, alternative treatment options for mild AE are of interest. The aim of this small pilot study was to assess the potential effects and risks of applying fresh human milk locally on eczema spots in children with AE. METHODS: This was a split body, controlled, randomized and physician blinded pilot study, of children with AE with two similar contralateral eczema spots having a mother breastfeeding the child or a sibling. Fresh expressed milk and emollient was applied on the intervention spot and emollient alone on the control area, three times a day for four weeks. The severity and area of the eczema spots was evaluated weekly, and samples from milk and the spots were analysed weekly with respect to bacterial colonisation. RESULTS: Of nine patients included, six completed the study. Mean age at inclusion was 18.5 months. The spots examined were localized on the arms, legs or cheeks. The spots were similar in severity, but differed in area. In one patient the eczema ceased after inclusion. In four patients both control and intervention areas increased during the intervention. The relative change in eczema area compared to baseline showed less increase in the intervention spots in two patients, whereas the opposite was observed in three. In four children Staphylococcus aureus was found in their eczema once or more. In three of the 28 human milk samples, Staphylococcus aureus, alfa haemolytic streptococci or coagulase negative staphylococci were detected. Staphylococcus aureus was found once both in human milk and in the eczema spots, no clinical signs of infection were however observed. No secondary infection due to milk application was detected. CONCLUSION: In this small pilot study, no effect was found on eczema spots treated with topical application of fresh human milk. (ClinicalTrials.gov Identifier, NCT02381028 ). PMID- 25935521 TI - Phosphomimicking within the transit peptide of pHCF136 leads to reduced photosystem II accumulation in vivo. AB - Most chloroplast resident proteins are equipped with N-terminal transit peptides to ensure targeting from the cytosol to the organelle. Import rates can be modulated by phosphorylation and 14-3-3 binding within the transit peptides. Using the phosphorylatable preprotein pHCF136, a photosystem II assembly factor, we investigated the function of preprotein phosphorylation in vivo by complementing the seedling lethal hcf136 mutant. HCF136 constructs containing mutations within the 14-3-3 binding site were generated, either abolishing or mimicking phosphorylation. Interestingly, phosphomimicking reduced the import rate and the hcf136 phenotype could only be partially rescued, as shown by hampered photosystem II complex accumulation, which was most prominently observed in cotyledons. PMID- 25935522 TI - Enhanced expression and phosphorylation of the MET oncoprotein by glioma-specific PTPRZ1-MET fusions. AB - PTPRZ1-MET (ZM) proteins are a group of fusion proteins identified in human gliomas by high-throughput transcriptome sequencing. ZM fusions are associated with poor prognosis in afflicted glioma patients and mediate oncogenic effects in assays. In this study, we show that ZM-carrying patients have increased hepatocyte growth factor receptor (MET) mRNA expression levels induced by fusion with receptor-type tyrosine-protein phosphatase zeta (PTPRZ1). Furthermore, ZM fusions preserve fundamental properties of wild-type MET with respect to processing and dimerization, and enhance phosphorylation in an hepatocyte growth factor (HGF)-dependent and independent manner. Our findings suggest that ZM induces gliomas through elevated expression and phosphorylation of the MET oncoprotein. PMID- 25935523 TI - The POCER Trial: Bet on Active Care. PMID- 25935524 TI - HCV/HIV Coinfection: A New Treatment Paradigm. PMID- 25935525 TI - An unusual cause of chronic painless hematochezia. PMID- 25935526 TI - An unusual case of esophageal ulcer and weight loss. PMID- 25935528 TI - In the Presence of Conceptual Heterogeneity, Results of Network Meta-analysis Comparing Therapies in Crohn's Disease Need to Be Interpreted With Caution. PMID- 25935529 TI - Constipation and weight loss in a Honduran immigrant. PMID- 25935530 TI - Reply: To PMID 25448924. PMID- 25935531 TI - Early enteral feeding does not improve outcomes in patients with predicted severe acute pancreatitis. PMID- 25935532 TI - A plunging case of intermittent dysphagia. PMID- 25935533 TI - Reply: To PMID 25244349. PMID- 25935534 TI - A young woman with abdominal pain. PMID- 25935535 TI - Low ATM protein expression in malignant tumor as well as cancer-associated stroma are independent prognostic factors in a retrospective study of early-stage hormone-negative breast cancer. AB - INTRODUCTION: The serine/threonine protein kinase ataxia telangiectasia mutated (ATM) is critical in maintaining genomic integrity. Upon DNA double-strand breaks, ATM phosphorylates key downstream proteins including p53 and BRCA1/2, thereby orchestrating complex signaling pathways involved in cell cycle arrest, DNA repair, senescence and apoptosis. Although sporadic mutation of ATM occurs rarely in breast cancer, the status of its protein expression and its clinical significance in breast cancer remain not well established. Our study was designed to investigate the influence of ATM protein in both tumor and cancer-associated stroma on clinical outcome in hormone-positive (HPBC) and hormone-negative (HNBC) early-stage breast cancer (EBC). METHODS: Tissue microarrays (TMAs), containing formalin-fixed, paraffin-embedded resected tumors from two cohorts of patients (HPBC cohort: n=130; HNBC cohort: n=168) diagnosed at the Tom Baker Cancer Centre, Calgary, Canada, were analyzed for ATM protein expression using fluorescence immunohistochemistry (IHC) and automated quantitative analysis (AQUA). ATM expression levels were measured within the tumor as a whole (tATM) as indicated by pan-cytokeratin expression, tumor nuclear compartment (nATM) as indicated by both DAPI and pan-cytokeratin-positive results, and cancer associated stroma (csATM) as indicated by vimentin-positive and pan-cytokeratin negative results. ATM expression levels within these compartments were correlated with clinical outcome. RESULTS: While tATM and nATM were significantly lower in tumors compared to normal breast epithelial tissues, csATM was significantly higher than the corresponding normal tissue compartment. In addition, the median expression level of both tATM and nATM were two- to threefold lower (P<0.001) in HNBC than in HPBC. In both HNBC and HPBC cohorts, patients with low tATM, nATM and csATM tumors had significantly poorer survival outcomes than those with a high tATM, nATM and csATM, but this effect was more pronounced in HNBC. A multivariate analysis demonstrates that these biomarkers predict survival independent of tumor size and lymph node status, but only in the HNBC cohort (P<0.001). CONCLUSIONS: Low ATM protein expression in both malignant tumor and stromal compartments likely contributes to the aggressive nature of breast cancer and is an independent prognostic factor associated with worse survival in HNBC patients. PMID- 25935536 TI - Sex-determining region Y-related high mobility group box (SOX)-2 is overexpressed in cervical squamous cell carcinoma and contributes cervical cancer cell migration and invasion in vitro. AB - Sex-determining region Y-related high mobility group box 2 (SOX-2) is a key pluripotency-associated transcription factor and may be implicated in the pathogenesis of cervical squamous cell carcinoma (SCC). The aim of this study was to explore SOX-2 expression in cervical SCC tissues and to examine whether and how SOX-2 regulates the malignant behaviors of cervical SCC cells in vitro. We here found that SOX-2 expression in the examined cervical SCC tissues was higher than that in the normal cervical and cervical intraepithelial neoplasia (CIN) tissues. Higher protein level of SOX-2 (nuclear positive staining cells >=50 %) was detected in 34.9 % (29 out of 83 cases) of cervical SCC patients. We also noted that 100 % of well-differentiated and 66.7 % of moderately differentiated cervical SCCs showed lower SOX-2 expression (nuclear positive staining cells <50 %), while 58.8 % of poorly differentiated tumors had higher SOX-2 expression (P < 0.05). Furthermore, the migratory and invasive capabilities of SiHa cervical cancer cells were enhanced when SOX-2 was upregulated whereas suppressed when SOX 2 was downregulated. Also, the phosphorylation levels of protein kinase B (Akt) and extracellular regulated protein kinases (ERK) 1/2 were increased in SOX-2 overexpressed cancer cells but decreased in SOX-2-depleted cells. Additionally, LY294002 (Akt pathway inhibitor) or U0126 (ERK pathway inhibitor) significantly suppressed SOX-2-overexpression-induced migration and invasion in SiHa cells. Our results indicate that differentially expressed SOX-2 is associated with tumor differentiation (P < 0.05) and that SOX-2 contributes to the migratory and invasive behaviors of cervical SCC in vitro. PMID- 25935537 TI - CD56-negative extranodal NK/T cell lymphoma should be regarded as a distinct subtype with poor prognosis. AB - Previous results about the clinical and prognostic significance concerning CD56 expression status in extranodal NK/T cell lymphoma (ENKTL) are controversial due to a small sample size and the heterogeneity nature of this disease. The complete data of 288 patients with early-stage upper aerodigestive tract ENKTL were retrospectively reviewed. One hundred eighty-three patients (63.5 %) had stage I disease, and the primary tumor site of 204 patients (70.8 %) was in the nasal cavity. Sixty patients (20.8 %) were categorized to CD56-negative ENKTL group. The complete remission rate in CD56-positive ENKTL group was 80.6 %, significantly higher than that in CD56-negative ENKTL group (60.8 %, P = 0.005). At a median follow-up time of 69 months, the 5-year and 10-year progression-free survival (PFS) rate were 52 and 41 %, respectively, and the 5-year and 10-year overall survival (OS) rate were 69 % and 68 %, respectively. Patients with primary tumor site located in the nasal cavity or CD56-positive expression had significantly superior PFS and OS (P < 0.05). In multivariate Cox regression model that included age, Ann Arbor stage, lactate dehydrogenase (LDH) level, primary tumor site, chemotherapy regimens, and CD56 expression status, all these six factors remained to be independent prognostic factors for PFS, and the first five factors were independent prognostic factors for OS, while CD56 expression status had a trend to be independently correlated with OS (P = 0.084). In a subgroup analysis according to primary tumor site location, CD56 expression status significantly correlated with survival outcomes in patients with primary nasal cavity involvement (P < 0.05). In conclusion, in this large cohort of patients with early-stage ENKTL, we found that CD56-negative ENKTL had significantly inferior survival outcomes, indicating CD56-negative ENKTL should be regarded as a distinct phenotype, and optimal treatment strategies need to be evaluated further for this entity. PMID- 25935538 TI - Assessment of benzene induced oxidative impairment in rat isolated pancreatic islets and effect on insulin secretion. AB - Benzene (C6H6) is an organic compound used in petrochemicals and numerous other industries. It is abundantly released to our environment as a chemical pollutant causing widespread human exposure. This study mainly focused on benzene induced toxicity on rat pancreatic islets with respect to oxidative damage, insulin secretion and glucokinase (GK) activity. Benzene was dissolved in corn oil and administered orally at doses 200, 400 and 800mg/kg/day, for 4 weeks. In rats, benzene significantly raised the concentration of plasma insulin. Also the effect of benzene on the release of glucose-induced insulin was pronounced in isolated islets. Benzene caused oxidative DNA damage and lipid peroxidation, and also reduced the cell viability and total thiols groups, in the islets of exposed rats. In conclusion, the current study revealed that pancreatic glucose metabolism is susceptible to benzene toxicity and the resultant oxidative stress could lead to functional abnormalities in the pancreas. PMID- 25935539 TI - Reduced zinc cytotoxicity following differentiation of neural stem/progenitor cells into neurons and glial cells is associated with upregulation of metallothioneins. AB - We investigated zinc cytotoxicity in mouse neural stem/progenitor cells (NSPCs) and their differentiated progeny (neuronal/glial cells) in correlation with expression of metallothionein (MT) gene. Differentiated cells were less sensitive than NSPCs to ZnCl2 (IC50: 128MUM vs. 76MUM). Differentiation of immature NSPCs to the differentiated cells led to an increase in expression of MT family genes (Mt1, Mt2, Mt3, and Mt4). Zinc exposure induced a dose-dependent increase in expression level of Mt1 and that of Mt2 in both NSPCs and the differentiated cells. Our results showed that the reduced cytotoxicity of zinc associated with differentiation from NSPCs into their progeny was related to the upregulation of MTs. PMID- 25935540 TI - Toxic effects of sub-chronic exposure of male albino rats to emamectin benzoate and possible ameliorative role of Foeniculum vulgare essential oil. AB - Emamectin benzoate (EB) is an avermectin insecticide used extensively in pest control on vegetable and field crops. Few studies have been done for evaluating adverse effects of EB. In the current study, we evaluated the toxic effects of EB on male rats and the possible ameliorative role of fennel essential oil (FEO). Thirty two male rats were randomly divided into 4 equal groups. All groups were treated orally with distilled water (control group), 0.5mlFEOkg(-1) BW (FEO group), 2.5mgEBkg(-1) BW (EB group), and 0.5mlFEOkg(-1) BW+2.5mgEBkg(-1) BW (FEO+EB group) for 28 days. The obtained results showed that EB treatment resulted in a significant decrease in body weight, body weight gain, RBC count, Hb concentration, % PCV, MCV and MCHC. Moreover, EB significantly decreased total leukocyte, lymphocyte, monocyte and platelet count but significantly increased granulocyte count. EB markedly decreased total protein, albumin, globulin, IgG and IgM concentrations with a significant increase in TNF-alpha secretion. EB had a negative impact on the liver as it significantly increased ALT, ALP, and MDA, while decreasing SOD activity. Regarding to the histopathological examination, EB treatment induced coagulative necrosis and blood vessels congestion of the liver in treated rats. Furthermore, it resulted in depletion and necrosis of the white pulp of the spleen in treated rats. The co-administration of FEO with EB, however, improved the majority of parameters studied, suggesting that FEO is an important substance in decreasing toxic effects of EB. PMID- 25935542 TI - Streptozocin/5-fluorouracil chemotherapy is associated with durable response in patients with advanced pancreatic neuroendocrine tumours. AB - BACKGROUND: The role of systemic chemotherapy for pancreatic neuroendocrine tumours (pNET) is controversially discussed. Objective response rates (RR) reported for streptozocin (STZ)-based chemotherapy are variable and novel targeted drugs have recently been approved. However, the sequence of treatment remains unclear. We aimed to evaluate the efficacy of STZ plus 5-fluorouracil (STZ/5-FU) in a large pNET cohort. METHODS: Data from 96 pNET patients treated with STZ/5-FU were analysed retrospectively. Endpoints of the study were RR, time to tumour progression (TTP) and overall survival (OS). RESULTS: Mean age of patients at the start of chemotherapy was 57.6years (range, 32.1-80.4). STZ/5-FU was the 1st line treatment in 56.3%. 11.5% had G1, 79.2% G2 and 6.3% G3 neoplasms. Baseline progression was evident in 74%. Objective response rate was 42.7%. 40.6% of patients showed stable disease as best response while 16.7% showed progressive disease. Treatment was discontinued due to toxicity in 16 patients. Median TTP and OS were 19.4 (95% confidence interval (CI), 13.6-25.2) and 54.8months (95% CI, 34.7-74.9), respectively. In Cox regression analysis, Ki67>15% was the only negative prognostic factor for TTP (hazard ratio (HR), 3.3; P<0.001), confirmed by multivariate analysis (HR, 6.7; P=0.001). CONCLUSIONS: STZ/5-FU was associated with considerable RR. Treatment was associated with durable TTP especially in patients with Ki67-index of ?15%. These findings along with good tolerability strengthen the value of this two-drug chemotherapy for the management of unresectable pNET. PMID- 25935541 TI - Proteoglycan-based diversification of disease outcome in head and neck cancer patients identifies NG2/CSPG4 and syndecan-2 as unique relapse and overall survival predicting factors. AB - BACKGROUND: Tumour relapse is recognized to be the prime fatal burden in patients affected by head and neck squamous cell carcinoma (HNSCC), but no discrete molecular trait has yet been identified to make reliable early predictions of tumour recurrence. Expression of cell surface proteoglycans (PGs) is frequently altered in carcinomas and several of them are gradually emerging as key prognostic factors. METHODS: A PG expression analysis at both mRNA and protein level, was pursued on primary lesions derived from 173 HNSCC patients from whom full clinical history and 2 years post-surgical follow-up was accessible. Gene and protein expression data were correlated with clinical traits and previously proposed tumour relapse markers to stratify high-risk patient subgroups. RESULTS: HNSCC lesions were indeed found to exhibit a widely aberrant PG expression pattern characterized by a variable expression of all PGs and a characteristic de novo transcription/translation of GPC2, GPC5 and NG2/CSPG4 respectively in 36%, 72% and 71% on 119 cases. Importantly, expression of NG2/CSPG4, on neoplastic cells and in the intralesional stroma (Hazard Ratio [HR], 6.76, p = 0.017) was strongly associated with loco-regional relapse, whereas stromal enrichment of SDC2 (HR, 7.652, p = 0.007) was independently tied to lymphnodal infiltration and disease-related death. Conversely, down-regulated SDC1 transcript (HR, 0.232, p = 0.013) uniquely correlated with formation of distant metastases. Altered expression of PGs significantly correlated with the above disease outcomes when either considered alone or in association with well-established predictors of poor prognosis (i.e. T classification, previous occurrence of precancerous lesions and lymphnodal metastasis). Combined alteration of all three PGs was found to be a reliable predictor of shorter survival. CONCLUSIONS: An unprecedented PG-based prognostic portrait is unveiled that incisively diversifies disease course in HNSCC patients beyond the currently known clinical and molecular biomarkers. PMID- 25935543 TI - Loci associated with adult stature also affect calf birth survival in cattle. AB - BACKGROUND: Understanding the underlying pleiotropic relationships among quantitative traits is necessary in order to predict correlated responses to artificial selection. The availability of large-scale next-generation sequence data in cattle has provided an opportunity to examine whether pleiotropy is responsible for overlapping QTL in multiple economic traits. In the present study, we examined QTL affecting cattle stillbirth, calf size, and adult stature located in the same genomic region. RESULTS: A genome scan using imputed whole genome sequence variants revealed one QTL with large effects on the service sire calving index (SCI), and body conformation index (BCI) at the same location (~39 Mb) on chromosome 6 in Nordic Red cattle. The targeted region was analyzed for SCI and BCI component traits. The QTL peak included LCORL and NCAPG genes, which had been reported to influence fetal growth and adult stature in several species. The QTL exhibited large effects on calf size and stature in Nordic Red cattle. Two deviant haplotypes (HAP1 and HAP2) were resolved which increased calf size at birth, and affected adult body conformation. However, the haplotypes also resulted in increased calving difficulties and calf mortality due to increased calf size at birth. Haplotype locations overlapped, however linkage disequilibrium (LD) between the sites was low, suggesting that two independent mutations were responsible for similar effects. The difference in prevalence between the two haplotypes in Nordic Red subpopulations suggested independent origins in different populations. CONCLUSIONS: Results of our study identified QTL with large effects on body conformation and service sire calving traits on chromosome 6 in cattle. We present robust evidence that variation at the LCORL and NCAPG locus affects calf size at birth and adult stature. We suggest the two deviant haplotypes within the QTL were due to two independent mutations. PMID- 25935544 TI - Metabolic profiling of chickpea-Fusarium interaction identifies differential modulation of disease resistance pathways. AB - Chickpea is the third most widely grown legume in the world and mainly used as a vegetarian source of human dietary protein. Fusarium wilt, caused by Fusarium oxysporum f. sp. ciceri (Foc), is one of the major threats to global chickpea production. Host resistance is the best way to protect crops from diseases; however, in spite of using various approaches, the mechanism of Foc resistance in chickpea remains largely obscure. In the present study, non-targeted metabolic profiling at several time points of resistant and susceptible chickpea cultivars using high-resolution liquid chromatography-mass spectrometry was applied to better understand the mechanistic basis of wilt resistance or susceptibility. Multivariate analysis of the data (OPLS-DA) revealed discriminating metabolites in chickpea root tissue after Foc inoculation such as flavonoids, isoflavonoids, alkaloids, amino acids and sugars. Foc inoculated resistant plants had more flavonoids and isoflavonoids along with their malonyl conjugates. Many antifungal metabolites that were induced after Foc infection viz., aurantion-obstine beta glucosides and querecitin were elevated in resistant cultivar. Overall, diverse genetic and biochemical mechanisms were operational in the resistant cultivar for Foc defense as compared to the susceptible plant. The resistant chickpea plants employed the above-mentioned metabolic pathways as potential defense strategy against Foc. PMID- 25935545 TI - High-resolution bioactivity profiling combined with HPLC-HRMS-SPE-NMR: alpha Glucosidase inhibitors and acetylated ellagic acid rhamnosides from Myrcia palustris DC. (Myrtaceae). AB - Type 2 diabetes (T2D) is an endocrine metabolic disease with a worldwide prevalence of more than 8%, and an expected increase close to 50% in the next 15 20years. T2D is associated with severe and life-threatening complications like retinopathy, neuropathy, nephropathy, and cardiovascular diseases, and therefore improved drug leads or functional foods containing alpha-glucosidase inhibitors are needed for management of blood glucose. In this study, leaves of Myrcia palustris were investigated by high-resolution alpha-glucosidase inhibition profiling combined with HPLC-HRMS-SPE-NMR. This led to identification of casuarinin, myricetin 3-O-beta-d-(6"-galloyl)galactopyranoside, kaempferol 3-O beta-d-galactopyranoside, myricetin, and quercetin as alpha-glucosidase inhibitors. In addition, four acetylated ellagic acid rhamnosides, i.e., 4-O (2",4"-O-diacetyl-alpha-l-rhamnopyranosyl)ellagic acid, 4-O-(2",3"-O-diacetyl alpha-l-rhamnopyranosyl)ellagic acid, 4-O-(3",4"-O-diacetyl-alpha-l rhamnopyranosyl)ellagic acid, and 4-O-(2",3",4"-O-triacetyl-alpha-l rhamnopyranosyl)ellagic acid were identified. PMID- 25935546 TI - u-CARE: user-friendly Comprehensive Antibiotic resistance Repository of Escherichia coli. AB - BACKGROUND AND AIMS: Despite medical advancements, Escherichia coli-associated infections remain a major public health concern and although an abundant information about E. coli and its antibiotic resistance mechanisms is available, no effective tool exists that integrates gene and genomic data in context to drug resistance, thus raising a need to develop a repository that facilitates integration and assimilation of factors governing drug resistance in E. coli. DESCRIPTIONS: User-friendly Comprehensive Antibiotic resistance Repository of Escherichia coli (u-CARE) is a manually curated catalogue of 52 antibiotics with reported resistance, 107 genes, transcription factors and single nucleotide polymorphism (SNPs) involved in multiple drug resistance of this pathogen. Each gene page provides detailed information about its resistance mechanisms, while antibiotic page consists of summary, chemical description and structural descriptors with links to external public databases like GO, CDD, DEG, Ecocyc, KEGG, Drug Bank, PubChem and UniProt. Moreover, the database integrates this reductive information to holistic data such as strain-specific and segment specific pathogenic islands and operons. In addition, the database offers rich user interface for the visualisation and retrieval of information using various search criteria such as sequence, keyword, image and class search. CONCLUSIONS: u CARE is aimed to cater to the needs of researchers working in the field of antimicrobial drug resistance with minimal knowledge of bioinformatics. This database is also intended as a guide book to medical practitioners to avoid use of antibiotics against which resistance has already been reported in E. coli. The database is available from: http://www.e-bioinformatics.net/ucare. PMID- 25935547 TI - Lessons from a survey of genotyping for hereditary haemochromatosis. PMID- 25935548 TI - Effects of alpha-thalassaemia mutations on the haematological parameters of beta thalassaemia carriers. AB - BACKGROUND: Thalassaemia is a haemoglobin disorder caused by a reduction in, or a complete absence of, the production of alpha- or beta-globin genes. Detection of beta-thalassaemia carriers is the first step in the prenatal diagnosis of the disease and is based primarily on the differences between levels of blood cell indices. Since co-inheritance of beta- and alpha-thalassaemia mutations modulates the haematological parameters of heterozygote beta-thalassaemia indices, understanding the influence of this interaction is helpful for identification of disease carriers. OBJECTIVE: To determine the effects of alpha-thalassaemia mutations on the haematological parameters of beta-thalassaemia carriers. METHOD: We used gap-PCR and amplification refractory mutation system techniques to find any alpha- and/or beta-thalassaemia mutations in 270 subjects who were suspected to be thalassaemia carriers. The mean values of the haematological parameters in alpha, beta-thalassaemia and beta-thalassaemia carriers were compared. RESULTS: Significant differences in mean corpuscular volume (MCV), mean corpuscular haemoglobin (MCH) and HbA2 were found between the two groups. Patients who were alpha, beta-thalassaemia carriers had higher mean values of MCV and MCH, whereas HbA2 levels were higher in simple beta-thalassaemia. No marked differences were found in mean cell haemoglobin (Hb) concentration and Hb blood cell indices. The value of MCV, MCH and HbA2 were significantly different between alpha,beta thalassaemia and simple beta-thalassaemia in men and women, but the mean values of Hb in the two groups differed markedly only in men. CONCLUSION: We conclude that co-inheritance of alpha- and beta-thalassaemia mutations may result in misdiagnosis of beta-thalassaemia carriers. Therefore, in genetic counselling of patients with a near-normal range of blood cell indices the possibility that they may carry alpha, beta-thalassaemia mutations must be considered. PMID- 25935549 TI - Serum level of soluble interleukin-2 receptor correlates with CD25 expression in patients with T lymphoblastic lymphoma. AB - Acute lymphoblastic leukaemia/lymphoma (ALL/LBL) is an aggressive form of non Hodgkin's lymphoma (NHL) affecting B-cells or T-cells, respectively. The serum level of soluble interleukin-2 receptor (sIL-2R) is known to reflect the immune activity and tumour volume in aggressive NHL; however, the release of sIL-2R in LBL has not been extensively studied. Further, the relationship between sIL-2R release and the expression level of IL-2R alpha subunit (CD25) remains unknown. In the present study, we examined the serum level of sIL-2R in 23 patients with T lymphoblactic lymphoma (T-LBL) and compared these with the levels in 20 patient with T acute lymphoblastic leukaemia (T-ALL), 40 patients with diffuse large B cell lymphoma (DLBCL) and 40 patients with peripheral T-cell lymphoma (PTCL), not otherwise specified. The release of sIL-2R into the serum in patients with T-LBL was significantly lower than that for T-ALL, DLBCL and PTCL (p<0.001). Immunohistochemistry revealed that CD25 expression was correlated with the serum level of sIL-2R in T-LBL (p=0.0069), whereas no correlation was found to exist between serum sIL-2R levels and CD25 expression in patients with DLBCL (p=0.348) and PTCL (p=0.266). Furthermore, double immunohistochemical analysis revealed that CD25-positive cells were also found to be Foxp3-positive non-neoplastic T cells. In conclusion, CD25-positive non-neoplastic T-cells in T-LBL are presumed to be the primary source of sIL-2R, and the low number of cells present results in a lower level of sIL-2R released into the serum compared with the other aggressive and highly aggressive lymphomas. PMID- 25935550 TI - High intensity of cytoplasmic peroxiredoxin VI expression is associated with adverse outcome in diffuse large B-cell lymphoma independently of International Prognostic Index. AB - AIMS: Diffuse large B-cell lymphoma (DLBCL) is an aggressive and potentially fatal disease. Prediction of risk of relapse is based on clinical markers. There is a need for more accurate biomarkers to select patients for more aggressive first-line treatments. Peroxiredoxins (Prxs) are a family of potent antioxidant proteins. Their prognostic role in DLBCL is unknown. METHODS: Altogether, 103 diagnostic biopsy samples from patients with DLBCL were immunohistochemically stained for Prxs I, II, III, V and VI. RESULTS: Strong Prx VI expression was associated with the presence of B-symptoms. There were no other significant associations with traditional risk factors. Five-year disease-specific survival was 68.6% in patients with high cytoplasmic Prx VI intensity vs 97.0% in those with low intensity. In multivariate analysis, high Prx VI expression (HR 12.846, 95% CI 1.722 to 95.807, p=0.013) was an independent risk factor of lymphoma associated death not related to International Prognostic Index score (HR 2.514, 95% CI 1.040 to 6.073, p=0.041). CONCLUSIONS: High intensity of cytoplasmic Prx VI expression in pretreatment DLBCL samples predicts worse outcome in patients with DLBCL. Whether Prx VI is associated with chemoresistance, and therefore a poorer outcome, needs to be evaluated. If Prx VI is a predictive marker and it proves causality, it would be crucial to study Prx VI ability to become a target enzyme for treatment. PMID- 25935552 TI - Editorial Commentary: Vaginal Biofilm: Much Ado About Nothing, or a New Therapeutic Challenge? PMID- 25935551 TI - Monitoring of Hepatitis B Virus (HBV) DNA and Risk of HBV Reactivation in B-Cell Lymphoma: A Prospective Observational Study. AB - BACKGROUND: There is no standard management of reactivation of hepatitis B virus (HBV) infection in HBV-resolved patients without hepatitis B surface antigen (HBsAg), but with antibodies against hepatitis B core antigen and/or antibodies against HBsAg (anti-HBs). METHODS: We conducted a prospective observational study to evaluate the occurrence of HBV reactivation by serial monthly monitoring of HBV DNA and to establish preemptive therapy guided by this monitoring in B-cell non-Hodgkin lymphoma (B-NHL) treated with rituximab plus corticosteroid containing chemotherapy (R-steroid-chemo). The primary endpoint was the incidence of HBV reactivation defined as quantifiable HBV DNA levels of >= 11 IU/mL. RESULTS: With a median HBV DNA follow-up of 562 days, HBV reactivation was observed in 21 of the 269 analyzed patients. The incidence of HBV reactivation at 1.5 years was 8.3% (95% confidence interval, 5.5-12.4). No hepatitis due to HBV reactivation was observed in patients who received antiviral treatment when HBV DNA levels were between 11 and 432 IU/mL. An anti-HBs titer of <10 mIU/mL and detectable HBV DNA remaining below the level of quantification at baseline were independent risk factors for HBV reactivation (hazard ratio, 20.6 and 56.2, respectively; P < .001). Even in 6 patients with a rapid increase of HBV due to mutations, the monthly HBV DNA monitoring was effective at preventing HBV-related hepatitis. CONCLUSIONS: Monthly monitoring of HBV DNA is useful for preventing HBV reactivation-related hepatitis among B-NHL patients with resolved HBV infection following R-steroid-chemo (UMIN000001299). PMID- 25935553 TI - Biofilms: An Underappreciated Mechanism of Treatment Failure and Recurrence in Vaginal Infections. AB - Biofilms are microbial communities of surface-attached cells embedded in a self produced extracellular matrix. They are of major medical significance because they decrease susceptibility to antimicrobial agents and enhance the spread of antimicrobial resistance. Biofilm-associated bacterial and fungal microorganisms have increasingly been recognized to play a role in multiple infectious diseases, particularly in their persistence and recurrence. More recently, biofilms have also been implicated in vaginal infections, notably bacterial vaginosis (BV) and vulvovaginal candidiasis (VVC), particularly in the setting of treatment failure and recurrence. The purpose of this review is to discuss the impact of biofilms on the management and treatment of BV and recurrent VVC and highlight the need for additional research and development of novel therapeutics targeting pathogenic vaginal biofilms. PMID- 25935554 TI - L-lactic acid production by Aspergillus brasiliensis overexpressing the heterologous ldha gene from Rhizopus oryzae. AB - BACKGROUND: Lactic acid is the building block of poly-lactic acid (PLA), a biopolymer that could be set to replace petroleum-based plastics. To make lactic acid production cost-effective, the production process should be carried out at low pH, in low-nutrient media, and with a low-cost carbon source. Yeasts have been engineered to produce high levels of lactic acid at low pH from glucose but not from carbohydrate polymers (e.g. cellulose, hemicellulose, starch). Aspergilli are versatile microbial cell factories able to naturally produce large amounts of organic acids at low pH and to metabolize cheap abundant carbon sources such as plant biomass. However, they have never been used for lactic acid production. RESULTS: To investigate the feasibility of lactic acid production with Aspergillus, the NAD-dependent lactate dehydrogenase (LDH) responsible for lactic acid production by Rhizopus oryzae was produced in Aspergillus brasiliensis BRFM103. Among transformants, the best lactic acid producer, A. brasiliensis BRFM1877, integrated 6 ldhA gene copies, and intracellular LDH activity was 9.2 * 10(-2) U/mg. At a final pH of 1.6, lactic acid titer reached 13.1 g/L (conversion yield: 26%, w/w) at 138 h in glucose-ammonium medium. This extreme pH drop was subsequently prevented by switching nitrogen source from ammonium sulfate to Na-nitrate, leading to a final pH of 3 and a lactic acid titer of 17.7 g/L (conversion yield: 47%, w/w) at 90 h of culture. Final titer was further improved to 32.2 g/L of lactic acid (conversion yield: 44%, w/w) by adding 20 g/L glucose to the culture medium at 96 h. This strain was ultimately able to produce lactic acid from xylose, arabinose, starch and xylan. CONCLUSION: We obtained the first Aspergillus strains able to produce large amounts of lactic acid by inserting recombinant ldhA genes from R. oryzae into a wild-type A. brasiliensis strain. pH regulation failed to significantly increase lactic acid production, but switching nitrogen source and changing culture feed enabled a 1.8 fold increase in conversion yields. The strain produced lactic acid from plant biomass. Our findings make A. brasiliensis a strong contender microorganism for low-pH acid production from various complex substrates, especially hemicellulose. PMID- 25935555 TI - Principles for consistent value assessment and sustainable funding of orphan drugs in Europe. AB - The European Orphan Medicinal Products (OMP) Regulation has successfully encouraged research to develop treatments for rare diseases resulting in the authorisation of new OMPs in Europe. While decisions on OMP designation and marketing authorisation are made at the European Union level, reimbursement decisions are made at the national level. OMP value and affordability are high priority issues for policymakers and decisions regarding their pricing and funding are highly complex. There is currently no European consensus on how OMP value should be assessed and inequalities of access to OMPs have previously been observed. Against this background, policy makers in many countries are considering reforms to improve access to OMPs. This paper proposes ten principles to be considered when undertaking such reforms, from the perspective of an OMP manufacturer. We recommend the continued prioritisation of rare diseases by policymakers, an increased alignment between payer and regulatory frameworks, pricing centred on OMP value, and mechanisms to ensure long-term financial sustainability allowing a continuous and virtuous development of OMPs. Our recommendations support the development of more consistent frameworks and encourage collaboration between all stakeholders, including research-based industry, payers, clinicians, and patients. PMID- 25935557 TI - Outbound medical tourism from Mongolia: a qualitative examination of proposed domestic health system and policy responses to this trend. AB - BACKGROUND: Medical tourism is the practice of traveling across international boundaries in order to access medical care. Residents of low-to-middle income countries with strained or inadequate health systems have long traveled to other countries in order to access procedures not available in their home countries and to take advantage of higher quality care elsewhere. In Mongolia, for example, residents are traveling to China, Japan, Thailand, South Korea, and other countries for care. As a result of this practice, there are concerns that travel abroad from Mongolia and other countries risks impoverishing patients and their families. METHODS: In this paper, we present findings from 15 interviews with Mongolian medical tourism stakeholders about the impacts of, causes of, and responses to outbound medical tourism. These findings were developed using a case study methodology that also relied on tours of health care facilities and informal discussions with citizens and other stakeholders during April, 2012. RESULTS: Based on these findings, health policy changes are needed to address the outflow of Mongolian medical tourists. Key areas for reform include increasing funding for the Mongolian health system and enhancing the efficient use of these funds, improving training opportunities and incentives for health workers, altering the local culture of care to be more supportive of patients, and addressing concerns of corruption and favouritism in the health system. CONCLUSIONS: While these findings are specific to the Mongolian health system, other low-to-middle income countries experiencing outbound medical tourism will benefit from consideration of how these findings apply to their own contexts. As medical tourism is increasing in visibility globally, continued research on its impacts and context-specific policy responses are needed. PMID- 25935556 TI - Neuropathic pain after brachial plexus avulsion--central and peripheral mechanisms. AB - REVIEW: The pain that commonly occurs after brachial plexus avulsion poses an additional burden on the quality of life of patients already impaired by motor, sensory and autonomic deficits. Evidence-based treatments for the pain associated with brachial plexus avulsion are scarce, thus frequently leaving the condition refractory to treatment with the standard methods used to manage neuropathic pain. Unfortunately, little is known about the pathophysiology of brachial plexus avulsion. Available evidence indicates that besides primary nerve root injury, central lesions related to the abrupt disconnection of nerve roots from the spinal cord may play an important role in the genesis of neuropathic pain in these patients and may explain in part its refractoriness to treatment. CONCLUSIONS: The understanding of both central and peripheral mechanisms that contribute to the development of pain is of major importance in order to propose more effective treatments for brachial plexus avulsion-related pain. This review focuses on the current understanding about the occurrence of neuropathic pain in these patients and the role played by peripheral and central mechanisms that provides insights into its treatment. Pain after brachial plexus avulsion involves both peripheral and central components; thereby it is characterized as a mixed (central and peripheral) neuropathic pain syndrome. PMID- 25935558 TI - The use of third and fourth generation cephalosporins affects the occurrence of extended-spectrum cephalosporinase-producing Escherichia coli in Danish pig herds. AB - Extended-spectrum cephalosporinase resistance is currently the fastest emerging antimicrobial resistance problem worldwide; however, evidence documenting the effect of potential risk factors is limited. The main objective of this study was to investigate the effect of using third and fourth generation cephalosporins on the occurrence of extended-spectrum cephalosporinase-producing Escherichia coli (ESC-Ec) in Danish pig herds. Conventional, integrated, medium to large herds were selected based on information from the Danish Central Husbandry Register and two groups were formed based on the use of third and fourth generation cephalosporins within a specified period, namely, 20 herds with no cephalosporin use (non-exposed) and 19 herds with frequent use (exposed). Data on prescribed antimicrobials were obtained from the National database (VetStat). Management data were obtained through a questionnaire. At the herd level, three pooled faecal samples were collected from sows with their piglets (farrowing pens), weaners, and finishers. ESC-Ec were then identified using selective enrichment. Because several of the herds only had a low number of weaners and/or finishers, analysis was only performed on samples from the farrowing pens. Logistic regression showed a significant effect of using cephalosporins-III/IV on the occurrence of ESC-Ec in the farrowing pens, even when adjusted for use of other antimicrobials 1 year prior to sampling. No confounding effect was identified in relation to management data. The relative risk ESC-Ec in exposed compared to non exposed was 4.7 (95% confidence interval 2.0-11.5), confirming that regular use of cephalosporins-III/IV was a significant risk factor for the occurrence of ESC Ec. PMID- 25935559 TI - Reliability and validity of the German translation of the de Morton Mobility Index (DEMMI) performed by physiotherapists in patients admitted to a sub-acute inpatient geriatric rehabilitation hospital. AB - BACKGROUND: Mobility is a key outcome in geriatric rehabilitation. The de Morton Mobility Index (DEMMI) is an internationally well-established, unidimensional measure of mobility with good psychometric properties. The aim of this study was to examine the reliability and construct validity of the German translation of the DEMMI in geriatric inpatients. METHODS: This cross-sectional study included patients admitted to a sub-acute inpatient geriatric rehabilitation hospital (reliability sample: N = 33; validity sample: N = 107). Reliability, validity, and unidimensionality were investigated. RESULTS: Inter-rater reliability between two graduate physiotherapists was excellent, with intra-class correlation coefficient of 0.94 (95% confidence interval: 0.88-0.97). The minimal detectable change with 90% confidence was 9 points. Construct validity for the DEMMI was evidenced by significant moderate to strong correlations with other measures of mobility and related constructs (Performance Oriented Mobility Assessment: rho = 0.89; Functional Ambulation Categories: rho = 0.70; six-minute walk test: rho = 0.73; gait speed: rho = 0.67; Falls Efficacy Scale International: rho = -0.68). Known-groups validity was indicated by significant DEMMI mean group differences between independent versus dependent walkers and walking aid users versus non users. Unidimensionality of the German DEMMI translation was confirmed by Rasch analysis. CONCLUSIONS: The German translation of the DEMMI is a unidimensional instrument producing valid and reproducible measurement of mobility in an inpatient geriatric rehabilitation setting. PMID- 25935560 TI - Retention and transport of an anaerobic trichloroethene dechlorinating microbial culture in anaerobic porous media. AB - The influence of solution chemistry on microbial transport was examined using the strictly anaerobic trichloroethene (TCE) bioaugmentation culture KB-1((r)). A column was employed to determine transport behaviors and deposition kinetics of three distinct functional species in KB-1((r)), Dehalococcoides, Geobacter, and Methanomethylovorans, over a range of ionic strengths under a well-controlled anaerobic condition. A quantitative polymerase chain reaction (qPCR) was utilized to enumerate cell concentration and complementary techniques were implemented to evaluate cell surface electrokinetic potentials. Solution chemistry was found to positively affect the deposition rates, which was consistent with calculated Derjaguin-Landau-Verwey-Overbeek (DLVO) interaction energies. Retained microbial profiles showed spatially constant colloid deposition rate coefficients, in agreement with classical colloid filtration theory (CFT). It was interesting to note that the three KB-1((r)) species displayed similar transport and retention behaviors under the defined experimental conditions despite their different cell electrokinetic properties. A deeper analysis of cell characteristics showed that factors, such as cell size and shape, concentration, and motility were involved in determining adhesion behavior. PMID- 25935561 TI - Hydroxyl radical and thermal annealing on amorphous InGaZnO4 films for DNA immobilizations. AB - The effect of hydroxyl radicals (OH) and thermal annealing on an amorphous InGaZnO4 (aIGZO) film surface was investigated for manipulation of DNA immobilization. X-ray photoemission and fluorescence measurements were conducted to reveal the status of surface OH coverage and DNA immobilization, respectively. Systematic examinations concerning OH termination on the film surface suggested that the surface coverage of OH leveling DNA immobilization was related to the local surface potential. Furthermore, OH affinity on the aIGZO film surface was sensitive to thermal annealing. A remarkable change in surface OH coverage was observed for the film surface annealed at high temperature. This behavior was framed by a structural change from amorphous to crystalline state, which regulated DNA immobilization. These results indicate that the OH affinity on aIGZO films is dependent on structural properties such as defects. This study suggests that an amorphous structure is critical for obtaining a high OH surface coverage governing DNA immobilization, and is hence more suitable for biosensing. PMID- 25935562 TI - Bovine serum albumin-sodium alkyl sulfates bioconjugates as drug delivery systems. AB - Precipitation of bovine serum albumin (BSA) by anionic surfactants with alkyl chains of increasing lengths (octyl, decyl, dodecyl sulfates) was studied at room temperature, at pH 3.0, in isotonic sodium chloride solution. The particle size of albumin, the zeta potential, the surface charge and fluorescent properties of BSA-surfactant composites were investigated concerning addition of increasing amount of surfactant. The thermal stability of the systems was monitored by calorimetric analysis (DSC). The formation of the well-ordered structure in the self-assembly process in liquid phase was studied by XRD measurement. The structure of the precipitated BSA-surfactant nanocomposites was characterized by small-angle X-ray scattering (SAXS). Finally, ibuprofen (IBU) molecules were enclosed in BSA-surfactant bioconjugate systems and the release properties of the drug were investigated. It has been found out that, as a consequence to the increasing number of carbon atoms in the alkyl chains of the surfactant, the structure and the fluorescent properties of the aggregates formed can be controlled due to the increase in the hydrophobicity of BSA-surfactant composites. The bioconjugates are well applicable as carrier to realize controlled release of drug molecules. PMID- 25935563 TI - Response to the letter by Andrea Mancuso. PMID- 25935564 TI - A Case of Advanced Mucinous Adenocarcinoma of Bladder in an Adult Patient Treated With Capecitabine-Based Chemotherapy and Review of Literature. PMID- 25935565 TI - Perceiving mental states. AB - This paper argues that our awareness of the mental states of other agents is often perceptual in character. It draws partly on recent experimental findings concerning perception of animacy and intentionality. But it also emphasizes the unencapsulated nature of perception generally, and argues that concepts (including mental-state concepts) can be bound into the contents of conscious perception. One of the main arguments used in support of this conclusion draws on recent work concerning the nature and contents of working memory. PMID- 25935566 TI - Direct social perception and dual process theories of mindreading. AB - The direct social perception (DSP) thesis claims that we can directly perceive some mental states of other people. The direct perception of mental states has been formulated phenomenologically and psychologically, and typically restricted to the mental state types of intentions and emotions. I will compare DSP to another account of mindreading: dual process accounts that posit a fast, automatic "Type 1" form of mindreading and a slow, effortful "Type 2" form. I will here analyze whether dual process accounts' Type 1 mindreading serves as a rival to DSP or whether some Type 1 mindreading can be perceptual. I will focus on Apperly and Butterfill's dual process account of mindreading epistemic states such as perception, knowledge, and belief. This account posits a minimal form of Type 1 mindreading of belief-like states called registrations. I will argue that general dual process theories fit well with a modular view of perception that is considered a kind of Type 1 process. I will show that this modular view of perception challenges and has significant advantages over DSP's phenomenological and psychological theses. Finally, I will argue that if such a modular view of perception is accepted, there is significant reason for thinking Type 1 mindreading of belief-like states is perceptual in nature. This would mean extending the scope of DSP to at least one type of epistemic state. PMID- 25935567 TI - Mothers' attitudes and beliefs about infant feeding highlight barriers to exclusive breastfeeding in American Samoa. AB - BACKGROUND: In American Samoa, initiation of breastfeeding is almost universal but exclusive breastfeeding, a promising target for obesity prevention, is short in duration. AIMS: (1) To examine American Samoan mothers' feeding experiences and attitudes and beliefs about infant feeding and (2) to identify potential barriers to exclusive breastfeeding. METHODS: Eighteen semi-structured interviews were conducted with American Samoan mothers at 16-32 days postpartum. Interviews focused on mother's knowledge and beliefs about infant feeding, how their infants were fed, why the mother had chosen this mode of infant feeding, and how decisions about feeding were made within her social surroundings. A thematic qualitative analysis was conducted to identify salient themes in the data. FINDINGS: Intention to exclusively breastfeed did not predict practice; most women supplemented with formula despite intending to exclusively breastfeed. The benefits of breastfeeding were well-recognized, but the importance of exclusivity was missed. Formula-use was not preferred but considered an innocuous "back-up option" where breastfeeding was not possible or not sufficient for infant satiety. Identified barriers to exclusive breastfeeding included: the convenience of formula; perceptions among mothers that they were not producing enough breast milk; and pain while breastfeeding. The important support role of family for infant feeding could be utilized in intervention design. CONCLUSION: This study identified barriers to exclusive breastfeeding that can be immediately addressed by providers of breastfeeding support services. Further research is needed to address the common perception of insufficient milk in this setting. PMID- 25935568 TI - A Comparison of Dietary Practices at or En Route to School between Elementary and Secondary School Students in Vancouver, Canada. AB - BACKGROUND: There is evidence that dietary quality declines as children age in North America, but few studies have explored whether food environment exposures in secondary schools as opposed to elementary schools are associated with changes in students' school-day food choices. METHODS: This study examined differences in dietary practices (at or en route to and/or from school) between students in their last years of elementary school (grades 5 to 7) and first year of secondary school (grade 8) in Vancouver, Canada, controlling for sociodemographic characteristics and school-level socioeconomic status. Demographic characteristics and dietary data were collected through a cross-sectional survey (n=950 from 26 schools) and combined with school-level socioeconomic data derived from the 2006 Canadian Census. RESULTS: Multilevel logistic regression analyses indicated that secondary school students were significantly more likely to report daily consumption of fast foods (odds ratio=1.92; 95% CI 1.18 to 3.12) and minimally nutritious packaged snacks (eg, candy or chocolate bars) (odds ratio=1.60; 95% CI 1.05 to 2.45), and to report regular purchases from off-campus retailers (odds ratio=1.63; 95% CI 1.10 to 2.42). Gender, food insecurity, lower acculturation to Canada, and access to more weekly spending money were associated with nutritionally poor practices. Students attending schools drawing from lower income neighborhoods were also significantly more likely to consume fast foods and packaged snacks daily. The majority of students sampled did not report consuming healthy foods, such as fruit and vegetables, daily at or en route to and/or from school. Intake of fruit, vegetables, and low-fat milk did not differ significantly between elementary and secondary school students. CONCLUSIONS: Findings suggest that research and intervention strategies should address modifiable school-level exposures and policies to improve dietary practices for both elementary and secondary school-aged youth, while at the same time addressing sociocultural factors associated with eating behavior. PMID- 25935569 TI - Enjoyment of tactile play is associated with lower food neophobia in preschool children. AB - Previous research has shown that parental reports of food neophobia and tactile sensitivity are associated with lower fruit and vegetable (F/V) intake in children. This study aimed to pilot a behavioral observation measure of tactile play in young children. The primary aim of the study was to see whether children's enjoyment of tactile play was associated with higher F/V consumption, as well as lower food neophobia. Seventy 2- to 5-year-old children (37 males and 33 females) and their parents were recruited through children's centers in the Leicester region of the United Kingdom during July to October 2012. Children's engagement in two tactile play tasks using sticky foods (mashed potatoes and vegetarian gelatin) was observed and rated by both the researcher and parent. Parents were asked to complete a series of questionnaires measuring F/V consumption, food neophobia, and sensory processing. It was found that lower child food neophobia was significantly related to enjoyment of tactile play, whereas child F/V consumption was associated with parental F/V consumption, but not enjoyment of tactile play. The findings strengthen the idea that tactile processing may be associated with the acceptance of food variety, but not the total amount of F/V consumed. Additional research is indicated to determine whether tactile play tasks can be used to lower child food neophobia. PMID- 25935570 TI - Lifestyle weight-loss intervention outcomes in overweight and obese adults with type 2 diabetes: a systematic review and meta-analysis of randomized clinical trials. AB - The majority of people with type 2 diabetes are overweight or obese, and weight loss is a recommended treatment strategy. A systematic review and meta-analysis was undertaken to answer the following primary question: In overweight or obese adults with type 2 diabetes, what are the outcomes on hemoglobin A1c (HbA1c) from lifestyle weight-loss interventions resulting in weight losses greater than or less than 5% at 12 months? Secondary questions are: What are the lipid (total cholesterol, low-density lipoprotein cholesterol, high-density lipoprotein cholesterol, and triglycerides) and blood pressure (systolic and diastolic) outcomes from lifestyle weight-loss interventions resulting in weight losses greater than or less than 5% at 12 months? And, what are the weight and metabolic outcomes from differing amounts of macronutrients in weight-loss interventions? Inclusion criteria included randomized clinical trial implementing weight-loss interventions in overweight or obese adults with type 2 diabetes, minimum 12 month study duration, a 70% completion rate, and an HbA1c value reported at 12 months. Eleven trials (eight compared two weight-loss interventions and three compared a weight-loss intervention group with a usual care/control group) with 6,754 participants met study criteria. At 12 months, 17 study groups (8 categories of weight-loss intervention) reported weight loss <5% of initial weight (-3.2 kg [95% CI: -5.9, -0.6]). A meta-analysis of the weight-loss interventions reported nonsignificant beneficial effects on HbA1c, lipids, or blood pressure. Two study groups reported a weight loss of >=5%: a Mediterranean style diet implemented in newly diagnosed adults with type 2 diabetes and an intensive lifestyle intervention implemented in the Look AHEAD (Action for Health in Diabetes) trial. Both included regular physical activity and frequent contact with health professionals and reported significant beneficial effects on HbA1c, lipids, and blood pressure. Five trials (10 study groups) compared weight-loss interventions of differing amounts of macronutrients and reported nonsignificant differences in weight loss, HbA1c, lipids, and blood pressure. The majority of lifestyle weight-loss interventions in overweight or obese adults with type 2 diabetes resulted in weight loss <5% and did not result in beneficial metabolic outcomes. A weight loss of >5% appears necessary for beneficial effects on HbA1c, lipids, and blood pressure. Achieving this level of weight loss requires intense interventions, including energy restriction, regular physical activity, and frequent contact with health professionals. Weight loss for many overweight or obese individuals with type 2 diabetes might not be a realistic primary treatment strategy for improved glycemic control. Nutrition therapy for individuals with type 2 diabetes should encourage a healthful eating pattern, a reduced energy intake, regular physical activity, education, and support as primary treatment strategies. PMID- 25935571 TI - Publishing nutrition research: a review of multivariate techniques--part 3: data reduction methods. AB - This is the ninth in a series of monographs on research design and analysis, and the third in a set of these monographs devoted to multivariate methods. The purpose of this article is to provide an overview of data reduction methods, including principal components analysis, factor analysis, reduced rank regression, and cluster analysis. In the field of nutrition, data reduction methods can be used for three general purposes: for descriptive analysis in which large sets of variables are efficiently summarized, to create variables to be used in subsequent analysis and hypothesis testing, and in questionnaire development. The article describes the situations in which these data reduction methods can be most useful, briefly describes how the underlying statistical analyses are performed, and summarizes how the results of these data reduction methods should be interpreted. PMID- 25935572 TI - Health care justice and its implications for current policy of a mandatory waiting period for elective tubal sterilization. AB - Tubal sterilization during the immediate postpartum period is 1 of the most common forms of contraception in the United States. This time of the procedure has the advantage of 1-time hospitalization, which results in ease and convenience for the woman. The US Collaborative Review of Sterilization Study indicates the high efficacy and effectiveness of postpartum tubal sterilization. Oral and written informed consent is the ethical and legal standard for the performance of elective tubal sterilization for permanent contraception for all patients, regardless of source of payment. Current health care policy and practice regarding elective tubal sterilization for Medicaid beneficiaries places a unique requirement on these patients and their obstetricians: a mandatory waiting period. This requirement originates in decades-old legislation, which we briefly describe. We then introduce the concept of health care justice in professional obstetric ethics and explain how it originates in the ethical concepts of medicine as a profession and of being a patient and its deontologic and consequentialist dimensions. We next identify the implications of health care justice for the current policy of a mandatory 30-day waiting period. We conclude that Medicaid policy allocates access to elective tubal sterilization differently, based on source of payment and gender, which violates health care justice in both its deontologic and consequentialist dimensions. Obstetricians should invoke health care justice in women's health care as the basis for advocacy for needed change in law and health policy, to eliminate health care injustice in women's access to elective tubal sterilization. PMID- 25935573 TI - Comparison of Grouping Schemes for Exposure to Total Dust in Cement Factories in Korea. AB - OBJECTIVE: The purpose of this study was to evaluate grouping schemes for exposure to total dust in cement industry workers using non-repeated measurement data. METHODS: In total, 2370 total dust measurements taken from nine Portland cement factories in 1995-2009 were analyzed. Various grouping schemes were generated based on work process, job, factory, or average exposure. To characterize variance components of each grouping scheme, we developed mixed effects models with a B-spline time trend incorporated as fixed effects and a grouping variable incorporated as a random effect. Using the estimated variance components, elasticity was calculated. To compare the prediction performances of different grouping schemes, 10-fold cross-validation tests were conducted, and root mean squared errors and pooled correlation coefficients were calculated for each grouping scheme. RESULTS: The five exposure groups created a posteriori by ranking job and factory combinations according to average dust exposure showed the best prediction performance and highest elasticity among various grouping schemes. CONCLUSION: Our findings suggest a grouping method based on ranking of job, and factory combinations would be the optimal choice in this population. Our grouping method may aid exposure assessment efforts in similar occupational settings, minimizing the misclassification of exposures. PMID- 25935574 TI - Reliability among central readers in the evaluation of endoscopic findings from patients with Crohn's disease. AB - OBJECTIVE: The Crohn's Disease Endoscopic Index of Severity (CDEIS) and Simple Endoscopic Score for Crohn's Disease (SES-CD) are commonly used to assess Crohn's disease (CD) activity; however, neither instrument has been fully validated. We assessed intra-rater and inter-rater reliability of these indices. DESIGN: Video recordings of colonoscopies obtained from 50 patients with CD who participated in an induction trial of a biological therapy were triplicated and reviewed in random order by four central readers. Data were used to assess intra-rater and inter-rater reliability for CDEIS, SES-CD and a global evaluation of lesion severity (GELS). Subsequently, readers participated in a consensus process that identified common sources of disagreement. RESULTS: Intraclass correlation coefficients (ICCs) for intra-rater reliability for CDEIS, SES-CD and GELS (95% CIs) were 0.89 (0.86 to 0.93), 0.91 (0.89 to 0.95) and 0.81 (0.77 to 0.89), respectively, with standard error of measurement (SEM) of 2.10, 2.42 and 1.15. The corresponding ICCs for inter-rater reliability were 0.71 (0.63 to 0.76), 0.83 (0.75 to 0.88) and 0.62 (0.52 to 0.70), with SEM of 3.42, 3.07 and 1.63, respectively. Correlation between CDEIS and GELS was 0.75, between SES-CD and GELS was 0.74 and between CDEIS and SES-CD was 0.92. The most common sources of disagreement were interpretation of superficial ulceration, definition of disease site at the ileocolonic anastomosis, assessment of anorectal lesions and grading severity of stenosis. CONCLUSIONS: Central reading of CDEIS and SES-CD had 'substantial' to 'almost perfect' intra-rater and inter-rater reliability; however, the responsiveness of these instruments is yet to be determined. TRIAL REGISTRATION NUMBER: Clinicaltrials.gov NCT01466374. PMID- 25935575 TI - Kidney transplantation in highly sensitized patients. AB - BACKGROUND: Desensitization, a term loosely referring to a collection of antibody reduction and B-cell depletional therapies aimed at improving rates of transplantation in highly HLA and ABO-incompatible transplant recipients, has seen significant growth in the last decade. Advancements relate to an increasing unmet medical need for FDA-approved therapies, advancements in antibody detection methodologies and improved renal pathological assessments of antibody-mediated rejection (ABMR). SOURCES OF DATA, AREAS OF AGREEMENT AND CONTROVERSY: Data reviewed include collective summaries of experience with high-dose intravenous immunoglobulin (IVIG), B-cell depletion with rituximab and the use of plasma exchange with low-dose IVIG. Consensus suggests that these protocols are the most commonly used while experiences with other agents (i.e. bortezomib) are evolving. Controversy exists as to the extent of resources required, expense and outcomes of desensitization protocols. GROWING POINTS OR AREAS TIMELY FOR DEVELOPING RESEARCH: Here we review and synthesize data from evolving protocols and summarize developments of novel biologics aimed at modification of B-cells, antibodies and complement activation which will likely improve desensitization and treatment of ABMR. PMID- 25935576 TI - Future projections of labor hours based on WBGT for Tokyo and Osaka, Japan, using multi-period ensemble dynamical downscale simulations. AB - Following the heatstroke prevention guideline by the Ministry of Health, Labor, and Welfare of Japan, "safe hours" for heavy and light labor are estimated based on hourly wet-bulb globe temperature (WBGT) obtained from the three-member ensemble multi-period (the 2000s, 2030s, 2050s, 2070s, and 2090s) climate projections using dynamical downscaling approach. Our target cities are Tokyo and Osaka, Japan. The results show that most of the current climate daytime hours are "light labor safe,", but these hours are projected to decrease by 30-40% by the end of the twenty-first century. A 60-80% reduction is projected for heavy labor hours, resulting in less than 2 hours available for safe performance of heavy labor. The number of "heavy labor restricted days" (days with minimum daytime WBGT exceeding the safe level threshold for heavy labor) is projected to increase from ~5 days in the 2000s to nearly two-thirds of the days in August in the 2090s. PMID- 25935577 TI - Seasonal differences in climate in the Chianti region of Tuscany and the relationship to vintage wine quality. AB - Climatic factors and weather type frequencies affecting Tuscany are examined to discriminate between vintages ranked into the upper- and lower-quartile years as a consensus from six rating sources of Chianti wine during the period 1980 to 2011. These rankings represent a considerable improvement on any individual publisher ranking, displaying an overall good consensus for the best and worst vintage years. Climate variables are calculated and weather type frequencies are matched between the eight highest and the eight lowest ranked vintages in the main phenological phases of Sangiovese grapevine. Results show that higher heat units; mean, maximum and minimum temperature; and more days with temperature above 35 degrees C were the most important discriminators between good- and poor quality vintages in the spring and summer growth phases, with heat units important during ripening. Precipitation influences on vintage quality are significant only during veraison where low precipitation amounts and precipitation days are important for better quality vintages. In agreement with these findings, weather type analysis shows good vintages are favoured by weather type 4 (more anticyclones over central Mediterranean Europe (CME)), giving warm dry growing season conditions. Poor vintages all relate to higher frequencies of either weather type 3, which, by producing perturbation crossing CME, favours cooler and wetter conditions, and/or weather type 7 which favours cold dry continental air masses from the east and north east over CME. This approach shows there are important weather type frequency differences between good- and poor quality vintages. Trend analysis shows that changes in weather type frequencies are more important than any due to global warming. PMID- 25935578 TI - Morphological Decomposition in Reading Hebrew Homographs. AB - The present work investigates whether and how morphological decomposition processes bias the reading of Hebrew heterophonic homographs, i.e., unique orthographic patterns that are associated with two separate phonological, semantic entities depicted by means of two morphological structures (linear and nonlinear). In order to reveal the nature of morphological processes involved in the reading of Hebrew homographs, we tested 146 university students with three computerized experiments, each experiment focusing on a different level of processing. Participants were divided into three experimental groups given that the three experiments used the same stimulus lists. Evidence obtained from the analysis of the participants' processing time and processing accuracy points to a propensity to process heterophonic homographs by default as morpho-syntactically simple rather than complex words. Findings are discussed with reference to assumptions made by Dual-Route models regarding the importance of morphological knowledge in fast and accurate access of written words' representations which mediate the retrieval of their meanings with direct reference to the context in which they occur. PMID- 25935579 TI - Selectivity in L1 Attrition: Differential Object Marking in Spanish Near-Native Speakers of English. AB - Previous research has shown L1 attrition to be restricted to structures at the interfaces between syntax and pragmatics, but not to occur with syntactic properties that do not involve such interfaces ('Interface Hypothesis', Sorace and Filiaci in Anaphora resolution in near-native speakers of Italian. Second Lang Res 22: 339-368, 2006). The present study tested possible L1 attrition effects on a syntax-semantics interface structure [Differential Object Marking (DOM) using the Spanish personal preposition] as well as the effects of recent L1 re-exposure on the potential attrition of these structures, using offline and eye tracking measures. Participants included a group of native Spanish speakers experiencing attrition ('attriters'), a second group of attriters exposed exclusively to Spanish before they were tested, and a control group of Spanish monolinguals. The eye-tracking results showed very early sensitivity to DOM violations, which was of an equal magnitude across all groups. The off-line results also showed an equal sensitivity across groups. These results reveal that structures involving 'internal' interfaces like the DOM do not undergo attrition either at the processing or representational level. PMID- 25935580 TI - Association between n-3 polyunsaturated fatty acids in erythrocytes and metabolic syndrome in Chinese men and women. AB - PURPOSE: Evidence of an association between n-3 polyunsaturated fatty acids (PUFAs) and metabolic syndrome (MS) is limited and inconsistent. We investigated the association between n-3 PUFAs in erythrocytes and the presence of MS in Chinese adults. METHODS: The levels of alpha-linolenic acid (ALA), eicosapentaenoic acid (EPA), docosapentaenoic acid (DPA), and docosahexaenoic acid (DHA) in erythrocytes were measured using gas chromatography in 3072 participants (900 men and 2172 women) aged 30-75 years from Guangzhou, China. Cardiometabolic factors were determined, and MS was defined using the updated Adult Treatment Panel III criteria. Other covariates were collected via interviewer-administered questionnaires. RESULTS: After adjusting for age and other confounders, higher levels of marine-derived n-3 PUFAs, including EPA, DPA, and DHA, were associated with a lower presence of metabolic syndrome in both men and women. The odds ratios (95 % confidence interval) for MS obtained by comparing extreme quartiles were 0.55 (0.35-0.88) (EPA), 0.54 (0.34-0.87) (DPA), 0.45 (0.27-0.73) (DHA), and 0.52 (0.32-0.84) (total n-3 PUFAs) in men (p trend <0.05 for all results); and 0.74 (0.56-0.99) (EPA), 0.73 (0.55-0.98) (DPA), 0.75 (0.56-1.02) (DHA), and 0.71 (0.53-0.96) (total n-3 PUFAs) in women, respectively. No significant association of ALA with MS was observed (p trend > 0.05). CONCLUSION: Higher levels of total n-3 PUFAs, EPA, DPA, and DHA, but not of ALA, in erythrocyte membranes are associated with a lower presence of metabolic syndrome in Chinese adults. PMID- 25935581 TI - Cause of Death in Patients With Diabetic CKD Enrolled in the Trial to Reduce Cardiovascular Events With Aranesp Therapy (TREAT). AB - BACKGROUND: The cause of death in patients with chronic kidney disease (CKD) varies with CKD severity, but variation has not been quantified. STUDY DESIGN: Retrospective analysis of prospective randomized clinical trial. SETTING & PARTICIPANTS: We analyzed 4,038 individuals with anemia and diabetic CKD from TREAT, a randomized trial comparing darbepoetin alfa and placebo. PREDICTORS: Baseline estimated glomerular filtration rate (eGFR) and protein-creatinine ratio (PCR). OUTCOMES: Cause of death as adjudicated by a blinded committee. RESULTS: Median eGFR and PCR ranged from 20.6 mL/min/1.73 m(2) and 4.1 g/g in quartile 1 (Q1) to 47.0 mL/min/1.73 m(2) and 0.1 g/g in Q4 (P<0.01). Of 806 deaths, 441, 298, and 67 were due to cardiovascular (CV), non-CV, and unknown causes, respectively. Cumulative CV mortality at 3 years was higher with lower eGFR (Q1, 15.5%; Q2, 11.1%; Q3, 11.2%; Q4, 10.3%; P<0.001) or higher PCR (Q1, 15.2%; Q2, 12.3%; Q3, 11.7%; Q4, 9.0%; P<0.001). Similarly, non-CV mortality was higher with lower eGFR (Q1, 12.7%; Q2, 8.4%; Q3, 6.7%; Q4, 6.1%; P<0.001) or higher PCR (Q1, 10.3%; Q2, 7.9%; Q3, 9.4%; Q4, 6.4%; P=0.01). Sudden death was 1.7-fold higher with lower eGFR (P=0.04) and 2.1-fold higher with higher PCR (P<0.001). Infection related mortality was 3.3-fold higher in the lowest eGFR quartile (P<0.001) and 2.8-fold higher in the highest PCR quartile (P<0.02). The overall proportion of CV and non-CV deaths was not significantly different across eGFR or PCR quartiles. LIMITATIONS: Results may not be generalizable to nondiabetic CKD or diabetic CKD in the absence of anemia. Measured GFR was not available. CONCLUSIONS: In diabetic CKD, both lower baseline GFR and higher PCR are associated with higher CV and non-CV mortality rates, particularly from sudden death and infection. Efforts to improve outcomes should focus on CV disease and early diagnosis and treatment of infection. PMID- 25935582 TI - CYP19A1 polymorphisms and clinical outcomes in postmenopausal women with hormone receptor-positive breast cancer in the BIG 1-98 trial. AB - To determine whether CYP19A1 polymorphisms are associated with abnormal activity of aromatase and with musculoskeletal and bone side effects of aromatase inhibitors. DNA was isolated from tumor specimens of 4861 postmenopausal women with hormone receptor-positive breast cancer enrolled in the BIG 1-98 trial to receive tamoxifen and/or letrozole for 5 years. Tumors were genotyped for six CYP19A1 polymorphisms using PCR-based methods. Associations with breast cancer free interval (BCFI), distant recurrence-free interval (DRFI), musculoskeletal and bone adverse events (AEs) were assessed using Cox proportional hazards models. All statistical tests were two-sided. No association between the CYP19A1 genotypes and BCFI or DRFI was observed overall. A reduced risk of a breast cancer event for tamoxifen-treated patients with rs700518 variants was observed (BCFI CC/TC vs. TT: HR 0.53, 95 % CI 0.34-0.82, interaction P = 0.08), but not observed for letrozole-treated patients. There was an increased risk of musculoskeletal AEs for patients with rs700518 variants CC/TC versus TT (HR 1.22, 95 % CI 1.03-1.45, P = 0.02), regardless of treatment. Tamoxifen-treated patients with rs4646 variants had a reduced risk of bone AEs (AA/CA vs. CC: HR 0.76, 95 % CI 0.59-0.98), whereas an increase of minor allele (C) of rs10046 was associated with an increased risk of bone AEs (HR 1.28, 95 % CI 1.07-1.52). rs936308 variants were associated with a reduced risk of bone AEs in letrozole-treated patients (GG/GC vs. CC: HR 0.73, 95 % CI 0.54-0.99), different from in tamoxifen treated patients (GG/GC vs. CC: HR 1.32, 95 % CI 0.92-1.90, interaction P = 0.01). CYP19A1 rs700518 variants showed associations with BCFI, DRFI, in tamoxifen treated patients and musculoskeletal AEs regardless of treatment. SNPs rs4646, rs10046, and rs936308 were associated with bone AEs. PMID- 25935583 TI - Prospective evaluation of alcohol consumption and the risk of breast cancer in BRCA1 and BRCA2 mutation carriers. AB - Given the adverse effect of alcohol in the development of breast cancer among women in the general population, we evaluated whether a similar association exists among women with a BRCA1 or BRCA2 mutation. Information regarding baseline daily alcohol consumption was abstracted from a research questionnaire for 3067 BRCA mutation carriers enrolled in a prospective cohort study. Women were followed biennially until the date of the last follow-up questionnaire, date of breast cancer diagnosis, date of prophylactic bilateral mastectomy, or date of death. Cox proportional hazards models were used to estimate relative risks (RRs) and 95 % confidence intervals (CIs) for invasive breast cancer associated with alcohol consumed at or prior to completion of the baseline questionnaire. After a mean of 5.4 years of follow-up, we observed 259 incident cases of primary invasive breast cancer. Compared with non-users, the adjusted RRs were 1.06 (95 % CI 0.78-1.44) for ever use and 1.08 (0.79-1.47) for current alcohol use. For women in the highest versus lowest quintile of cumulative alcohol consumption, the RR was 0.94 (95 % CI 0.63-1.40; P trend = 0.65). Our findings suggest that alcohol consumption is not a risk factor for breast cancer among women with a BRCA1 or BRCA2 mutation. PMID- 25935584 TI - Weight lifting and appendicular skeletal muscle mass among breast cancer survivors: a randomized controlled trial. AB - Low appendicular skeletal muscle mass (ASMM) is associated with premature mortality, hyperinsulinemia, frailty, disability, and low bone mineral density. We explored the potential efficacy of slowly progressive weight lifting to attenuate the decline of ASMM among breast cancer survivors by conducting a post hoc analysis of data from the Physical Activity and Lymphedema trial. Between October 2005 and August 2008, we conducted a single-blind, randomized controlled trial of twice weekly slowly progressive weight lifting or standard care among 295 non-metastatic breast cancer survivors. ASMM was quantified using dual-energy X-ray absorptiometry. Changes in ASMM were evaluated from baseline to 12 months between the weight lifting and control groups using repeated measures linear mixed effects regression models. Over 12 months, participants in the weight lifting group experienced attenuated declines in muscle mass compared to the control group, as reflected by relative ASMM (-0.01 +/- 0.02 kg/m(2) vs -0.08 +/- 0.03 kg/m(2); P = 0.041) and absolute ASMM (-0.02 +/- 0.06 kg vs -0.22 +/- 0.07 kg; P = 0.038), respectively. Weight lifting did not alter other body composition outcomes including body mass index, total body mass, body fat percentage, and fat mass compared to the control group. Weight lifting significantly increased upper and lower body muscle strength compared to the control group. The intervention was well tolerated with no serious adverse events related to weight lifting. Slowly progressive weight lifting attenuated the decline of ASMM among breast cancer survivors compared to standard care over 12 months. These data are hypothesis generating. Future studies should examine the efficacy of weight lifting to improve distal health outcomes among breast cancer survivors. PMID- 25935585 TI - Investigations of radicular dentin permeability and ultrastructural changes after irradiation with Er,Cr:YSGG laser and dual wavelength (2780 and 940 nm) laser. AB - The aim of this study was to assess the effectiveness of dual wavelength (2780 nm Er,Cr:YSGG, 940 nm diode) laser in elimination of smear layer comparing it with Er,Cr:YSGG laser in terms of radicular dentin permeability and ultrastructural changes of root canal walls. Fifty-one sound single-rooted extracted teeth were instrumented up to size F4 and divided into three groups: group Co, non irradiated samples; group A, irradiated with Er,Cr:YSGG laser; group B, irradiated with the dual wavelength laser. Afterward, the roots were made externally impermeable, filled with 2% methylene blue dye, divided horizontally into three segments reflecting the cervical, middle, and apical thirds then examined under microscope. Using analytical software, the root section area and dye penetration area were measured, and then, the percentage of net dye penetration area was calculated. Additionally, scanning electron microscope investigations were accomplished. Analysis of variance (ANOVA) showed significant differences between all groups over the three root thirds. Dye permeation in dual wavelength laser group was significantly higher over the whole root length: cervical, middle, and apical compared to Er,Cr:YSGG laser group and non irradiated samples (p < 0.001). Scanning electron micrographs of dual wavelength irradiated samples showed a distinctive removal of smear layer with preservation of the annular structure of dentinal tubules. Er,Cr:YSGG laser root canal irradiation produced uneven removal of smear layer, in efficient cleanliness especially in the apical third. There was no sign of melting and carbonization. Within the studied parameters, root canal irradiation with dual wavelength laser increased dentin permeability. PMID- 25935586 TI - Well-Differentiated Neuroendocrine Tumour of the Extrahepatic Bile Duct: a Case Report with Review of Literature. PMID- 25935588 TI - Does the "retrospectoscope" help define best practices in transfusion? PMID- 25935587 TI - Examining General Versus Condition-Specific Health-Related Quality of Life Across Weight Categories in an Adolescent Sample. AB - This study examined health-related quality of life (HRQoL) across weight categories in adolescents using both a general and a condition-specific measure sensitive to fatigue symptoms. Participants (N = 918) completed the Pediatric Quality of Life (PedsQL) Inventory and PedsQL Multidimensional Fatigue Scale measures. Actual height and weight were used to calculate body mass index for age and sex percentiles and assign weight categories. No interaction effects between total HRQoL and weight category and gender were found; however, main effects were found for both weight category and gender. Future research should examine the impact of using different measures to assess HRQoL outcomes across weight categories. PMID- 25935589 TI - Surgical repair for primary pulmonary vein stenosis: Single-institution, midterm follow-up. AB - BACKGROUND: Primary pulmonary vein stenosis (PVS) is a rare congenital heart condition and carries a poor prognosis. METHODS: A retrospective review of 18 patients who underwent surgical therapy for primary PVS (2006-2014) was conducted. According to the degree of stenosis severity, the involved pulmonary veins (PVs) were divided into 3 categories: mild (34 veins), moderate (8), and severe (3). Pericardial patch venoplasty was used in 10 involved veins, endarterectomy in 11, and sutureless pericardial marsupialization in 19. RESULTS: Median surgical age and weight were 19.8 (range: 7-100) months and 7.7 (range: 5.3-20.3) kg, respectively. Bilateral PVS was found in 10 patients (56%), and unilateral in 8 (44%). Moderate or severe stenosis was found more frequently in PVs on the left side (P = .035). Multivein involvement was more common in patients age <=18 months than in older patients (75% vs 20%, P = .054). No early operative death occurred. Median length of hospital stay was 16 (range: 8-60) days. One subsequent death occurred (6%), at the 2-month follow up after discharge. Median follow-up time for the remaining patients was 29 (range: 2-91) months. Three of the 6 PVs treated for moderate stenosis, compared with 7 of the 34 treated for mild stenosis, developed restenosis, irrespective of the surgical strategy (P = .153). Most surviving patients remained in relatively good condition, in New York Heart Association functional class I or II. CONCLUSIONS: Detailed morphologic evaluation of each PV involved is a consideration for surgery, and is closely related to the prognosis. Moderate or severe primary PVS is worse than mild PVS, and no differences were found in effectiveness among endarterectomy, pericardial patch venoplasty, and sutureless pericardial marsupialization in treating primary PVS. PMID- 25935590 TI - Letter in response to 'Classification algorithms for the identification of structural injury in TBI using brain electrical activity'. PMID- 25935591 TI - Atopy in children with the enthesitis-related arthritis (ERA) subtype of juvenile idiopathic arthritis is associated with a worse outcome. AB - We aimed to assess the influence of co-existing atopy on the prognosis of enthesitis-related arthritis (ERA). Patients diagnosed with ERA between March 2006 and August 2012 were enrolled in a prospective cohort study and followed for 2 years. Management of patients was evaluated using the American College of Rheumatology (ACR) pediatric (Pedi) 30/50/70 criteria and laboratory variables. A total of 151 ERA patients were enrolled at diagnosis and were divided into those with atopy (n = 62) and those without (n = 89). When compared with the non-atopic group, atopic patients had significantly more active joints at disease onset (4.72 vs. 3.75), more joints with limitation of motion (LOM) (1.45 vs. 0.87), more painful joints (3.61 vs. 2.80), and more swollen joints (1.02 vs. 0.69) (p < 0.05 for all comparisons). At 3, 6, 12, 18, and 24 months, fewer ERA patients with atopy reached the ACR Pedi 50 and 70 criteria (at 3 months, 25.8 vs. 60.7 % and 11.3 vs. 34.8 %, respectively; at 6 months, 50 vs. 77.5 % and 22.6 vs. 58.4 %, respectively; at 12 months, 53.2 vs. 70.8 % and 33.9 vs. 55.1 %, respectively; at 18 months, 62.9 vs. 86.5 % and 56.5 vs. 78.7 %, respectively; at 24 months, 66.1 vs. 89.9 % and 61.3 vs. 78.7 %, respectively; all p < 0.05). During the 2 years of follow-up, the number of flares was significantly higher in ERA patients with co-existing atopy (1.48 vs. 0.70, p < 0.05). CONCLUSION: Co-existing atopy in children with ERA may exert an adverse influence on ERA, with atopic patients manifesting more active disease at diagnosis and poorer outcome. ? PMID- 25935592 TI - Sex differences in adult craniofacial parameters. AB - PURPOSE: To compare normal male and female craniofacial parameters in adults and evaluate associations of sex and intercochlear distance with other craniofacial parameters. METHODS: In 60 normal adults (30 men and 30 women) who had no otitis media, craniofacial parameters were measured retrospectively on two-dimensional reformatted computed tomography scans. RESULTS: Compared with women, men had significantly greater mean osseous auditory tube length, cartilaginous auditory tube length, mastoid length, intercochlear distance, sella to posterior nasal spine distance, sella to basion distance, and nasopharynx sagittal area. The intercochlear distance was significantly correlated with mastoid depth, midpoint of the pharyngeal opening distance, sella to nasion distance, and nasopharynx sagittal area and inversely with angle of the auditory tube. Most men and women had Korner septum present, and mean thickness of Korner septum was significantly greater in men than women. CONCLUSIONS: Some craniofacial parameters, especially vertical parameters, differ with sex. These differences begin in childhood and continue in adulthood. Sex must be considered when planning a craniofacial morphologic study, and results of a craniofacial morphologic study should be evaluated with caution when there is no sex matching of the patient and control groups. PMID- 25935593 TI - The clinical anatomy of the musculotendinous part of the diaphragm. AB - The thoracoabdominal diaphragm is a composite musculotendinous structure, separating the thoracic and abdominal cavities. Reemphasis of the already well delineated variations of the muscular and tendinous portions, and blood and nerve supply of the diaphragm is becoming apparent. Scientific reports concerning reconstruction of the pericardium, activation of the muscle and the phrenic nerves by use of laparoscopically placed intramuscular electrodes, and repair of congenital and traumatic hernias reemphasize the importance of the muscular to tendinous relationships. The objective of this study, therefore, was to measure the ratio of the surface area of the tendinous central region to the muscular region of the diaphragm and provide a clear description across various specimens. We classified diaphragmatic measurements from 104 adult human diaphragms into six classes (I-VI) based on the ratio of surface area between its tendinous and muscular components. The majority of specimens, 56.7%, was attributed to class II and indicated a tendon-to-muscle ratio of between 10 and 15%; however, a small number of specimens indicated a very large tendon area at the expense of muscle bulk. Future research should be geared toward assessing the relationship between surface area of the musculature and its motor points with focus on interventions for herniation repair and recovery. Our results have shown that surgical interventions should be tailored to the individual, as diaphragm size may not necessarily predict tendon-to-muscle ratio. PMID- 25935594 TI - Use of Adaptive Focused AcousticsTM ultrasound in controlling liposome formation. AB - Many techniques for producing large unilamellar vesicles (LUVs) or small unilamellar vesicles (SUVs) have drawbacks, including exposure of sensitive biological materials to harsh organic solvents or high temperatures. Here we describe the use of controlled focused ultrasound, Adaptive Focused AcousticsTM (AFA), to make LUV or SUV at low temperature without organic solvents and at a consistent, chosen size. We studied the effects of peak incident power (PIP), cycles per burst (CPB), duty factor (DF), temperature, and lipid composition (natural or synthetic), on liposome size distribution. We found that an increase in PIP, DF, CPB, or temperature decreased liposome size. When processed under the same conditions as the natural lipid composition [Phospholipon 90 G], the synthetic lipid composition [HSPC, DSPE-PEG-2000, Chol] generally produced larger liposomes, although extending processing time reduced liposomes to similar size. In combination with AFA, these trends can help pinpoint parameter values that achieve a desired liposome size distribution. PMID- 25935595 TI - Some Reflections on the Microbiome and Obesity. PMID- 25935596 TI - Tumor thickness and adnexal extension of superficial basal cell carcinoma (sBCC) as determinants of treatment failure for methylaminolevulinate (MAL)-photodynamic therapy (PDT), imiquimod, and 5-fluorouracil (FU). AB - BACKGROUND: Noninvasive treatments are frequently used in treatment of superficial basal cell carcinoma (sBCC) because of better cosmetic results, lower costs, and less burden on health care services when compared with surgical excision. However, probability of treatment failure is higher after noninvasive therapies and may depend on histologic tumor characteristics. OBJECTIVE: We sought to investigate whether tumor thickness and adnexal extension are determinants of treatment failure in sBCC treated with topical methylaminolevulinate-photodynamic therapy, imiquimod, or 5-fluorouracil. METHODS: Data were derived from a randomized controlled trial on the effectiveness of methylaminolevulinate photodynamic therapy, imiquimod, and 5 fluorouracil for treatment of sBCC (ISRCTN79701845). For tumors with treatment failure (n = 112) and a randomly selected control group of tumors without treatment failure (n = 224) data on tumor thickness and adnexal extension were retrospectively collected. Treatment failure was defined as a clinically and histologically persistent or recurrent tumor within 1-year posttreatment. RESULTS: Tumor thickness of included patients ranged from 0.2 to 1.0 mm. Tumor thickness and adnexal extension of sBCC were not significantly associated with treatment failure of methylaminolevulinate photodynamic therapy, imiquimod, or 5 fluorouracil. LIMITATIONS: Follow-up period of 1 year is a limitation. CONCLUSION: There seems to be no need to determine tumor thickness or adnexal extension in sBCC before treatment. PMID- 25935597 TI - Correction of Non-Linear Propagation Artifact in Contrast-Enhanced Ultrasound Imaging of Carotid Arteries: Methods and in Vitro Evaluation. AB - Non-linear propagation of ultrasound creates artifacts in contrast-enhanced ultrasound images that significantly affect both qualitative and quantitative assessments of tissue perfusion. This article describes the development and evaluation of a new algorithm to correct for this artifact. The correction is a post-processing method that estimates and removes non-linear artifact in the contrast-specific image using the simultaneously acquired B-mode image data. The method is evaluated on carotid artery flow phantoms with large and small vessels containing microbubbles of various concentrations at different acoustic pressures. The algorithm significantly reduces non-linear artifacts while maintaining the contrast signal from bubbles to increase the contrast-to-tissue ratio by up to 11 dB. Contrast signal from a small vessel 600 MUm in diameter buried in tissue artifacts before correction was recovered after the correction. PMID- 25935598 TI - Tuberculosis in infants less than 3 months of age. AB - A review was conducted on infants less than 3 months of age diagnosed with tuberculosis between 1978 and 2014. Eight patients were diagnosed (1.4% of paediatric tuberculosis cases): 3 confirmed congenital tuberculosis, 3 suspected (endometrial biopsy was not performed), and 2 postnatal tuberculosis. Tuberculin skin test was negative in two patients. Diagnostic performance of culture (7/7, 100%) and PCR (3/3, 100%) of gastric aspirates was higher than that of acid-fast bacilli smears (5/8, 62%) and IGRA test (1/3, 33%). Three patients developed miliary disease, and one died. In conclusion, tuberculosis in this age group is rare, severe, and difficult to diagnose. In cases lacking known postnatal contacts, maternal genital tuberculosis should be ruled out by endometrial biopsy. PMID- 25935599 TI - [Staphylococcus aureus resistant to methicillin and usual decolonizers with a reservoir in a health worker in a tertiary hospital]. PMID- 25935600 TI - Percutaneous Removal of Inferior Vena Cava Filter after Migration to Pulmonary Artery using an 8-Fr Multipurpose Catheter. AB - An inferior vena cava filter migrated to the left pulmonary artery during removal. The legs of the filter were not open adequately due to thrombus accumulating around the legs and resulted in the filter floating up and migrating to the pulmonary artery through the right atrium and ventricle. The hook for retrieval placed at the top of the filter faced proximal in the pulmonary artery and the legs of filter remained closed, consequently the filter could be removed safely from the pulmonary artery. An 8-Fr multipurpose catheter with its flexibility was useful to retrieve the filter from the pulmonary artery. PMID- 25935601 TI - Inhibition of mercury release from forest soil by high atmospheric deposition of Ca2+ and SO42-. AB - As one of the most important natural mercury (Hg) sources, soil release (emission to the atmosphere or leaching to soil water) depends on various factors, some of which can be affected by atmospheric deposition. We studied the effect of flue gas desulfurization gypsum (FGDG) addition on soil Hg release in a Masson pine (Pinus massoniana) forest in southwestern China. FGDG addition simulated atmospheric deposition of Ca(2+), SO4(2-) and Hg, which are commonly high in China. Results showed that Hg concentration in soil water decreased with the gypsum treatment, suggesting that the mobility of Hg in mineral soil was reduced. Moreover, the application of gypsum also seems to have decreased Hg emission from the soil, shown by the lower Hg contents in leaf tissues of ground vegetation in the treated plots than in the reference. Both Hg mobility in the soil and Hg emission to the atmosphere were decreased despite the additional Hg input from FGDG. The decreased DOC concentration in soil water and the elevated organic sulfur content in the soil Oe & Oa horizons were speculated to result in an enhanced capacity of surface soil to bind Hg, and thus to reduce Hg release from the soil. However, with the increasingly stringent control of particulate matter (PM) and sulfur dioxide (SO2) emissions in China, the deposition of Ca(2+) and SO4(2-) is expected to decrease, and their ability to inhibit soil Hg release is likely to decline in the future. PMID- 25935602 TI - Pharmaceutical residues in water and sediment of Msunduzi River, KwaZulu-Natal, South Africa. AB - The little data about pharmaceutical residue contamination in African water bodies motivated our study on the occurrence of pharmaceutical residues in the water and sediment of Msunduzi River in the KwaZulu-Natal province of South Africa; and in the Darvill wastewater treatment plant found in Msunduzi catchment. Samples collected along the River and wastewater treatment plant were extracted and analysed for pharmaceutical residues selected based on statistics of drug usage in South Africa i.e. antipyretics, antibiotics, caffeine, an antiepileptic and an antipsychotic drug were determined using HPLC-MS/MS. In all the matrices investigated, the antipyretic ibuprofen had the highest concentration of up to 117 MUg L(-1), 84.60 MUg L(-1) and 659 ng g(-1) in wastewater, surface water and sediment respectively. Antibiotics were detected in generally low concentrations of<10 MUg L(-1) in surface water samples and up to 34.50 MUg L(-1) in wastewater; moreover they were not completely removed during wastewater treatment. The percentage removal efficiency of the studied group was 6.55-98.00% for antipyretics, 73.33-98.90% for antibiotics, 48.80% for the anti epileptic drug and 86.40% for Caffeine. Clozapine exhibited a negative removal. In surface water, Henley dam exhibited a high concentration of the pharmaceutical residues and the highest concentration of metronidazole in sediment (up to 1253.50 ng g(-1)) detected. Metronidazole was only detected in sediment and bio solids. PMID- 25935603 TI - Photosynthesis is induced in rice plants that associate with arbuscular mycorrhizal fungi and are grown under arsenate and arsenite stress. AB - The metalloid arsenic (As) increases in agricultural soils because of anthropogenic activities and may have phytotoxic effects depending on the available concentrations. Plant performance can be improved by arbuscular mycorrhiza (AM) association under challenging conditions, such as those caused by excessive soil As levels. In this study, the influence of AM on CO2 assimilation, chlorophyll a fluorescence, SPAD-chlorophyll contents and plant growth was investigated in rice plants exposed to arsenate (AsV) or arsenite (AsIII) and inoculated or not with Rhizophagus irregularis. Under AsV and AsIII exposure, AM rice plants had greater biomass accumulation and relative chlorophyll content, increased water-use efficiency, higher carbon assimilation rate and higher stomatal conductance and transpiration rates than non-AM rice plants did. Chlorophyll a fluorescence analysis revealed significant differences in the response of AM-associated and -non-associated plants to As. Mycorrhization increased the maximum and actual quantum yields of photosystem II and the electron transport rate, maintaining higher values even under As exposure. Apart from the negative effects of AsV and AsIII on the photosynthetic rates and PSII efficiency in rice leaves, taken together, these results indicate that AM is able to sustain higher rice photosynthesis efficiency even under elevated As concentrations, especially when As is present as AsV. PMID- 25935604 TI - Nonequilibrium leaching behavior of metallic elements (Cu, Zn, As, Cd, and Pb) from soils collected from long-term abandoned mine sites. AB - Leaching of metallic elements (Cu, Zn, As, Cd, and Pb) from two mine-impacted soils (DY and BS) was evaluated by batch decant-refill and seepage flow experiments. During eight consecutive leaching steps, aqueous As concentrations remained relatively constant (approx. 1.6 and 0.1 mg L(-)(1) for DY and BS, respectively), while Cu (0.01-3.2 mg L(-1)), Zn (0.2-42 mg L(-1)), and Cd (0.004 0.3 mg L(-1)) were quickly reduced. The reduction of Pb concentration (0.007-0.02 mg L(-1) and 0.2-0.9 mg L(-1) for DY and BS, respectively) was much lesser. This pattern was well-explained by the biphasic leaching model by allocating a large fast leaching fraction (ffast>0.2) for Cu, Zn, and Cd while a negligible ffast for As and Pb (<0.001). For all elements in column effluents, mass export through first-flush and steady-state concentration were elevated under slow seepage, with the greatest impact observed for As. Element export was enhanced after flow interruption, especially under fast seepage. A transient drop in As export in slow seepage was likely due to sorption back to soil phase during the quiescent period. The ratio of Fe(2+)/Fe(3+) and SO4(2-) concentration, related to the dissolution of sulfide minerals, were also seepage rate-dependent. The results of batch and column studies imply that the leachate concentration will be enhanced by initial seepage and will be perturbed after quiescent wetting period. The conversion from kinetically leachable pool to readily leachable pool is likely responsible for nonequilibrium metal leaching from the long-term abandoned mine soils. PMID- 25935605 TI - Proteasome inhibitors. AB - Proteasome inhibitors have a 20 year history in cancer therapy. The first proteasome inhibitor, bortezomib (Velcade, PS-341), a break-through multiple myeloma treatment, moved rapidly through development from bench in 1994 to first approval in 2003. Bortezomib is a reversible boronic acid inhibitor of the chymotrypsin-like activity of the proteasome. Next generation proteasome inhibitors include carfilzomib and oprozomib which are irreversible epoxyketone proteasome inhibitors; and ixazomib and delanzomib which are reversible boronic acid proteasome inhibitors. Two proteasome inhibitors, bortezomib and carfilzomib are FDA approved drugs and ixazomib and oprozomib are in late stage clinical trials. All of the agents are potent cytotoxics. The disease focus for all the proteasome inhibitors is multiple myeloma. This focus arose from clinical observations made in bortezomib early clinical trials. Later preclinical studies confirmed that multiple myeloma cells were indeed more sensitive to proteasome inhibitors than other tumor cell types. The discovery and development of the proteasome inhibitor class of anticancer agents has progressed through a classic route of serendipity and scientific investigation. These agents are continuing to have a major impact in their treatment of hematologic malignancies and are beginning to be explored as potential treatment agent for non-cancer indications. PMID- 25935606 TI - Two-Year Clinical Results of Lateral Collagen Meniscus Implant: A Multicenter Study. AB - PURPOSE: To present the 2-year results of the use of the lateral Collagen Meniscus Implant (CMI) for the treatment of irreparable lateral meniscal lesions or partial lateral meniscal defects, to investigate the potential predictors of clinical results, and to monitor device safety. METHODS: Forty-three patients with a mean age of 30.1 +/- 12.0 years were clinically evaluated 24 months after treatment of partial lateral meniscal defects with the CMI (Ivy Sports Medicine, Grafelfing, Germany). We used the Lysholm score, the Tegner Activity Scale, a visual analog scale for pain (during strenuous activity, during routine activity, and at rest), a functional questionnaire, and a satisfaction questionnaire for the evaluation. All demographic and surgical parameters were used for multiple regression analysis to find outcome predictors. Serious adverse events and reoperations were monitored. RESULTS: All clinical scores significantly improved from preoperatively to final evaluation at 24.2 +/- 1.9 months' follow-up. The Lysholm score improved significantly from 64.3 +/- 18.4 preoperatively to 93.2 +/ 7.2 at final follow-up (P = .0001). Functional improvement was detected from 6 months after surgery, whereas strenuous activities and knee swelling reached optimal results after 12 months. The highest pain ratings experienced during strenuous activity, during routine activity, and at rest significantly improved from 59 +/- 29, 29 +/- 25, and 20 +/- 25, respectively, preoperatively to 14 +/- 18, 3 +/- 5, and 2 +/- 6, respectively, at 2 years' follow-up (P = .0001). At final follow-up, 58% of patients reported activity levels similar to their preinjury values whereas 95% of patients reported that they were satisfied with the procedure. A higher body mass index, the presence of concomitant procedures, and a chronic injury pattern seemed to negatively affect the final outcomes. Serious adverse events with a known or unknown relation to the scaffold, such as pain, swelling, and scaffold resorption, were reported in 6% of patients, leading to CMI explantation, debridement, or synovectomy. CONCLUSIONS: The lateral CMI scaffold could be considered a potentially effective and safe procedure to treat both irreparable lateral meniscal tears and post-meniscectomy syndrome in appropriately selected patients. Chronic injury, high body mass index, and concomitant procedures have been shown to negatively affect the short-term results; however, the results appeared to slowly improve through the 24-month follow-up period. Thus patience is needed when evaluating the expectations for and results of the described procedure. LEVEL OF EVIDENCE: Level IV, therapeutic case series. PMID- 25935607 TI - [Food consumption and nutritional adequacy in Brazilian children: a systematic review]. AB - OBJECTIVE: To perform a review of studies of food consumption and nutritional adaptation in Brazilian infants pointing the main findings and limitations of these studies. DATA SOURCE: The articles were selected from Literatura Latino Americana e do Caribe em Ciencias da Saude (Lilacs) (Latin-American and Caribbean Literature in Health Sciences), Scientific Electronic Library Online (SciELO) and Science Direct in Portuguese and in English. The descriptors were: "food consumption", "nutritional requirements", "infant nutrition" and "child". The articles selected were read by two evaluators that decided upon their inclusion. The following were excluded: studies about children with pathologies; studies that approached only food practices or those adaptation of the food groups or the food offert; and studies that did not utilize the Dietary Reference Intakes (DRI). DATA SYNTHESIS: Were selected 16 studies published between 2003 and 2013. In the evaluation of the energy consumption, four studies presented energetic consumption above the individual necessities. The prevalence of micronutrients inadequacy ranged from 0.4% to 65% for iron, from 20% to 59.5% for vitamin A, from 20% to 99.4% for zinc, from 12.6% to 48.9% for calcium and from 9.6% 96.6% for vitamin C. CONCLUSIONS: The food consumption of Brazilian infants is characterized by high frequencies of inadequacy of micronutrients consumption, mainly iron, vitamin A and zinc. These inadequacies do not exist only as deficiencies, but also as excesses, as noted for energetic consumption. PMID- 25935608 TI - Organobromine compound profiling in human adipose: Assessment of sources of bromophenol. AB - Bromophenols (BRPs) have been widely detected in human tissues, however, relative proportions from natural products and/or anthropogenic flame retardants are not clear. 21 polybrominated diphenyl ethers (PBDEs), 15 MeO/OH-PBDEs, and 10 BRPs were simultaneously quantified in adipose collected from people from New York City, USA. An in vitro assay utilizing human liver microsomes was performed for detected predominant organobromine. High concentrations of 2,4,6-triBRP and PBDEs were observed, and extremely low concentrations of naturally occurring MeO/OH PBDEs were detected. Similar biotransformatioin rates of BRPs and MeO/OH-PBDEs indicated that the relative high concentration of 2,4,6-triBRP in humans was not of natural origin. Significant correlation observed between concentrations of 2,4,6-triBRP and BDE-209 suggested that the two chemicals may share a common source. Both 2,4,6-triBRP and BDE-209 were detected in commercial ABS resins, suggesting that plastic products made from ABS resins could be potential sources of co-exposure of the two compounds for humans. PMID- 25935609 TI - Drosophila subobscura flies adapted to low lead concentration carry no fitness cost. AB - As a response to the long-term presence of heavy metals in the environment, populations can evolve resistance. Its maintenance may have detrimental effect on population's fitness, causing a fitness cost. Lead is one of the widely distributed elements in the environment exhibiting high toxicity on organisms. By analyzing developmental stages viability and developmental time, we evaluated fitness cost in Drosophila subobscura flies adapted to low lead concentration and control flies derived from the same wild population, as well as their hybrids. Significant changes in specific developmental stages viability were detected in both lines, as well as their hybrids, suggesting complex response to low lead concentration. The results show that a long-term exposure to low lead concentration may have a significant impact on a population's survival, especially in a changing environment conditions. PMID- 25935610 TI - Passive control potentials of trees and on-street parked cars in reduction of air pollution exposure in urban street canyons. AB - This study investigates the passive-control-potentials of trees and on-street parked cars on pedestrian exposure to air pollutants in a street canyon using three-dimensional CFD. Since, according to some studies trees deteriorate air quality and cars parked roadside improve it, the combine as well as separate effects of trees and on-street parked cars have been examined. For this, different tree canopy layouts and parking configurations have been developed and pedestrian exposure for each has been analysed. The results showed, for example, tree crown with high porosity and low-stand density in combination with parallel or perpendicular car parking reduced the pedestrian exposure considerably. PMID- 25935611 TI - Can we improve pollen season definitions by using the symptom load index in addition to pollen counts? AB - Airborne pollen measurements are the foundation of aerobiological research and provide essential raw data for various disciplines. Pollen itself should be considered a relevant factor in air quality. Symptom data shed light on the relationship of pollen allergy and pollination. The aim of this study is to assess the spatial variation of local, regional and national symptom datasets. Ten pollen season definitions are used to calculate the symptom load index for the birch and grass pollen seasons (2013-2014) in Austria. (1) Local, (2) regional and (3) national symptom datasets are used to examine spatial variations and a consistent pattern was found. In conclusion, national datasets are suitable for first insights where no sufficient local or regional dataset is available and season definitions based on percentages provide a practical solution, as they can be applied in regions with different pollen loads and produce more constant results. PMID- 25935612 TI - Accumulation of floating microplastics behind the Three Gorges Dam. AB - We investigated the occurrence and distribution of microplastics in surface water from the Three Gorges Reservoir. Nine samples were collected via trawl sampling with a 112 MUmmesh net. The abundances of microplastics were from 3407.7 * 10(3) to 13,617.5 * 10(3) items per square kilometer in the main stream of the Yangtze River and from 192.5 * 10(3) to 11,889.7 * 10(3) items per square kilometer in the estuarine areas of four tributaries. The abundance of microplastics in the main stream of the Yangtze River generally increased as moving closer to the Three Gorges Dam. The microplastics are made exclusively of polyethylene (PE), polypropylene (PP), and polystyrene (PS). Together with microplastics, high abundance of coal/fly ash was also observed in the surface water samples. Comparing with previously reported data, microplastics in the TGR were approximately one to three orders of magnitudes greater, suggesting reservoirs as potential hot spot for microplastic pollution. PMID- 25935613 TI - Polychlorinated naphthalenes (PCNs) in Chinese forest soil: Will combustion become a major source? AB - We collected O- and A-horizon soil samples in 26 Chinese mountainous forests to investigate the content, spatial pattern, and potential sources of polychlorinated naphthalenes (PCNs). Spatial patterns were influenced mainly by the approximation to sources and soil organic contents. High concentrations often occurred close to populated or industrialized areas. Combustion-related activities contributed to PCN pollution. Relatively high proportions of CN-73 in northern China may be attributed to coke consumption, while CN-51 could be an indicator of biomass burning in Southwest China. There are evidences that PCNs may largely derived from unintentional production. If uncontrolled, UP-PCN (unintentionally produced PCNs) emissions could increase with industrial development. The abnormally high concentrations at Gongga and Changbai Mountains appear to be associated with the high efficient of forest filter of atmospheric contaminants at these densely forested sites. We question whether this is caused by ecotones between forests, and raise additional questions for future analyses. PMID- 25935614 TI - Bioactivity assay of porcine relaxin based on cAMP accumulation in THP-1 cells quantified by LC-MS/MS. AB - This study describes a reliable bioactivity assay of porcine relaxin (pRLX) based on cyclic adenosine 3',5'-monophosphate (cAMP) accumulation in the human monocyte cell-line quantified by liquid chromatography-tandem mass spectrometry (LC MS/MS). As a result, the LC-MS/MS was based on a positive selected reaction monitoring of cAMP with a stable internal standard, 8-Br-cAMP and a protein precipitation procedure by HClO4. The standard curve of cAMP was linear from 5.0 ng mL(-1) to 992.0 ng mL(-1), with lower limits of detection and quantification of 0.5 ng mL(-1) and 5.0 ng mL(-1), respectively. The satisfactory validation data including stability assay were obtained. When measured by the LC-MS/MS, the pRLX sample showed a time- and dose-dependent stimulation of cAMP with the concentration for 50% of the maximal effect (EC50) of 40.6 ng mL(-1). The developed method indicated higher precision and selectivity than the commercial enzyme linked immunosorbent assay kits, which showed EC50 of 66.6 ng mL(-1). PMID- 25935615 TI - Does smoking habit affect the randomized comparison of 6 versus 24-month dual antiplatelet therapy duration? Insights from the PRODIGY trial. PMID- 25935616 TI - Clinical significance of pulse pressure in patients with coronary artery disease. PMID- 25935617 TI - Family history of premature myocardial infarction, life course socioeconomic position and coronary heart disease mortality--A Cohort of Norway (CONOR) study. AB - BACKGROUND/OBJECTIVES: To investigate self-reported family history (FH) of premature myocardial infarction (MI) in first-degree relatives as a risk factor for coronary heart disease (CHD) mortality, and assess whether any observed effect could be explained by current or life course socioeconomic position. METHODS: 130,066 participants from Cohort of Norway were examined during 1994 2003. A subgroup (n=84,631) had additional life course socioeconomic data. Using Cox proportional hazard analyses, we calculated hazard ratios (HR) for CHD mortality, assessed by linkages to the Norwegian Cause of Death Registry through 2009. For subgroup analyses, we created an index of life course socioeconomic position, and assessed its role as a potential confounder in the association of FH with CHD. RESULTS: For men, MI in parents and siblings were both a significant risk factor for CHD mortality after adjusting for established risk factors and current socioeconomic conditions; the highest risk was with MI in siblings (HR: 1.44 [1.19-1.75]). For women, FH constituted significant risk after similar adjustment only for those with MI in parents plus siblings (HR: 1.78 [1.16 2.73]). Adjusting for current and life course socioeconomic conditions only marginally lowered the estimates, and those with FH did not have worse life course socioeconomic position than those without. CONCLUSIONS: FH of premature MI is an independent risk factor for CHD mortality that differs in magnitude of effect by the sex of the index person and type of familial relationship. Life course socioeconomic position has little impact on the association between FH and CHD, suggesting the effect is not confounded by this. PMID- 25935618 TI - Determinants and covariates of central pressures and wave reflections in systolic heart failure. AB - BACKGROUND: In general, higher blood pressure levels and increased central pulsatility are indicators for increased cardiovascular risk. However, in systolic heart failure (SHF), this relationship is reversed. Therefore, the aim of this work is to compare pulsatile hemodynamics between patients with SHF and controls and to clarify the relationships between measures of cardiac and arterial function in the two groups. METHODS: We used parameters derived from angiography, echocardiography, as well as from pulse wave analysis (PWA) and wave separation analysis (WSA) based on non-invasively assessed pressure and flow waves to quantify cardiac function, aortic stiffness and arterial wave reflection in 61 patients with highly reduced (rEF) and 122 matched control-patients with normal ejection fraction (nEF). RESULTS: Invasively measured pulse wave velocity was comparable between the groups (8.6/8.05 m/s rEF/nEF, P = 0.24), whereas all measures derived by PWA and WSA were significantly decreased (augmentation index: 18.1/24.8 rEF/nEF, P < 0.01; reflection magnitude: 56.3/62.1 rEF/nEF, P < 0.01). However, these differences could be explained by the shortened ejection duration (ED) in rEF (ED: 269/308 ms rEF/nEF, P < 0.01; AIx: 22.2/22.8 rEF/nEF, P = 0.7; RM: 59.3/60.6 rEF/nEF, P = 0.47 after adjustment for ED). Ventricular function was positively associated with central pulse pressures in SHF in contrast to no or even a slightly negative association in controls. CONCLUSIONS: The results suggest that the decreased measures of pulsatile function may be caused by impaired systolic function and altered interplay of left ventricle and vascular system rather than by a real reduction of wave reflections or aortic stiffness in SHF. PMID- 25935619 TI - Effect of pacemaker site on B-type natriuretic peptide levels and left ventricular function in a population with high prevalence of Chagas disease. PMID- 25935620 TI - Urinary 8-hydroxy-2'-deoxyguanosine as a novel biomarker of inflammatory activity in patients with cardiac sarcoidosis. AB - BACKGROUND: Inflammation and oxidative stress play a crucial role in the pathogenesis of cardiac sarcoidosis (SAR). We investigated whether urinary (U) 8 hydroxy-2'-deoxyguanosine (8-OHdG)--an oxidative DNA damage marker--was related to SAR inflammatory activity. METHODS: U-8-OHdG levels were measured in 31 SAR patients, classified as active (n=17) or non-active (n=14) based on (18)F fluorodeoxyglucose positron emission tomography-computed tomography ((18)F-FDG PET/CT), 28 dilated cardiomyopathy (DCM) patients, and 30 controls. In active SAR patients, U-8-OHdG levels were reexamined and compared with (18)F-FDG-PET/CT results at 6 months after corticosteroid treatment to assess therapeutic response. RESULTS: Immunohistochemical examination of left ventricle (LV) autopsy samples from SAR patients revealed positive 8-OHdG staining in cardiomyocyte nuclei from LV sections showing (18)F-FDG accumulation on PET/CT, while serum 8 OHdG levels were significantly higher in the coronary sinus than in the aortic root only in active SAR patients. U-8-OHdG levels in SAR patients were higher than those in controls, and significantly higher in active SAR patients than in non-active SAR and DCM patients. U-8-OHdG was a powerful predictor of active SAR in receiver operating characteristic curve analysis (AUC, 0.98; 95% CI, 0.94 1.02; optimal cutoff value, 13.1 ng/mg creatinine), with a sensitivity of 88.2% and a specificity of 92.9%. U-8-OHdG levels in responders significantly decreased at 6 months after corticosteroid treatment initiation, in proportion with the decrease in the focal cardiac uptake of (18)F-FDG. CONCLUSIONS: U-8-OHdG is a potentially clinically useful biomarker for evaluating inflammatory activity and monitoring the effectiveness of corticosteroid therapy in SAR patients. PMID- 25935621 TI - Cardiovascular imaging in arrhythmogenic right ventricular dysplasia/cardiomyopathy. PMID- 25935622 TI - Diagnostic and prognostic value of a novel cardiac calcification score for coronary artery disease by transthoracic echocardiography. PMID- 25935623 TI - The pivotal role of eNOS uncoupling in vascular endothelial dysfunction in patients with heart failure with preserved ejection fraction. PMID- 25935624 TI - Catheter ablation of idiopathic ventricular tachycardia without the use of fluoroscopy. AB - BACKGROUND: Catheter ablation is the treatment of choice for many patients with idiopathic ventricular tachycardia (VT). Unfortunately, conventional catheter ablation is guided by fluoroscopy, which is associated with a small but definite radiation risk for patients and laboratory personnel. The aim of our study is to assess feasibility, success rate and safety of idiopathic VT ablation procedure performed without the use of fluoroscopy. METHODS: Nineteen consecutive patients undergoing idiopathic VT ablation at our institution have been included. The ablation procedures were performed under the guidance of electroanatomical mapping (EAM) system and intracardiac echocardiography (ICE). RESULTS: Nineteen patients (mean age 38.7 years) underwent ablation procedure for idiopathic VT. Twelve (63%) had outflow tract VT, 3 (18%) fascicular tachycardia, 2 (11%) peri tricuspidal VT, 1 (5%) peri-mitral VT, and 1 (5%) lateral left free-wall VT. The mean procedural time was 170.2 +/- 45.7 min. No fluoroscopy was used in any procedural phase. Acute success rate was 100%. No complication was documented in any patients. After a mean follow up of 18 +/- 4 months, recurrences occurred in 2 patients. CONCLUSIONS: In our preliminary experience idiopathic VT ablation without the use of fluoroscopy was feasible and safe, using a combination of EAM and ICE. Success rate was excellent with no complication. PMID- 25935625 TI - Antiplatelet therapy in Japanese patients with atrial fibrillation without oral anticoagulants: Pooled analysis of Shinken Database, J-RHYTHM registry and Fushimi AF registry. PMID- 25935626 TI - PCI in STEMI reperfusion: Are we getting closer to tackling the STEMI pathophysiology? PMID- 25935627 TI - Effect of antithrombotic and antiplatelet agents for ischemic stroke in atrial fibrillation patients with dialysis. PMID- 25935628 TI - Decreasing prevalence of isolates with vancomycin heteroresistance and vancomycin minimum inhibitory concentrations >=2 mg/L in methicillin-resistant Staphylococcus aureus over 11 years: potential impact of vancomycin treatment guidelines. AB - We evaluated vancomycin MIC (V-MIC) and the prevalence of intermediately susceptible (VISA) and heteroresistant (hVISA) isolates trends in methicillin resistant Staphylococcus aureus bacteremia among 720 adults (>= 18 years) inpatients over 4 study periods (2002-2003, 2005-2006, 2008-2009, and 2010-2012). V-MIC (Etest) and the prevalence of hVISA and VISA (determined by population analysis profile-area under the curve) were stratified according to the study period. Mean vancomycin MIC was 1.78 +/- 0.39, 1.81 +/- 0.47, 1.68 +/- 0.26, and 1.54 +/- 0.28 mg/L in 2002-2003, 2005-2006, 2008-2009, and 2010-2012, respectively (P < 0.0001). We noted a steadily decreasing prevalence of isolates with V-MIC >= 2 mg/L (50.0%, 45.2%, 35.4%, and 18.7%; P < 0.0001) and hVISA (9.7%, 6.6%, 3.0%, and 2.1%; P=0.0003). VISA prevalence remained low (0-2%). These changes coincided with steadily increasing vancomycin trough levels (9.9 +/ 7.8, 11.1 +/- 8.4, 16.6 +/- 7.8, and 19.7 +/- 5.9 mg/L in 2002-2003, 2005-2006, 2008-2009, and 2010-2012, respectively; P < 0.0001). These changes imply that adherence to vancomycin treatment guidelines may suppress the development of less susceptible isolates. PMID- 25935629 TI - Induction of ROS generation by fluconazole in Candida glabrata: activation of antioxidant enzymes and oxidative DNA damage. AB - In this study, we assessed the generation of reactive oxygen species (ROS) induced by subinhibitory concentration of fluconazole in susceptible and resistant Candida glabrata strains at stationary growth phase and measured their oxidative responses parameters: glutathione peroxidase (GPx), superoxide dismutase (SOD), glutathione-S-transferase (GST), consumption of hydrogen peroxide, and total glutathione, as well as oxidative damage in lipids, proteins, and DNA. Data showed that fluconazole increased generation of ROS and GPx and SOD enzymatic activity in treated cells; however, these enzymatic activities did not differ between resistant and susceptible strains. Susceptible strains exhibited higher GST activity than resistant, and when susceptible cells were treated with fluconazole, GST activity decreased. Fluconazole treatment cause oxidative damage only in DNA. There are a possible participation of ROS, as organic peroxides and O2(*-), in antifungal mechanism of fluconazole, which results in higher GPx and SOD enzymatic activities and oxidative DNA damage in C. glabrata. PMID- 25935630 TI - Molecular epidemiology of KPC-2-producing Enterobacteriaceae (non-Klebsiella pneumoniae) isolated from Brazil. AB - In Brazil, since 2009, there has been an ever increasing widespread of the bla(KPC-2) gene, mainly in Klebsiella pneumoniae. This study aims to assess the molecular epidemiology and genetic background of this gene in Enterobacteriaceae (non-K. pneumoniae) species from 9 Brazilian states between 2009 and 2011. Three hundred eighty-seven isolates were analyzed exhibiting nonsusceptibility to carbapenems, in which the bla(KPC-2) gene was detected in 21.4%. By disk diffusion and E-test, these isolates exhibited high rates of resistance to most of the antimicrobials tested, including tigecycline (45.6% nonsusceptible) and polymyxin B (16.5%), the most resistant species being Enterobacter aerogenes and Enterobacter cloacae. We found great clonal diversity and a variety of bla(KPC-2) carrying plasmids, all of them exhibiting a partial Tn4401 structure. Therefore, this study demonstrates the dissemination of KPC-2 in 9 Enterobacteriaceae species, including species that were not previously described such as Pantoea agglomerans and Providencia stuartii. PMID- 25935631 TI - [Placental abruption: Background and revisited pronostic factors about a series of 171 cases]. AB - OBJECTIVE: To describe the epidemiological, clinical and prognostic factors of placental abruption and fetal death in utero and to investigate possible risk factors for their occurrence. PATIENTS AND METHODS: Observational retrospective study including the women having presented a placental abruption between January 2001 and January 2012, in a IIB maternity. Women's sociodemographic characteristics, clinical symptoms and the method used to detect placental abruption were collected. Patient data of those whose pregnancy resulted in fetal death were compared to those with more favorable outcomes. RESULTS: There were 171 cases of placental abruption among 21,913 patients having delivered, which represents a 0.78% incidence. Diagnosis was rarely based on clinical data (30%). The rate of fetal death in utero represented 25% of the pregnancy's outcomes. A history of fetal death in utero increased the risk of placental abruption (P<0.001). This complication was more frequent for patients who did not have pregnancy monitoring (P=0.054) and before 37 weeks of amenorrhoea (P=0.005). CONCLUSION: Placental abruption is an important cause of perinatal mortality and maternal morbidity. Among the observed risk factors, only regular pregnancy monitoring can be an easy way to prevent these complications. PMID- 25935632 TI - Fast three-dimensional superimposition of cone beam computed tomography for orthopaedics and orthognathic surgery evaluation. AB - The aim of this study was to validate a method for fast three-dimensional (3D) superimposition of cone beam computed tomography (CBCT) in growing patients and adults (surgical cases). The sample consisted of CBCT scans of 18 patients. For 10 patients, as the gold standard, the spatial position of the pretreatment CBCT was reoriented, saved as a reoriented volume, and then superimposed on the original image. For eight patients, four non-growing and four growing, the pre- and post-treatment scans were superimposed. Fast voxel-based superimposition was performed, with registration at the anterior cranial base. This superimposition process took 10-15s. The fit of the cranial base superimposition was verified by qualitative visualization of the semi-transparent axial, sagittal, and coronal cross-sectional slices of all corresponding anatomical structures. Virtual 3D surface models of the skull were generated via threshold segmentation, and superimposition errors in the reoriented models and the results of treatment for the treated cases were evaluated by 3D surface distances on colour-coded maps. The superimposition error of the spatial reorientation and for growing and non growing patients was <0.5mm, which is acceptable and clinically insignificant. The voxel-based superimposition method evaluated was reproducible in different clinical conditions, rapid, and applicable for research and clinical practice. PMID- 25935633 TI - Liver Fibrosis, but No Other Histologic Features, Is Associated With Long-term Outcomes of Patients With Nonalcoholic Fatty Liver Disease. AB - BACKGROUND & AIMS: Histologic analysis of liver biopsy specimens allows for grading and staging of nonalcoholic fatty liver disease (NAFLD). We performed a longitudinal study to investigate the long-term prognostic relevance of histologic features for patients with NAFLD. METHODS: We performed a retrospective analysis of 619 patients diagnosed with NAFLD from 1975 through 2005 at medical centers in the United States, Europe, and Thailand. Patients underwent laboratory and biopsy analyses, and were examined every 3-12 months after their diagnosis. Outcomes analyzed were overall mortality, liver transplantation, and liver-related events. Cumulative outcomes were compared by log-rank analysis. Cox proportional-hazards regression was used to estimate adjusted hazard ratios (HRs). Time at risk was determined from the date of liver biopsy to the date of outcome or last follow-up examination. RESULTS: Over a median follow-up period of 12.6 years (range, 0.3-35.1 y), 193 of the patients (33.2%) died or underwent liver transplantation. Features of liver biopsies significantly associated with death or liver transplantation included fibrosis stage 1 (HR, 1.88; 95% confidence interval [CI], 1.28-2.77), stage 2 (HR, 2.89; 95% CI, 1.93-4.33), stage 3 (HR, 3.76; 95% CI, 2.40-5.89), and stage 4 (HR, 10.9; 95% CI, 6.06-19.62) compared with stage 0, as well as age (HR, 1.07; 95% CI, 1.05 1.08), diabetes (HR, 1.61; 95% CI, 1.13-2.30), current smoking (HR, 2.62; 95% CI, 1.67-4.10), and statin use (HR, 0.32; 95% CI, 0.14-0.70). Twenty-six patients (4.2%) developed liver-related events; fibrosis stage 3 (HR, 14.2; 95% CI, 3.38 59.68) and stage 4 (HR, 51.5; 95% CI, 9.87-269.2) compared with stage 0, were associated significantly with the events. Patients with fibrosis, regardless of steatohepatitis or NAFLD activity score, had shorter survival times than patients without fibrosis. CONCLUSIONS: In a longitudinal study of patients with NAFLD, fibrosis stage, but no other histologic features of steatohepatitis, were associated independently with long-term overall mortality, liver transplantation, and liver-related events. PMID- 25935634 TI - Combining Data From Liver Disease Scoring Systems Better Predicts Outcomes of Patients With Alcoholic Hepatitis. AB - BACKGROUND & AIMS: Several models have been used to determine prognoses of patients with alcoholic hepatitis. These include static systems (the Maddrey discriminant function; age, bilirubin, international normalized ratio, creatinine [ABIC] score; and model for end-stage liver disease [MELD] score) and dynamic models (the Lille model). We aimed to combine features of all of these models to develop a better method to predict outcomes of patients with alcoholic hepatitis. METHODS: We collected data from several databases of patients with severe alcoholic hepatitis treated with corticosteroids in France and the United Kingdom to create a model to predict patient survival (derivation cohort, n = 538 patients). We compared the performances of 3 joint-effect models (Maddrey+Lille, MELD+Lille, and ABIC+Lille) to determine which combination had the best prognostic value, based on known patient outcomes. The model was validated using data from trials of the effects of corticosteroids in patients in the United States, France, Korea, and Belgium (n = 604 patients). RESULTS: We created a joint-effect model to predict patient survival after 2 and 6 months; in the derivation and validation cohorts it predicted outcome significantly better than either static or dynamic models alone (P < .01 for all comparisons). The joint model accurately predicted patient survival regardless of patient risk level. The MELD+Lille combination was better than the Maddrey+Lille or ABIC+Lille combination in predicting patient survival, with Akaike information criterion values of 1305, 1313, and 1312, respectively. For example, based on the MELD+Lille combination model, the predicted 6-month mortality of complete responders with MELD scores of 15-45 (Lille score, 0.16) was 8.5% to 49.7%, compared with 16.4%-75.2% for nonresponders (Lille score, 0.45). According to the joint-effect model, for 2 patients with the same baseline MELD score of 21, the patient with a Lille score of 0.45 had a 1.9-fold higher risk of death than the patient with a Lille score of 0.16 (23.7% vs 12.5%). CONCLUSIONS: By combining results from static and dynamic scoring systems for liver disease, we can better predict outcomes of patients with alcoholic hepatitis, compared with either model alone. This may help patient management and design of clinical trials. PMID- 25935635 TI - An Accurate Cancer Incidence in Barrett's Esophagus: A Best Estimate Using Published Data and Modeling. AB - BACKGROUND & AIMS: Published estimates for the rate of progression from Barrett's esophagus (BE) to esophageal adenocarcinoma (EAC) vary. We used simulation modeling to reconcile published data and more accurately estimate the incidence of EAC among people with BE. METHODS: We calibrated the ERASMUS/UW model (a collaboration between Erasmus Medical Center, Rotterdam, the Netherlands and the University of Washington, Seattle) for EAC to match the 0.18% annual rate of progression from population-based studies. This model was then used to simulate the design of prospective studies, introducing more endoscopic surveillance. We used the model to predict rates of progression for both types of studies and for different periods of follow-up, and compared the predicted rates with published data. RESULTS: For the first 5 years of follow-up, the model reproduced the 0.19% mean annual rate of progression observed in population-based studies; the same disease model predicted a 0.36% annual rate of progression in studies with a prospective design (0.41% reported in published articles). After 20 years, these rates each increased to 0.63% to 0.65% annually, corresponding with a 9.1% to 9.5% cumulative cancer incidence. Between these periods, the difference between the progression rates of both study designs decreased from 91% to 5%. CONCLUSIONS: In the first 5 years after diagnosis, the rate of progression from BE to EAC is likely to more closely approximate the lower estimates reported from population-based studies than the higher estimates reported from prospective studies in which EAC is detected by surveillance. Clinicians should use this information to explain to patients their short-term and long-term risks if no action is taken, and then discuss the risks and benefits of surveillance. PMID- 25935636 TI - Adrenal gland volume, intra-abdominal and pericardial adipose tissue in major depressive disorder. AB - Major depressive disorder (MDD) is associated with an increased risk for the development of cardio-metabolic diseases. Increased intra-abdominal (IAT) and pericardial adipose tissue (PAT) have been found in depression, and are discussed as potential mediating factors. IAT and PAT are thought to be the result of a dysregulation of the hypothalamus-pituitary-adrenal axis (HPAA) with subsequent hypercortisolism. Therefore we examined adrenal gland volume as proxy marker for HPAA activation, and IAT and PAT in depressed patients. Twenty-seven depressed patients and 19 comparison subjects were included in this case-control study. Adrenal gland volume, pericardial, intraabdominal and subcutaneous adipose tissue were measured by magnetic resonance imaging. Further parameters included factors of the metabolic syndrome, fasting cortisol, fasting insulin, and proinflammatory cytokines. Adrenal gland and pericardial adipose tissue volumes, serum concentrations of cortisol and insulin, and serum concentrations tumor-necrosis factor-alpha were increased in depressed patients. Adrenal gland volume was positively correlated with intra-abdominal and pericardial adipose tissue, but not with subcutaneous adipose tissue. Our findings point to the role of HPAA dysregulation and hypercortisolism as potential mediators of IAT and PAT enlargement. Further studies are warranted to examine whether certain subtypes of depression are more prone to cardio-metabolic diseases. PMID- 25935637 TI - The association between 2D:4D ratio and cognitive empathy is contingent on a common polymorphism in the oxytocin receptor gene (OXTR rs53576). AB - Both testosterone and oxytocin influence an individual's accuracy in inferring another's feelings and emotions. Fetal testosterone, and the second-to-forth digit ratio (2D:4D) as its proxy, plays a role in social cognitive development, often by attenuating socio-affective skill. Conversely, oxytocin generally facilitates socio-affiliative and empathic cognition and behavior. A common polymorphism in the oxytocin receptor gene, OXTR rs53576, has been repeatedly linked with psychosocial competence, including empathy, with individuals homozygous for the G allele typically characterized by enhanced socio-cognitive skills compared to A allele carriers. We examined the role of oxytocin and testosterone in collectively contributing to individual differences in cognitive empathy as measured by Baron-Cohen's "Reading the Mind in the Eyes" task (RMET). Findings are based on a large cohort of male and female students (N=1463) of Han Chinese ethnicity. In line with existing literature, women outperformed men in the RMET. Men showed significantly lower 2D:4D ratio compared to women, indicating higher exposure to testosterone during the prenatal period. Interestingly, variation in the OXTR gene was found to interact with 2D:4D to predict men's (but not women's) RMET performance. Among men with GG allelic variation, those with low fetal testosterone performed better on the RMET, compared to men with GG and high fetal testosterone, suggesting greater identification of another's emotional state. Taken together, our data lend unique support to the mutual influence of the oxytocin and testosterone systems in shaping core aspect of human social cognition early in development, further suggesting that this effect is gender-specific. PMID- 25935638 TI - Endovascular repair with contralateral external-to-internal iliac artery bypass grafting: a case series. AB - BACKGROUND: To report a technique of keeping unilateral blood flow in the internal iliac artery in cases of an abdominal aortic aneurysm in achieving successful Endovascular abdominal aortic aneurysm repair using an external-to internal artery bypass. CASE PRESENTATION: 6 japanese patients with infra-renal abdominal aortic aneurysms were treated using the retroperitoneal approach via a left (right) paramedian incision followed by an external-to-internal artery bypass. Endovascular abdominal aortic aneurysm repair was conducted on mean postoperative day 29 +/- 18 and was performed because the contralateral internal iliac artery, which was not involved in the external-to-internal artery bypass, was treated with a coil embolization. No complications developed during the postoperative follow-up period (17 +/- 1.5 months). In all 6 patients, patent grafts were evident on computed tomography angiography scans even after 1-3 months. CONCLUSIONS: Endovascular abdominal aortic aneurysm repair with unilateral internal iliac artery embolization and contralateral external-to internal artery bypass is feasible with a relatively low risk. It is a safe procedure and reduces the incidence of postoperative complications. PMID- 25935639 TI - Parkinsonism due to Fahr's disease with previous carbon monoxide intoxication. PMID- 25935640 TI - TDDFT study on the sensing mechanism of a fluorescent sensor for fluoride anion: Inhibition of the ESPT process. AB - The fluoride-sensing mechanism of a reported salicylaldehyde-based sensor (J. Photochem. Photobiol. B 2014, 138, 75) has been investigated by the TDDFT method. The present theoretical study indicates that there is an excited-state proton transfer (ESPT) process from the phenolic O-H moiety to the neighbor N atom in the sensor. The added fluoride anion could capture the proton in the O-H moiety and the corresponding phenolic anion is formed, which could inhibit the ESPT process. The experimental UV/Vis and fluorescence spectra are well reproduced by the calculated vertical excitation energies. Frontier molecular orbital analysis indicates that the local excited state of phenolic anion is responsible for its enhanced fluorescence. Due to this reason, the sensor can be used to sense fluoride anion by monitoring the fluorescent change. PMID- 25935641 TI - Structure-activity relationships of the prototypical TRPM8 agonist icilin. AB - A series of structural analogues of the TRPM8 agonist icilin was prepared. The compounds were examined for their ability to exert agonist or antagonist effects in HEK-293 cells expressing the TRPM8 receptor. Most structural modifications of the icilin structure largely met with diminished TRPM8 agonist activity. Cinnamamide 'open-chain' analogs of icilin, however, demonstrated significant antagonistic actions at the TRPM8 receptor. Optimal potency (IC50=73 nM) was observed in the 3-iodo derivative 18l. PMID- 25935642 TI - Discovery of novel N-aryl piperazine CXCR4 antagonists. AB - A novel series of CXCR4 antagonists with substituted piperazines as benzimidazole replacements is described. These compounds showed micromolar to nanomolar potency in CXCR4-mediated functional and HIV assays, namely inhibition of X4 HIV-1(IIIB) virus in MAGI-CCR5/CXCR4 cells and inhibition of SDF-1 induced calcium release in Chem-1 cells. Preliminary SAR investigations led to the identification of a series of N-aryl piperazines as the most potent compounds. Results show SAR that indicates type and position of the aromatic ring, as well as type of linker and stereochemistry are significant for activity. Profiling of several lead compounds showed that one (49b) reduced susceptibility towards CYP450 and hERG, and the best overall profile when considering both SDF-1 and HIV potencies (6-20 nM). PMID- 25935643 TI - N-Oxide derivatives of 3-(3-pyridyl)-2-phosphonopropanoic acids as potential inhibitors of Rab geranylgeranylation. AB - The N-oxide derivatives of [2-(3-pyridinyl)-1-hydroxyethylidene-1,1 phosphonocarboxylic acid (or PEHPC) and [2-(3-pyridinyl)-1-ethylidene-1,1 phosphonocarboxylic acid (or PEPC) have been prepared and evaluated for their activity against several enzymes which utilize isoprenoids. The parent pyridines are known inhibitors of GGTase II, but the N-oxide derivatives show no improvement in biological activity in assays with the isolated enzyme. However, the PEHPC N-oxide did induce significant accumulation of intracellular light chain in myeloma cells, consistent with inhibition of Rab geranylgeranylation. PMID- 25935644 TI - Pancreatic lipase inhibitory constituents from Morus alba leaves and optimization for extraction conditions. AB - The leaves of Morus alba (Moraceae) have been traditionally used for the treatment of metabolic diseases including diabetes and hyperlipidemia. Thus, inhibitory effect of M. alba leaves on pancreatic lipase and their active constituents were investigated in this study. Twenty phenolic compounds including ten flavonoids, eight benzofurans, one stilbene and one chalcones were isolated from the leaves of M. alba. Among the isolated compounds, morachalcone A (20) exerted strong pancreatic lipase inhibition with IC50 value of 6.2 MUM. Other phenolic compounds containing a prenyl group showed moderate pancreatic lipase inhibition with IC50 value of <50 MUM. Next, extraction conditions with maximum pancreatic lipase inhibition and phenolic content were optimized using response surface methodology with three-level-three-factor Box-Behnken design. Our results suggested the optimized extraction condition for maximum pancreatic lipase inhibition and phenolic content as ethanol concentration of 74.9%; temperature 57.4 degrees C and sample/solvent ratio, 1/10. The pancreatic lipase inhibition and total phenolic content under optimized condition were found to be 58.5% and 26.2 MUg GAE (gallic acid equivalent)/mg extract, respectively, which were well matched with the predicted value. PMID- 25935645 TI - Randomized phase III trial of radiotherapy or chemoradiotherapy with topotecan and cisplatin in intermediate-risk cervical cancer patients after radical hysterectomy. AB - BACKGROUND: In cervical cancer patients with intermediate-risk factors, the optimal adjuvant therapy is still controversial. We undertook a randomized trial (ClinicalTrials.gov Identifier: NCT01418859) to compare the efficacy and toxicity of concurrent chemoradiotherapy with topotecan and cisplatin with radiotherapy alone in intermediate-risk cervical cancer patients. METHODS: Eligible patients were randomly assigned to one of three treatment arms including arm A (radiotherapy only,RT), arm B(concurrent chemoradiotherapy only, CCRT), and arm C (concurrent chemoradiotherapy with following consolidation chemotherapy, CCRT + CT). All eligible patients completed external RT (IMRT or 3D-CRT), receiving 45 50 Gy /25 f uniformly to the pelvis. Concurrent chemotherapy regimen was topotecan 0.75 mg/m(2) for days 1, 2 and 3, followed by cisplatin 25 mg/m(2) for days 1, 2 and 3. Three cycles of consolidation chemotherapy regimen was topotecan 1.5 mg/m(2) for days 1 and 2, and 0.75 mg/m(2) for day 3; followed by cisplatin 25 mg/m(2) for days 1, 2 and 3, repeated every 21 days. Adverse events of each group were investigated and compared. RESULTS: Thirty-nine patients enrolled onto the remaining regimens: 14 to RT, 15 to CCRT and 10 to CCRT + CT. Six patients (15.4%) did not complete the protocol treatment. Hematologic toxicity was more frequent and more severe in the CCRT and CCRT + CT arms compared with the RT arm. The incidence of grade 3-4 neutropenia was significantly different statistically between the RT, CCRT and CCRT + RT groups (15.4%, 46.7% and 100%, respectively; P = 0.002). Specially, three patients in CCRT + CT arm of all six patients who did not complete the protocol treatment discontinued planned therapy because of persistent grade 4 neutropenia. However, there were no significant differences in grade 3-4 non-hematologic toxicities between the three groups(all P > 0.05). Recurrence-free survival and overall survival of each group were not analyzed on account of a median follow-up of only 16 months. CONCLUSIONS: Concurrent chemoradiotherapy with topotecan and cisplatin showed severe hematologic toxicity in intermediate-risk cervical cancer patients after radical hysterectomy. Thus, the study was closed ahead of schedule. TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT01418859 . PMID- 25935646 TI - Extreme expansion of NBS-encoding genes in Rosaceae. AB - BACKGROUND: Nucleotide binding site leucine-rich repeats (NBS-LRR) genes encode a large class of disease resistance (R) proteins in plants. Extensive studies have been carried out to identify and investigate NBS-encoding gene families in many important plant species. However, no comprehensive research into NBS-encoding genes in the Rosaceae has been performed. RESULTS: In this study, five whole genome sequenced Rosaceae species, including apple, pear, peach, mei, and strawberry, were analyzed to investigate the evolutionary pattern of NBS-encoding genes and to compare them to those of three Cucurbitaceae species, cucumber, melon, and watermelon. Considerable differences in the copy number of NBS encoding genes were observed between Cucurbitaceae and Rosaceae species. In Rosaceae species, a large number and a high proportion of NBS-encoding genes were observed in peach (437, 1.52%), mei (475, 1.51%), strawberry (346, 1.05%) and pear (617, 1.44%), and apple contained a whopping 1303 (2.05%) NBS-encoding genes, which might be the highest number of R-genes in all of these reported diploid plant. However, no more than 100 NBS-encoding genes were identified in Cucurbitaceae. Many more species-specific gene families were classified and detected with the signature of positive selection in Rosaceae species, especially in the apple genome. CONCLUSIONS: Taken together, our findings indicate that NBS encoding genes in Rosaceae, especially in apple, have undergone extreme expansion and rapid adaptive evolution. Useful information was provided for further research on the evolutionary mode of disease resistance genes in Rosaceae crops. PMID- 25935647 TI - A poly(glycerol sebacate)-coated mesoporous bioactive glass scaffold with adjustable mechanical strength, degradation rate, controlled-release and cell behavior for bone tissue engineering. AB - Various requirements in the field of tissue engineering have motivated the development of three-dimensional scaffold with adjustable physicochemical properties and biological functions. A series of multiparameter-adjustable mesoporous bioactive glass (MBG) scaffolds with uncrosslinked poly(glycerol sebacate) (PGS) coating was prepared in this article. MBG scaffold was prepared by a modified F127/PU co-templating process and then PGS was coated by a simple adsorption and lyophilization process. Through controlling macropore parameters and PGS coating amount, the mechanical strength, degradation rate, controlled release and cell behavior of the composite scaffold could be modulated in a wide range. PGS coating successfully endowed MBG scaffold with improved toughness and adjustable mechanical strength covering the bearing range of trabecular bone (2 12MPa). Multilevel degradation rate of the scaffold and controlled-release rate of protein from mesopore could be achieved, with little impact on the protein activity owing to an "ultralow-solvent" coating and "nano-cavity entrapment" immobilization method. In vitro studies indicated that PGS coating promoted cell attachment and proliferation in a dose-dependent manner, without affecting the osteogenic induction capacity of MBG substrate. These results first provide strong evidence that uncrosslinked PGS might also yield extraordinary achievements in traditional MBG scaffold. With the multiparameter adjustability, the composite MBG/PGS scaffolds would have a hopeful prospect in bone tissue engineering. The design considerations and coating method of this study can also be extended to other ceramic-based artificial scaffolds and are expected to provide new thoughts on development of future tissue engineering materials. PMID- 25935649 TI - Warfarin treatment quality is consistently high in both anticoagulation clinics and primary care setting in Sweden. AB - BACKGROUND: Warfarin treatment in Sweden holds a high standard with time in therapeutic range (TTR) over 75%. Internationally, specialized anticoagulation clinics (ACC) have shown higher TTR compared to primary health care centres (PHCC). OBJECTIVES: To compare warfarin treatment quality in Sweden for ACC versus PHCC, thereby clarifying whether centralization is for the better. PATIENTS/METHODS: In total 77.058 patients corresponding to 217.058 treatment years with warfarin in the Swedish national quality register AuriculA from 1. Jan 2006 to 31. Dec 2011. Information regarding TTR was calculated from AuriculA, while patient characteristics and complications were retrieved from the Swedish National Patient Register. RESULTS: Of the 100.554 treatment periods examined, 78.7% were monitored at ACC. Mean TTR for INR 2-3 for all patients irrespective of intended target range was 76.5% with an annual risk of bleeding or thrombotic events of 2.24% and 2.66%, respectively. TTR was significantly higher in PHCC compared to ACC (79.6% vs. 75.7%, p<0.001), with no significant difference in overall risk of complications. Treatment periods for atrial fibrillation, except intended direct current conversion, showed similar results between ACC and PHCC without significant difference in annual risk of bleeding (2.50% vs. 2.51%) or thrombosis (3.09% vs. 3.16%). After propensity score matching there was still no significant difference in complication risk found. CONCLUSIONS: Warfarin treatment quality is consistently high in both ACC and PHCC when monitored through AuriculA in Sweden, both measured as TTR and as risk of complications. In this setting, centralized warfarin monitoring is not likely to improve the results. PMID- 25935648 TI - Allosteric inhibition of factor XIa. Sulfated non-saccharide glycosaminoglycan mimetics as promising anticoagulants. AB - Recent development of sulfated non-saccharide glycosaminoglycan mimetics, especially sulfated pentagalloyl glucopyranoside (SPGG), as potent inhibitors of factor XIa (FXIa) (J. Med. Chem. 2013; 56:867-878 and J. Med. Chem. 2014; 57:4805 4818) has led to a strong possibility of developing a new line of factor XIa based anticoagulants. In fact, SPGG represents the first synthetic, small molecule inhibitor that appears to bind in site remote from the active site. Considering that allosteric inhibition of FXIa is a new mechanism for developing a distinct line of anticoagulants, we have studied SPGG's interaction with FXIa with a goal of evaluating its pre-clinical relevance. Comparative inhibition studies with several glycosaminoglycans revealed the importance of SPGG's non saccharide backbone. SPGG did not affect the activity of plasma kallikrein, activated protein C and factor XIIIa suggesting that SPGG-based anticoagulation is unlikely to affect other pathways connected with coagulation factors. SPGG's effect on APTT of citrated human plasma was also not dependent on antithrombin or heparin cofactor II. Interestingly, SPGG's anticoagulant potential was diminished by serum albumin as well as factor XI, while it could be reversed by protamine or polybrene, which implies possible avenues for developing antidote strategy. Studies with FXIa mutants indicated that SPGG engages Lys529, Arg530 and Arg532, but not Arg250, Lys252, Lys253 and Lys255. Finally, SPGG competes with unfractionated heparin, but not with polyphosphates and/or glycoprotein Ibalpha, for binding to FXIa. These studies enhance understanding on the first allosteric inhibitor of FXIa and highlight its value as a promising anticoagulant. PMID- 25935650 TI - Serological assessment of neutrophil elastase activity on elastin during lung ECM remodeling. AB - BACKGROUND: During the pathological destruction of lung tissue, neutrophil elastase (NE) degrades elastin, one of the major constituents of lung parenchyma. However there are no non-invasive methods to quantify NE degradation of elastin. We selected specific elastin fragments generated by NE for antibody generation and developed an ELISA assay (EL-NE) for the quantification of NE-degraded elastin. METHODS: Monoclonal antibodies were developed against 10 NE-specific cleavage sites on elastin. One EL-NE assay was tested for analyte stability, linearity and intra- and inter-assay variation. The NE specificity was demonstrated using elastin cleaved in vitro with matrix metalloproteinases (MMPs), cathepsin G (CatG), NE and intact elastin. Clinical relevance was assessed by measuring levels of NE-generated elastin fragments in serum of patients diagnosed with idiopathic pulmonary fibrosis (IPF, n = 10) or lung cancer (n = 40). RESULTS: Analyte recovery of EL-NE for human serum was between 85% and 104%, the analyte was stable for four freeze/thaw cycles and after 24 h storage at 4 degrees C. EL-NE was specific for NE-degraded elastin. Levels of NE generated elastin fragments for elastin incubated in the presence of NE were 900% to 4700% higher than those seen with CatG or MMP incubation or in intact elastin. Serum levels of NE-generated elastin fragments were significantly increased in patients with IPF (137%, p = 0.002) and in patients with lung cancer (510%, p < 0.001) compared with age- and sex-matched controls. CONCLUSIONS: The EL-NE assay was specific for NE-degraded elastin. The EL-NE assay was able to specifically quantify NE-degraded elastin in serum. Serum levels of NE-degraded elastin might be used to detect excessive lung tissue degradation in lung cancer and IPF. PMID- 25935651 TI - Claudin 3, 4, and 15 expression in solid tumors of lung adenocarcinoma versus malignant pleural mesothelioma. AB - Epithelioid malignant pleural mesothelioma (MPM) can easily be confused with lung adenocarcinomas (ACAs). In serous effusion, claudin (cldn) 3 is shown to be useful in the diagnosis of mesothelioma vs ACAs. Cldn15 is reported to be overexpressed in epithelioid mesothelioma and absent in human airway epithelium. The aim was to assess the value of cldn3 and cldn4 compared to that of BerEp4 and thyroid transcription factor-1 (TTF1) in differentiating lung ACA from epithelioid MPM and to examine the expression of cldn15 in these tumors. The expression of cldn3, cldn4, cldn15, BerEp4, and TTF1 was examined by immunohistochemistry in a total of 62 human specimen including 28 epithelioid MPMs and 34 ACAs of the lung. In lung ACA, cldn4 was strongly expressed in all 34 (100%) specimens followed by cldn3 in 33 (97%) of 34. BerEp4 was expressed in 32 (94.1%) of 34. TTF1 reacted for only 20 (58.82%) of 34 cases of lung ACA. In MPM specimens, the expression of cldn3 and4 as well as that of TTF1 was completely absent. In contrast, BerEp4 was focally expressed in 5 (17.85%) of 28 cases of epithelioid MPM. Cldn15 was strongly expressed in 53% pf epithelioid MPMs but also in 50% of lung ACAs. Its expression was moderate in normal pleura and limited in normal lung. Cldn3 and cldn4 appear to be the best performing carcinoma markers in discriminating lung ACA from mesothelioma compared with BerEp4 and TTF1. There is no differential expression of cldn15 between the 2 pathologies. However, the limited cldn15 expression in normal tissues and high expression in tumors make it an attractive candidate for cancer therapy. PMID- 25935652 TI - The influence of cardiac autonomic activity on the QT-variability index in able bodied and incomplete spinal cord injured individuals. AB - OBJECTIVES: To investigate, via autonomic blockade, if the QT-variability index (QTVI) is a measure of cardiac autonomic regulation in able-bodied (AB) and incomplete spinal cord injured (SCI) individuals. METHODS: Four SCI (41.6+/ 13.4years; C4-C7, AIS B-D, 13.4+/-13.4years post injury) and 4 AB (33.0+/ 7.8years) individuals were tested. QTVI was determined from electrocardiographic readings obtained during supine rest and cardiovascular (CV) stress, with and without autonomic blockade. CV stress was induced by 40 degrees head-up tilt, the hand submerged in 10 degrees C water and the jaw clenched. Autonomic blockade was achieved with metoprolol (beta-blockade) and atropine (cholinergic blockade). RESULTS: There was no group*condition interaction for QTVI, although there was a significant main effect for condition. After collapsing across groups, QTVI increased with CV stress (p=0.01) and decreased with subsequent beta-blockade (p=0.04), suggesting that during CV stress, QTVI is reflective of cardiac sympathetic activity. During supine rest, beta-blockade did not change QTVI (p=0.24), however, cholinergic blockade increased QTVI (p<0.001), suggesting that during rest, QTVI is inversely related to cardiac parasympathetic regulation. CONCLUSION: During times of CV stress, QTVI reflects cardiac sympathetic activity, while during resting conditions, QTVI is inversely related to cardiac parasympathetic activity. These relationships persist after autonomically incomplete SCI. PMID- 25935653 TI - Tradable permit system for PM(2.5) emissions from residential and industrial sources. AB - Residential wood combustion is a significant source of air pollution in urban areas of many countries with cold weather and low cost of firewood. These conditions worsen in urban areas where atmospheric emissions from industrial activities are present. This study addresses this problem and extends the existing literature to develop an optimization model that simulates a system of tradable permits for fine particulate matter emissions, which includes different options to reduce emissions for both industrial and residential sources. Results show that replacing wood heaters in urban areas is highly desirable from an economic and environmental perspective regardless if the expenses originate from each household, public programs or emission compensation mechanisms from the industrial sector. PMID- 25935654 TI - Wound care antiseptics - performance differences against Staphylococcus aureus in biofilm. AB - BACKGROUND: Staphylococcus aureus is commonly isolated from infected wounds both in animals and humans. It is known to be an excellent biofilm former and biofilms are present in as many as 60% of chronic wounds. Despite that the presence of biofilms in infections are common, antiseptics are usually qualified for in vivo testing according to their effect on planktonic cells. As it is well known that bacteria in biofilms are more tolerant to antiseptics than planktonic bacteria, biofilm infections can be difficult to treat. The aim of the study was to compare three different categories of antiseptics, biguanide (chlorhexidine), quaternary ammonium compound (QAC; Pyrisept) and iodine/iodophores (2% iodine liniment), with regards to efficacy in killing S. aureus in biofilm. If there was observed a difference in efficacy between these antiseptics, a second aim was to find the most effective of the three antiseptics. RESULTS: Large differences in the bactericidal effect of the different antiseptics against S. aureus in biofilm were observed in the present study. Iodine treatment was found to be the most effective followed by Pyrisept and chlorhexidine. CONCLUSIONS: The bactericidal effect of the different antiseptics used in the present study was found to vary significantly against S. aureus in biofilm. The present study gives valuable knowledge with regards to selecting the antiseptics that are most likely to be successful in treating biofilm infected wounds. This study also contributes to focus attention on the importance of qualifying antiseptics based on results using biofilm bacteria rather than planktonic bacteria. PMID- 25935655 TI - World Workshop on Oral Medicine VI: Controversies regarding dental management of medically complex patients: assessment of current recommendations. AB - OBJECTIVES: Current recommendations for safe and effective dental management are less than optimal for some medical conditions because of limited evidence, conflicting conclusions, or both. This review (1) compiled and evaluated dental management recommendations for select medical conditions; (2) summarized recommendations and their assigned levels of evidence; (3) identified areas of conflict, ambiguity, or both; and (4) identified issues that warrant future research, enhanced consensus statements, or both. STUDY DESIGN: Systematic literature searches were performed for guideline publications, systematic and narrative reviews, and opinion documents containing recommendations for (1) medication-related osteonecrosis of the jaw (MRONJ); (2) cardiovascular diseases (CVDs); (3) prosthetic joints (PJs); and (4) systemic steroid therapy (SST). RESULTS: The search yielded the following numbers of publications that met the inclusion criteria: MRONJ - 116; CVDs - 54; prosthetic joints - 39; and systemic steroids - 12. CONCLUSIONS: Very few of the compiled recommendations were assigned or linked to levels of evidence by their authors. Key conclusions include the following: MRONJ-expert recommendations trend toward proceeding with dental treatment with little to no modification in osteoporotic patients on bisphosphonates; CVDs-current recommendations are primarily directed to general surgery and applied to dentistry; PJs-routine antibiotic prophylaxis is not indicated for dental treatment; and SST-steroid supplementation is not indicated for most patients undergoing dental procedures under local anesthesia. PMID- 25935656 TI - Cytisine is more effective than nicotine replacement for smoking cessation. PMID- 25935657 TI - A team-based multidisciplinary approach to managing peripherally inserted central catheter complications in high-risk haematological patients: a prospective study. AB - PURPOSE: Use of peripherally inserted central catheters (PICCs) has markedly increased during the last decade. However, there are few studies on use of PICCs in patients with haematological malignancies (HM) receiving intensive chemotherapy. Preliminary data suggest a higher rate of PICC-related complications in these high-risk patients. This prospective observational single centre study aimed to investigate PICC-related complications after implementation of a multidisciplinary approach to PICC care and compared it with previous literature. METHODS: A total of 44 PICCs were inserted in 36 patients (27.3%, thrombocytopenia <50 * 10(9)/L at insertion) over 5045 PICC days (median duration, 114.5 days). RESULTS: No major insertion-related complications were observed. Major late complications were obstruction in 13.6% (1.19/1000 PICC days) of patients, catheter-related bloodstream infection in 6.8% (0.59/1000 PICC days), and catheter-related thrombosis in 4.5% (0.39/1000 PICC days). Premature PICC removal occurred in 34% (2.97/1000 PICC days) of patients. The overall rate of potentially major dangerous complications was particularly low (11.36%, 0.99/1000 PICC days) compared with previous studies. CONCLUSIONS: This study highlights the utility of a multidisciplinary approach for PICC care in adults with HM receiving intensive chemotherapy. We provide further data to support use of PICCs in such patient populations. PMID- 25935658 TI - Principled research ethics in practice? Reflections for neuroethics and bioethics. PMID- 25935659 TI - [Item 207 - UE 7 Sarcoidosis]. PMID- 25935660 TI - [Item 316 - UE 9 Malignant lymphomas: cutaneous lymphomas]. PMID- 25935661 TI - [Item 226 - UE 8 Leg ulcers]. PMID- 25935662 TI - Primary Cutaneous Coccidioidomycosis in an Italian Nun Working in South America and Review of Published Literature. AB - Coccidioidomycosis is a systemic disease caused by the dimorphic fungus Coccidioides, endemic in parts of the Southwestern USA and Central and South America. Two species, Coccidioides immitis and Coccidioides posadasii, were differentiated. Primary cutaneous coccidioidomycosis (PCC) has been reported rarely. An unusual case of PCC characterized by a persistent solitary lesion diagnosed in Italy in an immunocompetent Italian nun living in Argentina is described. The isolate was identified by sequence analysis as C. posadasii. Antibody screening was negative. A total of 39 cases of PCC have been reported in the literature. Infections occurred as a consequence of traumatic implantation in a natural setting in endemic areas or of accidental inoculation in laboratory workers. Importance of accurate investigation of travel history and of occupational hazards to laboratory workers is outlined. PMID- 25935663 TI - Pediatric atypical choroid plexus papilloma reconsidered: increased mitotic activity is prognostic only in older children. PMID- 25935664 TI - Effects of increased temperature on metabolic activity and oxidative stress in the first life stages of marble trout (Salmo marmoratus). AB - Climate change may result in future alterations in thermal regime which could markedly affect the early developmental stages of cold water fish due to their expected high sensitivity to increasing temperature. In the present study, the effect of temperature increase of 2, 4 and 6 degrees C on the oxygen consumption rate (R), the activity of respiratory electron transport system (ETS) and oxidative stress have been studied in four developmental stages of the marble trout (Salmo marmoratus)-eyed eggs, yolk-sac larvae and juveniles of 1 and 3 months. Oxygen consumption rate and ETS activity increased with level of development and with temperature in all four stages. ETS/R ratios decreased during development and correlated with temperature in eyed eggs, larvae and juveniles of 1 month, but not in juveniles of 3 months. Low ETS/R ratios at higher temperatures indicate stress response in eyed eggs, the most temperature sensitive developmental stage. Catalase (CAT) and glutathione reductase (GR) activities increased during development, but responded differently to elevated temperature in the different developmental stages. Stress in eyed eggs, caused by higher temperatures, resulted in increased oxygen consumption rate and increased activities of CAT and GR. Larvae were sensitive to increased temperature only at the highest experimental temperature of 16 degrees C. Increased temperature did not stress the metabolism of the juveniles, since they were able to compensate their metabolic activity. The earlier developmental stages of marble trout are thus more sensitive to temperature increase than juveniles and therefore more endangered by higher water temperatures. This is the first report connecting oxygen consumption, ETS activity and ETS/R ratio with the activities of antioxidant enzymes in relation to increased temperature in salmonids. PMID- 25935666 TI - Using the Theory of Planned Behaviour to examine health professional students' behavioural intentions in relation to medication safety and collaborative practice. AB - BACKGROUND: Safe medication practices depend upon, not only on individual responsibilities, but also effective communication and collaboration between members of the medication team. However, measurement of these skills is fraught with conceptual and practical difficulties. AIMS: The aims of this study were to explore the utility of a Theory of Planned Behaviour-based questionnaire to predict health professional students' behavioural intentions in relation to medication safety and collaborative practice; and to determine the contribution of attitudes, subjective norms, and perceived control to behavioural intentions. DESIGN: A descriptive cross-sectional survey based upon the Theory of Planned Behaviour was designed and tested. PARTICIPANTS: A convenience sample of 65 undergraduate pharmacy, nursing and medicine students from one semi-metropolitan Australian university were recruited for the study. METHODS: Participants' behavioural intentions, attitudes, subjective norms, and perceived control to behavioural intentions in relation to medication safety were measured using an online version of the Theory of Planned Behaviour Medication Safety Questionnaire. RESULTS: The Questionnaire had good internal consistency with a Cronbach's alpha of 0.844. The three predictor variables of attitudes, subjective norms, and perceived control accounted for between 30 and 46% of the variance in behavioural intention; this is a strong prediction in comparison to previous studies using the Theory of Planned Behaviour. Data analysis also indicated that attitude was the most significant predictor of participants' intention to collaborate with other team members to improve medication safety. CONCLUSION: The results from this study provide preliminary support for the Theory of Planned Behaviour-Medication Safety Questionnaire as a valid instrument for examining health professional students' behavioural intentions in relation to medication safety and collaborative practice. PMID- 25935665 TI - Impact of simulation training on Jordanian nurses' performance of basic life support skills: A pilot study. AB - BACKGROUND: Providing efficient basic life support (BLS) training is crucial for practicing nurses who provide direct patient care. Nevertheless, data addressing the impact of BLS courses on the skills and performance of Jordanian nurses are scarce. This study aimed to assess the effectiveness of a BLS simulation training on Jordanian nurses' skill improvement in cardiopulmonary resuscitation. METHODS: A prospective quasi-experimental, single group pretest-posttest design was used to study the effect of BLS simulation; using a 9-item checklist; on the spot training; American Heart Association, on a group of Jordanian nurses. A pre-test was conducted following a CPR scenario to test the skills using 9-item checklist extrapolated from the American Heart Association guidelines. After debriefing, an interactive on spot training was provided. Later, participants undertook an unscheduled post-test after four weeks that included the same nine items. RESULTS: Thirty registered nurses with a mean clinical experience of 6.1years participated in the study. Comparing pre-test (M=4.6, SD=2.9, range=0 to 9) with post-test results (M=7.5, SD=1.7, range=4 to 9) showed an overall improvement in skills and BLS scores after the simulation training program (t=7.4, df=29, p<0.0001). CONCLUSIONS: BLS simulation training sessions are associated with significant improvement in skills and performance among Jordanian nurses. A refreshment BLS training session for nurses is highly recommended to guarantee nurses' preparedness in actual CPR scenarios. PMID- 25935667 TI - Psychometric properties of an instrument to measure nursing students' quality of life. AB - It is important for clinical nursing teachers and managers to recognize the importance of nursing students' quality of life (QOL) since they are the source of future nurses. As yet, there is no quality of life evaluation scale (QOLES) specific to them. This study designed a quantitative instrument for evaluating QOL of nursing students. The study design was a descriptive survey with mixed methods including literature review, panel discussion, Delphi method, and statistical analysis. The data were collected from 880 nursing students from four teaching hospitals in Wuhan, China. The reliability and validity of the scale were tested through completion of the QOLES in a cluster sampling method. The total scale included 18 items in three domains: physical, psychological, and social functional. The cumulative contributing rate of the three common factors was 65.23%. Cronbach's alpha coefficient of the scale was 0.82. This scale had good reliability and validity to evaluate nursing students' QOL. PMID- 25935668 TI - Determination of hydroxylated polycyclic aromatic hydrocarbons by HPLC photoionization tandem mass spectrometry in wood smoke particles and soil samples. AB - A simple and fast method for analysis of hydroxylated polycyclic aromatic hydrocarbons using pressurized liquid extraction and high performance liquid chromatography utilizing photoionization tandem mass spectrometry was developed. Simultaneous separation and determination of nine hydroxylated polycyclic aromatic hydrocarbons and two hydroxy biphenyls could be performed in negative mode with a run time of 12 min, including equilibration in 5 min. The calibration curves were in two concentration ranges; 1-50 ng/mL and 0.01-50 MUg/mL, with coefficients of correlation R (2) > 0.997. The limits of detection and method quantification limits were in the range of 9-56 pg and 5-38 ng/g, respectively. A two-level full factorial experimental design was used for screening of conditions with the highest impact on the extraction. The extraction procedure was automated and suitable for a large number of samples. The extraction recoveries ranged from 70 to 102 % and the matrix effects were between 92 and 104 %. The overall method was demonstrated on wood smoke particles and soil samples with good analytical performance, and five OH-PAHs were determined in the concentration range of 0.19 210 MUg/g. As far as we know, hydroxylated polycyclic aromatic hydrocarbons were determined in wood smoke and soil samples using photoionization mass spectrometry for the first time in this present study. Accordingly, this study shows that high performance liquid chromatography photoionization tandem mass spectrometry can be a good option for the determination of hydroxylated polycyclic aromatic hydrocarbons in complex environmental samples. Graphical Abstract The method developed in this study was used to determine hydroxylated polycyclic aromatic hydrocarbons in wood smoke and soil. PMID- 25935669 TI - Ethanol contamination of cerebrospinal fluid during standardized sampling and its effect on (1)H-NMR metabolomics. AB - Standardization of body fluid sampling, processing and storage procedures is pivotal to ensure data quality in metabolomics studies. Yet, despite strict adherence to standard sampling guidelines, we detected variable levels of ethanol in the (1)H-NMR spectra of human cerebrospinal fluid (CSF) samples (range 9.2 * 10(-3)-10.0 mM). The presence of ethanol in all samples and the wide range of concentrations clearly indicated contamination of the samples of some sort, which affected the (1)H-NMR spectra quality and the interpretation. To determine where in the sampling protocol the ethanol contamination occurs, we performed a CSF sampling protocol simulation with 0.9 % NaCl (saline) instead of CSF and detected ethanol in all simulation samples. Ethanol diffusion through air during sampling and preparation stages appeared the only logical explanation. With a bench study, we showed that ethanol easily diffuses into ex vivo CSF samples via air transmission. Ethanol originated from routinely used skin disinfectants containing ethanol and from laboratory procedures. Ethanol affected the CSF sample matrix at concentrations above ~9.4 mM and obscured a significant part of the (1)H-NMR spectrum. CSF sample preparation for (1)H-NMR-based metabolomics analyses should therefore be carried out in a well-ventilated atmosphere with laminar flow, and use of ethanol should be avoided. PMID- 25935670 TI - Identification of isobaric lyso-phosphatidylcholines in lipid extracts of gilthead sea bream (Sparus aurata) fillets by hydrophilic interaction liquid chromatography coupled to high-resolution Fourier-transform mass spectrometry. AB - The numerous and varied biological roles of phosphatidylcholines (PC) and lysophosphatidylcholines (LPC) have fueled a great demand for technologies that enable rapid, in-depth structural examination of these lipids in foodstuffs. Here, we describe the capabilities of a newly configured combination of high efficiency liquid chromatography and high-resolution/accuracy Fourier-transform mass spectrometry with electrospray ionization (LC-ESI-FTMS), designed for lipidomics applications that require the identification of PC in their lyso forms. The devised strategy, involving a separation by hydrophilic interaction liquid chromatography (HILIC) on spherical, fused-core ultrapure silica particles (2.7 MUm) of a narrow-bore column (2.1 mm i.d.), enabled the identification of as many as 71 LPC species in the lipid extracts of gilthead sea bream (Sparus aurata) fillets. In this way, LPC as proton (43) and sodium (28) adducts, i.e., [M + H](+) and [M + Na](+) ions (with M representing the zwitterionic form), were identified. In several cases, the extremely high (sub-ppm) mass accuracy and the high chromatographic efficiency available with the adopted instrumentation enabled the distinction of isobaric and closely eluting LPC species. Informative tandem mass spectra, based on high-energy collision induced dissociation (HCD), were also obtained, thus distinguishing regioisomeric LPC species (i.e., LPC differing only for the location of the residual side chain on the glycerol backbone) and between proton and sodium adducts. Graphical Abstract Extracted Ion Current chromatogram (XIC) obtained for the m/z value 568.339, showing the presence of two regioisomeric Lysophosphatidylcholines. The corresponding high collisional energy tandem MS spectra, obtained using a HCD cell, are shown as insets. PMID- 25935671 TI - Simultaneous determination of major type A and B trichothecenes, zearalenone and certain modified metabolites in Finnish cereal grains with a novel liquid chromatography-tandem mass spectrometric method. AB - A reliable and sensitive liquid chromatography-tandem mass spectrometric method was developed for the simultaneous quantitative determination in cereals of the Fusarium mycotoxins HT-2 toxin, T-2 toxin, deoxynivalenol, nivalenol and zearalenone, as well as the modified metabolites 3-acetyl-deoxynivalenol, alpha zearalenol, beta-zearalenol, deoxynivalenol-3-glucoside, HT-2-3-glucoside, nivalenol-3-glucoside, zearalenone-14-glucoside, zearalenone-14-sulphate, zearalenone-16-glucoside, alpha-zearalenol-14-glucoside and beta-zearalenol-14 glucoside. The 'dilute and shoot' approach was used for sample preparation after extraction with acetonitrile:water:acetic acid (79:20:1, v/v/v). Separation was carried out using reversed-phase liquid chromatography, and detection was performed using tandem mass spectrometry in the selected reaction monitoring mode. The method was in-house validated according to performance characteristics, established in Commission Regulation EC No 401/2006 and Commission Decision EC No 657/2002, prior to its application in a nationwide survey for the analysis of barley, oat and wheat samples (n = 95) harvested in Finland during 2013. Deoxynivalenol and its glucosylated form were the most abundant of the analytes, being detected in 93 and 81 % of the samples, respectively. Concentrations of deoxynivalenol were unusually high in 2013, especially in oats, with some cases exceeding the maximum legislative limits for unprocessed oats placed on the market for first-stage processing. All modified mycotoxins analysed were detected, and the natural occurrence of some of these compounds (e.g. zearalenone 16-glucoside and nivalenol-3-glucoside) in barley, oats and/or wheat was documented for the first time. PMID- 25935672 TI - Imaging mass spectrometry analysis of renal amyloidosis biopsies reveals protein co-localization with amyloid deposits. AB - Amyloidosis is a heterogeneous group of protein misfolding diseases characterized by deposition of amyloid proteins. The kidney is frequently affected, especially by immunoglobulin light chain (AL) and serum amyloid A (SAA) amyloidosis as the most common subgroups. Current diagnosis relies on histopathological examination, Congo red staining, or electron microscopy. Subtyping is done by immunohistochemistry; however, commercially available antibodies lack specificity. The purpose of this study was to identify and map amyloid proteins in formalin-fixed paraffin-embedded tissue sections using matrix-assisted laser desorption/ionization imaging mass spectrometry (MALDI IMS) coupled with liquid chromatography-tandem mass spectrometry (LC-MS/MS) analysis in an integrated workflow. Renal amyloidosis and non-amyloidosis biopsies were processed for histological and MS analysis. Mass spectra corresponding to the congophilic areas were directly linked to the histological and MS images for correlation studies. Peptides for SAA and AL were detected by MALDI IMS associated to Congo red positive areas. Sequence determination of amyloid peptides by LC-MS/MS analysis provided protein distribution and identification. Serum amyloid P component, apolipoprotein E, and vitronectin proteins were identified in both AA and AL amyloidosis, showing a strong correlation with Congo red-positive regions. Our findings highlight the utility of MALDI IMS as a new method to type amyloidosis in histopathological routine material and characterize amyloid-associated proteins that may provide insights into the pathogenetic process of amyloid formation. PMID- 25935673 TI - Mass-spectrometry-based method for screening of new peptide ligands for G-protein coupled receptors. AB - G-protein-coupled receptors (GPCRs) constitute the largest family of transmembrane proteins. Although implicated in almost all physiological processes in the human body, most of them remain unexploited, mostly because of the lack of specific ligands. The objective of this work is to develop a new mass spectrometry-based technique capable of identifying new peptide ligands for GPCRs. The strategy is based on the incubation of cellular membranes overexpressing GPCRs with a mixture of peptides that contains potential ligands. Peptide ligands bind to the receptors, whereas other peptides remain in the binding buffer. Bound peptides are eluted from membranes and directly detected, identified, and characterized by MALDI TOF-TOF. The results reveal the efficacy of the procedure for selecting a specific ligand of GPCRs in both simple and complex mixtures of peptides. This new approach may offer direct purification, identification, and characterization of the new ligand in a single workflow. The proposed method is labeling-free and, unlike radio-binding and other techniques, it does not require a previously known labeled ligand of the studied GPCR. All these properties greatly reduce the experimental constraints. Moreover, because it is not based on the principle of a competitive specific binding, this technique constitutes a new tool to discover new ligands not only for known GPCRs, but also for orphan GPCRs. PMID- 25935674 TI - Label-free surface-enhanced Raman spectroscopy of biofluids: fundamental aspects and diagnostic applications. AB - In clinical practice, one objective is to obtain diagnostic information while minimizing the invasiveness of the tests and the pain for the patients. To this end, tests based on the interaction of light with readily available biofluids including blood, urine, or saliva are highly desirable. In this review we examine the state of the art regarding the use of surface-enhanced Raman spectroscopy (SERS) to investigate biofluids, focusing on diagnostic applications. First, a critical evaluation of the experimental aspects involved in the collection of SERS spectra is presented; different substrate types are introduced, with a clear distinction between colloidal and non-colloidal metal nanostructures. Then the effect of the excitation wavelength is discussed, along with anomalous bands and artifacts which might affect SERS spectra of biofluids. The central part of the review examines the literature available on the SERS spectra of blood, plasma, serum, urine, saliva, tears, and semen. Finally, diagnostic applications are critically discussed in the context of the published evidence; this section clearly reveals that SERS of biofluids is most promising as a rapid, cheap, and non-invasive tool for mass screening for cancer. PMID- 25935675 TI - Human sweat metabolomics for lung cancer screening. AB - Sweat is one of the less employed biofluids for discovery of markers in spite of its increased application in medicine for detection of drugs or for diagnostic of cystic fibrosis. In this research, human sweat was used as clinical sample to develop a screening tool for lung cancer, which is the carcinogenic disease with the highest mortality rate owing to the advanced stage at which it is usually detected. In this context, a method based on the metabolite analysis of sweat to discriminate between patients with lung cancer versus smokers as control individuals is proposed. The capability of the metabolites identified in sweat to discriminate between both groups of individuals was studied and, among them, a trisaccharide phosphate presented the best independent performance in terms of the specificity/sensitivity pair (80 and 72.7%, respectively). Additionally, two panels of metabolites were configured using the PanelomiX tool as an attempt to reduce false negatives (at least 80% specificity) and false positives (at least 80% sensitivity). The first panel (80% specificity and 69% sensitivity) was composed by suberic acid, a tetrahexose, and a trihexose, while the second panel (69% specificity and 80% sensitivity) included nonanedioic acid, a trihexose, and the monoglyceride MG(22:2). Thus, the combination of the five metabolites led to a single panel providing 80% specificity and 79% sensitivity, reducing the false positive and negative rates to almost 20%. The method was validated by estimation of within-day and between-days variability of the quantitative analysis of the five metabolites. PMID- 25935676 TI - Determination of direct alcohol markers: a review. AB - Alcohol is the most popular legal drug used in our society today, and its consumption by pregnant women remains an important public health problem. Gestational alcohol consumption can result in a continuum of adverse fetal outcomes known as fetal alcohol spectrum disorder (FASD). Effective strategies are needed to prevent the increasing adoption of risky drinking behaviors. Because ethanol itself is only measurable for a few hours after ethanol intake in conventional matrices including blood, urine, and sweat, these matrices are only useful to detect recent ethanol exposure. Since approximately early 2000, the non oxidative ethanol metabolites have received increasing attention because of their specificity and, in some cases, wide time window of detection in non-conventional matrices including hair and meconium. In the attempt to update analytical methods for the determination of non-oxidative markers of alcohol, the objective of this study is to review published studies that measure fatty-acid ethyl esters (FAEE), ethyl glucuronide (EtG), and phosphatidylethanol (PEth) in alternative biological matrices, focusing on the extraction and detection methods and full analytical conditions used. PMID- 25935678 TI - Analysis of 18 urinary mercapturic acids by two high-throughput multiplex-LC MS/MS methods. AB - Mercapturic acids (MAs) are metabolic end products formed from conjugates between glutathione and electrophilic compounds. MAs are, therefore, suitable biomarkers of exposure to toxicants, which are either electrophiles by themselves or metabolized to electrophilic intermediates. We developed and validated two LC MS/MS methods which allow the complementary, rapid, and sensitive determination of MAs derived from acrolein, acrylamide, acrylonitrile, benzene, 1,3-butadiene, crotonaldehyde, N,N-dimethylformamide, ethylene, ethylene oxide, vinyl chloride, propylene oxide, styrene, toluene as well as methylating and ethylating agents. Since separate determinations of single or small groups of MAs are time-consuming and expensive, we multiplexed several individual methods into two LC-MS/MS methods covering 18 individual mercapturic acids. Method validation according to FDA guidelines showed excellent results in terms of robustness, accuracy, and sensitivity of the methods. Moreover, the use of a minimal, simple, and straightforward sample cleanup procedure further accelerated the analytical workflow, which allows a time- and cost-efficient analysis of up to 18 MAs derived from various toxicants in environmental levels. The methods were applied to urine samples derived from a strictly diet-controlled clinical study, including 25 smoking and 25 non-smoking subjects. Significant increase in the urine concentrations in smokers as compared to non-smokers (p < 0.01; Student t test) was observed for 13 individual MAs. Moreover, a dose dependence was obtained for the majority of the analytes. In conclusion, the newly developed assays represent a powerful tool for the fast and reliable quantification of 18 MAs in clinical studies. A first method application suggests several suitable biomarkers for nine relevant toxicants in tobacco smoke. PMID- 25935679 TI - Determination of BMAA and three alkaloid cyanotoxins in lake water using dansyl chloride derivatization and high-resolution mass spectrometry. AB - A new analytical method was developed for the detection of alkaloid cyanotoxins in harmful algal blooms. The detection of the nonproteinogenic amino acid beta-N methylamino-L-alanine (BMAA) and two of its conformation isomers, 2,4 diaminobutyric acid (DAB) and N-(2-aminoethyl) glycine (AEG), as well as three alkaloid cyanotoxins, anatoxin-a (ANA-a), cylindrospermopsin (CYN), and saxitoxin (STX), is presented. The use of a chemical derivatization with dansyl chloride (DNS) allows easier separation with reversed phase liquid chromatography. Detection with high-resolution mass spectrometry (HRMS) with the Q-Exactive enables high selectivity with specific fragmentation as well as exact mass detection, reducing considerably the possibilities of isobaric interferences. Previous to analysis, a solid phase extraction (SPE) step is used for purification and preconcentration. After DNS derivatization, samples are submitted to ultra high-performance liquid chromatography coupled with heated electrospray ionisation and the Q-Exactive mass spectrometer (UHPLC-HESI-HRMS). With an internal calibration using isotopically-labeled DAB-D3, the method was validated with good linearity (R (2) > 0.998), and method limits of detection and quantification (MLD and MLQ) for target compounds ranged from 0.007 to 0.01 MUg L(-1) and from 0.02 to 0.04 MUg L(-1), respectively. Accuracy and within day/between-days variation coefficients were below 15%. SPE recovery values ranged between 86 and 103%, and matrix effects recovery values ranged between 75 and 96%. The developed analytical method was successfully validated with 12 different lakes samples, and concentrations were found ranging between 0.009 and 0.3 MUg L(-1) except for STX which was not found in any sample. PMID- 25935677 TI - Capillary electrophoresis applied to DNA: determining and harnessing sequence and structure to advance bioanalyses (2009-2014). AB - This review of capillary electrophoresis methods for DNA analyses covers critical advances from 2009 to 2014, referencing 184 citations. Separation mechanisms based on free-zone capillary electrophoresis, Ogston sieving, and reptation are described. Two prevalent gel matrices for gel-facilitated sieving, which are linear polyacrylamide and polydimethylacrylamide, are compared in terms of performance, cost, viscosity, and passivation of electroosmotic flow. The role of capillary electrophoresis in the discovery, design, and characterization of DNA aptamers for molecular recognition is discussed. Expanding and emerging techniques in the field are also highlighted. PMID- 25935680 TI - Absolute quantification of gammaH2AX using liquid chromatography-triple quadrupole tandem mass spectrometry. AB - Ser139-phosphorylated histone H2AX (gammaH2AX) is a useful biomarker of DNA double strand breaks. gammaH2AX has been conventionally detected by immunology based methods using anti-gammaH2AX antibody, but quantitative analysis is difficult to perform with such methods. Here, we describe an absolute quantification method using liquid chromatography-triple quadrupole tandem mass spectrometry that is applicable to peptides derived from gammaH2AX (ATQA(pS)QEY) and unphosphorylated H2AX (ATQASQEY). Our method was successfully applied to histones extracted from human cervix adenocarcinoma HeLa S3 cells. The estimated number of molecules of gammaH2AX (ATQA(pS)QEY) per vehicle-treated HeLa S3 cell was 9.4 * 10(4) and increased to 6.2 * 10(5) molecules/cell after exposure to the DNA-damaging agent camptothecin (10 MUM) for 1 h. The estimated total amount of H2AX (ATQA(pS)QEY + ATQASQEY) was 3.3-3.6 * 10(6) molecules/cell. Due to its broad adaptability and throughput performance, we believe that our method is a powerful tool for mechanistic studies of the DNA-damage response as well as for genotoxicity testing, cancer drug screening, clinical studies, and other fields. PMID- 25935681 TI - Rapid and specific SPRi detection of L. pneumophila in complex environmental water samples. AB - Legionellosis is a very devastating disease worldwide mainly due to unpredictable outbreaks in man-made water systems. Developing a highly specific and sensitive rapid detection system that detects only metabolically active bacteria is a main priority for water quality assessment. We previously developed a versatile technique for sensitive and specific detection of synthetic RNA. In the present work, we further investigated the performance of the developed biosensor for detection of Legionella pneumophila in complex environmental samples, particularly those containing protozoa. The specificity and sensitivity of the detection system were verified using total RNA extracted from L. pneumophila in spiked water co-cultured with amoebae. We demonstrated that the expression level of ribosomal RNA (rRNA) is extremely dependent on the environmental conditions. The presence of amoebae with L. pneumophila, especially in nutrition-deprived samples, increased the amount of L. pneumophila 15-fold after 1 week as measured through the expression of 16s rRNA. Using the developed surface plasmon resonance imaging (SPRi) detection method, we were also able to successfully detect L. pneumophila within 3 h, both in the presence and absence of amoebae in the complex environmental samples obtained from a cooling water tower. These findings suggest that the developed biosensing system is a viable method for rapid, real time and effective detection not only for L. pneumophila in environmental samples but also to assess the risk associated with the use of water contaminated with other pathogens. PMID- 25935682 TI - Intention to leave the workplace among nurses working with cancer patients in acute care hospitals in Sweden. AB - PURPOSE: To examine associations between perceived leadership and intention to leave the workplace due to job dissatisfaction among registered nurses (RNs) who care for patients with cancer. We also examine intention to leave in relation to proportion of cancer patients, length of time in practice, perceived adequacy of cancer care education, and burnout. METHODS AND SAMPLE: The data originated from the Swedish component of RN4CAST, based on a survey of RNs working with in patient care in all acute care hospitals in Sweden. The 7412 RNs reporting >=10% patients with cancer on their unit were included in this analysis. Data were collected on perceptions of work environment, burnout, future employment intentions, and demographic characteristics. Additional questions related to cancer care. KEY RESULTS: About 1/3 of all RNs intended to leave their workplace within the next year. Intention to leave was more prevalent among RNs reporting less favourable perceptions of leadership, who had worked <= two years as RN, who reported having inadequate cancer care education, and with higher burnout scores. Associations between leadership and intention to leave were stronger among RNs in the profession > two years, who reported having adequate cancer care education, and with lower burnout scores. CONCLUSIONS: Perception of leadership is strongly associated with intention to leave among RNs in both specialized and general cancer care. This suggests a crucial area for improvement in order to reduce turnover rates. PMID- 25935683 TI - Testing a Preliminary Live with Love Conceptual Framework for cancer couple dyads: A mixed-methods study. AB - PURPOSE: The purpose of this study was to test the previous proposed Preliminary Live with Love Conceptual Framework (P-LLCF) that focuses on spousal caregiver patient couples in their journey of coping with cancer as dyads. METHODS: A mixed methods study that included qualitative and quantitative approaches was conducted. Methods of concept and theory analysis, and structural equation modeling (SEM) were applied in testing the P-LLCF. RESULTS: In the qualitative approach in testing the concepts included in the P-LLCF, a comparison was made between the P-LLCF with a preliminary conceptual framework derived from focus group interviews among Chinese couples' coping with cancer. The comparison showed that the concepts identified in the P-LLCF are relevant to the phenomenon under scrutiny, and attributes of the concepts are consistent with those identified among Chinese cancer couple dyads. In the quantitative study, 117 cancer couples were recruited. The findings showed that inter-relationships exist among the components included in the P-LLCF: event situation, dyadic mediators, dyadic appraisal, dyadic coping, and dyadic outcomes. In that the event situation will impact the dyadic outcomes directly or indirectly through Dyadic Mediators. The dyadic mediators, dyadic appraisal, and dyadic coping are interrelated and work together to benefit the dyadic outcomes. CONCLUSIONS: This study provides evidence that supports the interlinked components and the relationship included in the P-LLCF. The findings of this study are important in that they provide healthcare professionals with guidance and directions according to the P-LLCF on how to plan supportive programs for couples coping with cancer. PMID- 25935684 TI - Surface marker cluster translation, rotation, scaling and deformation: Their contribution to soft tissue artefact and impact on knee joint kinematics. AB - When recording human movement with stereophotogrammetry, skin deformation and displacement (soft tissue artefact; STA) inhibits surface markers' ability to validly represent the movement of the underlying bone. To resolve this issue, the components of marker motions which contribute to STA must be understood. The purpose of this study is to describe and quantify which components of this marker motion (cluster translation, rotation, scaling and deformation) contribute to STA during the stance phase of walking, a cutting manoeuvre, and one-legged hops. In vivo bone pin-based tibio-femoral kinematics of six healthy subjects were used to study skin marker-based STA. To quantify how total cluster translation, rotation, scaling and deformation contribute to STA, a resizable and deformable cluster model was constructed. STA was found to be greater in the thigh than the shank during all three movements. We found that the non-rigid (i.e. scaling and deformation) movements contribute very little to the overall amount of error, rendering surface marker optimisation methods aimed at minimising this component superfluous. The results of the current study indicate that procedures designed to account for cluster translation and rotation during human movement are required to correctly represent the motion of body segments, however reducing marker cluster scaling and deformation will have little effect on STA. PMID- 25935685 TI - Dynamic knee stability estimated by finite helical axis methods during functional performance approximately twenty years after anterior cruciate ligament injury. AB - Finite helical axis (FHA) measures of the knee joint during weight-bearing tasks may capture dynamic knee stability following Anterior Cruciate Ligament (ACL) injury. The aim was to investigate dynamic knee stability during two-leg squat (TLS) and one-leg side hop (SH) in a long-term follow-up of ACL injury, and to examine correlations with knee laxity (KT-1000), osteoarthritis (OA, Kellgren Lawrence) and knee function (Lysholm score). Participants were injured 17-28 years ago and then treated with surgery (n=33, ACLR) or physiotherapy only (n=37, ACLPT) and healthy-knee controls (n=33) were tested. Movements were registered with an optical motion capture system. We computed three FHA inclination angles, its' Anterior-Posterior (A-P) position, and an index quantifying directional changes (DI), during stepwise knee flexion intervals of ~15 degrees . Injured knees were less stable compared to healthy controls' and to contralateral non injured knees, regardless of treatment: the A-P intersection was more anterior (indicating a more anterior positioning of tibia relative to femur) positively correlating with high laxity/low knee function, and during SH, the FHA was more inclined relative to the flexion-extension axis, possibly due to reduced rotational stability. During the TLS, A-P intersection was more anterior in the non-injured knee than the injured, and DI was higher, probably related to higher load on the non-injured knee. ACLR had less anterior A-P intersection than ACLPT, suggesting that surgery enhanced stability, although rotational stability may remain reduced. More anterior A-P intersection and greater inclination between the FHA and the knee flexion-extension axis best revealed reduced dynamic stability ~23 years post-injury. PMID- 25935686 TI - Wrist range of motion and motion frequency during toy and game play with a joint specific controller specially designed to provide neuromuscular therapy: A proof of concept study in typically developing children. AB - Upper extremities affected by hemiplegic cerebral palsy (CP) and other neuromuscular disorders have been demonstrated to benefit from therapy, and the greater the duration of the therapy, the greater the benefit. A great motivator for participating in and extending the duration of therapy with children is play. Our focus is on active motion therapy of the wrist and forearm. In this study we examine the wrist motions associated with playing with two toys and three computer games controlled by a specially-designed play controller. Twenty children (ages 5-11) with no diagnosis of a muscular disorder were recruited. The play controller was fitted to the wrist and forearm of each child and used to measure and log wrist flexion and extension. Play activity and enjoyment were quantified by average wrist range of motion (ROM), motion frequency measures, and a discrete visual scale. We found significant differences in the average wrist ROM and motion frequency among the toys and games, yet there were no differences in the level of enjoyment across all toys and games, which was high. These findings indicate which toys and games may elicit the greater number of goal directed movements, and lay the foundation for our long-term goal to develop and evaluate innovative motion-specific play controllers that are engaging rehabilitative devices for enhancing therapy and promoting neural plasticity and functional recovery in children with CP. PMID- 25935687 TI - Can optimal marker weightings improve thoracohumeral kinematics accuracy? AB - Local and global optimization algorithms have been developed to estimate joint kinematics to reducing soft movement artifact (STA). Such algorithms can include weightings to account for different STA occur at each marker. The objective was to quantify the benefit of optimal weighting and determine if optimal marker weightings can improve humerus kinematics accuracy. A pin with five reflective markers was inserted into the humerus of four subjects. Seven markers were put on the skin of the arm. Subjects performed 38 different tasks including arm elevation, rotation, daily-living tasks, and sport activities. In each movement, mean and peak errors in skin- vs. pins-orientation were reported. Then, optimal marker weightings were found to best match skin- and pin-based orientation. Without weighting, the error of the arm orientation ranged from 1.9 degrees to 17.9 degrees . With weighting, 100% of the trials were improved and the average error was halved. The mid-arm markers weights were close to 0 for three subjects. Weights of a subject applied to the others for a given movement, and weights of a movement applied to others for a given subject did not systematically increased accuracy of arm orientation. Without weighting, a redundant set of marker and least square algorithm improved accuracy to estimate arm orientation compared to data of the literature using electromagnetic sensor. Weightings were subject- and movement-specific, which reinforces that STA are subject- and movement-specific. However, markers on the deltoid insertion and on lateral and medial epicondyles may be preferred if a limited number of markers is used. PMID- 25935688 TI - Locomotor adaptation is influenced by the interaction between perturbation and baseline asymmetry after stroke. AB - Stroke survivors without cerebellar involvement retain the ability to adapt to the split-belt treadmill; however it has been suggested that their rate of adaptation may be slowed compared to those who are neurologically intact. Depending on limb placement, the split-belt treadmill can be configured to either exaggerate baseline asymmetry, or reduce it, which may affect the behavior of adaptation or de-adaptation. The objectives of this study were to characterize the rate and magnitude of locomotor (de)adaptation in chronic stroke survivors compared to healthy matched subjects, and to evaluate whether exaggeration or reduction of baseline asymmetry impact the responses. Seventeen stroke survivors and healthy subjects completed 10min of split-belt treadmill walking, then 5min of tied-belt walking. Stroke survivors completed this once with each leg on the fast belt. Magnitude and rate of (de)adaptation were evaluated for step length and limb phase asymmetry. There were no differences between the groups with the exception of the reduced step length asymmetry configuration, in which case there was a significantly reduced magnitude (p<=0.000) and rate (p=0.011) of adaptation when compared to controls. There was a similar trend observed during post adaptation for the exaggerated asymmetry group. The rate and magnitude of locomotor (de)adaptation is similar between chronic stroke survivors and neurologically intact controls, except when the adaptation or de-adaptation response would take the stroke survivors away from a symmetric step length pattern. This suggests that there may be some benefit to symmetry that is recognized by the system. PMID- 25935689 TI - Proprioceptive feedback contributes to the adaptation toward an economical gait pattern. AB - Humans generally prefer gait patterns with a low metabolic cost, but it is unclear how such patterns are chosen. We have previously proposed that humans may use proprioceptive feedback to identify economical movement patterns. The purpose of the present experiments was to investigate the role of plantarflexor proprioception in the adaptation toward an economical gait pattern. To disrupt proprioception in some trials, we applied noisy vibration (randomly varying between 40-120Hz) over the bilateral Achilles tendons while participants stood quietly or walked on a treadmill. For all 10min walking trials, the treadmill surface was initially level before slowly increasing to a 2.5% incline midway through the trial without participant knowledge. During standing posture, noisy vibration increased sway, indicating decreased proprioception accuracy. While walking on a level surface, vibration did not significantly influence stride period or metabolic rate. However, vibration had clear effects for the first 2 3min after the incline increase; vibration caused participants to walk with shorter stride periods, reduced medial gastrocnemius (MG) activity during mid stance (30-65% stance), and increased MG activity during late-stance (65-100% stance). Over time, these metrics gradually converged toward the gait pattern without vibration. Likely as a result of this delayed adaptation to the new mechanical context, the metabolic rate when walking uphill was significantly higher in the presence of noisy vibration. These results may be explained by the disruption of proprioception preventing rapid identification of muscle activation patterns which allow the muscles to operate under favorable mechanical conditions with low metabolic demand. PMID- 25935690 TI - Passive and active muscle stiffness in plantar flexors of long distance runners. AB - The aim of the present study was to compare passive and active muscle stiffness and tendon stiffness between long distance runners and untrained men. Twenty long distance runners and 24 untrained men participated in this study. Active muscle stiffness in the medial gastrocnemius muscle was calculated according to changes in estimated muscle force and fascicle length during fast stretching after submaximal isometric contractions. Passive muscle stiffness was also calculated from estimated passive muscle force and fascicle length during slow passive stretching. Tendon stiffness was determined during isometric plantar flexion by ultrasonography. Passive muscle stiffness of long distance runners was significantly higher than that of untrained men (p<0.001). Active muscle stiffness at all torque levels of long distance runners was also significantly higher than that of untrained men (p<0.001). No significant difference was observed in tendon stiffness between long distance runners and untrained men (p=0.869). These results suggested that passive and active muscle stiffness were higher in long distance runners than in untrained men, whereas no significant difference was observed in tendon stiffness between the two groups. PMID- 25935692 TI - Kinesthetic illusions attenuate experimental muscle pain, as do muscle and cutaneous stimulation. AB - In the present study, muscle pain was induced experimentally in healthy subjects by administrating hypertonic saline injections into the tibialis anterior (TA) muscle. We first aimed at comparing the analgesic effects of mechanical vibration applied to either cutaneous or muscle receptors of the TA or to both types simultaneously. Secondly, pain alleviation was compared in subjects in whom muscle tendon vibration evoked kinesthetic illusions of the ankle joint. Muscle tendon vibration, which primarily activated muscle receptors, reduced pain intensity by 30% (p<0.01). In addition, tangential skin vibration reduced pain intensity by 33% (p<0.01), primarily by activating cutaneous receptors. Concurrently stimulating both sensory channels induced stronger analgesic effects (-51%, p<0.01), as shown by the lower levels of electrodermal activity. The strongest analgesic effects of the vibration-induced muscle inputs occurred when illusory movements were perceived (-38%, p=0.01). The results suggest that both cutaneous and muscle sensory feedback reduce muscle pain, most likely via segmental and supraspinal processes. Further clinical trials are needed to investigate these new methods of muscle pain relief. PMID- 25935691 TI - Neuronal cytochrome P450 activity and opioid analgesia: relevant sites and mechanisms. AB - Recent studies suggest a functional role for neuronal cytochrome P450 monooxygenase (P450) activity in opioid analgesia. To characterize the relevant receptors, brain areas, and circuits, detailed in vitro and in vivo studies were performed with the highly selective MU opioid receptor agonist DAMGO in neuronal P450-deficient mutant (Null) and control mice. Homogenates of brain regions and spinal cord showed no differences in DAMGO-induced activation of [(35)S]- GTPgammaS binding between Null and control mice, indicating no genotype differences in u opioid receptor signaling, receptor affinities or receptor densities. Intracerebroventricular (icv) DAMGO produced robust, near-maximal, analgesic responses in control mice which were attenuated by 50% in Null mice, confirming a role for u opioid receptors in activating P450-associated responses. Intra-periaqueductal gray (PAG) and intra-rostral ventromedial medulla (RVM) injections of DAMGO revealed deficits in Null (vs. control) analgesic responses, yet no such genotype differences were observed after intrathecal DAMGO administration. Taken with earlier published findings, the present results suggest that activation of u opioid receptors in both the PAG and in the RVM relieves pain by mechanisms which include nerve-terminal P450 enzymes within inhibitory PAG-RVM projections. Spinal opioid analgesia, however, does not seem to require such P450 enzyme activity. PMID- 25935693 TI - Long-and short-range functional connectivity density alteration in non-alcoholic cirrhotic patients one month after liver transplantation: A resting-state fMRI study. AB - PURPOSE: To longitudinally evaluate long- and short-range functional connectivity density (FCD) alteration in cirrhotic patients one month after liver transplantation (LT) and their correlation with cognitive changes by using resting-state functional magnetic resonance imaging (rs-fMRI). METHODS: Twenty seven candidates awaiting LT and 24 age-, gender-, and education-matched healthy controls (HCs) were studied. All 27 patients and HCs performed rs-fMRI examinations. Of 27 cirrhotic patients, 13 patients received LT underwent the repeated rs-fMRI examinations one month after LT. Laboratory and psychometric tests were carried out. The long- and short-range FCD maps derived from degree centrality calculation were compared. Correlations between FCD alteration and laboratory/psychometric changes were evaluated as well. RESULTS: In cirrhotic patients, most of the brain areas with altered long- and short-range FCD could reverse one month after LT, which was accompanied with cognitive and liver functional improvement. The reduced long-range FCD in right posterior cingulate cortex (PCC) and Left middle frontal gyrus (MFG), and reduced short-range FCD in right precuneus (PCu) persisted in the early period after LT. In addition, one month after LT, the post-LT group showed reduced long-range FCD in right rectus gyrus (REC) and left medial prefrontal cortex (MPFC), and reduced short-range FCD in left middle temporal gyrus (MTG), when compared with the pre-LT group. We found Deltadigital symbol test (DeltaDST) score positively correlated with long range DeltaFCD in right precentral gyrus (preCG) (r = 0.72, P < 0.01) and right supplementary motor area (SMA) (r = 0.59, P < 0.05). CONCLUSION: LT results in favorable effect on cognitive function in cirrhotic patient, which can be reflected by FCD alteration. However, persistence of PCC/PCu functional connectivity disturbance one month after LT indicates complete cognitive function restoration may need a longer time. PMID- 25935694 TI - Farnesol attenuates lipopolysaccharide-induced neurodegeneration in Swiss albino mice by regulating intrinsic apoptotic cascade. AB - Neuronal apoptosis occurs as a sequel of oxidative stress associated with various neuropathies. In this study, we have investigated the protective effect of farnesol, a sequisterpene on lipopolysaccharide (LPS) induced neurodegeneration through modulation of intrinsic apoptotic cascade in the cortex and hippocampus of Swiss albino mice. Intraperitoneal (i.p.) injection of LPS (250 MUg/kg b.wt. for 7 days) resulted in elevated levels of lipid peroxidation, protein carbonyls and 8-Hydroxydeoxyguanosine (8OHdG), with subsequent depletion in the antioxidant status and severe histological aberrations. These anomalies were accompanied by increased expressions of pro-apoptotic Bax, caspase-3 and p53 with decrease in anti-apoptotic Bcl-2. Farnesol treatment (100mg/kg b.wt.) ameliorated LPS-induced oxidative stress by enhancing the antioxidant defense system as evident from the increased levels of SOD, CAT, GSH and GST and exhibited protected cellular morphology manifested from histopathological and nissl staining analyses. Farnesol treatment also reduced the expulsion of cytochrome c from mitochondria and downregulated caspase 3 activation as revealed by immunoblot analysis. Furthermore, farnesol treatment reduced the expression of Bax and antagonized LPS induced decrease in anti-apoptotic Bcl-2. Results of this study show that farnesol exerts neuroprotective effect by regulating intrinsic apoptotic cascade through its antioxidant effect during LPS-induced neurodegeneration. PMID- 25935695 TI - Modulation of the brain activity in outcome evaluation by the presence of an audience: An electrophysiological investigation. AB - The audience effect refers to the phenomenon that one's performance on a task is affected by the presence of others. Here we investigated how the audience effect modulates the neurocognitive signatures underlying people's evaluation of their own task performance/outcome. Participants in our study played a gambling game in two social contexts: an "audience" condition and an "alone" condition. The presence of others modulated the feedback-related negativity (FRN), which might reflect enhanced motivational significance or increased reward processing when participants were watched compared to when they were alone. We also observed increased P300 responses to outcome feedback in the audience condition, presumably reflecting more elaborative and sustained evaluation of outcomes in the audience than alone context. This audience effect on the evaluative processes complements previous observations on the social nature of outcome evaluation and extends a traditional topic in social psychology to the neuroscientific field. PMID- 25935696 TI - Intraperitoneal administration of thioredoxin decreases brain damage from ischemic stroke. AB - Recent studies demonstrate that Thioredixin (Trx) possesses a neuronal protective effect and closely relates to oxidative stress and apoptosis of cerebral ischemia injury. The present study was conducted to validate the neuroprotective effect of recombinant human Trx-1 (rhTrx-1) and its potential mechanisms against ischemia injury at middle cerebral artery occlusion (MCAO) in mice. rhTrx-1 was administrated intraperitoneally at a dose of 5, 10 and 20mg/kg 30 min before MCAO in mice, and its neuronal protective effect was evaluated by neurological deficit score, brain dry-wet weight, 2,3,5-triphenyltetrazolium chloride (TTC) staining. The protein carbonyl content and HO-1 were detected to investigate its potential anti-oxidative and anti-inflammatory property, and the anti-apoptotic ability of rhTrx-1 was assessed by casepase-3 and TUNEL staining. The results demonstrated that rhTrx-1 significantly improved neurological functions and reduced cerebral infarction and apoptotic cell death at 24h after MCAO. Moreover, rhTrx-1 resulted in a significant decrease in carbonyl contents and HO-1 against oxidative stress, which turned to be fast reduction during the first 24h and tended to be stable from 24h to 72h after MCAO. The study shows that rhTrx-1 exerts an neuroprotective effect in cerebral ischemia injury. The anti-oxidative, anti apoptotic and anti-inflammatory properties of rhTrx-1 are more likely to succeed as a therapeutic approach to diminish oxidative stress-induced neuronal apoptotic cell death in acute ischemic stroke. PMID- 25935697 TI - High-resolution MS and MS(n) investigation of ozone oxidation products from phenazone-type pharmaceuticals and metabolites. AB - Phenazone-type pharmaceuticals, such as aminopyrine, metamizole, phenazone and propyphenazone, are widely used analgesics that have been detected in wastewater treatment plant effluents in MUg L(-1) concentrations. Acetamido antipyrine (AAA) and formyl aminoantipyrine (FAA) - the main metabolites of aminopyrine and metamizole - have also been detected in sub MUg L(-1) concentrations in environmental water bodies and in resources used to produce drinking water, suggesting their highly persistent character. In this study phenazone, propyphenazone, AAA and FAA were treated with ozone under laboratory conditions and 17 degradation products were identified by an elucidation approach based on high-resolution mass spectrometry (LTQ Orbitrap). Typical oxidation of carbon carbon double bonds by ozone was observed among other mechanisms of ring opening. It was demonstrated that reactivity of these compounds with ozone is high (rate constants kO3 ranging from 6.5*10(4) to 2.4*10(6) M(-1) s(-1)). The toxicity of the degradation products from ozonation was estimated by quantitative structure activity relationships (QSAR). It was shown that, when the carbon-carbon double bond is partially oxidized to an epoxy, the toxicity towards fish and daphnids is higher than that of the parent compound. By further oxidizing the molecules, a common degradation product - 1-acetyl-1-methyl-2-phenylhydrazide (AMPH) - was also found to be more toxic than its parent compounds, which is of concern since this compound has previously been reported in environmental waters. PMID- 25935698 TI - Humic substances from sewage sludge compost as washing agent effectively remove Cu and Cd from soil. AB - Although commercially available biosurfactants are environmentally friendly and effectively remove heavy metals from soil, they are costly. Therefore, this study investigated whether inexpensive humic substances (HS) from sewage sludge compost could effectively remove copper (Cu) and cadmium (Cd) from highly contaminated sandy clay loam (S1) and clay (S2). The optimum HS concentration and pH were determined, as well process kinetics. Under optimum conditions, a single washing removed 80.7% of Cu and 69.1% of Cd from S1, and 53.2% and 36.5%, respectively, from S2. Triple washing increased removal from S1 to almost 100% for both metals, and to 83.2% of Cu and 88.9% of Cd from S2. Triple washing lowered the potential ecological risk (Er(i)) of the soils, especially the risk from Cd. HS substances show potential for treating soils highly contaminated with heavy metals, and HS from other sources should be tested with these and other contaminants. PMID- 25935699 TI - Photoelectrocatalytic/photoelectro-Fenton coupling system using a nanostructured photoanode for the oxidation of a textile dye: Kinetics study and oxidation pathway. AB - In this study, a coupled photoelectrocatalytic/photoelectro-Fenton reactor was designed to enhance the degradation efficiency of organic pollutants and tested using the azo dye Orange G as a model compound. Pt-decorated TiO2 nanotubes were used as a photoanode with an air-diffusion polytetrafluoroethylene cathode for H2O2 generation. The sum of individual effects of coupling the photoelectrocatalytic and photoelectro-Fenton processes was evaluated as a function of the decolorization and mineralization of Orange G solutions. The dye solutions were only completely decolorized in more acidic conditions (pH 3.0). The mineralization of the Orange G solutions increased in the sequence photoelectrocatalytic=2 clinically defined CDI episodes. Patient demographics and clinical data were recorded, and strain relatedness investigated by both polymerase chain reaction (PCR)-based ribotyping and WGS. FINDINGS: Nineteen patients were identified with >=2 clinically defined CDI episodes who cumulatively suffered 39 recurring CDI episodes (58 total episodes). Patients had a median length of stay (LOS) of 144 days and experienced between two and seven CDI episodes. Ribotyping indicated 27 apparent same-strain relapses, five reinfections and the predominance of ribotypes 078 (ST-11) and 020 (ST-2). WGS allowed characterization of relapse with increased certainty and identified emergent within-strain single nucleotide variants (SNVs) with potential functional impact on diverse genes. Shared ribotypes among 14 patients with recurrent CDI suggested 10 possible patient-to-patient transmission events. However, WGS revealed greater diversity at the sub-ribotype level, excluding all but four transmission events. CONCLUSION: WGS exhibits several advantages over PCR-based ribotyping in terms of its ability to distinguish relapse from reinfection, to identify patient-to-patient transmission events, and to exact fine structure characterization of recurrent CDI epidemiology. This offers the potential for more focused infection prevention strategies to eliminate strain transmission among patients with recurrent CDI. PMID- 25935701 TI - Role of healthcare apparel and other healthcare textiles in the transmission of pathogens: a review of the literature. AB - Healthcare workers (HCWs) wear uniforms, such as scrubs and lab coats, for several reasons: (1) to identify themselves as hospital personnel to their patients and employers; (2) to display professionalism; and (3) to provide barrier protection for street clothes from unexpected exposures during the work shift. A growing body of evidence suggests that HCWs' apparel is often contaminated with micro-organisms or pathogens that can cause infections or illnesses. While the majority of scrubs and lab coats are still made of the same traditional textiles used to make street clothes, new evidence suggests that current innovative textiles function as an engineering control, minimizing the acquisition, retention and transmission of infectious pathogens by reducing the levels of bioburden and microbial sustainability. This paper summarizes recent literature on the role of apparel worn in healthcare settings in the acquisition and transmission of healthcare-associated pathogens. It proposes solutions or technological interventions that can reduce the risk of transmission of micro organisms that are associated with the healthcare environment. Healthcare apparel is the emerging frontier in epidemiologically important environmental surfaces. PMID- 25935702 TI - Precision and predictive medicine in urothelial cancer: are we making progress? AB - Therapy for urothelial carcinoma appears poised for a breakthrough on the basis of information regarding molecular subtypes and promising activity of PD-1/PD-L1 inhibitors. Precision medicine may be possible using rational marker-driven trial designs with enriched information from tumor genotyping and extreme responders. PMID- 25935703 TI - ZNF804A Genetic Variation Confers Risk to Bipolar Disorder. AB - Genetic variation in the gene encoding zinc finger protein 804A gene (ZNF804A) has been identified to be associated with bipolar disorder in genome-wide association studies, while little is known regarding their association in Asian populations. In this study, we aimed to examine whether ZNF804A may confer susceptibility to BD in Han Chinese. We measured the mRNA expression level of ZNF804A in patients with BD and controls. Two functional variants (rs1344706 and rs359895) in ZNF804A were genotyped among 1508 individuals with or without BD. We then performed a meta-analysis based on present literature. Our results showed that ZNF804A mRNA level in peripheral blood mononuclear cells was significantly higher in BD patients than that in controls (P = 0.01). The rs1344706 showed significant allelic association with BD (P = 0.034). The frequency of T allele of rs1344706 was higher in patients than that in controls (odds ratio = 1.19, 95 % confidence interval 1.03-1.37). After pooling all data, meta-analysis indicated a significant association of rs1344706 with BD (P = 0.0003). Furthermore, we performed an eQTL analysis and observed significant associations between rs1344706 and ZNF804A expression level in hippocampus (P = 0.032) and occipital cortex (P = 0.036). After stratified by diagnosis, the association of rs1344706 with BD was only survived in BD-I (genotypic P = 0.04, allelic P = 0.014), but not in BD-II. Our findings provided supportive evidence for the involvement of ZNF804A rs1344706 in BD, especially in BD-I. PMID- 25935704 TI - The proximal serrated polyp detection rate is an easy-to-measure proxy for the detection rate of clinically relevant serrated polyps. AB - BACKGROUND AND AIMS: The adenoma detection rate (ADR) is the most important surrogate quality parameter for colorectal cancer (CRC) prevention. However, serrated polyps also are precursors of CRC. Large, prospective studies comparing the detection rate of serrated polyps among endoscopists in an era of awareness about the malignant potential of serrated polyps have not yet been performed. We aimed to compare the proximal serrated polyp (PSP) detection rate and the clinically relevant serrated polyp (RSP) detection rate among endoscopists and to analyze the association between these parameters and the ADR. METHODS: Colonoscopy data were retrieved in one expert center between January 2011 and July 2014 by using a structured reporting system, enabling prospective and automatic quality assessment. Endoscopists who performed at least 50 colonoscopies within the timeframe were included for analysis. Multivariate logistic regression was used to compare the ADR, PSP detection rate, and RSP detection rate among endoscopists. The association among these parameters was calculated by using the Pearson r correlation coefficient. All lesions were assessed by an expert pathologist. RESULTS: In total, 16 endoscopists and 2088 colonoscopies were included for analysis. The PSP detection rate ranged from 2.9% to 18.6% (mean 10.4%) among endoscopists. Corrected for confounders, the odds ratio to detect >=1 PSP, compared with endoscopists with the highest detection rate, ranged from 0.79 (95% confidence interval [CI], 0.41-1.52) to 0.12 (95% CI, 0.03-0.55). The PSP detection rate was highly correlated with the RSP detection rate (rho 0.94; P < .001), ranging from 4.3% to 20.9% (mean 13.9%). The PSP detection rate moderately correlated with the ADR (0.55; P = .03), which ranged from 23.2% to 49.2% (mean 35.2%). CONCLUSIONS: The PSP detection rate is widely variable among endoscopists, strongly correlated with the RSP detection rate, and moderately correlated with the ADR. These results suggest a high miss rate of RSPs among endoscopists with low rates of PSP detection. Future research should determine the association between endoscopists' PSP detection rates and the risk of interval cancer. PMID- 25935705 TI - The role of endoscopy in the management of premalignant and malignant conditions of the stomach. PMID- 25935706 TI - A cleavable cytolysin-neuropeptide Y bioconjugate enables specific drug delivery and demonstrates intracellular mode of action. AB - Myxobacterial tubulysins are promising chemotherapeutics inhibiting microtubule polymerization, however, high unspecific toxicity so far prevents their application in therapy. For selective cancer cell targeting, here the coupling of a synthetic cytolysin to the hY1-receptor preferring peptide [F(7),P(34)] neuropeptide Y (NPY) using a labile disulfide linker is described. Since hY1 receptors are overexpressed in breast tumors and internalize rapidly, this system has high potential as peptide-drug shuttle system. Molecular characterization of the cytolysin-[F(7),P(34)]-NPY bioconjugate revealed potent receptor activation and receptor-selective internalization, while viability studies verified toxicity. Triple SILAC studies comparing free cytolysin with the bioconjugate demonstrated an intracellular mechanism of action regardless of the delivery pathway. Treatments resulted in a regulation of proteins implemented in cell cycle arrest confirming the tubulysin-like effect of the cytolysin. Thus, the cytolysin-peptide bioconjugate fused by a cleavable linker enables a receptor specific delivery as well as a potent intracellular drug-release with high cytotoxic activity. PMID- 25935707 TI - PEG shielded MMP sensitive CPPs for efficient and tumor specific gene delivery in vivo. AB - Gene therapy has great potential to treat a range of different diseases, such as cancer. For that therapeutic gene can be inserted into a plasmid vector and delivered specifically to tumor cells. The most frequently used applications utilize lipoplex and polyplex approaches where DNA is non-covalently condensed into nanoparticles. However, lack of in vivo efficacy is the major concern that hinders translation of such gene therapeutic applications into clinics. In this work we introduce a novel method for in vivo delivery of plasmid DNA (pDNA) and efficient tumor-specific gene induction using intravenous (i.v) administration route. To achieve this, we utilize a cell penetrating peptide (CPP), PepFect14 (PF14), double functionalized with polyethylene glycol (PEG) and a matrix metalloprotease (MMP) substrate. We show that this delivery vector effectively forms nanoparticles, where the condensed CPP and pDNA are shielded by the PEG, in an MMP-reversible manner. Administration of the complexes results in efficient induction of gene expression specifically in tumors, avoiding normal tissues. This strategy is a potent gene delivery platform that can be used for tumor specific induction of a therapeutic gene. PMID- 25935708 TI - Fast vergence eye movements are disrupted in Parkinson's disease: A video oculography study. AB - BACKGROUND: Blurred near vision is a common non-motor symptom in patients with Parkinson's disease (PD), however detailed characterization of vergence eye movements (VEM) is lacking. METHODS: Convergence and divergence were examined in 18 patients with PD and 18 control subjects using infrared video-oculography. VEM metrics analyzed included latency, velocity and accuracy, in vertical and horizontal planes. RESULTS: The latency of convergence and divergence was significantly increased in PD subjects. Additionally, divergence was slow and hypometric, while other convergence metrics were similar to controls. CONCLUSION: We provide evidence in favor of disrupted VEM in PD. PMID- 25935709 TI - The regenerated tail of juvenile leopard geckos (Gekkota: Eublepharidae: Eublepharis macularius) preferentially stores more fat than the original. AB - The tail of many species of lizard is used as a site of fat storage, and caudal autotomy is a widespread phenomenon among lizards. This means that caudal fat stores are at risk of being lost if the tail is autotomized. For fat-tailed species, such as the leopard gecko, this may be particularly costly. Previous work has shown that tail regeneration in juveniles of this species is rapid and that it receives priority for energy allocation, even when dietary resources are markedly reduced. We found that the regenerated tails of juvenile leopard geckos are more massive than their original counterparts, regardless of dietary intake, and that they exhibit greater amounts of skeleton, inner fat, muscle and subcutaneous fat than original tails (as assessed through cross-sectional area measurements of positionally equivalent stations along the tail). Autotomy and regeneration result in changes in tail shape, mass and the pattern of tissue distribution within the tail. The regenerated tail exhibits enhanced fat storage capacity, even in the face of a diet that results in significant slowing of body growth. Body growth is thus sacrificed at the expense of rapid tail growth. Fat stores laid down rapidly in the regenerating tail may later be used to fuel body growth or reproductive investment. The regenerated tail thus seems to have adaptive roles of its own, and provides a potential vehicle for studying trade offs that relate to life history strategy. PMID- 25935711 TI - Left truncation results in substantial bias of the relation between time dependent exposures and adverse events. AB - PURPOSE: To assess the impact of random left truncation of data on the estimation of time-dependent exposure effects. METHODS: A simulation study was conducted in which the relation between exposure and outcome was based on an immediate exposure effect, a first-time exposure effect, or a cumulative exposure effect. The individual probability of truncation, the moment of truncation, the exposure rate, and the incidence rate of the outcome were varied in different simulations. All observations before the moment of left truncation were omitted from the analysis. RESULTS: Random left truncation did not bias estimates of immediate exposure effects, but resulted in an overestimation of a cumulative exposure effect and underestimation of a first-time exposure effect. The magnitude of bias in estimation of cumulative exposure effects depends on a combination of exposure rate, probability of truncation, and proportion of follow-up time left truncated. CONCLUSIONS: In case of a cumulative or first-time exposure, left truncation can result in substantial bias in pharmacoepidemiologic studies. The potential for this bias likely differs between databases, which may lead to heterogeneity in estimated exposure effects between studies. PMID- 25935710 TI - Emergency department utilization and subsequent prescription drug overdose death. AB - PURPOSE: Prescription drug overdose (PDO) deaths are a critical public health problem in the United States. This study aims to assess the association between emergency department (ED) utilization patterns in a cohort of ED patients and the risk of subsequent unintentional PDO mortality. METHODS: Using data from the New York Statewide Planning and Research Cooperative System for 2006-2010, a nested case-control design was used to examine the relationship between ED utilization patterns in New York State residents of age 18-64 years and subsequent PDO death. RESULTS: The study sample consisted of 2732 case patients who died of PDO and 2732 control ED patients who were selected through incidence density sampling. With adjustment for demographic characteristics, and diagnoses of pain, substance abuse, and psychiatric disorders, the estimated odds ratios of PDO death relative to one ED visit or less in the previous year were 4.90 (95% confidence interval [CI]: 4.50-5.34) for those with two ED visits, 16.61 (95% CI: 14.72-18.75) for those with three ED visits, and 48.24 (95% CI: 43.23-53.83) for those with four ED visits or more. CONCLUSIONS: Frequency of ED visits is strongly associated with the risk of subsequent PDO death. Intervention programs targeting frequent ED users are warranted to reduce PDO mortality. PMID- 25935712 TI - Data quality from a longitudinal study of adolescent health at schools near industrial livestock facilities. AB - PURPOSE: Longitudinal designs enable examination of temporal relationships between exposures and health outcomes, but extended participation can cause study fatigue. We present an approach for analyzing data quality and study fatigue in a participatory, longitudinal study of adolescents. METHODS: Participants (n = 340) in the Rural Air Pollutants and Children's Health study completed daily diaries for 3 to 5 weeks in 2009 while we monitored outdoor pollutant concentrations. We used regression models to examine established associations between disease, symptoms, anthropometrics, and lung function as indicators of internal consistency and external validity. We modeled temporal trends in data completeness, lung function, environmental odors, and symptoms to assess study fatigue. RESULTS: Of 5728 records, 94.2% were complete. Asthma and allergy status were associated with asthma-related symptoms at baseline and during follow-up, for example, prevalence ratio = 8.77 (95% confidence interval: 4.33-17.80) for awakening with wheeze among diagnosed asthmatics versus nonasthmatics. Sex, height, and age predicted mean lung function. Plots depicting outcome reporting over time and associated linear trends showed time-dependent declines for most outcomes. CONCLUSIONS: We achieved data completeness, internal consistency, and external validity, yet still observed study fatigue, despite efforts to maintain participant engagement. Future investigators should model time trends in reporting to monitor longitudinal data quality. PMID- 25935713 TI - Enhanced humoral response in pregnant mice immunized with liposome encapsulated recombinant neutralizing epitope protein of Hepatitis- E virus. AB - BACKGROUND: Pregnant women from developing countries are at high-risk of hepatitis E-associated high mortality and constitute priority population for vaccination. So far, candidate vaccines have not been evaluated during pregnancy. We evaluated our vaccine candidate, recombinant Neutralizing Epitope protein (rNEp) encapsulated in liposomes, in pregnant mice. METHODS: A single dose (10 MUg) of the formulation was administered intramuscularly on day 7 of pregnancy. Titres of serum IgG antibodies to hepatitis E virus (IgG-anti-HEV), levels of cytokines and biochemical parameters were determined. Spleens were harvested from pregnant and non-pregnant mice for immunophenotyping (flow cytometry), cytokines (cytometric bead array, CBA) and gene expression of immune response genes (Taqman low density array, TLDA). Histopathology studies of spleen, liver, kidneys, brain and muscle was carried out. RESULTS: The vaccine was well-tolerated during pregnancy as evidenced by histopathology and serum biochemical parameters. Anti HEV titres were significantly higher in the pregnant balb/c and C57BL/6 mice (3592 +/- 802 and 1016 +/- 138 respectively, than in non-pregnant groups (634 +/- 191 and 320 +/- 55 respectively, p < 0.001 for both) suggesting that the higher antibody response in pregnant mice was independent of the genetic makeup of the host but immunogen-driven. Pups receiving vertically transferred antibodies developed lower anti-HEV antibodies (p < 0.05) when immunized with the formulation after seronegativity than in the age-matched mice without such antibodies. In non-pregnant mice, a Th1 response and discordance between splenic and serum cytokines was evident while in pregnancy, a Th2 bias was observed irrespective of immunization. Increased CD19 levels correlated with higher anti HEV titres in pregnant mice. CONCLUSION: The single dose of the vaccine was safe and highly immunogenic in pregnant mice. Degree and type of immune response to vaccination during pregnancy is immunogen-driven. In-depth studies are needed to understand the underlying immunologic mechanism(s). These encouraging results for a vaccine intended for use in pregnant women should be confirmed in higher animals. PMID- 25935714 TI - Factors associated with willingness to take extended release naltrexone among injection drug users. AB - BACKGROUND: Although opioid-agonist therapy with methadone or buprenorphine/naloxone is currently the mainstay of medical treatment for opioid use disorder, these medications often are not well accepted or tolerated by patients. Recently, extended release naltrexone (XR-NTX), an opioid antagonist, has been advanced as an alternative treatment. The willingness of opioid-addicted patients to take XR-NTX has not been well described. METHODS: Opioid-using persons enrolled in a community-recruited cohort in Vancouver, Canada, were asked whether or not they would be willing to take XR-NTX. Logistic regression was used to independently identify factors associated with willingness to take the medication. RESULTS: Among the 657 participants surveyed between June 1, 2013, and November 30, 2013, 342 (52.1%) were willing to take XR-NTX. One factor positively associated with willingness was daily heroin injection (adjusted odds ratio [AOR] = 1.53; 95% confidence interval [CI] = 1.02-2.31), whereas Caucasian ethnicity was negatively associated (AOR = 0.59; 95% CI = 0.43-0.82). Satisfaction with agonist therapy (13.4%) and unwillingness to stop opioids being used for pain (26.9%) were the most common reasons for being unwilling to take XR NTX. CONCLUSIONS: A high level of willingness to take XR-NTX was observed in this setting. Interestingly, daily injection heroin use was positively associated with willingness, whereas Caucasian participants were less willing to take XR-NTX. Although explanations for unwillingness were described in this study, further research is needed to investigate real-world acceptability of XR-NTX as an additional option for the treatment of opioid use disorder. PMID- 25935715 TI - Development of the Carers' Alert Thermometer (CAT) to identify family carers struggling with caring for someone dying at home: a mixed method consensus study. AB - BACKGROUND: There is an increasing international policy direction to promote home death for dying patients which will impact on the demands placed on family carers. The early identification of carer needs and appropriate intervention can help avoid crisis situations for the carer and avoidable hospital admissions which are reported to be a global concern. The aim of the study was to explore what professionals and carers of patients with cancer and advanced progressive illness, in their last year of life, find burdensome and to develop an alert system for use by non-specialist staff. METHODS: A mixed-method, multi-phased, consensus study sequentially utilising qualitative and quantitative data to develop and pilot the Carers' Alert Thermometer (CAT). 245 people (117 carers and 128 professionals) participated in the study across a range of health and social care settings in the North West of England (2011-2014). RESULTS: A number of key domains were identified and prioritised by consensus for inclusion in the CAT. The 8 domains fit within two overarching themes of the reported carer experience; the support needed by the carer to provide care and the support needed for the carer's own health and well-being. The resultant CAT is an evidence-based alert thermometer consisting of 10 questions, guidance on the possible actions for each alert and space for an action plan to be jointly agreed by the assessor and carer. Preliminary piloting of the CAT has shown it to be valued, fit for purpose and it can be administered by a range of personnel. CONCLUSIONS: The CAT enables the identification of current and potential future needs so a proactive approach can be taken to supporting the carer as their role develops over time, with a view to enhancing their well-being and preventing avoidable hospital admissions; ultimately supporting patient choice to remain in their own home. PMID- 25935716 TI - Waist circumference, waist-to-hip ratio and waist-to-height ratio reference percentiles for abdominal obesity among Greek adolescents. AB - BACKGROUND: Indices predictive of adolescent central obesity include waist circumference (WC), waist-to-hip ratio (WHR) and waist-to-height ratio (WHtR). Such reference data are lacking for Greek adolescents. The aim of this study was to develop age- and gender-specific WC, WHR and WHtR smoothed reference percentiles for abdominal obesity among Greek adolescents aged 12-17 years, to investigate possible obesity cut-offs of WHR and WHtR and to compare WC percentiles to other adolescent populations. METHODS: A representative sample of 1610 high school adolescents (42.2% boys, 57.8% girls; mean age +/- sd 14.4 +/- 1.72 years) participated in this cross-sectional study in Attica, Greece, in 2013. Weight, height, body mass index (BMI), WC, hip circumference (HC), WHR and WHtR were measured and percentiles were calculated using the LMS method. The relation between WHR, WHtR and general obesity, as defined by the International Obesity Task Force, was investigated with receiver operating characteristic (ROC) analysis. The discriminating power of WHR and WHtR was expressed as area under the curve (AUC). Greek adolescents' WC measurements at the 50th and 90th percentile were compared with their counterparts' smoothed percentiles from Norway, Turkey, Poland, South India, Germany and Kuwait. RESULTS: Boys had significantly higher mean in all measures than girls, except for BMI where there was no statistical difference in terms of gender. BMI, WC and HC showed an increasing trend with age. WC leveled off in both genders at the age of 17 years. WHR and WHtR showed a continuous decrease with advancing age. WHtR was a better predictor for general obesity in both boys and girls (AUC 95% CI 0.945-0.992) than the WHR (AUC 95% CI 0.758-0.870); the WHtR cut-off of 0.5 had sensitivity 91% and specificity 95% for both genders and all age groups combined. International comparisons showed that Greek adolescents had relatively high levels of abdominal obesity in early-middle adolescence but this did not persist at the age of 17 years. CONCLUSIONS: These reference percentile curves could be used provisionally for early detection of abdominal obesity in Greek adolescents aged 12-17 years; WHtR of 0.5 could also be used as a threshold for obesity in this age group. PMID- 25935717 TI - Does gender moderate the subjective measurement and structural paths in behavioural and cognitive aspects of gambling disorder in treatment-seeking adults? AB - INTRODUCTION: Gender differences have been observed in the pathogenesis of gambling disorder and gambling related urge and cognitions are predictive of relapse to problem gambling. A better understanding of these mechanisms concurrently may help in the development of more directed therapies. METHODS: We evaluated gender effects on behavioural and cognitive paths to gambling disorder from self-report data. Participants (N=454) were treatment-seeking problem gamblers on first presentation to a gambling therapy service between January 2012 and December 2014. We firstly investigated if aspects of gambling related urge, cognitions (interpretive bias and gambling expectancies) and gambling severity were more central to men than women. Subsequently, a full structural equation model tested if gender moderated behavioural and cognitive paths to gambling severity. RESULTS: Men (n=280, mean age=37.4years, SD=11.4) were significantly younger than women (n=174, mean age=48.7years, SD=12.9) (p<0.001). There was no gender difference in conceptualising latent constructs of problem gambling severity, gambling related urge, interpretive bias and gambling expectancies. The paths for urge to gambling severity and interpretive bias to gambling severity were stronger for men than women and statistically significant (p<0.001 and p=0.004, respectively) whilst insignificant for women (p=0.164 and p=0.149, respectively). Structural paths for gambling expectancies to gambling severity were insignificant for both men and women. CONCLUSION: This study detected an important signal in terms of theoretical mechanisms to explaining gambling disorder and gender differences. It has implications for treatment development including relapse prevention. PMID- 25935718 TI - The impact of defensiveness and incident reactions on post-sanction drinking behaviors among mandated students. AB - INTRODUCTION: Prior studies with mandated students (students referred for an intervention following violation of a campus alcohol policy) have suggested that decreases in drinking behaviors may occur before clinical intervention. Others studies have suggested that greater reductions were associated with lower defensiveness and stronger incident reactions, such as responsibility and aversiveness. The current study sought to integrate these findings and examine the influence of pre-sanction drinking and perceptions on mandated students' post sanction drinking levels prior to attending a brief intervention. METHODS: Data were collected as part of a longitudinal study of brief interventions in a mandated student sample (N=61, 43% female, 97% White). Participants completed demographic measures, scales measuring incident reactions and defensiveness, and a Time Line Follow Back assessing drinking quantity and frequency both pre- and post-sanction. RESULTS: Analyses revealed significant post-sanction decreases in quantity (average total drinks per month) and frequency (number of monthly drinking days). Pre-sanction drinking quantity and frequency significantly predicted post-sanction quantity and frequency, respectively. Interaction effects suggest higher post-sanction quantities among moderate and heavier drinkers with higher defensiveness and lower aversiveness perceptions, while perceptions did not influence outcomes among light drinkers. None of the interactions involving blame or responsibility, or predicting post-sanction frequency, were significant. CONCLUSIONS: These findings suggest a complex relationship between pre-sanction drinking and student reactions. Implications for mandated student interactions and future research directions are discussed. PMID- 25935719 TI - Evaluating racial disparity in referral source and successful completion of substance abuse treatment. AB - Health disparity is a significant problem in the United States, and particularly for substance abuse treatment programs. A better understanding of racial differences in treatment pathways associated with successful treatment completion is needed to reduce the existing health disparities. Referral source is a strong predictor of treatment success and most research on health disparities has focused on the criminal justice referrals. However, little research has examined other types of referral sources, and the interaction with race. The current study sought to compare the effect of referral sources on national substance abuse successful treatment completion rates between Black clients (n=324,625) and White clients (n=1,060,444) by examining the interaction of race on referral source and successful treatment completion. Race significantly moderated the difference between referral source and successful treatment completion (Wald chi(2)=1477.73, df=6, p<0.0001). Employment referral was associated with the greatest percentage of successful treatment completion for Black clients. Criminal justice referral was associated with the greatest percentage of successful treatment completion for White clients. Results from the present study support a reevaluation of incentives leading to successful treatment completion with a multicultural perspective. PMID- 25935720 TI - Is there a distinction between malaria treatment and intermittent preventive treatment? Insights from a cross-sectional study of anti-malarial drug use among Ugandan pregnant women. AB - BACKGROUND: In Uganda, treatment of clinical malaria and intermittent preventive treatment with sulphadoxine-pyrimethamine (SP) are common during pregnancy. As a result, both formal and informal reports from antenatal sources suggest possible misuse of SP for malaria treatment among pregnant women. The objective of this study was to investigate anti-malarial drug use patterns among women who had recently suffered malaria illness before and during pregnancy. METHODS: A cross sectional study in which a structured questionnaire (interviewer-administered) was used to collect data from pregnant women attending an urban antenatal clinic. Details of medicines used to treat malaria episodes suffered before and during pregnancy were captured. A first order Markov probability model was used to estimate probabilities of transitioning between treatment choices made before and during pregnancy. Logistic regression was used to explore whether demographic and obstetric characteristics were associated with transition patterns. RESULTS: Seven hundred women were interviewed among whom 428 had suffered malaria in both instances. Three hundred thirty of these could recall the medicines used in both instances. Women who used ACT/QNN (correct choice) before pregnancy had higher probabilities of transitioning to SP than staying on ACT/QNN during pregnancy (0.463 versus 0.451). Access of medicines from private outlets (clinics and pharmacies) were more than nine times predictive of receiving correct medicines (p=0.035 and p=0.039 respectively). Access of medicines from clinics was 5.9 times protective against receiving SP for malaria treatment (p=0.033). Among those who used SP before pregnancy, there was a 0.75 probability of staying on it during pregnancy. None of the factors explored could explain this observation. CONCLUSION: Use of SP for malaria treatment is common during pregnancy. This may be contributing to adverse pregnancy outcomes. Antenatal care providers should endeavour to emphasize the distinction between treatment and prevention of malaria during pregnancy. PMID- 25935721 TI - Clinical and pharmacokinetic evaluation of S-ketamine for intravenous general anaesthesia in horses undergoing field castration. AB - BACKGROUND: Intravenous anaesthetic drugs are the primary means for producing general anaesthesia in equine practice. The ideal drug for intravenous anaesthesia has high reliability and pharmacokinetic properties indicating short elimination and lack of accumulation when administered for prolonged periods. Induction of general anaesthesia with racemic ketamine preceded by profound sedation has already an established place in the equine field anaesthesia. Due to potential advantages over racemic ketamine, S-ketamine has been employed in horses to induce general anaesthesia, but its optimal dose remains under investigation. The objective of this study was to evaluate whether 2.5 mg/kg S ketamine could be used as a single intravenous bolus to provide short-term surgical anaesthesia in colts undergoing surgical castration, and to report its pharmacokinetic profile. RESULTS: After premedication with romifidine and L methadone, the combination of S-ketamine and diazepam allowed reaching surgical anaesthesia in the 28 colts. Induction of anaesthesia as well as recovery were good to excellent in the majority (n = 22 and 24, respectively) of the colts. Seven horses required additional administration of S-ketamine to prolong the duration of surgical anaesthesia. Redosing did not compromise recovery quality. Plasma concentration of S-ketamine decreased rapidly after administration, following a two-compartmental model, leading to the hypothesis of a consistent unchanged elimination of the parent compound into the urine beside its conversion to S-norketamine. The observed plasma concentrations of S-ketamine at the time of first movement were various and did not support the definition of a clear cut-off value to predict the termination of the drug effect. CONCLUSIONS: The administration of 2.5 mg/kg IV S-ketamine after adequate premedication provided good quality of induction and recovery and a duration of action similar to what has been reported for racemic ketamine at the dose of 2.2 mg/kg. Until further investigations will be provided, close monitoring to adapt drug delivery is mandatory, particularly once the first 10 minutes after injection are elapsed. Taking into account rapid elimination of S-ketamine, significant inter-individual variability and rapid loss of effect over a narrow range of concentrations a sudden return of consciousness has to be foreseen. PMID- 25935722 TI - Parietofrontal motor pathways and their association with motor function after stroke. AB - Corticocortical interactions between the primary motor cortex, the ventral premotor cortex and posterior parietal motor areas, such as the anterior and caudal intraparietal sulcus, are relevant for skilled voluntary hand function. It remains unclear to what extent these brain regions and their interactions also contribute to basic motor functions after stroke. We hypothesized that white matter integrity of the underlying parietofrontal motor pathways between these brain regions might relate to residual motor function after stroke. Twenty-five chronic stroke patients were recruited (aged 64 +/- 8.8 years, range 46-75, 17 males, one left-handed) and evaluated 34 months after stroke (range 12-169 months) by means of grip force, pinch force and the Fugl-Meyer assessment of the upper extremity. Based on these measures, motor function was estimated applying a factor analysis with principal component extraction. Using diffusion tensor imaging and probabilistic tractography we reconstructed probable intrahemispheric trajectories between the primary motor cortex, the ventral premotor cortex and the anterior and caudal intraparietal sulcus in each patient. White matter integrity was estimated for each individual tract by means of fractional anisotropy. Generalized linear modelling was used to relate tract-related fractional anisotropy to the motor function. We found that the white matter integrity of the fibre tracts connecting the ventral premotor cortex and the primary motor cortex (P < 0.001) and the anterior intraparietal sulcus and the ventral premotor cortex (P < 0.01) positively correlated with motor function. The other tracts investigated did not show a similar structure-behaviour association. Providing first structural connectivity data for parietofrontal connections in chronic stroke patients, the present results indicate that both the ventral premotor cortex and the posterior parietal cortex might play a relevant role in generating basic residual motor output after stroke. PMID- 25935723 TI - Cortico-pallidal oscillatory connectivity in patients with dystonia. AB - Primary dystonia has been associated with an underlying dysfunction of a wide network of brain regions including the motor cortex, basal ganglia, cerebellum, brainstem and spinal cord. Dystonia can be effectively treated by pallidal deep brain stimulation although the mechanism of this effect is not well understood. Here, we sought to characterize cortico-basal ganglia functional connectivity using a frequency-specific measure of connectivity-coherence. We recorded direct local field potentials from the human pallidum simultaneously with whole head magnetoencephalography to characterize functional connectivity in the cortico pallidal oscillatory network in nine patients with idiopathic dystonia. Three dimensional cortico-pallidal coherence images were compared to surrogate images of phase shuffled data across patients to reveal clusters of significant coherence (family-wise error P < 0.01, voxel extent 1000). Three frequency specific, spatially-distinct cortico-pallidal networks have been identified: a pallido-temporal source of theta band (4-8 Hz) coherence, a pallido-cerebellar source of alpha band (7-13 Hz) coherence and a cortico-pallidal source of beta band (13-30 Hz) coherence over sensorimotor areas. Granger-based directionality analysis revealed directional coupling with the pallidal local field potentials leading in the theta and alpha band and the magnetoencephalographic cortical source leading in the beta band. The degree of pallido-cerebellar coupling showed an inverse correlation with dystonic symptom severity. Our data extend previous findings in patients with Parkinson's disease describing motor cortex-basal ganglia oscillatory connectivity in the beta band to patients with dystonia. Source coherence analysis revealed two additional frequency-specific networks involving the temporal cortex and the cerebellum. Pallido-cerebellar oscillatory connectivity and its association with dystonic symptoms provides further confirmation of cerebellar involvement in dystonia that has been recently reported using functional magnetic resonance imaging and fibre tracking. PMID- 25935724 TI - Wider minicolumns in autism: a neural basis for altered processing? AB - Previous studies have found alterations in the columnar organization of the cortex in autism spectrum disorders. Such changes have been suggested to be limited to higher order association areas and to spare primary sensory areas. In addition, evidence from gene-expression studies have suggested that there may be an attenuation of cortical differentiation in autism spectrum disorders. The present study specifically assessed the minicolumns of cells that span the depth of the cortex in a larger sample of autism spectrum disorder cases than have been studied previously, and across a broad age range. The cortical regions to be investigated were carefully chosen to enable hypotheses about cortical differentiation and the vulnerability of association cortex to be tested. Measures of the minicolumnar arrangement of the cortex (minicolumn width, spacing and width of the associated axon bundles) were made in four regions of cortex (primary auditory cortex, auditory association cortex, orbital frontal cortex and inferior parietal lobe) for 28 subjects with autism spectrum disorder and 25 typically developing control subjects. The present study found wider minicolumns in autism spectrum disorder [F(1,28) = 8.098, P = 0.008], which was particularly pronounced at younger ages, providing evidence for an altered developmental trajectory at the microstructural level. In addition, altered minicolumn width was not restricted to higher order association areas, but was also seen in the primary sensory region investigated. Finally, this study found evidence that cortical regional differentiation was still present in autism spectrum disorder [F(3,39) = 5.486, P = 0.003], although attenuated compared to typically developing subjects [F(3,45) = 18.615, P < 0.001]. It is suggested that wider spacing of the minicolumns may relate to the enhanced discrimination seen in some individuals with autism spectrum disorders. PMID- 25935726 TI - Sociodemographic and clinical features of postpartum depression among Turkish women: a prospective study. AB - BACKGROUND: Postpartum depression (PPD) is moderate to severe depression in a woman after she has given birth. Findings from several well-designed studies reflect great variability in rates, from 10 to 22%, and also in risk factors for PPD. This variability may reflect geographical location. The incidence and risk factors for PPD among Turkish women are not well documented. It is, however, important to understand the risk factors to develop preventive intervention strategies. This study aims to examine the prevalence of PPD and associated risk factors among a sample of women receiving services at a tertiary obstetrics hospital in Ankara, Turkey. METHODS: A sample of 671 women, between 36 and 40 gestational weeks, were enrolled and screened for depressive symptomatology using the Hospital Depression Inventory. Sociodemographic and clinical data were also collected. At a subsequent postpartum evaluation, 6-8 weeks post-delivery, 540 of the 671 were screened using the Edinburgh Postnatal Depression Scale (EPDS) for PPD. RESULTS: Eighty-three (15.4%) of the 540 women had scores above the cutoff point (>13) on the EPDS. Statistically significant correlations were found between antenatal, prenatal and postpartum depression scores (r = 0.24). Women reporting suicidal thoughts during pregnancy (OR: 6.99), history of past PPD (OR: 6.64), physical violence during pregnancy (OR: 6.20) or during the postpartum period (OR: 5.87), previous psychiatric history (OR: 4.16), depressive symptoms during pregnancy (OR: 1.70), subjectively lower level of satisfaction with the pregnancy (OR:0. 69), a history of premenstrual syndrome (PMS) (OR: 2.05), and unplanned pregnancy (OR: 1.69) had higher odds for developing PPD. CONCLUSION: One in six mothers screened as positive for PPD. Women who had previously been diagnosed with PPD, reported suicidal thoughts during pregnancy, or had been exposed to physical violence were at especially high risk for postpartum depression. To prevent and treat postpartum depression, special attention should be paid to women reporting these characteristics. PMID- 25935725 TI - Individualized differential diagnosis of schizophrenia and mood disorders using neuroanatomical biomarkers. AB - Magnetic resonance imaging-based markers of schizophrenia have been repeatedly shown to separate patients from healthy controls at the single-subject level, but it remains unclear whether these markers reliably distinguish schizophrenia from mood disorders across the life span and generalize to new patients as well as to early stages of these illnesses. The current study used structural MRI-based multivariate pattern classification to (i) identify and cross-validate a differential diagnostic signature separating patients with first-episode and recurrent stages of schizophrenia (n = 158) from patients with major depression (n = 104); and (ii) quantify the impact of major clinical variables, including disease stage, age of disease onset and accelerated brain ageing on the signature's classification performance. This diagnostic magnetic resonance imaging signature was then evaluated in an independent patient cohort from two different centres to test its generalizability to individuals with bipolar disorder (n = 35), first-episode psychosis (n = 23) and clinically defined at risk mental states for psychosis (n = 89). Neuroanatomical diagnosis was correct in 80% and 72% of patients with major depression and schizophrenia, respectively, and involved a pattern of prefronto-temporo-limbic volume reductions and premotor, somatosensory and subcortical increments in schizophrenia versus major depression. Diagnostic performance was not influenced by the presence of depressive symptoms in schizophrenia or psychotic symptoms in major depression, but earlier disease onset and accelerated brain ageing promoted misclassification in major depression due to an increased neuroanatomical schizophrenia likeness of these patients. Furthermore, disease stage significantly moderated neuroanatomical diagnosis as recurrently-ill patients had higher misclassification rates (major depression: 23%; schizophrenia: 29%) than first episode patients (major depression: 15%; schizophrenia: 12%). Finally, the trained biomarker assigned 74% of the bipolar patients to the major depression group, while 83% of the first-episode psychosis patients and 77% and 61% of the individuals with an ultra-high risk and low-risk state, respectively, were labelled with schizophrenia. Our findings suggest that neuroanatomical information may provide generalizable diagnostic tools distinguishing schizophrenia from mood disorders early in the course of psychosis. Disease course-related variables such as age of disease onset and disease stage as well alterations of structural brain maturation may strongly impact on the neuroanatomical separability of major depression and schizophrenia. PMID- 25935727 TI - Paternal behavior in the Mongolian gerbil (Meriones unguiculatus): Estrogenic and androgenic regulation. AB - Here, we analyzed the effects of testosterone (T) and its metabolites, estradiol (E2) and dihydrotestosterone (DHT), on the onset of paternal behavior in virgin male Mongolian gerbils (Meriones unguiculatus). We hypothesized that T and E2, but not DHT, would facilitate the onset of paternal behavior. Seventy males displaying aggression toward pups were selected through a paternal behavior screening test. Forty males were bilaterally castrated. Of them, 10 were implanted with T, 10 with E2, and 10 with DHT, and 10 received no treatment. Another 30 males underwent a sham procedure. In these gerbils, T, E2 and DHT were measured to obtain the basal levels of these hormones. After treatment, the paternal behavior test was conducted again. Blood samples were obtained immediately after the administration of the test for the quantification of T, E2 and DHT by radioimmunoassay. Surprisingly, 100% of the males that received T, E2 and DHT implants stopped being aggressive and became paternal. Castrated and sham operated males displayed no changes in their aggressive behaviors. This is the first report that T and its metabolites are involved in neuroendocrine mechanisms that inhibit aggression toward pups and facilitate paternal behavior in virgin male Mongolian gerbils. In addition, this is the first report of regulation of paternal behavior in a rodent by estrogenic and androgenic pathways. PMID- 25935729 TI - Neuroendocrine regulation of long-term pair maintenance in the monogamous zebra finch. AB - This article is part of a Special Issue "SBN 2014". Understanding affiliative behavior is critical to understanding social organisms. While affiliative behaviors are present across a wide range of taxa and contexts, much of what is known about the neuroendocrine regulation of affiliation comes from studies of pair-bond formation in prairie voles. This leaves at least three gaps in our current knowledge. First, little is known about long-term pair-bond maintenance. Second, few studies have examined non-mammalian systems, even though monogamy is much more common in birds than in mammals. Third, the influence of breeding condition on affiliation is largely unknown. The zebra finch (Taeniopygia guttata) is an excellent model system for examining the neuroendocrine regulation of affiliative behaviors, including the formation and maintenance of a long-term pair bond. Zebra finches form genetically monogamous pair bonds, which they actively maintain throughout the year. The genomic and neuroanatomical resources, combined with the wealth of knowledge on the ecology and ethology of wild zebra finches, give this model system unique advantages to study the neuroendocrine regulation of pair bonding. Here, we review the endocrinology of opportunistic breeding in zebra finches, the sex steroid profiles of breeding and non-breeding zebra finches (domesticated and wild), and the roles of sex steroids and other signaling molecules in pair-maintenance behaviors in the zebra finch and other monogamous species. Studies of zebra finches and other songbirds will be useful for broadly understanding the neuroendocrine regulation of affiliative behaviors, including pair bonding and monogamy. PMID- 25935728 TI - Postmenopausal hormone therapy and cognition. AB - This article is part of a Special Issue "Estradiol and cognition". Prior to the publication of findings from the Women's Health Initiative (WHI) in 2002, estrogen-containing hormone therapy (HT) was used to prevent age-related disease, especially cardiovascular disease, and to treat menopausal symptoms such as hot flushes and sleep disruptions. Some observational studies of HT in midlife and aging women suggested that HT might also benefit cognitive function, but randomized clinical trials have produced mixed findings in terms of health and cognitive outcomes. This review focuses on hormone effects on cognition and risk for dementia in naturally menopausal women as well as surgically induced menopause, and highlights findings from the large-scale WHI Memory Study (WHIMS) which, contrary to expectation, showed increased dementia risk and poorer cognitive outcomes in older postmenopausal women randomized to HT versus placebo. We consider the 'critical window hypothesis', which suggests that a window of opportunity may exist shortly after menopause during which estrogen treatments are most effective. In addition, we highlight emerging evidence that potential adverse effects of HT on cognition are most pronounced in women who have other health risks, such as lower global cognition or diabetes. Lastly, we point towards implications for future research and clinical treatments. PMID- 25935731 TI - Interstitial pulsed-dose-rate brachytherapy for the treatment of squamous cell anal carcinoma: A retrospective single institution analysis. AB - OBJECTIVE: To examine the outcome of patients receiving interstitial pulsed-dose rate brachytherapy (PDR-BT) after pelvic radiation therapy for treatment of an anal squamous cell carcinoma. METHODS AND MATERIALS: Twenty-one patients were identified: 13, six, and two with stages I, II, and III tumors, respectively. After receiving received pelvic irradiation +/- concurrent chemotherapy, patients were delivered a PDR-BT boost to the residual tumor, with intention to deliver a minimal total dose of 60 Gy. The greatest dimension of residual tumor at the time of brachytherapy procedure was 12.5 mm (range: 0-20 mm). Brachytherapy implantation was performed according to the Paris system, only one plane implant being used. RESULTS: Median dose delivered through BT was 20 Gy (range: 10-30 Gy). Median number of pulses was 48 (range: 20-80 pulses). Median treated volume was 9 cm(3) (range: 5-16 cm(3)). Median dose per pulse was 40 cGy (range: 37.5-50 cGy). No Grade 3 or more acute toxicity was reported. No Grade 3 or more delayed toxicity was seen among 18 patients with more than 6 months follow-up. Median followup was 47 months (range: 6-73 months). Twenty patients (95%) were alive at last follow-up. Tumor relapses were experienced in four patients (19%), including local relapse in three patients (14%). CONCLUSION: With almost 4 years median followup, this study confirms previous data suggesting that PDR-BT is effective and safe in this indication. Local control rate and toxicity were in the range of what was seen with continuous low-dose-rate BT. PMID- 25935730 TI - Changes in brachytherapy-based APBI patient selection immediately before and after publication of the ASTRO consensus statement. AB - PURPOSE: In July 2009, American Society of Radiation Oncology (ASTRO) released a consensus statement (CS) to guide patient selection for accelerated partial breast irradiation (APBI). The goal of this study was to examine how practice patterns changed following the guideline's release. METHODS: The Surveillance, Epidemiology, and End Results database was queried from 2008 to 2010 for females aged >=20 years receiving breast conservation via brachytherapy. Among the APBI cohort, characteristics and CS grouping ("suitable," "cautionary," or "unsuitable") of patients receiving APBI in the 18 months before (January 2008 to June 2009) and after (July 2009 to December 2010) guideline publication were analyzed. RESULTS: A total of 87,528 patients undergoing breast conservation therapy were identified. Of this, 4,253 patients (4.9%) received brachytherapy based APBI. Limiting the analysis to patients not missing data that would affect their CS classification rendered 3,828 patients. The proportion of breast conservation patients receiving brachytherapy-based APBI before and after CS release remained the same (4.9% vs. 4.8%, p = 0.36). Among patients receiving brachytherapy-based APBI, the unsuitable category decreased (15.8 vs. 11.1%, p < 0.01), whereas the suitable category increased (37.7% vs. 42.1%, p = 0.03), and the cautionary category was stable (46.5% vs. 46.7% p = 0.90) after guideline publication. Joinpoint regression analysis failed to reveal that the changes in practice patterns corresponded with the CS publication date. CONCLUSIONS: The period before and after publication of the ASTRO CS was associated with a decrease in "unsuitable" patients and an increase in "suitable" patients being treated with brachytherapy-based APBI. This trend began before guideline release and thus cannot be definitively attributed to the ASTRO CS. PMID- 25935733 TI - A rare submucosal tumour of stomach-glomus tumour: A case report. AB - INTRODUCTION: Glomus tumour (GT) of the stomach is a rare submucosal mesenchymal tumour. Gastric glomus tumours are clinically recognized as benign. Nevertheless, some show biological behaviour similar to that of malignant lesions and presurgical confirmation is often impossible. PRESENTATION OF CASE: A 32 year old female who presented with epigastric pain and was subsequently investigated for a antral tumour of the stomach and Wedge resection of tumour was done. Immunohistochemistry demonstrated strong positivity of smooth muscle actin and vimentin with low rate of mitosis studied by ki-67. DISCUSSION: We discuss the preoperative investigation, the diagnostic problems and the surgical treatment of the patient with gastric glomus tumour. CONCLUSION: Glomus tumours should be considered as differential diagnosis for submucosal tumours of stomach. PMID- 25935732 TI - All-ceramic or metal-ceramic tooth-supported fixed dental prostheses (FDPs)? A systematic review of the survival and complication rates. Part II: Multiple-unit FDPs. AB - OBJECTIVE: To assess the 5-year survival of metal-ceramic and all-ceramic tooth supported fixed dental prostheses (FDPs) and to describe the incidence of biological, technical and esthetic complications. METHODS: Medline (PubMed), Embase and Cochrane Central Register of Controlled Trials (CENTRAL) searches (2006-2013) were performed for clinical studies focusing on tooth-supported FDPs with a mean follow-up of at least 3 years. This was complemented by an additional hand search and the inclusion of 10 studies from a previous systematic review [1]. Survival and complication rates were analyzed using robust Poisson's regression models to obtain summary estimates of 5-year proportions. RESULTS: Forty studies reporting on 1796 metal-ceramic and 1110 all-ceramic FDPs fulfilled the inclusion criteria. Meta-analysis of the included studies indicated an estimated 5-year survival rate of metal-ceramic FDPs of 94.4% (95% CI: 91.2 96.5%). The estimated survival rate of reinforced glass ceramic FDPs was 89.1% (95% CI: 80.4-94.0%), the survival rate of glass-infiltrated alumina FDPs was 86.2% (95% CI: 69.3-94.2%) and the survival rate of densely sintered zirconia FDPs was 90.4% (95% CI: 84.8-94.0%) in 5 years of function. Even though the survival rate of all-ceramic FDPs was lower than for metal-ceramic FDPs, the differences did not reach statistical significance except for the glass infiltrated alumina FDPs (p=0.05). A significantly higher incidence of caries in abutment teeth was observed for densely sintered zirconia FDPs compared to metal ceramic FDPs. Significantly more framework fractures were reported for reinforced glass ceramic FDPs (8.0%) and glass-infiltrated alumina FDPs (12.9%) compared to metal-ceramic FDPs (0.6%) and densely sintered zirconia FDPs (1.9%) in 5 years in function. However, the incidence of ceramic fractures and loss of retention was significantly (p=0.018 and 0.028 respectively) higher for densely sintered zirconia FDPs compared to all other types of FDPs. CONCLUSIONS: Survival rates of all types of all-ceramic FDPs were lower than those reported for metal-ceramic FDPs. The incidence of framework fractures was significantly higher for reinforced glass ceramic FDPs and infiltrated glass ceramic FDPs, and the incidence for ceramic fractures and loss of retention was significantly higher for densely sintered zirconia FDPs compared to metal-ceramic FDPs. PMID- 25935734 TI - Internal hernia and small bowel obstruction following open ileoanal pouch formation: A case report. AB - INTRODUCTION: Internal herniae, although rare, can give rise to potentially serious morbidity and mortality. The protrusion and entrapment of the small bowel through an embryological or iatrogenic mesenteric aperture within the confines of the peritoneal cavity can be difficult to diagnose, and delay treatment (operative). Timely intervention must be achieved to minimize small bowel ischemia and infarction. CASE PRESENTATION: In this case, a young lady who had a previous laparoscopic total colectomy and ileostomy developed an unusual internal hernia. Small bowel was passing behind the lesser curvature of the stomach causing the stomach to be rotated to form of a tight "band" trapping bowel. The herniated small bowel was reduced, hence, avoiding resection; the defect closed by interupted 4-0 PDS. "Prompt" surgery avoided small bowel length resection and sacrifice of the ileoanal pouch reconstruction. DISCUSSION: It is theorized that a laparoscopic approach results in a more advanced mobilization of the mesentery right up to the small bowel origin, and with less adhesion formation may in fact promote unusual internal hernia and volvulus. CONCLUSION: The case presented highlights the difficulty in making the diagnosis, and the pictures clearly indicate an unusual hernia passing directly behind the stomach and involving a large section of the small bowel. The lead up history of several admissions with sub acute small bowel obstruction suggested the underlying problem was adhesional but quite clearly there was a well defined internal hernia. Without timely surgery she would have been at high risk of losing her pouch. PMID- 25935735 TI - Trends and characteristics of heroin overdoses in Wisconsin, 2003-2012. AB - BACKGROUND: Heroin abuse has increased substantially during the past decade in the United States. This study describes trends and demographic shifts of heroin overdoses and heroin-related fatalities in Wisconsin and contrasts these with prescription opioid overdoses. METHODS: This study was cross-sectional using databases of emergency department (ED) visits, hospital admissions, and death certificates in Wisconsin, United States, during 2003-2012. Cases were Wisconsin residents treated for heroin or prescription opioid overdose, and residents who died of heroin-related drug poisoning. Primary measurements were rates over time and by geographic region, and rates and rate ratios for selected demographic characteristics. RESULTS: During 2003-2012, age-adjusted rates of heroin overdoses treated in EDs increased from 1.0 to 7.9/100,000 persons; hospitalized heroin overdoses increased from 0.7 to 3.5/100,000. Whites accounted for 68% of hospitalized heroin overdoses during 2003-2007 but 80% during 2008-2012. Heroin related deaths were predominantly among urban residents; however, rural fatalities accounted for zero deaths in 2003 but 31 (17%) deaths in 2012. Among patients aged 18-34 years, those hospitalized with heroin overdose were more often men (73.0% versus 54.9%), uninsured (44.2% versus 29.9%), and urban (84.3% versus 73.2%) than those with prescription opioid overdose. Rates of ED visits for heroin overdose in this age group exceeded rates for prescription opioid overdose in 2012 (26.1/100,000 versus 12.6/100,000 persons, respectively). CONCLUSIONS: An epidemic of heroin abuse is characterized by demographic shifts toward whites and rural residents. Rates of heroin overdose in younger persons now exceed rates of prescription opioid overdose. PMID- 25935736 TI - Buprenorphine/naloxone treatment practices in Malaysia: Results of national surveys of physicians and patients. AB - OBJECTIVE: Medication assisted treatment with buprenorphine/naloxone (Bup/Nx), including prescribing and dispensing practices of general practitioners (GPs) in Malaysia and their patients' experiences with this treatment have not been systematically examined. The current study surveyed GPs providing Bup/Nx treatment and patients receiving office-based Bup/Nx treatment in Malaysia. METHODS: Two cross-sectional surveys of GPs (N=115) providing outpatient Bup/Nx maintenance treatment and of patients (N=253) currently receiving Bup/Nx treatment throughout peninsular Malaysia. RESULTS: Physicians prescribed Bup/Nx dosages in the range of 2-4mg daily for 70% of patients and conducted urine testing in the past month on approximately 16% of their patients. In the patient survey, 79% reported taking daily Bup/Nx doses of 2mg or less; 82% reported that no urine toxicology testing had been conducted on them in the past month, 36% had an opiate positive urine test at the time of the survey, 43% reported illicit opiate use, 15% reported injection of heroin and 22% reported injection of Bup/Nx in the past month. CONCLUSION: Low daily Bup/Nx doses, lack of behavioral monitoring or counseling, and high rates of continued drug use, including injection of drugs and medications during Bup/Nx treatment in Malaysia, indicate continuing problems with implementation and less than optimal treatment effectiveness. High cost of Bup/Nx in Malaysia may deter patients from seeking treatment and contribute to taking low Bup/Nx dosages. Improved training of physicians and establishing standards for Bup/Nx dosing, routine toxicology testing, and counseling may be needed to improve care and treatment response. PMID- 25935737 TI - Health and human rights: a statistical measurement framework using household survey data in Uganda. AB - BACKGROUND: Health is intertwined with human rights as is clearly reflected in the right to life. Promotion of health practices in the context of human rights can be accomplished if there is a better understanding of the level of human rights observance. In this paper, we evaluate and present an appraisal for a possibility of applying household survey to study the determinants of health and human rights and also derive the probability that human rights are observed; an important ingredient into the national planning framework. METHODS: Data from the Uganda National Governance Baseline Survey were used. A conceptual framework for predictors of a hybrid dependent variable was developed and both bivariate and multivariate statistical techniques employed. Multivariate post estimation computations were derived after evaluations of the significance of coefficients of health and human rights predictors. RESULTS: Findings, show that household characteristics of respondents considered in this study were statistically significant (p < 0.05) to provide a reliable assessment of human rights observance. For example, a unit increase of respondents' schooling levels results in an increase of about 34% level of positively assessing human rights observance. Additionally, the study establishes, through the three models presented, that household assessment of health and human rights observance was 20% which also represents how much of the entire continuum of human rights is demanded. CONCLUSION: Findings propose important evidence for monitoring and evaluation of health in the context human rights using household survey data. They provide a benchmark for health and human rights assessments with a focus on international and national development plans to achieve socio-economic transformation and health in society. PMID- 25935738 TI - The interaction of direct and indirect risk selection. AB - This paper analyzes the interaction of direct and indirect risk selection in health insurance markets. It is shown that direct risk selection - using measures unrelated to the benefit package like selective advertising or 'losing' applications of high risk individuals - nevertheless has an influence on the distortions of the benefit package caused by indirect risk selection. Direct risk selection (DRS) may either increase or decrease these distortions, depending on the type of equilibrium (pooling or separating), the type of DRS (positive or negative) and the type of cost for DRS (individual-specific or not). Regulators who succeed in reducing DRS by, e.g., banning excessive advertising or implementing fines for 'losing' applications, may therefore (unintendedly) mitigate or exacerbate the distortions of the benefit package caused by indirect risk selection. It is shown that the interaction of direct and indirect risk selection also alters the formula for optimal risk adjustment. PMID- 25935739 TI - Peer effects, fast food consumption and adolescent weight gain. AB - This paper aims at opening the black box of peer effects in adolescent weight gain. Using Add Health data on secondary schools in the U.S., we investigate whether these effects partly flow through the eating habits channel. Adolescents are assumed to interact through a friendship social network. We propose a two equation model. The first equation provides a social interaction model of fast food consumption. To estimate this equation we use a quasi maximum likelihood approach that allows us to control for common environment at the network level and to solve the simultaneity (reflection) problem. Our second equation is a panel dynamic weight production function relating an individual's Body Mass Index z-score (zBMI) to his fast food consumption and his lagged zBMI, and allowing for irregular intervals in the data. Results show that there are positive but small peer effects in fast food consumption among adolescents belonging to a same friendship school network. Based on our preferred specification, the estimated social multiplier is 1.15. Our results also suggest that, in the long run, an extra day of weekly fast food restaurant visits increases zBMI by 4.45% when ignoring peer effects and by 5.11%, when they are taken into account. PMID- 25935740 TI - The clinicopathological, ultrastructural, genetic features and diagnosis of small cell variant renal oncocytoma. AB - The small cell variant renal oncocytoma is until now a rarely described and easily misdiagnosed subtype of renal oncocytoma. The tissue morphology, immunohistochemical profile, ultrastructural and molecular characteristics of four cases of small cell variant renal oncocytoma were analyzed and the literature was reviewed. The patients were three women and one man with ages ranging from 51 to 76 years. The size of the tumors ranged from 3 to 8.5 cm in diameter. The follow-up duration ranged from 6 to 58 months. All patients lived uneventfully without tumor recurrence or metastasis. The tumors were grayish yellow to brown, well demarcated, with a central scar or cystic change. Microscopically, the tumor was arranged in lobular structure containing dense small acini or tubular structures, with small cells featuring weak eosinophilic and scant cytoplasm, small round nuclei and inconspicuous nucleoli. No mitotic figures or necrosis were discerned. The immunohistochemical profile of small cell variant of renal oncocytoma is partially consistent with classic oncocytoma, expressing EMA, CK18, CD117 and E-cad. However, MITO and S-100A1 were intensively expressed in classic RO, but neither of them was expressed in small cell variant RO. Ultrastructurally, a small number of organelles was revealed in the tumor cell, including a few mitochondria, lysosomes and microvilli, less than those in the classic oncocytoma. No genetic aberrations were found in all cases regardless of clinicopathological characteristics and tissue types. Small cell variant renal oncocytoma of the kidney is frequently difficult to be differentiated from other benign and malignant small cell tumors with eosinophilic cytoplasm. The immunohistochemical profile, ultrastructural and genetic features of the tumor are integrally presented here for the first time. Acquaintance with the special characteristics of the tumor could facilitate the correct diagnosis of the tumor. PMID- 25935741 TI - Criteria for Reporting the Development and Evaluation of Complex Interventions in healthcare: revised guideline (CReDECI 2). AB - BACKGROUND: Many healthcare interventions are of complex nature, consisting of several interacting components. Complex interventions are often described inadequately. A reporting guideline for complex interventions was published in 2012 (Criteria for Reporting the Development and Evaluation of Complex Interventions in healthcare, CReDECI) and was recently checked for its practicability. The reporting guideline was developed following the recommendations of the EQUATOR network but excluding a formal consensus process. Therefore, a consensus process was initiated, to revise the reporting guideline. METHODS: We used a three-phase consensus process consisting of (1) a web-based feedback survey on the published reporting guideline, (2) a face-to-face consensus conference, and (3) a final online review and feedback round to create the revised CReDECI. The consensus process was organized and conducted via the REFLECTION network. RESULTS: A total of 45 attendees from 16 European countries took part in the face-to-face consensus conference. The revised reporting guideline (CReDECI 2) comprises 13 items on three stages: development, feasibility and piloting, and evaluation of a complex intervention. Each item is illustrated by an explanation and an example. In contrast with most of the available reporting guidelines, CReDECI 2 does not focus on a specific study design, to reflect the use of different qualitative and quantitative designs and methods in the development and evaluation of complex interventions. CONCLUSIONS: CReDECI 2 is a formally consented reporting guideline aiming to improve the reporting quality of the development and evaluation stages of complex interventions in healthcare. Since the guideline does not focus on a specific study design, design-specific reporting guidelines may additionally be used. PMID- 25935742 TI - Prostate tumor delineation using multiparametric magnetic resonance imaging: Inter-observer variability and pathology validation. AB - BACKGROUND AND PURPOSE: Boosting the dose to the largest (dominant) lesion in radiotherapy of prostate cancer may improve treatment outcome. The success of this approach relies on the detection and delineation of tumors. The agreement among teams of radiation oncologists and radiologists delineating lesions on multiparametric magnetic resonance imaging (mp-MRI) was assessed by measuring the distances between observer contours. The accuracy of detection and delineation was determined using whole-mount histopathology specimens as reference. MATERIAL AND METHODS: Six observer teams delineated tumors on mp-MRI of 20 prostate cancer patients who underwent a prostatectomy. To assess the inter-observer agreement, the inter-observer standard deviation (SD) of the contours was calculated for tumor sites which were identified by all teams. RESULTS: Eighteen of 89 lesions were identified by all teams, all were dominant lesions. The median histological volume of these was 2.4cm(3). The median inter-observer SD of the delineations was 0.23cm. Sixty-six of 69 satellites were missed by all teams. CONCLUSION: Since all teams identify most dominant lesions, dose escalation to the dominant lesion is feasible. Sufficient dose to the whole prostate may need to be maintained to prevent under treatment of smaller lesions and undetected parts of larger lesions. PMID- 25935743 TI - High-resolution pulmonary ventilation and perfusion PET/CT allows for functionally adapted intensity modulated radiotherapy in lung cancer. AB - BACKGROUND AND PURPOSE: To assess the utility of functional lung avoidance using IMRT informed by four-dimensional (4D) ventilation/perfusion (V/Q) PET/CT. MATERIALS AND METHODS: In a prospective clinical trial, patients with non-small cell lung cancer (NSCLC) underwent 4D-V/Q PET/CT scanning before 60Gy of definitive chemoradiation. Both "highly perfused" (HPLung) and "highly ventilated" (HVLung) lung volumes were delineated using a 70th centile SUV threshold, and a "ventilated lung volume" (VLung) was created using a 50th centile SUV threshold. For each patient four IMRT plans were created, optimised to the anatomical lung, HPLung, HVLung and VLung volumes, respectively. Improvements in functional dose volumetrics when optimising to functional volumes were assessed using mean lung dose (MLD), V5, V10, V20, V30, V40, V50 and V60 parameters. RESULTS: The study cohort consisted of 20 patients with 80 IMRT plans. Plans optimised to HPLung resulted in a significant reduction of functional MLD by a mean of 13.0% (1.7Gy), p=0.02. Functional V5, V10 and V20 were improved by 13.2%, 7.3% and 3.8% respectively (p-values<0.04). There was no significant sparing of dose to functional lung when adapting to VLung or HVLung. Plan quality was highly consistent with a mean PTV D95 and D5 ranging from 60.8Gy to 61.0Gy and 63.4Gy to 64.5Gy, respectively, and mean conformity and heterogeneity index ranging from 1.11 to 1.17 and 0.94 to 0.95, respectively. CONCLUSION: IMRT plans adapted to perfused but not ventilated lung on 4D-V/Q PET/CT allowed for reduced dose to functional lung whilst maintaining consistent plan quality. PMID- 25935745 TI - The impact of structured decision making on absconding by forensic psychiatric patients: results from an A-B design study. AB - BACKGROUND: Few studies have investigated absconding from forensic hospitals and there are no published studies of interventions aimed at reducing these incidents in forensic settings. We present a study of the impact of a new policy using structured professional judgment and an interdisciplinary team-based approach to granting privileges to forensic patients. We assess the impact of this policy on the rate and type of absconding from a metropolitan forensic facility. METHODS: Following concern about the rate of absconding at our hospital, a new policy was implemented to guide the process of granting hospital grounds and community access privileges. Employing an A-B design, we investigated the rate, characteristics, and motivations of absconding events in the 18 months prior to, and 18 months following, implementation of this policy to assess its effectiveness. RESULTS: Eighty-six patients were responsible for 188 incidents of absconding during the 42-month study window. The rate of absconding decreased progressively from 17.8% of all patients at risk prior to implementation of the new policy, to 13.8% during implementation, and further to 12.0% following implementation. There was a differential impact of the policy on absconding events, in that the greatest reduction was witnessed in absconsions occurring from unaccompanied passes; this was offset, to some extent, by an increase in absconding occurring from within hospital units or from staff accompanied outings. Seven of the absconding events included incidents of minor violence, and two included the commission of other illegal behaviors. The most common reported motive for absconding across the time periods studied was a sense of boredom or frustration. Discharge rate from hospital was 22.9% prior to the implementation of the policy to 22.7% after its introduction, indicating no change in the rate of patients' eventual community reintegration. CONCLUSIONS: A structured and team based approach to decision making regarding hospital grounds and community access privileges appeared to reduce the overall rate of absconding without slowing community reintegration of forensic patients. PMID- 25935744 TI - Sesamol loaded solid lipid nanoparticles: a promising intervention for control of carbon tetrachloride induced hepatotoxicity. AB - BACKGROUND: Sesamol, a component of sesame seed oil, exhibited significant antioxidant activity in a battery of in vitro and ex vivo tests including lipid peroxidation induced in rat liver homogenates. Latter established its potential for hepatoprotection. However, limited oral bioavailability, fast elimination (as conjugates) and tendency towards gastric irritation/toxicity (especially forestomach of rodents) may limit its usefulness. Presently, we packaged sesamol into solid lipid nanoparticles (S-SLNs) to enhance its biopharmaceutical performance and compared the efficacy with that of free sesamol and silymarin, a well established hepatoprotectant, against carbon tetrachloride induced hepatic injury in rats, post induction. A self recovery group in which no treatment was given was used to observe the self-healing capacity of liver. METHODS: S-SLNs prepared by microemulsification method were administered to rats post-treatment with CCl4 (1 ml/kg body weight (BW) twice weekly for 2 weeks, followed by 1.5 ml/kg BW twice weekly for the subsequent 2 weeks). Liver damage and recovery on treatment was assessed in terms of histopathology, serum injury markers (alanine aminotransferase, aspartate aminotransferase), oxidative stress markers (lipid peroxidation, superoxide dismutase, and reduced glutathione) and a pro inflammatory response marker (tumor necrosis factor alpha). RESULT: S-SLNs (120.30 nm) at a dose of 8 mg/kg BW showed significantly better hepatoprotection than corresponding dose of free sesamol (FS; p < 0.001). Effects achieved with S SLNs were comparable with silymarin (SILY), administered at a dose of 25 mg/kg BW. Self recovery group confirmed absence of regenerative capacity of hepatic tissue, post injury. CONCLUSION: Use of lipidic nanocarrier system for sesamol improved its efficiency to control hepatic injury. Enhanced effect is probably due to: a) improved oral bioavailability, b) controlled and prolonged effect of entrapped sesamol and iii) reduction in irritation and toxicity, if any, upon oral administration. S-SLNs may be considered as a therapeutic option for hepatic ailments as effectiveness post induction of liver injury, is demonstrated presently. PMID- 25935746 TI - Effect of tetracycline and UV radiation on melanization and antioxidant status of melanocytes. AB - Tetracycline is a semisynthetic antibiotic and is used in several types of infections against both gram-positive and gram-negative bacteria. This therapy is often associated with phototoxic reactions that occur after exposure to UV radiation and lead to photo-onycholysis, pseudoporphyria, solar urticaria and the fixed drug eruption in the skin. The phototoxic reactions may be related to the melanin content which, on one side may bind drugs - leading to their accumulation, and on the other side, they have photoprotective and antioxidant properties. In this study the effect of tetracycline and UVA irradiation on cell viability, biosynthesis of melanin and antioxidant defense system in cultured normal human epidermal melanocytes (HEMn-DP) was analyzed. The viability of the cells treated with tetracycline and exposed to UVA radiation decreased in a drug concentration-dependent manner. At the same time, the induction of the melanization process was observed. The significant alterations in antioxidant defense system, on the basis of changes in SOD, CAT and GPx activities, were stated. The obtained results may give explanation for the phototoxic effects of tetracycline therapy observed in skin cells exposed to UVA radiation. PMID- 25935747 TI - Space and time in the sighted and blind. AB - Across many cultures people conceptualize time as extending along a horizontal Mental Time Line (MTL). This spatial mapping of time has been shown to depend on experience with written text, and may also depend on other graphic conventions such as graphs and calendars. All of this information is typically acquired visually, suggesting that visual experience may play an important role in the development of the MTL. Do blind people develop a MTL? If so, how does it compare with the MTL in sighted? In this study we tested early blind, late blind and sighted participants in a space-time congruity task. Participants had to classify temporal words by pressing a right and a left key, either with crossed or uncrossed hands. We found that the MTL develops in the absence of vision, and that it is based on the same external frame of reference in sighted and blind people. Reading braille may provide the same experiential link between space and time in the manual modality as reading printed text provides in the visual modality. These results showing a similar MTL in sighted and blind participants contrast with previous results showing that the Mental Number Line (MNL) depends on different spatial coordinates in the sighted and the blind, and suggest that spatial representations of time and number may have different experiential bases. PMID- 25935749 TI - The puzzle of intrafamilial child sexual abuse: a meta-analysis comparing intrafamilial and extrafamilial offenders with child victims. AB - Intrafamilial child sexual abuse is a serious social and health problem, yet explanations of sexual offending against children that emphasize antisocial tendencies and atypical sexual interests do not adequately explain intrafamilial offending. In this meta-analysis, we tested other explanations of intrafamilial child sexual abuse by examining 78 independent samples that compared a total of 6605 intrafamilial offenders to a total of 10,573 extrafamilial offenders, in studies disseminated between 1978 and 2013 (Mdn=2000). Intrafamilial offenders were significantly lower on variables reflecting antisocial tendencies (e.g., criminal history, juvenile delinquency, impulsivity, substance use, and psychopathy) and atypical sexual interests (e.g., pedophilia, other paraphilias, and excessive sexual preoccupation). Contrary to other explanations that have been proposed, intrafamilial offenders scored lower on offense-supportive attitudes and beliefs, emotional congruence with children, and interpersonal deficits; intrafamilial offenders also did not differ from extrafamilial offenders on most indicators of psychopathology. Intrafamilial offenders were, however, more likely to have experienced sexual abuse, family abuse or neglect, and poor parent-child attachments. There were too few studies to examine family dynamics - spousal relationship quality, parent-child victim relationship, and family functioning more generally - even though these factors have been frequently mentioned in the clinical and theoretical literatures. Implications for theories of intrafamilial sexual offending, treatment, and future directions for research are discussed. PMID- 25935748 TI - Signaling equilibria in sensorimotor interactions. AB - Although complex forms of communication like human language are often assumed to have evolved out of more simple forms of sensorimotor signaling, less attention has been devoted to investigate the latter. Here, we study communicative sensorimotor behavior of humans in a two-person joint motor task where each player controls one dimension of a planar motion. We designed this joint task as a game where one player (the sender) possesses private information about a hidden target the other player (the receiver) wants to know about, and where the sender's actions are costly signals that influence the receiver's control strategy. We developed a game-theoretic model within the framework of signaling games to investigate whether subjects' behavior could be adequately described by the corresponding equilibrium solutions. The model predicts both separating and pooling equilibria, in which signaling does and does not occur respectively. We observed both kinds of equilibria in subjects and found that, in line with model predictions, the propensity of signaling decreased with increasing signaling costs and decreasing uncertainty on the part of the receiver. Our study demonstrates that signaling games, which have previously been applied to economic decision-making and animal communication, provide a framework for human signaling behavior arising during sensorimotor interactions in continuous and dynamic environments. PMID- 25935750 TI - Adsorption and transport of methane in landfill cover soil amended with waste wood biochars. AB - The natural presence of methane oxidizing bacteria (MOB) in landfill soils can stimulate the bio-chemical oxidation of CH4 to CO2 and H2O under suitable environmental conditions. This mechanism can be enhanced by amending the landfill cover soil with organic materials such as biochars that are recalcitrant to biological degradation and are capable of adsorbing CH4 while facilitating the growth and activity of MOB within their porous structure. Several series of batch and small-scale column tests were conducted to quantify the CH4 sorption and transport properties of landfill cover soil amended with four types of waste hardwood biochars under different levels of amendment percentages (2, 5 and 10% by weight), exposed CH4 concentrations (0-1 kPa), moisture content (dry, 25% and 75% water holding capacity), and temperature (25, 35 and 45 degrees C). The linear forms of the pseudo second-order kinetic model and the Langmuir isotherm model were used to determine the kinetics and the maximum CH4 adsorption capacity of cover materials. The maximum CH4 sorption capacity of dry biochar-amended soils ranged from 1.03 * 10(-2) to 7.97 * 10(-2) mol kg(-1) and exhibited a ten fold increase compared to that of soil with 1.9 * 10(-3) mol kg(-1). The isosteric heat of adsorption for soil was negative and ranged from -30 to -118 kJ/mol, while that of the biochar-amended soils was positive and ranged from 24 to 440 kJ/mol. The CH4 dispersion coefficients for biochar-amended soils obtained through predictive transport modeling indicated that amending the soil with biochar enhanced the methane transport rates by two orders of magnitude, thereby increasing their potential for enhanced exchange of gases within the cover system. Overall, the use of hardwood biochars as a cover soil amendment to reduce methane emissions from landfills appears to be a promising alternative to conventional soil covers. PMID- 25935751 TI - Musculoskeletal injuries in British Army recruits: a prospective study of diagnosis-specific incidence and rehabilitation times. AB - BACKGROUND: Musculoskeletal injuries during initial military training are a significant medical problem facing military organisations globally. In order to develop an injury management programme, this study aims to quantify the incidence and rehabilitation times for injury specific diagnoses. METHODS: This was a prospective follow-up study of musculoskeletal injuries in 6608 British Army recruits during a 26-week initial military training programme over a 2-year period. Incidence and rehabilitation times for injury specific diagnoses were recorded and analysed. RESULTS: During the study period the overall incidence of musculoskeletal injuries was 48.6%, and the most common diagnosis was iliotibial band syndrome (6.2%). A significant proportion of the injuries occurred during the first 11 weeks of the programme. The longest rehabilitation times were for stress fractures of the femur, calcaneus and tibia (116 +/- 17 days, 92 +/- 12 days, and 85 +/- 11 days, respectively). The combination of high incidence and lengthy rehabilitation indicates that medial tibial stress syndrome had the greatest impact on training, accounting for almost 20% of all days spent in rehabilitation. CONCLUSION: When setting prevention priorities consideration should be given to both the incidence of specific injury diagnoses and their associated time to recovery. PMID- 25935752 TI - Guidelines for the use of survivorship care plans: a systematic quality appraisal using the AGREE II instrument. AB - BACKGROUND: Survivorship care plans (SCPs) are written treatment summaries and follow-up care plans that are intended to facilitate communication and coordination of care among survivors, cancer care providers, and primary care providers. A growing number of guidelines for the use of SCPs exist, yet SCP use in the United States remains limited. Limited use of SCPs may be due to poor quality of these guidelines. The purpose of the study was to evaluate the quality of guidelines for SCP use, tools that are intended to promote evidence-based medicine. METHODS: We conducted a comprehensive search of the literature using MEDLINE/PubMed, EMBASE (Excerpta Medica Database), and CINAHL (Cumulative Index to Nursing and Allied Health Literature) published through April 2014, in addition to grey literature sources and bibliographic and expert reviews. Guideline quality was assessed using the AGREE II instrument (Appraisal of Guidelines for Research and Evaluation, 2nd edition), a tool developed by an international group of scientists to advance the quality of clinical practice guidelines. To promote consistency with extant studies using the AGREE II instrument and to clearly and unambiguously identify potentially useful guidelines for SCP use, we also summarized AGREE II scores by strongly recommending, recommending, or not recommending the guidelines that we evaluated. RESULTS: Of 128 documents screened, we included 16 guidelines for evaluation. We did not strongly recommend any of the 16 guidelines that we evaluated; we recommended 5 and we did not recommend 11. Overall, guidelines scored highest on clarity of presentation (i.e., guideline language, structure, and format): Guidelines were generally unambiguous in their recommendations that SCPs should be used. Guidelines scored lowest on applicability (i.e., barriers and facilitators to implementation, implementation strategies, and resource implications of applying the guideline): Few guidelines discussed facilitators and barriers to guideline application; advice and tools for implementing guidelines were vague; and none explicitly discussed resource implications of implementing the guidelines. CONCLUSIONS: Guidelines often advocated survivorship care plan use without justification or suggestions for implementation. Improved guideline quality may promote survivorship care plan use. PMID- 25935753 TI - Molecular epidemiology and seroprevalence in asymptomatic Plasmodium falciparum infections of Malagasy pregnant women in the highlands. AB - BACKGROUND: Malaria epidemiology in Madagascar is classified into four different areas, ranging from unstable seasonal transmission in the highlands to hyperendemic perennial transmission areas in the costal level. Most malaria studies in Madagascar are focused on symptomatic children. However, because of the low transmission in some areas with correspondingly low level of semi immunity, adults are also at risk, in particular pregnant women. The objective of this study was to gain information on the genetic epidemiology of malarial infections in pregnant women in order to provide information for malaria control and elimination programmes in Madagascar. METHODS: Between May and August 2010, we carried out cross-sectional surveys targeting healthy pregnant women in six locations, three in the coastal area and three in the highlands at 850-1300 m. 1244 blood samples were screened for anti-Plasmodium falciparum antibodies by immunofluorescence test and for malarial infection by realtime-PCR. The prevalence of chloroquine and sulphadoxine-pyrimethamine resistance markers was also determined in all Plasmodium falciparum samples by PCR-RFLP as well as the multiplicity of infection through genotyping six neutral microsatellites. RESULTS: In the highlands, 67.4% of the women presented antibodies against Plasmodium falciparum and 9.2% were carrying parasites, at the coast 95.6% and 14.8%, respectively. In the mean, 1.2 clones were detected in infected pregnant woman in the highlands and 1.5 at the coast. A higher level of monoclonal infections was found in the highlands (85.4%) compared to the coast (61.8%). Resistance markers for sulphadoxine-pyrimethamine were present only in two sites. CONCLUSION: Immunity is triggered in Malagasy highland populations when they are infected with malaria parasites, but these populations could also serve as a reservoir for epidemics. PMID- 25935755 TI - The influence of environmental temperature on appetite-related hormonal responses. AB - BACKGROUND: Acute exercise in the heat has been shown to reduce appetite. However, the influence of exercise in the cold on appetite regulation remains unclear. The aim of this study was to compare exercise-induced appetite regulation under three different environmental temperatures. METHODS: Eleven male participants completed three experimental trials on the following separate days: exercise in the heat (36 degrees C), exercise at neutral temperature (24 degrees C), and exercise in the cold (12 degrees C). The exercise trials consisted of pedaling exercises for 30 min at 65% of maximal oxygen uptake (VO2max). Blood samples were collected repeatedly to determine plasma ghrelin, peptide YY (PYY) and other hormonal concentrations. Subjective feelings of hunger and tympanic temperature were also monitored. RESULTS: Tympanic temperature was significantly higher in the 36 degrees C trial than that of the other two trials (P < 0.05). The subjective feelings of hunger in the 36 degrees C and 24 degrees C trials were significantly lower than those in the 12 degrees C trial (P < 0.05). Plasma ghrelin concentration decreased significantly with exercise in all conditions (P < 0.05), and the responses were not significantly different among the three conditions. Plasma PYY concentration increased significantly after the exercise in the 24 degrees C trial only (P < 0.05), with no significant difference among the three trials. CONCLUSIONS: These results suggest that exposure to hot or cold temperatures during exercise did not affect exercise induced plasma ghrelin and PYY responses. However, the exercise-induced reduction of subjective hunger was significantly attenuated in a cold environment. PMID- 25935754 TI - Novel approaches in the management of pancreatic ductal adenocarcinoma: potential promises for the future. AB - Despite a few breakthroughs in therapy for advanced disease in the recent years, pancreatic ductal adenocarcinoma continues to remain one of the most challenging human malignancies to treat. The overall prognosis for the majority of patients with pancreatic cancer is rather dismal, and therefore, more effective treatment options are being desperately sought. The practical goals of management are to improve the cure rates for patients with resectable disease, achieve a higher conversion rate of locally advanced tumor into potentially resectable disease, and finally, prolong the overall survival for those who develop metastatic disease. Our understanding of the complex genetic alterations, the implicated molecular pathways, and the role of desmoplastic stroma in pancreatic cancer tumorigenesis has increased several folds in the recent years. This has facilitated the development of novel therapeutic strategies against pancreatic cancer, some of which are currently under evaluation in ongoing preclinical and clinical studies. This review will summarize the existing treatment approaches for this devastating disease and also discuss the promising therapeutic approaches that are currently in different stages of clinical development. PMID- 25935756 TI - Interaction of TGF-beta4 and IL-17 with IgA secretion in the intestine of chickens fed with E. faecium AL41 and challenged with S. Enteritidis. AB - The relative mRNA expression of IgA, TGF-beta4, IL-17, and concentration of secretory IgA (sIgA) in small intestine of chickens pretreated with Enterococcus faecium AL41 and challenged with Salmonella Enteritidis PT4 were studied. Salmonella-free day-old chicks (40) Cobb 500 breed, were divided into four groups of 10 chicks each (n = 10): control (C), treated with E. faecium AL41 strain (EFAL41), challenged with Salmonella Enteritidis PT4 (SE), and combined (EFAL41+SE). Expression of IgA and sIgA concentration was upregulated in EFAL41 group in jejunum and ileum on 4 days post-Salmonella infection (dpi). Chicks in combined group demonstrated upregulation of cytokines and IgA expression, and increased sIgA concentration in the intestine flush on 7 dpi. The experiment demonstrated beneficial effect of E. faecium AL41 on IgA production and secretion in intestine. Findings also indicated that IgA played important role in decrease of S. Enteritidis in the intestine, and cytokines TGF-beta4 and IL-17 contributed to the increased IgA secretion. PMID- 25935757 TI - Sodium houttuyfonate inhibits inflammation by blocking the MAPKs/NF-kappaB signaling pathways in bovine endometrial epithelial cells. AB - Sodium houttuyfonate (SH) has traditionally been used for the therapy of inflammatory diseases. In this research, we tried to assess the anti-inflammatory effects of SH on LPS-induced bovine endometrial epithelial cell (bEEC) inflammation. SH cell toxicity was measured using the MTT and LDH assays, and inflammatory cytokine expression was assessed by ELISA, qRT-PCR and Western blotting. We demonstrated that SH was not cytotoxic to bEECs, and that it significantly decreased the LPS-induced mRNA and protein expression of tumor necrosis factor (TNF) alpha, interleukin (IL)-1beta, IL-6 and IL-8. Furthermore, in LPS-induced bEECs, SH inhibited IkappaBalpha degradation and NF-kappaB p65 phosphorylation, and suppressed the phosphorylation of the mitogen-activated protein kinases (MAPKs), p38, c-Jun N-terminal kinase (JNK), and extracellular signal-regulated kinase (ERK). In conclusion, we found that SH could effectively block the NF-kappaB-mediated signaling pathway and reduce the inflammatory process, thereby exerting a protective effect on bEECs. PMID- 25935759 TI - How cells build totipotency and pluripotency: nuclear, chromatin and transcriptional architecture. AB - Totipotent and pluripotent cells display different degrees of cellular plasticity. After fertilization, embryonic cells transit naturally from a totipotent to a pluripotent state. Major changes in nuclear architecture, chromatin mobility and gene expression occur during this transition. In particular, nuclear architecture has recently emerged as a potential regulator of heterochromatin formation in the early embryo. Future research should address whether a causal, functional link between nuclear organization and gene regulation is a general theme during reprogramming and the formation of pluripotent cells. PMID- 25935758 TI - Administration of TLR7 agonist, resiquimod, in different types of chicken induces a mixed Th1 and Th2 response in the peripheral blood mononuclear cells. AB - This study evaluated the variation in immune response in peripheral blood mononuclear cells (PBMCs) of broiler, White Leghorn (WL) and Kadaknath breeds of chicken following administration of TLR7 agonist, resiquimod (R-848). Expression of different immune related genes viz., interferon-beta (IFN-beta), IFN-gamma, IL 1beta, IL-4, TLR7 and iNOS was assessed by quantitative real time PCR over a period of 24 h. The results indicated that there was a significant up-regulation in the relative expression of immune response genes post R-848 administration (P < 0.01). In conclusion, the transcriptional expression of IFN-beta, IFN-gamma, IL 1beta, IL-4, iNOS and TLR7 genes in the PBMCs was significantly up-regulated over 24 h in broiler, WL and Kadaknath breeds of birds after the administration of R 848. Overall, R-848 induced a mixed Th1 and Th2 response in PBMCs of chicken origin ex vivo. PMID- 25935760 TI - Role of chromatin, environmental changes and single cell heterogeneity in non coding transcription and gene regulation. AB - The number and variety of factors underlying control of gene expression have been frequently underestimated. Non-coding RNAs generated through pervasive transcription have recently been implicated in shaping the transcriptional landscape in different organisms from bacteria to higher eukaryotes, adding a previously unexpected layer of complexity to the process of gene regulation. In this review, we highlight non-coding transcription-dependent regulatory mechanisms linked to chromatin organization and environmental changes, and particular emphasis is given to single-cell approaches, which have been crucial in dissecting cell-to-cell variability. These studies have revealed that non coding transcription can underlie the extensive heterogeneity in patterns of gene expression within a cell population. PMID- 25935761 TI - IgG4-related disease of the aortic valve. PMID- 25935762 TI - From Environmental Sequences to Morphology: Observation and Characterisation of a Paulinellid Testate Amoeba (Micropyxidiella edaphonis gen. nov. sp. nov. Euglyphida, Paulinellidae) from Soil using Fluorescent in situ Hybridization. AB - High microbial diversity is revealed by environmental DNA surveys. However, nothing is known about the morphology and function of these potentially new organisms. In the course of an environmental soil diversity study, we found for the first time environmental sequences that reveal the presence of Paulinellidae (a mostly marine and marginally freshwater family of euglyphid testate amoebae) in samples of forest litter from different geographic origins. The new sequences form a basal, robust clade in the family. We used fluorescent in situ hybridization (FISH) to detect the organisms from which these sequences derived. We isolated the cells and documented them with light and scanning electron microscopy. Based on these observations, we described these organisms as Micropyxidiella edaphonis gen. nov. sp. nov. The organisms were very small testate amoebae (generally less than 10MUm) with an irregular proteinaceous test. This suggests an unknown diversity in testate amoebae, and calls for extending this type of investigations to other protist groups which are known only as environmental DNA sequences. PMID- 25935764 TI - Mitral leaflet clefts: innocent bystander or covert foe? PMID- 25935763 TI - Phenotype and prognostic correlations of the converter region mutations affecting the beta myosin heavy chain. AB - OBJECTIVES: The prognostic value of genetic studies in cardiomyopathies is still controversial. Our objective was to evaluate the outcome of patients with cardiomyopathy with mutations in the converter domain of beta myosin heavy chain (MYH7). METHODS: Clinical characteristics and survival of 117 affected members with mutations in the converter domain of MYH7 were compared with 409 patients described in the literature with mutations in the same region. RESULTS: Twenty five mutations were evaluated (9 in our families including 3 novel (Ile730Asn, Asp717Gly and Arg719Pro)). Clinical diagnoses were hypertrophic (n=407), dilated (n=15), non-compaction (n=4) and restrictive (n=5) cardiomyopathies, unspecified cardiomyopathy (n=11), sudden death (n=50) and 35 healthy carriers. One hundred eighty-four had events (cardiovascular death or transplant). Median event-free survival was 50+/-2 years in our patients and 53+/-3 years in the literature (p=0.27). There were significant differences in the outcome between mutation: Ile736Thr had fewer events than other mutations in the region (p=0.01), while Arg719Gln (p<0.01) had reduced event-free survival. CONCLUSIONS: Mutations in the converter region are generally associated with adverse prognosis although there are differences between mutations. The identification of a mutation in this particular region provides important prognostic information that should be considered in the clinical management of affected patients. PMID- 25935765 TI - Early detection of occult atrial fibrillation and stroke prevention. AB - Atrial fibrillation (AF) is a very common arrhythmia and significantly increases stroke risk. This risk can be mitigated with oral anticoagulation, but AF is often asymptomatic, or occult, preventing timely detection and treatment. Accordingly, occult AF may cause stroke before it is clinically diagnosed. Currently, guidelines for the early detection and treatment of occult AF are limited. This review addresses recent advancements in occult AF detection methods, identification of populations at high risk for occult AF, the treatment of occult AF with oral anticoagulation, as well as ongoing trials that may answer critically important questions regarding occult AF screening. PMID- 25935766 TI - Therapeutic hypothermia in patients with out-of-hospital arrest. AB - Therapeutic hypothermia (TH) is increasingly used in patients presenting with out of-hospital cardiac arrest (OHCA). Such strategies derive from data that suggest TH may improve survival and attenuate adverse neurological outcomes associated with the cardiac arrest. Consequently, TH has been integrated into various guidelines for the management of OHCA and has become a focussed strategy, particularly in patients with ST-segment elevation myocardial infarction. However, there remains uncertainty over the true impact of TH. In patients with OHCA due to asystole or pulseless electrical activity, overall available evidence suggests that TH does not improve neurological outcomes and survival. While in patients with OHCA due to ventricular fibrillation or ventricular tachycardia, observational studies and small, randomised studies have suggested there may be survival benefits and improved neurological recovery. However, even here, trial data robustness has been questioned, with ongoing debate regarding the optimum temperature for managing patients with OHCA and optimal timing of its initiation. More uniform and robust guidelines for the application of TH for patients with OHCA are required, but can only be formulated on appropriately sized robust trials. This review examines the current status of TH. PMID- 25935767 TI - Subclinical LV dysfunction and 10-year outcomes in type 2 diabetes mellitus. AB - OBJECTIVE: New imaging techniques have permitted the detection of subclinical LV dysfunction (LVD) in up to half of patients with type 2 diabetes mellitus (DM) with a normal EF. However, the connection between early LVD and prognosis is unclear. This study aimed to define the long-term outcome of LVD associated with type 2 DM. METHODS: In this prospective cohort study, 230 asymptomatic patients with type 2 DM underwent measurement of global longitudinal 2D strain (GLS) for detection of LVD and were followed for up to 10 years. All subjects had normal EF (>=50%) and no evidence of coronary artery disease at recruitment. Outcome data were obtained through centralised state-wide death and hospital admission registries. The primary endpoint was all-cause mortality and hospitalisation. RESULTS: On study entry, almost half (45%) of the cohort had evidence of LVD as detected by GLS. Over a median follow-up of 7.4+/-2.6 years (range 0.6-9.7 years), 68 patients (30%) met the primary endpoint (LVD: 37%; normal LV function: 24%). GLS was independently associated with the primary endpoint (HR=1.10; p=0.04), as was systolic blood pressure (HR=1.02; p<0.001) and levels of glycosylated haemoglobin (HR=1.28; p=0.011). Patients with LVD had significantly worse outcome than those without (chi(2)=4.73; p=0.030). CONCLUSIONS: Subclinical LVD is common in asymptomatic patients with type 2 DM, is readily detectable by GLS imaging and is independently associated with adverse outcome. TRIAL REGISTRATION NUMBER: Australian and New Zealand Clinical Trials Registry (ACTRN12612001178831). PMID- 25935768 TI - Cleft-like indentations in myxomatous mitral valves by three-dimensional echocardiographic imaging. AB - OBJECTIVES: Cleft-like indentations (CLI) are deep separations between scallops of the mitral posterior leaflet observed in myxomatous mitral valve disease (MMVD), but their diagnosis, mechanisms and implications are unknown. Using 3D transoesophageal echocardiography (3DTOC), we aimed at assessing diagnostic accuracy and defining mechanisms of CLI in patients undergoing surgery for MMVD. METHODS: 3DTOC of mitral valve was acquired in 49 patients with MMVD and severe regurgitation prior to valve repair. Qualitative review compared 3DTOC diagnosis of CLI with surgical inspection. Mitral, annular and leaflet dimensions were quantified with dedicated software and compared between those with and without CLI. RESULTS: Diagnosis of CLI was made by 3DTOC in 17 (35%) while none was identified by 2D and was confirmed in 15 (88%) by surgical inspection. Mechanistically, LV diameters and mitral regurgitant volume (RVol) were similar with and without CLI (p>0.49). Conversely, mitral annulus was smaller with CLI (anteroposterior diameter 42.2+/-7.1 vs 47.0+/-7.5 mm, p=0.04; circumference 133+/-16 vs 148+/-19 mm, p=0.009; area 1289+/-326 vs 1619+/-427 mm(2), p=0.008). Prolapse volume tended to be smaller with CLI (1.9+/-1.2 vs 4.0+/-4.3 mL, p=0.06) involving single posterior scallop at surgery (82% vs 44%, p=0.007) with smaller 3DTOC leaflet area (1574+/-409 vs 2019+/-652 mm(2), p=0.01). During valve repair, surgical closure of all surgically diagnosed CLI was required. CONCLUSIONS: Posterior leaflet CLI are frequent in MMVD, are identified by 3DTOC with high accuracy and require closure during valve repair. CLI are mechanistically not related to excess annular enlargement or excess prolapse. Conversely, CLI occur in the context of single scallop prolapse with tissue paucity causing excess separation of scallops. These 3DTOC data enhance diagnostic and mechanistic comprehension of the diversity of MMVD phenotypical presentation. PMID- 25935769 TI - Pembrolizumab shows promise in lung cancer. PMID- 25935770 TI - Are liveable neighbourhoods safer neighbourhoods? Testing the rhetoric on new urbanism and safety from crime in Perth, Western Australia. AB - New urbanism advocates for the design of the compact, pedestrian-friendly, mixed use developments thought to promote walking. New urbanist proponents also claim their developments incur other social and wellbeing benefits, including enhanced safety from crime; however there is limited empirical evidence supporting this. We tested the premise that new urbanism inhibits crime by examining the relationship between compliance with a planning policy based on new urbanism and: (1) residents' reports of victimisation; and (2) objective crime measures. RESIDE Participants (n = 603) who had lived in their new developments for 36 months completed a questionnaire that included items on their experiences of victimisation. Detailed measures quantifying the degree to which these developments (n = 36) complied with the policy requirements were generated in Geographic Information Systems. Logistic regression examined the associations between policy compliance and self-report victimisation, and negative binomial log-linear models examined area-level associations between compliance and objective crime. For each 10% increase in overall policy compliance, the odds of being a victim reduced by 40% (OR = 0.60, CI = 0.53-0.67, p = 0.000). Findings for the individual policy 'elements' were consistent with this: for each 10% increment in compliance with the community design, movement network, lot layout and public parkland elements, the odds of victimisation reduced by approximately 6% (p = 0.264), 51% (p = 0.001), 15% (p = 0.000) and 22% (p = 0.001) respectively. However, while policy compliance correlated with lower odds of self report victimisation among residents, the associations between compliance and development-wide (objective) crime were positive but non-significant. The results indicate that planning policies based on new urbanism may indeed deliver other social and wellbeing benefits for residents, however they also hint that the design of an 'objectively' safe place may differ from the design of a 'subjectively' safe space. PMID- 25935771 TI - The fructose tolerance test in patients with chronic kidney disease and metabolic syndrome in comparison to healthy controls. AB - BACKGROUND: Fructose acutely raises serum uric acid in normal subjects, but the effect in subjects with metabolic syndrome or subjects with chronic kidney disease is unknown. The aim of the study was to evaluate changes in serum uric acid during the fructose tolerance test in patients with chronic kidney disease, metabolic syndrome with comparison to healthy controls. METHODS: Studies were performed in 36 subjects with obesity (body mass index >30) and metabolic syndrome, 14 patients with stage 3 chronic kidney disease, and 25 healthy volunteers. The fructose tolerance test was performed in each patient. The change in serum uric acid during the fructose challenge was correlated with baseline ambulatory blood pressure, serum uric acid, metabolic, and inflammatory markers, and target organ injury including carotid intima media thickness and renal resistive index (determined by Doppler). RESULTS: Absolute serum uric acid values were highest in the chronic kidney disease group, followed by the metabolic syndrome and then healthy controls. Similar increases in serum uric acid in response to the fructose tolerance test was observed in all three groups, but the greatest percent rise was observed in healthy controls compared to the other two groups. No significant association was shown between the relative rise in uric acid and clinical or inflammatory parameters associated with kidney disease (albuminuria, eGFR) or metabolic syndrome. CONCLUSIONS: Subjects with chronic kidney disease and metabolic syndrome have higher absolute uric acid values following a fructose tolerance test, but show a relatively smaller percent increase in serum uric acid. Changes in serum uric acid during the fructose tolerance test did not correlate with changes in metabolic parameters, inflammatory mediators or with target organ injury. These studies suggest that acute changes in serum uric acid in response to fructose do not predict the metabolic phenotype or presence of inflammatory mediators in subjects with obesity, metabolic syndrome or chronic kidney disease. TRIAL REGISTRATION: The study was registered in ClinicalTrials.gov. Identifier : NCT01332526. www.register.clinicaltrials.gov/01332526. PMID- 25935772 TI - National trends of adnexal surgeries at the time of hysterectomy for benign indication, United States, 1998-2011. AB - OBJECTIVE: We sought to investigate the most recent national trends of bilateral salpingectomy (BS) and bilateral salpingo-oophorectomy (BSO) at the time of hysterectomy performed for benign indications. STUDY DESIGN: We conducted a national cross-sectional analysis of all inpatient discharges for women aged >=18 years who underwent a hysterectomy for benign indications from 1998 through 2011 using the largest publicly available all-payer inpatient database in the United States. We scanned International Classification of Diseases, Ninth Revision codes for an indication of specific bilateral adnexal surgeries, including BSO and BS. Joinpoint regression was used to characterize and estimate 14-year national trends in performing BSO and BS at the time of hysterectomy for benign indications, overall and in population subgroups. RESULTS: During the study period, there were approximately 428,523 inpatient hysterectomy procedures performed annually for benign indications. Of these, >53% had no adnexal surgery performed during the same hospitalization, whereas 43.7% and 1.3% of those discharges had BSO and BS procedures, respectively. The rate of BSO was directly correlated with increasing age for patients <65 years. Conversely, we observed an inverse relationship between BS and patient age, with the BS rate among women aged <25 years twice that of women aged >=45 years. From 1998 through 2001, there was a 2.2% increase in the rate of BSO per year (95% confidence interval, 0.4 4.0); however, this was followed by a consistent 3.6% (95% confidence interval, 4.0 to -3.3) annual decline in the BSO rate, from 49.7% in 2001 to 33.4% in 2011. National rates of BS among women undergoing hysterectomy for benign indications increased significantly throughout the study period, with an estimated 8% annual increase from 1998 through 2008, followed by a sharp 24% increase annually during the last 4 years of the study period. The BS rate nearly quadrupled in 14 years. CONCLUSION: The type of adnexal surgery performed concomitantly with hysterectomy for benign indications has undergone a significant shift since 2001. Significantly more BS and less BSO procedures are being performed among gynecologic surgeons in the United States. PMID- 25935773 TI - The clinical management of hyperglycemia in pregnancy complicated by maturity onset diabetes of the young. AB - OBJECTIVE: Women with maturity-onset diabetes of the young (MODY) are often first identified and diagnosed with diabetes during pregnancy. Genetics and hyperglycemia play an important role in determining fetal size in MODY pregnancies. The principal objective of the current study is to determine the outcomes and clinical management of hyperglycemia in pregnancies complicated by glucokinase gene (GCK) and hepatocyte nuclear factor (HNF)-1alpha MODY mutations. STUDY DESIGN: A retrospective chart review of 37 women with a GCK/HNF-1alpha mutation was conducted. Data on variables such as birthweight, mode of delivery, and the treatment of hyperglycemia were available on 89 pregnancies. RESULTS: The birthweight in unaffected GCK offspring was significantly higher than in the affected GCK offspring (4.8 [4.1-5.2] kg vs 3.2 [3.1-3.7] kg; P = .01). Seven point home blood glucose monitoring over a 7-day period in each trimester demonstrated higher fasting and postprandial glycemic excursions in the first trimester of GCK pregnancies when compared to HNF-1alpha pregnancies (fasting 104 [90-115] mg/dL vs 84 [77-88] mg/dL; P = .01 and postprandial 154 [135-196] mg/dL vs 111 [100-131] mg/dL; P = .04) despite insulin treatment. There was a higher percentage of miscarriages in the GCK group when compared to the HNF-1alpha MODY group (33.3% vs 14%; P = .07), which was similar to the background population. Insulin initiated at an early gestation appeared to lower the incidence of macrosomia in GCK unaffected offspring. CONCLUSION: Hyperglycemia in HNF-1alpha pregnancies is easily managed with current insulin protocols; in contrast, glycemic excursions are difficult to manage in GCK pregnancies. There was an increased percentage of miscarriages in GCK pregnancies highlighting the importance of a diagnosis of GCK-MODY in women prior to conception and the necessity for preconception care. PMID- 25935774 TI - Labor patterns in women attempting vaginal birth after cesarean with normal neonatal outcomes. AB - OBJECTIVE: We sought to describe labor patterns in women with a trial of labor after cesarean (TOLAC) with normal neonatal outcomes. STUDY DESIGN: In a retrospective observational study at 12 US centers (2002 through 2008), we examined time interval for each centimeter of cervical dilation and compared labor progression stratified by spontaneous or induced labor in 2892 multiparous women with TOLAC (second delivery) and 56,301 nulliparous women at 37 0/7 to 41 6/7 weeks of gestation. Analyses were performed including women with intrapartum cesarean delivery, and also limiting only to women who delivered vaginally. RESULTS: Labor was induced in 23.4% of TOLAC and 44.1% of nulliparous women (P < .001). Cesarean delivery rates were 57.7% in TOLAC vs 19.0% in nulliparous women (P < .001). Oxytocin was used in 52.4% of TOLAC vs 64.3% of nulliparous women with spontaneous labor (P < .001) and 89.8% of TOLAC vs 91.6% of nulliparous women with induced labor (P = .099); however, TOLAC had lower maximum doses of oxytocin compared to nulliparous women: median (90th percentile): 6 (18) mU/min vs 12 (28) mU/min, respectively (P < .001). Median (95th percentile) labor duration for TOLAC vs nulliparous women with spontaneous labor from 4-10 cm was 0.9 (2.2) hours longer (P = .007). For women who entered labor spontaneously and achieved vaginal delivery, labor patterns for TOLAC were similar to nulliparous women. For induced labor, labor duration for TOLAC vs nulliparous women from 4-10 cm was 1.5 (4.6) hours longer (P < .001). For women who achieved vaginal delivery, labor patterns were slower for induced TOLAC compared to nulliparous women. CONCLUSION: Labor duration for TOLAC was slower compared to nulliparous labor, particularly for induced labor. By improved understanding of the rates of progress at different points in labor, this new information on labor curves in women undergoing TOLAC, particularly for induction, should help physicians when managing labor. PMID- 25935775 TI - Prospective evaluation of a protocol for using transabdominal ultrasound to screen for short cervix. AB - OBJECTIVE: We sought to evaluate a recently proposed protocol whereby transabdominal ultrasound of the cervix might be used as a prescreen to select women to undergo or to forgo measurement of cervical length via transvaginal ultrasound (CLvag). STUDY DESIGN: This was a prospective cohort study. Measurements of cervical length via transabdominal ultrasound (CLabd) and CLvag were made in women with singleton pregnancy during routine obstetrical ultrasound examination at 18(0/7) to 23(6/7) weeks of gestation. The transabdominal screen was considered positive if CLabd was <=36 mm with the maternal bladder full or <=35 mm with the bladder empty, or adequate imaging of the cervix could not be obtained. Sensitivity, specificity, predictive values, and likelihood ratios of a positive screen to detect a short cervix (CLvag <=25 mm) were calculated. RESULTS: An interim analysis identified several technical problems with CLabd measurements, so the protocol was extensively revised. Under the revised protocol, 1580 women were included. Adequate views of the cervix were obtained via transabdominal imaging in 46% of subjects with the bladder empty and 56% with the bladder full. The correlation between CLabd and CLvag was poor (r = 0.38). Of the 17 patients with a short cervix, 15 had suboptimal transabdominal exams (screen positive) and 2 had CLabd <=35 mm with bladder empty (screen positive). Sensitivity of the screen was 100% (95% confidence interval, 80.5-100%) but specificity was only 32.2% (95% confidence interval, 29.9-34.6%) and screen positive rate was 66.3%. Several technical problems and limitations of transabdominal imaging of the cervix are shown. CONCLUSION: Using modern, high resolution ultrasound equipment, we were unable to adequately image the cervix via transabdominal ultrasound in half the cases. Although we confirmed that a CLabd cutoff value of 35-36 mm is appropriate for detection of short cervix, the technique for measuring CLabd is fraught with technical problems. Practitioners must validate the technique in their own practice before adopting this or similar prescreening protocols. We decided not to adopt this protocol. PMID- 25935776 TI - Labor and delivery outcomes among young adolescents. AB - OBJECTIVE: We sought to determine whether young adolescents aged 11-14 years and teens aged 15-17 and 18-19 years have an increased risk of cesarean or operative delivery, as well as maternal or neonatal delivery-related morbidity, compared to young adults aged 20-24 years. STUDY DESIGN: We conducted a retrospective population-based cohort study using Washington State birth certificate data linked to hospital records from 1987 through 2009 for 26,091 nulliparas with singleton gestations between 24-43 weeks. We compared young adolescents aged 11 14 years, young teens aged 15-17 years, and older teens aged 18-19 years to young adults aged 20-24 years. The primary outcome was method of delivery. Secondary outcomes included postpartum hemorrhage, shoulder dystocia, third- and fourth degree perineal lacerations, chorioamnionitis, prolonged maternal length of stay, gestational age at delivery, birthweight, respiratory distress syndrome, neonatal length of stay, and death. We used multivariate regression to assess associations between age and delivery outcomes. RESULTS: Young adolescents aged 11-14 years had a lower risk of cesarean (risk ratio [RR], 0.73; 95% confidence interval [CI], 0.65-0.83) and operative vaginal (RR, 0.87; 95% CI, 0.78-0.97) delivery compared to young adults aged 20-24 years. Compared to young adults, young adolescents had an increased risk of prolonged length of stay for both vaginal and cesarean delivery (RR, 1.34; 95% CI, 1.20-1.49, and RR, 1.71; 95% CI, 1.38 2.12, respectively), with no significant differences in indication for cesarean delivery or other measures of maternal morbidity. Young adolescents had an increased risk of preterm delivery (RR, 2.11; 95% CI, 1.79-2.48), low and very low birthweight (RR, 2.08; 95% CI, 1.73-2.50, and RR, 3.25; 95% CI, 2.22-4.77, respectively), and infant death (RR, 3.90; 95% CI, 2.36-6.44) compared to young adults. CONCLUSION: Young adolescents have a decreased risk of cesarean and operative vaginal delivery compared to young adults; however, their neonates face higher risks of preterm delivery, low and very low birthweight, and death. This information can be used to inform clinical care for this population. PMID- 25935777 TI - Endometriosis and atherosclerosis: what we already know and what we have yet to discover. AB - The possible association between endometriosis and atherosclerosis represents an emerging topic in the field of women's health. In this Clinical Opinion paper, we analyze this theme focusing on the pathogenetic mechanisms of both diseases, deeply discussing about what is already known about this association and producing starting points about what we consider suitable to research in the near future with regard to cardiovascular involvement in women affected by endometriosis. We have identified 5 reports specifically carried out to investigate the relationship between atherosclerosis and endometriosis; these studies show the presence of subclinical atherosclerosis in women affected by endometriosis, susceptible of regression after surgical removal of endometriosis, with a possible prognostic relevance for variations of cardiovascular risk in these women. However, to date, no studies in literature have been carried out to investigate the real incidence of cardiovascular events in women with endometriosis. PMID- 25935778 TI - The rate of preterm birth in the United States is affected by the method of gestational age assignment. AB - OBJECTIVE: The objective of the study was to examine the rate of preterm birth in the United States using 2 different methods of gestational age assignment and determine which method more closely correlates with the known morbidities associated with preterm birth. STUDY DESIGN: Using National Center for Health Statistics data from 2012 United States birth certificates, we computed the rate of preterm birth defined as a birth at 36 or fewer completed weeks with gestational age assigned using the obstetric estimate as specified in the revised birth certificate. This rate was then compared with the rate when gestational age is calculated using the last menstrual period alone. The rates of neonatal morbidities associated with preterm birth were examined for each method of assigning gestational age. RESULTS: The rate of preterm birth was 9.7% when the obstetric estimate is used to calculate gestational age, which is significantly different from the rate of 11.5% when gestational age is calculated using the last menstrual period alone. In addition, the neonates identified as preterm by obstetric estimate were more likely to qualify as low birthweight (54% vs 42%; P < .001) and suffer morbidities such as need for assisted ventilation and surfactant use than those identified with the last menstrual period alone. That is to say obstetric estimate is more sensitive and specific for preterm birth by all available markers of prematurity. CONCLUSION: The preterm birth rate is 9.7% vs 11.5% and more closely correlates with adverse neonatal outcomes associated with preterm birth when gestational age is assigned using the obstetric estimate. This method of gestational age assignment is currently used by most industrialized nations and should be considered for future reporting of US outcomes. PMID- 25935779 TI - Conservative management of morbidly adherent placenta: expert review. AB - Over the last century, the incidence of placenta accreta, increta, and percreta, collectively referred to as morbidly adherent placenta, has risen dramatically. Planned cesarean hysterectomy at the time of cesarean delivery is the standard recommended treatment in the United States. Recently, interest in conservative management has resurged, especially in Europe. The aims of this review are the following: (1) to provide an overview of methods used for conservative management, (2) to discuss clinical implications for both clinicians and patients, and (3) to identify areas in need of further research. PMID- 25935780 TI - A population-based study of US women's preferred versus usual sources of reproductive health care. AB - OBJECTIVE: We characterized US women's preferred and usual sources of reproductive health care. STUDY DESIGN: Data were drawn from the Women's Health Care Experiences and Preferences Study, an Internet survey of 1078 women aged 18 55 years randomly sampled from a national probability panel. We described and compared women's preferred and usual sources of care (women's health specialists including obstetricians-gynecologists and family-planning clinics, primary care, other) for Papanicolaou/pelvic examination, contraception, and sexually transmitted infection (STI) services using chi(2), logistic regression, and kappa statistics. RESULTS: Among women reporting health service utilization (n = 984, 92% overall; 77% Papanicolaou/pelvic; 33% contraception; 8% STI), women's health specialists were the most used sources of care for Papanicolaou/pelvic (68%), contraception (74%), and STI (75%) services. Women's health specialists were also the most preferred care sources for Papanicolaou/pelvic (68%), contraception (49%), and STI (35%) services, whereas the remainder of women preferred primary care/other sources or not to get care. Differences in preferred and usual care sources were noted across sociodemographic groups, including insurance status and income level (P < .05). Preference for women's health specialists was the strongest predictor of women's health specialist utilization for Papanicolaou/pelvic (adjusted odds ratio, 48.8; 95% confidence interval, 25.9 91.8; P < .001) and contraceptive (adjusted odds ratio, 194.5; 95% confidence interval, 42.3-894.6; P < .001) services. Agreement between preferred and usual care sources was high for Papanicolaou/pelvic (85%, kappa, 0.63) and contraception (86%; kappa, 0.64) services; disagreement (range, 15-22%) was associated with insurance, employment, income, race, and religion (P < .05). CONCLUSION: Women's preferences for and use of women's health specialists for reproductive health care has implications for efforts to define the role of obstetricians-gynecologists and family planning clinics in current health systems. PMID- 25935781 TI - Appropriate indications and alternatives to hysterectomy for benign conditions. PMID- 25935782 TI - Reply: To PMID 25542564. PMID- 25935783 TI - The effect of hydroxyquinoline-based gel on pessary-associated bacterial vaginosis: a multicenter randomized controlled trial. AB - OBJECTIVE: Pessaries are important options for women with pelvic floor disorders, but many pessary users experience bacterial vaginosis (BV). The aim of this study was to evaluate the effect of TrimoSan gel (Milex Pessaries, Cooper Surgical, Trumbull, CT) on BV prevalence among pessary users. STUDY DESIGN: Women presenting for a pessary fitting completed questionnaires on vaginal symptoms and hormone therapy use and underwent a BV BLUE test and slide collection for BV analysis by Nugent's criteria. Following pessary fitting, women were randomized to either standard pessary care with the use of TrimoSan placed vaginally twice weekly or to standard pessary care without TrimoSan gel. Women returned 2 weeks and 3 months later for a repeat slide collection for Gram stain, BV BLUE testing, and completion of questionnaires on vaginal symptoms and desire to continue the pessary. RESULTS: There were 184 women randomized after successful fitting (92 to the TrimoSan group), and 147 (79%) presented for 3-month follow up. Mean age was 56 +/- 16 years; patients were mostly white (57%) or Hispanic (23%), and 36% were using hormone therapy. The groups did not differ in the prevalence of BV by Nugent's criteria at 2 weeks (20% TrimoSan vs 26% no gel, P = .46) or 3 months (24% TrimoSan vs 23% no gel, P = .82), nor did they differ in BV by BV BLUE testing at 2 weeks (0% TrimoSan vs 4% no gel, P = .12) or 3 months (3% TrimoSan vs 0% no gel, P = .15). The prevalence of at least one vaginal symptom did not differ between groups at 2 weeks (44% TrimoSan vs 45% no gel, P = .98) or 3 months (42% TrimoSan vs 32% no gel, P = .30). The TrimoSan group was equally likely to want to continue their pessary use compared with the standard care group at 2 weeks (90% vs 86%, P = .64) and 3 months (63% vs 60%, P = .76). CONCLUSION: TrimoSan gel in the first 3 months of pessary use does not decrease the prevalence of BV or vaginal symptoms and does not alter the likelihood of a woman desiring to continue pessary use. PMID- 25935784 TI - Severe anemia from heavy menstrual bleeding requires heightened attention. AB - OBJECTIVE: The objective of the study was to analyze the behaviors of women that resulted in menstrually related severe anemia (hemoglobin <5 g/dL) from a single public hospital serving indigent women. STUDY DESIGN: This was a retrospective cohort study of all women identified as having been treated at Harbor-UCLA Medical Center for excessive menstruation (International Classification of Diseases, ninth revision, codes 285.9, 6256.2) and hemoglobin values less than 5 g/dL in the 6 years from 2008 to 2013. RESULTS: Approvals were obtained from the Human Subjects and Research Committees. This search identified 271 women with those 2 diagnoses; 122 were excluded because their severe anemia had nonmenstrual causes. The remaining 149 women had 168 episodes with hemoglobin levels below 5 g/dL attributed to chronic excessive menstrual bleeding. Mean age was 41 years (range, 19-55 years). Mean body mass index was 28.9 kg/m(2) (range, 18-57 kg/m(2)); 58.2% were actively bleeding at presentation, and 90.4% reported chronic excessive blood loss. Two thirds recognized heavy bleeding that had persisted for more than 6 months without seeking help. However, 7.8% described their bleeding as normal, and 40.5% had received at least 1 previous transfusion. Mean nadir hemoglobin was 4.15 g/dL (range, 1.6-4.9 g/dL). Mean corpuscular volume was 62.2 fL (range, 47.7-99.8 fL) and mean corpuscular hemoglobin concentration was 29.2 g/dL (range, 25.7-33.6 g/dL). Nearly a quarter had reactive thrombocytosis, which might have created a hypercoagulable state. Bleeding was ultimately attributed to leiomyoma in 47.9%; cancer was detected in 4.8%. A total of 33.9% were discharged without being offered any therapy to prevent subsequent bleeding; 3.0% declined any medical therapy; 35.1% were lost to follow-up prior to receiving effective therapy; and 26.8% had multiple subsequent transfusions before seeking/receiving definitive treatments. CONCLUSION: Even when faced with potentially life-threatening anemia because of chronic, excessive menstrual blood loss, some women are not impressed with the serious nature of their problem. Women will benefit from recognizing the health consequences of chronic excessive blood loss. Chronic excessive blood loss should be treated as both an urgent and potentially recurrent problem; physicians should address this clinical concern proactively. PMID- 25935785 TI - Association of in vitro fertilization outcome with circulating insulin-like growth factor components prior to cycle initiation. AB - OBJECTIVE: Components of the insulin-like growth factor (IGF) system enhance in vitro embryo quality and implantation rates in both animal models and human in vitro fertilization (IVF). We evaluated whether differences in serum levels of these components in women prior to initiation of an IVF cycle would be predictive of subsequent outcome. STUDY DESIGN: In this retrospective study sera from women obtained at day 2 of their IVF cycle (at baseline before stimulation) were assayed for IGF-I, IGF-II, and IGF binding protein (BP)-1 by enzyme-linked immunosorbent assay. Samples from 54 women with a live birth, 38 with a transient biochemical pregnancy, 45 with a spontaneous abortion, 54 who did not become pregnant, and 35 who had an ectopic pregnancy were available for analysis. Associations between the assays and outcome were evaluated by the Kruskal-Wallis test and receiver operating characteristic analysis. RESULTS: There were no differences in the number of oocytes retrieved, oocyte quality, fertilization rates, or embryo grade between groups. Median concentrations of IGF-I were elevated in women with a live birth (29.1 ng/mL) as compared to women with a biochemical pregnancy (25.6 ng/mL), with spontaneous abortion (21.2 ng/mL), who were not pregnant (18.7 pg/mL), or who had an ectopic pregnancy (4.2 pg/mL) (P < .001). Conversely, median levels of IGF-II were reduced in women with a live birth (294.5 ng/mL) as opposed to 357.5, 393.6, 407.2, and 426.9 ng/mL in women with a biochemical pregnancy, with ectopic pregnancy, with spontaneous abortion, or who were not pregnant, respectively (P < .001). Median IGFBP-1 concentrations were markedly elevated in women with a live birth (23.6 ng/mL) compared to 18.3, 14.1, 13.8, and 9.5 ng/mL in women with a biochemical pregnancy, with spontaneous abortion, who were not pregnant, or with an ectopic pregnancy (P < .001). The combination of IGF-I and IGFBP-1 best predicted the occurrence of a live birth with an area under the curve of 0.892. CONCLUSION: Maternal serum levels of IGF I, IGF-II, and IGFBP-1 prior to initiation of an IVF cycle are correlated with the likelihood of a live birth. Alterations in maternal IGF system components may influence oocyte quality or the success of early postfertilization events and embryo implantation. PMID- 25935786 TI - Systematic review and metaanalysis of perinatal outcomes after radiofrequency ablation and bipolar cord occlusion in monochorionic pregnancies. AB - The aim of this study was to analyze perinatal outcomes after selective reduction in monochorionic pregnancies with the use of either radiofrequency ablation (RFA) or bipolar cord occlusion (BCO). This was a systematic review and metaanalysis that included all studies with >=5 cases that described perinatal outcomes after BCO or RFA that were identified in PubMed, Embase, Web of Science, COCHRANE, CINAHL, Academic Search Premier, Science Direct, and MEDLINE that were published between 1965 and July 2014. For count data, incidence risk ratios (IRR; 95% confidence interval [CI]) were calculated with BCO as the reference standard. The analysis included 481 cases of BCO and 320 cases of RFA from 17 studies. The mean median gestations at procedure were 21.1 +/- 1.2 weeks (BCO) and 18.8 +/- 2.5 weeks (RFA; P = .03). The rate of cotwin death was higher in the RFA group (14.7%) vs the BCO group (10.6%; IRR, 1.38; 95% CI, 0.93-2.05; P = .11). The live birth rate was 81.3% for the RFA group and 86.7% in the BCO group (IRR, 0.93; 95% CI, 0.80-1.09; P = .41). BCO had higher neonatal death rates (8.1%) vs RFA (4.5%; IRR, 0.56; 95% CI, 0.30-1.04; P = .07). Overall survival was 76.8% for RFA and 79.1% for BCO (IRR, 0.97; 95% CI, 0.82-1.14; P = .72); however, none of these differences were statistically significant. Preterm premature rupture of membranes occurred in 17.7% of RFA cases and 28.2% of the BCO cases (IRR, 0.63; 95% CI, 0.43-0.91; P = .01). The mean median gestational age at delivery was 34.7 +/- 1.7 weeks in the RFA group and 35.1 +/- 1.6 weeks in the BCO group. Our data do not demonstrate clearly the superiority of 1 procedure over the other. The clinical situation and preference of the operator are important considerations. Rates of preterm delivery and preterm premature rupture of membranes remain substantial for both procedures. PMID- 25935787 TI - The Cost-Effectiveness of Ranibizumab for the Treatment of Diabetic Macular Edema. AB - PURPOSE: To assess the incremental, comparative effectiveness (patient value gain) and cost effectiveness (financial value gain) associated with 0.3-mg intravitreal ranibizumab injection therapy versus sham therapy for diabetic macular edema (DME). DESIGN: Value-Based Medicine (Center for Value-Based Medicine, Flourtown, PA) 14-year, cost-utility analysis using patient preferences and 2012 United States real dollars. PARTICIPANTS: Published data from the identical Ranibizumab Injection in Subjects with Clinically Significant Macular Edema with Center Involvement Secondary to Diabetes Mellitus (RISE and RIDE) clinical trials. METHODS: An incremental cost-utility analysis was performed using societal and third-party insurer cost perspectives. Costs and outcomes were discounted with net present value analysis at 3% per annum. MAIN OUTCOME MEASURES: The incremental comparative effectiveness was measured in: (1) quality adjusted life year (QALY) gain and (2) percent patient value (quality-of-life) gain. Cost effectiveness was quantified with the cost-utility ratio (CUR) measured as $/QALY. RESULTS: The 14-year, incremental patient value gain conferred by intravitreal ranibizumab therapy for diabetic maculopathy was 0.9981 QALY, equating to an 11.6% improvement in quality of life. The direct, ophthalmic medical cost for ranibizumab therapy in 1 eye was $30 116, whereas for 2 eyes it was $56 336. The direct, nonophthalmic, medical costs saved from decreased depression, injury, skilled nursing facility admissions, nursing home admissions, and other vision-associated costs totaled $51 758, resulting in an overall direct medical cost of $4578. The net mean societal cost for bilateral ranibizumab therapy was -$30 807. Of this total, decreased caregiver costs accrued a $31 406 savings against the direct medical costs, whereas decreased wage losses accrued a $3978 savings. The third-party insurer CUR for bilateral ranibizumab therapy was $4587/QALY. The societal cost perspective for bilateral therapy was -$30 807/QALY, indicating that ranibizumab therapy dominated sham therapy because it conferred both a positive QALY gain of 0.9981 and a financial value gain (positive financial return on investment) of $30 807 referent to the direct ophthalmic medical costs expended. CONCLUSIONS: Intravitreal ranibizumab therapy for the treatment of DME confers considerable patient (human) value gain. It also accrues financial value to patients, public and private insurers, and society. PMID- 25935788 TI - Spectral-Domain Optical Coherence Tomography in Acute Posterior Vitreous Detachment. PMID- 25935789 TI - Diabetic Macular Edema: Pathophysiology and Novel Therapeutic Targets. AB - Diabetic macular edema (DME) is the major cause of vision loss in diabetic persons. Alteration of the blood-retinal barrier is the hallmark of this disease, characterized by pericyte loss and endothelial cell-cell junction breakdown. Recent animal and clinical studies strongly indicate that DME is an inflammatory disease. Multiple cytokines and chemokines are involved in the pathogenesis of DME, with multiple cellular involvement affecting the neurovascular unit. With the introduction of anti-vascular endothelial growth factor (VEGF) agents, the treatment of DME has been revolutionized, and the indication for laser therapy has been limited. However, the response to anti-VEGF drugs in DME is not as robust as in proliferative diabetic retinopathy, and many patients with DME do not show complete resolution of fluid despite multiple intravitreal injections. Potential novel therapies targeting molecules other than VEGF and using new drug delivery systems currently are being developed and evaluated in clinical trials. PMID- 25935790 TI - Study on degradation kinetics of 2-(2-hydroxypropanamido) benzoic acid in aqueous solutions and identification of its major degradation product by UHPLC/TOF-MS/MS. AB - A RP-HPLC method was developed and validated for the degradation kinetic study of 2-(2-hydroxypropanamido) benzoic acid (HPABA), a promising anti-inflammatory drug, which would provide a basis for further studies on HPABA. The effects of pH, temperature, buffer concentration and ionic strength on the degradation kinetics of HPABA were discussed. Experimental parameters such as degradation rate constants (k), activation energy (Ea), acid and alkali catalytic constants (k(ac), k(al)), shelf life (t1/2) and temperature coefficient (Q10) were calculated. The results indicated that degradation kinetics of HPABA followed zero-order reaction kinetics; degradation rate constants (k) of HPABA at different pH values demonstrated that HPABA was more stable in neutral and near neutral conditions; the function of temperature on k obeyed the Arrhenius equation (r = 0.9933) and HPABA was more stable at lower temperature; with the increase of ionic strength and buffer concentration, the stability of HPABA was decreased. The major unknown degradation product of HPABA was identified by UHPLC/TOF-MS/MS with positive electrospray ionization. Results demonstrated that the hydrolysis product was the primary degradation product of HPABA and it was deduced as anthranilic acid. PMID- 25935791 TI - [Hereditary angioedema treatments: Recommendations from the French national center for angioedema (Bordeaux consensus 2014)]. AB - INTRODUCTION: Treatment of hereditary angioedema (HAE), associated or not with C1Inh deficiency, has dramatically changed these last five years. Four new therapeutic options are now available in France. The French Reference Centre for Angioedema has a consensus meeting to give recommendations about their use. METHODS: The proposals were based on a CREAK survey and a comprehensive review of the literature done by 4 experts. These proposals were submitted to a vote at a national CREAK meeting (Bordeaux, March 2014). Fifty-one participants, 15 experts and one expert-patient have participated. The consensus concerned HAE patients with or without C1Inh deficiency. Were excluded children, patients with acquired AE and with drug induced AE. RESULTS: Proposals were done for 4 cases: acute attack treatment, short-term prophylaxis, long-term prophylaxis and pregnant women. The drugs cited were: C1Inh concentrate, icatibant, tranexamic acid, danazol and chlormadinone acetate. CONCLUSION: Consensual proposals were obtained during this meeting. They will be now widely diffused. PMID- 25935792 TI - Identifying clinically relevant prognostic subgroups of postmenopausal women with node-positive hormone receptor-positive early-stage breast cancer treated with endocrine therapy: a combined analysis of ABCSG-8 and ATAC using the PAM50 risk of recurrence score and intrinsic subtype. AB - BACKGROUND: In the adjuvant treatment of hormone receptor-positive (HR+) breast cancer, variables like tumour size, grade and nodal status have great impact on therapy decisions. As most node-positive patients with HR+ breast cancer currently receive adjuvant chemotherapy improved methods for characterization of individuals' metastasis risk are needed to reduce overtreatment. PATIENTS AND METHODS: Tissue specimens from node-positive patients of the ABCSG-8 and ATAC trials who received adjuvant tamoxifen and/or anastrozole were included in this study. Analysing RNA from paraffin blocks using the PAM50 test, the primary objective was to evaluate the prognostic information of the risk of recurrence (ROR) score added to combined clinical standard variables in patients with one positive node (1N+) and in patients with two or three positive nodes (2-3N+), using log-likelihood ratio tests. RESULTS: At a median follow-up of 9.6 years, distant metastases occurred in 97 (18%) of 543 node-positive patients. In a multivariate analysis, the PAM50-derived ROR score provided reliable prognostic information in addition to and beyond established clinical factors for 1N+ (P < 0.0001) and 2-3N+ patients (P = 0.0002). Ten-year distant recurrence risk was significantly increased in the high-risk compared with the low-risk group derived from ROR score for 1N+ [25.5%, 95% confidence interval (CI) 17.5% to 36.1%versus 6.6%, 95% CI 3.3% to 12.8%] and compared with the combined low/intermediate risk group for 2-3N+ patients (33.7%, 95% CI 25.5% to 43.8% versus 12.5%, 95% CI 6.6% to 22.8%). Additionally, the luminal A intrinsic subtype (IS) exhibited significantly lower risk of distant recurrence compared with the luminal B subtype in 1N+ and 2-3N+ patients. CONCLUSION: PAM50 ROR score and IS can identify node-positive patient subgroups with limited risk of metastasis after endocrine therapy, for whom adjuvant chemotherapy can be spared. The PAM50 test is a valuable tool in determining treatment of node-positive early-stage breast cancer patients. PMID- 25935793 TI - Six versus 12 months of adjuvant trastuzumab in combination with dose-dense chemotherapy for women with HER2-positive breast cancer: a multicenter randomized study by the Hellenic Oncology Research Group (HORG). AB - BACKGROUND: Adjuvant trastuzumab in combination with chemotherapy improves survival of women with HER2-positive early breast cancer. In this study, we compared 12 versus 6 months of adjuvant trastuzumab. PATIENTS AND METHODS: Axillary node-positive or high-risk node-negative women with HER2-positive early breast cancer were randomized to receive 12 or 6 months of adjuvant trastuzumab concurrently with dose-dense, granulocyte colony-stimulating factor (G-CSF) supported docetaxel (75 mg/m(2) every 14 days for four cycles). All patients received upfront dose-dense, G-CSF-supported FEC (5-fluorouracil 700 mg/m(2), epirubicin 75 mg/m(2), cyclophosphamide 700 mg/m(2) every 14 days for four cycles). Randomization was carried out before commence of chemotherapy. The primary end point was the 3-year disease-free survival (DFS). RESULTS: A total of 481 patients were randomized to receive 12 months (n = 241) or 6 months (n = 240) of adjuvant trastuzumab. Chemotherapy was completed in 99% and 98% of patients, while trastuzumab therapy in 100% and 96% of patients in the 12- and 6-month groups, respectively. After 47 and 51 months of median follow-up, there were 17 (7.1%) and 28 (11.7%) disease relapses in the 12- and 6-month groups (P = 0.08). The 3-year DFS was 95.7% versus 93.3% in favor of the 12-month treatment group (hazard ratio = 1.57; 95% confidence interval 0.86-2.10; P = 0.137). There was no difference in terms of overall survival and cardiac toxicity between the two groups. CONCLUSIONS: Our study failed to show noninferiority for the 6-month arm. The results further support the current standard of care that is administration of adjuvant trastuzumab for 12 months. PMID- 25935794 TI - High-dose clarithromycin is an active monotherapy for patients with relapsed/refractory extranodal marginal zone lymphoma of mucosa-associated lymphoid tissue (MALT): the HD-K phase II trial. AB - BACKGROUND: Clarithromycin displays immunomodulatory and antineoplastic properties. As single agent, this macrolide is associated with tumor responses in anecdotal cases of relapsed/refractory extranodal marginal zone lymphoma (rrEMZL), with a putative dose-dependent effect. Tolerability and activity of high-dose clarithromycin (HD-K) in patients with rrEMZL were addressed in a phase II trial (clinicaltrials.gov NCT01516606). METHODS: HIV-negative adults with rrEMZL and at least one measurable/parametrable lesion were enrolled and treated with four courses of oral clarithromycin 2 g/day, days 1-14, every 21 days. Activity (overall response rate, ORR) was the primary end point. RESULTS: Twenty three patients were registered (median age 70 years, range 47-88 years; M:F ratio: 0.27). HD-K was given at greater than or equal to second relapse in 11 patients. Ocular adnexae were the most commonly involved organs. Five patients had hepatitis B virus/hepatitis C virus (HBV/HCV) infections; Helicobacter pylori and Chlamydophila psittaci infections were excluded at the time of patient registration.Tolerability was excellent, even among HBV/HCV-positive patients; only two patients had grade >2 toxicity (nausea). Six patients achieved a complete remission and six a partial response (ORR = 52%; 95% confidence interval 32% to 72%). Age, previous treatment and stage did not influence activity. At a median follow-up of 24 (16-33) months, only two patients with responsive disease experienced relapse, with a 2-year progression-free survival of 56 +/- 10%; all patients are alive. CONCLUSIONS: HD-K is a safe and active salvage treatment in EMZL patients. This macrolide deserves to be further investigated in EMZL and other lymphoma categories. PMID- 25935795 TI - Can neck exercises enhance the activation of the semispinalis cervicis relative to the splenius capitis at specific spinal levels? AB - The deep cervical extensor, semispinalis cervicis, displays changes in behaviour and structure in people with chronic neck pain yet there is limited knowledge on how activation of this muscle can be emphasized during training. Using intramuscular electromyography (EMG), this study investigated the activity of the deep semispinalis cervicis and the superficial splenius capitis muscle at two spinal levels (C2 and C5) in ten healthy volunteers during a series of neck exercises: 1. Traction and compression, 2. Resistance applied in either flexion or extension at the occiput, at the level of the vertebral arch of C1 and of C4, and 3. Maintaining the neck in neutral while inclined on the elbows, with and without resistance at C4. The ratio between semispinalis cervicis and the splenius capitis EMG amplitude was quantified as an indication of whether the exercise could emphasize the activation of the semispinalis cervicis muscle relative to the splenius capitis. Manual resistance applied in extension over the vertebral arch emphasized the activation of the semispinalis cervicis relative to the splenius capitis at the spinal level directly caudal to the site of resistance (ratio: 2.0 +/- 1.1 measured at C5 with resistance at C4 and 2.1 +/- 1.2 measured at C2 with resistance at C1). This study confirmed the possibility of emphasizing the activation of the semispinalis cervicis relative to the splenius capitis which may be relevant for targeted exercise interventions for this deep extensor muscle. Further studies are required to investigate the clinical efficacy of these exercises for people with neck pain. PMID- 25935796 TI - Interrater reliability of the modified scapular assistance test with and without handheld weights. AB - STUDY DESIGN: Prospective, blinded interrater reliability study. OBJECTIVE: To determine the interrater reliability of the modified Scapular Assistance Test (mSAT) with and without the use of additional handheld weights. METHODS: 110 Shoulder patients with various shoulder pathologies were consecutively recruited. Tests were performed independently and randomly on each participant by 2 different examiners, which were blinded to further clinical information (e.g. patient history, former diagnostic results). Percent agreement, Cohen's kappa (Kappa), proportion of positive/negative agreement, maximum Kappa, prevalence and bias indexes and prevalence-adjusted-bias-adjusted kappa (PABAK) were calculated as estimates of interrater reliability of the mSAT with and without additional handheld weights. Weights were chosen according to body weight. RESULTS: The reliability measures for the mSAT (Cohen's Kappa: 0.68, confidence interval (CI): 0.51-0.85; PABAK: 0.78, CI: 0.67-0.90) as well as for the mSAT with handheld weights (Cohen's Kappa: 0.63, CI: 0.44-0.81; PABAK: 0.76, CI: 0.64-0.88) showed substantial agreement according to the classification system proposed by Landis and Koch. CONCLUSIONS: Based on the results of this study, the mSAT with and without additional weights can be considered as reliable for clinical use. Since both tests showed substantial agreement, the use of additional handheld weights might not be necessary in case of obvious scapula dyskinesis. However, to perform the mSAT with/without additional weights should depend not only on its reliability values. Name of the public trials registry and the registration number: German Clinical Trials Register, protocol number DRKS00005377. PMID- 25935797 TI - Magnetic "one-step" quick, easy, cheap, effective, rugged and safe method for the fast determination of pesticide residues in freshly squeezed juice. AB - A "one-step" quick, easy, cheap, effective, rugged and safe (QuEChERS) method was proposed for pesticide residue analysis in freshly squeezed juice of fruits and vegetables. In this method, a new magnetic adsorbent prepared by simple physical blending was adopt, which could endow the sample mixture with magnetic separability. To achieve the best performance of the modified QuEChERS towards target analytes, the amounts of adsorbents were investigated. Under the optimized conditions, a simple, rapid and sensitive method for the determination of 11 pesticide residues in freshly squeezed juice was established by coupling modified QuEChERS to gas chromatography/mass spectrometry analysis. The limits of quantification of the proposed method for 11 pesticides ranged from 2.0 to 49.6ng/g. Good linearities (R value >=0.9993) were achieved at different concentration ranges, and acceptable method reproducibility was obtained by evaluating intra- and inter-day precisions with the relative standard deviations being less than 8.5% and 13.5%, respectively. The recoveries were in the range of 70.3-114.1% at different concentrations for real samples. Compared with the traditional QuEChERS methods, extraction/partitioning and purification were integrated into one step in the proposed method, which thus was time-saving (within 3.5min) with keeping good clean-up performance. PMID- 25935798 TI - Hydrophilic-subtraction model for the characterization and comparison of hydrophilic interaction liquid chromatography columns. AB - Nowadays more and more hydrophilic interaction liquid chromatography (HILIC) columns with diverse functional groups have become commercially available, which pose a challenge to select an appropriate one. However, there is no universal model to provide guidance for selecting HILIC columns. To handle this problem, a retention model named "hydrophilic-subtraction model" was developed to characterize and compare HILIC columns. The hydrophilic-subtraction model, which was designed based on the widely recognized HILIC retention mechanisms including hydrophilic partitioning, hydrogen-bonding and electrostatic interactions, was established by the retention of 41 solutes with various properties on 8 representative HILIC columns. High correlation coefficients (R(2)>=0.990) and small standard deviations (SD<=0.041) indicated that this model correlated effectively the retention with solute descriptors and column parameters. To evaluate reliability of the model, the model was further applied to characterize 15 additional HILIC columns using 41 solutes. The results of multiple linear regression confirmed the significance of the model. The regression coefficients of the model were used to investigate retention mechanisms occurring in different chromatographic systems. Based on these regression coefficients, selectivities of HILIC stationary phases were exhibited intuitively by an angle graph and a spider diagram, which could be used as guidance for researchers to select appropriate columns for HILIC separation. Additionally, a rapid and convenient procedure was proposed for characterizing HILIC columns. PMID- 25935799 TI - The surgical treatment of anterior knee pain due to infrapatellar fat pad pathology: A systematic review. AB - BACKGROUND: Anterior knee pain (AKP) encompasses a range of pathologies. As a result, there are a number of therapeutic options used to treat AKP. The non operative treatments have been analysed in a number of randomised controlled trials and systematic reviews. There is however a scarcity of such publications covering the surgical management of AKP. There are no systematic reviews that have investigated surgical interventions for AKP due to pathology of the infrapatellar fat pad (IFP). The aims of this study were to review the literature systematically, to establish which surgical procedures have been used to treat IFP disease and to determine their efficacy. METHODS: The review was conducted in accordance with the PRISMA reporting guidelines. A search of the literature was performed on 1st January 2014 using multiple databases including CENTRAL, MEDLINE, EMBASE, PubMed, and Google Scholar. The quality of the studies was assessed using Oxford Evidence-Based Medicine Levels of Evidence guidelines and the GRADE approach. RESULTS: Twenty-four eligible studies were found and included. The critical appraisal identified that the current evidence-base has low methodology quality. The clinical findings indicated that there is a positive trend towards the surgical management of IFP disease for AKP symptoms. Excision of IFP tumours and resection of the IFP in Hoffa's disease can lead to improvements in symptoms and function. CONCLUSIONS: Truly robust evidence to support the surgical management of IFP pathology requires randomised controlled trials; however the expenses involved to design such trials means that they are unlikely to be undertaken for this uncommon disorder. Consequently well-designed and well-reported case series need to be undertaken to improve our current understanding that includes recording quantitative measures such as range of knee motion, VAS Pain scores and a validated scoring system. PMID- 25935800 TI - Survival and functional results after a mean follow-up of 9 years with the Ceragyr(r) highly congruent mobile-bearing TKA. AB - INTRODUCTION: Fixed-bearing total knee arthroplasty (TKA) implants have excellent long-term survival. Mobile-bearing implants were developed to reduce bone-implant interface stresses and polyethylene insert wear. The primary objective of this study was to analyze the survival rate of a highly congruent mobile-bearing TKA implant (Ceragyr((r))) in patients having a minimum follow-up of 7 years. We hypothesized that the survival rate would be 95-100% at that time point. PATIENTS AND METHODS: A single-center prospective study included all the patients operated for a primary TKA procedure with a Ceragyr((r)) implant between 2000 and 2003. All the implants were cemented. Patellar resurfacing was not carried out systematically, but could be carried out secondarily in cases of persistent anterior knee pain. Clinical and radiological data were collected before the surgery, at 3 months postoperative, at 1 year and then at a minimum follow-up of 7 years. The primary endpoint was the overall revision-free survival rate. Secondary endpoints were the survival without mechanical failure, IKS scores, knee range of motion and implant positioning. RESULTS: One hundred and thirty four patients (143 Ceragyr((r)) TKA cases) were included; 9 patients (10 TKA) were lost to follow-up (6.7%) and the remaining 125 patients (133 TKA) were contacted. At the final review, 7 of the 133 TKA cases (5.3%) had been revised (6 men, 1 women; P = 0.002), 2 (1.5%) because of mechanical failure and 5 (3.8%) because of an infection. The overall revision-free survival rate was 94.8% [95% CI: 89.3-97.5]; survival was 98.4% [95% CI: 93.8-99.6] with mechanical failure as an endpoint. An in-person assessment was conducted on 76 patients (80 TKA cases) (49 women; 27 men) who had an average age of 70.3 +/- 8.4 years at the time of the arthroplasty procedure. The patella had been resurfaced during the initial procedure in 49 cases, and was either not resurfaced or secondarily resurfaced in 31 cases. The average follow-up was 8.7 +/- 1.1 years. The IKS score had significantly improved relative to the preoperative values (P < 0.00001). Knee flexion and the IKS knee score remained stable over time (P > 0.05). Patients who underwent patella resurfacing during the initial TKA procedure had better clinical results (P = 0.03). CONCLUSION: After a minimum follow-up of 7years, the overall revision-free survival rate for the Ceragyr((r)) was 94.8%; the survival was 98.4% with mechanical failure as an endpoint. The results were stable over time. PMID- 25935801 TI - Sedimentary hydrocarbons and sterols in a South Atlantic estuarine/shallow continental shelf transitional environment under oil terminal and grain port influences. AB - Sterols and hydrocarbons were determined in the surface sediments from the transitional environment between Paranagua Bay and the shallow continental shelf in the South Atlantic to assess the sources of organic matter (OM) and the contamination status of an area exposed to multiple anthropogenic inputs. Total aliphatic hydrocarbon concentrations were less than 10MUgg(-1), which is typical of unpolluted sediments, and related to recent inputs from higher terrestrial plants. Total polycyclic aromatic hydrocarbon ranged from
25 mL and critical pH <2.5 (Roberts and Shirley criteria) were considered to be at risk for pulmonary aspiration. RESULTS: The percentage of patients with gastric volume >25 mL and pH <2.5 was 5%, 30%, and 0% in groups I, II, and III, respectively. Statistically significant difference existed between groups I and II (P = .04) and groups II and III (P = .006). Premedicated morbidly obese and lean patients were comparable (P = .46). CONCLUSION: Morbidly obese patients undergoing elective surgery are at a higher risk for regurgitation and pulmonary aspiration when compared with lean patients. Preoperative aspiration prophylaxis decreases gastric volume and increases gastric pH and thus should be routinely prescribed. PMID- 25935830 TI - Study protocol: a stepped wedge cluster randomised controlled trial of a healthy lifestyle intervention for people attending residential substance abuse treatment. AB - BACKGROUND: Cardiovascular disease and cancer are leading causes of mortality for people with a history of alcohol or other substance use disorders. These chronic diseases share the same four primary behavioural risk factors i.e. excessive alcohol use, smoking, low intake of fruit and vegetables and physical inactivity. In addition to addressing problematic alcohol use, there is the potential for substance abuse treatment services to also address these other behaviours. Healthy Recovery is an 8-session group-based intervention that targets these multiple behavioural health risk factors and was developed specifically for people attending substance abuse treatment. This protocol describes a Cancer Institute NSW funded study that assesses the effectiveness of delivering Healthy Recovery for people who are attending residential alcohol and other substance abuse treatment. METHODS/DESIGN: The study uses a stepped wedge randomised controlled design, where randomisation occurs at the service level. Participants will be recruited from residential rehabilitation programs provided by The Australian Salvation Army. All participants who (1) currently smoke tobacco and (2) are expected to be in the residential program for the duration of the 5-week intervention will be asked to participate in the study. Those participants residing at the facilities assigned to the treatment condition will complete Healthy Recovery. The intervention is manual guided and will be delivered over a 5-week period, with participants attending 8 group sessions. All participants will continue to complete The Salvation Army residential program, a predominantly 12-step based, modified therapeutic community. Participants in the control condition will complete treatment as usual. Research staff blind to treatment allocation will complete the primary and secondary outcome assessments at baseline and then at weeks 8, 20 and 32 weeks post intervention. DISCUSSION: This study will provide comprehensive data on the effect of delivering a healthy lifestyle intervention (i.e. Healthy Recovery) within a residential substance abuse setting. If shown to be effective, this intervention can be disseminated within other residential substance abuse programs. TRIAL REGISTRATION: Australian and New Zealand Clinical Trials Register (ANZCTR): ACTRN12615000165583. Registered 19(th) February 2015. PMID- 25935832 TI - Dystonic reaction associated with ondansetron administration in a patient with normal pressure hydrocephalus. AB - A 77-year-old female with normal pressure hydrocephalus underwent urgent revision of the abdominal component of a ventriculoperitoneal shunt. Upon emergence from an uneventful general anesthetic, the patient exhibited cogwheel rigidity with decerebrate posturing and a markedly irregular respiratory rate. This prohibited extubation and prompted an unplanned intensive care unit admission. Ondansetron was the only medication administered that had previously been associated with dystonic reactions. In a previous procedure, the patient had been given ondansetron without a similar reaction. This presentation may have been provoked by existing pathology such as her underlying normal pressure hydrocephalus and small increases in intracranial pressure. PMID- 25935833 TI - Awake intubation using a tube balloon esophageal blocker in a patient with full stomach. PMID- 25935834 TI - Effect of body mass index on angle of needle insertion during ultrasound-guided lateral sagittal infraclavicular brachial plexus block. AB - STUDY OBJECTIVES: The aim of our study was to establish the angle of needle insertion from the anterior chest wall during ultrasound-guided infraclavicular brachial plexus block and to examine for any correlation between body mass index (BMI) and insertion angle. DESIGN: This is a prospective observational study. SETTING: The setting is at an operating room, university-affiliated teaching hospital. PATIENTS: The patients are 23 American Society of Anesthesiologists physical status 1-3 patients scheduled to undergo elbow, forearm, or hand surgery under regional anesthesia with or without general anesthesia. INTERVENTIONS: The intervention is infraclavicular brachial plexus block with or without perineural catheter insertion. MEASUREMENTS: The measurement is the angle of needle insertion in relation to the anterior chest wall, BMI, and needle visibility as graded by the anesthesiologist. MAIN RESULTS: Twenty-three patients were studied. The mean (SD) BMI was 28.5 (5.4). The median (range) of angle of needle insertion was 50 (33-60). The Pearson correlation coefficient for BMI and angle of needle insertion was 0.357. There were no reported complications. CONCLUSIONS: The median (range) angle of needle insertion in relation to chest for our study patients was 50 degrees (33 degrees -60 degrees ). The needle visibility was rated difficult, requiring hydrolocation or "heeling-in," in 39% of cases. There was a moderate correlation between BMI and angle of insertion. Despite difficulties with needle visualization, the ultrasound-guided infraclavicular brachial plexus block provided reliable analgesia. PMID- 25935835 TI - Evaluation of Singer's Voice Quality by Means of Visual Pattern Recognition. AB - The article presents a description of the algorithm of singing voice quality assessment that uses selected methods from the field of digital image processing and recognition. It adopts the assumption that an audio signal with recorded vocal exercise can be converted into a visual representation, and processed further, as an image. Presented approach is based on generating a sound spectrogram of a sample in the form of a rectangular matrix, objective improvement of its visual quality based on local changes in brightness and contrast, and scaling to a fixed size. Then, it uses a two-step approach: the construction of a representative database of reference samples and the identification of test samples. The process of building the database uses two dimensional linear discriminant analysis. Then, the recognition operation is carried out in a reduced feature space that has been obtained by two-dimensional Karhunen-Loeve projection. Classification is done by a variant of Support Vector Machines approach. As it is shown, the results are very encouraging and are competitive to the most powerful state-of-the-art methods. PMID- 25935836 TI - Epicardial fat thickness is associated to type 2 diabetes mellitus in Korean men: a cross-sectional study. AB - BACKGROUND: Visceral fat, including epicardial fat (EF) is recognized as a responsible factor of cardiovascular disease. The aim of this study was to investigate the relationship between EF and diabetes in Korean men. METHODS: EF thickness was measured in the left main coronary artery fat tissue (LMCA-fat) by low-dose chest CT scans in 1,048 Korean men (age above 20 years). LMCA-fat values were divided into quartiles and the prevalence of diabetes was analyzed based on the quartiles of LMCA-fat values using logistic regression. RESULTS: There were significant correlations between LMCA-fat and body mass index (r = 0.169, p = 0.004), waist circumference (r = 0.172, p < 0.001), fasting glucose (r = 0.106, p = 0.037) and HbA1c (r = 0.176, p < 0.001). The patients in the higher LMCA-fat quartiles were associated with higher prevalence of diabetes (p for trend <0.001). Even after adjustment for multiple covariates, this association still remained statistically significant (p for trend = 0.022). The highest LMCA-fat quartile group was significantly associated with diabetes compared to the lowest quartile group. (OR = 3.26, 95% CI = 1.17-9.12). CONCLUSION: These findings indicate that increased EF thickness is independently associated with the prevalence of diabetes in Korean men. PMID- 25935837 TI - miR-330-3p controls cell proliferation by targeting early growth response 2 in non-small-cell lung cancer. AB - Non-small-cell lung cancer (NSCLC) is one of the most common lung cancers, and microRNAs (miRNAs) have been reported to play essential roles in NSCLC. Recent studies have indicated that miR-330-3p expression is up-regulated in NSCLC samples and in tissues of NSCLC brain metastasis. In this study, up-regulation of miR-330-3p expression was confirmed in NSCLC and 20 NSCLC patient samples. Furthermore, miR-330-3p was over-expressed in NSCLC cell lines A549 and H23, and the promotive function of miR-330-3p was investigated in regulating NSCLC cell proliferation and cell cycle distribution. To identify potential target genes of miR-330-3p in NSCLC, the miRNA target prediction databases were used. Luciferase activity assay and real-time RT-PCR analysis confirmed that miR-330-3p is negatively correlated with the expression of early growth response 2 (EGR2). Moreover, it was also found that EGR2 mRNA contains two potential binding sites for miR-330-3p. Knock-down of EGR2 with siRNA was demonstrated to have a similar effect as the over-expression of miR-330-3p in NSCLC cell lines. Taken together, our results show that EGR2 is a target of miR-330-3p. PMID- 25935839 TI - Differences in metabolic rate and evaporative water loss associated with sexual dimorphism in thynnine wasps. AB - Species with sexual dimorphism provide powerful study systems for understanding adaptation to different lifestyles as it removes the potentially confounding effects of phylogeny. Thynnine wasps have a stark sexual dimorphism where males fly patrols in search of the flightless, predominantly fossorial females with which to mate. Using flow-through respirometry, we tested the prediction that the highly active males of the thynnine wasp Zaspilothynnus nigripes would have high metabolic rates (VCO2) relative to females. Further, the females, which spend more time underground, were predicted to exhibit lower evaporative water loss (EWL) than males. Metabolic rate of both sexes increased exponentially between 12 and 28 degrees C. As predicted, males had higher mass-corrected VCO2 at identical temperatures than females. Alternatively, there were no differences in the EWL at identical temperatures between sexes, suggesting that experiencing the same environmental conditions during mating may favour similar EWL. Interestingly, Z. nigripes were estimated to undergo a decrease in metabolism at approximately 30 degrees C. It is proposed that Z. nigripes persist despite sensitivity to high temperatures using a combination of behavioural strategies and emergence during a period of relatively benign climate that ameliorates the impacts of high temperatures. PMID- 25935838 TI - Thyroxine modifies the effects of growth hormone in Ames dwarf mice. AB - Ames dwarf (df/df) mice lack growth hormone (GH), thyroid stimulating hormone and prolactin. Treatment of juvenile df/df mice with GH alone stimulates somatic growth, reduces insulin sensitivity and shortens lifespan. Early-life treatment with thyroxine (T4) alone produces modest growth stimulation but does not affect longevity. In this study, we examined the effects of treatment of juvenile Ames dwarf mice with a combination of GH + T4 and compared them to the effects of GH alone. Treatment of female and male dwarfs with GH + T4 between the ages of 2 and 8 weeks rescued somatic growth yet did not reduce lifespan to match normal controls, thus contrasting with the previously reported effects of GH alone. While the male dwarf GH + T4 treatment group had no significant effect on lifespan, the female dwarfs undergoing treatment showed a decrease in maximal longevity. Expression of genes related to GH and insulin signaling in the skeletal muscle and white adipose tissue (WAT) of female dwarfs was differentially affected by treatment with GH + T4 vs. GH alone. Differences in the effects of GH + T4 vs. GH alone on insulin target tissues may contribute to the differential effects of these treatments on longevity. PMID- 25935840 TI - Effects of sugammadex on incidence of postoperative residual neuromuscular blockade: a randomized, controlled study. AB - BACKGROUND: This study aimed to investigate whether reversal of rocuronium induced neuromuscular blockade with sugammadex reduced the incidence of residual blockade and facilitated operating room discharge readiness. METHODS: Adult patients undergoing abdominal surgery received rocuronium, followed by randomized allocation to sugammadex (2 or 4 mg kg(-1)) or usual care (neostigmine/glycopyrrolate, dosing per usual care practice) for reversal of neuromuscular blockade. Timing of reversal agent administration was based on the providers' clinical judgement. Primary endpoint was the presence of residual neuromuscular blockade at PACU admission, defined as a train-of-four (TOF) ratio <0.9, using TOF-Watch(r) SX. Key secondary endpoint was time between reversal agent administration and operating room discharge-readiness; analysed with analysis of covariance. RESULTS: Of 154 patients randomized, 150 had a TOF value measured at PACU entry. Zero out of 74 sugammadex patients and 33 out of 76 (43.4%) usual care patients had TOF-Watch SX-assessed residual neuromuscular blockade at PACU admission (odds ratio 0.0, 95% CI [0-0.06], P<0.0001). Of these 33 usual care patients, 2 also had clinical evidence of partial paralysis. Time between reversal agent administration and operating room discharge-readiness was shorter for sugammadex vs usual care (14.7 vs. 18.6 min respectively; P=0.02). CONCLUSIONS: After abdominal surgery, sugammadex reversal eliminated residual neuromuscular blockade in the PACU, and shortened the time from start of study medication administration to the time the patient was ready for discharge from the operating room. CLINICAL TRIAL REGISTRATION: Clinicaltrials.gov:NCT01479764. PMID- 25935841 TI - Anaesthesia care with and without tracheal intubation during emergency endoscopy for peptic ulcer bleeding: a population-based cohort study. AB - BACKGROUND: Emergency upper gastrointestinal bleeding is a common condition with high mortality. Most patients undergo oesophagogastroduodenoscopy (OGD), but no universally agreed approach exists to the type of airway management required during the procedure. We aimed to compare anaesthesia care with tracheal intubation (TI group) and without airway instrumentation (monitored anaesthesia care, MAC group) during emergency OGD. METHODS: This was a prospective, nationwide, population-based cohort study during 2006-13. Emergency OGDs performed under anaesthesia care were included. End points were 90 day mortality (primary) and length of stay in hospital (secondary). Associations between exposure and outcomes were assessed in logistic and linear regression models, adjusted for the following potential confounders: shock at admission, level of anaesthetic expertise present, ASA score, Charlson comorbidity index score, BMI, age, sex, alcohol use, referral origin (home or in-hospital), Forrest classification, ulcer localization, and postoperative care. RESULTS: The study group comprised 3580 patients under anaesthesia care: 2101 (59%) for the TI group and 1479 (41%) for the MAC group. During the first 90 days after OGD, 18.9% in the TI group and 18.4% in the MAC group died, crude odds ratio=1.03 [95% confidence interval (CI)=0.87-1.23, P=0.701], adjusted odds ratio=0.95 (95% CI=0.79-1.15, P=0.590). Patients in the TI group stayed slightly longer in hospital [mean 8.16 (95% CI=7.63-8.60) vs 7.63 days (95%=CI 6.92-8.33), P=0.108 in adjusted analysis]. CONCLUSIONS: In this large population-based cohort study, anaesthesia care with TI was not different from anaesthesia care without airway instrumentation in patients undergoing emergency OGD in terms of 90 day mortality and length of hospital stay. PMID- 25935842 TI - Disease-specific differences in the use of traditional Korean medicine in Korea. AB - BACKGROUND: Though traditional Korean medicine plays an important role in the Korean parallel health care system, there is limited information about the preference and usage of traditional Korean medicine compared to Western medicine because they have different disease classification systems. The aim of this study is to determine the relative preference for traditional Korean medicine using data acquired nationwide. METHODS: Data from the 2008 Korea Health Panel were analyzed to determine the preference of medical services by disease. The use of traditional Korean medicine use is defined by the type of medical institution they used. Disease types, number of visits and out of pocket expenditures were analyzed. RESULTS: Traditional Korean medicine was used in only a small number of cases that were emergencies or hospitalization. However, in terms of outpatient services, traditional Korean medicine was used in 7.8% of all cases and represented 9.9% of total medical costs. Among disease groups, traditional Korean medicine use was higher in patients with nervous system and musculoskeletal system diseases. And patients with musculoskeletal and nervous system diseases such as arthrosis were the most likely to use traditional Korean medicine particularly in an outpatient setting. CONCLUSIONS: Korean characteristics of service use resemble the complementary and alternative medicine use in other countries in terms of disease group, and the complementary and alternative medicine should be considered to estimate the burden of disease in countries with parallel health care systems, such as Korea. This is the first study determined the actual preference of traditional Korean medicine for specific chronic diseases. PMID- 25935843 TI - A randomised trial into the effect of an isolated hip abductor strengthening programme and a functional motor control programme on knee kinematics and hip muscle strength. AB - BACKGROUND: Dynamic knee valgus and internal femoral rotation are proposed to be contributory risk factors for patellofemoral pain and anterior cruciate ligament injuries. Multimodal interventions including hip abductor strengthening or functional motor control programmes have a positive impact of pain, however their effect on knee kinematics and muscle strength is less clear. The aim of this study was to examine the effect of isolated hip abductor strengthening and a functional motor control exercise on knee kinematics and hip abductor strength. METHODS: This prospective, randomised, repeated measures design included 29 asymptomatic volunteers presenting with increase knee valgus and femoral internal rotation. Participants completed either isolated hip abductor strengthening or a functional motor control exercise for 5 weeks. Knee kinematics were measured using inertial sensors during 2 functional activities and hip abductor strength measured using a load cell during isometric hip abduction. RESULTS: There were no significant differences in dynamic knee valgus and internal rotation following the isolated hip abductor or functional motor control intervention, and no significant differences between the groups for knee angles. Despite this, the actual magnitude of reduction in valgus was 10 degrees and 5 degrees for the functional motor control group and strengthening group respectively. The actual magnitude of reduction in internal rotation was 9 degrees and 18 degrees for the functional motor control group and strengthening group respectively. Therefore there was a tendency towards clinically significant improvements in knee kinematics in both exercise groups. A statistically significant improvement in hip abductor strength was evident for the functional motor control group (27% increase; p = 0.008) and strengthening group (35% increase; p = 0.009) with no significant difference between the groups being identified (p = 0.475). CONCLUSIONS: Isolated hip strengthening and functional motor control exercises resulted in non-statistically significant changes in knee kinematics, however there was a clear trend towards clinically meaningful reductions in valgus and internal rotation. Both groups demonstrated similar significant gains in hip abductor strength suggesting either approach could be used to strengthen the hip abductors. PMID- 25935844 TI - A Randomized Clinical Trial of Jet-Injected Lidocaine to Reduce Venipuncture Pain for Young Children. AB - STUDY OBJECTIVE: The J-Tip (National Medical Products Inc, Irvine, CA) uses air instead of a needle to push lidocaine into the skin. To our knowledge, no studies have investigated its use for venipuncture in young children. We determine whether the J-Tip decreased venipuncture pain in young children compared with vapocoolant spray. METHODS: Children aged 1 to 6 years were randomized into 3 groups: intervention (J-Tip), control (vapocoolant spray), and sham (vapocoolant spray and pop of an empty J-Tip). The procedure was videotaped and scored with the Face, Legs, Activity, Cry and Consolability (FLACC) tool at 3 points; baseline, before approach; device, at J-Tip deployment; and at venipuncture. The FLACC tool was scored 0 (none) to 10 (severe). Comparisons of pain scores over time were made with the generalized estimating equation. Venipuncture success and adverse effects were assessed and compared with chi(2). RESULTS: Two hundred five children enrolled: intervention 96, control 53, and sham 56. There were no between-group differences in baseline characteristics. There was no mean change in pain scores from device to venipuncture in the intervention group (0.26; 95% confidence interval [CI] -0.31 to 0.82), but there was an increase in pain in the control (2.82; 95% CI 1.91 to 3.74) and sham (1.68; 95% CI 0.83 to 2.52) groups. This change was greater for the control and sham compared to the intervention group. There was no difference in venipuncture success between groups. No severe adverse events occurred. Minor adverse events were the same between groups. CONCLUSION: Use of the J-Tip for children aged 1 to 6 years reduced venipuncture pain compared with vapocoolant spray or sham treatment. PMID- 25935845 TI - Repellent efficacy of DEET, MyggA, neem (Azedirachta indica) oil and chinaberry (Melia azedarach) oil against Anopheles arabiensis, the principal malaria vector in Ethiopia. AB - BACKGROUND: In Ethiopia, Anopheles arabiensis is the main vector responsible for the transmission of malaria in the country and its control mainly involves application of indoor residual spraying (IRS) and use of insecticide-treated bed nets (ITNs). OBJECTIVE: Although the role of repellents for reducing man-vector contact is documented in the literature, the response of An. arabiensis to repellents was not previously evaluated under field conditions in Ethiopia. METHOD: The trial was conducted in Sodere village assessing the repellent activities of four repellents, of which, two of them were commercially available DEET (N, N-diethyl-1,3-methylbenzamide) and MyggA (p-methane diol) and the other two were laboratory- produced, 20% neem oil and 20% chinaberry oil. A 6 by 6 Latin square design was employed by involving six volunteers who received rotated treatments of repellents and the Ethiopian Niger seed, noog abyssinia (Guizotia abyssinia), and locally called as noog oil (diluents to the two plant oils). Each volunteer also served as control. Volunteers were positioned at a distance of 20 40 m from each other and each was treated with one of the repellents, Niger seed/noog/ oil or untreated. Landing mosquitoes were collected from dusk to down using tests tubes. The tests were done in three replicates. RESULTS: Both DEET and MyggA provided more than 96% protection. The mean protection time for DEET was 8 hrs while the time for MyggA was 6 hrs. Protection obtained from neem oil and chinaberry oil was almost similar (more than 70%), however, the complete protection time for neem was 3 hrs, while that of chinaberry oil was one hour. CONCLUSION: The commercial products and laboratory-produced repellents can be utilized by individuals to avoid contact with An. arabiensis in Ethiopia. PMID- 25935846 TI - Polymorphisms and expression analysis of SOX-6 in relation to porcine growth, carcass, and meat quality traits. AB - The aim of the study was to investigate single nucleotide polymorphisms (SNPs) and expression of SOX-6 to support its candidacy for growth, carcass, and meat quality traits in pigs. The first SNP, rs81358375, was associated with pH 45 min post mortem in loin (pH1L), the thickness of backfat and side fat, and carcass length in Pietrain (Pi) population, and related with backfat thickness and daily gain in Duroc * Pietrain F2 (DuPi) population. The other SNP, rs321666676, was associated with meat colour in Pi population. In DuPi population, the protein, not mRNA, level of SOX-6 in high pH1L pigs was significantly less abundant compared with low pH1L pigs, where microRNAs targeting SOX-6 were also differently regulated. This paper shows that SOX-6 could be a potential candidate gene for porcine growth, carcass, and meat quality traits based on genetic association and gene expression. PMID- 25935847 TI - Association between functional candidate genes and organoleptic meat traits in intensively-fed beef. AB - The aim of this study was to assess the associations between the single nucleotide polymorphisms in CAPN1, CAST, DGAT1, FABP4, LEP, RORC and SCD1 genes and the sensory meat quality in an intensively fed commercial population (Charolais, Limousin and Retinta breed). This work carried out analyses on a common Spanish population and evaluated the association between the markers and sensory traits. A total of 161 bulls were allocated to two different feedlots with two different finishing diets. Steaks aged for 7 and 21 days were assessed by both untrained and trained sensory panels. A significant association and allelic substitution effect were observed for markers UoG-CAST, LEP: g.73C>T and SCD1: g.878T>C on different descriptors evaluated by a consumer panel (tenderness and overall acceptability). There are no precedents of these kinds of association studies in a Spanish commercial population. The study suggested that CAST, LEP and SCD1 genes have a potential effect on the different measurements of sensory meat quality. PMID- 25935848 TI - Salt and intramuscular fat modulate dynamic perception of flavour and texture in dry-cured hams. AB - The present study aimed to evaluate the influence of salt and intramuscular fat (IMF) content on the sensory characteristics of two different types of dry-cured hams (Iberian and Serrano) using the time-intensity (TI) method. All studied TI parameters of flavour attributes (overall flavour, saltiness, cured and rancid flavours) were significantly (p < 0.05) affected by variations in the salt and/or IMF content. However, regarding texture attributes only the maximum intensity (Imax) of hardness was significantly (p < 0.05) affected by the salt content of hams. Compared to Iberian dry-cured hams, the dynamic perception of the flavour and texture of Serrano dry-cured hams was less influenced by variations in salt and/or IMF content. The dynamic sensory techniques may be helpful to guarantee the quality of dry-cured products subjected to strategies of salt and fat reduction. PMID- 25935849 TI - I-RREACH: an engagement and assessment tool for improving implementation readiness of researchers, organizations and communities in complex interventions. AB - BACKGROUND: Non-communicable chronic diseases are the leading causes of mortality globally, and nearly 80% of these deaths occur in low- and middle-income countries (LMICs). In high-income countries (HICs), inequitable distribution of resources affects poorer and otherwise disadvantaged groups including Aboriginal peoples. Cardiovascular mortality in high-income countries has recently begun to fall; however, these improvements are not realized among citizens in LMICs or those subgroups in high-income countries who are disadvantaged in the social determinants of health including Aboriginal people. It is critical to develop multi-faceted, affordable and realistic health interventions in collaboration with groups who experience health inequalities. Based on community-based participatory research (CBPR), we aimed to develop implementation tools to guide complex interventions to ensure that health gains can be realized in low-resource environments. METHODS: We developed the I-RREACH (Intervention and Research Readiness Engagement and Assessment of Community Health Care) tool to guide implementation of interventions in low-resource environments. We employed CBPR and a consensus methodology to (1) develop the theoretical basis of the tool and (2) to identify key implementation factor domains; then, we (3) collected participant evaluation data to validate the tool during implementation. RESULTS: The I-RREACH tool was successfully developed using a community-based consensus method and is rooted in participatory principles, equalizing the importance of the knowledge and perspectives of researchers and community stakeholders while encouraging respectful dialogue. The I-RREACH tool consists of three phases: fact finding, stakeholder dialogue and community member/patient dialogue. The evaluation for our first implementation of I-RREACH by participants was overwhelmingly positive, with 95% or more of participants indicating comfort with and support for the process and the dialogue it creates. CONCLUSIONS: The I RREACH tool was designed to (1) pinpoint key domains required for dialogue between the community and the research team to facilitate implementation of complex health interventions and research projects and (2) to identify existing strengths and areas requiring further development for effective implementation. I RREACH has been found to be easily adaptable to diverse geographical and cultural settings and can be further adapted to other complex interventions. Further research should include the potential use of the I-RREACH tool in the development of blue prints for scale-up of successful interventions, particularly in low resource environments. PMID- 25935850 TI - Acute response to barefoot running in habitually shod males. AB - The aim of this study was to examine the immediate effects of barefoot (BF) running on lower limb kinematics and muscle activity in a group of habitually shod runners. Ten male runners with no prior BF or minimalist running experience performed 1-min bouts of treadmill running at 3 velocities in both shod and BF conditions. 2D video data were recorded in order to quantify ankle, knee and hip kinematics. Synchronous kinetic data were recorded from a force plate supporting the treadmill in order to quantify spatiotemporal variables. EMG data were collected from 6 lower limb muscles, quantifying recruitment patterns during discrete phases of the gait cycle. BF running resulted in significantly higher stride frequency and shorter ground contact times (P < .001). Additionally, BF running significantly reduced knee and hip range of motion but increased ankle range of motion during the absorptive phase of the stance. Alterations in ankle kinematics during BF running resulted from increased pre-activation of the medial (P < .05) and lateral (P < .01) gastrocnemius in addition to reductions in pre activation of the tibialis anterior (P < .05). The results highlight that recruitment patterns and kinematics can change in as little as 30-s of BF running in individuals with no previous BF running experience. PMID- 25935851 TI - Increases in pre-hospitalization serum 25(OH)D concentrations are associated with improved 30-day mortality after hospital admission: A cohort study. AB - CONTEXT: Pre-hospital vitamin D status may be a modifiable risk factor for all cause mortality among hospitalized patients. OBJECTIVE: To examine the association between increases in serum 25-hydroxyvitamin D [25(OH)D] levels during the year before hospitalization and risk of 30-day all-cause mortality after hospital admission. DESIGN: Retrospective cohort study. SETTING: Two Boston teaching hospitals. PATIENTS OR OTHER PARTICIPANTS: We studied 4344 adults hospitalized between 1993 and 2011 who had serum 25(OH)D concentrations measured at least twice within 7-365 days before the index hospitalization. INTERVENTION(S): None. MAIN OUTCOME MEASURE(S): The exposure of interest was change in pre-hospital serum 25(OH)D concentrations. The main outcome was 30-day all-cause mortality. We used mixed-effects logistic regression to describe how 30 day mortality differed with changes in pre-hospital 25(OH)D concentrations. Additionally, the odds of 30-day mortality in patients with pre-hospital 25(OH)D increases of >=10 ng/mL was compared to that of patients with increases of <10 ng/mL. RESULTS: In a mixed-effect logistic regression model adjusted for age, gender, race, type (medical/surgical), Deyo-Charlson Index, creatinine and hematocrit, 30-day all-cause mortality rate was 8% (95%CI: 1-15) lower for each 10 ng/mL increase in pre-hospital 25(OH)D (P = 0.025) compared with the 30-day all-cause mortality rate in the entire cohort. In an adjusted logistic regression model, absolute changes of >=10 ng/mL in patients with initial 25(OH)D concentrations < 20 ng/mL (n = 1944) decreased the odds of 30-day all-cause mortality by 48% (adjusted OR 0.52; 95%CI 0.30-0.93; P = 0.026) compared to patients with changes of <10 ng/mL. CONCLUSIONS: In patients with initial 25(OH)D < 20 ng/mL, subsequent improvements in vitamin D status before hospitalization are associated with decreased odds of 30-day all-cause mortality after hospital admission. A causal relation may not be inferred from this observational study. PMID- 25935852 TI - Investigating the effects of an oral fructose challenge on hepatic ATP reserves in healthy volunteers: A (31)P MRS study. AB - BACKGROUND: Impaired homeostasis of hepatic ATP has been associated with NAFLD. An intravenous fructose infusion has been shown to be an effective challenge to monitor the depletion and subsequent recovery of hepatic ATP reserves using (31)P MRS. AIMS: The purpose of this study was to evaluate the effects of an oral rather than intravenous fructose challenge on hepatic ATP reserves in healthy subjects. METHODS: Self-reported healthy males were recruited. Following an overnight fast, baseline liver glycogen and lipid levels were measured using Magnetic Resonance Spectroscopy (MRS). Immediately after consuming a 500 ml 75 g fructose drink (1275 kJ) subjects were scanned continuously for 90 min to acquire dynamic (31)P MRS measurements of liver ATP reserves. RESULTS: A significant effect on ATP reserves was observed across the time course (P < 0.05). Mean ATP levels reached a minimum at 50 min which was markedly lower than baseline (80 +/- 17% baseline, P < 0.05). Subsequently, mean values tended to rise but did not reach statistical significance above minimum. The time to minimum ATP levels across subjects was negatively correlated with BMI (R(2) = 0.74, P < 0.005). Rates of ATP recovery were not significantly correlated with BMI or liver fat levels, but were negatively correlated with baseline glycogen levels (R(2) = 0.7, P < 0.05). CONCLUSIONS: Depletion of ATP reserves can be measured non-invasively following an oral fructose challenge using (31)P MRS. BMI is the best predictor of postprandial ATP homeostasis following fructose consumption. PMID- 25935853 TI - Short hairpin RNA- mediated gene knockdown of FOXM1 inhibits the proliferation and metastasis of human colon cancer cells through reversal of epithelial-to mesenchymal transformation. AB - BACKGROUND: The Forkhead box M1 (FOXM1) is an oncogenic transcription factor and plays a significant role in cell EMT, proliferation, metastasis in a multitude of human solid tumors including colorectal cancer (CRC). However, the underlying molecular mechanisms by which FoxM1 contributes to epithelial-to-mesenchymal (EMT) and metastasis have not been fully elucidated in CRC. METHODS: In our study, we investigated FOXM1 protein expression in 87 CRC tissue specimens, invasive lymph nodes and adjacent paired normal colorectal tissues by immunohistochemical analysis. Then we transfected FOXM1 specific shRNA into SW620 cells to examine effect of FOXM1 on proliferation, colony formation, migration and invasion in vitro. Western blotting and real-time PCR were used to detect the protein and mRNA expression of FOXM1 and EMT-related markers. RESULTS: FOXM1 was overexpressed in CRC tissues, invasive lymph nodes and CRC cell lines. FoxM1 overexpression was significantly associated with lymph node metastasis (P < 0.001), and tumor recurrence (P < 0.001). Moreover, downregulation of FOXM1 in SW620 cells by shRNA approach inhibited cell growth, clonogenicity, migration and invasion in vitro. In addition, decreased FOXM1 expression in SW620 cells reversed the acquisition of EMT phenotype by up-regulating E-cadherin, as well as reduction Vimentin and Snail expressions at protein and mRNA levels. CONCLUSIONS: FOXM1 may regulate CRC cells metastasis through EMT program and FOXM1 may be a potential target for treatment of CRC. PMID- 25935854 TI - [Bilateral subdural hematoma secondary to accidental dural puncture]. AB - We report the case of a 25-year-old woman, who received epidural analgesia for labour pain and subsequently presented post-dural puncture headache. Conservative treatment was applied and epidural blood patch was performed. In the absence of clinical improvement and due to changes in the postural component of the headache, a brain imaging test was performed showing a bilateral subdural hematoma. The post-dural puncture headache is relatively common, but the lack of response to established medical treatment as well as the change in its characteristics and the presence of neurological deficit, should raise the suspicion of a subdural hematoma, which although is rare, can be lethal if not diagnosed and treated at the right time. PMID- 25935855 TI - [Perioperative anaphylaxis]. AB - BACKGROUND AND OBJECTIVE: Anaphylaxis remains one of the potential causes of perioperative death, being generally unanticipated and quickly progressing to a life-threatening situation. A review of perioperative anaphylaxis is performed. CONTENT: The diagnostic tests are important mainly to avoid further major events. The mainstays of treatment are adrenaline and intravenous fluids. CONCLUSION: The anesthesiologist should be familiar with the proper diagnosis, management and monitoring of perioperative anaphylaxis. PMID- 25935856 TI - [Colloids versus crystalloids in objective-guided fluid therapy, systematic review and meta-analysis. Too early or too late to draw conclusions]. AB - INTRODUCTION: Several clinical trials on Goal directed fluid therapy (GDFT) were carried out, many of those using colloids in order to optimize the preload. After the decision of European Medicines Agency, there is such controversy regarding its use, benefits, and possible contribution to kidney failure. The objective of this systematic review and meta-analysis is to compare the use of last-generation colloids, derived from corn, with crystalloids, in GDFT, to determine complications and mortality associated associated. METHODS: A bibliographic research was carried out in Medline, Pubmed, Embase and Cochrane Library, corroborating randomized clinical trials in those crystalloids are compared to colloids in GDFT for mayor non-cardiac surgery in adults. RESULTS: One hundred thirty references were found, among those 38 were selected, and 29 analyzed; of these, 6 were included for systematic review and meta-analysis, including 390 patients. It was perceived that the use of colloids it not associated with the increase of complications, but rather with a tendency to a higher mortality (RR [95% IC] 3.87 [1.121, 13, 38]); I(2)=0.0%; p=0.635). CONCLUSIONES: Due to this meta-analysis' limitations for small number of randomized clinical trials and patients included, the results should be taken cautiously, and it is proposed to carry out new randomized clinical trials, with enough statistical power, comparing balanced and non-balanced colloids to balanced and non-balanced crystalloids, following the protocols of GDFT, respecting current guidelines and suggestions made by groups of experts. PMID- 25935857 TI - Outcome of primary orbital lymphoma treated with induction chemotherapy followed by conformal radiotherapy. AB - PURPOSE: To analyze the clinical outcome of primary orbital lymphoma (POL) patients treated with a combined modality approach with local radiotherapy after induction chemotherapy. METHODOLOGY: We retrospectively retrieved demographic, treatment and outcome data of patients treated for POL from 2000 to 2010. The charts were reviewed and the data were tabulated in a predesigned pro-forma. RESULTS: 23 patients of POL were found evaluable. Median age was 55 years (range 24-70 years). Of 23 patients, 15 were male and 8 female, making the male:female ratio approximately 1.9:1. Patients were thoroughly evaluated and staged. All but one patient received multi agent chemotherapy. Radiotherapy was delivered for all cases. Radiation was delivered by 3DCRT technique. Median dose of radiation was 45Gy (range 20-45Gy). Median follow up was 26.8 months. None of the patients had any evidence of local failure or systemic progression. CONCLUSION: A combined modality therapy with a combination of CHOP/COP based chemotherapy and moderate dose of radiotherapy imparts excellent long term local and systemic disease control. PMID- 25935858 TI - Breast cancer correlates in a cohort of breast screening program participants in Riyadh, KSA. AB - BACKGROUND: Breast cancer is the first cancer among females in the Kingdom of Saudi Arabia, accounting for 27.4% of all newly diagnosed female cancers in 2010. There are several risk factors affecting the incidence of breast cancer where some factors influence the risk more than the others. AIM: We aimed to identify the different risk factors related to breast cancer among females participating in the breast-screening program in Riyadh, KSA. METHODS: Based on data from phase I of the breast-screening program, a case-control study was conducted on women living in Riyadh, KSA. A sample of 349 women (58 cases and 290 controls) was recruited to examine the different breast cancer correlates. Multivariate regression model was built to investigate the most important risk factors. RESULTS: The mean age of cases was 48.5+/-7.1 years. Age at marriage, number of pregnancy, age at menopause, oral contraceptive pills, breast feeding and family history of breast cancer in first-degree relative were identified as the most important correlates among the studied cohort. CONCLUSIONS: The findings of the current work suggested that age at marriage, age at menopause ?50 years and 1st degree family history of breast cancer were risk factors for breast cancer, while, age at menopause <50 years, number of pregnancies and practicing breast feeding were protective factors against breast cancer. There was no effect of body mass index or physical inactivity. Further studies are needed to explore the hereditary, familial and genetic background risk factors in Saudi population. PMID- 25935859 TI - Predisposing factors to post-operative adhesion development. AB - BACKGROUND: Adhesion development is the most common sequelae of intra-abdominal and pelvic surgery and represents a significant, yet poorly understood, cause of morbidity among post-operative patients. It remains unclear, for example, exactly why adhesions form more frequently in certain tissues and/or patients, or at specific locations within them, as opposed to others. This review contributes to the growing knowledge pool by elucidating factors that potentially predispose to the development of adhesions. Given the strong correlation between a hypofibrinolytic state and adhesion formation, this review article will examine not only those factors that have been shown to directly predispose to adhesion development, but also those that are likely do so indirectly by means of altering the coagulation/fibrinolytic profile. METHODS: A literature search was performed using the PubMed database for all relevant English language articles up to February 2014. All of the identified articles were reviewed with particular attention to predisposing factors to post-operative adhesion development. In addition, the reference lists of each article were reviewed to identify additional relevant articles. RESULTS: Various factors have been shown to directly increase the risk of post-operative adhesion development; namely, certain genetic polymorphisms in the interleukin-1 receptor antagonist, increased estrogen exposure, and endometriosis. In addition, numerous factors are known to increase the risk of fibrosis, therefore likely increasing the risk of adhesion development indirectly. These factors include genetic polymorphisms in plasminogen activator inhibitor-1 and thrombin-activatable fibrinolysis inhibitor, diabetes mellitus, metabolic syndrome, hyperglycemia, obesity, depression, binge alcohol consumption, anti-Parkinsonian medications, oral hormone therapy, pregnancy, and cancer. CONCLUSIONS: The literature reviewed in this paper will help to direct future research aimed at understanding the mechanisms that underlie the association of certain factors with adhesion development. This information will be crucial in the creation of adequate preventative and treatment strategies. PMID- 25935860 TI - Emerging therapies in bone metastasis. AB - Skeletal lesions contribute substantially to morbidity and mortality in patients with cancer. Emerging treatments for metastatic bone disease have arisen from our understanding of the biology of bone metastases. Tumour cells alter the functions of bone-resorbing (osteoclasts) and bone-forming (osteoblasts) cells, promoting skeletal destruction. Drugs that inhibit osteoclast-mediated bone resorption (denosumab, bisphosphonates) are the standard of care for patients with skeletal metastases. In this review, we describe the progress and future directions of novel bone-targeted therapies that not only focus on osteoclasts, but also on osteoblasts and the bone microenvironment. PMID- 25935861 TI - Impacts of invading alien plant species on water flows at stand and catchment scales. AB - There have been many studies of the diverse impacts of invasions by alien plants but few have assessed impacts on water resources. We reviewed the information on the impacts of invasions on surface runoff and groundwater resources at stand to catchment scales and covering a full annual cycle. Most of the research is South African so the emphasis is on South Africa's major invaders with data from commercial forest plantations where relevant. Catchment studies worldwide have shown that changes in vegetation structure and the physiology of the dominant plant species result in changes in surface runoff and groundwater discharge, whether they involve native or alien plant species. Where there is little change in vegetation structure [e.g. leaf area (index), height, rooting depth and seasonality] the effects of invasions generally are small or undetectable. In South Africa, the most important woody invaders typically are taller and deeper rooted than the native species. The impacts of changes in evaporation (and thus runoff) in dryland settings are constrained by water availability to the plants and, thus, by rainfall. Where the dryland invaders are evergreen and the native vegetation (grass) is seasonal, the increases can reach 300-400 mm/year. Where the native vegetation is evergreen (shrublands) the increases are ~200-300 mm/year. Where water availability is greater (riparian settings or shallow water tables), invading tree water-use can reach 1.5-2.0 times that of the same species in a dryland setting. So, riparian invasions have a much greater impact per unit area invaded than dryland invasions. The available data are scattered and incomplete, and there are many gaps and issues that must be addressed before a thorough understanding of the impacts at the site scale can be gained and used in extrapolating to watershed scales, and in converting changes in flows to water supply system yields. PMID- 25935862 TI - The evolving role of toll-like receptors in diabetic vascular complications. PMID- 25935863 TI - Glucagon-like peptide 1 receptor agonist (GLP-1 RA): long-term effect on kidney function in patients with type 2 diabetes. AB - AIMS: In a short-term study including 31 patients with type 2 diabetes, glucagon like peptide 1 receptor agonist (GLP-1 RA) treatment was associated with a significant reversible decline in GFR. Twenty-three patients re-initiated GLP-1 RA treatment after the primary study, and the aim was to investigate the long term effect on kidney function. METHODS: We included 30 patients in a one-year extension study, all initially treated with liraglutide for seven weeks. During follow-up 23 were treated with liraglutide and seven untreated. Primary outcome was change in GFR ((51)Cr-EDTA plasma clearance). RESULTS: Patients were 61.5 (10.0) years and HbA(1c) 60.1 (13.8) mmol/mol. Baseline GFR was 100.6 (24.9) mL/min/1.73 m(2) and was reduced by 11 (95% CI: 6.6-15.7, p < 0.001) mL/min/1.73 m(2), independent of change in 24-h systolic blood pressure (SBP), weight, UAER or HbA(1c) (p>=0.33). Geometric mean (IQR) of UAER was 25.5 (9.9-50.9) mg/d and was reduced by 27 (95% CI: 5-44; p = 0.020)%, and 24-h SBP was reduced by 8.2 (p = 0.048) mmHg. No changes occurred in untreated patients. CONCLUSIONS: Long-term treatment with liraglutide was associated with a reduction in measured GFR similar to the effect during short-term treatment, suggesting a metabolic or haemodynamic reversible effect and not structural changes. Moreover, UAER and 24 h SBP were reduced. TRIAL REGISTRATION: ClinicalTrials.gov identifier: NCT01499108. PMID- 25935864 TI - Surgical treatment of primary mediastinal myelolipoma. AB - OBJECTIVES: Primary mediastinal myelolipoma (PMM) is a rare benign tumour composed of haematopoietic tissue and mature adipose tissue. Here, we report the largest series aiming to investigate the outcomes of surgical treatment for patients with PMM. METHODS: We retrospectively reviewed the data of 12 patients operated in a single institute during the period between April 2008 and December 2014. RESULTS: There were 7 female and 5 male patients between 54 and 73 years old (median age, 64 years). Among them, 11 patients underwent unilateral (n = 10) or bilateral (n = 1) mass resection via video-assisted thoracic surgery (VATS), and 1 patient underwent a planned open thoracotomy due to a large tumour volume. The VATS operating time ranged from 20 to 65 min (median, 30 min) and intraoperative blood loss ranged from 20 to 60 ml (median, 30 ml). The open thoracotomy operating time was 120 min, and the blood loss was 1000 ml; thus, the patient received blood transfusion (2 units of RBCs). No operative mortalities or major postoperative complications were observed. All patients experienced a regular follow-up ranging from 2 to 80 months with a median follow-up of 18 months. No recurrence was observed at the time of evaluation. CONCLUSIONS: Surgical treatment is recommended for the diagnosis and treatment of PMM, while VATS is a safe and feasible option in most cases. PMID- 25935865 TI - Maintenance of Geobacter-dominated biofilms in microbial fuel cells treating synthetic wastewater. AB - Geobacter-dominated biofilms can be selected under stringent conditions that limit the growth of competing bacteria. However, in many practical applications, such stringent conditions cannot be maintained and the efficacy and stability of these artificial biofilms may be challenged. In this work, biofilms were selected on low-potential anodes (-0.36 V vs Ag/AgCl, i.e. -0.08 V vs SHE) in minimal acetate or ethanol media. Selection conditions were then relaxed by transferring the biofilms to synthetic wastewater supplemented with soil as a source of competing bacteria. We tracked community succession and functional changes in these biofilms. The Geobacter-dominated biofilms showed stability in their community composition and electrochemical properties, with Geobacter sp. being still electrically active after six weeks in synthetic wastewater with power densities of 100+/-19 mW.m(-2) (against 74+/-14 mW.m(-2) at week 0) for all treatments. After six weeks, the ethanol-selected biofilms, despite their high taxon richness and their efficiency at removing the chemical oxygen demand (0.8 g.L(-1) removed against the initial 1.3 g.L(-1) injected), were the least stable in terms of community structure. These findings have important implications for environmental microbial fuel cells based on Geobacter-dominated biofilms and suggest that they could be stable in challenging environments. PMID- 25935866 TI - High IL-35 pleural expression in patients with tuberculous pleural effusion. AB - BACKGROUND: IL-35 is a novel anti-inflammatory and immunosuppressive cytokine primarily produced by Treg cells, and is involved in inflammatory diseases and autoimmune diseases. However, its roles in tuberculous pleural effusion (TPE) remain unknown. We aimed to investigate the potential involvement of IL-35 in TPE. MATERIAL/METHODS: Thirty TPE patients and 20 lung cancer patients with malignant pleural effusion (MPE) were recruited. Samples of pleural effusion (100 mL) were collected after traditional pleurocentesis. Blood was sampled from TPE patients. Mononuclear cells were isolated by Ficoll-Hypaque gradient. Proportions of Th1, Th17, and IL-35-producing cells were analyzed by flow cytometry. IL-35 was assessed by real-time RT-PCR, ELISA, and immunofluorescence. An ELISPOT assay was used to assess the effect of IL-35 on pleural effusion mononuclear cells (PEMCs). RESULTS: Proportions of IL-35-producing cells were higher in TPE compared with MPE (49.4+/-6.0 vs. 15.8+/-5.4%, P<0.001) and blood from TPE patients (49.4+/-6.0% vs. 16.6+/-3.1, P<0.001). IL-35, IL-17 and IFN-gamma were elevated in TPE compared with MPE (all P<0.01). ELISPOT assay showed that IL-35 reduced the proportion of IFN-gamma-producing CD4+ T cells in TPE. IL-35 mRNA expression was higher in TPE compared with MPE (P<0.001). Immunofluorescence showed that IL-35-positive cells were present in pleural tissues from TPE patients. CONCLUSIONS: Results suggest that there is an imbalance in IL-35 metabolism in TPE. However, further studies are required to assess the exact relationship with the immune system response to tuberculosis. IL-35 might play a role in TPE and might be targeted as a treatment for TPE. PMID- 25935867 TI - Strategies to intervene on causal systems are adaptively selected. AB - How do people choose interventions to learn about causal systems? Here, we considered two possibilities. First, we test an information sampling model, information gain, which values interventions that can discriminate between a learner's hypotheses (i.e. possible causal structures). We compare this discriminatory model to a positive testing strategy that instead aims to confirm individual hypotheses. Experiment 1 shows that individual behavior is described best by a mixture of these two alternatives. In Experiment 2 we find that people are able to adaptively alter their behavior and adopt the discriminatory model more often after experiencing that the confirmatory strategy leads to a subjective performance decrement. In Experiment 3, time pressure leads to the opposite effect of inducing a change towards the simpler positive testing strategy. These findings suggest that there is no single strategy that describes how intervention decisions are made. Instead, people select strategies in an adaptive fashion that trades off their expected performance and cognitive effort. PMID- 25935868 TI - Synchronization of repolarization by mechano-electrical coupling in the porcine heart. AB - AIMS: The aim of this study was to evaluate the effect of increase in left ventricular (LV) pressure on repolarization and activation-recovery intervals. METHODS AND RESULTS: Six pig hearts were Langendorff-perfused. A compliant liquid filled balloon, connected with a pressure transducer, inserted through the mitral orifice, could be filled until the required LV systolic pressure was obtained. A grid of 121 electrodes (11 * 11; 5 mm interelectrode distance) was sutured on the LV free wall. Ventricular pacing at 600 ms and at 400 or 450 ms was either performed from the LV wall or from the ventricular septum. Under all these four conditions, the pressure wave occurred at the same moment relative to the onset of the QRS complex. Consequently, the time relation between local repolarization and the pressure wave differed between the various pacing sites. Repolarization times (RTs) at a cycle length (CL) of 600 ms were prolonged by increased pressure. With stimulation from the LV, when the pressure wave coincides with the action potentials (APs) late in their phase (sites with relatively early repolarization), an increase in pressure from 0 to 100 mmHg delayed repolarization more than with stimulation from the septum, when the pressure wave occurs at a relatively earlier phase of the AP (sites with relatively late repolarization). At pacing at CL 400/450 ms, an increase in pressure caused RT prolongation at the LV free wall during LV stimulation, but less RT prolongation or even shortening during septal stimulation. CONCLUSION: The effect of increased LV pressure is synchronization of repolarization. PMID- 25935869 TI - MAb therapy against the IFN-alpha/beta receptor subunit 1 stimulates arteriogenesis in a murine hindlimb ischaemia model without enhancing atherosclerotic burden. AB - AIMS: IFN-beta (IFNbeta) signalling is increased in patients with insufficient coronary collateral growth (i.e. arteriogenesis) and IFNbeta hampers arteriogenesis in mice. A downside of most pro-arteriogenic agents investigated in the past has been their pro-atherosclerotic properties, rendering them unsuitable for therapeutic application. Interestingly, type I IFNs have also been identified as pro-atherosclerotic cytokines and IFNbeta treatment increases plaque formation and accumulation of macrophages. We therefore hypothesized that mAb therapy to inhibit IFNbeta signalling would stimulate arteriogenesis and simultaneously attenuate-rather than aggravate-atherosclerosis. METHODS AND RESULTS: In a murine hindlimb ischaemia model, atherosclerotic low-density lipoprotein receptor knockout (LDLR(-/-)) mice were treated during a 4-week period with blocking MAbs specific for mouse IFN-alpha/beta receptor subunit 1 (IFNAR1) or murine IgG isotype as a control. The arteriogenic response was quantified using laser Doppler perfusion imaging (LDPI) as well as immunohistochemistry. Effects on atherosclerosis were determined by quantification of plaque area and analysis of plaque composition. Downstream targets of IFNbeta were assessed by real-time PCR (RT-PCR) in the aortic arch. Hindlimb perfusion restoration after femoral artery ligation was improved in mice treated with anti-IFNAR1 compared with controls as assessed by LDPI. This was accompanied by a decrease in CXCL10 expression in the IFNAR1 MAb-treated group. Anti-IFNAR1 treatment reduced plaque apoptosis without affecting total plaque area or other general plaque composition parameters. Results were confirmed in a short-term model and in apolipoprotein E knockout (APOE)(-/-) mice. CONCLUSION: Monoclonal anti-IFNAR1 therapy during a 4-week treatment period stimulates collateral artery growth in mice and did not enhance atherosclerotic burden. This is the first reported successful strategy using MAbs to stimulate arteriogenesis. PMID- 25935870 TI - Thromboxane A2 induces blood flow recovery via platelet adhesion to ischaemic regions. AB - AIMS: Thromboxane A2 (TXA2) induces platelet adhesion through thromboxane prostanoid (TP) receptor. Platelets contain many pro-angiogenic factors and are recruited to the site of vascular injury. However, the cellular and molecular mechanisms of platelet-dependent angiogenesis, especially the involvement of TP signalling, have not been fully elucidated. The present study hypothesized that TP-dependent platelet adhesion would contribute to angiogenesis in a mouse hindlimb ischaemic model. METHODS AND RESULTS: Blood flow recovery was suppressed by the TXA2 receptor antagonist (S-1452) and the TXA2 synthase inhibitor (OKY 046) compared with control mice. TP knockout mice (TP(-/-)) showed delayed blood flow recovery from ischaemia and impaired angiogenesis compared with wild-type (WT) mice and prostacyclin receptor knockout mice (IP(-/-)). Selective platelet adhesion to ischaemic endothelial cells (ECs) via P-selectin was identified in WT and IP(-/-), but not in TP(-/-), via in vivo microscopy. IF analysis showed that P-selectin glycoprotein ligand-1 (PSGL-1) co-localized with endothelial CD31 in ischaemic muscle in WT and IP(-/-) but not diminished in TP(-/-). Platelet-rich plasma levels of stromal cell-derived factor-1 and VEGF were increased after ischaemia in WT, and suppressed by antibody against P-selectin in WT but not in TP(-/-). Furthermore, the blood flow recovery was suppressed by neutralizing antibodies against VEGF or C-X-C chemokine receptor type 4 in WT and IP(-/-) but not in TP(-/-). CONCLUSION: These results indicated that TP signalling facilitates ischaemia-induced angiogenesis via P-selectin-mediated platelet adhesion to PSGL-1 on the ECs at ischaemic sites and the supply of pro-angiogenic factors by the adherent platelets. PMID- 25935871 TI - The magnitude of injury problems among child labourers in a rural community of Bangladesh: findings from an injury surveillance system. AB - BACKGROUND: Child labour is an important topic in contemporary society. In this study we have tried to explore the magnitude of injury problems among child labourers in Bangladesh using an injury surveillance system. METHODS: An injury surveillance system (ISS) was performed under the Prevention of Child Injuries through Social intervention and Education (PRECISE) project in Bangladesh during 2006-2010 in three sub-districts covering a population of more than 700,000. We used the ISS for assessing child labour. Appropriate epidemiological methods were considered in the study. RESULTS: Considering the reported main occupation of the children, 30% of children from the surveillance households were identified as child labourers. More than two thirds of child labourers were educated to primary or secondary level. The majority of boys worked as unskilled labourers and girls were employed in domestic work. The incidence of injury and deaths among child labourers was estimated as 24 per 100,000 children years. More than 19 injury related illnesses of moderate to severe intensity were found among 1000 child labourers in a year. Fractures, sprains, dislocations, cuts/wounds, animal bites, abrasions or lacerations, burns, head injuries and internal organ injuries are most common among child labourers. CONCLUSIONS: Working children are at risk of injury, death and illness in Bangladesh. Child labourers are now even more clearly tied to quantified morbidity and mortality. PMID- 25935872 TI - Selecting the minimum prediction base of historical data to perform 5-year predictions of the cancer burden: The GoF-optimal method. AB - BACKGROUND: Predicting the future burden of cancer is a key issue for health services planning, where a method for selecting the predictive model and the prediction base is a challenge. A method, named here Goodness-of-Fit optimal (GoF optimal), is presented to determine the minimum prediction base of historical data to perform 5-year predictions of the number of new cancer cases or deaths. METHODS: An empirical ex-post evaluation exercise for cancer mortality data in Spain and cancer incidence in Finland using simple linear and log-linear Poisson models was performed. Prediction bases were considered within the time periods 1951-2006 in Spain and 1975-2007 in Finland, and then predictions were made for 37 and 33 single years in these periods, respectively. The performance of three fixed different prediction bases (last 5, 10, and 20 years of historical data) was compared to that of the prediction base determined by the GoF-optimal method. The coverage (COV) of the 95% prediction interval and the discrepancy ratio (DR) were calculated to assess the success of the prediction. RESULTS: The results showed that (i) models using the prediction base selected through GoF-optimal method reached the highest COV and the lowest DR and (ii) the best alternative strategy to GoF-optimal was the one using the base of prediction of 5-years. CONCLUSIONS: The GoF-optimal approach can be used as a selection criterion in order to find an adequate base of prediction. PMID- 25935874 TI - 3D anatomy and deformation of the seated buttocks. AB - AIM: To describe the 3D anatomy and deformation of the buttocks during sitting. MATERIALS AND METHODS: The buttocks of 4 able-bodied individuals and 3 individuals with spinal cord injury were scanned sitting in a FONAR Upright MRI. T1-weighted Fast Spin Echo scans were collected with the individuals seated on a custom wheelchair cushion to unload the ischial tuberosities (ITs) and seated on a 3 inch foam cushion. Multi-planar scans were analyzed, and the muscle, bone and adipose tissue was manually segmented for 3D rendering and analysis of the quantity, geometry, and location of tissues. RESULTS: The gluteus maximus was positioned lateral and posterior to the IT, covering the inferior portion of the IT for only 2 able-bodied participants. Adipose thickness directly under the IT did not differ by diagnosis, nor did it have a consistent response to loading. However, the envelopment of the IT by the surrounding adipose tissue was much greater in two of the participants with spinal cord injuries. These two subjects also had the most curved skin surface as the tissue wrapped around the IT. Tissue strains around the ischium were most visible in the adipose and connective tissue. The gluteus maximus displaced and distorted upwards, posterior and lateral, away from the inferior IT. CONCLUSIONS: Multi-planar imaging is necessary to investigate anatomy and deformation of the buttocks. 5 out of 7 participants did not sit directly on muscle. The tissue beneath their ITs was predominantly composed of fat and connective tissue, suggesting that these tissues might be most vulnerable to injury. PMID- 25935873 TI - Alternative modulation of protein-protein interactions by small molecules. AB - Protein-protein interactions (PPI) have become increasingly popular drug targets, with a number of promising compounds currently in clinical trials. Recent research shows, that PPIs can be modulated in more ways than direct inhibition, where novel non-competitive modes of action promise a solution for the difficult nature of PPI drug discovery. Here, we review recently discovered PPI modulators in light of their mode of action and categorise them as disrupting versus stabilising, orthosteric versus allosteric and by their ability to affect the proteins' dynamics. We also give recent examples of compounds successful in the clinic, analyse their physicochemical properties and discuss how to overcome the hurdles in discovering alternative modes of modulation. PMID- 25935875 TI - Effect of genetic variations on ticagrelor plasma levels and clinical outcomes. AB - AIMS: Ticagrelor, a direct-acting P2Y12-receptor antagonist, is rapidly absorbed and partly metabolized to the major metabolite AR-C124910XX (ARC). To identify single-nucleotide polymorphisms (SNPs) associated with pharmacokinetics of ticagrelor and clinical outcomes, we performed a genome-wide association study (GWAS) in patients treated with ticagrelor in the PLATO trial. METHODS AND RESULTS: A two-stage design was used for the GWAS with discovery (discovery phase: n = 1812) and replication cohorts (replication phase: n = 1941). The steady-state area under the curve (AUCss) values, estimated by the population pharmacokinetic (PK) models, were log transformed and analysed on a genome-wide scale using linear regression. SNPs were analysed against clinical events using Cox-regression in 4990 patients. An SNP (rs113681054) in SLCO1B1 was associated with levels of ticagrelor (P = 1.1 * 10(-6)) and ARC (P = 4.6 * 10(-13)). This SNP is in linkage disequilibrium with a functional variant (rs4149056) that results in decreased OATP1B1 transporter activity. Ticagrelor levels were also associated with two independent SNPs (rs62471956, P = 7.7 * 10(-15) and rs56324128, P = 9.7 * 10(-12)) in the CYP3A4 region. Further, ARC levels were associated with rs61361928 (P = 3.0 * 10(-14)) in UGT2B7. At all loci, the effects were small. None of the identified SNPs that affected ticagrelor PK were associated with the primary composite outcome (cardiovascular death myocardial infarction, and stroke), non-CABG-related bleeds or investigator-reported dyspnoea. CONCLUSION: In patients with ACS, ticagrelor pharmacokinetics is influenced by three genetic loci (SLCO1B1, UGT2B7, and CYP3A4). However, the modest genetic effects on ticagrelor plasma levels did not translate into any detectable effect on efficacy or safety during ticagrelor treatment. CLINICAL TRIAL REGISTRATION: NCT00391872. PMID- 25935876 TI - The detection and treatment of subclinical atrial fibrillation: evaluating the IMPACT of a comprehensive strategy based on remote arrhythmia monitoring. PMID- 25935878 TI - How e-biking can boost cardiovascular health. PMID- 25935877 TI - Marfan Sartan: a randomized, double-blind, placebo-controlled trial. AB - AIMS: To evaluate the benefit of adding Losartan to baseline therapy in patients with Marfan syndrome (MFS). METHODS AND RESULTS: A double-blind, randomized, multi-centre, placebo-controlled, add on trial comparing Losartan (50 mg when <50 kg, 100 mg otherwise) vs. placebo in patients with MFS according to Ghent criteria, age >10 years old, and receiving standard therapy. 303 patients, mean age 29.9 years old, were randomized. The two groups were similar at baseline, 86% receiving beta-blocker therapy. The median follow-up was 3.5 years. The evolution of aortic diameter at the level of the sinuses of Valsalva was not modified by the adjunction of Losartan, with a mean increase in aortic diameter at the level of the sinuses of Valsalva of 0.44 mm/year (s.e. = 0.07) (-0.043 z/year, s.e. = 0.04) in patients receiving Losartan and 0.51 mm/year (s.e. = 0.06) (-0.01 z/year, s.e. = 0.03) in those receiving placebo (P = 0.36 for the comparison on slopes in millimeter per year and P = 0.69 for the comparison on slopes on z scores). Patients receiving Losartan had a slight but significant decrease in systolic and diastolic blood pressure throughout the study (5 mmHg). During the study period, aortic surgery was performed in 28 patients (15 Losartan, 13 placebo), death occurred in 3 patients [0 Losartan, 3 placebo, sudden death (1) suicide (1) oesophagus cancer (1)]. CONCLUSION: Losartan was able to decrease blood pressure in patients with MFS but not to limit aortic dilatation during a 3 year period in patients >10 years old. beta-Blocker therapy alone should therefore remain the standard first line therapy in these patients. PMID- 25935879 TI - The radiation reduction methods in imaging need more attention. PMID- 25935880 TI - The association between smoking cessation and glycaemic control in patients with type 2 diabetes: a THIN database cohort study. AB - BACKGROUND: Smoking increases the risk of developing type 2 diabetes. However, several population studies also show a higher risk in people 3-5 years after smoking cessation than in continuing smokers. After 10-12 years the risk equates to that of never-smokers. Small cohort studies suggest diabetes control deteriorates temporarily during the first year after quitting. We examined whether or not quitting smoking was associated with altered diabetes control in a population study, for how long this association persisted, and whether or not this association was mediated by weight change. METHODS: We did a retrospective cohort study (Jan 1, 2005, to Dec 31, 2010) of adult smokers with type 2 diabetes using The Health Improvement Network (THIN), a large UK primary care database. We developed adjusted multilevel regression models to investigate the association between a quit event, smoking abstinence duration, change in HbA1c, and the mediating effect of weight change. FINDINGS: 10 692 adult smokers with type 2 diabetes were included. 3131 (29%) quit smoking and remained abstinent for at least 1 year. After adjustment for potential confounders, HbA1c increased by 0.21% (95% CI 0.17-0.25; p<0.001; [2.34 mmol/mol (95% CI 1.91-2.77)]) within the first year after quitting. HbA1c decreased as abstinence continued and became comparable to that of continual smokers after 3 years. This increase in HbA1c was not mediated by weight change. INTERPRETATION: In type 2 diabetes, smoking cessation is associated with deterioration in glycaemic control that lasts for 3 years and is unrelated to weight gain. At a population level, this temporary rise could increase microvascular complications. FUNDING: National Institute for Health Research School for Primary Care Research. PMID- 25935881 TI - Smoking and diabetes: strengthening causal inference. PMID- 25935882 TI - Jailing of a Pacemaker Lead During Tricuspid Valve-in-Valve Implantation With an Edwards SAPIEN XT Transcatheter Heart Valve. PMID- 25935883 TI - Right ventricular hypertrophy is associated with cardiovascular events in hypertrophic cardiomyopathy: evidence from study with magnetic resonance imaging. AB - BACKGROUND: Although left ventricular (LV) morphology and function have been well studied in hypertrophic cardiomyopathy (HCM), few data exist regarding the right ventricle. Accordingly, we studied right ventricular (RV) morphology and function and their effect on cardiovascular events in HCM using cardiac magnetic resonance (CMR) imaging. METHODS: This retrospective study included 106 HCM patients (age 61.6 +/- 14.5 years) examined using CMR imaging during January 2008 to September 2014. RV hypertrophy (RVH) was defined as RV maximal wall thickness > 5 mm. RESULTS: RVH was observed in 30 of the 106 patients (RVH group), with the remaining 76 patients assigned to the non-RVH group. The RVH group had higher brain natriuretic peptide levels (461.6 +/- 699.8 pg/mL vs. 225.3 +/- 254.5 pg/mL; P = 0.01) and also showed a reduced RV end-diastolic volume index (43.4 +/ 16.0 mL/m2 vs. 56.6+/-15.2 mL/m2; P = 0.0001), in keeping with a greater LV mass index (109.1 +/- 24.9 g/m2 vs. 78.6 +/- 23.0 g/m2; P < 0.0001). The RVH group was prominently associated with RV late gadolinium enhancement compared with the non RVH group (33.3% vs. 0%; P < 0.0001). After CMR imaging, 15 patients developed cardiovascular events that included admission for heart failure, ventricular tachyarrhythmia/fibrillation, stroke, and sudden cardiac death. Cox proportional hazard analysis revealed that RVH was an independent predictor of the occurrence of cardiovascular events after adjustments by sex, age, LV mass index, LV ejection fraction, and LV outflow tract obstruction (hazard ratio, 5.42; 95% confidence interval, 1.16-25.3; P = 0.03). CONCLUSIONS: These results suggest that HCM patients with RVH on CMR images have a greater incidence of cardiovascular events than non-RVH patients. Further work is needed to confirm this observation and assess its clinical importance. PMID- 25935884 TI - Effects of transcutaneous aortic valve implantation on aortic valve disease related hemostatic disorders involving von Willebrand factor. AB - BACKGROUND: Aortic valve stenosis (AVS) can be complicated by bleeding associated with acquired type 2A von Willebrand syndrome. The association of AVS and gastrointestinal bleeding from angiodysplasia is defined as Heyde syndrome. We sought to evaluate the effect of transcutaneous aortic valve implantation (TAVI) on hemostasis disorders and to assess its effectiveness to treat Heyde syndrome. METHODS: We prospectively enrolled 49 consecutive patients with severe AVS addressed for TAVI at our institution. Biological hemostasis parameters involving von Willebrand factor (vWF) were assessed at baseline and 1 week after the procedure. RESULTS: At baseline, a significant link between vWF abnormalities and the severity of AVS was evidenced: mean aortic transvalvular gradient was negatively correlated with the levels of vWF antigen (vWF:Ag) (r = -0.29; P < 0.05), vWF ristocetin cofactor activity (r = -0.402; P = 0.006), and vWF collagen binding activity (vWF:CB; r = -0.441; P = 0.005). One week after the procedure, a significant increase of vWF:Ag, vWF ristocetin cofactor activity, and vWF:CB was evidenced in the whole cohort (respectively, 3.32 vs. 2.29 IU/mL, P < 0.001; 2.98 vs. 1.86 IU/mL, P < 0.001; and 3.16 vs. 2.16 IU/mL, P < 0.001). Patients with pre TAVI vWF abnormalities consistent with a type 2A vWF syndrome (ratio vWF:CB/vWF:Ag < 0.7) preferentially improved their vWF function with respect to patients with a normal ratio (relative increase of vWF:CB of 63.8% vs. 3.5%). CONCLUSIONS: Hemostasis parameters involving vWF are improved after TAVI, especially in patients with pre-existing abnormalities consistent with acquired type 2A von Willebrand syndrome. PMID- 25935885 TI - Global longitudinal strain may identify preserved systolic function of the systemic right ventricle. AB - BACKGROUND: Assessment of systemic right ventricle (RV) function is a key point in the follow-up of patients with dextroposition of the great arteries (D-TGA) after the atrial switch procedure. Cardiac magnetic resonance (CMR) is considered the reference standard but is not feasible for a considerable number of patients. Experience with the application of 2-dimensional speckle tracking echocardiography for the assessment of systemic RV function in such patients is very limited, and the cutoff strain value differentiating normal and subnormal RV function is missing. METHODS: We prospectively examined, with echocardiography and CMR, 40 patients with D-TGA (mean age, 25.6 +/- 5 years; 25 men; 33 after the Senning, 7 after the Mustard procedure) who attended a tertiary adult congenital heart disease centre. RESULTS: There was a linear correlation between global longitudinal strain (GLS) and CMR systemic RV ejection fraction (EF) values (r = 0.4; P = 0.01), systemic RV fractional area change and CMR systemic RV EF (r = 0.41; P = 0.008). There was no correlation between systemic RV s', tricuspid annular plane systolic excursion or the rate of change of the systemic RV pressure with time and CMR systemic RV EF. Only 1 of 19 patients with GLS < 14.2% had CMR systemic RV EF < 45%. The GLS cutoff value of -14.2% predicted the CMR systemic RV EF of >= 45% with 90% specificity and 83% sensitivity. Its positive predictive value was 96%. CONCLUSIONS: The systemic RV GLS is able to discriminate between D-TGA patients after the atrial switch with, and those without, a CMR systemic RV EF of at least 45%. PMID- 25935886 TI - Using the CHA2DS2-VASc Score for Stroke Prevention in Atrial Fibrillation: A Focus on Vascular Disease, Women, and Simple Practical Application. PMID- 25935887 TI - Mortality in multiple sclerosis: meta-analysis of standardised mortality ratios. AB - OBJECTIVE: There are inconsistent data on mortality in people with multiple sclerosis (MS). We performed a meta-analysis of all-cause, cause-specific and gender-specific crude mortality rates (CMRs), and standardised mortality ratios (SMRs) in MS, and estimated the rate of change of CMR and SMR over the past 50 years. METHODS: Medline, Embase and the Cochrane Library were searched. KEYWORDS: 'Multiple Sclerosis' and ('standardised mortality' or 'standardized mortality'). INCLUSION CRITERIA: availability of data on the number of deaths; mean or median patient follow-up or reports of SMRs; being a longitudinal study. 12 studies were included covering the period 1949-2012 (27 423 patients; 6628 deaths; 437 832 person-years follow-up). CMR was calculated. SMRs were extracted. CMRs and natural logarithm of SMRs were pooled by the method of the inverse of the variance. Meta-regression models were used to investigate the secular trends. RESULTS: Pooled CMR was 9.78/1000 person-years (95% CI 6.81 to 14.02). Pooled all cause SMR was 2.80 (95% CI 2.74 to 2.87). All-cause SMR was 2.56 (95% CI 2.47 to 2.66) in males and 3.06 (95% CI 2.97 to 3.17) in females. SMR due to cancer was 0.89 (95% CI 0.83 to 0.97). SMRs due to cardiovascular diseases, suicide, infection and respiratory diseases were 1.29 (95% CI 1.20 to 1.38), 2.13 (95% CI 1.80 to 2.51) and 2.91 (95% CI 2.60 to 3.26). There was no trend in CMRs, all cause, and gender-specific SMRs. CONCLUSIONS: The excess mortality in MS relative to the general population has not changed over the past 50 years. Female patients with MS have higher survival disadvantage compared to that of males. Death due to cardiovascular diseases, suicide and infection is higher in patients with MS compared to the general population. PMID- 25935888 TI - Chronological changes of 123I-MIBG myocardial scintigraphy and clinical features of Parkinson's disease. AB - OBJECTIVES: The aim of this study was to investigate chronological changes of (123)I-meta-iodobenzylguanidine (MIBG) myocardial scintigraphy and its relation to clinical features in patients with Parkinson's disease (PD), and to characterise patients with PD with normal or mildly low MIBG uptakes at their early stages. METHODS: The participants were 70 patients with PD who underwent (123)I-MIBG myocardial scintigraphy twice or more. A cluster analysis was performed using parameters calculated from heart to mediastinum (H/M) ratio and washout ratio (WR). RESULTS: At baseline, the mean early H/M ratio (H/M(E)), delayed H/M ratio (H/M(D)) and WR were 1.83, 1.69 and 41.7%, respectively. After a mean interval of 3.0 years, follow-up studies showed significantly declined H/M(E) (1.69, p<0.001), declined H/M(D) (1.47, p<0.001) and enhanced WR (43.8%, p=0.007). Our longitudinal observations revealed that there existed heterogeneous changes in MIBG uptakes among patients. The cluster analysis classified the patients into two subgroups: 42 patients with markedly low MIBG uptakes at baseline (group A) and 28 patients with normal or mildly low MIBG uptakes at baseline (group B). Group B showed a significantly higher ratio of females, younger age at onset, lower Hoehn and Yahr stage and less demented, compared with group A. CONCLUSIONS: Follow-up studies of MIBG divided the patients with PD into two major subgroups. A subgroup of patients with PD with normal or mildly low MIBG uptakes at the early stages of illness was characterised by female-dominant, young onset, slow progression in motor dysfunctions and preserved cognitive function. TRIAL REGISTRATION NUMBER: 1033. PMID- 25935889 TI - Post-stroke fatigue: new evidence of a possible biological cause. PMID- 25935890 TI - Predictors for being offered epilepsy surgery: 5-year experience of a tertiary referral centre. AB - OBJECTIVES: To define factors that predict whether patients with pharmacoresistant focal epilepsy are offered epilepsy surgery (including invasive EEG) and the main reasons for not proceeding with these after non-invasive presurgical evaluation. METHODS: We retrospectively analysed data from 612 consecutive patients with focal epilepsy admitted to a video-EEG Telemetry Unit for presurgical evaluation, and used a multivariate logistic regression model to assess the predictive value of factors for being offered potentially curative surgery. RESULTS: In the multivariate analysis, bilateral lesions on MRI (OR: 0.10; 95% CI 0.03 to 0.24), no lesion (OR: 0.33; 95% CI 0.22 to 0.49) or extratemporal lobe epilepsy (OR: 0.30; 95% CI 0.20 to 0.45) were the only factors that significantly reduced the probability of being offered surgery. 32% of patients who were offered epilepsy surgery decided against proceeding. CONCLUSIONS: There was a low chance (<10%) of being offered surgery if there were bilateral lesions on MRI and extratemporal lobe epilepsy. Patients should be given advice on the risk/benefit ratio and of realistic outcomes of epilepsy surgery; this may help reduce the number of patients who refuse surgery after comprehensive workup. PMID- 25935891 TI - Quantitative correlation between cardiac MIBG uptake and remaining axons in the cardiac sympathetic nerve in Lewy body disease. AB - OBJECTIVES: Reduced cardiac meta-iodobenzylguanidine (MIBG) uptake and loss of cardiac sympathetic axons, as its possible anatomical substrate, were both recognised in Lewy body disease (LBD), while their direct correlation has so far remained speculative. Increasing availability of autopsy-confirmed cases of LBD prompted us to quantify residual cardiac sympathetic axons to establish their relationship to cardiac MIBG uptake. METHODS: We collected cardiac tissue samples from 23 patients with autopsy-confirmed LBD and two non-LBD control patients who underwent (123)I-MIBG cardiac scintigraphy in life. Samples of the left ventricular anterior wall were stained with anti-tyrosine hydroxylase (TH) and anti-neurofilament (NF) antibodies as markers of cardiac nerve axons. We quantified the immunolabelled areas and assessed their correlation to standardised heart to mediastinum (H/M) ratios of (123)I-MIBG cardiac scintigraphy. RESULTS: Cardiac MIBG uptake in the early and delayed phases was reduced in 90.9% and 95.7% of patients with LBD, respectively. The area of TH immunoreactive axons correlated significantly with the H/M ratio in the early (p=0.036) as well as in the delayed (p=0.018) phases. The area of NF immunoreactive axons also correlated with the H/M ratio in the early (p=0.003) as well as in the delayed (p=0.001) phases. CONCLUSIONS: Tight quantitative correlation between cardiac (123)I-MIBG uptake and corresponding loss of sympathetic axons in LBD, as established for the first time by this study, provides a scientific basis to confirm the reliability of MIBG cardiac scintigraphy as a powerful clinical tool to detect loss of these axons as a biomarker for the presence of Lewy body disease. PMID- 25935892 TI - Tracking motor neuron loss in a set of six muscles in amyotrophic lateral sclerosis using the Motor Unit Number Index (MUNIX): a 15-month longitudinal multicentre trial. AB - BACKGROUND: Motor Unit Number Index (MUNIX) is a novel neurophysiological measure that provides an index of the number of functional lower motor neurons in a given muscle. So far its performance across centres in patients with amyotrophic lateral sclerosis (ALS) has not been investigated. OBJECTIVE: To perform longitudinal MUNIX recordings in a set of muscles in a multicentre setting in order to evaluate its value as a marker of disease progression. METHODS: Three centres applied MUNIX in 51 ALS patients over 15 months. Six different muscles (abductor pollicis brevis, abductor digiti minimi, biceps brachii, tibialis anterior, extensor dig. brevis, abductor hallucis) were measured every 3 months on the less affected side. The decline between MUNIX and ALSFRS-R was compared. RESULTS: 31 participants reached month 12. For all participants, ALSFRS-R declined at a rate of 2.3%/month. Using the total score of all muscles, MUNIX declined significantly faster by 3.2%/month (p <= 0.02). MUNIX in individual muscles declined between 2.4% and 4.2%, which differed from ASLFRS-R decline starting from month 3 (p <= 0.05 to 0.002). Subgroups with bulbar, lower and upper limb onset showed different decline rates of ALSFRS-R between 1.9% and 2.8%/month, while MUNIX total scores showed similar decline rates over all subgroups. Mean intraclass correlation coefficient for MUNIX intra-rater reliability was 0.89 and for inter-rater reliability 0.80. CONCLUSION: MUNIX is a reliable electrophysiological biomarker to track lower motor neuron loss in ALS. PMID- 25935894 TI - Symptomatic Pneumorrhachis After an Epidural Blood Patch. AB - BACKGROUND: Pneumorrhachis (PR), the presence of air within the spinal canal, is a rare, radiologic epiphenomenon arising from traumatic, nontraumatic, and iatrogenic causes. Often asymptomatic, PR is usually managed conservatively. However, PR can be associated with underlying serious pathology and can become symptomatic, requiring more aggressive diagnostic and treatment modalities from the treating physician. Although well known in the anesthesia literature, this case report is the first in the emergency medicine literature to describe iatrogenic, symptomatic PR presenting in the emergency department (ED). CASE REPORT: A 34-year-old woman presented to the ED with a postural puncture headache after epidural anesthesia for a vaginal delivery. An epidural blood patch was administered, after which the patient acutely developed cervical radicular pain. Computed tomography angiography of the head and neck revealed epidural PR. Conservative treatment with analgesia, intravenous fluids, and bed rest was administered. Her pain improved significantly, and at 5-month follow-up, she remained symptom-free. WHY SHOULD AN EMERGENCY PHYSICIAN BE AWARE OF THIS?: PR is a rare and usually benign disease, especially in the setting of an iatrogenic cause such as lumbar puncture. However, in traumatic settings, PR in the intradural space should alert the emergency physician to search for underlying serious pathology if it has not already been found. Finally, PR can become symptomatic, and treatment will depend on the severity of symptoms. PMID- 25935893 TI - Hereditary leukoencephalopathy with axonal spheroids: a spectrum of phenotypes from CNS vasculitis to parkinsonism in an adult onset leukodystrophy series. AB - BACKGROUND: Hereditary diffuse leukoencephalopathy with neuroaxonal spheroids (HDLS) is a hereditary, adult onset leukodystrophy which is characterised by the presence of axonal loss, axonal spheroids and variably present pigmented macrophages on pathological examination. It most frequently presents in adulthood with dementia and personality change. HDLS has recently been found to be caused by mutations in the colony stimulating factor-1 receptor (CSF1R) gene. METHODS: In this study, we sequenced the CSF1R gene in a cohort of 48 patients from the UK, Greece and Ireland with adult onset leukodystrophy of unknown cause. RESULTS: Five pathogenic mutations were found, including three novel mutations. The presentations ranged from suspected central nervous system (CNS) vasculitis to extrapyramidal to cognitive phenotypes. The case histories and imaging are presented here, in addition to neuropathological findings from two cases with novel mutations. CONCLUSION: We estimate that CSF1R mutations account for 10% of idiopathic adult onset leukodystrophies and that genetic testing for CSF1R mutations is essential in adult patients presenting with undefined CNS vasculitis or a leukodystrophy with prominent neuropsychiatric signs or dementia. PMID- 25935895 TI - Lipopolysaccharides, cytokines, and nitric oxide affect secretion of prostaglandins and leukotrienes by bovine mammary gland during experimentally induced mastitis in vivo and in vitro. AB - The aim of the study was to determine the effects of lipopolysaccharide (LPS), tumor necrosis factor alpha (TNF), interleukin-1-alpha (IL-1alpha), and nitric oxide donor (NONOate) on both in vivo and in vitro secretion of prostaglandin (PG)E2, PGF2alpha, leukotriene (LT)B4, and LTC4 by the bovine mammary gland. In the first experiment, tissues isolated from the teat cavity and lactiferous sinus were treated in vitro with LPS (10 ng/mL), TNF (10 ng/mL), IL-1alpha (10 ng/mL), NONOate (10(-4) M), and the combination of TNF + IL-1alpha + NONOate for 4 or 8 h. PGE2 or PGF2alpha secretion was stimulated by all treatments (P < 0.05) excepting NONOate alone, which did not stimulate PGF2alpha secretion. Moreover, all factors increased LTB4 and LTC4 secretion (P < 0.05). In the second experiment, mastitis was experimentally mimicked in vivo by repeated (12 h apart) intramammary infusions (5 mL) of (1) sterile saline; (2) 250-MUg LPS; (3) 1 MUg/mL TNF; (4) 1-MUg/mL IL-1alpha; (5) 12.8-MUg/mL NONOate; and (6) TNF + IL 1alpha + NONOate into 2 udder quarters. All infused factors changed PGE2, 13,14 dihydro,15-keto-PGF2alpha, and LT concentrations in blood plasma collected from the caudal vena cava, the caudal superficial epigastric (milk) vein, the jugular vein, and the abdominal aorta (P < 0.05). In summary, LPS and other inflammatory mastitis mediators modulate PG and LT secretion by bovine mammary gland in both in vivo and in vitro studies. PMID- 25935897 TI - Randomized test of a brief psychological intervention to reduce and prevent emotional eating in a community sample. AB - BACKGROUND: Emotional eating is associated with mental health problems and weight gain, but research has focussed on treatment rather than prevention. The present research tests a brief theory-based psychological intervention to reduce and prevent emotional eating in a community sample. METHODS: Two hundred and forty women were randomized to a control condition in which they were asked to identify emotional eating triggers and strategies for change (a 'volitional help sheet') or to an experimental condition in which they were asked explicitly to use the volitional help sheet to link emotional eating triggers with strategies for change and so form implementation intentions. RESULTS: Results showed that eating in response to boredom was more common than eating in response to anxiety or depression. There was a significant condition * time interaction showing that the formation of implementation intentions resulted in significantly lower levels of emotional eating in response to boredom at follow-up (d = 0.29). CONCLUSIONS: The intervention shows promise in reducing and preventing emotional eating, but further research is required to refine the tool and to examine whether eating in response to anxiety or depression is more common among clinical populations. PMID- 25935896 TI - The relationship between changes in sitting time and mortality in post-menopausal US women. AB - BACKGROUND: Prolonged sitting is linked to various deleterious health outcomes. The alterability of the sitting time (ST)-health relationship is not fully established however and warrants study within populations susceptible to high ST. METHODS: We assessed the mortality rates of post-menopausal women from the Women's Health Initiative (WHI) observational study, a 15-year prospective study of post-menopausal women aged 50-79 years, according to their change in ST between baseline and year six. A total of 77 801 participants had information at both times on which to be cross-classified into the following: (i) high ST at baseline and follow-up; (ii) low ST at baseline and follow-up; (iii) increased ST and (iv) decreased ST. Cox regression was used to assess the relationship between all-cause, CVD and cancer mortality with change in ST. RESULTS: At the end of follow-up, there were 1855 deaths. Compared with high ST maintainers, low ST maintainers had a 51 and 48% lower risk of all-cause and cancer mortality, respectively. Reducing sitting also resulted in a protective rate of 29% for all cause and 27% for cancer mortality. CONCLUSIONS: These results highlight not only the benefit of maintaining minimal ST, but also the utility of decreasing ST in older women, if current levels are high. PMID- 25935898 TI - Evaluation of the proposed International Association for the Study of Lung Cancer (IASLC)/International Thymic Malignancies Interest Group (ITMIG) staging revisions in thymic well-differentiated neuroendocrine carcinoma patients. AB - OBJECTIVES: In 2014, the International Association for the Study of Lung Cancer (IASLC)/International Thymic Malignancies Interest Group (ITMIG) launched a worldwide Tumor Node Metastasis (TNM) staging proposal for the next edition of thymic tumours. The objective of the current study was to evaluate the proposed new staging system specific to the thymic well-differentiated neuroendocrine carcinoma (TWDNC). METHODS: From November 2003 to July 2014, 61 consecutive patients were enrolled in this study with pathologically confirmed TWDNC in Shanghai Chest Hospital. Clinical and pathological data were retrospectively reviewed. Survival analysis was performed using the Kaplan-Meier and log-rank tests. Validity evaluation was addressed by Cox proportional hazards regression model, after adjusting for potential confounders and visually assessing the distinction of curves generated based on the staging system of Masaoka-Koga and the proposed TNM ones. RESULTS: Thymic carcinoids made up 4% of total thymic tumours in our institution. The 5-year overall survival (OS) rate and the disease free survival (DFS) rate were 72 and 41%, respectively. Neither Masaoka-Koga staging system nor the proposed TNM system showed ordered appropriateness visually in survival curves and the prognostic demarcation between stages was poor on both OS and DFS. CONCLUSIONS: The IASLC/ITMIG suggested that the TNM and Masaoka-Koga staging systems fail to predict the clinical course of TWDNC patients. Collaborative effort is needed in the future staging validation as ITMIG recommended. PMID- 25935899 TI - Postinfarction ventricular septal defect secondary to infective endocarditis. PMID- 25935900 TI - Trans-pericardial penetration in a stab injury to the chest. PMID- 25935901 TI - THE STORM (acute coronary Syndrome in paTients end Of life and Risk assesMent) study. AB - INTRODUCTION: Elderly patients with coexisting frailty and multiple comorbidities frequently present to the emergency department (ED). Because non-cardiovascular comorbidities and declining health status may affect their life expectancy, management of these patients should start in the ED. This study evaluated the role of Gold Standards Framework (GSF) criteria for identifying patients with acute coronary syndromes (ACS) approaching end of life. METHODS: All consecutive patients admitted to the ED and hospitalised with a diagnosis of ACS between May 2012 and July 2012 were included. According to GSF criteria, patients were labelled as positive GSF status when they met at least one general criterion and two heart disease criteria; furthermore, traditional cardiovascular risk scores (the Global Registry for Acute Coronary Events (GRACE) score and the Age, Creatinine and Ejection Fraction (ACEF) score) were calculated and WHOQOL-BREF was assessed. Mortality and repeat hospitalisation due to cardiovascular and non cardiovascular causes were evaluated at 3-month and 12-month follow-up. RESULTS: From a total of 156 patients with ACS enrolled, 22 (14%) had a positive GSF. A positive GSF was associated with higher rate of non-cardiovascular events (22.7% vs 6.7%; p=0.03) at 3 months and higher rates of both cardiovascular and non cardiovascular events (36% vs 16.4%; p=0.04 and 27.3% vs 6.7%; p=0.009, respectively) at 12 months. In multivariate analysis, an in-hospital GRACE score was a predictor of cardiovascular events, while a positive GSF independently predicted non-cardiovascular events. CONCLUSIONS: The GSF score independently predicts non-cardiovascular events in patients presenting with ACS and may be used along with traditional cardiovascular risk scores in choosing wisely the most appropriate treatment. The present results need to be externally validated on larger samples. PMID- 25935902 TI - To CPR or not to CPR? That is the question. PMID- 25935903 TI - Extensive cervicomediastinal hematoma due to spontaneous hemorrhage of a parathyroid adenoma: a case report. AB - Spontaneous extracapsular hemorrhage is a rare but potentially life-threatening manifestation of parathyroid gland adenomas. We present a case demonstrating that even in a patient with increased bleeding tendency due to anticoagulants, combined with compression of trachea and esophagus, conservative treatment can be successful. PMID- 25935904 TI - Soft tissue 'mallet' injury to the hallux. AB - We describe a case of a delayed presentation of a traumatic soft tissue mallet injury to the distal phalanx of the hallux in a teenager. Reports of this rare injury are sparse and there is no consensus in their treatment. This injury was treated with open repair of the tendon using a Mitek suture anchor, and stabilization with a 1.2-mm K-wire and extension splinting for 8 weeks. Following this treatment, she regained full power and a range of movement compared with the contralateral side, and achieved full function. We advocate surgical reconstruction of these injuries with suture anchors and stabilization of the interphalangeal joint. PMID- 25935905 TI - Case Report: Jejunal gastrointestinal stromal tumour, a rare tumour, with a challenging diagnosis and a successful treatment. AB - Gastrointestinal stromal tumours (GISTs) are rare. GISTs comprise 0.2% of gastrointestinal tumours and only 0.04% of small intestinal tumours. Jejunal GISTs are the rarest subtype. Only 10-30% progress to malignancy [Choi (Response evaluation of gastrointestinal stromal tumors. Oncologist 2008; 13: :4-7)]. We present a 70-year-old male, with multiple co-morbidities, who had extensive investigations over 5 years for vague abdominal pain. All investigations were normal. He presented with symptoms and signs of small bowel obstruction (SBO), confirmed on a computed tomography scan and demonstrated to be secondary to lesion-induced intussusception. The patient had emergency small bowel resection, was discharged after 4 days and remains well. This case report highlights the rarity of jejunal GISTs and, as extensive initial investigation yielded all false negative results, indicates the difficulty in diagnosing jejunal GISTs. Adhesions are the commonest cause of SBO in patients with previous abdominal surgery, followed by newly diagnosed malignancies [Beardsley et al. (Small bowel obstruction in the virgin abdomen: the need for a mandatory laparotomy explored. Am J Surg 2014; 208: :243-8)]. Consequently, in patients with a virgin abdomen, underlying tumours should be considered. PMID- 25935906 TI - Treatment-resistant major depressive disorder and assisted dying. AB - Competent patients suffering from treatment-resistant depressive disorder should be treated no different in the context of assisted dying to other patients suffering from chronic conditions that render their lives permanently not worth living to them. Jurisdictions that are considering, or that have, decriminalised assisted dying are discriminating unfairly against patients suffering from treatment-resistant depression if they exclude such patients from the class of citizens entitled to receive assistance in dying. PMID- 25935907 TI - Clarification on Rotation Rates of Textured Breast Implants. PMID- 25935908 TI - Gallbladder perforation and massive intra-abdominal haemorrhage complicating acute cholecystitis in a patient with haemophilia A. AB - We present an unusual case of a 32-year-old man with haemophilia A, who sustained massive, haemodynamically significant intra-abdominal bleeding from a perforated gallbladder wall and from the greater omentum as a complication of acute ulcerophlegmonous and haemorrhagic cholecystitis. Recombinant coagulation factor VIII was given and an emergency laparotomy was performed, with open cholecystectomy and haemostasis. Coagulation factor VIII was given for a further 2 weeks postoperatively, and the patient was discharged in good condition. In most published cases of haemorrhagic cholecystitis, the haemoperitoneum arises via transhepatic perforation; in this case, there was a free rupture into the peritoneal cavity. Patients with coagulopathies may have severe haemorrhagic complications and therefore need interdisciplinary management before, during and after surgery. Replacement therapy with factor concentrates should be initiated at once, and early surgery for gallbladder disease should be considered. PMID- 25935909 TI - West Nile virus-associated acute flaccid paralysis. AB - A 43-year-old woman presented to George Washington emergency department with 48 h of new-onset inguinal pain. Physical examination revealed a diffuse maculopapular rash involving the palms and soles, as well as inguinal lymphadenopathy. The patient denied recent travel outside of Washington, DC, and had no known sick contacts. She was admitted to the hospital for observation. Within 24 h of admission she developed left lower extremity flaccid paralysis, with loss of left patellar and Achilles reflexes. cerebrospinal fluid was positive for West Nile virus IgG and IgM antibodies, so methylprednisone 125 mg intravenously two times per day was started. On day 7, the patient recovered reflexes and continued to regain strength in the left lower extremity. She was discharged on day 9 on prednisone taper, with outpatient follow-up. PMID- 25935910 TI - Four tumours including neuroendocrine tumour of the ileum. AB - Gastroenteropancreatic neuroendocrine tumours are associated with development of further primary tumours. Certain conditions give an inherited predisposition to developing neoplasia. To the best of our knowledge, this is the first paper to report a patient with neuroendocrine tumour and three other tumours: a further bowel cancer, a brain tumour and a skin cancer. We report a case of a 42-year-old Caucasian man presenting with clinical features of intestinal obstruction who on histopathology of surgical specimen was found to have two distinct tumours of the bowel: a colonic adenocarcinoma at the splenic flexure and a well-differentiated neuroendocrine tumour of the terminal ileum. His history included a basal cell carcinoma and a benign brain tumour. He had extensive family history of neoplasia suggesting an inherited predisposition. Our case demonstrates the importance of investigating patients with known neuroendocrine tumours for further malignancy and suggests that patients with multiple primary malignancies should be referred for genetic testing. PMID- 25935911 TI - Laryngeal verruca vulgaris. AB - Laryngeal verruca vulgaris is a rare disease of the larynx that is easily misdiagnosed as other laryngeal lesions. This article reports three patients with laryngeal verruca vulgaris and discusses the differential diagnosis of laryngeal verrucous lesions to avoid over treatment. PMID- 25935912 TI - Chronic tubulointerstitial nephritis induced by 5-aminosalicylate in an ulcerative colitis patient: a rare but serious adverse event. AB - The 5-aminosalicylate is widely prescribed in inflammatory bowel disease patients. Its potential for renal damage has been seldom described. We report a case of a 23-year-old man who started 5-aminosalicylate after being diagnosed with ulcerative colitis. One year after, a significant decline on his creatinine clearance was noted, however, at that time, he was on an acute flare of his bowel disease and the 5-aminosalicylate dose was increased. Six months later, his renal function kept worsening and, on drug-induced toxicity suspicion, 5 aminosalicylate was halted and a kidney biopsy demonstrated a chronic tubulointerstitial nephritis. Steroids and azathioprine were started leading to partial recovery and stabilisation of his renal function. Physicians who prescribe 5-aminosalicylate to patients with inflammatory bowel disease should be aware of this adverse event. PMID- 25935913 TI - Squamous cell carcinoma arising in a mature cystic teratoma invading the sigmoid colon: a rare presentation. AB - We discuss a rare presentation of malignant teratoma in a 63-year-old woman who was admitted to accident and emergency with abdominal distension, bloody diarrhoea and peritonitis. CT of the abdomen and pelvis showed free air in the abdomen and a gas-fluid filled cavity measuring 12*6 cm in the mid-pelvis with possible fistulation that was suspicious for malignancy. A 10*12 cm ruptured dermoid cyst was found intraoperatively, which was adherent to the bowel wall. Bulky lymph nodes were also appreciated. The surgeon suspected a metastatic malignant teratoma, and a Hartmann's procedure, total abdominal hysterectomy and bilateral salpingoopherectomy were performed with clearance of the para-aortic lymph nodes. Subsequent histological analysis revealed a squamous cell carcinoma arising from an ovarian malignant teratoma. The patient went on to have carboplatin and paclitaxel chemotherapy and is alive at 6 months follow-up. PMID- 25935914 TI - Primary mediastinal (thymic) B-cell lymphoma presenting as cutaneous vasculitis. AB - Cutaneous small vessel vasculitis is a severe neutrophilic vascular inflammation mediated by immune complexes that involves the dermal postcapillary venules. Neoplasms represent 2-5% of all causes of secondary cutaneous vasculitis. We present a case of a 52-year-old man who was admitted due to a 10-day history of respiratory symptoms and myalgia. From the third day of symptoms onwards, the patient noticed the appearance of cutaneous lesions in the lower limbs with palpable purpura and erythematous papules. Additionally, he reported of asthenia, anorexia and weight loss during the prior month. Chest radiography showed an enlarged mediastinum and thoracoabdominal-pelvic CT scan revealed a bulky left hilar mass. Biopsy of the left superior lobar bronchus' mucosa allowed for the histological diagnosis of diffuse large B-cell lymphoma (DLBL) of the thymus. The patient received symptomatic treatment with improvement of the purpuric lesions and a multiagent chemotherapy regimen was initiated. PMID- 25935915 TI - Rare adverse effect of a common drug: nitrofurantoin-induced ANCA-associated vasculitis. AB - Nitrofurantoin is commonly prescribed to treat urinary tract infections (UTI). Reported adverse effects include gastrointestinal, pulmonary, hepatic and neurological disorders. We report a case of a 67-year-old woman treated for UTI with nitrofurantoin who presented with antineutrophilic cytoplasmic antibody (ANCA)-associated renal and skin vasculitis 3 days after starting treatment. The symptoms resolved following withdrawal of the drug and treatment with steroids. This is the first reported case of nitrofurantoin causing ANCA-associated vasculitis. PMID- 25935916 TI - Corking the WEB and coiling through a jailed microcatheter: WEB assisted coiling, a useful technique avoiding the use of stents in treating wide-necked large intracranial aneurysms. AB - The WEB is an endovascular flow-disrupting device used in treating wide-necked intracranial aneurysms. Although the device is available in varying sizes, large aneurysms pose a challenge with the need for custom-made devices. We describe the use of coils as an adjunct to the WEB device in successfully treating large aneurysms in two patients, one with an acutely ruptured aneurysm. This novel technique of jailing a microcatheter, deploying the WEB and then coiling the aneurysm saves the need for intracranial stenting, thereby avoiding the need for antiplatelet therapy, which is of benefit in the setting of acute aneurysm rupture. PMID- 25935917 TI - Breathlessness in a drug user. AB - A 40-year-old heroin smoking man presented with acute onset severe shortness of breath. Radiological investigations revealed an unexpected loculated pneumothorax. Respiratory physicians inserted a chest drain which relieved his breathlessness. His exercise tolerance is much improved 6 months on. The side effects of smoking illicit substances are poorly understood. There is a growing trend for drug users to smoke rather than intravenously inject. It is therefore important for clinicians to be aware of the associated morbidity. The authors believe this is the first ever reported case of loculated pneumothorax associated with heroin smoking. PMID- 25935918 TI - The tooth, the whole tooth: an unusual fight bite with an unnoticed embedded tooth in the hand. AB - A 19-year-old man presented to the plastic surgeons with a wound between his fourth and fifth metacarpophalangeal joints, with associated hand swelling and pain. He admitted to accidentally striking his brother in the mouth the previous evening. His brother reportedly made a hasty exit, and the patient dismissed the wound to his hand until waking up the next morning with swelling, pain and ascending lymphangitis. Radiographs revealed the unusual extent of his 'fight bite' injury with an entire human tooth embedded in his hand. Removal of the tooth and aggressive debridement was performed in theatre. Establishing an accurate account of events in these injuries can be difficult, with the orientation of the tooth in the soft tissues being more consistent with an uppercut than the reported jab. The patient made a good recovery following elevation, intravenous antibiotics, rigorous surgical debridement and postoperative hand therapy. PMID- 25935919 TI - 5-Fluorouracil cardiotoxicity: reversible left ventricular systolic dysfunction with early detection. AB - A 33-year-old man presented to hospital with acute shortness of breath and evolving ST segment changes on ECG 3 days following a cycle of 5-fluorouracil (5 FU) for colon cancer. Despite no cardiac history, subsequent echocardiogram showed severe left ventricular systolic dysfunction. The patient was initially treated with heart failure medications and his coronary angiogram was normal. Chemotherapy was stopped and he was started on nitrates and calcium channel blockers. A repeat echocardiogram and cardiac MRI a week later showed complete resolution of his left ventricular dysfunction and he was discharged home. This case report summarises 5-FU cardiotoxicity, and emphasises the importance of early recognition and correct treatment, as left ventricular systolic dysfunction in this context is potentially reversible. PMID- 25935920 TI - A mass more ordinary. PMID- 25935921 TI - Isolated tuberculosis of scaphoid in the skeletally immature: a rare cause of chronic wrist pain. AB - The hand and wrist are rare sites for tuberculosis and account for less than 1% of all skeletal tuberculosis. Though rare, tuberculosis of the wrist is a cause of major morbidity. A common feature in the available reports on hand and wrist tuberculosis was a delay in diagnosis causing residual stiffness and pain after treatment. Minimal initial symptoms, rarity of the lesion and ability of wrist tuberculosis to mimic more common pathologies account for the delay. No report of isolated scaphoid lesion in the paediatric age group has ever been reported. We present one such case, which was treated with multidrug chemotherapy. At the end of treatment the patient regained complete range of motion was completely pain free. No reactivation of disease was seen over 2-year follow-up. PMID- 25935922 TI - Loperamide dependence and abuse. AB - Loperamide is a common over-the-counter antidiarrheal considered safe in a broad range of dosages and thought devoid of abuse potential. We describe the first case of a patient with loperamide dependence due to misuse of its opiate-like effects achieved by chronic massive oral ingestions. A 26-year-old man who was taking 800 mg of loperamide per day presented requesting detoxification referral. Loperamide has potential for euphoric effects and information on how to facilitate such effects is easily available. It is important for physicians to be aware of the potential for misuse of and dependence on loperamide, with symptoms mimicking opiate use. PMID- 25935923 TI - Focal middle cerebral artery ischemia in rats via a transfemoral approach using a custom designed microwire. AB - OBJECTIVES: The aim of this study was to develop a reliable and repeatable method of inducing focal middle cerebral artery occlusion (MCAo) in rats without ligation of the external carotid artery (ECA), while reducing the risk of subarachnoid hemorrhage. METHODS: We prototyped microwires with different diameters (0.0120 inch, 0.0115 inch, 0.0110 inch), materials, and construction methods (coil-on-core, extruded polymer jacket-on-core). Under fluoroscopic guidance and using femoral artery access, the microwires were navigated into the internal carotid artery of male Wistar rats (n=50, weight 376+/-64 g) to induce MCAo for 1 or 2 h. We performed neurological assessments at baseline, and at 3, 24, 72, and 168 h after MCAo. MRI measurements were performed on a 9.4 T scanner at 1 and 7 days post-injury. RESULTS: The 0.0115 inch microwire with polymer jacket-on-core provided the most successful outcome. At 1 and 7 days post-injury, we observed similar infarction volumes for 1 and 2 h MCAo in the MRI study. Infarcted lesion volumes in both MCAo groups were significantly reduced at 7 days compared with 1 day post-injury. The trend in longitudinal changes for the scores of different neurological assessments was confirmed to be significant after the injury, but both groups showed a similar trend of neurological deficits over the course of the study. CONCLUSIONS: We have developed a reliable and repeatable MCAo method in rats, allowing for precise occlusion of the MCA under direct fluoroscopic visualization without alteration of the cerebral hemodynamics associated with ECA ligation. The custom designed microwire can also be sized for targeted focal ischemia in larger animals. PMID- 25935924 TI - Arterial embolization with Onyx of head and neck paragangliomas. AB - OBJECT: To report the morbidity and long term results in the treatment of paragangliomas by transarterial embolization with ethylene vinyl alcohol (Onyx), either as preoperative or palliative treatment. METHODS: Between September 2005 and 2012, 18 jugulotympanic, 7 vagal, and 4 carotid body paragangliomas (CBPs) underwent Onyx embolization, accordingly to our head and neck multidisciplinary team's decision. CBPs were embolized preoperatively. Jugulotympanic and vagal paragangliomas underwent surgery when feasible, otherwise palliative embolization was carried out alone, or in combination with radiotherapy or tympanic surgery in the case of skull base or tympanic extension. Treatment results, and clinical and MRI follow-up data were recorded. RESULTS: In all cases, devascularization of at least 60% of the initial tumor blush was obtained; 6 patients underwent two embolizations. Post-embolization, 8 patients presented with cranial nerve palsy, with partial or complete regression at follow-up (mean 31 months, range 3-86 months), except for 2 vagal and 1 hypoglossal palsy. 10 patients were embolized preoperatively; 70% were cured after surgery and 30% showed residual tumor. 19 patients received palliative embolization, of whom 5 underwent radiotherapy and 3 received tympanic surgery post-embolization. Long term follow-up of palliative embolization resulted in tumor volume stability (75%) or extension in intracranial or tympanic compartments. Onyx embolization of CBPs resulted in more difficult surgical dissection in 2 of 4 cases. CONCLUSIONS: Onyx embolization is a valuable alternative to surgery in the treatment of jugulotympanic and vagal paragangliomas; tympanic surgery or radiosurgery of the skull base should be considered in selected cases. Preoperative Onyx embolization of CBPs is not recommended. PMID- 25935925 TI - Mechanical thrombectomy using a combined CT/C-arm X-ray system. AB - BACKGROUND: Mechanical thrombectomy (MT) using stent-retrievers has been proven to be a safe and effective treatment in acute ischemic stroke (AIS), particularly in large vessel occlusion. Other than patient characteristics, time to recanalization is the most important factor linked to outcome. MT is usually performed in a dedicated angiography suite using a floor- and/or ceiling-mounted biplane angiographic system. Here we report our first experience of MT with a new combined CT and mobile C-arm X-ray device setup. METHODS: Patients with AIS underwent stroke imaging (non-contrast enhanced CT, CT perfusion, and CT angiography) using a commercially available 64-slice CT scanner which was modified for combined use with a C-arm system. In patients with large vessel occlusion, MT was conducted without further patient transfer within the CT imaging suite using a mobile C-arm X-ray device equipped with a 30*30 cm (12*12 inch), 1.5*1.5 k full-view flat detector which was positioned between the gantry and patient table. The safety and feasibility of this new system was assessed in preliminary patients. RESULTS: Angiographic imaging quality of the mobile C-arm was feasible and satisfactory for diagnostic angiography and MT. Using this setup, time between stroke imaging and groin puncture (picture-to-puncture time) was reduced by up to 35 min (including time for preparation of the patient such as intubation). CONCLUSIONS: MT using a combined CT/C-arm system is safe and feasible. The potential advantages, particularly time saving and ensuing improvement in patient outcome, need to be assessed in a larger study. PMID- 25935926 TI - Corticosteroid-resistant bulbar neurosarcoidosis responsive to intravenous immunoglobulin. AB - We report an intriguing case of corticosteroid-resistant bulbar neurosarcoidosis responding to intravenous immunoglobulin. A 37-year-old man presented with dysphagia to solids and liquids, dysphonia, fatigue and 50 lb weight loss over 2 months. We suspected sarcoidosis, based on an elevated serum angiotensin converting enzyme concentration and hilar lymphadenopathy on chest imaging; we subsequently confirmed this after transbronchial biopsy found non-caseating granulomas. MR scan of brain was normal; barium swallow showed severe oropharyngeal dysphagia and electromyography identified bulbar muscle denervation. He took corticosteroids for 3 weeks without improvement, requiring a percutaneous endoscopic gastrostomy tube for nutrition, but then he promptly improved with a 2-day course of intravenous immunoglobulin. Although there have been a few reports of intravenous immunoglobulin helping peripheral neurosarcoidosis, this case suggests that it also helps bulbar neurosarcoidosis. This case shows that bulbar neurosarcoidosis can mimic the clinical and electrophysiological features of fatal neurological disorders such as progressive bulbar palsy. The case illustrates the diagnostic challenge particularly when imaging is inconclusive and there is no response to corticosteroids. It also suggests that intravenous immunoglobulin can be considered before cytotoxic therapy for corticosteroid-resistant neurosarcoidosis, particularly in decompensated patients, given its favourable side effect profile. We also review the literature on bulbar neurosarcoidosis. PMID- 25935927 TI - Sunflower cataract: do not forget Wilson's disease. AB - A 41-year-old man with liver cirrhosis of unknown aetiology for 6 years was admitted to our department to confirm the diagnosis of Wilson's disease. He consulted an ophthalmologist who suspected the presence of a sunflower cataract and Kayser-Fleischer ring. At admission, his liver function tests were modestly impaired (Child-Pugh C, 10 pts). Neurological examination was normal, but cognitive functions were mildly impaired. Based on the copper metabolism abnormalities and clinical manifestation, we diagnosed Wilson's disease (Ferenci score, 6 pts) and started treatment with d-penicillamine. Presenting the case we would like to emphasise the significance of the ophthalmological examination in Wilson's disease diagnosis. PMID- 25935928 TI - Role of cognition in generating and mitigating clinical errors. AB - Given the complexities of current clinical practice environments, strategies to reduce clinical error must appreciate that error detection and recovery are integral to the function of complex cognitive systems. In this review, while acknowledging that error elimination is an attractive notion, we use evidence to show that enhancing error detection and improving error recovery are also important goals. We further show how departures from clinical protocols or guidelines can yield innovative and appropriate solutions to unusual problems. This review addresses cognitive approaches to the study of human error and its recovery process, highlighting their implications in promoting patient safety and quality. In addition, we discuss methods for enhancing error recognition, and promoting suitable responses, through external cognitive support and virtual reality simulations for the training of clinicians. PMID- 25935930 TI - The performance of non-NAAT point-of-care (POC) tests and rapid NAAT tests for chlamydia and gonorrhoea infections. An assessment of currently available assays. AB - OBJECTIVES: To identify point-of-care (POC) and rapid nucleic acid amplification techniques (NAATs) for the diagnosis of chlamydia and gonorrhoea and assess their utility. METHODS: Literature search for available POC and rapid NAATs. The performance from the best-performing assays were applied hypothetically to patients in the clinic in which 100 consecutive patients with chlamydia and 100 with gonorrhoea were diagnosed in 1737 and 4575 patients respectively, with 44/100 and 54/100 treated at first attendance, respectively. RESULTS: 11 POC and 1 rapid NAAT were identified. Published performances for the best POC for chlamydia (CRT) were: sensitivity 41%-87%, specificity 89%-99.6%. Our data suggest that if this assay was used instead of our current NAAT, for every 100 patients diagnosed currently, 23-46 extra patients would be treated at first attendance; 10-35 would go undiagnosed with 7-191 false-positives. Best chlamydia rapid NAAT (GeneXpert): sensitivity 97.5%-98.7%, specificity 99.4%-99.9%. Anticipated performance for every 100 patients diagnosed currently: 0 extra patients treated at first attendance, 1-3 undiagnosed, 0-2 false-positives. Best POC for gonorrhoea (GC Check): sensitivity 54%-70%, specificity 97%-98%. Anticipated performance for every 100 patients diagnosed currently: 14-18 extra patients treated at first attendance, 28-32 undiagnosed, 92-137 false-positives. Best rapid NAAT for gonorrhoea (GeneXpert): sensitivity 96%-100%, specificity 99.9%-100%. Anticipated performance for every 100 patients diagnosed currently: 0 extra patients treated at first attendance, 0-4 undiagnosed, 0-5 false-positives. Rapid NAAT would reduce time to treatment by 4 days for initially untreated patients. CONCLUSIONS: POC assays would need to be used in conjunction with a NAAT, increasing early treatment rates expense and false-positive results. The rapid NAAT could be used alone, with a reduction in average time-to-treat and a small reduction in sensitivity and specificity. PMID- 25935929 TI - Prevention of mother-to-child HIV transmission cascade in China: a systematic review and meta-analysis. AB - INTRODUCTION: The Chinese government has invested US$140 million annually on prevention of mother-to-child transmission (PMTCT) of HIV. This study evaluates the programme by examining the improvements in programme coverage HIV testing and provision of antiviral drugs along the PMTCT cascade. METHODS: Data for PMTCT cascade indicators were collected through a comprehensive systematic review of published peer-reviewed English and Chinese literature during 2003-2011. Meta analysis was conducted according to Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines. RESULTS: This study included 113 publications. HIV prevalence among pregnant women in China who accessed antenatal care (ANC) remained below 0.1% during the past decade. HIV testing coverage in pregnant women attending ANC and in HIV-exposed infants at 18 months significantly increased from 62.4% (95% CI 4.7% to 98.2%) and 22.1% (16.3% to 32.3%) in 2003 to 90.3% (88.4% to 91.8%) and 82.8% (66.9% to 99.5%) in 2011 respectively, whereas antiretroviral (ARV) prophylaxis uptake increased from 35.2% (12.2% to 47.3%) and 26.9% (24.3% to 28.9%) to 86.2% (53.2% to 97.2%) and 90.3% (85.5% to 93.7%). HIV vertical transmission rate substantially decreased from 31.8% (25.7% to 38.6%) prior to the programme to 2.3% (1.4% to 3.8%) in 2011. During 2003-2011, among 25,312 (23,995-26,644) infants born to HIV-positive mothers who received ARV prophylaxis, 975 (564-1395) were diagnosed with HIV, corresponding to an average transmission rate of 3.9% (3.2% to 4.6%). However, while including transmissions among HIV-positive pregnant women who were lost along the cascade, the average transmission rate during 2003-2011 was 17.4% (15.8% to 19.0%). CONCLUSIONS: PMTCT programmes have reduced HIV mother-to-child transmission in China. Further improvements in the continuum of care remain essential in realising the full potential of the programme. PMID- 25935931 TI - Hepatitis E vaccine: WHO position paper, May 2015. PMID- 25935932 TI - Correlation of rupture dynamics to the nonlinear backscatter response from polymer-shelled ultrasound contrast agents. AB - Polymer-shelled ultrasound contrast agents (UCAs) may expel their encapsulated gas subject to ultrasound-induced shell buckling or rupture. Nonlinear oscillations of this gas bubble can produce a subharmonic component in the ultrasound backscatter. This study investigated the relationship between this gas release mechanism and shell-thickness-to-radius ratios (STRRs) of polymer-shelled UCAs. Three types of polylactide-shelled UCAs with STRRs of 7.5, 40, and 100 nm/MUm were studied. Each UCA population had a nominal mean diameter of 2 MUm. UCAs were subjected to increasing static overpressure ranging from 2 to 330 kPa over a duration of 2 h in a custom-designed test chamber while being imaged using a 200* magnification video microscope at a frame rate of 5 frames/s. Digitized video images were binarized and processed to obtain the cross-sectional area of individual UCAs. Integration of the normalized cross-sectional area over normalized time, defined as buckling factor (Bf), provided a dimensionless parameter for quantifying and comparing the degree of pre-rupture buckling exhibited by the UCAs of different STRRs in response to overpressure. The UCAs with an STRR of 7.5 nm/MUm exhibited a distinct shell-buckling phase before shell rupture (Bf < 1), whereas the UCAs with higher STRRs (40 and 100 nm/MUm) did not undergo significant prerupture buckling (Bf ~ 1). The difference in the overpressure response was correlated with the subharmonic response produced by these UCAs. When excited using 20-MHz ultrasound, individual UCAs (N = 3000) in populations that did not exhibit a buckling phase produced a subharmonic response that was an order of magnitude greater than the UCA population with a prominent pre-rupture buckling phase. These results indicate the mechanism of gas expulsion from these UCAs might be a relevant factor in determining the level of subharmonic response in response to high-frequency ultrasound. PMID- 25935934 TI - Experimental approaches to the production and perception of prosody. PMID- 25935933 TI - Quantitative analysis of vascular heterogeneity in breast lesions using contrast enhanced 3-D harmonic and subharmonic ultrasound imaging. AB - Ability to visualize breast lesion vascularity and quantify the vascular heterogeneity using contrast-enhanced 3-D harmonic (HI) and subharmonic (SHI) ultrasound imaging was investigated in a clinical population. Patients (n = 134) identified with breast lesions on mammography were scanned using power Doppler imaging, contrast-enhanced 3-D HI, and 3-D SHI on a modified Logiq 9 scanner (GE Healthcare). A region of interest corresponding to ultrasound contrast agent flow was identified in 4D View (GE Medical Systems) and mapped to raw slice data to generate a map of time-intensity curves for the lesion volume. Time points corresponding to baseline, peak intensity, and washout of ultrasound contrast agent were identified and used to generate and compare vascular heterogeneity plots for malignant and benign lesions. Vascularity was observed with power Doppler imaging in 84 lesions (63 benign and 21 malignant). The 3-D HI showed flow in 8 lesions (5 benign and 3 malignant), whereas 3-D SHI visualized flow in 68 lesions (49 benign and 19 malignant). Analysis of vascular heterogeneity in the 3-D SHI volumes found benign lesions having a significant difference in vascularity between central and peripheral sections (1.71 +/- 0.96 vs. 1.13 +/- 0.79 dB, p < 0.001, respectively), whereas malignant lesions showed no difference (1.66 ?+/- 1.39 vs. 1.24 ?+/- 1.14 dB, p = 0.24), indicative of more vascular coverage. These preliminary results suggest quantitative evaluation of vascular heterogeneity in breast lesions using contrast-enhanced 3-D SHI is feasible and able to detect variations in vascularity between central and peripheral sections for benign and malignant lesions. PMID- 25935935 TI - Quiet is the new loud: pausing and focus in child and adult Dutch. AB - In a number of languages, prosody is used to highlight new information (or focus). In Dutch, focus is marked by accentuation, whereby focal constituents are accented and post-focal constituents are de-accented. Even if pausing is not traditionally seen as a cue to focus in Dutch, several previous studies have pointed to a possible relationship between pausing and information structure. Considering that Dutch-speaking 4 to 5 year olds are not yet completely proficient in using accentuation for focus and that children generally pause more than adults, we asked whether pausing might be an available parameter for children to manipulate for focus. Sentences with varying focus structure were elicited from 10 Dutch-speaking 4 to 5 year olds and 9 Dutch-speaking adults by means of a picture-matching game. Comparing pause durations before focal and non focal targets showed pre-target pauses to be significantly longer when the targets were focal than when they were not. Notably, the use of pausing was more robust in the children than in the adults, suggesting that children exploit pausing to mark focus more generally than adults do, at a stage where their mastery of the canonical cues to focus is still developing. PMID- 25935936 TI - The development of prosodic features and their contribution to rhythm production in simultaneous bilinguals. AB - This study aims to analyse facilitatory and inhibitory effects of bilingualism on the acquisition of prosodic features, and their contribution to speech rhythm. Here, we concentrate on phrase-final lengthening and accentuation, prosodic features suggested to give rise to different rhythmic percepts even when syllable structure is kept constant across languages. In particular, we investigate whether the development of these two features in Spanish-English simultaneous bilinguals correlates with rhythm development. Our results demonstrate that, as is the case for bilingual rhythm development overall the development of prosodic head- and edge-marking suggests that the two languages are rhythmically separable from around the age of 4, with clearly separate rhythms at the age of 6. Additionally, we can confirm that bilinguals also start out with an even-timed bias in the development of final lengthening and accentuation as reflected by fewer durational differentiations between prosodic syllable types. Furthermore, we can observe the same advantages in bilingual prosodic acquisition in the structurally more complex language that were found in rhythm development. These advantages are manifested by the earlier mastery of robust durational differentiations between syllable types to an adult-like extent. Finally, the comparison with monolingual data demonstrates that bilinguals do, in fact, have an advantage in their development in comparison with monolinguals. We hypothesise that this advantage is borne out of more advanced motor control and possibly more stable mental representations as a result of the dual language input, and dual language production experience. PMID- 25935937 TI - A stress "deafness" effect in European Portuguese. AB - Research on the perception of word stress suggests that speakers of languages with non-predictable or variable stress (e.g., English and Spanish) are more efficient than speakers of languages with fixed stress (e.g., French and Finnish) at distinguishing nonsense words contrasting in stress location. In addition, segmental and suprasegmental cues to word stress may also impact on the ability of speakers to perceive stress. European Portuguese (EP) is a language with variable stress and vowel reduction. Previous studies on EP have identified duration as the main cue for stress. In the present study, we investigated the perception of word stress in EP, both in nuclear (NP) and post-nuclear (PN) positions, by means of three experiments. Experiment I was an ABX discrimination task with stress and phoneme contrasts, without vowel reduction. Experiments 2 and 3 were sequence recall tasks with stress and phoneme contrasts, vowel reduction being added to the stress contrast only in experiment 3. Results showed significantly higher error rates in the stress contrast condition than in the phoneme contrast condition, when duration alone (PN), or duration and pitch accents (NP), are present in the stimuli (experiments I and 2). When vowel reduction is added, EP speakers are able to perceive stress contrasts (experiment 3). The results show that vowel reduction appears to be the most robust cue for stress in EP. In the absence of vowel quality cues, a stress "deafness" effect may emerge in a language with non-predictable stress that combines both suprasegmental and segmental information to signal word stress. These findings have implications for claims of a prosodic-based cross-linguistic perception of word stress in the absence of vowel quality, and for stress "deafness" as a consequence of a predictable stress grammar. PMID- 25935938 TI - Vocative intonation preferences are sensitive to politeness factors. AB - Although intonation has been traditionally associated with the expression of attitudes and intentions on the part of the speaker, little is known about whether sociopragmatic factors, such as power or social distance, or situational ones, like physical distance or insistence, can constrain the use and felicity of pitch contours. This article investigates the felicity conditions underlying the choice of three vocative pitch contours in Central Catalan by means of two experiments, namely a production experiment based on the Discourse Completion Task (320 vocative contours produced by 20 speakers), and an acceptability judgment task in which 72 listeners were asked to rate the appropriateness match between a set of vocative contours and a previous discourse context (3,456 responses). The results from the two experiments show that both situational and social politeness factors govern the choice of vocative intonation. Finally, the results are discussed in line with the traditional classification of politeness strategies defined by Brown and Levinson, in the sense that the three intonation contours can be linked to negative, positive, and bald on-record politeness strategies. PMID- 25935939 TI - Drifting without an anchor: how pitch accents withstand vowel loss. AB - We offer an analysis of the influence exerted by segmental rules on the suprasegmental structure in the dialect of Ipiros Greek (IG). In particular we investigated how vowel deletion (VD) affects the phonetic realization of the L*+H pitch accent. Our data empirically establish that the H tone aligns much earlier when VD applies than when it does not. Furthermore, we show that there is a phonological contrast between the nuclear L+H* and the prenuclear L*+H which hinges on early versus late H alignment respectively. We demonstrate that the contrast between the L*+H and the L+H* pitch accents is not compromised by the earlier alignment caused by VD. In other words, intonational contrasts are not endangered by fine phonetic alignment variability within the same category. PMID- 25935940 TI - The role of tonal onglides in German nuclear pitch accents. AB - A perception experiment with native German listeners provided evidence for the relevance of the tonal onglide in nuclear accents--the pitch movement leading towards the target on the accented syllable. Listeners were able to distinguish between two pragmatic meanings of a short phrase (given/non-contrastive and new/contrastive) using the tonal onglide as the sole acoustic cue. On the basis of these findings, we argue that the onglide merits a phonological status in an intonation model of German and should not be regarded as merely phonetic detail. PMID- 25935941 TI - Geriatrics: the great awakening. PMID- 25935942 TI - The role of peri-operative use of alpha-blocker in preventing lower urinary tract symptoms in high risk patients of urinary retention undergoing inguinal hernia repair in males above 50 years. AB - Prevalence of lower urinary tract symptoms (LUTS) and groin hernia increase with rising age. Straining in itself is an important aetiology of inguinal hernia. Posthernioplasty retention of urine is one of the most significant complications. The aims of this study are to know the prevalence of signifi- cant LUTS in men > 50 years (n = 200) undergoing inguinal hernia surgery, to identify the high-risk patients for posthernioplasty urinary retention and to assess the role of peri operative use of alpha- blocker in reducing the incidence of postoperative urinary retention in these patients. This study was performed at RKMSP Hospital, Kolkata from August 2005 to January 2008. All findings were docu- mented. Prevalence of significant LUTS above 50 years undergoing inguinal hernioplasty was found to be 48% (96 out of 200). Out of 96 patients who had International Prostate Symptoms Score>7, 48 patients had maximal urine flow (Qmax) < 10 ml/second and postvoid residual urine > 100 ml, 48 patients belonged to high risk group for postoperative retention of urine. Incidence of postoperative retention of urine among high risk group among tamsulosin users was only 3(12.5%) out of 24 patients and among tamsulosin non-users was 10(41.6%) out of another 24 patients. Therefore, we concluded that among male patients > 50 years of age (undergoing groin hernia surgery) prevalence of significant LUTS increases per decade. We also concluded that tamsulosin is important for alleviation of LUTS and is quite effective for prevention of postoperative retention of urine and helpful for early discharge of patients. PMID- 25935943 TI - Clinicopharmacological comparative study of rizatriptan versus conventional therapy in migraine. AB - Migraine is a common neurological problem, which accounts for large morbidity and disability. Non-steroidal anti-inflammatory agents and triptans are mainly used to terminate the attack of moderate to severe migraine. This study compared the safety, efficacy and pharmaco-economics of rizatriptan (5HT(IB/ID) agonist) versus conventional therapy (paracetamol 500 mg + metoclopramide 10 mg + flunarizine 10 mg + alprazolam 0.5 mg). In this study, drug combinations used in conventional therapy was indigenously designed by the neurologist. Rizatriptan was found more efficacious than conventional therapy in terminating an attack of migraine and its' associated symptoms but looking into the contra-indications, side-effects and cost of the former there has been limitation in its prescription as well as the use. PMID- 25935944 TI - Genito-urinary tuberculosis in 67 cases: experience from a tertiary core centre in India. AB - Tuberculosis is very much prevalent in developing countries like India. Genito urinary tuberculosis usually occurs after 5 to 15 years of the primary lung infection. After lymph node involvement,it is the second common form of extrapulmonary tuberculosis. In this retrospective study, case records of 67 patients diagnosed with genito-urinary tuberculosis in our institute were thoroughly reviewed regarding age, sex, the urogenital organ involved by tuberculosis,mode of diagnosis,and treatment given to the patients. Median age of the patients was 38.5 years, males were more commonly involved than females, kidney was the most common organ involved by tuberculosis followed by ureter and urinary bladder.HIV infection was present in a single patient who had developed tuberculous perinephric abscess. Most common mode of diagnosis was by histopathological examination of the organ involved. Hydronephrosis of the involved kidney with echogenic debris in the dilated pelvicalyceal system on ultrasonography and non-visualised kidney on intravenous urogram was the most common findings on imaging studies who underwent nephrectomy. One patient was seen with tuberculosis of the glans penis which is not much common. Surgical intervention was ablative in nature in most of the cases in the form of nephrectomy. Early diagnosis is important and can prevent the anatomical defor- mity and loss of function of the involved organ. PMID- 25935945 TI - Retrospective observational study of penetrating keratoplasty in the management of non-responsive microbial keratitis. AB - Microbial keratitis tops the list of the diseases leading to corneal blindness. Corneal transplant, either partial or full thickness, is the most helpful technique for infective keratitis that remains non- responsive, even with the most suitable medical treatment. Aims of this study are to evaluate the success of therapeutic penetrating keratoplasty in non-responsive microbial keratitis in eradication of infection, restoration of anatomical integrity of the globe and prevention of complication that influence the visual prognosis in a positive way. Result of the retrospective study of 60 patients who underwent therapeutic penetrating keratoplasty, following infected keratitis showed restoration of anatomical integrity in 51 cases (85%). Success rate of penetrating keratoplasty was higher in non- perforated (92%) than in perforated group (74.28%) and in non mycotic than in mycotic group. Penetrating keratoplasty in non-responsive infected keratitis is thus helpful. PMID- 25935946 TI - Plasma malondialdehyde (MDA) and anti-oxidant status in diabetic retinopathy. AB - Hyperglycaemia and dyslipidaemia in diabetes mellitus induce increased lipid peroxidation and peroxyl radical formation is an important mechanism in genesis of micro-angiopathy. We took up a study on oxidative stress as measured by lipid peroxidation marker, malondialdehyde (MDA) and antioxidant enzyme status in type 2 diabetes mellitus patients with and without retinopathy and compared them with a control non-diabetic group. MDA was significantly elevated (p < 0.001) in both the diabetic groups whereas antioxidant enzymes superoxide dismutase (SOD), glutathione peroxidase (GPx), glutathione reductase (GR), catalase (CAT) and reduced glutathione (GSH), etc, were significantly decreased (p < 0.001) which might be helpful in risk assessment of various complications of diabetes mellitus. The study included 100 subjects of age group 50-70 years, out of which 50 patients were non-insulin dependent diabetes mellitus (NIDDM) with retinopathy and rest 50 age and sex matched apparently healthy individuals (control group). The status of fasting blood sugar (FBS), postprandial blood sugar (PPBS), total cholesterol (TC), triglyceride (Tg), HDL-cholesterol, LDL-cholesterol, VLDL- cholesterol, GPx, GR, CAT, SOD, MDA were determined. The results showed significant increase (p < 0.001) in FBS, PPBS, TC, TG, LDL-C, VLDL-C, CAT, MDA while HDL-C, GSH, GPx, GR and SOD were found to be decreased significantly (p < 0.001). The data suggest that alteration in anti-oxidant status and MDA may help to predict the risk of diabetic retinopathy. PMID- 25935947 TI - Xanthogranulomatous pyelonephritis: critical analysis of 18 cases from a rural tertiary care centre of India. AB - Xanthogranulomatous pyelonephritis is an uncommon disorder of the kidney that is characterised by chronic inflammation and extensive destruction of the involved kidney usually associated with renal calculus and obstruction. It commonly involves the middle aged people with an increased incidence among females and diabetic population. Confirmed diagnosis can be done only after histopathological examination of the diseased nephrectomy specimen. So early suspicion and timely intervention is important to reduce the morbidity. In this retrospective study, we analysed the case records of all patients diagnosed with xanthogranulomatous pyelonephritis in our institute over a period of 11 years. A total 18 patients were treated and diagnosed with xanthogranulomatous pyelonephritis from January 2002 to December 2012. Among them 13 were female and 5 male. Most common clinical presentation was flank pain, fever, dysuria and weight loss. Left kidney was affected in 15 cases and right kidney in 3 cases. All patients were having urinary calculus causing obstruction to the pelvicalyceal system of the kidney. Only 2 patients were diabetic. Urine culture was sterile in all patients. All patients were treated with antibiotics, other supportive measures pre-operatively and ultimate nephrectomy having good recovery. Early suspicion and prompt treatment is necessary in minimising morbidity and mortality from the condition. PMID- 25935948 TI - Mifepristone: current knowledge and emerging prospects. AB - The first clinically available antiprogestin, mifepristone has generated immense interest in the research community since its' discovery in 1980. Mifepristone is a synthetic orally active steroid with potent antiglucocorticoid, antiprogestogen and a weak anti-androgen activity, used primarily for termination of pregnancy. It acts as a competitive receptor antagonist at the progesterone receptor in the presence of progesterone, and acts as a partial agonist in the absence of progesterone. Extensive research has been carried out regarding its' antiprogestogen activity for use in medical abortion. Lately other medical uses of mifepristone are being explored like for induction of labour in late preg- nancy, as oestrogen free oral contraceptive and for treatment of endometriosis, uterine fibroids, ovarian cancer, prostate cancer, meningiomas, Cushing's syndrome and major psychotic depression. PMID- 25935949 TI - Implementation of PC and PNDT Act in Gulbarga region. AB - Denial to a girl child of her right to live is one of the heinous violations of the right to life committed by the society. Gender bias and deep rooted prejudice and discrimination against girl child and preference of male child have led to large scale female foeticide in the last decade. The declining sex ratio is a major concern for all. The census 2001 data indicates that female ratio is declining at an alarming rate and needs immediate action. In order to check the female foeticide, the Prenatal Diagnostic Techniques (regulation and prevention of misuse) Act 1994 was enacted and became operational from January, 1996. This article is an attempt to throw light on the successful implementatuion of PC and PNDT Act in the Gulbarga region and active participation of various organisations and people in proper implementation of the act. PMID- 25935950 TI - Squamous cell carcinoma arising in a chronic osteomyelitic sinus tract in the peri-anal region involving pelvis: a rare occurrence. AB - Squamous cell carcinoma is a rare, but well documented complication of chronic osteomyelitis. Squamous cell carcinoma arising in a sinus tract following chronic osteomyelitis of the pelvic bone is a very rare occurrence. The patient presented with multiple draining sinuses and an ulcerative growth at the mouth of one of the sinuses in the peri-anal region. X-ray findings and sinogram showed de- struction of part of pubic bone. Biopsy from the growth confirmed a well differentiated squamous cell carcinoma. Therefore it is imperative that these lesions be biopsied for accurate diagnosis, adequate therapy and follow-up. PMID- 25935951 TI - Anaesthetic management of a child with large occipital meningomyelocele. AB - A meningomyelocele is herniation of meninges along with neural elements through a congenital defect in the cranium or vertebral column. Reported incidence of occipital meningomyelocele is 1 in 5000 live births. Children with meningomyelocele may have varying degrees of sensory and motor deficits and other important associated congenital defects with clinical features of brain stem compression. The major anaesthetic challenges associated with myelomeningocoele repair includes difficulty in securing airway, intra-operative prone positioning, accurate assessment of blood loss and prevention of hypothermia. PMID- 25935952 TI - Hysterectomy: treatment for secondary infertility. AB - Infertility is a distressing condition but extenuating circumstances sometimes make the choice of treatment seem paradoxical. Here is discussed a challenging case of a 30-year-old woman with no living child and secondary infertility who presented with a large abdominal mass and severe abdominal pain, sequelae of previous obstructed labour. There was complex management dilemma. She was young, had no living child, had undergone vesicovaginal fistula (VVF) repair and vaginoplasty yet was wanting fertility; however she was distressed with the abdominal pain and desired a complete cure. Both she and her spouse were counselled about the high possibility of failure if repeat attempt at vaginoplasty was made, and possible damage to the VVF repair. Finally, decision of exploratory laparotomy with total abdominal hysterectomy was taken after counselling the couple about adoption as an option for childbearing. PMID- 25935954 TI - Submental intubation: a new approach in panfacial trauma. AB - The submental route for endotracheal intubation is an alternative to nasal intubation or tracheo- stomy in the surgical management of patients with complex craniomaxillofacial injuries. The critical indication for submental intubation is the requirement for intra-operative maxillomandibular fixation in the presence of injuries that preclude nasal intubation and in a situation where a tracheostomy is not otherwise required. Maxillomandibular fixation is essential to re establish dental occlusion for a normal functional result in dentate patients with fractures involving alveolar segments of the jaws. However, maxillomandibular fixation precludes orotracheal intubation. Nasotracheal intubation is often used but is contra-indicated in the presence of skull base fractures and will interfere with the access to certain fracture types. A tracheostomy has a high potential complication rate and in many patients, an alternative to the oral airway is not required beyond the peri-operative period. Submental intuba- tion is a simple and useful technique with low morbidity in selected cases of craniomaxillofacial trauma. PMID- 25935953 TI - Kikuchi's disease: an uncommon cause of cervical lymphadenopathy. AB - Kikuchi Fujimoto's disease is a benign self limiting disorder presenting with localised cervical lymphadenopathy, fever, weight loss and night sweats. It is a rare disease with worldwide distribution but commonly reported from Asia. It is diagnosed by excision biopsy of the lymph nodes. Clinical features suggest a viral aetiology though not proven. It is often misdiagnosed as either systemic lupus erythematosus or malignant lymphoma. Better understanding as well as high clinical suspicion would aid in the diagnosis of the disease. Treatment is mainly symptomatic, with non-steroidal analgesics and antipyretics. Corticosteroids are rarely indicated. Although patients show a spontaneous recovery in 1-4 months, a follow-up of several years would be required to study the development of SLE in these patients. PMID- 25935955 TI - A very rare case of intussusception of small bowel due to metastasis from renal cell carcinoma. AB - Bowel metastasis secondary to renal cell carcinoma causing intussusception is very rare condition. Here a case of a 52-year-old male, who presented with signs and symptoms of small bowel obstruction is reported. CT abdomen showed small bowel obstruction due to ileo-ileal intussusception and left renal mass. On exploratory laparotomy Ileo-ileal intussusception was present. FNAC taken from left kidney at same sitting. Histology of resected specimen reported metastatic nodule in small bowel of renal cell carcinoma. FNAC confirmed primary renal cell carcinoma of left kidney. Although abdominal CT scanning provides the most reliable indications, it is laparotomy, that establishes the diagnosis of intussusception, and the histological examination that determines the cause. PMID- 25935956 TI - Small cell carcinoma of the urinary bladder: a case report and review of the literature. AB - Small cell carcinoma of the urinary bladder is extremely rare. In this report, a case of non-metastatic small cell carcinoma of the urinary bladder treated by systemic chemotherapy followed by adjuvant external radiotherapy, with a brief review of the epidemiology, clinical features, diagnosis, pathological features, staging, treatment and prognosis about this neoplasm is reported. A 53 years old man attended with sign and symptoms suggestive of a bladder cancer. Computed tomography of the whole abdomen showed a large tumour at right lateral wall of the bladder. Transurethral resection and histopathological study of the bladder tumour established the diagnosis of a small cell carcinoma. The patient received six cycles of platinum based chemotherapy with adjuvant locoregional external radiotherapy. He had an invasive bladder recurrence thirteen months later and died shortly afterwards. PMID- 25935957 TI - Conjunctival malignant melanoma resembling a horn. AB - Conjunctival melanoma is a rare ocular malignancy occurring most frequently in aged patients. It is a potentially life-threatening condition. This article presents history and management of a case of malignant melanoma of conjunctiva resembling a horn. PMID- 25935958 TI - Holistic approach--relevance to global nations. PMID- 25935959 TI - Role of real-time PCR (RT-PCR) in rapid diagnosis of tuberculous mycobacteria in different clinical samples. AB - The study was aimed for molecular detection of mycobacterial DNA in different clinical samples using real-time polymerase chain reaction (RT-PCR) system and rapid diagnosis of tuberculosis. A total of 508 clinical specimens (blood 343, menstrual fluid 53, endometrial tissue 43, body fluid 36, pus from lymph nodes 18, sputum 8, urine 5 and semen 2) were included in this study. We extracted DNA using QIAamp DNA Mini Kit (QIAGEN, Germany) and performed real-time assay using Rotor-Gene Q machine from Corbett Research, Australia for specific amplification of IS6110 sequence of mycobacterial genome. The RT-PCR result was also compared with bacterial culture and acid-fast bacillus staining. RT-PCR assay showed positivity in 52 cases and negative in 456 cases. Corresponding positive results in culture and acid-fast bacillus staining methods were 49 cases and 24 cases respectively. The sensitivity and specificity of detecting Mycobacterium tuberculosis by RT-PCR were 93.87% and 98.69% respectively taking positive culture results as reference standards. The overall positive and negative predictive values were 88.46% and 99.34% respectively. RT-PCR is a useful diagnostic tool for rapid and sensitive detection of mycobacteria in different clinical samples. The easy processing, fast reporting and relative lack of contamination issues make it worthy as a possible replacement to time consuming culture techniques. Moreover, it has added advantage of quantification of mycobacterial DNA, hence bacterial load. PMID- 25935960 TI - Role of laporoscopy-hysteroscopy in cases of infertility with pregnancy outcome. AB - The study aims to analyse the role of hysteroscopy-laparoscopy in diagnosis and treatment of infertility with effect on pregnancy outcome. The study group comprised 200 patients of 20-30 years age (125 with primary and 75 with secondary infertility). Hysterosalpingography (HSG) was done in all. Diagnostic as well as operative hysteroscopy-laparoscopy if required were performed in the same sitting in cases who have already been treated for 6 months and did not conceive, with unexplained cause or with abnormal HSG findings. All cases were followed up till they conceived or up to 1 year. Fifty patients of unexplained infertility were used as control and given only folic acid 5 mg/day. HSG was normal in 102/200 (51%) and abnormal in 98/200 (49%) cases in form of fimbrial block in 48 (48.97%) out of 98, cornual block 25 (25.51%), peritubal adhesions 15 (15.31%), filling defect in uterus 10 cases (10.20%). Hysteroscopy was abnormal in 150/200 cases (75%) with uterine synechiae 58 (38.66%) out of 150, endometrial hypertrophy 22 (14.67%), endometrial polyps 20 (13.33%), submucus fibroids 20 (13.33%), atrophy 25 (16.66%) and malformations 5 (3.33%). Hysteroscopy surgery was performed in 70 (46.66%), alone in 14 and with laparoscopic procedures in 56 cases, with subsequent pregnancy rate of 35.71-42%. HSG missed the abnormalities in 58 cases (38.66%) which were diagnosed with hysteroscopy with difference in findings in 58 cases (38.66%). Operative laparoscopy was performed in 140 cases (70%), divided between adhesiolysis in 38(27.14%), tubal surgery in 53 (37.86%), electrocoagulation or excision of endometriotic nodule in 25(17.86%) and ovarian drilling for polycystic ovarian disease in 24(17.14%). The HSG missed 30(20%) abnormal tubal and peritubal findings which were diagnosed with laparoscopy. All cases were followed for one year. Subsequent pregnancy rate was 64 (45.71%) after laparoscopic surgery. The results were analysed by applying Chi-square test and calculating p-value at 1 df. Hysteroscopy-laparoscopy is diagnostic and therapeutic both for uterine, tubal infertility and ovarian abnormalities. They give an advantage in diagnosis and treatment of female infertility at the same sitting. As compared to HSG, it is more accurate in 25% cases and improves the rate of pregnancy to 35%-45% almost comparable to 56.52% in cases with normal hysteroscopy-laparoscopy findings. PMID- 25935961 TI - Bronchiectasis in western India: clinical presentations and socio-economic burden. AB - Bronchiectasis is an abnormal permanent dilatation distortion and destruction of the airways with both pulmonary and extrapulmonary side-effects. The aim of the study was to find out the presenting features, aetiologies and socioeconomic factors in patients of bronchiectasis. It is a prospective observational study comprising 53 patients over aperiod of two years. Aetiologies were determined using Kuppuswamy's socioeconomic scale. Number of exacerbations and mortality were noted. The age ranged from 14 to 80 years (mean: 43.33 +/- 16.37 years). There were 35 males (66%) and 18 females (34%). Clubbing was seen in 58% cases (n = 31); 11% patients (n = 6) had haemoptysis. Bilateral involvement was seen in 64% cases (n = 34). Allergic bronchopulmonary aspergillosis and post-tuberculous sequelae were the commonest causes (n = 12, 23% each). The range of household medical expenditure in these patients varied from 6% to 47%. Lower the Kuppuswamy scale poorer the follow-up (p-value < 0.05). Multiple exacerbations were seen in all classes of patients (p-value 0.09). Death occurred in 4 patients. It is concluded that bronchiectasis is a chronic illness with significant morbidity and socioeconomic implications. Lower the socio-economic scale, poorer the compliance of therapy. PMID- 25935962 TI - Post-traumatic seizure: a multicentric epidemiological study. AB - Post-traumatic seizure (PTS) is the development of recurrent seizures following head trauma and has a high clinical relevance. We tried to understand the epidemiology of PTS in a multicentric pro- spective study during the period May 2010 to April 2012. We included 320 patients excluding poor Glasgow coma scale (GCS) ie, <4 and history of previous epilepsy. At a median follow-up of one year, 49 patients (15.31%) developed PTS. Incidence of immediate, early and late onset seizures were 27 (8.4%), 14 (4.4%), 9 (2.8%) respectively. In this study incidence of PTS was high in patients of the age group 20-30 years, with road traffic accident, with poor GCS ie, < 9. High incidence of PTS was associated with x- ray findings of skull fracture and abnormal CT findings. Early use of anticonvulsants is ineffective in preventing early post-traumatic epilepsy. PMID- 25935963 TI - Minimal effective dose of mifepristone for medical abortion. AB - The aim of this study is to compare the effectiveness of 100 mg versus 200 mg mifepristone along with misoprostol for medical abortion in gestation upto 56 days. This is a prospective controlled study. Eighty women seeking medical abortion with a gestation up to 56 days were included in the study. The women were randomly allotted into two groups. They received 100 mg/200 mg mifepristone on day 1 followed by 800 mcg misoprostol two days later. Women who had not aborted completely by day 14, received a repeat dose of 400 mcg misoprostol and were evaluated on day 21 for completeness of the procedure. Five women in both the groups had incomplete abortion by day 14 (12.5%), while one woman in the test group had to undergo dilatation and evacuation on day 3 due to excessive bleeding. By repeating a second dose of misoprostol, all of them aborted completely and the complete abortion rates were markedly improved from 85% and 87.5% in the test and the control group, respectively to 97.5% and 100%, respectively. It may be concluded that 100 mg mifepristone is as effective as 200 mg and appears to be the lowest effective dose for medical abortion. PMID- 25935964 TI - New onset paediatric epilepsy in 1-5 years age group children--approach to management in a tertiary care centre with newer anti-epileptic levetiracetam. AB - Epilepsy is a common paediatric neurologic disorder that is difficult to manage in a substantial portion of children, highlighting the continued need for more effective and better tolerated drugs. A multicentric study was conducted from August, 2011 to July, 2013 using levetiracetam (LEV) in newely diagnosed epilepsy in 122 young children of 1-5 years age group to find its role in practical scenario depending upon the knowledge from prior literature available. It has been demonstrated effective as adjunctive therapy as well as monotherapy for new onset partial seizures and generalised tonic-clonic seizures (GTCS) but it acts better as adjunctive therapy than the monotherapy. When LEV was used as adjunctive therapy 15.4% children with partial seizure were seizure-free as compared to 11.12% in GTCS and when LEV was used as monotherapy 16.17% children with partial seizure were seizure-free as compared to 15.38% in GTCS. When LEV was used as add on therapy 16.67% children < 2 years were seizure-free as compared to 17.85% in > 2 years. When LEV was used as monotherapy 25.00% children < 2 years were seizure-free as compared to 18.18% > 2 years. So, it was found more efficacious in partial group of seizures than the GTCS variety. It also shows more efficacy in older age group (> 2 years) than the younger ones (< 2 years). Somnolence and behavioural changes were noted as ad- verse effects in a few cases. So, LEV is an important addition to the treatment of paediatric epilepsy. PMID- 25935965 TI - Biceps tendon sheath effusion as a diagnostic clue to rotator cuff pathology. AB - The objective of this study was to evaluate the role of biceps tendon sheath effusion detected on ultrasound as a diagnostic clue to rotator cuff pathology. Despite being the most common cause of shoulder pain in adults early sonographic changes of rotator cuff tendinopathy are easy to miss. A total of 31 patients out of whom 27 had unilateral shoulder pain and 4 had bilateral complaints under- went ultrasonographic examination of shoulder joint using high frequency linear array transducer. Any fluid surrounding the long head of biceps tendon was noted followed by a careful search for any associated sonographic abnormality involving the rotator cuff. Eighteen out of the 35 had presence of fluid in their biceps tendon sheath. Twelve had presence of both biceps tendon sheath effusion and rotator cuff pathologies. Among 17 patients, who had no fluid in their biceps tendon sheath, only 2 had rotator cuff involvement whereas rest 15 had neither biceps tendon sheath fluid nor rotator cuff pathologies. A significant association was found between presence of fluid in long head of biceps tendon sheath and rotator cuff pathologies. Thus the most common finding observed in association with the presence of fluid around the long head of biceps tendon sheath in this study was tendinosis of rotator cuff. On ultrasonography simple presence of fluid around the long head of biceps tendon sheath demands careful examination of rotator cuff. PMID- 25935966 TI - Recurrent headache in children. AB - Headache is a common symptom in paediatric hospital practice, the causes may be primary or secondary. A study was conducted in department of paediatrics from May 2005 to February 2007 in order to find out common causes for recurrent headache in children. A total of hundred children in age range of 3-14 years were included in the study. Children with secondary headache were excluded from the study. Various clinical characteristics were studied and based on these, types of headache were categorised using International Headache Society criteria. The most common type of headache observed was migraine (46%) followed by tension headache (31%), psychogenic headache (8%), mixed migraine and tension headache (7%) and other non-specific recurrent headaches (8%). There was clear cut female preponderance in adolescent patients having migraine. Tension headache is becoming a matter of concern in paediatric age group probably due to more competitive and stressful environment. PMID- 25935967 TI - Effect of anti-oxidant on tear film in patients suffering from diabetes mellitus. AB - To study the effects of anti-oxidant on tear film parameters in patients with diabetes mellitus, a total of 100 patients of diabetes mellitus with defective Schirmer test and tear film break-up time were enrolled in this study and they were given vitamin C (1000 mg/day) and vitamin E (400 IU/day) for 30 days. Schirmer test and tear break-up, time were re-examined after 1 month. There was significant improvement in values for Schirmer test (p < 0.001) and tear break-up time. Oxidative stress has an influence on how diabetes mellitus affects various systems of body. This study clearly depicted im- portant roles of vitamins C and E in improving the well-being of the ocular surface. PMID- 25935968 TI - Role of sentinel lymph node biopsy in early breast cancer. AB - Current literature has suggested that sentinel lymph node biopsy may replace axillary dissection as the nodal staging procedure of choice in early breast cancer. The aim of this study is to evaluate the effectiveness and accuracy of sentinel lymph node biopsy using methylene blue dye in predicting axillary nodal status in early breast cancer with clinically impalpable axillary lymph nodes. In the period between June 2005 and May 2009, 50 patients with early breast cancer and clinically impalpable axillary lymph nodes, underwent sentinel lymph node biopsy using methylene blue dye followed by completion of axillary dissection in the same setting after taking a written consent from the patients. Of the included 50 patients, sentinel lymph node biopsy was successful in 48 patients (96.0%). Accuracy of sentinel lymph node biopsy was 95.8%, sensitivity was 90.0%, false negative rate was 6.7%, negative predictive value was 93.3%. PMID- 25935969 TI - Travelling in aeroplane with medical conditions. AB - Air travel has become so common these days that about one billion people travel in one year. A few number of the persons travelling by air have suffered or are suffering from one or more medical conditions which may increase risk to passenger himself. There may be additional risk to copassengers, crew of aircraft or safety of aircraft may be compromised. The present article evaluates different medical conditions from pregnancy to cardiovascular diseases in relation to the air travel. PMID- 25935970 TI - Eosinophilic ascitis, an unusual presentation of eosinophilic gastro-enteritis. AB - Eosinophilic ascitis is probably the most unusual and rare presentation of eosinophilic gastroenteritis and is generally associated with the serosal form of eosinophilic gastroenteritis. It is characterised by eosinophilic infiltration of any or all layers of the gut wall and may involve any segment of the gastro intestinal tract. Peripheral eosinophilia may or may not be present. A case of eosinophilic ascitis that developed eight weeks postpartum in a 30-year-old young female has been reported. She presented with gastro-intestinal symptoms, ascitis and right sided pleurar effusion. Bood counts, ascitic fluid analysis and bone marrow examination showed evidence of eosinophilia. On high index of suspiscion, she was evaluated for eosinophilic gastroenteritis and treated with oral steroid (prednisolone). She responded well with satisfactory recovery. PMID- 25935971 TI - Disseminated intra-abdominal hydatid disease: surgical management. AB - Hydatid disease is a common parasitic disease of liver. Rupture of aliver hydatid into the peritoneal cavity, either spontaneous or iatrogenic (during surgery) leads to widespread dissemination and is a difficult problem to manage. Surgical management along with long term antihelminthic treatment offers the only hope for such cases. A case of disseminated intra-abdominal hydatid disease and its management has been reported. PMID- 25935972 TI - Proximal femoral focal deficiency revisited: a case report. AB - Proximal femoral focal deficiency (PFFD) is a rare anomaly with an estimated incidence of < 0.2/ 10,000 births. The aetiology of PFFD is unknown though various agents have been implicated including anoxia, ischaemia, mechanical or thermal injury. Herein is reported a case of a 22-year-old primigravida who delivered a baby with PFFD. This patient had developed high grade fever and had undergone ischiorectal abscess drainage at 7 weeks of gestation; maternal hyperthermia combined with anoxic injury might have been contributory factors in the causation of this disorder. So, it is of prudent importance to do prenatal targeted ultrasonography in patients who develop febrile illness in early pregnancy. PMID- 25935973 TI - Biliary colic with dilated common bile duct: simple "sheepish" problem? AB - A 40-year-old man, resident of a rural area of Rajasthan state of India presented with recurrent biliary colic and fever since last 2 years. Examination was normal and investigations revealed a dilated common bile duct with elevated alkaline phosphatase. Magnetic resonance cholangiopancreatography revealed a dilated biliary system without any evident cause. Patient was subjected to endoscopic retrograde cholangioancreatography and it demonstrated biliary dilatation with a linear filling defect in lower common bile duct, further sphinicterotomy was done and a live Fasciola hepatica was extracted using a biliary basket. PMID- 25935974 TI - Bilateral hip and knee arthroplasty in ochronotic arthritis. AB - No effective medical treatment is available for the treatment of ochronotic arthritis which is a manifestation of long standing alkaptonuria. A patient of long standing alkaptonuria progressing to debilitating ochronotic arthritis of both hip and knee jointswith severe deformities has been described. He was successfully treated with bilateral total hip and knee arthroplasty with an excellent four-year follow-up. The occurrence of severe osteoporosis in this condition and the importance of advocating surgery before development of severe deformities of the joints to improve the outcome of surgery has been highlighted in this article. PMID- 25935975 TI - Gynandroblastoma: a rare ovarian tumour with an unusual clinical presentation. AB - Gynandroblastoma is a rare ovarian mixed sex cord stromal tumour with very few cases reported in literature. These tumours are considered to be potentially malignant. Here a case of gynandroblastoma occurring in a 30-year female is reported who gave history of irregular menstrual bleeding and pain abdomen, there were no signs of virilisation. Computed tomography scan showed a left adnexal mixed density pelvic mass suggesting malignant ovarian tumour. Histological study revealed, the tumour was composed of mixed sex cord elements with predominantly intermediate differentiated Sertoli-Leydig cell component and a second adult type granulosa cell component. PMID- 25935976 TI - Chemically controllable fabrication of one-dimensional ZnO nanostructures and their applications in solar cells. AB - One-dimensional (1D) ZnO nanostructures have attracted much attention due to their interesting optical and electronic properties, which make them suitable for a wide variety of current and future technological applications, including photodetectors, photovoltaics, photocatalysis, field emissions, gas sensors and solar cells. This review gives a comprehensive overview of recent developments in chemically controllable fabrication of 1D ZnO nanomaterials. We will cover the synthetic techniques including chemical vapor deposition (CVD), metal-organic chemical vapor deposition (MOCVD), hydrothermal technique, solvothermal synthesis, sol-gel method, electrochemical deposition, and nanosphere lithography technique. Finally, we will also highlight their application in the energy conversion system. PMID- 25935977 TI - Hypoxia-inducible factor-1alpha and erythropoietin expression in the hippocampus of neonatal rats following hypoxia-ischemia. AB - In some regions of the hippocampus, neurogenesis persists throughout life and is upregulated following hypoxia/ischemia. The mechanisms underlying the upregulation of neurogenesis, however, are not known. Here we examined the expression of two factors thought to be involved in hypoxia-related neurogenesis, hypoxia-inducible factor-1alpha (HIF-1alpha) and brain-derived erythropoietin (EPO), in the hippocampus of neonatal rats following hypoxia-ischemia. Sprague Dawley rat pups were exposed to hypoxia-ischemia conditions or hypoxia conditions only. For the hypoxia-ischemia experiment, the left common carotid artery of Sprague-Dawley rat pups was ligated on postnatal day 7. The pups were exposed to hypoxic conditions and then returned to normoxia for re-oxygenation. Immunohistochemical staining was performed to evaluate EPO and HIF-1alpha expression at various time points after re-oxygenation (1 h, 6 h, 16 h, 1 d, 3 d, and 7 d). EPO expression in the hippocampus was verified using Western blot studies. For the hypoxia-only experiment, postnatal day 7 rat pups were continuously exposed to hypoxic conditions for different durations (0.5 h, 1 h, 2 h, 3 h, and 5 h). HIF-1alpha expression in the hippocampus was evaluated by immunohistochemical staining. In the hypoxia-ischemia group, EPO expression was significantly altered. The EPO expression increased during re-oxygenation, peaked at 16 h, and decreased thereafter. In the hypoxia-only group, the EPO protein was not detectable. When the rat pups were returned to normoxia for re-oxygenation, there was no HIF-1alpha expression. HIF-1alpha immunoreactivity was present in the hypoxia-only group and peaked in rats exposed to continuous hypoxic conditions for 3 h. In addition, endogenous EPO increased in the neonatal rats after the hypoxia-ischemia event. Furthermore, HIF-1alpha was induced as a result of hypoxia. We postulate that disruption of homeostasis triggers and enhances hippocampal neurogenesis. Thus, HIF-1alpha/EPO hypoxic signal transduction may initiate hippocampal neurogenesis following hypoxia-ischemia. PMID- 25935978 TI - Glutathione-mediated release of functional miR-122 from gold nanoparticles for targeted induction of apoptosis in cancer treatment. AB - MiRs was efficiently bound to water-soluble positively charged gold nanoparticles through complementary electrostatic interaction. MiR-122 has been considered to be specifically expressed in liver and involved in inducing hepatocyte apoptosis through bcl-w pathway, which could be efficiently bound to water dispersible positively charged gold nanoparticles and conjugated with folic acid (FA) to target specific cancer cells, through complementary electrostatic interaction. These gold nanoparticles-miR-122-FA nanocomplexes (GMN) were disrupted and miR 122 was released by glutathione (GSH) at intracellular concentrations. In contrast, there was almost no detectable miR-122 released from GMN by extracellular concentration of GSH. The formation of GMN and GSH-mediated miR-122 release from the complexes were corroborated by dye displacement assay, electrophoresis experiment and transmission electron microscopy (TEM). With FA funcition, the GMN can target to the HepG2 cell membrane efficiently revealed by scanning electron microscopy (SEM). The released miR-122 retained apoptosis inducing activity after being transfected into HepG2 cells. The transfection efficiency measured by MTT assay and flow cytometry was comparable with the positive control. We determined the effects of GMN on HepG2 cells viability and apoptosis by using fluorescence light microscopy and SDS-PAGE/immunoblots. The obvious concentration gradient of GSH in nature between the intra- and extracellular environments as well as the GSH concentration-dependent release suggest that these positively charged gold nanoparticles can be used as a novel visible vehicle for gene delivery and open up promising opportunities for target applications in the future. PMID- 25935979 TI - Effect of 5-aminolevulinic acid-encapsulate liposomes on photodynamic therapy in human cholangiocarcinoma cells. AB - Intracellular protoporphyrin IX (PpIX) generation following administration of 5 aminolevulinic acid (ALA) has been used in photodynamic therapy (PDT). Subsequent irradiation can lead to selective damage to photosensitizer-treated cells or tissues. In the present work, we describe the enhancement of ALA-induced PpIX accumulation using a liposome carrier. ALA-containing liposomes (Lipo-ALA) were prepared using dipalmitoyl-phosphatidyl choline and in vitro PDT effect was investigated against human cholangiocarcinoma HuCC-T1 cells. Lipo-ALA increased the uptake efficiency into tumor cells compared to ALA itself, which increased the phototoxic effect. A positive relationship was evident between small particle size, PpIX accumulation and cell death after Lipo-ALA based PDT. PMID- 25935980 TI - Antitumor activity of trigonelline-incorporated chitosan nanoparticles. AB - In this study, trigonelline, a niacin-related compound was incorporated into chitosan nanoparticles through ion-complex formation between anionic carboxylic acid group of trigonelline and cationic amine group of chitosan. Morphology of trigonelline-incorporated chitosan nanoparticles have spherical shape with less than 500 nm in size and thier size distribution showed quite unimodel phase. Even though trigonelline and trigonelline-incorporated chitosan nanoparticles were not significantly affected to the proliferation of tumor cells, invasion of tumor cells was effectively inhibited by trigonelline-incorporated chitosan nanoparticles. We suggested that trigonelline-incorporated chitosan nanoparticles are promising candidate for inhibition of tumor cell invasion. PMID- 25935981 TI - Evaluation of oral bioavailability and anticancer potential of raloxifene solid lipid nanoparticles. AB - The objective of the present investigation was formulation of raloxifene loaded solid lipid nanoparticles (R-SLN) for oral administration and evaluation of its anticancer potential in 7,12- dimethylbenzanthracene (DMBA)-induced breast cancer in Sprague-Dawley rats. Optimized R-SLN formulation prepared by modified micro emulsion method resulted in R-SLN of 288.0+/-28.5 nm size and 95.56% entrapment efficiency. R-SLN exhibited in vitro prolonged release of raloxifene for 72 h in phosphate buffered saline. R-SLN was stable in simulated gastro-intestinal (GIT) fluids consisting of pH 1.2, pH 7.4, simulated gastric fluid and simulated intestinal fluid. A two-fold increase was observed in raloxifene oral bioavailability from R-SLN. R-SLN exhibited enhanced efficacy and chemopreventive activity over pure raloxifene as indicated by evaluation of tumor burden (P < 0.001) and tumor incidence (P < 0.001). The results indicate the potential of raloxifene solid lipid nanoparticles in optimizing chemoprevention of breast cancer by R-SLN. PMID- 25935982 TI - Silica nanotube surface modification for multiplex detection of pathogenic bacteria. AB - This study described the prospect of silica nanotube surface modification in simultaneous detection of pathogenic bacteria by coupling cation exchange magnetic separation with quantum dot labeling. The outer surface of magnetic nanoparticles embedded long silica nanotube (capturing SNT) was modified with poly-L-lysine to serve as a cation exchange magnetic nano-complex to capture and isolate Escherichia coli (E. coli) O157:H7 and Salmonella enteritis typhimurium (S. typhimurium) in aqueous phase. Antibody conjugated quantum dot-embedded short SNT (reporting SNT) was used to simultaneously detect both bacteria, giving a high intensity and photo-stable fluorescent image that can detect single leveled bacterium binding on the capturing SNT. The fluorescent intensity generated from the capturing of both bacteria at different concentration was in the range of 10(2)-10(5) CFU/ml for both E. coli and S. typhimurium. PMID- 25935983 TI - Fabrication of the optical fiber pH sensor based on CdSe/ZnS quantum dot. AB - During the past decade, there has been a lot of research on the application of quantum dots (QDs) in photonics and biotechnology. QDs are semiconductor nanocrystals which show many peculiar optical and electrical properties due to their quantum confinement effects. In this work, the correlation of the fluorescence intensity of QDs and the pH under ambient temperature was studied. An optical fiber pH sensor was prepared using CdSe/ZnS carboxyl quantum dots as sensing media. QDs with different sizes and emission colors (green, yellow, and red) were immobilized on the surface of the optical fiber through EDC/sulfo-NHS coupling reaction. The optical fiber was immersed in water, and the photoluminescence (PL) spectra of QDs were obtained at ambient temperature under various pH conditions. The photoluminescence (PL) intensity of QDs increased linearly with the increase of pH, and among the QDs, the red emitting QDs show the largest change in PL intensity with pH. This shows that QDs can be used as pH sensing media and optical fiber pH probe can be prepared. PMID- 25935984 TI - Probing actin filament and binding protein interaction using an atomic force microscopy. AB - Actin filaments play essential roles in many kinds of cellular functions by interacting with hundreds of actin binding proteins. Here we probe the interaction between actin filament and a binding protein, alpha-actinin, using an atomic force microscopy (AFM) and dynamic force spectroscopy (DFS). The distribution of rupturing events including specific and non-specific interactions of actin filament/alpha- actinin and BSA/alpha-actinin were analyzed. The rupture force of the actin filament/alpha-actinin binding was significantly larger than that of the BSA/alpha-actinin non-specific interaction, and the peaks represent typical multiple parallel bonds. In addition, based on the rupture forces in different loading rate DFS experiments, the dissociation constant of actin filament/alpha-actinin binding was estimated. The value is in good agreement with a previously reported value obtained by optical tweezer measurement. We expect that the present method will be useful for interaction measurement of actin filaments and many kinds of binding protein. PMID- 25935985 TI - Localized surface plasmon resonance-based label-free biosensor for highly sensitive detection of dopamine. AB - Localized surface plasmon resonance (LSPR) is the phenomenon that is observed on specific metal nanoparticles (NPs) like Au, Ag which can be used for sensitive detection for many kinds of biomaterials. Dopamine (DA) is a typical neurotransmitter considered as indicator of some neural diseases. Due to its small size, it is very difficult to detect DA at low concentrations directly and sensitively with conventional sensing techniques. In this research, we propose a DA detection sensor based on LSPR phenomenon. Electrochemical deposition technique was used to make LSPR substrates, where Au NPs were electrochemically deposited on ITO glasses and these substrates showed optical characteristic of LSPR phenomenon. Different concentrations of DA solution were deposited on antibody immobilized LSPR substrates. With additions of increasing concentrations of DA, LSPR peak intensity was increased linearly. These results could be applied to many fields of clinical trials for diseases caused by small molecules. PMID- 25935987 TI - Corneal penetration of gold nanoparticles--therapeutic implications. AB - Gold nanoparticles can show anti-glycation activity thereby preventing the aggregation of proteins. As glycation is one of the leading causes of cataract formation, the finding is important in therapeutic management of ocular pathology that follows cataract formation (e.g., cortical changes often resulting in nuclear sclerosis). In the present study, we have successfully conducted in vivo experiments using guinea pig models. While the anti-glycation property of GNPs is known in vitro, the present work for the first time shows corneal penetration of GNPs. The therapeutic promise of using GNP as an anti-cataract agent thus seems imminent. GNPs traverse and get deposited into different layers of the cornea as examined by Transmission Electron Microscopy (TEM). PMID- 25935986 TI - Rolling circle amplification immunoassay combined with gold nanoparticle aggregates for colorimetric detection of protein. AB - A highly sensitive and novel colorimetric rolling circle amplification (RCA) immunoassay for detecting C-reactive protein (CRP) has been developed. In the assay, a CRP capture antibody was immobilized on magnetic beads and a CRP detection antibody was conjugated with single-stranded DNA (ssDNA) using N [epsilon-maleimidocaproyloxy] sulfosuccinimide ester. Along with the addition of CRP, a "sandwich" structure was formed. Subsequently, the ssDNA was used as a primer to initiate the RCA reaction in the presence of the circular template, phi29 DNA polymerase and deoxynucleotide triphosphates. The RCA product obtained by magnetic separation, and long tandem repeated sequences mediated the aggregation of gold nanoparticles (AuNPs), which could be observed by the naked eye or quantified using absorption spectra with a detection limit of 30 fg mL(-1) and a linear response range from 10 ng mL(-1) to 1 pg mL(-1). This assay offers the advantages of isothermal conditions, low cost and label-free quantification that could be hopeful for ultrasensitive and robust visual protein detection. PMID- 25935988 TI - PEO-b-PCL grafted DPPC liposomes: physicochemical characterization and stability studies of novel bio-inspired advanced Drug Delivery nano Systems (aDDnSs). AB - Amphiphilic block copolymers and lipids have attracted major scientific interest in recent years due to their intriguing self-assembly behavior, which results in a plethora of nanoassemblies and their potential applications in Pharmaceutical Nanotechnology, as bio-inspired chimeric or hybrid advanced Drug Delivery nano Systems (aDDns). In this work, we report on stability studies of chimeric systems consisted of DPPC (dipalmitoylphosphatidylcholine) and poly(ethylene oxide)-block poly(epsilon-caprolactone) (PEO-b-PCL) block copolymer in Phosphate Buffer Saline (PBS) and Fetal Bovine Serum (FBS). The incorporation of PEO-b-PCL leads to bio inspired nanovectors of smaller size, in comparison to DPPC neat liposomes. All the prepared chimeric liposomal formulations were found to retain their original physicochemical characteristics for at least five days. These nanocarriers could be characterized as stealth liposomes due to their biological stability. The composition of the bio-inspired aDDnSs play a key role on their physicochemical and structural properties, as well as on their biological response, which could be a road map for designing aDDnSs based on the bio-inspiration. PMID- 25935989 TI - Osteoblast cell adhesion and viability on nanostructured surfaces of porous titanium oxide layer. AB - Surface characteristics and osteoblast cell functions were investigated for the nano-structured oxide layer on commercially pure titanium (CP-Ti) fabricated using microarc oxidation (MAO) and hydrothermal treatment (HT) methods. Ti-MAO 135HT, Ti-MAO-150HT, and Ti-MAO-175HT groups were fabricated by hydrothermally treating the MAO-treated specimens (Ti-MAO) in phosphorus-containing alkaline solution at temperatures of 135, 150, or 175 degrees C, respectively. After hydrothermal treatment, a nanosheet-shaped morphology, nano-needles and nanorods were observed on the porous surface of the Ti-MAO-135HT, Ti-MAO-150HT and Ti-MAO 175HT groups, respectively. The roughness was not significantly different for all groups. However the contact angle decreased dramatically as the hydrothermal temperature increased. The osteoblastic cell adhesion and viability of the Ti-MAO 150HT and Ti-MAO-175HT groups were significantly lower compared to those of the Ti-MAO group. This study showed that nano-topology formed on micro porous oxide layer was more important than hydrophilicity in its effect upon initial osteoblastic cell functions. PMID- 25935990 TI - Toxicity of ZnO nanoparticles to macrophages due to cell uptake and intracellular release of zinc ions. AB - Although the ZnO nanoparticles (NPs) have been widely used in research and industry, their health risks are only concerned very recently. In this paper, attention is paid to elucidate the toxic effects and intrinsic mechanism of ZnO NPs to RAW 246.7 macrophage cells. The ZnO NPs from industry additives had a diameter of ~37 nm in a dry state and aggregated to submicron size in cell culture medium with slightly negative surface charge. Influences of ZnO NPs on cell toxicity and functions were then studied in terms of cell viability, mitochondrial membrane potential (MMP), total and released lactate dehydrogenase (LDH) activity, intracellular level of reactive oxygen species (ROS) and Zn2+ concentration. The ZnO NPs induced elevation of intracellular Zn2+ concentration, leading to the over generation of intracellular ROS, leakage of plasma membrane, dysfunction of mitochondria, and cell death. The solubility of ZnO NPs was found largely enhanced in acidic environment (pH 5.5), compared to physiological condition (pH 7.2). Inhibition of cell uptake of ZnO NPs would largely reduce the cytotoxicity. These results demonstrate that the cell uptake, intracellular dissolution and thereafter release of Zn2+ are the intrinsic reasons for the high toxicity of ZnO NPs. PMID- 25935991 TI - The joining of graphene sheets under Ar ion beam irradiation. AB - In this paper, Ar ion beam irradiation was proposed as a method to join the overlapped graphene sheets and the joining process was researched by classical molecular dynamics simulation. The results showed that the ion irradiation behavior could successfully induce the joining of overlapped graphene sheets. The joining results were found to be attributed to the saturation of dangling bonds generated during irradiation. Meanwhile, it was confirmed that the ion parameters had influence on the properties of the joint and the optimum ion parameters were obtained using tensile test simulation. The optimum ion dose and ion energy were 1.9 x 10(15) ions/cm2 and 60 eV, respectively. To emphasize the importance of the irradiation, we further studied the joining possibilities of graphene sheets when the irradiation was replaced by a large force (160 nN) acting on the upper sheet and we demonstrated that the joining results wouldn't happen without the irradiation. At last, the influence of the chirality of the graphene sheets on the joining process were discussed, and it was found that graphene sheets with the same chirality had higher matching-degree, which would result in better joint. PMID- 25935992 TI - Nylon 610/graphene oxide composites prepared by in-situ interfacial polymerization. AB - Nylon 610/nylon 610-grafted graphene oxide (nylon 610/GO-g-nylon 610) composites were fabricated using acyl chloride-functionalized graphene oxide by in-situ interfacial polymerization. GO-g-nylon 610 was synthesized by the condensation reaction between the acyl chloride groups of GO and the amino groups at the nylon 610 chains during the in-situ polymerization. Nylon 610/GO composites without grafting nylon 610 onto GO were also prepared to investigate the influence of grafting nylon 610 on the interfacial adhesion between GO and the nylon 610 matrix. The thermal properties of the nylon 610/GO-g-nylon 610 composites were enhanced with increasing GO-g-nylon 610 content in the nylon 610 matrix. The degradation temperature and thermal conductivity of the nylon 610/GO-g-nylon 610 10 composite were increased to 72.2 degrees C and 36.9%, respectively, compared with those of pure nylon 610. The crystallinity of the nylon 610/GO-g-nylon 610 10 composite was significantly lower than that of pure nylon 610 due to the hindered mobility of the nylon 610 chains by the strong interfacial adhesion between the GO-g-nylon 610 and the nylon 610 matrix. PMID- 25935993 TI - One-pot synthesis of conducting poly(3-methylthiophene)-grafted-graphene nanosheets. AB - We report a simple one-pot synthesis of graphene nanosheets wrapped poly(3 methylthiophene) (GNs-f-P3MT) composites. At first, natural graphite was oxidized using the Hummer's method followed by chemical reduction with hydrazine monohydrate to yield GNs. Subsequently, in-situ chemical oxidative polymerization of 3-methylthiophene was carried out to obtain noncovalently bonded GNs-f-P3MT composites. The morphology and microstructure of the composites together with pure graphene oxide and GNs were characterized using XPS, XRD, FT-IR, FESEM, HRTEM and TGA. The microscopic results indicated the homogeneous dispersion of GNs throughout the polymer matrix. Furthermore, thermogravimetric results illustrated that the addition of GNs into the P3MT matrix led to improvement in the thermal stability of the composites. PMID- 25935994 TI - Water soluble graphene oxide/poly(1-vinylimidazole) composites: synthesis and characterization. AB - Modified graphene oxide/poly(1-vinylimidazole) (mGO/PVIm) composites were prepared via surface-initiated free radical graft polymerization. First, the hydroxyl-enriched GO sheets were functionalized with 3 methacryloxypropyltrimethoxysilane to introduce active-vinyl groups on the GO surfaces. Subsequently, 1-vinylimidazole was chemically grafted and polymerized in the presence of mGO. The chemical structures and morphology of the covalently bonded composites were characterized using FTIR, XPS, TGA, HRTEM, FESEM and XRD measurements. The mGO/PVIm composites exhibit a stable dispersion in water and show high storage stability (>10 days). Furthermore, the morphological analysis showed that mGO was homogeneously dispersed in the polymer matrix. PMID- 25935995 TI - Thermal and mechanical properties of reduced graphene oxide/polyurethane nanocomposite. AB - Reduced graphene oxide (RGO) based polyurethane (PU) nanocomposites have been successfully prepared without using solvent by in-situ polymerization. RGO was derived from microwave (MW) irradiation of graphite oxide (GO) powder prepared by a modified Hummer's method. A minimum amount of poly(tetramethylene glycol) (PTMEG) was added during the dispersion of RGO in a solvent to stabilize the graphene sheets and to prevent RGO from the restacking after the removal of the solvent. After the reaction of RGO with 4,4'-diphenylmethane diisocyanate (MDI), we obtained the concentrate of RGO in MDI with a minimum amount of PTMEG. Our method facilitated the fine dispersion of RGO in PU elastomers and improved the interfacial strength between RGO and PU. With the incorporation of 2.0 wt% of RGO, the tensile strength and Young's modulus of the PU nanocomposites increased by 30% and 50%, respectively without sacrificing the elongation at break. It was found that the crystalline portion of hard segments of the PU was lowered by the RGO in the nanocomposites. PMID- 25935996 TI - A green preparation of nitrogen doped graphene using urine for oxygen reduction in alkaline fuel cells. AB - A simple, eco-friendly and efficient harmless chemical approach has been developed for the simultaneous nitrogen (N) doping and reduction of graphene oxide (GO) by cost free human urine using simple refluxing. Large-scale preparation of graphene has been hindered largely by several issues, such as highly toxic reducing agents that are harmful to human health and environment, complicated reduction process and costly chemicals. Human urine is a natural precursor of urea with no cost. In this process, the NH3 has acted as not only reducing but also doping agent that produced via thermal decomposition of urea, while the N doping level of ~11.1 at% is achieved. For the first time we have used urine as a reductant and doping agent in such a high class chemical technology. The simultaneous reduction and N-doping of GO using urine (denoted as UNG) have confirmed by X-ray photoelectron spectroscopy (XPS), X-ray diffraction (XRD), Fourier transform infrared (FTIR) spectroscopy, Raman spectroscopy, and UV vis spectroscopy. The resultant UNG has demonstrated to show remarkable electrocatalytic activity toward oxygen reduction reaction (ORR) with better fuel selectivity, and stability than that of the commercially available 20 wt% Pt/C electrode using cyclic voltammetry (CV) and chronoamperometry. PMID- 25935997 TI - Facile and green synthesis of CdSe quantum dots in protein matrix: tuning of morphology and optical properties. AB - Herein, we have demonstrated a facile and green approach for the synthesis of Cadmium selenide (CdSe) quantum dots (QDs). The process was mediated by bovine serum albumin (BSA) and it was found that BSA plays the dual role of reducing agent as well as a stabilizing agent. The QDs exhibited sharp excitonic absorption features at ~500 nm and subsequently showed reasonably good photoluminescence (PL) at room temperature. The PL is seen to be strongly dependent on the concentration of the precursors and hence, the luminescence of these QDs could be conveniently tuned across the visible spectrum simply by varying molar ratio of the precursors. It can be envisaged from the fact that a red-shift of about 100 nm in the PL peak position was observed when the molar ratio of the precursors ([Cd2+]:[Se2-], in mM) was varied from 10:5 to 10:40. Subsequently, the charge carrier relaxation dynamics associated with the different molar ratio of precursors has been investigated and very interesting information regarding the energy level structures of these QDs were revealed. Most importantly, in conjunction with the optical tuning, the nanomorphology of these nanoparticles was found to vary with the change in molar ratios of Se and Cd precursors. This aspect can provide a new direction of controlling the shape of CdSe nanoparticles. The possible mechanism of the formation as well as for the shape variation of these nanoparticles with the molar ratios of precursors has been proposed, taking into account the role of amino acid residues (present in BSA). Moreover, the QDs were water soluble and possessed fairly good colloidal stability therefore, can have potential applications in catalysis and bio labeling. On the whole, the present methodology of protein assisted synthesis is relatively new especially for semiconducting nanomaterials and may provide some unique and interesting aspects to control and fine tune the morphology vis-a-vis, their optical properties. PMID- 25935998 TI - Preparation and catalytic activity of poly(N-vinyl-2-pyrrolidone)-protected Au nanoparticles for the aerobic oxidation of glucose. AB - PVP-protected Au nanoparticles (NPs) for the aerobic oxidation of glucose were prepared by using NaBH4 reduction method. The effects of processing parameters such as Au3+ ion concentration, reaction temperature, ratio of NaBH4 or PVP to Au3+, and solvent composition on their particle sizes and catalytic activities were studied in detail and the synthesis conditions optimized. As-prepared Au NPs possessed a FCC structure, with an average size varying from about 100 to 2.6 nm depending on their preparation conditions. The size changes affected their catalytic activities in the aerobic oxidation of glucose. The Au NPs with the average size of 2.6 nm prepared under the optimal conditions showed a high instantaneous catalytic activity as well as a high long-time stability. Based on the kinetic study on the glucose oxidation over the PVP-protected Au NPs, the corresponding apparent activation energy was determined as 82 kJ mol(-1). PMID- 25935999 TI - Surface plasmon enhanced organic solar cell with different silver nanosphere sizes. AB - We have systematically investigated the plasmonic effects on the characteristics of OPV devices of a blend of poly(3-hexylthiophene) (P3HT) and [6,6]-phenyl-C61 butyric acid methyl ester (PCBM) as well as of blend of polymer poly[2,1,3 benzothiadiazole-4,7-diyl[4,4-bis(2-ethylhexyl)-4H-cyclopenta [2,1-b:3,4 b']dithioph-ene-2,6-diyl]] (PCPDTBT) and PCBM with an incorporated thin silver (Ag) film. Silver nanospheres (NSs) were introduced through a solution casting process to improve the performance of bulk-heterojunction organic solar cells. The Ag NSs with variable sizes were investigated, with the aim of optimizing the performance of devices. The power conversion efficiency (PCE) increases by a maximum 14% for the 40 nm Ag NSs. The larger-sized Ag NSs used in this study led to a larger enhancement of short circuit current JSC and PCE. Analysis of the changes in electronic performance leads to the conclusion that the plasmonic light trapping scheme improves the performance of OPV devices. This is caused by the increases of both fill factor and JSC, whilst open circuit voltage VOC remains relatively constant. These enhancements are mainly due to the localized surface plasmon resonance and light scattering of metal nanoparticles, which increase the light absorption of active layer and improve the exciton generation and dissociation. PMID- 25936000 TI - Chitosan-gold-Lithium nanocomposites as solid polymer electrolyte. AB - Lithium micro batteries are emerging field of research. For environmental safety biodegradable films are preferred. Recently biodegradable polymers have gained wide application in the field of solid polymer electrolytes. To make biodegradable polymers films plasticizers are usually used. However, use of plasticizers has disadvantages such as inhomogenities in phases and mechanical instability that will affect the performance of Lithium micro batteries. We have in this research used gold nanoparticles that are environmentally friendly, instead of plasticizers. Gold nanoparticles were directly template upon chitosan membranes by reduction process so as to enhance the interactions of Lithium with the polymer. In this article, for the first time the characteristics of Chitosan gold-Lithium nanocomposite films are investigated. The films were prepared using simple solution casting technique. We have used various characterization tools such as Small Angle Neutron Scattering (SANS), XRD, FTIR, Raman, FESEM, and AFM, Light scattering, Dielectric and electrical conductivity measurements. Our investigations show that incorporation of gold results in enhancement of conductivity in Lithium containing Chitosan films. Also it affects the dielectric characteristics of the films. We conclude through various characterization tools that the enhancement in the conductivity was due to the retardation of crystal growth of lithium salt in the presence of gold nanoparticles. A model is proposed regarding the formation of the new nanocomposite. The conductivity of these biodegradable films is comparable to those of the current inorganic Lithium micro batteries. This new chitosan-Au-Li nanocomposite has potential applications in the field of Lithium micro batteries. PMID- 25936001 TI - Dielectric and conductivity characteristics of CuCl2 doped poly(N-vinyl carbazole) and its hybrid nanocomposite with Fe3O4. AB - Copper(II) chloride (CuCl2) doped poly(N-vinyl carbazole) (PNVC)-ferric oxide (Fe3O4) hybrid composites have been prepared and characterized by Fourier transform infrared spectroscopic studies, UV-Vis spectroscopy, high resolution transmission electron microscopy (HRTEM) and X-ray diffraction analyses and evaluated in regard to dielectric response and ac/dc conductivity characteristics. HRTEM images for CuCl2-(PNVC-Fe3O4) composite indicate the co existence of both the CuCl2 and Fe3O4 nanoparticles in the composite and characteristic lattice fringes are clearly observed which endorse the formation of thin layer interfaces between Fe3O4 and CuCl2 nanoparticles. The dielectric constants of the CuCl2 doped PNVC and PNVC-Fe3O4 composites increase substantially relative to the corresponding values of the polymer and the polymer composite respectively. Likewise, the conductivities (ac and dc) are also improved substantially after doping with CuCl2. The dependence of these functional properties on the extent of metal salt loading has been evaluated and a quantitative estimation of the contribution of the grain boundary and resistance parameters has been attempted in terms of Maxwell-Wagner two-layered model. PMID- 25936002 TI - Facile synthesis and luminescence properties of Y2O3:Ln(3+) (Ln(3+) = Eu(3+), Tb(3+), Dy(3+), Sm(3+), Er(3+), Ho(3+), Tm(3+), Yb(3+)/Er(3+), Yb(3+)/Tm(3+), Yb(3+)/Ho(3+)) microspheres. AB - Multicolor and monodisperse Y2O3:Ln(3+) (Ln(3+) = Eu(3+), Tb(3+), Dy(3+), Sm(3+), Er(3+), Ho(3+), Tm(3+), Yb(3+)/Er(3+), Yb(3+)/Ho(3+)) microspheres were prepared through a facile urea-assisted homogeneous precipitation method followed by a subsequent calcination process. X-ray diffraction (XRD), scanning electron microscopy (SEM), transmission electron microscopy (TEM), high-resolution transmission electron microscopy (HRTEM), energy-dispersive X-ray spectrum (EDS), Fourier transformed infrared (FT-IR), thermogravimetric analysis (TGA), photoluminescence (PL) and cathodoluminescence (CL) spectra were employed to characterize the samples. The XRD results reveal that the as-prepared spheres can be well indexed to cubic Y2O3 phase with high purity. The SEM and TEM images show the obtained Y2O3:Ln(3+) samples consist of regular nanospheres with the mean diameter of 350 nm. And the possible formation mechanism is also proposed. Upon ultraviolet and low-voltage electron beams excitation, Y2O3:Ln(3+) (Ln(3+) = Eu(3+), Tb(3+), Dy(3+), Sm(3+), Er(3+), Ho(3+), Tm(3+)) samples exhibit respective bright red (Eu(3+), (5)D0 --> (7)F2), green (Tb(3+), (5)D4 --> (7)F5), blue (Dy(3+), (4)F9/2 --> (6)H13/2), yellow (Sm(3+), (4)G5/2 --> (6)H7/2), green (Er(3+), (4)S3/2 --> (4)I15/2), green (Ho(3+), (5)S2 --> (5)I8), blue (Tm(3+), (1)D2 --> (3)F4) down-conversion (DC) emissions. Under 980 nm NIR irradiation, Y2O3:Ln(3+) (Ln(3+) = Yb(3+)/Er(3+), Yb(3+)/Tm(3+) and Yb(3+)/Ho(3+)) exhibit characteristic up-conversion (UC) emissions of green (Er(3+), (2)H11/2, (4)S3/2, (2)H11/2 --> (4)I5/2), blue (Tm(3+), (1)G4 --> (3)H6) and green (Ho(3+), (5)F4, (5)S2 --> (5)I8), respectively. These merits of multicolor emissions in the visible region endow this kind of material with potential applications in the field of light display systems, lasers, and optoelectronic devices. PMID- 25936003 TI - Microwave assisted synthesis of magnetite nanoparticles. AB - Magnetite nanoparticles of size ranging from 7-10 nm are prepared from aqueous solutions of Fe2+ and Fe3+ by microwave irradiation at different reaction temperatures ranging from 50 to 200 degrees C. The effect of reaction temperature on the structural and magnetic properties of nanoparticles is studied using X-ray diffraction (XRD), Transmission electron microscopy (TEM), Small angle X-ray scattering (SAXS), Thermo gravimetry (TGA), Differential scanning calorimetry (DSC), Vibrating sample magnetometer (VSM) and Fourier transform infrared spectroscopy (FTIR) techniques. The average size of the prepared particles, obtained from SAXS, is found to vary from 11 to 15+/-1 nm as the reaction temperature is increased from 50 to 200 degrees C. The weight gain curves under an external magnetic field show slope changes at 300 and 596 degrees C because of the magnetite to maghemite phase transition and ferri to paramagnetic phase transitions, respectively. The ferromagnetic gamma-Fe2O3 to antiferromagnetic alpha-Fe2O3 phase transition temperature is found to be enhanced by 154 degrees C for the nanoparticles prepared at 200 degrees C, due to an enhanced activation energy for the cubic to a more compact hexagonal transition. The increase in the phase stability of nanoparticles prepared at elevated temperature is attributed to the diffusion of Na+ in the spinel structure. These results are useful to tailor magnetic particles with enhanced thermal stability for practical applications. PMID- 25936004 TI - Finite element analysis on the electrical and optical properties in HTL/mCP/ETL multilayer organic light emitting diode device structure. AB - In this paper, we report our numerical study on the electrical and optical properties in HTL/mCP/ETL multilayer organic light emitting diode (OLED) device structure. Our finite element method (FEM) model includes the transport behavior of electrons and holes, the generation and decay of excitons, and emission and extinction properties of excitons. We employ the multilayer structure which consists of 1,1-bis[(di-4-tolylamino)phenyl] cyclohexane (TAPC); 4,4'-bis[N-(1 naphthyl)-N-phenyl-amino]biphenyl (alpha-NPD); 4,4'-bis[N-(p-tolyl)-N phenylamino] biphenyl (TPD); 3,5'-N,N'-dicarbazole-benzene (mCP); 2,9-dimethyl 4,7-diphenyl-1,10-phenanthroline (BCP); 4,7-diphenyl-1, 10-phenanthroline (BPhen). We report our observation of the effect of the different hole transport layer following TAPC, alpha-NPD, TPD and also discuss the effect of different electron transport layer following BCP, BPhen. Our simulation revealed that the charge balance results in a significant effect on the recombination density which is related to the generation of excitons. PMID- 25936005 TI - The effect of a charge control layer on the electroluminescent characteristic of blue and white organic light-emitting diodes. AB - We investigated blue fluorescent organic light-emitting diode (OLED) with a charge control layer (CCL) to produce high efficiency and improve the half-decay lifetime. Three types of devices (device A, B, and C) were fabricated following the number of CCLs within the emitting layer (EML), maintaining the thickness of whole EML. The CCL and host material, 2-methyl-9,10-di(2-naphthyl)anthracene, which has a bipolar property, was able to control the carrier movement with ease inside the EML. Device B demonstrated a maximum luminous efficiency (LE) and external quantum efficiency (EQE) of 9.19 cd/A and 5.78%, respectively. It also showed that the enhancement of the half-decay lifetime, measured at an initial luminance of 1,000 cd/m2, was 1.5 times longer than that of the conventional structure. A hybrid white OLED (WOLED) was also fabricated using a phosphorescent red emitter, bis(2-phenylquinoline)-acetylacetonate iridium III doped in 4,4' N,N'-dicarbazolyl-biphenyl. The property of the hybrid WOLED with CCL showed a maximum LE and an EQE of 13.46 cd/A and 8.32%, respectively. It also showed white emission with Commission International de L'Eclairage coordinates of (x = 0.41, y = 0.33) at 10 V. PMID- 25936006 TI - Ultrafast response sensor to formaldehyde gas based on metal oxide. AB - Thick film semiconductor gas sensors based on indium oxide were fabricated on Si substrate. The sensing materials on Si substrate were characterized using optical microscopy, X-ray diffraction (XRD) and scanning electron microscopy (SEM), and so on. They were very fine and uniform and we found out that particle sizes were about 20~30 nm through XRD analysis. Gas responses of fabricated sensors were measured in a chamber where gas flow was controlled by mass flow controller (MFC). Their resistance changes were monitored in real time by using data acquisition board and personal computer. Gas response characteristics were examined for formaldehyde (HCHO) gas which was known as the cause of sick building syndrome. Particularly, the sensors showed responses to formaldehyde gas at sub ppm (cf, standard of natural environment in building is about 80 ppb by ministry of environment in Korea), as a function of operating temperatures and gas concentrations. Also, we investigated sensitivity, repetition, selectivity, response speed and reproducibility of the sensors. The lowest detection limit is HCHO 25 ppb and sensitivity at 800 ppb is over 25% at 350 degrees C operating temperature. The response time (8 s) and recovery time (15 s) to HCHO gas at 200 ppb were very fast compared to other commercial products in flow type measurement condition. Repetition measurement was very good with +/-3% in full measurement range. The fabricated metal oxide gas sensor showed good performance to HCHO gas and proved that it could be adaptable to indoor environment in building. PMID- 25936007 TI - Roles of metal/activated carbon hybridization on elemental mercury adsorption. AB - In this study, the elemental mercury removal behavior of metal (copper or nickel)/activated carbon hybrid materials were investigated. The pore structures and total pore volumes of the hybrid materials were analyzed using the N2/77 K adsorption isotherms. The microstructure and surface morphologies of the hybrid materials were characterized by X-ray diffraction and scanning electron microscopy, respectively. In the experimental results, the elemental mercury adsorption capacities of all copper/activated carbon hybrid materials were higher than that of the as-received material despite the decrease in specific surface areas and total pore volumes after the metal loading. All the samples containing the metal particles showed excellent elemental mercury adsorption. The Ni/ACs exhibited superior elemental mercury adsorption to those of Cu/ACs. This suggests that Ni/ACs have better elemental mercury adsorption due to the higher activity of nickel. PMID- 25936008 TI - Hydrothermal synthesis of high-quality type-II CdTe/CdSe core/shell quantum dots with dark red emission. AB - A hydrothermal method was used to synthesize type-II CdTe/CdSe core/shell quantum dots (QDs) using the thilglycolic acid (TGA) capped CdTe QDs as cores, which show a number of advantages. Because of the spatial separation of carriers the low excited states of CdTe/CdSe QDs, they exhibit many novel properties that are fundamentally different from the type-I QDs. On the other hand, our experiment results show that the wave function of the hole of the exciton in the CdTe core extends well into the CdSe shell. The results also reveal that a thick shell can confine the electrons inside the particles and thereby improve the PL efficiency and prolong the lifetime of the core/shell QDs. We use the UV-vis absorption and fluorescence spectrum measurements on growing particles in detail. We found that the fluorescence of the CdTe/CdSe QDs was strongly dependent on the thick of the shell and size of the core as well as the unique type-II heterostructure, which make the type-II core/shell QDs more suitable in photovoltaic or photoconduction applications. PMID- 25936009 TI - Deposition and thermal characterization of nano-structured aluminum nitride thin film on Cu-W substrate for high power light emitting diode package. AB - In this study, we developed AlN thick film on metal substrate for hybrid type LED package such as chip on board (COB) using metal printed circuit board (PCB). Conventional metal PCB uses ceramic-polymer composite as electrical insulating layer. Thermal conductivities of such type dielectric film are typically in the range of 1~4 W/m . K depending on the ceramic filler. Also, Al or Cu alloy are mainly used for metal base for high thermal conduction to dissipate heat from thermal source mounted on metal PCB. Here we used Cu-W alloy with low thermal expansion coefficient as metal substrate to reduce thermal stress between insulating layer and base metal. AlN with polyimide (PI) powder were used as starting materials for deposition. We could obtain very high thermal conductivity of 28.3 W/m . K from deposited AlN-PI thin film by AlN-3 wt% PI powder. We made hybrid type high power LED package using AlN-PI thin film. We tested thermal performance of this film by thermal transient measurement and compared with conventional metal PCB substrate. PMID- 25936010 TI - Optimization of the TiO2-surface modification temperature for performance enhancement of dye-sensitized solar cells. AB - A nanoporous TiO2 electrode was modified with magnesium salts (MSs), MgCO3 and Mg(CH3COO)2, by simple dip coating process at varied temperatures, and then applied to dye-sensitized solar cells (DSSCs). When the surface treatment was conducted at 40 degrees C, the DSSC with MS-modified TiO2 layer showed an increase in short circuit current (JSC) and open circuit voltage (VOC), resulting in a power conversion efficiency of 8.52%, compared to that (7.02%) of reference device with bare TiO2. The improved JSC value was attributed to the increased dye adsorption. Electrochemical impedance spectroscopy and dark current-voltage studies revealed that the VOC enhancement was caused by the suppression of charge recombination between injected electrons and I3(-) ions. PMID- 25936011 TI - Synthesis, structure, and gas-sensing properties of Pt-functionalized TiO2 nanowire sensors. AB - TiO2 one-dimensional (1D) nanostrutures were synthesized by using a three-step hydrothermal technique. Subsequently, Pt nanoparticles were coated on the nanowire surface by sputter-deposition of Pt followed by annealing at 800 degrees C in an Ar atmosphere for 30 min. The morphology, crystal structure, and enhanced sensing characteristics of the TiO2 nanostructures functionalized with Pt to CO and NO2 gases at 300 degrees C were investigated. The diameter of the 1D nanostructures was in a range from a few tens to a few hundreds of nanometers and the length was up to a few tens of micrometers. The TiO2 nanowires synthesized by the three-step hydrothermal technique comprised two polymorphic (rutile and anatase) TiO2 phases and a Ti2O3 phase. Pt nanoparticle with various sizes ranging from 30 to 200 nm were on the whole uniformly distributed around the surface of each TiO2 nanowire. The sensitivity of the TiO2 nanowires was improved by a factor of 1.55 at a CO concentration of 30 ppm and 1.18 at NO2 concentrations of 50 ppm, respectively, by Pt-functionalization at 300 degrees C. In addition, the mechanism for the improvement in the gas sensing properties of TiO2 nanowires by Pt functionalization are discussed. PMID- 25936012 TI - A numerical study on the charge transport in TPD/Alq3-based organic light emitting diodes. AB - We report our simulation study on the charge transport characteristic of the multi-layer structure for organic light emitting diodes (OLEDs). We performed a numerical simulation on a multilayer structure comprising a hole transport layer (HTL), an emission layer (EML), and an electron transport layer (ETL) between both electrodes. The material of the HTL is TPD (N,N'-Bis (3-methylphenyl)-N,N' bis(phenyl) benzidine), and the ETL includes Alq3 (Tris (8-hyroxyquinolinato) aluminium). Here, we investigated the parameters such as recombination rates which influence the efficiency of the charge transport between layers in bilayer OLEDs. We also analyzed a transient response during the turn on/off period and the carrier transport in accordance with the variation of the injection barrier and applied voltage. In addition, our numerical simulation revealed that the insertion of the EML affects the photonic characteristics in bilayer structure and also the efficiency due to the difference in the internal barrier height. PMID- 25936013 TI - Fabrication and optical characterization of multi-encoded rugate porous silicon/polymer composite. AB - Multi-encoded rugate porous silicon (MRPS)/polystyrene composite films were fabricated by using a free-standing multi-encoded rugate PS and polystyrene. MRPS exhibiting three reflection resonances was generated by an electrochemical etching of silicon wafer using a composite waveform summed three computer generated pseudo-sinusoidal current waveforms, which were corresponded to the each of the sine components varied from 0.40, 0.38, to 0.36 Hz, with a spacing of 0.02 Hz between each sine component. They displayed three sharp photonic reflection resonances in the optical reflectivity spectrum. MRPS/polymer composite films obtained by casting of polystyrene polymer solution exhibited excellent photonic characteristics and robust structure upon flexing. For a possible application as VOCs sensor, these films were served for the detection of organic vapors such hexane and methanol. PMID- 25936014 TI - Development of nanostructured ZnO thin film via electrohydrodynamic atomization technique and its photoconductivity characteristics. AB - This article presents the non-vacuum technique for the preparation of nanostructured zinc oxide (ZnO) thin film on glass substrate through electrohydrodynamic atomization (EHDA) technique. The detailed process parameters for achieving homogeneous ZnO thin films are clearly discussed. The crystallinity and surface morphology of ZnO thin film are investigated by X-ray diffraction and field emission scanning electron microscopy. The result shows that the deposited ZnO thin film is oriented in the wurtzite phase with void free surface morphology. The surface roughness of deposited ZnO thin film is found to be ~17.8 nm. The optical properties of nanostructured ZnO thin films show the average transmittance is about 90% in the visible region and the energy band gap is found to be 3.17 eV. The surface chemistry and purity of deposited ZnO thin films are analyzed by fourier transform infrared and X-ray photoelectron spectroscopy, conforming the presence of Zn-O in the deposited thin films without any organic moiety. The photocurrent measurement of nanostructured ZnO thin film is examined in the presence of UV light illumination with wavelength of 365 nm. These results suggest that the deposited nanostructured ZnO thin film through EHDA technique possess promising applications in the near future. PMID- 25936015 TI - Crystal symmetry breaking in few quintuple Bi2Te3 nanosheets: applications in nanometrology of topological insulators and low-temperature thermoelectrics. AB - Bismuth telluride (Bi2Te3) and its associated compounds are the best bulk thermoelectric (TE) materials known in present day. In addition, stacked two dimensional (2D) layers of Bi2Te3 have attracted brawny interest due to topologically protected surface state property. The authors herein report results of micro-Raman spectroscopy study of the "graphene-like" crystalline Bi2Te3 nanosheets with a thickness of a few atoms (few-quintuples) synthesized by convenient solvothermal route which is chiefly attractive from physics point of view. It is investigated that the optical phonon mode A1u, which is not-Raman active in bulk Bi2Te3 crystals, appears in atomically-thin nanosheets due to crystal-symmetry breaking in few quintuples layers (FQLs) and can be used in nanometrology of topological insulators (TIs). It is also suggested that sheets thinning to FQLs and tuning of Fermi level can help in achieving TI surface transport regime with enhance thermoelectric power. From seebeck measurements, Bi2Te3 sample exhibit p-type conduction having higher TE power at low temperature (40 K). Thus, Bi2Te3 nanosheets with strong spatial confinement of charge carriers are beneficial for TE devices. The developed technology for producing 2D layers of -Te(1)-Bi-Te(2)-Bi-Te(1)- creates an thrust for exploration of TIs and their possibility in practical applications. PMID- 25936016 TI - Solution combustion synthesis of Dy(3+) and Ce(3+) activated Na2ZnSi2O6 phosphors. AB - Here we first time reported Dy(3+) and Ce(3+) luminescence in novel Na2ZnSi2O6 phosphors by solution combustion synthesis prepared at 550 degrees C. Emission spectra of Na2ZnSi2O6:Dy(3+) phosphor was observed at 470 nm and 576 nm keeping excitation wavelength at 350 nm, where as Na2ZnSi2O6:Ce(3+) shows emission band at 452 nm monitoring excitation at 354 nm. XRD analysis was carried out to observe crystalline nature of the prepared phosphor. PMID- 25936017 TI - Synthesis of silicon quantum dots showing high quantum efficiency. AB - Quantum efficiencies of Si quantum dots (QDs) have been investigated from the reaction of magnesium silicide and ammonium chloride. The change of quantum yield and optical characterization of Si QDs are measured depending on the reaction time. Highly luminescent Si QDs were obtained as the reaction time increased. Absorption measurement indicated that the Si QDs consisted of only silicon and hydrogen atom. Optical characterizations of Si QDs were measured by UV-Vis and PL spectroscopy. The size distribution and orientation of Si QDs were measured by TEM and XRD. TEM image displays the spherical Si QDs with the size of 3-4 nm. As the reaction time increased, Si QDs grew and their emission wavelength shifted to the longer wavelength. The monotonic shift of the PL as a function of excitation wavelength resulted in the excitation of different sizes of QDs that had different optical transition energies. Photoluminescence quantum yields exceeding 60% have been achieved. PMID- 25936018 TI - Synthesis and photoluminescence of novel Ca(1-x)MgP2O7:xEu(3+) pyrophosphate phosphor for near ultraviolet light emitting diodes. AB - We studied the microstructure and photoluminescence properties of Ca(1 x)MgP2O7:xEu(3+) (0.01 <= x <= 0.2) phosphors, considering Eu(3+) content. The Ca(1-x)MgP2O7:xEu(3+) phosphors crystallized in the monoclinic structure, belonging to the space group of P2(1)/n. The Ca(1-x)MgP2O7:xEu(3+) phosphors showed a nanocrystalline nature. In the FT-IR and Raman spectra, the stretching vibrations of PO3 and P-O-P groups in (P2O7)(4-) were observed. The amount of Eu(3+) content significantly affected the magnitude of the excitation and emission intensities. The excitation intensity at 393 nm and the emission intensity at 605-628 nm were increased with an increase in Eu(3+) content up to x = 0.1 and then decreased with further increasing Eu(3+) content. The strong emission intensity under near ultraviolet excitation makes it possible red phosphor for generating white light based on LEDs. PMID- 25936019 TI - Photoluminescence properties of Na(Sr,Ca)VO4:Eu(3+) phosphors. AB - Eu(3+)-activated novel alkaline earth metal (Sr and Ca) vanadate phosphors, Na(Sr(0.97-x), Ca(x))VO4:Eu0.03(3+) (x = 0 to 0.97) has been successfully synthesized using solid state reaction method and characterized by XRD, XPS, FE SEM, luminescence (PLE, PL and CIE coordinate) and decay rate measurements as a function of Ca ion concentration. Phosphors show a broad excitation band (monitored for (5)D0 --> (7)F2 transition of Eu(3+)) in the 230-430 nm wavelength regions which make them highly suitable for LED chips. Material gives strong emission of Eu(3+) ion (lambdaex = 323 nm) and intensity of this emission increases with increase in the doping concentration of Ca ions until a maximum is reached for Na(Sr0.22, Ca0.75)VO4:Eu0.03(3+) (x = 0.75) phase phosphor. The intensity ratio of (5)D0 --> (7)F2 to (5)D0 --> (7)F1 transition (monochromaticity, R) suggest that local symmetry around the Eu(3+) ion increases with increase in Ca ion concentration, which is responsible for enhanced emission. PMID- 25936020 TI - Effects of growth and annealing temperatures on the structural and the optical properties of In0.6Al0.4As/Al0.4Ga0.6As quantum dots. AB - In0.Al0.4As/Al0.4Ga0.6As quantum dots (QDs) were grown on GaAs (001) substrates by using molecular beam epitaxy utilizing a modified Stranski-Krastanow method. Atomic force microscopy images showed that the size of the In0.6Al0.4As QDs increased with increasing growth temperature. Photoluminescence spectra at 300 K showed that the exciton peaks corresponding to the interband transitions from the ground electronic subband to the ground heavy-hole subband (E1-HH1) of the In0.6Al0.4As/Al0.4Ga0.6As QDs shifted to large energy side with increasing growth temperature resulting from an increase in the height of the In0.6Al0.4As QDs. While the (E1-HH1) peak position of the PL spectra shifted toward larger energy side with increasing up to an annealing temperature of 700 degrees C, it shifted toward lower energy above 700 degrees C. The structural and the optical properties of In0.6Al0.4As/Al0.4Ga0.6As QDs were affected by the growth and annealing temperatures. PMID- 25936021 TI - Application of soft lithography to metal-induced lateral crystallization of amorphous Si thin films involving self-assembly monolayers and atomic layer deposition. AB - Micro-contact printing of self-assembly monolayers (SAMs), i.e., octadecyl trichlorosilane (OTS) was combined with self limiting atomic layer deposition in order to fabricate the selective deposition of nickel oxide on amorphous Si thin films. The localized nickel species facilitated metal-induced crystallization (MIC) and at later stages, metal-induced lateral crystallization (MILC) in amorphous Si thin films at the elevated temperatures ranging from 500 degrees C to 550 degrees C. The uniform coating of SAMs onto amorphous Si thin films was monitored using physical/chemical characterization, i.e., atomic force microscopy, electron microscopy, and Raman spectroscopy. The crystalline feature was found to be superior to the counterpart solid-phase crystallization. The effectiveness of SAMs appears to provide the microscale patterning in addition to the sophisticated control against nickel-species. PMID- 25936022 TI - Synthesis and electroluminescent properties of a novel electroluminescence material of bis-2-(4-(diphenylphosphino)phenyl)benzo[d]oxazole (DPB). AB - A new light-emissive material, bis-2-(4-(diphenylphosphino)phenyl)benzo[d]oxazole (DPB), has been synthesized and characterized by FT-NMR, FT-IR, UV-Vis and elemental analysis. DPB has the band gap of 4.3 eV between HOMO and LUMO levels. The photoluminescence (PL) of DPB was measured at 410 nm from the chloroform solution. The electroluminescent (EL) devices with structures of ITO/NPB/DPB/LiF/Al and ITO/NPB/DPB/Alq3/LiF/Al were constructed and showed maximum emission at 540 nm. The device using DPB as emitting material showed the luminance of 1000 cd/m2 at 11 V. The CIE chromaticity of the device showed near the region of white color emission. PMID- 25936023 TI - Actuation of digital micro drops by electrowetting on open microfluidic chips fabricated in photolithography. AB - Basic manipulations of discrete liquid drops on opened microfluidic chips based on electrowetting on dielectrics were described. While most developed microfluidic chips are closed systems equipped with a top plate to cover mechanically and to contact electrically to drop samples, our chips are opened systems with a single plate without any electric contact to drops directly. The chips consist of a linear array of patterned electrodes at 1.8 mm pitch was fabricated on a glass plate coated with thin hydrophobic and dielectric layers by using various methods including photolithography, spin coating and ion sputtering. Several actuations such as lateral oscillation, colliding mergence and translational motion for 3-10 MUL water drops have been demonstrated satisfactory. All these kinetic performances of opened chips were similar to those of closed chip systems, indicating superiority of a none-contact method for the transport of drops on opened microfluidic chips actuated by using electrowetting technique. PMID- 25936024 TI - Fabrication of transparent Al:LiF composite/MoO3 interconnecting layers for tandem white organic light emitting devices. AB - We report transparent Al:LiF composite/molybdenum oxides (MoO3) as interconnecting layers for tandem white organic light emitting diodes (WOLEDs) consisting of blue and red phosphorescent unit devices. The Al:LiF (3 nm)/MoO3 (10 nm) interconnecting layers show a high transmittance, good carrier generation and injection capability for tandem WOLEDs. The performance of tandem WOLEDs is sensitive to the LiF doping concentration, which is mainly attributed to the difference in efficiency of carrier injection into the adjoining electroluminescent units. For 10~20% LiF concentration, the external quantum efficiency of tandem device is almost equal to the sum of the efficiencies of blue and red OLEDs at high current density; furthermore, a small variation of Commission Internationale de l'Eclairage (CIE) coordinates with the current density is obtained. PMID- 25936025 TI - Synthesis and characterization of nickel nanoparticles prepared using the aquolif approach. AB - We report on the synthesis of nickel nanoparticles using a combination of chemical reduction and freezing-drying processes that we named the aquolif approach. The X-ray diffraction (XRD) patterns reveal that the synthesized nanoparticles were composed of a single metallic nickel phase. The average crystallite sizes of the nickel nanoparticles were determined using the Scherrer method. The average crystallite sizes increased from 8+/-3 to 16+/-3 nm as the annealing temperature increased, which is consistent with the XRD and transmission electron microscopy results. The zero-field-cooling and field cooling (ZFC-FC) magnetization curves reveal that the nickel nanoparticles exhibited superparamagnetic behavior with a high blocking temperature and a surface effect at lower temperatures. Our experimental results demonstrate that the aquolif approach can be successfully scaled up to industrially prepare other types of metallic nanoparticles. PMID- 25936026 TI - Optical and dielectric properties of ion beam irradiated Ag/polymethyl methacrylate nanocomposites. AB - Changes in the dielectric, optical, structural and thermal properties of PMMA/silver nanocomposites of different concentrations of silver nanoparticles (5%, 10%, 15%) due to swift heavy ion irradiation were studied by means of impedance gain phase analyzer, UV-visible spectroscopy, X-ray diffraction and differential scanning calorimetry. Samples were irradiated with 120 MeV Si-ions at fluences of 1 x 10(11), 1 x 10(12) ions/cm2. Dependence of dielectric properties on frequency, ion beam fluence and filler concentration was studied. The results revealed the enhancement in dielectric properties after dopping nanoparticles and also upon irradiation. Optical properties like band gap was estimated for pure polymer and nanocomposite films from their optical absorption spectra in the wavelength region 200-800 nm. It was found that the band gap value shifted to lower energy (from 4.58 eV to 3.21 eV) on doping with silver nanoparticles. Differential scanning calorimetry analysis revealed a decrease in the glass transition temperature upon irradiation, which may be attributed to scissioning of polymer chain due to ion beam irradiation which is also confirmed with XRD analysis. PMID- 25936027 TI - Superior properties of homogeneously aligned twisted nematic liquid crystals on nanoscale molybdenum trioxide surfaces. AB - Homogeneously aligned twisted nematic liquid crystals (TN-LCs) were produced on molybdenum trioxide (MoO3) thin films via ion beam (IB) irradiation. Control of the pretilt angle was achieved by varying the IB incident angle. X-ray photoelectron spectroscopy (XPS) analysis revealed that the intensity of the Mo-O and O-Mo bonds at various IB incident angles exhibited the tendency that was opposite to that of the pretilt angle and the lowest intensity was produced at 45 degrees . Superior electro-optical (EO) characteristics were also observed. Furthermore, a TN-LC cell fabricated with the MoO3 thin films exhibited high thermal stability. Such stability could be maintained at temperatures greater than 150 degrees C. PMID- 25936028 TI - Efficiency enhancement of dye-sensitized solar cells by interface modification between photoanode and electrolyte. AB - A nanoporous TiO2 layer on a transparent electrode was modified with an aqueous lithium hydroxide solution by a simple dipping process, and effects of the modified electrode on the photovoltaic properties of dye-sensitized solar cells were investigated. The modification led to a considerable improvement of 23.6% in power conversion efficiency due to an increase in both open circuit voltage and fill factor. From the measurements of the electronic band structure, electrochemical impedance spectra and incident photon-to-current conversion efficiency, it was revealed that the modification by LiOH formed a surface dipole on the TiO2 electrode, leading to a negative shift of conduction band edge of TiO2. PMID- 25936029 TI - Bulk heterojunction organic solar cells fabricated using low-band-gap semiconducting polymers. AB - Semiconducting copolymers composed of 10-(2'-hexylphenothiazine) (PTZ), 9,9 dioctyl-dithienylfluorene (DTF8), {(2E,2'E)-3,3'-[2,5-bis(octyloxy)-1,4 phenylene]-bis[2-(thiophen-2-yl)acrylonitrile]} (OPTAN), and benzo-[1,2,5] thiadiazole (BT) units, i.e., poly(PTZ-co-OPTAN-co-BT) and poly(DTF8-co-OPTAN-co BT), were synthesized through Pd(0)-catalyzed Suzuki coupling with appropriate control of the monomer ratio. The optical band gap energies of the polymers were in the range of 1.95-1.77 eV. The energy levels of the highest occupied molecular orbitals and the lowest unoccupied molecular orbitals of the copolymers were determined via cyclic voltammetry and the optical band gap energies. Photovoltaic devices were fabricated using the polymers as p-type donors and [6,6]-phenyl C61 butyric acid methyl ester (PC60BM) or [6,6]-phenyl C71-butyric acid methyl ester (PC70BM) as electron acceptors. PMID- 25936030 TI - Application of thermal initiator for characteristic improvements of polymeric replica mold for UV nanoimprint lithography. AB - We report the improvement of the hardness and modulus properties in a silsesquioxane-based soft replica mold by adding thermal initiator, without deteriorating the UV transmittance at the wavelength of 365 nm. It is found that thermal initiator used for this work contributes to improving the hardness and modulus values up to 0.175 and 3.585 GPa, while the UV transmittance value is still above 75%. The optimized soft replica mold built on a flexible plastic substrate allows submicron-scale patterns to be transferred onto a rigid Si substrate by means of UV-NIL process. Consequently, we demonstrate that the developed soft replica mold can be a suitable replacement for typical hard molds, promising further use in mold-based nanolithography for the fabrication of high resolution nanopatterns over large areas. PMID- 25936031 TI - Improvement of operation lifetime in organic solar cell coated with diphenylacetylene polymer film. AB - To improve the operation lifetime of organic solar cell, two different diphenylacetylene polymers were tested as UV blocking layer. One of them showed either stronger UV absorption or a relatively intense fluorescence emission in the visible region which is well overlapped with the absorption of P3HT in the OSC. The diphenylacetylene polymer film significantly improved the operation lifetime of the OSC by efficiently absorbing the UV light, while reducing the UV light energy loss to a minimum by converting the UV light to visible light through a down-conversion process. PMID- 25936032 TI - Synthesis and characterization of a new poly(octathiophene) based copolymer for organic thin-film transistor. AB - A new poly(octathiophene) based copolymer was designed and synthesized by the palladium catalyzed Suzuki coupling reaction. The structure of the newly obtained copolymer was confirmed by 1H-NMR and IR. The number-average molecular weight (M(n)) of the polymer was 36,000 with a poly-dispersity index of 1.15. The polymer has good solubility in common solvents such as chloroform, toluene, chlorobenzene, dichlorobenzene and tetrahydrofuran at room temperature. The optical, thermal and electrochemical properties of the polymer were characterized by UV-vis absorption, TGA and DSC and cyclovoltametry, respectively. A thin film transistor using the new polymer as an organic semiconductor was found to exhibit typical p-channel FET characteristics with a hole mobility of 5 x 10(-4) cm2/Vs. PMID- 25936033 TI - Study on the lifetime decay of quantum dots as a function of temperature. AB - We have fabricated a temperature sensor which is characterized by fluorescence decay of quantum dots. In our previous work, we showed that the photoluminescence intensity of the quantum dots had negative correlation with the temperature. In this paper, the life time dependence of QDs on temperature was studied. Three kinds of Zn(x)Cd(1-x)S alloyed quantum dots have been prepared and the life time of QDs was measured with temperature changed from 33 to 43 degrees C. As the temperature increased, the fluorescence lifetime of QDs decreased. This shows that temperature sensor based on life time change of QDs can be fabricated. PMID- 25936034 TI - Preparation of Fe-doped TiO2 nanotube arrays and their room-temperature ferromagnetic properties. AB - Fe-doped titania nanotube arrays (NTs) were fabricated by electrochemical anodization on a Ti foil using Fe(NO3)3 . 2H2O as iron source. Their morphology, structure and optical properties were investigated by field emission scanning electron microscopy, X-ray diffraction, UV-visible absorption spectroscopy and photoluminescence spectroscopy. The UV-visible reflection spectrum of the Fe doped TiO2 NTs showed a red shift in wavelength of absorption and greater reflectivity compared with the undoped sample due to the Fe ion incorportion in TiO2 lattices. The photoluminescence spectrum of the Fe-doped TiO2 NTs shows two strong new peaks centered at 388 nm and 694 nm, besides the UV emission peak owing to the electronic transition mediated by the defect levels such as oxygen vacancies in the band gap. The magnetic property of the Fe-doped TiO2 NTs exhibits a room temperature ferromagnetic characteristic with a saturation magnetization (Ms) of 0.146 x 10(-2) emu/cm3 and a coercive field of 60 Oe. And the cause of the magnetic properties has been discussed in detail. PMID- 25936035 TI - Synthesis and photoluminescence of novel NaLi2PO4:Tb(3+) nanophosphors for near ultraviolet excited light emitting diodes. AB - A series of Tb(3+)-activated NaLi2PO4 novel nano-crystalline phosphors was synthesized by the solution combustion method. The prepared Na(1-x)Li2PO4:xTb(3+) (0.01 <= x <= 0.1) phosphors crystallized in the orthorhombic crystal structure. Its effective absorption in the near ultraviolet range allowed highly efficient green emission. The Na(1-x)Li2PO4:xTb(3+) phosphors showed characteristic (5)D4 - > (7)FJ (J = 3, 4, 5, and 6) transitions of Tb(3+), i.e., (5)D4 --> (7)F6 (488 nm), (5)D4 --> (7)F5 (545 nm), (5)D4 --> (7)F4 (583 nm), and (5)D4 --> (7)F3 (622 nm). The Na0.95Li2PO4:0.05Tb(3+) phosphor showed the most excellent emission efficiency. The present work suggests that the Na0.95Li2PO4:0.05Tb(3+) is a potential green-emitting phosphor for near ultraviolet excited light emitting diodes. PMID- 25936036 TI - Laser fabrication of gold nanoparticle clustered tips for use in apertureless near-field scanning optical microscopy. AB - A laser fabrication method was developed to make gold nanoparticle clustered (GNC) tips for apertureless near-field scanning optical microscopes (ANSOMs) and tip-enhanced Raman spectroscopy (TERS). The near-field Rayleigh and Raman scattering of samples are highly enhanced when a gold nanoparticle cluster is synthesized on the end of the tip. This is due to the lightning rod effect in the sharp tips. The localized electromagnetic field enhancement and the spatial resolution (~30 nm) of the fabricated GNC tip were verified by TERS and ANSOM measurements of carbon nanotubes. PMID- 25936037 TI - Light extraction enhancement of GaN based light emitting diodes by ZnO nanorod arrays. AB - This study examined the effects of the alignment of ZnO nanorod arrays (NRAs) on the light extraction enhancement of GaN-based light emitting diodes (LEDs), where ZnO NRAs were synthesized hydrothermally. The shape of the ZnO NRAs was controlled using seed layers for flower and vertical structures. Numerical analysis based on the two-dimensional (2D) finite difference of time domain (FDTD) method showed that the extraction efficiency of LED with bare (without ZnO NRA), vertical ZnO NRA and flower shaped ZnO NRA was 37%, 60% and 49%, respectively. The optical output power of the LEDs with vertical ZnO NRA and flower ZnO NRA was improved by 50% and 30% compared to that of the LED without ZnO NRA at an input current of 100 mA. These results suggest that the vertical alignment of ZnO NRA is important for enhancing the light extraction of GaN based LEDs. PMID- 25936038 TI - Effects of precursor concentration on the properties of ZnO nanowires grown on (1 102) r-plane sapphire substrates by hydrothermal synthesis. AB - In this study, we grew ZnO nanowires hydrothermally on (1-102) r-plane sapphire substrates in an aqueous solution which contained zinc nitrate hexahydrate and hexamethylenetetramine (HMT) at 90 degrees C. First, the AZO seed layer of 80 nm thickness was deposited on the r-plane sapphire substrate by a radio frequency magnetron sputter. After that, we grew the ZnO nanowires on the seed layer by changing the precursor concentration of the aqueous solution from 0.025 M to 0.01 M. When the molar concentration of the precursor was changed, the diameter, length, density and number of ZnO nanowires also changed significantly: diameter, length and density increased with increasing molar concentration but the number of ZnO nanowires decreased. The ZnO nanowires grown at the higher molar concentration tended to grow along with the c-axis direction, as revealed by atomic force microscope and X-ray diffraction peaks. Furthermore, the PL spectra measured at room-temperature revealed a UV emission of 380 nm which can be attributed to the radiative recombination of free and bound excitons (Near Band edge Emission). The NBE emission was also increased with increasing molar concentration. PMID- 25936039 TI - Synthesis and luminescence properties of Eu(2+) activated Ca2P2O7 pyrophosphate phosphor. AB - In the present study, calcium pyrophosphate activated with Eu(2+) rare earth ions prepared by solid state diffusion and confirmed by XRD. An average crystallite size is found out to be in sub-micrometer range of 2-5 MUm from SEM study. FTIR spectra suggest that Ca2P2O7 material belongs to the diphosphate family. The PL spectroscopic characterizations of the prepared phosphors were performed using excitation and emission spectra. Photoluminescence spectra of Ca2P2O7:Eu(2+) pyrophosphate phosphor shows emission at 426 nm when excited at 356 nm. PMID- 25936040 TI - Red fluorescent materials based on julolidine/chromene with the bulky tert-butyl and trimethylsilyl substituents for organic light-emitting diodes. AB - In this work, we designed and synthesized two red emitters 2-(6,8-di-tert-butyl-2 (2-(1,1-dimethyl-7-(trimethylsilyl)-7-((trimethylsilyl)methyl)-1,2,3,5,6,7 hexahydropyrido[3,2,1-ij]quinolin-9-yl)vinyl)-4H-chromen-4-ylidene)malononitrile (Red 1) and 2-(6,8-di-tert-butyl-2-(2-(1,1,7-trimethyl-7-t-butyl)-1,2,3,5,6,7 hexahydropyrido[3,2,1-ij]quinolin-9-yl)vinyl)-4H-chromen-4-ylidene)malononitrile (Red 2). To explore the electro-luminescence properties of these materials, multilayered OLEDs using these materials as dopants in a Alq3 host were fabricated. Particularly, by using Red 1 as a dopant in emitting layer, device 1 showed the luminous and power efficiencies of 0.81 cd/A and 0.43 lm/W at 20 mA/cm2, respectively. The CIE coordinates of this device was (0.65, 0.34) at 7.0 V, which is close to the NTSC standard CIE coordinates of (0.67,0.32) for red emission. PMID- 25936041 TI - Synthesis and characterization of poly(vinylpyrrolidone)-capped silicon nanoparticles. AB - Polymer-capped silicon nanoparticles (Si NPs) were prepared using poly(vinylpyrrolidone) (PVP) as a protection layer to minimize the surface oxidation of the surface. The wet synthetic procedure were performed at room temperature via a one-pot synthesis. The PVP capped Si-NPs were characterized by thermo gravimetric analysis (TGA), Fourier transform infrared spectroscopy (FT IR), high resolution transmission electron microscopy (HR-TEM) and field emission scanning electron microscopy (FE-SEM). HR-TEM micrograms confirm the presence of crystalline Si-NPs. The pattern by Selected Area Electron Diffraction (SAED) reveals (111), (220) lattice planes which are consistent with the cubic structured crystalline silicon. The mean size of Si-NPs is estimated to be ca. 10 nm, which is larger than those from conventional wet synthetic methods for silicon quantum dots. PMID- 25936042 TI - Improved photovoltaic properties of polymer solar cells with a phenyl compound as an additive. AB - A phenyl compound with electron withdrawing substituents, 3-fluoro-4-cyanophenol (FCP), was used as an additive in polymer solar cells with a P3HT [poly(3-hexyl thiophene)]:PCBM [[6,6]-phenyl-C61-butyric acid methyl ester] blend film. Under simulated solar illumination of AM 1.5 (100 mW/cm2), the devices fabricated using a P3HT:PCBM (1:0.9 w:w) layer blended with 5 wt% of FCP achieved an enhanced power conversion efficiency (PCE) of 4.8% due to the improved short circuit current and fill factor, as compared to reference cells with PCE = 4.1%. UV visible absorption spectra, X-ray measurements and carrier mobility studies revealed that FCP facilitated the ordering of the P3HT chains, resulting in higher absorbance, larger crystal size, closer packing and enhanced hole mobility. PMID- 25936043 TI - Relationship between the energy levels and the photovoltaic properties of oligothiophenes. AB - A series of linear pi-conjugated oligothiophenes, alpha,alpha' dihexylquinquethiophene (DH5T), 2,5-bis(5'-hexyl-2,2'-bithiophene-5-yl)thieno[3,2 b]thiophene (DH5TT), and alpha,alpha'-dihexylheptathiophene (DH7T), has been synthesized using the Suzuki coupling reaction. The optical and electrochemical properties of oligothiophenes were easily tuned by controlling the thiophene number. The UV-vis absorption and photoluminescence (PL) spectra are gradually red-shifted on going from DH5T and DH5TT to DH7T due to the increase in alpha conjugation length. The energy band gap decreased as the oligothiophene length increased. The optical band gaps of DH5T, DH5TT, and DH7T occur at 2.39, 2.25, and 2.01 eV, respectively. Bulk heterojunction organic photovoltaic cells (OPVs) fabricated from oligomers showed the power conversion efficiency of 0.45-0.8% under AM 1.5 (100 mW/cm2). Among them, DH5T showed the best OPV performance of an open circuit voltage (VOC) of 0.51 V, short-circuit current (JSC) of 4.25 mA/cm2, and fill factor (FF) of 0.37, resulting in the power conversion efficiency of 0.80%. Moreover, the relationship between conjugation length and photovoltaic properties was systematically investigated in terms of the energy band gap and open circuit voltage (VOC). PMID- 25936044 TI - Improved efficiency of red phosphorescent organic light-emitting diodes with combination of heterojunction and mixed host structure. AB - We report an improvement of efficiency in red phosphorescent organic light emitting diodes (PHOLEDs) based on a combination of heterojunction (HJ) structure and mixed host (MH) system using a phosphorescent red emitter: bis(2 phenylquinolinato)-acetylacetonate iridium III [Ir(pq)2(acac)] doped in 4,4,N,N' dicarbazolebiphenyl (CBP) of hole transport type host material and 1,3,5-tris(N phenylbenzimidazole-2-yl)benzene (TPBi) of electron transport type host material. This combination device resulted in an effective electron and hole balance and distribution of the recombination zone. Therefore, highly efficient red PHOLEDs with maximum luminous efficiency and external quantum efficiency of 21.93 cd/A and 14.09% were achieved. Moreover, the combination device showed a power efficiency of 9.51 lm/W, which is higher than 7.61 lm/W in the control device at a luminance of 1000 cd/m2. PMID- 25936045 TI - Synthesis and characterization of new silafluorene-based copolymers for polymer solar cells. AB - A series of silafluorene-based copolymers, poly[9-(2-ethylhexyl)-9-dodecyl silafluorene-2,7-diyl-alt-5,5-(4',7'-di-2-thienyl-2',1',3'-benzothiadiazole)] (P1), poly[9-(2-ethylhexyl)-9-dodecyl-silafluorene-2,7-diyl-alt-2,5-bis (thiophene-2-yl)thiazolo [5,4-d]thiazole] (P2), and poly[9-(2-ethylhexyl)-9 dodecyl-silafluorene-2,7-diyl-alt-5,5-(5',8'-di-2-thienyl-2,3-bis(4 octyloxyl)phenyl)quinoxaline] (P3), were synthesized and used as donor materials in polymer solar cells (PSCs). The optical, electrochemical, and photovoltaic properties of the copolymers were investigated. The results indicate that the acceptor units in the copolymers influenced the band gap, electronic energy levels, and photovoltaic properties of the copolymers significantly. The band gaps of the copolymers were in the range 1.82-2.10 eV. Under optimized conditions, the silafluorene-based polymers showed power conversion efficiencies (PCEs) for the PSCs in the range 1.31-1.69% under AM 1.5 illumination (100 mW/cm2). Among the three copolymers, P1, which contained a benzothiadiazole acceptor unit, showed a power conversion efficiency of 1.69% with a short circuit current of 4.59 mA/cm2, open circuit voltage of 0.88 V, and a fill factor of 0.42, under AM 1.5 illumination (100 mW/cm2). PMID- 25936046 TI - Optical fiber temperature sensor utilizing alloyed Zn(x)Cd(1-x)S quantum dots. AB - In this paper, optical fiber temperature sensors have been prepared by using alloyed Zn(x)Cd(1-x)S quantum dots as sensing media. The surface of the optical fiber was silanized to enhance covalent bond between quantum dots and optical fiber. The quantum dots were bonded to the surface of optical fiber and further encapsulated via sol-gel coating using 3-glycidoxypropyl trimethoxysilane (GPTMS) and 3-aminopropyl trimethoxysilane (APTMS) in ethyl alcohol in acidic condition. Quantum dots with green, yellow, and red fluorescence were used. The dependence of photoluminescence (PL) intensity from quantum dots on ambient temperature has been studied. Linear relation between the fluorescent intensity and temperature was obtained from alloyed quantum dots immobilized on the surface of optical fiber. The PL intensity, sensitivity, and thermal stability were increased by the silica encapsulation. PMID- 25936047 TI - Room temperature ferromagnetism and photoluminescence in Cu-doped ZnO nanocrystals. AB - The Zn(1-x)Cu(x)O (x = 0.0-3.5%) nanocrystals have been synthesized by a simple sol-gel method. X-ray diffraction, optical absorption and photoluminescence measurements were employed to validate consistently the incorporation of Cu ions into the ZnO wurtzite lattice without formation of secondary phases for Zn(1 x)Cu(x)O (x < 2.0%). Meanwhile, it was found that the substituted Cu-doping leads to the reduction of the band gap and the appearance of the structured green emission. Magnetization measurement showed that the low Cu-doping (x < 1.0%) develops the ferromagnetism, but the high Cu-doping destroys sharply the ferromagnetism due to the formation of the antiferromagnetic coupling among the neighboring Cu ions. It is indicated that the rational Cu-doping can tune optical and magnetic properties in ZnO. PMID- 25936048 TI - Electromagnetic interference (EMI) shielding of ordered mesoporous carbon (OMC)/paraffin composites. AB - The ordered mesoporous carbon (OMC)/paraffin composites were successfully prepared by a facile physical mixing method and an EMI SE of 21-23 dB was achieved at the OMC loading of 5.69 wt.% in the X band. This indicates that the composites are very suitable for an application as effective and lightweight EMI shielding materials. The EMI shielding of the composite shows an absorption dominant mechanism, i.e., a contribution shift from reflection to absorption is observed with the increase in OMC loading and frequency. This could be explained by the intrinsic properties (electrical conductivity, complex permittivity and potential large defects) and novel structure of the composites. PMID- 25936049 TI - Synthesis of water-dispersible silver nanoparticles by thermal decomposition of water-soluble silver oxalate precursors. AB - Silver oxalate, one of the coordination polymer crystals, is a promising synthetic precursor for transformation into Ag nanoparticles without any reducing chemicals via thermal decomposition of the oxalate ions. However, its insoluble nature in solvents has been a great disadvantage, especially for systematic control of crystal growth of the Ag nanoparticles, while such control of inorganic nanoparticles has been generally performed using soluble precursors in homogeneous solutions. In this paper, we document our discovery of water-soluble species from the reaction between the insoluble silver oxalate and N,N-dimethyl 1,3-diaminopropane. The water-soluble species underwent low-temperature thermal decomposition of the oxalate ions at 30 degrees C with evolution of CO2 to reduce Ag+ to Ag0. Water-dispersible Ag nanoparticles have been successfully synthesized from the water-soluble species in the presence of gelatin via similar thermal decomposition at 100 degrees C. The gelatin-protected and water dispersible Ag nanoparticles with a mean diameter of 25.1 nm appeared. In addition, antibacterial activity of the prepared water-dispersible Ag nanoparticles has been preliminarily investigated. PMID- 25936050 TI - Effects of hole and electron transporting interlayers for inverted polymer solar cells. AB - An efficient inverted polymer solar cell (PSC) with a transparent amorphous titanium oxide (TiOx) as an electron transporting layer (ETL) between bottom electrode and photo-active layer, and a tungsten oxide (WO3) inserted as a hole transporting layer (HTL) was fabricated. Introducing of ETL and HTL results in increases in the open circuit voltage (VOC), short circuit current (JSC) and the fill factor (FF). The inverted PSC device with TiOx and WO3 layer showed the higher power conversion efficiency (PCE) than that of conventional PSC. The PCE of 3.73% was achieved at inverted device, and was retained over 87% of its initial efficiency after 25 days in the ambient air without encapsulation. PMID- 25936051 TI - Controlling resonance frequencies of double-walled carbon-nanotube oscillators with divided outertubes. AB - We investigated the resonance frequency distributions of carbon nanotube (CNT) oscillators with an intertube gap using molecular dynamics simulations. The resonance frequency distributions could be regressed by the use of Gaussian distributions. The maximum resonance frequencies linearly decreased with increasing initial velocity of the coretube. For the same initial velocity of the coretube, the maximum resonance frequencies were constant regardless of gap spacing changes, and the center positions of the Gaussian distributions were shifted by changing the outertube length whereas their standard deviations were not changed. Although their standard deviations were influenced by the initial velocity of the coretube, the normalized resonance frequencies could be regressed into single Gaussian distribution within some error. So considering the difficulty of exactly controlling of the initial velocity, the resonance frequency distribution predicted by the gap spacing can give important revolution for CNT-oscillators to be utilized as components of nanoelectromechanical system. PMID- 25936052 TI - Synthesis and characterization of organic semiconducting polymers containing dithienylfluorenone for use in organic photovoltaic cells. AB - 2,7-Bis(5-bromo-4-hexylthiophen-2-yl)-9H-fluoren-9-one (DTFO) was synthesized as a new electron-accepting material in semiconducting polymers for use in photovoltaic devices. The synthesized DTFO was polymerized with two different electron-donating counter monomers: 2,7-dibromo-9,9-dioctyl-9H-fluorene (DOF) and 2,6-bis(trimethyltin)-4,8-di(2-ethylhexyloxyl)benzo [1,2-b:4,5-b']dithiophene (BDT). Two alternating copolymers, poly(DTFO-alt-DOF) and poly(DTFO-alt-BDT), were synthesized through the Suzuki and Stille coupling polymerizations, respectively. The synthesized polymers exhibited good solubility in common solvents and show good thermal stability up to 350 degrees C. The optical band gap energies of poly(DTFO-alt-DOF) and poly(DTFO-alt-BDT) were determined to be 2.44 and 2.23 eV, respectively. The positions of the highest occupied molecular orbital (HOMO) and lowest unoccupied molecular orbital (LUMO) of the polymers were determined by cyclic voltammetry (CV). One of these devices showed a power conversion efficiency of 0.50%, with an open-circuit voltage of 0.67 V, a short circuit current of 2.34 mA/cm2, and a fill factor of 0.30 under air mass (AM) 1.5 global (1.5 G) illumination conditions (100 mW/cm2). PMID- 25936053 TI - Synthesis and characterization of pentathiophene based copolymer for organic thin film transistor. AB - The new dialkylated pentathiophene based copolymer was synthesized by Suzuki coupling reaction. The PD5TADF is synthesized and used as an active material for organic thin film transistor (OTFTs). The copolymer has good solubility in common organic solvent such as toluene, tetrahydrofuran (THF), chloroform, chlorobenzene and dichlorobenzene. The number average molecular weight (Mn) was measured to be 148,000. The TGA curve shows that the polymers exhibit good thermal stability with a weight loss of less than 5% upon heating to 419 degrees C with glass temperature at 184.9 degrees C. The ultraviolet (UV) maximum of the polymer was found at 494 nm in solution and 498 nm in the film. A thin-film transistor with PD5TADF was found to exhibit typical p-channel FET characteristics with a hole mobility of 2.6 x 10(-4) cm2/Vs and an on/off ratio of 3.04 x 10(4) with a threshold voltage of -4.5 V. PMID- 25936054 TI - Mechanical property and thermal stability of polyurethane composites reinforced with polyhedral oligomeric silsesquioxanes and inorganic flame retardant filler. AB - Mechanical properties and thermal stability of polyurethane composites were investigated with a combination of polyhedral oligomeric silsesquioxane (POSS) molecules and inorganic barium sulfate. These hybrid composites were prepared using one-step method through the incorporation of flexible hydroxyl-terminated polybutadiene prepolymer, reactive POSS nanoparticles, and barium sulfate under isophorone diisocyanate curative system. In polyurethane composites, POSS and inorganic barium sulfate were utilized for mechanical reinforcement and flame retardant filler, respectively. The decomposition of POSS molecules during oxyacetylene torch exposure resulted in the formation of silica-based nanosized droplets, contributing on ablation behavior. PMID- 25936055 TI - Band gap control using electric field of photonic gel cells fabricated with block copolymer and hydrogel. AB - Optical and electrical characteristics of the devices using photonic gel film and hydrogel electrolyte were studied. Poly(styrene-b-2-vinylpyridine) (PS-b-P2VP) lamellar film with alternating hydrophobic block and hydrophilic polyelectrolyte block polymers (52 kg/mol-b-57 kg/mol) were prepared for the photonic gel. Poly(isobutylene-co-maleic acid) sodium salts were prepared for the hydrogel. This hydrogel fiber is common water swelling material and it owned ions for a device has conductivity. Photonic gel and hydrogel was spin coating onto Indium tin-oxide (ITO) glass for make electric fields. The reflectance maximum wavelength of photonic crystal device shifted from 538 nm and reached to 557 nm, 585 nm and 604 nm during 30 min voltage applying time. The bandwidth variation was very limited. Loss of electrolyte was much less with hydrogel compared to the pure water. We can control color of hydrogel used photonic device by electric field with reasonable time range under moderate electric field by applying 2 V between two facing electrodes. PMID- 25936056 TI - Enhanced efficiency of blue phosphorescent organic light-emitting diode base on triple-emitting layer with mixed host system. AB - We report an improvement of efficiency in blue phosphorescent organic light emitting diodes (PHOLEDs) based on triple-emitting layer (T-EML) with mixed host (MH) system using a phosphorescent blue emitter: iridium(III)bis[(4,6-di fluoropheny)-pyridinato-N,C2]picolinate (Flrpic) doped in N,N'-dicarbazolyl-3,5 benzene (mCP) of hole transport-type host material and 1,3,5-tris(N phenylbenzimidazole-2-yl)benzene (TPBi) of electron transport-type host material. This T-EML device resulted in both an effective electron and hole balance and efficient distribution of the recombination zone. As a result, the property of T EML device which demonstrated a maximum luminous efficiency of 24.45 cd/A and a external quantum efficiency of 10.9%. It also showed a high maximum power efficiency of 13.82 lm/W, which is approximately two times higher than that of the control device. PMID- 25936057 TI - Synthesis and characterization of dithieno[3,2-b:2',3'-d]thiophene-based copolymers for polymer solar cells. AB - New dithieno[3,2-b:2',3'-d]thiophene (DTT)-based copolymers were designed and synthesized for use as donor materials in polymer solar cells (PSCs). The optical, electrochemical, and photovoltaic properties of the copolymers were investigated. The results indicate that the acceptor units in the copolymers influenced the band gap, electronic energy levels, and photovoltaic properties of the copolymers significantly. The band gaps of the copolymers were in the range 1.85-2.02 eV. Under optimized conditions, the DTT-based polymers showed power conversion efficiencies (PCEs) for the PSCs in the range 0.97-1.19% under AM 1.5 illumination (100 mW/cm2). Among the copolymers, P2, which contained a pyrrolo[3,4-f]isoindole-tetraone acceptor unit, showed a power conversion efficiency of 1.19% with a short circuit current of 4.18 mA/cm2, open circuit voltage of 0.77 V, and a fill factor of 0.37, under AM 1.5 illumination (100 mW/cm2). PMID- 25936058 TI - Modeling and simulation of patterning diblock copolymers through nanoimprint lithography. AB - As the pattern size is cross to virus and molecular sizes, the fabrication cost becomes important. Advantages of the block copolymer lithography (BCPL) through the nanoimprint lithography (NIL) are no diffraction limits, simple and cheap process, and complementary for each of major draw- backs. In this paper, the directed self-assembly lithography of BCP with NIL is successfully modeled and simulated by using the Navier-Stokes equation for the BCP filling process, the multi-thin layer method and the Dill's equation for the UV exposure process, and the self-consistent field theory (SCFT) for the self-assemble process. The impact of the simulation parameters on the pattern formation is discussed and analyzed by using the response surface methodology (RSM). PMID- 25936059 TI - Biocompatible patterning of proteins on wettability gradient surface by thermo transfer printing. AB - We develop a simple and biocompatible method of patterning proteins on a wettability gradient surface by thermo-transfer printing. The wettability gradient is produced on a poly(dimethylsiloxane) (PDMS)-modified glass substrate through the temperature gradient during thermo-transfer printing. The water contact angle on the PDMS-modified surface is found to gradually increase along the direction of the temperature gradient from a low to a high temperature region. Based on the wettability gradient, the gradual change in the adsorption and immobilization of proteins (cholera toxin B subunit) is achieved in a microfluidic cell with the PDMS-modified surface. PMID- 25936060 TI - Synthesis of La2Ce2O7 nanoparticles by co-precipitation method and its characterization. AB - Lanthanum cerium oxide nanoparticles have been synthesized by co-precipitation method. In this method, nanoparticles in hydroxide form are obtained and then these nanoparticles are calcined at high temperature. Thermo gravimetric analysis (TGA), X-ray diffraction (XRD), electron dispersive spectroscopy (EDS), transmission electron microscopy (TEM) and fourier transform infrared spectroscopy (FT-IR) were utilized to characterize the thermal decomposition, phase structure and morphology of the products. Thermo gravimetric analysis (TGA) of the as prepared material shows almost 37% wt losses, which may be due to the presence of water and nitrate. X-ray diffraction (XRD) analysis of sample calcined at 600 degrees C shows the formation of standard cubic fluorite phase of lanthanum cerium oxide (La2Ce2O7). Electron dispersive spectroscopy (EDS) confirms the presence of both La and Ce. From Transmission electron microscopy (TEM) morphology, it is observed that particles are in the nano dimension having diameter in the range of 55 to 80 nm with cubic shape. Fourier transform infrared spectroscopy (FTIR) analysis shows the presence of residual nitrate, and absorption of water in the sample. PMID- 25936061 TI - ZnO nanoparticles co-doped with Fe3+ and Eu3+ ions for solar assisted photocatalysis. AB - In this study, ZnO nanoparticles co-doped with Fe3+ and Eu3+ were prepared by a facile co-precipitation method. The structure and morphology of the as-prepared nanoparticles were characterized by X-ray diffraction (XRD), scanning electron microscopy (SEM) and diffuse reflectance absorption spectra, respectively. The photocatalytic activities of the prepared catalysts were evaluated by photocatalytic degradation of methyl orange in aqueous solution with solar light irradiation. The co-doped Fe3+ and Eu3+ showed a synergistic effect, which significantly increased the photocatalytic activity of ZnO. The influences of calcination time, photocatalytic reaction temperature and catalyst loading on the photocatalytic activity of the catalyst were also investigated. It was found that there were an optimum photocatalytic reaction temperature and an optimum catalyst loading for high photocatalytic efficiency, and the photocatalytic efficiency decreased with increase in calcination time. The results of this study demonstrate that the as-prepared product of Eu3+/Fe3+/ZnO is a promising photocatalyst for solar assisted degradation of organic pollutions. PMID- 25936062 TI - Asymmetric behavior in flexible piezoelectric strain sensors made of single ZnO nanowires. AB - Piezoelectric strain sensors were fabricated using single ZnO nanowires on flexible polystyrene substrates and the asymmetric behavior in this kind of piezoelectric strain sensor made of single nanowire was firstly introduced. The I~V curves of the sensors under a serious of tensile and compressive strains were measured and agreed with the thermionic emission-diffusion theory. The Schottky barrier heights were obtained. The change in Schottky barrier heights of the sensors under compressive strain is much slower than that under tensile strain and the asymmetric elastic response of the sensors is caused by the bending of the ZnO nanowires under compressive strains when the applied strain is larger than a critical strain epsiloncr. And the conclusion that the critical strain epsiloncr only relates to the geometry parameters of the nanowire is drawn. The reduction of the axial compressive strain in compression was calculated. This asymmetric behavior in strain sensors is firstly introduced and is important for the design and fabrication of this type of strain sensors. PMID- 25936063 TI - Physiological investigation of gold nanorods toward watermelon. AB - The objective of the present study was to evaluate the phytotoxicity and oxidant stress of the gold nanorods toward watermelon, and hence give a quantitative risk assessment of both seeds and plants phase. The seed germination, the activity of antioxidant enzymes, and the contents of soluble protein and malondialdehyde (MDA) have been measured while the plant roots were observed by transmission electron microscopy (TEM). It was found that the gold nanorods significantly promoted the root elongation. Furthermore, the results on the enzymes activities of plant indicated that oxidative stress happened in the plant treated with gold nanorods. However, the gold nanorods resulted in the phytotoxicity toward plant especially at high concentration. The TEM images of the plant roots with and without the treatment of gold nanorods showed the significant different size of starch granules. In conclusion, significant physiological changes of plant occurred after treatment with the gold nanorods. PMID- 25936064 TI - Effect of porous structure on the electrochemical performance of FeS2 for lithium ion batteries. AB - Porous and solid FeS2 particles are both synthesized via solid-state reaction method using FeC2O4. 2H2O and S powder as the raw materials. The difference of the mophology is adjusted by the calcination time. The porous FeS2 electrode exhibits significantly improved and less improved electrochemical performance comparing to the solid one during the initial 15 cycles and the later cycling process, respectively. The significantly improvement in the initial 15 cycles is due to the large surface area and 3D conducting network of the porous structure, which provides large active electrochemical interface of the active particles and electrolyte, and shortens the path length for Li+ transport. The less improvement during the later cycling process is attributed to the unstable porous structure, which collapses into nanoparticles after long cycles. On the basis of the analysis, a theoretical proposal to optimize the structure of FeS2 electrode is provided. PMID- 25936065 TI - Natural nanomorphous Ni/NiO magnetic multilayers: structure and magnetism of the high-Ar pressure series. AB - Natural nanomorphous Ni/NiO multilayers have exhibited interesting magnetic properties, such as an unusual positive surface anisotropy and perpendicular magnetic anisotropy. Most attention has been paid to multilayers prepared by radio frequency magnetron sputtering under relatively low (3 x 10(-3) mbar) Ar pressure. Here we report on the correlation between structural and magnetic properties for a new series of multilayers, prepared under relatively high (3 x 10(-2) mbar) Ar pressure. The crystalline Ni individual layer thickness ranges between 5-8 nm. The amorphous NiO layer thickness is constant, about 1.1 nm thick. X-ray reflectivity showed that in some of the multilayers the high-order Bragg peaks become broader and diminish quickly. Cross-section transmission electron microscopy reveals that this occurs because the first bilayers are formed in accordance to the growth conditions, while the ones near the top are vanished. Despite the deterioration of the interface quality, all samples show tendency for perpendicular magnetic anisotropy even for large bilayer thickness of about 9 nm. Similar tendency is observed even by a 330 nm thick non multilayered Ni film grown under the same conditions. This observation reveals the important role of strain and magnetoelastic anisotropy as a source of perpendicular magnetic anisotropy in the Ni/NiO multilayers. PMID- 25936066 TI - Nano-scale SiO2 patterned n-type GaN substrate for 380 nm ultra violet light emitting diodes. AB - 380 nm Ultraviolet (UV) light emitting diodes (LEDs) were grown on patterned n type GaN substrate (PNS). Wet etched self-assembled indium tin oxide (ITO) nano clusters serves as dry etching mask for converting the SiO2 layer grown on n-GaN template into SiO2 nano dots by inductively coupled plasma etching. In the pre experiment, crystal quality and optical properties of n-GaN were greatly improved by applying PNS process. In this work, etch-pits density (EPD) method confirmed that PNS with SiO2 nano dots have superior crystalline properties. Thus Reference LED without PNS, 1-step PNS LEDs with SiO2 nano dots size were 200 nm, 250 nm, 300 nm and 300 nm 2-step PNS LED were fabricated. LEDs show almost the same operating voltage of about 3.4 V at an injection current of 50 mA. Light intensity was enhanced by ~2.1 times and 3.2 times for 300 nm 1-step and 300 nm 2 step PNS, respectively. FDTD simulation results show a similar tendency. As a result, PNS promotes epitaxial lateral overgrowth (ELOG) for defect reduction as well as act as a light scattering point. PMID- 25936067 TI - Effect of sapphire nitridation and group-III source flow rate ratio on In incorporation into InGaN grown by metalorganic vapor phase epitaxy. AB - In-composition of N-polar InGaN films on the sapphire substrate with the surface nitridation was investigated. By varying the ratio of the group-III source flow rate from 0.7 to 0.95, the In-composition and the surface morphologies of InGaN films were changed. The In-composition of N-polar InGaN films was affected by the strain relaxation and the surface morphologies. PMID- 25936068 TI - Blue organic light-emitting diodes based on new bipolar anthracene derivatives containing pyridine. AB - A series of bipolar anthracene derivatives containing pyridine as an electron withdrawing group and cabazole, triphenylamine and indole as electron donating groups were synthesized and characterized. Particularly, Device E, 9-(4'-(10 (pyridin-2-yl)anthracen-9-yl)biphenyl-4-yl)-9H-carbazol exhibits a high-efficient deep-blue EL emission with the luminous efficiency (LE) of 2.31 cd/A, power efficiency (PE) of 1.39 lm/W and quantum efficiency (QE) of 1.94% at 500 nit. This compound shows the maximum wavelength of the electroluminescence (EL) at 467 nm and the CIE x, y coordinates of (0.16,0.14) at 6 V. PMID- 25936069 TI - Effect of solution combusted TiO2 nanoparticles added to the dielectric layers for low power consumption AC powder electroluminescence devices. AB - A unique synthesis method was developed, which is called solution combustion method (SCM). TiO2 nanoparticles were synthesized by this method. These SCM TiO2 nanoparticles (~35 nm) were added to the dielectric layers of AC powder electroluminescence (EL) devices. The dielectric layers were made of commercial BaTiO3 particles (~1.2 MUm) and binding polymer. 0, 5, 10 and 15 wt% of SCM TiO2 nanoparticles were added to the dielectric layers during fabrication of AC powder EL devices respectively. Dielectric constants of these four kinds of dielectric layers were measured. The brightnesses and current densities of AC powder EL devices were also measured. When 10 wt% of SCM TiO2 nanoparticles was added, dielectric constant and brightness were increased by 30% and 60% respectively. Furthermore, the current density was decreased by 60%. This means that the addition of SCM TiO2 nanoparticles resulted in four fold higher luminous efficiency. PMID- 25936070 TI - Investigation of Mg doping profile in the p-cladding layer for high-brightness AlGaInP-based light emitting diodes. AB - We investigated 590 nm light-emitting diodes appropriate for full-color display applications in terms of their electrical and optical behaviors during operation according to their Mg doping profile in the p-cladding layer. As the hole concentration in the "b" zone of the p-cladding layer is increased from 3.4 x 10(17) to 6.7 x 10(17), the light output power increases by 41% due to the enhancement of the hole injection into the active region and also due to the minimization of the carrier overflow problem. However, at an oversaturation of Mg doping with excess [Cp2Mg]/[III] in the "b" zone, the internal quantum efficiency degrades because of the decrease in hole concentration because of the oversaturated material problem. PMID- 25936071 TI - Efficient red phosphorescent OLEDs using Ir(III) complexes based on bezoylphenylpyridine and the various ancillary ligands. AB - A series of red phosphorescent Ir(III) complexes 1-5 based on benzoylphenylpyridine and various ancillary ligands were synthesized and their photophysical properties were investigated. The EL efficiencies were quite sensitive to the structural features of the dopants in the emitting layers. Particularly, using complex 5 as a dopant in emitting layer, a high-efficiency orange-red OLED was fabricated, showing the maximum luminance of 16,900 cd/m2 at 12 V, the luminous efficiency of 12.8 cd/A, the power efficiency of 4.48 lm/W, the external quantum efficiency of 9.65% at 20 mA/cm2 and CIE x,y coordinates of (0.609, 0.390) at 12 V. PMID- 25936072 TI - Properties and microstructure of the Ru-coated carbon nano tube counter electrode for dye-sensitized solar cells. AB - In this study, we investigated the performance of dye-sensitized solar cells (DSSCs) with the ruthenium (Ru) coated multi-walled carbon nanotube (MWCNT) on the counter electrode (CE). High purity MWCNT (0.01~0.06 g) was sprayed on glass/fluorine-doped tin oxide (FTO). Then 30 nm-thick Ru thin films were coated on a MWCNT template at low temperature by atomic layer deposition (ALD) using RuDi and O2 as precursor to prepare Ru-CNT CE and the 0.45 cm2 DSSC device of glass/FTO/TiO2/Dye (N719)/electrolyte (C6DMII, GSCN)/Ru-CNT CE was fabricated. The surface morphology of CEs and the energy conversion efficiency of the DSSC device were characterized by scanning electron microscope (SEM), high-resolution transmission electron microscope (HRTEM), and photocurrent-voltage (I-V) measurement. We confirmed that effective surface of the CE increased linearly as the amount of MWCNT spray increased and the crystallized Ru was deposited very conformally around the MWCNT nano template. Moreover, the efficiency of the DSSC increased up to 3.3% as the amount of MWCNT increased. PMID- 25936073 TI - Molecular layer deposition of organic-inorganic hybrid films using diethylzinc and trihydroxybenzene. AB - We fabricated organic-inorganic hybrid thin films by using molecular layer deposition with diethylzinc and benzenetriol at temperatures of 100-160 degrees C. In this MLD process, the surface reactions were found to be self-terminating and complementary enough to make a uniform, conformal, high-quality hybrid thin film. The prepared zinc oxide-crosslinked hydroxybenzene and zinc oxide nanolaminated films (ZnOHB/ZnO) exhibited good stability and field effect mobility (> 0.6 cm2/V . s). The MLD method is an ideal technique for fabrication of various organic-inorganic hybrid thin films. PMID- 25936074 TI - Stochastic simulation studies of line-edge roughness in block copolymer lithography. AB - Because photoresist has the uncertain triangle relation among the higher resolution, the lower line-edge-roughness (LER) (or line-with-roughness (LWR)), and the improved sensitivity, for below 20-nm pattern formation, this relation makes hard to use the optical lithography. Directed self-assembly (DSA) has been considered as a potential candidate to extend the resolution limit of the optical lithography. The effects of DSA processing and DSA molecular geometry on LER should be well understood in order to meet the ITRS lithographic specifications. In this paper, for the optical lithography and the block copolymer (BCP) lithography such as graphoepitaxy, LER behavior is modeled by the stochastic methods such as the Monte Carlo method and the dissipative particle dynamics (DPD) method. Simulation results explain that the LER of the BCP lithography is smaller than that of the optical lithography because of a self-healing capability of block copolymers. PMID- 25936075 TI - Anisotropic thermal conductive MWCNT/polymer composites prepared with an immiscible PS/LDPE blend. AB - This study focuses on MWCNT/polymer composites with flexible, anisotropic heat transporting properties. For this study, an immiscible polymer blend of MWCNT/PS and LDPE (13.5:86.5 v:v) were used as a template. MWCNT/PS composites were first prepared by a solution process, and then melt-blended with LDPE using a brabender mixer. For achieving an alignment of MWCNT/PS in LDPE matrix, the blends of MWCNT/PS and LDPE were continuously treated under a fixed shear rate of 10 s(-1) at 210 degrees C. With partial extraction of PS in the aligned blends, FE-SEM images of the aligned blends revealed morphology of MWCNT in the PS/LDPE matrix, indicating local distribution of MWCNT selectively inside PS, where PS was elongated parallel to shear direction in LDPE matrix. The prepared MWCNT/PS and LDPE blends showed an anisotropic heat transporting behavior with anisotropic ratio of thermal conductivity (AR = lambdax/lambdaz) up to 1.330 at 10 wt% of MWCNT in PS (equivalent to 1.50 wt% of MWCNT in PS/LDPE). PMID- 25936076 TI - Measurement of contact resistance in CdSe-single-walled carbon nanotube hybrids. AB - The CdSe-single-walled carbon nanotube (SWNT) hybrids are synthesized for measuring contact resistance between CdSe quantum dots and SWNTs in two hybrid samples, i.e., spray-deposited CdSe on SWNTs, and pyrene-self assembled CdSe on SWNTs. Currents are measured through indium-tin oxide (ITO), CdSe-SWNT hybrids and the tip of conductive AFM (c-AFM) with and without light at 532 and 655 nm. PMID- 25936077 TI - Facile growth and characterization of alpha-Fe2O3 nanoparticles for photocatalytic degradation of methyl orange. AB - In this paper, we report synthesis and characterization of well-crystalline iron oxide (alpha-Fe2O3) nanoparticles; the synthesis was performed at temperature ~90 degrees C. The detailed structural and compositional characterizations confirmed the formation of well-crystalline, rhombohedral crystal structure and pure alpha Fe2O3 nanoparticles. The magnetic property, however, showed that the synthesized iron oxide nanoparticles are highly super paramagnetic. The as-synthesized Fe2O3 NPs were also utilized as an efficient photocatalysts for the photocatalytic degradation of methyl orange (MO) dye; degradation of MO was observed to be about 80% in the presence of alpha-Fe2O3 nanoparticles within 210 min under UV-light irradiation. PMID- 25936078 TI - The fabrication of patterned gold nanoparticle arrays via selective ion irradiation and plasma treatment. AB - A simple and facile method for the patterning of gold nanoparticles (GNPs) was described via selective ion irradiation and oxygen plasma etching. Thin Pluronic films containing HAuCI4 as the precursor of GNPs were selectively irradiated through a pattern mask with 200 keV proton ions to generate GNP-embedded Pluronic patterns. The Pluronic was then removed by an oxygen plasma etching process for the pattern formation of GNPs. Based on the results of the UV-Vis, FE-SEM, and EDX analyses, 50 MUm negative-tone line patterns of the GNP-embedded Pluronic were successfully generated at a fluence of less than 1 x 10(16) ions/cm2. The changes in the morphology and elemental composition of the formed GNP-embedded Pluronic patterns with different time periods of oxygen plasma etching were investigated using an FE-SEM with an EDX. The experimental results demonstrated that the patterns of GNPs were effectively generated by the oxygen plasma etching of the formed GNP-embedded Pluronic patterns for 15 min. Furthermore, the XRD results revealed that GNPs in the patterns formed by ion irradiation were further grown during the subsequent oxygen plasma etching. PMID- 25936079 TI - Orange phosphorescent iridium complexes chelated with phenylbenzothiazolate derivatives for white organic light-emitting diodes. AB - For the application to white organic light-emitting diodes (OLEDs), the iridium complexes containing phenylbenzothiazolate derivatives as main ligands were prepared and their photophysical properties were investigated. We introduced a series of substituted 2-phenylbenzothiazolate (pbt) ligands to the iridium complexes. Variation of the substituent (R) in the ligand backbones could lead to the emission color tuning of the complexes. As ancillary ligands, the anions of 2,3-diphenyl-4-methyl-quinoline-C2,N (4-Me-2,3-dpq) and phenylpyridine (ppy) were chelated to the iridium center to complete 6-coodinate complexes. The iridium complexes prepared herein are Ir(pbt-R)2(4-Me-2,3-dpq) (pbt-R = 2-(4-R phenylbenzothiazolate (R = H, OCH3, F); 4-Me-2,3-dpq = 2,3-diphenyl-4-methyl quinolinate-C2,N) and Ir(pbt-R)2(ppy) (ppy = 2-phenylpyridinate). The PL spectra of the iridium complexes showed yellow to orange emission at 540-595 nm with some variation in luminescence maxima depending on the ancillary ligand rather than on the substituents of the main ligands. The electrochemical characteristics of the complexes were also investigated with cyclic voltammetry and the resulting energy gaps between HOMOs and LUMOs were consistent with the PL maxima. The electroluminescence (EL) properties of the new iridium complexes were studied as possible phosphors for the application to orange and white OLEDs. PMID- 25936080 TI - Effect of electrode positions on the mixing characteristics of an electroosmotic micromixer. AB - In this study, an electrokinetic microchannel with a ring-type mixing chamber is introduced for fast mixing. The modeled micromixer that is used for the study of the electroosmotic effect takes two fluids from different inlets and combines them in a ring-type mixing chamber and, then, they are mixed by the electric fields at the electrodes. In order to compare the mixing performance in the modeled micromixer, we numerically investigated the flow characteristics with different positions of the electrodes in the mixing chamber using the commercial code, COMSOL. In addition, we discussed the concentration distributions of the dissolved substances in the flow fields and compared the mixing efficiency in the modeled micromixer with different electrode positions and operating conditions, such as the frequencies and electric potentials at the electrodes. PMID- 25936081 TI - Organic semiconductor based on asymmetric naphthalene-thiophene molecule for organic thin film transistor. AB - The new asymmetric semiconductor 5-(6-decylnaphthalen-2-yl)-5'-(naphthalene-2-yl) 2,2'-bithiophene (NBTND) was synthesized by Suzuki coupling reaction for an organic thin film transistor (OTFT) material. This asymmetric molecule was characterized by H-NMR, IR, HRMS, UV-visible spectroscopy, cyclovoltammetry, thermogravimetric analysis, differential scanning calorimetry. The thin film transistor using new asymmetric semiconductor exhibited the field effect mobility of 2.68 x 10(-2) cm2 V(-1) s(-1). PMID- 25936082 TI - Triphenylamine substituted anthracene derivatives for blue organic light-emitting diodes. AB - A series of bipolar anthracene derivatives containing triphenylamine as an electron donating group and pyridine, quinoline, isoquinoline and benzothiazole as electron withdrawing groups were synthesized and characterized. Particularly, a material, 9-quinolinyl-10-triphenylamin anthracene (3) exhibits a highly efficient sky-blue EL emission with the luminous efficiency (LE) of 9.36 cd/A, power efficiency (PE) of 5.94 lm/W and quantum efficiency (QE) of 4.23% at 500 nit. This material shows the maximum wavelength of the electroluminescence (EL) at 486 nm and the CIE x, y coordinates of (0.17, 0.36) at 6 V. PMID- 25936083 TI - Physical effects of DCNQI derivatives doping as an N type organic semiconductor in organic photovoltaic cell performance. AB - In the previous work, we have reported that organic photovoltaic (OPV) cells using DMDCNQI as an n-type second dopant material showed a high power conversion efficiency (PCE). In the present work, we have synthesized a novel DHDCNQI with long alkyl chains to improve the compatibility between the DHDCNQI dopant molecule and host P3HT polymer. We have fabricated OPV cells consisting of ITO/PEDOT:PSS/P3HT:PCBM:DHDCNQI/Al. We have investigated the characteristics of theses OPV cells using DCNQI derivative dopants from the measurements of the incident photon-to-current collection efficiency and photocurrent. The OPV cell using 3 wt% DHDCNQI exhibited a high PCE of 3.29% due to the high charge separation efficiency, good compatibility and low trap site effect. PMID- 25936084 TI - Fabrication and electroluminescence properties of white organic light-emitting diode with a new yellow fluorescent dopant. AB - A new yellow fluorescent material, (2Z)-3-[4,4"-bis(dimethylamino)-1,1':4',1" terphenyl-2'-yl]-2-phenylacrylonitrile (BDAT-P), have been synthesized for use in organic light-emitting diodes. Opto-electronic properties of device with the structure of ITO (180 nm)/NPB (50 nm)/MADN:PFVtPh (SYB-41) 8% (17 nm)/CBP (5 nm)/CBP:Ir(pq)2acac 8% (3 nm)/CBP (5 nm)/MADN:BDAT-P 8% (3 nm)/CBP (5 nm)/MADN:SYB-41 8% (17 nm)/TPBi (40 nm)/Liq (2 nm)/Al (100 nm) was measured and revealed that BDAT-P was sufficiently applicable as a dopant of one of emitting layers in white light-emitting diodes. Maximum luminance of device was measured to be 26,950 cd/m2. Maximum luminous and quantum efficiency were observed to be 14.22 cd/A and 6.58%, respectively. The device emitted warm white light corresponding to Commission Internationale de l'Eclairage (CIExy) coordinates of (0.372, 0.424) at 11 V, (0.375,0.417) at 12 V, (0.372,0.409) at 13 V, (0.366, 0.401) at 14 V, and (0.360, 0.393) at 15 V, respectively. PMID- 25936085 TI - Characteristics of room temperature silicon nitride deposited by internal inductively coupled plasma chemical vapor deposition. AB - The parallel inductively coupled plasma chemical vapor deposition system is used to directly control the activated radical and charged species in the plasma of a silicon nitride thin film, which is deposited at room temperature for flexible displays. By controlling the plasma characteristics of silicon nitride with plasma heating at 85 degrees C, this new technique produced low hydrogen content silicon nitride thin films at room temperature (25 degrees C). Deposition rates and refractive indices of the films ranged from 6.8 nm/min to 4.57 nm/min and from 2.125 to 1.749 with NH3 variation and ranged from 5.12 nm/min to 4.105 nm/min and from 1.81 to 1.92 with N2 variation, respectively. In the optical emission spectra of the plasmas investigated at fixed RF powers (1000 W), the peaks corresponding to the radical and charged species of SiH4, N2, and NH3 were related to the changes of the deposition rate and refractive index of the films. Current-voltage measurements with MIM capacitors revealed that these films had dielectric breakdown fields higher than 8 MV/cm, and FTIR showed their lower hydrogen contents than the conventional PECVD films. PMID- 25936086 TI - Controlled synthesis and near-infrared luminescence of LaOBr:Nd3+ nanofibers and nanobelts. AB - LaOBr:Nd(3+) nanofibers and nanobelts were synthesized for the first time via calcinating the electrospun PVP/[La(NO3)3 + Nd(NO3)3 + NH4Br] composites. X-ray diffraction (XRD) analysis revealed that LaOBr:Nd(3+) nanofibers and nanobelts are tetragonal in structure with the space group of P4/nmm. The morphologies and sizes of LaOBr:Nd(3+) nanostructures were investigated by scanning electron microscope (SEM). The mean diameter of the LaOBr:Nd(3+) nanofibers is 192.41 +/- 18.97 nm. The width and thickness of the LaOBr:Nd(3+) nanobelts are 5.50 +/- 0.48 MUm and 112 nm, respectively. Under the excitation of 532-nm laser, LaOBr:Nd(3+) nanostructures exhibit the characteristic emissions of predominant peaks at 922, 1072 and 1345 nm, attributed to (4)F3/2 --> (4)I9/2, (4)F3/2 --> (4)I11/2 and (4)F3/2 --> (4)I13/2 energy levels transitions of Nd(3+) ions, respectively. The optimum doping molar concentration of the Nd(3+) ions in the LaOBr:Nd(3+) nanofibers is 1.0%. Interestingly, we found that the luminescence intensity of nanobelts is obviously greater than that of the nanofibers for LaOBr:Nd(3+) under the same measuring conditions. The formation mechanisms of LaOBr:Nd(3+) nanofibers and nanobelts were also proposed. PMID- 25936087 TI - Root extracts of Polygala tenuifolia for the green synthesis of gold nanoparticles. AB - Traditional medicinal plants possess diverse active constituents for exerting their biological activities. Recently, the innovative applications of plant extracts have revealed their promise as 'green' reducing agents for the reduction of metal ions during the synthesis of metallic nanoparticles. Herein, we report the use of 70% ethanol extracts from Polygala tenuifolia roots as a 'green' reducing agent for the production of gold nanoparticles by reducing gold(III) chloride trihydrate. Gold nanoparticles were characterized using UV-Visible spectrophotometry, high-resolution transmission electron microscopy (HR-TEM), atomic force microscopy (AFM), X-ray diffraction (XRD), and Fourier transform infrared spectroscopy (FT-IR). The gold nanoparticles had characteristic surface plasmon resonance bands at 535 nm. HR-TEM and AFM images revealed major spherical shaped nanoparticles. The average diameter was measured to be 9.77+/-3.09 nm using HR-TEM images. The crystalline structure of the gold nanoparticles was confirmed through lattice fringes and circular spots within the selected area electron diffraction in the HR-TEM images along with the XRD peaks. The gold nanoparticles exhibited enhanced anticoagulant activity, as assessed by activated partial thromboplastin time. The current method is a straightforward, environmentally friendly, and inexpensive method for the production of gold nanoparticles using extracts from traditional medicinal plants. PMID- 25936088 TI - Enhancing field emission performance of aligned Si nanowires via in situ partial oxidization. AB - Partially oxidized Si nanowire (NW) arrays have been achieved via a combinatorial process of selectively etching Si wafer to obtain vertically aligned single crystalline Si NW arrays and subsequent in situ partially oxidizing the as-etched bare Si NWs. The resultant Si products are Si-SiOx nanocable-like structures consisting of single-crystalline Si NW inner cores and outer shells of insulating SiOx. Field emission measurements demonstrate that surface partial oxidization enhances the field emission current of the as-etched bare Si NWs effectively, which can be ascribed to the outer shell of insulating SiOx that has small electron affinity (0.6-0.8 eV) and can protect Si NW inner cores. The results indicate that the partially oxidized Si NW arrays would act as the excellent field emitters in the future vacuum micro- and nano-electronic devices. PMID- 25936089 TI - A synthetic study and characterization of the Pt(II) complexes with bipyridines back-born system. AB - The reaction of platinum [Pt(5,5-dmbpy)]Cl2 (5,5-dmbpy = 5,5'-dimethyl-2,2' bipyridine) with 4,4'-dimethyl-2,2'-bipyridine (4,4-dmbpy), [Pt(dbbpy)]Cl2 (dbbpy = 4,4'-dibutyl-2,2'-bipyridine), [Pt(dpbpy)]Cl2 (dpbpy = 4,4'-dipentyl-2,2' bipyridine) with 5,5'-dimethyl-2,2'-bipyridine (5,5-dmbpy) affords the following complexes: [(4,4-dmbpy)Pt(5,5-dmbpy)][PF6]2 (1) and [(dbbpy)Pt(5,5-dmbpy)][PF6]2 (2), [(dpbpy)Pt(5,5-dmbpy)][PF6]2 (3), [(5,5-dmbpy)Pt(5,5-dmbpy)][PF6]2 (4). This study was synthesized new platinum complex compounds utilizing ligand of 5,5' Dimethyl-2,2'-dipyridyl System. To study the chemical composition was used 1H(13C)-NMR, UV-vis, Spectro photometer and Measurements about optical physics and chemical properties were measured to use spectrofluorometer. UV-vis absorption area was measured 310 nm to 383 nm and luminous wavelength was measured 390 nm to 419 nm. PMID- 25936090 TI - Undoped blue organic light-emitting diodes using 2-diphenylaminofluoren-7 ylstyryl derivatives. AB - Blue fluorescent materials based on diphenylaminofluorenylstyryl derivatives connected with the various end-capping aromatic groups were synthesized and characterized. An OLED, using (E)-9,9-diethyl-7-(4-(4-fluoronaphthalen-1 yl)styryl)-N,N-diphenyl-9 H-fluoren-2-amine(5) in emitting layer, was fabricated. This device showed the highly efficient blue emission with the maximum luminance of 5138 cd/m2, the luminous efficiency of 3.92 cd/A, the power efficiency of 3.17 lm/W, the external quantum efficiency of 2.90% at 20 mA/cm2 and CIE x, y coordinates of (0.14, 0.17). PMID- 25936091 TI - Field emission properties of a three-dimensional network of single-walled carbon nanotubes inside pores of porous silicon. AB - We report characteristic field emission (FE) properties of single-walled carbon nanotubes (SWCNTs) synthesized inside the pores as well as on the top surface of a porous silicon (PS) substrate. Turn-on fields and emission current densities were measured and compared with those of other types of SWCNTs in similar environments. Investigation of the FE properties of SWCNTs synthesized inside the pores of a PS substrate revealed a low turn-on field of approximately 2.25 V/MUm at 10 MUA/cm2 and a high field-enhancement factor (6182) compared with other samples. A life-time stability test was performed by monitoring the current density before and after repeated exposure to O2, suggesting that the pore channel can effectively prevent O2(+) ion etching from destroying SWCNTs within the pores of the PS layer. PMID- 25936092 TI - Comparison of different structures of niobium oxide blocking layer for dye sensitized solar cells. AB - In this study, four different types of Nb2O5 thin layers were prepared using sol gel process to improve energy conversion efficiency of dye sensitized solar cells (DSSCs). Nb2O5 layer was prepared on the fluorine-doped tin oxide (FTO) layer, TiO2 electrode layer, and inside of TiO2 layer, respectively. The Nb2O5 layer was used to reduce the recombination of photo induced electrons and holes. The DSSCs were assembled with platinum (Pt) coated counter electrode, ruthenium dye, and iodine based electrolyte. The photocurrent-voltage (I-V) characteristics of DSSCs with different types of Nb2O5 were studied. The efficiency depends not only on the structure of DSSCs but also on the initial compositions for the preparation of Nb2O5. PMID- 25936093 TI - Fabrications of electrospun nanofibers containing inorganic fillers for dye sensitized solar cells. AB - Poly(vinylidenefluoride-co-hexafluoropropylene) (PVDF-HFP) nanofibers containing inorganic fillers were fabricated by electrospinning. Dye-sensitized solar cells (DSSCs) using these nanofibers showed improved short circuit currents without degraded fill factors or open circuit voltages. The long-term stabilities of cells using electrospun PVDF-HFP/titanium isopropoxide (TIP) nanofibers were significantly improved. PMID- 25936094 TI - Effect of reactive monomer on PS-b-P2VP film. AB - Poly(styrene-b-2-vinyl pyridine) (PS-b-P2VP) lamellar film which is hydrophobic block-hydrophilic polyelectrolyte block polymer of 52 kg/mol-b-57 kg/mol and PS-b P2VP film with reactive monomer (RM257) were prepared for photonic gel films. The lamellar stacks, which is alternating layer of hydrophilic and hydrophobic moiety of PS-b-P2VP, were obtained by exposing the spin coated film under chloroform vapor. The lamellar films were quaternized with 5 wt% of iodomethane diluted by n hexane. We reported about the influence of reactive monomer on those photonic gel films. Added reactive monomer photonic gel film had higher absorbance than pure photonic gel films. As a result the photonic gel film with RM had more clear color. The lamellar films were swollen by DI water, ethanol (aq) and calcium carbonate solution. The band gaps of the lamellar films were drastically shifted to longer wavelength swollen by calcium carbonate solution. And the lamellar films were shifted to shorter wave length swollen by ethanol. So each lamellar film showed different color. PMID- 25936095 TI - Photovoltaic and thermal properties of electrolytes based on electrospun poly(vinylidene fluoride-hexafluoro propylene)/poly(methyl methacrylate) nanofibers for dye-sensitized solar cells. AB - We prepared electrospun polymer nanofibers by electrospnning method and investigated about their applications to dye-sensitized solar cells (DSSCs). Electrospun polymer nanofibers applied to the polymer matrix in electrolyte for DSSCs. To improve the stiffness of polymer nanofiber, poly(vinylidene fluoride hexafluoro propylene)/Poly(methyl methacrylate) (PVDF-HFP/PMMA) blend nanofibers were prepared and examined. In the electrospun PVDF-HFP/PMMA (1:1) blend nanofibers, the best results of VOC, JSC, FF, and efficiency of the DSSC devices showed 0.71 V, 12.8 mA/cm2, 0.61, and 5.56% under AM 1.5 illumination. PMID- 25936096 TI - Gate length scaling effect on high-electron mobility transistors devices using AlGaN/GaN and AlInN/AlN/GaN heterostructures. AB - Compared to AlGaN/GaN HEMT with 0.15 MUm T-gate length, the AlInN/AlN/GaN one exhibits much higher current density and transconductance of 1558 mA/mm at Vd = 2 V and 330 mS/mm, respectively. The high extrinsic ft and fmax of 82 GHz and 70 GHz are extracted from AlInN/AlN/GaN HEMT. Besides, we find that the transconductance roll-off is significant in AlGaN/GaN, but largely improved in AlInN/AlN/GaN HEMT, suggesting that the high carrier density and lattice-matched epitaxial heterostructure is important to reach both large RF output power and high operation frequency, especially for an aggressively gate length scaling. PMID- 25936097 TI - Synthesis and characterization of an ionic conjugated polymer: poly[2-ethynyl-N (2-furoyl)pyridinium chloride]. AB - A new ionic polyacetylene derivative with furoyl substituents was prepared by the uncatalyzed polymerization of 2-ethynylpyridine by using 2-furoyl chloride in high yield. The polymer structure was characterized by such instrumental methods as NMR, IR, and UV-visible spectroscopies to have a polyacetylene backbone system with the N-(2-furoyl)pyridinium chloride. The electro-optical and electrochemical properties of poly[2-ethynyl-N-(2-furoyl)pyridinium chloride [PEFPC] were studied. The photoluminescence spectrum showed that the PL peak is at 578 nm corresponding to the photon energy of 2.15 eV. The cyclovoltammograms of PEFPC exhibited the irreversible electrochemical behaviors between the oxidation and reduction peaks. The oxidation current density of polymer versus the scan rates is approximately linear relationship in the range of 30 mV/sec-150 mV/sec. It was found that the kinetics of redox process is controlled by the reactant diffusion process from the oxidation current density of PEFPC versus the scan rates. PMID- 25936098 TI - Controlled synthesis, optical properties and cytotoxicity studies of CdSe poly(lactic acid) multifunctional nanocomposites by ring-opening polymerization. AB - A facile synthetic route has been developed for the covalent grafting of biocompatible poly(lactic acid) (PLA) onto CdSe Quantum Dots (QDs) using surface initiated ring opening polymerization (ROP) to afford CdSe-g-PLA nanocomposites. At first, 2-mercaptoethanol (ME) capped CdSe QDs were synthesized through a wet chemical process. The surface initiated ROP of lactide was accomplished with Sn(Oct)2 to give CdSe-g-PLA nanocomposites having surface hydroxyl functionality. FT-IR data suggested that a robust covalent bond was formed between ME capped CdSe QDs and polymer moieties. The grafting density of PLA on CdSe QDs was found to be moderate as measured by TGA analysis. The CdSe QDs were well dispersed in CdSe-g-PLA nanocomposites matrices as captured by TEM. The cubic phase crystal structure of CdSe QDs in the nanocomposites was determined by XRD. The optical properties of the CdSe-g-PLA nanocomposites were investigated by UV-vis and photoluminescence spectroscopy which suggested their potentialities as optical materials in biomedical application. Cell viability studies revealed that the biocompatibility of CdSe QDs was improved upon PLA immobilization. PMID- 25936099 TI - Cisplatin-incorporated nanoparticles of methoxy poly(ethylene glycol)-b-poly(L glutamic acid) copolymer. AB - We fabricated cisplatin-incorporated nanoparticles using block copolymer composed of methoxy poly(ethylene glycol) (MPEG) and poly(L-glutamic acid) (PGA) (abbreviated as GE). For synthesis of block copolymer, MPEG was directly conjugated to the terminal amine of PGA. Cisplatin-incorporated nanoparticles was prepared by ion complex formation of cisplatin and PGA domain of block copolymer. Size of cisplatin-incorporated nanoparticles was less than 200 nm at particle size measurement and their shapes were spherical at TEM observation. To study drug release properties, cispaltin release from nanoparticles were performed at phosphate-buffered saline (PBS, 0.01 M, pH 7.4) and distilled water, indicating that cisplatin release rate at PBS was approximately three times higher than that of deionized water. The cell growth inhibition of cisplatin incorporated nanoparticles in vitro was tested with HuCC-T1 cells. Cisplatin-incorporated nanoparticles were effectively inhibited tumor cell growth as similar as cisplatin itself. In other words, nanoparticles showed decreased inherent cytotoxicity compared to cisplatin against normal cells. We suggest that cisplatin incorporated GE nanoparticles is a good candidate for antitumor drug targeting. PMID- 25936100 TI - Fabrication of ZnO nanorods for gas sensing applications using hydrothermal method. AB - We showed well-aligned zinc oxide (ZnO) nanorod arrays synthesized using hydrothermal method at atmospheric pressure. The influence of fabrication conditions such as Zn2+/hexamethylentriamin concentration ratio, and growth temperature on the formation of ZnO nanorods was investigated. Scanning Electron Microscope (SEM) images and X-ray Diffraction (XRD) analysis were used to confirm the single crystal of ZnO nanorods, which showed wurtzite structure with growth direction of [0001] (the c-axis). Photoluminescence (PL) measurements of ZnO nanorods revealed an intense ultraviolet peak at 388.5 nm (3.19 eV) at room temperature. The results showed that the ZnO seed layers had strong influence on the growth of vertically aligned ZnO nanorods. The gas sensor based on ZnO nanorod arrays had the most selectivity with n-butanol gas (within 2 surveyed gas: ethanol and n-butanol) and showed a higher sensitivity of 222, fast response time of 15 seconds, recovery time of 110 seconds and lower operating temperature of 200-250 degrees C than the sensor based on the ZnO film in the same detecting conditions. PMID- 25936101 TI - One-step fabrication of poly(9,9-dioctylfluorene) nanowire arrays with pronounced beta-phase using liquid-bridge-mediated nanotransfer molding. AB - Poly(9,9-dioctylfluorene) nanowire arrays with pronounced beta-phase were prepared by a one-step fabrication method, liquid-bridge-mediated nanotransfer molding. Liquid-bridge-mediated nanotransfer molding is a new direct nano patterning method based on the direct transfer of various materials from a mold to a substrate via liquid layer. We fabricated poly(9,9-dioctylfluorene) nanowire arrays (80 nm parallel lines and 120 nm spaces) by Liquid-bridge-mediated nanotransfer molding using the poly(9,9-dioctylfluorene) ink solution. The formation of the beta-phase poly(9,9-dioctylfluorene) was proved by the present of an absorption peak at 435 nm. The most intense photoluminescence emission was obtained with the collection polarizer oriented parallel to the nanowire long axis, and an emission dichroic ratio of 3.7 was determined. PMID- 25936103 TI - Effects of preparation conditions of poly(lactide-co-glycolide) nanoparticles loaded with amphiphilic porphyrins and their photoactivities. AB - Three porphyrins, (5,10,15,20-tetra(3-hydroxyphenyl)porphyrin, 5-hexyl-10,20 bis(3-hydroxyphenyl)-porphyrin and 5-hexyl-10,15,20-tris(3 hydroxyphenyl)porphyrin), with different amphiphilicities and equal singlet oxygen quantum yields in ethanol, were encapsulated into 50:50 poly(lactide-co glycolide), nanoparticles prepared by the emulsion/evaporation technique. A 22 factorial design was utilized to evaluate the influence of the porphyrin/polymer mass ratio and the percentage of ethanol in the aqueous phase on the size and zeta potential of the nanoparticles. Increasing both the amount of ethanol and the porphyrin/polymer ratio decreases the size and increases zeta potential for the photosensitizers studied, except for 5-hexyl-10,15,20-tri(3 hydroxyphenyl)porphyrin. Entrapment efficiency depended on the individual m hydroxyphenylporphyrin and ranged from 69 to 97%. After 1.5 h incubation with m hydroxyphenylporphyrin-loaded nanoparticles the percentages of intracellular uptake were the same for all porphyrins since the molecules are confined in the nanoparticles, hampering the interaction of the amphiphilic photosensitizers with the cellular membrane. All encapsulated porphyrins caused the same decrease of cell viability and always localized in the perinuclear region of the cells. Results show that these m-hydroxyphenylporphyrins, although with different amphiphilicities, have equal photodynamic efficacies. PMID- 25936102 TI - Synthesis of triphenylsulfonium triflate bound copolymer for electron beam lithography. AB - Photoacid generator (PAG) has been widely used as a key component in photoresist for high-resolution patterning with high sensitivity. A novel acrylic monomer, triphenylsulfonium salt methyl methacrylate (TPSMA), was synthesized and includes triphenylsulfonium triflate as a PAG. The poly(MMA-co-TPSMA) (PMT) as a polymer bound PAG was synthesized with methyl methacrylate (MMA) and TPSMA for electron beam lithography. Characterization of PMT was carried out by NMR and FTIR. The molecular weight was analyzed by GPC. Thermal properties were studied using TGA and DSC. Thecharacterization results were in good agreement with corresponding chemical compositions and thermal stability. PMT was subsequently employed in electron beam lithography and its lithographic performance was confirmed by FE SEM. This PMT was accomplished to improve the lithographic performance including sensitivity, line width roughness (LWR) and resolution. We found that PMT was capable of 20 nm negative tone patterns with better sensitivity than hydrogensilsesquioxane (HSQ) which is a conventional negative tone resist. PMID- 25936104 TI - Aluminium electrodeposition in chloroaluminate ionic liquid. AB - An efficient microwave enhanced synthesis of ambient temperature chloroaluminate ionic liquid ([EMIM]Br) that preceeds reaction of 1-methylimidazolium with bromoethane in a closed vessel, was described in our work. The reaction time was drastically reduced as compared to the conventional methods. The electrochemical techniques of impedance spectroscopy, cyclic voltammetry and chronoamperometry were used to investigate the mechanism of Al electrodeposition from 2:1 (molar ratio) AlCl3/[EMIM]Br ionic liquid at room temperature. Results indicated that Al electrode- position from this ionic liqud was a quasi-reversible process, and the kinetic complications during the reaction was probably attributed to the electron transfer or mass transport cooperative controlled processes, instantaneous nucleation with diffusion-controlled growth was also investigated. Electrodepositon experiment was conducted using constant current density of 40 mA.cm(-2) for 20 minutes at room temperature and the qualitative analysis of the deposits were performed using X-ray diffraction (XRD), Scanning Electron Microscopy (SEM) and energy dispersive spectroscope (EDS). The deposits obtained on copper cathode were dense and compact and most Al crystal shows granular structure spherical with high purity. PMID- 25936105 TI - A new approach for white organic light-emitting diodes of single emitting layer using large stokes shift. AB - DPPZ showed UV-Vis. and PL maximum values of 412 and 638 nm, meaning the large stokes shift. Blue host compound, TAT was synthesized and used for co-mixed white emission. TAT exhibited UV-Vis. and PL maximum values of 403 nm and 445 nm in film state. Thus, when two compounds are used as co-mixed emitter in OLED device, there is no energy transfer from blue emission of TAT to DPPZ due to large stokes shift of DPPZ. Based on the PL result, it is available to realize two-colored white in PL and EL spectra. As a result of this, two-mixed compounds showed vivid their own PL emission peaks of 449 and 631 nm in film state. Also, white OLED device using two-mixed compounds system was fabricated. EL spectrum shows 457 and 634 nm peaks and two separate EL peaks, respectively. As the operation voltage is increased from 7 to 11 V, EL spectrum does not change the peak shape and maximum wavelength values. EL performance of white device showed 0.29 cd/A, 0.14 lm/W, and CIE (0.325, 0.195) at 7 V. PMID- 25936106 TI - Structural and optical properties of the In(x)Ga(1-x)As nanowires grown on SiO2 via vapor-liquid-solid method. AB - We report the crystal growth of the In(x)Ga(1-x)As nanowires (NWs) on SiO2 substrate using metal organic chemical vapor deposition. Au nanoparticles which are disintegrated from thin Au film have been used as a catalyst for the vapor liquid-solid growth. Electron microscopy characterization is performed to investigate the structural properties of the In(x)Ga(1-x)As NW. The In(x)Ga(1 x)As NW grown under an optimal condition has a single-crystal wurtzite structure without any misfit dislocation or stacking fault. Strong room temperature photoluminescence peaks are observed from In(x)Ga(1-x)As NWs passivated by GaAs. Very low light reflectance is measured at the NW surface in the wavelength range from 250 to 1200 nm. The single crystal In(x)Ga(1-x)As NWs are applicable to the various electrical and optical devices. PMID- 25936107 TI - Enhancement of the efficiency in p-i-n organic light-emitting devices containing organic p-type HAT-CN and n-type bis(ethylenedithio)- tetrathiafulvalene doped BPhen layers. AB - The p-i-n organic light-emitting devices (OLEDs) were fabricated by using a p type 1,4,5,8,9,11-hexaazatriphenylene hexacarbonitrile (HAT-CN) layer and an n type bis(ethylenedithio)-tetrathiafulvalene (BEDT-TTF) doped 4,7-diphenyl-1,10 phenanthroline (BPhen) electron transport layer. The p-i-n OLEDs containing a p type HAT-CN layer and BEDT-TTF-doped BPhen layer with a BEDT-TTF doping concentration of 1 wt.% demonstrated low operating voltage and the highest luminance efficiency. The enhancement of the luminance efficiency as well as a decrease in the operating voltage of the OLEDs was attributed to the improvement of the hole and electron injection due to the insertion of a HAT-CN layer and a BEDT-TTF-doped BPhen layer. PMID- 25936108 TI - Solvent effects of a dimethyldicyanoquinonediimine buffer layer as N-type material on the performance of organic photovoltaic cells. AB - In the present work, we have fabricated organic photovoltaic cells consisting of ITO/PEDOT:PSS/P3HT:PCBM/DMDCNQI/Al using a dip-coating method with various solvent systems. We have investigated solvent effects (such as solubility, viscosity and vapor pressure) in deposition of a thin DMDCNQI buffer layer on the performance of organic photovoltaic cells. The solvent system which had low viscosity and good solubility properties, made a dense and uniform DMDCNQI ultra thin film, resulting in a high performance device. In particular, a prepared organic photovoltaic cell was fabricated using a cosolvent system (methanol:methylenechloride = 3:1) and showed a maximum power conversion efficiency of 4.53%. PMID- 25936109 TI - Electroless chemical grafting of nitrophenyl groups on n-doped hydrogenated amorphous silicon surfaces. AB - The direct spontaneous grafting of 4-nitrophenyl molecules onto n-doped hydrogenated amorphous silicon (a-Si:H) surfaces without external ultraviolet, thermal, or electrochemical energy was invegtigated. Clean n-doped a-Si:H thin films were dipped in a solution of 4-nitrobenzenediazonium salts (PNBD) in acetonitrile. After the modified surfaces were rinsed, they were analyzed qualitatively and quantitatively by X-ray photoelectron spectroscopy (XPS) and atomic force microscopy (AFM). XPS and AFM results show that the reaction of an n doped a-Si:H thin film with PNBD self-terminates without polymerization, after 5 h, and the surface number density of 4-nitrophenyl molecules is 4.2 x 10(15)/cm2. These results demonstrate that the spontaneous grafting of nitrophenyl layers onto n-doped a-Si:H thin films is an attractive pathway toward forming interfaces between a-Si:H and organic layers under ambient conditions. PMID- 25936110 TI - Characteristics of vertical type polymer light emitting transistor using dimethyldicyanoquinonediimine as a N-type buffer layer. AB - Contact resistance between a metal electrode and an organic active layer is one of the most critical issues in the research and development of organic electronic devices. In the present work, we have fabricated vertical type organic light emitting transistor (OLET) using P3HT as a organic active semiconductor and DMDCNQI as a charge transfer material. The device configuration is ITO/PEDOT:PSS/P3HT/Al gate/P3HT/DMDCNQI/Al. The characteristics of OLET were investigated from the measurement of current-radiance voltage characteristics The needle form of highly conducting DMDCNQI-Al charge transfer complex was obtained, which resulted in the improvement of device performance due to the low organic metal contact resistance and the high electron transport ability. PMID- 25936111 TI - Thickness effect of single crystalline TiO2 nanorods for dye-sensitized solar cells. AB - A hydrothermal method was explored to synthesize single-crystalline (sc) rutile TiO2 nanorods (NRs) with a thickness ranging from 2.4 MUm to 6.4 MUm on a transparent conductive fluorine-doped tin oxide (FTO) substrate. The variation of precursor ratios in the synthesis solution modulates the length of sc-TiO2 NRs. That is, as the amount of the precursor (titanium butoxide) is decreased in the synthesis bath, the growth length of sc-TiO2 NRs is reduced steadily; the rod diameter is also decreased in the circumstance where all experimental conditions are identical. These samples were applied to dye-sensitized solar cells (DSSCs), the efficiency of which was increased with the thickness of the rods. However, the efficiency of 6.4 MUm-thick TiO2 NRs is inversely decreased, resulting from the blocking of pores between NRs from unfavourable electrolyte penetration. These results were confirmed by the incident photon to current efficiency (IPCE). PMID- 25936112 TI - Size-controlled synthesis of Pd nanomaterials via proton beam irradiation. AB - We present a facile one-pot synthetic route for the production of palladium nanoparticles via a simple proton beam irradiation process at room temperature. The synthesis of size-controlled palladium nanostructures was realized just by changing the mean current of the proton beam and by controlling the molar concentration ratios of surfactants to Pd precursors in an aqueous phase-based solution without the addition of any harsh reductants. As the beam current was increased under the same Pd ion concentration conditions, the average diameter of the prepared Pd nanoparticles tended to be decreased. We also found that the size of the synthesized Pd nanocrystals was decreased as the molar ratio of surfactants to palladium ion was increased. PMID- 25936113 TI - Response of a ZnO single crystal rod-based chemical sensor for hydrogen sulfide. AB - A zinc oxide single crystal rod was grown by a thermal evaporation method for application as a chemical gas-sensing material in this study. Zinc acetate (20 wt%) impregnated over activated carbon was used as the precursor for the epitaxial growth of ZnO single crystal rods. The response tests were carried out across a range of sensing temperatures (100, 150 and 200 degrees C) and the hydrogen sulfide content (10.2-51.0 ppmv) was balanced with nitrogen gas. The response of the ZnO single crystal rods grown on the gas sensors varied with the H2S content and the sensing temperature. A high response for H2S was obtained at 150 and 200 degrees C due to the high reactivity between H2S and ZnO at high temperature. Since H2S absorption rate and ZnS oxidation rate over ZnO single crystal rods at 100 degrees C lower than that at 150 and 200 degrees C, the changing rate of electric resistance decreased with the decrease of temperature. Meanwhile, a different response, which is the changing rate of electric resistance for H2S absorption and ZnS oxidation over ZnO single crystal rods at 100 degrees C, was observed with changing amount of H2S in feed gas. Therefore, it was concluded that the ZnO single crystal rods based gas sensor is operated above 200 degrees C for the shortly response time. PMID- 25936114 TI - Thieno[3,2-b]thiophene-based conjugated polyfluorene copolymer for efficient polymer solar cell. AB - We have synthesized and characterized a polyfluorene derivative composed of octyl substituted thieno[3,2,-b]thiophene and 2,1,3-benzothiadiazole as an acceptor unit. The best power conversion efficiencies of the polymer were showed with 1.63% and 2.31% by using PCBM and PC71BM, respectively. PMID- 25936115 TI - Experimental study of transition metal ion doping on TiO2 with photocatalytic behavior. AB - In this research, we have studied the doping behaviors of three transition metal ion dopants on the crystal phase, particle sizes, XRD patterns, EDAX spectra, and photoreactivity of TiO2 nanoparticles. Test metal ion concentrations ranged from 1% to 4 at.%, we report the growth of [Fe, Co and Mn]xTiO2 nanocrystals prepared by Sol-Gel technique, followed by freeze-drying treatment at -30 degrees C temperature for 12 hrs. The obtained Gel was thermally treated at different temperature like 200 degrees C, 400 degrees C, 600 degrees C, 800 degrees C. Thermal gravimetric analysis (TGA) shows that dopant concentration affects thermal decomposition. The photoreactivities of transition metal ion-doped TiO2 nanoparticles under UV irradiation were quantified by the degradation of formaldehyde. PMID- 25936116 TI - A top-down route for preparation of ultrathin zinc oxide nanowires. AB - Zinc oxide nanowires have been successfully obtained through the splitting of layered basic zinc acetates. The layered basic zinc acetates nanobelts served as intermediates are prepared by adding water into zinc oxide ethanol colloids. Zinc oxide nanowires have uniform diameters of about 3-5 nm and lengths of several hundred nanometers. The formation mechanism of zinc oxide nanowires is proposed. The mechanism is that zinc oxide nanowires are generated by the splitting of the layered compound. From this mechanism, we find that the structure characteristic of layered basic zinc acetates is essential for the formation of ZnO nanowires. We also discuss the relationship between the morphology of products obtained after incubating and incubating time. The products are characterized by X-ray powder diffraction, transmission electron microscopy, scanning transmission electron microscopy and infrared spectrum. PMID- 25936117 TI - Synthesis and characterization of alkyl ester functionalized multiwall carbon nanotubes. AB - Alkyl chains of different length were added onto surface of multiwall carbon nanotubes (MWCNT). Oxidized multiwall carbon nanotubes (MWCNT-COOH) were reacted with thionyl chloride (SOCl2) and further in esterification reaction with given alcohols gave corresponding methyl ester (MWCNT- COOCH3), n-butyl ester (MWCNT COOC4H9) and n-dodecyl ester (MWCNT-COOC12H25) modified carbon nanotubes. Functionalization of MWCNTs was confirmed by FTIR, Raman and X-ray photoelectron spectroscopy as well as by thermogravimetric analysis. n-Butyl ester and n dodecyl ester modified carbon nanotubes showed contact angle for water of about 142 and 150 degrees, while the oxidized and methyl ester modified carbon nanotubes showed seepage. Dispersibility of oxidized and alkyl ester modified carbon nanotubes in methanol and toluene was quantified by UV-Vis spectroscopy and differs significantly in both solvents for all systems. PMID- 25936118 TI - Modification of polysulfone membrane used in the water filtration process to reduce biofouling. AB - Polysulfone membranes (PSF) were modified with silver nanoparticles obtained by new synthesis (nAgNS), silver nanoparticles obtained commercially (nAgC), silver sulfadiazine (SP), dodecyltrimethylammonium bromide (DOTAB), benzalkonium chloride (CB) or sodium dodecylbenzene sulfonate (DBSS) to improve the efficiency of the water filtration process by reducing biofouling. All membranes had lower hydrophobicity compared with PSF. The zeta potentials of all membranes were negative at pH 7.0, except for CB 10%. In the agar diffusion test, E. coli was considered to be sensitive to the antimicrobial effect of the nAgNS 1%, 3%, 6%, 10% and DOTAB 10%, whereas S. aureus was sensitive to the nAgNS 1%, 3%, 6%, 10%, DOTAB 10%, CB 0.22%, 2% and 10%. The lowest adhesion of E. coli was found in the nAgNS 6% and 10%. In the evaluation of the loss of flow rate during filtration of the E. coli suspension and pure water, nAgNS showed higher flow rate values when compared with PSF. The nAgNS did not release quantities of silver (0.1 mg/l) above the amount considered safe by the World Health Organization. Membranes nAgNS 6% and 10% showed the best anti-biofouling characteristic. PMID- 25936119 TI - WO3 nanotubes prepared by a coaxial electrospinning method. AB - In this paper, WO3 nanotubes were prepared by a coaxial electrospinning method. Firstly, core-shell structured composite fibers were fabricated via coaxial electrospinning under the optimal electro-spinning parameters to get the best composite fibers with uniform diameters and smooth surface, which pure PVA being the core solution and PVA/AMT/alcohol being the shell one, respectively. Secondly, the composite fibers were calcined in air at 600 degrees C for 4 h to wipe out the pure PVA, leading to the formation of nanotubes. After sintering, the obtained WO3 nanotubes were characterized by Fourier transform infrared spectroscopy (FTIR), X-ray diffraction (XRD), Field emission scanning electron microscopy (FESEM) and high-resolution transmission electron microscopy (HRTEM). The XRD show that the resultant materials consist of pure tungsten trioxide (WO3) with good crystallinity, while FESEM and HRTEM images indicate that the materials are nanotubes with rough surface and consist of nanoparticles. The inner diameter and the wall thickness of nanotubes were calculated to be around 100 and 50 nm, respectively. PMID- 25936120 TI - Preparation and electrochemical characterization of polyaniline functionalized copper bridges carbon nanotube for supercapacitor applications. AB - Supercapacitor is an alternative power source due to its high energy density, fast charge/discharge time, low level of heating, safety, long-term operation stability. MWCNTs are used for supercapacitor applications due to their unique properties, structure, high surface area. In the present work nanocomposites were prepared from Cu modified MWCNTs (binary) from which ternary composite also prepared with HCI doped polyaniline (PANI). Cu modified MWCNTs were prepared by the reduction of copper sulphate with sodium borohydride in basic medium. The uniform coating of polymer, upon the Cu modified MWCNTs, was evidenced from the field emission scanning electron microscopic (FESEM) and high resolution transmission electron microscopic (HRTEM) images. The modification of MWCNTs with Cu, was confirmed from the X-ray Diffraction (XRD) and X-ray photoelectron spectroscopy (XPS) analysis. Cyclic voltammetry (CV) measurement and charge discharge test shows higher capacitance for the ternary composites (264 F/g) compared to the binary system (125 F/g). The cyclic stability and retention of specific capacitance also shows the better result for ternary system. PMID- 25936121 TI - New hole transporting materials based on hexaarylbenzene and aromatic amine moiety for organic light-emitting diodes. AB - Three different new hole transport compounds, namely DPAP-TB, 1-PNAP-TB and 2 PNAP-TB, were synthesized by Sonogashira coupling and Diels-Alder reaction. Synthesized materials exhibited high Tg in the range of 118 to 133 degrees C. These values are higher than that of NPB, which is commonly used as a hole transporting material. OLED devices were fabricated by the synthesized compounds using the solution process as a hole transporting layer. Device structure was ITO/PEDOT:PSS (40 nm)/synthesized compounds or NPB (20 nm)/Alq3 (70 nm)/LiF/Al. Luminance efficiencies and external quantum efficiencies of DPAP-TB, 1-PNAP-TB and 2-PNAP-TB devices were 3.98, 4.62, 4.22 cd/A, and 1.35, 1.56, 1.43% at 20 mA/cm2, respectively. In luminance efficiency and external quantum efficiency, 1 PNAP-TB especially had superior property to NPB. PMID- 25936122 TI - Titania produced from Ti-salt flocculated sludge: photocatalytic activity under solar light. AB - In this study, titania photocatalyst was produced from the wastewater sludge of Ti-salt flocculation. The high photocatalytic activity of titania reported was evaluated based on a single organic substrate. However, the photocatalytic activity is a substrate-specific; one photocatalyst showed different photocatalytic degradation rates for different substrates. Thus, to investigate the substrate-specific photocatalytic activity of titania, various substrates of humic acid (HA), dichloroacetic acid (DCA), rhodamine B (RhB), metsulfuron methyl (M&M) and phenol were used under simulated solar light irradiation. Results showed titania had a high activity rate for RhB, moderate activity for HA and DCA and low activity for M&M and phenol indicating substrate-specific activities. When compared with Degussa-P25, titania showed higher activity for M&M, while the opposite was observed for HA and phenol. The specific-substrate behaviour of titania could depend on specific physicochemical and electronic interactions between titania, substrates, and their intermediates compounds formed. PMID- 25936123 TI - Additive effect of nano-size platinum to pretreated iron based catalyst on complete oxidation of toluene. AB - Catalytic oxidation of toluene (VOC) was carried out to assess the properties and catalytic activities of iron oxide catalyst promoted with nano size platinum. The properties of the prepared catalysts were characterized by the Brunauer Emmett Teller (BET) surface area method and by conducting Temperature programmed reduction (TPR), X-ray diffraction (XRD), and Tansmission electron microscopy (TEM) analyses. The experimental results showed that the addition of platinum to spent iron based catalyst shifted its conversion curve for the total oxidation of toluene to lower temperature. It was also observed that the increase in toluene conversion due to the addition of nano-size platinum was highly dependent on the surface oxygen mobility of the catalyst. PMID- 25936124 TI - Formation and deposition of stable silver nanoparticles encapsulated in solid spheres. AB - We prepared solid spheres, with diameters between 100 and 400 nm, encapsulating silver nanocrystallites (about 20 +/- 10 nm in diameter), by heating colloidal solutions of silver in methoxyethanol at 120 degrees C. Stable coatings were obtained using spin coating and rapid thermal processing on optical glass substrates. UV-Vis spectroscopy measurements demonstrated the remarkable stability against aggregation and particle growth, even after prolonged heating at 120 degrees C and exposed at direct sunlight, of the solutions, even using high concentrations of silver (1 M), and coatings of spheres encapsulating silver. PMID- 25936125 TI - Mesoporous NiO-samaria doped ceria for low-temperature solid oxide fuel cells. AB - In order to prepare anode material for low-temperature solid oxide fuel cells (SOFCs), the mesoporous NiO-SDC was synthesized using a cationic surfactant (cetyltrimethyl-ammonium bromide; CTAB) for obtaining wide triple-phase boundary (TPB). In addition, Ni-SDC anode-supported SOFC single cells with YSZ electrolyte and LSM cathode were fabricated and the performance of single cells was evaluated at 600 degrees C. The microstructure of NiO-SDC was characterized by XRD, EDX, SEM, and BET, and the results showed that the mesoporous NiO-SDC with 10 nm pores could be obtained. It was found that the surface area and the electrical performance were strongly influenced by the Ni content in Ni-SDC cermets. After calcined at 600 degrees C, the surface area of NiO-SDC was between 90-117 m2/g at 35-45 Ni wt%, which was sufficiently high for providing large TPB in SOFC anode. The optimum Ni content for cell performance was around 45 wt% and the corresponding MPD was 0.36 W/cm2. Indeed, the mesoporous NiO-SDC cermet may be of interest for use as an anode for low-temperature SOFCs. PMID- 25936126 TI - Highly efficient new hole injection materials for organic light emitting diodes base on phenothiazine derivatives. AB - New hole injection materials for OLED based on phenothiazine were synthesized, and the electro-optical properties of synthesized materials were examined by through UV-Vis. and photoluminescence spectroscopy as well as cyclic voltammetry. 1-NDD-t-BPBP and 2-NDD-t-BPBP showed Tg of 180 and 177 degrees C. These are higher than that (110 degrees C) of 2-TNATA, commercial HIL material. As for the HOMO level of the synthesized materials, 1-NDD-t-BPBP and 2-NDD-t-BPBP were 4.99 and 5.02 eV, indicating well-matched values between HOMO (4.8 eV) of ITO and HOMO (5.4 eV) of NPB, HTL material. In addition, judging from the fact that the synthesized materials both barely showed any absorption in the range of over 450 nm, the synthesized materials could be effectively used as an HIL material. The synthesized materials were used as the HIL in OLED device, yielding luminance efficiencies of 4.51 cd/A (1-NDD-t-BPBP) and 4.44 cd/A (2-NDD-t-BPBP). These results indicated that 1-NDD-t-BPBP shows more excellent luminance efficiency which is about 11% improved over 2-TNATA a commercial HIL material. PMID- 25936127 TI - Selenate adsorption on pre-coordinated Fe3+-silane complexes grafted on mesoporous silicas. AB - Fe3+ was coordinated N-[2-(aminoethyl)-3-aminopropyltriethoxysilane], AEAPTES, followed by being grafted on MCM-41, SBA-15 and Cab-O-sil M7D. The mixing ratio, n = [AEAPTES]/[Fe], in the above coordination reaction was varied from 1 to 3. These nine functionalized silicas, denoted as Fe(en)n-silica (n = 1, 2, 3 and silica = MCM-41, SBA-15 and M7D), were used for the adsorption of aqueous selenate. The saturation of adsorption isotherm occurred at Se/Fe = 2 on Fe(en)2- MCM-41 and Fe(en)2-SBA-15, while Fe(en)- and Fe(en)3-MCM-41 and Fe(en)- and Fe(en)3-SBA-15 adsorbed selenate until Se/Fe = 1. The saturation at Se/Fe = 1 was obtained for all absorbents prepared with M7D substrate, suggesting a transformation of the adsorption sites realized on Fe(en)2-MCM-41 and Fe(en)2-SBA 15. The concave curvature of the surface of mesoporous silicas is possibly critical to retain the coordination structure of adsorption sites. The largest capacity obtained among these adsorbents was 1.1 mmol/g, found on Fe(en)2-SBA-15. The structure of adsorption sites was analysed by X-ray absorption spectroscopies in order to obtain the evidences for the distortion of coordination structure induced by grafting and the bond formation between Se and Fe after adsorption. PMID- 25936128 TI - Influence of reduction rate from Bi(3+) to Bi(0) on morphological characteristics of Bi2Te3 nanotubes. AB - Bi2Te3 nanotubes were synthesized by alloying Te nanorods and Bi(0) metal reduced from Bi(3+) using the solvothermal method. It was found that, when synthesizing Te nanorods, the concentration of NaOH was a greatly influential factor, where round-like Te nanorods were synthesized at the range of pH 12~13. Meanwhile, the alloying process between Bi(0) and Te nanorods was achieved through atomic diffusion in the interfacial surface of those two metals. The morphology of Bi2Te3 crystal was verified to be governed by the reduction rate changing to Bi(0) from Bi(3+). PMID- 25936129 TI - Synthesis and characterization of an anthracene-based low band gap polymer for photovoltaic devices. AB - We have synthesized an anthracene-based conjugated polymer, poly[(9,10-bis(oct-1 ynyl)anthracene)-alt-(5,6-bis(octyloxy)-4,7-bis(thiophen-2-yl)benzo-[c][1,2,5] thiadiazole)] (PANTBT), for application in organic photovoltaic devices. It exhibited a number average molecular weight of 14,300 g/mol and was fairly soluble in chlorinated organic solvents due to flexible octynyl- and octyloxy side chains on the anthracene and benzothiadiazole moieties. PANTBT showed absorption covering 300-660 nm. Through the bond alternation between the electron sufficient anthracene (and thiophene) and electron-deficient benzothiadiazole units, a band gap of PANTBT was decreased to 1.89 eV, showing a deep HOMO level of -5.31 eV. As a result, PANTBT exhibited promising photovoltaic properties with a PCE value of 1.90% (VOC = 0.77 V, JSC = -6.50 mA/cm2, FF = 0.38) upon blending with PC71, BM under AM 1.5G. PMID- 25936130 TI - Synthesis of organic/inorganic hybrid gel with acid activated clay after gamma ray radiation. AB - A hybrid gel was prepared from acid activated clay (AA clay) and acrylic acid by gamma ray irradiation. Irradiated inorganic particles which have peroxide groups act as initiator because it generates oxide radicals by increasing temperature. Inorganic nanoparticles which are rigid part in hybrid gel also contribute to increase the mechanical property as a crosslinker. We prepared two hybrid gels to compare the effect of acid activated treatment of clay; one is synthesized with raw clay particles and another is synthesized with AA clay particles. The composition and structure of AA clay particles and raw clay particles were confirmed by X-ray diffraction (XRD), X-ray fluorescence instrument and surface area analyzer. And chemical and physical property of hybrid gel with different ratios of acrylic acid and clay particle was tested by Raman spectroscope and universal testing machine (UTM). The synthesized hydrogel with 76% gel contents can elongated approximately 1000% of its original size. PMID- 25936131 TI - Fluorine effects in new indenofluorenedione derivatives for electron transporting layer in OLED devices. AB - New three indenofluorenedione derivatives were synthesized and proposed for electron transporting layer (ETL). Three compounds are indeno[1,2-b]fluorene-6,12 dione (IF-dione), 2,8-Difluoro-indeno[1,2-b]fluorene-6,12-dione (Mono-F-lF dione), and 1,2,3,7,8,9-Hexafluoro-indeno[1,2- b]fluorene-6,12-dione (Tri-F-IF dione). UV-visible (UV-Vis) absorption of three compounds in THF solution state showed different absorption maximum values as follows: 292, 318 and 334 nm (IF dione), 289, 314 and 329 nm (Mono-F-IF-dione), 285, 319 and 334 nm (Tri-F-IF dione). Three compounds were inserted between emitting layer (EML) and cathode electrode as an ETL in OLED device: ITO/2-TNATA (60 nm)/NPB (15 nm)/Alq3 (30 nm)/synthesized compounds (30 nm)/LiF (1 nm)/Al (200 nm). I-V characteristics of three devices were investigated at 20 mA/cm2. Operating voltages of three compounds were 7.06 V (IF-dione), 6.42 V (MonoF-IF-dione), 5.36 V (TriF-IF dione), respectively. PMID- 25936132 TI - New dyes based on anthraquinone derivatives for color filter colorants. AB - Two new compounds which substituted quinoline group in 1,4-position and 1,8 position of anthraquinone were synthesized for color filter. The change in physical properties according to the substituted position of the synthesized compound was systematically identified from the perspectives of optical property and thermal property. The extinction coefficient (epsilon) of the synthesized substance has a very high value more than 4.26 in log scale. Td value is more than 300 degrees C, which shows high thermal stability. This showed quite excellent results in optical property and thermal stability. PMID- 25936133 TI - Synthesis and characterization of phosphine/borane-terminated poly(silole-co germole) for the evaluation of luminescent polymer light-emitting diode. AB - Codehydrocoupling (using Red-Al) followed by borane/phosphine-capping (with Ph2BCl and Ph2PCl) of 1,1-dihydrotetraphenylsilole (1) and 1,1 dihydrotetraphenylgermole (2) (9:1 mole ratio) gave electroluminescent poly(silole-co-germole)s containing borane/phosphine-ends (3, 4) in high yield. The borane-terminated copolymer 3 emits at 522 nm and are electroluminescent at 521 nm. The fluorescence quantum yield of 3 in toluene is (1.60+/-0.30) x 10(-2). The phosphine-terminated copolymer 4 emits at 520 nm and are electroluminescent at 520 nm. The fluorescence quantum yield of 4 in toluene is (1.60+/-0.20) x 10( 2). 3 and 4 were then mixed in 1:1 ratio. The emission color of 3/4 mixture is green and the maximum brightness of the device is 2,760 cd/m2 with a luminous efficiency of 0.67 lm/W. The borane/phosphine end groups in the 1:1 mixture of 3 and 4 exhibited no appreciable effect on the luminescent properties in spite of possible B-P dative bonding. Ge-132 helped to increase the B-P dative bonding. The electroluminescent copolymers 3 and 4 are good candidates for PLED (polymer light-emitting diode) fabrication. PMID- 25936134 TI - Effect of environment on the preparation of CdSe quantum dots capped with mercaptoacetic acid. AB - We report a preparation of CdSe quantum dots in the presence of capping molecules under ambient air and argon atmospheres. The growth of the quantum dots with applying an equimolar ratio of precursor of Cd2+ and Se2- in the presence of a high percentage of the mercaptoacetic acid as capping molecules is studied. Quantum dots are characterized via EDX, transmission electron microscopy, X-ray diffraction, thermogravimetric analysis (TGA), UV-Vis optical absorption, Raman and infrared spectroscopy. Combination of EDX and Raman spectroscopy showed a graded diffusion of sulfur on the surface of CdSe quantum dots for the sample prepared under argon atmosphere, while the sample prepared under ambient air atmosphere the sulfur isn't diffused into the CdSe core. In addition, the sample prepared under air revealed a formation of oxides on the surface of the quantum dots. On the other hand, we have studied the nature of capping and how the surface of the quantum dots core is terminated for the prepared samples. In addition, we have studied the acoustic and optical phonons of the quantum dots cores. PMID- 25936135 TI - Effect of surface hydrophobicity on activity of immobilized Taq DNA polymerase, its reusability and storage. AB - Method of oriented and activity-preserved immobilization of biologically active proteins based on concepts of active-site masking and kinetic control was previously reported. We extended our study and found that the surface hydrophobicity had a noticeable effect on the activity of active-site protected immobilized (PIM) Taq DNA polymerase on mixed self-assembled monolayer (SAM) manufactured on Au surface. Hydrophobic SAM was created by using 12 mercaptododecanoic acid and 1-heptanethiol. The resulting Taq DNA polymerase activity was measured by performing PCR amplification and compared with previously reported values acquired with hydrophilic SAM. The maximum activity of immobilized Taq DNA polymerase was achieved at 17.5% of 12-mercaptododecanoic acid and within 90 min of reaction time which are higher than those acquired with hydrophilic SAM; maximum activity at 5% of 12-mercaptododecanoic acid and at 10 min. In order to be applicable to commercial level, immobilized enzyme need to be stable, reusable and storable. PIM Taq DNA polymerase was stably attached to the surface and could be used for as many as 10 PCR runs which were comparable to solution-phase enzyme. Even after 56 days of storage at 4 degrees C, immobilized enzyme pertained 70% of the initial PIM enzyme activity. These data suggest that PIM Taq DNA polymerase can be used for various commercial applications. PMID- 25936136 TI - Methoxy poly(ethylene glycol) conjugated doxorubicin micelles for effective killing of cancer cells. AB - Methoxy poly(ethylene glycol) conjugated doxorubicin (mPEG-DOX) micelles are prepared for delivering drug effectively. The core of the unimolecular micelle is a DOX (doxorubicin) which is an anti-cancer chemotherapy drug, while the outer hydrophilic shell is composed of poly(ethylene glycol) (PEG) segments. Dynamic light scattering (DLS) analysis shows that the unimolecular micelles are uniform with a mean hydrodynamic diameter around 250 nm. The mPEG-DOX micelles can be internalized by the cancer cells and exhibit good cell uptake by the fluorescence microscopy. Obvious cytotoxicity is also observed when the concentration (count on DOX) is over 1 MUg/mL. These findings indicate that these unique unimolecular micelles may offer a very promising approach for targeted cancer therapy. PMID- 25936137 TI - Fabrication and oil adsorption of carbon nanotube/polyvinylpyrrolidone surface composite. AB - It needs to assemble the industrial CNT powders into macroscopic porous surface composite to utilize the surface properties of CNTs, as well as to prevent them entering into environments. We demonstrate a method to fabricate the surface composites from CNTs and polyvinylpyrrolidone (PVP) by electrospinning, where CNTs distribute firmly and mainly on the surface PVP nanofibers. The CNTs/PVP surface composites have high pore volume of 10 cc/g and remarkable CNTs load of 98%. Thus the surface composites show high oil adsorption capacity of 0.9~1.1 g/cm3. It can absorb more oil than commercial sponges due to the surface composite swells after absorbing oil. It shows attractive potential application of the CNT/PVP surface composite in oil spill cleanup. PMID- 25936138 TI - [Sex differences in pharmacokinetics and pharmacodynamics]. PMID- 25936139 TI - [The history and perspective of gender-specific medicine in Japan]. AB - The history of gender-specific medicine started when Barbara Seaman, a female American journalist, started the women's health movement in 1957. Since then, the National Institutes of Health(NIH) and the Food and Drug Administration(FDA) have promoted gender-specific medicine in USA, including the Women's Health Initiative(WHI) by NIH in 1991 and the Office on Women's Health(OWH) by FDA in 1995. In Japan, being stimulated by the movements in USA, Dr. Chuwa Tei founded Japan' s first women' s clinic in Kagoshima University in 2001, and Dr. Keiko Amano founded the Association for Gender-Specific Medicine in 2004. These activities developed into the establishment of the Japanese Association for Gender-Specific Medicine in 2008, for which Dr.Tei served as the first president for 4 years, followed by Hiroaki Shimokawa since 2012. Furthermore, the importance of gender-specific medicine has been emerging worldwide, resulting in the establishment of International Society of Gender Medicine in 2012. Indeed, the history of gender-specific medicine is 60 years worldwide and is only 15 years in Japan. However, gender-specific medicine will become more and more important not only in medicine but also in the whole society. PMID- 25936140 TI - [Gender difference in the mortality and prevalence in Japan]. AB - For any given disease, incidence is the number of new cases each year, prevalence is the number of people with the disease at a point in time, and mortality is the number who die from that cause each year. The value of mortality rate male (per 100,000 male) was 1068.9 as of 2012 and that of female was 929.7. The top 5 cause specific mortality were malignant neoplasms, cardiac disease, pneumonia, cerebrovascular disease and accidents for male, and were malignant neoplasms, cardiac disease, cerebrovascular disease, pneumonia and senile decay for female. Although there are considerable uncertainty and limitations in data of incidence and prevalence survey, medical outpatient treatment recipients ratio (per 100,000 population) were 358.8 for male and 396.3 for female. PMID- 25936141 TI - [Women's clinic in Japan at present and in the future]. AB - Innovative women's clinic was first established in Kagoshima University Hospital in 2001, dedicated to offer gender-based evaluation and treatment of numerous medical problems of concern to women by female physicians. The clinic was welcomed enthusiastically by Japanese women, followed by new openings of clinics specifically for women with similar concepts throughout the country. However, two major problems have emerged later. One is the shortage of female doctors, and another is financial difficulty. We need to formulate and implement new strategies for further development of women's clinics in Japan. Among of all, establishment of educational and training programs would be the most important task. PMID- 25936143 TI - [Sex hormones and metabolic function]. AB - The biological actions of testosterone(T) and estrogens(E) are mediated via androgen receptor(AR) and estrogen receptor(ER), respectively. Testosterone also exerts its effect by conversion to estrogens by aromatase in peripheral tissues. Recently, from the detailed analysis of the phenotype of human or mouse mutant of AR, ER and aromatase, T-AR, E-ERs are protective against metabolic syndrome(MetS) and diabetes mellitus(DM). Both sex steroids are suggested to potentiate leptin signaling as a central mechanism and to suppress lipid synthesis and promote lipolysis as peripheral mechanism. Thus, the insufficiency of the amount or action of these sex steroids causes obesity and insulin resistance. Age associated decrease of sex steroids is an important background for the onset of visceral obesity and life-related diseases. PMID- 25936142 TI - [Sex hormones and physiological function]. AB - Sex hormones as estrogen, testosterone, dehydroepiandrosterone decline with age. Especially in women, bioavailable estrogen level rapidly decreases around the menopause. Estrogen acts against arteriosclerosis to vascular endothelial cells and vascular smooth muscle cells. The lack of estrogen with menopause accelerates arteriosclerosis that is the leading cause of cardiovascular diseases. The adipose distribution shifts from gluteo-femoral to abdominal depots after menopause, and it is well known that visceral obesity induce metabolic syndrome, which is also high risk state for cardiovascular disease. Estrogen replacement therapy may reduce the cardiovascular risk, and we should pay attention to the starting age of women who undergo hormone therapy. PMID- 25936144 TI - [Changes in neural excitability across the menstrual cycle via GABAergic signaling regulation by ovarian hormones]. AB - Ovarian hormones change neural excitability across the menstrual cycle via regulation of gamma-aminobutyric acid(GABA) signaling. Estrogen's trophic properties can be observed in hippocampal dendritic spine formation across a single estrus cycle in adult female experimental animals. Progesterone also changes the neuronal structure at the GABA receptor level. Estrogen and progesterone have opposite effects on neural excitability. Estrogen augments N methyl-D-aspartate-mediated glutamate receptor activity via reduction of GABA production, while progesterone enhances GABA neurotransmission and inhibits neural excitement. The kinetics of estrogen and progesterone continue changing throughout the menstrual cycle, and never stay in a fixed state. The fluctuation in ovarian hormones across the menstrual cycle alters neural activity, and therefore might affect women's behavior and mental phenomena complexly. PMID- 25936145 TI - [Female sex as a risk factor for adverse drug reactions]. AB - Females have nearly a two-fold greater risk of developing adverse drug reactions(ADRs) than males and they are also more likely to be hospitalized due to ADR. For all drug classes, significant differences exist between the sexes, including class-specific risks and the incidence and/or severity of ADR. We herein present our results regarding the surveillance of ADR in the general population and a questionnaire-based study carried out by the Japan Pharmaceutical Association Drug Event Monitoring Project in Kumamoto Prefecture. Our findings indicate that females are prone to ADR and that high-risk agents for this population should be identified and these subjects closely monitored based on the patient characteristics. PMID- 25936146 TI - [Laboratory medicine and sex differences]. AB - In the field of laboratory medicine, sex differences are found in many clinical tests. Human sex-determination system is at least doubly driven: by sex chromosomes and by sex-hormones. Karyogram and sex-hormones are typical clinical tests that show sexual dimorphism. Cases of Androgen-Insensitive Syndromes imply sex hormones exert great influences on sex differences found in clinical tests. While childhood, sex steroids secretions from sex-specific organs are inhibited in both sexes. After puberty onset, differences in sex steroids enlarge. In case of females, estrogen secretion decreases in postmenopausal periods. In some of clinical tests, sex differences enlarge after puberty onset, and decrease in postmenopausal periods. Some clinical tests in the field of bone metabolism and lipid metabolism show this kind of sex difference, which seem to be influenced by estrogen. PMID- 25936147 TI - [Gender differences on physiological function test]. AB - Recently, clinical findings showed sex differences in the manifestation of the cardiovascular diseases. There are gender differences in cardiac electrophysiologic properties and the incidence of various types of arrhythmias. Long QT syndrome is more common in women than in men, whereas the incidence of Brugada syndrome and J-wave syndrome are male predominant. The gender differences in QT interval are not observed before puberty but become obvious after puberty. ST-levels markedly increase after puberty in men but not in women, which suggested that the sex hormones have an important role for the ECG parameters and arrhythmias. In addition, gender differences were reported in age-related changes in echocardiographic parameters such as left ventricular diastolic function. PMID- 25936148 TI - [Gender-difference in diabetes mellitus]. AB - Gender-difference is thought to be an important factor in the pathogenesis of glucose metabolism. Imbalances in sex hormones, such as increasing levels of progesterone or testosterone, are associated with systemic insulin resistance. After menopause, women are at an increased risk to develop visceral obesity due to the loss of endogenous ovarian hormone production. On the other hand, insulin resistance caused excess secretion of androgen, leading to menstrual disorder in obese young female. For the better management of glucose intolerance in pregnancy, the diagnostic criteria for gestational diabetes was revised in Japan. Although glucose intolerance in pregnancy is usually recovered after delivery, the subjects who diagnosed gestational diabetes need to be followed for an early detection of type 2 diabetes development. In addition, gender-differences in living practice and attitude are related to their lifestyle, including diet and exercise, therefore, gender-specific medicine increasingly plays key roles in the treatment of diabetes. PMID- 25936150 TI - [Gender difference in cerebrovascular disease]. AB - We discuss about the gender difference of cerebrovascular disease according to the data of Japan Standard Stroke Registry Study. The male proportion was dominant in cerebrovascular disease except for subarachnoid hemorrhage(SAH). According to the data of Ministry of Health, Labour and Welfare, age-adjusted death rate in cerebral infarction and intracerebral hemorrhage were higher in male than in female, however, in SAH the rate was no different between male and female. The incidence of SAH is higher in women than in men, but this gender difference emerges not earlier than age 59. Most cases of SAH were occurring in the ages ranging from 50's in male and 70's in female. The total male-to-female ratio was approximately 1:2. The female proportion was dominant in older patients. PMID- 25936149 TI - [Hypertension]. AB - Hypertension is the largest risk factor for cardiovascular disease (CVD), and the most common life-style related disease in Japan. Hypertension is, overall, a male dominant disease, however its impact on CVD in female grows markedly after menopause. The alteration in estrogen/androgen balance causes endothelial dysfunction, obesity, sympathetic activation, renin-angiotensin-aldosterone system activation, salt sensitivity and oxidative stress. These mechanisms enhance the elevation of systemic blood pressure and get caught in a vicious circle in female hypertension. PMID- 25936151 TI - [Ischemic heart disease in women]. AB - Although significant advances in our knowledge about interventions to prevent and treat ischemic heart disease (IHD) have occurred, there are many differences between women and men in the symptom and pathophysiology of IHD. As IHD is one of the most prominent disease areas that gender difference exist; chest pain is not typical, sometimes angiography shows normal coronary, and poor prognosis because of delayed diagnosis in association with many risk factors in women. Smoking is the # 1 risk factor for the onset of acute myocardial infarction in women, whereas hypertension is the #1 risk in men. Overwhelming evidence suggests that IHD can be prevented in both women and men, however, much attention should be paid for female natients with IHD. PMID- 25936152 TI - [Differences between men and women with chronic kidney disease]. AB - It is well known that there are differences in prevalence and progression of kidney disease between men and women. Several experimental models of chronic kidney disease (CKD) have revealed the different effects of gender on the course and responses to salt and vascular modulating substances. The prominent differences between men and women are attributable to sex hormones. Estrogen has profound effects on the renin-angiotensin system, producing alteration of renal function and structures. In this article, first, the differences in renal structure and function are introduced and then the effects of estrogen on renal hemodynamics and progression of renal diseases will be discussed. PMID- 25936153 TI - [Involvement of eating disorders in metabolic syndrome]. AB - This article gives an outline about involvement of eating disorders in metabolic syndrome. Anorexia nervosa and bulimia nervosa become common diseases in woman in Japan. Binge-eating disorder and night eating syndrome are observed in men as well as women. Binge eating is characteristic of bulimia nervosa, binge-eating disorder and night eating syndrome. It should be noted that high energy availability observed in these diseases results in obesity and exacerbate metabolic syndrome. Cognitive-behavioral therapy and medication with selective serotonin reuptake inhibitors(SSRIs) can make patients to control symptoms and improve their QOL. Osteoporosis is one of chief complications and sequelae of anorexia nervosa. Low-birth weight babies born from emaciated patients with eating disorders are subject to metabolic syndrome in the future. PMID- 25936154 TI - [Osteoporosis: a gender specific disease]. AB - Osteoporosis is more commonly found in women, thus making women more susceptible to fracture than men. The growth period is crucial to skeletal development, resulting in larger and stronger bones in males than in females. Estrogen deficiency after menopause is strongly associated with rapid resorption and loss of bone density, which contrasts with the gradual decline in sex steroids and bone mineral density seen in aging men. Although estrogen deficiency is more pronounced in women, it also plays a major role in the pathogenesis of osteoporosis in men. PMID- 25936155 TI - [Rheumatic diseases and sex differences]. AB - Recently a concept of "sex differences" in medicine has been spreading. It is well known that autoimmune diseases, especially rheumatoid arthritis or systemic lupus erythematosus mostly affect women, and it is clear that there is a strong sex differences in many rheumatic diseases. Sex difference influences to progression or prognosis of the disease. Although the mechanisms of sex difference are not clear, the influence of sex hormones or sex chromosomes which gives immune system is partially elucidated. In addition, sex hormones may become the future new treatment target, and progress in the study regarding this event is expected in the future. PMID- 25936156 TI - [Dementia]. AB - A female tends to suffer from dementia and dementia is thought as a disease with sex difference clearly. A female has the longer life, so it has been thought that a female prevalence rate is higher than a man seemingly. However, even if sex difference was considered, it was demonstrated clearly in recent years that a female suffer from dementia with high frequencies. Now, it isn't clear yet why such sex difference exists. The strongest hypothesis may be influence by sex hormones, and role of androgen as well as estrogen is pointed out. Now, 15% of more than 65 years old suffer from dementia. Dementia is thought as a common disease". More than 65-year-old elderly people don' t want to suffer from dementia. Although many people have such great interest of dementia, they do not find the early stage symptom of dementia. Forgetfulness is often overlooked and early detection isn't done. There are many diseases which lead to dementia, but Alzheimer-type dementia accounts for the most part of dementia. Alzheimer-type dementia can be treated by medicines, therefore early detection and an early stage check are necessary. I explain how do general physicians notice dementia in their outpatient clinic and diagnose and treat. PMID- 25936157 TI - [Headache in consideration of gender]. AB - Among headaches sufferers in Japan, especially the number of migraine sufferers in Japan is estimated about 8,400 thousands, and the ratio of men and women is said to be about 1 to 4. The pathophysiology of migraines has been commonly explained by the trigeminovascular theory, and recent studies have suggested that the cause of migraines stems from cortical hypersensitivity. As to prophylactic treatment of migraine, anti-epileptic drugs such as valproic acid for cephalic hypersensitivity symptoms may be effective for reducing intensity and frequency of attacks and first line abortive medicine are triptans, which are widely prescribed. Considering from migraine treatment methods from childhood to elder women, to decreasing hypersensitivity of the brain in each life stage will lead falling into medication over used headache and also suppressing development of dizziness, tinnitus, or cephalic ringing in future, and shows that anti epileptics are effective for treating this condition. PMID- 25936158 TI - [Sleep in women]. AB - This paper reviews the sleep habit and sleep problems in Japanese women. Some nationwide surveys in Japan showed that average sleep duration of Japanese women has been decreasing in these years. Insomnia related with menopause, restless legs syndrome and sleep related breathing disorder are recognized in middle-aged women. Recent studies have provided evidence that these sleep disorders increase the occurrence of cardiovascular events or other comorbid physical disorders. It is important to promote health education on sleep hygiene and provide early interventions for insomnia. PMID- 25936159 TI - [Gender difference in clinical practice for cancer patients]. AB - Solid tumors are generally more detected in male than female patients, except for sexual organs. However, females are dominant in biliary tract cancer, especially gallbladder cancer. Gender difference is not recognized in hematological malignancies. Selection of therapeutic agents is not influenced by gender, but nausea and vomiting as side effects of anti-cancer agents are more common in young females. Therefore, sufficient anti-emetic agents should be used especially at the first cycle of chemotherapy with highly emetic drugs such as cisplatin in order to prevent anticipatory nausea and vomiting. Furthermore, neutropenia due to the combination regimen of platinum plus gemcitabine or the monotherapy of gemcitabine or amrubicin is reported to be more frequent in females than males. PMID- 25936160 TI - [Gender differences in patients with chronic heart failure in Japan: insights from the CHART-2 study]. AB - BACKGROUND: The gender differences in patients with chronic heart failure(CHF) remain to be elucidated in Japan. We examined gender differences in patients registered in the CHART-2 study. METHODS AND RESULTS: Compared with male patients, females were older and had lower prevalence of ischemic heart disease. Women had higher prevalence of preserved ejection fraction but had higher NYHA class and BNP levels. Women were treated with 2-blockers and statins less frequently, but treated with diuretics were more frequently. Although crude mortality rate was similar between the genders, women more frequently died due to cardiovascular causes than males. CONCLUSIONS: Female patients with CHF had severer clinical backgrounds and had higher cardiovascular mortality than males in the daily practice of Japan. PMID- 25936161 TI - [Outline of the JCS2010 guideline for gender-specific cardiovascular disease]. AB - The present review introduces the outline of the JCS2010 guideline for gender specific cardiovascular disease including the assessments according to the class of recommendation and the level of evidence based on totally 581 references. This guideline is started from the basic science of the gender-difference, and refers to gender-specific cardiovascular diseases: ischemic heart disease, heart failure, cardiomyopathy, valvular diseases, specific arrhythmias, aortic aneurism, peripheral vascular disease, venous thrombotic disease, and hypertensive heart disease. Much are focused on the recent issues regarding ischemic heart disease and heart failure reflecting the increasing prevalence accompanied with a society composed largely of elderly people in Japan. PMID- 25936162 TI - [Transition of differences between men and women about awareness of stress during the recent two decades: data from comparison of questionnaires at two different eras]. AB - Stress is one of the important factors on lifestyle diseases such as type 2 diabetes. Recent great changes of female roles in social activities and the introduction of Japanese public nursing care insurance in 2000 might lead to some changes in the household roles, which would have a big impact on the differences in stress between men and women. I herein investigated the two questionnaires about the awareness of stress in daily lives in 273 persons conducted in 1993 before the beginning of public nursing care insurance and in 590 persons in 2010 after the program was implemented. The understanding of the results and re thinking of so-called 'traditional sexual roles' will provide helpful clues to the precise solution for coping with stress. PMID- 25936163 TI - [Sexual dimorphism in developmental genetics]. AB - We review the current knowledge about the molecular mechanism of sex determination and differentiation. The first sex-specific differentiation starts at the gonad, which in turns influences the development of sexual duct systems and the external genitalia. The secondary sexual characteristics in puberty complete sexual dimorphism. Recent studies have provided compelling evidence for the presence of an alternative "backdoor pathway" to produce dihydrotestosterone(DHT: the most potent androgen) directly without testosterone intermediary. This pathway primarily is operated in the normal fetal testis to produce a sufficient amount of DHT for male sex development. As for ovary development, which had formerly been regarded as a static "default" pathway, recent studies have unequivocally demonstrated that RSPO1, WNT4, and FOXL2 have important roles. PMID- 25936164 TI - [Gateway Reflex, a regulator of the inflammation feedback loop by regional neural activation]. AB - Inflammation is observed in many diseases and disorders. We discovered a key machinery of inflammation, the inflammation amplifier, which is induced by the simultaneous activation of NFkappaB and STAT3 followed by the hyper-activation of NFkappaB in non-immune cells, including endothelial cells and fibroblasts. Since that discovery, we found the Gateway Reflex, which describes regional neural activations that enhance the inflammation amplifier to create a gateway for immune cells to bypass the blood-brain barrier. In addition, we have identified over 1,000 positive regulators and over 500 targets of the inflammation amplifier, which include a significant numbers of human disease-associated genes. In parallel, we performed a comprehensive analysis of human disease samples and found that the inflammation amplifier was activated during the development of chronic inflammation. Thus, we concluded that the inflammation amplifier is associated with various human diseases and disorders, including autoimmune diseases, metabolic syndromes, neurodegenerative diseases, and other inflammatory diseases. We are now attempting drug discovery for inflammatory diseases and disorders based on the inflammation amplifier and Gateway Reflex. In this review, we discuss the Gateway Reflex as an example for the neuro-immune interaction in vivo. PMID- 25936165 TI - [Treatment of hypertension in the elderly]. AB - Hypertension guideline has been revised as JSH2014. Because the elderly show marked individual differences in the physiological function, the therapeutic strategies should be individually selected, considering their QOL. As to general guidelines, drug therapy should be indicated for patients with a blood pressure of <= 140/90mmHg on principle. However, treatment indication must be individually assessed in persons, aged over 75 years, with a systolic blood pressure of 140 149 mmHg or frail elderly. Target blood pressure in persons aged 65-74 years should be < 140/90mmHg and that in those aged over 75 years should be < 150/90 mmHg. If treatment is well tolerated, more aggressive blood pressure control < 140/90mmHg may further improve the outcome. In patients with coronary artery disease, the risk of cardiac events may increase if diastolic blood pressure is < 70mmHg. Therefore, blood pressure control should be performed while monitoring the ischemic findings. PMID- 25936166 TI - [Contribution to the black fly fauna of the tribes Nevermanniini and Wilhelmiini (Diptera: Simuliidae) of the Sakha Republik (Yakutia)]. AB - In this paper, the data on fauna of Nevermanniini and Wilhelmiini tribes (Diptera: Simuliidae) were analyzed. All the accessible literature sources, institute collections and new materials recently collected in Yakutia were examined. Regional fauna was supplemented by two species: Schoenbaueria dendrofila (Patrusheva, 1962) and S. furculata Shewell, 1952, the latter being new for the Russian fauna also. The distribution of five more species from Simuliidae family was clarified. Processing of the collected material proved that 10 species previously registered in Yakutia can still be found in the region. PMID- 25936167 TI - [The study of daughter rediae Echinostoma caproni (Trematoda) in vitro cultivation]. AB - Methods of in vitro cultivation were used to examine the feeding and reproductive behaviors of daughter rediae of Echinostoma caproni. It was noted that under conditions of in vitro cultivation, rediae fed on tissues of the mollusc Biomphalaria glabrata, on rediae and cercariae of E. daikenaensis and E. congoensis, and on sporocysts and cercariae of Schistosoma mansoni. No cases of cannibalism of daughter rediae E. caproni by their offspring rediae were observed, although they could feed on their own cercariae. When kept in mediae containing (B. glabrata embryonic) Bge cells, rediae E. caproni gradually turned to feeding on these cells and stayed away other objects. Under conditions of in vitro cultivation, daughter rediae E. caproni were capable of forming redial and cercarial embryos. However, no cases of return from producing of cercariae to producing of rediae were observed. These in vitro data confirm the results of previous studies of this species's parthenithae performed in vivo (ATaeB and dp., 2007). PMID- 25936168 TI - Mites of the genus Schizocarpus Trouessart, 1896 (Acariformes: Chirodiscidae) from the North American beavers (Castor canadensis) in Russia. AB - Four native species of parasitic mites belonging to the genus Schizocarpus Trouessart, 1896 (Acariformes: Chirodiscidae) are recorded on the North American beaver Castor canadensis Kuhl, 1820 (Rodentia: Castoridae) from Russia. Totally ten beavers from all three main geographically isolated populations of in Russia (Leningrad Province, Voronezh Biosphere Reserve (beaver farm) and Khabarovsk Territory) were examined. Additionally, in captivity (Voronezh beaver farm) eight species were recorded switched from the Eurasian beaver Castor fiber Linnaeus, 1758 on C. canadensis. PMID- 25936169 TI - [On the validity of the genus Otidilepis Yamaguti, 1959 (Cestoda: Hymenolepididae) and the classification of the rostellar hooks of its type species, O. tetraciS (Cholodkowsky, 1906)]. AB - The type material on Otidilepis tetracis (Cholodkowsky, 1906), the type species of the genus Otidilepis Yamaguti, 1959 is reinvestigated. The validity of the genus Otidilepis is confirmed. It is clearly distinguished from the genus Hispaniolepis Lopez Neyra, 1942 by the form and dimensions of the rostellar hooks as well as by the proportions of the attachment organs of the scolex (diameter of suckers: width of the rostellum). "Orthodiorchoid" type based on the hooks of D. acuminata (Clerc, 1902), type species of the genus Diorchis Clerc, 1903, is introduced. The former "diorchoid" type, based on the hooks of D. americana Ransom, 1909, is renamed in "americanoid". Rostellar hooks of O. tetracis belong to the americanoid type. PMID- 25936171 TI - [The analysis of climatic and biological parameters for the pest spread risk modelling of the wood nematode species Bursaphelenchus spp. and Devibursaphelenchus teratospicularis (Rhabditida: Aphelenchoidea)]. AB - Based on the forest woody species wilt areassurvey in Nizhniy Novgorod region in August 2014, the possible factors of the pest spread risk modelling were analysed on six species of the genus Bursaphelenchus and Devibursaphelenchus teratospicularis using six parameters: plant host species, beetle vector species, average temperatures in July and January, annual precipitation. It was concluded that these parameters in the evaluated wilt spots correspond to climatic and biological data of the already published woody plants wilt records in Europe and Asia caused by the same nematode pest species. It was speculated that the annual precipitation of 600 mm and average July temperature of 25 degrees C or higher, are the critical combination that may be used to develop the predicative risk modelling in the forests' and parks' wilt monitoring. PMID- 25936170 TI - [Fine structure of glands forming porous areas (area porosa) in the European forest tick Ixodes rucinus (L.) (Ixodidae, Ixodinae)]. AB - The use of scanning and electron microscopy methods has shown that porous areas (area porosa) on the gnathosoma of Ixodes ricinus are formed of cuticular orifices of bicellular glands. Each gland is formed of a duct cell and a glandular cell, characterized by high degree of secretory activity. No difference in the gland structure between females and males were revealed. Questions associated with a probable function of these glands are discussed. PMID- 25936172 TI - [Homoxenous trypanosomatids from true bugs Pyrrhocoris apterus (L.) in the north of the Pskov region]. AB - In the north of the Pskov region (58 degrees 35' N, 28 degrees 55' E) the appearance of a single colony of true bugs Pyrrhocoris apterus has been recorded. Dissection of 95 individuals from this colony revealed 100% prevalence of infection with homoxenous trypanosomatids. In 3% of the cases intestinal infection was accompanied by hyperinvasion into the salivary glands and hemolyph of the hosts. Analysis of trypanosomatid morphotypes demonstrated mixed infections in all studied P. apterus individuals. At least 4 forms of promastigotes along with epimastigotes, choanomastigotes and amastigotes were found. The distribution of the trypanosomatid morphotypes over all intestinal parts as well as salivary glands and hemolymph was investigated. Three isolates of the flagellates were deposited into the living cultures collection of the laboratory of Protozoology of the Zoological institute of the Russian Academy of Sciences. PMID- 25936173 TI - [At the background of ecological parasitology]. AB - The data on scientific and teaching activities of A. A. Filipchenko, doctor of medicine and scientist-parasitologist, one of the founders of ecological parasitology in Russia is presented in this article. His fate and participation in the formation of this biological discipline were concealed for a long time. One of the reasons for this situation is the destruction of the scientist in 1938 during the course of mass repressions performed by Soviet State against its own citizens. PMID- 25936174 TI - [Sergei Alexeevich Beer (1941-2014)]. PMID- 25936175 TI - [Preconditioning by physical factors: role of active forms of oxygen]. AB - In the review mechanisms of protective action of a hyperthermia, light and low intensity ultrasonic radiation are considered. These physical factors don't cause oxygen starvation, however promote the increase of organ's tolerance to an ischemia/hypoxia. On materials of original articles the analysis of preconditioning mechanisms cause by high temperatures, low-intensive ultrasonic and laser irradiation was carried out at ischemia. By comparison of processes in tissues at influence by physical factors the general triggers--active forms of oxygen (O2*, H2O2, HO*) were revealed. PMID- 25936177 TI - [Physiological problems of alveolar circulation in the lungs]. AB - Since the volume of the blood passing the lungs is great in the norm and especially during stressed muscle activity the question arises about the rate of the blood oxygenation. In the norm, when about 6 1 of the blood passes the lungs per minute, each 500 ml of the blood, which comprises the blood capacity of the lungs, is oxygenated during approximately 5 seconds. During muscle work, when the minute volume of the blood increases to 18-20 1, each 500 ml of the blood are oxygenated during 1-1.5 seconds. It is necessary to reveal the mechanisms of accelerating the blood oxygenation in the alveoli. PMID- 25936176 TI - [Effects of stimulation and blockade of D2-dopaminergic receptors on behavior In gonadectomized male rats]. AB - The present study aims to perform the comparative assessment of stimulation and blockade for D2-dopaminergic receptors in depression-like behavior in male rats with deficiency of androgen hormones. Two weeks after surgery, GDX rats began 14 days of treatment with vehicle, a low dose of testosterone propionate (0.5 mg/kg, s.c.), quinpirole (0.1 mg/kg, i.p.), sulpiride (10.0 mg/kg, i.p.), quinpirole plus testosterone propionate or sulpiride plus testosterone propionate. The animals were then tested in forced swimming test (FST) and the open field test (OFT). Quinpirole administered alone or in a combination with a low dose of testosterone propionate resulted in antidepressant-like effect in GDX rats in the FST. Repeated treatment of quinpirole and testosterone propionate profoundly increased antidepressant-like effect of the single substances they exert per se. Application of neither quinpirole nor quinpirole plus testosterone propionate led to any changes of behavioral reactions in GDX rats in the OFT, except increased grooming behavior. On the contrary, sulpiride treatment failed to alter depression-like behavior in GDX rats in the FST. In addition, sulpiride blocked the antidepressant-like effect of testosterone propionate in GDX rats and its combination with a low dose of testosterone propionate induced prodepressant-like effect in GDX rats. Co-administration of sulpiride with testosterone propionate or its single application increased frequency of rearing and grooming in GDX rats in the OFT. In summary, the results of the present study suggest that stimulation of D2-dopaminergic receptors results in antidepressant-like effect at androgen deficiency in male rats, while blockade of D2-dopaminergic receptors resulted in prodepressant-like effect. PMID- 25936178 TI - [On the role of opioid system of myocardium in the implementation of the cardioprotective effect of postconditioning]. AB - Investigated the involvement of the endogenous opioid agonists attack in the implementation of the cardioprotective effect of postconditioning, playing with the model of isolated perfused on Langendorf rat heart. It is established that this phenomenon occurs when using three sessions reperfusion (30 s) and ischemia (30 s) played at the end of the period 45-min global ischemia. Using the selective blocker of different subtypes of opioid receptors, which was added in perfusion solution in early reperfusion period, found that the stability of the heart to action ischemia-reperfusion in ischemic postconditioning is implemented through the activation of the Delta-1 opioid receptor. Suggests that the mechanism cardioproteguoe phenomenon of postconditioning significant role belongs synthesized in the myocardium of endogenous opioids. PMID- 25936179 TI - [Hypothermia induced alteration of refractoriness in the ventricular myocardium of ground souirrel Citellus undulatus]. AB - Bioelectrical activity and refractoriness in ventricular myocardium of the hibernator--ground squirrel Citellus undulatus were investigated during hypothermia. Experiments were performed with use of isolated, perfused preparations of papillary muscle from right ventricular. Preparations were obtained from hibernating (HS), summer active (SAS) squirrels and from rats. Bioelectrical activity was registered using the standard microelectrode technique at 37-17 degrees C. Action potentials duration (APD), refractoriness duration (RD) and the velocity of the action potential wave front (dV/dt) were estimated. Hypothermia induced APD and RD prolongation were demonstrated in all groups of experimental animals. However, normalized RD was significantly longer in the HS group during hypothermia than in SAS and rats. Ratio of RD to APD in HS group exceeds unity at 17 degrees C, which allows to suggest so called "postrepolarization refractoriness" during hypothermia. Also, HS reveal more prominent preservation of dV/dt during hypothermia than SAS and rat. Significant prolongation of RD and maintenance of normal excitation conduction during hypothermia probably plays essential role in hibernators resistivity to cold induced arrhythmias. PMID- 25936180 TI - [The hypothalamic-pituitary-adrenal axis activity in prenatal stressed female rats in the model of posttraumatic stress disorder]. AB - The effects of immobilization stress from 15th to 19th days of gestation on hypothalamic-pituitary-adrenal (HPA) axis activity in the model of posttraumatic stress disorder (stress-restress paradigm) in adult female offspring were studied. The results showed that prenatal stressed female rats demonstrated enhanced stress reactivity and hypersensitive glucocorticoid feedback of HPA in response to the restress procedure. Moreover, decrease in basal level of corticosterone was detected only in prenatal stressed female rats. Immunocytochemical staining revealed that the effects of stress-restress procedure in control female rats were accompanied by the rise in corticotropin releasing hormone immunoreactivity in the hypothalamic paraventricular nucleus, although over-expression of hypothalamic vasopressin was founded only in prenatal stressed rats. These data suggest that hypothalamic vasopressin was involved predominantly in posttraumatic stress disorder-like state in prenatal stressed female rats. PMID- 25936181 TI - [Metyrapone effect on gastroprotective action of corticotropin-releasing factor administered centrally against indomethacin-induced gastric injury]. AB - In the present study, we investigated whether corticotropin-releasing factor (CRF) injected into the brain induces protection against indomethacin-caused gastric injury and the role of glucocorticoids in the protection. Gastric injury was caused by indomethacin (35 mg/kg, s.c.) in preliminary (24 h) fasted rats. CRF (10 microgram/rat, i.c.v.) was injected 30 min before administration of indomethacin. The participation of glucocorticoids was studied by metyrapone pretreatment (30 mg/kg, i.p., 30 min before CRF). Pretreatment by metyrapone, the inhibitor of glucocorticoid synthesis was the most suitable approach because of a short-lasting inhibiting effect of the drug. Metyrapone pretreatment allowed us to prevent the acute corticosterone response to CRF and avoid the lasting effects of glucocorticoid deficiency. Intracerebroventricular injection of CRF caused fast increase in plasma corticosterone levels and significantly suppressed the occurrence of gastric erosion induced by indomethacin. Metyrapone administration prevented CRF-induced corticosterone rise and significantly attenuated the protective effect of CRF on the gastric mucosa against indomethacin-produced injury. The results suggest that CRF injected into the brain may induce protection against indomethacin-caused gastric injury through the participation of glucocorticoids. PMID- 25936182 TI - [Role p53 and MAPK signaling integration in the regulation of PC12 cell neural differentiation]. AB - p53 is a transcription factor and then induced by cellular stress regulates ageing, cell cycle arrest and apoptosis. Published data also demonstrated that p53 participates in the regulation of neuronal differentiation. However, the data concerning the mechanisms of neuronal differentiation by p53 is very limited. In the present work we have studied a role and mechanisms of p53 activated by Nutlin 3 in the differentiation of PC12 cells. In our experiments Nutlin-3 stimulated the cell differentiation by significantly increasing of the neuritis upgrowth and upregulation of tyrosine hydroxylase (TH) expression, the catecholamine main rate limited ferment. We have also analyzed MAPK signaling cascade that tightly participate in the neuronal differentiation. Obtained data demonstrated that activation of p53 by Nutlin-3 injections increased the activity of cRaf and ERK1/2, as well as transcription factor CREB, which is one of the targets for ERK pathway and regulates transcription of TH. Thus, we demonstrated that p53 activation lead to increased differentiation of PC12 cells and this effect is mediated by cRaf/ERK/CREB pathway. PMID- 25936183 TI - [The influence of conscious and unconcious perception of emotional acoustic stimuli on time characteristics of respiration]. AB - A set of physiological studies proves that conscious perception of affective stimuli influence on respiratory activity. Less is known about the effect of unconscious perception of emotional information on human breathing. The aim of current research is to compare time characteristics of respiration during unconscious and conscious perception of emotional stimuli. As emotionally provocative stimuli we used natural vocalizations of 3-month-old infants in different emotional state. Both ways of acoustic presentation--first-order unconscious and second-order conscious stimuli--were applied to the one subject within one experiment with a brief inter-trial interval. A comparative data analysis revealed significant changes in time characteristics of respiration in response to acoustic emotional stimuli perceived either consciously or unconsciously. The differences in respiratory dynamics during two conditions of emotional stimuli perception are discussed. PMID- 25936184 TI - [Current reconstructive options of bone defect management of the femur in revision hip arthroplasty]. PMID- 25936185 TI - [Application of modular cementless femoral stems in complex revision hip arthroplasty]. AB - OBJECTIVE: To investigate and clarify the key surgical techniques and evaluate clinical effectiveness of modular cementless femoral stems(LINK MP modular stem) in complex revision hip arthroplasty. METHODS: From January 2002 to December 2013, 470 patients in Chinese PLA General Hospital received revision hip arthroplasties using MP stems. Among them, 246 patients were followed for an average of 5.7 years (ranged, 0.5 to 11 years). There were 148 males and 98 females, with an average age of 62.5 years old (ranged from 26 to 83 years old). The most common reason for revision was aseptic loosening of femoral stems (107 cases, 43.5%), followed by prosthetic joint infection (104 cases, 42.3%). Other reasons included unexplained hip or thigh pain, periprosthetic femoral fracture, prosthesis wear and dislocation. According to Paprosky classification of femoral deficiency, there were 171 cases of type IIIA (69.5%), 14 cases of type I, 39 cases of type II, and 22 cases of type IIIB. The average preoperative Harris hip score (HHS) was 37.4 +/- 7.5. In addition, radiographic presentation, degree of patients' subjective satisfaction, and clinical effectiveness were assessed as well. RESULTS: The average Harris score was im- proved to 87.8 +/- 4.2 after operation,with significant statistical difference when compared to preoperative score (t = 92.13,P = 0.00). Analysis of patients' subjective satisfaction for leg length discrepancy, stability and overall degree of satisfaction showed that the number of patients with great satisfaction were 27, 60, 61 respectively. The most common complication was the periprosthetic fracture (intraoperatively 21 cases and postoperatively 8 cases). Other complications included infection (7 cases), dislocation (5 cases), numbness possibly caused by incomplete sciatic nerve injury (6 cases) and thigh swelling (3 cases). The X-ray taken at the final follow-up revealed that prosthesis subsidence occurred in 4 cases, 2 of which needed a second revision. CONCLUSION: The application of modular cementless femoral stems (LINK MP modular stem) in complex revision hip arthroplasty (especially in cases with the serious defect of proximal femoral bone) shows good results at both the short-term and long-term follow-up, especially in the revision for prosthetic infection with the high success rate. In order to avoid complications and improve clinical outcomes,the surgeons should carefully select proper surgery candidates,perform the procedure with care, and master the key surgical techniques. PMID- 25936186 TI - [Analysis on morphology and stability of femoral hip prosthesis based on the revision operation]. AB - OBJECTIVE: According to the information obtained from the revision of total hip arthroplasty, the situations of the artificial femoral stem under physiological stress were analyzed preliminarily. In order to accumulate clinical experience, the discussions about how to enlongate the life of artifical joints were performed. METHODS: Fifty-three patients required revision operations were selected, including 28 males and 25 females,with an average age of 74.66 years old (61 to 84 years old). The average life of artificial joints was 18.24 years (3 to 27 years). The initial weightbearing was started 11 days (5 to 16 days) after the first operation. The main reasons for the revision were the spontaneous loosening and trauma. Based on imaging and surgical findings, as well as the histological pathology, the situations of the stems in human bodies were determined. RESULTS: Femoral prosthesis would sink under physiological stress. The design of femoral stems, motion of patients', and bone growth determined the secondary stability. Straight stems were helpful for physiological subsidence of prosthesis, achieving the stability with close bone-implant contact by bone growth,which allowed the patient to do early landing exercise. The collared prosthesis and prosthesis combined with internal fixation limited the subsidence of femoral stems. Their stability depends on the time of initial placement and the bone growth for supporting. Delaying the inital weightbearing was suggested for patients with these protheses. CONCLUSION: According to the actual situation of the patients, the appropriate chosen of femoral stems and time to perform the weightbearing can extend the life of the femoral prosthesis. PMID- 25936187 TI - [Case-control study on effects of vacuum drainage on perioperative blood loss after total hip arthroplasty for the treatment of femoral neck fractures]. AB - OBJECTIVE: To compare postoperative blood loss under different negative pressures of drainage after total hip arthroplasty for the treatment of femoral neck fractures. METHODS: From January 1st to December 30th 2013, 74 patients with femoral neck fractures treated with total hip arthroplasty were randomly divided into two groups: high negative pressure drainage group and low negative pressure drainage group. In high negative pressure drainage group, there were 34 cases including 10 males and 24 females, with a mean age of (75.94 +/- 9.02) years old, and the patients were treated with 60 kPa negative pressure of drainage. In the low negative pressure drainage group, there were 40 cases including 13 males and 27 females, with an average age of (74.93 +/- 8.90) years old, and the patients were treated with 30 kPa negative pressure of drainage. The amount of total drainage, total blood loss, and hemoglobin change were compared between these two groups. RESULTS: All the patients got primary healing without infections. In high negative pressure drainage group,the change of hemoglobin was (41.74 +/- 15.69) g/L, total blood loss was (1,217.73 +/- 459.50) ml and the drainage volume was (312.94 +/- 103.44) ml; while in low negative pressure drainage group,the results were (34.90 +/- 12.90) g/L, (904.01 +/- 381.58) ml and (129.25 +/- 44.25) ml separately. All the results in high negative pressure drainage group were higher than those in the other group. Three days after operation, the change of hemoglobin was (46.00 +/- 13.29) g/L and total blood loss was (1,304.72 +/- 421.75) ml; while in low negative pressure drainage group, the changes of hemoglobin was (43.87 +/- 11.39) g/L and total blood loss was (1,196.78 +/- 344.20) ml; there were no statistically significant differences between two groups. CONCLUSION: When placing drainage devices after total hip arthroplasty for the treatment of femoral neck fractures, the level of negative pressure should be chosen according to preoperative level of hemoglobin and HCT in patients. For old patients with femoral neck fracture, low negative pressure is more suitable. PMID- 25936188 TI - [Internal fixation with one-hole microplate for the treatment of collateral ligament injuries of the metacarpophalangeal joint of the thumb combined with fracture]. AB - OBJECTIVE: To study clinical effects of one-hole microplate internal fixation for the treatment of collateral ligament injuries of the metacarpophalangeal joint of the thumb combined with fracture. METHODS: Twenty-two patients (16 males, 6 females) with collateral ligament injuries of the metacarpophalangeal joint of the thumb combined fracture were treated with one-hole microplate internal fixation. The age of the patients ranged from 18 to 53 years old with a mean age of 28.5 years old. The duration from injury to surgery ranged from 2 hours to 2 months, and the mean time was 6 days. All the patients had collateral ligament injuries combined with fracture of the metacarpophalangeal joint of the thumb. Thirteen patients had injuries in the right hand and 9 patients had injuries in the left hand. There were 18 cases of closed wound and 4 cases of open wound. Eighteen patients had fresh injuries (< 2 weeks) and 4 had old injuries (> 2 weeks). Sixteen patients had injuries in the ulnar collateral ligament of the thumb combined with fracture, 6 patients had radial collateral ligament injuries of the thumb combined with fracture, 4 cases of which were complicated with injuries of abductor pollicis brevis and the end of the flexor pollicis brevis tender. The size of the avulsed fragment was about 3.0 mm x 4.0 mm to 6.0 mm x 7.0 mm. RESULTS: The incisions of 22 patients healed by first intention. The follow-up periods ranged from 6 months to 5 years old,with an average of 2.5 years old. The thumb function was evaluated by Saetta and other evaluation criteria, and 20 patients got an excellent result and 2 good. CONCLUSION: The application of one-hole microplate internal fixation in treating collateral ligament injuries with fracture of the metacarpophalangeal joint of the thumb is an effective method. PMID- 25936189 TI - [Clinical value of the ECT bone scan in diagnosis of prosthesis infection for revision]. AB - OBJECTIVE: To detect the clinical value of the ECT bone scan in evaluating of the situation of infection control after hip knee arthroplasty. METHODS: The clinical data were retrospectively analyzed in 62 patients, including 34 males and 28 females with an average age of 68.8 years old ranging from 65 to 74 years. The results of ECT bone scan, erythrocyte sedimentation rate, C-reactive protein were used to assess periprosthetic infection. The patients with positive ECT and ESR on CRP were considered to have periprosthetic infection; however, the patients with two or more negative, indexes were considered to have no infection. RESULTS: The sensitivity, specificity, accurate rate of ECT were 75.0%, 88.9%, 87.1% respectively; ESR 50.0%, 72.2%, 69.4%; CRP 62.5%, 81.4%, 79.0%. The combination of the three methods were 87.5%, 96.3% and 95.2%, CONCLUSION: Compared with ESR and CRP, ECT is a more effective way in the diagnosis of periprosthetic infection, which has great value and is worth popularizing. PMID- 25936190 TI - [Correlation analysis on the disorders of patella-femoral joint and torsional deformity of tibia]. AB - OBJECTIVE: To reveal the possible mechanism involved in patella-femoral degenerative arthritis (PFDA) in- duced by torsion-deformity of tibia via analyzing the relationship between torsion-deformity of the tibia in patients with PFDA and the disorder of patella-femoral joint under the static and dynamic conditions. METHODS: From October 2009 to October 2010, 50 patients (86 knees, 24 knees of male patients and 62 knees of female patients) with PFDA were classified as disease group and 16 people (23 knees, 7 knees of males and 16 knees of females) in the control group. The follow indexes were measured: the torsion angle of tibia on CT scanning imagings, the patella-femoral congruence angle and lateral patella-femoral angle under static and dynamic conditions when the knee bent at 30 degrees of flexion. Based on the measurement results, the relationship between the torsion-deformity of tibias and the disorders of patella-femoral joints in patients with PFDA were analyzed. Finally,the patients were divided into three groups including large torsion-angle group, small torsion-angle group and normal group according to the size of torsion-angle, in order to analyze the relationship between torsion-deformity and disorders of patella-femoral joint, especially under the dynamic conditions. RESULTS: Compared with patients without PFDA, the ones with PFDA had bigger torsion-angle (30.30 +/- 7.11) degrees of tibia, larger patella-femoral congruence angle (13.20 +/- 3.94) degrees and smaller lateral patella-femoral angle (12.30 +/- 3.04) degrees . The congruence angle and lateral patella-femoral angle under static and dynamic conditions had statistical differences respectively in both too-big torsion-angle group and too small torsion-angle group. The congruence angle and lateral patella-femoral angle under static and dynamic conditions had no statistical differences in normal torsion-angle group. CONCLUSION: Torsion-deformity of tibia is the main reason for disorder of patella-femoral joint in the patients with PFDA. Torsion deformity of tibia is always accompanied by instability of patella-femoral joint,especially under the dynamic condition, thus causing PFDA. It can not only provide arrangement information and degenerative condition of patella-femoral joint,but also provide guidance through the analysis on the relationship for better clinical prevention and early treatment of degenerative bone and joint disease. PMID- 25936191 TI - [Case-control study on effects of fracture of processus styloideus ulnae on prognosis after plate fixation for the treatment of distal radial fractures]. AB - OBJECTIVE: To analyze effects of fracture of processus styloideus ulnae on prognosis in the treatment of distal radial fracture of type C according to AO classification. METHODS: This was a retrospective case-control study, and the information was got ten through case evaluation and follow-up, including sex, age, patient satisfaction, Gartland & Werley score and radiographic score. There were 76 patient treated with open reduction and plate fixation in People's Hospital Affiliated to Peking University from July 2006 to July 2011. All the patients were divided into two groups: no combination with fracture of processus styloideus ulnae (group A, 56 cases), combination with fracture of processus styloideus ulnae (group B, 20 cases). The patients in group A and B were treated with open reduction and internal fixation; however the fracture of processus styloideus ulnae was not fixed. The indexes such as clinical data, bone grafting, joint movement, Gartland & Werley score and radiographic score were compared between two groups. RESULTS: The ulnaris pain of patients in group B was more obvious than that in group A. The local VAS, palmar and dorsal flexion degree of wrist joint, motion VAS, patients satisfaction score, radial and ulnar deviation degree, pronation and supination of forearm degree, Gartland & Werley score and radiographic score were separately 0.1 +/- 0.1, (51.1 +/- 1.9) degrees , (60.2 +/ 1.9) degrees , 0.6 +/- 0.1 (23.1 +/- 0.9) degrees , (28.7 +/- 1.3) degrees (81.5 +/- 2.6) degrees , (68.2 +/- 2.7) degrees 1.9 +/- 0.3, 89.6 +/- 12.3 in group A; and separately 0.3 +/- 0.3, (51.4 +/- 2.3) degrees , (66.6 +/- 1.7) degrees , 0.5 +/- 0.2, (24.5 +/- 2.0) degrees , (26.9 +/- 1.8) degrees , (80.3 +/ 2.5) degrees , (70.3 +/- 3.7) degrees , 1.2 +/- 0.4, 92.5 +/- 7.5 in group B; there were no statistical differences in above indexes between two groups. CONCLUSION: Whether the distal radial fracture with a concomitant unrepaired ulnar styloid fracture or not exerts no influence on mainly outcomes including function, radiography and motion of the wrist. PMID- 25936192 TI - [Case-control study on close reduction combined with minimally invasive percutaneous plate osteosynthesis for the treatment of distal fracture of tibial shaft]. AB - OBJECTIVE: To compare the effects of close reduction combined with minimally invasive percutaneous plate osteosynthesis for distal fracture of tibial shaft. METHODS: From March 2009 to May 2013, there were 124 patients (89 males and 35 females, 30 of them were injured in a traffic accident and 94 were falling down in daily life, the ages ranging from 21 to 81 years old) who suffered from distal fracture of tibial shaft. Sixty-six patients (48 males and 18 females, 45 cases of type A, 12 cases of type B and 9 cases of type C) were treated with close manipulative reduction combined with minimally invasive percutaneous plate fixation. After close reduction, a minimal incision was made and a anatomic plate was inserted just along the medial tibia periostea, and then the fracture was fixed without fracture exposure. The other 58 patients (41 males and 17 females, 41 cases of type A, 10 cases of type B and 7 cases of type C) were treated with conventional open reduction and internal fixation. Length of the incision, operating time, early postoperative pain (recorded using the Visual Analog Scale score) and the outcome results (recorded using the evaluation standard of Johner Wruhs) were compared. RESULTS: The length of incision was meanly (7.34 +/- 1.42) cm in MIPPO group and (21.82 +/- 2.35) cm in ORIF group; operation time was (44.48 +/- 10.00) min in MIPPO group and (59.42 +/- 11.84) min in ORIF group. The postoperative radiographs verified good position of all screws and satisfactory bone fracture reduction in both groups. All the patients were followed up, and the duration ranged from 10 to 24 months (mean 15.2 months) in both groups. In MIPPO group,only one patient had delayed union and got union after Chinese herb therapy. The other 65 patients got bony union during 15 to 20 weeks. While in ORIF group, 3 patients suffered from nonunion and received reoperation with bone grafting, and 4 patients got bone infection. CONCLUSION: Treatment of distal fracture of tibial shaft, combined with close reduction and MIPPO technique, has the advantages such as less invasion, less damage of blood supply, simplified procedure of operation and higher union rate, which is an ideal methods and is accordant to the biological demand. PMID- 25936193 TI - [Effects of Jisuikang on Nogo-NgR gene expression in spinal cord rats with injury]. AB - OBJECTIVE: To study the effects of Jisuikang (Chinese characters) on Nogo-NgR gene expression, and to explore the protective effects and mechanism of Jisuikang (Chinese characters) on spinal cord injury in rats. METHODS: One hundred eighty female rats were randomly assigned to 6 groups(30 rats per group). Sham group: T10 lamina was resected only and spinal cord was untreated. Model group: spine cord injury (SCI) was created with a modified impinger of Allen's by impacting on the T10 spinal cord. Prednisolone group: Prednisolone (0.06 g/kg) was given by intragastric administration at a time interval of 24 hours after operation. The Jisuikang (Chinese characters) high, moderate and low dose groups: Jisuikang (Chinese characters) was supplied with different dose (50 g/kg, 25 g/kg, 12.5 g/kg) by intragastric administration in rats after operation,for the first time at 30 min after surgery. Animals were killed 3, 7, 14 days after surgery. The expression levels of Nogo-A and NgR were observed by Western Blot and Real-time PCR. RESULTS: The expression of Nogo-A and NgR was at the basic level at all time points in sham group. Compared with model group, the protein expression levels of Nogo-A and NgR in sham, prednisolone, Jisuikang (Chinese characters) moderate dose groups were statistically significant at all time points (P < 0.05). No difference was found in Jisuikang (Chinese characters) high and low dose groups (P > 0.05). Three days after surgery, the mRNA levels of Nogo-A and NgR in treatment group were significantly lower than that in model group (P < 0.01); 7 days after surgery,Nogo-A and NgR mRNA expression were dramatically upregulated and peaked; 14 days after operation, the expression was decreased, but still significantly higher than that in other treatment groups (P < 0.01). Prednisolone and Jisuikang (Chinese characters) moderate dose groups showed the most significant effects among all groups,but there was no statistically significant difference between two groups (P > 0.05). CONCLUSION: The decoction Jisuikang (Chinese characters) can promote the nerve cell regeneration by regulating Nogo-A and NgR gene expression, activating Nogo- NgR signaling pathways after acute spinal cord injury. PMID- 25936194 TI - [Experimental study on internal fixation with screws through femoral epiphyseal plate]. AB - OBJECTIVE: To explore the effect of internal fixation with screw through femoral epiphyseal plate on growth in- hibition via an experimental study. METHODS: Forty New Zealand rabbits were randomly divided into 4 groups and 10 rabbits in each group. Epiphyseal plate was injured by penetrating of screws, and the size of damage area was controlled by changing the number of threads. Group A: blank group; group B: injury area accounted for 4% of the epiphyseal plate; group C: injury area accounted for 6%; group D: injury area accounted for 8%. The internal fixation was removed after 2 weeks, and the results were observed with X-ray film for 4 groups to judge the complications such as early closure of epiphyseal. RESULTS: In each group, there were no statistical differences in the length of the femoral neck, the diameter of femoral neck, the diameter of the femoral head, and the epiphyseal plate closure time. The growth speed of the length and diameter of the femoral neck, as well as the diameter of femoral head, were quicker on the early phase, and the speed was slowest when the epiphyseal plate was being closed. CONCLUSION: The injury area of epiphyseal plate under 8% is safe for its growth. Because no evidences demonstrate the growth inhibition of epiphyseal plate, the screws can be used for rabbit epiphyseal plates. PMID- 25936195 TI - [Meta-analysis of internal fixation versus hip replacement in the treatment of trochanteric fractures]. AB - OBJECTIVE: To compare the efficacy of internal fixation (including PFNA and PFN) versus hip replacement (including FHR or THA) in the treatment of trochanteric fractures in adults. METHODS: Reports of studies using randomized controlled trials (RCT) to compare internal fixationg with hip replacement in the management of intertrochanteric fractures were retrieved (up to January 1, 2013) from the Cochrane Library, PUBMED Data, CNKI (China National Knowledge infrastructure), Elsevier, the Chinese Biomedical Database, Wanfang Data, and manually. Methodological quality of the trials was critically assessed, and relevant data were extracted. Statistical software RevMan 5.0 was used for data-analysis. RESULTS: Seven articles were included in the meta-analysis. The results showed that,compared internal fixation with hip replacement,there were statistical significance in the duration of surgery time [WMD = -2.66, 95% CI (-5.25,-0.06), P = 0.05], intra-operative blood loss [WMD = -24.20, 95% CI (-30.38, -18.02), P < 0.000 01], hospital stays time [WMD = -4.72, 95% CI (-5.18, -4.25), P < 0.000 01], bearing load time [WMD = -29.54, 95% CI (-30.77, -28.31), P < 0.000 01], total complications rate [WMD = 0.15, 95% CI (0.11, 0.22), P < 0.000 01], the good rate of Harris scores [WMD = 1.09, 95% CI (0.54,1.32), P < 0.05]. However, there were no statistical significance in the rate of deep venous thrombosis [WMD = 1.09, 95% CI (0.47, 2.55), P > 0.05]. CON- CLUSION: Hip replacement (containing FHR or THA) for the treatment of intertrochanteric fractures is superior to internal fixa- tion in regards to the duration of surgery time, the mean duration of hosipital stays, mean post-operative down time, intra-opera- tive blood loss, the rate of post-operative good Harris scores. But there is not enough evidence to show any difference between hip replacement (containing THA or FHR) and internal fixation in regards to the rate of deep venous thrombosis. However, internal fixation for the treatment of intertrochanteric fractures is superior to hip replacement (containing FHR or THA) in regards to total complications rate. PMID- 25936196 TI - [Anatomical double bundle reconstruction of medial patellofemoral ligament with allograft tendon in the treatment of patellar dislocations]. AB - OBJECTIVE: To investigate the clinical therapeutic results of allograft tendon for anatomical reconstruction of medial patellofemoral ligament (MPFL) for the treatment of patellar dislocations. METHODS: From September 2008 to June 2013, 16 patients with patellar dislocation underwent MPFL reconstructions. There were 2 males and 14 females, aged 11 to 27 years old (16 years old on average). Patellar dislocations occurred in 11 left and 5 right knees. The disease course ranged from 3 to 10 years. The frequency of dislocation ranged from 9 to 33 times (19 times on average). Affected knee joints showed patellar instability; the range of action for patella obviously increased. The X-ray films showed patellar dislocation. The preoperative Q angle was (36 +/- 9) degrees , and the congruence angle was (63 +/- 18) degrees . Reconstruction was performed via allograft tendon. Allograft tendon was fixed through the superomedial pole of the patella, and the other end was fixed at the natural MPFL insertion site near the medial femoral condyle with an interference screw in a bone tunnel. All the patients were evaluated postoperatively; Kujala patellofemoral scores, objective knee function, complications, and reoperations were assessed. RESULTS: Primary healing was achieved in all cases. No infection or necrosis and absorption of grafts was observed. All the patients were followed up for an average of 16.4 months (ranged, 10 to 24 months) postoperatively. At the latest follow-up, all the patients had no pain, swelling and patellar instability; neither patella redislocation nor fracture occurred. The X-ray films showed good position of tunnel 6 months after operation, and the congruence angle was (5 +/- 9) degrees , showing statistically significant difference when compared with preoperation (P < 0.05). The postoperative Q angle was (17 +/- 8) degrees , the Kujala knee function score improved significantly from 45.20 +/- 9.20 to 89.30 +/- 6.40 at the latest follow-up, showing statistically significant difference (P < 0.05). CONCLUSION: MPFL reconstruction improves clinical symptoms. Anatomical MPFL reconstruction is effective for patellar dislocation, and it offers good recovery of the premorbid patella mechanics. The interference screw provides firm fixation. Allograft can avoid the graft harvest site morbidity, but it increases the cost of the surgery. PMID- 25936197 TI - [Treatment of depression fractures of posterolateral tibial plateau through a modified anterolateral approach]. AB - OBJECTIVE: To study the therapeutic effects of posterolateral depression fractures of the tibial plateau through a modified anterolateral approach. METHODS: From February 2011 to January 2012,13 patients with posterolateral depression fractures of the tibial plateau were treated through a modified anterolateral approach. There were 8 males and 5 females, ranging in age from 28 to 59 years old (49.2 years old on average). Data from patients were collected retrospectively as follows: X-ray, time of fracture healing and the complications of fracture healing. The patients were evaluated both clinically and radiologically according to the Rasmussen score system. RESULTS: All the patients were followed up, and the duration ranged from 6 to 18 months (mean 13.7 months). All the patients got bony union. The average radiographic bony union time was 15.1 weeks (ranged, 11 to 17 weeks). No case of secondary articular depression was found. No complications such as malunion or joint stiffness were found. But 1 patient had superficial infection and 1 patient had common peroneal nerve injury. According to the Rasmussen score system,the mean radiological score was 16.50 +/- 0.67 (ranged, 13 to 18), and the mean functional score was 25.20 +/- 2.21 (ranged, 13 to 30). The mean range of knee motion was (125.3 +/- 9.3) degrees (ranged, 0 degrees to 135 degrees ). CONCLUSION: Treatment of depression fractures of posterolateral tibial plateau with a modified anterolateral approach is a safe method with effective exposure, due to its stable fixation and relatively good outcome with minimal soft-tissue complications. It is regarded as an ideal procedure for depression fractures of posterolateral tibial plateau. PMID- 25936198 TI - [Early diagnosis and treatment for trauma around the knee with popliteal vascular injury]. AB - OBJECTIVE: To investigate the early diagnosis and treatment for trauma around the knee with popliteal vascular injury. METHODS: A retrospective analysis was employed to analyze the clinical data from 15 patients (9 males and 6 females were with a mean age of 39.2 years old,ranging from 26 to 62 years old) with fracture or dislocation around the knee with popliteal vascular injury from January 2007 to January 2013. Combined with clinical symptoms and signs, oxygen saturation monitors, color ultrasound, DSA angiography and interventional surgery were used to determine the vascular injury. The knee fracture and dislocation were fixed with hybrid external fixation and plate-screw fixation, respectively. Then, the blood circulation was reconstructed by thrombectomy, repair and autologous vein graft for individual injured vascular. The average total operation time, average hospitalization days, predictive salvage index (PSI), average blood transfusion amount, average medical expenses and infection cases were recorded to determine the effect of early diagnosis and treatment. RESULTS: There was one patient with death, 8 patients with amputation, and 6 patients with successful repair surgery for popliteal artery, anterior tibial and posterior tibial arteries. These six patients with surviving limbs were followed up for an average of 28.3 months (ranged, 12 to 60 months). Among the 6 successful patients, the joint function of 4 patients was good and excellent. CONCLUSION: The trauma around the knee with popliteal vascular injury is characterized by complex and serious injury, easy misdiagnosis and loss diagnosis, poor prognosis and high risk of amputation. The early diagnosis of trauma around the knee with popliteal vascular injury should depend on the mechanism of trauma, local anatomical characteristics of injury site, clinical presentations and appropriate auxiliary examinations. The appropriate indications for limb salvage and amputation should be used to achieve more effective clinical results. PMID- 25936199 TI - [Embryonal rhabdomyosarcoma of adult lower leg with bone marrow invasion: a case report]. PMID- 25936200 TI - [Clinical experience on postoperative balance of hemostasis and antithrombus for patients with hemophilic arthritis after arthroplasty]. AB - OBJECTIVE: To observe the clinical significance of postoperative personalized antithrombotic therapy for patients with hemophilic arthritis (HA) patients after arthroplasty. METHODS: From September 2005 to October 2013, 11 cases of arthroplasty for hemophilic arthritis in hip and knee total operation 14 times,including 1 case of double knees (calculated as one operation), operation in left knees 6 times, operation in right knees 5 times, 2 in hip. All the patients were male and the age ranged from 23 to 57 years old,with an average of (36.1 +/- 11.0) years old; the average weight was (64.1 +/- 8.9) kg. All the patients were preoperatively diagnosed and classified as hemophilic arthritis with the radiological images and laboratory tests. According to the function of joints, the risk of postoperative venous thromboembolism (VTE), and dynamic observation of Factor VIII:C (FVIII:C) activity, patients were treated with personalized antithrombus by adjusting the dosage of recombinant human coagulation factor VIII (Kogenate FS). All the patients were orderly divided into postoperatively distal joints moving group and none-moving group to observe the coagulation function. RESULTS: The enrolled patients had no postoperative complication of VTE and pulmonary embolism (PE). The APTT and D-2 were different between two groups in the postoperative early stage. Length of hospital day was shorter in the moving group than none-moving group. CONCLUSION: Because of the self-coagulation disorder, patients with HA tended to bleed. However it doesn't mean that there is no risk of postoperative thrombosis. Therefore,it's important to determine how to control the balance between postoperative antithrombus, hemostasis,and coagulation factor replacement therapy after arthroplasty for HA. Postoperative moving has proved helpful for HA, especially in reducing the risk of hemostasis and shortening the time in hospital. PMID- 25936201 TI - [Posterior capsule releasing in total knee arthroplasty for patients with rheumatoid arthritis with stiff knees in flexion]. AB - OBJECTIVE: To investigate the correct method of bone resection and posterior capsular soft tissue releasing in total knee arthroplasty (TKA) for the patients with rheumatoid arthritis with stiff knee in flexion. METHODS: From November 2009 to January 2012,15 patients with rheumatoid arthritis with stiff knee in flexion underwent primary TKA and releasing of the posterior soft tissues. There were 7 males and 8 females,aged 22 to 75 years old (58.7 years old on average). The preoperative range of movement(ROM) was (3.2 +/- 1.7) degrees . According to Knee Society score (KSS) criterion, the preoperative clinical score was 23.3 +/- 12.5 and functional score was 35.2 +/- 9.8. Based on the correct osteotomy, effective releasing of posterior structures was used for different degrees of flexion contracture during the TKA procedure. RESULTS: All the patients were followed up, and the average duration was 2.3 years (1.6 to 3 years). At the latest follow up,the KSS clinical score was 81.7 +/- 6.5 and functional score was 82.8 +/- 9.3. The flexion and extension ROM of the knee joint was (103.5 +/- 13.1). Three knees remained 50 flexion contracture deformity, but the function of the affect knees was good. CONCLUSION: The effective releasing of the soft tissue of posterior capsule is a major management for correction of the flexion contracture in TKA. The correct releasing of posterior structure can not only achieve fundamental gap of TKA but also effectively avoid bone over-resection. PMID- 25936202 TI - [Double-plating internal fixation through combined approaches for the treatment of medial tibial plateau fractures with fracture-dislocation type]. AB - OBJECTIVE: To investigate the clinical effects of double-plating internal fixation for the treatment of medial tibial plateau fractures with fracture dislocation type through combined anterior and inverted "L" posteromedial knee approaches. METHODS: From February 2010 to September 2013, 17 patients with medial tibial plateau fractures with fracture-dislocation type were treated by double-plating internal fixation at our department. Anterior knee approach was adopted for medial mass reduction and fixation,while the inverted "L" posteromedial approach was used for posteromedial mass. There were 11 males and 6 females, with an average age of 42 years old (ranged, 21 to 65 years old). The efficacy were investigated by comparing pre- and post-operative radiographic data, and by evaluating clinical symptoms using the HSS score system. RESULTS: All the patients were followed with a mean time of 18 months (ranged, 11 to 25 months). The tibial-plateau varus angle immediately after operation and at the latest follow-up were respectively (87.8 +/- 4.2) degrees and (88.2 +/- 4.6) degrees , and there was no statistical difference (P = 0.458). The posterior slope angle immediately after operation and at the latest follow-up were respectively (10.1 +/- 3.7) degrees and (10.3 +/- 4.1) degrees , and there was no statistical difference (P = 0.512). The knee joint HSS score was 86.7 +/- 6.1. No patient had complications such as infection, skin necrosis, internal fixation loosening or loss of fracture reduction. CONCLUSION: Doubl-plating internal fixation through combined approaches is an ideal operation method for medial tibial plateau fractures with fracture-dislocation type, because it can provide clear surgical field, satisfactory reduction, reliable fixation, and chance for early functional exercise. PMID- 25936203 TI - [Clinical effect of arthroscopic debridement and infusion-drainage on septic arthritis after arthroscopic anterior cruciate ligament reconstruction]. AB - OBJECTIVE: To investigate therapeutic strategy on septic arthritis after arthroscopic anterior cruciate ligament reconstruction. METHODS: The clinical data of 6 cases of septic arthritis after arthroscopic anterior cruciate ligament reconstruction in our department from March 2005 to February 2014 were analyzed. All the patients were male,ranging in age from 18 to 36 years old. After operation, the knee joint became painful and swollen, and ESR and CRP were both increased. Culture of joint fluid allowed the recovery of staphylococcus epidermidis. The patients were dealt with arthroscopic debridement and infusion drainage. The clinical results were evaluated by Lysholm rating system and range of motion. RESULTS: The infection of all the patients was controlled. The ESR and CRP both recovered to normal level. The score of Lysholm rating system ranged from 85 to 95,and the range of motion was 120 to 135 degree. CONCLUSION: Arthroscopic debridement combined with infusion-drainage is effective in septic arthritis after arthroscopic anterior cruciate ligament reconstruction. PMID- 25936204 TI - [Diagnostic value of 3D-indirect magnetic resonance arthrography in detecting meniscal tears of the knees]. AB - OBJECTIVE: To explore the diagnostic value of 3D-indirectmagnetic resonance (MR) arthrography in detecting meniscustears of the knees. METHODS: Form January 2013 to January 2014, routine plain MR of the knees followed by the 3D-indirect MR arthrography was performed in 42 patients with suspected meniscal tears clinically. There were 31 males and 11 females, with an average age of 38.4 years old (ranged, 21 to 67 years old). The duration of the course ranged from 2 h to 15 d. The clinical symptom was knee pain. All the patients got subsequently arthroscopic examination or operation. The sensitivity and specificity of routine plain MR and 3D-indirect MR arthrography were compared based on the results of arthroscopic examination or operation. RESULTS: The signal intensity in the area of meniscal tears on image of 3D-indirect MR arthrography was obviously higher than that of routine plain MR. The sensitivity of 3D-indirect MR arthrography was 85.79% (87/102), while the routine plain MR was 52.94% (54/102), and the specificity improved from 67.78%(61/90) to 86.67%(78/90). The difference was statistically significant (chi2 = 25.90, P < 0.01; chi2 = 9.13, P < 0.01). CONCLUSION: In comparison with the routine plain MR findings, 3D-indirect MR arthrography demonstrates meniscus tears of the knee with the better sensitivity and specificity. PMID- 25936205 TI - [Progress of clinical application of ETO in rTHR]. AB - How to remove the well fixed cement or cementless prosthesis and get a completely distal cement removal in the rTHR are critical to the outcome of revision. Because of higher rate of union, excellent intraoperative exposure, and adjustment of abductor tension, ETO has been widely applied to rTHR and complicated primary THR by foreign scholars. Furthermore, this technology has wide indications, very few contraindications, high cure rates,and low complications rate. ETO turns out to be a safe and effective revision technology. In the article, the indication, contraindication, complications and advantages of this technique were reviewed. PMID- 25936206 TI - Preface. Abortion is safer than childbirth. PMID- 25936207 TI - The medical assumption at the Foundation of Roe v. Wade & its implications for women's health. AB - Too little attention has been paid over the past forty years to the complete lack of a factual record in Roe v. Wade and Doe v. Bolton, and to the Court's fundamental assumption that drove the outcome. The decision and opinions were driven by the medical claim that "abortion was safer than childbirth," which was raised for the first time in the briefs in the Supreme Court without any lower court record. This medical premise directly and profoundly shaped virtually every major aspect of Roe and Doe, including the creation of the trimester system and the prohibition of health and safety regulations in the first trimester. Because of this medical assumption, the Justices extended the right to abortion throughout pregnancy. It was key to the Court's historical rationale for a "right" to abortion. Because of this notion, the Justices gave abortion providers complete discretion to manage any issues of health and safety, and they prohibited public health officials from regulating abortion in the first trimester. This medical assumption was the most consequential factual assumption of the abortion decisions of 1973 and it has been assumed to be true in subsequent abortion decisions by the Court. The notion that "abortion is safer than childbirth" has become even less tenable for at least five reasons: (1) the dysfunctional abortion data reporting system in the United States that relies completely on voluntary reporting; (2) the incomparability of the published abortion mortality rate and the published maternal (childbirth) mortality rate; (3) medical data on the increasing rate of maternal mortality in the second trimester; (4) the growing body of international medical studies finding long term risks to women from abortion; and (5) maternal mortality data from countries with superior abortion recordkeeping collection and reporting systems, which find a higher rate of abortion mortality than childbirth mortality. These concerns and the growth in international medical data over the past two decades should counsel the Supreme Court to give greater deference to the states in their attempt to protect maternal health. PMID- 25936208 TI - Improving the accuracy of maternal mortality and pregnancy related death. AB - Comparing abortion-related death and pregnancy-related death remains difficult due to the limitations within the Abortion Mortality Surveillance System and the International Statistical Classification of Diseases and Related Health Problems (ICD). These methods lack a systematic and comprehensive method of collecting complete records regarding abortion outcomes in each state and fail to properly identify longitudinal cause of death related to induced abortion. This article seeks to analyze the current method of comparing abortion-related death with pregnancy-related death and provide solutions to improve data collection regarding these subjects. PMID- 25936209 TI - Medical experiments on persons with special needs, a comparative study of Islamic jurisprudence vs. Arab laws: UAE law as case study. AB - This article is a comparative study of medical experiments on persons with special needs in Islamic jurisprudence and Arab laws; United Arab Emirates (UAE) law as case study. The current study adopts a comparative analytical and descriptive approach. The conclusion of this study points out that the Convention on the Rights of Persons with Special Needs, ratified by a number of Arab States, including the United Arab Emirates, approves conducting medical experiments on persons with special needs, subject to their free consent. As a result of ratifying this Convention, a number of special laws were enacted to be enforced in the United Arab Emirates. On the other hand, this issue is controversial from an Islamic jurisprudence point of view. One group of jurisprudents permits conducting these experimentations if they are designed to treat the person involved, and prohibits such experimentations for scientific advancement. Other jurisprudents permit conducting medical experimentations on persons with special needs, whether the purpose of such experimentations is treatment of the disabled or achieving scientific advancement. The opinion of this group is consistent with the International Convention and the Arab laws in this respect. However, neither the Convention nor the Arab laws regulate this matter by specific and comprehensive conditions, as addressed by some contemporary scholars. It is recommended that the Convention and the Arab laws adopt these conditions. Additionally, the Convention does not state whether the experimentations may be conducted for the interest of the person with disability or for the purpose of scientific advancement. The text of the Convention is unclear and therefore requires further illumination. PMID- 25936210 TI - The challenging theoretical and empirical approaches to the study of biology. PMID- 25936212 TI - Modelling ecological complexity for marine species conservation: the effect of variable connectivity on species spatial distribution and age-structure. AB - Connectivity is currently emphasized as a key factor in conservation for its role in enhancing biodiversity of an area and giving benefit to the adjacent areas. For most marine species, connectivity is synonomous of larval dispersal. We applied a spatially explicit meta-population model to test the hypothesis that larval dispersal can affect local demographical features, consequently misleading conservation practice in the marine environment. Simulations were carried out in the Gulf of Lions where coastal circulation displays highly variable temporal and spatial submeso-scale structures. Two different benthic invertebrate species were considered: a soft bottom short lived species and a hard bottom long lived one. In the first case, simulations showed that highest densities at equilibrium do not inform on self-persistent populations location. In the second case, simulations showed that connectivity effects may result in out-of-equilibria demographical structure. We emphasized the caveats in the parameterization of demographical models when local demography is controlled by connectivity. PMID- 25936211 TI - Interleukins (ILs), a fascinating family of cytokines. Part I: ILs from IL-1 to IL-19. AB - Every nucleated cell can produce and respond to cytokines, extracellular proteic/glycoproteic mediators that constitute a complex, interconnected, and flexible signaling network, addressed to modulate cell behavior and homeostasis through the interaction with high-affinity surface receptors. These messenger molecules, whose main characteristics are potency, pleiotropism, and redundancy, primarily act in autocrine, paracrine, and juxtacrine way, but can also display systemic activity in endocrine-like modality. They are generally classified according to their cellular sources, three-dimensional structure, or biological functions. Among cytokines, interleukins (ILs) represent a fascinating and multifunctional group of immunomodulators that primarily mediate the leukocyte cross-talk (hence the name), and mainly regulate the immune cell proliferation, differentiation, growth, survival, activation, and functions. Up to 38 ILs have been so far identified, numbered according to the order of discovery, and grouped in different subsets, based on distinguishing structural/functional features. Due to their crucial role in regulating inflammation and immune response, ILs are known to be involved in the pathogenesis of human inflammatory/autoimmune diseases. Therefore, they have increasingly attracted great interest as effective or promising therapeutic targets. The biology and functions of the hitherto identified human ILs are reviewed and discussed: in this first section of the article, ILs from IL-1 to IL-19 are presented. PMID- 25936213 TI - Modeling ant battles by means of a diffusion-limited Gillespie algorithm. AB - We propose two modeling approaches to describe the dynamics of ant battles, starting from laboratory experiments on the behavior of two ant species, the invasive Lasius neglectus and the authocthonus Lasius paralienus. This work is mainly motivated by the need to have realistic models to predict the interaction dynamics of invasive species. The two considered species exhibit different fighting strategies. In order to describe the observed battle dynamics, we start by building a chemical model considering the ants and the fighting groups (for instance two ants of a species and one of the other one) as a chemical species. From the chemical equations we deduce a system of differential equations, whose parameters are estimated by minimizing the difference between the experimental data and the model output. We model the fluctuations observed in the experiments by means of a standard Gillespie algorithm. In order to better reproduce the observed behavior, we adopt a spatial agent-based model, in which ants not engaged in fighting groups move randomly (diffusion) among compartments, and the Gillespie algorithm is used to model the reactions inside a compartment. PMID- 25936214 TI - Entropy of a network ensemble: definitions and applications to genomic data. AB - In this paper we introduce the framework for the application of statistical mechanics to network theory, with a particular emphasis to the concept of entropy of network ensembles. This formalism provides novel observables and insights for the analysis of high-throughput transcriptomics data, integrated with apriori biological knowledge, embedded in-to available public databases of protein protein interaction and cell signaling. PMID- 25936215 TI - On the dinucleotide circular codes of maximum cardinality. AB - In a recent paper, Michel and Pirillo prove that there are 24 dinucleotide circular codes of maximum cardinality over an alphabet of cardinality 4. In this paper we find the exact number of dinucleotide circular codes of maximum cardinality for any given (finite) cardinality of the alphabet. Moreover, we describe the structure of these codes. PMID- 25936216 TI - Elements of plant physiology in theophrastus' botany. AB - For thousands of years the plants were considered only as a source of food and medicine, and as ornamental objects. Only from the fifth century BC, some philosophers of Ancient Greece realized that the plants were living organisms but, unfortunately, their works have come to us as fragments that we often know from the biological works of Aristotle. This eminent philosopher and man of science, however, did not give us a complete work on the plants, which he often promised to write. From scattered fragments of his conspicuous biological work, it emerges a concept of nutritive soul that, in the presence of heat and moisture, allows plants to grow and reproduce. The task of writing a comprehensive botanical work was delegated to his first pupil, Theophrastus, who left us two treatises over time translated into the various languages up to the current versions (Enquiry into plants, On the causes of plants). The plant life is described and interpreted on the basis of highly accurate observations. The physiological part of his botany is essentially the nutrition: According to Theophrastus, plants get matter and moisture from the soil through root uptake and process the absorbed substances transforming them into food, thanks to the heat. The processing (pepsis, coction) of matter into the food represents an extraordinary physiological intuition because individual organs of a plant appear to perform its specific transformation. Despite that Theophrastus did not do scientific experiments or use special methods other than the sharpness of his observations, he can be considered the forerunner of a plant physiology that would take rebirth only after two millennia. PMID- 25936217 TI - Fractal analysis of dendrite morphology of rotated neuronal pictures: the modified box counting method. AB - The fractal dimension of a non-stellate neuron changes continuously with rotation of the neuronal picture. For a stellate neuron such changes cannot be noticed. During preprocessing for the box counting, non-stellate neurons should be arranged so that the major diameters of their dendrite fields are parallel. It was shown that a non-stellate neuronal picture had the smallest box dimension when the angle between the horizontal or vertical axis and its major diameter was about 45 degrees. The box counting method which uses ImageJ software does not consider the position of a picture on the computer's screen. A dispersion of the box dimension values of a sample is generally rather large so that their mean value is with larger standard deviation. Modified box counting method partly diminishes these findings. To improve a dependence on neuronal rotation for the box counting dimension of nonstellate neurons, prior to applying the box counting, the non-stellate neurons should be arranged so that the major diameters of their dendrite fields are parallel. PMID- 25936218 TI - Demography and conservation of the Mediterranean fin whale (Balaenoptera physalus): what clues can be obtained from photo-identification data. AB - Long-lived and slow reproducing species, such as cetaceans, are among the most critical conservation units: a demographic approach can be very useful for their management and conservation. In the present work, we examined, by demographic tools, the most exhaustive photo-identification database available for the Mediterranean fin whale (Balaenoptera physalus) population, recorded by Tethys Research Institute between 1990 and 2007 in the Western Ligurian Sea. A total of 31,782 km were covered and 548 fin whale sightings were recorded. The occurrence of the target species was uneven across the years and months: an anomalous reduction of sightings occurred between 2001 and 2004. Moreover, the target species is likely to concentrate in the study area in the summer months and probably moves to other areas in the early autumn. Using the photo-identification technique, 431 different individuals were photo-identified, but only 318 of them were sized: 6 calves (<= 10 meters), 33 immature (10-15 m), 261 adolescent-adult (> 15 m) and 18 olds (>= 20 m). For the first time the site of the fin whale sub population in the Pelagos Sanctuary was obtained by photo-identification and mark recapture techniques. These techniques were used to estimate the site of the sub population composed by individuals > 15 meters as 539 fin whales (95% confidence interval = 345-732) over the period 1990-1999. The number of calves was likely underestimated, as the sighting period (late spring-summer) was shifted with respect to the peak of births (late autumn). To fill this gap of knowledge we propose a simple mathematical model for the yearly dynamics of calves. After correcting the number of calves, a static life history table for the period 1990 2007 was set out. Our results highlight the highest survival proportions between calf and immature (61.1%) and the minimum between adolescent-adult and old (2.5%) vital stages. The overall life expectancy is estimated to be 6.3 years while the life expectancy of individuals entering the adolescent-adult stage is 14.3 years. This paper aims at providing a contribution for improving the conservation efforts and the demographic knowledge on fin whales in the Pelagos Sanctuary. PMID- 25936219 TI - Conscience dilemma: to become a bioengineer or to survive as a biologist. AB - Bioengineering is the consideration of biological problems from modern engineering, therefore money-oriented, perspective. Today, grant-giving bodies always favor bioengineering projects rather than pure biology projects (like those in ecology, entomology, etc.). Therefore, today's biologist is forced to be on the horns of a dilemma. They have to either submit a very powerful and valid reason for the proposal of their project, or change the project to one having a potential of money-based outcome. On the other hand, because of dealing with the living components of nature, conducting a research in pure biology is like a kind of worship. For this reason, from a believer scientist's view, a deviation (in terms of research) from biology to bioengineering can be considered like committing a sin. Unfortunately, today's wild capitalism has been bringing new sinners day by day, and this system will continue for the foreseeable future unless grant-giving bodies comprehend the real importance of pure biology. PMID- 25936220 TI - A dynamical model for influenza under seasonal variables. AB - In this study, influenza is modeled dynamically under seasonal variables. Seasonal variables made this model geometrically more complicated than without seasonal conditions. This modeling will be done in two cases with vaccination and without vaccination. These two models are solved in similar conditions by using Rung-Kutta method. The resulted data are shown in two diagrams and they are compared. We deduce a model for influenza without seasonal variable and vaccination and we consider its equilibrium points. PMID- 25936221 TI - Dynamics on genes network structures. An ago-antagonist approach. AB - This paper is a carrying on of the theme examined in (Bazzani, Freguglia 2013) where we discuss a proposal of studying of essential structural aspects of Darwinian Evolution Theory. Also in this case we apply a mathematical ago antagonist theory inspired by Y. Cherruault's ideas (Cherruault 1998). In the present paper we consider the network structure of genes activity and its dynamics. PMID- 25936222 TI - Linifanib: current status and future potential in cancer therapy. AB - Angiogenesis is one of the major mechanisms controlling tumor proliferation and metastatic spreading. Targeting of pro-angiogenic factors and their downstream effectors represents an appealing therapeutic option in the treatment of different cancer types. Linifanib (ABT-869) is a novel tyrosine-kinase inhibitor (TKI) inhibitor and its anti-angiogenic activity has been explored in numerous clinical trials. Here, we review preclinical development of linifanib focusing on its pharmacodynamic and pharmacokinetic characteristics and briefly summarize its evaluation in clinical trials. Linifanib selectively targets VEGFR and PDGFR and has low off-target inhibitory activity. Preclinical and early-phase trials have been showing promising efficacy results However, although signals of anti-tumor activity have been proven in some malignancies, linifanib late-phase development has been facing some challenges due to limited efficacy and increased toxicities. New strategies aimed at finding biomarkers of response and minimizing toxicities are needed to allow the further development of a promising compound. PMID- 25936223 TI - Specialized teams or specialist networks for rare cancers? PMID- 25936224 TI - Evolution of undifferentiated arthritis: a ten-year experience from the early arthritis clinic of a tertiary care hospital. AB - OBJECTIVES: Undifferentiated arthritis (UA) is an inflammatory oligo/polyarthritis where no definite diagnosis can be reached. Patients with UA may progress towards a chronic inflammatory disease, however, in some cases arthritis may completely resolve. To date, a universally accepted diagnostic and therapeutic algorithm for UA is not available. METHODS: We retrospectively studied 192 patients with UA followed by us over the last 10 years in the early arthritis clinic of our institution. RESULTS: A total of 192 patients, 91 men (47.4%) and 101 women (52.6%), with mean age 57.9+/-17.8 years, were included in the study. Eighty-four patients (43.7%) presented with acute/subacute mono-/pauci arthritis, 56 patients (29.2%) with chronic mono-/pauci arthritis, 42 patients (21.9%) with acute polyarthritis and 10 (5.2%) with chronic polyarthritis. From the total of 192 patients, 102 are currently followed. Current diagnosis at the time of this report included: rheumatoid arthritis in 18 (17.6%) patients, self limiting arthritis in 35 (34.4%), undifferentiated/unclassified arthritis in 45 (44.1%), spondyloarthropathy in 3 (2.9%), and crystal-induced arthritis in one (1%). The time between the initial evaluation and the definitive diagnosis of RA ranged between 6 and 15 months. Seropositivity (RF and/or ACPA) and disease duration were strong predictors of developing RA in our cohort. CONCLUSIONS: Our data indicate that seropositive patients with chronic symptoms carry an increased risk of developing RA, and that these patients may be candidates for a more aggressive treatment. PMID- 25936225 TI - Mucosal physical and chemical innate barriers: Lessons from microbial evasion strategies. AB - The innate immune system has evolved since millions of years under a selective pressure. Among the different host mechanisms selected and conserved as a first line of defense, the gastrointestinal mucus layer constitutes an efficient physical and chemical barrier against invading microbes. Mucin glycoproteins and antimicrobial peptides are the major components of the mucus barrier, and evidences prove that they form an effective protection against most microbes. However, successful pathogens have evolved evasion strategies to circumvent this defense barrier. Here, we discuss the interactions between pathogens, mucins, and antimicrobial peptides, and the mechanisms that pathogens have developed to evade the innate defense systems of the intestinal mucosal barrier. PMID- 25936227 TI - Frontal and rostral anterior cingulate (rACC) theta EEG in depression: implications for treatment outcome? AB - In major depressive disorder (MDD), elevated theta current density in the rostral anterior cingulate (rACC), as estimated by source localization of scalp-recorded electroencenphalogram (EEG), has been associated with response to antidepressant treatments, whereas elevated frontal theta has been linked to non-response. This study used source localization to attempt to integrate these apparently opposite results and test, whether antidepressant response is associated with elevated rACC theta and non-response with elevated frontal theta and whether theta activity is a differential predictor of response to different types of commonly used antidepressants. In the international Study to Predict Optimized Treatment in Depression (iSPOT-D), a multi-center, international, randomized, prospective practical trial, 1008 MDD participants were randomized to escitalopram, sertraline or venlafaxine-XR. The study also recruited 336 healthy controls. Treatment response and remission were established after eight weeks using the 17 item Hamilton Rating Scale for Depression (HRSD17). The resting-state EEG was assessed at baseline with eyes closed and source localization (eLORETA) was employed to extract theta from the rACC and frontal cortex. Patients with MDD had elevated theta in both frontal cortex and rACC, with small effect sizes. High frontal and rACC theta were associated with treatment non-response, but not with non-remission, and this effect was most pronounced in a subgroup with previous treatment failures. Low theta in frontal cortex and rACC are found in responders to antidepressant treatments with a small effect size. Future studies should investigate in more detail the role of previous treatment (failure) in the association between theta and treatment outcome. PMID- 25936226 TI - Tick microbiome: the force within. AB - Ticks are obligate blood-feeders and serve as vectors of human and livestock pathogens worldwide. Defining the tick microbiome and deciphering the interactions between the tick and its symbiotic bacteria in the context of tick development and pathogen transmission will likely reveal new insights and spawn new paradigms to control tick-borne diseases. Descriptive observations on the tick microbiome that began almost a century ago serve as forerunners to the gathering momentum to define the tick microbiome in greater detail. This review will focus on the current efforts to address the microbiomes of diverse ticks, and the evolving understanding of tick microbiomes. There is hope that these efforts will bring a holistic understanding of pathogen transmission by ticks. PMID- 25936228 TI - Assessment of upper airway obstruction by measuring peak oral and nasal inspiratory flow. AB - OBJECTIVE: We wanted to access upper airway obstruction in patients undergoing tonsillectomy by measuring peak oral and nasal inspiratory airflow. METHODS: We recruited study participants from a cohort of patients on the waiting list for tonsillectomy, with or without adenoidectomy, at University Hospital of Wales, Cardiff, UK. Fifty patients enrolled on phase I of the study and underwent pre operative measurement of the rate of peak oral and nasal inspiratory flow; 25 of these patients returned after one month for phase II of the study and underwent post-operative measurement of the rate of both peak oral and nasal inspiratory flow. RESULTS: Of the 25 participants who completed phase II of the study, 17 (68 per cent) showed an increase in post-operative peak oral inspiratory flow rate by an average of 45 per cent, while 18 (72 per cent) showed an increase in post operative peak nasal inspiratory flow rate by an average of 22 per cent. CONCLUSION: Both peak oral and nasal inspiratory flow rate measurements may be useful measures of oral and nasal obstruction. Further larger studies are needed to develop these measurements as screening and efficacy measures for adenotonsillectomy to relieve upper airway obstruction. PMID- 25936229 TI - Selective estrogen receptor modulators in clinical practice: a safety overview. AB - INTRODUCTION: Selective estrogen receptor (ER) modulators (SERMs) are a class of nonsteroidal compounds that interact with ERs, each with a distinct tissue specific profile. Depending upon the degree of ER agonism/antagonism at the target tissue, SERMs show efficacy for various indications including osteoporosis, dyspareunia, and breast cancer, and are associated with safety risks. AREAS COVERED: This review describes the safety profile of SERMs (tamoxifen, raloxifene, toremifene, bazedoxifene, lasofoxifene, and ospemifene) and fulvestrant (a pure ER antagonist) from Phase III trials, long-term extension studies, and active comparator studies. Tamoxifen, a first-generation SERM, is indicated for breast cancer prevention and treatment but is associated with serious safety concerns including endometrial cancer, venous thromboembolic events (VTE), and stroke. Toremifene, raloxifene, bazedoxifene, lasofoxifene, and ospemifene present generally improved, though distinctly different, safety profiles compared with tamoxifen, especially with endometrial cancer and stroke. However, the risk of VTE remains a concern for most SERMs. EXPERT OPINION: Each SERM presents a unique risk/benefit profile based on varying indications and tissue-specific ER agonist and antagonist effects, making careful patient selection and ongoing patient monitoring crucial aspects of treatment. Future research may focus on identifying new SERMs for endocrine-resistant and endocrine responsive cancers and post-menopausal symptoms. PMID- 25936230 TI - Effectiveness of and risk associated with aspirin therapy in hemodialysis patients with a background of antiplatelet factor 4/heparin complex antibody detection. AB - BACKGROUND: The optimal prevention measures against hemodialysis (HD)-associated complications, including all-cause thrombotic events and death, are unclear. METHODS: This prospective study was designed to assess the effect of aspirin on prevention of HD-associated complications. Patients were divided into four groups according to platelet factor-4/heparin-complex (PF4/H) antibody detection and aspirin prescription: Group 1, antibody(-)/aspirin(+); Group 2, antibody( )/aspirin(-); Group 3, antibody(+)/aspirin(+); and Group 4, antibody(+)/aspirin( ). Adverse events were compared among all four groups. Cox hazard regression was performed to analyze the effects of anti-PF4/H antibody and aspirin on thrombosis and death. RESULTS: This study included 648 patients undergoing HD; 142 were positive for anti-PF4/H antibodies, and 229 had received aspirin before enrollment. During the 4-year follow-up period, 138 patients developed thrombosis, and 63 of these events were anti-PF4/H antibody-associated. A total of 112 patients died; 75 died of coronary heart disease (CHD). Group 4 had a significantly higher incidence of total and anti-PF4/H antibody-associated thrombosis events as well as total and CHD-associated death than did the other three groups. Aspirin had a preventive effect against all adverse events in anti PF4/H antibody-positive patients, but not in antibody-negative patients. Group 1 patients with baseline D-dimer levels of <0.6MUg/mL developed more hemorrhagic events than did patients in the other groups. CONCLUSIONS: Aspirin prevention of thrombosis and death in patients undergoing HD might require consideration of the anti-PF4/H antibody status. In antibody-positive individuals, taking aspirin could improve the prognosis and therefore might be recommended. In antibody negative individuals, prevention was minimal and the bleeding risk was obviously increased; thus, aspirin should be avoided or at least require careful evaluation prior to aspirin treatment. PMID- 25936232 TI - Trends in clinical reproductive medicine research: 10 years of growth. AB - OBJECTIVE: To study the most important metrics of publication in the field of reproductive medicine over the decade 2003-2012 to aid in discerning the clinical, social, and epidemiologic implications of this relatively new but rapidly emerging area in medical sciences. DESIGN: Bibliometric analysis of most cited publications from Web of Science databases. SETTING: Not applicable. PATIENT(S): None. INTERVENTION(S): None. MAIN OUTCOME MEASURE(S): Most productive and frequently cited investigators, institutions, and countries and specific areas of research, scientific collaborations, and comparison of the growth of reproductive medicine research compared with other areas of medical investigation such as obstetrics and gynecology and related science categories. RESULT(S): We found that 90 investigators with more than 1,000 citations had jointly published 4,010 articles. A continued rise in the impact factor of reproductive medicine journals was seen. The number of publications in reproductive medicine grew more rapidly compared with other science categories. Presently 22% of highly cited articles in reproductive medicine research are published in journals belonging to science categories outside reproductive medicine. The most-cited study groups are situated in the Netherlands, Belgium, Spain, the United States, and the United Kingdom, and collaborative studies have been increasing. CONCLUSION(S): Reproductive medicine research and subsequent clinical development have attained scientific growth and maturity. High-quality research is increasingly being published in high-impact journals. The increase in (inter)national collaborations seems to be key to the field's success. PMID- 25936231 TI - Current use of oral contraceptives and the risk of first-ever ischemic stroke: A meta-analysis of observational studies. AB - OBJECTIVE: To evaluate the risk of first-ever ischemic stroke associated with current use of oral contraceptive pills (OCPs), and to describe how the risk was influenced by estrogen dose, progestin type, and study characteristics. METHODS: We obtained relevant articles published between 1970 and March 2014 by conducting a search of Pubmed, Embase and the Cochrane Library. Two investigators independently identified eligible studies based on selection criteria in a two step method. The quality of studies was assessed with the Newcastle-Ottawa scale. Pooled odds ratios were calculated with a random-effects meta-analysis model. RESULTS: A total of 18 independent studies (3 cohort studies and 15 case-control studies) were identified. The overall summary odds ratio for first-ever ischemic stroke risk associated with current OCP use compared with noncurrent OCP use was 2.47 [95% confidence interval (CI), 2.04-2.99]. The risk of ischemic stroke among current OCP users decreased significantly with decreasing estrogen dose: OCPs of >=50MUg ethinyl estradiol (EE), 30-40 ug EE, 20 ug EE and progestin only pills implied odds ratios of 3.28 (95%CI, 2.49-4.32), 1.75 (95%CI, 1.61-1.89), 1.56 (95%CI, 1.36-1.79), and 0.99 (95%CI, 0.71-1.37), respectively. All four generations of progestin were associated with an elevated risk of ischemic stroke, and the risk of ischemic stroke among users of the fourth-generation progestins seemed to be slightly lower than those of other generations of progestins. CONCLUSIONS: Data from observational studies suggest that current use of modern OCPs is associated with an increased risk of first-ever ischemic stroke. OCPs containing lower estrogen doses incline to contribute to a smaller elevated risk of ischemic stroke. PMID- 25936233 TI - Introduction: Childhood implications of parental aging. AB - Men and women are increasingly delaying childbearing to the late 30s, the 40s and beyond. The implications of this societal change on childhood health and well being have only recently been a focus of research. There are known increased perinatal risks associated with increasing maternal age, while paternal age seems to have a potentially greater negative impact on childhood health. Understanding the mechanisms underlying the aging of sperm and eggs, and how these changes impact offspring, is a critical next step as we work to help patients build healthy families. PMID- 25936234 TI - Effect of seminal leukocytes on in vitro fertilization and intracytoplasmic sperm injection outcomes. AB - OBJECTIVE: To investigate the influence of seminal leukocytes on conventional IVF and intracytoplasmic sperm injection (ICSI) outcomes, using a flow cytometry method. DESIGN: Prospective study. SETTING: Tertiary infertility center and research institute. PATIENT(S): One hundred sixty-four couples undergoing conventional IVF or ICSI. INTERVENTION(S): Seminal leukocytes were counted by flow cytometry. MAIN OUTCOME MEASURE(S): Correlation between seminal leukocytes concentration and reproductive outcomes in IVF and ICSI cycles. RESULT(S): The median number of oocytes retrieved, the fertilization and cleavage rate, the median number and grade of embryos transferred, the median number of good-quality embryos transferred, and the median percentage of good-quality embryos from total embryos transferred, in leukocytospermic and non-leukocytospermic patients were not statistically different after either IVF or ICSI. Similarly, there were no significant differences between the two groups for implantation rate and clinical pregnancy rate. Multivariate logistic regression analysis showed that the reproductive outcomes were not influenced by adjustment for female age, infertility diagnosis, number of previous attempts, treatment protocol (GnRH agonist or antagonist), assisted reproduction procedure (IVF or ICSI), and leukocytospermia. By profiling the proper Poisson regression models, no leukocytospermia cut-off value was able to identify the subjects at risk for oocyte fertilization or embryo cleavage failure. CONCLUSION(S): Using a flow cytometry method, we demonstrated that leukocytospermia does not significantly influence IVF or ICSI outcomes. The same results were obtained by using lower or higher cut-off values for leukocytospermia (from 0.2 to 2 * 10(6)/mL). PMID- 25936235 TI - Preconception blood pressure and risk of preterm birth: a large historical cohort study in a Chinese rural population. AB - OBJECTIVE: To examine the relationship between preconception blood pressure (BP) and the risk of preterm birth (PTB) using a historical cohort of reproductive aged women and girls from a Chinese rural population. DESIGN: A historical cohort study established between 2010 and 2013 in People's Republic of China. SETTING: Local family-planning service agencies and maternal-child care service centers. PATIENT(S): A total of 367,425 reproductive-aged women and girls who participated in the National Free Pre-pregnancy Checkups in 2010-2012 and subsequently had a live birth before October 2013. INTERVENTION(S): None. MAIN OUTCOME MEASURE(S): Incidence rates of PTB in reproductive-aged women and girls across preconception BP levels. RESULT(S): Preterm births were defined as babies born alive at 28 to 37 weeks of pregnancy. Compared with the participants with a systolic BP of <120 mm Hg, the multivariable-adjusted odds ratio (OR) for PTB was 0.99 (95% confidence interval [CI]: 0.95-1.03]), 1.21 (95% CI: 1.11-1.32), 1.47 (95% CI: 1.22-1.77), 1.80 (95% CI: 1.25-2.59), and 1.81 (95% CI: 1.20-2.73) for the participants with systolic BP of 120-129, 130-139, 140-149, 150-159, and >=160 mm Hg, respectively. When the participants with normal BP were used as the reference, the adjusted OR for PTB was 1.04 (95% CI: 1.01-1.08), 1.38 (95% CI: 1.25-1.53), and 1.54 (95% CI: 1.21-1.97) for the participants with prehypertension, stage-1 hypertension, and stage-2 hypertension, respectively. In addition, isolated systolic and diastolic hypertension increased the risk of PTB by 55% and 30%, respectively. CONCLUSION(S): Our results indicated a strong linear and independent relationship between BP levels and the risk of PTB in Chinese reproductive-aged women and girls. Maternal hypertension before pregnancy can significantly increase the risk of PTB. PMID- 25936236 TI - Potential long-term risks associated with maternal aging (the role of the mitochondria). AB - The mean age at which women create families in Western society is increasing. This is in spite of the fact that reproduction in later life is subject to various difficulties, such as the lower probability of conception in relation to maternal age, the increase in spontaneous pregnancy loss, and higher obstetric risk. In this review of recent data, we suggest that a fourth effect, the decrease in lifespan of children in relation to the age of conception of the mother, can be added to the list. We discuss this effect in relation to the transmission of the mitochondria exclusively through the female germ line and the effect of age on this organelle. Data from our own studies and the animal literature as a whole suggest that this effect could be due to the transmission of damaged mitochondrial DNA, and further indicate that the effect is more widespread than previously considered. PMID- 25936237 TI - Randomized, controlled trial comparing the efficacy of intrauterine balloon and intrauterine contraceptive device in the prevention of adhesion reformation after hysteroscopic adhesiolysis. AB - OBJECTIVE: To compare the efficacy of heart-shaped intrauterine balloon and intrauterine contraceptive device (IUD) in the prevention of adhesion reformation after hysteroscopic adhesiolysis. DESIGN: Prospective, randomized, controlled trial. SETTING: University hospital. PATIENT(S): A total of 201 women with Asherman syndrome. INTERVENTION(S): Women were randomized to having either a heart-shaped intrauterine balloon or an IUD fitted after hysteroscopic adhesiolysis. The devices were removed after 7 days. A second-look hysteroscopy was carried out 1 to 2 months after the surgery. MAIN OUTCOME MEASURE(S): Incidence of adhesion reformation and reduction of adhesion score before and after surgery. RESULT(S): Initially 201 cases were recruited; 39 cases dropped out, resulting in 82 cases in the balloon group and 80 cases in IUD group. The age, menstrual characteristics, pregnancy history, and American Fertility Society score before surgery were comparable between the two groups. The median adhesion score reduction (balloon group, 7; IUD group, 7) and the adhesion reformation rate (balloon group, 30%; IUD group, 35%) were not significantly different between the two groups. CONCLUSION(S): The heart-shaped intrauterine balloon and IUD are of similar efficacy in the prevention of adhesion reformation after hysteroscopic adhesiolysis for Asherman syndrome. CLINICAL TRIAL REGISTRATION NUMBER: ISRCTN 69690272. PMID- 25936238 TI - Diagnostic evaluation of the infertile female: a committee opinion. AB - Diagnostic evaluation for infertility in women should be conducted in a systematic, expeditious, and cost-effective manner to identify all relevant factors with initial emphasis on the least invasive methods for detection of the most common causes of infertility. The purpose of this committee opinion is to provide a critical review of the current methods and procedures for the evaluation of the infertile female, and it replaces the document of the same name, last published in 2012 (Fertil Steril 2012;98:302-7). PMID- 25936239 TI - Moving innovation to practice: a committee opinion. AB - The introduction of new strategies, tests and procedures into clinical practice raises challenging ethical issues involving evaluation of evidence, balancing benefits and harms, supporting patient autonomy, avoiding conflict of interest, and promoting advances in health care. The purpose of this document is to assist reproductive health practitioners as they introduce new interventions into the clinical care that they provide to patients. PMID- 25936240 TI - Preconception risk stratification before fertility care. PMID- 25936241 TI - Re: "Determining the level of evidence for the effectiveness of spinal manipulation in the upper limb: A systematic review meta-analysis". PMID- 25936242 TI - Translation and validation of the PREE (Patient Rated Elbow Evaluation) to a French version. AB - BACKGROUND: Only a few outcome measures specific to elbow pathology and the assessment of their impacts on function are valid and reliable when used in French speaking populations. The English version of the Patient Rated Elbow Evaluation (PREE) was determined to be an optimal candidate for translation. HYPOTHESIS: A French version of the PREE (PREE-Fr) will be generated and compared to its original version in terms of reliability and responsiveness. MATERIALS AND METHODS: The PREE was translated following the guidelines of the American Academy of Orthopedic Surgeons. Patients with a variety of elbow pathologies completed the French version of the PREE (PREE-Fr), the Quick Disabilities of the Arm, Shoulder and Hand (QuickDASH) and the Mayo Elbow Performance Score (MEPS) on three different occasions. The test-retest reliability of the PREE-Fr was calculated using questionnaires that were filled out with a one-week interval between them. The responsiveness was assessed using questionnaires filled out six months after treatment. RESULTS: A French version of the PREE was generated. Data gathered from 54 patients yielded an intra-class correlation coefficient for reliability of 0.89 (CI95%: 0.79-0.94) for the PREE-Fr. For construct validity, using the Pearson correlation coefficient, we obtained excellent correlation between the PREE-Fr and QuickDASH at day one, one week and six months (0.89-0.96) while that between the PREE and MEPS was good to excellent (0.70-0.95). Responsiveness of the PREE-Fr was assessed and yielded a standardized response mean of 1.03, meaning that a large change was recorded between day one and six months. DISCUSSION: The PREE-Fr should be considered in French speaking populations for patients with elbow pathology, whether it is for research or evaluation purposes as it is valid, reliable and responsive to change. PMID- 25936243 TI - How will I be after my operation for oral cancer? AB - Validated health-related quality of life measures for patients with oral cancer have been available for over a decade. We used the Liverpool head and neck cancer database to identify 1060 patients who had curative operations for primary squamous cell carcinoma of the head and neck at the regional maxillofacial unit between 1995 and 2010. We then produced one-page summary tables for subsites of oral cancer by stage and common treatments based on patient-reported outcomes from the University of Washington quality of life (UWQoL) head and neck cancer questionnaire. Data had been collected in a series of annual surveys. Sites included were buccal and retromolar (n=189), oral tongue (n=358), floor of the mouth (n=321), and other oral sites (n=192). A total of 633 patients completed at least one questionnaire (total 1931) between 9 and 60 months after treatment (71% of those alive at 9 months). Only questionnaires completed around 2 years from diagnosis or operation were analysed. Data include crude survival at 1, 2, and 5 years, the 12 UWQoL domains, which comprise the number of patients who chose the best 2 responses for each, overall health-related QoL, and the number who chose the worst responses (based on an algorithm). The data are sufficiently detailed to be used in discussions with patients about likely outcomes. They can help patients to make decisions about the type of treatment, provide a reference for realistic expectations, and enable them to be better informed when they give their consent. PMID- 25936245 TI - Is the age of genetic surgery finally upon us? AB - This review discusses gene editing and its potential in oncology. Gene editing has not evolved faster towards clinical application because of its difficulty in implementation. There have been many limitations of the tools thought to be useful in therapeutic gene editing. However, recently the combinatorial use of multiple biological tools appears to have broken the barrier impending clinical development. This review gives a short primer on gene editing followed by some of the foundational work in gene editing and subsequently a discussion of programmable nucleases leading to a description of Zinc Finger Nuclease, TALENs and CRISPRs. Gene editing tools are now being used routinely to re-engineer the human genome. Theoretically, any gene or chromosomal sequence for which a targeting site can be identified could be rendered nonfunctional by the chromosomal breakage activity of Zinc Finger Nucleases, TALENs or a CRISPR/Cas9 system. Since the initial work started on the mechanism and regulation of gene editing, investigators have been searching for a way to develop these technologies as a treatment for cancer. The issue is finding a practical application of gene editing in oncology. However, progressive ideas are working their way through the research arena which may have an impact on cancer treatment. PMID- 25936244 TI - The incidence and prognosis of true duodenal carcinomas. AB - INTRODUCTION: Primary duodenal carcinoma (PDC) is a rare gastrointestinal tumor. The difficult distinction between PDC and other types of carcinoma (e.g. within the periampullary region) is reflected in the scarce literature on true duodenal carcinomas. However, this distinction may be important in relation to the overall prognosis as well as in the choice of adjuvant or palliative treatment strategies. The aim of this study was to evaluate the incidence, management and prognosis of patients with true PDC within a well-defined geographical area. METHODS: Retrospective analysis of all patients diagnosed with true PDC from 1997 to 2012 within the Region of Southern Denmark. Only patients where the surgeon and the pathologist agreed on the tumor being classified as originating from the duodenum were included. RESULTS: Seventy-one patients (43 M, 28 F) with a mean age of 67 years (range 35-87) met the criteria for true PDC. The incidence was 5.4 per 1,000,000, and the pathological classification was: Adenocarcinoma 87%, mucinous adenocarcinoma 7%, carcinoma 4% and signet ring cell carcinoma 1%. Intended curative resection was performed in 28 patients (39%) (22 Whipple procedures and 6 local resections), and all but one patient had negative resection margins. Thirteen patients (46%) had lymph node metastasis. Twenty-nine (67%) of the palliative treated patients had a single (n = 24) or double by-pass procedure (n = 5). The median and 5-year survival for the resected patients were 23 months (CI 7-44) and 27% (CI 10-44). The median survival in the palliative group was 5 months (CI 2-11), and none of the patients were alive after three years. CONCLUSION: The incidence of true PDC within a geographical and histopathologically completely monitored area was 5.4 per 1,000,000. Less than 40% of the patients could be resected and they had a median survival of 23 month and an estimated 5-year survival of 27%. The prognosis of true PDC seemed lower than expected according to previously published data. PMID- 25936246 TI - Gene analysis techniques and susceptibility gene discovery in non-BRCA1/BRCA2 familial breast cancer. AB - Breast cancer is the leading cause of cancer deaths in females worldwide occurring in both hereditary and sporadic forms. Women with inherited pathogenic mutations in the BRCA1 or BRCA2 genes have up to an 85% risk of developing breast cancer in their lifetimes. These patients are candidates for risk-reduction measures such as intensive radiological screening, prophylactic surgery or chemoprevention. However, only about 20% of familial breast cancer cases are attributed to mutations in BRCA1 and BRCA2, while a further 5-10% are attributed to mutations in other rare susceptibility genes such as TP53, STK11, PTEN, ATM and CHEK2. A multitude of genome wide association studies (GWAS) have been conducted confirming low-risk common variants associated with breast cancer in excess of 90 loci, which may contribute to a further 23% of the heritability. We currently find ourselves in "the next generation", with technologies offering deep sequencing at a fraction of the cost. Starting off primarily in a research setting, multi-gene panel testing is now utilized in the clinic to sequence multiple predisposing genes simultaneously (otherwise known as multi-gene panel testing). In this review, we focus on the hereditary breast cancer discoveries, techniques and the challenges we face in this complex disease, especially in the light of the vast amount of data we now have at hand. It has been 20 years since the first breast cancer susceptibility gene has been discovered and there has been substantial progress in unraveling the genetic component of the disease. However, hereditary breast cancer remains a challenging topic subject to common debate. PMID- 25936247 TI - Variation in cost of total thyroidectomy across the United States, 2007 to 2008. AB - BACKGROUND: Variation in cost of surgical care across state lines is poorly understood. We sought to examine state-level variation in wage-adjusted total cost (WATC) of a common surgical procedure. METHODS: We performed a retrospective cohort study of patients undergoing total thyroidectomy in the Nationwide Inpatient Sample (2007 to 2008). WATC was calculated from charges and adjusted for the area wage index. Hierarchical linear modeling was used to investigate the variation in WATC explained by variables at the patient, hospital, and state levels. RESULTS: We identified 11,058 eligible patients from 35 states. The overall mean WATC was $8,132; 37% of the WATC variance was because of differences across hospitals, whereas 28% was explained by patient-level factors and 8% because of differences across states. CONCLUSIONS: More than a quarter of the variation in cost of total thyroidectomy was not explained by patient-, hospital , or state-level factors. Further research is needed to understand the unexplained residual variation. PMID- 25936248 TI - Genetic Basis of the Relationship Between Reproduction and Longevity: A Study on Common Variants of Three Genes in Steroid Hormone Metabolism--CYP17, HSD17B1, and COMT. AB - Evolutionary theories of aging predict an antagonistic relationship between fertility and life span in humans, but the genetic basis of this phenomenon is not clear. The variation of three genes in steroid hormone metabolism--CYP17 (rs743572), HSD17B1 (rs 605059), and COMT (rs4680)--was examined to elucidate the genetic basis of the relationship between fertility and life span. A sample of 277 individuals (mean age, 82.9 years) was recruited in 2000. On the basis of mortality data collected in 2009, the sample was divided into two groups of subjects surviving to over 90 years (long-lived) or not (controls). Fertility data (number of children) were collected in the same sample. The HSD17B1 AA genotype was found to be significantly associated (p = 0.0085) with longevity only in the females (estimated odds ratio = 3.77). Because the HSD17B1 AA genotype was also associated with a higher number of children (5.3 +/- 2.1) than the other genotypes (p = 0.006), we may infer that HSD17B1 genotypes could exert a positive pleiotropic action on longevity and fertility. CYP17 and COMT gene variation did not influence either life span or fertility. We then searched the literature for genes studied in relation to both reproduction and aging. A review of the studies showed a pleiotropic action for six out of 16 genes and revealed that genes may exert positive, or negative, or antagonistic pleiotropic actions. These potential actions may be modified by such environmental factors such as changing reproductive behaviors, which seem to be able to mitigate or enhance a gene's phenotypic effects. PMID- 25936249 TI - The neurobiology of aggression and violence. AB - Aggression and violence represent a significant public health concern and a clinical challenge for the mental healthcare provider. A great deal has been revealed regarding the neurobiology of violence and aggression, and an integration of this body of knowledge will ultimately serve to advance clinical diagnostics and therapeutic interventions. We will review here the latest findings regarding the neurobiology of aggression and violence. First, we will introduce the construct of aggression, with a focus on issues related to its heterogeneity, as well as the importance of refining the aggression phenotype in order to reduce pathophysiologic variability. Next we will examine the neuroanatomy of aggression and violence, focusing on regional volumes, functional studies, and interregional connectivity. Significant emphasis will be on the amygdala, as well as amygdala-frontal circuitry. Then we will turn our attention to the neurochemistry and molecular genetics of aggression and violence, examining the extensive findings on the serotonergic system, as well as the growing literature on the dopaminergic and vasopressinergic systems. We will also address the contribution of steroid hormones, namely, cortisol and testosterone. Finally, we will summarize these findings with a focus on reconciling inconsistencies and potential clinical implications; and, then we will suggest areas of focus for future directions in the field. PMID- 25936250 TI - [Disorders of skin appendages]. PMID- 25936252 TI - Parkinson's disease and intensive exercise therapy--a systematic review and meta analysis of randomized controlled trials. AB - OBJECTIVE: To evaluate and compare the effect of 3 intensive exercise therapy modalities - Resistance Training (RT), Endurance Training (ET) and Other Intensive Training Modalities (OITM) - in Parkinson's Disease (PD). Design A systematic review and meta-analysis of randomized controlled trials. METHODS: A systematic literature search was conducted (Embase, Pubmed, Cinahl, SPORTDiscus, Cochrane, PEDro), which identified 15 studies that were categorized as RT, ET or OITM. The different exercise modalities were reviewed and a meta-analysis evaluating the effect of RT on muscle strength was made. RESULTS: In PD intensive exercise therapy (RT, ET and OITM) is feasible and safe. There is strong evidence that RT can improve muscle strength in PD, which is underlined by the meta analysis (g'=0.54 [95%CI 0.22;0.86]). There is moderate evidence that ET can improve cardio-respiratory fitness in PD. RT, ET and OITM may have beneficial effects on balance, walking performance, Unified Parkinson's Disease Rating Scale III (UPDRS-III) score and quality of life in PD, but findings are inconsistent. No studies find deterioration in any outcomes following exercise therapy. CONCLUSION: RT, ET and OITM all represent feasible, safe and beneficial adjunct rehabilitation therapies in PD. PMID- 25936251 TI - [Item 326 - UE 10 Prescription and monitoring of steroidal and nonsteroidal anti inflammatory drugs]. PMID- 25936253 TI - Chronic manganism: A long-term follow-up study with a new dopamine terminal biomarker of 18F-FP-(+)-DTBZ (18F-AV-133) brain PET scan. AB - Recent experimental studies revealed that dopamine neuron dysfunction in chronic manganism may be due to a reduced capacity of dopamine release in the striatum. The findings imposed further difficulty in the differential diagnosis between manganism and IPD. We conducted a long-term clinical follow-up study of 4 manganism patients, applying a new tracer (18)F-9-fluoropropyl-(+) dihydrotetrabenazine ((18)F-AV-133) with positron emission tomography (PET). Twenty age-matched subjects including 4 manganism patients, 8 idiopathic Parkinson's disease (IPD) patients, and 8 healthy controls were enrolled for comparison. Volumes of interest of the bilateral putamen, caudate nuclei and occipital cortex as the reference region were delineated from individual magnetic resonance images. The clinical features of the manganism patients still progressed, with increased scores on the Unified Parkinson Disease Rating Scale. The (18)F-AV-133 uptake in the IPD patients decreased at the bilateral striatum, compared with the healthy controls. In the manganism patients, there was no decreased uptake of radioactivity involving the bilateral striatum, except Patient 4, who had a stroke with decreased uptake in the right posterior putamen. The (18)F-AV-133 PET finding reveals that nigrostriatum neurons are not degenerated in chronic manganism and can provide a useful neuroimage biomarker in the differential diagnosis. PMID- 25936254 TI - Incidence and prevalence of pediatric onset multiple sclerosis in Kuwait: 1994 2013. AB - OBJECTIVES: This study aimed to assess the incidence and prevalence of pediatric onset multiple sclerosis (POMS) along with temporal and gender differentials in these estimates in Kuwait. METHODS: We identified MS patients with pediatric (age <18 years) onset between 1994 and 2013 from national MS registry. Year and gender specific incidence rate and prevalence estimates were computed. Multivariable Poisson regression analyses of time-series cross-sectional panel data were conducted to evaluate temporal and gender related variations in yearly POMS incidence rate and prevalence. RESULTS: 122 POMS patients were identified; of which 90 (73.8%) were females. During 2013, POMS incidence rate and prevalence (per 100,000) were 2.1 and 6.0 respectively. Multivariable Poisson regression model revealed statistically significant 5% increase in POMS incidence rate (p=0.002) and 6% increase in prevalence (p<0.001) from 1994 to 2013. Furthermore, during the study period, female children were more likely to have higher POMS incidence rate (relative rate=2.9; p<0.001) and prevalence (prevalence ratio=2.8; p<0.001). CONCLUSIONS: The temporal increase and gender disparity in POMS incidence and prevalence corroborate the findings of earlier studies conducted elsewhere. Knowledge of increasing POMS burden may help in optimal planning for better management of patients in the region. PMID- 25936255 TI - Lingual dystonia as a new clinical feature in corticobasal syndrome. PMID- 25936257 TI - Lead-oriented synthesis: Investigation of organolithium-mediated routes to 3-D scaffolds and 3-D shape analysis of a virtual lead-like library. AB - Synthetic routes to six 3-D scaffolds containing piperazine, pyrrolidine and piperidine cores have been developed. The synthetic methodology focused on the use of N-Boc alpha-lithiation-trapping chemistry. Notably, suitably protected and/or functionalised medicinal chemistry building blocks were synthesised via concise, connective methodology. This represents a rare example of lead-oriented synthesis. A virtual library of 190 compounds was then enumerated from the six scaffolds. Of these, 92 compounds (48%) fit the lead-like criteria of: (i) 1?AlogP?3; (ii) 14?number of heavy atoms?26; (iii) total polar surface area?50A(2). The 3-D shapes of the 190 compounds were analysed using a triangular plot of normalised principal moments of inertia (PMI). From this, 46 compounds were identified which had lead-like properties and possessed 3-D shapes in under represented areas of pharmaceutical space. Thus, the PMI analysis of the 190 member virtual library showed that whilst scaffolds which may appear on paper to be 3-D in shape, only 24% of the compounds actually had 3-D structures in the more interesting areas of 3-D drug space. PMID- 25936258 TI - Synthesis and biological evaluation of thiabendazole derivatives as anti angiogenesis and vascular disrupting agents. AB - Thiabendazole, already approved by FDA for oral use as an anti-fungal and anti helminthic drug since 1967, has recently been repurposed as a vascular disrupting agent. By optimization of the structure of the lead compound, we successfully identified compound TBZ-19 and the new derivative is over 100-fold more potent than the lead compound against the growth of four different cell lines (A549, HCT 116, HepG2 and HUVECs). The most potent two candidates TBZ-07 and TBZ-19, exhibiting moderate inhibitory cell proliferation activity, were also verified as anti-angiogenesis and vascular disrupting agents. Therefore, TBZ-07 and TBZ-19 would be promising candidates with vasculature targeting activity and merit further development. PMID- 25936259 TI - Novel spirohydantoin derivative as a potent multireceptor-active antipsychotic and antidepressant agent. AB - A series of novel spirohydantoin derivatives with arylpiperazinylbutyl moiety were synthesized and evaluated for serotonin 5-HT1A, 5-HT2A, 5-HT7 and dopamine D2 receptors. Based on these data, four compounds were selected for further binding affinity assays on dopamine D1, D3, D4, and 5-HT2C, 5-HT6 as well as adrenergic alpha1 and alpha2C receptors, which are involved in various CNS diseases such as schizophrenia, anxiety and/or depression. The compound 14, 1-{4 [4-(2-metoxyphe-nyl)piperazin-1-yl]butyl}-3',4'-dihydro-2H,2'H,5H spiro[imidazolidine-4,1'-naphthalene]-2,5-dione, with the most promising functional profile, mixed 5-HT2A/D2 antagonist and 5-HT1A partial agonist, was selected. In the mouse d-amphetamine-induced locomotor hyperactivity model, compound 14 produced antipsychotic-like activity, which is devoid of cataleptogenic effects and in the forced swim test in mice, it showed a significant antidepressant-like effect unlike the reference drug aripiprazole. PMID- 25936260 TI - Synthesis, biological activities and pharmacokinetic properties of new fluorinated derivatives of selective PDE4D inhibitors. AB - A new series of selective PDE4D inhibitors has been designed and synthesized by replacing 3-methoxy group with 3-difluoromethoxy isoster moiety in our previously reported cathecolic structures. All compounds showed a good PDE4D3 inhibitory activity, most of them being inactive toward other PDE4 isoforms (PDE4A4, PDE4B2 and PDE4C2). Compound 3b, chosen among the synthesized compounds as the most promising in terms of inhibitory activity, selectivity and safety, showed an improved pharmacokinetic profile compared to its non fluorinated analogue. Spontaneous locomotor activity, assessed in an open field apparatus, showed that, differently from rolipram and diazepam, selective PDE4D inhibitors, such as compounds 3b, 5b and 7b, did not affect locomotion, whereas compound 1b showed a tendency to reduce the distance traveled and to prolong the immobility period, possibly due to a poor selectivity. PMID- 25936261 TI - Colloidal and antibacterial properties of novel triple-headed, double-tailed amphiphiles: exploring structure-activity relationships and synergistic mixtures. AB - Two novel series of tris-cationic, tripled-headed, double-tailed amphiphiles were synthesized and the effects of tail length and head group composition on the critical aggregation concentration (CAC), thermodynamic parameters, and minimum inhibitory concentration (MIC) against six bacterial strains were investigated. Synergistic antibacterial combinations of these amphiphiles were also identified. Amphiphiles in this study are composed of a benzene core with three benzylic ammonium bromide groups, two of which have alkyl chains, each 8-16 carbons in length. The third head group is a trimethylammonium or pyridinium. Log of critical aggregation concentration (log[CAC]) and heat of aggregation (DeltaHagg) were both inversely proportional to the length of the linear hydrocarbon chains. Antibacterial activity increases with tail length until an optimal tail length of 12 carbons per chain, above which, activity decreased. The derivatives with two 12 carbon chains had the best antibacterial activity, killing all tested strains at concentrations of 1-2MUM for Gram-positive and 4-16MUM for Gram-negative bacteria. The identity of the third head group (trimethylammonium or pyridinium) had minimal effect on colloidal and antibacterial activity. The antibacterial activity of several binary combinations of amphiphiles from this study was higher than activity of individual amphiphiles, indicating that these combinations are synergistic. These amphiphiles show promise as novel antibacterial agents that could be used in a variety of applications. PMID- 25936262 TI - Topoisomerase I and II inhibitory activity, cytotoxicity, and structure-activity relationship study of dihydroxylated 2,6-diphenyl-4-aryl pyridines. AB - A new series of thirty-six dihydroxylated 2,6-diphenyl-4-aryl pyridines containing hydroxyl groups at the ortho, meta, or para position of 2- and 6 phenyl rings attached to the central pyridine were designed and synthesized. They were evaluated for topoisomerase I and II inhibitory activity and cytotoxicity against several human cancer cell lines for the development of novel anticancer agents. Most of the compounds with hydroxyl moiety either at the meta or para position of 2- or 6-phenyl ring in combination with thienyl or furyl group at 4 position of central pyridine displayed significant topoisomerase II inhibitory activity and cytotoxicity. Positive correlation between topoisomerase II inhibitory activity and cytotoxicity was observed for the compounds 9-11, 15-17, 19, 21-23, 28, and 41. Among all the synthesized compounds, compound 17 emerged as the most promising topoisomerase II inhibitor with significant cytotoxicity. PMID- 25936264 TI - The closing-in phenomenon in Parkinson's disease. AB - INTRODUCTION: Closing-in (CI) is a peculiar phenomenon consisting in the tendency to copy drawings close to or superimposed on a model. Recent findings showed that CI can be associated with frontal/executive dysfunctions, likely determining a failure in high-level monitoring of attention-action circuits. CI has been often observed in demented patients, but scarce data are available about CI in patients with Parkinson's disease (PD). In the present study, we detected occurrence of CI and investigated the cognitive processes associated to this phenomenon in a large sample of non-demented PD patients. METHODS: We retrospectively analysed graphic reproductions in a copying task of 100 non-demented PD patients who had also completed cognitive, behavioural, and motor screening assessment. RESULTS: CI phenomenon occurred in 50/100 non-demented PD patients (50%; 118/700 drawings). Among these patients, 46/50 patients copied drawings close to the model (near CI), 2/50 patients superimposed their copy directly on the model (adherent-CI), whereas 2/50 patients showed both near-and adherent-CI. MANOVA showed that non demented PD patients with CI showed more severe impairment on frontal/executive functions and visuo-constructional abilities than non-demented PD patients without CI. However, the logistic regression model revealed that occurrence of CI was significantly associated to lower scores on frontal/executive tasks only. CONCLUSION: CI can be found in a large proportion of non-demented PD patients, and it is related to frontal monitoring defects that could hamper inhibition of action and attention toward a model. PMID- 25936263 TI - Effect of chirality on cellular uptake, imaging and photodynamic therapy of photosensitizers derived from chlorophyll-a. AB - We have previously shown that the (124)I-analog of methyl 3-(1'-m-iodobenzyloxy) ethyl-3-devinyl-pyropheophorbide-a derived as racemic mixture from chlorophyll-a can be used for PET (positron emission tomography)-imaging in animal tumor models. On the other hand, as a non-radioactive analog, it showed excellent fluorescence and photodynamic therapy (PDT) efficacy. Thus, a single agent in a mixture of radioactive ((124)I-) and non-radioactive ((127)I) material can be used for both dual-imaging and PDT of cancer. Before advancing to Phase I human clinical trials, we evaluated the activity of the individual isomers as well as the impact of a chiral center at position-3(1) in directing in vitro/in vivo cellular uptake, intracellular localization, epithelial tumor cell-specific retention, fluorescence/PET imaging, and photosensitizing ability. The results indicate that both isomers (racemates), either as methyl ester or carboxylic acid, were equally effective. However, the methyl ester analogs, due to subcellular deposition into vesicular structures, were preferentially retained. All derivatives containing carboxylic acid at the position-17(2) were noted to be substrate for the ABCG2 (a member of the ATP binding cassette transporters) protein explaining their low retention in lung tumor cells expressing this transporter. The compounds in which the chirality at position-3 has been substituted by a non-chiral functionality showed reduced cellular uptake, retention and lower PDT efficacy in mice bearing murine Colon26 tumors. PMID- 25936266 TI - Evolving Approaches to Tricuspid Valve Surgery: Moving To Europe? PMID- 25936265 TI - Impact of Concomitant Tricuspid Annuloplasty on Tricuspid Regurgitation, Right Ventricular Function, and Pulmonary Artery Hypertension After Repair of Mitral Valve Prolapse. AB - BACKGROUND: For patients undergoing mitral valve (MV) repair, the indications for and results of concomitant tricuspid annuloplasty remain controversial. OBJECTIVES: This study was designed to compare a strategy of routine concomitant tricuspid annuloplasty for moderate tricuspid regurgitation (TR) or tricuspid annular dilation in patients undergoing degenerative MV surgery. METHODS: Of 645 consecutive patients (mean age 57+/-13 years) undergoing primary repair of degenerative mitral regurgitation between 2003 and 2011, 419 (65%) underwent concomitant tricuspid annuloplasty for moderate TR and/or tricuspid annular dilation. These patients were retrospectively analyzed with longitudinal echocardiographic follow-up. RESULTS: Patients undergoing tricuspid valve repair were older (mean age 59.2 years vs. 52.3 years), had worse right and left ventricular function and higher pulmonary artery pressures, and were more likely to have had atrial fibrillation than patients undergoing isolated MV repair (all p<0.05). No significant difference in 30-day mortality, morbidity, or permanent pacemaker requirement was seen between treatment groups. Freedom from moderate TR at 7 years was not significantly different in the 2 groups, but multivariate analysis showed that tricuspid annuloplasty was independently associated with freedom from late moderate TR (p=0.04), and was an independent predictor of recovery of right ventricular function (p=0.02). CONCLUSIONS: In patients with moderate TR or tricuspid annular dilation who were undergoing degenerative mitral repair, concomitant tricuspid annuloplasty is safe, effective, and associated with improved long-term right-sided remodeling. Routine treatment of moderate TR or tricuspid annular dilation at the time of MV repair appears to be beneficial. PMID- 25936268 TI - p63 gene structure in the phylum mollusca. AB - Roles of p53 family ancestor (p63) in the organisms' response to stressful environmental conditions (mainly pollution) have been studied among molluscs, especially in the genus Mytilus, within the last 15 years. Nevertheless, information about gene structure of this regulatory gene in molluscs is scarce. Here we report the first complete genomic structure of the p53 family orthologue in the mollusc Mediterranean mussel Mytilus galloprovincialis and confirm its similarity to vertebrate p63 gene. Our searches within the available molluscan genomes (Aplysia californica, Lottia gigantea, Crassostrea gigas and Biomphalaria glabrata), found only one p53 family member present in a single copy per haploid genome. Comparative analysis of those orthologues, additionally confirmed the conserved p63 gene structure. Conserved p63 gene structure can be a helpful tool to complement or/and revise gene annotations of any future p63 genomic sequence records in molluscs, but also in other animal phyla. Knowledge of the correct gene structure will enable better prediction of possible protein isoforms and their functions. Our analyses also pointed out possible mis-annotations of the p63 gene in sequenced molluscan genomes and stressed the value of manual inspection (based on alignments of cDNA and protein onto the genome sequence) for a reliable and complete gene annotation. PMID- 25936267 TI - A literature review to identify factors that determine policies for influenza vaccination. AB - OBJECTIVES: To conduct a literature review of influenza vaccination policy, describing roles and interactions between stakeholders and the factors influencing policy-making. METHODS: Major databases were searched using keywords related to influenza vaccination, decision-making and health policy. Titles and abstracts were screened according to defined criteria using independent reviewers. Selected articles were analysed and compared against a checklist. RESULTS: 342 papers were identified, but only 111 included. A wide range of countries was represented in articles published in 1994-2012. We identified numerous stakeholders at the national and international level and found a variety of interactions between them. Using these data, we suggest a scheme for the most important stakeholders and their interactions. Determinants of policy-making were mainly related to the vaccine/disease, political-economic context, and stakeholders communication. The most relevant evidence was clinical/epidemiological studies. After the 2009 pandemic: the importance of mathematical modelling and ethical issues was greater; and the need for better communication between stakeholders was emphasised. CONCLUSIONS: The relevance of evidence and factors influencing policy-making varied between countries, according to complex interactions between the stakeholders involved at different levels of decision-making process. These interactions remain unclear, especially at national level, where the most important influenza policy decisions are made. To better define and understand the exact interactions and use of evidence, we recommend undertaking future qualitative studies at national level using small number of countries. PMID- 25936269 TI - Rhubarb extract has a protective role against radiation-induced brain injury and neuronal cell apoptosis. AB - Oxidative stress caused by ionizing radiation is involved in neuronal damage in a number of disorders, including trauma, stroke, Alzheimer's disease and amyotrophic lateral sclerosis. Ionizing radiation can lead to the formation of free radicals, which cause neuronal apoptosis and have important roles in the development of some types of chronic brain disease. The present study evaluated the effects of varying concentrations (2, 5 and 10 ug/ml) of ethanolic rhubarb extract on the neuronal damage caused by irradiation in primary neuronal cultures obtained from the cortices of rat embryos aged 20 days. Brain damage was induced with a single dose of gamma-irradiation that induced DNA fragmentation, increased lactate dehydrogenase release in neuronal cells and acted as a trigger for microglial cell proliferation. Treatment with rhubarb extract significantly decreased radiation-induced lactate dehydrogenase release and DNA fragmentation, which are important in the process of cell apoptosis. The rhubarb extract exhibited dose-dependent inhibition of lactate dehydrogenase release and neuronal cell apoptosis that were induced by the administration of ionizing radiation. The effect of a 10 ug/ml dose of rhubarb extract on the generation of reactive oxygen species (ROS) induced by radiation was also investigated. This dose led to significant inhibition of ROS generation. In conclusion, the present study showed a protective role of rhubarb extract against irradiation-induced apoptotic neuronal cell death and ROS generation. PMID- 25936270 TI - Design and Preclinical Validation of the Composite-Type Optical Fiberscope for Minimally Invasive Procedures of Intrauterine Disease. AB - STUDY OBJECTIVE: Because of the rapid growth of minimally invasive surgical procedures, we developed an ultrathin fiberscopic imaging system for laser surgery that could be an important instrument for clinical use in an office setting. METHODS AND MAIN RESULTS: A new device, consisting of a custom 1.1-mm diameter flexible fiberscope and ytterbium laser-supported ablation system (composite-type optical fiberscope), has been developed to achieve accurate laser irradiation for minimally invasive procedures of intrauterine disease. This system was validated ex vivo with successful laser ablation under observation. This study provides the design, characterization, performance, and preclinical validation of an optimized composite-type optical fiberscope system. The validation of this fiberscope for endometrial ablation was performed in 12 hysterectomy samples. The irradiated spot diameter and depth were (mean +/- SD) 2.80 +/- 0.28 mm and 1.53 +/- 0.58 mm, respectively, in the range of 185 to 400 J. The effects of the laser on endometrial tissue depended strongly on the combined effects of the output power density and duration of irradiation. The new device makes it possible to perform accurate ablation, because our technology concentrated on combining the 2 subsystems into a single prototype capable of simultaneously observing both the endometrial lesion and the laser spot on a monitor. CONCLUSIONS: In conclusion, the feasibility and performance of the composite-type fiberscope system were demonstrated in preclinical studies. PMID- 25936271 TI - Four Cases of Postoperative Pneumothorax Among 2814 Consecutive Laparoscopic Gynecologic Surgeries: A Possible Correlation Between Postoperative Pneumothorax and Endometriosis. AB - STUDY OBJECTIVES: To evaluate the frequency of pneumothorax after laparoscopic surgery and to identify possible correlations to endometriosis. DESIGN: Retrospective review. SETTING: Tokyo University Hospital between 2006 and 2013. PATIENTS: Four patients among a total of 2814 patients with a postoperative pneumothorax. INTERVENTION: Laparoscopic surgery for gynecologic benign disease. The main outcome was the clinical frequency and characteristics of the patients with postoperative pneumothorax. MEASUREMENTS AND MAIN RESULTS: We observed 4 (0.14%) cases of postoperative pneumothorax after laparoscopic surgery, all of whom were diagnosed with endometriomas and developed a right-sided pneumothorax. The incidence of postoperative pneumothorax in 1097 patients with endometriomas was 0.36%, which was significantly higher than those without endometriomas. CONCLUSION: The presence of endometrioma should be considered a risk factor for postoperative pneumothorax in gynecologic laparoscopic surgery. PMID- 25936272 TI - Making the case for change: What researchers need to consider when designing behavior change interventions aimed at improving medication dispensing. AB - There is a growing emphasis on behavior change in intervention development programmes aimed at improving public health and healthcare professionals' practice. A number of frameworks and methodological tools have been established to assist researchers in developing interventions seeking to change healthcare professionals' behaviors. The key features of behavior change intervention design involve specifying the target group (i.e. healthcare professional or patient cohort), the target behavior and identifying mediators (i.e. barriers and facilitators) of behavior change. Once the target behavior is clearly specified and understood, specific behavior change techniques can then be used as the basis of the intervention to target identified mediators of behavior change. This commentary outlines the challenges for pharmacy practice-based researchers in targeting dispensing as a behavior when developing behavior change interventions aimed at pharmacists and proposes a definition of dispensing to consider in future research. PMID- 25936273 TI - Repellent efficacy of DEET, Icaridin, and EBAAP against Ixodes ricinus and Ixodes scapularis nymphs (Acari, Ixodidae). AB - Repellent efficacy of 10% EBAAP (3-[N-butyl-N-acetyl]-aminopropionic acid, ethyl ester) and 10% Icaridin ((2-(2-hydroxyethyl)-1-piperidinecarboxylic acid 1 methylpropyl ester)) were evaluated against 20% DEET (N,N-diethyl-3 methylbenzamide) in human subject trials against ticks. Responses of host-seeking nymphs of the European castor bean tick (Ixodes ricinus L.; Acari: Ixodidae) and the North American blacklegged tick (I. scapularis Say; Acari: Ixodidae) were compared. Tests were carried out according to the US-EPA standard protocol with ethanolic solutions of the active ingredients of repellents being applied to the forearm of 10 volunteers. The upward movement of ticks was monitored until repellent failure taking up to 12.5 h. Application of 20% DEET resulted in median complete protection times (CPT; Kaplan-Meier median) between 4 and 4.5 h, while 10% EBAAP yielded CPTs of 3.5-4h. No significant differences were found between the efficacies of two repellents nor between the two species tested. The median of the CPT of a 10% Icaridin solution was 5h in nymphs of I. scapularis, but 8h in those of I. ricinus (P<0.01). Based on these studies, EBAAP and Icaridin are efficacious alternatives to DEET in their repellent activity against nymphs of the two Ixodes ticks with Icaridin demonstrating particularly promising results against I. ricinus. Future research should investigate whether similar results occur when adult Ixodes ticks or other tick species are tested. PMID- 25936274 TI - Next-generation sequencing as means to retrieve tick systematic markers, with the focus on Nuttalliella namaqua (Ixodoidea: Nuttalliellidae). AB - Nuclear ribosomal RNA (18S and 28S rRNA) and mitochondrial genomes are commonly used in tick systematics. The ability to retrieve these markers using next generation sequencing was investigated using the tick Nuttalliella namaqua. Issues related to nuclear markers may be resolved using this approach, notably, the monotypic status of N. namaqua and its basal relationship to other tick families. Four different Illumina datasets (~55 million, 100 bp reads each) were generated from a single tick specimen and assembled to give 350k-390k contigs. A genome size of ~1 Gbp was estimated with low levels of repetitive elements. Contigs (>1000 bp, >50-fold coverage) present in most assemblies (n=69), included host-derived 18S and 28S rRNA, tick and host-derived transposable elements, full length tick 18S and 28 rRNA, the mitochondrial genome in single contig assemblies and the histone cassette. Coverage for the nuclear rRNA genes was above 1000-fold confirming previous sequencing errors in the 18S rRNA gene, thereby maintaining the monotypic status of this tick. Nuclear markers for the soft tick Argas africolumbae were also retrieved from next-generation data. Phylogenetic analysis of a concatenated 18S-28S rRNA dataset supported the grouping of N. namaqua at the base of the tick tree and the two main tick families in separate clades. This study confirmed the monotypic status of N. namaqua and its basal relationship to other tick families. Next-generation sequencing of genomic material to retrieve high quality nuclear and mitochondrial systematic markers for ticks is viable and may resolve issues around conventional sequencing errors when comparing closely related tick species. PMID- 25936275 TI - Improving biodiversity assessment of anuran amphibians using DNA barcoding of tadpoles. Case studies from Southeast Asia. AB - Amphibian populations are dramatically declining, while their inventory is far from being achieved. Tadpoles are usually overlooked from biodiversity survey, whereas their consideration will optimize species counts and knowledge of their ecological and developmental requirements is essential in conservation planning. Two mitochondrial markers, 16S (397 new sequences obtained) and COI (343 new sequences obtained), are used to test DNA barcoding on a set of larval and adult Asian amphibians represented by 83 recognized species from 65 sites. The advantages and drawbacks of each marker are assessed, COI barcoding being advocated for global DNA barcoding, whereas 16S suits for taxonomically or geographically restricted DNA barcoding. About half of the collected tadpoles were badly identified or incompletely named in the field. All tadpole sequences (except one case of probable introgressive hybridization) were correctly assigned to their respective species. Finally six clusters of tadpole sequences without conspecific adults were revealed, stressing the importance of collecting and taking into account tadpoles in biodiversity survey and conservation planning. PMID- 25936277 TI - Comments on "Key issues in addressing the comorbidity of depression in pediatric epilepsy". PMID- 25936276 TI - Addressing the treatment gap and societal impact of epilepsy in Rwanda--Results of a survey conducted in 2005 and subsequent actions. AB - This study, supported by the Rwandan Ministry of Health and the World Health Organization, was conducted in 2005 to determine the prevalence of epilepsy and its sociocultural perception in Rwanda, as well as epilepsy-related knowledge and practices of health-care professionals (HCPs). A cross-sectional, nationally representative survey was conducted throughout Rwanda by trained investigators. Participants were recruited by random cluster sampling based on the organization of administrative units in the country. Overall, 1137 individuals (62% from rural areas) were interviewed. The prevalence of epilepsy was estimated to be 49 per 1000 people or 41 per 1000 for active epilepsy. Onset of epilepsy before the age of 2years was reported in 32% of the cases. Family history of epilepsy, head trauma, and premature delivery were reported in 53%, 50%, and 68% of the cases, respectively. Most (68%) patients did not receive any medical treatment for epilepsy; 21.5% had received some form of traditional treatment. According to responses from the general population, people with epilepsy should not be entitled to schooling (according to 66%), to work (according to 72%), to the use of public places (according to 69%), or to marriage (according to 66%). Furthermore, 50% believed that epilepsy was untreatable, and 40% thought that it was transmissible. Of the 29 HCPs interviewed, the majority knew the definition of epilepsy and status epilepticus, as well as basic treatment options and side effects. However, 90% believed that treatment was only necessary in the first week after a seizure. Living with epilepsy was associated heavily with stigma, and a significant treatment gap (68%) was identified. Following this study, numerous actions have been taken by the Rwandan government, the Rwandan League Against Epilepsy, and several nongovernmental organizations to increase awareness about epilepsy and to close the treatment gap. An overview of these activities is provided. PMID- 25936278 TI - T2 hyperintense signal in patients with temporal lobe epilepsy with MRI signs of hippocampal sclerosis and in patients with temporal lobe epilepsy with normal MRI. AB - BACKGROUND: Increased MRI T2 signal is commonly present not only in the hippocampus but also in other temporal structures of patients with temporal lobe epilepsy (TLE), and it is associated with histological abnormalities related to the epileptogenic lesion. OBJECTIVE: This study aimed to verify the distribution of T2 increased signal in temporal lobe structures and its correlations with clinical characteristics of TLE patients with (TLE-HS) or without (TLE-NL) MRI signs of hippocampal sclerosis. METHODS: We selected 203 consecutive patients: 124 with TLE-HS and 79 with TLE-NL. Healthy controls (N=59) were used as a comparison group/comparative group. T2 multiecho images obtained via a 3-T MRI were evaluated with in-house software. T2 signal decays were computed from five original echoes in regions of interest in the hippocampus, amygdala, and white matter of the anterior temporal lobe. Values higher than 2 standard deviations from the mean of controls were considered as abnormal. RESULTS: T2 signal increase was observed in the hippocampus in 78% of patients with TLE-HS and in 17% of patients with TLE-NL; in the amygdala in 13% of patients with TLE-HS and in 14% of patients with TLE-NL; and in the temporal lobe white matter in 22% of patients with TLE-HS and in 8% of patients with TLE-NL. Group analysis demonstrated a significant difference in the distribution of the T2 relaxation times of the hippocampus (ANOVA, p<0.0001), amygdala (p=0.003), and temporal lobe white matter (p<0.0001) ipsilateral to the epileptogenic zone for patients with TLE-HS compared with controls but only for the amygdala (p=0.029) and temporal lobe white matter (ANOVA, p=0.025) for patients with TLE-NL compared with controls. The average signal from the hippocampus ipsilateral to the epileptogenic zone was significantly higher in patients with no family history of epilepsy (two-sample T-test, p=0.005). CONCLUSION: Increased T2 signal occurs in different temporal structures of patients with TLE-HS and in patients with TLE NL. The hippocampal hyperintense signal is more pronounced in patients without family history of epilepsy and is influenced by earlier seizure onset. These changes in T2 signal may be associated with structural abnormalities related to the epileptogenic zone or to the nature of the initial precipitating injury in patients with TLE. PMID- 25936279 TI - C-reactive protein in urologic cancers. AB - C-reactive protein is an acute-phase reactant that is elevated in the setting of systemic infections, trauma, and malignancies. Urologic cancers have been shown to promote changes in c-reactive protein levels. Pre-treatment serum levels can predict disease characteristics, extent of disease, and prognosticate survival after intervention in renal cell carcinoma, prostate cancer, bladder cancer, upper tract urothelial carcinoma, and penile cancer. Changes in post-treatment serum levels have also shown promise in determining survival. As a result, c reactive protein has been incorporated into various survival nomograms to improve predictive accuracy. While the association between c-reactive protein and survival in testicular cancer has not been studied, elevated serum levels may correlate with treatment side effects, such as cardiovascular disease and chronic cancer-related fatigue. Understanding the relationship between c-reactive protein and urologic cancers can help physicians determine the appropriate course of treatment and improve patient care. PMID- 25936280 TI - Expression of an Aspergillus niger xylanase in yeast: Application in breadmaking and in vitro digestion. AB - The cDNA of the beta-1,4-endoxylanase of Aspergillus niger US368 was cloned and expressed in Pichia pastoris under the constitutive GAP promoter. The maximum activity obtained was 41 U mL(-1), which was about 3-fold higher than that obtained with the native species. The purified enzyme showed a specific activity of 910 U mg(-1) and a molecular mass of 24 kDa. It had an optimal activity at pH 4 and 50 degrees C, stable in a wide range of pH and in the presence of some detergents and organic solvents. r-XAn11-His6 (recombinant xylanase) was used as an additive in breadmaking. A decrease in water absorption, an increase in dough rising and improvements in volume and specific volume of the bread were recorded. The r-XAn11-His6 was also used in in vitro digestion of barley and wheat bran leading to a decrease of the viscosities and an increase of the reducing sugars and total sugars contents. PMID- 25936281 TI - Ion-induced fabrication of silk fibroin nanoparticles from Chinese oak tasar Antheraea pernyi. AB - Silk protein fibroin in nanoparticles form is a promising material for drug delivery due to its pleiotropic properties, including biocompatibility, biodegradability, ease in fabrication into smaller diameters, high bioavailability, and therapeutic retention at target sites. In the present study, silk nanoparticles are fabricated from regenerated fibroin solution of the Chinese temperate oak tasar Antheraea pernyi by novel ion-induced self-assembly in a very short time under mild conditions. The resultant fibroin nanoparticles range in size from 100 to 500 nm. The molecular conformation of regenerated fibroin changes from alpha-helical to a beta-sheet structure as a rapid function of the ionic strength and the hydrophobic and electrostatic interactions. The mild conditions are potentially advantageous for the encapsulation of sensitive drugs and therapeutic molecules such as doxorubicin hydrochloride, an amphiphilic anticancer therapeutic. In vitro release of doxorubicin from nanoparticles is pH sensitive, with approx. 65% doxorubicin remaining in the fibroin nanoparticles after 11 days. The activity of fibroin nanoparticles on hepatomas indicates the efficacy of the fibroin nanoparticles to maintain the bioactivity of the loaded doxorubicin and impart a dose-dependent cell growth inhibition. The results suggest that Chinese temperate oak tasar silk fibroin nanoparticles can be used as a sustained drug delivery vehicle. PMID- 25936283 TI - Chronotherapeutic drug delivery of Tamarind gum, Chitosan and Okra gum controlled release colon targeted directly compressed Propranolol HCl matrix tablets and in vitro evaluation. AB - The main objective of this investigation is to develop a chronotherapeutic drug delivery of various natural polymers based colon targeted drug delivery systems to treat early morning sign in BP. The polymers such as Tamarind gum, Okra gum and Chitosan were used in the formulation design. A model drug Propranolol HCl was incorporated in the formulation in order to assess the controlled release and time dependent release potential of various natural polymers. A novel polymer Tamarind gum was extracted and used as a prime polymer in this study to prove the superiority of this polymer over other leading natural polymer. Propranolol HCl was used as a model drug which undergoes hepatic metabolism and witnesses the poor bioavailability. The matrix tablets of Propranolol HCl were prepared by direct compression. The tablets were evaluated for various quality control parameters and found to be within the limits. Carbopol 940 was used as an auxiliary polymer to modify the drug release and physicochemical characteristics of the tablets. The in vitro release studies were performed in 0.1N HCl for 1.5h, followed by pH 6.8 phosphate buffer for 2h and pH 7.4 phosphate buffer till maximum amount of drug release. The in vitro release profile of the formulations were fitted with various pharmacokinetic mathematical models and analyzed for release profile. The formulations prepared with Tamarind gum prolonged the release for an extended period of time compared to other polymer based formulation and showed an excellent compression characteristic. PMID- 25936282 TI - Preparation of food grade carboxymethyl cellulose from corn husk agrowaste. AB - Alpha-cellulose extracted from corn husks was used as the raw material for the production of food-grade carboxymethyl cellulose (CMC). Preparation of CMC from husk cellulose was carried out by an etherification process, using sodium hydroxide and monochloroacetic acid (MCA), with ethanol as the supporting medium. Characterizations of CMC were carried out by analyzing the spectra of FTIR, XRD patterns and SEM photomicrographs. Degree of substitution (DS) was determined with respect to particle size using chemical methods. Solubility, molecular weight and DS of CMC increased with decreased cellulose particle sizes. Microbiological testing of the prepared CMC was done by the pour plate method. Concentrations of heavy metals such as arsenic, lead, cadmium and mercury in the purified CMC were measured by Atomic Absorption Spectroscopy technique and found to be within the WHO/FAO recommended value. A comparative study with CMC available in the international market was conducted. The purity of the prepared CMC was higher, at 99.99% well above the purity of 99.5% for standard CMC. High purity CMC showed a yield 2.4 g/g with DS 2.41, water holding capacity 5.11 g/g, oil holding capacity 1.59 g/g. The obtained product is well suited for pharmaceutical and food additives. PMID- 25936284 TI - Macromolecular changes and nano-structural arrangements in gliadin and glutenin films upon chemical modification: Relation to functionality. AB - Protein macromolecules adopted for biological and bio-based material functions are known to develop a structured protein network upon chemical modification. In this study, we aimed to evaluate the impact of chemical additives such as, NaOH, NH4OH and salicylic acid (SA), on the secondary and nano-structural transitions of wheat proteins. Further, the effect of chemically induced modifications in protein macromolecular structure was anticipated in relation to functional properties. The gliadin-NH4OH-SA film showed a supramolecular protein organization into hexagonal structures with 65 A lattice parameter, and other not previously observed structural entities having a characteristic distance of 50 A. Proteins in gliadin-NH4OH-SA films were highly polymerized, with increased amount of disulfide crosslinks and beta-sheets, causing improved strength and stiffness. Glutenin and WG proteins with NH4OH-SA showed extensive aggregation and an increase in beta-sheet content together with irreversible crosslinks. Irreversible crosslinks hindered a high order structure formation in glutenins, and this resulted in films with only moderately improved stiffness. Thus, formation of nano-hierarchical structures based on beta-sheets and disulfide crosslinks are the major reasons of high strength and stiffness in wheat protein based films. PMID- 25936285 TI - Fermentation optimization for the production of bioactive polysaccharides from Cordyceps sinensis fungus UM01. AB - The optimal fermentation conditions and medium for the production of bioactive polysaccharides from the mycelium of Cordyceps sinensis fungus UM01 were investigated by using orthogonal design and high performance size exclusion chromatography coupled with multi-angel laser light scattering and refractive index detector (HPSEC-MALLS-RID). Results showed that the optimal temperature, initial pH, rotation speed, medium capacity (ratio of medium volume to the volume of flask bottle) and inoculums volume for the mycelium growth were 15 degrees C, pH 6.0, 150 rpm, 2/5 (v/v), and 3% (v/v), respectively. Furthermore, bioactive polysaccharides from the mycelium of C. sinensis fungus UM01 were determined as polysaccharide fractions with the molecular weight above 10 kDa. The optimal fermentation medium was determined as a composition of glucose 30.0 g/L, sucrose 30.0 g/L, KH2PO4 1.0 g/L, CaCl2 0.5 g/L, yeast extract 3.0 g/L, and MgCl2 0.1g/L according to the maximum amount of the bioactive polysaccharides (486.16+/-19.60 mg/L) measured by HPSEC-MALLS/RID. Results are helpful to establish an efficient and controllable fermentation process for the industrial production of bioactive polysaccharides from C. sinensis UM01, and beneficial to develop a unique health and functional product in future. PMID- 25936286 TI - Expression and characterization of a lytic polysaccharide monooxygenase from Bacillus thuringiensis. AB - Lytic polysaccharide monooxygenases (LPMOs) are recently discovered oxidative enzymes that are capable of oxidative cleavage of recalcitrant polysaccharides such as chitin or cellulose. Despite the importance of LPMOs in biomass conversion and the large number of lpmo genes in microorganisms, only a few LPMOs have been well studied, and further characterization of these proteins is thus of interest. In this study, a chitin-active AA10 family LPMO from Bacillus thuringiensis subsp. kurstaki, BtLPMO10A, is described. This enzyme generates even-numbered oxidized oligosaccharides as the dominated products from crystalline chitin, however, interestingly, when colloidal chitin is used as the substrate, a ladder of oxidized oligosaccharides is observed. These results provide new insights into the action mode of LPMOs that may be affected by the substrates. PMID- 25936287 TI - The Specificity of Psychological Factors Associated with Binge Eating in Adolescent Boys and Girls. AB - Low self-esteem, lack of interoceptive awareness, perfectionism, body dissatisfaction, dietary restraint, weight teasing, and internalization of the societal body ideal are known to be associated with binge eating (BE) in adolescents. The purpose of the present cross-sectional study was to investigate whether these attributes are BE-specific and whether different patterns exist for boys and girls. We assessed BE, internalizing symptoms and psychological factors in 1039 adolescents from a community sample by self-report. Using multinomial logistic regression and controlling for measured height and weight, we compared adolescents with BE with individuals from a healthy control group and adolescents reporting internalizing symptoms. Individuals from the BE-group reported a greater lack of interoceptive awareness and higher body dissatisfaction than individuals from the healthy control group. Additionally, we found a significant interaction between gender and body dissatisfaction. Internalization of the societal body ideal was related to BE when compared to internalizing symptoms. Results suggest, that the lack of interoceptive awareness and body dissatisfaction display substantial associations with BE, and that the latter effect is especially strong in boys. The internalization of societal standards of beauty emerged as a BE-specific factor and this finding emphasizes the role of the societal body ideal in the nature of eating pathology in boys and in girls. Increasing body satisfaction and the acceptance of realistic body ideals might be effective strategies in preventing eating pathology. PMID- 25936288 TI - Aggression in Children with Conduct Problems and Callous-Unemotional Traits: Social Information Processing and Response to Peer Provocation. AB - Callous/unemotional traits (CU) moderate children's conduct problems (CP) in numerous domains, including social functioning. The present study examined whether CU traits also moderate the aggressiveness of children's social information processing (SIP) and responses to varying intensities of peer provocation. Sixty elementary school-age children (46 males) were grouped into those without CP or CU (controls, n = 32), those with CP but not CU (CP-only; n = 14), and those with both CP and CU (CPCU, n = 14). Participants completed a task that measured two aspects of SIP (response generation and hostile attribution bias) and a computerized reaction time task (CRTT) that measured behavior, affect, and communication before and after provocation under instrumental and hostile aggressive conditions. Children with CPCU generated more aggressive responses than controls on measures of SIP. On the CRTT, all children exhibited reactive aggression following high provocation, but only children with CPCU exhibited proactive aggression, and reactive aggression following low provocation; no differences in affect were found. In a series of exploratory analyses, CPCU children communicated antisocially, while CP-only communicated prosocially. Finally, children with CPCU did not seem to hold a grudge following the final instance of provocation, instead gradually returning to baseline like their non-CU peers. These distinct social cognitive and behavioral profiles hint at different etiologies of CP and CPCU, underscoring the variability of aggression in these populations. PMID- 25936289 TI - Maternal child-feeding practices and dietary inadequacy of 4-year-old children. AB - This study aimed to evaluate the association between maternal perceived responsibility and child-feeding practices and dietary inadequacy of 4-year-old children. We studied 4122 mothers and children enrolled in the population-based birth cohort - Generation XXI (Porto, Portugal). Mothers self-completed the Child Feeding Questionnaire and a scale on covert and overt control, and answered to a food frequency questionnaire in face-to-face interviews. Using dietary guidelines for preschool children, adequacy intervals were defined: fruit and vegetables (F&V) 4-7 times/day; dairy 3-5 times/day; meat and eggs 5-10 times/week; fish 2-4 times/week. Inadequacy was considered as below or above these cut-points. For energy-dense micronutrient-poor foods and beverages (EDF), a tolerable limit was defined (<6 times/week). Associations between maternal perceived responsibility and child-feeding practices (restriction, monitoring, pressure to eat, overt and covert control) and children's diet were examined by logistic regression models. After adjustment for maternal BMI, education, and diet, and children's characteristics (sex, BMI z-scores), restriction, monitoring, overt and covert control were associated with 11-18% lower odds of F&V consumption below the interval defined as adequate. Overt control was also associated with 24% higher odds of their consumption above it. Higher perceived responsibility was associated with higher odds of children consuming F&V and dairy above recommendations. Pressure to eat was positively associated with consumption of dairy above the adequate interval. Except for pressure to eat, maternal practices were associated with 14-27% lower odds of inadequate consumption of EDF. In conclusion, children whose mothers had higher levels of covert control, monitoring, and restriction were less likely to consume F&V below recommendations and EDF above tolerable limits. Higher overt control and pressure to eat were associated, respectively, with higher possibility of children consuming F&V and dairy above recommendations. PMID- 25936290 TI - Watching reality weight loss TV. The effects on body satisfaction, mood, and snack food consumption. AB - The present study investigated the influence of a weight loss reality TV show on body satisfaction, mood and food consumption. Young Australian women (N = 99) first completed baseline measures of state body satisfaction and mood. They were then randomly allocated to either a weight loss or a home renovation programme and were provided with snack foods during viewing. Post-measures included state body satisfaction, state mood and trait dietary restraint and snack food consumption. BMI moderated the relationship between condition and body satisfaction and mood. Larger women experienced less body satisfaction and less positive mood in response to the weight loss programme. Dietary restraint moderated the relationship between condition and food consumption. A greater percentage of women with lower dietary restraint ate in the control condition; whilst a greater percentage of women with higher dietary restraint ate food whilst watching the weight loss programme. These findings highlight the potential negative impact of weight-focused reality TV on mood, body satisfaction and snack food consumption among some women. PMID- 25936292 TI - "Dinner's ready!" A qualitative exploration of the food domain across the lifecourse. AB - The influence of the childhood food domain on adult food-related practices is only partially understood. Through an interpretive study using in-depth life story interviewing and narrative analysis, we aimed to discover how preferences and perceptions relating to the food domain become embodied during childhood, and once embodied, how these influence practices in adulthood. We observed distinct 'food mood' pathways seemingly anchored in childhood memories about dinnertime. One pathway led to food philosophies participants perceived to be beneficial for their health and wellbeing, whilst another led to perceptions of food as a chore and bore they would rather ignore. Parental attitudes were very important to the food domain of childhood, as this is now recalled through life-story narratives. Our findings suggest a positive relationship with the food domain needs to be fostered during childhood for the long-term protection and promotion of health and wellbeing in adulthood. PMID- 25936293 TI - Frequency of the MSTN Lys(K)-153Arg(R) polymorphism among track & field athletes and swimmers. AB - The myostatin (MSTN) Lys(K)-153Arg(R) polymorphism may influence skeletal muscle phenotypes. Carrying the rare R allele was associated with greater muscle mass. PURPOSE: The aim of the present study was to assess the frequency of the MSTN Lys(K)-153Arg(R) polymorphism among Israeli track and field athletes (n=185) and swimmers (n=80). METHODS: Track and field athletes were divided into long distance runners (major event 5000 m-marathon, n=113) and power athletes (major event 100200 m sprints and long jump, n=72). Swimmers were divided into long distance swimmers (major event: 800-1500 m, n=38), and short-distance swimmers (major event: 50-100 m, n=42). The control group included 118 non-athletes healthy participants. RESULTS: Twenty-seven track and field athletes (14.6%) and 7 swimmers (8.8%) were carriers of the rare MSTN R allele, and only two carried the 153RR genotype (0.8%). MSTN 153R allele frequency was significantly higher in top-compared to national-level among long-distance runners (26% versus 8%, p<0.05), short distance runners (16% versus 9%, p<0.05), and all runners combined (20% versus 8%, p<0.05), but not in top- compared to national-level swimmers. The frequency of arginine carriers was significantly greater among long compared to short-distance swimmers (16% versus 2%, p<0.03). CONCLUSION: In contrast to elite endurance and power track and field athletes, the MSTN 153RR genotype was not found in short distance-swimmers, and among the long distance-swimmers it was not associated with top level swimming performance. Whether evaluation of the MSTN K153R polymorphism can be used for sports selection in young athletes needs to be further studied. PMID- 25936291 TI - Depressed affect and dietary restraint in adolescent boys' and girls' eating in the absence of hunger. AB - Data suggest that depressed affect and dietary restraint are related to disinhibited eating patterns in children and adults. Yet, experimental research has not determined to what extent depressed affect acutely affects eating in the absence of physiological hunger (EAH) in adolescents. In the current between subjects experimental study, we measured EAH in 182 adolescent (13-17 y) girls (65%) and boys as ad libitum palatable snack food intake after youth ate to satiety from a buffet meal. Just prior to EAH, participants were randomly assigned to view either a sad or neutral film clip. Dietary restraint was measured with the Eating Disorder Examination. Adolescents who viewed the sad film clip reported small but significant increases in state depressed affect relative to adolescents who viewed the neutral film clip (p < .001). Yet, there was no main effect of film condition on EAH (p = .26). Instead, dietary restraint predicted greater EAH among girls, but not boys (p < .001). These findings provide evidence that adolescent girls' propensity to report restrained eating is associated with their greater disinhibited eating in the laboratory. Additional experimental research, perhaps utilizing a more potent laboratory stressor and manipulating both affective state and dietary restraint, is required to elucidate how state affect may interact with dietary restraint to influence EAH during adolescence. PMID- 25936294 TI - Microcrystalline preparation of akebia saponin D for its bioavailability enhancement in rats. AB - Akebia Saponin D (ASD) or asperosaponin VI is the most abundant constituent of the rhizome of Dipsacus asper, which has been used for the treatment of lower back pain, traumatic hematoma and bone fractures. In recent years, it was reported that ASD was a potential treatment strategy for Alzheimer's disease (AD). However, the low bioavailability of ASD limited its clinical utility. Microcrystalline preparation is one of the effective methods to improve drug absorption. The drugs prepared by different methods can present different solid forms (polymorphs), and different polymorphs have significantly different bioavailabilities. The objective of this study was to prepare ASD polymorphs using the different preparation processes and to evaluate their physicochemical properties and oral absorption. ASD-2 obtained by the antisolvent process was simpler and had higher recovery (78.5%) than that of ASD-1 by a two-step macroporous resin column separation (56.5%). The ASD polymorphs were characterized using differential scanning calorimetry (DSC), thermogravimetry analysis (TGA), powder X-ray diffraction (PXRD) and scanning electron microscopy (SEM). The results revealed that ASD-2 existed in microcrystalline form, while ASD-1 was amorphous. Furthermore, the equilibrium solubility, dissolution in aqueous solution and pharmacokinetic parameters of the samples were determined. ASD-2 showed lower aqueous solubility than that of ASD-1 (p < 0.01). In addition, ASD-2 showed lower dissolution with only 65% of the drug released while ASD-1 had a higher dissolution with 99% of drug released at the end of the 180 min testing period. Although ASD-1 significantly increased solubility and dissolution, the AUC 0-20h of ASD-2 was 4.3 times that of the amorphous ASD-1 in vivo. Data suggest that the microcrystalline preparation of ASD-2 is not only reasonable in economy and suitable for large-scale preparation, but also a promising method to enhance bioavailability of ASD. PMID- 25936295 TI - Is there any role for the hydroxychloroquine (HCQ) in refractory obstetrical antiphospholipid syndrome (APS) treatment? AB - The best therapy regimen for refractory obstetrical antiphospholipid syndrome remains to be determined. Additional treatments with steroids, plasma exchanges and immunoglobulins failed to show any beneficial effect. We present a case of a woman who had a better pregnancy outcome after the administration of hydroxychloroquine (HCQ) as additional treatment. Furthermore, we highlighted that HCQ was able to dramatically reduce the antiphospholipid antibodies levels. PMID- 25936296 TI - Juvenile idiopathic arthritis and physical activity: possible inflammatory and immune modulation and tracks for interventions in young populations. AB - Juvenile idiopathic arthritis (JIA) is a chronic inflammatory disease characterized by persistent joint inflammation that manifests as joint pain and swelling and limited range of joint motion. In healthy subjects, the literature reports that physical activity has an anti-inflammatory effect. In JIA patients, exercise could be used as a therapeutic tool to counteract disease-related inflammation and thereby improve clinical symptoms, although transient flare of pain could be the price to pay. Indeed, in patients with a chronic inflammatory disease, physical activity is prone to exacerbate underlying inflammatory stress. Physical activity improves quality of life and symptoms in JIA patients, but the mechanisms of action remain unclear. This review focuses on the mechanisms underlying exercise-induced immune and hormonal changes. Data on the impact of acute and chronic physical activities on the secretion of hormones and other molecules such as miRNA or peptides involved in the inflammatory process in JIA was compiled and summarized, and the key role of the biological effect of muscle derived interleukin 6 in the exercise-induced modulation of pro/anti-inflammatory balance is addressed. We also go on to review the effect of training and type of exercise on cytokine response. This review highlights the beneficial effect of physical exercise in children with JIA and potential effect of exercise on the balance between pro- and anti-inflammatory response. PMID- 25936297 TI - Different responses of the retinal and cutaneous microcirculation to transient dysmetabolic conditions. AB - OBJECTIVE: This study evaluated the responses of the retinal and cutaneous microcirculation to acute hyperlipidemia and hyperhomocysteinemia. METHODS: Twenty-five clinically healthy men (mean age 24 +/- 2 years) were studied four times in a randomized order, with intervals of at least one week between the two dietary interventions always preceded by a day for baseline assessment. The two interventions consisted of either 0.1 g/kg l-methionine to induce hyperhomocysteinemia or of 500 ml whipping cream (30% fat) to induce hyperlipidemia. Microvascular vasodilator responses to flickering-light and to cutaneous acetylcholine iontophoresis were assessed by retinal vessel analysis and laser Doppler flowmetry respectively. RESULTS: The fat load produced significant increases in triglycerides and total cholesterol which was accompanied by a reduction of the retinal arterial flicker response. Methionine administration induced a threefold increase in homocysteine levels and a concomitant decrease in retinal venous flicker response. Acute hyperlipidemia and hyperhomocysteinemia had no effect on cutaneous microvascular vasodilator responses to acetylcholine. The inter- and intra-subject reproducibility was higher for retinal vessel analysis as compared to laser Doppler flowmetry. CONCLUSION: The retinal microcirculation is more sensitive to metabolic changes than the cutaneous microcirculation and can be reliably assessed by retinal vessel analysis. Reproducibility of retinal vessel analysis may be enhanced by multi-vessel assessment. PMID- 25936298 TI - Acute hyperlipidemia but not hyperhomocysteinemia impairs reflex regulation of the cardiovascular system. AB - BACKGROUND: Elevated circulating lipids and homocysteine may affect autonomic cardiovascular function by decreasing baroreflex sensitivity (BRS) and cardiovagal outflow and by increasing sympathetic drive. METHODS: To test this hypothesis 25 clinically healthy men (mean age 24 +/- 2 years) received 500 ml whipping cream (30% fat) and 0.1 g/kg l-methionine, respectively, at intervals of one week apart to induce hyperlipidemia and hyperhomocysteinemia, respectively. Cardiovascular parameters and endothelial function were assessed before and 2 h after the fat load and before and 4 h after the methionine load, respectively. Cardiovascular responses to sublingual application of a nitrovasodilator and a beta-agonist were also determined. RESULTS: Hyperlipidemia elicited a significant decline in BRS and an increase in heart rate and sympathetic drive. Reductions in BRS were associated with changes in total cholesterol but not with triglycerides or endothelial function. Autonomic and hemodynamic variables remained unaltered during transient hyperhomocysteinemia although there was a trend to lower BRS. Autonomic and hemodynamic responses to pharmacological vasodilation and beta adrenoceptor stimulation were preserved under both conditions. CONCLUSIONS: These data provide experimental support for the concept that acute hyperlipidemia but not hyperhomocysteinemia impairs reflex regulation of the circulatory system. PMID- 25936299 TI - Managing homozygous familial hypercholesterolaemia from cradle to grave. AB - OBJECTIVE: To describe the phenotypic and genotypic features and management of clinically homozygous familial hypercholesterolaemia (FH). METHODS: An analysis of current knowledge based on personal experience and published evidence. RESULTS: Atherosclerotic involvement of the aortic root is common in homozygous FH and can cause death before age 5. Receptor negative patients are at greatest risk, irrespective of whether they have identical mutations (homozygous) or dissimilar mutations (compound heterozygous). CONCLUSIONS: Lipoprotein apheresis combined with high dose statin and ezetimibe slows but does not arrest progression of atherosclerosis. Adjunctive use of novel compounds such as lomitapide and evolocumab should facilitate achieving the latter objective by enhancing the reduction in LDL cholesterol. PMID- 25936301 TI - Mipomersen and lomitapide: Two new drugs for the treatment of homozygous familial hypercholesterolemia. AB - Familial hypercholesterolemia (FH) is a disease associated with very high plasma concentrations of low-density lipoprotein cholesterol (LDL-C) and premature cardiovascular disease. It is difficult in these high risk patients, exposed lifelong to very high LDL-C, to reach target LDL-C concentrations, which require >50% LDL-C reduction, even when on maximally tolerated statin therapy and on apheresis if available. Therefore, there is an unmet need for new therapeutic options for these patients. In 2013 two new drugs were approved for the treatment of homozygous FH, namely the apolipoprotein B synthesis inhibitor mipomersen and the microsomal transfer protein inhibitor lomitapide. Objective of this narrative review is to discuss the available evidence on the safety and efficacy profile of these new drugs. PMID- 25936300 TI - PCSK9 antibodies: A new class of lipid-lowering drugs. AB - The serine protease proprotein convertase subtilisin/kexin type 9 (PCSK9) binds to the low-density lipoprotein (LDL) receptor (LDLR) and directs it to the lysosome for degradation. This results in decreased numbers of LDLR available on the cell surface to bind LDL particles and remove them from the circulation and a subsequent increase in circulating LDL-cholesterol (LDL-C) concentrations. Since the role PCSK9 plays in LDL-C metabolism has been discovered in 2003, there have been major efforts in finding efficient and safe methods to inhibit it. Amongst those, the PCSK9 antibodies are the furthest in development, with multiple phase III and cardiovascular endpoint trials already underway. These fully human monoclonal antibodies have been extensively studied in a wide range of subjects such as in those with statin intolerance, as add-on to statin therapy, as monotherapy and in patients with familial hypercholesterolemia. PCSK9 antibodies have shown to be associated with a consistent robust additional decrease in LDL-C concentrations of around 50-70%. If the safety data from the ongoing phase III trials remain as reassuring as the data available till now, PCSK9 antibodies are going to offer a new, powerful therapeutic option to decrease LDL-C concentrations and hopefully cardiovascular risk. PMID- 25936302 TI - Lipoprotein apheresis for Lp(a)-hyperlipoproteinemia with progressive cardiovascular disease--Additional particular aspects of the Pro(a)LiFe multicenter trial. AB - Lipoprotein apheresis (LA) can lower LDL-cholesterol and Lp(a) by 60%-70% and is the final escalating option in patients with hyperlipoproteinemias involving LDL or Lp(a) particles. Major therapeutic effect of LA is preventing cardiovascular events. In Germany since 2008 a reimbursement guideline has been implemented accepting to establish the indication for LA not only for familial or severe forms of hypercholesterolemia but also based on Lp(a)-hyperlipoproteinemia associated with a progressive course of cardiovascular disease, that persists despite effective treatment of other concomitant cardiovascular risk factors. The Pro(a)LiFe-study confirmed with a prospective multicenter design that LA can be regarded as an important therapeutic approach to effectively reduce Lp(a) plasma levels and prevent cardiovascular events in this particular high-risk patient group. Results support that Lp(a) may be a major causal factor for precipitating mechanisms of accelerated progression of cardiovascular disease (CVD). Indication for LA based on measurement of Lp(a) as part of risk assessment is supported by the following conditions: progressive CVD as assessed clinically and with imaging techniques, established maximally tolerated lipid lowering drug treatment, recent cardiovascular events despite efficient drug treatment, out of the ordinary frequency of cardiovascular events, early CVD, or positive family history of early CVD. Still existing difficulties with Lp(a) laboratory measurement require a practical approach to establish the indication for LA considering the 60 mg/dl threshold of German guidelines with selecting an Lp(a) assay which has been calibrated for mass. PMID- 25936303 TI - First data from the German Lipoprotein Apheresis Registry (GLAR). AB - OBJECTIVE: In recent years the Federal Joint Committee (G-BA), a paramount decision-making body of the German health care system challenged the approval of diagnostic and therapeutic procedures for regular reimbursement, including lipoprotein apheresis therapy. Years before an interdisciplinary German apheresis working group, established by members of both German Societies of Nephrology (Verband Deutsche Nierenzentren (VDN), Deutsche Gesellschaft fur Nephrologie (DGfN)), initiated a revision of the indication of lipoprotein apheresis therapy according to current guidelines and recommendations for the treatment of lipid disorders. This working group was convinced, that data derived from a registry would support lipoprotein apheresis as a therapy for severe hyperlipidemic patients suffering from progressive cardiovascular diseases. METHODS AND RESULTS: In 2009 the working group established the indication for lipoprotein apheresis with respect to current cardiovascular guidelines and scientific knowledge for the registry, which are in line with the reimbursement guidelines. In 2011 financing by sponsors was secured and an internet-based registry was created. A pilot project with 5 apheresis centers finished in 2012 - since then the registry is available to all German apheresis centers. CONCLUSIONS: There has been consensus between the medical societies and health care carriers regarding the need for a German Lipoprotein Apheresis Registry (GLAR). The launch of this registry complies with requirements of the Federal Joint Committee (G-BA). Complementing the Pro(a)LiFe-Study, first data from GLAR support the safety of the different apheresis treatment procedures. In addition these first data suggest, with respect to the results of Pro(a)LiFe-Study, effectiveness in preventing cardiovascular progression as well. Here, further data are needed to statistically substantiate these early findings. PMID- 25936304 TI - Adverse events of lipoprotein apheresis and immunoadsorption at the Apheresis Center at the University Hospital Dresden. AB - BACKGROUND: Lipoprotein apheresis and immunoadsorption methods have a firm place among therapeutic approaches in order to treat disorders of lipoprotein metabolism or anti-body induced diseases. The extracorporeal treatment is associated with adverse effects, we wanted to report the Dresden experience. METHODS: In this study we retrospectively analyzed the adverse events of several lipoprotein apheresis and immunoadsorption methods at the Apheresis Center in Dresden (Germany). We carefully looked into all available documents. The first extracorporeal lipoprotein apheresis was performed in 1990 and the first extracorporeal immunoadsorption was executed in 1995. Throughout the 23 years study period, 10 different methods were employed in treating 268 patients for a total of 25,293 treatments. RESULTS: Adverse events of varying severity occurred in 1948 of the treatments (7.7%). We subdivided them into mild (61.3% no treatment was necessary), moderate (37.0% oral medication or infusion was given) and severe (1.7% emergency hospitalization was necessary). Therapy had to be stopped prematurely in 1.5% of the treatments. We compared adverse events profiles among the different methods and evaluated for differences by gender. Females were found to have a significantly higher risk of adverse events than male patients. In males, the rate of adverse events ranged from 3.3% (Liposorber((r)) D) to 11% (TherasorbTM Ig); in females the minimum rate was 7.8% (DALI) and the maximum 30% (rheopheresis). Adverse events were evenly distributed between the ages of 30-69, the age range at which most of the therapies were performed. We also found that all methods had a higher rate of adverse events during the first year of treatment. Puncture problems and hypotension were the most common adverse events. CONCLUSION: It can be stressed that in general the extracorporeal methods used can be regarded as safe. PMID- 25936305 TI - Lowering of lipoprotein(a) level under niacin treatment is dependent on apolipoprotein(a) phenotype. AB - BACKGROUND: Lipoprotein(a) [Lp(a)] is a cardiovascular risk factor; in addition to being a low-density lipoprotein (LDL)-like particle, it contains highly heterogeneous apolipoprotein(a) [apo(a)]. No prior studies have evaluated extended-release (ER) niacin effect on Lp(a) level depending on apo(a) phenotype. METHODS: For this 24-week, prospective, open-label clinical trial we recruited 30 men (mean age 46.2 +/- 7.5 years) with Lp(a) levels >20 mg/dL. No participant had previously received lipid lowering therapy, and started ER niacin 500 mg with stepwise dose increasing up to 1.5-2.0 g. Subjects were evaluated for Lp(a), lipids, high-sensitivity C-reactive protein, lipoprotein-associated phospholipase A2 (Lp-PLA2), and fibrinolytic markers (plasminogen activator inhibitor-1, tissue plasminogen activator/plasminogen activator inhibitor-1 complex, plasmin antiplasmin complex). Patients were divided into two groups with major low- (LMW) or high-molecular weight (HMW) apo(a) isoforms determined by sodium dodecyl sulfate-polyacrylamide gel electrophoresis of plasma under reducing conditions followed by immunoblotting. RESULTS: At baseline, groups were comparable in age, lipid, inflammatory and fibrinolytic biomarkers levels. There was a significant difference in baseline Lp(a) concentrations: 92 +/- 29 mg/dL versus 54 +/- 46 mg/dL in LMW and HMW apo(a) groups, respectively, p < 0.01. During the course of niacin treatment Lp(a) decreased by 28% (p < 0.003), Lp-PLA2 by 22% (p < 0.001), C-reactive protein by 24% (p = 0.07) in LMW apo(a) group, whereas no changes in Lp(a) and biomarkers levels were obtained in HMW apo(a) group. CONCLUSION: High dose ER niacin declines elevated Lp(a) level in male subjects with low- but not high-molecular weight apo(a) phenotype. PMID- 25936306 TI - Impact of high-fat diet and voluntary running on body weight and endothelial function in LDL receptor knockout mice. AB - OBJECTIVE: Obesity and physical inactivity are important cardiovascular risk factors. Regular physical exercise has been shown to mediate beneficial effects in the prevention of cardiovascular diseases. However, the impact of physical exercise on endothelial function in proatherosclerotic low-density lipoprotein receptor deficient (LDLR(-/-)) mice has not been studied so far. METHODS: Six week-old male LDLR(-/-) mice were fed a standard diet or a high-fat diet (39 kcal% fat diet) for 20 weeks. The impact of high-fat diet and voluntary running on body weight and amount of white adipose tissue was monitored. Basal tone and endothelial function was investigated in aortic rings using a Mulvany myograph. RESULTS: LDLR(-/-) mice on high-fat diet had increased cumulative food energy intake, but also higher physical activity compared to mice on control diet. Body weight and amount of visceral and retroperitoneal white adipose tissue of LDLR(-/ ) mice were significantly increased by high-fat diet and partially reduced by voluntary running. Endothelial function in aortae of LDLR(-/-) mice was impaired after 20 weeks on standard and high-fat diet and could not be improved by voluntary running. Basal tone showed a trend to be increased by high-fat diet. CONCLUSION: Voluntary running reduced body weight and amount of white adipose tissue in LDLR(-/-) mice. Endothelial dysfunction in LDLR(-/-) mice could not be improved by voluntary running. In a clinical context, physical exercise alone might not have an influence on functional parameters and LDL-C levels in patients with familial hypercholesterolemia. However, physical activity in these patients may be in general beneficial and should be performed. PMID- 25936307 TI - Treatment of antibody-mediated rejection including immunoadsorption during first year after renal transplantation--Clinical results and regulation of endothelial progenitor cells. AB - OBJECTIVE: Antibody-mediated rejection (AMR) is associated with poor allograft survival. Therefore, effective treatment strategies are required. Extracorporeal strategies are increasingly included in treatment of antibody-mediated rejection to eliminate the detrimental alloantibodies. Yet, other mechanisms contributing to the beneficial effect of apheresis besides the removal of antibodies are under consideration. METHODS: We retrospectively analyzed data of 427 transplant patients from 2006 to 2013 with special focus on occurrence, treatment - always including immunoadsorption - and 12-months outcome of antibody-mediated rejection. Besides, we prospectively monitored how the number and phenotype of endothelial progenitor cells in four patients experiencing antibody-mediated rejection changed during the treatment course of 6-20 sessions of immunoadsorption in comparison to seven patients subjected to immunoadsorption because of preparation for ABO-incompatible transplantation. RESULTS: 24 patients were diagnosed with acute AMR and treated with immunoadsorption resulting in patient and allograft survival of 100% and 87.5%, respectively. In patients with antibody-mediated rejection, the endothelial progenitor cell number after successful immunoadsorption therapy was always transiently decreased and the adhesive and migratory ability improved. This regulation of circulating endothelial precursor cells was not seen in patients undergoing repetitive immunoadsorptions before ABO-incompatible transplantation. CONCLUSION: Combined therapy with immunoadsorption allows a successful treatment of AMR. Treatment seems to be associated with a transient regulation of circulating endothelial precursor cells. PMID- 25936308 TI - Treatment of minor severe acquired haemophilia. Is there a rationale for immunoadsorption? AB - OBJECTIVES: In Acquired Haemophilia (AH) autoantibodies against blood coagulation factors, mainly FVIII, inhibit the blood coagulation cascade. The clinical symptoms can vary from minor to severe life threatening bleedings. At present it is unclear if the intensity of the treatment needs to be adapted to the severity of the disease. METHODS: The clinical data and long term outcome from 20 patients suffering from minor severe AH were summarized. Bleedings requiring no blood transfusions were defined as less severe. In case of FVIII concentration <5% an immunosuppressive treatment (IT) consisting of cyclophosphamide 1-2 mg/kg BW/d and/or prednisolone 1-2 mg/kg BW/d was initiated. RESULTS: IT induced complete remission (CR) in only 40% of patients (8/20) after a mean time of 133.4 d (+/ 90.7 d). Treatment associated severe side effects occurred in all patients. 15 patients required a factor substitution therapy due to proceeding bleedings. In 7 patients a partial remission (PR) of AH could be achieved; bleedings progressed in 5 of them and they underwent successfully second line immunoadsorption-based protocol. The inhibitor titer differed statistically significant between CR and PR with a mean of 3.7 BU vs. 16 BU. 5 patients had a fatal outcome mainly due to severe disease associated co morbidities. CONCLUSION: Immunosuppressive treatment failed in nearly a half of AH patients. Mortality was with 25% still high. The majority of patients required an intense long-term IT and developed severe treatment related side effect. Immediate start of IT did not control bleeding. In consequence, less severe AH also should be treated with a more rigorous regime because the occurrence of minors bleedings at initial presentation is not a predictive of clinical outcome. An Immunoadsorption-based protocol should be considered first line or even as a salvage strategy. PMID- 25936309 TI - Long-term therapeutic efficacy of lipoprotein apheresis on circulating oxidative stress parameters--A comparison of two different apheresis techniques. AB - BACKGROUND: A chronic lipoprotein apheresis therapy leads to an expressed reduction in the incidence of cardiovascular events in high-risk patients. In addition to the elimination of atherogenic lipoproteins such as LDL and lipoprotein(a), an antioxidative effect of lipoprotein apheresis has been suspected. OBJECTIVES AND METHODS: We investigated long-term biochemical effects in sixteen patients undergoing lipoprotein apheresis - lipid filtration (LF, n = 7) or dextran sulfate adsorption (DSA, n = 9). Systemic oxidative stress markers (blood phagocyte chemiluminescence, levels of oxidized LDL and antioxLDL antibodies) were examined at the 1st, 40th and 80th apheresis sessions. RESULTS: In DSA patients, the 80th apheresis session was associated with significantly higher LDL cholesterol removal and lower HDL cholesterol deprivation as compared to LF patients. In contrast to LF patients, DSA patients showed a long-term progressive decrease in circulating oxidant generating activity as evaluated by whole blood chemiluminescence (p < 0.05). Moreover, a single LF apheresis session was associated with higher systemic generation of reactive oxygen species over time. CONCLUSION: Compared to LF, long-term DSA apheresis is associated with a gradual reduction of circulating oxidative burden and may be considered a beneficial molecular mechanism of this technique. PMID- 25936310 TI - Treatment of primary hypertriglyceridemia states--General approach and the role of extracorporeal methods. AB - Hypertriglyceridemia (HTG) is a common metabolic disorder in which the concentration of very low density lipoproteins (VLDL) and of chylomicrons (CMs) is elevated in the plasma. HTG may be caused by primary and/or secondary causes and affected subjects may express HTG when children or in adulthood. In children and adults a genetic cause may underlie HTG which can be expressed as CMs a severe clinical picture known as Familial Hyperchylomicronemia due to lipoprotein lipase (LPL) or apolipoprotein (apo) CII deficiencies. Genetically determined HTG includes Familial Dysbetalipoproteinemia due to deficiency of apolipoprotein EIII of VLDL and Familial HTG. However, recent data suggest that classical Fredrickson phenotypes describing clinically HTG, which were once considered to be distinct based on biochemical features, have a shared genetic set up. The HTG has been classified according to a recent international paper: mild HTG: 2-10 mmol/L (176 882 mg/dL); severe HTG: > 10 mmol/L (>882 mg/dL) associated to CMs remnants, or Intermediate Density lipoprotein (IDL) like particles, and/or CMs. The treatment includes limitation of dietary content of saturated fat and alcohol, fibrates and omega3 fatty acids. When TG are severely elevated and associated to CMs the risk of acute pancreatitis suggests the use of more drastic therapeutic option such as therapeutic plasma exchange. This paper summarizes the experience with conventional plasmapheresis (Plasma-Exchange, PEX) and different Lipoprotein Apheresis methods with respect to acutely lowering TG levels in patients with normal TG, with mild and severe HTG. Upcoming promising therapies are gene therapy, novel apolipoprotein CIII inhibitors and lomitapide. PMID- 25936311 TI - Effects of different lipoprotein apheresis methods on serum protein levels. AB - BACKGROUND: A total plasma exchange was the first extracorporeal method to treat patients with severe hypercholesterolemia. But in the long run it has several disadvantages. The newer lipoprotein apheresis (LA) methods claim to be more selective with respect to the removal of atherogenic lipoproteins and thus are supposed to avoid an additional protein loss. METHODS: We wanted to compare the effect of these methods on serum protein concentrations (total serum protein, albumin, proteins measured with electrophoresis, immunoglobulins, fibrinogen, transferrin, and ferritin) which were checked before and after a single LA session in 75 patients. All patients underwent active LA treatment using 6 different LA methods (HELP, TheraSorb((r)) LDL, DALI, Lipidfiltration, Liposorber D, MONET). Post-apheresis concentrations were corrected for changes in hematocrit. RESULTS: The slightest impact on total serum protein was observed with the whole-blood methods. Liposorber D showed the least reduction of albumin levels. All LA methods had a small effect on alpha1-globulins and beta-globulins, but alpha2-and gamma-globulins were reduced to a different extent. A major effect was seen on the immunoglobulins when filtration methods were applied. In the patients treated with MONET, both pre- and post-apheresis Immunoglobulin M concentrations were below the normal range. HELP and the filtration methods significantly reduced the fibrinogen concentrations. The filtration methods also decreased ferritin levels but the post-apheresis ferritin levels were still in the normal range. CONCLUSION: All LA methods had an influence on protein concentrations. At present, these findings will not yield an individualized treatment approach for any selective LA method due to the lack of prospective comparative studies. At minimum, special attention should be paid to protein concentrations in patients suffering from protein deficit. PMID- 25936312 TI - The impact of lipoprotein apheresis in patients with refractory angina and raised lipoprotein(a): Objectives and methods of a randomised controlled trial. AB - It is well established that Lipoprotein(a) [Lp(a)] is an independent cardiovascular risk factor and predictor of major adverse cardiovascular events. Lipoprotein apheresis is currently the most effective approved treatment available, with minimal effect conferred by conventional lipid lowering agents. A growing body of evidence suggests that aggressively lowering raised Lp(a) may improve cardiovascular and clinical outcomes, although more prospective research is required in this field. Angina which is refractory to conventional medical therapy and revascularisation is extremely challenging to manage. There is a significant unmet need to establish therapeutic options. Our goal is to determine the impact of lipoprotein apheresis on clinical parameters and symptoms of patients with refractory angina secondary to advanced coronary disease and raised Lp(a). Determining whether we should aggressively lower Lp(a) in such patients remains a very important question, which could potentially impact on the management of a large population. We will also gain insight into how this treatment works and the mechanisms via which Lp(a) increases cardiovascular risk. We are currently conducting a prospective, randomised controlled crossover study of patients with refractory angina and raised Lp(a), randomised to undergoing three months of weekly lipoprotein apheresis or sham apheresis. Patients will then crossover to the opposite study arm after a 1 month wash-out phase. We will assess myocardial perfusion, carotid atherosclerosis, endothelial vascular function, thrombogenesis, oxidised LDL and their antibodies, exercise capacity, angina and quality of life at the beginning and end of treatment, to determine the net true treatment effect on the above parameters. This is a novel area of research, as previous studies have not assessed the role of lipoprotein apheresis in patients with refractory angina and raised Lp(a) in a prospective randomised controlled manner. PMID- 25936313 TI - Increasing HDL-cholesterol and prevention of atherosclerosis: A critical perspective. AB - The relationship between atherosclerosis and HDL is more complex than between LDL and atherosclerosis. Low HDL-cholesterol is associated with atherosclerotic disease not in a causal way but because low HDL-cholesterol reflects an increased concentration of triglyceride-rich lipoproteins. At the same time the functionality of the HDL system plays an important role in atherosclerosis prevention (for example by mediating reverse cholesterol transport). However, these two observations are not directly linked to each other. Therefore therapeutic strategies must either aim at decreasing the concentration of triglyceride-rich lipoproteins (and thereby increase HDL-cholesterol concentration) or at improving HDL function (which may or may not affect HDL cholesterol concentration). Simply increasing HDL-cholesterol concentration without improving function or decreasing triglyceride-rich lipoproteins will not be beneficial with respect to atherosclerosis prevention. PMID- 25936314 TI - Antibodies against AT1-receptor in transplantation (diagnostics, treatment, clinical relevance). AB - BACKGROUND: The influence of ATR-1-autoantibodies on antibody mediated rejection (AMR) is still discussed controversially. Here we demonstrate some aspects as to diagnostics, treatment, clinical relevance and graft outcome. METHODS: A total of 27 transplant recipients (6 heart, 16 kidney, 3 lung and 2 multi-organ) suffering from AMR and a control group without transplant (8 pre-Tx, 1 pregnancy and 16 autoimmune and haematological diseases) were studied. In total, 290 IA eluates and the corresponding patient serum samples before and after immunoadsorption (IA) were analysed. RESULTS: ATR-1-and ETR-auto-antibodies (aAB) were found only in 4.5% of sera previous to IA treatment by using ELISA, but could be detected in 42% of IA eluates. AB with very high titres (>1:8 to 1:256) in the eluate were found more frequently in heart than in kidney recipients. These strong aAB are clinically relevant and cause dysfunction or loss of the grafts. A quick and reliable diagnosis of the aAB is essential for successful application of the therapeutic possibilities, like removal of the pathogenic autoantibodies or the blockage of their actions. CONCLUSION: The use of eluates for antibody detection was more sensitive and more reliable than patient serum. Yet, the test results are only meaningful when AB titres are measured, as this allows for a quick statement about the actual antibody elimination. The removal of pathogenic aAB via IA is better than medication-based treatment. PMID- 25936315 TI - Immunoadsorption with regenerating systems in neurological disorders --A single center experience. AB - In recent years, immunoadsorption is increasingly recognized as an alternative treatment approach replacing therapeutic plasma exchange in a variety of neurological disorders. While most experience is based on the application of single-use tryptophan adsorbers, less data exists on the application of more efficient regenerating adsorber columns. We here report the systematic use of a regenerating adsorber system in various neurological indications such as multiple sclerosis, encephalitis, myasthenia gravis and chronic inflammatory demyelinating polyneuropathy, providing the expected treatment success in regard to reduction of immunoglobulins and antibody clearance, together with a low rate of adverse events. As it has been shown for single-use columns before, immunoadsorption with regenerating adsorbers can be successfully applied in disorders without known specific antibodies such as multiple sclerosis. Regenerating systems offer the perspective to provide a more efficacious long term treatment perspective for such patients. PMID- 25936316 TI - Immunoadsorption can improve cardiac function in transplant candidates with non ischemic dilated cardiomyopathy associated with diabetes mellitus. AB - BACKGROUND: Diabetes mellitus (DM) is a risk factor for death from heart failure (HF) in patients with dilated cardiomyopathy (DCM) but DM patients are less eligible for heart transplantation (HTx) and DM is a risk factor for death also after HTx. New therapies are therefore necessary to improve survival of diabetic DCM patients. Immunoadsorption (IA) can improve heart function in DCM but its usefulness for therapy of DM-associated DCM is unknown. We assessed this aspect. METHODS: Cardiac function and HTx-free survival were evaluated in diabetic HTx candidates with DCM who underwent IA (Globaffin((r)), a broadband-immunoadsorber containing synthetic peptide-GAM((r))) in 6/2003-6/2012 (follow-up 1-10 yrs). Non diabetic HTx-candidates with DCM who received IA in the same time-period served as controls. Before and after IA patients were tested for serum beta1 autoantibodies (beta1-AABs). RESULTS: We evaluated 31 patients with and 31 without DM. Before IA there were no differences between the 2 groups in LV size, LVEF and beta1-AAB levels. However, DM patients were older, their HF duration was longer and their peak oxygen-uptake was lower (p < 0.005). During the 1st post-IA year in both groups there was a decrease in LV size and improvement in both LVEF and NYHA-class (p < 0.05). Post-IA 3-year HTx-free survival and prevalence of responders to IA in patients with and without DM was 81.3 +/- 8% and 78.4 +/- 8%, respectively and 73.3% and 67.7%, respectively. Post-IA 3-year freedom from beta1 AAB reappearance in patients with and without DM reached 72.1 +/- 9.0% and 71.1 +/- 8.6%, respectively. CONCLUSIONS: IA improves heart function, exercise tolerance and Tx-free survival in patients with DM-associated end-stage DCM. Our results also suggest that IA can delay HTx-listing, improve survival on HTx lists and even spare some diabetic patients from HTx, benefits of particular importance for these patients who are at high risk for pre-HTx and post-HTx mortality. PMID- 25936317 TI - Pregnancy in homozygous familial hypercholesterolemia--Importance of LDL apheresis. AB - INTRODUCTION: Rare cases of pregnancy in women with homozygous familial hypercholesterolemia (HFH) have been reported. HFH might pose significant risks for the mother and her fetus. Statins, the most potent agents for low-density lipoprotein (LDL) cholesterol reduction, are contraindicated; thus lipoprotein apheresis remains the only effective treatment. CASE REPORT: We report on a 34 year-old pregnant woman with HFH who was treated throughout the entire pregnancy by lipoprotein apheresis (immunoadsorption method). Increasing levels of LDL cholesterol were stabilized at 9-10 mmol/L by lipoprotein apheresis (performed every 10 days). No complications were observed during the treatment procedures. Monitoring of the fetus revealed no impairment of the umbilical cord and blood flow in the uterine arteries, as well as no intrauterine growth retardation. The delivery was spontaneous and the child was breastfed for two months. CONCLUSION: Intensive treatment by lipoprotein apheresis is an effective and safe therapeutic strategy during pregnancy, even in severe cases of HFH, as it can stabilize progressively increasing lipoprotein levels and prevent severe complications. PMID- 25936318 TI - Changes of the complement system and rheological indicators after therapy with rheohemapheresis. AB - INTRODUCTION: In the last 10 years, many studies have been published on the role of the complement system in microcirculation disorders. However, as for the changes of complement components after rheohemapheresis, there is still a lack of detailed data in the literature. Complement changes may play an important role in pathogenesis of some microcirculation disorders, such as age-related macular degeneration and acute hearing loss. The objective of this study was to investigate the effect of rheohemapheresis on the basic complement pathways. PATIENTS AND METHODS: 32 patients were treated with rheohemapheresis, including 16 patients (10 men and 6 women) for age-related macular degeneration (AMD), mean age 69.7 +/- 6.06 years (range 62-87 years) and 16 patients (11 men and 5 women) aged 56.4 +/- 11.5 (range 34-73 years) for acute hearing loss. RESULTS: Rheohemapheresis led to a significant drop of all three complement-activation pathways in both groups of patients. Moreover, complement factor H was also reduced. CONCLUSION: The observed reduction in all three basic complement activation pathways after rheohemapheresis could be clinically important. The search continues both to find substances which influence complement systems and to develop more effective new drugs that require less frequent administration and that provide improved intraocular therapy for AMD patients. PMID- 25936319 TI - Hypertriglyceridemia in an outpatient department--Significance as an atherosclerotic risk factor. AB - BACKGROUND: Although a relationship between elevated triglycerides (TG) and cardiovascular diseases is generally accepted, its extent is still discussed. This retrospective study analyzed the incidence of cardiovascular events (CVE) and pancreatitis as well as the therapeutic regimen in patients being treated for hypertriglyceridemia (HTG) at an outpatient department. METHODS: The cohort included 183 patients with mild and 49 patients with severe HTG; subgroups were formed and compared according to gender, presence of metabolic vascular syndrome (MVS) and lipid values. RESULTS: Patients in this study seem to have had CVE at younger age than reported event rates in the general population. TG levels, rates of CVE and pancreatitis were reduced in all groups during therapy, which could be linked to use of omega-3 fatty acids and fibrates. Patients with persisting severe HTG as a result of incompliance showed massive risk for pancreatitis. CONCLUSION: Although no significant association between TG levels and CVE could be established, the combination of HTG and other cardiovascular risk factors such as MVS seems to be especially dangerous. The lipid-lowering drug therapy appeared to be effective with respect to CVE and pancreatitis incidence. PMID- 25936320 TI - Efficacy, safety, and tolerability of long-term lipoprotein apheresis in patients with LDL- or Lp(a) hyperlipoproteinemia: Findings gathered from more than 36,000 treatments at one center in Germany. AB - LDL cholesterol (LDL-C) and lipoprotein(a) (Lp(a)) are main risk factors for cardiovascular disease (CVD). Efficacy, safety, and tolerability of lipoprotein apheresis (LA) were investigated in 36,745 LA treatments of 118 patients with CVD in a retrospective, monocentric study. Indications were severe hypercholesterolemia (n = 83) or isolated Lp(a) hyperlipoproteinemia (n = 35). Average age of patients at start of LA treatment was 58.1 years for males and 62.5 years for females. Medium interval between the first cardiovascular event and LA treatment was 6.4 +/- 5.6 years and the average LA treatment period was 6.8 +/- 4.9 years. On average treatments were performed once a week, via peripheral venous access in 79.3% of non-hemodialysis patients. In patients with hypercholesterolemia initial pre-LA LDL-C was lowered from 176.4 +/- 67.0 mg/dL by 66.7 +/- 10.8% per session, achieving a long-term interval mean value of 119.8 +/- 34.7 mg/dL, i.e. reduction by 32.1 +/- 19.6% (p < 0.0001). In patients with isolated elevated Lp(a) initial pre-LA Lp(a) was lowered from 127.2 +/- 67.3 mg/dL by 66.8 +/- 5.8% per session, achieving a long-term interval mean value of 60.0 +/- 19.5 mg/dL, i.e. reduction by 52.8 +/- 23.0% (p < 0.0001). After start of LA the average annual rate of major adverse coronary events (MACE) of all patients declined by 79.7% (p < 0.0001). Subgroup analysis showed decline by 73.7% (p < 0.0001) in patients with severe hypercholesterolemia, and by 90.4% (p < 0.0001) in patients with isolated elevated Lp(a). Adverse events (AE) occurred in 1.1% of treatments. LA treatment of patients with high risk for CVD due to LDL and/or Lp(a) hyperlipoproteinemia was effective, safe, and well tolerated. The number of cardiovascular events, at least during a six-year period, declined by 80%. PMID- 25936321 TI - Specific Lipoprotein(a) apheresis attenuates progression of carotid intima-media thickness in coronary heart disease patients with high lipoprotein(a) levels. AB - BACKGROUND: To date, there have been no studies evaluating the effect of isolated lipoprotein(a) (Lp(a)) lowering therapy on carotid atherosclerosis progression. METHODS: We enrolled 30 patients who had coronary heart disease (CHD) verified by angiography, Lp(a) level >=50 mg/dL, and low density lipoprotein cholesterol (LDL C) level <=2.6 mmol/L (100 mg/dL) on chronic statin therapy. Subjects were allocated in a 1:1 ratio to receive apheresis treatment on a weekly basis with immunoadsorption columns ("Lp(a) Lipopak"((r)), POCARD Ltd., Russia) added to atorvastatin, or atorvastatin monotherapy. The primary efficacy end-point was the change from baseline in the mean intima-media thickness (IMT) of the common carotid arteries. RESULTS: After one month run-in period with stable atorvastatin dose, LDL-C level was 2.3 +/- 0.3 mmol/L and Lp(a) - 105 +/- 37 mg/dL. As a result of acute effect of specific Lp(a) apheresis procedures, Lp(a) level decreased by an average of 73 +/- 12% to a mean of 29 +/- 16 mg/dL, and mean LDL C decreased by 17 +/- 3% to a mean of 1.8 +/- 0.2 mmol/L. In the apheresis group, changes in carotid IMT at 9 and 18 months from baseline were -0.03 +/- 0.09 mm (p = 0.05) and -0.07 +/- 0.15 mm (p = 0.01), respectively. In the atorvastatin group no significant changes in lipid and lipoprotein parameters as well as in carotid IMT were received over 18-month period. Two years after study termination carotid IMT increased by an average of 0.02 +/- 0.08 mm in apheresis group and by 0.06 +/ 0.10 mm in the control group (p = 0.033). CONCLUSION: Isolated extracorporeal Lp(a) elimination over an 18 months period produced regression of carotid intima media thickness in stable CHD patients with high Lp(a) levels. This effect was maintained for two years after the end of study. TRIAL REGISTRATION: Clinicaltrials.gov (NCT02133807). PMID- 25936322 TI - Increasing plasma lysophosphatidylcholine levels in patients with regular dextran sulfate lipoprotein apheresis. AB - OBJECTIVES: Previously we found a highly significant increase of phosphatidylethanolamines (PE) in response to acute lipoprotein apheresis (LA) with whole blood dextran sulfate adsorption (DSA) in contrast to the overall tendency of reduction of lipid metabolites of all lipid classes in post-apheresis plasma. Therefore, the aim of the present study was to analyze long-term modifications of the plasma lipidomic profile in patients with repeated DSA apheresis. METHODS: Nine patients weekly treated with DSA were followed for 40 weeks. Pre- and post-apheresis levels of routine lipid parameters and lipidomic profiles of five apheresis sessions were assessed. RESULTS: The main finding of the present study was a progressive increase of pre- and post-apheresis plasma lysophosphatidylcholine (LPC) levels, which doubled in concentration at the end of the 40 week observation period. LPC metabolites which mainly contributed to this increase were LPC 20:4 > 18:0 > 18:1 > 16:0 > 20:3 > 18:2. CONCLUSION: These data indicate that long-term application of DSA technology may be associated with a continuous increase in LPC levels. Possible pro- or anti-atherogenic consequences should be elucidated in further studies. PMID- 25936323 TI - Cholesterol-lowering therapy: Old evidence, new guidelines--Which one to follow? A critical appraisal. AB - Current guidelines of the European Society of Cardiology and the European Atherosclerosis Society (ESC/EAS), of the American College of Cardiology and the American Heart Association (ACC/AHA), and of the International Atherosclerosis Society (IAS) are all based on the same body of evidence, but come to strikingly different conclusions with regard to lipid lowering therapy. While the ESC/EAS guidelines assign appropriate treatments to distinct lipid disorders, the ACC/AHA guidelines focus exclusively on evidence from randomized controlled trials for statins, but lack advice for those lipid disorders without evidence from randomized trials. Thus, evidence based medicine in its strict sense may leave a clinically significant gap. In striking contrast, the position paper of the IAS suggests the most advanced evidence-based innovative concept of a goal of one and the same healthy cholesterol level for anyone. PMID- 25936324 TI - Effects of lipoprotein apheresis on PCSK9 levels. AB - BACKGROUND: PCSK9 (Proprotein Convertase Subtilisin/Kexin Type 9) increases LDL cholesterol (LDL-C) levels by stimulating the degradation of Low Density Lipoprotein receptors (LDL-r). This protein is now of high interest because antibodies which inhibit its effect on LDL-r are being developed. A severe hypercholesterolemia and / or an elevation of lipoprotein(a) can be treated with lipoprotein apheresis (LA) in high-risk patients. METHODS: We measured serum PCSK9 levels in patients eligible for the extracorporeal treatment: in 40 patients (Cohort I) who were treated with different systems before and after apheresis sessions and in the intervals between sessions. 10 patients (Cohort II) who were eligible but did not start LA yet served as controls. RESULTS: Patients' baseline serum PCSK9 levels were elevated relative to healthy volunteers and LA sessions acutely reduced the mean PCSK9 concentrations by 51%. Comparison of the effectiveness of the different LA methods demonstrated the DSA and HELP were more effective than the DALI system. After 24 h PCSK9 levels had returned to baseline compared to 8 days for the LDL-C concentrations to return to its pre-apheresis levels. In Cohort II baseline PCSK9 levels were similar to those in Cohort I. CONCLUSION: The acute reductions of PCSK9 by apheresis may be beneficial with respect to increasing the effectiveness of lipid-lowering drugs and with respect to an anti-atherosclerotic effect. In the future, antagonists to PCSK9 will probably be combined with or possibly replace LA in patients with a very high cardiovascular risk. PMID- 25936325 TI - Lipoprotein apheresis in patients with peripheral artery disease and hyperlipoproteinemia(a). AB - OBJECTIVE: Hyperlipoproteinemia(a) [Lp(a)-HLP] is a major risk factor for severe atherosclerosis. The present investigation sought to assess the effect of lipoprotein apheresis (LA) in patients with peripheral artery disease (PAD) and Lp(a)-HLP. METHODS: In January 2013, we started a registry for Lp(a)-HLP patients who receive weekly LA in our center. So far, ten patients with severe PAD and isolated Lp(a)-HLP who recently underwent revascularization (index procedure) have been included. Pain level, ankle-brachial-index (ABI), transcutaneous oxygen pressure (tcpO2) and walking distance were determined before, as well as 1, 3, 6 and 12 months after initiation of LA. Furthermore, the mean time interval between revascularizations within the 12 months prior to the index procedure and up to 12 months after the index procedure was assessed. RESULTS: All analyzed parameters significantly improved under LA. When comparing the results before LA with the results after 12 months, the ankle-brachial-index increased from 0.5 +/- 0.2 to 0.9 +/- 0.1 (P < 0.001). The tcpO2 levels also increased from 42.9 +/- 2.3 mmHg to 59.0 +/- 8.9 mmHg (P < 0.001). The improved microcirculation was associated with a reduction of the mean pain level from 7.0 +/- 1.5 to 2.0 +/- 0.8 (P < 0.001) as determined using the visual analog scale. The walking distance increased from 87 +/- 60 m to 313 +/- 145 m (P < 0.001). Importantly, the frequency of revascularization procedures was strongly decreased under LA. All patients combined underwent 35 revascularizations within the 12 months prior to the index procedure (mean interval between two revascularizations: 104.3 days). Since the index procedure, only one revascularization was necessary within 79 patient-months under LA (mean interval: 2404.5 days, P < 0.001). CONCLUSION: LA improves circulation, oxygen supply, level of pain and walking distance in patients with severe PAD and Lp(a)-HLP. The frequency of revascularization procedures is strongly reduced under LA treatment. PMID- 25936326 TI - Practical recommendations for the management of hyperlipidemia. AB - Hyperlipidemia is a risk factor for atherosclerosis. Raised low-density lipoprotein cholesterol (LDL-C) and lipoprotein(a) levels are severe risk factors for atherosclerosis. The role of high-density lipoprotein cholesterol (HDL-C) is controversial. Total cholesterol, LDL-C, HDL-C, triglycerides and lipoprotein(a) levels should be determined in a fasting state. The basis of treating hyperlipidemia remains diet, physical exercise and weight reduction. Olive oil and nuts have been shown to be beneficial. Statins remain first line drug treatment. Further treatment options are ezetimibe, bile acid sequestrants, fibrates and fish oil. Side effects of statins include myopathies and, as shown during the last years, also an increased risk of diabetes mellitus. In patients with statin-related myopathies first results of a gene analysis have been published showing a means of predicting which statin can be administered at which dose for the individual patient with least risk of side effects. Most convincing data have been shown for simvastatin. Patients with renal insufficiency have been shown to have a raised cardiovascular risk. In the SHARP Study the combination of simvastatin plus ezetimibe was effective in reducing cardiovascular events in patients with severe renal insufficiency (especially before dialysis but also in dialysis dependent patients). Important aspects of treating patients with chylomicronemia syndrome are illustrated. Treating young patients with hyperlipidemia as primary prevention remains problematic. PMID- 25936327 TI - TIDILAP: Treatment of iron deficiency in lipoprotein apheresis patients --A prospective observational multi-center cohort study comparing efficacy, safety and tolerability of ferric gluconate with ferric carboxymaltose. AB - OBJECTIVES: Iron deficiency (ID) and iron deficiency anemia (IDA) are common findings in patients undergoing lipoprotein apheresis (LA). Different intravenous (iv) formulations are used to treat ID in LA patients, however guidelines and data on ID/IDA management in LA patients are lacking. We therefore performed a prospective observational multi-center cohort study of ID/IDA in LA patients, comparing two approved i.v. iron formulations, ferric gluconate (FG) and ferric carboxymaltose (FCM). METHODS: Inclusion criteria were a) serum ferritin <100 MUg/L or b) serum ferritin <300 MUg/L and transferrin saturation <20%. Patients received either FG (62.5 mg weekly) or FCM (500 mg once in ID or up to 1000 mg if IDA was present) i.v. until iron deficiency was resolved. Efficacy and safety were determined by repeated laboratory and clinical assessment. Iron parameters pre and post apheresis were measured to better understand the pathogenesis of ID/IDA in LA patients. RESULTS: 80% of LA patients treated at the three participating centers presented with ID/IDA; 129 patients were included in the study. Serum ferritin and transferrin levels were reduced following apheresis (by 18% (p < 0.0001) and by 13% (p < 0.0001) respectively). Both FG and FCM were effective and well tolerated in the treatment of ID/IDA in LA patients. FCM led to a quicker repletion of iron stores (p < 0.05), while improvement of ID/IDA symptoms was not different. Number and severity of adverse events did not differ between FG and FCM, no severe adverse events occurred. CONCLUSIONS: Our results suggest that FG and FCM are equally safe, well-tolerated and effective in treating ID/IDA in LA patients. These data form the basis for follow-up randomized controlled trials to establish clinical guidelines. PMID- 25936328 TI - Detailed description of the cardiovascular situation in patients who have started lipoprotein apheresis treatment. AB - BACKGROUND: Lipoprotein apheresis (LA) therapy is effective in eliminating atherogenic lipoproteins and reducing the rate of cardiovascular events (CVE) in patients suffering from severe hypercholesterolemia or increased lipoprotein(a) (Lp(a)) levels despite maximal tolerated lipid lowering therapy. METHODS: We examined the rate of CVE in 116 patients (63% males) with an isolated increase of LDL-cholesterol (LDL-C) (Group 1), an isolated increase of Lp(a) (Group 2), a combined increase of LDL-C and Lp(a) (Group 3) and patients who were referred for LA, but never started (Group 4). RESULTS: Patients with increased Lp(a) (Groups 2 and 3) showed a higher prevalence of advanced atherosclerotic changes, defined as involvement of 3 or 4 vascular territories, including the abdominal aorta and leg arteries, and an involvement of more coronary vessels compared to patients in group 1. Prior to initiation of LA, on average patients suffered 4.4 (range: 0 14) CVE during a period of 7.2 (range: 0-41) years. Group 1 patients suffered fewer CVE per patient-year compared to the other groups (Group 1: 0.75, Group 2: 1.7, Groups 3 and 4: 1.4). 55-63% of patients applying for LA experienced a CVE within the last year (on average 1.3 CVE per patient in the last year). Among patients referred to LA there is a high rate of intolerance to nicotinic acid (42% of patients in Group 3) and statins (58% of patients in Group 1). CONCLUSION: Patients referred to LA represent a high risk population for CVE in all vascular territories. Increased Lp(a) levels cause a higher percentage of patients with advanced atherosclerosis. PMID- 25936329 TI - Actual situation of lipoprotein apheresis in Saxony in 2013. AB - BACKGROUND: Lipoprotein apheresis (LA) is an officially accepted therapeutic approach in Germany. Reliable population-based data on the patients are scarce. It is of special interest to learn what are the main indications for this extracorporeal treatment and how many new patients started over the last years. METHODS: This paper is a summary of the situation of the treatment of high-risk patients via LA in the federal state of Saxony, Germany. The documentation of all patients who agreed to be included into this study have been evaluated. Patients were treated at the University Hospital Dresden (UHD) and in private practices of nephrologists. This evaluation aimed at the characterization of patients treated with LA in Saxony with respect to age, gender, lipid pattern, to the number of new patients per year and the development of the ratio of patients to the Saxon population between 2010 and 2013. The obtained data were compared with the official statistics published by the National Association of Statutory Health Insurance Physicians for whole Germany. RESULTS: In 2013, 181 patients, primarily males, were treated in 15 LA centers by 32 doctors. Still, the number of apheresis doctors per 1 million inhabitants is under the average in Germany (Saxony: 7.7/1 million inhabitants, average: 12/1 million inhabitants). The usage of LA is 45 per 1 million inhabitants in Saxony; in comparison to 2010, this is an increase of 16 per 1 million inhabitants. The number of new patients in 2013 with an isolated elevation of Lipoprotein(a) (Lp(a)) is twice as high than it was in 2011. The mean duration of all patients being treated with LA, most on a weekly basis, was 5.75 years (UHD: 6.2 years, range: 1 month to 23.1 years; other centers: 5.3 years, range: 1 month to 19.2 years). About 19.3% of all patients suffered from elevated triglyceride (TG) levels (>5 mmol/L). Non-high- density lipoprotein cholesterol (Non-HDL-C) was calculated, which is also acutely reduced by LA sessions. The following data were reported for those patients who are treated outside the UHD: risk factors such as hypertension and familial predisposition could be seen in almost every patient, and several others such as type 2 diabetes mellitus, genetic defects and obesity were also present. Almost all patients had suffered from cardiovascular events (CVE) occurring before the start of apheresis treatment. LA therapy led to a reduction in occurrence of CVE during LA therapy. In particular, patients with an isolated increased Lp(a) had the highest reduction when comparing CVE before and during apheresis therapy. In the official statistics published by the National Association of Statutory Health Insurance Physicians the number of LA patients with homozygous familial hypercholesterolemia (HoFH) is clearly too high. Moreover, these statistics do not include patients who are treated at hospitals like the UHD. CONCLUSION: All in all it can be shown that the extracorporeal therapy is performed effectively in Saxony, and that more centers than 2010 (additional 5) were conducting this therapy when lipid-lowering medication was not sufficiently effective. It is certain that the number of patients requiring LA will increase in the future. PMID- 25936330 TI - Effects of Lipoprotein apheresis on the Lipoprotein(a) levels in the long run. AB - BACKGROUND: Lipoprotein(a) (Lp(a)) is a low density lipoprotein-like particle to which apolipoprotein(a) is bound. It is recognized as an atherosclerosis-inducing risk factor. Up to now a detailed description of the effect of Lipoprotein apheresis (LA) on Lp(a) levels in the long run is lacking. METHODS: We studied 59 patients with elevated Lp(a) levels who were treated with LA at the Lipoprotein Apheresis Center at the University Hospital Dresden. We analyzed Lp(a) concentrations before the start of the LA treatment and during this extracorporeal therapy. RESULTS: Comparing the Lp(a) levels before the start of LA therapy and pre-apheresis (measured before the LA sessions) Lp(a) levels, we observed a reduction of the Lp(a) levels of about 22.8% in all patients. Lp(a) levels were acutely (comparing post-apheresis with pre-apheresis concentrations) reduced by all 6 available LA methods (by about 70%). A linear regression analysis was performed to differentiate the long term course of pre-apheresis Lp(a) levels. In 30 patients we saw an increase of the pre-apheresis Lp(a) levels over the time, in 15 patients a constancy and in 14 patients a decrease. Patients with a decrease of pre-apheresis Lp(a) levels over the time had significantly higher initial (before the start of the extracorporeal treatment) and pre apheresis values and they were significantly older. These patients had significantly more severe peripheral arterial disease as well as cardiac valve and carotid stenosis. The patients with the lowest initial Lp(a) levels and an increase of the pre-apheresis Lp(a) levels over the time had the highest percentage of intake of Tredaptive((r))/Niaspan((r)) though after stopping the intake of these nicotinic acid preparations no clear increase of Lp(a) concentrations was observed. The applied LA systems did not seem to have a significant influence on the course of pre-apheresis Lp(a) levels. In all patients there was a high variability of Lp(a) concentrations between LA sessions which may in part be due to the inaccuracy of the method used to measure Lp(a) concentrations. CONCLUSION: Pre-apheresis Lp(a) levels (before the LA sessions) are lower than those before the start of a LA treatment but they behave differently among patients during LA treatment. PMID- 25936331 TI - Mental symptoms and quality of life in lipoprotein apheresis patients in comparison to hemodialysis patients, platelet donors and normal population. AB - BACKGROUND: Despite the fact that extracorporeal methods such as lipoprotein apheresis (LA) and hemodialysis (HD) are highly effective in improving the physical status of patients, these treatment options may possibly harm the psychological status and the health related quality of life (HRQL). METHODS: The occurrences of anxiety, depression and the HRQL of 111 study participants treated with LA (n = 41), HD (n = 41) or undergoing plateletpheresis (PD) (n = 29) were compared to the normal population (NP), using standardized questionnaires (anxiety and depression: Hospital Anxiety and Depression Scale (HADS), heart focused anxiety: Cardiac Anxiety Questionnaire (CAQ) and HRQL: Short-Form Health Survey (SF-12)). Additionally, the subjective mental and physical stress of study participants was evaluated. RESULTS: LA females had a significantly elevated HADS A score compared to PD and NP. Additionally, there was a trend toward higher HADS A scores in the LA group compared to the HD group in females. In HD males HADS-A and -D scores increased compared to PD and NP. The CAQ revealed a significant increase in the CAQ-Fear scale in LA compared to HD and PD participants. The CAQ Avoidance score showed significantly increased scores in LA and HD patients compared to PD and NP. In the CAQ-Attention scale the LA patients also showed significantly increased scores compared to PD and NP. The increased psychological symptoms were associated with significantly lower levels of objective and subjective HRQL in LA and HD patients compared to PD and NP. CONCLUSIONS: LA and HD patients had similarly increased presence of psychological symptoms with concurrent decreased quality of life compared to PD and the normal population, which may affect the outcome of the LA patients. Therefore, early psychosomatic screening and probable psychosomatic treatment should be performed. PMID- 25936332 TI - First on-line survey of an international multidisciplinary working group (MightyMedic) on current practice in diagnosis, therapy and follow-up of dyslipidemias. AB - The MightyMedic (Multidisciplinary International Group for Hemapheresis TherapY and MEtabolic DIsturbances Contrast) Working Group has been founded in 2013. The leading idea was to establish an international network of interdisciplinary nature aimed at working to cross national borders research projects, clinical trials, educational initiatives (meetings, workshops, summer schools) in the field of metabolic diseases, namely hyperlipidemias, and diabetes, preventive cardiology, and atherosclerosis. Therapeutic apheresis, its indications and techniques, is a parallel field of investigation. The first on-line survey of the Group has been completed in the first half of 2014. The survey included # 24 Centers in Italy, Germany, Greece, UK, Sweden, Japan and USA. Relevant data have been collected on current practice in diagnosis, therapy and follow-up of dyslipidemias. 240 subjects with hyperlipidemia and treated with lipoprotein apheresis have been reported in the survey, but a large percentage of patients (35%) who could benefit from this therapeutic option are still treated by conventional drug approach. Genetic molecular diagnosis is performed in only 33% of patients while Lipoprotein(a) (Lp(a)) is included in cardiovascular disease risk assessment in 71% of participating Centers. New detailed investigations and prospective multicenter studies are needed to evaluate changes induced by the impact of updated indications and strategies, as well as new treatment options, targeting standardization of therapeutic and diagnostic approaches. PMID- 25936333 TI - Apheresis in treatment of acute inflammatory demyelinating disorders. AB - Therapeutic apheresis has reached an important value in the treatment of neurologic disorders. In the indication of acute relapses of inflammatory demyelinating conditions plasma exchange (PE) is currently mentioned in guidelines in adults and children. Immunoadsorption (IA) is a younger but more selective apheresis method. Compared to PE, data on IA in these indications are less substantiated. Hitherto existing studies indicate IA as effective and safe with similar response rates versus PE. Our own study of 140 adult patients treated with PE or IA in steroid refractory multiple sclerosis or neuromyelitis optica affirm previous findings showing no significant difference in efficacy and treatment safety. Analogue to adult patients, children seem to benefit from apheresis therapy in steroid resistant inflammatory demyelinating conditions but their treatment implies certain challenges concerning physiology, anatomy and psychological aspects necessitating a multidisciplinary therapeutic setting. PMID- 25936334 TI - An elevated lipoprotein(a) plasma level as a cardiovascular risk factor. AB - INTRODUCTION: The causal association of elevated lipoprotein(a) (Lp(a)) plasma levels with the increased cardiovascular risk is still controversial and presently there are no standard recommendations on managing of hyperLp(a)emia. Our retrospective analysis is aimed to explore the Lp(a) thresholds, the magnitude of various cardiovascular risk factors and their combinations. METHODS: The files of 544 outpatients from our Outpatient Department of Lipid Disorders were divided into quintiles with respect to Lp(a) levels and reviewed regarding age, gender, Body Mass Index, dyslipidemias, arterial hypertension, diabetes mellitus, smoking and incidence of vascular events in coronaries, carotids and lower extremities. Furthermore we built 15 small quantiles to identify the Lp(a) threshold more precisely. RESULTS: The incidence odds ratio for cardiovascular events rose from 2.65 in the 2nd quintile with Lp(a) 483-821 mg/L to 6.36 in the 5th quintile (Lp(a) >= 1495 mg/L). The relative risk of cardiovascular events was 0.08 in subjects with a Lp(a) level under 232 mg/l and 3.6 at Lp(a) >= 315 mg/L. The magnitude of the combination of elevated Lp (a) with arterial hypertension factor exceeded that of gender, age and combination of arterial hypertension with smoking. CONCLUSIONS: A Lp(a) plasma level of higher than about 300 mg/L seems to be a threshold for occurring of cardiovascular events. The combination of raised Lp(a) with arterial hypertension was found to be the most important cardiovascular risk factor. Lp(a) levels under 232 mg/L appeared to be a marker for good prognosis. PMID- 25936335 TI - Lipoprotein(a)--An independent causal risk factor for cardiovascular disease and current therapeutic options. AB - It is widely accepted that elevated levels of lipoprotein(a) (Lp(a)) are associated with an increased risk for cardiovascular diseases. Several studies have identified Lp(a) as independent cardiovascular risk factor. Consequently, therapeutic concepts are targeting at lowering Lp(a) serum levels. To date, in Europe no pharmaceutical treatment to lower levels of Lp(a) is available. Current developments of pharmaceutical agents like the apolipoprotein-(B-100)-antisense mipomersen, inhibitors of PCSK9 and apolipoprotein-(a)-antisense have shown promising results in lowering Lp(a). Presently, the only available therapy to effectively reduce levels of Lp(a) is regular extracorporeal lipoprotein apheresis. Different apheresis methods show a similar lowering effect of about 60 70 % by a single session. Apart from one small-scale study there has been no randomized, controlled study which could prove that lowering Lp(a) will result in a risk reduction for cardiovascular disease. This review looks into the current scientific evidence of. PMID- 25936336 TI - The incidence of cardiovascular events is largely reduced in patients with maximally tolerated drug therapy and lipoprotein apheresis. A single-center experience. AB - AIM: Lipoprotein apheresis (LA) is the elective therapy for homozygous and other forms of familial hypercholesterolemia (FH) and familial combined hypercholesterolemia (FCH), resistant/intolerant to lipid lowering drugs, and hyperlipoproteinemia(a) for which drugs are not available. To assess the effect of LA on the incidence of adverse cardiac or vascular events (ACVE) at the time period of pre-initiation of apheresis and during the LA treatment. METHODS: We collected data of 30 patients (mean age 62 +/- 8 years, males 73%), with FH, or FCH and cardiovascular disease on maximally tolerated lipid lowering therapy and LA treatment (median 5 years, interquartile range 3-8 years). Associated hyperlipoproteinemia(a) was present in 16/30 subjects. The LA treatment was performed biweekly as clinically indicated by dextran-sulfate or heparin-induced LDL precipitation apheresis. The ACVE incidence, before and after treatment, was evaluated by statistical analyses. RESULTS: The ACVE incidence occurred before and after the LA treatment inception, were 86 and 15 events respectively. Notably, 6/15 of ACVE were secondary to stent restenosis and 7/15 follow-up events occurred during the first 5 years. The AVCE rates/year were 0.58 and 0.13 respectively (p < 0.001). CONCLUSIONS: Our data confirm long-term efficacy and positive impact of LA on morbidity in patients with FH and FCH and atherosclerotic disease at maximally tolerated lipid lowering therapy. PMID- 25936337 TI - Engineering L-arabinose metabolism in triacylglycerol-producing Rhodococcus opacus for lignocellulosic fuel production. AB - Advanced biofuels from lignocellulosic biomass have been considered as a potential solution for the issues of energy sustainability and environmental protection. Triacylglycerols (TAGs) are potential precursors for the production of lipid-based liquid biofuels. Rhodococcus opacus PD630 can accumulate large amounts of TAGs when grown under physiological conditions of high carbon and low nitrogen. However, R. opacus PD630 does not utilize the sugar L-arabinose present in lignocellulosic hydrolysates. Here, we report the engineering of R. opacus to produce TAGs on L-arabinose. We constructed a plasmid (pASC8057) harboring araB, araD and araA genes derived from a Streptomyces bacterium, and introduced the genes into R. opacus PD630. One of the engineered strains, MITAE-348, was capable of growing on high concentrations (up to 100 g/L) of L-arabinose. MITAE-348 was grown in a defined medium containing 16 g/L L-arabinose or a mixture of 8 g/L L arabinose and 8 g/L D-glucose. In a stationary phase occurring 3 days post inoculation, the strain was able to completely utilize the sugar, and yielded 2.0 g/L for L-arabinose and 2.2 g/L for L-arabinose/D-glucose of TAGs, corresponding to 39.7% or 42.0%, respectively, of the cell dry weight. PMID- 25936338 TI - Effect of toothpaste with nano-sized trimetaphosphate on dental caries: In situ study. AB - OBJECTIVES: This in situ study was to evaluate the remineralizing effect of a fluoride toothpaste supplemented with nano-sized sodium trimetaphosphate (TMP). METHODS: This blind and cross-over study was performed in 4 phases of 3 days each. Twelve subjects used palatal appliances containing four bovine enamel blocks with artificial caries lesions. Volunteers were randomly assigned into the following treatment groups: Placebo (without F and TMP); 1100 ppm F (1100), 1100 supplemented with 3% micrometric TMP (1100 TMP) and with nano-sized TMP (1100 TMPnano). Volunteers were instructed to brush their natural teeth with the palatal appliances in the mouth during 1min (3 times/day), so that blocks were treated with natural slurries of toothpastes. After each phase, the percentage of surface hardness recovery (%SHR), integrated mineral recovery (IMR) and integrated differential mineral area profile (DeltaIMR) in enamel lesions were calculated. F in enamel was also determined. Data were analyzed by ANOVA and Student-Newman-Keuls test. RESULTS: Enamel surface became 20% harder when treated with 1100 TMPnano in comparison with 1100 (p<0.001). 1100 TMPnano showed remineralizing capacity (IMR; DeltaIMR) 66% higher when compared with 1100 TMP (p<0.001). Enamel F uptake in the 1100 TMPnano group was 2-fold higher when compared to its counterpart without TMP (p<0.001). CONCLUSION: The addition of 3% TMPnano to a conventional toothpaste was able to promote an additional remineralizing effect of artificial caries lesions. CLINICAL SIGNIFICANCE: Toothpaste containing 1100 ppm F associated with TMPnano showed a potential of higher remineralization to 1100 ppm F and 1100 ppm F micrometric TMP. PMID- 25936339 TI - Eating well with Canada's food guide? Authoritative knowledge about food and health among newcomer mothers. AB - PROBLEM: Current versions of Canada's Food Guide (CFG) aim to inform a culturally diverse population, but it is not known how intended audiences from different cultural and linguistic groups within Canada's diverse population understand and apply its messages. METHODS: We analyzed data from qualitative interviews conducted with 32 newcomer mothers of children aged 1-5 years to explore how conceptions of food and health change with migration to Canada among Spanish speaking Latin American and Tamil Speaking Sri Lankan newcomers and may influence the appropriateness and applicability of Canada's Food Guide (CFG) as a nutrition education tool. We applied Jordan's model of authoritative knowledge to identify different forms of newcomer maternal nutrition knowledge, how they influence child feeding practices, and shifts causing some forms of knowledge to be devalued in favor of others. RESULTS: Awareness of CFG differed between groups, with all Latin American and only half of Tamil participants familiar with it. Three distinct, overlapping ways of knowing about the relationship between food and health are identified within both groups of mothers: "natural" foods as healthy; influence of foods on illness susceptibility, and the nutritional components of food. CFG was found to be limited in its representations of recommended foods and its exclusive utilization of biomedical concepts of nutrition. CONCLUSIONS: Development of new, culturally competent versions of CFG that depict a variety of ethno-culturally meaningful diets and encompass both non biomedical conceptualizations of food and health has the potential to enhance effective knowledge translation of CFG's key messages to an increasingly cosmopolitan Canadian population. PMID- 25936340 TI - Polyethylene glycol protects primary hepatocytes during supercooling preservation. AB - Cold storage (at 4 degrees C) offers a compromise between the benefits and disadvantages of cooling. It allows storage of organs or cells for later use that would otherwise quickly succumb to warm ischemia, but comprises cold ischemia that, when not controlled properly, can result in severe damage as well by both similar and unique mechanisms. We hypothesized that polyethylene glycol (PEG) 35 kDa would ameliorate these injury pathways and improve cold primary hepatocyte preservation. We show that reduction of the storage temperature to below zero by means of supercooling, or subzero non-freezing, together with PEG supplementation increases the viable storage time of primary rat hepatocytes in University of Wisconsin (UW) solution from 1 day to 4 days. We find that the addition of 5% PEG 35 kDa to the storage medium prevents cold-induced lipid peroxidation and maintains hepatocyte viability and functionality during storage. These results suggest that PEG supplementation in combination with supercooling may enable a more optimized cell and organ preservation. PMID- 25936341 TI - Downregulation of A disintegrin and metallopeptidase with thrombospondin motif type 1 by DNA hypermethylation in human gastric cancer. AB - A disintegrin and metallopeptidase with thrombospondin motif type 1 (ADAMTS1) is a metalloproteinase with antiangiogenic activity. It was previously observed that the mRNA and protein levels of ADAMTS1 are downregulated in primary gastric tumors. The aim of the present study was to examine whether the reduction in the expression of ADAMTS1 is due to aberrant methylation of the gene in primary gastric tumor tissues and gastric cancer cell lines. In addition, the association between ADAMTS1 methylation and clinicopathological features in were investigated in patients with primary gastric cancer. The results revealed that the frequency of ADAMTS1 methylation in primary gastric tumor tissues was significantly higher, compared with the corresponding normal gastric tissues. The relative mRNA expression levels of ADAMTS1 were significantly lower in the methylated primary gastric tumor tissues, compared with the unmethylated primary gastric tumor tissues. A significant association was observed between the ADAMTS1 methylation status and the depth of tumor invasion and tumor, node, metastasis stage in primary gastric cancer. The mRNA expression of ADAMTS1 was significantly lower in 60% (3 of 5) of the gastric cancer cell lines. The relative mRNA expression levels of ADAMTS1 were significantly lower in the methylated gastric cancer cell lines, compared with the unmethylated gastric cancer cell lines. Furthermore, the expression of ADAMTS1 was significantly restored following treatment with the 5 Aza-2'-deoxycytidine demethylating agent in the MGC-803, HGC-27 and AGS gastric cancer cell lines, and the demethylation of the MGC-803 cell line inhibited cell invasion. Together, these results suggested for the first time, to the best of our knowledge, ADAMTS1 as a novel antitumor protease, and this function was lost following epigenetic silencing in the gastric cancer cells and gastric tumor tissues. Therefore, the aberrant methylation of ADAMTS1 may be involved in the development and progression of gastric cancer. PMID- 25936342 TI - MicroRNA-383 expression regulates proliferation, migration, invasion, and apoptosis in human glioma cells. AB - This study aims to evaluate microRNA-383 (miR-383) expression level in glioma cells and its influences on proliferation, migration, invasion, apoptosis, and cell cycle in glioma cells. miR-383 expression levels were determined by real time quantitative reverse transcription polymerase chain reaction (qRT-PCR). Thirty BALB/c-nu mice were randomly assigned into three groups: U87-miR-383 group, vector-control group, and blank group. Tumorigenicity experiment was conducted to confirm the function of miR-383. U251 and U87 glioma cells were divided into three groups: non-transfected control cells (NT group), glioma cells transfected with miR-383 (miR-383 group), and glioma cells transfected with negative sequence (NC group). Transfection efficiency was measured by qRT-PCR. Cell counting kit-8 (CCK-8) assay was used to detect cell proliferation. Cell migration and invasion were examined by utilizing a Transwell chamber. Cell cycle and apoptosis were analyzed by flow cytometry. The qRT-PCR results revealed that miR-383 expression was down-regulated in human glioma cells, and was negatively related to the pathological grading of glioma. The rates of tumor growth in vector-control group and blank group were significantly faster than that in U87 miR-383 group, and the average tumor volume and weight in vector-control group and blank group were increased as compared with U87-miR-383 group. Additionally, miR-383 levels in miR-383 group were higher than those in NT group and NC group. CCK-8 assay indicated lower cell viability in miR-383 group as compared with NT group and NC group. Flow cytometry implied that the percentages of cells in miR 383 group reduced, while the cell apoptosis rate enhanced compared with NT group and NC group. In conclusion, our findings suggest that miR-383 expression is down regulated in glioma cells, inhibiting cell proliferation, migration, and invasion, affecting the cell cycle, and inducing cell apoptosis. PMID- 25936343 TI - Strong expression of paired-like homeodomain transcription factor 1 (PITX1) is associated with a favorable outcome in human osteosarcoma. AB - Paired-like homeodomain transcription factor 1 (PITX1) has been implicated as a tumor suppressor in various cancers. However, the biological and clinical significance of PITX1 in osteosarcoma has not been fully elucidated. Here, we studied the expression and clinical significance of PITX1 in 6 normal lower limb bone tissue specimens and 35 osteosarcoma tissue samples by immunohistochemistry. PITX1 was expressed in all normal tissues (6/6, 100 %) and in 85.7 % (30/35) of tumor tissues (P > 0.05). In addition, all normal tissue specimens showed high PITX1 expression (6/6, 100 %) while only 23.3 % (7/30) osteosarcoma tissue specimens had high PITX1 expression (P < 0.05). Patients with median overall survival (OS) >12 months had significantly higher PITX1 levels compared with those whose median OS was less than or equal to 12 months (P < 0.05 or 0.001). Furthermore, patients with lung metastasis had significantly lower PITX1 levels than patients without lung metastasis. In conclusion, PITX1 expression is downregulated in osteosarcoma and correlates with patient survival and lung metastasis. PMID- 25936344 TI - Protective effect of enterovirus-71 (EV71) virus-like particle vaccine against lethal EV71 infection in a neonatal mouse model. AB - Enterovirus-71 (EV71) is a viral pathogen that causes severe cases of hand, foot and mouth disease (HFMD) among young children, with significant mortality. Effective vaccines against HFMD are urgently required. Several EV71 virus-like particle (VLP) vaccine candidates were found to be protective in the neonatal mouse EV71 challenge model. However, to what extent the VLP vaccine protects susceptible organs against EV71 infection in vivo has remained elusive. In the present study, the comprehensive immunogenicity of a potential EV71 vaccine candidate based on VLPs was evaluated in a neonatal mouse model. Despite lower levels of neutralizing antibodies to EV71 in the sera of VLP-immunized mice compared with those in mice vaccinated with inactivated EV71, the VLP-based vaccine was shown to be able to induce immunoglobulin (Ig)G and IgA memory associated cellular immune responses to EV71. Of note, the EV71 VLP vaccine candidate was capable of inhibiting viral proliferation in cardiac muscle, skeletal muscle, lung and intestine of immunized mice and provided effective protection against the pathological damage caused by viral attack. In particular, the VLP vaccine was able to inhibit the transportation of EV71 from the central nervous system to the muscle tissue and greatly protected muscle tissue from infection, along with recovery from the viral infection. This led to nearly 100% immunoprotective efficacy, enabling neonatal mice delivered by VLP-immunized female adult mice to survive and grow with good health. The present study provided valuable additional knowledge of the specific protective efficacy of the EV71 VLP vaccine in vivo, which also indicated that it is a promising potential candidate for being developed into an EV71 vaccine. PMID- 25936345 TI - Synergistic combined effect between CD40-1C>T and CTLA-4+6230G>A polymorphisms in Graves' disease. AB - The aim of this study was to investigate whether a genetic combined effect exists between CD40-1C>T and CTLA-4+6230G>A (CT60) polymorphisms and whether the combined effect renders susceptibility to Graves' disease (GD). We recruited 260 patients with GD and 248 healthy controls. Single nucleotide polymorphisms were genotyped by polymerase chain reaction-high resolution melting. Genetic polymorphisms related to GD were identified, levels of thyroid stimulating hormone receptor antibodies (TRAb) were measured, and genetic interactions were assessed by logistic regression analysis. Significant difference in allele and genotype frequency of CD40-1C>T polymorphism was observed between the patients and control subjects (P<0.001, 0.002 respectively). As for CTLA-4+6230G>A polymorphism, significant difference was observed only in allele frequencies between the patient and control groups (P=0.014). Moreover, a significant combined effect was presented in CD40-1C>T and CTLA-4+6230G>A polymorphism (P=0.020), and all, but one, combination CC-genotype of CD40-1C>T and GG-genotype of CTLA-4+6230G>A polymorphism has 54% lower risk of GD development than subjects with the CC and GG genotypes (OR=0.46, 95% CI=0.25-0.84). In newly onset GD group, neither single SNP (CD40-1C>T or CTLA-4+6230G>A polymorphism) nor their combined effect was showed a significant association with TRAb concentration (all P>0.05). Our findings suggest a possible additive combined effect between CD40 1C>T and CTLA4+6230G>A polymorphisms in the development of GD. PMID- 25936346 TI - Rare intracranial cholesterol deposition and a homozygous mutation of LDLR in a familial hypercholesterolemia patient. AB - Familial hypercholesterolemia (FH MIM# 143890) is one of the most common autosomal inherited diseases. FH is characterized by elevated plasma levels of total cholesterol and low-density lipoprotein-cholesterol. Mutation in the LDLR gene, which encodes the LDL receptor protein, is responsible for most of the morbidity of FH. The incidence of heterozygous FH is about 1/500, whereas the incidence of homozygous FH is only 1/1,000,000 in Caucasian population. In this study, we report a homozygous LDLR mutation (c.298G>A) in a familial hypercholesterolemia patient, who exhibited intracranial cholesterol deposition, which is a rare addition to the common FH phenotypes. The proband's consanguineous parents have the same heterozygous mutation with elevated concentrations of LDL-C but no xanthoma. PMID- 25936348 TI - Evolutionary dynamics of group fairness. AB - The emergence and impact of fairness is commonly studied in the context of 2 person games, notably the Ultimatum Game. Often, however, humans face problems of collective action involving more than two individuals where fairness is known to play a very important role, and whose dynamics cannot be inferred from what is known from 2-person games. Here, we propose a generalization of the Ultimatum Game for an arbitrary number of players--the Multiplayer Ultimatum Game. Proposals are made to a group of responders who must individually reject or accept the proposal. If the total number of individual acceptances stands below a given threshold, the offer will be rejected; otherwise, the offer will be accepted, and equally shared by all responders. We investigate the evolution of fairness in populations of individuals by means of evolutionary game theory, providing both analytical insights and results from numerical simulations. We show how imposing stringent consensuses significantly increases the value of the proposals, leading to fairer outcomes and more tolerant players. Furthermore, we show how stochastic effects--such as imitation errors and/or errors when assessing the fitness of others--may further enhance the overall success in reaching fair collective action. PMID- 25936347 TI - Interference of therapeutic antibodies used in desensitization protocols on lymphocytotoxicity crossmatch results. AB - BACKGROUND: Therapeutic antibodies used to desensitize patients awaiting a human leukocyte antigen (HLA) or ABO-mismatched graft are suspected to interfere with the lymphocytotoxicity crossmatch (LCT-XM) test when they are present in the tested sera because of their potential ability to activate or inhibit the complement. METHODS: The most frequent therapeutic antibodies (Abs) used in desensitization protocols (intravenous immunoglobulins, rituximab, basiliximab, eculizumab, antithymocyte globulin) were added to a negative- or a positive control serum at various concentrations, and tested in vitro in a LCT-XM test. RESULTS: Rituximab turned the LCT-XM positive on B cells at 0.2 MUg/mL and antithymocyte globulin turned the LCT-XM positive with T and B cells at 20 MUg/mL and 200 MUg/mL, respectively. Treatment with dithiothreitol sera, supplemented with rituximab (0.2 and 2 MUg/mL) and antithymocyte globulins (20 and 200 MUg/mL), partially or totally reduced this positive interference. Intravenous immunoglobulin, eculizumab, and basiliximab did not trigger any interference with the negative control serum. In a positive LCT-XM, eculizumab did not annihilate activation of the rabbit complement. Intravenous immunoglobulins (25 g/L) could partially or totally reduced lysis score of positive crossmatch with weak lysis scores. CONCLUSION: If eculizumab within the serum did not annihilate rabbit complement activation and basiliximab did not interfere with the crossmatch reaction, treatments based on rituximab, antithymocyte globulin and intravenous immunoglobulins need to be taken into account when interpreting a positive or negative crossmatch test. PMID- 25936349 TI - In silico analyses of Wilms' tumor protein to designing a novel multi-epitope DNA vaccine against cancer. AB - Predefined and pre-weighted objective criteria and essential role of Wilms' tumor wild type gene (WT1) for maintaining transformed features of cancer cells confirm the high potency of WT1 as a valuable cancer antigen. The antigen was at the top of the ranking among 75 representative cancer antigens. In the present study, an in silico approach was launched to characterized novel CTL epitopes and design a novel multi-epitope DNA vaccine to elicit a desirable immune response against cancers over expressing WT1. Forty-four novel epitopes were described. A multi epitope construct was designed based on predicted epitopes which is 310 residues in length. The vaccine candidate designed here displays acceptable population coverage (>65%) in different ethnicities as well as high probability of eliciting WT1 antibodies which both are pertinent goals in the context of appropriate multi epitope vaccines. Various in silico analyses indicate that final vaccine is a qualified immunotherapy candidate capable of eliciting both CD4+ and CD8+ T cell responses. PMID- 25936350 TI - Mesenchymal stem cells abrogate experimental asthma by altering dendritic cell function. AB - Mesenchymal stem cells (MSCs) have been investigated in the treatment of numerous autoimmune diseases. However, the immune properties of MSCs on the development of asthma have remained to be fully elucidated. Airway dendritic cells (DCs) have an important role in the pathogenesis of allergic asthma, and disrupting their function may be a novel therapeutic approach. The present study used a mouse model of asthma to demonstrate that transplantation of MSCs suppressed features of asthma by targeting the function of lung myeloid DCs. MSCs suppressed the maturation and migration of lung DCs to the mediastinal lymph nodes, and thereby reducing the allergen-specific T helper type 2 (Th2) response in the nodes. In addition, MSC-treated DCs were less potent in activating naive and effector Th2 cells and the capacity of producing chemokine (C-C motif) ligand 17 (CCL17) and CCL22, which are chemokines attracting Th2 cells, to the airways was reduced. These results supported that MSCs may be used as a potential treatment for asthma. PMID- 25936352 TI - Rosmarinic acid up-regulates the noise-activated Nrf2/HO-1 pathway and protects against noise-induced injury in rat cochlea. AB - Noise-induced hearing loss depends on progressive increase of reactive oxygen species and lipoperoxidative damage in conjunction with the imbalance of antioxidant defenses. The redox-sensitive transcription factor nuclear factor erythroid 2-related factor 2 (Nrf2) plays a critical role in the regulation of cellular defenses against oxidative stress, including heme oxygenase-1 (HO-1) activation. In this work we describe a link between cochlear oxidative stress damage, induced by noise exposure, and the activation of the Nrf2/HO-1 pathway. In our model, noise induces superoxide production and overexpression of the lipid peroxidation marker 4-hydroxy-nonenals (4-HNE). To face the oxidative stress, the endogenous defense system is activated as well, as shown by the slight activation of superoxide dismutases (SODs). In addition, we observed the activation of the Nrf2/HO-1 pathway after noise exposure. Nrf2 appears to promote the maintenance of cellular homeostasis under stress conditions. However, in this model the endogenous antioxidant system fails to counteract noise-induced cell damage and its activation is not effective enough in preventing cochlear damage. The herb derived phenol rosmarinic acid (RA) attenuates noise-induced hearing loss, reducing threshold shift, and promotes hair cell survival. In fact, RA enhances the endogenous antioxidant defenses, as shown by decreased superoxide production, reduced expression of 4-HNE, and up-regulation of SODs. Interestingly, RA potentiates the Nrf2/HO-1 signaling pathway, as shown by immunohistochemical and Western blot analyses. Thus, protective effects of RA are associated with the induction/activation of the Nrf2-ARE signaling pathway in addition to RA direct scavenging capability. PMID- 25936351 TI - The MAPK signaling pathway mediates the GPR91-dependent release of VEGF from RGC 5 cells. AB - Vascular endothelial growth factor (VEGF) is one of the major regulatory molecules in diabetic retinopathy (DR). In our previous study, we demonstrated that succinate levels were elevated in the retinas of diabetic rats and that the knockdown of the succinate receptor, G-protein-coupled receptor 91 (GPR91), inhibited the release of VEGF and attenuated retinal vascular disorder in the early stages of DR. In the present study, we examined the signaling pathways involved in the GPR91-dependent release of VEGF in the retinal ganglion cell line, RGC-5. The cells were infected with a lentiviral small hairpin RNA (shRNA) expression vector targeting GPR91 (LV.shGPR91). Immunofluorescence staining revealed that GPR91 was predominantly localized in the cell bodies of the RGC-5 cells. RT-qPCR, western blot analysis and ELISA indicated that succinate exposure upregulated VEGF expression, activated the extracellular signal-regulated protein kinase (ERK)1/2, c-Jun N-terminal kinase (JNK) and p38 mitogen-activated protein kinase (MAPK) signaling pathways and led to the release of cyclooxygenase-2 (COX 2) and prostaglandin E2 (PGE2). The knockdown of GPR91 inhibited ERK1/2 and JNK activity, but did not inhibit the activation of the p38 MAPK pathway. The increase in COX-2 expression and the release of PGE2 were inhibited by transduction with LV.shGPR91 and ERK1/2, JNK and COX-2 inhibitors. The expression and release of VEGF showed similar results. Cell Counting Kit-8 (CCK-8) assays revealed that the shRNA-mediated knockdown of GPR91 decreased the proliferation of RF/6A cells cultured in succinate-conditioned medium. Our data suggest that GPR91 modulates the succinate-induced release of VEGF through the MAPK/COX-2/PGE2 signaling pathway. PMID- 25936353 TI - Plasma thiopurine S-methyltransferase levels and azathioprine-related adverse events in patients with Behcet's disease. AB - OBJECTIVES: Thiopurine S-methyltransferase (TPMT) is the key enzyme inactivating azathioprine (AZA), an immunosuppressive agent commonly used for treating inflammatory diseases including Behcet's disease (BD), systemic lupus erythematosus (SLE) and systemic vasculitis. Low TPMT levels facilitate occurrence of AZA-related adverse effects. We investigated TPMT levels in patients with BD, compared to healthy controls and patients with SLE or systemic vasculitis. METHODS: This cross-sectional study included 101 BD (77 using AZA), 74 SLE (35 using AZA), and 44 vasculitis (18 using AZA) patients and 101 healthy controls. Plasma TPMT levels were measured using ELISA. Student's t- and Kruskal Wallis tests were used to compare TPMT levels according to possible risk factors. Receiver operating characteristic (ROC) analysis was used to determine whether a cut-off TPMT level could be found to predict AZA-related adverse effects. RESULTS: Plasma TPMT levels (mean+/- SD ng/mL) in BD (22.80+/-13.81) were comparable with healthy controls (22.71+/-13.49), but significantly lower than in SLE group (29.37+/-11.39) (p<0.001). TPMT levels in 130 patients receiving AZA were similar to the rest of the group. AZA-related adverse effects were identified in only 8 patients (5 with BD and 3 with SLE). TPMT levels were significantly lower in those 8 patients (14.08+/-9.49 vs. 25.62+/-12.68) (p=0.013), besides a cut-off value for predicting adverse effects was determined for the BD group with ROC analysis (area under the curve: 0.813). CONCLUSIONS: This is the first study to evaluate TPMT activity in a Turkish adult population. Although low plasma TPMT level is not the only factor determining AZA toxicity, a TPMT cut-off value may help to predict AZA-related adverse effects in BD. PMID- 25936354 TI - Regulatory acceptance and use of serology for inactivated veterinary rabies vaccines. AB - In April 2013 the mouse antibody serum neutralization test (SNT) was formally incorporated into European Pharmacopoeia monograph 0451 for potency testing of inactivated veterinary rabies vaccines. The SNT is designed to replace the highly variable and pain and distress causing NIH mouse rabies challenge assay. The adoption of the SNT meets the European ambition (i.e., EC and CoE) to replace, reduce and/or refine laboratory animal testing. However, regulatory acceptance and use of 3R models, such as the SNT, remains challenging. This paper aims at clarifying the process of acceptance and use of the SNT. For this purpose it reconstructs the process and reveals barriers and drivers that have been observed by involved stakeholders to have played a role. In addition it extracts lessons to stimulate regulatory acceptance in similar future processes. The incorporation of the SNT into the monographs went relatively quick due to a thorough test development and pre-validation phase, commitment and cooperation of relevant stakeholders and a strong project coordination of the international validation study. The test was developed by the Paul Ehrlich Institut; a leading European OMCLs. This facilitated its European regulatory use. The use by industry is in a critical phase. At this stage product specific validation and the question whether the SNT will be accepted outside Europe are important influencing factors. PMID- 25936355 TI - Neutrophil-to-lymphocyte ratio in patients with severe tinnitus: prospective, controlled clinical study. AB - OBJECTIVE: To determine the relationship between severe tinnitus and inflammation using the neutrophil-to-lymphocyte ratio as a marker of stress. METHODS: A total of 107 patients who had been suffering with severe tinnitus (tinnitus handicap inventory scale grades of 3-5) for at least 2 weeks were recruited. Patients underwent detailed ENT examinations and audiometric tests to exclude a relevant pathological cause of the tinnitus. Patients with systemic diseases, malignancy or inflammatory diseases that could alter neutrophil-to-lymphocyte ratio were excluded. A total of 107 age- and sex-matched healthy control participants were also recruited. Routine laboratory test results and neutrophil-to-lymphocyte ratio were compared between the patients and controls. RESULTS: Lipid profile, liver function, white blood cell count, haemoglobin level, mean corpuscular volume, and vitamin B12 and folate levels were similar among the patients and controls. However, mean neutrophil-to-lymphocyte ratio was significantly higher among the patients than the controls (p < 0.05). CONCLUSION: The findings of this novel study suggest that neutrophil-to-lymphocyte ratio should be considered during the evaluation of tinnitus patients as a potential clinical marker of tinnitus. Further studies are required to verify the findings. PMID- 25936356 TI - Impact of school lunch type on nutritional quality of English children's diets. AB - OBJECTIVE: Nutrient and food standards exist for school lunches in English primary schools although packed lunches brought from home are not regulated. The aim of the present study was to determine nutritional and dietary differences by lunch type. DESIGN: A cross-sectional survey was carried out in 2007 assessing diet using the Child and Diet Evaluation Tool (CADET), a validated 24 h estimated food diary. The data were analysed to determine nutritional and dietary intakes over the whole day by school meal type: school meals and packed lunches. SETTING: Fifty-four primary schools across England. SUBJECTS: Children (n 2709) aged 6-8 years. RESULTS: Children having a packed lunch consumed on average 11.0 g more total sugars (95 % CI 6.6, 15.3 g) and 101 mg more Na (95 % CI 29, 173 mg) over the whole day. Conversely, children having a school meal consumed, on average, 4.0 g more protein (95 % CI 2.3, 5.7 g), 0.9 g more fibre (NSP; 95 % CI 0.5, 1.3 g) and 0.4 mg more Zn (95 % CI 0.1, 0.6 mg). There was no difference in daily energy intake by lunch type. Children having a packed lunch were more likely to consume snacks and sweetened drinks; while children having a school meal were more likely to consume different types of vegetables and drink water over the whole day. CONCLUSIONS: Compared with children having a school meal, children taking a packed lunch to school consumed a lower-quality diet over the whole day, including higher levels of sugar and Na and fewer vegetables. These findings support the introduction of policies that increase school meal uptake. PMID- 25936358 TI - Locomotion and the Cost of Hunting in Large, Stealthy Marine Carnivores. AB - Foraging by large (>25 kg), mammalian carnivores often entails cryptic tactics to surreptitiously locate and overcome highly mobile prey. Many forms of intermittent locomotion from stroke-and-glide maneuvers by marine mammals to sneak-and-pounce behaviors by terrestrial canids, ursids, and felids are involved. While affording proximity to vigilant prey, these tactics are also associated with unique energetic costs and benefits to the predator. We examined the energetic consequences of intermittent locomotion in mammalian carnivores and assessed the role of these behaviors in overall foraging efficiency. Behaviorally linked, three-axis accelerometers were calibrated to provide instantaneous locomotor behaviors and associated energetic costs for wild adult Weddell seals (Leptonychotes weddellii) diving beneath the Antarctic ice. The results were compared with previously published values for other marine and terrestrial carnivores. We found that intermittent locomotion in the form of extended glides, burst-and-glide swimming, and rollercoaster maneuvers while hunting silverfish (Pleuragramma antarcticum) resulted in a marked energetic savings for the diving seals relative to continuously stroking. The cost of a foraging dive by the seals decreased by 9.2-59.6%, depending on the proportion of time gliding. These energetic savings translated into exceptionally low transport costs during hunting (COTHUNT) for diving mammals. COTHUNT for Weddell seals was nearly six times lower than predicted for large terrestrial carnivores, and demonstrates the importance of turning off the propulsive machinery to facilitate cost-efficient foraging in highly active, air-breathing marine predators. PMID- 25936357 TI - Colorectal cancer stem cell and chemoresistant colorectal cancer cell phenotypes and increased sensitivity to Notch pathway inhibitor. AB - Colorectal cancer stem cells (Co-CSCs) are a small subpopulation of tumor cells which have been proposed to be tumor-initiating cells in colorectal cancer (CRC) and to be implicated in resistance to standard chemotherapy. Chemoresistance is a common problem in the clinic. However, the interrelation between Co-CSCs and chemoresistant cells has yet to be elucidated. The present study investigated the Co-CSC phenotype in colonospheres and chemoresistant CRC cell lines and aimed to identify targets for therapy. Colonospheres and chemoresistant CRC cells were found to be enriched with the CSC markers CD133 and CD44, and exhibited similar phenotypes. Furthermore, it was found that Notch signaling may simultaneously regulate Co-CSCs and chemoresistant cells and may represent a novel strategy for targeting this pathway in CRC. PMID- 25936359 TI - A Solution Strategy to Include the Opening of the Opercular Slits in Moving-Mesh CFD Models of Suction Feeding. AB - The gill cover of fish and pre-metamorphic salamanders has a key role in suction feeding by acting as a one-way valve. It initially closes and avoids an inflow of water through the gill slits, after which it opens to allow outflow of the water that was sucked through the mouth into the expanded buccopharyngeal cavity. However, due to the inability of analytical models (relying on the continuity principle) to calculate the flow of fluid through a cavity with two openings and that was changing in shape and size, stringent boundary conditions had to be used in previously developed mathematical models after the moment of the valve's opening. By solving additionally for the conservation of momentum, computational fluid dynamics (CFD) has the capacity to dynamically simulate these flows, but this technique also faces complications in modeling a transition from closed to open valves. Here, I present a relatively simple solution strategy to incorporate the opening of the valves, exemplified in an axisymmetrical model of a suction feeding sunfish in ANSYS Fluent software. By controlling viscosity of a separately defined fluid entity in the region of the opercular cavity, early inflow can be blocked (high viscosity assigned) and later outflow can be allowed (changing viscosity to that of water). Finally, by analyzing the CFD solution obtained for the sunfish model, a few new insights into the biomechanics of suction feeding are gained. PMID- 25936360 TI - Hydrodynamic Constraints of Suction Feeding in Low Reynolds Numbers, and the Critical Period of Larval Fishes. AB - Larval fishes suffer prodigious mortality rates, eliminating 99% of the cohort within a few days after their first feeding. Hjort (1914) famously attributed this "critical period" of low survival to larval inability to obtain sufficient food. We discuss recent experimental and modeling work, suggesting that the viscous hydrodynamic regime have marked effects on the mechanism of suction feeding in larval fish. As larvae grow, the size of the gape and associated volume of the mouth increase. At the same time, larvae swim faster and can generate faster suction flows, thus transiting to a hydrodynamic regime of higher Reynolds numbers. This hydrodynamic regime further leads to changes in the spatio temporal patterns of flow in front of the mouth, and an increasing ability in larger larvae to exert suction forces on the prey. Simultaneously, the increase in swimming speed and the distance from which the prey is attacked result in higher rates of encountering prey by larger (older) larvae. In contrast, during the first few days after feeding commence the lower rates of encounter and success in feeding translate to low feeding rates. We conclude that young larvae experience "hydrodynamic starvation," in which low Reynolds numbers mechanically limit their feeding performance even under high densities of prey. PMID- 25936361 TI - Linear accuracy and reliability of volume data sets acquired by two CBCT-devices and an MSCT using virtual models: a comparative in-vitro study. AB - OBJECTIVE: To discriminate clinically relevant aberrance, the accuracy of linear measurements in three-dimensional (3D) reconstructed datasets was investigated. MATERIALS AND METHODS: Three partly edentulous human skulls were examined. Landmarks were defined prior to acquisition. Two CBCT-scanners and a Quad-slice CT-scanner were used. Actual distances were physically measured with calipers and defined as a reference. Subsequently, from digital DICOM datasets, 3D virtual models were generated using maximum intensity projections (MIPs). Linear measurements were performed by semi-automated image analysis. Virtual and analogue linear measurements were compared using repeated measurements in a mixed model (p <= 0.05). RESULTS: No significant difference was found among all of the digital measurements when compared to one another, whereas a significant difference was found in matched-pairs analysis between CBCT and calipers (p = 0.032). All digitally acquired data resulted in lower mean values compared to the measurements via calipers. A high level of inter-observer reliability was obtained in the digital measurements (inter-rater correlation = 0.988-0.993). CONCLUSIONS: The reconstructed datasets led to highly consistent values among linear measurements. Yielding sub-millimeter precision, these modalities are assumed to reflect reality in a clinically irrelevant altered manner. During data acquisition and evaluation, a maximum of precision must be achieved. PMID- 25936363 TI - Romidepsin for the treatment of non-Hodgkin's lymphoma. AB - INTRODUCTION: Patients with relapsed or refractory lymphoma remain a population with unmet medical needs. Histone deacetylase inhibitors (HDACIs) represent a novel class of anticancer drugs currently in development in several malignancies. Inhibition of HDACs leads to acetylation of histone and non-histone proteins, which in turn results in epigenetic modification of gene expression that leads to a plethora of effects, such as cell cycle arrest, apoptosis and inhibition of angiogenesis. Romidepsin is a novel HDACI that has demonstrated preclinical and clinical activity. AREAS COVERED: This review discusses the different HDACs and epigenetic regulation with a particular focus on the preclinical and clinical development of romidepsin in lymphoma. The review of romidepsin includes: the mechanism of action, its synergistic interaction with novel agents, pivotal clinical trials that lead to its US FDA approval in cutaneous T-cell lymphoma and peripheral T-cell lymphoma as well as active combinations currently in clinical trials. EXPERT OPINION: Romidepsin is a potent HDACI with clinical activity in T cell lymphoma where novel agents and combinations are desperately needed. A deeper understanding of the molecular characteristics of this class of agents will allow the design of more potent drugs with improved toxicity profiles and future rational combinations that will expand the indication and benefit from these novel agents. PMID- 25936362 TI - D-Galactose High-Dose Administration Failed to Induce Accelerated Aging Changes in Neurogenesis, Anxiety, and Spatial Memory on Young Male Wistar Rats. AB - The model of accelerated senescence with the prolonged administration of d galactose is used in anti-aging studies because it mimics several aging associated alterations such as increase of oxidative stress and decline of cognition. However, there is no standardized protocol for this aging model, and recently some reports have questioned its effectiveness. To clarify this issue, we used a model of high-dose d-galactose on 1-month-old male Wistar rats and studied the hippocampus, one of the most affected brain regions. In one group (n = 10), d-galactose was daily administered intraperitoneally (300 mg/kg) during 8 weeks whereas age-matched controls (n = 10) were injected intraperitoneally with saline. A third group (n = 10) was treated with the same dose of d-galactose and with oral epigallocatechin-3-gallate (EGCG) (2 grams/L), a green tea catechin with anti-oxidant and neuroprotective properties. After treatments, animals were submitted to open-field, elevated plus-maze and Morris water maze tests, and neurogenesis in the dentate gyrus subgranular layer was quantified. There were no significant alterations when the three groups were compared in the number of doublecortin- and Ki-67-immunoreactive cells, and also on anxiety levels, spatial learning, and memory. Therefore, d-galactose was not effective in the induction of accelerated aging, and EGCG administered to d-galactose-treated animals did not improve behavior and had no effects on neurogenesis. We conclude that daily 300 mg/kg of d-galactose administered intraperitoneally may not be a suitable model for inducing age-related neurobehavioral alterations in young male Wistar rats. More studies are necessary to obtain a reliable and reproducible model of accelerated senescence in rodents using d-galactose. PMID- 25936364 TI - The effect of endocannabinoid system in ischemia-reperfusion injury: a friend or a foe? AB - INTRODUCTION: In recent years, the endocannabinoid system has emerged as a new therapeutic target in variety of disorders associated with inflammation and tissue injury, including those of the neuronal, liver, renal and cardiovascular system. The aim of the present review is to elucidate the effect of endocannabinoid system on ischemia reperfusion injury (IRI) in different organs and systems. AREAS COVERED: The MEDLINE/PubMed database was searched for publications with the medical subject heading Cannabinoids* (CBs), CB receptors*, organ*, ischemia/reperfusion injury*, endocannabinoid* and system*. The initial relevant studies retrieved from the literature were 91 from PubMed. This number was initially limited to 35, after excluding the reviews and studies reporting data for receptors other than cannabinoid. EXPERT OPINION: CB2 receptors may play an important compensatory role in controlling tissue inflammation and injury in cells of the neuronal, cardiovascular, liver and renal systems, as well as in infiltrating monocytes/macrophages and leukocytes during various pathological conditions of the systems (atherosclerosis, restenosis, stroke, myocardial infarction, heart, liver and renal failure). These receptors limit inflammation and associated tissue injury. On the basis of preclinical results, pharmacological modulation of CB2 receptors may hold a unique therapeutic potential in stroke, myocardial infarction, atherosclerosis, IRI and liver disease. PMID- 25936365 TI - Molecular hydrogen: An inert gas turns clinically effective. AB - Molecular hydrogen (H2) appeared as an experimental agent in biomedicine approximately 40 years ago, yet the past 5 years seem to confirm its medicinal value in the clinical environment. H2 improves clinical end-points and surrogate markers in several clinical trials, from metabolic diseases to chronic systemic inflammatory disorders to cancer. However, less information is available concerning its medicinal properties, such as dosage and administration, or adverse reactions and use in specific populations. The present paper overviews the clinical relevance of molecular hydrogen, and summarizes data from clinical trials on this innovative medical agent. Clinical profiles of H2 provide evidence based direction for practical application and future research on molecular hydrogen for the wider health care community. PMID- 25936366 TI - Photolysis Kinetics, Mechanisms, and Pathways of Tetrabromobisphenol A in Water under Simulated Solar Light Irradiation. AB - The photolysis of tetrabromobisphenol A (TBBPA) in aqueous solution under simulated solar light irradiation was studied under different conditions to find out mechanisms and pathways that control the transformation of TBBPA during photoreaction. Particular attention was paid to the identification of intermediates and elucidation of the photolysis mechanism of TBBPA by UPLC, LC/MS, FT-ICR-MS, NMR, ESR, and stable isotope techniques ((13)C and (18)O). The results showed that the photolysis of TBBPA could occur under simulated solar light irradiation in both aerated and deaerated conditions. A magnetic isotope effect (MIE)-hydrolysis transformation was proposed as the predominant pathway for TBBPA photolysis in both cases. 2,6-Dibromophenol and two isopropylphenol derivatives were identified as photooxidation products of TBBPA by singlet oxygen. Reductive debromination products tribromobisphenol A and dibromobisphenol A were also observed. This is the first report of a photolysis pathway involving the formation of hydroxyl-tribromobisphenol A. PMID- 25936367 TI - Poly(vinylidene fluoride)/NH2-Treated Graphene Nanodot/Reduced Graphene Oxide Nanocomposites with Enhanced Dielectric Performance for Ultrahigh Energy Density Capacitor. AB - This work describes a ternary nanocomposite system, composed of poly(vinylidene fluoride) (PVDF), NH2-treated graphene nanodots (GNDs), and reduced graphene oxides (RGOs), for use in high energy density capacitor. When the RGO sheets were added to PVDF matrix, the beta-phase content of PVDF became higher than that of the pristine PVDF. The surface-treatment of GNDs with an ethylenediamine can promote the hydrogen bonding interactions between the GNDs and PVDF, which promote the formation of beta-phase PVDF. This finding could be extended to combine the advantages of both RGO and NH2-treated GND for developing an effective and reliable means of preparing PVDF/NH2-treated GND/RGO nanocomposite. Relatively small amounts of NH2-treated GND/RGO cofillers (10 vol %) could make a great impact on the alpha -> beta phase transformation, dielectric, and ferroelectric properties of the ternary nanocomposite. The resulting PVDF/NH2 treated GND/RGO nanocomposite exhibited higher dielectric constant (epsilon' ~ 60.6) and larger energy density (U(e) ~ 14.1 J cm(-3)) compared with the pristine PVDF (epsilon' ~ 11.6 and U(e) ~ 1.8 J cm(-3)). PMID- 25936368 TI - Appropriate salt concentration of nanodiamond colloids for electrostatic self assembly seeding of monosized individual diamond nanoparticles on silicon dioxide surfaces. AB - Monosized (~4 nm) diamond nanoparticles arranged on substrate surfaces are exciting candidates for single-photon sources and nucleation sites for ultrathin nanocrystalline diamond film growth. The most commonly used technique to obtain substrate-supported diamond nanoparticles is electrostatic self-assembly seeding using nanodiamond colloidal suspensions. Currently, monodisperse nanodiamond colloids, which have a narrow distribution of particle sizes centering on the core particle size (~4 nm), are available for the seeding technique on different substrate materials such as Si, SiO2, Cu, and AlN. However, the self-assembled nanoparticles tend to form small (typically a few tens of nanometers or even larger) aggregates on all of those substrate materials. In this study, this major weakness of self-assembled diamond nanoparticles was solved by modifying the salt concentration of nanodiamond colloidal suspensions. Several salt concentrations of colloidal suspensions were prepared using potassium chloride as an inserted electrolyte and were examined with respect to seeding on SiO2 surfaces. The colloidal suspensions and the seeded surfaces were characterized by dynamic light scattering and atomic force microscopy, respectively. Also, the interaction energies between diamond nanoparticles in each of the examined colloidal suspensions were compared on the basis of the Derjaguin-Landau-Verwey-Overbeek (DLVO) theory. From these investigations, it became clear that the appropriate salt concentration suppresses the formation of small aggregates during the seeding process owing to the modified electrostatic repulsive interaction between nanoparticles. Finally, monosized (<10 nm) individual diamond nanoparticles arranged on SiO2 surfaces have been successfully obtained. PMID- 25936369 TI - Detection of adenovirus and respiratory syncytial virus in patients with chronic obstructive pulmonary disease: Exacerbation versus stable condition. AB - Latent infection with adenovirus and respiratory syncytial virus (RSV) is associated with chronic obstructive pulmonary disease (COPD). The role of respiratory viral infections are emerging in COPD exacerbations. The present study aimed to investigate the prevalence of adenovirus and RSV serotypes A and B in individuals with acute exacerbations of COPD (COPD-AE) and stable COPD. Twenty seven patients with COPD-AE were evaluated using a prospective longitudinal study design. Induced sputum, sera and nasal smears were sampled from patients experiencing COPD-AE and those in a stable condition. Adenoplex(r) multiplex polymerase chain reaction (PCR) kits and Invitek RTP(r) DNA/RNA Virus Mini kits were used for PCR assays of adenovirus and RSV, respectively. Eighteen patients who experienced a COPD-AE were also evaluated while in a stable condition. The results showed that three sputum samples were positive for adenovirus in patients experiencing an exacerbation, while one was positive among the patients in a stable condition. RSV serotype A was detected in 17/27 (63%) patients with COPD AE and 10/18 (55.6%) patients in a stable condition. RSV serotype B was not detected. Patients with COPD-AE, who were positive for RSV serotype A exhibited higher serum fibrinogen levels than those who were negative (438.60 +/- 126.08 mg/dl compared with 287.60 +/- 85.91 mg/dl; P=0.004). Eight/ten patients who were positive for RSV serotype A while in a stable condition, were also positive during COPD-AE. The results of the present study suggested that RSV infection may be prevalent in patients with COPD-AE and in those in a stable condition. Therefore, chronic RSV infection may occur in COPD. The detection and prevention of RSV may be useful in the management of COPD. PMID- 25936370 TI - Strong Visible Absorption and Broad Time Scale Excited-State Relaxation in (Ga(1 x)Zn(x))(N(1-x)O(x)) Nanocrystals. AB - (Ga(1-x)Zn(x))(N(1-x)O(x)) is a visible absorber of interest for solar fuel generation. We present a first report of soluble (Ga(1-x)Zn(x))(N(1-x)O(x)) nanocrystals (NCs) and their excited-state dynamics over the time window of 10( 13)-10(-4) s. Using transient absorption spectroscopy, we find that excited-state decay in (Ga0.27Zn0.73)(N0.27O0.73) NCs has both a short (<100 ps) and a long lived component, with a long overall average lifetime of ~30 MUs. We also find that the strength of the visible absorption is comparable to that of direct band gap semiconductors such as GaAs. We discuss how these results may relate to the origin of visible absorption in (Ga(1-x)Zn(x))(N(1-x)O(x)) and its use in solar fuel generation. PMID- 25936371 TI - Establishment of an interleukin-1beta-induced inflammation-activated endothelial cell-smooth muscle cell-mononuclear cell co-culture model and evaluation of the anti-inflammatory effects of tanshinone IIA on atherosclerosis. AB - Increasing evidence supports the hypothesis that inflammatory reactions serves an important function in the formation, progression and plaque rupture of atherosclerosis. Interleukin (IL)-1 primarily induces inflammation and is closely associated with the inflammatory environment and the formation of atherosclerosis. The present study aimed to establish an in vitro model for the evaluation of drug efficacy in the intervention of atherosclerosis from the inflammatory perspective, and to observe the anti-inflammatory effects of tanshinone IIA and andrographolide on atherosclerosis. The IL-1beta-induced inflammation-activated endothelial cell (EC)-smooth muscle cell (SMC)-mononuclear cell (MC) co-culture model was established, based on the changes in a series of atherosclerosis-associated inflammatory markers secreted by ECs and SMCs. The expression of connexin in ECs, adhesion of MCs and changes in inflammatory signalling molecules were selected as evaluation indices for the inflammatory microenvironment of atherosclerosis. The use of this model revealed that tanshinone IIA exhibited significant efficacy against atherosclerosis and its inflammatory reactions. Inflammatory reactions were regarded as the primary mechanism underlying atherosclerosis. The established model simulated a series of relevant changes in the arterial wall under the inflammatory cytokines with oxidized low-density lipoprotein during the atherosclerotic process. The present study presented a reliable method for the identification of drugs with potential anti-inflammatory activity in atherosclerosis, for investigating the mechanisms of action, considering the improvement of the inflammatory state and the increase in plaque stability observed. PMID- 25936373 TI - Improvement of psoriasis-associated arthritis and skin lesions by treatment with molecular hydrogen: A report of three cases. AB - Psoriasis, a chronic inflammatory skin disease, is caused by infiltrating lymphocytes and associated cytokines, including tumor necrosis factor (TNF)alpha, interleukin (IL)-6, and IL-17. Effective treatments, including pathogenesis-based biological agents against psoriasis, are currently under development. Although the role of reactive oxygen species (ROS) in the pathogenesis of psoriasis has been investigated, it remains to be fully elucidated; ROS-targeted therapeutic strategies are also lacking at present. Therefore, the objective of the present study was to assess whether H2, a ROS scavenger, has a therapeutic effect on psoriasis-associated inflammation by reducing hydroxyl radicals or peroxynitrite in the immunogenic psoriasis cascade. Three methods were used to administer H2: Drop infusion of saline containing 1 ppm H2 (H2-saline), inhalation of 3% H2 gas, and drinking of water containing a high concentration (5-7-ppm) of H2 (high-H2 water). Treatment efficacy was estimated using the disease activity score 28 (DAS28) system, based on C-reactive protein levels, and the psoriasis area and severity index (PASI) score, determined at baseline and following each H2 treatment. Furthermore, levels of TNFalpha, IL-6, and IL-17 were analyzed. The DAS28 and PASI score of the three patients decreased during H2 treatment, regardless of the administration method. The psoriatic skin lesions almost disappeared at the end of the treatment. IL-6 levels decreased during H2 treatment in Case 1 and 2. IL-17, whose concentration was high in Case 1, was reduced following H2 treatment, and TNFalpha also decreased in Case 1. In conclusion, H2 administration reduced inflammation associated with psoriasis in the three cases examined and it may therefore be considered as a treatment strategy for psoriasis-associated skin lesions and arthritis. PMID- 25936372 TI - MFG-E8 inhibits neutrophil migration through alphavbeta3-integrin-dependent MAP kinase activation. AB - We have previously demonstrated the involvement of milk fat globule-epidermal growth factor-factor 8 (MFG-E8) in reducing neutrophil infiltration in a murine model of acute lung injury (ALI). In the present study, we aimed to delineate the mechanisms through which MFG-E8 attenuates neutrophil migration. Recombinant human MFG-E8 (rhMFG-E8) was expressed and purified in our facility. The human differentiated neutrophil cell line, dHL-60, was treated with rhMFG-E8 and cell migration assay was performed in a Boyden chamber using recombinant interleukin-8 (IL-8) as the chemoattractant. Surface CXCR2 and intracellular G protein-coupled receptor kinase 2 (GRK2) levels were evaluated by flow cytometry or western blot analysis. The levels of mitogen-activated protein (MAP) kinases were determined by western blot analysis. Treatment with rhMFG-E8 resulted in a significant inhibition of dHL-60 cell migration in a dose-dependent manner. There was a 46% decrease in CXCR2 expression in the rhMFG-E8-treated dHL-60 cells, which was associated with a 32% increase in GRK2 expression. In the dHL-60 cells, treatment with rhMFG-E8 promoted the phosphorylation of p38 and extracellular signal regulated kinase (ERK) within 10-30 min. The use of SB203580, a p38 inhibitor, and PD98059, an ERK inhibitor, resulted in the restoration of dHL-60 cell migration which was significantly inhibited treatment with rhMFG-E8. Furthermore, blocking the MFG-E8 receptors, alphavbeta3/alphavbeta5-integrins, by anti-alphav integrin neutralizing antibody (Ab) inhibited the activation of p38 and ERK, and reversed the rhMFG-E8-induced inhibition of dHL-60 cell migration. Finally, treatment of the dHL-60 cells with SB203580 and PD98059 neutralized the rhMFG-E8 induced downregulation of CXCR2 expression and upregulation of GRK2 expression, as well as the inhibitory effects on cell migration. Our findings reveal a novel mechanism of action of MFG-E8 through which it inhibits neutrophil migration through alphavbeta3-integrin-dependent MAP kinase activation. PMID- 25936374 TI - No increased cardiovascular mortality among early rheumatoid arthritis patients: a nationwide register study in 2000-2008. AB - OBJECTIVES: To assess cardiovascular (CV) mortality in early rheumatoid arthritis (RA), and the impact of RA medications on CV mortality. METHODS: We identified all incident RA patients over 18 years of age diagnosed between 2000 and 2007 in Finland. Causes of death were analysed until the end of the year 2008. We used competing-risks regression models to assess the impact of different variables such as RA medications on CV mortality. CV mortality was compared with that of the age- and sex-specific general population. RESULTS: We identified 14,878 incident RA patients (68% women, 63% rheumatoid factor (RF) positive, mean age 55.8/57.5 years in men/women), of whom more than 80% received RA medications for longer than 90% of their individual patient-years. By the end of 2008, 1,157 patients died, 501 (43%) of whom of CV causes. The standardised mortality ratio (SMR) for CV deaths in the entire RA cohort was 0.57 (95% CI 0.52 to 0.62). Along with traditional CV risk factors, the presence of RF and the use of glucocorticoids was associated with a higher risk of CV death, whereas the use of methotrexate was associated with a lower risk. CONCLUSIONS: These nationwide results suggest that patients with recent-onset RA who receive consistent RA medication have no increased risk for CV mortality compared to the general population, at least in the early years of the disease. The use of methotrexate is associated with lower CV mortality, whereas the use of glucocorticoids is associated with a higher than average CV mortality. PMID- 25936377 TI - A jack-of-all-trades: 2-mercaptosuccinic acid. AB - 2-Mercaptosuccinic acid (MS) is an important and versatile substance for diverse fields of applications of which the most significant are surveyed in this article. Biological, chemical, and physical properties of MS as well as the knowledge of its synthesis and microbial degradation are illustrated. In addition, exemplary structural analogs of the organic sulfur compound are commented. The key application of MS in nanotechnology is discussed in detail with particular emphasis on quantum dots (nanocrystals) and self-assembled monolayers in combination with gold or silver. Furthermore, some medical and pharmaceutical applications are given, inter alia in bioimaging, as a nanocarrier, and with regard to the antimicrobial activity of MS-silver and MS gold nanoparticles. Moreover, biological and chemical applications of MS are exemplified: the thiol compound can serve as an inhibitor for glutathione peroxidase, or the toxicity of substances can be increased due to the presence of MS in the respective cells or tissues. In the field of cosmetics, MS is widely utilized as a reducing agent for numerous products as explained in this article. Additionally, the microbial utilization of MS as a carbon and energy source for growth is elucidated in-depth, providing insight into different catabolic mechanisms. PMID- 25936375 TI - Optimization of synergism of a recombinant auxiliary activity 9 from Chaetomium globosum with cellulase in cellulose hydrolysis. AB - Auxiliary activity family 9 (AA9, formerly known as glycoside hydrolase family 61 or polysaccharide monooxygenase) is a group of fungal proteins that were recently found to have a significant synergism with cellulase in cellulose hydrolysis via the oxidative cleavage of glycosidic bonds of cellulose chains. In this study, we report the active expression of a recombinant fungal AA9 from Chaetomium globosum (CgAA9) in a bacterial host, Escherichia coli, and the optimization of its synergistic activity in cellulose hydrolysis by using cellulase. The recombinant CgAA9 (0.9 mg/g cellulose) exhibited 1.7-fold synergism in the hydrolysis of Avicel when incubated with 0.9 filter paper units of Celluclast 1.5 L/g cellulose. The first study of the active expression of AA9 using a bacterial host and its synergistic optimization could be useful for the industrial application of AA9 for the saccharification of lignocellulose. PMID- 25936376 TI - Targeting surface-layer proteins with single-domain antibodies: a potential therapeutic approach against Clostridium difficile-associated disease. AB - Clostridium difficile is a leading cause of death from gastrointestinal infections in North America. Antibiotic therapy is effective, but the high incidence of relapse and the rise in hypervirulent strains warrant the search for novel treatments. Surface layer proteins (SLPs) cover the entire C. difficile bacterial surface, are composed of high-molecular-weight (HMW) and low-molecular weight (LMW) subunits, and mediate adherence to host cells. Passive and active immunization against SLPs has enhanced hamster survival, suggesting that antibody mediated neutralization may be an effective therapeutic strategy. Here, we isolated a panel of SLP-specific single-domain antibodies (VHHs) using an immune llama phage display library and SLPs isolated from C. difficile hypervirulent strain QCD-32g58 (027 ribotype) as a target antigen. Binding studies revealed a number of VHHs that bound QCD-32g58 SLPs with high affinity (K D = 3-6 nM) and targeted epitopes located on the LMW subunit of the SLP. The VHHs demonstrated melting temperatures as high as 75 degrees C, and a few were resistant to the gastrointestinal protease pepsin at physiologically relevant concentrations. In addition, we demonstrated the binding specificity of the VHHs to the major C. difficile ribotypes by whole cell ELISA, where all VHHs were found to bind 001 and 027 ribotypes, and a subset of antibodies were found to be broadly cross reactive in binding cells representative of 012, 017, 023, and 078 ribotypes. Finally, we showed that several of the VHHs inhibited C. difficile QCD-32g58 motility in vitro. Targeting SLPs with VHHs may be a viable therapeutic approach against C. difficile-associated disease. PMID- 25936378 TI - Mutant screening for oncogenes of Ewing's sarcoma using yeast. AB - Many fusion genes, which are the result of chromosomal translocation and work as an oncogene, have been recently identified, but their mode of actions is still unclear. Here, we performed a yeast mutant screening for oncogenes of Ewing's sarcoma to easily identify essential regions responsible for fusion protein functions using a yeast genetic system. Three kinds of oncogenes including EWS/FLI1, EWS/ERG, and EWS/E1AF exhibited growth inhibition in yeast. In this screening, we identified 13 single amino acid substitution mutants which could suppress growth inhibition by oncogenes. All of the point mutation positions of the EWS/ETS family proteins were located within the ETS domain, which is responsible for the interaction with a specific DNA motif. Eight-mutated residues within the ETS domain matched to 13 completely conserved amino acid residues in the human ETS domains. Moreover, mutants also showed reduced transcriptional activities on the DKK2 promoter, which is upregulated by the EWS/ETS family, compared to that of the wild type. These results suggest that the ETS domain in the EWS/ETS family proteins may be a primary target for growth inhibition of Ewing's sarcoma and that this yeast screening system can be applied for the functional screening of the oncogenes. PMID- 25936379 TI - A three-step method for analysing bacterial biofilm formation under continuous medium flow. AB - For the investigation and comparison of microbial biofilms, a variety of analytical methods have been established, all focusing on different growth stages and application areas of biofilms. In this study, a novel quantitative assay for analysing biofilm maturation under the influence of continuous flow conditions was developed using the interesting biocatalyst Pseudomonas taiwanensis VLB120. In contrast to other tubular-based assay systems, this novel assay format delivers three readouts using a single setup in a total assay time of 40 h. It combines morphotype analysis of biofilm colonies with the direct quantification of biofilm biomass and pellicle formation on an air/liquid interphase. Applying the Tube-Assay, the impact of the second messenger cyclic diguanylate on biofilm formation of P. taiwanensis VLB120 was investigated. To this end, 41 deletions of genes encoding for protein homologues to diguanylate cyclase and phosphodiesterase were generated in the genome of P. taiwanensis VLB120. Subsequently, the biofilm formation of the resulting mutants was analysed using the Tube-Assay. In more than 60 % of the mutants, a significantly altered biofilm formation as compared to the parent strain was detected. Furthermore, the potential of the proposed Tube-Assay was validated by investigating the biofilms of several other bacterial species. PMID- 25936380 TI - A Swedish national twin study of criminal behavior and its violent, white-collar and property subtypes. AB - BACKGROUND: We sought to clarify the etiological contribution of genetic and environmental factors to total criminal behavior (CB) measured as criminal convictions in men and women, and to violent (VCB), white-collar (WCCB) and property criminal behavior (PCB) in men only. METHOD: In 21 603 twin pairs from the Swedish Twin Registry, we obtained information on all criminal convictions from 1973 to 2011 from the Swedish Crime Register. Twin modeling was performed using the OpenMx package. RESULTS: For all criminal convictions, heritability was estimated at around 45% in both sexes, with the shared environment accounting for 18% of the variance in liability in females and 27% in males. The correlation of these risk factors across sexes was estimated at +0.63. In men, the magnitudes of genetic and environmental influence were similar in the three criminal conviction subtypes. However, for violent and white-collar convictions, nearly half and one third of the genetic effects were respectively unique to that criminal subtype. About half of the familial environmental effects were unique to property convictions. CONCLUSIONS: The familial aggregation of officially recorded CB is substantial and results from both genetic and familial environmental factors. These factors are moderately correlated across the sexes suggesting that some genetic and environmental influences on criminal convictions are unique to men and to women. Violent criminal behavior and property crime are substantially influenced respectively by genetic and shared environmental risk factors unique to that criminal subtype. PMID- 25936381 TI - Calcium, vitamin D, casein and whey protein intakes and periodontitis among Danish adults. AB - OBJECTIVE: To investigate whether intakes of Ca, vitamin D, casein and whey are associated with periodontitis and to investigate the possibility of interactions between them. DESIGN: Cross-sectional study. An Internet-based, 267-item FFQ was used to assess dietary intake. Intakes of casein (32.0 g/d), whey proteins (9.6 g/d) and vitamin D (5.8 MUg/d) were classified as within v. above the 50th percentile. Ca intake was classified as within v. below age-specific recommendations. Severe periodontitis was defined as having >=2 inter-proximal sites with clinical attachment loss >=6 mm (not on the same tooth) and >=1 inter proximal site with pocket depth >=5 mm. Since vitamin D influences Ca absorption, models were stratified by lower and higher (<5.8 v. >=5.8 ug/d) vitamin D intake. SETTING: Danish Health Examination Survey (DANHES) 2007-2008. SUBJECTS: Adult participants (n 3287) in the oral health study of DANHES 2007-2008. RESULTS: Intakes of Ca within recommendations (OR=0.76; 95% CI 0.58, 0.99), whey >=9.6 g/d (OR=0.75; 95% CI 0.58, 0.97) and casein >=32 g/d (OR=0.75 95% CI 0.58, 0.97) were associated with lower likelihood of severe periodontitis after adjustment for age, gender, education, smoking, sucrose intake, alcohol consumption, number of teeth, daily brushing, regular visits to the dentist and chronic illness, irrespective of vitamin D intake levels. Intake of vitamin D alone was not associated severe with periodontitis. CONCLUSIONS: Intakes of Ca, casein and whey protein were inversely associated with periodontitis. Consumption of foods rich in Ca, casein and whey (e.g. dairy foods) should be promoted, as they may contribute to the prevention of periodontitis. Further longitudinal studies are required to confirm these associations. PMID- 25936382 TI - Iptakalim attenuates hypoxia-induced pulmonary arterial hypertension in rats by endothelial function protection. AB - The present study aimed to investigate the protective effects of iptakalim, an adenosine triphosphate (ATP)-sensitive potassium channel opener, on the inflammation of the pulmonary artery and endothelial cell injury in a hypoxia induced pulmonary arterial hypertension (PAH) rat model. Ninety-six Sprague Dawley rats were placed into normobaric hypoxia chambers for four weeks and were treated with iptakalim (1.5 mg/kg/day) or saline for 28 days. The right ventricle systolic pressures (RVSP) were measured and small pulmonary arterial morphological alterations were analyzed with hematoxylin and eosin staining. Enzyme-linked immunosorbent assay (ELISA) was performed to analyze the content of interleukin (IL)-1beta and IL-10. Immunohistochemical analysis for ED1(+) monocytes was performed to detect the inflammatory cells surrounding the pulmonary arterioles. Western blot analysis was performed to analyze the expression levels of platelet endothelial cell adhesion molecule-1 (PECAM-1) and endothelial nitric oxide synthase (eNOS) in the lung tissue. Alterations in small pulmonary arteriole morphology and the ultrastructure of pulmonary arterial endothelial cells were observed via light and transmission electron microscopy, respectively. Iptakalim significantly attenuated the increase in mean pulmonary artery pressure, RVSP, right ventricle to left ventricle plus septum ratio and small pulmonary artery wall remodeling in hypoxia-induced PAH rats. Iptakalim also prevented an increase in IL-1beta and a decrease in IL-10 in the peripheral blood and lung tissue, and alleviated inflammatory cell infiltration in hypoxia induced PAH rats. Furthermore, iptakalim enhanced PECAM-1 and eNOS expression and prevented the endothelial cell injury induced by hypoxic stimuli. Iptakalim suppressed the pulmonary arteriole and systemic inflammatory responses and protected against the endothelial damage associated with the upregulation of PECAM-1 and eNOS, suggesting that iptakalim may represent a potential therapeutic agent for PAH. PMID- 25936383 TI - Do changes in oral health-related quality-of-life, facial pain and temporomandibular disorders correlate after treatment of severe malocclusion? AB - INTRODUCTION: The aim was to evaluate the relationships of changes in facial pain, temporomandibular disorders (TMDs) and oral health-related quality-of-life (OHRQoL) in adults who underwent orthodontic or orthodontic/surgical treatment. METHODS: Sixty-four patients (46 women, 18 men, range 18-64 years) with severe malocclusion and functional problems were treated in Oulu University Hospital. Of these, 44 underwent orthodontic-surgical and 20 orthodontic treatment. Data were collected with questionnaires and clinical stomatognathic examinations before and on average 3 years after treatment. The OHRQoL was measured with OHIP-14 (The Oral Health Impact Profile), the intensity of facial pain with the Visual Analogue Scale (VAS) and the severity of TMD with the Helkimo's anamnestic (Ai) and clinical (Di) dysfunction indices. RESULTS: A significant improvement was found in facial pain, signs and symptoms of TMD and OHRQoL after the treatment (p < 0.05). The decrease in VAS was associated with improvement in OHIP-14 severity (r = 0.296, p = 0.019). The correlations between changes in OHIP-14 severity and Ai and Di were not statistically significant. CONCLUSION: Treatment of severe malocclusion seemed to improve OHRQoL via decreased facial pain. Decreased facial pain was associated especially with improved OHRQoL dimensions of physical pain, physical disability and social disability. PMID- 25936384 TI - Pharmacokinetics and clinical evaluation of the alogliptin plus pioglitazone combination for type 2 diabetes. AB - INTRODUCTION: Type 2 diabetes is a complex disease with multiple defects, which generally requires a combination of several pharmacological approaches to reach glucose control targets. A unique fixed-dose combination combines a thiazolidinedione (pioglitazone) and a dipeptidyl peptidase-4 inhibitor (alogliptin). AREA COVERED: An extensive literature search was performed to analyze the pharmacokinetics of pioglitazone and alogliptin when used separately and in combination as well as to summarize clinical and toxicological considerations about the combined therapy. EXPERT OPINION: Pioglitazone, a potent insulin sensitizer, and alogliptin, an incretin-based agent that potentiates post meal insulin secretion and reduces glucagon secretion, have complementary mechanisms of action. The clinical efficacy of a combined therapy is superior to any single therapy in patients treated with diet or with metformin (with or without sulphonylurea). These two drugs can be administered once daily, with or without a meal. No clinically relevant pharmacokinetic interactions between the two agents have been described and the fixed-dose combination has shown bioequivalence with alogliptin and pioglitazone given separately. Combining alogliptin with pioglitazone does not alter the safety profile of each compound. Weight gain observed with pioglitazone may be limited with the addition of alogliptin. The concern of an increased risk of heart failure remains to be better investigated. PMID- 25936385 TI - Overactive bladder symptoms in patients with multiple sclerosis: Frequency, severity, diagnosis and treatment. AB - OBJECTIVE: To determine the frequency and severity as well as the diagnosis and treatment of overactive bladder problems in patients with multiple sclerosis (MS) followed up at five centers in Turkey. DESIGN: Survey study. SETTING: Outpatient tertiary clinics of physical medicine and rehabilitation and neurology. PARTICIPANTS: Consecutive MS patients scheduled for outpatient follow-up (n = 309). INTERVENTION: MS patients were asked to complete a questionnaire regarding the frequency and severity, as well as the diagnosis and treatment of their overactive bladder problems. RESULTS: The mean age +/- SD was 39.3 +/- 10.6 years. Urinary urgency was the most common urinary symptom (62%), followed by frequency (50.4%), urge incontinence (44.7%) and nocturia (33%). Residual urine volume was measured using a portable ultrasound instrument in 13.3% of the patients and by catheterization in 16.2% of them. Urodynamic investigations and urinary tract ultrasound were performed on 26.5% and 35.3% of the patients, respectively. Anticholinergic medications were prescribed for 27.5% of the patients. Intermittent catheterization and indwelling catheterization were used on 8.1% and 1.9% of the patients, respectively. The overactive bladder symptom score (OABSS) was significantly higher in patients who had had residual urine measurement (P < 0.001), upper urinary tract assessment by ultrasound (P < 0.001), urodynamic assessment (P < 0.001), admitted to a doctor for urinary symptoms (P < 0.001), and current or past catheter use (P = 0.002). CONCLUSION: Urgency was the most common urinary symptom followed by frequency, urge incontinence and nocturia in MS patients. The patients with lower OABSS had detailed urological assessments less frequently than the patients with higher OABSS. PMID- 25936386 TI - External Validation and Predictive Accuracy Assessment of Guy's Stone Score as a Preoperative Tool for Estimating Percutaneous Nephrolithotomy Outcomes. AB - OBJECTIVE: To externally validate Guy's stone score system and estimate its predictive accuracy. PATIENTS AND METHODS: An analysis of 282 consecutive patients, who underwent a percutaneous nephrolithotomy, was performed. The association between Guy's stone score and several pre-, intra-, and postoperative parameters was assessed. A univariate and multivariate analysis was conducted to identify the independent predictors for stone-free rates. Area under the curve was used for predictive accuracy estimation. RESULTS: Stone burden, multiple stone locations, number of stones, number of implicated caliceal groups, and Guy's stone score were significantly associated with stone-free outcomes. The multivariate analysis showed that Guy's stone score, number of stones, and number of implicated caliceal groups are independent predictors of stone-free status. Receiver operating characteristic curve analysis revealed a significant predictive accuracy for the Guy's stone score. CONCLUSIONS: The present study externally validated Guy's stone score. Significant predictive ability combined with great predictive accuracy was found. PMID- 25936387 TI - Current Australian speech-language pathology practice in addressing psychological well-being in people with aphasia after stroke. AB - PURPOSE: Psychological well-being is essential to overall health; however, there is a paucity of research on how to address psychological well-being in stroke survivors with aphasia. This study describes the current beliefs, attitudes and practices of Australian speech-language pathologists in addressing psychological well-being in people with aphasia after stroke. METHOD: A 26-item web-based survey consisting of open and closed questions was distributed to Australian speech-language pathologists through four electronic databases. RESULT: Australian speech-language pathologists (n = 111) utilized counselling and clinical approaches to address psychological well-being in people with post stroke aphasia. The majority of speech-language pathologists did not feel comfortable with addressing psychological well-being in people with aphasia and sought support from other health professionals in this practice. Self-perception of being under-skilled was the main barrier identified to adequate practice in this domain, followed by inadequate time, inadequate staffing and people with aphasia declining referral to counselling. The main facilitators reported by speech-language pathologists to address psychological well-being included personal interest, personal and professional experience and availability of counselling health professionals for people with aphasia. There were small-to medium statistically significant correlations between speech-language pathologists reporting additional training in counselling and perceived knowledge of, confidence in and satisfaction with managing psychological well-being in people with aphasia. CONCLUSION: This study identifies factors requiring attention in order to enable speech-language pathologists to facilitate improved psychological well-being in people with aphasia. PMID- 25936388 TI - Long-Term Satellite Observations of Microcystin Concentrations in Lake Taihu during Cyanobacterial Bloom Periods. AB - Microcystins (MCs) produced by cyanobacteria pose a serious threat to public health. Intelligence on MCs distributions in freshwater is therefore critical for environmental agencies, water authorities, and public health organizations. We developed and validated an empirical model to quantify MCs in Lake Taihu during cyanobacterial bloom periods using the atmospherically Rayleigh-corrected moderate resolution imaging spectroradiometer (MODIS-Aqua) (Rrc) products and in situ data by means of chlorophyll a concentrations (Chla). First, robust relationships were constructed between MCs and Chla (r = 0.91; p < 0.001; t-test) and between Chla and a spectral index derived from Rrc (r = -0.86; p < 0.05; t test). Then, a regional algorithm to analyze MCs in Lake Taihu was constructed by combining the two relationships. The model was validated and then applied to an 11-year series of MODIS-Aqua data to investigate the spatial and temporal distributions of MCs. MCs in the lake were markedly variable both spatially and temporally. Cyanobacterial bloom scums, temperature, wind, and light conditions probably affected the temporal and spatial distribution of MCs in Lake Taihu. The findings demonstrate that remote sensing reconnaissance in conjunction with in situ monitoring can greatly aid MCs assessment in freshwater. PMID- 25936389 TI - Blood-brain barrier endogenous transporters as therapeutic targets: a new model for small molecule CNS drug discovery. AB - INTRODUCTION: The blood-brain barrier (BBB) limits the uptake of most drugs by brain, and the traditional approach to the BBB problem is the use of medicinal chemistry to increase drug lipid solubility, and increase lipid-mediated transport across the BBB. This review advocates a new model to CNS drug discovery of BBB-penetrating small molecules, whereby drug candidates are screened for carrier-mediated transport (CMT) across the BBB. AREAS COVERED: CMT systems are expressed by genes within the Solute Carrier (SLC) Transporter Gene Family, which now totals > 400 transporter genes. Emphasis is placed on reconciliation of the substrate transporter profile (STP) of BBB transport in vivo with the STP of the cloned SLC transporter in vitro. This reconciliation is crucial to the identification, from sometimes a large number of candidates, of the respective SLC transporter that is responsible for BBB transport in vivo for a given class of nutrients. EXPERT OPINION: Dual track screening of a small molecule library for drugs that have the dual properties of affinity for a neural cell drug receptor target, and affinity for a BBB CMT transporter target, can lead to a revolution in how small molecule drugs are identified in CNS drug discovery programs. PMID- 25936390 TI - Protective effects of extendin-4 on hypoxia/reoxygenation-induced injury in H9c2 cells. AB - Glucagon-like peptide-1 (GLP-1) analogues are likely to exert cardioprotective effects via balancing the energy metabolism in cardiomyocytes following ischemic or hypoxic insults. The present study aimed to explore the protective effects and mechanism of exendin-4, a GLP-1 analogue, on cardiomyocyte glucose uptake using an in vitro model of hypoxia/reoxygenation (H/R) of H9c2 cardiomyocyte cells. Pre treatment with exendin-4 (200 nM) prior to H/R increased the cell viability, decreased cell apoptosis, enhanced cardiomyocyte glucose uptake and increased the production of adenosine triphosphate. Exendin-4 also decreased the levels of lactate dehydrogenase and creatine kinase-MB in the culture medium. Furthermore, the activity of carnitine palmitoyltransferase-1 in the H9c2 cells was decreased, while the activity of phosphofructokinase-1 was increased following exendin-4 treatment. Moreover, pre-treatment with exendin-4 increased the expression of p38 mitogen-activated protein kinase (p38MAPK) gamma and translocation of glucose transporter-1 in H9c2 cells subjected to H/R. However, these effects were attenuated by the p38MAPK inhibitors BIRB796 and SB203580. The results suggested that exendin-4 exerted significant cardioprotective effects against H/R-induced cell injury and restored the metabolic imbalance of cardiomyocytes by activating the p38MAPK signaling pathway in the H9c2 cell model. Importantly, p38MAPKgamma, one subunit of p38MAPK, may have the most important function in this process. The results of the present study may be helpful in the development of novel drugs to treat patients with coronary heart disease. PMID- 25936392 TI - Electrochemical vapor deposition of semiconductors from gas phase with a solid membrane cell. AB - We demonstrate the feasibility of semiconductor deposition via the electrochemical reduction of gaseous precursors by the use of an anhydrous proton conducting membrane, the solid acid CsHSO4, at 165 degrees C. This membrane electrode assembly was operated within the oxidation of hydrogen on a porous Pt anode and the deposition of Si or Ge under bias at the cathode from chloride based gaseous precursors; SiCl4 and GeCl4 in an Ar flow with a reduction potential over -1.0 V (vs RHE). PMID- 25936391 TI - Effects of high-intensity interval versus continuous moderate-intensity aerobic exercise on apoptosis, oxidative stress and metabolism of the infarcted myocardium in a rat model. AB - The optimal aerobic exercise training (AET) protocol for patients following myocardial infarction (MI) has remained under debate. The present study therefore aimed to compare the effects of continuous moderate-intensity training (CMT) and high-intensity interval training (HIT) on cardiac functional recovery, and to investigate the potential associated mechanisms in a post-MI rat model. Female Sprague Dawley rats (8-10 weeks old) undergoing MI or sham surgery were subsequently submitted to CMT or HIT, or kept sedentary for eight weeks. Prior to and following AET, echocardiographic parameters and exercise capacity of the rats were measured. Western blotting was used to evaluate the levels of apoptosis and associated signaling pathway protein expression. The concentrations of biomarkers of oxidative stress were also determined by ELISA assay. Messenger (m)RNA levels and activity of the key enzymes for glycolysis and fatty acid oxidation, as well as the rate of adenosine triphosphate (ATP) synthesis, were also measured. Compared with the MI group, exercise capacity and cardiac function were significantly improved following AET, particularly following HIT. Left ventricular ejection fraction and fraction shortening were further improved in the MI-HIT group in comparison to that of the MI-CMT group. The two forms of AET almost equally attenuated apoptosis of the post-infarction myocardium. CMT and HIT also alleviated oxidative stress by decreasing the concentration of malondialdehyde and increasing the concentration of superoxide dismutase and glutathione peroxidase (GPx). In particular, HIT induced a greater increase in the concentration of GPx than that of CMT. AET, and HIT in particular, significantly increased the levels of mRNA and the maximal activity of phosphofructokinase-1 and carnitine palmitoyl transferase-1, as well as the maximal ratio of ATP synthesis. In addition, compared with the MI group, the expression of signaling proteins PI3K, Akt, p38mapk and AMPK was significantly altered in the MI-CMT and MI-HIT groups. HIT was superior to CMT in its ability to improve cardiac function and exercise capability in a post-MI rat model. HIT was also superior to CMT with regard to attenuating oxidative stress and improving glucolipid metabolism of the post-MI myocardium. PMID- 25936393 TI - The immunomodulator, ammonium trichloro[1,2-ethanediolato-O,O']-tellurate, suppresses the propagation of herpes simplex virus 2 by reducing the infectivity of the virus progeny. AB - Persistent investigations for the identification of novel anti-herpetic drugs are being conducted worldwide, as current treatment options are sometimes insufficient. The immunomodulator, ammonium trichloro[1,2-ethanediolato-O,O'] tellurate (AS101), a non-toxic tellurium (IV) compound, has been shown to exhibit anti-viral activity against a variety of viruses in cell cultures and in animal models. In the present study, the anti-viral activity of AS101 against herpes simplex virus (HSV)-1 and 2 was investigated in vitro. The results demonstrated that AS101 significantly restricted HSV-2-induced plaque formation and reduced the infectivity of the HSV-2 yield, while HSV-1 was affected to a lesser extent. The incubation of mature HSV-1 and HSV-2 viruses with AS101 had no effect on viral infectivity, indicating that the compound interrupts de novo viral synthesis. The addition of AS101 at up to 9 h post-infection had almost the same effect as did the addition of the drug together with the virus (it maintained 80% of its total anti-viral capacity). Quantitative PCR and immunofluoresence staining of viral structural proteins revealed that the viral DNA and protein synthesis stages were not interrupted by the administration of AS101. By contrast, in the presence of the compound, significantly fewer viable viruses (>=2 log reduction) were recovered from the AS10-treated cell cultures. Of note, when we determined the viability of the intracellular virus, formed in the presence of the compound, a less severe (<=1 log) effect was observed. Taken together, these data strongly suggest that AS101 primarily interferes with late stages of viral replication, such as viral particle envelopment or egress, leading to the production of a defective virus progeny. PMID- 25936394 TI - MicroRNA-135b exerts oncogenic activity in glioblastoma via the inhibition of glycerol kinase 5 expression. AB - Glioblastoma is the most common primary malignancy of the adult central nervous system and is associated with a markedly poor prognosis. Elucidating the pathogenesis and molecular changes will assist in further understanding the pathogenesis and progression of the disease and offer novel targets for therapies. The present study demonstrated that the expression level of GK5 was lower in high-grade glioblastoma tissues compared with low-grade ones and it can promote proliferation in glioblastoma cells. The regulatory mechanism of GK5 in glioblastoma were also investigated. It was revealed that GK5 is a target of miR 135b in U87MG glioblastoma cells. Controry to GK5, the expression of miR-135b is upregulated in glioblastoma and its expression is positively associated with the grade of the disease. Finally, it was demonstrated that miR-135b promoted the proliferation of U87MG cells. Therefore, miR-135b may function as an oncogene by inhibiting GK5 in glioblastoma. PMID- 25936395 TI - Leptin and adiponectin as predictors of disease activity in rheumatoid arthritis. AB - OBJECTIVES: To assess whether baseline levels of leptin and adiponectin predict disease activity or response to treatment in patients with RA at 6 months, 1 and 2 years of follow-up. METHODS: A consecutive cohort of patients, classified according to the 2010 ACR/EULAR RA criteria, was evaluated at baseline, 6 months, 1 and 2 years. All were treated with steroids and/or DMARDs. None received biologics. Blood was taken at a baseline to determine plasma anti-CCP, leptin and adiponectin. The relationship between leptin, adiponectin, DAS28 and changes in DAS28 was assessed by multivariable linear and logistic regression from baseline to follow-up. RESULTS: 127 patients completed 6 months, 91 one year and 52 two years of follow-up. All were female, mean age 45 years (18-70), time since onset of disease 7.5 years (0-36). A U-shaped relationship between DAS28 and leptin baseline levels was seen. Adjusting for different factors, leptin levels at baseline predicted higher DAS28 at 6 months and, in patients who were not overweight or obese, predicted disease activity at 6 months, 1 and 2 years. In patients who were not overweight or obese, baseline leptin was able to predict response to treatment at 6 and 12 months. CONCLUSIONS: In the short term, baseline leptin levels predict disease activity in all RA patients and response to treatment in RA patients with normal weight. PMID- 25936396 TI - Hippocampal volume change relates to clinical outcome in childhood-onset schizophrenia. AB - BACKGROUND: Fixed hippocampal volume reductions and shape abnormalities are established findings in schizophrenia, but the relationship between hippocampal volume change and clinical outcome has been relatively unexplored in schizophrenia and other psychotic disorders. In light of recent findings correlating hippocampal volume change and clinical outcome in first-episode psychotic adults, we hypothesized that fewer decreases in hippocampal volume would be associated with better functional outcome and fewer psychotic symptoms in our rare and chronically ill population of childhood-onset schizophrenia (COS) patients. METHOD: We prospectively obtained 114 structural brain magnetic resonance images (MRIs) from 27 COS subjects, each with three or more scans between the ages of 10 and 30 years. Change in hippocampal volume, measured by fit slope and percentage change, was regressed against clinical ratings (Children's Global Assessment Scale, Scale for the Assessment of Positive Symptoms, Scale for the Assessment of Negative Symptoms) at last scan (controlling for sex, time between scans and total intracranial volume). RESULTS: Fewer negative symptoms were associated with less hippocampal volume decrease (fit slope: p = 0.0003, and percentage change: p = 0.005) while positive symptoms were not related to hippocampal change. There was also a relationship between improved clinical global functioning and maintained hippocampal volumes (fit slope: p = 0.025, and percentage change: p = 0.043). CONCLUSIONS: These results suggest that abnormal hippocampal development in schizophrenia can be linked to global functioning and negative symptoms. The hippocampus can be considered a potential treatment target for future therapies. PMID- 25936397 TI - Prevalence and correlates of anaemia in adolescents in Riyadh city, Kingdom of Saudi Arabia. AB - OBJECTIVE: To determine the prevalence and correlates of anaemia in male and female adolescents in Riyadh, Kingdom of Saudi Arabia. DESIGN: A cross-sectional community-based study. SETTING: Five primary health-care centres in Riyadh. SUBJECTS: We invited 203 male and 292 female adolescents aged 13-18 years for interview, anthropometric measurements and complete blood count. Blood Hb was measured with a Coulter Cellular Analysis System using the light scattering method. RESULTS: Using the WHO cut-off of Hb<12 g/dl, 16.7 % (n 34) of males and 34.2 % (n 100) of females were suffering from anaemia. Mean Hb in males and females was 13.5 (sd 1.4) and 12.3 (sd 1.2) g/dl, respectively. Values for mean cell volume, mean cell Hb, mean corpuscular Hb concentration and red cell distribution width in male and female adolescents were 77.8 (sd 6.2) v. 76.4 (sd 10.3) MUm(3), 26.1 (sd 2.7) v. 25.5 (sd 2.6) pg, 32.7 (sd 2.4) v. 32.2 (sd 2.6) g/dl and 13.9 (sd 1.4) v. 13.6 (sd 1.3) %, respectively. Multivariate logistic regression revealed that a positive family history of Fe-deficiency anaemia (OR=4.7; 95 % CI 1.7, 12.2), infrequent intake (OR=3.7; 95 % CI 1.3, 10.0) and never intake of fresh juices (OR=3.5; 95 % CI 1.4, 9.5) and being 13-14 years of age (OR=3.1; 95 % CI 1.2, 9.3) were significantly associated with anaemia in male adolescents; whereas in females, family history of Fe-deficiency anaemia (OR=3.4; 95 % CI 1.5, 7.6), being overweight (OR=3.0; 95 % CI 1.4, 6.1), no intake of fresh juices (OR=2.6; 95 % CI 1.4, 5.1), living in an apartment (OR=2.0; 95 % CI 1.1, 3.8) and living in a small house (OR=2.5; 95 % CI 1.2, 5.3) were significantly associated with anaemia. CONCLUSIONS: Anaemia is more prevalent among Saudi female adolescents as compared with males. Important factors like positive family history of Fe-deficiency anaemia, overweight, lack of fresh juice intake and low socio-economic status are significantly associated with anaemia in adolescents. PMID- 25936398 TI - Jiedu Xiaozheng Yin decoction inhibits hepatoma cell proliferation by inducing apoptosis via the mitochondrial-mediated pathway. AB - Jiedu Xiaozheng Yin decoction (JXY) is a type of Chinese traditional medicine, which has been used to treat various types of cancer. The present study explored the mechanisms underlying the anticancer activity of JXY. The effects of ethyl acetate extraction of JXY (EE-JXY) were evaluated on the HepG2 human hepatoma cell line in vitro and in vivo. Following treatment of the HepG2 cells with EE JXY for 24 h, cell viability, apoptosis, mitochondrial membrane potential, caspase enzyme activity and the expression levels of apoptotic-associated proteins (Bcl-2 and Bax) were detected by MTT, flow cytometry, ELISA and western blotting respectively. In addition, HepG2 cells were subcutaneously transplanted into BALB/c nude mice, and the tumor bearing mice were treated with either EE-JXY (0.06 g/kg) or normal saline for 21 days. Tumor volume and weight were measured and recorded. The apoptotic index, and the expression levels of Bax and cytochrome c were determined with immunohistochemical staining. Treatment with EE JXY inhibited the proliferation of HepG2 cells, and reduced cell viability in a dose-and time-dependent manner. Furthermore, EE-JXY induced HepG2 cell apoptosis, as demonstrated by a loss of plasma membrane asymmetry and externalization of phosphatidylserine, collapse of mitochondrial membrane potential, activation of caspase-9 and caspase-3, and an increased ratio of pro-apoptotic Bax to anti apoptotic Bcl-2. Furthermore, EE-JXY inhibited tumor growth and increased the apoptotic index of tumors in tumor-bearing mice. In conclusion, the results of the present study suggest that JXY inhibits HepG2 cell proliferation through mitochondrion-mediated apoptosis, which may partially explain its anticancer activity. PMID- 25936399 TI - Titanium alloy femoral neck fracture--clinical and metallurgical analysis in 6 cases. PMID- 25936400 TI - Tools for predicting the PK/PD of therapeutic proteins. AB - INTRODUCTION: Assessments of the pharmacokinetic/pharmacodynamic (PK/PD) characteristics are an integral part in the development of novel therapeutic agents. Compared with traditional small molecule drugs, therapeutic proteins possess many distinct PK/PD features that necessitate the application of modified or separate approaches for assessing their PK/PD relationships. AREAS COVERED: In this review, the authors discuss tools that are utilized to describe and predict the PK/PD features of therapeutic proteins and that are valuable additions in the armamentarium of drug development approaches to facilitate and accelerate their successful preclinical and clinical development. EXPERT OPINION: A variety of state-of-the-art PK/PD tools is currently being applied and has been adjusted to support the development of proteins as therapeutics, including allometric scaling approaches, target-mediated disposition models, first-in-man dose calculations, physiologically based PK models and empirical and semi-mechanistic PK/PD modeling. With the advent of the next generation of biologics including bioengineered antibody constructs being developed, these tools will need to be further refined and adapted to ensure their applicability and successful facilitation of the drug development process for these novel scaffolds. PMID- 25936401 TI - Subfascial expansive plasty for intrathecal baclofen pump replacement. A technical note. AB - PURPOSE: Although intratechal pump replacement is a common technique, it can be sometimes complicated when aiming to replace a 20 ml pump with a bigger one (40 ml). We developed a simple and straightforward technique to relax the wall of the pocket of the pump, preserving its fascial layer. METHODS: A 20-year-old boy with spastic tetraparesia was admitted for pump replacement. After scar opening and pump removal, various lineal incisions were performed in the posterior layer of the subfascial pocket in a cranio-caudal direction. RESULTS: A 40 ml pump was placed without skin incision ampliation and preserving subfascial plane. CONCLUSIONS: This easy, expansive technique for infusion pump replacement preserves subfascial plane and prevents the need for more extensive surgeries. PMID- 25936402 TI - Editorial Comment for Bolton et al. PMID- 25936403 TI - C-reactive protein, not cardiac troponin T, improves risk prediction in hypertensives with type A aortic dissection. AB - BACKGROUND: The aim of the study was to evaluate prognostic role of inflammatory biomarkers, cardiac troponin T (cTnT) and D-dimer in type A acute aortic dissection (AAD) and to examine whether they might help in risk stratification beyond values of International Registry of Acute Aortic Dissection (IRAD) score. METHODS: Baseline biomarkers were determined in 54 consecutive predominantly hypertensive patients with type A AAD and evaluated for in-hospital mortality. RESULTS: After multivariable adjustment, the independent predictors of outcome were age (OR = 1.09; 95% CI 1.02-1.18), treatment strategy (OR = 0.11; 95% CI 0.02-0.06) and C-reactive protein (CRP) either as binary (OR = 7.06; 95% CI 1.34 37.36) or continuous variable (OR = 1.10; 95% CI 1.01-1.21). cTnT did not independently influence mortality. Receiver- operating characteristic (ROC) curve analysis showed significant link between CRP and outcome (area under the ROC curve, AUC = 0.79; p < 0.01). Values of CRP > 9.8 mg/l had 83% sensitivity and 80% specificity for predicting in-hospital mortality. Addition of CRP to IRAD score improved prediction of short-term outcome, AUC increased from 0.74 to 0.89 (p = 0.004). CONCLUSION: Admission CRP has independent prognostic value in type A AAD and the addition of CRP to IRAD score improved discriminative capacity of in hospital mortality irrespective of symptom duration and treatment strategy. PMID- 25936404 TI - Speciation of Cu and Zn in Two Colored Oyster Species Determined by X-ray Absorption Spectroscopy. AB - In oysters, Cu and Zn concentration can reach extraordinarily high (1-2% of tissue dry weights), leading to intense green or blue colors in oyster tissues. It is thus puzzling how oysters detoxify the excessively accumulated metals. Here, we used X-ray absorption spectroscopy to examine the Cu and Zn speciation in two "colored" oysters (Crassostrea hongkongensis and Crassostrea sikamea) collected from a severely metal-contaminated estuary. In contaminated oysters, we found a much higher proportion of tissue Cu and Zn as oxygen- or nitrogen-bonded species, contrasting to the sulfur-bonded (thiolate) species in normal oysters. Speciation of Cu and Zn in mantle was similar to that in gills, both of which were different from that in the digestive gland. In C. sikamea, the difference of metal speciation between normal and contaminated individuals was of similar pattern but less pronounced than that in C. hongkongensis. In normal oysters, Cu existed mainly as Cu(I) bound to sulfur, whereas in contaminated oysters mainly as Cu(II) bound to oxygen or nitrogen. Our study provided direct and semiquantitative information on the changes of metal speciation in contaminated oysters, indicating that oysters could efficiently detoxify the excessively accumulated Cu and Zn by storing them in oxygen- and nitrogen-bonded complexes in metal-rich environments. PMID- 25936405 TI - Is there potential to target FOXM1 for 'undruggable' lung cancers? AB - Published studies with transgenic mice convincingly showed that Forkhead Box transcription factor M1 (FOXM1) transcription factor is an important component of the KRAS/ERK signaling pathway in respiratory epithelial cells. FOXM1 is required for oncogenic KRAS signaling in mouse lung cancer models and therefore, clear potential exists to target FOXM1 in human NSCLC driven by activated KRAS mutations. To date, several approaches to inhibit FOXM1 in cancer cells have been explored. These include siRNA/shRNA-mediated inhibition of Foxm1 mRNA, sequestration of FOXM1 protein in nucleoli using ARF peptide, inhibition of FOXM1 binding to its target promoter DNAs by the FDI-6 small-molecule compound and inhibition of proteasomes by thiazole antibiotics. Additional studies are needed to determine if inhibition of FOXM1 is beneficial for treatment of KRAS mutant NSCLCs in human patients and to develop effective delivery systems for FOXM1 inhibitors. If successful, additional strategies can be explored to screen for novel FOXM1 inhibitors, such as targeting FOXM1 nuclear localization, nuclear export or protein-protein interactions with activating kinases and co-activator proteins. Altogether, inhibition of FOXM1, either alone or in combination with other anticancer drugs, could be beneficial for treatment of KRAS mutant NSCLCs that are resistant to conventional chemotherapy. PMID- 25936406 TI - Antitumor effect of resveratrol on chondrosarcoma cells via phosphoinositide 3 kinase/AKT and p38 mitogen-activated protein kinase pathways. AB - Chondrosarcoma is one of the most common types of primary bone cancer that develops in cartilage cells. Resveratrol (Res), a natural polyphenol compound isolated from various fruits, has a suppressive effect on various human malignancies. It has been shown that Res inhibits matrix metalloproteinase (MMP) induced differentiation in chondrosarcoma cells. However, the effects of Res on cell proliferation, apoptosis and invasion of chondrosarcoma cells, as well as the underlying mechanisms, remain largely unknown. To the best of our knowledge, the present study showed for the first time that Res inhibited proliferation and induced apoptosis in chondrosarcoma cells in a dose-dependent manner. Furthermore, it was shown that Res also suppressed chondrosarcoma cell invasion in a dose-dependent manner, probably via the inhibition of MMP2 and MMP9 protein expression. Molecular mechanism investigations revealed that Res could inhibit the activity of phosphoinositide 3-kinase/AKT and p38 mitogen-activated protein kinase signaling pathways, which has been demonstrated to be important in the regulation of proliferation, apoptosis and invasion in various cancer cell types. In conclusion, this study suggests that Res may serve as a promising agent for the treatment of chondrosarcoma. PMID- 25936407 TI - Regulation of gene expression in rats with spinal cord injury based on microarray data. AB - The present study aimed to investigate the molecular mechanisms of spinal cord injury (SCI) in rats. First, the differentially expressed genes (DGEs) were screened based on GSE45006 microarray data downloaded from Gene Expression Omnibus using the significant analysis of microarray (SAM) method. Screening was performed for DEGs which were negatively or possibly correlated with time and subsequently subjected to gene ontology (GO) functional annotation. Furthermore, pathway enrichment analysis using the Kyoto Encyclopedia of Genes and Genomes was also performed. In addition, a protein-protein interaction (PPI) network was constructed using the Search Tool for the Retrieval of Interacting Genes/Proteins database. Finally, GeneCodis was used to seek transcription factors and microRNAs that are involved in the regulation of DEGs. A total of 806 DEGs were upregulated and 549 DEGs were downregulated in the rats with SCI. Cholesterol metabolism associated genes (e.g. HMGCS1, FDFT1 and IDI1) were negatively correlated with time, while injury genes (e.g. SERPING1, C1S and RAB27A) were positively correlated with time after SCI. PCNA, MCM2, JUN and SNAP25 were the hub proteins of the PPI network. The transcription factors LEF1 and SP1 were observed to be associated with the regulation of two DEGs that were involved in the cholesterol associated metabolism as well as injury responses. A number of microRNAs (e.g. miR210, miR-487b and miR-16) were observed to target cholesterol metabolism associated DGEs. The hub genes PCNA, MCM2, JUN and SNAP25 presumably have critical roles in rats with SCI, and the transcription factors LEF1 and SP1 may be important for the regulation of cholesterol metabolism and injury responses following SCI. PMID- 25936408 TI - Rate law analysis of water oxidation on a hematite surface. AB - Water oxidation is a key chemical reaction, central to both biological photosynthesis and artificial solar fuel synthesis strategies. Despite recent progress on the structure of the natural catalytic site, and on inorganic catalyst function, determining the mechanistic details of this multiredox reaction remains a significant challenge. We report herein a rate law analysis of the order of water oxidation as a function of surface hole density on a hematite photoanode employing photoinduced absorption spectroscopy. Our study reveals a transition from a slow, first order reaction at low accumulated hole density to a faster, third order mechanism once the surface hole density is sufficient to enable the oxidation of nearest neighbor metal atoms. This study thus provides direct evidence for the multihole catalysis of water oxidation by hematite, and demonstrates the hole accumulation level required to achieve this, leading to key insights both for reaction mechanism and strategies to enhance function. PMID- 25936409 TI - Smaller hippocampal volume as a vulnerability factor for the persistence of post traumatic stress disorder. AB - BACKGROUND: Smaller hippocampal volume has often been observed in patients with post-traumatic stress disorder (PTSD). However, there is no consensus whether this is a result of stress/trauma exposure, or constitutes a vulnerability factor for the development of PTSD. Second, it is unclear whether hippocampal volume normalizes with successful treatment of PTSD, or whether a smaller hippocampus is a risk factor for the persistence of PTSD. METHOD: Magnetic resonance imaging (MRI) scans and clinical interviews were collected from 47 war veterans with PTSD, 25 healthy war veterans (combat controls) and 25 healthy non-military controls. All veterans were scanned a second time with a 6- to 8-month interval, during which PTSD patients received trauma-focused therapy. Based on post treatment PTSD symptoms, patients were divided into a PTSD group who was in remission (n = 22) and a group in whom PTSD symptoms persisted (n = 22). MRI data were analysed with Freesurfer. RESULTS: Smaller left hippocampal volume was observed in PTSD patients compared with both control groups. Hippocampal volume of the combat controls did not differ from healthy controls. Second, pre- and post-treatment analyses of the PTSD patients and combat controls revealed reduced (left) hippocampal volume only in the persistent patients at both time points. Importantly, hippocampal volume did not change with treatment. CONCLUSIONS: Our findings suggest that a smaller (left) hippocampus is not the result of stress/trauma exposure. Furthermore, hippocampal volume does not increase with successful treatment. Instead, we demonstrate for the first time that a smaller (left) hippocampus constitutes a risk factor for the persistence of PTSD. PMID- 25936410 TI - Increased osteopontin in muscle and serum from patients with idiopathic inflammatory myopathies. AB - OBJECTIVES: Osteopontin (OPN) is a non-traditional pro-inflammatory cytokine and is involved in muscle regeneration and inflammation. The aim of this study was to investigate the expression of OPN in skeletal muscle and serum of patients with IIMs. METHODS: 45 patients with IIMs (27 with PM and 18 with DM) were included in the study. Patients received initial prednisone therapy (1-1.5 mg/kg/day) without other immunosuppressive agents. Muscle biopsies were taken before start of treatment and serum samples were collected from each patient before and after corticosteroid treatment. The expression of OPN in skeletal muscle was using immunofluorescence staining and western blotting. Serum OPN levels were detected by enzyme-linked immunosorbent assays (ELISA). RESULTS: OPN expression was increased in muscle samples from IIM patients compared to control muscle. The serum level of OPN was significantly higher in IIM patients than in controls. Moreover, the serum concentrations in the DM subgroup were significantly higher compared to the PM groups. Serum OPN levels positively correlated with creatinine kinase (CK), C-reactive protein (CRP) in PM and DM patients, respectively. After corticosteroid treatment, serum OPN levels decreased significantly in steroid responders compared to baseline, but no significant decrease was observed in steroid non-responders. CONCLUSIONS: OPN is increased in patients with DM and PM, both in muscle and serum. OPN may play an important role in the pathogenesis of IIMs. Moreover, serum OPN may be a potential biomarker for this illness, and changes in serum OPN may provide an index of therapeutic efficacy. PMID- 25936411 TI - A comprehensive analysis of differentially expressed genes and pathways in abdominal aortic aneurysm. AB - The current study aimed to investigate the molecular mechanism underlying abdominal aortic aneurysm (AAA) via various bioinformatics techniques. Gene expression profiling analysis of differentially expressed genes (DEGs) between AAA samples and normal controls was conducted. The Database for Annotation, Visualization and Integrated Discovery tool was utilized to perform Gene ontology (GO) and Kyoto Encyclopedia of Genes and Genomes analyses for DEGs and clusters from the protein-protein interaction (PPI) network, which was constructed using the Search Tool for the Retrieval of Interacting Genes. In addition, important transcription factors (TFs) that regulated DEGs were investigated. A total of 346 DEGs were identified between AAA samples and healthy controls. Additionally, four clusters were identified from the PPI network. Cluster 1 was associated with sensory perception of smell and the olfactory transduction subpathway. The most significant GO function terms for cluster 2 and 3 were response to virus and defense response, respectively. Cluster 4 was associated with mitochondria associated functions and the oxidative phosphorylation subpathway. Early growth response-1 (EGR-1), Myc, activating transcription factor 5 (ATF5) and specificity protein (SP) 1:SP3 were identified to be critical TFs in this disease. The present study suggested that the olfactory transduction subpathway, mitochondria and oxidative phosphorylation pathways were involved in AAA, and TFs, such as EGR 1, Myc, ATF5 and SP1:SP3, may be potential candidate molecular targets for this disease. PMID- 25936412 TI - Differential hippocampal protein expression between normal aged rats and aged rats with postoperative cognitive dysfunction: A proteomic analysis. AB - The aim of the present study was to investigate the differences in the expression of hippocampal proteins between normal control aged rats and aged rats with postoperative cognitive dysfunction (POCD). A total of 24 aged rats were randomly divided into a surgery group (n=12) and a control group (n=12). The rats in the surgery group were treated with 2 h isoflurane anesthesia and splenectomy, while the rats in the control group received 40% oxygen for 2 h without surgery. The cognitive functions of the two groups were examined using a Y-maze test. The protein expression profiles of the hippocampus of six aged rats (three rats with POCD and three from the normal control group) were assessed using two-dimensional gel electrophoresis and matrix-assisted laser desorption/ionization time of flight mass spectrometry. A total of three differential proteins were further confirmed between the POCD rats and normal rats using reverse transcription quantitative polymerase chain reaction (RT-qPCR). The expression levels of 21 proteins in the rats with POCD were significantly different compared with the normal control rats. These proteins were functionally clustered to synaptic plasticity (three proteins), oxidative stress (four proteins), energy production (six proteins), neuroinflammation (three proteins) and glutamate metabolism (two proteins). In addition, three proteins (fatty acid binding protein 7, brain, glutamate dehydrogenase 1 and glutamine synthetase), associated with astrocytic function, were significantly different in the rats with POCD compared with those in the normal control (P<0.05). Similar changes in the mRNA expression levels of the three proteins in the hippocampi of POCD rats were also detected using RT qPCR. Neuroinflammation, glutamate toxicity and oxidative stress were possibly involved in the pathological mechanism underlying POCD in aged rats. In addition, astrocytes may also be important in POCD in aged rats. PMID- 25936413 TI - Irregular eating of meals in adolescence and the metabolic syndrome in adulthood: results from a 27-year prospective cohort. AB - OBJECTIVE: The objective was to investigate whether irregular eating of meals in adolescence predicts the metabolic syndrome and its components in adulthood, and if any specific meal is of particular importance. DESIGN: Prospective cohort study with 27 years of follow-up. Information on meals (breakfast, school lunch and dinner with family), lifestyle (alcohol consumption, smoking habits, physical activity, consumption of sweets and pastries) at age 16 years was assessed from questionnaires, and presence or not of the metabolic syndrome and its components were defined at age 43 years in 889 participants (82.1% of total cohort). Logistic regression was used to calculate odds ratios and confidence intervals. SETTING: The Northern Swedish Cohort; all school-leavers of the 9th grade in the town Lulea in 1981. SUBJECTS: Adolescents (age 16 years). RESULTS: Irregular eating of meals at age 16 years was associated with higher prevalence of the metabolic syndrome at age 43 years (OR=1.74; 95% CI 1.12, 2.71), but this was explained by concurrent unhealthy lifestyle at age 16 years. Poor breakfast at age 16 years was the only meal associated with the metabolic syndrome at age 43 years, independent of other meals, BMI (kg/m2) and lifestyle at age 16 years (OR=1.67; 95% CI 1.00, 2.80). CONCLUSIONS: Irregular eating of meals in adolescence predicted the metabolic syndrome in adulthood, but not independently of BMI and lifestyle in adolescence. Poor breakfast in adolescence was the only specific meal associated with future metabolic syndrome, even after adjustments. Breakfast eating should be encouraged in adolescence. PMID- 25936414 TI - Neonatal hyperthermia and thermal stress in low- and middle-income countries: a hidden cause of death in extremely low-birthweight neonates. AB - BACKGROUND: Over 70% of neonatal deaths in Nigeria occur within the first 7 days of life and, despite the millennium development goals, there has been no significant reduction of this figure. OBJECTIVE: To investigate how rapid changes of temperature outside the physiologically allowable range in extremely low birthweight infants are associated with increased mortality. METHODS: Ninety eight neonatal cases in three Nigerian tertiary-care hospitals were retrospectively recruited; on the basis of birthweight < 1500 g, this number was reduced to 41 for a two-stage analysis. In the first stage, 34 cases recruited over 24 months were analysed. In the second stage, seven cases recruited over 6 months were analysed; these were neonates managed with a new temperature control technique (the 'handy approach') to enable comparison of outcomes. The mean (SD) birthweight of the infants analysed was 991 g (251), and 28 of them were of extremely low-birthweight (ELBW) [mean (SD) 846 g (128)]. A lifetime temperature plot with a clearly visible reference zone was developed, from which all thermal stresses and their duration associated with mortality were identified and defined on the basis of their characteristics. Methods of quantifying the magnitude and duration of these thermal stresses were devised to enable definition of critical values. This was then applied to calculate a measure of the various thermal stresses which may have contributed to neonatal death. RESULTS: Hypothermic events were very common in all the infants in the study period, but were not significantly associated with mortality. However, hyperthermic events occurred in 35% of the infants and were more likely to be associated with mortality. Most neonates with prolonged hypothermia culminating in rapid hyperthermia survived. However, all ELBW neonates who experienced prolonged hyperthermia culminating in rapid hypothermia died within 8 hours of the event. There was greater ELBW survival (6/6) in the second stage using the 'handy approach' than in the first stage (2/22). CONCLUSION: Hyperthermia is a high-risk event in ELBW infants and methods of cooling a high and prolonged temperature must be reviewed. PMID- 25936415 TI - Improving attending rounds: Qualitative reflections from multidisciplinary providers. AB - BACKGROUND: Attending rounds, the time for the attending physician and the team to discuss the team's patients, take place at teaching hospitals every day, often with little standardization. OBJECTIVE: This hypothesis-generating qualitative study sought to solicit improvement recommendations for standardizing attending rounds from the perspective of a multi-disciplinary group of providers. METHODS: Attending physicians, housestaff (residents and interns), medical students, nurses and pharmacists at an academic medical center participated in a quality improvement initiative between January and April 2013. Participants completed an individual or focus group interview or an e-mail survey with three open-ended questions: (1) What are poor or ineffective practices for attending rounds? (2) How would you change attending rounds structure and function? (3) What do you consider best practices for attending rounds? We undertook content analysis to summarize each clinical stakeholder group's improvement recommendations. RESULTS: Sixty stakeholders participated in our study including 23 attending hospitalists, 24 housestaff, 7 medical students, 2 pharmacists and 4 nurses. Key improvement recommendations included (1) performing a pre-rounds huddle, (2) planning of the visit schedule based on illness or pending discharge, (3) real-time order writing, (4) patient involvement in rounds with shared decision-making, (5) bedside nurse inclusion and (6) minimizing interruption of intern or student presentations. CONCLUSIONS: The practice improvement recommendations identified in this study will require deliberate systems changes and training to implement, and they warrant rigorous evaluation to determine their impact on the clinical and educational goals of rounds. PMID- 25936417 TI - Retrograde intrarenal surgery by flexible ureteroscope in patients with spinal deformities. AB - OBJECTIVE: To present our experience with retrograde intrarenal surgery (RIRS) for managing renal stones in patients with spinal deformities. DESIGN: We retrospectively reviewed the records of patients. METHODS: We retrospectively reviewed the records of seven patients with congenital scoliosis (n = 5), spina bifida (n = 2) who had undergone RIRS for renal stones. Stone-free status was determined by CT 30 days after the procedure and was defined as the absence of stones in the kidney or residual fragments <=1 mm. RESULTS: Mean patient age was 27 years (18-45 years), and mean stone size was 176 mm (143-340 mm). The average operative time was 38 minutes (25-53 minutes), and postoperative hospital stay was 1 day (1-2 days). A stone-free status was obtained in six (85.7 %) patients, and one patient was considered to have treatment failure. This patient was managed by a repeat RIRS. A Double-J stent was placed at the end of the procedure in all (100 %) patients. No severe complications, either from anesthesia or the surgical procedure, were observed, and no blood transfusion was reported. CONCLUSIONS: The good clearance rate with a low incidence of complications shown by the present study has demonstrated that RIRS is a safe and effective procedure for renal stones in patients with spinal deformities. PMID- 25936416 TI - Alterations in left ventricular function during intermittent hypoxia: Possible involvement of O-GlcNAc protein and MAPK signaling. AB - Obstructive sleep apnea, characterized by recurrent episodes of hypoxia [intermittent hypoxia (IH)], has been identified as a risk factor for cardiovascular diseases. The O-linked beta-N-acetylglucosamine (O-GlcNAc) modification (O-GlcNAcylation) of proteins has important regulatory implications on the pathophysiology of cardiovascular disorders. In this study, we examined the role of O-GlcNAcylation in cardiac architecture and left ventricular function following IH. Rats were randomly assigned to a normoxia and IH group (2 min 21% O2; 2 min 6-8% O2). Left ventricular function, myocardial morphology and the levels of signaling molecules were then measured. IH induced a significant increase in blood pressure, associated with a gradually abnormal myocardial architecture. The rats exposed to 2 or 3 weeks of IH presented with augmented left ventricular systolic and diastolic function, which declined at week 4. Consistently, the O-GlcNAc protein and O-GlcNAcase (OGA) levels in the left ventricular tissues steadily increased following IH, reaching peak levels at week 3. The O-GlcNAc transferase (OGT), extracellular signal-regulated kinase 1/2 (ERK1/2) and the p38 mitogen-activated protein kinase (p38 MAPK) phosphorylation levels were affected in an opposite manner. The phosphorylation of calcium/calmodulin-dependent protein kinase II (CaMKII) remained unaltered. In parallel, compared with exposure to normoxia, 4 weeks of IH augmented the O GlcNAc protein, OGT, phosphorylated ERK1/2 and p38 MAPK levels, accompanied by a decrease in OGA levels and an increase in the levels of myocardial nuclear factor kappaB (NF-kappaB), inflammatory cytokines, caspase-3 and cardiomyocyte apoptosis. Taken together, our suggest a possible involvement of O-GlcNAc protein and MAPK signaling in the alterations of left ventricular function and cardiac injury following IH. PMID- 25936418 TI - Pharmacokinetics, pharmacodynamics and clinical efficacy of abiraterone acetate for treating metastatic castration-resistant prostate cancer. AB - INTRODUCTION: Androgen signaling axis (ASA) continues to play a crucial role in castration-resistant prostate cancer (CRPC). One of the proposed mechanisms is the activation of ASA by adrenal and intratumoral androgens. Targeted therapy to deplete such androgen sources should be effective in treating men with CRPC. AREAS COVERED: Abiraterone acetate (AA) is a selective irreversible inhibitor of CYP 17. It is orally administered and is converted to its active metabolite abiraterone by the liver. Increased adrenocorticotrophic hormone drive, however, results in increased risks of hypertension and hypokalemia. In Phase III trials, AA with prednisone was shown to improve survivals in men with metastatic CRPC (mCRPC). The overall tolerability and safety profiles were acceptable. EXPERT OPINION: It is now accepted that CRPC is not independent of androgen signaling, and targeted therapies to suppress ASA have recently been developed. With multiple high-level evidences of efficacy and safety, AA is considered a breakthrough in the treatment of mCRPC. Current clinical challenge, however, is to better delineate the mechanisms of the disease progression for developments of resistance to targeted therapies. Identification of the drug-resistance patterns would allow better patient selection for each treatment modality. PMID- 25936419 TI - Mercury sources and trophic ecology for Hawaiian bottomfish. AB - In Hawaii, some of the most important commercial and recreational fishes comprise an assemblage of lutjanids and carangids called bottomfish. Despite their importance, we know little about their trophic ecology or where the mercury (Hg) that ultimately resides in their tissue originates. Here we investigated these topics, by analyzing muscle samples for mercury content, nitrogen, carbon, and amino acid specific nitrogen isotope ratios in six species distributed across different depths from the Northwestern Hawaiian Islands (NWHI) and the Main Hawaiian Islands (MHI). Fishes had different sources of nitrogen and carbon, with isotopic values suggesting benthic food sources for shallow nearshore species. High trophic position lutjanids that foraged in deeper water, benthic environments generally had higher Hg levels. Model results also suggested that benthic Hg methylation was an important source of Hg for shallow benthic feeders, while deepwater sources of mercury may be important for those with a diet that derives, at least in part, from the pelagic environment. Further, despite the lack of freshwater sources of Hg in the NWHI, statistical models explaining the variation in tissue Hg in the MHI and NWHI were nearly identical, suggesting freshwater Hg inputs were not a major source of Hg in fish tissue. PMID- 25936420 TI - Comparing Expert Reported Outcomes to National Surgical Quality Improvement Program Risk Calculator-Predicted Outcomes: Do Reporting Standards Differ? AB - INTRODUCTION: Expert-reported outcomes and complications may not reflect the standardized coding that can be provided by independent, third-party evaluations. The goal of this article is to compare expert-reported complications with standardized coding by the National Surgical Quality Improvement Program (NSQIP). The procedures evaluated were laparoscopic radical nephrectomy (LRN), robot assisted radical prostatectomy (RARP), and radical cystectomy (RC). METHODS: The 10 largest LRN, RARP, and RC series were reviewed for reported complications. An index patient was derived from each series using patient demographic data. Index patients were entered into the NSQIP surgical risk calculator (SRC), which provides 11 predicted outcomes based on inputted data. SRC-predicted outcomes were compared with available complication rates in each series. RESULTS: Across the 30 studies, 172 out of 330 (52%) of NSQIP-provided outcome types were presented within expert manuscripts. Death and venous thromboembolism (VTE) were the most commonly reported (27 and 23 studies, respectively), whereas urinary tract infection (UTI) (9) and pneumonia (10) were the least commonly presented. Comorbidities and follow-up duration were reported in 8 out of 30 and 17 out of 30 studies, respectively. For LRN, the median number of reported outcomes was 3 (range 1-5). LRN experts demonstrated a shorter mean length of stay (LOS) (2.5 days, SD=1.7) (p<0.001). In RARP studies, a median of 7.5 (3-11) outcomes was reported. Experts outperformed NSQIP RARP predictions in serious complications (p<0.001), any complication (p<0.001), surgical site infection (p=0.025), UTI (p<0.001), and VTE (p=0.002). RC manuscripts reported a median of 7 (2-11) outcomes. RC experts had higher rates of serious complications (p<0.001), reoperation (p<0.001), and death (p<0.001) than predicted by SRC. CONCLUSION: The level of standardization in reporting of outcomes differs between expert series and NSQIP, thus making comparisons difficult. PMID- 25936421 TI - Let it shine: a transparent and photoluminescent foldable nanocellulose/quantum dot paper. AB - Exploration of environmentally friendly light-emitting devices with extremely low weight has been a trend in recent decades for modern digital technology. Herein, we describe a simple suction filtration method to develop a transparent and photoluminescent nanocellulose (NC) paper, which contains ZnSe quantum dot (QD) with high quantum yield as a functional filler. ZnSe QD can be dispersed uniformly in NC, and a quite low coefficient of thermal expansion is determined for the resultant composite paper, suggesting its good dimensional stability. These results indicate that the meeting of NC with ZnSe QD can bring a brilliant future during the information age. PMID- 25936422 TI - VEGF-C inhibition reverses resistance of bladder cancer cells to cisplatin via upregulating maspin. AB - The aim of the current study was to elucidate the association between vascular endothelial growth factor C (VEGF-C) and resistance of bladder cancer cells to cisplatin and the underlying mechanism involving maspin. A total of 32 bladder cancer tissue samples from patients (18 males and 14 females with an average age of 65.9 years) were collected from the Fifth Affiliated Hospital of Zhengzhou University (Zhengzhou, China). All patients had undergone cisplatin-based combination chemotherapy. In addition, the BIU87 human bladder cancer cell line was cultured and a cisplatin-resistant subline (BIU87-CisR) was established by continuous exposure to cisplatin. The mRNA expression levels of VEGF-C and maspin in tissue samples, BIU87 cells and BIU87-CisR cells were analyzed by reverse transcription-quantitative polymerase chain reaction (RT-qPCR). Targeted inhibition of VEGF-C in BIU87-CisR cells was performed using small interfering (si)RNA technology and the alteration in levels of maspin was confirmed by RT qPCR and western blot analysis. siRNA-treated and -untreated BIU87-CisR cells were divided into the following four groups: Control group (no drug treatment), 3 MUM cisplatin treated group, 3 MUM cisplatin + siRNA treated group and the siRNA treated group. Cell viability following treatment in each group was evaluated by the cell counting kit 8 assay. The cell cycle and apoptotic rate of BIU87-CisR cells was analyzed by propidium iodide (PI) staining and Annexin V-PI double staining with flow cytometry. Furthermore, pcDNA-maspin transfected BIU78-CisR cells were used to establish the effect of maspin on the sensitivity to cisplatin. VEGF-C expression in chemoresistant patients and BIU87-CisR cells was significantly increased compared with chemosensitive patients and normal BIU87 cells, respectively. By contrast, maspin levels were lower in chemoresistant patients and BIU87-CisR cells. Subsequent to VEGF-C inhibition, maspin expression was markedly increased. Cisplatin (3 MUM) resulted in moderate proliferation inhibition of BIU87-CisR cells without siRNA pretreatment; however, significant inhibition was observed in the VEGF-C siRNA treated group. In addition, the cell cycle arrest and apoptosis induced by cisplatin was enhanced by VEGF-C inhibition. Overexpression of maspin was able to improve the sensitivity of BIU87 CisR cells to cisplatin. In conclusion, the resistance of bladder cancer cells to cisplatin may be induced by upregulation of VEGF-C, and inhibition of VEGF-C reverses resistance by elevating maspin expression levels. PMID- 25936423 TI - Selection of suitable reference genes for reverse transcription-quantitative polymerase chain reaction analysis of neuronal cells differentiated from bone mesenchymal stem cells. AB - Reverse transcription-quantitative polymerase chain reaction (RT-qPCR) is a technique widely used for the quantification of mRNA transcription, It is well recognized that the reference genes used in RT-qPCR require appropriate validation to ensure that gene expression is unaffected by experimental conditions. The differentiation of bone mesenchymal stem cells (BMSCs) into neurons is important in the treatment of nerve injury. In gene expression analysis of the differentiation of BMSCs into neuronal cells by, the commonly used reference genes for RNA analysis are often selected without any preliminary evaluation of their suitability. The present study aimed to evaluate the mRNA expression levels of 11 putative reference genes, including ACTB, ARBP, B2M, CYCA, GAPDH, GUSB, HPRT, PPIA, RPL13A, TBP and PGK1, in order to select the most suitable reference genes for RT-qPCR of the differentiation of neuronal cells by BMSCs. The mRNA expression levels of the 11 putative reference genes were examined using RT-qPCR in rat BMSCs differentiated into neuronal cells. Normal BMSCs and three types of rat BMSCs, which were chemically induced to differentiate into neurons using neurotrophic cytokines and co-culture with retinal cells. The geNorm, NormFinder and BestKeeper software programs were used to select the most suitable reference genes. The results of the analyses using the three software programs demonstrated that RPL13A was the most stable among all the groups, while ACTB was the least stable. The combination of CYCA and PPIA reference genes contributed the most to increasing stability. The suitability of selected reference genes requires previous pre-selection in every investigation. Based on the three software programs, RPL13A, and the combination of CYCA and PPIA were identified as the most suitable reference genes for RT-qPCR in neuronal cells differentiated from BMSCs. PMID- 25936424 TI - Protein Induces Layer-by-Layer Exfoliation of Transition Metal Dichalcogenides. AB - Here, we report a general and facile method for effective layer-by-layer exfoliation of transition metal dichalcogenides (TMDs) and graphite in water by using protein, bovine serum albumin (BSA) to produce single-layer nanosheets, which cannot be achieved using other commonly used bio- and synthetic polymers. Besides serving as an effective exfoliating agent, BSA can also function as a strong stabilizing agent against reaggregation of single-layer nanosheets for greatly improving their biocompatibility in biomedical applications. With significantly increased surface area, single-layer MoS2 nanosheets also exhibit a much higher binding capacity to pesticides and a much larger specific capacitance. The protein exfoliation process is carefully investigated with various control experiments and density functional theory simulations. It is interesting to find that the nonpolar groups of protein can firmly bind to TMD layers or graphene to expose polar groups in water, facilitating the effective exfoliation of single-layer nanosheets in aqueous solution. The present work will enable to optimize the fabrication of various 2D materials at high yield and large scale, and bring more opportunities to investigate the unique properties of 2D materials and exploit their novel applications. PMID- 25936425 TI - Diagnostic change 10 years after a first episode of psychosis. AB - BACKGROUND: A lack of an aetiologically based nosology classification has contributed to instability in psychiatric diagnoses over time. This study aimed to examine the diagnostic stability of psychosis diagnoses using data from an incidence sample of psychosis cases, followed up after 10 years and to examine those baseline variables which were associated with diagnostic change. METHOD: Data were examined from the AESOP and AESOP-10 studies, an incidence and follow up study, respectively, of a population-based cohort of first-episode psychosis cases from two sites. Diagnosis was assigned using ICD-10 and DSM-IV-TR. Diagnostic change was examined using prospective and retrospective consistency. Baseline variables associated with change were examined using logistic regression and likelihood ratio tests. RESULTS: Slightly more (59.6%) cases had the same baseline and lifetime ICD-10 diagnosis compared with DSM-IV-TR (55.3%), but prospective and retrospective consistency was similar. Schizophrenia, psychotic bipolar disorder and drug-induced psychosis were more prospectively consistent than other diagnoses. A substantial number of cases with other diagnoses at baseline (ICD-10, n = 61; DSM-IV-TR, n = 76) were classified as having schizophrenia at 10 years. Many variables were associated with change to schizophrenia but few with overall change in diagnosis. CONCLUSIONS: Diagnoses other than schizophrenia should to be regarded as potentially provisional. PMID- 25936426 TI - Tuberculous pyomyositis in a rheumatoid arthritis patient treated with anakinra. AB - Musculoskeletal tuberculosis (TB) occurs in only 3% of patients with TB while tuberculous pyomyositis is rare. It usually affects immunocompromised or patients with underlying comorbidities. We present a case of tuberculous pyomyositis in a 85-year-old Caucasian patient with rheumatoid arthritis (RA) treated with steroids and anakinra. The patient presented with fever as well as redness, swelling and induration on the lateral side of the hip and thigh. Under ultrasound guidance fluid collection of the thigh was aspirated. Polymerase chain reaction (PCR) and cultures of the fluid were positive for Mycobacterium TB. The patient underwent bronchoscopy. PCR and cultures from the bronchoalveolar lavage were also positive for Mycobacterium TB. The patient was treated with anti TB treatment with amelioration of the inflammation in the hip and thigh. This is the first reported case of tuberculous pyomyositis in a RA patient treated with anakinra. PMID- 25936427 TI - Apigenin induces caspase-dependent apoptosis by inhibiting signal transducer and activator of transcription 3 signaling in HER2-overexpressing SKBR3 breast cancer cells. AB - Phytoestrogens have been demonstrated to inhibit tumor induction; however, their molecular mechanisms of action have remained elusive. The present study aimed to investigate the effects of a phytoestrogen, apigenin, on proliferation and apoptosis of the human epidermal growth factor receptor 2 (HER2)-expressing breast cancer cell line SKBR3. Proliferation assay, MTT assay, fluorescence activated cell sorting analysis, western blot analysis, immunocytochemistry, reverse transcription-polymerase chain reaction and ELISA assay were used in the present study. The results of the present study indicated that apigenin inhibited the proliferation of SKBR3 cells in a dose-and time-dependent manner. This inhibition of growth was accompanied by an increase in the sub-G0/G1 apoptotic population. Furthermore, apigenin enhanced the expression levels of cleaved caspase-8 and -3, and induced the cleavage of poly(adenosine diphosphate ribose) polymerase in SKBR3 cells, confirming that apigenin promotes apoptosis via a caspase-dependent pathway. Apigenin additionally reduced the expression of phosphorylated (p)-janus kinase 2 and p-signal transducer and activator of transcription 3 (STAT3), inhibited CoCl2-induced vascular endothelial growth factor (VEGF) secretion and decreased the nuclear localization of STAT3. The STAT3 inhibitor S31-201 decreased the cellular proliferation rate and reduced the expression of p-STAT3 and VEGF. Therefore, these results suggested that apigenin induced apoptosis via the inhibition of STAT3 signaling in SKBR3 cells. In conclusion, the results of the present study indicated that apigenin may be a potentially useful compound for the prevention or treatment of HER2 overexpressing breast cancer. PMID- 25936428 TI - Application of mixsep software package: Performance verification of male-mixed DNA analysis. AB - An experimental model of male-mixed DNA (n=297) was constructed according to the mixed DNA construction principle. This comprised the use of the Applied Biosystems (ABI) 7500 quantitative polymerase chain reaction system, with scientific validation of mixture proportion (Mx; root-mean-square error <= 0.02). Statistical analysis was performed on locus separation accuracy using mixsep, a DNA mixture separation R-package, and the analytical performance of mixsep was assessed by examining the data distribution pattern of different mixed gradients, short tandem repeat (STR) loci and mixed DNA types. The results showed that locus separation accuracy had a negative linear correlation with the mixed gradient (R(2)=-0.7121). With increasing mixed gradient imbalance, locus separation accuracy first increased and then decreased, with the highest value detected at a gradient of 1:3 (>= 90%). The mixed gradient, which is the theoretical Mx, was one of the primary factors that influenced the success of mixed DNA analysis. Among the 16 STR loci detected by Identifiler(r), the separation accuracy was relatively high (>88%) for loci D5S818, D8S1179 and FGA, whereas the median separation accuracy value was lowest for the D7S820 locus. STR loci with relatively large numbers of allelic drop-out (ADO; >15) were all located in the yellow and red channels, including loci D18S51, D19S433, FGA, TPOX and vWA. These five loci featured low allele peak heights, which was consistent with the low sensitivity of the ABI 3130xl Genetic Analyzer to yellow and red fluorescence. The locus separation accuracy of the mixsep package was substantially different with and without the inclusion of ADO loci; inclusion of ADO significantly reduced the analytical performance of the mixsep package, which was consistent with the lack of an ADO functional module in this software. The present study demonstrated that the mixsep software had a number of advantages and was recommended for analysis of mixed DNA. This software was easy to operate and produced understandable results with a degree of controllability. PMID- 25936429 TI - In Situ Mapping of the Molecular Arrangement of Amphiphilic Dye Molecules at the TiO2 Surface of Dye-Sensitized Solar Cells. AB - Amphiphilic sensitizers are central to the function of dye-sensitized solar cells. It is known that the cell's performance depends on the molecular arrangement and the density of the dye on the semiconductor surface, but a molecular-level picture of the cell-electrolyte interface is still lacking. Here, we present subnanometer in situ atomic force microscopy images of the Z907 dye at the surface of TiO2 in a relevant liquid. Our results reveal changes in the conformation and the lateral arrangement of the dye molecules, depending on their average packing density on the surface. Complementary quantitative measurements on the ensemble of the film are obtained by the quartz-crystal microbalance with dissipation technique. An atomistic picture of the dye coverage-dependent packing, the effectiveness of the hydrophobic alkyl chains as blocking layer, and the solvent accessibility is obtained from molecular dynamics simulations. PMID- 25936430 TI - The cutlery effect: do designed products for people with disabilities stigmatise them? AB - The purpose of this study was to investigate of how assistive cutlery design effects perception of the user. Studies regarding the usage and development of assistive cutlery have primarily focused on the ergonomics, whereas research into the aesthetics of assistive cutlery has been minimal. A method based on Canter's "Room Inference Protocol" from the field of environmental psychology was used to evaluate the aesthetics of the assistive cutlery. A series of images were digitally composited and a survey was deployed online, with an outcome of 562 usable responses. The results demonstrated that the female model with assistive cutlery was perceived to be less attractive, less stylish and less sporty in comparison with the male model that was utilising identical pieces of assistive cutlery. The research contributes to the existing literature in the field, complimenting the study by Torrens and Smith and validating the need for greater aesthetic consideration in addition to an ergonomically acceptable response for assistive cutlery. This in turn highlights the importance of industrial design for the context and adaptations of use, rather than just a design response given to the physical manifestation of a product. Implications for Rehabilitation Reduced grip can be not only physically debilitating but also socially isolating through stigmatisation. Current assistive cutlery may be ergonomically sound, but aesthetically lacking. Large, multinational study demonstrates significant gender effect relating to the perception of women using these devices. PMID- 25936431 TI - Tag team simulation: An innovative approach for promoting active engagement of participants and observers during group simulations. AB - Active participation in immersive simulation experiences can result in technical and non-technical skill enhancement. However, when simulations are conducted in large groups, maintaining the interest of observers so that they do not disengage from the learning experience can be challenging. We implemented Tag Team Simulation with the aim of ensuring that both participants and observers had active and integral roles in the simulation. In this paper we outline the features of this innovative approach and provide an example of its application to a pain simulation. Evaluation was conducted using the Satisfaction with Simulation Experience Scale. A total of 444 year nursing students participated from a population of 536 (response rate 83%). Cronbach's alpha for the Scale was .94 indicating high internal consistency. The mean satisfaction score for participants was 4.63 compared to 4.56 for observers. An independent sample t test revealed no significant difference between these scores (t (300) = -1.414, p = 0.16). Tag team simulation is an effective approach for ensuring observers' and participants' active involvement during group-based simulations and one that is highly regarded by students. It has the potential for broad applicability across a range of leaning domains both within and beyond nursing. PMID- 25936432 TI - Sulforaphane prevents doxorubicin-induced oxidative stress and cell death in rat H9c2 cells. AB - Sulforaphane, a natural isothiocyanate compound found in cruciferous vegetables, has been shown to exert cardioprotective effects during ischemic heart injury. However, the effects of sulforaphane on cardiotoxicity induced by doxorubicin are unknown. Thus, in the present study, H9c2 rat myoblasts were pre-treated with sulforaphane and its effects on cardiotoxicity were then examined. The results revealed that the pre-treatment of H9c2 rat myoblasts with sulforaphane decreased the apoptotic cell number (as shown by trypan blue exclusion assay) and the expression of pro-apoptotic proteins (Bax, caspase-3 and cytochrome c; as shown by western blot analysis and immunostaining), as well as the doxorubicin-induced increase in mitochondrial membrane potential (measured by JC-1 assay). Furthermore, sulforaphane increased the mRNA and protein expression of heme oxygenase-1 (HO-1, measured by RT-qPCR), which consequently reduced the levels of reactive oxygen species (ROS, measured using MitoSOX Red reagent) in the mitochondria which were induced by doxorubicin. The cardioprotective effects of sulforaphane were found to be mediated by the activation of the Kelch-like ECH associated protein 1 (Keap1)/NF-E2-related factor-2 (Nrf2)/antioxidant-responsive element (ARE) pathway, which in turn mediates the induction of HO-1. Taken together, the findings of this study demonstrate that sulforaphane prevents doxorubicin-induced oxidative stress and cell death in H9c2 cells through the induction of HO-1 expression. PMID- 25936434 TI - Necrotizing pneumonia and acute purulent pericarditis caused by Streptococcus pneumoniae serotype 19A in a healthy 4-year-old girl after one catch-up dose of 13-valent pneumococcal conjugate vaccine. AB - Streptococcus pneumoniae is a common cause of infectious diseases in children that may lead to life-threatening complications. Acute purulent pericarditis is an uncommon complication of S. pneumoniae in the antibiotic era. A healthy 4-year old girl was admitted with pneumonia and pleural effusion. She had received one catch-up dose of 13-valent pneumococcal conjugate vaccine at 2 years of age. She rapidly developed necrotizing pneumonia, complicated by bronchopleural fistula presenting as subcutaneous emphysema and pneumothorax and acute purulent pericarditis. S. pneumoniae serotype 19A was subsequently identified from blood, empyema and pericardial fluid cultures. After appropriate antibiotic therapy and a right lower lobectomy, her condition stabilized and she promptly recovered. This case highlights two rare potential clinical complications of pneumococcal disease in a child: necrotizing pneumonia and acute purulent pericarditis. This is the first report of a child who received just one catch-up dose of 13-valent pneumococcal conjugate vaccine at 2 years of age, as per the United States' Advisory Committee on Immunization Practice's recommendations, but who still developed severe invasive pneumococcal disease with life-threatening complications caused by S. pneumoniae serotype 19A. PMID- 25936433 TI - Enhancement of the antigen-specific cytotoxic T lymphocyte-inducing ability in the PMDC11 leukemic plasmacytoid dendritic cell line via lentiviral vector mediated transduction of the caTLR4 gene. AB - The aim of the present study was to enhance the efficiency of leukemia immunotherapy by increasing the antigen-specific cytotoxic T lymphocyte-inducing ability of leukemia cells. The leukemic plasmacytoid dendritic cell line PMDC05 containing the HLA-A02/24 antigen, which was previously established in our laboratory (Laboratory of Hematology and Oncology, Graduate School of Health Sciences, Niigata University, Niigata, Japan), was used in the present study. It exhibited higher expression levels of CD80 following transduction with lentiviruses encoding the CD80 gene. This CD80-expressing PMDC05 was named PMDC11. In order to establish a more potent antigen-presenting cell for cellular immunotherapy of tumors or severe infections, PMDC11 cells were transduced with a constitutively active (ca) toll-like receptor 4 (TLR4) gene using the Tet-On system (caTLR4-PMDC11). CD8(+) T cells from healthy donors with HLA-A02 were co cultured with mutant WT1 peptide-pulsed PMDC11, lipopolysaccharide (LPS) stimulated PMDC11 or caTLR4-PMDC11 cells. Interleukin (IL)-2 (50 IU/ml) and IL-7 (10 ng/ml) were added on day three of culture. Priming with mutant WT1 peptide pulsed PMDC11, LPS-stimulated PMDC11 or caTLR4-PMDC11 cells was conducted once per week and two thirds of the IL-2/IL-7 containing medium was replenished every 3-4 days. Immediately prior to the priming with these various PMDC11 cells, the cultured cells were analyzed for the secretion of interferon (IFN)-gamma in addition to the percentage and number of CD8(+)/WT1 tetramer(+) T cells using flow cytometry. caTLR4-PMDC11 cells were observed to possess greater antigen presenting abilities compared with those of PMDC11 or LPS-stimulated PMDC11 cells in a mixed leukocyte culture. CD8 T cells positive for the WT1 tetramer were generated following 3-4 weeks of culture and CD8(+)/WT1 tetramer+ T cells were markedly increased in caTLR4-PMDC11-primed CD8(+) T cell culture compared with PMDC11 or LPS-stimulated PMDC11-primed CD8(+) T cell culture. These CD8(+) T cells co-cultured with caTLR4-PMDC11 cells were demonstrated to secrete IFN-gamma and to be cytotoxic to WT1-expressing target cells. These data suggested that the antigen-specific cytotoxic T lymphocyte (CTL)-inducing ability of PMDC11 was potentiated via transduction of the caTLR4 gene. The present study also suggested that caTLR4-PMDC11 cells may be applied as potent antigen-presenting cells for generating antigen-specific CTLs in adoptive cellular immunotherapy against tumors and severe viral infections. PMID- 25936435 TI - Macrocyclic lactone resistance in Dirofilaria immitis: Failure of heartworm preventives and investigation of genetic markers for resistance. AB - Macrocyclic lactone (ML) endectocides are used as chemoprophylaxis for heartworm infection (Dirofilaria immitis) in dogs and cats. Claims of loss of efficacy (LOE) of ML heartworm preventives have become common in some locations in the USA. We directly tested whether resistance to MLs exists in LOE isolates of D. immitis and identified genetic markers that are correlated with, and therefore can predict ML resistance. ML controlled studies showed that LOE strains of D. immitis established infections in dogs despite chemoprophylaxis with oral ivermectin or injectable moxidectin. A whole genome approach was used to search for loci associated with the resistance phenotype. Many loci showed highly significant differences between pools of susceptible and LOE D. immitis. Based on 186 potential marker loci, Sequenom((r)) SNP frequency analyses were conducted on 663 individual parasites (adult worms and microfilariae) which were phenotypically characterized as susceptible (SUS), confirmed ML treatment survivors/resistant (RES), or suspected resistant/loss of efficacy (LOE) parasites. There was a subset of SNP loci which appears to be promising markers for predicting ML resistance, including SNPs in some genes that have been associated with ML resistance in other parasites. These data provide unequivocal proof of ML resistance in D. immitis and identify genetic markers that could be used to monitor for ML resistance in heartworms. PMID- 25936436 TI - Baylisascaris procyonis larva migrans in two white-headed lemurs (Eulemur albifrons) in Spain and response to treatment derived from a human pediatric protocol. AB - Baylisascaris procyonis is a well-known ascaridoid nematode that causes larva migrans in humans and many other animal species. The North American raccoon (Procyon lotor) is the definitive host, which has been successfully introduced in the past decades to other geographical regions around the world. Two white-headed lemurs (Eulemuralbifrons) from a Zoological Park in Lugo, Spain, developed severe neurological signs within a brief period after being transferred from exhibit and placed in close contact with three captive raccoons from the same zoo. One lemur was euthanized due to the severity of disease progression and histopathology revealed granulomatous inflammation and ascaridoid larvae in kidneys, lung, spleen and brain. Larvae were identified as B. procyonis larvae by real time PCR. In light of the results, the cage mate with similar neurological signs was put on an albendazole treatment regimen adapted from a human pediatric protocol. The aggressive anthelmintic treatment likely contributed to the arrest of clinical signs and recovery of some motor skills. Importantly, Baylisascaris procyonis infection might occur in wild raccoon populations in Spain. PMID- 25936437 TI - Comparison of Fasciola hepatica genotypes in relation to their ability to establish patent infections in the final host. AB - Fasciola hepatica is a common and economically important parasite of sheep and cattle. Although its marked genetic heterogeneity is well recognised, an association between haplotypes and specific phenotypic traits has yet to be identified. Using experimental infections in cattle this study investigated whether a fragment of mitochondrial DNA (coding for cytochrome c oxidase subunit III, transfer RNA histidine and cytochrome b) and 3 nuclear microsatellite loci (Fh15, Fh23 and Fh25) could be used as markers for the parasite's ability to complete its tissue migration and establish in the liver of the final host. While we did not detect any shift in the frequency of the various genotypes in the population of metacercariae used for the infection on the one hand and the flukes collected from the liver on the other, there was an indication that parasites with heterozygous microsatellite alleles may have a selective advantage over homozygote parasites during their migration in the final host. PMID- 25936438 TI - Electroacupuncture pretreatment attenuates blood-brain barrier disruption following cerebral ischemia/reperfusion. AB - Disruption of the blood-brain barrier (BBB) and subsequent brain edema are major contributors to the pathogenesis of ischemic stroke, however, current clinical therapeutic methods remains unsatisfactory. Electroacupuncture (EA) pretreatment has a protective effect against cerebral ischemia/reperfusion (I/R). However, the underlying mechanisms remain to be fully elucidated. In the present study, the effect of EA pretreatment on BBB disruption was investigated in a focal I/R rat model. Male Sprague-Dawley rats (280-320 g) were pretreated with EA at the acupoint 'Baihui' (GV20) 30 min/day, for five days consecutively prior to focal cerebral I/R, which was induced by middle cerebral artery occlusion (MCAO) for 2 h. The results demonstrated that the infarction volume, brain water content and neurological deficits increased in the MCAO model rats at 3 h and 24 h post reperfusion, and were attenuated significantly by EA pretreatment. Furthermore, electron microscopy examination confirmed a reduction in brain edema reduction in the EA pretreated rats. Western blot analysis revealed that the tight junction proteins between endothelial cells, including claudin-5, occludin, were significantly degraded, while the protein expression of phosphorylated (p )caveolin-1 and p-Akt increased following reperfusion, all of which were alleviated by EA pretreatment. However, no significant differences were observed in the expression of caveolin-1 or Akt. Overall, the results demonstrated that EA pretreatment significantly reduced BBB permeability and brain edema, which were correlated with alleviation of the degradation of tight junction proteins and inhibition of the expression of p-caveolin-1 in the endothelial cells. PMID- 25936439 TI - Age Dating from Electron Microprobe Analyses of U, Th, and Pb: Geological Advantages and Analytical Difficulties. AB - Electron microprobe analysis of U, Th, and Pb in naturally occurring minerals can indicate their age. Where the Pb is entirely due to the radioactive decay of U and Th, the time since mineral formation or equilibration can be calculated. Uraninite (UO2), monazite (REE PO4), zircon (ZrSiO4), and xenotime (YPO4) have been used, the latter containing U and/or Th in minor proportions. Any stable U- or Th-bearing phase can be considered. Careful analysis is required with attention to interferences, background measurement, detection limits, and Pb-free sample preparation. Extended counting times (600 s) at a probe current >200 nA are recommended. Ages can be determined from uraninite older than 2 Ma for a Pb detection limit of 0.02% and up to 700-1,000 Ma, after which Pb can be lost from the structure. The youngest monazite ages permitted by the Pb detection limit are 50-100 Ma and ages greater than 3,000 Ma have been determined. The method does not provide the detail of isotopic methods, but results can be obtained more readily. Examples show dating of cheralite ((Ca,Ce)(Th,Ce)(PO4)2), a rock containing primary and secondary UO2, and a suite of detrital uraninite grains that formed a part of a mineral exploration program. PMID- 25936440 TI - Efficacy of indacaterol as a single therapy versus salmeterol/fluticasone therapy in patients with milder chronic obstructive pulmonary disease. AB - INTRODUCTION: In non-exacerbation chronic obstructive pulmonary disease (COPD) with mild lung function impairment, single bronchodilator therapy might be as effective as combined inhaled corticosteroid/bronchodilator therapy, whereas the risk of pneumonia associated with the latter would be practically absent. AREAS COVERED: We performed an analysis of a recent study evaluating the efficacy and safety of inhaled indacaterol versus inhaled salmeterol/fluticasone in COPD patients. EXPERT OPINION: Both therapies were found to exert comparable effects on lung function, symptom severity and health status. PMID- 25936442 TI - Hydrolytic depolymerization of hydrolysis lignin: Effects of catalysts and solvents. AB - Hydrolytic depolymerization of hydrolysis lignin (HL) in water and water-ethanol co-solvent was investigated at 250 degrees C for 1h with 20% (w/v) HL substrate concentration with or without catalyst (H2SO4 or NaOH). The obtained depolymerized HLs (DHLs) were characterized with GPC-UV, FTIR, GC-MS, (1)H NMR and elemental analyzer. In view of the utilization of depolymerized HL (DHL) for the preparation of rigid polyurethane foams/resins un-catalyzed depolymerization of HL employing water-ethanol mixture appeared to be a viable route with high yield of DHL ~70.5wt.% (SR yield of ~9.8wt.%) and with Mw as low as ~1000g/mole with suitable aliphatic (227.1mgKOH/g) and phenolic (215mgKOH/g) hydroxyl numbers. The overall % carbon recovery under the selected best route was ~87%. Acid catalyzed depolymerization of HL in water and water-ethanol mixture lead to slightly increased Mw. Alkaline hydrolysis helped in reducing Mw in water and opposite trend was observed in water-ethanol mixture. PMID- 25936441 TI - Geospatial and Temporal Analysis of Thyroid Cancer Incidence in a Rural Population. AB - BACKGROUND: The increasing incidence of thyroid cancer has resulted in the rate tripling over the past 30 years. Reasons for this increase have not been established. Geostatistics and geographic information system (GIS) tools have emerged as powerful geospatial technologies to identify disease clusters, map patterns and trends, and assess the impact of ecological and socioeconomic factors (SES) on the spatial distribution of diseases. In this study, these tools were used to analyze thyroid cancer incidence in a rural population. METHODS: Thyroid cancer incidence and socio-demographic factors in Vermont (VT), United States, between 1994 and 2007 were analyzed by logistic regression and geospatial and temporal analyses. RESULTS: The thyroid cancer age-adjusted incidence in Vermont (8.0 per 100,000) was comparable to the national level (8.4 per 100,000), as were the ratio of the incidence of females to males (3.1:1) and the mortality rate (0.5 per 100,000). However, the estimated annual percentage change was higher (8.3 VT; 5.7 U.S.). Incidence among females peaked at 30-59 years of age, reflecting a significant rise from 1994 to 2007, while incidence trends for males did not vary significantly by age. For both females and males, the distribution of tumors by size did not vary over time; <=1.0 cm, 1.1-2.0 cm, and >2.0 cm represented 38%, 22%, and 40%, respectively. In females, papillary thyroid cancer (PTC) accounted for 89% of cases, follicular (FTC) 8%, medullary (MTC) 2%, and anaplastic (ATC) 0.6%, while in males PTC accounted for 77% of cases, FTC 15%, MTC 1%, and ATC 3%. Geospatial analysis revealed locations and spatial patterns that, when combined with multivariate incidence analyses, indicated that factors other than increased surveillance and access to healthcare (physician density or insurance) contributed to the increased thyroid cancer incidence. Nine thyroid cancer incidence hot spots, areas with very high normalized incidence, were identified based on zip code data. Those locations did not correlate with urban areas or healthcare centers. CONCLUSIONS: These data provide evidence of increased thyroid cancer incidence in a rural population likely due to environmental drivers and SES. Geospatial modeling can provide an important framework for evaluation of additional associative risk factors. PMID- 25936443 TI - Sediment microbial fuel cell prefers to degrade organic chemicals with higher polarity. AB - By operating a SMFC in heavily contaminated sediment and analyzing its global organic chemical degradation profile, this study showed a brief trend that SMFC prefers to stimulate the degradation of organic chemicals with higher polarity. As a comparison, adding nitrate as a microbial respiration-based sediment remediation strategy preferred lower polarity chemicals. Both SMFC and nitrate reactors showed high degradation capacity in benzene homologs. These results provide crucial information for the selective and proper application of SMFC in bioremediation. PMID- 25936447 TI - Magnets for therapy in the GI tract: a systematic review. PMID- 25936445 TI - Motivations for prescription drug misuse among young men who have sex with men (YMSM) in Philadelphia. AB - BACKGROUND: Prescription drug misuse (i.e. opioids, tranquilizers and stimulants) has become the fastest growing area of substance abuse among young adults. Limited studies focus on prescription drug misuse among young men who have sex with men (YMSM, aged 18-29 years). Furthermore, little is known about YMSM's motivations for misuse. The purpose of this study was to explore personal motivations for prescription drug misuse among YMSM, including the possible connection between misuse and sexual behaviors. METHODS: As part of a larger mixed methods study of 191 YMSM recruited in Philadelphia during 2012-2013, we conducted semi-structured qualitative interviews with 25 of these participants to gather additional contextual information about their prescription drug misuse. We conducted thematic analysis of qualitative data. RESULTS: While our results corroborated previous literature on motives for misuse of prescription drugs, our data yielded some distinct motivations specific among YMSM. These motives included social/recreational motives, facilitating sex with other men (including motives such as use of opioids for less painful anal receptive sex), and psychological motives such as depression, stress management, coping with everyday hardships (opioids and tranquilizers) or feeling more energized (stimulants). Prescription drugs were commonly misused within the broader contexts of participants' polysubstance use, adding to the significance of this problem. CONCLUSIONS: Our findings offer insights into YMSM's motivations for prescription drug misuse, and point to the importance of recognizing and addressing them. While substance use is likely related to various psychosocial issues impacting YMSM, it also may lead to significant health consequences. Results support the need to include prescription drugs and polysubstance use in harm reduction messages and treatment approaches aimed at substance using YMSM. PMID- 25936448 TI - Nitinol stents loaded with a high dose of antitumor 5-fluorouracil or paclitaxel: esophageal tissue responses in a porcine model. AB - BACKGROUND: A poor prognosis associated with esophageal cancer leads to surgical resection not suitable for most patients. Nitinol stents loaded with 50% 5 fluorouracil (5-FU) or paclitaxel (PTX), functioning both as a stent and local chemotherapy, could provide a new therapy modality for these patients. OBJECTIVE: To investigate esophageal tissue responses to nitinol stents loaded with 50% 5-FU or PTX implanted in the esophagus of healthy pigs. DESIGN: Twenty-three healthy Bama mini-pigs were randomly divided into 4 groups for stent implantation: group A (PTX stent, n = 13), group B (5-FU stent, n = 8), group C (blank film-covered stent, n = 1), and group D (bare stent, n = 1). Tissue responses were observed by endoscopy or pathologic analyses, and 5-FU or PTX concentrations were measured in the esophagus at the stent implantation site at different time points. SETTING: Animal laboratory. INTERVENTIONS: Endoscopic placement of esophagus stent. MAIN OUTCOME MEASUREMENTS: Endoscopic examination, histology, and drug concentration analysis. RESULTS: In general, the esophageal tissue responses varied according to different parts of 5-FU or PTX stent (middle part [drug-containing part] and bare ends [drug-free part]). Severe tissue responses at the bare ends of the stent included inflammation, ulceration, and granulation. However, the tissue responses were greatly reduced in the middle part of the stent. The drug concentrations in the esophagus that had contact with the 5-FU stent or PTX stent were very high, especially for the first period after implantation, which did not cause obvious tissue damage. LIMITATION: Some subjects had incomplete follow-up because of unexpected deaths and stent migration. CONCLUSION: The nitinol stents loaded with 50% 5-FU or PTX did not cause severe esophageal tissue responses, although there was a large concentration of the drug in these tissues. PMID- 25936449 TI - Protective association of colonoscopy against proximal and distal colon cancer and patterns in interval cancer. AB - BACKGROUND: The protective effect of colonoscopy against proximal colorectal cancer is variable and depends on the detection and complete removal of precancerous polyps. OBJECTIVE: To estimate the efficacy of colonoscopy in a medical center with open-access screening colonoscopy since 1998. DESIGN: Nested case-control study with incidence density sampling. SETTING: University affiliated Veterans Affairs Medical Center. PATIENTS: Colorectal cancer (CRC) cases and control subjects selected from screening age patients matched by age, gender, and date of first primary care visit. MAIN OUTCOME MEASUREMENT: Colonoscopy preceding the CRC diagnosis date. RESULTS: A total of 20.2% of CRC cases had a colonoscopy in the preceding 10 years compared with 49.0% of control subjects (adjusted odds ratio [aOR], 0.20; 95% confidence interval [CI], 0.11 0.34). Colonoscopy was strongly associated with decreased odds of both distal CRC (aOR, 0.16; 95% CI, 0.07-0.34) and proximal CRC (aOR, 0.26; 95% CI, 0.11-0.58). The fraction of cases attributed to interval cancers was 10.5%. Missed lesions predominantly localized to the cecum and rectum, and recurrent lesions clustered in the hepatic flexure. Cecal intubation rate was 93% (98% in adequately prepped patients), and the adenoma detection rate was 45.2% in the control group. LIMITATIONS: Single-center, retrospective case-control design. CONCLUSION: In an open access colonoscopy program characterized by a high cecal intubation rate and adenoma detection rate, colonoscopy was strongly associated with reduced odds of both distal and proximal CRC. Among interval cancers, missed lesions clustered in the cecum and rectum and recurrent lesions in the hepatic flexure. PMID- 25936450 TI - Evaluation of the clinical efficacy of colon capsule endoscopy in the detection of lesions of the colon: prospective, multicenter, open study. AB - BACKGROUND: Colon capsule endoscopy (CCE) is a new procedure for colon imaging. Limited information is available regarding visualization of flat colon lesions and patient acceptability in Japan. OBJECTIVE: The aims of this study were to evaluate the sensitivity of CCE in detecting polyps and other lesions compared with optical colonoscopy (OC) and to evaluate its safety and acceptability in a cohort of Japanese patients. DESIGN: A prospective, open-label, clinical study in Japan. SETTING: Multicenter. PATIENTS: Patients referred for OC because of personal history of polyps >=6 mm or any other colon lesion that required endoscopic or surgical treatment. INTERVENTIONS: CCE followed by therapeutic colonoscopy. MAIN OUTCOME MEASUREMENTS: The primary endpoint was per-patient sensitivity of CCE in detecting significant colon lesion. The secondary endpoints were CCE safety and patient acceptability. RESULTS: Sixty-six of the 72 patients enrolled in the study were evaluated for efficacy. The per-patient sensitivity was 94% (95% confidence interval [CI], 88.2%-99.7%). The per-polyp sensitivity was 86.6% (95% CI, 81.3%-91.9%) when pathology-confirmed polyps were considered true positives. There were no adverse events related to CCE, and the acceptability of CCE was high. LIMITATIONS: All patients had previously confirmed colon lesions, which may have falsely elevated the sensitivity of CCE. CONCLUSION: CCE had a high sensitivity for detecting significant colon lesions. CCE was safe and had a high level of patient acceptability. ( CLINICAL TRIAL REGISTRATION NUMBER: University Hospital Medical Information Network, UMIN000007258.). PMID- 25936451 TI - A newly designed plastic stent for EUS-guided hepaticogastrostomy: a prospective preliminary feasibility study (with videos). AB - BACKGROUND: There are currently no dedicated plastic stents for EUS-guided hepaticogastrostomy (EUS-HGS). OBJECTIVE: We prospectively evaluated the feasibility and the technical and functional success rates of our newly designed plastic stent for EUS-HGS. DESIGN: Prospective preliminary feasibility study. SETTING: A tertiary-care referral center. PATIENTS: Twenty-three consecutive patients were treated. The reasons for requiring EUS-HGS were periampullary tumor invasion (n=9), altered anatomy (n=7), failed duodenal intubation (n=3), and previous ERCP failure (n=4). INTERVENTIONS: An 8F single-pigtail plastic stent with 4 flanges was placed for EUS-HGS. MAIN OUTCOME MEASUREMENTS: Technical success, clinical success, and adverse events according to the American Society for Gastrointestinal Endoscopy lexicon. RESULTS: All stents were successfully deployed without procedural adverse events (100% technical success rate). Bleeding from the punctured gastric wall occurred in 1 patient 3 days postoperatively. We exchanged the plastic stent for a fully covered self expandable metal stent. A mild adverse event of self-limited abdominal pain occurred in 3 patients. Treatment success was achieved in all patients. The occlusion rate was 13.7% (3/22) during the median follow-up period (5.0 months, range 0.5-12.5 months). The median duration of stent patency was 4.0 months (range 0.5-9.0 months). There was no stent migration or dislocation during the follow-up period. LIMITATIONS: Small number of patients and lack of a control group. CONCLUSIONS: This newly designed single-pigtail plastic stent dedicated for EUS-HGS was technically feasible and can possibly be used for highly selected patients with advanced malignancy or benign stricture. ( TRIAL REGISTRATION: http://www.umin.ac.jp/english/: UMIN000012993.). PMID- 25936453 TI - Metal versus plastic for pancreatic pseudocyst drainage: clinical outcomes and success. AB - BACKGROUND: Endoscopic transmural drainage of pancreatic pseudocysts (PPs) by using double-pigtail (DP) plastic stents requires placement of multiple stents and can be restricted by inadequate drainage and leakage risk. Recently, the use of fully covered self-expanding metal stents (FCSEMSs) has been reported as an alternative to DP plastic stents. OBJECTIVE: To evaluate the clinical outcomes, success rate, and adverse events of EUS-guided drainage of PPs with DP plastic stents and FCSEMSs. DESIGN: Retrospective cohort study. SETTING: Two tertiary care academic medical centers. PATIENTS: This study involved 230 patients (mean age, 52.6 years) with PPs who underwent EUS-guided transmural drainage including 118 that were drained by using DP plastic stents and 112 by using FCSEMSs. A transgastric approach was used in 210 patients (91%), and transduodenal drainage was performed in 20 patients (9%). INTERVENTIONS: Stent deployment under EUS guidance. MAIN OUTCOME MEASUREMENTS: Technical success, early adverse events, stent occlusion requiring reintervention, and long-term success. RESULTS: At 12 month follow-up after the initial procedure, complete resolution of PPs by using DP plastic stents was lower compared with those that underwent drainage with FCSEMSs (89% vs 98%; P = .01). Procedural adverse events were noted in 31% in the DP plastic stent group and 16% in the FCSEMS group (P = .006). On multivariable analysis, patients with plastic stents were 2.9 times more likely to experience adverse events (odds ratio 2.9; 95% confidence interval, 1.4-6.3). LIMITATIONS: Retrospective study. CONCLUSION: In patients with PPs, EUS-guided drainage by using FCSEMSs improves clinical outcomes and lowers adverse event rates compared with those drained with DP plastic stents. PMID- 25936454 TI - Large impacted pancreatic stone removed with single-operator pancreatoscopy and electrohydraulic lithotripsy. PMID- 25936452 TI - Effect of a stylet on a histological specimen in EUS-guided fine-needle tissue acquisition by using 22-gauge needles: a multicenter, prospective, randomized, controlled trial. AB - BACKGROUND: EUS-guided FNA (EUS-FNA) has become the most efficacious way to obtain specimens from a solid lesion adjacent to the GI tract. Previous reports regarding the use of a stylet during EUS-FNA were all based on cytological diagnosis and have showed no significant superiority in terms of diagnostic yield. OBJECTIVE: To clarify the noninferiority of EUS-FNA without a stylet (S-) compared with EUS-FNA with a stylet (S+) on histological assessment. DESIGN: A prospective, single-blind, randomized, controlled crossover study. SETTING: Five tertiary referral centers in Japan. PATIENTS: Patients referred for EUS-FNA of a solid lesion. INTERVENTION: EUS-FNA S+ and S- in a total of 4 alternate passes with randomization to S+ first or S- first. MAIN OUTCOME MEASUREMENTS: The primary endpoint was the acquisition rate of an appropriate and sufficient specimen for histological assessment. The secondary endpoints were cellularity, contamination, bloodiness, diagnostic ability, and diagnostic accuracy. RESULTS: We enrolled 107 patients (110 lesions) and analyzed 220 specimens each in the S+ and S- groups. The acquisition rate of appropriate and sufficient specimens in the S+ group was 121 of 220 (55.0%) and 122 of 220 (55.5%) in the S- group. The difference in the acquisition rate of the specimen (S- minus S+) based on the generalized estimating equation was 0.42% (95% confidence interval, -6.72% to 7.56%), which was less than 10% of the prespecified noninferiority margin of this study. With regard to cellularity, contamination, bloodiness score, diagnostic ability, and diagnostic accuracy, there were no significant differences between both groups. There were no dropouts in the study. LIMITATIONS: A variety of target lesions, multiple pathologists, lack of an assessment of intraobserver and interobserver variability, and a single-blind study for the pathologists. CONCLUSION: EUS-FNA S- is noninferior to EUS-FNA S+ on histological assessment. ( CLINICAL TRIAL REGISTRATION NUMBER: UMIN000008695.). PMID- 25936455 TI - Diamond-shaped flexible endoscopic cricopharyngeal myotomy for treatment of Zenker's diverticulum. PMID- 25936456 TI - Endoscopic application of polysaccharide powder for hemostasis in anticoagulated pigs (with video). AB - BACKGROUND: Acute GI bleeding remains a clinical problem of daily importance. Increasing numbers of patients with compromised coagulation challenge the established methods of endoscopic hemostasis. Therefore, new powders for the treatment of GI bleeding have been developed. OBJECTIVE: To clarify the efficacy of a newly available anticoagulant powder in stopping hemorrhage. DESIGN: A randomized prospective comparative study regarding the potential of an endoscopically applicable polysaccharide powder in pigs receiving antithrombotic medication. SETTING: A professional veterinary animal laboratory. PATIENTS: Twenty-two pigs were anticoagulated with heparin (n = 8), aspirin (n = 8), or no antithrombotic medication (n = 6), in a randomized order. INTERVENTIONS: A bleeding ulcer with continuous bleeding (Forrest I b) was established in the stomach. Endoscopic hemostasis was performed using the powder. MAIN OUTCOME MEASUREMENTS: Time to hemostasis and the amount of powder used were recorded. Follow-up occurred for 3 days, final hemoglobin measurement, followed by autopsy with control for post-interventional bleeding. RESULTS: Endoscopic hemostasis was successful in all cases. Post-interventional bleeding was not recorded. LIMITATIONS: Animal study, artificial superficial bleeding source. CONCLUSION: Polysaccharide powder is able to stop active bleeding from Forrest I b lesions in pigs receiving antithrombotic therapy. PMID- 25936457 TI - High-resolution imaging by using 2-balloon radial EUS sonography in the esophagus. PMID- 25936458 TI - Shared Medical Appointments for Adolescents With Type 1 Diabetes Mellitus: Important Learning Communities. PMID- 25936459 TI - We Need to Talk: The Impact on Care When Electronic Communication Replaces Verbal Communication Between Clinicians. PMID- 25936460 TI - Non-enzymatic antioxidant capacity and risk of gastric cancer. AB - BACKGROUND: Consumption of fruit and vegetables has been inversely related to gastric cancer. Two studies found that dietary antioxidant capacity has some role in explaining this association. We investigated the overall antioxidant effect from diet on gastric cancer using three measures of non-enzymatic antioxidant capacity (NEAC). METHODS: We used data from an Italian case-control study including 230 patients with incident, histologically confirmed gastric cancer, and 547 frequency matched controls admitted to the same hospitals for acute non neoplastic diseases. A reproducible and valid food frequency questionnaire was used to assess subjects' usual diet. NEAC was measured using Italian food composition tables in terms of Trolox equivalent antioxidant capacity (TEAC), Ferric reducing-antioxidant power (FRAP) and Total radical-trapping antioxidant parameter (TRAP). We estimated the odds ratios (OR) of gastric cancer and the corresponding 95% confidence intervals (CI) using conditional logistic regression models including terms for recognized gastric cancer risk factors and total energy intake. RESULTS: NEAC was inversely related with gastric cancer risk with ORs for the highest versus the lowest quintile of 0.54 (95%CI, 0.33-0.88) for TEAC, 0.67 (95%CI, 0.42-1.07) for FRAP and 0.57 (95%CI, 0.36-0.90) for TRAP. CONCLUSIONS: A diet rich in antioxidant capacity reduced gastric cancer risk, suggesting a high consumption of fruit and vegetables and a moderate consumption of wine and whole cereals. PMID- 25936461 TI - Low-level prenatal mercury exposure in north China: an exploratory study of anthropometric effects. AB - In order to investigate anthropometric effects of mercury (Hg) exposure, we examined the status of human prenatal exposure to Hg species, including total mercury (THg), methylmercury (MeHg) and inorganic mercury (IHg), in North China, as well as their potential effects on fetal and infant growth. Hg concentrations in various bioindicators were measured from 50 Chinese women and newborns in 2011. The participants were followed for 12 months to collect anthropometric information. Linear and two-level regression analyses were performed to determine the associations between Hg levels and body growth. The geometric mean levels of THg in the placenta, cord blood, fetal hair, and maternal blood, hair, and urine were 25.88 MUg/kg dry wt, 2.73 MUg/L, 572.98 MUg/kg, 2.29 MUg/L, 576.54 MUg/kg, and 0.58 MUg/g creatinine, respectively. Nearly 100% of Hg presented as IHg in urine, and the percentage of IHg in other bioindicators was 14.86-48.73%. We observed significantly negative associations between Hg levels in some matrixes and anthropometry of neonates (weight and height) and infants (height) (p < 0.05). THg levels in maternal hair were also negatively associated with infant growth rate of weight during 12 months after delivery (p = 0.017). This study suggests that low-level prenatal Hg exposure could play a role in attenuating fetal and infant growth, and the effects of MeHg and IHg are different. PMID- 25936462 TI - Unusual case of desmotropy. Combined spectroscopy (1H-14N NQDR) and quantum chemistry (periodic hybrid DFT/QTAIM and Hirshfeld surface-based) study of solid dacarbazine (anti-neoplastic). AB - Antineoplastic chemo-therapeutic drug 5-(3,3-dimethyl-1-triazenyl)imidazole-4 carboxamide (Dacarbazine, DTIC), has been studied experimentally in solid state by 1H-14N NQDR double resonance at 295 K and theoretically by the Density Functional Theory (DFT)/Quantum Theory of Atoms in Molecules (QTAIM) and Hirshfeld surfaces analysis. Only one set of eighteen resonance frequencies was found in the experiment. This indicates the presence of six inequivalent nitrogen sites: -N(CH3), -NH2, -NH- and three -N= (of which one is a ring, two are from triazene) in the DTIC molecule. This contradicts the X-ray data which revealed the multiplication of nitrogen sites due to unusual desmotropism. The averaging of NQR frequencies caused by the fast in NQR time-scale exchange of protons in a double-well potential combined with the oscillations of twisted supramolecular synthons was proposed as a potential mechanism responsible for this apparent contradiction. An effective improvement in the quality of the spectrum reproduction was achieved when the calculations were performed assuming the periodic boundary conditions, BLYP functional, the DNP basis set and taking the 3*3*3 k-point separation. The ordering of the nitrogen sites according to the increasing quadrupole coupling constant (QCC): N(3) .1). Incidence of RTAD was observed to be higher among women (P = .034), patients with stent-graft oversizing >=10% (P = .018), and patients treated with a stent-graft of diameter >42 mm (P = .01). Aortic morphology analysis showed that an indexed aortic diameter of >=20 mm/m(2) (P = .003); aortic root morphology, specifically loss of the sinotubular junction (P = .004); and presence of an aortic arch malformation (P = .03) were correlated with risk of RTAD. Two patients in the zone-0 group with severe angulation (>120 degrees ) between the ascending and the transverse aorta suffered RTAD. CONCLUSIONS: The occurrence of RTAD after hybrid aortic arch repair is common. To prevent this complication, preoperative screening of the aortic arch, ascending aorta, and aortic root morphology is critical. PMID- 25936470 TI - Quadricuspid aortic valve repair: Pushing the limits! PMID- 25936471 TI - A new PET/CT volumetric prognostic index for non-small cell lung cancer. AB - OBJECTIVES: Whole-body metabolic tumor volume (MTVWB) has been shown of prognostic value for non-small cell lung cancer (NSCLC) beyond that of TNM stage, age, gender, performance status, and treatment selection. The current TNM staging system does not incorporate tumor volumetric information. We propose a new PET/CT volumetric prognostic (PVP) index that combines the prognostic value of MTVWB and TNM stage. MATERIALS AND METHODS: Based on 328 consecutive NSCLC patients with a baseline PET/CT scan before treatment, from which MTVWB was measured semi automatically, we estimated hazard ratios (HRs) for ln(MTVWB) and TNM stage from a Cox proportional hazard regression model that consisted of only ln(MTVWB) and TNM stage as prognostic variables of overall survival. We used the regression coefficients, which gave rise to the HRs, as weights to formulate the PET/CT volumetric prognostic (PVP) index. We also compared the prognostic value of the PVP index against that of TNM stage alone and ln(MTVWB) alone with univariate and multivariate survival analyses and C-statistics. RESULTS: Univariate analysis C statistic for the PVP index (C=0.71) was statistically significantly greater than those for TNM stage alone (C=0.67, p<0.01) and for ln(MTVWB) alone (C=0.69, p=0.033). Multivariate analyses showed that the PVP index yielded significantly greater discriminatory power (C=0.74) than similar models based on either TNM stage (C=0.72, p<0.01) or ln(MTVWB) (C=0.73, p<0.01). Lower values of the PVP index were associated with significantly better overall survival (adjusted HR=2.70, 95%CI [2.16, 3.37]). CONCLUSION: The PVP index provides a practical means for clinicians to combine the prognostic value of MTVWB and TNM stage and offers significantly better prognostic accuracy for overall survival of NSCLC patients than the current TNM staging system or metabolic tumor burden alone. PMID- 25936472 TI - Immunohistochemical characterization of the mTOR pathway in stage-I non-small cell lung carcinoma. AB - BACKGROUND: Dysregulation of mammalian target of rapamycin (mTOR) pathway has been linked with malignant tumorigenesis. This study explored the expression profiles of proteins involved in the mTOR pathway and their relationships with clinicopathologic characteristics in stage-I non-small-cell lung carcinoma (NSCLC). METHODS: The protein expression profiles of PTEN, p-Akt, p-mTOR, p-S6, and eIF4E were examined using immunohistochemical staining and tissue microarray method in 408 patients with stage-I NSCLC (250 adenocarcinomas [ADC] and 158 squamous cell carcinomas). RESULTS: Retained PTEN expression (P<0.001), p-mTOR expression (P<0.001), and p-S6 expression (P=0.007) were associated with ADC histology. Expression of PTEN (P=0.001), p-Akt (P=0.005), p-mTOR (P=0.007), p-S6 (P<0.001) were correlated with lower pathologic T stage. PTEN loss was correlated with male gender and smoking history and p-mTOR expression was inversely correlated with these factors (P<0.001). Subgroup analysis of ADCs indicated that male gender, high pT stage, lymphovascular invasion, and PTEN loss were poor prognostic factors. Multivariate analysis revealed that the PTEN(-)/p-Akt(+)/p mTOR(+) combination more effectively determined the prognosis of ADC (hazard ratio=2.2, P=0.004) than PTEN alone. CONCLUSIONS: Activation of the mTOR pathway in early-stage ADCs suggests a significant role for the mTOR axis in early carcinogenesis. The combination of PTEN(-)/p-Akt(+)/p-mTOR(+) expression was correlated with poor overall survival in patients with stage-I lung ADC. PMID- 25936473 TI - Severity of depressive symptoms as a predictor of mortality: the English longitudinal study of ageing. AB - BACKGROUND: Major depressive disorder and subthreshold depression have been associated with premature mortality. We investigated the association between depressive symptoms and mortality across the full continuum of severity. METHOD: We used Cox proportional hazards models to examine the association between depressive symptom severity, assessed using the eight-item Center for Epidemiological Studies Depression Scale (CES-D; range 0-8), and the risk of all cause mortality over a 9-year follow-up, in 11 104 members of the English Longitudinal Study of Ageing. RESULTS: During follow-up, one fifth of study members died (N = 2267). Depressive symptoms were associated with increased mortality across the full range of severity (p trend < 0.001). Relative to study members with no symptoms, an increased risk of mortality was found in people with depressive symptoms of a low [hazard ratio (HR) for a score of 2 was 1.59, 95% confidence interval (CI) 1.40-1.82], moderate (score of 4: HR 1.80, 95% CI 1.52 2.13) and high (score of 8: HR 2.27, 95% CI 1.69-3.04) severity, suggesting risk emerges at low levels but plateaus thereafter. A third of participants (36.4%, 95% CI 35.5-37.3) reported depressive symptoms associated with an increased mortality risk. Adjustment for physical activity, physical illnesses, and impairments in physical and cognitive functioning attenuated this association (p trend = 0.25). CONCLUSIONS: Depressive symptoms are associated with an increased mortality risk even at low levels of symptom severity. This association is explained by physical activity, physical illnesses, and impairments in physical and cognitive functioning. PMID- 25936474 TI - What factors affect documentation by midwives? A prospective study assessing relationship between length of shift, workload and quality of note keeping. AB - OBJECTIVE: The objective of this study was to assess the association between the quality of basic note keeping and partogram documentation with progression of shift and workload on labour ward. DESIGN: This was a prospective observational study. SETTING: The setting of this study was a labour ward of a teaching district hospital in an inner city London hospital. METHODS: Intrapartum notes and partograms of 61 consecutive labouring women were assessed for quality of midwifery documentation at the beginning, middle and end of a 12-h shift. MEASUREMENTS: The measurements of this study were a basic note-keeping composite score based on validated criteria by the Nursing and Midwifery Record Keeping Guidance 2010 and a partogram completion score based on the National Institute for Clinical Excellence (NICE) Guidelines for Intrapartum Care 2007. FINDINGS: The basic note keeping deteriorated between the middle and the end of the 12-h shift, but it appeared unaffected by workload, with no statistically significant difference between day and night shifts. Partogram documentation was poorer in the middle compared to the beginning of the shift, and there was no statistical difference between day and night shifts. Partogram completion appeared to be influenced by women: midwife ratio as well as progression through a shift. KEY CONCLUSIONS: The basic note keeping and partogram documentation were best at the beginning of the shift, and fatigue may play a role in poorer documentation towards the middle and the end of the shifts. IMPLICATION FOR PRACTICE: Appropriately scheduled breaks especially during the final third of the shifts may help improve the quality of documentation. PMID- 25936475 TI - A randomized comparison of the Laryngoscope with Fiber Optic Reusable Flexible Tip English Macintosh blade to the conventional Macintosh laryngoscope for intubation in simulated easy and difficult child airway with chest compression scenarios. AB - INTRODUCTION: We hypothesized that the Laryngoscope with Fiber Optic Reusable Flexible Tip English Macintosh blade (TMAC) is beneficial for the intubation of child manikins while performing cardiopulmonary resuscitation (CPR). In the present study, we evaluated the effectiveness of the conventional Macintosh laryngoscope (MAC) and TMAC in 3 simulated CPR scenarios. METHODS: A randomized crossover simulation trial was designed. One hundred seven paramedics intubated the trachea of a PediaSIM CPR training manikin (FCAE HealthCare, Sarasota, FL) using the MAC and TMAC in a normal airway scenario (scenario A), normal airway with chest compression scenario (scenario B), and difficult airway with chest compression scenario (scenario C). The participants were directed to make a maximum of 3 attempts in each scenario. The success rate, time required for intubation, Cormack-Lehane grade, dental compression, and the ease of intubation were measured. RESULTS: The median time of intubation with MAC and TMAC in scenario A was 19.6 (interquartile range [IQR], 18-23) vs 19 (IQR, 16.2-21.8); in scenario B, 29.5 (IQR, 25-31) vs 26 (IQR, 23.5-29) seconds; and in scenario C, 38 (IQR, 32.5-45) vs 29 (IQR, 25-31) seconds, respectively. The overall efficacy for each of the scenarios was as follows: in scenario A, it was 100% vs 100%; in scenario B, it was 79.4% vs 100% (P = .007); and in scenario C, it was 68.2% vs 90.7% (P < .001), respectively. CONCLUSIONS: The TMAC seems to be a superior intubating device compared with the conventional MAC when used in simulated normal and difficult child airway with chest compression scenarios. Future studies should explore the efficacy of TMAC in pediatric clinical emergency settings. PMID- 25936476 TI - Femoral venous oxygen saturation obtained during CPR predicts successful resuscitation in a pig model. AB - PURPOSE: Central venous oxygen saturation has been shown to reflect the adequacy of tissue oxygenation during cardiopulmonary resuscitation (CPR), thereby enabling the assessment of CPR quality and the prediction of restoration of spontaneous circulation (ROSC). The femoral vein can be easily accessed during CPR. We determined if femoral venous oxygen saturation (SFVO2) values obtained during CPR could reliably predict ROSC in a pig model. METHODS: After 15 minutes of untreated ventricular fibrillation followed by 8 minutes of basic life support, 19 pigs underwent advanced cardiovascular life support. During advanced cardiovascular life support, femoral venous blood samples were obtained at 4 minute intervals. The abilities of SFVO2 and coronary perfusion pressure (CPP) to predict ROSC were evaluated by calculating the areas under receiver operating characteristic curves (AUCs). RESULTS: Eight pigs (42.1%) achieved ROSC. The resuscitated animals had significantly higher CPP (P < .001) and SFVO2 (P < .001) values than the nonresuscitated animals, and there was a significant correlation between SFVO2 and CPP values (r = 0.684; P < .001). The CPPs of the resuscitated and nonresuscitated animals overlapped considerably; however, there was minimal overlap between the 2 groups for SFVO2. Femoral venous oxygen saturation significantly predicted ROSC with an AUC of 0.997 (95% confidence interval, 0.911 1.000; P < .001), and it had a larger AUC than CPP (AUC, 0.964; 95% confidence interval, 0.855-0.997; P < .001). The AUC difference, however, was not statistically significant (P = .157). CONCLUSION: In this study, SFVO2 values obtained during CPR exhibited a significant correlation with CPP and reliably predicted ROSC. PMID- 25936477 TI - Emergency medicine in the Veterans Health Administration-results from a nationwide survey. AB - STUDY OBJECTIVE: We describe emergency physician staffing, capabilities, and academic practices in US Veterans Health Administration (VHA) emergency departments (EDs). METHODS: As part of an ongoing process improvement effort for the VHA emergency care system, VHA-wide surveys are conducted among ED medical directors every 3 years. Web-based surveys of VHA ED directors were conducted in 2013 on clinical operations and academic program development. We describe the results from the 2013 survey. When available, we compare responses with the previously administered survey from 2010. RESULTS: A total of 118 of 118 ED directors filled out the survey in 2013 (100% response rate). Respondents reported that 45.5% of VHA emergency physicians are board certified in emergency medicine, and 95% spend most their time in direct patient care. Clinical care is also provided by part-time (<0.5 full-time employee equivalent) emergency physicians in 59.3% of EDs. More than half of EDs (57%) provide on-site tissue plasminogen activator for acute ischemic stroke patients, and only 39% can administer tissue plasminogen activator 24 hours per day, 7 days per week. Less than half (48.3%) of EDs have emergency Obstetrics and Gynecology consultation availability. Most VHA EDs (78.8%) have a university affiliation, but only 21.5% participated in the respective academic emergency medicine program. CONCLUSIONS: Veterans Health Administration emergency physicians have primarily clinical responsibilities, and less than half have formal emergency medicine board certification. Despite most VHA EDs having university affiliations, traditional academic activities (eg, teaching and research) are performed in only 1 in 3 VHA EDs. Less than half of VHA EDs have availability of consulting services, including advanced stroke care and women's health. PMID- 25936478 TI - Comparison of different techniques for in microgravity-a simple mathematic estimation of cardiopulmonary resuscitation quality for space environment. AB - BACKGROUND: Since astronauts are selected carefully, are usually young, and are intensively observed before and during training, relevant medical problems are rare. Nevertheless, there is a certain risk for a cardiac arrest in space requiring cardiopulmonary resuscitation (CPR). Up to now, there are 5 known techniques to perform CPR in microgravity. The aim of the present study was to analyze different techniques for CPR during microgravity about quality of CPR. MATERIAL AND METHODS: To identify relevant publications on CPR quality in microgravity, a systematic analysis with defined searching criteria was performed in the PubMed database (http://www.pubmed.com). For analysis, the keywords ("reanimation" or "CPR" or "resuscitation") and ("space" or "microgravity" or "weightlessness") and the specific names of the techniques ("Standard-technique" or "Straddling-manoeuvre" or "Reverse-bear-hug-technique" or "Evetts-Russomano technique" or "Hand-stand-technique") were used. To compare quality and effectiveness of different techniques, we used the compression product (CP), a mathematical estimation for cardiac output. RESULTS: Using the predefined keywords for literature search, 4 different publications were identified (parabolic flight or under simulated conditions on earth) dealing with CPR efforts in microgravity and giving specific numbers. No study was performed under real-space conditions. Regarding compression depth, the handstand (HS) technique as well as the reverse bear hug (RBH) technique met parameters of the guidelines for CPR in 1G environments best (HS ratio, 0.91 +/- 0.07; RBH ratio, 0.82 +/- 0.13). Concerning compression rate, 4 of 5 techniques reached the required compression rate (ratio: HS, 1.08 +/- 0.11; Evetts-Russomano [ER], 1.01 +/- 0.06; standard side straddle, 1.00 +/- 0.03; and straddling maneuver, 1.03 +/- 0.12). The RBH method did not meet the required criteria (0.89 +/- 0.09). The HS method showed the highest cardiac output (69.3% above the required CP), followed by the ER technique (33.0% above the required CP). CONCLUSIONS: Concerning CPR quality, the HS seems to be most effective to treat a cardiac arrest. In some environmental conditions where this technique cannot be used, the ER technique is a good alternative because CPR quality is only slightly lower. PMID- 25936479 TI - Venous lactate in predicting the need for intensive care unit and mortality among nonelderly sepsis patients with stable hemodynamic. AB - OBJECTIVES: Our study aims to investigate the role of initial venous lactate in predicting the probability of clinical deterioration and 30-day mortality in nonelderly sepsis patients with acute infections, without hemodynamic shock. METHODS: We enrolled emergency department patients aged 18 to 65 years with acute major infections, but without organ hypoperfusion, and obtained a single venous lactate measurement at initial presentation. As the primary end point, the eligible patients were tracked for the need for vasopressor or mechanical ventilation (MV) in the next 72 hours. The patients' venous lactate and related risk factors were analyzed. We also followed the cohort and the predictors to investigate their prognostic role for 30-day mortality. RESULTS: Of 392 patients, 74 required vasopressor/MV, and 388 patients were available for mortality analysis. An initial lactate greater than or equal to 2 mmol/L was the strongest independent predictor for the requirement of vasopressor/MV (adjusted odds ratio, 6.2; 95% confidence interval, 3.4-11.3). The other independent risk factors were immunosuppressive drug users and positive blood culture. However, the initial lactate was not associated with 30-day mortality. The factors that were associated with mortality were the use of vasopressor/MV, active malignancy, Rapid Emergency Medicine Score greater than or equal to 6, and hospitalization within 90 days. CONCLUSIONS: In nonelderly sepsis patients with stable hemodynamic, elevated venous lactate (>=2 mmol/L) was associated with an increased probability of the need for vasopressor/MV. However, unfavorable medical histories and the severity of physiologic changes may be associated with short-term mortality to a greater extent than the single value of initial lactate. PMID- 25936480 TI - Changes in gene expression of cytochrome P-450 in liver, kidney and aorta of cirrhotic rats. AB - INTRODUCTION: Liver cirrhosis is characterized by structural and hemodynamic changes that affect mainly the liver, the kidney and the vascular system. Cytochrome P-450 (CYP) is a variegated family of enzymes that, among many other activities, metabolize arachidonic acid to the vasoactive epoxyeicosatrienoic acids (EETs). AIM: To investigate in an animal model of cirrhosis the m-RNA expression of CYPs in liver, kidney and aorta and to evaluate the effect of epoxygenase inhibition by N-(methylsulfonyl)-2-(2-propynyloxy)-benzenehexanamide (MS-PPOH). METHODS: In aorta, liver and kidney from 3 control, 3 cirrhotic and 6 cirrhotic rats treated with MS-PPOH, quantitative real-time PCR reactions were performed and the m-RNA expression of CYP2J3, CYP2J4, CYP2J10, CYP2C11, CYP2C12 and CYP2C23 was calculated. RESULTS: In cirrhotic rats, the gene expression of hepatic CYP2C11 and CYP2J10 was increased, of aortic CYP2J4 was increased, of aortic CYP2C12 was reduced and of renal CYP2C11 was increased. In cirrhotic rats, MS-PPOH reduced CYP2J10 hepatic and CYP2C11 renal gene expression to levels similar to the ones of control rats. CONCLUSIONS: Changes in CYPs gene expression may contribute to the hemodynamic alterations typical of cirrhosis. The altered gene expression of CYPs can, in some cases, be reversed by epoxygenase inhibition. PMID- 25936481 TI - The cell secretome, a mediator of cell-to-cell communication. AB - We are witnessing the emergence of a novel type of biological regulation, namely, the communication between cells via their secreted substances, the secretome. This brief overview is based on the available published data and our own experience. We discuss three vignettes illustrating the importance of communication via the secretome: (1) the secretome of stem cells and its effects in sepsis and systemic inflammatory response; (2) the profibrotic secretomes partially responsible for development of fibrotic complications; and (3) the contribution of senescence-associated secretory products to the propagation of the senescence phenotype. Considering the richness of secretomes of different cells under diverse conditions, it becomes imperative to gain insights into their individual components in an attempt to harness cell secretomes for therapeutic purposes. PMID- 25936482 TI - Combined Measures of Dynamic Bone Quality and Postural Balance--A Fracture Risk Assessment Approach in Osteoporosis. AB - We evaluated functional measures of neuromuscular integrity and bone's resistance to fracture as a combined tool in discriminating osteoporosis patients with and without fractures. Functional aspects of neuromuscular integrity were quantified with a noninvasive measure of static and dynamic functional postural stability (FPS), and fracture resistance was obtained with bone shock absorption in patients with osteoporosis aged 65-85 and compared our measures with dual-energy X-ray absorptiometry and Fracture Risk Assessment Tool (FRAX [World Health Organization Collaborating Center for Metabolic Bone Diseases, Sheffield, UK]) in women with osteoporosis, some with and some without vertebral fractures. Patients with vertebral fracture showed larger static FPS (postural sway excursion) in the mediolateral and anterior-posterior directions, suggesting poorer balance. Most of the variables of dynamic FPS showed significant differences between fracture and no-fracture groups (e.g., the fracture group took significantly longer during turning, implying poorer dynamic balance control). Also, compared with healthy control subjects, all 4 dynamic FPS responses for osteoporosis patients with and without fracture were significantly poorer, suggesting potential risk for falls. In summary, patients with osteoporosis who have vertebral fractures (compared with patients with similarly low bone mineral density and other nonfracture risk fractures) have not only lower bone shock absorption damping (zeta) but also increased postural imbalance. PMID- 25936484 TI - The case against using hypertension as the only criterion for oral anticoagulation in atrial fibrillation. AB - According to recent guidelines for atrial fibrillation (AF) management, the presence of hypertension warrants anticoagulation, often involving the use of newer oral anticoagulants (NOACs). To discuss this idea, we posited the case against this proposition. We note that the data on hypertension that formulated the most commonly used Congestive Heart Failure, Hypertension, Age, Diabetes, Stroke/Transient Ischemic Attack (CHADS2) risk algorithm were not clearly defined and that there are insufficient data that hypertension in the presence of AF produces a meaningful incremental increase in stroke risk over and above the stroke risk increase for hypertension alone. Data exist that persons younger than 65 years of age with only 1 stroke risk factor such as hypertension, have a very small stroke risk. We further note that there are no quantitative data to allow clinicians to decide the level of blood pressure that meaningfully increases stroke risk in AF. Furthermore, there are insufficient data on the blood pressure level at which the risk of cerebral hemorrhage outweighs the risk of cardioembolic events. Clinical trials of NOACs in AF did not usually include hypertension as the only entry criteria. Another issue is the recent changes in the level of blood pressure for the diagnosis of hypertension based on home and ambulatory blood pressure measurement, which were not used to construct either stroke risk algorithms or entry criteria for NOAC clinical trials. These considerations highlight some of the complexities of using hypertension as a sole criterion for decision-making for anticoagulation in AF. PMID- 25936485 TI - New Hope for Lipid-Lowering Beyond Statins: Effect of IMPROVE-IT on Understanding and Implementation of Atherosclerosis Prevention. PMID- 25936483 TI - The 2015 Canadian Hypertension Education Program recommendations for blood pressure measurement, diagnosis, assessment of risk, prevention, and treatment of hypertension. AB - The Canadian Hypertension Education Program reviews the hypertension literature annually and provides detailed recommendations regarding hypertension diagnosis, assessment, prevention, and treatment. This report provides the updated evidence based recommendations for 2015. This year, 4 new recommendations were added and 2 existing recommendations were modified. A revised algorithm for the diagnosis of hypertension is presented. Two major changes are proposed: (1) measurement using validated electronic (oscillometric) upper arm devices is preferred over auscultation for accurate office blood pressure measurement; (2) if the visit 1 mean blood pressure is increased but < 180/110 mm Hg, out-of-office blood pressure measurements using ambulatory blood pressure monitoring (preferably) or home blood pressure monitoring should be performed before visit 2 to rule out white coat hypertension, for which pharmacologic treatment is not recommended. A standardized ambulatory blood pressure monitoring protocol and an update on automated office blood pressure are also presented. Several other recommendations on accurate measurement of blood pressure and criteria for diagnosis of hypertension have been reorganized. Two other new recommendations refer to smoking cessation: (1) tobacco use status should be updated regularly and advice to quit smoking should be provided; and (2) advice in combination with pharmacotherapy for smoking cessation should be offered to all smokers. The following recommendations were modified: (1) renal artery stenosis should be primarily managed medically; and (2) renal artery angioplasty and stenting could be considered for patients with renal artery stenosis and complicated, uncontrolled hypertension. The rationale for these recommendation changes is discussed. PMID- 25936486 TI - Complex percutaneous interventions: what is the role for specialized bifurcation stents? PMID- 25936487 TI - Blood pressure control in Canada: the view from a stroke prevention clinic. PMID- 25936488 TI - Metabolic Syndrome Sinkholes: What to Do When Occam's Razor Gets Blunted. AB - The real promise of the metabolic syndrome concept was the opportunity to elucidate a singular common mechanism for its component abnormalities and consequently a singular therapy. That promise has not produced. This relates to the following considerations: (1) metabolic syndrome remains a syndrome not a disease, (2) its diagnosis offers little more than what can be determined by measuring waist circumference, (3) risk assessment is not improved by the diagnosis of metabolic syndrome, (4) the diagnosis of metabolic syndrome does not impact the treatment of each component of the syndrome, and (5) there is no effective therapy for metabolic syndrome in its entirety. PMID- 25936489 TI - Oxidative stress and human hypertension: vascular mechanisms, biomarkers, and novel therapies. AB - Hypertension is a major cardiovascular risk factor. Of the many processes involved in the pathophysiology of hypertension, vascular damage due to oxidative stress (excess bioavailability of reactive oxygen species [ROS]) is particularly important. Physiologically, ROS regulate vascular function through redox sensitive signalling pathways. In hypertension, oxidative stress promotes endothelial dysfunction, vascular remodelling, and inflammation, leading to vascular damage. Vascular ROS are derived primarily by nicotinamide adenine dinucleotide phosphate oxidases, which are prime targets for therapeutic development. Although experimental evidence indicates a causative role for oxidative stress in hypertension, human data are less convincing. This might relate, in part, to suboptimal methods to accurately assess the redox state. Herein we review current knowledge on oxidative stress in vascular pathobiology and implications in human hypertension. We also discuss biomarkers to assess the redox state in the clinic, highlight novel strategies to inhibit ROS production, and summarize how lifestyle modifications promote vascular health by reducing oxidative stress. PMID- 25936490 TI - Screening Strategies and Primary Prevention Interventions in Relatives of People With Coronary Artery Disease: A Systematic Review and Meta-analysis. AB - BACKGROUND: Relatives of people with coronary artery disease are at high risk of cardiovascular (CV) disease, but the effect of focused screening and treatment of this population is uncertain. METHODS: We searched the Cochrane Library, Medline, and Embase from inception until June 30, 2014 for articles that described screening strategies and primary prevention interventions targeting family members of patients with coronary artery disease to reduce CV risk. Results were pooled using a random-effects meta-analysis. RESULTS: We identified 18 studies that reported screening strategies and 15 reporting interventions to reduce CV risk. Proband willingness to refer relatives for screening was high (n = 6 studies, pooled rate = 87%; 95% confidence interval [CI], 80%-95%). Studies using a screening strategy in which the relative was contacted by health care professionals reported a pooled participation rate of 88% (95% CI, 78%-99%). The quality of interventional studies was highly variable. Random-effects meta analysis of the highest quality randomized studies (n = 6) consisting of a specialized risk factor intervention compared with usual care was consistent with modest improvements in low-density lipoprotein cholesterol control (-0.18 mmol/L low-density lipoprotein cholesterol, 95% CI, -0.35 to -0.001; P = 0.048). Improvements in diet, smoking rates, exercise, and blood pressure were also observed with active intervention; however, reported outcomes were heterogeneous precluding a formal meta-analysis. CONCLUSIONS: Screening strategies that target family members, particularly when led by a health care professional, achieve a high participation rate. Although the available evidence is of variable quality, interventions that target individuals with a family history of coronary artery disease appear to be feasible and might be effective in improving certain risk factors or health behaviours but their long-term CV benefits remain uncertain. PMID- 25936491 TI - Unreliability of home blood pressure measurement and the effect of a patient oriented intervention. AB - BACKGROUND: Home blood pressure (BP) measurement (HBPM) is recommended for the diagnosis and follow-up of high BP. It is unclear how this aspect of BP monitoring has evolved over the years and whether interventions could influence patient adherence to HBPM guidelines. METHODS: After a questionnaire-based cross sectional study performed in 2010, a passive, multimodal intervention, focused on improving adherence to HBPM guidelines, was implemented. A second study was conducted in 2014 to measure its effect. RESULTS: In 2010 and 2014, 1010 and 1005 patients, respectively, completed the questionnaire. In 2010 and 2014, 82% and 84% of patients, respectively, self-measured their BP. Reporting of HBPM and adherence to recommended procedures was suboptimal. Only 34.0% of patients in 2010 and 31.7% in 2014 brought > 80% of their measurements to their doctor. Only 49.6% in 2010 and 52.9% in 2014 prepared > 80% of the time for HBPM. Only 48.1% in 2010 and 52.1% in 2014 rested for 5 minutes > 80% of the time before HBPM. Only 15% of patients in 2010 and 18% in 2014 were defined as sufficiently compliant with all HBPM procedures. Paired analysis of a subset of 535 patients who participated in the 2010 and 2014 studies showed no clinically significant differences in reliability between the 2 surveys. CONCLUSIONS: Adherence to HBPM guidelines was suboptimal in 2010 and still is in 2014 despite a passive, multimodal intervention. Active training in HBPM procedures should be studied. Greater automation could improve HBPM reliability. PMID- 25936492 TI - Contemporary Management and Control of Uncomplicated Hypertension in Canada: Insight From the Primary Care Audit of Global Risk Management (PARADIGM) Study. AB - BACKGROUND: Although clinical practice guidelines for the management of hypertension exist in Canada, the rate of contemporary blood pressure (BP) control remains unclear. METHODS: In the Primary Care Audit of Global Risk Management (PARADIGM) study, 3015 healthy, middle-aged Canadians, free of cardiovascular disease (CVD) or diabetes were evaluated. In this analysis, we characterized the CVD risk factors, treatment patterns, and BP control rates in subjects with uncomplicated hypertension. RESULTS: A total of 917 subjects (30.4%) had a diagnosis of hypertension. The median age was 59 +/- 8 years. The mean treated systolic/diastolic BP were 134 +/- 14 mm Hg/82 +/- 9 mm Hg, respectively. CVD risk factors included past/current smoking (35.9%), abdominal obesity (62.5%), and dyslipidemia (59.4%). Using the Framingham Risk Score, 20.4%, 41.0%, and 38.5% of the subjects were at low, intermediate, and high risk, respectively. Of the 88% with treated hypertension, 46.9%, 38.7%, and 14.3% received 1, 2, or >=3 drugs, respectively. The rate of BP control was 57.4% (systolic BP < 140 and diastolic BP < 90 mm Hg). The rate of BP control was lower in patients prescribed diuretic monotherapy (53.2%) vs those who received angiotensin converting enzyme inhibitor/angiotensin receptor blocker monotherapy (66.5%; P < 0.01). Importantly, BP control deteriorated with increasing Framingham Risk Score, and was lower in patients with metabolic syndrome vs those without (P < 0.00001 for both). CONCLUSIONS: PARADIGM demonstrated that CVD risk factors are prevalent in Canadians with uncomplicated hypertension. BP control was modest (57.4%) and was lowest in patients prescribed diuretic monotherapy and in those at highest CVD risk. Despite the success of national hypertension strategies, enhanced efforts are warranted to improve BP control in Canada. PMID- 25936494 TI - Managing bioabsorbable vascular scaffold failure: combined scaffold restenosis and late-acquired coronary aneurysm treated with self-expandable stent. AB - A 50-year-old man underwent coronary angiography for stable angina with evidence of chronic total occlusion of the right coronary artery. Chronic total occlusion recanalization was performed with implantation of 4 overlapping bioresorbable vascular scaffolds. At 12 months, elective follow-up coronary angiography documented an asymptomatic 90% in-scaffold restenosis of the right coronary artery located in the mid portion of a newly late-acquired aneurysm. To address the challenging issue introduced by the varying reference vessel diameters, a self-expandable stent was implanted. PMID- 25936493 TI - MicroRNA-208a Increases Myocardial Endoglin Expression and Myocardial Fibrosis in Acute Myocardial Infarction. AB - BACKGROUND: MicroRNAs (miRs) play a role in cardiac remodelling, and acute myocardial infarction (AMI) can regulate miR expression. MiR-208a is essential for the expression of the genes involved in cardiac hypertrophy and fibrosis. MiR 208a activates endoglin expression and may result in cardiac fibrosis. The role of miR-208a and endoglin in AMI is not known. We sought to investigate the regulation of miR-208a and endoglin in AMI. METHODS: Ligation of the proximal left anterior descending artery was performed in adult Sprague-Dawley rats to induce AMI. Echocardiography was used to measure heart size and left ventricular function. The TaqMan miR real-time quantitative assay was used to quantitate miR 208a. Myocardial fibrosis was detected by Masson trichrome staining. RESULTS: AMI and overexpression of miR-208a in the sham group without infarction significantly increased myocardial miR-208a, endoglin, and beta-myosin heavy chain (beta-MHC) expression. Overexpression of antagomir-208a significantly inhibited the increase of myocardial endoglin and beta-MHC protein expression induced by infarction. Overexpression of mutant miR-208a in the sham group did not induce myocardial endoglin and beta-MHC expression. Pretreatment with atorvastatin and the angiotensin-receptor antagonist valsartan significantly attenuated the increase of endoglin and beta-MHC induced by infarction. AMI and overexpression of miR 208a in the sham group significantly increased the area of myocardial fibrosis compared with the sham group. Overexpression of antagomir-208a and pretreatment with atorvastatin and valsartan in the AMI group significantly decreased the area of myocardial fibrosis induced by infarction. CONCLUSIONS: MiR-208a increases endoglin expression to induce myocardial fibrosis in rats with AMI. Treatment with atorvastatin and valsartan can decrease myocardial fibrosis induced by AMI through attenuating miR-208a and endoglin expression. PMID- 25936495 TI - [Testing for respiratory viruses in the neonatal intensive care unit: Ready for prime time?]. PMID- 25936496 TI - An evolutionary analysis of nitric oxide reductase gene norV in enterohemorrhagic Escherichia coli O157. AB - A novel virulence gene, norV, that encodes nitric oxide (NO) reductase, was examined to investigate the emergence of enterohemorrhagic Escherichia coli (EHEC) O157 subgroup C clusters 2 and 3 from subgroup C cluster 1. Deletion of norV occurred at a point between cluster 1 and cluster 2 just after or at the same time that an stx2 bacteriophage, which retains Shiga toxin 2 gene, was inserted into wrbA, which encodes a novel multimeric flavodoxin-like protein, in EHEC O157. Sensitivity of NO to anaerobic growth was correlated with the deletion of norV in all EHEC O157 individuals tested. The C467A mutation of fimH, which encodes minor component of type 1 fimbriae, occurred within cluster 1, not as a transition from cluster 1 to cluster 2, indicating that there is a cluster 1 minority branch that leads to cluster 2. These data refine the evolutionary history of an emerging EHEC O157. PMID- 25936497 TI - De-novo transcriptome analysis of the banana shrimp (Fenneropenaeus merguiensis) and identification of genes associated with reproduction and development. AB - The banana shrimp Fenneropenaeus merguiensis is a commercially important marine crustacean for world aquaculture and fisheries. Despite this, limited genetic information is available for it and many other penaeid shrimp species. Here we present the first in-depth analysis of the transcriptional content of 8 different tissues from the banana shrimp using RNA-Seq technologies. A total of over 1 million single-end and over 49 million paired-end reads were obtained from Roche 454FLX and illumina sequencing platforms, respectively, resulting in an assembly of 124,631 transcripts with an N50 of 1,332 and mean length of 514 nt. A total of 59,179 putative protein sequences obtained from the assembled transcripts were annotated using public protein sequence databases and assigned 20,430 BLAST hits, 16,866 GO terms and 13,304 KOG categories. Further analysis revealed a rich set of transcript sequences exhibiting homology with genes associated with reproduction, sex determination and development and distinguished the tissues responsible for this expression. This report adds a substantial contribution to the sequence data currently available for F. merguiensis, providing valuable resources for further research. PMID- 25936498 TI - Domain repeats related to innate immunity in the South African abalone, Haliotis midae. AB - Molluscs predominately use the cellular defence system as the primary mechanism of defence against pathogenic infection, in which haemocytes play a pivotal role. Haliotis midae is a commercially important South African species that it is susceptible to bacterial pathogens, fungal and yeast infections in the farming environment. The current study aims to enrich the current knowledge regarding H. midae innate immunity by investigating the presence and evolution of domain repeats. The bioinformatics approach used in this study, detected five repeat families in the H. midae transcriptome. These repeats families include mixed alpha and beta (leucine-rich and ankyrin), spectrin repeats, beta-propellers (WD40) and alfa-structure repeat (TPR-like). The expansion of key gene families related to host defence may be important to abalone adaptation to life in a pathogen-rich environment. PMID- 25936499 TI - Assessment of neuropsychiatric symptoms in patients with systemic lupus erythematosus. PMID- 25936500 TI - Composite alginate and gelatin based bio-polymeric wafers containing silver sulfadiazine for wound healing. AB - Lyophilized wafers comprising sodium alginate (SA) and gelatin (GE) (0/100, 75/25, 50/50, 25/75, 0/100 SA/GE, respectively) with silver sulfadiazine (SSD, 0.1% w/w) have been developed for potential application on infected chronic wounds. Polymer-drug interactions and physical form were characterized by Fourier transform infrared spectroscopy (FTIR) and X-ray diffraction (XRD), respectively, while morphological structure was examined using scanning electron microscopy (SEM). Functional characteristics [(mechanical hardness and adhesion using texture analyzer, and swelling capacity)] of blank wafers were determined in order to select the optimal formulations for drug loading. Finally, the in vitro drug dissolution properties of two selected drug loaded wafers were investigated. There was an increase in hardness and a decrease in mucoadhesion with increasing GE content. FTIR showed hydrogen bonding and electrostatic interaction between carboxyl of SA and amide of GE but no interaction between the polymers and drug was observed, with XRD showing that SSD remained crystalline during gel formulation and freeze-drying. The results suggest that 75/25 SA/GE formulations are the ideal formulations due to their uniformity and optimal mucoadhesivity and hydration. The drug loaded wafers showed controlled release of SSD over a 7h period which is expected to reduce bacterial load within infected wounds. PMID- 25936501 TI - Steady shear flow properties of Cordia myxa leaf gum as a function of concentration and temperature. AB - The steady shear flow properties of dispersions of Cordia myxa leaf gum (CMLG) were determined as a function of concentration (0.5-2.5%, w/w), and temperature (10-50 degrees C). The CMLG dispersions exhibited strong shear-thinning behavior at all concentrations and temperatures. The Power-law (Ostwald-Waele's) and Herschel-Bulkley models were employed to characterize flow behavior of CMLG solutions at 0.1-100 s(-1) shear rate. Non-Newtonian shear-thinning behavior was observed at all temperatures and concentrations. While increase in temperature decreased the viscosity and increased the flow behavior indices, adverse effect was obtained by increasing the concentration. The Power-law model was found the best model to describe steady shear flow behavior of CMLG. The pseudoplasticity of CMLG increased markedly with concentration. An Arrhenius-type model was also used to describe the effect of temperature. The activation energy (Ea) appeared in the range of 5.972-18.104 kJ/mol, as concentration increased from 0.5% to 2.5%, at a shear rate of 10 s(-1). PMID- 25936502 TI - Effect of Dextran 70 on the thermodynamic and structural properties of proteins. AB - Biological macromolecules are known to evolve and function under crowded intracellular environments that comprises of a wealth of soluble and insoluble macromolecules like proteins, nucleic acids, ribosomes and carbohydrates etc. Crowded environment is known to result in altered biological properties including thermodynamic, structural and functional aspect of macromolecules as compared to the macromolecules present in our commonly used experimental dilute buffers. In this study, we have investigated the effect of Dextran 70 on the thermodynamic and structural properties of three different proteins (Ribonuclease-A, lysozyme and holo alpha-lactalbumin) at different pH values. We discovered that Dextran 70 has a protein-independent effect in terms of protein stability and structure. PMID- 25936503 TI - Physicochemical properties and release characteristics of starches from seeds of Indian Shahi Litchi. AB - Many conventional sources of starches are from staple foods. Non-conventional and cheap sources of starch are being explored. Starch was isolated from Shahi Litchi seeds using two extraction media; acidic (citric acid 0.3%, w/w; LC) and alkaline (NaOH 0.5%, w/w; LN). Each starch was investigated for various properties such as structural, morphological and functional. The percentage yield of LN and LC was 11% and 12.6%, respectively. Morphological properties of both starches show same structural makeup, but compound granules were in LN starch. Moisture content, amylose content was found to be higher LC starch than in LN starch, which indicates that extraction media affects the properties of starch. FTIR confirmed the carbohydrate nature of the both isolated starches. TGA data of both starches reveal slight difference in stability with temperature. In vitro release of both starches shows the release up to 58.95+/-0.04% and 67.184+/-0.07% in 5h for LN and LC, respectively, that indicates that these starches can be used in delayed drug delivery and targeting drugs to the colon. PMID- 25936505 TI - Notch activity modulates the responsiveness of neural progenitors to sonic hedgehog signaling. AB - Throughout the developing nervous system, neural stem and progenitor cells give rise to diverse classes of neurons and glia in a spatially and temporally coordinated manner. In the ventral spinal cord, much of this diversity emerges through the morphogen actions of Sonic hedgehog (Shh). Interpretation of the Shh gradient depends on both the amount of ligand and duration of exposure, but the mechanisms permitting prolonged responses to Shh are not well understood. We demonstrate that Notch signaling plays an essential role in this process, enabling neural progenitors to attain sufficiently high levels of Shh pathway activity needed to direct the ventral-most cell fates. Notch activity regulates subcellular localization of the Shh receptor Patched1, gating the translocation of the key effector Smoothened to primary cilia and its downstream signaling activities. These data reveal an unexpected role for Notch shaping the interpretation of the Shh morphogen gradient and influencing cell fate determination. PMID- 25936507 TI - Prostacyclin receptors: Transcriptional regulation and novel signalling mechanisms. AB - The prostanoid Prostacyclin plays diverse physiologic roles within the vasculature and other systems, and is widely implicated in several cardiovascular, pulmonary and renal diseases. Despite this, knowledge of the factors regulating expression of the I prostanoid receptor (the IP) remained largely unknown. This review details recent advances in understanding the key transcriptional regulators determining expression of the PTGIR gene in the human vasculature and the identification of novel interacting partners of the IP that impact on its function therein. Included in this are the trans-acting factors that regulate expression of the PTGIR under basal- and regulated-conditions, particularly those determining its up-regulation in response to cellular differentiation, estrogen and low serum-cholesterol. Moreover, the functional implications of the interactions between the IP with PDZK1, a multi PDZ-domain containing protein essential for reverse-cholesterol transport and endothelialization, and the IP with IKEPP, the intestinal and kidney enriched PDZ protein, for the role of the prostacyclin-IP axis within the vasculature are reviewed. PMID- 25936506 TI - How actin initiates the motor activity of Myosin. AB - Fundamental to cellular processes are directional movements driven by molecular motors. A common theme for these and other molecular machines driven by ATP is that controlled release of hydrolysis products is essential for using the chemical energy efficiently. Mechanochemical transduction by myosin motors on actin is coupled to unknown structural changes that result in the sequential release of inorganic phosphate (Pi) and MgADP. We present here a myosin structure possessing an actin-binding interface and a tunnel (back door) that creates an escape route for Pi with a minimal rotation of the myosin lever arm that drives movements. We propose that this state represents the beginning of the powerstroke on actin and that Pi translocation from the nucleotide pocket triggered by actin binding initiates myosin force generation. This elucidates how actin initiates force generation and movement and may represent a strategy common to many molecular machines. PMID- 25936508 TI - Computational modeling and biological validation of novel non-steroidal ligands for the cholesterol recognition/interaction amino acid consensus (CRAC) motif of the mitochondrial translocator protein (TSPO). AB - Mitochondria play a critical role in the physiological homeostasis of the cell, contributing to numerous cellular processes, including bioenergetics, metabolism and cell life and death. Owing to their keystone role, mitochondria have gained much attention as pharmacological targets. The outer mitochondrial integral membrane translocator protein (TSPO) has attracted a significant degree of pharmacological interest owing to its ability to bind a number of classes of drugs with high affinity and specificity. In addition to its well-characterized drug binding site, TSPO possess an additional high-affinity ligand binding site, originally identified for its ability to bind the lipid cholesterol, which was named the cholesterol recognition/interaction amino acid consensus (CRAC) motif. Previous investigations from our laboratory identified additional ligands targeted to TSPO's CRAC motif which are able to potently inhibit mitochondrial cholesterol transport and steroid biosynthesis, processes for which TSPO has been well-characterized. However, all of these compounds possessed the steroidal backbone common to cholesterol and steroid hormones. In our efforts to expand our understanding of TSPO's CRAC motif, we performed studies aimed at identifying non steroidal ligands for this motif. Molecular modeling and in silico screening of large chemical libraries identified a panel of compounds which were subsequently screened for bioactivity in a number of steroidogenic model systems. These efforts identified a family of non-steroidal CRAC ligands able to potently inhibit steroidogenesis, and at higher concentrations, promote apoptosis. In addition, the best candidate in this family was able to suppress testosterone synthesis when administered to rats, indicating that this novel family of non steroidal CRAC ligands may serve as prototypes for the development of drugs useful for treatment of diseases of steroid overproduction, such as Cushing's syndrome and steroidogenic cell tumors in humans and animals. PMID- 25936504 TI - Brains in the city: Neurobiological effects of urbanization. AB - With a majority of humans now living in cities, strategic research is necessary to elucidate the impact of this evolutionarily unfamiliar habitat on neural functions and well-being. In this review, both rodent and human models are considered in the evaluation of the changing physical and social landscapes associated with urban dwellings. Animal models assessing increased exposure to artificial physical elements characteristic of urban settings, as well as exposure to unnatural sources of light for extended durations, are reviewed. In both cases, increased biomarkers of mental illnesses such as major depression have been observed. Additionally, applied human research emphasizing the emotional impact of environmental threats associated with urban habitats is considered. Subjects evaluated in an inner-city hospital reveal the impact of combined specific genetic vulnerabilities and heightened stress responses in the expression of posttraumatic stress disorder. Finally, algorithm-based models of cities have been developed utilizing population-level analyses to identify risk factors for psychiatric illness. Although complex, the use of multiple research approaches, as described herein, results in an enhanced understanding of urbanization and its far-reaching effects--confirming the importance of continued research directed toward the identification of putative risk factors associated with psychiatric illness in urban settings. PMID- 25936509 TI - The metabolism of histamine in rat hypothalamus and cortex after reserpine treatment. AB - The effect of reserpine on histamine (HA) and tele-methylhistamine (N(tau)-MHA) in hypothalamus and cortex of rats was analyzed and compared to catecholamines. IP injection of reserpine (5 mg/kg) confirmed the effectiveness of reserpine treatment on noradrenaline and dopamine levels. Our in-vitro experiment with synaptosomal/crude mitochondrial fraction from hypothalamus and cortex confirmed that while mono amine oxidase (MAO) is an efficient metabolic enzyme for catecholamines, HA is not significantly affected by its enzymatic action. HMT activity after reserpine, pargyline and L-histidine treatment showed no differences compared to the control values. However HDC was significantly increased in both hypothalamus and cortex. In this study, Ws/Ws rats with deficiency of mast cells were used to clarify aspects of HA metabolism in HAergic neurons by eliminating the contribution of mast cells. The irreversible MAO-B inhibitor Pargyline (65 mg/kg) failed to accumulate N(tau)-MHA in the hypothalamus. However, when animals treated with reserpine and pargyline/reserpine were compared, the last group showed higher N(tau)-MHA values (p < 0.01). Moreover, the precursor of HA, L-histidine (1 g/kg), produced an increase of HA in the hypothalamus to 166% and the cortex to 348%. In conclusion, our results suggest that the effect of reserpine on the HA pools in the brain might be different. The neuronal HA pools are more resistant to reserpine as compared to those of catecholamine. Moreover, the HAergic pool appears to be more resistant to depletion than mast cells' pool, and thus HDC/HMT activity and its localization may play a key role in the understanding of HA metabolism in brain after reserpine treatment. PMID- 25936511 TI - William D. Steers, MD (1955-2015): Editor, The Journal of Urology(r), 2007-2015. PMID- 25936510 TI - Medullomyoblastoma treated with craniospinal radiation and adjuvant chemotherapy: Report of 4 cases and review of the literature. AB - Medullomyoblastoma (MMB) is a rare primitive neuro-epithelial tumor and seen in mainly pediatric age group1. There have been about 50 cases reported so far in the literature. In this report, we describe the clinical features and treatment of 4 cases of MMB. PMID- 25936512 TI - Post-infarct treatment with [Pyr(1)]apelin-13 improves myocardial function by increasing neovascularization and overexpression of angiogenic growth factors in rats. AB - Ischemic heart disease is the leading cause of mortality in the world. Angiogenesis is important for cardiac repair after myocardial infarction (MI) as restores blood supply to the ischemic myocardium and preserves cardiac function. Apelin is a peptide that has been recently shown to potentiate angiogenesis. The aim of this study was to investigate angiogenic effects of [Pyr(1)]apelin-13 in the rat model of post-MI. Male Wistar rats (n=36) were randomly divided into three groups: (1) sham (2) MI and (3) MI treated with [Pyr(1)]apelin-13 (MI+Apel). MI animals were subjected to 30min left anterior descending coronary artery (LAD) ligation and 14 days of reperfusion. Twenty-four hours after LAD ligation, [Pyr(1)]apelin-13 (10nmol/kg/day) was administered i.p. for 5 days. Hemodynamic functions by catheter introduced into the left ventricle (LV), myocardial fibrosis by Masson's trichrome staining, gene expression of vascular endothelial growth factor-A (VEGFA), VEGF receptor-2 (Kdr), Ang-1 (angiopoietin 1), Tie2 (tyrosine kinase with immunoglobulin and epidermal growth factor homology domains 2) and eNOS by Real-time polymerase chain reaction (Real-Time PCR) and myocardial angiogenesis by CD31 imunostaining were assessed at day 14 post-MI. Post-infarct treatment with [Pyr(1)]apelin-13 improved LV function and decreased myocardial fibrosis. [Pyr(1)]apelin-13 treatment led to a significant increase in the expression of VEGFA, Kdr, Ang-1, Tie2 and eNOS. Further, treatment with [Pyr(1)]apelin-13 promoted capillary density. [Pyr(1)]apelin-13 has angiogenic and anti-fibrotic activity via formation of new blood vessels and overexpression of VEGFA, Kdr, Ang-1, Tie2 and eNOS in the infarcted myocardium which could in turn repair myocardium and improve LV function. PMID- 25936513 TI - Animal models of Parkinson's disease: Effects of two adenosine A2A receptor antagonists ST4206 and ST3932, metabolites of 2-n-Butyl-9-methyl-8-[1,2,3]triazol 2-yl-9H-purin-6-ylamine (ST1535). AB - Antagonism of the adenosine A2A receptor represents a promising strategy for non dopaminergic treatment of Parkinson's disease (PD). Previously, the adenosine A2A receptor antagonist ST1535 was shown to possess potential beneficial effects in animal models of PD. Two metabolites of ST1535, namely ST3932 and ST4206, were tested in vitro to assess their affinity and activity on cloned human A2A adenosine receptors, and their metabolic profile. Additionally, ST3932 and ST4206 were investigated in vivo in animal models of PD following oral/intraperitoneal administration of 10, 20 and 40mg/kg using ST1535 as a reference compound. ST3932 and ST4206 displayed high affinity and antagonist behaviour for cloned human adenosine A2A receptors. The Ki values for ST1535, ST3932 and ST4206 were 8, 8 and 12nM, respectively, and their IC50 values on cyclic AMP were 427, 450 and 990nM, respectively. ST1535, ST3932 and ST4206 antagonized (orally) haloperidol induced catalepsy in mice, potentiated (intraperitoneally) the number of contralateral rotations induced by l-3,4-dihydroxyphenylalanine (l-DOPA) (3mg/kg) plus benserazide (6mg/kg) in 6-Hydroxydopamine hydrobromide (6-OHDA)-lesioned rats, and increased mouse motor activity by oral route. Thus, ST3932 and ST4206, two ST1535 metabolites, show a pharmacological activity similar to ST1535, both in vitro and in vivo, and may be regarded as an interesting pharmacological alternative to ST1535. PMID- 25936514 TI - MDMA-induced loss of parvalbumin interneurons within the dentate gyrus is mediated by 5HT2A and NMDA receptors. AB - MDMA is a widely abused psychostimulant which causes a rapid and robust release of the monoaminergic neurotransmitters dopamine and serotonin. Recently, it was shown that MDMA increases extracellular glutamate concentrations in the dorsal hippocampus, which is dependent on serotonin release and 5HT2A/2C receptor activation. The increased extracellular glutamate concentration coincides with a loss of parvalbumin-immunoreactive (PV-IR) interneurons of the dentate gyrus region. Given the known susceptibility of PV interneurons to excitotoxicity, we examined whether MDMA-induced increases in extracellular glutamate in the dentate gyrus are necessary for the loss of PV cells in rats. Extracellular glutamate concentrations increased in the dentate gyrus during systemic and local administration of MDMA. Administration of the NMDA receptor antagonist, MK-801, during systemic injections of MDMA, prevented the loss of PV-IR interneurons seen 10 days after MDMA exposure. Local administration of MDL100907, a selective 5HT2A receptor antagonist, prevented the increases in glutamate caused by reverse dialysis of MDMA directly into the dentate gyrus and prevented the reduction of PV-IR. These findings provide evidence that MDMA causes decreases in PV within the dentate gyrus through a 5HT2A receptor-mediated increase in glutamate and subsequent NMDA receptor activation. PMID- 25936515 TI - Critical role of renal dipeptidyl peptidase-4 in ameliorating kidney injury induced by saxagliptin in Dahl salt-sensitive hypertensive rats. AB - Saxagliptin, a potent dipeptidyl peptidase-4 (DPP-4) inhibitor, is currently used to treat type 2 diabetes mellitus, and it has been reported to exhibit a slower rate of dissociation from DPP-4 compared with another DPP-4 inhibitor, sitagliptin. In this study, we compared the effects of saxagliptin and sitagliptin on hypertension-related renal injury and the plasma and renal DPP-4 activity levels in Dahl salt-sensitive hypertensive (Dahl-S) rats. The high-salt diet (8% NaCl) significantly increased the blood pressure and quantity of urinary albumin excretion and induced renal glomerular injury in the Dahl-S rats. Treatment with saxagliptin (14mg/kg/day via drinking water) for 4 weeks significantly suppressed the increase in urinary albumin excretion and tended to ameliorate glomerular injury without altering the blood glucose levels and systolic blood pressure. On the other hand, the administration of sitagliptin (140mg/kg/day via drinking water) did not affect urinary albumin excretion and glomerular injury in the Dahl-S rats. Meanwhile, the high-salt diet increased the renal DPP-4 activity but did not affect the plasma DPP-4 activity in the Dahl-S rats. Both saxagliptin and sitagliptin suppressed the plasma DPP-4 activity by 95% or more. Although the renal DPP-4 activity was also inhibited by both drugs, the inhibitory effect of saxagliptin was more potent than that of sitagliptin. These results indicate that saxagliptin has a potent renoprotective effect in the Dahl-S rats, independent of its glucose-lowering actions. The inhibition of the renal DPP-4 activity induced by saxagliptin may contribute to ameliorating renal injury in hypertension-related renal injury. PMID- 25936516 TI - Chimeric peptides as modulators of CK2-dependent signaling: Mechanism of action and off-target effects. AB - Protein kinase CK2 is a tetrameric enzyme composed of two catalytic (alpha/alpha') and two regulatory (beta) subunits. It has a global prosurvival function, especially in cancer, and represents an attractive therapeutic target. Most CK2 inhibitors available so far are ATP-competitive compounds; however, the possibility to block only the phosphorylation of few substrates has been recently explored, and a compound composed of a Tat cell-penetrating peptide and an active cyclic peptide, selected for its ability to bind to the CK2 substrate E7 protein of human papilloma virus, has been developed [Perea et al., Cancer Res. 2004; 64:7127-7129]. By using a similar chimeric peptide (CK2 modulatory chimeric peptide, CK2-MCP), we performed a study to dissect its molecular mechanism of action and the signaling pathways that it affects in cells. We found that it directly interacts with CK2 itself, counteracting the regulatory and stabilizing functions of the beta subunit. Cell treatment with CK2-MCP induces a rapid decrease of the amount of CK2 subunits, as well as of other signaling proteins. Concomitant cell death is observed, more pronounced in tumor cells and not accompanied by apoptotic events. CK2 relocalizes to lysosomes, whose proteases are activated, while the proteasome machinery is inhibited. Several sequence variants of the chimeric peptide have been also synthesized, and their effects compared to those of the parental peptide. Intriguingly, the Tat moiety is essential not only for cell penetration but also for the in vitro efficacy of the peptide. We conclude that this class of chimeric peptides, in addition to altering some properties of CK2 holoenzyme, affects several other cellular targets, causing profound perturbations of cell biology. This article is part of a Special Issue entitled: Inhibitors of Protein Kinases. PMID- 25936517 TI - Integration of kinetic isotope effect analyses to elucidate ribonuclease mechanism. AB - The well-studied mechanism of ribonuclease A is believed to involve concerted general acid-base catalysis by two histidine residues, His12 and His119. The basic features of this mechanism are often cited to explain rate enhancement by both protein and RNA enzymes that catalyze RNA 2'-O-transphosphorylation. Recent kinetic isotope effect analyses and computational studies are providing a more chemically detailed description of the mechanism of RNase A and the rate limiting transition state. Overall, the results support an asynchronous mechanism for both solution and ribonuclease catalyzed reactions in which breakdown of a transient dianoinic phosphorane intermediate by 5'OP bond cleavage is rate limiting. Relative to non-enzymatic reactions catalyzed by specific base, a smaller KIE on the 5'O leaving group and a less negative betaLG are observed for RNase A catalysis. Quantum mechanical calculations consistent with these data support a model in which electrostatic and H-bonding interactions with the non-bridging oxygens and proton transfer from His119 render departure of the 5'O less advanced and stabilize charge buildup in the transition state. Both experiment and computation indicate advanced 2'OP bond formation in the rate limiting transition state. However, this feature makes it difficult to resolve the chemical steps involved in 2'O activation. Thus, modeling the transition state for RNase A catalysis underscores those elements of its chemical mechanism that are well resolved, as well as highlighting those where ambiguity remains. This article is part of a Special Issue entitled: Enzyme Transition States from Theory and Experiment. PMID- 25936518 TI - The Ys and wherefores of protein kinase autoinhibition. AB - Protein phosphorylation is a key reaction in the regulation of cellular events and is catalysed by over 500 protein kinases in humans. The activities of protein kinases are strictly controlled through a diverse set of mechanisms. Structural studies have shown that the conformation adopted by kinases in their active state is highly similar, whereas inactive kinases can adopt a variety of conformations. Many kinases are maintained in a catalytically inactive state through autoinhibition. This involves a conformation of the kinase active site that is unable to support catalysis and requires activation through a signal such as binding of a regulatory protein. In this review, we briefly summarise some of the well-established autoinhibitory mechanisms and then focus on a relatively unexplored mode of autoinhibition that was first discovered in the Nek family of kinases and is also relevant to IRE1. This involves a tyrosine side-chain that blocks the active site and which must undergo a conformational change to enable kinase activity. We have termed this the Tyr-down autoinhibitory mechanism. We summarise the evidence for this mechanism and describe its role in kinase inhibitor design. Finally, we survey the kinome to identify other kinases with the potential to be governed by an autoinhibitory Tyr-down mechanism. This article is part of a Special Issue entitled: Inhibitors of Protein Kinases. PMID- 25936519 TI - Quantitative analysis of glycans, related genes, and proteins in two human bone marrow stromal cell lines using an integrated strategy. AB - Altered expression of glycans is associated with cell-cell signal transduction and regulation of cell functions in the bone marrow micro-environment. Studies of this micro-environment often use two human bone marrow stromal cell lines, HS5 and HS27a, co-cultured with myeloid cells. We hypothesized that differential protein glycosylation between these two cell lines may contribute to functional differences in in vitro co-culture models. In this study, we applied an integrated strategy using genomic, proteomic, and functional glycomic techniques for global expression profiling of N-glycans and their related genes and enzymes in HS5 cells versus HS27a cells. HS5 cells had significantly enhanced levels of bisecting N-glycans (catalyzed by MGAT3 [beta-1,4-mannosyl-glycoprotein 4-beta-N acetylglucosaminyltransferase]), whereas HS27a cells had enhanced levels of Galbeta1,4GlcNAc (catalyzed by beta4GalT1 [beta4-galactosyltransferase I]). This integrated strategy provides useful information regarding the functional roles of glycans and their related glycogenes and glycosyltransferases in the bone marrow microenvironment, and a basis for future studies of crosstalk among stromal cells and myeloma cells in co-culture. PMID- 25936520 TI - Expression profile of plasma microRNAs in premature infants with respiratory distress syndrome. AB - As well-known regulators of gene expression, microRNAs (miRNAs) are important not only in cell proliferation and differentiation, but also in tumorigenesis and organ development. It has been estimated that miRNAs may be responsible for regulating the expression of almost one third of the human genome. Simultaneously, with advances in neonatal care in the clinic, an increased number of premature infants are being saved and, thus, respiratory distress syndrome (RDS) has become more common. However, previous non-miRNA studies have suggested their connection with RDS. In the present study, a miRNA microarray, including >1,891 capture probes was used to compared the expression profiles of plasma miRNAs between RDS and control groups. miRNAs, which were observed to have consistent fold-changes (fold-change >= 1.3) between the two groups were selected and validated using reverse transcription-quantitative polymerase chain reaction. As a result, 171 differentially expressed miRNAs were identified, including two upregulated and seven downregulated miRNAs. Of these miRNAs, four were selected as having higher fold-changes between the two groups. This is the first time, to the best of our knowledge, that these nine miRNAs have been reported in RDS. It was hypothesized that these novel miRNAs may be important in RDS, and may provide meaningful biomarkers for the diagnosis of RDS. PMID- 25936521 TI - Olfactory recognition memory is disrupted in young mice with chronic low-level lead exposure. AB - Chronic developmental lead exposure yielding very low blood lead burden is an unresolved child public health problem. Few studies have attempted to model neurobehavioral changes in young animals following very low level exposure, and studies are needed to identify tests that are sensitive to the neurobehavioral changes that may occur. Mechanisms of action are not yet known however results have suggested that hippocampus/dentate gyrus may be uniquely vulnerable to early chronic low-level lead exposure. This study examined the sensitivity of a novel odor recognition task to differences in pre-adolescent C57BL/6J mice chronically exposed from birth to PND 28, to 0 ppm (control), 30 ppm (low-dose), or 330 ppm (higher-dose) lead acetate (N=33). Blood lead levels (BLLs) determined by ICP-MS ranged from 0.02 to 20.31 MUg/dL. Generalized linear mixed model analyses with litter as a random effect showed a significant interaction of BLL*sex. As BLLs increased olfactory recognition memory decreased in males. Among females, non linear effects were observed at lower but not higher levels of lead exposure. The novel odor detection task is sensitive to effects associated with early chronic low-level lead exposure in young C57BL/6J mice. PMID- 25936522 TI - Coronin 1A depletion protects endothelial cells from TNFalpha-induced apoptosis by modulating p38beta expression and activation. AB - Coronins are conserved actin-binding proteins that regulate various cellular processes such as migration and endocytosis. Among coronin family members, coronin 1A is highly expressed in hematopoietic lineage cells where it regulates cell homeostasis. However, the expression and function of coronin 1A in endothelial cells have not yet been elucidated. We found that coronin 1A is expressed in the human umbilical vein endothelial cell (HUVEC) and human brain microvascular endothelial cell (HBMVEC). In HUVEC depleted of coronin 1A by siRNA transfection, tumor necrosis factor alpha (TNFalpha)+cyclohexamide (CHX) treatment resulted in a decrease in the number of terminal deoxynucleotidyl transferase dUTP nick end labeling (TUNEL) positive apoptotic cells. Coronin 1A depletion also resulted in the suppression of caspase 3 and poly(ADP-ribose) polymerase cleavage and a reduction in caspase 3 activity. Next, we examined TNFalpha-induced activation of several pro- and anti-apoptotic signaling molecules to find the target molecule of coronin 1A and found that p38 phosphorylation was enhanced by TNFalpha stimulation in coronin 1A-depleted HUVEC. Among the p38 isoforms, the expression of p38beta was significantly upregulated after coronin 1A depletion, suggesting that the expression and phosphorylation of anti-apoptotic p38beta were significantly induced in coronin 1A-depleted HUVEC. Inhibition of p38beta upregulation in coronin 1A-depleted HUVEC restored the cleavage of caspase 8 and caspase 3 and induced more apoptosis than in coronin 1A-depleted HUVEC in response to TNFalpha+CHX. These findings suggest that coronin 1A modulates endothelial cell apoptosis by regulating p38beta expression and activation. PMID- 25936523 TI - Growth-factor dependent expression of the translationally controlled tumour protein TCTP is regulated through the PI3-K/Akt/mTORC1 signalling pathway. AB - Translationally controlled tumour protein TCTP (gene symbol: TPT1) is a highly conserved, cyto-protective protein implicated in many physiological and disease processes, in particular cancer, where it is associated with poor patient outcomes. To understand the mechanisms underlying the accumulation of high TCTP levels in cancer cells, we studied the signalling pathways that control translation of TCTP mRNA, which contains a 5'-terminal oligopyrimidine tract (5' TOP). In HT29 colon cancer cells and in HeLa cells, serum increases the expression of TCTP two- and four-fold, respectively, and this is inhibited by rapamycin or mTOR kinase inhibitors. Polysome profiling and mRNA quantification indicate that these effects occur at the level of mRNA translation. Blocking this pathway upstream of mTOR complex 1 (mTORC1) by inhibiting Akt also prevented increases in TCTP levels in both HeLa and HT29 colon cancer cells, whereas knockout of TSC2, a negative regulator of mTORC1, led to derepression of TCTP synthesis under serum starvation. Overexpression of eIF4E enhanced the polysomal association of the TCTP mRNA, although it did not protect its translation from inhibition by rapamycin. Conversely, expression of a constitutively-active mutant of the eIF4E inhibitor 4E-BP1, which is normally inactivated by mTORC1, inhibited TCTP mRNA translation in HEK293 cells. Our results demonstrate that TCTP mRNA translation is regulated by signalling through the PI3-K/Akt/mTORC1 pathway. This explains why TCTP levels are frequently increased in cancers, since mTORC1 signalling is hyperactive in ~80% of tumours. PMID- 25936524 TI - Serine-Threonine Kinase 38 regulates CDC25A stability and the DNA damage-induced G2/M checkpoint. AB - Cells respond to DNA damage by activating protein kinase-mediated signaling pathways that promote cell-cycle arrest, DNA repair, or apoptosis. A key regulator of cell-cycle arrest is the CDC25A (cell division cycle 25 homologue A) phosphatase. CDC25A normally plays a pivotal role in regulating the G1/S and G2/M transitions by dephosphorylating and activating cyclin/cyclin-dependent kinase (CDK) complexes; however, CDC25A is specifically degraded in response to DNA damage. Here, we demonstrate that the depletion of serine-threonine kinase 38 (STK38) prevents the DNA-damage-induced degradation of CDC25A and subsequent G2 arrest, and that STK38 directly phosphorylates CDC25A at Ser-76, resulting in CDC25A's degradation. Taken together, these results indicate that the STK38 mediated phosphorylation of CDC25A at Ser-76 and the subsequent degradation of CDC25A are required to promote DNA damage-induced G2/M checkpoint activation. PMID- 25936525 TI - Two novel mutations in the bestrophin-1 gene and associated clinical observations in patients with best vitelliform macular dystrophy. AB - The purpose of the current study was to investigate the 11 bestrophin-1 (BEST1) exons in patients with best vitelliform macular dystrophy (BVMD), and to characterize the associated clinical features. Complete ophthalmic examinations were conducted on two families, and two family members were diagnosed with BVMD. Genomic DNA was extracted from the leukocytes of peripheral blood collected from the patients and their family members, in addition to 100 unrelated control subjects recruited from the same population. The polymerase chain reaction was used to amplify a total of 11 exons of the BEST1 gene, which were directly sequenced. Ophthalmic examinations, including best-corrected visual acuity, slit lamp examination, fundus examination, fundus photography and fluorescein angiography imaging, as well as anterior segment analysis with Pentacam and optical coherence tomography, were conducted. The patients exhibited yellowish lesions in the macular area. A heterozygous mutation c.910_912delGAT (p.304del Asp) in exon 7 was identified in Case 1. A heterozygous BEST1 missense mutation c.685T>G (p.Trp229Gly) in exon 5 was identified in Case 2, but not in any of the unaffected family members or normal controls. Although BEST1 gene mutations and polymorphisms have previously been reported in various ethnic groups, the current study identified, for the first time to the best of our knowledge, two novel BEST1 gene mutations in patients with BVMD. PMID- 25936526 TI - Addressing the unmet need in lung cancer: The potential of immuno-oncology. AB - Chemotherapy is currently the standard of care for non-oncogene-driven advanced non-small cell lung cancer (NSCLC). Due to improvements in chemotherapeutic choices and supportive care, patients currently typically undergo multiple lines of chemotherapy as their disease progresses. Although treatments have improved over recent years, limited benefits are seen, especially in patients receiving later-line chemotherapy, as response rates can be low, response duration short and survival poor. Furthermore, only a small percentage of patients derive benefit from later-line therapy, with most experiencing deteriorating quality of life and significant toxicities. More recently, molecular targeted therapies have provided improvements in outcomes. However, these treatments only offer a clear benefit in subsets of tumours harbouring the appropriate genomic alteration (mutation, amplification, translocation). Most of the genomic abnormalities susceptible to therapeutic intervention are detected in adenocarcinoma, mainly in never smokers, while alterations in the genome of other histological subtypes are known but specific agents targeting these alterations have yet to be developed. Thus, the therapeutic management of these subtypes represents an ongoing challenge. Recent advances in immunotherapy have highlighted the potential of immuno-oncology based treatments for NSCLC, offering the potential to provide durable responses and outcomes regardless of histology or mutation status. This review discusses the current unmet medical needs in NSCLC, the limits of current first-line and later-line chemotherapy and targeted agents, and the emergence of new therapeutic strategies. PMID- 25936527 TI - Cost-Effectiveness Analysis Comparing Pre-diagnosis Autism Spectrum Disorder (ASD)-Targeted Intervention with Ontario's Autism Intervention Program. AB - Novel management strategies for autism spectrum disorder (ASD) propose providing interventions before diagnosis. We performed a cost-effectiveness analysis comparing the costs and dependency-free life years (DFLYs) generated by pre diagnosis intensive Early Start Denver Model (ESDM-I); pre-diagnosis parent delivered ESDM (ESDM-PD); and the Ontario Status Quo (SQ). The analyses took government and societal perspectives to age 65. We assigned probabilities of Independent, Semi-dependent or Dependent living based on projected IQ. Costs per person (in Canadian dollars) were ascribed to each living setting. From a government perspective, the ESDM-PD produced an additional 0.17 DFLYs for $8600 less than SQ. From a societal perspective, the ESDM-I produced an additional 0.53 DFLYs for $45,000 less than SQ. Pre-diagnosis interventions targeting ASD symptoms warrant further investigation. PMID- 25936529 TI - Engineering Stent Based Delivery System for Esophageal Cancer Using Docetaxel. AB - Esophageal cancer patients are often diagnosed as "advanced" cases. These patients are subjected to palliative stenting using self-expanding metallic stents (SEMS) to maintain oral alimentation. Unfortunately, SEMS get reoccluded due to tumor growth, in and over the stent struts. To investigate potential solutions to this problem, docetaxel (DTX) delivery films were prepared using PurSil AL 20 (PUS), which can be used as a covering material for the SEMS. Drug polymer miscibility and interactions were studied. Bilayer films were prepared by adhering the blank film to the DTX loaded film in order to maintain the unidirectional delivery to the esophagus. In vitro release and the local DTX delivery were studied using in vitro permeation experiments. It was found that DTX and PUS were physically and chemically compatible. The bilayer films exhibited sustained release (>30 days) and minimal DTX permeation through esophageal tissues in vitro. The rate-determining step for the DTX delivery was calculated. It was found that >0.9 fraction of rate control lies with the esophageal tissues, suggesting that DTX delivery can be sustained for longer periods compared to the in vitro release observed. Thus, the bilayer films can be developed as a localized sustained delivery system in combination with the stent. PMID- 25936528 TI - The regulatory interaction of EVI1 with the TCL1A oncogene impacts cell survival and clinical outcome in CLL. AB - Dysregulated T-cell leukemia/lymphoma-1A (TCL1A), a modulator in B-cell receptor (BCR) signaling, is causally implicated in chronic lymphocytic leukemia (CLL). However, the mechanisms of the perturbed TCL1A regulation are largely unknown. To characterize TCL1A-upstream networks, we functionally screened for TCL1A repressive micro-RNAs (miRs) and their transcriptional regulators. We identified the novel miR-484 to target TCL1A's 3'-UTR and to be downregulated in CLL. In chromatin immunoprecipitations and reporter assays, the oncogenic transcription factor of myeloid cells, EVI1, bound and activated the miR-484 promoter. Most common in CLL was a pan-EVI1 transcript variant. EVI1 protein expression revealed distinct normal-tissue and leukemia-associated patterns of EVI1/TCL1A co regulation. EVI1 levels were particularly low in TCL1A-high CLL or such cellular subsets. Global gene expression profiles from a 337-patient set linked EVI1 networks to BCR signaling and cell survival via TCL1A, BTK and other molecules of relevance in CLL. Enforced EVI1, as did miR-484, repressed TCL1A. Furthermore, it reduced phospho-kinase levels, impaired cell survival, mitigated BCR-induced Ca flux and diminished the in vitro ibrutinib response. Moreover, TCL1A and EVI1 showed a strongly interactive hazard prediction in prospectively treated patients. Overall, we present regressive EVI1 as a novel regulatory signature in CLL. Through enhanced TCL1A and other EVI1-targeted hallmarks of CLL, this contributes to an aggressive cellular and clinical phenotype. PMID- 25936530 TI - Evaluation of telaprevir-containing triple therapy in the treatment of chronic hepatitis C in hemodialysed patients. AB - Hepatitis C virus (HCV) infection is associated with increased morbidity and mortality in patients undergoing hemodialysis for end-stage renal disease (ESRD). Eradication of HCV before transplantation is therefore of utmost importance in HCV-infected patients with ESRD who are candidates for kidney transplantation. The appropriate treatment for HCV infection in patients with ESRD and suboptimal response rates is still unclear. Here, we present our data from five cases who were being monitored by two healthcare centers for ESRD and HCV infection, who were candidates for kidney transplantation and were treated with a triple regimen containing telaprevir. All patients were started on triple therapy from the beginning including pegylated interferon-alfa2a (135 MUg once a week), ribavirin (200 mg three times a week), and telaprevir (750 mg three times a day). Rapid virologic response was observed in all of the patients but treatment was discontinued in one patient at week 6 because the patient developed nausea and vomiting and was unable to feed orally. For the remaining four patients, side effects included weakness, lack of appetite, metallic taste, and mild anemia. The triple therapy with telaprevir seemed to be successful in HCV-infected patients who were candidates for renal transplantation. PMID- 25936532 TI - Neonatal care in Brazil: hospital structure and adequacy according to newborn obstetric risk. AB - BACKGROUND: In Brazil, hospital birth care is available to all, but there are important differences between hospitals in the public and private sectors, geographical regions and capitals/inland cities, resulting in inequalities of infant health. AIMS: To assess the hospital structure for birth care in Brazil and analyze hospital adequacy to care for newborns according to levels of risk. METHODS: Data were collected as part of a nationwide hospital-based cohort study, 'Birth in Brazil'. The hospitals were classified according to whether they had a neonatal intensive care unit and divided into two models of governance: public and private financing. Three structure domains were assessed: human resources, medications and equipment for post-natal women and newborn emergency care. Newborns were classified according to the obstetric risk. RESULTS: There are more NICUs in private hospitals and they cater mostly for low obstetric risk newborns; the public sector serves 50% of at-risk patients in hospitals without an NICU. The differences between hospital service structures according to geographic region and capital/inland cities were evident. Hospitals in less developed regions and inland cities had poorer adequacy in the three domains. CONCLUSION: The distribution of neonatal care to Brazilian infants varied between the public and private sectors. The public sector offered less complex services for newborns at risk, and infants without obstetric risk were born in facilities with an NICU, creating the possibility of unnecessary intervention, especially in the private sector. PMID- 25936531 TI - Gut microbes may facilitate insect herbivory of chemically defended plants. AB - The majority of insect species consume plants, many of which produce chemical toxins that defend their tissues from attack. How then are herbivorous insects able to develop on a potentially poisonous diet? While numerous studies have focused on the biochemical counter-adaptations to plant toxins rooted in the insect genome, a separate body of research has recently emphasized the role of microbial symbionts, particularly those inhabiting the gut, in plant-insect interactions. Here we outline the "gut microbial facilitation hypothesis," which proposes that variation among herbivores in their ability to consume chemically defended plants can be due, in part, to variation in their associated microbial communities. More specifically, different microbes may be differentially able to detoxify compounds toxic to the insect, or be differentially resistant to the potential antimicrobial effects of some compounds. Studies directly addressing this hypothesis are relatively few, but microbe-plant allelochemical interactions have been frequently documented from non-insect systems-such as soil and the human gut-and thus illustrate their potential importance for insect herbivory. We discuss the implications of this hypothesis for insect diversification and coevolution with plants; for example, evolutionary transitions to host plant groups with novel allelochemicals could be initiated by heritable changes to the insect microbiome. Furthermore, the ecological implications extend beyond the plant and insect herbivore to higher trophic levels. Although the hidden nature of microbes and plant allelochemicals make their interactions difficult to detect, recent molecular and experimental techniques should enable research on this neglected, but likely important, aspect of insect-plant biology. PMID- 25936533 TI - Simplified strategy for rapid first-line screening of fragile X syndrome: closed tube triplet-primed PCR and amplicon melt peak analysis. AB - Premutation and full-mutation hyperexpansion of CGG-triplets in the X-linked Fragile X Mental Retardation 1 (FMR1) gene have been implicated in fragile X associated tremor/ataxia syndrome, fragile X-associated primary ovarian insufficiency, and fragile X syndrome (FXS), respectively. The currently available molecular diagnostic tests are either costly or labour-intensive, which prohibits their application as a first-line FMR1 test in large-scale population based screening programs. In this study, we demonstrate the utility of a simplified closed-tube strategy for rapid first-line screening of FXS based on melt peak temperature (Tm) analysis of direct triplet-primed polymerase chain reaction amplicons (dTP-PCR MCA). In addition, we also evaluated the correlation between Tm and CGG-repeat size based on capillary electrophoresis (CE) of dTP-PCR amplicons. The assays were initially tested on 29 FMR1 reference DNA samples, followed by a blinded validation on 107 previously characterised patient DNA samples. The dTP-PCR MCA produced distinct melt profiles of higher Tm for samples carrying an expanded allele. Among the samples tested, we also observed a good correlation between Tm and CGG-repeat size. In the blinded validation study, dTP PCR MCA accurately classified all normal and expansion carriers, and the FMR1 genotypic classification of all samples was completely concordant with the previously determined genotypes as well as the dTP-PCR CE results. This simple and cost-effective MCA-based assay may be useful as a first-line FXS screening tool that could rapidly screen out the large majority of unaffected individuals, thus minimising the number of samples that need to be analysed by Southern blot analysis. PMID- 25936534 TI - The possibility of inventing new technologies in the detection of cancer by applying elements of the canine olfactory apparatus. AB - In order to find better tools in the diagnosis of cancer in an earlier and more precise manner, researchers have explored the use of volatile organic compound (VOCs) as a way to detect this disease. Interestingly, the canine olfactory apparatus was observed to detect cancer in two anecdotal reports. After the description of these events, researchers began to study this phenomenon in a structured way in order to assess the ability of canines in detecting cancer related VOCs. Due to the fact that some of these studies have shown that the canine olfactory apparatus is highly proficient in the detection of cancer related VOCs, in this article we assess the possibility of constructing a bioelectronic-nose, based on canine olfactory receptors (ORs), for the purpose of diagnosing cancer in a more sensitive, specific, and cost effective manner than what is available nowadays. Furthermore, in order to prove the feasibility and the need of the proposed apparatus, we searched for the following type of articles: all of the studies that have examined, to our knowledge, the ability of dogs in detecting cancer; articles that assess the dog olfactory receptor (OR) gene repertoire, since a central part of the proposed bioelectronic nose is being able to recognize the odorant that emanates from the cancerous lesion, and for that purpose is necessary to express the canine ORs in heterologous cells; examples of articles that depict different devices that have been built for the purpose of detecting cancer-related VOCs, so as to assess if the construction of the proposed apparatus is needed; and articles that describe examples of already constructed bioelectronic noses, in order to demonstrate the existence of a technical precedent and thus the plausibility of the proposed device. PMID- 25936535 TI - WITHDRAWN: High-power Nd:YAG laser triggers the osteogenesis of osteoblasts by activating the bone morphogenetic protein 2 and insulin-like growth factor-1 signaling pathways. AB - Ahead of Print article withdrawn by publisher. PMID- 25936536 TI - Differential expression of miRNAs and their relation to active tuberculosis. AB - The aim of this work was to screen miRNA signatures dysregulated in tuberculosis to improve our understanding of the biological role of miRNAs involved in the disease. Datasets deposited in publically available databases from microarray studies on infectious diseases and malignancies were retrieved, screened, and subjected to further analysis. Effect sizes were combined using the inverse variance model and between-study heterogeneity was evaluated by the random effects model. 35 miRNAs were differentially expressed (12 up-regulated, 23 down regulated; p < 0.05) by combining 15 datasets of tuberculosis and other infectious diseases. 15 miRNAs were found to be significantly differentially regulated (7 up-regulated, 8 down-regulated; p < 0.05) by combining 53 datasets of tuberculosis and malignancies. Most of the miRNA signatures identified in this study were found to be involved in immune responses and metabolism. Expression of these miRNA signatures in serum samples from TB subjects (n = 11) as well as healthy controls (n = 10) was examined by TaqMan miRNA array. Taken together, the results revealed differential expression of miRNAs in TB, but available datasets are limited and these miRNA signatures should be validated in future studies. PMID- 25936537 TI - Development of a Mycobacterium smegmatis transposon mutant array for characterising the mechanism of action of tuberculosis drugs: Findings with isoniazid and its structural analogues. AB - The development of new drugs is required to control human tuberculosis (TB). This study examined whether drug hypersensitive mutants could be used to reveal novel aspects of the mechanism of action of a TB drug. A transposon mutant collection with an estimated 1.1-fold genome coverage (7680 mutants) was constructed in Mycobacterium smegmatis and screened in high-throughput against isoniazid. Hypersensitive transposants with mutations in genes known to influence the mode of action of isoniazid were isolated. To further investigate the role of one of these genes, nudC, the corresponding mutant was tested for sensitivity towards isoniazid structural analogues. Overexpression of nudC, as well as inhA which encodes a known target of isoniazid, increased M. smegmatis resistance to isoniazid, but failed to increase resistance to three of the analogues, NSC27607, NSC33759, and NSC40350. In contrast, overexpression of katG resulted in increased sensitivity to each of the isoniazid analogues tested including NSC27607, NSC33759, and NSC40350. This provides evidence that the latter isoniazid analogues are activated by KatG in a NudC-independent manner and that InhA may not be their primary target. In summary, characterisation of drug hypersensitive mutants detected genes involved in the mode of action of isoniazid. Furthermore, it identified isoniazid analogues which are resilient to both InhA- and NudC dependent mechanisms of resistance. PMID- 25936540 TI - Modified Berg Balance Scale: making assessment appropriate for people with aphasia. AB - OBJECTIVE: Modifying assessments for people with aphasia has the potential to increase the validity of healthcare assessments across professional domains. This pilot study addressed the challenges of giving people with aphasia the power to fully participate in the assessment process. The study aimed to investigate the feasibility of using an aphasia-modified version of the Berg Balance Scale (BBS), a physical therapy assessment tool to quantify dynamic sitting and standing balance. METHOD: The study compared how people with aphasia performed on the original BBS to an aphasia-modified version (MBBS), created for this study. We examined the relationship between auditory comprehension scores and balance performance of 15 participants with chronic aphasia and three control participants. We tested the hypothesis that individuals with aphasia would perform higher on the MBBS rather than the BBS, thus more closely approaching a score reflective of their true physical abilities. RESULTS: Overall people with aphasia performed significantly better on the MBBS than the BBS, indicating that at least some portion of their performance difficulty was likely due to poor auditory comprehension of test instructions rather than true balance difficulty. CONCLUSION: Implications of this study suggest that modifying assessments, such as the BBS, by reducing linguistic complexity and adding visual and written cues along with modeling and repetition has the potential to increase the validity of healthcare assessments for individuals with aphasia. PMID- 25936538 TI - Identification of human leukemia antigen A*0201-restricted epitopes derived from epidermal growth factor pathway substrate number 8. AB - T-cell-mediated immunotherapy of hematological malignancies requires selection of targeted tumor-associated antigens and T-cell epitopes contained in these tumor proteins. Epidermal growth factor receptor pathway substrate 8 (EPS8), whose function is pivotal for tumor proliferation, progression and metastasis, has been found to be overexpressed in most human tumor types, while its expression in normal tissue is low. The aim of the present study was to identify human leukemia antigen (HLA)-A*0201-restricted epitopes of EPS8 by using a reverse immunology approach. To achieve this, computer algorithms were used to predict HLA-A*0201 molecular binding, proteasome cleavage patterns as well as translocation of transporters associated with antigen processing. Candidate peptides were experimentally validated by T2 binding affinity assay and brefeldin-A decay assay. The functional avidity of peptide-specific cytotoxic T lymphocytes (CTLs) induced from peripheral blood mononuclear cells of healthy volunteers were evaluated by using an enzyme-linked immunosorbent spot assay and a cytotoxicity assay. Four peptides, designated as P455, P92, P276 and P360, had high affinity and stability of binding towards the HLA-A*0201 molecule, and specific CTLs induced by them significantly responded to the corresponding peptides and secreted IFN-gamma. At the same time, the CTLs were able to specifically lyse EPS8-expressing cell lines in an HLA-A*0201-restricted manner. The present study demonstrated that P455, P92, P276 and P360 were CTL epitopes of EPS8, and were able to be used for epitope-defined adoptive T-cell transfer and multi-epitope based vaccine design. PMID- 25936541 TI - Association of ideomotor apraxia with lesion site, etiology, neglect, and functional independence in patients with first ever stroke. AB - BACKGROUND: Ideomotor apraxia (IMA) is characterized by the inability to correctly imitate hand gestures and voluntarily pantomime tool use. The relationship between IMA and characteristics of stroke has not been totally elucidated. OBJECTIVE: This study aimed to find out associations between presence of IMA and stroke etiology, site of the lesions, neglect, and temporal and functional parameters of stroke in patients with first ever stroke. METHODS: Thirty-nine patients with first ever stroke were included. Patients with severe cognitive deficits were excluded. Assessment tools included Ideomotor Apraxia Test, Functional Independence Measure (FIM), Brunnstrom recovery stages, Mini Mental Test (MMT), and star cancellation test. Etiology (hemorrhagic or ischemic) and site of stroke was assessed through brain imaging methods. Location and size of ischemic lesion was determined by using the Oxfordshire Community Stroke Project system. RESULTS: IMA was identified in 35.9% of the patients. Patients with IMA had significantly lower FIM scores both on admission and discharge (P = 0.001, P = 0.001). Presence of IMA was significantly associated with the presence of neglect (P = 0.004), total anterior circulation ischemia (TACI) (P < 0.001), and lower MMT scores (P < 0.001). Lesion site, patient age, time since onset, and stroke etiology had no impact on the presence of IMA. CONCLUSION: IMA was in concordance with poor cognitive and functional state and was not limited to left hemisphere lesions. The study revealed strong associations between IMA, neglect, and TACI. Every patient with stroke should be evaluated for the presence of IMA on admission to rehabilitation unit. PMID- 25936542 TI - The utility of a care model to individualize rehabilitation in adults aged over 80 years. AB - OBJECTIVE: The objectives of the present study were to assess the complexity and multidimensionality of rehabilitation needs of very old stroke patients aged >= 80 years and report how rehabilitation interventions are customized to meet the complex needs of patients at a hospital with a majority of old patients. METHODS: The complex problems faced by 18 post-stroke patients (age, range: 80-92 years) were characterized in terms of the following multiple dimensions: (1) clinical features, (2) functional (motor/cognitive) impairment features, (3) psychological aspects, and (4) environmental aspects. We then evaluated the rehabilitation interventions designed to address the problems identified in these different dimensions in detail. RESULTS: The needs of very old stroke patients were extremely complex and unique. To cope with this complexity, rehabilitation interventions were customized in a flexible manner, considering the different dimensions of the needs of these patients. Although the interventions were customized, the complex problems experienced by patients could be divided into stroke conditions on the basis of some invariant patterns in rehabilitation intervention. CONCLUSIONS: We obtained empirical data that illustrated the necessity of considering not only clinical features, but also multiple dimensions of problems faced by very old stroke patients during rehabilitation interventions. PMID- 25936543 TI - Evaluation of brief interventions for managing depression and anxiety symptoms during early discharge period after stroke: a pilot randomized controlled trial. AB - BACKGROUND: Prevalence estimates for depression and anxiety in individuals post stroke are approximately 33 and 29%, yet there are few effective preventive interventions. Interventions which commence pre-discharge and continue during the early post-discharge period may support individuals during the critical transition to home adjustment period. This study aimed to evaluate the efficacy of a self-management intervention and a coping skills intervention, compared to usual care, on anxiety and depression post-stroke. METHODS: A pilot, three-arm randomized trial involving 33 stroke patients (coping skills: n = 11, self management: n = 12, usual care: n = 10) recruited from an Australian stroke unit. Both interventions were eight 1-hour weekly sessions, with the first two pre discharge and the remainder at home; targeted both anxiety and depression; and tailored content to individuals. Primary outcome was severity of depressive and anxiety symptoms (measured using Montgomery andAsberg Depression Rating Scale and Hospital Anxiety and Depression Scale). Secondary measures were: self-efficacy, stroke knowledge, basic and extended activities of daily living, and quality of life. Outcome measures were administered at baseline, one week post-intervention, and at a three month follow-up by a blinded assessor. RESULTS: Thirty (91%) participants completed the trial. Immediately post-intervention there was a small improvement in stroke knowledge and a small increase in depression symptoms (on one of the two measures of depression symptoms) in the coping skills group compared to usual care. These differences did not remain significant at the 3 month follow-up, nor were there any other significant differences. CONCLUSION: Neither a coping skills nor self-management intervention reduced anxiety nor depression symptoms early post-stroke more than usual care. Lack of statistical power may have contributed to the non-significant findings in this pilot study. PMID- 25936544 TI - Consistent determinants of health-related quality of life in the first 12 months after stroke: a prospective study in Nigeria. AB - BACKGROUND: Health-related quality of life (HRQoL) of stroke survivors can be described as an important and holistic index of stroke outcome. To enhance this all encompassing construct, information on its predictors at different phases of stroke is required. OBJECTIVE: This study sought to identify consistent determinants of HRQoL over the course of 1 year after stroke in Nigeria. METHODS: Information on socio-demographic, clinical, and functioning attributes of 55 consecutive individuals with first-ever stroke were obtained during acute admission and at 1, 3, 6, and 12 months post-stroke. Attributes of functioning namely, motor performance, functional activity, and participation were assessed using the Simplified Fugl-Meyer Assessment, the motor-Functional Independence Measure, and the London Handicap Scale, respectively. HRQoL was also assessed with the Health-Related Quality of Life in Stroke Patients-40 scale at 1, 3, 6, and 12 months. Attributes that were associated with HRQoL at these time points were identified using bivariate and multivariable regression analyses. RESULTS: Among the independent variables, concurrently assessed participation was the sole significant (P < 0.0001) determinant of HRQoL at 1, 3, and 6 months, respectively accounting for 70%, 64%, and 75% variance in HRQoL. At 12 months, participation (P < 0.0001), and functional activity (P < 0.05) accounted for 83% variance in HRQoL, with better functional activity and participation associated with better HRQoL. CONCLUSION: The outcome of this study indicates that optimizing post stroke functional activity and participation through proven and effective rehabilitation strategies may result in better HRQoL in stroke survivors. PMID- 25936545 TI - The impact of a community re-engagement cue to action trigger tool on re-engaging in activities post-stroke: a mixed-methods study. AB - OBJECTIVES: This study evaluated the guided use of the Community Re-engagement Cue to Action Trigger Tool (CRCATT), a patient-mediated question prompt list, and its impact on self-reported re-engagement in activities post-stroke. METHODS: A multi-site, single-blind randomized controlled study in which 77 persons with stroke participated from three rehab organizations in Toronto, Canada. Of the 77 participants, a total 57 within the two groups completed the study and Reintegration to Normal Living Index (mailed response questionnaire) and a sub set of all participants participated in qualitative interviews. Data collection occurred 3-4 months after enrollment. Quantitative responses were analyzed in SPSS (Chicago, IL, USA) for descriptive frequencies and differences between groups. Qualitative responses were analyzed using an inductive approach with thematic analytic procedures. RESULTS: No between group differences were observed due to small sample size. A multi-variable regression model including age, gender, level of education, treatment group, and language, suggests those with higher education are more likely to participate in activities. Interview analysis revealed participants' ability to recover and re-engage is influenced by an interplay of the CRCATT with external factors. These factors include social support, interactions with providers, and ability to access information. CONCLUSION: The CRCATT was perceived as a useful tool as it assisted persons with stroke to take a more self-directed role in their care by asking relevant questions and anticipating their needs. The tool complemented the external factors that persons with stroke draw on to support recovery and participate in activities post-stroke. PMID- 25936546 TI - Cognitive impairments and mood disruptions negatively impact instrumental activities of daily living performance in the first three months after a first stroke. AB - BACKGROUND: Cognition and mood play crucial roles in post-stroke recovery; however, the stroke literature is unclear as to how impairments in both domains influence performance of instrumental activities of daily living (IADL). OBJECTIVE: (1) Evaluate the extent to which mood and cognition at two weeks post stroke predict performance three months post-stroke. (2) Assess performance differences in patients with impairments in both cognition and mood to patients with impairments in either cognition or mood. METHODS: Inpatients with a first ever ischemic or hemorrhagic stroke were assessed at 2 weeks (n = 52) and at 3 months (n = 41) post-stroke. Patients completed a battery of neuropsychological tests, self-report measures and performance-based tests. Cognitive impairments and mood disruptions were assessed at 2 weeks and three months and IADL performance, as assessed by the Executive Function Performance Test, was evaluated at three months. RESULTS: Complete data from the 41 patients assessed at both time points were analyzed. Regression analysis showed that composite cognition and composite mood variables at two weeks post-stroke predicted 48% of the variance in IADL performance at three months (F3,37 = 12.04; adjusted R(2) = 0.48, P < 0.001). Statistically significant differences were found in performance scores for patients with a single impairment (M = 7.86, SD = 7.81) and for those with impairments in both mood and cognition (M = 19.2, SD = 13.2) (t(39) = - 3.41, P = 0.008). CONCLUSION: The results of this study suggest that cognitive and mood impairments at two weeks post-stroke are important predictors of performance in complex activities required for full independence at home and should be routinely assessed in stroke rehabilitation. PMID- 25936547 TI - Qualitative analysis of a nurse's responses to stroke caregivers on a web-based supportive intervention. AB - BACKGROUND: Approximately 800 000 people experience a stroke every year; most are cared for by unpaid family members in home settings. Web-based interventions provide 24/7 access to education/support services and have been explored in the literature with family caregivers dealing with chronic conditions. Current research into nurses' web-based interactions with caregivers in these interventions is lacking. OBJECTIVE: The aim of this qualitative secondary data analysis was to examine a nurse specialist's responses and advice that she gave in a web-based supportive intervention for stroke family caregivers used in a randomized controlled trial for 1 year. METHODS: Using a qualitative research design, caregivers were recruited from rehabilitation facilities in Ohio and Michigan (n = 36). They accessed the intervention's email forum and discussion group facilitated by the nurse. These email message data were examined using rigorous content analysis. RESULTS: The caregivers were primarily white women caring for a spouse, with an average age of 54 years. From the 2148 email messages between the nurse and caregivers, five themes emerged and were drawn to Friedemann's Framework. These themes included: getting to know the situation (Friedemann's coherence and individuation), validating emotions (individuation), promoting self-care (individuation), assisting in role adaptation (system maintenance and individuation), and providing healthcare information (system maintenance and individuation). CONCLUSIONS: These caregivers of stroke survivors were asking for advice, seeking support, and looking for information from an advanced practice nurse. Nurses, and others, in supportive roles can use these findings to promote informed care and directed interventions for caregivers dealing with stroke and its outcomes. PMID- 25936548 TI - Vacuolar CBL-CIPK12 Ca(2+)-sensor-kinase complexes are required for polarized pollen tube growth. AB - Polarized tip growth is a fundamental process of specialized eukaryotic cells like neuronal axons, fungal hyphae, and plant root hairs and pollen tubes. In pollen tubes, a tip-focused oscillating Ca(2+) gradient governs ions fluxes, vesicle transport, and cytoskeleton dynamics to ensure proper polarized cell growth [1, 2]. While a crucial role of vacuolar Ca(2+) signaling is established for cellular movements like guard cell dynamics [3-5], its contribution to polarized growth remains to be defined. Here we identified the two closely related tonoplast-localized Ca(2+)-sensor proteins CBL2 and CBL3 as crucial regulators of vacuolar dynamics and polarized pollen tube growth. Overexpression of CBL2 or CBL3 in Arabidopsis and tobacco pollen tubes affected vacuolar morphology, pollen germination, and tube growth, but did not alter actin organization, PI(4,5)P2 distribution, or tip-focused Ca(2+) oscillations. Similarly, loss of function of each single Ca(2+) sensor and cbl2/cbl3 double mutants exhibited impaired pollen tube growth in vitro and in vivo. Both Ca(2+) sensors interacted with the kinase CIPK12, which translocated from the cytoplasm to the vacuolar membrane upon this interaction. Also, overexpression of CIPK12 induced severe vacuolar phenotypes, and loss of function of CIPK12 lead to impairment of polar growth. Remarkably, co-expression of CBL2 or CBL3 with CIPK12 resulted in a phosphorylation-dependent, massively enhanced vacuolar inflation and further disruption of polar growth. Together, these findings identify an essential role of the vacuole and vacuolar Ca(2+) signaling for polarized tip growth. We propose that a faithfully balanced activity of Ca(2+)-activated CBL2/3 CIPK12 complexes fulfills fundamental functions to enable the fast growth of pollen tubes in higher plants. PMID- 25936550 TI - Posterior cingulate cortex integrates the senses of self-location and body ownership. AB - The senses of owning a body and being localized somewhere in space are two key components of human self-consciousness. Despite a wealth of neurophysiological and neuroimaging research on the representations of the spatial environment in the parietal and medial temporal cortices, the relationship between body ownership and self-location remains unexplored. To investigate this relationship, we used a multisensory out-of-body illusion to manipulate healthy participants' perceived self-location, head direction, and sense of body ownership during high resolution fMRI. Activity patterns in the hippocampus and the posterior cingulate, retrosplenial, and intraparietal cortices reflected the sense of self location, whereas the sense of body ownership was associated with premotor intraparietal activity. The functional interplay between these two sets of areas was mediated by the posterior cingulate cortex. These results extend our understanding of the role of the posterior parietal and medial temporal cortices in spatial cognition by demonstrating that these areas not only are important for ecological behaviors, such as navigation and perspective taking, but also support the perceptual representation of the bodily self in space. Our results further suggest that the posterior cingulate cortex has a key role in integrating the neural representations of self-location and body ownership. PMID- 25936549 TI - Innate Predator Odor Aversion Driven by Parallel Olfactory Subsystems that Converge in the Ventromedial Hypothalamus. AB - The existence of innate predator aversion evoked by predator-derived chemostimuli called kairomones offers a strong selective advantage for potential prey animals. However, it is unclear how chemically diverse kairomones can elicit similar avoidance behaviors. Using a combination of behavioral analyses and single-cell Ca(2+) imaging in wild-type and gene-targeted mice, we show that innate predator evoked avoidance is driven by parallel, non-redundant processing of volatile and nonvolatile kairomones through the activation of multiple olfactory subsystems including the Grueneberg ganglion, the vomeronasal organ, and chemosensory neurons within the main olfactory epithelium. Perturbation of chemosensory responses in specific subsystems through disruption of genes encoding key sensory transduction proteins (Cnga3, Gnao1) or by surgical axotomy abolished avoidance behaviors and/or cellular Ca(2+) responses to different predator odors. Stimulation of these different subsystems resulted in the activation of widely distributed target regions in the olfactory bulb, as assessed by c-Fos expression. However, in each case, this c-Fos increase was observed within the same subnuclei of the medial amygdala and ventromedial hypothalamus, regions implicated in fear, anxiety, and defensive behaviors. Thus, the mammalian olfactory system has evolved multiple, parallel mechanisms for kairomone detection that converge in the brain to facilitate a common behavioral response. Our findings provide significant insights into the genetic substrates and circuit logic of predator-driven innate aversion and may serve as a valuable model for studying instinctive fear and human emotional and panic disorders. PMID- 25936551 TI - BOLD fMRI Correlation Reflects Frequency-Specific Neuronal Correlation. AB - The brain-wide correlation of hemodynamic signals as measured with BOLD fMRI is widely studied as a proxy for integrative brain processes. However, the relationship between hemodynamic correlation structure and neuronal correlation structure remains elusive. We investigated this relation using BOLD fMRI and spatially co-registered, source-localized MEG in resting humans. We found that across the entire cortex BOLD correlation reflected the co-variation of frequency specific neuronal activity. Resolving the relation between electrophysiological and hemodynamic correlation structures locally in cortico-cortical connection space, we found that this relation was subject specific and even persisted on the centimeter scale. At first sight, this relation was strongest in the alpha to beta frequency range (8-32 Hz). However, correcting for differences in signal-to noise ratios across electrophysiological frequencies, we found that the relation extended over a broad frequency range from 2 to 128 Hz. Moreover, we found that the frequency with the tightest link to BOLD correlation varied across cortico cortical space. For every cortico-cortical connection, we show which specific correlated oscillations were most related to BOLD correlations. Our work provides direct evidence for the neuronal origin of BOLD correlation structure. Moreover, our work suggests that, across the brain, BOLD correlation reflects correlation of different types of neuronal network processes and that frequency-specific electrophysiological correlation provides information about large-scale neuronal interactions complementary to BOLD fMRI. PMID- 25936553 TI - Wild bearded capuchin monkeys crack nuts dexterously. AB - Dexterous tool use has been crucial in the evolution of hominid percussive technology. According to Newell, "dexterity" is the ability of an organism to make goal-directed corrections in movements to optimize effort. Dexterous movements are smooth and effective and accomplish the same goal with less energy than less dexterous movements. Dexterity develops during the later phases of refining a motor skill as the actor becomes sensitive to the outcome of the preceding movement, or to its modulation. In the present study, we examined how wild bearded capuchin monkeys, Sapajus libidinosus, at Fazenda Boa Vista in Piaui, Brazil, that routinely crack palm nuts using stones by placing them on rock outcrops, boulders, and logs (collectively termed anvils) modulate the kinematic parameters of the strikes while processing a single tucum, Astrocaryum campestre nut. The monkeys cracked the nuts by repeatedly striking them with moderate force (i.e., not exceeding a threshold), rather than by striking them more forcefully once, and modulated the kinematic parameters of the current strike on the basis of the condition of the nut following the preceding strike (i.e., the development of any fracture or crack). Repeatedly striking the nuts with moderate force is energetically more efficient than forcefully striking them once and reduces the likelihood of smashing the kernel. Determining the changing energetic constraints of the task and dynamically optimizing movements using those as criteria are dexterous accomplishments. We discuss the implications of the present findings. PMID- 25936552 TI - Traffic of p24 Proteins and COPII Coat Composition Mutually Influence Membrane Scaffolding. AB - Eukaryotic protein secretion requires efficient and accurate delivery of diverse secretory and membrane proteins. This process initiates in the ER, where vesicles are sculpted by the essential COPII coat. The Sec13p subunit of the COPII coat contributes to membrane scaffolding, which enforces curvature on the nascent vesicle. A requirement for Sec13p can be bypassed when traffic of lumenally oriented membrane proteins is abrogated. Here we sought to further explore the impact of cargo proteins on vesicle formation. We show that efficient ER export of the p24 family of proteins is a major driver of the requirement for Sec13p. The scaffolding burden presented by the p24 complex is met in part by the cargo adaptor Lst1p, which binds to a subset of cargo, including the p24 proteins. We propose that the scaffolding function of Lst1p is required to generate vesicles that can accommodate difficult cargo proteins that include large oligomeric assemblies and asymmetrically distributed membrane proteins. Vesicles that contain such cargoes are also more dependent on scaffolding by Sec13p, and may serve as a model for large carrier formation in other systems. PMID- 25936554 TI - Reverse logistics system and recycling potential at a landfill: A case study from Kampala City. AB - The rapid growing population and high urbanisation rates in Sub-Saharan Africa has caused enormous pressure on collection services of the generated waste in the urban areas. This has put a burden on landfilling, which is the major waste disposal method. Waste reduction, re-use and recycling opportunities exist but are not fully utilized. The common items that are re-used and re-cycled are plastics, paper, aluminum, glass, steel, cardboard, and yard waste. This paper develops an overview of reverse logistics at Kiteezi landfill, the only officially recognised waste disposal facility for Kampala City. The paper analyses, in details the collection, re-processing, re-distribution and final markets of these products into a reversed supply chain network. Only 14% of the products at Kiteezi landfill are channeled into the reverse chain while 63% could be included in the distribution chain but are left out and disposed of while the remaining 23% is buried. This is because of the low processing power available, lack of market value, lack of knowledge and limited value addition activities to the products. This paper proposes possible strategies of efficient and effective reverse logistics development, applicable to Kampala City and other similar cities. PMID- 25936555 TI - Crop residue stabilization and application to agricultural and degraded soils: A review. AB - Agricultural activities produce vast amounts of organic residues including straw, unmarketable or culled fruit and vegetables, post-harvest or post-processing wastes, clippings and residuals from forestry or pruning operations, and animal manure. Improper disposal of these materials may produce undesirable environmental (e.g. odors or insect refuges) and health impacts. On the other hand, agricultural residues are of interest to various industries and sectors of the economy due to their energy content (i.e., for combustion), their potential use as feedstock to produce biofuels and/or fine chemicals, or as a soil amendments for polluted or degraded soils when composted. Our objective is review new biotechnologies that could be used to manage these residues for land application and remediation of contaminated and eroded soils. Bibliographic information is complemented through a comprehensive review of the physico chemical fundamental mechanisms involved in the transformation and stabilization of organic matter by biotic and abiotic soil components. PMID- 25936556 TI - How should greenhouse gas emissions be taken into account in the decision making of municipal solid waste management procurements? A case study of the South Karelia region, Finland. AB - The ongoing trend in the public sector is to make more sustainable procurements by taking into account the impacts throughout the entire life cycle of the procurement. Despite the trend, the only deciding factor can still be the total costs. This article answers the question of how greenhouse gas (GHG) emissions should be taken into account in municipal solid waste (MSW) management when selecting an incineration plant for source separated mixed MSW. The aim is to guide the decision making of MSW management towards more environmentally friendly procurements. The study was carried out by calculating the global warming potentials (GWPs) and costs of mixed MSW management by using the waste composition from a case area in Finland. Scenarios of landfilling and combustion in three actual waste incineration plants were used to recognise the main processes that affect the results. GWP results show that the combustion of mixed MSW is a better alternative than landfilling the waste. The GHG results from combustion are greatly affected by emissions from the combustion and substituted energy production. The significance of collection and transportation is higher from the costs' perspective than from the point of view of GHG emissions. The main costs, in addition to collection and transportation costs, result from the energy utilization or landfilling of mixed MSW. When tenders are invited for the incineration location of mixed MSW, the main focus should be: What are the annual electricity and heat recovery efficiencies and which are the substituted fuels in the area? In addition, in the case of a fluidized bed combustor it is crucial to know the combusted share of mixed MSW after preparing solid recovered fuel (SRF) and the treatment of rejects. The environmental criteria for the waste incineration plant procurements should be made in order to obtain clear instructions for the procurement units. The results can also be utilized more widely. The substituted fuels in the area and the effect of the plant location on the utilization of the produced energy can already be identified when planning an appropriate site for the waste incineration plant. PMID- 25936558 TI - National and Hospital Registries: An Invaluable Source and Wealth of Information. PMID- 25936559 TI - Molecular principles of membrane microdomain targeting in plants. AB - Plasma membranes (PMs) are heterogeneous lipid bilayers comprising diverse subdomains. These sites can be labeled by various proteins in vivo and may serve as hotspots for signal transduction. They are found at apical, basal, and lateral membranes of polarized cells, at cell equatorial planes, or almost isotropically distributed throughout the PM. Recent advances in imaging technologies and understanding of mechanisms that allow proteins to target specific sites in PMs have provided insights into the dynamics and complexity of their specific segregation. Here we present a comprehensive overview of the different types of membrane microdomain and describe the molecular modes that determine site directed targeting of membrane-resident proteins at the PM. PMID- 25936560 TI - Anti-sessile bacterial and cytocompatibility properties of CHX-loaded nanohydroxyapatite. AB - Nanohydroxyapatite possesses exceptional biocompatibility and bioactivity regarding bone cells and tissues, justifying its use as a coating material or as a bone substitute. Unfortunately, this feature may also encourage bacterial adhesion and biofilm formation. Surface functionalization with antimicrobials is a promising strategy to reduce the likelihood of bacterial infestation and colonization on medical devices. Chlorhexidine digluconate is a common and effective antimicrobial agent used for a wide range of medical applications. The purpose of this work was the development of a nanoHA biomaterial loaded with CHX to prevent surface bacterial accumulation and, simultaneously, with good cytocompatibility, for application in the medical field. CHX (5-1500 mg/L) was loaded onto nanoHA discs and the materials were evaluated for CHX adsorption and release profile, physic-chemical features, antibacterial activity against Escherichia coli, Staphylococcus aureus and Staphylococcus epidermidis, and cytocompatibility toward L929 fibroblasts. Results showed that the adsorption of CHX on nanoHA surface occurred by electrostatic interactions between the cationic group of CHX and the phosphate group of nanoHA. The release of CHX from CHX loaded nanoHA showed a fast initial rate followed by a slower kinetics release, due to constraints caused by dilution and diffusion-limiting processes. NanoHA.50 to nanoHA.1500 showed strong anti-sessile activity, inhibiting bacterial adhesion and the biofilm formation. CHX-nanoHA caused a dose- and time-dependent inhibitory effect on the proliferation of fibroblasts for nanoHA.100 to nanoHA.1500. Cellular behavior on nanoHA.5 and nanoHA.50 was similar to control. Therefore, CHX-loaded nanoHA surfaces appear as a promising alternative to prevention of devices-related infections. PMID- 25936561 TI - Therapeutic efficacy of artemisinin-loaded nanoparticles in experimental visceral leishmaniasis. AB - Visceral leishmaniasis (VL) is a fatal vector-borne parasitic syndrome attributable to the protozoa of the Leishmania donovani complex. The available chemotherapeutic options are not ideal due to their potential toxicity, high cost and prolonged treatment schedule. In the present study, we conjectured the use of nano drug delivery systems for plant-derived secondary metabolite; artemisinin as an alternative strategy for the treatment of experimental VL. Artemisinin-loaded poly lactic co-glycolic acid (ALPLGA) nanoparticles prepared were spherical in shape with a particle size of 220.0+/-15.0 nm, 29.2+/-2.0% drug loading and 69.0+/-3.3% encapsulation efficiency. ALPLGA nanoparticles administered at doses of 10 and 20mg/kg body weight showed superior antileishmanial efficacy compared with free artemisinin in BALB/c model of VL. There was a significant reduction in hepatosplenomegaly as well as in parasite load in the liver (85.0+/-5.4%) and spleen (82.0+/-2.4%) with ALPLGA nanoparticles treatment at 20mg/kg body weight compared to free artemisinin (70.3+/-0.6% in liver and 62.7+/-3.7% in spleen). In addition, ALPLGA nanoparticle treatment restored the defective host immune response in mice with established VL infection. The protection was associated with a Th1-biased immune response as evident from a positive delayed-type hypersensitivity reaction, escalated IgG2a levels, augmented lymphoproliferation and enhancement in proinflammatory cytokines (IFN-gamma and IL-2) with significant suppression of Th2 cytokines (IL-10 and IL-4) after in vitro recall, compared to infected control and free artemisinin treatment. In conclusion, our results advocate superior efficacy of ALPLGA nanoparticles over free artemisinin, which was coupled with restoration of suppressed cell-mediated immunity in animal models of VL. PMID- 25936562 TI - Electrospinning polyvinylidene fluoride fibrous membranes containing anti bacterial drugs used as wound dressing. AB - The aim of this study was to synthesis drug-loaded fibrous membrane scaffolds for potential applications as wound dressing. Polyvinylidene fluoride (PVDF) fibrous membranes were loaded with enrofloxacin (Enro) drugs by using an electrospinning process, and their mechanical strength, drug release profile and anti-bacterial properties were evaluated. Enro drug-loaded PVDF membranes exhibited good elasticity, flexibility and excellent mechanical strength. The electrospinning Enro/PVDF membranes showed a burst drug release in the initial 12h, followed by sustained release for the next 3 days, which was an essential property for antibiotic drugs applied for wound healing. The drug-loaded PVDF fibrous membranes displayed excellent anti-bacterial activity toward Escherichia coli and Staphylococcus aureus. The results suggest that electrospinning PVDF membrane scaffolds loaded with drugs can be used as wound dressing. PMID- 25936563 TI - Water stress alters lignin content and related gene expression in two sugarcane genotypes. AB - The lignin deposition in the stem of two sugarcane genotypes was assessed on exposure to water stress. The lignin content and the morphoanatomical characterization of the stem indicated that IACSP94-2094 plants are more lignified than those of IACSP95-5000 genotype, under normal water supply conditions, which was especially associated with higher lignin contents in the rind of mature internodes. Water deficit had negative impact on the biomass production, mostly with IACSP94-2094 plants, possibly due to stress severity or higher susceptibility of that genotype during the stem-lengthening phase. Water deficit led to significant alterations in the expression levels of lignin biosynthesis genes and led to an approximate 60% increase of lignin content in the rind of young internodes in both genotypes. It is concluded that the young rind region was more directly affected by water stress and, depending on the genotype, a higher lignin accumulation may occur in the stem, thus implying lower quality biomass for bioethanol production. PMID- 25936564 TI - Skin-homing and systemic T-cell subsets show higher activation in atopic dermatitis versus psoriasis. PMID- 25936565 TI - Magnitude of effect of asthma treatments on Asthma Quality of Life Questionnaire and Asthma Control Questionnaire scores: Systematic review and network meta analysis. AB - BACKGROUND: The Asthma Quality of Life Questionnaire (AQLQ) and the Asthma Control Questionnaire (ACQ) are widely used in asthma research; however, in studies of newer asthma treatments, mean improvements in these measures compared with placebo arms do not exceed the minimal important difference (MID), particularly when a new treatment is added to current treatment. OBJECTIVE: We performed a systematic review and network meta-analysis to examine the magnitude of AQLQ and ACQ responses achieved with commonly used asthma drugs and factors influencing these end points in clinical trials. METHODS: A systematic literature search was conducted to identify blinded randomized controlled trials reporting AQLQ or ACQ results. Mixed treatment comparisons, combined with meta-regression, were then performed. RESULTS: Of the 64 randomized controlled trials (42,527 patients) identified, 54 included the AQLQ and 11 included the ACQ as end points. The presence of a run-in period, the nature of treatment during the run-in period, concurrent treatment during the treatment period, and instrument version significantly influenced the change in AQLQ score from baseline and whether it exceeded the MID. When compared with placebo, only inhaled corticosteroids (ICSs), with or without a long-acting beta-agonist, achieved the MID. The ACQ results were comparable with those of the AQLQ: no differences from placebo exceeded the MID, and ICS-based treatments provided the greatest improvements. CONCLUSION: The established within-patient MID for the ACQ and AQLQ is not achievable as a group-wise efficacy threshold between treatment arms in clinical studies in which controllers are added to ICS treatment. Thus in addition to reporting mean changes of the instruments, other measurement criteria should be considered, including responder analyses. PMID- 25936566 TI - Higher B-cell activating factor levels at birth are positively associated with maternal dairy farm exposure and negatively related to allergy development. AB - BACKGROUND: A high proportion of circulating immature/naive CD5(+) B cells during early infancy is a risk factor for allergy development. B-cell activating factor (BAFF) is an important cytokine for B-cell maturation. OBJECTIVE: We sought to investigate whether BAFF levels are related to environmental exposures during pregnancy and early childhood and whether BAFF levels are associated with postnatal B-cell maturation and allergic disease. METHODS: In the FARMFLORA study, including both farming and nonfarming families, we measured BAFF levels in plasma from mothers and their children at birth and at 1, 4, 18, and 36 months of age. Infants' blood samples were also analyzed for B-cell numbers and proportions of CD5(+) and CD27(+) B cells. Allergic disease was clinically evaluated at 18 and 36 months of age. RESULTS: Circulating BAFF levels were maximal at birth, and farmers' children had higher BAFF levels than nonfarmers' children. Higher BAFF levels at birth were positively associated with proportions of CD27(+) memory B cells among farmers' children and inversely related to proportions of CD5(+) immature/naive B cells among nonfarmers' children. Children with allergic disease at 18 months of age had lower cord blood BAFF levels than nonallergic children. At birth, girls had higher BAFF levels and lower proportions of CD5(+) B cells than boys. CONCLUSIONS: Farm exposure during pregnancy appears to induce BAFF production in the newborn child, and high neonatal BAFF levels were associated with more accelerated postnatal B-cell maturation, which lend further strength to the role of B cells in the hygiene hypothesis. PMID- 25936567 TI - Correlation between CCL26 production by human bronchial epithelial cells and airway eosinophils: Involvement in patients with severe eosinophilic asthma. AB - BACKGROUND: High pulmonary eosinophil counts are associated with asthma symptoms and severity. Bronchial epithelial cells (BECs) produce CC chemokines, notably CCL26 (eotaxin-3), which recruits and activates eosinophils from asthmatic patients. This suggests that CCL26 production by BECs might be involved in persistent eosinophilia in patients with severe asthma despite treatment with high corticosteroid doses. OBJECTIVE: We sought to determine whether CCL26 levels correlate with eosinophilia and asthma severity. METHODS: Human CC chemokine expression was assessed by means of quantitative PCR or a quantitative PCR array in vehicle- or IL-13-treated BECs. CCL26 was quantitated by means of ELISA. Immunohistochemistry analyses of CCL26 and major basic protein were done on bronchial biopsy specimens. RESULTS: IL-13 selectively induced CCL26 expression by BECs. This increase was time-dependent and more prominent in BECs from patients with severe eosinophilic asthma. CCL26 levels measured in supernatants of IL-13-stimulated BECs also increased with asthma severity as follows: patients with severe eosinophilic asthma > patients with mild asthma ~ healthy subjects. Immunohistochemistry analyses of bronchial biopsy specimens confirmed increased levels of CCL26 in the epithelium of patients with mild and those with severe eosinophilic asthma. Tissue eosinophil counts did not correlate with CCL26 staining. However, sputum CCL26 levels significantly correlated with sputum eosinophil counts (P < .0001), suggesting that CCL26 participates in the movement of eosinophils from the tissues to the airway lumen. CONCLUSIONS: These results show a relation between CCL26 production by IL-13-stimulated BECs, sputum eosinophil counts, and asthma severity. They also suggest a role for CCL26 in the sustained inflammation observed in patients with severe eosinophilic asthma and reveal CCL26 as a potential target for treating patients with eosinophilic asthma that are refractory to classic therapies. PMID- 25936568 TI - CCCTC-binding factor controls the homeostatic maintenance and migration of Langerhans cells. AB - BACKGROUND: Langerhans cells (LCs) are skin-resident dendritic cells (DCs) that orchestrate skin immunity. CCCTC-binding factor (CTCF) is a highly conserved DNA binding protein that regulates higher-order chromatin organization and is involved in various gene regulation processes. OBJECTIVE: We sought to clarify a possible role for CTCF in LC homeostasis and function in vivo. METHODS: We used a conditional gene deletion mouse system to generate DC- and LC-specific CTCF ablated mice. Short hairpin RNA-mediated RNA interference was used to silence CTCF expression in human monocyte-derived Langerhans cells. DC populations were assessed by using flow cytometry and immunofluorescence. Gene expression arrays were performed to identify genes regulated by CTCF in LCs. Contact hypersensitivity and epicutaneous sensitization responses were measured to examine the functional significance of CTCF ablation. RESULTS: DC-specific CTCF deletion led to a reduced pool of systemic DCs, with LCs most severely affected. Decreases in epidermal LC numbers were specifically associated with self-turnover defects. Interestingly, CTCF-deficient LCs demonstrated impaired migration out of the epidermis. Whole-transcriptome analyses revealed that genes that promoted cell adhesion were highly expressed, but CCR7 was downregulated in CTCF-depleted LCs. Hapten-induced contact hypersensitivity responses were more sustained in LC specific CTCF-deficient mice, whereas epicutaneous sensitization to protein antigen was attenuated, indicating that CTCF-dependent LC homeostasis is required for optimal immune function of LCs in a context-dependent manner. CONCLUSION: Our results show that CTCF positively regulates the homeostatic pool and the efficient emigration of LCs, which are required for modulating the functional immune network of the skin. PMID- 25936569 TI - A new clinico-tomographic classification and management algorithm for Descemet's membrane detachment. AB - OBJECTIVE: To propose a new clinico-tomographic classification of Descemet's detachment (DD). METHODS: Interventional case series of 35 eyes with DD were clinico-tomographically classified as: (1)Rhegmatogenous DD (RDD)-lax, free floating DM secondary to DM tear/hole/dialysis; ASOCT showing undulating linear signal with total length equalling overlying stromal arc length. (2) Tractional DD (TDD)-foreshortened, taut DM with tractional/fibrotic component; ASOCT showing detached DM chord length less than overlying stromal arc length. (3) Bullous DD (BDD)-bulge of DM into AC in absence of DM break or needle puncture break too small to allow egress of contents; ASOCT showing convex signal. (4) Complex DD (CDD)-Complex variants and combinations seen clinically and on ASOCT. RESULTS: RDD was most common (n=23), 19 were RDD with tear (post-surgical) treated by observation(n=3)/pneumodescemetopexy(n=16), 2 were RDD with hole due to inadvertent DM perforation in deep anterior lamellar keratoplasty treated by pneumodescemetopexy and fibrin glue, 2 were RDD with dialysis post Descemetorhexis in Descemet's Membrane Endothelial Keratoplasty, not requiring treatment. TDD (n=4) was treated by relaxing Descemetotomy (n=3) or EK (n=1, poor endothelium); BDD (n=3) with two improving spontaneously; CDD (n=5) treated by refloatation with air (n=3)/EK (n=1)/penetrating keratoplasty (n=1). CONCLUSION: Treatment and prognosis of DD varies based on etio-morphology. This classification allows systematic approach for diagnosis, management and prognostication. PMID- 25936570 TI - Potential genetic markers for prediction of treatment response in Egyptian children infected with HCV genotype 4. AB - BACKGROUND: Egypt has a high prevalence of hepatitis C virus (HCV) infection. Limitations of the current HCV treatment in children are low rate of sustained virological response, significant side effects and high expenses, making prediction of treatment response crucial. AIM: This study aimed to investigate association of single nucleotide polymorphisms (SNPs) in interleukins (IL) 10, 28 and 29 genes in predicting the response to therapy in HCV infected children. METHODS: Sixty-six Egyptian children infected with HCV genotype 4, receiving pegylated interferon alpha 2b and ribavirin, were included. Genotyping of six SNPs in interleukin 10, 28B and 29 gene as well as HCV genotype were analyzed by real-time polymerase chain reaction. RESULTS: The CC genotype in IL28B; rs12979860 had 8.547 folds higher chance to develop sustained virological response than CT and TT genotypes (P=0.014). Genotype distribution of rs8099917 in IL28B gene (TG and GG genotypes) was found to be 3.348 more likely not to respond to treatment than the TT genotype (P=0.018). In multivariate analysis, interleukin 28 gene single nucleotide polymorphisms rs 12979860, interleukin 10 single nucleotide polymorphisms -592A > C and basal viral load were independent variables that significantly improved prediction of response to HCV therapy. CONCLUSION: This association can be translated into clinical decision making for HCV treatment. PMID- 25936571 TI - Prospective assessment of cytokine IL-15 activity in patients with refractory atrial fibrillation episodes. AB - AIMS: Inflammatory state is considered a risk factor of atrial fibrillation (AF) occurrence. The aim of this study was a prospective evaluation of the inflammation parameters in patients with different forms of AF without structural heart disease. METHODS AND RESULTS: One hundred fifty-eight patients with paroxysmal/persistent AF (87; 55.1% men, mean age 65.8+/-9.6 years) without structural heart disease were enrolled in the study. Inflammatory parameters: WBC, ESR, hs-CRP, IL-6, IL-15 and TNF-alpha were measured at baseline and after one year follow-up. Despite frequent AF episodes median values of WBC, ESR and C reactive protein at baseline and after follow up were within normal ranges. There were no significant differences between WBC, ESR and hs-CRP regarding AF types. In patients who developed permanent AF form (n=14) hs-CRP concentrations were higher at baseline: 0.35 (IQR1: 0.09 IQR: 0.61) vs 0.15 (IQR1: 0.07 IQR: 0.29), p<0.01. Nevertheless, after one year's observation these differences were not significant. Among all cytokines were studied only IL-15 was significantly correlated with the number of AF episodes (r=0.26), mean (IQ1-IQ3): 10 (3-30) vs 60 (50-100), p=0.00681. CONCLUSION: Basic inflammatory markers were not changed in patients with refractory atrial fibrillation episodes in prospective one year's observation. Only cytokine IL-15 was correlated to numbers of AF episodes. It's potential role as a marker of arrhythmia deserves further evaluation. PMID- 25936572 TI - Using a forensic science approach to minimize environmental contamination and to identify microfibres in marine sediments. AB - There is growing evidence of extensive pollution of the environment by microplastic, with microfibres representing a large proportion of the microplastics seen in marine sediments. Since microfibres are ubiquitous in the environment, present in the laboratory air and water, evaluating microplastic pollution is difficult. Incidental contamination is highly likely unless strict control measures are employed. Here we describe methods developed to minimize the amount of incidental post-sampling contamination when quantifying marine microfibre pollution. We show that our protocol, adapted from the field of forensic fibre examination, reduces fibre abundance by 90% and enables the quick screening of fibre populations. These methods therefore allow an accurate estimate of microplastics polluting marine sediments. In a case study from a series of samples collected on a research vessel, we use these methods to highlight the prevalence of microfibres as marine microplastics. PMID- 25936573 TI - Assessing responses of the Hiroshima Bay ecosystem to increasing or decreasing phosphorus and nitrogen inputs. AB - The Japanese Government is seeking an appropriate level of nutrient load from the land to maintain the highest possible estuarine fishery production and water transparency simultaneously. To provide a scientific basis for the governmental inquiry, we conducted sensitivity analyses using an ecosystem model of Hiroshima Bay in order to assess the ecosystem's responses to phosphorus and nitrogen inputs. Load levels of phosphorus (Case P), nitrogen (Case N) and both phosphorus and nitrogen (Case NP) that were different from the average loading recorded during 1991-2000 (+/-25%, +/-50%, and +/-75%) were applied. The results showed that phosphorus had a significantly greater impact on the primary production of the bay than nitrogen. Case P+25 increased the primary production but led to N limitation. However, it was found that Case NP at the levels over +25% could bring the Hiroshima Bay ecosystem back to its eutrophic state of 30 years ago. PMID- 25936574 TI - First evidence of presence of plastic debris in stomach of large pelagic fish in the Mediterranean Sea. AB - This study focuses, for the first time, on the presence of plastic debris in the stomach contents of large pelagic fish (Xiphias gladius, Thunnus thynnus and Thunnus alalunga) caught in the Mediterranean Sea between 2012 and 2013. Results highlighted the ingestion of plastics in the 18.2% of samples. The plastics ingested were microplastics (<5mm), mesoplastics (5-25mm) and macroplastics (>25mm). These preliminary results represent an important initial phase in exploring two main ecotoxicological aspects: (a) the assessment of the presence and impact of plastic debris on these large pelagic fish, and (b) the potential effects related to the transfer of contaminants on human health. PMID- 25936575 TI - Are groups more or less than the sum of their members? The moderating role of individual identification. AB - This paper seeks to make a theoretical and empirical case for the importance of differentiated identities for group function. Research on groups has found that groups sometimes perform better and other times perform worse than the sum of their individual members. Differentiation of selves is a crucial moderator. We propose a heuristic framework that divides formation of work or task groups into two steps. One step emphasizes shared common identity and promotes emotional bonds. In the other step, which we emphasize, group members take increasingly differentiated roles that improve performance through specialization, moral responsibility, and efficiency. Pathologies of groups (e.g., social loafing, depletion of shared resources/commons dilemmas, failure to pool information, groupthink) are linked to submerging the individual self in the group. These pathologies are decreased when selves are differentiated, such as by individual rewards, individual competition, accountability, responsibility, and public identification. Differentiating individual selves contributes to many of the best outcomes of groups, such as with social facilitation, wisdom-of-crowds effects, and division of labor. Anonymous confidentiality may hamper differentiation by allowing people to blend into the group (so that selfish or lazy efforts are not punished), but it may also facilitate differentiation by enabling people to think and judge without pressure to conform. Acquiring a unique role within the group can promote belongingness by making oneself irreplaceable. PMID- 25936576 TI - Cardiac differentiation of mouse embryonic stem cells is influenced by a PPAR gamma/PGC-1alpha-FNDC5 pathway during the stage of cardiac precursor cell formation. AB - Peroxisome proliferator-activated receptor (PPAR) gamma co-activator 1alpha (PGC 1alpha) up-regulation induces FNDC5 expression in muscle and consequently causes browning of white adipose tissue (WAT). In addition to skeletal muscle, FNDC5 is mainly expressed in heart and brain tissues. Here, we demonstrate that FNDC5 expression increased during the process of cardiac differentiation of mouse embryonic stem cells (mESCs) similar to PGC-1alpha and PPARalpha. To testify the correlation between PGC-1alpha and FNDC5 in cardiac cell differentiation of mESCs, we utilized specific PPARgamma agonist and antagonist in two stages of cardiac differentiation, during and post-cardiac precursor cells (CPCs) formation. Our results indicated that a reduction in PGC-1alpha expression, via treatment with GW9662 during CPCs formation stage, down-regulated FNDC5 transcript levels as well as mitochondrial markers which negatively influenced on the whole process of cardiac differentiation efficiency. On the other hand, increase PGC-1alpha expression during CPCs formation stage via rosiglitazone treatment increase FNDC5 and mitochondrial markers transcript levels which enhanced cardiac differentiation efficiency. Importantly, such alteration in PGC 1alpha expression at post-CPCs formation stage did not affect overall cardiac differentiation rate as expression of FNDC5 and mitochondrial markers were not significantly changed. We concluded that PPARgamma agonist and antagonist induced up and down-regulation of PGC-1alpha and subsequently modulated the process of CPCs formation through an alteration in FNDC5 and mitochondrial markers expression. PMID- 25936577 TI - Identification of a conserved B-cell epitope on the GapC protein of Streptococcus dysgalactiae. AB - Streptococcus dysgalactiae (S. dysgalactia) GapC is a highly conserved surface dehydrogenase among the streptococcus spp., which is responsible for inducing protective antibody immune responses in animals. However, the B-cell epitope of S. dysgalactia GapC have not been well characterized. In this study, a monoclonal antibody 1F2 (mAb1F2) against S. dysgalactiae GapC was generated by the hybridoma technique and used to screen a phage-displayed 12-mer random peptide library (Ph.D.-12) for mapping the linear B-cell epitope. The mAb1F2 recognized phages displaying peptides with the consensus motif TRINDLT. Amino acid sequence of the motif exactly matched (30)TRINDLT(36) of the S. dysgalactia GapC. Subsequently, site-directed mutagenic analysis further demonstrated that residues R31, I32, N33, D34 and L35 formed the core of (30)TRINDLT(36), and this core motif was the minimal determinant of the B-cell epitope recognized by the mAb1F2. The epitope (30)TRINDLT(36) showed high homology among different streptococcus species. Overall, our findings characterized a conserved B-cell epitope, which will be useful for the further study of epitope-based vaccines. PMID- 25936578 TI - Knee alignment in the transverse plane during weight-bearing activity and its implication for the tibial rotational alignment in total knee arthroplasty. AB - BACKGROUND: The alignment of the knee in the transverse plane is important to the biomechanical functions of the lower limb, and is also associated with the outcomes of the total knee arthroplasty. This study aimed to evaluate the dynamic tibiofemoral alignment in the transverse plane during a weight-bearing activity. METHODS: Knee kinematics of weight-bearing flexion from 0 degrees to 120 degrees was obtained in 16 healthy subjects utilizing biplanar radiography and 3D-2D registration techniques. The anteroposterior axes of the femur at multiple flexion angles in the range of knee motion were used to calculate the anteroposterior axis of motion using the least square method. The latter was compared to six surface-derived anatomical axes in the proximal tibia which were most commonly reported in the literature. The relationship between the anteroposterior axis of motion and the tibial tubercle was also quantified. FINDINGS: The anteroposterior axis of motion did not coincide with any of the six anatomical axes tested. Their orientations varied from 10.3 degrees of external rotation to 9.9 degrees of internal rotation in relation to the former. The anteroposterior axis of motion tended to intersect the tibial tubercle between the medial border and the medial 1/3 point. INTERPRETATION: Instead of any of the tested anatomical axes, the transverse knee alignment during functional movements is associated with the medial 1/3 portion of the tibial tubercle. This region may be helpful for the rotational alignment of the tibial components in total knee arthroplasty. PMID- 25936580 TI - New vector-transmitted pathogens. PMID- 25936579 TI - ABCs or 123s? The independent contributions of literacy and numeracy skills on health task performance among older adults. AB - OBJECTIVE: To investigate the relationship between literacy and numeracy and their association with health task performance. METHODS: Older adults (n=304) completed commonly used measures of literacy and numeracy. Single factor literacy and numeracy scores were calculated and used to predict performance on an established set of health self-management tasks, including: (i) responding to spoken information; (ii) comprehension of print and (iii) multimedia information; and (iv) organizing and dosing medication. Total and sub-scale scores were calculated. RESULTS: Literacy and numeracy measures were highly correlated (rs=0.68; ps<0.001). In multivariable models adjusted for age, gender, race, education, and comorbidity, lower literacy (beta=0.44, p<0.001) and numeracy (beta=0.44, p<0.001) were independently associated with worse overall task performance and all sub-scales (literacy range, beta=0.23-0.45, ps<0.001; numeracy range, beta=0.31-0.41, ps<0.001). Multivariable analyses with both constructs entered explained more variance in overall health task performance compared with separate literacy and numeracy models (8.2% and 10% respectively, ps<0.001). CONCLUSION: Literacy and numeracy were highly correlated, but independent predictors of health task performance. These skill sets are complementary and both are important for health self-management. PRACTICE IMPLICATIONS: Self-management interventions may be more effective if they consider both literacy and numeracy skills rather than focusing on one specific ability. PMID- 25936581 TI - Which high-risk HPV assays fulfil criteria for use in primary cervical cancer screening? AB - Several countries are in the process of switching to high-risk human papillomavirus (hrHPV) testing for cervical cancer screening. Given the multitude of available tests, validated assays which assure high-quality screening need to be identified. A systematic review was conducted to answer the question which hrHPV tests fulfil the criteria defined by an international expert team in 2009, based on reproducibility and relative sensitivity and specificity compared to Hybrid Capture-2 or GP5+/6+ PCR-enzyme immunoassay. These latter two hrHPV DNA assays were validated in large randomized trials and cohorts with a follow-up duration of 8 years or more. Eligible studies citing the 2009 guideline were retrieved from Scopus (http://www.scopus.com) and from a meta-analysis assessing the relative accuracy of new hrHPV assays versus the standard comparator tests to detect high-grade cervical intraepithelial neoplasia or cancer in primary screening. The cobas 4800 HPV test and Abbott RealTime High Risk HPV test were consistently validated in two and three studies, respectively, whereas the PapilloCheck HPV-screening test, BD Onclarity HPV assay and the HPV-Risk assay were validated each in one study. Other tests which partially fulfil the 2009 guidelines are the following: Cervista HPV HR Test, GP5+/6+ PCR-LMNX, an in-house E6/E7 RT quantitative PCR and MALDI-TOF (matrix-assisted laser desorption ionization time-of-flight). The APTIMA HPV assay targeting E6/E7 mRNA of hrHPV was also fully validated. However, the cross-sectional equivalency criteria of the 2009 guidelines were set up for HPV DNA assays. Demonstration of a low risk of CIN3+ after a negative APTIMA test over a longer period is awaited to inform us about its utility in cervical cancer screening at 5-year or longer intervals. PMID- 25936582 TI - Islet insulin content and release are increased in male mice with elevated endogenous GH and IGF-I, without evidence of systemic insulin resistance or alterations in beta-cell mass. AB - It is clear that elevations in circulating GH can lead to an increase in insulin levels. This increase in insulin may be due to GH-mediated insulin resistance and enhanced lipolysis. However, there is also in vitro and in vivo evidence that GH acts directly to increase beta-cell proliferation and insulin production. Our laboratory recently developed an animal model with elevated endogenous GH levels associated with a small (25%), but significant, increase in IGF-I (HiGH mice). As expected, insulin levels were elevated in HiGH mice; however, whole body insulin sensitivity was not altered and glucose tolerance was improved. This metabolic phenotype suggests that modest elevations in circulating GH and IGF-I may enhance beta-cell mass and/or function, in the absence of systemic insulin resistance, thus improving glucose homeostasis. OBJECTIVE: To determine if beta-cell mass and/or function is altered in HiGH mice. DESIGN: Male HiGH mice and their littermate controls were fed a low-fat or high-fat diet. Body composition and circulating metabolic endpoints were monitored overtime. The pancreas was recovered and processed for assessment of beta-cell mass or in vitro basal and glucose-stimulated insulin secretion. RESULTS: HiGH mice showed elevated circulating insulin and normal glucose levels, while non-esterified FFA levels and triglycerides were reduced or normal, depending on diet and age. beta-cell mass did not differ between HiGH and control mice, within diet. However, islets from HiGH mice contained and released more insulin under basal conditions, as compared to control islets, while the relative glucose-stimulated insulin release did not differ. CONCLUSIONS: Taken together, these results suggest moderate elevations in circulating GH and IGF-I can directly increase basal insulin secretion without impacting beta-cell mass, independent of changes in whole body insulin sensitivity and hyperlipidemia. PMID- 25936583 TI - Infections and risk-adjusted length of stay and hospital mortality in Polish Neonatology Intensive Care Units. AB - BACKGROUND: The objectives of this study were to analyze the impact of infections on prolonging hospital stay with consideration of underlying risk factors and determining the mortality rates and its association with infections. METHODS: An electronic database developed from a continuous prospective targeted infection surveillance program was used in the study. Data were collected from 2009 to 2012 in five Polish tertiary academic neonatal intensive care units (NICUs). The length of stay (LOS) of 2,003 very low birth weight (VLBW) neonates was calculated as the sum of the number of days since birth until death or until reaching a weight of 1,800g. RESULTS: The median LOS for neonates with infections was twice as high as for neonates without infection. LOS was significantly affected by the overall general condition of the neonate, as expressed by both gestational age and birth weight as well as by the Clinical Risk Index for Babies (CRIB) score; another independent factor was presence of at least one infection. Risk of in-hospital mortality was significantly increased by male sex and vaginal birth and was lower among breastfed neonates. Deaths were significantly more frequent in neonates without infection. CONCLUSIONS: The general condition of VLBW infants statistically increase both their risk of mortality and LOS; this is in contrast to the presence of infection, which significantly prolonged LOS only. PMID- 25936585 TI - Weaknesses in executive functioning predict the initiating of adolescents' alcohol use. AB - Recently, it has been suggested that impairments in executive functioning might be risk factors for the onset of alcohol use rather than a result of heavy alcohol use. In the present study, we examined whether two aspects of executive functioning, working memory and response inhibition, predicted the first alcoholic drink and first binge drinking episode in young adolescents using discrete survival analyses. Adolescents were selected from several Dutch secondary schools including both mainstream and special education (externalizing behavioral problems). Participants were 534 adolescents between 12 and 14 years at baseline. Executive functioning and alcohol use were assessed four times over a period of two years. Working memory uniquely predicted the onset of first drink (p=.01) and first binge drinking episode (p=.04) while response inhibition only uniquely predicted the initiating of the first drink (p=.01). These results suggest that the association of executive functioning and alcohol consumption found in former studies cannot simply be interpreted as an effect of alcohol consumption, as weaknesses in executive functioning, found in alcohol naive adolescents, predict the initiating of (binge) drinking. Though, prolonged and heavy alcohol use might further weaken already existing deficiencies. PMID- 25936584 TI - The impact of initiation: Early onset marijuana smokers demonstrate altered Stroop performance and brain activation. AB - Marijuana (MJ) use is on the rise, particularly among teens and emerging adults. This poses serious public health concern, given the potential deleterious effects of MJ on the developing brain. We examined 50 chronic MJ smokers divided into early onset (regular MJ use prior to age 16; n=24) and late onset (age 16 or later; n=26), and 34 healthy control participants (HCs). All completed a modified Stroop Color Word Test during fMRI. Results demonstrated that MJ smokers exhibited significantly poorer performance on the Interference subtest of the Stroop, as well as altered patterns of activation in the cingulate cortex relative to HCs. Further, early onset MJ smokers exhibited significantly poorer performance relative to both HCs and late onset smokers. Additionally, earlier age of MJ onset as well as increased frequency and magnitude (grams/week) of MJ use were predictive of poorer Stroop performance. fMRI results revealed that while late onset smokers demonstrated a more similar pattern of activation to the control group, a different pattern was evident in the early onset group. These findings underscore the importance of assessing age of onset and patterns of MJ use and support the need for widespread education and intervention efforts among youth. PMID- 25936586 TI - In vitro inhibition of human cytochrome P450 by cudratricusxanthone A. AB - Cudratricusxanthone A (CTXA) isolated from the roots of Cudrania tricuspidata Bureau (Moraceae) has several biological activities, including hepatoprotective, neuroprotective, anti-inflammatory, monoamine oxidase inhibitory, and antithrombotic activities. In this study, we investigated the potential herb-drug interaction of CTXA and nine cytochrome P450 (CYP) isoforms in pooled human liver microsomes (HLMs) using a cocktail probe assay. CTXA reversibly inhibited the CYP1A2-catalyzed phenacetin O-deethylation, CYP2C8-catalyzed paclitaxel 6 hydroxylation, and CYP2C9-catalyzed diclofenac 4'-hydroxylation with half-maximal inhibitory concentration (IC50) values of 3.9, 4.7, and 2.9 uM, respectively. The IC50 values did not change under different preincubation conditions. CTXA showed marked dose-dependent, but not time-dependent, inhibition of CYP1A2 and 2C9 activities in HLMs. Dixon plots showed typical competitive inhibition of CYP1A2 and CYP2C9 with Ki values of 1.3 and 1.5 uM, respectively. Further, CTXA inhibited CYP2C8 in a non-competitive manner with a Ki value of 2.2 uM. Our results showed that CTXA reversibly inhibits CYP1A2, 2C8, and 2C9. PMID- 25936587 TI - Primary "Pure" Large Cell Neuroendocrine Carcinoma of the Urinary Bladder: A Case Report and Review of the Literature. PMID- 25936588 TI - High Ki-67 Expression Predicts Favorable Survival in Muscle-Invasive Bladder Cancer Patients Treated With Chemoradiation-Based Bladder-Sparing Protocol. AB - PURPOSE: To evaluate associations of Ki-67 expression with oncologic outcomes in muscle-invasive bladder cancer (MIBC) patients treated with chemoradiotherapy (CRT)-based bladder-sparing protocol. MATERIALS AND METHODS: Between 1998 and 2011, 190 consecutive MIBC patients were treated with CRT-based bladder-sparing protocol. After transurethral resection of the bladder tumor, the patients underwent induction CRT (40 Gy with concurrent cisplatin) followed by partial cystectomy for bladder preservation or radical cystectomy (RC). Included in this study were 94 patients who were histologically diagnosed with urothelial carcinoma and whose tumor tissues before CRT were available for immunohistochemical evaluation of Ki-67 expression status. RESULTS: After induction CRT, 16 (17%) and 53 (56%) patients underwent partial cystectomy and RC, respectively, while the remaining 25 (27%) did not undergo cystectomy. Successful bladder preservation was achieved in 34 patients (36%). Higher Ki-67 labeling index (LI) independently predicted CRT response clinically and pathologically. Among the clinicopathologic variables available before CRT and cystectomy, high Ki-67 LI (>= 20%) was independently associated with better cancer-specific survival (CSS) (5-year CSS rate, 78% vs. 46% for low Ki-67 LI; P = .019). The difference in CSS according to Ki-67 expression status was more remarkable in patients with cT3 disease (5-year CSS rate, 72% vs. 29%; P = .0098). CONCLUSION: High Ki-67 expression predicts favorable CSS in MIBC patients treated with CRT-based bladder-sparing protocol. MIBC patients with high Ki-67 expression status might benefit from CRT-based multimodal approaches in terms of prognosis and quality of life as a result of bladder preservation. PMID- 25936589 TI - Local and systemic adaptive immune responses toward viral infection via gills in ginbuna crucian carp. AB - Recent studies on fish immunity highlighted the significance of gills as mucosal immune tissues. To understand potential of gills as vaccination sites for inducing adaptive systemic immunity, we investigated virus-specific cell-mediated and humoral immune responses following a "per-gill infection method", which directly exposes virus only to gills. The viral load in crucian carp hematopoietic necrosis virus (CHNV)-infected gills decreased after peaking at a particular time point. Furthermore, the viral titers in the gills following the secondary infection were lower than that after the primary infection, indicating that local adaptive immunity helped the elimination of virus. Gene expression analysis demonstrated that IFN-gamma in gills and perforin in kidney were increased after the gill infection. CD8(+) cells in kidney leukocytes increased after the secondary infection, whereas IgM(+) cells decreased. These results suggest that IFN-gamma and CTL contribute in controlling CHNV-replication in gills and kidney. Gill infection could induce specific cell-mediated cytotoxicity of peripheral blood leukocytes (PBL) and secretion of CHNV-specific IgM in serum, indicating that local priming of the gill site can generate adaptive systemic immunity. Thus, the gills could be prospective antigen-sensitization sites for mucosal vaccination. PMID- 25936590 TI - Increased serum carcinoembryonic antigen level can predict poor survival of patients with small cell lung cancer. AB - Increased serum tumor biomarkers are usually associated with huge tumor burden, but the prognostic value of these markers remains controversial. The serum levels of carcinoembryonic antigen (CEA), nerve cell-specific enolase, and lactate dehydrogenase in 281 patients with small cell lung cancer (SCLC) were analyzed in this study. Increased serum CEA levels were observed in 92 (32.7%) patients. Survival was superior in patients with normal serum CEA levels compared with those with increased serum CEA levels. The median survival time, 2-year overall survival (OS) rate, and 3-year OS rate were 19.1 months vs 14.6 months, 42.7% vs 28.3%, and 30.6% vs 14.1%, respectively (P = 0.002). In multivariate analysis, extensive-stage (ES)-SCLC (hazard ratio [HR] = 1.936, P = 0.001), an increased serum CEA level (HR = 1.432, P = 0.021) at diagnosis, and <4 cycles of chemotherapy (ChT) (HR = 0.432, P = 0.001) were independent negative prognostic factors for the OS. Additionally, normal CEA level (HR = 1.678, P = 0.012), treatment modalities including surgery (HR = 1.595, P = 0.049), and >= 4 cycles of ChT (HR = 1.880, P = 0.004) were independent positive prognostic factors for OS in patients with local disease. In the subgroup with ES-SCLC, normal serum CEA level (HR = 1.608, P = 0.043), thoracic radiation therapy (HR = 1.744, P = 0.005), and >= 4 cycles of ChT (HR = 2.626, P = 0.001) were independent positive prognostic factors for OS. PMID- 25936591 TI - The tegmental-accumbal dopaminergic system mediates the anxiolytic effect of acupuncture during ethanol withdrawal. AB - This study investigated the involvement of the mesolimbic dopamine (DA) system in the anxiolytic effects of acupuncture during ethanol withdrawal (EW). Rats were intraperitoneally treated with 3g/kg/day of ethanol for 28 days and experienced 3 days of withdrawal. During EW, the rats were bilaterally treated with acupuncture at acupoints HT7 (Shenmen) or PC6 (Neiguan) or at a non-acupoint (tail) once daily for 1min over 3 days. High-performance liquid chromatographic (HPLC) analysis showed that EW significantly decreased both DA and 3,4 dihydroxyphenylacetic acid (DOPAC) levels in the nucleus accumbens shell (NaccSh); however, these processes were inhibited by acupuncture at HT7 but not at PC6. Real-time polymerase chain reaction and western blot assays also revealed that acupuncture at HT7 prevented the EW-induced reductions in tyrosine hydroxylase mRNA expression in the ventral tegmental area (VTA) and tyrosine hydroxylase protein expression in the NaccSh. A prior intra-NaccSh infusion of a cocktail of the selective DA1 receptor antagonist SCH23390 and the selective DA2 receptor antagonist eticlopride blocked the anxiolytic effect of acupuncture at HT7 in elevated plus maze tests. In addition, acupuncture at HT7 suppressed EW induced increased BDNF levels in the VTA. These findings suggest that acupuncture at HT7 improves the VTA-Nacc DAergic function via inhibition of BDNF expression in the VTA, thereby exerting anxiolytic effects during EW. PMID- 25936592 TI - Wistar Audiogenic Rats (WAR) exhibit altered levels of cytokines and brain derived neurotrophic factor following audiogenic seizures. AB - Increasing body of evidence suggests that inflammatory and neurotrophic factors might be important for epileptogenesis. Most animal studies demonstrated altered levels of these mediators in drug-induced models of seizures and epilepsy. In the present study, we investigated the production of cytokines and a neurotrophin in the brain of Wistar Audiogenic Rats (WAR), a genetic model of epilepsy, stimulated with high-intensity sound. Four hours after stimulation, animals were decapitated and the hippocampus, inferior colliculus, striatum and cortex were removed for evaluation of the levels of interleukin (IL)-1beta, IL-6, tumor necrosis factor (TNF)-alpha and brain derived neurotrophic factor (BDNF). All the cytokines and BDNF levels were increased in the cortex. Increased levels of TNF alpha and IL-6 were also observed in the striatum. Finally, TNF-alpha also increased in the inferior colliculus after the seizures induced by high-intensity sound. Although different studies have demonstrated that the levels of cytokines and BDNF increase in animal models of epilepsy induced by chemical stimuli, we provided here evidence that these mediators are also increased in WAR, a genetic model of epilepsy. Thus, the observed increase in these mediators might be involved in the pathophysiology of epilepsy. PMID- 25936593 TI - Potential interactions between pericytes and oligodendrocyte precursor cells in perivascular regions of cerebral white matter. AB - Pericytes are embedded within basal lamina and play multiple roles in the perivascular niche in brain. Recently, oligodendrocyte precursor cells (OPCs) have also been reported to associate with cerebral endothelium. Is it possible that within this gliovascular locus, there may also exist potential spatial and functional interactions between pericytes and OPCs? Here, we demonstrated that in the perivascular region of cerebral white matter, pericytes and OPCs may attach and support each other. Immunostaining showed that pericytes and OPCs are localized in close contact with each other in mouse white matter at postnatal days 0, 60 and 240. Electron microscopic analysis confirmed that pericytes attached to OPCs via basal lamina in the perivascular region. The close proximity between these two cell types was also observed in postmortem human brains. Functional interaction between pericytes and OPCs was assessed by in vitro media transfer experiments. When OPC cultures were treated with pericyte-conditioned media, OPC number increased. Similarly, pericyte number increased when pericytes were maintained in OPC-conditioned media. Taken together, our data suggest a potential anatomical and functional interaction between pericytes and OPCs in cerebral white matter. PMID- 25936595 TI - Flavonoids from Triticum aestivum inhibit adipogenesis in 3T3-L1 cells by upregulating the insig pathway. AB - The present study aimed to compare the potential anti-adipogenic effects and underlying mechanisms of the luteolin, isoscoparin and isoorientin flavonoids, purified from Triticum aestivum sprout (TA) in 3T3-L1 cells. The cells were treated with different concentrations of flavonoids for 8 days and the lipid accumulation was assessed using Oil-Red-O staining. The expression levels of the transcription factors and the genes involved in adipogenesis in the cells were assessed by reverse transcription-quantitative polymerase chain reaction and western blotting. The results demonstrated that 10 MUM luteolin, isoscoparin or isoorientin inhibited lipid deposition in the cells by 74, 63 and 65%, respectively. The flavonoids also significantly inhibited the transcriptional regulators of adipogenesis, including peroxisome proliferator-activated receptor gamma, CAAT/enhancer binding protein-alpha and sterol regulatory element binding protein (SREBP)-1c, compared with the control cells. Similarly, there was a significant downregulation of the adipocyte specific markers associated with lipid metabolism, including activating protein-2, fatty acid synthase, hormone sensitive lipase and lipoprotein lipase, in the flavonoid treated cells. Notably, the cells treated with the flavonoids demonstrated increased expression levels of the insulin-induced genes, insig-1 and insig-2, which may have inhibited the activation of the adipogenic transcription factor, SREBP, eventually leading to the inhibition of adipogenesis. Taken together, these results revealed that the flavonoids from TA possessed an inhibitory effect on adipogenesis through downregulation of adipogenic transcription factors and genes associated with lipid metabolism, and the upregulation of insig 1 and 2, suggesting that the flavonoids from TA may be potential therapeutic agents for the prevention and treatment of obesity. PMID- 25936594 TI - Genome wide identification of new genes and pathways in patients with both autoimmune thyroiditis and type 1 diabetes. AB - Autoimmune thyroid diseases (AITD) and Type 1 diabetes (T1D) frequently occur in the same individual pointing to a strong shared genetic susceptibility. Indeed, the co-occurrence of T1D and AITD in the same individual is classified as a variant of the autoimmune polyglandular syndrome type 3 (designated APS3v). Our aim was to identify new genes and mechanisms causing the co-occurrence of T1D + AITD (APS3v) in the same individual using a genome-wide approach. For our discovery set we analyzed 346 Caucasian APS3v patients and 727 gender and ethnicity matched healthy controls. Genotyping was performed using the Illumina Human660W-Quad.v1. The replication set included 185 APS3v patients and 340 controls. Association analyses were performed using the PLINK program, and pathway analyses were performed using the MAGENTA software. We identified multiple signals within the HLA region and conditioning studies suggested that a few of them contributed independently to the strong association of the HLA locus with APS3v. Outside the HLA region, variants in GPR103, a gene not suggested by previous studies of APS3v, T1D, or AITD, showed genome-wide significance (p < 5 * 10(-8)). In addition, a locus on 1p13 containing the PTPN22 gene showed genome wide significant associations. Pathway analysis demonstrated that cell cycle, B cell development, CD40, and CTLA-4 signaling were the major pathways contributing to the pathogenesis of APS3v. These findings suggest that complex mechanisms involving T-cell and B-cell pathways are involved in the strong genetic association between AITD and T1D. PMID- 25936596 TI - Low-fluence rate, long duration photodynamic therapy in glioma mouse model using organic light emitting diode (OLED). AB - BACKGROUND: The treatment of gliomas poses significant clinical challenges due to resistance to chemo and radiation therapy, and treatment side effects. Metronomic photodynamic therapy (mPDT), which involves long treatment time with low fluence rate and multiple or continuous photosensitizer administrations, has potential in treating gliomas without threatening the quality of life and has been demonstrated in rats and rabbits. mPDT in small animals such as mouse is not yet shown due to lack of lightweight illumination device for long periods of time. METHODS: We presented low fluence rate (3mW/cm(2)) and long duration (3.7h) PDT treatment in a nude mouse model of human glioblastoma by using organic light emitting diode (OLED) with single dose of 5-aminolevulinic acid (ALA) administration as photosensitizer. Tumor volume was measured using bioluminescent imaging and the animal survival time was recorded. Additionally, we have performed limited PDT dosimetric measurements of PpIX fluorescence, tumor oxygenation and hemoglobin concentration in 3 PDT mice. RESULTS: For animals with similar pre- and immediate post-light tumor volume, the averaged total survival time of PDT mice is 40.5+/-9.2 days that are significantly longer than the control mice (26.0+/-2.0 days). The post-light survival time of PDT mice is 14.3+/-5.9 days that are marginally longer than the control group (8.0+/-0.0 days). In the dosimetric measurement, good maintenance of PpIX fluorescence in one PDT mouse has relatively improved survival time, compared with the other two PDT mice (i.e., 24 days versus 16 and 17 days). CONCLUSIONS: This pilot study demonstrated the feasibility of low-fluence rate and long treatment time of ALA PDT using OLED without anesthetization of animals. The response of PDT treated animals with similar pre- and post-light tumor volume is encouraging to show a longer survival time than the controls. The dosimetric indices such as photosensitizer fluorescence and tissue oxygenation would help understand the possible treatment barriers for further improvement of treatment plans. PMID- 25936597 TI - A Phase 1/2 Trial of Brief Androgen Suppression and Stereotactic Radiation Therapy (FASTR) for High-Risk Prostate Cancer. AB - PURPOSE: To initiate a phase 1/2 trial to examine the tolerability of a condensed combined-modality protocol for high-risk prostate cancer. METHODS AND MATERIALS: Men scoring >=3 on the Vulnerable Elderly Scale (VES) or refusing conventionally fractionated treatment for high-risk prostate cancer were eligible to participate. Androgen suppression was delivered for 12 months, and radiation therapy was delivered using 25 Gy to pelvic nodes delivered synchronously with 40 Gy to the prostate given as 1 fraction per week over 5 weeks. The phase 1 component included predetermined stopping rules based on 6-month treatment related toxicity, with trial suspension specified if there were >=6 of 15 patients (40%) or >=3 of 15 (20%) who experienced grade >=2 or >=3 gastrointestinal (GI) or genitourinary (GU) toxicity, respectively. RESULTS: Sixteen men were enrolled, with 7 men meeting the criteria of VES >=3 and 9 men having a VES <3 but choosing the condensed treatment. One man was not treated owing to discovery of a synchronous primary rectal cancer. Four patients (26%) experienced grade >=2 toxicity at 6 weeks after treatment. There were 9 of 15 (60%) who experienced grade >=2 GI or GU toxicity and 4 of 15 (26%) grade >=3 GI or GU toxicity at 6 months, and 5 of 15 (30%) grade >=2 GI and GU toxicity at 6 months. A review of the 15 cases did not identify any remedial changes, thus the phase 1 criteria were not met. CONCLUSION: This novel condensed treatment had higher than anticipated late toxicities and was terminated before phase 2 accrual. Treatment factors, such as inclusion of pelvic lymph node radiation therapy, planning constraints, and treatment margins, or patient factors related to the specific frail elderly population may be contributing. PMID- 25936598 TI - Verification of Accuracy of CyberKnife Tumor-tracking Radiation Therapy Using Patient-specific Lung Phantoms. AB - PURPOSE: To investigate the accuracy of the CyberKnife Xsight Lung Tracking System (XLTS) compared with that of a fiducial-based target tracking system (FTTS) using patient-specific lung phantoms. METHODS AND MATERIALS: Three dimensional printing technology was used to make individualized lung phantoms that closely mimicked the lung anatomy of actual patients. Based on planning computed tomographic data from 6 lung cancer patients who underwent stereotactic ablative radiation therapy using the CyberKnife, the volume above a certain Hounsfield unit (HU) was assigned as the structure to be filled uniformly with polylactic acid material by a 3-dimensional printer (3D Edison, Lokit, Korea). We evaluated the discrepancies between the measured and modeled target positions, representing the total tracking error, using 3 log files that were generated during each treatment for both the FTTS and the XLTS. We also analyzed the gamma index between the film dose measured under the FTTS and XLTS. RESULTS: The overall mean values and standard deviations of total tracking errors for the FTTS were 0.36 +/- 0.39 mm, 0.15 +/- 0.64 mm, and 0.15 +/- 0.62 mm for the craniocaudal (CC), left-right (LR), and anteroposterior (AP) components, respectively. Those for the XLTS were 0.38 +/- 0.54 mm, 0.13 +/- 0.18 mm, and 0.14 +/- 0.37 mm for the CC, LR, and AP components, respectively. The average of gamma passing rates was 100% for the criteria of 3%, 3 mm; 99.6% for the criteria of 2%, 2 mm; and 86.8% for the criteria of 1%, 1 mm. CONCLUSIONS: The XLTS has segmentation accuracy comparable with that of the FTTS and small total tracking errors. PMID- 25936600 TI - High expression of PKM2 as a poor prognosis indicator is associated with radiation resistance in cervical cancer. AB - Our study aimed to investigate the association of Pyruvate Kinase isozyme type M2 (PKM2) with radiation resistance in locally advanced cervical squamous cell carcinoma (LACSCC). We retrospectively reviewed 132 female patients who received primary radiation therapy to treat LACSCC at Federation Internationale of Gynecologie and Obstetrigue (FIGO) stages IB-IVA. Forty-seven patients with progression free survival (PFS) of less than 36 months were regarded to have radiation resistance. Eighty-five patients with PFS no less than 36 months were regarded as radiation sensitive. Using immunohistochemistry, we found that the overexpression rate of PKM2 in radiation resistant and radiation sensitive patients was 87.2% and 57.6%, respectively, and the difference was statistically significant (p<0.001). The 5-year progress free survival rates in patients with low and high expression of PKM2 was 80.4% and 60.5%, respectively, and the difference was statistically significant (p=0.008). Multivariate Cox regression analysis identified that high expression of PKM2 is an independent negative prognostic factor in cervical cancer patients [Hazard ratio (95% CI), 2.888 (1.347, 6.194) p=0.006]. These results demonstrate that overexpression of PKM2 contributes to radiation resistance and acts a poor prognosis indicator in patients with LACSCC. PMID- 25936599 TI - A Validated Prediction Model for Overall Survival From Stage III Non-Small Cell Lung Cancer: Toward Survival Prediction for Individual Patients. AB - PURPOSE: Although patients with stage III non-small cell lung cancer (NSCLC) are homogeneous according to the TNM staging system, they form a heterogeneous group, which is reflected in the survival outcome. The increasing amount of information for an individual patient and the growing number of treatment options facilitate personalized treatment, but they also complicate treatment decision making. Decision support systems (DSS), which provide individualized prognostic information, can overcome this but are currently lacking. A DSS for stage III NSCLC requires the development and integration of multiple models. The current study takes the first step in this process by developing and validating a model that can provide physicians with a survival probability for an individual NSCLC patient. METHODS AND MATERIALS: Data from 548 patients with stage III NSCLC were available to enable the development of a prediction model, using stratified Cox regression. Variables were selected by using a bootstrap procedure. Performance of the model was expressed as the c statistic, assessed internally and on 2 external data sets (n=174 and n=130). RESULTS: The final multivariate model, stratified for treatment, consisted of age, gender, World Health Organization performance status, overall treatment time, equivalent radiation dose, number of positive lymph node stations, and gross tumor volume. The bootstrapped c statistic was 0.62. The model could identify risk groups in external data sets. Nomograms were constructed to predict an individual patient's survival probability (www.predictcancer.org). The data set can be downloaded at https://www.cancerdata.org/10.1016/j.ijrobp.2015.02.048. CONCLUSIONS: The prediction model for overall survival of patients with stage III NSCLC highlights the importance of combining patient, clinical, and treatment variables. Nomograms were developed and validated. This tool could be used as a first building block for a decision support system. PMID- 25936601 TI - Rapamycin increases neuronal survival, reduces inflammation and astrocyte proliferation after spinal cord injury. AB - Spinal cord injury (SCI) frequently leads to a permanent functional impairment as a result of the initial injury followed by secondary injury mechanism, which is characterised by increased inflammation, glial scarring and neuronal cell death. Finding drugs that may reduce inflammatory cell invasion and activation to reduce glial scarring and increase neuronal survival is of major importance for improving the outcome after SCI. In the present study, we examined the effect of rapamycin, an mTORC1 inhibitor and an inducer of autophagy, on recovery from spinal cord injury. Autophagy, a process that facilitates the degradation of cytoplasmic proteins, is also important for maintenance of neuronal homeostasis and plays a major role in neurodegeneration after neurotrauma. We examined rapamycin effects on the inflammatory response, glial scar formation, neuronal survival and regeneration in vivo using spinal cord hemisection model in mice, and in vitro using primary cortical neurons and human astrocytes. We show that a single injection of rapamycin, inhibited p62/SQSTM1, a marker of autophagy, inhibited mTORC1 downstream effector p70S6K, reduced macrophage/neutrophil infiltration into the lesion site, microglia activation and secretion of TNFalpha. Rapamycin inhibited astrocyte proliferation and reduced the number of GFAP expressing cells at the lesion site. Finally, it increased neuronal survival and axonogenesis towards the lesion site. Our study shows that rapamycin treatment increased significantly p-Akt levels at the lesion site following SCI. Similarly, rapamycin treatment of neurons and astrocytes induced p-Akt elevation under stress conditions. Together, these findings indicate that rapamycin is a promising candidate for treatment of acute SCI condition and may be a useful therapeutic agent. PMID- 25936603 TI - Septic arthritis in adults in a tertiary care center. AB - OBJECTIVE: To describe the history, clinical features and microorganisms involved in a group of adult subjects with and without septic arthritis (SA) at a tertiary care in Mexico. MATERIAL AND METHODS: A cross-sectional descriptive study was conducted on 96 adults with clinical suspicion of AS in one or more joints. In all cases synovial fluid arthrocentesis and culture was performed. The comparison group subjects were culture negative. A descriptive statistical analysis and binary logistic regression model was performed between the variables associated with the development of AS. A value of P<=.05 was significant. RESULTS: A total of 49 out of 96 subjects had a positive culture, mostly of the monoarticular type (96%; P=.02). The knee was the most common site (61%; P=.06) and pain was the main clinical manifestation (59%; P=.001). Staphylococcus was the most common etiological agent (65%; P<.001). The risk factors revealed in the final regression model were SA the history of joint disease (OR=25; P=.03) and volume increase (OR=13.16; P=.06). Functional limitation (OR=8.54; P=.04) showed a significant risk among borderline for SA. CONCLUSIONS: Our results are consistent with previous studies, and can be generalized to geographical areas with similar clinical features to those observed in this study. PMID- 25936602 TI - Dopamine transporter is enriched in filopodia and induces filopodia formation. AB - Dopamine transporter (DAT, SLC6A3) controls dopamine (DA) neurotransmission by mediating re-uptake of extracellular DA into DA neurons. DA uptake depends on the amount of DAT at the cell surface, and is therefore regulated by DAT subcellular distribution. Hence we used spinning disk confocal microscopy to demonstrate DAT localization in membrane protrusions that contained filamentous actin and myosin X (MyoX), a molecular motor located in filopodia tips, thus confirming that these protrusions are filopodia. DAT was enriched in filopodia. In contrast, R60A and W63A DAT mutants with disrupted outward-facing conformation were not accumulated in filopodia, suggesting that this conformation is necessary for DAT filopodia targeting. Three independent approaches of filopodia counting showed that DAT expression leads to an increase in the number of filopodia per cell, indicating that DAT can induce filopodia formation. Depletion of MyoX by RNA interference resulted in a significant loss of filopodia but did not completely eliminate filopodia, implying that DAT-enriched filopodia can be formed without MyoX. In cultured postnatal DA neurons MyoX was mainly localized to growth cones that displayed highly dynamic DAT-containing filopodia. We hypothesize that the concave shape of the DAT molecule functions as the targeting determinant for DAT accumulation in outward-curved membrane domains, and may also allow high local concentrations of DAT to induce an outward membrane bending. Such targeting and membrane remodeling capacities may be part of the mechanism responsible for DAT enrichment in the filopodia and its targeting to the axonal processes of DA neurons. PMID- 25936604 TI - Knee hemarthros secondary to osteochondritis dissecans (Konig disease). AB - A case is presented of a hemarthrosis associated with osteochondritis dissecans in a young man who arrived in the Emergency unit due to tender and swelling of his right knee one hour after a slightly rotational gesture of the lower limb. Many years before the patient suffered a sports injury in the same knee, but it was never assessed. Radiography studies showed bone fragments inside the synovial capsule, and the joint aspiration was compatible with hemarthrosis. A review of the available information of this uncommon condition is also presented. PMID- 25936605 TI - Periarticular nodules, arthritis and chronic nephropathy. PMID- 25936606 TI - The pros and cons of vertebrate animal models for functional and therapeutic research on inherited retinal dystrophies. AB - Over the last decade, huge progress has been made in the understanding of the molecular mechanisms underlying inherited retinal dystrophy (IRD), as well as in the development and implementation of novel therapies, especially in the field of gene therapy. The use of mutant animal models, either naturally occurring or generated by genetic modification, have contributed greatly to our knowledge on IRD. Yet, these mutant animal models do not always mimic the retinal phenotype that is observed in humans with mutations in the orthologous gene, often due to species-specific characteristics of the retina, and/or diverse functions of the gene products in different species. In this manuscript, we compare general and ocular characteristics of a series of widely used vertebrate animal models, i.e. zebrafish, chicken, rodents, cats, dogs, sheep, pigs and monkeys, in terms of genetic architecture and sequence homology, methods to modify genomes, anatomy of the eye, and structural details of the retina. Furthermore, we present an overview of mutant vertebrate animal models that have been used to study or develop treatments for the various genetic subtypes of IRD, and correlate the suitability of these models to the specific characteristics of each animal. Herewith, we provide tools that will help to select the most suitable animal model for specific research questions on IRDs in the future, and thereby assist in an optimal use of animals and resources to further increase our understanding of inherited retinal dystrophies, and develop novel treatments for these disorders. PMID- 25936607 TI - Autoimmune mechanisms in pernicious anaemia & thyroid disease. AB - Pernicious anaemia (PA) and some types of thyroid disease result from autoimmune processes. The autoimmune mechanisms in these conditions have not been fully elucidated. This review discusses the autoimmune mechanisms involved in PA and how these affect diagnosis and disease progression. In addition to gastric antibodies, antibodies to the vitamin B12 binding protein transcobalamin which can result in high serum B12 levels are also addressed with regard to how they affect clinical practice. The role of autoimmune susceptibility is investigated by comparing PA to one of its most common comorbidities, autoimmune thyroid disease (AITD). Thyroid disease (although not exclusively AITD) and B12 deficiency are both also implicated in the pathology of hyperhomocysteinemia, an elevated homocysteine in plasma. Since hyperhomocysteinemia is a risk factor for cardiovascular occlusive disease, this review also addresses how thyroid disease in particular leads to changes in homocysteine levels. PMID- 25936608 TI - Recommendations on the use of biosimilars by the Brazilian Society of Rheumatology, Brazilian Society of Dermatology, Brazilian Federation of Gastroenterology and Brazilian Study Group on Inflammatory Bowel Disease--Focus on clinical evaluation of monoclonal antibodies and fusion proteins used in the treatment of autoimmune diseases. AB - The Brazilian Societies of Rheumatology (SBR) and Dermatology (SBD), the Brazilian Federation of Gastroenterology (FBG) and the Brazilian Study Group on Inflammatory Bowel Disease (GEDIIB) gathered a group of their respective specialists on the topic of interest to discuss the most relevant issues regarding the clinical use of biosimilar medicines in Brazil. The main aim of that meeting was to prepare a document with recommendations to guide medical specialists and to help the national regulatory and policy-making agencies as concerns the authorization for marketing biosimilars used in autoimmune diseases, such as rheumatoid arthritis, ankylosing spondylitis, psoriatic arthritis, Crohn's disease, juvenile idiopathic arthritis and ulcerative colitis. In addition to considerations on the typical differences between innovator medicines and biosimilars, the specialists established a set of seven recommendations on regulatory advances related to clinical studies, indication extrapolation, nomenclature, interchangeability, automatic substitution and pharmacovigilance. PMID- 25936609 TI - The novel anti-neuroblastoma agent PF403, inhibits proliferation and invasion in vitro and in brain xenografts. AB - Neuroblastoma is the most common cancer in infants and the fourth most common cancer in children. Our previous study showed that PF403 had a potent antitumor ability. In the present study, we evaluated the anti-neuroblastoma property of PF403 and investigated the underlying mechanisms. MTT assay, colony formation assay and flow cytometry assay were used to assess cytotoxicity of PF403 on SH SY5Y cells. Transwell assay was chosen to estimate the anti-invasion ability of PF403 on neuroblastoma cells. The protein expression was detected by western blot analysis. The SH-SY5Y brain xenograft model was used to assess in vivo antitumor activity of PF403. PF403-mediated SH-SY5Y cell death was found to be dose- and time-dependent, and PF403 was able to limit invasion and metastasis of neuroblastoma cells. MRI and pathology analysis proved that the pro-drug of PF403, CAT3, inhibited SH-SY5Y cells in vivo. PF403 decreased expression of phosphorylated FAK, MMP-2 and MMP-9 proteins, and downregulated the activity of PI3K/AKT and Raf/ERK pathways, followed by regulation of the proteins expression of Bcl-2 family, activated caspase-3, -9 and PARP and initiation of apoptosis of neuroblastoma cells. PF403 exerted cytotoxicity against SH-SY5Y neuroblastoma cell both in vitro and in vivo, and inhibited its invasion ability, suggesting PF403 has potential as a new anticancer drug for the treatment of neuroblastoma. PMID- 25936610 TI - Shigella flexneri serotype 3a: the rise of a superbug. PMID- 25936611 TI - Intercontinental dissemination of azithromycin-resistant shigellosis through sexual transmission: a cross-sectional study. AB - BACKGROUND: Shigellosis is an acute, severe bacterial colitis that, in high income countries, is typically associated with travel to high-risk regions (Africa, Asia, and Latin America). Since the 1970s, shigellosis has also been reported as a sexually transmitted infection in men who have sex with men (MSM), in whom transmission is an important component of shigellosis epidemiology in high-income nations. We aimed to use sophisticated subtyping and international sampling to determine factors driving shigellosis emergence in MSM linked to an outbreak in the UK. METHODS: We did a large-scale, cross-sectional genomic epidemiological study of shigellosis cases collected from 29 countries between December, 1995, and June 8, 2014. Focusing on an ongoing epidemic in the UK, we collected and whole-genome sequenced clinical isolates of Shigella flexneri serotype 3a from high-risk and low-risk regions, including cases associated with travel and sex between men. We examined relationships between geographical, demographic, and clinical patient data with the isolate antimicrobial susceptibility, genetic data, and inferred evolutionary relationships. FINDINGS: We obtained 331 clinical isolates of S flexneri serotype 3a, including 275 from low-risk regions (44 from individuals who travelled to high-risk regions), 52 from high-risk regions, and four outgroup samples (ie, closely related, but genetically distinct isolates used to determine the root of the phylogenetic tree). We identified a recently emerged lineage of S flexneri 3a that has spread intercontinentally in less than 20 years throughout regions traditionally at low risk for shigellosis via sexual transmission in MSM. The lineage had acquired multiple antimicrobial resistance determinants, and prevailing sublineages were strongly associated with resistance to the macrolide azithromycin. Eight (4%) of 206 isolates from the MSM-associated lineage were obtained from patients who had previously provided an isolate; these serial isolations indicated atypical infection patterns (eg, reinfection). INTERPRETATION: We identified transmission facilitating behaviours and atypical course(s) of infection as precipitating factors in shigellosis-affected MSM. The intercontinental spread of antimicrobial resistant shigella through established transmission routes emphasises the need for new approaches to tackle the public health challenge of sexually transmitted infections in MSM. FUNDING: Wellcome Trust (grant number 098051). PMID- 25936612 TI - Aspirin-exacerbated respiratory disease: characteristics and management strategies. AB - Aspirin-exacerbated respiratory disease is a clinical entity comprising chronic rhinosinusitis with nasal polyposis, asthma and intolerance to COX-1 inhibiting drugs. The pathogenesis is not completely understood at this point, but abnormal arachidonic acid metabolism is a key feature in this syndrome. The diagnosis is confirmed only by direct drug challenge. Aspirin desensitization followed by daily aspirin therapy is a useful treatment option in these patients. In this review article are discussed the important characteristics and treatment of aspirin-exacerbated respiratory disease. PMID- 25936613 TI - Satisfaction with medical care in patients with atrial fibrillation treated with vitamin K antagonists versus new oral anticoagulants. PMID- 25936614 TI - Constrictive Pericarditis: Etiologic Spectrum, Patterns of Clinical Presentation, Prognostic Factors, and Long-term Follow-up. AB - INTRODUCTION AND OBJECTIVES: Some reports have described a change in the etiologic spectrum of constrictive pericarditis. In addition, data on the relationship between its clinical presentation and etiology are lacking. We sought to describe the etiologies of the disease, their relationship with its clinical presentation and surgical findings, and to identify predictors of poor outcome. METHODS: We analyzed 140 consecutive patients who underwent surgery for constrictive pericarditis over a 34-year period in a single center. RESULTS: The etiology was idiopathic in 76 patients (54%), acute idiopathic pericarditis in 24 patients (17%), tuberculous pericarditis in 15 patients (11%), purulent pericarditis in 10 patients (7%), and cardiac surgery, radiation and uremia in 5, 3 and 2 patients respectively (4%, 2% and 1%). Mean duration of symptoms before pericardiectomy was 19 months (standard deviation, 44 months), the most acute presentation being for purulent pericarditis (26 days [range, 7-60 days]) and the most chronic for idiopathic cases (29 months [range, 4 days-360 months]). Perioperative mortality was 11%. There was no difference in mortality between etiologies. Median follow-up was 12 years (range, 0.1-33.0 years) in which 50 patients died. In a Cox-regression analysis, age at surgery, advanced New York Heart Association functional class (III to IV) and previous acute idiopathic pericarditis were associated with increased mortality during follow-up. CONCLUSIONS: Most cases of constrictive pericarditis are idiopathic. Cardiac surgery and radiation accounted for a minority of cases. Etiologic investigations are warranted only in acute or subacute presentations. Age, advanced functional class, and previous acute idiopathic pericarditis are associated with increased mortality. PMID- 25936615 TI - Diffuse Coronary Artery Disease Not Amenable to Revascularization: Long-term Prognosis. PMID- 25936616 TI - Life away from the coverslip: Comment on "Extracting physics of life at the molecular level: A review of single-molecule data analyses" by W. Colomb and S.K. Sarkar. PMID- 25936617 TI - Systems mapping has potential to overcome inherent problems of genetic mapping: Comment on "Mapping complex traits as a dynamic system" by L. Sun and R. Wu. PMID- 25936618 TI - Musical rhythm and affect: Comment on "The quartet theory of human emotions: An integrative and neurofunctional model" by S. Koelsch et al. PMID- 25936619 TI - The difference between emotion and affect: Comment on "The quartet theory of human emotions: An integrative and neurofunctional model" by S. Koelsch et al. PMID- 25936620 TI - Response to "Failed epilepsy surgery: It is not too late". PMID- 25936621 TI - Improved normal tissue protection by proton and X-ray microchannels compared to homogeneous field irradiation. AB - The risk of developing normal tissue injuries often limits the radiation dose that can be applied to the tumour in radiation therapy. Microbeam Radiation Therapy (MRT), a spatially fractionated photon radiotherapy is currently tested at the European Synchrotron Radiation Facility (ESRF) to improve normal tissue protection. MRT utilizes an array of microscopically thin and nearly parallel X ray beams that are generated by a synchrotron. At the ion microprobe SNAKE in Munich focused proton microbeams ("proton microchannels") are studied to improve normal tissue protection. Here, we comparatively investigate microbeam/microchannel irradiations with sub-millimetre X-ray versus proton beams to minimize the risk of normal tissue damage in a human skin model, in vitro. Skin tissues were irradiated with a mean dose of 2 Gy over the irradiated area either with parallel synchrotron-generated X-ray beams at the ESRF or with 20 MeV protons at SNAKE using four different irradiation modes: homogeneous field, parallel lines and microchannel applications using two different channel sizes. Normal tissue viability as determined in an MTT test was significantly higher after proton or X-ray microchannel irradiation compared to a homogeneous field irradiation. In line with these findings genetic damage, as determined by the measurement of micronuclei in keratinocytes, was significantly reduced after proton or X-ray microchannel compared to a homogeneous field irradiation. Our data show that skin irradiation using either X-ray or proton microchannels maintain a higher cell viability and DNA integrity compared to a homogeneous irradiation, and thus might improve normal tissue protection after radiation therapy. PMID- 25936622 TI - An effective model of blood flow in capillary beds. AB - In this article we derive applicable expressions for the macroscopic compliance and resistance of microvascular networks. This work yields a lumped-parameter model to describe the hemodynamics of capillary beds. Our derivation takes into account the multiscale nature of capillary networks, the influence of blood volume and pressure on the effective resistance and compliance, as well as, the nonlinear interdependence between these two properties. As a result, we obtain a simple and useful model to study hypotensive and hypertensive phenomena. We include two implementations of our theory: (i) pulmonary hypertension where the flow resistance is predicted as a function of pulmonary vascular tone. We derive from first-principles the inverse proportional relation between resistance and compliance of the pulmonary tree, which explains why the RC factor remains nearly constant across a population with increasing severity of pulmonary hypertension. (ii) The critical closing pressure in pulmonary hypotension where the flow rate dramatically decreases due to the partial collapse of the capillary bed. In both cases, the results from our proposed model compare accurately with experimental data. PMID- 25936623 TI - Suberin fatty acids isolated from outer birch bark improve moisture barrier properties of cellulose ether films intended for tablet coatings. AB - We showed that the addition of suberin fatty acids (SFAs) even at small concentrations significantly improves the water vapor barrier properties of hydroxypropyl methylcellulose (HPMC) films. SFAs were isolated from the outer birch bark using extractive hydrolysis. The effects of SFAs on the film formation of aqueous HPMC were investigated with free films plasticized with polyethylene glycol (PEG 400). Special attention was paid on the physical solid-state, moisture barrier and mechanical stress-strain properties of films intended for tablet film coatings. Topography and surface morphology, glass transition temperature (Tg), tensile strength, Young's modulus, and water vapor permeation (WVP) of films were studied. The addition of SFAs lowered the Tg of films suggesting partial enhancement in film plasticization. The WVP of films decreased with increasing SFAs concentration up to 15% (calculated as a % w/w from a polymer weight). The WVP value for a non-suberized reference film and suberized film plasticized with PEG 400 was 2.13*10(-6) and 0.69[*10(-6) g/(mm(2)*h)*mm/Pa], respectively. The addition of SFAs impaired the mechanical stress-strain properties of HPMC films by reducing the deformation capacity of film. In conclusion, the film properties and performance of aqueous HPMC can be modified by including SFAs in the films. PMID- 25936624 TI - Evaluation of a combined drug-delivery system for proteins assembled with polymeric nanoparticles and porous microspheres; characterization and protein integrity studies. AB - This work presents an evaluation of the adsorption/infiltration process in relation to the loading of a model protein, alpha-amylase, into an assembled biodegradable polymeric system, free of organic solvents and made up of poly(D,L lactide-co-glycolide) acid (PLGA). Systems were assembled in a friendly aqueous medium by adsorbing and infiltrating polymeric nanoparticles into porous microspheres. These assembled systems are able to load therapeutic amounts of the drug through adsorption of the protein onto the large surface area characteristic of polymeric nanoparticles. The subsequent infiltration of nanoparticles adsorbed with the protein into porous microspheres enabled the controlled release of the protein as a function of the amount of infiltrated nanoparticles, since the surface area available on the porous structure is saturated at different levels, thus modifying the protein release rate. Findings were confirmed by both the BET technique (N2 isotherms) and in vitro release studies. During the adsorption process, the pH of the medium plays an important role by creating an environment that favors adsorption between the surfaces of the micro- and nano-structures and the protein. Finally, assays of alpha-amylase activity using 2-chloro-4 nitrophenyl-alpha-D-maltotrioside (CNP-G3) as the substrate and the circular dichroism technique confirmed that when this new approach was used no conformational changes were observed in the protein after release. PMID- 25936625 TI - Targeted and controlled release delivery of daunorubicin to T-cell acute lymphoblastic leukemia by aptamer-modified gold nanoparticles. AB - Clinical administration of daunorubicin (Dau) in treatment of leukemia has been limited by its cardiotoxicity. Targeted delivery of chemotherapy drugs could reduce their side effects and increase the therapeutic efficacy of these drugs. Biocompatibility and large surface area of gold nanoparticles (AuNPs) make these nanoparticles great candidates for biomedical applications. In this study sgc8c aptamer (Apt)-Dau-AuNPs complex was designed and evaluated for treatment of Molt 4 cells (human acute lymphoblastic leukemia T-cell, target). Apt-Dau-AuNPs complex formation was analyzed by fluorometric analysis and gel retardation assay. Dau release profiles from the complex were evaluated in pHs 5.5 and 7.4. For cytotoxic studies (MTT assay) U266 (B lymphocyte human myeloma, nontarget) and Molt-4 cells (target) were treated with Dau Apt-Dau conjugate and Apt-Dau AuNPs complex. Internalization was monitored by flow cytometry and confocal imaging. 12 MUM Dau was efficiently loaded onto 1 mL of Apt-modified AuNPs. Dau was released from the complex in a pH-dependent manner (higher rate of release at pH 5.5). The results of flow cytometry analysis and confocal imaging showed that the complex was effectively internalized into Molt-4 cells, but not into U266 cells. The results of MTT assay also confirmed the internalization data. Apt-Dau AuNPs complex was less cytotoxic in U266 cells compared to Dau alone and even Apt Dau conjugate. The complex was more cytotoxic in target cells in comparison with Dau alone and even Apt-Dau conjugate. In conclusion, Apt-Dau-AuNPs complex was able to selectively target Molt-4 cells. Another advantage of this system was pH dependent release of drug from the complex. Furthermore, this complex has characteristics which make it ideal for clinical use. PMID- 25936626 TI - Preparation, characterization and in vivo evaluation of curcumin self-nano phospholipid dispersion as an approach to enhance oral bioavailability. AB - The aim of this study was to examine the efficacy of self-nano phospholipid dispersions (SNPDs) based on Phosal((r)) to improve the oral bioavailability of curcumin (CUR). SNPDs were prepared with Phosal((r)) 53 and Miglyol 812 at different surfactant ratio. Formulations were evaluated for particle size, polydispersity index, zeta potential, and robustness toward dilution, TEM as well as in vitro drug release. The in vivo oral absorption of selected formulations in comparison to drug suspension was evaluated in rats. Moreover, formulations were assessed for in vitro characteristic changes before and after storage. The SNPDs were miscible with water in any ratio and did not show any phase separation or drug precipitation. All the formulas were monodisperse with nano range size from 158+/-2.6 nm to 610+/-6.24 nm. They passed the pharmacopeial tolerance for CUR dissolution. No change in dissolution profile and physicochemical characteristics was detected after storage. CUR-SNPDs are found to be more bioavailable compared with suspension during an in vivo study in rats and in vitro release studies failed to imitate the in vivo conditions. These formulations might be new alternative carriers that enhance the oral bioavailability of poorly water soluble molecules, such as CUR. PMID- 25936627 TI - Adult-onset tumour necrosis factor receptor-associated periodic syndrome presenting with refractory chronic arthritis. PMID- 25936629 TI - AMAROS Study: Overall Survival in Breast Cancer Subtypes. PMID- 25936628 TI - Statistical structure of neural spiking under non-Poissonian or other non-white stimulation. AB - Nerve cells in the brain generate sequences of action potentials with a complex statistics. Theoretical attempts to understand this statistics were largely limited to the case of a temporally uncorrelated input (Poissonian shot noise) from the neurons in the surrounding network. However, the stimulation from thousands of other neurons has various sorts of temporal structure. Firstly, input spike trains are temporally correlated because their firing rates can carry complex signals and because of cell-intrinsic properties like neural refractoriness, bursting, or adaptation. Secondly, at the connections between neurons, the synapses, usage-dependent changes in the synaptic weight (short-term plasticity) further shape the correlation structure of the effective input to the cell. From the theoretical side, it is poorly understood how these correlated stimuli, so-called colored noise, affect the spike train statistics. In particular, no standard method exists to solve the associated first-passage-time problem for the interspike-interval statistics with an arbitrarily colored noise. Assuming that input fluctuations are weaker than the mean neuronal drive, we derive simple formulas for the essential interspike-interval statistics for a canonical model of a tonically firing neuron subjected to arbitrarily correlated input from the network. We verify our theory by numerical simulations for three paradigmatic situations that lead to input correlations: (i) rate-coded naturalistic stimuli in presynaptic spike trains; (ii) presynaptic refractoriness or bursting; (iii) synaptic short-term plasticity. In all cases, we find severe effects on interval statistics. Our results provide a framework for the interpretation of firing statistics measured in vivo in the brain. PMID- 25936630 TI - Formulation of Convenient, Easily Scalable, and Efficient Granisetron HCl Intranasal Droppable Gels. AB - Deacetylated gellan gum and two sodium alginate polymer types were used each at three concentrations in the suitable range for their sol-gel transition. The prepared nine droppable gels were evaluated in vitro, ex vivo through sheep nasal mucosa, as well as in vivo in comparison to drug solution given intravenously and orally at the same dose. The prepared formulas gelled instantaneously in simulated nasal fluid and the obtained gels sustained their shear thinning and thixotropic behavior up to 48 h. Polymer type and concentration had significant effects on the apparent viscosities and the in vitro release profile of granisetron from the prepared gels. The drug release data best fitted a modified Higuchi equation with initial burst and followed Fickian diffusion mechanism. A 0.5% gellan-gum-based formula sustained the in vitro drug release up to 3 h and enhanced the drug permeation without need for an enhancer. The histopatholgical study revealed the safety of the tested formula. Intranasal delivery recorded double the drug bioavailabilty in comparison to the oral route. It had an absolute bioavailability of 0.6539 and the maximum plasma drug concentration reached after 1.5 h. The developed formula could be promising for the management of chemotherapy-induced nausea and vomiting regarding its improved bioavailability, patient acceptability, and ease of production. PMID- 25936631 TI - Drosophila melanogaster Hedgehog cooperates with Frazzled to guide axons through a non-canonical signalling pathway. AB - We report that the morphogen Hedgehog (Hh) is an axonal chemoattractant in the midline of Drosophila melanogaster embryos. Hh is present in the ventral nerve cord during axonal guidance and overexpression of hh in the midline causes ectopic midline crossing of FasII-positive axonal tracts. In addition, we show that Hh influences axonal guidance via a non-canonical signalling pathway dependent on Ptc. Our results reveal that the Hh pathway cooperates with the Netrin/Frazzled pathway to guide axons through the midline in invertebrates. PMID- 25936632 TI - Dramatic reduction of clindamycin serum concentration in staphylococcal osteoarticular infection patients treated with the oral clindamycin-rifampicin combination. AB - OBJECTIVES: Pharmacokinetics of clindamycin in combination with rifampicin or levofloxacin were prospectively evaluated for the oral treatment of severe staphylococcal osteo articular infections. METHODS: Thirty-four patients (25 males, 9 females), with a mean age of 52.4 +/- 17 years (range, 24-81 years), were randomly assigned either to the clindamycin-rifampicin or to the clindamycin levofloxacin arm (control), following surgical debridement and intravenous adapted treatment. Trough and peak serum concentrations of clindamycin were measured at day-1 (D1), D15 and D30 of oral treatment. Cure was evaluated at a minimum of one year after the initiation of treatment. RESULTS: The oral treatment was interrupted in 4 cases because of adverse events. Mean trough and peak serum concentrations of clindamycin in the clindamycin-rifampicin arm were lower than in the clindamycin-levofloxacin arm during the time of oral antibiotic regimen (0.79 +/- 0.3 MUg/ml vs 4.7 +/- 1.2 MUg/ml, p < 0.001, and 3.48 +/- 1.1 MUg/ml vs 10.2 +/- 1.8 MUg/ml, p < 0.001, respectively). A consistent decrease in clindamycin serum concentration was observed at each time-point of follow-up. At a mean of 23 +/- 7.8 months (range, 12-47 months), 24 patients were available for clinical evaluation. No difference could be detected in the cure rates between the groups. CONCLUSIONS: Our results indicate a significant influence of rifampicin on clindamycin pharmacokinetics using the oral route. Clindamycin serum concentrations (trough and peak) were systematically below the recommended therapeutic ranges when associated with rifampicin, as opposed to the control. Considering the potential risk of selection of mutant resistant to clindamycin, we do not recommend the clindamycin-rifampicin combination in the oral treatment of severe staphylococcal osteoarticular infection, unless clindamycin serum concentration is thoroughly controlled. The study has been registered on the clinicaltrials.gov website under the number NCT 01500837. PMID- 25936633 TI - Altered cytokine profiles in children with indeterminate quantiferon results and common infections. AB - OBJECTIVES: An increased rate of indeterminate quantiferon results (low IFN-gamma release in the phytohemagglutinin-stimulated tube) has been reported in children with clinical signs compatible with tuberculosis but with the final diagnosis of infectious diseases different from tuberculosis. Here, we addressed the mechanisms involved and assessed potential alternative biomarkers to overcome indeterminate quantiferon results under these conditions. METHODS: Cytokine concentrations were measured in residual plasma from quantiferon assays performed in immunocompetent children (cases, median age: 3 years 9 months) with indeterminate results and community acquired pneumonia (n = 7) or meningoencephalitis (n = 1). Controls were age-matched immunocompetent children with determinate quantiferon results (infected with mycobacterium tuberculosis, n = 7 or not, n = 8). RESULTS: Lower IFN-gamma expression in phytohemagglutinin stimulated cultures from cases was accompanied by lower Th1 (IL-2, TNF-alpha, IP 10) and Th2 (IL-5, IL-13), but similar IL-10 secretion capacities as the controls. CONCLUSIONS: A state of hyporesponsiveness that resembles the concept of immunoparalysis in severe infection was observed in children with milder infections. Though IP-10, IL-2, IL-5 and IL-13 were confirmed as promising alternative biomarkers for discriminating controls with and without tuberculosis in this study, defective induction of these biomarkers by phytohemagglutinin in cases precluded their usefulness in overcoming quantiferon indeterminate results in the above-mentioned clinical conditions. PMID- 25936634 TI - A combination of topographic and pachymetric parameters in keratoconus diagnosis. AB - PURPOSE: To evaluate the utility of topographic and pachymetric parameters of Scheimpflug system in keratoconus diagnosis. METHODS: This study included 183 eyes of 183 patients with keratoconus (keratoconus group) and 131 eyes of 131 age and sex-matched healthy subjects (control group). Mean keratometry (K, front), topographic astigmatism, pupil-center pachymetry, apical pachymetry, thinnest pachymetry (TP), corneal volume and maximum K (Kmax) were obtained from the Scheimpflug imaging system. A receiver operating characteristic (ROC) analysis was performed and area under the curve (AUC) was calculated to determine the diagnostic ability of each parameter in eyes with <= stage 3, <= stage 2 and stage 1 keratoconus based on the Amsler-Krumeich grading system. RESULTS: The Kmax and TP showed the highest individual performance (with sensitivity specificity of 92.9-92.4% and 89.6-93.3%, respectively) in diagnosis of keratoconus. The AUCs and sensitivity-specificity values for the Kmax/TP and Kmax(2)/TP were calculated to improve the diagnostic performance. As expected, sensitivity-specificity values significantly increased by using Kmax/TP (97.3 94.7% at the level >=0.08) and Kmax(2)/TP (99.5-95.7% at the level >=4.1) in discrimination of keratoconic eyes from normals. Moreover, Kmax(2)/TP had very high sensitivity (>99%) and specificity (>94%) in diagnosis of stage 1 and stage 2 keratoconus. CONCLUSIONS: Although Kmax and TP appear to have high diagnostic ability in keratoconus, the use of either single parameter in isolation might be unsatisfactory in differential diagnosis. Therefore, the Kmax(2)/TP ratio has been introduced, which reflects major characteristics of keratoconus and might be used as an important criterion in keratoconus diagnosis. PMID- 25936635 TI - Propranolol attenuates hemorrhage and accelerates wound healing in severely burned adults. AB - INTRODUCTION: Propranolol, a nonselective beta-blocker, exerts an indirect effect on the vasculature by leaving alpha-adrenergic receptors unopposed, resulting in peripheral vasoconstriction. We have previously shown that propranolol diminishes peripheral blood following burn injury by increasing vascular resistance. The purpose of this study was to investigate whether wound healing and perioperative hemodynamics are affected by propranolol administration in severely burned adults. METHODS: Sixty-nine adult patients with burns covering >= 30% of the total body surface area (TBSA) were enrolled in this IRB-approved study. Patients received standard burn care with (n = 35) or without (control, n = 34) propranolol. Propranolol was administered within 48 hours of burns and given throughout hospital discharge to decrease heart rate by approximately 20% from admission levels. Wound healing was determined by comparing the time between grafting procedures. Blood loss was determined by comparing pre- and postoperative hematocrit while factoring in operative graft area. Data were collected between first admission and first discharge. RESULTS: Demographics, burn size, and mortality were comparable in the control and propranolol groups. Patients in the propranolol group received an average propranolol dose of 3.3 +/- 3.0 mg/kg/day. Daily average heart rate over the first 30 days was significantly lower in the propranolol group (P < 0.05). The average number of days between skin grafting procedures was also lower in propranolol patients (10 +/- 5 days) than in control patients (17 +/- 12 days; P = 0.02), indicative of a faster donor site healing time in the propranolol group. Packed red blood cell infusion was similar between groups (control 5.3 +/- 5.4 units vs. propranolol 4.4 +/- 3.1 units, P = 0.89). Propranolol was associated with a 5 to 7% improvement in perioperative hematocrit during grafting procedures of 4,000 to 16,000 cm(2) compared to control (P = 0.002). CONCLUSIONS: Administration of propranolol during the acute hospitalization period diminishes blood loss during skin grafting procedures and markedly improves wound healing in severely burned adults. As burn patients require serial surgical interventions for motor and cosmetic repair, restricting blood loss during operative intervention is optimal. PMID- 25936636 TI - N-cadherin, a novel prognostic biomarker, drives malignant progression of colorectal cancer. AB - Recent studies have indicated that the epithelial-mesenchymal transition (EMT) is a key molecular mechanism involved in the development of colorectal cancer (CRC). N-cadherin is a mesenchymal marker of the EMT and has been closely linked to several human malignancies. However, its role in CRC has remained elusive. In the present study, qRT-PCR and western blot analysis indicated that N-cadherin expression was higher in tumor tissues than in that in their adjacent normal tissues. Immunohistochemical evaluation of N-cadherin and E-cadherin (an epithelial marker of the EMT), indicated that N-cadherin expression was significantly associated with tumor differentiation, tumor size as well as tumor, nodes and metastasis stage. Correlation analysis suggested the expression of N cadherin was negatively correlated with that of E-cadherin in CRC tissues. Kaplan Meier analysis indicated that patients with high N-cadherin expression had a significantly lower overall survival and disease-free survival rate than those with low N-cadherin expression, while the opposite was found for E-cadherin. Of note, the present study found that high N-cadherin expression was an independent prognostic factor for CRC. In vitro assays showed that N-cadherin was widely expressed in CRC cell lines and silencing of N-cadherin suppressed the proliferation and migration of the CRC cell line HT-29 by upregulating E cadherin, suggesting a potential role of N-cadherin in inducing EMT. In conclusion, the present study suggested that N-cadherin has the potential of serving as a novel prognostic predictor and a promising therapeutic target for CRC. PMID- 25936637 TI - Sports participation and radiographic findings of adolescents treated nonoperatively for displaced clavicle fractures. AB - BACKGROUND: There is a relative paucity of high-level evidence that guides the treatment of displaced midshaft clavicle fractures in adolescents. Some use overhead sports or significant shortening as relative indications for surgical treatment, while others rarely consider operative intervention for these patients. The purpose of this study is to determine the effect of overhead sports participation and fracture shortening on subjective and objective outcomes after nonoperative treatment of displaced midshaft clavicle fractures in those aged 10 17 years. METHODS: Using a radiographic database, adolescents with displaced clavicle fractures were identified and contacted over the phone. These subjects were invited to take part in the study in return for compensation. Radiographic measurements of dedicated clavicle films around the time of injury were performed, and a custom survey aimed at elucidating participation in overhead or contact sports was given. The Nottingham Clavicle Score (NCS) and the Constant Shoulder Score were obtained for each patient to provide both subjective and objective outcome data. Statistical Package for Social Science (SPSS) software (version 22, IBM) was used to compare radiographic and sports data to the outcome measures. RESULTS: Gender, age at the time of fracture, time since fracture, relative and absolute radiographic shortening, and hand dominance were all not significantly correlated with subjective or objective outcomes. Five patients (23%) reported not feeling happy with the appearance of their shoulder at the beach or at the pool. This group had statistically lower NCS results. Eleven of 22 participated in >=6 months per year of overhead or contact sports; they did not have worse subjective or objective outcomes. CONCLUSIONS: Fracture shortening and sports participation do not have a significant impact in adolescents on outcomes after displaced midshaft clavicle fracture. PMID- 25936638 TI - Analysis of hyponatraemia associated post-operative mortality in 3897 hip fracture patients. AB - Hyponatraemia is common in hospitalised patients. In recent years the relationship between hyponatraemia and bone metabolism, falls and fractures has become more established. This study evaluates the prevalence of hyponatraemia (plasma sodium<135mmol/l) in 3897 patients undergoing operative treatment for hip fracture and the relationship between hyponatraemia and mortality in these patients. Hyponatraemia was an independent risk factor for increased post operative mortality on multivariate analysis. Median age at admission was 83 years. Hyponatraemia was present in 19.1% of patients with hip fracture on admission, 29.5% of patients in the first 24h post-operatively and 20% of patients at discharge. There was a significant association between hyponatraemia and time from admission to surgery indicating that patients admitted with hyponatraemia waited longer. The median follow-up time was 863 (range 0-4352) days. There were 2460 deaths (63.1% of the original 3897 patients) prior to the censor date. A total of 1144 patients (29.4% of the original 3897 patients) died within 12 months of discharge. Median time to death for patients with and without hyponatraemia on admission was 34 months (SE 1.7 months) and 41 months (SE 2.5 months) respectively (p=0.003). Median time to death for patients with and without hyponatraemia within 24h post-operatively was 35 months (SE 2.5 months) and 42 months (SE 1.7 months) respectively (p=0.004). Following elimination of other independent variables associated with increased mortality, hyponatraemia on admission was associated with an increased risk of death (adjusted HR 1.15, p=0.005). Post-operative hyponatraemia was also associated with an increased risk of death (adjusted HR 1.15, p=0.006). Trends suggested that hyponatraemia within 48h of discharge was associated with an increased risk of death (adjusted HR 1.15, p=0.636). Hyponatraemia is common in elderly patients with hip fractures both at initial presentation and during admission. In this vulnerable patient group, hyponatraemia may delay time to definitive surgery and is a potentially reversible cause of increased post-operative mortality. Every effort should be made to identify and correct hyponatraemia in hip fracture patients. PMID- 25936639 TI - Perinatal methylmercury exposure perturbs the expression of Plp1 and Cnp splice variants in cerebellum of rat pups. AB - Early life exposure to environmental chemicals can interfere with myelin formation in the developing brain, leading to neurological disorders. The Proteolipid Protein 1 (Plp1), Myelin Basic Protein (Mbp) and 2',3'-Cyclic Nucleotide 3'Phosphodiesterase (Cnp) genes expressed in oligodendrocytes and involved in myelination processes can be useful biomarkers of potential developmental neurotoxicity. In an earlier study, we concluded that the reduction in the expression levels of Mbp splice variants in juvenile rat cerebellum following perinatal methylmercury (MeHg) exposure were compatible with an overall reduction of mature oligodendrocytes population. This observation prompted us to analyze the expression of Plp1 and Cnp in developing rat cerebellum to further confirm and investigate the toxic effects of MeHg on vulnerable oligodendrocytes. Splice variants of Plp1 in human and of Cnp in mouse are curated in NCBI RefSeq database, but not for rat. Lack of annotation of splice variants can pose significant challenge for the reliable quantification of gene expression levels in toxicological studies. Therefore, we applied a "comparative sequence analysis" approach, relying on annotated splice variants in human/mouse and on evolutionary conservation of intron-exon structures, to identify additional splice variants of Plp1 and Cnp in rat. Then, we confirmed their identity by nucleotide sequencing and characterized their temporal expression patterns during brain development by RT-PCR. The measurement of total transcripts and individual splice variants of Plp1 and Cnp in the cerebellum of MeHg-exposed rat pups revealed a relatively similar level of reduction in their expression levels. This study further confirms that perinatal exposure to MeHg can impact oligodendrocytes in pups. Based on these observations, we conclude that monitoring the expression of these oligodendrocyte-enriched genes can be useful to identify toxic chemicals affecting myelination. PMID- 25936640 TI - Neuroimaging-Aided Prediction of the Effect of Methylphenidate in Children with Attention-Deficit Hyperactivity Disorder: A Randomized Controlled Trial. AB - Although methylphenidate hydrochloride (MPH) is a first-line treatment for children with attention-deficit hyperactivity disorder (ADHD), the non-response rate is 30%. Our aim was to develop a supplementary neuroimaging biomarker for predicting the clinical effect of continuous MPH administration by using near infrared spectroscopy (NIRS). After baseline assessment, we performed a double blind, placebo-controlled, crossover trial with a single dose of MPH, followed by a prospective 4-to-8-week open trial with continuous MPH administration, and an ancillary 1-year follow-up. Twenty-two drug-naive and eight previously treated children with ADHD (NAIVE and NON-NAIVE) were compared with 20 healthy controls (HCs) who underwent multiple NIRS measurements without intervention. We tested whether NIRS signals at the baseline assessment or DeltaNIRS (single dose of MPH minus baseline assessment) predict the Clinical Global Impressions-Severity (CGI S) score after 4-to-8-week or 1-year MPH administration. The secondary outcomes were the effect of MPH on NIRS signals after single-dose, 4-to-8-week, and 1-year administration. DeltaNIRS significantly predicted CGI-S after 4-to-8-week MPH administration. The leave-one-out classification algorithm had 81% accuracy using the NIRS signal. DeltaNIRS also significantly predicted CGI-S scores after 1 year of MPH administration. For secondary analyses, NAIVE exhibited significantly lower prefrontal activation than HCs at the baseline assessment, whereas NON NAIVE and HCs showed similar activation. A single dose of MPH significantly increased activation compared with the placebo in NAIVE. After 4-to-8-week administration, and even after MPH washout following 1-year administration, NAIVE demonstrated normalized prefrontal activation. Supplementary NIRS measurements may serve as an objective biomarker for clinical decisions and monitoring concerning continuous MPH treatment in children with ADHD. PMID- 25936641 TI - Increased GABAergic Efficacy of Central Amygdala Projections to Neuropeptide S Neurons in the Brainstem During Fear Memory Retrieval. AB - The canonical view on the central amygdala has evolved from a simple output station towards a highly organized microcircuitry, in which types of GABAergic neurons in centrolateral (CeL) and centromedial (CeM) subnuclei regulate fear expression and generalization. How these specific neuronal populations are connected to extra-amygdaloid target regions remains largely unknown. Here we show in mice that a subpopulation of GABAergic CeL and CeM neurons projects monosynaptically to brainstem neurons expressing neuropeptide S (NPS). The CeL neurons are PKCdelta-negative and are activated during conditioned fear. During fear memory retrieval, the efficacy of this GABAergic influence on NPS neurons is enhanced. Moreover, a large proportion of these neurons (~50%) contain prodynorphin and somatostatin, two neuropeptides inhibiting NPS neurons. We conclude that CeL and CeM neurons inhibit NPS neurons in the brainstem by GABA release and that efficacy of this connection is strengthened upon fear memory retrieval. Thereby, this pathway provides a possible feedback mechanism between amygdala and brainstem routes involved in fear and stress coping. PMID- 25936642 TI - Mice Lacking the Serotonin Htr2B Receptor Gene Present an Antipsychotic-Sensitive Schizophrenic-Like Phenotype. AB - Impulsivity and hyperactivity share common ground with numerous mental disorders, including schizophrenia. Recently, a population-specific serotonin 2B (5-HT2B) receptor stop codon (ie, HTR2B Q20*) was reported to segregate with severely impulsive individuals, whereas 5-HT2B mutant (Htr2B(-/-)) mice also showed high impulsivity. Interestingly, in the same cohort, early-onset schizophrenia was more prevalent in HTR2B Q*20 carriers. However, the putative role of 5-HT2B receptor in the neurobiology of schizophrenia has never been investigated. We assessed the effects of the genetic and the pharmacological ablation of 5-HT2B receptors in mice subjected to a comprehensive series of behavioral test screenings for schizophrenic-like symptoms and investigated relevant dopaminergic and glutamatergic neurochemical alterations in the cortex and the striatum. Domains related to the positive, negative, and cognitive symptom clusters of schizophrenia were affected in Htr2B(-/-) mice, as shown by deficits in sensorimotor gating, in selective attention, in social interactions, and in learning and memory processes. In addition, Htr2B(-/-) mice presented with enhanced locomotor response to the psychostimulants dizocilpine and amphetamine, and with robust alterations in sleep architecture. Moreover, ablation of 5-HT2B receptors induced a region-selective decrease of dopamine and glutamate concentrations in the dorsal striatum. Importantly, selected schizophrenic-like phenotypes and endophenotypes were rescued by chronic haloperidol treatment. We report herein that 5-HT2B receptor deficiency confers a wide spectrum of antipsychotic-sensitive schizophrenic-like behavioral and psychopharmacological phenotypes in mice and provide first evidence for a role of 5-HT2B receptors in the neurobiology of psychotic disorders. PMID- 25936643 TI - Diffuse epithelial keratopathy following a single instillation of topical lignocaine: the damaging drop. AB - Toxic corneal epitheliopathies are a known occurrence following chronic use of topical anesthetic agents in ophthalmology. We report two cases of diffuse epithelial keratopathy following a single drop of 4% lignocaine in two diabetic patients scheduled for fundus fluorescein angiography. PMID- 25936644 TI - LKB1 Inactivation Elicits a Redox Imbalance to Modulate Non-small Cell Lung Cancer Plasticity and Therapeutic Response. AB - LKB1 regulates both cell growth and energy metabolism. It remains unclear how LKB1 inactivation coordinates tumor progression with metabolic adaptation in non small cell lung cancer (NSCLC). Here in Kras(G12D);Lkb1(lox/lox) (KL) mouse model, we reveal differential reactive oxygen species (ROS) levels in lung adenocarcinoma (ADC) and squamous cell carcinoma (SCC). ROS can modulate ADC-to SCC transdifferentiation (AST). Further, pentose phosphate pathway deregulation and impaired fatty acid oxidation collectively contribute to the redox imbalance and functionally affect AST. Similar tumor and redox heterogeneity also exist in human NSCLC with LKB1 inactivation. In preclinical trials toward metabolic stress, certain KL ADC can develop drug resistance through squamous transdifferentiation. This study uncovers critical redox control of tumor plasticity that may affect therapeutic response in NSCLC. PMID- 25936648 TI - Confronting stillbirths and newborn deaths in areas of conflict and political instability: a neglected global imperative. AB - BACKGROUND: Despite considerable improvements in reproductive and newborn health throughout the world, relatively poor outcomes persist in areas plagued by conflict or political instability. OBJECTIVES: To assess the contribution of areas of conflict and instability to global patterns of stillbirths and newborn deaths and to identify opportunities for effective intervention in these areas. METHODS: Analysis of the available data on stillbirths and neonatal mortality in association with conflict and governance indicators, and review of epidemiological and political literature pertaining to the provision of health and public services in areas of conflict and instability. RESULTS: Of the 15 countries with the highest neonatal mortality rates in the world, 14 are characterized by chronic conflict or political instability. If India and China are excluded, countries experiencing chronic conflict or political instability account for approximately 42% of all neonatal deaths worldwide. Efforts to address adverse reproductive and newborn outcomes in these areas must adapt recommended intervention protocols to the special security and governance conditions associated with unstable political environment. CONCLUSION: Despite troubling relative and absolute indicators, the special requirements of improving reproductive and neonatal outcomes in areas affected by conflict and political instability have not received adequate attention. New integrated political and technical strategies will be required. This should include moving beyond traditional approaches concerned with complex humanitarian emergencies. Rather, global efforts must be based on a deeper understanding of the specific governance requirements associated with protracted and widespread health requirements. A focus on women's roles, regional strategies which take advantage of relative stability and governance capacity in neighbouring states, virtual infrastructure, and assistance regimens directed specifically to unstable areas may prove useful. PMID- 25936647 TI - Excellent prognosis following endoscopic resection of patients with rectal neuroendocrine tumors despite the frequent presence of lymphovascular invasion. AB - BACKGROUND: Endoscopic resection (ER) has been increasingly used for the treatment of rectal neuroendocrine tumors (NETs); however, only limited data are available on its long-term outcomes. This study analyzed the long-term outcomes of rectal NETs treated by ER and characterized potential risk factors for metastasis in these cases, with emphasis on lymphovascular invasion. METHODS: We retrospectively analyzed the clinicopathological features and outcomes of 86 patients with 90 rectal NETs who had been treated by ER. Lymphovascular invasion was reevaluated using elastic-staining and double-staining immunohistochemistry. RESULTS: En bloc resection with tumor-free margins was achieved in 87 lesions (96.7%). The median tumor size was 5 mm (range 2-13), and all the lesions were confined to the submucosal layer. The Ki-67 index was less than 3% in all the lesions, which were therefore classified as NET G1. Elastic-staining and double staining immunohistochemistry revealed the presence of lymphatic and venous invasion in 23 (25.6%) and 35 lesions (36.7%), respectively. Collectively, lymphatic and/or vascular invasion was identified in 42 lesions (46.7%). All cases were followed up without additional surgery, and no metastasis or recurrence was detected during the median follow-up period of 67.5 months. CONCLUSIONS: This study showed an excellent long-term prognosis following ER of patients with rectal NETs, confirming that ER is a valid treatment option for small rectal NETs. The present study also revealed highly prevalent lymphovascular invasion even in minute rectal NETs; this observation raises a question regarding its significance as a risk factor for metastasis. PMID- 25936649 TI - Novel approaches for treating diabetic retinopathy based on recent pathogenic evidence. AB - Diabetic retinopathy remains as a leading cause of blindness in developed countries. Current treatments target late stages of DR when vision has already been significantly affected. A better understanding of the pathogenesis of DR would permit the development of more efficient preventional/interventional strategies against early stages of DR. In this article a critical review of the state of the art of this issue is provided along with a discussion of problems which have yet to be overcome. Neuroprotection as a new approach for the treatment of the early stages of DR has been particularly emphasized. The development and progression of DR is not homogeneous and, apart from blood glucose levels and blood pressure, it depends on genetic factors which remain to be elucidated. In addition, the role of the pathogenic pathways is not the same in all patients. All these factors should be taken into account in the near future when an individualized oriented treatment for DR could become feasible. The new techniques in retinal imaging acquisition, the identification of useful circulating biomarkers and the individualized analysis of biological samples could facilitate the development of early and personalized therapy in the setting of DR. Finally, it should be noted that only a coordinated action among ophthalmologists, diabetologists, basic researchers, experts in pharmaco economics and health care providers addressed to the design of rational strategies targeting prevention and the early stages of DR will be effective in reducing the burden and improving the clinical outcome of this devastating complication of diabetes. PMID- 25936651 TI - Comparison of every 3 week cisplatin or weekly cetuximab with concurrent radiotherapy for locally advanced head and neck cancer. AB - BACKGROUND: Cisplatin dosed every 3 weeks (CIS) or weekly cetuximab (CTX) concurrent with radiotherapy are standards of care for locally advanced head and neck squamous cell carcinoma (LAHNC). Retrospective comparisons of CIS and CTX have offered mixed conclusions. We compared outcomes between CIS and CTX in this patient population. METHODS: Between January 2006 and December 2011, we identified 279 patients who underwent definitive radiotherapy and concurrent systemic therapy for LAHNC. The median age difference between the CIS and CTX groups was relatively small (58 vs. 62 years, respectively) and CIS patients had a slightly higher rate of N2 disease than CTX patients (74% vs. 61%, respectively). RESULTS: Median follow-up was 27 months. Systemic therapy consisted of CIS in 241 (86.4%) and CTX in 38 (13.6%). Actuarial locoregional control of the CIS and CTX groups at 2 years were 91% and 90% (p=0.74), respectively. Actuarial 2 year distant metastasis rates between the groups were 8% and 12%, respectively (p=0.55), and actuarial 2 year overall survival between the groups were 87% and 89%, respectively (p=0.47). CONCLUSIONS: We found no difference in locoregional control, distant metastasis rate, or overall survival between patients treated with concurrent CIS or CTX. PMID- 25936652 TI - Implications of the MSLT-1 for sentinel lymph node biopsy in cutaneous head and neck melanoma. PMID- 25936653 TI - Cluster randomized trials must be better designed and reported. PMID- 25936650 TI - The Mechanism and Function of Group II Chaperonins. AB - Protein folding in the cell requires the assistance of enzymes collectively called chaperones. Among these, the chaperonins are 1-MDa ring-shaped oligomeric complexes that bind unfolded polypeptides and promote their folding within an isolated chamber in an ATP-dependent manner. Group II chaperonins, found in archaea and eukaryotes, contain a built-in lid that opens and closes over the central chamber. In eukaryotes, the chaperonin TRiC/CCT is hetero-oligomeric, consisting of two stacked rings of eight paralogous subunits each. TRiC facilitates folding of approximately 10% of the eukaryotic proteome, including many cytoskeletal components and cell cycle regulators. Folding of many cellular substrates of TRiC cannot be assisted by any other chaperone. A complete structural and mechanistic understanding of this highly conserved and essential chaperonin remains elusive. However, recent work is beginning to shed light on key aspects of chaperonin function and how their unique properties underlie their contribution to maintaining cellular proteostasis. PMID- 25936654 TI - A new technique for intra-abdominal arteries revascularization via extra-anatomic bypass from the brachiocephalic artery with a videoscopic retrosternal tunnel. AB - Extra-anatomic revascularizations of intra-abdominal or lower limbs arteries, or both, are indicated (1) when the aorta is unsuitable for anatomic bypasses, (2) in patients unfit for aortic surgery, (3) for graft infections, and (4) for visceral debranching during hybrid treatment of a thoracoabdominal aneurysm. We describe a new extra-anatomic bypass from the brachiocephalic artery with video guided retrosternal tunneling. We discuss the advantages and drawbacks of this technique. PMID- 25936655 TI - Modifying interpretation biases: Effects on symptomatology, behavior, and physiological reactivity in social anxiety. AB - BACKGROUND AND OBJECTIVES: The present study investigated the effects of computerized interpretation training and cognitive restructuring on symptomatology, behavior, and physiological reactivity in an analogue social anxiety sample. METHODS: Seventy-two participants with elevated social anxiety scores were randomized to one session of computerized interpretation training (n = 24), cognitive restructuring (n = 24), or an active placebo control condition (n = 24). Participants completed self-report questionnaires focused on interpretation biases and social anxiety symptomatology at pre and posttraining and a speech task at posttraining during which subjective, behavioral, and physiological measures of anxiety were assessed. RESULTS: Only participants in the interpretation training condition endorsed significantly more positive than negative interpretations of ambiguous social situations at posttraining. There was no evidence of generalizability of interpretation training effects to self report measures of interpretation biases and symptomatology or the anxiety response during the posttraining speech task. Participants in the cognitive restructuring condition were rated as having higher quality speeches and showing fewer signs of anxiety during the posttraining speech task compared to participants in the interpretation training condition. LIMITATIONS: The present study did not include baseline measures of speech performance or computer assessed interpretation biases. CONCLUSIONS: The results of the present study bring into question the generalizability of computerized interpretation training as well as the effectiveness of a single session of cognitive restructuring in modifying the full anxiety response. Clinical and theoretical implications are discussed. PMID- 25936656 TI - Pachymic acid protects H9c2 cardiomyocytes from lipopolysaccharide-induced inflammation and apoptosis by inhibiting the extracellular signal-regulated kinase 1/2 and p38 pathways. AB - Pachymic acid (PA), a lanostane-type triterpenoid and the major component of Poria cocos alcoholic extracts, has various pharmacological effects, including anti-inflammatory, anti-oxidative and anti-apoptotic. However, few studies have investigated the effects of PA on lipopolysaccharide (LPS)-induced H9c2 cell apoptosis and inflammation, or identified the possible mechanisms underlying these effects. In the present study, H9c2 cardiomyocytes were stimulated by LPS and treated with or without PA. The increased mRNA expression levels of tumor necrosis factor-alpha, interleukin (IL)-1 and IL-6 induced by LPS were attenuated following treatment with PA. PA also attenuated LPS-induced apoptosis, as determined by a terminal deoxynucleotidyl transferase dUTP nick end labeling assay, and regulated the LPS-induced protein expression levels of caspase 3, 8 and 9. Furthermore, the phosphorylations of extracellular-regulated kinase (Erk)1/2 and p38 in the LPS-treated H9c2 cells were inhibited by PA. These results suggested that treatment with PA prevented the LPS-induced inflammatory and apoptotic response in cardiomyocytes, which may be mediated by inhibition of the Erk1/2 and p38 pathways. PMID- 25936657 TI - Gene expression profiling via bioinformatics analysis reveals biomarkers in laryngeal squamous cell carcinoma. AB - The present study aimed to identify key genes and relevant microRNAs (miRNAs) involved in laryngeal squamous cell carcinoma (LSCC). The gene expression profiles of LSCC tissue samples were analyzed with various bioinformatics tools. A gene expression data set (GSE51985), including ten laryngeal squamous cell carcinoma (LSCC) tissue samples and ten adjacent non-neoplastic tissue samples, was downloaded from the Gene Expression Omnibus. Differential analysis was performed using software package limma of R. Functional enrichment analysis was applied to the differentially expressed genes (DEGs) using the Database for Annotation, Visualization and Integrated Discovery. Protein-protein interaction (PPI) networks were constructed for the protein products using information from the Search Tool for the Retrieval of Interacting Genes/Proteins. Module analysis was performed using ClusterONE (a software plugin from Cytoscape). MicroRNAs (miRNAs) regulating the DEGs were predicted using WebGestalt. A total of 461 DEGs were identified in LSCC, 297 of which were upregulated and 164 of which were downregulated. Cell cycle, proteasome and DNA replication were significantly over represented in the upregulated genes, while the ribosome was significantly over represented in the downregulated genes. Two PPI networks were constructed for the up- and downregulated genes. One module from the upregulated gene network was associated with protein kinase. Numerous miRNAs associated with LSCC were predicted, including miRNA (miR)-25, miR-32, miR-92 and miR-29. In conclusion, numerous key genes and pathways involved in LSCC were revealed, which may aid the advancement of current knowledge regarding the pathogenesis of LSCC. In addition, relevant miRNAs were also identified, which may represent potential biomarkers for use in the diagnosis or treatment of the disease. PMID- 25936658 TI - The Surrogate Daughter. PMID- 25936659 TI - Sensitivity and negative predictive value of treadmill exercise stress testing for the diagnosis of catecholaminergic polymorphic ventricular tachycardia. Response. PMID- 25936660 TI - Simple and inexpensive quantification of ammonia in whole blood. AB - Quantification of ammonia in whole blood has applications in the diagnosis and management of many hepatic diseases, including cirrhosis and rare urea cycle disorders, amounting to more than 5 million patients in the United States. Current techniques for ammonia measurement suffer from limited range, poor resolution, false positives or large, complex sensor set-ups. Here we demonstrate a technique utilizing inexpensive reagents and simple methods for quantifying ammonia in 100 MUL of whole blood. The sensor comprises a modified form of the indophenol reaction, which resists sources of destructive interference in blood, in conjunction with a cation-exchange membrane. The presented sensing scheme is selective against other amine containing molecules such as amino acids and has a shelf life of at least 50 days. Additionally, the resulting system has high sensitivity and allows for the accurate reliable quantification of ammonia in whole human blood samples at a minimum range of 25 to 500 MUM, which is clinically for rare hyperammonemic disorders and liver disease. Furthermore, concentrations of 50 and 100 MUM ammonia could be reliably discerned with p = 0.0001. PMID- 25936661 TI - Activation of novel estrogen receptor GPER results in inhibition of cardiocyte apoptosis and cardioprotection. AB - Several studies have recently demonstrated that G protein-coupled estrogen receptor (GPER) 30 directly binds to estrogen and mediates its action. The aim of the present study was to investigate the effects of GPER on cardiocyte apoptosis following ischemia/reperfusion injury (MIRI) in H9C2 myocardial cells. H9C2 cells were treated with a specific GPER agonist (G1), 17beta-estradiol (E2) or the vehicle. The cells were subjected to 20 min of myocardial ischemia followed by 120 min of reperfusion. They were then randomly assigned to three experimental groups: Control, G1, E2. B-cell lymphoma 2 (Bcl-2) and Bcl-2 associated X (Bax) levels were measured, Hoechst 33258 staining was performed to assess apoptosis, and superoxide dismutase (SOD), tumor necrosis factor (TNF)-alpha and adenosine triphosphatase (ATPase) levels were determined. To test the specificity of G1, GPER-knockout cells were treated with G1 and analyzed as stated above. Compared with the vehicle-treated groups, G1 and E2-treated groups exhibited elevated Bcl 2 levels, decreased Bax levels and cell apoptosis, significantly increased SOD and ATP levels and decreased TNF-alpha levels following ischemia-reperfusion. However, G1 had no evident effects on the GPER-knockout cells. In conclusion, the present study suggested that GPER activation provided a cardioprotective effect following ischemia-reperfusion by inhibiting cardiocyte apoptosis. PMID- 25936662 TI - The 23-valent pneumococcal polysaccharide vaccine is effective in elderly adults over 75 years old--Taiwan's PPV vaccination program. AB - BACKGROUND: Pneumococcal infection is a serious cause of mortality and morbidity in the elderly. A nationwide pneumococcal polysaccharide vaccine (PPV) program for elderly adults aged 75 years and older was conducted in Taiwan in 2008. The efficacy of the PPV in this very elderly population was evaluated. METHODS: The data were analyzed using the Taiwan National Health Insurance Research Database (NHIRD), the cause-of-death registration database and the invasive pneumococcal disease (IPD) notification database of Taiwan's Ministry of Health and Welfare. The efficacy of PPV administration in this very elderly population was evaluated using multivariate logistic regression after propensity score matching (PSM). The rates of IPD, death from IPD, pneumonia hospitalization, death from pneumonia, and all-cause mortality were compared for those who did and did not receive the PPV. RESULTS: Among the 1078,955 eligible people, 318,257 (29.5%) received the PPV, and 760,698 (70.5%) were not vaccinated. Using PSM to adjust for confounding factors, including age, gender, influenza vaccination status, associated chronic diseases and health care utilization, those who received the PPV had significantly lower odds ratios (ORs) for IPD (OR=0.24, 95% CI=0.123-0.461, p<0.001), death from IPD (OR=0.09, 95% CI=0.011-0.704, p<0.022, p<0.001), pneumonia hospitalization (OR=0.40, 95% CI=0.395-0.415, p<0.001), death from pneumonia (OR=0.07, 95% CI=0.059-0.082, p<0.001), and all-cause mortality (OR=0.07, 95% CI=0.069-0.072, p<0.001) compared with those who were not vaccinated. CONCLUSIONS: PPV vaccination in the previous year was associated with a 60% reduction in pneumonia hospitalization, a 76% reduction in IPD, and a greater than 90% reduction in death from pneumonia, IPD and all causes among people over 75 years old in Taiwan. Data from subsequent years in Taiwan and similar populations elsewhere are needed to evaluate the contribution of underlying variations in the mortality rate and the confounding effects of prior disease severity to these findings. PMID- 25936663 TI - The causal effect of childhood measles vaccination on educational attainment: A mother fixed-effects study in rural South Africa. AB - BACKGROUND: Because measles vaccination prevents acute measles disease and morbidities secondary to measles, such as undernutrition, blindness, and brain damage, the vaccination may also lead to higher educational attainment. However, there has been little evidence to support this hypothesis at the population level. In this study, we estimate the causal effect of childhood measles vaccination on educational attainment among children born between 1995 and 2000 in South Africa. METHODS AND FINDINGS: We use longitudinal data on measles vaccination status and school grade attainment among 4783 children. The data were collected by the Wellcome Trust Africa Centre Demographic Information System (ACDIS), which is one of Africa's largest health and demographic surveillance systems. ACDIS is located in a poor, predominantly rural, Zulu-speaking community in KwaZulu-Natal, South Africa. Using mother fixed-effects regression, we compare the school grade attainment of siblings who are discordant in their measles vaccination status but share the same mother and household. This fixed-effects approach controls for confounding due to both observed and unobserved factors that do not vary between siblings, including sibling-invariant mother and household characteristics such as attitudes toward risk, conscientiousness, and aspirations for children. We further control for a range of potential confounders that vary between siblings, such as sex of the child, year of birth, mother's age at child's birth, and birth order. We find that measles vaccination on average increases school grade attainment by 0.188 grades (95% confidence interval, 0.0424-0.334; p=0.011). CONCLUSIONS: Measles vaccination increased educational attainment in this poor, largely rural community in South Africa. For every five to seven children vaccinated against measles, one additional school grade was gained. The presence of a measles vaccination effect in this community is plausible because (i) measles vaccination prevents measles complications including blindness, brain damage, and undernutrition; (ii) a large number of number of children were at risk of contracting measles because of the comparatively low measles vaccination coverage; and (iii) significant measles transmission occurred in the community where this study took place during the study observation period. Our results demonstrate for the first time that measles vaccination affects human development not only through its health effects but also through its effects on education. PMID- 25936664 TI - Whole genome analysis to detect potential vaccine-induced changes on Shigella sonnei genome. AB - Shigellosis or bacillary dysentery is endemic worldwide and is a significant cause of death in children less than five years of age in developing countries. There are no licensed Shigella vaccines and glycoconjugates are among the leading candidate vaccines against shigellosis today. We used whole genome sequence analysis (WGA) to find out whether immunization, with an investigational Shigella sonnei glycoconjugate, could induce selective pressure leading to changes in the genome of S. sonnei. An outbreak of culture-proven S. sonnei shigellosis which occurred immediately after vaccination in one of the cohorts of volunteers participating in a phase III trial of the vaccine in Israel created a unique condition in which the epidemic agent "co-existed" with the developing immune responses induced by the vaccine and natural infection among vaccinees who developed S. sonnei shigellosis. By comparing the whole genomes of S. sonnei isolated from vaccinees and from volunteers in the control group, we show at a very high sensitivity that a potent S. sonnei glycoconjugate that conferred 74% protective efficacy against the homologous disease did not induce changes in the genome of S. sonnei and in particular on the O-antigen gene cluster. PMID- 25936665 TI - The use of pseudotypes to study viruses, virus sero-epidemiology and vaccination. AB - The globalization of the world's economies, accompanied by increasing international travel, changing climates, altered human behaviour and demographics is leading to the emergence of different viral diseases, many of which are highly pathogenic and hence are considered of great public and animal health importance. To undertake basic research and therapeutic development, many of these viruses require handling by highly trained staff in BSL-3/4 facilities not readily available to the majority of the global R&D community. In order to circumvent the enhanced biosafety requirement, the development of non-pathogenic, replication defective pseudotyped viruses is an effective and established solution to permit the study of many aspects of virus biology in a low containment biosafety level (BSL)-1/2 laboratory. Under the spectre of the unfolding Ebola crisis, this timely conference (the second to be organised by the Viral Pseudotype Unit, www.viralpseudotypeunit.info*) discusses the recent advances in pseudotype technology and how it is revolutionizing the study of important human and animal pathogens (human and avian influenza viruses, rabies/lyssaviruses, HIV, Marburg and Ebola viruses). Key topics addressed in this conference include the exploitation of pseudotypes for serology and serosurveillance, immunogenicity testing of current and next-generation vaccines and new pseudotype assay formats (multiplexing, kit development). The first pseudotype-focused Euroscicon conference organised by the Viral Pseudotype Unit was recently reviewed [1]. PMID- 25936666 TI - Determinants of maternal immunization in developing countries. AB - BACKGROUND: Maternal immunization is an effective intervention to protect newborns and young infants from infections when their immune response is immature. Tetanus toxoid vaccination of pregnant women is the most widely implemented maternal vaccine in developing countries where neonatal mortality is the highest. We identified barriers to maternal tetanus vaccination in developing African and Asian countries to identify means of improving maternal immunization platforms in these countries. METHOD: We categorized barriers into health system, health care provider and patient barriers to maternal tetanus immunization and conducted a literature review on each category. Due to limited literature from Africa, we conducted a pilot survey of health care providers in Malawi on barriers they experience in immunizing pregnant women. RESULTS: The major barriers of the health system are due to inadequate financial and human resources which translate to inadequate vaccination services delivery and logistics management. Health care providers are limited by poor attendance of Antenatal Care and inadequate knowledge on vaccinating pregnant women. Patient barriers are due to lack of education and knowledge on pregnancy immunization and socioeconomic factors such as low income and high parity. CONCLUSION: There are several factors that affect maternal tetanus immunization. Increasing knowledge in health care providers and patients, increasing antenatal care attendance and outreach activities will aid the uptake of maternal immunization. Health system barriers are more difficult to address requiring an improvement of overall immunization services. Further analyses of maternal immunization specific barriers and the means of addressing them are required to strengthen the existing program and provide a more efficient delivery system for additional maternal vaccines. PMID- 25936668 TI - WITHDRAWN: Let us now praise famous men. AB - This article has been withdrawn at the request of the author(s) and/or editor. The Publisher apologizes for any inconvenience this may cause. The full Elsevier Policy on Article Withdrawal can be found at http://www.elsevier.com/locate/withdrawalpolicy. PMID- 25936667 TI - Programmed death-ligand 1 (PD-L1) may play a role in malignant glioma infiltration. AB - Infiltration is the main cause of death of malignant glioma patients. However, the mechanisms of the infiltration in the development of brain cancer (glioblastoma multiforme) are not completely understood. Here, we hypothesized that, in the development of human brain cancer, infiltration is primarily due to differentiated cancer cells and that the cell surface molecule programmed death ligand 1 (PD-L1) may play an important role in brain tumor infiltration. PD-L1 is highly expressed in differentiated glioma cells in comparison to undifferentiated ones. As PD-L1 has both pro-survival and immunoinhibitory functions in tumor cells, the potential role of PD-L1 in tumor propagation suggest a new therapeutic target for preventing glioma infiltration and recurrence. PMID- 25936669 TI - The vascular endothelial growth factors and receptors family: Up to now the only target for anti-angiogenesis therapy. AB - Angiogenesis is a complex biological phenomenon essential for a correct embryonic development and for post-natal growth. In adult life, it is a tightly regulated process but in several pathological conditions, angiogenesis results abnormal with either excessive or insufficient proliferation of blood vessels. The pro angiogenic members of VEGF family, VEGF-A, VEGF-B and placental growth factor (PlGF), and the related receptors, VEGFR-1 and VEGFR-2, have a central and decisive role in pathological angiogenesis. Indeed, they are the targets for anti angiogenic drugs currently approved: bevacizumab and ranibizumab, that specifically inhibit VEGF-A; aflibercept, that is able to prevent the activity of VEGF-A, VEGF-B and PlGF; several multirtarget tyrosine kinase inhibitors that are able to prevent VEGFR-1 and/or VEGFR-2 signaling. The anti-angiogenesis therapy has represented one of the most active fields of drug discovery of last decade and promises to be further expanded due the wide number of diseases for which it may by applied. PMID- 25936670 TI - Epigenetic-based therapies in the preclinical and clinical treatment of Huntington's disease. AB - The study of epigenetics is providing novel insights about the functional and developmental complexity of the nervous system. In neuropathology, therapies aimed at correcting epigenetic dysregulation have been extensively documented in a large variety of models for neurodegenerative, neurodevelopmental and psychiatric disorders. Taking the treatment of Huntington's disease as a paradigm for the study of these ameliorative strategies, this review updates the main conclusions derived from the use of epigenetic drugs at the preclinical and clinical stages, including actions beyond epigenetics. This article is part of a Directed Issue entitled: Epigenetics dynamics in development and disease. PMID- 25936671 TI - Reducing viral contamination from finger pads: handwashing is more effective than alcohol-based hand disinfectants. AB - BACKGROUND: Hand hygiene is important for interrupting transmission of viruses through hands. Effectiveness of alcohol-based hand disinfectant has been shown for bacteria but their effectiveness in reducing transmission of viruses is ambiguous. AIM: To test efficacy of alcohol hand disinfectant against human enteric and respiratory viruses and to compare efficacy of an alcohol-based hand disinfectant and handwashing with soap and water against norovirus. METHODS: Efficacies of a propanol and an ethanol-based hand disinfectant against human enteric and respiratory viruses were tested in carrier tests. Efficacy of an alcohol-based hand disinfectant and handwashing with soap and water against noroviruses GI.4, GII.4, and MNV1 were tested using finger pad tests. FINDINGS: The alcohol-based hand disinfectant reduced the infectivity of rotavirus and influenza A virus completely within 30s whereas poliovirus Sabin 1, adenovirus type 5, parechovirus 1, and MNV1 infectivity were reduced <3 log10 within 3 min. MNV1 infectivity reduction by washing hands with soap and water for 30s (>3.0 +/- 0.4 log10) was significantly higher than treating hands with alcohol (2.8 +/- 1.5 log10). Washing with soap and water for 30s removed genomic copies of MNV1 (>5 log10), noroviruses GI.4 (>6 log10), and GII.4 (4 log10) completely from all finger pads. Treating hands with propanol-based hand disinfectant showed little or no reduction to complete reduction with mean genomic copy reduction of noroviruses GI.4, GII.4, and MNV1 being >2.6, >3.3, and >1.2 log10 polymerase chain reaction units respectively. CONCLUSIONS: Washing hands with soap and water is better than using alcohol-based hand disinfectants in removing noroviruses from hands. PMID- 25936672 TI - Living kidney donors and ESRD. AB - There are more than 325 living kidney donors who have developed end-stage renal disease and have been listed on the Organ Procurement and Transplantation Network (OPTN)/United Network for Organ Sharing (UNOS) deceased donor kidney wait list. The OPTN/UNOS database records where these kidney donors are listed and, if they donated after April 1994, where that donation occurred. These 2 locations are often not the same. In this commentary, I examine whether a national living donor registry should be created and whether transplantation centers should be notified when one of their living kidney donors develops end-stage renal disease. I consider and refute 5 potential objections to center notification. I explain that transplantation centers should look back at these cases and input data into a registry to attempt to identify patterns that could improve donor evaluation protocols. Creating a registry and mining the information it contains is, in my view, our moral and professional responsibility to future patients and the transplantation endeavor. As individuals and as a community, we need to acknowledge the many unknown risks of living kidney donation and take responsibility for identifying these risks. We then must share information about these risks, educate prospective donors about them, and attempt to minimize them. PMID- 25936673 TI - Gender differences in antipsychotics prescribed to veterans with serious mental illness. AB - OBJECTIVE: To examine gender differences in prescribing of antipsychotic medications (APMs) according to their liability for weight gain and other metabolic side effects. METHOD: We identified 4510 patients with schizophrenia or bipolar disorders receiving usual care in a Veterans Affairs (VA) health care network in the U.S. mid-Atlantic region who initiated treatment with an APM between October 2006 and September 2011. We used multivariable logistic regression to examine gender differences in the likelihood of incident prescription of APMs with low versus medium/high metabolic risk, adjusting for fiscal year of prescribing and selected Veteran demographic, mental health and physical health characteristics. RESULTS: Overall, 58% of women were prescribed an APM with a low risk of metabolic side effects compared to 45% of men (P<.001). In multivariable analysis, women Veterans were 1.47 times as likely as men to be prescribed a low-metabolic-risk APM (95% confidence interval: 1.26-1.73, P<.001). Several demographic and clinical covariates were also independently related to prescribing of APMs by level of metabolic risk. CONCLUSIONS: The results may suggest that prescribing choices for APMs by VA mental health prescribers and female Veterans reflect a growing awareness of the potential adverse health consequences of these treatments in women. PMID- 25936674 TI - Health care utilization and expenditures of persons with diabetes comorbid with anxiety disorder: a national population-based cohort study. AB - OBJECTIVE: The aim of this study was to investigate and compare health care utilization and expenditures between persons with diabetes comorbid with and without anxiety disorder in Taiwan. METHODS: Health care utilization and expenditures among persons with diabetes with and without comorbid anxiety disorder in the period 2000-2004 were examined using the Taiwan's National Health Insurance claims data. Health care utilization included outpatient visits and use of hospital inpatient services, while expenditures included outpatient, inpatient and total medical expenditures. General estimation equation (GEE) models were used to analyze the factors associated with outpatient visits and expenditures, and multiple logistic regression analysis was applied to identify factors associated with hospitalization. RESULTS: In the study period, the average number of annual outpatient visits was 43.11-50.37 and 29.82-31.42 for persons with diabetes comorbid with anxiety disorder and for those without anxiety disorder, respectively. The average annual total expenditure was NT$74,875-92,781 and NT$63,764-81,667, respectively. Controlling for covariates, the GEE models revealed that age and time were associated with outpatient visits. Income and time factor were associated with total expenditure. CONCLUSIONS: Health care utilization and expenditures for persons with diabetes with comorbid anxiety disorder are significantly higher than those without anxiety disorder. The factors associated with health care utilization and expenditures are age, income and time. PMID- 25936675 TI - Editorial overview: Environmental biotechnology. PMID- 25936676 TI - A Host KH RNA-Binding Protein Is a Susceptibility Factor Targeted by an RXLR Effector to Promote Late Blight Disease. AB - Plant pathogens deliver effector proteins that alter host processes to create an environment conducive to colonization. Attention has focused on identifying the targets of effectors and how their manipulation facilitates disease. RXLR effector Pi04089 from the potato blight pathogen Phytophthora infestans accumulates in the host nucleus and enhances colonization when transiently expressed in planta. Its nuclear localization is required for enhanced P. infestans colonization. Pi04089 interacts in yeast and in planta with a putative potato K-homology (KH) RNA-binding protein, StKRBP1. Co-localization of Pi04089 and StKRBP1, and bimolecular fluorescence complementation between them, indicate they associate at nuclear speckles. StKRBP1 protein levels increased when it was co-expressed with Pi04089. Indeed, such accumulation of StKRBP1 was observed also on the first day of leaf colonization by the pathogen. Remarkably, overexpression of StKRBP1 significantly enhances P. infestans infection. Mutation of the nucleotide-binding motif GxxG to GDDG in all three KH domains of StKRBP1 abolishes its interaction with Pi04089, its localization to nuclear speckles, and its increased accumulation when co-expressed with the effector. Moreover, the mutant StKRBP1 protein no longer enhances leaf colonization by P. infestans, implying that nucleotide binding is likely required for this activity. We thus argue that StKRBP1 can be regarded as a susceptibility factor, as its activity is beneficial to the pathogen. PMID- 25936677 TI - Increasing the Genetic Recombination Frequency by Partial Loss of Function of the Synaptonemal Complex in Rice. PMID- 25936678 TI - Protective effects of thrombomodulin on microvascular permeability after subarachnoid hemorrhage in mouse model. AB - The enhanced vascular permeability is a major early brain injury following subarachnoid hemorrhage (SAH). However, its mechanism is not clear yet. In this work, we explored its potential mechanism and investigated the roles of thrombomodulin (TM) in maintaining microvascular integrity after SAH. SAH models were established in adult male ICR mice (28-32 g) by endovascular perforation. TM was immediately administered by femoral vein injection following SAH. The brain water content, Evans Blue content and neurological functions were evaluated. Brain edema was also detected by magnetic resonance imaging (MRI) (T2 map). The siRNA technique, enzyme-linked immunosorbent assay (ELISA), immunofluorescence staining and western blotting were performed to explore the potential mechanism of TM treatment. The number of microthrombi in the hippocampus microvessels was also recorded. TM significantly decreased brain water content and Evans Blue content, alleviated brain edema and neurological deficits after SAH. The plasma concentration of activated protein C was increased after TM treatment. In addition, the levels of phospho-p38MAPK, phospho-p53, cleaved caspase-3, phospho NF-kappaB (p65) were markedly decreased. Additionally, the loss of VE-cadherin and Occludin (markers of vascular integrity) and the number of microthrombi in the hippocampus were also reduced. Our results indicated that TM has protective effects on preserving microvascular integrity following SAH partly through preserving endothelial junction proteins and quenching apoptosis/inflammation in endothelial cells via blocking p38MAPK-p53/NF-kappaB (p65) pathway. PMID- 25936679 TI - Fentanyl effects on breath generation in C57BL/6J and A/J mouse strains. AB - We examined the effect of fentanyl on chemoresponsiveness in mouse strains divergent in the expression of spontaneous and post-hypoxic pauses. Frequency and tidal volume were recorded with plethysmography in A/J and C57BL/6J (B6) male mice. Mice selected at random received an intraperitoneal (IP) injection of either saline, low dose fentanyl (LDF = 0.04 mg/kg), or high dose fentanyl (HDF = 0.4 mg/kg) under hypoxia (8% O2) or hyperoxia (100%O2). LDF produced a decrease in frequency during hypoxia in B6, but not A/J, mice. HDF significantly decreased frequency and tidal volume in both strains under hypoxia and hyperoxia (p<0.01); naloxone, an opioid antagonist, reversed this response. The acute administration of fentanyl at any dose did not promote apneas in strains of mice exhibiting regular or irregular respiratory patterns. However, higher doses depressed respiratory frequency in both strains. The B6 mice responded with a depressive response to hypoxia that did not recover with reoxygenation, but did recover with time or naloxone. PMID- 25936680 TI - Anaplastic glioma: current treatment and management. AB - Anaplastic glioma (AG) is divided into three morphology-based groups (anaplastic astrocytoma, anaplastic oligodendroglioma, anaplastic oligoastrocytoma) as well as three molecular groups (glioma-CpG island methylation phenotype [G-CIMP] negative, G-CIMP positive non-1p19q codeleted tumors and G-CIMP positive codeleted tumors). The RTOG 9402 and EORTC 26951 trials established radiotherapy plus (procarbazine, lomustine, vincristine) chemotherapy as the standard of care in 1p/19q codeleted AG. Uni- or non-codeleted AG are currently best treated with radiotherapy only or alkylator-based chemotherapy only as determined by the NOA 04 trial. Maturation of NOA-04 and results of the currently accruing studies, CODEL (for codeleted AG) and CATNON (for uni or non-codeleted AG), will likely refine current up-front treatment recommendations for AG. PMID- 25936681 TI - Prediction of refractive outcomes with toric intraocular lens implantation. AB - PURPOSE: To evaluate and compare the accuracy of different methods to measure and predict postoperative astigmatism with toric intraocular lens (IOL) implantation. SETTING: Ein-Tal Ophthalmology Center, Tel-Aviv, Israel. DESIGN: Retrospective case series. METHODS: Postoperative corneal astigmatism was measured with 3 devices (IOLMaster 500; optical low-coherence reflectometry [OLCR]-based Lenstar LS 900; Atlas topographer) and compared with the manifest astigmatic refractive outcome in patients with toric IOLs. The error in the predicted residual astigmatism was calculated by vector analysis according to the measurement and calculation method used to predict the required toric IOL cylinder power. RESULTS: The centroid errors in predicted residual astigmatism were against the rule with the Alcon and Holladay toric calculators (0.53 to 0.56 diopter [D]), were lower with the Baylor nomogram (0.21 to 0.26 D), and were lowest for the Barrett toric calculator (0.01 to 0.16 D) (P <.001). The Barrett toric calculator had the lowest median absolute error in predicted residual astigmatism (0.35 to 0.54 D, all devices) compared with the Alcon and Holladay toric calculators with or without the Baylor nomogram (P <.021). The Barrett toric calculator and the OLCR device achieved the most accurate results; 75.0% and 97.1% of eyes were within +/-0.50 D and +/-0.75 D of the predicted residual astigmatism, respectively. CONCLUSION: Prediction of astigmatic outcomes with toric IOLs can be improved with appropriate measuring devices and methods to establish the required toric IOL power. PMID- 25936682 TI - The contribution of neighbours to an individual's risk of typhoid outcome. AB - An individual's risk of infection from an infectious agent can depend on both the individual's own risk and protective factors and those of individuals in the same community. We hypothesize that an individual's exposure to an infectious agent is associated with the risks of infection of those living nearby, whether their risks are modified by pharmaceutical interventions or by other factors, because of the potential for transmission from them. For example, unvaccinated individuals living in a highly vaccinated community can benefit from indirect protection, or living near more children in a typhoid-endemic region (where children are at highest risk) might result in more exposure to typhoid. We tested this hypothesis using data from a cluster-randomized typhoid vaccine trial. We first estimated each individual's relative risk of confirmed typhoid outcome using their vaccination status and age. We defined a new covariate, potential exposure, to be the sum of the relative risks of all who live within 100 m of each person. We found that potential exposure was significantly associated with an individual's typhoid outcome, and adjusting for potential exposure affected estimates of vaccine efficacy. We suggest that it is useful and feasible to adjust for spatially heterogeneous distributions of individual-level risk factors, but further work is required to develop and test such approaches. PMID- 25936683 TI - Three-dimensional cardiac cine imaging using the kat ARC acceleration: Initial experience in clinical adult patients at 3T. AB - OBJECTIVE: Three-dimensional cardiac cine imaging has demonstrated promising clinical 1.5-Tesla results; however, its application to 3T scanners has been limited because of the higher sensitivity to off-resonance artifacts. The aim of this study was to apply 3D cardiac cine imaging during a single breath hold in clinical patients on a 3T scanner using the kat ARC (k- and adaptive-t auto calibrating reconstruction for Cartesian sampling) technique and to evaluate the interchangeability between 2D and 3D cine imaging for cardiac functional analysis and detection of abnormalities in regional wall motion. METHODS: Following institutional review board approval, we obtained 2D cine images with an acceleration factor of two during multiple breath holds and 3D cine images with a net scan acceleration factor of 7.7 during a single breath hold in 20 patients using a 3T unit. Two readers independently evaluated the wall motion of the left ventricle (LV) using a 5-point scale, and the consistency in the detection of regional wall motion abnormality between 2D and 3D cine was analyzed by Cohen's kappa test. The LV volume was calculated at end-diastole and end-systole (LVEDV, LVESV); the ejection fraction (LVEF) and myocardial weight (LVmass) were also calculated. The relationship between functional parameters calculated for 2D and 3D cine images was analyzed using Pearson's correlation analysis. The bias and 95% limit of agreement (LA) were calculated using Bland-Altman plots. In addition, a qualitative evaluation of image quality was performed with regard to the myocardium-blood contrast, noise level and boundary definition. RESULTS: Despite slight degradation in image quality for 3D cine, excellent agreement was obtained for the detection of wall motion abnormalities between 2D and 3D cine images (kappa=0.84 and 0.94 for each reader). Excellent correlations between the two imaging methods were shown for the evaluation of functional parameters (r>0.97). Slight differences in LVEDV, LVESV, LVEF and LVmass were observed, with average values of 1.6+/-8.9mL, -0.6+/-5.9mL, 1.4+/-3.6%, and 1.3+/-8.7g, respectively. CONCLUSIONS: Images obtained using the kat ARC 3D and conventional 2D cine techniques were equivalent in the detection of regional wall motion abnormalities and the evaluation of cardiac functional parameters. PMID- 25936684 TI - Dose and pulse sequence considerations for hyperpolarized (129)Xe ventilation MRI. AB - PURPOSE: The aim of this study was to evaluate the effect of hyperpolarized (129)Xe dose on image signal-to-noise ratio (SNR) and ventilation defect conspicuity on both multi-slice gradient echo and isotropic 3D-radially acquired ventilation MRI. MATERIALS AND METHODS: Ten non-smoking older subjects (ages 60.8+/-7.9years) underwent hyperpolarized (HP) (129)Xe ventilation MRI using both GRE and 3D-radial acquisitions, each tested using a 71ml (high) and 24ml (low) dose equivalent (DE) of fully polarized, fully enriched (129)Xe. For all images SNR and ventilation defect percentage (VDP) were calculated. RESULTS: Normalized SNR (SNRn), obtained by dividing SNR by voxel volume and dose was higher for high DE GRE acquisitions (SNRn=1.9+/-0.8ml(-2)) than low-DE GRE scans (SNRn=0.8+/ 0.2ml(-2)). Radially acquired images exhibited a more consistent, albeit lower SNRn (High-DE: SNRn=0.5+/-0.1ml(-2), low-DE: SNRn=0.5+/-0.2ml(-2)). VDP was indistinguishable across all scans. CONCLUSIONS: These results suggest that images acquired using the high-DE GRE sequence provided the highest SNRn, which was in agreement with previous reports in the literature. 3D-radial images had lower SNRn, but have advantages for visual display, monitoring magnetization dynamics, and visualizing physiological gradients. By evaluating normalized SNR in the context of dose-equivalent formalism, it should be possible to predict (129)Xe dose requirements and quantify the benefits of more efficient transmit/receive coils, field strengths, and pulse sequences. PMID- 25936685 TI - The effects of negative emotion on encoding-related neural activity predicting item and source recognition. AB - We report here a study that obtained reliable effects of emotional modulation of a well-known index of memory encoding--the electrophysiological "Dm" effect- using a recognition memory paradigm followed by a source memory task. In this study, participants performed an old-new recognition test of emotionally negative and neutral pictures encoded 1 day before the test, and a source memory task involving the retrieval of the temporal context in which pictures had been encoded. Our results showed that Dm activity was enhanced for all emotional items on a late positivity starting at ~400 ms post-stimulus onset, although Dm activity for high arousal items was also enhanced at an earlier stage (200-400 ms). Our results also showed that emotion enhanced Dm activity for items that were both recognised with or without correct source information. Further, when only high arousal items were considered, larger Dm amplitudes were observed if source memory was accurate. Three main conclusions are drawn from these findings. First, negative emotion can enhance encoding processes predicting the subsequent recognition of central item information. Second, if emotion reaches high levels of arousal, the encoding of contextual details can also be enhanced over and above the effects of emotion on central item encoding. Third, the morphology of our ERPs is consistent with a hybrid model of the role of attention in emotion enhanced memory (Pottage and Schaefer, 2012). PMID- 25936687 TI - A meta-analysis of single-stage versus two-stage management for concomitant gallstones and common bile duct stones. AB - OBJECTIVE: To conduct a randomized controlled trial (RCT) meta-analysis to evaluate the safety and effectiveness of single-stage [laparoscopic cholecystectomy (LC)+laparoscopic common bile duct exploration (LCBDE)] vs. two stage management [preoperative endoscopic retrograde cholangiopancreatography (ERCP)+LC] for concomitant gallstones and common bile duct stones. METHODS: RCTs that met the inclusion criteria for data extraction were identified from electronic databases (PubMed, Embase, Science Citation Index, and the Cochrane Library) up to August 2014. The relevant congressional proceedings were also searched. The primary outcomes were stone clearance from the common bile duct, postoperative morbidity and mortality. The secondary outcomes were conversion to other procedures, length of hospital stay, total operative time, and hospitalization charges. The outcomes were calculated as odds ratios (ORs) with 95% confidence intervals (CIs) using RevMan 5.2. RESULTS: Eight RCTs, which included 1130 patients, were identified for analysis in our study. The meta analysis revealed that the common bile duct stone clearance rate in the single stage group was higher (OR=1.56, 95% CI: 1.05 to 2.33, P=0.03). The lengths of hospital stay (MD=-1.02, 95% CI: -1.99 to -0.04, P=0.04) and total operative times (MD=-16.78, 95% CI: -27.55 to -6.01, P=0.002) were also shorter in the single-stage group. There was no statistically significant difference between the two groups regarding postoperative morbidity (OR=1.12, 95% CI: 0.79 to 1.59, P=0.52), mortality (OR=0.29, 95% CI: 0.06 to 1.41, P=0.13) and conversion to other procedures (OR=0.82, 95% CI: 0.37 to 1.82, P=0.62). CONCLUSION: Single- and two-stage management for cholecysto-choledocholithiasis had similar mortality and complication rates; however, the single-stage strategy was better in terms of stone clearance, hospital stay and total operative time. PMID- 25936686 TI - Quality of medical care for persons with serious mental illness: A comprehensive review. AB - OBJECTIVES: Prior studies suggest variation in the quality of medical care for somatic conditions such as cardiovascular disease and diabetes provided to persons with SMI, but to date no comprehensive review of the literature has been conducted. The goals of this review were to summarize the prior research on quality of medical care for the United States population with SMI; identify potential sources of variation in quality of care; and identify priorities for future research. METHODS: Peer-reviewed studies were identified by searching four major research databases and subsequent reference searches of retrieved articles. All studies assessing quality of care for cardiovascular disease, diabetes, dyslipidemia, and HIV/AIDs among persons with schizophrenia and bipolar disorder published between January 2000 and December 2013 were included. Quality indicators and information about the study population and setting were abstracted by two trained reviewers. RESULTS: Quality of medical care in the population with SMI varied by study population, time period, and setting. Rates of guideline concordant care tended to be higher among veterans and lower among Medicaid beneficiaries. In many study samples with SMI, rates of guideline adherence were considerably lower than estimated rates for the overall US population. CONCLUSIONS: Future research should identify and address modifiable provider, insurer, and delivery system factors that contribute to poor quality of medical care among persons with SMI and examine whether adherence to clinical guidelines leads to improved health and disability outcomes in this vulnerable group. PMID- 25936688 TI - Immunomodulation of intestinal macrophages by mercury involves oxidative damage and rise of pro-inflammatory cytokine release in the fresh water fish Channa punctatus Bloch. AB - Mercury and its compounds have been parts of widespread pollutants of the aquatic environment. The present study was designed to assess the effect of mercury on fish immune responses. Since the metal is absorbed by fish and passed up the food chain to other fish-eating species, it not only affects aquatic ecosystems but also humans through bioaccumulation. In the present study, it was found that innate immunity of the fresh water fish Channa punctatus Bloch. was significantly debilitated after a periods of exposure to a sub-lethal concentration of mercury (0.3 mg/L). After 7 days of exposure, phagocytosis, cell adhesion and intracellular killing activity were found to decrease significantly along with significant decreases in nitric oxide (NO) and myeloperoxidase (MPO) production from macrophages as compared to the control group indicating intracellular damages. Levels of pro-inflammatory cytokines like TNF-alpha and IL-6 were found to be significantly more in mercury treated groups than that of control group indicating inflammatory damage. This included significant ultrastructural changes like fragmented epithelium, lesions in mucosal foldings, degenerated mitochondria, reduction in the number of goblet cells and disoriented microvilli as evident from transmission electron micrographs. PMID- 25936689 TI - The increasing role of phosphatidylethanolamine as a lipid receptor in the action of host defence peptides. AB - Host defence peptides (HDPs) are antimicrobial agents produced by organisms across the prokaryotic and eukaryotic kingdoms. Many prokaryotes produce HDPs, which utilise lipid and protein receptors in the membranes of bacterial competitors to facilitate their antibacterial action and thereby survive in their niche environment. As a major example, it is well established that cinnamycin and duramycins from Streptomyces have a high affinity for phosphatidylethanolamine (PE) and exhibit activity against other Gram-positive organisms, such as Bacillus. In contrast, although eukaryotic HDPs utilise membrane interactive mechanisms to facilitate their antimicrobial activity, the prevailing view has long been that these mechanisms do not involve membrane receptors. However, this view has been recently challenged by reports that a number of eukaryotic HDPs such as plant cyclotides also use PE as a receptor to promote their antimicrobial activities. Here, we review current understanding of the mechanisms that underpin the use of PE as a receptor in the antimicrobial and other biological actions of HDPs and describe medical and biotechnical uses of these peptides, which range from tumour imaging and detection to inclusion in topical microbicidal gels to prevent the sexual transmission of HIV. PMID- 25936690 TI - A comparison of the Monti and spiral Monti procedures: A long-term analysis. AB - INTRODUCTION/BACKGROUND: The Monti ileovesicostomy provides an excellent substitution for an appendicovesicostomy when the appendix is unavailable or suitable for use. The spiral Monti is a useful modification to the traditional Monti as it allows creation of a longer channel when needed. In 2007, the short term outcomes were reported; they compared traditional and spiral Monti in 188 patients with an average follow-up of 43 months. In the present population, a total of 25 subfasical revisions were performed in 21 patients: nine (8.3%) subfascial revisions in the traditional Monti (TM) patients and 12 (15.2%) subfascial revisions in the spiral Monti (SM) patients. The study found an increased risk of subfascial revisions of either TM or SM when the stoma was located at the umbilicus versus right lower quadrant (16.8% vs 6.3%, P < 0.05). On subgroup analysis, this increased subfascial revision rate appeared to be driven by SM channels to the umbilicus rather than other stomal locations, but this trend was not statistically significant. OBJECTIVE: It was hypothesized that with longer follow-up, the spiral Monti would require more subfascial revisions due to progressive lengthening of the channel. STUDY DESIGN: A retrospective chart review was performed for all patients undergoing a traditional Monti (TM) or spiral Monti (SM) procedure at the present institution (1997-2013). Patient demographics, bowel segment used, stomal location, channel or stomal revisions, number of anesthetic endoscopic procedures performed, and indications for revision were reviewed. Kaplan-Meier analysis and Cox proportional hazards modeling was used for analysis. RESULTS: Of the 296 patients identified, 146 had Monti procedures and 150 had spiral Monti procedures (median follow-up 7.7 years). Median age at surgery was 10.6 years. Myelomeningocele was the most common underlying cause of neuropathic bladder, totaling 169 (57.1%) patients. Stomas were located at the umbilicus (106, 35.8%), right lower quadrant (183, 61.8%) and left lower quadrant (seven, 2.4%). Median follow-up for the entire cohort was 7.7 years (range: 1 month-15.7 years). Stomal stenosis rate was 7.4%, and 96.6% of the channels were continent. A total of 87 revisions were performed in 74 patients (25.0%). Of these, 55 were subfascial revisions in 49 patients (16.6%). The umbilical spiral Monti on univariate and multivariate analysis was found to be over twice as likely to undergo subfascial revision. DISCUSSION: The majority of patients with a Monti channel had durable results and did not require further channel surgery with long-term follow-up. Spiral Monti channels to the umbilicus were more than twice as likely to undergo subfascial revision compared to all other Monti channels. Overall, one in three umbilical SM channels required a subfascial revision at 10 years after the initial surgery, compared to one in six of all other Monti channels. The study was limited by being a retrospective, single-center series; however, it does represent the largest series of pure SM and TM patients. It focused only on surgical interventions, thus was likely to underestimate the overall risk of complications, as some complications were managed conservatively. As in all studies, some patients were lost to follow-up and inevitably some of these may have had complications. Correction for this was attempted through survival analysis. CONCLUSION: The present study reported durable and reliable long-term results with Monti and spiral Monti procedures based on a large patient cohort. Spiral Monti to the umbilicus was more than twice as likely to require a subfascial revision. PMID- 25936691 TI - Real life adherence of chronic hepatitis B patients to entecavir treatment. AB - BACKGROUND: Real-life prospective data on adherence to nucleos(t)ide analogues in chronic hepatitis B patients are scarce. AIMS: We investigated adherence to entecavir in relation to virological response. METHODS: In this prospective study, we provided 100 consecutive chronic hepatitis B patients with a medication dispenser that monitored entecavir intake during 16 weeks therapy. Hepatitis B virus (HBV) DNA was measured at baseline and after 16 weeks. Beliefs about medicines were evaluated using a questionnaire. RESULTS: Adherence over 16 weeks averaged 85 +/- 17%, with 70% of patients exhibiting good (i.e. >= 80%) adherence. Patients with poor (i.e. <80%) adherence were significantly younger (p=0.01), with more often indifferent attitudes towards entecavir (p=0.03) Viral breakthrough did not occur during the study. Adherence in patients with HBV DNA after 16 weeks > 20 IU/mL (n=18) and <= 20 IU/mL (n=81) averaged 83% and 91% respectively (p=0.19). In multivariate analysis, adherence was not a significant predictor of HBV DNA negativity (adjusted OR 1.02; p=0.34), after adjustment for duration of entecavir treatment (p<0.001) and HBe-status (p=0.001). CONCLUSIONS: 70% of chronic hepatitis B patients exhibited good adherence to entecavir, with younger age and an indifferent attitude being risk factors for poor adherence. Poor adherence was not an independent predictor of virological response. PMID- 25936692 TI - Hepatic artery dissection with retrograde extension to the celiac trunk and splenic artery after liver transplantation: A clinical challenge. PMID- 25936693 TI - Small bowel lymphangioma: A rare case of intestinal bleeding. PMID- 25936694 TI - A novel approach to detect KRAS/BRAF mutation for colon cancer: Highly sensitive simultaneous detection of mutations and simple pre-treatment without DNA extraction. AB - It has been reported that colon cancer patients with KRAS and BRAF mutations that lie downstream of epidermal growth factor receptor (EGFR) acquire resistance against therapy with anti-EGFR antibodies, cetuximab and panitumumab. On the other hand, some reports say KRAS codon 13 mutation (p.G13D) has lower resistance against anti-EGFR antibodies, thus there is a substantial need for detection of specific KRAS mutations. We have established a state-of-the-art measurement system using QProbe (QP) method that allows simultaneous measurement of KRAS codon 12/13, p.G13D and BRAF mutation, and compared this method against Direct Sequencing (DS) using 182 specimens from colon cancer patients. In addition, 32 biopsy specimens were processed with a novel pre-treatment method without DNA purification in order to detect KRAS/BRAF. As a result of KRAS mutation measurement, concordance rate between the QP method and DS method was 81.4% (144/177) except for the 5 specimens that were undeterminable. Among them, 29 specimens became positive with QP method and negative with DS method. BRAF was measured with QP method only, and the mutation detection rate was 3.9% (6/153). KRAS measurement using a simple new pre-treatment method without DNA extraction resulted in 31 good results out of 32, all of them matching with the DS method. We have established a simple but highly sensitive simultaneous detection system for KRAS/BRAF. Moreover, introduction of the novel pre-treatment technology eliminated the inconvenient DNA extraction process. From this research achievement, we not only anticipate quick and accurate results returned in the clinical field but also contribution in improving the test quality and work efficiency. PMID- 25936695 TI - Cyclopamine-loaded core-cross-linked polymeric micelles enhance radiation response in pancreatic cancer and pancreatic stellate cells. AB - Pancreatic ductal adenocarcinoma (PDAC) is one of the most lethal cancers. Cyclopamine (CPA), a potent inhibitor for sonic hedgehog pathway (SHH), shows great promises in PDAC treatment, including the disruption of tumor-associated stroma, and enhancement of radiation therapy. However, CPA is insoluble in water and therefore requires a nanometric delivery platform to achieve satisfactory performance. We herein encapsulated CPA in a core-cross-linked polymeric micelle system (M-CPA). M-CPA was combined with Cs-137 radiation and evaluated in vitro in PDAC cell lines and a human pancreatic stellate cell line. The results showed that M-CPA had higher cytotoxicity than CPA, abolished Gli-1 expression (a key component of SHH), and enhanced the radiation therapy of Cs-137. M-CPA radiosensitization correlated with its ability to disrupt the repair of radiation induced DNA damage. These findings indicate that the combination therapy of M-CPA and radiation is an effective strategy to simultaneously treat pancreatic tumors and tumor-associated stroma. PMID- 25936696 TI - Direct in vivo assessment of human stem cell graft-host neural circuits. AB - Despite the potential of stem cell-derived neural transplants for treating intractable neurological diseases, the global effects of a transplant's electrical activity on host circuitry have never been measured directly, preventing the systematic optimization of such therapies. Here, we overcome this problem by combining optogenetics, stem cell biology, and neuroimaging to directly map stem cell-driven neural circuit formation in vivo. We engineered human induced pluripotent stem cells (iPSCs) to express channelrhodopsin-2 and transplanted resulting neurons to striatum of rats. To non-invasively visualize the function of newly formed circuits, we performed high-field functional magnetic resonance imaging (fMRI) during selective stimulation of transplanted cells. fMRI successfully detected local and remote neural activity, enabling the global graft-host neural circuit function to be assessed. These results demonstrate the potential of a novel neuroimaging-based platform that can be used to identify how a graft's electrical activity influences the brain network in vivo. PMID- 25936697 TI - Disseminated fusariosis and hematologic malignancies, a still devastating association. Report of three new cases. AB - BACKGROUND: Fungi of the genus Fusarium are primarily plant pathogens and saprobes that produce disseminated infections in immunologically deficient humans. After aspergillosis, disseminated fusariosis is the second most common cause of invasive infection by filamentous fungi in patients with hematologic malignancies or those undergoing transplants of hematopoietic progenitors. AIMS: Disseminated fusariosis (DF) is considered an extremely rare infection and has reached a stable incidence rate, but its high mortality rate and the lack of an optimal management protocol have raised increasing interest in this mycosis. METHODS: We present three cases of DF produced by Fusarium oxysporum species complex, Fusarium solani species complex and the highly unusual Fusarium dimerum in patients with advanced hematological malignancies diagnosed in our hospital between 2007 and 2011. The species level identification of the Fusarium isolates was established by sequencing their TEF1 gene. RESULTS: The isolates showed low susceptibility to most of the antifungal agents analyzed, except that observed for F. dimerum to amphotericin B (AmB) and terbinafine, and F. oxysporum species complex to AmB. Interestingly, the strain of F. solani species complex exhibited high MIC values for AmB and voriconazole, notwithstanding these drugs were used for treatment with good results. Other relevant aspects to be considered in the treatment of DF are surgically cleaning foci of infection, withdrawing presumably contaminated catheters and recovery from neutropenia. CONCLUSIONS: The prevention of infection in colonized patients, the maintenance of a high level of diagnostic suspicion for early diagnosis, and the combined, vigorous and prolonged use of L AmB and voriconazole are essential to decrease the mortality rate of this devastating infection. PMID- 25936698 TI - Virtual screening approach of sirtuin inhibitors results in two new scaffolds. AB - Sirtuins (SIRT1-SIRT7) are NAD dependent deacetylases and intriguing drug targets in for example neurodegenerative diseases and cancer. Virtual screening has been shown to be a fast and efficient method of discovering new sirtuin inhibitors. In this study, a new putative binding site on the zinc binding domain of sirtuins was utilized to screen the ZINC database virtually in order to discover new sirtuin inhibiting scaffolds. Altogether 26 compounds were tested in vitro and initially 15 inhibitors displayed >30% SIRT3 inhibition. However, the evaluation of raw data from in vitro assay revealed that many of the compounds had intrinsic property to interfere with the fluorescence signal at the assay wavelengths resulting in false positives. All compounds with over 30% SIRT3 inhibition were studied more closely for their behavior in the assay and eventually, three compounds were identified as novel sirtuin inhibitors. They displayed 32-40% SIRT3 and 21-60% SIRT2 inhibition. The inhibitors display two new scaffolds, the smaller of which can be considered as a promising fragment, which offers a base for structural optimization. PMID- 25936699 TI - Outcome of the treatment of osteonecrosis of femoral head using the core decompression with bone impaction grafting. AB - OBJECTIVE: To evaluate the outcome of core decompression with bone impaction grafting for the treatment of osteonecrosis of femoral head. METHODS: Totally 39 cases (46 hips) of osteonecrosis of femoral head were treated with core decompression and impaction bone grafting. According to the Association Research Circulation Osseous (ARCO) system, 3 hips were graded for stage 1,16 for stage 2a,7 for 2b,11 for 2c, and 9 for 3.The Harris hip score (HHS) was evaluated before operation and at the latest follow-up. RESULTS: In all these patients, 22 hips had hormone-related lesions, 11 had alcohol-related lesions, and 13 had idiopathic lesions. The average HHS was changed from (66 +/- 6.6) before surgery to (80.2 +/- 9.7) after surgery during an average follow-up of 26 months(from 9 to 48 months). The postoperative HHS showed no significant difference among osteonecrosis of femoral head due to different etiologies.Also,the postoperative HHS and clinical effectiveness were not significantly different among patients with different preoperative stages.The postoperative outcome was excellent in 7 cases, good in 23 cases, mild in 4 cases,and poor in 12 cases. The rate of excellent and good was 65% in this series,with 78% for patients with early stages and 52.6% for those with grade 2c or higher lesions. The femoral head collapsed in 7 cases,and 5 of which were preoperatively graded as in stage 2c and higher. The postoperative complications included intertrochanteric fracture (n=1) and infection (n=1). Four hips were converted to total hip arthroplasty. All of other hips had no obvious progression of osteonecrosis. CONCLUSIONS: Core decompression with bone impaction allografting is effective for the treatment of osteonecrosis of femoral head. Patients with lesions in earlier ARCO stages can have better outcomes. PMID- 25936700 TI - Correlation of creatine kinase with patency of stents using coronary computed tomography angiography. AB - OBJECTIVE: To explore the potential correlation between creatine kinase and the long-term patency of coronary drug eluting stents. METHODS: The clinical data of 74 patients who had undergone coronary computed tomography angiography after drug eluting stents implantation were retrospecpectively analyzed. Based on the computed tomography angiography findings,these patients were divided into patency group and non-patency group. The mean follow-up time was (20.5 +/- 13.1) months. The serum levels of creatine kinase and creatine kinase isoenzyme were measured to determine the relationship of stent patency with these oxidative-related biomarkers after long-term follow-up. The T test or non-parametric test was adopted to compare the intergroup difference of measurement data,whereas chi square test was conducted to test the difference of enumeration data. Logistic regression was adopted to analyze the biochemical indexes and clinical information. Only variables with a P value of less than 0.05 in the univariable analyses entered the multivariate Logistic regression model. RESULTS: Patients in the non-patency group had significantly higher serum creatine kinase level compared with patients in patency group [(115.5 +/- 51.5)U/L vs.(75.9 +/- 29.4)U/L, P=0.012] and significantly higher level of creatine kinase isoenzyme [(3.5 +/- 5.3)U/L vs.(1.7 +/- 1.3)U/L,P=0.034]. Furthermore,the Logistic analysis showed that serum creatine kinase level (odds ratio=1.573,95% CI=1.022-2.421, P=0.039)was an independent predictor of stent patency. CONCLUSION: Creatine kinase is an independent risk factor associated with stent non-patency. PMID- 25936701 TI - Incidences of aortic and mitral valve strands in patients with migraine with aura. AB - OBJECTIVE: To analyze the potential association between valvular strands and migraine with aura. METHODS: During a 1-year period,transesophageal echocardiography was performed in 51 consecutive patients with migraine with aura and 75 control subjects who underwent transesophageal echocardiography for other purposes and had no history of migraine. The presence of aortic and mitral valve strands was evaluated. RESULTS: The incidence of valvular strands was 21.5% (11/51) in migraine patients and 28.0% (21/75) in control subjects (Chi2=0.663, P=0.416). The incidence of patent foramen ovale was significantly higher in patients with migraine with aura than in control subjects (50.9% vs.29.3%) (Chi2=6.302, P=0.012). The incidence of aortic valve strands was significantly higher than that of mitral valve strands in migraine patients (Chi2=4.320,P=0.038). CONCLUSION: Valvular strands are not associated with migraine with aura and show little clinical significance. PMID- 25936702 TI - Establishment and assessment of rat models of glucocorticoid-induced osteonecrosis. AB - OBJECTIVE: To establish the rat models of glucocorticoid-induced osteonecrosis and evaluate the osteonecrosis by high-resolution micro-CT and histomorphology. METHODS: Totally 30 Sprague-Dawley male adult rats (age:12 weeks; body weight:400 450 g) were randomized into two groups:one group received two doses of intraperitoneal injection of lipopolysaccharide (20 MUg/kg) at an interval of 24 hours, 24 hours later, the rats received three doses of intramuscular injection of methylprednisolone (40 mg/kg) at an interval of 24 hours; in the control group,the rats received same amount of normal saline. Four weeks later, 5 rats in each group were sacrificed randomly.Eight weeks later, all the remaining rats were sacrificed and the femur specimens were scanned by micro-CT. The trabeculae parameters of the femoral head were calculated. The hematoxylin and eosin staining were performed to calculated the success rate. RESULTS: The incidence of osteonecrosis was 80% in the experimental group. The micro-CT demonstrated broken and cystic degeneration. The quantitative analysis showed that the bone volume/total volume (experimental group:0.55 +/- 0.13 vs. CONTROL GROUP: 0.68 +/- 0.12;P<0.05), bone surface area / bone volume (experimental group:20.45 +/- 5.13 vs. CONTROL GROUP: 24.00 +/- 5.20;P<0.05), and trabeculae number(experimental group: 5.67 +/- 0.50 vs. CONTROL GROUP: 6.24 +/- 0.96; P<0.05) were significantly lower in experimental group than those in control group. CONCLUSIONS: A rat model of glucocorticoid-induced osteonecrosis was successfully established by lipopolysaccharide and methylpredniso- lone. High-resolution micro-CT is useful for the qualitative and quantitative analyses of the morphology and structure of trabeculae, showing good consistence with the histomorphological findings. PMID- 25936703 TI - Roles of acoustic radiation force impulse and two-dimensional shearwave elastography in grading liver fibrosis in rabbits. AB - OBJECTIVE: To explore the difference between acoustic radiation force impulse (ARFI) and two-dimensional shearwave elastography (2D-SWE) in grading liver fibrosis (LF). METHODS: Sixty New Zealand rabbits were divided into control group (n=10; without any treatment) and LF group (n=50; treated with CCl4 to induce LF at different degrees). Liver stiffness (LS) were measured in all the animals using ARFI and 2D-SWE, and liver tissues in the same sites were collected for pathological analysis. Spearman's rank-correlation coefficient was used for analysis between LF and LS,and the receiver operating characteristic curve was constructed to analyze the difference of the diagnostic performance of the two techniques. RESULTS: Data were obtained from 37 animals, among which 14 sites was at F0,11 sites at F1,12 sites at F3,and 22 sites at F4.All the LS measurements were successfully performed.A significant correlation between LS and ARFI results (r=0.802,P<0.01)as well as a significant correlation between LF and 2D-SWE results (r=0.892, P<0.01)were found. The receiver operating characteristic curves were successfully constructed. The area under the curve for diagnosing LF higher than F0, F1, F2 and F3 were 0.809,0.916,0.938, and 0.934, respectively, for ARFI, and those were 0.917,0.935,0.976, and 0.974, respectively,for 2D-SWE. CONCLUSION: ARFI and 2D-SWE can accurately grade LF,and 2D-SWE has a better diagnostic performance than ARFI. PMID- 25936704 TI - Correlations between pathologic subtypes/immunohistochemical implication and CT characteristics of lung adenocarcinoma <= 1 cm with ground-glass opacity. AB - OBJECTIVE: To discuss the correlation of pathologic subtypes and immunohistochemical implication with CT features of lung adenocarcinoma 1 cm or less in diameter with focal ground-glass opacity (fGGO). METHODS: CT appearances of 59 patients who underwent curative resection of lung adenocarcinoma <= 1 cm with fGGO were analyzed in terms of lesion location, size, density, shape (round, oval, polygonal, irregular), margin (smooth, lobular, spiculated, lobular and spiculated), bubble-like sign, air bronchogram, pleural tag, and tumor-lung interface. Histopathologic subtypes were classified according to International Association for the Study of Lung Cancer/ American Thoracic Society/European Respiratory Society classification of lung adenocarcinoma. Common molecular markers in immunohistochemical study included human epidermal growth factor receptor (HER)-1,HER-2,Ki-67, vascular endothelial growth factor (VEGF) and DNA topoisomerase 2Alpha.Patients' age and lesions' size and density were compared with pathologic subtypes using analysis of variance or nonparametric Wilcoxon tests. Patients' gender, lesion location, shape and margin, bubble-like sign, air bronchogram, pleural tag, and tumor-lung interface were compared with histopathologic subtypes and immunohistochemical implication using psi2 test or Fisher's exact test. RESULTS: The patients' gender, age, lesion location, shape, air bronchogram, pleural tag, and tumor-lung interface were not significantly different among different histopathologic subtypes (P=0.194, 0.126, 0.609, 0.678, 0.091, 0.374, and 0.339, respectively), whereas the lesion size,density,bubble like sign, and margin showed significant differences (P=0.028, 0.002, 0.003, 0.046, respectively). The expression of Ki-67 significantly differed among nodules with different shapes(P=0.015). Statistically significant difference also existed between tumor-lung interface and HER-1 expression (P=0.019) and between bubble sign and HER-2 expression (P=0.049). CONCLUSIONS: Of lung adenocarcinoma <= 1 cm with fGGO,bubble-like sign occurs more frequently in invasive pulmonary adenocarcinoma and less frequently in atypical adenomatous hyperplasia. In addition, preinvasive lesions (atypical adenomatous hyperplasia and adenocarcinoma in situ) more frequently demonstrates smooth margin,while invasive lesions (minimally invasive adenocarcinoma and invasive pulmonary adenocarcinoma) more frequently demonstrates lobular and spiculated margin. Some CT features are associated with immunohistochemical implication of lung adenocarcinoma <= 1 cm with fGGO. PMID- 25936705 TI - Application of plasma clearance of iohexol in evaluating renal function in chinese children with chronic kidney disease. AB - OBJECTIVE: To evaluate the accuracy of plasma clearance of iohexol (PCio) for glomerular filtration rate (GFR) measurement in Chinese children with chronic kidney disease (CKD) and assess the feasibility of single-blood-sample method or dried capillary blood spots in determining the PCio. METHODS: Totally 45 CKD children were included,in whom the (99m) Technetium-diethylenetriaminepentaacetic acid ((99m)Tc-DTPA) plasma clearance and iohexol plasma clearance were simultaneously determined. Blood samples were obtained 2,4,and 5 hours after injection. In addition, we also evaluated the efficacy of single blood sample method and dried blood spots method in iohexol plasma clearance. RESULTS: Forty five CKD children completed the iohexol plasma clearance and thirty-six children completed the (99m)Tc-DTPA plasma clearance at the same time among them. Thirteen children finished the iohexol dried blood spot clearance. The correlation coefficient between (99m)Tc-DTPA plasma clearance and iohexol plasma clearance was 0.941 and the bias was (6.53 +/- 11.6) ml/ (min.1.73 m2), and the intraclass correlation coefficient (ICC) was high (ICC=0.947). The correlation between iohexol single-sample plasma clearance and double samples was also strong (r=0.958), with the bias being (4.26 +/- 9.06)ml/(min.1.73 m2) and the ICC being 0.970. The iohexol clearance by dried blood spots showed a good correlation with the serum iohexol clearance (r=0.950), with the bias still being small [(0.48 +/- 10.89)ml/(min.1.73 m2)]. CONCLUSIONS: Iohexol plasma clearance has satisfactory agreement with (99m)Tc-DTPA plasma clearance and can be used as an ideal method to measure GFR in CKD children. The single-sample method and dried blood spots method make iohexol plasma clearance more convenient and practical. PMID- 25936706 TI - Effects of stroke volume variation, pulse pressure variation, and pleth variability index in predicting fluid responsiveness during different positive end expiratory pressure in prone position. AB - OBJECTIVE: To investigate the effects of different positive end expiratory pressures (PEEP) on functional hemodynamic parameters in patients lying in prone position during operation under general anesthesia. METHODS: Totally 60 patients undergoing cervical vertebra operation or lumbar vertebra operation were studied. All patients were also monitored with Vigileo/FloTrac system. The functional hemodynamic parameters including stroke volume variation (SVV), pulse pressure variation (PPV), and pleth variability index (PVI) under PEEP levels of 0 mmHg, 5 mmHg, 10 mmHg, and 15 mmHg were recorded before and after volume expansion (hydroxyethyl starch 6%,7 ml/kg). Fluid responsiveness was defined as an increase in stroke volume index (SVI) >= 15%(?SVI >= 15%). Responders were defined as patients demonstrating an increase in SVI >= 15% after intravascular volume expansion and non-responders as patients whose SVI changed <15%. Receiver operating characteristic (ROC) curves were generated for SVV, PPV, and PVI under different PEEP levels to determine their diagnosis accuracies and thresholds and their potential correlations. RESULTS: In the prone position, SVV, PPV, and PVI were significantly higher compared to those in the supine position (P<0.05) and the mean arterial pressure significantly decreased (P<0.05); however, the changes of heart rate, stroke volume, SVI, cardiac output, and cardiac index showed no significant difference (P>0.05). In the prone position, along with the elevation of PEEP (0 mmHg, 5 mmHg, 10 mmHg, and 15 mmHg), the areas under the ROC curves of SVV were 0.864, 0.759, 0.718, and 0.521, the area under the ROC of PPV were 0.873, 0.792,0.705, and 0.505, and the area under the ROC of PVI were 0.851, 0.765 ,0.709, and 0.512. Under PEEP=0 mmHg, the diagnostic thresholds of SVV, PPV, and PVI were 10.5, 11.5, and 13.5. Under PEEP=5 mmHg, the diagnostic thresholds of SVV,PPV, and PVI were 11.5,13.5, and 14.5.Under PEEP=10 mmHg,the diagnostic thresholds of SVV, PPV, and PVI were 13.5,14.5, and 16.5.In the prone position,there was a significant correlation between SVV,PPV,PVI,and PEEP. CONCLUSIONS: SVV,PPV and PVI can predict fluid responsiveness similarly under the PEEP levels of 0,5, and 10 mmHg. Their diagnostic thresholds increases with the PEEP and the diagnostic accuracies decrease with the PEEP. However, under the PEEP level of 15 mmHg, SVV, PPV, and PVI can not predict fluid responsiveness accurately. PMID- 25936707 TI - Effect of accutase or trypsin dissociation on the apoptosis of human striatum derived neural stem cells. AB - OBJECTIVE: To observe the apoptosis of neural stem cells (NSCs) at differential time points after the dissociation of neurospheres by Accutase or trypsin. METHODS: The NSCs were isolated from striatum of human fetals that suffered abortion at 12-16 weeks of pregnancy. The 3(rd)-5(th) passages of NSCs were digested by Accutase or trypsin. Only vortexing was applied, and the triturating by Pasteur pipette was avoided to attenuate the injury to the cells during the dissociation. The single cells were then stained by Annexin V/propidium iodide and Hoechst 33342. The apoptosis rates 2 and 24 hours after passaging were evaluated. RESULTS: The trypan blue staining confirmed that immediately after the dissociation,the viability of cells digested by trypsin was (83.10 +/- 6.76)%, which was significantly lower than that digested by Accutase,which was (91.65 +/- 4.43)% (P<0.05). The apoptosis of the NSCs digested by Accutase was higher than that digested by trypsin at both 2 and 24 hours after passaging (P<0.01). Four days after the passaging, both the new clone formation rate and diameter of new spheres after trypsin digestion were significantly higher than those after Accutase digestion (P<0.01). CONCLUSIONS: Although the viability of NSCs immediately after the disassociation by trypsin is lower than that digested by Accutase, the apoptosis of NSCs subsequently caused by trypsin is lower than that caused by Accutase. Trypan blue test immediately after the disassociation can not be used as an indicator in estimating the apoptosis of NSCs during the expanding. PMID- 25936708 TI - Establishment of a stable mouse model of brain death by the method of the gradually increasing intracranial pressure. AB - OBJECTIVE: To establish a stable and modified mouse model of brain death (BD) and to share our experiences in BD induction and maintenance. METHODS: Totally 35 C57BL/6 male mice were randomized into BD group (n=25) or sham control group (n=10). BD was induced by inserting a 2F Fogarty catheter connected to a syringe pump after trepanation of the left frontoparietal area and injecting volume at the speed of 6 MUl/min until spontaneous respiration ceased. BD was diagnosed by electroencephalogram, apnea testing,as well as testing of brain stem reflexes. Mechanical ventilation was performed by orotracheal intubation. Right carotid artery was intubated by a PE-10 cannula for the continuous monitoring of mean blood pressure (MAP) and heart rate (HR). The right external jugular vein was catheterized for volume resuscitation.The sham control group underwent the same procedure with catheter insertion but without balloon inflation.Livers were removed and fixed in paraffin to evaluate the histological alterations with the light microscopy. RESULTS: Mouse models of BD were successfully established about 20 minutes after balloon inflation, and the mean balloon volume at the time of BD was (105.77 +/- 21.57)MUl. The MAP and HR rapidly increased on occurrence of BD and the peak value was (128.28 +/- 17.16) mmHg and (434.16 +/- 55.75) beat/min, respectively, which were significant higher than those in the sham control group at the same time point (P=0.000). During the 4-hour follow-up time, MAP and HR in 72% (18/25) of BD animals remained haemodynamically stable. No animal died due to anesthesia and surgical operation.Hepatic tissues in BD mice showed mild focal ischemic damages (cellular edema, congestion, and inflammatory infiltration), which were slighter and fewer in sham control group. CONCLUSION: The mouse model of BD was successfully established with lower surgical difficulty and can be performed in a standardized, reproducible and successful way. PMID- 25936709 TI - Impact of comprehensive psychological training on mental health of recruits in Xinjiang. AB - OBJECTIVE: To examine the effect of comprehensive psychological training on the mental health of recruits and to provide basis for promoting mental health among recruits in Xinjiang. METHODS: From September to December, 2013, a convenience sampling was used to select 613 recruits from Xinjiang. These recruits were assigned to the training group (n=306) and the control group (n=307). The Simplified Coping Style Questionnaire,the Questionnaire of Armymen's Emotion Regulation Types and the Chinese Military Personnel Social Support Scale were used to evaluate the levels of mental health at the baseline and at the end of comprehensive psychological training. RESULTS: After comprehensive psychological training, the negative coping style score of the training group were significantly lower than the control group (P=0.000), and there were difference in cognitive focus (P=0.000) and behavior restrain (P=0.005); also, there was significant difference in social support scale (P<0.05). The coping style showed positive correlation with emotion regulation and all factors (P<0.05). Social support and all factors was positively correlated with positive coping style (P<0.05) and negatively correlated with negative coping style (P<0.05). Social support and all factors showed positive correlation with affective appeal and self comfort (P<0.05) and negative correlation with congnitive focus and behavior restrain (P<0.05). As shown by stepwise regression analysis,the positive and negative coping styles had statistically significant impacts on cognitive focus, affective appeal, behavior restrain, and self comfort (all P<0.05). CONCLUSION: Comprehensive psychological training is useful in improving the mental health of recruits. PMID- 25936710 TI - Preparation and pharmacodynamic evaluation of naringenin lyophilized liposome. AB - OBJECTIVE: To prepare the lyophilized powder of naringenin liposome and investigate its pharmacodynamics in rat models of acute lung injury (ALI). METHODS: Naringenin liposome was prepared by ethanol injection method and then its quality was evaluated. Also, the related characteristics was evaluated by adding mannitol (5%,W/V) as lyoprotectant to be freeze-dried. The rat ALI models were established by inhaling lipopolysaccharide (LPS) (5 mg/kg). Totally 48 female Sprague-Dawley rats were randomly divided into six groups:control group(A), LPS group(B), LPS+naringenin group(C), LPS+lyophilized liposome group(D), LPS+dexamethasone group(E), and LPS+blank liposome group(F), with 8 rats in each group. Lung wet/dry weight ratio was calculated, and the histopathological morphologies were observed under the light microscope. RESULTS: The encapsulation efficiency of the prepared liposome was (82.44 +/- 0.98)%, the average particle size was (133 +/- 11)nm, and the Zeta potential was (-35.9 +/- 5)mV. The angle of repose of lyophilized powder was 36C and the bulk density was 0.3 g/ml. Compared with the group A, the lung tissues from groups B to F showed different remarkable histopathological changes under a light microscope, including infiltration of inflammatory cells, capillary congestion, hemorrhage, and marked thickening of the alveolar wall,among which group B and F changed the most significant, followed by group C, whereas groups D and E were the lightest. The wet/dry weight ratios increased in groups B to F compared with group A in some degree, and the increase of the lung wet/dry weight ratio in group D and E was significantly lower than in group B(P=0.0012, P=0.0018). CONCLUSION: The technology of preparing naringenin liposome by ethanol injection is simple and feasible, and lyophilized powder has an obvious therapeutic effect on ALI. PMID- 25936711 TI - Effects of melatonin combined with Cis-platinum or methotrexate on the proliferation of osteosarcoma cell line SaOS-2. AB - OBJECTIVE: To evaluate the effects of melatonin (Mel) combined with cis-platinum (DDP) or methotrexate (MTX) on the proliferation of osteosarcoma cell line SaOS 2, and to explore whether Mel combined with DDP or MTX could play a synergistic antitumor effect. METHODS: SaOS-2 was treated with Mel alone or Mel combined with DDP or MTX. Cell counting kit-8 assay was used to measure the cell activities. Combination index(CI) value was used to evaluate the combined effects: CI<1 indicating synergetic effect, CI=1 additive, and CI>1 antagonistic.Flow cytometry was used to analyze cell cycle distribution and cell apoptosis. RESULTS: After treated with Mel (0.5,1,2,4,5 mmol/L), DDP (6.67, 16.67, 33.33, 66.66 MUmol/L) or MTX(0.1, 0.5, 1, 2, 4 mmol/L)alone,SaOS-2 cell activities decreased in a dose dependent manner (all P<0.05). The activities of SaOS-2 cell treated with both Mel (1 mmol/L) and DDP or MTX were significantly lower than that of DDP or MTX alone (all P<0.05).CI values of cells exposed to 1 mmol/L Mel plus 6.67, 16.67, 33.33, and 66.66 MUmol/L DDP were 1.18, 1.21, 1.09, and 0.84, respectively,and CI values of cells exposed to 1 mmol/L Mel plus 0.1, 0.5, 1, 2, and 4 mmol/L MTX were 0.88, 0.88 ,0.83, 0.78, and 0.81, respectively. The G1-stage cells were increased and the S-stage cells were reduced when the cells were treated with Mel (1 mmol/L) alone or combined with MTX (0.5 mmol/L) (P<0.05). The S-stage cells were increased when the cells treated with MTX (0.5 mmol/L) (P<0.05). The apoptotic cells were increased when they treated with Mel (1 mmol/L) alone or combined with DDP (16.67 MUmol/L) or MTX (0.5 mmol/L) (P<0.05). When the cells were treated with Mel combined with DDP or MTX, the apoptotic cells were more than that of DDP or Mel alone(P<0.05). CONCLUSIONS: Mel can inhibit SaOS-2 cells activity,block the cell cycle at G1-stage,and induce apoptosis. Mel has an antagonistic effect with lower concentration of DDP but a synergistic effect with MTX or higher concentration of DDP. PMID- 25936712 TI - Values of iodine metabolism biomarkers in assessing the iodine nutrition status in surgically treated patients with thyroid disease. AB - OBJECTIVE: To assess the clinical application value of iodine metabolism biomarkers in assessing iodine nutrition status in surgically treated patients with thyroid disease. METHODS: Blood,morning urine and 24-hour urine samples were collected in 31 healthy volunteers and in 30 surgically treated patients with thyroid disease before and after surgery. Iodine concentration was analyzed by inductively coupled plasma mass spectrometry. The iodine metabolism biomarkers including serum iodine (SI), morning urine iodine(UI), morning urine iodine/urine creatinine ratio (UI/UCr), 24-hour urine iodine (24 h UI), and 24-hour urine iodine excretion (24 h UIE) were evaluated in these two groups. In addition, the validation coincidence rate of iodine metabolism biomarkers in healthy volunteers to different reference ranges including World Health Organization, Mayo Clinic, and Quest Diagnostics were calculated. RESULTS: The UI/UCr ratio of pre-operative thyroid disease patients was significantly lower than that of healthy volunteers (P<0.05), while the other biomarkers showed no significant differences (all P>0.05) between these two groups. The SI, UI ,and 24 h UI in postoperative thyroid disease patients were significantly higher than those of the pre operative patients (all P<0.05). Though the medians of all biomarkers in healthy volunteers were within the reference ranges,only the validation coincidence rates of SI, UI, and UI/UCr in the 41-70-year populations were over than 90% according to Mayo Clinic; furthermore, the area under the receiver operating characteristic curve about UI/UCr ratio (0.737) was the biggest within the iodine metabolism biomarkers. CONCLUSION: The UI/UCr ratio may be used for iodine nutrition evaluation in surgically treated patients with thyroid disease. PMID- 25936713 TI - Characteristic dermoscopic features of melasma. AB - OBJECTIVE: To discribe the characteristic dermoscopic features of melasma. METHODS: Totally 20 patients with typical clinical presentations of melasma were included in this study. The melasma lesion and its surrounding normal skin were evaluated using dermatoscope. RESULTS: Melasma lesions manifested light yellow brown uniform patches in all patients, among whom dark brown patches were found in 19 patients, capillary network in 14 patients,and coarse hair in 6 patients. In contrast, no light yellow brown uniform patch was found in the normal skin in all patients (P<0.001), among whom dark brown patches were found in 10 patients (P<0.001), capillary network in 12 patients (P>0.05), and coarse hair in 2 patients (P>0.05). CONCLUSION: Light yellow brown uniform patches and dark brown patches are two major dermoscopic features of melasma. PMID- 25936714 TI - Application of vacuum assisted venous drainage in heart surgeries for newborns. AB - OBJECTIVE: To explore the role of cardiopulmonary bypass (CPB) with vacuum assisted venous drainage(VAVD)in the management of newborns with congenital heart diseases. METHODS: Total 15 newborns with congenital heart diseases (11 males and 4 females)underwent heart operations. Their age ranged from 2 days to 28 days [mean:(15.67 +/- 2.22)days], and their body weight from 2.3 kg to 4.8 kg [mean: (3.75 +/- 0.19)kg]. Sternal median incision was made to establish CPB,during which VAVD was applied for all the newborns. RESULTS: In these 15 newborns,the mean CPB time was from 50 minutes to 343 minutes [mean:(170.3 +/- 26.6)minutes], and the mean aortic clamping time ranged from 20 minutes to 172 minutes [mean:(85.8 +/- 14.6)minutes]. No macroscopic hematuria, inadequate drainage, or cannulation vena cava difficulty was observed during the procedures. All the newborns were successfully weaned from the machine. No neurological complication due to micro air embolus caused by negative pressure was noted. No vena cava infarction, thrombosis, or other complication was reported after the surgery, although one patient died after the surgery and another patient was discharged upon its family's own decision. CONCLUSIONS: VAVD is a safe, simple, and cost effective technique. Appropriate negative pressure can the resistance during thinner venous intubation and thus speed up blood drainage,provide adequate perfusion flow,and reduce the pre-filling volume. PMID- 25936715 TI - Surgical treatment of diffuse pigmented villonodular synovitis of the knee. AB - OBJECTIVE: To compare the roles of open synovectomy and arthroscopic synovectomy in the treatment of diffuse pigmented villonodular synovitis (D-PVNS). METHODS: Forty-seven patients suffered from D-PVNS of knee joint who underwent surgical treatment with complete follow-up data from March 1994 to October 2013 were retrospectively analyzed. All patients were divided into two groups as open synovectomy group (n=17) and arthroscopic synovectomy group (n=30) according to the surgical procedure. Routine radiation therapy was applied in both groups after the surgery. The mean follow-up period wa s(15.7 +/- 16.3) months (range:10 30 month). The range of motion, International Knee Documentation Committee (IKDC) score and Lysholm score before the surgery and at the final follow-up were compared respectively. RESULTS: Recurrence was noted in 8 patients (17.0%), among whom 3 were from the open synovectomy group and 5 from the arthroscopic synovectomy group, resulting a recurrence rate of 17.6% and 16.7%, respectively, in these two groups (P>0.05). The range of motion,IKDC score, and Lysholm score at final follow-up and before the operation were (97.5 +/- 14.3)C vs.(69.7 +/- 12.6)C, (74.5 +/-6.1) vs. (38.6 +/- 5.4) scores, and (77.5 +/- 5.8) vs. (42.4 +/- 4.6)scores, respectively, in the open synovectomy group,and were (128.6 +/- 13.9)C vs. (64.9 +/- 13.2)C, (87.4 +/- 6.7) vs. (37.2 +/- 4.9)scores, and (86.2 +/- 6.2) vs. (41.9 +/- 5.3) cores, respectively, in the arthroscopic synovectomy group (all P<0.05). Obviously,the range of motion,IKDC score, and Lysholm score at the final follow-up were significantly superior to the pre-operative findings, and were also significantly better in the arthroscopic synovectomy group than in the open synovectomy group (P<0.05). CONCLUSIONS: Open synovetomy and arthroscopic synovetomy have similar recurrent rates in treating D-PVNS of the knee joint, while the latter has better postoperative range of motion and functional scores. Thus, arthroscopic synovectomy is a better option for the surgical treatment of D-PVNS. PMID- 25936716 TI - Application of cloud database in the management of clinical data of patients with skin diseases. AB - OBJECTIVE: To evaluate the needs and applications of using cloud database in the daily practice of dermatology department. METHODS: The cloud database was established for systemic scleroderma and localized scleroderma. Paper forms were used to record the original data including personal information, pictures, specimens, blood biochemical indicators, skin lesions,and scores of self-rating scales. The results were input into the cloud database. The applications of the cloud database in the dermatology department were summarized and analyzed. RESULTS: The personal and clinical information of 215 systemic scleroderma patients and 522 localized scleroderma patients were included and analyzed using the cloud database. The disease status,quality of life, and prognosis were obtained by statistical calculations. CONCLUSIONS: The cloud database can efficiently and rapidly store and manage the data of patients with skin diseases. As a simple, prompt, safe, and convenient tool, it can be used in patients information management, clinical decision-making, and scientific research. PMID- 25936717 TI - Advances in the proinflammatory effects of visfatin and its relationship with diabetic kidney disease. AB - Visfatin, also known as the pre-B-cell colony enhancing factor, is a new member of the adipocytokines. It serves as a nicotinamide phosphoribosyltransferase in cells. Visfatin has complex biological functions and may be involved in the pathogenesis of diabetic kidney disease; it may contribute to the chronic inflammatory status at systemic and renal levels and thus aggravate renal injury. Further research on visfatin will provide new insights in the treatment of diabetic kidney disease. This article reviews the recent advances in the proinflammatory effects of visfatin and its relationship with diabetic kidney disease. PMID- 25936718 TI - Surgical attenuation of spontaneous congenital portosystemic shunts in dogs resolves hepatic encephalopathy but not hypermanganesemia. AB - Hypermanganesemia is commonly recognized in human patients with hepatic insufficiency and portosystemic shunting. Since manganese is neurotoxic, increases in brain manganese concentrations have been implicated in the development of hepatic encephalopathy although a direct causative role has yet to be demonstrated. Evaluate manganese concentrations in dogs with a naturally occurring congenital shunt before and after attenuation as well as longitudinally following the changes in hepatic encephalopathy grade. Our study demonstrated that attenuation of the shunt resolved encephalopathy, significantly reduced postprandial bile acids, yet a hypermanganasemic state persisted. This study demonstrates that resolution of hepatic encephalopathy can occur without the correction of hypermanganesemia, indicating that increased manganese concentrations alone do not play a causative role in encephalopathy. Our study further demonstrates the value of the canine congenital portosystemic shunt as a naturally occurring spontaneous model of human hepatic encephalopathy. PMID- 25936719 TI - Metformin improves anxiety-like behaviors through AMPK-dependent regulation of autophagy following transient forebrain ischemia. AB - Stroke is one of the main threats to the public health worldwide. Metformin, an anti-diabetic drug, is an activator of AMP-activated protein kinase (AMPK). Metformin plays an important role on improving behavior in neurodegenerative diseases through diverse pathways. In the current study we aimed to investigate the probable effects of metformin on anxiety and autophagy pathway in global cerebral ischemia. Rats were divided into seven groups; Sham, ischemia (I/R), metformin (met), compound c (CC), CC+ischemia, met+ischemia, met+CC+ischemia. Metformin was pretreated for 2 weeks and CC administrated half an hour before global cerebral ischemia. Blood glucose, body weight, sensorimotor scores, elevated plus maze and open field test were evaluated after ischemia. Autophagy related factors were measured by Western blot and immunofluorescent assay in hippocampus of rats. Based on our results, pretreatment of rats by metformin improved sensory motor signs, anxiolytic behavior and locomotion in ischemic rats. CC injection in I/R rats attenuated the therapeutic effects of metformin. Autophagy factors such as light chain 3B, Atg7, Atg5-12 and beclin-1 decreased in ischemic rats compared to the sham group (P < 0.001 in all proteins). Level of autophagic factors increased in metformin pretreated rats compared to global cerebral ischemia (P < 0.001 in all proteins). These data indicated that the beneficial role of metformin in behavior and autophagy flux mediates via AMPK. Our results recommended that metformin therapy could improve psychological disorders and movement disability following I/R and profound understanding of AMPK-dependent autophagy would enhance its development as a promising target for intracellular pathway. PMID- 25936720 TI - Maternal and post-weaning high-fat, high-sucrose diet modulates glucose homeostasis and hypothalamic POMC promoter methylation in mouse offspring. AB - Substantial evidence demonstrated that maternal dietary nutrients can significantly determine the susceptibility to developing metabolic disorders in the offspring. Therefore, we aimed to investigate the later-life effects of maternal and postweaning diets interaction on epigenetic modification of the central nervous system in the offspring. We examined the effects of dams fed a high-fat, high-sucrose (FS) diet during pregnancy and lactation and weaned to FS diet continuously until 32 weeks of age. Then, DNA methylation and gene expressions of hypothalamic proopiomelanocortin (POMC) and melanocortin receptor 4 (MC4R) were determined in the offspring. Offspring of FS diet had heavier body weight, impaired glucose tolerance, decreased insulin sensitivity and higher serum leptin level at 32-week age (p < 0.05). The expression of POMC and MC4R genes were significantly increased in offspring exposed to FS diet during gestation, lactation and into 32-week age (p < 0.05). Consistently, hypomethylation of POMC promoter in the hypothalamus occurred in the FS diet offspring (p < 0.05), compared with the C group. However, no methylation was detected of MC4R promoter in both the two groups. Furthermore, POMC-specific methylation (%) was negatively associated with glucose response to a glucose load (r = -0.273, p = 0.039). Maternal and post-weaning high-fat diet predisposes the offspring for obesity, glucose intolerance and insulin resistance in later life. Our findings can advance our thinking around the DNA methylation status of the promoter of the POMC and MC4R genes between long-term high-fat, high-sucrose diet and glucose homeostasis in mouse. PMID- 25936721 TI - Acquisition of Pseudomonas aeruginosa and its resistance phenotypes in critically ill medical patients: role of colonization pressure and antibiotic exposure. AB - INTRODUCTION: The objective of this work was to investigate the risk factors for the acquisition of Pseudomonas aeruginosa and its resistance phenotypes in critically ill patients, taking into account colonization pressure. METHODS: We conducted a prospective cohort study in an 8-bed medical intensive care unit during a 35-month period. Nasopharyngeal and rectal swabs and respiratory secretions were obtained within 48 hours of admission and thrice weekly thereafter. During the study, a policy of consecutive mixing and cycling periods of three classes of antipseudomonal antibiotics was followed in the unit. RESULTS: Of 850 patients admitted for >= 3 days, 751 (88.3%) received an antibiotic, 562 of which (66.1%) were antipseudomonal antibiotics. A total of 68 patients (8%) carried P. aeruginosa upon admission, and among the remaining 782, 104 (13%) acquired at least one strain of P. aeruginosa during their stay. Multivariate analysis selected shock (odds ratio (OR) = 2.1; 95% confidence interval (CI), 1.2 to 3.7), intubation (OR = 3.6; 95% CI, 1.7 to 7.5), enteral nutrition (OR = 3.6; 95% CI, 1.8 to 7.6), parenteral nutrition (OR = 3.9; 95% CI, 1.6 to 9.6), tracheostomy (OR = 4.4; 95% CI, 2.3 to 8.3) and colonization pressure >0.43 (OR = 4; 95% CI, 1.2 to 5) as independently associated with the acquisition of P. aeruginosa, whereas exposure to fluoroquinolones for >3 days (OR = 0.4; 95% CI, 0.2 to 0.8) was protective. In the whole series, prior exposure to carbapenems was independently associated with carbapenem resistance, and prior amikacin use predicted piperacillin-tazobactam, fluoroquinolone and multiple-drug resistance. CONCLUSIONS: In critical care settings with a high rate of antibiotic use, colonization pressure and non-antibiotic exposures may be the crucial factors for P. aeruginosa acquisition, whereas fluoroquinolones may actually decrease its likelihood. For the acquisition of strains resistant to piperacillin-tazobactam, fluoroquinolones and multiple drugs, exposure to amikacin may be more relevant than previously recognized. PMID- 25936722 TI - Characterization of a novel oil-in-water emulsion adjuvant for swine influenza virus and Mycoplasma hyopneumoniae vaccines. AB - Vaccines consisting of subunit or inactivated bacteria/virus and potent adjuvants are widely used to control and prevent infectious diseases. Because inactivated and subunit antigens are often less antigenic than live microbes, a growing need exists for the development of new and improved vaccine adjuvants that can elicit rapid and long-lasting immunity. Here we describe the development and characterization of a novel oil-in-water emulsion, OW-14. OW-14 contains low-cost plant-based emulsifiers and was added to antigen at a ratio of 1:3 with simple hand mixing. OW-14 was stable for prolonged periods of time at temperatures ranging from 4 to 40 degrees C and could be sterilized by autoclaving. Our results showed that OW-14 adjuvanted inactivated swine influenza viruses (SIV; H3N2 and H1N1) and Mycoplasma hyopneumoniae (M. hyo) vaccines could be safely administered to piglets in two doses, three weeks apart. Injection sites were monitored and no adverse reactions were observed. Vaccinated pigs developed high and prolonged antibody titers to both SIV and M. hyo. Interestingly, antibody titers were either comparable or greater than those produced by commercially available FluSure (SIV) or RespiSure (M. hyo) vaccines. We also found that OW-14 can induce high antibody responses in pigs that were vaccinated with a decreased antigen dose. This study provides direct evidence that we have developed an easy to-use and low-cost emulsion that can act as a powerful adjuvant in two common types of swine vaccines. PMID- 25936723 TI - The European I-MOVE Multicentre 2013-2014 Case-Control Study. Homogeneous moderate influenza vaccine effectiveness against A(H1N1)pdm09 and heterogenous results by country against A(H3N2). AB - BACKGROUND: In the first five I-MOVE (Influenza Monitoring Vaccine Effectiveness in Europe) influenza seasons vaccine effectiveness (VE) results were relatively homogenous among participating study sites. In 2013-2014, we undertook a multicentre case-control study based on sentinel practitioner surveillance networks in six European Union (EU) countries to measure 2013-2014 influenza VE against medically-attended influenza-like illness (ILI) laboratory-confirmed as influenza. Influenza A(H3N2) and A(H1N1)pdm09 viruses co-circulated during the season. METHODS: Practitioners systematically selected ILI patients to swab within eight days of symptom onset. We compared cases (ILI positive to influenza A(H3N2) or A(H1N1)pdm09) to influenza negative patients. We calculated VE for the two influenza A subtypes and adjusted for potential confounders. We calculated heterogeneity between sites using the I(2) index and Cochrane's Q test. If the I(2) was <50%, we estimated pooled VE as (1 minus the OR)*100 using a one-stage model with study site as a fixed effect. If the I(2) was >49% we used a two-stage random effects model. RESULTS: We included in the A(H1N1)pdm09 analysis 531 cases and 1712 controls and in the A(H3N2) analysis 623 cases and 1920 controls. For A(H1N1)pdm09, the Q test (p=0.695) and the I(2) index (0%) suggested no heterogeneity of adjusted VE between study sites. Using a one-stage model, the overall pooled adjusted VE against influenza A(H1N1)pdm2009 was 47.5% (95% CI: 16.4-67.0). For A(H3N2), the I(2) was 51.5% (p=0.067). Using a two-stage model for the pooled analysis, the adjusted VE against A(H3N2) was 29.7 (95% CI: -34.4 63.2). CONCLUSIONS: The results suggest a moderate 2013-2014 influenza VE against A(H1N1)pdm09 and a low VE against A(H3N2). The A(H3N2) estimates were heterogeneous among study sites. Larger sample sizes by study site are needed to prevent statistical heterogeneity, decrease variability and allow for two-stage pooled VE for all subgroup analyses. PMID- 25936725 TI - Reply to letter to the editor. PMID- 25936724 TI - A double-blind, randomised, placebo-controlled, dose-finding trial of the novel tuberculosis vaccine AERAS-402, an adenovirus-vectored fusion protein, in healthy, BCG-vaccinated infants. AB - BACKGROUND: Several novel tuberculosis vaccines are currently in clinical trials, including AERAS-402, an adenovector encoding a fusion protein of Mycobacterium tuberculosis antigens 85A, 85B, and TB10.4. A multicentred trial of AERAS-402 safety and immunogenicity in healthy infants was conducted in three countries in sub-Saharan Africa, using an adaptive design. METHODS: In a double-blind, randomised, placebo-controlled, dose-finding trial, we enrolled BCG-vaccinated, HIV-uninfected infants aged 16-26 weeks. Infants in the safety/dose-finding phase received two doses of AERAS-402 across three dose levels, or placebo, intramuscularly on days 0 and 28. Infants in the expanded safety phase received three doses of the highest dose level, with the 3rd dose at day 280. Follow up for safety and immunogenicity was for up to two years. RESULTS: We enrolled 206 infants (52 placebo and 154 AERAS-402 recipients) into the dose-finding phase and 281 (141 placebo and 140 AERAS-402 recipients) into the expanded safety phase. Safety data were acceptable across all dose levels. No vaccine-related deaths were recorded. A single serious adverse event of tachypnoea was deemed related to study vaccine. Antibodies directed largely against Ag85A and Ag85B were detected. Low magnitude CD4+ and CD8+ polyfunctional T cell responses were observed at all dose levels. The addition of a third dose of AERAS-402 at the highest dose level did not increase frequency or magnitude of antibody or CD8+ T cell responses. CONCLUSIONS: AERAS-402 has an acceptable safety profile in infants and was well tolerated at all dose levels. Response rate was lower than previously seen in BCG vaccinated adults, and frequency and magnitude of antigen-specific T cells were not increased by a third dose of vaccine. PMID- 25936726 TI - Promoting influenza vaccination: insights from a qualitative meta-analysis of 14 years of influenza-related communications research by U.S. Centers for Disease Control and Prevention (CDC). AB - INTRODUCTION: A primary mission of the U.S. Centers for Disease Control and Prevention's (CDC) is promoting immunization against seasonal influenza. As with most education efforts, CDC's influenza-related communications are often informed by formative research. METHODS: A qualitative meta-analysis of 29 unpublished, primarily qualitative CDC-sponsored studies related to flu and flu vaccination knowledge, attitudes and beliefs (KABs). The studies, undertaken between 2000 and 2013, involved focus groups, in-depth interviews, message testing and surveys. Some involved health care professionals, while others involved members of the public, including sub-populations at risk for severe illness. FINDINGS: The themes that emerged suggested progress in terms of KABs related to influenza and influenza vaccination, but also the persistence of many barriers to vaccine acceptance. With respect to the public, recurring themes included limited understanding of influenza and immunization recommendations, indications of greater sub-group recognition of the value of flu vaccination, continued resistance to vaccination among many, and overestimation of the effectiveness of non-vaccine measures. Seven cognitive facilitators of vaccination were identified in the studies along with six cognitive barriers. For health care providers, the analysis suggests greater knowledge and more favorable beliefs, but many misperceptions persist and are similar to those held by the public. KABs often differed by type or category of health care provider. CONCLUSIONS: The themes identified in this qualitative analysis illustrate the difficulty in changing KABs related to influenza and influenza vaccine, particularly on the scope and scale needed to greatly improve uptake. Even with an influenza pandemic and more vaccine options available, public and some health care provider perceptions and beliefs are difficult and slow to change. This meta-analysis does, however, provide important insights from previously unpublished information that can help those who are promoting influenza vaccination to health care providers, the general public and specific populations within the general population. PMID- 25936727 TI - Surveillance of adverse events following immunization in China: Past, present, and future. AB - Surveillance for adverse events following immunization (AEFI) is an important component of any national immunization program. In the People's Republic of China (China), a populous, middle-income country, development of an AEFI surveillance system began in 2005. In 2008, the AEFI surveillance system was implemented as a nationwide, online system and called the Chinese National AEFI Information System (CNAEFIS). Since then, CNAEFIS has provided useful, national-level data on vaccine safety. National AEFI surveillance guidelines were issued jointly by the Ministry of Health and the China Food and Drug Administration in 2010. This article reviews the development, status, and key aspects of the Chinese AEFI surveillance system, and describes challenges and future plans for vaccine safety assessment in China. PMID- 25936728 TI - Information seeking and retrieval skills of nurses: Nurses readiness for evidence based practice in hospitals of a medical university in Iran. AB - BACKGROUND: With the explosion of medical information, and emergence of evidence based practice (EBP) in healthcare system, searching, retrieving and selecting information for clinical decision-making are becoming required skills for nurses. AIMS: The aims of this study were to examine the use of different medical information resources by nurses and their information searching and retrieving skills in the context of EBP. METHOD: A descriptive, cross-sectional study was conducted in four teaching hospitals in Iran. Data were collected from 182 nurses using a questionnaire in 2014. RESULTS: The nurses indicated that they use more human and printed resources than electronic resources to seek information (mean=2.83, SD=1.5; mean=2.77, SD=1.07; and mean=2.13, SD=0.88, respectively). To search online resources, the nurses use quick/basic search features more frequently (mean=2.45, SD=1.15) than other search features such as advanced search, index browsing and MeSH term searching. (1.74<=mean<=2.30, SD=1.01). At least 80% of the nurses were not aware of the purpose or function of search operators such as Boolean and proximity operators. In response to the question measuring skills of the nurses in developing an effective search statement by using Boolean operators, only 20% of them selected the more appropriate statement, using some synonyms of the concepts in a given subject. CONCLUSION: The study showed that the information seeking and retrieval skills of the nurses were poor and there were clear deficits in the use of updated information resources. To compensate their EBP incompetency, nurses may resort to human resources. In order to use the latest up to date evidence independently, nurses need to improve their information literacy. To reach this goal, clinical librarians, health information specialists, nursing faculties, and clinical nurse educators and mentors can play key roles by providing educational programs. Providing access to online resources in clinical wards can also encourage nurses to learn and use these resources. PMID- 25936729 TI - Production of recombinant protein G through high-density fermentation of engineered bacteria as well as purification. AB - Recombinant Streptococcus Protein G (PG) is a cell wall protein, which, when combined with mammal immunoglobulin, is used in separating antibody technology. High-density fermentation technologies using an engineered recombinant PG producing bacteria as well as PG separation and purification technologies have a direct impact on the availability and application of PG. Through primary and secondary seed cultivation, a recombinant E. coli strain was subjected to high density fermentation with controlled feed supplement concentration under stimulation with isopropyl beta-D-1-thiogalactopyranoside. The present study investigated the effect of factors including inoculum size, oxygen levels, pH and the cultivating method on the fermentation process, as well as the effect of the separation and purification technologies, including ultrasonication, nickel column affinity chromatography, Sephadex G-25 gel filtration chromatography and diethylaminoethanol-sepharose fast flow ion exchange chromatography on the yield and purity of PG. The efficiency of extraction was detected using SDS-PAGE. High density fermentation yielded 80-150 g/l of bacteria and 1 g PG was obtained from one liter broth. The present study delivered a highly efficient novel method via which PG can be obtained at a high concentration and a purity >95%. PMID- 25936730 TI - Physical activity profiles and sedentary behaviour in people following stroke: a cross-sectional study. AB - PURPOSE: To measure and compare physical activity profiles and sedentary time between community dwelling stroke survivors and healthy volunteers. METHODS: Twenty-two stroke survivors (10 men, age 55.3 +/- 9.9 years; 4.2 +/- 4.0 years since their stroke) were recruited from local stroke support groups, and 22 controls were matched for sex, age and body mass index (BMI). All participants wore an ActivPALTM physical activity monitor for seven days and from these data activity profiles, including the number of steps per day, time spent sedentary and time in different cadence bands, were recorded. RESULTS: Stroke survivors took significantly fewer steps per day than the controls (4035 +/- 2830 steps/day versus 8394 +/- 2941 steps/day, p < 0.001) and sedentary time (including sleep time) was significantly higher for stroke participants compared to the controls (20.4 +/- 2.7 h versus 17.5 +/- 3.8 h, p < 0.001). People with stroke spent a significantly higher proportion of their walking time in lower self-selected cadences compared to the controls. CONCLUSIONS: Community dwelling stroke survivors spent more time sedentary, took fewer steps and walked at a slower self selected cadence. Interventions to increase walking and reduce sedentary time following stroke are required which may have the added benefit of reducing cardiovascular risk in this group. Implications for Rehabilitation Stroke survivors are predisposed to reduced physical activity and increased cardiovascular risk. This study showed that community dwelling stroke survivors spent more time sedentary, took fewer steps and walked at a slower self-selected cadence. Interventions are required which focus on reducing sedentary time as well as increasing step counts in people following stroke. PMID- 25936731 TI - Associations of multiple chronic health conditions with active life expectancy in the United States. AB - PURPOSE: To estimate associations of eight common health conditions with life expectancy (LE) and disabled life expectancy (DLE), the percentage of life disabled in an activity of daily living. METHODS: Data from the Panel Study of Income Dynamics represented Americans ages 55+ (1999-2011, n = 2118, mean baseline age 63.3, 19 447 person-years). We estimated probabilities of death and disability with multinomial logistic Markov models adjusted for age, sex, race/ethnicity and education. We used the probabilities to create large populations with microsimulations, each individual having a known monthly disability status, age 55 through death. We calculated LE and DLE for the populations, repeating each microsimulation 100 times for confidence intervals. RESULTS: Nearly half (48.8%) of the participants had two or more conditions, 24.7% had three or more, 11.5% had four or more. Having any one condition significantly reduced LE. For example, white women lived to age 87.3 (95% confidence interval 86.5-88.1) with no conditions, 75.8 (70.9-80.7) with heart disease. Multiple conditions did not further reduce LE but often increased DLE, which for white women was 12.2% (11.1-13.2) with no conditions, 39.1% (28.3-49.8) with heart disease and 47.0% (46.9-47.1) with heart disease, diabetes and hypertension. CONCLUSION: The increasing prevalence of multiple chronic conditions may substantially increase disability. Implications for Rehabilitation The growing number of individuals with multiple chronic conditions will greatly increase the prevalence of disability in later life. It is important for rehabilitation science, practice and policy to address this emerging epidemiological transition. Rehabilitation is especially important for people with pre-diabetes, developing heart disease or early stages of other cardiovascular-related diseases as avoiding the development of multiple chronic diseases through increased activity may greatly reduce disability and mortality. PMID- 25936732 TI - Improving survival for children with sickle cell disease: newborn screening is only the first step. AB - Invited commentary on 'Survival of children with sickle cell disease in the comprehensive newborn screening programme in Minas Gerais, Brazil', Sabarense et al. PMID- 25936733 TI - Language translation challenges with Arabic speakers participating in qualitative research studies. AB - This paper discusses how a research team negotiated the challenges of language differences in a qualitative study that involved two languages. The lead researcher shared the participants' language and culture, and the interviews were conducted using the Arabic language as a source language, which was then translated and disseminated in the English language (target language). The challenges in relation to translation in cross-cultural research were highlighted from a perspective of establishing meaning as a vital issue in qualitative research. The paper draws on insights gained from a study undertaken among Arabic speaking participants involving the use of in-depth semi-structured interviews. The study was undertaken using a purposive sample of 15 participants with Type 2 Diabetes Mellitus and co-existing depression and explored their perception of self-care management behaviours. Data analysis was performed in two phases. The first phase entailed translation and transcription of the data, and the second phase entailed thematic analysis of the data to develop categories and themes. In this paper there is discussion on the translation process and its inherent challenges. As translation is an interpretive process and not merely a direct message transfer from a source language to a target language, translators need to systematically and accurately capture the full meaning of the spoken language. This discussion paper highlights difficulties in the translation process, specifically in managing data in relation to metaphors, medical terminology and connotation of the text, and importantly, preserving the meaning between the original and translated data. Recommendations for future qualitative studies involving interviews with non-English speaking participants are outlined, which may assist researchers maintain the integrity of the data throughout the translation process. PMID- 25936734 TI - Management of soft tissue defects of the hand. AB - Soft tissue coverage of the hand remains a challenging problem to the hand surgeon, but advances in the field of microsurgery have provided improved thin, pliable, durable flaps that offer cosmetic reconstructive options. The reconstructive elevator is poised to replace the reconstructive ladder, thereby allowing early reconstruction by the best available option. This reviews focus on the variety of pedicled, free fasciocutaneous, and venous flaps available for successful soft tissue coverage of the hand. PMID- 25936735 TI - International Federation of Societies for Surgery of the Hand Committee report: the role of nerve transfers in the treatment of neonatal brachial plexus palsy. AB - Nerve transfers have gained popularity in the treatment of adult brachial plexus palsy; however, their role in the treatment of neonatal brachial plexus palsy (NBPP) remains unclear. Brachial plexus palsies in infants differ greatly from those in adults in the patterns of injury, potential for recovery, and influences of growth and development. This International Federation of Societies for Surgery of the Hand committee report on NBPP is based upon review of the current literature. We found no direct comparisons of nerve grafting to nerve transfer for primary reconstruction of NBPP. Although the results contained in individual reports that use each strategy for treatment of Erb palsy are similar, comparison of nerve transfer to nerve grafting is limited by inconsistencies in outcomes reported, by multiple confounding factors, and by small numbers of patients. Although the role of nerve transfers for primary reconstruction remains to be defined, nerve transfers have been found to be effective and useful in specific clinical circumstances including late presentation, isolated deficits, failed primary reconstruction, and multiple nerve root avulsions. In the case of NBPP more severe than Erb palsy, nerve transfers alone are inadequate to address all of the deficits and should only be considered as adjuncts if maximal re innervation is to be achieved. Surgeons who commit to care of infants with NBPP need to avoid an over-reliance on nerve transfers and should also have the capability and inclination for brachial plexus exploration and nerve graft reconstruction. PMID- 25936736 TI - De Quervain tendinopathy: survivorship and prognostic indicators of recurrence following a single corticosteroid injection. AB - PURPOSE: To determine short- and long-term success rates of a single corticosteroid injection for de Quervain tendinopathy while identifying prognostic indicators for symptom recurrence and repeat intervention. METHODS: Fifty consecutive patients with de Quervain tendinopathy treated with corticosteroid injections (lidocaine plus triamcinolone acetonide or dexamethasone) were prospectively enrolled. Patients with inflammatory arthritis, carpometacarpal osteoarthritis, or a previous distal radius fracture affecting the symptomatic wrist were excluded. Demographic data and information on existing comorbidities were recorded. Patients were seen in clinic at 6 weeks after injection and contacted at 3, 6, 9, and 12 months following injection to determine symptom recurrence and further intervention. Medical records were also reviewed for this purpose. Kaplan-Meier survival analysis and Cox regression modeling were used to estimate recurrence rates and identify predictors of symptom recurrence and repeat intervention. RESULTS: Fifty wrists in 50 patients (average age, 49 y) were included. One patient was lost to follow-up. Eighty-two percent of patients had resolved symptoms 6 weeks after a steroid injection. Twenty-four patients had a recurrence of symptoms at a median of 84 days after the injection. Eleven patients underwent additional intervention (7 surgical releases and 4 repeat injections) at a median of 129 days (range, 42-365) after the injection. Estimated freedom from symptom recurrence was 52% at 6 and 12 months. Estimated freedom from repeat intervention was 81% at 6 months and 77% at 12 months. Two of 3 patients with a history of trigger finger required subsequent de Quervain surgery. CONCLUSIONS: We demonstrated that a single cortisone injection was effective in alleviating symptoms of de Quervain tendinopathy in 82% of patients and that over half remained symptom-free for at least 12 months. All patients with recurring symptoms developed them within the first 6 months. TYPE OF STUDY/LEVEL OF EVIDENCE: Prognostic IV. PMID- 25936737 TI - Arthroscopically diagnosed scapholunate ligament injuries associated with distal radial fractures: a 13- to 15-year follow-up. AB - PURPOSE: To evaluate the natural history of untreated complete or partial scapholunate (SL) ligament tears associated with displaced distal radius fractures. METHODS: Between 1995 and 1997, 51 consecutive patients aged < 60 years with displaced distal radius fractures were examined arthroscopically to assess for concomitant soft tissue injuries. Thirty-two of 51 patients had an SL ligament tear, 10 had a complete tear (Lindau grade 3), and 22 had a partial tear (Lindau grades 1 and 2). Thirty-two patients had AO type-C fractures, 3 had type B fractures, and 16 had type-A fractures. In 2010, 47 of the 51 patients were still alive, and they were invited for an interview, clinical examination, and radiography. RESULTS: Thirty-eight of the 51 original patients participated in the long-term follow-up. Mean grip strength was 83% relative to the contralateral hand in patients with a complete tear, as compared with 92% in patients with partial or no SL tears (nonsignificant). Median Disabilities of the Arm, Shoulder, and Hand questionnaire score was 2 (range, 0-55) for complete SL tears, compared with 9 (range, 0-70) for the others (nonsignificant). No differences were found regarding visual analog scale pain or wrist motion/forearm rotation. None of the patients developed a static SL dissociation or a SL advanced collapse wrist. CONCLUSIONS: No major differences were found in the subjective, objective, or radiographic outcome after a complete (grade 3) or partial (grade 1 or 2) SL untreated tear associated with displaced distal radius fracture. It should be noted that none of the patients had a grade 4 SL tear, which may have a different outcome. TYPE OF STUDY/LEVEL OF EVIDENCE: Prognostic II. PMID- 25936738 TI - The impact of pediatric brachial plexus injury on families. AB - PURPOSE: To determine the impact of brachial plexus injuries on families to best meet their clinical and social needs. METHODS: Our cross-sectional study included families with children between the ages of 1 and 18 years with birth or non neonatal brachial plexus injuries (BPIs). The consenting parent or guardian completed a demographic questionnaire and the validated Impact on Family Scale during a single assessment. Total scores can range from 0 to 100, with the higher the score indicating a higher impact on the family. Factor analysis and item total correlations were used to examine structure, individual items, and dimensions of family impact. RESULTS: A total of 102 caregivers participated. Overall, families perceived various dimensions of impact on having a child with a BPI. Total family impact was 43. The 2 individual items correlating most strongly with the overall total score were from the financial dimension of the Impact on Family Scale. The strongest demographic relationship was traveling nationally for care and treatment of the BPI. Severity of injury was marginally correlated with impact on the family. Parent-child agreement about the severity of the illness was relatively high. CONCLUSIONS: Caretakers of children with a BPI perceived impact on their families in the form of personal strain, family/social factors, financial stress, and mastery. A multidisciplinary clinical care team should address the various realms of impact on family throughout the course of treatment. TYPE OF STUDY/LEVEL OF EVIDENCE: Prognostic II. PMID- 25936739 TI - Multifactorial intervention in diabetes care using real-time monitoring and tailored feedback in type 2 diabetes. AB - AIMS: In 2011, we demonstrated that an individualized health management system employing advanced medical information technology, designated ubiquitous (u) healthcare, was helpful in achieving glycemic control without hypoglycemia in patients with diabetes. Following this, we generated a new multidisciplinary u healthcare system by upgrading our clinical decision support system (CDSS) rule engine and integrating a physical activity-monitoring device and dietary feedback into a comprehensive package. METHODS: In a randomized, controlled clinical trial, patients with type 2 diabetes aged over 60 years were assigned randomly to a self-monitored blood glucose (SMBG) group (N = 50) or u-healthcare group (N = 50) for 6 months. The primary endpoint was the proportion of patients achieving glycated hemoglobin (HbA1c) <7 % without hypoglycemia. Changes in body composition and lipid profiles were also investigated. The u-healthcare group was educated to use a specially designed glucometer and an activity monitor that automatically transferred test results to a hospital-based server. An automated CDSS rule engine generated and sent patient-specific messages about glucose, diet, and physical activity to their mobile phones and a Web site. RESULTS: After 6 months of follow-up, the HbA1c level was significantly decreased in the u healthcare group [8.0 +/- 0.7 % (64.2 +/- 8.8 mmol/mol) to 7.3 +/- 0.9 % (56.7 +/ 9.9 mmol/mol)] compared with the SMBG group [8.1 +/- 0.8 % (64.9 +/- 9.1 mmol/mol) to 7.9 +/- 1.2 % (63.2 +/- 12.3 mmol/mol)] (P < 0.01). The proportion of patients with HbA1c < 7 % without hypoglycemia was greater in the u-healthcare group (26 %) than in the SMBG group (12 %; P < 0.05). Body fat mass decreased and lipid profiles improved in the u-healthcare group but not in the SMBG group. CONCLUSION: This u-healthcare service provided effective management for older patients with type 2 diabetes (ClinicalTrial.Gov: NCT01137058). PMID- 25936741 TI - IFN-gamma/TNF-alpha ratio in response to immuno proteomically identified human T cell antigens of Mycobacterium tuberculosis - The most suitable surrogate biomarker for latent TB infection. AB - The enormous reservoir of latent TB infection (LTBI) poses a major hurdle for global TB control. The existing Tuberculin skin test (TST) and IFN-gamma release assays (IGRAs) are found to be suboptimal for LTBI diagnosis. Previously we had taken an immunoproteomic approach and identified 10 protein fractions (contains 16 proteins), which are solely recognized by LTBI. In a cohort of 40 pulmonary TB patients (PTB) and 35 healthy household contacts (HHC), IFN-gamma and TNF-alpha response were measured against 16 antigens by using 1:10 diluted whole blood assay. Among all the antigens, IFN-gamma response to Rv2626c has shown positivity of 88.57% in HHC and 7.5% in PTB group. IFN-gamma response to combination of Rv2626c + Rv3716c has demonstrated 100% positivity in HHC and 17.5% positivity in PTB respectively. Compared to individual cytokines (i.e. IFN-gamma and TNF alpha), ratio of IFN-gamma/TNF-alpha has shown promising results for diagnosis of LTBI. IFN-gamma/TNF-alpha ratio against Rv3716c and TrxC has exhibited a positivity of 94.29% in HHC and 5% in PTB group. Accession of Rv2626c and Rv3716c may improve the diagnostic performance of existing QFT-GIT. Independent of QFT GIT assay, ratio of IFN-gamma/TNF-alpha in response to either Rv3716c or TrxC may acts as suitable surrogate biomarker for LTBI. PMID- 25936740 TI - Fenofibrate prevents the disruption of the outer blood retinal barrier through downregulation of NF-kappaB activity. AB - AIMS: There is clinical evidence that fenofibrate, a PPARalpha agonist, arrests the progression of diabetic macular edema (DME). However, the underlying mechanisms of this beneficial effect remain to be elucidated. We previously reported that fenofibric acid (FA), the active metabolite of fenofibrate, prevents the disorganization of tight junction proteins and the hyperpermeability provoked by the diabetic milieu in the retinal pigment epithelium (RPE). The aim of the present study was to evaluate whether this effect is mediated by inhibiting the proinflammatory transcription factor NF-kappaB, as well as the expression of several proinflammatory cytokines involved in the pathogenesis of DME. METHODS: Human RPE cells were cultured under standard conditions and under conditions leading to the disruption of the monolayer [IL-1beta (10 ng/ml)]. The effect of FA, QNZ (a NF-kappaB inhibitor), WY14643 (a PPARalpha agonist), and MK 866 (a PPARalpha antagonist) in the disruption of the monolayer was determined by dextran permeability and immunohistochemistry analyses. The effect of FA on NF kappaB activity was assessed by EMSA and by NF-kappaB/p65 nuclear translocation analyses. The expression of cytokines (IL-6, IL-8, MCP-1) was measured by RT-PCR. RESULTS: FA prevented RPE monolayer disruption, and the consequent hyperpermeability induced by IL-1beta, through inhibition of NF-kappaB activity. This effect was due to PPARalpha activation and was associated with a significant downregulation of the expression of proinflammatory cytokines. CONCLUSIONS: Our findings suggest that the anti-inflammatory effects of FA through inhibition of NF-kappaB activity play a key role in the beneficial effect of fenofibrate for treating DME. PMID- 25936742 TI - Diagnostic accuracy study of multiplex PCR for detecting tuberculosis drug resistance. AB - OBJECTIVE: To study the diagnostic accuracy of a multiplex real-time PCR (Anyplex II MTB/MDR/XDR, Seegene, Corea) that detects Mycobacterium tuberculosis resistant to isoniazid (INH), rifampicin (RIF), fluoroquinolones (FLQ) and injectable drugs (kanamycin [KAN], amikacin [AMK] and capreomycin [CAP]) in isolates and specimens. METHODS: One hundred fourteen cultured isolates and 73 sputum specimens were retrospectively selected. Results obtained with multiplex PCR were compared with those obtained with BACTEC. Discordant results between multiplex PCR and BACTEC were tested by alternative molecular methods. RESULTS: Sensitivity and specificity of multiplex PCR for detecting drug resistance in isolates were 76.5% and 100%, respectively, for INH; 97.2% and 96.0%, respectively, for RIF; 70.4% and 87.9%, respectively, for FLQ; 81.5% and 84.8%, respectively, for KAN; 100% and 60%, respectively, for AMK, and 100% and 72.3%, respectively, for CAP. Sensitivity and specificity of Anyplex for detecting drug resistance in specimens were 93.3% and 100%, respectively, for INH; 100% and 100%, respectively, for RIF; 50.0% and 100%, respectively, for FLQ; and 100% and 94.4%, respectively, for both KAN and CAP. Among the discordant results, 87.7% (71/81) of results obtained with the multiplex PCR were concordant with at least one of the alternative molecular methods. CONCLUSIONS: This multiplex PCR may be a useful tool for the rapid identification of drug resistant tuberculosis in isolates and specimens, thus allowing an initial therapeutic approach. Nevertheless, for a correct management of patients, results should be confirmed by a phenotypic method. PMID- 25936743 TI - Increased risk of arterial thromboembolic events after Staphylococcus aureus bacteremia: A matched cohort study. AB - OBJECTIVES: An association between infection and arterial thromboembolic events (ATE) has been suggested. Here we examined the risk of myocardial infarction (MI), stroke and other ATE after Staphylococcus aureus bacteremia (SAB). METHODS: Danish register-based nation-wide observational cohort study between 1995 and 2008 with matched control subjects from the general population. RESULTS: Within a year, 278 of 15,669 SAB patients and 2570 of 156,690 controls developed MI, stroke or another ATE. The incidence rates among SAB patients were highest within the first 30 days and decreased over a year. The adjusted relative risk of MI, stroke and other ATE during the first 30 days after SAB in patients compared to controls were 2.2 (95% CI: 1.6-3.1), 5.5 (95% CI: 3.8-8.3) and 15.5 (95% CI: 6.9 35), respectively. Compared to controls, the increased adjusted relative risk persisted for 30 days for MI, 180 days for stroke and one year for other ATE. Increasing age, hypertension, atrial flutter/fibrillation, prior ATE and endocarditis in SAB patients were associated with an increased risk of ATE. CONCLUSIONS: SAB was associated with a short-term increased risk of ATE that persisted longer dependent on type of event. Studies are warranted to investigate treatment strategies to diminish ATE after SAB. PMID- 25936744 TI - Prevalence and risk factors of mixed Mycobacterium tuberculosis complex infections in China. AB - OBJECTIVES: Mixed infections have been considered as a potential obstacle for tuberculosis treatment and control. To date, few studies have been done to determine the rate of mixed infections of Mycobacterium tuberculosis in China. METHODS: In this study, we used the standard 24-loci MIRU-VNTR method to genotype the representative M. tuberculosis isolates from the national drug-resistant survey conducted in China. A total of 3248 M. tuberculosis complex (MTBC) strains had complete 24-loci MIRU-VNTR results and available for the analyses. RESULTS: Overall, MIRU-VNTR typing identified 115 (3.5%) isolates as being mixed MTBC infections in China. Statistical analysis revealed that mixed infections were significantly more likely to occur in men than women. Compared with the percentage of mixed infection from patients aged 45-56 years, the percentages of mixed infections were higher among patients aged 25-44 years [OR (95% CI): 1.844(1.129-3.014)] and old patients [older than 65 years OR (95% CI): 1.908(1.097-3.319)]. In addition, significantly higher frequencies of hemoptysis (P = 0.022) and chest pain (P = 0.012) were observed among mixed infections, using patients infected with a single strain as a reference. CONCLUSIONS: In conclusion, this study has provided the first comprehensive understanding of mixed MTBC infections in China, which will be essential to generate the effective TB control strategies. PMID- 25936745 TI - Recent developments in the management of common childhood skin infections. AB - A literature review and clinical commentary on diagnosis and treatment of common childhood bacterial, fungal and viral skin infections is presented including impetigo, folliculitis, staphylococcal scalded skin syndrome, tinea capitis, warts and molluscum contagiosum. PMID- 25936754 TI - An essential role of cAMP response element-binding protein in epidermal growth factor-mediated induction of sodium/glucose cotransporter 1 gene expression and intestinal glucose uptake. AB - The sodium/glucose cotransporter 1 (SGLT1) is responsible for glucose uptake in intestinal epithelial cells. Its expression is decreased in individuals with intestinal inflammatory disorders and is correlated with the pathogenesis of disease. The aim of this study was to understand the regulatory mechanism of the SGLT1 gene. Using the trinitrobenzene sulfonic acid-induced mouse models of intestinal inflammation, we observed decreased SGLT1 expression in the inflamed intestine was positively correlated with the mucosal level of epidermal growth factor (EGF) and activated CREB. Overexpression of EGF demonstrated that the effect of EGF on intestinal glucose uptake was primarily due to the increased level of SGLT1. We identified an essential cAMP binding element (CRE) confers EGF inducibility in the human SGLT1 gene promoter. ChIP assay further demonstrated the increased binding of CREB and CBP to the SGLT1 gene promoter in EGF-treated cells. In addition, the EGFR- and PI3K-dependent CREB phosphorylations are involved in the EGF-mediated SGLT1 expression. This is the first report to demonstrate that CREB is involved in EGF-mediated transcription regulation of SGLT1 gene in the normal and inflamed intestine, which can provide potential therapeutic applications for intestinal inflammatory disorders. PMID- 25936755 TI - Epigenetic modulators promote mesenchymal stem cell phenotype switches. AB - Discoveries in recent years have suggested that some tissue specific adult stem cells in mammals might have the ability to differentiate into cell types from different germ layers. This phenomenon has been referred to as stem cell transdifferentiation or plasticity. Despite controversy, the current consensus holds that transdifferentiation does occur in mammals, but only within a limited range. Understanding the mechanisms that underlie the switches in phenotype and development of the methods that will promote such type of conversions can open up endless possibilities for regenerative medicine. Epigenetic control contributes to various processes that lead to cellular plasticity and DNA and histone covalent modifications play a key role in these processes. Recently, we have been able to convert human mesenchymal stem cells (hMSCs) into neural-like cells by exposing cells to epigenetic modifiers and neural inducing factors. The goal of this study was to investigate the stability and plasticity of these transdifferentiated cells. To this end, neurally induced MSCs (NI-hMSCs) were exposed to adipocyte inducing factors. Grown for 24-48 h in fat induction media NI-hMSCs reversed their morphology into fibroblast-like cells and regained their proliferative properties. After 3 weeks approximately 6% of hMSCs differentiated into multilocular or plurivacuolar adipocyte cells that demonstrated by Oil Red O staining. Re-exposure of these cultures or the purified adipocytes to neural induction medium induced the cells to re-differentiate into neuronal-like cells. These data suggest that cell plasticity can be manipulated by the combination of small molecule modulators of chromatin modifying enzymes and specific cell signaling pathways. PMID- 25936756 TI - Mitogen-activated protein kinase signaling pathways promote low-density lipoprotein receptor-related protein 1-mediated internalization of beta-amyloid protein in primary cortical neurons. AB - Mounting evidence suggests that the pathological hallmarks of Alzheimer's disease (AD) are caused by the intraneuronal accumulation of beta-amyloid protein (Abeta). Reuptake of extracellular Abeta is believed to contribute significantly to the intraneuronal Abeta pool in the early stages of AD. Published reports have claimed that the low-density lipoprotein receptor-related protein 1 (LRP1) mediates Abeta1-42 uptake and lysosomal trafficking in GT1-7 neuronal cells and mouse embryonic fibroblast non-neuronal cells. However, there is no direct evidence supporting the role of LRP1 in Abeta internalization in primary neurons. Our recent study indicated that p38 MAPK and ERK1/2 signaling pathways are involved in regulating alpha7 nicotinic acetylcholine receptor (alpha7nAChR) mediated Abeta1-42 uptake in SH-SY5Y cells. This study was designed to explore the regulation of MAPK signaling pathways on LRP1-mediated Abeta internalization in neurons. We found that extracellular Abeta1-42 oligomers could be internalized into endosomes/lysosomes and mitochondria in cortical neurons. Abeta1-42 and LRP1 were also found co-localized in neurons during Abeta1-42 internalization, and they could form Abeta1-42-LRP1 complex. Knockdown of LRP1 expression significantly decreased neuronal Abeta1-42 internalization. Finally, we identified that p38 MAPK and ERK1/2 signaling pathways regulated the internalization of Abeta1-42 via LRP1. Therefore, these results demonstrated that LRP1, p38 MAPK and ERK1/2 mediated the internalization of Abeta1-42 in neurons and provided evidence that blockade of LRP1 or inhibitions of MAPK signaling pathways might be a potential approach to lowering brain Abeta levels and served a potential therapeutic target for AD. PMID- 25936757 TI - Numerical responses in resource-based mutualisms: A time scale approach. AB - Many mutualisms involve inter-specific resource exchanges, making consumer resource approaches ideal for studying their dynamics. Also in many cases these resources are short lived (e.g. flowers) compared with the population dynamics of their producers and consumers (e.g. plants and insects), which justifies a separation of time scales. As a result, we can derive the numerical response of one species with respect to the abundance of another. For resource consumers, the numerical responses can account for intra-specific competition for mutualistic resources (e.g. nectar), thus connecting competition theory and mutualism mechanistically. For species that depend on services (e.g. pollination, seed dispersal), the numerical responses display saturation of benefits, with service handling times related with rates of resource production (e.g. flower turnover time). In both scenarios, competition and saturation have the same underlying cause, which is that resource production occurs at a finite velocity per individual, but their consumption tracks the much faster rates of population growth characterizing mutualisms. The resulting models display all the basic features seen in many models of facultative and obligate mutualisms, and they can be generalized from species pairs to larger communities. PMID- 25936758 TI - Discrete and ultradiscrete models for biological rhythms comprising a simple negative feedback loop. AB - Many biological rhythms are generated by negative feedback regulation. Griffith (1968) proved that a negative feedback model with two variables expressed by ordinary differential equations do not generate self-sustained oscillations. Kurosawa et al. (2002) expanded Griffith's result to the general type of negative feedback model with two variables. In this paper, we propose discrete and ultradiscrete feedback models with two variables that exhibit self-sustained oscillations. To obtain the model, we applied tropical discretization and ultradiscretization to a continuous model with two variables and then investigated its bifurcation structures and the conditions of parameters for oscillations. We found that when the degradation rate of the variables is lower than their synthesis rate, the proposed models generate oscillations by Neimark Sacker bifurcation. We further demonstrate that the ultradiscrete model can be reduced to a Boolean system under some conditions. PMID- 25936759 TI - A coarse-grained biophysical model of sequence evolution and the population size dependence of the speciation rate. AB - Speciation is fundamental to understanding the huge diversity of life on Earth. Although still controversial, empirical evidence suggests that the rate of speciation is larger for smaller populations. Here, we explore a biophysical model of speciation by developing a simple coarse-grained theory of transcription factor-DNA binding and how their co-evolution in two geographically isolated lineages leads to incompatibilities. To develop a tractable analytical theory, we derive a Smoluchowski equation for the dynamics of binding energy evolution that accounts for the fact that natural selection acts on phenotypes, but variation arises from mutations in sequences; the Smoluchowski equation includes selection due to both gradients in fitness and gradients in sequence entropy, which is the logarithm of the number of sequences that correspond to a particular binding energy. This simple consideration predicts that smaller populations develop incompatibilities more quickly in the weak mutation regime; this trend arises as sequence entropy poises smaller populations closer to incompatible regions of phenotype space. These results suggest a generic coarse-grained approach to evolutionary stochastic dynamics, allowing realistic modelling at the phenotypic level. PMID- 25936760 TI - The validity and reliability of modelled neural and tissue properties of the ankle muscles in children with cerebral palsy. AB - Spastic cerebral palsy (CP) is characterized by increased joint resistance, caused by a mix of increased tissue stiffness, as well as involuntary reflex and background muscle activity. These properties can be quantified using a neuromechanical model of the musculoskeletal complex and instrumented assessment. The construct validity of the neuromechanical parameters was examined (i.e. the internal model validity, effect of knee angle, speed and age, sensitivity to patients versus controls, spasticity severity and treatment), together with the repeatability. We included 38 children with CP and 35 controls. A motor driven footplate applied two slow (15 degrees /s) and two fast (100 degrees /s) rotations around the ankle joint, at two different knee angles. Ankle angle, torque and EMG of the gastrocnemius (GA), soleus (SO) and tibialis anterior (TA) muscle were used to optimize a nonlinear neuromuscular model. Outcome measures were tissue stiffness, reflex and background activity for GA, SO and TA. The internal model validity showed medium to high parameter confidence and good model fits. All parameter could discriminate between patients with CP and controls according to CP pathology. Other measures of external model validity (effect of test position, speed and age) showed behaviour along the lines of current knowledge of physiology. GA/SO background activity was sensitive to spasticity severity, but reflex activity was not. Preliminary data indicated that reflex activity was reduced after spasticity treatment. The between-trial and -day repeatability was moderate to good. The large variance between patients in the ratio of stiffness and neural resistance indicates that the method could potentially contribute to patient-specific treatment selection. PMID- 25936761 TI - Potential of graphene for tissue engineering applications. PMID- 25936762 TI - Melatonin attenuates carbon tetrachloride-induced liver fibrosis via inhibition of necroptosis. AB - We investigated the protective mechanisms of melatonin (MLT) associated with necroptosis signaling and damage-associated molecular patterns, which are mediated by the activation of pattern recognition receptors in liver fibrosis. Rats were given an intraperitoneal injection of carbon tetrachloride (CCl4) dissolved in olive oil (1:3, vol/vol) twice a week (0.5 mL/kg) for 8 weeks. During this period, MLT was administered orally at 2.5, 5, and 10 mg/kg once a day. Chronic CCl4 administration increased hepatic hydroxyproline content and hepatocellular damage. MLT attenuated these increases. The expression levels of transforming growth factor beta1 and alpha-smooth muscle actin that were increased by chronic CCl4 exposure were attenuated by MLT. CCl4 significantly increased receptor-interacting protein 1 (RIP1) expression, the formation of the RIP1 and RIP3 necrosome complex, and the level of mixed lineage kinase domain like protein in liver tissue, which were attenuated by MLT. MLT also attenuated CCl4-induced increases in serum high-mobility group box 1 (HMGB1) and interleukin 1alpha, as well as the interaction between HMGB1 receptors for advanced glycation end products (RAGE). The increases in toll-like receptor 4 expression, p38, c-Jun N-terminal kinases phosphorylation, and nuclear factor kappaB translocation were suppressed by MLT. MLT attenuated the overexpression of RAGE, increased level of early growth response protein 1, and increased messenger RNA level of macrophage inflammatory protein 2. Our findings suggest MLT may prevent liver fibrosis by inhibiting necroptosis-associated inflammatory signaling. PMID- 25936763 TI - Application of flow cytometry and PMA-qPCR to distinguish between membrane intact and membrane compromised bacteria cells in an aquatic milieu. AB - The paper compares two methods of distinguishing between alive and dead cells by differentiation on the basis of their membrane structure: LIVE/DEAD flow cytometry and PMA-qPCR. LIVE/DEAD flow cytometry was established using the LIVE/DEAD((r)) BacLightTM Bacterial Viability Kit with different ratios of Legionella pneumophila and Escherichia coli cells with intact and compromised membranes (heat treated). The PMA-qPCR method was tested and modified, and results were compared with those from LIVE/DEAD flow cytometry using L. pneumophila cells. Ratios of membrane intact to membrane compromised cells were well shown by LIVE/DEAD flow cytometry in all combinations. PMA-qPCR seems to work best in even mixed ratios (1:1) of intact and compromised cells. In other respects, we noticed an overestimation of intact cells in the samples which contained a high percentage of membrane compromised cells, and an underestimation of intact cells in samples with a small percentage of membrane compromised cells. However, looking at total counts instead of ratios, the results were within an order of magnitude. This implies that the use of PMA-qPCR is appropriate only for a qualitative analysis to monitor the success of a process such as disinfection. Furthermore, we were able to assess that both methods have advantages and disadvantages: LIVE/DEAD flow cytometry as applied in this study works well on some bacteria monocultures, but does not distinguish between bacteria species. The PMA-qPCR method allows the possibility of distinguishing between membrane intact cells and membrane compromised cells and can be used to screen for specific bacteria. PMID- 25936764 TI - Complete versus incomplete cytoreduction in peritoneal carcinosis from gastric cancer, with consideration to PCI cut-off. Systematic review and meta-analysis. AB - INTRODUCTION: The completeness of cytoreduction has been considerated as fundamental in increasing the life expectancy in patients with peritoneal carcinosis (PC) in gastric cancer. However no definitive data about the real effect of complete cytoreduction (CC) have still been published. Moreover the PCI cut-off to attempt CC with a reasonable risk-benefit ratio still lacks. MATERIAL AND METHODS: A systematic review with meta-analysis of trials of complete vs incomplete cytoreduction in patients with peritoneal carcinosis from GC was performed. RESULTS: Nine trials have been included (748 patients: 417 with CC0 CC1 and 324 with CC2-CC3 cytoreduction). 1, 2, 3 and 5 years survival is favorable to CC0-CC1 (Risk Ratio: 2.41, 8.18, 8.66, and 7.96 respectively). CC0 vs. CC1 survival benefit at 1 and 3 years: RR 2.28 and 6.36 respectively, favoring CC0. 1, 2, 3 and 5 years survival changes significantly above and below a PCI of 12. CONCLUSIONS: 1, 2, 3 and 5-year overall survival is increased by CC0 CC1 cytoreduction in patients with PC from gastric origin. Moreover CC0 increases the 1 and 3 years survival when compared to CC1 cytoreduction. PMID- 25936765 TI - MicroRNA-19a regulates proliferation and apoptosis of castration-resistant prostate cancer cells by targeting BTG1. AB - MicroRNAs (miRNAs) play a significant role in tumor development. Recent studies indicate that miRNAs are implicated in prostate cancer (PCa). In this study, we found that miR-19a expression was significantly increased in castration-resistant prostate cancer (CRPC) tissues compared with androgen-dependent prostate cancer (ADPC) tissues. We found that inhibiting the overexpression of miR-19a in CRPC cells suppressed proliferation and increased apoptosis. Additionally, we found that miR-19a repressed BTG1 expression by binding to its 3'-untranslated region. The overexpression of BTG1 in CRPC cells significantly suppressed proliferation and increased apoptosis. We conclude that miR-19a regulates proliferation and apoptosis of CRPC cells by directly targeting the tumor suppressor gene BTG1. PMID- 25936766 TI - Mutational analysis of HIV-2 Vpx shows that proline residue 109 in the poly proline motif regulates degradation of SAMHD1. AB - In this study, we performed a mutational analysis to determine whether the mechanism by which HIV-2 Vpx confers the capacity for infectivity and viral replication in macrophages is solely dependent on its ability to degrade the host antiviral factor SAMHD1. Contrary to expectations, we demonstrated that P(109) in the C-terminal poly-proline motif of HIV-2 Vpx has two unique roles: to facilitate the specific degradation of SAMHD1 in macrophages, and to facilitate multimerization of Vpx, therefore preventing SAMHD1 degradation in the presence of high levels of Vpx. PMID- 25936768 TI - Operon and non-operon gene clusters in the C. elegans genome. AB - Nearly 15% of the ~20,000 C. elegans genes are contained in operons, multigene clusters controlled by a single promoter. The vast majority of these are of a type where the genes in the cluster are ~100 bp apart and the pre-mRNA is processed by 3' end formation accompanied by trans-splicing. A spliced leader, SL2, is specialized for operon processing. Here we summarize current knowledge on several variations on this theme including: (1) hybrid operons, which have additional promoters between genes; (2) operons with exceptionally long (> 1 kb) intercistronic regions; (3) operons with a second 3' end formation site close to the trans-splice site; (4) alternative operons, in which the exons are sometimes spliced as a single gene and sometimes as two genes; (5) SL1-type operons, which use SL1 instead of SL2 to trans-splice and in which there is no intercistronic space; (6) operons that make dicistronic mRNAs; and (7) non-operon gene clusters, in which either two genes use a single exon as the 3' end of one and the 5' end of the next, or the 3' UTR of one gene serves as the outron of the next. Each of these variations is relatively infrequent, but together they show a remarkable variety of tight-linkage gene arrangements in the C. elegans genome. PMID- 25936767 TI - A cortical astrocyte subpopulation inhibits axon growth in vitro and in vivo. AB - Astrocytes are the most heterogeneous and predominant glial cell type in the central nervous system. However, the functional significance of this heterogeneity remains to be elucidated. Following injury, damaged astrocytes inhibit axonal regeneration in vivo and in vitro. Cultured primary astrocytes are commonly considered good supportive substrates for neuron attachment and axon regeneration. However, it is not known whether different populations of cells in the heterogeneous astrocyte culture affect neuron behavior in the same way. In the present study, the effect of astrocyte heterogeneity on neuronal attachment and neurite outgrowth was examined using an in vitro and in vivo coculture system. In vitro, neonatal cortical astrocytes were co-cultured with purified dorsal root ganglia (DRG) neurons and astrocyte growth morphology, neuron attachment and neurite growth were evaluated. The results demonstrated that the heterogeneous astrocyte cells showed two different types of growth pattern, typical and atypical. Typical astrocytes were supportive to neuron attachment and neurite growth, which was consistent with previous studies, whereas atypical astrocytes inhibited neuron attachment and neurite growth. These inhibitory astrocytes exhibited a special growth pattern with various shapes and sizes, a high cell density, few oligodendrocytes on the top layer and occupied a smaller growth area compared with typical astrocytes. Neurites extended freely on typical supportive astrocyte populations, however, moved away when they reached atypical astrocyte growth pattern. Neurons growing on the atypical astrocyte pattern demonstrated minimal neurite outgrowth and these neurites had a dystrophic appearance, however, neuronal survival was unaffected. Immunocytochemistry studies demonstrated that these atypical inhibitory astrocytes were glial fibrillary acidic protein (GFAP) positive cells. The existence of inhibitory astrocyte subpopulations in normal astrocytes reflects the complexity of the function of astrocyte populations. In vivo, DRG neurons in grey matter did not show neurite growth, while DRG neurons survived and showed robust axon outgrowth along the corpus callosum. In conclusion, further studies on this new type of inhibitory astrocyte subpopulation may deepen our understanding of the complex biology of astrocytes. PMID- 25936770 TI - Attenuation of stress-induced gastrointestinal motility disorder by gentiopicroside, from Gentiana macrophylla Pall. AB - AIM: The current study was designed to explore the mechanism of the prokinetic activity of Gentiopicroside (Ge), from Gentiana macrophylla Pall which is widely used to strengthen gastric motility in clinic. METHODS: Gastrointestinal motility disorder rats were induced by stress stimulation and the rats were treated with Ge. The functions of gastric emptying and intestinal propelling were measured after blood was obtained to assay the levels of plasmatic motilin (MTL), vasoactive intestinal peptide (VIP), somatostatin (SST), gastrin (GAS), neurotensin (NT) and substance of P (SP). The expressions of MTL receptor (MTLR), VIP receptor 2 (VIPR2) and SST receptor 2 (SSTR2) were measured also. In addition, an isolated guinea pig ileum was applied to evaluate the influences of Ge on M-R, H1-R, 5-HT4-R and D-R in vitro. RESULTS: Ge increased gastric emptying and intestinal propelling obviously. It also decreased the level of SST and increased GAS in plasma significantly. Moreover, it promoted the expressions of MTLR in gastric antrum, duodenum, jejunum and ileum, and restrained the expression of VIPR2 in duodenum. Piboserod and loratadine had no obvious restrain to Ge' exciting ileum effect and Ge also didn't affect dopamine paralyzing ileum. However, Ge failed to improve the hypofunction of guinea pigs ileums pre-treated with atropine sulfate. CONCLUSION: The mechanisms of Ge' prokinetic effect were associated with modulating the levels of SST and GAS in plasma, raising the expressions of MTLR in gastric antrum, duodenum, ileum and jejunum, reducing the expression of VIPR2 in duodenum and activating M-R. PMID- 25936769 TI - Impact of immunosuppressive agents on the expression of indoleamine 2,3 dioxygenase, heme oxygenase-1 and interleukin-7 in mesangial cells. AB - Chronic allograft nephropathy (CAN) is a major cause of graft loss following kidney transplantation and may result from the interactions of various immune and non-immune factors. The aim of the present study was to establish an in vitro model of glomerular mesangial cell injury in order to examine the gene expression levels of indoleamine 2,3-dioxygenase (IDO), heme oxygenase-1 (HO-1) and interleukin-7 (IL-7) in mesangial cells during the healing process as well as to investigate the effects of various immunosuppressants on the expression of these genes. The HBZY-1 glomerular mesangial cell line was pre-treated in vitro with cytochalasin B for 2 h to induce reversible damage. Following the pre-treatment, the HBZY-1 cells were divided into five groups: Blank control group, cyclosporine A (CsA) group, tacrolimus (Tac) group, mycophenolate mofetil (MMF) group and rapamycin (RAPA) group. After treating the mesangial cells with each immunosuppressive drug for 6, 12 or 24 h, the mRNA and protein expression levels of IDO, HO-1 and IL-7 were examined using reverse transcription quantitative polymerase chain reaction (RT-qPCR), western blot and immunohistochemical analyses. The results showed that expression levels of HO-1 were significantly upregulated in response to treatment with CsA, FK506, RAPA and MMF, whereas the expression levels of IL-7 were markedly downregulated by treatment with the above immunosuppressants. CsA, FK506 and MMF significantly enhanced the expression levels of IDO, whereas RAPA exhibited no apparent effect on IDO. The present study may contribute to the understanding of the pathogenesis of CAN and provide novel strategies for the prevention and treatment of CAN. PMID- 25936771 TI - Dolabrane-type diterpenes from the mangrove plant Ceriops tagal with antitumor activities. AB - Chemical examination of the barks of mangrove plant Ceriops tagal resulted in the isolation of six new dolabrane-type diterpenes with the trivial names of tagalenes A-F (1-6), together with 10 known analogues. The structures of new compounds were elucidated by extensive spectroscopic data analyses. Tagalenes A-C (1-3) are characterized by 18-nordolabrane scaffold, while tagalene F (6) featured by a 2,3-seco dolabrane derivative. Antitumor assay revealed that seven compounds exhibited potent inhibitory effects against a panel of tumor cell lines with IC50<10 MUM, while tagalsin C (8) exerted the most potent activities in comparison with the IC50 values of the rest compounds. The primary structure activity relationship is discussed. Tagalsin C also exerted the potent effects against a panel of drug-resistant human tumor cell lines, indicating it to be a promising molecule for further evaluation as an antitumor lead compound. PMID- 25936772 TI - ABT737 enhances cholangiocarcinoma sensitivity to cisplatin through regulation of mitochondrial dynamics. AB - Cholangiocarcinoma responses weakly to cisplatin. Mitochondrial dynamics participate in the response to various stresses, and mainly involve mitophagy and mitochondrial fusion and fission. Bcl-2 family proteins play critical roles in orchestrating mitochondrial dynamics, and are involved in the resistance to cisplatin. Here we reported that ABT737, combined with cisplatin, can promote cholangiocarcinoma cells to undergo apoptosis. We found that the combined treatment decreased the Mcl-1 pro-survival form and increased Bak. Cells undergoing cisplatin treatment showed hyperfused mitochondria, whereas fragmentation was dominant in the mitochondria of cells exposed to the combined treatment, with higher Fis1 levels, decreased Mfn2 and OPA1 levels, increased ratio of Drp1 60kD to 80kD form, and more Drp1 located on mitochondria. More p62 aggregates were observed in cells with fragmented mitochondria, and they gradually translocated to mitochondria. Mitophagy was induced by the combined treatment. Knockdown p62 decreased the Drp1 ratio, increased Tom20, and increased cell viability. Our data indicated that mitochondrial dynamics play an important role in the response of cholangiocarcinoma to cisplatin. ABT737 might enhance cholangiocarcinoma sensitivity to cisplatin through regulation of mitochondrial dynamics and the balance within Bcl-2 family proteins. Furthermore, p62 seems to be critical in the regulation of mitochondrial dynamics. PMID- 25936774 TI - Safety of cyanoacrylate-based adhesives in creating layered septal cartilage grafts during open structure septorhinoplasty. AB - PURPOSE: Patients having suffered severe nasal trauma or having undergone prior septal surgery present particular problems during open structure septorhinoplasty. Septal cartilage deficient noses often require costal or conchal cartilage grafting or the use of allograft material, resulting in secondary donor site morbidity, longer operative times and variable results. The present study evaluated the utility of cyanoacrylate-based adhesives (CBA) in creating layered septal cartilage grafts from remnant septal cartilage for L strut reconstruction during open septorhinoplasty. STUDY DESIGN: A retrospective clinical review was performed at a university-based facial plastic and reconstructive surgical practice, identifying patients undergoing open structure septorhinoplasty performed by the senior authors. Procedures involved construction of a layered caudal or dorsal L-strut graft from at least two smaller autologous septal cartilage grafts. The grafts were adhered together with CBA with 5-0 polydioxanone suture (Ethicon, Somerville, NJ) used for reinforcement. Stability of the final construct was assessed postoperatively. RESULTS: Fifteen patients were included with mean age of thirty-nine years (range: 15-65). Fifty-three percent of the patients had undergone prior nasal surgery: Seven had undergone at least one prior external septorhinoplasty and one had undergone prior endonasal septoplasty. Median follow-up was 144 days (range: 45-405). Postoperatively, one local infection was noted and two patients complained of post-operative columellar deviation. No other complications were encountered. CONCLUSION: CBAs provide a safe technique in the crafting of layered grafts to provide reliable tip/dorsal support when performing open structure septorhinoplasty among patients with cartilage deficient or severely traumatized septa. PMID- 25936773 TI - Omega-3 fatty acids for breast cancer prevention and survivorship. AB - Women with evidence of high intake ratios of the marine omega-3 fatty acids eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) relative to the omega 6 arachidonic acid have been found to have a reduced risk of breast cancer compared with those with low ratios in some but not all case-control and cohort studies. If increasing EPA and DHA relative to arachidonic acid is effective in reducing breast cancer risk, likely mechanisms include reduction in proinflammatory lipid derivatives, inhibition of nuclear factor-kappaB-induced cytokine production, and decreased growth factor receptor signaling as a result of alteration in membrane lipid rafts. Primary prevention trials with either risk biomarkers or cancer incidence as endpoints are underway but final results of these trials are currently unavailable. EPA and DHA supplementation is also being explored in an effort to help prevent or alleviate common problems after a breast cancer diagnosis, including cardiac and cognitive dysfunction and chemotherapy induced peripheral neuropathy. The insulin-sensitizing and anabolic properties of EPA and DHA also suggest supplementation studies to determine whether these omega 3 fatty acids might reduce chemotherapy-associated loss of muscle mass and weight gain. We will briefly review relevant omega-3 fatty acid metabolism, and early investigations in breast cancer prevention and survivorship. PMID- 25936775 TI - Review of computer simulations of isotope effects on biochemical reactions: From the Bigeleisen equation to Feynman's path integral. AB - Enzymatic reactions are integral components in many biological functions and malfunctions. The iconic structure of each reaction path for elucidating the reaction mechanism in details is the molecular structure of the rate-limiting transition state (RLTS). But RLTS is very hard to get caught or to get visualized by experimentalists. In spite of the lack of explicit molecular structure of the RLTS in experiment, we still can trace out the RLTS unique "fingerprints" by measuring the isotope effects on the reaction rate. This set of "fingerprints" is considered as a most direct probe of RLTS. By contrast, for computer simulations, oftentimes molecular structures of a number of TS can be precisely visualized on computer screen, however, theoreticians are not sure which TS is the actual rate limiting one. As a result, this is an excellent stage setting for a perfect "marriage" between experiment and theory for determining the structure of RLTS, along with the reaction mechanism, i.e., experimentalists are responsible for "fingerprinting", whereas theoreticians are responsible for providing candidates that match the "fingerprints". In this Review, the origin of isotope effects on a chemical reaction is discussed from the perspectives of classical and quantum worlds, respectively (e.g., the origins of the inverse kinetic isotope effects and all the equilibrium isotope effects are purely from quantum). The conventional Bigeleisen equation for isotope effect calculations, as well as its refined version in the framework of Feynman's path integral and Kleinert's variational perturbation (KP) theory for systematically incorporating anharmonicity and (non-parabolic) quantum tunneling, are also presented. In addition, the outstanding interplay between theory and experiment for successfully deducing the RLTS structures and the reaction mechanisms is demonstrated by applications on biochemical reactions, namely models of bacterial squalene-to-hopene polycyclization and RNA 2'-O-transphosphorylation. For all these applications, we used our recently-developed path-integral method based on the KP theory, called automated integration-free path-integral (AIF-PI) method, to perform ab initio path-integral calculations of isotope effects. As opposed to the conventional path-integral molecular dynamics (PIMD) and Monte Carlo (PIMC) simulations, values calculated from our AIF-PI path-integral method can be as precise as (not as accurate as) the numerical precision of the computing machine. Lastly, comments are made on the general challenges in theoretical modeling of candidates matching the experimental "fingerprints" of RLTS. This article is part of a Special Issue entitled: Enzyme Transition States from Theory and Experiment. PMID- 25936776 TI - The kinetic characterization and X-ray structure of a putative benzoylformate decarboxylase from M. smegmatis highlights the difficulties in the functional annotation of ThDP-dependent enzymes. AB - Benzoylformate decarboxylase (BFDC) is a thiamin diphosphate (ThDP)-dependent enzyme that catalyzes the nonoxidative decarboxylation of benzoylformate. It is the penultimate enzyme in both the mandelate pathway and the d-phenylglycine degradation pathway. The ThDP-dependent Enzyme Engineering Database (TEED) now lists more than 800 sequences annotated as BFDCs, including one from Mycobacterium smegmatis (MsBFDC). However, there is no evidence that either pathway for benzoylformate formation exists in the M. smegmatis genome. Further, sequence alignments of MsBFDC with the well characterized enzyme isolated from Pseudomonas putida (PpBFDC) indicate that there will be active site substitutions in MsBFDC likely to reduce activity with benzoylformate. Taken together these data would suggest that the annotation is unlikely to be correct. To test this hypothesis the putative MsBFDC was cloned, expressed, purified, and the X-ray structure was solved to a resolution of 2.2A. While showing no evidence for ThDP in the active site, the structure was very similar to that of PpBFDC. A number of 2-oxo acids were tested as substrates. For MsBFDC the K(m) value for benzoylformate was ~23 mM, nearly 100-fold greater than that of PpBFDC while the k(cat) value was reduced 60-fold. These values would suggest that benzoylformate is not the physiological substrate for this enzyme, and that annotation as a 2 oxo acid decarboxylase may be more appropriate. PMID- 25936777 TI - A new role for sphingosine: Up-regulation of Fam20C, the genuine casein kinase that phosphorylates secreted proteins. AB - Fam20C is an atypical kinase implicated in bio-mineralization and phosphate homeostasis disorders, and has recently been shown to account for the activity of an orphan enzyme ("genuine casein kinase", G-CK) previously characterized for its ability to phosphorylate casein and a plethora of secreted proteins at serine residues specified by the S-x-E/pS motif. Fam20C/G-CK activity is only appreciable in the presence of high Mn2+ concentration (>1 mM), and is negligible if Mn2+ is replaced by physiological Mg2+ concentrations. Here we show that sphingosine (but not its biological precursor ceramide) not only stimulates several-fold Fam20C activity in the presence of Mn2+, but also confers a comparable activity to Fam20C assayed with Mg2+. Activation by sphingosine is evident using a variety of substrates, and is accounted for by both higher Vmax and decreased KmATP, as judged from kinetics run with the beta(28-40) substrate peptide and a physiological substrate, BMP-15. Sphingosine also protects Fam20C from thermal inactivation. Consistent with the in vitro results, by treating Fam20C expressing HEK293T cells with myriocin, a potent inhibitor of the sphingosine biosynthetic pathway, the activity of Fam20C released into the conditioned medium is substantially decreased corroborating the concept that sphingosine (or related metabolite(s)) is a co-factor required by Fam20C to optimally display its biological functions. None of the small molecule kinase inhibitors tested so far were able to inhibit Fam20C. Interestingly however fingolimod, an immunosuppressive drug structurally related to sphingosine, used for the treatment of multiple sclerosis, is a powerful activator of Fam20C, both wild type and its pathogenic, loss of function, T268M mutant. This article is part of a Special Issue entitled: Inhibitors of Protein Kinases. PMID- 25936778 TI - The study of transient protein-nanoparticle interactions by solution NMR spectroscopy. AB - The rapid development of novel nanoscale materials for applications in biomedicine urges an improved characterization of the nanobio interfaces. Nanoparticles exhibit unique structures and properties, often different from the corresponding bulk materials, and the nature of their interactions with biological systems remains poorly characterized. Solution NMR spectroscopy is a mature technique for the investigation of biomolecular structure, dynamics, and intermolecular associations, however its use in protein-nanoparticle interaction studies remains scarce and highly challenging, particularly due to unfavorable hydrodynamic properties of most nanoscale assemblies. Nonetheless, recent efforts demonstrated that a number of NMR observables, such as chemical shifts, signal intensities, amide exchange rates and relaxation parameters, together with newly designed saturation transfer experiments, could be successfully employed to characterize the orientation, structure and dynamics of proteins adsorbed onto nanoparticle surfaces. This review provides the first survey and critical assessment of the contributions from solution NMR spectroscopy to the study of transient interactions between proteins and both inorganic (gold, silver, and silica) and organic (polymer, carbon and lipid based) nanoparticles. This article is part of a Special Issue entitled: Physiological Enzymology and Protein Functions. PMID- 25936780 TI - NDRG3-mediated lactate signaling in hypoxia. AB - Hypoxia is associated with many pathological conditions as well as the normal physiology of metazoans. We identified a lactate-dependent signaling pathway in hypoxia, mediated by the oxygen- and lactate-regulated protein NDRG family member 3 (NDRG3). Oxygen negatively regulates NDRG3 expression at the protein level via the PHD2/VHL system, whereas lactate, produced in excess under prolonged hypoxia, blocks its proteasomal degradation by binding to NDRG3. We also found that the stabilized NDRG3 protein promotes angiogenesis and cell growth under hypoxia by activating the Raf-ERK pathway. Inhibiting cellular lactate production abolishes NDRG3-mediated hypoxia responses. The NDRG3-Raf-ERK axis therefore provides the genetic basis for lactate-induced hypoxia signaling, which can be exploited for the development of therapies targeting hypoxia-induced diseases in addition to advancing our understanding of the normal physiology of hypoxia responses. PMID- 25936779 TI - Oral administration of fermented wild ginseng ameliorates DSS-induced acute colitis by inhibiting NF-kappaB signaling and protects intestinal epithelial barrier. AB - Ginseng has been widely used for therapeutic and preventive purposes for thousands of years. However, orally administered ginseng has very low bioavailability and absorption in the intestine. Therefore, fermented ginseng was developed to enhance the beneficial effects of ginseng in the intestine. In this study, we investigated the molecular mechanisms underlying the anti-inflammatory activity of fermented wild ginseng (FWG). We found that FWG significantly alleviated the severity of colitis in a dextran sodium sulfate (DSS)-induced colitis mouse model, and decreased expression level of pro-inflammatory cytokines in colonic tissue. Moreover, we observed that FWG suppressed the infiltration of macrophages in DSS-induced colitis. FWG also attenuated the transcriptional activity of nuclear factor-kappaB (NF-kappaB) by reducing the translocation of NF kappaB into the nucleus. Our data indicate that FWG contains anti-inflammatory activity via NF-kappaB inactivation and could be useful for treating colitis. PMID- 25936781 TI - Ciliary subcompartments: how are they established and what are their functions? AB - Cilia are conserved subcellular organelles with diverse sensory and developmental roles. Recently, they have emerged as crucial organelles whose dysfunction causes a wide spectrum of disorders called ciliopathies. Recent studies on the pathological mechanisms underlying ciliopathies showed that the ciliary compartment is further divided into subdomains with specific roles in the biogenesis, maintenance and function of cilia. Several conserved sets of molecules that play specific roles in each subcompartment have been discovered. Here we review recent progress on our understanding of ciliary subcompartments, especially focusing on the molecules required for their structure and/or function. PMID- 25936782 TI - Application of the Mandible Injury Severity Score to Pediatric Mandibular Fractures. AB - PURPOSE: The Mandible Injury Severity Score (MISS) has been used to evaluate adult mandibular fractures. The purpose of this study was to evaluate the MISS in a cohort of pediatric patients. PATIENTS AND METHODS: This was a retrospective study of pediatric patients treated for mandibular fractures over a 20-year period. Patients were included if they had computed tomographic imaging available for review and had at least 1 post-treatment visit. The primary predictor variable was the MISS. Secondary predictors were demographic and injury associated factors. The outcome was treatment-associated complications. Descriptive, bivariate, and multiple logistic regression statistics were computed. RESULTS: One hundred sixteen patients with mandibular fractures were identified; 73 (62.9%) met the inclusion criteria. The sample's mean age was 8.5 +/- 4.1 years; 44% were girls. Motor vehicle collisions (60%) and falls (15.1%) were the most common mechanisms. More than 50% of patients had an extra mandibular injury. The mean MISS was 13.5 +/- 7.8. Forty-five percent of the sample underwent open reduction and internal fixation. Complications were noted in 20.5% of patients, of which malocclusion was the most common (8.2%). Increasing MISS was associated with complications (P < .001). After controlling for the effects of age, mechanism, cervical spine and skull base injuries, and treatment, patients with an MISS of at least 14 were significantly more likely to have a complication (odds ratio = 4.0; 95% confidence interval, 1.05-15.0; P = .04). CONCLUSIONS: In pediatric patients with mandibular fractures, increased severity of injury is associated with complications, even after controlling for the effects of multiple confounders, including open treatment. PMID- 25936783 TI - Anesthetic management of super-morbidly obese parturients for cesarean delivery with a double neuraxial catheter technique: a case series. AB - Parturients with super-morbid obesity, defined as body mass index greater than 50kg/m(2), represent a growing segment of patients who require anesthetic care for labor and delivery. Severe obesity and its comorbid conditions place the parturient and fetus at greater risk for pregnancy complications and cesarean delivery, as well as surgical and anesthetic complications. The surgical approach for cesarean delivery in these patients may require a supra-umbilical vertical midline incision due to a large pannus. The dense T4-level of spinal anesthesia can cause difficulties with ventilation for the obese patient during the procedure, which can be prolonged. Patients also may have respiratory complications in the postoperative period due to pain from the incision. We describe the anesthetic management of three parturients with body mass index ranging from 73 to 95kg/m(2) who had a cesarean delivery via a supra-umbilical vertical midline incision. Continuous lumbar spinal and low thoracic epidural catheters were placed in each patient for intraoperative anesthesia and postoperative analgesia, respectively. Continuous spinal catheters were dosed with incremental bupivacaine boluses to achieve surgical anesthesia. In one case, the patient required respiratory support with non-invasive positive pressure ventilation. Two cases were complicated by intraoperative hemorrhage. All patients had satisfactory postoperative analgesia with a thoracic epidural infusion. None suffered postoperative respiratory complications or postdural puncture headache. The use of a continuous lumbar spinal catheter and a low thoracic epidural provides several advantages in the anesthetic management of super-morbidly obese parturients for cesarean delivery. PMID- 25936784 TI - Pencil-point needle bevel direction influences ED50 of isobaric ropivacaine with fentanyl in spinal anesthesia for cesarean delivery: a prospective, double-blind sequential allocation study. AB - BACKGROUND: There is little evidence on the influence of bevel direction of a pencil-point needle on the median effective dose (ED50) of isobaric ropivacaine and fentanyl in spinal anesthesia for cesarean delivery. METHODS: In this prospective, double-blind, sequential allocation study, 82 parturients scheduled for elective cesarean delivery under combined spinal-epidural anesthesia were included. We sought to determine the median effective dose of intrathecal 0.75% isobaric ropivacaine plus fentanyl 15MUg with two different bevel directions of a 26-gauge Whitacre needle using up-down sequential allocation. Parturients were randomly allocated to either Group Ce (needle aperture oriented in a cephalad direction) or Group Ca (aperture directed caudally). The initial dose was 0.75% ropivacaine 11.25mg plus fentanyl 15MUg in both groups. Each dose was classified as effective if, after 15min and during the next 60min, there was inability to appreciate pin-prick as sharp at T4, a visual analogue pain score <2 and no requirement for an epidural rescue bolus. RESULTS: Eighty patients were included in the analysis. The ED50 in group Ca was significantly higher (13.09mg, 95% CI 12.19-14.00) than in group Ce (10.10mg, 95% CI 9.54-10.65, P <0.001). CONCLUSION: The orientation of the distal aperture of a 26-gauge Whitacre needle during induction of spinal anesthesia for cesarean delivery influences the ED50 of 0.75% ropivacaine. PMID- 25936785 TI - What's new in obstetric anesthesia? Focus on preeclampsia. AB - Recent advances in the diagnosis, pathogenesis, and understanding of preeclampsia related morbidity provide opportunities to optimize clinical management of the mother and fetus. These discoveries are timely, as contemporary data suggest that the prevalence of preeclampsia, affecting 7.5% of pregnancies globally and 2-5% in the USA, has increased by up to 30% over the last decade. Managing pregnant patients with preeclampsia can be challenging for all members of the obstetric care team due to the disease's multi-organ system maternal and fetal effects. This review presents recent updates in the definition of preeclampsia, etiology, comorbidities and therapeutic interventions and discusses how they impact the care of these high-risk patients. PMID- 25936786 TI - Scheduled acetaminophen with as-needed opioids compared to as-needed acetaminophen plus opioids for post-cesarean pain management. AB - BACKGROUND: Combination opioid-acetaminophen drugs are commonly used for pain management after cesarean delivery. The aim of this study was to determine if scheduled acetaminophen decreases opioid use compared to as-needed combination acetaminophen-opioid administration. METHODS: We performed a retrospective chart review of women who underwent cesarean delivery before and after a clinical practice change. All patients received spinal anesthesia containing intrathecal morphine 200MUg and scheduled non-steroidal anti-inflammatory drugs for 48h postoperatively. The first group (As-Needed Group, n=120) received combination oral opioid-acetaminophen analgesics as needed for breakthrough pain. The second group (Scheduled Group, n=120) received oral acetaminophen 650mg every 6h for 48h postoperatively with oral oxycodone administered as needed for breakthrough pain. The primary outcome was opioid use, measured in intravenous morphine mg equivalents, in the first 48h postoperatively. RESULTS: The Scheduled Group used 9.1+/-2.1mg (95% CI 5.0-13.2) fewer intravenous morphine equivalents than the As Needed Group (P <0.0001) over the study period. Fewer patients in the Scheduled Group exceeded acetaminophen 3g daily compared to the As-Needed Group (P=0.008). Pain scores were similar between study groups. CONCLUSIONS: After cesarean delivery, scheduled acetaminophen results in decreased opioid use and more consistent acetaminophen intake compared to acetaminophen administered as needed via combination acetaminophen-opioid analgesics, without compromising analgesia. PMID- 25936787 TI - Ultrasonographic evaluation of major salivary glands in primary Sjogren's syndrome: comparison of two scoring systems. AB - OBJECTIVE: To assess the diagnostic value of salivary gland ultrasonography (SGUS) for primary SS (pSS) and to compare the usefulness of two existing SGUS scoring systems. METHODS: Ultrasonography examination of major salivary glands was conducted for 105 pSS patients and 41 disease control subjects without SS and 16 healthy control subjects. The imaging features were graded using two different scoring systems (0-16 and 0-48, respectively) obtained from the grades of bilateral parotid and submandibular glands. Receiver operating characteristic curves were used to describe and compare the diagnostic accuracy of the two ultrasonography echostructure scoring systems for pSS. The agreement of diagnosis for pSS between the two scoring systems was determined by kappa-statistics. RESULTS: SGUS scores for the pSS group were significantly higher than those for the non-pSS group (P < 0.001). The best score cut-off was 7 in the 0-16 system (80% sensitivity and 93% specificity, respectively), and it was 15 in the 0-48 system (88.6% sensitivity and 84.2% specificity, respectively). Compared with the 0-16 system, combined evaluation of all four glands when using the 0-48 system improved the diagnostic accuracy. Association analysis of both scoring systems showed a positive correlation of SGUS scores with RF and gamma-globulin% (P < 0.05, overall). CONCLUSION: SGUS is a feasible method for pSS diagnosis with higher sensitivity using the 0-48 system and better specificity using the 0-16 system. SGUS scores are related to RF and gamma-globulin%. PMID- 25936788 TI - Chronic recurrent multifocal osteomyelitis in children: nine years' experience at a statewide tertiary paediatric rheumatology referral centre. AB - OBJECTIVE: To describe the clinical features, management and outcome of 34 children with chronic recurrent multifocal osteomyelitis (CRMO) diagnosed at a single centre over 9 years. METHODS: All children identified with CRMO for the period 2005-13 were identified from a prospectively collected database, with additional data from hospital records. RESULTS: Thirty-four patients, 21 female and 13 male, were identified. The average age at symptom onset was 9.8 years (range 3.8-17.9) and at diagnosis was 10.9 years (range 5.2-18.2), with an average delay in diagnosis of 12 months. Follow-up was 0.3-7.9 years (average 2.1), with 104 individual bony lesions identified, with a median of 3 (range 1-9) per patient. Six patients had unifocal disease. The sites involved included the tibia (n = 19), femur (n = 14), clavicle (n = 12), vertebrae (n = 10) and fibula (n = 8). Approximately half of patients had an inflammatory arthritis at diagnosis, and two-thirds in total eventually developed an arthritis. Pustulosis occurred in eight patients (24%), severe acne in four (12%) and psoriasis in three (9%). NSAIDs were used in 91%, CSs in 82% and MTX in 38%. Two patients were treated with anti-TNF agents. Episodic disease was most common (79%), while 21% had a monophasic pattern. Clinical remission occurred in 94% of children, with prolonged remission in 17%. Seven patients did not require medications for >12 months. CONCLUSION: CRMO is more common than previously recognized, but diagnosis may be delayed. Episodic multifocal disease was most common, but some had unifocal and/or monophasic disease. Most patients responded to NSAIDs and/or intermittent CSs, but many required DMARDs. PMID- 25936789 TI - Comment on: Benefits and risks of low-dose glucocorticoid treatment in the patient with rheumatoid arthritis. PMID- 25936790 TI - Comment on: Ultrasonography as a useful modality for documenting sacroiliitis in radiographically negative inflammatory back pain: a comparative evaluation with MRI. PMID- 25936791 TI - Comment on: The validation of a diagnostic rule for gout without joint fluid analysis: a prospective study. PMID- 25936792 TI - Male and female patients with axial spondyloarthritis experience disease activity, physical function and quality of life differently: results from the Groningen Leeuwarden Axial Spondyloarthritis cohort. PMID- 25936793 TI - Patient age, gender and extent of purpura may suggest short-term outcomes in adults with IgA vasculitis. PMID- 25936794 TI - Two-dimensional retention indices improve component identification in comprehensive two-dimensional gas chromatography of saffron. AB - Comprehensive two-dimensional gas chromatography hyphenated with accurate mass time-of-flight mass spectrometry (GC * GC-accTOFMS) was applied for improved analytical accuracy of saffron analysis, by using retention indices in the two dimensional separation. This constitutes 3 dimensions of identification. In addition to accTOFMS specificity, and first dimension retention indices ((1)I), a simple method involving direct multiple injections with stepwise isothermal temperature programming is described for construction of isovolatility curves for reference alkane series in GC * GC. This gives access to calculated second dimension retention indices ((2)I). Reliability of the calculated (2)I was evaluated by using a Grob test mixture, and saturated alkanes, revealing good correlation between previously reported I values from the literature, with R(2) correlation being 0.9997. This essentially recognizes the retention property of peaks in the GC * GC 2D space as being reducible to a retention index in each dimension, which should be a valuable tool supporting identification. The benefit of (2)I data, in supplementing (1)I and MS library matching, was clearly demonstrated by the progressive reduction of the number of possible compound matches for peaks observed in saffron. 114 analytes were assessed according to (1)I and (2)I values within +/-20 index unit of reference values, and by MS spectrum matching above a match statistic of 750 (including mass accuracy of the molecular ion <20 ppm) and their possible identities derived. The described method provides a new avenue to utilize the full capability of the two dimensional separation (GC * GC), in combination with MS library matching in complex sample analysis, to provide improved component identification. PMID- 25936795 TI - Prevalence of pulmonary tuberculosis in Wardha district of Maharashtra, Central India. AB - A house based survey was conducted during 2007-2009 in a representative sample of population in Wardha district implementing Directly Observed Treatment Short Course strategy for tuberculosis (TB) control since 2001. The objective was to estimate prevalence of bacillary pulmonary TB (PTB) in individuals aged 15 years or above, and to estimate trends in prevalence when compared to a previous survey carried out in mid 1980's. Two sputum samples (one spot, one early morning) collected from individuals having symptoms suggestive of PTB, history of previous anti-TB treatment (ATT) or abnormal pulmonary shadow on Mass Miniature Radiography (MMR) consistent with possibly or probably active tuberculosis were subjected to Ziehl-Neelsen microscopy and culture on Lowenstein-Jensen medium. Of 55,096 individuals registered into the survey, 50,332 (91.4%) were screened by interview for symptoms and history of ATT and/or by MMR. Of them, 4805 were eligible for sputum collection; both specimens were collected in 4285 (89.2%) and only one specimen in 27 (0.6%). A total of 86 bacillary cases were detected during the survey. Prevalence of bacillary PTB was estimated at 188.7 (140.3 236.9) per 100,000 populations. There was a decline of 61% in the prevalence of PTB over a period of 22 years. PMID- 25936796 TI - Anti-angiogenic effects of resveratrol in combination with 5-fluorouracil on B16 murine melanoma cells. AB - 5-Fluorouracil (5-FU) has been used as a chemotherapeutic drug for various types of cancer, although the development of resistance remains a major limitation for its use in clinical settings. In the present study, the anti-angiogenic effects of resveratrol and 5-FU either alone or in combination were examined in a B16 murine melanoma model. Co-treatment using resveratrol and 5-FU inhibited cell proliferation more efficiently compared with use of either drug alone and the antiproliferative effect coincided with changes in the expression levels of AMP activated protein kinase (AMPK), cyclooxygenase-2, vasodilator-stimulated phosphoprotein (VASP) and vascular endothelial growth factor (VEGF). Furthermore, co-treatment with resveratrol and 5-FU reduced tumor growth compared with that in the control group and this growth-inhibitory effect was associated with changes in the expression levels of AMPK, VASP and VEGF. Immunohistochemical staining for angiogenesis demonstrated that co-treatment with resveratrol and 5-FU reduced the number of microvascular vessels compared with that in the control group. These results suggested that co-treatment with resveratrol and 5-FU suppressed cell growth and angiogenesis in B16 murine melanoma tumors. PMID- 25936797 TI - Structural basis for the NAD binding cooperativity and catalytic characteristics of sperm-specific glyceraldehyde-3-phosphate dehydrogenase. AB - Catalytic properties of enzymes used in biotechnology can be improved by eliminating those regulatory mechanisms that are not absolutely required for their functioning. We exploited mammalian glyceraldehyde-3-phosphate dehydrogenase as a model protein and examined the structural basis of the NAD(+) cooperative binding exhibited by its homologous isoenzymes: the somatic enzyme (GAPD) and the recombinant sperm-specific enzyme (dN-GAPDS). Moreover, we obtained a mutant dN-GAPDS, which misses the cooperativity, but exhibits a twofold increase in the specific activity instead (92 and 45 MUmol NADH/min per mg protein for the mutant and the wild type proteins, respectively). Such an effect was caused by the disruption of the interdomain salt bridge D311-H124, which is located close to the active site of the enzyme. The thermal stability of the mutant protein also increased compared to the wild type form (heat absorption peak values were 70.4 and 68.6 degrees C, respectively). We expect our findings to be of importance for the purposes of biotechnological applications. PMID- 25936798 TI - Quality control in protein synthesis. PMID- 25936799 TI - Humoral Immunity in the Gut Selectively Targets Phenotypically Virulent Attaching and-Effacing Bacteria for Intraluminal Elimination. AB - Virulence factors expressed by enteric bacteria are pivotal for pathogen colonization and induction of intestinal disease, but the mechanisms by which host immunity regulates pathogen virulence are largely unknown. Here we show that specific antibody responses are required for downregulation of virulence gene expression in Citrobacter rodentium, an enteric pathogen that models human infections with attaching-and-effacing bacteria. In the absence of antibodies against the pathogen, phenotypically virulent C. rodentium, accumulated and infected the epithelium and subsequently invaded the lamina propia, causing host lethality. IgG induced after infection recognized virulence factors and bound virulent bacteria within the intestinal lumen, leading to their engulfment by neutrophils, while phenotypically avirulent pathogens remained in the intestinal lumen and were eventually outcompeted by the microbiota. Thus, the interplay of the innate and adaptive immune system selectively targets virulent C. rodentium in the intestinal lumen to promote pathogen eradication and host survival. PMID- 25936800 TI - SMADs and YAP compete to control elongation of beta-catenin:LEF-1-recruited RNAPII during hESC differentiation. AB - The Wnt3a/beta-catenin and Activin/SMAD2,3 signaling pathways synergize to induce endodermal differentiation of human embryonic stem cells; however, the underlying mechanism is not well understood. Using ChIP-seq and GRO-seq analyses, we show here that Wnt3a-induced beta-catenin:LEF-1 enhancers recruit cohesin to direct enhancer-promoter looping and activate mesendodermal (ME) lineage genes. Moreover, we find that LEF-1 and other hESC enhancers recruit RNAPII complexes (eRNAPII) that are highly phosphorylated at Ser5, but not Ser7. Wnt3a signaling further increases Ser5P-RNAPII at LEF-1 sites and ME gene promoters, indicating that elongation remains limiting. However, subsequent Activin/SMAD2,3 signaling selectively increases transcription elongation, P-TEFb occupancy, and Ser7P RNAPII levels at these genes. Finally, we show that the Hippo regulator, YAP, functions with TEAD to regulate binding of the NELF negative elongation factor and block SMAD2,3 induction of ME genes. Thus, the Wnt3a/beta-catenin and Activin/SMAD2,3 pathways act in concert to counteract YAP repression and upregulate ME genes during early hESC differentiation. PMID- 25936802 TI - The ubiquitination of rag A GTPase by RNF152 negatively regulates mTORC1 activation. AB - mTORC1 is essential for regulating cell growth and metabolism in response to various environmental stimuli. Heterodimeric Rag GTPases are required for amino acid-mediated mTORC1 activation at the lysosome. However, the mechanism by which amino acids regulate Rag activation remains not fully understood. Here, we identified the lysosome-anchored E3 ubiquitin ligase RNF152 as an essential negative regulator of the mTORC1 pathway by targeting RagA for K63-linked ubiquitination. RNF152 interacts with and ubiquitinates RagA in an amino-acid sensitive manner. The mutation of RagA ubiquitination sites abolishes this effect of RNF152 and enhances the RagA-mediated activation of mTORC1. Ubiquitination by RNF152 generates an anchor on RagA to recruit its inhibitor GATOR1, a GAP complex for Rag GTPases. RNF152 knockout results in the hyperactivation of mTORC1 and protects cells from amino-acid-starvation-induced autophagy. Thus, this study reveals a mechanism for regulation of mTORC1 signaling by RNF152-mediated K63 linked polyubiquitination of RagA. PMID- 25936801 TI - Cancer/Testis Antigen PASD1 Silences the Circadian Clock. AB - The circadian clock orchestrates global changes in transcriptional regulation on a daily basis via the bHLH-PAS transcription factor CLOCK:BMAL1. Pathways driven by other bHLH-PAS transcription factors have a homologous repressor that modulates activity on a tissue-specific basis, but none have been identified for CLOCK:BMAL1. We show here that the cancer/testis antigen PASD1 fulfills this role to suppress circadian rhythms. PASD1 is evolutionarily related to CLOCK and interacts with the CLOCK:BMAL1 complex to repress transcriptional activation. Expression of PASD1 is restricted to germline tissues in healthy individuals but can be induced in cells of somatic origin upon oncogenic transformation. Reducing PASD1 in human cancer cells significantly increases the amplitude of transcriptional oscillations to generate more robust circadian rhythms. Our results describe a function for a germline-specific protein in regulation of the circadian clock and provide a molecular link from oncogenic transformation to suppression of circadian rhythms. PMID- 25936803 TI - Coordinated Ribosomal L4 Protein Assembly into the Pre-Ribosome Is Regulated by Its Eukaryote-Specific Extension. AB - Eukaryotic ribosome biogenesis requires nuclear import and hierarchical incorporation of ~80 ribosomal proteins (RPs) into the ribosomal RNA core. In contrast to prokaryotes, many eukaryotic RPs possess long extensions that interdigitate in the mature ribosome. RpL4 is a prime example, with an ~80 residue-long surface extension of unknown function. Here, we identify assembly chaperone Acl4 that initially binds the universally conserved internal loop of newly synthesized RpL4 via its superhelical TPR domain, thereby restricting RpL4 loop insertion at its cognate nascent rRNA site. RpL4 release from Acl4 is orchestrated with pre-ribosome assembly, during which the eukaryote-specific RpL4 extension makes several distinct interactions with the 60S surface, including a co-evolved site on neighboring RpL18. Consequently, mutational inactivation of this contact site, on either RpL4 or RpL18, impairs RpL4-Acl4 disassembly and RpL4 pre-ribosome incorporation. We propose that hierarchical ribosome assembly can be achieved by eukaryotic RP extensions and dedicated assembly chaperones. PMID- 25936804 TI - An Inhibitor of PIDDosome Formation. AB - The PIDDosome-PIDD-RAIDD-caspase-2 complex-is a proapoptotic caspase-activation platform of elusive significance. DNA damage can initiate complex assembly via ATM phosphorylation of the PIDD death domain (DD), which enables RAIDD recruitment to PIDD. In contrast, the mechanisms limiting PIDDosome formation have remained unclear. We identify the mitotic checkpoint factor BubR1 as a direct PIDDosome inhibitor, acting in a noncanonical role independent of Mad2. Following its phosphorylation by ATM at DNA breaks, "primed" PIDD relocates to kinetochores via a direct interaction with BubR1. BubR1 binds the PIDD DD, competes with RAIDD recruitment, and negates PIDDosome-mediated apoptosis after ionizing radiation. The PIDDosome thus sequentially integrates DNA damage and mitotic checkpoint signals to decide cell fate in response to genotoxic stress. We further show that by sequestering PIDD at the kinetochore, BubR1 acts to delay PIDDosome formation until the next cycle, defining a new mechanism by which cells evade apoptosis during mitosis. PMID- 25936805 TI - Rapid mitogenic regulation of the mTORC1 inhibitor, DEPTOR, by phosphatidic acid. AB - The mammalian target of rapamycin complex 1 (mTORC1) is regulated, in part, by the endogenous inhibitor DEPTOR. However, the mechanism of DEPTOR regulation with regard to rapid mTORC1 activation remains unknown. We report that DEPTOR is rapidly and temporarily dissociated from mTORC1 upon mitogenic stimulation, suggesting a mechanism underlying acute mTORC1 activation. This mitogen stimulated DEPTOR dissociation is blocked by inhibition or depletion of the mTORC1 regulator, phospholipase D (PLD), and recapitulated with the addition of the PLD product phosphatidic acid (PA). Our mass spectrometry analysis has independently identified DEPTOR as an mTOR binding partner dissociated by PA. Interestingly, only PA species with unsaturated fatty acid chains, such as those produced by PLD, are capable of displacing DEPTOR and activating mTORC1, with high affinity for the FRB domain of mTOR. Our findings reveal a mechanism of mTOR regulation and provide a molecular explanation for the exquisite specificity of PA function. PMID- 25936806 TI - The Age-ility Project (Phase 1): Structural and functional imaging and electrophysiological data repository. AB - Our understanding of the complex interplay between structural and functional organisation of brain networks is being advanced by the development of novel multi-modal analyses approaches. The Age-ility Project (Phase 1) data repository offers open access to structural MRI, diffusion MRI, and resting-state fMRI scans, as well as resting-state EEG recorded from the same community participants (n=131, 15-35 y, 66 male). Raw imaging and electrophysiological data as well as essential demographics are made available via the NITRC website. All data have been reviewed for artifacts using a rigorous quality control protocol and detailed case notes are provided. PMID- 25936808 TI - Dosimetry Modeling for Focal Low-Dose-Rate Prostate Brachytherapy. AB - PURPOSE: Focal brachytherapy targeted to an individual lesion(s) within the prostate may reduce side effects experienced with whole-gland brachytherapy. The outcomes of a consensus meeting on focal prostate brachytherapy were used to investigate optimal dosimetry of focal low-dose-rate (LDR) prostate brachytherapy targeted using multiparametric magnetic resonance imaging (mp-MRI) and transperineal template prostate mapping (TPM) biopsy, including the effects of random and systematic seed displacements and interseed attenuation (ISA). METHODS AND MATERIALS: Nine patients were selected according to clinical characteristics and concordance of TPM and mp-MRI. Retrospectively, 3 treatment plans were analyzed for each case: whole-gland (WG), hemi-gland (hemi), and ultra-focal (UF) plans, with 145-Gy prescription dose and identical dose constraints for each plan. Plan robustness to seed displacement and ISA were assessed using Monte Carlo simulations. RESULTS: WG plans used a mean 28 needles and 81 seeds, hemi plans used 17 needles and 56 seeds, and UF plans used 12 needles and 25 seeds. Mean D90 (minimum dose received by 90% of the target) and V100 (percentage of the target that receives 100% dose) values were 181.3 Gy and 99.8% for the prostate in WG plans, 195.7 Gy and 97.8% for the hemi-prostate in hemi plans, and 218.3 Gy and 99.8% for the focal target in UF plans. Mean urethra D10 was 205.9 Gy, 191.4 Gy, and 92.4 Gy in WG, hemi, and UF plans, respectively. Mean rectum D2 cm(3) was 107.5 Gy, 77.0 Gy, and 42.7 Gy in WG, hemi, and UF plans, respectively. Focal plans were more sensitive to seed displacement errors: random shifts with a standard deviation of 4 mm reduced mean target D90 by 14.0%, 20.5%, and 32.0% for WG, hemi, and UF plans, respectively. ISA has a similar impact on dose-volume histogram parameters for all plan types. CONCLUSIONS: Treatment planning for focal LDR brachytherapy is feasible. Dose constraints are easily met with a notable reduction to organs at risk. Treating smaller targets makes seed positioning more critical. PMID- 25936809 TI - Delineation of Supraclavicular Target Volumes in Breast Cancer Radiation Therapy. AB - PURPOSE: To map the location of gross supraclavicular metastases in patients with breast cancer, in order to determine areas at highest risk of harboring subclinical disease. METHODS AND MATERIALS: Patients with axial imaging of gross supraclavicular disease were identified from an institutional breast cancer registry. Locations of the metastatic lymph nodes were transferred onto representative axial computed tomography images of the supraclavicular region and compared with the Radiation Therapy Oncology Group (RTOG) breast cancer atlas for radiation therapy planning. RESULTS: Sixty-two patients with 161 supraclavicular nodal metastases were eligible for study inclusion. At the time of diagnosis, 117 nodal metastases were present in 44 patients. Forty-four nodal metastases in 18 patients were detected at disease recurrence, 4 of whom had received prior radiation to the supraclavicular fossa. Of the 161 nodal metastases, 95 (59%) were within the RTOG consensus volume, 4 nodal metastases (2%) in 3 patients were marginally within the volume, and 62 nodal metastases (39%) in 30 patients were outside the volume. Supraclavicular disease outside the RTOG consensus volume was located in 3 regions: at the level of the cricoid and thyroid cartilage (superior to the RTOG volume), in the posterolateral supraclavicular fossa (posterolateral to the RTOG volume), and in the lateral low supraclavicular fossa (lateral to the RTOG volume). Only women with multiple supraclavicular metastases had nodal disease that extended superiorly to the level of the thyroid cartilage. CONCLUSIONS: For women with risk of harboring subclinical supraclavicular disease warranting the addition of supraclavicular radiation, coverage of the posterior triangle and the lateral low supraclavicular region should be considered. For women with known supraclavicular disease, extension of neck coverage superior to the cricoid cartilage may be warranted. PMID- 25936810 TI - Dosimetric Predictors of Radiation-Induced Vaginal Stenosis After Pelvic Radiation Therapy for Rectal and Anal Cancer. AB - PURPOSE: Although vaginal stenosis (VS) is a recognized toxicity in women who receive pelvic radiation therapy (RT), the relationship between RT dose and the volume and extent of toxicity has not been analyzed. We modeled this relationship to identify predictors of VS. METHODS AND MATERIALS: We evaluated 54 women, aged 29 to 78 years, who underwent pelvic RT for rectal or anal cancer during 2008 to 2011 and were enrolled in a prospective study evaluating vaginal dilator use. Maximum dilator size was measured before RT (baseline) and 1 month and 12 months after RT. Dilator use was initiated at 1 month. The difference (D) in dilator size before and after RT was recorded. Those with D <=-1 were classified as having VS (n=35); those with D >=0 were classified as having no VS (n=19 at 1 month). Dose-volume parameters were extracted, and the generalized equivalent uniform dose (gEUD) was used to build a predictive model. RESULTS: The mean vaginal doses were 50.0 Gy and 36.8 Gy for anal and rectal cancer patients, respectively. One month after RT, a gEUD model using a wide range of a values suggests that sparing of vaginal volume to a low dose may be important. When gEUD (a = -1) was <35 Gy and the mean vaginal dose was <43 Gy, severe VS was reduced (P=.02). A 1-year analysis suggests increasingly negative D values with increasing mean dose. However, patients with compliance <40% were more likely to have toxicity. CONCLUSIONS: Vaginal stenosis is influenced by multiple RT dose volume characteristics. Mean dose and gEUD constraints together may reduce the risk of severe VS. Patients receiving higher mean vaginal doses should have greater compliance with dilator therapy to minimize risk of toxicity. Further validation with independent datasets is needed. PMID- 25936811 TI - Integrity of the National Resident Matching Program for Radiation Oncology: National Survey of Applicant Experiences. AB - PURPOSE: The aim of this study was to examine the experiences of radiation oncology applicants and to evaluate the prevalence of behaviors that may be in conflict with established ethical standards. METHODS AND MATERIALS: An anonymous survey was sent to all 2013 applicants to a single domestic radiation oncology residency program through the National Resident Matching Program (NRMP). Questions included demographics, survey of observed behaviors, and opinions regarding the interview and matching process. Descriptive statistics were presented. Characteristics and experiences of respondents who matched were compared with those who did not match. RESULTS: Questionnaires were returned by 87 of 171 applicants for a 51% response rate. Eighty-two questionnaires were complete and included for analysis. Seventy-eight respondents (95.1%) reported being asked at least 1 question in conflict with the NRMP code of conduct. When asked where else they were interviewing, 64% stated that this query made them uncomfortable. Forty-five respondents (54.9%) reported unsolicited post-interview contact by programs, and 31 (37.8%) felt pressured to give assurances. Fifteen respondents (18.3%) reported being told their rank position or that they were "ranked to match" prior to Match day, with 27% of those individuals indicating this information influenced how they ranked programs. Half of respondents felt applicants often made dishonest or misleading assurances, one-third reported that they believed their desired match outcome could be improved by deliberately misleading programs, and more than two-thirds felt their rank position could be improved by having faculty from their home institutions directly contact programs on their behalf. CONCLUSIONS: Radiation oncology applicants report a high prevalence of behaviors in conflict with written NRMP policies. Post-interview communication should be discouraged in order to enhance fairness and support the professional development of future radiation oncologists. PMID- 25936812 TI - Double-Blind, Placebo-Controlled Pilot Study of Processed Ultra Emu Oil Versus Placebo in the Prevention of Radiation Dermatitis. AB - PURPOSE: The purpose of this single-institution pilot study was to evaluate the feasibility and safety of an oil-based skin agent, Ultra Emu Oil, on skin-related toxicity in patients undergoing radiation therapy to the breast or chest wall. METHODS AND MATERIALS: Patients were randomized 2:1 in a double-blind fashion and were instructed to apply processed Ultra Emu Oil or placebo (cottonseed oil) twice daily during the course of radiation therapy. The oils were applied before the third fraction and continued for 6 weeks after completion of treatment. The primary endpoint was the area under the curve (AUC) of Skindex-16 scale scores over time. Secondary outcomes included maximum grade of radiation dermatitis using the Common Terminology Criteria (CTC) for Adverse Events (CTCAE 3.0), the Skin Toxicity Assessment Tool, quality of life (QOL) measured by Linear Analogue Self-Assessment, and a symptom experience diary (SED). RESULTS: In all, 42 of 45 patients completed the study and were evaluable. The median times to peak rash, skin redness, peeling, and skin swelling were weeks 6, 6, 7, and 7, respectively as measured by the SED. The Skindex AUC scores tended to be lower in emu oil patients than in placebo patients (mean total AUC 7.2 vs 10.4, respectively). This trend was also seen in all the Skindex subdomains. The overall QOL was slightly better in the emu oil group but remained stable throughout the study for both arms. Peak CTC toxicity occurred at week 6. Patients using emu oil appeared slightly worse on maximum CTC grade, but the difference was not significant. CONCLUSIONS: This pilot study confirmed the safety of oil-based skin treatments during radiation therapy and suggests a trend for reduced skin toxicity for patients receiving emu oil. A larger study is needed to evaluate the efficacy of emu oil in reducing radiation dermatitis in patients receiving breast radiation. PMID- 25936813 TI - Analysis of Long-Term 4-Dimensional Computed Tomography Regional Ventilation After Radiation Therapy. AB - PURPOSE: To determine whether regional ventilation, as measured using 4 dimensional computed tomography (4D-CT), declines after radiation therapy (RT). METHODS AND MATERIALS: We analyzed pretreatment 4D-CT scans associated with 2 RT courses. We quantified regional pulmonary function over equivalent dose in 2 Gy (EQD2alpha/beta=3) intervals of 0 to 5 Gy, 5 to 20 Gy, 20 to 40 Gy, and >40 Gy using percentile-normalized intensity-based (VentInt) and Jacobian-based (VentJac) ventilation metrics. We modeled the impact of dose on mean ventilation (Vent-) and regional tidal volume (rTV: tidal volume [TV] within a dose interval normalized to total lung TV). We also identified clinical and dosimetric factors that affected regional ventilation changes (DeltaVent- and DeltarTV) after RT for the >20 Gy dose interval. RESULTS: After RT, Vent-Int exhibited statistically significant dose-dependent declines within the 20 to 40 Gy (-5.0%; P=.03) and >40 Gy (-6.8%; P<.01) intervals. Vent-Jac exhibited a declining trend after RT only for the >40 Gy interval (-4.6%; P=.07). Factors associated with DeltaVent-Int for the >20 Gy dose interval included airway stenosis progression (P=.03) and gross tumor volume (P=.09). Both rTVInt and rTVJac were associated with small (<2%) but significant declines after RT for 20 to 40 Gy and >40 Gy intervals. Factors associated with declining rTVInt (P<.05) for the >20 Gy dose interval included airway stenosis progression, greater V20 (volume of lung receiving >20 Gy), and smaller fraction of emphysema in V20. The association between the absence of chronic obstructive pulmonary disease and declining rTV trended toward significance (P=.09). CONCLUSIONS: Regional ventilation, as measured using 4D-CT, demonstrates a dose-dependent decline after RT. Our results support the use of 4D CT ventilation imaging for monitoring regional pulmonary function change after RT. PMID- 25936814 TI - Prospective Randomized Comparison of the Effectiveness of Radiation Therapy and Local Steroid Injection for the Treatment of Plantar Fasciitis. AB - PURPOSE: The purpose of this study was to conduct a randomized trial of radiation therapy for plantar fasciitis and to compare radiation therapy with local steroid injections. METHODS AND MATERIALS: Between March 2013 and April 2014, 128 patients with plantar fasciitis were randomized to receive radiation therapy (total dose of 6.0 Gy applied in 6 fractions of 1.0 Gy three times a week) or local corticosteroid injections a 1 ml injection of 40 mg methylprednisolone and 0.5 ml 1% lidocaine under the guidance of palpation. The results were measured using a visual analog scale, a modified von Pannewitz scale, and a 5-level function score. The fundamental phase of the study was 3 months, with a follow-up period of up to 6 months. RESULTS: The median follow-up period for all patients was 12.5 months (range, 6.5-18.6 months). For the radiation therapy patients, the median follow-up period was 13 months (range, 6.5-18.5 months), whereas in the palpation-guided (PG) steroid injection arm, it was 12.1 months (range, 6.5-18.6 months). After 3 months, results in the radiation therapy arm were significantly superior to those in the PG steroid injection arm (visual analog scale, P<.001; modified von Pannewitz scale, P<.001; 5-level function score, P<.001). Requirements for a second treatment did not significantly differ between the 2 groups, but the time interval for the second treatment was significantly shorter in the PG steroid injection group (P=.045). CONCLUSION: This study confirms the superior analgesic effect of radiation therapy compared to mean PG steroid injection on plantar fasciitis for at least 6 months after treatment. PMID- 25936815 TI - Rates of Reconstruction Failure in Patients Undergoing Immediate Reconstruction With Tissue Expanders and/or Implants and Postmastectomy Radiation Therapy. AB - OBJECTIVES: Mastectomy rates for breast cancer have increased, with a parallel increase in immediate reconstruction. For some women, tissue expander and implant (TE/I) reconstruction is the preferred or sole option. This retrospective study examined the rate of TE/I reconstruction failure (ie, removal of the TE or I with the inability to replace it resulting in no final reconstruction or autologous tissue reconstruction) in patients receiving postmastectomy radiation therapy (PMRT). METHODS AND MATERIALS: Between 2004 and 2012, 99 women had skin-sparing mastectomies (SSM) or total nipple/areolar skin-sparing mastectomies (TSSM) with immediate TE/I reconstruction and PMRT for pathologic stage II to III breast cancer. Ninety-seven percent had chemotherapy (doxorubicin and taxane-based), 22% underwent targeted therapies, and 78% had endocrine therapy. Radiation consisted of 5000 cGy given in 180 to 200 cGy to the reconstructed breast with or without treatment to the supraclavicular nodes. Median follow-up was 3.8 years. RESULTS: Total TE/I failure was 18% (12% without final reconstruction, 6% converted to autologous reconstruction). In univariate analysis, the strongest predictor of reconstruction failure (RF) was absence of total TE/I coverage (acellular dermal matrix and/or serratus muscle) at the time of radiation. RF occurred in 32.5% of patients without total coverage compared to 9% with coverage (P=.0069). For women with total coverage, the location of the mastectomy scar in the inframammary fold region was associated with higher RF (19% vs 0%, P=.0189). In multivariate analysis, weight was a significant factor for RF, with lower weight associated with a higher RF. Weight appeared to be a surrogate for the interaction of total coverage, thin skin flaps, interval to exchange, and location of the mastectomy scar. CONCLUSIONS: RFs in patients receiving PMRT were lowered with total TE/I coverage at the time of radiation by avoiding inframammary fold incisions and with a preferred interval of 6 months to exchange. PMID- 25936807 TI - A computational atlas of the hippocampal formation using ex vivo, ultra-high resolution MRI: Application to adaptive segmentation of in vivo MRI. AB - Automated analysis of MRI data of the subregions of the hippocampus requires computational atlases built at a higher resolution than those that are typically used in current neuroimaging studies. Here we describe the construction of a statistical atlas of the hippocampal formation at the subregion level using ultra high resolution, ex vivo MRI. Fifteen autopsy samples were scanned at 0.13 mm isotropic resolution (on average) using customized hardware. The images were manually segmented into 13 different hippocampal substructures using a protocol specifically designed for this study; precise delineations were made possible by the extraordinary resolution of the scans. In addition to the subregions, manual annotations for neighboring structures (e.g., amygdala, cortex) were obtained from a separate dataset of in vivo, T1-weighted MRI scans of the whole brain (1mm resolution). The manual labels from the in vivo and ex vivo data were combined into a single computational atlas of the hippocampal formation with a novel atlas building algorithm based on Bayesian inference. The resulting atlas can be used to automatically segment the hippocampal subregions in structural MRI images, using an algorithm that can analyze multimodal data and adapt to variations in MRI contrast due to differences in acquisition hardware or pulse sequences. The applicability of the atlas, which we are releasing as part of FreeSurfer (version 6.0), is demonstrated with experiments on three different publicly available datasets with different types of MRI contrast. The results show that the atlas and companion segmentation method: 1) can segment T1 and T2 images, as well as their combination, 2) replicate findings on mild cognitive impairment based on high-resolution T2 data, and 3) can discriminate between Alzheimer's disease subjects and elderly controls with 88% accuracy in standard resolution (1mm) T1 data, significantly outperforming the atlas in FreeSurfer version 5.3 (86% accuracy) and classification based on whole hippocampal volume (82% accuracy). PMID- 25936816 TI - Novel Radiobiological Gamma Index for Evaluation of 3-Dimensional Predicted Dose Distribution. AB - PURPOSE: To propose a gamma index-based dose evaluation index that integrates the radiobiological parameters of tumor control (TCP) and normal tissue complication probabilities (NTCP). METHODS AND MATERIALS: Fifteen prostate and head and neck (H&N) cancer patients received intensity modulated radiation therapy. Before treatment, patient-specific quality assurance was conducted via beam-by-beam analysis, and beam-specific dose error distributions were generated. The predicted 3-dimensional (3D) dose distribution was calculated by back-projection of relative dose error distribution per beam. A 3D gamma analysis of different organs (prostate: clinical [CTV] and planned target volumes [PTV], rectum, bladder, femoral heads; H&N: gross tumor volume [GTV], CTV, spinal cord, brain stem, both parotids) was performed using predicted and planned dose distributions under 2%/2 mm tolerance and physical gamma passing rate was calculated. TCP and NTCP values were calculated for voxels with physical gamma indices (PGI) >1. We propose a new radiobiological gamma index (RGI) to quantify the radiobiological effects of TCP and NTCP and calculate radiobiological gamma passing rates. RESULTS: The mean RGI gamma passing rates for prostate cases were significantly different compared with those of PGI (P<.03-.001). The mean RGI gamma passing rates for H&N cases (except for GTV) were significantly different compared with those of PGI (P<.001). Differences in gamma passing rates between PGI and RGI were due to dose differences between the planned and predicted dose distributions. Radiobiological gamma distribution was visualized to identify areas where the dose was radiobiologically important. CONCLUSIONS: RGI was proposed to integrate radiobiological effects into PGI. This index would assist physicians and medical physicists not only in physical evaluations of treatment delivery accuracy, but also in clinical evaluations of predicted dose distribution. PMID- 25936817 TI - The Role of Pretreatment FDG-PET in Treating Cervical Cancer Patients With Enlarged Pelvic Lymph Node(s) Shown on MRI: A Phase 3 Randomized Trial With Long Term Follow-Up. AB - PURPOSE: This report is the second analysis of a prospective randomized trial to investigate the impact of (18)F-fluorodeoxyglucose positron emission tomography (FDG-PET) on cervical cancer patients with enlarged pelvic lymph nodes identified by magnetic resonance imaging. METHODS AND MATERIALS: Patients with newly diagnosed cervical cancer with enlarged pelvic lymph nodes but free of enlarged para-aortic lymph nodes (PALN) were eligible. Patients were randomized to receive either pretreatment FDG-PET (PET arm) or not (control arm). The whole pelvis was the standard irradiation field for all patients except those with FDG-avid extrapelvic findings. RESULTS: In all, 129 patients were enrolled. Pretreatment PET detected extrapelvic metastases in 7 patients. No new patient experienced treatment failure during the additional 4-year follow-up period. There were no significant differences between the PET arm and the control arm regarding overall survival, disease-free survival, and freedom from extrapelvic metastasis. In the control arm, 8 of 10 patients with PALN relapse had limited extrapelvic nodal failures; their 5-year disease-specific survival was 34.3%. By contrast, only 1 of 5 patients with PALN relapse in the PET arm experienced such limited failures; their 5-year survival rate was 0%. CONCLUSIONS: Although the pretreatment detection of PALN did not translate into survival benefit, it indeed decreased the need for extended-field concurrent chemoradiation therapy. PMID- 25936819 TI - Androgens in a female primate: Relationships with reproductive status, age, dominance rank, fetal sex and secondary sexual color. AB - A comprehensive understanding of the role of androgens in reproduction, behavior and morphology requires the examination of female, as well as male, hormone profiles. However, we know far less about the biological significance of androgens in females than in males. We investigated the relationships between fecal androgen (immunoreactive testosterone) levels and reproductive status, age, dominance rank, fetal sex and a secondary sexual trait (facial color) in semi free-ranging female mandrills (Mandrillus sphinx), using samples collected from 19 reproductively mature females over 13months. Fecal androgens varied with reproductive status, being highest during gestation. Fecal androgens began to increase at 3months of gestation, and peaked at 5months. This pattern is more similar to that found in a platyrrhine than in other cercopithecine species, suggesting that such patterns are not necessarily phylogenetically constrained. Fecal androgens did not vary systematically with rank, in contrast to the relationship we have reported for male mandrills, and in line with sex differences in how rank is acquired and maintained. Offspring sex was unrelated to fecal androgens, either prior to conception or during gestation, contrasting with studies of other primate species. Mean facial color was positively related to mean fecal androgens across females, reflecting the same relationship in male mandrills. However, the relationship between color and androgens was negative within females. Future studies of the relationship between female androgens and social behavior, reproduction and secondary sexual traits will help to elucidate the factors underlying the similarities and differences found between the sexes and among studies. PMID- 25936821 TI - A quantitative assessment of the eating capability in the elderly individuals. AB - Ageing process implies physiologically weakened muscles, loss of natural teeth and movement coordination, causing difficulties in the eating process. A term "eating capability" has been proposed to measure objectively how capable an elderly individual is in overall food management. Our objectives were to establish feasible methodologies of eating capability assessment, examine correlations between hand and oro-facial muscle strengths and grade elderly subjects into groups based on their eating capabilities. This study was performed with 203 elderly subjects living in the UK (n=103, 7 community centres, 2 sheltered accommodation) and Spain (n=100, 3 nursing homes, 1 community centre). Hand gripping force, finger gripping force, biting force, lip sealing pressure, tongue pressing pressure and touching sensitivity were measured for elderly subjects. Measured parameters were normalised and scored between 1 and 5, with 1 being the weakest. Subjects were then grouped into 4 groups based on their eating capability scores, being participants of cluster 1 the weakest group and 4 the strongest. Perception of oral processing difficulty was assessed by showing food images. Hand gripping force showed a strong linear correlation with tongue pressure (UK: 0.35; Spain: 0.326) and biting force (UK: 0.351; Spain: 0.427). Biting force was strongly dependent on the denture status. Elderly of the first three groups perceived food products with more hardness and/or fibrous structure as difficult to process orally. The objective measurements of various physiological factors enabled quantitative characterisation of the eating capabilities of elderly people. The observed relationship between hand and oro facial muscle strengths provides possibility of using non-invasive hand gripping force measurement for eating capability assessment. PMID- 25936820 TI - Estrogens, androgens and generalized behavioral arousal in gonadectomized female and male C57BL/6 mice. AB - General arousal has been operationally defined as an enhanced motor activity and enhanced intensity of response to sensory stimuli. Even though the effects of gonadal hormones on mating behavior have been much studied, their potential effect on generalized arousal, as defined above, has never been evaluated. In the present study we employed a thoroughly validated assay of general arousal to determine the effects of estradiol (E) and testosterone (T) in gonadectomized female and male mice, respectively. The steroids were administered in three different ways: A fast-acting, water soluble preparation given intraperitoneally, an oil solution given subcutaneously, and an oil solution in a subcutaneous Silastic capsule. Motor activity and responses to sensory stimuli were recorded for 24h, 91h, and seven days following hormone administration, respectively. All measures of arousal varied according to the day/night cycle. The water soluble steroid preparation had no reliable effect. When the same doses of estradiol and testosterone were administered subcutaneously in an oil vehicle no effect of either treatment on arousal was observed. The subcutaneously implanted capsule containing estradiol or testosterone had a delayed effect on motor activity in females (four to seven days) but no effect in males. The long time required by the gonadal hormones for affecting arousal would be consistent with, but does not prove, a genomic action. The limited effects of E and T in our arousal assay suggest to us that the strongest actions of these hormones on arousal occur in the context of sequences of responses to sexually relevant stimuli. PMID- 25936822 TI - Effect of food restriction on energy budget in warm-acclimated striped hamsters. AB - The capacity of small mammals to sustain periods of food shortage largely depends on the adaptive regulation of energy budget in response to the decrease in food supply. In addition to food availability, ambient temperature (Ta) is an important factor affecting the rates of both energy intake and expenditure. To examine the effect of Ta on energy strategy and the capacity to sustain food shortage, striped hamsters were exposed to a warm condition (30 degrees C) and were then restricted to 70% of ad libitum food intake. Body mass, energy intake and expenditure and physiological markers indicative of thermogenesis were measured. Warm exposure had no effect on body mass and digestibility, but decreased energy intake, basal metabolic rate and maximum nonshivering thermogenesis. The mitochondria protein content, cytochrome c oxidase activity and uncoupling protein 1 level of brown adipose tissue were significantly lower in hamsters at 30 degrees C than at 21 degrees C. Food restriction induced a significant decrease in body mass, but the decreased body mass was attenuated at 30 degrees C relative to 21 degrees C. This suggests that striped hamsters could not compensate for the limited food supply by decreasing daily energy expenditure at 21 degrees C, whereas they could at 30 degrees C. The significant reductions in the rates of metabolism and thermogenesis in warm-acclimated hamsters increase the capacity to cope with food shortage. Although, it remains uncertain whether this response represents some generalized evolutionary adaptation, the Ta dependent adjustment in the capacity to survive food restriction may reflect that warm acclimation plays an important role in adaptive regulation of both physiology and behavior in response to the variations of food availability. PMID- 25936823 TI - Prior chronic stress induces persistent polyI:C-induced allodynia and depressive like behavior in rats: Possible involvement of glucocorticoids and microglia. AB - When animals suffer from viral infections, they develop a set of symptoms known as the "sickness response." Recent studies suggest that psychological stress can modulate the sickness response. However, it remains uncertain whether acute and chronic psychosocial stresses have the same effect on viral infection-induced sickness responses. To address this question, we compared changes in polyI:C induced sickness responses, such as fever, change of body weight and food intake, mechanical allodynia, and depressive-like behavior, in rats that had been pre exposed to single and repeated social defeat stresses. Intraperitoneal injection of polyI:C induced a maximal fever of 38.0 degrees C 3h after injection. Rats exposed to prior social defeat stress exhibited blunted febrile responses, which were more pronounced in the repeated stress group. Furthermore, only the repeated stress group showed late-onset and prolonged mechanical allodynia lasting until 8days after injection in the von Frey test and prolonged immobility time in the forced swim test 9days post-injection. To assess the role of glucocorticoids and microglia in the delayed and persistent development of these sickness responses in rats exposed to repeated stress, we investigated the effect of pretreatment with RU486, a glucocorticoid receptor antagonist, and minocycline, an inhibitor of microglial activation, on polyI:C-induced allodynia and depressive-like behavior. Pretreatment with either drug inhibited both the delayed allodynia and depressive-like behavior. The present study demonstrates that repeated, but not single, social defeat stress followed by systemic polyI:C administration induced prolonged allodynia and depressive-like behavior in rats. Our results show that even though a single-event psychosocial stress does not have any effect by itself, animals may develop persistent allodynia and depressive-like behavior when they suffer from an infectious disease if they are pre-exposed to repeated or chronic psychosocial stress. Furthermore, this study suggests that stress induced corticosterone and microglial activation play a pivotal role in this phenomenon. PMID- 25936824 TI - A prospective 1-year study of postural tachycardia and the relationship to non postural versus orthostatic symptoms. AB - PURPOSE: Healthy subjects with asymptomatic postural tachycardia at baseline were evaluated over a one year period to determine whether they developed non-postural versus orthostatic symptoms that could predispose them to develop Postural Tachycardia Syndrome (POTS). METHODS: Participants (n=30) were recruited for a 1 year follow-up (FUP) study if at baseline they demonstrated a heart rate increment of >=30bpm on head-up tilt (HUT). At FUP, HUT was repeated and four self-report questionnaires were used to assess symptoms. RESULTS: Heart rate (HR) increment was reduced in 19 subjects (-11.8+/-7.4bpm) and increased in 11 subjects (8.3+/-6.1bpm) at FUP versus baseline. Heart rate increment at FUP demonstrated no correlation to general fatigue (r=0.006), body vigilance (r=0.195), or the component scores for physical (r=-0.087) and mental (r=-0.137) health of the SF-36. Similarly, there was no correlation between HR increment at FUP and orthostatic scores (r=0.04). However, orthostatic scores did show a significant positive correlation with general fatigue and body vigilance scores (r=0.374, r=0.392, respectively; p<0.05). CONCLUSIONS: Despite meeting the heart rate criteria for POTS, these findings further support that the majority of young individuals express benign orthostatic tachycardia. In addition, after one year this patient population showed no predisposition to develop non-postural or postural symptoms that could lead to the full syndrome of POTS. These data further argue for the re-evaluation of the heart rate criteria for diagnosing POTS in young populations. PMID- 25936825 TI - Nosocomial transmission of dengue fever via needlestick. An occupational risk. PMID- 25936826 TI - P53 suppresses cell proliferation, metastasis, and angiogenesis of osteosarcoma through inhibition of the PI3K/AKT/mTOR pathway. AB - OBJECTIVE: To investigate the role of P53 in the pathogenesis of osteosarcoma and the possible mechanism involved in it. METHODS: The anti-proliferative effect of P53 was assessed using the cell counting Kit-8 assay. The migration and invasion potential were analyzed using wound-healing and transwell assays, respectively. The Matrigel capillary tube formation assay was performed to mimic in-vivo angiogenesis. Immunoblotting and immunofluorescence were used to observe protein levels and distribution of actin fibers. Finally, S2448p-mammalian target of rapamycin (mTOR) expression was detected on osteosarcoma tissues using immunohistochemistry. RESULTS: Firstly, P53 potently inhibited cell proliferation in osteosarcoma cell line (MG63) and in human normal osteoblasts (hFOB1.19) in vitro at the IC50 ranged from 50 to 500 nmol/l. Then, an inhibitory effect of P53 on metastasis was observed in osteosarcoma cell line MG63, along with the cytoskeletal rearrangements and suppression of the phosphorylation of PI3K downstream factors including AKT and mTOR. CONCLUSION: These results show that P53 suppresses cell proliferation and angiogenesis of osteosarcoma through inhibition of the PI3K/AKT/mTOR pathway, which might be an effective novel therapeutic candidate against osteosarcoma in the future. PMID- 25936827 TI - Residents' performance in open versus laparoscopic bench-model cholecystectomy in a hands-on surgical course. AB - INTRODUCTION: Laparoscopy has become the gold standard for many abdominal procedures. Among young surgeons, experience in laparoscopic surgery increasingly outweighs experience in open surgery. This study was conducted to compare residents' performance in laparoscopic versus open bench-model task. METHODS: In an international surgical skills course, we compared trainees' performance in open versus laparoscopic cholecystectomy in a cadaveric animal bench-model. Both exercises were evaluated by board-certified surgeons using an 8-item checklist and by the trainees themselves. RESULTS: 238 trainees with a median surgical experience of 24 months (interquartile range 14-48) took part. Twenty-two percent of the trainees had no previous laparoscopic and 62% no previous open cholecystectomy experience. Significant differences were found in the overall score (median difference of 1 (95% CI: 1, 1), p < 0.001), gallbladder perforation rate (73% vs. 29%, p < 0.001), safe dissection of the Calot's triangle (98% vs. 90%, p = 0.001) and duration of surgery (42 (13) minutes vs. 26 (10) minutes (mean differences 17.22 (95% CI: 15.37, 19.07), p < 0.001)), all favouring open surgery. The perforation rate in open and laparoscopic cholecystectomies was not consistently decreasing with increasing years of experience or number of previously performed procedures. Self-assessment was lower than the assessment by board-certified surgeons. CONCLUSION: Despite lower experience in open compared to laparoscopic cholecystectomy, better performance was observed in open task. It may be explained by a wider access with easier preparation. Open cholecystectomy is the rescue manoeuvre and therefore, it is important to provide also enough training opportunities in open surgery. PMID- 25936828 TI - Combined treatment with tamoxifen and a fusicoccin derivative (ISIR-042) to overcome resistance to therapy and to enhance the antitumor activity of 5 fluorouracil and gemcitabine in pancreatic cancer cells. AB - Although progress has been made in chemotherapeutic strategies against pancreatic cancer, overall survival has not significantly improved over the past decade. Thus, the development of better therapeutic regimens remains a high priority. Pancreatic cancer cell lines were treated with tamoxifen, a novel antitumor fusicoccin derivative (ISIR-042), and anticancer drugs, and their effects on cell growth, signaling and gene expression were determined. Xenografts of Panc-1 cells were treated with tamoxifen, ISIR-042 and 5-fluorouracil (5FU) to determine the effects on tumor growth. The inhibition of the growth of pancreatic cancer cells induced by tamoxifen was effectively reduced by alpha-tocopherol, a membrane stabilizer. ISIR-042 produced synergistic effects with tamoxifen in inhibiting cell growth. Tamoxifen elevated lipid peroxidation and the release of cytochrome c, and these effects of tamoxifen were reduced by alpha-tocopherol. ISIR-042 significantly inhibited colony formation and the expression of stemness-related genes of pancreatic cancer cells. The triple combination of tamoxifen, ISIR-042, and 5FU or gemcitabine was effective at inhibiting cell growth and the appearance of drug-resistant cells. This combined treatment significantly inhibited the growth of Panc-1 cells as xenografts without apparent adverse effects. The triple combination of tamoxifen and ISIR-042 with 5FU or gemcitabine may be highly effective against pancreatic cancer by overcoming resistance to therapy. PMID- 25936830 TI - Correction to: Inotuzumab ozogamicin in B-cell acute lymphoblastic leukemias and non-Hodgkin's lymphomas. PMID- 25936829 TI - Comparison of epidemiologically linked Campylobacter jejuni isolated from human and poultry sources. AB - Campylobacter jejuni is responsible for most foodborne bacterial infections worldwide including Australia. The aim of this study was to investigate a combination of typing methods in the characterization of C. jejuni isolated from clinical diarrhoeal samples (n = 20) and chicken meat (n = 26) in order to identify the source of infection and rank isolates based on their relative risk to humans. Sequencing of the flaA short variable region demonstrated that 86% of clinical isolates had genotypes that were also found in chicken meat. A polymerase chain reaction binary typing system identified 27 different codes based on the presence or absence of genes that have been reported to be associated with various aspects of C. jejuni pathogenicity, indicating that not all isolates may be of equal risk to human health. The lipooligosaccharide (LOS) of the C. jejuni isolates was classified into six classes (A, B, C, E, F, H) with 10.4% remaining unclassified. The majority (72.7%) of clinical isolates possessed sialylated LOS classes. Sialylated LOS classes were also detected in chicken isolates (80.7%). Antimicrobial tests indicated a low level of resistance, with no phenotypic resistance found to most antibiotics tested. A combination of typing approaches was useful to assign isolates to a source of infection and assess their risk to humans. PMID- 25936818 TI - Broad targeting of resistance to apoptosis in cancer. AB - Apoptosis or programmed cell death is natural way of removing aged cells from the body. Most of the anti-cancer therapies trigger apoptosis induction and related cell death networks to eliminate malignant cells. However, in cancer, de regulated apoptotic signaling, particularly the activation of an anti-apoptotic systems, allows cancer cells to escape this program leading to uncontrolled proliferation resulting in tumor survival, therapeutic resistance and recurrence of cancer. This resistance is a complicated phenomenon that emanates from the interactions of various molecules and signaling pathways. In this comprehensive review we discuss the various factors contributing to apoptosis resistance in cancers. The key resistance targets that are discussed include (1) Bcl-2 and Mcl 1 proteins; (2) autophagy processes; (3) necrosis and necroptosis; (4) heat shock protein signaling; (5) the proteasome pathway; (6) epigenetic mechanisms; and (7) aberrant nuclear export signaling. The shortcomings of current therapeutic modalities are highlighted and a broad spectrum strategy using approaches including (a) gossypol; (b) epigallocatechin-3-gallate; (c) UMI-77 (d) triptolide and (e) selinexor that can be used to overcome cell death resistance is presented. This review provides a roadmap for the design of successful anti cancer strategies that overcome resistance to apoptosis for better therapeutic outcome in patients with cancer. PMID- 25936831 TI - Morphological alterations in the liver of yellow perch (Perca flavescens) from a biological mercury hotspot. AB - Mercury (Hg) contamination is a global issue due to its anthropogenic release, long-range transport, and deposition in remote areas. In Kejimkujik National Park and National Historic Site, Nova Scotia, Canada, high concentrations of total mercury (THg) were found in tissues of yellow perch (Perca flavescens). The aim of this study was to evaluate a possible relationship between THg concentrations and the morphology of perch liver as a main site of metal storage and toxicity. Yellow perch were sampled from five lakes known to contain fish representing a wide range in Hg concentrations in fall 2013. The ultrastructure of hepatocytes and the distribution of Hg within the liver parenchyma were analyzed by transmission electron microscopy (TEM) and electron energy loss spectrometry (EELS). The relative area of macrophage aggregates (MAs) in the liver was determined using image analysis software and fluorescence microscopy. No relation between general health indicators (Fulton's condition index) and THg was observed. In line with this, TEM examination of the liver ultrastructure revealed no prominent pathologies related to THg accumulation. However, a morphological parameter that appeared to increase with muscle THg was the relative area of MAs in the liver. The hepatic lysosomes appeared to be enlarged in samples with the highest THg concentrations. Interestingly, EELS analysis revealed that the MAs and hepatic lysosomes contained Hg. PMID- 25936833 TI - Propofol as a transformative drug in anesthesia: insights from key early investigators. PMID- 25936832 TI - Maternal and early life factors of tooth emergence patterns and number of teeth at 1 and 2 years of age. AB - Various environmental factors have been associated with the timing of eruption of primary dentition, but the evidence to date comes from small studies with limited information on potential risk factors. We aimed to investigate associations between tooth emergence patterns and pre-conception, pregnancy and postnatal influences. Dentition patterns were recorded at ages 1 and 2 years in 2915 children born to women in the Southampton Women's Survey from whom information had been collected on maternal factors before conception and during pregnancy. In mutually adjusted regression models we found that: children were more dentally advanced at ages 1 and 2 years if their mothers had smoked during pregnancy or they were longer at birth; mothers of children whose dental development was advanced at age 2 years tended to have poorer socioeconomic circumstances, and to have reported a slower walking speed pre-pregnancy; and children of mothers of Asian ethnicity had later tooth development than those of white mothers. The findings add to the evidence of environmental impacts on the timing of the eruption of primary dentition in indicating that maternal smoking during pregnancy, socio-economic status and physical activity (assessed by reported walking speed) may influence the child's primary dentition. Early life factors, including size at birth are also associated with dentition patterns, as is maternal ethnicity. PMID- 25936834 TI - Identifying latent profiles of posttraumatic stress and major depression symptoms in Canadian veterans: Exploring differences across profiles in health related functioning. AB - Posttraumatic stress disorder (PTSD) has been consistently reported as being highly comorbid with major depressive disorder (MDD) and as being associated with health related functional impairment (HRF). We used archival data from 283 previously war-zone deployed Canadian veterans. Latent profile analysis (LPA) was used to uncover patterns of PTSD and MDD comorbidity as measured via the PTSD Checklist-Military version (PCL-M) and the Patient Health Questionnaire-9 (PHQ 9). Individual membership of latent classes was used in a series of one-way ANOVAs to ascertain group differences related to HRF as measured via the Short Form-36 Health Survey (SF-36). LPA resulted in three discrete patterns of PTSD and MDD comorbidity which were characterized by high symptoms of PTSD and MDD, moderate symptoms, and low symptoms. All ANOVAs comparing class membership on the SF-36 subscales were statistically significant demonstrating group differences across levels of HRF. The group with the highest symptoms reported the worst HRF followed by the medium and low symptom groups. These findings are clinically relevant as they demonstrate the need for continual assessment and targeted treatment of co-occurring PTSD and MDD. PMID- 25936835 TI - Neonatal echocardiography. AB - Echocardiography is a technique within neonatal care increasingly used in acute management of patients because of its potential to guide care and hemodynamic management. However, its use continues to provoke controversy, as it was originally within the purview of pediatric cardiologists trained to identify structural as well as functional heart disease. This article examines some of the echocardiographic techniques available to the neonatologist, their applications, and the concerns surrounding their use on neonatal units. PMID- 25936836 TI - An Adenine Code for DNA: A Second Life for N6-Methyladenine. AB - DNA N6-methyladenine (6mA) protects against restriction enzymes in bacteria. However, isolated reports have suggested additional activities and its presence in other organisms, such as unicellular eukaryotes. New data now find that 6mA may have a gene regulatory function in green alga, worm, and fly, suggesting m6A as a potential "epigenetic" mark. PMID- 25936837 TI - N6-methyldeoxyadenosine marks active transcription start sites in Chlamydomonas. AB - N(6)-methyldeoxyadenosine (6mA or m(6)A) is a DNA modification preserved in prokaryotes to eukaryotes. It is widespread in bacteria and functions in DNA mismatch repair, chromosome segregation, and virulence regulation. In contrast, the distribution and function of 6mA in eukaryotes have been unclear. Here, we present a comprehensive analysis of the 6mA landscape in the genome of Chlamydomonas using new sequencing approaches. We identified the 6mA modification in 84% of genes in Chlamydomonas. We found that 6mA mainly locates at ApT dinucleotides around transcription start sites (TSS) with a bimodal distribution and appears to mark active genes. A periodic pattern of 6mA deposition was also observed at base resolution, which is associated with nucleosome distribution near the TSS, suggesting a possible role in nucleosome positioning. The new genome-wide mapping of 6mA and its unique distribution in the Chlamydomonas genome suggest potential regulatory roles of 6mA in gene expression in eukaryotic organisms. PMID- 25936838 TI - N6-methyladenine DNA modification in Drosophila. AB - DNA N(6)-methyladenine (6mA) modification is commonly found in microbial genomes and plays important functions in regulating numerous biological processes in bacteria. However, whether 6mA occurs and what its potential roles are in higher eukaryote cells remain unknown. Here, we show that 6mA is present in Drosophila genome and that the 6mA modification is dynamic and is regulated by the Drosophila Tet homolog, DNA 6mA demethylase (DMAD), during embryogenesis. Importantly, our biochemical assays demonstrate that DMAD directly catalyzes 6mA demethylation in vitro. Further genetic and sequencing analyses reveal that DMAD is essential for development and that DMAD removes 6mA primarily from transposon regions, which correlates with transposon suppression in Drosophila ovary. Collectively, we uncover a DNA modification in Drosophila and describe a potential role of the DMAD-6mA regulatory axis in controlling development in higher eukaryotes. PMID- 25936839 TI - DNA Methylation on N6-Adenine in C. elegans. AB - In mammalian cells, DNA methylation on the fifth position of cytosine (5mC) plays an important role as an epigenetic mark. However, DNA methylation was considered to be absent in C. elegans because of the lack of detectable 5mC, as well as homologs of the cytosine DNA methyltransferases. Here, using multiple approaches, we demonstrate the presence of adenine N(6)-methylation (6mA) in C. elegans DNA. We further demonstrate that this modification increases trans-generationally in a paradigm of epigenetic inheritance. Importantly, we identify a DNA demethylase, NMAD-1, and a potential DNA methyltransferase, DAMT-1, which regulate 6mA levels and crosstalk between methylations of histone H3K4 and adenines and control the epigenetic inheritance of phenotypes associated with the loss of the H3K4me2 demethylase spr-5. Together, these data identify a DNA modification in C. elegans and raise the exciting possibility that 6mA may be a carrier of heritable epigenetic information in eukaryotes. PMID- 25936840 TI - Long chain polyunsaturated fatty acid supplementation in infancy increases length and weight-for-age but not BMI to 6 years when controlling for effects of maternal smoking. AB - Long chain polyunsaturated fatty acids (LCPUFA) are added to infant formula but their effect on long-term growth of children is under studied. We evaluated the effects of feeding LCPUFA-supplemented formula (n = 54) compared to control formula (n = 15) throughout infancy on growth from birth-6 years. Growth was described using separate models developed with the MIXED procedure of SAS((r)) that included maternal smoking history and gender. Compared to children fed control formula, children who consumed LCPUFA supplemented formula had higher length-/stature-/and weight-for-age percentiles but not body mass index (BMI) percentile from birth to 6 years. Maternal smoking predicted lower stature (2-6 years), higher weight-for-length (birth-18 months) and BMI percentile (2-6 years) independent of LCPUFA effects. Gender interacted with the effect of LCPUFA on stature, and the relationship between smoking and BMI, with a larger effect for boys. Energy intake did not explain growth differences. A relatively small control sample is a limitation. PMID- 25936841 TI - The translation and validation of the Japanese version of the patient assessment of constipation quality of life scale. AB - PURPOSE: The aim of the present study was to conduct a psychometric evaluation of the patient assessment of constipation quality of life scale (PAC-QOL) in the Japanese language. METHODS: The PAC-QOL was translated into Japanese. After being linguistically validated, the Japanese version of the PAC-QOL was administered to a sample of 121 patients. Validation studies were conducted to evaluate the internal consistency reliability (Cronbach's alpha), reproducibility [intraclass correlation coefficients (ICCs)], the convergent validity (correlated with the Short-Forum 36 Health Survey), the discriminant validity [correlated with the constipation scoring system (CSS)], the cross-sectional validity (analysis of variance models), and responsiveness (effect size) of the PAC-QOL scales. RESULTS: The internal consistency was good for all of the scales (Cronbach's alpha coefficient >0.7) and reproducible (ICCs >0.7). The four scales of the PAC QOL were significantly correlated with the Short-Forum 36 Health Survey (P < 0.01 except for the satisfaction subscale) and the CSS scores (P < 0.01 except for the satisfaction subscale). The PAC-QOL scale scores were significantly associated with constipation severity (P < 0.05). The effect size in patients reporting improvements in constipation over the treatment period was moderate to large, with a subscale effect size ranging from 0.69 to 1.18 and an overall scale effect size of 1.12. Similar findings were observed in the original validation study. CONCLUSIONS: The linguistic and psychometric evaluation demonstrated the validity of the Japanese version of the PAC-QOL. PMID- 25936842 TI - Intracranial SEPs recordings - The new way to go? PMID- 25936843 TI - Child and Adolescent Suicide Attempts, Suicidal Behavior, and Adverse Childhood Experiences in South Africa: A Prospective Study. AB - PURPOSE: This is the first known prospective study of child suicidal behavior in sub-Saharan Africa. Aims were to determine whether (1) cumulative exposure to adverse childhood experiences (ACEs) predicts later suicidality and (2) heightened risks are mediated by mental health disorder and drug/alcohol misuse. METHODS: Longitudinal repeated interviews were conducted 1 year apart (97% retention) with 3,515 adolescents aged 10-18 years in South Africa (56% female; <2.5% refusal). Random selection of census enumeration areas from urban/rural sites within two provinces and door-to-door sampling included all homes with a resident adolescent. Measures included past-month suicide attempts, planning, and ideation, mental health disorders, drug/alcohol use, and ACE, for example, parental death by AIDS or homicide, abuse, and exposure to community violence. Analyses included multivariate logistic regression and multiple mediation tests. RESULTS: Past-month suicidality rates were 3.2% of adolescents attempting, 5.8% planning, and 7.2% reporting ideation. After controlling for baseline suicidality and sociodemographics, a strong, graded relationship was shown between cumulative ACE and all suicide behaviors 1 year later. Baseline mental health, but not drug/alcohol misuse, mediated relationships between ACE and subsequent suicidality. Suicide attempts rose from 1.9% among adolescents with no ACE to 6.3% among adolescents with >5 ACEs (cumulative odds ratio [OR], 2.46; confidence interval [CI], 1.00-6.05); for suicide planning, from 2.4% to 12.5% (cumulative OR, 4.40; CI, 2.08-9.29); and for suicide ideation, from 4.2% to 15.6% (cumulative OR, 2.99; CI, 1.68-5.53). CONCLUSIONS: Preventing and mitigating childhood adversities have the potential to reduce suicidality. Among adolescents already exposed to adversities, effective mental health services may buffer against future suicidality. PMID- 25936844 TI - Potential therapeutic targets and the role of technology in developing novel antileishmanial drugs. AB - Leishmaniasis is the most prevalent pathogenic disease in many countries around the world, but there are few drugs available to treat it. Most antileishmanial drugs available are highly toxic, have resistance issues or require hospitalization for their use; therefore, they are not suitable for use in most of the affected countries. Over the past decade, the completion of the genomes of many human pathogens, including that of Leishmania spp., has opened new doors for target identification and validation. Here, we focus on the potential drug targets that can be used for the treatment of leishmaniasis and bring to light how recent technological advances, such as structure-based drug design, structural genomics, and molecular dynamics (MD), can be used to our advantage to develop potent and affordable antileishmanial drugs. PMID- 25936846 TI - Neurosarcoidosis: diagnosis, therapy and biomarkers. AB - Sarcoidosis is a multi-organ immune-mediated disease, which manifests as neurosarcoidosis (NS) in approximately 10% of all affected patients. The diagnosis of NS requires a high degree of suspicion as well as histological confirmation. Neurological symptoms in patients with systemic sarcoidosis should not be assumed to be due to NS unless proven true. The etiopathogenesis of NS is not yet fully elucidated and a reliable biomarker assessing disease progression is missing. As a probable result, there is no definitive cure for NS. The goals of available treatments include: halting inflammation, prevention of disease worsening and restoring neurological functions whenever possible. With immunosuppression, clinical remission of NS occurs in the majority of patients. However, in some others, the disease may still progress, as no permanent cure is yet available. PMID- 25936845 TI - Focused ultrasound-mediated drug delivery through the blood-brain barrier. AB - Despite recent advances in blood-brain barrier (BBB) research, it remains a significant hurdle for the pharmaceutical treatment of brain diseases. Focused ultrasound (FUS) is one method to transiently increase permeability of the BBB to promote drug delivery to specific brain regions. An introduction to the BBB and a brief overview of the methods, which can be used to circumvent the BBB to promote drug delivery, is provided. In particular, we discuss the advantages and limitations of FUS technology and the efficacy of FUS-mediated drug delivery in models of disease. MRI for targeting and evaluating FUS treatments, combined with administration of microbubbles, allows for transient, reproducible BBB opening. The integration of a real-time acoustic feedback controller has improved treatment safety. Successful clinical translation of FUS has the potential to transform the treatment of brain disease worldwide without requiring the development of new pharmaceutical agents. PMID- 25936847 TI - Parkinson's disease: a review of non-motor symptoms. AB - Parkinson's disease (PD) is a neurodegenerative disorder resulting from degeneration of the substantia nigra and the dopaminergic nigrostriatal pathway. Most treatments are geared toward the management and relief of motor symptoms in Parkinson's patients; however, as the disease progresses, various complications can be observed. Non-motor symptoms (NMS) may arise simply from the disease itself and are highly destructive to quality of life. These symptoms include mood disorders, cognitive dysfunction, pain, sensory dysfunction, and dysautonomia. Though it is undisputed that many NMS may appear years or even decades prior to the clinical diagnosis of PD, the focus of this review will be the overt motor phase of the condition. As such, the focus of this paper is to review the major NMS found in PD patients status post-diagnosis, their etiology, as well as treatment options available for the individual NMS. PMID- 25936849 TI - A comparative study of electrical potential sensors and Ag/AgCl electrodes for characterising spontaneous and event related electroencephalagram signals. AB - BACKGROUND: Electroencephalography (EEG) is still a widely used imaging tool that combines high temporal resolution with a relatively low cost. Ag/AgCl metal electrodes have been the gold standard for non-invasively monitoring electrical brain activity. Although reliable, these electrodes have multiple drawbacks: they suffer from noise, such as offset potential drift, and usability issues, for example, difficult skin preparation and cross-coupling of adjacent electrodes. NEW METHOD: In order to tackle these issues a prototype Electric Potential Sensor (EPS) device based on an auto-zero operational amplifier was developed and evaluated. The EPS is a novel active ultrahigh impedance capacitively coupled sensor. The absence of 1/f noise makes the EPS ideal for use with signal frequencies of ~10Hz or less. A comprehensive study was undertaken to compare neural signals recorded by the EPS with a standard commercial EEG system. RESULTS: Quantitatively, highly similar signals were observed between the EPS and EEG sensors for both free running and evoked brain activity with cross correlations of higher than 0.9 between the EPS and a standard benchmark EEG system. COMPARISON WITH EXISTING METHOD(S): These studies comprised measurements of both free running EEG and Event Related Potentials (ERPs) from a commercial EEG system and EPS. CONCLUSIONS: The EPS provides a promising alternative with many added benefits compared to standard EEG sensors, including reduced setup time and elimination of sensor cross-coupling. In the future the scalability of the EPS will allow the implementation of a whole head ultra-dense EPS array. PMID- 25936850 TI - Critical differences between two classical surgical approaches for middle cerebral artery occlusion-induced stroke in mice. AB - BACKGROUND: Stroke is the third leading cause of death and the leading cause of long-term disability in North America. On average, someone in the US has a stroke every 45 s, and worldwide, stroke claims 15 million lives each year. Therefore, reliable stroke models are vital to the production of effective new therapies for the treatment of this devastating cerebral vascular accident. NEW METHOD: Middle cerebral artery occlusion (MCAo) is considered to be the most clinically relevant surgical model of ischemic stroke, in which a variety of methods may be employed to block the MCA (the most common being through insertion of a monofilament). In this study, we have compared two different approaches that are currently used arbitrarily in various laboratories worldwide: one involving insertion of a monofilament via the common carotid artery (Koizumi et al.) and one via the external carotid artery (Longa et al.). RESULTS AND COMPARISONS WITH EXISTING METHODS: We assessed various parameters, including: mortality rates, neurological scores, inflammation levels, cellular trafficking (using intravital microscopy) and infarct volumes in mice after using each of the two approaches. We found that the Longa method produced a greater, and robust, inflammatory response, versus the Koizumi method. CONCLUSIONS: In conclusion, we suggest that the Longa method is superior for the study of both short and long-term outcomes of ischemic stroke. These results have considerable implications on stroke model selection for researchers. PMID- 25936851 TI - Athymic rat model for studying acellular human allograft. AB - BACKGROUND: Although human acellular nerve allograft is a promising nerve repair tool, optimizing graft application and understanding effective graft dimensions has been hampered by lack of an appropriate animal model. Rodent nerve acellular allograft can be tested in the utilitarian rodent nerve repair model, but testing different size options is limited by the size of the rodent donor animal. Human acellular nerve allograft offers the variety of sizes desired for more complete study but poses a high risk of rejection as xenograft tissue in the rodent model. Athymic nude rats are less prone to reject xenograft tissue due to their immunocompromised state and may offer an animal model for testing human acellular allograft. METHODS: Fifteen athymic nude and 15 Sprague-Dawley rats underwent unilateral excision and repair of a 10mm tibial nerve segment using 10mm of human acellular nerve graft. Testing at 3 months consisted of muscle force measurements, wet muscle weight, and histological assessment from the middle of the nerve grafts. RESULTS: Athymic rats repaired with human acellular xenograft demonstrated higher reinnervated muscle weight Gross inspection of the xenograft in euthymic rats revealed a brown and scarred center and histological inspection demonstrated larger axon diameters, and higher midgraft axon counts in the grafts of athymic rats. COMPARISON WITH EXISTING METHODS: The athymic rat has been used in many studies that require an immunocompromised host, including implantation of foreign nervous tissue. Previous attempts at implanting acellular nerve xenograft into immunocompetent rats have yielded suboptimal results when compared to allograft. This study is the first to test acellular human nerve allograft in an athymic rat. CONCLUSION: The nerve regeneration was better in human acellular nerve allograft implanted into immunocompromised athymic rats when compared to euthymic rats supporting a potential role of this model in studying acellular human nerve tissue. PMID- 25936852 TI - In vitro study of sirolimus release from a drug-eluting stent: Comparison of the release profiles obtained using different test setups. AB - In this study drug release from the CYPHERTM stent, the gold standard in drug eluting stent therapy until the end of its marketing in 2011/2012, was systematically evaluated using different in vitro release tests. The test systems included incubations setups, the reciprocating holder apparatus (USP7), the flow through cell apparatus (USP4) and the vessel-simulating flow-through cell (vFTC) specifically designed for stent testing. The results obtained show a large variability regarding the fractions released into the media after 7d ranging from 38.6% +/- 4.5% to 74.6% +/- 1.2%. The lowest fraction released was observed in the vFTC and the highest in an incubation setup with frequently changed media of a volume of 2 mL. Differences were even observed when using fairly similar and simple incubations setups with mere changes of the media volume, under maintenance of sink conditions, and of the vessel geometry. From these data it can be concluded, that in vitro release even from a slow releasing drug-eluting stent is greatly influenced by the experimental conditions and care must be taken when choosing a suitable setup. Comparison of the obtained in vitro release profiles to published in vivo data did not result in a distinct superiority of any of the tested methods regarding the predictability for the situation in vivo due to large differences in the reported in vivo data. However, this comparison yielded that the release observed in vitro using the 2 mL incubation setup and the reciprocating holder apparatus may be faster than the reported in vivo release. The results of this study also emphasize the necessity to use highly standardized release tests when comparisons between results from different experiments or even different labs are to be performed. In this context, the compendial methods are most likely offering the highest degree of standardization. PMID- 25936853 TI - Chain length affects pancreatic lipase activity and the extent and pH-time profile of triglyceride lipolysis. AB - Triglycerides (TG) are one of the most common excipients used in oral lipid-based formulations. The chain length of the TG plays an important role in the oral bioavailability of the co-administered drug. Fatty acid (FA) chain-length specificity of porcine pancreatic lipase was studied by means of an in vitro lipolysis model under bio-relevant conditions at pH 6.80. In order to determine the total extent of lipolysis, back-titration experiments at pH 11.50 were performed. Results suggest that there is a specific chain length range (C2-C8) for which pancreatic lipase shows higher activity. This specificity could result from a combination of physicochemical properties of TGs, 2-monoglycerides (2-MGs) and FAs, namely the droplet size of the TGs, the solubility of 2-MGs within mixed micelles, and the relative stability of the FAs as leaving groups in the hydrolysis reaction. During experimentation, it was evident that an optimisation of lipolysis conditions was needed for tighter control over pH levels so as to better mimic in vivo conditions. 1M NaOH, 3.5 mL/min maximum dosing rate, and 3 MUL/min minimum dosing rate were the optimised set of conditions that allowed better pH control, as well as the differentiation of the lipolysis of different lipid loads. PMID- 25936854 TI - Hemisynthetic trifluralin analogues incorporated in liposomes for the treatment of leishmanial infections. AB - Leishmaniasis, a vector-borne parasitic disease caused by Leishmania protozoa, is one of the most neglected tropical diseases in terms of drug discovery and development. Current treatment is based on a limited number of chemotherapeutic agents all of which present either/or resistance issues, severe toxicities and adverse reactions associated with extended treatment regimens, and high cost of therapy. Dinitroanilines are a new class of drugs with proven in vitro antileishmanial activity. In previous work a liposomal formulation of one dinitroaniline (TFL) was found to be active against Leishmania parasites in a murine model of visceral leishmaniasis (VL) and in the treatment of experimental canine leishmaniasis. In this study we have investigated the use of dinitroaniline analogues (TFL-A) associated to liposomes, as means to further improve TFL antileishmanial activity. The potential of the liposomal formulations was assessed in vitro against Leishmania infantum promastigotes and intracellular amastigotes and in vivo in a murine model of zoonotic VL. Free and liposomal TFL A were active in vitro against Leishmania parasites, and they also exhibited reduced cytotoxicity and haemolytic activity. Treatment of infected mice with liposomal TFL-A reduced the amastigote loads in the spleen up to 97%, compared with the loads for untreated controls. These findings illustrate that chemical synthesis of new molecules associated with the use of Nano Drug Delivery Systems that naturally target the diseased organs could be a promising strategy for effective management of VL. PMID- 25936855 TI - Protein-polyelectrolyte interactions: Monitoring particle formation and growth by nanoparticle tracking analysis and flow imaging microscopy. AB - The purpose of this study was to investigate the formation and growth kinetics of complexes of proteins and oppositely charged polyelectrolytes. Equal volumes of IgG and dextran sulfate (DS) solutions, 0.01 mg/ml each in 10mM phosphate, pH 6.2, were mixed. At different time points, samples were taken and analyzed by nanoparticle tracking analysis (NTA), Micro-Flow Imaging (MFI) and size-exclusion chromatography (SEC). SEC showed a huge drop in monomer content (approximately 85%) already 2 min after mixing, while a very high nanoparticle (size up to 500 nm) concentration (ca. 9 * 10(8)/ml) was detected by NTA. The nanoparticle concentration gradually decreased over time, while the average particle size increased. After a lag time of about 1.5h, a steady increase in microparticles was measured by MFI. The microparticle concentration kept increasing up to about 1.5 * 10(6)/ml until it started to slightly decrease after 10h. The average size of the microparticles remained in the low-MUm range (1-2 MUm) with a slight increase and broadening of the size distribution in time. The experimental data could be fitted with Smoluchowski's perikinetic coagulation model, which was validated by studying particle growth kinetics in IgG:DS mixtures of different concentrations. In conclusion, the combination of NTA and MFI provided novel insight into the kinetics and mechanism of protein-polyelectrolyte complex formation. PMID- 25936856 TI - Drug delivery of Insulin-like growth factor I. AB - This review starts off outlining the control of Insulin-like growth factor I (IGF I) kinetics in Nature and by virtue of a complex system of 6 binding proteins controlling half-life and tissue distribution of this strong anabolic peptide. In addition, alternative splicing is known to result in IGF-I variants with modulated properties in vivo and this insight is currently translated into advanced IGF-I variants for therapeutic use. Insights into these natural processes resulted in biomimetic strategies with the ultimate goal to control pharmacokinetics and have recently propelled new developments leading to optimized pharmaceutical performance of this protein in vivo. Aside from parenteral administration routes, IGF-I was successfully delivered across various epithelial barriers from liquid as well as from solid pharmaceutical forms opening novel and more convenient delivery modalities. IGF-I decoration yielded effective targeting upon systemic administration expanding the options for optimally deploying the growth factor for therapy. This review summarizes the exciting biotechnological and pharmaceutical progress seen for IGF-I delivery in recent years and critically discusses outcome in light of translational application for future IGF-I therapeutics. PMID- 25936857 TI - Rapid and repeatable fabrication of high A/R silk fibroin microneedles using thermally-drawn micromolds. AB - Thermal drawing is a versatile rapid prototyping method that can freely form microneedle (MN) structures with ultra-high aspect ratio without relying on any complex and expensive process. However, it is still challenging to repeatedly produce MNs with identical shapes using this thermal drawing due to small fluctuations in processing conditions such as temperatures, drawing speeds, drawing heights, or parallelism in the drawing setup. In addition, thermal drawing is only applicable to thermoplastic materials and most natural biomaterials are incompatible with this method. Thus, we propose use of thermal drawing to fabricate master molds with high aspect ratios and replicate the shape by micromolding. In this work, high A/R MNs with various body profiles were fabricated by thermal drawing and replicated to silk fibroin (SF) MNs multiple times using micromolding. The original MN shape was precisely copied to the SF MNs. Methanol treatment enhanced the mechanical strength of SF MNs up to about 113% more depending on the treatment duration. We also demonstrated that methanol exposure time could effectively control drug release rates from SF MNs. PMID- 25936858 TI - Inhalable tranexamic acid for haemoptysis treatment. AB - PURPOSE: An inhalable dry powder formulation of tranexamic acid (TA) was developed and tested in a novel high-dose Orbital(r) multi-breath inhaler. The formulation was specifically intended for the treatment of pulmonary haemorrhage and wound healing associated with haemoptysis. METHODS: Inhalable TA particles were prepared by spray drying and the powder characterised using laser diffraction, electron microscopy, thermal analysis, moisture sorption and X-ray powder diffraction. The aerosol performance was evaluated using cascade impaction and inline laser diffraction and interaction with epithelia cells and wound healing capacity investigated using Calu-3 air interface model. RESULTS: The spray dried TA particles were crystalline and spherical with a D0.5 of 3.35 MUm. The powders were stable and had limited moisture sorption (0.307%w/w at 90%RH). The Orbital device delivered ca. 38 mg powder per 'inhalation' at 60 l . min(-1) across four sequential shots with an overall fine particle fraction (? 6.4 MUm) of 59.3 +/- 3.5% based on the emitted mass of ca. 150 mg. The TA particles were well tolerated by Calu-3 bronchial epithelia cells across a wide range of doses (from 1 nM to 10nM) and no increase in inflammatory mediators was observed after deposition of the particles (a decrease in IL-1beta, IL-8 and INFgamma was observed). Time lapse microscopy of a damaged confluent epithelia indicated that wound closure was significantly greater in TA treated cells compared to control. CONCLUSION: A stable, high performance aerosol of TA has been developed in a multi-breath DPI device that can be used for the treatment of pulmonary lesions and haemoptysis. PMID- 25936859 TI - Bipolar tetraether lipids derived from thermoacidophilic archaeon Sulfolobus acidocaldarius for membrane stabilization of chlorin e6 based liposomes for photodynamic therapy. AB - The initial burst release of water-soluble photosensitizers is one of the major problems encountered the development of controlled release formulations. In this study, the freely water soluble chlorin e6 (Ce6) was assembled with cationic lipid 1,2-dioleoyl-3-trimethylammonium-propane (DOTAP) to improve its loading efficiency in the liposomal bilayer. Tetraether lipids (TELs) derived from Sulfolobus acidocaldarius were added to DOTAP:Ce6 assembly in a concentration range of 2.5*10(-4)-1.6*10(-3)M to stabilize the membrane rigidity of the liposomes and to provide controlled release system. From the comparative spectroscopic experiments, it has been shown that the assembled DOTAP:Ce6 along with addition of TELs have improved the loading efficiency of Ce6 in TELs liposomes and obviously modified the release profile of Ce6. The in vitro cell viability of Ce6 in mouse neuro-blastoma (Neuro-2a) and ovarian cell carcinoma (SK-OV-3) confirmed neglected dark cytotoxicity and presented potential photo induced cytotoxicity with the effect was being more pronounced in Neuro 2a than in SK-OV-3. In-situ IV-injection of chick chorioallantoic membrane (CAM) showed hemorrhage and necrosis 30 min post irradiation at 1.8 mol% TELs (19.9J/cm(2)). Higher TELs of 2.2 and 3.7 mol% in particular demonstrated localized vascular destruction within the irradiated area. Our results suggest that TELs favored slower release rates of Ce6. This, in turn, tetraether lipids can be considered as a versatile class of lipids for photodynamic modality for destruction of cancer cells and tumor vasculature while sparing the quiescent ones. PMID- 25936860 TI - Phospholipid-stabilized mesoporous carbon nanospheres as versatile carriers for systemic delivery of amphiphobic SNX-2112 (a Hsp90 inhibitor) with enhanced antitumor effect. AB - Systemic delivery of amphiphobic drugs (insoluble in both water and oil) represents a formidable challenge in drug delivery. This work aimed to engineer a functional mesoporous carbon material to efficiently load SNX-2112, an amphiphobic anticancer agent, and to evaluate its performance in tumor-targeting delivery. Hydrothermal reaction combined with high-temperature activation was used to fabricate glucose-based mesoporous carbon nanospheres (MCNs). SNX-2112 loaded MCNs stabilized by phospholipid (SN-PMCNs) were prepared by the absorption/solvent diffusion/high-pressure homogenization method. The obtained SN PMCNs were 180nm around in particle size, showing a high drug load (42.7%) and acceptable physical stability. SN-PMCNs demonstrated an enhanced in vitro antitumor effect and increased uptake into cancer cells in comparison with the formulation of SNX-2112 solution (SN-Sol). The in vivo antitumor effect and biodistribution in 4T1 xenograft tumor mice, a breast cancer model, were also significantly improved through SN-PMCNs. It was shown that specific clathrin dependent and nonspecific caveolae-dependent endocytosis were involved in the cellular trafficking of SN-PMCNs. Glucose transporter-mediated transport, prolonged body residence time and improved biodistribution via EPR effect were the main mechanisms of enhanced antitumor effect. SN-PMCNs have presented excellent tumor targeting properties and should be a promising carrier to address the systemic delivery of SNX-2112. PMID- 25936861 TI - The impact of blood-borne viruses on cause-specific mortality among opioid dependent people: An Australian population-based cohort study. AB - BACKGROUND: Blood-borne viruses (BBV) are prevalent among people with opioid dependence but their association with cause-specific mortality has not been examined at the population-level. METHODS: We formed a population-based cohort of 29,571 opioid substitution therapy (OST) registrants in New South Wales, Australia, 1993-2007. We ascertained notifications of infection and death by record linkage between the Pharmaceutical Drugs of Addiction System (OST data), registers of hepatitis C (HCV), hepatitis B (HBV) and human immunodeficiency virus (HIV) diagnoses, and the National Death Index. We used competing risks regression to quantify associations between notification for BBV infection and causes of death. BBV status, age, year, OST status, and OST episodes were modelled as time-dependent covariates; sex was a fixed covariate. RESULTS: OST registrants notified with HCV infection were more likely to die from accidental overdose (subdistribution hazard ratio, 95% Confidence Interval: 1.7, 1.5-2.0), cancer (2.0, 1.3-3.2) and unintentional injury (1.4, 1.0-2.0). HBV notification was associated with a higher hazard of mortality due to unintentional injury (2.1, 1.1-3.9), cancer (2.8, 1.5-5.5), and liver disease (2.1, 1.0-4.3). Liver related mortality was higher among those notified with HIV only (11, 2.5-50), HCV only (5.9, 3.2-11) and both HIV and HCV (15, 3.2-66). Registrants with an HIV notification had a higher hazard of cardiovascular-related mortality (4.0, 1.6 9.9). CONCLUSIONS: Among OST registrants, BBVs are a direct cause of death and also a marker of behaviours that can result in unintended death. Ongoing and enhanced BBV prevention strategies and treatment, together with targeted education strategies to reduce risk, are justified. PMID- 25936862 TI - Progress on hypoxia-inducible factor-3: Its structure, gene regulation and biological function (Review). AB - Hypoxia inducible factors (HIFs) are transcription factors, which are commonly expressed in mammals, including humans. The HIFs consist of hypoxia-regulated alpha and oxygen-insensitive beta subunits, and are key regulators of gene expression during hypoxia in normal and solid tumor tissues. Three members of the HIF family, HIF-1alpha, HIF-2alpha, and HIF-3alpha, are currently known. HIF 3alpha differs from HIF-1alpha and HIF-2alpha in protein structure and regulation of gene expression. For a long time, HIF-3alpha was considered as a negative mediator of HIF-regulated genes. HIF-3 has a transcriptional regulatory function, which negatively affects gene expression by competing with HIF-1alpha and HIF 2alpha in binding to transcriptional elements in target genes during hypoxia. Previously, certain target genes of HIF-3alpha have been identified, confirming the role of HIF-3alpha as a transcription factor. In this review, the protein structure, gene regulation and biological function of HIF-3 are discussed based on the literature. PMID- 25936863 TI - Advances in the management of primary monosymptomatic nocturnal enuresis in children. AB - Intermittent incontinence of urine in a sleeping child who has previously been dry for less than 6 months without any other lower urinary tract symptoms is considered to be primary monosymptomatic nocturnal enuresis (PMNE). Although, most children outgrow PMNE with age, the psychological impact on the child warrants parental education and patient motivation and treatment. Motivational therapy, alarm therapy and drug therapy are the mainstay of treatment. Motivational and alarm therapy have better success rates than drug therapy alone. Desmopressin is the commonly used first-line drug and is best for short-term relief. Other drugs such as anti-cholinergics, imipramine and sertraline are used in resistant cases. This review focuses on the assessment and treatment of PMNE. PMID- 25936864 TI - Compliance with American Urological Association Guidelines for Post-Percutaneous Nephrolithotomy Antibiotics Does Not Appear to Increase Rates of Infection. AB - PURPOSE: We compared infection rates after percutaneous nephrolithotomy in a group of patients without a history of infection or struvite calculi who received 24 hours or less of antibiotics postoperatively (ie compliance with AUA guidelines) vs a group that received 5 to 7 days of antibiotics postoperatively. MATERIALS AND METHODS: We retrospectively reviewed the records of consecutive percutaneous nephrolithotomy procedures in patients without a history of urinary tract infection. Group 1 received 24 hours or less of antibiotics postoperatively and group 2 received a mean of 6 days of antibiotics postoperatively. RESULTS: A total of 52 patients in group 1 (24 hours or less of antibiotics) and 30 in group 2 (mean 6 days of antibiotics) met study inclusion criteria. In 5 group 1 patients (9.6%) fever developed within 72 hours of percutaneous nephrolithotomy but none demonstrated bacteriuria or bacteremia on cultures. No patient in group 1 was treated for urinary tract infection on postoperative days 3 to 14. In 4 group 2 patients (13.3%) fever developed within 72 hours of percutaneous nephrolithotomy. A single patient showed bacteriuria (less than 10,000 cfu mixed gram-positive bacteria) on culture while no patient demonstrated bacteremia. No patient in group 2 was treated for urinary tract infection on postoperative days 3 to 14. There was no difference in stone-free rates or the need for additional procedures between the 2 groups. CONCLUSIONS: In this pilot series compliance with AUA guidelines for antibiotic prophylaxis did not result in higher rates of infection than in a comparable group of 30 patients who received approximately 6 days of antibiotics postoperatively. PMID- 25936865 TI - Does Stone Removal Help Patients with Recurrent Urinary Tract Infections? AB - PURPOSE: We evaluated the impact of surgical extraction of nonobstructing asymptomatic stones on recurrent urinary tract infections and identified predictors of patients who may be rendered infection-free. MATERIALS AND METHODS: We retrospectively reviewed charts to identify patients with recurrent urinary tract infections who underwent surgical stone extraction and were rendered stone free. Demographic variables as well as procedure, infectious etiology, stone composition and the systemic inflammatory response syndrome rate were also recorded. Patients were divided into 2 groups. Group 1 had no evidence of recurrent infection following surgery while recurrent infection developed in group 2. Univariate analysis was performed using the Wilcoxon signed rank and Fisher exact tests. Logistic regression was used for multivariate analysis. RESULTS: We identified 120 patients with recurrent urinary tract infections and a nonobstructive renal stone. Surgical management included shock wave lithotripsy in 32% of cases, ureteroscopy in 7% and percutaneous nephrolithotomy in 61%. Of the 120 patients 58 (48%) remained infection-free after surgery while 62 (52%) experienced recurrent infection. Factors associated with a higher risk of recurrent infections included type 2 diabetes mellitus (OR 1.73, p = 0.01), hypertension (OR 2.8, p = 0.007) and black ethnicity (OR 13.7, p = 0.009). Escherichia coli infections were more likely to resolve (OR 0.34, p = 0.01). In contrast, Enterococcus infections were more likely to persist (OR 2.5, p = 0.04). On multiple logistic regression analysis only race, hypertension and E. coli infections were significant predictors of infection clearance. CONCLUSIONS: Of patients with recurrent urinary tract infections and asymptomatic renal calculi 50% may be rendered infection-free following stone extraction. Patients with risk factors for recurrent infections after surgery should be counseled that stone extraction might not eradicate the infection. PMID- 25936866 TI - Utilization and Outcomes of Inpatient Urological Care at Safety Net Hospitals. AB - PURPOSE: Because proposed funding cuts in the Patient Protection and Affordable Care Act may impact care for urological patients at safety net hospitals, we examined the use, outcomes and costs of inpatient urological surgery at safety net vs nonsafety net facilities prior to health care reform. MATERIALS AND METHODS: Using the Nationwide Inpatient Sample we performed a retrospective cohort study of patients who underwent inpatient urological surgeries from 2007 through 2011. We defined the safety net burden of each hospital based on the proportion of Medicaid and self-pay discharges. We examined the distribution of urological procedures performed and compared in-hospital mortality, prolonged length of stay and costs in the highest quartile of burden (safety net) vs the lowest quartile (nonsafety net). RESULTS: The distribution of urological procedures differed by safety net status with less benign prostate surgery (9.1% safety net vs 11.4% nonsafety net) and major cancer surgery (26.9% vs 34.3%), and more reconstructive surgery (8.1% vs 5.5%) at safety net facilities (p <0.001). Higher mortality at safety net hospitals was seen for nephrectomy (OR 1.68, 95% CI 1.15-2.45) and transurethral resection of the prostate (OR 2.17, 95% CI 1.22 3.87). Patients in safety net hospitals demonstrated greater prolonged length of stay after endoscopic stone surgery (OR 1.20, 95% CI 1.01-1.41). Costs were similar across procedures except for radical prostatectomy and cystectomy. For these procedures the average admission was more expensive at nonsafety net facilities (prostatectomy $11,457 vs $9,610 and cystectomy $27,875 vs $24,048, each p <0.02). CONCLUSIONS: Reductions in funding to safety net hospitals with health care reform could adversely impact access to care for patients with a broad range of urological conditions, potentially exacerbating existing disparities for vulnerable populations served by these facilities. PMID- 25936867 TI - Gut bacteria and necrotizing enterocolitis: cause or effect? AB - Development of necrotising enterocolitis (NEC) is considered to be dependent on the bacterial colonisation of the gut. With little concordance between published data and a recent study failing to detect a common strain in infants with NEC, more questions than answers are arising about our understanding of this complex disease. PMID- 25936868 TI - Chemotypic and genetic diversity in Epimedium sagittatum from different geographical regions of China. AB - Different geographical plant populations within a single species can exhibit variation, in the production of secondary metabolites. Genetic and environmental variations both contribute to differences between populations; however, the relative importance of these factors is unclear. Here, the extent of variation in the production of four flavonoid glycosides (epimedin A, B, C and icariin) were investigated in eleven wild populations of Epimedium sagittatum used in traditional Chinese medicine. Secondary metabolite profiles were classified into five chemotypes. A common garden experiment indicated this chemotype variation has a significant genetic basis. Extensive genetic variation among intraspecific populations was shown using a retrotransposon-based molecular marker system. These results will assist in development of strategies for conservation, utilization and domestication of E. sagittatum. PMID- 25936869 TI - UV irradiation-induced production of monoglycosylated biglycan through downregulation of xylosyltransferase 1 in cultured human dermal fibroblasts. AB - BACKGROUND: Biglycan (BGN) is a proteoglycan composed of a 42-kDa core protein and two glycosaminoglycan (GAG) chains, and known to be involved in structural, space-filling functions and many physiological regulations in the skin. OBJECTIVE: To investigate ultraviolet (UV) irradiation-induced changes of BGN protein and its GAG chain synthesis in cultured human dermal fibroblasts. METHODS: UV irradiation-induced or xylosyltransferase (XYLT) 1 siRNA-mediated smaller-sized protein bands detected by Western blot using BGN antibodies were identified as monoglycosylated forms of BGN, using BGN siRNA-mediated knockdown and chondroitinase ABC (ChABC). Differential activity of XYLT1 and 2 on BGN core protein was investigated by size shift of S42A- and S47A-BGN mutants to core protein size caused by XYLT1 siRNA transfection or UV irradiation. RESULTS: After UV irradiation, intact form of BGN protein (I-BGN) and core protein form were reduced in cultured fibroblasts, but other smaller-sized bands were observed to be increased. These smaller-sized ones were reduced by transfection of BGN siRNA, and shifted to the core protein size by treatment with ChABC, suggesting that they are defectively-glycosylated forms of BGN (D-BGN) protein. UV irradiation also decreased mRNA expression levels of XYLT1 and 2, which are responsible for initiation of GAG chain synthesis. UV-mediated reduction of XYLT1 expression was much stronger than that of XYLT2. Furthermore, siRNA-mediated down-regulation of XYLT1 resulted in the increase of D-BGN and the decrease of I-BGN, while down regulation of XYLT2 resulted in no change of D-BGN and I-BGN, suggesting that the XYLT1 may react with both GAG-attaching serine sites of BGN; however, XYLT2 may prefer to react one of them. Another dermatan sulfate (DS) proteoglycan, decorin, showed no or a little change of its molecular weight by UV irradiation or XYLT1 siRNA transfection, suggesting that DS synthesis may not be a critical factor in formation of D-BGN. Co-transfection with XYLT1, 2 siRNAs and wild-type or mutant forms of BGN overexpression vectors revealed that S42A-BGN showed size reduction to core protein size by XYLT1 downregulation, but S47A-BGN did not, suggesting that XYLT2 can react only with S42 on BGN core protein. With UV irradiation, both S42A-BGN and S47A-BGN showed size reduction, which is probably because UV-caused downregulation of both XYLTs and overexpression condition resulted in incomplete glycosylation and secretion. CONCLUSIONS: UV irradiation-induced increase of BGN monoglycosylated forms in cultured human dermal fibroblasts is resulted from dominance of XYLT2 activity, which acts only at S42 on BGN core protein, caused by UV-mediated stronger reduction of XYLT1. PMID- 25936870 TI - Correlation of Merkel cell polyomavirus positivity with PDGFRalpha mutations and survivin expression in Merkel cell carcinoma. AB - BACKGROUND: Merkel cell carcinoma (MCC) is a neuroendocrine cancer of the skin postulated to originate through Merkel cell polyomavirus (MCPyV) oncogenesis and/or by mutations in molecules implicated in the regulation of cell growth and survival. Despite the fact that MCPvV is detected more broadly within the population, only a part of the infected people also develop MCC. It is thus conceivable that together, virus and for example mutations, are necessary for disease development. However, apart from a correlation between MCPyV positivity or mutations and MCC development, less is known about the association of these factors with progressive disease. OBJECTIVES: To analyze MCPyV positivity, load and integration in MCC as well as presence of mutations in PDGFRalpha and TP53 genes and correlate these with clinical features and disease progression to identify features with prognostic value for clinical progression. METHODS: This is a study on a MCC population group of 64 patients. MCPyV positivity, load and integration in parallel to mutations in the PDGFRalpha and TP53 were analyzed on genomic DNA from MCC specimens. In addition, expression of PDGFRalpha, survivin and p53 proteins was analyzed by immunodetection in tissues specimens. All these parameters were analyzed as function of patient's disease progression status. RESULTS: 83% of MCCs were positive for the MCPyV and among these 36% also displayed virus-T integration. Viral load ranged from 0.006 to 943 viral DNA copies/beta-globin gene and was highest in patients with progressive disease. We detected more than one mutation within the PDGFRalpha gene and identified two new SNPs in 36% of MCC patients, whereas no mutations were found in TP53 gene. Survivin was expressed in 78% of specimens. We could not correlate either mutations in PDGFR or expression of PDGFR, p53 and surviving either to the disease progression or to the MCPyV positivity. CONCLUSIONS: In conclusion, our data indicate that the viral positivity when associated with high viral load, correlates with poor disease outcome. Frequent mutations in the PDGFRalpha gene and high survivin expression were found in MCC independent of the viral positivity. These data suggest that these three factors independently contribute to Merkel cell carcinoma development and that only the viral load can be used as indicator of disease progression in virus positive patients. PMID- 25936871 TI - Indications for Omega-3 Long Chain Polyunsaturated Fatty Acid in the Prevention and Treatment of Cardiovascular Disease. AB - BACKGROUND: The National Heart Foundation of Australia (NHFA) 2008 review on omega-3 long-chain polyunsaturated fatty acids (LCPUFA) made recommendations with respect to supplementation for primary and secondary prevention of cardiovascular disease. Since then, new findings have been published regarding the relationship between omega-3 polyunsaturated fatty acids, including supplementation, and cardiovascular health. METHODS: A literature search was undertaken in PubMed and Medline, for literature published between January 1, 2007 and August 31, 2013. RESULTS AND CONCLUSIONS: A total of eight research questions were developed and, using the National Health and Medical Research Council's evidence assessment framework, conclusions were made in relation to dietary intake of fish and omega 3 LCPUFA for cardiovascular health. In the evidence published since 2007, this summary of evidence concludes that dietary intake of fish was found to be mostly consistent with respect to protection from heart disease and stroke. Higher fish intake was associated with lower incident rates of heart failure in addition to lower sudden cardiac death, stroke and myocardial infarction. In relation to omega-3 LCPUFA supplementation, neither a beneficial nor adverse effect was demonstrated in primary or secondary prevention of coronary heart disease (CHD). Although the evidence continues to be positive for the role of omega-3 LCPUFA in the treatment of hypertriglyceridaemia and a modest positive benefit in heart failure. No further evidence was found to support the consumption of 2g alpha linolenic acid (ALA)/day over the current Australian guidelines for 1 g/day. PMID- 25936872 TI - Ruxolitinib is manageable in patients with myelofibrosis and severe thrombocytopenia: a report on 12 Danish patients. AB - We report 12 Danish myelofibrosis patients who have been treated successfully with ruxolitinib despite having low platelet counts (< 50 * 10(9)/L) during their treatment-course. The majority of the patients experienced marked clinical improvement. Serious side effects were only recorded in a single patient. It is concluded that JAK-inhibition with ruxolitinib is manageable in patients with low platelet counts and should be considered in symptomatic patients who otherwise might not be candidates for treatment. PMID- 25936873 TI - Desert hedgehog is a mediator of demyelination in compression neuropathies. AB - The secreted protein desert hedgehog (dhh) controls the formation of the nerve perineurium during development and is a key component of Schwann cells that ensures peripheral nerve survival. We postulated that dhh may play a critical role in maintaining myelination and investigated its role in demyelination induced compression neuropathies by using a post-natal model of a chronic nerve injury in wildtype and dhh(-/-) mice. We evaluated demyelination using electrophysiological, morphological, and molecular approaches. dhh transcripts and protein are down-regulated early after injury in wild-type mice, suggesting an intimate relationship between the hedgehog pathway and demyelination. In dhh( /-) mice, nerve injury induced more prominent and severe demyelination relative to their wild-type counterparts, suggesting a protective role of dhh. Alterations in nerve fiber characteristics included significant decreases in nerve conduction velocity, increased myelin debris, and substantial decreases in internodal length. Furthermore, in vitro studies showed that dhh blockade via either adenovirus-mediated (shRNA) or pharmacological inhibition both resulted in severe demyelination, which could be rescued by exogenous Dhh. Exogenous Dhh was protective against this demyelination and maintained myelination at baseline levels in a custom in vitro bioreactor to applied biophysical forces to myelinated DRG/Schwann cell co-cultures. Together, these results demonstrate a pivotal role for dhh in maintaining myelination. Furthermore, dhh signaling reveals a potential target for therapeutic intervention to prevent and treat demyelination of peripheral nerves in compression neuropathies. PMID- 25936874 TI - Endogenous neurogenic cell response in the mature mammalian brain following traumatic injury. AB - In the mature mammalian brain, new neurons are generated throughout life in the neurogenic regions of the subventricular zone (SVZ) and the dentate gyrus (DG) of the hippocampus. Over the past two decades, extensive studies have examined the extent of adult neurogenesis in the SVZ and DG, the role of the adult generated new neurons in normal brain function and the underlying mechanisms regulating the process of adult neurogenesis. The extent and the function of adult neurogenesis under neuropathological conditions have also been explored in varying types of disease models in animals. Increasing evidence has indicated that these endogenous neural stem/progenitor cells may play regenerative and reparative roles in response to CNS injuries or diseases. This review will discuss the potential functions of adult neurogenesis in the injured brain and will describe the recent development of strategies aimed at harnessing this neurogenic capacity in order to repopulate and repair the injured brain following trauma. PMID- 25936875 TI - MFGE8/Integrin beta3 pathway alleviates apoptosis and inflammation in early brain injury after subarachnoid hemorrhage in rats. AB - BACKGROUND: Milk fat globule-epidermal growth factor-factor 8(MFGE8)/Integrin beta3 pathway was reported to be involved in reducing oxidative stress and early brain injury after subarachnoid hemorrhage (SAH). In the present study, the potential effects of MFGE8 and its receptor Integrin beta3 in the inhibition of apoptosis and neuroinflammation in early brain injury after SAH were investigated. METHODS: Ninety-five (95) male Sprague-Dawley rats were used. The SAH model was induced by endovascular perforation. Recombinant human MFGE8 (rhMFGE8), MFGE8 small interfering RNA (siRNA) and Integrin beta3 siRNA were injected intracerebroventricularly. SAH grade, neurologic scores, Western blots and immunofluorescence were employed to study the mechanisms of MFGE8 and its receptor Integrin beta3, as well as neurological outcome. RESULTS: SAH induced significant neuronal apoptosis and inflammation and exhibited neurological dysfunction in rats. Knockdown endogenous MFGE8 with siRNA significantly increased the protein levels of cleaved caspase 3 and IL-1beta, accompanied with more neurological deficits. rhMFGE8 significantly reduced neural cell death in cortex, decreased cleaved caspase 3 and IL-1beta expressions, and improved neurological functions 24h after SAH. The anti-apoptosis and anti-inflammation effects of rhMFGE8 were abolished by Integrin beta3 siRNA. CONCLUSION: MFGE8 could alleviate neurologic damage in early brain injury after SAH via anti inflammation and anti-apoptosis effects. MFGE8 may serve as a promising therapeutic target for future management of SAH patients. PMID- 25936876 TI - Renewal, resurgence, and alternative reinforcement context. AB - Resurgence, relapse induced by the removal of alternative reinforcement, and renewal, relapse induced by a change in contextual stimuli, are typically studied separately in operant conditioning paradigms. In analogous treatments of operant problem behavior, aspects of both relapse phenomena can operate simultaneously. Therefore, the purpose of this study was to examine a novel method for studying resurgence and renewal in the same experimental preparation. An alternative source of reinforcement was available during extinction for one group of rats (a typical resurgence preparation). Another group experienced an operant renewal preparation in which the extinction context was distinguished via olfactory and visual stimuli. A third group experienced alternative reinforcement delivery in the new context, a novel combination of typical resurgence and renewal preparations. Removal of alternative reinforcement and/or a change in context induced relapse relative to an extinction-only control group. When alternative reinforcement was delivered in a novel context, the alternative response was less persistent relative to when extinction of the alternative response took place in the context in which it was trained. This methodology might be used to illustrate shared (or distinct) mechanisms of resurgence and renewal, and to determine how delivering alternative reinforcement in another context may affect persistence and relapse. PMID- 25936877 TI - Two families with Leber's hereditary optic neuropathy carrying G11778A and T14502C mutations with haplogroup H2a2a1 in mitochondrial DNA. AB - The mitochondrial haplogroup has been reported to affect the clinical expression of Leber's hereditary optic neuropathy (LHON). The present study aimed to investigate the interaction between mutations and the haplogroup of mitochondrial DNA (mtDNA) in families. Two unrelated families with LHON were enrolled in the study, and clinical, genetic and molecular characterizations were determined in the affected and unaffected family members. Polymerase chain reaction direct sequencing was performed using 24 pairs of overlapping primers for whole mtDNA to screen for mutations and haplogroup. Bioinformatics analysis was performed to evaluate the pathogenic effect of these mtDNA mutations and the haplogroup. The G11778A mutation was identified in the two families. In addition, the members of family 2 exhibited the T14502C mutation and those in family 1 exhibited the T3394C and T14502C mutations, which were regarded as secondary mutations. The penetrance of visual loss in families 1 and 2 were 30.8 and 33.3%, respectively. In addition, the two families were found to be in the H2a2a1 haplogroup. In this limited sample size, it was demonstrated that the H2a2a1 haplogroup had a possible protective effect against LHON. Additional modifying factors, including environmental factors, lifestyle, estrogen levels and nuclear genes may also be important in LHON. PMID- 25936878 TI - Epsilon wave uncovered by exercise test in a patient with desmoplakin-positive arrhythmogenic right ventricular cardiomyopathy. AB - Epsilon waves are a major criterion for the diagnosis of arrhythmogenic right ventricular cardiomyopathy (ARVC) but are an insensitive sign. Recently, exercise testing has been shown to uncover epsilon waves in asymptomatic patients carrying mutations in the PKP2 gene. We describe a case of an asymptomatic carrier of a mutation in the DSP gene who had a normal baseline electrocardiogram and an exercise-induced epsilon wave. This finding suggests that exercise testing may be valuable for the diagnosis of ARVC and that exercise-induced epsilon waves may be found in various genetic subtypes of this disease. PMID- 25936879 TI - Optical coherence tomography evidence of spontaneous healing of an intramural coronary hematoma. PMID- 25936880 TI - Ultrasound-targeted microbubble destruction enhances polyethylenimine-mediated gene transfection in vitro in human retinal pigment epithelial cells and in vivo in rat retina. AB - The aim of the present study was to investigate the efficacy and safety of ultrasound-targeted microbubble destruction (UTMD)-mediated polyethylenimine (PEI) transfection in cultured human retinal pigment epithelial (RPE) cells in vitro and rat retinas in vivo. An enhanced green fluorescent protein plasmid (pEGFP) was incubated with PEI to prepare a cationic complex (PEI/pEGFP), which was confirmed using a gel retardation assay. In the in vitro study, cultured human RPE cells were subjected to US waves under different conditions with or without microbubbles. The effect of UTMD on the viability of the cells was evaluated. In the in vivo study, gene transfer was examined by injecting PEI/pEGFP into the subretinal space of the rats. The rats treated with PEI/pEGFP and UTMD served as the experimental group, while rats treated with PEI/pEGFP alone served as the control group. The transfected tissue was visualized using an inverted fluorescence microscope. The expression of EGFP was classified into three groups, negative, weak positive and strong positive. Hematoxylin and eosin staining of frozen sections was used to observe tissue damage and the location of the EGFP gene expression. The electrophoresis experiment revealed that PEI treatment was able to condense DNA efficiently. In the in vitro study, the gene transfer efficiency under the optimal UTMD condition was enhanced and significantly higher than control groups. In the in vivo study, UTMD was able to enhance transgene expression in the retina without marked tissue damage. Frozen sections of the optic cups exhibited pEGFP-positive cells, predominantly distributed in the retina. This noninvasive novel combination of UTMD with PEI was able to enhance targeted gene delivery and gene expression in the rat retina without causing any apparent tissue damage, and may be a safe method to transfer genes and drug treatments directly to the retina, therefore being of potential therapeutic value. PMID- 25936881 TI - [Effect of Inhibiting NGAL Gene Expression on A549 Lung Cancer Cell Migration and Invasion]. AB - BACKGROUND: To detect the expression of neutrophil gelatinase-assoeiated lipocalin (NGAL) in the different differentiations of lung cancer tissues and to study the mechanism of invasion of A549 cells affected by NGAL. METHODS: The expression of NGAL was detected by immunochemistry in lung cancer tissue and the tissue around edge of the cancer. The effect of NGAL expression on A549 cells was observed by using qRT-PCR and Western blot. The abilities of invasion and metastasis were evaluated by transwell invasion and migration assay, and cell scratch assay in vitro. The protein expression of E-cadherin, Vimentin was measured by immunofluoresence and Western blot. RESULTS: The positive expression rate of NGAL was 76.32% (58/76) in the lung cancer, 13.3% (4/30) in adjacent tissue by immunochemistry. NGAL expression levels in the lung cancer tissues were significantly higher than that in adjacent tissues. The rate of migration and invasion in NGAL-siRNA group was 60.4% +/- 6.4% compared to 50.5% +/- 4.4% in the control group, there was a significant difference (P < 0.05). Vimentin was suppressed, and E-cadherin was upregulated when NGAL was inhibited. MMP-2 and MMP 9 decreased when NGAL was knocked down. CONCLUSIONS: The expression level of NGAL is highly expressed in lung cancer. NGAL may be one of important indicators involved in lung cancer infiltrated and transferred. NGAL might be one of potential targets for lung cancer treatment. PMID- 25936882 TI - [Relationship between EGFR Promoter Region Methylation and Secondary Resistance Which may be Induced by Gefitinib]. AB - BACKGROUND: Nowadays the secondary resistance of gefitinib in the treatment of lung adenocarcinoma is an outstanding problem. This research is to explore whether the gefitinib secondary resistance can be induced by gefitinib, to explore whether epidermal growth factor receptor (EGFR) promotor methylation correlate with the gefitinib-resistance in PC9/GR cell lines and to find a new therapeutic target to overcome the gefitinib secondary resistance in lung adenocarcinoma. METHODS: In vitro cultivation of lung adenocarcinoma PC9 cell lines, apply gefitinib on lung adenocarcinoma PC9 cell lines, and improve drug concentration. MTT for test of gefitinib resistance index in PC9 cell and PC9/GR cell. Bisulfite sequencing polymerase chain reaction (BSP) and Reverse transcription-polymerase chain reaction (RT-PCR) for detection of EGFR promoter methylation status and mRNA expression. In vitro cultivation of lung adenocarcinoma PC9 cell lines, apply 1 MUmol/L 5-Aza-dc on lung adenocarcinoma PC9/GR cell lines for 72 h. MTT method for test of gefitinib resistance index in PC9/GR cell. RESULTS: After improving the gefitinib concentration, MTT results showed that half maximal inhibitory concentration (IC50) of PC9 cell lines increase from (0.01 +/- 0.002) MUmol/L to (3.95 +/- 0.23) MUmol/L (P<0.05). BSP results showed that abnormal methylation sites compared the degree of methylation change: PC9: 59%; PC9/GR: 74% (P<0.05). RT-PCR results showed in PC9/GR cell lines, EGFR mRNA expression quantity increased (P<0.05). After applying 5-Aza-dc on PC9 cell lines, IC50 of PC9/GR decrease from (3.87 +/- 0.034) MUmol/L to (2.55 +/- 0.14) MUmol/L. CONCLUSIONS: The PC9 cell line which is induced by improving gefitinib concentration will be resistant to gefitinib, and the gefitinib resistant cell line PC9/GR could be built. EGFR gene promoter methylation may be one of the mechanisms for the secondary resistance to gefitinib. PMID- 25936883 TI - [Clinical Research of EGFR and KRAS Mutation in Fine Needle Aspiration Cytology Specimens of Non-small Cell Lung Carcinoma]. AB - BACKGROUND: Epidermal growth factor receptor (EGFR) and KRAS must be detected mutation status before patients of lung cancer use targeted drugs. The aim of this study is to elucidate the significance of EGFR and KRAS mutation in fine needle aspiration (FNA) cytology suspension specimens of non-small cell lung carcinoma. METHODS: EGFR gene exons 18-21 and KRAS codons 12, 13 of exons 2 were performed by Real-time PCR methods in fine needle aspiration cytology suspension specimens of lymph nodes. RESULTS: 85 metastasis lymph nodes were detected in fine needle aspiration cytology samples of lung cancer. EGFR mutation rate was 37.3%. KRAS mutation rate was 7.2%. 19 formalin fixed paraffin-embedded tissue specimens were available and match cytology specimens. Analysis of EGFR mutation status in those samples revealed agreement with the results obtained in cytological samples (kappa=1.0). Clinical follow-up was available for 13 who presented with stage IV disease. Based on the identification of such mutations, these patients received subsequent therapy with a TKI in clinic. We observed two cases complete remission (16.7%) and 8 cases partial remission (66.7%) and three had ongoing stable disease. CONCLUSIONS: Fine-needle aspiration cytology samples were detected EGFR and KRAS mutation. The method which collects samples was easier, simple and convenient. This method has higher application value in clinical treatment.?. PMID- 25936884 TI - [Analysis of the Choice of Operation Mode and Prognosis Factors of Patients with Tumors of the Lung Metastasis]. AB - BACKGROUND: Concept of treatment for pulmonary metastatic tumor has been changed. The aim of this study is to analysis of the choice of operation mode and prognosis factors of patients with tumors of the lung metastasis. METHODS: The clinical data of 57 patients with pulmonary metastases who underwent operations from January 2006 to December 2009 were retrospectively analyzed. Difference of conventional open thoracic surgery and thoracoscope surgery was compared. The relationship between gender, age, type of surgery, disease-free interval (DFI), the number of metastatic tumor, the size of tumor, chemotherapy and prognosis was explored. RESULTS: Among the patients, there was no perioperative mortality. Postoperative 1-, 3-, 5-year survival rates were 81.3%, 46.5% and 29.2%, the median survival time was 33.8 months. Multivariate analysis showed that DFI, the number and diameter of metastasis tumor were independent prognostic factors. CONCLUSIONS: Reasonable choice of surgical treatment can improve the survival of pulmonary metastatic tumor patient. Thoracoscopic surgery method is preferred. Operation effect of patients with tumor diameter less than 4 cm in solitary pulmonary metastasis has better effect. PMID- 25936885 TI - [Immunohistochemical detections of EGFR status in NSCLC]. AB - BACKGROUND: Patients with non-small cell lung cancer (NSCLC) harboring mutations of the epidermal growth factor receptor (EGFR) respond well to EGFR-tyrosine kinase inhibitor therapy. Immunohistochemistry (IHC) is a simple and widely used technique in clinical pathology laboratories. IHC also features cost effectiveness and rapid detection of EGFR mutations compared with molecular methods. This study aims to determine the accuracy of IHC for EGFR mutation detection in NSCLC. METHODS: Specimens (obtained from surgery or biopsy) from 97 NSCLC cases were stained through IHC with mutation-specific antibodies. The clinicopathological features of patients with positive immunostaining results were analyzed. Positive specimens were subjected to liquid chip technology to detect the actual EGFR status. Forty NSCLC specimens obtained from surgery and confirmed to have EGFR mutations through liquid chip technology were collected. These specimens were then subjected to IHC analyses with mutation-specific antibodies. The sensitivity of IHC in detecting EGFR mutations was calculated. RESULTS: Seventeen of the 97 NSCLC specimens were stained positive, and positive results were mostly observed in females, patients with adenocarcinoma, and non smokers. About 76.9% of specimens with positive IHC results harbored mutations. The sensitivity of IHC was 40% among the 40 cases identified as containing EGFR mutations through liquid chip technology. CONCLUSIONS: The strong positive immunostaining result is accurate, but the sensitivity of the method may not be optimal and significantly varies in different studies. The widespread application of IHC in clinics must be further investigated. PMID- 25936886 TI - [Cancer Genome Atlas Pan-cancer Analysis Project]. AB - Cancer can exhibit different forms depending on the site of origin, cell types, the different forms of genetic mutations which also affect cancer therapeutic effect. Although many genes have been demonstrated to change a direct result of the change in phenotype, however, many cancers lineage complex molecular mechanisms are still not fully elucidated. Therefore, The Cancer Genome Atlas (TCGA) Research Network analyzed a large human tumors, in order to find the molecular changes in DNA, RNA, protein and epigenetic level, The results contain a wealth of data provides us with an opportunity for common, personality and new ideas throughout the cancer lineages form a whole description. Pan-cancer genome program first compares the 12 kinds of cancer types. Analysis of different tumor molecular changes and their functions, will tell us how effective treatment method is applied to a similar phenotype of the tumor. PMID- 25936887 TI - [Effect of Chemical Prevention Drugs-based MicroRNAs and Their Target Genes on Tumor Inhibition]. AB - Chemopreventive drugs including natural chemopreventive drugs and synthetic chemopreventive drugs, it not only can prevent cancer, can also play a role in tumor treatment. MicroRNAs (miRNAs) is a kind of short chains of non-coding RNA, regulating the expression of many genes through the way of degradation of mRNA or inhibitting mRNA translation. In recent years, more and more studies have shown that chemopreventive drugs through influence the expression of miRNAs and their target genes play a role in the prevention and treatment in a variety of tumors, and chemopreventive drugs on the experimental study of miRNAs and their target genes in tumor have demonstrated a good safety and efficacy. Effect on chemopreventive drugs-based microRNAs and their target genes into cancer cells will be expected as a new starting point for cancer research. The thesis expounds and analyzes between the natural chemopreventive drugs and synthetic chemopreventive drugs and miRNAs and their target genes in tumor research progress. PMID- 25936888 TI - [Metronomic Chemotherapy--A New Path to Treat Advanced Non-small Cell Lung Cancer]. AB - Metronomic chemotherapy is an emerging strategy to fight cancer. Unlike traditional chemotherapy, metronomic chemotherapy is defined by the frequent, repetitive administration of chemotherapeutic drugs at relatively low doses, and without prolonged drug-free break. Initially thought to play a role inhibiting tumor angiogenesis by targeting activated endothelial cells in tumors, metronomic chemotherapy is a multi-targeted therapy,including activation of immunity, effect on tumour initiating cells, induction of tumor dormancy. It is from eradicateing tumor cells to improve effect, reduce the toxicity and improve quality of life for treatment of advanced non-small cell lung cancer (NSCLC). Metronomic chemotherapy which can avoid the toxicity of traditional chemotherapy and rebounding is explored in clinical studies of advanced NSCLC, as a promising treatment strategy. PMID- 25936889 TI - [Research Progress of HGF/c-MET Inhibitor in the Treatment of Non-small Cell Lung Cancer]. AB - Molecular targeted therapy has become more and more important in the treatment of non-small cell lung cancer (NSCLC). HGF/c-MET plays the pivotal role in the growth, development and tolerance to epidermal growth factor receptor tyrosine kinase inhibitor of NSCLC. Moreover it has become another heat point in the molecular targeted therapy of NSCLC. c-MET amplification or high expression was deemed to another significant gene modification beyond EGFR and ALK. In the preclinical studies, HGF/c-MET inhibitors have showed the promising anti-tumor effect. Recently, some phase II/III clinical trials have proved that these inhibitors could improve the survival of patients with NSCLC. Hence we performed this review to elaborate the research progress of c-MET inhibitor in the treatment of NSCLC. PMID- 25936890 TI - [TKI Resistance for T790M Mutation]. AB - BACKGROUND AND OBJECTIVE: Epidermal growth factor receptor (EGFR) the development of orally activesmall molecule inhibitors for non-small cell lung cancer (NSCLC) provides anew treatment plan. EGFR gene mutation in patients with activation EGFR tyrosine kinase inhibitor (EGFR-TKIs) therapy for the treatment of sensitive, so that a large number of clinical benefit. The first generation of reversible ATP competitive EGFR-TKIs, gefitinib and erlotinib as first-line, second-line or has the effect of maintenance therapy. Although the initial effect of these drugs have, but most patients will produce drug resistance. Within a year, 50%-60% patients had T790M housekeeping gene mutation associated with. Irreversible EGFR TKIs recent background: afatinib and dac-omitinib covalent binding and inhibition of multiple ErbB family receptors (EGFR, HER2 and HER4). People evaluate these drugs as first-line treatment of significance, and acquired drug resistance situation significance on the first generation EGFR-TKIs. Afatinib is the first ErbB family approved blocking agent, used to treat with EGFR activating mutations in patients with non small cell lung cancer; dacomitinib are in the later stages of clinical development. EGFR inhibitors specifically targeting T790M resistance mutations (AZD9291, CO-1686, HM61713) are in the early stages of development. As discussed in this paper, the scope of the EGFR-TKIs kinase to target different, EGFR receptor binding was reversible and drug interaction potential is also different. For clinicians, these differences of the multi drug treatment of patients with non-small cell lung cancer with meaning, from the innovative anticancer drug combination therapy strategy point of view, these differences are also of great significance. PMID- 25936891 TI - Brain diffusion tensor imaging in children with tuberous sclerosis. AB - PURPOSE: To evaluate diffusion characteristics of tubers and white matter lesions in children with tuberous sclerosis (TS) using diffusion tensor imaging (DTI). MATERIALS AND METHODS: Eighteen children (11 male, 7 female; mean age 9.3years, age range 1-16years) with a definite diagnosis of TS were recruited in this study. Apparent diffusion coefficient (ADC), fractional anisotropy (FA), radial diffusivity (RD), and axial diffusivity (AD) values in 89 tubers and 37 white matter lesions were measured and compared with those of contralateral normal regions. RESULTS: ADC, AD, and RD values were significantly higher and FA values were lower in lesions, than the ones measured in contralateral normal regions for tubers (P<0.001). Similarly RD values were significantly higher and FA values were lower in white matter lesions (P<0.05). ADC and AD measures were detected to increase in white matter lesions, however no statistically significant difference was observed. The increase in the mean values of RD was significantly greater than the increase in the AD values for tubers and white matter lesions (P<0.05). CONCLUSION: DTI can provide valuable information about the cytoarchitectural changes in TS lesions beyond morphologic MRI findings alone. PMID- 25936892 TI - Phantom evaluation of a navigation system for out-of-plane CT-guided puncture. AB - OBJECTIVE: The purpose of this phantom study was to assess a new real time electromagnetically-guided navigation system and compare it to standard computed tomography (CT) guidance. MATERIAL AND METHODS: A prospective, randomized, comparative study was carried out over a two-day period. Operators without prior experience on the new navigation system sequentially attempted to puncture two 6 mm-diameter targets (one attempt for each target) with out-of-plane trajectories using both the standard CT-guided method and the new navigation station (NAV method). RESULTS: Intention-to-treat analysis was performed for 54 operators. Twenty-two operators out of 54 (40.7%) reached the target on first attempt with the NAV method versus none (0%) using CT-guidance (P<0.001). The median distance of the puncture from the center of the target was 3.7mm [Q1-Q3=2-6.7] using NAV versus 15 mm [10-20] using CT-guidance (P<0.001). Overall planning and puncture time were shorter using NAV: 76s [50-118] versus 214s [181-264] using CT-guidance (P<0.001). CONCLUSION: Novice operators consistently performed faster and more accurate phantom punctures with out-of-plane trajectories using the electromagnetically-guided navigation system than with the standard CT-guided method. PMID- 25936894 TI - Trends in Reporting of Abuse and Neglect to Long Term Care Ombudsmen: Data from the National Ombudsman Reporting System from 2006 to 2013. AB - We utilized the National Ombudsman Reporting System (NORS) to describe national trends in reporting of abuse and neglect in nursing facilities to long term care ombudsmen (LTCO) from 2006 to 2013. We investigated complaints made against facility staff or residents with the following codes: physical abuse, verbal/mental abuse, sexual abuse, financial exploitation, gross neglect, and resident to resident physical or sexual abuse. Nationally, LTCO received an annual average of 11,749 abuse and neglect-related complaints in nursing homes from 2006 to 2013. These complaints trended down significantly, from 7.5 to 5.6 reports per 1000 beds (P < 0.0001). Physical abuse by a non-resident was the most frequently reported, representing an average of 28% of total abuse/neglect complaints. Improved understanding of the reasons for declines in reporting, increased training on other types of abuse and neglect, and expansion of the NORS database to allow for more comprehensive analysis are needed. PMID- 25936896 TI - Nonlinear Viscous Water at Nanoporous Two-Dimensional Interfaces Resists High Speed Flow through Cooperativity. AB - Recently emerging ultrathin two-dimensional carbon materials provide potentially game-changing membranes for water filtration. Here we discover a changed water behavior at the nanoscale that is significantly distinct from its bulk state as water flows through two-dimensional carbon allotropes. We find that water exhibits a very high viscosity due to the cooperativity of water molecules that enhances the nonbonded H-bond interactions with the dense lattice of carbon structures, which renders flow significantly more viscous, with a resistance that is inversely proportional to the sixth power of the characteristic length of the nanopores. This is in contrast to a constant value as assumed in conventional knowledge. Our findings reveal how water molecules behave drastically different from their bulk state under extreme nanoconfinement conditions. These insights enable us to incorporate the size analysis of particles in variant untreated water into membrane design and propose the design of more efficient devices with higher filtration throughput and greater mechanical resilience. PMID- 25936897 TI - Small intestine and ovarian metastasis in a patient with a history of cardiac fibrosacoma. AB - Metastatic tumors involving the small bowel are much more common than primary neoplasms. The most common metastases to the small intestine are those arising from other intra-abdominal organs. Metastases from extra-abdominal tumors are rare but may be found in patients with adenocarcinoma of the breast and carcinoma of the lung. Cutaneous melanoma is the most common extra-abdominal source involving the small intestine, with involvement of the small intestine noted in more than half of the patients dying from malignant melanoma [1]. While intestinal metastasis from sarcoma has been described, this is an extremely rare occurrence especially from a rare malignant sarcoma of cardiac origin. The dismal prognosis of cardiac sarcomas results from extensive local invasion at presentation or distant metastasis. Metastasis to the small bowel may cause obstruction, bleeding, or intussusception in which the diagnosis may be delayed because of rarity of the condition and mild and vague abdominal symptoms at early presentation. In this report, a 35 year old woman a known case of cardiac fibrosarcoma was admitted to the emergency ward with abdominal pain and distention, bloody diarrhea, and recurrent nausea and vomiting. Jejuno-jejunal invagination was diagnosed at laparotomy along with tumoral involvement of the left ovary. Histopathological study showed that there was a fibrosarcoma compatible with the earlier diagnosis of primary cardiac tumor. We have described some aspects of diagnosis and treatment of this rare cause of intestinal intussusception. PMID- 25936895 TI - Long non-coding RNAs and their biological roles in plants. AB - With the development of genomics and bioinformatics, especially the extensive applications of high-throughput sequencing technology, more transcriptional units with little or no protein-coding potential have been discovered. Such RNA molecules are called non-protein-coding RNAs (npcRNAs or ncRNAs). Among them, long npcRNAs or ncRNAs (lnpcRNAs or lncRNAs) represent diverse classes of transcripts longer than 200 nucleotides. In recent years, the lncRNAs have been considered as important regulators in many essential biological processes. In plants, although a large number of lncRNA transcripts have been predicted and identified in few species, our current knowledge of their biological functions is still limited. Here, we have summarized recent studies on their identification, characteristics, classification, bioinformatics, resources, and current exploration of their biological functions in plants. PMID- 25936898 TI - Advanced treatment of biologically pretreated coal gasification wastewater by a novel integration of catalytic ultrasound oxidation and membrane bioreactor. AB - Laboratorial scale experiments were conducted to investigate a novel system integrating catalytic ultrasound oxidation (CUO) with membrane bioreactor (CUO MBR) on advanced treatment of biologically pretreated coal gasification wastewater. Results indicated that CUO with catalyst of FeOx/SBAC (sewage sludge based activated carbon (SBAC) which loaded Fe oxides) represented high efficiencies in eliminating TOC as well as improving the biodegradability. The integrated CUO-MBR system with low energy intensity and high frequency was more effective in eliminating COD, BOD5, TOC and reducing transmembrane pressure than either conventional MBR or ultrasound oxidation integrated MBR. The enhanced hydroxyl radical oxidation, facilitation of substrate diffusion and improvement of cell enzyme secretion were the mechanisms for CUO-MBR performance. Therefore, the integrated CUO-MBR was the promising technology for advanced treatment in engineering applications. PMID- 25936900 TI - Chip-based high-performance liquid chromatography for high-speed enantioseparations. AB - In this work, the first high-performance chiral liquid chromatography in packed microfluidic chips is presented. The chromatographic separation was performed on a column integrated into the microfluidic glass chip and packed with the particulate chiral stationary phase. Cellulose tris(3,5-dimethylphenylcarbamate) coated on 5-MUm fully porous silica was used as chiral stationary phase material. Several racemic analytes including pharmaceutical products were baseline separated into their corresponding enantiomers under reversed-phase, polar organic and normal-phase conditions, demonstrating the versatility of the glass chip in the field of chiral separations. Van Deemter plots revealed a reduced plate height of 2.2 and a trend to enhanced mass transfer processes for solutes under low retention conditions. The utilization of very short column lengths of down to 12 mm led to ultrafast separations of enantiomers within 5 s. PMID- 25936899 TI - Secreted protein acidic and rich in cysteine antagonizes bufalin-induced apoptosis in gastric cancer cells. AB - Bufalin is an active compound in the traditional Chinese medicine Chan Su, which has been shown to induce apoptosis in a range of cancer cell types. However, certain gastric cancer cells are known to be resistant to bufalin. Intracellular secreted protein acidic and rich in cysteine (SPARC) regulates proliferation and apoptosis. This study aimed to evaluate the role of SPARC in bufalin-induced apoptosis in SGC7901 and MGC803 gastric cancer cells. SGC7901 cells with high SPARC expression were more resistant to bufalin than MGC803 cells with low SPARC expression. This resistance was significantly reversed by small interfering (si)RNA-mediated knockdown of SPARC. Furthermore, it was shown that SPARC negatively regulated bufalin-induced intrinsic apoptosis by protecting mitochondrial integrity, decreasing the release of cytoplasmic cytochrome c and increasing the ratio of Bcl-2/Bax. In addition, SPARC overcame bufalin-induced G2/M phase arrest by increasing levels of Cyclin B1 and Cyclin A protein expression. SPARC also activated cellular survival signals, including Src and Akt, but not extracellular signal-regulated kinase. This study demonstrated that SPARC antagonizes bufalin-induced apoptosis via inhibition of the intrinsic apoptosis pathway, inhibition of cell cycle arrest and activation of certain pathways involved in proliferation. This provides novel evidence for SPARC as a potential target by which to sensitize gastric cancer cells to bufalin. PMID- 25936901 TI - Diabetes technology and devices transform the lives of people with diabetes. PMID- 25936902 TI - In vivo corneal confocal microscopy and prediction of future-incident neuropathy in type 1 diabetes: a preliminary longitudinal analysis. AB - OBJECTIVE: In vivo corneal confocal microscopy (IVCCM) has been established in cross-sectional studies as a valid measure for the identification of diabetic sensorimotor polyneuropathy (DSP). We aimed to determine the predictive validity of a baseline IVCCM measure in identifying future DSP onset in patients with type 1 diabetes. METHODS: We followed 65 patients with type 1 diabetes without DSP at baseline. They were followed longitudinally for a mean of 3.5+/-0.9 years and underwent IVCCM, clinical and electrophysiologic examinations at baseline and follow up. At the end of follow up, participants were assigned as new-onset cases of DSP or as controls. Predictive validity was assessed using receiver operating characteristic curves. RESULTS: At baseline, participants were 34+/-15 years of age with mean diabetes duration of 18+/-12 years. The 11 (17%) new-onset cases of DSP were similar to the 54 (83%) controls in baseline age, diabetes duration, gender, glycated hemoglobin levels and electrophysiologic parameters (p>=0.20). However, cases of new onset had significantly lower baseline corneal nerve fibre length (CNFL) and branch density (p<0.05). For identification of new-onset cases, area under the receiver operating characteristic curve for CNFL was 0.78 with an optimal threshold of 14.9 mm/mm(2) (sensitivity=0.82, specificity=0.69). CONCLUSIONS: Despite similar clinical and electrophysiologic parameters, participants with type 1 diabetes at risk for future DSP had significantly lower baseline IVCCM measures. CNFL may have applicability in identifying high-risk patients for therapeutic intervention in clinical research and practice. PMID- 25936903 TI - Differences in Brain Adaptive Functional Reorganization in Right and Left Total Brachial Plexus Injury Patients. AB - OBJECTIVE: Total brachial plexus avulsion injury (BPAI) results in the total functional loss of the affected limb and induces extensive brain functional reorganization. However, because the dominant hand is responsible for more cognitive-related tasks, injuries on this side induce more adaptive changes in brain function. In this article, we explored the differences in brain functional reorganization after injuries in unilateral BPAI patients. METHODS: We applied resting-state functional magnetic resonance imaging scanning to 10 left and 10 right BPAI patients and 20 healthy control subjects. The amplitude of low frequency fluctuation (ALFF), which is a resting-state index, was calculated for all patients as an indication of the functional activity level of the brain. Two sample t-tests were performed between left BPAI patients and controls, right BPAI patients and controls, and between left and right BPAI patients. RESULTS: Two sample t-tests of the ALFF values revealed that right BPAIs induced larger scale brain reorganization than did left BPAIs. Both left and right BPAIs elicited a decreased ALFF value in the right precuneus (P < 0.05, Alphasim corrected). In addition, right BPAI patients exhibited increased ALFF values in a greater number of brain regions than left BPAI patients, including the inferior temporal gyrus, lingual gyrus, calcarine sulcus, and fusiform gyrus. CONCLUSION: Our results revealed that right BPAIs induced greater extents of brain functional reorganization than left BPAIs, which reflected the relatively more extensive adaptive process that followed injuries of the dominant hand. PMID- 25936904 TI - Dhaga Technique for Tissue Plane Preservation after Decompressive Craniectomy: Comparison of New Technique with Institutional Standard. AB - BACKGROUND: During cranioplasty after decompressive craniectomy, the temporalis muscle is firmly attached to the dural patch and intermixed with fibrotic tissue leading to considerable difficulty in dissecting the plane between the dura, galea and the temporalis muscle. This leads to increased surgical time, intraoperative blood loss, risk of complications and also affects rehabilitation. We have developed the "dhaga technique," which aids in preserving the plane between the muscle and dura in order to improve outcomes. Here we describe our technique and also compare the "dhaga technique" with the generally accepted standard procedure. METHODS: A retrospective review was carried out of all patients undergoing cranioplasty following decompressive craniectomy either through the "dhaga technique" or the institutional standard (control group). Both techniques were compared using intra operative blood loss, duration of surgery and any complications as study variables. RESULTS: There were 133 patients were included in the study. The control group included 68 patients who underwent the procedure according to institutional standard, and 65 patients were included in the "dhaga technique group." Both groups were well matched for baseline characteristics. Patients in the "dhaga technique" group had statistically significant lower operating time (P value = 0.037) and intra operative blood loss (P value = 0.025). However, there was no significant difference in complications. CONCLUSION: The utilization of "dhaga technique" can potentially improve outcomes and reduce costs by decreasing operative time and blood loss. Moreover, the temporalis muscle preservation in the "dhaga technique" may also enhance aesthetic outcomes and chewing, which were not assessed in this study. There were no differences in complication between the two techniques. PMID- 25936905 TI - Evaluation of Posterior Hippocampal Epileptogenicity During Epilepsy Surgery For Temporal Lobe Cavernoma by the Occipital Approach. AB - BACKGROUND: Cavernomas frequently are associated with intractable epilepsy. When cavernomas located in the temporal lobe are associated with intractable epilepsy, the hippocampus also may have an epileptic focus. The objective in the present study was to clarify the importance of evaluation of the posterior hippocampal epileptogenicity during epilepsy surgery for posteromedial temporal lobe cavernoma. CASE DESCRIPTIONS: In this study, we describe 2 rare cases of medically intractable epilepsy in patients with posteromedial temporal lobe cavernomas who underwent surgery via the occipital approach. Using longitudinal insertion of depth electrodes into the hippocampus, we evaluated epileptogenicity in both patients from the cavernoma cavity and its surrounding hemosiderin, as well as from the posterior hippocampus near the cavernoma. We show that the transoccipital approach to the posteromedial temporal lobe is compatible with depth electrode insertion and subdural electrode placement on the temporal lobe, enabling an accurate evaluation of potential epileptogenic zones in the posterior part of the hippocampus. Both patients did not experience any seizures and had no postoperative neurologic deficits, and their cognitive functions were intact. CONCLUSIONS: The transoccipital approach enables the optimization of the extent of posterior hippocampectomy while avoiding unnecessary resection for seizure control. We suggest resecting the posterior part of the hippocampus in addition to the cavernoma and surrounding areas in patients with medically refractory epilepsy due to a posteromedial temporal cavernoma. Tailored systematic resection guided by intraoperative electrocorticography and electroencephalography with a depth electrode was important and necessary in the present cases. PMID- 25936906 TI - The Look AHEAD Trial: Implications for Lifestyle Intervention in Type 2 Diabetes Mellitus. AB - Given the array of adverse health consequences of obesity, including increased risk for type 2 diabetes mellitus (T2DM) and cardiovascular disease (CVD), the Look AHEAD trial (N=5145) was conducted to test the hypothesis that an intensive lifestyle intervention (ILI) for weight loss would achieve significantly greater reductions in CVD morbidity and mortality than a control condition of diabetes support and education (DSE) among participants with T2DM. A number of significant and long-term improvements were observed for ILI, including body weight, physical fitness and physical function, glucose control, quality-of-life (QoL), and healthcare costs. However, ILI did not significantly reduce CVD-related morbidity/mortality (i.e., CVD death, non-fatal MI, non-fatal stroke, hospitalized angina) after nearly 10 years of follow-up. There was a suggestion of heterogeneity of response based on the history of prior CVD at baseline (p=0.06). Despite the overall lack of CVD risk reduction, ILI remains important for care of patients with T2DM, particularly when accompanied by medication management. In particular, ILI may be an appealing option for patients wanting to minimize medication intensification. Also, ILI carries with it other potential benefits important to patients (e.g., improvements in physical functioning and QoL). Based on data from other trials, intensive medication management, such as tight glycemic control, is not without potential risks, which should be weighed in making treatment decisions. Future research is needed to determine if results observed in this trial would be replicated among younger patients, those without established T2DM, and/or those with no pre-existing CVD. PMID- 25936907 TI - Proprotein Convertase Subtilisin/Kexin Type 9 (PCSK9) Inhibition and the Future of Lipid Lowering Therapy. AB - Low-density lipoprotein cholesterol (LDL-C) reduction with statins is the cornerstone of atherosclerotic cardiovascular disease (CVD) prevention. The LDL-C lowering non-statin therapy ezetimibe also modestly reduces CVD risk when added to statin therapy. There remains a clinical need for additional LDL-C lowering agents to reduce CVD risk in patients with genetic hypercholesterolemia, statin intolerance, or who are at high risk due to clinical CVD or diabetes. In clinical trials, proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibition using monoclonal antibodies has demonstrated robust LDL-C lowering efficacy of 50-65% and a favorable safety profile. These agents are a promising therapeutic strategy for addressing the unmet needs for additional CVD risk reduction. Regulatory approval for PCSK9 monoclonal antibodies may occur in the near future, and additional agents for PCSK9 inhibition are under development. This review focuses on the mechanism of LDL-C reduction using PCSK9 inhibition, as well as the phase I to III clinical trials of PCSK9 inhibitors. Results of the ongoing phase III CVD outcome trials are eagerly awaited. PMID- 25936908 TI - Development and Implementation of Worksite Health and Wellness Programs: A Focus on Non-Communicable Disease. AB - The development and implementation of worksite health and wellness programs (WHWPs) in the United States (US) hold promise as a means to improve population health and reverse current trends in non-communicable disease incidence and prevalence. However, WHWPs face organizational, economic, systematic, legal, and logistical challenges which have combined to impact program availability and expansion. Even so, there is a burgeoning body of evidence indicating WHWPs can significantly improve the health profile of participating employees in a cost effective manner. This foundation of scientific knowledge justifies further research inquiry to elucidate optimal WHWP models. It is clear that the development, implementation and operation of WHWPs require a strong commitment from organizational leadership, a pervasive culture of health and availability of necessary resources and infrastructure. Since organizations vary significantly, there is a need to have flexibility in creating a customized, effective health and wellness program. Furthermore, several key legal issues must be addressed to facilitate employer and employee needs and responsibilities; the US Affordable Care Act will play a major role moving forward. The purposes of this review are to: 1) examine currently available health and wellness program models and considerations for the future; 2) highlight key legal issues associated with WHWP development and implementation; and 3) identify challenges and solutions for the development and implementation of as well as adherence to WHWPs. PMID- 25936909 TI - Diagnostic Decision Points of Specific IgE Titers in Patients With Food Allergy: Are They Appropriate in All Clinical Settings? PMID- 25936910 TI - Distinct inflammatory profiles in atopic and nonatopic patients with chronic rhinosinustis accompanied by nasal polyps in Western china. AB - PURPOSE: The role of systemic sensitization in the pathophysiology of chronic rhinosinusitis with nasal polyps (CRSwNP) remains elusive. This study sought to characterize the pattern of cytokines in polyp tissues from atopic and nonatopic patients with CRSwNP. METHODS: Atopic and nonatopic polyp and normal tissues were collected from 70 CRSwNP patients and 26 control subjects, respectively. The distribution of inflammatory cells (eosinophils, neutrophils, mast cells, etc.) were examined using immunohistochemistry, the mRNA levels of the transcription factors GATA-3, T-bet, RORc, and FOXP3 were determined using quantitative real time polymerase chain reaction. The levels of inflammatory mediators (IFN-gamma, IL-5, IL-17A, etc.) in tissue homogenates were measured using enzyme-linked immunosorbent assay (ELISA). Moreover, the levels of inflammatory mediators in the supernatant of anti-IgE stimulated polyp tissues were measured using ELISA. RESULTS: Atopic CRSwNP patients were characterized by increased eosinophil accumulation, enhanced eosinophilic inflammation (elevated IL-5, ECP, and total IgE), and significantly increased GATA-3 mRNA levels (P<0.05), whereas both atopic and non-atopic CRSwNP patients showed decreased FOXP3 mRNA expression (P<0.05). After addition of anti-IgE stimulation, atopic CRSwNP patients produced more IL-5, IL-2, IL-10, IL-17A, and PGD2 in the supernatant of stimulated polyp tissues than nonatopic CRSwNP patients did. CONCLUSIONS: Atopic and nonatopic CRSwNP patients may possess the patterns of inflammatory response in polyp tissues. PMID- 25936911 TI - Effect of Traffic-Related Air Pollution on Allergic Disease: Results of the Children's Health and Environmental Research. AB - PURPOSE: This study evaluated the relationship of living near to main roads to allergic diseases, airway hyperresponsiveness (AHR), allergic sensitization, and lung function in Korean children. METHODS: A total of 5,443 children aged 6-14 years from 33 elementary schools in 10 cities during 2005-2006 were included in a baseline survey of the Children's Health and Environmental Research. We assessed association of traffic-related air pollution (TAP) exposure with the distance to the nearest main road, total road length of main roads and the proportion of the main road area within the 200-m home area. RESULTS: Positive exposure-response relationships were found between the length of the main road within the 200-m home area and lifetime wheeze (adjusted prevalence ratio [PR] for comparison of the longest to the shortest length categories=1.24; 95% CIs, 1.04-1.47; P for trend=0.022) and diagnosed asthma (PR=1.42; 95% CIs, 1.08-1.86; P for trend=0.011). Living less than 75 m from the main road was significantly associated with lifetime allergic rhinitis (AR), past-year AR symptoms, diagnosed AR, and treated AR. The distance to the main road (P for trend=0.001), the length of the main road (P for trend=0.041), and the proportion of the main road area (P for trend=0.006) had an exposure-response relationship with allergic sensitization. A strong inverse association was observed between residential proximity to the main load and lung function, especially FEV1, FEV1/FVC, and FEF25-75. The length of the main road and the proportion of the main road area were associated with reduced FEV1 in schoolchildren. CONCLUSIONS: The results of this study suggest that exposure to traffic-related air pollution may be associated with increased risk of asthma, AR, and allergic sensitization, and with reduced lung function in schoolchildren. PMID- 25936912 TI - The epidemiology of common mental disorders from age 20 to 50: results from the Zurich cohort study. PMID- 25936913 TI - Reconciling morphological and molecular classification of predatory ciliates: Evolutionary taxonomy of dileptids (Ciliophora, Litostomatea, Rhynchostomatia). AB - The order Dileptida is a small group of predatory ciliates characterized by a proboscis serving for prey capture. Although monophyly of the order is strongly supported, generic relationships between dileptid taxa were left mostly unresolved in 18S rRNA gene phylogenies. To overcome this problem, we applied the synergistic effect of combining multiple molecular markers with morphological data. Furthermore, we inferred dileptid evolutionary history by a multifaceted analysis strategy, including tree-building methods, phylogenetic networks, split spectrum analysis, quartet likelihood mapping, and reconstruction of ancestral morphologies. This complex approach revealed: (1) monophyly of the families Dimacrocaryonidae and Dileptidae; (2) polyphyly of Microdileptus, Pseudomonilicaryon, and Rimaleptus; and (3) homoplastic nature of several generic diagnostic features, viz., macronuclear pattern, size of oral bulge opening, and orientation of preoral kineties. Controversies in the internal phylogeny of the family Dimacrocaryonidae could be elucidated after reconstruction of ancestral morphologies at deeper nodes of phylogenetic trees in a combination with budding evolutionary processes. Moreover, we solved the "Rimaleptus" dilemma by splitting the family Dimacrocaryonidae into two new subfamilies, the Dimacrocaryoninae with two-rowed dorsal brush and the Rimaleptinae with multi-rowed brush as well as by establishing a new genus, Rurikoplites, from whose species several dimacrocaryonid genera very likely evolved by budding. PMID- 25936914 TI - Recent radiation of Brachystelma and Ceropegia (Apocynaceae) across the Old World against a background of climatic change. AB - The genera Brachystelma Sims and Ceropegia L. of the Ceropegieae (Apocynaceae Asclepiadoideae) consist of +/-320 species of geophytes and slender climbers with a tendency to stem-succulence in Ceropegia. They occur in and around the semi arid, mainly tropical parts of the Old World. For 146 species (around half of the total) from most of the geographic range of the genera, we analysed data from two nuclear and five plastid regions. The evolution of Ceropegia is very complex, with at least 13 mostly well-supported lineages, one of which is sister to the +/ 350 species of stapeliads. Species of Brachystelma have evolved at least four times, with most of them nested within two separate major lineages. So, neither Brachystelma nor Ceropegia is monophyletic. We recover a broad trend, in two separate major lineages, from slender climbers to small, geophytic herbs. Several clades are recovered in which all species possess an underground tuber. Small, erect, non-climbing, geophytic species of Ceropegia with a tuber are nested among species of Brachystelma. Consequently, the distinctive tubular flowers used to define Ceropegia do not reflect relationships. This re-iterates the great floral plasticity in the Ceropegieae, already established for the stapeliads. Both major lineages exhibit a trend from tubular flowers with faint, often fruity odours, pollinated by very small Dipteran flies, to flatter flowers often with a bad odour, pollinated by larger flies. Most of the diversity in Brachystelma and Ceropegia is recent and arose within the last 3my against a background of increased aridification or extreme climatic variability during the Pliocene. In the ingroup, diversity is highest in Southern Africa, followed by Tropical East Africa and other arid parts of Africa, the Arabian Peninsula and India. Many disjunctions are revealed and these are best explained by recent, long distance dispersal. In Africa, the diversity arises from the presence of many different lineages over wide areas but there is also evidence of closely related species growing together with different pollinators. PMID- 25936915 TI - Filia Is an ESC-Specific Regulator of DNA Damage Response and Safeguards Genomic Stability. AB - Pluripotent stem cells (PSCs) hold great promise in cell-based therapy, but the genomic instability seen in culture hampers their full application. A greater understanding of the factors that regulate genomic stability in PSCs could help address this issue. Here we describe the identification of Filia as a specific regulator of genomic stability in mouse embryonic stem cells (ESCs). Filia expression is induced by genotoxic stress. Filia promotes centrosome integrity and regulates the DNA damage response (DDR) through multiple pathways, including DDR signaling, cell-cycle checkpoints and damage repair, ESC differentiation, and apoptosis. Filia depletion causes ESC genomic instability, induces resistance to apoptosis, and promotes malignant transformation. As part of its role in DDR, Filia interacts with PARP1 and stimulates its enzymatic activity. Filia also constitutively resides on centrosomes and translocates to DNA damage sites and mitochondria, consistent with its multifaceted roles in regulating centrosome integrity, damage repair, and apoptosis. PMID- 25936916 TI - An Apela RNA-Containing Negative Feedback Loop Regulates p53-Mediated Apoptosis in Embryonic Stem Cells. AB - Maintaining genomic integrity is of paramount importance to embryonic stem cells (ESCs), as mutations are readily propagated to daughter cells. ESCs display hypersensitivity to DNA damage-induced apoptosis (DIA) to prevent such propagation, although the molecular mechanisms underlying this apoptotic response are unclear. Here, we report that the regulatory RNA Apela positively regulates p53-mediated DIA. Apela is highly expressed in mouse ESCs and is repressed by p53 activation, and Apela depletion compromises p53-dependent DIA. Although Apela contains a coding region, this coding ability is dispensable for Apela's role in p53-mediated DIA. Instead, Apela functions as a regulatory RNA and interacts with hnRNPL, which prevents the mitochondrial localization and activation of p53. Together, these results describe a tri-element negative feedback loop composed of p53, Apela, and hnRNPL that regulates p53-mediated DIA, and they further demonstrate that regulatory RNAs add a layer of complexity to the apoptotic response of ESCs after DNA damage. PMID- 25936918 TI - ICD-10 coding in otorhinolaryngological malformations: Analyses of 2342 Q diagnoses. AB - INTRODUCTION: The 10th revision of the International Statistical Classification of Diseases and Related Health Problems (ICD-10) includes more than 14,400 codes. The aim of this study was to study the prevalence and demographics of otorhinolaryngological congenital malformations in an outpatient clinic based of the ICD-10 Q-diagnoses used for congenital malformations, deformations and chromosomal abnormalities. MATERIALS AND METHODS: Electronic hospital records covering six years (2007-2013) were searched to identify all patients with ICD-10 Q-diagnosis. RESULTS: 2342 patients were identified. Malformations of the face and neck were most prevalent (30%). The gender distribution was equal except malformations of tongue, mouth and pharynx, where 70% of the patients were male. CONCLUSIONS: There seems to be a significant excess of ICD-10 codes for otorhinolaryngological malformations. Ten most common otorhinolaryngological malformation codes cover more than 94% of the diagnoses. In addition, the illogicalities and the possibility of coding by diagnosis, symptoms or clinical findings makes the coding suboptimal for the purposes it was originally created for. Malformations of the nose and larynx are rare compared to other anatomic localizations. The age at diagnosis of branchial cysts differs significantly from all other congenital malformations supporting the theory of cystic transformation of cervical lymph nodes. PMID- 25936919 TI - The outcomes of endoscopic dacryocystorhinostomy in children: A systematic review. AB - OBJECTIVES: To systematically review and discuss the published results about the application of endoscopic dacryocystorhinostomy in treating children with nasolacrimal duct obstruction. METHODS: In October 2014 an appropriate string was run on PubMed to retrieve all relevant articles. A cross-check was performed by two of the authors on abstracts and full-text articles found using the selected inclusion and exclusion criteria. A non-comparative meta-analysis concerning the procedures' rate of success and failure was performed. RESULTS: Fourteen studies were identified comprising a total of 346 subjects affected by nasolacrimal duct obstruction (unilateral or bilateral). Overall there were 393 surgical procedures, all performed with an exclusive endoscopic approach. The average length of follow-up was reported in twelve studies resulting 15.2 months and ranging from 3 to 27.1 months. On the basis of our statistical analysis the mean (95% CI) rate of failure was 0.14 (0.09-0.21). The mean (95% CI) rate of success resulted 0.87 (0.80-0.91). CONCLUSIONS: Although in young patients the nasal anatomy is more complex and narrow than in adults our review showed as the endoscopic dacryocystorhinostomy allows similar results in terms of success compared to the external approach. PMID- 25936917 TI - Tex10 Coordinates Epigenetic Control of Super-Enhancer Activity in Pluripotency and Reprogramming. AB - Super-enhancers (SEs) are large clusters of transcriptional enhancers that are co occupied by multiple lineage-specific transcription factors driving expression of genes that define cell identity. In embryonic stem cells (ESCs), SEs are highly enriched for the core pluripotency factors Oct4, Sox2, and Nanog. In this study, we sought to dissect the molecular control mechanism of SE activity in pluripotency and reprogramming. Starting from a protein interaction network surrounding Sox2, we identified Tex10 as a key pluripotency factor that plays a functionally significant role in ESC self-renewal, early embryo development, and reprogramming. Tex10 is enriched at SEs in a Sox2-dependent manner and coordinates histone acetylation and DNA demethylation at SEs. Tex10 activity is also important for pluripotency and reprogramming in human cells. Our study therefore highlights Tex10 as a core component of the pluripotency network and sheds light on its role in epigenetic control of SE activity for cell fate determination. PMID- 25936920 TI - A novel transcript variant of proteasome activator 28gamma: Identification and function in oral cancer cells. AB - Proteasome activator 28gamma (PA28gamma) binds to and activates the proteasome in an ATP-independent manner to promote mainly ubiquitin-independent protein degradation in cells. Previously, four transcript variants of PA28gamma have been identified, which have been closely correlated with the progression of cancers. In the present study, we predicted the alternative splicing of PA28gamma via the bioinformatics tool ASPicDB and 49 splices were predicted. Then, we cloned some new segment according to predication in oral cancer cells using reverse transcription PCR and a novel variant of PA28gamma was found. The novel transcript encodes a truncated form compared with other isoforms of PA28gamma. However, it contains most of the conserved residues and the 'activation loop' of the PA28gamma family. In order to explore its function, we overexpressed the variant in HEK293 cells and demonstrated that this variant is likely to further regulate cell cycle and apoptosis via regulating p53 and the mouse double minute2 homolog (Mdm2). PMID- 25936921 TI - Book lung development in the embryo, postembryo and first instar of the cobweb spider, Parasteatoda tepidariorum C. L Koch, 1841 (Araneomorphae, Theridiidae). AB - Light and electron microscopy were used to compare spider book lung development with earlier studies of the development of horseshoe crab book gills and scorpion book lungs. Histological studies at the beginning of the 20th century provided evidence that spider and scorpion book lungs begin with outgrowth of a few primary lamellae (respiratory furrows, saccules) from the posterior surface of opisthosomal limb buds, reminiscent of the formation of book gills in the horseshoe crab. In spider embryos, light micrographs herein also show small primary lamellae formed at the posterior surface of opisthosomal limb buds. Later, more prominent primary lamellae extend into each book lung sinus from the inner wall of the book lung operculum formed from the limb bud. It appears most primary lamellae continue developing and become part of later book lungs, but there is variation in the rate and sequence of development. Electron micrographs show the process of air channel formation from parallel rows of precursor cells: mode I (cord hollowing), release of secretory vesicles into the extracellular space and mode II (cell hollowing), alignment and fusion of intracellular vesicles. Cell death (cavitation) is much less common but occurs in some places. Results herein support the early 20th century hypotheses that 1) book lungs are derived from book gills and 2) book lungs are an early step in the evolution of spider tracheae. PMID- 25936922 TI - Two types of embryos with different functions are generated in the polyembryonic wasp Macrocentrus cingulum (Hymenoptera: Braconidae). AB - In this study, we report that two types of embryos, normal and pseudogerm, are generated from a single egg of the polyembryonic larval endoparasitoid Macrocentrus cingulum (Braconidae). M. cingulum larvae develop in the host hemocoel, emerging from the host to pupate. After egg cleavage and embryo proliferation dozens of normal embryos and thousands of pseudogerms are generated in the host larva. The difference between normal embryos and pseudogerms is that the former develop into larvae while the latter do not. The primordium that develops in normal embryos is surrounded by an extraembryonic membrane that originates from the syncytium. Pseudogerms in contrast consist only of a syncytium containing many large nuclei and are continuously generated during embryonic development. Both pseudogerms and early embryos possess dense microvilli that function to absorb nutrients from the host. After eclosion wasp larvae produced from normal embryos feed on pseudogerms. Therefore, two types of embryos originating from the same egg serve different functions. These results contribute to our understanding of the development of polyembryonic parasitoids. PMID- 25936924 TI - Regarding the use of the serratus anterior muscle pedicle as recipient vessels in DIEP flap breast reconstruction. PMID- 25936923 TI - Oligoclonal antibodies to target the ErbB family. AB - INTRODUCTION: Use of mAbs to inhibit signaling through the ErbB receptor tyrosine kinase family has proven to be an effective strategy for treating ErbB-driven cancers. Advances in the field of antibody engineering and manufacturing now allow us to more effectively mimic the natural immune response by generating oligoclonal mixtures of antibodies against desired targets of interest. AREAS COVERED: In this review, we examine the literature describing the development of oligoclonal mixtures of antibodies against ErbB family members and the impact of those mixtures on preclinical and clinical efficacy. EXPERT OPINION: Oligoclonal antibodies, facilitated by the improved antibody engineering and manufacturing techniques, hold the promise of improving patient outcomes. Through the use of empirical methods, oligoclonal mixtures with enhanced capacity to block signaling through ErbB family members can be identified. The intrinsic mechanisms associated with each of the component mAbs provide an opportunity to block signaling via multiple mechanisms of action. In addition, combinations of antibodies targeting multiple ErbB family members provide the capacity to down regulate signaling through multiple components of this critical pathway. PMID- 25936925 TI - The effects of the interplay of genetics and early environmental risk on the course of internalizing symptoms from late childhood through adolescence. AB - Internalizing symptoms during adolescence and beyond is a major public health concern, particularly because severe symptoms can lead to the diagnosis of a number of serious psychiatric conditions. This study utilizes a unique sample with a complex statistical method in order to explore Gene * Environment interactions found in internalizing symptoms during adolescence. Data for this study were drawn from a longitudinal prevention intervention study (n = 798) of Baltimore city school children. Internalizing symptom data were collected using self-report and blood or saliva samples genotyped using Affymetrix 6.0 microarrays. A major depression polygenic score was created for each individual using information from the major depressive disorder Psychiatric Genetics Consortium and used as a predictor in a latent trait-state-occasion model. The major depressive disorder polygenic score was a significant predictor of the stable latent trait variable, which captures time-independent phenotypic variability. In addition, an early childhood stressor of death or divorce was a significant predictor of occasion-specific variables. A Gene * Environment interaction was not a significant predictor of the latent trait or occasion variables. These findings support the importance of genetics on the stable latent trait portion of internalizing symptoms across adolescence. PMID- 25936927 TI - Antenatal tests of fetal wellbeing. AB - In current obstetric practice, there is frequently a need to assess fetal wellbeing. This is particularly so in those fetuses at risk, including the small for-gestational-age fetus or the fetus of a mother who presents with reduced fetal movements or who has an obstetric complication such as pre-eclampsia. It is important that the clinician is able to assess fetal wellbeing in such cases, especially in preterm gestations, when inappropriate delivery could have serious adverse consequences. In this paper, we review the current evidence for the use and the limitations of widely used methods of antenatal monitoring including the use of cardiotocography, biophysical profile, and ultrasound-derived parameters including umbilical artery, middle cerebral artery, and ductus venosus Doppler flow. PMID- 25936926 TI - PMT1 deficiency enhances basal UPR activity and extends replicative lifespan of Saccharomyces cerevisiae. AB - Pmt1p is an important member of the protein O-mannosyltransferase (PMT) family of enzymes, which participates in the endoplasmic reticulum (ER) unfolded protein response (UPR), an important pathway for alleviating ER stress. ER stress and the UPR have been implicated in aging and age-related diseases in several organisms; however, a possible role for PMT1 in determining lifespan has not been previously described. In this study, we report that deletion of PMT1 increases replicative lifespan (RLS) in the budding yeast Saccharomyces cerevisiae, while overexpression of PMT1 (PMT1-OX) reduces RLS. Relative to wild-type and PMT1-OX strains, the pmt1Delta strain had enhanced HAC1 mRNA splicing and elevated expression levels of UPR target genes. Furthermore, the increased RLS of the pmt1Delta strain could be completely abolished by deletion of either IRE1 or HAC1, two upstream modulators of the UPR. The double deletion strains pmt1Deltahac1Delta and pmt1Deltaire1Delta also displayed generally reduced transcription of UPR target genes. Collectively, our results suggest that PMT1 deficiency enhances basal activity of the ER UPR and extends the RLS of yeast mother cells through a mechanism that requires both IRE1 and HAC1. PMID- 25936928 TI - Association of presence and timing of invasive airway placement with outcomes after pediatric in-hospital cardiac arrest. AB - BACKGROUND: Little data exist regarding the association of presence of an invasive airway before cardiac arrest or early placement of an invasive airway after cardiac arrest with outcomes in children who experience in-hospital cardiac arrest. METHODS: We conducted a retrospective review of patients aged 1 day to 18 years who received cardiopulmonary resuscitation (CPR) for >= 1 min in any of the three intensive care units (ICUs) at a tertiary care, academic children's hospital between 2002 and 2010. Specific outcomes evaluated included survival to hospital discharge, return of spontaneous circulation (ROSC), 24-h survival, and good neurological status at hospital discharge. We fitted multivariable logistic regression models to evaluate the association between the presence of an invasive airway prior to cardiac arrest and timing of placement of an invasive airway with these outcomes. RESULTS: Three hundred and ninety-one patients were included. Of these, 197 (51%) patients were already tracheally intubated before the occurrence of cardiac arrest. Median time to intubation was 6 min [interquartile range (IQR): 2, 12] among the 194 patients tracheally intubated following cardiac arrest. We found lower survival to hospital discharge among patients intubated prior to cardiac arrest (intubated vs. non-intubated group, 43% vs. 61%, p < 0.001). After adjusting for patient and event characteristics, presence of an invasive airway prior to cardiac arrest was not associated with a significant improvement in survival to hospital discharge [odds ratio (OR): 0.70, 95% confidence interval (CI): 0.42-1.16, p = 0.17], or good neurological outcomes (OR: 0.60, 95% CI: 0.34-1.05, p = 0.07). Similarly, early placement of an invasive airway after cardiac arrest was also not associated with an improvement in survival to hospital discharge (OR: 1.05, 95% CI: 0.78-1.42, p = 0.73), or good neurological outcomes (OR: 1.08, 95% CI: 0.77-1.53, p = 0.65). CONCLUSIONS: Our study demonstrates that presence of an invasive airway prior to cardiac arrest or early placement of an invasive airway after cardiac arrest is not associated with an improvement in survival to hospital discharge or good neurological outcomes. Further study of the relationship between invasive airway management and survival following cardiac arrest is warranted. PMID- 25936929 TI - Call for an internationally recognized interprofessional simulation-based disease/injury independent, crisis resource management training certification. PMID- 25936930 TI - Managing cardiac arrest with refractory ventricular fibrillation in the emergency department: Conventional cardiopulmonary resuscitation versus extracorporeal cardiopulmonary resuscitation. AB - AIM: Refractory ventricular fibrillation, resistant to conventional cardiopulmonary resuscitation (CPR), is a life threatening rhythm encountered in the emergency department. Although previous reports suggest the use of extracorporeal CPR can improve the clinical outcomes in patients with prolonged cardiac arrest, the effectiveness of this novel strategy for refractory ventricular fibrillation is not known. We aimed to compare the clinical outcomes of patients with refractory ventricular fibrillation managed with conventional CPR or extracorporeal CPR in our institution. METHOD: This is a retrospective chart review study from an emergency department in a tertiary referral medical center. We identified 209 patients presenting with cardiac arrest due to ventricular fibrillation between September 2011 and September 2013. Of these, 60 patients were enrolled with ventricular fibrillation refractory to resuscitation for more than 10 min. The clinical outcome of patients with ventricular fibrillation received either conventional CPR, including defibrillation, chest compression, and resuscitative medication (C-CPR, n = 40) or CPR plus extracorporeal CPR (E-CPR, n = 20) were compared. RESULTS: The overall survival rate was 35%, and 18.3% of patients were discharged with good neurological function. The mean duration of CPR was longer in the E-CPR group than in the C CPR group (69.90 +/- 49.6 min vs 34.3 +/- 17.7 min, p = 0.0001). Patients receiving E-CPR had significantly higher rates of sustained return of spontaneous circulation (95.0% vs 47.5%, p = 0.0009), and good neurological function at discharge (40.0% vs 7.5%, p = 0.0067). The survival rate in the E-CPR group was higher (50% vs 27.5%, p = 0.1512) at discharge and (50% vs 20%, p = 0. 0998) at 1 year after discharge. CONCLUSIONS: The management of refractory ventricular fibrillation in the emergency department remains challenging, as evidenced by an overall survival rate of 35% in this study. Patients with refractory ventricular fibrillation receiving E-CPR had a trend toward higher survival rates and significantly improved neurological outcomes than those receiving C-CPR. PMID- 25936931 TI - Chest compression release velocity: Association with survival and favorable neurologic outcome after out-of-hospital cardiac arrest. AB - PURPOSE: We evaluated the association between chest compression release velocity (CCRV) and outcomes after out-of-hospital cardiac arrest (OHCA). MATERIALS AND METHODS: CPR quality was measured using a defibrillator with accelerometer-based technology (E Series, ZOLL Medical) during OHCA resuscitations by 2 EMS agencies in Arizona between 10/2008 and 06/2013. All non-EMS-witnessed adult (>= 18 years) arrests of presumed cardiac etiology were included. The association between mean CCRV (assessed as an appropriate measure of central tendency) and both survival to hospital discharge and neurologic outcome (Cerebral Performance Category score = 1 or 2) was analyzed using multivariable logistic regression to control for known and potential confounders and multiple imputation to account for missing data. RESULTS: 981 OHCAs (median age 68 years, 65% male, 11% survival to discharge) were analyzed with 232 (24%) missing CPR quality data. All-rhythms survival varied significantly with CCRV [fast (>= 400 mm/s) = 18/79 (23%); moderate (300-399.9 mm/s) = 50/416 (12%); slow (<300 mm/s) 17/255 (7%); p < 0.001], as did favorable neurologic outcome [fast = 14/79 (18%); moderate = 43/415 (10%); slow = 11/255 (4%); p < 0.001]. Fast CCRV was associated with increased survival compared to slow [adjusted odds ratio (aOR) 4.17 (95% CI: 1.61, 10.82) and moderate CCRV [aOR 3.08 (1.39, 6.83)]. Fast CCRV was also associated with improved favorable neurologic outcome compared to slow [4.51 (1.57, 12.98)]. There was a 5.2% increase in the adjusted odds of survival for each 10mm/s increase in CCRV [aOR 1.052 (1.001, 1.105)]. CONCLUSION: CCRV was independently associated with improved survival and favorable neurologic outcome at hospital discharge after adult OHCA. PMID- 25936932 TI - The use of prehospital variables to predict acute coronary artery disease in failed resuscitation attempts for out-of-hospital cardiac arrest. AB - AIM OF THE STUDY: To determine the ability of readily available prehospital variables to predict acute coronary artery disease (CAD) as the cause of arrest in failed out-of hospital cardiac arrest (OHCA) resuscitations. METHODS: Retrospective analysis of a prospectively collected database of all adult cases of OHCA who underwent resuscitation attempts and later post-mortem examination by the state Medical Examiner (ME) over a 6 year period. Multivariable logistic regression modeling was used to identify predictors. RESULTS: Among the 151 cases linked to ME reports, CAD was judged to be the cause of arrest in 65/151 (43%). In multivariable modeling, CAD was more likely to be found at autopsy among older victims (Odds ratio [OR] 2.3 per decade of life, 95% confidence interval [CI] 1.6 3.4), males (OR 7.3, 95% CI 1.9-27.4), and those with an initial shockable rhythm (OR 5.3, 95% CI 2.0-14.2). The combination of these three variables correctly classified 75% of victims with an area under the ROC curve (AUC) of 0.85. CONCLUSION: As hospital-based salvage therapies offer opportunities to extend survival for victims of OHCA who fail prehospital treatment, an ability to predict CAD may help guide protocols for appropriate use. In this derivation analysis, a simple set of variables available on scene can be used to predict CAD with good accuracy among OHCA victims who fail prehospital resuscitation attempts. An initial shockable rhythm should still be considered the result of acute coronary artery disease until proven otherwise. PMID- 25936933 TI - Can gentle chest compressions result in substantial ventilation? PMID- 25936934 TI - Reply to: Benefits of simulation based training for neonatal resuscitation education: A systematic review. PMID- 25936936 TI - New onset heart failure--Clinical characteristics and short-term mortality. A RICA (Spanish registry of acute heart failure) study. AB - BACKGROUND: Heart failure (HF) is a growing global epidemic. The main study aims is to evaluate the differences between new-onset and chronic-decompensated HF patients. Secondary objectives related only to new-onset HF patients include the role of left ventricular ejection fraction (LVEF) and mid-term mortality related risk factors METHODS: We analyzed 2190 patients hospitalized for acute HF. We compare the 683 patients with a new-onset HF episode with the rest. Restricting the analysis to the new-onset HF patients, we also compare patients with preserved LVEF (EF>50%) with those with reduced LVEF, and analyze the factors associated with three-month mortality. RESULTS: A total of 683 (31.2%) patients fulfill the criteria for "new-onset HF". These patients are older, their HF is more often related to hypertension, show higher blood pressure and heart rate values upon admission, and present with less global and disease-specific comorbidity and better baseline overall functional status. New-onset HF is more often characterized by preserved LVEF, milder baseline NYHA class and lower plasma natriuretic peptide values. After 3 months; 33 (5.2%) new-onset HF patients had died (p<0.001). Cox multivariate analysis showed a correlation between mortality and older age (hazard ratio - HR - 1.08), higher global comorbidity (HR 1.20) and lesser prescription of beta-blockers at discharge (HR 0.34). LVEF was unrelated to mortality. CONCLUSIONS: New-onset HF patients show a clinical profile different to that of chronic-decompensated patients. For this subset of acute HF patients older age, higher comorbidity and beta-blocker nonprescription predict a higher risk of mid-term post-discharge mortality. PMID- 25936937 TI - Does Continuous Hospice Care Help Patients Remain at Home? AB - CONTEXT: In the U. S., hospices sometimes provide high-intensity "continuous care" in patients' homes. However, little is known about the way that continuous care is used or what impact continuous care has on patient outcomes. OBJECTIVES: To describe patients who receive continuous care and determine whether continuous care reduces the likelihood that patients will die in an inpatient unit or hospital. METHODS: Data from 147,137 patients admitted to 11 U.S. hospices between 2008 and 2012 were extracted from the electronic medical records. The hospices are part of a research-focused collaboration. The study used a propensity score-matched cohort design. RESULTS: A total of 99,687 (67.8%) patients were in a private home or nursing home on the day before death, and of these, 10,140 (10.2%) received continuous care on the day before death. A propensity score-matched sample (n = 24,658) included 8524 patients who received continuous care and 16,134 patients who received routine care on the day before death. Using the two matched groups, patients who received continuous care on the day before death were significantly less likely to die in an inpatient hospice setting (350/8524 vs. 2030/16,134; 4.1% vs. 12.6%) (odds ratio [OR] 0.29; 95% CI 0.27-0.34; P < 0.001). When patients were cared for by a spouse, the use of continuous care was associated with a larger decrease in inpatient deaths (OR 0.12; 95% CI 0.09-0.16; P < 0.001) compared with those patients cared for by other family members (OR 0.37; 95% CI 0.32-0.42; P < 0.001). It is possible that unmeasured covariates were not included in the propensity score match. CONCLUSION: Use of continuous care on the day before death is associated with a significant reduction in the use of inpatient care on the last day of life, particularly when patients are cared for by a spouse. PMID- 25936939 TI - Melanotic Neuroectodermal Tumor of Infancy: A Systematic Review. AB - Melanotic neuroectodermal tumor of infancy (MNTI) is a rare tumor, usually diagnosed within the first year of age, with a predilection for the maxilla. Although the tumor is usually benign, its rapidly growing nature and ability to cause major deformities in surrounding structures necessitate early diagnosis and intervention. It is important that medical and dental specialists are prepared to make the diagnosis and proceed with appropriate intervention. The authors performed a systematic review of the 472 reported cases from 1918 through 2013 and provided a comprehensive update on this rare entity that can have devastating effects on young patients. This investigation uncovered age at diagnosis as an important prognostic indicator, because younger age correlated with a higher recurrence rate. The authors also present a case report of a 5-month-old girl diagnosed with MNTI and review her clinical presentation and imaging and histopathologic findings. PMID- 25936938 TI - Understanding Models of Palliative Care Delivery in Sub-Saharan Africa: Learning From Programs in Kenya and Malawi. AB - The need for palliative care has never been greater. From being significantly present in only five African countries in 2004, palliative care is now delivered in nearly 50% of African countries; however, less than 5% of people in need receive it. To scale-up palliative care, we need greater knowledge about how different models of palliative care work within different health systems. A case study evaluation was undertaken in Kenya and Malawi to define the models used, contextualize them, and identify challenges, best practices, and transferable lessons for scale-up. Visits were made to seven sites and, using an audit tool, data were collected from program staff, hospital staff, and local stakeholders, and care observed as appropriate. Three models of palliative care service delivery were identified, which supports the existing literature, that is, specialist, district hospital level, and community level. However, in looking further, findings show that the major determinants for each model were a set of philosophical questions and assumptions underpinning each and influencing staff and patient decision-making, planning, and allocation of resources. The health system structure and the beliefs about palliative care determined, and were determined most by, referrals, the patient journey, the centeredness of the model, and role definition and training. The models are also closely associated with the physical setting of services. Understanding how the services have developed because of, and indeed despite the geographical setting and the system level, provides us with a different set of indicators of program structure incorporated into the three models. The analysis of models provides pointers to future planning for palliative care. PMID- 25936935 TI - The role of TREM2 R47H as a risk factor for Alzheimer's disease, frontotemporal lobar degeneration, amyotrophic lateral sclerosis, and Parkinson's disease. AB - A rare variant in TREM2 (p.R47H, rs75932628) was recently reported to increase the risk of Alzheimer's disease (AD) and, subsequently, other neurodegenerative diseases, i.e. frontotemporal lobar degeneration (FTLD), amyotrophic lateral sclerosis (ALS), and Parkinson's disease (PD). Here we comprehensively assessed TREM2 rs75932628 for association with these diseases in a total of 19,940 previously untyped subjects of European descent. These data were combined with those from 28 published data sets by meta-analysis. Furthermore, we tested whether rs75932628 shows association with amyloid beta (Abeta42) and total-tau protein levels in the cerebrospinal fluid (CSF) of 828 individuals with AD or mild cognitive impairment. Our data show that rs75932628 is highly significantly associated with the risk of AD across 24,086 AD cases and 148,993 controls of European descent (odds ratio or OR = 2.71, P = 4.67 * 10(-25)). No consistent evidence for association was found between this marker and the risk of FTLD (OR = 2.24, P = .0113 across 2673 cases/9283 controls), PD (OR = 1.36, P = .0767 across 8311 cases/79,938 controls) and ALS (OR = 1.41, P = .198 across 5544 cases/7072 controls). Furthermore, carriers of the rs75932628 risk allele showed significantly increased levels of CSF-total-tau (P = .0110) but not Abeta42 suggesting that TREM2's role in AD may involve tau dysfunction. PMID- 25936940 TI - Effect of Hospital Volume on Outcomes of Surgery for Cleft Lip and Palate. AB - PURPOSE: Cleft lip and cleft palate are the most common craniofacial anomalies. However, the effect of hospital volume on outcomes of surgery for cleft lip and palate is unknown. MATERIALS AND METHODS: The Japanese Diagnosis Procedure Combination database was searched to identify patients who underwent surgery for cleft lip and palate from July 2010 through March 2013. Hospital volume was divided into tertiles (<=28, 29 to 82, and >=83 admissions/yr). Outcomes included total cost, length of hospital stay, duration of anesthesia, and length of antibiotic use. The relation between hospital volume and surgical outcomes was analyzed by multivariable regression analyses. RESULTS: The authors identified 7,405 admissions for cleft lip alone, cleft palate alone, or cleft lip and palate during the study period. Compared with the reference low-volume hospital category, a shorter duration of anesthesia was seen in the medium-volume group ( 15 minutes; 95% confidence interval, -37 to 7 minutes) and high-volume group (-22 minutes; 95% confidence interval, -65 to 3 minutes). No statistical associations were observed between hospital volume and total cost or length of stay. Although not statistically important, a higher hospital volume was associated with a shorter length of antibiotic use after adjusting for duration of anesthesia. CONCLUSION: In the present study of surgical outcomes for cleft lip and palate, hospital volume was inversely associated with duration of anesthesia and length of antibiotic use, but was not statistically associated with length of hospital stay or total cost. PMID- 25936941 TI - Routine Screening Radiography for Retained Wire Following Arch Bar Removal Is Not Indicated. AB - PURPOSE: To estimate the screening test value of routine radiography after arch bar wire removal by assessing the incidence of retained wires and the importance of their sequelae. MATERIALS AND METHODS: This was a retrospective medical record review. Records of arch bar removal procedures were examined and divided into those screened with radiography after removal (screen group) and those that were not screened (comparison group). The incidence of retained wire was calculated for each group. Study variables included wire-related radiographic or clinical findings. RESULTS: Records of 546 mandible fractures were reviewed; 95 met the study criteria. Most exclusions were due to lack of arch bars, missing postoperative radiographs, or insufficient postoperative documentation. Of the 55 records in the screen group, 1 wire was detected (2%); of the 40 records in the comparison group, 1 wire was detected (3%). The total incidence of retained wire findings was not statistically different between the 2 groups and there were no adverse wire-related sequelae reported by any of the 95 patients. CONCLUSION: Because of the low incidence of retained wires and wire-related sequelae, routine imaging after wire removal is probably not an effective screening test for retained wire and should be limited to situations in which there is clinical suspicion of retained wire. PMID- 25936942 TI - The Duffy blood group system in the Tunisian population. AB - BACKGROUND: Tunisia was described to as genetically heterogenous. Besides the 1% native Berber, the genetically influence of the Europeans seems much larger than that of sub-Saharan populations. Due to their ethnic variability, blood group variants have the potential to support population analyses. The aim of this study was to estimate the Duffy blood group system in this mixed population with enhanced characterization of samples with aberrant expression. MATERIALS AND METHODS: Standard serological testing for the Duffy antigen was done for 105 Tunisian blood donors. Samples with altered Fy expression underwent DNA sequencing of the DARC, RHD and RHCE genes. RESULTS: The Fy(a-b+) was the most common phenotype identified in the Tunisian population (38.1%). Five samples with Fy(a-b-) phenotype were determined as FY*02N.01/FY*02N.01 by a homozygous occurrence of the FY*B-67C>T alteration. Another three individuals exhibited a Fy(b+(w))Fy(x) expression, confirmed by a FY*A/FY*02M.01 (n = 1) and a FY*02M.01/FY*02M.01 (n = 2) genotype. RHD and RHCE sequencing (n= 8) revealed altered alleles observed in black populations in 5 samples. One individual with FY*02M.01/FY*02M.01 have the silent 165C>T nucleotide substitution each in the RHD and RHCE gene. DISCUSSION: The composition of blood group variants determined in this study confirms the genetically proximity of Tunisia to Europe. The small sub-Saharan genetic influence was approved by a limited number of variant samples associated with the black population. PMID- 25936943 TI - Patient labels as a quality indicator of identitovigilance in French hospitals. AB - INTRODUCTION: Identity risk is frequent and serious. Between 2007 and 2010, 25.6% of 1572 serious adverse events declared in France are related to identitovigilance. No regulation clearly defines an ideal patient label even when a delivery refusal is applied in case of absent or incomplete identity (absence of surname and/or first name and/or birth date). The aim of the study was to draw up the current situation of patient labels in hospitals connected with our blood transfusion center and being used for blood products delivery and immuno hematology analyses. MATERIALS AND METHODS: We defined an ideal label with 5 items which must be present and clearly identified: surname, usual or marital name, first name, birth date and sex. It contains also an identifier, if possible with a bar code. We compare it with labels used in our hospitals. RESULTS: Only 22% (17/76) had a patient label in compliance with our ideal label. Most of the items, even if they were not clearly identified on the label, were present. The surname was present and clearly indicated in 75% of cases (57/76). In approximately 50% of cases, there was a barcoded permanent and/or stay identifier. CONCLUSION: Our results, with only 22% of labels considered as 'ideal', show all the work which remains to be done. A temporary solution can be the elaboration by hospitals of an identification guide of their present labels. PMID- 25936944 TI - Unreliable patient identification warrants ABO typing at admission to check existing records before transfusion. AB - BACKGROUND AND OBJECTIVES: This study describes patient identification errors leading to transfusional near-misses in blood issued by the Alps Mediterranean French Blood Establishment (EFSAM) to Marseille Public Hospitals (APHM) over an 18-month period. The EFSAM consolidates 14 blood banks in southeast France. It supplies 149 hospitals and maintains a centralized database on ABO types used at all area hospitals. As an added precaution against incompatible transfusion, the APHM requires ABO testing at each admission regardless of whether the patient has an ABO record. The study goal was to determine if admission testing was warranted. MATERIALS AND METHODS: Discrepancies between ABO type determined by admission testing and records in the centralized database were investigated. The root cause for each discrepancy was classified as specimen collection or patient admission error. Causes of patient admission events were further subclassified as namesake (name similarity) or impersonation (identity fraud). RESULTS: The incidence of ABO discrepancies was 1:2334 including a 1:3329 incidence of patient admission events. Impersonation was the main cause of identity events accounting for 90.3% of cases. The APHM's ABO control policy prevented 19 incompatible transfusions. In relation to the 48,593 packed red cell units transfused, this would have corresponded to a risk of 1:2526. CONCLUSION: Collecting and storing ABO typing results in a centralized database is an essential public health tool. It allows crosschecking of current test results with past records and avoids redundant testing. However, as patient identification remains unreliable, ABO typing at each admission is still warranted to prevent transfusion errors. PMID- 25936945 TI - QSAR based docking studies of marine algal anticancer compounds as inhibitors of protein kinase B (PKBbeta). AB - Marine algae are prolific source of bioactive secondary metabolites and are found to be active against different cancer cell lines. QSAR studies will explicate the significance of a particular class of descriptor in eliciting anticancer activity against a cancer type. Marine algal compounds showing anticancer activity against six different cancer cell lines namely MCF-7, A431, HeLa, HT-29, P388 and A549 taken from Seaweed metabolite database were subjected to comprehensive QSAR modeling studies. A hybrid-GA (genetic algorithm) optimization technique for descriptor space reduction and multiple linear regression analysis (MLR) approach was used as fitness functions. Cell lines HeLa and MCF-7 showed good statistical quality (R(2)~0.75, Q(2)~0.65) followed by A431, HT29 and P388 cell lines with reasonable statistical values (R(2)~0.70, Q(2)~0.60). The models developed were interpretable, with good statistical and predictive significance. Molecular descriptor analyses revealed that Baumann's alignment-independent topological descriptors had a major role in variation of activity along with other descriptors. Incidentally, earlier QSAR analysis on a variety of chemically diverse PKBalpha inhibitors revealed Baumann's alignment-independent topological descriptors that differentiated the molecules binding to Protein kinase B (PKBalpha) kinase or PH domain, hence a docking study of two crystal structures of PKBbeta was performed for identification of novel ATP-competitive inhibitors of PKBbeta. Five compounds had a good docking score and Callophycin A showed better ligand efficiency than other PKBbeta inhibitors. Furthermore in silico pharmacokinetic and toxicity studies also showed that Callophycin A had a high drug score (0.85) compared to the other inhibitors. These results encourages discovering novel inhibitors for cancer therapeutic targets by screening metabolites from marine algae. PMID- 25936946 TI - Reply: To PMID 25542620. PMID- 25936947 TI - An unusual cause of abdominal pain in an elderly woman. PMID- 25936948 TI - An increasingly uncommon presentation of a common disease. PMID- 25936949 TI - Reply: To PMID 25409371. PMID- 25936950 TI - A rare cause of diarrhea and weight loss. PMID- 25936951 TI - An unusual ileocecal valve mass. PMID- 25936952 TI - Not a Usual Flare up of Ulcerative Colitis. PMID- 25936953 TI - Prevalence of chronic kidney disease among individuals with diabetes in the SUPREME-DM Project, 2005-2011. AB - AIMS: Diabetes is a leading cause of chronic kidney disease (CKD). Different methods of CKD ascertainment may impact prevalence estimates. We used data from 11 integrated health systems in the United States to estimate CKD prevalence in adults with diabetes (2005-2011), and compare the effect of different ascertainment methods on prevalence estimates. METHODS: We used the SUPREME-DM DataLink (n = 879,312) to estimate annual CKD prevalence. Methods of CKD ascertainment included: diagnosis codes alone, impaired estimated glomerular filtration rate (eGFR) alone (eGFR < 60 mL/min/1.73 m(2)), albuminuria alone (spot urine albumin creatinine ratio > 30 mg/g or equivalent), and combinations of these approaches. RESULTS: CKD prevalence was 20.0% using diagnosis codes, 17.7% using impaired eGFR, 11.9% using albuminuria, and 32.7% when one or more method suggested CKD. The criteria had poor concordance. After age- and sex standardization to the 2010 U.S. Census population, prevalence using diagnosis codes increased from 10.7% in 2005 to 14.3% in 2011 (P < 0.001). The prevalence using eGFR decreased from 9.7% in 2005 to 8.6% in 2011 (P < 0.001). CONCLUSIONS: Our data indicate that CKD prevalence and prevalence trends differ according to the CKD ascertainment method, highlighting the necessity for multiple sources of data to accurately estimate and track CKD prevalence. PMID- 25936954 TI - Molecular detection of Mikrocytos mackini in Pacific oysters using quantitative PCR. AB - Mikrocytos mackini is an internationally regulated pathogen and causative agent of Denman Island disease in Pacific oysters Crassostrea gigas. Recent phylogenetic breakthroughs have placed this parasite within a highly divergent and globally distributed eukaryotic lineage that has been designated a new taxonomic order, Mikrocytida. The discovery of this new radiation of parasites is accompanied by a heightened awareness of the many knowledge gaps that exist with respect to the general biology, epizootiology, and potential impact of mikrocytid parasites on hosts, ecosystems, and commercial fisheries. It has also highlighted current shortcomings regarding our ability to detect these organisms. In this study, we developed a species-specific, sensitive, and quantitative method for detecting M. mackini DNA from host tissues using probe-based real-time qPCR technology. A limit of sensitivity between 2 and 5 genome copy equivalents was achieved in a reaction matrix containing >= 40 ng/MUL host gDNA without inhibition. This detection proved superior to existing methods based on conventional PCR, histology or gross pathology and is the first species-specific diagnostic test for M. mackini. Quantitative assessment of parasite DNA using this assay remained accurate to between 10 and 50 copies identifying that during infection, M. mackini DNA was significantly more prevalent in hemolymph, labial palp, and mid-body cross-sections compared to mantle or adductor muscle. DNA extracted from a mid-body cross-section also provided the highest likelihood for detection during diagnostic screening of infected oysters. Taken together, these findings provide strong analytical evidence for the adoption of qPCR as the new reference standard for detecting M. mackini and give preliminary insight into the distribution of the parasite within host tissues. Standardised operating methodologies for sample collection and qPCR testing are provided to aid in the international regulatory diagnosis of M. mackini and serve as a useful platform for the future development of multiplexed or alternate mikrocytid species detection. PMID- 25936955 TI - Association of lipid profile alterations with severe forms of dengue in humans. AB - Previous studies have shown a relationship between circulating lipids and dengue virus infection; however, the association of altered lipid profiles with severe dengue remains little studied. The aim of this study was to determine the association between circulating lipid content and severe dengue and/or platelet counts. Ninety-eight patients (2-66 years old) classified as having dengue without warning signs (DNWS), dengue with warning signs (DWWS), or severe dengue (SD) and 62 healthy individuals were studied. Blood samples were tested for NS1, anti-dengue IgM, platelet content, total cholesterol (TC), triglycerides (T), high-density lipoproteins (HDL), low-density lipoproteins (LDL) and very-low density lipoproteins (VLDL). Lipid alterations were observed mainly in patients with SD. Increased T and VLDL was observed in SD, and increased HDL was observed in DWWS and SD. Decreased TC was found in all forms of dengue, and the lowest LDL values were found in SD. Platelet counts were significantly decreased in DWWS and SD when compare to DNWS. A positive correlation (p = 0.019) between LDL values and platelet counts and a negative correlation (p = 0.0162) between VLDL values and platelet counts were found. Lipid profile alterations were associated with severe dengue. PMID- 25936956 TI - Occurrence and genetic diversity of human cosavirus in influent and effluent of wastewater treatment plants in Arizona, United States. AB - Human cosavirus (HCoSV) is a novel member of the family Picornaviridae. We investigated the prevalence and genetic diversity of HCoSV in influent and effluent wastewater in Arizona over a 12-month period, from August 2011 to July 2012. HCoSV sequences were identified in six (25%) influent samples and one (4%) effluent sample, with the highest concentration of 3.24 * 10(5) and 1.54 * 10(3) copies/liter in influent and effluent, respectively. The strains were characterized based on their 5' untranslated region and classified into species A and D, demonstrating that genetically heterogeneous HCoSV were circulating with a clear temporal shift of predominant strains in the study area. PMID- 25936957 TI - Nano-plasmonic exosome diagnostics. AB - Exosomes have emerged as a promising biomarker. These vesicles abound in biofluids and harbor molecular constituents from their parent cells, thereby offering a minimally-invasive avenue for molecular analyses. Despite such clinical potential, routine exosomal analysis, particularly the protein assay, remains challenging, due to requirements for large sample volumes and extensive processing. We have been developing miniaturized systems to facilitate clinical exosome studies. These systems can be categorized into two components: microfluidics for sample preparation and analytical tools for protein analyses. In this report, we review a new assay platform, nano-plasmonic exosome, in which sensing is based on surface plasmon resonance to achieve label-free exosome detection. Looking forward, we also discuss some potential challenges and improvements in exosome studies. PMID- 25936959 TI - Acute respiratory infection in children from developing nations: a multi-level study. AB - BACKGROUND: Worldwide, acute respiratory infections (ARI) are the leading cause of death of children under 5 years of age. AIM: To assess the accomplishment of the Millennium Development Goal on under-5 mortality particularly related to ARI in developing countries, and to explore the associations between country characteristics and ARI in children under 5 taking into account child, mother and household attributes. METHODS: The study included a representative sample of 354,633 children under 5 years from 40 developing nations. A multilevel analysis of data from the Demographic and Health Surveys and the World Bank was conducted. RESULTS: The prevalence of ARI was 13%. Country inequalities were associated with the disease - GINI index (95% CI 1.01-1.04). The country's per capita gross domestic product (GDP) (95% CI 1.00-1.01) and health expenditure (95% CI 1.01 1.01) affected the relationship between immunization and ARI, while inequalities influenced the relationship between household wealth (95% CI 0.99-0.99) and the disease. Other factors positively associated with ARI were male gender, low birthweight, working mothers and a high-risk indoor environment. Factors associated with ARI reduction were older children, immunization, breastfeeding for more than 6 months, older maternal age, maternal education and planned pregnancy. CONCLUSIONS: In developing countries, public health campaigns to target ARI should consider the country's macro characteristics. At country level, inequalities but not health expenditure or GDP were associated with the disease and were independent of child, family and household characteristics. The effect of immunization on reducing ARI is greater in countries with a higher GDP and health expenditure. The effect of household wealth on ARI is less in countries with fewer inequalities. Reduction of inequalities is an important measure to decrease ARI in developing countries. PMID- 25936960 TI - Purification and enzymatic characterization of secretory glycoside hydrolase family 3 (GH3) aryl beta-glucosidases screened from Aspergillus oryzae genome. AB - By a global search of the genome database of Aspergillus oryzae, we found 23 genes encoding putative beta-glucosidases, among which 10 genes with a signal peptide belonging to glycoside hydrolase family 3 (GH3) were overexpressed in A. oryzae using the improved glaA gene promoter. Consequently, crude enzyme preparations from three strains, each harboring the genes AO090038000223 (bglA), AO090103000127 (bglF), and AO090003001511 (bglJ), showed a substrate preference toward p-nitrophenyl-beta-d-glucopyranoside (pNPGlc) and thus were purified to homogeneity and enzymatically characterized. All the purified enzymes (BglA, BglF, and BglJ) preferentially hydrolyzed aryl beta-glycosides, including pNPGlc, rather than cellobiose, and these enzymes were proven to be aryl beta glucosidases. Although the specific activity of BglF toward all the substrates tested was significantly low, BglA and BglJ showed appreciably high activities toward pNPGlc and arbutin. The kinetic parameters of BglA and BglJ for pNPGlc suggested that both the enzymes had relatively higher hydrolytic activity toward pNPGlc among the fungal beta-glucosidases reported. The thermal and pH stabilities of BglA were higher than those of BglJ, and BglA was particularly stable in a wide pH range (pH 4.5-10). In contrast, BglJ was the most heat- and alkaline-labile among the three beta-glucosidases. Furthermore, BglA was more tolerant to ethanol than BglJ; as a result, it showed much higher hydrolytic activity toward isoflavone glycosides in the presence of ethanol than BglJ. This study suggested that the mining of novel beta-glucosidases exhibiting higher activity from microbial genome sequences is of great use for the production of beneficial compounds such as isoflavone aglycones. PMID- 25936961 TI - Metabolic characterization of cultured mammalian cells by mass balance analysis, tracer labeling experiments and computer-aided simulations. AB - Studying metabolic directions and flow rates in cultured mammalian cells can provide key information for understanding metabolic function in the fields of cancer research, drug discovery, stem cell biology, and antibody production. In this work, metabolic engineering methodologies including medium component analysis, (13)C-labeling experiments, and computer-aided simulation analysis were applied to characterize the metabolic phenotype of soft tissue sarcoma cells derived from p53-null mice. Cells were cultured in medium containing [1-(13)C] glutamine to assess the level of reductive glutamine metabolism via the reverse reaction of isocitrate dehydrogenase (IDH). The specific uptake and production rates of glucose, organic acids, and the 20 amino acids were determined by time course analysis of cultured media. Gas chromatography-mass spectrometry analysis of the (13)C-labeling of citrate, succinate, fumarate, malate, and aspartate confirmed an isotopically steady state of the cultured cells. After removing the effect of naturally occurring isotopes, the direction of the IDH reaction was determined by computer-aided analysis. The results validated that metabolic engineering methodologies are applicable to soft tissue sarcoma cells derived from p53-null mice, and also demonstrated that reductive glutamine metabolism is active in p53-null soft tissue sarcoma cells under normoxia. PMID- 25936962 TI - Pituitary tumor transforming gene as a novel regulatory factor of liver fibrosis. AB - AIMS: Pituitary tumor-transforming gene (PTTG) is involved in multiple cellular pathways. We studied the development of liver fibrosis induced by thioacetamide (TAA) in knockout (PTTG-/-) and wildtype (PTTG+/+) mice. MAIN METHODS: Liver fibrosis in PTTG+/+ and PTTG-/- mice was induced by escalating dose TAA treatment (50-400mg/kg, i.p.) for 12 weeks and assessed by histochemistry, immunohistochemistry, liver hydroxyproline, serum fibrosis markers and fibrosis related mRNA expression by real-time PCR determination. KEY FINDINGS: Both PTTG+/+ and PTTG-/- mice treated with TAA developed signs of fibrosis and inflammatory cell infiltration. However, histological signs of bridging fibrosis and connective tissue square morphometry were significantly attenuated in mice lacking PTTG. alpha-SMA immunohistochemistry revealed that hepatic stellate cell activation was markedly reduced in PTTG-/- mice compared to wildtype controls. Hepatic hydroxyproline levels were significantly lower in fibrotic PTTG-/- group. The serum TNFalpha and hepatic TNFalpha mRNA expression were significantly lower in fibrotic PTTG-/- animals, as well as hepatic TGFbeta and VEGF mRNA levels compared to TAA-treated wildtype controls. Serum hyaluronate and TGFbeta levels were markedly elevated in fibrotic mice of both genotypes, but were not altered by the absence of PTTG. SIGNIFICANCE: TAA-induced fibrosis development is significantly ameliorated in PTTG-/- mice. These animals demonstrated diminished stellate cell activation, suppressed circulating serum markers of inflammation, fibrogenesis and angiogenesis. The presented findings suggest that PTTG is functionally required for hepatic fibrosis progression in an animal model of chronic liver injury. PTTG can be considered as a new important target for prevention and treatment of liver fibrosis/cirrhosis. PMID- 25936963 TI - Trans-fat supplementation over two generations of rats exacerbates behavioral and biochemical damages in a model of mania: Co-treatment with lithium. AB - AIMS: We investigated whether trans-fat supplemented over two generations of rats could alter neuronal membranes and influence mania-like behaviors, as well as the effects of lithium (Li). MAIN METHODS: Two generations of female rats were supplemented with soybean oil (SO-C, rich in n-6 fatty acids - FA) or hydrogenated vegetable fat (HVF, rich in trans-fatty acids - TFA). Male rats born from the 1st and 2nd generations were maintained in the same supplementation until adulthood, when they were exposed to an amphetamine (AMPH)-induced model of mania and co-treated with Li or not. KEY FINDINGS: AMPH increased locomotion of both generations and this influence was higher in the HVF than in the SO-C group. Conversely, AMPH increased long-term memory in SO-C group of the 2nd generation. HVF supplementation allowed hippocampal TFA incorporation in rats of both generations (0.1 and 0.2%, respectively). Oxidative parameters indicated higher levels of protein carbonyl (PC) in the HVF group with no changes in catalase (CAT) activity in the 1st generation. In the 2nd generation, AMPH increased PC levels of both experimental groups, whereas CAT activity was lower per se in the HVF group only. The co-treatment with Li leveled out all behavioral parameters, PC levels and CAT activity indicating a significant neuroprotective role. SIGNIFICANCE: These findings suggest that chronic HVF consumption allows a rising incorporation of TFA in the brain, which may be reflected on the neuropsychiatric conditions related to mania, whereas the effects of Li are not modified in the course of this harmful dietary habit. PMID- 25936964 TI - The hepatitis B virus (HBV) core protein enhances the transcription activation of CRE via the CRE/CREB/CBP pathway. AB - We previously reported that hepatitis B virus core protein (HBc) can bind to the Enhancer I (Enh I) domain and can accumulate with transcription coactivator cAMP response element (CRE). This raises the possibility that HBc may interact with CRE/CREB and regulate CRE transcription activation. In this study, we investigated the function and mechanisms of HBc in regulating CRE transcriptional activation using the HepG2 cell line. Our results showed the following: (1) HBc expression significantly increases HBV CRE transcriptional activation; (2) phosphorylation of the serine residues in the arginine-rich domain (ARD) of HBc protein impacts the function of transcriptional activation by the CRE; (3) HBc protein significantly increases HBV CRE transcriptional activation following forskolin treatment; (4) HBc nonspecifically binds to CRE and enhances the binding of the cAMP response element-binding protein (CREB) to CRE; and (5) HBc increases the concurrent accumulation of CREB and CBP at the CRE region. HBc activates Enh I through its binding to CRE, increasing the concurrent accumulation of CREB/CBP on CRE, and thus increases CRE transcriptional activation. PMID- 25936965 TI - Development of a novel cell-based assay to monitor the transactivation activity of the HSV-1 protein ICP0. AB - The herpes simplex virus type 1 (HSV-1) immediate-early phosphoprotein infected cell protein 0 (ICP0) is a potent transcriptional activator of viral genes and is required for efficient viral replication and reactivation from latency. However, it is largely unknown what role specific cellular factors play in the transactivator function of ICP0. With the long-term goal of identifying these factors, we developed a cell-based assay in a 96-well format to measure this activity of ICP0. We designed a system using a set of HSV-1 GFP reporter viruses in which the expression of GFP is potently induced by ICP0 in cell culture. The initial feasibility of this system was confirmed over a 24-h period by fluorescence microscopy. We adapted this assay to a 96-well plate format, quantifying GFP expression with a fluorescence scanner. Our results indicate that the cell-based assay we developed is a valid and effective method for examining the transactivating activity of ICP0. This assay can be used to identify cellular factors that regulate the transactivating activity of ICP0. PMID- 25936966 TI - Rabbit antithymocyte globulin induction and risk of post-transplant lymphoproliferative disease in adult and pediatric solid organ transplantation: An update. AB - The most modifiable risk factor for post-transplant lymphoproliferative disease (PTLD) is the type and dose of induction and maintenance immunosuppressive therapy. It is challenging to identify the contribution of a single agent such as rabbit antithymocyte globulin (rATG) in the setting of multidrug therapy. Registry analyses can be helpful but are limited by methodological restrictions and inclusion of historical patient cohorts. These are typically from eras when rATG dosing was markedly higher than current dosing (e.g. total dose 14 mg/kg versus 6 mg/kg now), accompanied by higher exposure to maintenance therapies, and often an absence of antiviral prophylaxis. The largest registry analysis to assess rATG specifically found no risk of PTLD after kidney transplantation, but conflicting results have been reported, highlighting the difficulty of interpreting this type of analysis. The relative rarity of PTLD means that individually controlled trials are underpowered to assess its occurrence, but the available data do not suggest an effect of rATG. A pooled analysis of data from studies of rATG induction in kidney and heart transplantation found the incidence of PTLD to be comparable to published reports in the overall transplant population. Data on the effect of rATG dose are inconclusive, but in patients receiving antiviral prophylaxis it does not appear to be influential. Nevertheless, it would seem reasonable to employ the lowest dose of rATG compatible with effective induction, particularly in EBV-seronegative recipients and other high-risk groups such as heart-lung transplant recipients. Overall, the risk of PTLD following rATG induction therapy with modern dosing regimens and under current management conditions appears unlikely to make an important contribution to the risk:benefit balance. PMID- 25936967 TI - WITHDRAWN: Reproductive biomechanics: Innovations and challenges. AB - The Publisher regrets that this article is an accidental duplication of an article that has already been published, http://dx.doi.org/10.1016/j.jbiomech.2015.03.019. The duplicate article has therefore been withdrawn. The full Elsevier Policy on Article Withdrawal can be found at http://www.elsevier.com/locate/withdrawalpolicy. PMID- 25936969 TI - WITHDRAWN: Meniscus mechanics and mechanobiology. AB - The Publisher regrets that this article is an accidental duplication of an article that has already been published, http://dx.doi.org/10.1016/j.jbiomech.2015.03.020. The duplicate article has therefore been withdrawn. The full Elsevier Policy on Article Withdrawal can be found at http://www.elsevier.com/locate/withdrawalpolicy. PMID- 25936968 TI - Embryonic stem cell-derived osteocytes are capable of responding to mechanical oscillatory hydrostatic pressure. AB - Osteoblasts can be derived from embryonic stem cells (ESCs) by a 30 day differentiation process, whereupon cells spontaneously differentiate upon removal of LIF and respond to exogenously added 1,25alpha(OH)2 vitamin D3 with enhanced matrix mineralization. However, bone is a load-bearing tissue that has to perform under dynamic pressure changes during daily movement, a capacity that is executed by osteocytes. At present, it is unclear whether ESC-derived osteogenic cultures contain osteocytes and whether these are capable of responding to a relevant cyclic hydrostatic compression stimulus. Here, we show that ESC osteoblastogenesis is followed by the generation of osteocytes and then mechanically load ESC-derived osteogenic cultures in a compression chamber using a cyclic loading protocol. Following mechanical loading of the cells, iNOS mRNA was upregulated 31-fold, which was consistent with a role for iNOS as an immediate early mechanoresponsive gene. Further analysis of matrix and bone specific genes suggested a cellular response in favor of matrix remodeling. Immediate iNOS upregulation also correlated with a concomitant increase in Ctnnb1 and Tcf7l2 mRNAs along with increased nuclear TCF transcriptional activity, while the mRNA for the repressive Tcf7l1 was downregulated, providing a possible mechanistic explanation for the noted matrix remodeling. We conclude that ESC derived osteocytes are capable of responding to relevant mechanical cues, at least such that mimic oscillatory compression stress, which not only provides new basic understanding, but also information that likely will be important for their use in cell-based regenerative therapies. PMID- 25936970 TI - Molecular phylogenetic analysis of Fasciola flukes from eastern India. AB - Fasciola flukes from eastern India were characterized on the basis of spermatogenesis status and nuclear ITS1. Both Fasciola gigantica and aspermic Fasciola flukes were detected in Imphal, Kohima, and Gantoku districts. The sequences of mitochondrial nad1 were analyzed to infer their phylogenetical relationship with neighboring countries. The haplotypes of aspermic Fasciola flukes were identical or showed a single nucleotide substitution compared to those from populations in the neighboring countries, corroborating the previous reports that categorized them in the same lineage. However, the prevalence of aspermic Fasciola flukes in eastern India was lower than those in the neighboring countries, suggesting that they have not dispersed throughout eastern India. In contrast, F. gigantica was predominant and well diversified, and the species was thought to be distributed in the area for a longer time than the aspermic Fasciola flukes. Fasciola gigantica populations from eastern India were categorized into two distinct haplogroups A and B. The level of their genetic diversity suggests that populations belonging to haplogroup A have dispersed from the west side of the Indian subcontinent to eastern India with the artificial movement of domestic cattle, Bos indicus, whereas populations belonging to haplogroup B might have spread from Myanmar to eastern India with domestic buffaloes, Bubalus bubalis. PMID- 25936973 TI - Playing with fire? Factors influencing risk willingness with the unlicensed fat burner drug 2,4-Dinitrophenol (DNP) in young adults. PMID- 25936971 TI - Co-immunization of cattle with a vaccine against babesiosis and Lactobacillus casei increases specific IgG1 levels to Babesia bovis and B. bigemina. AB - The effect of Lactobacillus casei administered along with a live attenuated vaccine vs. bovine babesiosis (VAC) on induction of IgG1 and IgG2 antibodies to Babesia bovis and Babesia bigemina was assessed by the indirect fluorescent antibody test (IFAT) in bovines of an endemic babesiosis area before (day 0) and after vaccination (days 15 and 30). We previously reported that L. casei increases the efficiency of VAC under controlled conditions and under extreme conditions in the field; however, the levels of IgG1 and IgG2 antibodies to B. bovis and B. bigemina are not known in vaccinated animals. Twenty-one dairy cows were allocated into three groups (seven animals per group): unvaccinated, vaccinated with VAC and vaccinated simultaneously with VAC and L. casei (VAC-LC). All animals were kept in a babesiosis endemic area at Tlalixcoyan, Veracruz. At days 15 and 30 after vaccination, the average levels of IgG1 to B. bovis and to B. bigemina were significantly higher in VAC-LC group than levels observed in VAC and control groups (P<0.01). Levels of IgG2 were similar in VAC and VAC-LC groups but higher than in the control group (P<0.01). When tested in in vitro cultures of B. bovis, sera from VAC-LC group significantly inhibited parasite growth as compared with the sera of the other two groups. It is suggested that the efficiency improvement of VAC, in part, is due to the L. casei boost of IgG1 over IgG2 antibodies to B. bovis and B. bigemina when the bacteria is co-inoculated with this vaccine. PMID- 25936972 TI - Taxi drivers' attitudes toward road safety in Pakistan. PMID- 25936974 TI - Freedom and the state: nanny or nightwatchman? AB - There are two rival images often offered of the state. In one the state serves like a nanny to provide for the welfare of its members; in the other it requires people to look after themselves, providing only the service of a night-watchman. But this dichotomy, which is routinely invoked in debates about public health and welfare provision in general, is misleading. What the rival images turn on is not competing pictures of how the state should function in people's lives but competing pictures of what it is to guard the freedom of its people. On the neo liberal theory, which has been dominant over the last century or so, providing for people's freedom means leaving them to their own devices and fortunes. On the neo-republican theory, which answers to a much longer tradition, it means democratically identifying a common set of basic liberties in the exercise of which everyone should be protected by law and, if necessary, resourced. This older way of thinking about freedom has important merits missing in the newer and argues strongly against the nightwatchman state. PMID- 25936975 TI - Family structure, social capital, and mental health disparities among Canadian mothers. AB - OBJECTIVES: To examine the extent to which inequities in mental health between single and partnered mothers can be explained by social capital, independently and in concert with socio-economic circumstances. STUDY DESIGN: Cross-sectional study. METHODS: The sample consisted of 2920 mothers participating in Statistics Canada's 2010 General Social Survey. Chi-square and logistic regression analyses were used to investigate the extent to which family structure differences in self rated mental health, if observed, were mediated by various dimensions of social capital. RESULTS: Compared with partnered mothers, fair/poor self-rated mental health was more common among previously married mothers (OR = 3.14; 95% CI 2.15 4.59) and never married mothers (OR = 3.01; 95% CI 1.95-4.65). After adjustment for socio-economic and social capital variables, the odds ratio between single mother family structure and fair/poor mental health decreased but remained significant (ORpreviously married = 1.90, 95% CI 1.22-2.98; ORnever married = 1.90, 95% CI 1.14-3.16). CONCLUSION: Single mothers' more limited access to economic and social capital resources partially explain their compromised self rated mental health. Longitudinal research with multi-item measures of mental health is needed to corroborate these findings and extend their understanding of the relationship between family structure, social capital, and mothers' mental health. PMID- 25936976 TI - Is high relative humidity associated with childhood hand, foot, and mouth disease in rural and urban areas? AB - OBJECTIVE: To examine the relationship between relative humidity and childhood hand, foot and mouth disease (HFMD) in Hefei, China, and to explore whether the effect is different between urban and rural areas. STUDY DESIGN: Retrospective ecological study. METHODS: A Poisson generalized linear model combined with a distributed lag non-linear model was used to examine the relationship between relative humidity and childhood HFMD in a temperate Chinese city during 2010 2012. RESULTS: The effect of relative humidity on childhood HFMD increased above a humidity of 84%, with a 0.34% (95% CI: 0.23%-0.45%) increase of childhood HFMD per 1% increment of relative humidity. Notably, urban children, male children, and children aged 0-4 years appeared to be more vulnerable to the effect of relative humidity on HFMD. CONCLUSIONS: This article study indicates that high relative humidity may trigger childhood HFMD in a temperate area, Hefei, particularly for those who are young and from urban areas. PMID- 25936977 TI - Axon glycoprotein routing in nerve polarity, function, and repair. AB - Nervous system function relies on the capacity of neurons to organize specialized domains for impulse reception or transmission. Such a polarized architecture relies on highly discriminatory and efficient mechanisms for the transport and targeting of required molecules to their functional positions. Glycans play a central role in polarized traffic based on their extraordinary capacity to encrypt bio-information. Glycan-based interactions exquisitely regulate cargo selection, trafficking, and targeting to the axon membrane. This generates segregated functional domains, where basal nerve processes such as axon growth, synaptic activity, or myelination take place. Deciphering the details of the glycan structures and carbohydrate-binding molecules that underlie these mechanisms improves our knowledge of nerve physiology and defines novel specific approaches for neurological treatments. PMID- 25936978 TI - Twenty years later, the evolution of origami DNA. AB - Twenty years ago Trends in Biochemical Sciences published an innovative origami template for modeling the DNA double helix. Presented here are adaptations of this, including a chemical structure designed for transparent acetate, plus hybrid DNA/RNA, RNA hairpin, and single-stranded models. These models are useful teaching tools for understanding the 3D structure of DNA. PMID- 25936979 TI - Sugar coating: bacterial protein glycosylation and host-microbe interactions. AB - Bacterial surfaces are rich in glycoconjugates such as capsules, lipopolysaccharides, and peptidoglycans. The discovery of prokaryotic protein glycosylation systems has revealed that many bacteria also have the capacity to synthesise a diverse array of protein glycans, in some cases using novel strategies that differ from those of eukaryotes. Despite advances in our understanding of glycan biosynthesis and the proteins that are targets of glycosylation in bacteria, the roles of these modifications are relatively less well explored. We present an overview of bacterial protein glycosylation systems in bacteria that are relevant to human health, and discuss current evidence which indicates that glycosylation of proteins may impact upon fundamental processes such as bacterial motility, adhesion, and the modulation of immune responses. PMID- 25936980 TI - Expression of tumor necrosis factor alpha-induced protein 8 is upregulated in human gastric cancer and regulates cell proliferation, invasion and migration. AB - Tumor necrosis factor alpha-induced protein 8 (TNFAIP8) has been associated with the tumorigenicity of various types of cancer, however, the expression of TNFAIP8 and its function in gastric cancer remain to be fully elucidated. Therefore, the present study examined the expression and biological function of TNFAIP8 in gastric cancer. The expression levels of TNFAIP8 were determined in 86 gastric cancer tissue samples and adjacent normal tissues using immunohistochemistry, and in four gastric cancer cell lines and GES-1 cells using reverse transcription quantitative polymerase chain reaction. The expression of TNFAIP8 and its association with the tumor, node, metastasis (TNM) status and lymphatic metastasis of gastric cancer was evaluated. Furthermore, the functions of decreased expression levels of TNFAIP8 were analyzed in human gastric cancer cell lines. The expression of TNFAIP8 was significantly upregulated in the gastric cancer tissues and in the gastric cancer cell lines, and its expression levels were associated with the TNM staging and lymphatic metastasis. Furthermore, decreased expression of TNFAIP8 inhibited the growth, invasion and migration of gastric cancer cells. These data provided an innovative insight suggesting the downregulation of TNFAIP8 as a meaningful approach for treating human gastric cancer and other types of cancer. In addition, the expression levels of TNFAIP8 may be considered as a biomarker of gastric cancer progression. PMID- 25936981 TI - The combination of the aliphatic diamine AA0029 in ADAD vaccination system with a recombinant fatty acid binding protein could be a good alternative for the animal schistosomiasis control. AB - Fatty acid binding proteins (FABP) from Fasciola hepatica have demonstrated immune cross-protection against schistosomes. The present study was conducted to develop a new formulation of the recombinant FABP rFh15 with the synthetic immunomodulator AA0029 in the adjuvant adaptation (ADAD) vaccination system and to evaluate its ability to induce immune response and protection against the challenge with Schistosoma bovis cercariae. Immunization of BALB/c mice showed high levels of TNFalpha, IFNgamma, interleukin (IL)-2, IL-6, and IL-4 in splenocyte supernatant culture and also high levels of serum specific anti-rFh15 IgG, IgG1, IgG2a IgE and IgM antibodies suggesting a mixed Th1/Th2 immune response. Using this approach, high levels of protection against experimental challenge with S. bovis cercariae were observed in the mouse and hamster models. A marked reduction up to 64% in worm burden, as well as in the number of eggs retained in liver (66%) and intestine (77%) and hepatic lesions (42%), was achieved in vaccinated BALB/c mice. Golden hamsters vaccinated and challenged in similar conditions had reductions in recovered worms (83%), liver eggs (90%), intestine eggs (96%), liver lesions (56%) and worm fecundity (48-80%). These data suggest that formulation of rFh15 in the ADAD vaccination system using the AA0029 immunomodulator could be a good option to drive an effective immunological response against schistosomiasis. PMID- 25936982 TI - Immunization of Wistar female rats with 255-Gy-irradiated Toxoplasma gondii: Tissue parasitic load and lactogenic quantification. AB - Toxoplasma gondii is one of the most significant parasite, due its importance in veterinary medicine and in public health, considered a food-borne pathogens, there is no available drug treatments to eliminate it from animal tissue, this reinforce the search for a vaccine against this parasite. This study was aimed to evaluate the dynamic of the distribution of T. gondii in tissues of female Wistar rats and their milk, after the immunization by oral rote with irradiated tachyzoites. One week after pregnancy confirmation, rats was challenged by gavage with T. gondii bradyzoites, oocysts or tachyzoites of T. gondii. Forty-eight pregnant rats were grouped as follows: immunized and challenged with bradyzoites (BZ*); non-immunized and challenged with bradyzoites (BZ); immunized and challenged with oocysts (OC*); non-immunized and challenged with oocysts (OC); immunized and challenged with tachyzoites (TZ*); non-immunized and challenged with tachyzoites (TZ); only immunized (I); control group (C). After parturition, milk samples were collected for 3 weeks and then rats were sacrificed and the tissues and milk samples were researched for T. gondii parasite load determined by the quantitative PCR (qPCR). It was verified that the immunization with irradiated tachyzoites of T. gondii induced the reduction of parasitic load in muscle samples in rats challenged by bradyzoites and oocysts, although not enabled the development of sterile immunity. The detection of parasite DNA in milk was found throughout the lactation period, from immunized and non-immunized rats, however no differences were found in the parasite load caused by immunization. PMID- 25936983 TI - Band-selective ballistic energy transport in alkane oligomers: toward controlling the transport speed. AB - Intramolecular transport of vibrational energy in two series of oligomers featuring alkane chains of various length was studied by relaxation-assisted two dimensional infrared spectroscopy. The transport was initiated by exciting various end-group modes (tags) such as different modes of the azido (nu(N=N) and nu(N?N)), carboxylic acid (nu(C?O)), and succinimide ester (nuas(C?O)) with short mid-IR laser pulses. It is shown that the transport via alkane chains is ballistic and the transport speed is dependent on the type of the tag mode that initiates the transport. The transport speed of 8.0 A/ps was observed when initiated by either nu(C?O) or nuas(C?O). When initiated by nu(N=N) and nu(N?N), the transport speed of 14.4 +/- 2 and 11 +/- 4 A/ps was observed. Analysis of the vibrational relaxation channels of different tags, combined with the results for the group velocity evaluation, permits identification of the chain bands predominantly contributing to the transport for different cases of the transport initiation. For the transport initiated by nu(N=N) the CH2 twisting and wagging chain bands were identified as the major energy transport channels. For the transport initiated by nu(C?O), the C-C stretching and CH2 rocking chain bands served as major energy transporters. The transport initiated by nu(N?N) results in direct formation of the wave packet within the CH2 twisting and wagging chain bands. These developments can aid in designing molecular systems featuring faster and more controllable energy transport in molecules. PMID- 25936985 TI - Negative PET: good prognosis for Hodgkin's lymphoma. PMID- 25936984 TI - Improvement and decline in vision with gene therapy in childhood blindness. AB - Retinal gene therapy for Leber's congenital amaurosis, an autosomal recessive childhood blindness, has been widely considered to be safe and efficacious. Three years after therapy, improvement in vision was maintained, but the rate of loss of photoreceptors in the treated retina was the same as that in the untreated retina. Here we describe long-term follow-up data from three treated patients. Topographic maps of visual sensitivity in treated regions, nearly 6 years after therapy for two of the patients and 4.5 years after therapy for the third patient, indicate progressive diminution of the areas of improved vision. (Funded by the National Eye Institute; ClinicalTrials.gov number, NCT00481546.). PMID- 25936986 TI - US National Cancer Institute investigates PSA coding errors. PMID- 25936987 TI - Immunotherapy combination promising for melanomas. PMID- 25936988 TI - Anti-PD-L1 for metastatic triple-negative breast cancer. PMID- 25936989 TI - Hepatitis C virus associated with high rates of cancer. PMID- 25936990 TI - [Life style and occupational factors and prevention of second primary cancers after childhood and adolescent cancer: Current state of knowledge]. AB - CONTEXT: Survival of children, adolescents and young adults treated for cancer increased with improved treatments. But there is still an increased risk of second primary cancer (SPC) in the long term compared to the population of the same age, especially related to treatments. A reflection on the follow-up of this population and the prevention of SPC is an important issue. OBJECTIVES: To perform a synthesis of the available literature on SCP risk factors, related risk behaviors, occupational exposures and prevention strategies. METHODS: Literature search on PubMed from the following equation: "cancer [Tiab] AND young adult [Tiab] or teen [Tiab] or childhood [Tiab] AND prevention [Tiab] AND survivors [Mesh term]". RESULTS: Twenty-seven articles were included in this synthesis. Children, adolescents and young adults have similar risk behaviors than those of their peers regarding tobacco, diet and sun exposure; however, they have lower physical activity. There are few studies on prevention strategies focused on this population. Results of available studies remain inconclusive. No publication was found in relation to occupational exposure and risk of second cancer. CONCLUSIONS: Children, adolescents and young adults treated for cancer are a population at risk and require long-term follow-up and the implementation of effective prevention strategies tailored to this population. PMID- 25936991 TI - Mitogen-activated protein kinase mediates mevalonate-stimulated human mesangial cell proliferation. AB - The metabolic products of intracellular mevalonate (MVA) are important for the growth of eukaryotic cells. These products include cholesterol and several non sterol isoprenoids. It has been reported that 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitors ameliorate glomerular injury in several experimental models of progressive glomerular disease by inhibiting the production of MVA and its metabolites. However, the mechanisms by which MVA stimulates the growth of human mesangial cells (HMCs) remain to be elucidated. To investigate the role of MVA in HMC proliferation, apoptosis, cell cycle and accumulation of extracellular matrix (ECM), the effects of MVA on HMCs at different durations and at various doses were evaluated. To examine the mechanisms of the effects of MVA on HMCs, the cells were treated with MVA, with or without PD98059, an extracellular signal regulated kinase (ERK) inhibitor, SP600125, c-Jun NH2-teminal kinase (JNK) inhibitor, or SB203580, a P38 mitogen-activated protein kinase (MAPK) inhibitor. A 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyl tetrazolium bromide reduction assay was used to measure the proliferation of the HMCs, a flow cytometric assay was used to assess the proliferative index, and an ELISA was performed to determine the expression of transforming growth factor-beta1 (TGF-beta1), Type IV and Type I collagen (Col-IV and Col-I). The expression of B-cell lymphoma 2 (Bcl-2), Bcl-2 associated X protein (Bax), phosphorylated (p)-ERK1/2, p-JNK and p-p38 were also examined using western blot analysis. MVA significantly stimulated HMC proliferation and markedly increased the secretion of TGF-beta1 and expression levels of Col-IV and Col-I. In addition, treatment with MVA significantly upregulated the expression of Bcl-2 and suppressed the expression of Bax in the HMCs. These responses were partially inhibited by the addition of inhibitors of ERK or JNK, however, they were not inhibited by the p38 MAPK inhibitor. These results demonstrated that MVA promoted HMC proliferation and ECM protein expression, which were associated with an increase in the expression of TGF-beta1 and the inhibition of apoptosis. These effects were mediated, at least in part, by the JNK and ERK pathways. PMID- 25936992 TI - Start codon targeted (SCoT) and target region amplification polymorphism (TRAP) for evaluating the genetic relationship of Dendrobium species. AB - Two molecular marker systems, start codon targeted (SCoT) and target region amplification polymorphism (TRAP), were used for genetic relationship analysis of 36 Dendrobium species collected from China. Twenty-two selected SCoT primers produced 337 loci, of which 324 (96%) were polymorphic, whereas 13 TRAP primer combinations produced a total of 510 loci, with 500 (97.8%) of them being polymorphic. An average polymorphism information content of 0.953 and 0.983 was detected using the SCoT and TRAP primers, respectively, showing that a high degree of genetic diversity exists among Chinese Dendrobium species. The partition of clusters in the unweighted pair group method with arithmetic mean dendrogram and principal coordinate analysis plot based on the SCoT and TRAP markers was similar and clustered the 36 Dendrobium species into four main groups. Our results will provide useful information for resource protection and will also be useful to improve the current Dendrobium breeding programs. Our results also demonstrate that SCoT and TRAP markers are informative and can be used to evaluate genetic relationships between Dendrobium species. PMID- 25936993 TI - Muscle LIM Protein: Master regulator of cardiac and skeletal muscle functions. AB - Muscle LIM Protein (MLP) has emerged as a key regulator of striated muscle physiology and pathophysiology. Mutations in cysteine and glycine-rich protein 3 (CSRP3), the gene encoding MLP, are causative of human cardiomyopathies, whereas altered expression patterns are observed in human failing heart and skeletal myopathies. In vitro and in vivo evidences reveal a complex and diverse functional role of MLP in striated muscle, which is determined by its multiple interacting partners and subcellular distribution. Experimental evidence suggests that MLP is implicated in both myogenic differentiation and myocyte cytoarchitecture, although the full spectrum of its intracellular roles still unfolds. PMID- 25936994 TI - Alpha-thalassemia X-linked intellectual disability syndrome identified by whole exome sequencing in two boys with white matter changes and developmental retardation. AB - Alpha-thalassemia X-linked intellectual disability (ATRX) syndrome is a genetic syndrome caused by mutation of the ATRX gene associated with chromatin remodeling. Recently, a wide spectrum of brain MRI abnormalities and clinical manifestations has been recognized. We describe two male patients with genetically confirmed ATRX syndrome, both presented with developmental delay and white matter changes without typical clinical characteristics of ATRX. Whole exome sequencing revealed the presence of ATRX mutations: a novel c.6472A>G mutation in Case 1 and a previously reported c.6532C>T mutation in Case 2. These two cases expanded the genetic and clinical spectrum of ATRX syndrome, including brain MRI abnormalities. Our results suggest that male patients with developmental delay and widespread white matter changes, even without distinctive facial dysmorphism and hematologic abnormalities, should be suspected as ATRX syndrome. We support the clinical utility of whole-exome sequencing, particularly in ultra-rare neurological diseases with nonspecific developmental disabilities and atypical presentation. PMID- 25936995 TI - Recurrent and novel GLB1 mutations in India. AB - GM1 gangliosidosis is a lysosomal storage disorder caused by mutations in the GLB1 gene, leading to the deficiency of the enzyme beta-d-galactosidase. In this study, we report molecular findings in 50 Asian Indian families with GM1 gangliosidosis. We sequenced all the exons and flanking intronic sequences of GLB1 gene. We identified 33 different mutations (20 novel and 13 previously reported). The novel mutations include 12 missense (p.M1?, p.E129Q, p.G134R, p.L236P, p.G262E, p.L297F, p.Y331C, p.G414V, p.K493N, p.L514P, p.P597L, p.T600I), four splicing (c.246-2A>G, c.397-2A>G, c.552+1G>T, c.956-2A>G), three indels (p.R22Qfs*8, p.L24Cfs*47, p.I489Qfs*4) and one nonsense mutation (p.Q452*). Most common mutations identified in this study were c.75+2InsT (14%) and p.L337P (10%). Known mutations accounted for 67% of allele frequency in our cohort of patients, suggesting that these mutations in GLB1 are recurrent across different populations. Twenty three mutations were localized in the TIM barrel domain, beta domain 1 and beta-domain 2. In silico sequence and structure analysis of GLB1 reveal that all the novel mutations affect the function and structure of the protein. We hereby report on the largest series of patients with GM1 gangliosidosis and the first from India. PMID- 25936996 TI - Susceptibility of domestic animals to a pseudotype virus bearing RD-114 virus envelope protein. AB - Retroviral vectors are used for gene transduction into cells and have been applied to gene therapy. Retroviral vectors using envelope protein (Env) of RD 114 virus, a feline endogenous retrovirus, have been used for gene transduction. In this study, we investigated the susceptibility to RD-114 Env-pseudotyped virus in twelve domestic animals including cattle, sheep, horse, pig, dog, cat, ferret, mink, rabbit, rat, mouse, and quail. Comparison of nucleotide sequences of ASCT2 (SLC1A5), a receptor of RD-114 virus, in 10 mammalian and 2 avian species revealed that insertion and deletion events at the region C of ASCT2 where RD-114 viral Env interacts occurred independently in the mouse and rat lineage and in the chicken and quail lineage. By the pseudotype virus infection assay, we found that RD-114 Env-pseudotyped virus could efficiently infect all cell lines except those from mouse and rat. Furthermore, we confirmed that bovine ASCT2 (bASCT2) functions as a receptor for RD-114 virus infection. We also investigated bASCT2 mRNA expression in cattle tissues and found that it is expressed in various tissues including lung, spleen and kidney. These results indicate that retrovirus vectors with RD-114 virus Env can be used for gene therapy in large domestic animals in addition to companion animals such as cat and dog. PMID- 25936997 TI - Experiences, Functioning and Needs of Low-Income African American Mothers of Children With Asthma. AB - The purpose of this proposed study was to explore experiences, needs and functioning of low-income, African American caregivers of children with asthma in order to better understand symptom management. METHOD: A qualitative, descriptive design was used. A purposive sampling technique was used to screen 32 caregivers of children with asthma, and 15 caregivers agreed to participate. RESULTS: Three main themes were identified: managing the symptoms; cultural beliefs and values; and culturally competent health care provider. CONCLUSION: For the caregivers culture disparity is not just about access to health services but instead the healthcare providers' understanding of the complexity of symptoms management. PMID- 25936998 TI - Factors Associated with Asthma Self-Management in African American Adolescents. AB - Few studies have focused on asthma self-management in African American adolescents, a group with high rates of the disease. This study examined factors associated with asthma self-management in 133 African Americans aged 14-16 years including gender, asthma impairment, prior asthma education, cognitive and emotional illness representations. Twenty-five percent of the variance in asthma self-management was explained by having attended an asthma education program, perceiving more asthma consequences (illness consequences), and reporting greater understanding of asthma as an illness (illness coherence). Findings suggest that these variables may be important targets of interventions to improve asthma self management in African American middle adolescents. PMID- 25936999 TI - Downregulated microRNA-510-5p acts as a tumor suppressor in renal cell carcinoma. AB - MicroRNA (miR)-510-5p has been demonstrated to be involved in a number of types of malignancy; however, the function of miR-510-5p in renal cancer remains unclear. The present study aimed to determine the expression of miR-510-5p in renal cell carcinoma (RCC) specimens and analyzed the impact of miR-510-5p on renal cancer by 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide, wound scratch and apoptosis assays. The results showed that miR-510-5p was significantly downregulated in RCC specimens compared with normal renal specimens. Overexpression of miR-510-5p by synthetic mature mimics reduced cell proliferation and migration and induced an increase in cell apoptosis, indicating that miR-510-5p may act as a tumor suppressor in RCC. The present study firstly revealed that downregulated miR-510-5p functioned as a tumor suppressor by reducing cellular proliferation and migration, and inducing apoptosis in RCC. Further research is required to define target genes of miR-510-5p to determine the cellular mechanism of miR-510-5p in the carcinogenesis of RCC. PMID- 25937000 TI - Whole-genome sequencing in critically ill infants and emerging ethical challenges. PMID- 25937002 TI - Absent organs--present selves: exploring embodiment and gender identity in young Norwegian women's accounts of hysterectomy. AB - In this paper, we explore how younger women in Norway construct their embodiment and sense of self after hysterectomy. To do this, we conducted in-depth interviews with eight ethnic Norwegian women aged between 25 and 43 who had undergone hysterectomy. In line with a broad phenomenological approach to illness, the study was designed to explore the trajectories of the women's illness with a specific focus on concrete human experience and identity claims from a subjective point of view. In analysing the stories, we encountered feelings of suffering due to the loss of the uterus as well as profound side effects, such as menopause. However, we also found evidence of relief from being treated for heavy bleeding and serious illness. In order to accentuate the individual voices in these illness stories, we chose a case-oriented analysis in line with Radley and Chamberlain (2001) and Riessman (2008). From this, two main seemingly contradictory storylines stood out: They have removed what made me a woman versus Without a uterus, I feel more like a woman. We also identified heteronormativity as an unstated issue in both these storylines and in the research data as a whole. Acknowledging diversity in the way women experience hysterectomy is important for a better understanding of the ways in which hysterectomy may affect women as humans as well as for developing more cultural competent healthcare services for this group. PMID- 25937001 TI - Whole-genome sequencing for identification of Mendelian disorders in critically ill infants: a retrospective analysis of diagnostic and clinical findings. AB - BACKGROUND: Genetic disorders and congenital anomalies are the leading causes of infant mortality. Diagnosis of most genetic diseases in neonatal and paediatric intensive care units (NICU and PICU) is not sufficiently timely to guide acute clinical management. We used rapid whole-genome sequencing (STATseq) in a level 4 NICU and PICU to assess the rate and types of molecular diagnoses, and the prevalence, types, and effect of diagnoses that are likely to change medical management in critically ill infants. METHODS: We did a retrospective comparison of STATseq and standard genetic testing in a case series from the NICU and PICU of a large children's hospital between Nov 11, 2011, and Oct 1, 2014. The participants were families with an infant younger than 4 months with an acute illness of suspected genetic cause. The intervention was STATseq of trios (both parents and their affected infant). The main measures were the diagnostic rate, time to diagnosis, and rate of change in management after standard genetic testing and STATseq. FINDINGS: 20 (57%) of 35 infants were diagnosed with a genetic disease by use of STATseq and three (9%) of 32 by use of standard genetic testing (p=0.0002). Median time to genome analysis was 5 days (range 3-153) and median time to STATseq report was 23 days (5-912). 13 (65%) of 20 STATseq diagnoses were associated with de-novo mutations. Acute clinical usefulness was noted in 13 (65%) of 20 infants with a STATseq diagnosis, four (20%) had diagnoses with strongly favourable effects on management, and six (30%) were started on palliative care. 120-day mortality was 57% (12 of 21) in infants with a genetic diagnosis. INTERPRETATION: In selected acutely ill infants, STATseq had a high rate of diagnosis of genetic disorders. Most diagnoses altered the management of infants in the NICU or PICU. The very high infant mortality rate indicates a substantial need for rapid genomic diagnoses to be allied with a novel framework for precision medicine for infants in NICU and PICU who are diagnosed with genetic diseases to improve outcomes. FUNDING: Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Human Genome Research Institute, and National Center for Advancing Translational Sciences. PMID- 25937003 TI - Polymers modified with double-tailed fluorous compounds for efficient DNA and siRNA delivery. AB - Cationic polymers are widely used as gene carriers, however, these polymers are usually associated with low transfection efficacy and non-negligible toxicity. Fluorination on polymers significantly improves their performances in gene delivery, but a high density of fluorous chains must be conjugated on a single polymer. Here we present a new strategy to construct fluorinated polymers with minimal fluorous chains for efficient DNA and siRNA delivery. A double-tailed fluorous compound 2-chloro-4,6-bis[(perfluorohexyl)propyloxy]-1,3,5-triazine (CBT) was conjugated on dendrimers of different generations and low molecular weight polyethylenimine via a facile synthesis. The yielding products with average numbers of 1-2 conjugated CBT moieties showed much improved EGFP and luciferase transfection efficacy compared to unmodified polymers. In addition, these polymers show high siRNA delivery efficacy on different cell lines. Among the synthesized polymers, generation 1 (G1) dendrimer modified with an average number of 1.9 CBT moieties (G1-CBT1.9) shows the highest efficacy when delivering both DNA and siRNA and its efficacy approaches that of Lipofectamine 2000. G1 CBT1.9 also shows efficient gene silencing in vivo. All of the CBT-modified polymers exhibit minimal toxicity on the cells at their optimal transfection conditions. This study provides a new strategy to design efficient fluorous polymers for DNA and siRNA delivery. PMID- 25937004 TI - Long-term NMDA receptor inhibition affects NMDA receptor expression and alters glutamatergic activity in developing rat hippocampal neurons. AB - Ketamine and its stereoisomer S(+)-ketamine are widely used for sedation in pediatric anesthesia and intensive care medicine. Numerous experimental studies indicate that ketamine is potentially toxic to the developing brain. Here, we examined the long-term effects of NMDA receptor blockade on NMDA receptor subunit expression, alterations in neuronal Ca(2+)-oscillations and apoptosis. Hippocampal neurons, 15 days in culture, were exposed to either S(+)-ketamine or the NMDA receptor blocker MK801 for 24h. Cytosolic Ca(2+)-concentration was determined by fluorescence microscopy and the expression of the NMDA subunits NR1, NR2A and 2B was assessed by qRT-PCR, whereas Western blots and activated Caspase-3 served to measure the extent of apoptosis. Long-term incubation with MK801 or higher doses of S(+)-ketamine resulted in a dose-dependent decreased ability of MK801 to reduce amplitude and frequency of the Ca(2+)-oscillations 15min following washout of the drug. This was accompanied by an increase in NR1 mRNA but not the NR2A and B subunit expression at the same time point. 24h following washout of the specific drug, a significant elevation of the pro apoptotic marker BAX, as well as activated Caspase-3 positive neurons, could be detected in cultures exposed to 100MUM MK801 and 25MUM S(+)-ketamine. Here, we show that long-term blockade of the NMDA receptor in developing rat hippocampal neurons significantly increased NR1 subunit expression, and that this was associated with an alteration in neuronal activity. Apoptosis was only induced 24h after withdrawal of long-term blockade for high doses of S(+)-ketamine. PMID- 25937005 TI - Concise synthesis of the core structures of saundersiosides. AB - A divergent synthesis of three core pentacyclic lactones of nine rearranged cholestane sapogenins, saundersiosides A-H (1-8) and candicanoside A (9), is reported. Key features include a one-flask CBS reduction/Brown hydroboration oxidation, a SmI2-mediated intramolecular Reformatskii reaction, and an intramolecular transesterification. This synthesis provides a general strategy and key precursors for the collective synthesis of natural and designed saundersiosides. An efficient formal synthesis of candicanoside A is also achieved. PMID- 25937006 TI - Eye lens exposure to medical staff during endoscopic retrograde cholangiopancreatography. AB - The paper presents a study of the radiation doses to eye lens of medical staff during endoscopic retrograde cholangiopancreatography (ERCP) procedures performed in a busy gastroenterology department. For each procedure the dose equivalent to the eye, exposure time, dose rate, Kerma Area Product and fluoroscopy time were recorded. Measurements were performed for a period of two months in four main positions of the operating staff, and then extrapolated to estimate annual doses. The fluoroscopy time per ERCP procedure varied between 1.0 min and 28.8 min, with a mean value of 4.6 min. The calculated mean eye dose per procedure varied between 34.9 MUSv and 93.3 MUSv. The results demonstrated that if eye protection is not used, annual doses to the eye lens of the gastroenterologist performing the procedure and the anesthesiologist can exceed the dose limit of 20 mSv per year. PMID- 25937007 TI - Microbeam radiosurgery: An industrial perspective. AB - In spite of its long demonstrated potential, microbeam radiosurgery (MBRS) has yet to be developed into a clinical tool. This article examines the problems associated with MBRS, and potential solutions. It is shown that a path to a clinically useful device is emerging. PMID- 25937008 TI - Synthesis of new thiazolylmethoxyphenyl pyrimidines and antihyperglycemic evaluation of the pyrimidines, analogues isoxazolines and pyrazolines. AB - New thiazolylmethoxyphenyl pyrimidines (7a-g) have been conveniently synthesized with better yields by cyclocondensing 3-(4-((2-phenylthiazol-4-yl)methoxy)phenyl) 1-(4-substituted phenyl)prop-2-en-1-ones (4a-g) with thiourea in aqueous emulsion of tetradecyltrimethylammonium bromide (TTAB) at 80 degrees C. Antihyperglycemic activity of the new thiazolylmethoxyphenyl pyrimidines (7a-d), thiazolylmethoxyphenyl pyrazolines (5a-d) and thiazolylmethoxyphenyl isoxazolines (6a-d) has been evaluated in sucrose loaded rat model. Among these compounds; 5a, 5c, 6b, 7c and 7d have displayed noticeable antihyperglycemic activity. Pyrimidines and pyrazolines have displayed better antihyperglycemic activity than the analogues isoxazolines. PMID- 25937009 TI - Effect of L-cysteine on the oxidation of cyclohexane catalyzed by manganeseporphyrin. AB - Effect of L-cysteine as the cocatalyst on the oxidation of cyclohexane by tert butylhydroperoxide (TBHP) catalyzed by manganese tetraphenylporphyrin (MnTPP) has been investigated. The results showed that L-cysteine could moderately improve the catalytic activity of MnTPP and significantly increase the selectivity of cyclohexanol. Different from imidazole and pyridine, the L-cysteine may perform dual roles in the catalytic oxidation of cyclohexane. Besides as the axial ligand for MnTPP, the L-cysteine could also react with cyclohexyl peroxide formed as the intermediate to produce alcohol as the main product. PMID- 25937011 TI - Synthesis and QSAR study of novel anti-inflammatory active mesalazine metronidazole conjugates. AB - Novel, mesalazine, metronidazole conjugates 6a-e with amino acid linkers were synthesized utilizing benzotriazole chemistry. Biological data acquired for all the novel bis-conjugates showed (a) some bis-conjugates exhibit comparable anti inflammatory activity with parent drugs and (b) the potent bis-conjugates show no visible stomach lesions. 3D-pharmacophore and 2D-QSAR modeling support the observed bio-properties. PMID- 25937010 TI - Non-electrophilic modulators of the canonical Keap1/Nrf2 pathway. AB - Nrf2 is the major transcription factor that regulates many of the cytoprotective enzymes involved in the adaptive stress response. Modulation of Nrf2 could be therapeutically useful in a number of disease states. Activation can occur through either an electrophilic or non-electrophilic mechanism. To date, most of the research has focused on electrophilic Nrf2 activators, but there is increasing interest in non-electrophilic modulators of Nrf2. This Digest examines the current selection of small molecules that modulate Nrf2 through non electrophilic mechanisms, and it highlights new opportunities for this important therapeutic target. PMID- 25937012 TI - De novo design of caseinolytic protein proteases inhibitors based on pharmacophore and 2D molecular fingerprints. AB - Caseinolytic protein proteases (ClpP) are large oligomeric protein complexes that contribute to cell homeostasis as well as virulence regulation in bacteria. Inhibitors of ClpP can significantly attenuate the capability to produce virulence factors of the bacteria. In this work, we developed a workflow to expand the chemical space of potential ClpP inhibitors based on a set of beta lactones. In our workflow, an artificial pharmacophore model was generated based on HipHop and HYPOGEN method. A de novo compound library based on molecular fingerprints was constructed and virtually screened by the pharmacophore model. The results were further investigated by molecular docking study. The workflow successfully achieved potential ClpP inhibitors. It could be applied to design more novel potential ClpP inhibitors and provide theoretical basis for the further optimization of the hit compounds. PMID- 25937013 TI - Rapid development of two factor IXa inhibitors from hit to lead. AB - Two high-throughput screening hits were investigated for SAR against human factor IXa. Both hits feature a benzamide linked to a [6-5]-heteroaryl via an alkyl amine. In the case where this system is a benzimidazolyl-ethyl amine the binding potency for the hit was improved >500-fold, from 9 MUM to 0.016 MUM. For the other hit, which contains a tetrahydropyrido-indazole amine, potency was improved 20-fold, from 2 MUM to 0.09 MUM. X-ray crystal structures were obtained for an example of each class which improved understanding of the binding, and will enable further drug discovery efforts. PMID- 25937014 TI - 2,6,9-Trisubstituted purines as CRK3 kinase inhibitors with antileishmanial activity in vitro. AB - Here we describe the leishmanicidal activities of a library of 2,6,9 trisubstituted purines that were screened for interaction with Cdc2-related protein kinase 3 (CRK3) and subsequently for activity against parasitic Leishmania species. The most active compound inhibited recombinant CRK3 with an IC50 value of 162 nM and was active against Leishmania major and Leishmania donovani at low micromolar concentrations in vitro. Its mode of binding to CRK3 was investigated by molecular docking using a homology model. PMID- 25937015 TI - Cyclopropyl-containing positive allosteric modulators of metabotropic glutamate receptor subtype 5. AB - Positive allosteric modulators (PAMs) binding to the transmembrane (TM) domain of metabotropic glutamate receptor 5 (mGluR5) are promising therapeutic agents for psychiatric disorders and traumatic brain injury (TBI). Novel PAMs based on a trans-2-phenylcyclopropane amide scaffold have been designed and synthesized. Facilitating ligand design and allowing estimation of binding affinities to the mGluR5 TM domain was the novel computational strategy, site identification by ligand competitive saturation (SILCS). The potential protective activity of the new compounds was evaluated using nitric oxide (NO) production in BV2 microglial cell cultures treated with lipopolysaccharide (LPS), and the toxicity of the new compounds tested using a cell viability assay. One of the new compounds, 3a, indicated promising activity with potency of 30 MUM, which is 4.5-fold more potent than its lead compound 3,3'-difluorobenzaldazine (DFB), and showed no detectable toxicity with concentrations as high as 1000 MUM. Thus this compound represents a new lead for possible development as treatment for TBI and related neurodegenerative disorders. PMID- 25937016 TI - alpha-Substituted 2-(3-fluoro-4-methylsulfonamidophenyl)acetamides as potent TRPV1 antagonists. AB - A series of alpha-substituted acetamide derivatives of previously reported 2-(3 fluoro-4-methylsulfonamidophenyl)propanamide leads (1, 2) were investigated for antagonism of hTRPV1 activation by capsaicin. Compound 34, which possesses an alpha-m-tolyl substituent, showed highly potent and selective antagonism of capsaicin with Ki(CAP)=0.1 nM. It thus reflected a 3-fold improvement in potency over parent 1. Docking analysis using our homology model indicated that the high potency of 34 might be attributed to a specific hydrophobic interaction of the m tolyl group with the receptor. PMID- 25937017 TI - Pyridine hydroxamic acids are specific anti-HCV agents affecting HDAC6. AB - Recently we reported benzohydroxamic acids (BHAs) as potent and selective inhibitors of hepatitis C virus (HCV) replicon propagation. In this work 12 pyridine hydroxamic acids (PHAs) were synthesized and tested in full-genome replicon assay. It was found that PHAs possessed very similar anti-HCV properties compared to BHAs. Both classes of hydroxamic acids caused hyperacetylation of alpha-tubulin pointing to inhibition of histone deacetylase 6 (HDAC6) as part of their antiviral activity. The tested compounds did not inhibit the growth of poliovirus, displaying high selectivity against HCV. PMID- 25937018 TI - Inflammatory cytokine expression following the use of bipolar electrocoagulation, ultracision harmonic scalpel and cold knife biopsy. AB - Electrical surgical devices may determine tissue damage through lateral thermal spread and activation of inflammatory processes. Several tissue effects are associated with the use of different surgical instruments. The aim of the present study was to compare tissue damage following the application of cold knife biopsy, bipolar electrocoagulation and the ultracision harmonic scalpel, through the analysis of inflammatory gene mediator expression. Three fragments of the round ligament (length 0.5 cm) were obtained from 22 females who had undergone total or subtotal laparoscopic hysterectomy using three different modes of resection: Cold knife biopsy, bipolar electrocoagulation and ultracision harmonic scalpel. The tissue fragments were examined by quantitative polymerase chain reaction (qPCR) analysis of selected cytokines. Gene expression analysis demonstrated large standard deviations due to individual variability among patients and indicated variability in the concentrations of cytokines in the three different samples. The quantity of cytokine mRNA in the cold knife biopsy samples was generally greater than those obtained by other techniques. Tumor necrosis factor-alpha expression was significantly higher in the sample obtained with the ultracision harmonic scalpel and bipolar electrocoagulation (P=0.033) when compared with cold knife biopsy. The inflammatory response was analyzed by the quantification of gene expression through the use of qPCR. The ultracision harmonic scalpel and bipolar electrocoagulation triggered the inflammatory cascade and resulted in an increased production of cytokines compared with cold knife biopsy. PMID- 25937019 TI - Development and Validation of the Guide for Effective Nutrition Interventions and Education (GENIE): A Tool for Assessing the Quality of Proposed Nutrition Education Programs. AB - OBJECTIVE: To develop and validate the Guide for Effective Nutrition Interventions and Education (GENIE), a checklist of research-based quality indicators for nutrition education programs. DESIGN: A prospective test of criterion validity and inter-rater reliability of a new tool comparing expert assessments and trained reviewer GENIE scores of the same nutrition education proposals. PARTICIPANTS: Ten nutrition education experts; 13 volunteer reviewers. VARIABLES MEASURED: GENIE's face, content, and criterion validity and inter-rater reliability compared using expert assessments and reviewer objective and subjective scores. ANALYSIS: Reviewer scores compared using Spearman correlation. Inter-rater reliability tested using intra-class correlation (ICC), Cronbach alpha, and ANOVA. Criterion validity tested using independent t test and point bi serial correlation to compare reviewer with expert scores. RESULTS: Correlation found between total objective and total subjective scores. Agreement found between reviewers across proposals and categories considering subjective scores (F = 7.21, P < .001; ICC = 0.76 [confidence interval, 0.53-0.92]) and objective scores (F = 7.88, P < .001; ICC = 0.82 [confidence interval, 0.63-0.94]). Relationship was not significant (r = .564, P = .06) between expert and reviewer proposal scoring groups (high, medium, and low). CONCLUSIONS AND IMPLICATIONS: Results support the validity and reliability of GENIE as a tool for nutrition education practitioners, researchers, and program funding agencies to accurately assess the quality of a variety of nutrition program plans. PMID- 25937020 TI - Subacromial-Subdeltoid Bursal Rice Bodies Causing Shoulder Pain. PMID- 25937021 TI - Effect of Hypertonic Saline in Intra-Articular Hydraulic Distension for Adhesive Capsulitis. AB - BACKGROUND: Maintaining the integrity of the capsule along with infusing a sufficient amount of fluid is 1 of the therapeutic concepts in intra-articular hydraulic distension (IHD) for adhesive capsulitis. It has been known that hypertonic saline solution decreases tissue edema and increases the fluid volume within the epidural space, causing microdissection, in epidural adhesiolysis. OBJECTIVE: To investigate the effect of hypertonic saline solution in capsule preserving intra-articular hydraulic distension (CPIHD) for adhesive capsulitis. DESIGN: Prospective randomized controlled trial. SETTING: University outpatient clinic of physical medicine and rehabilitation. PARTICIPANTS: A total of 64 patients who were diagnosed as adhesive capsulitis of shoulder were randomly assigned to 1 of 2 treatment groups. The hypertonic saline group was treated by CPIHD with hypertonic saline (3% NaCl), and the normal saline group with normal saline solution (0.9% NaCl). METHODS: Both groups were treated with CPIHD, a method that preserves the capsule with maximal distension without inducing capsule rupture. The volume of saline solution necessary to adequately distend the capsule was recorded. Injection materials contained 4 mL of 1% lidocaine, 1 mL of triamcinolone (10 mg), and saline solution (hypertonic or normal saline). The intra-articular injection was monitored with ultrasound to maximize the infused volume while preserving the capsule. MAIN OUTCOME MEASUREMENTS: The Shoulder Pain and Disability Index (SPADI) and shoulder passive range of motion (PROM) was measured before the procedure and 2 weeks after CPIHD. RESULTS: The mean CPIHD volume was 20.2 +/- 5.2 mL for the hypertonic saline group and 19.5 +/ 5.9 mL for the normal saline group. The hypertonic saline group showed statistically significant improvement in shoulder PROM and SPADI score compared with the normal saline group. Side effects such as soreness or complications related to injection were not reported. CONCLUSIONS: Our results suggest that CPIHD with hypertonic saline solution is more effective than that using normal saline solution in patients with adhesive capsulitis. PMID- 25937022 TI - Stigma and discrimination related to mental illness in low- and middle-income countries. AB - AIMS: This paper aims to provide an overview of evidence from low- and middle income countries (LAMICs) worldwide to address: the nature of stigma and discrimination, relevant context-specific factors, global patterns of these phenomena and their measurement and quantitative and qualitative evidence of interventions intended to reduce their occurrence and impact. The background to this study is that the large majority of studies concerned with identifying effective interventions to reduce stigma and discrimination originate in high income countries (HICs). This paper therefore presents such evidence from, and relevant to, LAMICs. METHODS: Conceptual overview of the relevant peer-reviewed and grey literature on stigma and discrimination related to mental illness in LAMICs are available in English, Spanish, French and Russian. RESULTS: Few intervention studies were identified related to stigma re-education in LAMICs. None of these addressed behaviour change/discrimination, and there were no long term follow-up studies. There is therefore insufficient evidence at present to know which overall types of intervention may be effective and feasible and in LAMICs, how best to target key groups such as healthcare staff, and how far they may need to be locally customised to be acceptable for large-scale use in these settings. In particular, forms of social contacts, which have been shown to be the most effective intervention to reduce stigma among adults in HICs, have not yet been assessed sufficiently to know whether these methods are also effective in LAMICs. CONCLUSION: Generating information about effective interventions to reduce stigma and discrimination in LAMICs is now an important mental health priority worldwide. PMID- 25937023 TI - On the Use of Meta-analysis in Neuromodulatory Non-invasive Brain Stimulation. PMID- 25937024 TI - The efficacy of 12 weeks non-surgical treatment for patients not eligible for total knee replacement: a randomized controlled trial with 1-year follow-up. AB - OBJECTIVE: To compare the efficacy of a 12-week non-surgical treatment program with usual care in patients with knee osteoarthritis (OA) not eligible for total knee replacement (TKR). METHOD: This two-arm parallel group assessor-blinded randomized controlled trial (RCT) included 100 adults from secondary care with knee OA, confirmed by radiography (Kellgren-Lawrence grade >=1), but not eligible for a TKR. The 12-week non-surgical treatment program consisted of individualized progressed neuromuscular exercise, patient education, insoles, dietary advice and prescription of pain medication if indicated, while usual care comprised two leaflets with information and advice on knee OA and recommended treatments. The primary outcome was the change from baseline to 12 months in the Knee injury and Osteoarthritis Outcome Score (KOOS)4 defined as the average score for the KOOS subscales of pain, symptoms, activities of daily living (ADL), and quality of life (QOL). RESULTS: 91% of the patients completed the 12 months follow-up on the primary outcome. Compared with usual care, patients undergoing the treatment program improved more in KOOS4 (adjusted mean difference (95% CI) of 9.6 (4.4 14.8)) with no serious treatment-related adverse events (AE). The number needed to treat (NNT), defined as the number of patients needed to treat for one person to improve 15% was 7.2. Secondary outcomes supported the primary findings. CONCLUSION: In patients with mostly moderate to severe knee OA not eligible for TKR, a 12-week individualized, non-surgical treatment program is more efficacious at 12 months compared with usual care and has few treatment-related AE. TRIAL REGISTRATION: ClinicalTrials.gov (NCT01535001). PMID- 25937025 TI - Type II collagen C2C epitope in human synovial fluid and serum after knee injury- associations with molecular and structural markers of injury. AB - PURPOSE: Investigate in a cross-sectional study time-dependent changes of synovial fluid type II collagen epitope C2C concentrations after knee injury and correlate to other joint injury biomarkers. METHODS: Synovial fluid samples were aspirated between 0 days and 7 years after injury (n = 235). Serum was collected from 71 of the knee injured patients. Synovial fluid from 8 knee-healthy subjects was used as reference. C2C was quantified by immunoassay and structural injury was determined from magnetic resonance images (MRI) of the injured knee acquired 1-38 days after injury (n = 98). Additional joint injury biomarker results were from earlier investigations of the same samples. RESULTS: Synovial fluid C2C concentrations were higher in injured knees than in knees of reference subjects from 1 day up to 7 years after injury. C2C concentrations in synovial fluid and serum were correlated (r = 0.403, P < 0.001). In synovial fluid from subjects early after injury (0-33 days), C2C concentrations were correlated with cross linked C-telopeptide of type II collagen (r = 0.444, P = 0.003), ARGS-aggrecan (r = 0.337, P < 0.001), osteocalcin (r = 0.345, P < 0.001), osteopontin (r = 0.371, P < 0.001) and IL-8 (r = -0.385, P < 0.001), but not with structural joint injury as visualized on MRI. CONCLUSION: The increased levels of synovial fluid C2C after injury, together with the associations seen with several other injury related biomarkers, suggest that an acute knee injury is associated with an immediate and sustained local degradation of type II collagen. PMID- 25937026 TI - Racial differences in biochemical knee cartilage composition between African American and Caucasian-American women with 3 T MR-based T2 relaxation time measurements--data from the Osteoarthritis Initiative. AB - OBJECTIVE: To determine whether knee cartilage composition differs between African-American and Caucasian-American women at risk for Osteoarthritis (OA) using in vivo 3 T MRI T2 relaxation time measurements. METHODS: Right knee MRI studies of 200 subjects (100 African-American women, and 100 closely matched Caucasian-American women) were selected from the Osteoarthritis Initiative (OAI). Knee cartilage was segmented in the patellar (PAT), medial and lateral femoral (MF/LF), and medial and lateral tibial compartments (MT/LT)). Mean T2 relaxation time values per compartment and per whole joint cartilage were generated and analyzed spatially via laminar and grey-level co-occurrence matrix (GLCM) texture methods. Presence and severity of cartilage lesions per compartment were graded using a modified WORMS grading. Statistical analysis employed paired t- and McNemar testing. RESULTS: While African-American women and Caucasian-Americans had similar WORMS cartilage lesion scores (P = 0.970), African-Americans showed significantly lower mean T2 values (~1 ms difference; ~0.5SD) than Caucasian Americans in the whole knee cartilage (P < 0.001), and in the subcompartments (LF: P = 0.001, MF: P < 0.001, LT: P = 0.019, MT: P = 0.001) and particularly in the superficial cartilage layer (whole cartilage: P < 0.001, LF: P < 0.001, MF: P < 0.001, LT: P = 0.003, MT: P < 0.001). T2 texture parameters were also significantly lower in the whole joint cartilage of African-Americans than in Caucasian-Americans (variance: P = 0.001; contrast: P = 0.018). In analyses limited to matched pairs with no cartilage lesions in a given compartment, T2 values remained significantly lower in African-Americans. CONCLUSION: Using T2 relaxation time as a biomarker for the cartilage collagen network, our findings suggest racial differences in the biochemical knee cartilage composition between African-American and Caucasian-American women. PMID- 25937027 TI - Heparin-binding epidermal growth factor-like growth factor (HB-EGF) is increased in osteoarthritis and regulates chondrocyte catabolic and anabolic activities. AB - OBJECTIVE: We determined if the epidermal growth factor receptor ligand HB-EGF is produced in cartilage and if it regulates chondrocyte anabolic or catabolic activity. METHODS: HB-EGF expression was measured by quantitative PCR using RNA isolated from mouse knee joint tissues and from normal and osteoarthritis (OA) human chondrocytes. Immunohistochemistry was performed on normal and OA human cartilage and meniscus sections. Cultured chondrocytes were treated with fibronectin fragments (FN-f) as a catabolic stimulus and osteogenic protein 1 (OP 1) as an anabolic stimulus. Effects of HB-EGF on cell signaling were analyzed by immunoblotting of selected signaling proteins. MMP-13 was measured in conditioned media, proteoglycan synthesis was measured by sulfate incorporation, and matrix gene expression by quantitative PCR. RESULTS: HB-EGF expression was increased in 12-month old mice at 8 weeks after surgery to induce OA and increased amounts of HB-EGF were noted in human articular cartilage from OA knees. FN-f stimulated chondrocyte HB-EGF expression and HB-EGF stimulated chondrocyte MMP-13 production. However, HB-EGF was not required for FN-f stimulation of MMP-13 production. HB-EGF activated the ERK and p38 MAP kinases and stimulated phosphorylation of Smad1 at an inhibitory serine site which was associated with inhibition of OP-1 mediated proteoglycan synthesis and reduced aggrecan (ACAN) but not COL2A1 expression. CONCLUSION: HB-EGF is a new factor identified in OA cartilage that promotes chondrocyte catabolic activity while inhibiting anabolic activity suggesting it could contribute to the catabolic-anabolic imbalance seen in OA cartilage. PMID- 25937028 TI - The type 2 cannabinoid receptor regulates susceptibility to osteoarthritis in mice. AB - OBJECTIVE: Cannabinoid receptors and their ligands have been implicated in the regulation of various physiological processes but their role in osteoarthritis has not been investigated. The aim of this study was to evaluate the role of the type 2 cannabinoid receptor (Cnr2) in regulating susceptibility to osteoarthritis in mice. METHODS: We analysed the severity of knee osteoarthritis as assessed by the Osteoarthritis Research Society International (OARSI) scoring system in mice with targeted deletion of Cnr2 (Cnr2(-/-)) and wild type (WT) littermates. Studies were conducted in mice subjected to surgical destabilisation of the medial meniscus (DMM) and in those with spontaneous age-related osteoarthritis (OA). RESULTS: Osteoarthritis was more severe following DMM in the medial compartment of the knee in Cnr2(-/-) compared with WT mice (mean +/- sem score = 4.9 +/- 0.5 vs 3.6 +/- 0.3; P = 0.017). Treatment of WT mice with the CB2 selective agonist HU308 following DMM reduced the severity of OA in the whole joint (HU308 = 8.4 +/- 0.2 vs vehicle = 10.4 +/- 0.6; P = 0.007). Spontaneous age related osteoarthritis was also more severe in the medial compartment of the knee in 12-month old Cnr2(-/-) mice compared with WT (5.6 +/- 0.5 vs 3.5 +/- 0.3, P = 0.008). Cultured articular chondrocytes from Cnr2(-/-) mice produced less proteoglycans in vitro than wild type chondrocytes. CONCLUSION: These studies demonstrate that the Cnr2 pathway plays a role in the pathophysiology of osteoarthritis in mice and shows that pharmacological activation of CB2 has a protective effect. Further studies of the role of cannabinoid receptors in the pathogenesis of osteoarthritis in man are warranted. PMID- 25937029 TI - Disulfiram sensitizes pituitary adenoma cells to temozolomide by regulating O6 methylguanine-DNA methyltransferase expression. AB - O6-methylguanine-DNA methyltransferase (MGMT) activity is responsible for temozolomide (TMZ) resistance in patients harboring aggressive pituitary adenomas. Recently, disulfiram (DSF) has been shown to induce the loss of MGMT protein and increase TMZ efficacy in glioblastoma cells, while CD133+ nestin+ cells isolated from the cell population have been implicated as pituitary adenoma stem-like cells. However, whether DSF is able to potentiate the cytotoxic effects of TMZ on human pituitary adenoma cells has not been investigated to date. In the present study, CD133+ nestin+ phenotype cells were isolated from primary cultured human pituitary adenoma cells using microbeads. It was found that DSF reduced MGMT protein expression and sensitized human pituitary adenoma cells and stem like cells to TMZ in vitro, while the proteasome inhibitor PS-341 abrogated the inhibitory effect of DSF on MGMT in vitro. The sensitizing effect of DSF was also verified in primary cultured human pituitary adenoma cells in vivo. The results of the present study suggested that DSF can increase the efficacy of the anti tumor effect of TMZ on human pituitary adenoma cells and CD133+ nestin+ stem like cells via the ubiquitin-proteasomal MGMT protein elimination route. DSF combined with TMZ may be an effective therapeutic strategy against aggressive pituitary adenomas. PMID- 25937030 TI - Development of thermosensitive chitosan/glicerophospate injectable in situ gelling solutions for potential application in intraoperative fluorescence imaging and local therapy of hepatocellular carcinoma: a preliminary study. AB - OBJECTIVES: Thermosensitive chitosan/glycerophosphate (C/GP) solutions exhibiting sol-gel transition around body temperature were prepared to develop a class of injectable hydrogel platforms for the imaging and loco-regional treatment of hepatocellular carcinoma (HCC). Indocyanine green (ICG) was loaded in the thermosensitive solutions in order to assess their potential for the detection of tumor nodules by fluorescence. METHODS: The gel formation of these formulations as well as their gelling time, injectability, compactness and resistance of gel structure, gelling temperature, storage conditions, biodegradability, and in vitro dye release behavior were investigated. Ex vivo studies were carried out for preliminary evaluation using an isolated bovine liver. RESULTS: Gel strengths and gelation rates increased with the cross-link density between C and GP. These behaviors are more evident for C/GP solutions, which displayed a gel-like precipitation at 4 degrees C. Furthermore, formulations with the lowest cross link density between C and GP exhibited the best injectability due to a lower resistance to flow. The loading of the dye did not influence the gelation rate. ICG was not released from the hydrogels because of a strong electrostatic interaction between C and ICG. Ex vivo preliminary studies revealed that these injectable formulations remain in correspondence of the injected site. CONCLUSIONS: The developed ICG-loaded hydrogels have the potential for intraoperative fluorescence imaging and local therapy of HCC as embolic agents. They form in situ compact gels and have a good potential for filling vessels and/or body cavities. PMID- 25937031 TI - Development of an International Classification of Functioning, Disability and Health (ICF)-based standard set to describe the impact of joint contractures on participation of older individuals in geriatric care settings. AB - INTRODUCTION: Joint contractures are characterized as impairment of the physiological movement of joints due to deformity, disuse or pain and have major impact especially for older individuals in geriatric care. Some measures for the assessment of the impact of joint contractures exist. However, there is no consensus on which aspects should constantly be measured. Our objective was to develop a standard-set based on the ICF for describing functioning and disability in older individuals with joint contractures in geriatric care settings, giving special emphasis to activities and participation. METHODS: The ICF-based standard set was developed in a formal decision-making and consensus process and based on an adapted version of the protocol to develop ICF Core Sets. These are sets of categories from the ICF, serving as standards for the assessment, communication and reporting of functioning and health for clinical studies, clinical encounters and multi-professional comprehensive assessment and management. RESULTS: Twenty three experts from Germany and Switzerland selected 105 categories of the ICF component Activities and Participation for the ICF-based standard set. The largest number of categories was selected from the chapter Mobility (50 categories, 47.6%). CONCLUSIONS: The standard set for older individuals with joint contractures provides health professionals with a standard for describing patients' activity limitations and participation restrictions. The standard set also provides a common basis for the development of patient-centered measures and intervention programs. The preliminary version of the ICF-based standard set will be tested in subsequent studies with regard to its psychometric properties. PMID- 25937035 TI - "Primitives" and Protected Areas: International Conservation and the "Naturalization" of Indigenous People, ca. 1910-1975. PMID- 25937032 TI - Micro and nanoparticle drug delivery systems for preventing allotransplant rejection. AB - Despite decades of advances in transplant immunology, tissue damage caused by acute allograft rejection remains the primary cause of morbidity and mortality in the transplant recipient. Moreover, the long-term sequelae of lifelong immunosuppression leaves patients at risk for developing a host of other deleterious conditions. Controlled drug delivery using micro- and nanoparticles (MNPs) is an effective way to deliver higher local doses of a given drug to specific tissues and cells while mitigating systemic effects. Herein, we review several descriptions of MNP immunotherapies aimed at prolonging allograft survival. We also discuss developments in the field of biomimetic drug delivery that use MNP constructs to induce and recruit our bodies' own suppressive immune cells. Finally, we comment on the regulatory pathway associated with these drug delivery systems. Collectively, it is our hope the studies described in this review will help to usher in a new era of immunotherapy in organ transplantation. PMID- 25937043 TI - Influences on the perception of elder financial abuse among older adults in Southern California. AB - BACKGROUND: Under-reporting of elder financial abuse is partly due to failure of those around the victim to perceive the financial mistreatment as abuse. This study explored the effect of victim and perceiver factors on perception of elder financial abuse in the context of Routine Activity Theory (RAT). METHODS: 488 older adults in Ventura County (CA) were surveyed about financial abuse using vignette method. In the study's Vignette 1, the amount of money taken, the type of frailty, and the relationship of perpetrator and victim were manipulated. In Vignette 2, the victim's age and relationship of perpetrator and victim were manipulated. Respondents' demographics (age, gender, education, and ethnicity) were collected. RESULTS: Logistic regression analyses revealed that children of the victim were least likely to be seen as committing abuse in both vignettes. In Vignette 1, there was an interaction of gender of respondent and the amount of money taken. In Vignette 2, non-Whites were less likely to perceive the signing over of the house as financial abuse. Respondents endorsed the concept of a special court with expertize in elder abuse as a way to increase the likelihood that they would report. CONCLUSIONS: Even though most financial abuse is perpetrated by family members, older adults are less likely to perceive a financial situation as abuse when it involves a child of the victim, thus making reporting and prevention less likely. The support for a specialty Elder Abuse Court (EAC) suggests that some reluctance to report is based on misgivings about punishing the perpetrator. PMID- 25937044 TI - Reprogramming the conduction system: Onward toward a biological pacemaker. AB - Diseases of the cardiac conduction system can be debilitating and deadly. Electronic pacemakers are incredibly effective in the treatment of sinus and AV node dysfunction, yet there remain important limitations and complications. These issues have driven interest in the development of a biological pacemaker. Here, we review experimental progress in animal models and discuss future directions, with a focus on reprogramming endogenous cells in the heart to treat defects of rhythm and conduction. PMID- 25937045 TI - Cardiac magnetic resonance for prediction of arrhythmogenic areas. AB - Catheter ablation has been widely used to manage recurrent atrial and ventricular arrhythmias. It has been established that contrast-enhanced magnetic resonance can accurately characterize the myocardium. In this review, we summarize the role of cardiac magnetic resonance in identification of arrhythmogenic substrates, and the potential utility of cardiac magnetic resonance for catheter ablation of complex atrial and ventricular arrhythmias. PMID- 25937047 TI - Avoiding a sticky problem: Protecting flexor tendon repair in preschool children. PMID- 25937046 TI - Risk Stratification Models: How Well do They Predict Adverse Outcomes in a Large Dutch Bariatric Cohort? AB - BACKGROUND: Risk prediction models are useful tools for informing patients undergoing bariatric surgery about their risk for complications and correcting outcome reports. The aim of this study is to externally validate risk models assessing complications after laparoscopic Roux-en-Y gastric bypass (LRYGB) surgery. METHODS: All 740 patients who underwent a primary LRYGB between December 2007 and July 2012 were included in the validation cohort. PubMed was systematically searched for risk prediction models. Eight risk models were selected for validation. We classified our complications according to the Clavien Dindo classification. Predefined criteria of a good model were a non-significant Hosmer and Lemeshow test, Nagelkerke R (2) >= 0.10, and c-statistic >=0.7. RESULTS: There were 85 (7.8 %) grade 1, 54 (7.3 %) grade 2, 5 (0.7 %) grade 3a, 14 (1.9 %) grade 3b, and 14 (1.9 %) grade 4a complications in our validation cohort. Only one model predicted adverse events satisfactorily. This model consisted of one patient-related factor (age) and four surgeon- or center related factors (conversion to open surgery, intraoperative events, the need for additional procedures during LRYGB and the learning curve of the center). CONCLUSIONS: The overall majority of the included risk models are unsuitable for risk prediction. Only one model with an emphasis on surgeon- and center-related factors instead of patient-related factors predicted adverse outcome correctly in our external validation cohort. These findings support the establishment of specialty centers and warn benchmark data institutions not to correct bariatric outcome data by any other patient-related factor than age. PMID- 25937048 TI - ROR1-targeted delivery of OSU-2S, a nonimmunosuppressive FTY720 derivative, exerts potent cytotoxicity in mantle-cell lymphoma in vitro and in vivo. AB - Mantle-cell lymphoma (MCL) remains incurable despite numerous therapeutic advances. OSU-2S, a novel nonimmunosuppressive FTY720 (Fingolimod) derivative, exhibits potent cytotoxicity in MCL cell lines and primary cells. OSU-2S increased the surface expression of CD74, a therapeutic antibody target in MCL cells. OSU-2S, in combination with anti-CD74 antibody milatuzumab, enhanced cytotoxicity in MCL. Moreover, MCL tumor antigen receptor tyrosine kinase-like orphan receptor 1 (ROR1) targeted immunonanoparticle-carrying OSU-2S (2A2-OSU-2S ILP)-mediated selective cytotoxicity of MCL in vitro, as well as activity in a xenografted mouse model of MCL in vivo. The newly developed OSU-2S delivery using ROR1-directed immunonanoparticles provide selective targeting of OSU-2S to MCL and other ROR1(+) malignancies, sparing normal B cells. PMID- 25937049 TI - Adrenomedullin optimises mortality prediction in COPD patients. AB - BACKGROUND: Current multicomponent scores that predict mortality in COPD patients might underestimate the systemic component of COPD. Therefore, we evaluated the accuracy of circulating levels of proadrenomedullin (MR-proADM) alone or combined with the ADO (Age, Dyspnoea, airflow Obstruction), updated ADO or BOD (Body mass index, airflow Obstruction, Dyspnoea) index to predict all-cause mortality in stable COPD patients. METHODS: This study pooled data of 1285 patients from the COMIC and PROMISE-COPD study. RESULTS: Patients with high MR-proADM levels (>=0.87 nmol/l) had a 2.1 fold higher risk of dying than those with lower levels (p < 0.001). Based on the C-statistic, the ADOA index (ADO plus MR-proADM) (C = 0.72) was the most accurate predictor followed by the BODA (BOD plus MR-proADM) (C = 0.71) and the updated ADOA index (updated ADO plus MR-proADM) (C = 0.70). Adding MR-proADM to ADO and BOD was superior in forecasting 1- and 2-year mortality. The net percentages of persons with events correctly reclassified (NRI+) within respectively 1-year and 2-year was 31% and 20% for ADO, 31% and 20% for updated ADO and 25% and 19% for BOD. The net percentages of persons without events correctly reclassified (NRI-) within respectively 1-year and 2-year was 26% and 27% for ADO, 27% and 28% for updated ADO and 34% and 34% for BOD. CONCLUSIONS: Adding MR-proADM increased the predictive power of BOD, ADO and updated ADO index. PMID- 25937050 TI - IL-5, IL-8 and MMP -9 levels in exhaled breath condensate of atopic and nonatopic asthmatic children. AB - RATIONALE: Asthma is a heterogeneous disease, and a great majority of pediatric patients with asthma demonstrate atopic characteristics and develop a Th2 type cytokine response. Nonatopic asthma, on the other hand, is seen more rarely. METHODS: In this study, levels of IL-5, IL-8 and MMP-9 were measured in exhaled breath condensate (EBC) of the subjects to demonstrate the extent of tissue damage as well as eosinophilic and neutrophilic inflammation in children with atopic and nonatopic asthma. A total of 37 children with atopic asthma and 37 children with nonatopic asthma were enrolled in the study. Patients who exhibited protease positive aeroallergen (House dust mite, mould mix, olea, grass mix) sensitivity in allergen skin prick test were included in the atopic asthma group. To evaluate the EBC, the fluid content of the breath was collected by having the patients exhale into an EBC device, after which the IL-5, IL-8 and MMP-9 levels were assayed using the ELISA method. RESULTS: The atopic asthmatics exhibited significantly higher IL-5 levels in their EBC samples than the nonatopic asthmatics (0.271 [0.198-0.489] pg/ml and 0.198 [0.125-0.344] pg/ml, respectively, p = 0.04), while no significant differences were observed in the levels of IL-8 and MMP-9 in the EBC samples of the atopic and nonatopic asthmatics. CONCLUSIONS: IL-5 levels, as a marker of eosinophilic inflammation, were demonstrated to be higher in the children with atopic asthma when compared to those with nonatopic asthma in EBC. The fact that no significant difference was apparent in the IL-8 levels between the groups suggests that it is the severity of the disease rather than the atopic state that plays an important role in IL-8 levels. Since no difference was recorded between the groups in terms of MMP-9 levels, lung damage in asthma sufferers seems to develop independent of atopia. PMID- 25937053 TI - Triple Threat Among the Elderly: Depression, Suicide Risk, and Handguns. PMID- 25937052 TI - Metabolic gene expression changes in astrocytes in Multiple Sclerosis cerebral cortex are indicative of immune-mediated signaling. AB - Emerging as an important correlate of neurological dysfunction in Multiple Sclerosis (MS), extended focal and diffuse gray matter abnormalities have been found and linked to clinical manifestations such as seizures, fatigue and cognitive dysfunction. To investigate possible underlying mechanisms we analyzed the molecular alterations in histopathological normal appearing cortical gray matter (NAGM) in MS. By performing a differential gene expression analysis of NAGM of control and MS cases we identified reduced transcription of astrocyte specific genes involved in the astrocyte-neuron lactate shuttle (ANLS) and the glutamate-glutamine cycle (GGC). Additional quantitative immunohistochemical analysis demonstrating a CX43 loss in MS NAGM confirmed a crucial involvement of astrocytes and emphasizes their importance in MS pathogenesis. Concurrently, a Toll-like/IL-1beta signaling expression signature was detected in MS NAGM, indicating that immune-related signaling might be responsible for the downregulation of ANLS and GGC gene expression in MS NAGM. Indeed, challenging astrocytes with immune stimuli such as IL-1beta and LPS reduced their ANLS and GGC gene expression in vitro. The detected upregulation of IL1B in MS NAGM suggests inflammasome priming. For this reason, astrocyte cultures were treated with ATP and ATP/LPS as for inflammasome activation. This treatment led to a reduction of ANLS and GGC gene expression in a comparable manner. To investigate potential sources for ANLS and GGC downregulation in MS NAGM, we first performed an adjuvant-driven stimulation of the peripheral immune system in C57Bl/6 mice in vivo. This led to similar gene expression changes in spinal cord demonstrating that peripheral immune signals might be one source for astrocytic gene expression changes in the brain. IL1B upregulation in MS NAGM itself points to a possible endogenous signaling process leading to ANLS and GGC downregulation. This is supported by our findings that, among others, MS NAGM astrocytes express inflammasome components and that astrocytes are capable to release Il-1beta in vitro. Altogether, our data suggests that immune signaling of immune- and/or central nervous system origin drives alterations in astrocytic ANLS and GGC gene regulation in the MS NAGM. Such a mechanism might underlie cortical brain dysfunctions frequently encountered in MS patients. PMID- 25937054 TI - Efficacy of cognitive-behavioral therapy for obsessive-compulsive disorder. AB - Cognitive-behavioral therapy (CBT), which encompasses exposure with response prevention (ERP) and cognitive therapy (CT), has demonstrated efficacy in the treatment of obsessive-compulsive disorder (OCD). However, the samples studied (reflecting the heterogeneity of OCD), the interventions examined (reflecting the heterogeneity of CBT), and the definitions of treatment response vary considerably across studies. This review examined the meta-analyses conducted on ERP and cognitive therapy (CT) for OCD. Also examined was the available research on long-term outcome associated with ERP and CT. The available research indicates that ERP is the first line evidence based psychotherapeutic treatment for OCD and that concurrent administration of cognitive therapy that targets specific symptom related difficulties characteristic of OCD may improve tolerance of distress, symptom-related dysfunctional beliefs, adherence to treatment, and reduce drop out. Recommendations are provided for treatment delivery for OCD in general practice and other service delivery settings. The literature suggests that ERP and CT may be delivered in a wide range of clinical settings. Although the data are not extensive, the available research suggests that treatment gains following ERP are durable. Suggestions for future research to refine therapeutic outcome are also considered. PMID- 25937051 TI - Bidirectional psychoneuroimmune interactions in the early postpartum period influence risk of postpartum depression. AB - More than 500,000 U.S. women develop postpartum depression (PPD) annually. Although psychosocial risks are known, the underlying biology remains unclear. Dysregulation of the immune inflammatory response and the hypothalamic-pituitary adrenal (HPA) axis are associated with depression in other populations. While significant research on the contribution of these systems to the development of PPD has been conducted, results have been inconclusive. This is partly because few studies have focused on whether disruption in the bidirectional and dynamic interaction between the inflammatory response and the HPA axis together influence PPD. In this study, we tested the hypothesis that disruption in the inflammatory HPA axis bidirectional relationship would increase the risk of PPD. Plasma pro- and anti-inflammatory cytokines were measured in women during the 3rd trimester of pregnancy and on Days 7 and 14, and Months 1, 2, 3, and 6 after childbirth. Saliva was collected 5 times the day preceding blood draws for determination of cortisol area under the curve (AUC) and depressive symptoms were measured using the Edinburgh Postpartum Depression Survey (EPDS). Of the 152 women who completed the EPDS, 18% were depressed according to EDPS criteria within the 6months postpartum. Cortisol AUC was higher in symptomatic women on Day 14 (p=.017). To consider the combined effects of cytokines and cortisol on predicting symptoms of PPD, a multiple logistic regression model was developed that included predictors identified in bivariate analyses to have an effect on depressive symptoms. Results indicated that family history of depression, day 14 cortisol AUC, and the day 14 IL8/IL10 ratio were significant predictors of PPD symptoms. One unit increase each in the IL8/IL10 ratio and cortisol AUC resulted in 1.50 (p=0.06) and 2.16 (p=0.02) fold increases respectively in the development of PPD. Overall, this model correctly classified 84.2% of individuals in their respective groups. Findings suggest that variability in the complex interaction between the inflammatory response and the HPA axis influence the risk of PPD. PMID- 25937055 TI - Oral magnesium supplementation improves glycaemic status in subjects with prediabetes and hypomagnesaemia: A double-blind placebo-controlled randomized trial. AB - AIM: This study evaluated the efficacy of oral magnesium supplementation in the reduction of plasma glucose levels in adults with prediabetes and hypomagnesaemia. METHODS: A total of 116 men and non-pregnant women, aged 30 to 65 years with hypomagnesaemia and newly diagnosed with prediabetes, were enrolled into a randomized double-blind placebo-controlled trial to receive either 30 mL of MgCl2 5% solution (equivalent to 382 mg of magnesium) or an inert placebo solution once daily for four months. The primary trial endpoint was the efficacy of magnesium supplementation in reducing plasma glucose levels. RESULTS: At baseline, there were no significant statistical differences in terms of anthropometric and biochemical variables between individuals in the supplement and placebo groups. At the end of follow-up, fasting (86.9 +/- 7.9 and 98.3 +/- 4.6 mg/dL, respectively; P = 0.004) and post-load glucose (124.7 +/- 33.4 and 136.7 +/- 23.9 mg/dL, respectively; P = 0.03) levels, HOMA-IR indices (2.85 +/- 1.0 and 4.1 +/- 2.7, respectively; P = 0.04) and triglycerides (166.4 +/- 90.6 and 227.0 +/- 89.7, respectively; P = 0.009) were significantly decreased, whereas HDL cholesterol (45.6 +/- 10.9 and 46.8 +/- 9.2 mg/dL, respectively; P = 0.04) and serum magnesium (1.96 +/- 0.27 and 1.60 +/- 0.26 mg/dL, respectively; P = 0.005) levels were significantly increased in those taking MgCl2 compared with the controls. A total of 34 (29.4%) people improved their glucose status (50.8% and 7.0% in the magnesium and placebo groups, respectively; P < 0.0005). CONCLUSION: Our results show that magnesium supplementation reduces plasma glucose levels, and improves the glycaemic status of adults with prediabetes and hypomagnesaemia. PMID- 25937056 TI - Antennal gustatory perception and behavioural responses in Trissolcus brochymenae females. AB - Trissolcus brochymenae (Hymenoptera: Platygastridae) is an egg parasitoid that could be used to control stink bugs like Murgantia histrionica (Heteroptera: Pentatomidae), a pest of brassicaceous crops. Before laying their eggs, parasitoid females spend considerable time examining the substrate with their antennae, which are also used during feeding and mating behaviours. This suggests that contact chemoreception plays a prominent role in many aspects of parasitoid ecology. Therefore, we examined the sensitivity of antennal taste sensilla chaetica to several classical tastants including those that are appetitive or aversive. In addition we studied the taste preferences of wasps when presented with these chemicals alone or mixed. The sensilla chaetica of T. brochymenae responded to serial concentrations of sucrose, salts, and quinine, but no concentration-dependent effect was observed when testing sinigrin, a secondary metabolite found in many brassicaceae. However, both sinigrin and quinine inhibited responses to 0.1 M sucrose when mixed with this sugar. Behavioural taste preference assays confirmed that wasps showed a dose dependent preference for sucrose over agarose. In addition, a behavioural avoidance of sucrose solutions containing quinine was observed. This effect was not observed when sinigrin was used as a feeding deterrent. In the two-choice tests the wasp did not discriminate between sucrose solutions mixed with salts and sucrose alone. Further no preference for salts or sinigrin compared to agarose alone was observed. This work represents the first step towards the identification of gustatory receptor neurons implicated in the detection of different types of chemical cues in egg parasitoids. PMID- 25937057 TI - Predominant expression and activity of vacuolar H(+)-ATPases in the mixed segment of the wood-feeding termite Nasutitermes takasagoensis. AB - The mixed segment is a unique part of the gut present only in the most apical lineage of termites and consists of a complex of overlapping mesenteric and proctodeal epithelia. In spite of its unique structure, the physiological functions of the mixed segment have been poorly studied. We performed transcriptome analysis to identify functional enzymes acting in the mixed segment of the wood-feeding higher termite Nasutitermes takasagoensis. We sequenced the transcripts (4563 isotigs) of the mixed segment and compared them with those of the midgut (4813 isotigs) and the first proctodeal segment (3629 isotigs). We found that vacuolar H(+)-ATPase (V-ATPase) subunits were predominant in the mixed segment, which was confirmed by RT-qPCR analysis. The V-ATPase activity in these three tissues was in a good agreement with the expression patterns, suggesting that V-ATPase is a prevalent enzyme in the mixed segment of the termites. The results confirmed the proposed role of the mixed segment as a transporting epithelium. PMID- 25937058 TI - Morphological and molecular characterisation of Diaporthe species associated with grapevine trunk disease in China. AB - Trunk diseases in grapevine (Vitis spp.) are major problems in the wine and table grape industries reducing the productivity, quality and longevity of vineyards. Species of Diaporthe are important fungal pathogens of grapevine trunk disease worldwide. A survey of 14 grape vineyards located in different provinces of China was yielded Diaporthe isolates associated with symptomatic grapevine wood. These isolates were identified based on morphology and a combined data matrix of rDNA ITS, partial sequences of translation elongation factor 1-alpha (EF 1-alpha), beta-tubulin (TUB) and calmodulin (CAL) gene regions. Four species of Diaporthe were identified, which included Diaporthe eres, Diaporthe hongkongensis, Diaporthe phaseolorum and Diaporthe sojae. All isolates of Diaporthe caused disease on detached grape shoots in pathogenicity experiments but differed in virulence. The incidence in local vineyards and the pathogenicity results indicate that D. eres is an important pathogen of grapevine in Chinese vineyards, where it may significantly limit grape production. This is the first detailed report of Diaporthe species associated with grapevine trunk diseases in China with morphology, pathogenicity and molecular data. PMID- 25937059 TI - Diaporthe species occurring on Lithocarpus glabra in China, with descriptions of five new species. AB - The Diaporthe species include important plant pathogenic fungi with wide host ranges and geographic distributions. In this paper, species associated with Lithocarpus glabra were examined using a multi-locus phylogeny based on a combined rDNA-internal transcribed spacer (ITS), and partial translation elongation factor 1-alpha (TEF1), beta tubulin (TUB), and calmodulin (CAL) regions. The phylogenies inferred from combined multi-locus sequences grouped isolates from L. glabra into seven distinct lineages with high branch support, which corresponded to two previously described species and five novel species described in this paper. Our results indicate a high species diversity of Diaporthe associated with L. glabra, and host association is further proved not reliable for species delimitation. Three species previously described in Phomopsis were transferred to Diaporthe in the present paper. A synopsis of morphological characters of the 14 species currently known from Fagaceae is provided. PMID- 25937060 TI - Cytospora species associated with walnut canker disease in China, with description of a new species C. gigalocus. AB - Cytospora species associated with canker disease are presently difficult to identify because of lack of ex-types cultures with molecular data, few distinguishable characters, and only Internal transcribed spacer (ITS) sequence data is available for most Cytospora strains in GenBank. We report on Cytospora species from the walnut tree in China. Collections were subjected to morphological and phylogenetic study. The relatedness of species associated with walnut canker were established using combined ITS, nrLSU, beta-tubulin, and actin gene sequence data. Cytospora atrocirrhata, Cytospora chrysosperma, Cytospora sacculus, and a new species, Cytospora gigalocus, were identified causing canker disease of walnut. Cytospora gigalocus is formally described and compared with most similar species. Cytospora chrysosperma and C. sacculus have previously been recorded from walnut, whereas C. atrocirrhata is reported as associated with walnut canker for the first time. This is the first study that has established the Cytospora species causing walnut canker in China using a multi-phasic approach. All species are recorded as being associated with walnut canker disease in China for the first time. PMID- 25937061 TI - Identification of a novel phylogenetic lineage of Alternaria alternata causing citrus brown spot in China. AB - Alternaria alternata sensu lato, casual agent of citrus brown spot, first identified in Yunnan province in 2010 and subsequently found in Zhejiang, Hunan, Guangdong provinces, Chongqing municipality andGuangxi autonomous region in China. During 2010-2012, 86 isolates were collected from diseased citrus, of which 85 % isolates were pathogenic to Ponkan tangerine. Phylogenetic analyses of Chinese and worldwide isolates using partial sequences of an endopolygalacturonase gene (endoPG) and combined dataset ofendoPG and two anonymous loci (OPA1-3, OPA2-1) found that Chinese isolates fell into two of three previously described clades. One clade ('clade 3') contained isolates from Turkey and Israel, and the other clade ('clade 1') contained isolates from Florida, USA. None of the isolates from China fell into the last previously described clade ('clade 2'). However, 24 isolates from Hunan, Guangdong and Guangxi fell into a fourth clade ('clade 4') not previously reported to be associated with citrus brown spot. This clade included multilocus haplotypes known to infect Japanese pear and strawberry. The observation that Chinese brown spot isolates fell into only two of three known worldwide lineages suggests that this fungus may not have co-evolved with its host in China but elsewhere in Southeast Asia and introduced to China. PMID- 25937062 TI - Endophytic Diaporthe associated with Citrus: A phylogenetic reassessment with seven new species from China. AB - Phytopathogenic species of Diaporthe are associated with melanose, stem-end rot and gummosis diseases of Citrus. However, little is known about the occurrence of species of Diaporthe as endophytes and saprobes. In this study, we obtained 58 strains of Diaporthe, including 44 endophytic isolates from cultivated Citrus in China. The nuclear ribosomal internal transcribed spacer (ITS), partial sequences of translation elongation factor 1-alpha (EF1-alpha), beta-tubulin (TUB), and histone-3 (HIS) gene regions were analysed to determine the species of the isolates collected. In combined analysis of four gene regions, these strains grouped in 16 distinct clades in Diaporthe. The isolates were identified in Diaporthe arecae species complex, Diaporthe citri, Diaporthe citriasiana, Diaporthe citrichinensis, Diaporthe endophytica, Diaporthe eres, Diaporthe hongkongensis, and Diaporthe sojae based on molecular phylogeny and morphology. Seven new species are described from Citrus namely, Diaporthe biconispora, Diaporthe biguttulata, Diaporthe discoidispora, Diaporthe multigutullata, Diaporthe ovalispora, Diaporthe subclavata, and Diaporthe unshiuensis with descriptions and illustrations. PMID- 25937063 TI - Identification and characterization of Pestalotiopsis-like fungi related to grapevine diseases in China. AB - Pestalotiopsis-like fungi are an important plant pathogenic genus causing postharvest fruit rot and trunk diseases in grapevine in many countries. Pestalotiopsis-like fungi diseases were studied in vineyards in nine provinces across China. Multi-gene (ITS, beta-tubulin and tef1) analysis coupled with morphology showed that a Neopestalotiopsis sp. and Pestalotiopsis trachicarpicola are associated in causing grapevine fruit rot and trunk diseases in China. Pestalotiopsis trachicarpicola is reported as the causative agent of grapevine diseases in the world for the first time. Neopestalotiopsis sp. caused significantly longer lesions than the other taxon present. This study represents the first attempt to identify and characterize the Pestalotiopsis-like fungi causing grapevine diseases in China using both morphological and molecular approaches. PMID- 25937064 TI - Novel species of Cercospora and Pseudocercospora (Capnodiales, Mycosphaerellaceae) from Australia. AB - Novel species of Cercospora and Pseudocercospora are described from Australian native plant species. These taxa are Cercospora ischaemi sp. nov. on Ischaemum australe (Poaceae); Pseudocercospora airliensis sp. nov. on Polyalthia nitidissima (Annonaceae); Pseudocercospora proiphydis sp. nov. on Proiphys amboinensis (Amaryllidaceae); and Pseudocercospora jagerae sp. nov. on Jagera pseudorhus var. pseudorhus (Sapindaceae). These species were characterised by morphology and an analysis of partial nucleotide sequence data for the three gene loci, ITS, LSU and EF-1alpha. Recent divergence of closely related Australian species of Pseudocercospora on native plants is proposed. PMID- 25937065 TI - Evolutionary history and variation in host range of three Stagonosporopsis species causing gummy stem blight of cucurbits. AB - Recently diverged species may form complexes of morphologically similar, yet genetically distinct lineages that occur in overlapping geographic ranges and niches. Using a multilocus sequencing approach we discovered that gummy stem blight of cucurbits is caused by three genetically distinct species: Stagonosporopsis cucurbitacearum (syn. Didymella bryoniae), Stagonosporopsis citrulli, and Stagonosporopsis caricae, which had previously been considered only a pathogen of papaya. Experiments showed that all three species are pathogenic to cucurbits in the genera Cucurbita, Cucumis, and Citrullus, but only S. caricae is aggressive to papaya. Species tree estimates show that S. citrulli and S. cucurbitacearum are phylogenetically distinct sister species, and that S. caricae is the ancestral lineage. The time estimate for divergence of S. caricae from the ancestor of S. cucurbitacearum and S. citrulli at 72 900 YBP pre-dates domestication of papaya and Cucurbita species in the American tropics. The divergence estimate observed for S. cucurbitacearum and S. citrulli at 10 900 YBP suggests that diversification of Cucurbita species and domestication of gourds and squashes could have driven their divergence. This work highlights the use of molecular systematics and population genetics to elucidate genetic identity among previously unassociated fungi and to understand the patterns of pathogen diversification. PMID- 25937066 TI - The Diaporthe sojae species complex: Phylogenetic re-assessment of pathogens associated with soybean, cucurbits and other field crops. AB - Phytopathogenic species of Diaporthe are associated with a number of soybean diseases including seed decay, pod and stem blight and stem canker and lead to considerable crop production losses worldwide. Accurate morphological identification of the species that cause these diseases has been difficult. In this study, we determined the phylogenetic relationships and species boundaries of Diaporthe longicolla, Diaporthe phaseolorum, Diaporthe sojae and closely related taxa. Species boundaries for this complex were determined based on combined phylogenetic analysis of five gene regions: partial sequences of calmodulin (CAL), beta-tubulin (TUB), histone-3 (HIS), translation elongation factor 1-alpha (EF1-alpha), and the nuclear ribosomal internal transcribed spacers (ITS). Phylogenetic analyses revealed that this large complex of taxa is comprised of soybean pathogens as well as species associated with herbaceous field crops and weeds. Diaporthe arctii, Diaporthe batatas, D. phaseolorum and D. sojae are epitypified. The seed decay pathogen D. longicolla was determined to be distinct from D. sojae. D. phaseolorum, originally associated with stem and leaf blight of Lima bean, was not found to be associated with soybean. A new species, Diaporthe ueckerae on Cucumis melo, is introduced with description and illustrations. PMID- 25937067 TI - Identification of the MAT1 locus in Stagonosporopsis tanaceti, and exploring its potential for sexual reproduction in Australian pyrethrum fields. AB - Stagonosporopsis chrysanthemi, S. inoxydabilis, and S. tanaceti are closely related Ascomycetes associated with ray blight of the Asteraceae. To date, only S. tanaceti has been identified in Australia, incurring substantial losses to the pyrethrum industry. In contrast to the homothallic S. chrysanthemi and S. inoxydabilis, a sexual state has not been observed for S. tanaceti. The MAT1 locus in S. tanaceti was identified through de novo assembly of shotgun reads, and was further used to develop primers for amplification of the full-length MAT1/2 locus in S. chrysanthemi and S. inoxydabilis. As expected, S. chrysanthemi and S. inoxydabilis possessed a MAT1/2 locus typical of homothallic Dothideomycetes with two adjacent MAT1-1 and MAT1-2 idiomorphs. However, only MAT1-1 could be detected in the assembled genome of S. tanaceti. Although a sexual mode of reproduction cannot be ruled out for S. tanaceti, evidence so far suggests this is absent or occurring at very low frequency in Australian pyrethrum fields. PMID- 25937068 TI - Cytospora species from Populus and Salix in China with C. davidiana sp. nov. AB - Poplar and willow plantations have become widespread in China, in order to meet national economic and environmental needs. The emergence of several pathogens is enhanced by climatic change and associated human factors. Species of Cytospora are well-known pathogens on poplar and willow, and cause stem cankers and diebacks. In the present study, we conducted a survey of Cytospora species occurring on Populus spp. and Salix spp. in China. We used morphological examination and phylogenetic inferences, based on the DNA sequence data from the internal transcribed spacer regions (ITS1, 5.8S rDNA, and ITS2) and partial beta tubulin gene, to identify six Cytospora species occurring on poplar and willow. Five of these species belonged to known taxa, viz. Cytospora chrysosperma (asexual state of Valsa sordida), Cytospora translucens (asexual state of Leucostoma translucens), Cytospora fugax (asexual state of Valsa salicina), Cytospora atrocirrhata, and Cytospora kantschavelii. Our study yielded a new species, Cytospora davidiana sp. nov., on poplar. The new species is characterized by typical torsellioid conidiomata. An additional Cytospora sp. 1, which formed a distinct clade in the phylogenetic inferences, remains unnamed; the paucity of available materials prevented phenotypical characterization. PMID- 25937069 TI - Polyphasic characterization of four new plant pathogenic Phyllosticta species from China, Japan, and the United States. AB - The black rot disease of Vitis species and other host genera of Vitacease is caused by Phyllosticta ampelicida and allied taxa which is considered to be a species complex. In this paper, we introduce four new species of Phyllosticta, including two from the P. ampelicida complex, based on a polyphasic characterization including disease symptoms and host association, morphology, and molecular phylogeny. The phylogenetic analysis was conducted based on the ribosomal internal transcribed spacer (ITS) region and a combined multi-locus alignment of the ITS, actin (ACT), partial translation elongation factor 1-alpha (TEF-1), and glyceraldehydes 3-phosphate dehydrogenase (GPDH) gene regions. Our study confirms the phylogenetic distinctions of the four new species, as well as their phenotypic differences with known species in the genus. PMID- 25937070 TI - O-GlcNAcylation of eIF2alpha regulates the phospho-eIF2alpha-mediated ER stress response. AB - O-GlcNAcylation is highly involved in cellular stress responses including the endoplasmic reticulum (ER) stress response. For example, glucosamine-induced flux through the hexosamine biosynthetic pathway can promote ER stress and ER stress inducers can change the total cellular level of O-GlcNAcylation. However, it is largely unknown which component(s) of the unfolded protein response (UPR) is directly regulated by O-GlcNAcylation. In this study, eukaryotic translation initiation factor 2alpha (eIF2alpha), a major branch of the UPR, was O GlcNAcylated at Ser 219, Thr 239, and Thr 241. Upon ER stress, eIF2alpha is phosphorylated at Ser 51 by phosphorylated PKR-like ER kinase and this inhibits global translation initiation, except for that of specific mRNAs, including activating transcription factor 4, that induce stress-responsive genes such as C/EBP homologous protein (CHOP). Hyper-O-GlcNAcylation induced by O-GlcNAcase inhibitor (thiamet-G) treatment or O-GlcNAc transferase (OGT) overexpression hindered phosphorylation of eIF2alpha at Ser 51. The level of O-GlcNAcylation of eIF2alpha was changed by dithiothreitol treatment dependent on its phosphorylation at Ser 51. Point mutation of the O-GlcNAcylation sites of eIF2alpha increased its phosphorylation at Ser 51 and CHOP expression and resulted in increased apoptosis upon ER stress. These results suggest that O GlcNAcylation of eIF2alpha affects its phosphorylation at Ser 51 and influences CHOP-mediated cell death. This O-GlcNAcylation of eIF2alpha was reproduced in thiamet-G-injected mouse liver. In conclusion, proper regulation of O GlcNAcylation and phosphorylation of eIF2alpha is important to maintain cellular homeostasis upon ER stress. PMID- 25937071 TI - Functional and physiopathological implications of TRP channels. AB - Transient Receptor Potential (TRP) channel proteins are a diverse family of proteins that are expressed in many organisms, tissues and cell types. TRP channels respond to a variety of stimuli, including light, mechanical or chemical stimuli, temperature, pH or osmolarity. In addition, several TRP family members have been identified as downstream molecules in the G protein-coupled receptor signaling pathway. TRP proteins are involved in a variety of cell functions both in non-excitable and excitable cells due to their diverse permeability to cations and their ability to modulate intracellular Ca2+ signaling. Emerging evidence suggests that TRP channel dysfunction significantly contributes to the physiopathology of a number of diseases, including cardiovascular, neurological, metabolic or neoplastic disorders. This review focuses on the implication of TRP proteins in the pathogenesis of some of the most prevalent disorders in human. We summarize the current findings regarding the role of TRP proteins in the development of cardiovascular disease, diabetes mellitus as well as diabetic complications, and tumorigenesis and present TRP proteins as targets of potential diagnostic and therapeutic strategies. PMID- 25937072 TI - Relationship between gene mutation and lung cancer metastasis. AB - Cancer is a genetic disease occurring through a multi-step process. Many important genes responsible for the genesis of various cancers have been discovered, their mutations precisely identified and the pathways through which they act characterized. One question that remains unanswered is whether the development of new, more specific therapeutic agents is the best way to minimize cancer morbidity and mortality in the long-term. Metastasis is the relentless pursuit of cancer to escape its primary site and colonize distant organs. Phenotypic changes during cancer progression reflect the sequential accumulation of genetic alterations, which endow cancer cells with the ability to undergo their own divergent evolution and create distinct metastatic species. In order to understand this process, it is crucial to identify genes whose alterations accumulate during cancer progression and correlate with metastatic phenotypes of cancer cells. PMID- 25937073 TI - Global analysis of chromosome 1 genes among patients with lung adenocarcinoma, squamous carcinoma, large-cell carcinoma, small-cell carcinoma, or non-cancer. AB - The present study aimed at investigating genetic variations, specific signal pathways, or biological processes of chromosome 1 genes between subtypes and stages of lung cancer and prediction of selected targeting genes for patient survival rate. About 537 patients with lung adenocarcinoma (ADC), 140 with lung squamous carcinoma (SCC), 9 with lung large-cell carcinoma (LCC), 56 with small cell lung cancer (SCLC), and 590 without caner were integrated from 16 databases and analyzed in the present study. Three (ASPM, CDC20, KIAA1799) or 28 genes significantly up- or down-expressed in four subtypes of lung cancer. The activated cell division and down-regulated immune responses were identified in patients with lung cancer. Keratinocyte development associated genes S100 and SPRR families dominantly up-expressed in SCC and AKT3 and NRAS in SCLC. Subtype specific genes of ADC, SCC, LCC, or SCLC were also identified. C1orf106, CAPN8, CDC20, COL11A1, CRABP2, and NBPF9 up-expressed at four stages of ADC. Fifty six related with keratinocytes or potassium channels up-expressed in three stages of SCC. CDC20, IL10, ECM1, GABPB2, CRABP2, and COL11A1 significantly predicted the poor overall survival of ADC patients and S100A2 and TIMM17A in SCC patients. Our data indicate that a number of altered chromosome 1 genes have the subtype and stage specificities of lung cancer and can be considered as diagnostic and prognosis biomarkers. PMID- 25937074 TI - Prevention of bleeding in hemophilia patients with high-titer inhibitors. AB - Inhibitor development is the most serious adverse event linked to the treatment of hemophilia, as it renders standard hemostatic therapy ineffective. Consequently, inhibitor patients are at increased risk for difficult-to-control bleeding and complications, particularly arthropathy and physical disability. Three randomized clinical trials in patients with inhibitors have demonstrated that compared with on-demand bypassing therapy, prophylaxis with a bypassing agent reduces joint and other types of bleeding and improves health-related quality of life. In hemophilia patients without inhibitors, the initiation of prophylaxis with factor (F) VIII or IX prior to the onset of recurrent hemarthroses can prevent the development of joint disease. Whether this is also true for bypassing agent prophylaxis remains to be determined. PMID- 25937078 TI - Gemcitabine sensitizes pancreatic cancer cells to the CTLs antitumor response induced by BCG-stimulated dendritic cells via a Fas-dependent pathway. AB - BACKGROUND/OBJECTIVES: There are increasing evidences suggesting that chemotherapeutic agents can enhance the cytotoxic T lymphocytes (CTLs) antitumor effect, but the precise mechanism is not fully explained. This study aims to investigate whether gemcitabine (GEM) can sensitize pancreatic cancer cells to the CTLs antitumor response, and explore the potential mechanism. METHODS: Cell counting kit-8 assays (CCK-8) were performed to determine the tumor cell proliferation. Flow cytometric analysis was conducted to analyze maturation of DCs and the expression of Fas. An Annexin V FITC Apoptosis Detection Kit was performed to detect tumor cell apoptosis. CytoTox 96 Nonradioactive Cytotoxicity assays were used to determine T cell-mediated tumor cell lysis. RESULTS: First, it was demonstrated that Bacillus Calmette Guerin (BCG) could be used to induce effective CTLs antitumor response. Then, GEM inhibited the growth of SW1990 cells, induced apoptosis and upregulated the Fas expression even at a low concentration. When antagonistic anti-Fas mAb ZB4 was preincubated with GEM treated SW1990 cells, the lysis induced by CTLs was reduced. Moreover, agonistic anti-Fas mAb CH11 induced more apoptosis of GEM-treated SW1990 cells. CONCLUSION: Our results show that GEM sensitizes pancreatic cancer cells to the CTLs antitumor response, and the sensitization is associated with upregulation of Fas on pancreatic cancer cells. PMID- 25937080 TI - A novel technique for distal fingertip replantation: Polypropylene suture guided interpositional vein graft. AB - BACKGROUND: Despite current advances in microsurgery, fingertip replantation is still controversial, mainly due to its difficulty and cost. The purpose of this study is to describe a new technique of interposition vein graft guided by polypropylene suture in distal fingertip replantation. METHODS: A total of eight consecutive Tamai zone 1 fingertip replantations performed by the same author were included. All replantations were performed using interposition vein graft guided by polypropylene suture. This technique involved a vein graft of ~ 2 cm, with appropriate calibration, obtained from the volar part of the forearm and a 2 0 polyprolene suture passed through the interposition vein graft. Then, a polypropylene suture guide carrying the vein graft was inserted into the artery. The anastomosis was easily performed with the aid of 10-0 or 11-0 nylon in a bloodless medium and without encountering the posterior wall problem. RESULTS: Average surgery time was 2.5 hours (range = 2-3 hours). Among eight Tamai zone 1 replantations, six were successful (75%). There were two replantations lost because of arterial failure. CONCLUSION: This technique may ease fingertip replantations and increase the success rate for Tamai zone 1 injuries. PMID- 25937079 TI - Severity and natural history of acute pancreatitis in diabetic patients. AB - BACKGROUND: There is limited data on the prevalence of coexistent diabetes in acute pancreatitis and subsequent natural history in these patients. METHODS: Using Pennsylvania Health Care Cost Containment Council data set, we identified 7399 unique White and Black Allegheny County, PA residents with first hospitalization for acute pancreatitis from 1996 to 2005. We evaluated the prevalence of coexistent diabetes, demographic and etiologic profile, severity of index hospitalization, and risk of readmission for acute or chronic pancreatitis during follow up (median 39 months) in this cohort. RESULTS: The prevalence of coexisting diabetes was 18% (1349/7399). When compared with non-diabetics, diabetics were significantly more likely to be older (63 vs. 56 yrs), male (OR 1.4, 95% CI 1.2-1.6), black (OR 2.4, 95% CI 2.1-2.7) and have non-alcoholic etiologies (biliary, OR 1.5, 95% CI 1.2-1.9; idiopathic, OR 2.0, 95% CI 1.7-2.5; metabolic, OR 5.2, 95% CI 4.0-6.7). While diabetic patients had a significantly longer length of stay (median 5 vs. 4 days, p < 0.05), their severity of acute pancreatitis (multivariable OR 1.18, 95% CI 0.94-1.48) or in-hospital mortality (1.9% each, p = 0.98) did not differ than non-diabetics. The overall risk of pancreatitis-related readmissions in diabetics was similar (33% each, p = 0.99), but their risk of subsequent admission for chronic pancreatitis (multivariable HR 0.65, 95% CI 0.44-0.97) was lower than non-diabetics. CONCLUSION: About 20% patients with acute pancreatitis have coexistent diabetes. Demographic and etiologic profile of diabetic patients with acute pancreatitis differs from non diabetics. Diabetic status has limited effect on the severity of and natural history following acute pancreatitis. PMID- 25937081 TI - Regio- and stereoselective cleavage of steroidal 22-oxo-23-spiroketals catalyzed by BF3.Et2O. AB - The regioselective opening of the F ring of 22-oxo-23-spiroketals using BF3.OEt2 in acetic anhydride yielded novel cholestanic frameworks with pyranone E ring 20 23. The structures of the new derivatives of botogenin, diosgenin, hecogenin and tigogenin thus obtained were established using one and two dimensional (1)H, (13)C experiments (DEPT, COSY, HETCOR, HMBC). The X-ray diffraction analysis unequivocally confirmed the R configuration at C-23 in the starting 22-oxo-23 spiroketal 18 and the Z configuration of the C23-C24 double bond in the reaction product 20. PMID- 25937082 TI - Vascular function and ocular involvement in sarcoidosis. AB - Ocular involvement occurs in sarcoidosis (Sar) patients mainly in the form of uveitis. This study was designed to determine if uveitis in Sar patients is associated with vascular impairment. We enrolled 82 Sar patients and 77, age and sex matched, control subjects (Cl). Sar patients were divided into those with ocular sarcoidosis (OS) and those without ocular sarcoidosis (WOS). Endothelial function was evaluated by flow-mediated dilation (FMD). Pulse wave velocity (PWV) was measured as an index of aortic stiffness and augmentation index (AIx) as a measure of arterial wave reflections. Although there was no significant difference in sex, age and mean arterial pressure, patients with OS compared to WOS patients and Cl subjects had impaired FMD (p<0.001), increased AIx (p=0.02) and increased PWV (p=0.001). Interestingly, impaired FMD in Sar patients was independently, from possible covariates (age, sex, smoking habits, arterial hypertension, dyslipidemia), associated with increased odds of ocular involvement (odds ratio=1.69, p=0.001). More precisely ROC curve analysis revealed that FMD had a significant diagnostic ability for the detection of OS (AUC=0.77, p<0.001) with a sensitivity of 79% and a specificity of 68% for an FMD value below 6.00%. To conclude in the present study we have shown that ocular involvement in Sar patients is associated with impaired endothelial function and increased arterial stiffness. These results strengthen the vascular theory which considers uveitis a consequence of vascular dysfunction in Sar patients and reveals a possible clinical importance of the use of endothelial function tests. PMID- 25937083 TI - Peroxisome proliferator-activated receptor gamma attenuates serotonin-induced pulmonary artery smooth muscle cell proliferation and apoptosis inhibition involving ERK1/2 pathway. AB - Serotonin (5-HT) has been shown to be involved in pulmonary vascular remodeling in pulmonary arterial hypertension (PAH) by inducing pulmonary artery smooth muscle cells (PASMCs) proliferation and inhibiting PASMC apoptosis. Peroxisome proliferator-activated receptor gamma (PPARgamma) plays a crucial role in regulating proliferation and apoptosis of many cell types. Moreover, recently, loss of PPARgamma has also been reported to be associated with the development of PAH. The present study is aimed to assess whether PPARgamma is involved in 5-HT induced PASMC proliferation and apoptosis inhibition and the possible mechanism. We found that 5-HT could induce PASMC proliferation and inhibit PASMC apoptosis in a dose-dependent manner. Furthermore, we found that 5-HT negatively regulated PPARgamma expression and gene promoter activity in PASMCs and 5-HT induced PASMC proliferation and apoptosis resistance could be abolished by PPARgamma agonists and enhanced by PPARgamma inhibitor. In addition, we found that extracellular signal-regulated kinase (ERK) signaling pathway mediated the 5-HT-induced inhibition of PPARgamma expression. Our results might provide novel insights into the mechanisms for the pro-remodeling action of 5-HT in pulmonary vasculature. PMID- 25937084 TI - Escherichia coli BL21(DE3) chromosome-based controlled intracellular processing system for fusion protein separation. AB - A chromosome-based controlled intracellular processing system was constructed by integrating the TEV protease gene into the chromosome of E. coli BL21(DE3) with lambda-Red recombineering. The system is highly efficient in processing maltose binding protein fusion protein; the separated protein could be purified to near homogeneity with Ni-NTA affinity chromatography. PMID- 25937085 TI - Microbial food safety: Potential of DNA extraction methods for use in diagnostic metagenomics. AB - The efficiency of ten widely applied DNA extraction protocols was evaluated for suitability for diagnostic metagenomics. The protocols were selected based on a thorough literature study. Chicken fecal samples inoculated with about 1*10(3) and 1*10(6) CFU/g Campylobacter jejuni were used as a model. The evaluation was performed based on total DNA yield measured by fluorometry, and quality and quantity of C. jejuni DNA measured by real-time PCR. There was up to a 25-fold variance between the lowest (NucliSens miniMAG, BIOMERIEUX) and highest (PowerLyzer PowerSoil DNA Isolation Kit, MO BIO Laboratories) yielding protocols. The PowerLyzer PowerSoil DNA Isolation Kit performed significantly better than all other protocols tested. Selected protocols were modified, i.e., extended heating and homogenization, resulting in increased yields of total DNA. For QIAamp Fast DNA Stool Mini Kit (Qiagen) a 7-fold increase in total DNA was observed following the protocol for human DNA analysis and including a 5 min heating step at 70 degrees C. For the PowerLyzer PowerSoil and the PowerFecal DNA Isolation Kit (MO BIO Laboratories) the total DNA fold increase was 1.6 to 1.8 when including an extra 10 min of bead-vortexing. There was no correlation between the yield of total DNA and the amount of PCR-amplifiable DNA from C. jejuni. The protocols resulting in the highest yield of total DNA did not show correspondingly increased levels of C. jejuni DNA as determined by PCR. In conclusion, substantial variation in the efficiency of the protocols to extract DNA was observed. The highest DNA yield was obtained with the PowerLyzer PowerSoil DNA Isolation Kit, whereas the FastDNA SPIN Kit for Feces (MP Biomedicals) resulted in the highest amount of PCR-amplifiable C. jejuni DNA. PMID- 25937086 TI - Immunoblotting conditions for small peptides from streptococci. AB - Streptococci secrete small peptides with important biological functions. These peptides are not amenable to standard immunoblotting, and are often detected indirectly using activity assays, or by alternative approaches that may be expensive and laborious. Here we describe an immunoblotting method that enables reproducible detection of these small streptococcal peptides. PMID- 25937087 TI - Bioluminescent whole-cell reporter gene assays as screening tools in the identification of antimicrobial natural product extracts. AB - We describe novel tools, bioluminescent whole-cell reporter gene assays, for facilitating the use of natural products in antimicrobial drug discovery. As proof-of-concept, a plant extract library was screened and follow-up experiments were carried out. Primary results can be obtained in 2-4h with high sensitivity, leading to significant improvements of the process. PMID- 25937088 TI - Generation and characterization of novel conformation-specific monoclonal antibodies for alpha-synuclein pathology. AB - alpha-Synuclein (alpha-syn), a small protein that has the intrinsic propensity to aggregate, is implicated in several neurodegenerative diseases including Parkinson's disease (PD), dementia with Lewy bodies (DLB), and multiple system atrophy (MSA), which are collectively known as synucleinopathies. Genetic, pathological, biochemical, and animal modeling studies provided compelling evidence that alpha-syn aggregation plays a key role in the pathogenesis of PD and related synucleinopathies. It is therefore of utmost importance to develop reliable tools that can detect the aggregated forms of alpha-syn. We describe here the generation and characterization of six novel conformation-specific monoclonal antibodies that recognize specifically alpha-syn aggregates but not the soluble, monomeric form of the protein. The antibodies described herein did not recognize monomers or fibrils generated from other amyloidogenic proteins including beta-syn, gamma-syn, beta-amyloid, tau protein, islet amyloid polypeptide and ABri. Interestingly, the antibodies did not react to overlapping linear peptides spanning the entire sequence of alpha-syn, confirming further that they only detect alpha-syn aggregates. In immunohistochemical studies, the new conformation-specific monoclonal antibodies showed underappreciated small micro-aggregates and very thin neurites in PD and DLB cases that were not observed with generic pan antibodies that recognize linear epitope. Furthermore, employing one of our conformation-specific antibodies in a sandwich based ELISA, we observed an increase in levels of alpha-syn oligomers in brain lysates from DLB compared to Alzheimer's disease and control samples. Therefore, the conformation-specific antibodies portrayed herein represent useful tools for research, biomarkers development, diagnosis and even immunotherapy for PD and related pathologies. PMID- 25937090 TI - Self-assembled polyoxometalates nanoparticles as pickering emulsion stabilizers. AB - We easily produced a series of polyoxometalate (POM) nanoparticles by taking benefit from electrostatic attractions between various POMs and alkylammonium cations. These self-assembled supramolecular nanoparticles are fully characterized in terms of shape, nanostructure, and physicochemical properties. The nanoparticle differences are discussed on the basis of the chemical composition of the initial POM. Moreover, such particles have the ability to stabilize water-in-oil Pickering emulsions. Using a gel-trapping technique coupled to atomic force microscopy (AFM) observations, we determined their affinity toward oil by the contact angle of adsorbed nanoparticles. We show that the emulsion droplet size and stability can be directly linked to the nanoparticle hydrophobicity, which is tuned by the charge localization and molecular packing of POMs with the ammonium cations. Such particles are of special interest as they open large possibilities for Pickering interfacial catalysis. PMID- 25937089 TI - Long-term expression of metabolism-associated genes in the rat hippocampus following recurrent neonatal seizures and its regulation by melatonin. AB - Despite the effective use of antiepileptic drugs (AEDs) for epilepsy, therapeutic failure occurs in 30% of patients. Novel approaches are targeting the inhibition of epileptogenesis. N-acetyl-5-methoxytryptamine (melatonin) is an indoleamine produced mainly by the pineal gland, and has been observed to exhibit antiepileptic and neuroprotective effects in experimental and clinical investigations. In the present study, the underlying protective mechanism of melatonin on neonatal seizure-induced long-term excitotoxicity was examined in the hippocampus of rats, predominantly on the metabolism-associated genes. Sprague Dawley rats (6-day-old; P6) were randomly divided into four groups, the control (Cont), melatonin-treated control (Mel), recurrent neonatal seizure (RS) and treatment with melatonin and RS combined (Mel+RS). At P35, mossy fiber sprouting and changes in gene expression in hippocampus were assessed using Timm staining, reverse transcription-quantitative polymerase chain reaction and use of the 2(-DeltaCT) methods, respectively. The aberrant mossy fiber sprouting in the supra granular region of the dentate gyrus and CA3 subfield of the hippocampus was suppressed by pretreatment with melatonin. In addition, among the nineteen genes identified, four energy metabolism-associated genes (Kcnj11, leptin receptor, dopamine receptor D2 and melanocortin 4 receptor), four lipid metabolism-associated genes (apolipoprotein A-I, opioid receptor kappa 1, pyruvate dehydrogenase kinase, isozyme 4 and cytochrome P450, family 46, subfamily a, polypeptide 1) and zinc transporter 1 (ZnT1), sphingomyelinase (nSMase) and Cathepsin-E, were markedly downregulated by melatonin treatment in the Mel group or in the developmental seizure RS and Mel + RS groups, compared with that in the Cont group. Furthermore, the melatonin-pretreated seizure rats (Mel + RS) exhibited a significantly upregulated expression of calcium/calmodulin dependent protein kinase II alpha (CaMKIIalpha), acetyl-Coenzyme A acetyltransferase 1 (ACAT1), ZnT-1, metallothionein 1 (MT-1), nSMase and Cathepsin-E, compared with the RS rats. Thus, the present study investigated changes in the expression of metabolic genes in the hippocampus following pretreatment with melatonin. Fluorthyl-induced decreases in the expression levels of ACAT1/nSMase/Cathepsin-E, ZnT-1/MT-1 and CaMKIIalpha in the hippocampus, and the reversal by melatonin may be associated with a decrease in neonatal seizure induced aberrant mossy fiber sprouting, which requires further investigation. PMID- 25937091 TI - Quinolone-indolone conjugate induces apoptosis by inhibiting the EGFR-STAT3-HK2 pathway in human cancer cells. AB - The epidermal growth factor receptor (EGFR) is involved in the proliferation of human tumors and is an effective target for the treatment of cancer. In the present study, a novel quinolone-indolone conjugate, QIC1 [9-Fluoro-3,7-dihydro-3 methyl-10-(4-methyl -1-piperazinyl) -6-(2-oxo-1,2-dihydro-indol-3-ylidenemethyl) 7-oxo-2H-(1,4) oxazino(2,3,4-ij)quinoline], which targeted EGFR, was synthesized in order to investigate the anticancer activity and the potential mechanisms underlying the effect of this compound in human cancer cells. Using MTT assays it was observed that QIC1 inhibited the growth of HepG2 human hepatoma cells, MCF7 human breast cancer cells, HeLa human cervical cancer cells and A549 human lung adenocarcinoma cells. QIC1 arrested cell cycle progression at the G2/M phase in HepG2 cells. QIC1 inhibited the synthesis of DNA in A549 cells. In addition, it resulted in cell apoptosis, in association with increased expression of Bax and reduced expression of Bcl-2. Further analyses demonstrated that QIC1 attenuated the activity of EGFR, and the downstream signal transducer and activator of transcription 3 (STAT3)-mediated hexokinase II (HK2) signaling pathways. Furthermore, QIC1 exhibited antiproliferative effects in MCF7/DOX human doxorubicin-resistant breast cancer cells and also enhanced the anticancer activity of doxorubicin in these cells. In conclusion, the inhibition of proliferation and the induction of apoptosis was associated with reduced expression of phospho-EGFR-phospho-STAT3-HK2. The present results suggest a potential role for QIC1 in the treatment of human cancer. PMID- 25937092 TI - Factors influencing the outcome of deep infection following total knee arthroplasty. AB - BACKGROUND: Whereas clinical studies have revealed a number of important risk factors for postoperative infection following total knee arthroplasty (TKA), it is unclear which factor influences clinical results. A multicenter study was therefore performed by reviewing 51 patients with deep infection after TKA and seeking for the factors related to clinical outcomes. METHODS: Fifty-one deep infections after TKA were treated from 2000 to 2011 at the multicenter including a university or three arthroplasty centers. Among them, two clinical outcome measures including retention of prosthesis at initial treatment and functional prosthetic knee were assessed for several factors such as age, sex, primary diagnosis, onset time after primary TKA, type of hospital where the primary TKA was performed and the organism's resistance to methicillin using the logistic regression analysis model. RESULTS: Among the factors, type of hospital where the primary TKA was performed and onset time after primary TKA had higher multivariable-adjusted odds ratios (ORs) for retention of primary prosthesis (ORs 35.21 and 11.69, respectively.). The cases which primary surgery were performed in arthroplasty centers had higher multivariable-adjusted ORs for functional prosthetic knee (OR 4.9). Thirty-one infection cases with non-methicillin resistant organisms were all able to keep functional prosthetic knee after the operation, whereas 13 out of 20 infection cases with methicillin-resistant organisms lost their knee function after the operation. CONCLUSIONS: Onset time after primary TKA, type of hospital where the primary surgery was performed and the organism's resistance to methicillin are important factors influencing the clinical outcomes after infected TKA. LEVEL OF EVIDENCE: Level 3. Retrospective comparative study. PMID- 25937093 TI - Evaluation and comparison of clinical results of femoral fixation devices in arthroscopic anterior cruciate ligament reconstruction. AB - BACKGROUND: Several femoral fixation devices are available for hamstring tendon autograft in anterior cruciate ligament (ACL) reconstruction, but the best technique is debatable. PURPOSE: We hypothesised that different suspensory femoral fixation techniques have no superiority over each other. The aim of this study was to evaluate and compare the clinical results of different suspensory femoral fixation devices in arthroscopic ACL reconstruction. STUDY DESIGN: This was a Level III, retrospective, comparative study. METHODS: A total of 100 consecutive patients who underwent arthroscopic ACL reconstruction in a single institution with a mean follow-up time of 40 months (12-67 months) were divided into three groups according to femoral fixation devices as 'Endobutton' (n=34), 'Transfix' (n=35) and 'Aperfix' (n=31). The length of painful period after surgery, time to return to work and sporting activities, final range of motion, anterior drawer and Lachman tests, knee instability symptoms, International Knee Documentation Committee (IKDC) subjective knee evaluation score, Short Form 36 (SF-36) score, Lysholm knee score and Tegner point of the patients were evaluated and compared between groups. RESULTS: There were no significant differences between the groups. All techniques led to significant recovery in knee instability tests and symptoms. CONCLUSION: In this study, the clinical results of different suspensory femoral fixation techniques were found to be similar. We believe that different femoral fixation techniques have no effect on clinical results provided that the technique is correctly applied. The surgeon must choose a technique appropriate to his or her experience. PMID- 25937094 TI - Unique patellofemoral alignment in a patient with a symptomatic bipartite patella. AB - BACKGROUND: A symptomatic bipartite patella is rarely seen in athletic adolescents or young adults in daily clinical practice. To date, only a limited number of studies have focused on patellofemoral alignment. The current study revealed a unique patellofemoral alignment in a patient with a symptomatic bipartite patella. METHODS: Twelve patients with 12 symptomatic bipartite patellae who underwent arthroscopic vastus lateralis release (VLR) were investigated (10 males and two females, age: 15.7+/-4.4years). The radiographic data of contralateral intact and affected knees were reviewed retrospectively. From the lateral- and skyline-view imaging, the following parameters were measured: the congruence angle (CA), the lateral patellofemoral angle (LPA), and the Caton-Deschamps index (CDI). As an additional parameter, the bipartite fragment angle (BFA) was evaluated against the main part of the patella in the skyline view. RESULTS: Compared with the contralateral side, the affected patellae were significantly medialized and laterally tilted (CA: P=0.019; LPA: P=0.016), although there was no significant difference in CDI (P=0.877). This patellar malalignment was found to significantly change after VLR (CA: P=0.001; LPA: P=0.003) and the patellar height was significantly lower than in the preoperative condition (P=0.016). In addition, the BFA significantly shifted to a higher degree after operation (P=0.001). CONCLUSIONS: Patients with symptomatic bipartite patellae presented significantly medialized and laterally tilted patellae compared with the contralateral intact side. This malalignment was corrected by VLR, and the alignment of the bipartite fragment was also significantly changed. LEVEL OF EVIDENCE: Level IV, case series. PMID- 25937095 TI - Participatory citizenship: Critical perspectives on client-centred occupational therapy. AB - BACKGROUND/AIMS: This article aims to discuss client-centred practice, the current dominant approach within occupational therapy, in relation to participatory citizenship. Occupational therapists work within structures and policies that set boundaries on their engagement with clients, while working with complex, multidimensional social realities. METHODS: The authors present a critical discussion shaped by their research, including a survey, discussions at workshops at international conferences, and critical engagement with the literature on occupational therapy, occupation, and citizenship. CONCLUSION: A focus on citizenship suggests reframing professional development based on the participation in public life of people as citizens of their society. While occupational therapists often refer to clients in the context of communities, groups, families, and wider society, the term client-centred practice typically represents a particular view of the individual and may sometimes be too limited in application for a more systemic and societal approach. SIGNIFICANCE: The authors question the individual focus which has, until recently, been typical of client-centred occupational therapy. Placing citizenship at the core of intervention is a transformative process that assumes all people are citizens and conceives of health as a collective issue, influencing the way we educate, do research, and practise. PMID- 25937096 TI - MicroRNA-218, microRNA-191*, microRNA-3070a and microRNA-33 are responsive to mechanical strain exerted on osteoblastic cells. AB - MicroRNA (miRNA) is an important regulator of cell differentiation and function. Mechanical strain is important in the growth and differentiation of osteoblasts. Therefore, mechanresponsive miRNA may be important in the response of osteoblasts to mechanical strain. The purpose of the present study was to select and identify the mechanoresponsive miRNAs of osteoblasts. Mouse osteoblastic MC3T3-E1 cells were cultured in cell culture dishes and stimulated with a mechanical tensile strain of 2,50 MUepsilon at 0.5 Hz, and the activity of alkaline phosphatase (ALP), mRNA levels of ALP, osteocalcin (OCN), and collagen type I (Col I), and protein levels of bone morphogenetic proteins (BMPs) in the cell culture medium were assayed. Following miRNA microarray and reverse transcription-quantitative polymerase chain reaction analyses, differentially expressed miRNAs in the mechanically strained cells and unstrained cells were selected and identified. Using bioinformatics analysis, the target genes of the miRNAs were then predicted. The results revealed that the mechanical strain of 2,500 MUepsilon increased the activity of ALP, the mRNA levels of ALP, OCN and Col I, and the protein levels of bone morphogenetic protein(BMP)-2 and BMP-4 Continuous mechanical stimulation for 8 h had the most marked stimulant effects. miR-218, miR-191*, miR-3070a and miR-33 were identified as differentially expressed miRNAs in the mechanically strained MC3T3-E1 cells. Certain target genes of these four miRNAs were involved in osteoblastic differentiation. These findings indicated that a mechanical strain of 2,500 MUepsilon, particularly for a period of 8 h, promoted osteoblastic differentiation, and the four mechanoresponsive miRNAs identified may be a potential regulator of osteoblastic differentiation and their response to mechanical strain. PMID- 25937097 TI - Enhancement of the antibiofilm activity of amphotericin B by polyamine biosynthesis inhibitors. AB - The aim of this study was to investigate the effect of polyamine biosynthesis inhibitors on the activity of amphotericin B (AmB) against Candida albicans biofilms and to clarify the underlying mechanisms. The antibiofilm activity of AmB was significantly enhanced when used in combination with the polyamine biosynthesis inhibitors 1,4-diamino-2-butanone (DAB) and alpha difluoromethylornithine (DFMO). Further study showed that DAB and DFMO also enhanced the antibiofilm activity of several other antifungal agents. Moreover, the combination of AmB and polyamine biosynthesis inhibitors resulted in an increase in intracellular levels of reactive oxygen species. In addition, caspase activity and transcription of the caspase-encoding gene CaMCA1 were greatly increased upon combined treatment with polyamine biosynthesis inhibitors and AmB. Consistently, the biofilm formed by a Deltacamca1 mutant exhibited greater viability and lower caspase activity than that of the wild-type strain upon combined treatment. These data provide useful information for the development of new strategies to enhance the antibiofilm activities of antifungal agents. PMID- 25937098 TI - Natural killer cells dominate a Th-1 polarized response in Behcet's disease patients with uveitis. AB - OBJECTIVES: Behcet's disease (BD) is a systemic inflammatory disorder of unknown etiology, characterised by recurring relapses and remissions. BD manifestations have been thought to be associated with the immunological abnormalities triggered by environmental factors in genetically susceptible individuals. Natural killer (NK) cells are important members of innate immunity with their cytotoxic activity and also cytokine secretions. They have the capacity to induce or dampen immune responses. Different study groups have reported conflicting results about NK cell activity in the BD pathogenesis, however, contribution of NK cells to BD is still unclear. METHODS: NK cells from BD patients with uveitis (n=11) as well as age- and gender-matched healthy controls (n=9) were purified and intracytoplasmic cytokine levels of TNF-alpha, IFN-gamma, IL-2, IL-4, IL-10, IL-12 and IL-13 were determined. RESULTS: Increased TNF-alpha, IFN-gamma and IL-2 in relapse period and increased IL-4 as well as a slight increase of IL-10 in remission period were observed. CONCLUSIONS: Our results show that NK cells are the contributors of BD pathogenesis with their NK1 profile in relapse periods, and also with their NK2 profile in remission periods, in BD patients with uveitis. An increase in IL-10 observed in remission periods may be linked to the regulatory potential of NK cells in the recurrent nature of BD manifestations. PMID- 25937099 TI - Two-Stage Revision Protocol in Multidrug Resistant Periprosthetic Infection Following Total Hip Arthroplasty Using a Long Interval Between Stages. AB - We retrospectively reviewed the medical records of 31 patients with periprosthetic hip infections attempting to evaluate the outcome of a two-stage revision protocol characterized by prolonged interim period (mean=9.2 months, range 8-12 months) prior to the final re-implantation. In 3 cases (9.6%) the 1st stage was repeated after a mean period of 12.3 weeks due to relapse of infection. Five spacer dislocations occurred, not affecting the final clinical outcome after reimplantation, as evaluated by the Harris Hip Score. No protrusions or additional acetabular bone loss was noticed. Our proposed protocol is a simple, safe, efficient and reproducible treatment approach that may be successfully utilized predominantly when dealing with multidrug resistant pathogens. PMID- 25937100 TI - Functional Outcome and Quality of Life after Patient-Specific Instrumentation in Total Knee Arthroplasty. AB - Patient-specific instrumentation (PSI) surgery may represent the next advancement in total knee arthroplasty (TKA). In 2011, 60 patients were prospectively recruited and divided into two groups based on the patient's choice: (1) PSI surgery; and (2) conventional TKA. At two years after surgery, the Knee Society Function Score, Oxford Knee Score and SF-36 scores were comparable between the two groups. Although the Knee Society Knee Score (KSKS) was 9 +/- 3 points better in the PSI group (P=0.008), the two years improvement in KSKS was comparable between the two groups. None of the patients required revision surgery. These findings cannot justify the additional costs and waiting time incurred by the patients with PSI surgery in the practice of a high volume surgeon. PMID- 25937101 TI - Multiscale spectroscopy using a monolithic liquid core waveguide with laterally attached fiber ports. AB - In conventional absorption spectrometers, the range of accessible concentrations of analytes in aqueous solution is significantly limited by the dynamic range of the measurement system. Here we introduce the concept of multiscale spectroscopy allowing extending that range by orders of magnitude within one single device. The concept relies on using multiple light-sample interaction lengths, boosting the accessible concentration range by a particular extension factor. We experimentally implement our concept by a liquid core waveguide having multiple fiber ports side-wise attached to the waveguide, thus probing the light propagating inside the core at predefined distances from the input. This configuration provides three orders of magnitude of interaction length in one device. To verify the concept we exemplarily determine the concentrations of nitrate and of Rhodamine 6G in water, showing one hundred times improved measurement capabilities. The multiscale spectrometer uses the entire sample volume and allows the simultaneous measurement of fluorescence and attenuance. Due to its integrated design and the extended measurements capabilities, we anticipate application of our device in many application-relevant areas such as water quality analysis or environmental science. PMID- 25937102 TI - Vapor generation - atomic spectrometric techniques. Expanding frontiers through specific-species preconcentration. A review. AB - We review recent progress in preconcentration strategies associated to vapor generation techniques coupled to atomic spectrometric (VGT-AS) for specific chemical species detection. This discussion focuses on the central role of different preconcentration approaches, both before and after VG process. The former was based on the classical solid phase and liquid-liquid extraction procedures which, aided by automation and miniaturization strategies, have strengthened the role of VGT-AS in several research fields including environmental, clinical, and others. We then examine some of the new vapor trapping strategies (atom-trapping, hydride trapping, cryotrapping) that entail improvements in selectivity through interference elimination, but also they allow reaching ultra-low detection limits for a large number of chemical species generated in conventional VG systems, including complete separation of several species of the same element. This review covers more than 100 bibliographic references from 2009 up to date, found in SCOPUS database and in individual searches in specific journals. We finally conclude by giving some outlook on future directions of this field. PMID- 25937103 TI - Thermally induced solid-state transformation of cimetidine. A multi spectroscopic/chemometrics determination of the kinetics of the process and structural elucidation of one of the products as a stable N3-enamino tautomer. AB - Exposure of cimetidine (CIM) to dry heat (160-180 degrees C) afforded, upon cooling, a glassy solid containing new and hitherto unknown products. The kinetics of this process was studied by a second order chemometrics-assisted multi-spectroscopic approach. Proton and carbon-13 nuclear magnetic resonance (NMR), as well as ultraviolet and infrared spectroscopic data were jointly used, whereas multivariate curve resolution with alternating least squares (MCR-ALS) was employed as the chemometrics method to extract process information. It was established that drug degradation follows a first order kinetics. One of the products was structurally characterized by mono- and bi-dimensional NMR experiments. It was found to be the N3-enamino tautomer (TAU) of CIM, resulting from the thermal isomerization of the double bond of the cyanoguanidine moiety of the drug, from the imine form to its N3-enamine state. The thus generated tautomer demonstrated to be stable for months in the glassy solid and in methanolic solutions. A theoretical study of CIM and TAU revealed that the latter is less stable; however, the energy barrier for tautomer interconversion is high enough, precluding the process to proceed rapidly at room temperature. PMID- 25937104 TI - An integrated platform for gas-diffusion separation and electrochemical determination of ethanol on fermentation broths. AB - An integrated platform was developed for point-of-use determination of ethanol in sugar cane fermentation broths. Such analysis is important because ethanol reduces its fuel production efficiency by altering the alcoholic fermentation step when in excess. The custom-designed platform integrates gas diffusion separation with voltammetric detection in a single analysis module. The detector relied on a Ni(OH)2-modified electrode. It was stabilized by uniformly depositing cobalt and cadmium hydroxides as shown by XPS measurements. Such tests were in accordance with the hypothesis related to stabilization of the Ni(OH)2 structure by insertion of Co(2+) and Cd(2+) ions in this structure. The separation step, in turn, was based on a hydrophobic PTFE membrane, which separates the sample from receptor solution (electrolyte) where the electrodes were placed. Parameters of limit of detection and analytical sensitivity were estimated to be 0.2% v/v and 2.90 MUA % (v/v)(-1), respectively. Samples of fermentation broth were analyzed by both standard addition method and direct interpolation in saline medium based analytical curve. In this case, the saline solution exhibited ionic strength similar to those of the samples intended to surpass the tonometry colligative effect of the samples over analyte concentration data by attributing the reduction in quantity of diffused ethanol vapor majorly to the electrolyte. The approach of analytical curve provided rapid, simple and accurate analysis, thus contributing for deployment of point-of-use technologies. All of the results were accurate with respect to those obtained by FTIR method at 95% confidence level. PMID- 25937105 TI - Sample preparation techniques coupled to advanced chromatographic methods for marine organisms investigation. AB - OBJECTIVE: of this work was to develop suitable extraction methodologies for the isolation of lipids from fish, mussels and clams from the Mediterranean sea, and their successive analysis by means of advanced chromatographic instrumentation. More specifically, three different sample preparation methodologies were adopted: Folch's, Bligh & Dyer's and maceration. The lipidic extracts, after application of two different methylation procedures, were subjected to monodimensional and comprehensive two-dimensional GC analyses, in order to compare the fingerprints of samples derived from different extraction and transesterification methodologies. Triacylglycerols (TAGs) were analyzed by an off-line combination of silver-ion liquid chromatography with non-aqueous reversed phase liquid chromatography. In both LC and GC analyses, mass spectrometric detectors were used, which greatly supported the identification procedure. In particular, with respect to HPLC, mass spectrometry with atmospheric pressure chemical ionization in positive mode was applied. PMID- 25937106 TI - Air-assisted liquid-liquid microextraction by solidifying the floating organic droplets for the rapid determination of seven fungicide residues in juice samples. AB - A novel air assisted liquid-liquid microextraction using the solidification of a floating organic droplet method (AALLME-SFO) was developed for the rapid and simple determination of seven fungicide residues in juice samples, using the gas chromatography with electron capture detector (GC-ECD). This method combines the advantages of AALLME and dispersive liquid-liquid microextraction based on the solidification of floating organic droplets (DLLME-SFO) for the first time. In this method, a low-density solvent with a melting point near room temperature was used as the extraction solvent, and the emulsion was rapidly formed by pulling in and pushing out the mixture of aqueous sample solution and extraction solvent for ten times repeatedly using a 10-mL glass syringe. After centrifugation, the extractant droplet could be easily collected from the top of the aqueous samples by solidifying it at a temperature lower than the melting point. Under the optimized conditions, good linearities with the correlation coefficients (gamma) higher than 0.9959 were obtained and the limits of detection (LOD) varied between 0.02 and 0.25 MUgL(-1). The proposed method was applied to determine the target fungicides in juice samples and acceptable recoveries ranged from 72.6% to 114.0% with the relative standard deviations (RSDs) of 2.3-13.0% were achieved. Compared with the conventional DLLME method, the newly proposed method will neither require a highly toxic chlorinated solvent for extraction nor an organic dispersive solvent in the application process; hence, it is more environmentally friendly. PMID- 25937107 TI - Gold nanoparticle-enhanced target (AuNPET) as universal solution for laser desorption/ionization mass spectrometry analysis and imaging of low molecular weight compounds. AB - Preparation is described of a durable surface of cationic gold nanoparticles (AuNPs), covering commercial and custom-made MALDI targets, along with characterization of the nanoparticle surface properties and examples of the use in MS analyses and MS imaging (IMS) of low molecular weight (LMW) organic compounds. Tested compounds include nucleosides, saccharides, amino acids, glycosides, and nucleic bases for MS measurements, as well as over one hundred endogenous compounds in imaging experiment. The nanoparticles covering target plate were enriched in sodium in order to promote sodium-adduct formation. The new surface allows fast analysis, high sensitivity of detection and high mass determination accuracy. Example of application of new Au nanoparticle-enhanced target for fast and simple MS imaging of a fingerprint is also presented. PMID- 25937108 TI - Towards the chiral metabolomics: Liquid chromatography-mass spectrometry based DL amino acid analysis after labeling with a new chiral reagent, (S)-2,5 dioxopyrrolidin-1-yl-1-(4,6-dimethoxy-1,3,5-triazin-2-yl)pyrrolidine-2 carboxylate, and the application to saliva of healthy volunteers. AB - A novel triazine-type chiral derivatization reagent, i.e., (S)-2,5 dioxopyrrolidin-1-yl-1-(4,6-dimethoxy-1,3,5-triazin-2-yl) pyrrolidine-2 carboxylate (DMT-(S)-Pro-OSu), was developed for the highly sensitive and selective detection of chiral amines and amino acids by UPLC-MS/MS analysis. The enantiomers of amino acids were easily labeled with the reagents at room temperature within 40 min in an alkaline medium containing triethylamine. The diastereomers derived from proteolytic amino acids, except serine, were well separated under isocratic elution conditions by reversed-phase chromatography using an ODS column (Rs=1.2-9.0). DL-Serine was separated by use of an ADME column which has relatively higher polar surface than the conventional ODS column. The characteristic product ions, i.e., m/z 195.3 and m/z 209.3, were detected from all the diastereomers by the collision-induced dissociation of the protonated molecule. A highly sensitive detection on the amol-fmol level was obtained from the selected reaction monitoring (SRM) chromatogram. The chiral amines (e.g., adrenaline and noradrenaline) labeled with DMT-(S)-Pro-OSu were also well separated and sensitively detected by the present procedure. The method using DMT-(S)-Pro-OSu was used for the determination of DL-amino acids in the human saliva from healthy volunteers. Various L-amino acids were identified in the saliva. Furthermore, D-alanine (D-Ala) and D-proline (D-Pro) were also detected in relatively high concentrations (>5%). The ratio was higher in male saliva than in female saliva. However, the difference in the ratio of D-Ala for one day was not very high and the effect of foods and beverage seemed to be negligible. Based on the results using L-Ala-d3, the D-Ala in saliva seemed to be produced due to the racemization with some enzymes such as racemase. The racemization reaction was reversible, i.e., D-Ala-d3 was also racemized to L-Ala d3 in saliva. Thus, care should be taken during the analysis of DL-amino acids in saliva. The present method using DMT-(S)-Pro-OSu may be applicable for the determination of chiral amine metabolomics, because the resulting derivatives produce the same product ions without relation to the compounds and show highly sensitive detection in the SRM mode of MS/MS. Consequently, DMT-(S)-Pro-OSu seems to be a useful chiral derivatization reagent for the determination of amines and amino acids in biological samples. PMID- 25937109 TI - Double-ion imprinted polymer @magnetic nanoparticles modified screen printed carbon electrode for simultaneous analysis of cerium and gadolinium ions. AB - A typical, reproducible, and rugged screen printed carbon electrode, modified with dual-ion imprinted beads, was fabricated employing the "surface grafting from" approach. For this, the acyl chloride functionalized magnetic nanoparticles were first immobilized and chemically attached with a typical functional monomer (but-2-enedioic acid bis-[(2-amino-ethyl)-amide]) on the electrode surface. This was subsequently subjected to the thermal polymerization in the presence of template ions (Ce(IV) and Gd(III)), cross-linker (ethylene glycol dimethacrylate), initiator (AIBN), and multiwalled carbon nanotubes. The modified sensor was used for the simultaneous analysis of both template ions in aqueous, blood serum, and waste-water samples, using differential pulse anodic stripping voltammetry which revealed two oxidation peaks for respective templates with resolution as much as 950 mV, without any cross reactivity, interferences and false-positives. The detection limits realized by the proposed sensor, under optimized conditions, were found to be as low as 0.07 ng mL(-1) for Ce(IV) and 0.19 ng mL(-1) for Gd(III) (S/N=3) that could eventually be helpful for lanthanide estimation at stringent levels. PMID- 25937110 TI - Sensitive colorimetric assays for alpha-glucosidase activity and inhibitor screening based on unmodified gold nanoparticles. AB - A colorimetric sensor has been developed in this work to sensitively detect alpha glucosidase activity and screen alpha-glucosidase inhibitors (AGIs) utilizing unmodified gold nanoparticles (AuNPs). The sensing strategy is based on triple catalytic reaction triggered by alpha-glucosidase. In the presence of alpha glucosidase, aggregation of AuNPs is prohibited due to the oxidation of cysteine to cystine in the system. However, with addition of AGIs, cysteine induced aggregation of AuNPs occurs. Thus, a new method for alpha-glucosidase activity detection and AGIs screening is developed by measuring the UV-vis absorption or visually distinguishing. A well linear relation is presented in a range of 0.0025 0.05 U mL(-1). The detection limit is found to be 0.001 U mL(-1) for alpha glucosidase assay, which is one order of magnitude lower than other reports. The IC50 values of four kinds of inhibitors observed with this method are in accordance with other reports. The using of unmodified AuNPs in this work avoids the complicated and time-consuming modification procedure. This simple and efficient colorimetric method can also be extended to other enzymes assays. PMID- 25937111 TI - Characteristics of dendroaspis natriuretic peptide and its receptor in streptozotocin-induced diabetic rats. AB - Dendroaspis natriuretic peptide (DNP) shares a functionally important sequence homology with other natriuretic peptides. However, the characteristics of DNP and its receptor in the context of diabetes remafin to be fully elucidated. In the present study, alterations in the plasma levels and tissue contents of DNP and the properties of its receptor in diabetic rats, induced by streptozotocin (STZ) injection, were investigated. The plasma levels of DNP were 90.01 +/- 4.12 and 196.68 +/- 5.60 pg/ml in the control and STZ-induced diabetic rats, respectively. The tissue contents of DNP in the cardiac atrium, ventricle, renal cortex and inner medulla of the STZ-induced diabetic rats were also significantly increased compared with the control rats. Specific (125)I-DNP-binding sites were located predominantly in the glomeruli and inner medulla of the rat kidney. In the glomeruli of the kidney, the apparent dissociation constants (Kd) of (125)I-DNP in the control and STZ-induced diabetic rats were 0.41 +/- 0.03 and 0.56 +/- 0.06 nM, respectively. The maximum binding capacities (Bmax) of (125)I-DNP in control and STZ-induced diabetic rats were 2.98 +/- 0.21 and 6.22 +/- 1.06 fmol/mg protein, respectively. However, no differences were observed in the apparent Kd and Bmax of (125)I-DNP in the inner medulla of the kidney between the control and STZ-induced diabetic rats. In the glomerular and inner medullary kidney membranes, DNP stimulated the production of cyclic guanosine monophosphate (cGMP) in a dose-dependent manner. The magnitude of cGMP production in glomerular membranes was greater in the STZ-induced diabetic rats, whereas the magnitude of cGMP production in the inner medullary membranes was lower in the STZ-induced diabetic rats compared with the control rats. These results indicated that STZ induced diabetes modulate DNP and its receptor, and also suggested that modulation of the DNP system is involved in the renal function of diabetic animals via the intracellular domain of the kidney NP receptor. PMID- 25937112 TI - Traumatic high-grade L5-S1 spondylolisthesis with vertebral physeal injury. PMID- 25937113 TI - Type II Klippel-Feil syndrome with accompanying rare costa deformity: rib fusion. PMID- 25937114 TI - Intraspinal neuroblastoma. PMID- 25937115 TI - Spinal meningioma causing cervicothoracic rotoscoliosis. PMID- 25937116 TI - A rare cause of episodic paresthesia: spinal cavernoma. PMID- 25937117 TI - A quantitative analysis of posterolateral approaches to the ventral thoracic spinal canal. AB - BACKGROUND CONTEXT: Various posterolateral approaches exist to access ventral thoracic spinal canal pathologies. Selecting the optimal surgical approach requires sound understanding of the exposure and working angle afforded by each approach. PURPOSE: The purpose of this study was to quantify exposure of the ventral spinal canal with various posterolateral thoracic spinal approaches and to determine how regional anatomical differences affect measurements. STUDY DESIGN: This is a quantitative anatomical cadaveric study. METHODS: Four fresh cadaveric C7-L1 specimens were used with a saline infusion model to mimic in vivo thecal sac dimensions. Using stereotactic navigation, we measured exposure (expressed as percentage of total width) and maximum approach angle of the ventral spinal canal without thecal sac retraction after each surgical condition: laminectomy (L), 50% medial facetectomy (MF), transpedicular (TP), costotransversectomy (CTV), and lateral extracavitary (LE). The thoracic spine was divided into four regions (T1-T2, T3-T6, T7-T10, and T9-T12). A two-sided paired t test was used. RESULTS: At T1-T2, visualized exposures were 25.8%, 31.5%, 42.3%, 45.1%, and 46.8%, respectively, after each surgical condition. Costotransversectomy and LE did not provide significant increase in exposure compared with the preceding condition. At T3-T6, exposures were 19.1%, 29.6%, 38.7%, 44.4%, and 44.5%, respectively. Only LE did not provide significant increase in exposure compared with the preceding condition. At T7-T10, visualized exposures were 17.9%, 30.6%, 39.9%, 44.9%, and 53.3%, respectively. All successive surgical conditions provided a significant increase in exposure. At T11-T12, visualized exposures were 14.2%, 25.8%, 43.1%, 47.7%, and 52.7%, respectively. Only LE did not provide a significant increase in exposure compared with the preceding condition. Each successive surgical condition provided a significantly increased lateral approach angle compared with the preceding condition, except LE at T1-T2. Maximum approach angle was more favorable at T1-T2 for L, MF, TP, and CTV compared with other thoracic regions. CONCLUSIONS: Medial facetectomy and TP approaches provide significantly increased exposure of the ventral spinal canal at all thoracic regions. Costotransversectomy provided significantly increased exposure compared with TP at T3-T12. Lateral extracavitary only provided significantly increased exposure compared with CTV at T7-T10. The results of this study can be used preoperatively to determine the optimal approach based on quantitative measurements and region-specific anatomical differences. PMID- 25937118 TI - RSRC1 SUMOylation enhances SUMOylation and inhibits transcriptional activity of estrogen receptor beta. AB - The transcription factor estrogen receptor beta (ERbeta) plays roles in the central nervous, endocrine, cardiovascular, and immune systems. ERbeta can be SUMOylated. However, the underlying mechanism remains unclear. Here, we show that RSRC1/SRrp53 interacts with ERbeta and SUMOylation of RSRC1 is required for regulation of PIAS1-mediated ERbeta SUMOylation. RSRC1 promotes ERbeta SUMOylation through enhanced interaction between ERbeta and PIAS1. RSRC1 represses ERbeta transcriptional activity through regulation of ERbeta SUMOylation. By establishing RSRC1 as a novel cofactor for SUMOylation, our data provide insight into regulation of ERbeta SUMOylation and indicate that SUMOylation of one protein can regulate another protein SUMOylation. PMID- 25937119 TI - VPS29-VPS35 intermediate of retromer is stable and may be involved in the retromer complex assembly process. AB - Retromer is a complex of proteins that functions in the endosome-to-Golgi retrieval cargo transport pathway. VPS35 works as the central subunit of retromer to recognize the cargos and binds with VPS29 and VPS26 via distinct domains. We show that deficiency of VPS35 or VPS29 accompanies degradation of other subunits, whereas VPS26 deficiency had no effect on VPS29 and VPS35 levels. Although VPS35 forms VPS26-VPS35 and VPS29-VPS35 sub-complexes with similar efficiency in vitro, VPS26-VPS35 was more easily degradable by the ubiquitin-proteasome-system than VPS29-VPS35. These results indicate that VPS29 and VPS35 form a biologically stable sub-complex in vivo. PMID- 25937120 TI - Growth control mechanisms in neuronal regeneration. AB - Neurons grow during development and extend long axons to make contact with their targets with the help of an intrinsic program of axonal growth as well as a range of extrinsic cues and a permissive milieu. Injury events in adulthood induce some neuron types to revert to a regenerative state in the peripheral nervous system (PNS). Neurons from the central nervous system (CNS), however, reveal a much lower capacity for regenerative growth. A number of intrinsic regeneration promoting mechanisms have been described, including priming by calcium waves, epigenetic modifications, local mRNA translation, and dynein-driven retrograde transport of transcription factors (TFs) or signaling complexes that lead to TF activation and nuclear translocation. Differences in the availability or recruitment of these mechanisms may partially explain the limited response of CNS neurons to injury. PMID- 25937121 TI - Membrane protein production in Escherichia coli cell-free lysates. AB - Cell-free protein production has become a core technology in the rapidly spreading field of synthetic biology. In particular the synthesis of membrane proteins, highly problematic proteins in conventional cellular production systems, is an ideal application for cell-free expression. A large variety of artificial as well as natural environments for the optimal co-translational folding and stabilization of membrane proteins can rationally be designed. The high success rate of cell-free membrane protein production allows to focus on individually selected targets and to modulate their functional and structural properties with appropriate supplements. The efficiency and robustness of lysates from Escherichia coli strains allow a wide diversity of applications and we summarize current strategies for the successful production of high quality membrane protein samples. PMID- 25937123 TI - Similar regulation of two distinct UL24 promoters by regulatory proteins of equine herpesvirus type 1 (EHV-1). AB - To characterise the pattern of the transcriptional regulation of equine herpesvirus type 1 (EHV-1) UL24 by regulatory proteins, we identified two distinct promoter regions and two transcription initiation (Tci) sites located upstream of the UL24 open reading frame (ORF). The ORF proximal promoter exhibited higher cis-activity than that of the distal one. Contrary to the former, the latter performed its function dependent on an initiator (INR) due to its lack of a TATA box. Our results showed that the EHV-1 regulatory proteins EICP0, EICP22 and ETIF trans-activated the two promoters, whereas IEP and IR2P displayed negative regulation. In summary, the regulatory proteins exhibited similar regulatory patterns for the two distinct promoters of EHV-1 UL24. PMID- 25937122 TI - Selective permeabilization of cervical cancer cells to an ionic DNA-binding cytotoxin by activation of P2Y receptors. AB - Extracellular ATP is known to permeabilize certain cell types to polyatomic cations like YO-PRO1. Here, we report that extracellularly applied ATP stimulated rapid uptake and accumulation of an otherwise weakly membrane permeable fluorescent DNA-binding cytotoxin, Hoechst 33258, into cervical cancer cells. While ATP stimulated Hoechst 33258 uptake in 20-70% of cells from seven cervical cancer cell lines, it stimulated uptake in less than 8% of cervical epithelial cells obtained from the normal transformation zone and ectocervix tissue of 11 patients. ATP-evoked Hoechst 33258 uptake was independent of ionotropic P2X receptors, but dependent on activation of P2Y receptors. Thus, we show here that cervical cancer cells can be selectively induced to take up and accumulate an ionic cytotoxin by exposure to extracellular ATP. PMID- 25937124 TI - Mechanisms of RNA loading into exosomes. AB - Upon fusion of multivesicular bodies (MVBs) with the plasma membrane, intraluminal vesicles (ILVs) are released into the extracellular space as exosomes. Since the lipid composition of the exosomal membrane resembles that of raft microdomains, the inward budding process involves the raft-like region of the MVB limiting membrane. Although published research suggests that cellular RNAs may be selectively sorted into exosomes, the molecular mechanisms remain elusive. In this review, we suggest that there is a continuous interaction of cellular RNAs with the outer (cytoplasmic) surface of MVBs and that the selection for incorporation of these RNAs into ILVs is based on their affinity to the raft like region in the outer layer of the MVB membrane. PMID- 25937125 TI - Cotranslational incorporation of non-standard amino acids using cell-free protein synthesis. AB - Over the last years protein engineering using non-standard amino acids has gained increasing attention. As a result, improved methods are now available, enabling the efficient and directed cotranslational incorporation of various non-standard amino acids to equip proteins with desired characteristics. In this context, the utilization of cell-free protein synthesis is particularly useful due to the direct accessibility of the translational machinery and synthesized proteins without having to maintain a vital cellular host. We review prominent methods for the incorporation of non-standard amino acids into proteins using cell-free protein synthesis. Furthermore, a list of non-standard amino acids that have been successfully incorporated into proteins in cell-free systems together with selected applications is provided. PMID- 25937126 TI - Epstein-Barr virus-induced gene 3 (EBI3) polymorphisms and expression are associated with susceptibility to pulmonary tuberculosis. AB - Tuberculosis (TB) remains a major global health problem and host genetic factors play a critical role in susceptibility and resistance to TB. The aim of this study was to identify novel candidate genes associated with TB susceptibility. We performed a population-based case-control study to genotype 13 tag SNPs spanning Epstein-Barr virus-induced gene 3 (EBI3), colony stimulating factor 2 (CSF2), IL 4, interferon beta 1 (IFNB1), chemokine (C-X-C motif) ligand 14 (CXCL14) and myeloid differentiation primary response gene 88 (Myd88) genes in 435 pulmonary TB patients and 375 health donors from China. We observed that EBI3 gene rs4740 polymorphism was associated with susceptibility to pulmonary tuberculosis (PTB) and the allele G was associated with a protective effect against PTB. Furthermore, EBI3 deficiency led to reduced bacterial burden and histopathological impairment in the lung of mice infected with Mycobacterium bovis BCG. Meanwhile, higher abundance of EBI3 was observed in the granuloma of PTB patients and in the lung tissue of BCG-infected mice. Of note, the expression of EBI3 in macrophages was remarkably induced by mycobacteria infection at both mRNA and protein level. In conclusion, EBI3 gene rs4740 polymorphism is closely associated with susceptibility to PTB and the elevation and enrichment of EBI3 in the lung which at least partially derived from macrophages may contribute to the exacerbation of mycobacterial infection. PMID- 25937127 TI - [The "two positions" lipoabdominoplasty]. AB - BACKGROUNDS: Lipoabdominoplasty is a way to improve morphological outcomes by treating the areas not accessible to resection during classical abdominoplasty, especially hips. However, patients can present a lateral and posterior fat extension, not accessible to an anterior liposuction. This situation is managed by a first step with liposuction in the prone position. The aim of this study was to determine whether lipoabdominoplasty performed in two positions increases morbidity compared with lipoabdominoplasty in supine position only. METHODS: This was a retrospective study of 137 patients who underwent lipoabdominoplasty between 2009 to 2013. Eighty-five patients underwent a one position lipoabdomynoplasty and 52 a two positions lipoabdomynoplasty. Medical records were reviewed to collect data regarding patient demographics, operative technique, volume of liposuction and complications. RESULTS: The posterior liposuction has significantly increased the length of procedure (mean: 43.3 minutes). The volume of liposuction was significantly higher when the procedure was performed with prone and supine position (2789.6 mL versus 1373.8 mL, P<0.001). There was no significant difference between the two groups regarding complications and blood loss. CONCLUSION: Lipoabdominoplasty in two positions is an effective technique with the same morbidity as a lipoabdominoplasty in supine position only. The procedure finds its indication, between classic abdominoplasty and bodylift, for patients with lateral and posterior fat extension without posterior skin excess. PMID- 25937128 TI - A validated ultra-high-performance liquid chromatography-tandem mass spectrometry method for the selective analysis of free and total folate in plasma and red blood cells. AB - A stable isotope dilution LC-MS/MS method is the method of choice for the selective quantitative determination of several folate species in clinical samples. By implementing an integrated approach to determine both the plasma and red blood cell (RBC) folate status, the use of consumables and time remains limited. Starting from a single 300MUl whole blood sample, the folate status in plasma and RBCs can be determined after separating plasma and RBCs and sequential washing of the latter with isotonic buffer, followed by reproducible lysis using an ammonium-based buffer. Acidification combines both liberation of protein bound folates and protein precipitation. Sample cleanup is performed using a 96-well reversed-phase solid-phase extraction procedure, similar for both plasma and RBC samples. Analyses are performed by UHPLC-MS/MS. Method validation was successfully performed based on EMA-guidelines and encompassed selectivity, carry over, linearity, accuracy, precision, recovery, matrix effect and stability. Plasma and RBC folates could be quantified in the range of 1-150nmol/l and 5 1500nmol/l, respectively. This method allows for the determination of 6 folate monoglutamates in both plasma and RBCs. It can be used to determine short and long term folate status in both normal and severely deficient subjects in a single analytical sequence. PMID- 25937129 TI - Performance of graphene sheets as stationary phase for capillary gas chromatographic separations. AB - This work presents the investigation of graphene as a new type of stationary phase for capillary GC separations. Graphene capillary column (0.25 mm, i.d.) achieved column efficiency of 3100 plates/m determined by n-dodecane at 120 degrees C. The obtained McReynolds constants suggested the weakly polar nature of graphene sheets as GC stationary phase. As evidenced, graphene stationary phase differs from the conventional phase (5% phenyl polysiloxane) in its resolving ability and retention behaviors, and achieved better separation for the Grob and other mixtures. The advantages of graphene stationary phase may mainly originate from its specific pi-pi stacking interaction as well as H-bonding interaction. Furthermore, graphene column exhibited good repeatability with relative standard deviation (RSD%) in the range of 0.01-0.07% for run-to-run and 2.5-6.7% for column-to-column, respectively. PMID- 25937130 TI - Chromatographic resolution of atropisomers for toxicity and biotransformation studies in pharmaceutical research. AB - Atropisomerism can be a complex concept for those who have not encountered it before. This paper discusses the experiments for identification, isolation, thermal stability, toxicity and biotransformation of various species. The identified atropisomers are a series of rotational hindered biaryl, rotational hindered amide, ring flip, and macrocycles atropisomers identified using supercritical fluid chromatography (SFC) and high performance liquid chromatography (HPLC). These technologies offered the advantage of separating various atropoenantiomers, atropdiastereomers and mixed atropisomers with other forms of stereoisomers in both analytical and preparative scales. With ultra performance convergence chromatography (UPC(2)), the detection of N-oxide atropisomer metabolites can be obtained at very low level thus enabling the observation of conversion in human plasma possible. As the resolution of atropisomers are related to the energy barriers on the rotational axis, a calculated computational protocol was developed to predict the formation. A threshold of 10kcal/mol was established for possible detection of the atropisomers' existence with chromatographic technologies at room temperature or above. The atropisomer with higher energy barrier (>20kcal/mol) were isolated via preparative chromatography and the isolates studied in vitro and in vivo for evaluation of their stability in human plasma. The detailed analytical method development to analyze the biotransformation of the atropisomers in human plasma are also discussed in this paper. PMID- 25937131 TI - Development and validation of a liquid chromatography-tandem mass spectrometry method for the quantitative determination of gamithromycin in animal plasma, lung tissue and pulmonary epithelial lining fluid. AB - A sensitive and specific method for the quantitative determination of gamithromycin in animal plasma, lung tissue and pulmonary epithelial lining fluid (PELF) using liquid chromatography combined with heated electrospray ionization tandem mass spectrometry (LC-MS/MS) was developed. The sample preparation was rapid, straightforward and consisted of a deproteinization and phospholipid removal step using an Oasis((r)) OstroTM 96-well plate (chicken, turkey and calf plasma) or HybridSPE((r))-Phospholipid SPE cartridges (pig plasma and turkey lung tissue), while a liquid-liquid extraction with diethyl ether in alkaline medium was used for PELF of turkey poults. Chromatography was performed on a C18 Hypersil GOLD column using 0.01M ammonium acetate in water with a pH of 9, and acetonitrile as mobile phases. The MS/MS instrument was operated in the positive electrospray ionization mode and the following selected reaction monitoring transitions were monitored for gamithromycin (protonated molecule>product ion): m/z 777.45>619.35 and m/z 777.45>157.80 for quantification and identification, respectively. The method was validated in-house: matrix-matched calibration graphs were prepared and good linearity (r>=0.99) was achieved over the concentration ranges tested (2.5-10,000ngmL(-1) for chicken, pig and calf plasma; 5.0-2500ngmL(-1) for turkey plasma; 50-10,000ngg(-1) for turkey lung tissue and 20-1000ngmL(-1) for turkey PELF). Limits of quantification (LOQ) were 2.5ngmL(-1) for chicken, pig and calf plasma and 5.0ngmL(-1) for turkey plasma, while the limits of detection (LOD) ranged between 0.007 and 0.07ngmL(-1). For lung tissue and PELF, respective LOQ and LOD values of 50ngg(-1) and 0.76ngg(-1) (lung tissue) and 20ngmL(-1) and 0.1ngmL(-1) (PELF) were obtained. The results for the within-day and between-day precision, expressed as relative standard deviation (RSD), fell within the maximal RSD values. The accuracy fell within -30% to +10% (concentrations 1-10ngmL(-1)) or -20% to +10% (concentrations>10ngmL(-1) or ngg( 1)) of the theoretical concentration. The method was successfully applied for the quantitative determination of gamithromycin in plasma samples of chickens, turkeys, pigs and calves; and in lung tissues and PELF of turkeys, all derived from pharmacokinetic studies in these animal species. PMID- 25937132 TI - The effects of electrolysis on operational solutions in electromembrane extraction: The role of acceptor solution. AB - Fundamental operational principle and instrumental set-up of electromembrane extraction (EME) suggest that electrolysis may play an important role in this recently developed micro-extraction technique. In the present study, the effect of electrolysis in EME is described comprehensively for the first time and it is demonstrated that electrolysis considerably influences EME performance. Micro electromembrane extraction (MU-EME) across free liquid membrane formed by 1 pentanol was utilized for real-time monitoring of the electrolytically induced changes in composition of MU-EME solutions. These changes were visualized with a set of acid-base indicators. Changes in colours of their aqueous solutions revealed serious variations in their pH values, which occurred within seconds to minutes of the MU-EME process. Variations of up to eight pH units were observed for indicator solutions initially prepared in 1, 5 and 10mM hydrochloric acid. No or only negligible pH changes (less than 0.15 pH unit) were observed for indicator solutions prepared in 50 and 100mM acetic acid demonstrating that initial composition of the aqueous solutions was the crucial parameter. These results were also confirmed by theoretical calculations of maximum pH variations in the solutions, which were based on total electric charge transfers measured in the MU-EME systems, and by exact measurements of their pH values after MU-EMEs. Acceptor solutions that, in the current practice, consist predominantly of low concentrations of strong mineral acids or alkali hydroxides may thus not always ensure adequate EME performance, which was manifested by decrease in extraction recoveries of a basic drug papaverine. A suitable remedy to the observed effects is the application of acceptor solutions containing high concentrations of weak acids or bases. These solutions not only eliminate the decrease in recoveries but also serve well as matrices of extracted samples for subsequent analysis by capillary electrophoresis. PMID- 25937133 TI - Potassium ion channel openers, Maxipost and Retigabine, protect against peripheral salicylate ototoxicity in rats. AB - Sodium Salicylate (SS) reliably induces a sensorineural hearing loss and tinnitus when administered in high doses. Recent animal modeled studies indicate that potassium channel openers such as Maxipost and Retigabine (RTG) can block SS- or noise-induced tinnitus respectively; however, the origins and mechanisms are poorly understood. Since SS blocks the same potassium channels that Maxipost and RTG open, we postulated that these drugs might influence peripheral auditory function. To test this hypothesis Maxipost or RTG were administered alone or in combination with SS in rats. When administered alone, Maxipost and RTG had no effect on distortion product otoacoustic emissions (DPOAE) or compound action potentials (CAPs). However when Maxipost or RTG were administered with SS, Maxipost prevented the SS-reduced CAP amplitudes at high frequencies (>=20 kHz) and RTG prevented SS-reduced CAP amplitudes at low frequencies (<=8 kHz). These results suggest that Maxipost and RTG can protect against peripheral damage and therefore reduce the incidence of tinnitus. PMID- 25937134 TI - Evidence for differential modulation of primary and nonprimary auditory cortex by forward masking in tinnitus. AB - It has been proposed that tinnitus is generated by aberrant neural activity that develops among neurons in tonotopic of regions of primary auditory cortex (A1) affected by hearing loss, which is also the frequency region where tinnitus percepts localize (Eggermont and Roberts 2004; Roberts et al., 2010, 2013). These models suggest (1) that differences between tinnitus and control groups of similar age and audiometric function should depend on whether A1 is probed in tinnitus frequency region (TFR) or below it, and (2) that brain responses evoked from A1 should track changes in the tinnitus percept when residual inhibition (RI) is induced by forward masking. We tested these predictions by measuring (128 channel EEG) the sound-evoked 40-Hz auditory steady-state response (ASSR) known to localize tonotopically to neural sources in A1. For comparison the N1 transient response localizing to distributed neural sources in nonprimary cortex (A2) was also studied. When tested under baseline conditions where tinnitus subjects would have heard their tinnitus, ASSR responses were larger in a tinnitus group than in controls when evoked by 500 Hz probes while the reverse was true for tinnitus and control groups tested with 5 kHz probes, confirming frequency-dependent group differences in this measure. On subsequent trials where RI was induced by masking (narrow band noise centered at 5 kHz), ASSR amplitude increased in the tinnitus group probed at 5 kHz but not in the tinnitus group probed at 500 Hz. When collapsed into a single sample tinnitus subjects reporting comparatively greater RI depth and duration showed comparatively larger ASSR increases after masking regardless of probe frequency. Effects of masking on ASSR amplitude in the control groups were completely reversed from those in the tinnitus groups, with no change seen to 5 kHz probes but ASSR increases to 500 Hz probes even though the masking sound contained no energy at 500 Hz (an "off frequency" masking effect). In contrast to these findings for the ASSR, N1 amplitude was larger in tinnitus than control groups at both probe frequencies under baseline conditions, decreased after masking in all conditions, and did not relate to RI. These results suggest that aberrant neural activity occurring in the TFR of A1 underlies tinnitus and its modulation during RI. They indicate further that while neural changes occur in A2 in tinnitus, these changes do not reflect the tinnitus percept. Models for tinnitus and forward masking are described that integrate these findings within a common framework. PMID- 25937136 TI - Insulin-like growth factor 1: A novel treatment for the protection or regeneration of cochlear hair cells. AB - Sensorineural hearing loss (SNHL) is mainly caused by cochlear hair cell damage. Because cochlear hair cells and supporting cells lose their ability to proliferate in postnatal mammals, SNHL was thought to be an intractable disease. The maintenance of hair cell and supporting cell numbers after cochlear injury is therefore important for the treatment of sensorineural hearing loss. To achieve such treatment, protection and/or regeneration of hair cells is necessary. Progress in cochlear injury research, developmental biology, and regenerative medicine has led to the discovery of cochlear hair cells being protected or regenerated not only by direct reaction of hair cells themselves but also by that of supporting cells. Insulin-like growth factor 1 (IGF1) is considered a novel and potent treatment for SNHL based on the findings of various in vivo and in vitro experiments and clinical trials. The application of IGF1 maintains hair cell number of postnatal mammalian cochleae after various kinds of ototoxicity including aminoglycoside treatment, noise exposure, and ischemia. The positive effects of IGF1 on hair cell damage have been confirmed with in vivo animal experiments; hearing recovery in patients with sudden sensorineural hearing loss refractory to systemic glucocorticoid treatment has also been shown to occur following IGF1 treatment. The mechanisms of IGF1-induced maintenance of hair cell number have been investigated using a cochlear explant culture system, which demonstrated that IGF1 acts on supporting cells, leading to the inhibition of hair cell apoptosis and the proliferation of supporting cells. Netrin1 has furthermore been identified as one of the effectors whose expression is increased by IGF1 treatment. PMID- 25937137 TI - Serpentine supravenous hyperpigmentation induced by docetaxel. PMID- 25937135 TI - No longer falling on deaf ears: mechanisms of degeneration and regeneration of cochlear ribbon synapses. AB - Cochlear ribbon synapses are required for the rapid and precise neural transmission of acoustic signals from inner hair cells to the spiral ganglion neurons. Emerging evidence suggests that damage to these synapses represents an important form of cochlear neuropathy that might be highly prevalent in sensorineural hearing loss. In this review, we discuss our current knowledge on how ribbon synapses are damaged by noise and during aging, as well as potential strategies to promote ribbon synapse regeneration for hearing restoration. PMID- 25937138 TI - Multifocal scrofuloderma overlying tuberculous dactylitis in an immunocompetent child. PMID- 25937139 TI - Diaper dermatitis with psoriasiform id eruptions. PMID- 25937140 TI - Pityriasis rubra pilaris mixed type III/IV successfully treated with narrow band ultraviolet B. PMID- 25937141 TI - Jellyfish dermatitis. PMID- 25937142 TI - Performance of a commercially available plant allergen series in the assessment of suspected occupational contact dermatitis to plants in north Indian patients. AB - BACKGROUND: Parthenium hysterophorus is the leading cause of phytogenic allergic contact dermatitis in India. The Indian Standard Series currently supplied by Systopic Laboratories Ltd and manufactured by Chemotechnique Diagnostics (r) contains parthenolide as the only allergen representing plant allergens. AIM: The study was conducted to assess the performance of the Chemotechnique plant series (PL-1000), consisting of 14 allergens, in patients with clinically suspected occupational contact dermatitis to plant allergens. METHODS: Ninety patients were patch tested with the Chemotechnique plant series from 2011 to 2013. Demographic details, clinical diagnosis and patch test results were recorded in the contact dermatitis clinic proforma. RESULTS: Of 90 patients, 24 (26.7%) showed positive reactions to one or more allergens in the plant series. Positive patch tests were elicited most commonly by sesquiterpene lactone mix in 19 (78.6%) patients, followed by parthenolide in 14 (57.1%), Achillea millefolium in 10 (42.9%) and others in decreasing order. CONCLUSION: The plant allergen series prepared by Chemotechnique Diagnostics is possibly not optimal for diagnosing suspected allergic contact dermatitis to plants in north Indians. Sesquiterpene lactone mix should replace parthenolide as the plant allergen in the Indian Standard Series until relevant native plant extracts are commercially available for patch testing. PMID- 25937143 TI - A first step toward liposome-mediated intracellular bacteriophage therapy. AB - OBJECTIVES: The emergence of antibiotic-resistant bacteria presents a severe challenge to medicine and public health. While bacteriophage therapy is a promising alternative to traditional antibiotics, the general inability of bacteriophages to penetrate eukaryotic cells limits their use against resistant bacteria, causing intracellular diseases like tuberculosis. Bacterial vectors show some promise in carrying therapeutic bacteriophages into cells, but also bring a number of risks like an overload of bacterial antigens or the acquisition of virulence genes from the pathogen. METHODS: As a first step in the development of a non-bacterial vector for bacteriophage delivery into pathogen-infected cells, we attempted to encapsulate bacteriophages into liposomes. RESULTS: Here we report effective encapsulation of the model bacteriophage lambdaeyfp and the mycobacteriophage TM4 into giant liposomes. Furthermore, we show that liposome associated bacteriophages are taken up into eukaryotic cells more efficiently than free bacteriophages. CONCLUSION: These are important milestones in the development of an intracellular bacteriophage therapy that might be useful in the fight against multi-drug-resistant intracellular pathogens like Mycobacterium tuberculosis. PMID- 25937144 TI - Cutaneous abscess caused by Corynebacterium lactis in a companion dog. AB - Many new, emerging and re-emerging diseases of humans are caused by pathogens which originate from animals or products of animal origin. Corynebacterium lactis, a recently described species of the genus Corynebacterium, was first isolated from milk of asymptomatic cows. In the present study a cutaneous abscess caused by C. lactis in a dog was recognized by cytologic and histologic examination in addition to 16S rRNA gene analysis of the microorganism. Therefore, C. lactis should be included among other bacterial species recognized as emerging pathogens for companion animals. PMID- 25937145 TI - Antimicrobial resistance and population structure of Staphylococcus epidermidis recovered from animals and humans. AB - While Staphylococcus epidermidis, as part of the commensal flora, is a well-known human opportunistic pathogen, only little is known about the genetic relatedness of S. epidermidis carriage isolates from animal and human origin. This study aimed to compare S. epidermidis recovered from livestock, livestock-farmers and humans associated with the hospital environment. A total of 193 S. epidermidis isolates from three populations [animals (n=33), farmers (n=86) and hospital associated (n=74)] were characterized by broth microdilution antimicrobial susceptibility testing, staphylococcal cassette chromosome mec (SCCmec) typing, pulsed field gel electrophoresis (PFGE) and multilocus sequence typing (MLST). The overall S. epidermidis nasal colonization rate was low in animals (1-9%) but high among farmers (75%). High levels of multi-resistance were found in all populations. Tetracycline resistance was high in animal and farmer isolates; resistance to erythromycin, clindamycin and trimethoprim was high in animal and hospital-associated isolates. Methicillin-resistant S. epidermidis - MRSE isolates were found in all collections, with 22 (67%) MRSE in animals, 44 (51%) MRSE in farmers and 42 (57%) MRSE associated with the hospital-setting. Known SCCmec types and variants were detected in 79% of MRSE; the rest were non typeable cassettes. In total 79 PFGE-types were found, of which 22 were shared between livestock, farmers and the hospital settings. Clonal complex 2 was predominant in all three populations and most STs corresponded to types previously observed in community and nosocomial S. epidermidis populations. S. epidermidis isolates from livestock, farmers and hospital-setting showed a high level of diversity, but some clones can be found in humans as well as in animals. PMID- 25937146 TI - Inhaled Milrinone After Left Ventricular Assist Device Implantation. AB - BACKGROUND: Proven strategies to reduce right ventricular (RV) dysfunction after continuous-flow left ventricular assist device (CF-LVAD) implantation are lacking. We sought to evaluate the tolerability, feasibility, efficacy, and pharmacokinetics of inhaled milrinone (iMil) delivery after CF-LVAD implantation. METHODS AND RESULTS: We prospectively evaluated fixed-dose nebulized iMil delivered into a ventilator circuit for 24 hours in 10 postoperative CF-LVAD (Heartmate-II) patients. Tolerability (arrhythmias, hypotension, and hypersensitivity reaction), efficacy (hemodynamics), pharmacokinetics (plasma milrinone levels), and cost data were collected.Mean age was 56 +/- 9 years, 90% were male, and mean INTERMACS profile was 2.5 +/- 0.8. No new atrial arrhythmia events occurred, although 3 (30%) ventricular tachycardia (1 nonsustained, 2 sustained) events occurred. Sustained hypotension, drug hypersensitivity, death, or need for right ventricular assist device were not observed. Invasive mean pulmonary arterial pressure from baseline to during iMil therapy was improved (P = .017). Mean plasma milrinone levels (ng/mL) at baseline, and 1, 4, 8, 12, and 24 hours were 74.2 +/- 35.4, 111.3 +/- 70.9, 135.9 +/- 41.5, 205.0 +/- 86.7, 176.8 +/- 61.3 187.6 +/- 105.5, respectively. Reduced institutional cost was observed when iMil was compared with nitric oxide therapy over 24 hours ($165.29 vs $1,944.00, respectively). CONCLUSIONS: iMil delivery after CF-LVAD implantation was well tolerated, feasible, and demonstrated favorable hemodynamic, pharmacokinetic, and cost profiles. iMil therapy warrants further study in larger clinical trials. PMID- 25937147 TI - Dystroglycanopathy muscles lacking functional glycosylation of alpha-dystroglycan retain regeneration capacity. AB - In dystroglycanopathies, lack of glycosylated alpha-dystroglycan (alpha-DG) alters membrane fragility leading to fiber damage and repetitive cycles of muscle degeneration and regeneration. However the effect of the glycosylation of alpha DG on muscle regeneration is not clearly understood. In this study, we examined the regenerative capacity of dystrophic muscles in vivo in FKRP mutant and LARGE(myd) mice with little and complete lack of functionally glycosylated alpha DG (F-alpha-DG) respectively. The number of regenerating fibers expressing embryonic myosin heavy chain (eMyHC) in the diseased muscles up to the age of 10 months is higher than or at similar levels to wild type muscle after notexin and polyethyleminine insults. The process of fiber maturation is not significantly affected by the lack of F-alpha-DG assessed by size distribution. The earlier appearance of a larger number of regenerating fibers after injury is consistent with the observation that the populations of myogenic satellite cells are increased and being readily activated in the dystroglycanopathy muscles. F-alpha DG is expressed at trace amounts in undifferentiated myoblasts, but increases in differentiated myotubes in vitro. We therefore conclude that muscle regeneration is not impaired in the early stage of the dystroglycanopathies, and F-alpha-DG does not play a significant role in myogenic cell proliferation and fiber formation and maturation. PMID- 25937148 TI - Total Synthesis of Paecilomycin B. AB - Starting from the glucose-derived delta-lactone and the functionalized aryl bromide, the first total synthesis of naturally occurring paecilomycin B was achieved via functionalized aryl-beta-C-glycoside synthesis using 2,4,6 triisopropylphenyllithium under Barbier-type reaction conditions and ring-closing metathesis as the key steps. PMID- 25937149 TI - Tubeless versus standard PCNL in geriatric population. AB - INTRODUCTION AND OBJECTIVES: Percutaneous nephrolithotomy (PCNL) is a standard, safe, and efficient method for large-volume renal calculi for all age groups. Nephrostomy tube constitutes an invaluable part of the nephrolithotomy operation. However, the nephrostomy tube has been recently replaced with ureteral catheter or double J-stent thanks to advances in urotechnology and operation equipment. The aim of the current article was to evaluate the safety and reliability of tubeless percutaneous nephrolithotomy in the geriatric population. METHODS: Between January 2009 and September 2013, a total of 52 patients aged 65 years or elder with renal calculi bigger than 2cm underwent PCNL operation. The first group of 25 patients (48%) with a mean age of 70.0 years (std:+/-3,8) underwent tubeless PCNL whereas the second group consisting of 27 (52%) patients with a mean age of 71.3 years (std: +/-4,0) underwent standard PCNL. The patients were randomly compared retrospectively in terms of burden of calculus, analgesic requirement, creatinine value, renal parenchymal thickness, Body-mass index (BMI), clavien score, length of hospitalization, and being calculus-free. RESULTS: The groups were found to be similar in age, BMI, and gender (P>.05). Burden of calculus, duration of operation, and rate of narcotic analgesic use were found to be statistically significantly higher in the group of Standard PCNL group than in the Tubeless PCNL group (P<.05). Length of hospital stay was 1.7 days in the group of tubeless PCNL and 2.6 days in the standard PCNL group (P<.05). No significant difference was found between the groups in terms of fall in hemoglobin, creatinine, values of parenchymal thickness, and clavien score, preoperative blood transfusion, previous SWL, location of calculi, number of access, and rate of success (P>.05). Burden of calculus was 900 mm2 (304-4232) in the standard PCNL group and 600mm(2) (220-2660) in the tubeless PCNL group with the difference being statistically significant (P=.014). Overall success was achieved in 96.0 and 96.3% of tubeless PCNL and standard PCNL patients after one session of PCNL, respectively. CONCLUSIONS: Tubeless percutaneous nephrolithotomy was found to be as safe and effective as standard PCNL in the geriatric population. It is recommended especially in this group of patients because of its advantages such as shorter length of hospitalization, less analgesic requirement, and earlier mobilization. PMID- 25937150 TI - Protective Roles of Selenium on Nitric Oxide and the Gene Expression of Inflammatory Cytokines Induced by Cadmium in Chicken Splenic Lymphocytes. AB - Cadmium (Cd) is an environmental toxicant and an inflammation-related xenobiotic. Selenium (Se) is a well-known nutritional trace element and a potent chemopreventive agent. The present study aimed to investigate the effect of Se on the cytotoxicity of Cd in bird immunocytes in vitro. Chicken splenic lymphocytes exposed to CdCl2 (10(-6) mol/L), Na2SeO3 (10(-7) mol/L), or a mixture of the two (10(-7) mol/L Na2SeO3 and 10(-6) mol/L CdCI2) were incubated for 12, 24, 36, 48, or 60 h. Cd significantly increased (P < 0.05 or P < 0.01) the messenger RNA (mRNA) expression levels of nuclear factor kappaB (NF-kappaB), inducible nitric oxide synthase (iNOS), cyclooxygenase-2 (COX-2), tumor necrosis factor (TNF alpha), and prostaglandin E2 (PGE2), and similar results were observed in the protein expression levels of NF-kappaB and COX-2. In addition, the nitric oxide (NO) content and the inducible iNOS activity were increased in the Cd-treated group compared to the control group. Furthermore, the protective effects of Se against Cd toxicity in chicken splenic lymphocytes were illustrated by the increase in select cytokines (NF-kappaB, iNOS, COX-2, TNF-alpha, and PGE2), NO content and iNOS activity. The biochemical parameters exhibited sensitivity to Se and Cd, suggesting that they may act as potential biomarkers for assessing the effects of Se and Cd risk on chicken splenic lymphocytes. PMID- 25937151 TI - Enteropathogenic Escherichia coli (EPEC): Does it have a role in colorectal tumourigenesis? A Prospective Cohort Study. AB - BACKGROUND: Despite the characterization of many aetiologic genetic changes. The specific causative factors in the development of sporadic colorectal cancer remain unclear. This study was performed to detect the possible role of Enteropathogenic Escherichia coli (EPEC) in developing colorectal carcinoma. PATIENTS AND METHOD: Fresh biopsy specimens have been obtained from the colonic mucosa overlying the colorectal cancer as well as from the colon of the healthy controls. Culture, genotyping and virulence of EPEC were done using (nutrient broth culture, and PCR). Strains biochemically identified as Escherichia coli were selected from the surface of a MacConkey's plate and were serogrouped by slide agglutination tests. RESULTS: From January 2011 to June 2014, 213 colorectal cancer patients (Group 1) and 248 healthy controls (Group 2) were prospectively enrolled in this study. EPEC was positive in 108 (50.7%) in group 1 and 51 (20.6%) in group 2 (P = 0.0001). A significant difference between both groups was observed regarding serotyping, genotyping (eae gene) and virulence category (P = 0.0001). A significant difference between the 2 subgroups of colorectal cancer cases was observed regarding genotyping (eae, bfb genes) and virulence category. CONCLUSION: The incidence EPEC was higher significantly in patients with colorectal cancer. E. coli in patients with colorectal cancer significantly differed serotypically and genotypically from the E. coli in normal population. E. coli colonization of the colonic mucosa may be a cause colorectal cancer. PMID- 25937152 TI - Postoperative delirium in elderly after elective and acute colorectal surgery: A prospective cohort study. AB - OBJECTIVE: To assess the frailty and the incidence of delirium in elderly patients undergoing elective and acute colorectal surgery in correlation with morbidity and mortality. METHODS: Patients aged 65 years and older having elective and acute colorectal surgery, between April 2013 and December 2013 were included in a prospective database. Patients diagnosed with a colorectal carcinoma or diverticulitis who were operated on were included. Factors that characterize frailty of patients were noted. The incidence rates of delirium after elective and acute surgery were recorded. Delirium was diagnosed using the Delirium Observation Screening Scale (DOSS). Preoperative evaluation, surgical outcome including morbidity, hospital stay and mortality were analyzed. RESULTS: Patients >= 65 years were included, 83 (75%) received elective and 28 (25%) acute surgery. The overall incidence of delirium was 21%, 18% for elective and 29% for patients having urgent surgery (p = 0.24). Patients with delirium were older than the non-delirious patients (median 82 years vs. 74 years; p < 0.001). Delirious patients showed higher incidence of adverse events. Hospital stay, mortality and discharge to a nursing home were significant higher in the delirious compared to the non-delirious group (p = 0.01; 0.01; 0.02 respectively). CONCLUSION: High incidence of delirium was found in both acute and elective colorectal surgery. Delirium was associated with adverse outcomes. PMID- 25937153 TI - First recorded use of hernia mesh fixation solely with fibrin glue. PMID- 25937154 TI - ASA class is a reliable independent predictor of medical complications and mortality following surgery. AB - METHODS: The American Society of Anesthesiologists Physical Status classification system (ASA PS) is a method of characterizing patient operative risk on a scale of 1-5, where 1 is normal health and 5 is moribund. Every anesthesiologist is trained in this measure, and it is performed before every procedure in which a patient undergoes anesthesia. We measured the independent predictive value of ASA PS for complications and mortality in the ACS-NSQIP database by multivariate regression. We conducted analogous regressions after standardizing ASA-PS to control for interprocedural variations in risk in the overall model and sub analyses by surgical specialty and the most common procedures. RESULTS: For 2,297,629 cases (2005-2012; median age 55, min = 16, max > 90 [90 and above are coded as 90+]), at increasing levels of ASA-PS (2-5), odds ratios (OR's) from 2.05 to 63.25 (complications, p < 0.001) and 5.77-2011.92 (mortality, p < 0.001) were observed, with non-overlapping 95% confidence intervals. Standardization of ASA-PS (OR = 1.426 [per standard deviation above the mean ASA-PS per procedure], p < .001) and subgroup analyses yielded similar results. DISCUSSION: ASA PS was not only found to be associated with increased morbidity and mortality, but independently predictive when controlling for other comorbidities. Even after standardization based on procedure type, increases in ASA predicted significant increases in complication rates for morbidity and mortality post-operatively. CONCLUSIONS: ASA PS has strong, independent associations with post-operative medical complications and mortality across procedures. This capability, along with its simplicity, makes it a valuable prognostic metric. PMID- 25937156 TI - Factors influencing forces during laparoscopic pinching: Towards the design of virtual simulator. AB - BACKGROUND: The design of good virtual simulators for laparoscopic training requires realistic visual and tactile perception. This is a study to characterize the factors that contribute to forces during laparoscopic pinching. METHODS: Surgeons were divided into four groups according to years of experience in laparoscopic surgery. They were asked to grasp six different types of porcine abdominal tissue in a randomly sequenced manner, using two different types of sensorized graspers, under two regimes of perceptual feedback (with and without visual feedback). The forces (grasper handle force and grasper tip force) and grasper handle angle were recorded and analyzed. RESULTS: The factors that determine forces during laparoscopic pinching can be ranked as follows: surgical experience (p < .001), tissue type (p = .007) and visual feedback (p = .033), but not grasper type (p = .071). Handle force depends significantly on surgical experience (p < .001), tissue type (p = .001) and visual feedback (p = .019), but not on grasper type (p = .203). Tip force depends significantly on surgical experience (p < .001) and marginally on tissue type (p = .082) and visual feedback (p = .053) but not on the grasper type (p = .180). CONCLUSION: Forces during laparoscopic pinching depend on surgical experience, tissue type and presence of visual feedback but not on grasper type. Our data can be an input in the design of virtual simulators with force feedback, for training laparoscopic pinching. PMID- 25937155 TI - Single incision transumbilical laparoscopic varicocelectomy versus the conventional laparoscopic technique: A randomized clinical study. AB - BACKGROUND: Varicocele is the most common correctable cause of infertility. We analyzed the outcomes of single incision laparoscopic varicocelectomy (SIL-V) in comparison with conventional transperitoneal varicocelectomy (CTL-V). METHODS: Patients with clinically palpable varicocele treated by laparoscopic varicocelectomy were randomly allocated into two groups: SIL-V and CTL-V group. The primary outcome measures were improvement in semen parameters and resolution of testicular pain. Secondary outcome measures included operating time, postoperative pain scores, time to return to normal activity, patient satisfaction and postoperative complications. RESULTS: Eighty patients completed the study. No vascular or intestinal complications occurred during both procedures. All patients were discharged 24 h postoperatively. The parameters measuring the success of varicocelectomy had improved for the majority of patients with no significant difference between the two groups. There was significantly longer operating time in SIL-V group (44.6 +/- 5.4 min) than in CTL V group (41.3 +/- 8.5 min) (P = 0.03). The difference in operating time was lost when bilateral procedures were compared (P = 0.21). The mean VAS scores for pain at 3, 24 and 48 h postoperatively were significantly lower in SIL-V group (P = 0.02, P = 0.03 and P < 0.001 respectively). Time to return to normal activity was significantly shorter in SIL-V (P < 0.001). Patient satisfaction was significantly higher in SIL-V group (P < 0.01). Postoperative complications were comparable in both groups. CONCLUSION: SIL-V is a safe and effective straightforward alternative to the well-established and accepted CTL-V. The tendency toward decreased postoperative pain, rapid return to normal activity and the high patients' satisfaction rate regarding cosmetic results are potential benefits of SIL-V procedure. CLINICAL TRIAL: (NCT02335385). PMID- 25937157 TI - Randomized clinical trial comparing cold knife conization of the cervix with and without lateral hemostatic sutures. AB - OBJECTIVE: Compare blood loss during cold knife conization of the cervix with and without lateral hemostatic sutures in the cervical branches of the uterine arteries. DESIGN: Randomized clinical trial. SETTING: Hospital de Clinicas de Porto Alegre (HCPA). POPULATION: 102 patients that underwent cold knife conization. METHODS: Women that underwent cold knife conization of the cervix were randomized to undergo the procedure with or without lateral hemostatic sutures. MAIN OUTCOME MEASURES: PRIMARY OUTCOME MEASURE: blood loss measured in grams. SECONDARY OUTCOME MEASURES: operative time and postoperative intervention. Only the participants were blinded to group assignment. RESULTS: From March 2009 to August 2012, patients were randomly assigned to one of the study groups. There were no differences in amount of blood loss between patients that underwent the procedure with and without sutures (p = 0.39). Operative time was shorter in the group without suture (p = 0.020). There were no differences in intervention due to bleeding (p = 0.20). Blood loss was greater among menstruating women than for menopausal women (p = 0.011). There were no differences in amount of blood lost between smoking and nonsmoking patients (p = 0.082). CONCLUSIONS: Lateral hemostatic sutures do not affect the amount of intraoperative bleeding or the number of postoperative interventions. Their use is not necessary because they result in longer operative time, have a higher cost due to the use of suture material and pose the risk of ureter lesion in case the sutures are not placed at a lower position in the cervix. ClinicalTrials. gov identifier: NCT02184975. PMID- 25937158 TI - A canadian perspective on the first-line treatment of chronic lymphocytic leukemia. AB - Despite important advances in the treatment of first-line chronic lymphocytic leukemia (CLL) over the past decade, CLL remains an incurable disease with significant unmet needs. The combination of rituximab with fludarabine and cyclophosphamide (FCR) significantly improved overall survival and progression free survival compared with fludarabine and cyclophosphamide alone in first-line treatment of CLL. However, because of its high toxicity, FCR is only recommended for younger, fit patients who can tolerate the treatment. This excludes a large fraction of CLL patients who are elderly and/or who have comorbidities. Thus, determining the appropriate treatment choices for this group of patients who are unfit for FCR treatment is a significant challenge in CLL. Current treatment choices in Canadian practice include bendamustine with rituximab, fludarabine with rituximab, and chlorambucil with rituximab. Two novel monoclonal antibodies, ofatumumab and obinutuzumab, have also recently received Health Canada approval for the first-line treatment of CLL patients in combination with chlorambucil. In addition, the Bruton tyrosine kinase inhibitor, ibrutinib, has recently been approved by Health Canada for the first-line treatment of CLL patients with deletion 17p. In the coming years, several other novel agents that are being developed are likely to change the CLL treatment landscape dramatically, however, because these novel agents are currently unavailable, the purpose of this review is to recommend the best treatment approaches in Canada using currently available therapies. PMID- 25937159 TI - Effects of totally extraperitoneal (TEP) and Lichtenstein hernia repair on testicular blood flow and volume. AB - BACKGROUND: Laparoscopic totally extraperitoneal hernia repair (TEP) has been compared with the open technique in several studies in terms of technical properties and perioperative outcomes. There are few studies that compare the long-term effects of each technique on testicular structure and function on the side of the hernia repair. The objective of this study is to investigate the effects at 6 months of the TEP and the Lichtenstein technique on testicular volume and arterial flow by the use of Doppler ultrasonography. METHODS: A total of 148 men with a unilateral hernia were randomized prospectively to undergo TEP or Lichtenstein repair. In both groups, unilateral resistive indices, pulsatile indices of capsular and intratesticular artery flow, and testicular volume (in milliliters) were measured preoperatively and 6 months postoperatively by the use of grayscale and color Doppler ultrasonography (CDUS). The primary outcomes of the study were postoperative findings from history, physical examination, and CDUS measurements at 6 months postoperatively. Demographics, clinical and operative data, CDUS measurements, and recurrence patterns were analyzed. RESULTS: Of 148 procedures, 134 cases consisting of 64 TEP and 70 Lichtenstein repairs were evaluated. Pre- and postoperative CDUS findings, rates of complications, and recurrence in both groups did not show any difference. Operative time was greater with a Lichtenstein repair (36 vs 30 minutes; P = .01). CONCLUSION: Complications and recurrence rates and effects on testicular perfusion and testicular volume in both laparoscopic and open techniques are similar, whereas the laparoscopic approach has shorter operative time than open hernia repair. PMID- 25937160 TI - Feasibility and safety of porcine Descemet's membrane as a carrier for generating tissue-engineered corneal endothelium. AB - The aim of this study was to evaluate the feasibility and safety of porcine Descemet's membrane (DM) as a carrier for the generation of tissue-engineered corneal endothelium by analyzing porcine endogenous retroviruses (PERVs) and the alpha-gal epitope. The morphology of porcine and human DM was observed by hematoxylin and eosin staining and scanning electron microscopy. Immunohistochemical staining was used to investigate the location of alpha-gal epitopes on porcine DM used for xenotransplantation. The porcine DM was treated with ethylene glycol diglycidyl ether (EDGE) for 2 weeks, and then the PERV gene sequences in porcine DM and DM-EDGE were detected by polymerase chain reaction (PCR) and real-time PCR, respectively. The porcine DM had tight basement membrane morphology, which was similar to human DM in terms of thickness. No positive immunohistochemical staining of the alpha-gal epitope was detected in porcine DM. PERV expression of pol, gag, env-A and env-B was noted in porcine DM, but in DM EDGE it was completely degraded. Based on structural, immunological and etiological studies, porcine DM may be an ideal and viable carrier for the generation of tissue-engineered corneal endothelium. PMID- 25937161 TI - Prevalence of physical violence in a forensic psychiatric hospital system during 2011-2013: Patient assaults, staff assaults, and repeatedly violent patients. AB - Introduction We examined physical violence in a large, multihospital state psychiatric system during 2011-2013, and associated demographic and clinical characteristics of violent patients to better understand issues of patient and staff safety. METHOD: Acts of physical violence committed by patients against other patients (n=10,958) or against staff (n=8429) during 2011-2013 were collected and analyzed for all hospitalized patients during the same time period to derive prevalence rates and associated odds ratios. RESULTS: Overall, 31.4% of patients committed at least 1 violent assault during their hospitalization. Differential risk factor patterns were noted across patient and staff assault. Younger age was associated with a higher prevalence of both patient and staff assault, as was nonforensic legal status. Females had a higher prevalence of staff assault than patient assault. Ethnic groups varied on rates of patient assault, but had no significant differences for staff assault. Schizoaffective disorder was associated with higher prevalence and odds of patient (OR 1.244, 95% CI 1.131 to 1.370) and staff (OR 1.346, 95% CI 1.202 to 1.507) assault when compared to patients diagnosed with schizophrenia. Most personality disorder diagnoses also had a higher prevalence and odds of physical violence. One percent of patients accounted for 28.7% of all assaults. Additionally, violent patients had a significantly longer length of hospitalization. Discussion Implications of these findings to enhance patient safety and inform future violence reduction efforts, including the need for new treatments in conjunction with the use of violence risk assessments, are discussed. PMID- 25937163 TI - [Management of neonatal epidermolysis bullosa: clinical case]. PMID- 25937162 TI - The lateral prefrontal cortex mediates the hyperalgesic effects of negative cognitions in chronic pain patients. AB - Although high levels of negative affect and cognitions have been associated with greater pain sensitivity in chronic pain conditions, the neural mechanisms mediating the hyperalgesic effect of psychological factors in patients with pain disorders are largely unknown. In this cross-sectional study, we hypothesized that 1) catastrophizing modulates brain responses to pain anticipation and 2) anticipatory brain activity mediates the hyperalgesic effect of different levels of catastrophizing in fibromyalgia (FM) patients. Using functional magnetic resonance imaging, we scanned the brains of 31 FM patients exposed to visual cues anticipating the onset of moderately intense deep-tissue pain stimuli. Our results indicated the existence of a negative association between catastrophizing and pain-anticipatory brain activity, including in the right lateral prefrontal cortex. A bootstrapped mediation analysis revealed that pain-anticipatory activity in the lateral prefrontal cortex mediates the association between catastrophizing and pain sensitivity. These findings highlight the role of the lateral prefrontal cortex in the pathophysiology of FM-related hyperalgesia and suggest that deficits in the recruitment of pain-inhibitory brain circuitry during pain-anticipatory periods may play an important contributory role in the association between various degrees of widespread hyperalgesia in FM and levels of catastrophizing, a well-validated measure of negative cognitions and psychological distress. PERSPECTIVE: This article highlights the presence of alterations in pain-anticipatory brain activity in FM. These findings provide the rationale for the development of psychological or neurofeedback-based techniques aimed at modifying patients' negative affect and cognitions toward pain. PMID- 25937164 TI - Accuracy of body weight perception and obesity among Chinese Americans. AB - BACKGROUND: Accuracy of body weight perception is an individual's perception of their body weight in comparison with actual body weight and is associated with weight-related behaviors. Chinese Americans have increased risk for obesity but no studies have examined accuracy of body weight perception. METHODS: This study was a descriptive and cross-sectional study, which was conducted in a community health center in New York. Study subjects were all Chinese-American adults. Demographic information, accuracy of perception of body weight, anthropometric measures (weight, height, body mass index [BMI], waist circumference [WC], hip circumference [HC], weight to height ratio, weight to hip ratio), fasting plasma glucose (FPG), glycosylated hemoglobin (HbA1C) and obesity-related diseases (hypertension, diabetes, heart disease, and stroke) were assessed. RESULTS: A total of 162 Chinese Americans were recruited. 52 subjects (32%) did not perceive body weight correctly: 32 subjects had underestimation and 20 subjects had overestimation of body weight. Significant differences were found among subjects in the three groups of different accuracy of body weight perception in terms of gender (p=0.003), age (p=0.003), education years (p=0.047), WC (p<0.001), HC (p<=0.001), weight/height ratio (p=0.001), and BMI (p<0.001). Accuracy of perception of body weight significantly predicted WC (p<0.001), HC (p<0.001), weight to height ratio (p=0.001), BMI (p<0.001) and weight (<0.001) even after controlling for all demographic factors. DISCUSSION AND CONCLUSION: The study identified that around one-third of Chinese Americans did not perceive their body weight correctly. Intervention studies for obesity management in Chinese Americans should address gender difference, target on older subjects, and focus on educating the normal values and significances of WC, HC and HbA1C among Chinese Americans. PMID- 25937165 TI - Should weight loss and maintenance programmes be designed differently for men? A systematic review of long-term randomised controlled trials presenting data for men and women: The ROMEO project. AB - We systematically reviewed the randomised controlled trial (RCT) evidence for long-term (>=12 months) weight management interventions for obese men in contrast to women to help understand whether programmes should be designed differently for men. We searched 11 databases up to October 2014. Twenty-two RCTs reported data separately for men and women in weight loss or weight maintenance interventions. We found men were under-represented in RCTs of weight loss interventions open to both sexes. Men comprised 36% of participants (4771 from 13,305 participants). Despite this, men were 11% (95% CI 8-14%, p<0.001) more likely to be trial completers compared to women. The trials did not report service user consultation and none were designed to investigate whether men and women responded differently to given interventions. Our meta-analysis of 13 trials showed no significant difference in weight loss between men and women, either for weight loss in kg (p=0.90) or percentage weight loss (p=0.78), although men tended to lose more weight with intensive low fat reducing diets, with or without meal replacements, and structured physical activity/exercise programmes than women. Orlistat was less beneficial for men for weight maintenance. Individual support and tailoring appeared more helpful for men than women. We found evidence that men and women respond differently to, and have different preferences for, varying types of weight management programme. We suggest that it is important to understand men's views on weight loss, as this is likely to also improve the uptake and effectiveness of programmes for men. PMID- 25937166 TI - Transcatheter retrieval of device entrapment: management of a rare complication of percutaneous coronary intervention: case report and literature review. AB - With the continued advancement in PCI equipment and techniques, complications arising from intracoronary manipulation are encountered. Such complications are associated with major adverse outcome including death; myocardial infarction (MI) and the need for urgent coronary artery bypass surgery (CABG), and they require prompt recognition and mediation by the interventional cardiologist. We report a case of a broken stent shaft system in the setting of acute coronary syndrome and its successful retrieval using a non-compliant balloon to trap the proximal portion of the shaft within the guide ("trapping" a procedure used in coronary Chronic Total Occlusions (CTO) interventions) followed by slow withdrawal of the whole system. This was followed by successful PCI of the culprit lesion using a drug eluting stent without any residual complications. PMID- 25937167 TI - Immuno-detection of OCTN1 (SLC22A4) in HeLa cells and characterization of transport function. AB - OCTN1 was immuno-detected in the cervical cancer cell HeLa, in which the complete pattern of acetylcholine metabolizing enzymes is expressed. Comparison of immuno staining intensity of HeLa OCTN1 with the purified recombinant human OCTN1 allowed measuring the specific OCTN1 concentration in the HeLa cell extract and, hence calculating the HeLa OCTN1 specific transport activity that was about 10 nmol*min(-1)*mg protein(-1), measured as uptake of [(3)H]acetylcholine in proteoliposomes reconstituted with HeLa extract. This value was very similar to the specific activity of the recombinant protein. Acetylcholine transport was suppressed by incubation of the protein or proteoliposomes with the anti-OCTN1 antibody and was strongly inhibited by PLP and MTSEA, known inhibitors of OCTN1. The absence of ATP in the internal side of proteoliposomes strongly impaired transport function of both the HeLa and, as expected, the recombinant OCTN1. HeLa OCTN1 was inhibited by spermine, NaCl (Na(+)), TEA, gamma-butyrobetaine, choline, acetylcarnitine and ipratropium but not by neostigmine. Besides acetylcholine, choline was taken up by HeLa OCTN1 proteoliposomes. The transporter catalyzed also acetylcholine and choline efflux which, differently from uptake, was not inhibited by MTSEA. Time course of [(3)H]acetylcholine uptake in intact HeLa cells was measured. As in proteoliposomes, acetylcholine transport in intact cells was inhibited by TEA and NaCl. Efflux of [(3)H]acetylcholine occurred in intact cells, as well. The experimental data concur in demonstrating a role of OCTN1 in transporting acetylcholine and choline in HeLa cells. PMID- 25937168 TI - Prediction of respiratory disease and diarrhea in veal calves based on immunoglobulin levels and the serostatus for respiratory pathogens measured at arrival. AB - Failure of passive transfer is a common problem in calves destined for veal production. At present it is unknown whether the risk for respiratory disease (BRD) or neonatal calf diarrhea (NCD) in the veal herd is associated with total immunoglobulin (Ig) and/or on the serostatus for respiratory pathogens measured at arrival. Therefore, the first objective of this prospective longitudinal cohort study was to determine associations between serum protein fractions as determined by routine electrophoresis (total protein, albumin, alpha-1 and -2 globulins, beta-globulins and Ig's) at arrival and BRD and NCD in the first 3 weeks of the production cycle. The second objective was to determine whether the serostatus (seropositive/seronegative) of seven respiratory pathogens (bovine respiratory syncytial virus (BRSV), parainfluenzavirus-3, bovine coronavirus (BCV), bovine herpesvirus-1, bovine viral diarrhea virus, Mannheimia haemolytica and Mycoplasma bovis) of these arrival serum samples could be associated with the risk of having BRD. The third objective was to determine which of the electrophoresis proteins and respiratory serostatuses were associated with average daily gain (ADG) in the study period. The study population consisted of 150 rose veal calves housed in a single air-space. The study period ended at day 18 post arrival, when BRD incidence was judged to be too high to further postpone a group treatment. A Cox regression model was used to determine the effect of the studied protein fractions and antibodies on the time to BRD and NCD occurrence. The effect of the studied predictors on ADG was determined by linear regression. Calves with Ig levels under 7.5g/L had an increased BRD hazard (hazard ratio (HR)=1.9 (95% confidence interval (CI)=1.2-3.0)). NCD was only positively associated with the alpha-2 globulin concentration. Calves with a negative serostatus for BCV (HR=1.7 (95% CI=1.0-2.8)) or BRSV (HR=2.0 (95% CI=1.0-3.9)) had an increased BRD hazard. Average daily gain (ADG) was 0.242kg/day (SD=0.142) and was not related to the occurrence of BRD or NCD. Calves with Ig's below 7.5g/L and with increased levels of alpha-2 globulins showed a decrease in ADG. This study showed the importance of providing sufficient colostrum to veal calves and the potential benefit of the presence of BCV and BRSV antibodies at arrival to reduce the BRD hazard in the first 3 weeks. PMID- 25937169 TI - Injury-induced decline of intrinsic regenerative ability revealed by quantitative proteomics. AB - Neurons differ in their responses to injury, but the underlying mechanisms remain poorly understood. Using quantitative proteomics, we characterized the injury triggered response from purified intact and axotomized retinal ganglion cells (RGCs). Subsequent informatics analyses revealed a network of injury-response signaling hubs. In addition to confirming known players, such as mTOR, this also identified new candidates, such as c-myc, NFkappaB, and Huntingtin. Similar to mTOR, c-myc has been implicated as a key regulator of anabolic metabolism and is downregulated by axotomy. Forced expression of c-myc in RGCs, either before or after injury, promotes dramatic RGC survival and axon regeneration after optic nerve injury. Finally, in contrast to RGCs, neither c-myc nor mTOR was downregulated in injured peripheral sensory neurons. Our studies suggest that c myc and other injury-responsive pathways are critical to the intrinsic regenerative mechanisms and might represent a novel target for developing neural repair strategies in adults. PMID- 25937170 TI - A New DREADD Facilitates the Multiplexed Chemogenetic Interrogation of Behavior. AB - DREADDs are chemogenetic tools widely used to remotely control cellular signaling, neuronal activity, and behavior. Here we used a structure-based approach to develop a new Gi-coupled DREADD using the kappa-opioid receptor as a template (KORD) that is activated by the pharmacologically inert ligand salvinorin B (SALB). Activation of virally expressed KORD in several neuronal contexts robustly attenuated neuronal activity and modified behaviors. Additionally, co-expression of the KORD and the Gq-coupled M3-DREADD within the same neuronal population facilitated the sequential and bidirectional remote control of behavior. The availability of DREADDs activated by different ligands provides enhanced opportunities for investigating diverse physiological systems using multiplexed chemogenetic actuators. PMID- 25937171 TI - Inhibitory Neuron Transplantation into Adult Visual Cortex Creates a New Critical Period that Rescues Impaired Vision. AB - The maturation of inhibitory circuits in juvenile visual cortex triggers a critical period in the development of the visual system. Although several manipulations of inhibition can alter the timing of the critical period, none have demonstrated the creation of a new critical period in adulthood. We developed a transplantation method to reactivate critical period plasticity in the adult visual cortex. Transplanted embryonic inhibitory neurons from the medial ganglionic eminence reinstate ocular dominance plasticity in adult recipients. Transplanted inhibitory cells develop cell-type-appropriate molecular characteristics and visually evoked responses. In adult mice impaired by deprivation during the juvenile critical period, transplantation also recovers both visual cortical responses and performance on a behavioral test of visual acuity. Plasticity and recovery are induced when the critical period would have occurred in the donor animal. These results reveal that the focal reactivation of visual cortical plasticity using inhibitory cell transplantation creates a new critical period that restores visual perception after childhood deprivation. PMID- 25937172 TI - Biased mGlu5-Positive Allosteric Modulators Provide In Vivo Efficacy without Potentiating mGlu5 Modulation of NMDAR Currents. AB - Schizophrenia is associated with disruptions in N-methyl-D-aspartate glutamate receptor subtype (NMDAR)-mediated excitatory synaptic signaling. The metabotropic glutamate receptor subtype 5 (mGlu5) is a closely associated signaling partner with NMDARs and regulates NMDAR function in forebrain regions implicated in the pathology of schizophrenia. Efficacy of mGlu5 positive allosteric modulators (PAMs) in animal models of psychosis and cognition was previously attributed to potentiation of NMDAR function. To directly test this hypothesis, we identified VU0409551 as a novel mGlu5 PAM that exhibits distinct stimulus bias and selectively potentiates mGlu5 coupling to Galphaq-mediated signaling but not mGlu5 modulation of NMDAR currents or NMDAR-dependent synaptic plasticity in the rat hippocampus. Interestingly, VU0409551 produced robust antipsychotic-like and cognition-enhancing activity in animal models. These data provide surprising new mechanistic insights into the actions of mGlu5 PAMs and suggest that modulation of NMDAR currents is not critical for in vivo efficacy. VIDEO ABSTRACT. PMID- 25937173 TI - Spatiotemporal control of opioid signaling and behavior. AB - Optogenetics is now a widely accepted tool for spatiotemporal manipulation of neuronal activity. However, a majority of optogenetic approaches use binary on/off control schemes. Here, we extend the optogenetic toolset by developing a neuromodulatory approach using a rationale-based design to generate a Gi-coupled, optically sensitive, mu-opioid-like receptor, which we term opto-MOR. We demonstrate that opto-MOR engages canonical mu-opioid signaling through inhibition of adenylyl cyclase, activation of MAPK and G protein-gated inward rectifying potassium (GIRK) channels and internalizes with kinetics similar to that of the mu-opioid receptor. To assess in vivo utility, we expressed a Cre dependent viral opto-MOR in RMTg/VTA GABAergic neurons, which led to a real-time place preference. In contrast, expression of opto-MOR in GABAergic neurons of the ventral pallidum hedonic cold spot led to real-time place aversion. This tool has generalizable application for spatiotemporal control of opioid signaling and, furthermore, can be used broadly for mimicking endogenous neuronal inhibition pathways. PMID- 25937174 TI - A surviving intact branch stabilizes remaining axon architecture after injury as revealed by in vivo imaging in the mouse spinal cord. AB - The complex morphology of axons presents a challenge in understanding axonal responses to injury and disease. By in vivo two-photon imaging of spinal dorsal column sensory axons, we systematically examined the effect of injury location relative to the main bifurcation point on axon degeneration and regeneration following highly localized laser injuries. Retrograde but not anterograde degeneration was strongly blocked at the bifurcation point at both the acute and subacute phases. Eliminating either the ascending or descending branch led to a poor regenerative response, while eliminating both led to a strong regenerative response. Thus, a surviving intact branch suppresses both retrograde degeneration and regeneration of the injured branch, thereby preserving the remaining axon architecture. Regenerating axons exhibited a dynamic pattern with alternating phases of regeneration and pruning over a chronic period. In vivo imaging continues to reveal new insights on axonal responses to injury in the mammalian spinal cord. PMID- 25937175 TI - Protective effects of grape seed proanthocyanidins on cardiovascular remodeling in DOCA-salt hypertension rats. AB - Cardiovascular remodeling, as a hallmark of hypertension-induced pathophysiology, causes substantial cardiovascular morbidity and mortality. There is increasing evidence that has demonstrated a broad spectrum of pharmacological and therapeutic benefits of grape seed proanthocyanidins (GSP) against oxidative stress and cardiovascular diseases. In this study, 180- to 200-g SD rats treated with DOCA (120 mg/week sc with 1% NaCl and 0.2% KCl in drinking water) and GSP (150, 240, 384 mg/kg) or amlodipine (ALM) (5 mg/kg) for 4 weeks were recruited. The protective effects of GSP on blood pressure and cardiovascular remodeling in rats with DOCA-salt-induced hypertension were investigated. Our results indicated that DOCA-salt could induce hypertension, cardiovascular remodeling and dysfunction, oxidative stress and the release of endothelin-1 (ET-1) and could increase JNK1/2 and p38MAPK phosphorylation. GSP or ALM treatments significantly improved hypertension, cardiovascular remodeling and dysfunction and oxidative stress, restrained the release of ET-1 and down-regulated the JNK1/2 and p38MAPK phosphorylation. These findings demonstrate that GSP has protective effects against increase of blood pressure induced by DOCA-salt hypertension and cardiovascular remodeling by inhibiting the reactive oxygen species/mitogen activated protein kinase pathway via restraining the release of ET-1. PMID- 25937176 TI - Therapeutic targeting of oxidative stress with coenzyme Q10 counteracts exaggerated diabetic cardiomyopathy in a mouse model of diabetes with diminished PI3K(p110alpha) signaling. AB - Diabetes-induced cardiac complications include left ventricular (LV) dysfunction and heart failure. We previously demonstrated that LV phosphoinositide 3-kinase p110alpha (PI3K) protects the heart against diabetic cardiomyopathy, associated with reduced NADPH oxidase expression and activity. Conversely, in dominant negative PI3K(p110alpha) transgenic mice (dnPI3K), reduced cardiac PI3K signaling exaggerated diabetes-induced cardiomyopathy, associated with upregulated NADPH oxidase. The goal was to examine whether chronic supplementation with the antioxidant coenzyme Q(10) (CoQ(10)) could attenuate LV superoxide and diabetic cardiomyopathy in a setting of impaired PI3K signaling. Diabetes was induced in 6 week-old nontransgenic and dnPI3K male mice via streptozotocin. After 4 weeks of diabetes, CoQ(10) supplementation commenced (10 mg/kg ip, 3 times/week, 8 weeks). At study end (12 weeks of diabetes), markers of LV function, cardiomyocyte hypertrophy, collagen deposition, NADPH oxidase, oxidative stress (3 nitrotyrosine), and concentrations of CoQ(9) and CoQ(10) were determined. LV NADPH oxidase (Nox2 gene expression and activity, and lucigenin-enhanced chemiluminescence), as well as oxidative stress, were increased by diabetes, exaggerated in diabetic dnPI3K mice, and attenuated by CoQ(10). Diabetes-induced LV diastolic dysfunction (prolonged deceleration time, elevated end-diastolic pressure, impaired E/A ratio), cardiomyocyte hypertrophy and fibrosis, expression of atrial natriuretic peptide, connective tissue growth factor, and beta-myosin heavy chain were all attenuated by CoQ(10). Chronic CoQ(10) supplementation attenuates aspects of diabetic cardiomyopathy, even in a setting of reduced cardiac PI3K protective signaling. Given that CoQ(10) supplementation has been suggested to have positive outcomes in heart failure patients, chronic CoQ(10) supplementation may be an attractive adjunct therapy for diabetic heart failure. PMID- 25937178 TI - Oxidative stress in paroxysmal nocturnal hemoglobinuria and other conditions of complement-mediated hemolysis. AB - The complement (C') system and redox status play important roles in the physiological functioning of the body, such as the defense system, but they are also involved in various pathological conditions, including hemolytic anemia. Herein, we review the interaction between the C' and the redox systems in C' mediated hemolytic anemias, paroxysmal nocturnal hemoglobinuria (PNH) and autoimmune hemolytic anemia, including acute hemolytic transfusion reaction. Blood cells in these diseases have been shown to have increased oxidative status, which was further elevated by interaction with activated C'. The results suggest that oxidative stress, in conjunction with activated C', may cause the underlying symptoms of these diseases, such as intra- and extravascular hemolysis and thrombotic complications. Antioxidants ameliorate oxidative stress by preventing generation of free radicals, by scavenging and preventing their accumulation, and by correcting their cellular damage. Antioxidants have been shown to reduce the oxidative stress and inhibit hemolysis as well as platelet activation mediated by activated C'. This raises the possibility that treatment with antioxidants might be considered as a potential therapeutic modality for C'-mediated hemolytic anemias. Currently, eculizumab, a humanized monoclonal antibody that specifically targets the C' protein C5, is the main treatment modality for PNH. However, because antioxidants are well tolerated and relatively inexpensive, they might be considered as potential adjuvants or an alternative therapeutic modality for PNH and other C'-mediated hemolytic anemias. PMID- 25937177 TI - Structural and functional characterization of Nrf2 degradation by glycogen synthase kinase 3/beta-TrCP. AB - Nuclear factor (erythroid-derived 2)-like 2 (Nrf2) is a master regulator of cellular homeostasis that controls the expression of more than 1% of human genes related to biotransformation reactions, redox homeostasis, energetic metabolism, DNA repair, and proteostasis. Its activity has a tremendous impact on physiology and pathology and therefore it is very tightly regulated, mainly at the level of protein stability. In addition to the very well established regulation by the ubiquitin E3 ligase adapter Keap1, recent advances have identified a novel mechanism based on signaling pathways that regulate glycogen synthase kinse-3 (GSK-3). This kinase phosphorylates specific serine residues in the Neh6 domain of Nrf2 to create a degradation domain that is then recognized by the ubiquitin ligase adapter beta-TrCP and tagged for proteasome degradation by a Cullin1/Rbx1 complex. Here we review the mechanistic elements and the signaling pathways that participate in this regulation by GSK-3/beta-TrCP. These pathways include those activated by ligands of tyrosine kinase, G protein-coupled, metabotropic, and ionotropic receptors that activate phosphatidyl inositol 3-kinase (PI3K)/ATK and by the canonical WNT signaling pathway, where a fraction of Nrf2 interacts with Axin1/GSK-3. Considering that free Nrf2 protein is localized in the nucleus, we propose a model termed "double flux controller" to explain how Keap1 and beta TrCP coordinate the stability of Nrf2 in several scenarios. The GSK-3/beta-TrCP axis provides a novel therapeutic strategy to modulate Nrf2 activity. PMID- 25937179 TI - Color Stability of Teeth Restored with Biodentine: A 6-month In Vitro Study. AB - INTRODUCTION: White mineral trioxide aggregate (WMTA) has been reported to cause dental discoloration. A previous study on the color stability of 5 calcium silicate-based materials investigated the color stability of Biodentine (Septodont, Saint-Maur-des-Fosses, France) in different experimental environments; however, no data are available on the color stability of teeth restored with Biodentine. In this study, we assessed the color stability under artificial light of ex vivo human teeth restored coronally with WMTA or Biodentine. METHODS: Cavities were prepared on coronal tooth specimens and restored with WMTA + composite (n = 16), Biodentine + composite (n = 16), or composite alone (control, n = 3). Color was assessed spectrophotometrically at 6 time points (initial, 1 week, 2 weeks, 1 month, 3 months, and 6 months), and color difference values were calculated. Statistical analysis was performed using analysis of variance and the Fisher least significant difference test for which P < .05 was considered statistically significant. RESULTS: The WMTA group showed discoloration at 1 week, which increased over time. The Biodentine and control groups showed color stability and were not significantly different from one another. CONCLUSIONS: Teeth treated with WMTA exhibited discoloration, whereas those treated with Biodentine maintained color stability throughout the study. However, further in vivo studies are necessary to corroborate these results. PMID- 25937180 TI - Validation of Optical Coherence Tomography against Micro-computed Tomography for Evaluation of Remaining Coronal Dentin Thickness. AB - INTRODUCTION: Optical coherence tomography (OCT) is a noninvasive modality to obtain in-depth images of biological structures. A dental OCT system has become available for chairside application. This in vitro study hypothesized that swept source OCT can be used to measure the remaining dentin thickness (RDT) at the roof of the dental pulp chamber during excavation of deep caries. METHODS: Human molar teeth with deep occlusal caries were investigated. After obtaining 2 dimensional and 3-dimensional OCT scans using a swept-source OCT system at a 1330 nm center wavelength, RDT was evaluated by image analysis software. Microfocus x ray computed tomographic (micro-CT) images were obtained from the same cross sections to confirm OCT findings. The smallest RDT values at the visible pulp horn were measured on OCT and micro-CT imaging and compared using the Pearson correlation. Pulpal horns and pulp chamber roof observation under OCT and micro CT imaging resulted in comparable images that allowed the measurement of coronal dentin thickness. RESULTS: RDT measured by OCT showed optical values range between 140 and 2300 MUm, which corresponded to the range of 92-1524 MUm on micro CT imaging. A strong correlation was found between the 2 techniques (r = 0.96, P < .001). CONCLUSIONS: Further analysis indicated linear regression with a slope of 1.54 and no intercept, closely matching the bulk refractive index of dentin. OCT enables visualization of anatomic structures during deep caries excavation. Exposure of the vital dental pulp because of the removal of very thin remaining coronal dentin can be avoided with this novel noninvasive technique. PMID- 25937181 TI - Inhibition of platelet-derived growth factor (PDGF) receptor affects follicular development and ovarian proliferation, apoptosis and angiogenesis in prepubertal eCG-treated rats. AB - The platelet-derived growth factor (PDGF) system is crucial for blood vessel stability. In the present study, we evaluated whether PDGFs play a critical intraovarian survival role in gonadotropin-dependent folliculogenesis. We examined the effect of intrabursal administration of a selective platelet-derived growth factor receptor (PDGFR) inhibitor (AG1295) on follicular development, proliferation, apoptosis and blood vessel formation and stability in ovaries from rats treated with equine chorionic gonadotropin (eCG). The percentages of preantral follicles (PAFs) and early antral follicles (EAFs) were lower in AG1295 treated ovaries than in control ovaries (p < 0.01-0.05). The percentage of atretic follicles (AtrFs) increased in AG1295-treated ovaries compared to control (p < 0.05). The ovarian weight and estradiol concentrations were lower in AG1295 treated ovaries than in the control group (p < 0.01 and p < 0.05, respectively), whereas progesterone concentrations did not change. AG1295 decreased the proliferation index in EAFs (p < 0.05) and increased the percentage of nuclei positive for cleaved caspase-3 and apoptotic DNA fragmentation (p < 0.01-0.05). AG1295 increased the expression of Bax (p < 0.05) without changes in the expression of Bcl-2 protein. AG1295-treated ovaries increased the cleavage of caspase-8 (p < 0.05) and decreased AKT and BAD phosphorylation compared with control ovaries (p < 0.05). AG1295 caused a decrease not only in the endothelial cell area but also in the area of pericytes and vascular smooth muscle cells (VSMCs) in the ovary (p < 0.05). Our findings suggest that the local inhibition of PDGFs causes an increase in ovarian apoptosis through an imbalance in the ratio of antiapoptotic to proapoptotic proteins, thus leading a larger number of follicles to atresia. PDGFs could exert their mechanism of action through an autocrine/paracrine effect on granulosa and theca cells mediated by PDGFRs. In conclusion, these data clearly indicate that the PDGF system is necessary for follicular development induced by gonadotropins. PMID- 25937182 TI - Increasing trend in emergency department visits for hypoglycemia from patients with type 2 diabetes mellitus in Taiwan. AB - AIMS: We analyze the time trends of hypoglycemia-related emergency department visits in Taiwan between 2000 and 2010, focusing on type 2 diabetic patients receiving antidiabetic agents. METHODS: From a national dataset containing longitudinal medical claims of one million persons, we ascertained 4479 hypoglycemia-related emergency department visits from 3184 type 2 diabetic patients for analysis. We used negative binomial regression to calculate the incidence rate ratios (IRRs) for comparing event rates of hypoglycemia-related emergency department visits in different study periods. RESULTS: Rates of hypoglycemia-related emergency department visits increased 4.8 folds from year 2000 to 2010 (adjusted IRR 4.88, 95% CI 3.94-6.05, P<0.001). Severe hypoglycemia requiring emergency department visits prevailed among women, older patients (>= 65 years), and those not lived in the urban areas. CONCLUSIONS: Within a 10-year period, there was a substantial increase in the rates of hypoglycemia-related emergency department visits from type 2 diabetic patients in Taiwan. Appropriate risk management plans should be developed to prevent the occurrence of severe hypoglycemia in patients with type 2 diabetes in Taiwan. PMID- 25937183 TI - Diabetes treatment in people with type 2 diabetes and schizophrenia: Retrospective primary care database analyses. AB - AIMS: Aim of this study were to compare outcomes (HbA1c, BMI) and antidiabetic treatment of type 2 diabetes patients with and without schizophrenia under real life conditions in primary care practices in Germany. METHODS: 1321 type 2 diabetes patients with and 1321 matched controls (age, sex, diabetes duration, diabetologist care, practice) without schizophrenia in 1072 general practices throughout Germany were retrospectively analyzed (Disease Analyser: 01/2009 12/2013). Antidiabetic treatment, HbA1c and BMI were compared using paired t tests, McNemar tests and conditional logistic regression adjusting for macro- and microvascular comorbidity (ICD-10). RESULTS: Mean age (+/-SD) of patients and controls was 67.4+/-13.2 years (males: 38.9%). Diabetes duration was 5.7+/-4.3 years, 6% were in diabetologist care. Private health insurance was less often found among patients with schizophrenia than controls (2.2% vs 6.3%; p<0.0001). There was no difference in the mean HbA1c values (cases: 7.1+/-1.4%; controls: 7.2+/-1.5%) (54.1 vs. 55.2 mmol/mol) (p=0.8797) and in the average BMI (32.4+/ 6.6 vs. 31.0+/-5.0 kg/m(2); p=0.2072) between the two groups. Novel cost intensive antidiabetic agents (DPP-4- or SGLT2-inhibitors, GLP-1 receptor agonists) were less often prescribed in cases (15.3 vs. 18.3%; p=0.0423). However, in multivariable logistic regression, schizophrenia (odds ratio, 95%CI: 1.101; 0.923-1.317) was not associated with prescription use of novel antidiabetic agents (reference: other antidiabetic agents) after adjusting for private health insurance (OR: 2.139; 1.441-3.177) and comorbidity. CONCLUSIONS: There is no evidence that type 2 diabetes patients with schizophrenia have worse diabetes control than those without a severe mental illness in general practices. PMID- 25937184 TI - Change in estimated glomerular filtration rate and fracture risk in the Action to Control Cardiovascular Risk in Diabetes Trial. AB - OBJECTIVE: Patients with type 2 diabetes (T2DM) are at increased risk of fracture. High prevalence of chronic kidney disease (CKD) in T2DM may contribute to bone fragility, but whether dynamic change in kidney function is associated with fracture risk is unclear. RESEARCH DESIGN AND METHODS: To evaluate the association of pre-randomization baseline estimated glomerular filtration (eGFR) and its change over time with subsequent fracture risk in the Bone substudy of Action to Control Cardiovascular Risk in Diabetes (ACCORD) Trial, we conducted an observational study of 2262 women and 4737 men with T2DM and with at least 2 eGFR values. RESULTS: During a mean follow-up of 4.40+/-1.54 years, 235 women and 223 men sustained a new non-vertebral fracture. In multivariable adjusted sex specific models, pre-randomization baseline eGFR was not a significant predictor of fracture risk in either men or women. However, a steeper decline in eGFR was associated with greater risk of fracture in women (hazard ratio [HR] per standard deviation [SD] decrement in eGFR slope, 1.30; 95% CI 1.17-1.44) but not men (HR per SD decrement in eGFR slope, 0.97; 95%CI 0.82-1.13). Accounting for competing risk of death modestly attenuated the association in women (HR per SD decrement in eGFR slope, 1.19; 95% CI 1.04-1.37), with the relationship in men remaining non-significant (HR per SD decrement in eGFR slope, 0.96; 95% CI 0.77-1.18). CONCLUSIONS: Declining kidney function predicts fracture risk in women but not in men with T2DM. Future studies should investigate the mechanisms for these associations. PMID- 25937186 TI - Evaluation of larvicidal activity and effects on post embrionary development of laboratory reared Lucilia cuprina (Wiedemann, 1830) (Diptera: Calliphoridae), treated with Brevibacillus laterosporus. AB - The blowfly Lucilia cuprina is an economically important livestock pest that is also associated with human myiasis. To date, methods including the application of chemical pesticides, plant extracts, insect growth regulators and a range of Bacillus thuringiensis strains have been used, with varying degrees of success, to control this pest. The present study evaluated the larvicidal activity and the induction of sub lethal effects upon post embrionary development following ingestion of 12 strains of Brevibacillus laterosporus, presented individually in the diet as spores. All strains were shown to be larvicidal, with corrected mortality levels of 29 to 54%. No significant differences were observed, in terms of larval weight at the time of abandoning the diet, in the time taken for the initiation of the pupation process, in the duration of the pupation process, the period of adult emergence or cumulative mortality during the transition from larvae to adult. However, an influence upon sex ratio was observed. This study suggests that strains of B. laterosporus hold potential for development as a tool in the biological control of L. cuprina. PMID- 25937187 TI - [Does nodal irradiation (clavicular and internal mammary chains) increase the toxicity of adjuvant breast radiotherapy?]. AB - Treatment volume is a major risk factor of radiation-induced toxicity. As nodal irradiation increases treatment volume, radiation toxicity should be greater. Nevertheless, scientific randomised data do not support this fact. However, a radiation-induced toxicity is possible outside tangential fields in the nodal volumes not related to breast-only treatment. Treatment should not be adapted only to the disease but personalized to the individual risk of toxicity for each patient. PMID- 25937185 TI - Follistatin-like 3 is a mediator of exercise-driven bone formation and strengthening. AB - Exercise is vital for maintaining bone strength and architecture. Follistatin like 3 (FSTL3), a member of follistatin family, is a mechanosensitive protein upregulated in response to exercise and is involved in regulating musculoskeletal health. Here, we investigated the potential role of FSTL3 in exercise-driven bone remodeling. Exercise-dependent regulation of bone structure and functions was compared in mice with global Fstl3 gene deletion (Fstl3-/-) and their age-matched Fstl3+/+ littermates. Mice were exercised by low-intensity treadmill walking. The mechanical properties and mineralization were determined by MUCT, three-point bending test and sequential incorporation of calcein and alizarin complexone. ELISA, Western-blot analysis and qRT-PCR were used to analyze the regulation of FSTL3 and associated molecules in the serum specimens and tissues. Daily exercise significantly increased circulating FSTL3 levels in mice, rats and humans. Compared to age-matched littermates, Fstl3-/- mice exhibited significantly lower fracture tolerance, having greater stiffness, but lower strain at fracture and yield energy. Furthermore, increased levels of circulating FSTL3 in young mice paralleled greater strain at fracture compared to the lower levels of FSTL3 in older mice. More significantly, Fstl3-/- mice exhibited loss of mechanosensitivity and irresponsiveness to exercise-dependent bone formation as compared to their Fstl3+/+ littermates. In addition, FSTL3 gene deletion resulted in loss of exercise-dependent sclerostin regulation in osteocytes and osteoblasts, as compared to Fstl3+/+ osteocytes and osteoblasts, in vivo and in vitro. The data identify FSTL3 as a critical mediator of exercise-dependent bone formation and strengthening and point to its potential role in bone health and in musculoskeletal diseases. PMID- 25937188 TI - [Dental state in patients with head and neck cancers]. AB - In France, in 2005, there were approximately 16,000 new cases of head and neck cancer. These cancers have an unfavourable prognosis: the survival rates at 3 and 10 years are 50% and 10% respectively. The consumption of alcohol and tobacco is the most important risk factor; in some countries HPV infection was identified as a risk factor of head and neck tumours. Furthermore, a poor oral hygiene seems to raise this risk. We found many decay and periodontium problems in patients with an upper aerodigestive tract cancer. An evaluation of dental state is necessary before any cancer treatment. Treatments by radiotherapy engender noxious effects: hypocellular, hypovascularization, hypoxie of the irradiated tissues, which lead to immediate and chronically oral complications such as mucositis, fibrosis, xerostomia, decay, or osteoradionecrosis. An oral follow-up of these patients can prevent these complications, or reduce the severity of oral complications, and promote a good oral state. PMID- 25937190 TI - Strain Echocardiography and LQTS Subtypes: Mechanical Alterations in an Electrical Disorder. PMID- 25937191 TI - In pursuit of the holy grail. PMID- 25937189 TI - Adversomics: a new paradigm for vaccine safety and design. AB - Despite the enormous population benefits of routine vaccination, vaccine adverse events (AEs) and reactions, whether real or perceived, have posed one of the greatest barriers to vaccine acceptance--and thus to infectious disease prevention--worldwide. A truly integrated clinical, translational, and basic science approach is required to understand the mechanisms behind vaccine AEs, predict them, and then apply this knowledge to new vaccine design approaches that decrease, or avoid, these events. The term 'adversomics' was first introduced in 2009 and refers to the study of vaccine adverse reactions using immunogenomics and systems biology approaches. In this review, we present the current state of adversomics research, review known associations and mechanisms of vaccine AEs/reactions, and outline a plan for the further development of this emerging research field. PMID- 25937192 TI - Rheumatoid arthritis: mapping the future. PMID- 25937193 TI - The prognostic value of global circumferential strain in patients with suspected myocardial disease. PMID- 25937194 TI - Multimodality Imaging for CAD Detection Before Renal Transplantation. PMID- 25937195 TI - Clinical Imaging of ACS With Ruptured or Intact Fibrous Caps. PMID- 25937196 TI - Coronary artery calcium scanning: past, present, and future. AB - Coronary artery calcium scanning (CAC) has emerged as the most robust predictor of coronary events in the asymptomatic primary prevention population, particularly in the intermediate-risk cohort. Every study has demonstrated its superiority to risk factor-based paradigms, e.g., the Framingham Risk Score, with outcome-based net reclassification indexes ranging from 52.0% to 65.6% in the intermediate-risk, 34.0% to 35.8% in the high-risk, and 11.6% to 15.0% in the low risk cohorts. CAC improves medication and lifestyle adherence and is cost effective in specified populations, with the ability to effectively stratify the number needed to treat and scan for different therapeutic strategies and patient cohorts. Data have emerged clearly demonstrating the worse prognosis associated with increasing CAC on serial scans, suggesting a potential role for evaluating residual risk and treatment success or failure. CAC is also strongly associated with the development of stroke and congestive heart failure. PMID- 25937197 TI - Noninvasive Multimodality Imaging in ARVD/C. AB - Arrhythmogenic right ventricular dysplasia/cardiomyopathy (ARVD/C) is a familial cardiomyopathy resulting in progressive right ventricular (RV) dysfunction and malignant ventricular arrhythmias. Although ARVD/C is generally considered an inherited cardiomyopathy, the arrhythmogenic nature of the disease is striking. Affected individuals typically present in the second to fourth decade of life with arrhythmias originating from the right ventricle. Over the past decade, pathogenic ARVD/C-causing mutations have been identified in 5 genes encoding the cardiac desmosome. Disruption of the desmosomal connection system between cardiomyocytes may be represented structurally by ventricular enlargement, global or regional contraction abnormalities, RV aneurysms, or fibrofatty replacement. These abnormalities are typically observed in predilection areas, including the subtricuspid region, basal RV free wall, and left ventricular posterolateral wall. As such, structural and functional abnormalities on cardiac imaging constitute an important diagnostic criterion for the disease. This paper discusses the current status and role of echocardiography, cardiac magnetic resonance imaging, and computed tomography for suspected ARVD/C. PMID- 25937198 TI - Mitral Annular Evaluation With CT in the Context of Transcatheter Mitral Valve Replacement. PMID- 25937199 TI - Reply: physical examination is still necessary and important. PMID- 25937200 TI - Physical Examination Is Still Necessary and Important. PMID- 25937201 TI - Handheld Ultrasound is a Valuble Bedside Tool Which Can Supplement the Bedside Cardiac Exam but not Replace It. PMID- 25937202 TI - Reply: Handheld Ultrasound is a Valuble Bedside Tool Which Can Supplement the Bedside Cardiac Exam but not Replace It. PMID- 25937203 TI - Emergence of plaque erosion as an important clinical entity. PMID- 25937204 TI - Environmental health risk assessment of dioxin in foods at the two most severe dioxin hot spots in Vietnam. AB - BACKGROUND: Bien Hoa and Da Nang airbases were bulk storages for Agent Orange during the Vietnam War and currently are the two most severe dioxin hot spots. OBJECTIVES: This study assesses the health risk of exposure to dioxin through foods for local residents living in seven wards surrounding these airbases. METHODS: This study follows the Australian Environmental Health Risk Assessment Framework to assess the health risk of exposure to dioxin in foods. Forty-six pooled samples of commonly consumed local foods were collected and analyzed for dioxin/furans. A food frequency and Knowledge-Attitude-Practice survey was also undertaken at 1000 local households, various stakeholders were involved and related publications were reviewed. RESULTS: Total dioxin/furan concentrations in samples of local "high-risk" foods (e.g. free range chicken meat and eggs, ducks, freshwater fish, snail and beef) ranged from 3.8 pg TEQ/g to 95 pg TEQ/g, while in "low-risk" foods (e.g. caged chicken meat and eggs, seafoods, pork, leafy vegetables, fruits, and rice) concentrations ranged from 0.03 pg TEQ/g to 6.1 pg TEQ/g. Estimated daily intake of dioxin if people who did not consume local high risk foods ranged from 3.2 pg TEQ/kg bw/day to 6.2 pg TEQ/kg bw/day (Bien Hoa) and from 1.2 pg TEQ/kg bw/day to 4.3 pg TEQ/kg bw/day (Da Nang). Consumption of local high risk foods resulted in extremely high dioxin daily intakes (60.4-102.8 pg TEQ/kg bw/day in Bien Hoa; 27.0-148.0 pg TEQ/kg bw/day in Da Nang). CONCLUSIONS: Consumption of local "high-risk" foods increases dioxin daily intakes far above the WHO recommended TDI (1-4 pg TEQ/kg bw/day). Practicing appropriate preventive measures is necessary to significantly reduce exposure and health risk. PMID- 25937205 TI - A method for establishing human primary gastric epithelial cell culture from fresh surgical gastric tissues. AB - At present, biopsy specimens, cancer cell lines and tissues obtained by gastric surgery are used in the study and analysis of gastric cancer, including the molecular mechanisms and proteomics. However, fibroblasts and other tissue components may interfere with these techniques. Therefore, the present study aimed to develop a procedure for the isolation of viable human gastric epithelial cells from gastric surgical tissues. A method was developed to culture human gastric epithelial cells using fresh, surgically excised tissues and was evaluated using immunocytochemistry, periodic acid-Schiff (PAS) staining and cell viability assays. Low cell growth was observed surrounding the gastric tissue on the seventh day of tissue explant culture. Cell growth subsequently increased, and at 12 days post-explant a high number of pure epithelial cells were detected. The gastric cancer cells exhibited rapid growth with a doubling time of 13-52 h, as compared to normal cells, which had a doubling time of 20-53 h. Immunocytochemical analyses of primary gastric cells revealed positive staining for cytokeratin 18 and 19, which indicated that the culture was comprised of pure epithelial cells and contained no fibroblasts. Furthermore, PAS staining demonstrated that the cultured gastric cells produced neutral mucin. Granulin and carbohydrate antigen 724 staining confirmed the purity of gastric cancer and normal cells in culture. This method of cell culture indicated that the gastric cells in primary culture consisted of mucin-secreting gastric epithelial cells, which may be useful for the study of gastric infection with Helicobacter pylori and gastric cancer. PMID- 25937206 TI - High expression of RELM-alpha correlates with poor prognosis and promotes angiogenesis in gastric cancer. AB - Accumulating evidence indicates that resistin-like molecule-alpha (RELM-alpha) is involved in angiogenesis, while the clinical significance and the exact role of RELM-alpha in gastric cancer remain obscure. The aim of the present study was to evaluate the clinical significance of RELM-alpha in gastric cancer, and to investigate its effective mechanisms in order to identify a potential therapeutic target. The expression levels of RELM-alpha in 92 gastric cancer and adjacent normal tissues were investigated and the relationship between RELM-alpha expression and the clinicopathological characteristics was explored. To investigate the potential role of RELM-alpha in gastric cancer cell biological behavior, the cell proliferation, migration and invasion assays were conducted using two gastric cancer cell lines (SGC7901 and MKN45). We also assessed whether RELM-alpha gene silencing modulates angiogenesis using small interference RNA in cancer cell lines, and investigated its effect on nuclear factor (NF)-kappaB activation and vascular endothelial growth factor (VEGF) and MMP-9 expression. Contrasting sharply with the strong RELM-alpha-positive tumors, adjacent normal tissues and cell lines exhibited negative or weakly positive expression (P<0.01). High expression level of RELM-alpha was associated with advanced stage and tumor size (P<0.01). The silencing of RELM-alpha expression by Ad5/F35-siRNA treatment significantly inhibited cell migratory and invasive ability in SGC7901 and MKN45 gastric cancer cells compared with the control and Ad5/F35 vector-transfected cell lines (P<0.01). However, the silencing of RELM-alpha expression also significantly blocked NF-kappaB activation and attenuated VEGF and MMP-9 expression. The data demonstrated that RELM-alpha is a promising novel biomarker of angiogenesis in patients with gastric cancer. The study identified that the silencing of RELM-alpha expression may regulate the proliferation, invasion and migration of gastric cancer cells by targeting VEGF/MMP-9, and the mechanism involved tissue angiogenesis via the NF-kappaB signaling pathway. PMID- 25937209 TI - How does reactivity to frustrative non-reward increase risk for externalizing symptoms? AB - Frustration is a normative affective response with an adaptive value in motivating behavior. However, excessive anger in response to frustration characterizes multiple forms of externalizing psychopathology. How a given trait subserves both normative and pathological behavioral profiles is not entirely clear. One hypothesis is that the magnitude of response to frustration differentiates normative versus maladaptive reactivity. Disproportionate increases in arousal in response to frustration may exceed normal regulatory capacity, thus precipitating aggressive or antisocial responses. Alternatively, pathology may arise when reactivity to frustration interferes with other cognitive systems, impairing the individual's ability to respond to frustration adaptively. In this paper we examine these two hypotheses in a sample of kindergarten children. First we examine whether children with conduct problems (CP; n=105) are differentiated from comparison children (n=135) with regard to magnitude of autonomic reactivity (cardiac and electrodermal) across a task that includes a frustrative non-reward block flanked by two reward blocks. Second we examine whether cognitive processing, as reflected by magnitude of the P3b brain response, is disrupted in the context of frustrative non-reward. Results indicate no differences in skin conductance, but a greater increase in heart rate during the frustration block among children in the CP group. Additionally, the CP group was characterized by a pronounced decrement in P3b amplitude during the frustration condition compared with both reward conditions. No interaction between cardiac and P3b measures was observed, suggesting that each system independently reflects a greater sensitivity to frustration in association with externalizing symptom severity. PMID- 25937210 TI - Direct visualisation of internalization of the adenosine A3 receptor and localization with arrestin3 using a fluorescent agonist. AB - Fluorescence based probes provide a novel way to study the dynamic internalization process of G protein-coupled receptors (GPCRs). Recent advances in the rational design of fluorescent ligands for GPCRs have been used here to generate new fluorescent agonists containing tripeptide linkers for the adenosine A3 receptor. The fluorescent agonist BY630-X-(D)-A-(D)-A-G-ABEA was found to be a highly potent agonist at the adenosine A3 receptor in both reporter gene (pEC50 = 8.48 +/- 0.09) and internalization assays (pEC50 = 7.47 +/- 0.11). Confocal imaging studies showed that BY630-X-(D)-A-(D)-A-G-ABEA was internalized with A3 linked to yellow fluorescent protein, which was blocked by the competitive antagonist MRS1220. Internalization of untagged adenosine A3 could also be visualized with BY630-X-(D)-A-(D)-A-G-ABEA treatment. Further, BY630-X-(D)-A-(D) A-G-ABEA stimulated the formation of receptor-arrestin3 complexes and was found to localize with these intracellular complexes. This highly potent agonist with excellent imaging properties should be a valuable tool to study receptor internalization. This article is part of the Special Issue entitled 'Fluorescent Tools in Neuropharmacology'. PMID- 25937211 TI - Carbonic anhydrase inhibition by acetazolamide reduces in vitro epileptiform synchronization. AB - Depolarizing GABAA receptor-mediated currents are contributed by HCO3(-) efflux, and play a role in initiating ictal-like epileptiform events in several cortical structures supporting the view that GABAA receptor signaling actively participates to epileptiform synchronization. We employed here field potential recordings to analyze the effects of the carbonic anhydrase inhibitor acetazolamide (10 MUM) on the epileptiform activity generated in vitro by piriform and entorhinal cortices (PC and EC, respectively) during application of the K(+) channel blocker 4-aminopyridine (4AP, 50 MUM). Under these experimental conditions ictal- and interictal-like discharges along with high-frequency oscillations (ripples: 80-200 Hz, fast ripples: 250-500 Hz) occurred in these two regions. In both PC and EC, acetazolamide: (i) reduced the duration and the interval of occurrence of ictal discharges along with the associated ripples and fast ripples; (ii) decreased the interval of occurrence of interictal discharges and the rates of associated fast ripples; and (iii) diminished the duration and amplitude of pharmacologically isolated GABAergic events while increasing their interval of occurrence. Our results indicate that acetazolamide effectively controls 4AP-induced epileptiform synchronization in PC and EC. We propose that this action may rest on decreased GABAA receptor-mediated HCO3(-) efflux leading to diminished depolarization of principal cells and, perhaps, of interneurons. PMID- 25937213 TI - The effect of trans-resveratrol on post-stroke depression via regulation of hypothalamus-pituitary-adrenal axis. AB - Post-stroke depression (PSD) occurs about 40% among all stroke survivors, but the effective pharmacotherapy is inadequately understood. The present study investigated the effects of a natural polyphenol trans-resveratrol (RES) on behavioral changes after middle cerebral artery occlusion (MCAO) and examined what its molecular targets may be. RES was shown to decrease the infarct size and neurological scores after MCAO, suggesting the amelioration of brain damage and motor activity. RES also reversed the depressive-like behaviors 13 days after MCAO, both in the forced swimming and sucrose consumption tests. Moreover, MCAO induced series abnormalities related to depressive-like behaviors, such as an abnormal adrenal gland weight to body weight ratio, an increased expression of the corticotropin-releasing factor (CRF) in the frontal cortex, hippocampus and hypothalamus, the differential expression of glucocorticoid receptor (GR) in these three brain regions, and a decreased brain-derived neurotrophic factor (BDNF) level, were ameliorated after treatment with increasing doses of RES at 10, 20 and 40 mg/kg via gavage. These findings provide compelling evidence that RES protects the brain against focal cerebral ischemia-induced injury, but most of all is its antidepressant-like effect on PSD, which might at least in part be mediated by regulation of hypothalamus-pituitary-adrenal axis function. PMID- 25937214 TI - Muscarinic receptor-mediated excitation of rat intracardiac ganglion neurons. AB - Modulation of the membrane excitability of rat parasympathetic intracardiac ganglion neurons by muscarinic receptors was studied using an amphotericin B perforated patch-clamp recording configuration. Activation of muscarinic receptors by oxotremorine-M (OxoM) depolarized the membrane, accompanied by repetitive action potentials. OxoM evoked inward currents under voltage-clamp conditions at a holding potential of -60 mV. Removal of extracellular Ca(2+) markedly increased the OxoM-induced current (IOxoM). The inward IOxoM in the absence of extracellular Ca(2+) was fully inhibited by removal of extracellular Na(+), indicating the involvement of non-selective cation channels. The IOxoM was inhibited by organic cation channel antagonists including SKF-96365 and ML-204. The IOxoM was antagonized by muscarinic receptor antagonists with the following potency: 4-DAMP > pirenzepine = darifenacin > methoctramine. Muscarinic toxin 7 (MT-7), a highly selective inhibitor for M1 receptor, produced partial inhibition of the IOxoM. In the presence of MT-7, concentration-inhibition curve of the M3 preferring antagonist darifenacin was shifted to the left. These results suggest the contribution of M1 and M3 receptors to the OxoM response. The IOxoM was inhibited by U-73122, a phospholipase C inhibitor. The membrane-permeable IP3 receptor blocker xestospongin C also inhibited the IOxoM. Furthermore, pretreatment with thapsigargin and BAPTA-AM inhibited the IOxoM, while KN-62, a blocker of Ca(2+)/calmodulin-dependent protein kinase II, had no effect. These results suggest that the activation mechanism involves a PLC pathway, release of Ca(2+) from intracellular Ca(2+) stores and calmodulin. The cation channels activated by muscarinic receptors may play an important role in neuronal membrane depolarization in rat intracardiac ganglion neurons. PMID- 25937212 TI - Activation of alpha7 nicotinic acetylcholine receptors increases intracellular cAMP levels via activation of AC1 in hippocampal neurons. AB - The activation of alpha7 nAChRs has been shown to improve hippocampal-dependent learning and memory. However, the molecular mechanism of alpha7 nAChRs' action remains elusive. We previously reported that activation of alpha7 nAChRs induced a prolonged enhancement of glutamatergic synaptic transmission in a PKA-dependent manner. Here, we investigated any connection between the activation of the alpha7 nAChR and cAMP signaling in hippocampal neurons. To address this question, we employed a FRET-based biosensor to measure the intracellular cAMP levels directly via live cell imaging. We found that application of the alpha7 nAChR-selective agonist choline, in the presence of the alpha7 nAChR positive allosteric modulator PNU-120596, induced a significant change in emission ratio of F535/F470, which indicated an increase in intracellular cAMP levels. This choline induced increase was abolished by the alpha7 nAChR antagonist MLA and the calcium chelator BAPTA, suggesting that the cAMP increase depends on the alpha7 nAChR activation and subsequent intracellular calcium rise. The selective AC1 inhibitor CB-6673567 and siRNA-mediated deletion of AC1 both blocked the choline-induced cAMP increase, suggesting that calcium-dependent AC1 is required for choline's action. Furthermore, alpha7 nAChR activation stimulated the phosphorylation of synapsin, which serves as a downstream effector to regulate neurotransmitter release. Our findings provide the first direct evidence to link activation of alpha7 nAChRs to a cAMP rise via AC1, which defines a new signaling pathway employed by alpha7 nAChRs. Our study sheds light into potential molecular mechanisms of the positive cognitive actions of alpha7 nAChR agonists and development of therapeutic treatments for cognitive impairments. PMID- 25937216 TI - Components of the luminescent system of the luminous fungus Neonothopanus nambi. PMID- 25937215 TI - Subchronic phencyclidine treatment in adult mice increases GABAergic transmission and LTP threshold in the hippocampus. AB - Repeated administration of non-competitive N-methyl-d-aspartate (NMDA) receptor antagonists such as phencyclidine (PCP) to rodents causes long-lasting deficits in cognition and memory, and has effects on behaviors that have been suggested to be models of the cognitive impairment associated with schizophrenia (CIAS). Despite this being a widely studied animal model, little is known about the long lasting changes in synapses and circuits that underlie the altered behaviors. Here we examined synaptic transmission ex-vivo in the hippocampus of mice after a subchronic PCP (scPCP) administration regime. We found that after at least one week of drug free washout period when mice have impaired cognitive function, the threshold for long-term potentiation (LTP) of CA1 excitatory synapses was elevated. This elevated LTP threshold was directly related to increased inhibitory input to CA1 pyramidal cells through increased activity of GABAergic neurons. These results suggest repeated PCP administration causes a long-lasting metaplastic change in the inhibitory circuits in the hippocampus that results in impaired LTP, and could contribute to the deficits in hippocampal-dependent memory in PCP-treated mice. Changes in GABA signaling have been described in patients with schizophrenia, therefore our results support using scPCP as a model of CIAS. This article is part of the Special Issue entitled 'Synaptopathy--from Biology to Therapy'. PMID- 25937217 TI - Chemical control of adaptive function of plant pathogenic fungi. PMID- 25937218 TI - Electronic relaxation in P* state of Rhodobacter sphaeroides reaction centers. PMID- 25937219 TI - Chaperone Hsp70 is involved in the molecular mechanisms of slow wave sleep regulation. PMID- 25937220 TI - Analgesic effect of novel Kunitz-type polypeptides of the sea anemone Heteractis crispa. PMID- 25937221 TI - Sequencing of the complete genome of an araphid pennate diatom Synedra acus subsp. radians from Lake Baikal. AB - High-throughput method of sequencing was applied to determine the complete nucleotide sequence of an araphid pennate diatom Synedra acus subsp. radians from Lake Baikal (East Siberia). The assembled genome has a total length of 98 Mbp, the mean coverage is 33x. Structure-functional annotation of the genome was performed. PMID- 25937222 TI - Functional organization of the white gene enhancer in Drosophila melanogaster. PMID- 25937223 TI - The ability of Alphitobius diaperinus homogenates immobilized on plant sorbent to block the development of mouse parkinsonism. PMID- 25937224 TI - Antipathogenic phenomenon of cycloheximide. PMID- 25937225 TI - Design of multicomponent reagents for enzymatic assays. PMID- 25937226 TI - Rational design of new ligands for nicotinic receptors on the basis of alpha conotoxin PnIA. PMID- 25937227 TI - Ectopic expression of the HAM59 gene causes homeotic transformations of reproductive organs in sunflower (Helianthus annuus L.). AB - The function of the HAM59 MADS-box gene in sunflower (Helianthus annuus L.) was studied to clarify homeotic C activity in the Asteraceae plant family. For the first time, transgenic sunflower plants with a modified pattern of HAM59 expression were obtained. It was shown that the HAM59 MADS-box transcription factor did mediate C activity in sunflower. In particular, it participated in termination of the floral meristem, repression of the cadastral function of A activity, and together with other C-type sunflower protein HAM45-in the specification of the identity of stamens and pistils. PMID- 25937228 TI - Interaction of messengers--endogenous NO and H2S gasotransmitters--in signaling and regulatory processes in bacterial cells. PMID- 25937229 TI - Novel antagonists of nicotinic acetylcholine receptors--proteins from venoms of Viperidae snakes. PMID- 25937230 TI - Modeling of chronic selective inhibition of noradrenaline synthesis in the brain of neonatal rats. PMID- 25937231 TI - Extraction of info chemicals inducing the production of resting eggs in cladocerans. PMID- 25937232 TI - Molecular design of selective ligands of chemokine receptors. PMID- 25937233 TI - Interplay of insulin and dopamine signaling pathways in the control of Drosophila melanogaster fitness. PMID- 25937234 TI - Nature of active intermediate particles formed during ozone-induced oxidation. PMID- 25937235 TI - Anticancer activity of koningic acid and semisynthetic derivatives. AB - A screening program aimed at discovering novel anticancer agents based on natural products led to the selection of koningic acid (KA), known as a potent inhibitor of glycolysis. A method was set up to produce this fungal sesquiterpene lactone in large quantities by fermentation, thus allowing (i) an extensive analysis of its anticancer potential in vitro and in vivo and (ii) the semi-synthesis of analogues to delineate structure-activity relationships. KA was characterized as a potent, but non-selective cytotoxic agent, active under both normoxic and hypoxic conditions and inactive in the A549 lung cancer xenograft model. According to our SAR, the acidic group could be replaced to keep bioactivity but an intact epoxide is essential. PMID- 25937236 TI - Synthesis and biological evaluation of diarylthiazole derivatives as antimitotic and antivascular agents with potent antitumor activity. AB - By switching position of the N and S atom in the thiazole ring which were similar to the previously reported agent 5-(4-ethoxyphenyl)-4-(3',4',5' trimethoxyphenyl)thiazol-2-amine, a series of 4,5-diarylthiazole derivatives were synthesized using Friedel-Crafts reaction based on chemical modification of Combrestatatin A-4 (CA-4). Their antiproliferative activities were evaluated and identified as new microtubule destabilizing agents. Structure-activity relationship study indicated that compound 8a with 3,4,5-trimethoxyphenyl group at the C-4 position and 4-ethoxyphenyl group at the C-5 position of 2-amino substituted thiazole was of the most potent inhibitory activity in this series. 8a was found to exhibit the IC50 values of 8.4-26.4nM in five human cancer cell lines, with comparable inhibition effects to CA-4. Moreover, 8a showed potency as a tubulin polymerization inhibitor, with colchicine site binding ability and comparable extent of inhibition against the growth of P-glycoprotein over expressing multidrug resistant cell lines. Mechanism studies revealed that 8a could block the progression of cell cycle in the G2/M phase and result in cellular apoptosis in cancer cells. As a new tubulin destabilizing agent, 8a was also found high antivascular activity as it concentration-dependently reduced the cell migration and disrupted capillary like tube formation of HUVEC cells. Furthermore, 8a significantly suppressed the tumor growth in HCT116 and SK-OV-3 xenograft models with tumor growth inhibitory rate of 55.12% and 72.7%, respectively. Our studies highlighted that 8a was a promising microtubule targeting antitumor agent. PMID- 25937237 TI - Design, synthesis and anxiolytic-like activity of 1-arylpyrrolo[1,2-a]pyrazine-3 carboxamides. AB - A series of 1-arylpyrrolo[1,2-a]pyrazine-3-carboxamides were designed and synthesized as 18kDa translocator protein (TSPO) ligands. Anxiolytic-like activity of compounds was evaluated in the open field test and elevated plus maze test. Compounds 1a and 1b demonstrated high anxiolytic-like effect in the dose range of 0.1-1.0mg/kg comparable with that of diazepam. The involvement of TSPO receptor in the mechanism of anxiolytic-like activity of new compounds was proved by antagonism of the most active compound 1a with TSPO selective inhibitor PK11195. In vitro binding studies demonstrated high TSPO affinities for compounds 1a and 1b. PMID- 25937238 TI - Chitosan-shelled oxygen-loaded nanodroplets abrogate hypoxia dysregulation of human keratinocyte gelatinases and inhibitors: New insights for chronic wound healing. AB - BACKGROUND: In chronic wounds, efficient epithelial tissue repair is hampered by hypoxia, and balances between the molecules involved in matrix turn-over such as matrix metalloproteinases (MMPs) and tissue inhibitors of metalloproteinases (TIMPs) are seriously impaired. Intriguingly, new oxygenating nanocarriers such as 2H,3H-decafluoropentane-based oxygen-loaded nanodroplets (OLNs) might effectively target chronic wounds. OBJECTIVE: To investigate hypoxia and chitosan shelled OLN effects on MMP/TIMP production by human keratinocytes. METHODS: HaCaT cells were treated for 24h with 10% v/v OLNs both in normoxia or hypoxia. Cytotoxicity and cell viability were measured through biochemical assays; cellular uptake by confocal microscopy; and MMP and TIMP production by enzyme linked immunosorbent assay or gelatin zymography. RESULTS: Normoxic HaCaT cells constitutively released MMP-2, MMP-9, TIMP-1 and TIMP-2. Hypoxia strongly impaired MMP/TIMP balances by reducing MMP-2, MMP-9, and TIMP-2, without affecting TIMP-1 release. After cellular uptake by keratinocytes, nontoxic OLNs abrogated all hypoxia effects on MMP/TIMP secretion, restoring physiological balances. OLN abilities were specifically dependent on time-sustained oxygen diffusion from OLN core. CONCLUSION: Chitosan-shelled OLNs effectively counteract hypoxia-dependent dysregulation of MMP/TIMP balances in human keratinocytes. Therefore, topical administration of exogenous oxygen, properly encapsulated in nanodroplet formulations, might be a promising adjuvant approach to promote healing processes in hypoxic wounds. PMID- 25937239 TI - The simultaneous use of a heat and moisture exchanger and a heated humidifier causes critical airway occlusion in less than 24 hours. AB - PURPOSE: Heat and moisture exchangers (HMEs) and heated humidifiers (HHs) may be used together inadvertently. Such an incident occurred at our institution resulting in airway occlusion. MATERIAL AND METHODS: A bench-top study was conducted to compare the incidence of airway occlusion when using (1) no airway humidification, (2) HME alone, (3) HH alone, and (4) both HME and HH in combination as part of a standard breathing circuit. RESULTS: The simultaneous use of a HME and a HH was associated with a reduction in tidal volume (no airway humidification, P <= .05; HME alone, P <= .01; and HH alone, P <= .01) and an increased incidence of airway occlusion (no airway humidification, 0/7; HME alone, 0/7; HH alone, 0/7; and HME and HH in combination, 7/7; P < .0001). CONCLUSIONS: The use of a HME and a HH in combination is likely to result in airway occlusion. Precautions should be taken to ensure that both systems are not used together in clinical practice. PMID- 25937240 TI - Increased mesolimbic cue-reactivity in carriers of the mu-opioid-receptor gene OPRM1 A118G polymorphism predicts drinking outcome: a functional imaging study in alcohol dependent subjects. AB - The endogenous opioid system is involved in the pathophysiology of alcohol-use disorders. Genetic variants of the opioid system alter neural and behavioral responses to alcohol. In particular, a single nucleotide polymorphism rs1799971 (A118G) in the mu-opioid receptor gene (OPRM1) is suggested to modulate alcohol related phenotypes and neural response in the mesocorticolimbic dopaminergic system. Little is known about the clinical implications of these changes. The current study investigated the relationship of genotype effects on subjective and neural responses to alcohol cues and relapse in a sample of abstinent alcohol dependent patients. Functional magnetic resonance imaging (fMRI) was used to investigate alcohol cue-reactivity and drinking outcome of 81 abstinent alcohol dependent patients. G-allele carriers displayed increased fMRI cue-reactivity in the left dorsal striatum and bilateral insulae. Neural responses to alcohol cues in these brain regions correlated positively with subjective craving for alcohol and positive expectations of alcohol's effects. Moreover, alcohol cue-reactivity in the left dorsal striatum predicted time to first severe relapse. Current results show that alcohol-dependent G-allele carriers' increased cue-reactivity is associated with an increased relapse risk. This suggests that genotype effects on cue-reactivity might link the OPRM1 A118G risk allele with an increased relapse risk that was reported in earlier studies. From a clinical perspective, risk-allele carriers might benefit from treatments, such as neuro-feedback or extinction-based therapy that are suggested to reduce mesolimbic reactivity. PMID- 25937241 TI - Hyperprolactinemia and medications for bipolar disorder: systematic review of a neglected issue in clinical practice. AB - Drug-induced changes in serum prolactin (sPrl) levels constitute a relevant issue due to the potentially severe consequences on physical health of psychiatric patients such as sexual dysfunctions, osteoporosis and Prl-sensitive tumors. Several drugs have been associated to sPrl changes. Only antipsychotics have been extensively studied as sPrl-elevating agents in schizophrenia, but the extent to which bipolar disorder (BD) treatments affect sPrl levels is much less known. The objective of this systematic review is to summarize the evidence of the effects of drugs used in BD on Prl. This review followed the PRISMA statement. The MEDLINE/PubMed/Index Medicus, EMBASE, and Cochrane Library databases were systematically searched for articles in English appearing from any time to May 30, 2014. Twenty-six studies were included. These suggest that treatments for BD are less likely to be associated with Prl elevations, with valproate, quetiapine, lurasidone, mirtazapine, and bupropion reported not to change PRL levels significantly and lithium and aripiprazole to lower them in some studies. Taking into account the effects of the different classes of drugs on Prl may improve the care of BD patients requiring long-term pharmacotherapy. Based on the results of this review, lithium and valproate appear to be safer due to their low potential to elevate sPrL; among antipsychotics, quetiapine, lurasidone and aripiprazole appear to be similarly safe. PMID- 25937242 TI - Caesarean section combined with temporary aortic balloon occlusion followed by uterine artery embolisation for the management of placenta accreta. AB - AIM: To determine the efficacy and safety of caesarean section combined with temporary aortic balloon occlusion followed by uterine artery embolisation (UAE) for the treatment of patients with placenta accreta. MATERIALS AND METHODS: This retrospective study involved 42 patients with placenta accreta. All patients underwent caesarean section combined with temporary aortic balloon occlusion followed by UAE through the right femoral approach. RESULTS: All patients were confirmed to have placenta praevia and accreta, including five patients with placenta percreta, at the time of delivery. The technical success rate of the combined treatment was 97.6% (41/42). Forty-one patients underwent successful caesarean section with conservation of the uterus. Hysterectomy was required in one (3.1%) patient. The amount of blood loss and blood transfusion, and the operation time were was 586 +/- 355 ml, 422 +/- 83 ml and 65.5 +/- 10.6 minutes, respectively. The mean postoperative hospital stay, occlusion time and fetal radiation dose were 5.5 +/- 2.6 days, 22.4 +/- 7.2 minutes and 4.2 +/- 2.9 mGy, respectively. There were no significant changes before and 7 days after the endovascular procedure in creatinine levels (56.8 +/- 13.8 MUmol/l versus 63.4 +/ 16.7 MUmol/l, p = 0.09) or urea nitrogen (6.3 +/- 2.5 MUmol/l versus 7.4 +/- 3.8 MUmol/l, p = 0.17). There were no access-site complications after the endovascular procedure and no complications related to the intervention during follow-up. CONCLUSION: Temporary aortic balloon occlusion followed by UAE can effectively control postpartum haemorrhage during placental dissection, and reduce transfusion requirements, hysterectomy rate, and operation time in patients with placenta accreta. PMID- 25937243 TI - Quercetin induces the apoptosis of human ovarian carcinoma cells by upregulating the expression of microRNA-145. AB - Ovarian cancer is one of the most malignant types of cancer of the female human reproductive track, posing a severe threat to the health of the female population. Numerous previous studies have demonstrated that microRNA (miR)-145 is downregulated in ovarian cancer, and that quercetin can inhibit the growth of cancer cells via regulating the expression of miRs. Therefore, the present study investigated the effect of quercetin on the expression of miR-145 in SKOV-3 and A2780 human ovarian cancer cell lines. The results revealed that the expression levels of cleaved caspase-3 in the SKOV-3 and A2780 cells were significantly increased following treatment to induce overexpression of miR-145 compared with treatment with quercetin alone (P<0.01). However, the expression of cleaved caspase-3 in the anti-miR-145 (miR-145 inhibitor) group of cells was markedly decreased compared with that in the miR-145 overexpression group (P<0.01). Taken together, the results suggested that treatment with quercetin induced the apoptosis of human ovarian carcinoma cells through activation of the extrinsic death receptor mediated and intrinsic mitochondrial apoptotic pathways. PMID- 25937244 TI - Correlation between clinimetric approach and German US7 score in rheumatoid arthritis patients treated with tocilizumab: a pilot study. PMID- 25937245 TI - Mechanisms of anterior gradient-2 regulation and function in cancer. AB - Proteins targeted to secretory pathway enter the endoplasmic reticulum where they undergo post-translational modification and subsequent quality control executed by exquisite catalysts of protein folding, protein disulphide isomerases (PDIs). These enzymes can often provide strict conformational protein folding solutions to highly cysteine-rich cargo as they facilitate disulphide rearrangement in the endoplasmic reticulum. Under conditions when PDI substrates are not isomerised properly, secreted proteins can accumulate in the endoplasmic reticulum leading to endoplasmic reticulum stress initiation with implications for human disease development. Anterior Gradient-2 (AGR2) is an endoplasmic reticulum-resident PDI superfamily member that has emerged as a dominant effector of basic biological properties in vertebrates including blastoderm formation and limb regeneration. AGR2 perturbation in mammals influences disease processes including cancer progression and drug resistance, asthma, and inflammatory bowel disease. This review will focus on the molecular characteristics, function, and regulation of AGR2, views on its emerging biological functions and misappropriation in disease, and prospects for therapeutic intervention into endoplasmic reticulum-resident protein folding pathways for improving the treatment of human disease. PMID- 25937246 TI - Long-term survival of Streptococcus pneumoniae, Haemophilus influenzae and Moraxella catarrhalis as isolates and in nasopharyngeal specimens in frozen STGG storage medium. AB - We evaluated survival in WHO-recommended STGG storage medium of bacteria causing respiratory-tract infection. Streptococcus pneumoniae and Moraxella catarrhalis survived as single and mixed isolates stored at -70 degrees C for 12.5 years, but Haemophilus influenzae less than 4 years. All the bacteria survived in the nasopharyngeal specimens at -70 degrees C for 11 years. PMID- 25937247 TI - High-throughput screening assays for antibacterial and antifungal activities of Lactobacillus species. AB - We describe high-throughput screening techniques to rapidly detect either antimicrobial activity, using an agar-well diffusion assay in microtiter plates, or antifungal activity using an agar-spot assay in 24-well plates. 504 Lactobacillus isolates were screened with minimal laboratory equipment and screening rates of 2000-5000 individual antimicrobial interactions. PMID- 25937248 TI - Early and current days of transfusion medicine help to understand longevity and particularities of transfusion therapy in the elderly. PMID- 25937250 TI - Characterization and sexual dimorphic expression of Cytochrome P450 genes in the hypothalamic-pituitary-gonad axis of yellow catfish. AB - Yellow catfish (Pelteobagrus fulvidraco) is an important freshwater fish species in China. In particular, an all-male population has been commercially produced for the males grow faster than females. However, the molecular mechanisms underlying sexual dimorphism of body size and sex differentiation are still unclear in yellow catfish. This study attempts to characterize and analyze the expression of Cytochrome P450 (CYP) family members that have been shown to play an important role in sex differentiation and metabolism in teleosts. A total of 25 CYP genes were identified from our transcriptomes by 454 pyrosequencing and Solexa sequencing, including 17 genes with complete open reading frame (ORF). Phylogenetic analyses were conducted to compare these genes with their counterparts from other teleosts. In the tissues of hypothalamic-pituitary-gonad (HPG) axis, most of the genes were expressed at uniform level in both sexes. However, multiple CYP genes displayed sexual dimorphic expression, such as cyp2AD, cyp4b, cyp8a, cyp11b2, cyp17a and cyp27a expressed at higher level in testis than in ovary, whereas cyp2g, cyp7a, cyp8b, cyp19a1a and cyp26a expressed at higher level in ovary than in testis. The expression response of six CYP genes in ovary was also assessed after 17alpha-methyltestosterone (MT) treatment. Testis-biased expressed cyp11b2 and cyp17a were significantly up-regulated, while cyp11a and cyp19a1a were reduced in ovary after MT treatment. Our work is helpful for understanding molecular evolution of CYP genes in vertebrates and the mechanism of sexual dimorphism in teleosts. PMID- 25937251 TI - Role of L-type Ca(2+) channels, sarcoplasmic reticulum and Rho kinase in rat basilar artery contractile properties in a new model of subarachnoid hemorrhage. AB - We have previously described that L-type Ca(2+) channels' (LTCCs) activation and metabotropic Ca(2+) release from the sarcoplasmic reticulum (SR) regulate RhoA/Rho kinase (ROCK) activity and sustained arterial contraction. We have investigated whether this signaling pathway can be altered in a new experimental model of subarachnoid hemorrhage (SAH). For this purpose, arterial reactivity was evaluated on days 1 to 5 after surgery. A significant increase of basal tone, measured 4 and 60min after normalization, was observed on day 5 after SAH and at 60min on days 2 and 3 after SAH. This phenomenon was suppressed with LTCCs and ROCK inhibitors. We have also studied arterial rings vasoreactivity in response to high K(+) solutions. Interestingly, there were no significant differences in the phasic component of the high K(+)-induced contraction between sham and SAH groups, whereas a significant increase in the sustained contraction was observed on day 5 after SAH. This latter component was sensitive to fasudil, and selectively reduced by low nifedipine concentration, and phospholipase C and SR ATPase inhibitors. Therefore, our data suggest that the metabotropic function of LTCCs is potentiated in SAH. Our results could provide a new strategy to optimize the pharmacological treatment of this pathological process. PMID- 25937252 TI - Long-term Impact of Continuous Positive Airway Pressure Therapy on Arrhythmia and Heart Rate Variability in Patients With Sleep Apnea. AB - INTRODUCTION: Autonomic dysfunction can alter heart rate variability and increase the incidence of arrhythmia. We analyzed the impact of continuous positive airway pressure (CPAP) on this pathophysiological phenomenon in patients with severe sleep apnea-hypopnea syndrome. METHODS: Consecutive patients with recently diagnosed severe sleep apnea-hypopnea syndrome were prospectively considered for inclusion. Incidence of arrhythmia and heart rate variability (recorded on a 24 hour Holter monitoring device) were analyzed before starting CPAP therapy and 1 year thereafter. RESULTS: A total of 26 patients were included in the study. CPAP was administered for 6.6 +/- 1.8 hours during Holter monitoring. After starting CPAP, we observed a marginally significant reduction in mean HR (80 +/- 9 to 77 +/- 11 bpm, p=.05). CPAP was associated with partial modulation (only during waking hours) of r-MSSD (p=.047) and HF (p=.025) parasympathetic parameters and LF (p=.049) sympathetic modulation parameters. None of these parameters returned completely to normal levels (p<.001). The number of unsustained episodes of atrial tachycardia diminished (p=.024), but no clear effect on other arrhythmias was observed. CONCLUSIONS: CPAP therapy only partially improves heart rate variability, and exclusively during waking hours, and reduces incidence of atrial tachycardia, both of which can influence cardiovascular morbidity and mortality in sleep apnea-hypopnea syndrome patients. PMID- 25937253 TI - Piscroside C, a novel iridoid glycoside isolated from Pseudolysimachion rotundum var. subinegrum suppresses airway inflammation induced by cigarette smoke. AB - ETHNOPHARMACOLOGICAL RELEVANCE: Pseudolysimachion rotundum var. subintegrum (Speedwell, Plantaginaceae) is used as a traditional herbal medicine for treating bronchitis, cough and asthma in Korea, China, Russia, and Europe. AIM OF THE STUDY: In this study, we investigated the protective effects of the novel iridoid glycoside, piscroside C (compound 1) isolated from the methanolic extract of P. rotundum var. subintegrum against inflammatory responses using a cigarette smoke induced chronic obstructive pulmonary disease (COPD) and TNF-alpha-stimulated human airway epithelial NCI-H292 cells. MATERIALS AND METHODS: The novel iridoid glycoside piscroside C was isolated from the methanolic extract of P. rotundum var. subintegrum. The chemical structure was established by NMR, HRESIMS, and optical rotation. In in vivo experiment, the mice received 1h of cigarette smoke for 3 days. Piscroside C was administered to mice by oral gavage 1h before cigarette smoke exposure for 3 days. In in vitro experiment, we evaluated the effect of piscroside C on proinflammatory mediators in H292 cells stimulated with TNF-alpha. RESULTS: Piscroside C significantly reduced the neutrophil influx, reactive oxygen species production, IL-6, TNF-alpha, and elastase activity in bronchoalveolar lavage fluid in COPD animals. In addition, piscroside C attenuated NF-kappaB and IkappaB phosphorylation, leading to reduced recruitment of inflammatory cells into the lung tissue. Consistent with the results of in vivo experiment, piscroside C significantly inhibited the expression of inflammatory cytokines (IL-6, IL-8 and IL-1beta) by inhibiting NF-kappaB activation, as resulting decrease in the phosphorylation of IKKbeta, IkappaBalpha and TAK1 in TNF-alpha-stimulated H292 cells. CONCLUSION: These findings indicate that piscroside C effectively inhibits inflammatory responses, which is an important process in the development of COPD through suppression of IKK/NF-kappaB activation. Our study suggest that piscroside C might represent a useful therapeutic for the treatment of inflammatory airway disease. PMID- 25937254 TI - Cytotoxic and genotoxic effects of ethanolic extract of Euphorbia hyssopifolia L. on HepG2 cells. AB - ETHNOPHARMACOLOGICAL RELEVANCE: Euphorbia hyssopifolia L. is a weed with recognized antimicrobial potential employed in Indian, Asian and Latin-American popular medicine. However, little is known with regard to its toxic potential. The present study aimed to investigate the cytotoxic and genotoxic effects of ethanolic extract of E. hyssopifolia in HepG2 cell culture. MATERIALS AND METHODS: Phytochemical screening of ethanolic extract was carried out to determine the presence of active secondary plant metabolites. Six concentrations (0.00001, 0.0001, 0.001, 0.01, 0.1 and 1.0mg/mL) of ethanolic extract were tested by the MTT assay to verify cytotoxicity. Then, genotoxic evaluations (alkaline comet assay and cytokinesis-block micronucleus assay - CBMN) were carried out in HepG2 cells with extract concentrations of 0.01, 0.1 and 1.0mg/mL. RESULTS: Mono and sesquiterpenes, triterpenes and steroids, and flavonoids were the main classes found in the phytochemical screening. Extract concentrations used in the MTT assay showed no cytotoxic activity. On the other hand, genotoxic activity was verified at 0.1 and 1.0mg/mL in the alkaline comet assay. Additionally, the 1.0mg/mL concentration induced severe cell damage leading to death in the CBMN assay, indicating a cytotoxic effect for this concentration in the latter method. CONCLUSION: The use of E. hyssopifolia extract for medicinal purposes should be avoided, because concentrations above 0.01mg/mL may pose risk to human health due to cytotoxic and/or genotoxic effects. PMID- 25937255 TI - Shenfu decoction as adjuvant therapy for improving quality of life and hepatic dysfunction in patients with symptomatic chronic heart failure. AB - ETHNOPHARMACOLOGICAL RELEVANCE: Shenfu decoction (SFD) is a water extract of the dried root or root stalk of Panax ginseng C. A. Mey (Asian ginseng) and the lateral root of Aconitum carmichaeli Debx (prepared by Fuzi, Heishunpian in Chinese). It has been used to treat heart failure for over a thousand years. The main active components of SFD, ginsenosides and higenamine, enhance heart contractility, increase the coronary blood supply, improve ischemic myocardial metabolism, scavenge free radicals and protect myocardial ultrastructure. AIM OF THE STUDY: To investigate the effect of SFD on quality of life (QOL) and hepatic function in symptomatic chronic heart failure (CHF) patients. MATERIALS AND METHODS: Forty patients enrolled in the study were randomized into two groups: an SFD group (18 cases) and a control group (22 cases). All the patients received standard heart failure therapy, and the SFD group patients were also treated with Shenfu granules for 14 days as an adjunctive therapy. The effects of SFD on QOL, plasma alanine aminotransferase (ALT) level, cardiac function, left ventricular ejection fraction (LVEF) and tumor necrosis factor-alpha (TNF-alpha) level were studied. ALT threshold in hepatic injury are 21U/L for men and 17U/L for women. RESULTS: Minnesota Living with Heart Failure Questionnaire (MLHFQ) scores were improved by 35.27+/-10.72 vs. 23.87+/-11.96 in the SFD and control groups respectively (p<0.01). Subgroup analysis of the MLHFQ results demonstrated that both physical and emotional scores were significantly higher in the SFD group (21.00+/-5.66 vs. 16.75+/-6.25, p<0.05; 4.64+/-4.84 vs. 1.13+/-2.85, p<0.05). Circulating ALT was significantly decreased by SFD (13.3IU/L vs. 0.6IU/L, p<0.01). The grading of cardiac function and LVEF were increased by 1.6+/-0.5 vs. 1.1+/-0.3 and 18%+/-13% vs. 8%+/-8% in the SFD and control groups respectively (p<0.05 and p<0.05). The level of TNF-alpha declined more in SFD than control group (64.8+/-5.0 to 57.6+/-4.1, p<0.05; vs. 61.6+/-5.9 vs. 57.7+/-3.2. p>0.05). CONCLUSION: Compared with standard heart failure treatment, oral SFD as an adjuvant therapy significantly improved QOL and hepatic injury in CHF patients. PMID- 25937256 TI - Ethnomedicinal uses, pharmacological activities, and cultivation of Lignosus spp. (tiger's milk mushrooms) in Malaysia - A review. AB - ETHNOPHARMACOLOGICAL RELEVANCE: Several members of the genus Lignosus, which are collectively known as cendawan susu rimau (in Malay) or tiger's milk mushrooms (TMM), are regarded as important local medicine particularly by the indigenous communities in Malaysia. The mushroom sclerotia are purportedly effective in treating cancer, coughs, asthma, fever, and other ailments. The most commonly encountered Lignosus spp. in Malaysia was authenticated as Lignosus rhinocerotis (Cooke) Ryvarden (synonym: Polyporus rhinocerus), which is also known as hurulingzhi in China and has been used by Chinese physicians to treat liver cancer, gastric ulcers, and chronic hepatitis. In spite of growing interest in the therapeutic potential of TMM, there is no compilation of scientific evidence that supports the ethnomedicinal uses of these mushrooms. Therefore, the present review is intended (i) to provide a comprehensive, up-to-date overview of the ethnomedicinal uses, pharmacological activities, and cultivation of TMM in general and L. rhinocerotis in particular, (ii) to demonstrate how recent scientific findings have validated some of their traditional uses, and (iii) to identify opportunities for future research and areas to prioritize for TMM bioprospecting. MATERIALS AND METHODS: A detailed literature search was conducted via library search (books, theses, reports, newspapers, magazines, and conference proceedings) and electronic search (Web of Science, PubMed, and Google Scholar) for articles published in peer-reviewed journals. These sources were scrutinized for information on TMM and specifically for L. rhinocerotis. RESULTS: Ethnomycological knowledge about TMM, with an emphasis on cultural associations and use as local medicine, has been comprehensively and systematically compiled for the first time. Some of the reported medicinal properties of TMM have been validated by scientific studies. The anti-tumor, immuno-modulatory, anti inflammatory, anti-oxidative, anti-microbial, neurite outgrowth stimulation, and other pharmacological activities of L. rhinocerotis sclerotial extracts have been explored. The nature of sclerotial bioactive components, such as proteins, polysaccharides, and/or polysaccharide-protein complexes, has been identified, whereas the low-molecular-weight constituents remain poorly studied. The artificial cultivation of L. rhinocerotis via solid substrate and liquid fermentations successfully yielded fruiting bodies, sclerotium, mycelium, and culture broth that could be exploited as substitutes for the wild resources. The cultivated sclerotium and mycelium were shown to be safe from a toxicological point of view. Other research areas, e.g., chemical studies, genomics, and proteomics, have been employed to gain insights into the medicinal properties of TMM. CONCLUSIONS: This review clarified the medicinal properties of TMM as recorded in various ethnomycological records, and it simultaneously highlighted the current efforts to provide scientific evidence by using various in vitro and in vivo models. Thus far, only the anti-tumor and immuno-modulatory effects of L. rhinocerotis sclerotial aqueous extracts have been extensively investigated, and other medicinal properties relevant to their traditional uses, e.g., anti-tussive and anti-pyretic properties, have yet to be validated. Further studies focusing on (i) the isolation and characterization of active components, (ii) the elucidation of their modes of action, and (iii) an evaluation of their safety and efficacy, when compared with the crude aqueous preparations, are warranted to accelerate potential drug discovery from TMM. PMID- 25937257 TI - Antibacterial activities of the methanol extracts, fractions and compounds from Fagara tessmannii. AB - ETHNOPHARMACOLOGICAL RELEVANCE: Fagara tessmannii is a shrub of the African rainforests used to treat bacterial infections, cancers, swellings and inflammation. In the present study, the methanol extract from the leaves (FTL), bark (FTB), and roots (FTR) of this plant as well as fractions (FTR1-5) and compounds isolated from FTR namely beta-sitosterol-3-O-beta-d-glucopyranoside (1), nitidine chloride (2) and buesgenine (3), were tested for their antimicrobial activities against a panel of Gram-negative bacteria including multidrug resistant (MDR) phenotypes. MATERIALS AND METHODS: The broth microdilution method was used to determine the minimal inhibitory concentration (MIC) and minimal bactericidal concentration (MBC) of the above samples; Column chromatography was used for the fractionation and purification of the roots extract whilst the chemical structures of compounds were determined using spectroscopic techniques. RESULTS: Results of the MIC determinations indicated that the crude extracts from the roots as well as fraction FTRa4 were active on all the 26 tested bacterial strains. MIC values below 100ug/mL were obtained with roots, leaves and bark extract respectively against 30.8%, 15.4% and 11.5% tested bacteria. The lowest MIC value below of 8ug/mL was obtained with extract from the roots against Escherichia coli MC100 strain. The lowest MIC value of 4ug/mL was also obtained with compound 3 against E. coli AG102 and Klebsiella pneumoniae ATCC11296 CONCLUSIONS: The present study demonstrates that F. tessmannii is a potential source of antimicrobial drugs to fight against MDR bacteria. Benzophenanthrine alkaloids 2 and 3 are the main antibacterial consituents of the roots of the plant. PMID- 25937258 TI - Flavonoids as a scaffold for development of novel anti-angiogenic agents: An experimental and computational enquiry. AB - Relationship between structural diversity and biological activities of flavonoids has remained an important discourse in the mainstream of flavonoid research. In the current study anti-angiogenic, cytotoxic, antioxidant and cyclooxygenase (COX) inhibitory activities of diverse class of flavonoids including hydroxyl and methoxy substituted flavones, flavonones and flavonols have been evaluated in the light of developing flavonoids as a potential scaffold for designing novel anti antiangiogenic agents. We demonstrate anti-angiogenic potential of flavonoids using in vivo chorioallantoic membrane model (CAM) and further elaborate the possible structural reasoning behind observed anti-angiogenic effect using in silico methods. Additionally, we report antioxidant potential and kinetics of free radical scavenging activity using DPPH and SOR scavenging assays. Current study indicates that selected flavonoids possess considerable COX inhibition potential. Furthermore, we describe cytotoxicity of flavonoids against selected cancer cell lines using MTT cell viability assay. Structural analysis of in silico docking poses and predicted binding free energy values are not only in accordance with the experimental anti-angiogenic CAM values from this study but also are in agreement with the previously reported literature on crystallographic data concerning EGFR and VEGFR inhibition. PMID- 25937259 TI - Analysis of bile colonization and intestinal flora may improve management in liver transplant recipients undergoing ERCP. AB - BACKGROUND: Immunosuppression, denervation of biliary tract, and presence of biliary strictures favor colonization of bile with microorganisms after liver transplantation. Little is known about spectrum and antibiotic susceptibility of this colonization. MATERIAL AND METHODS: Bile and feces were collected prospectively from 38 patients who underwent endoscopic retrograde cholangiopancreaticography after liver transplantation. Samples were analyzed for colonization and antibiotic susceptibility. RESULTS: From the 38 tested bile samples, 86.6% tested positive. Of those, 26 (78.8%) were polymicrobial. Of isolated bile samples, 52 (64.2%) were gram-positive, 22.2% were gram-negative, and 13.6% revealed Candida albicans. Most detectable gram-positive bacteria were Enterococcus faecium. Most detectable gram-negative bacteria were E. coli and Klebsiella pneumonia. Our analyses revealed high resistance rates of the isolates. Only 55.6% of isolates were sensitive to ciprofloxacin, 54% were sensitive to piperacillin/tazobactam, and 60.3% were sensitive to imipenem. High susceptibility rates were found for linezolid and vancomycin (72.9% and 72.6%, respectively). We found a high correlation between microorganisms found in bile and those isolated from stool. CONCLUSIONS: Bile of liver transplant recipients is frequently colonized with microorganisms. The starting point of this colonization is usually the intestine. Systematic analysis of bile colonization during endoscopic interventions on biliary tracts of liver transplant recipients might help to select effective prophylactic antibiotic regimes as well as to facilitate the choice of suitable antimicrobial therapy in case of septic complications. PMID- 25937260 TI - [To cure sometimes, to relieve often, to comfort always]. PMID- 25937261 TI - Apparent diffusion coefficient values and dynamic contrast enhancement patterns in differentiating seminomas from nonseminomatous testicular neoplasms. AB - INTRODUCTION: The aim of this study is to investigate the role of apparent diffusion coefficient (ADC) values and dynamic contrast enhancement (DCE) patterns in differentiating seminomas from nonseminomatous germ cell tumors (NSGCTs). MATERIALS AND METHODS: The MRI examinations of the scrotum of 26 men with histologically proven testicular GCTs were reviewed. DWI was performed in all patients, using a single shot, multi-slice spin-echo planar diffusion pulse sequence and b-values of 0 and 900 s/mm(2). Subtraction DCE-MRI was performed in 20 cases using a 3D fast-field echo sequence after gadolinium administration. Time-signal intensity curves were created and semi-quantitative parameters (peak enhancement, time to peak, wash-in and wash-out rate) were calculated. The Student's t-test was used to compare the mean values of ADC, peak enhancement, time to peak, wash-in and wash-out rate between seminomas and NSGCTs. ROC analysis was also performed. RESULTS: Histopathology disclosed the presence of 15 seminomas and 11 NSGCTs. The mean +/- s.d. of ADC values (*10(-3)mm(2)/s) of seminomas (0.59 +/- 0.009) were significantly lower than those of NSGCTs (0.90 +/ 0.33) (P=0.01). The optimal ADC cut-off value was 0.68 * 10(-3)mm(2)/s. No differences between the two groups were observed for peak enhancement (P=0.18), time to peak (P=0.63) wash-in rate (P=0.32) and wash-out rate (P=0.18). CONCLUSIONS: ADC values may be used to preoperatively differentiate seminomas from NSGCTs. PMID- 25937262 TI - Optimal spore germination in Clostridium botulinum ATCC 3502 requires the presence of functional copies of SleB and YpeB, but not CwlJ. AB - Germination, the process by which dormant endospores return to vegetative growth, is a critical process in the life cycle of the notorious pathogen Clostridium botulinum. Crucial is the degradation by hydrolytic enzymes of an inner peptidoglycan spore layer termed the cortex. Two mechanistically different systems of cortex lysis exist in spores of Clostridium species. C. botulinum ATCC 3502 harbours the Bacillus-like system of SleB, CwlJ and YpeB cortex lytic enzymes (CLEs). Through the construction of insertional gene knockout mutants in the sleB, cwlJ and ypeB genes of C. botulinum ATCC 3502 and the production of spores of each mutant strain, the effect on germination was assessed. This study demonstrates a reduced germination efficiency in spores carrying mutations in either sleB or ypeB with an approximate 2-fold reduction in heat resistant colony forming units (CFU/OD600) when plated on rich media. This reduction could be restored to wild-type levels by removing the spore coat and plating on media supplemented with lysozyme. It was observed that cwlJ spores displayed a similar germination efficiency as wild-type spores (P > 0.05). An optimal germinant commixture was identified to include a combination of l-alanine with sodium bicarbonate as it resulted in a 32% drop in OD600, while the additional incorporation of l-lactate resulted in a 57% decrease. Studies of the germination efficiency of spores prepared from all three CLE mutants was performed by monitoring the associated decrease in optical density but a germination defect was not observed in any of the CLE mutant strains. This was likely due to the lack of specificity of this particular assay. Taken together, these data indicate that functional copies of SleB and YpeB, but not CwlJ are required for the optimal germination of the spores of C. botulinum ATCC 3502. PMID- 25937263 TI - Early stage cost-effectiveness analysis of a BRCA1-like test to detect triple negative breast cancers responsive to high dose alkylating chemotherapy. AB - PURPOSE: Triple negative breast cancers (TNBC) with a BRCA1-like profile may benefit from high dose alkylating chemotherapy (HDAC). This study examines whether BRCA1-like testing to target effective HDAC in TNBC patients can be more cost-effective than treating all patients with standard chemotherapy. Additionally, we estimated the minimum required prevalence of BRCA1-like and the required positive predictive value (PPV) for a BRCA1-like test to become cost effective. METHODS: Our Markov model compared 1) the incremental costs; 2) the incremental number of respondents; 3) the incremental number of Quality Adjusted Life Years (QALYs); and 4) the incremental cost-effectiveness ratio (ICER) of treating TNBC women with personalized HDAC based on BRCA1-like testing vs. standard chemotherapy, from a Dutch societal perspective and a 20-year time horizon, using probabilistic sensitivity analysis. Furthermore, we performed one way sensitivity analysis (SA) to all model parameters, and two-way SA to prevalence and PPV. Data were obtained from a current trial (NCT01057069), published literature and expert opinions. RESULTS: BRCA1-like testing to target effective HDAC would presently not be cost-effective at a willingness-to-pay threshold of ?80.000/QALY (?81.981/QALY). SAs show that PPV drives the ICER changes. Lower bounds for the prevalence and the PPV were found to be 58.5% and 73.0% respectively. CONCLUSION: BRCA1-like testing to target effective HDAC treatment in TNBC patients is currently not cost-effective at a willingness-to pay of ?80.000/QALY, but it can be when a minimum PPV of 73% is obtained in clinical practice. This information can help test developers and clinicians in decisions on further research and development of BRCA1-like tests. PMID- 25937264 TI - Management of axilla in breast cancer - The saga continues. AB - Prospective trials investigating the accuracy of SLNB for cN0 (primary surgical therapy) and cN1 patients (neoadjuvant chemotherapy) have not utilized likelihood ratios (LR) to assess the impact of false negative SLNB. This review evaluates the evidence on accuracy of SLNB using STARD and QUADAS-2 (revised) criteria for patients undergoing primary surgical therapy and primary chemotherapy. It utilizes the: (i) Reported rates for pre-test probabilities of node positive disease from Surveillance, Epidemiology, and End Results (SEER) database for the cN0 patients (primary surgical therapy) for each T stage; calculates the negative LR from cumulative evidence; and uses the Bayesian nomogram to compute the post test probability of missing the metastatic axillary node based on negative SLNB. (ii) Reported rates of complete axillary response in ACOSOG-Z1071 trial for cN1 patients to calculate the pre-test probabilities of residual nodal disease for each biological tumor sub-type; calculates the negative LR from ACOSOG-Z1071, and SENTINA trial data; and uses the Bayesian nomogram to compute the post-test probability of missing the residual metastatic axillary node based on negative SLNB. For cN0 disease, the odds of missing axillary disease based on negative SLNB for each T stage are: T1a = 0.7%; T1b = 1.5%; T1c = 3%; T2 = 7%; T3 = 18%. For cN1 disease, the odds of missing residual axillary disease based on negative SLNB for each biological subtype are: HER2neu+ = 8%; Triple negative = 15%; ER+/PR+/HER2neu- = 45%. Negative LR is more accurate and superior to false negative rate for determining the clinical utility of SLNB by taking into account the changing pre-test probability of disease. PMID- 25937265 TI - Protective effect of compression socks in a marathon runner with a genetic predisposition to thrombophilia due to Factor V Leiden. AB - INTRODUCTION: The present case study is an analysis of the effect of compression socks on hemostatic activation following a marathon in a female endurance athlete found to be heterozygous for the coagulation factor V (F5 1691 G>A [Arg>Gln rs6025/560]) risk allele that predisposes one to a genetically inherited disorder of blood clotting, Factor V Leiden. METHODS: Markers for coagulation and fibrinolysis were obtained 24 h prior to (PRE), immediately after (FINISH) and 24 h after (POST) completion of two marathons: the first in which the runner was not wearing compression socks, and the second in which the runner wore compression socks throughout the race. RESULTS: Compression socks worn during a marathon appeared to lower the overall impact on hemostasis as well as clot formation in this particular athlete as evidenced by lower t-PA (-56%), TAT (-63%) and D-dimer (-30%). CONCLUSIONS: Hemostatic activation may be lower with the use of compression socks, and thus may be effective for preserving hemostasis in endurance athletes at risk. PMID- 25937266 TI - [Crystalloids and colloids in the resuscitation of critical patients: two considerations]. PMID- 25937267 TI - Palladium-Catalyzed Asymmetric Arylation of C(sp(3))-H Bonds of Aliphatic Amides: Controlling Enantioselectivity Using Chiral Phosphoric Amides/Acids. AB - Enantioselective arylation of secondary beta-C(sp(3))-H bonds of 8-aminoquinoline amides was realized with a palladium catalyst. Chiral phosphoric amides and acids were used for the first time to control the stereoselectivity at the C-H bond cleavage step in the C-H activation reactions. PMID- 25937268 TI - Is Personality a System? Stability, Process and Plasticity. AB - The nomothetic thrust of personality research has been the subject of some significant recent criticism. One major problem is the failure in much personality research to sufficiently scrutinize its methods and its background beliefs. This produces conceptual schematizations of personality that do not sufficiently take into account the disunity and plasticity that affects what is construed as personality; it also underplays the necessity of more fully theorizing the network of infrapsychic and transpersonal systems, processes, structures, templates, interfaces, flows of stimuli, qualities of embodiment and contingencies that dynamically manifest as personality. It is through unfolding the complexity inherent in this network that personality theorization can move forward in new ways. This paper provides a provisional, beginning taxonomy of this network in order to start a research dialogue about personality that doesn't begin with the operative background beliefs of nomothetic methodology, that doesn't tacitly or overtly construe the individual to be a self-regulating, homeostatic system, and that resists presupposing personality as a cohesive, stable quality of personhood. PMID- 25937269 TI - Towards multiplexed protein-protein interaction analysis using protein tag specific nanobodies. AB - Dynamic protein-protein interactions (PPIs) are an integral part of cellular processes. The discovery of modulators that disrupt or stabilize such interactions is highly important to understand PPIs and address correlating diseases. Bead-based protein assays analyzing PPIs between bait- and prey proteins exemplify emerging methodologies. To date, most studies employ purified bait-proteins from bacteria. Such proteins are of limited use as they do not undergo eukaryotic folding and lack posttranslational modifications. Here, we present a novel method to generate bead-based protein arrays combining MU-scale purification of bait-proteins combined with site-directed immobilization. First, we express individual bait-proteins as GST- or GFP-fusion constructs in bacterial and mammalian cells. Next, we purify and immobilize these bait-proteins from crude lysates using high affinity tag-specific nanobodies coupled to color-coded beads. Finally, we combined those bait-coupled beads in a protein-array for miniaturized multiplexed GST- and GFP pulldown studies. In a proof-of-principle we study dynamic changes of the endogenous prey-protein beta-catenin following proteasomal inhibition or signaling pathway perturbation. Our strategy enables a fast isolation of highly pure and stable bait-proteins derived from small-scale expression cultures. We propose that this approach enables the generation of bead based protein arrays comprising hundreds of bait-proteins from different expression systems to study complex PPIs. BIOLOGICAL SIGNIFICANCE: Protein arrays and multiplexed sandwich immunoassays, are widely applied to study protein protein interaction or to investigate the signaling status of stimulated cells. This study describes for the first time the application of tag-specific nanobodies for site directed immobilization of bait-proteins from different expression systems to generate bead based protein arrays. The analysis of the Wnt pathway activation by multiplexed MU-scale pulldowns demonstrated the advantages of eukaryotic expression systems regarding the stability and binding properties of individual bait proteins. This article is part of a Special Issue entitled: HUPO 2014. PMID- 25937270 TI - Reliability of Small Biopsy Samples Compared With Resected Specimens for the Determination of Programmed Death-Ligand 1 Expression in Non--Small-Cell Lung Cancer. AB - BACKGROUND: Several studies have assessed the expression of programmed death ligand 1 (PD-L1) in resected surgical specimens of non-small-cell lung cancer (NSCLC). However, the expression of PD-L1 in smaller biopsy samples of advanced NSCLC has not been reported. PATIENTS AND METHODS: A total of 79 patients with NSCLC at our institution with available biopsy samples and resected specimens were retrospectively enrolled in the present study. PD-L1 expression was assessed by immunohistochemistry and scored using the hybrid scoring method. The concordance rates for the expression of PD-L1 between the 2 samples were analyzed. RESULTS: The pathologic stage of the patients (51 men, 28 women; median age, 68 years) was stage I in 37, stage II in 18, and stage III in 24. The diagnostic procedures included transbronchial biopsy in 59, transbronchial needle aspiration biopsy in 14, and computed tomography (CT)-guided needle biopsy in 6. The positivity rate of PD-L1 in these samples was 38.0% (27 transbronchial biopsies, 6 transbronchial needle aspiration biopsies, 3 CT-guided needle biopsies) versus 35.4% in the resected specimens. The median hybrid score was 0 (range, 0-170), and the mean score was 28.7 +/- 43.4. Comparing the biopsy samples and resected specimens with a score of >= 1 as positive for PD-L1 staining, 6 tumors were discordant for PD-L1 expression and 73 were concordant, for a concordance rate of 92.4% and kappa value of 0.8366. CONCLUSION: PD-L1 status showed good concordance between the biopsy samples and resected specimens. These small samples, even those derived from transbronchial needle aspiration biopsies, appear adequate for the assessment of PD-L1 expression. PMID- 25937271 TI - Sasanquasaponin from Camellia oleifera Abel. induces apoptosis via Bcl-2, Bax and caspase-3 activation in HepG2 cells. AB - The present study aimed to elucidate the molecular mechanisms underlying the induction of cytotoxic effects by sasanquasaponin (SQS) in HepG2 cells. Following SQS treatment, time- and dose-dependent increases in the apoptotic rate were observed. The induction of cell death by SQS mainly occurs via programmed cell death, as indicated by Annexin V-fluorescein isothiocyanate and propidium iodide staining, where up to 30% apoptotic cells were detected following 12 h SQS treatment. Reverse transcription-polymerase chain reaction analysis demonstrated that SQS treatment upregulated B-cell lymphoma-2 (Bcl-2)-associated x protein and caspase-3 mRNA expression and downregulated Bcl-2 mRNA expression. Greater alterations in Bax, Bcl-2 and caspase-3 expression were observed with increasing treatment duration. The decrease in Bcl-2, increase in Bax and, finally, the activation of caspase-3 in HepG2 cells indicated that the apoptotic process induced by SQS was irreversible. The results of the present study therefore suggested that SQS induced HepG2 cell apoptosis via the activation of mitochondrial apoptotic pathways. PMID- 25937272 TI - [Acute hammer toe]. PMID- 25937273 TI - Strokes and vision: The management of ischemic arterial disease affecting the retina and occipital lobe. AB - Embolic disease of the anterior or posterior vascular territories may lead to disturbance of vision. Although death from this is uncommon, morbidity remains relatively high: Visual field loss may impair or preclude reading and driving and these are important influences on quality of life. Visual symptoms of stroke mean that patients may present to ophthalmologists with isolated visual symptoms, rather than directly to an emergency department. It is important to diagnose stroke and transient ischemic attacks accurately, as well as to manage them appropriately, as they are important harbingers of further cerebrovascular events. Ophthalmologists are therefore well placed to ensure that these patients receive appropriate acute treatment and secondary prevention. This article reviews the evidence for managing patients presenting with visual symptoms of vascular events. It reviews management of ischemic stroke in general, and compares this with management of events involving the anterior circulation by way of transient monocular visual loss or retinal artery occlusion, and posterior circulation by way of transient binocular visual loss or infarction of the visual cortex. PMID- 25937274 TI - On the identification of low allele frequency mosaic mutations in the brains of Alzheimer's disease patients. AB - INTRODUCTION: The cause of sporadic Alzheimer's disease (AD) remains unclear. Given the growing evidence that protein aggregates can spread in a "prion-like" fashion, we reasoned that a small population of brain cells producing such "prion like" particles due to a postzygotic acquired mutation would be sufficient to trigger the disease. Deep DNA sequencing technology should in principle allow the detection of such mosaics. METHODS: To detect the somatic mutations of genes causing AD present in a small number of cells, we developed a targeted deep sequencing approach to scrutinize the genomic loci of APP, PSEN1, and PSEN2 genes in DNA extracted from the entorhinal cortex, one of the brain regions showing the earliest signs of AD pathology. We also included the analysis of the MAPT gene because mutations may promote tangle formation. We validated candidate mutations with an independent targeted ultradeep amplicon sequencing technique. RESULTS: We demonstrate that our approach can detect single-nucleotide mosaic variants with a 1% allele frequency and copy number mosaic variants present in as few as 10% of cells. We screened 72 AD and 58 control brain samples and identified three mosaic variants with low allelic frequency (~1%): two novel MAPT variants in sporadic AD patients and a known PSEN2 variant in a Braak II control subject. Moreover, we detected both novel and known pathogenic nonmosaic heterozygous variants in PSEN1 and PSEN2 in this cohort of sporadic AD patients. DISCUSSION: Our results show that mosaic mutations with low allelic frequencies in AD-relevant genes can be detected in brain-derived DNA, but larger samples need to be investigated before a more definitive conclusion with regard to the pathogenicity of such mosaics can be made. PMID- 25937275 TI - Increased airway reactivity and hyperinsulinemia in obese mice are linked by ERK signaling in brain stem cholinergic neurons. AB - Obesity is a major risk factor for asthma, which is characterized by airway hyperreactivity (AHR). In obesity-associated asthma, AHR may be regulated by non TH2 mechanisms. We hypothesized that airway reactivity is regulated by insulin in the CNS, and that the high levels of insulin associated with obesity contribute to AHR. We found that intracerebroventricular (ICV)-injected insulin increases airway reactivity in wild-type, but not in vesicle acetylcholine transporter knockdown (VAChT KD(HOM-/-)), mice. Either neutralization of central insulin or inhibition of extracellular signal-regulated kinases (ERK) normalized airway reactivity in hyperinsulinemic obese mice. These effects were mediated by insulin in cholinergic nerves located at the dorsal motor nucleus of the vagus (DMV) and nucleus ambiguus (NA), which convey parasympathetic outflow to the lungs. We propose that increased insulin-induced activation of ERK in parasympathetic pre ganglionic nerves contributes to AHR in obese mice, suggesting a drug-treatable link between obesity and asthma. PMID- 25937276 TI - Regulation of liver metabolism by the endosomal GTPase Rab5. AB - The liver maintains glucose and lipid homeostasis by adapting its metabolic activity to the energy needs of the organism. Communication between hepatocytes and extracellular environment via endocytosis is key to such homeostasis. Here, we addressed the question of whether endosomes are required for gluconeogenic gene expression. We took advantage of the loss of endosomes in the mouse liver upon Rab5 silencing. Strikingly, we found hepatomegaly and severe metabolic defects such as hypoglycemia, hypercholesterolemia, hyperlipidemia, and glycogen accumulation that phenocopied those found in von Gierke's disease, a glucose-6 phosphatase (G6Pase) deficiency. G6Pase deficiency alone can account for the reduction in hepatic glucose output and glycogen accumulation as determined by mathematical modeling. Interestingly, we uncovered functional alterations in the transcription factors, which regulate G6Pase expression. Our data highlight a requirement of Rab5 and the endosomal system for the regulation of gluconeogenic gene expression that has important implications for metabolic diseases. PMID- 25937277 TI - Somatosensory substrates of flight control in bats. AB - Flight maneuvers require rapid sensory integration to generate adaptive motor output. Bats achieve remarkable agility with modified forelimbs that serve as airfoils while retaining capacity for object manipulation. Wing sensory inputs provide behaviorally relevant information to guide flight; however, components of wing sensory-motor circuits have not been analyzed. Here, we elucidate the organization of wing innervation in an insectivore, the big brown bat, Eptesicus fuscus. We demonstrate that wing sensory innervation differs from other vertebrate forelimbs, revealing a peripheral basis for the atypical topographic organization reported for bat somatosensory nuclei. Furthermore, the wing is innervated by an unusual complement of sensory neurons poised to report airflow and touch. Finally, we report that cortical neurons encode tactile and airflow inputs with sparse activity patterns. Together, our findings identify neural substrates of somatosensation in the bat wing and imply that evolutionary pressures giving rise to mammalian flight led to unusual sensorimotor projections. PMID- 25937278 TI - Glucose-based regulation of miR-451/AMPK signaling depends on the OCT1 transcription factor. AB - In aggressive, rapidly growing solid tumors such as glioblastoma multiforme (GBM), cancer cells face frequent dynamic changes in their microenvironment, including the availability of glucose and other nutrients. These challenges require that tumor cells have the ability to adapt in order to survive periods of nutrient/energy starvation. We have identified a reciprocal negative feedback loop mechanism in which the levels of microRNA-451 (miR-451) are negatively regulated through the phosphorylation and inactivation of its direct transcriptional activator OCT1 by 5' AMP-activated protein kinase (AMPK), which is activated by glucose depletion-induced metabolic stress. Conversely, in a glucose-rich environment, unrestrained expression of miR-451 suppresses AMPK pathway activity. These findings uncover miR-451 as a major effector of glucose regulated AMPK signaling, allowing tumor cell adaptation to variations in nutrient availability in the tumor microenvironment. PMID- 25937279 TI - Ensemble force changes that result from human cardiac myosin mutations and a small-molecule effector. AB - Cardiomyopathies due to mutations in human beta-cardiac myosin are a significant cause of heart failure, sudden death, and arrhythmia. To understand the underlying molecular basis of changes in the contractile system's force production due to such mutations and search for potential drugs that restore force generation, an in vitro assay is necessary to evaluate cardiac myosin's ensemble force using purified proteins. Here, we characterize the ensemble force of human alpha- and beta-cardiac myosin isoforms and those of beta-cardiac myosins carrying left ventricular non-compaction (M531R) and dilated cardiomyopathy (S532P) mutations using a utrophin-based loaded in vitro motility assay and new filament-tracking software. Our results show that human alpha- and beta-cardiac myosin, as well as the mutants, show opposite mechanical and enzymatic phenotypes with respect to each other. We also show that omecamtiv mecarbil, a previously discovered cardiac-specific myosin activator, increases beta-cardiac myosin force generation. PMID- 25937280 TI - Chronic optogenetic activation augments abeta pathology in a mouse model of Alzheimer disease. AB - In vivo experimental evidence indicates that acute neuronal activation increases Abeta release from presynaptic terminals, whereas long-term effects of chronic synaptic activation on Abeta pathology remain unclear. To address this issue, we adopted optogenetics and transduced stabilized step-function opsin, a channelrhodopsin engineered to elicit a long-lasting neuronal hyperexcitability, into the hippocampal perforant pathway of APP transgenic mice. In vivo microdialysis revealed a ~24% increase in the hippocampal interstitial fluid Abeta42 levels immediately after acute light activation. Five months of chronic optogenetic stimulation increased Abeta burden specifically in the projection area of the perforant pathway (i.e., outer molecular layer of the dentate gyrus) of the stimulated side by ~2.5-fold compared with that in the contralateral side. Epileptic seizures were observed during the course of chronic stimulation, which might have partly contributed to the Abeta pathology. These findings implicate functional abnormalities of specific neuronal circuitry in Abeta pathology and Alzheimer disease. PMID- 25937281 TI - Efficient CRISPR-Cas9-mediated generation of knockin human pluripotent stem cells lacking undesired mutations at the targeted locus. AB - The CRISPR-Cas9 system has the potential to revolutionize genome editing in human pluripotent stem cells (hPSCs), but its advantages and pitfalls are still poorly understood. We systematically tested the ability of CRISPR-Cas9 to mediate reporter gene knockin at 16 distinct genomic sites in hPSCs. We observed efficient gene targeting but found that targeted clones carried an unexpectedly high frequency of insertion and deletion (indel) mutations at both alleles of the targeted gene. These indels were induced by Cas9 nuclease, as well as Cas9-D10A single or dual nickases, and often disrupted gene function. To overcome this problem, we designed strategies to physically destroy or separate CRISPR target sites at the targeted allele and developed a bioinformatic pipeline to identify and eliminate clones harboring deleterious indels at the other allele. This two pronged approach enables the reliable generation of knockin hPSC reporter cell lines free of unwanted mutations at the targeted locus. PMID- 25937282 TI - The adhesion GPCR latrophilin/CIRL shapes mechanosensation. AB - G-protein-coupled receptors (GPCRs) are typically regarded as chemosensors that control cellular states in response to soluble extracellular cues. However, the modality of stimuli recognized through adhesion GPCR (aGPCR), the second largest class of the GPCR superfamily, is unresolved. Our study characterizes the Drosophila aGPCR Latrophilin/dCirl, a prototype member of this enigmatic receptor class. We show that dCirl shapes the perception of tactile, proprioceptive, and auditory stimuli through chordotonal neurons, the principal mechanosensors of Drosophila. dCirl sensitizes these neurons for the detection of mechanical stimulation by amplifying their input-output function. Our results indicate that aGPCR may generally process and modulate the perception of mechanical signals, linking these important stimuli to the sensory canon of the GPCR superfamily. PMID- 25937284 TI - Proteome- and transcriptome-driven reconstruction of the human myocyte metabolic network and its use for identification of markers for diabetes. AB - Skeletal myocytes are metabolically active and susceptible to insulin resistance and are thus implicated in type 2 diabetes (T2D). This complex disease involves systemic metabolic changes, and their elucidation at the systems level requires genome-wide data and biological networks. Genome-scale metabolic models (GEMs) provide a network context for the integration of high-throughput data. We generated myocyte-specific RNA-sequencing data and investigated their correlation with proteome data. These data were then used to reconstruct a comprehensive myocyte GEM. Next, we performed a meta-analysis of six studies comparing muscle transcription in T2D versus healthy subjects. Transcriptional changes were mapped on the myocyte GEM, revealing extensive transcriptional regulation in T2D, particularly around pyruvate oxidation, branched-chain amino acid catabolism, and tetrahydrofolate metabolism, connected through the downregulated dihydrolipoamide dehydrogenase. Strikingly, the gene signature underlying this metabolic regulation successfully classifies the disease state of individual samples, suggesting that regulation of these pathways is a ubiquitous feature of myocytes in response to T2D. PMID- 25937283 TI - Porous silicon microparticle potentiates anti-tumor immunity by enhancing cross presentation and inducing type I interferon response. AB - Micro- and nanometer-size particles have become popular candidates for cancer vaccine adjuvants. However, the mechanism by which such particles enhance immune responses remains unclear. Here, we report a porous silicon microparticle (PSM) based cancer vaccine that greatly enhances cross-presentation and activates type I interferon (IFN-I) response in dendritic cells (DCs). PSM-loaded antigen exhibited prolonged early endosome localization and enhanced cross-presentation through both proteasome- and lysosome-dependent pathways. Phagocytosis of PSM by DCs induced IFN-I responses through a TRIF- and MAVS-dependent pathway. DCs primed with PSM-loaded HER2 antigen produced robust CD8 T cell-dependent anti tumor immunity in mice bearing HER2+ mammary gland tumors. Importantly, this vaccination activated the tumor immune microenvironment with elevated levels of intra-tumor IFN-I and MHCII expression, abundant CD11c+ DC infiltration, and tumor-specific cytotoxic T cell responses. These findings highlight the potential of PSM as an immune adjuvant to potentiate DC-based cancer immunotherapy. PMID- 25937285 TI - ATM couples replication stress and metabolic reprogramming during cellular senescence. AB - Replication stress induced by nucleotide deficiency plays an important role in cancer initiation. Replication stress in primary cells typically activates the cellular senescence tumor-suppression mechanism. Senescence bypass correlates with development of cancer, a disease characterized by metabolic reprogramming. However, the role of metabolic reprogramming in the cellular response to replication stress has been little explored. Here, we report that ataxia telangiectasia mutated (ATM) plays a central role in regulating the cellular response to replication stress by shifting cellular metabolism. ATM inactivation bypasses senescence induced by replication stress triggered by nucleotide deficiency. This was due to restoration of deoxyribonucleotide triphosphate (dNTP) levels through both upregulation of the pentose phosphate pathway via increased glucose-6-phosphate dehydrogenase (G6PD) activity and enhanced glucose and glutamine consumption. These phenotypes were mediated by a coordinated suppression of p53 and upregulation of c-MYC downstream of ATM inactivation. Our data indicate that ATM status couples replication stress and metabolic reprogramming during senescence. PMID- 25937286 TI - Single-cell telomere-length quantification couples telomere length to meristem activity and stem cell development in Arabidopsis. AB - Telomeres are specialized nucleoprotein caps that protect chromosome ends assuring cell division. Single-cell telomere quantification in animals established a critical role for telomerase in stem cells, yet, in plants, telomere-length quantification has been reported only at the organ level. Here, a quantitative analysis of telomere length of single cells in Arabidopsis root apex uncovered a heterogeneous telomere-length distribution of different cell lineages showing the longest telomeres at the stem cells. The defects in meristem and stem cell renewal observed in tert mutants demonstrate that telomere lengthening by TERT sets a replicative limit in the root meristem. Conversely, the long telomeres of the columella cells and the premature stem cell differentiation plt1,2 mutants suggest that differentiation can prevent telomere erosion. Overall, our results indicate that telomere dynamics are coupled to meristem activity and continuous growth, disclosing a critical association between telomere length, stem cell function, and the extended lifespan of plants. PMID- 25937287 TI - Antisense RNA controls LRP1 Sense transcript expression through interaction with a chromatin-associated protein, HMGB2. AB - Long non-coding RNAs (lncRNAs), including natural antisense transcripts (NATs), are expressed more extensively than previously anticipated and have widespread roles in regulating gene expression. Nevertheless, the molecular mechanisms of action of the majority of NATs remain largely unknown. Here, we identify a NAT of low-density lipoprotein receptor-related protein 1 (Lrp1), referred to as Lrp1 AS, that negatively regulates Lrp1 expression. We show that Lrp1-AS directly binds to high-mobility group box 2 (Hmgb2) and inhibits the activity of Hmgb2 to enhance Srebp1a-dependent transcription of Lrp1. Short oligonucleotides targeting Lrp1-AS inhibit the interaction of antisense transcript and Hmgb2 protein and increase Lrp1 expression by enhancing Hmgb2 activity. Quantitative RT-PCR analysis of brain tissue samples from Alzheimer's disease patients and aged matched controls revealed upregulation of LRP1-AS and downregulation of LRP1. Our data suggest a regulatory mechanism whereby a NAT interacts with a ubiquitous chromatin-associated protein to modulate its activity in a locus-specific fashion. PMID- 25937288 TI - The parvalbumin/somatostatin ratio is increased in Pten mutant mice and by human PTEN ASD alleles. AB - Mutations in the phosphatase PTEN are strongly implicated in autism spectrum disorder (ASD). Here, we investigate the function of Pten in cortical GABAergic neurons using conditional mutagenesis in mice. Loss of Pten results in a preferential loss of SST(+) interneurons, which increases the ratio of parvalbumin/somatostatin (PV/SST) interneurons, ectopic PV(+) projections in layer I, and inhibition onto glutamatergic cortical neurons. Pten mutant mice exhibit deficits in social behavior and changes in electroencephalogram (EEG) power. Using medial ganglionic eminence (MGE) transplantation, we test for cell autonomous functional differences between human PTEN wild-type (WT) and ASD alleles. The PTEN ASD alleles are hypomorphic in regulating cell size and the PV/SST ratio in comparison to WT PTEN. This MGE transplantation/complementation assay is efficient and is generally applicable for functional testing of ASD alleles in vivo. PMID- 25937289 TI - Strategies for improving the physiological relevance of human engineered tissues. AB - This review examines important robust methods for sustained, steady-state, in vitro culture. To achieve 'physiologically relevant' tissues in vitro additional complexity must be introduced to provide suitable transport, cell signaling, and matrix support for cells in 3D environments to achieve stable readouts of tissue function. Most tissue engineering systems draw conclusions on tissue functions such as responses to toxins, nutrition, or drugs based on short-term outcomes with in vitro cultures (2-14 days). However, short-term cultures limit insight with physiological relevance because the cells and tissues have not reached a steady-state. PMID- 25937290 TI - Determination of hepatitis delta virus ribozyme N(-1) nucleobase and functional group specificity using internal competition kinetics. AB - Biological catalysis involves interactions distant from the site of chemistry that can position the substrate for reaction. Catalysis of RNA 2'-O transphosphorylation by the hepatitis delta virus (HDV) ribozyme is sensitive to the identity of the N(-1) nucleotide flanking the reactive phosphoryl group. However, the interactions that affect the conformation of this position, and in turn the 2'O nucleophile, are unclear. Here, we describe the application of multiple substrate internal competition kinetic analyses to understand how the N( 1) nucleobase contributes to HDV catalysis and test the utility of this approach for RNA structure-function studies. Internal competition reactions containing all four substrate sequence variants at the N(-1) position in reactions using ribozyme active site mutations at A77 and A78 were used to test a proposed base pairing interaction. Mutants A78U, A78G, and A79G retain significant catalytic activity but do not alter the specificity for the N(-1) nucleobase. Effects of nucleobase analog substitutions at N(-1) indicate that U is preferred due to the ability to donate an H-bond in the Watson-Crick face and avoid minor groove steric clash. The results provide information essential for evaluating models of the HDV active site and illustrate multiple substrate kinetic analyses as a practical approach for characterizing structure-function relationships in RNA reactions. PMID- 25937291 TI - Rapid PCR of STR markers: Applications to human identification. AB - Multiplex PCR with fluorescently labeled primers has been an essential method for the amplification of short tandem repeats used in human identify testing. Within the STR workflow of extraction, quantitation, amplification, separation, and detection, multiplex PCR is commonly identified as the bottleneck in the process. The time requirement of up to three hours to complete 28-30 cycles of multiplex PCR for STR genotyping is the greatest amount of time required for a single step within the process. The historical use of commercially available thermal cyclers and heat stable polymerases may have given the impression that large multiplex will always require long PCR cycling times to ensure that all of the varying sized targets (typically 100-400bp) can be amplified in a balanced manner throughout the multiplex. However, with the advent of improved polymerases and faster thermal cyclers the time required for the amplification of large STR multiplexes is no longer on the order of three hours, but as little as 14min. Faster amplification times can be performed while retaining the balance and integrity of large multiplex PCRs by implementation of alternate polymerases and thermal cyclers. With the reduction in PCR cycling times there has also been an impact on the development of integrated and microfluidics devices which employ the use of reduced or rapid thermal cycling protocols as part of their integration. Similarly, PCR inhibitor resistant polymerases can also reduce overall STR processing times for reference samples by eliminating the need for DNA extraction and purification that is additionally implemented within the development of integrated DNA typing devices. PMID- 25937292 TI - Spinal Fusion from Non-operative Management of Lytic Myelomatous Vertebrae. PMID- 25937293 TI - Complication rates are reduced for revision adult spine deformity surgery among high-volume hospitals and surgeons. AB - BACKGROUND CONTEXT: Revision adult spinal deformity surgery (RASDS) is a particularly high-risk intervention. PURPOSE: The aim was to assess complication rates in RASDS by surgeon and hospital operative volume. STUDY DESIGN/SETTING: This was a retrospective analysis of prospectively collected data. PATIENT SAMPLE: Based on a Nationwide Inpatient Sample (NIS) database (2001-2010), patients aged older than 21 years (International Classification of Diseases, Ninth Revision, Clinical Modification) with spine arthrodesis for scoliosis were included. For longitudinal analysis, the 2008-2011 New York State Inpatient Database (NY SID) was queried. OUTCOME MEASURES: The outcome measures included complication rate after RASDS. METHODS: Cases were identified as primary or revision surgery with or without osteotomy performed. Annual surgeon and hospital volumes were stratified into quartiles via identifier codes. Case complexity was determined using a novel operative complexity index, based on available NIS operative parameters: levels fused, approach, osteotomy, and revision status. The primary end point was morbidity during the hospital stay. New York State Inpatient Database analysis allowed for identification of rate of reoperation for infection or pseudarthrosis/implant failure. One-way analysis of variance was used to assess continuous measures, chi-square for categorical measures. RESULTS: Of 139,150 adult spinal deformity surgery (ASDS) cases, 4,888 revision with hospital identifiers and 1,978 with surgeon identifiers were identified. Higher volume surgeons performed more revision cases and cases requiring osteotomy. With increasing hospital volume, complication rate for RASDS decreased (9.7% vs. 12.9% at highest- vs. lowest-volume centers, p< .001). The highest-volume surgeons showed significant decreases in the rate of major complications for RASDS (8.8% vs. 10.7% for lowest-volume surgeons, p< .001). A similar trend was observed for ASDS cases requiring osteotomy. Multiple logistic regression analysis showed that the highest-volume hospitals and surgeons showed a reduced odds ratio for all complications compared with lowest-volume hospitals. For the NY SID, 528 RASDS cases indicated reoperation rates for infection and pseudarthrosis/implant failure after RASDS were increased for the lowest-volume hospitals and surgeons. CONCLUSIONS: Perioperative complication rate associated with RASDS is lower when patients are treated by high-volume surgeons at high-volume centers. As complex cases requiring osteotomy and combined approaches are more frequent at high volume centers, an operative complexity index helps predict the likelihood of volume-dependent complication rates. Future interhospital and intersurgeon comparisons should account for these case characteristics so that similar case complexity is compared in these analyses. PMID- 25937294 TI - Tension hydropneumopericardium after routine intubation. PMID- 25937295 TI - Intensified association between waist circumference and hypertension in abdominally overweight children. AB - BACKGROUND: Abdominal adiposity is an important risk factor for childhood hypertension. The present study aimed to compare the strength of the association between waist circumference (WC) and hypertension in children with different WC levels. METHODS: A total of 82,413 Chinese children aged 9-17 years were selected. An abdominally overweight child was defined as a child with WC >=75th sex- and age-specific percentile. Hypertension was categorised as >=95th sex-, age- and height-specific percentile. Logistic regression model was applied to calculate the odds ratio (OR) and 95% confidence interval (CI) of WC for hypertension after WC was transformed into sex- and age-specific z-score. RESULTS: Abdominally overweight children presented a higher risk of hypertension (OR: 2.39; 95% CI: 2.26, 2.54) than children with normal WC. In children with normal WC, one sex- and age-specific standard deviation increase in WC was associated with a 42% increase in odds of hypertension (OR: 1.42; 95% CI: 1.30, 1.55). That increase was elevated to 74% in abdominally overweight children (OR: 1.74; 95% CI: 1.66, 1.82). A similar pattern was also observed in different sex and area groups, and in children 9-14 years old. CONCLUSIONS: An intensified association between WC and hypertension was observed in abdominally overweight Chinese children. The gain in WC was associated with greater increase in hypertensive risk in abdominally overweight children than that of children with normal WC. These findings could improve intervention strategies for hypertension risk reduction in children. PMID- 25937296 TI - Therapy response assessment after radioembolization of patients with hepatocellular carcinoma--comparison of MR imaging with gadolinium ethoxybenzyl diethylenetriamine penta-acetic acid and gadobutrol. AB - PURPOSE: To compare the utility of gadolinium ethoxybenzyl diethylenetriamine penta-acetic acid (Gd-EOB-DTPA), a liver-specific magnetic resonance (MR) imaging contrast agent, versus gadobutrol for treatment response evaluation of hepatocellular carcinoma (HCC) after radioembolization. MATERIALS AND METHODS: This prospective study included 50 patients with HCC undergoing radioembolization. All patients underwent contrast-enhanced computed tomography (CT) and MR imaging with gadobutrol and Gd-EOB-DTPA on 2 consecutive days before radioembolization and 30 days, 90 days, 180 days, and 270 days after radioembolization. The standard of reference indicating tumor progression was CT combined with either alpha-fetoprotein or gamma-glutamyltransferase. Gadobutrol enhanced MR imaging, Gd-EOB-DTPA-enhanced MR imaging without late phase imaging (Gd-EOB-DTPA-), and Gd-EOB-DTPA-enhanced MR imaging with late phase imaging (Gd EOB-DTPA+) were evaluated by 2 radiologists in consensus using a 4-point scale: 1 = definitely no tumor progression; 2 = probably no tumor progression; 3 = probably tumor progression; 4 = definitely tumor progression. Diagnostic accuracy was assessed with receiver operating characteristic analysis. RESULTS: Tumor progression was detected in 14 of 82 study visits according to the reference standard. Pairwise comparison of the area under the curve showed a tendency toward a larger area under the curve for Gd-EOB-DTPA+ compared with gadobutrol (P = .056). Sensitivity and specificity were higher in Gd-EOB-DTPA+ (0.929 and 0.971) than in Gd-EOB-DTPA- (0.786 and 0.941) or gadobutrol (0.643 and 0.956). In 2 cases, tumor progression was detected by Gd-EOB-DTPA+ and by an increase in alpha-fetoprotein, but not by CT, gadobutrol, or Gd-EOB-DTPA-. CONCLUSIONS: Gd EOB-DTPA+ MR imaging was not inferior to gadobutrol-enhanced MR imaging in therapy response evaluation after radioembolization and may allow a more accurate detection of early HCC recurrence in single cases. PMID- 25937297 TI - A single-center experience in capturing inpatient evaluation and management for an IR practice. AB - PURPOSE: To demonstrate that interventional radiologists can capture work relative value units (wRVUs) for the work that is already being performed providing evaluation and management (E&M) clinical services. MATERIALS AND METHODS: A team approach was implemented to optimize revenue capture for inpatient E&M. Structured templates were created for inpatient documentation to ensure that maximum wRVUs were captured. Inpatient billing was audited from fiscal year 2011 (1 year before meeting and structured template creation) through fiscal year 2014. Specifically, data were collected on total charges, collections, wRVUs and total number of inpatient E&M encounters, and the level of the billed encounter. RESULTS: Retrospective annual audits revealed that overall inpatient E&M billing charges increased by 722%, whereas collections increased by 831% from 2011 to 2014. The wRVUs increased in 2011 from 181.74 to 1,396.9 (669% increase) in 2014, and the number of inpatient E&M encounters billed increased from 130 to 693 (433% increase) over that same time period. Lower level billing (level I) declined from 30% to 19%, and complex billing levels (level II or higher) increased from 70% to 81%. CONCLUSIONS: By implementing a systems approach to revenue management, which includes physician and billing staff meetings and the use of structured templates, billing capture from inpatient E&M services can be improved. PMID- 25937298 TI - Politics of prevention: The emergence of prevention science. AB - BACKGROUND: This article critically examines the political dimension of prevention science by asking how it constructs the problems for which prevention is seen as the solution and how it enables the monitoring and control of these problems. It also seeks to examine how prevention science has established a sphere for legitimate political deliberation and which kinds of statements are accepted as legitimate within this sphere. METHODS: The material consists of 14 publications describing and discussing the goals, concepts, promises and problems of prevention science. The analysis covers the period from 1993 to 2012. RESULTS: The analysis shows that prevention science has established a narrow definition of "prevention", including only interventions aimed at the reduction of risks for clinical disorders. In publications from the U.S. National Institute of Drug Abuse, the principles of prevention science have enabled a commitment to a zero tolerance policy on drugs. The drug using subject has been constructed as a rational choice actor lacking in skills in exerting self-control in regard to drug use. Prevention science has also enabled the monitoring and control of expertise, risk groups and individuals through specific forms of data gathering. Through the juxtaposition of the concepts of "objectivity" and "morality", prevention science has constituted a principle of delineation, disqualifying statements not adhering to the principles of prevention science from the political field, rendering ethical and conflictual dimensions of problem representations invisible. CONCLUSION: The valorisation of scientific accounts of drugs has acted to naturalise specific political ideals. It simultaneously marginalises the public from the public policy process, giving precedence to experts who are able to provide information that policy-makers are demanding. Alternative accounts, such as those based on marginalisation, poverty or discrimination are silenced within prevention science. PMID- 25937299 TI - Enhancing therapeutic efficacy of the MEK inhibitor, MEK162, by blocking autophagy or inhibiting PI3K/Akt signaling in human lung cancer cells. AB - Human non-small cell lung cancer (NSCLC) displays activated MEK/ERK signaling due to a high frequency of K-Ras mutation and is thus a potential candidate for MEK targeted therapy. The current study focuses on demonstrating the activity of MEK162 (binimetinib), a MEK inhibitor under clinical testing, against NSCLC and exploring possible mechanism-driven strategies to enhance its therapeutic efficacy. MEK162 inhibits the growth of human NSCLC cell lines with varied potencies through induction of G1 cell cycle arrest and apoptosis. Moreover, it induces autophagy and accordingly the combination of MEK162 with the autophagy inhibitor, chloroquine, synergistically inhibits the growth of NSCLC cells and enhances apoptosis. MEK162 activates Akt signaling while effectively inhibiting MEK/ERK signaling. Accordingly, the combination of MEK162 and BKM120 (buparlisib), a pan-PI3K inhibitor, abrogates induced Akt activation and significantly augments therapeutic efficacy against the growth of NSCLC cells both in vitro and in vivo. Hence our findings warrant further evaluation of these rational combinations in the clinic. PMID- 25937300 TI - Nelfinavir, an HIV protease inhibitor, induces apoptosis and cell cycle arrest in human cervical cancer cells via the ROS-dependent mitochondrial pathway. AB - HIV protease inhibitors (HIV-PIs) are a class of antiretroviral drugs designed to target the viral protease. Strikingly, these drugs have also been reported to possess antitumor effect. In this study, we evaluated the activity of one HIV-PI, Nelfinavir, against human cervical cancer cells. We found that Nelfinavir inhibited the growth of cervical cancer cell lines at the lowest micromolar concentrations clinically attainable. Nelfinavir promoted apoptosis and arrested the cell cycle at G1 phase. Apoptosis is attributed to the promotion of mitochondrial reactive oxygen species (ROS) production, which results in the translocation of mitochondrial apoptosis inducing factor (AIF) to the nucleus. We further showed that Nelfinavir increased mitochondrial ROS production by decreasing manganese superoxide dismutase (MnSOD) protein levels. Taken together, our results suggest that Nelfinavir can be repositioned as a cervical cancer therapeutic. PMID- 25937301 TI - Improved differentiation between hepatic hemangioma and metastases on diffusion weighted MRI by measurement of standard deviation of apparent diffusion coefficient. AB - BACKGROUND: Diffusion-weighted magnetic resonance imaging (DW-MR) can be useful in the differentiation of hemangiomata from liver metastasis, but improved methods other than by mean apparent diffusion coefficient (mADC) are needed. METHODS: A retrospective review identified 109 metastatic liver lesions and 86 hemangiomata in 128 patients who had undergone DW-MR. For each lesion, mADC and the standard deviation of the mean ADC (sdADC) were recorded and compared by receiver operating characteristic analysis. RESULTS: Mean mADC was higher in benign hemangiomata (1.52+/-0.12 mm(2)/s) than in liver metastases (1.33+/-0.18 mm(2)/s), but there was significant overlap in values. The mean sdADC was lower in hemangiomata (101+/-17 mm(2)/s) than metastases (245+/-25 mm(2)/s) and demonstrated no overlap in values, which was significantly different (P<.0001). CONCLUSIONS: Hemangiomata may be better able to be differentiated from liver metastases on the basis of sdADC than by mADC, although further studies are needed. PMID- 25937302 TI - The neuronal ceroid lipofuscinoses: Opportunities from model systems. AB - The neuronal ceroid lipofuscinoses are a group of severe and progressive neurodegenerative disorders, generally with childhood onset. Despite the fact that these diseases remain fatal, significant breakthroughs have been made in our understanding of the genetics that underpin these conditions. This understanding has allowed the development of a broad range of models to study disease processes, and to develop new therapeutic approaches. Such models have contributed significantly to our knowledge of these conditions. In this review we will focus on the advantages of each individual model, describe some of the contributions the models have made to our understanding of the broader disease biology and highlight new techniques and approaches relevant to the study and potential treatment of the neuronal ceroid lipofuscinoses. This article is part of a Special Issue entitled: "Current Research on the Neuronal Ceroid Lipofuscinoses (Batten Disease)". PMID- 25937303 TI - The declining use of bone densitometry. PMID- 25937304 TI - Differing measurement sites produce significant differences of measured variables in high-resolution peripheral quantitative computed tomography. PMID- 25937305 TI - Dual-Energy X-ray Absorptiometry Image Resolution and TBS Precision. PMID- 25937306 TI - Discriminatory Performance of the Calcaneal Quantitative Ultrasound and Osteoporosis Self-Assessment Tool to Select Older Women for Dual-Energy X-ray Absorptiometry. AB - The objective of this cross-sectional study was to evaluate the accuracy of the calcaneal quantitative ultrasound (QUS) and the Osteoporosis Self-Assessment Tool (OST) in identifying older women with osteoporosis as defined by dual-energy X ray absorptiometry (DXA), and to establish optimal cutoffs to determine risk. We assessed bone mineral density of the femoral neck and lumbar spine using DXA and subsequent calcaneal QUS and OST measurements in 174 women aged 50-80 years. Pearson product correlation coefficients between QUS, OST, and DXA parameters were calculated. Receiver operating characteristic curves were constructed and areas under the curves (AUCs) and optimal thresholds for QUS and OST were defined based on sensitivity, specificity, and likelihood ratio analysis. The ability of calcaneal QUS to identify women with a T-score <=-2.5 at the femoral neck (AUC = 0.892) consistently outperformed a T-score <=-2.5 at the lumbar spine (AUC = 0.696) and OST at both the femoral neck and lumbar spine (AUC = 0.706-0.807). Stiffness index cutoff values that fall between 65 and 78 were found to warrant DXA screening, with a cutoff <65 indicating high likelihood of osteoporosis. Further prospective research is needed to examine the gender-related differences of QUS and OST diagnostic performance and their usefulness in clinical practice. PMID- 25937307 TI - Quantification of visceral fat using dual-energy x-ray absorptiometry and its reliability according to the amount of visceral fat in Korean adults. AB - Recently, a fully automated method for segmenting abdominal fat into subcutaneous fat and visceral fat (VF) within the android region using dual-energy X-ray absorptiometry (DXA) has been newly developed. The purpose of this study was to validate a new DXA method by comparing it to the gold standard, computed tomography (CT), in the Korean population. Furthermore, we examined its reliability regarding VF and explored whether it is applicable to the Asian population, which has relatively larger amount of VF. We studied 123 adult men and women, aged 22-73 yr, representing a wide range of body mass index values (17.1-36.0 kg/m(2)), who underwent both DXA and CT in a fasting state within 1 h. The coefficient of determination (r(2)) for regression of the CT on DXA values was 0.892 for females, 0.838 for males, and 0.931 combined. Bland-Altman bias was -451.4 cm(3) with 95% limits of agreement of 149.8 to -1052.6 cm(3). The DXA measured VF showed a better correlation with CT-measured VF volume than common indices for adiposity, including the body mass index and waist circumference. There was a lesser discrepancy ratio between DXA- and CT-measured VF with an increase of VF volume. DXA, a relatively convenient, inexpensive, and safe method with minimum radiation dosage, can be a reliable technique for VF assessment in the Asian population. PMID- 25937308 TI - Association between duration of playing video games and bone mineral density in Chinese adolescents. AB - The aim of the study was to investigate the association between duration of playing video games and bone mineral density (BMD) in Chinese adolescents. Three hundred eighty-four Chinese adolescents aged 14-18 yr (148 males and 236 females) were analyzed. Anthropometric measurements were obtained using standard procedures. Total body and regional BMD were measured using dual-energy X-ray absorptiometry. Duration of playing video games, defined as hours per day, was measured by a self-report questionnaire. We examined the association between duration of playing video games and BMD using multiple linear regression analysis. After adjustment for age, sex, pubertal stage, parental education, body mass index, adolescents with longer video game duration were more likely to have lower legs, trunk, pelvic, spine, and total BMD (p < 0.05). We concluded that duration of video game was negatively associated with BMD in Chinese adolescents. These findings provide support for reducing duration of playing video games as a possible means to increase BMD in adolescents. Future research is needed to elucidate the underlined mechanisms linking playing video games and osteoporosis. PMID- 25937309 TI - Letter to the Editor on "Appropriate Osteoporosis Treatment by Family Physicians in Response to FRAX vs CAROC Reporting: Results From a Randomized Controlled Trial". PMID- 25937310 TI - Subcutaneous rupture of the superficial branch of the radial nerve at the wrist. A case report and review of literature. AB - Isolated neuropathy of the superficial branch of the radial nerve (SBRN) is a rarely recognized pathology. It was initially described by Wartenberg in 1932. Various causes have been published. We report a case of an unusual injury of the SBRN at the wrist, never been previously reported in the literature. A 40-year old woman presented with pain and paresthesia over the area of the lateral aspect of the wrist, thumb and first web two months after a blunt trauma of the left forearm. After failure of conservative treatment, surgical exploration found a neuroma of one branch of the SBRN. No distal nerve stump was found. Neuroma resection was performed and the nerve was transposed and embedded into the flexor pollicis longus muscle. With a six months follow-up, the result was satisfactory. PMID- 25937311 TI - Structuring Microbial Metabolic Responses to Multiplexed Stimuli via Self Organizing Metabolomics Maps. AB - Secondary metabolite biosynthesis in microorganisms responds to discrete chemical and biological stimuli; however, untargeted identification of these responses presents a significant challenge. Herein we apply multiplexed stimuli to Streptomyces coelicolor and collect the resulting response metabolomes via ion mobility-mass spectrometric analysis. Self-organizing map (SOM) analytics adapted for metabolomic data demonstrate efficient characterization of the subsets of primary and secondary metabolites that respond similarly across stimuli. Over 60% of all metabolic features inventoried from responses are either not observed under control conditions or produced at greater than 2-fold increase in abundance in response to at least one of the multiplexing conditions, reflecting how metabolites encode phenotypic changes in an organism responding to multiplexed challenges. Using abundance as an additional filter, each of 16 known S. coelicolor secondary metabolites is prioritized via SOM and observed at increased levels (1.2- to 22-fold compared with unperturbed) in response to one or more challenge conditions. PMID- 25937312 TI - Surface-Induced Dissociation of Homotetramers with D2 Symmetry Yields their Assembly Pathways and Characterizes the Effect of Ligand Binding. AB - Understanding of protein complex assembly and the effect of ligand binding on their native topologies is integral to discerning how alterations in their architecture can affect function. Probing the disassembly pathway may offer insight into the mechanisms through which various subunits self-assemble into complexes. Here, a gas-phase dissociation method, surface-induced dissociation (SID) coupled with ion mobility (IM), was utilized to determine whether disassembly pathways are consistent with the assembly of three homotetramers and to probe the effects of ligand binding on conformational flexibility and tetramer stability. The results indicate that the smaller interface in the complex is initially cleaved upon dissociation, conserving the larger interface, and suggest that assembly of a D2 homotetramer from its constituent monomers occurs via a C2 dimer intermediate. In addition, we demonstrate that ligand-mediated changes in tetramer SID dissociation behavior are dependent on where and how the ligand binds. PMID- 25937314 TI - The longevity of anti NSP antibodies and the sensitivity of a 3ABC ELISA - A 3 years follow up of repeatedly vaccinated dairy cattle infected by foot and mouth disease virus. AB - ELISA tests for detection of anti NSP antibodies are extensively used in surveys estimating exposure of livestock to foot and mouth disease virus as a part of endemic and post epidemic surveillance programs. Yet, estimation of the longevity of anti NSP antibodies in naturally infected cattle and the sensitivity of ELISA tests based on them were rarely studied to date. Our research aim was to estimate the long term (up to 1118 days after exposure) change in levels of anti NSP antibodies in dairy cattle individuals naturally infected by FMDV and to evaluate the sensitivity of a commercially available ELISA kit in detecting anti NSP antibodies during the follow up period. A 3ABC blocking ELISA kit (PrioCHECK((r)) FMDV NS) was used in a 3 years follow up study of repeatedly vaccinated cattle, which were found to be NSP positive during an FMD outbreak in a dairy farm. In order to rule out the possibility of a recurrent FMD outbreak involving the study population we combined clinical and laboratory monitoring: Cattle which were located in the same herd and were previously found as negative to anti NSP antibodies were followed and did not present FMD symptoms or a serological conversion. The overall sensitivity for infection detection was calculated using two approaches. When a conservative approach was taken and equivocal results (45%<=PI<=55%) were treated as negative, the sensitivities were 95% (CI95%=75.1 99.9%), 88.2% (CI95%=63.6-98.5%) and 76.9% (CI95%=46.2-95%) 311, 689 and 1118 days after the outbreak, respectively. However, when equivocal results were treated as positive, the sensitivities were 100% (CI95%=83.2-100%), 94.1% (CI95%=71.3-99.9%) and 92.3% (CI95%=64-99.8%) 311, 689 and 1118 days after the outbreak, respectively. We therefore conclude that this test can serve as a valuable tool for detection of previous FMDV infection in cattle in endemic countries, where routine vaccinations are implied, even several years after exposure. PMID- 25937313 TI - Accelerometer measured sedentary behavior and physical activity in white and black adults: The REGARDS study. AB - OBJECTIVES: Health disparities between subgroups may be partially due to differences in lifestyle behaviors such as sedentariness and physical activity. To obtain a more accurate description of these two lifestyle behaviors, accelerometry was employed among a large sample of white and black adults (ages 49-99 years) living in the United States. DESIGN: Cross-sectional. METHODS: 7967 participants from the REasons for Geographic and Racial Differences in Stroke cohort wore an ActicalTM accelerometer >=10h/day for >=4 days. Time (mean minutes/day and proportion of total wear time) spent in sedentary behavior, light intensity physical activity, and moderate-vigorous intensity physical activity was compared by sex, age, body mass index, race, and geographic location. RESULTS: Proportion of total wear time spent in sedentary behavior was 75-90%, light intensity physical activity was 10-23%, and moderate-vigorous intensity physical activity was 0-1.7% across subgroups. Mean moderate-vigorous intensity physical activity was 0-16min/day and associated with 3-12% accumulating >=150min/wk using a 10-min bout criterion. Persons >=85 years, those classified obese, persons living in the southeastern United States, and black women were the most inactive. The proportion achieving at least one 10-min bout of moderate vigorous intensity physical activity per week was only 36%. The number of 10-min bouts/week was 1.5+/-0.08bouts/week. The distribution of weekly moderate-vigorous intensity physical activity was similar across nearly all subgroups with a distinct reverse J-shaped configuration. CONCLUSIONS: The vast majority of white and black midlife and older adults in this study engaged sparingly in moderate vigorous intensity physical activity, accumulated tremendous amounts of sedentary behavior, and seldom engaged in continuous bouts of health-enhancing physical activity. PMID- 25937315 TI - A molecular epidemiology of treponemes in beef cattle digital dermatitis lesions and comparative analyses with sheep contagious ovine digital dermatitis and dairy cattle digital dermatitis lesions. AB - Bovine digital dermatitis (BDD) is an infective foot disease commonly reported in dairy cattle where Treponema are considered as the primary causative infectious agents. There still remains little definitive information on the etiology of BDD in beef cattle suggesting further investigations are warranted. Beef BDD lesions (n=34) and healthy beef foot tissues (n=38) were analysed by PCR for three BDD associated Treponema phylogroups and also for Dichelobacter nodosus and Fusobacterium necrophorum. Spirochete culture was attempted on all BDD lesion samples. One or more BDD-associated Treponema phylogroups were detected in 100% of beef BDD lesions. "Treponema medium/Treponema vincentii-like", "Treponema phagedenis-like" and Treponema pedis spirochetes were identified in 27/34 (79%), 31/34 (91%) and 24/34 (71%) of BDD lesions, respectively. No BDD-associated treponeme DNA was amplified from beef healthy foot tissues. D. nodosus and F. necrophorum were present in 24/34 (71%) and 15/34 (44%) of lesions and 10/38 (26%) and 12/38 (32%) of healthy foot tissues, respectively. Twenty spirochetes were isolated from beef BDD lesions; 19 were representatives of the three BDD associated Treponema phylogroups. One spirochete isolate shared less than 97% 16S rRNA gene similarity to the three cultivable BDD-associated Treponema phylogroups and therefore may represent a novel taxa of Treponema. Upon comparison, sheep contagious ovine digital dermatitis (CODD), dairy cattle and beef cattle BDD lesions appear to have extremely similar bacteriological data and therefore provides evidence of a shared etiopathogenesis posing concerns for cross-species transmission. PMID- 25937316 TI - Clinical and virological dynamics of a serotype O 2010 South East Asia lineage foot-and-mouth disease virus in sheep using natural and simulated natural inoculation and exposure systems. AB - Within-host infection dynamics of a recent field isolate of foot-and-mouth disease virus (FMDV), serotype O, topotype South East Asia, lineage Myamar'98 were evaluated in sheep using four different systems for virus exposure. Two novel, simulated natural, inoculation systems consisting of intra-nasopharyngeal (INP) deposition and aerosol inoculation were evaluated in comparison with two conventional systems: coronary band inoculation and direct contact exposure. All four exposure systems were efficient in generating consistently severe, generalized FMD with synchronous clinical characteristics within exposure groups, indicating that this Myanmar98 strain is highly virulent in sheep. Clinical and virological dynamics were similarly rapid following INP- and coronary band inoculation, with both systems leading to significantly earlier detection of virus shedding when compared to aerosol inoculation and contact exposure. The data presented herein support application of the two optimized simulated natural inoculation systems as valid alternatives to conventionally used exposure systems for studies of FMDV pathogenesis and vaccinology in sheep. Furthermore, the data suggest that targeted exposure of the ovine pharynx is highly efficient for generating consistent FMDV infection, which supports critical involvement of this anatomic region as a site of primary virus replication in sheep. PMID- 25937317 TI - Exploitation of plasmin(ogen) by bacterial pathogens of veterinary significance. AB - The plasminogen (Plg) system plays an important homeostatic role in the degradation of fibrin clots, extracellular matrices and tissue barriers important for cellular migration, as well as the promotion of neurotransmitter release. Plg circulates in plasma at physiologically high concentrations (150-200MUg ml(-1)) as an inactive proenzyme. Proteins enriched in lysine and other positively charged residues (histidine and arginine) as well as glycosaminoglycans and gangliosides bind Plg. The binding interaction initiates a structural adjustment to the bound Plg that facilitates cleavage by proteases (plasminogen activators tPA and uPA) that activate Plg to the active serine protease plasmin. Both pathogenic and commensal bacteria capture Plg onto their cell surface and promote its conversion to plasmin. Many microbial Plg-binding proteins have been described underpinning the importance this process plays in how bacteria interact with their hosts. Bacteria exploit the proteolytic capabilities of plasmin by (i) targeting the mammalian fibrinolytic system and degrading fibrin clots, (ii) remodeling the extracellular matrix and generating bioactive cleavage fragments of the ECM that influence signaling pathways, (iii) activating matrix metalloproteinases that assist in the destruction of tissue barriers and promote microbial metastasis and (iv) destroying immune effector molecules. There has been little focus on the exploitation of the fibrinolytic system by veterinary pathogens. Here we describe several pathogens of veterinary significance that possess adhesins that bind plasmin(ogen) onto their cell surface and promote its activation to plasmin. Cumulative data suggests that these attributes provide pathogenic and commensal bacteria with a means to colonize and persist within the host environment. PMID- 25937318 TI - p62 participates in the inhibition of NF-kappaB signaling and apoptosis induced by sulfasalazine in human glioma U251 cells. AB - Nuclear factor-kappaB (NF-kappaB) is constitutively activated in most malignant gliomas and is involved in cancer progression and drug resistance to chemotherapy. Sulfasalazine (SAS) is a classic inhibitor of NF-kappaB. Apoptosis and autophagy were induced by SAS accompanied by inhibition of NF-kappaB signaling in U251 cells. Inhibition of autophagy by 3-MA suppressed the effects of SAS on NF-kappaB signaling and apoptosis in U251 cells. Multifunctional scaffold protein p62 is well known as an autophagy marker protein and provides crosstalk for important signaling pathways, including NF-kappaB signaling. SAS induced decrease in the p62 protein levels may be the result of degradation through autophagy. SAS induced the inhibition of NF-kappaB signaling and apoptosis at least partly via a p62-dependent effect in U251 cells. Collectively, our data shed light on the link between p62 and the NF-kappaB signaling pathway, particularly in glioma cells. The results may facilitate the design of more effective targeted therapies for the treatment of tumors in which NF-kappaB signaling is altered. PMID- 25937319 TI - The effect of ligand density on in vivo tumor targeting of nanographene oxide. AB - Recently, the application of nanographene oxide (nGO) as a drug delivery system has significantly increased. But, the rational engineering of nGO surface to improve its in vivo targeting and biodistribution remains mostly unexplored. In this study, we have prepared folic acid conjugated Pluronic for non-covalent functionalization of nanographene oxide (nGO) sheets and active tumor targeting. To modulate the ligand density on the nGO surface, different ratios of folate conjugated Pluronic and unmodified Pluronic were combined and used for coating nGO sheets. The surface density of targeting ligand linearly increased as the relative amount of folate conjugated Pluronic was increased. The association of functionalized nGOs with folate receptor overexpressing human epithelial mouth carcinoma cells (KB cells) was evaluated by flow cytometry. Cellular uptake of nGO by KB cells increased steadily with the increase in ligand density. In contrast, the in vivo experiment in mouse xenograft model did not show the steady increase in tumor targeting by increasing ligand density. Upon intravenous administration into KB tumor-bearing mice, tumor accumulation of nGO did not show a significant targeting effect up to 25% of ligand coating density. However, a strong and similar tumor accumulation of nGO was observed for both 50% and 100% folate coatings. Thus, a significant difference in tumor accumulation of nGO was observed between the low folate density groups and high folate density groups, suggesting the existence of a critical ligand density for tumor targeting. The significant difference of tumor targeting of nGO depending on ligand density also resulted in the dramatic change in photothermal tumor ablation by the irradiation of NIR laser. PMID- 25937320 TI - Impact insertion of transfer-molded microneedle for localized and minimally invasive ocular drug delivery. AB - It has been challenging for microneedles to deliver drugs effectively to thin tissues with little background support such as the cornea. Herein, we designed a microneedle pen system, a single microneedle with a spring-loaded microneedle applicator to provide impact insertion. To firmly attach solid microneedles with 140 MUm in height at the end of macro-scale applicators, a transfer molding process was employed. The fabricated microneedle pens were then applied to mouse corneas. The microneedle pens successfully delivered rhodamine dye deep enough to reach the stromal layer of the cornea with small entry only about 1000 MUm(2). When compared with syringes or 30 G needle tips, microneedle pens could achieve more localized and minimally invasive delivery without any chances of perforation. To investigate the efficacy of microneedle pens as a way of drug delivery, sunitinib malate proven to inhibit in vitro angiogenesis, was delivered to suture-induced angiogenesis model. When compared with delivery by a 30 G needle tip dipped with sunitinib malate, only delivery by microneedle pens could effectively inhibit corneal neovascularization in vivo. Microneedle pens could effectively deliver drugs to thin tissues without impairing merits of using microneedles: localized and minimally invasive delivery. PMID- 25937321 TI - Enema ion compositions for enhancing colorectal drug delivery. AB - Delivering drugs to the colorectum by enema has advantages for treating or preventing both local and systemic diseases. However, the properties of the enema itself are not typically exploited for improving drug delivery. Sodium ions are actively pumped out of the lumen of the colon, which is followed by osmotically driven water absorption, so we hypothesized that this natural mechanism could be exploited to drive nanoparticles and drugs to the colorectal tissue surface. Here, we report that sodium-based, absorption-inducing (hypotonic) enemas rapidly transport hydrophilic drugs and non-mucoadhesive, mucus penetrating nanoparticles (MPP), deep into the colorectal folds to reach virtually the entire colorectal epithelial surface. In contrast, isotonic and secretion-inducing (hypertonic) vehicles led to non-uniform, poor surface coverage. Sodium-based enemas induced rapid fluid absorption even when moderately hyper-osmolal (~350 mOsm) compared to blood (~300 mOsm), which suggests that active sodium absorption plays a key role in osmosis-driven fluid uptake. We then used tenofovir, an antiretroviral drug in clinical trials for preventing HIV, to test the effects of enema composition on local and systemic drug delivery. We found that strongly hypotonic and hypertonic enemas caused rapid systemic drug uptake, whereas moderately hypotonic enemas with ion compositions similar to feces resulted in high local tissue levels with minimal systemic drug exposure. Similarly, moderately hypotonic enemas provided improved local drug retention in colorectal tissue, whereas hypertonic and isotonic enemas provided markedly reduced drug retention in colorectal tissue. Lastly, we found that moderately hypotonic enema formulations caused little to no detectable epithelial damage, while hypertonic solutions caused significant damage, including epithelial sloughing; the epithelial damage caused increased systemic drug absorption and penetration of MPP into colorectal tissue, a potential advantage in certain drug delivery applications. In summary, we illustrate that enema composition can be adjusted to maximize local versus systemic drug delivery, and that mildly hypotonic, sodium-based vehicles can provide uniform drug and MPP delivery in the colon that maximizes local drug concentrations. PMID- 25937322 TI - Inhibition of replication of hepatitis B virus in transgenic mice following administration of hepatotropic lipoplexes containing guanidinopropyl-modified siRNAs. AB - Chronic infection with hepatitis B virus (HBV) occurs commonly and complications that arise from persistence of the virus are associated with high mortality. Available licensed drugs have modest curative efficacy and advancing new therapeutic strategies to eliminate the virus is therefore a priority. HBV is susceptible to inactivation by exogenous gene silencers that harness RNA interference (RNAi) and the approach has therapeutic potential. To advance RNAi based treatment for HBV infection, use in vivo of hepatotropic lipoplexes containing siRNAs with guanidinopropyl (GP) modifications is reported here. Lipoplexes contained polyglutamate, which has previously been shown to facilitate formulation and improve efficiency of the non-viral vectors. GP moieties were included in a previously described anti-HBV siRNA that effectively targeted the conserved viral X sequence. Particles had physical properties that were suitable for use in vivo: average diameter was approximately 50-200 nm and surface charge (zeta potential) was +65 mV. Efficient hepatotropic delivery of labeled siRNA was observed following systemic intravenous injection of the particles into HBV transgenic mice. Good inhibition of markers of viral replication was observed without evidence of toxicity. Efficacy of the GP-modified siRNAs was significantly more durable and formulations made up with chemically modified siRNAs were less immunostimulatory. An RNAi-mediated mechanism was confirmed by demonstrating that HBV mRNA cleavage occurred in vivo at the intended target site. Collectively these data indicate that GP-modified siRNAs formulated in anionic polymer-containing lipoplexes are effective silencers of HBV replication in vivo and have therapeutic potential. PMID- 25937323 TI - Lifelong physical activity and executive functions in older age assessed by memory based task switching. AB - Aging is accompanied by compromised executive control. Training studies point to beneficial effects of physical activity on executive functions. Here, we investigate the relationship between lifelong habitual physical activity (about 50 years) and switch ability in healthy seniors. Participants switched among three tasks in a memorized task sequence. Mixing costs for speed were lower in habitually active than low active participants whereas switch costs were not affected. Active participants revealed also lower mixing and switch costs for accuracy. These parameters were negatively correlated with the self-reported level of physical activity. The frontal CNV was smaller in the active than low active group. In contrast, in the target-locked ERPs active individuals showed an earlier P2, a larger frontocentral N2 and the typical pattern of smaller P3b in switch than non-switch trials relative to low-active individuals. These data suggest that lifelong physical activity is associated with faster recall of stimulus-response sets (P2), enhanced response selection during interference processing (N2) and working memory updating (P3b) leading to lower mixing and switch costs. PMID- 25937324 TI - Specifics of pulmonary gas exchange after replacing the inert components of inspired mixtures. PMID- 25937325 TI - Characteristics of sleep-related arousals depend on trait anxiety. PMID- 25937326 TI - The 5HT4 receptor agonist prucalopride suppresses abdominal nociception. PMID- 25937327 TI - Neuronal cells in the dorsal and ventral roots of the spinal cord of a frog. PMID- 25937328 TI - Phylogeography of the earthworm Eisenia nordenskioldi nordenskioldi (Lumbricidae, Oligochaeta) in northeastern Eurasia. PMID- 25937329 TI - Effect of selenium and arabinogalactan nanocomposite on viability of the phytopathogen Clavibacter michiganensis subsp. sepedonicus. PMID- 25937330 TI - Non-symbiotic nitrogen fixation in the intestine of click beetle larvae (Coleoptera, Elateridae). PMID- 25937331 TI - Alternative types of small mammal ontogeny: Contribution to the radiobiology and radioecology. PMID- 25937332 TI - Seabird helminth fauna and parasite life cycles on the Murman coast of the Barents Sea in winter. PMID- 25937333 TI - Free-living stages of the life cycle of the parasitic dinoflagellate Ichthyodinium chabelardi Hollande et J. Cachon, 1952 (Alveolata: Dinoflagellata). PMID- 25937334 TI - Territoriality as a factor of separation of species in artiodactyl communities. PMID- 25937335 TI - Effect of mixed culture supernatants of Pseudomonas aeruginosa and Escherichia coli on apoptosis, necrosis, and oxidative activity of neutrophils. PMID- 25937336 TI - Model study of biological effects of weak static magnetic fields at the organismic and subcellular levels. PMID- 25937337 TI - A saxitoxin-binding aptamer with higher affinity and inhibitory activity optimized by rational site-directed mutagenesis and truncation. AB - Saxitoxin (STX), a member of the family of paralytic shellfish poisoning toxins, poses toxicological and ecotoxicological risks. To develop an analytical recognition element for STX, a DNA aptamer (APT(STX1)) was previously discovered via an iterative process known as Systematic Evolution of Ligands by Exponential Enrichment (SELEX) by Handy et al. Our study focused on generating an improved aptamer based on APT(STX1) through rational site-directed mutation and truncation. In this study, we generated the aptamer, M-30f, with a 30-fold higher affinity for STX compared with APT(STX1). The Kd value for M-30f was 133 nM, which was calculated by Bio-Layer Interferometry. After optimization, we detected and compared the interaction of STX with aptamers (APT(STX1) or M-30f) through several techniques (ELISA, cell bioassay, and mouse bioassay). Both aptamers' STX binding ability was demonstrated in all three methods. Moreover, M-30f performs better than its parent sequence with higher suppressive activity against STX. As a molecular recognition element, M-30f has good prospects for practical application. PMID- 25937338 TI - Microcystins and anatoxin-a in Arctic biocrust cyanobacterial communities. AB - In the polar regions cyanobacteria are an important element of plant communities and represent the dominant group of primary producers. They commonly form thick highly diverse biological soil crusts that provide microhabitats for other organisms. Cyanobacteria are also producers of toxic secondary metabolites. In the present study we demonstrated that biocrust-forming cyanobacteria inhabiting the Kaffioyra Plain, the north-west coast of Spitsbergen, are able to synthesize toxins, especially microcystins (MCs, from 0.123 to 11.058 MUg MC-LR per g dry weight, DW) and anatoxin-a (ANTX-a, from 0.322 to 0.633 MUg ANTX-a per g DW). To the best of our knowledge, this is the first report on the presence of ANTX-a in the entire polar region. The occurrence of cyanotoxins can exert a long-term impact on organisms co-existing in biocrust communities and can have far-reaching consequences for the entire polar ecosystem. PMID- 25937340 TI - Anterior capsule integrity after femtosecond laser-assisted cataract surgery. PMID- 25937339 TI - Activity of botulinum neurotoxin type D (strain 1873) in human neurons. AB - Botulinum Neurotoxin type D (BoNT/D) causes periodic outbreaks of botulism in cattle and horses, but is rarely associated with human botulism. Previous studies have shown that humans responded poorly to peripheral injection of up to 10U of BoNT/D. Isolated human pyramidalis muscle preparations were resistant to BoNT/D, whereas isolated human intercostal muscle preparations responded to BoNT/D similarly as to other BoNT serotypes. In vitro data indicate that BoNT/D does not cleave human VAMP1 efficiently, and differential expression of the VAMP 1 and 2 isoforms may be responsible for the above observations. Here we examined sensitivity of cultured human neurons derived from human induced pluripotent stem cells to BoNT/D. Our data indicate that BoNT/D can enter and cleave VAMP 2 in human neurons, but at significantly lower efficiency than other BoNT serotypes. In addition, BoNT/D had a short duration of action in the cultured neurons, similar to that of BoNT/E. In vivo analyses indicated a slower time to death in mice, as well as a later onset and shorter duration of action than BoNT/A1. Finally, examination of BoNT/D activity in various rodent and human cell models resulted in dramatic differences in sensitivity, indicating a unique cell entry mechanism of BoNT/D. PMID- 25937341 TI - Rotation stability of a toric intraocular lens with a second capsular tension ring. AB - An Acrysof toric intraocular lens (IOL) and a capsular tension ring (CTR) were implanted in the highly myopic eye of a 74-year-old white man during cataract surgery. On the first postoperative day, the IOL was found 90 degrees from the required position, with a consequent high amount of astigmatism. A second procedure was performed and because it was not possible to secure the toric IOL in the correct position, an additional in-the-bag CTR was inserted, with an immediate optimal outcome. The IOL remained stable up to the final follow-up examination. Co-implantation of a toric IOL and a single CTR has been reported. In our case, 2 CTRs were required to fixate the toric IOL in the correct position. This procedure is simple and safe and should be considered in cases of postoperatively misaligned toric IOLs. PMID- 25937342 TI - Symptom severity and disgust-related traits in borderline personality disorder: The role of amygdala subdivisions. AB - The majority of morphometric studies on borderline personality disorder (BPD) found that diagnosed patients have a reduced amygdala volume. We sought to extend this finding by focusing on amygdala subdivisions (centromedial, laterobasal, superficial) and their association with symptom severity and disgust-related traits. Additional disorder-/disgust-relevant regions (insula, somatosensory cortex) were also investigated. We compared structural imaging data from 25 female BPD patients and 25 healthy women via voxel-based morphometry. Scores on self-report measures for symptom severity, disgust proneness, and self-disgust were correlated with gray matter volume (GMV) of regions of interest. Relative to controls, BPD patients had more GMV in the laterobasal amygdala. The volume of this region was positively correlated with symptom severity. In contrast, GMV of the centromedial amygdala showed a negative correlation with symptom severity. The degree of reported self-injury and self-disgust correlated negatively with the volume of the secondary somatosensory cortex (SII). Our data point to a differential contribution of amygdala subdivisions to symptom severity in BPD. Future longitudinal studies should focus on these subregions and possible volume changes during the course of the disorder. The meaning of altered SII volume for dysfunctional auto-aggressive behavior needs further investigation. PMID- 25937344 TI - Changes in the acoustic environment alter the foraging and sheltering behaviour of the cichlid Amititlania nigrofasciata. AB - Anthropogenic noise can affect behaviour across a wide range of species in both terrestrial and aquatic environments. However, behaviours might not be affected in isolation. Therefore, a more holistic approach investigating how environmental stressors, such as noise pollution, affect different behaviours in concert is necessary. Using tank-based noise exposure experiments, we tested how changes in the acoustic environment affect the behaviour of the cichlid Amatitlania nigrofasciata. We found that exposure to anthropogenic noise affected a couple of behaviours: an increase in sheltering was accompanied by a decrease in foraging. Our results highlight the multiple negative effects of an environmental stressor on an individual's behaviour. PMID- 25937345 TI - Depressive states amplify both upward and downward counterfactual thinking. AB - Depression has been linked to counterfactual thinking in many behavioral studies, but the direction of this effect remains disputed. In the current study, the relationship between depression and counterfactual thinking was examined using the event-related potential (ERP) technique. In a binary choice gambling task, outcome feedback of the chosen option and that of the alternative option were both provided, so as to elicit the process of counterfactual comparison. By investigating ERP signals in response to outcome presentation, we discovered that when the fictive outcome was better or worse than the factual outcome, the amplitude of the P3 component was positively correlated with individual levels of depression, but not levels of anxiety. These results indicate that depression strengthens both upward counterfactual thinking and downward counterfactual thinking. The implication of this finding to clinical research is discussed. PMID- 25937343 TI - The Dlx5 and Foxg1 transcription factors, linked via miRNA-9 and -200, are required for the development of the olfactory and GnRH system. AB - During neuronal development and maturation, microRNAs (miRs) play diverse functions ranging from early patterning, proliferation and commitment to differentiation, survival, homeostasis, activity and plasticity of more mature and adult neurons. The role of miRs in the differentiation of olfactory receptor neurons (ORNs) is emerging from the conditional inactivation of Dicer in immature ORN, and the depletion of all mature miRs in this system. Here, we identify specific miRs involved in olfactory development, by focusing on mice null for Dlx5, a homeogene essential for both ORN differentiation and axon guidance and connectivity. Analysis of miR expression in Dlx5(-/-) olfactory epithelium pointed to reduced levels of miR-9, miR-376a and four miRs of the -200 class in the absence of Dlx5. To functionally examine the role of these miRs, we depleted miR-9 and miR-200 class in reporter zebrafish embryos and observed delayed ORN differentiation, altered axonal trajectory/targeting, and altered genesis and position of olfactory-associated GnRH neurons, i.e. a phenotype known as Kallmann syndrome in humans. miR-9 and miR-200-class negatively control Foxg1 mRNA, a fork head transcription factor essential for development of the olfactory epithelium and of the forebrain, known to maintain progenitors in a stem state. Increased levels of z-foxg1 mRNA resulted in delayed ORN differentiation and altered axon trajectory, in zebrafish embryos. This work describes for the first time the role of specific miR (-9 and -200) in olfactory/GnRH development, and uncovers a Dlx5 Foxg1 regulation whose alteration affects receptor neuron differentiation, axonal targeting, GnRH neuron development, the hallmarks of the Kallmann syndrome. PMID- 25937346 TI - Is meditation always relaxing? Investigating heart rate, heart rate variability, experienced effort and likeability during training of three types of meditation. AB - Meditation is often associated with a relaxed state of the body. However, meditation can also be regarded as a type of mental task and training, associated with mental effort and physiological arousal. The cardiovascular effects of meditation may vary depending on the type of meditation, degree of mental effort, and amount of training. In the current study we assessed heart rate (HR), high frequency heart rate variability (HF-HRV) and subjective ratings of effort and likeability during three types of meditation varying in their cognitive and attentional requirements, namely breathing meditation, loving-kindness meditation and observing-thoughts meditation. In the context of the ReSource project, a one year longitudinal mental training study, participants practiced each meditation exercise on a daily basis for 3 months. As expected HR and effort were higher during loving-kindness meditation and observing-thoughts meditation compared to breathing meditation. With training over time HR and likeability increased, while HF-HRV and the subjective experience of effort decreased. The increase in HR and decrease in HF-HRV over training was higher for loving-kindness meditation and observing-thoughts meditation compared to breathing meditation. In contrast to implicit beliefs that meditation is always relaxing and associated with low arousal, the current results show that core meditations aiming at improving compassion and meta-cognitive skills require effort and are associated with physiological arousal compared to breathing meditation. Overall these findings can be useful in making more specific suggestions about which type of meditation is most adaptive for a given context and population. PMID- 25937347 TI - Management and Long-Term Prognosis of Spontaneous Coronary Artery Dissection. AB - The optimal management and short- and long-term prognoses of spontaneous coronary artery dissection (SCAD) remain not well defined. The aim of this observational multicenter study was to assess long-term clinical outcomes in patients with SCAD. In-hospital and long-term outcomes were assessed in 134 patients with documented SCAD, as well as the clinical impact and predictors of a conservative rather than a revascularization strategy of treatment. The mean age was 52 +/- 11, years and 81% of patients were female. SCAD presented as an acute coronary syndromes in 93% of patients. A conservative strategy was performed in 58% of patients and revascularization in 42%. On multivariate analysis, distal versus proximal or mid location of dissection (odds ratio 9.27) and basal Thrombolysis In Myocardial Infarction (TIMI) flow grade 2 or 3 versus 0 or 1 (odds ratio 0.20) were independent predictors of conservative versus revascularization strategy. A conservative strategy was associated with better in-hospital outcomes compared with revascularization (rates of major adverse cardiac events 3.8% and 16.1%, respectively, p = 0.028); however, no significant differences were observed in the long-term outcomes. In conclusion, in this large observational study of patients with SCAD, angiographic features significantly influenced the treatment strategy, providing an excellent short- and long-term prognosis. PMID- 25937349 TI - Meta-Analysis of Large-Scale Randomized Trials to Determine the Effectiveness of Inhibition of the Renin-Angiotensin Aldosterone System in Heart Failure. AB - Renin-angiotensin-aldosterone system (RAAS) inhibition is 1 of the most effective strategies for the management of heart failure with reduced systolic function. However, trials that included patients with preserved systolic function have not shown a clear beneficial effect. Pooling evidence from several heart failure trials provides the opportunity to better assess the differential effects of RAAS inhibition across the continuum of systolic function. The authors searched MEDLINE for large-scale trials published from 1966 to March 2014 that compared RAAS inhibitors against placebos. Studies were eligible for inclusion if they were conducted in heart failure populations with either clinical signs of heart failure or reduced ejection fractions. Inverse variance-weighted fixed-effects meta-analysis was used to pool outcomes of interest, with metaregression used to test for trends. In 16 trials with 54,621 randomized heart failure participants, RAAS inhibition reduced the risks for hospitalization for heart failure by 20% (relative risk [RR] 0.80, 95% confidence interval [CI] 0.77 to 0.83), cardiovascular mortality by 14% (RR 0.86, 95% CI 0.83 to 0.90), and all-cause mortality by 11% (RR 0.89, 95% CI 0.85 to 0.92). However, proportional effects decreased with increasing mean left ventricular ejection fraction (LVEF) for all outcomes (p for trend <0.01). Although there was no significant proportional effect on cardiovascular and all-cause mortality in trials with a mean LVEF >50%, RAAS inhibition was still found to decrease the risk for heart failure hospitalization in patients with preserved LVEFs (RR 0.88, 95% CI 0.80 to 0.97). In conclusion, the relative beneficial effects of RAAS inhibition in heart failure decreases with increasing left ventricular systolic function. Nonetheless, RAAS inhibition significantly reduces the risks for all-cause mortality and cardiovascular mortality in patients with moderately reduced LVEFs and the incidence of hospitalization in patients with preserved left ventricular function. PMID- 25937348 TI - Frequency and Effects of Excess Dosing of Anticoagulants in Patients <=55 Years With Acute Myocardial Infarction Who Underwent Percutaneous Coronary Intervention (from the VIRGO Study). AB - Excess dosing of anticoagulant agents has been linked to increased risk of bleeding after percutaneous coronary intervention (PCI) for women compared with men, but these studies have largely included older patients. We sought to determine the prevalence and gender-based differences of excess dosing of anticoagulants including glycoprotein IIb/IIIa inhibitors, bivalirudin, and unfractionated heparin in young patients with acute myocardial infarction who underwent PCI and to examine its association with bleeding. Of 2,076 patients enrolled in the Variation in Recovery: Role of Gender on Outcomes of Young Acute Myocardial Infarction Patients study who underwent PCI, we abstracted doses of unfractionated heparin, bivalirudin, and glycoprotein IIb/IIIa inhibitors administered during PCI from the medical records. At least 47.2% received at least 1 excess dose of an anticoagulant, which did not differ by gender. We used logistic regression to determine the predictors of excess dosing and the association of excess dosing with bleeding. In multivariable analysis, only lower body weight and younger age were significant predictors of excess dosing. Bleeding was higher in young women who received excess dosing versus those who did not (9.3% vs 6.0%, p = 0.03) but was comparable among men (5.2% vs 5.9%, p = 0.69) in univariate analysis. In multivariable analysis, there was a trend to an association between excess dosing and bleeding (odds ratio 1.33, 95% confidence interval 0.92 to 1.91) although not statistically significant. In conclusion, approximately half of the patients received excess dosing of anticoagulant drugs during PCI, which did not vary based on gender. There was a trend toward an association between excess dosing and increased bleeding, although not statistically significant. PMID- 25937350 TI - Isolated Complete Heart Block in the Fetus. AB - Isolated congenital complete heart block (CCHB) is a rare disease with significant associated morbidity and mortality. A diagnosis is often made in fetal life, but data regarding long-term outcomes are limited, and fetal therapy to improve prognosis is controversial. In our institution, 85 fetuses were diagnosed with CCHB from 1981 to 2013 in 80 mothers. There were 37 anti-Ro positive pregnancies, 36 both anti-Ro and anti-La positive, 10 antibody negative, and 2 of unknown antibody status. Antenatal treatments were given in 14 fetuses, with 8 given fluorinated steroids, 4 beta sympathomimetics, and both in 2. Of the original 85, 74 babies survived to delivery. Fetal hydrops was the only risk factor found to be significantly associated with intrauterine death (p <0.001). Four babies died before pacemaker implantation, 56 have had pacemakers implanted, and 14 are pacemaker free. The Kaplan-Meier estimate for median time to pacemaker implantation was 2.6 years, with 15 implanted in the neonatal period. There have been 14 postnatal deaths, with a Kaplan-Meier estimate of survival at 30 years of 76.8% (95% confidence interval 65% to 90%). Dilated cardiomyopathy was uncommon, occurring in 6 patients. Prematurity and hydrops were associated with increased postnatal mortality (p = 0.02 and 0.005, respectively). In conclusion, we present the largest single-unit experience of prenatally diagnosed CCHB in the published literature. Our cohort was conservatively managed, with survival similar to those previously published. These data offer insight into the long-term natural history of CCHB. PMID- 25937351 TI - Electrocardiogram in a 35-Year-Old Man. PMID- 25937352 TI - Impact on Left Ventricular Function and Remodeling and on 1-Year Outcome in Patients With Left Bundle Branch Block After Transcatheter Aortic Valve Implantation. AB - Conflicting results have been reported about the prognostic impact of left bundle branch block (LBBB) after transcatheter aortic valve implantation (TAVI). The aim of this study was to evaluate the impact of LBBB after TAVI on left ventricular (LV) function and remodeling and on 1-year outcomes. Of 101 TAVI patients, 9 were excluded. All complications were evaluated according to the Valve Academic Research Consortium 2 definition. Of 92 patients, 34 developed LBBB without more advanced myocardial damage or inflammation biomarkers in comparison with patients without LBBB. The only predictor of new LBBB was larger baseline LV end-diastolic volume. LBBB plus advanced atrioventricular block was strongly correlated with permanent pacemaker implantation (p <0.0001). Patients with LBBB had a higher rate of permanent pacemaker implantation at 30 days (59% vs 19%, p <0.0001) and less recovery of LV systolic function and a trend toward a lower rate of LV reverse remodeling at 1 year. The development of acute kidney injury and the logistic European System for Cardiac Operative Risk Evaluation score were associated with poor outcomes (all-cause mortality and heart failure) (hazard ratio 6.86, 95% confidence interval 2.51 to 18.74, p <0.0001, and hazard ratio 1.04, 95% confidence interval 1.01 to 1.08, p = 0.021, respectively), but not LBBB. In conclusion, after TAVI, 37% of patients developed new LBBB without more advanced myocardial damage or inflammation biomarkers. LBBB was associated with a higher rate of permanent pacemaker implantation, which negatively affected the recovery of LV systolic function. The development of acute kidney injury, rather than LBBB, increases the 1-year risk for mortality and hospitalization for heart failure. PMID- 25937353 TI - Reply: To PMID 25772741. PMID- 25937354 TI - Intraoperative Magnetic Resonance Imaging in Intracranial Glioma Resection: A Single-Center, Retrospective Blinded Volumetric Study. AB - BACKGROUND: Intraoperative magnetic resonance imaging (IoMRI) was devised to overcome brain shifts during craniotomies. Yet, the acceptance of IoMRI is limited. OBJECTIVE: To evaluate impact of IoMRI on intracranial glioma resection outcome including overall patient survival. METHODS: A retrospective review of records was performed on a cohort of 164 consecutive patients who underwent resection surgery for newly diagnosed intracranial gliomas either with or without IoMRI technology performed by 2 neurosurgeons in our center. Patient follow-up was at least 5 years. Extent of resection (EOR) was calculated using pre- and postoperative contrast-enhanced and T2-weighted MR-images. Adjusted analysis was performed to compare gross total resection (GTR), EOR, permanent surgery associated neurologic deficit, and overall survival between the 2 groups. RESULTS: Overall median EOR was 92.1%, and 97.45% with IoMRI use and 89.9% without IoMRI, with crude (unadjusted) P < 0.005. GTR was achieved in 49.3% of IoMRI cases, versus in only 21.4% of no-IoMRI cases, P < 0.001. GTR achieved was more with the use of IoMRI among gliomas located in both eloquent and noneloquent brain areas, P = 0.017 and <0.001, respectively. Permanent surgery-associated neurologic deficit was not (statistically) more significant with no-IoMRI, P = 0.284 (13.8% vs. 6.7%). In addition, the IoMRI group had better 5-year overall survival, P < 0.001. CONCLUSION: This study shows that the use of IoMRI was associated with greater rates of EOR and GTR, and better overall 5-year survival in both eloquent brain areas located and non-eloquent brain areas located gliomas, with no increased risk of neurologic complication. PMID- 25937355 TI - Tibioperoneal Short Circuiting for Stump Neuroma Pain in Amputees: Revival of an Old Technique. AB - BACKGROUND: Stump neuroma pain in amputees can be quite challenging. Surgical treatment may be largely subdivided into neuromodulative and non-neuromodulative methods. The latter includes neurocapsis, insertion of nerve stump into the bone marrow, centro-central short circuit (CCSC), and coverage with vascularized soft tissue flaps. CCSC was shown to be extremely effective in alleviation of pain. Reports on CCSC for the treatment of stump neuroma pain have disappeared from the literature, with a shift toward neuromodulation for the treatment of pain irrespective of etiology. METHODS: We observed 8 lower limb amputees undergoing CCSC of the sciatic nerve during a follow-up of 12 years. All had the same stump neuroma pain rendering them unable to wear their prostheses. The sciatic nerve was explored at the midthigh area, much proximal to the amputation site, and a short circuit was established between the tibial and peroneal parts of the nerve. Assessment was by means of pain quantification as per the quadruple visual analogue scale, medication intake, and ability to use prostheses. RESULTS: The median worst quadruple visual analogue scale before surgery was 8.0. After surgery it decreased to 2.5 (P = 0.00094). Medication intake was reduced from regular intake of a combination of opioids, nonsteroidal anti-inflammatory drugs, tricyclic antidepressants, and pregabalin in all patients to irregular intake of nonsteroidal anti-inflammatory drug alone in 3 of 8 patients. All patients were able to wear their limb prosthesis since surgery. CONCLUSIONS: CCSC is a simple, effective, and long-lasting method to treat painful stump neuromas in amputees. It should be strongly considered in deserving cases before resorting to neuromodulative methods. PMID- 25937356 TI - Chronic Cerebral Ischemia: Where "Evidence-Based Medicine" Fails Patients. AB - BACKGROUND AND IMPORTANCE: The publication of the COSS (Carotid Occlusion Surgery Study) trial in 2011 concluded that the addition of external carotid to internal carotid (EC-IC) bypass to a medical regimen "did not reduce the risk of ipsilateral ischemic stroke at 2 years" for patients with symptomatic internal carotid artery occlusion. This has resulted in decreasing referrals for surgical management under the guise of "evidence-based" medicine. The conclusions drawn from a study can only be as good as the selected end points. COSS did not consider important end points such as the effects of long-term cerebral ischemia or recurrent debilitating transient ischemic attacks (TIAs). However, the study is often quoted as "proof" that EC-IC bypass has no role in the treatment of these patients. CLINICAL PRESENTATION: A middle-aged patient presented to a primary neurologist with left-sided weakness and 2 months of personality changes. Magnetic resonance imaging (MRI) showed small watershed infarcts in the right hemisphere. An angiogram showed right carotid occlusion. Perfusion scans confirmed hypoperfusion. The patient was managed medically. Without any further clinical stroke events, the patient progressed to complete hemispheric infarction on MRI over the next 5 months. CONCLUSION: The public perception of the results of large randomized clinical trials is significantly altered by their ubiquitous dissemination and broad generalization without adequate understanding of the details. Careful assessment of the methodology and end points of a trial are essential when applying the results for evidence-based medicine to individual patients. This patient would have been considered a medical "success" in COSS, but her outcome with surgical intervention will never be known. PMID- 25937357 TI - Electrocardiographic detection of left ventricular hypertrophy: Time to forget the Sokolow-Lyon index? PMID- 25937358 TI - Sex-related differences after contemporary primary percutaneous coronary intervention for ST-segment elevation myocardial infarction. AB - BACKGROUND: Whether outcomes differ for women and men after percutaneous coronary intervention (PCI) for ST-segment elevation myocardial infarction (STEMI) remains controversial. AIM: To compare 1-year outcomes after primary PCI in women and men with STEMI, matched for age and diabetes. METHODS: Consecutive women with STEMI of<24 hours' duration referred (August 2007 to January 2011) for primary PCI were compared with men matched for age and diabetes. Rates of all-cause mortality, target vessel revascularization (TVR) and major cardiovascular and cerebrovascular events (MACCE) (death/myocardial infarction/stroke) were assessed at 1 year. RESULTS: Among 775 consecutive patients, 182 (23.5%) women were compared with 182 matched men. Mean age was 69+/-15 years, 18% had diabetes. Patient characteristics were similar, except for lower creatinine clearance (73+/ 41 vs 82+/-38 MUmol/L; P=0.041), more cardiogenic shock (14.8% vs 6.6%; P=0.017) and less radial PCI (81.3% vs 90.1%; P=0.024) in women. Rates of 1-year death (22.7% vs 18.1%), TVR (8.3% vs 6.0%) and MACCE (24.3% vs 20.9%) were not statistically different in women (P>0.05 for all). After exclusion of patients with shock (10.7%) and out-of-hospital cardiac arrest (6.6%), death rates were even more similar (11.3% vs 11.8%; P=0.10). Female sex was not independently associated with death (odds ratio 1.01, 95% confidence interval 0.55-1.87; P=0.97). CONCLUSION: In our consecutive unselected patient population, women had similar 1-year outcomes to men matched for age and diabetes, after contemporary primary PCI for STEMI, despite having a higher risk profile at baseline. PMID- 25937359 TI - Isolation, enrichment and primary characterisation of vitelline cells from Schistosoma mansoni obtained by the organ isolation method. AB - In the emerging era of post-genomic research on schistosomes, new methods are required to functionally analyse genes of interest in more detail. Among other tools, schistosome cell lines are needed to overcome present research constraints. Based on a recently established organ isolation protocol for adult Schistosoma mansoni, we report here on the successful enrichment of vitellarium tissue and isolation of vitelline cells. Morphological analyses performed by bright field, fluorescence, scanning and transmission electron microscopy showed typical features of S1 to S4 stage vitelline cells. In addition, molecular analyses using reverse transcription-PCR confirmed the identity of vitelline cells. Cytological and physiological studies included staining experiments with viability dyes and a neutral lipid stain, as well as calcium (Ca2+) imaging. Together they demonstrated cell viability, the possibility to define the differentiation stage of individual vitelline cells, and the suitability to investigate Ca(2+)-associated processes herein. Finally, fluorescence-activated cell sorting was shown to be a convenient way to separate and enrich S1 to S4 stage vitelline cells. In summary, these results demonstrate the expedience of the organ isolation protocol to obtain vitellarium tissue. Importantly, the protocol allows vitelline cells representing defined differentiation stages to be purified, which can be cultured in vitro and used to investigate diverse aspects of schistosome reproductive biology in the post-genomic era. PMID- 25937360 TI - Analysis of the protective immune response following intramuscular vaccination of calves against the intestinal parasite Cooperia oncophora. AB - Recently we reported the successful vaccination of calves against Cooperia oncophora with a double domain activation-associated secreted protein, purified from the excretory-secretory material of adult stage parasites. In an attempt to elucidate the immune mechanisms involved in protection, the humoral and cell mediated immune responses following vaccination and infection were compared with non-vaccinated control animals. Antigen-specific IgG1, IgG2 and IgA levels were significantly increased in sera of vaccinated animals post vaccination, whereas no effect was observed for IgM. Antigen-specific intestinal IgG1 levels were significantly increased in the vaccinated animals, whereas no differences were observed for antigen-specific IgA, IgM and IgG2 levels. Upon re-stimulation in vitro with the vaccine antigen, a significant proliferation of both alphabeta- and gammadelta-T cells, and B cells, collected from mesenteric lymph nodes, was only observed in vaccinated animals. RNA-seq analysis of intestinal tissue yielded a list of 67 genes that were differentially expressed in vaccinated animals following challenge infection, amongst which were several cell adhesion molecules, lectins and glycosyl transferases. A correlation analysis between all immunological and parasitological parameters indicated that intestinal anti double domain activation-associated secreted protein IgG1 levels correlated negatively with cumulative faecal egg counts and positively with the proportion of L4s and L5s. The proportion of immature stages was also positively correlated with the proliferation of alphabeta T cells. Worm length was negatively correlated with the transcript levels of several lectins and cell adhesion molecules. Overall, the results indicate that intramuscular administration of the vaccine resulted in an immune memory response particularly characterised by increased antigen-specific IgG1 levels in the intestinal mucosa. PMID- 25937362 TI - Erratum. PMID- 25937361 TI - Serotonin-mediated modulation of hypoxia-induced intracellular calcium responses in glomus cells isolated from rat carotid body. AB - In the present study, we examined serotonin (5-HT)-induced intracellular Ca(2+) ([Ca(2+)]i) responses to hypoxia in glomus cells isolated from carotid body (CB) of the rat. 5-HT did not induce any [Ca(2+)]i responses in clustered glomus cells during normoxia (21% O2), whereas, the perfusion of hypoxic solution (1% O2) induced repetitive increases in [Ca(2+)]i in the same specimens. The frequency and magnitude of hypoxia-induced [Ca(2+)]i changes observed in the glomus cells were enhanced in the presence of 5-HT, and this response was inhibited by the 5 HT2 receptor antagonist, ketanserin. Furthermore, RT-PCR analysis detected the expression of 5-HT1A, 5-HT1B, 5-HT1D, 5-HT1F, 5-HT2A, 5-HT2B, 5-HT3A, and 5-HT3B receptor mRNAs in extracts of the CB. These results suggest that 5-HT increases hypoxia-induced [Ca(2+)]i responses in glomus cells. 5-HT may elevate hypoxic responses in glomus cells in order to increase chemosensory activity of the CB. PMID- 25937363 TI - Portal Annular Pancreas With Retroportal Pancreatic Duct Diagnosed With Endoscopic Ultrasound. PMID- 25937364 TI - A prospective epidemiological study on odontogenic tumours in a black African population, with emphasis on the relative frequency of ameloblastoma. AB - The persistent view in the literature is that the relative frequency of ameloblastomas is higher in the black population than in Caucasians. The aim of this study was to determine the relative frequency of all odontogenic tumours (OT) in a 100% black population and to compare our findings with those of previous studies. A prospective study was undertaken of all patients presenting with OT to all 16 Nigerian departments of oral and maxillofacial surgery over a 4 year period. The following data were obtained: patient demographics, delay to presentation, extent of the lesion, and histological diagnosis. Six hundred and twenty-two cases were studied. A slight male preponderance was observed (male to female ratio 1.17:1). Patients ranged in age from 5 to 89 years, with a peak incidence in the third decade. The relative frequency of OT was 0.99 per million and that of ameloblastoma was 0.76 per million. Ameloblastoma was the most prevalent OT (76.5%), followed by adenomatoid odontogenic tumours (5.6%), odontogenic myxoma (4.5%), and keratocystic odontogenic tumours (KCOT) (3.1%). The relative frequency of ameloblastoma among Nigerians was not different from frequencies reported previously among Caucasian and Tanzanian black populations. KCOTs were, however, rarely diagnosed in Nigerians as compared to the white population in the Western world. PMID- 25937365 TI - Urethral catheter-related bladder wall lesions simulating inflammatory pseudotumor in a neonate. AB - BACKGROUND: Inflammatory pseudotumors of the bladder are rare in newborns. Considering the potential for malignancy, invasive diagnostic assessment and therapeutic surgical excision have been described as the approach of choice. CASE REPORT: We present a case of urethral catheter-related injury causing multifocal lesions simulating inflammatory pseudotumors of the bladder, diagnosed in a newborn presenting with persistent priapism. This case is distinct by virtue of its very rapid spontaneous regression of the bladder wall lesions within 4 days. CONCLUSIONS: Our neonatal case, along with previously described pediatric pseudotumor of the bladder, show the potential for spontaneous regression of these lesions and emphasizes the importance of balancing the potential risks and benefits of aggressive diagnostic or therapeutic interventions. Frequent diagnostic imaging and close follow-up should be considered as an alternative in young pediatric populations. PMID- 25937366 TI - [Conflicts of interest and need for transparency: in light of consensus on prescribing of new oral anticoagulants]. PMID- 25937367 TI - Improving bioavailability and biodistribution of anti-HIV chemotherapy. AB - In the context of the treatment of HIV/AIDS, many improvements have been achieved since the introduction of the combination therapy (HAART). Nevertheless, no cure for this disease has been so far possible, because of some particular features of the therapies. Among them, two important ones have been selected and will be the subject of this review. The first main concern in the treatments is the poor drug bioavailability, resulting in repeated administrations and therefore a demanding compliance (drug regimens consist of multiple drugs daily intake, and non adherence to therapy is among the important reasons for treatment failure). A second important challenge is the need to target the drugs into the so-called reservoirs and sanctuaries, i.e. cells or body compartments where drugs cannot penetrate or are distributed in sub-active concentrations. The lack of antiviral action in these regions allows the virus to lie latent and start to replicate at any moment after therapy suspension. Recent drug delivery strategies addressing these two limitations will be presented in this review. In the first part, strategies to improve the bioavailability are proposed in order to overcome the absorption or the target cell barrier, or to extend the efficacy time of drugs. In the second section, the biodistribution issues are considered in order to target the drugs into the reservoirs and the sanctuaries, in particular the mononuclear phagocyte system and the brain. PMID- 25937368 TI - PSA-NCAM-negative neural crest cells emerging during neural induction of pluripotent stem cells cause mesodermal tumors and unwanted grafts. AB - Tumorigenic potential of human pluripotent stem cells (hPSCs) is an important issue in clinical applications. Despite many efforts, PSC-derived neural precursor cells (NPCs) have repeatedly induced tumors in animal models even though pluripotent cells were not detected. We found that polysialic acid-neural cell adhesion molecule (PSA-NCAM)(-) cells among the early NPCs caused tumors, whereas PSA-NCAM(+) cells were nontumorigenic. Molecular profiling, global gene analysis, and multilineage differentiation of PSA-NCAM(-) cells confirm that they are multipotent neural crest stem cells (NCSCs) that could differentiate into both ectodermal and mesodermal lineages. Transplantation of PSA-NCAM(-) cells in a gradient manner mixed with PSA-NCAM(+) cells proportionally increased mesodermal tumor formation and unwanted grafts such as PERIPHERIN(+) cells or pigmented cells in the rat brain. Therefore, we suggest that NCSCs are a critical target for tumor prevention in hPSC-derived NPCs, and removal of PSA-NCAM(-) cells eliminates the tumorigenic potential originating from NCSCs after transplantation. PMID- 25937369 TI - High glutathione and glutathione peroxidase-2 levels mediate cell-type-specific DNA damage protection in human induced pluripotent stem cells. AB - Pluripotent stem cells must strictly maintain genomic integrity to prevent transmission of mutations. In human induced pluripotent stem cells (iPSCs), we found that genome surveillance is achieved via two ways, namely, a hypersensitivity to apoptosis and a very low accumulation of DNA lesions. The low apoptosis threshold was mediated by constitutive p53 expression and a marked upregulation of proapoptotic p53 target genes of the BCL-2 family, ensuring the efficient iPSC removal upon genotoxic insults. Intriguingly, despite the elevated apoptosis sensitivity, both mitochondrial and nuclear DNA lesions induced by genotoxins were less frequent in iPSCs compared to fibroblasts. Gene profiling identified that mRNA expression of several antioxidant proteins was considerably upregulated in iPSCs. Knockdown of glutathione peroxidase-2 and depletion of glutathione impaired protection against DNA lesions. Thus, iPSCs ensure genomic integrity through enhanced apoptosis induction and increased antioxidant defense, contributing to protection against DNA damage. PMID- 25937370 TI - Small-molecule-driven hepatocyte differentiation of human pluripotent stem cells. AB - The differentiation of pluripotent stem cells to hepatocytes is well established, yet current methods suffer from several drawbacks. These include a lack of definition and reproducibility, which in part stems from continued reliance on recombinant growth factors. This has remained a stumbling block for the translation of the technology into industry and the clinic for reasons associated with cost and quality. We have devised a growth-factor-free protocol that relies on small molecules to differentiate human pluripotent stem cells toward a hepatic phenotype. The procedure can efficiently direct both human embryonic stem cells and induced pluripotent stem cells to hepatocyte-like cells. The final population of cells demonstrates marker expression at the transcriptional and protein levels, as well as key hepatic functions such as serum protein production, glycogen storage, and cytochrome P450 activity. PMID- 25937371 TI - Treatment of macular degeneration using embryonic stem cell-derived retinal pigment epithelium: preliminary results in Asian patients. AB - Embryonic stem cells hold great promise for various diseases because of their unlimited capacity for self-renewal and ability to differentiate into any cell type in the body. However, despite over 3 decades of research, there have been no reports on the safety and potential efficacy of pluripotent stem cell progeny in Asian patients with any disease. Here, we report the safety and tolerability of subretinal transplantation of human embryonic-stem-cell (hESC)-derived retinal pigment epithelium in four Asian patients: two with dry age-related macular degeneration and two with Stargardt macular dystrophy. They were followed for 1 year. There was no evidence of adverse proliferation, tumorigenicity, ectopic tissue formation, or other serious safety issues related to the transplanted cells. Visual acuity improved 9-19 letters in three patients and remained stable (+1 letter) in one patient. The results confirmed that hESC-derived cells could serve as a potentially safe new source for regenerative medicine. PMID- 25937373 TI - [A prospective trial comparing consecutive series of open retropubic and robot assisted laparoscopic radical prostatectomy in a centre: Oncologic and functional outcomes]. AB - OBJECTIVE: Radical prostatectomy (RP) is an oncologic and functional challenge. Few series compare prospectively the two approaches, open retropubic (ORP) and laparoscopic robot-assisted RP (LRARP). The objective was to compare the oncological and functional results of ORP and LRARP. MATERIAL AND METHODS: From January 2009 to March 2012, two practiced surgeons conducted 304 consecutive RP: respectively 129 ORP and 175 LRARP. Preoperative, perioperative and postoperative data (location and size of positive surgical margins [PSM]) were recorded prospectively and compared with oncological results (PSM, biochemical recurrence free survival [BCR]) and functional outcomes (urinary and erectile) by self validated questionnaires (USP, IIEF-15). The comparison was made by the Chi(2) test and Student t-test for qualitative and quantitative variables. RESULTS: The preoperative data 2 groups were comparable. MCP rate was 13.2% for the ORP and 20% for the LRARP (ns) and was 1.4% and 29.6% (ORP) versus 9.4% and 36.7% (LRARP) for pT2 and pT3 for respectively (P=0.078). BCR was the same in both groups (95.2% at 13.1 months). At 12 months, the results of continence showed no difference (P=0.49) and about erectile function, the EF-score was significantly higher in LRARP: 22 versus 17 for the ORP (P=0.03). CONCLUSION: Oncological results were comparable after ORP and LRARP. The recovery of continence was excellent regardless of the surgical technique, the recovery of erectile function a bit faster by LRARP. LEVEL OF EVIDENCE: 3. PMID- 25937374 TI - Dietary restriction mitigates age-related accumulation of DNA damage, but not all changes in mouse corneal epithelium. AB - The cornea protects the anterior eye and accounts for two thirds of the eyes refractive capacity. The homeostasis of corneal epithelium is thought to be maintained by putative stem cells residing in the epithelial basal layer. As a tissue constantly exposed to environmental stress, the cornea is hypothesised to accumulate persistent DNA damage events with time in stem cell populations. Recently, telomere associated DNA damage foci (TAFs) have been suggested as a marker for persistent DNA damage which can be used to detect senescent cells during ageing. Dietary restriction (DR) is the only known non-genetic intervention that is able to increase both life and health span among various animal species. The aim of this study was to analyse changes in corneal properties with age and under 16 months of DR. We employed immunofluorescence staining for gammaH2A.X together with telomere fluorescence in situ hybridisation (immuno-FISH) on mouse corneas from young, old ad libitum (AL) fed as well as dietary restricted (DR) mice. Our data show that the central corneas of old mice had significantly more general and telomere-associated DNA damage compared to young mice while DR treatment was able to reduce the amount of DNA damage significantly. We also found that the thickness of the peripheral region of the cornea, where the putative stem cells may reside, decreased with age regardless of whether the animals underwent DR treatment or not. Number of bullae, which indicates corneal edema, accumulated in old corneas in the central area and DR treatment mitigated the formation of these bullae. Moreover, the protein levels of the stem cell marker TAp63 decreased with age only in the central but not the peripheral region of the cornea. This finding suggests that epithelial progenitors might be better maintained in the peripheral than the central cornea during ageing. Together with the finding that the peripheral corneal showed no increase in DNA damage during age, we speculate that in mice, like humans, the putative stem cells reside in the peripheral cornea. PMID- 25937372 TI - Castration-resistant Lgr5(+) cells are long-lived stem cells required for prostatic regeneration. AB - The adult prostate possesses a significant regenerative capacity that is of great interest for understanding adult stem cell biology. We demonstrate that leucine rich repeat-containing G protein-coupled receptor 5 (Lgr5) is expressed in a rare population of prostate epithelial progenitor cells, and a castration-resistant Lgr5(+) population exists in regressed prostate tissue. Genetic lineage tracing revealed that Lgr5(+) cells and their progeny are primarily luminal. Lgr5(+) castration-resistant cells are long lived and upon regeneration, both luminal Lgr5(+) cells and basal Lgr5(+) cells expand. Moreover, single Lgr5(+) cells can generate multilineage prostatic structures in renal transplantation assays. Additionally, Lgr5(+) cell depletion revealed that the regenerative potential of the castrated adult prostate depends on Lgr5(+) cells. Together, these data reveal insights into the cellular hierarchy of castration-resistant Lgr5+ cells, indicate a requirement for Lgr5(+) cells during prostatic regeneration, and identify an Lgr5(+) adult stem cell population in the prostate. PMID- 25937376 TI - Vision research special issue: Sight restoration: Prosthetics, optogenetics and gene therapy. PMID- 25937375 TI - Perception of shape and space across rigid transformations. AB - Objects in our environment are subject to manifold transformations, either of the physical objects themselves or of the object images on the retina. Despite drastic effects on the objects' physical appearances, we are often able to identify stable objects across transformations and have strong subjective impressions of the transformations themselves. This suggests the brain is equipped with sophisticated mechanisms for inferring both object constancy, and objects' causal history. We employed a dot-matching task to study in geometrical detail the effects of rigid transformations on representations of shape and space. We presented an untransformed 'base shape' on the left side of the screen and its transformed counterpart on the right (rotated, scaled, or both). On each trial, a dot was superimposed at a given location on the contour (Experiment 1) or within and around the shape (Experiment 2). The participant's task was to place a dot at the corresponding location on the right side of the screen. By analyzing correspondence between responses and physical transformations, we tested for object constancy, causal history, and transformation of space. We find that shape representations are remarkably robust against rotation and scaling. Performance is modulated by the type and amount of transformation, as well as by contour saliency. We also find that the representation of space within and around a shape is transformed in line with the shape transformation, as if shape features establish an object-centered reference frame. These findings suggest robust mechanisms for the inference of shape, space and correspondence across transformations. PMID- 25937377 TI - Clinical outcomes of ED patients with bandemia. AB - BACKGROUND: Although an elevated white blood cell count is a widely utilized measure for evidence of infection and an important criterion for evaluation of systemic inflammatory response syndrome, its component band count occupies a more contested position within clinical emergency medicine. Recent studies indicate that bandemia is highly predictive of a serious infection, suggesting that clinicians who do not appreciate the value of band counts may delay diagnosis or overlook severe infections. OBJECTIVES: Whereas previous studies focused on determining the quantitative value of the band count (ie, determining sensitivity, threshold for bandemia, etc.), this study directs attention to patient-centered outcomes, hypothesizing that the degree of bandemia predisposes patients to subsequent negative clinical outcomes associated with underappreciated severe infections. METHODS: This retrospective study of electronic medical records includes patients who initially presented to the emergency department (ED) with bandemia and were subsequently discharged from the ED. These patients were screened for repeat ED visits within 7 days and death within 30 days. RESULTS: In patients with severe bandemia who were discharged from the ED, there was a 20.9% revisit rate at 7 days and a 4.9% mortality rate at 30 days, placing severely bandemic patients at 5 times significantly greater mortality compared to nonbandemic patients (P = .032). CONCLUSION: Our review of patient outcomes suggests that the degree of bandemia, especially in the setting of concurrent tachycardia or fever, is associated with greater likelihood of negative clinical outcomes. PMID- 25937378 TI - Compressing with dominant hand improves quality of manual chest compressions for rescuers who performed suboptimal CPR in manikins. AB - OBJECTIVE: The question of whether the placement of the dominant hand against the sternum could improve the quality of manual chest compressions remains controversial. In the present study, we evaluated the influence of dominant vs nondominant hand positioning on the quality of conventional cardiopulmonary resuscitation (CPR) during prolonged basic life support (BLS) by rescuers who performed optimal and suboptimal compressions. METHODS: Six months after completing a standard BLS training course, 101 medical students were instructed to perform adult single-rescuer BLS for 8 minutes on a manikin with a randomized hand position. Twenty-four hours later, the students placed the opposite hand in contact with the sternum while performing CPR. Those with an average compression depth of less than 50 mm were considered suboptimal. RESULTS: Participants who had performed suboptimal compressions were significantly shorter (170.2 +/- 6.8 vs 174.0 +/- 5.6 cm, P = .008) and lighter (58.9 +/- 7.6 vs 66.9 +/- 9.6 kg, P < .001) than those who performed optimal compressions. No significant differences in CPR quality were observed between dominant and nondominant hand placements for these who had an average compression depth of greater than 50 mm. However, both the compression depth (49.7 +/- 4.2 vs 46.5 +/- 4.1 mm, P = .003) and proportion of chest compressions with an appropriate depth (47.6% +/- 27.8% vs 28.0% +/- 23.4%, P = .006) were remarkably higher when compressing the chest with the dominant hand against the sternum for those who performed suboptimal CPR. CONCLUSIONS: Chest compression quality significantly improved when the dominant hand was placed against the sternum for those who performed suboptimal compressions during conventional CPR. PMID- 25937379 TI - Diagnostic value of platelet indexes for pulmonary embolism: we need to know more. PMID- 25937380 TI - Comparison of intubation through the McGrath MAC, GlideScope, AirTraq, and Miller Laryngoscope by paramedics during child CPR: a randomized crossover manikin trial. AB - BACKGROUD: Advanced airway management and endotracheal intubation (ETI) during cardiopulmonary resuscitation (CPR) is more difficult than, for example, during anesthesia. However, new devices such as video laryngoscopes should help in such circumstances. The aim of this study was to compare the performance of 4 intubation devices in pediatric manikin-simulated CPR. METHODS: One hundred two paramedics participated in this study. None had prior experience in video laryngoscopy. After a standardized audiovisual lecture lasting 45 minutes, the paramedics participated in a practical demonstration using the advanced pediatric patient simulator PediaSIM CPR (FCAE HealthCare, Sarasota, FL), which was designed to be an accurate representation of a 6-year-old child. Cardiopulmonary resuscitation was performed using LUCAS-2 (Physio-Contro, Redmond, WA). Afterward, paramedics were instructed to perform ETI using 4 intubation devices (MacGrathMAC, GlideScope, AirTraq, and Miller Laryngoscope Blade [Miller]) in a randomized sequence. The primary outcome was the success rate of tracheal intubation. The secondary outcome was the time to intubation. RESULTS: The mean time to intubation was 30.7 +/- 15.3, 28.6 +/- 15.9, 24.1 +/- 5.0, and 39.3 +/- 14.7 seconds (McGrath, GlideScope, AirTraq, and Miller, respectively); and the success ratio of intubation for the devices was 100% vs 100% vs 100% vs 77.5%, respectively. CONCLUSIONS: Child ETI performed by paramedics during uninterrupted chest compression often has a low success rate. In contrast, McGrath, GlideScope, and AirTraq intubation devices are fast, safe, and easy to use. Within the limitations of a manikin study, this study suggests that inexperienced medical staff might benefit from using video laryngoscopy devices for child emergency airway management. PMID- 25937381 TI - Endotracheal tube-assisted orogastric tube insertion in intubated patients in an ED: some pragmatical concerns. PMID- 25937382 TI - Identification of olfactory receptor neurons in Uraba lugens (Lepidoptera: Nolidae) and its implications for host range. AB - Phytophagous insects detect volatile compounds produced by host and non-host plants, using species-specific sets of olfactory receptor neurons (ORNs). To investigate the relationship between the range of host plants and the profile of ORNs, single sensillum recordings were carried out to identify ORNs and corresponding active compounds in female Uraba lugens (Lepidoptera: Nolidae), an oligophagous eucalypt feeder. Based on the response profiles to 39 plant volatile compounds, 13 classes of sensilla containing 40 classes of ORNs were identified in female U. lugens. More than 95% (163 out of 171) of these sensilla contained 16 classes of ORNs with narrow response spectra, and 62.6% (107 out of 171) 18 classes of ORNs with broad response spectra. Among the specialized ORNs, seven classes of ORNs exhibited high specificity to 1,8-cineole, (+/-)-citronellal, myrcene, (+/-)-linalool and (E)-beta-caryophyllene, major volatiles produced by eucalypts, while nine other classes of ORNs showed highly specialized responses to green leaf volatiles, germacrene D, (E)-beta-farnesene and geranyl acetate that are not produced by most eucalypts. We hypothesize that female U. lugens can recognize their host plants by detecting key host volatile compounds, using a set of ORNs tuned to host volatiles, and discriminate them from non-host plants using another set of ORNs specialized for non-host volatiles. The ORNs with broad response spectra may enhance the discrimination between host and non-host plants by adding moderately selective sensitivity. Based on our finding, it is suggested that phytophagous insects use the combinational input from both host-specific and non-host specific ORNs for locating their host plants, and the electrophysiological characterization of ORN profiles would be useful in predicting the range of host plants in phytophagous insects. PMID- 25937383 TI - Impacts of oxidative stress on acetylcholinesterase transcription, and activity in embryos of zebrafish (Danio rerio) following Chlorpyrifos exposure. AB - Organophosphate pesticides cause irreversible inhibition of AChE which leads to neuronal overstimulation and death. Thus, dogma indicates that the target of OP pesticides is AChE, but many authors postulate that these compounds also disturb cellular redox processes, and change the activities of antioxidant enzymes. Interestingly, it has also been reported that oxidative stress plays also a role in the regulation and activity of AChE. The aims of this study were to determine the effects of the antioxidant, vitamin C (VC), the oxidant, t-butyl hydroperoxide (tBOOH) and the organophosphate Chlorpyrifos (CPF), on AChE gene transcription and activity in zebrafish embryos after 72h exposure. In addition, oxidative stress was evaluated by measuring antioxidant enzymes activities and transcription, and quantification of total glutathione. Apical effects on the development of zebrafish embryos were also measured. With the exception of AChE inhibition and enhanced gene expression, limited effects of CPF on oxidative stress and apical endpoints were found at this developmental stage. Addition of VC had little effect on oxidative stress or AChE, but increased pericardial area and heartbeat rate through an unknown mechanism. TBOOH diminished AChE gene expression and activity, and caused oxidative stress when administered alone. However, in combination with CPF, only reductions in AChE activity were observed with no significant changes in oxidative stress suggesting the adverse apical endpoints in the embryos may have been due to AChE inhibition by CPF rather than oxidative stress. These results give additional evidence to support the role of prooxidants in AChE activity and expression. PMID- 25937384 TI - Surface modification of PLGA nanoparticles by carbopol to enhance mucoadhesion and cell internalization. AB - Mucoadhesive poly (lactic-co-glycolic acid) (PLGA) nanoparticles having a modified shell-matrix derived from polyvinyl alcohol (PVA) and Carbopol (CP), a biodegradable polymer coating, to improve the adhesion and cell transfection properties were developed. The optimum formulations utilized a CP concentration in the range of 0.05-0.2%w/v, and were formed using modified emulsion-solvent evaporation technique. The resulting CP-PLGA nanoparticles were characterized in terms of their physical and chemical properties. The absorbed CP on the PLGA shell-matrix was found to affect the particle size and surface charge, with 0.05% CP giving rise to smooth spherical particles (0.05CP-PLGA) with the smallest size (285.90 nm), and strong negative surface charge (-25.70 mV). The introduction of CP results in an enhancement of the mucoadhesion between CP-PLGA nanoparticles and mucin particles. In vitro cell internalization studies highlighted the potential of 0.05CP-PLGA nanoparticles for transfection into SiHa cells, with uptake being time dependent. Additionally, cytotoxicity studies of CP-PLGA nanoparticles against SiHa cancer cells indicated that low concentrations of the nanoparticles were non-toxic to cells (cell viability >80%). From the various formulations studied, 0.05CP-PLGA nanoparticles proved to be the optimum model carrier having the required mucoadhesive profile and could be an alternative therapeutic efficacy carrier for targeted mucosal drug delivery systems with biodegradable polymer. PMID- 25937385 TI - Cervical Synovial Cyst in a 16-Year-Old Girl. PMID- 25937386 TI - Pharmacoresistent Partial Epilepsy Secondary to Progressive Inflammatory Poliodystrophy. AB - BACKGROUND: Epilepsy with progressive cortical volume loss is described secondary to energy failure such as mitochondrial disorders, infectious, or inflammatory etiologies and associated with temporal lobe epilepsy. Postmortem studies do not support that spontaneous seizures even if present for prolonged periods universally result in cortical volume loss. MAIN FINDINGS: We describe two children with extratemporal pharmacoresistent epilepsy, slowly progressive gray matter volume loss over several years, and evidence of central nervous system inflammation. Brain magnetic resonance imaging changes and antibody profiles were not typical of a well-defined, antibody-mediated central nervous system syndrome such as N-methyl-D-aspartate receptor encephalitis. CONCLUSIONS: These patients illustrate a novel presentation of a subacute inflammatory central nervous system process with epilepsy and progressive cortical volume loss, supporting the role of sequential brain imaging in children with epilepsy. PMID- 25937387 TI - "Wrong Side" Tongue Deviation in Hemiplegia From Stroke. PMID- 25937388 TI - Trigeminal Neuralgia in a Child With a Cerebellopontine Angle Arachnoid Cyst. PMID- 25937389 TI - Fatal Acute Necrotizing Encephalopathy: Clinical Presentation and Imaging Findings. PMID- 25937390 TI - Ictal Asystole Captured on Polysomnograph. PMID- 25937391 TI - Migraine and the risk of stroke. PMID- 25937392 TI - Clinical assays for quantitation of insulin-like-growth-factor-1 (IGF1). AB - Insulin-like growth factor 1 (IGF1), a 70 amino acid peptide hormone is the principal mediator of effects of growth hormone (GH). Since GH secretion is pulsatile in nature and is affected by many factors including sleep, feeding and exercise it is not a reliable marker for diagnosis of GH related disorders. On the other hand, IGF1 levels does not undergo short-term fluctuations in the manner that GH does making it the preferred IGF1 biomarker for the diagnosis of growth related disorders. There are several immunoassays available for IGF1 determination. Since majority (>90%) of IGF1 circulates as a ternary complex bound to its principal carrier/binding protein, IGF binding protein 3 (IGFBP3) and acid labile subunit (ALS), the assay methodology used to quantitate IGF1 has to dissociate IGF1 from IGFBPs prior to quantitation. IGFBPs are known to be a source of interference in immunoassays and many techniques have been employed to circumvent this issue. Immunoassays rely on antibody specificity towards IGF1 and differential cross reactivity towards IGFBPs. Mass spectrometry (MS) has also been employed for quantitation of IGF1. Liquid chromatography tandem mass spectrometry (LC-MS/MS) assays for IGF1 rely on generating tryptic peptides followed by selective reaction monitoring (SRM) while LC high resolution accurate mass mass spectrometry (LC-HRAMS) approaches for intact IGF1 rely on mass accuracy for reliable, robust and accurate quantitation. This review article will focus on the clinical assays available and the clinical utility of quantitative assessment of IGF1. IGF1 quantitation using diverse assay platforms including immunoassay, LC-MS/MS and LC-HRAMS are discussed in detail. PMID- 25937393 TI - Next Generation Sequencing-based analysis of RNA polymerase functions. AB - Next Generation Sequencing (NGS) that revolutionized genome wide studies allows analysis of complex nucleic acids mixtures containing thousands of sequences. This extraordinary analytical power of NGS can be harnessed for the analysis of in vitro experiments where DNA template sequence dependence of protein activity acting on DNA can be studied in a single reaction for thousands of DNA sequence variants. This allows a rapid accumulation of data on DNA sequence dependence of the process of interest to a depth not accessible by standard experimentation. We use an example of bacterial RNA polymerase promoter melting activity to describe the NGS-based methodology to study DNA template dependence of protein activity. PMID- 25937396 TI - An Unusual Complication of the Ventricular Septal Defect Closure by Device: Late Right Aortic Cusp Perforation. AB - Aortic regurgitation (AR) is a rare complication of transcatheter closure of perimembranous ventricular septal defects (pmVSD). It results from iatrogenic pinching of the aortic valve by the VSD occluder or perforation by the catheter. It is usually detected during control echocardiography (ECHO). The current study reports the first case of a late AR, which resulted from late right coronary cusp perforation by the VSD occluder. The current manuscript discusses the possible causes of late cusp erosion due to occluder, advantages of early operation in such cases, and an alternative treatment method where the occluder removal is not possible at the operation. PMID- 25937394 TI - Probing structures of large protein complexes using zero-length cross-linking. AB - Structural mass spectrometry (MS) is a field with growing applicability for addressing complex biophysical questions regarding proteins and protein complexes. One of the major structural MS approaches involves the use of chemical cross-linking coupled with MS analysis (CX-MS) to identify proximal sites within macromolecules. Identified cross-linked sites can be used to probe novel protein protein interactions or the derived distance constraints can be used to verify and refine molecular models. This review focuses on recent advances of "zero length" cross-linking. Zero-length cross-linking reagents do not add any atoms to the cross-linked species due to the lack of a spacer arm. This provides a major advantage in the form of providing more precise distance constraints as the cross linkable groups must be within salt bridge distances in order to react. However, identification of cross-linked peptides using these reagents presents unique challenges. We discuss recent efforts by our group to minimize these challenges by using multiple cycles of LC-MS/MS analysis and software specifically developed and optimized for identification of zero-length cross-linked peptides. Representative data utilizing our current protocol are presented and discussed. PMID- 25937395 TI - In vitro effects on biofilm viability and antibacterial and antiadherent activities of silymarin. AB - Limited treatment options in infectious diseases caused by resistant microorganisms created the need to search new approaches. Several herbal extracts are studied for their enormous therapeutic potential. Silymarin extract, from Silybum marianum (milk thistle), is an old and a new remedy for this goal. The purpose of this study is to evaluate the antibacterial and antiadherent effects of silymarin besides biofilm viability activity on standard bacterial strains. Minimal inhibitory concentration (MIC), minimal bactericidal concentration (MBC), antiadherent/antibiofilm activity, and effects on biofilm viability of silymarin were evaluated against standard bacterial strains. MIC values were observed between 60 and >241 MUg/mL (0.25->1 mmol/L). Gram-positive bacteria were inhibited at concentrations between 60 and 120 MUg/mL. Gram-negative bacteria were not inhibited by the silymarin concentrations included in this study. MBC values for Gram-positive bacteria were greater than 241 MUg/mL. Adherence/biofilm formations were decreased to 15 MUg/mL silymarin concentration when compared with silymarin-untreated group. Silymarin reduced the biofilm viabilities to 13 and 46 % at 1 and 0.5 mmol/L concentrations, respectively. We demonstrated that silymarin shows antibacterial and antiadherent/antibiofilm activity against certain standard bacterial strains which may be beneficial when used as a dietary supplement or a drug. PMID- 25937397 TI - Hematopoietic Progenitor Cell Harvesting Is Feasible after Treatment with Brentuximab Vedotin in CD30(+) Lymphoma Patients Who Received Multiple Prior Lines of Treatment. AB - Brentuximab vedotin (BV), an antibody-drug conjugate that targets CD30, induces high response rates in CD30(+) lymphoid malignancies. It is unknown if BV use affects procurement of autologous CD34(+) stem cells and hematopoietic engraftment after autologous stem cell transplantation (ASCT). We examined 42 patients treated with BV before mobilization. Median times from diagnosis to transplantation, from initial BV treatment to transplantation, and from last BV treatment to stem cell collection were 21 months (range, 10 to 210), 5 months (range, 1.5 to 16.8), and 30 days (range, 2 to 280), respectively. Mobilization was successful on the first attempt in 38 patients (90.4%). The median number of infused CD34(+) cells was 5.46 * 10(6)/kg (range, 1.65 to 54.78 * 10(6)/kg). The median times to neutrophil and platelet engraftment were 10 (range, 9 to 13), and 10.5 days (range, 7 to 35), respectively. BV before high-dose chemotherapy-ASCT did not adversely affect peripheral blood stem cell mobilization and subsequent engraftment in a cohort of heavily pretreated patients with CD30(+) lymphomas. PMID- 25937399 TI - Drift in centrality of different brain regions in an anatomical neural network with Parkinson's disease: A view from complex network analysis. AB - Understanding the role of brain regions in anatomical neural networks with Parkinson's disease (PD) is essential for improving the clinical protocol or finding new targets for deep brain stimulation (DBS). Although numerous changes have been reported in local functional studies, few studies have reported on the anatomical network of the entire brain. Here, by developing a series of algorithms, this study provided a whole anatomical neural network of the macaque monkey. Then, the drifts in centrality from normal to PD networks were described in terms of complex network analysis and summarized with principal component analysis. Results revealed that the areas including the striatum, globus pallidus, amygdala, prefrontal lobe, thalamus, hippocampus, visual cortex, insula, etc., showed relatively notable drifts in their own patterns. The present study also demonstrated that the current targets of DBS shared a common feature: their centrality values being relatively low in the normal brain while intensely drifting with PD. PMID- 25937398 TI - Sleep deprivation and hippocampal vulnerability: changes in neuronal plasticity, neurogenesis and cognitive function. AB - Despite the ongoing fundamental controversy about the physiological function of sleep, there is general consensus that sleep benefits neuronal plasticity, which ultimately supports brain function and cognition. In agreement with this are numerous studies showing that sleep deprivation (SD) results in learning and memory impairments. Interestingly, such impairments appear to occur particularly when these learning and memory processes require the hippocampus, suggesting that this brain region may be particularly sensitive to the consequences of sleep loss. Although the molecular mechanisms underlying sleep and memory formation remain to be investigated, available evidence suggests that SD may impair hippocampal neuronal plasticity and memory processes by attenuating intracellular cyclic adenosine monophosphate (cAMP)-protein kinase A (PKA) signaling which may lead to alterations in cAMP response element binding protein (CREB)-mediated gene transcription, neurotrophic signaling, and glutamate receptor expression. When restricted sleep becomes a chronic condition, it causes a reduction of hippocampal cell proliferation and neurogenesis, which may eventually lead to a reduction in hippocampal volume. Ultimately, by impairing hippocampal plasticity and function, chronically restricted and disrupted sleep contributes to cognitive disorders and psychiatric diseases. PMID- 25937400 TI - Are renal ciliopathies (replication) stressed out? AB - Juvenile renal failure is commonly caused by the ciliopathy nephronophthisis (NPHP). Since all NPHP genes regulate cilia function, it has been assumed that NPHP onset is due to cilia loss. However, recent data suggest that DNA damage caused by replication stress, possibly concomitant with or upstream of cilia dysfunction, causes NPHP. PMID- 25937401 TI - Relation between Ku80 and microRNA-99a expression and late rectal bleeding after radiotherapy for prostate cancer. AB - BACKGROUND AND PURPOSE: Late rectal bleeding is one of the severe adverse events after radiotherapy for prostate cancer. New biomarkers are needed to allow a personalized treatment. MATERIALS AND METHODS: Four patients each with grade 0-1 or grade 2-3 rectal bleeding were randomly selected for miRNA array to examine miRNA expression in peripheral blood lymphocytes (PBLs). Based on results of miRNA array, 1 of 348 miRNAs was selected for microRNA assays. Then, expression of DNA-dependent protein kinase mRNA and miR-99a was analyzed in the PBLs of 97 patients. PBLs were exposed to 4Gy of X-ray ex-vivo. RESULTS: In the discovery cohort, grade 2-3 rectal bleeding was significantly higher in the Ku80 <1.09 expression group compared with ?1.09 group (P=0.011). In radiation-induced expression of miR-99a, grade 2-3 rectal bleeding was significantly higher in the miR-99a IR(+)/IR(-) >0.93 group compared with ?0.93 group (P=0.013). Most patients with grade 2-3 rectal bleeding were in the group with low Ku80 and high miR-99a expression. In the validation cohort, similar results were obtained. CONCLUSION: A combination of low Ku80 expression and highly-induced miR-99a expression could be a promising marker for predicting rectal bleeding after radiotherapy. PMID- 25937402 TI - [The Jn'GOF 2014: Perpetuated by the peers and confirmed by obstetricians and gynecologists in training]. PMID- 25937403 TI - [Diagnosis of placental chorioangioma in context of severe neonatal anemia]. PMID- 25937404 TI - Osteolytic cysts with total ankle replacement: Frequency and causes? PMID- 25937405 TI - Gastrocnemius recession for foot and ankle conditions in adults: Evidence-based recommendations. AB - BACKGROUND: Gastrocnemius recession is a surgical technique commonly performed on individuals who suffer from symptoms related to the restricted ankle dorsiflexion that results when tight superficial posterior compartment musculature causes an equinus contracture. Numerous variations for muscle-tendon unit release along the length of the calf have been described for this procedure over the past century, although all techniques share at least partial or complete release of the gastrocnemius muscle given its role as the primary plantarflexor of the ankle. There exists strong evidence to support the use of this procedure in pediatric patients suffering from cerebral palsy, and increasingly enthusiastic support-but less science-behind its application in treating adult foot and ankle pathologies perceived to be associated with gastrocnemius tightness. The purpose of this study, therefore, was to evaluate currently available evidence for using gastrocnemius recession in three adult populations for whom it is now commonly employed: Achilles tendinopathy, midfoot-forefoot overload syndrome, and diabetic foot ulcers. METHODS: A systematic review of the literature was performed on December 21, 2013 using the PubMed, Scopus, and Cochrane databases along with the search term "(gastrocnemius OR gastrocsoleus) AND (recession OR release OR lengthening)." This search generated 1141 results; 12 articles found in the references of these papers were also screened for inclusion. In total, 18 articles met our inclusion criteria. These articles were reviewed and assigned a classification (I-V) of Level of Evidence, according to the criteria recommended by the Journal of Bone & Joint Surgery. Based on these classifications, a Grade of Recommendation was assigned for each of the indications of interest. RESULTS: Grade B evidence-based literature ("fair") exists to support the use of gastrocnemius recession for the treatment of isolated foot pain due to midfoot/forefoot overload syndrome in adults. There are some data in support of utilizing gastrocnemius recession to treat midfoot or forefoot ulcers and non insertional Achilles tendinopathy in adults, but to date this evidence remains Grade Cf. Insufficient evidence (Grade I) is currently available to make any recommendation either for or against this procedure for the treatment of insertional Achilles tendinopathy. CONCLUSION: Scientific literature continues to grow in support of using isolated gastrocnemius recession as an effective treatment strategy for a variety of lower limb pathologies, although it remains clear that higher evidence levels and more carefully controlled investigations will be necessary to more convincingly define the true efficacy and ideal applications of gastrocnemius recession in the adult population. LEVEL OF EVIDENCE: Level IV systematic review. PMID- 25937406 TI - The effect of different methods of stability assessment on fixation rate and complications in supination external rotation (SER) 2/4 ankle fractures. AB - BACKGROUND: Distinguishing stable supination-external rotation (SER) 2 from unstable SER 4 ankle fractures, using standard radiographs, is controversial. Examination under anaesthesia (EUA), gravity-stress (GS) and weight-bearing (WB) radiographs can aid surgical decision-making. We evaluated the effect of three methods of fracture stability assessment. METHODS: Radiographs and case-notes of 312 consecutive patients with SER 2/4 fractures were reviewed. We recorded ankle stability assessment (plain film (PF) and EUA vs. GS vs. WB radiographs), management (conservative vs. operative), unplanned surgery and complications. RESULTS: Forty five percent assessed with GS underwent surgery (6% for PF/EUA, 4% for WB; P=0.0001). Amongst GS patients, 11% underwent additional surgery (0.1% PF/EUA, 0% WB; P=0.0001). Complications occurred in 2% of the WB group (8% for PF/EUA, 22% for GS; P=0.007). CONCLUSION: This study associates GS assessment with higher rates of surgery and complications. Subsequent studies may determine the longer term effect stability assessments have on post-traumatic arthritis. PMID- 25937407 TI - Early radiographic and clinical results of Salto total ankle arthroplasty as a fixed-bearing device. AB - BACKGROUND: Total ankle replacement has increased in popularity in the management of severe tibiotalar arthritis. Most previous clinical reports focused on mobile bearing designs. This study evaluates early radiographic and clinical results of the Salto fixed bearing design. METHODS: Twenty-three Salto fixed-bearing implants were prospectively studied. Records were reviewed for clinical outcome scores (VAS, AOFAS, SF36), subsequent surgeries, complications, radiographic data and implant survivorship. Average follow-up was 36 months. RESULTS: Statistically significant improvements in VAS, AOFAS ankle/hindfoot scores, and SF36 scores were shown at an average of 3 years postoperatively. At 3 years followup, survivorship of the implant was 82.6% with any reoperation as the endpoint and 95.6% for revision or removal of components. Seven patients had radiolucencies around the implant, one of which required revision to arthrodesis. CONCLUSION: The fixed-bearing Salto ankle replacement has comparable early radiographic and clinical results to reports of the mobile-bearing Salto of comparable followup. LEVEL OF EVIDENCE: Level IV. PMID- 25937408 TI - Arthroscopic triple and modified double hindfoot arthrodesis. AB - BACKGROUND: Arthroscopic arthrodesis is an accepted technique for the ankle but less commonly reported for multiple hindfoot joints. We present a case series review to establish the feasibility of this surgery. METHODS: In a consecutive series of 112 arthroscopic hindfoot arthrodeses, 18 involved decortication and fusion of 2 or 3 hindfoot joints. These were reviewed to identify complications, union rates and improvement over preoperative state. RESULTS: Mean age was 62 (45 78). Mean follow-up was 4.4 (1.75-7.5) years. There were no perioperative complications. The four patients with triple fusions united with good or excellent outcomes. Of 14 patients with subtalar and talonavicular arthrodeses there were three talonavicular non-unions. CONCLUSIONS: Arthroscopic double and triple arthrodeses appear feasible salvage options for pain and deformity. Decortication of all three joints and rotatory correction of deformity is possible whilst preserving the soft tissue envelope. Late adjacent joint pain and arthrosis can occur. PMID- 25937409 TI - First metatarsophalangeal joint arthrodesis - Do joint configuration and preparation technique matter? AB - BACKGROUND: The purpose of this study was to investigate the influence of joint configuration and preparation on first metatarsophalangeal (MTPJ) union rates. METHODS: We performed a retrospective analysis of first MTPJ arthrodeses undertaken in our institution. Clinical notes, radiographs and postal questionnaires were used to determine outcome. RESULTS: Two hundred first MTPJ arthrodeses (172 patients) were included in the analysis (34 male: 138 female; mean age 62 yr). The overall union rate was 93.5%. Union was achieved in 109/118 MTPJs (92.4%) prepared in the flat-on-flat configuration and in 78/82 (95%) prepared in the ball-and-socket configuration (p=0.438). Higher union rates favoured low-velocity joint preparation [using rongeur only 21/21 (100%), rongeur and burr 26/27 (96.3%) and conical reamer 31/34 (91.2%)] but this did not reach statistical significance (p=0.317). There was a 95% satisfaction rate with surgery but male patients were less satisfied (p=0.031). CONCLUSION: Union rates were not influenced by joint configuration or preparation techniques. PMID- 25937410 TI - Use of Smart Toe((c)) implant for small toe arthrodesis: A smart concept? AB - BACKGROUND: Arthrodesis of small joints for hammer and claw toe deformities is a common forefoot operative procedure. Our objective was to review patients who underwent small toe arthrodesis with Smart Toe((c)) intramedullary monobloc implant. Our aim was to assess patient's surgical outcome and to ascertain implant suitability. METHODS: This procedure was undertaken in 90 patients from February 2011 to December 2012. We present our review of 82 (91.1%) patients who attended the final six 6-month follow up. Mean age was 56.5 years. There were 7 (8.5%) males and 75 (8.5%) males and 75 (91.5%) females. Clinical and radiological evaluation was undertaken. A questionnaire was used to assess general symptoms, clinical outlook, deformity and patient's perceptions and acceptance. Foot and Ankle Outcome Score and Foot and Ankle Disability Index were used to judge outcome. RESULTS: There were 71 (86.6%) proximal and 11 (13.4%) distal interphalangeal joints with 69 (84.1%) second, 7 (8.5%) third, 6 (84.1%) second, 7 (8.5%) third, 6 (7.3%) fourth toes. There was persistent swelling in 7 (8.5%) and tenderness in 1 (1.2%). Appearance of toes was symmetrical in 71 (86.6%) and 11 (13.4%) were asymmetrical but asymptomatic. The mean range of movement of the adjacent joint was 53.9 degrees . Control of toes was good in 72 (87.8%) patients. Mean percentage of improvement was 76.1% with 100% in 17 (20.7%) and over 80% in 47 (57.3%). Seventy (85.3%) would recommend and undergo repeat surgery. There were 2 (2.4%) cases of metal cut out. There was one (1.2%) implant failure. Union was achieved in 79 (96.3%) patients. CONCLUSION: We feel that Smart Toe((c)) small toe arthrodesis is a safe and reliable technique with good patient outcome and acceptance. PMID- 25937411 TI - Lateral soft-tissue release through a medial incision: Anatomic comparison of two techniques. AB - BACKGROUND: The distal soft tissue procedure is an integral part of hallux valgus surgery, providing soft tissue balance and alignment restoration of the first metatarsophalangeal joint. Various approaches have been established to this end. For techniques that do not include a separate dorsal incision, lateral release may be achieved via a transarticular approach or via a medial incision and a dorsal flap over the first metatarsal. Compared to the double-incision technique, these techniques are not only cosmetically superior and thus meet the demands of most surgeons and patients. MATERIAL AND METHODS: Using six pairs of frozen cadaveric feet, lateral release was performed using one of the above techniques in a randomized manner with pair comparison. The specimens were then dissected and the completeness of the release as well as any damage to anatomic structures was documented. RESULTS: The transarticular technique enabled complete release of the metatarsal-sesamoid suspensory ligament (MSL) and the transverse and oblique head of the adductor hallucis muscle in five of six specimens. The comparative technique enabled the same in only two of six cases for the adductor hallucis muscle and in four cases for the MSL. The transarticular approach achieved complete release of the lateral joint capsule in three of six specimens, whereas the dorsal approach achieved no release in any specimen. Neither of the methods caused any macroscopic injury to the surfaces of the first metatarsophalangeal joint. The examined arteries, veins, and nerves remained intact in all specimens treated with the transarticular approach, but dorsal release resulted in one documented injury to the first dorsal metatarsal artery and its concomitant veins. CONCLUSIONS: Compared to release by dissection superficially to the extensor tendons, transarticular release provides a more complete lateral release and less injuries to neurovascular bundles. Further anatomic and clinical studies are needed, however, before conclusive recommendations can be made. PMID- 25937412 TI - Outcome following first metatarsophalangeal joint replacement using TOEFIT PLUSTM: A mid term alert. AB - BACKGROUND: We aim to evaluate the mid-term results of first metatarsophalangeal joint replacement for hallux rigidus using Toefit-PlusTM in a single surgeon series. METHODS: We prospectively studied the outcomes of 86 toes in 73 patients using the AOFAS-HMI score and radiological follow up. The mean follow up was 33 months (2-72). Ten patients have been lost to follow up. RESULTS: Eight patients sustained intraoperative fractures or impending fractures requiring circlage wiring. Eighteen joints have either been revised or listed for revision giving a revision rate of 24%; this occurred at a mean of 33 months post-surgery. CONCLUSIONS: First MTPJ replacement is an option in hallux rigidus and patients who are not revised experience significant improvement in AOFAS scores in the medium term. We have previously published satisfactory results with this prosthesis. However the revision rate is unacceptably high and we have discontinued its use completely. Future design evolutions should address the issue of osteointegration on the phalangeal side. PMID- 25937413 TI - Correlation of visual analogue scale foot and ankle (VAS-FA) to AOFAS score in malleolar fractures using Indian language questionnare. AB - BACKGROUND: Visual analogue scale foot and ankle (VAS-FA score) is a new score, validated in previous studies, but never compared to AOFAS score. OBJECTIVE: Analysis of the two scores using Indian language questionnaire. METHODS: Fifty patients with Malleolar fractures were assessed for functional outcome, time for calculation of scores, difficulty in correlation and comprehension of the questionnaire, in Malayalam language. The score parameters were compared by SSPSS. RESULTS: There was similarity in pattern of score values in both systems but also a difference between values in each category, with VAS-FA having lower values, reflecting its efficacy. There was significant correlation, similar sensitivity and agreement between the scoring systems. VAS-FA correlated better with patient's outcome and required less time for assessment. CONCLUSION: This study shows that Indian language VAS-FA has a similar pattern of extracting scores as AOFAS and can be an efficient tool in ankle outcome assessment in Indian patients. PMID- 25937414 TI - Etiopathogenesis of osteolytic cysts associated with total ankle arthroplasty, a histological study. AB - BACKGROUND: Osteolytic cyst formation after total ankle arthroplasty has been identified in recent years and is probably an important problem with longer follow-up. The aim of this study is to describe the outcome of a histological analysis of samples from periprosthetic intra-osseous cysts and joint capsules, retrieved during revision surgery after primary total ankle arthroplasty. METHODS: All samples (n=22) were analyzed and scored using a semi-quantitative grading system. The main items of interest were polyethylene (PE) particles, metal particles, histiocytes, and giant cells. RESULTS: All cyst samples contained PE particles. A similar number of PE particles were found in talar and tibial cysts. No significant correlation between the number of PE particles and time to reoperation was found. Metal particles were found in 16 cysts. CONCLUSIONS: We suggest that PE particles are not the primary cause of osteolytic cyst formation but a secondary contributing factor probably accelerating the process of osteolysis. It is likely that implant design, biomechanical factors and local anatomic-physiological factors play an important role. PMID- 25937415 TI - Endoscopic curettage and bone grafting of the enchondroma of the proximal phalanx of the great toe. AB - Enchondromas are the most commonly found benign tumors of the small bones of the foot, mainly involve the phalanges and metatarsals. They are usually asymptomatic, and are found as an incidental finding on routine X-rays. Surgical intervention is indicated in symptomatic lesions as well as larger lesions (greater than 3-4cm) even if these lesions are asymptomatic. Enchondroma most often can be adequately treated with intralesional curettage and bone grafting. A technique of endoscopic curettage and bone grafting of enchondroma of the proximal phalanx of the hallux is described. This has the advantage of minimally invasive surgery of better cosmesis, less surgical trauma and preservation of the cortical integrity. PMID- 25937416 TI - Technical tip: Dorsal transmetatarsal approach to intermetatarsal and deep plantar lesions. AB - Synovial and chondromatous lesions can extend dorsally, intermetatarsally and deep into the vault of the longitudinal and transverse plantar arches of the foot. The lesions may prove difficult to excise even with combined approaches. Two cases where a transmetatarsal approach by excision of the base of the third metatarsal enabled successful complete excision of the lesions are presented. LEVEL OF EVIDENCE: Level V, expert opinion. PMID- 25937417 TI - Re: "An anatomical and cadaveric study examining the risk of sural nerve injury in percutaneous achilles tendon repair using the achillon device" by Porter et al. [Foot Ankle Surg 20 (2) (2014) 90-94]. PMID- 25937418 TI - Re: An anatomical and cadaveric study examining the risk of sural nerve injury in percutaneous achilles tendon repair using the Achillon device. PMID- 25937419 TI - Multiple intratendinous ossified deposits of the Achilles tendon: Case report of an unusual pattern of ossification. AB - True ossification of the Achilles tendon is a rare condition as compared to calcification. The etiology of ossification is multifactorial, however, previous surgery, trauma and degenerative changes have been attributed to be the major causes. Three different patterns of ossification have been described within the Achilles tendon based on their location. We present a case of multiple discrete deposits of ossification within the main substance of the Achilles tendon in a young male with a previous history of clubfoot surgery in childhood. The pattern of ossification was different than all the previously reported cases. Pain was the predominant symptom. He was investigated by using plain radiographs, ultrasonography, computed tomography and magnetic resonance imaging. Surgical excision of all the bony lumps lead to satisfactory outcome without any complications. PMID- 25937420 TI - Rare case of acral calcified angioleiomyoma with macroscopic calcium extrusion. AB - Acral calcified angioleiomyoma is an uncommon tumor that presents as a non descript papule or subcutaneous nodule, classically on the foot. Biopsy or excision is typically the diagnostic method of choice as well as the treatment for these sometimes painful tumors. We report an uncommon clinical presentation of acral calcified angioleiomyoma with considerable extrusion of calcium perforating through the skin. PMID- 25937421 TI - Isolated osteochondral fracture of the metatarsal head of lesser toes. AB - Isolated fracture of the metatarsal head is very rare and no consensus has been reached regarding their best management. We reported four cases of isolated osteochondral fracture of the metatarsal head with different method of treatment to achieve the common goal of restoration of the congruity of the metatarsal head. PMID- 25937422 TI - Treatment and outcome of destructive tuberculosis of the talus. AB - We describe a case of isolated destructive talar tuberculosis that is, to the best of our knowledge, the first reported case in Germany. Caseous talar necrosis was finally detected after repeated surgical debridements of an infection eight months after subtalar screw arthrodesis. Following the diagnosis of TB, we performed a total of three additional surgical revisions within a three-month period; these revisions included a talectomy and an induction of a septic tibiocalcaneal arthrodesis with an external fixator that was removed after solid fusion six months later. Following this treatment regime, which included pharmaceutical anti-tuberculosis therapy, the 50-year-old male patient was fitted with orthopaedic shoes. He resumed work as a professional farmer with a number of restrictions 12 months after the diagnosis and treatment of destructive talar tuberculosis. PMID- 25937423 TI - Flexor digitorum accessorius causing tarsal tunnel syndrome in a paediatric patient: A case report and review of the literature. AB - The flexor digitorium accessorius muscle is an unusual anatomical variant found in the posteromedial aspect of the hindfoot and ankle. As previously described, its location predisposes patients to developing tarsal tunnel syndrome. This case illustrates the diagnosis, treatment and resolution of tarsal tunnel syndrome in a paediatric patient, secondary to the presence of flexor digitorium accessorius muscle. PMID- 25937424 TI - Earlier prostate-specific antigen testing in African American men--Clinical support for the recommendation. AB - BACKGROUND: To determine whether prostate-specific antigen (PSA) testing in African American veterans (AAVs) aged 40 to 54 years is associated with high-risk prostate cancer characteristics compared with AAVs aged 55 to 70 years or white veterans (WVs) aged 40 to 54 years. METHODS: A total of 231,174 healthy veterans aged 40 to 70 years without clinical evidence of prostate cancer underwent PSA testing between October 1, 2000, and September 30, 2007. Clinicopathologic tumor characteristics were available for 1,044/1,059 AAVs and 1,006/1,971 age-matched WVs diagnosed with prostate cancer after a PSA level>4 ng/ml triggered prostate biopsy. Tumor characteristics of AAVs aged 40 to 54 years were compared with AAVs 55 to 70 years, WVs 40 to 54 years, and WVs 55 to 70 years. RESULTS: Of PSA tested veterans aged 40 to 54 years diagnosed with prostate cancer, there were no racial differences in prebiopsy PSA levels, prostate cancer grade, or clinical stage at diagnosis. AAVs aged 40 to 54 years were more likely to have >= 3 positive cores (P = 0.0229) and were less likely to be active surveillance candidates (P = 0.0340) compared with similarly aged WVs. AAVs aged 55 to 70 years were more likely to have high-grade (P = 0.0204) and higher clinical stage (P = 0.0195) prostate cancer than AAVs aged 40 to 54 years. CONCLUSIONS: This large national cohort study suggests that PSA testing at an earlier age for African American men may allow diagnosis of lower risk prostate cancer, potentially reducing disparate outcomes between AAVs and WVs. PMID- 25937425 TI - Commentary on: "Randomized phase III trial of temsirolimus and bevacizumab versus interferon alfa and bevacizumab in metastatic renal cell carcinoma: INTORACT trial." Rini BI, Bellmunt J, Clancy J, Wang K, Niethammer AG, Hariharan S, Escudier B. Brian I. Rini, Cleveland Clinic Taussig Cancer Institute, Cleveland, OH; Joaquim Bellmunt, University Hospital del Mar-IMIM, Barcelona, Spain; Jill Clancy, Kongming Wang, Andreas G. Niethammer, Subramanian Hariharan, Pfizer, New York, NY; and Bernard Escudier, Institut Gustave Roussy, Villejuif, France.: J Clin Oncol. 2014 Mar 10;32(8):752-9; doi: 10.1200/JCO.2013.50.5305. [Epub 2013 Dec 2]. AB - PURPOSE: To prospectively determine the efficacy of combination therapy with temsirolimus plus bevacizumab versus interferon alfa (IFN) plus bevacizumab in metastatic renal cell carcinoma (mRCC). PATIENTS AND METHODS: In a randomized, open-label, multicenter, phase III study, patients with previously untreated predominantly clear cell mRCC were randomly assigned, stratified by prior nephrectomy and Memorial Sloan-Kettering Cancer Center prognostic group, to receive the combination of either temsirolimus (25mg intravenously, weekly) or IFN (9MIU subcutaneously thrice weekly) with bevacizumab (10mg/kg intravenously, every 2weeks). The primary end point was independently assessed progression-free survival (PFS). RESULTS: Median PFS in patients treated with temsirolimus/bevacizumab (n = 400) versus IFN/bevacizumab (n = 391) was 9.1 and 9.3 months, respectively (hazard ratio [HR] = 1.1; 95% CI: 0.9 to 1.3; P = .8). There were no significant differences in overall survival (25.8 nu 25.5 months; HR = 1.0; P = .6) or objective response rate (27.0% nu 27.4%) with temsirolimus/bevacizumab versus IFN/bevacizumab, respectively. Patients receiving temsirolimus/bevacizumab reported significantly higher overall mean scores in the Functional Assessment of Cancer Therapy-Kidney Symptom Index (FKSI)-15 and FKSI Disease-Related Symptoms subscale compared with IFN/bevacizumab (indicating improvement); however, no differences in global health outcome measures were observed. Treatment-emergent all-causality grade>=3 adverse events more common (P<.001) with temsirolimus/bevacizumab were mucosal inflammation, stomatitis, hypophosphatemia, hyperglycemia, and hypercholesterolemia, whereas neutropenia was more common with IFN/bevacizumab. Incidence of pneumonitis with temsirolimus/bevacizumab was 4.8%, mostly grade 1 or 2. CONCLUSION: Temsirolimus/bevacizumab combination therapy was not superior to IFN/bevacizumab for first-line treatment in clear-cell mRCC. PMID- 25937426 TI - Commentary on: "Enzalutamide monotherapy in hormone-naive prostate cancer: primary analysis of an open-label, single-arm, phase 2 study." Tombal B, Borre M, Rathenborg P, Werbrouck P, Van Poppel H, Heidenreich A, Iversen P, Braeckman J, Heracek J, Baskin-Bey E, Ouatas T, Perabo F, Phung D, Hirmand M, Smith MR. Institut de Recherche Clinique, Universite Catholique de Louvain, Brussels, Belgium. Electronic address: bertrand.tombal@uclouvain.be. Aarhus University Hospital, Aarhus, Denmark. Herlev Hospital, Herlev, Denmark. AZ Groeninge Kortrijk, Kortrijk, Belgium. UZ Leuven, Leuven, Belgium. Klinik und Poliklinik fur Urologie, RWTH University Aachen, Aachen, Germany. Rigshospitalet, University of Copenhagen, Copenhagen, Denmark. UZ Brussel, Brussels, Belgium. Univerzita Karlova v Praze, Prague, Czech Republic. Astellas Pharma Global Development, Leiden, Netherlands. Astellas Pharma Global Development, Northbrook, IL, USA. Medivation Inc, San Francisco, CA, USA. Massachusetts General Hospital Cancer Center, Boston, MA, USA: Lancet Oncol. 2014 May;15(6):592-600; doi: 10.1016/S1470 2045(14)70129-9. [Epub 2014 Apr 14]. AB - BACKGROUND: The androgen receptor inhibitor enzalutamide is approved for the treatment of metastatic castration-resistant prostate cancer that has progressed on docetaxel. Our aim was to assess the activity and safety of enzalutamide monotherapy in men with hormone-naive prostate cancer. METHODS: This trial is an ongoing open-label, single-arm, phase 2 study, done across 12 European sites. Men aged over 18 years with hormone-naive prostate cancer for whom hormone therapy was indicated, and who had noncastration levels of testosterone and prostate specific antigen (PSA) of 2ng/mL or greater at screening, and an Eastern Cooperative Oncology Group score of 0, received oral enzalutamide 160mg/day. The primary outcome was the proportion of patients with an 80% or greater decline in PSA at week 25. All analyses included all patients who had received at least one dose of the study drug. This study is registered with ClinicalTrials.gov, number NCT01302041. FINDINGS: 67 men were enrolled into the study. 62 patients (92.5%, 95% CI: 86.2-98.8) had a decline in PSA of 80% or greater at week 25. The most commonly reported treatment-emergent adverse events up to week 25 were gynaecomastia (n = 24), fatigue (n = 23), nipple pain (n = 13), and hot flush (n = 12), all of which were of mild to moderate severity. Overall, 9 patients had a treatment-emergent adverse event of grade 3 or higher, most of which were reported in one patient each, except for pneumonia (grade 3, two patients) and hypertension (grade 3, four patients). Five patients reported serious adverse events, none of which were deemed to be treatment related. INTERPRETATION: Our findings suggest that enzalutamide monotherapy in men with hormone-naive prostate cancer of varying severity provides a level of disease suppression and was generally well tolerated. These findings provide a rationale for further investigation of clinical response and outcomes with enzalutamide in noncastrated men with prostate cancer. PMID- 25937427 TI - Commentary on: "Randomized, controlled, double-blind, cross-over trial assessing treatment preference for pazopanib versus sunitinib in patients with metastatic renal cell carcinoma: PISCES study." Escudier B, Porta C, Bono P, Powles T, Eisen T, Sternberg CN, Gschwend JE, De Giorgi U, Parikh O, Hawkins R, Sevin E, Negrier S, Khan S, Diaz J, Redhu S, Mehmud F, Cella D. Bernard Escudier, Institut Gustave Roussy, Villejuif; Emmanuel Sevin, Centre Francois Baclesse, Caen; Sylvie Negrier, Leon Berard Cancer Center, Lyon, France; Camillo Porta, Fondazione Istituto di Ricovero e Cura a Carattere Scientifico (IRCCS) Policlinico S. Matteo, Pavia; Cora N Sternberg, San Camillo Forlanini Hospital, Rome; Ugo De Giorgi, IRCCS Istituto Scientifico Romagnolo per lo Studio e la Cura dei Tumori, Meldola, Italy; Petri Bono, Helsinki University Central Hospital, Helsinki, Finland; Thomas Powles, Barts Experimental Cancer Medicine Centre, Barts Cancer Institute, Queen Mary University of London, London; Tim Eisen, Cambridge University Health Partners, Cambridge; Omi Parikh, Royal Preston Hospital, Lancashire; Robert Hawkins, Christie Cancer Research UK, Manchester; Sadya Khan, Jose Diaz, and Faisal Mehmud, GlaxoSmithKline, Uxbridge, United Kingdom; Jurgen E Gschwend, Klinikum Rechts der Isar der Technischen Universitat Munchen, Munich, Germany; Suman Redhu, GlaxoSmithKline, Collegeville, PA; David Cella, Northwestern University Feinberg School of Medicine, Chicago, IL.: J Clin Oncol. 2014 May 10;32(14):1412-1418; doi: 10.1200/JCO.2013.50.8267. [Epub 2014 Mar 31]. AB - PURPOSE: Patient-reported outcomes may help inform treatment choice in advanced/metastatic renal cell carcinoma (RCC), particularly between approved targeted therapies with similar efficacy. This double-blind crossover study evaluated patient preference for pazopanib or sunitinib and the influence of health-related quality of life (HRQoL) and safety factors on their stated preference. PATIENTS AND METHODS: Patients with metastatic renal cell carcinoma were randomly assigned to pazopanib 800mg per day for 10 weeks, a 2-week washout, and then sunitinib 50mg per day (4 weeks on, 2 weeks off, 4weeks on) for 10 weeks, or the reverse sequence. The primary end point, patient preference for a specific treatment, was assessed by questionnaire at the end of the two treatment periods. Other end points and analyses included reasons for preference, physician preference, safety, and HRQoL. RESULTS: Of 169 randomly assigned patients, 114 met the following prespecified modified intent-to-treat criteria for the primary analysis: exposure to both treatments, no disease progression before cross over, and completion of the preference questionnaire. Significantly more patients preferred pazopanib (70%) over sunitinib (22%); 8% expressed no preference (P<.001). All preplanned sensitivity analyses, including the intent-to-treat population, statistically favored pazopanib. Less fatigue and better overall quality of life were the main reasons for preferring pazopanib, with less diarrhea being the most cited reason for preferring sunitinib. Physicians also preferred pazopanib (61%) over sunitinib (22%); 17% expressed no preference. Adverse events were consistent with each drug's known profile. Pazopanib was superior to sunitinib in HRQoL measures evaluating fatigue, hand/foot soreness, and mouth/throat soreness. CONCLUSION: This innovative crossover trial demonstrated a significant patient preference for pazopanib over sunitinib, with HRQoL and safety as key influencing factors. PMID- 25937428 TI - The Pediatric Stroke Code: Early Management of the Child with Stroke. PMID- 25937429 TI - Vasculitis Causing Complete Occlusion of Aorta. PMID- 25937430 TI - A phase II study of bevacizumab with modified OPTIMOX1 as first-line therapy for metastatic colorectal cancer: the TCOG-GI 0802 study. AB - BACKGROUND: Although bevacizumab plus FOLFOX is a standard treatment for metastatic colorectal cancer, oxaliplatin must be withdrawn in many patients because of cumulative neurotoxicity. We postulated that a reduced dose of oxaliplatin and modified treatment schedule would prolong the time to treatment failure and evaluated bevacizumab combined with a modified OPTIMOX1 regimen (mOPTIMOX1, oxaliplatin dose: 85 mg/m(2)). METHODS: Eligible patients had a histologically confirmed diagnosis of metastatic colorectal cancer and a performance status of 0-1. Patients were excluded if they had grade 1 or higher peripheral sensory neuropathy or had previously received chemotherapy for metastatic colorectal cancer. Patients received bevacizumab plus mFOLFOX6 every 2 weeks for 6 cycles, followed by 12 cycles of a simplified biweekly regimen of leucovorin and fluorouracil (sLV5FU2) plus bevacizumab. Oxaliplatin was then reintroduced, and bevacizumab plus mFOLFOX6 was continued until progressive disease. RESULTS: The median duration of disease control was 11.7 months (95 % confidence interval [CI], 9.7-13.5 months). The median overall survival was 23.1 months (95 % CI, 18.8-27.9 months). The overall response rate according to both the RECIST and WHO criteria was 51.3 %. The most common grade 3 or 4 toxicities were neutropaenia (32.5 %), hypertension (17.5 %), leukocytopaenia, sensory neuropathy, and diarrhoea (10.0 %). There were no treatment-related deaths. CONCLUSIONS: Bevacizumab plus mFOLFOX6 was well tolerated, and patients could continue chemotherapy for longer than with conventional FOLFOX regimens. This regimen might be an effective treatment option for patients with metastatic colorectal cancer. PMID- 25937431 TI - Pharmacokinetic assessment of dacomitinib (pan-HER tyrosine kinase inhibitor) in patients with locally advanced head and neck squamous cell carcinoma (LA SCCHN) following administration through a gastrostomy feeding tube (GT). AB - BACKGROUND: Dacomitinib is an irreversible oral pan-HER tyrosine kinase inhibitor with antitumor activity demonstrated in patients with recurrent/metastatic (RM) SCCHN. A Phase I trial of dacomitinib with standard therapy in LA SCCHN is ongoing (NCT01737008). As enteral feeding is needed for many SCCHN patients, this study investigated the PK properties of dacomitinib when administered via GT (NCT01484847). Since patients with GT are difficult to recruit, this study also determined the feasibility of PK assessments using a unique design in LA SCCHN patients with GT, by giving a single dose of drug during their radiotherapy (co administration with chemotherapy avoided). METHODS: Eligible patients were given a single dose of crushed dacomitinib at 45 mg in water suspension via GT. All doses were administered in fasting state and supine position. PK samples were drawn prior to dose (t = 0), 30 min and 1, 2, 3, 4, 6, 12, 24, 48, 72, 96, 144, 168, 192 and 216 hrs post-dose, and analyzed by HPLC-MS/MS. PK parameters (mean [CV%]) of this study were compared with those of dacomitinib given orally using Student t test. RESULTS: Six patients with LA SCCHN patients were enrolled. The median age of patients was 54 years. Two different types of GT were used: 14 F Cope-loop tube (n = 3), 20 F PEG/disc retention tube (n = 3). PK study showed t1/2 of 58 h, Cmax of 17 ng/ml, Tmax of 8 h, AUC0-inf of 1185 ng*hr/ml, Vd/F of 3310 L and CL/F of 41 L/hr. CONCLUSION: Compared with oral dosing of intact immediate release (IR) tablets, GT administration resulted in 34 % reduction in Cmax and 33-44 % decrease in AUC (all p <0.05) (Janne et al., Clin Cancer Res 2011). Such differences were not detected when compared with the PK properties of dacomitinib administered orally in aqueous suspension (Bello et al., Cancer Chemother Pharm 2013). These differences may be attributed to aqueous suspension of dacomitinib. Caution should be taken with GT administration of orally active small molecule targeted therapy. This study also demonstrated that PK trials in GT patients are feasible using novel designs. PMID- 25937432 TI - Extracorporeal liver assist device to exchange albumin and remove endotoxin in acute liver failure: Results of a pivotal pre-clinical study. AB - BACKGROUND & AIMS: In acute liver failure, severity of liver injury and clinical progression of disease are in part consequent upon activation of the innate immune system. Endotoxaemia contributes to innate immune system activation and the detoxifying function of albumin, critical to recovery from liver injury, is irreversibly destroyed in acute liver failure. University College London-Liver Dialysis Device is a novel artificial extracorporeal liver assist device, which is used with albumin infusion, to achieve removal and replacement of dysfunctional albumin and reduction in endotoxaemia. We aimed to test the effect of this device on survival in a pig model of acetaminophen-induced acute liver failure. METHODS: Pigs were randomised to three groups: Acetaminophen plus University College London-Liver Dialysis Device (n=9); Acetaminophen plus Control Device (n=7); and Control plus Control Device (n=4). Device treatment was initiated two h after onset of irreversible acute liver failure. RESULTS: The Liver Dialysis Device resulted in 67% reduced risk of death in acetaminophen induced acute liver failure compared to Control Device (hazard ratio=0.33, p=0.0439). This was associated with 27% decrease in circulating irreversibly oxidised human non-mercaptalbumin-2 throughout treatment (p=0.046); 54% reduction in overall severity of endotoxaemia (p=0.024); delay in development of vasoplegia and acute lung injury; and delay in systemic activation of the TLR4 signalling pathway. Liver Dialysis Device-associated adverse clinical effects were not seen. CONCLUSIONS: The survival benefit and lack of adverse effects would support clinical trials of University College London-Liver Dialysis Device in acute liver failure patients. PMID- 25937434 TI - Liver disease in the UK: Startling findings & urgent need for action. PMID- 25937433 TI - High hepatic and extrahepatic mortality and low treatment uptake in HCV coinfected persons in the Swiss HIV cohort study between 2001 and 2013. AB - BACKGROUND & AIMS: The landscape of HCV treatments is changing dramatically. At the beginning of this new era, we highlight the challenges for HCV therapy by assessing the long-term epidemiological trends in treatment uptake, efficacy and mortality among HIV/HCV-coinfected people since the availability of HCV therapy. METHODS: We included all SHCS participants with detectable HCV RNA between 2001 and 2013. To identify predictors for treatment uptake uni- and multivariable Poisson regression models were applied. We further used survival analyses with Kaplan-Meier curves and Cox regression with drop-out as competing risk. RESULTS: Of 12,401 participants 2107 (17%) were HCV RNA positive. Of those, 636 (30%) started treatment with an incidence of 5.8/100 person years (PY) (95% CI 5.3 6.2). Sustained virological response (SVR) with pegylated interferon/ribavirin was achieved in 50% of treated patients, representing 15% of all participants with replicating HCV-infection. 344 of 2107 (16%) HCV RNA positive persons died, 59% from extrahepatic causes. Mortality/100 PY was 2.9 (95% CI 2.6-3.2) in untreated patients, 1.3 (1.0-1.8) in those treated with failure, and 0.6 (0.4 1.0) in patients with SVR. In 2013, 869/2107 (41%) participants remained HCV RNA positive. CONCLUSIONS: Over the last 13 years HCV treatment uptake was low and by the end of 2013, a large number of persons remain to be treated. Mortality was high, particularly in untreated patients, and mainly due to non-liver-related causes. Accordingly, in HIV/HCV-coinfected patients, integrative care including the diagnosis and therapy of somatic and psychiatric disorders is important to achieve mortality rates similar to HIV-monoinfected patients. PMID- 25937435 TI - Curcumin effectively inhibits oncogenic NF-kappaB signaling and restrains stemness features in liver cancer. AB - BACKGROUND & AIMS: The cancer stem cells (CSCs) have important therapeutic implications for multi-resistant cancers including hepatocellular carcinoma (HCC). Among the key pathways frequently activated in liver CSCs is NF-kappaB signaling. METHODS: We evaluated the CSCs-depleting potential of NF-kappaB inhibition in liver cancer achieved by the IKK inhibitor curcumin, RNAi and specific peptide SN50. The effects on CSCs were assessed by analysis of side population (SP), sphere formation and tumorigenicity. Molecular changes were determined by RT-qPCR, global gene expression microarray, EMSA, and Western blotting. RESULTS: HCC cell lines exposed to curcumin exhibited differential responses to curcumin and were classified as sensitive and resistant. In sensitive lines, curcumin-mediated induction of cell death was directly related to the extent of NF-kappaB inhibition. The treatment also led to a selective CSC depletion as evidenced by a reduced SP size, decreased sphere formation, down regulation of CSC markers and suppressed tumorigenicity. Similarly, NF-kappaB inhibition by SN50 and siRNA against p65 suppressed tumor cell growth. In contrast, curcumin-resistant cells displayed a paradoxical increase in proliferation and expression of CSC markers. Mechanistically, an important component of the CSC-depleting activity of curcumin could be attributed to a NF kappaB-mediated HDAC inhibition. Co-administration of the class I/II HDAC inhibitor trichostatine sensitized resistant cells to curcumin. Further, integration of a predictive signature of curcumin sensitivity with human HCC database indicated that HCCs with poor prognosis and progenitor features are most likely to benefit from NF-kappaB inhibition. CONCLUSIONS: These results demonstrate that blocking NF-kappaB can specifically target CSC populations and suggest a potential for combined inhibition of NF-kappaB and HDAC signaling for treatment of liver cancer patients with poor prognosis. PMID- 25937436 TI - Sofosbuvir plus ribavirin for treating Egyptian patients with hepatitis C genotype 4. AB - BACKGROUND & AIMS: Egypt has the highest prevalence of chronic hepatitis C virus (HCV) infection in the world, and more than 90% of patients are infected with genotype 4 virus. We evaluated the efficacy and safety of the HCV polymerase inhibitor sofosbuvir in combination with ribavirin in HCV genotype 4 patients in Egypt. METHODS: Treatment-naive or treatment-experienced patients with genotype 4 HCV infection (n=103) were randomly assigned to receive either 12 or 24 weeks of sofosbuvir 400 mg and ribavirin 1000-1200 mg daily. Randomization was stratified by prior treatment experience and by presence or absence of cirrhosis. The primary endpoint was the percentage of patients with HCV RNA <25 IU/ml 12 weeks after therapy (SVR12). RESULTS: Among all patients, 52% had received prior HCV treatment and 17% had cirrhosis at baseline. SVR12 rates were 90% (46/51) with 24 weeks and 77% (40/52) with 12 weeks of sofosbuvir and ribavirin therapy. Patients with cirrhosis at baseline had lower rates of SVR12 (63% 12 weeks, 78% 24 weeks) than those without cirrhosis (80% 12 weeks, 93% 24 weeks). The most common adverse events were fatigue, headache, insomnia, and anemia. Two patients experienced serious adverse events (cerebral ischemia, dyspnea). No adverse events resulted in treatment discontinuation. CONCLUSION: Sofosbuvir plus ribavirin for 12 or 24 weeks is effective in treating both treatment-naive and treatment-experienced Egyptian patients with genotype 4 HCV. PMID- 25937438 TI - Loss of RPS41 but not its paralog RPS42 results in altered growth, filamentation and transcriptome changes in Candida albicans. AB - Although ribosomal proteins (RPs) are components of the ribosome, and function centrally in protein synthesis, several lines of evidence suggest that S4 ribosomal proteins (Rps4ps) can function in other cellular roles. In Candida albicans, ribosomal protein S4 (Rps4p) is encoded by two distinct but highly similar genes, RPS41 (C2_10620W_A) and RPS42 (C1_01640W_A). Previous studies indicated that in Saccharomyces cerevisiae loss of one isoform generated distinct phenotypes. To probe this relationship in C. albicans, rps41Delta and rps42Delta homozygous null mutants were generated. The transcript levels of the RPS41 and RPS42 genes are asymmetric in C. albicans, RPS41 mRNA levels were similar in wild type strains and rps42Delta null mutants, while RPS42 gene transcript levels were induced 20 fold relative to wild type in rps41Delta null mutants. We found that the rps41Delta homozygous null mutant showed a reduced growth rate, and had defects in filament formation in liquid media and on solid media, while these phenotypes were not observed in the rps42Delta mutant strain. Neither the rps41Delta nor rps42Delta mutant strains displayed differential sensitivity to azoles, although intriguingly ectopic expression of either RPS41 or RPS42 in a wild-type strain leads to decreased sensitivity to fluconazole (FLC). C. albicans cDNA microarray analysis experiments found that carbohydrate and nitrogen metabolic processes were repressed but transport-process-related genes were up regulated in the rps41Delta mutant. Overall, our present study suggests that loss of the RPS41 gene but not its paralog the RPS42 gene can generate distinct phenotypes including effects on growth rate, morphological transitions, and susceptibility to osmotic stress due to the fact that mRNA levels of RPS41 is much higher than RPS42 in C. albicans. PMID- 25937439 TI - Myocardial edema as a substrate of electrocardiographic abnormalities and life threatening arrhythmias in reversible ventricular dysfunction of takotsubo cardiomyopathy: Imaging evidence, presumed mechanisms, and implications for therapy. PMID- 25937437 TI - Increased incidence of cancer and cancer-related mortality among persons with chronic hepatitis C infection, 2006-2010. AB - BACKGROUND & AIMS: Persons chronically infected with the hepatitis C virus (HCV) may be at higher risk for developing and dying from non-liver cancers than the general population. METHODS: 12,126 chronic HCV-infected persons in the Chronic Hepatitis Cohort Study (CHeCS) contributed 39,984 person-years of follow-up from 2006 to 2010 and were compared to 133,795,010 records from 13 Surveillance, Epidemiology and End Results Program (SEER) cancer registries, and approximately 12 million U.S. death certificates from Multiple Cause of Death (MCOD) data. Measurements included standardized rate ratios (SRR) and relative risk (RR). RESULTS: The incidence of the following cancers was significantly higher among patients with chronic HCV infection: liver (SRR, 48.6 [95% CI, 44.4-52.7]), pancreas (2.5 [1.7-3.2]), rectum (2.1 [1.3-2.8]), kidney (1.7 [1.1-2.2]), non Hodgkin lymphoma (NHL) (1.6 [1.2-2.1]), and lung (1.6 [1.3-1.9]). Age-adjusted mortality was significantly higher among patients with: liver (RR, 29.6 [95% CI, 29.1-30.1]), oral (5.2 [5.1-5.4]), rectum (2.6 [2.5-2.7]), NHL (2.3 [2.2-2.31]), and pancreatic (1.63 [1.6-1.7]) cancers. The mean ages of cancer diagnosis and cancer-related death were significantly younger among CHeCS HCV cohort patients compared to the general population for many cancers. CONCLUSIONS: Incidence and mortality of many types of non-liver cancers were higher, and age at diagnosis and death younger, in patients with chronic HCV infection compared to the general population. PMID- 25937440 TI - Effect on in vitro cell response of the statistical insertion of N-(2 hydroxypropyl) methacrylamide on linear pro-dendronic polyamine's gene carriers. AB - Statistical copolymers of N-(2-hydroxypropyl) methacrylamide (HPMA) and the dendronic methacrylic monomer 2-(3-(Bis(2 (diethylamino)ethyl)amino)propanamido)ethyl methacrylate (TEDETAMA, derived from N,N,N',N'-tetraethyldiethylenetriamine, TEDETA), were synthesized through radical copolymerization and evaluated in vitro as non-viral gene carriers. Three copolymers with nominal molar percentages of HPMA of 25%, 50% and 75% were prepared and studied comparatively to the positive controls poly-TEDETAMA and hyperbranched polyethyleneimine (PEI, 25kDa). Their ability to complex DNA at different N/P molar ratios, from 1/1 up to 8/1, was determined through agarose gel electrophoresis and Dynamic Light Scattering. The resulting complexes (polyplexes) were characterized and evaluated in vitro as possible non-viral gene carriers for Swiss-3T3 fibroblasts, using luciferase as reporter gene and a calcein cytocompatibility assay. All the copolymers, except the one with highest HPMA proportion (75 molar %) at the lowest N/P ratio, condensed DNA to a particle size between 100 and 300 nm. The copolymers with 25 and 50 molar % of HPMA displayed higher transfection efficiency and cytocompatibility than the positive controls poly-TEDETAMA and PEI. A higher proportion of HPMA (75 molar %) led to copolymers that displayed very low transfection efficiency, despite their full cytocompatibility even at the highest N/P ratio. These results indicate that the statistical combination of TEDETAMA and HPMA and its fine compositional tuning in the copolymers may fulfill the fine balance of transfection efficiency and cytocompatibility in a superior way to the control poly-TEDETAMA and PEI. PMID- 25937441 TI - Desmoteplase for late treatment of stroke: still in the dark. PMID- 25937442 TI - A chance to transform pain care in the USA. PMID- 25937443 TI - Safety and efficacy of desmoteplase given 3-9 h after ischaemic stroke in patients with occlusion or high-grade stenosis in major cerebral arteries (DIAS 3): a double-blind, randomised, placebo-controlled phase 3 trial. AB - BACKGROUND: Current treatment of ischaemic stroke with thrombolytic therapy is restricted to 3-4.5 h after symptom onset. We aimed to assess the safety and efficacy of desmoteplase, a fibrin-dependent plasminogen activator, given between 3 h and 9 h after symptom onset in patients with occlusion or high-grade stenosis in major cerebral arteries. METHODS: In a prospective, double-blind, multicentre, parallel-group, randomised trial, we enrolled patients from 77 hospitals in 17 countries who had ischaemic stroke and occlusion or high-grade stenosis in major cerebral arteries. We randomly assigned patients in a 1:1 ratio, using computer generated randomisation lists with stratification for baseline National Institutes of Health Stroke Scale and age, to treatment with desmoteplase (90 MUg/kg) given 3-9 h after symptom onset or to placebo. Patients, investigators, staff, and the funder were masked to treatment assignment. The primary outcome was a favourable modified Rankin Scale score (0-2) at day 90 in all treated patients who had at least one postbaseline measurement of the modified Rankin Scale. Safety was assessed in all randomly assigned patients who received study drugs. This trial is registered with ClinicalTrials.gov, number NCT00790920. FINDINGS: Between Feb 6, 2009, and Nov 27, 2013, we enrolled 492 patients and randomly assigned 247 to desmoteplase and 245 to placebo (236 in the desmoteplase group and 237 in the placebo group were included in the analysis of the primary endpoint). Median time from stroke onset to treatment was 6.9 h (IQR 5.7-8.0) for placebo and 7.0 h (6.0-7.9) for desmoteplase. Modified Rankin Scale score (0-2) at day 90 occurred in 121 (51%) patients given desmoteplase and 118 (50%) patients given placebo (adjusted odds ratio 1.20, 95% CI 0.79-1.81, p=0.40). 24 (10%) of 240 patients given desmoteplase died compared with 23 (10%) of 238 patients given placebo. Serious adverse events occurred in 64 (27%) of 240 patients receiving desmoteplase compared with 69 (29%) of 238 patients receiving placebo; frequency of symptomatic intracranial haemorrhage (six [3%] patients in the desmoteplase group vs five [2%] in the placebo group), symptomatic cerebral oedema (five [2%] vs four [2%]), and major haemorrhage (ten [4%] vs 15 [6%]) was much the same between treatment groups. INTERPRETATION: Treatment with desmoteplase did not cause safety concerns and did not improve functional outcome when given to patients who had ischaemic stroke and major cerebral artery occlusion beyond 3 h of symptom onset. FUNDING: H Lundbeck A/S. PMID- 25937444 TI - Low-frequency coding variants at 6p21.33 and 20q11.21 are associated with lung cancer risk in Chinese populations. AB - Genome-wide association studies have successfully identified a subset of common variants associated with lung cancer risk. However, these variants explain only a fraction of lung cancer heritability. It has been proposed that low-frequency or rare variants might have strong effects and contribute to the missing heritability. To assess the role of low-frequency or rare variants in lung cancer development, we analyzed exome chips representing 1,348 lung cancer subjects and 1,998 control subjects during the discovery stage and subsequently evaluated promising associations in an additional 4,699 affected subjects and 4,915 control subjects during the replication stages. Single-variant and gene-based analyses were carried out for coding variants with a minor allele frequency less than 0.05. We identified three low-frequency missense variants in BAT2 (rs9469031, c.1544C>T [p.Pro515Leu]; odds ratio [OR] = 0.55, p = 1.28 * 10(-10)), FKBPL (rs200847762, c.410C>T [p.Pro137Leu]; OR = 0.25, p = 9.79 * 10(-12)), and BPIFB1 (rs6141383, c.850G>A [p.Val284Met]; OR = 1.72, p = 1.79 * 10(-7)); these variants were associated with lung cancer risk. rs9469031 in BAT2 and rs6141383 in BPIFB1 were also associated with the age of onset of lung cancer (p = 0.001 and 0.006, respectively). BAT2 and FKBPL at 6p21.33 and BPIFB1 at 20q11.21 were differentially expressed in lung tumors and paired normal tissues. Gene-based analysis revealed that FKBPL, in which two independent variants were identified, might account for the association with lung cancer risk at 6p21.33. Our results highlight the important role low-frequency variants play in lung cancer susceptibility and indicate that candidate genes at 6p21.33 and 20q11.21 are potentially biologically relevant to lung carcinogenesis. PMID- 25937445 TI - The Kalash genetic isolate: ancient divergence, drift, and selection. AB - The Kalash represent an enigmatic isolated population of Indo-European speakers who have been living for centuries in the Hindu Kush mountain ranges of present day Pakistan. Previous Y chromosome and mitochondrial DNA markers provided no support for their claimed Greek descent following Alexander III of Macedon's invasion of this region, and analysis of autosomal loci provided evidence of a strong genetic bottleneck. To understand their origins and demography further, we genotyped 23 unrelated Kalash samples on the Illumina HumanOmni2.5M-8 BeadChip and sequenced one male individual at high coverage on an Illumina HiSeq 2000. Comparison with published data from ancient hunter-gatherers and European farmers showed that the Kalash share genetic drift with the Paleolithic Siberian hunter gatherers and might represent an extremely drifted ancient northern Eurasian population that also contributed to European and Near Eastern ancestry. Since the split from other South Asian populations, the Kalash have maintained a low long term effective population size (2,319-2,603) and experienced no detectable gene flow from their geographic neighbors in Pakistan or from other extant Eurasian populations. The mean time of divergence between the Kalash and other populations currently residing in this region was estimated to be 11,800 (95% confidence interval = 10,600-12,600) years ago, and thus they represent present-day descendants of some of the earliest migrants into the Indian sub-continent from West Asia. PMID- 25937447 TI - Bibliometric assessment of scientific production of literature on chikungunya. PMID- 25937448 TI - Development of a candidate influenza vaccine based on virus-like particles displaying influenza M2e peptide into the immunodominant loop region of hepatitis B core antigen: Insertion of multiple copies of M2e increases immunogenicity and protective efficiency. AB - The extracellular domain of the transmembrane protein M2 (M2e) of influenza A virus is a promising target for the development of "universal" vaccines against influenza. M2e is a poor immunogen by itself; however, when M2e is linked to an appropriate carrier, such as hepatitis B virus core (HBc) particles, it becomes highly immunogenic. Insertions of target peptides into the surface-exposed major immunodominant loop region (MIR) of the HBc antigen are especially immunogenic, but such insertions often affect the protein folding and formation of recombinant virus-like particles. To facilitate an appropriate conformation of the M2e insert, we introduced flexible linkers at the junction points between the insert and flanking HBc sequences. This approach allowed the construction of recombinant HBc particles carrying 1, 2 and 4 copies of M2e in the MIR region. These particles were produced in Escherichia coli and purified to homogeneity. The immune response and protective activity of hybrid HBc particles in mice correlated with the number of inserted M2e peptides: the highest immunogenicity and complete protection of mice against the lethal challenge by influenza virus was observed with particles carrying four copies of M2e. The possibility of the simultaneous presentation of M2e peptides from several important influenza strains on a single HBc particle could also facilitate the development of a broad specificity vaccine efficient not only against influenza A strains of human origin but also for newly emerging strains of animal origin, such as the avian influenza. PMID- 25937449 TI - Field evaluation of measles vaccine effectiveness among children in the Democratic Republic of Congo. AB - BACKGROUND: Large-scale measles outbreaks in areas with high administrative vaccine coverage rates suggest the need to re-evaluate measles prevention and control in the Democratic Republic of Congo (DRC). Monitoring of measles Vaccine Effectiveness (VE) is a useful measure of quality control in immunization programs. We estimated measles VE among children aged 12-59 months in the Democratic Republic of Congo (DRC) using laboratory surveillance data from 2010 2012. METHODS: We used the case-based surveillance system with laboratory confirmation to conduct a case-control study using the test negative design. Cases and controls were selected based on presence (n=1044) or absence (n=1335) of measles specific antibody IgM or epidemiologic linkage. Risk factors for measles were assessed using unconditional logistic regression, stratified by age. RESULTS: Among children 12-59 months, measles vaccination was protective against measles [aOR (95%C)], 0.20 (0.15-0.26) and estimated VE was 80% (95% CI 74-85%). Year of diagnosis, 2011: 6.02 (4.16-8.72) and 2012; 8.31 (5.57-12.40) was a risk factor for measles when compared to 2010. Compared to Kinshasa, children in Bas Congo, Kasai-Oriental, Maniema and South Kivu provinces all had higher odds of developing measles. Measles VE was similar for children 12-23 months and 24-59 months (80% and 81% respectively). CONCLUSIONS: Repeated occurrences of measles outbreaks and lower than expected VE estimates suggest the need to further evaluate measles vaccine efficacy and improve vaccine delivery strategies in DRC. PMID- 25937446 TI - A Potential Contributory Role for Ciliary Dysfunction in the 16p11.2 600 kb BP4 BP5 Pathology. AB - The 16p11.2 600 kb copy-number variants (CNVs) are associated with mirror phenotypes on BMI, head circumference, and brain volume and represent frequent genetic lesions in autism spectrum disorders (ASDs) and schizophrenia. Here we interrogated the transcriptome of individuals carrying reciprocal 16p11.2 CNVs. Transcript perturbations correlated with clinical endophenotypes and were enriched for genes associated with ASDs, abnormalities of head size, and ciliopathies. Ciliary gene expression was also perturbed in orthologous mouse models, raising the possibility that ciliary dysfunction contributes to 16p11.2 pathologies. In support of this hypothesis, we found structural ciliary defects in the CA1 hippocampal region of 16p11.2 duplication mice. Moreover, by using an established zebrafish model, we show genetic interaction between KCTD13, a key driver of the mirrored neuroanatomical phenotypes of the 16p11.2 CNV, and ciliopathy-associated genes. Overexpression of BBS7 rescues head size and neuroanatomical defects of kctd13 morphants, whereas suppression or overexpression of CEP290 rescues phenotypes induced by KCTD13 under- or overexpression, respectively. Our data suggest that dysregulation of ciliopathy genes contributes to the clinical phenotypes of these CNVs. PMID- 25937450 TI - A national study on the prevalence of child abuse and neglect in Suriname. AB - The prevalence of child maltreatment in Suriname has never been subjected to a reliable assessment. The only data available include rough estimates of a range of internationally comparable indicators extrapolated from child protection and police corps statistics for offenses against children. This study aimed to provide a reliable estimate of the prevalence of all forms of child maltreatment in Suriname. One thousand three hundred and ninety-one (1,391) adolescents and young adults of different ethnicities completed a questionnaire about child maltreatment. The study sample, obtained by random probability sampling, consisted of students (ages 12 through 22) from five districts in Suriname. A significant proportion of Surinamese children experienced maltreatment. In total, 86.8% of adolescents and 95.8% of young adults reported having been exposed to at least one form of child maltreatment during their lives. Among the adolescents, 57.1% were exposed to child maltreatment in the past year. When the definition of the National Incidence Study was applied, 58.2% of adolescents and 68.8% of young adults had been exposed to at least one form of maltreatment. Among adolescents, 36.8% reported having experienced at least one form of maltreatment in the past year. The results indicate the (extremely) high lifetime and year prevalence of child maltreatment in Suriname. The serious and often lifelong consequences of such maltreatment indicate that a national approach to child abuse and neglect, including the development of a national strategic plan, a national surveillance system and changes to the state's programmatic and policy response, is urgently needed. PMID- 25937451 TI - Hypophosphatasia due to uniparental disomy. PMID- 25937452 TI - Expression optimization and biochemical properties of two glycosyl hydrolase family 3 beta-glucosidases. AB - The beta-glucosidases from Saccharomycopsis fibuligera (SfBGL1) and Trichoderma reesei (TrBGL1) were cloned and expressed in Pichia pastoris. Methanol concentration and pH significantly affected the production. The combined effects of the two factors were optimized by using the response surface method, resulting in a 137% and 84% increase in rTrBGL1 and rSfBGL1 yield compared to single-factor experiment. Structure and biochemical properties of the two enzyme were investigated and compared. They belong to glycosyl hydrolase family 3 and exhibit significant hydrolysis activity and low-level transglycosylation activity. The two enzymes show similar substrate affinity and ion-tolerance, and both of them can be activated by Cr(6+), Mn(2+) and Fe(2+). The rSfBGL1 has greater catalytic speed, higher specific activity and acid-tolerance than rTrBGL1, but rTrBGL1 is more thermostable and has higher optimal temperature than rSfBGL1. This study provides a useful and quick optimal method for recombinant enzyme production and makes a valuable comparison of biochemical properties, which opens important avenues of exploration for relationship between structure and function and further practical applications. PMID- 25937453 TI - Complete genome sequence of Paenibacillus beijingensis 7188(T) (=DSM 24997(T)), a novel rhizobacterium from jujube garden soil. AB - We present here the complete genome sequence of a novel species Paenibacillus beijingensis 7188(T) (=DSM 24997(T)) from jujube rhizosphere soil that consists of one circular chromosome of 5,749,967 bp with a GC content of 52.5%. On the significance of first genome information in this species, the genome sequence of strain 7188(T) will provide a better comprehension of Paenibacillus species for the practical uses as a biofertilizer in agriculture. PMID- 25937454 TI - Health and sustainable development: a call for papers. PMID- 25937455 TI - [Human papillomavirus vaccine. Efficacy and safety]. AB - Human papillomavirus (HPV) related disease remains a major cause of morbidity and mortality worldwide. Prophylactic vaccines have been recognized as the most effective intervention to control for HPV-related diseases. This article reviews the major phaseii/iii trials of the bivalent (HPVs16/18), quadrivalent (HPVs6/11/16/18), and the recently approved 9-valent vaccine (HPVs6/11/16/18/31/33/45/52/58). Large trials have been conducted showing the safety, immunogenicity and high efficacy of the bivalent and quadrivalent vaccines in the prevention of pre-invasive lesions and infection, especially when administered at young ages before exposure to HPV. Trials of the 9-valent vaccine have also demonstrated the safety, immunogenicity and efficacy of the vaccine in the prevention of infection and disease associated with the vaccine types, and its potential to substantially increase the overall prevention of HPV-related diseases. Post-licensure country reports have shown the recent and early impact of these vaccines at population level after the implementation of established HPV vaccination programs, including decreases in the prevalence of vaccine HPV types, the incidence of genital warts, and the incidence of high-grade cervical abnormalities. If widely implemented, current HPV vaccines may drastically reduce the incidence of cervical cancer and other HPV-related cancers and diseases. PMID- 25937456 TI - Executive summary of the diagnosis and treatment of bacteremia and endocarditis due to Staphylococcus aureus. A clinical guideline from the Spanish Society of Clinical Microbiology and Infectious Diseases (SEIMC). AB - Bacteremia and infective endocarditis caused by Staphylococcus aureus are common and severe diseases. Optimization of treatment is fundamental in the prognosis of these infections. The high rates of treatment failure and the increasing interest in the influence of vancomycin susceptibility in the outcome of infections caused by both methicillin-susceptible and -resistant isolates have led to research on novel therapeutic schemes. The interest in the new antimicrobials with activity against methicillin-resistant staphylococci has been extended to susceptible strains, which still carry the most important burden of infection. New combinations of antimicrobials have been investigated in experimental and clinical studies, but their role is still being debated. Also, the appropriateness of the initial empirical therapy has acquired relevance in recent years. The aim of this guideline is to update the 2009 guidelines and to provide an ensemble of recommendations in order to improve the treatment of staphylococcal bacteremia and infective endocarditis, in accordance with the latest published evidence. PMID- 25937457 TI - Diagnosis and treatment of bacteremia and endocarditis due to Staphylococcus aureus. A clinical guideline from the Spanish Society of Clinical Microbiology and Infectious Diseases (SEIMC). AB - Both bacteremia and infective endocarditis caused by Staphylococcus aureus are common and severe diseases. The prognosis may darken not infrequently, especially in the presence of intracardiac devices or methicillin-resistance. Indeed, the optimization of the antimicrobial therapy is a key step in the outcome of these infections. The high rates of treatment failure and the increasing interest in the influence of vancomycin susceptibility in the outcome of infections caused by both methicillin-susceptible and -resistant isolates has led to the research of novel therapeutic schemes. Specifically, the interest raised in recent years on the new antimicrobials with activity against methicillin-resistant staphylococci has been also extended to infections caused by susceptible strains, which still carry the most important burden of infection. Recent clinical and experimental research has focused in the activity of new combinations of antimicrobials, their indication and role still being debatable. Also, the impact of an appropriate empirical antimicrobial treatment has acquired relevance in recent years. Finally, it is noteworthy the impact of the implementation of a systematic bundle of measures for improving the outcome. The aim of this clinical guideline is to provide an ensemble of recommendations in order to improve the treatment and prognosis of bacteremia and infective endocarditis caused by S. aureus, in accordance to the latest evidence published. PMID- 25937458 TI - Multi-frequency localization of aberrant brain activity in autism spectrum disorder. AB - OBJECTIVE: The abnormality of intrinsic brain activity in autism spectrum disorders (ASDs) is still inconclusive. Contradictory results have been found pointing towards hyper-activity or hypo-activity in various brain regions. The present research aims to investigate the spatial and spectral signatures of aberrant brain activity in an unprecedented frequency range of 1-2884 Hz at source levels in ASD using newly developed methods. MATERIALS AND METHODS: Seven ASD subjects and age- and gender-matched controls were studied using a high sampling rate magnetoencephalography (MEG) system. Brain activity in delta (1-4 Hz), theta (4-8 Hz), alpha (8-12 Hz), beta (12-30 Hz), low gamma (30-55 Hz), high gamma (65-90 Hz), ripples (90-200 Hz), high-frequency oscillations (HFOs, 200 1000 Hz), and very high-frequency oscillations (VHFOs, 1000-2884 Hz) was volumetrically localized and measured using wavelet and beamforming. RESULTS: In comparison to controls, ASD subjects had significantly higher odds of alpha activity (8-12 Hz) in the sensorimotor cortex (mu rhythm), and generally high frequency activity (90-2884 Hz) in the frontal cortex. The source power of HFOs (200-1000 Hz) in the frontal cortex in ASD was significantly elevated as compared with controls. CONCLUSION: The results suggest that ASD has significantly altered intrinsic brain activity in both low- and high-frequency ranges. Increased intrinsic high-frequency activity in the frontal cortex may play a key role in ASD. PMID- 25937459 TI - #Schizophrenia: Use and misuse on Twitter. AB - BACKGROUND: The role and prevention of stigma in mental illness is an area of evolving research. AIMS: The present study is the first to examine the use and misuse of the word 'schizophrenia' on Twitter.com in comparison with another illness (diabetes) by analyzing Tweets that use the adjective and noun forms of schizophrenia and diabetes. METHOD: Tweets containing one of four search terms (#schizophrenia, #schizophrenic, #diabetes, #diabetic) were collected over a forty-day time period. After establishing inter-rater reliability, Tweets were rated along three dimensions: medical appropriateness, negativity, and sarcasm. Chi square tests were conducted to examine differences in the distributions of each parameter across illnesses and across each word form (noun versus adjective). RESULTS: Significant differences were seen between the two illnesses (i.e., among "schizophrenia", "schizophrenic", "diabetes", and "diabetic") along each parameter. Tweets about schizophrenia were more likely to be negative, medically inappropriate, sarcastic, and used non-medically. The adjective ("schizophrenic") was more often negative, medically inappropriate, sarcastic, and used non-medically than the noun "schizophrenia." Schizophrenia tweets were more likely to be negative and sarcastic when used non-medically and in a medically inappropriate manner. CONCLUSIONS: Our findings confirm the presence of a great deal of misuse of the term schizophrenia on Twitter, and that this misuse is considerably more pronounced by the adjectival use of the illness. These findings have considerable implications for efforts to combat stigma, particularly for youth anti-stigma efforts. PMID- 25937460 TI - On the use of the Positive and Negative Syndrome Scale in randomized clinical trials. AB - In the last 25 years, the Positive and Negative Syndrome Scale (PANSS) has been largely used to assess schizophrenia symptom intensity, but little information is available on how this scale was generally applied when evaluating the efficacy of schizophrenia therapies in randomized clinical trials. In the attempt to address this topic, a systematic PubMed Search was carried out using the keywords "PANSS" and "Randomized Clinical Trials". The analysis of retrieved articles highlighted that PANSS has constituted a suitable psychometric instrument to investigate the efficacy of pharmacological and non-pharmacological therapies. However, the information potentially provided by this scale was only partially reported in research articles, when characterizing the symptomatic features of patients at baseline. Furthermore, a consensus is needed to identify methodological strategies that may properly adapt PANSS-subscale structure with the symptomatic profiles of individuals enrolled in randomized controlled trials. The possibility that PANSS interview procedures and enrollment eligibility criteria may influence the symptomatic composition of patients involved in these studies is also discussed. PMID- 25937461 TI - A randomized pilot study of MOtiVation and Enhancement (MOVE) Training for negative symptoms in schizophrenia. AB - INTRODUCTION: Among individuals with schizophrenia, those who have persistent and clinically significant negative symptoms (PNS) have the poorest functional outcomes and quality of life. The NIMH-MATRICS Consensus Statement indicated that these symptoms represent an unmet therapeutic need for large numbers of individuals with schizophrenia. No psychosocial treatment model addresses the entire constellation of PNS. METHOD: 51 patients with PNS were randomized into one of two groups for a period of 9 months: 1) MOtiVation and Enhancement (MOVE) or 2) treatment as usual. MOVE is a home based, manual-driven, multi-modal treatment that employs a number of cognitive and behavioral principles to address the broad range of factors contributing to PNS and their functional consequences. The components of MOVE include: Environmental supports to prompt initiation and persistence, in-vivo skills training to ameliorate deficits and encourage interaction, cognitive behavioral techniques to address self-defeating attitudes, in-vivo training in emotional processing to address affective blunting and problems in identifying emotions, and specific techniques to address the deficits in anticipatory pleasure. Patients were assessed at baseline and each 3 months with multiple measures of negative symptoms. RESULTS: Repeated measures analyses of variance for mixed models indicated significant Group by Time effects for the Negative Symptom Assessment (NSA; p<.02) and the Clinical Assessment Interview for Negative Symptoms (CAINS; p<.04). Group differences were not significant until 9 months of treatment and were not significant for the Brief Negative Symptom Scale (BNSS). CONCLUSION: Further investigation of a comprehensive treatment for PNS, such as MOVE, is warranted. PMID- 25937462 TI - Alpha-lipoic acid alone and combined with clozapine reverses schizophrenia-like symptoms induced by ketamine in mice: Participation of antioxidant, nitrergic and neurotrophic mechanisms. AB - Oxidative stress has important implications in schizophrenia. Alpha-lipoic acid (ALA) is a natural antioxidant synthesized in human tissues with clinical uses. We studied the effect of ALA or clozapine (CLZ) alone or in combination in the reversal of schizophrenia-like alterations induced by ketamine (KET). Adult male mice received saline or KET for 14 days. From 8th to 14th days mice were additionally administered saline, ALA (100 mg/kg), CLZ 2.5 or 5 mg/kg or the combinations ALA+CLZ2.5 or ALA+CLZ5. Schizophrenia-like symptoms were evaluated by prepulse inhibition of the startle (PPI) and locomotor activity (positive like), social preference (negative-like) and Y maze (cognitive-like). Oxidative alterations (reduced glutathione - GSH and lipid peroxidation - LP) and nitrite in the prefrontal cortex (PFC), hippocampus (HC) and striatum (ST) and BDNF in the PFC were also determined. KET caused deficits in PPI, working memory, social interaction and hyperlocomotion. Decreased levels of GSH, nitrite (HC) and BDNF and increased LP were also observed in KET-treated mice. ALA and CLZ alone reversed KET-induced behavioral alterations. These drugs also reversed the decreases in GSH (HC) and BDNF and increase in LP (PFC, HC and ST). The combination ALA+CLZ2.5 reversed behavioral and some neurochemical parameters. However, ALA+CLZ5 caused motor impairment. Therefore, ALA presented an antipsychotic-like profile reversing KET-induced positive- and negative-like symptoms. The mechanism partially involves antioxidant, neurotrophic and nitrergic pathways. The combination of ALA+CLZ2.5 improved most of the parameters evaluated in this study without causing motor impairment demonstrating, thus, that possibly when combined with ALA a lower dose of CLZ is required. PMID- 25937463 TI - Identification of 7 stress-related NAC transcription factor members in maize (Zea mays L.) and characterization of the expression pattern of these genes. AB - NAC proteins are plant-specific transcription factors that play essential roles in plant development and various abiotic stress responses. A comprehensive analysis of maize NAC genes was performed in this study. A total of 157 non redundant maize NAC genes including seven membrane-bound members were identified and found to be unevenly distributed on 10 maize chromosomes. Motif composition analysis indicated that the maize NAC proteins share three relatively conserved motifs in the NAC domain within the N-terminal region. Phylogenetic analysis of 157 maize NAC proteins accompanied by 117 NAC proteins from Arabidopsis and 151 from rice were presented. The NAC proteins evaluated were divided into two large groups including 18 subgroups. Gene duplication analysis indicated that gene loss occurred during maize evolution. Seven NAC members that belong to the same clade of maize NAC domain genes were isolated, and overlapping expression patterns were observed under various abiotic stresses, including low temperature, high salinity and dehydration, and phytohormone abscisic acid treatments. This suggested that NAC members function as stress-responsive transcription factors in ABA-dependent signaling pathways. Relatively higher expression levels of these selected maize NAC genes were detected in roots. The stress responsive NAC genes may have applications in molecular breeding to improve crop stress tolerance. PMID- 25937464 TI - Corticosteroid responses following hypoxic preconditioning provide neuroprotection against subsequent hypoxic-ischemic brain injury in the newborn rats. AB - Limited research has evaluated the corticosteroids (CS) response in hypoxic preconditioning (PC) induced neuroprotection against subsequent hypoxic-ischemic (HI) brain injury in newborns. To measure, CS response to hypoxic PC, at postnatal day 6 (P6), rat pups were randomly divided into sham, NoPC (exposure to 21% O2) and PC (exposure to 8% O2 for 3h) groups. In a separate experiment, at P6, rat pups were randomly divided into three groups (sham, NoPC+HI, PC+HI). Rat pups in NoPC+HI and PC+HI groups, respectively had normoxic or hypoxic exposure for 3h at P6 and then had the right carotid artery permanently ligated followed by 140 min of hypoxia at P7 (HI). Plasma CS levels were measured at 0.5, 1, 3, 6 and 12h after hypoxic PC and hypoxic PC followed by HI. To investigate whether CS response to hypoxic PC provides neuroprotection against HI, at P6, rat pups were randomly divided into five groups. Fifteen minutes prior to PC or normoxic exposure, rat pups in DMSO+PC+HI and DMSO+NoPC+HI groups received DMSO while in RU486+PC+HI and RU486+NoPC+HI groups received RU486 (glucocorticoid receptor blocker, 60 mg/kg) s.c., respectively. Afterwards, rat pups were exposed to normoxia (DMSO+NoPC+HI, RU486+NoPC+HI) or hypoxia (DMSO+PC+HI, RU486+PC+HI) for 3h and then HI 24h later (P7). Rat pups at the corresponding age without any exposure to PC or HI or RU486/DMSO were used as sham. We found that hypoxic PC caused CS surge as well as augmented CS surge and preserved the glucocorticoid feedback regulation after HI. Hypoxic PC reduced HI induced early and delayed brain damage. RU486 partially but significantly inhibited hypoxic PC induced neuroprotection. PMID- 25937466 TI - ZNRF3/RNF43--A direct linkage of extracellular recognition and E3 ligase activity to modulate cell surface signalling. AB - The interactions of extracellular ligands with single membrane spanning receptors, such as kinases, typically serve to agonise or antagonise the intracellular activation of signalling pathways. Within the cell, E3 ligases can act to alter the localisation and activity of proteins involved in signalling systems. Structural and functional characterisation of two closely related single membrane spanning molecules, RNF43 and ZNRF3, has recently revealed the receptor like functionalities of a ligand-binding ectodomain combined with the intracellular architecture and activity of an E3 ligase. This direct link provides a hereto novel mechanism for extracellular control of ubiquitin ligase activity that is used for the modulation of Wnt signalling, a pathway of major importance in embryogenesis, stem cell biology and cancer. In this review we discuss recent findings for the structure and interactions of the extracellular region of RNF43/ZNRF3 and draw parallels with the properties and function of signalling receptor ectodomains. PMID- 25937465 TI - Cytoplasmic sensing by the inner membrane histidine kinase EnvZ. AB - Two-component regulatory systems drive signal transduction in bacteria. The simplest of these employs a membrane sensor kinase and a cytoplasmic response regulator. Environmental sensing is typically coupled to gene regulation. The histidine kinase EnvZ and its cognate response regulator OmpR regulate expression of outer membrane proteins (porins) in response to osmotic stress. We used hydrogen:deuterium exchange mass spectrometry to identify conformational changes in the cytoplasmic domain of EnvZ (EnvZc) that were associated with osmosensing. The osmosensor localized to a seventeen amino acid region of the four-helix bundle of the cytoplasmic domain and flanked the His(243) autophosphorylation site. High osmolality increased autophosphorylation of His(243), suggesting that these two events were linked. The transmembrane domains were not required for osmosensing, but mutants in the transmembrane domains altered EnvZ activity. A photoactivatable fusion protein composed of EnvZc fused to the fluorophore mEos2 (EnvZc-mEos2) was as capable as EnvZc in supporting OmpR-dependent ompF and ompC transcription. Over-expression of EnvZc reduced activity, indicating that the EnvZ/OmpR system is not robust. Our results support a model in which osmolytes stabilize helix one in the four-helix bundle of EnvZ by increased hydrogen bonding of the peptide backbone, increasing autophosphorylation and downstream signaling. The likelihood that additional histidine kinases use similar cytoplasmic sensing mechanisms is discussed. PMID- 25937467 TI - Lipid in T-cell receptor transmembrane signaling. AB - T-cell receptor (TCR) is a key receptor in the immune system that can recognize antigen and initiate adaptive immune response. TCR activity needs to be regulated in a precise manner to trigger sufficient response to foreign pathogens but avoid unnecessary harm to the host. Despite of its importance, the molecular mechanism of TCR transmembrane signaling still remains elusive. Emerging studies show that lipid can play sophisticated roles in regulating the structure and function of TCR. This review mainly discusses how acidic phospholipids regulate TCR signaling through ionic protein-lipid interaction. PMID- 25937468 TI - Meta-analysis of self-reported daytime napping and risk of cardiovascular or all cause mortality. AB - BACKGROUND: Whether self-reported daytime napping is an independent predictor of cardiovascular or all-cause mortality remains unclear. The aim of this study was to investigate self-reported daytime napping and risk of cardiovascular or all cause mortality by conducting a meta-analysis. MATERIAL/METHODS: A computerized literature search of PubMed, Embase, and Cochrane Library was conducted up to May 2014. Only prospective studies reporting risk ratio (RR) and corresponding 95% confidence intervals (CI) of cardiovascular or all-cause mortality with respect to baseline self-reported daytime napping were included. RESULTS: Seven studies with 98,163 subjects were included. Self-reported daytime napping was associated with a greater risk of all-cause mortality (RR 1.15; 95% CI 1.07-1.24) compared with non-nappers. Risk of all-cause mortality appeared to be more pronounced among persons with nap duration >60 min (RR 1.15; 95% CI 1.04-1.27) than persons with nap duration <60 min (RR 1.10; 95% CI 0.92-1.32). The pooled RR of cardiovascular mortality was 1.19 (95% CI 0.97-1.48) comparing daytime nappers to non-nappers. CONCLUSIONS: Self-reported daytime napping is a mild but statistically significant predictor for all-cause mortality, but not for cardiovascular mortality. However, whether the risk is attributable to excessive sleep duration or napping alone remains controversial. More prospective studies stratified by sleep duration, napping periods, or age are needed. PMID- 25937469 TI - Use of Conventional and Alternative Tobacco and Nicotine Products Among a Sample of Canadian Youth. AB - PURPOSE: The purpose of this study was to examine the use of conventional and alternative tobacco and nicotine products among secondary school students. METHODS: Respondents were 44,163 grade 9-12 students who participated in Year 2 (2013-2014) of COMPASS, a cohort study of 89 purposefully sampled secondary schools in Ontario and Alberta, Canada. Past-month use of various tobacco and nicotine products was assessed, as well as correlates of use, using a generalized linear mixed effects model. RESULTS: Overall, 21.2% of the sample reported past month use of any tobacco or nicotine product, with 7.2% reporting past-month use of e-cigarettes. E-cigarette users reported significantly greater prevalence of current use for all products. Students who were male, white, had more spending money, and had a history of tobacco use were more likely to report past-month use of e-cigarettes. CONCLUSIONS: Approximately one fifth of youth reported past month use of a nicotine product, with e-cigarettes being the third most common product. Overall, the findings suggest a rapidly evolving nicotine market. PMID- 25937470 TI - Assertive Communication in Condom Negotiation: Insights From Late Adolescent Couples' Subjective Ratings of Self and Partner. AB - PURPOSE: Assertive communication has been associated with higher levels of condom use among youth using self-report survey methodology. The purpose of this study was to examine the subjective ratings of assertiveness among young, romantically involved couples in the context of a condom negotiation task. METHODS: Using an innovative video-recall procedure, 32 couples (64 youth) engaged in a videotaped condom negotiation task and then rated self and partners' level of assertiveness. Both individual ratings of assertiveness and couple-level assertiveness were assessed using dyadic hierarchical linear modeling. RESULTS: Individuals' assertiveness was positively associated with condom use. Unexpectedly, the overall level of assertiveness in couples showed a curvilinear association with condom use. Very high and very low assertiveness was associated with lower condom use, whereas moderate levels of assertiveness were associated with higher condom use. CONCLUSIONS: Moderate levels of assertiveness during condom negotiation may facilitate condom use in young couples. Increasing condom use among romantic partners may require developing interventions that strengthen youths' ability to engage in assertive communication strategies that balance emotional intimacy with self-advocacy. PMID- 25937473 TI - Overgrowth syndromes with vascular anomalies. AB - Overgrowth syndromes with vascular anomalies encompass entities with a vascular anomaly as the predominant feature vs those syndromes with predominant somatic overgrowth and a vascular anomaly as a more minor component. The focus of this article is to categorize these syndromes phenotypically, including updated clinical criteria, radiologic features, evaluation, management issues, pathophysiology, and genetic information. A literature review was conducted in PubMed using key words "overgrowth syndromes and vascular anomalies" as well as specific literature reviews for each entity and supportive genetic information (e.g., somatic mosaicism). Additional searches in OMIM and Gene Reviews were conducted for each syndrome. Disease entities were categorized by predominant clinical features, known genetic information, and putative affected signaling pathway. Overgrowth syndromes with vascular anomalies are a heterogeneous group of disorders, often with variable clinical expression, due to germline or somatic mutations. Overgrowth can be focal (e.g., macrocephaly) or generalized, often asymmetrically (and/or mosaically) distributed. All germ layers may be affected, and the abnormalities may be progressive. Patients with overgrowth syndromes may be at an increased risk for malignancies. Practitioners should be attentive to patients having syndromes with overgrowth and vascular defects. These patients require proactive evaluation, referral to appropriate specialists, and in some cases, early monitoring for potential malignancies. Progress in identifying vascular anomaly-related overgrowth syndromes and their genetic etiology has been robust in the past decade and is contributing to genetically based prenatal diagnosis and new therapies targeting the putative causative genetic mutations. PMID- 25937472 TI - High School Sports Involvement Diminishes the Association Between Childhood Conduct Disorder and Adult Antisocial Behavior. AB - PURPOSE: Life course-persistent antisocial behavior manifests as a display of aggressive and antisocial behavior beginning in childhood (conduct disorder [CD]) and lasting through adulthood (adult antisocial personality disorder). This study aimed to build on prior research by evaluating whether involvement in high school sports helped attenuate the association between CD and subsequent adult antisocial behavior (AAB). METHODS: A prospective sample of 967 male and female adolescents (56% adopted) was used. Structured interviews were used to assess CD (symptoms before the age of 15 years), involvement in sports during high school, and past-year adult antisocial personality disorder symptoms in young adulthood (M age = 22.4 years). RESULTS: As expected, the association between CD and AAB was significantly less for those involved in sports (beta = .28; p < .001) compared with those not involved in sports (beta = .49; p < .001), chi(2)(1) = 4.13; p = .04. This difference remained after including known covariates of antisocial behavior in the model (age, gender, adoption status), and results were consistent across males and females. Involvement in other extracurricular activities (e.g., student government, plays, clubs) did not significantly moderate the relationship between CD and AAB. CONCLUSIONS: Although selection effects were evident (those with more CD symptoms were less likely to be involved in sports), findings nevertheless suggest high school sports involvement may be a notable factor related to disrupting persistent antisocial behavior beginning in childhood and adolescence and lasting through young adulthood. Implications are discussed. PMID- 25937471 TI - Gender Identity, Sexual Orientation, and Eating-Related Pathology in a National Sample of College Students. AB - PURPOSE: This study examined associations of gender identity and sexual orientation with self-reported eating disorder (SR-ED) diagnosis and compensatory behaviors in transgender and cisgender college students. METHODS: Data came from 289,024 students from 223 U.S. universities participating in the American College Health Association-National College Health Assessment II (median age, 20 years). Rates of past-year SR-ED diagnosis and past-month use of diet pills and vomiting or laxatives were compared among transgender students (n = 479) and cisgender sexual minority (SM) male (n = 5,977) and female (n = 9,445), unsure male (n = 1,662) and female (n = 3,395), and heterosexual male (n = 91,599) and female (n = 176,467) students using chi-square tests. Logistic regression models were used to estimate the odds of eating-related pathology outcomes after adjusting for covariates. RESULTS: Rates of past-year SR-ED diagnosis and past-month use of diet pills and vomiting or laxatives were highest among transgender students and lowest among cisgender heterosexual men. Compared to cisgender heterosexual women, transgender students had greater odds of past-year SR-ED diagnosis (odds ratio [OR], 4.62; 95% confidence interval [CI], 3.41-6.26) and past-month use of diet pills (OR, 2.05; 95% CI, 1.48-2.83) and vomiting or laxatives (OR, 2.46; 95% CI, 1.83-3.30). Although cisgender SM men and unsure men and women also had elevated rates of SR-ED diagnosis than heterosexual women, the magnitudes of these associations were lower than those for transgender individuals (ORs; 1.40 1.54). CONCLUSIONS: Transgender and cisgender SM young adults have elevated rates of compensatory behavior and SR-ED diagnosis. Appropriate interventions for these populations are urgently needed. PMID- 25937474 TI - A prospective study of factors influencing morbidity after iliac crest harvesting for oral onlay grafting. AB - OBJECTIVE: The present study evaluates the morbidity after iliac crest harvesting from the anterior iliac rim for oral onlay grafting and identifies influential factors. MATERIAL AND METHODS: Twenty partially edentulous or edentulous patients (15 females and 5 males) with a mean age of 54.25 years (range 20-78 years, SD 13.86 years, remaining bone height <5 mm of the alveolar ridge) underwent iliac onlay bone grafting. The postoperative clinical morbidity was classified in minor and major complications and was evaluated with respect to body mass index (BMI). RESULTS: The grafting procedure was successfully performed in all patients with a mean BMI of 23.34 (range 18-29, SD 3.36). A significant difference between BMI and walking aid necessity (p = 0.018) was demonstrated, but no difference between BMI and hip pain, duration of disturbance, gait disturbance, complication rate, and sensory loss was identified (p > 0.05). Between hip pain and scar length, age and hip/jaw pain did not demonstrate a significant difference (p > 0.05). Postoperative complications were minor and consisted of hematoma, seroma, and transient sensory disturbance. CONCLUSION: Patients undergoing bone harvest from the anterior superior iliac crest with oral grafting show a low minor complication rate and a high overall satisfaction of 95%. PMID- 25937475 TI - Tricalcium phosphate-based biocomposites for mandibular bone regeneration--A histological study in sheep. AB - The present study investigated the suitability of three different absorbable biocomposites for the repair of critical sized bone defects created at the mandibular angle of adult sheep. Each biocomposite was composed of a three dimensional individualized polylactide scaffold, containing a tricalcium phosphate biomaterial (chronOS). Either autologous bone marrow (chOS/BoneMarrow) or coagulation factor XIII (chOS/FactorXIII) was added to the biomaterial for osteopromotion. Venous whole blood (chOS/Blood) added to the biomaterial served as a control. A total of 18 adult sheep were used for implantation studies, subdivided into three groups of six animals each. After 12 weeks of observation, the animals were sacrificed and the mandibles were retrieved for qualitative and quantitative histologic assessment within three regions of interest (transitional zone, center, and periphery) throughout the biocomposites. Successful bone regeneration was defined by the absence of scaffold deformation and the presence of new bone formation within the biocomposites. In histomorphometry, only chOS/BoneMarrow showed elevated area fractions of newly formed bone in all regions of interest (transitional zone 50.7 +/- 7.5, center 31.9 +/- 9.3, periphery 23.1 +/- 13.5). This led to preservation of the macroscopic scaffold structure in all specimens. Zero hurdle regression confirmed this by validating the factor biocomposite as significant (p < 0.001) for regeneration success. In our experiment, chOS/BoneMarrow was the only biocomposite passing the hurdle of regeneration in all three regions of interest. In contrast, bone formation was less pronounced and uniform in chOS/FactorXIII and chOS/blood-containing specimens. In these groups, scaffolds showed obvious to significant deformation. Overall, autologous bone marrow showed the most promising results in our experimental setting. As opposed to reports in the literature, we could not confirm the suitability of coagulation factor XIII to promote bone formation, since bone formation rates were comparable only to those of the control venous blood. PMID- 25937476 TI - PROGNOSTIC VALUE OF THE MULTIPLE MINI-INTERVIEW FOR EMERGENCY MEDICINE RESIDENCY PERFORMANCE. AB - BACKGROUND: The Multiple Mini-Interview (MMI) uses short, structured contacts, and is known to predict medical school success better than traditional interviews and application materials. Its utility in Emergency Medicine residency selection is untested. OBJECTIVES: We investigate whether it provides additional information regarding future first-year resident performance that can be useful in resident selection. METHODS: From three Emergency Medicine residency programs, 71 interns in their first month completed an MMI developed to focus on desirable resident characteristics. Application data were reviewed. First-year resident performance assessments covering the American Council for Graduate Medical Education (ACGME) core competencies, along with professionalism and performance concerns, were obtained. Multiple logistic regressions were employed and MMI correlations were compared with program rank lists and typical selection factors. RESULTS: An individual's score on the MMI correlated with overall performance (p < 0.05) in single logistic regression. MMI correlated with ACGME individual competencies patient care and procedural skills at a less robust level (p < 0.1), but not with any other outcomes. Rank list position correlated with the diagnostic skill competency (p < 0.05), but no others. Traditional selection factors correlated with overall performance, disciplinary action, patient care, medical knowledge, and diagnostic skills (p < 0.05). MMI was not correlated significantly with the outcomes when included in multiple ordinal logistic regression with other selection factors. CONCLUSIONS: MMI scores correlate with overall performance, but are not statistically significant when other traditional selection factors were considered. The MMI process seems potentially superior to program rank list at correlating with first-year performance. The MMI may provide additional benefit when examined using a larger and more diverse sample. PMID- 25937477 TI - Failure of Emergency Department Observation Unit Treatment for Skin and Soft Tissue Infections. AB - BACKGROUND: The effectiveness of observation unit (OU) management of skin and soft tissue infections (SSTI) has not been fully evaluated. OBJECTIVE: This study was performed to determine the rate and risk factors. METHODS: Retrospective cohort study of children ages 2 months to 18 years admitted to the OU for an SSTI between 2007 and 2010 from a pediatric emergency department (ED). Failure of OU therapy was defined as subsequent inpatient ward admission, re-admission after discharge from OU, initial or repeat incision and drainage after OU admission, or change in antibiotic therapy. Demographic, clinical, and lesion characteristics were collected. Comparative analyses were conducted to determine factors associated with OU failure; prolonged OU admission, defined as length of stay >= 36 h was evaluated. RESULTS: One hundred ninety-two (63.2%) of 304 subjects with SSTI were eligible; mean age was 6.2 +/- 5.3 years, and 52% were male. Fever (>=38 degrees C) in the ED was present for 77 (40%). Most lesions were skin abscesses (53%) and were located on the lower extremity (36%) and buttock/genitourinary (21%). OU treatment failure occurred in 22% (95% confidence interval [CI] 16.5-28.3), primarily due to inpatient admission. Fever on ED presentation was significantly associated with OU failure (odds ratio 2.02; 95% CI 1.02-4.02). Demographics, body site, presence of abscess, and methicillin resistant Staphylococcus aureus were not associated with OU failure. Prolonged OU admission occurred in 18 subjects (9.4%). CONCLUSION: SSTI can be successfully treated in the OU, though febrile children with SSTI are at risk for OU treatment failure and should be considered for inpatient admission. PMID- 25937478 TI - Proliferating Pilar Tumor of Scalp Metastasizing to Pancreas: Diagnosis With Endoscopic Ultrasound-guided Fine-needle Aspiration. PMID- 25937479 TI - Treating severe phantom limb pain by applying far infrared ray to 'phantom limb'. PMID- 25937480 TI - Topical photodynamic therapy is the first-line treatment of choice for oral erythroleukoplakia and oral verrucous hyperplasia. PMID- 25937481 TI - Trastuzumab-based chemotherapy modulates systemic redox homeostasis in women with HER2-positive breast cancer. AB - Trastuzumab is an immunotargeting therapeutic against breast tumors with amplification of the human epithelial growth factor receptor 2 (HER2). HER2 patients naturally exhibit disruption in the pro-oxidant inflammatory profiling; however, the impact of trastuzumab-based chemotherapy in modulating this process is still unknown. Here we determined the systemic pro-inflammatory profile of women diagnosed with HER2-amplified tumors, undergoing trastuzumab-based chemotherapy (TZ), and compared the results with that of healthy controls (CTR) and untreated patients with HER2-amplified breast cancer (CA). The plasmatic inflammatory profile was assessed by evaluating pro-oxidant parameters such as lipid peroxidation, total antioxidant capacity (TRAP), levels of advanced oxidation protein products (AOPPs), nitric oxide (NO), C-reactive protein (CRP), and total thiol content. Markers of cardiac damage were also assessed. Our findings showed increased NO levels in TZ than that in either CA or CTR groups. Furthermore, TZ augmented TRAP and reduced total thiol than that of the CA group. Our data also revealed that AOPP levels were significantly higher in the TZ than the CA group. AOPP and the MB fraction of creatine-kinase (CKMB) levels were positively correlated in TZ patients. These findings suggest that trastuzumab associated chemotherapy can modulate the pro-inflammatory markers of HER2 positive breast cancer patients to the levels found in healthy controls. PMID- 25937482 TI - Blockage of P2X7 attenuates acute lung injury in mice by inhibiting NLRP3 inflammasome. AB - NLRP3 inflammasome is engaged in the inflammatory response during acute lung injury (ALI). Purinergic receptor P2X7 has been reported to be upstream of NLRP3 activation. However, the therapeutic implication of P2X7 in ALI remains to be explored. The present study used lipopolysaccharide (LPS)-induced mouse model to investigate the therapeutic potential of P2X7 blockage in ALI. Our results showed that P2X7/NLRP3 inflammasome pathway was significantly upregulated in the lungs of ALI mice as compared with control mice. P2X7 antagonist A438079 suppressed NLRP3/ASC/caspase 1 activation, production of IL-1beta, IL-17A and IFN-gamma and neutrophil infiltration but not the production of IL-10, resulting in a significant amelioration of lung injury. Moreover, blockage of P2X7 significantly inhibited NLRP3 inflammasome activation and IL-1beta production in bone marrow derived macrophages. Similar results were obtained using another P2X7 inhibitor brilliant blue G (BBG) in vivo. Thus, pharmacological blockage of P2X7/NLRP3 pathway can be considered as a potential therapeutic strategy in patients with ALI. PMID- 25937483 TI - Effects of curcumin on growth performance, jejunal mucosal membrane integrity, morphology and immune status in weaned piglets challenged with enterotoxigenic Escherichia coli. AB - The aim of this study was to evaluate the effect of dietary curcumin supplementation on growth performance and intestinal mucosal barrier function of weaned piglets. Fifty piglets, weaned at 21+/-2 days of age, were randomly allotted to five treatments for 21 days. The dietary treatments were the control (basal diet), and the basal diet supplemented with 50mg/kg quinocetone, or 200 mg/kg, 300 mg/kg or 400mg/kg curcumin. The piglets were housed in individual pens and orally challenged with enterotoxigenic Escherichia coli (ETEC) during the preliminary trial period. The jejunal morphology and histology analysis were detected under light microscope. The plasma D-lactate and diamine oxidase (DAO) were determined by using enzymatic spectrophotometric assay. Immunohistochemistry assays were used to examine secretory immunoglobulin (sIgA) protein expression. Real-time PCR was used to determine mRNA levels of cytokine and Toll-like receptor 4 (TLR4) in jejunal mucosa. The results showed that, compared with the control, dietary addition of 300 mg/kg or 400 mg/kg curcumin decreased (P<0.05) feed/gain ratio and crypt depth, improved (P<0.05) villus height and villus height:crypt depth ratio, reduced (P<0.05) plasma D-lactate and DAO activity, up regulated the protein expression of sIgA (P<0.05), increased (P<0.05) the number of goblet cells (GCs) and reduced (P<0.05) the number of intraepithelial lymphocytes (IELs). The mRNA levels of interleukin 1beta (IL-1beta) and TLR4 and tumor necrosis factor alpha (TNF-alpha) were also decreased (P<0.05), but mRNA level of interleukin 10 (IL-10) was increased (P<0.05). There was no difference in the above parameters between the 300 mg/kg and 400 mg/kg curcumin groups. Pigs fed with 50 mg/kg quinocetone also decreased (P<0.05) feed/gain ratio, increased villus height:crypt depth ratio (P<0.05), and reduced (P<0.05) crypt depth and mRNA levels of TLR4. In conclusion, curcumin and the quinocetone have similar effects in improving piglet growth, but dietary addition of 300 mg/kg or 400 mg/kg curcumin was more effective than quinocetone in improving intestinal mucosal barrier integrity, morphology, and immune status of weaned pigs. This indicates that curcumin could be used as a potential feed additive replacing quinocetone in weaned piglets. PMID- 25937484 TI - Transarterial chemoembolization in unresectable hepatocellular carcinoma- assessing the factors affecting the survival: An audit from a tertiary care center in northern India. AB - INTRODUCTION: Hepatocellular carcinoma (HCC) is the most common primary malignant tumor of the liver and third most common cause of cancer-related mortality. According to Barcelona Clinic Liver Cancer (BCLC) staging system, transarterial chemoembolization (TACE) is considered a recommended option for intermediate HCC. OBJECTIVES: The purposes of our study were to evaluate the various factors affecting the outcome of TACE, to study the efficacy of TACE by evaluating the imaging response by European Association for the Study of the Liver (EASL) necrosis criteria, and to study the survival of patients. METHODS: Fifty-three patients (M = 48, F = 5) with unresectable HCC and treated with TACE were included in our study. Baseline laboratory and imaging characteristics were obtained. Clinical and laboratory toxicities were assessed. EASL necrosis response criteria were used to determine imaging response. Survival from the time of the first chemoembolization treatment was calculated. Univariate, multivariate, and survival analyses were performed using Kaplan-Meier estimations. RESULTS: A total of 53 patients underwent chemoembolization. Median age was 63 years (range 21-81 years). Thirty-one patients (58.4 %) belonged to Child-Pugh class A, while 22 patients belonged to Child-Pugh class B. Thirty-five patients died during the study period. Median study period was 13 months. Overall survival rate at 1 year was 62.26 %. Prognostic factors found to be significant on multivariate analysis were Child-Pugh class, presence of metastasis, and initial tumor size, while on univariate analysis, portal vein thrombosis, EASL response, and baseline AFP levels were also significant. CONCLUSION: Chemoembolization was an effective and safe treatment in Child A and early Child B patients. Factors that had adverse effect on survival were Child class B, larger tumor size, presence of portal vein thrombosis and metastasis, and high baseline alpha-fetoprotein levels. PMID- 25937485 TI - Cholestatic liver disease masquerading as Wilson disease. AB - Wilson disease and cholestatic liver diseases may present as a diagnostic dilemma if standard guidelines incorporating markers of copper overload are followed. We hereby present a series of four cases of sclerosing cholangitis masquerading as Wilson disease. True Wilson disease cases had significantly lower ceruloplasmin (6 vs. 16 mg/dL) and higher 24-hour urinary copper (322.3 vs. 74.5 MUg/day) as compared to mimickers. Initial low serum ceruloplasmin levels normalized in mimickers on follow up, and this may used as a diagnostic indicator. Standard Wilson disease diagnostic criteria thus need further modification especially in developing countries to help avoid mismanagement. PMID- 25937486 TI - Propylthiouracil induced ANCA-associated vasculitis in a 14-year-old girl. AB - BACKGROUND: Antineutrophil cytoplasmic antibodies (ANCAs) are the serologic hallmark of ANCA-associated primary small-vessel vasculitides (AAVs), but these antibodies have also been described in other autoimmune diseases such as inflammatory bowel diseases. Furthermore, different drugs are linked to the induction of ANCA, including propylthiouracil (PTU). However progression into clinical overt vasculitis is less common. CASE-DIAGNOSIS/TREATMENT: We describe the case of a young girl with Graves' disease presenting with fatigue, fever, episcleritis and arthritis. The unexpected double myeloperoxidase/proteinase 3 ANCA positivity triggered a multidisciplinary diagnostic work-up and resulted in the diagnosis of a clinically overt PTU-induced AAV. After PTU-withdrawal and treatment with high-dose corticosteroids, a favorable clinical and biochemical evolution was obtained. CONCLUSIONS: The use of PTU in the management of hyperthyroidism is not considered first-line treatment in Europe and is even less commonly used in children. Nevertheless, pediatricians should be aware of the possibility of PTU-induced AAV, especially in the presence of multiple ANCA reactivities. Therefore, the use of this drug should be weighed carefully in children. PMID- 25937487 TI - A First Description of Prune Belly Syndrome in Central Africa. PMID- 25937488 TI - The Pediatric Imaging, Neurocognition, and Genetics (PING) Data Repository. AB - The main objective of the multi-site Pediatric Imaging, Neurocognition, and Genetics (PING) study was to create a large repository of standardized measurements of behavioral and imaging phenotypes accompanied by whole genome genotyping acquired from typically-developing children varying widely in age (3 to 20 years). This cross-sectional study produced sharable data from 1493 children, and these data have been described in several publications focusing on brain and cognitive development. Researchers may gain access to these data by applying for an account on the PING portal and filing a data use agreement. Here we describe the recruiting and screening of the children and give a brief overview of the assessments performed, the imaging methods applied, the genetic data produced, and the numbers of cases for whom different data types are available. We also cite sources of more detailed information about the methods and data. Finally we describe the procedures for accessing the data and for using the PING data exploration portal. PMID- 25937489 TI - Expectation modulates neural representations of valence throughout the human brain. AB - The brain's sensitivity to unexpected gains or losses plays an important role in our ability to learn new behaviors (Rescorla and Wagner, 1972; Sutton and Barto, 1990). Recent work suggests that gains and losses are ubiquitously encoded throughout the human brain (Vickery et al., 2011), however, the extent to which reward expectation modulates these valence representations is not known. To address this question, we analyzed recordings from 4306 intracranially implanted electrodes in 39 neurosurgical patients as they performed a two-alternative probability learning task. Using high-frequency activity (HFA, 70-200 Hz) as an indicator of local firing rates, we found that expectation modulated reward related neural activity in widespread brain regions, including regions that receive sparse inputs from midbrain dopaminergic neurons. The strength of unexpected gain signals predicted subjects' abilities to encode stimulus-reward associations. Thus, neural signals that are functionally related to learning are widely distributed throughout the human brain. PMID- 25937491 TI - The West Haven Yale Multidimensional Pain Inventory: Reliability and validity of the Turkish version in individuals with cancer. AB - PURPOSE: Pain is a complex, multidimensional and subjective phenomenon that is common in patients with cancer. The translation of existing pain measurement scales is considered important in producing internationally comparable measures for evidence based practice. In measuring the pain experience, the WHYMPI is a widely used instrument to measure assessment of clinical pain, and it has not been validated in Turkey. The present study aimed to assess the reliability and validity of the Turkish version of the West Haven Yale Multidimensional Pain Inventory (WHYMPI). METHOD: In this methodological study, the scale was translated into simplified Turkish by the cross-culture translation method, and 520 participants with cancer were assessed. The internal consistency, item analysis, and test-retest methods were used to determine the reliability of the Turkish WHYMPI. Content validity, criterion validity, convergent/divergent validity, and exploratory factor analysis were used to test the construct validity of the Turkish WHYMPI. RESULTS: Cronbach's alpha and item-total correlations results suggested that there was good internal reliability. The Cronbach's alpha for internal consistency of the pain experience, responses by significant others, and daily activities were 0.85, 0.60, and 0.83, respectively. The internal consistency coefficient for test-retest reliability of the pain experience, responses by significant others, and daily activities were acceptable: 0.82, 0.66, and 0.81, respectively. Factor loadings were significant, with standardised loadings ranging from 0.40 to 0.92. CONCLUSIONS: WHYMPI is reliable and valid instrument for the measurement of pain in patients with cancer in Turkey. Its use is recommended for clinical and research purposes. PMID- 25937490 TI - Functional organization of human subgenual cortical areas: Relationship between architectonical segregation and connectional heterogeneity. AB - Human subgenual anterior cingulate cortex (sACC) is involved in affective experiences and fear processing. Functional neuroimaging studies view it as a homogeneous cortical entity. However, sACC comprises several distinct cyto- and receptorarchitectonical areas: 25, s24, s32, and the ventral portion of area 33. Thus, we hypothesized that the areas may also be connectionally and functionally distinct. We performed structural post mortem and functional in vivo analyses. We computed probabilistic maps of each area based on cytoarchitectonical analysis of ten post mortem brains. Maps, publicly available via the JuBrain atlas and the Anatomy Toolbox, were used to define seed regions of task-dependent functional connectivity profiles and quantitative functional decoding. sACC areas presented distinct co-activation patterns within widespread networks encompassing cortical and subcortical regions. They shared common functional domains related to emotion, perception and cognition. A more specific analysis of these domains revealed an association of s24 with sadness, and of s32 with fear processing. Both areas were activated during taste evaluation, and co-activated with the amygdala, a key node of the affective network. s32 co-activated with areas of the executive control network, and was associated with tasks probing cognition in which stimuli did not have an emotional component. Area 33 was activated by painful stimuli, and co-activated with areas of the sensorimotor network. These results support the concept of a connectional and functional specificity of the cyto- and receptorarchitectonically defined areas within the sACC, which can no longer be seen as a structurally and functionally homogeneous brain region. PMID- 25937493 TI - Propagation of flexural waves in inhomogeneous plates exhibiting hysteretic nonlinearity: Nonlinear acoustic black holes. AB - Theory accounting for the influence of hysteretic nonlinearity of micro inhomogeneous material on flexural wave in the plates of continuously varying thickness is developed. For the wedges with thickness increasing as a power law of distance from its edge strong modifications of the wave dynamics with propagation distance are predicted. It is found that nonlinear absorption progressively disappearing with diminishing wave amplitude leads to complete attenuation of acoustic waves in most of the wedges exhibiting black hole phenomenon. It is also demonstrated that black holes exist beyond the geometrical acoustic approximation. Applications include nondestructive evaluation of micro inhomogeneous materials and vibrations damping. PMID- 25937494 TI - Growth and decline of shoreline industry in Sydney estuary (Australia) and influence on adjacent estuarine sediments. AB - Sydney estuary (Australia), like many urbanised waterways, is degraded due to an extended history of anthropogenic activity. Two major sources of contamination to this estuary are discharge by former shoreline industries and historic and contemporary catchment stormwater. The objectives of the present study were to document changes in shoreline land use from European settlement to the present day and determine the influence of this trend on the metal content of adjacent estuarine sediments. Temporal analysis of land use for seven time horizons between 1788 and 2010 showed rapid expansion of industry along much of the Sydney estuary foreshore soon after European settlement due to the benefits of easy and inexpensive access and readily available water for cooling and power. Shoreline industry attained maximum development in 1978 (32-km length) and declined rapidly to the present-day (9-km length) through redevelopment of industrial sites into medium- to high-density, high-value residential housing. Cores taken adjacent to 11 long-term industrial sites showed that past industrial practices contributed significantly to contamination of estuarine sediment. Subsurface metal concentrations were up to 35 times that of present-day surface sediment and over 100 times greater than natural background concentrations. Sedimentation rates for areas adjacent to shoreline industry were between 0.6 and 2.5 cm/year, and relaxation times were estimated at 50 to 100 years. Natural relaxation and non disturbance of sediments may be the best management practice in most locations. PMID- 25937492 TI - Transgenerational inheritance of metabolic disease. AB - Metabolic disease encompasses several disorders including obesity, type 2 diabetes, and dyslipidemia. Recently, the incidence of metabolic disease has drastically increased, driven primarily by a worldwide obesity epidemic. Transgenerational inheritance remains controversial, but has been proposed to contribute to human metabolic disease risk based on a growing number of proof-of principle studies in model organisms ranging from Caenorhabditis elegans to Mus musculus to Sus scrofa. Collectively, these studies demonstrate that heritable risk is epigenetically transmitted from parent to offspring over multiple generations in the absence of a continued exposure to the triggering stimuli. A diverse assortment of initial triggers can induce transgenerational inheritance including high-fat or high-sugar diets, low-protein diets, various toxins, and ancestral genetic variants. Although the mechanistic basis underlying the transgenerational inheritance of disease risk remains largely unknown, putative molecules mediating transmission include small RNAs, histone modifications, and DNA methylation. Due to the considerable impact of metabolic disease on human health, it is critical to better understand the role of transgenerational inheritance of metabolic disease risk to open new avenues for therapeutic intervention and improve upon the current methods for clinical diagnoses and treatment. PMID- 25937495 TI - The influence of water quality variables on cyanobacterial blooms and phytoplankton community composition in a shallow temperate lake. AB - Cyanobacterial blooms and their detrimental effects on water quality have become a worldwide problem. Vancouver Lake, a tidally influenced shallow temperate freshwater lake in Washington state, U.S.A., exhibits annual summer cyanobacterial blooms that are of concern to local resource managers. Our objectives were to describe changes in phytoplankton community composition in Vancouver Lake over seasonal, annual, and interannual time scales, and to identify strong water quality predictors of phytoplankton community structure, with an emphasis on cyanobacterial blooms, from 2007 through 2010. Cluster analysis, indicator species analysis, and non-metric multidimensional scaling were used to identify significantly different phytoplankton community groupings and to determine which environmental factors influenced community changes. From 2007 through 2009, depletion of NO3-N followed by elevated PO4-P concentration was associated with increased biomass and duration of each cyanobacterial bloom. Time-lag analysis suggested that NO3-N availability contributed to interannual changes within the summer phytoplankton community. Specifically, in summer 2010, a distinct cyanobacteria community was not present, potentially due to increased NO3-N and decreased PO4-P and NH4-N availability. Our study provides a comprehensive assessment of species-level responses to water quality variables in a shallow non-stratifying temperate lake, contributes to a better understanding of phytoplankton dynamics, and may aid in predicting and managing cyanobacterial blooms. PMID- 25937496 TI - Screening of multiple hormonal activities in water and sediment from the river Nile, Egypt, using in vitro bioassay and gonadal histology. AB - In Egypt, until yet no records are available regarding possible multiple hormonal activities in the aquatic systems and especially in the river Nile. In this paper, in vitro yeast estrogen screen (YES) and yeast androgen screen (YAS) were used to assess (for the first time) the multiple hormonal activities in surface waters and sediments of the river Nile. This study aimed to determine whether river Nile water can cause changes in gonadal histology of Nile tilapia (Oreochromis niloticus niloticus). All water samples exhibited extremely low levels of estrogenicity. Estrogenicity was nearly not detected in any of the sediment samples. Unlike the estrogenicity, significant androgenic activities were recorded in the water and sediment samples along the course of the river Nile. The present study reports for the first time quantification anti-estrogenic and anti-androgenic activities with high levels in both water and sediment of the river Nile. The greatest anti-estrogenic and anti-androgenic activities were observed in samples from downstream river Nile. These results indicated that the anti-estrogenic and anti-androgenic activities along the Nile course were great and the pollution of the sites at downstream was more serious than the upstream sites due to industrial and anthropogenic activities at these sites. Good correlations were observed among some hormonal activities, suggesting coexistence of these contaminants in the environmental matrices. There were no signs of sexual disruption in any of the gonads analyzed from either male or female Nile tilapia, demonstrating that no hormonal activity present along the Nile course was sufficient to induce adverse effects on reproductive development. Further investigation is necessary to identify the compounds responsible for the hormonal activities in the river Nile and to examine effects of very low levels of hormonally active compounds on gonadal histology, as well as in the development of more sensitive biomarkers. PMID- 25937497 TI - Monitoring and assessment of environmental disturbance on natural Gambusia affinis populations--histopathological analysis. AB - Physiological investigations are often used to assess the toxic effects of aquatic pollutants in fish and to establish criteria for water quality. In the present study, we tend to investigate the growth performance, skeletal abnormalities, and histological alterations noticed in three natural populations of the mosquitofish Gambusia affinis captured from three estuary sites. The analysis of growth performance demonstrated that the studied populations showed different growth patterns. Additionally, various types of skeletal deformities were observed, and the most commonly affected were the hemal and pre-hemal regions of fishes. For the histological study, gills, liver, and kidney tissues were selected for field monitoring. The major alterations observed in gill tissues were partial fusion of adjacent secondary lamellae, hypertrophy of epithelial cells, and disorganization of pillar cells in many areas of the secondary lamellae. In the liver, significant desquamation of tissues, congestion of the central hepatic vein, and hypertrophy of hepatocytes were noticed. For the kidney tissue, the frequencies of histological alterations showed a significant difference between the studied sites. Moreover, the histological aberrations consisted mainly in glomerule alteration and vacuolation of tubular epithelial cells. Taken together, these data support the hypothesis that the physiological alterations noticed in the present investigation are indicators of sensitivity towards environmental disturbance. PMID- 25937498 TI - Paddy crop yield estimation in Kashmir Himalayan rice bowl using remote sensing and simulation model. AB - The Kashmir Himalayan region of India is expected to be highly prone to the change in agricultural land use because of its geo-ecological fragility, strategic location vis-a-vis the Himalayan landscape, its trans-boundary river basins, and inherent socio-economic instabilities. Food security and sustainability of the region are thus greatly challenged by these impacts. The effect of future climate change, increased competition for land and water, labor from non-agricultural sectors, and increasing population adds to this complex problem. In current study, paddy rice yield at regional level was estimated using GIS-based environment policy integrated climate (GEPIC) model. The general approach of current study involved combining regional level crop database, regional soil data base, farm management data, and climatic data outputs with GEPIC model. The simulated yield showed that estimated production to be 4305.55 kg/ha (43.05 q h(-1)). The crop varieties like Jhelum, K-39, Chenab, China 1039, China-1007, and Shalimar rice-1 grown in plains recorded average yield of 4783.3 kg/ha (47.83 q ha(-1)). Meanwhile, high altitude areas with varieties like Kohsaar, K-78 (Barkat), and K-332 recorded yield of 4102.2 kg/ha (41.02 q ha( 1)). The observed and simulated yield showed a good match with R (2) = 0.95, RMSE = 132.24 kg/ha, respectively. PMID- 25937499 TI - Anti-TMV activity flavones from the leaves of Yunnan local air cured tobacco. AB - Four new flavones, tobaflavones E-H (1-4), together with two known flavones (5 and 6), were isolated from the leaves of Dali Tiandeng tobacco (a variety of Yunnan local air cured tobacco). Their structures were elucidated by spectroscopic methods, including extensive 1D- and 2D NMR techniques. Compound 2 is the first naturally occurring flavone bearing a (4-hydroxy-6-methyl-2-oxo-2H pyran-3-yl)methyl moiety. These compounds were also evaluated for their anti tobacco mosaic virus (anti-TMV) activity. The results revealed that compounds 1 and 2 exhibited high anti-TMV activity with inhibition rate of 35.3% and 39.6%, respectively. The rates are higher than those of positive control. The other compounds also showed potential anti-TMV activity with inhibition rates in the range of 18.7-28.4%, respectively. PMID- 25937500 TI - Five new cycloartane triterpenoids from Beesia calthifolia. AB - Phytochemical study on rhizomes of Beesia calthifolia resulted in the isolation of five new (1-5) and three known (6-8) cycloartane triterpenoids possessing a hemiketal or ketal group at C-24 from the EtOAc fraction of 95% ethanol extract. Their structures were determined by spectroscopic and chemical methods, especially HRMS and 2D NMR techniques. Compounds 3 and 4 showed potential hepatoprotective activities against D-galactosamine induced human hepatic L02 cell damage. PMID- 25937501 TI - Is Campylobacter to esophageal adenocarcinoma as Helicobacter is to gastric adenocarcinoma? AB - Esophageal adenocarcinoma develops through a cascade of cellular changes that shares similarities to the etiology of Helicobacter pylori-associated intestinal type gastric adenocarcinoma. While host genetics and immune response have been implicated in the progression to esophageal adenocarcinoma, studies investigating esophageal microbial communities suggest that bacteria may also play an important role in driving the inflammation that leads to disease. Of these, emerging Campylobacter species have been found to be more prevalent and abundant in patients progressing through the esophageal adenocarcinoma cascade compared to controls. Given that these bacteria possess several virulence mechanisms such as toxin production, cellular invasion, and intracellular survival, emerging Campylobacter species should be investigated as etiological agents of the chronic esophageal inflammation that leads to cancer. PMID- 25937502 TI - The effects of n-acetylcysteine and/or deferoxamine on manic-like behavior and brain oxidative damage in mice submitted to the paradoxal sleep deprivation model of mania. AB - Bipolar disorder (BD) is a severe psychiatric disorder associated with social and functional impairment. Some studies have strongly suggested the involvement of oxidative stress in the pathophysiology of BD. Paradoxal sleep deprivation (PSD) in mice has been considered a good animal model of mania because it induces similar manic-like behavior, as well as producing the neurochemical alterations which have been observed in bipolar patients. Thus, the objective of the present study was to evaluate the effects of the antioxidant agent's n-acetylcysteine (Nac) and/or deferoxamine (DFX) on behavior and the oxidative stress parameters in the brains of mice submitted to the animal model of mania induced by PSD. The mice were treated for a period of seven days with saline solution (SAL), Nac, DFX or Nac plus DFX. The animals were subject to the PSD protocol for 36 h. Locomotor activity was then evaluated using the open-field test, and the oxidative stress parameters were subsequently evaluated in the hippocampus and frontal cortex of mice. The results showed PSD induced hyperactivity in mice, which is considered a manic-like behavior. In addition to this, PSD increased lipid peroxidation and oxidative damage to proteins, as well as causing alterations to antioxidant enzymes in the frontal cortex and hippocampus of mice. The Nac plus DFX adjunctive treatment prevented both the manic-like behavior and oxidative damage induced by PSD. Improving our understanding relating to oxidative damage in biomolecules, and the antioxidant mechanisms presented in the animal models of mania are important in helping to improve our knowledge concerning the pathophysiology and development of new therapeutical treatments for BD. PMID- 25937503 TI - Reduced paralimbic system gray matter volume in schizophrenia: Correlations with clinical variables, symptomatology and cognitive function. AB - BACKGROUND: Psychopathy is associated with dysfunction in regions that compose the paralimbic system, such as the orbitofrontal cortex (OFC), insular cortex (IC), temporal pole (TP), parahippocampal gyrus (PHG) and cingulate cortex (CC). However, findings of structural alterations in these regions are inconsistent in schizophrenia, and correlations between paralimbic system measures and symptomatology and cognitive function have not been investigated. METHOD: 93 patients with schizophrenia and 99 healthy controls received structural magnetic resonance imaging and clinical and cognitive assessment. We compared gray matter volume (GMV) between the two groups using voxel-based morphometry, and evaluated correlations between abnormal GMVs and clinical variables, symptomatology and cognitive function. The assessment of cognition included measures of processing speed, verbal fluency and memory. RESULTS: Patients with schizophrenia demonstrated significant GMV decreases in the paralimbic system, including bilateral OFC, IC and TP (p < 0.05, FWE corrected). GMV decreases were also observed in bilateral superior temporal gyri (STG). The GMVs in bilateral OFC, left IC, left TP and bilateral STG were positively correlated with processing speed, and the GMVs in bilateral OFC were positively correlated with memory function in all participants. In our patient group, the GMV deficits were also associated with earlier age of onset, longer duration of illness, greater number of hospitalizations and more severe positive symptoms. CONCLUSIONS: GMVs in the paralimbic system were significantly reduced in schizophrenia, and these abnormalities were correlated with clinical variables, symptomatology and cognitive function. These results suggest the paralimbic system plays an important role in the pathophysiology of schizophrenia. PMID- 25937504 TI - Predictors of switch from depression to mania in bipolar disorder. AB - Manic switch is a relevant issue when treating bipolar depression. Some risk factors have been suggested, but unequivocal findings are lacking. We therefore investigated predictors of switch from depression to mania in the Systematic Treatment Enhancement Program for Bipolar Disorder (STEP-BD) sample. Manic switch was defined as a depressive episode followed by a (hypo)manic or mixed episode within the following 12 weeks. We assessed possible predictors of switch using generalized linear mixed models (GLMM). 8403 episodes without switch and 512 episodes with switch (1720 subjects) were included in the analysis. Several baseline variables were associated with a higher risk of switch. They were younger age, previous history of: rapid cycling, severe manic symptoms, suicide attempts, amphetamine use and some pharmacological and psychotherapeutic treatments. During the current depressive episode, the identified risk factors were: any possible mood elevation, multiple mania-associated symptoms with at least moderate severity, and comorbid panic attacks. In conclusion, our study suggests that both characteristics of the disease history and clinical features of the current depressive episode may be risk factors for manic switch. PMID- 25937505 TI - Using patient engagement in the design and rationale of a trial for women with depression in obstetrics and gynecology practices. AB - INTRODUCTION: Significant health disparities exist among socioeconomically disadvantaged women, who experience elevated rates of depression and increased risk for poor depression treatment engagement and outcomes. We aimed to use stakeholder input to develop innovative methods for a comparative effectiveness trial to address the needs of socioeconomically disadvantaged women with depression in women's health practices. METHODS: Using a community advisory board, focus groups, and individual patient input, we determined the feasibility and acceptability of an electronic psychosocial screening and referral tool; developed and finalized a prioritization tool for women with depression; and piloted the prioritization tool. Two intervention approaches, enhanced screening and referral using an electronic psychosocial screening, and mentoring using the prioritization tool, were developed as intervention options for socioeconomically disadvantaged women attending women's health practices. We describe the developmental steps and the final design for the comparative effectiveness trial evaluating both intervention approaches. CONCLUSIONS: Stakeholder input allowed us to develop an acceptable clinical trial of two patient-centered interventions with patient-driven outcomes. PMID- 25937507 TI - I wish my mother had had me when she was younger! PMID- 25937506 TI - College students as facilitators in reducing adolescent obesity disparity in Southern Appalachia: Team Up for Healthy Living. AB - The proportion of obese adolescents in Southern Appalachia is among the highest in the nation. Through funding from the National Institute on Minority Health and Health Disparities--National Institutes of Health, the Team Up for Healthy Living project was a cluster-randomized trial targeting obesity prevention in adolescents through a cross-peer intervention. The specific aims of the project were to: 1) develop a peer-based health education program focusing on establishing positive peer norms towards healthy eating and physical activity (PA) among high school students, 2) test program efficacy, and 3) explore mechanisms underlying the program. The study was guided by the Theory of Planned Behavior, which presupposes that human behavior is primarily driven by attitude, subjective norms, perceived behavioral control, and social support. To deliver the intervention, undergraduate students from the disciplines of public health, nutrition, and kinesiology were hired as peer facilitators. Ten area high schools were invited to participate, were matched on demographics and then randomized to intervention or control. The primary outcomes of the study included body mass status, dietary behaviors, PA, and sedentary behaviors which were assessed at baseline and at three and twelve months post baseline. Intervention schools received Team Up for Healthy Living curriculum, which consists of eight 40-minute sessions. The curriculum focused on improving nutrition awareness, PA, leadership and communication. Control schools received their regularly scheduled Lifetime Wellness curriculum. The long-term goal of the study was to establish an effective academia-community partnership program to address adolescent obesity disparity in Southern Appalachia. PMID- 25937508 TI - Response to Correspondence by de Borst re: 'The True Risk of Early Recurrent Stroke: Importance of Cohort Composition and Index Event Definition'. PMID- 25937509 TI - Ultrasound assisted combustion synthesis of TiC in Al-Ti-C system. AB - This research investigated the effects of high-intensity ultrasound on the combustion synthesis of TiC particles in Al-Ti-C system. The process involved that high-intensity ultrasound was applied on the surface of a compacted Al-Ti-C pellet directly through a Nb probe during the thermal explosion reaction. By comparing with the sample without ultrasonic treatment, it was found that the thermal explosion reaction for synthesizing TiC phase could take place thoroughly in the ultrasonically treated sample. During the process of synthesizing TiC phase, the dissolution of solid graphite particles into the Al-Ti melt, as well as the nucleation and growth of TiC particles could be promoted effectively due to the effects of ultrasound, leading to an enhancement of the formation of TiC particles. Ultrasound assisted combustion synthesis as a simple and effective approach was proposed for synthesizing materials in this research. PMID- 25937510 TI - Higher proportion of total and fat energy intake during the morning may reduce absolute intake of energy within the day. An observational study in free-living Japanese adults. AB - BACKGROUND: Although the distribution of energy intake throughout the day appears to impact overall daily energy intake, little is known about the ad libitum distribution of energy intake. OBJECTIVE: Our aim was to investigate associations between the distribution of energy intake during the day and subsequent or overall energy intake, and food choice in free-living adults. DESIGN: A total of 119 women and 116 men completed 16-day semi-weighed dietary records. The longitudinal dietary intake data for each participant were analyzed using a mixed model to examine the effect of energy intake at various times of day on subsequent or overall energy intake. RESULTS: Mean proportion of total energy intake in the morning (4:00 a.m.-10:29 a.m.), afternoon (10:30 a.m.-4:59 p.m.) and evening (5:00 p.m.-3:59 a.m.) meal was 22.6%, 33.8% and 43.6% in men, and 24.7%, 36.5%, 38.8% in women, respectively. Proportion of energy intake (%) in the morning meal was significantly and negatively associated with energy intake (kcal) in the subsequent afternoon and evening meals, and consequently in the whole day in both sexes. This significant and negative association was also observed for proportion of energy intake (%) of fat, but not of carbohydrate or protein, in both sexes. Proportion of energy intake (%) in the morning meal was negatively associated with overall energy intake (kcal) from the group of meats, fish, and eggs in both sexes, and from the group of confectioneries and soft drinks in women. CONCLUSIONS: More energy in the morning meal may reduce energy intake, especially that from fat, in the subsequent meals, and consequently in the whole day. PMID- 25937511 TI - Evaluation of the impact of school gardening interventions on children's knowledge of and attitudes towards fruit and vegetables. A cluster randomised controlled trial. AB - Involvement of children in gardening has the potential to increase liking of fruit and vegetables (FV) and consequently, intake, but research results are mixed. School gardening led by external specialists such as the Royal Horticultural Society (RHS) could have more impact than teacher-led gardening on children's knowledge of, and attitudes towards, FV. Data from a cluster randomised controlled trial were used to compare a RHS-led school gardening intervention with a teacher-led gardening intervention amongst 7-10 year olds in 21 London schools. A short questionnaire was developed and used to identify children's knowledge and attitudes towards FV consumption before the garden intervention and 18 months afterwards. Results from multilevel regression models, both unadjusted and adjusted for baseline responses and socio-demographic factors, were reported. Attitudes to FV intake were compared between groups. Change in FV knowledge was used to predict change in FV consumption assessed using 24-hour food diaries. In comparison with the RHS-led group (n = 373), teacher-led children (n = 404) were more likely to agree they ate lots of fruit (p < 0.009) and tried new fruits (p = 0.045), but RHS-led gardening was associated with a greater increase in the total number of vegetables recognised (p = 0.031). No other differences in improvements in attitudes, or associations between change in FV recognition and intake were found. In relation to improvements in children's recognition and attitudes towards eating FV, this trial produced limited evidence that gardening activity packages led by external specialists (RHS-led) provide additional benefits over those led by teachers trained by the RHS. Indeed, the latter were potentially more effective. PMID- 25937512 TI - Apples or candy? Internal and external influences on children's food choices. AB - The goal of this concise narrative review is to examine the current literature regarding endogenous and exogenous influences on youth food choices. Specifically, we discuss internal factors such as interoception (self-awareness) of pain and hunger, and neural mechanisms (neurofunctional aspects) of food motivation. We also explore external factors such as early life feeding experiences (including parenting), social influences (peers), and food marketing (advertising). We conclude with a discussion of the overlap of these realms and future directions for the field of pediatric food decision science. PMID- 25937513 TI - CD44S-hyaluronan interactions protect cells resulting from EMT against anoikis. AB - The detachment of normal epithelial cells from matrix triggers an apoptotic response known as anoikis, during homeostatic turnover. Metastatic tumor cells evade anoikis, by mechanisms that are only partly characterized. In particular, the epithelial-mesenchymal transition (EMT) in a subset of invasive tumor cells confers anoikis-resistance. In some cases, EMT up-regulates the cancer stem cell marker CD44S and the enzyme hyaluronic acid synthase-2 (HAS2). CD44S is the major receptor for hyaluronan in the extracellular matrix. Herein, we demonstrate that CD44S, unlike the CD44E isoform expressed in normal epithelial cells, contributes to the protection against anoikis. This protection requires the interaction of CD44S with hyaluronan (HA). CD44S-HA interaction is proposed to play an important role in tumor metastasis through enhanced cell survival under detached conditions. PMID- 25937514 TI - Translational research will fail without surgical leadership: SCOTRRCC a successful surgeon-led Nationwide translational research infrastructure in renal cancer. AB - BACKGROUND: High quality human biosamples with associated high quality clinical data are essential for successful translational research. Despite this, the traditional approach is for the surgeon to act as a technician in the tissue collection act. Biomarker research presents multiple challenges and the field is littered with failures. Tissue quality, poor clinical information, small sample numbers and lack of validation cohorts are just a few reasons for failure. It is clear that the surgeon involved in tissue acquisition must be fully engaged in the process of biosampling for a specific condition, as this will negate many of the issues for translational research failure due to an inadequate bioresource. APPROACH: In this Matter for Debate paper, the Scottish Collaboration On Translational Research into Renal Cell Cancer (SCOTRRCC) is discussed as an example of a urological surgery lead bioresource which has resulted in a National collection of renal cancer tissue and blood (from over 900 patients to date), negating all of the traditional issues with biobanks because of close enagagement and acknowledgement of urologists and uropathologists from seven centres around Scotland. SCOTRRCC has leveraged renal cancer research in Scotland resulting in several high impact publications and providing a springboard for future research in this disease in Scotland and beyond. CONCLUSIONS: The SCOTRRCC model presented here can be transferred to other surgical disciplines for success in translational research. PMID- 25937515 TI - Professionalism and Communication Education in Pediatric Critical Care Medicine: The Learner Perspective. AB - OBJECTIVE: Communication and professionalism are often challenging to teach, and the impact of the use of a given approach is not known. We undertook this investigation to establish pediatric critical care medicine (PCCM) trainee perception of education in professionalism and communication and to compare their responses from those obtained from PCCM fellowship program directors. METHODS: The Education in Pediatric Intensive Care (E.P.I.C.) Investigators used the modified Delphi technique to develop a survey examining teaching of professionalism and communication. After piloting, the survey was sent to all 283 PCCM fellows in training in the United States. RESULTS: Survey response rate was 47% (133 of 283). Despite high rates of teaching overall, deficiencies were noted in all areas of communication and professionalism assessed. The largest areas of deficiency included not being specifically taught how to communicate: as a member of a nonclinical group (reported in 24%), across a broad range of socioeconomic and cultural backgrounds (19%) or how to provide consultation outside of the intensive care unit (17%). Only 50% of fellows rated education in communication as "very good/excellent." However, most felt confident in their communication abilities. For professionalism, fellows reported not being taught accountability (12%), how to conduct a peer review (12%), and how to handle potential conflict between personal beliefs, circumstances, and professional values (10%). Fifty seven percent of fellows felt that their professionalism education was "very good/excellent," but nearly all expressed confidence in these skills. Compared with program directors, fellows reported more deficiencies in both communication and professionalism. CONCLUSIONS: There are numerous components of communication and professionalism that PCCM fellows perceive as not being specifically taught. Despite these deficiencies, fellow confidence remains high. Substantial opportunities exist to improve teaching in these areas. PMID- 25937516 TI - Active and Healthy Families: A Randomized Controlled Trial of a Culturally Tailored Obesity Intervention for Latino Children. AB - OBJECTIVE: There is a critical need for culturally relevant interventions to address obesity among Latino children, who have a greater risk of obesity and diabetes than non-Hispanic white children. To test the impact of a family centered, culturally tailored obesity intervention delivered through group medical appointments on body mass index (BMI) and other measures of cardiovascular risk among Latino children. METHODS: In a randomized controlled trial, 55 parent-child dyads were assigned to Active and Healthy Families (AHF) or a usual care wait-list control condition. Dyads were eligible if they spoke Spanish and if the child received care in a federally qualified health center, was aged 5 to 12 years, had a BMI in the 85th percentile or higher, and had not participated in AHF. The 10-week AHF intervention included biweekly group sessions delivered by a registered dietitian, physician, and promotora triad. Sessions covered topics such as parenting, screen time, healthy beverages, physical activity, and stress due to immigration. RESULTS: Child BMI (kg/m(2)) decreased (-0.50) in the AHF group and increased (+0.32) in the control group, yielding an adjusted difference in change of -0.78 (95% confidence interval [CI] 1.28, -0.27). Children assigned to AHF also exhibited relative improvements over controls in BMI z score (-0.10; 95% CI -0.19, -0.02) and triglycerides (-26.8 mg/dL; 95% CI -50.1, -3.6), but no significant between-group differences were observed for blood pressure or other fasting blood measures. CONCLUSIONS: AHF resulted in reductions in child BMI, BMI z score, and triglycerides. AHF, which was designed for low-income Latino families, has potential to reduce health disparities, but future studies are needed to determine long-term impact. PMID- 25937518 TI - Statistical correlates of perceived gloss in natural images. AB - It is currently debated whether the perception of gloss is linked to the statistical parameters of the retinal image. In particular, it has been suggested that gloss is highly correlated with the skewness of the luminance histogram. However, other psychophysical work with artificial stimuli has shown that skewness alone is not enough to induce the perception of gloss. Here, we analyzed many images of natural surfaces to search for potential statistical correlates of perceived gloss. We found that skewness indeed correlates with gloss when using rendered stimuli, but that the standard deviation, a measure of contrast, correlates better with perceived gloss when using photographs of natural surfaces. We verified the important role of contrast by manipulating skewness and contrast within images. Changing the contrast in images significantly modulates perceived gloss, but manipulating the skewness of the luminance histogram had only a small effect. PMID- 25937517 TI - History and current status of newborn screening for severe combined immunodeficiency. AB - The development of a T-cell receptor excision circle (TREC) assay utilizing dried blood spots in universal newborn screening has allowed the early detection of T cell lymphopenia in newborns. Diagnosis of severe combined immunodeficiency (SCID) in affected infants in the neonatal period, while asymptomatic, permits early treatment and restoration of a functional immune system. SCID was the first immunodeficiency disease to be added to the Recommended Uniform Screening Panel of Core Conditions in the United States in 2010, and it is now implemented in 26 states in the U.S. This review covers the development of newborn screening for SCID, the biology of the TREC test, its current implementation in the U.S., new findings for SCID in the newborn screening era, and future directions. PMID- 25937519 TI - RSV P-protein impairs extrinsic apoptosis pathway in a macrophage-like cell line persistently infected with respiratory syncytial virus. AB - Disabling apoptosis is practically a mandatory step for establishing and maintaining viral persistence in host cells. Thus, persisting viruses have evolved strategies to impair apoptosis mechanisms. Apoptosis can be induced through either the intrinsic or the extrinsic pathway. Previously, we reported that staurosporine-induced intrinsic apoptotic pathway was down-regulated in a macrophage cell line persistently infected with respiratory syncytial virus (RSV, MPhiP). In the present study, our results showed that the extrinsic apoptotic pathway was also impaired in this cell line and that RSV P-protein interfered with the onset of the extrinsic apoptotic process. In this work, we analyzed and compared the expression of several components of the DISC complex (i.e., TNF alpha, TNFR1, caspase-8, and cIAP2) in MPhiP cells with that in mock-infected macrophages. Additionally, by using DNA sequence analysis in silico, we searched for an RSV protein putatively interfering with the triggering of the extrinsic apoptotic process. The analysis showed that viral P-protein shared a 52% homology with the caspase-8 death domain. Subsequently, the nucleic acid sequence of the viral P-protein was cloned and transfected into the macrophage cell line; the effect of this transfection on staurosporine-induced apoptosis was evaluated by assaying for cell viability and caspases-8 and -9 activity. The results revealed that although caspase-9 was activated, the activity of the caspase-8 was impaired in the RSV P-protein transfected cells; more of these cells survived than did mock-transfected cells. These findings suggest that P-protein impaired the extrinsic pathway of apoptosis. Our findings contribute to the understanding of the mechanism by which viral proteins subvert the extrinsic apoptosis process in cells persistently infected with RSV. PMID- 25937520 TI - Incidental pathologic extracardiac uptake of (99m)Tc-tetrofosmin in myocardial perfusion imaging: Importance of patient background evaluation. AB - (99m)Tc-tetrofosmin single photon emission computed tomography ((99m)Tc tetrofosmin SPECT) has an important role in the assessment of coronary artery disease. Despite being its main indication, this study does not only evaluate myocardial perfusion, but much more. Moreover, during the SPECT acquisition, the field area covered includes many important organs of the thorax and abdomen, so extracardiac abnormalities can be observed. The correct etiologic diagnosis of them is only possible if we understand how (99m)Tc-tetrofosmin works and make a comprehensive investigation of the clinical history of the patient. PMID- 25937521 TI - Ultrasound-Guided Perineural Injection at Guyon's Tunnel: An Anatomic Feasibility Study. AB - Compression of the ulnar nerve (UN) at the wrist causes neuropathy in the ulnar tunnel (UT), or Guyon's tunnel. In the absence of trauma and motor syndromes, primarily conservative treatment is considered. As in carpal tunnel syndrome, a perineural injection of corticosteroids may be beneficial. The aim of this study was to investigate the feasibility of ultrasound-guided injections at the UT. We performed ultrasound-guided injections of ink at the UN within the UT in 21 limbs from 11 non-embalmed cadavers. In all cases, we stained the perineural sheath of the superficial branch of the ulnar nerve within the UT. No ink was found inside the nerve or in adjacent structures such as blood vessels and tendons. In conclusion, perineural injection of the UN in the UT seems to be a technically feasible procedure. On the basis of these anatomic data, clinical trials are needed to prove the concept for routine use. PMID- 25937522 TI - FOLFOX4 plus cetuximab treatment and RAS mutations in colorectal cancer. AB - BACKGROUND: The OPUS study demonstrated that addition of cetuximab to 5 fluorouracil, folinic acid and oxaliplatin (FOLFOX4) significantly improved objective response and progression-free survival (PFS) in the first-line treatment of patients with KRAS exon 2 wild-type metastatic colorectal cancer (mCRC). In patients with KRAS exon 2 mutations, a detrimental effect was seen upon addition of cetuximab to FOLFOX4. The current study reports outcomes in subgroups defined by extended RAS testing. PATIENTS AND METHODS: Samples from OPUS study KRAS exon 2 wild-type tumours were reanalysed for other RAS mutations in four additional KRAS codons (exons 3-4) and six NRAS codons (exons 2-4) using BEAMing. A cutoff of ?5% mutant/wild-type sequences was selected to define RAS status; we also report an analysis using a cutoff based on the technical lower limit for mutation identification (0.1%). RESULTS: Other RAS mutations were detected in 31/118 (26%) evaluable patients. In the extended analysis of RAS wild type tumours (n=87), objective response was significantly improved by addition of cetuximab to FOLFOX4 (58% versus 29%; odds ratio 3.33 [95% confidence interval 1.36-8.17]; P=0.0084); although limited by population size, there also appeared to be trends favouring the cetuximab arm in terms of PFS and overall survival in the RAS wild-type group compared with the RAS evaluable group. There was no evidence that patients with other RAS mutations benefited from cetuximab, but small numbers precluded precise estimations of treatment effects. In the combined population of patients with any RAS mutation (KRAS exon 2 or other RAS), a clear detrimental effect was associated with addition of cetuximab to FOLFOX4. CONCLUSION: Patients with RAS-mutant mCRC, as defined by mutations in KRAS and NRAS exons 2-4, derive no benefit and may be harmed by the addition of cetuximab to FOLFOX4. Restricting cetuximab administration to patients with RAS wild-type tumours will further tailor therapy to maximise benefit. PMID- 25937523 TI - Roles of human UDP-glucuronosyltransferases in clearance and homeostasis of endogenous substrates, and functional implications. AB - Human UDP-glucuronosyltransferases (UGTs) are major phase II enzymes in the drug metabolism system. Despite major advances in characterization of UGT gene family members, their role in clearance and homeostasis of endogenous substrates is insufficiently understood. Endobiotic substrates including bilirubin, serotonin, eicosanoids, steroid hormones, bile acids, thyroxine and fat-soluble vitamins A and D are discussed. Species- and tissue/cell-dependent regulation of UGT expression by ligand-activated transcription factors is often involved in endobiotic homeostasis. However, roles of particular UGTs are often difficult to delineate since they function together with other enzymes and transporters. Better knowledge of endobiotic UGT substrates and consequences of their conjugation may help to understand evolutionary conserved UGT functions. PMID- 25937524 TI - Cancer immunotherapy and immune-related response assessment: The role of radiologists in the new arena of cancer treatment. AB - The recent advances in the clinical application of anti-cancer immunotherapeutic agents have opened a new arena for the treatment of advanced cancers. Cancer immunotherapy is associated with a variety of important radiographic features in the assessments of tumor response and immune-related adverse events, which calls for radiologists' awareness and in-depth knowledge on the topic. This article will provide the state-of-the art review and perspectives of cancer immunotherapy, including its molecular mechanisms, the strategies for immune related response assessment on imaging and their pitfalls, and the emerging knowledge of radiologic manifestations of immune-related adverse events. The cutting edge clinical and radiologic investigations are presented to provide future directions. PMID- 25937525 TI - Role of shear-wave elastography (SWE) in complex cystic and solid breast lesions in comparison with conventional ultrasound. AB - OBJECTIVE: To evaluate the additional role of shear-wave elastography (SWE) in differential diagnosis of complex cystic and solid breast lesions. MATERIALS AND METHODS: From January 2013 to November 2013, 140 complex cystic and solid breast lesions from 139 consecutive patients were performed ultrasound and SWE prior to biopsy. BI-RADS ultrasound final assessment and SWE parameters were recorded for each lesion. Histopathologic diagnosis was used as the reference standard. RESULTS: Among the 140 lesions, 30 lesions (21.4%) were malignant. The mean maximum elasticity (Emax) of malignant lesions (184.3 kPa) was significantly higher than that of benign lesions (45.5 kPa) (P<0.001). Homogeneity of elasticity and color pattern were significantly different from malignancy and benign lesions (P<0.05). Emax with cutoff value at 108.5 kPa showed Az value of 0.968 (95% CI, 0.932-0.985) with sensitivity of 86.7% and specificity of 97.3%. Using this cutoff value, false-positive rate was 2.7% and false-negative rate was 13.3%. By applying an Emax value of 108.5 kPa or less as a criterion for downgrading BI-RADS category 4a lesions to category 3 lesions, 103/123 (83.7%) lesions could be downgraded to category 3 lesions. CONCLUSION: Additional use of SWE could reduce unnecessary benign biopsies in complex cystic and solid breast lesions. PMID- 25937526 TI - Re: Emotions, immunity and sport: Winner and loser athlete's profile of fighting sport. PMID- 25937527 TI - Thirteen-year nationwide trends in use of implantable cardioverter-defibrillators and subsequent long-term survival. AB - BACKGROUND: Long-term trends in use of implantable cardioverter-defibrillators (ICDs) and outcomes are rare. OBJECTIVE: We examined 13-year nationwide trends in ICD implantation and survival rates in Denmark. METHODS: Using medical databases, we identified all first time ICD recipients in Denmark during 2000-2012 (N = 8460) and ascertained all-cause mortality. We computed standardized annual implantation rates and mortality rate ratios according to age, sex, comorbidity level, indication, and device type. RESULTS: The standardized annual implantation rate increased from 42 per million persons in 2000 to 213 per million persons in 2012 (from 34 to 174 for men and from 8 to 39 for women). The increase was driven by secondary prophylactic ICDs until 2006 and primary prophylactic ICDs thereafter. The increase occurred particularly in older patients and those with a high level of comorbidity. Independent of indication, 76% of all patients with ICD were alive after 5 years. Men had a higher mortality rate compared with women (mortality rate ratio 1.28; 95% confidence interval 1.10-1.49). Compared with low comorbidity level, moderate, severe, and very severe comorbidity levels were associated with 1.6-, 2.5-, and 4.9-fold increased mortality rates, respectively. The most influential individual comorbidities were heart failure, diabetes, liver disease, and renal disease. CONCLUSION: The annual implantation rate of ICDs increased 5-fold in Denmark between 2000 and 2012. The rate increase occurred for both men and women, but particularly in the elderly and patients with severe comorbidity. Five-year survival probability was high, but severe comorbidity and male sex were associated with shorter survival. PMID- 25937528 TI - Real-time atrial wall imaging. PMID- 25937530 TI - Pharmacological treatment and prevention of chronic venous ulcers: a review. AB - Chronic venous insufficiency and chronic venous ulcers represent an important medical problem, because of the high incidence and prevalence in the general population, and need to be considered as a lifelong degenerative condition, with socioeconomic consequences. Ulceration is a severe complication of the post thrombotic syndrome, often precipitated by minor trauma. The rate of post thrombotic syndrome varies between 20% and 100% of patients with deep vein thrombosis, mostly occurring within two years of an initial thrombotic event. This syndrome is difficult to treat, causes significant disability and reduces the quality of life. To date, there are no effective therapies of chronic venous ulcers and no definite strategies for identifying patients at risk for the development of ulceration. The role of adequate compression with elastic stockings is well recognized. Several systemic drugs have been tested for a possible effect on chronic venous ulcer healing, but none has been widely accepted as standard therapy in this setting. It has been suggested that extended oral anticoagulation should be investigated as a possible preventative measure. Waiting for the results in this field, an adequate management of anticoagulation in terms of anticoagulant intensity and duration should be recommended for the prevention of recurrent deep vein thrombosis, post-thrombotic syndrome and chronic venous ulcers. PMID- 25937529 TI - Patient and physician factors associated with participation in cervical and uterine cancer trials: an NRG/GOG247 study. AB - PURPOSE: The aim of this study was to identify patient and physician factors related to enrollment onto Gynecologic Oncology Group (GOG) trials. METHODS: Prospective study of women with primary or recurrent cancer of the uterus or cervix treated at a GOG institution from July 2010 to January 2012. Logistic regression examined probability of availability, eligibility and enrollment in a GOG trial. Odds ratios (OR) and 95% confidence intervals (CI) for significant (p<0.05) results reported. RESULTS: Sixty institutions, 781 patients, and 150 physicians participated, 300/780 (38%) had a trial available, 290/300 had known participation status. Of these, 150 women enrolled (59.5%), 102 eligible did not enroll (35%), 38 (13%) were ineligible. Ethnicity and specialty of physician, practice type, data management availability, and patient age were significantly associated with trial availability. Patients with >4 comorbidities (OR 4.5; CI 1.7-11.8) had higher odds of trial ineligibility. Non-White patients (OR 7.9; CI 1.3-46.2) and patients of Black physicians had greater odds of enrolling (OR 56.5; CI 1.1-999.9) in a therapeutic trial. Significant patient therapeutic trial enrollment factors: belief trial may help (OR 76.9; CI 4.9->1000), concern about care if not on trial (OR12.1; CI 2.1-71.4), pressure to enroll (OR .27; CI 0.12 .64), caregiving without pay (OR 0.13; CI .02-.84). Significant physician beliefs were: patients would not do well on standard therapy (OR 3.6; CI 1.6-8.4), and trial would not be time consuming (OR 3.3; CI 1.3-8.1). CONCLUSIONS: Trial availability, patient and physician beliefs were factors identified that if modified could improve enrollment in cancer cooperative group clinical trials. PMID- 25937531 TI - Celebrating the cause of mental health literacy in India with a celebrity. PMID- 25937532 TI - The principles of ultrasound and its application in freezing related processes of food materials: A review. AB - Ultrasonic processing is a novel and promising technology in food industry. The propagation of ultrasound in a medium generates various physical and chemical effects and these effects have been harnessed to improve the efficiency of various food processing operations. Ultrasound has also been used in food quality control as diagnostic technology. This article provides an overview of recent developments related to the application of ultrasound in low temperature and closely related processes such as freezing, thawing, freeze concentration and freeze drying. The applications of high intensity ultrasound to improve the efficiency of freezing process, to control the size and size distribution of ice crystals and to improve the quality of frozen foods have been discussed in considerable detail. The use of low intensity ultrasound in monitoring the ice content and to monitor the progress of freezing process has also been highlighted. PMID- 25937533 TI - Evaluation of dendrimer type bio-reducible polymer as a siRNA delivery carrier for cancer therapy. AB - Small interfering ribonucleic acid (siRNA), 20-25 base pairs in length, can interfere with the expression of specific genes. Recently, many groups reported the therapeutic intervention of siRNA in various cancer cells. In this study, dendrimer type bio-reducible polymer (PAM-ABP) which was synthesized using arginine grafted bio-reducible poly(cystaminebisacrylamide-diaminohexane) (ABP) and polyamidoamine (PAMAM) was used to deliver anti-VEGF siRNA into cancer cell lines including human hepatocarcinoma (Huh-7), human lung adenocarcinoma (A549), and human fibrosarcoma (HT1080) cells and access their potential as a siRNA delivery carrier for cancer therapy. PAM-ABP and siRNA formed polyplexes with average diameter of 116 nm and charge of around +24.6 mV. The siRNA in the PAM ABP/siRNA polyplex was released by 5mM DTT and heparin. VEGF gene silencing efficiency of PAM-ABP/siRNA polyplexes was shown to be more effective than PEI/siRNA polyplexes in three cell lines with the following order HT1080>A549>Huh 7. PMID- 25937534 TI - SM22alpha inhibits vascular inflammation via stabilization of IkappaBalpha in vascular smooth muscle cells. AB - Smooth muscle (SM) 22alpha, an actin-binding protein, is down-regulated in atherosclerotic arteries. Disruption of SM22alpha promotes arterial inflammation through activation of reactive oxygen species (ROS)-mediated nuclear factor (NF) kappaB pathways. This study aimed to investigate the mechanisms by which SM22alpha regulates vascular inflammatory response. The ligation injury model of SM22alpha(-/-) mice displayed up-regulation of inflammatory molecules MCP-1, VCAM 1, and ICAM-1 in the carotid arteries. Similar results were discovered in human atherosclerotic samples. In vitro studies, overexpression of SM22alpha attenuated TNF-alpha-induced IkappaBalpha phosphorylation and degradation, accompanied by decreased NF-kappaB activity and reduced inflammatory molecule expression. Using coimmunoprecipitation, we found that SM22alpha interacted with and stabilized IkappaBalpha in quiescent VSMCs. Upon TNF-alpha stimulation, SM22alpha was phosphorylated by casein kinase (CK) II at Thr139, leading to dissociation of SM22alpha from IkappaBalpha, followed by IkappaBalpha degradation and NF-kappaB activation. Our findings demonstrate that SM22alpha is a phosphorylation regulated suppressor of IKK-IkappaBalpha-NF-kappaB signaling cascades. SM22alpha may be a novel therapeutic target for human vascular diseases and other inflammatory conditions. PMID- 25937535 TI - The changing landscape of cardiac metabolism. PMID- 25937536 TI - The role of volunteer support in the community for adults with hearing loss and hearing aids. AB - OBJECTIVES: To explore interactions between audiology patients and volunteers, to describe encounters and define the role of volunteers. METHODS: Qualitative ethnographic and interview study of volunteer-patient interactions. Ten volunteer participants from two volunteer schemes in South West England were observed and interviewed. Three patient participants were interviewed. RESULTS: Analysis of observational data showed that volunteers provided support relating to local services and hearing aids, but did not engage in discussions about hearing loss. Interviews with volunteers identified gaps in audiology provision, including accessible services and clear information and highlighted a need for more support from audiology services to enable them to fulfil their role. Volunteer interactions with patients mimicked a clinician-patient encounter and volunteers employed strategies and behaviours used by professional audiologists. CONCLUSIONS: Audiology volunteers could provide an accessible bridge between health services and the community but their care is limited to focus on hearing aids. PRACTICE IMPLICATIONS: Volunteers enable patients to use hearing aids appropriately and are a core element of current care arrangements. However, volunteers express a need for adequate support from audiology services. Volunteers have the potential to increase service capacity and to bridge the gaps between community and audiology healthcare services. PMID- 25937537 TI - Transcriptional and proteomic analyses of two-component response regulators in multidrug-resistant Mycobacterium tuberculosis. AB - Two-component systems (TCSs) have been reported to exhibit a sensing and responding role under drug stress that induces drug resistance in several bacterial species. However, the relationship between TCSs and multidrug resistance in Mycobacterium tuberculosis has not been comprehensively analysed to date. In this study, 90 M. tuberculosis clinical isolates were analysed using 15 loci mycobacterial interspersed repetitive unit (MIRU)-variable number tandem repeat (VNTR) typing and repetitive extragenic palindromic (rep)-PCR-based DNA fingerprinting. The results showed that all of the isolates were of the Beijing lineage, and strains with a drug-susceptible phenotype had not diverged into similar genotype clusters. Expression analysis of 13 response regulators of TCSs using real-time PCR and tandem mass spectrometry (MS/MS) proteomic analysis demonstrated that four response regulator genes (devR, mtrA, regX3 and Rv3143) were significantly upregulated in multidrug-resistant (MDR) strains compared with the laboratory strain H37Rv as well as drug-susceptible and isoniazid monoresistant strains (P<0.05). DNA sequencing revealed that the promoter regions of devR, mtrA, regX3 and Rv3143 did not contain any mutations. Moreover, expression of the four genes could be induced by most of the four first-line antitubercular agents. In addition, either deletion or overexpression of devR in Mycobacterium bovis BCG did not alter its sensitivity to the four antitubercular drugs. This suggests that upregulation of devR, which is common in MDR-TB strains, might be induced by drug stress and hypoxic adaptation following the acquisition of multidrug resistance. PMID- 25937538 TI - Proteomic analysis of the mouse brain after repetitive exposure to hypoxia. AB - Hypoxic preconditioning (HPC) is known to have a protective effect against hypoxic damage; however, the precise mechanisms involved remain unknown. In this study, an acute and repetitive hypoxia mouse model, two-dimensional fluorescence difference gel electrophoresis (2D-DIGE) coupled with matrix-assisted laser desorption ionization-time of flight mass spectrometry (MALDI-TOF/TOF-MS), and Western blot experiments were used to identify the differential expression of key proteins in the mouse brain during HPC. Approximately 2100 2D-DIGE spots were observed following gel imaging and spot detection. Significant differences (p < 0.05) in the expression of 66 proteins were observed between the 3* HPC treatment group and the control group, 45 proteins were observed between the 6* HPC treatment group and the control group, and 70 proteins were observed between the 3* HPC treatment group and the 6* HPC group. Consistent results among Western blot, 2D-DIGE and MS methods were observed for the proteins, ATP synthase subunit alpha, malate dehydrogenase, guanine nucleotide-binding protein subunit beta-1 and proteasome subunit alpha type-2. The proteins associated with ATP synthesis and the citric acid cycle were down-regulated, while those linked to glycolysis and oxygen-binding were up-regulated. This proteomic analysis of the mouse brain after HPC furthers understanding of the molecular pathways involved in the protective effect of HPC and these findings provide new insight into the mechanisms of hypoxia and HPC. PMID- 25937539 TI - Prospective, randomized, multinational study of prostatic urethral lift versus transurethral resection of the prostate: 12-month results from the BPH6 study. AB - BACKGROUND: Transurethral resection of the prostate (TURP) is considered the gold standard for male lower urinary tract symptoms (LUTS) secondary to benign prostatic hyperplasia (BPH). However, TURP may lead to sexual dysfunction and incontinence, and has a long recovery period. Prostatic urethral lift (PUL) is a treatment option that may overcome these limitations. OBJECTIVE: To compare PUL to TURP with regard to LUTS improvement, recovery, worsening of erectile and ejaculatory function, continence and safety (BPH6). DESIGN, SETTING, AND PARTICIPANTS: Prospective, randomized, controlled trial at 10 European centers involving 80 men with BPH LUTS. INTERVENTION: PUL or TURP. OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS: The BPH6 responder endpoint assesses symptom relief, quality of recovery, erectile function preservation, ejaculatory function preservation, continence preservation, and safety. Noninferiority was evaluated using a one-sided lower 95% confidence limit for the difference between PUL and TURP performance. RESULTS AND LIMITATIONS: Preservation of ejaculation and quality of recovery were superior with PUL (p<0.01). Significant symptom relief was achieved in both treatment arms. The study demonstrated not only noninferiority but also superiority of PUL over TURP on the BPH6 endpoint. Study limitations were the small sample size and the inability to blind participants to enrollment arm. CONCLUSIONS: Assessment of individual BPH6 elements revealed that PUL was superior to TURP with respect to quality of recovery and preservation of ejaculatory function. PUL was superior to TURP according to the novel BPH6 responder endpoint, which needs to be validated in future studies. PATIENT SUMMARY: In this study, participants who underwent prostatic urethral lift responded significantly better than those who underwent transurethral resection of the prostate as therapy for benign prostatic hyperplasia with regard to important aspects of quality of life. TRIAL REGISTRATION: ClinicalTrials.gov NCT01533038. PMID- 25937541 TI - The influence of age and metformin treatment status on reported gastrointestinal side effects with liraglutide treatment in type 2 diabetes. AB - AIM: Treatment of type 2 diabetes with glucagon-like peptide-1 (GLP-1) receptor agonists may be limited by gastrointestinal side effects (GISE) in some patients. Risk factors for developing GISE are not known. We analysed patient characteristics that were associated with GISE among patients treated with the GLP-1 receptor agonist liraglutide. METHODS: Data was obtained from an audit database of liraglutide use based in clinical practice in the UK. Patients were grouped into those who did not report GISE, those who reported GISE but continued liraglutide and those who discontinued liraglutide due to GISE within 26 weeks of treatment. Baseline variables of age, diabetes duration, HbA1c, weight, BMI, blood pressure, lipids, gender, ethnicity, alanine transaminotransferase, estimated glomerular filtration rate (eGFR) and diabetes treatment types were tested for possible associations with GISE outcome. Significant variables in univariate analyses were entered into ordinal logistic regression analyses. RESULTS: A total of 4442 patients were suitable for analysis. A total of 3905 (87.9%) did not report GISE, 297 (6.7%) and 240 (5.4%) had GISE and continued and discontinued treatment, respectively. Age, weight, eGFR, metformin status and insulin status were associated with GISE outcome in univariate analyses (P all <0.05). In the final regression model, age (adjusted OR 1.15 [95%CI 1.05,1.26], P=0.002) and non-metformin use (adjusted OR 0.76 [95%CI 0.60,0.96], P=0.020) were associated with worse GISE outcome. CONCLUSION: Older age and non-metformin use were associated with more significant GISE leading to discontinuation of liraglutide treatment. The reasons for these findings are unclear and warrant further investigation. PMID- 25937542 TI - Change in cardio-protective medication and health-related quality of life after diagnosis of screen-detected diabetes: Results from the ADDITION-Cambridge cohort. AB - AIMS: Establishing a balance between the benefits and harms of treatment is important among individuals with screen-detected diabetes, for whom the burden of treatment might be higher than the burden of the disease. We described the association between cardio-protective medication and health-related quality of life (HRQoL) among individuals with screen-detected diabetes. METHODS: 867 participants with screen-detected diabetes underwent clinical measurements at diagnosis, one and five years. General HRQoL (EQ5D) was measured at baseline, one and five-years, and diabetes-specific HRQoL (ADDQoL-AWI) and health status (SF 36) at one and five years. Multivariable linear regression was used to quantify the association between change in HRQoL and change in cardio-protective medication. RESULTS: The median (IQR) number of prescribed cardio-protective agents was 2 (1 to 3) at diagnosis, 3 (2 to 4) at one year and 4 (3 to 5) at five years. Change in cardio-protective medication was not associated with change in HRQoL from diagnosis to one year. From one year to five years, change in cardio protective agents was not associated with change in the SF-36 mental health score. One additional agent was associated with an increase in the SF-36 physical health score (2.1; 95%CI 0.4, 3.8) and an increase in the EQ-5D (0.05; 95%CI 0.02, 0.08). Conversely, one additional agent was associated with a decrease in the ADDQoL-AWI (-0.32; 95%CI -0.51, -0.13), compared to no change. CONCLUSIONS: We found little evidence that increases in the number of cardio-protective medications impacted negatively on HRQoL among individuals with screen-detected diabetes over five years. PMID- 25937543 TI - Vertically-resolved profiles of mass concentrations and particle backscatter coefficients of Asian dust plumes derived from lidar observations of silicon dioxide. AB - This study presents a method to retrieve vertically-resolved profiles of dust mass concentrations by analyzing Raman lidar signals of silicon dioxide (quartz) at 546nm. The observed particle plumes consisted of mixtures of East Asian dust with anthropogenic pollution. Our method for the first time allows for extracting the contribution of the aerosol component "pure dust" contained in the aerosol type "polluted dust". We also propose a method that uses OPAC (Optical Properties of Aerosols and Clouds) and the mass concentrations profiles of dust in order to derive profiles of backscatter coefficients of pure dust in mixed dust/pollution plumes. The mass concentration of silicon dioxide (quartz) in the atmosphere can be estimated from the backscatter coefficient of quartz. The mass concentration of dust is estimated by the weight percentage (38-77%) of mineral quartz in Asian dust. The retrieved dust mass concentrations are classified into water soluble, nucleation, accumulation, mineral-transported and coarse mode according to OPAC. The mass mixing ratio of 0.018, 0.033, 0.747, 0.130 and 0.072, respectively, is used. Dust extinction coefficients at 550nm were calculated by using OPAC and prescribed number concentrations for each of the 5 components. Dust backscatter coefficients were calculated from the dust extinction coefficients on the basis of a lidar ratio of 45+/-3sr at 532nm. We present results of quartz-Raman measurements carried out on the campus of the Gwangju Institute of Science and Technology (35.10 degrees N, 126.53 degrees E) on 15, 16, and 21 March 2010. PMID- 25937544 TI - Dissection of voltage-gated sodium channels in developing cochlear sensory epithelia. PMID- 25937545 TI - A method for subject-specific modelling and optimisation of the cushioning properties of insole materials used in diabetic footwear. AB - This study aims to develop a numerical method that can be used to investigate the cushioning properties of different insole materials on a subject-specific basis. Diabetic footwear and orthotic insoles play an important role for the reduction of plantar pressure in people with diabetes (type-2). Despite that, little information exists about their optimum cushioning properties. A new in-vivo measurement based computational procedure was developed which entails the generation of 2D subject-specific finite element models of the heel pad based on ultrasound indentation. These models are used to inverse engineer the material properties of the heel pad and simulate the contact between plantar soft tissue and a flat insole. After its validation this modelling procedure was utilised to investigate the importance of plantar soft tissue stiffness, thickness and loading for the correct selection of insole material. The results indicated that heel pad stiffness and thickness influence plantar pressure but not the optimum insole properties. On the other hand loading appears to significantly influence the optimum insole material properties. These results indicate that parameters that affect the loading of the plantar soft tissues such as body mass or a person's level of physical activity should be carefully considered during insole material selection. PMID- 25937546 TI - Subject specific finite element modeling of periprosthetic femoral fracture using element deactivation to simulate bone failure. AB - Subject-specific finite element (FE) modeling methodology could predict peri prosthetic femoral fracture (PFF) for cementless hip arthoplasty in the early postoperative period. This study develops methodology for subject-specific finite element modeling by using the element deactivation technique to simulate bone failure and validate with experimental testing, thereby predicting peri prosthetic femoral fracture in the early postoperative period. Material assignments for biphasic and triphasic models were undertaken. Failure modeling with the element deactivation feature available in ABAQUS 6.9 was used to simulate a crack initiation and propagation in the bony tissue based upon a threshold of fracture strain. The crack mode for the biphasic models was very similar to the experimental testing crack mode, with a similar shape and path of the crack. The fracture load is sensitive to the friction coefficient at the implant-bony interface. The development of a novel technique to simulate bone failure by element deactivation of subject-specific finite element models could aid prediction of fracture load in addition to fracture risk characterization for PFF. PMID- 25937547 TI - The Effect of Environmental Temperature on Glucose and Insulin After an Oral Glucose Tolerance Test in Healthy Young Men. AB - OBJECTIVE: The purpose of this study was to compare glucose and insulin responses during an oral glucose tolerance test (OGTT) in cold (C), neutral (N), and hot (H) environments. METHODS: Eleven males completed three 4-hour climate-controlled OGTT trials (C, 7.2 degrees C; N, 22 degrees C; and H, 43 degrees C). Participants remained semireclined for 60 minutes before ingesting a 1.8 g/kg glucose beverage. Skin and rectal core temperatures were continuously monitored. Blood was collected just before glucose ingestion (time 0) and at 15, 30, 60, 90, 120, and 180 minutes, and analyzed for serum glucose, insulin, hematocrit, and hemoglobin. Expired gases were collected upon entering the chamber (-60 minutes), before glucose ingestion (0 minutes), and at 60, 120, and 180 minutes to determine V(O2) and respiratory exchange ratio. RESULTS: Rectal core temperature was greater in the H condition compared with both C and N (P < .001). Rectal core temperature was not different between C and N, whereas skin temperature was different across all trials (H greater than N greater than C). The V(O2) was greater in C than in both H and N during all time points. Carbohydrate oxidation was greater in C compared with H and N (P < 0.001). Glucose was higher during H compared with C and N (P <= 0.002). Glucose was elevated in C compared with N. Insulin was higher in H compared with C (P = 0.009). Area under the curve for serum glucose was greater in H compared with C and N (P <= 0.001); however, there was no significant difference in area under the curve for insulin. CONCLUSIONS: These data indicate that after an OGTT, glucose and insulin are elevated in a hot environment. PMID- 25937548 TI - The Hand-Powered Ring Cutter: A Useful Tool in Your Wilderness Medical Bag. PMID- 25937549 TI - An Attack by a Teiidae Lizard (Tegu) on a Human: Is There a Pattern of the Injuries? PMID- 25937550 TI - Retained Stingray Barb and the Importance of Imaging. AB - Stingray envenomation is a common occurrence. X-ray evaluation of stingray wounds is an unnecessarily misunderstood diagnostic concept. We present the case of a patient stung by a stingray with a prolonged and complicated course and permanent disability due to a retained barb. The patient had undergone multiple medical evaluations before an X-ray was obtained. PMID- 25937551 TI - Advanced Avalanche Safety Equipment of Backcountry Users: Current Trends and Perceptions. AB - OBJECTIVE: Backcountry travelers should carry a standard set of safety gear (transceiver, shovel, and probe) to improve rescue chances and reduce mortality risk. Many backcountry enthusiasts are using other advanced equipment such as an artificial air pocket (eg, the AvaLung) or an avalanche air bag. Our goal was to determine the numbers of backcountry users carrying advanced equipment and their perceptions of mortality and morbidity benefit while carrying this gear. METHODS: A convenience sample of backcountry skiers, snowboarders, snowshoers, and snowmobilers was surveyed between February and April 2014. Participants of this study were backcountry mountain users recruited at trailheads in the Wasatch and Teton mountain ranges of Utah and Wyoming, respectively. Questions included prior avalanche education, equipment carried, and perceived safety benefit derived from advanced equipment. RESULTS: In all, 193 surveys were collected. Skiers and snowboarders were likely to have taken an avalanche safety course, whereas snowshoers and snowmobilers were less likely to have taken a course. Most backcountry users (149, 77.2%), predominantly skiers and snowboarders, carried standard safety equipment. The AvaLung was carried more often (47 users) than an avalanche air bag (10 users). The avalanche air bag had a more favorable perceived safety benefit. A majority of participants reported cost as the barrier to obtaining advanced equipment. CONCLUSIONS: Standard avalanche safety practices, including taking an avalanche safety course and carrying standard equipment, remain the most common safety practices among backcountry users in the Wasatch and Tetons. Snowshoers remain an ideal target for outreach to increase avalanche awareness and safety. PMID- 25937552 TI - Complete Spinal Accessory Nerve Palsy From Carrying Climbing Gear. AB - We report an unusual case of spinal accessory nerve palsy sustained while transporting climbing gear. Spinal accessory nerve injury is commonly a result of iatrogenic surgical trauma during lymph node excision. This particular nerve is less frequently injured by blunt trauma. The case reported here results from compression of the spinal accessory nerve for a sustained period-that is, carrying a load over the shoulder using a single nylon rope for 2.5 hours. This highlights the importance of using proper load-carrying equipment to distribute weight over a greater surface area to avoid nerve compression in the posterior triangle of the neck. The signs and symptoms of spinal accessory nerve palsy and its etiology are discussed. This report is particularly relevant to individuals involved in mountaineering and rock climbing but can be extended to anyone carrying a load with a strap over one shoulder and across the body. PMID- 25937553 TI - Hysteroscopy and the treatment of uterine fibroids. AB - Fibroids or (leio)myomas are benign tumours that very commonly derive from smooth muscle cells of the myometrium. They are the most common indication for a hysterectomy. However, in women desirous of preservation of their uterus or of their fertility, a myomectomy may be a more appropriate form of surgical therapy. The submucous variant is often associated with heavy menstrual bleeding or subfertility. It can be removed with hysteroscopic surgery. Refinements of hysteroscopic surgical techniques have resulted in a better ability to remove submucous myomas. The state of the art of such hysteroscopical techniques and instrumentation to treat submucous myomas and what has been proven is discussed. PMID- 25937554 TI - What is the impact of multi-professional emergency obstetric and neonatal care training? AB - This paper reviews evidence regarding change in health-care provider behaviour and maternal and neonatal outcomes as a result of emergency obstetric and neonatal care (EmONC) training. A refined version of the Kirkpatrick classification for programme evaluation was used to focus on change in efficiency and impact of training (levels 3 and 4). Twenty-three studies were reviewed - five randomised controlled trials, two quasi-experimental studies and 16 before and-after observational studies. Training programmes had all been developed in high-income countries and adapted for use in low- and middle-income countries. Nine studies reported on behaviour change and 13 on process and patient outcomes. Most showed positive results. Every maternity unit should provide EmONC teamwork training, mandatory for all health-care providers. The challenges are as follows: scaling up such training to all institutions, sustaining regular in-service training, integrating training into institutional and health-system patient safety initiatives and 'thinking out of the box' in evaluation research. PMID- 25937555 TI - Complications of hysteroscopy and how to avoid them. AB - The advances in surgical technology such as bipolar electrosurgery, endometrial ablation devices, hysteroscopic sterilization, and morcellators have revolutionized this surgical modality. This article reviews the potential complications in hysteroscopic surgery and the means by which they may be minimized or avoided. PMID- 25937556 TI - Impact of training on emergency resuscitation skills: Impact on Millennium Development Goals (MDGs) 4 and 5. AB - Although significant progress has been made towards Millennium Development Goal (MDG) 4 and 5 targets, maternal and neonatal mortality rates remain unacceptably high in low- and middle-income countries (LMICs). The potential for improvements in maternal and neonatal health outcomes with increased facility utilization in these countries is undermined by a lack of appropriate and timely treatment. Skilful emergency resuscitation can be the difference between life and death; therefore, training in emergency resuscitation is essential for health-care practitioners at all levels, with regular refresher sessions to ensure skill retention. Whilst there is little robust evidence on the impact of resuscitation training interventions on practitioner skills or patient outcomes, such training interventions are likely to have the greatest impact if integrated into a broader approach to improve the quality of care. Accelerated investments in training must go hand in hand with ensuring the availability of quality equipment and upgrading infrastructure to reduce the gap between current MDG status and what is achieved by the end of 2015; and to accelerate reductions in mortality rates beyond 2015 towards new Countdown targets. PMID- 25937557 TI - TIM-3 Genetic Variations Affect Susceptibility to Osteoarthritis by Interfering with Interferon Gamma in CD4+ T Cells. AB - Osteoarthritis (OA) is the most common type of arthritis, in which T cell responses and cytokines may play critical roles in the development of the disease. TIM-3 may affect immune responses and is correlated with decreased expression of interferon gamma (INF-gamma) in CD4+ T cells. In the current study, we investigated the association between polymorphisms in the TIM-3 gene and susceptibility to OA. Two polymorphisms in TIM-3, -574G/T and +4259T/G polymorphisms, were identified in OA cases and healthy donors by polymerase chain reaction-restriction fragment length polymorphism method. Data revealed that the prevalence of TIM-3 +4259T/G genotype was significantly elevated in OA patients than in the healthy donors after adjustment (Odds ratio [OR] = 2.67, 95% confidence interval [CI] 1.32-5.11, P < 0.001). Similarly, the TIM-3 +4259G allele presented a positive association with the risk of OA after adjustment (OR = 2.58, 95% CI 1.29-4.82, P = 0.003). The TIM-3 -574G/T polymorphism did not show any correlation with the disease. We further examined whether the two TIM-3 polymorphisms could affect INF-gamma expression in CD4+ T cells. Data revealed that subjects carrying polymorphic +4259TG genotype had significantly higher mRNA and protein levels of INF-gamma in CD4+ T cells compared to wild-type GG genotype (P < 0.001 and P < 0.01). These results indicated that TIM-3 polymorphism is associated with increased susceptibility to OA possibly by upregulating INF-gamma expression in CD4+ T cells. PMID- 25937558 TI - Putative floral brood-site mimicry, loss of autonomous selfing, and reduced vegetative growth are significantly correlated with increased diversification in Asarum (Aristolochiaceae). AB - The drivers of angiosperm diversity have long been sought and the flower arthropod association has often been invoked as the most powerful driver of the angiosperm radiation. We now know that features that influence arthropod interactions cannot only affect the diversification of lineages, but also expedite or constrain their rate of extinction, which can equally influence the observed asymmetric richness of extant angiosperm lineages. The genus Asarum (Aristolochiaceae; ~100 species) is widely distributed in north temperate forests, with substantial vegetative and floral divergence between its three major clades, Euasarum, Geotaenium, and Heterotropa. We used Binary-State Speciation and Extinction Model (BiSSE) Net Diversification tests of character state distributions on a Maximum Likelihood phylogram and a Coalescent Bayesian species tree, inferred from seven chloroplast markers and nuclear rDNA, to test for signal of asymmetric diversification, character state transition, and extinction rates of floral and vegetative characters. We found that reduction in vegetative growth, loss of autonomous self-pollination, and the presence of putative fungal-mimicking floral structures are significantly correlated with increased diversification in Asarum. No significant difference in model likelihood was identified between symmetric and asymmetric rates of character state transitions or extinction. We conclude that the flowers of the Heterotropa clade may have converged on some aspects of basidiomycete sporocarp morphology and that brood-site mimicry, coupled with a reduction in vegetative growth and the loss of autonomous self-pollination, may have driven diversification within Asarum. PMID- 25937559 TI - Molecular phylogenetics of Micromeria (Lamiaceae) in the Canary Islands, diversification and inter-island colonization patterns inferred from nuclear genes. AB - Here we reconstruct the evolutionary history of Micromeria in the Canary Islands using eight nuclear markers. Our results show two centers of diversification for Micromeria, one in the eastern islands Gran Canaria and Lanzarote, the other in the western islands, Tenerife, La Palma and El Hierro. Suggested directions of inter-island colonization are the following: Gran Canaria to Lanzarote and La Gomera; Tenerife to La Palma (from the paleoisland of Teno), to El Hierro (from the younger, central part), and to La Gomera and Madeira (from the paleoislands). Colonization of La Gomera probably occurred several times from Gran Canaria and Tenerife. The taxonomic implications of these results are discussed. Incongruence among the different markers was evaluated and, using next generation sequencing, we investigated if this incongruence is due to gene duplication. PMID- 25937560 TI - Trimetazidine protects cardiomyocytes against hypoxia-induced injury through ameliorates calcium homeostasis. AB - Intracellular calcium (Ca(2+)i) overload induced by chronic hypoxia alters Ca(2+)i homeostasis, which plays an important role on mediating myocardial injury. We tested the hypothesis that treatment with trimetazidine (TMZ) would improve Ca(2+)i handling in hypoxic myocardial injury. Cardiomyocytes isolated from neonatal Sprague-Dawley rats were exposed to chronic hypoxia (1% O2, 5% CO2, 37 degrees C). Intracellular calcium concentration ([Ca(2+)]i) was measured with Fura-2/AM. Perfusion of cardiomyocytes with a high concentration of caffeine (10 mM) was carried out to verify the function of the cardiac Na(+)/Ca(2+) exchanger (NCX) and the activity of sarco(endo)-plasmic reticulum Ca(2+)-ATPase (SERCA2a). For TMZ-treated cardiomyocytes exposured in hypoxia, we observed a decrease in mRNA expression of proapoptotic Bax, caspase-3 activation and enhanced expression of anti-apoptotic Bcl-2. The cardiomyocyte hypertrophy were also alleviated in hypoxic cardiomyocyte treated with TMZ. Moreover, we found that TMZ treatment cardiomyocytes enhanced "metabolic shift" from lipid oxidation to glucose oxidation. Compared with hypoxic cardiomyocyte, the diastolic [Ca(2+)]i was decreased, the amplitude of Ca(2+)i oscillations and sarcoplasmic reticulum Ca(2+) load were recovered, the activities of ryanodine receptor 2 (RyR2), NCX and SERCA2a were increased in cardiomyocytes treated with TMZ. TMZ attenuated abnormal changes of RyR2 and SERCA2a genes in hypoxic cardiomyocytes. In addition, cholinergic signaling are involved in hypoxic stress and the cardioprotective effects of TMZ. These results suggest that TMZ ameliorates Ca(2+)i homeostasis through switch of lipid to glucose metabolism, thereby producing the cardioprotective effect and reduction in hypoxic cardiomyocytes damage. PMID- 25937561 TI - In vivo RNAi screens: concepts and applications. AB - Functional genomics approaches that leverage the RNAi pathway have been applied in vivo to examine the roles of hundreds or thousands of genes; mainly in the context of cancer. Here, we discuss principles guiding the design of RNAi screens, parameters that determine success and recent developments that have improved accuracy and expanded the applicability of these approaches to other in vivo settings, including the immune system. We review recent studies that have applied in vivo RNAi screens in T cells to examine genes that regulate T cell differentiation during viral infection, and that control their accumulation in tumors in a model of adoptive T cell therapy. In this context, we put forward an argument as to why RNAi approaches in vivo are likely to provide particularly salient insight into immunology. PMID- 25937562 TI - Sodium valproate effect on the structure of rat glandule thymus: Gender-related differences. AB - Sodium valproate (VPA) was shown to inhibit cell growth mechanisms such as cell cycle arrest, proliferation suppression, increase of apoptosis. Many aspects of the contribution of the VPA pharmacological mechanisms and their significance in gender-related processes have not been investigated. In our study, we have tested hypothesis that the influence of VPA on thymus weight and structure might be gender-related. The thymus of Wistar rats of both genders aged 8 weeks was investigated in the following groups (n = 6 each): controls, treated with VPA, castrated male and female treated with VPA, and the castrated control of both genders. The thymus weight, structural changes and area of cortical and medullar parts of the gland in slides stained with hematoxylin and eosin and immunohistochemically were assessed. A comparison of thymus weight of castrated male and of castrated VPA-treated male rats showed a significant thymus weight loss after VPA treatment (0.66 +/- 0.04 g vs. 0.43 +/- 0.03 g, p < 0.05). The treatment with VPA caused an about 6-fold (0.39 +/- 0.12 vs. 0.07 +/- 0.03) increase of Hassall's corpuscles (HCs) numbers per 1mm(2) in male and more than 4 fold increase (0.46 +/- 0.07 vs. 0.10 +/- 0.04) in female rats. In castrated males and females, the HCs number was also increased, but this increase was statistically significant only in male animals vs. controls (0.46 +/- 0.10 vs. 0.07 +/- 0.03, p < 0.001 in males; 0.29 +/- 0.13 vs. 0.10 +/- 0.04, p > 0.05 in females). When castrated male and female rats were treated with VPA, further increase of HC numbers was found. In our study, VPA has inhibited the proliferative capacity of thymocytes by diminishing the thymus weight and inducing a differentiation of thymic medullar epithelial cells into HCs. The diminishing of the gl. thymus weight under the influence of VPA was significant in castrated male rats. The number of HCs increased in animals of both genders under the influence of VPA. Gender differences in HCs development were noted in castrated animals. PMID- 25937564 TI - Nail Braces as an Alternative Treatment for Ingrown Toenails: Results From a Comparison With the Winograd Technique. AB - Ingrown toenails are one of the most frequent nail disorders and can be treated with conservative or surgical approaches. Although discovered a long time ago, the available data are still very limited on the potential effectiveness of nail braces for ingrown toenail treatment. In the present retrospective study, we compared nail braces with surgical wedge excision using the Winograd technique with respect to the time to return to work, recurrence, interval to recurrence, and patient satisfaction. A total of 159 patients were divided into the nail brace (n = 74; mean age 29.51 +/- 8.48 years) and Winograd technique (n = 85; mean age 26.95 +/- 8.06 years) groups. In the nail brace group, the mean time to return to work (4.15 +/- 1.07 days) was significantly shorter than that in the Winograd technique group (13.8 +/- 2.26 days; p < .001). Patient satisfaction was significantly greater in the nail brace group (94.6%) compared with the Winograd technique group (82.4%; p = .018). Of the 159 patients, 6 (8.1%) in the nail brace group and 8 (9.4%) in the Winograd technique group developed recurrence; however, this difference was not statistically significant (p > .05). A statistically significant difference was observed in the mean interval to recurrence (12.46 +/- 1.60 versus 13.24 +/- 2.48 months, respectively; p = .031). The progression-free follow-up periods for the nail brace and Winograd technique groups were 15.45 +/- 0.22 months (95% confidence interval 15.02 to 15.88) and 17.18 +/- 0.29 months (95% confidence interval 16.61 to 17.84), respectively. We have concluded that the use of nail braces is an appropriate alternative treatment of ingrown toenails with high patient satisfaction, fast recovery times, and a low recurrence rate. PMID- 25937565 TI - US emergency nurses' perceptions of challenges and facilitators in the management of behavioural health patients in the emergency department: A mixed-methods study. AB - BACKGROUND: Behavioural health patients often have longer lengths of stay in the emergency department compared with general medical patients, and their modalities of care are not well documented. This study's purpose is to describe US emergency nurses' estimates of lengths of stay for behavioural health patients, explore factors affecting length of stay, and assess nurses' perceptions of their skills, beliefs/attitudes, and confidence in caring for this population. METHODS: Using a mixed-methods design with demographically-diverse samples of emergency nurses, survey data (N=1229) were analysed using descriptive statistics, correlation coefficients, and linear regression. Focus group participant data (N=20) were analysed for themes using constant comparison. RESULTS: Findings suggest that shorter lengths of stay are associated with higher levels of perceived nursing confidence/preparation to care for this population, along with the availability of appropriate resources and protocols/standards of care (p=0.01). Longer lengths of stay are associated with an absence of dedicated inpatient space for managing the care of these patients. CONCLUSIONS: Participants note a lack of education, resources, and treatment options tailored to the delivery of safe, effective care for behavioural health patients. The use of trained specialists and additional guidelines/protocols may help move patients through the emergency department faster and with greater surety. PMID- 25937563 TI - Altered corpus callosum morphology associated with autism over the first 2 years of life. AB - Numerous brain imaging studies indicate that the corpus callosum is smaller in older children and adults with autism spectrum disorder. However, there are no published studies examining the morphological development of this connective pathway in infants at-risk for the disorder. Magnetic resonance imaging data were collected from 270 infants at high familial risk for autism spectrum disorder and 108 low-risk controls at 6, 12 and 24 months of age, with 83% of infants contributing two or more data points. Fifty-seven children met criteria for ASD based on clinical-best estimate diagnosis at age 2 years. Corpora callosa were measured for area, length and thickness by automated segmentation. We found significantly increased corpus callosum area and thickness in children with autism spectrum disorder starting at 6 months of age. These differences were particularly robust in the anterior corpus callosum at the 6 and 12 month time points. Regression analysis indicated that radial diffusivity in this region, measured by diffusion tensor imaging, inversely predicted thickness. Measures of area and thickness in the first year of life were correlated with repetitive behaviours at age 2 years. In contrast to work from older children and adults, our findings suggest that the corpus callosum may be larger in infants who go on to develop autism spectrum disorder. This result was apparent with or without adjustment for total brain volume. Although we did not see a significant interaction between group and age, cross-sectional data indicated that area and thickness differences diminish by age 2 years. Regression data incorporating diffusion tensor imaging suggest that microstructural properties of callosal white matter, which includes myelination and axon composition, may explain group differences in morphology. PMID- 25937566 TI - Trauma education in a state of emergency: a curriculum-based analysis. AB - BACKGROUND: Trauma is the leading cause of death from ages 1-44-y in the United States and the fifth leading cause of death overall, but there are few studies quantifying trauma education in medical school. This study reviews curriculum hours devoted to trauma education at a northeastern medical school. MATERIALS AND METHODS: We reviewed the preclinical curriculum at a northeastern medical school affiliated with three adult and two pediatric level I trauma centers verified by the American College of Surgeons. We reviewed curricular hours and we categorized them according to the leading ten causes of death in the United States. We also compared the number of educational hours devoted to trauma to other leading causes of death. RESULTS: The total amount of time devoted to trauma education in the first 2 y of medical school was 6.5 h. No lectures were given on the fundamentals of trauma management, traumatic brain injury, or chest or abdominal trauma. The most covered topic was heart disease (128 h), followed by chronic lower respiratory disease (80 h). Curricular time for heart disease, chronic lower respiratory disease, cancer, diabetes, renal disease, and influenza and pneumonia far exceeded that devoted to trauma, after adjusting for the mortality burden of these diseases (P < 0.05 for all). CONCLUSIONS: Our study demonstrates that trauma education at a northeastern medical school is nearly absent. With the large burden of trauma and rise in mass casualty incidence, the preclinical curriculum might not be sufficient to expose students to the fundamentals of trauma management. A broader multi-institutional study may shed more insight on these curricular deficiencies in trauma education and detect if these deficiencies are widespread nationally. PMID- 25937567 TI - Gangrenous cholecystitis: a contemporary review. AB - BACKGROUND: Despite the established superiority of laparoscopic cholecystectomy (LC) for acute cholecystitis, gangrenous cholecystitis (GC) is commonly treated with open cholecystectomy (OC). This study aimed to characterize outcomes of GC in the modern era and between LC or OC surgical approach. MATERIALS AND METHODS: Patients with a diagnosis of GC were identified using the 2005-2011 National Surgical Quality Improvement Project Participant User File. Baseline patient and operative characteristics and 30-d outcomes were established for all patients. Patients were stratified by surgical approach (LC or OC), and groups were propensity matched with a nearest-neighbor matching algorithm. Primary outcomes were 30-d mortality and any 30-d complication. A nonparsimonious multiple logistic regression model was used in the matched subset to adjust for patient comorbidities, demographics, and laboratory values. RESULTS: A total of 141,970 cholecystectomies were identified with 7017 having a diagnosis of GC. Overall 30 d mortality for the entire cohort was 0.8% (n = 239) and overall 30-d complication rate was 8.0% (n = 2485). For GC patients, the 30-d mortality was 1.2% (n = 84) and overall complication rate was 10.8% (n = 761). The multivariate logistic regression model demonstrated a significant decrease in overall (odds ratio = 0.46; P < 0.001) complication rates for LC patients but did not reveal a significant difference in 30-d mortality (odds ratio = 0.59; P = 0.12). CONCLUSIONS: GC is associated with increased morbidity and mortality compared with that of acute cholecystitis. A LC approach is a safe option for patients with GC and is associated with decreased 30-d morbidity. Although LC should be used when possible for GC to minimize postoperative complications, OC should not be avoided if necessary to ensure patient safety. PMID- 25937568 TI - Outcomes after ileoanal pouch surgery in frail and older adults. AB - BACKGROUND: Evidence from single-center studies suggests that ileal pouch-anal anastomosis (IPAA) can be safely performed in selected older patients with ulcerative colitis. The impact of age and frailty on surgical outcomes and hospital length of stay after IPAA has not been examined. METHODS: We identified all patients with ulcerative colitis who underwent total proctocolectomy or completion proctectomy with IPAA in the National Surgery Quality Improvement Program database from 2005-2012. We examined the associations of age and frailty trait count with length of hospital stay and surgical complications using multivariate regression. RESULTS: IPAA was performed in 2493 patients with ulcerative colitis. Thirty-day mortality was 0.2% (n = 6). The majority of patients had no serious postoperative complications (age <=50 y: 79.5%, age 51-60 y: 80.4%, and age >60 y: 79.1%). After multivariate risk adjustment, patients aged >60 y had a similar mean number of complications as patients aged <=50 y (0.31 versus 0.35, P = 0.47) and a 0.8-d longer mean length of hospital stay (7.4 versus 8.2 d, P = 0.035). Compared to patients with zero frailty traits, a frailty trait count >=1 was associated with a similar mean number of complications (0.31 versus 0.34, P = 0.36) and length of hospital stay (7.4 versus 7.7 d, P = 0.25). CONCLUSIONS: In this analysis of patients undergoing IPAA at National Surgery Quality Improvement Program hospitals, surgical complications were not substantially increased in older patients or those with frailty traits. Older age was associated with a small increase in hospital length of stay. These findings suggest that IPAA is safe in selected older adults with ulcerative colitis. PMID- 25937569 TI - Genetic Basis of Common Human Disease: Insight into the Role of Missense SNPs from Genome-Wide Association Studies. AB - Recent genome-wide association studies (GWAS) have led to the reliable identification of single nucleotide polymorphisms (SNPs) at a number of loci associated with increased risk of specific common human diseases. Each such locus implicates multiple possible candidate SNPs for involvement in disease mechanism. A variety of mechanisms may link the presence of an SNP to altered in vivo gene product function and hence contribute to disease risk. Here, we report an analysis of the role of one of these mechanisms, missense SNPs (msSNPs) in proteins in seven complex trait diseases. Linkage disequilibrium information was used to identify possible candidate msSNPs associated with increased disease risk at each of 356 loci for the seven diseases. Two computational methods were used to estimate which of these SNPs has a significant impact on in vivo protein function. 69% of the loci have at least one candidate msSNP and 33% have at least one predicted high-impact msSNP. In some cases, these SNPs are in well established disease-related proteins, such as MST1 (macrophage stimulating 1) for Crohn's disease. In others, they are in proteins identified by GWAS as likely candidates for disease relevance, but previously without known mechanism, such as ADAMTS13 (ADAM metallopeptidase with thrombospondin type 1 motif, 13) for coronary artery disease. In still other cases, the missense SNPs are in proteins not previously suggested as disease candidates, such as TUBB1 (tubulin, beta 1, class VI) for hypertension. Together, these data support a substantial role for this class of SNPs in susceptibility to common human disease. PMID- 25937571 TI - Remote acute demyelination after focal proton radiation therapy for optic nerve meningioma. AB - We present a unique patient with delayed onset, acute demyelination that occurred distant to the effective field of radiation after proton beam radiotherapy for an optic nerve sheath meningioma. The use of stereotactic radiotherapy as an effective treatment modality for some brain tumors is increasing, given technological advances which allow for improved targeting precision. Proton beam radiotherapy improves the precision further by reducing unnecessary radiation to surrounding tissues. A 42-year-old woman was diagnosed with an optic nerve sheath meningioma after initially presenting with vision loss. After biopsy of the lesion to establish diagnosis, the patient underwent stereotactic proton beam radiotherapy to a small area localized to the tumor. Subsequently, the patient developed a large enhancing mass-like lesion with edema in a region outside of the effective radiation field in the ipsilateral frontal lobe. Given imaging features suggestive of possible primary malignant brain tumor, biopsy of this new lesion was performed and revealed an acute demyelinating process. This patient illustrates the importance of considering delayed onset acute demyelination in the differential diagnosis of enhancing lesions in patients previously treated with radiation. PMID- 25937570 TI - Crosstalk between Hippo and TGFbeta: Subcellular Localization of YAP/TAZ/Smad Complexes. AB - The Hippo pathway plays a crucial role in growth control, proliferation and tumor suppression. Activity of the signaling pathway is associated with cell density sensing and tissue organization. Furthermore, the Hippo pathway helps to coordinate cellular processes through crosstalk with growth-factor-mediated signaling pathways such as TGFbeta. Here we have examined the localization of interactions between proteins of the Hippo pathway (YAP/TAZ) and TGFbeta (Smad2/3) signaling pathway by using in situ proximity ligation assays. We investigated the formation of protein complexes between YAP/TAZ and Smad2/3 and examined how these interactions were affected by TGFbeta stimulation and cell density in HaCaT keratinocytes and in Smad4-deficient HT29 colon cancer cells. We demonstrate that TGFbeta induces formation of YAP/TAZ-Smad2/3 complexes in HaCaT cells. Under sparse cell conditions, the complexes were detected to a higher degree and were predominantly located in the nucleus, while under dense culture conditions, the complexes were fewer and mainly located in the cytoplasm. Surprisingly, we could not detect any YAP/TAZ-Smad2/3 complexes in HT29 cells. To examine if Smad4 deficiency was responsible for the absence of interactions, we treated HaCaT cells with siRNA targeting Smad4. However, we could still observe complex formation in the siRNA-treated cells, suggesting that Smad4 is not essential for the YAP-Smad2/3 interaction. In conclusion, this study shows localized, density-dependent formation of YAP/TAZ-Smad2/3 complexes in HaCaT cells and provides evidence supporting a crosstalk between the Hippo and the TGFbeta signaling pathways. PMID- 25937572 TI - O-arm failure traps patient prone on a Jackson table. AB - The O-arm Surgical Imaging System (Medtronic Sofamor Danek, Memphis, TN, USA) is an increasingly popular tool for spinal surgical procedures that allows for intraoperative acquisition of multi-dimensional spinal imaging that can be used either to confirm placement of spinal instrumentation or to guide spinal screw placement in conjunction with a navigation system. The machine is typically placed open from the side of the patient positioned prone on the Jackson spinal table (Mizuho OSI, Union City, CA, USA) and then closed to complete a ring around the patient to acquire images. A failure of the O-arm opening mechanism can lead to a patient becoming effectively trapped within the device with limited physician access to the patient's body, a situation that may be remedied by using a manual opening procedure. This report highlights a patient safety issue encountered when a mechanical failure of the O-arm occurred and one of the two tools required for its manual opening was missing. We describe the improvised method employed to successfully open the device. PMID- 25937573 TI - BRAF V600E mutation in neocortical posterior temporal epileptogenic gangliogliomas. AB - The aim of this study was to verify the presence of BRAF mutations in a series of six patients affected by drug-resistant focal epilepsy associated with neocortical posterior temporal gangliogliomas (GG) who were subjected to lesionectomy between June 2008 and November 2013. GG are an increasingly recognized cause of epilepsy and represent the most common tumor in young patients undergoing surgery for intractable focal epilepsy. BRAF mutations have been identified in up to 50% of GG. Interestingly, these six patients shared a specific anatomical posterior temporal site. In all patients, histological examination confirmed the diagnosis of GG, and two were also associated with a focal cortical dysplasia (FCD) type IIa. BRAF mutations were found in four out of six GG (66.6%). Furthermore, dysplastic tissue of Patient 2 showed a concomitant BRAF V600E mutation. All patients but one (83.3%) achieved Engel Class Ia seizure control. The patient carrying a concomitant BRAF mutation in GG and FCD fell into Engel Class II. Further analyses will be required in order to better understand the meaning of BRAF mutations in epilepsy-associated tumors and FCD and their possible role as a prognostic seizure outcome and tumor behavior marker. PMID- 25937574 TI - L-Menthone confers antidepressant-like effects in an unpredictable chronic mild stress mouse model via NLRP3 inflammasome-mediated inflammatory cytokines and central neurotransmitters. AB - L-Menthone (MTN) is a Chinese old remedy extracted from the genus Mentha. It has been widely used as a cooling agent and a counterirritant for pain relief, although its antidepressant-like effects have not yet been reported. The present study was designed to investigate whether MTN confers an antidepressant-like effect in mice exposed to unpredictable chronic mild stress (UCMS) and to explore its potential mechanisms. The effects of MTN on mouse behavioral changes were investigated in our study. We determined the levels of the nucleotide binding, oligomerization domain-like receptor family pyrin domain-containing 3 (NLRP3) inflammasome, inflammatory cytokines and neurotransmitters in the hippocampus of mice. Behavioral tests, including the sucrose preference test (SPT), open field test (OFT), forced swimming test (FST) and tail suspension test (TST) revealed that MTN (15 and 30mg/kg) treatments for 3weeks alleviated the depression symptoms of UCMS in mice. Mice receiving MTN treatments exhibited reduced levels of NLRP3 and caspase-1. Moreover, MTN treatments reversed the UCMS-induced alterations in the concentrations of neurotransmitter norepinephrine (NE) and serotonin (5-HT) and inhibited the expression of pro-inflammatory cytokines (PIC) interleukin (IL)-1beta, IL-6, and tumor necrosis factor (TNF)-alpha in the hippocampus of mice. Taken together, our findings suggested that MTN may play a potential antidepressant-like role in the UCMS mouse model by regulating the NLRP3 inflammasome and mediating inflammatory cytokines and central neurotransmitters, which together provide insight towards the development of novel therapeutic treatments for depression. PMID- 25937575 TI - Intrathecal injection of KN93 attenuates paradoxical remifentanil-induced postoperative hyperalgesia by inhibiting spinal CaMKII phosphorylation in rats. AB - AIMS: Remifentanil is a short-acting and highly selective mu opiate agonist that is used in many clinical surgical situations for intraoperative pain relief. Under certain conditions, remifentanil can produce "paradoxical" hyperalgesia. This study aims to investigate mechanisms of actions mediating this "paradoxical" effect. METHODS: Sprague-Dawley rats were divided into 6 groups including control and treatment groups. The paw withdrawal mechanical threshold and the paw withdrawal thermal latency of the rats were tested. The changes of rat behaviors were measured at 24h before intrathecal injection and at 2h, 6h, 24h, and 48h after operation. According to the changes in behavioral indicators of pain, the specimens of all groups were collected at 2h, 6h, 24h, and 48h after the operation. The level of calcium/calmodulin-dependent protein kinase II (CaMKII) phosphorylation in the spinal dorsal horn was analyzed by Western blotting. RESULTS: Intraoperative infusion of remifentanil induced postoperative hyperalgesia in the rats. Intrathecal KN93 injection increased nociceptive thresholds of paw withdrawal mechanical threshold and paw withdrawal thermal latency in a dose-dependent manner. Western blotting results showed that CaMKII phosphorylation in the spinal dorsal horn was increased significantly by remifentanil. Inhibition of CaMKII phosphorylation relieved the hyperalgesia pain state. CONCLUSIONS: Intrathecal injection of KN93 attenuates postoperative hyperalgesia induced by intraoperative infusion of remifentanil in rats through inhibiting spinal CaMKII phosphorylation. PMID- 25937576 TI - A novel sucrose hydrolase from the bombycoid silkworms Bombyx mori, Trilocha varians, and Samia cynthia ricini with a substrate specificity for sucrose. AB - Although membrane-associated sucrase activity has been detected in the midgut of various lepidopteran species, it has not yet been identified and characterized at the molecular level. In the present study, we identified a novel sucrose hydrolase (SUH) gene from the following three bombycoid silkworms: Bombyx mori, Trilocha varians, and Samia cynthia ricini and named them BmSuh, TvSuh, and ScSuh, respectively. The EST dataset showed that BmSuh is one of the major glycoside hydrolase genes in the larval midgut of B. mori. These genes were almost exclusively expressed in the larval midgut in all three species, mainly at the feeding stage. SUHs are classified into the glycoside hydrolase family 13 and show significant homology to insect maltases. Enzymatic assays revealed that recombinant SUHs were distinct from conventional maltases and exhibited substrate specificity for sucrose. The recombinant BmSUH was less sensitive to sugar-mimic alkaloids than TvSUH and ScSUH, which may explain the reason why the sucrase activity in the B. mori midgut was less affected by the sugar-mimic alkaloids derived from mulberry. PMID- 25937577 TI - Rapid palatal expansion: the role of microcirculation. AB - AIM: Transverse palate modifications fall under expansive orthopedic therapy of the upper maxilla. The only practical approach to the problem on the transverse plane is that of performing the expansion of the maxillary arch through an opening of the median palatal suture. It is important to understand the changes of the vascular network in midpalatal suture following the starting of rapid maxillary expansion. It is critical to maintain the blood supply and circulation for the osteogenesis and bone remodeling after the expansion. The aim of this research was to evaluate the effects of rapid orthopedic expansion (REP) at the microcirculatory level through capillaroscopic examination. METHODS: Fifteen patients in their developing years between 9 and 15 years of age (average age 12.16 years) were examined. The application of the REP was the first step in the planning of orthopedic-orthodontic treatment which foresaw further stages in the odonto-osseous movement. The method of Biomicroscopic Video-Imaging of the microcirculation of oral mucosa is performed through the technique of computerized capillaroscopy and the related software. RESULTS: From the results it is evident that immediately after achieving the expansion of the upper maxilla (t1), a slight decrease in the number of vessels per mm2 can be observed. In addition, a slight ectasia can be observed in these vessels in comparison to t0. Comparing the videocapillaroscopic images of t1 and t2, an increase in the capillaries per mm2 can be observed. CONCLUSION: Ectasia of the capillaries, though subject to strictly individual variables, can be considered perfectly normal and it is compatible with the normal biology and physiology of vessel microcirculation. PMID- 25937578 TI - Clinical evaluation of the oral health status in vascular-type dementia patients. A case-control study. AB - AIM: The aim of this study was to evaluate the oral health status in patients with vascular dementia (VaD). Moreover, the association of the disease severity and the patients' cognitive and functional impairment with the oral findings have been recorded. METHODS: The study was directed on the study group (86 VaD patients) and the control group (82 healthy volunteers of the same age) from the IRCSS Neurolesi Bonino-Pulejo in Messina, Italy. Cognitive status was evaluated with the MMSE scoring system. Oral parameters, such as decaying, missing, filled teeth (DMFT) index, plaque index (PI), periodontal probing depth (PPD) and bleeding on probing (BOP) were evaluated in all patients. Denture condition and denture-induced stomatitis were also analysed. The frequency of untreated caries, periodontal diseases and missing teeth of the Study Group was significantly higher than in Control Group. RESULTS: Particularly, VaD patients presented higher number of decayed teeth and deeper periodontal pockets. Decreased cognitive functions in VaD patients have been demonstrated to result in a decline of denture care and increased denture-related mucosal lesions. CONCLUSION: These results underlined that clinicians should direct high attention to oral hygiene of patients with VaD in order to prevent the evolution of those pathologic dental and periodontal conditions, especially in patients with decreased cognitive functions. PMID- 25937579 TI - Assessment of difficulty in third impacted mandibular molar surgery: the Conti Scale. AB - AIM: We suggest a numerical method for the preoperative assessment of difficulty in mandibular third molar surgeries. METHODS: This study enrolled 1000 subjects ranging in, age from 17 to 91 years, who presented to the Clinic of Maxillary Facial Surgery at the, University of Florence in Italy, for impacted mandibular third molars removal in 2013. The difficulty of extraction was analyzed for each patient. RESULTS: Comparison of preoperative difficulty assessment scores with the actual difficulty encountered by an operator, confirming the reliability of our protocol. CONCLUSION: Careful preoperative analysis of the extraction difficulties and correct surgical planning can reduce intra and postoperative complications, in the third impacted mandibular molar surgeries. The use of an easy and rapid method for the assessment of difficulty in third molar surgeries, is an efficient clinical methodology for preoperative analysis. PMID- 25937580 TI - Oral complications of head and neck radiotherapy: prevalence and management. AB - AIM: The aim of the study was to evaluate the short-term and long-term toxicity caused by radiation treatment in the head and neck with the technique of intensity-modulated radiotherapy (IMRT). METHODS: We selected 20 patients, 18 men and 2 women aged between 21 and 71 years, undergoing radiation therapy (IMRT) in head and neck. Patients were visited during radiotherapy and followed for six months after the end of the therapy. We assessed the presence of: mucositis, xerostomia, dysgeusia, dysphagia, pain, trismus and, in the case of late-onset complications, radiation cavities. RESULTS: Acute toxicity: in 20 patients, 18 reported mucositis, 19 xerostomia, 17, dysgeusia, 15 dysphagia, 18 had pain and 3 patients had trismus. Tardive toxicity: in 14 patients, 5 reported mucositis, 11 xerostomia, 6 dysgeusia, 2 dysphagia, 3 had pain, 4 trismus and in 4 patients were found radiation cavities. CONCLUSION: Acute complications with higher prevalence were xerostomia (19 of 20 patients), dysgeusia of 2nd grade (11 patients of 20), mucositis of 1st grade and pain of 1st grade (10 patients of 20). Among the late complications it was noted a maintenance of the high prevalence of xerostomia (11 patients of 14) and an increase in prevalence of trismus (4 patients of 14) against a reduction of all other complications. The presence of radiation cavities in 4 patients of 14 was also recorded. PMID- 25937581 TI - Unilateral cleft lip repair during charity missions: a consideration about simultaneously lip and nose repair. AB - AIM: Cleft nose is an important sequela after primary cheiloplasty in cleft lip patients. Not touching the cleft lip nose in primary cleft lip repair was dogmatic in the past, although it meant severe functional, aesthetic, and psychologic problems for the child. Authors present their experience in one step lip, septum and nasal tip repair for this patients population. METHODS: From March 2012 to January 2013, during charity missions organized in Africa, 56 patients affected by cleft lip deformity and sequelas of previous cleft lip surgery were operated. RESULTS: Two complications were recorded. A good nostril symmetry was reached in all the cases. CONCLUSION: Authors present their experience in one step lip, septum and nasal tip repair for unilateral cleft lip patients. The big lack of this study is the absence of a long follow-up due to the surgery performed during charity missions. Thanks to the recent papers published in literature we can state that primary septal repositioning is a safe adjunctive technique to primary lip closure, although this operation reduces the psychosocial consequences of an otherwise uncorrected cleft nose deformity, it does not necessarily eliminate the need for a future operation. PMID- 25937582 TI - Pigmented villonodular synovitis of temporomandibular joint: pathological aspects and surgical treatment. AB - Pigmented villonodular synovitis (PVNS) is an uncommon, benign, tumour-like disorder of unknown etiology affecting synovium-lined joints, tendon sheaths, and bursae. It results in proliferative, locally invasive lesions, usually presenting in monoarticular form in adults. PVNS rarely presents in the temporomandibular joint (TMJ). The treatment of choice is complete surgical excision of the lesion, followed by immediate reconstruction. We report a case of PVNS with masticatory space involvement, and focus on the pathological aspects and surgical treatment of the lesion. PMID- 25937583 TI - Analysis of risk factors of long-term complications in congenital diaphragmatic hernia: A single institution's experience. AB - OBJECTIVE: To establish better management practices to reduce morbidities in survivors with congenital diaphragmatic hernia (CDH). METHODS: Of 60 patients treated for CDH at our institution between 1991 and 2011, 49 patients without severe anomalies were retrospectively reviewed. RESULTS: Since 2004, gentle ventilation (GV) has been the main treatment for CDH. Patients were divided into the following two groups: the non-GV group (n = 29) who were treated before GV treatment was implemented, and the GV group (n = 20). The overall survival rate was 62.1% (18/29) and 95% (19/20) in the non-GV and GV groups, respectively (p = 0.016). Despite the high survival rate, the incidence of long-term complications in survivors was still high (14/19, 73.7%) in the GV group. In the GV group, liver-up (p = 0.106) and the need for patch repair (p = 0.257) tended to be associated with the development of long-term complications, but did not reach statistical significance. The presence of perioperative complications was associated with the development of long-term complications (p = 0.045) in the GV group. CONCLUSION: Patients who developed short-term complications seemed to be at risk of long-term complications. Therefore, to minimize long-term morbidities in CDH survivors, the prevention of short-term complications might be important. PMID- 25937584 TI - Comparison of Ho:Yag laser and pneumatic lithotripsy combined with transurethral prostatectomy in high burden bladder stones with benign prostatic hyperplasia. AB - OBJECTIVES: To compare the efficacy and reliability of Ho:YAG laser lithotripsy (HLL) and pneumatic lithotripsy (PL) in the treatment of bladder stones in patients with benign prostatic hyperplasia and stones >= 20 mm who were transurethrally treated in the same surgical session. METHODS: We studied the data of patients with benign prostatic hyperplasia and >=20 mm bladder stones who were treated with transurethral resection of the prostate and cystolithotripsy in the same session, obtained between January 2010 and February 2014 from three urology clinics. All patients underwent bipolar plasmakinetic (PK) transurethral resection of the prostate. For treatment of the bladder stone, either HLL or PL was applied. A total of 62 patients were divided into two groups: PK-PL (Group 1, n = 29) and PK-HLL (Group 2, n = 33). The data of both groups were analyzed for stone dimensions, stone fragmentation time, total operating time, hospitalization duration, prostate dimensions, success rates, and complications. RESULTS: Group 1 included 29 patients with a mean age of 70 +/- 7.6 (range, 57-85) years, whereas Group 2 included 33 patients with a mean age of 67.5 +/- 10.5 (range, 45-84) years. In Group 1, five patients had mucosa injury, one patient had residual stone, and one patient had bladder perforation. In Group 2, three patients had mucosa injury, three patients had postoperative fever, and one patient had residual stone. Total operation time and stone fragmentation time were significantly lower in Group 2 (p < 0.05). The remaining analyzed data were similar (p > 0.05). CONCLUSION: PK-HLL using a single shaft without the need for repeated access has the advantages of shorter fragmentation and operation time. PMID- 25937585 TI - Diagnostic imaging of intracranial metastasis. PMID- 25937586 TI - Foreword. Brain metastases. PMID- 25937587 TI - Bouts and breaks in children's sedentary time: currently used operational definitions and recommendations for future research. AB - Increasing attention is paid to the potential health effects of children's sedentary bouts and breaks, rather than total sedentary time. This paper discusses currently used operational definitions of sedentary bouts and breaks in studies among children. Remarkably, these studies applied different operational definitions, complicating comparison between studies. To advance the field of sedentary behaviour epidemiology, we need a clear and 'evidence-based' operationalization for such sedentary bouts and breaks. PMID- 25937588 TI - Trends in prolonged sitting time among European adults: 27 country analysis. AB - OBJECTIVE: To examine trends in adult sitting time across 27 European countries. METHOD: Data were from the Eurobarometer surveys collected in 2002, 2005, and 2013. Sitting time data were used to categorise respondents into 'low' (0 to 4h30min), 'middle' (4h31min to 7h30min), and 'high' levels of sitting (>7h30min). We modelled the likelihood of being in the high sitting group within a given country and overall across the three time points, controlling for age, gender, education, employment status, and physical activity. RESULTS: In total 17 countries had sitting data at all three time points; among these countries the prevalence of 'high sitting' decreased steadily from 23.1% (95% CI=22.2-24.1) in 2002 to 21.8% (95% CI=20.8-22.8) in 2005, and 17.8% (95% CI=16.9-18.7) in 2013. A further 10 countries had data only over the latter two time points; among these countries the prevalence of high sitting decreased from 27.7% (95% CI=26.0-29.4) in 2005 to 19.0% (95% CI=17.6-20.5) in 2013. CONCLUSION: Time spent in sedentary behaviour may not be increasing in the European region, and prolonged sitting may, in fact, be decreasing. This finding has important implications for the sedentary behaviour debate and the policy response. PMID- 25937589 TI - Healthy eating index and metabolically healthy obesity in U.S. adolescents and adults. AB - OBJECTIVE: To determine whether dietary quality differs between metabolically healthy-obese (MHO) and metabolically-abnormal-obesity (MAO) in a nationally representative sample. METHODS: National Health and Nutrition Examination Survey (NHANES) data (2007-2008; 2009-2010) were used to identify obese adolescents (>=95th body mass index (BMI) %tile) and adults (>=30kg/m(2)). MHO was defined as <2 abnormal cardiometabolic risk factors (elevated blood pressure, triglycerides, glucose, low high density lipoprotein cholesterol (HDL-C); or on medications). Healthy Eating Index 2005 (HEI-2005) scores were calculated from 24-hour recall data. General linear regression models determined whether HEI-2005 scores differed between MHO and MAO after controlling for age, race, gender, NHANES wave, BMI, physical activity and health status by age group (12-18; 19-44; 45 85years). RESULTS: Compared with MAO, MHO adolescents (n=133) had higher total HEI-2005 score, higher milk scores, and higher scores from calories from solid fats, alcohol beverages and added sugars. MHO women 19-44years (n=240) had higher total HEI-2005, higher whole fruit, higher whole grain and higher meat and bean scores compared with MAO. No significant differences were observed between MHO and MAO for HEI-2005 total scores in men 19-44years, or adults 45-85years. CONCLUSION: MHO adolescents and women 19-44years have better dietary compliance to the U.S. guidelines when compared with MAO, suggesting potential intervention targets to improve cardiometabolic risk within obesity. PMID- 25937590 TI - Psychological distress as a determinant of changes in body mass index over a period of 10years. AB - OBJECTIVE: To examine the longitudinal relationship between psychological distress and body mass index (BMI) changes over a period of five and ten years. METHOD: Data were used from the Dutch, prospective, population based Doetinchem Cohort study over the period 1995/1999 until 2005/2009 (N=5504). Psychological distress was assessed using the Mental Health Inventory (MHI-5). BMI (kg/m(2)) was calculated from measured body height and body weight. GEE analyses were used to examine the relationship between psychological distress at baseline and BMI change, and the development of overweight over five years. Linear and logistic regression analyses were used to examine these relations over ten years. RESULTS: Psychological distress predicted an extra overall increase in BMI of 0.14kg/m(2) (95% CI 0.03-0.25) over five years and an increase of 0.18kg/m(2) (95% CI 0.01 0.35) over ten years, when comparing psychologically distressed participants to psychologically healthy participants. This was especially the case among persons with normal weight (five years; B=0.26kg/m(2), 95% CI=0.12-0.40/ten years; B=0.32kg/m(2) 95% CI=0.11-0.53) and moderate overweight (five years: B=0.18kg/m(2), 95% CI=0.02-0.35) at baseline. Psychological distress did not predict the development of overweight five and ten years later. CONCLUSION: The results in this study indicated that psychological distress predicted an increased risk in gaining weight, but did not result in an increased risk for developing overweight. PMID- 25937591 TI - City planning as preventive medicine. AB - The health and well-being of rapidly growing urban populations is a global health issue. Cities in the global north and south are faced with rising health inequities - or avoidable differences in health determinants and outcomes based on place, social status and ethnicity. This commentary suggests that focusing only on treatment interventions in cities is likely to fail because populations will be forced to go back into the urban living and working conditions that likely made them sick in the first place. City planning as preventive medicine includes taking a relational and systems approach to urban health, requiring health assessments for all urban policy making, promoting neighborhood health centers as engines of community economic development and gathering place-based health indicator data to track progress and adapt interventions over time as conditions change. PMID- 25937592 TI - Sources of guns to dangerous people: what we learn by asking them. AB - Gun violence exacts a lethal toll on public health. This paper focuses on reducing access to firearms by dangerous offenders, contributing original empirical data on the gun transactions that arm offenders in Chicago. Conducted in the fall of 2013, analysis of an open-ended survey of 99 inmates of Cook County Jail focuses on a subset of violence-prone individuals with the goal of improving law enforcement actions. Among our principal findings: *Our respondents (adult offenders living in Chicago or nearby) obtain most of their guns from their social network of personal connections. Rarely is the proximate source either direct purchase from a gun store, or theft. *Only about 60% of guns in the possession of respondents were obtained by purchase or trade. Other common arrangements include sharing guns and holding guns for others. *About one in seven respondents report selling guns, but in only a few cases as a regular source of income. *Gangs continue to play some role in Chicago in organizing gun buys and in distributing guns to members as needed. *The Chicago Police Department has a considerable effect on the workings of the underground gun market through deterrence. Transactions with strangers and less-trusted associates are limited by concerns over arrest risk (if the buyer should happen to be an undercover officer or a snitch), and about being caught with a "dirty" gun (one that has been fired in a crime). PMID- 25937594 TI - Alcohol misuse, firearm violence perpetration, and public policy in the United States. AB - OBJECTIVE: Firearm violence is a significant public health problem in the United States, and alcohol is frequently involved. This article reviews existing research on the relationships between alcohol misuse; ownership, access to, and use of firearms; and the commission of firearm violence, and discusses the policy implications of these findings. METHOD: Narrative review augmented by new tabulations of publicly-available data. RESULTS: Acute and chronic alcohol misuse is positively associated with firearm ownership, risk behaviors involving firearms, and risk for perpetrating both interpersonal and self-directed firearm violence. In an average month, an estimated 8.9 to 11.7 million firearm owners binge drink. For men, deaths from alcohol-related firearm violence equal those from alcohol-related motor vehicle crashes. Enforceable policies restricting access to firearms for persons who misuse alcohol are uncommon. Policies that restrict access on the basis of other risk factors have been shown to reduce risk for subsequent violence. CONCLUSION: The evidence suggests that restricting access to firearms for persons with a documented history of alcohol misuse would be an effective violence prevention measure. Restrictions should rely on unambiguous definitions of alcohol misuse to facilitate enforcement and should be rigorously evaluated. PMID- 25937593 TI - Interim treatment: Bridging delays to opioid treatment access. AB - OBJECTIVE: Despite the undisputed effectiveness of agonist maintenance for opioid dependence, individuals can remain on waitlists for months, during which they are at significant risk for morbidity and mortality. To mitigate these risks, the Food and Drug Administration in 1993 approved interim treatment, involving daily medication+emergency counseling only, when only a waitlist is otherwise available. We review the published research in the 20years since the approval of interim opioid treatment. METHODS: A literature search was conducted to identify all randomized trials evaluating the efficacy of interim treatment for opioid dependent patients awaiting comprehensive treatment. RESULTS: Interim opioid treatment has been evaluated in four controlled trials to date. In three, interim treatment was compared to waitlist or placebo control conditions and produced greater outcomes on measures of illicit opioid use, retention, criminality, and likelihood of entry into comprehensive treatment. In the fourth, interim treatment was compared to standard methadone maintenance and produced comparable outcomes in illicit opioid use, retention, and criminal activity. CONCLUSIONS: Interim treatment significantly reduces patient and societal risks when conventional treatment is unavailable. Further research is needed to examine the generality of these findings, further enhance outcomes, and identify the patient characteristics which predict treatment response. PMID- 25937595 TI - Laparoscopic Double Discoid Resection With a Circular Stapler for Bowel Endometriosis. AB - STUDY OBJECTIVE: To demonstrate the technique of laparoscopic double discoid resection with a circular stapler for bowel endometriosis. DESIGN: Case report (Canadian Task Force classification III). SETTING: Private hospital in Curitiba, Parana, Brazil. PATIENT: A 33-year-old woman was referred to our service complaining about cyclic dysmenorrhea, dyspareunia, chronic pelvic pain, and cyclic dyschezia. Transvaginal ultrasound with bowel preparation showed a 6-cm endometriotic nodule at the retrocervical area, uterosacral ligaments, posterior vaginal fornix, and anterior rectal wall, infiltrating up to the submucosa, 5 cm far from the anal verge. INTERVENTIONS: Under general anesthesia, the patient was placed in the dorsal decubitus position with her arms alongside her body and her lower limbs in abduction. Pneumoperitoneum was achieved using a Veres needle placed at the umbilicus. Four trocars were placed: a 10-mm trocar at the umbilicus for the zero-degree laparoscope; a 5-mm trocar at the right anterosuperior iliac spine; a 5-mm trocar in the midline between the umbilicus and the pubic symphysis, approximately 8 to 10 cm inferior to the umbilical trocar; and a 5-mm trocar at the left anterosuperior iliac spine. The entire pelvis was inspected for endometriotic lesions, and all implants in the anterior compartment of the pelvis were resected. The lesions located at the ovarian fossae were completely removed. The ureters were identified bilaterally, and both para-rectal fossae were dissected. The right hypogastric nerve was released from the disease laterally. The lesion was separated from the retrocervical area, and the posterior vaginal fornix was resected (reverse technique), leaving the disease attached to the anterior surface of the rectum. The lesion was shaved off the anterior rectal wall using a harmonic scalpel. A x-shaped stitch was placed at the anterior rectal wall using 2-0 mononylon suture. A 33-mm circular stapler was placed transanally under laparoscopic control, and once it reached the area to be resected, it was opened. A gap was created between the envil and the stapler. The anterior rectal wall was placed inside this gap with the aid of the stitch at the anterior rectal wall. The stapler was fired, and a piece of the anterior rectal wall was resected. The same procedure was performed using a 29-mm circular stapler, which allowed for the complete removal of the lesion. We usually perform the second discoid resection using a 29-mm circular stapler to allow an easy progression of the stapler through the rectum beyond the first stapler line, so not to put too much pressure on it. In our experience, the first discoid resection removes most of the disease, and the second discoid resection is only needed to remove a small amount of residual disease, along with the first staple line. MEASUREMENTS AND MAIN RESULTS: The procedure took 177 min, and the estimated blood loss was 100 mL. The patient started clear liquids 6 hours after the procedure, and was discharged 19 hours after that [1]. Pathological examination of the 2 strips of the anterior rectal wall revealed infiltration of the bowel wall by endometriotic tissue. She had an uneventful postoperative course, and was able to re-start sexual intercourse 50 days after surgery. Between January 2010 and January 2015, 315 women underwent laparoscopic surgery for the treatment of bowel endometriosis in our service. Among them, 16 (5.1%) were operated on by using the double discoid resection technique. Median age of the patients was 34 years, and median body mass index was 25.9 kg/m(2). Median preoperative cancer antigen-125 level was 26.5 U/mL (normal value is <35 U/mL). Median size of the rectosigmoid nodule was 35 mm (range: 30-60), and median distance from the anal verge was 10.5 cm (range: 5-15 cm). Median surgical time was 160 min (range: 54-210 min). Concomitant procedures included hysterectyomy (n = 5), partial cystectomy (n = 3), resection of the posterior vaginal fornix (n = 4), and appendectomy (n = 1). Median estimated intraoperative bleeding was 32.5 mL (range: 30-100), and median time of hospitalization was 19 hours (range: 10 41). Median American Fertility Society score was 46 (10-102). Two minor complications (12.5%) occurred in this initial series: 1 patient required bladder catheterization for urinary retention; and 1 patient developed a urinary tract infection that required oral antibiotic treatment. One major complication (6.2%) was observed; the patient developed fever and abdominal pain on the fourth postoperative day. She was re-operated, and the intraoperative diagnosis was pelviperitonitis. The abdominal cavity was inspected for any dehiscence of the bowel and then washed. She was discharged on the second day after re-operation with oral antibiotic therapy. In our daily practice, we are used to discharging our patients soon in the postoperative setting (19 hours for rectal shaving or discoid resection and 28 hours for segmental bowel resection) [1] because the rate of postoperative fistula seems to be low [2]. Because we still have not seen any fistulas after conservative surgery (rectal shaving, discoid resection, and double discoid resection), we usually prefer to perform this type of surgery compared with segmental bowel resection, when possible. CONCLUSIONS: Laparoscopic double discoid resection with circular stapler may be an alternative to segmental bowel resection in selected patients with bowel endometriosis. PMID- 25937596 TI - Tips and Tricks: Preconceptional Laparoscopic Cervical Cerclage Made Easier and Safer With the Titiz Uterovaginal Manipulator. AB - STUDY OBJECTIVE: To demonstrate safe and easy surgical steps to facilitate preconceptional laparoscopic cervical cerclage with the Titiz uterovaginal manipulator. DESIGN: Narrated step-by-step video demonstration of preconceptional laparoscopic cervical cerclage under the guidance of the Titiz uterovaginal manipulator. SETTING: Cervical incompetence or cervical insufficiency is 1 of the causes of preterm birth. Incidence is 0.1% to 1% of all pregnancies. Traditionally, cervical cerclage is placed vaginally, but sometimes it is not possible to perform this procedure vaginally. When this occurs, cerclage needs to be inserted abdominally either by laparotomy or by laparoscopy. Laparoscopic cervical cerclage is indicated when vaginal cerclage has failed or is not possible due to a deficient or a short cervix caused by previous cervical surgery. Although laparoscopic cervical cerclage has a good success rate (90% 100% live births), there is a risk of injury to the bladder, sigmoid colon, and the uterine vessels. It is also important to put the suture in the right place, which is at the internal cervical os (cervico-isthmic junction) and medial to the uterine vessels. Therefore, it can be a challenging operation, especially when the uterus is bulky and more vascular due to adenomyosis or fibroids. INTERVENTION: A 32-year-old woman, G0P0, with the surgical history of cone biopsy presented with a history of infertility. On vaginal examination, there was no vaginal portion of the anterior cervix, and there was only 0.5 cm of the vaginal portion of the posterior cervix. After extensive counseling, the decision was made to perform a preconceptional laparoscopic abdominal cerclage. This video demonstrates the Titiz uterovaginal manipulator components and how to insert the manipulator. It also shows tips and tricks on laparoscopic cervical cerclage: (1) how to determine the anatomic relationships among the bladder, uterine vessels, cervico-vaginal junction and cervico-isthmic part of uterus; (2) how the Titiz uterovaginal manipulator helps to dissect the bladder and uterine arteries and veins safely; and (3) how to determine where and how to pass the sutures. MEASUREMENT AND MAIN RESULTS: The patient was discharged the same day and did not have any postoperative complications. The patient had transvaginal ultrasound 1 week after the operation. Tape was shown to be at the internal cervical os level. CONCLUSIONS: The Titiz uterovaginal manipulator can make preconceptional laparoscopic abdominal cerclage safer and easier. PMID- 25937597 TI - An update of juvenile animal studies in the European Union: What do the numbers say? AB - Concern has been raised about the number of juvenile animal studies (JAS) being conducted in the European Union (EU) and the number of species required. The question of whether there has been an increase in the number of JAS requested by European Medicines Agency (EMA) and the question of single or multiple species studies are the focus of this manuscript. All source data on Pediatric Investigation Plans (PIP) were obtained from EMA pediatrics website and evaluated by year as obtained and adjusted to the date of the original PIP agreement rather than the newly assigned date of the PIP modification. The analysis of the data originally suggested an increase in the number of juvenile animal studies per year post 2010. However, a thorough examination of the adjusted PIP data from the EMA from December 2007 through 2013 support that the number of JAS being included in PIPs per year is not increasing but is in fact fairly stable at 15-30% per year. The data also, as expected, support that the JAS are mostly proposed with a single species and that species is predominately the rat and that multi-species JAS for an agreed PIP are infrequent. PMID- 25937598 TI - Nesfatin-1 antagonized rotenone-induced neurotoxicity in MES23.5 dopaminergic cells. AB - Nesfatin-1 is a recently identified brain-gut peptide involved in feeding and energy homeostasis. Recently, it has been proved that nesfatin-1 could exert its neuroprotective effect against subarachnoid hemorrhage-induced injury via its anti-apoptotic and anti-inflammatory properties. However, whether it has neuroprotective effect on dopamine neurons is largely unknown. In the present study, we investigated the neuroprotective effect of nesfatin-1 on rotenone treated MES23.5 dopaminergic cells and illustrated the underlying mechanisms. Our results showed that nesfatin-1 pretreatment could significantly attenuate rotenone-induced cell loss. Further studies showed that the neuroprotective effect of nesfatin-1 against rotenone was mediated by reversing rotenone-induced mitochondrial dysfunction. Nesfatin-1 could rescue rotenone-induced mitochondrial transmembrane potential collapse and restore the function of mitochondrial respiratory chain complex I. In addition, rotenone-induced release of cytochrome C from mitochondria, ROS production and the subsequent caspase-3 activation were also attenuated by nesfatin-1 pretreatment. Our data suggested that nesfatin-1 exerted its neuroprotective effect on dopaminergic cells against rotenone by ameliorating mitochondrial dysfunction and its anti-apoptotic property. This suggested that nesfatin-1 had the potential to be considered as an aid for prevention of Parkinson's disease. PMID- 25937600 TI - Incidence and outcomes of intraoperative vascular surgery consultations. AB - OBJECTIVE: Vascular surgeons may aid in primarily nonvascular procedures. Such activity has not been quantified, and hospital administrators may be unaware of the importance of vascular surgeons to support other hospital-based surgical programs. This study reviewed intraoperative consultations by vascular surgeons to support other surgical services. METHODS: Intraoperative vascular consultations were reviewed from January 2006 to January 2014 for consulting service, indication, and whether consultation occurred with advanced notice. Patient demographics, operative times, estimated blood loss, length of stay, and relative value units (RVUs) assigned for each consultation were also assessed. Consultations for trauma and iatrogenic injuries occurring outside the operating theater were excluded. RESULTS: Vascular surgeons performed 225 intraoperative consultations in support of procedures by nonvascular surgeons. Requesting services were surgical oncology (46%), orthopedics (17%), urology (11%), otolaryngology (7%), and others (19%). Reasons for consultation overlapped and included vascular reconstruction (53%), control of hemorrhage (39%), and assistance with difficult dissections (43%). Seventy-four percent were for intra abdominal procedures, and venous (53%) and arterial (50%) problems were encountered equally with some overlap. Most patients were male (59%), overweight (56%; body mass index >=25 kg/m(2)), had previous surgery (72%) and were undergoing elective procedures (89%). Mean total procedural anesthesia time was 9.4 hours, mean procedural operating time was 7.9 hours, and mean total and vascular-related estimated blood loss was 1702 mL and 327 mL, respectively. Mean length of stay was 14.7 days, mean intensive care unit stay was 2.9 days, and 30 day mortality was 6.2%. Mean nonvascular RVUs per operation were 46.0, and mean vascular RVUs per operation were 30.9. CONCLUSIONS: Unexpected intraoperative need for vascular surgical expertise occurs often enough that vascular surgeons should be regarded as an essential operating room resource to the general operating room, nonvascular surgeons, and their patients. Intraoperative vascular surgical consultation in support of other surgeons requires a high level of open technical operative skills and is time and labor intensive. PMID- 25937601 TI - Variability in transfer criteria for patients with ruptured abdominal aortic aneurysm in the western United States. AB - BACKGROUND: No standards exist for interhospital transfer of patients with ruptured abdominal aortic aneurysm (rAAA). As such, many facilities have developed individual approaches to transfer of these patients. The purpose of this study was to investigate areas of agreement and discord for transfer and to determine if current practices may serve as a starting point for developing universal transfer guidelines. METHODS: A survey was prepared regarding requirements for transfer, factors regarding transport, and available resources at the accepting hospital. The survey was then offered to members of the Western Vascular Society. Responses were analyzed by physician practice type. Consensus was defined as at least 70% agreement for a response. RESULTS: Response rate was 40%. The cohort comprised 51% from academic institutions and 94% from metropolitan areas. Patients with rAAA were accepted in transfer by 88% of respondents; a majority accepted transfers from distances of up to 100 miles or more. Most had no formal protocol for transfer or treatment of patients with rAAA. Wide variation was observed regarding local evaluation, clinical status at presentation, pre-existing medical comorbidity and required tests for determining suitability for transfer, and management during transport. Academic physicians were more likely to accept clinically unstable patients and to have capability to offer endovascular aneurysm repair. CONCLUSIONS: Wide variation was observed regarding clinical suitability for transfer, diagnostic criteria and tests before transfer, and essential resources required at the receiving hospital. Reducing existing variation and inefficiencies in the transfer process by developing standard guidelines may improve population-based outcomes for rAAA. PMID- 25937599 TI - Peptides at the blood brain barrier: Knowing me knowing you. AB - When the Davis Lab was first asked to contribute to this special edition of Peptides to celebrate the career and influence of Abba Kastin on peptide research, it felt like a daunting task. It is difficult to really understand and appreciate the influence that Abba has had, not only on a generation of peptide researchers, but also on the field of blood brain barrier (BBB) research, unless you lived it as we did. When we look back at our careers and those of our former students, one can truly see that several of Abba's papers played an influential role in the development of our personal research programs. PMID- 25937602 TI - Relationship between histologic features and outcomes of carotid revascularization for radiation-induced stenosis. AB - OBJECTIVE: This study aimed to elucidate the relationships between preoperative carotid imaging results, histologic characteristics, and surgical treatment outcomes of radiation-induced carotid stenosis (RICS), using control subjects without RICS for comparison. METHODS: We retrospectively reviewed records of 17 patients who underwent carotid revascularization for 22 instances of RICS, including 10 cases of carotid artery stenting (CAS), 11 cases of carotid endarterectomy (CEA), and 1 case of CEA with retrograde CAS, between July 2004 and April 2013. The controls were 475 patients with no history of radiation therapy who underwent carotid revascularization in a similar period. Preoperative magnetic resonance imaging (MRI), ultrasonography (US), and computed tomography angiography results were correlated with outcomes of histologic analysis of CEA specimens. End points included ipsilateral and contralateral stroke, myocardial infarction, restenosis, in-stent thrombosis, and target lesion revascularization. RESULTS: Vulnerable plaques on carotid MRI (86% vs 64.2%; P = .010) and mobile (27% vs 8.0%; P = .008) and ulcerative (50% vs 15.8%; P < .001) plaques on US were more frequent in the RICS group. All revascularization procedures were successful, and no occlusion occurred. Adverse events in the CAS group, including one minor stroke and one transient ischemic attack within 30 days as well as five ipsilateral neurologic events after 30 days, including three minor strokes and two transient ischemic attacks, were significantly more frequent than in the CEA group. All three cases of late ipsilateral stroke displayed vulnerable plaque on preoperative MRI and late in-stent thrombosis or restenosis on US. CONCLUSIONS: Our radiologic and histologic analyses revealed that advanced RICS is often accompanied by formation of vulnerable plaque. CEA can prevent undesirable late outcomes in such cases. PMID- 25937603 TI - Outcomes after celiac artery coverage during thoracic endovascular aortic aneurysm repair. AB - OBJECTIVE: Coverage of celiac artery (CA) during thoracic endovascular aortic aneurysm repair (TEVAR) has been performed to extend the distal seal zone for which preliminary results and short-term follow-up have been reported. We aim to show the outcomes up to 81 months after CA coverage during TEVAR. METHODS: Patients undergoing TEVAR with coverage of the CA origin from 2005 to 2013 were retrospectively analyzed. Points of analysis include indications for covering the CA, demonstration of collateral circulation between the CA and superior mesenteric artery (SMA), anatomic features of the distal landing zone, rate of reintervention, technical success, presence of clinical ischemic symptoms after the procedure, and mortality. RESULTS: During the 9-year period, 366 patients underwent TEVAR, 18 (5%) of whom had CA coverage. Eleven (61%) had TEVAR with CA coverage due to a thoracic aneurysm, three (17%) had thoracic aortic dissection related to aneurysm, and four (22%) had previous TEVAR with a type Ib endoleak (EL) requiring distal coverage. Mesenteric angiography in preparation for TEVAR with CA coverage diagnosed a critical SMA stenosis in one patient that was treated with stenting before the index procedure. At the conclusion of the indicated procedure, two patients (11%) had a type Ia EL and two patients (11%) had a type Ib EL. Three of the type I ELs required reintervention. Two patients (11%) had a type II EL, both of which were managed with observation and resolved. Reintervention was required in 27% of patients. Postoperative complications included visceral ischemia in 2 (11%), weight loss in 1 (5%), spinal cord ischemia in 2 (11%), a cerebrovascular event in 1 (6%), and death in 1 (6%). The mean follow-up period was 38 months (range, 0.5-81 months). CONCLUSIONS: This analysis of outcomes up to 81 months supports the suitability of covering the CA in selected patients for extending the distal landing zone to the visceral aortic level above the SMA or when alternative branch vessel treatment is unavailable. Preoperative angiographic evaluation of the mesenteric collaterals and early postoperative surveillance may limit postoperative complications. Once the CA is covered, new symptoms do not develop unless the SMA is compromised. PMID- 25937604 TI - The association of chronic kidney disease and dialysis treatment with foot ulceration and major amputation. AB - OBJECTIVE: The objective of this study was to investigate the risk of chronic kidney disease (CKD) stage 4-5 and dialysis treatment on incidence of foot ulceration and major lower extremity amputation in comparison to CKD stage 3. METHODS: In this retrospective study, all individuals who visited our hospital between 2006 and 2012 because of CKD stages 3 to 5 or dialysis treatment were included. Medical records were reviewed for incidence of foot ulceration and major amputation. The time from CKD 3, CKD 4-5, and dialysis treatment until first foot ulceration and first major lower extremity amputation was calculated and analyzed by Kaplan-Meier curves and multivariate Cox proportional hazards model. Diabetes mellitus, peripheral arterial disease, peripheral neuropathy, and foot deformities were included for potential confounding. RESULTS: A total of 669 individuals were included: 539 in CKD 3, 540 in CKD 4-5, and 259 in dialysis treatment (individuals could progress from one group to the next). Unadjusted foot ulcer incidence rates per 1000 patients per year were 12 for CKD 3, 47 for CKD 4-5, and 104 for dialysis (P < .001). In multivariate analyses, the hazard ratio for incidence of foot ulceration was 4.0 (95% confidence interval [CI], 2.6 6.3) in CKD 4-5 and 7.6 (95% CI, 4.8-12.1) in dialysis treatment compared with CKD 3. Hazard ratios for incidence of major amputation were 9.5 (95% CI, 2.1 43.0) and 15 (95% CI, 3.3-71.0), respectively. CONCLUSIONS: CKD 4-5 and dialysis treatment are independent risk factors for foot ulceration and major amputation compared with CKD 3. Maximum effort is needed in daily clinical practice to prevent foot ulcers and their devastating consequences in all individuals with CKD 4-5 or dialysis treatment. PMID- 25937605 TI - Incidence of acute lower extremity venous thrombosis after percutaneous endovascular aneurysm repair. AB - BACKGROUND: Improvements in endovascular aortic aneurysm repair (EVAR) have led many physicians to embrace a purely percutaneous approach using the suture mediated "preclose" technique. Whereas there are a number of theoretical benefits, the rate of periprocedural iatrogenic acute deep venous thrombosis (DVT) is unknown. We sought to determine the incidence of acute DVT after percutaneous EVAR (PEVAR). METHODS: This was a single-center, retrospective review of 52 consecutive patients undergoing elective PEVAR. Demographics, procedural data, and postprocedure lower extremity venous duplex ultrasound data were analyzed by univariate statistical analysis. RESULTS: Among the 52 patients, the average age was 73 years, and the majority were men (n = 44). Only 6% (n = 3) had a prior history of DVT. The majority of procedures were performed under general anesthesia (n = 51 [98%]) with systemic intravenous heparin. Protamine was used in only 13 cases (25%). Sheath sizes ranged from 9F to 20F, with an average of 16F, and closure was achieved using the preclose technique. Postprocedure chemoprophylaxis was administered to 85% of patients (n = 44) during their hospitalization. Median length of stay was 1 day. Acute DVT was identified in 8% of patients (n = 4) on postoperative day 1. Among the 4 DVTs, 25% were femoropopliteal (n = 1) and 75% were calf vein DVTs (n = 3). On follow up imaging 2 weeks later, 75% of DVTs were resolved. Among the four patients with acute DVT on postoperative day 1, three had associated risk factors: history of DVT (n = 2), active smokers (n = 1), and obesity (body mass index >30; n = 3). The remaining patient had no risk factors but developed an ipsilateral calf vein DVT. CONCLUSIONS: The risk of acute DVT after PEVAR is low. Lower extremity venous duplex ultrasound screening is not necessary unless there exist preclinical risk factors or postprocedural clinical indications suggestive of DVT. PMID- 25937606 TI - Performance of the Endurant stent graft in challenging anatomy. AB - OBJECTIVE: This study aimed to compare perioperative and postoperative outcomes after endovascular repair of abdominal aortic aneurysms (AAAs) in patients with various neck morphologic features. METHODS: Data from the Endurant Stent Graft Natural Selection Global Postmarket Registry (ENGAGE) were used for the analyses. Patients were categorized into three different groups according to proximal aortic neck anatomy: regular (REG), intermediate (INT), and challenging (CHA). REG was defined as AAAs with a proximal neck >=15 mm combined with a suprarenal angulation (alpha) <=45 degrees and an infrarenal neck angulation (beta) <=60 degrees. INT was defined as AAAs with a proximal neck of 10 to 15 mm combined with alpha <=45 degrees and beta <=60 degrees or with a proximal neck of >15 mm combined with alpha <=60 degrees and beta = 60 to 75 degrees or alpha = 45 to 60 degrees and beta <=75 degrees. CHA was defined as infrarenal necks that exceed at least one of the three defining factors. RESULTS: Overall, 925 patients (75.9%) had REG anatomy, 189 patients (15.5%) had INT anatomy, and 104 patients (8.5%) had CHA anatomy. Patient demographics and risk factors were similar. There was a significant difference in AAA diameter between the REG and CHA groups (59.4 mm vs 65.2 mm; P < .001). Technical success was similar among groups (REG 99.1% vs INT 99.5% vs CHA 97.1%). There were no differences in mortality or the need for secondary procedures within 30 days or at 1 year. A significantly higher rate of type I endoleaks within 30 days was seen in CHA compared with REG (adjusted odds ratio, 0.15; 95% confidence interval, 0.05-0.46) and INT (adjusted odds ratio, 0.08; 95% confidence interval, 0.01-0.70), but there was no difference at 1-year follow-up. CONCLUSIONS: This real-world, global experience shows promising results and indicates that endovascular AAA repair with the Endurant stent graft (Medtronic Vascular, Santa Rosa, Calif) is safe and effective in patients with challenging aortic neck anatomy. However, long-term follow-up of patients is required to confirm results. PMID- 25937607 TI - A new technique to explant an infected aortic endograft. AB - The management of an infected aortic endograft can be challenging both operatively and clinically. Although aortic endograft infection is rare, the incidence is likely to increase in the coming years because of ever rising numbers of endovascular aneurysm repairs. Definitive management involves the removal of the endograft through laparotomy. Removal of the graft is technically challenging; no manufacturer's device is available to assist in disengagement of barbed hooks that hold the endograft in position. We present a new technique using the disposable proctoscope as a device to facilitate safe removal of the endograft with minimal damage to the aortic wall. PMID- 25937608 TI - Surgeon radiation dose during complex endovascular procedures. AB - BACKGROUND: Surgeon radiation dose during complex fluoroscopically guided interventions (FGIs) has not been well studied. We sought to characterize radiation exposure to surgeons during FGIs based on procedure type, operator position, level of operator training, upper vs lower body exposure, and addition of protective shielding. METHODS: Optically stimulable, luminescent nanoDot (Landauer, Inc, Glenwood, Ill) detectors were used to measure radiation dose prospectively to surgeons during FGIs. The nanoDot dosimeters were placed outside the lead apron of the primary and assistant operators at the left upper chest and left lower pelvis positions. For each case, the procedure type, the reference air kerma, the kerma-area product, the relative position of the operator, the level of training of the fellow, and the presence or absence of external additional shielding devices were recorded. Three positions were assigned on the right-hand side of the patient in decreasing relative proximity to the flat panel detector (A, B, and C, respectively). Position A (main operator) was closest to the flat panel detector. Position D was on the left side of the patient at the brachial access site. The nanoDots were read using a microSTARii medical dosimetry system (Landauer, Inc) after every procedure. The nanoDot dosimetry system was calibrated for scattered radiation in an endovascular suite with a National Institute of Standards and Technology traceable solid-state radiation detector (Piranha T20; RTI Electronics, Fairfield, NJ). Comparative statistical analysis of nanoDot dose levels between categories was performed by analysis of variance with Tukey pairwise comparisons. Bonferroni correction was used for multiple comparisons. RESULTS: There were 415 nanoDot measurements with the following case distribution: 16 thoracic endovascular aortic repairs/endovascular aneurysm repairs, 18 fenestrated endovascular aneurysm repairs (FEVARs), 13 embolizations, 41 lower extremity interventions, 10 fistulograms, 13 visceral interventions, and 3 cerebrovascular procedures. The mean operator effective dose for FEVARs was higher than for other case types (P < .03), 20 MUSv at position A and 9 MUSv at position B. For all case types, position A (9.0 MUSv) and position D (20 MUSv) received statistically higher effective doses than position B (4 MUSv) or position C (0.4 MUSv) (P < .001). However, the mean operator effective dose for position D was not statistically different from that for position A. The addition of the lead skirt significantly decreased the lower body dose (33 +/- 3.4 MUSv to 6.3 +/- 3.3 MUSv) but not the upper body dose (6.5 +/- 3.3 MUSv to 5.7 +/- 2.2 MUSv). Neither ceiling-mounted shielding nor level of fellow training affected operator dose. CONCLUSIONS: Surgeon radiation dose during FGIs depends on case type, operator position, and table skirt use but not on the level of fellow training. On the basis of these data, the primary operator could perform approximately 12 FEVARs/wk and have an annual dose <10 mSv, which would not exceed lifetime occupational dose limits during a 35-year career. With practical case loads, operator doses are relatively low and unlikely to exceed occupational limits. PMID- 25937609 TI - Type II endoleak prevention with coil embolization during endovascular aneurysm repair in high-risk patients. AB - OBJECTIVE: This study evaluated endoleak level and size decrease of infrarenal abdominal aortic aneurysm (AAA) after endovascular aneurysm repair (EVAR) with coil embolization in patients at high risk for type II endoleak. METHODS: Between 2009 and 2013, 83 of 187 patients (44.3%) who underwent EVAR for AAA also underwent coil embolization of the aneurysm sac immediately after complete stent graft release because of risk factors for type II endoleak, including absence of a circumferential thrombus, two or more pairs of patent lumbar arteries, or a patent inferior mesenteric artery. Coil embolization was achieved using a 4F catheter with a microcatheter placed between the stent graft and the aneurysm wall. Computed tomography and color duplex ultrasound imaging were performed 1, 6, 12, and 24 months later to look for an endoleak and assess aneurysm sac diameter. RESULTS: Mean follow-up was 24 +/- 11 months (range, 6-53 months). A mean of 12 coils (range, 4-23) was used. Technical success was achieved in all patients, with no procedurally related complications. Follow-up computed tomography showed type II endoleak in one patient. Aneurysm sac diameter was significantly decreased after 6 months (P = .001), 12 months (P = .001), and 24 months (P = .001). Surgery was required in one patient for common femoral artery occlusion unrelated to the procedure and in another patient for distal type I endoleak. CONCLUSIONS: Aneurysm sac coil embolization during EVAR for patients at risk for type II endoleak is technically feasible, safe, and effective in preventing type II endoleak. This procedure leads to rapid AAA shrinkage. Thus, coil embolization could be used routinely to improve EVAR outcomes for patients at risk for type II endoleak. PMID- 25937610 TI - Overweight and Obesity in a Sample of Children With Autism Spectrum Disorder. AB - OBJECTIVE: To determine the prevalence of overweight/obese status in children with autism spectrum disorders (ASD), identify associated characteristics, and develop a model to predict weight status. METHODS: The prevalence of overweight and obesity was determined in 2769 children with ASD enrolled in the Autism Speaks Autism Treatment Network, a collaboration of 17 academic centers, and compared with a national sample matched for age, sex, and race. Associations in the ASD sample between weight status and demographic and clinical variables, such as age, race, head circumference, and adaptive functioning, were tested using ordinal logistic regression. The accuracy of a final model that predicted weight status based on early life variables was evaluated in a validation sample. RESULTS: The prevalence of overweight and obesity were 33.9% and 18.2%, respectively; ASD was associated with a higher risk of obesity (but not overweight) relative to the national sample (odds ratio [OR], 1.16; 95% confidence interval [CI], 1.05-1.28; P = .003). In the adjusted analysis, overweight/obese status was significantly associated with Hispanic ethnicity (OR, 1.99; 95% CI, 1.37-2.89), parental high school education (OR, 1.56; 95% CI, 1.09 2.21), high birth weight (OR, 1.56; 95% CI, 1.11-2.18), macrocephaly (OR, 4.01; 95% CI, 2.96-5.43), and increased somatic symptoms (OR, 1.41; 95% CI, 1.01-1.95). A prediction model designed to have high sensitivity predicted low risk of overweight/obesity accurately, but had low positive predictive value. CONCLUSIONS: The prevalence of obesity in children with ASD was greater than a national sample. Independent associations with increased weight status included known risk factors and macrocephaly and increased level of somatic symptoms. A model based on early life variables accurately predicted low risk of overweight/obesity. PMID- 25937612 TI - Typhoid vaccine introduction: An evidence-based pilot implementation project in Nepal and Pakistan. AB - The World Health Organization (WHO) in 2008 recommended the use of currently licensed typhoid vaccines using a high risk or targeted approach. The epidemiology of disease and the vaccine characteristics make school-based vaccination most feasible in reducing typhoid disease burden in many settings. To assess feasibility of school-based typhoid vaccination, two districts in Kathmandu, Nepal and two towns in Karachi, Pakistan were selected for pilot program. Vaccination campaigns were conducted through the departments of health and in partnerships with not-for-profit organizations. In total 257,015 doses of Vi polysaccharide vaccine were given to students in grades 1-10 of participating schools. The vaccination coverage ranged from 39 percent (38,389/99,503) in Gulshan town in Karachi, to 81 percent (62,615/77,341) in Bhaktapur in Kathmandu valley. No serious adverse event was reported post vaccination. The coverage increased for vaccination of the second district in Pakistan as well as in Nepal. There was an initial concern of vaccine safety. However, as the campaign progressed, parents were more comfortable with vaccinating their children in schools. Supported and conducted by departments of health in Pakistan and Nepal, a school-based typhoid vaccination was found to be safe and feasible. PMID- 25937611 TI - Diagnostics for invasive Salmonella infections: Current challenges and future directions. AB - Invasive Salmonellosis caused by Salmonella enterica serotype Typhi or Paratyphi A, B, C, or invasive non-typhoidal Salmonella serotypes, is an immensely important disease cluster for which reliable, rapid diagnostic tests are not available. Blood culture remains the gold standard but is insensitive, slow, and resource-intensive. Existing molecular diagnostics have poor sensitivity due to the low organism burden in bodily fluids. Commercially available serologic tests for typhoidal Salmonella have had limited sensitivity and specificity. In high burden, resource-limited settings, reliance on clinical diagnosis or inaccurate tests often results in frequent, unnecessary treatment, which contributes selective pressure for the emergence of antimicrobial resistance. This practice also results in inadequate therapy for other etiologies of acute febrile illnesses, including leptospirosis and rickettsial infections. A number of novel serologic, molecular, transcriptomic and metabolomic approaches to diagnostics are under development. Target product profiles that outline specific needs may focus development and investment, and establish benchmarks for accuracy, cost, speed, and portability of new diagnostics. Of note, a critical barrier to diagnostic assay rollout will be the low cost and low perceived harm of empiric therapy on behalf of providers and patients, which leaves few perceived incentives to utilize diagnostics. Approaches that align incentives with societal goals of limiting inappropriate antimicrobial use, such as subsidizing diagnostics, may be essential for stimulating development and uptake of such assays in resource-limited settings. New diagnostics for invasive Salmonellosis should be developed and deployed alongside diagnostics for alternative etiologies of acute febrile illnesses to improve targeted use of antibiotics. PMID- 25937613 TI - Use of wearable technology for performance assessment: a validation study. AB - The prevalence of osteoarthritis is increasing globally but current compliance with rehabilitation remains poor. This study explores whether wearable sensors can be used to provide objective measures of performance with a view to using them as motivators to aid compliance to osteoarthritis rehabilitation. More specifically, the use of a novel attachable wearable sensor integrated into clothing and inertial measurement units located in two different positions, at the waist and thigh pocket, was investigated. Fourteen healthy volunteers were asked to complete exercises adapted from a knee osteoarthritis rehabilitation programme whilst wearing the three sensors including five times sit-to-stand test, treadmill walking at slow, preferred and fast speeds. The performances of the three sensors were validated against a motion capture system and an instrumented treadmill. The systems showed a high correlation (r(2) > 0.7) and agreement (mean difference range: -0.02-0.03 m, 0.005-0.68 s) with gold standards. The novel attachable wearable sensor was able to monitor exercise tasks as well as the inertial measurement units (ICC > 0.95). Results also suggested that a functional placement (e.g., situated in a pocket) is a valid position for performance monitoring. This study shows the potential use of wearable technologies for assessing subject performance during exercise and suggests functional solutions to enhance acceptance. PMID- 25937614 TI - Multi-selective catheter for MR-guided endovascular interventions. AB - Selective catheters have predefined distal shapes and need to be exchanged to change tip geometry to facilitate selective catheterization of vascular side branches. These repeated insertions increase the risk of endovascular injury and radiation dose in conventional catheterization laboratories. The aim of this study is to develop a multi-selective catheter that can replace three conventional selective catheters that are commonly used sequentially in a single procedure. By integrating the different shapes in one instrument, it is possible to avoid the required time-consuming exchange. This new instrument is also made compatible with magnetic resonance imaging (MRI) guidance, which, unlike X-ray, presents variable soft tissue contrast without the use of ionizing radiation. A 1.2 m long and 2.15 mm diameter deflectable polymer-based catheter was assembled and three widely used selective catheters could be mimicked. The instrument was visible on the images without producing unwanted artifacts in an abdominal model and in an animal under real-time MRI guidance. Simple navigation tasks were performed together with a 0.035 in. MRI-safe guidewire. In these tasks, the iliac, renal, brachiocephalic, and left subclavian arteries were cannulated only by using the shape setting and without exchange of the instruments. PMID- 25937615 TI - Alterations in the limbic/paralimbic cortices of Parkinson's disease patients with hyposmia under resting-state functional MRI by regional homogeneity and functional connectivity analysis. AB - BACKGROUND: Hyposmia is a cardinal early symptom of Parkinson's disease (PD), but the pathophysiological mechanisms underlying it remain unclear. Resting-state functional MRI (RS-fMRI) demonstrates spontaneous neuronal activity. We hypothesized that there would be alterations in the olfaction-related regions of the limbic/paralimbic cortices in PD patients with obvious hyposmia by RS-fMRI. METHODS: We used the "Five Odors for Olfactory Detection Arrays" to test the threshold of olfactory detection (TOD) for 54 PD patients and 22 age-matched controls. Using the mean TOD of the control group, patients were subdivided into two groups: PD with obvious hyposmia (OH-PD, n = 38) and PD with none/less obvious hyposmia (NOH-PD, n = 16). The regional brain activity of all subjects was investigated using RS-fMRI, in combination with regional homogeneity (ReHo) and functional connectivity (FC) analysis. RESULTS: There were different ReHo values in the limbic/paralimbic cortices between the OH-PD and NOH-PD groups. ReHo was significantly decreased in OH-PD patients in parts of the traditional olfactory regions (e.g. the amygdala, olfactory gyrus, orbital frontal cortex, parahippocampal gyrus and insula) and some non-traditional olfactory centers (e.g. the rectal gyrus and superior temporal pole), while increased in the left anterior/posterior cingulate cortex. FC analysis revealed decreased functional connectivity within the limbic/paralimbic cortices, especially in regions with reduced ReHo in the OH-PD group. CONCLUSIONS: PD with hyposmia is related to altered functional activity not only in the traditional olfactory center, but also in some non-traditional olfactory regions of the limbic/paralimbic cortices. PMID- 25937616 TI - [(18)F] FP-CIT PET study in parkinsonian patients with leukoaraiosis. AB - BACKGROUNDS: Leukoaraiosis may present with slowly progressive parkinsonism indistinguishable from primary degenerative parkinsonism. Both leukoaraiosis and degenerative parkinsonism are an age-related disorder. Thus, comorbidity is expected to be common in elderly patients with parkinsonism. However, no systematic study has been reported on the clinical features indicating concomitant nigrostriatal dopaminergic denervation (NDD) in parkinsonian patients with leukoaraiosis. METHODS: We performed [(18)F] FP-CIT positron emission tomography studies in 42 consecutive parkinsonian patients with diffuse leukoaraiosis, but no basal ganglia vascular lesions. RESULTS: Twenty (48%) of the 42 patients had coexisting NDD. Compared to parkinsonian patients with isolated leukoaraiosis, those with coexisting NDD more frequently had asymmetric onset. They had similar degree of parkinsonian motor deficits in the legs, but greater rigidity and resting tremor in the arms. Consequently, they had less prominent lower body parkinsonism. They more frequently showed favorable response to levodopa treatment. They had similar burden of regional and total leukoaraiosis. Among a variety of clinical variables and MRI findings, only asymmetric onset and more than 30% improvement in UPDRS motor score by levodopa treatment were valuable indicators of coexisting NDD. CONCLUSIONS: We would like to recommend dopaminergic functional imaging studies for all parkinsonian patients with leukoaraiosis. Further studies are needed to confirm sensitivity and specificity of asymmetric onset and good levodopa response for the prediction of coexisting NDD in a different group of parkinsonian patients with leukoaraiosis. PMID- 25937618 TI - Evaluation of the Real-Q BRAF V600E Detection Assay in Fine-Needle Aspiration Samples of Thyroid Nodules. AB - Recently, several molecular assays for detecting the BRAF V600E mutation in fine needle aspiration (FNA) specimens have been developed. Herein, we tested 294 consecutive FNA samples from patients with thyroid nodules with the Real-Q BRAF V600E detection assay (Real-Q). These results were compared with an allele specific PCR-based kit using dual-priming oligonucleotides (AS-PCR). Any discordant results between the two tests were also analyzed by mutant enrichment with 3'-modified oligonucleotide sequencing. A total of 128 cases were confirmed histologically; of these, 121 were diagnosed as papillary thyroid carcinoma (PTC). The BRAF mutation was detected by Real-Q and AS-PCR testing in 80.2% (95% CI, 71.9%-86.9%) and 76.9% (95% CI, 68.3%-84.0%), respectively, of FNA specimens with PTC. Combining the BRAF V600E molecular assays (Real-Q and AS-PCR) with cytological diagnoses of malignant and suspicious for malignant cells, the detection rates (sensitivity) of Real-Q and AS-PCR for diagnosis of PTC increased to 94.2% (95% CI, 88.4%-97.6%) and 92.6% (95% CI, 86.4%-96.5%), respectively. In conclusion, the detection of BRAF V600E mutations in PTC by Real-Q is compatible to that of AS-PCR. PMID- 25937617 TI - Comparing Platforms for Messenger RNA Expression Profiling of Archival Formalin Fixed, Paraffin-Embedded Tissues. AB - Archival formalin-fixed, paraffin-embedded (FFPE) tissue specimens represent a readily available but largely untapped resource for gene expression profiling based biomarker discovery. Several technologies have been proposed to cope with the bias from RNA cross-linking and degradation associated with archival specimens to generate data comparable with RNA from fresh-frozen materials. Direct comparison studies of these RNA expression platforms remain rare. We compared two commercially available platforms for RNA expression profiling of archival FFPE specimens from clinical studies of prostate and ovarian cancer: the Affymetrix Human Gene 1.0ST Array following whole-transcriptome amplification using the NuGen WT-Ovation FFPE System V2, and the NanoString nCounter without amplification. For each assay, we profiled 7 prostate and 11 ovarian cancer specimens, with a block age of 4 to 21 years. Both platforms produced gene expression profiles with high sensitivity and reproducibility through technical repeats from FFPE materials. Sensitivity and reproducibility remained high across block age within each cohort. A strong concordance was shown for the transcript expression values for genes detected by both platforms. We showed the biological validity of specific gene signatures generated by both platforms for both cohorts. Our study supports the feasibility of gene expression profiling and large-scale signature validation on archival prostate and ovarian tumor specimens using commercial platforms. These approaches have the potential to aid precision medicine with biomarker discovery and validation. PMID- 25937619 TI - A Variant Detection Pipeline for Inherited Cardiomyopathy-Associated Genes Using Next-Generation Sequencing. AB - In inherited cardiomyopathies, genetic testing is recognized as an enriching procedure in the diagnostic closure of a cardiac condition. Many genetic mutations have been described as pathogenically related to cardiomyopathies, turning next-generation sequencing into an extremely reliable scenario. Here we describe the validation process of a pipeline constructed with a target panel of 74 cardiomyopathy-related genes sequenced using a next-generation sequencing system. Fifty-two samples from a hypertrophic cardiomyopathy casuistic with previous molecular diagnostics (Sanger-sequenced for MYH7, MYBCP3, and TNNT2; 19 positives and 33 negatives) were processed in parallel with a HapMap reference sample (NA12878) applied for a complete panel assessment. Sequencing coverage values were satisfactory, with a mean of 250* (95% CI, 226.03-273.91) and 95.2% of target bases with a coverage of >=10*. With a total of 567 variants, variant call sensitivity was tested in five scenarios of coverage and variant allele frequency cutoffs. Maximum achieved sensitivity was 96.7% for single-nucleotide variants and 28.5% for indels, and positive predictive values remained above 0.959 during the whole process. Inter- and intra-assay reproducibility values were 89.5% and 87.3%, respectively. After a careful assessment of analytical performance, we infer that the assay presents potential feasibility for application in diagnostic routines, with minimal time requirements and a simple bioinformatics structure. PMID- 25937620 TI - Transport characteristics and morphology of the colon and coprodeum in two wild birds of different habitats, the rock ptarmigan (Lagopus mutus) and the common murre (Uria aalge). AB - Dietary salt intake in domestic fowl affects epithelial transport and morphology of the lower intestine (colon and coprodeum). This study investigated lower intestinal morphology and transport activity in two wild bird species with natural diets containing either low or high salt. Tissues from rock ptarmigan (Lagopus mutus) and common murres (Uria aalge) were sampled for histology and electrophysiological analyses. The ptarmigan exists on a low salt diet, while the murre lives on a high protein and high salt diet. The ptarmigan colon and coprodeum had villi/folds and crypts and the epithelium contained absorptive epithelial cells, mitochondria-rich cells and goblet cells. The colon had significant amiloride-inhibitable Isc, 5-15 MUA/cm(2), with no glucose-stimulated Isc, and no significant phloridzin inhibition. The coprodeum also had high amiloride-inhibitable Isc. This transport pattern corresponded to that of chickens on low-salt diets. However, the ptarmigan colon also had a significant lysine/leucine-stimulated Isc of 3+/-1.0 MUA/cm(2). The short U. aalge colon was similar to that of ptarmigans, but with no villi. It demonstrated a significant lysine/leucine-stimulated Isc (11+/-3.5 MUA/cm(2)) with no amiloride-inhibitable Isc, similar to the high-salt chicken colon, but with no Na(+)-glucose cotransport. The murre coprodeum was inert to all substances and showed high resistance (1000 Omega.cm(2)), with a multilayered squamous epithelium. Despite some variations possibly associated with dietary protein intake, we conclude that natural high and low salt diets in different avian species are associated with different lower intestinal transport patterns, providing for post-renal adjustments in ion and water excretion. PMID- 25937621 TI - Nitrate pharmacokinetics: Taking note of the difference. AB - It is now recognised that administration of oral nitrate (NO3(-)), in its various forms, increases the level of nitric oxide (NO) metabolites in the circulation of humans. Its application to modulate physiology and alleviate cardiovascular dysfunction in some patients is now recorded and shows particular promise in hypertension, in modifying platelet activation/aggregation, and in conditions where tissue ischaemia prevails. The potential of oral NO3(-) to modify exercise/performance via elevation of plasma nitrite concentration ([NO2(-)]) has been applied across a range of human test systems. Herein we discuss how the choice of NO3(-) source, route of administration and resulting pharmacokinetics might influence the outcome of physiological measures and potentially contribute to discrepancies in performance trials. There are but a few examples of detailed pharmacokinetic data on which the majority of researchers base their test protocols in different cohorts/settings. We compare and contrast the results of key publications with the aim of highlighting a consensus of our current understanding and critical considerations for those entering the field. PMID- 25937622 TI - Ageing modifies the effects of beetroot juice supplementation on 24-hour blood pressure variability: An individual participant meta-analysis. AB - OBJECTIVES: Abnormal circadian oscillations of blood pressure (BP) and nocturnal diurnal BP differences (i.e., dipping) increase cardiovascular risk. Whether inorganic nitrate supplementation influences 24-hr BP variability is currently unknown. We studied the effects of high-nitrate beetroot juice supplementation on BP variability measured by 24-hr ambulatory BP monitoring (24-hr ABPM) in older subjects. METHODS: Data from four independent randomised clinical trials were collated. Eighty-five older participants (age range: 55-76 years) were included in the final database. Two trials had an open-label, parallel design and two trials had a cross-over, double-blind design. Participants were randomised to either beetroot juice or placebo. Changes in 24-hr ABPM (daily, diurnal, nocturnal), variability (weighted-SDs), night-dipping, morning surge for systolic and diastolic BP were measured. Meta-analysis was conducted to obtain pooled estimates of the effect size for each BP outcome. Sub-group analyses were conducted to evaluate the influence of age, BMI, gender, BP status and changes in nitrite concentrations on the effect size. RESULTS: The pooled effect of beetroot juice on all BP outcomes was not significant. Beetroot juice ingestion determined a significant decrease in nocturnal systolic BP variability in subjects aged less than 65 y (2.8 mmHg, -4.5 -1.0, p = 0.002) compared to the older group (>= 65 y; 1.0 mmHg, -2.2 4.2, p = 0.54). A greater change in NO2(-) concentrations after beetroot supplementation was associated with significant differences for nocturnal mean (-3.4 mmHg, -0.6 -2.4, p = 0.02) and variability (-0.8 mmHg, -1.5 0.06, p = 0.03) of systolic BP. CONCLUSIONS: The vascular responsiveness to inorganic nitrate may be modified by mechanisms of vascular ageing influencing the reducing capacity to convert inorganic nitrate into nitrite and tissue specific responses to dietary nitrate supplementation. PMID- 25937623 TI - Promises and challenges of fluorescence cystoscopy. AB - INTRODUCTION: Fluorescence based photodynamic diagnostic (PDD) techniques have been developed to improve detection and treatment of non-muscle invasive bladder cancer. The goal of this article is to evaluate the promises and challenges of blue light cystoscopy. METHODS: The literature was reviewed regarding articles pertaining to fluorescent cystoscopy and blue light cystoscopy (BLC). RESULTS: Blue light cystoscopy improves detection of bladder cancer tumors especially CIS. Randomized trials have demonstrated a reduction of recurrences. BLC has been demonstrated to be safe and effective in treatment of NMIBC of varying risk. The main obstacle to BLC will be adoption by urologists. Purchase cost of capital equipment may impact usage especially if adopted for outpatient clinics. CONCLUSIONS: BLC has been demonstrated to be safe and effective in treatment of NMIBC of varying risk. The reduction of recurrences and yet unproven but potential reduction in progression should be viewed favorably by urologists and patients. The main obstacle to BLC will be adoption by urologists who can put pressure on hospitals to acquire the capital equipment and who will seek the training to become proficient in using the technology. Patient demand for the technology may also help increase availability. Finally, the companies involved with BLC need to support trials that will demonstrate reduction in progression and that will answer the practical issues regarding usage in proximity to BCG and repeated usage. PMID- 25937624 TI - Diagnosis and treatment of faecal incontinence: Consensus statement of the Italian Society of Colorectal Surgery and the Italian Association of Hospital Gastroenterologists. AB - Faecal incontinence is a common and disturbing condition, which leads to impaired quality of life and huge social and economic costs. Although recent studies have identified novel diagnostic modalities and therapeutic options, the best diagnostic and therapeutic approach is not yet completely known and shared among experts in this field. The Italian Society of Colorectal Surgery and the Italian Association of Hospital Gastroenterologists selected a pool of experts to constitute a joint committee on the basis of their experience in treating pelvic floor disorders. The aim was to develop a position paper on the diagnostic and therapeutic aspects of faecal incontinence, to provide practical recommendations for a cost-effective diagnostic work-up and a tailored treatment strategy. The recommendations were defined and graded on the basis of levels of evidence in accordance with the criteria of the Oxford Centre for Evidence-Based Medicine, and were based on currently published scientific evidence. Each statement was drafted through constant communication and evaluation conducted both online and during face-to-face working meetings. A brief recommendation at the end of each paragraph allows clinicians to find concise responses to each diagnostic and therapeutic issue. PMID- 25937625 TI - Interferon-free therapy for hepatitis C: The hurdles amid a golden era. AB - The long awaited all-oral therapy for hepatitis C virus infection has officially been inaugurated by the registration of the hepatitis C nucleotide inhibitor sofosbuvir in a combination regimen with ribavirin. More recently, the oral array to treat hepatitis C has been enriched by the arrival of the NS5A inhibitors ledipasvir (also in a single formulation with sofosbuvir, Harvoni((r))) and daclatasvir; the protease inhibitor simeprevir, and the Viekirax((r))+ExvieraTM regimen based on the ritonavir boosted protease inhibitor paritaprevir; the NS5A inhibitor ombitasvir, and the non-nucleoside inhibitor dasabuvir. Owing to the budget-breaking price of the newer oral medicines, the Italian National Health System elected to restrict reimbursement of oral anti-hepatitis C therapy to patients with advanced liver disease or transplanted organs, and those who are interferon unable, only. While this therapeutic strategy harmonizes with principles of distributive justice, at the same time it fuelled the argument of its doubtful cost-effectiveness, owing to the National Health System's reimbursement of the sole sofosbuvir+ribavirin regimen, which has suboptimal efficacy against the prevalent hepatitis C virus genotype 1b. As a consequence, we are left with a number of uncertainties regarding the optimal treatment modality for certain subgroups of hepatitis C patients, and the clinical benefits provided by hepatitis C virus clearance in patients with advanced liver disease. PMID- 25937626 TI - Retrospective evaluation of prognostic score performances in cirrhotic patients admitted to an intermediate care unit. AB - BACKGROUND: The prognosis of cirrhotic patients in the Intensive Care Unit requires the development of predictive tools for mortality. We aimed to evaluate the ability of different prognostic scores to predict hospital mortality in these patients. METHODS: A single-centre retrospective analysis was conducted of 281 hospital stays of cirrhotic patients at an Intermediate Care Unit between June 2009 and December 2010. The performance of the Simplified Acute Physiology Score (SOFA), the Simplified Acute Physiology Score (SAPS) II or III, Child-Pugh, Model for End-Stage Liver Disease (MELD), MELD-Na and the Chronic Liver Failure Consortium Acute-on-Chronic Liver Failure score (CLIF-C ACLF) in predicting hospital mortality were compared. RESULTS: Mean age was 58.2+/-12.1 years; 77% were male. The main cause of admission was acute gastrointestinal bleeding (47%). The in-hospital mortality rate was 25.3%. Receiver operating characteristic curve analyses demonstrated that SOFA (0.82) MELD-Na (0.82) or MELD (0.81) scores at admission predicted in-hospital mortality better than Child-Pugh (0.76), SAPS II (0.77), SAPS III (0.75) or CLIF-C ACLF (0.75). We then developed the cirrhosis prognostic score (Ci-Pro), which performed better (0.89) than SOFA. CONCLUSION: SOFA, MELD and especially the Ci-Pro score show the best performance in predicting hospital mortality of cirrhotic patients admitted to an Intermediate Care Unit. PMID- 25937627 TI - Gene dosage imbalances: action, reaction, and models. AB - Single-gene deletions, duplications, and misregulation, as well as aneuploidy, can lead to stoichiometric imbalances within macromolecular complexes and cellular networks, causing their malfunction. Such alterations can be responsible for inherited or somatic genetic disorders including Mendelian diseases, aneuploid syndromes, and cancer. We review the effects of gene dosage alterations at the transcriptomic and proteomic levels, and the various responses of the cell to counteract their effects. Furthermore, we explore several biochemical models and ideas that can provide the rationale for treatments modulating the effects of gene dosage imbalances. PMID- 25937628 TI - The significantly lower risk of cervical cancer at and after the recommended age to begin and end screening compared to breast and colorectal cancer. AB - OBJECTIVE: We compare risk of cervical, colorectal, and breast cancer (and two pre-cancers: cervical intraepithelial neoplasia (CIN) grade 2-3 and colorectal adenomas) at and after the recommended ages to begin and end screening in the United States. METHODS: Surveillance, Epidemiology, and End Results data were used with Monte Carlo simulations to estimate risk at and after the ages to screen. RESULTS: At the age to begin screening, absolute risk of breast and colorectal cancer was 381 and 53 times higher, respectively, than cervical cancer (0.0122, 95% CI: 0.0089-0.0162 and 0.0017, 95% CI: 0.0012-0.0023 vs. 3.2e(-5), 95% CI: 2.3e(-5)-4.3e(-5)). Risk of colorectal adenomas and breast cancer was 45 and 2.4 times higher than CIN 2-3 (0.2319, 95% CI: 0.1287-0.3624 and 0.0122, 95% CI: 0.0089-0.0017 vs. 0.0051, 95% CI: 0.0029-0.0081). After the age to end screening, breast and colorectal cancer risk was 17 and 11 times higher, respectively, than cervical cancer. CONCLUSIONS: Risk of cervical cancer at and after the recommended ages for screening is significantly lower than that of breast and colorectal cancer. Differences may become more pronounced in the era of HPV vaccines. Comparison of risk between cancers provides a novel perspective to inform future guideline development. PMID- 25937629 TI - A tribute to Jean Lindenmann, co-discoverer of interferon (1924-2015). AB - In 1957, the discovery of interferon was reported by Isaacs and Lindenmann in the prestigious journal Proceedings of the Royal Society (1957) [1,2]. This discovery was definitely one of the scientific landmarks in cell biology of the past century. It was the result of an initially unplanned and amazingly creative collaboration with Alick Isaacs that lasted from July 1956 to June 1957 at Mill Hill in London. Jean Lindenmann died in Zurich on January 15, 2015, at the age of 90, after having survived Alick Isaacs (1921-1967) for almost five decades. PMID- 25937630 TI - Characterization of TiO2 and ZnO nanoparticles and their applications in photocatalytic degradation of azodyes. AB - TiO2 nanoparticles have been synthesized from the inorganic precursor Ti [OC3H7]4via sol-gel technique. Similarly, ZnO nanoparticles have also been synthesized from zinc sulfate precursor using precipitation method. The prepared nanoparticles was characterized by scanning electron microscopy (SEM), energy dispersive X-ray spectroscopy (EDX), X-ray diffraction (XRD) and Fourier transform infrared (FTIR) techniques to study the morphology, structural configuration and its functionality. The average particle size for TiO2 and ZnO nanoparticles was 15.4nm and 17.9nm, respectively. The synthesized TiO2 and ZnO nanoparticles have been used for degradation of acid red 27 and coralene red F3BS dyes under the UV light. The regeneration of TiO2 photocatalyst was also tested. PMID- 25937631 TI - In-silico identification of the binding mode of synthesized adamantyl derivatives inside cholinesterase enzymes. AB - AIM: To investigate the binding mode of synthesized adamantly derivatives inside of cholinesterase enzymes using molecular docking simulations. METHODS: A series of hybrid compounds containing adamantane and hydrazide moieties was designed and synthesized. Their inhibitory activities against acetylcholinesterase (AChE) and (butyrylcholinesterase) BChE were assessed in vitro. The binding mode of the compounds inside cholinesterase enzymes was investigated using Surflex-Dock package of Sybyl7.3 software. RESULTS: A total of 26 adamantyl derivatives were synthesized. Among them, adamantane-1-carboxylic acid hydrazide had an almost equal inhibitory activity towards both enzymes, whereas 10 other compounds exhibited moderate inhibitory activity against BChE. The molecular docking studies demonstrated that hydrophobic interactions between the compounds and their surrounding residues in the active site played predominant roles, while hydrophilic interactions were also found. When the compounds were docked inside each enzyme, they exhibited stronger interactions with BChE over AChE, possibly due to the larger active site of BChE. The binding affinities of the compounds for BChE and AChE estimated were in agreement with the experimental data. CONCLUSION: The new adamantly derivatives selectively inhibit BChE with respect to AChE, thus making them good candidates for testing the hypothesis that BChE inhibitors would be more efficient and better tolerated than AChE inhibitors in the treatment of Alzheimer's disease. PMID- 25937632 TI - DanHong injection dose-dependently varies amino acid metabolites and metabolic pathways in the treatment of rats with cerebral ischemia. AB - AIM: To determine how the relative amino acid contents and metabolic pathways regulate the pharmacological phenotypes in rats with cerebral ischemia after treatment with varying doses of DanHong injection (DHI). METHODS: Adult male rats underwent middle cerebral artery occlusion (MCAO), and were injected with DHI (DH 1: 1 mL/kg; DH-2: 2.5 mL/kg; DH-3: 5 mL/kg, and DH-4: 10 mL/kg, iv) daily for 3 d. The neurological deficit score, body weights and infarct volume were assessed. Serum levels of 20 free amino acids were determined using HPLC, and the values were transformed through the quantitative analysis of the amino acids in the serum metabolic spectrum. Multivariate statistical analysis methods (PCA and PLS DA) and web-based metabolomics tools (MetPa and MetaboAnalyst) were used to analyze the biological data sets for the amino acids. RESULTS: Administration of DHI dose-dependently decreased cerebral infarct volume, and ameliorated neurological deficits. A total of 5, 6, 7 and 7 non-overlapping metabolites were identified in the DH-1, DH-2, DH-3, and DH-4 groups, respectively. Eight metabolites were shared between the DHI groups and the vehicle group. In addition, the serum levels of glutamic acid, aspartic acid and serine increased with increasing DHI dose. A total of 3, 2, 2 and 5 non-overlapping metabolic pathways were identified in the DH-1, DH-2, DH-3 and DH-4 groups, respectively, and glycine, serine, threonine and histidine metabolism were identified as overlapping pathways among the 4 dose groups. CONCLUSION: Overlapping and non overlapping amino acid metabolites and metabolic pathways are associated with the dose-dependent neuroprotective effect of DHI. PMID- 25937633 TI - Intratumoral estrogen sulfotransferase induction contributes to the anti-breast cancer effects of the dithiocarbamate derivative TM208. AB - AIM: Sulfotransferase-catalyzed sulfation is the most important pathway for inactivating estrogens. Thus, activation of estrogen sulfotransferase (EST) may be an alternative approach for the treatment of estrogen-dependent breast cancer. In this study we investigated the involvement of EST in anti-breast cancer effects of the dithiocarbamate derivative TM208 in vitro and in vivo. METHODS: The viability of human breast cancer MCF-7 cells was determined using a SBB assay. Nude mice bearing MCF-7 cells were orally administered TM208 (50 and 150 mg.kg(-1).d(-1)) for 18 days. The xenograft tumors and uteri were collected. The mRNA expression of EST was examined with real-time PCR. EST protein was detected with Western blot, ELISA or immunohistochemical staining assays. A radioactive assay was used to measure the EST activity. Uterotropic bioassay was used to examine the uterine estrogen responses. RESULTS: Treatment with TM208 (10, 15 and 20 MUmol/L) concentration-dependently increased EST expression in MCF-7 cells in vitro. Co-treatment with triclosan, an inhibitor of sulfonation, abolished TM208 induced cytotoxicity in MCF-7 cells. TM208 exhibited an apparent anti-estrogenic property: it exerted more potent cytotoxicity in E2-treated MCF-7 cells. In the nude mice bearing MCF-7 cells, TM208 administration time-dependently increased the expression and activity of EST, and blocked the gradual increase of E2 concentration in the xenograft tumors. Furthermore, TM208 administration blocked the estrogens-stimulated uterine enlargement. Tamoxifen, a positive control drug, produced similar effects on the expression and activity of EST in vitro and in vivo. CONCLUSION: The induction of EST and reduction of estrogen concentration contribute to the anti-breast cancer action of TM208 and tamoxifen. TM208 may be developed as anticancer drug for the treatment of estrogen receptor-positive breast cancer. PMID- 25937634 TI - Deciphering the pharmacological mechanism of the Chinese formula huanglian-jie-du decoction in the treatment of ischemic stroke using a systems biology-based strategy. AB - AIM: Huanglian-jie-du decoction (HLJDD) is an important multiherb remedy in TCM, which is recently demonstrated to be effective to treat ischemic stroke. Here, we aimed to investigate the pharmacological mechanisms of HLJDD in the treatment of ischemic stroke using systems biology approaches. METHODS: Putative targets of HLJDD were predicted using MetaDrug. An interaction network of putative HLJDD targets and known therapeutic targets for the treatment of ischemic stroke was then constructed, and candidate HLJDD targets were identified by calculating topological features, including 'Degree', 'Node-betweenness', 'Closeness', and 'K coreness'. The binding efficiencies of the candidate HLJDD targets with the corresponding compositive compounds were further validated by a molecular docking simulation. RESULTS: A total of 809 putative targets were obtained for 168 compositive compounds in HLJDD. Additionally, 39 putative targets were common to all four herbs of HLJDD. Next, 49 major nodes were identified as candidate HLJDD targets due to their network topological importance. The enrichment analysis based on the Gene Ontology (GO) annotation system and the Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway demonstrated that candidate HLJDD targets were more frequently involved in G-protein-coupled receptor signaling pathways, neuroactive ligand-receptor interactions and gap junctions, which all played important roles in the progression of ischemic stroke. Finally, the molecular docking simulation showed that 170 pairs of chemical components and candidate HLJDD targets had strong binding efficiencies. CONCLUSION: This study has developed for the first time a comprehensive systems approach integrating drug target prediction, network analysis and molecular docking simulation to reveal the relationships between the herbs contained in HLJDD and their putative targets and ischemic stroke-related pathways. PMID- 25937635 TI - An integrated metabonomic and proteomic study on Kidney-Yin Deficiency Syndrome patients with diabetes mellitus in China. AB - AIM: To investigate specific changes in metabolites and proteins of Kidney-Yin Deficiency Syndrome (KYDS) patients with diabetes mellitus (DM) in China. METHODS: KYDS (n=29) and non-KYDS (n=23) patients with DM were recruited for this study. The KYDS was diagnosed by two senior TCM clinicians separately. The metabonomic and proteomic profiles of the patients were assessed using a metabonomic strategy based on NMR with multivariate analysis and a proteomic strategy based on MALDI-TOF-MS, respectively. RESULTS: Eighteen upregulated peptides and thirty downregulated peptides were observed in the plasma of the KYDS patients. Comparing the proteomic profiles of the KYDS and non-KYDS groups, however, no significantly differentially expressed peptides were found. At the same time, major metabolic alterations were found to distinguish the two groups, including eight significantly changed metabolites (creatinine, citrate, TMAO, phenylalanine, tyrosine, alanine, glycine and taurine). The levels of creatinine, citrate, TMAO, phenylalanine and tyrosine were decreased, whereas the levels of alanine, glycine and taurine were increased in the KYDS patients. These biochemical changes were found to be associated with alterations in amino acid metabolism, energy metabolism and gut microflora. CONCLUSION: The identification of distinct expression profiles of metabolites and signaling pathways in KYDS patients with DM suggests that there are indeed molecular signatures underlying the principles of 'Syndrome Differentiation' in traditional Chinese medicine. PMID- 25937636 TI - Blocking VEGF/Caveolin-1 signaling contributes to renal protection of fasudil in streptozotocin-induced diabetic rats. AB - AIM: RhoA/ROCK signaling plays an important role in diabetic nephropathy, and ROCK inhibitor fasudil exerts nephroprotection in experimental diabetic nephropathy. In this study we investigated the molecular mechanisms underlying the protective actions of fasudil in a rat model of diabetic nephropathy. METHODS: Streptozotocin (STZ)-induced diabetic rats, to which fasudil or a positive control drug enalapril were orally administered for 8 months. Metabolic parameters and blood pressure were assessed during the treatments. After the rats were euthanized, kidney samples were collected for histological and molecular biological studies. VEGF, VEGFR1, VEGFR2 and fibronectin expression, and Src and caveolin-1 phosphorylation in the kidneys were assessed using RT-PCR, Western blot and immunohistochemistry assays. The association between VEGFR2 and caveolin 1 was analyzed with immunoprecipitation. RESULTS: Chronic administration of fasudil (30 and 100 mg.kg(-1).d(-1)) or enalapril (10 mg/kg, bid) significantly attenuated the glomerular sclerosis and albuminuria in the diabetic rats. Furthermore, fasudil treatment prevented the upregulation of VEGF, VEGFR1, VEGFR2 and fibronectin, and the increased association between VEGFR2 and caveolin-1 in the renal cortices, and partially blocked Src activation and caveolin-1 phosphorylation on tyrosine 14 in the kidneys, whereas enalapril treatment had no effects on the VEGFR2/Src/caveolin-1 signaling pathway. CONCLUSION: Fasudil exerts protective actions in STZ-induced diabetic nephropathy by blocking the VEGFR2/Src/caveolin-1 signaling pathway and fibronectin upregulation. Thus, VEGFR2 may be a potential therapeutic target for the treatment of diabetic nephropathy. PMID- 25937638 TI - Race/ethnicity and sex in U.S. occupations, 1970-2010: Implications for research, practice, and policy. AB - We used census data on the civilian non-institutional adult population to analyze trends in labor force participation by race/ethnicity and sex in U.S. occupations from 1970 to 2010 in decennial periods. We examined these data for the main effects and interactions of race/ethnicity and sex across the total labor market and within 35 detailed occupations. Results from a log-linear analysis revealed that, as a whole (across race/ethnicity), more women participated in the labor force from 1970 to 2010. The proportions of working racial/ethnic minorities to both the population and the people in the labor force increased across all decades except for Black men. Although White (Caucasian) men continuously comprised the largest racial/ethnic-sex group working across five decades in absolute numbers, their percentage of the total working population declined from 1970 (54%) to 2010 (37%). In our analyses of 35 occupations, significant sex differences within racial/ethnic groups emerged. Overall, with some exceptions, Asian men and women and White women were more likely to be absorbed into occupations typically associated with professional status whereas Black, Hispanic, and American Indian men and women were more likely to be absorbed into occupations typically associated with low skill, low wages, and low status. Implications for the role of psychologists in future research, practice, and policy are discussed. PMID- 25937637 TI - Argonaute 2 promotes angiogenesis via the PTEN/VEGF signaling pathway in human hepatocellular carcinoma. AB - AIM: Argonaute2 (AGO2) protein is the active part of RNA-induced silencing complex, cleaving the target mRNA strand complementary to their bound siRNA. An increasing number of miRNAs has been identified as essential to angiogenesis of hepatocellular carcinoma (HCC). In this study we investigated how AGO2 affected HCC angiogenesis. METHODS: Human HCC cell lines HepG2, Hep3B, Huh7, SMMC-7721, Bel-7404, MHCC97-H and LM-3, and human umbilical vein endothelial cells (HUVEC) were tested. The expression of AGO2 in HCC cells was knocked down with siRNA and restored using recombinant adenovirus expressing Ago2. The levels of relevant mRNAs and proteins were examined using RT-PCR, Western blot and EILSA. Nude mice were implanted with Huh7 or SMMC-7721 cells, and tumor volumes were measured. After the mice were euthanized, the xenograft tumors were used for immunohistological analysis. RESULTS: In 6 HCC cell lines, AGO2 protein expression was significantly correlated with VEGF expression (r=+0.79), and with VEGF secretion (r=+0.852). Knockdown of Ago2 in Huh7 cells and SMMC-7721 cells substantially decreased VEGF expression, whereas the restoration of AGO2 reversed both VEGF expression and secretion. Furthermore, knockdown of Ago2 significantly up-regulated the expression of PTEN (a tumor suppressor involved in the inhibition of HCC angiogenesis), and vice versa. Moreover, the specific PTEN inhibitor bisperoxovanadate (7, 14, 28 nmol/L) dose-dependently restored the expression of VEGF and the capacity of HCC cells to induce HUVECs to form capillary tubule structures. In the xenograft nude mice, knockdown of Ago2 markedly suppressed the tumor growth and decreased PTEN expression and CD31 positive microvascular in the xenograft tumors. CONCLUSION: A direct relationship exists between the miRNA processing machinery AGO2 and HCC angiogenesis that is mediated by the AGO2/PTEN/VEGF signaling pathway. The results suggest the high value of Ago2 knockdown in anti-angiogenesis therapy for HCC. PMID- 25937640 TI - Issues in Identifying Poor Comprehenders. AB - Studies of poor comprehenders vary in the selection criteria and tests that they use to define poor comprehension. Could these differences play a role in determining findings about poor comprehension? This study assessed the extent to which differences in selection methods affect who gets identified as poor comprehenders, and examined how their cognitive profiles differ. Over 1,500 children, ages 8 - 19, took multiple tests of reading comprehension, listening comprehension, single word reading and nonword reading. Poor comprehension was defined by performing in the low-tail and by discrepancies either with word or nonword reading. Odds of any two selection methods identifying the same individuals were generally low, and depended on type of comprehension test more than modality, as well as selection criteria, and comprehender's age. Poor comprehenders selected by the different methods were found to vary in IQ, working memory, but not attention. The findings show that differences across studies in tests and selection criteria used to define poor comprehension are not insignificant and can have substantial consequences for what is meant by poor comprehension and its associated deficits. PMID- 25937639 TI - Friends of friends: are indirect connections in social networks important to animal behaviour? AB - Friend of a friend relationships, or the indirect connections between people, influence our health, well-being, financial success and reproductive output. As with humans, social behaviours in other animals often occur within a broad interconnected network of social ties. Yet studies of animal social behaviour tend to focus on associations between pairs of individuals. With the increase in popularity of social network analysis, researchers have started to look beyond the dyad to examine the role of indirect connections in animal societies. Here, I provide an overview of the new knowledge that has been uncovered by these studies. I focus on research that has addressed both the causes of social behaviours, i.e. the cognitive and genetic basis of indirect connections, as well as their consequences, i.e. the impact of indirect connections on social cohesion, information transfer, cultural practices and fitness. From these studies, it is apparent that indirect connections play an important role in animal behaviour, although future research is needed to clarify their contribution. PMID- 25937641 TI - Doubly Robust Learning for Estimating Individualized Treatment with Censored Data. AB - Individualized treatment rules recommend treatments based on individual patient characteristics in order to maximize clinical benefit. When the clinical outcome of interest is survival time, estimation is often complicated by censoring. We develop nonparametric methods for estimating an optimal individualized treatment rule in the presence of censored data. To adjust for censoring, we propose a doubly robust estimator which requires correct specification of either the censoring model or survival model, but not both; the method is shown to be Fisher consistent when either model is correct. Furthermore, we establish the convergence rate of the expected survival under the estimated optimal individualized treatment rule to the expected survival under the optimal individualized treatment rule. We illustrate the proposed methods using simulation study and data from a Phase III clinical trial on non-small cell lung cancer. PMID- 25937642 TI - Towards a global environmental sociology? Legacies, trends and future directions. AB - A current debate on environmental sociology involves how the subdiscipline should conceptualise and investigate the environment and whether it should be prescriptive and deliver policy recommendations. Taking this debate as a point of departure this article discusses the current and future role of sociology in a globalised world. It discusses how environmental sociology in the US and Europe differ in their understandings of sociology's contribution to the study of the environment. Particular stress is placed on how these two regions differ with respect to their use of the tradition of sociological thought, views on what constitutes the environment and ways of institutionalising environmental sociology as a sociological field. In conclusion, the question is raised of whether current versions of environmental sociology are appropriate for analysing a globalised world environment; or whether environmental sociology's strong roots in European and US cultures make it less relevant when facing an increasingly globalised world. Finally, the article proposes some new rules for a global environmental sociology and describes some of their possible implications for the sociological study of climate change. PMID- 25937643 TI - Degradable PEGylated Protein Conjugates Utilizing RAFT Polymerization. AB - Poly(ethylene glycol) (PEG)-protein therapeutics exhibit enhanced pharmacokinetics, but have drawbacks including decreased protein activities and polymer accumulation in the body. Therefore a major aim for second-generation polymer therapeutics is to introduce degradability into the backbone. Herein we describe the synthesis of poly(poly(ethylene glycol methyl ether methacrylate)) (pPEGMA) degradable polymers with protein-reactive end-groups via reversible addition-fragmentation chain transfer (RAFT) polymerization, and the subsequent covalent attachment to lysozyme through a reducible disulfide linkage. RAFT copolymerization of cyclic ketene acetal (CKA) monomer 5,6-benzo-2-methylene-1,3 dioxepane (BMDO) with PEGMA yielded two polymers with number-average molecular weight (Mn ) (GPC) of 10.9 and 20.9 kDa and molecular weight dispersities (D) of 1.34 and 1.71, respectively. Hydrolytic degradation of the polymers was analyzed by 1H-NMR and GPC under basic and acidic conditions. The reversible covalent attachment of these polymers to lysozyme, as well as the hydrolytic and reductive cleavage of the polymer from the protein, was analyzed by gel electrophoresis and mass spectrometry. Following reductive cleavage of the polymer, an increase in activity was observed for both conjugates, with the released protein having full activity. This represents a method to prepare PEGylated proteins, where the polymer is readily cleaved from the protein and the main chain of the polymer is degradable. PMID- 25937644 TI - Widespread supplementary feeding in domestic gardens explains the return of reintroduced Red Kites Milvus milvus to an urban area. AB - Reintroductions are commonly used to mitigate biodiversity loss. One prominent example is that of the Red Kite Milvus milvus, a charismatic raptor of conservation concern. This species has been reintroduced across the UK over the last 25 years following its near extinction after centuries of persecution. The species was not expected to recolonize urban areas; its historical association with human settlements is attributed to scavenging on human waste and refuse, a resource now greatly reduced on the streets of modern European cities. However, the species has become a common daytime visitor to a large conurbation centred on the town of Reading, southern England, approximately 20 km from the first English reintroduction site. Given a near-absence of breeding and roost sites, we investigated foraging opportunities and habitat associations that might explain use by Red Kites of this urban area. Surveys of discarded human foods and road kill suggested that these could support at most 13-29 Kites per day. Face-to-face surveys of a cross-section of residents revealed that 4.5% (equivalent to 4349 households) provided supplementary food for Red Kites in their gardens. Using estimates of per-household resource provision from another study, we calculated that this is potentially sufficient to feed 142-320 Kites, a substantial proportion of the total estimated to visit the conurbation each day (between 140 and 440). Road transects found positive associations between Red Kites and residential areas. We suggest that the decision made by thousands of householders to provide supplementary food for Red Kites in their gardens is the primary factor explaining their daytime abundance in this urban area. PMID- 25937645 TI - Pyrexia: An update on importance in clinical practice. AB - Pyrexic patients are usually attended with some scepticism by anaesthesiologists. Main reasons are the absence of comprehensible guidelines pertaining to anaesthesia in such patients and the presence of innumerable aetiologies of pyrexia. This article has tried to fill the existing void in the medical literature regarding anaesthesia in a patient with pyrexia. The article aims to discuss common and relevant causes of pyrexia, their pathophysiology in anaesthetic perspective, and the subsequent anaesthetic management, though a detailed discourse on all the entities causing pyrexia is beyond the scope of this article. This article will also touch upon the thermoregulatory alterations during anaesthesia. The literature search was performed manually using text and reference books, peer-reviewed journals, online and offline and through internet search engines Google, PubMed and Medline databases, using search terms 'perioperative pyrexia or fever, anaesthesia and thermoregulation'. Articles from 1980 to 2013 in English language were selected. PMID- 25937646 TI - Clinical evaluation of nares-vocal cord distance and its correlation with various external body parameters. AB - BACKGROUND AND AIMS: The optimal visualisation of vocal cords during fibreoptic intubation may be utilised for the nares-vocal cord distance (NVD) estimation. The present study was conducted to measure NVD and to correlate with various external body parameters. METHODS: This study was conducted on 50 males and 50 females. We measured NVD and analysed its relationship with height, nares to tragus of ear distance (NED), nares to angle of mandible distance (NMD), sternal length (SL), thyro-mental distance (TMD), sterno-mental distance (SMD) and arm span (AS). RESULTS: The mean NVD of the males was 18.5 +/- 1.5 cm, and that of the females was 15.9 +/- 1.1 cm. The relationship between the NVD and body height (males P = 0.001, r = 0.463, females P = 0.000, r = 0.555), SL (males P = 0.000, r = 0.463, females P < 0.000, r = 0.801) or AS (males P = 0.000, r = 0.561, females P = 0.000, r = 0.499) showed a significant correlation but NED, NMD, TMD, SMD did not. After combining male and female groups, (n = 100), the correlation of NVD with external body parameters is as follows SL (r = 0.887), height (r = 0.791), AS (r = 0.769), weight (r = 0.531), SMD (r = 0.466), NED (r = 0.459), NMD (r = 0.391), TMD (r = 0.379). CONCLUSION: The relationship of NVD to external body parameters had strong correlation in all parameters in the combined group; whereas when gender was taken into consideration NVD correlated significantly only with SL, height and AS. PMID- 25937647 TI - Effect of positive airway pressure during pre-oxygenation and induction of anaesthesia upon safe duration of apnoea. AB - BACKGROUND AND AIMS: Induction of general anaesthesia per se as also the use of 100% oxygen during induction of anaesthesia, results in the development of atelectasis in dependent lung regions within minutes of anaesthetic induction. We aimed to assess the effect of application of a continuous positive airway pressure (CPAP) of 5 cm H2O during pre-oxygenation and induction of anaesthesia on the period of apnoea before the occurrence of clinically significant desaturation. METHODS: In this prospective, randomised, and double-blind study, 40 patients posted for elective surgery were enrolled. Duration of apnoea was measured as the time from the administration of succinylcholine hydrochloride to the time when oxygen saturation fell to 93%. Student's t-test was used for comparing the duration of apnoea. RESULTS: The safe duration of apnoea was found to be significantly longer in patients receiving CPAP of 5 cm H2O (Group P; n = 16) compared to the group receiving no CPAP (Group Z; n = 20), that is, 496.56 +/ 71.68 s versus 273.00 +/- 69.31 s (P < 0.001). CONCLUSION: The application of CPAP of 5 cm H2O using a Mapleson A circuit with a fixed positive end-expiratory pressure device during 5 min of pre-oxygenation with 100% oxygen prior to the induction of anaesthesia provides a clearly longer duration of apnoea before clinically significant arterial desaturation occurs. PMID- 25937648 TI - Comparison of ramosetron with ondansetron for the prevention of post-operative nausea and vomiting in high-risk patients. AB - BACKGROUND AND AIMS: Post-operative nausea and vomiting (PONV) has an 80% incidence in high-risk patients. This is despite the availability of several antiemetic drugs. Selective 5-hydroxytryptamine type 3 (5-HT3) receptor antagonists are considered first-line for prophylaxis, ondansetron being the most commonly used agent. Ramosetron, another selective 5-HT3 receptor antagonist, is more potent and longer acting than ondansetron. This study was conducted to evaluate the antiemetic efficacy of ramosetron in comparison with ondansetron in patients at a high risk of PONV. METHODS: This was a prospective randomised double-blind study carried out over a 6-month period in which 206 patients with at least two risk factors for PONV were randomised to receive ramosetron 0.3 mg or ondansetron 8 mg, 30 min before the end of surgery. The incidence of PONV, severity of nausea and need for rescue antiemetic were recorded over the next 24 h. Primary outcome was the incidence of PONV. Secondary outcomes included severity of nausea and need for rescue. The data were analysed using the Predictive Analytics Software (PASW, version 18: Chicago, IL, USA). RESULTS: The incidence of PONV was found to be 35% in the ramosetron group as opposed to 43.7% in the ondansetron group (P = 0.199). Need for rescue antiemetic was 23.3% in the ramosetron group and 32% in the ondansetron group (P = 0.156) in the 24 h following surgery. CONCLUSION: Ramosetron 0.3 mg and ondansetron 8 mg were equally effective in reducing the incidence of PONV in high risk patients. PMID- 25937649 TI - Outcomes of implementation of enhanced goal directed therapy in high-risk patients undergoing abdominal surgery. AB - BACKGROUND AND AIMS: Advanced monitoring targeting haemodynamic and oxygenation variables can improve outcomes of surgery in high-risk patients. We aimed to assess the impact of goal directed therapy (GDT) targeting cardiac index (CI) and oxygen extraction ratio (O2ER) on outcomes of high-risk patients undergoing abdominal surgery. METHODS: In a prospective randomised trial, forty patients (American Society of Anaesthesiologists II and III) undergoing major abdominal surgeries were randomised into two groups. In-Group A mean arterial pressure >= 65 mmHg, central venous pressure >= 8-10 mmHg, urine output >= 0.5 mL/kg/h and central venous oxygen saturation >= 70% were targeted intra-operatively and 12 h postoperatively. In-Group-B (enhanced GDT), in addition to the monitoring in Group-A, CI >= 2.5 L/min/m(2) and O2ER <= 27% were targeted. The end-points were lactate levels and base deficit during and after surgery. The secondary end points were length of Intensive Care Unit (ICU) and hospital stay and postoperative complications. Wilcoxon Mann Whitney and Chi-square tests were used for statistical assessment. RESULTS: Lactate levels postoperatively at 4 and 8 h were lower in-Group-B (P < 0.05). The mean base deficit at 3, 4, 5 and 6 h intra operatively and postoperatively after 4, 8 and 12 h were lower in-Group-B (P < 0.05). There were no significant differences in ICU stay (2.10 +/- 1.52 vs. 2.90 +/- 2.51 days) or hospital stay (10.85 + 4.39 vs. 13.35 + 6.77 days) between Group A and B. CONCLUSIONS: Implementation of enhanced GDT targeting CI and OER was associated with improved tissue oxygenation. PMID- 25937650 TI - Intraperitoneal bupivacaine alone or with dexmedetomidine or tramadol for post operative analgesia following laparoscopic cholecystectomy: A comparative evaluation. AB - BACKGROUND AND AIMS: Intraperitoneal instillation of local anaesthetics has been shown to minimise post-operative pain after laparoscopic surgeries. We compared the antinociceptive effects of intraperitoneal dexmedetomidine or tramadol combined with bupivacaine to intraperitoneal bupivacaine alone in patients undergoing laparoscopic cholecystectomy. METHODS: A total of 120 patients were included in this prospective, double-blind, randomised study. Patients were randomly divided into three equal sized (n = 40) study groups. Patients received intraperitoneal bupivacaine 50 ml 0.25% +5 ml normal saline (NS) in Group B, bupivacaine 50 ml 0.25% + tramadol 1 mg/kg (diluted in 5 ml NS) in Group BT and bupivacaine 50 ml 0.25% + dexmedetomidine 1 MUg/kg, (diluted in 5 ml NS) in Group BD before removal of trocar at the end of surgery. The quality of analgesia was assessed by visual analogue scale score (VAS). Time to the first request of analgesia, total dose of analgesic in the first 24 h and adverse effects were noted. Statistical analysis was performed using Microsoft (MS) Office Excel Software with the Student's t-test and Chi-square test (level of significance P = 0.05). RESULTS: VAS at different time intervals, overall VAS in 24 h was significantly lower (1.80 +/- 0.36, 3.01 +/- 0.48, 4.5 +/- 0.92), time to first request of analgesia (min) was longest (128 +/- 20, 118 +/- 22, 55 +/- 18) and total analgesic consumption (mg) was lowest (45 +/- 15, 85 +/- 35, 175 +/- 75) in Group BD than Group BT and Group B. CONCLUSION: Intraperitoneal instillation of bupivacaine in combination with dexmedetomidine is superior to bupivacaine alone and may be better than bupivacaine with tramadol. PMID- 25937651 TI - Management of tracheomalacia in an infant with Tetralogy of Fallot. AB - Most infants with tracheomalacia do not need specific therapy as it usually resolves spontaneously by the age of 1-2 years. Severe forms of tracheomalacia characterized by recurrent respiratory infections require active treatment which includes chest physiotherapy, long term intubation or tracheostomy. Aortopexy seems to be the treatment of choice for secondary and even primary forms of severe tracheomalacia. Itentails tracking and suturing the anterior wall of the aorta to the posterior surface of the sternum. Consequently, the anterior wall of the trachea is also pulled forward preventing its collapse. A 3-month-old girl baby who was on ventilatory support for 2 months due to severe tracheomalacia associated with a cyanotic congenital heart disease underwent intracardiac repair and aortopexy along with Lecompte's procedure as all the conservative measures to wean off the ventilator failed. The baby was extubated on the third post operative day and the post-operative period was uneventful. PMID- 25937652 TI - Anaesthetic management for drainage of frontoparietal abscess in a patient of uncorrected Tetralogy of Fallot. PMID- 25937653 TI - Prone position ventilation in Acute Respiratory Distress Syndrome: An overview of the evidences. PMID- 25937654 TI - Anaesthetic management of a patient with anti-NMDA receptor encephalitis. PMID- 25937655 TI - Immune-mediated thrombocytopaenia secondary to pulmonary tuberculosis: Diagnostic and therapeutic dilemma. PMID- 25937656 TI - Emergency tracheal intubation through intubating laryngeal mask airway in patients with stereotactic frame in situ. PMID- 25937657 TI - Cardiac arrest from tramadol and fentanyl combination. PMID- 25937658 TI - Our encounter with left superior vena cava. PMID- 25937659 TI - Bilateral asymptomatic pneumothorax in early post-operative period. PMID- 25937660 TI - Anaesthetic in the garb of a propellant. PMID- 25937661 TI - New approach to treat an old problem: Mannitol for post dural puncture headache! PMID- 25937662 TI - Prevention of migration of endotracheal tubes used for aided nasogastric tube placement in anaesthetized patients. PMID- 25937663 TI - Transfusion practices in trauma. PMID- 25937664 TI - Transfusion practices in trauma. PMID- 25937665 TI - Blood transfusion practices in liver transplantation. PMID- 25937666 TI - Erratum: Survey of supraglottic airway devices usage in anaesthetic practice in South Indian State: Erratum. AB - [This corrects the article on p. 190 in vol. 59, PMID: 25838594.]. PMID- 25937668 TI - Social Consequences of Academic Teaming in Middle School: The Influence of Shared Course-Taking on Peer Victimization. AB - This study examined the influence of academic teaming (i.e., sharing academic classes with the same classmates) on the relationship between social preference and peer victimization among 6th grade students in middle school. Approximately 1,000 participants were drawn from 5 middle schools that varied in their practice of academic teaming. A novel methodology for measuring academic teaming at the individual level was employed, in which students received their own teaming score based on the unique set of classmates with whom they shared academic courses in their class schedule. Using both peer- and self-reports of victimization, the results of two path models indicated that students with low social preference in highly teamed classroom environments were more victimized than low preference students who experienced less teaming throughout the school day. This effect was exaggerated in higher performing classrooms. Implications for the practice of academic teaming were discussed. PMID- 25937667 TI - Towards an understanding of dimensions, predictors, and gender gap in written composition. AB - We had three aims in the present study: (1) to examine the dimensionality of various evaluative approaches to scoring writing samples (e.g., quality, productivity, and curriculum based writing [CBM]) , (2) to investigate unique language and cognitive predictors of the identified dimensions, and (3) to examine gender gap in the identified dimensions of writing. These questions were addressed using data from second and third grade students (N = 494). Data were analyzed using confirmatory factor analysis and multilevel modeling. Results showed that writing quality, productivity, and CBM scoring were dissociable constructs, but that writing quality and CBM scoring were highly related (r = .82). Language and cognitive predictors differed among the writing outcomes. Boys had lower writing scores than girls even after accounting for language, reading, attention, spelling, handwriting automaticity, and rapid automatized naming. Results are discussed in light of writing evaluation and a developmental model of writing. PMID- 25937669 TI - Value Development Underlies the Benefits of Parents' Involvement in Children's Learning: A Longitudinal Investigation in the United States and China. AB - This research examined whether the benefits of parents' involvement in children's learning are due in part to value development among children. Four times over the seventh and eighth grades, 825 American and Chinese children (mean age = 12.73 years) reported on their parents' involvement in their learning and their perceptions of the value their parents place on school achievement as well as the value they themselves place on it. Children's academic functioning was assessed via children's reports and school records. Value development partially explained the effects of parents' involvement on children's academic functioning in the United States and China. For example, the more children reported their parents as involved, the more they perceived them as placing value on achievement six months later; such perceptions in turn predicted the subsequent value children placed on achievement, which foreshadowed enhanced grades. PMID- 25937670 TI - Intergenerational Exchanges of Middle-Aged Adults With Their Parents and Parents In-Law in Korea. AB - The authors investigated patterns of support exchanges between Korean adult children and their parents and parents-in-law, gender differences in these patterns, and implications of children's marital quality for exchange patterns. Data were from a nationally representative sample of married adults (N = 920, age 30-59 years) with at least 1 living parent and 1 living parent-in-law. Latent class analysis was applied to 12 indicators of exchanges (financial, instrumental, emotional support given to and received from parents and parents-in law). Five classes of exchanges were identified, 3 showing balanced patterns of exchanges with parents and parents-in-law across three types of support and 2 classes with unbalanced patterns (e.g., giving instrumental and financial, but not emotional support). The findings revealed variability in intergenerational exchange patterns, with a mix of patrilineal traditional and balanced patterns. Significant associations of exchange patterns with adult children's marital quality suggest the importance of balanced exchanges with parents for marriage. PMID- 25937671 TI - Vibrational analysis of alpha-cyanohydroxycinnamic acid. AB - In the present study, a comparative Raman vibrational analysis of alpha-cyano-4 hydroxycinnamic acid (4CHCA) and its derivative, alpha-cyano-3-hydroxycinnamic acid (3CHCA), was performed. The Raman spectra of the 4CHCA and 3CHCA in solid form were obtained and analyzed to determine differences between the two structurally similar derivatives. For comparison, the CHCA derivatives cyanocinnamic acid (CCA) and coumaric acid (CA) were also studied. The plausible vibrational assignments were made and matched with those obtained theoretically using density functional theory (DFT) based method employing a 6-31 g basis set. The computational wavenumbers obtained were in good agreement with the observed experimental results. This was the first reported Raman study of CCA, 3CHCA and 4CHCA. PMID- 25937672 TI - 16S and 23S plastid rDNA phylogenies of Prototheca species and their auxanographic phenotypes. AB - Because algae have become more accepted as sources of human nutrition, phylogenetic analysis can help resolve the taxonomy of taxa that have not been well studied. This can help establish algal evolutionary relationships. Here, we compare Auxenochlorella protothecoides and 23 strains of Prototheca based on their complete 16S and partial 23S plastid rDNA sequences along with nutrient utilization (auxanographic) profiles. These data demonstrate that some of the species groupings are not in agreement with the molecular phylogenetic analyses and that auxanographic profiles are poor predictors of phylogenetic relationships. PMID- 25937673 TI - Evolution of extreme proboscis lengths in Neotropical Hesperiidae (Lepidoptera). AB - Exaggerated morphologies have evolved in insects as adaptations to nectar feeding by natural selection. For example, the suctorial mouthparts of butterflies enable these insects to gain access to floral nectar concealed inside deep floral tubes. Proboscis length in Lepidoptera is known to scale with body size, but whether extreme absolute proboscis lengths of nectar feeding butterflies result from a proportional or disproportional increase with body size that differs between phylogenetic lineages remains unknown. We surveyed the range of variation that occurs in scaling relationships between proboscis length and body size against a phylogenetic background among Costa Rican Hesperiidae. We obtained a new record holder for the longest proboscis in butterflies and showed that extremely long proboscides evolved at least three times independently within Neotropical Hesperiidae. We conclude that the evolution of extremely long proboscides results from allometric scaling with body size, as demonstrated in hawk moths. We hypothesize that constraints on the evolution of increasingly long butterfly proboscides may come from (1) the underlying scaling relationships, i.e., relative proboscis length, combined with the butterfly's flight style and flower visiting behaviour and/or (2) developmental constraints during the pupal phase. Lastly, we discuss why butterflies did not evolve similar scaling relationships as hawk moths. PMID- 25937674 TI - Estimation of integral curves from high angular resolution diffusion imaging (HARDI) data. AB - We develop statistical methodology for a popular brain imaging technique HARDI based on the high order tensor model by Ozarslan and Mareci [10]. We investigate how uncertainty in the imaging procedure propagates through all levels of the model: signals, tensor fields, vector fields, and fibers. We construct asymptotically normal estimators of the integral curves or fibers which allow us to trace the fibers together with confidence ellipsoids. The procedure is computationally intense as it blends linear algebra concepts from high order tensors with asymptotical statistical analysis. The theoretical results are illustrated on simulated and real datasets. This work generalizes the statistical methodology proposed for low angular resolution diffusion tensor imaging by Carmichael and Sakhanenko [3], to several fibers per voxel. It is also a pioneering statistical work on tractography from HARDI data. It avoids all the typical limitations of the deterministic tractography methods and it delivers the same information as probabilistic tractography methods. Our method is computationally cheap and it provides well-founded mathematical and statistical framework where diverse functionals on fibers, directions and tensors can be studied in a systematic and rigorous way. PMID- 25937675 TI - The Chimera of Proportionality: Institutionalising Limits on Punishment in Contemporary Social and Political Systems. AB - The concept of proportionality has been central to the retributive revival in penal theory, and underlies desert theory's normative and practical commitment to limiting punishment. Theories of punishment combining desert-based and consequentialist considerations also appeal to proportionality as a limiting condition. In this paper we argue that these claims are founded on an exaggerated idea of what proportionality can offer, and in particular fail properly to consider the institutional conditions needed to foster robust limits on the state's power to punish. The idea that appeals to proportionality as an abstract ideal can help to limit punishment is, we argue, a chimera: what has been thought of as proportionality is not a naturally existing relationship, but a product of political and social construction, cultural meaning-making, and institution building. Drawing on evolutionary psychology and comparative political economy, we argue that philosophers and social scientists need to work together to understand how the appeal of the idea of proportionality can best be realised through substantive institutional frameworks under particular conditions. PMID- 25937676 TI - Insurers' Negotiating Leverage and the External Effects of Medicare Part D. AB - By influencing the size and bargaining power of private insurers, public subsidization of private health insurance may project effects beyond the subsidized population. We test for such spillovers by analyzing how increases in insurer size resulting from the implementation of Medicare Part D affected drug prices negotiated in the non-Medicare commercial market. On average, Part D lowered prices for commercial enrollees by 3.7%. The external commercial market savings amount to $1.5 billion per year, which, if passed to consumers, approximates the internal cost-savings of newly-insured subsidized beneficiaries. If retained by insurers, it corresponds to a 5% average increase in profitability. PMID- 25937677 TI - Synthesis of 1,2-dihydro-2-oxo-4-quinolinyl phosphates from 2-acyl-benzoic acids. AB - We report a facile synthesis of 1,2-dihydro-2-oxo-4-quinolinyl phosphates (1a-l) starting from 2-acyl-benzoic acids (2a-l) in the presence of phosphoryl azides via a one-pot cascade reaction involving a Curtius rearrangement, an intramolecular nucleophilic addition of the enol carbon to the isocyanate intermediate, and an addition-elimination of the enol oxygen to the phosphoryl azide. During the reaction three new bonds are formed under mild conditions to yield 1,2-dihydro-2-oxo-4-quinolinyl phosphates in modest yields. PMID- 25937678 TI - A continuous flow microfluidic calorimeter: 3-D numerical modeling with aqueous reactants. AB - A computational analysis of the reacting flow field, species diffusion and heat transfer processes with thermal boundary layer effects in a microchannel reactor with a coflow configuration was performed. Two parallel adjacent streams of aqueous reactants flow along a wide, shallow, enclosed channel in contact with a substrate, which is affixed to a temperature controlled plate. The Fluent computational fluid dynamics package solved the Navier-Stokes, mass transport and energy equations. The energy model, including the enthalpy of reaction as a nonuniform heat source, was validated by calculating the energy balance at several control volumes in the microchannel. Analysis reveals that the temperature is nearly uniform across the channel thickness, in the direction normal to the substrate surface; hence, measurements made by sensors at or near the surface are representative of the average temperature. Additionally, modeling the channel with a glass substrate and a silicone cover shows that heat transfer is predominantly due to the glass substrate. Finally, using the numerical results, we suggest that a microcalorimeter could be based on this configuration, and that temperature sensors such as optical nanohole array sensors could have sufficient spatial resolution to determine enthalpy of reaction. PMID- 25937679 TI - CULTURALLY COMPETENT SERVICES WITHIN A STATEWIDE BEHAVIORAL HEALTHCARE TRANSFORMATION: A MIXED-METHOD ASSESSMENT. AB - In 2005, New Mexico created a single health plan to administer all publicly funded behavioral health services. Our mixed-method study combined surveys, document review, and ethnography to examine this reform's influence on culturally competent services (CCS). Participants were executives, providers, and support staff of behavioral healthcare agencies. Key variables included language access services and organizational supports, i.e., training, self-assessments of CCS, and maintenance of client-level data. Survey and document review suggested minimal effects on statewide capacity for CCS during the first three years of the reform. Ethnographic research helped explain these findings: (1) state government, the managed behavioral health plan and agencies failed to champion CCS; and (2) increased administrative requirements minimized time and financial resources for CCS. There was also insufficient appreciation among providers for CCS. Although agencies made progress in addressing language assistance services, availability and quality remained limited. PMID- 25937680 TI - Measurement of water colour using AVIRIS imagery to assess the potential for an operational monitoring capability in the Pamlico Sound Estuary, USA. AB - The monitoring of water colour parameters can provide an important diagnostic tool for the assessment of aquatic ecosystem condition. Remote sensing has long been used to effectively monitor chlorophyll concentrations in open ocean systems; however, operational monitoring in coastal and estuarine areas has been limited because of the inherent complexities of coastal systems, and the coarse spectral and spatial resolutions of available satellite systems. Data were collected using the National Aeronautics and Space Administration (NASA) Advanced Visible-Infrared Imaging Spectrometer (AVIRIS) flown at an altitude of approximately 20000 m to provide hyperspectral imagery and simulate both MEdium Resolution Imaging Spectrometer (MERIS) and Moderate Resolution Imaging Spectrometer (MODIS) data. AVIRIS data were atmospherically corrected using a radiative transfer modelling approach and analysed using band ratio and linear regression models. Regression analysis was performed with simultaneous field measurements data in the Neuse River Estuary (NRE) and Pamlico Sound on 15 May 2002. Chlorophyll a (Chl a) concentrations were optimally estimated using AVIRIS bands (9.5 nm) centred at 673.6 and 692.7 nm, resulting in a coefficient of determination (R2 ) of 0.98. Concentrations of Chromophoric Dissolved Organic Matter (CDOM), Total Suspended Solids (TSS) and Fixed Suspended Solids (FSS) were also estimated, resulting in coefficients of determination of R2=0.90, 0.59 and 0.64, respectively. Ratios of AVIRIS bands centred at or near those corresponding to the MERIS and MODIS sensors indicated that relatively good satellite-based estimates could potentially be derived for water colour constituents at a spatial resolution of 300 and 500 m, respectively. PMID- 25937681 TI - Mapping alteration minerals at prospect, outcrop and drill core scales using imaging spectrometry. AB - Imaging spectrometer data (also known as 'hyperspectral imagery' or HSI) are well established for detailed mineral mapping from airborne and satellite systems. Overhead data, however, have substantial additional potential when used together with ground-based measurements. An imaging spectrometer system was used to acquire airborne measurements and to image in-place outcrops (mine walls) and boxed drill core and rock chips using modified sensor-mounting configurations. Data were acquired at 5 nm nominal spectral resolution in 360 channels from 0.4 to 2.45 MUm. Analysis results using standardized hyperspectral methodologies demonstrate rapid extraction of representative mineral spectra and mapping of mineral distributions and abundances in map-plan, with core depth, and on the mine walls. The examples shown highlight the capabilities of these data for mineral mapping. Integration of these approaches promotes improved understanding of relations between geology, alteration and spectral signatures in three dimensions and should lead to improved efficiency of mine development, operations and ultimately effective mine closure. PMID- 25937682 TI - Perspectives on ageing, later life and ethnicity: ageing research in ethnic minority contexts. AB - This special issue focuses broadly upon questions and themes relating to the current conceptualisations, representations and use of 'ethnicity' (and ethnic minority experiences) within the field of social gerontology. An important aim of this special issue is to explore and address the issue of 'otherness' within the predominant existing frameworks for researching those who are ageing or considered aged, compounded by the particular constructions of their ethnicity and ethnic 'difference'. The range of theoretical, methodological and empirical papers included in this collection provide some critical insights into particular facets of the current research agendas, cultural understandings and empirical focus of ethnic minority ageing research. The main emphasis is on highlighting the ways in which ethnic cultural homogeneity and 'otherness' is often assumed in research involving older people from ethnic minority backgrounds, and how wider societal inequalities are concomitantly (re)produced, within (and through) research itself - for example, based on narrowly defined research agendas and questions; the assumed age and/or ethnic differences of researchers vis-a-vis their older research participants; the workings of the formalised ethical procedures and frameworks; and the conceptual and theoretical frameworks employed in the formulation of research questions and interpretation of data. We examine and challenge here the simplistic categorisations and distinctions often made in gerontological research based around research participants' ethnicity, age and ageing and assumed cultural differences. The papers presented in this collection reveal instead the actual complexity and fluidity of these concepts as well as the cultural dynamism and diversity of experiences within ethnic groups. Through an exploration of these issues, we address some of the gaps in existing knowledge and understandings as well as contribute to the newly emerging discussions surrounding the use of particular notions of ethnicity and ethnic minority ageing as these are being employed within the field of ageing studies. PMID- 25937683 TI - Dominance rank is associated with body condition in outdoor-living domestic horses (Equus caballus). AB - The aim of our study was to explore the association between dominance rank and body condition in outdoor group-living domestic horses, Equus caballus. Social interactions were recorded using a video camera during a feeding test, applied to 203 horses in 42 herds. Dominance rank was assigned to 194 individuals. The outcome variable body condition score (BCS) was recorded using a 9-point scale. The variables age and height were recorded and considered as potential confounders or effect modifiers. Results were analysed using multivariable linear and logistic regression techniques, controlling for herd group as a random effect. More dominant (p = 0.001) individuals generally had a higher body condition score (p = 0.001) and this association was entirely independent of age and height. In addition, a greater proportion of dominant individuals fell into the obese category (BCS >= 7/9, p = 0.005). There were more displacement encounters and a greater level of interactivity in herds that had less variation in age and height, lending strength to the hypothesis that phenotypic variation may aid cohesion in group-living species. In addition there was a strong quadratic relationship between age and dominance rank (p < 0.001), where middle aged individuals were most likely to be dominant. These results are the first to link behavioural predictors to body condition and obesity status in horses and should prompt the future consideration of behavioural and social factors when evaluating clinical disease risk in group-living animals. PMID- 25937684 TI - Energy dispersive CdTe and CdZnTe detectors for spectral clinical CT and NDT applications. AB - We are developing room temperature compound semiconductor detectors for applications in energy-resolved high-flux single x-ray photon-counting spectral computed tomography (CT), including functional imaging with nanoparticle contrast agents for medical applications and non destructive testing (NDT) for security applications. Energy-resolved photon-counting can provide reduced patient dose through optimal energy weighting for a particular imaging task in CT, functional contrast enhancement through spectroscopic imaging of metal nanoparticles in CT, and compositional analysis through multiple basis function material decomposition in CT and NDT. These applications produce high input count rates from an x-ray generator delivered to the detector. Therefore, in order to achieve energy resolved single photon counting in these applications, a high output count rate (OCR) for an energy-dispersive detector must be achieved at the required spatial resolution and across the required dynamic range for the application. The required performance in terms of the OCR, spatial resolution, and dynamic range must be obtained with sufficient field of view (FOV) for the application thus requiring the tiling of pixel arrays and scanning techniques. Room temperature cadmium telluride (CdTe) and cadmium zinc telluride (CdZnTe) compound semiconductors, operating as direct conversion x-ray sensors, can provide the required speed when connected to application specific integrated circuits (ASICs) operating at fast peaking times with multiple fixed thresholds per pixel provided the sensors are designed for rapid signal formation across the x-ray energy ranges of the application at the required energy and spatial resolutions, and at a sufficiently high detective quantum efficiency (DQE). We have developed high flux energy-resolved photon-counting x-ray imaging array sensors using pixellated CdTe and CdZnTe semiconductors optimized for clinical CT and security NDT. We have also fabricated high-flux ASICs with a two dimensional (2D) array of inputs for readout from the sensors. The sensors are guard ring free and have a 2D array of pixels and can be tiled in 2D while preserving pixel pitch. The 2D ASICs have four energy bins with a linear energy response across sufficient dynamic range for clinical CT and some NDT applications. The ASICs can also be tiled in 2D and are designed to fit within the active area of the sensors. We have measured several important performance parameters including; the output count rate (OCR) in excess of 20 million counts per second per square mm with a minimum loss of counts due to pulse pile-up, an energy resolution of 7 keV full width at half maximum (FWHM) across the entire dynamic range, and a noise floor about 20keV. This is achieved by directly interconnecting the ASIC inputs to the pixels of the CdZnTe sensors incurring very little input capacitance to the ASICs. We present measurements of the performance of the CdTe and CdZnTe sensors including the OCR, FWHM energy resolution, noise floor, as well as the temporal stability and uniformity under the rapidly varying high flux expected in CT and NDT applications. PMID- 25937685 TI - A feasibility study of a PET/MRI insert detector using strip-line and waveform sampling data acquisition. AB - We are developing a time-of-flight Positron Emission Tomography (PET) detector by using silicon photo-multipliers (SiPM) on a strip-line and high speed waveform sampling data acquisition. In this design, multiple SiPMs are connected on a single strip-line and signal waveforms on the strip-line are sampled at two ends of the strip to reduce readout channels while fully exploiting the fast time response of SiPMs. In addition to the deposited energy and time information, the position of the hit SiPM along the strip-line is determined by the arrival time difference of the waveform. Due to the insensitivity of the SiPMs to magnetic fields and the compact front-end electronics, the detector approach is highly attractive for developing a PET insert system for a magnetic resonance imaging (MRI) scanner to provide simultaneous PET/MR imaging. To investigate the feasibility, experimental tests using prototype detector modules have been conducted inside a 9.4 Tesla small animal MRI scanner (Bruker BioSpec 94/30 imaging spectrometer). On the prototype strip-line board, 16 SiPMs (5.2 mm pitch) are installed on two strip-lines and coupled to 2 * 8 LYSO scintillators (5.0 * 5.0 * 10.0 mm3 with 5.2 mm pitch). The outputs of the strip-line boards are connected to a Domino-Ring-Sampler (DRS4) evaluation board for waveform sampling. Preliminary experimental results show that the effect of interference on the MRI image due to the PET detector is negligible and that PET detector performance is comparable with the results measured outside the MRI scanner. PMID- 25937686 TI - Tolerance and Social Facilitation in the Foraging Behaviour of Free-Ranging Crows (Corvus corone corone; C. c. cornix). AB - Social foraging provides animals with opportunities to gain knowledge about available food. Studies indicate that animals are influenced by social context during exploration and are able to learn socially. Carrion and hooded crows, which are opportunistic generalists with flexible social systems, have so far received little focus in this area. We combined observational and experimental approaches to investigate social interactions during foraging and social influences on crow behaviour within a free-ranging population at Vienna Zoo, which included 115 individually marked crows. We expected the crows to be tolerant of conspecifics during foraging due to high food abundance. We predicted that social context would enhance familiar object exploration, as well as a specific foraging strategy: predation by crows on other species. We found that crows were highly tolerant of one another, as reflected by their high rates of cofeeding - where they fed directly beside conspecific(s) - relative to affiliative or agonistic interactions. Evidence for social facilitation - when the observer's behaviour is affected by the mere presence of a model - was found in both object exploration and predation behaviour. Specifically, crows touched the objects more frequently when others were present (whilst only approaching the objects when alone), and conspecifics were present more frequently during predation events involving the high-risk target species. Evidence for enhancement during object exploration - where the observer's attention is drawn to a place or object by a model's actions - was not confirmed in this context. Our results highlight the role played by the presence of conspecifics across different contexts: natural foraging behaviour, familiar object exploration and a specific foraging strategy. To our knowledge, this is one of the first corvid studies aimed at teasing apart specific social influence and learning mechanisms in the field. These crows therefore make promising candidates for studying social learning and its consequences under naturalistic conditions. PMID- 25937687 TI - "I Want to be There When He Graduates:" Foster Parents Show Higher Levels of Commitment than Group Care Providers. AB - Group care is a frequent placement for adolescents placed in out of home care when their birth parents' care is deemed unsafe. In the present study, we assessed whether foster parents show greater commitment to children than group care providers. Given that group care represents a number of living arrangements, we considered both shift care (where staff work shifts and do not live with the children) and cottage care (where staff live for extended periods of time with the children in a group living context). Commitment was assessed using the This Is My Child Interview (adapted for adolescents). Thirty-one foster parents, 18 shift workers, and 28 cottage care providers were interviewed. As predicted, foster parents showed higher levels of commitment than both shift care workers and cottage care providers, and the associations held when children's externalizing behaviors and the number of children the caregivers had cared for were controlled. The results suggest that foster care promotes greater commitment among caregivers than other out of home placements, and add to other findings that favor foster care as the out of home placement of choice for adolescents. PMID- 25937688 TI - Conflict with Friends, Relationship Blindness, and the Pathway to Adult Disagreeableness. AB - The ability to form and maintain relationships with friends and romantic partners is a major developmental task for adolescents. Disagreeable youth are likely to struggle with this task, yet little is known about how they maintain their oppositional style from adolescence to adulthood. The current study examines the long-term implications of disagreeableness in a diverse sample of 164 adolescents assessed repeatedly across a 10-year period along with their friends and romantic partners. Disagreeableness at age 14-15 was assessed in observation with friends. Disagreeableness was then examined as a predictor of both future relationship quality with friends at age 16 and romantic relationships at age 21. The results indicate that although disagreeable youth do not report any relationship struggles, both their friends and romantic partners see their relationships as being low in quality. Findings suggest a developmental process by which disagreeable adolescents maintain their oppositional style through a mechanism of relationship blindness, as they simply are unable to see the relationship issues that their friends and partners clearly perceive. PMID- 25937689 TI - Climate Variability and Human Migration in the Netherlands, 1865-1937. AB - Human migration is frequently cited as a potential social outcome of climate change and variability, and these effects are often assumed to be stronger in the past when economies were less developed and markets more localized. Yet, few studies have used historical data to test the relationship between climate and migration directly. In addition, the results of recent studies that link demographic and climate data are not consistent with conventional narratives of displacement responses. Using longitudinal individual-level demographic data from the Historical Sample of the Netherlands (HSN) and climate data that cover the same period, we examine the effects of climate variability on migration using event history models. Only internal moves in the later period and for certain social groups are associated with negative climate conditions, and the strength and direction of the observed effects change over time. International moves decrease with extreme rainfall, suggesting that the complex relationships between climate and migration that have been observed for contemporary populations extend into the nineteenth century. PMID- 25937690 TI - Direct fermentation of potato starch and potato residues to lactic acid by Geobacillus stearothermophilus under non-sterile conditions. AB - BACKGROUND: Lactic acid is an important biorefinery platform chemical. The use of thermophilic amylolytic microorganisms to produce lactic acid by fermentation constitutes an efficient strategy to reduce operating costs, including raw materials and sterilization costs. RESULTS: A process for the thermophilic production of lactic acid by Geobacillus stearothermophilus directly from potato starch was characterized and optimized. Geobacillus stearothermophilus DSM 494 was selected out of 12 strains screened for amylolytic activity and the ability to form lactic acid as the major product of the anaerobic metabolism. In total more than 30 batches at 3-l scale were run at 60 degrees C under non-sterile conditions. The process developed produced 37 g L-1 optically pure (98%) L-lactic acid in 20 h from 50 g L-1 raw potato starch. As co-metabolites smaller amounts (<7% w/v) of acetate, formate and ethanol were formed. Yields of lactic acid increased from 66% to 81% when potato residues from food processing were used as a starchy substrate in place of raw potato starch. CONCLUSIONS: Potato starch and residues were successfully converted to lactic acid by G. stearothermophilus. The process described in this study provides major benefits in industrial applications and for the valorization of starch-rich waste streams. (c) 2015 The Authors.Journal of Chemical Technology & Biotechnology published by John Wiley & Sons Ltd on behalf of Society of Chemical Industry. PMID- 25937691 TI - Oligosilanylated Antimony Compounds. AB - By reactions of magnesium oligosilanides with SbCl3, a number of oligosilanylated antimony compounds were obtained. When oligosilanyl dianions were used, either the expected cyclic disilylated halostibine was obtained or alternatively the formation of a distibine was observed. Deliberate formation of the distibine from the disilylated halostibine was achieved by reductive coupling with C8K. Computational studies of Sb-Sb bond energies, barriers of pyramidal inversion at Sb, and the conformational behavior of distibines provided insight for the understanding of the spectroscopic properties. PMID- 25937692 TI - Metalated Oligosilanylstibines. AB - The reaction of a cyclic disilylated bromostibine with magnesium yields a rare example of a magnesium stibide that can be silylated with trimethylchlorosilane. Reaction of the thus-obtained trisilylated stibine with potassium tert-butoxide gives a potassium stibide in a clean reaction. Attempts to obtain an antimony containing oligosilanide did not lead to the expected compound but to another potassium stibide, which presumably forms from the initially formed silanide by a 1,2-silyl shift. The synthetic potential of the obtained stibides to serve as building blocks could be shown by the preparation of stibylated zircono- and hafnocenes. PMID- 25937693 TI - Micromagnetic simulation of exchange coupled ferri-/ferromagnetic heterostructures. AB - Exchange coupled ferri-/ferromagnetic heterostructures are a possible material composition for future magnetic storage and sensor applications. In order to understand the driving mechanisms in the demagnetization process, we perform micromagnetic simulations by employing the Landau-Lifshitz-Gilbert equation. The magnetization reversal is dominated by pinning events within the amorphous ferrimagnetic layer and at the interface between the ferrimagnetic and the ferromagnetic layer. The shape of the computed magnetization reversal loop corresponds well with experimental data, if a spatial variation of the exchange coupling across the ferri-/ferromagnetic interface is assumed. PMID- 25937694 TI - 'Bats, Rats and Barristers': The Lancet, libel and the radical stylistics of early nineteenth-century English medicine. PMID- 25937695 TI - Definition and solution of a stochastic inverse problem for the Manning's n parameter field in hydrodynamic models. AB - The uncertainty in spatially heterogeneous Manning's n fields is quantified using a novel formulation and numerical solution of stochastic inverse problems for physics-based models. The uncertainty is quantified in terms of a probability measure and the physics-based model considered here is the state-of-the-art ADCIRC model although the presented methodology applies to other hydrodynamic models. An accessible overview of the formulation and solution of the stochastic inverse problem in a mathematically rigorous framework based on measure theory is presented. Technical details that arise in practice by applying the framework to determine the Manning's n parameter field in a shallow water equation model used for coastal hydrodynamics are presented and an efficient computational algorithm and open source software package are developed. A new notion of "condition" for the stochastic inverse problem is defined and analyzed as it relates to the computation of probabilities. This notion of condition is investigated to determine effective output quantities of interest of maximum water elevations to use for the inverse problem for the Manning's n parameter and the effect on model predictions is analyzed. PMID- 25937696 TI - Adult mortality and household food security in rural South Africa: Does AIDS represent a unique mortality shock? AB - HIV/AIDS has been described as a household shock distinct from others faced by rural households. This study examines this characterisation by analysing the impact of an adult HIV/AIDS-related death on household food security, compared with households experiencing either no mortality or a sudden non-HIV/AIDS adult death. The research is based in the Agincourt Health and Demographic Surveillance Site in rural South Africa, and focuses on a sample of 290 households stratified by experience of a recent prime-age adult death. HIV/AIDS-related mortality was associated with reduced household food security. However, much of this negative association also characterised households experiencing a non-HIV/AIDS mortality. In addition, other household characteristics, especially socioeconomic status, were strong determinants of food security regardless of mortality experience. We therefore recommend that development policy and interventions aimed at enhancing food security target vulnerable households broadly, rather than solely targeting those directly affected by HIV/AIDS mortality. PMID- 25937697 TI - The dynamics of household dissolution and change in socio-economic position: A survival model in a rural South Africa. AB - This paper investigates household dissolution and changes in asset wealth (socio economic position) in a rural South African community containing settled refugees. Survival analysis applied to a longitudinal dataset indicated that the covariates increasing the risk of forced household dissolution were a reduction in socio-economic position (asset wealth), adult deaths and the permanent outmigration of more than 40% of the household. Conversely, the risk of dissolution was reduced by bigger households, state grants and older household heads. Significant spatial clusters of former refugee villages also showed a higher risk of dissolution after 20 years of permanent residence. A discussion of the dynamics of dissolution showed how an outflow/inflow of household assets (socio-economic position) was precipitated by each of the selected covariates. The paper shows how an understanding of the dynamics of forced household dissolution, combined with the use of geo-spatial mapping, can inform inter disciplinary policy in a rural community. PMID- 25937698 TI - Morphology of the Physiological Apical Foramen in Maxillary and Mandibular First Molars. AB - Information regarding the anatomy of the physiological apical foramen is limited. Knowing its diameter and shapes contributes to clinical work, specifically to the cleaning and shaping of the apical third. The aim of this ex vivo study was to determine the minimum and maximum diameters and shape of the physiological apical foramen in the roots of maxillary and mandibular first molars. A descriptive study was conducted on 89 recently extracted first molars. Roots 3-5 mm from the apex were sectioned and prepared for analysis at 40* magnification. The minimum and maximum diameters of each physiological foramen were measured using the program Motic Images plus 2.0 ML. The shape of the foramina, classified as round, oval or irregular, was determined by the difference between the maximum and minimum diameters. A total of 174 physiological foramina were analyzed. The average of the minimum and maximum diameters was between 0.24-0.33 mm in maxillary first molars and between 0.25-0.33 mm in mandibular first molars. In maxillary molars, the most common shape of the foramen was oval (50%), then irregular (32%), then round (18%). In mandibular molars, the oval shape was also the most frequent (59%), followed by irregular (23%) and round (18%). The findings of this study regarding the morphology of physiological apical foramina in first molars make it easier for the operator to choose the appropriately-sized instruments to perform endodontic therapy successfully. PMID- 25937699 TI - Bridging the Divide: Using UTAUT to predict multigenerational tablet adoption practices. AB - This study examined the "Unified Theory of Acceptance and Use of Technology" (UTAUT) in the context of tablet devices across multiple generations. We tested the four UTAUT determinants, performance expectancy, effort expectancy, social influence, and facilitating conditions, to determine their contributions for predicting behavioral intention to use tablets with age, gender, and user experience as moderators. 899 respondents aged 19-99 completed the survey. We found consistent generational differences in UTAUT determinants, most frequently between the oldest and youngest generations. Effort expectancy and facilitating conditions were the only determinants that positively predicted tablet use intentions after controlling for age, gender, and tablet use. We also discuss the implications of ageism and gender discrimination of technology adoption. Finally, we argue that our findings can be extended to create effective training programs for the teaching, learning, and adoption of new technologies in a variety of organizational settings. PMID- 25937700 TI - Measuring Client Experiences of Motivational Interviewing during a Lifestyle Intervention. AB - The Client Evaluation of Motivational Interviewing was used to assess MI experiences in a predominantly female, African American sample from the Southeastern U.S. who received MI-based feedback during a multi-component lifestyle intervention. MI was experienced differently than a primarily White, male, Northeastern mental health sample. PMID- 25937701 TI - HIGH-PRECISION BIOLOGICAL EVENT EXTRACTION: EFFECTS OF SYSTEM AND OF DATA. AB - We approached the problems of event detection, argument identification, and negation and speculation detection in the BioNLP'09 information extraction challenge through concept recognition and analysis. Our methodology involved using the OpenDMAP semantic parser with manually written rules. The original OpenDMAP system was updated for this challenge with a broad ontology defined for the events of interest, new linguistic patterns for those events, and specialized coordination handling. We achieved state-of-the-art precision for two of the three tasks, scoring the highest of 24 teams at precision of 71.81 on Task 1 and the highest of 6 teams at precision of 70.97 on Task 2. We provide a detailed analysis of the training data and show that a number of trigger words were ambiguous as to event type, even when their arguments are constrained by semantic class. The data is also shown to have a number of missing annotations. Analysis of a sampling of the comparatively small number of false positives returned by our system shows that major causes of this type of error were failing to recognize second themes in two-theme events, failing to recognize events when they were the arguments to other events, failure to recognize nontheme arguments, and sentence segmentation errors. We show that specifically handling coordination had a small but important impact on the overall performance of the system. The OpenDMAP system and the rule set are available at http://bionlp.sourceforge.net. PMID- 25937702 TI - Specific Associations between Anxiety Sensitivity Dimensions and Fear and Distress Dimensions of Emotional Distress Disorders. AB - Anxiety sensitivity (AS) comprises three lower-order dimensions, physical concerns, cognitive concerns, and social concerns, all of which are related to unipolar mood and anxiety disorders (emotional distress disorders). The pattern of these relations suggests that AS cognitive concerns might be best classified as associated with emotional distress disorders clustered together as distress disorders whereas AS physical concerns might be best classified as associated with emotional distress disorders clustered together as fear disorders. In contrast, AS social concerns appears to be generally associated with both fear and distress disorders. To test the specificity of lower-order AS dimensions, structural equation modeling was employed in a sample of 579 individuals (M age = 36.87 years, SD = 13.47; 51.6% male) constituting a sample at risk for psychopathology as these individuals were seeking smoking cessation treatment. AS physical concerns was associated with the fear disorders dimension, even when controlling for negative affect (NA). AS cognitive concerns was associated with the distress disorder dimension, only when the effects of NA were not included. Finally, AS social concerns demonstrated non-specific relations with both the distress and fear disorders dimensions. Given that measures of AS and psychopathology were collected concurrently, these findings cannot address the role of lower-order AS dimensions as risk factors for specific psychopathology clusters. These results provide further support for the hierarchical model of emotional distress disorders as well as implicate AS cognitive and physical concerns as important variables at the intermediate level of this model. PMID- 25937703 TI - Neighborhood Economic Disadvantage and Children's Cognitive and Social-Emotional Development: Exploring Head Start Classroom Quality as a Mediating Mechanism. AB - Past research has shown robust relationships between neighborhood socioeconomic disadvantage and children's school achievement and social-emotional outcomes, yet the mechanisms for explaining these relationships are poorly understood. The present study uses data from 1,904 Head Start participants enrolled in the Head Start Impact Study to examine the role that classroom structural and relational quality play in explaining the association between neighborhood poverty and children's developmental gains over the preschool year. Results suggest that neighborhood poverty is directly related to lower levels of classroom quality, and lower gains in early literacy and math scores. Indirect relationships were also found between neighborhood poverty and children's social-emotional outcomes (i.e., approaches to learning and behavior problems) via differences in the physical resources and negative student-teacher relationships within classrooms. These findings highlight the need for policy initiatives to consider community characteristics as potential predictors of disparities in classroom quality and children's cognitive and social-emotional development in Head Start. PMID- 25937704 TI - The development of children's concepts of invisibility. AB - One of the most striking examples of appearance-reality discrepancy is invisibility - when something has no appearance yet still exists. The issue of invisibility sits at the juncture of two foundational ontological distinctions, that between appearance and reality and that between reality and non-reality. We probed the invisibility concepts of 47 3-7-year-olds using two sets of tasks: (1) an entity task, in which children were queried about the visibility and reality status of a variety of both visible and invisible entities, and (2) two standard appearance-reality tasks. Results showed that children's concepts of visibility and reality status are intertwined, and that an understanding that some entities are impossible to see develops between the ages of 3 and 7. PMID- 25937705 TI - Discovery of False Identification Using Similarity Difference in GC-MS based Metabolomics. AB - Compound identification is a critical process in metabolomics. The widely used approach for compound identification in gas chromatography-mass spectrometry (GC MS) based metabolomics is the spectrum matching, in which the mass spectral similarity between an experimental mass spectrum and each mass spectrum in a reference library is calculated. While various similarity measures have been developed to improve the overall accuracy of compound identification, little attention has been paid to reducing the false discovery rate. We, therefore, develop an approach for controlling false identification rate using the distribution of the difference between the first and the second highest spectral similarity scores. We further propose a model-based approach to achieving a desired true positive rate. The developed method is applied to the NIST mass spectral library and its performance is compared with the conventional approach that uses only the maximum spectral similarity score. The results show that the developed method achieves a significantly higher F1 score and positive predictive value than those of the conventional approach. PMID- 25937706 TI - Development of a Single-Sided Nuclear Magnetic Resonance Scanner for the In Vivo Quantification of Live Cattle Marbling. AB - Non-invasive in vivo marbling quantification helps owners to choose the optimum nutritional management for growing cattle and buyers to more precisely evaluate grown cattle at auctions. When using time-domain proton nuclear magnetic resonance (NMR) relaxometry, it is possible to quantify muscle and fat separately by taking advantage of the difference in the spin-spin relaxation time (T2) between water molecules in muscles and fat molecules, which would contribute to the non-invasive and objective determination of marbling scores. With this in mind, we developed a prototype NMR scanner (4.1 MHz for protons) using an original single-sided magnetic circuit and a plane radio frequency (RF) coil for use in the non-invasive quantification of water and fat in live cattle. The sensed region of the developed scanner is compact and almost cubical (19 * 19 * 16 mm3) while the investigation depth (the distance from the RF coil to the center of the sensed region) has been lengthened to 30 mm, which is sufficient for the in vivo trapezius muscle measurement of live cattle. Measurements of 17 samples of beef meat blocks kept at 39 degrees C were taken in a laboratory to successfully obtain the calibration lines used to convert the NMR signals into water and fat weight fractions at correlation coefficients in excess of 0.9. We also showed that each meat sample could be measured in about 10 s with a measurement error as small as approximately 10 wt%. Accordingly, we believe that our prototype scanner would be useful for in vivo marbling measurements of live cattle trapezius muscles. PMID- 25937707 TI - Walking or Waiting? Topologies of the Breeding Ground in Malaria Control. AB - Few places bear as much historical and scientific significance as the breeding ground, the accumulation of stagnant water where disease-carrying insects lay their eggs. Since the turn of the twentieth century, when mosquitoes of the Anopheles genus were identified as the vector of malaria transmission, these aquatic habitats have been a key object of epidemiological research and public health intervention against the disease. Yet the breeding ground can be incorporated into a number of different topologies, each implying a different spatialization of malaria and a distinct imagination of what kind of mosquito control is 'doable'. A contemporary example of malaria control in Dar es Salaam, Tanzania, illuminates an essential tension between what we characterize as territorial and bionomic approaches to the breeding ground-that is, between control strategies premised on treating all mosquito habitats within a given region, and those that prioritize certain sites on the basis of their position within ecological networks. Each topology localizes the breeding ground by reference to a distinct set of relations, and thus advances an idiosyncratic understanding of what sort of research is worthwhile conducting and what kinds of intervention are sustainable. The multiple ways in which the breeding ground can become an object of research and action clarifies the role of topology as an infra-logic of public health, and makes explicit the politics implicit in efforts to bring different orders of the local to scale. PMID- 25937708 TI - "Altered Fear in Mice and Humans". AB - Fear learning is an adaptive, evolutionarily conserved process that allows us to respond appropriately to threats in the environment. These threats can vary across different contexts (e.g., a lion in your yard versus a lion in a zoo) and by age (e.g., a dentist viewed by a child before cavities versus by an adult after cavities). Using the high degree of neural and behavioral conservation across species in fear regulation and the underlying neural circuitry, we examined how fear learning changes across contexts and development, focusing specifically on the environmentally changing and challenging period of adolescence. We show two surprising developmental findings specific to adolescents relative to older and younger ages: 1) diminished fear to previously aversive contexts; and 2) heightened fear to previously aversive cues. These behavioral changes are paralleled by developmental changes in frontolimbic circuitry. We discuss how these evolutionarily conserved mechanisms may be essential to survival of the species with the changing environmental demands (social, sexual and physical) of adolescence. Our findings also have important implications for unremitting forms of fear at the very core of anxiety related disorders that peak during the period of adolescence and when, during development, specific treatments for these disorders may be most effective. PMID- 25937709 TI - Developing Sensorimotor Systems in Our Sleep. AB - Every animal must learn how to use its limbs within the developmental context of an ever-changing body. Typically, investigations of sensorimotor development focus on waking movements. Here I consider another class of behavior: Twitching movements that occur exclusively during active (REM) sleep. Twitches are particularly abundant in early infancy when critical sensorimotor networks are established. In light of behavioral, electrophysiological, neurophysiological, and computational investigations of this unique behavior, twitches may prove critical for the development and maintenance of the sensorimotor system, as well as its repair after injury or disease. PMID- 25937710 TI - Direct-to-Consumer Marketing: A Complementary Approach to Traditional Dissemination and implementation Efforts for Mental Health and Substance Abuse Interventions. AB - The overall chasm between those who need treatment for mental health and substance abuse (M/SU) and those who receive effective treatment consists of two, interrelated gaps: the research-to-practice gap and the treatment gap. Prior efforts to disseminate evidence-based practice (EBP) for M/SU have predominantly targeted the research-to-practice gap, by focusing efforts toward treatment providers. This article introduces direct-to-consumer (DTC) marketing that targets patients and caregivers as a complementary approach to existing dissemination efforts. Specific issues discussed include: rationale for DTC marketing based on the concept of push versus pull marketing; overview of key stakeholders involved in DTC marketing; and description of the Marketing Mix planning framework. The applicability of these issues to the dissemination of EBP for M/SU is discussed. PMID- 25937711 TI - A quantitative analysis of the effect of baseplate and glenosphere position on deltoid lengthening in reverse total shoulder arthroplasty. AB - CONTEXT: Optimizing deltoid tension is important to achieve maximal function after reverse total shoulder arthroplasty (RTSA), but the effects of baseplate and glenosphere positions on deltoid tension have not been quantified. AIMS: To quantify deltoid elongation and elongation to failure under physiologic loads with three baseplate-glenosphere configurations with increasing inferior offset. SETTINGS AND DESIGN: Cadaver biomechanical study. MATERIALS AND METHODS: Twenty four cadaver shoulders were divided into three groups. The starting point for baseplate insertion in Group 1 was the center of the glenoid, with glenospheres placed in minimal inferior offset (0.5 mm). Groups 2 and 3 baseplates were placed 2 mm inferior to the center point and glenospheres in minimal (2.5 mm) offset (Group 2) or maximal (4.5 mm) offset (Group 3). Tensile testing was done to quantify deltoid elongation and evaluate failure. STATISTICAL ANALYSIS USED: A one-way analysis of variance was performed to detect statistically significant differences among treatment groups. A post-hoc Neuman-Keul's comparison was conducted to perform discrete comparisons among treatment groups. RESULTS: Deltoid elongation after loading decreased with increasing inferior offset of >2.5 mm. No significant difference in deltoid yield load was found among groups. The percent of elongation was decreased significantly between groups 2 and 3. Deltoid displacement at failure decreased from 33.3 mm for Group 2-17.3 mm for Group 3. 16 of the 24 specimens (67%) failed by anterior deltoid detachment from the acromion. CONCLUSIONS: Increasing inferior offset in RTSA constructs appears to increase stretch forces on the deltoid, resulting in a diminished ability of the deltoid to further elongate under physiologic loads, (most pronounced when the inferior offset exceeds 2.5 mm) and significantly decreasing the yield displacement of the construct. PMID- 25937712 TI - Scapular neck length and implications for reverse total shoulder arthroplasty: An anatomic study of 442 cadaveric specimens. AB - PURPOSE: Reverse total shoulder arthroplasty (RTSA) may be used to treat a variety of pathologic shoulder conditions, but complications such as scapular notching continue raise concerns. Variable anatomy surrounding the glenoid may have implications for future RTSA design, but at present the anatomy of the scapular neck in the human population has not been clearly defined. MATERIALS AND METHODS: 442 human scapulae from the Hamann-Todd Osteological Collection were measured for scapular neck length (SNL) and scapular neck angle (SNA). SNL was defined as the distance from the most lateral portion of the infraglenoid tubercle to the most inferolateral portion of the glenoid fossa. The SNA was measured according to Gerber et al. previously. The mean, standard deviation and ranges for SNL and SNA were calculated and compared based on sex and race, and interobserver variability was calculated. RESULTS: The mean SNL was 1.06 cm +/- 0.33 cm (0.37-2.43 cm). Males demonstrated a larger SNL (1.08 cm +/- 0.33 cm) than females (1.01 cm +/- 0.32 cm) (P < 0.12), and Caucasians (1.09 cm +/- 0.33 cm) demonstrated a significantly larger SNL than African-Americans (1.00 cm +/- 0.32) (P < 0.01). The mean SNA was 106.7 degrees +/- 11.0 degrees (76.9-139.4 degrees ). No significant correlation was found between SNL and SNA (Pearson Correlation Coefficient = 0.018) (P < 0.702). CONCLUSION: Scapular neck length and SNA vary widely within the population but there appears to be a tendency towards increased SNL in males and Caucasians. CLINICAL RELEVANCE: The anatomy of the scapular neck may have significant implications for RTSA design, surgical planning, and reduction of associated complications. PMID- 25937713 TI - The accuracy of "subacromial grind test" in diagnosis of supraspinatus rotator cuff tears. AB - PURPOSE: The aim of this study is to assess the accuracy of a simple clinical test (subacromial grind test) in diagnosing supraspinatus tendon tears. PATIENTS AND METHODS: The test is considered positive if palpable crepitus or grinding is detected on passive internal and external rotation of the shoulder while abducted in the scapular plane. Data were collected prospectively on 47 patients undergoing shoulder arthroscopy, and the results of the test and arthroscopy compared. RESULTS: During arthroscopy, 17 patients had full thickness (FT) tears of supraspinatus tendon and 10 had partial thickness tears. For any supraspinatus tear, the sensitivity of the test was 63%, specificity 95%, positive predictive value 94%, negative predictive value 66% and overall accuracy 79%. For FT tears, the sensitivity was 82%, specificity 87%, positive predictive value 78%, negative predictive value 90% and overall accuracy 85%. CONCLUSION: We found that this is a useful single test for diagnosing FT supraspinatus tears. LEVEL OF EVIDENCE: Level IV diagnostic study. PMID- 25937714 TI - Performance of antegrade suture passers according to tendon thickness. AB - PURPOSE: To determine the effect of tendon thickness on the needle penetration ability of four different designs of antegrade suture passers. MATERIALS AND METHODS: Four antegrade suture passers were tested: (a) ExpresSew II (Depuy Mitek Inc., Raynham, MA), (b) Arthrex Scorpion (Arthrex, Naples, FL), (c) Concept (Linvatec Corp, Largo, FL), and (d) ElitePass (Smith and Nephew Endoscopy, Andover, MA). Bovine tendons were divided into five thickness groups: 3, 5, 7, 9 and 11 mm. At each tendon thickness, we performed 15 trials with the suture loaded and 15 unloaded per device. Successful needle penetration was recorded, and in case of success, the exit point of the needle was noted in relation to the superior arm of the grasping component. RESULTS: All tested suture passing devices successfully penetrated tendon thicknesses of 3 and 5 mm. With the suture loaded, one device (Concept) only successfully penetrated 7 mm group tendons in 3/15 (20%) trials. Success rates at 9 mm with the suture loaded were 40% in ExpresSew II, 53% in Arthrex Scorpion, 0% in Concept and 53% in ElitePass. Among successful passages with a loaded suture in the 7 and 9 mm-groups, about 20-50% of passages were oblique, and the needle came out distal to the superior arm of grasping the component. No trial with any device succeeded with 11 mm tendons in the suture loading condition. CONCLUSION: Using an antegrade suture passer during arthroscopic rotator cuff repair should be carefully considered when the torn end of the tendon is thicker than about 7-9 mm due to potential failure of needle penetration and/or too oblique a suture passage. LEVEL OF EVIDENCE: Controlled laboratory study. PMID- 25937715 TI - Proximal coracobrachialis tendon rupture, subscapularis tendon rupture, and medial dislocation of the long head of the biceps tendon in an adult after traumatic anterior shoulder dislocation. AB - Rupture of the coracobrachialis is a rare entity, in isolation or in combination with other muscular or tendinous structures. When described, it is often a result of direct trauma to the anatomic area resulting in rupture of the muscle belly. The authors present a case of a 57-year-old female who suffered a proximal coracobrachialis tendon rupture from its origin at the coracoid process, with concomitant subscapularis tear and medial dislocation of the long head of biceps tendon after first time traumatic anterior shoulder dislocation. Two weeks after injury, magnetic resonance imaging suggested the diagnosis, which was confirmed during combined arthroscopic and open technique. Soft-tissue tenodesis of coracobrachialis to the intact short head of the biceps, tenodesis of the long head of biceps to the intertubercular groove, and double-row anatomic repair of the subscapularis were performed. The patient did well postoperatively, and ultimately at 6 months follow-up, she was without pain, and obtained 160 degrees of active forward elevation, 45 degrees of external rotation, internal rotation to T8, 5/5 subscapularis and biceps strength. Scoring scales had improved from the following preoperative to final follow-up: American Shoulder and Elbow Surgeons, 53.33-98.33; constant, 10-100; visual analogue scale-pain, 4-0. DASH score was 5. PMID- 25937716 TI - An innovative method of fracture reduction in an arthroscopically assisted cannulated screw fixation of an Ideberg type III glenoid fracture. AB - Significantly displaced intra-articular glenoid fractures treated nonoperatively have been found to have poor functional outcomes. For this reason, most are treated with open reduction and internal fixation. Conventional open techniques involve extensive exposure and soft tissue dissection. Moreover, visualization of the fracture and its reduction can also be difficult even with standard open techniques. We present a case of an Ideberg type III glenoid fracture treated with an arthroscopically assisted percutaneous screw fixation, using the coracoid as a reduction aide. This reduction technique is not previously reported in the literature. Arthroscopically assisted percutaneous glenoid fixation has showed promising early results in the literature. In our case, the fracture united and the patient returned to all his normal daily activities by 7 weeks postoperatively. This suggests arthroscopically assisted glenoid fixation provides good functional and radiological outcomes, without the need for extensive soft tissue dissection. PMID- 25937718 TI - Undiagnosed pediatric condylar fractures and ankylosis of the temporomandibular joint. PMID- 25937717 TI - Reverse shoulder arthroplasty. Part 2: Systematic review of reoperations, revisions, problems, and complications. AB - PURPOSE: Many factors influence the reoperations, revisions, problems, and complications of reverse shoulder arthroplasty (RSA). The purpose of this study was to compare those depending on the surgical approach, type of prosthesis, and indication for surgery through a comprehensive, systematic review. MATERIALS AND METHODS: A literature search was conducted (1985 to June 2012) using PubMed, CINAHL, EBSCO-SPORTDiscus, and Cochrane Central Register of Controlled Trials. Levels I-IV evidence, in-vivo human studies (written in English with minimum of 2 years of follow-up and sample size of 10 patients) reporting reoperations, revisions, problems, and complications after RSA were included. The data obtained were analyzed depending on the surgical approach, type of prosthesis (with medialized or lateralized center of rotation), or indication for surgery. RESULTS: About 37 studies were included involving 3150 patients (mean [SD] percentage of females, age, and follow-up of 72% [13], 71.6 years [3.8], and 45 months [20], respectively). Use of deltopectoral approach and lateralized prostheses had significantly higher risk of need for revision surgery (P = 0.008) and glenoid loosening (P = 0.01), but lower risk of scapular notch (P < 0.001), compared with medialized prostheses with same approach. RSA for revision of anatomic prosthesis demonstrated higher risk of reoperation (P < 0.001), revision (P < 0.001), hematoma (P = 0.001), instability (P < 0.001), and infection (P = 0.02) compared with most of the other indications. CONCLUSIONS: Lateralized prostheses had significantly higher glenoid loosening and need for revision surgery, but a significantly lower rate of scapular notching compared to medialized prostheses. The risk of reoperations, revisions, problems, and complications after RSA was increased in revision cases compared with other indications. LEVEL OF EVIDENCE: Level IV. PMID- 25937719 TI - Trends in management of myofacial pain. AB - We systematically reviewed the myofascial pain publications in the literature. The aim of this article is to review the methods of management and their outcome and factors associated with prognosis. The topics of interest in the diagnostic process are myofascial trigger points electromyography, jaw tracking, joint sound recorder, sonography, and vibratography, exclusion of other orofacial pain and temporomandibular disorders. Management modalities are occlusal therapy, physiotherapy, multidimensional rehabilitation antinociceptive therapy, anti inflammatory and analgesics, muscle relaxants, stretch, and spray technique, transcutaneous electric nerve stimulation, and in severe cases botulinum toxin may be tried. The disease required interdisciplinary interaction in terms of occlusal therapy, antinociceptive therapy and physiotherapy because management of the disease may be influenced by the specialist primarily treating the patients. PMID- 25937720 TI - Dental care during and after radiotherapy in head and neck cancer. AB - Head and neck cancer is a major health problem. Oral cancer is increasing in Indian subcontinent mainly due to lack of hygiene, tobacco use, chewing tobacco, smoking, and many other factors. Radiation therapy is the most common form of treatment along with surgery and chemotherapy. There are 2 types of complication that occurs during and after radiotherapy, that occur because of effects on normal tissue. Radiotherapy-induced effects occur on the oral mucosa salivary glands, bone, teeth, and musculature of face and neck. These complications needs special attention for their prevention and treatment, Preradiotherapy evaluation and disease stabilization are necessary in every patient, counseling of patients before during and after radiotherapy is important to help them become aware of several oral complications and their prevention. PMID- 25937721 TI - A radiological evaluation of marginal bone around dental implants: An in-vivo study. AB - CONTEXT: This article presents an original research conducted at Government Dental College, PGIDS, Rohtak. AIMS: (1) To evaluate the marginal bone level changes around dental implants based on the radiological examination. (2) To evaluate the relationship of various parameters, i.e., gender, implant length, implant diameter and location of implants on the amount of bone loss around dental implants. MATERIALS AND METHODS: An in-vivo study was undertaken to evaluate the crestal bone loss on mesial and distal aspect of implants, using standardized intra-oral periapical at the end of 6 months after placing the implants, but before prosthetically loading it. STATISTICAL ANALYSIS USED: Student's unpaired t-test. RESULTS: Bone loss was measured and values were recorded immediately after implant placement and after 6 months. CONCLUSIONS: (1) Bone loss on mesial and distal aspects of implants was found to be same after period of 6 months. (2) Bone loss was found to be same in both 13 mm and 10 mm implants on mesial aspect, whereas on distal aspect, it was more in 10 mm implants. (3) Bone loss was found to be same in both 3.5 mm and 4.3 mm diameter implants on both mesial and distal aspects of implants. (4) Bone loss was found to be same in both maxilla and mandible on both mesial and distal aspects of implants. (5) Bone loss was found to be more in females on both mesial as well as distal aspects of implants. PMID- 25937722 TI - Airway management using transmylohyoid oroendotracheal (submental) intubation in maxillofacial trauma. AB - Successful management of airway in complex maxillofacial injuries is quite challenging. The complications and the post-operative care associated with tracheotomy makes it an unpopular choice for airway management meant solely for surgery in these patients. A retrospective analysis of 12 patients from June 2008 to December 2011, seeking treatment for pan facial fractures who underwent transmylohyoid oroendotracheal (submental) intubation is discussed here. The stepwise procedure is explained along with problems of intubation in pan facial fractures. The advantages, disadvantages and complications of transmylohyoid intubation are discussed and compared with alternative methods of air way management in such cases. This reliable, safe and easy method of airway management gives sterile surgical field without a change of tube. PMID- 25937723 TI - Prevalence of oral cancer and pre-cancerous lesions and the association with numerous risk factors in North India: A hospital based study. AB - BACKGROUND: Oral cancer is one of the most common life-threatening diseases all over the world. Developing countries face several challenges to identify and remove potential risk factors. Chewing tobacco/pan masala is considered to be the most potent risk factor for oral precancerous lesions and oral cancer. OBJECTIVES: To investigate the relative occurrence of different oral pre cancerous lesions and oral cancer in North India and to identify the associated risk factors. MATERIALS AND METHODS: A hospital-based study was conducted and 471 subjects were recruited in the study. The subjects comprised patients with squamous cell carcinoma (n = 85), oral submucous fibrosis (n = 240), leukoplakia (n = 32), lichen planus (n = 15), and controls (n = 99). Statistical analysis of the data was done using Chi-square and regression analysis. RESULTS: A strong correlation was observed between the presence of the chewing habit in all the oral precancerous lesions and oral cancer. Duration of the habit and intensity of habit ware also strongly correlated with the risk of oral precancerous lesions and oral cancer. Other factors such as alcohol and smoking were found to be less important in concern with oral cancer and precancerous lesions. PMID- 25937725 TI - Prevalence and pattern of mandibular fracture in Central India. AB - INTRODUCTION: The etiology and pattern of mandibular fracture vary considerably among different study populations. Despite many reports about the incidence, diagnosis and treatment of mandibular fracture there is limited knowledge about the specific type or pattern of mandibular fractures in South Asian countries. This study attempts to delineate predictable patterns of fracture based on patient demographics and mechanism of injury in central part of India. MATERIALS AND METHODS: The medical records of patients with mandibular fractures treated over a 3 years period were identified and analyzed based on age, sex, mechanism of trauma, seasonal variation, drug/alcohol abuse, number and anatomic location. RESULTS: We reviewed 464 patients having mandibular fractures with age ranging from 7 to 89 years. Male (343, 79%) to female (91, 21%) ratio was 3.7:1, significantly higher for males. The highest incidence (37.5%) of mandibular fractures was in the age group of 21-30 years. The main cause was road traffic accidents (RTAs, 68.8%) followed by falls (16.8%), assaults (11%) and other reasons (3.8%). Parasymphyseal fractures were the most frequent 331 (41.1%), followed by condyle (135) and angle (124) fractures in occurrence. Mandibular angle fractures were found mostly to be associated with assault victims. CONCLUSION: The mechanism of injury correlates significantly with the anatomic location of fracture and knowledge of these associations should guide the surgeons for appropriate and timely management. Because RTAs are most frequent, good traffic sense needs to be imbibed and developed by the government as well as the public. PMID- 25937724 TI - A 2-year retrospective analysis of facial injuries in patients treated at department of oral and maxillofacial surgery, IGGDC, Jammu, India. AB - INTRODUCTION: The incidence of maxillofacial injuries is on the rise due to motor vehicle accidents and increased incidence of violence in recent times. The aim of this retrospective study was to determine the incidence, etiology, and the pattern of fractures in the maxillofacial region. MATERIALS AND METHODS: After obtaining permission from the concerned authorities, a predesigned questionnaire was used to collect the necessary data from the department. A retrospective analysis of 787 patients, who suffered trauma and were managed in the Department of Oral and Maxillofacial Surgery, Indira Gandhi Government Dental College (IGGDC), Jammu over a period of 2 years was carried out. RESULTS: Road traffic accident (RTA) was the common cause of maxillofacial injuries. Men sustained more injuries as compared to women. Injuries were most commonly sustained in the age group of 11-40 years, constituting about 76% of all injuries, mandibular fractures were the most common. CONCLUSION: RTAs were the commonest cause for the maxillofacial injuries. PMID- 25937726 TI - Evaluation of soft and hard tissue changes after bimaxillary surgery in class III orthognathic surgery and aesthetic consideration. AB - AIMS: The aim of this study was to evaluate hard and soft tissue change after bimaxillary surgery in class III patients by focusing on sella, nasion, A point (SNA) and sella, nasion, B point (SNB) angle and aesthetic outcome. MATERIALS AND METHODS: The sample consisted of 96 skeletal Class III patients (42 women, 54 men) with a mean age of 25 years with standard deviation (SD) of 8.4. The youngest patient was 16-years-old and the oldest 51-years-old at the time of surgery. In total, seven skeletal parameters, eight soft tissue parameters, and two dental parameters were evaluated on the cephalograms. RESULT: At the beginning of the treatment 49 Patients had SNA between 80 degrees and 84 degrees , 34 had SNA of less than 80 degrees and 13 had SNA of more than 84 degrees . Post surgically, 25 patients had SNA of 78 degrees -84 degrees , 19 had SNA less than 78 degrees and 52 patients had SNA of more than 84 degrees . Out of 96 patients 22 had SNB of 78 degrees -82 degrees before surgery, 16 had less than 78 degrees and 58 had SNA of more than 84 degrees . Postoperatively, we measured SNB of 78 degrees -80 degrees in 42, less than 78 degrees in 18 and of more than 82 degrees in 36 patients. The inclination of the maxilla relative to the cranial base changed from 7.2 degrees (SD = 4)-8 degrees (SD = 5.1) and the mandible changed from 35.7 degrees (SD = 6.6) to 36 degrees (SD = 6.3) postoperatively which was not significant. The distance from upper lip to E-line increased by 2.6 mm (SD = 3.9) after surgery (P < 0.001), while, the lower lip distance to E-line decreased slightly by 0.9 mm (SD = 3.2) (P < 0.01). Nasolabial angle was decreased by 9.5 degrees (SD = 9.4) after surgery (P < 0.001). The nose prominence also decreased from 18.2 mm (SD = 3.5) -16.5 mm (SD = 3.3). CONCLUSION: Although in many cases we did not have a SNA angle or SNB angle in normal range but a good aesthetic outcome have been observed. Consequently our study showed that soft tissue change and aesthetic aspects should be considered in surgical planning and achieving SNA angle or SNB angle of norm range should not be the only goal. As we could show the advancement of maxilla will result in a better lip and nose profile and this should be considered in treatment planning. PMID- 25937727 TI - Evaluation of microbial flora in orofacial space infections of odontogenic origin. AB - BACKGROUND: The microbiology of acute dental infections has been in the midst of many researches. Various bacteriological studies show variations in their conclusion. The purpose of our study was to evaluate the microbial flora in orofacial space infections of odontogenic origin, which is essential for appropriate antibiotic selection. MATERIALS AND METHODS: Thirty-five patients with odontogenic infection causing fascial space involvement were included. Aspirated specimen was transported in nutrient broth and thyoglycollate media within an hour for further culture and sensitivity testing. RESULT AND CONCLUSION: This study indicates that orofacial odontogenic infections are usually polymicrobial, consisting of a complex mixture of both anaerobes and aerobes. PMID- 25937728 TI - Antibiotics in third molar extraction; are they really necessary: A non inferiority randomized controlled trial. AB - INTRODUCTION: Antibiotic resistance is now a serious problem, although it was not so only a few years ago. The need of the hour is to give clear evidence of the efficacy of antibiotic use, or lack thereof, to the surgeon for a procedure as common as mandibular third molar surgery. AIM: This study aimed to evaluate whether postoperative combined amoxicillin and clavulanic acid in mandibular third molar extraction is effective in preventing inflammatory complications. STUDY AND DESIGN: The study was structured as a prospective randomized double blind placebo-controlled clinical trial. MATERIALS AND METHODS: A study was designed wherein the 96 units (two bilaterally similar impacted mandibular third molars per head in 48 patients) were randomly assigned to two treatment groups (Group I and Group II). Each patient served as his/her own control. Each patient received 625 mg of combined amoxicillin and clavulanic acid 1 h before surgery. In the case of third molars belonging to Group I, 625 mg of combined amoxicillin and clavulanic acid TDS was continued for 3 days; in Group II, placebo in similar looking packs was continued for 3 days. The patients were evaluated on the third and seventh postoperative days for signs of clinical infection and for microbial load evaluation. STATISTICAL ANALYSIS: The data between the two groups were statistically analyzed by the two-tailed Fisher's exact test, with a 95% confidence interval. RESULTS: The difference was not statistically significant between the test group and the control group with regard to erythema, dehiscence, swelling, pain, trismus, and infection based on microbial load. The data were statistically significant for alveolar osteitis, with the occurrence of alveolar osteitis (14.58%) in the placebo group. CONCLUSION: Postoperative antibiotics are recommended only for patients undergoing contaminated, long-duration surgery. PMID- 25937729 TI - Amelogenin in odontogenic cysts and tumors: An immunohistochemical study. AB - BACKGROUND: Amelogenins are the major enamel proteins that play a major role in the biomineralization and structural organization of enamel. Aberrations of enamel-related proteins are thought to be involved in oncogenesis of odontogenic epithelium. The expression of amelogenin is possibly an indicator of differentiation of epithelial cells in the odontogenic lesions. AIMS AND OBJECTIVES: The present study aimed to observe the expression of amelogenin immunohistochemically in various odontogenic lesions. MATERIALS AND METHODS: Paraffin sections of 40 odontogenic lesions were stained immunohistochemically with amelogenin antibodies. The positivity, pattern and intensity of expression of the amelogenin antibody were assessed, graded and statistically compared between groups of odontogenic cysts and tumors. RESULTS: Almost all the odontogenic lesions expressed amelogenin in the epithelial component with the exception of an ameloblastic carcinoma. Differing grades of intensity and pattern were seen between the cysts and tumors. Intensity of expression was uniformly prominent in all odontogenic lesions with hard tissue formation. Statistical analysis however did not indicate significant differences between the two groups. CONCLUSION: The expression of amelogenin antibody is ubiquitous in odontogenic tissues and can be used as a definitive marker for identification of odontogenic epithelium. PMID- 25937730 TI - Internal jugular vein thrombosis due to heterozygote methylene tetrahydrofolate reductase (MTHFR) 1298C and Factor V G1691A mutations after a minor trauma. AB - Internal jugular vein thrombosis usually appears in central venous catheterization, distant malignancies, hypercoagulation, infections, or secondary to ovarian hyperstimulation syndrome. A 44-year-old female patient presented to us with sore throat, and pain and swelling on the right side of her neck. She had a history of simple neck trauma 10 days ago. Ultrasonography and computed tomography showed bilateral multiple lymphadenopathies and right internal jugular vein thrombosis. Patient was put on parenteral antibiotherapy and oral anticoagulant treatment. Genomic DNA tests for hypercoagulation revealed methylene tetrahydrofolate reductase 1298C heterozygote mutation and Factor V G1691A (Leiden) mutation. Patient has been under clinical control for 1 year and does not have any complaints. In this article, diagnosis, treatment, and the etiology of internal jugular vein thrombosis, which is a rare and potentially fatal condition, have been discussed through this case. PMID- 25937731 TI - A rare case of breast carcinoma metastasis to mandible and vertebrae. AB - Oral cavity metastases are considered rare and represent approximately 1% of all oral malignancies. Due to their rarity and atypical clinical and radiographic appearance, metastatic lesions are considered a diagnostic challenge. This article presents a rare case of breast carcinoma with metastasis to mandible and vertebrae. A case is presented of a 40-year-old female patient with a history of breast carcinoma which was surgically treated approximately 2 years back. The diagnosis of metastatic breast carcinoma was confirmed by radiographic examination, bone scan and histopathologic findings. She was referred to radiotherapy department since it was not amenable to surgery due to metastasis in vertebrae. A high index of clinical suspicion of metastatic cancer is necessary when evaluating patients who complaint of jaw pain and swelling with a history of non-head and neck carcinoma. PMID- 25937732 TI - Tuberculous osteomyelitis of the maxilla: A rarest of rare case report. AB - Tuberculosis is a chronic granulomatous systemic infectious disease caused by Mycobacterium tuberculosis. The oral lesions found in tuberculosis are relatively rare and may present as ulcers, erythematous patches, indurated lesions, nodules or as bony jaw lesions. Oral tubercular lesions sometimes present a confusing clinical presentation and can be overlooked. Hence, we document a case of tuberculous osteomyelitis of the maxilla in a 19-year-old female patient, who was initially treated for multiple periodontal dental abscesses, which later proved to be tubercular osteomyelitis of the maxilla. Although it is a rare occurrence, the differential diagnosis of tuberculous osteomyelitis must always be considered when it fails to respond to routine therapy. PMID- 25937733 TI - An unusual case of compound odontome associated with maxillary impacted central incisor. AB - Odontomas are the most common type of odontogenic tumor occurring within the jaws and are frequently associated with the retained deciduous teeth interfering with the eruption of permanent teeth. Compound odontomas are usually diagnosed in the anterior portion of the jaws and resemble tooth-like structure. These are usually asymptomatic. Complex odontomas are normally diagnosed in the posterior part of the jaws and consist of a disorganized mass with no morphologic resemblance to a tooth. The present case report of a 16-year-old female is a typical case of compound odontoma in the maxillary anterior region associated with retained deciduous incisor, which also resulted in failure of eruption of the permanent maxillary right central incisor. An intraoral periapical radiograph revealed the presence of a radio-opaque tooth-like structure in the apical region of retained deciduous incisor and an impacted permanent right central incisor whose path of eruption was impeded by the structure. Treatment included the surgical removal of the lesion followed by orthodontic extrusion of the impacted incisor. Follow-up was done for one 1 year and no recurrence was seen. PMID- 25937734 TI - Epithelial-myoepithelial carcinoma of floor of mouth: A case report with cytological, histological and immunohistochemical correlation. AB - A 61-year-old female presented with a 3-year-old swelling in the right floor of mouth. Clinical examination and fine needle aspiration cytology suggested a benign lesion. The mass was excised locally along with the involved sublingual and deep part of submandibular gland and duct. Post-operative histopathological examination revealed features of pleomorphic adenoma. However, on revision of histological sections, features were predominantly of a rare malignancy of the salivary glands, epithelial-myoepithelial carcinoma (EMC), along with focal areas of adenoid cystic carcinoma (Ad CC). The tumor was p-63, s-100 and smooth muscle actin positive but C-kit was negative, which ruled out Ad CC and the possibility of a hybrid carcinoma. The aim of this article is to describe a rare case of EMC in the floor of mouth and the confusing cytological picture that it created. PMID- 25937735 TI - Use of indomethacin as an adjuvant to surgery for recurrent temporomandibular joint ankylosis in adults. AB - Two cases with multiple recurrences of temporomandibular joint ankylosis and multiple failed interposition/gap arthroplasty procedures are presented here. Heterotopic bone formation was thought to be the reason. Indomethacin prophylaxis for prevention of heterotopic new bone formation at the osteoarthrectomy site was used as an adjuvant to surgery, in dosages of 75 mg/day for six weeks. Indomethacin is used frequently in hip and elbow arthroplasties to prevent heterotopic ossification, but its use in temporomandibular joint is not routine. The presented cases did not develop further recurrence and attained stable mouth opening over two-year follow-up after osteoarthrectomy and oral indomethacin. PMID- 25937736 TI - Cellular infiltrative angiolipoma of cheek in an infant. AB - Lipomas represent about 1 to 5% of all neoplasms of the oral cavity most commonly presenting as painless, mobile, soft, round mass. Angiolipoma, spindle cell lipoma, mylelolipoma, chondrolipoma and myxolipoma are histological variants of lipoma arising from fat tissues. Although the angiolipoma is the most common tumour in the trunk and the extrimities of young people, it occurs infrequently in the head and neck region. In this article we present clinical, radiological and histological features of a cellular infiltrative angiolipoma exicised from the buccal mucosa of a 9 months old female child. PMID- 25937737 TI - Cleidocranial dysplasia. AB - Cleidocranial dysplasia (CCD) is an autosomal dominant disorder resulting in the skeletal and dental abnormalities due to the disturbance in ossification of the bones. Clavicle is the most commonly affected bone. The prevalence of CCD is one in millions of live births. In this report, we present a case of 10-years-old boy showing features of this condition. PMID- 25937738 TI - Gorlin-Goltz syndrome: A series of three cases. AB - The Gorlin-Goltz syndrome (GGS) is also known as nevoid basal cell carcinoma syndrome. It is characterized by multiple keratocystic odontogenic tumors (KCOTs) in the jaw, multiple basal cell nevi carcinomas and skeletal abnormities. The syndrome may be diagnosed early by a dentist during the routine radiographic exams in the first decade of life, since the KCOTs are usually one of the first manifestations of the syndrome. This article reports the series of 3 cases, emphasizing its clinical and radiographic manifestations of GGS. PMID- 25937739 TI - Double mandibular osteotomy with segmental mandibular swing approach to parapharyngeal space. AB - Surgical removal of benign tumors of the Parapharyngeal space (PPS) is the treatment of choice. PPS tumors may remain undetected for long periods of time and large tumors in the PPS can extend into the Retropharyngeal Space or into the Infra-Temporal Fossa. Anatomically, the mandible represents a significant obstacle to successful PPS surgery. Except for very small tumors, it is difficult to remove larger tumors from this region without some form of mandibular retraction. The standard mandibular "swing" approach involves splitting of the lower lip and a single parasymphysis osteotomy for retraction of the mandible laterally to expose the PPS. However, the morbidity associated with midline lip split and anesthesia of the hemi-labial region caused by the severing of the mental nerve is an unwanted complication of this approach. In this article, we describe an easier double mandibular osteotomy (Segmental Mandibular Swing Approach) which avoids the morbidity associated with lip splitting or intra-oral mucosal incision but allows excellent exposure of the superior and lateral aspect of PPS for easier removal of large tumors in this region. PMID- 25937740 TI - Lateral orbital approach: Gateway to intraorbital lesions. AB - Several approaches to the intraorbital space have been described in the literature. Selection of a proper approach to intraorbital lesions depends on various factors including the location of the tumor, the size of the lesion, and the probable pathology anticipated. The approach should provide a good exposure of intraorbital anatomical structures, allow their functional preservation, and provide good cosmetic results. Intraconal lesions of the orbit usually necessitate transcranial approaches although some intraconal and laterally situated lesions could be removed effectively via lateral orbitotomy. Lateral orbitotomy is a well-known approach for lesions of the lateral orbital cone. In this case report, the lateral orbital approach has been used for exposure of intraorbital lesion, as it is minimally invasive compared to the transcranial approach. PMID- 25937741 TI - Clear cell odontogenic carcinoma of the mandible and temporomandibuar joint with cervical lymph nodal metastasis. AB - Clear cell odontogenic carcinoma (CCOC) is a rare aggressive tumor that has the ability to invade locally as well as cause regional and distant metastasis. The etiology of this neoplasm remains poorly understood and the diagnosis of CCOC is done by exclusion of other clear cell tumors. To date, approximately 75 cases of CCOC have been described in the English literature, all involving a single jaw. The majority of cases have been reported to arise from the mandible, the maxilla is less frequently involved, and no case had involvement of the temporomandibuar joint. Lymph node metastasis at initial presentation is reportedly rare (<10%). We describe possibly the first case of CCOC in a 50-year-old woman with involvement of the mandible and the temporomandibuar joint along with cervical lymph nodal metastasis. We share our experiences and challenges in the management of this unusual tumor. PMID- 25937742 TI - Extensive ossifying fibroma of jaw. AB - Ossifying fibroma of bone is a central neoplasm of bone and it is more common in young adult with marked predilection for mandible and also it is more common in female. Lesion is generally asymptomatic until growth produces a noticeable swelling and mild deformity. It presents an extremely variable roentographic appearance depending upon the stage of development. This lesion is composed basically of many delicate interlacing collagen fibers, seldom arranged in discrete bundle, interspersed by large numbers of active, proliferating fibroblasts. The lesion should be excised conservatively. We present a case of huge ossifying fibroma arising from maxilla. PMID- 25937743 TI - Penetrating facial injury by a wooden log. AB - Penetrating facial injuries are potentially dangerous and require emergency management because of the presence of vital structures in the face and it may be life threatening especially when the injury involves airway, major blood vessels, spinal cord and cervical spines. Penetrating injuries of facial region can occur due to missile injuries, blast injuries, accidental fall on sharp objects such as sticks or glass and motor vehicle accidents etc., Indications for immediate surgical management of penetrating neck injuries include airway management and hemodynamic instability according to advanced trauma life support protocol. PMID- 25937744 TI - Immediate reconstruction of palato-maxillary defect following tumor ablation using temporalis myofascial flap. AB - The resection of oral cavity tumor and malignancies often causes functional disabilities like deglutition and articulation. Maxillectomy is a very common surgical procedure carried out for the management of benign and malignant tumors of maxilla. Irrespective of the procedure, there is a common end result that is the defect. Several soft tissue flaps can be used for reconstruction of maxillectomy defect. Keeping the parameters of reconstruction in mind it is ideal to reconstruct the maxillary defect with either the free flaps or the regional flaps. Of all regional flaps, the temporalis myofascial flap (TMF) provides a high degree of reliability, vascularity, adequate bulk, and proximity to the defect in the oral and maxillofacial region. PMID- 25937745 TI - Accessory parotid gland with ectopic fistulous duct - Surgical view: A case report and review of current literature. AB - Accessory parotid glands are a common clinical occurrence and usually drain into the main Stenson's duct by small ductules and thereby, into the buccal cavity. Presence of an accessory parotid gland with an ectopic fistulous duct is a rare occurrence. Clinical findings, imaging studies, biochemical tests, histopathological examination are needed for appropriate surgical management. It is extremely rare case with ectopic fistulous duct in an accessory parotid gland managed surgically by internalization of the duct to open into the buccal mucosa and excision of pre-aural appendages. Further to this, we give a comprehensive review of literature on accessory parotid gland and duct anomalies. PMID- 25937746 TI - Peripheral osteoma of maxilla: A case report. AB - Osteoma is a benign osteogenic lesion with a very slow growth, characterized by proliferation of either compact or cancellous bone. Most cases of peripheral osteomas are asymptomatic and produce swelling and asymmetry. Its pathogenesis is unclear but commonly accepted theories propose embryologic, traumatic, or infectious causes. The osteoma may appear in the form of a limited peripheral lesion involving the alveoli or cheek or as a tumoral growth developing inward toward the sinus. Recurrences of osteomas have not been reported in the literature. We report a rare case of maxillary peripheral osteoma with impacted right canine in a 32-year-old female patient. PMID- 25937747 TI - Modified microdissection electrocautery needle. AB - Electrocautery is routinely used in surgical procedures. The commercially available microdissection electrocautery needles are costly. To overcome this disadvantage, we have modified monopolar electrocautery tip to function as well as commercially available systems. PMID- 25937748 TI - Lower third molars. AB - There has always been a debate whether to remove or leave asymptomatic mesioangular impacted lower third molars. The present short communication discusses the merit of prophylactic removal to avoid clinical complications in future and the consequences to second molars. PMID- 25937749 TI - Mitochondrial C-tract and tobacco exposure in oral precancer cases. PMID- 25937750 TI - Isolated lower lip pits. PMID- 25937751 TI - Modified mask ventilation in post rhinoplasty patient. PMID- 25937752 TI - Osteolipoma of the palate - An unusual presentation. PMID- 25937753 TI - Hair discharging from the frenulum: Unusual presentation of a lingual dermoid cyst. PMID- 25937754 TI - Platelet-rich plasma in periodontal defect treatment after extraction of impacted mandibular third molars: Retraction. AB - [This retracts the article on p. 139 in vol. 3, PMID: 23833487.]. PMID- 25937755 TI - Desk of the editor vol.6 issue 1. PMID- 25937756 TI - Current status and future directions in the management of pancreatic cancer. PMID- 25937758 TI - Resection after neoadjuvant chemotherapy in advanced carcinoma of the gallbladder: a retrospective study. AB - Although rare over most of the world, Gallbladder cancer is very common in northern india. A delayed presentation, aggressive nature,lack of randomised trials and a poor prognosis have all contributed to the nihilistic halo encircling gallbladder cancer. None of the advances in oncology have been exploited enough to shatter the nihilistic halo. In this background we sought to analyze if the addition of neoadjuvant chemotherapy had any impact on the resectability, overall and disease free survival in patients with advanced carcinoma of the gallbladder. We reviewed the records of all patients who underwent surgery for carcinoma of the gall bladder from 2004 to 2010 at our institute retrospectively. Twenty-one patients received neoadjuvant chemotherapy and subsequently taken up for surgery. Outcome analysis of these 21 patients were done by Kaplan meier method and graphs plotted. Out of the 21 patients who were taken up for surgery after neoadjuvant chemotherapy, fourteen patients underwent R0 resection (Group 1). Seven patients had been rendered inoperable on exploration (Group 2). Thus about 66.67 % of patients deemed resectable after neoadjuvant chemotherapy on imaging underwent R0 resection. The mean overall survival of the group 1 was 42.8 months versus 6.6 months of group 2(Hazard Ratio: 3.42). Neoadjuvant chemotherapy improves resectability in some patients with unresectable gall bladder cancer. Resection after neoadjuvant chemotherapy is feasible and may improve survival in a select group of patients. However randomized studies are required to establish its definitive role. PMID- 25937759 TI - Comparison of Pathological Radicality between Open and Laparoscopic Pancreaticoduodenectomy in a Tertiary Centre. AB - Laparoscopic pancreaticoduodenectomy (LPD) remained a formidable challenge owing to retroperitoneal location, difficult dissection near great vessels and critical intracorporeal anastomoses. Recent reviews of literature have established the feasibility and comparable short term outcomes of laparoscopic pancreaticoduodenectomy (LPD) with that of open pancreaticoduodenectomy (OPD). This study was undertaken to compare the pathological radicality of LPD with OPD. A prospective database of all patients who underwent standard pancreaticoduodenectomy from Mar 2006 to Feb 2011 was taken up for this study. 45 patients who underwent LPD and 118 patients who underwent OPD for periampullary and pancreatic head malignancy were taken up for analysis. The study groups were comparable in terms of age of presentation, ASA grades, comorbidity, type of surgery and BMI. There was no statistically significant difference with regard to tumor size, lymph node yield, node positivity rates, R1 rates and margin lengths. The pathological radicality of laparoscopic pancreaticoduodenectomy is comparable with that of open approach when performed by experienced minimal-access surgeons. Standardized protocols for evaluation of the resection margins should be mandatory in studies reporting outcomes of pancreaticoduodectomy. PMID- 25937757 TI - Pancreatoduodenectomy - preventing complications. AB - Increased awareness of periampullary & pancreatic head cancers, and the accompanying improved outcomes following pancreatoduodenectomy (PD), has possibly led to an increase in patients seeking treatment for the same. While there has definitely been a reduction in morbidity rates following PD in the last few decades, this decline has not mirrored the drastic fall in mortality. Amongst the foremost in the factors responsible for this reduction in mortality is the standardization of surgical technique and development of dedicated teams to manage all aspects of this demanding procedure. This review intends to provide the reader with an overview of major complications following this major surgery and measures to prevent them based on the authors' experience. PMID- 25937760 TI - Castleman's Disease Presenting as Peri - Pancreatic Neoplasm. AB - Castleman's disease (CD) is a relatively singular disorder. Usually presenting as a mediastinal mass, peri pancreatic localization of CD is even rarer. Diagnosis is seldom established pre-operatively. We report two such cases of CD in which peri pancreatic region was involved and were diagnosed on biopsy, hence avoiding complex and high risk surgery. PMID- 25937761 TI - Incidental detection of carcinoma gall bladder in laparoscopic cholecystectomy specimens: a thirteen year study of 23 cases and literature review. AB - Carcinoma of gall bladder is the most common malignancy of the biliary tract worldwide and is usually associated with poor prognosis. In this era of laparoscopic cholecystectomy, there has been increase in detection of early stage incidental gall bladder carcinoma in cholecystectomy specimens. A retrospective study was carried out in tertiary care hospital in central India. A total of 2990 patients underwent laparoscopic cholecystectomy during the year 2001-2013. Hospital records and histopathology reports of these patients were studied in detail. Twenty three cases of gall bladder carcinoma were detected incidentally accounting for an incidence of 0.76 %. It was more common in females with an M: F ratio of 1:1.9. Mean age of presentation was 57.8 years. Gall stones were present in 22 cases and one patient presented with features of acute cholecystitis. Three patients had associated xanthogranulomatous inflammation and 10 had associated intestinal metaplasia. It is not uncommon to encounter incidental malignancies of gall bladder in laparoscopic cholecystectomy specimens sent to histopathology for presumably benign disease. Histopathology reports must include comments on extent of infiltration, perineural invasion, tumor differentiation and nodal involvement for oncologist information and subsequent management of patients. PMID- 25937762 TI - Comparison of resident operative case logs during a surgical oncology rotation in the United States and an international rotation in India. AB - This study compared the operative case log experience between rotations during General Surgery residency in the United States and an international rotation in India. A resident from the General Surgery residency program at University of Nebraska Medical Center participated in an international rotation in Surgical Oncology at Mehdi Nawaz Jung Institute of Oncology in Hyderabad, India for 3 months in 2009. The operative case log of this resident (INT) was compared to those of another resident (US) on a rotation in surgical oncology at the parent institution during the same time period. Both institutions were tertiary care centers. We noted that the INT resident performed a greater number of cases (132) when compared to the US resident (61). The INT resident also performed cases in a wider variety of disease categories such as: head and neck (26 %), gynecology (19 %), breast (14 %) and urology (4 %). In contrast, abdominal cases accounted for 68 % of the cases performed by the US resident with fewer cases in the other categories. The INT resident performed 98 % of the cases by the open approach, whereas the US resident performed only 81 % of cases by the open approach, with the remaining 19 % of cases performed by the laparoscopic approach. The results demonstrate that the INT resident performed a greater number of operative cases when compared to a resident (US) at the parent institution, and performed cases in more diverse disease categories with an emphasis on the open operative approach. PMID- 25937763 TI - Beyond the whipple operation: radical resections for cancers of the head of the pancreas. AB - Pancreatic adenocarcinoma is the most common pancreatic malignancy, and it occurs most commonly in the pancreatic head. It has a relatively low incidence; however it is a deadly disease and is the fourth most common cause of cancer deaths for males and females in the United States. Surgical resection in the form of pancreaticoduodenectomy is the mainstay of treatment and can lead to improved overall survival as well as the possibility of a cure, although only 10 % of patients are resectable at presentation. In an attempt to improve outcomes and survival, surgeons over the decades have employed various aggressive resectional strategies to combat this disease. In this paper we review the development of pancreaticoduodenectomy and touch on the role played by the American surgeon Allan Whipple in this development. We review modern data regarding radical pancreaticoduodenectomy and extended lymphadenectomy for pancreatic head cancers, as well as data and controversies regarding arterial and venous resection performed during the course of pancreaticoduodenectomy. The role of extended and vascular resections in the treatment of pancreatic neuroendocrine tumors in contrast to adenocarcinomas is also examined. We summarize the current state of data regarding radical pancreaticoduodenectomy and discuss pushing the boundaries of surgical resection to help improve outcomes for select groups of patients. PMID- 25937765 TI - Pancreatic cancer in chronic pancreatitis. AB - Data exists to indicate a definite association between chronic pancreatitis and pancreatic cancer. The strength of this association varies between various causes of pancreatitis, with hereditary and tropical pancreatitis more likely to result in malignancy. Pathogenesis may involve genetic factors, diabetes, smoking and alcohol consumption. Clinically a significant overlap exists between the two conditions, with histology difficult to obtain and interpret in this setting. Biomarkers like CA19-9 and others may be useful, as is a variety of newer imaging modalities. Treatment needs to be individualised as surgery offers the only chance of cure, albeit in but a few. PMID- 25937764 TI - Advances in chemotherapy for pancreatic cancer. AB - Pancreatic cancer remains challenging to treat. Over the past decade, there have been some major improvements in systemic therapy. Gemcitabine remains the key drug for both early and advanced cancer but combination chemotherapy is emerging as a new paradigm for patients with good performance status. This review focuses on current chemotherapy status for patients with pancreatic cancer. PMID- 25937766 TI - Borderline resectable pancreatic cancer. AB - Borderline resectable pancreatic cancer (BRPC) is an evolving diagnostic entity that blurs the distinction between resectable and locally advanced pancreatic cancer (Varadhachary et al. Ann Surg Oncol 13:1035-1046, 2006). Until recently the management of this disease has been poorly defined; however, consensus guidelines have been developed regarding the proper management of this diagnostic entity. Recent studies have shown that if appropriately identified and treated, this subset of disease can have outcomes similar to pancreatic cancer that is defined as resectable (Laurence et al. J Gastrointest Surg 15:2059-2069, 2011). The aim of this review is to outline the current consensus on definitions, workup and management of BRPC, and also provide a summary of issues that require progress as defined by the International Study Group of Pancreatic Surgery (ISGPS). PMID- 25937767 TI - Mesopancreas in pancreatic cancer: where do we stand - review of literature. AB - Pancreatic cancer is associated with poor prognosis and surgery remains the main modality of treatment. Negative resection margin is an important prognostic factor for survival. Retropancreatic margin or the medial margin is the most common site of positive resection margin. Mesopancreas was proposed in analogy with mesorectum, which is considered as a fusion fascia formed embryologically during the development of pancreas. This mesopancreas lies posterior to the pancreas and contains pancreaticoduodenal vessels, lymphatics, nerve plexus and loose areolar tissue. Various technical modifications were proposed for better dissection of mesopancreas like posterior approach and artery first approach. There is an increased rate of R0 resection by these technical modifications but whether this will turn to increase in survival rates is yet to be established. PMID- 25937768 TI - Review: the role of hyperthermia in treating pancreatic tumors. AB - There is only marginal improvement in outcome of treating pancreatic cancer in the last two decades. Time to open up and have a fresh look at complementary adjuvant treatment options. Hyperthermia may be one such option. Hyperthermic intraperitoneal chemotherapy (HIPEC) predominantly as a intrasurgical procedure has already proved its justification. Non-invasive loco regional hyperthermia as complement to either chemo or radiation has not yet reached a comparable status of evidence. However the potential to eventually grow into such evidence is already clearly observable. This review presents the various methodologies available for hyperthermia, covers the initial clinical data that has been published and gives an outlook to what can be expected in the next 2-3 years to come. Hyperthermia has the potential to significantly prolong life expectancies and this while maintaining a satisfying quality of life! PMID- 25937769 TI - Serous microcystic adenoma to adenocarcinoma of pancreas-a case report. PMID- 25937770 TI - Hilar Inflammatory Pseudotumour with Hepatic Artery Atheroma- mimicker of Klatskin Tumour. AB - Inflammatory pseudotumour of hilar biliary structures is an extremely rare benign lesion that can mimic hilar cholangiocarcinoma. Clinical presentation and imaging findings often pose diagnostic difficulties. Main histopathological findings are the presence of myofibroblastic spindle cells, plasma cells, macrophages, and lymphocytes without cellular atypia or atypical mitotic figures. We describe a case of 62 year old male who presented with surgical obstructive jaundice. Imaging revealed a mass lesion involving the biliary confluence with upstream dilatation of biliary tree. Diagnosis of hilar cholangiocarcinoma with type III hilar block was made. Intraoperately hilar mass lesion was found which was encasing right hepatic artery with no evidence of metastasis. The patient underwent Right hepatectomy with caudate lobectomy with complete common bile duct (CBD) excision with Roux en Y hepaticojejunostomy. Unexpectedly histopathological examination showed no evidence of malignancy and revealed hilar inflammatory pseudotumour with hepatic artery atherosclerosis. Preoperative imaging, operative management, pathologic diagnosis and literature review are being presented in view of rarity of the case. PMID- 25937771 TI - Rash: annoying but prognostic. AB - Targeted therapies are commonly utilised in modern oncology practice. Skin toxicity is a frequently encountered problem associated with them. Some of the skin toxicites carry prognostic significance and it is important to identify them. Though annoying, treatment interruption is seldom required. PMID- 25937773 TI - Progression of targeted therapy in advanced cholangiocarcinoma. AB - It is necessary to establish an effective therapy to improve the survival of patients with advanced cholangiocarcinoma (CCA). Recently, with the development of pathology research in CCA, a lot of special bio-markers such as EGFR, VEGF, HER2, and MEK et al. could be over expression or mutations in CCA patients. According to their changes, combinations of targeted therapy plus chemotherapy are now recognized as effective therapies for advanced CCA. The aim of this paper is to analyze recent promising studies about targeted therapy alone or combination with each other or with chemotherapies. PMID- 25937772 TI - Transcatheter embolization therapy in liver cancer: an update of clinical evidences. AB - Transarterial chemoembolization (TACE) is a form of intra-arterial catheter-based chemotherapy that selectively delivers high doses of cytotoxic drug to the tumor bed combining with the effect of ischemic necrosis induced by arterial embolization. Chemoembolization and radioembolization are at the core of the treatment of liver hepatocellular carcinoma (HCC) patients who cannot receive potentially curative therapies such as transplantation, resection or percutaneous ablation. TACE for liver cancer has been proven to be useful in local tumor control, to prevent tumor progression, prolong patients' life and control patient symptoms. Recent evidence showed in patients with single-nodule HCC of 3 cm or smaller without vascular invasion, the 5-year overall survival (OS) with TACE was similar to that with hepatic resection and radiofrequency ablation. Although being used for decades, Lipiodol((r)) (Lipiodol((r)) Ultra Fluid((r)), Guerbet, France) remains important as a tumor-seeking and radio-opaque drug delivery vector in interventional oncology. There have been efforts to improve the delivery of chemotherapeutic agents to tumors. Drug-eluting bead (DEB) is a relatively novel drug delivery embolization system which allows for fixed dosing and the ability to release the anticancer agents in a sustained manner. Three DEBs are available, i.e., Tandem((r)) (CeloNova Biosciences Inc., USA), DC Beads((r)) (BTG, UK) and HepaSphere((r)) (BioSphere Medical, Inc., USA). Transarterial radioembolization (TARE) technique has been developed, and proven to be efficient and safe in advanced liver cancers and those with vascular complications. Two types of radioembolization microspheres are available i.e., SIR-Spheres((r)) (Sirtex Medical Limited, Australia) and TheraSphere((r)) (BTG, UK). This review describes the basic procedure of TACE, properties and efficacy of some chemoembolization systems and radioembolization agents which are commercially available and/or currently under clinical evaluation. The key clinical trials of transcatheter arterial therapy for liver cancer are summarized. PMID- 25937774 TI - The status, limitation and improvement of adoptive cellular immunotherapy in advanced urologic malignancies. AB - In recent years, immunotherapy has been gradually established as the fourth frequently adopted antitumor therapy, following surgery, chemotherapy and radiotherapy, for advanced urologic malignancies with an improved understanding of theoretical basis, such as molecular biology and immunology. Thereinto, adoptive cellular immunotherapy (ACI) has become one of the hotspots, which comprises a variety of treatment approaches, such as TIL, CIK cell, gammadelta T cell, CAR-engineered T cell and Allogeneic stem cell transplantation (alloSCT). Although preclinical efficacy has been demonstrated remarkably, clinical trials could not consistently show the benefit due to multi-factors in complex immunosuppressive microenvironment in vivo compared to that of in vitro. Here we review some timely aspects of ACI for advanced urologic malignancies, and describe the current status and limitation of immunotherapy from the cellular level. It's our expectation to provide prompting consideration of novel combinatorial ACI strategies and a resurgence of interest in ACI for advanced urologic malignancies. PMID- 25937775 TI - China's landscape in oncology drug research: perspectives from research collaboration networks. AB - OBJECTIVE: Better understanding of China's landscape in oncology drug research is of great significance for discovering anti-cancer drugs in future. This article differs from previous studies by focusing on Chinese oncology drug research communities in co-publication networks at the institutional level. Moreover, this research aims to explore structures and behaviors of relevant research units by thematic community analysis and to address policy recommendations. METHODS: This research used social network analysis to define an institutions network and to identify a community network which is characterized by thematic content. RESULTS: A total of 675 sample articles from 2008 through 2012 were retrieved from the Science Citation Index Expanded (SCIE) database of Web of Science, and top institutions and institutional pairs are highlighted for further discussion. Meanwhile, this study revealed that institutions based in the Chinese mainland are located in a relatively central position, Taiwan's institutions are closely assembled on the side, and Hong Kong's units located in the middle of the Chinese mainland's and Taiwan's. Spatial division and institutional hierarchy are still critical barriers to research collaboration in the field of anti-cancer drugs in China. In addition, the communities focusing on hot research areas show the higher nodal degree, whereas communities giving more attention to rare research subjects are relatively marginalized to the periphery of network. CONCLUSIONS: This paper offers policy recommendations to accelerate cross-regional cooperation, such as through developing information technology and increasing investment. The brokers should focus more on outreach to other institutions. Finally, participation in topics of common interest is conducive to improved efficiency in research and development (R&D) resource allocation. PMID- 25937776 TI - Kaiso mainly locates in the nucleus in vivo and binds to methylated, but not hydroxymethylated DNA. AB - OBJECTIVE: Kaiso is upregulated in many cancers and proposed to bind with both methylated- and unmethylated-DNA in the nucleus as a transcriptional repressor. The objective is to define its subcellular localization in vivo and exact binding DNA sequences in cells. METHODS: Compartmentalization of exogenous Kaiso in cells was tracked with enhanced green fluorescence protein (EGFP) tag. The endogenous Kaiso expression in gastric carcinoma tissue was examined with immunohistochemical staining. Kaiso-DNA binding was tested using electrophoretic mobility shift assay (EMSA) and chromatin immunoprecipitation assay (ChIP). RESULTS: Kaiso mainly localized in the nucleus of cancer and stromal cells in vivo, but remained in the cytoplasm of cultured cells. Most importantly, nuclear Kaiso can bind with the methylated-CGCG-containing sequence in the CDKN2A promoter, but not with the hydroxymethylated-CGCG sequence in HCT116 cells. CONCLUSIONS: Kaiso locates mainly in the nucleus in vivo where it binds with the methylated-CGCG sequences, but does not bind with the hydroxymethylated-CGCG sequences. PMID- 25937777 TI - Variant TP53BP1 rs560191 G>C is associated with risk of gastric cardia adenocarcinoma in a Chinese Han population. AB - OBJECTIVE: To investigate the association between gastric cardia adenocarcinoma (GCA) and ten functional single nucleotide polymorphisms (SNPs), including TP53BP1 rs560191 G>C, CASP8 rs1035142 G>T, CASP7 rs3127075 G>C, CASP7 rs7907519 C>A, and six C1orf10/CRNN variants. We performed a hospital-based case-control study to evaluate the genetic effects of these SNPs. METHODS: Two hundred and forty-three GCA cases and 476 controls were enrolled in this study. A custom-by design 48-Plex SNPscan(TM) Kit was used to determine their genotypes. RESULTS: When the TP53BP1 rs560191 GG homozygote genotype was used as the reference group, the GC genotype was associated with a significantly increased risk of GCA. The CC genotype was not associated with the risk of GCA compared with the GG genotype. None of the CASP8 rs1035142 G>T, CASP7 rs3127075 G>C, CASP7 rs7907519 C>A or the six C1orf10/CRNN polymorphisms showed a significant difference in genotype distributions between the cases and the controls. CONCLUSIONS: The results demonstrated that the functional polymorphism TP53BP1 rs560191 G>C might contribute to GCA susceptibility. However, the statistical power of our study was limited. Large, well-designed studies and further functional investigations are needed to confirm our findings. PMID- 25937778 TI - HER2 discordance between paired primary gastric cancer and metastasis: a meta analysis. AB - BACKGROUND: A number of studies have examined human epidermal growth factor receptor 2 (HER2) status in primary gastric cancer (GC) and associated metastasis, some showed their great concordance in HER2 expression, but others demonstrated notable discordance. There is still little consensus on HER2 discordance, therefore, a systematic review and meta-analysis was conducted to assess the status on HER2 discordance between primary GC and its paired metastasis. METHODS: PubMed, EMBASE, ASCO and The Cochrane Library were searched for studies that explored the concordance between primary tumor and metastasis in patients with GC up to 10 March, 2014. Data of discordance of HER2 between primary GC and corresponding metastasis were extracted from the publications and random-effects models were used to estimate pooled discordance proportions. RESULTS: Eighteen articles including 1,867 patients were included for the meta analysis in accordance with the selection criteria. Pooled discordance proportions were 7% [95% confidence interval (CI): 5-10%] for HER2 status. Pooled proportions of tumors shifting from positive to negative and from negative to positive were 17% (95% CI: 7-29%) and 4% (95% CI: 2-6%) respectively. No publication bias was found in the meta-analysis. CONCLUSIONS: The discordance of HER2 status is not rare in primary and metastatic GC through our meta-analysis. Prospective studies are needed to testify the clinical significance of the discordance of HER2 status. PMID- 25937779 TI - Feasibility of cetuximab and chemoradiotherapy combination in Chinese patients with unresectable stage III non-small cell lung cancer: a preliminary report. AB - OBJECTIVE: In recent years, the combination of cetuximab and chemoradiotherapy (CRT) has been used to treat stage III non-small cell lung cancer (NSCLC); however, limited data are available for Chinese patients. Herein, we report preliminary data from a phase I/II study testing the combination of cetuximab with inductive chemotherapy, followed by concurrent CRT (CCRT) in Chinese patients with stage III NSCLC. METHODS: Eligibility criteria were Zubrod performance status (PS) 0-1, forced expiratory volume in 1 second (FEV1) >=1.2 L and adequate organ function. Enrolled patients received weekly cetuximab (initial dose of 400 mg/m(2) on day 1 of week 1 and a maintenance dose of 250 mg/m(2) on week 2 to the end of CCRT) with cisplatin/vinorelbine (NP) chemotherapy (every 3 weeks for 2 cycles from week 2, followed by two cycles of concomitant NP chemotherapy and intensity-modulated thoracic radiotherapy (TRT) (60-66 Gy/2 Gy). The primary endpoints were toxicity and feasibility. All patients received positron emission tomography-computerized tomography (PET-CT) scans within the 2 weeks prior to enrollment. Univariate analyses were used to assess the correlation between SUV-T, SUV-N, SUV-TOTAL, gender, age, histology, tumor-node metastasis (TNM) stage, PS and smoking status and survival. Survival curves were generated for different populations using the Kaplan-Meier method and compared using a log-rank test. RESULTS: Seventeen patients were enrolled and 16 completed the full regime. The overall response rate (ORR) was 58.8% and 82.3% after the induction and CCRT phases, respectively. With a median follow-up duration of 27.6 months, the median survival was 27.6 months [95% confidence interval (CI): 11.3 43.9 months] with 1- and 2-year survival rates of 88.2% (95% CI, 60.6-96.9%) and 58.8% (95% CI, 60.6-77.8%), respectively. Three patients remain progression-free to date, and the median progression-free survival (PFS) was 13.5 months (95% CI, 6.8-20.2 months). No treatment-related death occurred; however, 76% of the patients experienced grade 3+ adverse events (AEs), including nausea/vomiting, intestinal obstruction, and esophagitis (<6%), while other AEs were mostly of hematological nature (71%). The cut-off values for SUV-T and SUV-TOTAL were 11 and 20, respectively. Univariate analyses revealed SUV-TOTAL (P=0.027), SUV-T (P=0.025), and PS (P=0.006) as potential survival predictors, with a hazard ratio (HR) of 3.4, 3.7, and 9.9, respectively. CONCLUSIONS: The combination of cetuximab with induction chemotherapy followed by CCRT appears feasible and promising. Local and locoregional maximal SUVs, defined by (18)F-FDG PET-CT scanning, may represent a prognostic indicator for long-term survival for these patients, which warrants further study. PMID- 25937780 TI - Activation of Toll-like receptors signaling in non-small cell lung cancer cell line induced by tumor-associated macrophages. AB - BACKGROUND: Inflammation is often linked with the progress and poor outcome of lung cancer. The understanding of the relationship between tumor-associated macrophages (TAMs) and lung cancer cells involves in the underlying mechanism of inflammatory cytokine production. Toll-like receptors (TLRs) are engaged in promoting the production of pro-inflammatory cytokines and play an important role in tumor immunology. METHODS: To investigate the mechanisms by which TAMs influence the production of pro-inflammatory cytokines in lung cancer cells, we established an in vitro coculture system using TAMs and human non-small cell lung cancer (NSCLC) cell line SPC-A1. Levels of interleukin (IL)-1beta, IL-6 and IL-8 in SPC-A1 were evaluated by RT-PCR and cytometric bead array assay after being cocultured with TAMs. Expression changes of TLRs and TLRs signaling pathway proteins in SPC-A1 were further confirmed by RT-PCR and western blot. The level changes of IL-1beta, IL-6 and IL-8 in SPC-A1 were also detected after the stimulation of TLRs agonists. RESULTS: We found that the phenotype markers of TAMs were highly expressed after stimulating human monocyte cell line THP-1 by phorbol-12-myristate-13-acetate (PMA). Higher mRNA and supernate secretion levels of IL-1beta, IL-6 and IL-8 were detected in SPC-A1 after being cocultured with TAMs. We also found that TLR1, TLR6 and TLR7 were up-regulated in SPC-A1 in the coculture system with TAMs. Meanwhile, TLRs signaling pathway proteins were also significantly activated. Moreover, pre-treatment with agonist ligands for TLR1, TLR6 and TLR7 could dramatically promote inductions of IL-1beta, IL-6 and IL-8. CONCLUSIONS: These findings demonstrated that TAMs may enhance IL-1beta, IL-6 and IL-8 expressions via TLRs signaling pathway. We conclude that TAMs contribute to maintain the inflammation microenvironment and ultimately promote the development and progression of lung cancer. PMID- 25937781 TI - Nab-paclitaxel (abraxane)-based chemotherapy to treat elderly patients with advanced non-small-cell lung cancer: a single center, randomized and open-label clinical trial. AB - BACKGROUND: The purpose of this study is to evaluate the clinical efficacy and safety of abraxane-based chemotherapy with/without nedaplatin in elderly patients with non-small-cell lung cancer (NSCLC). MATERIALS AND METHODS: From October 2009 to January 2013, 48 elderly patients (>=65 years) with NSCLC were investigated in this clinical trial. The patients were randomized and equally allocated into arms A and AP: (A) abraxane (130 mg/m(2), days 1, 8); (B) abraxane + nedaplatin (20 mg/m(2) days 1-3, q3w). The parameters of objective response rate (ORR), disease control rate (DCR), progression-free survival (PFS), overall survival (OS) and side effects were evaluated between two arms. RESULTS: Over 80% of the patients completed four cycles of chemotherapy. The total ORR was 21.3%, DCR was 55.3%, PFS 4.5 months and OS 12.6 months. No significant difference was found between arms A and AP in terms of ORR (16.7% vs. 26.1%, P=0.665) or DCR (55.3% vs. 56.5%, P=0.871). The median PFS in arm A was 3.3 months [25-75% confidence interval (CI): 3.1-7.2] and 5.5 months (25-75% CI: 3.2-7.0) in arm AP with no statistical significance (P=0.640). The median OS in arm A was 12.6 months (25-75% CI: 5.7 26.2) and 15.1 months (25-75% CI: 6.4-35.3) in arm AP with no statistical significance (P=0.770). The side effects were mainly grade 1-2. The incidence of grade 3-4 toxicities was 29.1% in arm A and 62.5% in arm AP with a statistical significance (P=0.020). CONCLUSIONS: Compared with combined therapy, abraxane alone chemotherapy was beneficial for elderly NSCLC patients with better tolerability and less adverse events, whereas did not significantly differ in terms of ORR, DCR, PFS or OS. PMID- 25937782 TI - Nonintubated uniportal video-assisted thoracoscopic surgery for primary spontaneous pneumothorax. AB - OBJECTIVE: The objective of the current study was to evaluate the feasibility and safety of nonintubated uniportal video-assisted thoracoscopic surgery (VATS) for the management of primary spontaneous pneumothorax (PSP). METHODS: From November 2011 to June 2013, 32 consecutive patients with PSP were treated by nonintubated uniportal thoracoscopic bullectomy using epidural anaesthesia and sedation without endotracheal intubation. An incision 2 cm in length was made at the 6(th) intercostal space in the median axillary line. The pleural space was entered by blunt dissection for placement of a soft incision protector. Instruments were then inserted through the incision protector to perform thoracoscopic bullectomy. Data were collected within a minimum follow-up period of 10 months. RESULTS: The average time of surgery was 49.0 min (range, 33-65 min). No complications were recorded. The postoperative feeding time was 6 h. The mean postoperative chest tube drainage and hospital stay were 19.3 h and 41.6 h, respectively. The postoperative pain was mild for 30 patients (93.75%) and moderate for two patients (6.25%). No recurrences of pneumothorax were observed at follow-up. CONCLUSIONS: The initial results indicated that nonintubated uniportal video assisted thoracoscopic operations are not only technically feasible, but may also be a safe and less invasive alternative for select patients in the management of PSP. This is the first report to include the use of a nonintubated uniportal technique in VATS for such a large number of PSP cases. Further work and development of instruments are needed to define the applications and advantages of this technique. PMID- 25937783 TI - Activity estimation in radioimmunotherapy using magnetic nanoparticles. AB - OBJECTIVE: Estimation of activity accumulated in tumor and organs is very important in predicting the response of radiopharmaceuticals treatment. In this study, we synthesized (177)Lutetium ((177)Lu)-trastuzumab-iron oxide nanoparticles as a double radiopharmaceutical agent for treatment and better estimation of organ activity in a new way by magnetic resonance imaging (MRI). METHODS: (177)Lu-trastuzumab-iron oxide nanoparticles were synthesized and all the quality control tests such as labeling yield, nanoparticle size determination, stability in buffer and blood serum up to 4 d, immunoreactivity and biodistribution in normal mice were determined. In mice bearing breast tumor, liver and tumor activities were calculated with three methods: single photon emission computed tomography (SPECT), MRI and organ extraction, which were compared with each other. RESULTS: The good results of quality control tests (labeling yield: 61%+/-2%, mean nanoparticle hydrodynamic size: 41+/-15 nm, stability in buffer: 86%+/-5%, stability in blood serum: 80%+/-3%, immunoreactivity: 80%+/-2%) indicated that (177)Lu-trastuzumab-iron oxide nanoparticles could be used as a double radiopharmaceutical agent in mice bearing tumor. Results showed that (177)Lu-trastuzumab-iron oxide nanoparticles with MRI had the ability to measure organ activities more accurate than SPECT. CONCLUSIONS: Co-conjugating radiopharmaceutical to MRI contrast agents such as iron oxide nanoparticles may be a good way for better dosimetry in nuclear medicine treatment. PMID- 25937784 TI - Diffusion-tensor imaging as an adjunct to dynamic contrast-enhanced MRI for improved accuracy of differential diagnosis between breast ductal carcinoma in situ and invasive breast carcinoma. AB - OBJECTIVE: To determine the value of diffusion-tensor imaging (DTI) as an adjunct to dynamic contrast-enhanced magnetic resonance imaging (DCE-MRI) for improved accuracy of differential diagnosis between breast ductal carcinoma in situ (DCIS) and invasive breast carcinoma (IBC). METHODS: The MRI data of 63 patients pathologically confirmed as breast cancer were analyzed. The conventional MRI analysis metrics included enhancement style, initial enhancement characteristic, maximum slope of increase, time to peak, time signal intensity curve (TIC) pattern, and signal intensity on FS-T2WI. The values of apparent diffusion coefficient (ADC), directionally-averaged mean diffusivity (Davg), exponential attenuation (EA), fractional anisotropy (FA), volume ratio (VR) and relative anisotropy (RA) were calculated and compared between DCIS and IBC. Multivariate logistic regression was used to identify independent factors for distinguishing IBC and DCIS. The diagnostic performance of the diagnosis equation was evaluated using the receiver operating characteristic (ROC) curve. The diagnostic efficacies of DCE-MRI, DWI and DTI were compared independently or combined. RESULTS: EA value, lesion enhancement style and TIC pattern were identified as independent factor for differential diagnosis of IBC and DCIS. The combination diagnosis showed higher diagnostic efficacy than a single use of DCE-MRI (P=0.02), and the area of the curve was improved from 0.84 (95% CI, 0.67-0.99) to 0.94 (95% CI, 0.85-1.00). CONCLUSIONS: Quantitative DTI measurement as an adjunct to DCE-MRI could improve the diagnostic performance of differential diagnosis between DCIS and IBC compared to a single use of DCE-MRI. PMID- 25937785 TI - Erratum. AB - [This corrects the article on p. 94 in vol. 27, PMID: 25717232.][This corrects the article on p. 602 in vol. 26, PMID: 25400427.]. PMID- 25937786 TI - Cyclodextrin-promoted energy transfer for broadly applicable small-molecule detection. AB - Reported herein is the development of non-covalent, proximity-induced energy transfer from small-molecule toxicants to organic fluorophores bound in the cavity of gamma-cyclodextrin. This energy transfer occurs with exceptional efficiency for a broad range of toxicants in complex biological media, and is largely independent of the spectral overlap between the donor and acceptor. This generally applicable phenomenon has significant potential in the development of new turn-on detection schemes. PMID- 25937787 TI - Synthesis of a Disulfonated Derivative of Cucurbit[7]uril and Investigations of its Ability to Solubilize Insoluble Drugs. AB - Cucurbit[7]uril (CB[7]) is currently being investigated as a solubilizing agent for insoluble drugs. We recently found that acyclic CB[n]-type receptors that bear sulfonate solubilizing groups are well suited for this application. Herein, we report cucurbit[7]uril derivative (1) that bears two sulfonate groups on its convex face that we hypothesized would be a superior solubilizing excipient for insoluble drugs. Before using 1 for drug solubilization experiments we showed that 1 does not self-associate and that it retained its ability to bind to diammonium compounds as common guests for CB[7] sized cavities. X-ray crystallography shows that 1 maintains the key structural features of CB[7] with only minor ellipsoidal deformations at the equator and carbonyl portals of 1. Unfortunately, the aqueous solubility of 1 (20 mM) is slightly lower than CB[7] (20-30 mM) which limits its potential as a solubilizing excipient for insoluble drugs. We created phase solubility diagrams for the solubilization of three drugs (camptothecin, albendazole, cinnarizine) with two different containers (1 and CB[7]). CB[7] and 1 exhibit comparable solubilization abilities (e.g. Ka and maximum solubility) toward camptothecin and albendazole but 1 is an inferior solubilizing agent for cinnarizine because of the low solubility exhibited by the 1*cinnarizine complex. PMID- 25937788 TI - The secret to a successful relationship: lasting chemistry between ascidians and their symbiotic bacteria. AB - Bioactive secondary metabolites are common components of marine animals. In many cases, symbiotic bacteria, and not the animals themselves, synthesize the compounds. Among marine animals, ascidians are good models for understanding these symbioses. Ascidians often contain potently bioactive secondary metabolites as their major extractable components. Strong evidence shows that ~8% of the known secondary metabolites from ascidians are made by symbiotic bacteria, and indirect evidence implicates bacteria in the synthesis of many more. Far from being "secondary" to the animals, secondary metabolites are essential components of the interaction between host animals and their symbiotic bacteria. These interactions have complex underlying biology, but the chemistry is clearly ascidian-species specific. The chemical interactions are ancient in at least some cases, and they are widespread among ascidians. Ascidians maintain secondary metabolic symbioses with bacteria that are phylogenetically diverse, indicating a convergent solution to obtaining secondary metabolites and reinforcing the importance of secondary metabolism in animal survival. PMID- 25937789 TI - NO RELATIONSHIP BETWEEN INTELLIGENCE AND FACIAL ATTRACTIVENESS IN A LARGE, GENETICALLY INFORMATIVE SAMPLE. AB - Theories in both evolutionary and social psychology suggest that a positive correlation should exist between facial attractiveness and general intelligence, and several empirical observations appear to corroborate this expectation. Using highly reliable measures of facial attractiveness and IQ in a large sample of identical and fraternal twins and their siblings, we found no evidence for a phenotypic correlation between these traits. Likewise, neither the genetic nor the environmental latent factor correlations were statistically significant. We supplemented our analyses of new data with a simple meta-analysis that found evidence of publication bias among past studies of the relationship between facial attractiveness and intelligence. In view of these results, we suggest that previously published reports may have overestimated the strength of the relationship and that the theoretical bases for the predicted attractiveness intelligence correlation may need to be reconsidered. PMID- 25937790 TI - Are There Long-Run Effects of the Minimum Wage? AB - An empirical consensus suggests that there are small employment effects of minimum wage increases. This paper argues that these are short-run elasticities. Long-run elasticities, which may differ from short-run elasticities, are policy relevant. This paper develops a dynamic industry equilibrium model of labor demand. The model makes two points. First, long-run regressions have been misinterpreted because even if the short- and long-run employment elasticities differ, standard methods would not detect a difference using US variation. Second, the model offers a reconciliation of the small estimated short-run employment effects with the commonly found pass-through of minimum wage increases to product prices. PMID- 25937792 TI - Multivariate spatio-temporal modelling for assessing Antarctica's present-day contribution to sea-level rise. AB - Antarctica is the world's largest fresh-water reservoir, with the potential to raise sea levels by about 60 m. An ice sheet contributes to sea-level rise (SLR) when its rate of ice discharge and/or surface melting exceeds accumulation through snowfall. Constraining the contribution of the ice sheets to present-day SLR is vital both for coastal development and planning, and climate projections. Information on various ice sheet processes is available from several remote sensing data sets, as well as in situ data such as global positioning system data. These data have differing coverage, spatial support, temporal sampling and sensing characteristics, and thus, it is advantageous to combine them all in a single framework for estimation of the SLR contribution and the assessment of processes controlling mass exchange with the ocean. In this paper, we predict the rate of height change due to salient geophysical processes in Antarctica and use these to provide estimates of SLR contribution with associated uncertainties. We employ a multivariate spatio-temporal model, approximated as a Gaussian Markov random field, to take advantage of differing spatio-temporal properties of the processes to separate the causes of the observed change. The process parameters are estimated from geophysical models, while the remaining parameters are estimated using a Markov chain Monte Carlo scheme, designed to operate in a high performance computing environment across multiple nodes. We validate our methods against a separate data set and compare the results to those from studies that invariably employ numerical model outputs directly. We conclude that it is possible, and insightful, to assess Antarctica's contribution without explicit use of numerical models. Further, the results obtained here can be used to test the geophysical numerical models for which in situ data are hard to obtain. (c) 2015 The Authors. Environmetrics published by John Wiley & Sons Ltd. PMID- 25937793 TI - Distribution of the most Common Genetic Variants Associated with a Variable Drug Response in the Population of the Republic of Macedonia. AB - Genetic variation in the regulation, expression and activity of genes coding for Phase I, Phase II drug metabolizing enzymes (DMEs) and drug targets, can be defining factors for the variability in both the effectiveness and occurrence of drug therapy side effects. Information regarding the geographic structure and multi-ethnic distribution of clinically relevant genetic variations is becoming increasingly useful for improving drug therapy and explaining inter-individual and inter-ethnic differences in drug response. This study summarizes our current knowledge about the frequency distribution of the most common allelic variants in three broad gene categories: the Phase I oxidation-cytochrome P450 (CYP450) family (CYP2C9, CYP2C19, CYP3A5, CYP2D6); the Phase II conjugation (GSTT1, SULT1A1; UGT1A1) and drug target (TYMS-TSER, MTHFR and VKORC1) in the population of the Republic of Macedonia and compares the information obtained with data published for other indigenous European populations. Our findings define the population of the Republic of Macedonia as an ethnic group with a highly polymorphic genetic profile. These results add to the evidence regarding the distribution of clinically important variant alleles in DME and drug target genes in populations of European ancestry. PMID- 25937791 TI - Antiretroviral treatment in HIV-1 infected pediatric patients: focus on efavirenz. AB - Efavirenz is a non-nucleoside reverse transcriptase inhibitor (NNRTI), used for the treatment of human immunodeficiency virus (HIV)-1 infection. Approved by the US Food and Drug Administration in 1998, its indication was recently extended to include children as young as 3 months of age. The World Health Organization and many national guidelines consider efavirenz to be the preferred NNRTI for first line treatment of children over the age of 3 years. Clinical outcomes of patients on three-drug antiretroviral regimens which include efavirenz are as good as or better than those for patients on all other currently approved HIV medications. Efavirenz is dosed once daily and has pediatric-friendly formulations. It is usually well tolerated, with central nervous system side effects being of greatest concern. Efavirenz increases the risk of neural tube defects in nonhuman primates and therefore its use during the first trimester of pregnancy is limited in some settings. With minimal interactions with antituberculous drugs, efavirenz is preferred for use among patients with HIV/tuberculosis coinfection. Efavirenz can be rendered inactive by a single point mutation in the reverse transcriptase enzyme. Newer NNRTI drugs such as etravirine, not yet approved for use in children under the age of 6 years, may maintain their activity following development of efavirenz resistance. This review highlights key points from the existing literature regarding the use of efavirenz in children and suggests directions for future investigation. PMID- 25937794 TI - Genome-wide methylation profiling of schizophrenia. AB - Schizophrenia is one of the major psychiatric disorders. It is a disorder of complex inheritance, involving both heritable and environmental factors. DNA methylation is an inheritable epigenetic modification that stably alters gene expression. We reasoned that genetic modifications that are a result of environmental stimuli could also make a contribution. We have performed 26 high resolution genome-wide methylation array analyses to determine the methylation status of 27,627 CpG islands and compared the data between patients and healthy controls. Methylation profiles of DNAs were analyzed in six pools: 220 schizophrenia patients; 220 age-matched healthy controls; 110 female schizophrenia patients; 110 age-matched healthy females; 110 male schizophrenia patients; 110 age-matched healthy males. We also investigated the methylation status of 20 individual patient DNA samples (eight females and 12 males. We found significant differences in the methylation profile between schizophrenia and control DNA pools. We found new candidate genes that principally participate in apoptosis, synaptic transmission and nervous system development (GABRA2, LIN7B, CASP3). Methylation profiles differed between the genders. In females, the most important genes participate in apoptosis and synaptic transmission (XIAP, GABRD, OXT, KRT7), whereas in the males, the implicated genes in the molecular pathology of the disease were DHX37, MAP2K2, FNDC4 and GIPC1. Data from the individual methylation analyses confirmed, the gender-specific pools results. Our data revealed major differences in methylation profiles between schizophrenia patients and controls and between male and female patients. The dysregulated activity of the candidate genes could play a role in schizophrenia pathogenesis. PMID- 25937795 TI - Intellectual ability in the duchenne muscular dystrophy and dystrophin gene mutation location. AB - Duchenne muscular dystrophy (DMD) is the most common form of muscular dystrophy during childhood. Mutations in dystrophin (DMD) gene are also recognized as a cause of cognitive impairment. We aimed to determine the association between intelligence level and mutation location in DMD genes in Serbian patients with DMD. Forty-one male patients with DMD, aged 3 to 16 years, were recruited at the Clinic for Neurology and Psychiatry for Children and Youth in Belgrade, Serbia. All patients had defined DMD gene deletions or duplications [multiplex ligation dependent probe amplification (MLPA), polymerase chain reaction (PCR)] and cognitive status assessment (Wechsler Intelligence Scale for Children, Brunet Lezine scale, Vineland-Doll scale). In 37 patients with an estimated full scale intelligence quotient (FSIQ), six (16.22%) had borderline intelligence (70T) and 34 (C>T) polymorphisms, all alleles were of the wild type. The CYP2C19 and P2Y12 gene polymorphisms may cause recurring strokes linked to insufficient response to treatment of ischemic cerebrovascular disease. In our patient group, three patients suffered repeated strokes and these patients had the CYP2C19*2 gene polymorphism. As a result, before medication use, genetic testing is important for human life, quality of life and economic burden. PMID- 25937798 TI - An Investigation of the Relationship between the eNOS Gene Polymorphism and Diagnosed Migraine. AB - We investigated the phenotype-genotype association of the following endothelial nitric oxide synthase (eNOS) gene polymorphisms, rs743506, rs2070744, rs1799983, rs180079, rs3918226, rs207468799 and rs148554851, in patients suffering from migraine living in Edirne, Turkey. A total of 175 individuals, who had been diagnosed with migraine between April 2013 and December 2013, at the Neurology Department, Trakya University Medical Faculty, Edirne, Turkey, and 125 healthy controls were recruited. The above gene polymorphisms were analyzed from genomic DNA in both patient and control groups, using the pyro-sequencing method. The eNOS rs1799983 TT genotype frequency in migraine patients who had a headache duration of longer than 24 hours was statistically significantly higher than in patients who had migraine attacks that lasted under 24 hours (p = 0.047). In terms of the AGGTGGA haplotype, the severity of headache was statistically significant, and was found to be severe in 61.0% (p = 0.0001). Also in terms of the AGGTGGA haplotype, the duration of headache was statistically significant, and was >24 hours in 56.0% of patients (p = 0.008). In our study, there was no significant genotypephenotype relationship between eNOS rs743506, rs2070744, rs1799983, rs180079, rs3918226, rs207468799 and rs148554851 gene polymorphisms and migraine patients with and without aura living in Edirne, Turkey. The AGGTGGA haplotype constitutes a risk in terms of the severity and the duration of headaches in patients with migraine. This risk is significantly higher in patients with migraine with aura than patients with migraine without aura. PMID- 25937797 TI - The 3' end prothrombin gene variants in serbian patients with idiopathic thrombophilia. AB - Thrombophilia is a multifactorial disorder that arises from the interaction of acquired and genetic risk factors. Despite the significant efforts made to understand the etiology of this disease, there are still a certain number of patients suffering from idiopathic thrombophilia. The aim of this study was to screen the 3' end of the prothrombin (FII) gene, which is susceptible to gain-of function mutations due to its non canonical architecture, in patients with idiopathic thrombophilia and to determine its eventual role in the pathogenesis of thrombophilia. This study was carried out in 100 patients with idiopathic thrombophilia and 100 healthy controls. DNA variants in the 715 bp long region of the 3' end of the prothrombin gene were identified by sequencing. In our study, we detected two variants: A19911G and C20068T. The frequency of the A19911G gene variant was slightly increased in the group of patients compared to controls, however with no statistically significant difference compared to controls [odds ratio (OR) = 1.06; 95% confidence interval (95% CI) 0.53-2.13]. Heterozygous carriers of the FII C20068T gene variant were four times more frequent in patients (4.0%) than in controls (1.0%), but this difference did not reach statistical significance (OR = 4.12; 95% CI 0.45-37.57). Our findings suggest that variant A19911G is not a significant risk factor, while C20068T may represent a potential risk factor for idiopathic thrombophilia. To confirm our results, further studies should be conducted in a larger cohort of patients. PMID- 25937799 TI - Study of Three Single Nucleotide Polymorphisms in the SLC6A14 Gene in Association with Male Infertility. AB - Although several genetic causes of male infertility are known, the condition in around 60.0-75.0% of infertile male patients appears to be idiopathic. In some, genetic causes may be polygenic and require several low-penetrance genes to produce a phenotype outcome. In others, pleiotropy, when a gene can produce several phenotypic traits, may be involved. We have investigated whether single nucleotide polymorphisms (SNPs) in the SLC6A14 [solute carrier family 6 (amino acid transporter), member 14] gene are associated with male infertility. This gene has previously been linked with obesity and cystic fibrosis, which are associated with male infertility. It has a role in the transport of tryptophan and synthesis of serotonin that are important for normal spermatogenesis and testicular function. We have analyzed three SNPs (rs2312054, rs2071877 and rs2011162) in 370 infertile men and 241 fertile controls from two different populations (Macedonian and Slovenian). We found that the rs2011162(G) allele and rs2312054(A)-rs2071877(C)-rs2011162(G) haplotype are present at lower frequencies in the infertile rather than the fertile men (p = 0.044 and p = 0.0144, respectively). We concluded that the SLC6A14 gene may be a population-specific, low-penetrance locus which confers susceptibility to male infertility/subfertility. Additional follow-up studies of a large number of infertile men of different ethnic backgrounds are needed to confirm such a susceptibility. PMID- 25937800 TI - Frequencies of the Common MEFV Gene Mutations in Adiyaman, Southeast Anatolia, Turkey. AB - Familial Mediterranean fever (FMF) is an autosomal recessive disorder characterized by fever and serosal inflammation. The reasons for the disorder are mutations in the Mediterranean fever (MEFV) gene; the most common of which are M694V, M680I, M694I and V726A. In this study, we aimed to screen these common mutations of the MEFV gene and then determine the prevalence of FMF according to these mutations in Adiyaman, Southeast Anatolia, Turkey. Seven hundred and sixty seven healthy individuals from the region of Adiyaman participated in the study. Polymerase chain reaction-amplification refractory mutation system (PCR-ARMS) methods were used to determine the common mutations of the MEFV gene. Twenty-six (3.9%) individuals had only one mutation in the MEFV gene, 25 individuals were heterozygous and one person was homozygous for the V726A mutation (0.15%). In the present study, the V726A mutation (50.0%) was the most frequent, followed by M694V (38.5%), M680I (7.7%) and M694I (3.8%). It was seen that the carrier rate was very low and the prevalence of FMF was 0.15%, according to the common mutations of the MEFV gene in Adiyaman, Southeast Anatolia, Turkey. PMID- 25937801 TI - A novel angiogenesis inhibitor bevacizumab induces apoptosis in the rat endometriosis model. AB - Our aim was to investigate the effects of anti-vascular endothelial growth factor (anti-VEGF) antibody Bevacizumab on endometrial explants and on apoptotic gene expression levels in the rat endometriosis model. Endometriotic implants were surgically formed, and rats treated with (i) 1 mg/kg single subcutaneous injection of depot leuprolide acetate; (ii) 2.5 mg/kg of single intaperitoneal injection of bevacizumab; (iii) intraperitoneal injection of saline. Histopathologic scores and adhesion scores of endometriotic foci and levels of Bcl-2-associated X protein (Bax), Cytochrome c (Cyt-c), B-cell lymphoma/leukemia 2 (Bcl-2) and B-cell lymphoma-extra large (Bcl-xl) mRNA gene expressions of endometriotic foci. Bevacizumab treatment decreased the endometriotic explant size compared with control. Bevacizumab-treated rats had lower total adhesion scores when compared with the control group. Semi-quantitative evaluation of the persistence of endometrial epithelial cells in the explants showed a lower score in gonadotropin-releasing hormone (GnRH) agonist-treated rats compared with control rats. In Bevacizumab increased expression of Bax 3.1-fold, Cyt-c 1.3-fold and decreased expression of Bcl-2 0.4-fold, Bcl-xl 0.8-fold compared with the control group. The GnRH agonist increased expression of Bax 3.0 fold, Cyt-c 1.3 fold and decreased expression of Bcl-2 0.4-fold, Bcl-xl 0.8-fold, compared with the control group. This study suggests that a novel angiogenesis inhibitor, anti VEGF antibody bevacizumab is as effective as GnRH agonist in the regression of the endometriotic lesions in rat endometriosis model. One possible mechanism of this effect is the induction of apoptosis. PMID- 25937802 TI - X-Linked Recessive form of Nephrogenic Diabetes Insipidus in a 7-Year-Old Boy. AB - Nephrogenic diabetes insipidus (NDI) is caused by the inability of renal collecting duct cells to respond to arginine vasopressin (AVP)/antidiuretic hormone (ADH). We present the case of a 7-year-old boy with a history of excretion of large amounts of dilute urine and polydipsia since infancy. The boy had several vomiting episodes with mild dehydration during the first 3 years of life. There was no evidence of headaches, dizziness or visual problems. He drinks between 2 and 3 L/day and has 24-hour diuresis of 2 liters, now. He has prepubertal appearance with appropriate weight [+0.85 standard deviation score (SDS)] and height (+0.15 SDS) for his age. His intelligence was also normal. The water deprivation test showed low urine osmolality after 8 hours of dehydration. After desmopressin administration, urine osmolality remained low. Serum osmolality was in the normal range for sex and age before and after desmopressin administration. This indicated a nephrogenic form of diabetes insipidus. Molecular analyses revealed a P286L [p.Pro(CCC)286Leu(CTC)] mutation in the AVPR2 gene, that was inherited from his mother. This patient is the first case with genetically confirmed X-linked inherited form of NDI in the Republic of Macedonia. Molecular analysis confirmed the clinical diagnosis and enabled genetic advice for this family. PMID- 25937803 TI - Pressure-sensitive paint technique for surface pressure measurements in a low density wind tunnel. AB - ABSTRACT: A low-density wind tunnel called the Mars wind tunnel, has been developed at Tohoku University that can produce a high subsonic flow at low pressures for aerodynamic measurements of low-Reynolds-number aircraft wings aimed at developing aircraft applicable to the atmosphere on the planet Mars. Accurate surface pressure measurements on the wing are essential for analysis of not only aerodynamic performance, including lift and drag, but also the flow fields around the wing. This paper presents a surface pressure measurement technique using pressure-sensitive paint (PSP) applicable for Mars wind tunnel tests under low-pressure conditions. The results show that a PSP composed of palladium tetra(pentafluorophenyl) porphyrin (PdTFPP) and poly[1-(trimethylsilyl) propyne] [poly(TMSP)] exhibits a high-pressure sensitivity at pressures as low as 1 kPa, and the absolute values of the static pressures measured by the PSP accorded well with the values derived from static pressure sensors used as a reference. A calibration methodology for the non-uniform pressure sensitivity on the test model, including a temperature calibration, is also established. The PSP technique clearly demonstrated pressure sensitivity over a distinctive low pressure region inside a leading edge separation bubble on a flat plate at low Reynolds numbers. GRAPHICAL ABSTRACT: PMID- 25937804 TI - Television documentary, history and memory. An analysis of Sergio Zavoli's The Gardens of Abel. AB - This article examines a celebrated documentary made for Italian state TV in 1968 and transmitted in 1969 to an audience of millions. The programme - The Gardens of Abel - looked at changes introduced by the radical psychiatrist Franco Basaglia in an asylum in the north-east of Italy (Gorizia). The article examines the content of this programme for the first time, questions some of the claims that have been made for it, and outlines the sources used by the director, Sergio Zavoli. The article argues that the film was as much an expression of Zavoli's vision and ideas as it was linked to those of Franco Basaglia himself. Finally, the article highlights the way that this programme has become part of historical discourse and popular memory. PMID- 25937805 TI - The influence of a brittle Cr interlayer on the deformation behavior of thin Cu films on flexible substrates: Experiment and model. AB - Thin metal films deposited on polymer substrates are used in flexible electronic devices such as flexible displays or printed memories. They are often fabricated as complicated multilayer structures. Understanding the mechanical behavior of the interface between the metal film and the substrate as well as the process of crack formation under global tension is important for producing reliable devices. In the present work, the deformation behavior of copper films (50-200 nm thick), bonded to polyimide directly or via a 10 nm chromium interlayer, is investigated by experimental analysis and computational simulations. The influence of the various copper film thicknesses and the usage of a brittle interlayer on the crack density as well as on the stress magnitude in the copper after saturation of the cracking process are studied with in situ tensile tests in a synchrotron and under an atomic force microscope. From the computational point of view, the evolution of the crack pattern is modeled as a stochastic process via finite element based cohesive zone simulations. Both, experiments and simulations show that the chromium interlayer dominates the deformation behavior. The interlayer forms cracks that induce a stress concentration in the overlying copper film. This behavior is more pronounced in the 50 nm than in the 200 nm copper films. PMID- 25937806 TI - Individualism and sociocultural adaptation: Discrimination and social capital as moderators among rural-to-urban migrants in China. AB - This study examined the associations of sociocultural adaptation with individualism and collectivism and the moderating roles of discrimination and social capital in the associations among rural-to-urban migrants (N = 641) in Beijing, China. Results indicated that individualism was associated with poorer adaptation for migrants reporting low perceived discrimination or low social capital. However, migrants reporting high perceived discrimination showed poorer adaptation, regardless of individualism; and migrants reporting high social capital showed better adaptation, regardless of individualism. Collectivism was not related to adaptation. Findings suggest that individualism may be detrimental to migrants' adjustment to a collectivistic society. PMID- 25937807 TI - Top-down analysis of low mass proteins in exosomes shed by murine myeloid-derived suppressor cells. AB - Top-down analysis is reported for a portion of the protein cargo of exosomes shed by myeloid-derived suppressor cells that participate in intracellular signaling in the tumor microenvironment. Instrument mass resolution limited the study to proteins of molecular masses below 30 kDa. A two-step fractionation strategy was used, including open tubular gel electrophoresis and C3 reverse phase high performance liquid chromatography. Twenty-one unique proteins were identified among more than 200 proteoforms, and comprising primarily two functionally important protein families: the S100 proinflammatory mediators and an abundance of histones. Fifty-six percent of the total protein in these exosomes was determined to comprise histones, of which H2B variants contribute 42 %. PMID- 25937809 TI - Editorial. PMID- 25937810 TI - Reverse Engineering of Genome-wide Gene Regulatory Networks from Gene Expression Data. AB - Transcriptional regulation plays vital roles in many fundamental biological processes. Reverse engineering of genome-wide regulatory networks from high throughput transcriptomic data provides a promising way to characterize the global scenario of regulatory relationships between regulators and their targets. In this review, we summarize and categorize the main frameworks and methods currently available for inferring transcriptional regulatory networks from microarray gene expression profiling data. We overview each of strategies and introduce representative methods respectively. Their assumptions, advantages, shortcomings, and possible improvements and extensions are also clarified and commented. PMID- 25937811 TI - siRNA-directed DNA Methylation in Plants. AB - DNA cytosine methylationis an important epigenetic process that is correlated with transgene silencing, transposon suppression, and gene imprinting. In plants, small interfering RNAs (siRNAs) can trigger DNA methylation at loci containing their homolog sequences through a process called RNA-directed DNA methylation (RdDM). In canonical RdDM, 24 nucleotide (nt) siRNAs (ra-siRNAs) will be loaded into their effector protein called ARGONAUTE 4 (AGO4) and subsequently targeted to RdDM loci through base-pairing with the non-coding transcripts produced by DNA directed RNA Polymerase V. Then, the AGO4-ra-siRNA will recruit the DNA methyltransferase to catalyze de novo DNA methylation. Recent studies also identified non-canonical RdDM pathways that involve microRNAs or 21 nt siRNAs. These RdDM pathways are biologically important since they control responses biotic and abiotic stresses, maintain genome stability and regulate development. Here, we summarize recent pro-gresses of mechanisms governing canonical and non canonical RdDM pathways. PMID- 25937813 TI - Genetics and vaccines in the era of personalized medicine. AB - Vaccines represent the most successful and sustainable tactic to prevent and counteract infection. A vaccine generally improves immunity to a particular disease upon administration by inducing specific protective and efficient immune responses in all of the receiving population. The main known factors influencing the observed heterogeneity for immune re-sponses induced by vaccines are gender, age, co-morbidity, immune system, and genetic background. This review is mainly focused on the genetic status effect to vaccine immune responses and how this could contribute to the development of novel vaccine candidates that could be better directed and predicted relative to the genetic history of an individual and/or population. The text offers a brief history of vaccinology as a field, a description of the genetic status of the most relevant and studied genes and their functionality and correlation with exposure to specific vaccines; followed by an inside look into autoimmunity as a concern when designing vaccines as well as perspectives and conclusions looking towards an era of personalized and predictive vaccinology instead of a one size fits all approach. PMID- 25937815 TI - The logarithmic contributions to the [Formula: see text] asymptotic massive Wilson coefficients and operator matrix elements in deeply inelastic scattering. AB - We calculate the logarithmic contributions to the massive Wilson coefficients for deep-inelastic scattering in the asymptotic region [Formula: see text] to 3-loop order in the fixed flavor number scheme and present the corresponding expressions for the massive operator matrix elements needed in the variable flavor number scheme. Explicit expressions are given in Mellin [Formula: see text]-space. PMID- 25937812 TI - Genes and Conditions Controlling Mammalian Pre- and Post-implantation Embryo Development. AB - Embryo quality during the in vitro developmental period is of great clinical importance. Experimental genetic studies during this period have demonstrated the association between specific gene expression profiles and the production of healthy blastocysts. Although the quality of the oocyte may play a major role in embryo development, it has been well established that the post - fertilization period also has an important and crucial role in the determination of blastocyst quality. A variety of genes (such as OCT, SOX2, NANOG) and their related signaling pathways as well as transcription molecules (such as TGF-beta, BMP) have been implicated in the pre- and post-implantation period. Furthermore, DNA methylation has been lately characterized as an epigenetic mark since it is one of the most important processes involved in the maintenance of genome stability. Physiological embryo development appears to depend upon the correct DNA methylation pattern. Due to the fact that soon after fertilization the zygote undergoes several morphogenetic and developmental events including activation of embryonic genome through the transition of the maternal genome, a diverse gene expression pattern may lead to clinically important conditions, such as apoptosis or the production of a chromosomically abnormal embryo. The present review focused on genes and their role during pre-implantation embryo development, giving emphasis on the various parameters that may alter gene expression or DNA methylation patterns. The pre-implantation embryos derived from in vitro culture systems (in vitro fertilization) and the possible effects on gene expression after the prolonged culture conditions are also discussed. PMID- 25937814 TI - DNA secondary structure at chromosomal fragile sites in human disease. AB - DNA has the ability to form a variety of secondary structures that can interfere with normal cellular processes, and many of these structures have been associated with neurological diseases and cancer. Secondary structure-forming sequences are often found at chromosomal fragile sites, which are hotspots for sister chromatid exchange, chromosomal translocations, and deletions. Structures formed at fragile sites can lead to instability by disrupting normal cellular processes such as DNA replication and transcription. The instability caused by disruption of replication and transcription can lead to DNA breakage, resulting in gene rearrangements and deletions that cause disease. In this review, we discuss the role of DNA secondary structure at fragile sites in human disease. PMID- 25937819 TI - Students' understanding of "Women-Centred Care Philosophy" in midwifery care through Continuity of Care (CoC) learning model: a quasi-experimental study. AB - BACKGROUND: The philosophy of midwifery education is based on the 'Women-centred care' model, which provides holistic care to women. Continuity of care (CoC) is integral to the concept of holistic women-centred care and fundamental to midwifery practice. The objective of this study was to determine any differences in students' understanding of midwifery care philosophy between students who underwent the CoC learning model and those who underwent the fragmented care learning model. METHOD: We used a quasi-experiment design. This study was conducted by all final year midwifery students at two schools of midwifery in Indonesia. Fifty four students from one school attended 6 months of clinical training using the CoC learning model. The control group was comprised of 52 students from the other school. These students used the conventional clinical training model (the fragmented care learning model). The independent T-test using SPSS was used to analyse the differences between the two groups of students in terms of understanding midwifey care philosophy in five aspects (personalized, holistic, partnership, collaborative, and evidence-based care). RESULTS: There were no significant differences between the groups before interventon. There were significant differences between the two groups after clinical training (p < 0.01). The mean post-clinical score of students using all five aspects of the CoC clinical learning model (15.96) was higher than that of the students in the control group (10.65). The CoC clinical learning model was shown to be a unique learning opportunity for students to understand the philosophy of midwifery. Being aligned with midwifery patients and developing effective relationships with them offered the students a unique view of midwifery practice. This also promoted an increased understanding of the philosophy of women-centred care. Zero maternal mortality rate was found in the experiment group. CONCLUSION: The results of this study suggest that clinical trainingwith a CoC learning model is more likely to increase students' understanding of midwifery care philosophy. This in turn improves the quality ofclinical care, thereby enhancing overall health benefits for women. PMID- 25937818 TI - Health promotion in schools: a multi-method evaluation of an Australian School Youth Health Nurse Program. AB - BACKGROUND: Health promotion provides a key opportunity to empower young people to make informed choices regarding key health-related behaviours such as tobacco and alcohol use, sexual practices, dietary choices and physical activity. This paper describes the evaluation of a pilot School Youth Health Nurse (SYHN) Program, which aims to integrate a Registered Nurse into school communities to deliver health promotion through group education and individual sessions. METHODS: The evaluation was guided by the RE-AIM (reach, effectiveness, adoption, implementation, maintenance) framework. The objectives were to explore: 1) whether the Program was accessible to the high school students; 2) the impacts of the Program on key stakeholders; 3) which factors affected adoption of the Program; 4) whether implementation was consistent with the Program intent; and 5) the long-term sustainability of the Program. Research included retrospective analysis of Program records, administration of a survey of student experiences and interviews with 38 stakeholders. RESULTS: This evaluation provided evidence that the SYHN Program is reaching students in need, is effective, has been adopted successfully in schools, is being implemented as intended and could be maintained with sustained funding. The nurses deliver an accessible and acceptable primary health care service, focused on health promotion, prevention and early intervention. After some initial uncertainty about the scope and nature of the role, the nurses are a respected source of health information in the schools, consulted on curriculum development and contributing to whole-of-school health activities. CONCLUSIONS: Findings demonstrate that the SYHN model is feasible and acceptable to the students and schools involved in the pilot. The Program provides health promotion and accessible primary health care in the school setting, consistent with the Health Promoting Schools framework. PMID- 25937817 TI - Impact of chronic obstructive pulmonary disease (COPD) in the Asia-Pacific region: the EPIC Asia population-based survey. AB - BACKGROUND: Chronic obstructive pulmonary disease (COPD) is a clinical syndrome encompassing a group of chronic, progressive, and debilitating respiratory conditions, that are characterized by incompletely reversible airflow limitation. Within the Asia-Pacific region, prevalence estimates have been derived using various protocols and study methods, and there is little data on the impact of COPD exacerbations. This study aimed to provide a comprehensive picture of the current prevalence and burden of COPD in this region. METHODS: A population-based survey was conducted in nine Asia-Pacific territories between 01 February 2012 and 16 May 2012. Overall, 112,330 households were screened to identify eligible subjects (aged >=40 years, with a physician diagnosis of COPD, chronic bronchitis or emphysema, or with identifiable symptoms of chronic bronchitis). Out of a sample of 69,279 individuals aged >=40 years, 4,289 subjects with COPD were identified. Data were collected via face-to-face interviews or by fixed-line telephone, using a structured questionnaire. A total of 1,841 completed questionnaires were analyzed. RESULTS: The overall estimated COPD prevalence was 6.2%, with 19.1% of subjects having severe COPD. In the 12 months prior to the survey, nearly half of all subjects (46%) had experienced exacerbations, and 19% had been hospitalized as a result of their condition. When subjects were asked about the impact of their condition on employment, 23% said their condition kept them from working, and 42% felt that their condition limited their ability to work or their activities. Of those who reported taking prescription drugs, 20% did not know the name of the drugs they were taking. Prescription of oral corticosteroids was common, with 44% of subjects having used these during the previous year to manage their respiratory symptoms; in contrast, inhaler use was low (25%). Only 37% of subjects had taken a lung function test, and the majority (89%) of those tested did not know their test results. CONCLUSIONS: Across the Asia-Pacific territories surveyed, the prevalence of COPD is high, indicating a substantial socioeconomic burden. Our findings suggest that there is considerable room for improvement in the management of COPD, and highlight a need to enhance patient and physician education in the region. PMID- 25937820 TI - A general review of major global coagulation assays: thrombelastography, thrombin generation test and clot waveform analysis. AB - Thrombosis and hemorrhage are major contributors to morbidity and mortality. The traditional laboratory tests do not supply enough information to diagnose and treat patients timely and according to their phenotype. Global hemostasis tests might improve this circumstance. The viscoelastic tests (ROTEM/TEG) demonstrated to ameliorate treatment of acute hemorrhage in terms of decreased amount of transfusion and lowered costs. Thrombin generation measurement is indicative for thrombosis and might also become an important tool in managing hemorrhage. While the clot waveform analysis is less well known it could be of worth in staging sepsis patients, early detection of DIC and also in diagnosis and treatment monitoring of hemophiliac patients. Although in different degree all three methods still need more background, standardization and acceptance before a wide clinical application. PMID- 25937822 TI - Hybrid Steered Molecular Dynamics Approach to Computing Absolute Binding Free Energy of Ligand-Protein Complexes: A Brute Force Approach That Is Fast and Accurate. AB - Computing the free energy of binding a ligand to a protein is a difficult task of essential importance for which purpose various theoretical/computational approaches have been pursued. In this paper, we develop a hybrid steered molecular dynamics (hSMD) method capable of resolving one ligand-protein complex within a few wall-clock days with high enough accuracy to compare with the experimental data. This hSMD approach is based on the relationship between the binding affinity and the potential of mean force (PMF) in the established literature. It involves simultaneously steering n (n = 1, 2, 3, ...) centers of mass of n selected segments of the ligand using n springs of infinite stiffness. Steering the ligand from a single initial state chosen from the bound state ensemble to the corresponding dissociated state, disallowing any fluctuations of the pulling centers along the way, one can determine a 3n-dimensional PMF curve connecting the two states by sampling a small number of forward and reverse pulling paths. This PMF constitutes a large but not the sole contribution to the binding free energy. Two other contributors are (1) the partial partition function containing the equilibrium fluctuations of the ligand at the binding site and the deviation of the initial state from the PMF minimum and (2) the partial partition function containing rotation and fluctuations of the ligand around one of the pulling centers that is fixed at a position far from the protein. We implement this hSMD approach for two ligand-protein complexes whose structures were determined and whose binding affinities were measured experimentally: caprylic acid binding to bovine beta-lactoglobulin and glutathione binding to Schistosoma japonicum glutathione S-transferase tyrosine 7 to phenylalanine mutant. Our computed binding affinities agree with the experimental data within a factor of 1.5. The total time of computation for these two all-atom model systems (consisting of 96K and 114K atoms, respectively) was less than one wall-clock week using 512 cores (32 Xeon E5-2680 processors). PMID- 25937821 TI - Pathways from Racial Discrimination to Multiple Sexual Partners Among Male African American Adolescents. AB - African American male adolescents' involvement with multiple sexual partners has important implications for public health as well as for their development of ideas regarding masculinity and sexuality. The purpose of this study was to test hypotheses regarding the pathways through which racial discrimination affects African American adolescents' involvement with multiple sexual partners. We hypothesized that racial discrimination would engender psychological distress, which would promote attitudes and peer affiliations conducive to multiple sexual partnerships. The study also examined the protective influence of parenting practices in buffering the influence of contextual stressors. Participants were 221 African American male youth who provided data at ages 16 and 18; their parents provided data on family socioeconomic disadvantages. Of these young men, 18.5% reported having 3 or more sexual partners during the past 3 months. Structural equation models indicated that racial discrimination contributed to sexual activity with multiple partners by inducing psychological distress, which in turn affected attitudes and peer affiliations conducive to multiple partners. The experience of protective parenting, which included racial socialization, closeness and harmony in parent-child relationships, and parental monitoring, buffered the influence of racial discrimination on psychological distress. These findings suggest targets for prevention programming and underscore the importance of efforts to reduce young men's experience with racial discrimination. PMID- 25937823 TI - Tensor-based Multi-view Feature Selection with Applications to Brain Diseases. AB - In the era of big data, we can easily access information from multiple views which may be obtained from different sources or feature subsets. Generally, different views provide complementary information for learning tasks. Thus, multi view learning can facilitate the learning process and is prevalent in a wide range of application domains. For example, in medical science, measurements from a series of medical examinations are documented for each subject, including clinical, imaging, immunologic, serologic and cognitive measures which are obtained from multiple sources. Specifically, for brain diagnosis, we can have different quantitative analysis which can be seen as different feature subsets of a subject. It is desirable to combine all these features in an effective way for disease diagnosis. However, some measurements from less relevant medical examinations can introduce irrelevant information which can even be exaggerated after view combinations. Feature selection should therefore be incorporated in the process of multi-view learning. In this paper, we explore tensor product to bring different views together in a joint space, and present a dual method of tensor-based multi-view feature selection (dual-Tmfs) based on the idea of support vector machine recursive feature elimination. Experiments conducted on datasets derived from neurological disorder demonstrate the features selected by our proposed method yield better classification performance and are relevant to disease diagnosis. PMID- 25937824 TI - A retrospective analysis of the association between tobacco smoking and deaths from respiratory and cardiovascular diseases in the Kassena-Nankana districts of Northern Ghana. AB - BACKGROUND: Tobacco use is a public health problem, responsible for approximately six million deaths annually worldwide. It is a risk factor for many diseases including cancers, respiratory and cardiovascular diseases. In low-and middle income countries, respiratory and cardiovascular diseases are important causes of death. Tobacco use is prevalent in Ghana, but no study had examined the relationship between tobacco use and deaths from respiratory and cardiovascular diseases in the Upper East Region of Northern Ghana. Hence the paper assessed the association between tobacco use and deaths from respiratory and cardiovascular diseases in that region. METHODS: The study used verbal autopsy data collected from the Kassena-Nankana East and West districts of the Upper East Region of Northern Ghana. Data from deceased individuals aged 15 to 59 years whose deaths occurred between January 1, 2004 and December 31, 2011 and with a known cause as well as smoking status were analyzed. Two binary outcome variables were generated from the cause of death data; whether an individual died from respiratory diseases or not, and from cardiovascular diseases or not. Multiple logistic regression models were used to assess the relationship between tobacco use and deaths from respiratory and cardiovascular diseases. RESULTS: Out of 3,492 deaths with a known cause of death and smoking status, a third of them smoked. About 16.6% of smokers and 8.1% of non-smokers died from respiratory diseases. Approximately, 10.7% of smokers died from cardiovascular diseases compared to 10.6% of non-smokers. In multivariate analyses, individuals with a history of smoking had two-fold increased odds [OR=2.18, 95% CI (1.6-2.9)] of dying from respiratory diseases. Besides, the number of years of smoking as well as the frequency of smoking is significantly associated with deaths from respiratory diseases. No association existed between tobacco use and deaths from cardiovascular diseases. CONCLUSIONS: Within our study we identified a strong relationship between tobacco use and deaths from respiratory diseases, but not an association with deaths from cardiovascular diseases. Our findings highlight the need to make appropriate health interventions to control tobacco use and thus help reduce premature deaths from respiratory and other tobacco linked diseases. PMID- 25937825 TI - Nutritional status and its association with quality of life among people living with HIV attending public anti-retroviral therapy sites of Kathmandu Valley, Nepal. AB - BACKGROUND: Little evidence exists on the connections between nutrition, diet intake, and quality of life (QoL) among people living with HIV (PLHIV). The study aimed to estimate the prevalence of under-nutrition among PLHIV in Nepal, and identify risk factors and assess correlations with PLHIVs' QoL and nutritional status. METHODS: This quantitative cross-sectional study used Body Mass Index (BMI) as an indicator for nutritional status, and additional information on opportunistic infections (OIs), CD4 count, and World Health Organization (WHO) clinical staging was collected from medical records. Participants were asked to complete surveys on food security and QoL. Descriptive analysis was used to estimate the prevalence of under nutrition. To assess associations between nutrition status and independent variables, bivariate and multivariate analysis was completed. Spearman's rank correlation test was used to assess the association between nutritional status and QoL. RESULTS: One in five PLHIVs was found to be under nourished (BMI <18.5 kg/m(2)). Illiteracy, residence in care homes, CD4 cells count <350 cells/mm(3), OIs, and illness at WHO clinical stages III and IV were found to be significant predictors of under nutrition. BMI was significantly correlated with three domains of QoL (psychological, social and environmental). CONCLUSION: Nutrition interventions should form an integral part of HIV care programs. Understanding the presence of OI, decline in CD4 count, and advancing WHO clinical stages as risk factors can be helpful in preventing under nutrition from developing. Longitudinal research is necessary to further explicate associations between nutritional status and QoL. PMID- 25937826 TI - Hyperspectral phenotyping on the microscopic scale: towards automated characterization of plant-pathogen interactions. AB - BACKGROUND: The detection and characterization of resistance reactions of crop plants against fungal pathogens are essential to select resistant genotypes. In breeding practice phenotyping of plant genotypes is realized by time consuming and expensive visual rating. In this context hyperspectral imaging (HSI) is a promising non-invasive sensor technique in order to accelerate and to automate classical phenotyping methods. A hyperspectral microscope was established to determine spectral changes on the leaf and cellular level of barley (Hordeum vulgare) during resistance reactions against powdery mildew (Blumeria graminis f.sp. hordei, isolate K1). Experiments were conducted with near isogenic barley lines of cv. Ingrid, including the susceptible wild type (WT), mildew locus a 12 (Mla12 based resistance) and the resistant mildew locus o 3 (mlo3 based resistance), respectively. The reflection of inoculated and non-inoculated leaves was recorded daily with a hyperspectral linescanner in the visual (400 - 700 nm) and near infrared (700 - 1000 nm) range 3 to 14 days after inoculation. RESULTS: Data analysis showed no significant differences in spectral signatures between non-inoculated genotypes. Barley leaves of the near-isogenic genotypes, inoculated with B. graminis f.sp. hordei differed in the spectral reflectance over time, respectively. The susceptible genotypes (WT, Mla12) showed an increase in reflectance in the visible range according to symptom development. However, the spectral signature of the resistant mlo-genotype did not show significant changes over the experimental period. In addition, a recent data driven approach for automated discovery of disease specific signatures, which is based on a new representation of the data using Simplex Volume Maximization (SiVM) was applied. The automated approach - evaluated in only a fraction of time revealed results similar to the time and labor intensive manually assessed hyperspectral signatures. The new representation determined by SiVM was also used to generate intuitive and easy to interpretable summaries, e.g. fingerprints or traces of hyperspectral dynamics of the different genotypes. CONCLUSION: With this HSI based and data driven phenotyping approach an evaluation of host-pathogen interactions over time and a discrimination of barley genotypes differing in susceptibility to powdery mildew is possible. PMID- 25937827 TI - Selective inhibition of liver X receptor alpha-mediated lipogenesis in primary hepatocytes by licochalcone A. AB - BACKGROUND: Sterol regulatory element binding protein-1c (SREBP-1c) is a regulator of the lipogenic pathway and is transcriptionally activated by liver X receptor alpha (LXRalpha). This study aims to investigate phytochemicals inhibiting the autonomous transactivity of LXRalpha with potentials as SREBP-1c inhibitors. Licochalcone A (LicA) is a flavonoid isolated from licorice root of Glycyrrhiza plant. METHODS: The effects of 238 natural chemicals on autonomous transactivity of LXRalpha were determined by the Gal4-TK-luciferase reporter system. The inclusion criteria for chemical selection was significant (P < 0.05) inhibition of autonomous transactivity of LXRalpha from three independent experiments. Transcript levels of mouse primary hepatocytes were measured by conventional or quantitative RT-PCR. Luciferase assay was used to assess synthetic or natural promoter activities of LXRalpha target genes. The effect of LicA on lipogenic activity was evaluated by measuring cellular triglycerides in mouse primary hepatocytes. The recruitment of RNA polymerase II to the LXR response element (LXRE) region was examined by chromatin immunoprecipitation. RESULTS: Among 238 natural compounds, LicA considerably inhibited the autonomous transactivity of LXRalpha and decreased the LXRalpha-dependent expression of SREBP-1c. LicA inhibited not only LXRalpha-dependent activation of the synthetic LXRE promoter but also that of the natural SREBP-1c promoter. As a consequence, LicA reduced the LXRalpha agonist-stimulated transcription of several lipogenic genes. Furthermore, LXRalpha-dependent hepatic lipid accumulation was repressed by LicA in mouse primary hepatocytes. Interestingly, the LXRalpha-dependent activation of ATP-binding cassette transporter A1 (ABCA1) and ATP-binding cassette transporter G1 (ABCG1), other LXR target genes involved in reverse cholesterol transport (RCT), was not inhibited by LicA. LicA hindered the recruitment of RNA polymerase II to the LXRE of the SREBP-1c gene, but not of the ABCA1 gene. CONCLUSIONS: LicA is a selective inhibitor of LXRalpha, repressing lipogenic LXRalpha target genes but not RCT-related LXRalpha target genes. PMID- 25937828 TI - An experimental study of the effect of pre-operative administration of cilostazol on random skin flap survival in rats: double blinded randomized controlled trial. AB - BACKGROUND: Insufficient arterial blood flow is the one cause of flap necrosis. Cilostazol is an inhibitor of phosphodiesterase III and increases cyclic AMP level in vascular smooth muscle cell causing vasodilation. Therefore, effect of cilostazol is expected to improve the viability of the flap. METHODS: Double blinded randomized controlled trial was conducted. The study was to compare the survival of dorsal rat flaps between preoperative cilostazol supplemented diet and regular diet. The flap survival area was measured using PixArea Image software on post operative day 1,3,5 and 7. Fluorescein injection was performed to evaluate the exactly area of flap survival on postoperative day 7 and morphology of arterioles and venules were examined by histopathologic examination. RESULTS: A statistical significance was found in the percentage of area of flap survival between cilostazol supplemented diet and control group on postoperative day 3, 5 and 7 (p < 0.05). Fluorescein injection showed the higher area of flap survival in cilostazol group than the control group (p < 0.05). Histopathologic examination showed dilation of vessels in the cilostazol group. CONCLUSION: Preoperative cilostazol in rats can enhance skin flap survival. PMID- 25937829 TI - The Autonomy-Connection Challenge in Adolescent Peer Relationships. AB - The world of peers presents a unique developmental challenge to adolescents-one that is likely to be linked to prior experiences within the family, affected by concurrent experiences with adults outside the family, and predictive of future mental and physical health. To negotiate relationships with peers successfully, adolescents must manage the challenge of connecting with peers while establishing autonomy regarding peer influences. Both the nature of this challenge and how it is handled are linked closely to the ways adolescents are treated by the adults in their lives. Adolescents' capacities for autonomy and connection can be developed both in the family and in interventions that engage youth with adults outside the family, suggesting a substantial role for adults in easing adolescents' peer challenges. PMID- 25937830 TI - Protecting the Health and Safety of Cell and Tissue Donors. AB - Centers involved with collecting the starting material for cell and tissue therapies are obligated to protect the recipient's and donor's health and safety. All donors face risks during and after the collection which can be minimized by prescreening donors and excluding those that the collection would place at increased risk of physical harm. Another important part of protecting donors is the use of appropriate collection facilities. Donor risk can also be reduced by using specially designed collection devices and ancillary equipment, using only trained collection staff and limiting the volume or quantity of biologic material collected. Donors should be monitored during and after the collection for adverse events, and should adverse events occur, they should be promptly and appropriately treated. Protecting the safety of cell, gene and tissue donors is particularly difficult because of the wide variety in the types of donors and material collected. Biological material used to manufacture cell and tissue therapies is collected from healthy volunteers, matched-related, matched unrelated and autologous donors. Precautions should be taken to ensure that the team of medical professionals evaluating related donors is not the same as the team caring for the transplant recipient in order to be sure that the donor evaluation is not biased and the donor is not coerced into donating. In conclusion, protecting cell and tissue donors requires the use of the practices developed to protect blood donors and the implementation of many other measures. PMID- 25937832 TI - Ionizing radiation induced degradation of diuron in dilute aqueous solution. AB - BACKGROUND: Cutting edge technologies based on Advanced Oxidation Processes (AOP) are under development for the elimination of highly persistent organic molecules (like pesticides) from water matrices. Among them, ionizing radiation treatment represents a promising technology that requires no additives and can be easily adapted to an industrial scale. In these processes several reactive species are produced, mainly powerful oxidizing radicals inducing the degradation. This paper investigates the reactions taking place in dilute aqueous solutions of a hazardous pollutant (diuron) during irradiation. RESULTS: Irradiation of aqueous diuron solutions resulted in effective degradation of the solute mainly due to the reactions of hydroxyl radicals formed in water radiolysis. Hydroxyl radical reacts with diuron with a second order rate constant of (5.8 +/- 0.3) * 10(9) mol(-1) dm(3) s(-1). The main reaction is addition to the ring forming hydroxycyclohexadienyl radical. 30 - 50% of hydroxyl radical reactions induce dechlorination. Reactions with the methyl groups or with the alpha-amino group have low contribution to the transformation. The presence of dissolved oxygen enhances the rate of degradation; one hydroxyl radical on average induces five electron oxidations. The high oxidation rate is attributed to the reaction of some of the primarily formed organic radicals with dissolved O2 and the subsequent reactions of the peroxy radicals. CONCLUSION: The presence of dissolved oxygen is highly important to achieve efficient ionizing radiation induced degradation of diuron in dilute aqueous solution. PMID- 25937831 TI - Diabetes in an emergency context: the Malian case study. AB - BACKGROUND: The World Health Organization proposes 6 building blocks for health systems. These are vulnerable to challenges in many contexts. Findings from a 2004 assessment of the health system in Mali for diabetes care found many barriers were present for the management and care of this condition. Following this assessment different projects to strengthen the healthcare system for people living with diabetes were undertaken by a local NGO, Sante Diabete. CASE DESCRIPTION: In March 2012, following a Coup in Bamako, the northern part of Mali was occupied and cut-off from the rest of the country. This had a major impact on the health system throughout the country. Due to the lack of response by humanitarian actors, Sante Diabete in close collaboration with other local stakeholders developed a humanitarian response for patients with diabetes. This response included evacuation of children with Type 1 diabetes from northern regions to Bamako; supplies of medicines and tools for management of diabetes; and support to people with diabetes who moved from the north to the south of the country. DISCUSSION: It has been argued that diabetes is a good tracer for health systems and based on Sante Diabete's experience in Mali, diabetes could also be used as a tracer in the context of emergencies. One lesson from this experience is that although people with diabetes should be included as a vulnerable part of the population they are not considered as such. Also within a complex emergency different "diabetes populations" may exist with different needs requiring tailored responses, such as internally displaced people versus those still in conflict areas. From Sante Diabete's perspective, the challenge was changing the ways it operated from a development NGO to an emergency NGO. In this role it could rely on its knowledge of the local situation and its function as part of the post-conflict situation. CONCLUSION: The lessons learnt from this experience by Sante Diabete in Mali may be useful for other NGOs and the humanitarian response in general in addressing the challenge of managing non communicable diseases and diabetes in conflict and disaster situations in countries with weak health systems. PMID- 25937833 TI - Social Norms: Do We Love Norms Too Much? AB - Social norms are often cited as the cause of many social phenomena, especially as an explanation for prosocial family and relationship behaviors. And yet maybe we love the idea of social norms too much, as suggested by our failure to subject them to rigorous test. Compared to the detail in social norms theoretical orientations, there is very little detail in tests of normative theories. To provide guidance to researchers who invoke social norms as explanations, we catalog normative orientations that have been proposed to account for consistent patterns of action. We call on researchers to conduct tests of normative theories and the processes such theories assert. PMID- 25937834 TI - Extracting research-quality phenotypes from electronic health records to support precision medicine. AB - The convergence of two rapidly developing technologies - high-throughput genotyping and electronic health records (EHRs) - gives scientists an unprecedented opportunity to utilize routine healthcare data to accelerate genomic discovery. Institutions and healthcare systems have been building EHR linked DNA biobanks to enable such a vision. However, the precise extraction of detailed disease and drug-response phenotype information hidden in EHRs is not an easy task. EHR-based studies have successfully replicated known associations, made new discoveries for diseases and drug response traits, rapidly contributed cases and controls to large meta-analyses, and demonstrated the potential of EHRs for broad-based phenome-wide association studies. In this review, we summarize the advantages and challenges of repurposing EHR data for genetic research. We also highlight recent notable studies and novel approaches to provide an overview of advanced EHR-based phenotyping. PMID- 25937835 TI - Novel method for reducing plasma cholesterol: a ligand replacement therapy. AB - Despite wide use of statins, significant cardiovascular disease risk persists. High-density lipoprotein based therapy has not yielded any positive results in combating this disease. Newer methods to rapidly decrease plasma cholesterol are much needed. While apolipoprotein B is a ligand for low-density lipoprotein receptor, which clears low-density lipoprotein cholesterol in a highly regulated pathway, apolipoprotein E (apoE) is a ligand for clearing other apolipoprotein B containing atherogenic lipoproteins via an alternate receptor pathway, especially the heparin sulfate proteoglycans on the liver cell surface. We describe here a novel method that replaces apoE as a ligand to clear all of the atherogenic lipoproteins via the heparin sulfate proteoglycans pathway. This ligand replacement apoE mimetic peptide therapy, having been designated as an orphan drug by the US FDA, is in clinical trials. PMID- 25937836 TI - Neuroendocrine and metabolic components of dopamine agonist amelioration of metabolic syndrome in SHR rats. AB - BACKGROUND: The hypertensive, pro-inflammatory, obese state is strongly coupled to peripheral and hepatic insulin resistance (in composite termed metabolic syndrome [MS]). Hepatic pro-inflammatory pathways have been demonstrated to initiate or exacerbate hepatic insulin resistance and contribute to fatty liver, a correlate of MS. Previous studies in seasonally obese animals have implicated an important role for circadian phase-dependent increases in hypothalamic dopaminergic tone in the maintenance of the lean, insulin sensitive condition. However, mechanisms driving this dopaminergic effect have not been fully delineated and the impact of such dopaminergic function upon the above mentioned parameters of MS, particularly upon key intra-hepatic regulators of liver inflammation and lipid and glucose metabolism have never been investigated. OBJECTIVE: This study therefore investigated the effects of timed daily administration of bromocriptine, a potent dopamine D2 receptor agonist, on a) ventromedial hypothalamic catecholamine activity, b) MS and c) hepatic protein levels of key regulators of liver inflammation and glucose and lipid metabolism in a non-seasonal model of MS - the hypertensive, obese SHR rat. METHODS: Sixteen week old SHR rats maintained on 14 hour daily photoperiods were treated daily for 16 days with bromocriptine (10 mg/kg, i.p.) or vehicle at 1 hour before light offset and, subsequent to blood pressure recordings on day 14, were then utilized for in vivo microdialysis of ventromedial hypothalamic catecholamine activity or sacrificed for the analyses of MS factors and regulators of hepatic metabolism. Normal Wistar rats served as wild-type controls for hypothalamic activity, body fat levels, and insulin sensitivity. RESULTS: Bromocriptine treatment significantly reduced ventromedial hypothalamic norepinephrine and serotonin levels to the normal range and systolic and diastolic blood pressures, retroperitoneal body fat level, plasma insulin and glucose levels and HOMA-IR relative to vehicle treated SHR controls. Such treatment also reduced plasma levels of C-reactive protein, leptin, and norepinephrine and increased that of plasma adiponectin significantly relative to SHR controls. Finally, bromocriptine treatment significantly reduced hepatic levels of several pro-inflammatory pathway proteins and of the master transcriptional activators of lipogenesis, gluconeogenesis, and free fatty acid oxidation versus control SHR rats. CONCLUSION: These findings indicate that in SHR rats, timed daily dopamine agonist treatment improves hypothalamic and neuroendocrine pathologies associated with MS and such neuroendocrine events are coupled to a transformation of liver metabolism potentiating a reduction of elevated lipogenic and gluconeogenic capacity. This liver effect may be driven in part by concurrent reductions in hyperinsulinemia and sympathetic tone as well as by reductions in intra-hepatic inflammation. PMID- 25937837 TI - Melatonin supplementation to treat the metabolic syndrome: a randomized controlled trial. AB - BACKGROUND: Supplemental melatonin may ameliorate metabolic syndrome (MetS) components, but data from placebo-controlled trials are lacking. METHODS: We conducted a double-blind, placebo-controlled, crossover, Phase II randomized pilot clinical trial to estimate the effects of melatonin supplementation on MetS components and the overall prevalence of MetS. We randomized 39 subjects with MetS to receive 8.0 mg oral melatonin or matching placebo nightly for 10 weeks. After a 6-week washout, subjects received the other treatment for 10 more weeks. We measured waist circumference, triglycerides, HDL cholesterol, fasting glucose, and blood pressure (BP) in each subject at the beginning and end of both 10-week treatment periods. The primary outcome was the mean 10-week change in each MetS component, and a secondary outcome was the proportion of subjects free from MetS, after melatonin versus placebo. RESULTS: The mean 10-week change for most MetS components favored melatonin over placebo (except fasting glucose): waist circumference -0.9 vs. +1.0 cm (p = 0.15); triglycerides -66.3 vs. -4.2 mg/dL (p = 0.17); HDL cholesterol -0.2 vs. -1.1 mg/dL (p = 0.59); fasting glucose +0.3 vs. -3.1 mg/dL (p = 0.29); systolic BP -2.7 vs. +4.7 mmHg (p = 0.013); and diastolic BP -1.1 vs. +1.1 mmHg (p = 0.24). Freedom from MetS tended to be more common following melatonin versus placebo treatment (after the first 10 weeks, 35.3% vs. 15.0%, p = 0.25; after the second 10 weeks, 45.0% vs. 23.5%, p = 0.30). Melatonin was well-tolerated. CONCLUSIONS: Melatonin supplementation modestly improved most individual MetS components compared with placebo, and tended to increase the proportion of subjects free from MetS after treatment. TRIAL REGISTRATION: NCT01038921, clinicaltrials.gov. PMID- 25937838 TI - Plasma and urine metabolic profiles are reflective of altered beta-oxidation in non-diabetic obese subjects and patients with type 2 diabetes mellitus. AB - OBJECTIVES: The two primary pathophysiological characteristics of patients with type 2 diabetes mellitus (T2DM) are insulin resistance (IR) and beta cell dysfunction. It has been proposed that the development of IR is secondary to the accumulation of triacylglycerols and fatty acids in the muscle and liver, which is in turn thought to be secondary to an enzymatic defect in mitochondrial beta oxidation. The purpose of the present study was to analyze the molecules of intermediary metabolism to determine if an alteration in mitochondrial function exists in T2DM patients and, if so, to determine whether this alteration is caused by excess nutrients or an enzymatic defect. DESIGN AND METHODS: Seventy seven subjects were recruited and divided into four groups (21 T2DM patients, 17 non-diabetic overweight/obese subjects, 20 offspring of T2DM patients, and 19 healthy subjects). Anthropometric parameters were determined by air plethysmography, and biochemical and metabolic parameters were measured, including 31 acylcarnitines (ACs) and 13 amino acids quantified by MS/MS and 67 organic acids measured by GC/MS. RESULTS: Patients with T2DM showed elevation of short-chain ACs (C2, C4), a glycogenic amino acid (valine), a glycogenic and ketogenic amino acid (tyrosine), and a ketogenic amino acid (leucine) as well as altered excretion of dicarboxylic acids. T2DM offspring with abnormal glucose tolerance test GTT showed increased levels of C16. Subjects in the obese group who were dysglycemic also showed altered urinary excretion of dicarboxylic acids and lower levels of a long-chain AC (C14:2). CONCLUSIONS: These results suggest that mitochondrial beta-oxidation is altered in T2DM patients and that the alteration is most likely caused by nutrient overload through a different pathway from that observed in obese subjects. PMID- 25937839 TI - Insulin resistance and associated factors in patients with Type 1 Diabetes. AB - OBJECTIVE: To assess the presence of insulin resistance (IR) in patients with type 1 diabetes (T1DM) according to the estimated glucose disposal rate formula (eGDR) and the insulin sensitivity score (ISS) and to estimate the correlation between these two measures and identify the clinical and laboratory markers related to IR. RESEARCH DESIGN AND METHODS: Cross-sectional study of adults with T1DM (n = 135). The results of the formulas that estimate IR were separated into quartiles and correlated with demographic data, clinical characteristics and laboratory parameters. We analyzed the total and regional adiposity by dual energy X-ray absorptiometry and skin fold thickness measurements. RESULTS: Two thirds of the patients were overweight or obese. A moderate correlation was found between eGDR and ISS (r = 0.612). The results of both formulas were positively correlated with BMI (r = -0.373 eGDR and r = -0.721 ISS), thoracic-abdominal fat (r = -0.484 eGDR and r = -0.758 ISS), waist/height ratio (r = -0.537 eGDR and r = -0.779 ISS), subscapular skinfold (mm) (r = -0.356 eGDR and r = -0.569 ISS), total dose insulin IU/lean mass (kg) (r = -0.279 eGDR and r = -0.398 ISS), age (years) (r = -0.495 eGDR and r = -0.190 ISS) and diabetes duration (years) (r = 0.428 eGDR and r = -0.187 ISS). A moderate agreement (Kappa 0.226) was observed between the 1st quartile of results determined by the formulas in 10.4% of the patients, but the 4th quartile presented a strong correlation (Kappa 0.679). The individuals with IR that were classified in the 1st quartile by the ISS formula had a higher chance of presenting with acanthosis nigricans (OR = 5.58, 95% CI =1.46-21.3). CONCLUSIONS: The correlations found in this study indicate the possibility of using clinical and laboratory data to estimate IR in patients with TDM1. The detection of IR in T1DM patients may allow early intervention and possibly impact on future diabetes complications. PMID- 25937840 TI - Total testosterone and neuropsychiatric symptoms in elderly men with Alzheimer's disease. AB - INTRODUCTION: There has been a significant increase in the use of testosterone in aging men, but little investigation into its impact on men with Alzheimer's disease (AD). The findings of the few studies that have been done are inconsistent. In the present study, we investigated the relationship between total testosterone (TT) and neuropsychiatric symptoms (NPS) in a well characterized sample of elderly men with mild to moderate AD. METHODS: The sample, which was drawn from the Texas Alzheimer's Research Care Consortium Longitudinal Research Cohort, included 87 men who met the criteria for mild to moderate AD. The occurrence of NPS was gathered from caregivers and/or family members with the Neuropsychiatric Inventory. TT was analyzed, and the sample was divided into a low-testosterone group (TT <=2.5 ng/ml; n = 44) and a borderline/normal group (TT >=2.6 ng/ml; n = 43). RESULTS: TT was correlated with symptoms of hallucinations, delusions, agitation, irritability and motor activity. The borderline/normal group was significantly more likely to have hallucinations (odds ratio (OR) = 5.56), delusions (OR = 3.87), motor activity (OR = 3.13) and irritability (OR = 2.77) than the low-testosterone group. Health status and apolipoprotein E epsilon4 status were not significant factors. CONCLUSIONS: The findings of the present study have implications for the use of testosterone replacement therapy in men with AD or the prodromal stage of the disease. PMID- 25937841 TI - FASN and CD36 predict survival in rituximab-treated diffuse large B-cell lymphoma. AB - Diffuse large B-cell lymphoma is the most common lymphoid malignancy, as it accounts for approximately one third of all patient cases of non-Hodgkin's lymphoma. Patients with diffuse large B-cell lymphoma have markedly different treatment outcomes, suggesting a need for reliable prognostic factors and novel therapeutic approaches. De novo fatty acid synthesis is an important metabolic driver of tumor in multiple malignancies. In this retrospective study, we analyzed expression of fatty acid synthase (a key enzyme in de novo fatty acid synthesis), Spot 14 (thyroid hormone responsive Spot 14, a nuclear protein that promotes expression of genes involved in fatty acid synthesis), and CD36 (the cell surface channel for exogenous fatty acid uptake) in patients with diffuse large B-cell lymphoma and their clinical significance. We observed that overexpression of fatty acid synthase is negatively associated with overall survival (p=0.001) and progression-free period (p=0.004) in patients with diffuse large B-cell lymphoma. Multivariate analysis showed that fatty acid synthase overexpression is an independent prognostic marker of aggressive clinical course. For the first time, we report CD36 as an independent protective factor in patients treated with rituximab. Thus, fatty acid synthase and CD36 expression may serve as prognostic markers to predict response to treatment and survival in diffuse large B-cell lymphoma patients. Fatty acid synthase may also be a potential therapeutic target in lymphoid malignancies. PMID- 25937842 TI - Hippocampal glutamate-glutamine (Glx) in adults with Down syndrome: a preliminary study using in vivo proton magnetic resonance spectroscopy ((1)H MRS). AB - BACKGROUND: Down syndrome (DS), or trisomy 21, is one of the most common autosomal mutations. People with DS have intellectual disability (ID) and are at significantly increased risk of developing Alzheimer's disease (AD). The biological associates of both ID and AD in DS are poorly understood, but glutamate has been proposed to play a key role. In non-DS populations, glutamate is essential to learning and memory and glutamate-mediated excitotoxicity has been implicated in AD. However, the concentration of hippocampal glutamate in DS individuals with and without dementia has not previously been directly investigated. Proton magnetic resonance spectroscopy ((1)H MRS) can be used to measure in vivo the concentrations of glutamate-glutamine (Glx). The objective of the current study was to examine the hippocampal Glx concentration in non demented DS (DS-) and demented DS (DS+) individuals. METHODS: We examined 46 adults with DS (35 without dementia and 11 with dementia) and 39 healthy controls (HC) using (1)H MRS and measured their hippocampal Glx concentrations. RESULTS: There was no significant difference in the hippocampal Glx concentration between DS+ and DS-, or between either of the DS groups and the healthy controls. Also, within DS, there was no significant correlation between hippocampal Glx concentration and measures of overall cognitive ability. Last, a sample size calculation based on the effect sizes from this study showed that it would have required 6,257 participants to provide 80% power to detect a significant difference between the groups which would indicate that there is a very low likelihood of a type 2 error accounting for the findings in this study. CONCLUSIONS: Individuals with DS do not have clinically detectable differences in hippocampal Glx concentration. Other pathophysiological processes likely account for ID and AD in people with DS. PMID- 25937843 TI - Event-related potentials to repeated speech in 9-month-old infants at risk for autism spectrum disorder. AB - BACKGROUND: Atypical neural responses to repeated auditory and linguistic stimuli have been reported both in individuals with autism spectrum disorder (ASD) and their first-degree relatives. Recent work suggests that the younger siblings of children with ASD have atypical event-related potentials (ERPs) to repeated tones at 9 months of age; however, the functional significance is unclear, and it is unknown whether this atypicality is also present in response to linguistic stimuli. METHODS: We analyzed ERPs to repetitive and deviant consonant-vowel stimuli at 9 months in 35 unaffected high-risk-for-autism (HRA) infant siblings of children with ASD and 45 low-risk control (LRC) infants. We examined a positive component, the P150, over frontal and central electrode sites and investigated the relationships between this component and later behavior. RESULTS: Over frontal electrodes, HRA infants had larger-amplitude ERPs to repetitions of the standard than LRC infants, whereas ERPs to the deviant did not differ between HRA and LRC infants. Furthermore, for HRA infants, the amplitude of ERPs to the standards was positively correlated with later language ability. CONCLUSIONS: Our work suggests that atypical ERPs to repeated speech during infancy are a possible endophenotype of ASD but that this atypicality is associated with beneficial, rather than disordered, language development. Potential mechanisms driving these relationships and implications for development are discussed. PMID- 25937844 TI - A cross-sectional analysis of orienting of visuospatial attention in child and adult carriers of the fragile X premutation. AB - BACKGROUND: Fragile X premutation carriers (fXPCs) have an expansion of 55-200 CGG repeats in the FMR1 gene. Male fXPCs are at risk for developing a neurodegenerative motor disorder (fragile X-associated tremor/ataxia syndrome (FXTAS)) often accompanied by cognitive decline. Several broad domains are implicated as core systems of dysfunction in fXPCs, including perceptual processing of spatial information, orienting of attention to space, and inhibiting attention to irrelevant distractors. We tested whether orienting of spatial attention is impaired in fXPCs. METHODS: Participants were fXPCs or healthy controls (HCs) asymptomatic for FXTAS. In experiment 1, they were male and female children and adults (aged 7-45 years). They oriented attention in response to volitional (endogenous) and reflexive (exogenous) cues. In experiment 2, the participants were men (aged 18-48 years). They oriented attention in an endogenous cueing task that manipulated the amount of information in the cue. RESULTS: In women, fXPCs exhibited slower reaction times than HCs in both the endogenous and exogenous conditions. In men, fXPCs exhibited slower reaction times than HCs in the exogenous condition and in the challenging endogenous cueing task with probabilistic cues. In children, fXPCs did not differ from HCs. CONCLUSIONS: Because adult fXPCs were slower even when controlling for psychomotor speed, results support the interpretation that a core dysfunction in fXPCs is the allocation of spatial attention, while perceptual processing and attention orienting are intact. These findings indicate the importance of considering age and sex when interpreting and generalizing studies of fXPCs. PMID- 25937845 TI - Self-Assembly of Amyloid Fibrils That Display Active Enzymes. AB - Enzyme immobilization is an important strategy to enhance the stability and recoverability of enzymes and to facilitate the separation of enzymes from reaction products. However, enzyme purification followed by separate chemical steps to allow immobilization on a solid support reduces the efficiency and yield of the active enzyme. Here we describe polypeptide constructs that self-assemble spontaneously into nanofibrils with fused active enzyme subunits displayed on the amyloid fibril surface. We measured the steady-state kinetic parameters for the appended enzymes in situ within fibrils and compare these with the identical protein constructs in solution. Finally, we demonstrated that the fibrils can be recycled and reused in functional assays both in conventional batch processes and in a continuous-flow microreactor. PMID- 25937846 TI - Catalytic Properties of Unsupported Palladium Nanoparticle Surfaces Capped with Small Organic Ligands. AB - This Minireview summarizes a variety of intriguing catalytic studies accomplished by employing unsupported, either solubilized or freely mobilized, and small organic ligand-capped palladium nanoparticles as catalysts. Small organic ligands are gaining more attention as nanoparticle stabilizers and alternates to larger organic supports, such as polymers and dendrimers, owing to their tremendous potential for a well-defined system with spatial control in surrounding environments of reactive surfaces. The nanoparticle catalysts are grouped depending on the type of surface stabilizers with reactive head groups, which include thiolate, phosphine, amine, and alkyl azide. Applications for the reactions such as hydrogenation, alkene isomerization, oxidation, and carbon carbon cross coupling reactions are extensively discussed. The systems defined as "ligandless" Pd nanoparticle catalysts and solvent (e.g. ionic liquid)-stabilized Pd nanoparticle catalysts are not discussed in this review. PMID- 25937847 TI - CRAFFT: An Activity Prediction Model based on Bayesian Networks. AB - Recent advances in the areas of pervasive computing, data mining, and machine learning offer unique opportunities to provide health monitoring and assistance for individuals facing difficulties to live independently in their homes. Several components have to work together to provide health monitoring for smart home residents including, but not limited to, activity recognition, activity discovery, activity prediction, and prompting system. Compared to the significant research done to discover and recognize activities, less attention has been given to predict the future activities that the resident is likely to perform. Activity prediction components can play a major role in design of a smart home. For instance, by taking advantage of an activity prediction module, a smart home can learn context-aware rules to prompt individuals to initiate important activities. In this paper, we propose an activity prediction model using Bayesian networks together with a novel two-step inference process to predict both the next activity features and the next activity label. We also propose an approach to predict the start time of the next activity which is based on modeling the relative start time of the predicted activity using the continuous normal distribution and outlier detection. To validate our proposed models, we used real data collected from physical smart environments. PMID- 25937848 TI - Design and Synthesis of Novel Arylketo-containing P1-P3 Linked Macro-cyclic BACE 1 Inhibitors. AB - A series of arylketo-containing P1-P3 linked macrocyclic BACE-1 inhibitors were designed, synthesized, and compared with compounds with a previously known and extensively studied corresponding P2 isophthalamide moiety with the aim to improve on permeability whilst retaining the enzyme- and cell-based activities. Several inhibitors displayed substantial increases in Caco-2 cell-based permeability compared to earlier synthesized inhibitors and notably also with retained activities, showing that this approach might yield BACE-1 inhibitors with improved properties. PMID- 25937849 TI - The Kinematics and Kinetics Analysis of the Lower Extremity in the Landing Phase of a Stop-jump Task. AB - Large number of studies showed that landing with great impact forces may be a risk factor for knee injuries. The purpose of this study was to illustrate the different landing loads to lower extremity of both genders and examine the relationships among selected lower extremity kinematics and kinetics during the landing of a stop-jump task. A total of 35 male and 35 female healthy subjects were recruited in this study. Each subject executed five experiment actions. Lower extremity kinematics and kinetics were synchronously acquired. The comparison of lower extremity kinematics for different genders showed significant difference. The knee and hip maximum flexion angle, peak ground reaction force and peak knee extension moment have significantly decreased during the landing of the stop-jump task among the female subjects. The hip flexion angle at the initial foot contact phase showed significant correlation with peak ground reaction force during landing of the stop-jump task (r=-0.927, p<0.001). The knee flexion angle at the initial foot contact phase had significant correlation with peak ground reaction force and vertical ground reaction forces during landing of the stop-jump task (r=-0.908, p<0.001; r=0.812, P=0.002). A large hip and knee flexion angles at the initial foot contact with the ground did not necessarily reduce the impact force during landing, but active hip and knee flexion motions did. The hip and knee flexion motion of landing was an important technical factor that affects anterior cruciate ligament (ACL) loading during the landing of the stop-jump task. PMID- 25937850 TI - Multi-dimension and Comprehensive Assessment on the Utilizing and Sharing of Regional Large-Scale Scientific Equipment. AB - Based on the data from 30 provincial regions in China, an assessment and empirical analysis was carried out on the utilizing and sharing of the large scale scientific equipment with a comprehensive assessment model established on the three dimensions, namely, equipment, utilization and sharing. The assessment results were interpreted in light of relevant policies. The results showed that on the whole, the overall development level in the provincial regions in eastern and central China is higher than that in western China. This is mostly because of the large gap among the different provincial regions with respect to the equipped level. But in terms of utilizing and sharing, some of the Western provincial regions, such as Ningxia, perform well, which is worthy of our attention. Policy adjustment targeting at the differentiation, elevation of the capacity of the equipment management personnel, perfection of the sharing and cooperation platform, and the promotion of the establishment of open sharing funds, are all important measures to promote the utilization and sharing of the large-scale scientific equipment and to narrow the gap among different regions. PMID- 25937851 TI - Research of amoxicillin microcapsules preparation playing micro-jetting technology. AB - With polylactic-co-glycolic acid(PLGA) as shell material of microcapsule, amoxicillin as the model, poly(vinyl alcohol) and twain as surfactant, amoxicillin-PLGA microcapsules were manufactured using digital micro-jetting technology and a glass nozzle of 40MUm diameter. The influences of the parameters of micro-jetting system on the mean grain size and size distribution of amoxicillin-PLGA microcapsules were studied with single factor analysis and orthogonal experiment method, namely, PLGA solution concentration, driving voltage, jetting frequency, stirrer speed, etc. The optimal result was obtained; the form representation of microcapsule was analyzed as well. The results show that, under certain conditions of experimental drug prescription, driving voltage was proportional to the particle size; jetting frequency and stirrer speed were inversely proportional. When the PLGA concentration for 3%, driving voltage for 80V, the jetting frequency for 10000Hz and the stirrer speed for 750rpm, the particles were in an ideal state with the mean grain size of 60.246MUm, the encapsulation efficiency reached 62.39% and 2.1% for drug loading. PMID- 25937852 TI - Protosemiosis: agency with reduced representation capacity. AB - Life has semiotic nature; and as life forms differ in their complexity, functionality, and adaptability, we assume that forms of semiosis also vary accordingly. Here we propose a criterion to distinguish between the primitive kind of semiosis, which we call "protosemiosis" (following Prodi) from the advanced kind of semiosis, or "eusemiosis". In protosemiosis, agents associate signs directly with actions without considering objects, whereas in eusemiosis, agents associate signs with objects and only then possibly with actions. Protosemiosis started from the origin of life, and eusemiosis started when evolving agents acquired the ability to track and classify objects. Eusemiosis is qualitatively different from protosemiosis because it can not be reduced to a small number of specific signaling pathways. Proto-signs can be classified into proto-icons that signal via single specific interaction, proto-indexes that combine several functions, and proto-symbols that are processed by a universal subagent equipped with a set of heritable adapters. Prefix "proto" is used here to characterize signs at the protosemiotic level. Although objects are not recognized by protosemiotic agents, they can be reliably reconstructed by human observers. In summary, protosemiosis is a primitive kind of semiosis that supports "know-how" without "know-what". Without studying protosemiosis, the biosemiotics theory would be incomplete. PMID- 25937853 TI - Facilitating Intimate Partner Violence Education among Pharmacy Students: What Do Future Pharmacists Want to Know? AB - This paper describes the first step toward creating training tools to improve pharmacy students' and pharmacists' ability to identify intimate partner violence (IPV) among patients and facilitate referrals. The paper's objectives are to evaluate an IPV didactic session adapted for pharmacy students and describe student quantitative and qualitative feedback on the session. Almost 90% of students believed IPV was relevant to their pharmacy careers and that the session improved their ability to recognize IPV. Twenty one percent believed they had encountered a patient they suspected was a victim of IPV. Legal and liability issues, course logistics, skill development, greater specificity and student engagement were themes that emerged. Greater specificity toward pharmacy was recommended to understand the intricacies of legal and professional responsibilities, patient and personal safety risks, and maintaining strong provider/patient relationships. To overcome barriers to screening, assessment and referral, students need opportunities to engage in role-playing and practical application of the knowledge gained. PMID- 25937856 TI - A Real-time D-bar Algorithm for 2-D Electrical Impedance Tomography Data. AB - The aim of this paper is to show the feasibility of the D-bar method for real time 2-D EIT reconstructions. A fast implementation of the D-bar method for reconstructing conductivity changes on a 2-D chest-shaped domain is described. Cross-sectional difference images from the chest of a healthy human subject are presented, demonstrating what can be achieved in real time. The images constitute the first D-bar images from EIT data on a human subject collected on a pairwise current injection system. PMID- 25937855 TI - Germline MUTYH gene mutations are not frequently found in unselected patients with papillary breast carcinoma. AB - MUTYH-associated polyposis (MAP) is an autosomal recessive disease, which predisposes to polyposis and colorectal cancer. There is a trend towards an increased risk of breast cancer in MAP patients, with a remarkable proportion of papillary breast cancers. To determine whether MUTYH mutations are associated with this specific and rare type of breast cancer, 53 unselected patients with papillary breast cancer were analyzed for founder mutations in the MUTYH gene. No germline mutations were identified, indicating that biallelic MUTYH mutations are not a frequent underlying cause for the development of papillary carcinomas of the breast. PMID- 25937857 TI - The Effect of H-bonding and Proton Transfer on the Voltammetry of 2,3,5,6 Tetramethyl-p-phenylenediamine in Acetonitrile. An Unexpectedly Complex Mechanism for a Simple Redox Couple. AB - The voltammetry of 2,3,5,6-tetramethyl-p-phenylenediamine, H2PD, has been studied and compared to that of its isomer N,N,N'N'-tetramethyl-p-phenylenediamine, Me2PD. Both undergo two reversible electron transfer processes in acetonitrile that nominally correspond to 1e- oxidation to the radical cations, Me2PD+ and H2PD+, and a second 1e- oxidation at more positive potentials to the quinonediimine dications, Me2PD2+ and H2PD2+. While the voltammetry of Me2PD agrees with this simple mechanism, that of H2PD does not. The second voltammetric wave is too small. UV/Vis spectroelectrochemical experiments indicate that the second wave does correspond to oxidation of H2PD+ to H2PD2+ in solution. The fact that the second wave is not present at all at the lowest concentrations (5 uM), and that it increases at longer times and higher concentrations, indicates that H2PD+ is not the initial solution product of the first oxidation. A number of lines of evidence suggest instead that the initial product is a mixed valent, H bonded dimer between one H2PD in the the full reduced, fully protonated state, H4PD2+, and another in the fully oxidized, fully deprotonated state, PD. A mechanism is proposed in which this dimer is formed on the electrode surface through proton transfer and H-bonding. Once desorbed into solution, it breaks apart via reaction with other H2PD's, to give 2 H2PD+, which is the thermodynamically favored species in solution. PMID- 25937854 TI - 4Ps medicine of the fatty liver: the research model of predictive, preventive, personalized and participatory medicine-recommendations for facing obesity, fatty liver and fibrosis epidemics. AB - Relationship between adipose tissue and fatty liver, and its possible evolution in fibrosis, is supported by clinical and research experience. Given the multifactorial pathogenesis of non-alcoholic fatty liver disease (NAFLD), treatments for various contributory risk factors have been proposed; however, there is no single validated therapy or drug association recommended for all cases which can stand alone. Mechanisms, diagnostics, prevention and treatment of obesity, fatty liver and insulin resistance are displayed along with recommendations and position points. Evidences and practice can get sustainable and cost-benefit valuable outcomes by participatory interventions. These recommendations can be enhanced by comprehensive research projects, addressed to societal issues and innovation, market appeal and industry development, cultural acceptance and sustainability. The basis of participatory medicine is a greater widespread awareness of a condition which is both a disease and an easy documented and inclusive clue for associated diseases and unhealthy lifestyle. This model is suitable for addressing prevention and useful for monitoring improvement, worsening and adherence with non-invasive imaging tools which allow targeted approaches. The latter include health psychology and nutritional and physical exercise prescription expertise disseminated by continuous medical education but, more important, by concrete curricula for training undergraduate and postgraduate students. It is possible and recommended to do it by early formal teaching of ultrasound imaging procedures and of practical lifestyle intervention strategies, including approaches aimed to healthier fashion suggestions. Guidelines and requirements of research project funding calls should be addressed also to NAFLD and allied conditions and should encompass the goal of training by research and the inclusion of participatory medicine topics. A deeper awareness of ethics of competences in health professionals and the articulation of knowledge, expertise and skills of medical doctors, dieticians, health psychologists and sport and physical exercise graduates are the necessary strategy for detectin a suboptimal health status and achieving realistically beneficial lifestyle changes. "The devil has put a penalty on all things we enjoy in life. Either we suffer in health or we suffer in soul or we get fat" (Albert Einstein); the task of medical research and intervention is to make possible to enjoy life also without things that make sufferance in health and souls and which excessively increase body fat. PMID- 25937858 TI - Time-Resolved Fluorescence Anisotropy of Bicyclo[1.1.1]pentane/Tolane-Based Molecular Rods Included in Tris(o-phenylenedioxy)cyclotriphosphazene (TPP). AB - We examine the fluorescence anisotropy of rod-shaped guests held inside the channels of tris(o-phenylenedioxy)cyclotriphosphazene (TPP) host nanocrystals, characterized by powder X-ray diffraction and solid state NMR spectroscopy. We address two issues: (i) are light polarization measurements on an aqueous colloidal solution of TPP nanocrystals meaningful, or is depolarization by scattering excessive? (ii) Can measurements of the rotational mobility of the included guests be performed at low enough loading levels to suppress depolarization by intercrystallite energy transfer? We find that meaningful measurements are possible and demonstrate that the long axis of molecular rods included in TPP channels performs negligible vibrational motion. PMID- 25937859 TI - Role natural killer group 2D-ligand interactions in hepatitis B infection. AB - Hepatitis B virus (HBV) infection is the leading cause of liver disease and hepatocellular carcinoma (HCC) worldwide, in spite of prophylactic vaccination and antiviral treatment modalities. The immunopathogenesis of HBV infection has been intensively studied and is propelled by complex interactions between the virus and the host immune system. Natural killer group 2D (NKG2D) is a well characterized activating receptor, expressed on natural killer (NK) cells, NK T cells and CD8(+) cytotoxic T cells. This receptor is present in both humans and mice and binds to a diverge family of ligands that resemble the MHC-class I molecules. Increasing evidence shows that NKG2D-ligand interactions are critical in the establishment of HBV persistence and the development of liver injury and HCC. The expression of NKG2D ligands depends on the presence of several polymorphisms and is also modulated post-transcriptionally by HBV. While it is known that HBV circumvents host's innate immunity via the NKG2D pathway but the exact mechanisms involved are still elusive. This letter discusses previous accomplishments on the role of NKG2D ligand regulation in the development of chronic HBV, liver injury and HCC. PMID- 25937860 TI - Hepatitis B virus reactivation during immunosuppressive therapy: Appropriate risk stratification. AB - Our understanding of hepatitis B virus (HBV) reactivation during immunosuppresive therapy has increased remarkably during recent years. HBV reactivation in hepatitis B surface antigen (HBsAg)-positive individuals has been well-described in certain immunosuppressive regimens, including therapies containing corticosteroids, anthracyclines, rituximab, antibody to tumor necrosis factor (anti-TNF) and hematopoietic stem cell transplantation (HSCT). HBV reactivation could also occur in HBsAg-negative, antibody to hepatitis B core antigen (anti HBc) positive individuals during therapies containing rituximab, anti-TNF or HSCT.For HBsAg-positive patients, prophylactic antiviral therapy is proven to the effective in preventing HBV reactivation. Recent evidence also demonstrated entecavir to be more effective than lamivudine in this aspect. For HBsAg negative, anti-HBc positive individuals, the risk of reactivations differs with the type of immunosuppression. For rituximab, a prospective study demonstrated the 2-year cumulative risk of reactivation to be 41.5%, but prospective data is still lacking for other immunosupressive regimes. The optimal management in preventing HBV reactivation would involve appropriate risk stratification for different immunosuppressive regimes in both HBsAg-positive and HBsAg-negative, anti-HBc positive individuals. PMID- 25937862 TI - Non-alcoholic fatty liver disease: The diagnosis and management. AB - Non-alcoholic fatty liver disease (NAFLD) is now the most frequent chronic liver disease that occurs across all age groups and is recognized to occur in 14%-30% of the general population, representing a serious and growing clinical problem due to the growing prevalence of obesity and overweight. Histologically, it resembles alcoholic liver injury but occurs in patients who deny significant alcohol consumption. NAFLD encompasses a spectrum of conditions, ranging from benign hepatocellular steatosis to inflammatory nonalcoholic steatohepatitis, fibrosis, and cirrhosis. The majority of hepatocellular lipids are stored as triglycerides, but other lipid metabolites, such as free fatty acids, cholesterol, and phospholipids, may also be present and play a role in disease progression. NAFLD is associated with obesity and insulin resistance and is considered the hepatic manifestation of the metabolic syndrome, a combination of medical conditions including type 2 diabetes mellitus, hypertension, hyperlipidemia, and visceral adiposity. Confirmation of the diagnosis of NAFLD can usually be achieved by imaging studies; however, staging the disease requires a liver biopsy. Current treatment relies on weight loss and exercise, although various insulin-sensitizing agents, antioxidants and medications appear promising. The aim of this review is to highlight the current information regarding epidemiology, diagnosis, and management of NAFLD as well as new information about pathogenesis, diagnosis and management of this disease. PMID- 25937864 TI - Liver cirrhosis in hepatic vena cava syndrome (or membranous obstruction of inferior vena cava). AB - Hepatic vena cava syndrome (HVCS) also known as membranous obstruction of inferior vena cava reported mainly from Asia and Africa is an important cause of hepatic venous outflow obstruction (HVOO) that is complicated by high incidence of liver cirrhosis (LC) and moderate to high incidence of hepatocellular carcinoma (HCC). In the past the disease was considered congenital and was included under Budd-Chiari syndrome (BCS). HVCS is a chronic disease common in developing countries, the onset of which is related to poor hygienic living condition. The initial lesion in the disease is a bacterial infection induced localized thrombophlebitis in hepatic portion of inferior vena cava at the site where hepatic veins open which on resolution transforms into stenosis, membrane or thick obstruction, and is followed by development of cavo-caval collateral anastomosis. The disease is characterized by long asymptomatic period and recurrent acute exacerbations (AE) precipitated by clinical or subclinical bacterial infection. AE is managed with prolonged oral antibiotic. Development of LC and HCC in HVCS is related to the severity and frequency of AEs and not to the duration of the disease or the type or severity of the caval obstruction. HVOO that develops during severe acute stage or AE is a pre-cirrhotic condition. Primary BCS on the other hand is a rare disease related to prothrombotic disorders reported mainly among Caucasians that clinically manifest as acute, subacute disease or as fulminant hepatic failure; and is managed with life-long anticoagulation, porto-systemic shunt/endovascular angioplasty and stent or liver transplantation. As epidemiology, etiology and natural history of HVCS are different from classical BCS, it is here, recognized as a separate disease entity, a third primary cause of HVOO after sinusoidal obstruction syndrome and BCS. Understanding of the natural history has made early diagnosis of HVCS possible. This paper describes epidemiology, natural history and diagnosis of HVCS and discusses the pathogenesis of LC in the disease and mentions distinctive clinical features of HVCS related LC. PMID- 25937861 TI - Hepatitis C virus genetic variability and evolution. AB - Hepatitis C virus (HCV) has infected over 170 million people worldwide and creates a huge disease burden due to chronic, progressive liver disease. HCV is a single-stranded, positive sense, RNA virus, member of the Flaviviridae family. The high error rate of RNA-dependent RNA polymerase and the pressure exerted by the host immune system, has driven the evolution of HCV into 7 different genotypes and more than 67 subtypes. HCV evolves by means of different mechanisms of genetic variation. On the one hand, its high mutation rates generate the production of a large number of different but closely related viral variants during infection, usually referred to as a quasispecies. The great quasispecies variability of HCV has also therapeutic implications since the continuous generation and selection of resistant or fitter variants within the quasispecies spectrum might allow viruses to escape control by antiviral drugs. On the other hand HCV exploits recombination to ensure its survival. This enormous viral diversity together with some host factors has made it difficult to control viral dispersal. Current treatment options involve pegylated interferon-alpha and ribavirin as dual therapy or in combination with a direct-acting antiviral drug, depending on the country. Despite all the efforts put into antiviral therapy studies, eradication of the virus or the development of a preventive vaccine has been unsuccessful so far. This review focuses on current available data reported to date on the genetic mechanisms driving the molecular evolution of HCV populations and its relation with the antiviral therapies designed to control HCV infection. PMID- 25937866 TI - Lamivudine resistance in children with chronic hepatitis B. AB - Currently, although lamivudine (LAM) has a low genetic barrier, only interferon alpha and LAM are available as a first-line treatment in children with chronic hepatitis B (CHB). LAM is a potent inhibitor of hepatitis B virus deoxyribonucleic acid (HBV-DNA) polymerase replication by termination of the proviral HBV-DNA chain. LAM has a good safety and tolerability profile in CHB patients with hepatic decompensation. However, the main disadvantages of this HBV reverse transcriptase inhibitor are: (1) pre-existing covalently closed circular DNA cannot be eradicated by LAM, thus relapse after therapy withdrawal is frequent; and (2) although the longer LAM treatment induced the higher seroconversion rate, the risk of viral resistance increased through the selection of YMDD (tyrosine, methionine, aspartate, aspartate) motif. Insufficient suppression of viral replication leads to the emergence of resistant strains that could result in virological breakthrough which is usually followed by biochemical breakthrough. Mutant strains affects additional resistance and cross resistance, leading to drug resistance in a significant number of CHB patients. In this case, efficacy of more powerful anti-viral agents with higher genetic barrier against development of resistance is diminished. Furthermore, strains that are resistant to LAM could bring about vaccine escape mutants, decreasing the efficacy of HBV vaccine. A more potent drug with a high genetic barrier to resistance needs to be approved as the first-line treatment option for CHB in children. PMID- 25937865 TI - Hepatitis C infection in hemodialysis patients: A review. AB - Hepatitis C virus (HCV)-related liver disease is a significant cause of morbidity and mortality in patients with end-stage renal disease (ESRD) who is treated with dialysis or kidney transplantation (KT). The survival rate for HCV-infected renal transplant recipients is better than that for HCV-infected hemodialysis patients on transplant waiting lists. Early diagnosis and treatment HCV infection prior to KT prevents complications post-transplantation and reduces mortality. In addition to screening for anti-HCV antibodies and detecting HCV RNA, percutaneous liver biopsy is particularly valuable for assessing the stage of liver damage in HCV infected patients, because the stage of fibrosis is important determining optimal treatment for HCV. Studies have been demonstrated that with conventional interferon (IFN) monotherapy or pegylated IFN monotherapy are similar efficacy and safety in HCV-infected hemodialysis patients. Sustained viral responses (SVRs) with these monotherapies have ranged approximately 30% to 40%. Limited reports support the use of IFN and ribavirin combination therapy as antiviral treatment for ESRD patients or patients on hemodialysis. Ribavirin can be started at low dose and careful monitoring for side effects. Patients that show SVR after treatment are strong candidates for KT. It is also generally accepted that ESRD patients with decompensated cirrhosis and portal hypertension should be referred to the liver transplant team for consideration of combined liver-KT. PMID- 25937863 TI - Progress and prospects of engineered sequence-specific DNA modulating technologies for the management of liver diseases. AB - Liver diseases are one of the leading causes of mortality in the world. The hepatic illnesses, which include inherited metabolic disorders, hemophilias and viral hepatitides, are complex and currently difficult to treat. The maturation of gene therapy has heralded new avenues for developing effective intervention for these diseases. DNA modification using gene therapy is now possible and available technology may be exploited to achieve long term therapeutic benefit. The ability to edit DNA sequences specifically is of paramount importance to advance gene therapy for application to liver diseases. Recent development of technologies that allow for this has resulted in rapid advancement of gene therapy to treat several chronic illnesses. Improvements in application of derivatives of zinc finger proteins (ZFPs), transcription activator-like effectors (TALEs), homing endonucleases (HEs) and clustered regularly interspaced palindromic repeats (CRISPR) and CRISPR associated (Cas) systems have been particularly important. These sequence-specific technologies may be used to modify genes permanently and also to alter gene transcription for therapeutic purposes. This review describes progress in development of ZFPs, TALEs, HEs and CRISPR/Cas for application to treating liver diseases. PMID- 25937867 TI - Aetiological factors of Budd-Chiari syndrome in Algeria. AB - AIM: To study the clinical presentation of Budd-Chiari syndrome (BCS) and identify the aetiologies of this disease in Algeria. METHODS: Patients with BCS, hospitalised in our unit from January 2004 until June 2010 were included and the aetiological factors were assessed. Patients presenting a BCS in the setting of advanced-stage cirrhosis or a liver transplantation were excluded from the study. The diagnosis was established when an obstruction of hepatic venous outflow (thrombosis, stenosis or compression) was demonstrated. We diagnosed myeloproliferative disease (MPD) by bone marrow biopsy and V617F JAK2 mutation. Anti-phospholipid syndrome (APLS) was detected by the presence of anticardiolipin antibodies, anti-beta2 glycoprotein antibodies and Lupus anticoagulant. We also detected paroxysmal nocturnal haemoglobinuria (PNH) by flow cytometry. Celiac disease and Behcet disease were systematically investigated in our patients. Hereditary anticoagulant protein deficiencies were also assessed. We tested our patients for the G20210A mutation at Beaujon Hospital. Imaging procedures were performed to determine a local cause of BCS, such as a hydatid cyst or a liver tumour. RESULTS: One hundred and fifteen patients were included. Mean follow up: 32.12 mo. Mean age: 34.41 years, M/F = 0.64. Chronic presentation was frequent: 63.5%. The revealing symptoms for the BCS were ascites (74.8%) and abdominal pain (42.6%). The most common site of thrombosis was the hepatic veins (72.2%). Involvement of the inferior vena cava alone was observed in 3 patients. According to the radiological investigations, BCS was primary in 94.7% of the cases (n = 109) and secondary in 5.2% (n = 6). An aetiology was identified in 77.4% of the patients (n = 89); it was multifactorial in 27% (n = 31). The predominant aetiology of BCS in our patients was a myeloproliferative disease, observed in 34.6% of cases. APLS was found in 21.7% and celiac disease in 11.4%. Other acquired conditions were: PNH (n = 4), systemic disease (n = 6) and inflammatory bowel disease (n = 5). Anticoagulant protein deficiency was diagnosed in 28% of the patients (n = 18), dominated by protein C deficiency (n = 13). Secondary BCS was caused by a compressing hydatic cyst (n = 5) and hepatocellular carcinoma (n = 1). CONCLUSION: The main aetiologic factor of BCS in Algeria is MPD. The frequency of celiac disease justifies its consideration when BCS is diagnosed in our region. PMID- 25937868 TI - Disease control with sunitinib in advanced intrahepatic cholangiocarcinoma resistant to gemcitabine-oxaliplatin chemotherapy. AB - Advanced cholangiocarcinoma is associated with poor prognostic survival and has limited therapeutic options available at present. The importance of angiogenesis and expression of pro-angiogenic factors in intrahepatic forms of cholangiocarcinoma suggest that therapies targeting angiogenesis might be useful for the treatment of this disease. Here we report three cases of patients with advanced intrahepatic cholangiocarcinoma progressive after standard chemotherapy and treated with sunitinib 50 mg/d in 6-wk cycles of 4 wk on treatment followed by 2 wk off treatment (Schedule 4/2). In all three patients, sunitinib treatment was associated with a sustained disease control superior to 4 mo, patients achieving either a partial response or stable disease. A reduction in tumor size and density was observed in all cases, suggesting tumor necrosis as a result of sunitinib treatment in these patients. In addition, sunitinib was generally well tolerated and the occurrence of side effects was managed with standard medical interventions, as required. Our results suggest that sunitinib therapy may be associated with favorable outcomes and tolerability in patients with advanced cholangiocarcinoma. Those observations contributed to launch a prospective phase II multicenter trial investigating sunitinib in advanced intrahepatic cholangiocarcinoma (SUN-CK study; NCT01718327). PMID- 25937869 TI - Deciphering the Finger Prints of Brain Cancer Glioblastoma Multiforme from Four Different Patients by Using Near Infrared Raman Spectroscopy. AB - To explore the effectiveness of Raman spectra to diagnose brain cancer glioblastoma multiforme (GBM), we investigated the Raman spectra of single cell from four different GBM cell lines developed from four different patients and analyzed the spectra. The Raman spectra of brain cancer (GBM) cells were similar in all these cell lines. The results indicate that Raman spectra can offer the experimental basis for the cancer diagnosis and treatment. PMID- 25937870 TI - Ultrathin CdSe in Plasmonic Nanogaps for Enhanced Photocatalytic Water Splitting. AB - Enhanced plasmonic fields are a promising way to increase the efficiency of photocatalytic water splitting. The availability of atomically thin materials opens up completely new opportunities. We report photocatalytic water splitting on ultrathin CdSe nanoplatelets placed in plasmonic nanogaps formed by a flat gold surface and a gold nanoparticle. The extreme field intensity created in these gaps increases the electron-hole pair production in the CdSe nanoplatelets and enhances the plasmon-mediated interfacial electron transfer. Compared to individual nanoparticles commonly used to enhance photocatalytic processes, gap plasmons produce several orders of magnitude higher field enhancement, strongly localized inside the semiconductor sheet thus utilizing the entire photocatalyst efficiently. PMID- 25937871 TI - A comparative analysis of technical efficiency of smallholder tobacco and maize farmers in Tabora, Tanzania. PMID- 25937872 TI - What is the Risk of Having Offspring with Cleft Lip/Palate in Pre-Maternal Obese/Overweight Women When Compared to Pre-Maternal Normal Weight Women? A Systematic Review and Meta-Analysis. AB - OBJECTIVES: The purpose of the study was to identify the risk of orofacial cleft in the offspring of women with pre-maternal obesity/overweight when compared with pre-maternal normal weight women. MATERIAL AND METHODS: MEDLINE and EMBASE were searched from 1980 to July 2014 for cohort, case control and cross sectional studies. BMI were categorized according to WHO recommendation: normal weight (BMI 18.5 - 24.9), overweight (BMI 25 - 29.9) and obese (BMI >= 30). RESULTS: Six studies were identified; three case control studies which were used for the meta analysis and two cross sectional studies and one cohort study. Compared with women of recommended BMI, obese women were at increased odds of pregnancy affected by CLP (OR = 1.16; 95% CI 1, 1.34) and CP (OR = 1.14; 95% CI 0.95, 1.37). Overweight women were also at increased odds of pregnancy affected by CLP (OR = 1.06; 95% CI 0.93, 1.21) but not CP (OR = 0.89; 95% CI 0.75, 1.06). The results of the risk ratios reported in the cross sectional and cohort studies were similar to the results of the meta-analysis. CONCLUSIONS: The results of this study reveal that there is an increased risk of having offspring with orofacial cleft in obese/overweight women. The reason for this association is not known. Although, the risk is small, it is important because of the increasing incidence of obesity. PMID- 25937873 TI - Inferior alveolar nerve lateralization and transposition for dental implant placement. Part I: a systematic review of surgical techniques. AB - OBJECTIVES: The purpose of this first part of a two-part series was to review the literature concerning the indications, contraindications, advantages, disadvantages and surgical techniques of the lateralization and transposition of the inferior alveolar nerve, followed by the placement of an implant in an edentulous atrophic posterior mandible. MATERIAL AND METHODS: A comprehensive review of the current literature was conducted according to the PRISMA guidelines by accessing the NCBI PubMed and PMC database, academic sites and books. The articles were searched from January 1997 to July 2014 and comprised English language articles that included adult patients between 18 and 80 years old with minimal residual bone above the mandibular canal who had undergone inferior alveolar nerve (IAN) repositioning with a minimum 6 months of follow-up. RESULTS: A total of 16 studies were included in this review. Nine were related to IAN transposition, 4 to IAN lateralization and 3 to both transposition and lateralization. Implant treatment results and complications were presented. CONCLUSIONS: Inferior alveolar nerve lateralization and transposition in combination with the installation of dental implants is sometimes the only possible procedure to help patients to obtain a fixed prosthesis, in edentulous atrophic posterior mandibles. With careful pre-operative surgical and prosthetic planning, imaging, and extremely precise surgical technique, this procedure can be successfully used for implant placement in edentulous posterior mandibular segments. PMID- 25937874 TI - Inferior Alveolar Nerve Lateralization and Transposition for Dental Implant Placement. Part II: a Systematic Review of Neurosensory Complications. AB - OBJECTIVES: This article, the second in a two-part series, continues the discussion of inferior alveolar nerve lateralization/transposition for dental implant placement. The aim of this article is to review the scientific literature and clinical reports in order to analyse the neurosensory complications, risks and disadvantages of lateralization/transposition of the inferior alveolar nerve followed by implant placement in an edentulous atrophic posterior mandible. MATERIAL AND METHODS: A comprehensive review of the current literature was conducted according to the PRISMA guidelines by accessing the NCBI PubMed and PMC databases, as well as academic sites and books. The articles were searched from January 1997 to July 2014. Articles in English language, which included adult patients between 18 - 80 years of age who had minimal residual bone above the mandibular canal and had undergone inferior alveolar nerve (IAN) repositioning, with minimum 6 months of follow-up, were included. RESULTS: A total of 21 studies were included in this review. Ten were related to IAN transposition, 7 to IAN lateralization and 4 to both transposition and lateralization. The IAN neurosensory disturbance function was present in most patients (99.47% [376/378]) for 1 to 6 months. In total, 0.53% (2/378) of procedures the disturbances were permanent. CONCLUSIONS: Inferior alveolar nerve repositioning is related to initial transient change in sensation in the majority of cases. The most popular causes of nerve damage are spatula-caused traction in the mucoperiosteal flap, pressure due to severe inflammation or retention of fluid around the nerve and subsequent development of transient ischemia, and mandibular body fracture. PMID- 25937875 TI - The influence of a mandibular advancement plate on polysomnography in different grades of obstructive sleep apnea. AB - OBJECTIVES: The purpose of this study was to investigate the effect of a mandibular advancement device on different grades of obstructive sleep apnea using a relatively simple test for the apnea-hypopnea index to determine if a mandibular device will be effective. MATERIAL AND METHODS: A total of 68 patients with obstructive sleep apnea syndrome (OSAS) including, 31 with mild, 23 with moderate and 14 with severe OSAS were treated with a mandibular advancement device (MAD) and monitored with polysomnography. RESULTS: 25 of the 31 mild, 15 of the 23 moderate and 2 of the 14 severe OSAS patients were cured of their OSAS if a post treatment apnea-hypopnea index of less than 5 is regarded as cured. The odds ratios for success with MAD therapy are 3 for women over men, 14.9 for mild obstructive sleep apnea, 5.42 for moderate obstructive sleep apnea if severe obstructive sleep apnea is assigned an odds ratio of 1. CONCLUSIONS: The use of the apnea-hypopnea index alone is useful in mild and moderate disease to predict the effectiveness of mandibular advancement device. Treatment with a mandibular advancement device is very effective in treating mild and moderate obstructive sleep apnea. Conservative treatment with a mandibular advancement device can be successful in less severe grades of sleep apnea and may be an alternative for non surgical patients with severe obstructive sleep apnea intolerant of Continuous Positive Airway Pressure management. PMID- 25937876 TI - Can MRI Observations Predict Treatment Outcome of Lavage in Patients with Painful TMJ Disc Displacement without Reduction? AB - OBJECTIVES: The purpose of this study was to examine magnetic resonance imaging findings in patients with painful disc displacement without reduction of the temporomandibular joint to determine whether the findings were able to predict treatment outcome of lavage and a control group treated with local anaesthesia without lavage in a short-term: 3-month perspective. MATERIAL AND METHODS: Bilateral magnetic resonance images were taken of 37 patients with the clinical diagnosis of painful disc displacement without reduction. Twenty-three patients received unilateral extra-articular local anaesthetics and 14 unilateral lavage and extra-articular local anaesthetics. The primary treatment outcome defining success was reduction in pain intensity of at least 30% during jaw movement at the 3-month follow-up. RESULTS: Bilateral disc displacement was found in 30 patients. In 31 patients the disc on the treated side was deformed, and bilaterally in 19 patients. Osteoarthritis was observed in 28 patients, and 13 patients had bilateral changes. Thirty patients responded to treatment and 7 did not, with no difference between the two treated groups. In neither the treated nor the contralateral temporomandibular joint did treatment outcome depend on disc diagnosis, disc shape, joint effusion, or osseous diagnoses. Magnetic resonance imaging findings of disc position, disc shape, joint effusion or osseous diagnosis on the treated or contralateral side did not give information of treatment outcome. CONCLUSIONS: Magnetic resonance imaging findings could not predict treatment outcome in patients treated with either local anaesthetics or local anaesthetics and lavage. PMID- 25937877 TI - Cutting efficiency of instruments with different movements: a comparative study. AB - OBJECTIVES: The aim of the present study was to evaluate the cutting efficiency of two new reciprocating instruments, Twisted File Adaptive and WaveOne Primary. MATERIAL AND METHODS: 10 new Twisted File Adaptive (TF Adaptive) (SybronEndo, Glendora, CA, USA) and 10 new WaveOne Primary files (Dentsply Maillefer, Ballaigues, Switzerland) were activated using a torque-controlled motor, respectively TFA motor (SybronEndo, Glendora, CA, USA) and Silver motor (VDW, Munich, Germany). The device used for the cutting test consisted on a mainframe to which a mobile plastic support for the hand-piece is connected and a stainless steel block containing a Plexiglas block against which the cutting efficiency of the instruments was tested. The length of the block cut in 1 minute was measured in a computerized program with a precision of 0.1 mm. Mean and standard deviations of each group were calculated and data were statistically analyzed with one-way ANOVA and Bonferroni t test (P < 0.05). RESULTS: TF Adaptive displayed significantly greater maximum penetration depth than WaveOne Primary (P < 0.05). In fact, TF Adaptive instruments (Group 1) cut the Plexiglas block to a mean depth of 8.7 (SD 0.5) mm, while WaveOne Primary instruments cut the Plexiglas block to a mean depth of 6.4 (SD 0.3) mm. CONCLUSIONS: Twisted File Adaptive instruments demonstrated statistically higher cutting efficiency than WaveOne instruments. PMID- 25937879 TI - Evaluating the Emotion Ontology through use in the self-reporting of emotional responses at an academic conference. AB - BACKGROUND: We evaluate the application of the Emotion Ontology (EM) to the task of self-reporting of emotional experience in the context of audience response to academic presentations at the International Conference on Biomedical Ontology (ICBO). Ontology evaluation is regarded as a difficult task. Types of ontology evaluation range from gauging adherence to some philosophical principles, following some engineering method, to assessing fitness for purpose. The Emotion Ontology (EM) represents emotions and all related affective phenomena, and should enable self-reporting or articulation of emotional states and responses; how do we know if this is the case? Here we use the EM 'in the wild' in order to evaluate the EM's ability to capture people's self-reported emotional responses to a situation through use of the vocabulary provided by the EM. RESULTS: To achieve this evaluation we developed a tool, EmOntoTag, in which audience members were able to capture their self-reported emotional responses to scientific presentations using the vocabulary offered by the EM. We furthermore asked participants using the tool to rate the appropriateness of an EM vocabulary term for capturing their self-assessed emotional response. Participants were also able to suggest improvements to the EM using a free-text feedback facility. Here, we present the data captured and analyse the EM's fitness for purpose in reporting emotional responses to conference talks. CONCLUSIONS: Based on our analysis of this data set, our primary finding is that the audience are able to articulate their emotional response to a talk via the EM, and reporting via the EM ontology is able to draw distinctions between the audience's response to a speaker and between the speakers (or talks) themselves. Thus we can conclude that the vocabulary provided at the leaves of the EM are fit for purpose in this setting. We additionally obtained interesting observations from the experiment as a whole, such as that the majority of emotions captured had positive valence, and the free form feedback supplied new terms for the EM. AVAILABILITY: EmOntoTag can be seen at http://www.bioontology.ch/emontotag; source code can be downloaded from http://emotion-ontology.googlecode.com/svn/trunk/apps/emontotag/and the ontology is available at http://purl.obolibrary.org/obo/MFOEM.owl. PMID- 25937878 TI - The chemistry and pharmacology of privileged pyrroloquinazolines. AB - The advent of next-generation sequencing (NGS) technology has plummeted the cost of whole genome sequencing, which has provided a long list of putative drug targets for a variety of diseases ranging from infectious diseases to cancers. The majority of these drug targets are still awaiting high-quality small molecule ligands to validate their therapeutic potential and track their druggability. Screening compound libraries based on privileged scaffolds is an efficient strategy to identify potential ligands to distinct biological targets. 7H Pyrrolo[3,2-f]quinazoline (PQZ) is a potential privileged heterocyclic scaffold with diverse pharmacological properties. A number of biological targets have been identified for different derivatives of PQZ. This review summarized the synthetic strategies to access the chemical space associated with PQZ and discussed their unique biological profiles. PMID- 25937880 TI - Making species checklists understandable to machines - a shift from relational databases to ontologies. AB - BACKGROUND: The scientific names of plants and animals play a major role in Life Sciences as information is indexed, integrated, and searched using scientific names. The main problem with names is their ambiguous nature, because more than one name may point to the same taxon and multiple taxa may share the same name. In addition, scientific names change over time, which makes them open to various interpretations. Applying machine-understandable semantics to these names enables efficient processing of biological content in information systems. The first step is to use unique persistent identifiers instead of name strings when referring to taxa. The most commonly used identifiers are Life Science Identifiers (LSID), which are traditionally used in relational databases, and more recently HTTP URIs, which are applied on the Semantic Web by Linked Data applications. RESULTS: We introduce two models for expressing taxonomic information in the form of species checklists. First, we show how species checklists are presented in a relational database system using LSIDs. Then, in order to gain a more detailed representation of taxonomic information, we introduce meta-ontology TaxMeOn to model the same content as Semantic Web ontologies where taxa are identified using HTTP URIs. We also explore how changes in scientific names can be managed over time. CONCLUSIONS: The use of HTTP URIs is preferable for presenting the taxonomic information of species checklists. An HTTP URI identifies a taxon and operates as a web address from which additional information about the taxon can be located, unlike LSID. This enables the integration of biological data from different sources on the web using Linked Data principles and prevents the formation of information silos. The Linked Data approach allows a user to assemble information and evaluate the complexity of taxonomical data based on conflicting views of taxonomic classifications. Using HTTP URIs and Semantic Web technologies also facilitate the representation of the semantics of biological data, and in this way, the creation of more "intelligent" biological applications and services. PMID- 25937881 TI - Automatically exposing OpenLifeData via SADI semantic Web Services. AB - BACKGROUND: Two distinct trends are emerging with respect to how data is shared, collected, and analyzed within the bioinformatics community. First, Linked Data, exposed as SPARQL endpoints, promises to make data easier to collect and integrate by moving towards the harmonization of data syntax, descriptive vocabularies, and identifiers, as well as providing a standardized mechanism for data access. Second, Web Services, often linked together into workflows, normalize data access and create transparent, reproducible scientific methodologies that can, in principle, be re-used and customized to suit new scientific questions. Constructing queries that traverse semantically-rich Linked Data requires substantial expertise, yet traditional RESTful or SOAP Web Services cannot adequately describe the content of a SPARQL endpoint. We propose that content-driven Semantic Web Services can enable facile discovery of Linked Data, independent of their location. RESULTS: We use a well-curated Linked Dataset - OpenLifeData - and utilize its descriptive metadata to automatically configure a series of more than 22,000 Semantic Web Services that expose all of its content via the SADI set of design principles. The OpenLifeData SADI services are discoverable via queries to the SHARE registry and easy to integrate into new or existing bioinformatics workflows and analytical pipelines. We demonstrate the utility of this system through comparison of Web Service-mediated data access with traditional SPARQL, and note that this approach not only simplifies data retrieval, but simultaneously provides protection against resource-intensive queries. CONCLUSIONS: We show, through a variety of different clients and examples of varying complexity, that data from the myriad OpenLifeData can be recovered without any need for prior-knowledge of the content or structure of the SPARQL endpoints. We also demonstrate that, via clients such as SHARE, the complexity of federated SPARQL queries is dramatically reduced. PMID- 25937882 TI - TopFed: TCGA tailored federated query processing and linking to LOD. AB - BACKGROUD: The Cancer Genome Atlas (TCGA) is a multidisciplinary, multi institutional effort to catalogue genetic mutations responsible for cancer using genome analysis techniques. One of the aims of this project is to create a comprehensive and open repository of cancer related molecular analysis, to be exploited by bioinformaticians towards advancing cancer knowledge. However, devising bioinformatics applications to analyse such large dataset is still challenging, as it often requires downloading large archives and parsing the relevant text files. Therefore, it is making it difficult to enable virtual data integration in order to collect the critical co-variates necessary for analysis. METHODS: We address these issues by transforming the TCGA data into the Semantic Web standard Resource Description Format (RDF), link it to relevant datasets in the Linked Open Data (LOD) cloud and further propose an efficient data distribution strategy to host the resulting 20.4 billion triples data via several SPARQL endpoints. Having the TCGA data distributed across multiple SPARQL endpoints, we enable biomedical scientists to query and retrieve information from these SPARQL endpoints by proposing a TCGA tailored federated SPARQL query processing engine named TopFed. RESULTS: We compare TopFed with a well established federation engine FedX in terms of source selection and query execution time by using 10 different federated SPARQL queries with varying requirements. Our evaluation results show that TopFed selects on average less than half of the sources (with 100% recall) with query execution time equal to one third to that of FedX. CONCLUSION: With TopFed, we aim to offer biomedical scientists a single-point-of-access through which distributed TCGA data can be accessed in unison. We believe the proposed system can greatly help researchers in the biomedical domain to carry out their research effectively with TCGA as the amount and diversity of data exceeds the ability of local resources to handle its retrieval and parsing. PMID- 25937883 TI - TermGenie - a web-application for pattern-based ontology class generation. AB - BACKGROUND: Biological ontologies are continually growing and improving from requests for new classes (terms) by biocurators. These ontology requests can frequently create bottlenecks in the biocuration process, as ontology developers struggle to keep up, while manually processing these requests and create classes. RESULTS: TermGenie allows biocurators to generate new classes based on formally specified design patterns or templates. The system is web-based and can be accessed by any authorized curator through a web browser. Automated rules and reasoning engines are used to ensure validity, uniqueness and relationship to pre existing classes. In the last 4 years the Gene Ontology TermGenie generated 4715 new classes, about 51.4% of all new classes created. The immediate generation of permanent identifiers proved not to be an issue with only 70 (1.4%) obsoleted classes. CONCLUSION: TermGenie is a web-based class-generation system that complements traditional ontology development tools. All classes added through pre defined templates are guaranteed to have OWL equivalence axioms that are used for automatic classification and in some cases inter-ontology linkage. At the same time, the system is simple and intuitive and can be used by most biocurators without extensive training. PMID- 25937884 TI - Exploring adverse drug events at the class level. AB - BACKGROUND: While the association between a drug and an adverse event (ADE) is generally detected at the level of individual drugs, ADEs are often discussed at the class level, i.e., at the level of pharmacologic classes (e.g., in drug labels). We propose two approaches, one visual and one computational, to exploring the contribution of individual drugs to the class signal. METHODS: Having established a dataset of ADEs from MEDLINE, we aggregate drugs into ATC classes and ADEs into high-level MeSH terms. We compute statistical associations between drugs and ADEs at the drug level and at the class level. Finally, we visualize the signals at increasing levels of resolution using heat maps. We also automate the exploration of drug-ADE associations at the class level using clustering techniques. RESULTS: Using our visual approach, we were able to uncover known associations, e.g., between fluoroquinolones and tendon injuries, and between statins and rhabdomyolysis. Using our computational approach, we systematically analyzed 488 associations between a drug class and an ADE. CONCLUSIONS: The findings gained from our exploratory techniques should be of interest to the curators of ADE repositories and drug safety professionals. Our approach can be applied to different drug-ADE datasets, using different drug classification systems and different signal detection algorithms. PMID- 25937887 TI - Detecting individual ancestry in the human genome. AB - Detecting and quantifying the population substructure present in a sample of individuals are of main interest in the fields of genetic epidemiology, population genetics, and forensics among others. To date, several algorithms have been proposed for estimating the amount of genetic ancestry within an individual. In the present review, we introduce the most widely used methods in population genetics for detecting individual genetic ancestry. We further show, by means of simulations, the performance of popular algorithms for detecting individual ancestry in various controlled demographic scenarios. Finally, we provide some hints on how to interpret the results from these algorithms. PMID- 25937886 TI - Re-inventing ancient human DNA. AB - For a long time, the analysis of ancient human DNA represented one of the most controversial disciplines in an already controversial field of research. Scepticism in this field was only matched by the long-lasting controversy over the authenticity of ancient pathogen DNA. This ambiguous view on ancient human DNA had a dichotomous root. On the one hand, the interest in ancient human DNA is great because such studies touch on the history and evolution of our own species. On the other hand, because these studies are dealing with samples from our own species, results are easily compromised by contamination of the experiments with modern human DNA, which is ubiquitous in the environment. Consequently, some of the most disputed studies published - apart maybe from early reports on million year old dinosaur or amber DNA - reported DNA analyses from human subfossil remains. However, the development of so-called next- or second-generation sequencing (SGS) in 2005 and the technological advances associated with it have generated new confidence in the genetic study of ancient human remains. The ability to sequence shorter DNA fragments than with PCR amplification coupled to traditional Sanger sequencing, along with very high sequencing throughput have both reduced the risk of sequencing modern contamination and provided tools to evaluate the authenticity of DNA sequence data. The field is now rapidly developing, providing unprecedented insights into the evolution of our own species and past human population dynamics as well as the evolution and history of human pathogens and epidemics. Here, we review how recent technological improvements have rapidly transformed ancient human DNA research from a highly controversial subject to a central component of modern anthropological research. We also discuss potential future directions of ancient human DNA research. PMID- 25937885 TI - Towards the identification of the loci of adaptive evolution. AB - 1. Establishing the genetic and molecular basis underlying adaptive traits is one of the major goals of evolutionary geneticists in order to understand the connection between genotype and phenotype and elucidate the mechanisms of evolutionary change. Despite considerable effort to address this question, there remain relatively few systems in which the genes shaping adaptations have been identified. 2. Here, we review the experimental tools that have been applied to document the molecular basis underlying evolution in several natural systems, in order to highlight their benefits, limitations and suitability. In most cases, a combination of DNA, RNA and functional methodologies with field experiments will be needed to uncover the genes and mechanisms shaping adaptation in nature. PMID- 25937888 TI - Comparative efficacy and acceptability of five anti-tubercular drugs in treatment of multidrug resistant tuberculosis: a network meta-analysis. AB - Multidrug resistant tuberculosis (MDR-TB) is a serious form of tuberculosis (TB). There is no recognized effective treatment for MDR-TB, although there are a number of publications that have reported positive results for MDR-TB. We performed a network meta-analysis to assess the efficacy and acceptability of potential antitubercular drugs. We conducted a network meta-analysis of randomized controlled clinical trials to compare the efficacy and acceptability of five antitubercular drugs, bedaquiline, delamanid, levofloxacin, metronidazole and moxifloxacin in the treatment of MDR-TB. We included eleven suitable trials from nine journal articles and six clinical trials from ClinicalTrials.gov, with data for 1472 participants. Bedaquiline (odds ratio [OR] 2.69, 95% CI 1.02-7.43), delamanid (OR 2.45, 95% CI 1.36-4.89) and moxifloxacin (OR 2.47, 95% CI 1.01, 7.31) were significantly more effective than placebo. For efficacy, the results indicated no statistical significance between each antitubercular drug. For acceptability, the results indicated no statistically significant difference between each compared intervention. There is insufficient evidence to suggest that any one of the five antitubercular drugs (bedaquiline, delamanid, levofloxacin, metronidazole and moxifloxacin) has superior efficacy compared to the others. PMID- 25937889 TI - SMASH - semi-automatic muscle analysis using segmentation of histology: a MATLAB application. AB - BACKGROUND: Histological assessment of skeletal muscle tissue is commonly applied to many areas of skeletal muscle physiological research. Histological parameters including fiber distribution, fiber type, centrally nucleated fibers, and capillary density are all frequently quantified measures of skeletal muscle. These parameters reflect functional properties of muscle and undergo adaptation in many muscle diseases and injuries. While standard operating procedures have been developed to guide analysis of many of these parameters, the software to freely, efficiently, and consistently analyze them is not readily available. In order to provide this service to the muscle research community we developed an open source MATLAB script to analyze immunofluorescent muscle sections incorporating user controls for muscle histological analysis. RESULTS: The software consists of multiple functions designed to provide tools for the analysis selected. Initial segmentation and fiber filter functions segment the image and remove non-fiber elements based on user-defined parameters to create a fiber mask. Establishing parameters set by the user, the software outputs data on fiber size and type, centrally nucleated fibers, and other structures. These functions were evaluated on stained soleus muscle sections from 1-year-old wild type and mdx mice, a model of Duchenne muscular dystrophy. In accordance with previously published data, fiber size was not different between groups, but mdx muscles had much higher fiber size variability. The mdx muscle had a significantly greater proportion of type I fibers, but type I fibers did not change in size relative to type II fibers. Centrally nucleated fibers were highly prevalent in mdx muscle and were significantly larger than peripherally nucleated fibers. CONCLUSIONS: The MATLAB code described and provided along with this manuscript is designed for image processing of skeletal muscle immunofluorescent histological sections. The program allows for semi-automated fiber detection along with user correction. The output of the code provides data in accordance with established standards of practice. The results of the program have been validated using a small set of wild-type and mdx muscle sections. This program is the first freely available and open source image processing program designed to automate analysis of skeletal muscle histological sections. PMID- 25937890 TI - Induction of the intrinsic apoptotic pathway via a new antimitotic agent in an esophageal carcinoma cell line. AB - BACKGROUND: 2-Ethyl-3-O-sulphamoyl-estra-1,3,5(10)16-tetraene (ESE-16) is a unique, in silico-designed compound with possible anticancer properties, which were identified in our laboratory. This compound is capable of interfering with microtubule dynamics and is believed to have potential carbonic anhydrase IX inhibiting activity. In this study, it was investigated whether ESE-16 is capable of inducing apoptosis in vitro in the esophageal carcinoma SNO cell line via the intrinsic pathway at a concentration of 0.2 MUM with an exposure time of 24 hours. RESULTS: Qualitative results were obtained via light microscopy, transmission electron microscopy and confocal microscopy. Results showed hallmarks of apoptosis in the ESE-16-treated cells. In addition, data revealed an increase in the number of ESE-16-treated cells blocked in metaphase. Cell death via apoptosis in the ESE-16-treated cells was confirmed by studying the internal ultrastructure of the cells via transmission electron microscopy, while confocal microscopy revealed abnormal spindle formation and condensed chromatin in ESE-16 treated cells, thus confirming metaphase block. Quantitative results were obtained via flow cytometry and spectrophotometry. Cell death via apoptosis in ESE-16-treated cells was quantitatively confirmed by the Annexin V-FITC apoptosis detection assay. Flow cytometry and spectrophotometry revealed dissipation of mitochondrial membrane potential and an increase in superoxide levels in the ESE 16-treated cells when compared to the relevant controls. Both initiator caspase 9 and effector caspase 3 activities were increased, which demonstrates that ESE-16 causes cell death in a caspase-dependent manner. CONCLUSIONS: This was the first in vitro study conducted to investigate the action mechanism of ESE-16 on an esophageal carcinoma cell line. The results provided valuable information on the action mechanism of this potential anticancer agent. It can be concluded that the novel in silico-designed compound exerts an anti-proliferative effect on the esophageal carcinoma SNO cell line by disrupting microtubule function resulting in metaphase block. This culminates in apoptotic cell death via the intrinsic apoptotic pathway. This research provided cellular targets warranting in vivo assessment of ESE-16's potential as an anticancer agent. PMID- 25937891 TI - Evolving concepts of tumor heterogeneity. AB - Past and recent findings on tumor heterogeneity have led clinicians and researchers to broadly define cancer development as an evolving process. This evolutionary model of tumorigenesis has largely been shaped by seminal reports of fitness-promoting mutations conferring a malignant cellular phenotype. Despite the major clinical and intellectual advances that have resulted from studying heritable heterogeneity, it has long been overlooked that compositional tumor heterogeneity and tumor microenvironment (TME)-induced selection pressures drive tumor evolution, significantly contributing to tumor development and outcomes of clinical cancer treatment. In this review, we seek to summarize major milestones in tumor evolution, identify key aspects of tumor heterogeneity in a TME dependent evolutionary context, and provide insights on the clinical challenges facing researchers and clinicians alike. PMID- 25937892 TI - Induction of ER stress-mediated apoptosis by ceramide via disruption of ER Ca(2+) homeostasis in human adenoid cystic carcinoma cells. AB - BACKGROUND: Ceramides are a class of sphingolipids that form the structural component of the cell membrane and also act as second messengers in cell signaling pathways. Emerging results suggest that ceramide induces growth arrest and apoptosis in various human cancer cells. However, the mechanisms underlying its antitumor activity are yet to be identified. Endoplasmic reticulum stress (ER stress), a cellular adaptive response, is believed to initially compensate for damage but can eventually trigger cell death if the stimulus is severe or prolonged. In this study, we investigated whether ceramide induces cell death in human salivary adenoid cystic carcinoma (ACCs) through activation of the apoptotic ER stress. RESULTS: RT-PCR, real-time PCR and western blot demonstrated that exogenous ceramide treatment up-regulated GRP78 and p-eIF2alpha expression and XBP1 splicing. Moreover, the ceramide synthase inhibitor FB1 abolished ceramide-induced ER stress. Up-regulation of the ER stress-associated apoptosis promoting transcription factor CHOP and p-JNK suggested that the antitumor activity of ceramide is owing to activation of apoptotic ER stress. Mechanistically, [Ca(2+)]ER depletion and SERCA inhibition by ceramide treatment suggested that it induces ER stress by disrupting [Ca(2+)]ER homeostasis. The chemical chaperone TUDCA inhibited ceramide-induced ER stress and cell death. In addition, the downstream metabolite of ceramide, S1P, cannot activate ER stress. CONCLUSIONS: These results demonstrated that exogenous ceramide induces cancer cell death through a mechanism involving severe ER stress triggered by the disruption of ER Ca(2+) homeostasis. PMID- 25937893 TI - Genetic deletion of IL-25 (IL-17E) confers resistance to dextran sulfate sodium induced colitis in mice. AB - BACKGROUND: IL-25 is emerging as a key regulator of inflammation in the intestinal mucosa because of its ability to promote type 2 while suppressing Th1 and Th17 responses. Several previous studies reported inconsistent results on the role of exogenous IL-25 in development of colonic inflammation and none were performed in animals with a genetic deletion of IL-25. We investigated the contribution of endogenous IL-25 to DSS-induced colitis using mice deficient in IL-25. RESULTS: Mice were exposed to DSS in drinking water ad libitum either for seven days (acute) or for three cycles of seven days with DSS followed by 14 days without DSS (chronic) to induce colitis, respectively. The loss of body weight, appearance of diarrhea and bloody stools, and shortening of colon length were significantly less pronounced in IL-25(-/-) mice compared to WT mice after exposure to acute DSS. Histological examination showed that DSS-treated IL-25(-/ ) mice had only mild inflammation in the colon, while severe inflammation developed in DSS-treated WT mice. A significant up-regulation of IL-33 was observed in acute DSS-treated WT but not in the IL-25(-/-) mice. There was significantly lower expression of pro-inflammatory cytokines in the colon of acute DSS-treated IL-25(-/-) compared to WT mice. IL-25(-/-) mice were also partially protected from chronic DSS challenge especially during the first 2 cycles of DSS exposure. In contrast to IL-25(-/-) mice, IL-13(-/-) mice were more susceptible to DSS-induced colitis. Finally, stimulation of T84 colonic epithelial cells with IL-25 up-regulated the expression of IL-33 and several pro inflammatory cytokines. CONCLUSIONS: These data indicate that endogenous IL-25 acts as a pro-inflammatory factor in DSS-induced colitis, which is unlikely to be mediated by IL-13 but possibly the induction of IL-33 and other pro-inflammatory mediators from colonic epithelial cells. The present study suggests that IL-25 may contribute to the pathogenesis of inflammatory bowel disease in at least a subgroup of patients. PMID- 25937895 TI - Loureirin B, an essential component of Sanguis Draxonis, inhibits Kv1.3 channel and suppresses cytokine release from Jurkat T cells. AB - Sanguis draxonis (SD), also known as "Dragon's Blood", is a traditional herb medicine that has been used to treat a variety of complications with unknown mechanisms. Recent studies show that SD displays immunosuppressive activities and improves symptoms of type I diabetes in animal models. However, the mechanisms underlying SD's immunosuppressive actions are not completely understood. The voltage-gated Kv1.3 channel plays a critical role in the pathogenesis of autoimmune diseases by regulating the functions of both T cells and B cells. Here we investigated the effect of SD and one of its active components loureirin B (LrB) on Kv1.3. Both SD and LrB inhibited Kv1.3-mediated currents, produced a membrane depolarization, and reduced Ca(2+) influx in Jurkat T cells. In addition, application of LrB inhibited phytohemagglutinin (PHA)-induced IL-2 release from activated Jurkat T cells. Furthermore, point mutations in the selective filter region significantly reduced the inhibitory effect of LrB on Kv1.3. The results of these experiments provide evidence that LrB is a channel blocker of Kv1.3 by interacting with amino acid residues in its selective filter region. Direct inhibition of Kv1.3 in T cells by SD and LrB might be the cellular and molecular basis of SD-mediated immunosuppression. PMID- 25937896 TI - Income-related inequalities in health and health services use in Israel. AB - BACKGROUND: Income-related inequalities in health and in health services use pose a disturbing and challenging issue in health systems, which are based on social health insurance such as Israel. OBJECTIVE: To explore income-related inequalities in health and in health services use in Israel in 2009-2010. METHODS: We used the Central Bureau of Statistics file, which linked information on 7,175 households (24,595 persons) from the 2009 Health Survey and the 2010 Incomes Survey. Raw and adjusted concentration curves and indices were calculated for ten chronic conditions (adjusting for age), visits to physicians and hospitalizations (adjusting for health and location). RESULTS: There is no income related inequality in asthma and in cancer. The income-related inequality in the remaining eight conditions is 'pro-poor', namely, they are more prevalent among poor households. The order of the level of inequality is (from the least unequally distributed): any condition, hypertension, heart diseases, diabetes, depression, respiratory diseases, digestive diseases, and the condition with the highest income-related inequality is activities of daily living (ADL) limitations. The income-related inequality in secondary physicians' services is 'pro-rich'. The income-related inequality in primary care is 'pro- poor'. Hospitalization days are significantly more unequally - 'pro-poor' - distributed in the population. DISCUSSION: International findings are basically similar to the ones found in this paper. Three reasons are believed to have caused these income-related inequalities: the use of preventive services, health behavior and compliance with the doctors' directions; they might constitute a useful framework for strategizing interventions. The efforts of the Ministry of Health and of the sickness funds launched in 2010 to reduce inequalities should be evaluated by repeating the present analysis with newer data. PMID- 25937897 TI - Characteristics of individuals not visiting their primary care provider. AB - The observational study by Rosen and colleagues described the proportion and characteristics of individuals who do not visit their primary care physician regularly. Overall, they identify a very low rate of non-attendance, high rates of visit frequency, and describe predictors of non-attendance. In this study of 421,012 individuals, only 6,217 (or, 1.5% of the study population) did not visit their primary care physician over the four-year study period. Multivariate analysis showed that the strongest predictors of non-attendance were being male, being a new immigrant, and the presence of fewer chronic diseases. This study raises important questions about why patients seem to be so engaged with primary care in Israel, whether this engagement explains part of the Israeli health system's success, and ways to best structure primary care services in the future. PMID- 25937894 TI - Epigenetic regulation of thyroid hormone-induced adult intestinal stem cell development during anuran metamorphosis. AB - Epigenetic modifications of histones are emerging as key factors in gene regulation by diverse transcription factors. Their roles during vertebrate development and pathogenesis are less clear. The causative effect of thyroid hormone (T3) on amphibian metamorphosis and the ability to manipulate this process for molecular and genetic studies have led to the demonstration that T3 receptor (TR) is necessary and sufficient for Xenopus metamorphosis, a process that resembles the postembryonic development (around birth) in mammals. Importantly, analyses during metamorphosis have provided some of the first in vivo evidence for the involvement of histone modifications in gene regulation by TR during vertebrate development. Furthermore, expression and functional studies suggest that various histone modifying epigenetic enzymes likely participate in multiple steps during the formation of adult intestinal stem cells during metamorphosis. The similarity between intestinal remodeling and the maturation of the mammalian intestine around birth when T3 levels are high suggests conserved roles for the epigenetic enzymes in mammalian adult intestinal stem cell development and/or proliferation. PMID- 25937898 TI - Tobacco policy in Israel: 1948-2014 and beyond. AB - BACKGROUND: Tobacco is the only consumer product known to kill half of its users, and is a significant cause of death and disability to exposed nonsmokers. This presents a unique conundrum for modern democracies, which emphasize personal liberty, yet are obligated to protect citizens. In Israel, the death toll in 2014 from smoking is expected to reach 8000 deaths; nearly a fifth of the population smokes, and over two-thirds of the population are exposed to tobacco smoke. AIM: This paper provides an overview of tobacco policy in Israel since the inception of the State, presents the development of the National Tobacco Control Plan, and recommends future actions. METHODS: Sources for this article included the Knesset (Israeli Parliament) and Ministry of Health websites, Health Minister Reports to the Knesset on Smoking, and the scientific literature. RESULTS: Israel has an impressive record on tobacco control policy, beginning with taxation in 1952, landmark smoke-free air and marketing legislation in the early 1980's, tax increases and expansions of smoke-free air and marketing legislation in the ensuing years, and the addition of subsidized smoking cessation technologies in 2010. Until 2011, actions were taken by various organizations without formal coordination; since the passage of the National Tobacco Control Plan in 2011, the Ministry of Health has held responsibility for coordinating tobacco control, with an action plan. The plan has been partially implemented. Smoke-free air laws were expanded, but enforcement is poor. Passage of critical marketing and advertising restrictions is stalled. Requested funds for tobacco control did not materialize. RECOMMENDATIONS: In order to prevent hundreds of thousands of preventable premature deaths in the coming decades, Israel should considerably strengthen tobacco control policies to include: guaranteed funding for tobacco control; strong curbs on advertising, promotion and sponsorship of tobacco and smoking products; public education; law enforcement; protection of children from exposure to tobacco; regulation of electronic cigarettes and other alternative harm reducing products; tobacco control research; and systematic monitoring of, and periodic updates to, the National Tobacco Control Plan. Israel should also begin discussions of Endgame scenarios, and consider abolition of tobacco, as it continues its progress towards making smoking history. PMID- 25937899 TI - High-dose intravenous immunoglobulin therapy for eosinophilic granulomatosis with polyangiitis. AB - BACKGROUND: Regulatory T (Treg) cells are implicated in the development and progression of eosinophilic granulomatosis with polyangiitis (EGPA). We previously showed beneficial effects of intravenous immunoglobulin (IVIG) therapy combined with corticosteroid and immunosuppressant treatment on clinical symptoms, including mononeuritis multiplex and cardiac dysfunction, and Treg cell frequency, during EGPA. Whether the timing of administration (during initial treatment or at relapse after remission) or previous treatment affects the clinical and immunologic efficacy of IVIG is unknown. We evaluated whether the frequency of Treg cells varied depending on when IVIG was provided relative to the start of conventional therapy for EGPA. METHODS: The patient population for this retrospective analysis comprised 17 patients with severe mononeuritis multiplex or heart failure whose EGPA did not respond to corticosteroids combined with immunosuppressant therapy. Ten patients first received IVIG during initial treatment, whereas the remaining 7 patients first received IVIG on relapse after remission. We measured the percentage of Treg cells, defined as FOXP3(+)CD4(+) T cells, present before the first round of IVIG and at 1 month after the last IVIG treatment. RESULTS: FOXP3(+)CD4(+) T cells were increased in patients who required only a single course of IVIG to achieve remission compared with those who needed two or more courses. The dosage of prednisolone at initial IVIG was inversely correlated with the ratio of the number of FOXP3(+)CD4(+) T cells before IVIG and that at 1 month thereafter. CONCLUSION: Patients with severe EGPA who receive IVIG after nonresponse to high-dose prednisolone during initial treatment may need multiple courses of IVIG to achieve remission. An increase in the frequency of Treg cells after IVIG may predict the need for additional IVIG in EGPA. PMID- 25937900 TI - Asymmetric dominance and asymmetric mate choice oppose premating isolation after allopatric divergence. AB - Assortative mating promotes reproductive isolation and allows allopatric speciation processes to continue in secondary contact. As mating patterns are determined by mate preferences and intrasexual competition, we investigated male male competition and behavioral isolation in simulated secondary contact among allopatric populations. Three allopatric color morphs of the cichlid fish Tropheus were tested against each other. Dyadic male-male contests revealed dominance of red males over bluish and yellow-blotch males. Reproductive isolation in the presence of male-male competition was assessed from genetic parentage in experimental ponds and was highly asymmetric among pairs of color morphs. Red females mated only with red males, whereas the other females performed variable degrees of heteromorphic mating. Discrepancies between mating patterns in ponds and female preferences in a competition-free, two-way choice paradigm suggested that the dominance of red males interfered with positive assortative mating of females of the subordinate morphs and provoked asymmetric hybridization. Between the nonred morphs, a significant excess of negative assortative mating by yellow-blotch females with bluish males did not coincide with asymmetric dominance among males. Hence, both negative assortative mating preferences and interference of male-male competition with positive assortative preferences forestall premating isolation, the latter especially in environments unsupportive of competition-driven spatial segregation. PMID- 25937901 TI - Studying the movement behavior of benthic macroinvertebrates with automated video tracking. AB - Quantifying and understanding movement is critical for a wide range of questions in basic and applied ecology. Movement ecology is also fostered by technological advances that allow automated tracking for a wide range of animal species. However, for aquatic macroinvertebrates, such detailed methods do not yet exist. We developed a video tracking method for two different species of benthic macroinvertebrates, the crawling isopod Asellus aquaticus and the swimming fresh water amphipod Gammarus pulex. We tested the effects of different light sources and marking techniques on their movement behavior to establish the possibilities and limitations of the experimental protocol and to ensure that the basic handling of test specimens would not bias conclusions drawn from movement path analyses. To demonstrate the versatility of our method, we studied the influence of varying population densities on different movement parameters related to resting behavior, directionality, and step lengths. We found that our method allows studying species with different modes of dispersal and under different conditions. For example, we found that gammarids spend more time moving at higher population densities, while asellids rest more under similar conditions. At the same time, in response to higher densities, gammarids mostly decreased average step lengths, whereas asellids did not. Gammarids, however, were also more sensitive to general handling and marking than asellids. Our protocol for marking and video tracking can be easily adopted for other species of aquatic macroinvertebrates or testing conditions, for example, presence or absence of food sources, shelter, or predator cues. Nevertheless, limitations with regard to the marking protocol, material, and a species' physical build need to be considered and tested before a wider application, particularly for swimming species. Data obtained with this approach can deepen the understanding of population dynamics on larger spatial scales and of the effects of different management strategies on a species' dispersal potential. PMID- 25937902 TI - An optimal proportion of mixing broad-leaved forest for enhancing the effective productivity of moso bamboo. AB - Moso bamboos (Phyllostachys edulis) are important forestry plants in southern China, with substantial roles to play in regional economic and ecological systems. Mixing broad-leaved forests and moso bamboos is a common management practice in China, and it is fundamental to elucidate the interactions between broad-leaved trees and moso bamboos for ensuring the sustainable provision of ecosystem services. We examine how the proportion of broad-leaved forest in a mixed managed zone, topology, and soil profile affects the effective productivity of moso bamboos (i.e., those with significant economic value), using linear regression and generalized additive models. Bamboo's diameter at breast height follows a Weibull distribution. The importance of these variables to bamboo productivity is, respectively, slope (25.9%), the proportion of broad-leaved forest (24.8%), elevation (23.3%), gravel content by volume (16.6%), slope location (8.3%), and soil layer thickness (1.2%). Highest productivity is found on the 25 degrees slope, with a 600-m elevation, and 30% broad-leaved forest. As such, broad-leaved forest in the upper slope can have a strong influence on the effective productivity of moso bamboo, ranking only after slope and before elevation. These factors can be considered in future management practice. PMID- 25937903 TI - The effect of biogeographic and phylogeographic barriers on gene flow in the brown smoothhound shark, Mustelus henlei, in the northeastern Pacific. AB - We assessed the effects of the prominent biogeographic (Point Conception and the Peninsula of Baja California) and phylogeographic barriers (Los Angeles Region) of the northeastern Pacific on the population connectivity of the brown smoothhound shark, Mustelus henlei (Triakidae). Data from the mitochondrial control region and six nuclear microsatellite loci revealed significant population structure among three populations: northern (San Francisco), central (Santa Barbara, Santa Catalina, Punta Lobos, and San Felipe), and southern (Costa Rica). Patterns of long-term and contemporary migration were incongruent, with long-term migration being asymmetric and occurring in a north to south direction and a lack of significant contemporary migration observed between localities with the exception of Punta Lobos that contributed migrants to all localities within the central population. Our findings indicate that Point Conception may be restricting gene flow between the northern and central populations whereas barriers to gene flow within the central population would seem to be ineffective; additionally, a contemporary expansion of tropical M. henlei into subtropical and temperate waters may have been observed. PMID- 25937904 TI - Investment in sensory structures, testis size, and wing coloration in males of a diurnal moth species: trade-offs or correlated growth? AB - For dioecious animals, reproductive success typically involves an exchange between the sexes of signals that provide information about mate location and quality. Typically, the elaborate, secondary sexual ornaments of males signal their quality, while females may signal their location and receptivity. In theory, the receptor structures that receive the latter signals may also become elaborate or enlarged in a way that ultimately functions to enhance mating success through improved mate location. The large, elaborate antennae of many male moths are one such sensory structure, and eye size may also be important in diurnal moths. Investment in these traits may be costly, resulting in trade-offs among different traits associated with mate location. For polyandrous species, such trade-offs may also include traits associated with paternity success, such as larger testes. Conversely, we would not expect this to be the case for monandrous species, where sperm competition is unlikely. We investigated these ideas by evaluating the relationship between investment in sensory structures (antennae, eye), testis, and a putative warning signal (orange hindwing patch) in field-caught males of the monandrous diurnal painted apple moth Teia anartoides (Lepidoptera: Lymantriidae) in southeastern Australia. As predicted for a monandrous species, we found no evidence that male moths with larger sensory structures had reduced investment in testis size. However, contrary to expectation, investment in sensory structures was correlated: males with relatively larger antennae also had relatively larger eyes. Intriguingly, also, the size of male orange hindwing patches was positively correlated with testis size. PMID- 25937905 TI - Evolution of mating behavior between two populations adapting to common environmental conditions. AB - Populations from the same species may be differentiated across contrasting environments, potentially affecting reproductive isolation among them. When such populations meet in a novel common environment, this isolation may be modified by biotic or abiotic factors. Curiously, the latter have been overlooked. We filled this gap by performing experimental evolution of three replicates of two populations of Drosophila subobscura adapting to a common laboratorial environment, and simulated encounters at three time points during this process. Previous studies showed that these populations were highly differentiated for several life-history traits and chromosomal inversions. First, we show initial differentiation for some mating traits, such as assortative mating and male mating rate, but not others (e.g., female mating latency). Mating frequency increased during experimental evolution in both sets of populations. The assortative mating found in one population remained constant throughout the adaptation process, while disassortative mating of the other population diminished across generations. Additionally, differences in male mating rate were sustained across generations. This study shows that mating behavior evolves rapidly in response to adaptation to a common abiotic environment, although with a complex pattern that does not correspond to the quick convergence seen for life history traits. PMID- 25937906 TI - Prolonged experimental drought reduces plant hydraulic conductance and transpiration and increases mortality in a pinon-juniper woodland. AB - Plant hydraulic conductance (k s) is a critical control on whole-plant water use and carbon uptake and, during drought, influences whether plants survive or die. To assess long-term physiological and hydraulic responses of mature trees to water availability, we manipulated ecosystem-scale water availability from 2007 to 2013 in a pinon pine (Pinus edulis) and juniper (Juniperus monosperma) woodland. We examined the relationship between k s and subsequent mortality using more than 5 years of physiological observations, and the subsequent impact of reduced hydraulic function and mortality on total woody canopy transpiration (E C) and conductance (G C). For both species, we observed significant reductions in plant transpiration (E) and k s under experimentally imposed drought. Conversely, supplemental water additions increased E and k s in both species. Interestingly, both species exhibited similar declines in k s under the imposed drought conditions, despite their differing stomatal responses and mortality patterns during drought. Reduced whole-plant k s also reduced carbon assimilation in both species, as leaf-level stomatal conductance (g s) and net photosynthesis (A n) declined strongly with decreasing k s. Finally, we observed that chronically low whole-plant k s was associated with greater canopy dieback and mortality for both pinon and juniper and that subsequent reductions in woody canopy biomass due to mortality had a significant impact on both daily and annual canopy E C and G C. Our data indicate that significant reductions in k s precede drought-related tree mortality events in this system, and the consequence is a significant reduction in canopy gas exchange and carbon fixation. Our results suggest that reductions in productivity and woody plant cover in pinon-juniper woodlands can be expected due to reduced plant hydraulic conductance and increased mortality of both pinon pine and juniper under anticipated future conditions of more frequent and persistent regional drought in the southwestern United States. PMID- 25937907 TI - Genetic structure in insular and mainland populations of house sparrows (Passer domesticus) and their hemosporidian parasites. AB - Small and isolated populations usually exhibit low levels of genetic variability, and thus, they are expected to have a lower capacity to adapt to changes in environmental conditions, such as exposure to pathogens and parasites. Comparing the genetic variability of selectively neutral versus functional loci allows one to assess the evolutionary history of populations and their future evolutionary potential. The genes of the major histocompatibility complex (MHC) control immune recognition of parasites, and their unusually high diversity is genes which is likely driven by parasite-mediated balancing selection. Here, we examined diversity and differentiation of neutral microsatellite loci and functional MHC class I genes in house sparrows (Passer domesticus), living in six insular and six mainland populations, and we aimed to determine whether their diversity or differentiation correlates with the diversity and the prevalence of infection of hemosporidian parasites. We found that island bird populations tended to have lower neutral genetic variability, whereas MHC variability gene was similar between island and mainland populations. Similarly, island populations tended to show greater genetic differentiation than mainland populations, especially at microsatellite markers. The maintenance of MHC genetic diversity and its less marked structure in the island populations could be attributed to balancing selection. The greater MHC differentiation among populations was negatively correlated with similarity in blood parasites (prevalence and diversity of parasite strains) between populations. Even at low prevalence and small geographical scale, haemosporidian parasites might contribute to structure the variability of immune genes among populations of hosts. PMID- 25937908 TI - Association with pathogenic bacteria affects life-history traits and population growth in Caenorhabditis elegans. AB - Determining the relationship between individual life-history traits and population dynamics is an essential step to understand and predict natural selection. Model organisms that can be conveniently studied experimentally at both levels are invaluable to test the rich body of theoretical literature in this area. The nematode Caenorhabditis elegans, despite being a well-established workhorse in genetics, has only recently received attention from ecologists and evolutionary biologists, especially with respect to its association with pathogenic bacteria. In order to start filling the gap between the two areas, we conducted a series of experiments aiming at measuring life-history traits as well as population growth of C. elegans in response to three different bacterial strains: Escherichia coli OP50, Salmonella enterica Typhimurium, and Pseudomonas aeruginosa PAO1. Whereas previous studies had established that the latter two reduced the survival of nematodes feeding on them compared to E. coli OP50, we report for the first time an enhancement in reproductive success and population growth for worms feeding on S. enterica Typhimurium. Furthermore, we used an age specific population dynamic model, parameterized using individual life-history assays, to successfully predict the growth of populations over three generations. This study paves the way for more detailed and quantitative experimental investigation of the ecology and evolution of C. elegans and the bacteria it interacts with, which could improve our understanding of the fate of opportunistic pathogens in the environment. PMID- 25937909 TI - Lake size and fish diversity determine resource use and trophic position of a top predator in high-latitude lakes. AB - Prey preference of top predators and energy flow across habitat boundaries are of fundamental importance for structure and function of aquatic and terrestrial ecosystems, as they may have strong effects on production, species diversity, and food-web stability. In lakes, littoral and pelagic food-web compartments are typically coupled and controlled by generalist fish top predators. However, the extent and determinants of such coupling remains a topical area of ecological research and is largely unknown in oligotrophic high-latitude lakes. We analyzed food-web structure and resource use by a generalist top predator, the Arctic charr Salvelinus alpinus (L.), in 17 oligotrophic subarctic lakes covering a marked gradient in size (0.5-1084 km(2)) and fish species richness (2-13 species). We expected top predators to shift from littoral to pelagic energy sources with increasing lake size, as the availability of pelagic prey resources and the competition for littoral prey are both likely to be higher in large lakes with multispecies fish communities. We also expected top predators to occupy a higher trophic position in lakes with greater fish species richness due to potential substitution of intermediate consumers (prey fish) and increased piscivory by top predators. Based on stable carbon and nitrogen isotope analyses, the mean reliance of Arctic charr on littoral energy sources showed a significant negative relationship with lake surface area, whereas the mean trophic position of Arctic charr, reflecting the lake food-chain length, increased with fish species richness. These results were supported by stomach contents data demonstrating a shift of Arctic charr from an invertebrate-dominated diet to piscivory on pelagic fish. Our study highlights that, because they determine the main energy source (littoral vs. pelagic) and the trophic position of generalist top predators, ecosystem size and fish diversity are particularly important factors influencing function and structure of food webs in high-latitude lakes. PMID- 25937910 TI - Pathogenic bacteria and timing of laying. AB - Pathogenic bacteria constitute a serious threat to viability of many organisms. Because growth of most bacteria is favored by humid and warm environmental conditions, earlier reproducers in seasonal environments should suffer less from the negative consequences of pathogenic bacteria. These relationships, and the effects on reproductive success, should be particularly prominent in predators because they are frequently exposed to pathogenic microorganisms from sick prey. Here, we presented and tested this hypothesis by sampling bacteria on adult and nestling goshawks Accipiter gentilis. We predicted that early breeders and their offspring should have fewer bacteria than those reproducing later during the breeding season. Adult goshawks with a high abundance of Staphylococcus on their beak and claws were easier to capture and their laying date was delayed. Moreover, goshawks that laid their eggs later had offspring with more Staphylococcus on their beaks and claws. The strength of the association between laying date and bacterial density of nestlings was stronger during the warm spring of 2013, when nestlings suffered from a higher abundance of pathogenic bacteria. Hatching failure and fledging failure were more common in nests with a higher abundance of Staphylococcus independently of the number of years occupied, laying date, and age of the female nest owner. These findings imply that timing of reproduction may be under the influence of pathogenic bacteria. Because early breeding goshawks produce more recruits than later breeders, our results suggest a role for pathogenic bacteria in the optimal timing of reproduction. PMID- 25937911 TI - Polyandry in dragon lizards: inbred paternal genotypes sire fewer offspring. AB - Multiple mating in female animals is something of a paradox because it can either be risky (e.g., higher probability of disease transmission, social costs) or provide substantial fitness benefits (e.g., genetic bet hedging whereby the likelihood of reproductive failure is lowered). The genetic relatedness of parental units, particularly in lizards, has rarely been studied in the wild. Here, we examined levels of multiple paternity in Australia's largest agamid lizard, the eastern water dragon (Intellagama lesueurii), and determined whether male reproductive success is best explained by its heterozygosity coefficient or the extent to which it is related to the mother. Female polyandry was the norm: 2/22 clutches (9.2%) were sired by three or more fathers, 17/22 (77.2%) were sired by two fathers, and only 3/22 (13.6%) clutches were sired by one father. Moreover, we reconstructed the paternal genotypes for 18 known mother-offspring clutches and found no evidence that females were favoring less related males or that less related males had higher fitness. However, males with greater heterozygosity sired more offspring. While the postcopulatory mechanisms underlying this pattern are not understood, female water dragons likely represent another example of reproduction through cryptic means (sperm selection/sperm competition) in a lizard, and through which they may ameliorate the effects of male-driven precopulatory sexual selection. PMID- 25937912 TI - Relationships between climate and growth of Gymnocypris selincuoensis in the Tibetan Plateau. AB - The consequences of climate change are becoming increasingly evident in the Tibetan Plateau, represented by glaciers retreating and lakes expanding, but the biological response to climate change by plateau-lake ecosystems is poorly known. In this study, we applied dendrochronology methods to develop a growth index chronology with otolith increment widths of Selincuo naked carp (Gymnocypris selincuoensis), which is an endemic species in Lake Selincuo (4530 m), and investigated the relationships between fish growth and climate variables (regional and global) in the last three decades. A correlation analysis and principle component regression analysis between regional climate factors and the growth index chronology indicated that the growth of G. selincuoensis was significantly and positively correlated with length of the growing season and temperature-related variables, particularly during the growing season. Most of global climate variables, which are relevant to the Asian monsoon and the midlatitude westerlies, such as El Nino Southern Oscillation Index, the Arctic Oscillation, North Atlantic Oscillation, and North America Pattern, showed negative but not significant correlations with the annual growth of Selincuo naked carp. This may have resulted from the high elevation of the Tibetan Plateau and the high mountains surrounding this area. In comparison, the Pacific Decade Oscillation (PDO) negatively affected the growth of G. selincuoensis. The reason maybe that enhancement of the PDO can lead to cold conditions in this area. Taken together, the results indicate that the Tibetan Plateau fish has been affected by global climate change, particularly during the growing season, and global climate change likely has important effects on productivity of aquatic ecosystems in this area. PMID- 25937913 TI - Effects of pine wilt disease invasion on soil properties and Masson pine forest communities in the Three Gorges reservoir region, China. AB - Pine wilt disease (PWD) has caused significant Masson pine mortality in the Three Gorges reservoir region in central China. In this study, five uniform Masson pine stand types infected by PWD were selected and surveyed on slopes and aspects with similar environmental conditions. In sites that had been infected, soil bulk density was reduced, and the difference among the groups was statistically significant (P < 0.05) at the 0-10 cm and 10-20 cm soil layers, but not at 20-40 cm. Other soil water-related physical properties, excluding noncapillary porosity, significantly differed among the groups in all soil layers. Additionally, the values of available phosphorus, sodium, potassium, calcium, and magnesium were higher in the invaded stands, but the total nitrogen and organic matter contents were lower. Masson pine does not become reestablished following PWD-induced mortality but is instead replaced by broad-leaved tree species. Among the 19 examined environmental variables, five were found to be significantly related with the ordination of plant community structure: Masson pine stumps (MPS), K(+), capillary water holding capacity (CWHC), capillary porosity (CP), and soil water content (SWC). Among these factors, the plant community structure was principally related to MPS and K(+). The findings of this study show that the outbreak of PWD has impacted Masson pine forest soil properties and altered forest community composition. The disease is negatively related with the presence of Masson pine and positively associated with that of broad-leaved tree species. PMID- 25937914 TI - Limited connectivity and a phylogeographic break characterize populations of the pink anemonefish, Amphiprion perideraion, in the Indo-Malay Archipelago: inferences from a mitochondrial and microsatellite loci. AB - To enhance the understanding of larval dispersal in marine organisms, species with a sedentary adult stage and a pelagic larval phase of known duration constitute ideal candidates, because inferences can be made about the role of larval dispersal in population connectivity. Members of the immensely diverse marine fauna of the Indo-Malay Archipelago are of particular importance in this respect, as biodiversity conservation is becoming a large concern in this region. In this study, the genetic population structure of the pink anemonefish, Amphiprion perideraion, is analyzed by applying 10 microsatellite loci as well as sequences of the mitochondrial control region to also allow for a direct comparison of marker-derived results. Both marker systems detected a strong overall genetic structure (PhiST = 0.096, P < 0.0001; mean D est = 0.17; F ST = 0.015, P < 0.0001) and best supported regional groupings (PhiCT = 0.199 P < 0.0001; F CT = 0.018, P < 0.001) that suggested a differentiation of the Java Sea population from the rest of the archipelago. Differentiation of a New Guinea group was confirmed by both markers, but disagreed over the affinity of populations from west New Guinea. Mitochondrial data suggest higher connectivity among populations with fewer signals of regional substructure than microsatellite data. Considering the homogenizing effect of only a few migrants per generation on genetic differentiation between populations, marker-specific results have important implications for conservation efforts concerning this and similar species. PMID- 25937916 TI - Temporal patterns in Saturnidae (silk moth) and Sphingidae (hawk moth) assemblages in protected forests of central Uganda. AB - Forest-dependent biodiversity is threatened throughout the tropics by habitat loss and land-use intensification of the matrix habitats. We resampled historic data on two moth families, known to play central roles in many ecosystem processes, to evaluate temporal changes in species richness and community structure in three protected forests in central Uganda in a rapidly changing matrix. Our results show some significant declines in the moth species richness and the relative abundance and richness of forest-dependent species over the last 20-40 years. The observed changes in species richness and composition among different forests, ecological types, and moth groups highlight the need to repeatedly monitor biodiversity even within protected and relatively intact forests. PMID- 25937915 TI - Exogenous selection rather than cytonuclear incompatibilities shapes asymmetrical fitness of reciprocal Arabidopsis hybrids. AB - Reciprocal crosses between species often display an asymmetry in the fitness of F1 hybrids. This pattern, referred to as isolation asymmetry or Darwin's corollary to Haldane's rule, is a general feature of reproductive isolation in plants, yet factors determining its magnitude and direction remain unclear. We evaluated reciprocal species crosses between two naturally hybridizing diploid species of Arabidopsis to assess the degree of isolation asymmetry at different postmating life stages. We found that pollen from Arabidopsis arenosa will usually fertilize ovules from Arabidopsis lyrata; the reverse receptivity being less complete. Maternal A. lyrata parents set more F1 hybrid seed, but germinate at lower frequency, reversing the asymmetry. As predicted by theory, A. lyrata (the maternal parent with lower seed viability in crosses) exhibited accelerated chloroplast evolution, indicating that cytonuclear incompatibilities may play a role in reproductive isolation. However, this direction of asymmetrical reproductive isolation is not replicated in natural suture zones, where delayed hybrid breakdown of fertility at later developmental stages, or later-acting selection against A. arenosa maternal hybrids (unrelated to hybrid fertility, e.g., substrate adaptation) may be responsible for an excess of A. lyrata maternal hybrids. Exogenous selection rather than cytonuclear incompatibilities thus shapes the asymmetrical postmating isolation in nature. PMID- 25937918 TI - Repetitive stress-related injury of the proximal metacarpus in a seven-year old Thoroughbred racehorse with emphasis on diagnostic analgesia of the proximopalmar metacarpus. AB - This report describes the diagnosis and management of repetitive stress-related injury (RSRI) of the proximal metacarpus in a seven-year old Thoroughbred racehorse. Intra-articular analgesia of the middle carpal joint (MCJ) as well as perineural analgesia of the lateral palmar nerve (LPN) abolished lameness and a diagnosis of RSRI of the proximopalmar metacarpus was made after nuclear scintigraphic examination. Given the response to intra-articular analgesia, the authors undertook a cadaver study in order to better describe the relationship between the medial and lateral palmar pouches of carpo-metacarpal joint (CMCJ), the LPN and the deep branch of the lateral palmar nerve (DBLPaN). PMID- 25937919 TI - Traumatic odontoid process synchondrosis fracture with atlantoaxial instability in a calf: clinical presentation and imaging findings. AB - A 6-week-old female Simmental calf was evaluated for acute non-ambulatory tetraparesis. Physical and laboratory examinations revealed no clinically relevant abnormalities. Neurological findings were consistent with acute, progressive and painful cervical myelopathy. Radiographs displayed a fractured odontoid process (dens axis) and vertebral step misalignment at the fracture site. A traumatic origin was suspected. Advanced diagnostic imaging was considered to allow better planning of potential surgical stabilisation and to exclude any additional lesions of the cervical vertebral column. However, during trailer transportation to the advanced diagnostic imaging and surgery site, the calf deteriorated neurologically and was humanely euthanised. Magnetic resonance imaging (MRI) and computed tomography (CT) were performed immediately post-mortem for scientific reasons. The MRI examination reflected the radiographic findings and confirmed severe spinal cord compression at the fracture site. In addition, a T2W-hyperintense signal change within the paravertebral soft tissue dorsal to the fracture site was indicative of a traumatic event. CT identified the fracture site at the synchondrosis between the odontoid process and the body of the axis, and this finding was confirmed by post-mortem examination. Advanced diagnostic imaging and post-mortem examination did not identify any other cervical lesion. In summary, this calf was diagnosed with a traumatic odontoid process synchondrosis fracture, which has not been reported previously in calves but presents a challenging and well-known fracture type in young children. This case report indicates that the odontoid process synchondrosis is a potential predisposed injury site and that traumatic odontoid process synchondrosis fractures should be considered as a potential differential in calves with acute cervical pain and/or signs of a cervical myelopathy. PMID- 25937920 TI - Methylation of free-floating deoxyribonucleic acid fragments in the bronchoalveolar lavage fluid of dogs with chronic bronchitis exposed to environmental tobacco smoke. AB - BACKGROUND: The etiology of canine chronic bronchitis (CB) is not completely understood, although exposure to environmental tobacco smoke (ETS) affects the airway inflammatory responses in some dogs with CB. The mechanism by which this occurs is unknown. FINDINGS: We investigated the concentrations and methylation rates of free-floating DNA fragments in bronchoalveolar lavage fluid (BALF) from dogs with chronic bronchitis. Based on serum cotinine levels, dogs with CB were divided into 2 groups: dogs that either had or had not been exposed to ETS. Our results demonstrated that the total nucleated cell and macrophage numbers increased in BALF of ETS-exposed dogs with CB. There were no significant differences in DNA concentrations and methylation rates in BALF between the 2 groups. However, 3 out of 8 dogs exposed to ETS had high DNA methylation rates in their BALF samples. CONCLUSION: Our results suggest that ETS exposure leads to epigenetic modifications of cellular components in BALF in dogs diagnosed with CB. PMID- 25878772 TI - Diversion at the ER: How Plasmodium falciparum exports proteins into host erythrocytes. AB - Malaria is caused by parasites which live in host erythrocytes and remodel these cells to provide optimally for the parasites' needs by exporting effector proteins into the host cells. Eight years ago the discovery of a host cell targeting sequence present in both soluble and transmembrane P. falciparum exported proteins generated a starting point for investigating the mechanism of parasite protein transport into infected erythrocytes. Since then many confusing facts about this targeting signal have emerged. In this paper, I try to make sense of them. PMID- 25937922 TI - The effect of improved hand hygiene on nosocomial MRSA control. AB - The purpose of this review is to examine studies that have assessed the association between hand hygiene enhancement and methicillin-resistant Staphylococcus aureus (MRSA) rates and to explore controversies surrounding this association. Many studies have been published confirming the link between improved hand hygiene compliance and reduction in MRSA acquisition and infections, including bacteremia. These studies have also shown the cost beneficial nature of these programmes. Despite considerable research some issues remain unanswered still, including the temporal relationship between hand hygiene enhancement strategies and decrease in MRSA rates, association between hand hygiene enhancement and MRSA-related surgical site infections, diminishing effect of hand hygiene compliance on MRSA rates after reaching a threshold and the role of instituting contact precautions in the setting of low MRSA rates and sufficient hand hygiene compliance. In conclusion, enhancement of hand hygiene compliance has been shown to reduce MRSA rates; however, some open issues warrant further investigation. PMID- 25937923 TI - Community acquired multi-drug resistant clinical isolates of Escherichia coli in a tertiary care center of Nepal. AB - BACKGROUND: Multi-drug resistance (MDR) in Gram-negative organisms is an alarming problem in the world. MDR and extensively-drug resistance (XDR) is in increasing trend due to the production of different types of beta (beta)-lactamases. Thus the aim of this study was to document the incidence of MDR and XDR in clinical isolates of Escherichia coli and also to find out the enzymatic mechanisms of beta-lactam antibiotics resistance. METHODS: Two hundred clinical isolates of Escherichia coli (E. coli) identified by standard laboratory methods were studied. Antibiotic susceptibility profile was performed for all the isolates and the suspected isolates were phenotypically tested for the production of extended spectrum beta-lactamase (ESBL), metallo beta-lactamase (MBL) and AmpC beta lactamase (AmpC) by recommended methods. RESULTS: Around three-fourth (78%) of the total isolates were multi-drug resistant. ESBL, MBL and AmpC production was found in 24%, 15% and 9% of isolates respectively. Amikacin, chloramphenicol and colistin were found to be the most effective antibiotics. CONCLUSIONS: High percentage of MDR was observed. beta-lactamase mediated resistance was also high. Thus, regular surveillance of drug resistance due to beta-lactamases production and infection control policy are of utmost importance to minimize the spread of resistant strains. PMID- 25937924 TI - Mineralized collagen scaffolds induce hMSC osteogenesis and matrix remodeling. AB - Biomaterials for bone tissue engineering must be able to instruct cell behavior in the presence of the complex biophysical and biomolecular environments encountered in vivo. While soluble supplementation strategies have been identified to enhance osteogenesis, they are subject to significant diffusive loss in vivo or the need for frequent re-addition in vitro. This investigation therefore explored whether biophysical and biochemical properties of a mineralized collagen-GAG scaffold were sufficient to enhance human mesenchymal stem cell (hMSC) osteogenic differentiation and matrix remodeling in the absence of supplementation. We examined hMSC metabolic health, osteogenic and matrix gene expression profiles, as well as matrix remodeling and mineral formation as a function of scaffold mineral content. We found that scaffold mineral content enhanced long term hMSC metabolic activity relative to non-mineralized scaffolds. While osteogenic supplementation or exogenous BMP-2 could enhance some markers of hMSC osteogenesis in the mineralized scaffold, we found the mineralized scaffold was itself sufficient to induce osteogenic gene expression, matrix remodeling, and mineral formation. Given significant potential for unintended consequences with the use of mixed media formulations and potential for diffusive loss in vivo, these findings will inform the design of instructive biomaterials for regenerative repair of critical-sized bone defects, as well as for applications where non-uniform responses are required, such as in biomaterials to address spatially-graded interfaces between orthopedic tissues. PMID- 25937926 TI - Concept and application of ideal protein for pigs. AB - Knowledge about the amino acid requirements and the response of pigs to the amino acid supply is essential in feed formulation. A deficient AA supply results in a reduction in performance while an oversupply is costly and leads to excessive nitrogen excretion with a potentially negative environmental impact. Amino acid requirements are determined to a large extent by the protein deposition in the body and, for lactating sows, by the protein exported in the milk. The concept of ideal protein was developed more than 50 years ago and refers to a protein with an amino acid profile that exactly meets the animal's requirement so that all amino acids are equally limiting for performance. Because Lys typically is the first-limiting amino acid, the ideal amino acid profile is often expressed relative to Lys. Although the ideal protein profile is often assumed to be constant for a given production stage, (small) changes in the ideal protein profile can occur within a production stage. This can be caused by changes in the relative contribution of the different components of amino acid requirements during the productive life on the animal (e.g. changes in the relative contribution of growth and maintenance). Amino acids requirements can be determined experimentally using dose-response studies. The design of the study, the chosen response criterion, and the statistical model affect the requirement estimate. Although considerable experimental work has been carried out to determine the requirements for Lys, Met, Thr, and Trp in growing pigs (and to a lesser extent in sows), little is known about the requirements for the other essential amino acids. Experimental dose-response studies generally focus on the requirement and less on the overall response (i.e. what are the consequences of an amino acid deficiency?). This latter aspect is, to some extent, accounted for in modelling approaches that quantify the response of the animal to the amino acid supply in a dynamic way. The paper describes the origin of ideal protein and illustrates how fundamental concepts of amino acid nutrition have been integrated in practical modeling approaches for the nutrition of growing pigs and sows. PMID- 25937925 TI - Placental accommodations for transport and metabolism during intra-uterine crowding in pigs. AB - Litter size and birth weights are limited by uterine capacity, defined as the ability of the uterus to maintain the appropriate development of some number of conceptuses. Uterine capacity is the result of the combined effects of uterine, placental and embryo/fetal function. The number of living conceptuses that the uterus is capable of supporting is greater during early gestation compared to later gestation. Plots of log fetal weight versus log placental weight also indicate that fetal weights are less sensitive to reduced placental weight (and therefore reduced intrauterine space) in early gestation compared to late gestation. However, even in late gestation, mechanisms still exist that maintain fetal growth when the size of the placenta is reduced. One such mechanism is likely to be improved development of the folded placental-epithelial/maternal epithelial bilayer. Fold depth, and therefore the maternal fetal interactive surface, increases as gestation advances and is greater in placenta from small fetuses. On the fetal side of the placenta, the epithelial bilayer is embedded in stromal tissue. Glycosaminoglycans are major components of stroma, including hyaluronan and heparan sulfate. Hyaluronidases and heparanases are present within placental tissues, and likely play roles in modification of stromal components to facilitate fold development. Glycosaminoglycans are polymers of forms of glucose (glucosamine, glucuronic acid, iduronic acid) suggesting that glycosaminoglycan synthesis may compete with the glucose needs of the developing fetus. Pig conceptuses are fructogenic, such that a substantial portion of glucose transferred from mother to fetus is converted to fructose. Fructose is an intermediate product in the synthesis of glucosamine from glucose, and glucosamine is linked to regulation of trophoblast cell proliferation through regulation of mTOR. These findings suggest a link between glucose, fructose, glucosamine synthesis, GAG production, and placental morphogenesis, but the details of these interactions remain unclear. In addition, recent placental epithelial transcriptome analysis identified several glucose, amino acid, lipid, vitamin, mineral and hormone transporter mechanisms within the placenta. Further elucidation of mechanisms of placental morphogenesis and solute transport could provide clues to improving nutrient transport to the pig fetus, potentially increasing litter size and piglet birth weights. PMID- 25937928 TI - Bivariate Gaussian bridges: directional factorization of diffusion in Brownian bridge models. AB - BACKGROUND: In recent years high resolution animal tracking data has become the standard in movement ecology. The Brownian Bridge Movement Model (BBMM) is a widely adopted approach to describe animal space use from such high resolution tracks. One of the underlying assumptions of the BBMM is isotropic diffusive motion between consecutive locations, i.e. invariant with respect to the direction. Here we propose to relax this often unrealistic assumption by separating the Brownian motion variance into two directional components, one parallel and one orthogonal to the direction of the motion. RESULTS: Our new model, the Bivariate Gaussian bridge (BGB), tracks movement heterogeneity across time. Using the BGB and identifying directed and non-directed movement within a trajectory resulted in more accurate utilisation distributions compared to dynamic Brownian bridges, especially for trajectories with a non-isotropic diffusion, such as directed movement or Levy like movements. We evaluated our model with simulated trajectories and observed tracks, demonstrating that the improvement of our model scales with the directional correlation of a correlated random walk. CONCLUSION: We find that many of the animal trajectories do not adhere to the assumptions of the BBMM. The proposed model improves accuracy when describing the space use both in simulated correlated random walks as well as observed animal tracks. Our novel approach is implemented and available within the "move" package for R. PMID- 25937927 TI - Mortality and morbidity patterns in under-five children with severe acute malnutrition (SAM) in Zambia: a five-year retrospective review of hospital-based records (2009-2013). AB - BACKGROUND: Severe acute malnutrition has continued to be growing problem in Sub Saharan Africa. We investigated the factors associated with morbidity and mortality of under-five children admitted and managed in hospital for severe acute malnutrition. METHODS: It was a retrospective quantitative review of hospital based records using patient files, ward death and discharge registers. It was conducted focussing on demographic, clinical and mortality data which was extracted on all children aged 0-60 months admitted to the University Teaching Hospital in Zambia from 2009 to 2013. Cox proportional Hazards regression was used to identify predictors of mortality and Kaplan Meier curves where used to predict the length of stay on the ward. RESULTS: Overall (n = 9540) under-five children with severe acute malnutrition were admitted during the period under review, comprising 5148 (54%) males and 4386 (46%) females. Kwashiorkor was the most common type of severe acute malnutrition (62%) while diarrhoea and pneumonia were the most common co-morbidities. Overall mortality was at 46% with children with marasmus having the lowest survival rates on Kaplan Meier graphs. HIV infected children were 80% more likely to die compared to HIV uninfected children (HR = 1.8; 95%CI: 1.6-1.2). However, over time (2009-2013), admissions and mortality rates declined significantly (mortality 51% vs. 35%, P < 0.0001). CONCLUSIONS: We find evidence of declining mortality among the core morbid nutritional conditions, namely kwashiorkor, marasmus and marasmic-kwashiorkor among under-five children admitted at this hospital. The reasons for this are unclear or could be beyond the scope of this study. This decline in numbers could be either be associated with declining admissions or due to the interventions that have been implemented at community level to combat malnutrition such as provision of "Ready to Use therapeutic food" and prevention of mother to child transmission of HIV at health centre level. Strategies that enhance and expand growth monitoring interventions at community level to detect malnutrition early to reduce incidence of severe cases and mortality need to be strengthened. PMID- 25937930 TI - Bio-ethanol production by a novel autochthonous thermo-tolerant yeast isolated from wastewater. AB - BACKGROUND: It has been known for years that ethanol is a bio-fuel to replace fossil fuels. The ethanol industry requires the utilization of micro-organisms capable production with stresses. The purpose of present study was to isolate and characterize ethanologenic yeast with high potential application at high temperature to produce bio-ethanol. METHODS: To isolate ethanologenic yeasts, wastewater samples from a starch producer plant in Varamin, Iran were used. The isolates were identified by molecular characterization. Characteristics of the isolated strains were determined at 30, 35, 40 and 45 degrees C for 48 hours. RESULTS: 50 yeast strains capable of growing well in agar plates in a temperature range of 30-45 degrees C were isolated. Out of the isolated strains, only three strains were screened for their ability to grow at 45 degrees C. Selected yeast, designated as AT-3 strain which showed efficient flocculation capabilities with higher ethanol production and grew faster as compared to the rest of strains in media with 180 g/L glucose at 35 degrees C. The selected yeast was identified as a new strain of Saccharomyces cerevisiae and submitted to the Gene-Bank database. Its' optimum growth temperature was between 35 and 40 degrees C. The results showed that during the bio-ethanol production 2.5 * 10(10) and 8.5 * 10(9) (CFU/mL) were a good indication of strain capability in heat tolerance. Also, ethanol produced at a raise of 6.9% and 6.85% (w/v) at 35 and 40 degrees C, respectively, whereas glucose-to-ethanol conversion yield was about 75% of the theoretical value. CONCLUSIONS: Results emphasized that the isolated strain identified as Saccharomyces cerevisiae. This specific strain has thermo-tolerant, osmo-tolerant, flocculating capabilities with potential for application in developing a low cost ethanol industry. PMID- 25937929 TI - Contemporary management of 'Inguinal disruption' in the sportsman's groin. AB - BACKGROUND: This article helps define the basic principles to diagnosis and manage one of the surgically correctable causes of the 'painful groin', which is commonly described as the sportsman's groin. DISCUSSION: Often many surgeons will describe a single pathology for the sportsman's groin such as a 'hernia' but often other coexisting etiologies may be present. Management relies on a multidisciplinary approach with a diagnosis initially made by a history of pain in the groin on exercise. Physiotherapy is the recommended first line treatment and is designed to concentrate on strengthening of the abdominal wall muscle and tendon groups around the groin area. Surgery does have a role in the sportsman's groin but only once all conservative measures have been exhausted or if there is a clear identified pathology causing the groin symptoms such as posterior wall defect. Surgical principles for an inguinal disruption include either open or laparoscopic techniques reinforcing the inguinal canal with a mesh or suture repair followed by an active rehabilitation programme. SUMMARY: Once an accurate diagnosis has been achieved, contemporary guidance for inguinal disruption requires a multidisciplinary approach including a specially designed physiotherapy regime and possibly surgery. PMID- 25937931 TI - Use of mobile phone during pregnancy and the risk of spontaneous abortion. AB - BACKGROUND: Exposure to electromagnetic fields of cell phones increasingly occurs, but the potential influence on spontaneous abortion has not been thoroughly investigated. METHODS: In a case-control study, 292 women who had an unexplained spontaneous abortion at < 14 weeks gestation and 308 pregnant women > 14 weeks gestation were enrolled. Two data collection forms were completed; one was used to collect data about socioeconomic and obstetric characteristics, medical and reproductive history, and lifestyles. Another was used to collect data about the use of cell phones during pregnancy. For the consideration of cell phone effects, we measured the average calling time per day, the location of the cell phones when not in use, use of hands-free equipment, use of phones for other applications, the specific absorption rate (SAR) reported by the manufacturer and the average of the effective SAR (average duration of calling time per day * SAR). Analyses were carried out with statistical package state software(SPSS)v.16. RESULTS: All the data pertaining to mobile phones were different between the two groups except the use of hands free devices (p < 0.001). CONCLUSION: Our result suggests that use of mobile phones can be related to the early spontaneous abortions. PMID- 25937932 TI - (Why) should we require consent to participation in research? AB - It is widely accepted that informed consent is a requirement of ethical biomedical research. It is less clear why this is so. As an argumentative strategy the article asks whether it would be legitimate for the state to require people to participate in research. This article argues that the consent requirement cannot be defended by appeal to any simple principle, such as not treating people merely as a means, bodily integrity, and autonomy. As an argumentative strategy the article asks whether it would be legitimate for the state to require people to participate in research. I argue that while it would be legitimate and potentially justifiable to coerce people to participate in research as a matter of first-order moral principles, there are good reasons to adopt a general prohibition on coercive participation as a matter of second-order morality. PMID- 25937933 TI - Ethical, legal, social, and policy issues in the use of genomic technology by the U.S. Military. AB - Advances in genomic science are attracting the interest of the U.S. military for their potential to improve medical care for members of the military and to aid in military recruitment, training, specialization, and mission accomplishment. While researchers have explored the ethical, legal, and social issues raised by the use of genomic science in a wide variety of contexts, there has been virtually no examination of these issues in connection with the use of genomics by the military. This article identifies potential uses of genomic science by the military, proposes an applicable ethical and legal framework, and applies the framework to provide ethical and legal guidance for military decision-makers. PMID- 25937934 TI - The ethics of promulgating principles of research ethics: the problem of diversion effects. AB - There is an important distinction between ethical standards for the conduct of research with human subjects and the ethics of promulgating principles of research ethics. Those who promulgate ethical standards for the conduct of research have an ethical responsibility to consider the consequences to which those promulgations give rise. In particular, they must consider whether their promulgations will give researchers incentives not to conduct research or not to conduct research in locales in which participants would benefit from participation. I first show how such 'diversion effects' are possible and then examine four principles of research ethics in that light. I then consider several objections to the argument that those who promulgate principles of research ethics should consider diversion effects. PMID- 25937935 TI - Organization and implementation of mass medical rescue after an earthquake. AB - On May 12, 2008, an 8.0-magnitude earthquake occurred in Wenchuan, Sichuan Province. In this disaster, 69,000 people were killed, 18,000 people were reported missing, and 37,000 people were injured, including more than 10,000 who were seriously injured. Trauma was the most commonly observed type of injury, with fractures accounting for 74% of all injury cases. On April 14, 2010, a 7.1 magnitude earthquake occurred in Yushu of Qinghai Province. In this disaster, 2,698 people were killed, 270 people were reported missing, and 11,000 people were injured, including more than 3,100 who were seriously injured. Fracture injury accounted for 58.4% of all injury cases. After each earthquake, the Chinese Army Medical Services responded promptly, according to the previously established guidelines, and sent out elite forces to the disaster areas, with the objectives of organizing, coordinating and participating in an efficient and evidence-based medical rescue effort. After the Wenchuan earthquake, 397 mobile medical service teams including 7,061 health workers were sent to the disaster areas. A total of 69,000 casualties were treated, and 22,000 surgeries were performed. After the Yushu earthquake, 25 mobile medical service teams involving 2,025 health workers were sent. They performed 1,635 surgeries and created an astounding outcome of "zero deaths" in the aftermath of the earthquake during their treatment of casualties in a high-altitude region. Within a week after each earthquake, the military teams rescued approximately 60% of the total number of rescued casualties and evacuated approximately 80% of the total number of evacuated sick or wounded victims, playing a critical role and making invaluable contributions to earthquake relief. The experience and lessons learned from the rescue efforts of the Chinese military after the two earthquakes have highlighted several key aspects in emergency medical rescue: (1) medical rescue theories must be updated; (2) military-civilian cooperation must be stressed; (3) professional rescue forces must be strengthened; (4) supporting facilities must be improved; and (5) international exchanges and cooperation must be deepened. PMID- 25937936 TI - High altitude medicine in China in the 21st century: opportunities and challenges. AB - China has the largest plateau, Qinghai-Tibet Plateau, where inhabited the most high altitude populations. Moreover, millions of people from plain areas come to the plateau for travel and work purposes and the number of the newcomers has been increasing every year. The hypoxic environment of plateau raised a series of related health issues in the new immigrants, so have created a special medical discipline - High Altitude Medicine. Over the past decades, researches on high altitude medicine have never being ceased in China, and lots of research findings have been reported. Application and practice of these achievements have greatly decreased the mobility and mortality of high-altitude diseases, however, there remained lots of questions to be elucidated. In view of this, the authors were granted a special project from the National Health and Family Planning Commission of China, and conducted a multi-center, prospective, on-scene high altitude medicine study for the acute mountain sickness. Some innovative findings were achieved, and the parameters for diagnosis and application conditions were proposed. Furthermore, the different diagnoses and treatment effects were compared, and a more standardized, reasonable scheme was drawn up. Regarding the unbalanced medical resources in the vast high altitude area, an application system for the public and the army has been established. In the 21st century, innovations in China and novel research approaches have provided great opportunities for the development of high altitude medicine. It is believed that the researchers in China are able to catch the opportunities and address the challenges. PMID- 25937937 TI - Health and sanitary status in 1970 of Tubu nomads dwelling in Northeastern Niger. AB - BACKGROUND: The Tubu are nomadic people who live in remote parts of the central Sahara, primarily in the Tibesti massif (Chad), and in both Northeastern Niger and Southern Libya. No data about the Tubu's health and sanitary status are currently available. METHODS: In 1970, the "Mission Anthropologique Belge au Niger" (MABN) investigated a Tubu tribe named Broaya that lived on the northeastern rim of the Tenere desert. One hundred and fifty-one adult volunteers were investigated. The environmental fauna of medical importance was also studied. RESULTS: Albeit 43 year-old, these results have not been previously published. The estimated age of death for fathers was approximately 56 years, and that for mothers was 60 years. The overall perinatal mortality rate was 232%, the overall infant mortality rate was 153%, and the overall child mortality rate was 99%. The physical examination found 6 cases of blindness (4.0%). Five subjects presented with an elevated blood pressure (3.3%), and 5 (3.3%) displayed an abnormal thoracic auscultation evocative of tuberculosis or of an acute lung infection. In the field, no blood-fluke eggs were found in the urine samples. The blood thin films and stool samples were preserved then subsequently examined in Toulouse. The search for blood parasites was negative. Three subjects (2%) passed E. histolytica/E. dispar cysts in stools, 16 (10.6%) were parasitized with Giardia sp. and 4 (2.65%) were parasitized with Hymenolepis nana. Two specimens of scorpions captured in the camp were subsequently identified as belonging to the harmful genus Androctonus or Leiurus. An investigation into the freshwater fauna was conducted in the marshy ponds surrounding the ghost city of Djado, and no intermediate snail hosts for schistosomiasis haematobium were found. Larvae and nymphs, of Anopheles hispaniola and of An. multicolor, which are not efficient vectors for malaria, were collected. CONCLUSIONS: Infection-related blindness and trachoma, along with acute pulmonary infections and probably tuberculosis were the major health burden in this tribe. The harsh dry and hot climate may explain the low prevalence of soil-transmitted protozoan diseases or helminthiases. PMID- 25937938 TI - Diagnosis and Management of Hyponatremia in Patients with Aneurysmal Subarachnoid Hemorrhage. AB - Hyponatremia is the most common, clinically-significant electrolyte abnormality seen in patients with aneurysmal subarachnoid hemorrhage. Controversy continues to exist regarding both the cause and treatment of hyponatremia in this patient population. Lack of timely diagnosis and/or providing inadequate or inappropriate treatment can increase the risk of morbidity and mortality. We review recent literature on hyponatremia in subarachnoid hemorrhage and present currently recommended protocols for diagnosis and management. PMID- 25937939 TI - CallSim: Evaluation of Base Calls Using Sequencing Simulation. AB - Accurate base calls generated from sequencing data are required for downstream biological interpretation, particularly in the case of rare variants. CallSim is a software application that provides evidence for the validity of base calls believed to be sequencing errors and it is applicable to Ion Torrent and 454 data. The algorithm processes a single read using a Monte Carlo approach to sequencing simulation, not dependent upon information from any other read in the data set. Three examples from general read correction, as well as from error-or variant classification, demonstrate its effectiveness for a robust low-volume read processing base corrector. Specifically, correction of errors in Ion Torrent reads from a study involving mutations in multidrug resistant Staphylococcus aureus illustrates an ability to classify an erroneous homopolymer call. In addition, support for a rare variant in 454 data for a mixed viral population demonstrates "base rescue" capabilities. CallSim provides evidence regarding the validity of base calls in sequences produced by 454 or Ion Torrent systems and is intended for hands-on downstream processing analysis. These downstream efforts, although time consuming, are necessary steps for accurate identification of rare variants. PMID- 25937940 TI - Nonlinear dependence in the discovery of differentially expressed genes. AB - Microarray data are used to determine which genes are active in response to a changing cell environment. Genes are "discovered" when they are significantly differentially expressed in the microarray data collected under the differing conditions. In one prevalent approach, all genes are assumed to satisfy a null hypothesis, H 0, of no difference in expression. A false discovery (type 1 error) occurs when H 0 is incorrectly rejected. The quality of a detection algorithm is assessed by estimating its number of false discoveries, ??. Work involving the second-moment modeling of the z-value histogram (representing gene expression differentials) has shown significantly deleterious effects of intergene expression correlation on the estimate of ??. This paper suggests that nonlinear dependencies could likewise be important. With an applied emphasis, this paper extends the "moment framework" by including third-moment skewness corrections in an estimator of ??. This estimator combines observed correlation (corrected for sampling fluctuations) with the information from easily identifiable null cases. Nonlinear-dependence modeling reduces the estimation error relative to that of linear estimation. Third-moment calculations involve empirical densities of 3 * 3 covariance matrices estimated using very few samples. The principle of entropy maximization is employed to connect estimated moments to ?? inference. Model results are tested with BRCA and HIV data sets and with carefully constructed simulations. PMID- 25937941 TI - Chemical Entity Recognition and Resolution to ChEBI. AB - Chemical entities are ubiquitous through the biomedical literature and the development of text-mining systems that can efficiently identify those entities are required. Due to the lack of available corpora and data resources, the community has focused its efforts in the development of gene and protein named entity recognition systems, but with the release of ChEBI and the availability of an annotated corpus, this task can be addressed. We developed a machine-learning based method for chemical entity recognition and a lexical-similarity-based method for chemical entity resolution and compared them with Whatizit, a popular dictionary-based method. Our methods outperformed the dictionary-based method in all tasks, yielding an improvement in F-measure of 20% for the entity recognition task, 2-5% for the entity-resolution task, and 15% for combined entity recognition and resolution tasks. PMID- 25937942 TI - Differential Expression Analysis for RNA-Seq Data. AB - RNA-Seq is increasingly being used for gene expression profiling. In this approach, next-generation sequencing (NGS) platforms are used for sequencing. Due to highly parallel nature, millions of reads are generated in a short time and at low cost. Therefore analysis of the data is a major challenge and development of statistical and computational methods is essential for drawing meaningful conclusions from this huge data. In here, we assessed three different types of normalization (transcript parts per million, trimmed mean of M values, quantile normalization) and evaluated if normalized data reduces technical variability across replicates. In addition, we also proposed two novel methods for detecting differentially expressed genes between two biological conditions: (i) likelihood ratio method, and (ii) Bayesian method. Our proposed methods for finding differentially expressed genes were tested on three real datasets. Our methods performed at least as well as, and often better than, the existing methods for analysis of differential expression. PMID- 25937943 TI - NucVoter: A Voting Algorithm for Reliable Nucleosome Prediction Using Next Generation Sequencing Data. AB - Nucleosomes, which consist of DNA wrapped around histone octamers, are dynamic, and their structure, including their location, size, and occupancy, can be transformed. Nucleosomes can regulate gene expression by controlling the DNA accessibility of proteins. Using next-generation sequencing techniques along with such laboratory methods as micrococcal nuclease digestion, predicting the genomic locations of nucleosomes is possible. However, the true locations of nucleosomes are unknown, and it is difficult to determine their exact locations using next generation sequencing data. This paper proposes a novel voting algorithm, NucVoter, for the reliable prediction of nucleosome locations. Multiple models verify the consensus areas in which nucleosomes are placed by the model with the highest priority. NucVoter significantly improves the performance of nucleosome prediction. PMID- 25937944 TI - Modern Computational Techniques for the HMMER Sequence Analysis. AB - This paper focuses on the latest research and critical reviews on modern computing architectures, software and hardware accelerated algorithms for bioinformatics data analysis with an emphasis on one of the most important sequence analysis applications-hidden Markov models (HMM). We show the detailed performance comparison of sequence analysis tools on various computing platforms recently developed in the bioinformatics society. The characteristics of the sequence analysis, such as data and compute-intensive natures, make it very attractive to optimize and parallelize by using both traditional software approach and innovated hardware acceleration technologies. PMID- 25937945 TI - Transcriptome Analysis of Spermophilus lateralis and Spermophilus tridecemlineatus Liver Does Not Suggest the Presence of Spermophilus-Liver Specific Reference Genes. AB - The expressions of reference genes used in gene expression studies are assumed to be stable under most circumstances. However, studies had demonstrated that genes assumed to be stably expressed in a species are not necessarily stably expressed in other organisms. This study aims to evaluate the likelihood of genus-specific reference genes for liver using comparable microarray datasets from Spermophilus lateralis and Spermophilus tridecemlineatus. The coefficient of variance (CV) of each probe was calculated and there were 178 probes common between the lowest 10% CV of both datasets (n = 1258). All 3 lists were analysed by NormFinder. Our results suggest that the most invariant probe for S. tridecemlineatus was 02n12, while that for S. lateralis was 24j21. However, our results showed that Probes 02n12 and 24j21 are ranked 8644 and 926 in terms of invariancy for S. lateralis and S. tridecemlineatus respectively. This suggests the lack of common liver specific reference probes for both S. lateralis and S. tridecemlineatus. Given that S. lateralis and S. tridecemlineatus are closely related species and the datasets are comparable, our results do not support the presence of genus specific reference genes. PMID- 25937946 TI - Exploiting identifiability and intergene correlation for improved detection of differential expression. AB - Accurate differential analysis of microarray data strongly depends on effective treatment of intergene correlation. Such dependence is ordinarily accounted for in terms of its effect on significance cutoffs. In this paper, it is shown that correlation can, in fact, be exploited to share information across tests and reorder expression differentials for increased statistical power, regardless of the threshold. Significantly improved differential analysis is the result of two simple measures: (i) adjusting test statistics to exploit information from identifiable genes (the large subset of genes represented on a microarray that can be classified a priori as nondifferential with very high confidence], but (ii) doing so in a way that accounts for linear dependencies among identifiable and nonidentifiable genes. A method is developed that builds upon the widely used two-sample t-statistic approach and uses analysis in Hilbert space to decompose the nonidentified gene vector into two components that are correlated and uncorrelated with the identified set. In the application to data derived from a widely studied prostate cancer database, the proposed method outperforms some of the most highly regarded approaches published to date. Algorithms in MATLAB and in R are available for public download. PMID- 25937947 TI - A Computational Approach towards the Understanding of Plasmodium falciparum Multidrug Resistance Protein 1. AB - The emergence of drug resistance in Plasmodium falciparum tremendously affected the chemotherapy worldwide while the intense distribution of chloroquine resistant strains in most of the endemic areas added more complications in the treatment of malaria. The situation has even worsened by the lack of molecular mechanism to understand the resistance conferred by Plasmodia species. Recent studies have suggested the association of antimalarial resistance with P. falciparum multidrug resistance protein 1 (PfMDR1), an ATP-binding cassette (ABC) transporter and a homologue of human P-glycoprotein 1 (P-gp1). The present study deals about the development of PfMDR1 computational model and the model of substrate transport across PfMDR1 with insights derived from conformations relative to inward- and outward-facing topologies that switch on/off the transportation system. Comparison of ATP docked positions and its structural motif binding properties were found to be similar among other ATPases, and thereby contributes to NBD domains dimerization, a unique structural agreement noticed in Mus musculus Pgp and Escherichia coli MDR transporter homolog (MsbA). The interaction of leading antimalarials and phytochemicals within the active pocket of both wild-type and mutant-type PfMDR1 demonstrated the mode of binding and provided insights of less binding affinity thereby contributing to parasite's resistance mechanism. PMID- 25937948 TI - Stormbow: A Cloud-Based Tool for Reads Mapping and Expression Quantification in Large-Scale RNA-Seq Studies. AB - RNA-Seq is becoming a promising replacement to microarrays in transcriptome profiling and differential gene expression study. Technical improvements have decreased sequencing costs and, as a result, the size and number of RNA-Seq datasets have increased rapidly. However, the increasing volume of data from large-scale RNA-Seq studies poses a practical challenge for data analysis in a local environment. To meet this challenge, we developed Stormbow, a cloud-based software package, to process large volumes of RNA-Seq data in parallel. The performance of Stormbow has been tested by practically applying it to analyse 178 RNA-Seq samples in the cloud. In our test, it took 6 to 8 hours to process an RNA Seq sample with 100 million reads, and the average cost was $3.50 per sample. Utilizing Amazon Web Services as the infrastructure for Stormbow allows us to easily scale up to handle large datasets with on-demand computational resources. Stormbow is a scalable, cost effective, and open-source based tool for large scale RNA-Seq data analysis. Stormbow can be freely downloaded and can be used out of box to process Illumina RNA-Seq datasets. PMID- 25937949 TI - Discovery of YopE Inhibitors by Pharmacophore-Based Virtual Screening and Docking. AB - Gram-negative bacteria Yersinia secrete virulence factors that invade eukaryotic cells via type III secretion system. One particular virulence member, Yersinia outer protein E (YopE), targets Rho family of small GTPases by mimicking regulator GAP protein activity, and its secretion mainly induces cytoskeletal disruption and depolymerization of actin stress fibers within the host cell. In this work, potent drug-like inhibitors of YopE are investigated with virtual screening approaches. More than 500,000 unique small molecules from ZINC database were screened with a five-point pharmacophore, comprising three hydrogen acceptors, one hydrogen donor, and one ring, and derived from different salicylidene acylhydrazides. Binding modes and features of these molecules were investigated with a multistep molecular docking approach using Glide software. Virtual screening hits were further analyzed based on their docking score, chemical similarity, pharmacokinetic properties, and the key Arg144 interaction along with other active site residue interactions with the receptor. As a final outcome, a diverse set of ligands with inhibitory potential were proposed. PMID- 25937950 TI - SUMOhunt: Combining Spatial Staging between Lysine and SUMO with Random Forests to Predict SUMOylation. AB - Modification with SUMO protein has many key roles in eukaryotic systems which renders the identification of its target proteins and sites of considerable importance. Information regarding the SUMOylation of a protein may tell us about its subcellular localization, function, and spatial orientation. This modification occurs at particular and not all lysine residues in a given protein. In competition with biochemical means of modified-site recognition, computational methods are strong contenders in the prediction of SUMOylation-undergoing sites on proteins. In this research, physicochemical properties of amino acids retrieved from AAIndex, especially those involved in docking of modifier and target proteins and optimal presentation of target lysine, in combination with sequence information and random forest-based classifier presented in WEKA have been used to develop a prediction model, SUMOhunt, with statistics significantly better than all previous predictors. In this model 97.56% accuracy, 100% sensitivity, 94% specificity, and 0.95 MCC have been achieved which shows that proposed amino acid properties have a significant role in SUMO attachment. SUMOhunt will hence bring great reliability and efficiency in SUMOylation prediction. PMID- 25937951 TI - IsoPlotter(+): A Tool for Studying the Compositional Architecture of Genomes. AB - Eukaryotic genomes, particularly animal genomes, have a complex, nonuniform, and nonrandom internal compositional organization. The compositional organization of animal genomes can be described as a mosaic of discrete genomic regions, called "compositional domains," each with a distinct GC content that significantly differs from those of its upstream and downstream neighboring domains. A typical animal genome consists of a mixture of compositionally homogeneous and nonhomogeneous domains of varying lengths and nucleotide compositions that are interspersed with one another. We have devised IsoPlotter, an unbiased segmentation algorithm for inferring the compositional organization of genomes. IsoPlotter has become an indispensable tool for describing genomic composition and has been used in the analysis of more than a dozen genomes. Applications include describing new genomes, correlating domain composition with gene composition and their density, studying the evolution of genomes, testing phylogenomic hypotheses, and detect regions of potential interbreeding between human and extinct hominines. To extend the use of IsoPlotter, we designed a completely automated pipeline, called IsoPlotter(+) to carry out all segmentation analyses, including graphical display, and built a repository for compositional domain maps of all fully sequenced vertebrate and invertebrate genomes. The IsoPlotter(+) pipeline and repository offer a comprehensive solution to the study of genome compositional architecture. Here, we demonstrate IsoPlotter(+) by applying it to human and insect genomes. The computational tools and data repository are available online. PMID- 25937952 TI - Construction and Analysis of the Cell Surface's Protein Network for Human Sperm Egg Interaction. AB - Sperm-egg interaction is one of the most impressive processes in sexual reproduction, and understanding the molecular mechanism is crucial in solving problems in infertility and failed in vitro fertilization. The main purpose of this study is to map the sperm-egg interaction network between cell-surface proteins and perform an interaction analysis on this new network. We built the first protein interaction network of human sperm-egg binding and fusion proteins that consists of 84 protein nodes and 112 interactions. The gene ontology analysis identified a number of functional clusters that may be involved in the sperm-egg interaction. These include G-protein coupled receptor protein signaling pathway, cellular membrane fusion, and single fertilization. The PPI network showed a highly interconnected network and identified a set of candidate proteins: ADAM-ZP3, ZP3-CLGN, IZUMO1-CD9, and ADAM2-IZUMO1 that may have an important role in sperm-egg interaction. The result showed that the ADAM2 may mediate interaction between two essential factors CD9 and IZUMO1. The KEGG analysis showed 12 statistically significant pathways with 10 proteins associated with cancer, suggesting a common pathway between tumor fusion and sperm-egg fusion. We believe that the availability of this map will assist future researches in the fertilization mechanism and will also facilitate biological interpretation of sperm-egg interaction. PMID- 25937953 TI - Comparison of merging and meta-analysis as alternative approaches for integrative gene expression analysis. AB - An increasing amount of microarray gene expression data sets is available through public repositories. Their huge potential in making new findings is yet to be unlocked by making them available for large-scale analysis. In order to do so it is essential that independent studies designed for similar biological problems can be integrated, so that new insights can be obtained. These insights would remain undiscovered when analyzing the individual data sets because it is well known that the small number of biological samples used per experiment is a bottleneck in genomic analysis. By increasing the number of samples the statistical power is increased and more general and reliable conclusions can be drawn. In this work, two different approaches for conducting large-scale analysis of microarray gene expression data-meta-analysis and data merging-are compared in the context of the identification of cancer-related biomarkers, by analyzing six independent lung cancer studies. Within this study, we investigate the hypothesis that analyzing large cohorts of samples resulting in merging independent data sets designed to study the same biological problem results in lower false discovery rates than analyzing the same data sets within a more conservative meta analysis approach. PMID- 25937955 TI - The essence of ATP coupling. AB - The traditional explanation of ATP coupling is based on the raising of the equilibrium constants of the biochemical reactions. But in the frames of the detailed balance, no coupling occurs under thermodynamic equilibrium. The role of ATP in coupling is not that it provides an increase in the equilibrium constants of thermodynamically unfavorable reactions but that the unfavorable reactions are replaced by other reactions which kinetically are more favorable and give rise to the same products. The coupling with ATP hydrolysis results in the formation of quasistationary intermediate states. PMID- 25937954 TI - Hierarchical ensemble methods for protein function prediction. AB - Protein function prediction is a complex multiclass multilabel classification problem, characterized by multiple issues such as the incompleteness of the available annotations, the integration of multiple sources of high dimensional biomolecular data, the unbalance of several functional classes, and the difficulty of univocally determining negative examples. Moreover, the hierarchical relationships between functional classes that characterize both the Gene Ontology and FunCat taxonomies motivate the development of hierarchy-aware prediction methods that showed significantly better performances than hierarchical-unaware "flat" prediction methods. In this paper, we provide a comprehensive review of hierarchical methods for protein function prediction based on ensembles of learning machines. According to this general approach, a separate learning machine is trained to learn a specific functional term and then the resulting predictions are assembled in a "consensus" ensemble decision, taking into account the hierarchical relationships between classes. The main hierarchical ensemble methods proposed in the literature are discussed in the context of existing computational methods for protein function prediction, highlighting their characteristics, advantages, and limitations. Open problems of this exciting research area of computational biology are finally considered, outlining novel perspectives for future research. PMID- 25937956 TI - Serum prolidase activity, oxidant and antioxidant status in nonulcer dyspepsia and healthy volunteers. AB - Helicobacter pylori (H. pylori) infection is associated with increased oxidative stress and serum prolidase activity (SPA) in many diseases. We aimed to observe SPA and oxidative stress in nonulcer dyspepsia (NUD) infected with and without H. pylori among eastern Indians. 106 patients with H. pylori positive NUD, 82 patients with H. pylori negative NUD, and 50 healthy individuals were selected. SPA, total antioxidant capacity (TAOC), and total oxidant status (TOS) were measured with the use of spectrophotometer and an automated measurement method. SPA, TOS, and oxidative stress index (OSI) were significantly higher in patients with H. pylori positive than H. pylori negative NUD and healthy individuals (all P < 0.0001), whereas TAOC was significantly lower (P < 0.0001). Nonsignificant, increased SPA (P value = 0.6083) and decreased TAOC (P value = 0.1186) were observed in patients with H. pylori negative NUD than healthy individuals, while increased TOS and OSI were significant (P < 0.0001). Weak, nonsignificant correlations were observed between serum prolidase activity and TAOC, TOS, and OSI in H. pylori positive cases. Thus, increased SPA along with increased oxidative stress was observed, which seem to be closely associated with H. pylori infection. SPA and oxidative stress seem to be used as biomarkers for H. pylori infection in NUD. PMID- 25937957 TI - Biochemical Studies on Methylglyoxal-Mediated Glycated Histones: Implications for Presence of Serum Antibodies against the Glycated Histones in Patients with Type 1 Diabetes Mellitus. AB - Reactive carbonyl species (RCS) mainly reacts with lysine and arginine residues of proteins to form advanced glycation end products (AGEs). Histone was glycoxidated with glyoxal and methylglyoxal. It was characterized by polyacrylamide gel electrophoresis and quenching studies involving penicillamine and aminoguanidine as carbonyl scavengers. Further characterization of histone modified with methylglyoxal was done by UV, fluorescence, and IR spectrophotometry. Spectral analysis of the protein clearly demonstrates structural perturbation in the histone by methylglyoxal. Methylglyoxal-induces cross-linking in the protein leading to aggregation. Role of methylglyoxal mediated glycoxidation of histone in type 1 diabetes was also undertaken. Antibodies were detected against glycoxidated histone in sera of type 1 diabetes patients by solid-phase enzyme immunoassay. The findings indicate that as a result of structural perturbation in histone by methylglyoxal, the modified histone may be involved in production of serum antibodies in the diabetes patients. PMID- 25937959 TI - A sequence-specific nicking endonuclease from streptomyces: purification, physical and catalytic properties. AB - A sequence-specific nicking endonuclease from Streptomyces designated as DC13 was purified to near homogeneity. Starting with 30 grams of wet cells, the enzyme was purified by ammonium sulfate fractionation, DEAE cellulose, and phenyl-Sepharose chromatography. The purified protein had a specific activity 1000 units/mg and migrated on SDS-PAGE gel with an estimated molecular weight of 71 kDa. Determination of subunit composition by gel filtration chromatography indicated that the native enzyme is a monomer. When incubated with different DNA substrates including pBluescript II KS, pUC118, pET-15b, and pET-26b, the enzyme converted these supercoiled plasmids to a mixture of open circular and linear DNA products, with the open circular DNA as the major cleavage product. Analysis of the kinetic of DNA cleavage showed that the enzyme appeared to cleave super-coiled plasmid in two distinct steps: a rapid cleavage of super-coiled plasmid to an open circular DNA followed a much slower step to linear DNA. The DNA cleavage reaction of the enzyme required Mg(2+) as a cofactor. Based on the monomeric nature of the enzyme, the kinetics of DNA cleavage exhibited by the enzyme, and cofactor requirement, it is suggested here that the purified enzyme is a sequence-specific nicking endonuclease that is similar to type IIS restriction endonuclease. PMID- 25937958 TI - Nanoparticles for brain drug delivery. AB - The central nervous system, one of the most delicate microenvironments of the body, is protected by the blood-brain barrier (BBB) regulating its homeostasis. BBB is a highly complex structure that tightly regulates the movement of ions of a limited number of small molecules and of an even more restricted number of macromolecules from the blood to the brain, protecting it from injuries and diseases. However, the BBB also significantly precludes the delivery of drugs to the brain, thus, preventing the therapy of a number of neurological disorders. As a consequence, several strategies are currently being sought after to enhance the delivery of drugs across the BBB. Within this review, the recently born strategy of brain drug delivery based on the use of nanoparticles, multifunctional drug delivery systems with size in the order of one-billionth of meters, is described. The review also includes a brief description of the structural and physiological features of the barrier and of the most utilized nanoparticles for medical use. Finally, the potential neurotoxicity of nanoparticles is discussed, and future technological approaches are described. The strong efforts to allow the translation from preclinical to concrete clinical applications are worth the economic investments. PMID- 25937960 TI - Cav1.2, cell proliferation, and new target in atherosclerosis. AB - Cav1.2 calcium channels are the principal proteins involved in electrical, mechanical, and/or signaling functions of the cell. Cav1.2 couples membrane depolarization to the transient increase in intracellular Ca(2+) concentration that is a trigger for muscle contraction and CREB-dependent transcriptional activation. The CACNA1C gene coding for the Cav1.2 pore-forming alpha 1C subunit is subject to extensive alternative splicing. This review is the first attempt to follow the association between cell proliferation, Cav1.2 expression and splice variation, and atherosclerosis. Based on insights into the association between the atherosclerosis-induced molecular remodeling of Cav1.2, proliferation of vascular smooth muscle cells, and CREB-dependent transcriptional signaling, this review will give a perspective outlook for the use of the CACNA1C exon skipping as a new potential gene therapy approach to atherosclerosis. PMID- 25937961 TI - Human sprouty1 suppresses urokinase receptor-stimulated cell migration and invasion. AB - The urokinase-type plasminogen activator receptor (uPAR) has been implicated in several processes in tumor progression including cell migration and invasion in addition to initiation of signal transduction. Since uPAR lacks a transmembrane domain, it uses the interaction with other proteins to modulate intracellular signal transduction. We have previously identified hSpry1 as a partner protein of uPAR, suggesting a physiological role for hSpry1 in the regulation of uPAR signal transduction. In this study, hSpry1 was found to colocalize with uPAR upon stimulation with epidermal growth factor (EGF), urokinase (uPA), or its amino terminal fragment (uPA-ATF), implicating a physiological role of hSpry1 in regulation of uPAR signalling pathway. Moreover, hSpry1 was able to inhibit uPAR stimulated cell migration in HEK293/uPAR, breast carcinoma, and colorectal carcinoma cells. In addition, hSpry1 was found to inhibit uPAR-stimulated cell invasion in breast carcinoma and osteosarcoma cell lines. Increasing our understanding of how hSpry1 negatively regulates uPAR-stimulated cellular functions may determine a distinctive role for hSpry1 in tumour suppression. PMID- 25937962 TI - Variable-temperature size exclusion chromatography for the study of the structural changes in g-quadruplex. AB - The conformational equilibria of a guanine-rich sequence found at the promoter region of the human c-kit oncogene are studied by means of circular dichroism spectroscopy (CD) and variable-temperature size exclusion chromatography (SEC). It is shown that the wild sequence ckit21 exists as a mixture of monomeric and multimeric G-quadruplexes. Appropriate mutation of several bases in the wild sequence produces the shift from parallel to antiparallel G-quadruplex, as well as the disappearance of multimeric species. The shift from the antiparallel to the parallel conformation induced by temperature is reflected in both CD and SEC profiles. PMID- 25937964 TI - Evaluation of the In Vitro Efficacy of Artemisia annua, Rumex abyssinicus, and Catha edulis Forsk Extracts in Cancer and Trypanosoma brucei Cells. AB - The current drugs against sleeping sickness are derived from cancer chemotherapeutic approaches. Herein, we aimed at evaluating the in vitro effect of alcoholic extracts of Artemisia annua (AMR), Rumex abyssinicus (RMA), and Catha edulis Forsk (CEF) on proliferation/viability of 1321N1 astrocytoma, MCF-7 breast cancer, THP-1 leukemia, and LNCaP, Du-145, and PC-3 prostate cancer cells and on Trypanosoma brucei cells. Proliferation of tumor cells was evaluated by WST-1 assay and viability/behaviour of T. brucei by cell counting and light microscopy. CEF was the most efficient growth inhibitor in comparison to AMR and RMA. Nevertheless, in LNCaP and THP-1 cells, all extracts significantly inhibited tumor growth at 3 MUg/mL. All extracts inhibited proliferation of T. brucei cells in a concentration-dependent manner. Microscopic analysis revealed that 95% of the T. brucei cells died when exposed to 33 MUg/mL CEF for 3 hrs. Similar results were obtained using 33 MUg/mL AMR for 6 hrs. In case of RMA, however, higher concentrations were necessary to obtain similar effects on T. brucei. This demonstrates the antitumor efficacy of these extracts as well as their ability to dampen viability and proliferation of T. brucei, suggesting a common mechanism of action on highly proliferative cells, most probably by targeting cell metabolism. PMID- 25937965 TI - Production of Alkaline Protease by Solvent-Tolerant Alkaliphilic Bacillus circulans MTCC 7942 Isolated from Hydrocarbon Contaminated Habitat: Process Parameters Optimization. AB - In the present investigation, a newly isolated organic solvent-tolerant and alkaliphilic bacterial strain was reported from a hydrocarbon (gasoline and diesel) contaminated soil collected from the petrol station, Shirpur (India). The strain was identified as Bacillus circulans MTCC 7942, based on phenotype, biochemical, and phylogenetic analysis of 16S rRNA gene sequence. The capability of Bacillus circulans to secrete an extracellular, thermostable, alkaline protease and grow in the presence of organic solvents was explored. Bacillus circulans produced maximum alkaline protease (412 U/mL) in optimized medium (g/L): soybean meal, 15; starch, 10; KH2PO4, 1; MgSO4.7H2O, 0.05; CaCl2, 1; Na2CO3, 8; pH 10.0 at 37 degrees C and 100 rpm. The competence of strain to grow in various organic solvents-n-octane, dodecane, n-decane, N,N-dimethylformamide, n-hexane, and dimethyl sulfoxide, establishes its potential as solvent-stable protease source for the possible applications in nonaqueous reactions and fine chemical synthesis. PMID- 25937966 TI - New Lipase for Biodiesel Production: Partial Purification and Characterization of LipSB 25-4. AB - The lipolytic activities of 300 Streptomyces isolates were determined in Tributyrin and Rhodamine-B Agar. Lipase activities were also measured with p nitrophenyl palmitate (p-NPP) as a substrate. The strain of Streptomyces bambergiensis OC 25-4 used in this study was selected among 300 strains of Streptomyces from MUCC as the best lipase producer. The incubation conditions were optimized and the inoculum amount, incubation period, effect of carbon and nitrogen sources, and rates of MgSO4 and CaCO3 were investigated. LipSB 25-4 (the lipase produced by S. bambergiensis OC 25-4 strain) was partially purified with ammonium sulphate precipitation, dialysis, and gel filtration chromatography 2.73 fold and with 92.12 U/mg specific activity. The optimal pH and temperature for LipSB 25-4 were determined as 8.0 and 50 degrees C, respectively. The lipase has high stability in all pH and temperature values used in this study. While LipSB 25-4 was slightly activated in the presence of beta-mercaptoethanol, it was slightly reduced by PMSF. The enzyme conserved approximately 75% of its activity at the end of 60 h, in the presence of methanol and ethanol. Since LipSB 25-4 displays high activity in the thermophilic conditions and stability in the presence of organic solvents, this lipase can catalyse the biodiesel production from olive oil by the transesterification reactions. PMID- 25937967 TI - Tumor microenvironment: a new treatment target for cancer. AB - Recent advances in cancer therapy encounter a bottleneck. Relapsing/recurrent disease almost always developed eventually with resistance to the initially effective drugs. Tumor microenvironment has been gradually recognized as a key contributor for cancer progression, epithelial-mesenchymal transition of the cancer cells, angiogenesis, cancer metastasis, and development of drug resistance, while dysregulated immune responses and interactions between various components in the microenvironment all play important roles. Future development of anticancer treatment should take tumor microenvironment into consideration. Besides, we also discuss the limitations of current pre-clinical testing models that mainly come from the impossibility in simulating all detailed carcinogenic mechanisms in human, especially failure to create the same tumor microenvironment. With the cumulating knowledge about tumor microenvironment, the design of a novel anticancer therapy may be facilitated and may have better chance for success in cancer eradication. PMID- 25937963 TI - Metabolic Regulation of a Bacterial Cell System with Emphasis on Escherichia coli Metabolism. AB - It is quite important to understand the overall metabolic regulation mechanism of bacterial cells such as Escherichia coli from both science (such as biochemistry) and engineering (such as metabolic engineering) points of view. Here, an attempt was made to clarify the overall metabolic regulation mechanism by focusing on the roles of global regulators which detect the culture or growth condition and manipulate a set of metabolic pathways by modulating the related gene expressions. For this, it was considered how the cell responds to a variety of culture environments such as carbon (catabolite regulation), nitrogen, and phosphate limitations, as well as the effects of oxygen level, pH (acid shock), temperature (heat shock), and nutrient starvation. PMID- 25937816 TI - Search for [Formula: see text] decays in [Formula: see text] collisions at [Formula: see text] = 8 TeV with the ATLAS detector. AB - A search for a massive [Formula: see text] gauge boson decaying to a top quark and a bottom quark is performed with the ATLAS detector in [Formula: see text] collisions at the LHC. The dataset was taken at a centre-of-mass energy of [Formula: see text] and corresponds to [Formula: see text] of integrated luminosity. This analysis is done in the hadronic decay mode of the top quark, where novel jet substructure techniques are used to identify jets from high momentum top quarks. This allows for a search for high-mass [Formula: see text] bosons in the range 1.5-3.0 [Formula: see text]. [Formula: see text]-tagging is used to identify jets originating from [Formula: see text]-quarks. The data are consistent with Standard Model background-only expectations, and upper limits at 95 % confidence level are set on the [Formula: see text] cross section times branching ratio ranging from [Formula: see text] to [Formula: see text] for left handed [Formula: see text] bosons, and ranging from [Formula: see text] to [Formula: see text] for [Formula: see text] bosons with purely right-handed couplings. Upper limits at 95 % confidence level are set on the [Formula: see text]-boson coupling to [Formula: see text] as a function of the [Formula: see text] mass using an effective field theory approach, which is independent of details of particular models predicting a [Formula: see text] boson. PMID- 25937968 TI - Synthetic melatoninergic ligands: achievements and prospects. AB - Pineal hormone melatonin is widely used in the treatment of disorders of circadian rhythms. The presence of melatonin receptors in various animal tissues motivates the use of this hormone in some other diseases. For this reason, in recent years investigators continued the search for synthetic analogues of melatonin which are metabolically stable and selective to receptors. This review includes recent information about the most famous melatonin analogues, their structure, properties, and physiological features of the interaction with melatonin receptors. PMID- 25937970 TI - Improvement of Polyunsaturated Fatty Acid Production in Echium acanthocarpum Transformed Hairy Root Cultures by Application of Different Abiotic Stress Conditions. AB - Fatty acids are of great nutritional, therapeutic, and physiological importance, especially the polyunsaturated n-3 fatty acids, possessing larger carbon chains and abundant double bonds or their immediate precursors. A few higher plant species are able to accumulate these compounds, like those belonging to the Echium genus. Here, the novel E. acanthocarpum hairy root system, which is able to accumulate many fatty acids, including stearidonic and alpha-linolenic acids, was optimized for a better production. The application of abiotic stress resulted in larger yields of stearidonic and alpha-linolenic acids, 60 and 35%, respectively, with a decrease in linoleic acid, when grown in a nutrient medium consisting of B5 basal salts, sucrose or glucose, and, more importantly, at a temperature of 15 degrees C. The application of osmotic stress employing sorbitol showed no positive influence on the fatty acid yields; furthermore, the combination of a lower culture temperature and glucose did not show a cumulative boosting effect on the yield, although this carbon source was similarly attractive. The abiotic stress also influenced the lipid profile of the cultures, significantly increasing the phosphatidylglycerol fraction but not the total lipid neither their biomass, proving the appropriateness of applying various abiotic stress in this culture to achieve larger yields. PMID- 25937969 TI - Use of PCR-DGGE Based Molecular Methods to Analyse Microbial Community Diversity and Stability during the Thermophilic Stages of an ATAD Wastewater Sludge Treatment Process as an Aid to Performance Monitoring. AB - PCR and PCR-DGGE techniques have been evaluated to monitor biodiversity indexes within an ATAD (autothermal thermophilic aerobic digestion) system treating domestic sludge for land spread, by examining microbial dynamics in response to elevated temperatures during treatment. The ATAD process utilises a thermophilic population to generate heat and operates at elevated pH due to degradation of sludge solids, thus allowing pasteurisation and stabilisation of the sludge. Genera-specific PCR revealed that Archaea, Eukarya and Fungi decline when the temperature reaches 59 degrees C, while the bacterial lineage constitutes the dominant group at this stage. The bacterial community at the thermophilic stage, its similarity index to the feed material, and the species richness present were evaluated by PCR-DGGE. Parameters such as choice of molecular target (16S rDNA or rpoB genes), and electrophoresis condition, were optimised to maximise the resolution of the method for ATAD. Dynamic analysis of microbial communities was best observed utilising PCR-DGGE analysis of the V6-V8 region of 16S rDNA, while rpoB gene profiles were less informative. Unique thermophilic communities were shown to quickly adapt to process changes, and shown to be quite stable during the process. Such techniques may be used as a monitoring technique for process health and efficiency. PMID- 25937971 TI - Sequentially Integrated Optimization of the Conditions to Obtain a High-Protein and Low-Antinutritional Factors Protein Isolate from Edible Jatropha curcas Seed Cake. AB - Jatropha curcas seed cake is a protein-rich byproduct of oil extraction which could be used to produce protein isolates. The purpose of this study was the optimization of the protein isolation process from the seed cake of an edible provenance of J. curcas by an alkaline extraction followed by isoelectric precipitation method via a sequentially integrated optimization approach. The influence of four different factors (solubilization pH, extraction temperature, NaCl addition, and precipitation pH) on the protein and antinutritional compounds content of the isolate was evaluated. The estimated optimal conditions were an extraction temperature of 20 degrees C, a precipitation pH of 4, and an amount of NaCl in the extraction solution of 0.6 M for a predicted protein content of 93.3%. Under these conditions, it was possible to obtain experimentally a protein isolate with 93.21% of proteins, 316.5 mg 100 g(-1) of total phenolics, 2891.84 mg 100 g(-1) of phytates and 168 mg 100 g(-1) of saponins. The protein content of the this isolate was higher than the content reported by other authors. PMID- 25937973 TI - Decolourisation of Synthetic Dyes by Endophytic Fungal Flora Isolated from Senduduk Plant (Melastoma malabathricum). AB - A total of twenty endophytic fungi successfully isolated from Melastoma malabathricum (Senduduk) were examined for their ability to decolourise azo dyes: Congo red, Orange G, and Methyl red and an anthraquinone dye, Remazol Brilliant Blue R. Initial screening on the glucose minimal media agar plates amended with 200 mg L(-1) of each respective dye showed that only isolate MS8 was able to decolourise all of the four dyes. The isolate decolourised completely both the RBBR and Orange G in the agar medium within 8 days. Further quantitative analysis of the dye decolourisation by isolate MS8 in aqueous minimal medium showed that isolate MS8 was able to decolourise all the tested dyes at varying levels. Dye decolourisation by the isolate MS8 was determined to be 97% for RBBR, 33% for Orange G, 48% for Congo red, and 56% for Methyl red, respectively, within a period of 16 days. Molecular identification of the fungal isolate MS8 using primer ITS1 and ITS4 showed that isolate MS8 shared 99% sequence similarity with Marasmius cladophyllus, a Basidiomycete. The ability to decolourise different types of dyes by isolate MS8 thus suggested a possible application of this fungus in the decolourisation of dyestuff effluents. PMID- 25937975 TI - Encapsulation of Phaseolus lunatus Protein Hydrolysate with Angiotensin Converting Enzyme Inhibitory Activity. AB - The objective of recent research has been to seek alternative therapeutic treatments; for this reason, the use of protein hydrolysates from diverse sources has been studied. A way to guarantee that these treatments reach the site of action is through protection with covers, such as microcapsules. Therefore, proteins from the legume Phaseolus lunatus were hydrolyzed and encapsulated with a blend of Delonix regia carboxymethylated gum/sodium alginate (50 : 50 w/w). Hydrolysis release conditions in a simulated gastrointestinal system were obtained using CaCl2 concentrations as the main factor, indicating that lower CaCl2 concentrations lead to an increased hydrolysis release. Beads obtained with 1.0 mM of CaCl2 exhibited a better hydrolysate release rate under intestinal simulated conditions and the proteins maintained an IC50 of 2.9 mg/mL. Capsules obtained with the blend of Delonix regia carboxymethylated gum/sodium alginate would be used for the controlled delivery of hydrolysates with potential use as nutraceutical or therapeutic agents. PMID- 25937972 TI - Biofilm-mediated enhanced crude oil degradation by newly isolated pseudomonas species. AB - The bioavailability of organic contaminants to the degrading bacteria is a major limitation to efficient bioremediation of sites contaminated with hydrophobic pollutants. Such limitation of bioavailability can be overcome by steady-state biofilm-based reactor. The aim of this study was to examine the effect of such multicellular aggregation by naturally existing oil-degrading bacteria on crude oil degradation. Microorganisms, capable of utilizing crude oil as sole carbon source, were isolated from river, estuary and sea-water samples. Biochemical and 16S rDNA analysis of the best degraders of the three sources was found to belong to the Pseudomonas species. Interestingly, one of the isolates was found to be close to Pseudomonas otitidis family which is not reported yet as a degrader of crude oil. Biodegradation of crude oil was estimated by gas chromatography, and biofilm formation near oil-water interface was quantified by confocal laser scanning microscopy. Biofilm supported batches of the isolated Pseudomonas species were able to degrade crude oil much readily and extensively than the planktonic counterparts. Volumetric and topographic analysis revealed that biofilms formed in presence of crude oil accumulate higher biomass with greater thickness compared to the biofilms produced in presence of glucose as sole carbon source. PMID- 25937974 TI - Zinc uptake by lactic Acid bacteria. AB - The study aims to investigate zinc biosorption by strains of lactobacilli and bifidobacteria with a view to exploit them as organic matrixes for zinc dietary supplementation. Sixteen human strains of Lactobacillus and Bifidobacterium were assayed for zinc uptake. The minimum inhibitory concentration of zinc salts differed among the strains, but was never below 15 mmol L(-1). When cultured in MRS broth containing 10 mmol L(-1) ZnSO4, all the strains were capable of accumulating zinc in the range between 11 and 135 MUmol g(-1). The highest amount of cell-bound zinc was obtained in L. acidophilus WC 0203. pH-controlled batch cultures of this strain revealed that zinc uptake started in the growth phase, but occurred mostly during the stationary phase. Pasteurized and viable cultures accumulated similar amount of zinc, suggesting that a nonmetabolically mediated mechanism is involved in zinc uptake. These results provide new perspectives on the specific use of probiotics, since L. acidophilus WC 0203 could function as an organic matrix for zinc incorporation. The bioavailability of Lactobacillus-bound zinc deserves to be investigated to provide a future basis for optimization of zinc supplementation or fortification. PMID- 25937978 TI - Fermentation and hydrogen metabolism affect uranium reduction by clostridia. AB - Previously, it has been shown that not only is uranium reduction under fermentation condition common among clostridia species, but also the strains differed in the extent of their capability and the pH of the culture significantly affected uranium(VI) reduction. In this study, using HPLC and GC techniques, metabolic properties of those clostridial strains active in uranium reduction under fermentation conditions have been characterized and their effects on capability variance of uranium reduction discussed. Then, the relationship between hydrogen metabolism and uranium reduction has been further explored and the important role played by hydrogenase in uranium(VI) and iron(III) reduction by clostridia demonstrated. When hydrogen was provided as the headspace gas, uranium(VI) reduction occurred in the presence of whole cells of clostridia. This is in contrast to that of nitrogen as the headspace gas. Without clostridia cells, hydrogen alone could not result in uranium(VI) reduction. In alignment with this observation, it was also found that either copper(II) addition or iron depletion in the medium could compromise uranium reduction by clostridia. In the end, a comprehensive model was proposed to explain uranium reduction by clostridia and its relationship to the overall metabolism especially hydrogen (H2) production. PMID- 25937977 TI - Differential Inhibition of Helicoverpa armigera (Hubner) Gut Proteinases by Proteinase Inhibitors of Okra and It's Wild Relatives. AB - The seeds of ten genotypes and twenty-nine wild relatives of okra were analysed for the presence of trypsin, chymotrypsin, and Helicoverpa gut proteinases (HGPs) inhibitors (HGPIs), with the aim to identify potent inhibitors of H. armigera gut proteinases. Proteinase inhibitors (PIs) obtained from wild relatives of okra exhibited stronger inhibition of HGPs than the genotypes of okra. In in vitro inhibitory assay against HGPs, A. tuberculatus 90396 and 90515 showed high tryptic inhibitory (71.8% and 69.2%), chymotryptic inhibitory (68.5% and 66.2%), and Helicoverpa gut proteinase activity (70.2% and 68.2%). In electrophoretic profile showed the same variation in the number of trypsin inhibitors (TIs), chymotrypsin Inhibitors (CIs), and HGPIs isoforms with different intensities, whereas genotypes of okra mostly showed monomorphic profile. Maximum eight HGPIs isoforms were found in A. tuberculatus (90396 and 90515). In bioassay studies, significant reduction in weight of H. armigera larvae was found, when larvae fed on PIs obtained from A. tuberculatus (90396 and 90515). Thus, the result of the present investigation indicates that further exploration of PIs obtained from A. tuberculatus (90396 and 90515) will be helpful for developing PIs-based insect resistance management strategies. PMID- 25937976 TI - NaCl Effects on In Vitro Germination and Growth of Some Senegalese Cowpea (Vigna unguiculata (L.) Walp.) Cultivars. AB - Cowpea (Vigna unguiculata (L.) Walp.) is one of the most important grain legumes in sub-Saharian regions. It contributes to man food security by providing a protein-rich diet. However, its production is limited by abiotic stresses such as salinity. This study aims to evaluate the salt tolerance of 15 cowpea cultivars, at germination stage. The seed germination process consisted of sowing them in agarified water (8 g.L(-1)) supplemented with 6 different concentrations of NaCl (0, 10, 50, 100, 150, and 200 mM). Results highlighted that high salt concentrations drastically reduced germination and significantly delayed the process for all varieties. A cowpea varietal effect towards the salt tolerance was noticed. Genotypes Diongoma, 58-78, and 58-191 were more salt-tolerant cultivars while Mougne and Yacine were more salt-sensitive ones as confirmed in the three groups of the dendrogram. NaCl effects on the early vegetative growth of seedlings were assessed with a tolerant (58-191) and a susceptible (Yacine) cultivar. Morphological (length and dry biomass) and physiological (chlorophyll and proline contents) parameter measurements revealed a negative effect of high (NaCl). However, 58-191 was much more salt tolerant, and the chlorophyll and proline contents were higher than those of Yacine genotype at increasing salt concentrations. PMID- 25937979 TI - Application of Plackett-Burman Experimental Design for Lipase Production by Aspergillus niger Using Shea Butter Cake. AB - Plackett-Burman design was used to efficiently select important medium components affecting the lipase production by Aspergillus niger using shea butter cake as the main substrate. Out of the eleven medium components screened, six comprising of sucrose, (NH4)2SO4, Na2HPO4, MgSO4, Tween-80, and olive oil were found to contribute positively to the overall lipase production with a maximum production of 3.35 U/g. Influence of tween-80 on lipase production was investigated, and 1.0% (v/w) of tween-80 resulted in maximum lipase production of 6.10 U/g. Thus, the statistical approach employed in this study allows for rapid identification of important medium parameters affecting the lipase production, and further statistical optimization of medium and process parameters can be explored using response surface methodology. PMID- 25937981 TI - Genetically modified plants: public and scientific perceptions. AB - The potential of genetically modified plants to meet the requirements of growing population is not being recognized at present. This is a consequence of concerns raised by the public and the critics about their applications and release into the environment. These include effect on human health and environment, biosafety, world trade monopolies, trustworthiness of public institutions, integrity of regulatory agencies, loss of individual choice, and ethics as well as skepticism about the real potential of the genetically modified plants, and so on. Such concerns are enormous and prevalent even today. However, it should be acknowledged that most of them are not specific for genetically modified plants, and the public should not forget that the conventionally bred plants consumed by them are also associated with similar risks where no information about the gene(s) transfer is available. Moreover, most of the concerns are hypothetical and lack scientific background. Though a few concerns are still to be disproved, it is viewed that, with proper management, these genetically modified plants have immense potential for the betterment of mankind. In the present paper, an overview of the raised concerns and wherever possible reasons assigned to explain their intensity or unsuitability are reviewed. PMID- 25937980 TI - Identification of Appropriate Reference Genes for qRT-PCR Analysis of Heat Stressed Mammary Epithelial Cells in Riverine Buffaloes (Bubalus bubalis). AB - Gene expression studies require appropriate normalization methods for proper evaluation of reference genes. To date, not many studies have been reported on the identification of suitable reference genes in buffaloes. The present study was undertaken to determine the panel of suitable reference genes in heat stressed buffalo mammary epithelial cells (MECs). Briefly, MEC culture from buffalo mammary gland was exposed to 42 degrees C for one hour and subsequently allowed to recover at 37 degrees C for different time intervals (from 30 m to 48 h). Three different algorithms, geNorm, NormFinder, and BestKeeper softwares, were used to evaluate the stability of 16 potential reference genes from different functional classes. Our data identified RPL4, EEF1A1, and RPS23 genes to be the most appropriate reference genes that could be utilized for normalization of qPCR data in heat-stressed buffalo MECs. PMID- 25937982 TI - Potential of aqueous ozone to control aflatoxigenic fungi in Brazil nuts. AB - This study aimed to verify the use of aqueous ozone as alternative technology for fungal control. Brazil nuts sterilized were inoculated with either 1 * 10(6) or 1 * 10(7) conidia mL(-1) of Aspergillus flavus (MUM 9201) to determine optimal treatment parameters and different aqueous ozone contact times. These assays showed that the effect of ozone is almost immediate against A. flavus, and the optimum ozone concentration depended on the number of initial viable spores on the shell. The remaining viable spores in the ozone solution were recorded, and the rate of inactivation for each treatment was determined by assessing the ratio between the cfu of each treatment and the control. The ozonized nuts were also cultured to recover the fungal population. Aqueous ozone was effective in reducing the conidia of A. flavus and the natural fungal population associated with Brazil nuts. Aqueous ozone presented a great potential to reduce microorganisms counts in Brazil nuts with a great potential use in packing houses for decontamination step. PMID- 25937983 TI - Yield and properties of ethanol biofuel produced from different whole cassava flours. AB - The yield and properties of ethanol biofuel produced from five different whole cassava flours were investigated. Ethanol was produced from five different whole cassava flours. The effect of quantity of yeast on ethanol yield, effect of whole cassava flour to acid and mineralized media ratio on the yield of ethanol produced, and the physical properties of ethanol produced from different cassava were investigated. Physical properties such as distillation range, density, viscosity, and flash point of ethanol produced differ slightly for different cultivars, while the yield of ethanol and electrical conductivity of ethanol from the different cassava cultivars varies significantly. The variation in mineral composition of the different whole cassava flours could also lead to variation in the electrical conductivity of ethanol produced from the different cassava cultivars. The differences in ethanol yield are attributed to differences in starch content, protein content, and dry matter of cassava cultivars. High yield of ethanol from whole cassava flour is best produced from cultivars with high starch content, low protein content, and low fiber. PMID- 25937984 TI - Variations in the Regulatory Region of Alpha S1-Casein Milk Protein Gene among Tropically Adapted Indian Native (Bos Indicus) Cattle. AB - Regulatory region of milk protein alpha S1-casein (alphaS1-CN) gene was sequenced, characterized, and analyzed to detect variations among 13 Indian cattle (Bos indicus) breeds. Comparative analysis of 1,587 bp region comprising promoter (1,418 bp), exon-I (53 bp), and partial intron-I (116 bp) revealed 35 nucleotide substitutions (32 within promoter region, 1 in exon-I, and 2 in partial intron-I region) and 4 Indels. Within promoter, 15 variations at positions -1399 (A > G), -1288 (G > A), -1259 (T > C), -1158 (T > C), -1016 (A > T), -941 (T > G), -778 (C > T), -610 (G > A), -536 (A > G), -521 (A > G), -330 (A > C), -214 (A > G), -205 (A > T), -206 (C > A), and -175 (A > G) were located within the potential transcription factor binding sites (TFBSs), namely, NF kappaE1/c-Myc, GATA-1, GATA-1/NF-E, Oct-1/POU3F2, MEF-2/YY1, GATA-1, AP-1, POU1F1a/GR, TMF, GAL4, YY1/Oct-1, HNF-1, GRalpha/AR, GRalpha/AR, and AP-1, respectively. Seventy-four percent (26/35) of the observed SNPs were novel to Indian cattle and 11 of these novel SNPs were located within one or more TFBSs. Collectively, these might influence the binding affinity towards their respective nuclear TFs thus modulating the level of transcripts in milk and affecting overall protein composition. The study provides information on several distinct variations across indicine and taurine alphaS1-CN regulatory domains. PMID- 25937985 TI - Enhanced Cellulase Production from Bacillus subtilis by Optimizing Physical Parameters for Bioethanol Production. AB - Effect of physical parameters such as initial pH, agitation (rpm), and temperature ( degrees C) for cellulase production from Bacillus subtilis AS3 was investigated. Central composite design of experiments followed by multiple desirability function was applied for the optimization of cellulase activity and cell growth. The effect of the temperature and agitation was found to be significant among the three independent variables. The optimum levels of initial pH, temperature, and agitation for alkaline carboxymethylcellulase (CMCase) production predicted by the model were 7.2, 39 degrees C, and 121 rpm, respectively. The CMCase activity with unoptimized physical parameters and previously optimized medium composition was 0.43 U/mL. The maximum activity (0.56 U/mL) and cell growth (2.01 mg/mL) predicted by the model were in consensus with values (0.57 U/mL, 2.1 mg/mL) obtained using optimized medium and optimal values of physical parameters. After optimization, 33% enhancement in CMCase activity (0.57 U/mL) was recorded. On scale-up of cellulase production process in bioreactor with all the optimized conditions, an activity of 0.75 U/mL was achieved. Consequently, the bacterial cellulase employed for bioethanol production expending (5%, w/v) NaOH-pretreated wild grass with Zymomonas mobilis yielded an utmost ethanol titre of 7.56 g/L and 11.65 g/L at shake flask and bioreactor level, respectively. PMID- 25937986 TI - Optimization of cellulase production from bacteria isolated from soil. AB - Cellulase-producing bacteria were isolated from soil and identified as Pseudomonas fluorescens, Bacillus subtilIs, E. coli, and Serratia marcescens. Optimization of the fermentation medium for maximum cellulase production was carried out. The culture conditions like pH, temperature, carbon sources, and nitrogen sources were optimized. The optimum conditions found for cellulase production were 40 degrees C at pH 10 with glucose as carbon source and ammonium sulphate as nitrogen source, and coconut cake stimulates the production of cellulase. Among bacteria, Pseudomonas fluorescens is the best cellulase producer among the four followed by Bacillus subtilis, E. coli, and Serratia marscens. PMID- 25937987 TI - The Medicinal Timber Canarium patentinervium Miq. (Burseraceae Kunth.) Is an Anti Inflammatory Bioresource of Dual Inhibitors of Cyclooxygenase (COX) and 5 Lipoxygenase (5-LOX). AB - The barks and leaves extracts of Canarium patentinervium Miq. (Burseraceae Kunth.) were investigated for cyclooxygenase (COX) and 5-lipoxygenase (LOX) inhibition via in vitro models. The corresponding antioxidative power of the plant extract was also tested via nonenzyme and enzyme in vitro assays. The ethanolic extract of leaves inhibited the enzymatic activity of 5-LOX, COX-1, and COX-2 with IC50 equal to 49.66 +/- 0.02 MUg/mL, 0.60 +/- 0.01 MUg/mL, and 1.07 +/ 0.01 MUg/mL, respectively, with selective COX-2 activity noted in ethanolic extract of barks with COX-1/COX-2 ratio of 1.22. The ethanol extract of barks confronted oxidation in the ABTS, DPPH, and FRAP assay with EC50 values equal to 0.93 +/- 0.01 MUg/mL, 2.33 +/- 0.02 MUg/mL, and 67.00 +/- 0.32 MUg/mL, respectively, while the ethanol extract of leaves confronted oxidation in beta carotene bleaching assay and superoxide dismutase (SOD) assay with EC50 value of 6.04 +/- 0.02 MUg/mL and IC50 value of 3.05 +/- 0.01 MUg/mL. The ethanol extract acts as a dual inhibitor of LOX and COX enzymes with potent antioxidant capacity. The clinical significance of these data is quite clear that they support a role for Canarium patentinervium Miq. (Burseraceae Kunth.) as a source of lead compounds in the management of inflammatory diseases. PMID- 25937988 TI - Effect of Chitosan on Rhizome Rot Disease of Turmeric Caused by Pythium aphanidermatum. AB - Chitosan was evaluated for its potential to induce antifungal hydrolases in susceptible turmeric plant (Curcuma longa L.). Under field conditions, the application of chitosan (crab shell) to turmeric plants by foliar spray method induces defense enzymes such as chitinases and chitosanases. Such an increase in enzyme activity was enhanced by spraying chitosan (0.1% w/v) on leaves of turmeric plants at regular intervals. Gel electrophoresis revealed new chitinase and chitosanase isoforms in leaves of turmeric plants treated with chitosan. Treated turmeric plants showed increased resistance towards rhizome rot disease caused by Pythium aphanidermatum, whereas control plants expressed severe rhizome rot disease. Increased activity of defense enzymes in leaves of chitosan treated turmeric plants may play a role in restricting the development of disease symptoms. The eliciting properties of chitosan make chitosan a potential antifungal agent for the control of rhizome rot disease of turmeric. PMID- 25937990 TI - Detection of tannery effluents induced DNA damage in mung bean by use of random amplified polymorphic DNA markers. AB - Common effluent treatment plant (CETP) is employed for treatment of tannery effluent. However, the performance of CETP for reducing the genotoxic substances from the raw effluent is not known. In this study, phytotoxic and genotoxic effects of tannery effluents were investigated in mung bean (Vigna radiata (L.) Wilczek). For this purpose, untreated and treated tannery effluents were collected from CETP Unnao (UP), India. Seeds of mung bean were grown in soil irrigated with various concentrations of tannery effluents (0, 25, 50, 75, and 100%) for 15 days. Inhibition of seed germination was 90% by 25% untreated effluent and 75% treated effluent, compared to the control. Plant growth was inhibited by 51% and 41% when irrigated with untreated and treated effluents at 25% concentration. RAPD technique was used to evaluate the genotoxic effect of tannery effluents (untreated and treated) irrigation on the mung bean. The RAPD profiles obtained showed that both untreated and treated were having genotoxic effects on mung bean plants. This was discernible with appearance/disappearance of bands in the treatments compared with control plants. A total of 87 RAPD bands were obtained using eight primers and 42 (48%) of these showed polymorphism. Irrigating plants with untreated effluent caused 12 new bands to appear and 18 to disappear. Treated effluent caused 8 new bands and the loss of 15 bands. The genetic distances shown on the dendrogram revealed that control plants and those irrigated with treated effluent were clustered in one group (joined at distance of 0.28), whereas those irrigated with untreated effluent were separated in another cluster at larger distance (joined at distance of 0.42). This indicates that treated effluent is less genotoxic than the untreated. Nei's genetic similarity indices calculated between the treatments and the control plants showed that the control and the plants irrigated with treated tannery effluent had a similarity index of 0.75, the control and plants irrigated with untreated 0.65, and between the treatments 0.68. We conclude that both untreated and treated effluents contain genotoxic substances that caused DNA damage to mung beans. CETP Unnao removes some, but not all, genotoxic substances from tannery effluent. Consequently, use of both untreated and treated wastewater for irrigation poses health hazard to human and the environment. PMID- 25937991 TI - Use of Metagenomics and Isolation of Actinobacteria in Brazil's Atlantic Rainforest Soil for Antimicrobial Prospecting. AB - Modern techniques involving molecular biology, such as metagenomics, have the advantage of exploiting a higher number of microorganisms; however, classic isolation and culture methods used to obtain antimicrobials continue to be promising, especially in the isolation of Actinobacteria, which are responsible for the production of many of these compounds. In this work, two methodologies were used to search for antimicrobial substances-isolation of Actinobacteria and metagenomics of the Atlantic Rainforest soil and of the cultivation of cocoa intercropped with acai berry in the Atlantic Rainforest. The metagenomic libraries were constructed with the CopyControl Fosmid Library kit EPICENTRE, resulting in a total of 2688 clones, 1344 of each soil sample. None of the clones presented antimicrobial activity against the microorganisms tested: S. aureus, Bacillus subtilis, and Salmonella choleraesuis. A total of 46 isolates were obtained from the isolation of soil Actinobacteria: 24 isolates from Atlantic Rainforest soil and 22 isolates from the intercrop cultivation soil. Of these, two Atlantic Rainforest soil isolates inhibited the growth of S. aureus including a clinical isolate of S. aureus MRSA-a promising result, since it is an important multidrug-resistant human pathogen. PMID- 25937992 TI - Powering Brain Power: GLUT1 and the Era of Structure Based Human Transporter Biology. PMID- 25937989 TI - Current challenges in commercially producing biofuels from lignocellulosic biomass. AB - Biofuels that are produced from biobased materials are a good alternative to petroleum based fuels. They offer several benefits to society and the environment. Producing second generation biofuels is even more challenging than producing first generation biofuels due the complexity of the biomass and issues related to producing, harvesting, and transporting less dense biomass to centralized biorefineries. In addition to this logistic challenge, other challenges with respect to processing steps in converting biomass to liquid transportation fuel like pretreatment, hydrolysis, microbial fermentation, and fuel separation still exist and are discussed in this review. The possible coproducts that could be produced in the biorefinery and their importance to reduce the processing cost of biofuel are discussed. About $1 billion was spent in the year 2012 by the government agencies in US to meet the mandate to replace 30% existing liquid transportation fuels by 2022 which is 36 billion gallons/year. Other countries in the world have set their own targets to replace petroleum fuel by biofuels. Because of the challenges listed in this review and lack of government policies to create the demand for biofuels, it may take more time for the lignocellulosic biofuels to hit the market place than previously projected. PMID- 25937993 TI - Mining Recent Temporal Patterns for Event Detection in Multivariate Time Series Data. AB - Improving the performance of classifiers using pattern mining techniques has been an active topic of data mining research. In this work we introduce the recent temporal pattern mining framework for finding predictive patterns for monitoring and event detection problems in complex multivariate time series data. This framework first converts time series into time-interval sequences of temporal abstractions. It then constructs more complex temporal patterns backwards in time using temporal operators. We apply our framework to health care data of 13,558 diabetic patients and show its benefits by efficiently finding useful patterns for detecting and diagnosing adverse medical conditions that are associated with diabetes. PMID- 25937994 TI - Two CGD Families with a Hypomorphic Mutation in the Activation Domain of p67phox. AB - STUDY BACKGROUND: Chronic granulomatous Disease (CGD) is a rare immunodeficiency caused by a defect in the leukocyte NADPH oxidase. This enzyme generates superoxide, which is needed for the killing of bacteria and fungi by phagocytic leukocytes. Most CGD patients have mutations in CYBB, the X-linked gene that encodes gp91phox, the catalytic subunit of the leukocyte NADPH oxidase. We report here three autosomal recessive CGD patients from two families with a homozygous mutation in NCF2, the gene that encodes p67phox, the activator subunit of the NADPH oxidase. METHODS: Leukocyte NADPH oxidase activity, expression of oxidase components and gene sequences were measured with standard methods. The mutation found in the patients' NCF2 gene was expressed as Ala202Val-p67phox in K562 cells to measure its effect on NADPH oxidase activity. Translocation of the mutated p67phox from the cytosol of the patients' neutrophils to the plasma membrane was measured by confocal microscopy and by Western blotting after membrane purification. RESULTS: The exceptional feature of the A67 CGD patients reported here is that the p.Ala202Val mutation in the activation domain of p67phox was clearly hypomorphic: substantial expression of p67phox protein was noted and the NADPH oxidase activity in the neutrophils of the patients was 20-70% of normal, dependent on the stimulus used to activate the cells. The extent of Ala202Val p67phox translocation to the plasma membrane during cell activation was also stimulus dependent. Ala202Val-p67phox in K562 cells mediated only about 3% of normal oxidase activity compared to cells transfected with the wild-type p67phox. CONCLUSION: The mutation found in NCF2 is the cause of the decreased NADPH oxidase activity and the (mild) clinical problems of the patients. We propose that the p.Ala202Val mutation has changed the conformation of the activation domain of p67phox, resulting in reduced activation of gp91phox. PMID- 25937995 TI - Differences in Cerebrospinal Fluid Biomarkers between Clinically Diagnosed Idiopathic Normal Pressure Hydrocephalus and Alzheimer's Disease. AB - OBJECTIVE: In the present study, cerebrospinal fluid (CSF) profiles were assessed to determine how idiopathic normal pressure hydrocephalus (NPH) and Alzheimer's disease (AD) differs. METHODS: Subjects were drawn from patients who underwent lumbar punctures as part of their diagnostic evaluations in the Banner Sun Health Research Institute Memory Disorders clinic. The clinical sample included 11 iNPH subjects (mean age 81.36+/-2.58) and 11 AD subjects (mean age 61.46+/-8.24). Concentrations of amyloid-beta (Abeta42), total-tau (t-tau), phospho-tau181 (p tau) Abeta42, and an Abeta42-Tau Index (ATI) were measured by commercial assay (Athena Diagnostics). and compared to each other. The Mann-Whitney test was used to assess group differences on the raw values for Abeta42, t-tau, p-tau, ATI, age, education, and MMSE. RESULTS: In a univariate analysis, p-tau was found to be significantly (P = 0.009) lower in patients diagnosed with iNPH than those with AD. Amyloid-beta (Abeta42), total-tau (t-tau) did not differ between groups. In multi-variate analysis, the differences in p-tau between groups did not differ. CONCLUSION: Although age could represent a significant confound, p-tau is significantly lower in iNPH compared to AD. P-tau would be expected to increase with age but in this sample is lower suggesting the difference might be explained by the underlying condition. PMID- 25937996 TI - Ubiquitin carboxyl-terminal esterase L1 promotes proliferation of human choroidal and retinal endothelial cells. AB - PURPOSE: We aimed: (1) to establish endothelial expression of ubiquitin carboxyl terminal esterase L1 (UCHL1) in human choroid and retina and; (2) to investigate a role for UCHL1 in basic processes involved in intraocular neovascularization. DESIGN: Controlled translational experimental study. METHODS: Ethanol-fixed human choroid and retina (n = 3 eyes) were indirectly immunostained with rabbit anti human UCHL1 antibody. Endothelial proliferation and migration assays were performed using cultured human choroidal and retinal endothelial cells (n = 6 isolates/assay). Cells were transfected with UCHL1-targeted or non-targeted small interfering (si)RNA and a commercially available transfection system, and used 48 hours later in experiments. Cell proliferation was evaluated using an assay in which cellular DNA was fluorescently tagged for quantification by microplate reader. Cell migration was examined in an assay that involved counting the number of endothelial cells moving across a perforated membrane. Transcript silencing was verified by Western blot for all assays. RESULTS: Immunohistochemistry confirmed expression of UCHL1 by endothelium in human choroid and retina in vivo. UCHL1-specific knockdown resulted in significantly less proliferation (p < 0.0001) for 3 human choroidal endothelial isolates and 3 human retinal endothelial isolates, and significantly less migration (p <= 0.016) for 2 of 3 human choroidal endothelial isolates and 1 of 3 human retinal endothelial isolates. CONCLUSIONS: Our results suggest that UCHL1 may be involved in choroidal and retinal endothelial proliferation in most persons, and endothelial migration in some persons. UCHL1 may be a suitable target for a new treatment of intraocular neovascularisation. PMID- 25937997 TI - Modulation of deoxycytidine kinase (dCK) and glycogen synthase kinase (GSK-3beta) by anti-CD20 (rituximab) and 2-chlorodeoxyadenosine (2-CdA) in human lymphoid malignancies. AB - BACKGROUND: The combination of rituximab and 2-CdA is an effective therapy for B cell tumors. However, the molecular mechanisms and enzymatic pathways involved in the interaction between the two agents are not fully understood. In this study, we provide molecular evidence for positive interaction between these two agents with resultant therapeutic benefit. METHODS: Efficacy of the R-2CdA regimen was evaluated in thirteen patients with B-cell tumors (9 CLL; 3 WM and 1 FL), in vitro against 3 lymphoma cell lines and in a xenograft mouse model. Treatment induced changes involving phenotype, kinase activity and protein expression were assessed in vitro and in the mouse xenograft tumors. The interaction between RTX and 2-CdA was analyzed using the multiple comparison method, Tukey's honestly significant difference (HSD). For the clinical and animal data, survival functions were estimated using the Kaplan-Meier method and compared by the log rank test. P-values <0.05 were considered statistically significant. All statistical analyses were evaluated using GraphPad Prism 4 (San Diego, CA). RESULTS: 9 of 12 (75%) evaluable patients responded to the R-2-CdA regimen with median duration of response of 34 months. Median survival of patients from diagnosis and from completion of R-2-CdA treatment was 13.3 and 7.9 years, respectively. In vitro, the combination was effective in all 3 cell lines of lymphomas but with higher sensitivity in the follicular lymphoma cell line. The combination was also effective in the WSU-WM-SCID xenograft model with dose dependent response and synergistic benefit. All animals were tumor-free for up to 120 days post 2 cycles of this regimen. Rituximab induced activation of deoxycytidine kinase (dCK), p38 mitogen activated protein kinase (p38MAPK) and glycogen synthase kinase-3beta (GSK-3beta) in the xenograft WSU-WM tumors. Chemical inhibition of p38MAPK led to inhibition of the GSK-3beta phosphorylation suggesting that GSK-3beta is regulated by p38MAPK in this model. CONCLUSION: Collectively, our studies show concordance between the activity of R-2-CdA in vitro, in human and in WSU-WM xenograft model attesting to the validity of this model in predicting clinical response. Modulation of dCK and GSK-3beta by rituximab may contribute to the positive therapeutic interaction between rituximab and 2-CdA. PMID- 25937998 TI - Distinct genetic alterations in small cell carcinoma from different anatomic sites. AB - Small cell carcinoma (SmCC) is a distinct clinicopathological entity first described in the lung. It represents approximately 15% of all bronchogenic carcinoma. Extrapulmonary small cell carcinoma (EPSmCC) morphologically indistinguishable from small cell lung cancer (SCLC) was first reported in 1930. Since its first description, EPSmCC has been reported in virtually all anatomical sites, including: gynecologic organs (ovary and cervix); genitourinary organs (urinary bladder and prostate); the gastrointestinal tract (esophagus); skin (Merkel cell carcinoma) and head and neck region. Regardless of the anatomic sites, all SmCCs have similar, if not identical, histo-pathology features and immunohistochemical profile. SmCC is one of the most aggressive malignancies. The molecular mechanisms underlying its development and progression remain poorly understood. Herein, we reviewed the literature in SmCC in respect to its site of occurrence, clinical features, immunohistochemical characteristics. SmCCs have heterogeneous molecular mutations. Dinstinct genetic alterations associated with SmCC from different body sites were reviewed. Some genetic alterations such as RB1, TP53 are commonly seen in different origins of SmCC. Other genes with site specificity were also summarized, such as bladder SmCC with TERT promoter mutations; prostate SmCC with ERG translocations; ovarian SmCC with SMARCA4 mutations; Merkel cell carcinoma (skin) and cervical SmCC with Merkel cell polyomavirus (MCV or MCPyV) and human papillomavirus (HPV). Further studies are needed to employ a genetically oriented approach for the diagnosis and therapy of SmCC. PMID- 25937999 TI - The effect of caffeine on cisplatin-induced apoptosis of lung cancer cells. AB - BACKGROUND: Cisplatin is an important DNA-damaging anticancer drug that has been used to treat many cancer types. However, the effectiveness of cisplatin treatment diminishes quickly as cancer cells develop resistance to the drug, which eventually results in treatment failure. Caffeine is an ingredient contained in many food sources. Caffeine can inhibit activities of both ATM and ATR, two important protein kinases involved in DNA damage-induced cell cycle arrest and apoptosis. The effect of caffeine on cisplatin-based cancer treatment is not well known. METHODS: Caspase-3 activation and cell growth inhibition assays were used to determine the effect of caffeine on cisplatin-induced apoptosis and cell growth in lung cancer cells. Real time PCR, immunoblotting, and flow cytometry assays were used determine a mechanism through which the presence of caffeine increased cisplatin-induced apoptosis of the lung cancer cells. RESULTS: Our caspase-3 activation studies demonstrated that the presence of caffeine increased the cisplatin-induced apoptosis in both HTB182 and CRL5985 lung cancer cells. Our cell growth inhibition studies indicated that the presence of caffeine caused a more increase for cisplatin-induced cell growth inhibition. The results obtained from our real time PCR and western blot studies revealed that the presence of caffeine increased cisplatin-induced expression of the PUMA pro-apoptotic protein in these lung cancer cells. The results of our protein phosphorylation studies indicated that the presence of caffeine caused a decrease in CHK1 phosphorylation at Ser(317)/Ser(345) but an increase in ATM phosphorylation at Ser(1981) in the lung cancer cells treated with cisplatin. In addition, our flow cytometry studies also revealed that the presence of caffeine caused an increase in G1 cell population but a decrease for cisplatin-induced cell cycle arrests at the S and the G2 checkpoints in HTB182 and CRL5985 cells respectively. CONCLUSION: Our results suggest that the presence of caffeine increases the cisplatin-induced lung cancer cell killings by inhibiting ATR but inducing ATM activation, resulting in an increase in expression of PUMA protein and an increase in apoptosis. PMID- 25938000 TI - Immunohistochemical analysis indicates that the anatomical location of B-cell non Hodgkin's lymphoma is determined by differentially expressed chemokine receptors, sphingosine-1-phosphate receptors and integrins. AB - BACKGROUND: The aim of this study was to elucidate the mechanisms responsible for the location of B-cell non-Hodgkin's lymphoma (B-NHL) at different anatomical sites. We speculated that the malignant B cells in these disorders have the potential for trafficking between blood and secondary lymphoid organs (SLO) or extranodal sites and that their preferential accumulation at different locations is governed by the expression of key molecules that regulate the trafficking of normal lymphocytes. METHODS: Biopsy or blood samples from 91 cases of B-NHL affecting SLO (n = 27), ocular adnexae (n = 51) or blood (n = 13) were analysed by immunohistochemistry or flow cytometry for the expression of the following molecules: CCR7, CCL21 and alphaL (required for the entry of normal lymphocytes into SLO); CXCR4, CXCL12 and alpha4 (required for entry into extranodal sites); CXCR5, CXCL13 and S1PR2 (required for tissue retention); S1PR1 and S1PR3 (required for egress into the blood). The expression of each of these molecules was then related to anatomical location and histological subtype. RESULTS: The expression of motility/adhesion molecules varied widely between individual patient samples and correlated much more strongly with anatomical location than with histological subtype. SLO lymphomas [comprising 10 follicular lymphoma (FL), 8 diffuse large B-cell lymphoma (DLBCL), 4 mantle-cell lymphoma (MCL) and 5 marginal-zone lymphoma (MZL)] were characterised by pronounced over-expression of S1PR2, suggesting that the malignant cells in these lymphomas are actively retained at the site of clonal expansion. In contrast, the malignant B cells in ocular adnexal lymphomas (10 FL, 9 DLBCL, 4 MCL and 28 MZL) expressed a profile of molecules suggesting a dynamic process of trafficking involving not only tissue retention but also egress via S1PR3 and homing back to extranodal sites via CXCR4/CXCL12 and alpha4. Finally, leukaemic lymphomas (6 FL, 5 MCL and 2 MZL) were characterised by aberrant expression of the egress receptor S1PR1 and low expression of molecules required for tissue entry/retention. CONCLUSIONS: In summary, our study strongly suggests that anatomical location in B-NHL is governed by the differential expression of specific adhesion/motility molecules. This novel observation has important implications for therapeutic strategies that aim to disrupt protective micro-environmental interactions. PMID- 25938001 TI - Effect of prognostic classification on temsirolimus efficacy and safety in patients with relapsed or refractory mantle cell lymphoma: a retrospective analysis. AB - BACKGROUND: Temsirolimus, a selective inhibitor of the mammalian target of rapamycin, has demonstrated clinical benefit versus investigator's choice (INV) of therapy in patients with relapsed/refractory mantle cell lymphoma (MCL). METHODS: This post hoc study retrospectively assigned simplified Mantle Cell Lymphoma International Prognostic Index (MIPI) scores (ie, secondary MIPI) based on parameters at the time of randomization in patients with MCL (N = 162) who received temsirolimus 175 mg once weekly for 3 weeks followed by once-weekly 75 mg or 25 mg or the INV of active therapy. Outcomes were analyzed according to the low-, intermediate- or high-risk category. RESULTS: Patient distribution by MIPI risk category was 31%, 39%, and 30% in the low-, intermediate-, and high-risk groups, respectively. Among patients in all categories, objective response rate (complete response + partial response) was higher in patients in the temsirolimus 175/75-mg group versus the INV group, respectively: 42% versus 0% (low-risk); 33% versus 5% (intermediate-risk); 10% versus 0% (high-risk). Median progression-free survival was significantly longer with temsirolimus 175/75 mg versus INV, respectively, in patients with intermediate (4.3 vs 1.9 months; P = 0.035) or high (4.5 vs 1.6 months; P = 0.0025) risk, and a trend toward improvement was observed in patients with low risk (5.3 vs 2.6 months; P = 0.091). Improvement in median overall survival was observed with temsirolimus 175/75 mg versus INV in low-risk patients (18.0 vs 10.5 months, respectively; P = 0.069). CONCLUSIONS: This analysis suggests that, compared with INV, temsirolimus demonstrated benefit in all MIPI risk categories in patients with MCL. In all treatment groups, patients with high secondary MIPI scores at baseline faced a dismal prognosis. TRIAL REGISTRATION: ClinicalTrials.gov NCT00117598. PMID- 25938002 TI - VFMA: Topographic Analysis of Sensitivity Data From Full-Field Static Perimetry. AB - PURPOSE: To analyze static visual field sensitivity with topographic models of the hill of vision (HOV), and to characterize several visual function indices derived from the HOV volume. METHODS: A software application, Visual Field Modeling and Analysis (VFMA), was developed for static perimetry data visualization and analysis. Three-dimensional HOV models were generated for 16 healthy subjects and 82 retinitis pigmentosa patients. Volumetric visual function indices, which are measures of quantity and comparable regardless of perimeter test pattern, were investigated. Cross-validation, reliability, and cross sectional analyses were performed to assess this methodology and compare the volumetric indices to conventional mean sensitivity and mean deviation. Floor effects were evaluated by computer simulation. RESULTS: Cross-validation yielded an overall R2 of 0.68 and index of agreement of 0.89, which were consistent among subject groups, indicating good accuracy. Volumetric and conventional indices were comparable in terms of test-retest variability and discriminability among subject groups. Simulated floor effects did not negatively impact the repeatability of any index, but large floor changes altered the discriminability for regional volumetric indices. CONCLUSIONS: VFMA is an effective tool for clinical and research analyses of static perimetry data. Topographic models of the HOV aid the visualization of field defects, and topographically derived indices quantify the magnitude and extent of visual field sensitivity. TRANSLATIONAL RELEVANCE: VFMA assists with the interpretation of visual field data from any perimetric device and any test location pattern. Topographic models and volumetric indices are suitable for diagnosis, monitoring of field loss, patient counseling, and endpoints in therapeutic trials. PMID- 25938003 TI - Reliability of VEP Recordings Using Chronically Implanted Screw Electrodes in Mice. AB - PURPOSE: Visual evoked potentials (VEPs) are widely used to objectively assess visual system function in animal models of ophthalmological diseases. Although use of chronically implanted electrodes is common in longitudinal VEP studies using rodent models, reliability of recordings over time has not been assessed. We compared VEPs 1 and 7 days after electrode implantation in the adult mouse. We also examined stimulus-independent changes over time, by assessing electroencephalogram (EEG) power and approximate entropy of the EEG signal. METHODS: Stainless steel screws (600-MUm diameter) were implanted into the skull overlying the right visual cortex and the orbitofrontal cortex of adult mice (C57Bl/6J, n = 7). Animals were reanesthetized 1 and 7 days after implantation to record VEP responses (flashed gratings) and EEG activity. Brain sections were stained for glial activation (GFAP) and cell death (TUNEL). RESULTS: Reliability analysis, using intraclass correlation coefficients, showed VEP recordings had high reliability within the same session, regardless of time after electrode implantation and peak latencies and approximate entropy of the EEG did not change significantly with time. However, there was poorer reliability between recordings obtained on different days, and a significant decrease in VEP amplitudes and EEG power. This amplitude decrease could be normalized by scaling to EEG power (within-subjects). Furthermore, glial activation was present at both time points but there was no evidence of cell death. CONCLUSIONS: These results indicate that VEP responses can be reliably recorded even after a relatively short recovery period but decrease response peak amplitude over time. Although scaling the VEP trace to EEG power normalized this decrease, our results highlight that time dependent cortical excitability changes are an important consideration in longitudinal VEP studies. TRANSLATIONAL RELEVANCE: This study shows changes in VEP characteristics over time in chronically implanted mice. Thus, future preclinical longitudinal studies should consider time in addition to amplitude and latency when designing and interpreting research. PMID- 25938004 TI - Repeatability and Reproducibility of Corneal Biometric Measurements Using the Visante Omni and a Rabbit Experimental Model of Post-Surgical Corneal Ectasia. AB - PURPOSE: To investigate the repeatability and reproducibility of the Visante Omni topography in obtaining topography measurements of rabbit corneas and to develop a post-surgical model of corneal ectasia. METHODS: Eight rabbits were used to study the repeatability and reproducibility by assessing the intra- and interobserver bias and limits of agreement. Another nine rabbits underwent different diopters (D) of laser in situ keratosmileusis (LASIK) were used for the development of ectasia model. All eyes were examined with the Visante Omni, and corneal ultrastructure were evaluated with transmission electron microscopy (TEM). RESULTS: There was no significant intra- or interobserver difference for mean steep and flat keratometry (K) values of simulated K, anterior, and posterior elevation measurements. Eyes underwent -5 D LASIK had a significant increase in mean amplitude of astigmatism and posterior surface elevation with time (P for trend < 0.05). At 2 and 3 months, the -5 D LASIK group had significant greater mean amplitude of astigmatism (P = 0.036; P = 0.027) and posterior surface elevation (both P < 0.005) compared with control group. On TEM, the mean collagen fibril diameter and interfibril distance in the -5 D LASIK eyes were significantly greater than in controls at 3 months (P = 0.018; P < 0.001). CONCLUSIONS: The Visante Omni provided imaging of the rabbit cornea with good repeatability and reproducibility. Application of -5 D LASIK treatment produced a rabbit model of corneal ectasia that was gradual in development and simulated the human condition. TRANSLATIONAL RELEVANCE: The results provide the foundations for the future evaluation of novel treatment modalities for post-surgical ectasia and keratoconus. PMID- 25938005 TI - Deformable Surface Accommodating Intraocular Lens: Second Generation Prototype Design Methodology and Testing. AB - PURPOSE: Present an analysis methodology for developing and evaluating accommodating intraocular lenses incorporating a deformable interface. METHODS: The next generation design of extruded gel interface intraocular lens is presented. A prototype based upon similar previously in vivo proven design was tested with measurements of actuation force, lens power, interface contour, optical transfer function, and visual Strehl ratio. Prototype verified mathematical models were used to optimize optical and mechanical design parameters to maximize the image quality and minimize the required force to accommodate. RESULTS: The prototype lens produced adequate image quality with the available physiologic accommodating force. The iterative mathematical modeling based upon the prototype yielded maximized optical and mechanical performance through maximum allowable gel thickness to extrusion diameter ratio, maximum feasible refractive index change at the interface, and minimum gel material properties in Poisson's ratio and Young's modulus. CONCLUSIONS: The design prototype performed well. It operated within the physiologic constraints of the human eye including the force available for full accommodative amplitude using the eye's natural focusing feedback, while maintaining image quality in the space available. The parameters that optimized optical and mechanical performance were delineated as those, which minimize both asphericity and actuation pressure. The design parameters outlined herein can be used as a template to maximize the performance of a deformable interface intraocular lens. TRANSLATIONAL RELEVANCE: The article combines a multidisciplinary basic science approach from biomechanics, optical science, and ophthalmology to optimize an intraocular lens design suitable for preliminary animal trials. PMID- 25938006 TI - Computed Tomographic Assessment of Body Fat in Dachshunds: A Pilot Study. AB - Obesity has not been linked to causing intervertebral disc degeneration, but has been shown to influence time to ambulation, a strong long-term prognostic indicator in dogs with intervertebral disc disease. However, monitoring obesity to date is imprecise and subjective in the clinical setting. Having an objective formula based on morphometric measurements would potentially be more precise to track our patients' weights. Dogs have been shown to gain weight along their lumbar spine more rapidly than other areas. Varying body conformations make extrapolation from nonchondrodystrophic dogs to Dachshunds difficult. This study aimed to establish the region of fat accumulation along the thoracolumbar spine in Dachshunds. Retrospective computed tomographic (CT) analysis was performed on healthy Dachshunds that presented for intervertebral disc disease (IVDD). Fat area measured at L3 and L5 using attenuation ranges -135/-105 Hounsfield units (HU) was the most dependent on body weight (p = 0.05). There appeared to be no difference between subcutaneous, visceral or total percent body fat with weight agreement. T13, L3 and L5 all had linear relationships with patient weight and will likely be helpful for body mass index (BMI) formula creation (p < 0.01). This study indicates that any consistent location between L3 and L5 will give an accurate representation of the abdominal circumference and most obese area of the Dachshund with the umbilicus used as a landmark. PMID- 25938007 TI - Parents with Intellectual Disability in a Population Context. AB - Parenting by people with intellectual disability continues to confront societal sensibilities. On the one hand, parents with intellectual disability engage in the valued social role of raising children; on the other, their parenting attracts (typically negative) attention based on an expectation of their limited capacities to parent. The literature primarily addresses the question of whether or not parents with intellectual disability can be adequate parents or reports on methods for improving their parenting skills. An emerging trend in the literature over the last decade takes a different perspective. Rather than concentrating exclusively on parents with intellectual disability, this perspective focuses on their parenting situation compared to that of other parents more generally. This paper reviews the current state of knowledge about parents and parenting with intellectual disability in this broader population context. The focus of the paper is on the use of larger scale datasets to understand the situation of parents with intellectual disability compared with other parents and to examine the contextual variables that influence their parenting. PMID- 25938008 TI - Clinical and Research Criteria for Developmental Coordination Disorder-Should They Be One and the Same? AB - The aim of this paper is to discuss if criteria used for diagnosing children for clinical purposes should be the same as for the selection of children with Developmental Coordination Disorder for research. Next, we give an overview of the criteria mentioned in the development of the European guideline for diagnosing Developmental Coordination Disorder and the implementation of this guideline in different countries. To gain insight into current clinical practice, we also reviewed the medical files of children attending rehabilitation centers for the criteria used to diagnose Developmental Coordination Disorder in the Netherlands. To conclude, we state our expert opinion on why and when research and clinical criteria for Developmental Coordination Disorder should or should not be the same. PMID- 25938009 TI - Is Treating Motor Problems in DCD Just a Matter of Practice and More Practice? AB - Developmental coordination disorder (DCD) is often called a motor learning deficit. The question addressed in this paper is whether improvement of motor skills is just a matter of mere practice. Without any kind of intervention, children with DCD do not improve their motor skills generally, whereas they do improve after task-oriented intervention. Merely offering children the opportunity to practice motor skills, for instance by playing active video games, did lead to improved motor performance according to recent research findings, but to a lesser extent than task-oriented intervention. We argue that children with DCD lack the required motor problem-solving skills necessary to further improve their performance. Explicit motor teaching with an emphasis on developing these problem-solving skills is a necessary ingredient of intervention in DCD, leveraging the effectiveness of intervention above that of mere practicing. PMID- 25938010 TI - Influenza Burden and Transmission in the Tropics. AB - Each year, influenza causes substantial mortality and morbidity worldwide. It is important to understand influenza in the tropics because of the significant burden in the region and its relevance to global influenza circulation. In this review, influenza burden, transmission dynamics, and their determinants in the tropics are discussed. Environmental, cultural, and social conditions in the tropics are very diverse and often differ from those of temperate regions. Theories that account for and predict influenza dynamics in temperate regions do not fully explain influenza epidemic patterns observed in the tropics. Routine surveillance and household studies have been useful in understanding influenza dynamics in the tropics, but these studies have been limited to only some regions; there is still a lack of information regarding influenza burden and transmission dynamics in many tropical countries. Further studies in the tropics will provide useful insight on many questions that remain. PMID- 25938014 TI - From seoul to lima: korean doctors in peru. PMID- 25938011 TI - Adoptive T Regulatory Cell Therapy for Tolerance Induction. AB - There is a clear need to develop strategies to induce tolerance without the need of chronic immunosuppression in transplant recipient and in patients with autoimmunity. Adoptive T regulatory cell (Treg) therapy offers the potential of long-lasting protection. However, based on results of clinical trials so far with ex vivo expanded autologous Tregs in type 1 diabetic (T1D) patients, it seems unlikely that single immunotherapy with Treg infusion without immunomodulation regimens that promote stable donor Treg engraftment and persistence would afford truly significant clinical benefit. Combination therapies could provide improved outcomes with consideration of the fundamental factors required for Treg generation, homeostasis, and function to promote long-term donor Treg persistence to provoke beneficial therapeutic outcomes. PMID- 25938012 TI - Recent Advances in the Measurement of Arsenic, Cadmium, and Mercury in Rice and Other Foods. AB - Trace element analysis of foods is of increasing importance because of raised consumer awareness and the need to evaluate and establish regulatory guidelines for toxic trace metals and metalloids. This paper reviews recent advances in the analysis of trace elements in food, including challenges, state-of-the-art methods, and use of spatially resolved techniques for localizing the distribution of arsenic and mercury within rice grains. Total elemental analysis of foods is relatively well-established, but the push for ever lower detection limits requires that methods be robust from potential matrix interferences, which can be particularly severe for food. Inductively coupled plasma mass spectrometry (ICP MS) is the method of choice, allowing for multi-element and highly sensitive analyses. For arsenic, speciation analysis is necessary because the inorganic forms are more likely to be subject to regulatory limits. Chromatographic techniques coupled to ICP-MS are most often used for arsenic speciation, and a range of methods now exist for a variety of different arsenic species in different food matrices. Speciation and spatial analysis of foods, especially rice, can also be achieved with synchrotron techniques. Sensitive analytical techniques and methodological advances provide robust methods for the assessment of several metals in animal- and plant-based foods, particularly for arsenic, cadmium, and mercury in rice and arsenic speciation in foodstuffs. PMID- 25938013 TI - Chemoprotective epigenetic mechanisms in a colorectal cancer model: Modulation by n-3 PUFA in combination with fermentable fiber. AB - Colorectal cancer is the third major cause of cancer-related mortality in both men and women worldwide. The beneficial role of n-3 polyunsaturated fatty acids (PUFA) in preventing colon cancer is substantiated by experimental, epidemiological, and clinical data. From a mechanistic perspective, n-3 PUFA are pleiotropic and multifaceted with respect to their molecular mechanisms of action. For example, this class of dietary lipid uniquely modulates membrane and nuclear receptors, sensors/ion channels, and membrane structure/cytoskeletal function, thereby regulating signaling processes that influence patterns of gene expression and cell phenotype. In addition, n-3 PUFA can synergize with other potential chemoprotective agents known to reprogram the chromatin landscape, such as the fermentable fiber product, butyrate. Nutri-epigenomics is an emerging field of research that is focused on the interaction between nutrition and epigenetics. Epigenetics refers to a group of heterogeneous processes that regulate transcription without changing the DNA coding sequence, ranging from DNA methylation, to histone tail modifications and transcription factor activity. One implication of the nutri-epigenome is that it may be possible to reprogram epigenetic marks that are associated with increased disease risk by nutritional or lifestyle interventions. This review will focus on the nutri-epigenomic role of n-3 PUFA, particularly DHA, as well as the combinatorial effects of n-3 PUFA and fermentable fiber in relation to colon cancer. PMID- 25938015 TI - Knowledge and attitude toward informed consent among private dental practitioners in bathinda city, punjab, India. AB - OBJECTIVES: A study was conducted with the purpose to assess the knowledge and attitude towards informed consent among private dental practitioners in Bathinda City, Punjab, India. METHODS: A cross-sectional survey was conducted among all private dental practitioners in Bathinda City. A self-administered structured questionnaire consisting of 14 items was used to assess their knowledge and attitude regarding informed consent. The response format was based on a 3-point Likert scale. One-way analysis of variance, independent sample t test, and stepwise multiple linear regression analysis were utilized for statistical analysis. Confidence level and level of significance were set at 95% and 5%, respectively. RESULTS: The mean scores for knowledge and attitude were 19.37 +/- 31.82 and 9.40 +/- 1.72, respectively. Analysis revealed that qualification and years of experience was statistically significant among both dependent variables (p <= 0.05). CONCLUSION: An unbalanced knowledge of informed consent among the current dentists has suggested the need for awareness programs to fill the knowledge gaps and instill positive attitudes. PMID- 25938016 TI - Antibiotic Resistance of Acinetobacter baumannii in Iran: A Systemic Review of the Published Literature. AB - OBJECTIVES: Acinetobacter baumannii is a bacterium responsible for health care associated infections, and it frequently develops multiple drug resistance (MDR). The prevalence of antibiotic-resistant A. baumannii in Iran has increased, and this may cause significant clinical problems. Therefore, in order to elucidate the development of antibiotic resistance, we performed a systematic review of the literature published on antibiotic-resistant A. baumannii reported in Iran. METHODS: Thirty-six publications that met the criteria for inclusion were reviewed from an initial 87 papers. Selected papers published between 2008 and September 2014, were categorized on the basis of the sample collecting year been between 2001 and 2013. RESULTS: Analysis of data revealed that, in general, there was an increase in antimicrobial resistance. During the initial time point of these studies (2001-2007) there was a high rate of resistance to all antibiotics, with the exception of carbapenems, lipopeptides, and aminoglycosides that had a low resistance rate in comparison with the others. Also, the resistance rate was increased in one group of these three antimicrobial groups from 2010 to 2013. In particular, there was an increase in resistance to carbapenems (imipenem and meropenem) from 2010-2011 and 2012-2013, whereas no significant change in the resistance rate of the other two antimicrobial groups (lipopeptides and aminoglycosides) during the study time was observed, although we did observe certain trends in amikacin (aminoglycoside group antibiotic) between 2011-2012 and 2012-2013. CONCLUSION: These findings indicate that antimicrobial resistance of A. baumannii in Iran has increased, which may very well affect the antimicrobial resistance of this organism worldwide. Based on these results, novel prevention and treatment strategies against A. baumannii infections are warranted. Furthermore, these data may assist in revising treatment guidelines and regional policies in care units to slow the emergence of antimicrobial resistance. PMID- 25938017 TI - Effects of Fenugreek Seed Extract and Swimming Endurance Training on Plasma Glucose and Cardiac Antioxidant Enzymes Activity in Streptozotocin-induced Diabetic Rats. AB - OBJECTIVE: Diabetes mellitus is a group of metabolic diseases characterized by chronic hyperglycemia condition resulting from defective insulin secretion or resistance insulin action, or both. The purpose of this study was to evaluate the effect of 6 weeks swimming training and Trigonella foenum-graecum seed (fenugreek) extract, alone and in combination, on plasma glucose and cardiac antioxidant enzyme activity of streptozotocin-induced diabetic rats. METHODS: Fifty male Wistar rats were divided into five groups: diabetic control (DC, n = 8); healthy control (HC, n = 11); swimming training (S, n = 11); swimming training + fenugreek seed extract (1.74 g/kg body weight; SF1, n = 11); and swimming training + fenugreek seed extract (0.87 g/kg body weight; SF2, n = 9). Streptozotocin was used for the induction of diabetes. Results were analyzed using one-way analysis of variance followed by Tukey test. RESULTS: In comparison with the DC group, all groups exhibited a significant decrease in body weight (p < 0.05), except for the HC group. SF1 and HC groups showed significant decreases in plasma glucose levels compared with the DC group (p < 0.05). S, SF1, SF2, and HC groups showed significant elevations in cardiac antioxidant enzymes activity in comparison with the DC group. CONCLUSION: The results indicated that the combination of endurance swimming training and fenugreek seed extract can significantly reduce the plasma glucose levels and increase cardiac antioxidant enzymes activity in diabetic rats. Our findings suggest that this combination could be useful for the treatment of hyperglycemia and cardiac oxidative stress induced by diabetes mellitus. PMID- 25938018 TI - Association of TNF-alpha 308 G/A Polymorphism With Type 2 Diabetes: A Case Control Study in the Iranian Kurdish Ethnic Group. AB - OBJECTIVES: Tumor necrosis factor-alpha (TNF-alpha) plays roles in the development of obesity, insulin resistance, and possibility of Type 2 diabetes mellitus (T2DM). The objective of the current study was to evaluate the association of TNF-alpha promoter-308 G/A polymorphism with T2DM. METHODS: In all, 1038 patients with T2DM and 1023 normoglycemic controls were included in this study. All participants were genotyped using the polymerase chain reaction restriction fragment length polymorphism method. Genotypic and allelic frequencies were then analyzed in each group. Serum lipids, fasting glucose, fasting serum insulin, homeostatic model assessment of insulin resistance, and hemoglogin A1c levels were determined by conventional methods. RESULTS: The allelic frequency of the A allele was significantly different between case and control participants (p = 0.006). Genotypes GA and AA were found to be significantly associated with 2.24- and 3.18-fold increased risk for T2DM, respectively. Similarly, the dominant model of -308 G/A polymorphism was found to have a higher risk for T2DM (odds ratio = 2.34, p = 0.001). Individuals with T2DM carrying the GA + AA genotypes of -308 G/A variation had significantly lower fasting plasma insulin than those carrying GG genotype. CONCLUSION: Our findings revealed that there is an association between the TNF-alpha promoter -308 G/A polymorphism and T2DM in this population. PMID- 25938019 TI - Gastric and esophageal cancers incidence mapping in golestan province, iran: using bayesian-gibbs sampling. AB - OBJECTIVES: Recent studies of esophageal cancer (EC) and gastric cancer (GC) have been reported to have high incidence rates of these cancers in Golestan Province of Iran. The present study describes the geographical patterns of EC and GC incidence based on cancer registry data and display statistically significant regions within this province. METHODS: In order to map the distribution of upper gastrointestinal cancer, relative risk (RR) were calculated. Therefore, to estimate a more reliable RR, Poisson regression models were used. The adjusted models (adjusted to urban-rural area, sex, and grouped age proportion) were utilized. We considered two-component random effects for each observation, an unstructured (noncorrelated) and a group of "neighbor" (correlated) heterogeneities. We estimated the model parameters using Gibbs sampling and empirical Bayes method. We used EC and GC data that were registered with Golestan Research Center of Gastroenterology and Hepatology in the years 2004-2008. RESULTS: The EC and GC maps were drawn for 2004-2008 in the province. Kalaleh and Minoodasht counties have a high RR of EC and GC in the years of study. In almost all years, the areas with a high RR were steady. CONCLUSION: The EC and GC maps showed significant spatial patterns of risk in Golestan province of Iran. Further study is needed to multivariate clustering and mapping of cancers RRs with considering diet and socioeconomic factors. PMID- 25938020 TI - H5N8 Highly Pathogenic Avian Influenza in the Republic of Korea: Epidemiology During the First Wave, from January Through July 2014. AB - OBJECTIVES: This study describes the outbreaks of H5N8 highly pathogenic avian influenza (HPAI) in Korea during the first wave, from January 16, 2014 through July 25, 2014. Its purpose is to provide a better understanding of the epidemiology of H5N8 HPAI. METHODS: Information on the outbreak farms and HPAI positive wild birds was provided by the Animal and Plant Quarantine Agency. The epidemiological investigation sheets for the outbreak farms were examined. RESULTS: During the 7-month outbreak period (January-July 2014), H5N8 HPAI was confirmed in 212 poultry farms, 38 specimens from wild birds (stools, birds found dead or captured). Ducks were the most frequently infected poultry species (159 outbreak farms, 75.0%), and poultry in 67 (31.6%) outbreak farms was asymptomatic. CONCLUSION: As in the previous four H5N1 epidemics of HPAI that occurred in Korea, this epidemic of H5N8 proved to be associated with migratory birds. Poultry farms in Korea can hardly be free from the risk of HPAI introduced via migratory birds. The best way to overcome this geographical factor is to reinforce biosecurity to prevent exposure of farms, related people, and poultry to the pathogen. PMID- 25938021 TI - Application of gap-constraints given sequential frequent pattern mining for protein function prediction. AB - OBJECTIVES: Predicting protein function from the protein-protein interaction network is challenging due to its complexity and huge scale of protein interaction process along with inconsistent pattern. Previously proposed methods such as neighbor counting, network analysis, and graph pattern mining has predicted functions by calculating the rules and probability of patterns inside network. Although these methods have shown good prediction, difficulty still exists in searching several functions that are exceptional from simple rules and patterns as a result of not considering the inconsistent aspect of the interaction network. METHODS: In this article, we propose a novel approach using the sequential pattern mining method with gap-constraints. To overcome the inconsistency problem, we suggest frequent functional patterns to include every possible functional sequence-including patterns for which search is limited by the structure of connection or level of neighborhood layer. We also constructed a tree-graph with the most crucial interaction information of the target protein, and generated candidate sets to assign by sequential pattern mining allowing gaps. RESULTS: The parameters of pattern length, maximum gaps, and minimum support were given to find the best setting for the most accurate prediction. The highest accuracy rate was 0.972, which showed better results than the simple neighbor counting approach and link-based approach. CONCLUSION: The results comparison with other approaches has confirmed that the proposed approach could reach more function candidates that previous methods could not obtain. PMID- 25938022 TI - Perception of childhood obesity in mothers of preschool children. AB - OBJECTIVES: The purpose of this study was to identify the perception of childhood obesity in mothers of preschool children using Q methodology. METHODS: A total of 38 Q statements about childhood obesity were obtained from 41 participants. The QUANL PC program was used to analyze the results. RESULTS: There were three types of perception toward obesity in mothers of preschool children: the "authoritative discipline type," the "generous home meal focused type," and the "home meal based on household financial situation type." CONCLUSION: The perception of mothers toward childhood obesity can affect the extent of maternal interaction with children or meal preparation for the family. Based on these results, it is necessary to plan specific programs according to the types of maternal perception toward childhood obesity. PMID- 25938023 TI - Comparison of Consensus on Life-sustaining Treatment of the Elderly in Care Facilities and Family Member Dyad. AB - OBJECTIVES: The purpose of this study is to compare the agreement in opinion between the elderly in care facilities and their family members regarding the life-sustaining treatment at the deathbed and to find out if the intentions of the elderly are being properly reflected in their deathbed treatment. METHODS: Data were collected from 85 elderly individuals at five care facilities in Chunkcheongnam-do and 85 family members. The data were collected with a self administered questionnaire from July 22, 2013 to August 15, 2014. A total of 170 cases were analyzed using SPSS version 21. RESULTS: First, the family members' preference for life-sustaining treatment was higher than the patients' preference. The preference between the elderly and their family members regarding life-sustaining treatment was statistically significant with regards to oral nutrition, pain control through oral and anal administration, pain control through intravenous administration, transfusion, and admission to an intensive care unit. Second, looking at the agreement between elderly and guardians regarding life-sustaining treatment, there was significant concordance about general testing, oral nutrition, intravenous hydration, intravenous nutrition, antibiotic treatment for severe infection with low resiliency, admission to an intensive care unit, blood pressure increase medication use, cardiopulmonary resuscitation, and tracheotomy. CONCLUSION: It is essential for the medical staff to confirm agreement between the elderly and their family members regarding life sustaining treatment, and if such a prior agreement is not feasible, the patient's intention should be considered more actionable than their family members. PMID- 25938024 TI - Review for the Korean Health Professionals and International Cooperation Doctors Dispatched to Peru by the Korea International Cooperation Agency (KOICA). AB - South Korea dispatches Korean nationals to partner developing countries as an Official Development Assistance (ODA) project through the Korea International Cooperation Agency (KOICA). In the health sector, KOICA dispatches international cooperation doctors (ICDs), nurses, physical therapists, radiologic technologists, nutritionists, medical laboratory technologists, occupational therapists, and dental hygienists. A total of 216 ICDs were dispatched over 19 times from 1995 until 2013. There were 19 areas of specialties among the ICDs. The most common specialty was internal medicine (61/216, 28.2%), the second most common specialty was general surgery (43/216, 19.9%), followed by oriental medicine (27/216, 12.5%), pediatrics (17/216, 7.9%), orthopedics (16/216, 7.4%), family medicine (16/216, 7.4%), and odontology (14/216, 6.5%). The ICDs have worked in 21 countries. KOICA dispatched the highest number of ICDs to Asia (97/216, 44.9%), followed by Africa (50/216, 23.1%), Latin America (34/216, 15.7%), the commonwealth of independent states (31/216, 14.4%), and Oceania (4/216, 1.9%). Nobody was dispatched to the Middle East. A total of 134 KOICA health professionals were dispatched to Peru from 1996 until October 1, 2014. Of these, 19.4% (26/134) were ICDs, 44.8% (60/216) were nurses, 20.1% (27/134) were physical therapists, 6.7% (9/134) were radiologic technologists, 2.2% (3/134) were nutritionists, and 6.7% (9/134) were medical laboratory. ICDs' specialties comprised internal medicine (13/26, 50%), family medicine (8/26, 30.8%), pediatrics (2/26, 7.7%), otorhinolaryngology (1/26, 3.8%), orthopedics (1/26, 3.8%), and oriental medicine (1/26, 3.8%). Most of the dispatched health professionals worked at institutions that were supported by KOICA. For this reason, the proportion of health professionals who worked at public health centers (PHCs) was the highest (58.2%, 78/134) when classified by workplace type. Other KOICA health professionals worked at hospitals, governmental organizations (GOs), or schools. PMID- 25938025 TI - Extended-depth spectral-domain optical coherence tomography imaging of the crystalline lens in Weill-Marchesani-like syndrome. AB - A 26-year-old woman presented with signs and symptoms of acute angle-closure glaucoma (ACG) in her left eye. Extended-depth spectral-domain optical coherence tomography (SD-OCT) was performed to biometrically assess the anterior chamber depth and crystalline lens conformation. Extended-depth SD-OCT imaging of the crystalline lens showed bilateral spherophakia without dislocation. Neither eye manifested a highly myopic refractive error despite spherophakia. Unanticipated conformation of the anterior and posterior lenticular curvatures, increased thickness of the crystalline lenses, and short axial lengths explained the lack of a highly myopic refractive error. These findings demonstrated a lens-related cause of the ACG. The use of extended-depth SD-OCT supported the diagnosis of subclinical Weill-Marchesani syndrome in a patient without other commonly associated findings and provided a better understanding of the mechanism of angle closure in this patient. PMID- 25938026 TI - Anticoagulant modulation of inflammation in severe sepsis. AB - Inflammation and coagulation are so tightly linked that the cytokine storm which accompanies the development of sepsis initiates thrombin activation and the development of an intravascular coagulopathy. This review examines the interaction between the inflammatory and coagulation cascades, as well as the role of endogenous anticoagulants in regulating this interaction and dampening the activity of both pathways. Clinical trials attempting to improve outcomes in patients with severe sepsis by inhibiting thrombin generation with heparin and or endogenous anticoagulants are reviewed. In general, these trials have failed to demonstrate that anticoagulant therapy is associated with improvement in mortality or morbidity. While it is possible that selective patients who are severely ill with a high expected mortality may be shown to benefit from such therapy, at the present time none of these anticoagulants are neither approved nor can they be recommended for the treatment of sepsis. PMID- 25938028 TI - Tumor lysis syndrome: A clinical review. AB - Tumor lysis syndrome is an oncometabolic emergency resulting from rapid cell death. Tumor lysis syndrome can occur as a consequence of tumor targeted therapy or spontaneously. Clinicians should stratify every hospitalized cancer patient and especially those receiving chemotherapy for the risk of tumor lysis syndrome. Several aspects of prevention include adequate hydration, use of uric acid lowering therapies, use of phosphate binders and minimization of potassium intake. Patients at high risk for the development of tumor lysis syndrome should be monitored in the intensive care unit. Established tumor lysis syndrome should be treated in the intensive care unit by aggressive hydration, possible use of loop diuretics, possible use of phosphate binders, use of uric acid lowering agents and dialysis in refractory cases. PMID- 25938027 TI - Fluid and electrolyte overload in critically ill patients: An overview. AB - Fluids are considered the cornerstone of therapy for many shock states, particularly states that are associated with relative or absolute hypovolemia. Fluids are also commonly used for many other purposes, such as renal protection from endogenous and exogenous substances, for the safe dilution of medications and as "maintenance" fluids. However, a large amount of evidence from the last decade has shown that fluids can have deleterious effects on several organ functions, both from excessive amounts of fluids and from their non-physiological electrolyte composition. Additionally, fluid prescription is more common in patients with systemic inflammatory response syndrome whose kidneys may have impaired mechanisms of electrolyte and free water excretion. These processes have been studied as separate entities (hypernatremia, hyperchloremic acidosis and progressive fluid accumulation) leading to worse outcomes in many clinical scenarios, including but not limited to acute kidney injury, worsening respiratory function, higher mortality and higher hospital and intensive care unit length-of-stays. In this review, we synthesize this evidence and describe this phenomenon as fluid and electrolyte overload with potentially deleterious effects. Finally, we propose a strategy to safely use fluids and thereafter wean patients from fluids, along with other caveats to be considered when dealing with fluids in the intensive care unit. PMID- 25938029 TI - Designing drug regimens for special intensive care unit populations. AB - This review is intended to help clinicians design drug regimens for special populations of critically ill patients with extremes of body size, habitus and composition that make drug choice or dosing particularly challenging due to the lack of high-level evidence on which to make well-informed clinical decisions. The data sources included a literature search of MEDLINE and EMBASE with reviews of reference lists of retrieved articles. Abstracts of original research investigations and review papers were reviewed for their relevance to drug choice or dosing in the following special critically ill populations: patients with more severe forms of bodyweight or height, patients with amputations or missing limbs, pregnant patients, and patients undergoing extracorporeal membrane oxygenation or plasma exchange. Relevant papers were retrieved and evaluated, and their associated reference lists were reviewed for citations that may have been missed through the electronic search strategy. Relevant original research investigations and review papers that could be used to formulate general principles for drug choice or dosing in special populations of critically ill patients were extracted. Randomized studies with clinically relevant endpoints were not available for performing quantitative analyses. Critically ill patients with changes in body size, habitus and composition require special consideration when designing medication regimens, but there is a paucity of literature on which to make drug-specific, high-level evidence-based recommendations. Based on the evidence that is available, general recommendations are provided for drug choice or dosing in special critically ill populations. PMID- 25938030 TI - Comparison of cytotoxicity and wound healing effect of carboxymethylcellulose and hyaluronic acid on human corneal epithelial cells. AB - AIM: To investigate the cytotoxic effect on human corneal epithelial cells (HCECs) and the ability to faciliate corneal epithelial wound healing of carboxymethylcellulose (CMC) and hyaluronic acid (HA). METHODS: HCECs were exposed to 0.5% CMC (Refresh plus((r)), Allergan, Irvine, California, USA) and 0.1% and 0.3% HA (Kynex((r)), Alcon, Seoul, Korea, and Hyalein mini((r)), Santen, Osaka, Japan) for the period of 30min, and 4, 12, and 24h. Methyl thiazolyl tetrazolium (MTT)-based calorimetric assay was performed to assess the metabolic activity of cellular proliferation and lactate dehydrogenase (LDH) leakage assay to assess the cytotoxicity. Apoptotic response was evaluated with flow cytometric analysis and fluorescence staining with Annexin V and propiodium iodide. Cellular morphology was evaluated by inverted phase-contrast light microscopy and electron microscopy. The wound widths were measured 24h after confluent HCECs were scratch wounded. RESULTS: The inhibitory effect of human corneal epithelial proliferation and cytotoxicity showed the time-dependent response but no significant effect. Apoptosis developed in flow cytometry and apoptotic cells were demonstrated in fluorescent micrograph. The damaged HCECs were detached from the bottom of the dish and showed the well-developed vacuole formations. Both CMC and HA stimulated reepithehlialization of HCECs scratched, which were more observed in CMC. CONCLUSION: CMC and HA, used in artificial tear formulation, could be utilized without any significant toxic effect on HCECs. Both significantly stimulated HCEC reepithelialization of corneal wounds. PMID- 25938031 TI - TREM-1 expression in rat corneal epithelium with Aspergillus fumigatus infection. AB - AIM: To investigate the expression of triggering receptor expressed on myeloid cells-1 (TREM-1) in the aberrant inflammation within the corneal epithelium at early period of fungal infection. METHODS: A total of 65 Wistar rats were randomly divided into control group, sham group and fungal keratitis (FK) group, in which the cornea was infected by Aspergillus fumigatus (A. fumigatus). After executed randomly at 8, 16, 24, 48 and 72h after experimental model being established, the severity of keratomycosis in rats was scored visually with the aid of a dissecting microscope and slit lamp. Then corneas in three groups were collected to assess the expression of TREM-1 through quantitative reverse transcription-polymerase chain reaction (RT-PCR), immunofluorescence technique and Western blot analysis. The correlation between FK inflammation and expression of TREM-1 was also analyzed. RESULTS: Corneal inflammation scores increased with time after fungal infection (F=49.74, P=0.000). The inflammation scores in FK group were obviously higher than those in sham group on the whole (F=137.78, P=0.000). Levels of TREM-1 in the infected rat corneal epithelium had elevated at 8h and peaked at 48h (P<0.001, compared with control group). Western blot analysis also showed an obviously elevated TREM-1 level in rat corneal epithelium at 24h and 48h after fungal infection. Immunofluorescence technique showed that TREM-1 mainly existed in corneal epithelium and infected corneal stoma of rat. TREM-1 protein expression was enhanced after fungal infection. Moreover, severity of FK inflammation was significantly related to TREM-1 expression in FK (r=0.942, P=0.000). CONCLUSION: TREM-1 may contribute to amplify the inflammation in the cornea infected with A. fumigatus and play critical roles in the battle against A. fumigatus in the innate immune responses. PMID- 25938032 TI - Therapeutic effects of topical netrin-4 in a corneal acute inflammatory model. AB - AIM: To evaluate the therapeutic effect of netrin-4 on the early acute phase of inflammation in the alkali-burned eye. METHODS: Eye drops containing netrin-4 or phosphate buffered saline (PBS) were administered to a alkali-burn-induced corneal acute inflammatory model four times daily. The clinical evaluations, including fluorescein staining and inflammatory index, were performed on day 1, 4 and 7 using slit lamp microscopy. Global specimens were collected on day 7 and processed for immunofluorescent staining. The levels of inflammatory mediators in the corneas were determined by real-time polymerase chain reaction (PCR). RESULTS: Exogenous netrin-4 administered on rat ocular surfaces showed more improvements in decreasing fluorescein staining on day 4 and 7, and resolved alkali burn-induced corneal inflammation index on day 7 (P<0.01). The levels of IL-1beta, IL-6, intercellular cell adhesion molecule-1 (ICAM-1), vascular cell adhesion molecule-1 (VCAM-1), monocyte chemotactic protein-1 (MCP-1) and macrophage inflammatory protein-1 (MIP-1) in corneas were decreased in netrin-4 treated groups (P<0.05). In addition, netrin-4 significantly reduced the expression of leukocyte common antigen 45 (CD45) in the alkali-burn cornea (P<0.001). CONCLUSION: Topical netrin-4 accelerated wound healing and reduced the inflammation on alkali-burn rat model, suggesting a potential as an anti inflammatory agent in the clinical to treat the acute inflammation. PMID- 25938033 TI - Inhibitory effect of polysulfated heparin endostatin on alkali burn induced corneal neovascularization in rabbits. AB - AIM: To investigate anti-angiogenic effects of polysulfated heparin endostatin (PSH-ES) on alkali burn induced corneal neovascularization (NV) in rabbits. METHODS: An alkali burn was made on rabbit corneas to induce corneal NV in the right eye of 24 rabbits. One day after burn creation, a 0.2 mL subconjunctival injection of 50 ug/mL PSH-ES, 50 ug/mL recombinant endostatin (ES), or normal saline was administered every other day for a total of 14d (7 injections). Histology and immunohistochemisty were used to examine corneas. Corneal NV growth was evaluated as microvessel quantity and corneal vascular endothelial growth factor (VEGF) expression was measured by immunohistochemical assay. RESULTS: Subconjunctival injection of ES and PSH-ES resulted in significant corneal NV suppression, but PSH-ES had a more powerful anti-angiogenic effect than ES. Mean VEGF concentration in PSH-ES treated corneas was significantly lower than in ES treated and saline treated corneas. Histological examination showed that corneas treated with either PSH-ES or ES had significantly fewer microvessels than eyes treated with saline. Additionally corneas treated with PSH-ES had significantly fewer microvessels than corneas treated with ES. CONCLUSION: Both PSH-ES and recombinant ES effectively inhibit corneal NV induced by alkali burn. However, PSH-ES is a more powerful anti-angiogenic agent than ES. This research has the potential to provide a new treatment option for preventing and treating corneal NV. PMID- 25938034 TI - Neuroprotective effect of edaravone in experimental glaucoma model in rats: a immunofluorescence and biochemical analysis. AB - AIM: To evaluate the neuroprotective activity of systemically administered edaravone in early and late stage of experimental glaucoma in rats. METHODS: In this study, 60 Wistar albino rats were used. Experimental glaucoma model was created by injecting hyaluronic acid to the anterior chamber once a week for 6wk in 46 of 60 subjects. Fourteen subjects without any medication were included as control group. Edaravone administered intraperitoneally 3 mg/kg/d to the 15 of 30 subjects starting at the onset of glaucoma induction and also administered intraperitoneally 3 mg/kg/d to the other 15 subjects starting at three weeks after the onset of glaucoma induction. The other 16 subjects who underwent glaucoma induction was administered any therapy. Retinal ganglion cells (RGCs) have been marked with dextran tetramethylrhodamine (DTMR) retrograde at the end of the sixth week and after 48h, subjects were sacrificed by the method of cardiac perfusion. Alive RGC density was assessed in the whole-mount retina. Whole-mount retinal tissues homogenized and nitric oxide (NO), malondialdehyde (MDA) and total antioxidant capacity (TAC) values were measured biochemically. RESULTS: RGCs counted with Image-Pro Plus program, in the treatment group were found to be statistically significantly protected, compared to the glaucoma group (Bonferroni, P<0.05). The neuroprotective activity of edaravone was found to be more influential by administration at the start of the glaucoma process. Statistically significant lower NO levels were determined in the glaucoma group comparing treatment groups (Bonferroni, P<0.05). MDA levels were found to be highest in untreated glaucoma group, TAC levels were found to be lower in the glaucoma induction groups than the control group (Bonferroni, P<0.05). CONCLUSION: Systemic administration of Edaravone in experimental glaucoma showed potent neuroprotective activity. The role of oxidative stress causing RGC damage in glaucoma was supported by this study results. PMID- 25938035 TI - Bevacizumab modulates retinal pigment epithelial-to-mesenchymal transition via regulating Notch signaling. AB - AIM: To investigate the effect of bevacizumab treatment on Notch signaling and the induction of epithelial-of-mesenchymal transition (EMT) in human retinal pigment epithelial cells (ARPE-19) in vitro. METHODS: In vitro cultivated ARPE-19 cells were treated with 0.25 mg/mL bevacizumab for 12, 24, and 48h. Cell morphology changes were observed under an inverted microscope. The expression of zonula occludens-1 (ZO-1), vimentin and Notch-1 intracellular domain (NICD) was examined by immunofluorescence. The mRNA levels of ZO-1, alpha-SMA, Notch-1, Notch-2, Notch-4, Dll4, Jagged-1, RBP-Jk and Hes-1 expression were evaluated with quantitative real-time polymerase chain reaction (qRT-PCR). The protein levels of alpha-SMA, NICD, Hes-1 and Dll-4 expression were examined with Western blot. RESULTS: Bevacizumab stimulation increased the expression of alpha-SMA and vimentin in ARPE-19 cells which changed into spindle-shaped fibroblast-like cells. Meanwhile, the mRNA expression of Hes-1 increased and the protein expression of Hes-1 and NICD also increased, which Notch signaling was activated. The mRNA expression of Notch-1, Jagged-1 and RBP-Jk increased at 48h, and while Dll4 mRNA and protein expression did not change after bevacizumab treatment. CONCLUSION: Jagged-1/Notch-1 signaling may play a critical role in bevacizumab induced EMT in ARPE-19 cells, which provides a novel insight into the pathogenesis of intravitreal bevacizumab-associated complication. PMID- 25938036 TI - In vitro induction and differentiation of umbilical cord mesenchymal stem cells into neuron-like cells by all-trans retinoic acid. AB - AIM: To determine the optimal concentration for inducing the differentiation of human umbilical cord-derived mesenchymal stem cells (hUC-MSCs) into neuron-like cells, although it is understood that all-trans retinoic acid (ATRA) regulates cell proliferation in the nervous system by modulating the balance between mitosis and apoptosis. METHODS: The abilities of ATRA to promote apoptosis as well as neural differentiation were assessed in cultured hUC-MSCs by morphological observation, MTT assay, annexin V-FITC/PI flow cytometry and immunocytochemistry. RESULTS: The data showed that low concentrations of ATRA (0.5 umol, 0.25 umol) had no effect on the number of cells. However, treatment with 1.0 umol or 2.0 umol ATRA induced a 24.16% and 52.67% reduction in cell number, respectively, compared with vehicle-treated cultures. Further, 4.0 umol ATRA had a potent effect on cell number, with almost no adherent cells recovered after 24h. We further showed that 0.5 umol ATRA caused these cells to express characteristic markers of neuronal progenitor cells. CONCLUSION: Taken together, we conclude that ATRA has a dose-dependent influence on the neural differentiation and apoptosis of hUC-MSCs. These findings have implications on the use of ATRA-differentiated hUC-MSCs for the study of neural degeneration diseases. PMID- 25938037 TI - A comparative study on the transplantation of different concentrations of human umbilical mesenchymal cells into diabetic rats. AB - AIM: To observe the effects of intravitreal injections of different concentrations of human umbilical mesenchymal stem cells on retinopathy in rats with diabetes mellitus. METHODS: Healthy and adult male Sprague-Dawley (SD) rats were randomly assigned to a normal control group (group A), a diabetic retinopathy (DR) blank control group (group B), a high-concentration transplantation group (group C), a low-concentration transplantation group (group D) and a placebo transplantation group (group E). The expression of nerve growth factor (NGF) protein in the retinal layers was detected by immunohistochemical staining at 2, 4, 6 and 8wk. RESULTS: The expression of NGF was positive in group A and most positive in the retinal ganglion cell layer. In groups B and E, the expression of NGF was positive 2wk after transplantation and showed an increase in all layers. However, the level of expression had decreased in all layers at 4wk and was significantly reduced at 8wk. In groups C and D, the expression of NGF had increased at 2wk and continued to increase up to 8wk. The level of expression in group C was much higher than that in group D. CONCLUSION: DR can be improved by intravitreal injection of human umbilical mesenchymal stem cells. High concentrations of human umbilical mesenchymal stem cells confer a better protective effect on DR than low concentrations. PMID- 25938038 TI - Comparison of pre-treatment and post-treatment use of selenium in retinal ischemia reperfusion injury. AB - AIM: To investigate the effects of selenium in rat retinal ischemia reperfusion (IR) model and compare pre-treatment and post-treatment use. METHODS: Selenium pre-treatment group (n=8) was treated with intraperitoneal (i.p.) selenium 0.5 mg/kg for 7d and terminated 24h after the IR injury. Selenium post-treatment group (n=8) was treated with i.p. selenium 0.5 mg/kg for 7d after the IR injury with termination at the end of the 7d period. Sham group (n=8) received i.p. saline injections identical to the selenium volume for 7d with termination 24h after the IR injury. Control group (n=8) received no intervention. Main outcome measures were retina superoxide dismutase (SOD), glutathione (GSH), total antioxidant status (TAS), malondialdehyde (MDA), DNA fragmentation levels, and immunohistological apoptosis evaluation. RESULTS: Compared to the Sham group, selenium pre-treatment had a statistical difference in all parameters except SOD. Post-treatment selenium also resulted in statistical differences in all parameters except the MDA levels. When comparing selenium groups, the pre treatment selenium group had a statistically higher success in reduction of markers of cell damage such as MDA and DNA fragmentation. In contrast, the post selenium treatment group had resulted in statistically higher levels of GSH. Histologically both selenium groups succeeded to limit retinal thickening and apoptosis. Pre-treatment use was statistically more successful in decreasing apoptosis in ganglion cell layer compared to post-treatment use. CONCLUSION: Selenium was successful in retinal protection in IR injuries. Pre-treatment efficacy was superior in terms of prevention of tissue damage and apoptosis. PMID- 25938040 TI - Comparison of corneal measurements in keratoconic eyes using rotating Scheimpflug camera and scanning-slit topography. AB - AIM: To compare the anterior segment measurements obtained by rotating Scheimpflug camera (Pentacam) and Scanning-slit topography (Orbscan IIz) in keratoconic eyes. METHODS: A total of 121 patients, 71 males (58.7%) and 50 females (41.3%) (214 eyes) with the diagnosis of keratoconus (KC) were enrolled in this study. Following diagnosis of KC by slit-lamp biomicroscopic examination, central corneal thickness (CCT), thinnest corneal thickness (TCT), anterior chamber depth (ACD), and pupil diameter (PD) were measured by a single examiner using successive instrumentation by Pentacam and Orbscan. RESULTS: There was no significant difference between the two instruments for the measurement of CCT and TCT. In contrast, scanning-slit topography measured ACD (3.46+/-0.40 mm vs. 3.38+/-0.33 mm, P=0.019) and PD (4.97+/-1.26 mm vs 4.08+/-1.19 mm, P<0.001) significantly larger than rotating Scheimpflug camera. The two devices made similar measurements for CCT (95% CI: -2.94 to 5.06, P=0.602). However, the mean difference for TCT was -6.28 (95% CI: -10.51 to -2.06, P=0.004) showing a thinner measurement by Orbscan than by Pentacam. In terms of the ACD, the mean difference was 0.08 mm (95% CI: 0.04 to 0.12, P<0.001) with Orbscan giving a slightly larger value than Pentacam. Similarly, Orbscan measurement for PD was longer than Pentacam (95% CI: 0.68 to 1.08, P<0.001). CONCLUSION: A good agreement was found between Pentacam and Orbscan concerning CCT measurement while comparing scanning slit topography and rotating Scheimpflug camera there was an underestimation for TCT and overestimation for ACD and PD. PMID- 25938039 TI - Identify the signature genes for diagnose of uveal melanoma by weight gene co expression network analysis. AB - AIM: To identify and understand the relationship between co-expression pattern and clinic traits in uveal melanoma, weighted gene co-expression network analysis (WGCNA) is applied to investigate the gene expression levels and patient clinic features. Uveal melanoma is the most common primary eye tumor in adults. Although many studies have identified some important genes and pathways that were relevant to progress of uveal melanoma, the relationship between co-expression and clinic traits in systems level of uveal melanoma is unclear yet. We employ WGCNA to investigate the relationship underlying molecular and phenotype in this study. METHODS: Gene expression profile of uveal melanoma and patient clinic traits were collected from the Gene Expression Omnibus (GEO) database. The gene co-expression is calculated by WGCNA that is the R package software. The package is used to analyze the correlation between pairs of expression levels of genes. The function of the genes were annotated by gene ontology (GO). RESULTS: In this study, we identified four co-expression modules significantly correlated with clinic traits. Module blue positively correlated with radiotherapy treatment. Module purple positively correlates with tumor location (sclera) and negatively correlates with patient age. Module red positively correlates with sclera and negatively correlates with thickness of tumor. Module black positively correlates with the largest tumor diameter (LTD). Additionally, we identified the hug gene (top connectivity with other genes) in each module. The hub gene RPS15A, PTGDS, CD53 and MSI2 might play a vital role in progress of uveal melanoma. CONCLUSION: From WGCNA analysis and hub gene calculation, we identified RPS15A, PTGDS, CD53 and MSI2 might be target or diagnosis for uveal melanoma. PMID- 25938041 TI - Effect of torsional mode phacoemulsification on cornea in eyes with/without pseudoexfoliation. AB - AIM: To evaluate the effect of torsional mode phacoemulsification on central corneal thickness, corneal endothelial cell density, and morphology in eyes with/without pseudoexfoliation (PEX) syndrome. METHODS: Fourty-two consecutive patients with and 42 patients without PEX as a control group scheduled for cataract surgery was studied. Phacoemulsification, using OZiL IP system, was performed with quick chop technique. Using noncontact specular microscopy, the central endothelial cell density (ECD), coefficient of variation, percentage of hexagonal cells, and the central corneal thickness (CCT) were evaluated preoperatively and postoperatively at 1, 7 and 30d. RESULTS: The ECD in PEX syndrome was statistically significantly lower than that in the control group preoperatively and postoperatively (P<=0.001). Percentage change in ECD was statistically significantly higher in PEX than that in control group after surgery follow up (P<=0.04). There was no statistically significant difference between both groups comparing percentage of hexagonal cells and coefficient of variation in the cell size before and after the surgery. At 1 and 7d after surgery, percentage change in CCT was statistically significantly higher in PEX group than that in the control group (P<=0.041). CONCLUSION: Although torsional mode phacoemulsification and intraocular lens (IOL) implantation provided a safe and favorable surgical outcome in patients with/without PEX, torsional phacoemulsification led to significantly higher ECD loss in the PEX group than that in the control group during the whole follow up period. In addition, more corneal swelling in the PEX group than that in the control group during the early postoperative period has indicated that the corneal endothelium, in presence of PEX endotheliopathy, seems to be more susceptible to the effects of phacoemulsification surgery in eyes with PEX. The increased risk of anterior chamber manipulations in patients with PEX should be taken into account for an increased risk of bullous keratopathy. PMID- 25938042 TI - Comparison of laser iridotomy using short duration 532-nm Nd: YAG laser (PASCAL) vs conventional laser in dark irides. AB - AIM: To evaluate the outcome of laser iridotomy using 532-nm Nd: YAG laser (PASCAL) with short pulse duration and Nd: YAG laser compared to conventional combined laser iridotomy. METHODS: Retrospective, nonrandomized, comparative case series. Forty-five eyes of 34 patients underwent laser iridotomy. Twenty-two eyes underwent iridotomy using short duration PASCAL and Nd: YAG laser, and 23 eyes underwent iridotomy using conventional combined laser method. The average settings of PASCAL were 60 um and 700-900 mW with a short duration of 0.01s to reduce the total applied energy. The conventional laser was 50 um and 700-900 mW for 0.1s. After photocoagulation with these laser, the Nd: YAG laser was added in each group. Endothelial cell counts of pre-iridotomy and 2mo after iridotomy were measured and compared. RESULTS: All eyes completed iridotomy successfully. The total energy used in the PASCAL group was 1.85+/-1.17 J. Compared to conventional laser 13.25+/-1.67 J, the energy used was very small due to the short exposure time of PASCAL. Endothelial cell counts were reduced by 0.88% in the PASCAL group and 6.72% in the conventional laser group (P=0.044). The change in corneal endothelial cell counts before and after iridotomy was significant in conventional combined laser iridotomy group (P=0.004). CONCLUSION: Combined PASCAL and Nd:YAG laser iridotomy is an effective and safe technique in the dark brown irides of Asians. Furthermore, the short duration of exposure in PASCAL offers the advantages of reducing the total energy used and minimizing the corneal damage. PMID- 25938043 TI - Assessment of visual outcomes of cataract surgery in Tujia nationality in Xianfeng County, China. AB - AIM: To evaluate the visual outcome and factors influencing visual outcome of manual small incision cataract surgery (MSICS) in the rural area in the Xianfeng County. METHODS: Eighty-two eyes of 82 patients who underwent cataract surgery performed by using MSICS technique were identified. Data collected included each patient's age, gender, the level of education. Uncorrected and corrected distance visual acuity (UDVA and CDVA) at presentation and at 1, 6, 8wk postoperatively, pre-existing eye disease, operative findings and complications, the risk factors were evaluated. RESULTS: In 82 patients, the average age was 69.6+/-0.6y, illiterate were 52 (63.4%). Of 82 eyes, pseudophakia was present in 77 eyes (93.9%). At 1wk postoperatively, 47 eyes (57.3%) had the UDVA of >=6/18, and 52 eyes (63.4%) had the CDVA of >=6/18. At 6 to 8wk postoperatively, 50 eyes (61.0%) had UDVA of >=6/18, and 57 eyes (69.5%) had the CDVA of >=6/18. Postoperative visual status was significantly related to the co-morbidities, such as corneal pathology, glaucoma (P<0.001). Operative complications, such as posterior capsule opacity and cystoid macular edema were main operative cause for the poor visual outcome. CONCLUSION: MSICS provides a good visual recovery in our study but the vision outcome did not fulfill the standards proposed by WHO, which highlights the need for an improvement in local socioeconomic understanding, population education and surgery quality. PMID- 25938044 TI - Comparison of Goldmann applanation tonometry, rebound tonometry and dynamic contour tonometry in normal and glaucomatous eyes. AB - AIM: To compare the intraocular pressure (IOP) measurements obtained with the rebound tonometry (RT), dynamic contour tonometry (DCT) and Goldmann applanation tonometry (GAT) in normal and glaucomatous eyes and investigate the effects of central corneal thickness (CCT) and corneal curvature (CC) on IOP measurements. METHODS: One hundred and twenty-four eyes of 124 subjects were enrolled in this cross-sectional study. Fifty-six of participants were healthy individuals and 68 of them were glaucomatous patients. IOP was measured on each subject always in the same order, ICare RT-Pascal DCT-GAT, after a minimum interval of 10min between measurements. CCT and CC were measured using a rotating Scheimpflug camera before the IOP measurements in all subjects. One way repeated measures ANOVA, Pearson correlation coefficient and regression analysis, and Bland-Altman analysis was used for the statistical assessment. RESULTS: Mean IOP for all enrolled eyes was 16.00+/-3.80 mm Hg for GAT, 16.99+/-4.91 mm Hg for RT, and 20.40+/-4.44 mm Hg for DCT. Mean differences between GAT and RT was -1.75+/-3.41 mm Hg in normal (P<0.001) and -0.37+/-3.00 mm Hg in glaucomatous eyes (P=0.563). Mean differences between GAT and DCT was -4.06+/-3.42 mm Hg in normal (P<0.001) and -4.67+/-3.12 mm Hg in glaucomatous eyes (P<0.001). GAT and RT were significantly positive correlated with CCT in normal (r=0.317, P=0.017 and r=0.576, P<0.001, respectively) and glaucomatous eyes (r=0.290, P=0.016 and r=0.351, P=0.003, respectively). DCT was also significantly positive correlated with CCT in normal eyes (r=0.424, P=0.001) but not in glaucomatous eyes (r=0.170, P=0.165). All tonometers were unaffected by CC. CONCLUSION: IOP measurements by RT and DCT were significantly higher than GAT. DCT has highest IOP measurements among these tonometers. RT was most influenced tonometer from CCT although all tonometers were significantly positive correlated with CCT except DCT in glaucomatous eyes. CC did not influence IOP measurements. PMID- 25938045 TI - Central retinal artery resistive index and optical coherence tomography in assessment of glaucoma progression. AB - AIM: To assess the relation between central retinal artery (CRA) resistive index (RI) and retinal nerve fiber thickness measured by optical coherence tomography (OCT) in assessment of disease progress in cases of open angle glaucoma. METHODS: Twenty-three patients with diagnosed open angle glaucoma were included in this study. They were examined by colored duplex ultrasonography of CRA with estimation of RI of CRA and ophthalmic artery (OA) with estimation of CRA/OA RI ratio as well as OCT measurement of the average retinal nerve fiber layer (RNFL) thickness in order to assess the disease progress. RESULTS: There was strong inverse relation between the increased RI in CRA as well as the increased CRA/OA RI ratio and the decrease in average RNFL thickness in cases of open angle glaucoma. CONCLUSION: Assessment of CRA RI can indirectly assess the vascular changes associated with glaucoma and can assess the degree of retinal atrophy helping in evaluating prognosis thus guiding the choice of treatment. PMID- 25938046 TI - Oral eplerenone for the management of chronic central serous chorioretinopathy. AB - AIM: To examine eplerenone (Inspra, Pfizer), a mineralocorticoid receptor antagonist, as a treatment option for chronic central serous chorioretinopathy (CSCR). METHODS: A retrospective consecutive case series was conducted for patients receiving oral eplerenone for chronic CSCR. At baseline and each follow up visit, spectral domain optical coherence tomography (SD-OCT) imaging was performed, including manual measurements of the height and diameter size of subretinal fluid. The primary outcome measure was the reduction in subretinal fluid following initiation of therapy. RESULTS: A total of 17 eyes of 13 patients treated with 25 and 50 mg of oral eplerenone per day were identified. Subretinal fluid (SRF) decreased over time following eplerenone therapy (P= 0.007 and P = 0.002, diameter and height respectively). Maximum SRF height decreased from a mean of 131.5 um at baseline to 15.3 um at day 181+. SRF diameter decreased from an average of 2174.4 um at baseline to 46.9 um at day 181+. LogMAR visual acuity improved from 0.42 (Snellen equivalent: 20/53) at baseline to 0.29 (Snellen equivalent: 20/39) at day 181+ (P = 0.024). Central subfield thickness (CST) decreased from 339.5 um at baseline to 270.3 um at day 181+ (P = 0.029). CONCLUSION: Eplerenone therapy resulted in significant anatomic and visual improvements in eyes with chronic CSCR. PMID- 25938047 TI - Retraction notice. AB - [This retracts the article DOI: 10.3980/j.issn.2222-3959.2014.01.30.]. PMID- 25938048 TI - Effects of three consecutive monthly intravitreal injection of ranibizumab for polypoidal choroidal vasculopathy in Korea. AB - AIM: To evaluate the efficacy and safety of three consecutive monthly injections of intravitreal ranibizumab for the treatment of polypoidal choroidal vasculopathy (PCV) in Korea. METHODS: A retrospective chart review of 25 patients (27 eyes) with PCV was conducted. Patients received three initial monthly intravitreal injections (0.5 mg) of ranibizumab and were monitored monthly for 12mo between January 2010 and October 2011. Reinjection of ranibizumab after three initial monthly loading was administered on an as-needed basis, guided by the optical coherence tomography (OCT), fluorescein angiography (FA) and indocyanine green angiography (ICGA). The main outcomes were the changes of the mean best corrected Snellen visual acuity (VA), central macular thickness (CMT) by OCT, the changes of polyps and branching vascular network by FA and ICGA, and total number of injections received by patients during the 12mo. RESULTS: The mean best corrected Snellen visual acuities at baseline, 1, 3, 6 and 12mo after primary injection were 0.77+/-0.59, 0.76+/-0.53, 0.70+/-0.47, 0.63+/-0.43, 0.61+/ 0.43, 0.62+/-0.42 logMAR, respectively, and showed significant improvement at 3, 6, 12mo (P=0.003, P=0.002, P=0.018, Wilcoxon signed-rank test). The mean CMT at baseline, 1, 2, 3, 6, and 12mo was 312.41+/-66.38 um, 244.59+/-71.47 um, 232.32+/ 69.41 um, 226.69+/-69.03 um, 228.62+/-37.07 um, 227.59+/-51.01 um respectively, and showed significant reduction (all P<0.001, Wilcoxon signed-rank test). Polypoidal lesions resolved on ICGA in 3 eyes (11.1%) and a branching vascular network remained in all 24 eyes (88.9%). A total of 106 injections were given in the 12-month period, which equaled to a mean of 3.92 (range, 3-6) times. Sixteen of the 27 treated eyes had additional 1.56+/-0.91 injections. The others (11 eyes) had just 3 consecutive injections. CONCLUSION: An initial loading dose of three monthly ranibizumab injections is a safe and effective method in treating PCV, with visual and anatomical improvement over one year follow-up. PMID- 25938049 TI - Measurement of choroidal thickness and macular thickness during and after pregnancy. AB - AIM: To investigate the effect of pregnancy on subfoveal choroidal thickness (SFCT) and macular thickness in both pregnant and not pregnant healthy women. METHODS: Twenty-nine healthy pregnant women in their third trimester and 36 age matched healthy women were enrolled in a prospective, cross-sectional study. Foveal and parafoveal thickness in the four quadrants and SFCT were measured by optical coherence tomography (OCT) in the healthy pregnant women (i.e. study group) and healthy women (i.e. control group). OCT measurements were again measured 3mo after delivery in the study group. RESULTS: Mean SFCT measurements in the control group, pregnant women of the study group, and after delivery of the study group were 320.86+/-59.18 um, 387.97+/-59.91 um, and 332.40+/-26.03 um, respectively. There was a statistically significant difference in the mean SFCT values between pregnant women of the study group and the control group (P=0.000). Foveal and parafoveal thickness values were not statistically significant in either the study or control group. CONCLUSION: SFCT increases during pregnancy and returns to normal range in the three months after delivery. Macular thickness does not show any change during pregnancy. PMID- 25938050 TI - Is there any correlation between vitamin D insufficiency and diabetic retinopathy? AB - AIM: To determine a relation between vitamin D level, which is an inhibitor of angiogenesis, and diabetic retinopathy and its risk factors. METHODS: In a clinic based cross sectional study two hundred and thirty-five type 2 diabetic patients older than 20y were selected. Patients were classified according to ophthalmologic examination as following: no diabetic retinopathy (NDR) (n=153), non-proliferative diabetic retinopathy (NPDR) (n=64) and proliferative diabetic retinopathy (PDR) (n=18). Study subjects were tested for fasting blood glucose, glycated hemoglobin A1C (HbA1C), lipid profile, microalbuminuria, HsCRP, IGF1, insulin (in patients without history of insulin taking) and 25 hydroxy vitamin D [25 (OH) D] levels. Vitamin D insufficiency was defined according to 25 (OH) D level less than 30 ng/mL. The relationship between diabetic retinopathy and serum 25 (OH) D insufficiency was evaluated. RESULTS: The prevalence of diabetic retinopathy was 34.8% in our patients. Long duration of diabetes, hypertension, poor glycemic control, diabetic nephropathy, hyperinsulinemia and insulin resistance were risk factors for diabetic retinopathy but 25 (OH) D level was not significant different between NDR, NPDR and PDR groups. Correlation between 25 (OH) D level and other known risk factors of diabetic retinopathy was not significant. CONCLUSION: This study did not find any association between diabetic retinopathy and its severity and vitamin D insufficiency. Vitamin D insufficiency is not related to risk factors of diabetic retinopathy. PMID- 25938051 TI - Retinal vessel diameters and their correlation with retinal nerve fiber layer thickness in patients with pseudoexfoliation syndrome. AB - AIM: To compare retinal artery-vein diameters (RAVDs) of patients with pseudoexfoliation (PSX) syndrome with healthy controls and investigate the correlations between retinal nerve fiber layer (RNFL) thickness parameters and RAVDs. METHODS: Seventeen eyes with PSX and 17 eyes of age-matched controls were included in the study. All participants underwent routine ophthalmological examination, Humphrey visual field and RNFL examination by using Stratus OCT. Retinal images were obtained by using a retinal camera (Topcon 501X). RAVDs were measured from inferior nasal, inferior temporal, superior nasal and superior temporal arcuates by using IMAGEnet software. Superior, inferior, nasal, temporal and average RNFL thicknesses were recorded. RAVDs and RNFL parameters in groups and correlations were analyzed by Mann-Whitney U and Spearmann correlation tests. RESULTS: Only inferior quadrant and average RNFL thickness were detected thinner in the PSX group compared with control group (P=0.009, P=0.038, respectively). No statistically significant difference regarding RAVDs was found between two groups. CONCLUSION: RAVDs seems to be comparable in the PSX and control group. RNFL is thinner in the inferior quadrant in the PSX group. RNFL thickness and RAVDs show significant correlations in both groups. This correlation doesn't seem to be specific to PSX. PMID- 25938052 TI - Clinical patterns and characteristics of uveitis in a secondary hospital in southern China. AB - AIM: To investigate the characteristics of uveitis in a secondary hospital in southern China. METHODS: We reviewed all records of patients with uveitis at Hengli Hospital from January 2008 to December 2011. Demographic data, past history, ophthalmic examinations and other laboratory tests were analyzed. RESULTS: One hundred and ninety-nine uveitis patients were enrolled in this study, including 134 (67.3%) males and 65 females (32.7%) with an average age of 41.0+/-15.1y. The anatomical distribution included 103 (51.8%) cases of anterior uveitis, followed by panuveitis (65, 32.7%), posterior uveitis (29, 14.6%) and intermediate uveitis (2, 1.0%). Of the 98 (49.2%) non-idiopathic cases, there were 10.1% Behcet's disease, 9.5% Vogt-Koyanagi-Harada (VKH) syndrome, 7.5%infectious uveitis, 7.5% traumatic uveitis and 3.5% postoperative uveitis. CONCLUSION: Idiopathic anterior and posterior uveitis, Behcet's disease, VKH syndrome, infectious uveitis and traumatic uveitis are the most common uveitis entities in a secondary hospital in southern China. Additional measures should be taken to prevent infectious and traumatic uveitis. PMID- 25938053 TI - Agreement of angle closure assessments between gonioscopy, anterior segment optical coherence tomography and spectral domain optical coherence tomography. AB - AIM: To determine angle closure agreements between gonioscopy and anterior segment optical coherence tomography (AS-OCT), as well as gonioscopy and spectral domain OCT (SD-OCT). A secondary objective was to quantify inter-observer agreements of AS-OCT and SD-OCT assessments. METHODS: Seventeen consecutive subjects (33 eyes) were recruited from the study hospital's Glaucoma clinic. Gonioscopy was performed by a glaucomatologist masked to OCT results. OCT images were read independently by 2 other glaucomatologists masked to gonioscopy findings as well as each other's analyses of OCT images. RESULTS: Totally 84.8% and 45.5% of scleral spurs were visualized in AS-OCT and SD-OCT images respectively (P<0.01). The agreement for angle closure between AS-OCT and gonioscopy was fair at k=0.31 (95% confidence interval, CI: 0.03-0.59) and k=0.35 (95% CI: 0.07-0.63) for reader 1 and 2 respectively. The agreement for angle closure between SD-OCT and gonioscopy was fair at k=0.21 (95% CI: 0.07-0.49) and slight at k=0.17 (95% CI: 0.08-0.42) for reader 1 and 2 respectively. The inter reader agreement for angle closure in AS-OCT images was moderate at 0.51 (95% CI: 0.13-0.88). The inter-reader agreement for angle closure in SD-OCT images was slight at 0.18 (95% CI: 0.08-0.45). CONCLUSION: Significant proportion of scleral spurs were not visualised with SD-OCT imaging resulting in weaker inter-reader agreements. Identifying other angle landmarks in SD-OCT images will allow more consistent angle closure assessments. Gonioscopy and OCT imaging do not always agree in angle closure assessments but have their own advantages, and should be used together and not exclusively. PMID- 25938054 TI - Efficacy and safety of active silicone oil removal through a 23-gauge transconjunctival cannula using an external vacuum pump. AB - AIM: To evaluate the efficacy and safety of active removal of silicone oil with low and high viscosity through a 23-gauge transconjunctival cannula using an external vacuum pump. METHODS: This study was conducted as a prospective, interventional case series. A total of 22 eyes of 21 patients [1000 centistokes (cSt): 17 eyes, 5700 cSt: 5 eyes] were included in this study. All patients underwent active silicone oil removal via the entire lumen of a 23-gauge microcannula with suction pressure of a 650-700 mm Hg vacuum using an external vacuum pump. A tubing adaptor from the Total Plus Pak((r)) (Alcon, Fort Worth, USA) was used to join the microcannula and silicone vacuum tube connected to an external vacuum pump. Main outcome measures were mean removal time, changes of intraocular pressure (IOP) and visual acuity, and intraoperative and postoperative complications. RESULTS: Mean removal time (min) was 1.49+/-0.43 for 1000 cSt and 7.12+/-1.27 for 5700 cSt. The IOP was 18.57+/-7.48 mm Hg at baseline, 11.68+/-4.55 mm Hg at day 1 postoperatively (P<0.001), and 15.95+/ 4.92, 16.82+/-3.81, 17.41+/-3.50, and 17.09+/-3.01 mm Hg after one week, one month, three months, and six months, respectively. All patients showed improved or stabilized visual acuity. There was no occurrence of intraoperative or postoperative complications during the follow up period. CONCLUSION: This technique for active removal of silicone oil through a 23-gauge cannula using an external vacuum pump is fast, effective, and safe as well as economical for silicone oil with both low and high viscosity in all eyes with pseudophakia, aphakia, or phakia. PMID- 25938055 TI - Outcome comparison between transcanalicular and external dacryocystorhinostomy. AB - AIM: To compare the outcomes achieved with external dacryocystorhinostomy (EX DCR) and transcanalicular dacryocystorhinostomy (TC-DCR) using a multidiode laser in patients with bilateral nasolacrimal duct obstruction (NLDO). METHODS: This prospective study was conducted on 38 eyes of 19 patients with bilateral NLDO. Simultaneous bilateral surgery was performed on all patients. TC-DCR (Group 1) with a diode laser was used in the right eye, and EX-DCR (Group 2) was used in the left eye. All patients were placed under general anesthesia. Routine follow ups were scheduled at 1wk; 1, 3, 6 and 12mo postoperative intervals. Objective (lacrimal system irrigation) and subjective [tearing, irritation, pain, discharge and visual analogue scale (VAS) score] outcomes were evaluated. RESULTS: The overall objective success rate at 12mo was 73.7% (14/19) in Group 1 and 89.5 % (17/19) in Group 2. This difference was statistically significant. There were no significant between-group differences in the subjective results, such as tearing, pain and irritation. Only the discharge scores were found to be significantly higher in Group 1 compared to Group 2 at the 1y follow-up. The average VAS score was 6.8 in Group 1 and 8.7 in Group 2, with no statistically significant differences. CONCLUSION: Although TC-DCR allows surgeons to perform a minimally invasive and safe procedure, EX-DCR offers better objective and subjective outcomes than TC-DCR. PMID- 25938056 TI - Ocular surface changes in type II diabetic patients with proliferative diabetic retinopathy. AB - AIM: To detect and analyze the changes on ocular surface and tear function in type II diabetic patients with proliferative diabetic retinopathy (PDR), an advanced stage of diabetic retinopathy (DR), using conventional ophthalmic tests and the high-resolution laser scanning confocal microscopy. METHODS: Fifty-eight patients with type II diabetes were selected. Based on the diagnostic criteria and stage classification of DR, the patients were divided into the non-DR (NDR) group and the PDR group. Thirty-six patients with cataract but no other ocular and systemic disease were included as non-diabetic controls. All the patients were subjected to the conventional clinical tests of corneal sensitivity, Schirmer I Test, and corneal fluorescein staining. The non-invasive tear film break-up time (NIBUT) and tear interferometry were conducted by a Tearscope Plus. The morphology of corneal epithelia and nerve fibers was examined using the high resolution confocal microscopy. RESULTS: The NDR group exhibited significantly declined corneal sensitivity and Schirmer I test value, as compared to the non diabetic controls (P< 0.001). The PDR group showed significantly reduced corneal sensitivity, Schirmer I test value, and NIBUT in comparison to the non-diabetic controls (P < 0.001). Corneal fluorescein staining revealed the progressively injured corneal epithelia in the PDR patients. Moreover, significant decrease in the corneal epithelial density and morphological abnormalities in the corneal epithelia and nerve fibers were also observed in the PDR patients. CONCLUSION: Ocular surface changes, including blunted corneal sensitivity, reduced tear secretion, tear film dysfunction, progressive loss of corneal epithelia and degeneration of nerve fibers, are common in type II diabetic patients, particularly in the diabetic patients with PDR. The corneal sensitivity, fluorescein staining scores, and the density of corneal epithelial cells and nerve fibers in the diabetic patients correlate with the duration of diabetes. Therefore, ocular surface of the patients with PDR should be examined regularly by conventional approaches and confocal microscopy to facilitate early diagnosis and treatment of keratopathy. PMID- 25938057 TI - Effect of pathological myopia on biomechanical properties: a study by ocular response analyzer. AB - AIM: To evaluate the ocular response analyzer (ORA) measurements of patients with pathological myopia in comparison with those of emmetropic control subjects, and to investigate the correlation between these ORA measurements and spherical equivalent (SE). METHODS: Measurements of 53 eyes of 53 subjects with pathological myopia (SE>-6.00 D) were compared with those of 60 eyes of 60 emmetropic controls. Corneal hysteresis (CH), corneal resistance factor (CRF), noncontact tonometer intraocular pressure (IOPg), and corneal-compensated IOP (IOPcc) were obtained for each subject. The refractive error value was determined as SE via a cycloplegic refraction test. RESULTS: The mean age was 54.1+/-18.9y (ranging from 5 to 88) in the pathological myopic group and 56.2+/-19.0y (ranging from 6 to 89) in the control group. There were no significant differences between the groups concerning age and sex. CH and CRF were significantly lower in the pathological myopic group than in the control group (P<0.001, P=0.005, respectively). IOPcc and IOPg were significantly higher in the pathological myopic group than in the control group (P<0.001, P=0.009, respectively). There were significantly positive correlations between CH and SE (r=0.565, P<0.001) and between CRF and SE (r=0.364, P=0.007). There were significantly negative correlations between IOPcc and SE (r=-0.432, P=0.001) and between IOPg and SE (r= 0.401, P=0.003). CONCLUSION: The present study displayed that pathological myopia affected biomechanical properties measured by ORA. The results of corneal biomechanical properties measured by ORA may need to be appreciated by taking refraction into account. Further, pathological myopia might be related with the increased IOP. PMID- 25938058 TI - Refractive errors in high myopic eyes after phacovitrectomy for macular hole. AB - AIM: To examine the refractive prediction error in high myopic eyes after phacovitrectomy. METHODS: This retrospective comparative case series included 91 eyes (18 high myopic eyes and 73 non-high myopic eyes) of 91 patients who underwent successful phacovitrectomy (phacoemulsification, intraocular lens implantation, and pars plana vitrectomy). The high myopic eyes were defined as the eye with more than 26.0 mm of axial length. The postoperative prediction error of mean error and mean absolute error were evaluated at 4mo postoperatively. Axial length and keratometry measurement were performed preoperatively and 4mo postoperatively using the IOL Master. RESULTS: The refractive outcome after phacovitrectomy showed significantly greater myopic shift in the high myopic eyes [-1.08+/-0.87 diopters (D)] than that in the non high myopic eyes (-0.43+/-0.63 D, P=0.004). Axial length and keratometric value in the high myopic eyes were significantly increased (P=0.043, 0.037 respectively), whereas those in the non-high myopic group were not significantly increased (P=0.135, 0.347 respectively). The change of the axial length in the myopic eye (0.46+/-0.28 mm) was greater than that in the non-high myopic eye (0.11 +/- 0.34 mm; P<0.001). CONCLUSION: High myopic eyes showed more myopic shift than non-high myopic eyes after phacovitrectomy. The cause of myopic shift in high myopic eyes seems to be attributed to actual elongation of the axial length in high myopia. PMID- 25938059 TI - Intraexaminer repeatability and agreement in stereoacuity measurements made in young adults. AB - AIM: To determine the repeatability and agreement of stereoacuity measurements made using some of the most widely used clinical tests: Frisby, TNO, Randot and Titmus. METHODS: Stereoacuity was measured in two different sessions separated by a time interval of at least 24h but no longer than 1wk in 74 subjects of mean age 20.6y using the four methods. The study participants were divided into two groups: subjects with normal binocular vision and subjects with abnormal binocular vision. RESULTS: Best repeatability was shown by the Frisby and Titmus [coefficient of repeatability (COR): +/-13 and +/-12s arc respectively] in the subjects with normal binocular vision though a clear ceiling effect was noted. In the subjects with abnormal binocular vision, best repeatability was shown by the Frisby (COR: +/-69s arc) and Randot (COR: +/-72s arc). In both groups, the TNO test showed poorest agreement with the other tests. CONCLUSION: The repeatability of stereoacuity measures was low in subjects with poor binocular vision yet fairly good in subjects with normal binocular vision with the exception of the TNO test. The reduced agreement detected between the tests indicates they cannot be used interchangeably. PMID- 25938060 TI - Visual pathways involvement in clinically isolated syndrome in children. AB - AIM: To investigate extent and nature of visual pathways involvement in children with clinically isolated syndrome (CIS). METHODS: Forty-seven patients (age 11 17y) with CIS, which later proved to be multiple sclerosis (MS) onset, and 30 controls underwent visual evoked potentials (VEP) investigation within 12d from the appearance of the first signs of disease. Latency and amplitude of P100 peak were compared with normative data and between groups. RESULTS: In 58% patients, including those without signs of retrobulbar neuritis, significant slowing of conduction along the central visual pathways (P100 latency lengthening) is seen. P100 amplitudes drop (signs of axonal damage) are registered less frequently (29% cases). CONCLUSION: The results indicate that visual pathways are often affected in the MS onset; mostly demyelination signs are seen. Despite MRI significance for MS diagnostic, VEPs proved to be still effective in early diagnosis of MS in children. PMID- 25938061 TI - Association between SERPING1 rs2511989 polymorphism and age-related macular degeneration: Meta-analysis. AB - AIM: To investigate the association between SERPING1 rs2511989 (G>A) polymorphism and age-related macular degeneration (AMD). METHODS: A number of electronic databases (up to July 15, 2014) were searched independently by two investigators. A Meta-analysis was performed on the association between SERPING1 rs2511989 polymorphism and AMD. Pooled odds ratios (ORs) with 95% confidence intervals (CIs) were estimated. RESULTS: Eight studies with 16 cohorts consisting of 9163 cases and 6813 controls were included in this Meta-analysis. There was no significant association between rs2511989 polymorphism and AMD under all genetic models in overall estimates (A vs G: OR= 0.938, 95%CI =0.858-1.025; AA vs GG:OR =0.871, 95%CI =0.719-1.056; AG vs GG: OR =0.944, 95%CI =0.845-1.054; AA+AG vs GG: OR =0.927, 95% CI =0.823-1.044; AA vs AG+GG: OR =0.890, 95%CI =0.780-1.034). Cumulative Meta-analyses also showed a trend of no association between rs2511989 polymorphism and AMD as information accumulated by year. Subgroup analysis and Meta-regression analysis indicated that age-matching status was the main source of heterogeneity. Sensitivity analysis found the results in overall comparisons and subgroup comparisons of white subjects under the allele model were found to have significantly statistical differences after studies deviating from Hardy Weinberg equilibrium (HWE) were excluded (overall: OR=0.918, 95%CI = 0.844-0.999, P =0.049; whites: OR =0.901, 95%CI = 0.817-0.994, P =0.038). However, the results were not sufficiently robust for further sensitivity analysis and statistical differences disappeared on applying Bonferroni correction (with a significance level set at 0.05/25). CONCLUSION: This Meta-analysis indicates that SERPING1 rs2511989 polymorphism and AMD tend to have no association with each other. Age matching status is a big confounding factor, and more studies with subtle designs are warranted in future. PMID- 25938062 TI - Bioinformatics analysis of potential essential genes that response to the high intraocular pressure on astrocyte due to glaucoma. AB - AIM: To study the gene expression response and predict the network in cell due to pressure effects on optic nerve injury of glaucoma. METHODS: We used glaucoma related microarray data in public database [Gene Expression Omnibus (GEO)] to explore the potential gene expression changes as well as correspondent biological process alterations due to increased pressure in astrocytes during glaucoma development. RESULTS: A total of six genes were identified to be related with pressure increasing. Through the annotation and network analysis, we found these genes might be involved in cell morphological remodeling, angiogenesis, mismatch repair. CONCLUSION: Increasing pressure in glaucoma on astrocytes might cause gene expression alterations, which might induce some cellular responses changes. PMID- 25938063 TI - Difference in normal corneal thickness and curvature between Mongolian and Han nationalities. AB - AIM: To investigate the differences in central corneal thickness (CCT) and curvature in myopic patients with different genders between Mongolian and Han nationalities in the Inner Mongolia region. METHODS: Patients with myopia, among whom 122 cases (244 eyes) were Mongolian and 150 cases (300 eyes) were Han, were selected. Pentacam was used to measure the corneal curvature, whereas CCT was determined by Pentacam, Orbscan and ultrasound pachymetry. RESULTS: Comparisons of the curvature of men and women in Mongolia showed a significant difference (P<0.05) by comparing of the CCT values measured by three methods in Han and Mongolian in Inner Mongolia, we can draw a conclusion that the CCT values measured by Pentacam are less than the values by Orbscan and ultrasound pachymetry, and there are statistically significant difference in CCT measurement among the instruments except between the Orbscan and ultrasound pachymetry. The CCT values of Mongolians are more than Han people, and the analysis exhibited statistical significance. The CCT values measured by Orbscan in Mongolia of women are more than men, the difference showed statistical significance. CONCLUSION: Corneal curvature in Mongolian females was significantly higher than that in males. However, no significant difference was observed among Han males and females. The CCT values of Mongolian females were higher than those of males. The normal CCT values measured by Pentacam in Mongolian myopic patients were smaller than those obtained by Orbscan or ultrasound. The normal CCT values of Mongolian patients with myopia were higher than those reported for domestic people. PMID- 25938064 TI - Metabolic syndrome: a risk factor for high intraocular pressure in the Israeli population. AB - AIM: To evaluate the association among elevated intraocular pressure (IOP), the metabolic syndrome (MetS), body mass index (BMI), and some of their components in the Israeli population. METHODS: We retrospectively reviewed the charts of 12 747 soldiers of the Israeli Defense Forces, aged 35y or older, who underwent a routine periodical medical examination between 1991 and 2004. None of the subjects received medical treatment for either glaucoma or ocular hypertension. High IOP (>21 mm Hg) was correlated with age, sex, arterial blood pressure, total blood cholesterol levels, triglyceride levels, high-density lipoprotein cholesterol, low-density lipoprotein cholesterol, smoking, BMI and MetS. RESULTS: A statistically significant difference was found between the IOP of subjects with a low risk and higher risk for the development of MetS (P<0.0001 for males, P=0.0026 for females). A statistically significant positive correlation was found in male subjects between high BMI and elevated IOP (r=0.11677, P<0.0001). CONCLUSION: MetS and BMI were significantly more prevalent in subjects with increased IOP levels. We suggest that both should be taken into consideration in the assessment of glaucoma suspects. PMID- 25938065 TI - Corneal collagen crosslinking in keratoconus and other eye disease. AB - Keratoconus is a condition characterized by biomechanical instability of the cornea, presenting in a progressive, asymmetric and bilateral way. Corneal collagen crosslinking (CXL) with riboflavin and Ultraviolet-A (UVA) is a new technique of corneal tissue strengthening that combines the use of riboflavin as a photo sensitizer and UVA irradiation. Studies showed that CXL was effective in halting the progression of keratoconus over a period of up to four years. The published studies also revealed a reduction of max K readings by more than 2 D, while the postoperative spherical equivalent (SEQ) was reduced by an average of more than 1 D and refractive cylinder decreased by about 1 D. The major indication for the use of CXL is to inhibit the progression of corneal ecstasies, such as keratoconus and pellucid marginal degeneration. CXL may also be effective in the treatment and prophylaxis of iatrogenic keratectasia, resulting from excessively aggressive photo ablation. This treatment has been used to treat infectious corneal ulcers with apparent favorable results. Most recent studies demonstrate the beneficial impact of CXL for iatrogenic ecstasies, pellucid marginal degeneration, infectious keratitis, bullous keratopathy and ulcerative keratitis. Several long-term and short-term complications of CXL have been studied and documented. The possibility of a secondary infection after the procedure exists because the patient is subject to epithelial debridement and the application of a soft contact lens. Formation of temporary corneal haze, permanent scars, endothelial damage, treatment failure, sterile infiltrates, bullous keratopathy and herpes reactivation are the other reported complications of this procedure. PMID- 25938067 TI - Ophthalmic findings in two cases of methanol optic neuropathy with relapsed vision disturbance. PMID- 25938066 TI - Femtosecond laser in refractive and cataract surgeries. AB - In the past few years, 9 unique laser platforms have been brought to the market. As femtosecond (FS) laser-assisted ophthalmic surgery potentially improves patient safety and visual outcomes, this new technology indeed provides ophthalmologists a reliable new option. But this new technology also poses a range of new clinical and financial challenges for surgeons. We provide an overview of the evolution of FS laser technology for use in refractive and cataract surgeries. This review describes the available laser platforms and mainly focuses on discussing the development of ophthalmic surgery technologies. PMID- 25938068 TI - Severe prelenticular membrane formation on the surface of a hydrophilic acrylic intraocular lens after cataract surgery in an eye with an Ahmed valve implant. PMID- 25938069 TI - In this issue of Asia Pacific allergy. PMID- 25938070 TI - Recent advances of pharmacogenomics in severe cutaneous adverse reactions: immune and nonimmune mechanisms. AB - Stevens-Johnson syndrome (SJS), toxic epidermal necrolysis (TEN), and drug reaction with eosinophilia and systemic symptoms (DRESS) are severe cutaneous adverse reactions (SCAR) which are majorly caused by drugs. Though the incidence rate is low, SCAR sometimes can be life-threatening and leads to lifelong sequelae. Many pharmacogenomic associations in immune and nonimmune related genes with the development of SCAR have been discovered recently and the pharmacogenetic tests have been applied to prevent specific drug-induced SCAR. In this review, we discuss the recent advances of pharmacogenomics in SCAR. PMID- 25938071 TI - HLA-B*1502 and carbamazepine-induced severe cutaneous adverse drug reactions in Vietnamese. AB - BACKGROUND: In Vietnam, we observed a high incidence of carbamazepine (CBZ) induced severe cutaneous adverse drug reactions (SCARs)-Stevens-Johnson syndrome (SJS)/toxic epidermal necrolysis (TEN), and drug-induced hypersensitivity rash with eosinophilia and systemic symptoms (DRESS). In other Asian countries, HLA B(*)1502 is an established risk factor for SCARs. OBJECTIVE: The aim of our study was to determine the frequency of HLA-B(*)1502 in SCARs patients at a large University Medical Center in Hanoi, Vietnam. METHODS: Thirty-eight cases of SCARs caused by CBZ and 25 patients with epilepsy tolerating CBZ were enrolled in a case-controlled study. Clinical manifestations and laboratory findings were recorded for each subject. Genomic DNA was isolated using the QIAamp DNA purification system. The combination of polymerase chain reaction and sequence specific oligonucleotide probes with the Luminex 100*MAP flow cytometry dual laser system was then used to quantitate fluorescently labelled oligonucleotides attached to colour-coded microbeads. RESULTS: Cases comprised 20 SJS (52.6%), 7 TEN (18.4%), 8 overlap syndrome (21.1%), and 3 DRESS patients (7.9%). A strong association between HLA B(*)1502 and bullous skin reactions such as SJS/TEN and overlap was confirmed with an odds ratio (OR) of 33.78 (95% confidence interval [CI], 7.55-151.03), p < 0.0001, Sensitivity 91.4%, Specificity 76.0%, positive predictive value 84.2%, and negative predictive value 86.4%. We did not, however, observe any correlation between the presence of this allele and CBZ-induced nonbullous skin reactions (DRESS) (OR, 6.33; 95% CI, 0.48-82.74; p = 0.1592). CONCLUSION: Our results indicate the presence of HLA-B(*)1502 in Vietnamese is a pharmacogenetic risk factor for developing CBZ-induced SJS/TEN. PMID- 25938072 TI - Clinical manifestation and sensitization of allergic children from Malaysia. AB - BACKGROUND: An epidemiological rise of allergic diseases in developing countries raises new challenges. Currently a paucity of data exists describing allergy symptomology and sensitization to common food and aeroallergens in young children from developing countries. OBJECTIVE: To compare changes in symptomology, food allergen sensitization and aeroallergen sensitization in a cross-sectional study of children <2 years and 2-10 years. METHODS: A total of 192 allergic children (aged <2 years, 35 children; aged 2-10 years, 157 children) underwent specific IgE (>0.35 kU/L) to common food (egg white, cow's milk, cod fish, wheat, peanut, soya, peanut, and shrimp) and house dust mites (Dermatophagoides pteronyssinus and Blomia tropicalis). RESULTS: In children <2 years, atopic dermatitis (65.7%) was the most common symptom whereas in children 2-10 years it was rhinoconjunctivitis (74.5%). Higher sensitization rate to eggs (p < 0.01) and cow's milk (p = 0.044) was seen in <2 years group when compared to the 2-10 years group, but no significant differences for shrimp (p = 0.29), wheat (p = 0.23) and soya (p = 0.057). Interestingly, sensitization to peanut (p = 0.012) and fish (p = 0.035) was significantly decreased in the 2-10 years group. Sensitization to house dust mites (p < 0.01) dramatically increased in the older children. CONCLUSION: Our study supports concept of atopic march from a developing country like Malaysia. PMID- 25938073 TI - Economic value of atopic dermatitis prevention via infant formula use in high risk Malaysian infants. AB - BACKGROUND: Breastfeeding is best for infants and the World Health Organization recommends exclusive breastfeeding for at least the first 6 months of life. For those who are unable to be breastfed, previous studies demonstrate that feeding high-risk infants with hydrolyzed formulas instead of cow's milk formula (CMF) may decrease the risk of atopic dermatitis (AD). OBJECTIVE: To estimate the economic impact of feeding high-risk, not exclusively breastfed, urban Malaysian infants with partiallyhydrolyzed whey-based formula (PHF-W) instead of CMF for the first 17 weeks of life as an AD risk reduction strategy. METHODS: A cohort Markov model simulated the AD incidence and burden from birth to age 6 years in the target population fed with PHF-W vs. CMF. The model integrated published clinical and epidemiologic data, local cost data, and expert opinion. Modeled outcomes included AD-risk reduction, time spent post AD diagnosis, days without AD flare, quality-adjusted life years (QALYs), and costs (direct and indirect). Outcomes were discounted at 3% per year. Costs are expressed in Malaysian Ringgit (MYR; MYR 1,000 = United States dollar [US $]316.50). RESULTS: Feeding a high risk infant PHF-W vs. CMF resulted in a 14% point reduction in AD risk (95% confidence interval [CI], 3%-23%), a 0.69-year (95% CI, 0.25-1.10) reduction in time spent post-AD diagnosis, additional 38 (95% CI, 2-94) days without AD flare, and an undiscounted gain of 0.041 (95% CI, 0.007-0.103) QALYs. The discounted AD related 6-year cost estimates when feeding a high-risk infant with PHF-W were MYR 1,758 (US $556) (95% CI, MYR 917-3,033) and with CMF MYR 2,871 (US $909) (95% CI, MYR 1,697-4,278), resulting in a per-child net saving of MYR 1,113 (US $352) (95% CI, MYR 317-1,884) favoring PHF-W. CONCLUSION: Using PHF-W instead of CMF in this population is expected to result in AD-related costs savings. PMID- 25938074 TI - The association of forced expiratory volume in one second and forced expiratory flow at 50% of the vital capacity, peak expiratory flow parameters, and blood eosinophil counts in exercise-induced bronchospasm in children with mild asthma. AB - BACKGROUND: Exercise-induced bronchoconstriction (EIB), which describes acute airway narrowing that occurs as a result of exercise, is associated with eosinophilic airway inflammation, bronchial hyperresponsiveness. The forced expiratory volume in one second (FEV1) is the most commonly used spirometric test in the diagnosis of EIB in exercise challenge in asthma. Other parameters such as forced expiratory flow at 50% of the vital capacity (FEF50%) and peak expiratory flow (PEF) are used less often in the diagnosis of EIB. OBJECTIVE: The purpose of this study is to evaluate the association of FEV1 and FEF50%, PEF parameters, blood eosinophil counts in EIB in children with mild asthma. METHODS: Sixty-seven children (male: 39, female: 28) with mild asthma were included in this study. Pulmonary functions were assessed before and at 1, 5, 10, 15, and 20 minutes after exercise. The values of spirometric FEV1, FEF50%, PEF, and blood eosinophil counts were evaluated in EIB in children with mild asthma. RESULTS: There was a positive correlation between FEV1 with FEF50% and PEF values (p<0.05; FEF50%, r=0.68; PEF, r=0.65). Also, a positive correlation was found between blood eosinophil counts and the values of spirometric FEV1, FEF50%, and PEF (p<0.05; FEV1, r=0.54; FEF50%, r=0.42; PEF, r=0.26). In addition to these correlations, in the exercise negative group for FEV1, the FEF50% and PEF values decreased more than the cutoff values in 3, and 2 patients, respectively. CONCLUSION: According to the presented study, eosinophil may play a major role in the severity of EIB in mild asthma. FEF50% and PEF values can decrease in response to exercise without changes in FEV1 in mild asthmatic patients. PMID- 25938075 TI - Bronchial asthma and hypovitaminosis D in Saudi children. AB - BACKGROUND: Asthma, a common lung disease in children, is caused by excessive immune responses to environmental antigens. OBJECTIVE: Given the immuno modulatory properties of vitamin D, the aim of the current study was to investigate the relationship between vitamin D levels and markers of asthma severity. METHODS: This was investigated in a 70 Saudi children with and without asthma and were recruited from the King Abdul Aziz University Hospital, Jeddah, Saudi Arabia, over the period of 11 months (May 2011-April 2012). Childhood asthma control test instrument was employed to assess the level of asthma control among asthmatic patients. Anthropometric measurements were taken and interviewer administrated questionnaire was completed for all study participants. Pulmonary function test was performed by recording changes in the peak expiratory flow. Venous blood samples were withdrawn for measurements of vitamin D, bone profile, cytokines profile (interleukin-10, tumor necrosis factor-alpha, platelets derived growth factor), and atopy markers (IgE and eosinophil count). RESULTS: Hypovitaminosis D is highly prevalent among asthmatic children with highly significant increase in several markers of allergy and asthma severity as compared with healthy control children. Significant correlations between several inflammatory and immunological markers and vitamin D levels were also found. Finally, lower 25-hydroxyvitamin D levels were associated with a higher asthma prevalence in multivariable analysis. CONCLUSION: Our study showed that hypovitaminosis D is highly prevalent in the whole population in addition to a highly significant increase in several markers of allergy and asthma severity among asthmatic children as compared with healthy control children. PMID- 25938076 TI - Reduced IRF7 response to rhinovirus unrelated with DNA methylation in peripheral mononuclear cells of adult asthmatics. AB - BACKGROUND: Human rhinoviruses are the major cause of asthma exacerbation in both children and adults. Recently, impaired antiviral interferon (IFN) response in asthmatics has been indicated as a primary reason of the susceptibility to respiratory virus, but the mechanism of defective IFN production is little understood to date. The expression of IFN regulatory factor 7 (IRF7), a transcriptional factor for virus-induced type I IFN production is known to be regulated epigenetically by DNA methylation. OBJECTIVE: We aimed to investigate the expression of IFN-alpha, IFN-beta, and IRF7 in response to rhinovirus infection in the adult asthmatics and evaluate DNA methylation status of IRF7 gene promotor. METHODS: Twenty symptomatic adult asthmatics and 10 healthy subjects were enrolled and peripheral blood was collected from each subject. Peripheral blood mononuclear cells (PBMCs) were isolated, cultured, and ex vivo stimulated with rhinovirus-16. The mRNA expressions of IFN-alpha, IFN-beta, and IRF7 were analyzed using real time quantitative polymerase chain reaction. Genomic DNA was isolated from untreated PBMCs and the methylation status of IRF7 gene promotor was investigated using bisulfite pyrosequencing. RESULTS: The mean age of asthmatics was 45.4 +/- 15.7 years and 40% was male, which were not different with those of control group. Asthmatics showed significantly decreased mRNA expressions (relative expression to beta-actin) of IFN-alpha and IFN-beta compared with normal control. The mRNA expression of IRF7 in the asthmatics was also significantly lower than those in the normal control. No significant difference of DNA methylation was observed between asthmatics and controls in all analyzed positions of IRF7 promotor CpG loci. CONCLUSION: The mRNA expression of type I IFN in response to rhinovirus was impaired in the PBMCs of adult asthmatics. The mRNA expression of IRF7, transcriptional factor inducing type I IFN was also reduced, but not caused by altered DNA methylation in the IRF7 gene promotor. PMID- 25938077 TI - Eosinophilic myocarditis: case series and literature review. AB - Eosinophilic myocarditis is a condition resulting from various eosinophilic diseases, including helminth infection, drug hypersensitivity, systemic vasculitis or idiopathic hypereosinophilic syndromes. Clinical manifestations of eosinophilic myocarditis may vary from early necrosis to endomyocardial fibrosis. Eosinophilic myocarditis is one of the most fatal complications of hypereosinophilia. However, eosinophilic myocarditis has been rarely reported in the literature, particularly in Asia Pacific regions, reflecting the under recognition of the disease among clinicians. Early recognition is crucial for improving clinical outcomes of eosinophilic myocarditis. Early administration of systemic corticosteroid is necessary in eosinophilic myocarditis regardless of underlying causes, as delayed treatment may result in fatal outcomes. In addition, differential diagnoses of underlying causes for eosinophilia are necessary to improve long-term outcomes. PMID- 25938078 TI - Anaphylaxis due to ruptured pulmonary hydatid cyst in a 13-year-old boy. AB - Hydatid cyst, a common disease in the world, is usually transmitted to humans through dog feces. Hydatid cyst is caused by Echinococcus granulosus. Diagnostic interventions for hydatid cyst include physical examination and chest x-ray tomography. Although the treatment options of hydatid cyst vary according to the clinical findings of the patients, the primary treatment may be considered as surgery. We herein reported the case of a child hospitalized due to pneumonia who developed anaphylaxis as a result of the rupture of a pulmonary hydatid cyst. PMID- 25938079 TI - Psychometric Properties of the Persian Version of the Tinnitus Handicap Inventory (THI-P). AB - INTRODUCTION: Tinnitus can have a significant effect on an individual's quality of life, and is very difficult quantify. One of the most popular questionnaires used in this area is the Tinnitus Handicap Inventory (THI). The aim of this study was to determine the reliability and validity of a Persian translation of the Tinnitus Handicap Inventory (THI-P). MATERIALS AND METHODS: This prospective clinical study was performed in the Otolaryngology Department of Guilan University of Medical Sciences, Iran. A total of 102 patients aged 23-80 years with tinnitus completed the (THI-P). The patients were instructed to complete the Beck Depression Inventory (BDI) and the State-Trait Anxiety Inventory (STAI). Audiometry was performed. Eight-five patients were asked to complete the THI-P for a second time 7-10 days after the initial interview. We assessed test-retest reliability and internal reliability of the THI-P. Validity was assessed by analyzing the THI-P of patients according to their age, tinnitus duration and psychological distress (BDI and STAI). A factor analysis was computed to verify if three subscales (functional, emotional, and catastrophic) represented three distinct variables. RESULTS: Test-retest correlation coefficient scores were highly significant. The THI-P and its subscales showed good internal consistency reliability (alpha = 0.80 to 0.96). High-to-moderate correlations were observed between THI-P and psychological distress and tinnitus symptom ratings. A confirmatory factor analysis failed to validate the three subscales of THI, and high inter-correlations found between the subscales question whether they represent three distinct factors. CONCLUSION: The results suggest that the THI-P is a reliable and valid tool which can be used in a clinical setting to quantify the impact of tinnitus on the quality of life of Iranian patients. PMID- 25938080 TI - Results of Acellular Dermis Matrix graft used for Tympanoplasty in Guinea pig model. AB - INTRODUCTION: To describe the underlay tympanoplasty technique using an acellular dermal graft(AlloDerm) for tympanic membrane (TM) reconstruction in a guinea pig model and to demonstrate the feasibility of the technique using AlloDerm tissue harvested from the prepuce as a source of tissue for future grafting in human TM reconstruction. MATERIALS AND METHODS: The prepuce was divided during circumcision and the acellular dermis was prepared using a number of standard processes. Two groups of guinea pigs were prepared. In the case group (20 guinea pigs and 40 ears) removal of TM was performed with tympanoplasty using AlloDerm, and in the control group (eight guinea pigs and 16 ears), removal of TM was performed without tympanoplasty. In each group, the TM was completely removed in one ear and partially removed on the other side, and the integrity of the TMs was re-evaluated after 8 weeks. RESULTS: In the case group, the healing rates in the completely and partially removed TMs were 83.3% and 94.4%, respectively. The difference in healing rate (0% and 66.7%, respectively) was statistically significant (P<0.05). CONCLUSION: The use of AlloDerm is safe and effective in the repair of TM perforations in a guinea pig model. Acceptable results of AlloDerm tympanoplasty in a guinea pig model may pave the way for the effective use of this material in human TM reconstructions. PMID- 25938081 TI - Tympanoplasty outcomes: a review of 789 cases. AB - INTRODUCTION: Tympanoplasty is indicated to restore hearing disability and prevent recurrent otorrhea. MATERIALS AND METHODS: This study was a retrospective review of patients who underwent tympanoplasty with or without mastoidectomy over a 1-year period. RESULTS: A total of 789 tympanoplasties were reviewed, with a male-to-female ratio of 1:1.1. In total, 91% and 9% of tympanoplasties were performed without and with mastoidectomy, respectively. Complete graft take was observed in 98.6% of cases. Approximately 25% of patients had an air-bone gap (ABG) gap <=20dB pre-operatively, increasing to 75.6% post-operatively. ABG closure improved from 0.8% to 46.7%. Mean ABG improved from 26.30 +/-8.1dB pre operatively to 14 +/- 10.41dB post- operatively (t=28.7, P<0.001). Generally, over 86% of patients had improvement in their hearing function post-operatively (mean= 12.5 +/-9.5dB) (chi2= 104.2, P<0.001). CONCLUSION: Tympanoplasty is an effective procedure that can lead to improvement in hearing function in patients and prevention of recurrent ear discharge. Optimal results can be achieved through use of the appropriate surgical technique. PMID- 25938082 TI - Stigma in mothers of deaf children. AB - INTRODUCTION: A deaf child creates a feeling of stigma in many hearing parents. Stigma in mothers can have a negative impact on a child's treatment and rehabilitation process. Therefore, this study was conducted to evaluate the extent of stigma in mothers with deaf children. MATERIALS AND METHODS: This descriptive, cross-sectional study was conducted in 2013 among 90 mothers with deaf children. The data-collection instrument included the stigma scale in the mothers of children with disabilities. The reliability and validity of the instrument were confirmed through content validity and Cronbach's alpha coefficient (alpha=86%), respectively. Data were analyzed using SPSS-15 software. RESULTS: Results showed that most mothers suffer from stigma due to having a deaf child. The mean stigma score was 96.48 +/-27.72. In total, 24.4% of mothers reported that they had received strange and mocking looks; 72.2% regarded child deafness as a sign of divine retribution; and 33.3% felt ashamed of their child's deafness. There was an inverse relationship between the mother's level of education and mean stigma scores (P<0.033). The stigma score was higher in mothers who were living independently of their relatives (P<0.029). The mean stigma score in mothers of children with a cochlear implant was lower than that of mothers of children with earphones (86.70 vs. 99.64), and this difference tended towards significance (P=0.057). CONCLUSION: This study showed that half of all mothers with deaf children were scorned and felt ashamed of having a deaf child in the family because of the stigma. The majority of mothers with deaf children felt stigmatized, and only their education and residency status affected this issue. The mothers of cochlear-implanted children perceived less stigma. Due to the various social and psychological problems caused by hearing impairment, it is necessary to consider the emotional health and psychological state of the mothers in addition to rehabilitation programs and standard services for the children themselves. PMID- 25938083 TI - The effect of pimecrolimus cream 1% compared with triamcinolone acetonide paste in treatment of atrophic-erosive oral lichen planus. AB - INTRODUCTION: Oral lichen planus (OLP) is a common chronic mucocutaneous disease. Patients with atrophic and erosive types of OLP often have symptoms of soreness, and require proper treatment. The main treatment for OLP has been the administration of topical or systemic corticosteroids. The objective of this study was to compare the efficacy of adcortyl cream (triamcinolone acetonide in orabase) with topical pimecrolimus cream for the treatment of erosive OLP. MATERIALS AND METHODS: Twenty-eight patients with OLP were enrolled in a single blind clinical trial and assigned to either a pimecrolimus 1% cream group or an adcortyl 0.1% cream group. The medication was applied every day for 2 months and patients were assessed every 2 weeks. RESULTS: The mean lesion size and mean pain and burning sensation scores did not differ between the pimecrolimus and adcortyl cream groups. The pimecrolimus cream was well tolerated. No clinical drug-related adverse events were observed. CONCLUSION: Topical pimecrolimus cream may be recommended as a safe and effective alternative therapy in the treatment of OLP. Pimecrolimus cream is as effective as adcortyl cream in managing the signs and symptoms of OLP. PMID- 25938084 TI - Tongue-tie Repair: Z-Plasty Vs Simple Release. AB - INTRODUCTION: Ankyloglossia is a congenital anomaly in which the lingual frenulum is unusually short and thick, thus decreasing tongue mobility. In the context of the newborn or young infant it is a subject of ongoing controversy within and between medical specialties. The controversy involves not only the definition but also the management of this anomaly. A tight lingual frenulum is considered a minor malformation by some investigators. Usual treatments for ankyloglossia include speech therapy, as well as simple frenulotomy and frenuloplasty. The aim of this study was to compare the latter two methods with respect to postoperative results and complications. MATERIALS AND METHODS: A total of 50 patients referred for surgical care were randomly assigned into two groups: simple release (frenulotomy ) or Z-plasty (frenuloplasty), and underwent a pre-surgical assessment. After 3 months, patients were followed with a scheduled interview and questionnaire comparing the outcomes of the two methods. The data were analyzed using SPSS version 18. RESULTS: Surgery had a significant effect on all variables measured in our study (P<0.05). Z-plasty had a greater effect on articulation, breast pain, tongue movement and parent satisfaction than simple release (P<0.05). Z-plasty and simple release had the same effect on breast feeding, latching, and sucking. CONCLUSION: Z-plasty is the preferred surgical method to address tongue-tie due to a greater improvement in mother's breast pain, pronunciation and speech, tongue movement, and parental satisfaction. PMID- 25938085 TI - Reactive hyperplastic lesions of the oral cavity. AB - INTRODUCTION: Peripheral reactive lesions of soft tissue are common oral lesions that dentists face during routine examinations. Diagnosis and development of a treatment plan is difficult if dentists are not aware of the prevalence and clinical symptoms of these lesions. The frequency of these lesions differs across various populations. The aim of this study was to determine the frequency and distribution of oral reactive lesions over a period of 7 years (2006-2012). MATERIALS AND METHODS: In this retrospective study, available records from the archives of the Department of Pathology, Dental School and the two main hospitals in southeast of Iran (Zahedan) over a period of 7 years (2006-2012) were reviewed. Information relating to the type of reactive lesion, age, gender and location was extracted and recorded on data forms. Data were analyzed using SPSS statistical software (V.18) using the chi-square and Fisher's exact test. RESULTS: Of 451 oral lesions, 91 cases (20.2%) were reactive hyperplastic lesions. The most common lesions were pyogenic granuloma and irritation fibroma, respectively. These lesions were more frequent in women (60%) than men (40%). The most common locations of involvement were the gingiva and alveolar mucosa of the mandible, and lesions were more common in the 21-40-year age group. The relationship between age group and reactive lesions was statistically significant (P=0.01). CONCLUSION: The major findings in this study are broadly similar to the results of previous studies, with differences observed in some cases. However, knowledge of the frequency and distribution of these lesions is beneficial when establishing a diagnosis and treatment plan in clinical practice. PMID- 25938086 TI - Halitosis in otorhinolaryngology practice. AB - Halitosis is a common and devastating condition, which may affect up to 1/3 of the population. It can be classified either as genuine halitosis, pseudohalitosis, or halitophobia. Genuine halitosis is more common and usually related to an organic pathology such as periodontitis. Malodour molecules such as sulfur compounds that arise from bacterial interactions generate the basis of oral malodour. Pathologies of the tongue, poor oral hygiene, deep caries, cryptic tonsillary hypertrophia, and postnasal drainage are also associated with halitosis. Gastro-esophageal pathologies and systemic problems are accepted as extra-oral sources of halitosis. There are various methods for the diagnosis of halitosis including objective and subjective methods. General oral hygiene recommendations and specific interventions for the related etiological factors have to be addressed in order to achieve satisfactory results after the treatment. Clinicians have to be aware of these aspects regarding this unfavorable condition to achieve the best results. PMID- 25938087 TI - Delayed esophageal pseudodiverticulum after anterior cervical spine fixation: report of 2 cases. AB - INTRODUCTION: Although perforation of the esophagus, in the anterior cervical spine fixation, is well established, cases with delayed onset, especially cases that present pseudodiverticulum, are not common. In addition, management of the perforation in this situation is debated. CASE REPORT: Delayed esophageal pseudodiverticulum was managed in two patients with a history of anterior spine fixation. Patients were operated on, the loose plate and screws were extracted, the wall of the diverticulum was excised, the perforation on the nasogastric tube was suboptimally repaired, and a closed suction drain was placed there. The NGT was removed on the 7th day and barium swallow demonstrated no leakage at the operation site; therefore, oral feeding was started without any problem. CONCLUSION: In cases with delayed perforation, fistula, or diverticulum removal of anterior fixation instruments, gentle repair of the esophageal wall without persistence on definitive and optimal perforation closure, wide local drainage, early enteral nutrition via NGT, and antibiotic prescription is suggested. PMID- 25938088 TI - Oral verrucous carcinoma and ameloblastoma: a rare coincidence. AB - INTRODUCTION: Oral verrucous carcinoma (OVC) is a rare malignancy of the oral cavity that was first described by Ackerman. This tumor is a well-differentiated low-grade, slow growing cancer that is locally invasive without metastasis. Ameloblastoma is one of the most common odontogenic tumors, which originates from the odontogenic epithelium. Verrucous carcinoma along with central ambloblastoma is a rare phenomenon. CASE REPORT: A case of verrucous carcinoma along with central ambloblastoma in a 49-year-old man, which was referred with a painless exophytic lesion with a verrucous and granular surface, is reported. Panoramic radiography revealed a well-defined radiolucency with sclerotic borders. To the best available knowledge, this phenomenon has not yet been reported. CONCLUSION: Verrucous carcinoma could occur in the wall of odontogenic cysts and tumors and should be considered during the differential diagnosis of a radiolucency, which is observed in the jaws with rapid growth or which presents some changes from its previous appearance. PMID- 25938089 TI - Huge tongue lipoma: a case report. AB - INTRODUCTION: Lipomas are among the most common tumors of the human body. However, they are uncommon in the oral cavity and are observed as slow growing, painless, and asymptomatic yellowish submucosal masses. Surgical excision is the treatment of choice and recurrence is not expected. CASE REPORT: The case of a 30 year-old woman with a huge lipoma on the tip of her tongue since 3 years, is presented. She had difficulty with speech and mastication because the tongue tumor was filling the oral cavity. Clinical examination revealed a yellowish lesion, measuring 8 cm in maximum diameter, protruding from the lingual surface. The tumor was surgically excised with restoration of normal tongue function and histopathological examination of the tumor confirmed that it was a lipoma. CONCLUSION: Tongue lipoma is rarely seen and can be a cause of macroglossia. Surgical excision for lipoma is indicated for symptomatic relief and exclusion of associated malignancy. PMID- 25938090 TI - Primary tuberculosis of the vallecula and pyriform sinus: a case report and review of literature. AB - INTRODUCTION: Tuberculosis (TB) is a relatively prevalent infectious disease caused by a bacterium called mycobacterium tuberculosis. It primarily involves the lungs, but it can also affect other organs causing a variety of symptoms. CASE REPORT: In this report, a rare case with primary involvement of pyriform sinus and vallecula due to tuberculosis in a 74-year-old woman who complained of odynophagia for 6 months, is reported. There were no clinical or radiological pulmonary findings. CONCLUSION: The authors point out the epidemiological importance of tuberculosis and the need for more suspicion when dealing with uncommon lesions to make an early diagnosis. PMID- 25938091 TI - Effects of a botulinum toxin type A injection on the masseter muscle: An animal model study. AB - BACKGROUND: The aim of this study was to investigate the effect of a botulinum toxin type A (BTX-A) injection in the masseter muscle using electromyography (EMG) in an animal model. METHODS: Ten male adult (>3 months of age) New Zealand white rabbits were used. Muscle activity was continuously recorded from 8 hours before to 8 hours after BTX-A injection. The rabbits received unilateral BTX-A injections of either 5 units (group 1, n = 5) or 20 units (group 2, n = 5). RESULTS: The masseter muscle activity of the rabbits was significantly reduced immediately after BTX-A injection (P < 0.05 for both groups). When the results from group 1 were compared with those from group 2, only the peak voltage was significantly decreased in group 2 (P = 0.013). CONCLUSION: Masseter muscle activity measured by EMG was immediately decreased after a BTX-A injection. PMID- 25938093 TI - Anatomical variations of lumbar arteries and their clinical implications: a cadaveric study. AB - Lumbar arteries arise from the abdominal aorta. Some abdominal and spinal surgeries can damage these arteries, and that can lead to serious consequences. This study aimed at studying the types and frequencies of variations of lumbar vasculature. We dissected both sides of 109 adult human cadavers and studied the variations of lumbar vasculature. Age range was 43-90 years. Fifty-seven percent were males and 43% were females. The number of lumbar arteries arising from either side of the abdominal aorta varied between 3 and 5 pairs. The lumbar arteries arose from a common single stem in 12% of the cadavers. The third and fourth pairs of lumbar arteries arose from a common single stem in 3% and 11% of cadavers, respectively, and the first and second pairs of lumbar arteries arose from a common single stem in 1% and 2% of cadavers, respectively. The first and second lumbar arteries on the right side traveled anterior to the right crus of the diaphragm in 7% and 8% of cadavers, respectively. There were several variations with regard to the number, origin from the abdominal aorta, and pathway of lumbar arteries from what is described in the literature. PMID- 25938094 TI - Occurrence of metopism in dry crania of adult brazilians. AB - The metopic suture is located between the tubercles of the frontal bone. There are divergences regarding the exact time at which it closes, which ranges from the first to the tenth year of life, although it may persist into adulthood. This study was conducted on 134 dry crania from adult Brazilians, of which 95 were male and 39 were female. These were available in the anatomy laboratories of higher education institutions in Maceio, AL, Brazil. All the crania were examined macroscopically with regard to the presence (metopism: M) on absence of the metopic suture. M was considered to be complete (Mc) when it continued uninterruptedly from the nasium to the bregma and incomplete (Mi) when it was not present over its entire length. It was observed that Mc was present in 4.48% (6/134) of the skull examined, of which 50% (3/134) were male and 50% (3/134) were female. An incomplete metopic suture was found in 5.22% (7/144) of the crania and more frequently among males (3.73%; 5/134). Among the crania with a metopic suture, the dolichocephalic type predominated (7.46%) in relation to brachycephalic crania (1.49%) and mesocephalic crania (0.74%). There was no predominance of metopism between the sexes, while an incomplete metopic suture was slightly more common among males. PMID- 25938095 TI - Review of bicipital groove morphology and its analysis in north Indian population. AB - The variant morphometry of bicipital groove is reported to be associated with pathologies of biceps tendon and is useful in surgical procedures in this region. The pathologies of biceps tendon are frequent causes of shoulder pain. Therefore, under the condition of paucity of data pertaining to north Indians, not only morphometric analysis of bicipital groove and a new definition of narrow/shallow groove to provide logical explanation for dependence of pathologies of biceps tendon on groove morphology is done but also a review of the literature has been carried out. Various dimensions such as lengths of medial and lateral walls, width, depth, medial wall, and opening angles including incidence of supratubercular ridge of bicipital groove from 101 humerii are 23 +/- 5, 32 +/- 5, 8 +/- 2, 6 +/- 1, 48.91 +/- 10.31, 82.20 +/- 22.62, and 37%, respectively. The average height along with average width of biceps tendon and average width along with average depth of bicipital groove from two cadavers are 1.8, 10.5, 11.3, and 5.5 mm, respectively. The knowledge of bicipital groove will be of paramount importance to anatomists for new data, for orthopaedic surgeons in carrying out surgical procedures in this region, and for physicians in the management of anterior shoulder pain in north Indian population. PMID- 25938092 TI - Understanding structure, function, and mutations in the mitochondrial ATP synthase. AB - The mitochondrial ATP synthase is a multimeric enzyme complex with an overall molecular weight of about 600,000 Da. The ATP synthase is a molecular motor composed of two separable parts: F1 and Fo. The F1 portion contains the catalytic sites for ATP synthesis and protrudes into the mitochondrial matrix. Fo forms a proton turbine that is embedded in the inner membrane and connected to the rotor of F1. The flux of protons flowing down a potential gradient powers the rotation of the rotor driving the synthesis of ATP. Thus, the flow of protons though Fo is coupled to the synthesis of ATP. This review will discuss the structure/function relationship in the ATP synthase as determined by biochemical, crystallographic, and genetic studies. An emphasis will be placed on linking the structure/function relationship with understanding how disease causing mutations or putative single nucleotide polymorphisms (SNPs) in genes encoding the subunits of the ATP synthase, will affect the function of the enzyme and the health of the individual. The review will start by summarizing the current understanding of the subunit composition of the enzyme and the role of the subunits followed by a discussion on known mutations and their effect on the activity of the ATP synthase. The review will conclude with a summary of mutations in genes encoding subunits of the ATP synthase that are known to be responsible for human disease, and a brief discussion on SNPs. PMID- 25938096 TI - Clinical insight into the precaval right renal artery: a multidetector row computed tomography angiographic study. AB - Variations of course and number of renal vessels are not so uncommon and their knowledge is important for planning of minimally invasive renal surgeries. The earlier literature reports a prevalence of precaval right renal artery between 0.8% and 5%. Normally, the right renal artery passes posterior to the inferior vena cava, but it can also be precaval where it passes anterior to inferior vena cava. The multidetector row contrast enhanced computed tomography angiography allows precise evaluation of renal vasculature. The aim of this retrospective study is to determine the prevalence of precaval right renal artery. Amongst 73 MDCT scans studied, we identified 4 cases of precaval right renal artery with the prevalence being 5.48%, more than what is reported in the earlier literature. We also report a single and dominant precaval right renal artery in one of the cases, which is a rare finding. On the basis of these results, we conclude that precaval right renal artery appears to be more common and so the knowledge of this variant holds a major clinical implication in preventing misinterpretation of radiological images and proper planning of interventional procedures and minimally invasive surgeries. PMID- 25938097 TI - The sagittal pelvic thickness: a determining parameter for the regulation of the sagittal spinopelvic balance. AB - Objective. To propose and validate a dimensional parameter, the sagittal pelvic thickness (SPT) (distance between the middle point of the upper sacral plate and the femoral heads axis, expressed as a ratio with the length of the upper plate of S1: (SPT/S1) for the analysis of the sagittal balance of the pelvispinal unit. Methods. The parameters were analysed on standing radiographic imaging and compared for normal, low back pain, children, and spondylolysis cases. Results. Values of SPT/S1 were observed significantly higher in high grade spondylolysis populations and in children (3,5 and 3,7) than in normal population (3,3). A geometrical connection with the classical angular parameters validated SPT/S1. Conclusion. SPT/S1 was considered reflecting the lever arm of action of spinopelvic muscles and ligaments and describing the ability of a subject to compensate a sagittal unbalance. It was proposed as an anatomical and functional pelvic parameter. PMID- 25938098 TI - Study of the location and morphology of the pterion in adult nigerian skulls. AB - The pterion which marks the union of 4 bones of the cranium is located superior to the zygomatic arch and posterior to the frontozygomatic suture. It is an important neurosurgical landmark for the lateral/pterional approach and has racial differences in both its location and pattern of union of the bones. This study aims to analyze the location and types of pterion in adult Nigerian skulls. Bilateral sides of 37 adult dry skulls were studied. The pterion types were classified; linear distances from the centre of the pterion to the midpoint of the zygomatic arch and to the frontozygomatic suture were measured; these were analyzed for side and gender differences. Sphenoparietal was the most common pterion type (86.1%) followed by frontotemporal (8.3%), stellate (5.6%), and epipteric types (0%). The mean distances from the pterion to the midpoint of zygomatic arch were 39.74 +/- 0.505 mm and 37.95 +/- 0.657 mm in males and females, respectively, while the distances to the frontozygomatic suture were 31.87 +/- 0.642 mm and 30.35 +/- 0.836 mm. The vertical position of the pterion was significantly higher in males than females. Bilateral occurrence is statistically insignificant. This information will be of neurosurgical and anthropological importance. PMID- 25938099 TI - Supernumerary renal arteries and their embryological and clinical correlation: a cadaveric study from north India. AB - Background. Classically, each kidney is supplied by a single renal artery originating from abdominal aorta. The present study aimed at its variations and their embryological and clinical correlation. Material and Methods. The formalin fixed thirty-seven cadavers from north India constituted the material for the study. During routine abdominal dissection conducted for medical undergraduates at the department of anatomy, the kidneys along with their arteries were explored and the morphological variations of renal arteries were noted. Results. We observed supernumerary renal arteries in 23/37 (62.2%) cases (48.6% of aortic origin and 13.5% of renal origin) on the right side and 21/37 (56.8%) cases (45.9% of aortic origin and 10.8% of renal origin) on the left side. Supernumerary renal arteries entered the kidney through hilum, superior pole, and inferior pole. Conclusion. Awareness of variations of renal artery is necessary for surgical management during renal transplantation, repair of abdominal aorta aneurysm, and urological procedures and for angiographic interventions. PMID- 25938100 TI - The posterior epidural ligaments: a cadaveric and histological investigation in the lumbar region. AB - Purpose. Incidental durotomy is a relatively common complication for patients undergoing posterior spinal surgery. Delineating anatomical variants in the posterior lumbar spinal canal is crucial in reducing future rates of incidental durotomy. Materials and Methods. The ligamentous attachments between the dura mater and ligamentum flavum in the lumbar region of 17 soft-fixed cadavers were investigated. The lumbar vertebral columns were removed, and cross-sectional dissection was performed at levels L1-S1. Anterior retraction of the dorsal dura mater identified attachments between the dorsal surface of the dura mater and the ligamentum flavum. Histological staining of the ligamentous attachments was carried out with hematoxylin and eosin (H&E) and elastic van Gieson (EVG). Results. Posterior epidural ligaments were present in 9 (52.9%) cadavers. Nine (9) separate ligaments were identified in these cadavers, with 3 (33.3%) at L3/L4, 5 (55.5%) at L4/L5, and 1 (11.1%) at L5/S1. Histology confirmed the presence of poorly differentiated collagen-based connective tissue, distinct from the normal anatomy. Conclusions. This study confirms the presence of multiple dorsomedial posterior epidural ligaments at the main sites for posterior spinal surgery (L3-S1). An intraoperative awareness of the variability of such connections may be an important step in reducing static rates of incidental durotomy. PMID- 25938101 TI - A new insight into the morphology of the human liver: a cadaveric study. AB - Background. Day to day advances in the fields of radiology like sonography and CT need to revive interest in the cadaveric study of morphological features of liver, as the accessory fissures are a potential source of diagnostic errors. Accessory fissures vary from single to multiple over different parts of the liver. Aim. In the present study the morphological features of human liver specimens were evaluated by macroscopic examination and morphometric analysis. Methods. The study was conducted on 58 specimens obtained from cadavers utilized for routine dissection for medical undergraduates from the year 2004 to 2012 in the Anatomy Department of MIMS Medical College. Results. In the present study the livers as described in the established anatomical literature with normal surfaces, fissures, and borders were considered normal. Out of the 58 specimens, 24 were normal without any accessory fissures or lobes and with normal contours. Two specimens were with hypoplastic left lobes. Lingular process of left lobe was observed in only one specimen. Conclusions. Knowledge of the various accessory fissures of liver prevents misdiagnosis of cystic lesions or any pathological lesions of the liver. PMID- 25938102 TI - Occipital emissary foramina in South Indian modern human skulls. AB - An occipital emissary foramen has been traditionally described as a foramen present in the squamous part of the occipital bone at the occipital protuberance transmitting a vein that connects the confluence of sinuses with the occipital vein. The present study was done on 221 South Indian adult modern human skulls of unknown sex in the Department of Anatomy, St John's Medical College, Bangalore, India. The foramen was observed in 21/221 (9.50%) skulls, 6/21 (28.57%) to the right of, 10/21 (47.61%) to the left of, and 2/21 (9.52%) on the External Occipital Crest. It was seen more often near the posterior margin of foramen magnum rather than at the External Occipital Protuberance as has been traditionally described. A new finding is that bilateral foramina were observed in 3 skulls (14.28%). The incidence was higher than seen in other Indian population. Since it is present near the foramen magnum in most cases, knowledge of the number and position of the foramen is important for suboccipital craniotomies. The extensive connections of the veins with cranial venous sinuses may lead to intracranial infections and vice versa. PMID- 25938103 TI - Prevalence of duodenal diverticulum in South indians: a cadaveric study. AB - Background. Duodenum is the second most common site of diverticula after the colon. Diagnosis of duodenal diverticula is incidental and found during other therapeutic procedures. In 90% of cases, they are asymptomatic, and less than 10% develop clinical symptoms. The difficulty to ascertain the true incidence of duodenal diverticula demanded for the present study to elucidate the prevalence of the duodenal diverticulum in South Indians. Materials and Methods. One hundred and twenty specimens of duodenum were utilized for the study. The prevalence, anatomical location, and dimension of duodenal diverticulum were studied. Results. Among the 120 specimens of duodenum, five specimens had solitary, extraluminal, and globular-shaped diverticula in the medial wall of the duodenum. In three (60%) cases, it was found in the second part of duodenum and in two (40%) cases in the third part. The mean size of the diverticula was 1.4 cm. Conclusion. In the present study in South Indian people, the prevalence (4.2%) of duodenal diverticula is low comparable to other studies in the literature. Even though most of the duodenal diverticula are asymptomatic, the knowledge about its frequency and location is of great importance to prevent complications like diverticulitis, hemorrhage, obstructive jaundice, and perforation. PMID- 25938104 TI - Crista terminalis, musculi pectinati, and taenia sagittalis: anatomical observations and applied significance. AB - Background. The complex architecture of the right atrium, crista terminalis (CT), and the musculi pectinati (MP) poses enormous challenges in electrophysiology and cardiac conduction. Few studies have been undertaken to substantiate the gross features of MP, in relation to the CT, but there is still scarcity of data regarding this. We tried to reinvestigate the gross arrangement of muscle bundles in the right atrium. Methods. Utilizing 151 human hearts and orientation of MP and its variations and relationship to the CT were investigated along with taenia sagittalis (TS). Patterns of MP were grouped in 6 categories and TS under three groups. Result. A plethora of variations were observed. Analysis of all the specimen revealed that 68 samples (45%) were of type 1 category and 27 (18%) fell into type 2 category. Prominent muscular columns were reported in 12 samples (8%). 83 samples (55%) presented with a single trunk of TS. Multiple trunks of TS were reported in 38 samples (25%). Conclusion. Samples with type 6 MP and type B/type C TS, which have a more complex arrangement of fibers, have a tendency to be damaged during cardiac catheterization. Nonetheless, the area as a whole is extremely significant considering the pragmatic application during various cardiac interventions. PMID- 25938105 TI - Study of sural nerve complex in human cadavers. AB - Aim. The sural nerve complex (SNC) consists of four named components: medial sural cutaneous nerve (MSCN), lateral sural cutaneous nerve (LSCN), peroneal communicating nerve (PCN), and sural nerve (SN). The formation and distribution of the sural nerve vary in different individuals. SN is universally recognized by surgeons as a site for harvesting an autologous nerve graft. The nerve is widely used for electrophysiological studies. Hence the study of sural nerve complex was taken up. Method. SNC was observed by dissecting 100 lower limbs in the department of anatomy at three different medical colleges, over a period of 10 years. Result. Typical SN was observed in 60% of the cases. MSCN was present in all the cases; in 15% of the cases the MSCN followed an intramural course. LSCN was present in 80% of the cases. PCN was present in 70% of the cases and in most of the cases calibre was larger than that of MSCN. Conclusion. The knowledge about the variation in the origin and course of the SN is important in evaluating sensory axonal loss in distal axonal neuropathies and should be borne in mind by clinicians and surgeons. PMID- 25938106 TI - Anatomical variations in the branching pattern of human aortic arch: a cadaveric study from central India. AB - Variations of the branches of aortic arch are due to alteration in the development of certain branchial arch arteries during embryonic period. Knowledge of these variations is important during aortic instrumentation, thoracic, and neck surgeries. In the present study we observed these variations in fifty-two cadavers from Indian populations. In thirty-three (63.5%) cadavers, the aortic arch showed classical branching pattern which includes brachiocephalic trunk, left common carotid artery, and left subclavian artery. In nineteen (36.5%) cadavers it showed variations in the branching pattern, which include the two branches, namely, left subclavian artery and a common trunk in 19.2% cases, four branches, namely, brachiocephalic trunk, left common carotid artery, left vertebral artery, and left subclavian artery in 15.3% cases, and the three branches, namely, common trunk, left vertebral artery, and left subclavian artery in 1.9% cases. PMID- 25938107 TI - Luteinizing hormone-releasing hormone distribution in the anterior hypothalamus of the female rats. AB - Luteinizing hormone-releasing hormone (LHRH) neurons and fibers are located in the anteroventral hypothalamus, specifically in the preoptic medial area and the organum vasculosum of the lamina terminalis. Most luteinizing hormone-releasing hormone neurons project to the median eminence where they are secreted in the pituitary portal system in order to control the release of gonadotropin. The aim of this study is to provide, using immunohistochemistry and female brain rats, a new description of the luteinizing hormone-releasing hormone fibers and neuron localization in the anterior hypothalamus. The greatest amount of the LHRH immunoreactive material was found in the organum vasculosum of the lamina terminalis that is located around the anterior region of the third ventricle. The intensity of the reaction of LHRH immunoreactive material decreases from cephalic to caudal localization; therefore, the greatest immunoreaction is in the organum vasculosum of the lamina terminalis, followed by the dorsomedial preoptic area, the ventromedial preoptic area, and finally the ventrolateral medial preoptic area, and in fibers surrounding the suprachiasmatic nucleus and subependymal layer on the floor of the third ventricle where the least amount immunoreactive material is found. PMID- 25938108 TI - Learning Anatomy: Can Dissection and Peer-Mediated Teaching Offer Added Benefits over Prosection Alone? AB - Purpose. To evaluate the impact of an optional thoracic dissection elective upon anatomy subject acquisition and determine whether peer-mediated teaching has a beneficial effect. Methodology. First year medical students' results on thoracic anatomy laboratory examinations over a five-year period were obtained. All students were taught in the laboratory using prosected specimens as part of a standard curriculum. A subset of students from each class volunteered to participate in an optional thoracic dissection. A comparison of exam performance between the two groups was made, and the results were analyzed to see if incorporating peer teaching into the elective had an impact on the students' performance on anatomy examinations. Results. With the exception of one year's results, no significant statistical difference was found in student performance on anatomy examinations between the two groups. The addition of peer teaching did not result in superior performance. Conclusion. It is believed that prosected specimens are suitable for anatomy laboratory teaching in an undergraduate medical curriculum. Our study did not reveal that an opportunity for dissection offered any added benefit in terms of exam performance. In addition, peer teaching did not affect exam performance. This study strictly compared student exam results. It did not assess the possible impact of the dissection process to influence student attitudes towards death or the development of clinically relevant visuospatial abilities and procedural skills. PMID- 25938109 TI - Role of neuronal apoptosis in volumetric change of hippocampus in diabetes mellitus type 1: a predictive model. AB - Background. Neuronal apoptosis is the major cause of diabetes central neuropathy, but its role in volumetric changes of hippocampus has not been clarified. The aims of this study were to assess the role of apoptosis in volumetric changes of dentate gyrus (DG) and CA3 region of hippocampus and to determine a reference point in which these neuropathological changes reach a meaningful level. Methods and Materials. Diabetes was induced in male Wistar rats (N = 10) by streptozotocin (60 mg/kg). Six weeks after diabetes, verification animals were divided into four groups as follows: diabetic treated with insulin (3-5 U), diabetic treated with vitamin C (80 mg/kg), and diabetic and control groups. At the end of 8 weeks, numerical density of apoptotic neurons and volume of dentate gyrus and CA3 were calculated by stereological methods. Results. The number of apoptotic neurons in DG and CA3 in diabetic group showed significant level of difference in comparison with the control (P < 0.001). The volume of DG and CA3 in diabetic and vitamin C showed significant level of difference compared with control (P < 0.001). Conclusion. Our results suggest that DG and CA3 volume reduction begins and progresses independently of neuronal loss. PMID- 25938110 TI - Three-Dimensional Structure and Disposition of the Air Conducting and Gas Exchange Conduits of the Avian Lung: The Domestic Duck (Cairina moschata). AB - The anatomy of the domestic duck lung was studied macroscopically, by casting and by light, transmission, and scanning electron microscopy. The lung had four categories of secondary bronchi (SB), namely, the medioventral (MV, 4-5), laterodorsal (LD, 6-10), lateroventral (LV, 2-4), and posterior secondary bronchi (PO, 36-44). The neopulmonic parabronchi formed an intricate feltwork on the ventral third of the lung and inosculated those from the other SB. The lung parenchyma was organized into cylindrical parabronchi separated by thin septa containing blood vessels. Atria were shallow and well-fortified by epithelial ridges reinforced by smooth muscle bundles and gave rise to 2-6 elongate infundibulae. Air capillaries arose either directly from the atria or from infundibulae and were tubular or globular in shape with thin interconnecting branches. The newly described spatial disposition of the conducting air conduits closely resembles that of the chicken. This remarkable similarity between the categories, numbers, and 3D arrangement of the SB in the duck and chicken points to a convergence in function-oriented design. To illuminate airflow dynamics in the avian lung, precise directions of airflow in the various categories of SB and parabronchi need to be characterized. PMID- 25938111 TI - Neural Structures within Human Meniscofemoral Ligaments: A Cadaveric Study. AB - Aim. To investigate the existence of neural structures within the meniscofemoral ligaments (MFLs) of the human knee. Methods. The MFLs from 8 human cadaveric knees were harvested. 5 MUm sections were H&E-stained and examined under light microscopy. The harvested ligaments were then stained using an S100 monoclonal antibody utilising the ABC technique to detect neural components. Further examination was performed on 60-80 nm sections under electron microscopy. Results. Of the 8 knees, 6 were suitable for examination. From these both MFLs existed in 3, only anterior MFLs were present in 2, and an isolated posterior MFL existed in 1. Out of the 9 MFLs, 4 demonstrated neural structures on light and electron microscopy and this was confirmed with S100 staining. The ultrastructure of these neural components was morphologically similar to mechanoreceptors. Conclusion. Neural structures are present in MFLs near to their meniscal attachments. It is likely that the meniscofemoral ligaments contribute not only as passive secondary restraints to posterior draw but more importantly to proprioception and may therefore play an active role in providing a neurosensory feedback loop. This may be particularly important when the primary restraint has reduced function as in the posterior cruciate ligament-deficient human knee. PMID- 25938112 TI - Variations in the position and length of the vermiform appendix in a black kenyan population. AB - Background. Topography of the appendix influences its mobility, degree of mobilization of the cecum, and need for additional muscle splitting during appendectomy. Although appendectomy is a common surgical procedure, there is a paucity of data on its topography in black Africans. Methods. The position and length of the appendix and relation of the appendicular base with spinoumbilical line were determined in 48 cadavers obtained from the Department of Human Anatomy, University of Nairobi, Kenya. Results. The commonest appendicular types in males were retrocecal 10 (27%) while in females was subileal 4 (36.4%). The average length of the appendix was 76.5 +/- 23.6 mm. The base of the appendix was located along, below, and above the spinoumbilical line in 25 (52.1%), 9 (18.8%), and 14 (29.2%) cases, respectively. Conclusion. The topography of appendix in Kenyans shows variations from other populations. Knowledge of these variations is important during appendicectomy. PMID- 25938113 TI - Parent and peer influence on recreational use of pain medication: are their influences similar to that of marijuana use? AB - Parent and peer disapproval were examined as potential predictors of recreational use of over-the-counter (OTC) and prescription pain medication. Risk perception was studied as a potential mediator of the effects of parent and peer disapproval. Four hundred and sixty-five college students (M age = 18.57, SD = 0.86) were recruited between September 2009 and September 2010. Participants completed an online survey about their recreational medication use, other substance use, and correlates of use. Path analyses showed that predictors of OTC and prescription pain medication recreational use are largely similar to predictors of marijuana use in college students such that risk perception mediated both the effect of parent and peer disapproval on dichotomous misuse, and peer disapproval had a significant direct effect on dichotomous misuse. Prevention interventions for recreational use of pain medication should target risk perception and peer disapproval. PMID- 25938115 TI - An Analysis on the Correlation and Gender Difference between College Students' Internet Addiction and Mobile Phone Addiction in Taiwan. AB - This study is aimed at constructing a correlative model between Internet addiction and mobile phone addiction; the aim is to analyse the correlation (if any) between the two traits and to discuss the influence confirming that the gender has difference on this fascinating topic; taking gender into account opens a new world of scientific study to us. The study collected 448 college students on an island as study subjects, with 61.2% males and 38.8% females. Moreover, this study issued Mobile Phone Addiction Scale and Internet Addiction Scale to conduct surveys on the participants and adopts the structural equation model (SEM) to process the collected data. According to the study result, (1) mobile phone addiction and Internet addiction are positively related; (2) female college students score higher than male ones in the aspect of mobile addiction. Lastly, this study proposes relevant suggestions to serve as a reference for schools, college students, and future studies based on the study results. PMID- 25938114 TI - Illicit drug use and problem gambling. AB - Problem gambling, substance use disorders, and their cooccurrence are serious public health concerns. We conducted a comprehensive review of the literature to understand the present state of the evidence on these coaddictions. Our main focus was illicit drug use rather than misuse of legal substances. The review covers issues related to gambling as a hidden problem in the illicit drug use community; prevalence, problem gambling, and substance use disorders as kindred afflictions; problem gambling as an addiction similar to illicit drug use; risk factors and problems associated with comorbidity, and gender issues. We end with some suggestions for future research. PMID- 25938116 TI - The destructive capacity of drug abuse: an overview exploring the harmful potential of drug abuse both to the individual and to society. AB - From a public health perspective, substance abuse has long been a source of major concern, both for the individual's health and for wider society as a whole. The UK has the highest rates of recorded illegal drug misuse in the western world. In particular, it has comparatively high rates of heroin and crack cocaine use. Substances that are considered harmful are strictly regulated according to a classification system that takes into account the harms and risks of taking each drug (see the tables) (Nutt et al. (2007)). The adverse effects of drug abuse can be thought of in three parts that together determine the overall harm in taking it: (1) the direct physical harm of the substance to the individual user, (2) the tendency of the drug to induce dependence, and (3) the effect of abuse of the drug on families, communities, and society (Gable (2004, 1993)). In this report, we discuss published evidence relating to the harm of substance misuse and consider the neuropsychopharmacological mechanisms behind addiction in an attempt to gain an improved picture of the potential devastation that abuse of these substances may evoke. PMID- 25938118 TI - Active Drug-Using Women Use Female-Initiated Barrier Methods to Reduce HIV/STI Risk: Results from a Randomized Trial. AB - Background. We tested an original, woman-focused intervention, based on body empowerment, and female-initiated barrier methods, including the female condom (FC) and cervical barriers. Methods. Eligible women were >= 18 years of age, HIV seronegative, and active drug users, reporting 30% or greater unprotected sex acts. Both controls (C) and intervention (I) participants received enhanced HIV/STI harm reduction counseling. I participants underwent 5 additional weekly group sessions. We compared change in frequency of unprotected vaginal intercourse across arms at 12 months. Results. Among 198 enrolled women, over 95% completed followup. Two-thirds were African-American; most of them used crack, had a primary partner, and reported sex exchange. In paired t-tests from baseline to followup, the frequency of unprotected vaginal sex dropped significantly for I (primary P < 0.00, nonprimary P < 0.002) and C (primary P < 0.008, nonprimary P < 0.000) arms with all partners. The difference in change across arms was of borderline significance for primary partner (P = 0.075); no difference was seen for nonprimary partner (P = 0.8). Use of male condom and FC increased with both partner types over time, but more consistently among I women. CONCLUSION: The "value-added" impact of the intervention was observed mainly with primary partners. Body knowledge with routine FC counseling should be incorporated into interventions for drug-using women. PMID- 25938117 TI - Neuropsychological Functions of MU- and delta-Opioid Systems. AB - Brain opioid innervation is involved in many pathophysiological processes related to drug addiction. The main idea of the present review is that MU-/delta-opioid innervation is an intrinsic component of the motor/approach behavior network, which is activated synergetically with dopaminergic mesocorticolimbic network. Contribution of opioid innervation to the motor/approach behavior processing includes generation of positive emotions and inhibition of pain and stress reactions in order that the individual would be able to reach the vital goal. We cite the neuroanatomical data which showed that motor subcortical nuclei contain the most abundant opioid innervation and its activation is an obligatory component of positive emotions. In the majority of life situations, motor/approach behavior network concomitantly activates pain/stress control opioid network. Intensive cognitive activity induces activation of opioid innervation as well, and both enhancing and impairing effects of opioid agonists on cognitive functioning were demonstrated. Overall, the functioning of endogenous opioid networks may be summarized as following: NO physical/cognitive activity = NO positive emotions plus NO pain/stress control. We suppose that contemporary findings concerning neuropsychological functions of endogenous opioid system explain many controversial issues in neuropsychiatric conditions predisposing to drug addiction and neurological mechanisms of opioid addiction. PMID- 25938119 TI - Korean American Women's Experiences with Smoking and Factors Associated with Their Quit Intentions. AB - This study explored Korean American women's experiences with smoking and tested the theory of planned behavior to identify factors associated with their intentions to quit smoking. It employed a mixed-methods research design, using qualitative and quantitative data. Participants were recruited via a combination of random (N = 49) and convenience (N = 45) sampling techniques. Women in this study initiated smoking at age of 23 on average, and nearly half smoked at indoor houses. They initiated smoking out of curiosity about the effect and belief that smoking would relieve their stress. Reasons for continued smoking were (a) to avoid nicotine withdrawal symptoms, (b) to cope with life stressors, including acculturative stress, and (c) to fulfill one's destiny as a lifetime smoker. Many attempted to quit due to health issues and pregnancy. Fear of disclosure and limited English proficiency were found to be major barriers to seeking help for quitting. Past-year quit attempt(s), attitudes toward quitting, and perceived family norm favoring quitting explained 25% of the variance in intentions to quit smoking (F [3,90] = 11.58, P < 0.001). Findings suggest that gender- and culture specific intervention strategies are needed to assist Korean American women in smoking cessation. PMID- 25938120 TI - Older adults and substance-related disorders: trends and associated costs. AB - Purpose. The aim of this study is to examine the changing service profile of older adults receiving substance abuse services over the past decade and the increased costs of treating this population. Design and Methods. Medicaid claims for mental health and substance abuse services data from a medium sized county in an eastern state were analyzed for individuals aged 50 years and older in calendar year 2000 or 2009. Univariate statistics are presented to describe the substance abuse and mental health services used by older adults in these two years. Results. The number of low-income older adults who accessed services for treatment and who had a substance-related diagnosis grew from 545 individuals in 2000 to 1,653 individuals in 2009. Costs for services utilized by older adults with a substance-related diagnosis rose by 358% from $2.1 million in 2000 to $9.5 million in 2009. Implications. The increase in the number of low-income older adults with a substance-related disorder and the concomitant rise in total spending for Medicaid reimbursed services indicate that local and state social service providers need to prepare for an older adult population who will need appropriate substance abuse prevention and treatment programs. PMID- 25938122 TI - Substance use disorders in men presenting to a psychosexual clinic. AB - Introduction. Substance use disorders (SUDs) are commonly associated with a variety of psychiatric disorders. Community-based studies have found a significant association between SUDs and sexual dysfunction in men, with a possible causal relation in the case of nicotine. Methods. The case records of 105 men presenting to a clinic for patients with psychosexual disorders were reviewed. Men with and without comorbid SUDs were compared in terms of demographic, clinical, and familial variables. Results. 25 of the 105 men (23.8%) had a lifetime diagnosis of SUD, and 19 (18.1%) had a current SUD. The commonest substances involved were nicotine (n = 21, 20%) and alcohol (n = 9, 9.5%). Men with comorbid SUDs were more likely to report a family history of substance dependence, particularly alcoholism. Single men with SUDs were more likely to have a comorbid mood disorder. Conclusion. SUDs, particularly nicotine and alcohol use disorders, are common comorbidities in patients with psychosexual disorders. Identifying and treating these disorders in this population are important aspects of management. PMID- 25938121 TI - Family-based interventions for the prevention of substance abuse and other impulse control disorders in girls. AB - Standardized family-based interventions are the most effective way of preventing or treating adolescent substance abuse and delinquency. This paper first reviews the incidence of adolescent substance abuse worldwide emphasizing gender and causes by etiological risk and protective factors. New epigenetic research is included suggesting that nurturing parenting significantly prevents the phenotypic expression of inherited genetic diseases including substance abuse. Evidence-based family interventions are reviewed including family change theories behind their success, principles and types of family-based interventions, research results, cultural adaptation steps for ethnic and international translation, and dissemination issues. The author's Strengthening Family Program is used as an example of how these principles of effective prevention and cultural adaptation can result in highly effective prevention programs not only for substance abuse, but for other impulse control disorders as well. The conclusions include recommendations for more use of computer technologies to cut the high cost of family interventions relative to youth-only prevention programs and increase the public health impact of evidence-based prevention programs. The paper recommends that to reduce health care costs these family-based approaches should be applied to the prevention and treatment of other impulse control disorders such as obesity and type 2 diabetes, sexually transmitted diseases, and delinquency. PMID- 25938123 TI - Adolescents smoking in the crosslight of other substance use and parental and peers' smoking behaviors. AB - This study investigates the connectedness of adolescents' smoking status, history of alcohol and cannabis use, and parental and peers' smoking, dimensions only rarely explored concurrently. Multinomial regression models that compared the smoking status of adolescents were estimated based on a representative sample of 3,560 adolescents aged 14-15 from Switzerland. While 49.0% of respondents had never smoked, 9.0% smoked on a daily basis and 12.0% occasionally; 32.6% had never drank alcohol and 74.7% had never used cannabis. Overall, parental and peers' smoking and other substance use factors are significantly associated with smoking status. Yet, history of substance use revealed less consistent associations with smoking status among current smokers (daily versus occasional smoking). The findings highlight the connectedness of adolescents' and other substance use behaviors and support the relevance of concurrent prevention initiatives targeting adolescents with specific substance use profiles and/or growing up in prosmoking social milieus. PMID- 25938124 TI - An Evaluation of Substance Abuse Treatment and HIV Education on Safe Sex Practices in Cocaine Dependent Individuals. AB - Background. There is a strong association between crack/cocaine use and increased sexual risk behavior, but little research on the efficacy of HIV education for decreasing such behavior in crack/cocaine-addicted individuals in substance abuse treatment. Method. Datasets from two cocaine dependence trials including either one or three HIV education sessions, respectively, were analyzed for changes over time in the proportion of participants practicing safe sex. A pooled dataset from two earlier trials not offering HIV education was also analyzed. Results. We included 83 participants from the 1-session trial and 65 participants from the 3 session trial. Both sets of participants evidenced a significant increase in the proportion of participants having safe sex with casual partners. Participants in the 3-session HIV education study also evidenced a significant increase in the proportion of participants having safe sex with regular partners. In the trials without HIV education, no change in safe sex practices was found, and change in condom use was observed only among female participants. Conclusions. These findings are consistent with recommendations that HIV education/counseling should be provided to individuals in substance abuse treatment. A randomized controlled trial to confirm these results may be warranted. This trial is registered with NCT00033033, NCT00086255, NCT00015106, and NCT00015132. PMID- 25938125 TI - In vivo neuronal co-expression of mu and delta opioid receptors uncovers new therapeutic perspectives. AB - Opioid receptors belong to the G protein coupled receptor family. They modulate brain function at all levels of neural integration and therefore impact on autonomous, sensory, emotional and cognitive processing. In vivo functional interaction between mu and delta opioid receptors are known to take place though it is still debated whether interactions occur at circuitry, cellular or molecular level. Also, the notion of receptor crosstalk via mu-delta heteromers is well documented in vitro but in vivo evidence remains scarce. To identify neurons in which receptor interactions could take place, we designed a unique double mutant knock-in mouse line that expresses functional red-fluorescent mu receptors and green-fluorescent delta receptors. We mapped mu and delta receptor distribution and co-localization throughout the nervous system and created the first interactive brain atlas with concomitant mu-delta visualization at subcellular resolution (http://mordor.ics-mci.fr/). Mu and delta receptors co localize in neurons from subcortical networks but are mainly detected in separate neurons in the forebrain. Also, co-immunoprecipitation experiments indicated physical proximity in the hippocampus, a prerequisite to mu-delta heteromerization. Altogether, data suggest that mu-delta functional interactions take place at systems level for high-order emotional and cognitive processing whereas mu-delta may interact at cellular level in brain networks essential for survival, which has potential implications for innovative drug design in pain control, drug addiction and eating disorders. PMID- 25938126 TI - Drug-induced regulatory overcompensation has motivational consequences: Implications for homeostatic and allostatic models of drug addiction. AB - Initial administration of 60% nitrous oxide (N2O) at 21 degrees C ambient temperature (Ta) reduces core temperature (Tc) in rats, but tolerance develops to this hypothermic effect over several administrations. After additional N2O administrations, a hyperthermic overcompensation (sign-reversal) develops such that Tc exceeds control levels during N2O inhalation. This study investigated whether rats would employ behavioral thermoregulation to facilitate, or oppose, a previously acquired hyperthermic overcompensation during N2O administration. To establish a hyperthermic sign-reversal, male Long-Evans rats (N=12) received ten 3-h administrations of 60% N2O while housed in a gas-tight, live-in, "inactive" thermal gradient (~21 degrees C). Following the tenth N2O exposure, the thermal gradient was activated (range of 10-37 degrees C), and rats received both a control gas session and a 60% N2O test session in counterbalanced order. Mean Tc during N2O inhalation in the inactive gradient was reliably hypothermic during the first exposure but was reliably hyperthermic by the tenth exposure. When subsequently exposed to 60% N2O in the active gradient, rats selected a cooler Ta, which blunted the hyperthermic sign-reversal and lowered Tc throughout the remainder of the N2O exposure. Thus, autonomic heat production effectors mediating the hyperthermia were opposed by a behavioral effector that promoted increased heat loss via selection of a cooler ambient temperature. These data are compatible with an allostatic model of drug addiction that suggests that dysregulatory overcompensation in the drugged-state may motivate behaviors (e.g., drug taking) that oppose the overcompensation, thereby creating a vicious cycle of escalating drug consumption and recurring dysregulation. PMID- 25938127 TI - Repeated nitrous oxide exposure in rats causes a thermoregulatory sign-reversal with concurrent activation of opposing thermoregulatory effectors. AB - Initial administration of 60% nitrous oxide (N2O) to rats at an ambient temperature of 21 degrees C decreases core temperature (Tc), primarily via increased heat loss (HL). Over repeated N2O administrations, rats first develop tolerance to this hypothermia and subsequently exhibit hyperthermia (a sign reversal) due primarily to progressive increases in heat production (HP). When rats initially receive 60% N2O in a thermal gradient, they become hypothermic while selecting cooler ambient temperatures that facilitate HL. This study investigated whether rats repeatedly administered 60% N2O in a thermal gradient would use the gradient to behaviorally facilitate, or oppose, the development of chronic tolerance and a hyperthermic sign-reversal. Male Long-Evans rats (N=16) received twelve 3-h administrations of 60% N2O in a gas-tight, live-in thermal gradient. Hypothermia (Sessions 1-3), complete chronic tolerance (Sessions 4-6), and a subsequent transient hyperthermic sign-reversal (Sessions 7-12) sequentially developed. Despite the progressive recovery and eventual hyperthermic sign-reversal of Tc, rats consistently selected cooler ambient temperatures during all N2O administrations. A final 60% N2O administration in a total calorimeter indicated that the hyperthermic sign-reversal resulted primarily from increased HP. Thus, rats did not facilitate chronic tolerance development by moving to warmer locations in the gradient, and instead selected cooler ambient temperatures while simultaneously increasing autonomic HP. The inefficient concurrent activation of opposing effectors and the development of a sign-reversal are incompatible with homeostatic models of drug-adaptation and may be better interpreted using a model of drug-induced allostasis. PMID- 25938128 TI - Persistence of a hyperthermic sign-reversal during nitrous oxide inhalation despite cue-exposure treatment with and without a drug-onset cue. AB - We asked whether chronic tolerance and the hyperthermic sign-reversal induced by repeated 60% N2O exposures could be extinguished using a cue-exposure paradigm. Rats received 18 N2O administrations in a total calorimetry system that simultaneously measures core temperature (Tc), metabolic heat production (HP), and body heat loss (HL). Each exposure entailed a 2-h baseline period followed by a 1.5-h N2O exposure. The 18 drug exposures induced a robust intra-administration hyperthermia in which the initial hypothermic effect of N2O inverted to a significant hyperthermic sign-reversal during N2O inhalation due primarily to an acquired robust increase in HP. The rats were then randomized to one of three extinction procedures (n=8/procedure) over a 20-d interval: 1) a N2O-abstinent home-cage group (HC) that received only the usual animal care; 2) a cue-exposure group (CEXP) in which the animals were placed in the calorimeter 8 times but received no N2O; and 3) a drug-onset-cue group (DOC) in which animals received a brief N2O exposure in the calorimeter that mimicked the first 3 min of an actual 60% N2O trial. Following the extinction sessions, all rats received a 60% N2O test trial and Tc, HP and HL were assessed. The hyperthermic sign-reversal remained fully intact during the test trial, with no significant differences observed among groups in any post-baseline change in any thermal outcome. These data suggest that cue exposure may not be an efficacious strategy to reduce sign reversals that develop with chronic drug use. PMID- 25938129 TI - Astrocytes: Everything but the glue. AB - The current knowledge in neuroscience indicates that neural tissue has two major cell populations: neurons and glia (term derived from the Greek word for glue). Neuronal population is characterized by the capacity to produce action potentials, whereas glial cells are typically identified as the subordinate cell population of neurons. To date, this point of view has changed dramatically and growing evidence indicates that glial cells play a crucial role in normal mental functions and the pathogenesis of neurological diseases. Classically, glial cells include four major populations clearly discernible in the adult brain: astrocytes, oligodendrocytes, microglia cells and NG2 glia. Astrocytes, also referred as to astroglia, are by far the most abundant cell lineage in the adult brain. These cells are in close contact with several tissue components of the brain parenchyma including neurons, vasculature, extracellular matrix and other glial populations. Hence, the number and strategic position of astrocytes provide them with exceptional capacity for modulating multiple functions in the neural tissue. PMID- 25938130 TI - Escalated Aggression in Animal Models: Shedding New Light on Mesocorticolimbic Circuits. AB - Recent developments promise to significantly advance the understudied behavioral and neurobiology of aggression: (1) Animal models that capture essential features of human violence and callousness have been developed. These models range from mice that have been selectively bred for short attack latencies, monogamous prairie voles, and glucocorticoid-compromised rats to rodents and non-human primates that escalate their aggression after consuming or when withdrawing from alcohol. (2) Optogenetic stimulation and viral vector-based approaches have begun to identify overlapping and distinctive neural microcircuits and intracellular molecules for adaptive vs. excessive, maladaptive aggressive behavior in several rodent models. Projections from hypothalamic and mesencephalic neurons to the medial prefrontal cortex contain microcircuits that appear pivotal for the escalation of aggression. PMID- 25938131 TI - Topical sodium nitrite for chronic leg ulcers in patients with sickle cell anaemia: a phase 1 dose-finding safety and tolerability trial. AB - BACKGROUND: Well-tolerated and effective treatments are needed for chronic leg ulcers in sickle cell anaemia. Topical sodium nitrite, a known nitric oxide donor, enhances blood flow in ulcers and has known bacteriostatic effects. We aimed to assess the safety, tolerability, and pharmacokinetics of topical sodium nitrite in patients with sickle cell disease and chronic leg ulcers. METHODS: We enrolled adult patients from an ambulatory clinic at the National Institutes of Health (Bethesda, MD, USA) with sickle cell anaemia with leg ulcers (with a surface area of 2.5-100 cm2) persisting for at least 4 weeks into a safety and tolerability phase 1 dose-escalation trial of topical sodium nitrite. Increasing concentrations of sodium nitrite cream were applied twice weekly for 4 weeks to one ulcer per patient at five dose levels (0.5%, 1%, 1.5%, 1.8%, and 2%). The primary endpoints were safety and tolerability, with secondary endpoints of pharmacokinetics, blood flow, and wound healing. Pain relief was analysed post hoc. Endpoints were analysed over time for the whole study population and according to dose level. This study is registered with ClinicalTrials.gov, number NCT01316796. FINDINGS: Between April 4, 2011, and March 19, 2013, we enrolled 18 adult patients with sickle cell anaemia and leg ulcers into our trial. We assigned three patients into each cohort, and each cohort was treated with a different concentration of sodium nitrite cream (cohort 1: 0.5%, cohort 2: 1.0%, cohort 3: 1.5%, and cohort 4: 2.0%). Patients were not enrolled into the next cohort dose until we were able to establish that no dose-limiting toxicities were observed. An additional six patients were enrolled to cohort 3a: 1.8%, after two patients in cohort 4 had asymptomatic drops in diastolic blood pressure. No grade 3-4 adverse events were observed, and there were no serious adverse events or dose-limiting side-effects. Pharmacokinetic analysis showed that systemic absorption of sodium nitrite was very low. Application of topical sodium nitrite was associated with a significant increase in peri-wound cutaneous blood flow measured by laser speckle contrast imaging (p=0.0002), corroborated by increased peri-wound skin temperature by infrared thermography (p=0.0119). We recorded a dose-dependent decrease in leg ulcer size (p=0.0012) and pain (p<0.0001). Ulcers healed completely in three patients who received the highest concentrations of topical sodium nitrite (the 1.8% and 2% cream). In our post-hoc analysis of pain, brief pain inventory scores improved in pain severity (p=0.0048) and pain interference (p=0.0013). INTERPRETATION: Our results indicate that topical sodium nitrite 2% cream is suitable for additional clinical trials in adults with sickle cell anaemia to promote healing of leg ulcers. FUNDING: National Heart, Lung and Blood Institute Division of Intramural Research (National Institutes of Health). PMID- 25938132 TI - Subjective memory complaints, cortical thinning, and cognitive dysfunction in middle-aged adults at risk for AD. AB - BACKGROUND: Subjective memory complaints (SMCs) represent an individual's perception of subtle changes in memory in the absence of objective impairment in memory. However, it is not fully known whether persons with SMCs harbor brain alterations related to Alzheimer's disease (AD) or whether they indeed demonstrate poorer cognitive performance. METHODS: Participants were 261 middle aged adults (mean age=54.30 years) enrolled in the Wisconsin Registry for Alzheimer's Prevention, a registry of cognitively normal adults at risk for AD. They answered a question pertaining to subjective memory, completed a comprehensive neuropsychological exam, and subsequently underwent a volumetric MRI scan. Cortical thickness measurements were derived from 10 a priori regions of interest involved in AD. Analyses of covariance were conducted to investigate group differences in cortical thickness and neuropsychological measures. RESULTS: Compared with individuals without SMCs, individuals with SMCs had significant cortical thinning in the entorhinal, fusiform, posterior cingulate, and inferior parietal cortices, as well as significantly reduced amygdala volume. Similarly, those with SMCs had significantly lower test scores on measures of Immediate Memory, Verbal Learning & Memory, and Verbal Ability. Additional adjustment for depressive symptoms (which differed between the groups) attenuated only the findings for the entorhinal cortex (p=.061) and Verbal Ability (p=.076). CONCLUSIONS: At-risk, cognitively healthy individuals with SMCs exhibit cortical thinning in brain regions affected by AD as well as poorer performance on objective memory tests. These findings suggest that, in some individuals, SMCs might represent the earliest stages of AD. PMID- 25938133 TI - Psychological Aspects of Contraception, Unintended Pregnancy, and Abortion. AB - The knowledge of important biopsychosocial factors linking women's reproductive health and mental health is increasing. This review focuses on psychological aspects of contraception, unintended pregnancy, and abortion because these are common reproductive health experiences in U.S. women's lives. This review addresses the mental-health antecedents and consequences of these experiences, mostly focusing on depression and depressive symptoms before and after unintended pregnancy and contraception. As mental-health antecedents, depressive symptoms predict contraceptive behaviors that lead to unintended pregnancy, and mental health disorders have been associated with having subsequent abortions. In examining the mental-health consequences, most sound research does not find abortion or contraceptive use to cause mental-health problems. Consequently, evidence does not support policies based on the notion that abortion harms women's mental health. Nevertheless, the abortion-care setting may be a place to integrate mental-health services. In contrast, women who have births resulting from unintended pregnancies may be at higher risk of postpartum depression. Social policies (e.g., paid maternity leave, subsidized child care) may protect women from mental-health problems and stress of unplanned children interrupting employment, education, and pre-existing family care responsibilities. PMID- 25938134 TI - Role for Endogenous BDNF in Endocannabinoid-Mediated Long-Term Depression at Neocortical Inhibitory Synapses AB - The endogenous cannabinoid (endocannabinoid) system is an important regulator of synaptic function. Endocannabinoids acutely modulate inhibitory and excitatory transmission, and also mediate long-term depression at GABAergic and glutamatergic synapses. Typically, endocannabinoid synthesis and release is stimulated by depolarization-induced calcium influx and/or activation of phospholipase-C (PLC) signaling triggered by mGluR activation. Recently it has been shown that brain-derived neurotrophic factor (BDNF) can also induce endocannabinoid release. Although there is growing evidence for cross-talk between BDNF and endocannabinoid signaling, little is known about the functional relevance of these interactions. In the present studies, we examined BDNF - endocannabinoid interactions in regulating activity-dependent long-term depression at inhibitory synapses (iLTD). We found that theta burst stimulation (TBS) in layer 2/3 of mouse somatosensory cortical slices can induce a form of endocannabinoid-mediated iLTD that is independent of metabotropic glutamate receptor (mGluR) activation. This endocannabinoid-dependent iLTD, however, requires endogenous BDNF-trkB signaling, as it is blocked by a trk tyrosine kinase inhibitor and by a trkB receptor antagonist, and also requires activation of diacylglycerol lipase (DAG-lipase, DGL). In addition, endocannabinoid-mediated iLTD can be induced by combining a subthreshold concentration of exogenous BDNF with weak TBS stimulation that by itself is insufficient to induce iLTD. Taken together, our results suggest that TBS can induce the release of endogenous BDNF, which triggers DGL-dependent endocannabinoid mobilization and cannabinoid receptor-dependent iLTD at layer 2/3 cortical synapses. PMID- 25938135 TI - The Role of Vitamin D in Pediatric Asthma. AB - The detrimental effects of vitamin D deficiency in pediatrics have become increasingly apparent and extend beyond skeletal health. Unfortunately, vitamin D deficiency is highly prevalent in atopic pediatric patients, in whom it may disrupt the immune system and induce significant worsening of reactive airways. This review presents evidence that lung development and immune regulatory functions are vitamin D-dependent. We also review clinical studies that explore how vitamin D supplementation may prevent respiratory infections and help improve asthma control, and we elaborate how these effects may vary among populations. We reveal the strong need of screening measures for vitamin D deficiency in high risk pediatric populations, particularly African-Americans, Hispanic-Americans, and children with obesity. Finally, we emphasize that all children, especially those who are asthmatic, should be assessed to ensure adequate intake or supplementation with at least the minimum recommended doses of vitamin D. The simple intervention of vitamin D supplementation may provide significant clinical improvement in atopic disease, especially asthma. PMID- 25938136 TI - A Bayesian Scoring Technique for Mining Predictive and Non-Spurious Rules. AB - Rule mining is an important class of data mining methods for discovering interesting patterns in data. The success of a rule mining method heavily depends on the evaluation function that is used to assess the quality of the rules. In this work, we propose a new rule evaluation score - the Predictive and Non Spurious Rules (PNSR) score. This score relies on Bayesian inference to evaluate the quality of the rules and considers the structure of the rules to filter out spurious rules. We present an efficient algorithm for finding rules with high PNSR scores. The experiments demonstrate that our method is able to cover and explain the data with a much smaller rule set than existing methods. PMID- 25938137 TI - A Virtual Therapist for Speech and Language Therapy. AB - A virtual therapist (VT) capable of modeling visible speech and directing speech and language therapy is presented. Three perspectives of practical and clinical use are described. The first is a description of treatment and typical roles that the VT performs in directing participation, practice and performance. The second is a description of techniques for modeling visible speech and implementing tele rehabilitation. The third is an analysis of performance of a system (AphasiaRxTM) for delivering speech and language therapy to people with aphasia, with results presented from a randomized controlled cross-over study in which the VT provided two levels of cuing. Compared to low cue treatment, high cue treatment resulted in 2.3 times faster learning. The paper concludes with a discussion of the benefits of speech and language therapy delivered by the VT. PMID- 25938138 TI - [In vitro study of electrospun polycaprolactone/chitosan nano fiber membrane guided bone regeneration]. AB - PURPOSE: To explore the effect of electrospining chitosan/polycaprolactone nano fiber membrane on regeneration of bone defects in vitro. METHODS: Chitosan/polycaprolactone nanofiber membrane was prepared by electrospinning technique. According to alkaline phosphatase activity and Western blot results, the ability of osteogenic differentiation of cells by fiber membrane as carrier was evaluated. The data was analyzed statistically with SPSS17.0 software package. RESULTS: The osteogenic differentiation capacity of electrospining chitosan/polycaprolactone nano fiber membrane was significantly higher than the control (without materials), and the difference was significant (P<0.05). CONCLUSIONS: Electrospinning chitosan/polycaprolactone nano fiber membrane can promote osteogenic differentiation of cells in vitro, which provides a scientific basis for clinical regeneration of bone defects. PMID- 25938139 TI - [Immortalization of human dental pulp stem cells caused by transferring hTERT gene]. AB - PURPOSE: To establish an immortalized human dental pulp stem cell line used for basic and clinical research of oral science. METHODS: Human telomerase reverse transcriptase (hTERT) cDNA was transferred into human dental pulp stem cells (hDPSCs) by lentivirus. The resultant stable clones reproduced successively and the expression of hTERT was identified. RESULTS: The hTERT gene was transferred into human dental pulp stem cells successfully. The transformed cells expressed telomerase activity and divided vigorously. p35 had been obtained so far. CONCLUSIONS: The hDPSCs can be immortalized by transferring exogenous hTERT gene to constitute telomerase activity. PMID- 25938140 TI - [The effect of fluoride on adhesion of Streptococcus mutans and Streptococcus sanguis on the dental pure titanium surface]. AB - PURPOSE: This study was to investigate the effect of fluoride on adhesion of Streptococcus mutans and Streptococcus sanguis on the dental pure titanium surface. METHODS: The adhesion of Streptococcus mutans and Streptococcus sanguis on the dental pure titanium surface were examined by 3-(4,5-dimethylthiazol-2-yl) 2,5-diphenyltetrazolium bromide (MTT) assay after soaked in artificial saliva containing different concentrations of sodium fluoride for 24 h. Then the surface roughness and surface morphology of the pure titanium were analyzed by atomic force microscope after bacterial adhesion experiments. The data was statistically analyzed by analysis of variance(ANOVA) with SPSS11.0 software package. RESULTS: After soaked in artificial saliva containing different concentrations of sodium fluoride for 24 h, the sequence of OD values showed the adhesion of Streptococcus mutans and Streptococcus sanguis on dental pure titanium surface was 0 g/L < 0.5 g/L < 1.0g/L < 2.0 g/L (P<0.05). In addition, the sequence of Ra values showed the surface roughness of pure titanium after bacterial adhesion experiments was 0 g/L < 0.5 g/L < 1.0g/L < 2.0 g/L (P<0.05). And the surface morphology of pure titanium was consistent with the changes of OD value and Ra value. CONCLUSIONS: The results of adhesion of Streptococcus mutans and Streptococcus sanguis, surface roughness and surface morphology reveal that fluoride aggravates the corrosion of pure titanium, increases the surface roughness, and thus promots the adhesion of Streptococcus mutans and Streptococcus sanguis on the titanium surface. PMID- 25938141 TI - [Preparation and examination of BMP-2 loaded chitosan nanospheres in vitro]. AB - PURPOSE: To prepare chitosan nanospheres for loading of BMP-2 and to evaluate its size, zeta potential, appearance, degradation and release characteristic in vitro, and then to investigate its feasibility as a carrier for sustained release of BMP-2. METHODS: The BMP-2 loaded chitosan nanospheres were prepared using ionic crosslinking method with tripolyphosphate (TPP) and chitosan. Transmission electron microscope was used to evaluate the morphological properties, and laser particle size analyzer was used to analyze particle size, Zeta potential and distribution. Lysozyme degradation experiment was performed to assess the biodegradation behavior. ELISA assay was used to determine the loading efficiency, encapsulation efficiency and in vitro drug release kinetics. The data was analyzed by SPSS 19.0 software package. RESULTS: The BMP-2 loaded chitosan nanospheres were spherical in shape, smooth on surface and uniform dispersion without aggregation. The mean diameter was 150.85 nm. The dispersion index was 0.37, and zeta potential was +35.42 mV. The average loading efficiency and encapsulation efficiency were (56.83 +/- 2.26)% and (68.24 +/- 3.83)%, respectively. Release experiment in vitro showed that the releasing property of BMP-2 loaded chitosan nanospheres was consistent with two-phase kinetic regulation and BMP-2 was controlled to release from the chitosan nanospheres over 30 days. CONCLUSIONS: The BMP-2 loaded chitosan nanospheres prepared by ionic crosslinking method are successfully prepared which show a good controlled release property. It provides the basis for further application in bone tissue engineering. PMID- 25938142 TI - [Effect of IL-1beta on inflammatory factors synthesis of human gingival fibroblasts attached to different titaniums]. AB - PURPOSE: To evaluate the effects of IL-1beta on inflammatory factors synthesis of human gingival fibroblasts on different surfaces of titaniums in vitro. METHODS: Human gingival fibroblasts were cultured on 3 different kinds of titaniums. The cells were stimulated with IL-1beta, and the IL-6 and IL-8 production was detected by polymerase chain reaction (PCR) after 3, 6 and 24 h. The date was statistically analyzed with SPSS13.0 software package. RESULTS: A significant increase of the expression of gingival fibroblasts to inflammatory factors (IL-6, IL-8) after IL-1beta was noted; PCR results of the production of inflammatory factors in gingival fibroblasts with the intervention of IL-1beta showed that the production of inflammatory factors (IL-6, IL-8) on titanium and titanium alloy were less than that on the titanium nitride. CONCLUSIONS: IL-1beta can stimulate high expression of inflammatory factors; The production of IL-6 and IL-8 on titanium and titanium alloy are less, suggesting that implant made of titanium and titanium alloy can reduce the incidence of peri-implant inflammation, and improve the successful rate of implantation. PMID- 25938143 TI - [Finite element analysis of the angulation designment of implant planning in the anterior maxilla]. AB - PURPOSE: To provide theoretical reference for maxillary anterior restoration designment in clinics by observing the masticatory stress distribution of the implant-bone interface and the displacement of implant. METHODS: This study built simplified 3 dimensional finite models with different angles, which included partial implant (4.3 mm*11.5 mm), abutment and all ceramic crown (Zirconia) and combined with angle of implant A between the long axis of ideal implant and factual implant (0 degrees , 5 degrees , 10 degrees , 15 degrees , 20 degrees , 25 degrees ), as well as angle of abutment B between the long axis of abutment and implant (0 degrees , 5 degrees ,10 degrees ,15 degrees ,20 degrees ,25 degrees ). A force load of 178 N was applied 2 mm below the incisal edge on the palatal surface of the crown, with an approximately 130 degrees angle to the long axis of the crown. The displacement of implant maximum principal stress value and distribution of the implant-bone interface were determined by using Ansys 13.0 software. RESULTS: Sixteen 3-dimensional models of different implant restoration plan of implant dentures of maxillary incisor were built. When the angle of abutment was increasing with the same labial inclination of implant, the objective functions were enhanced. When the labial inclination of implant was increasing with the same angle of abutment, the objective functions were also improved. With the change of labial inclination of implant and angled abutment, the labial inclination of implant concentrated more than the angle of abutment on the objective functions. When the angle of abutment was between 0 degree and 20 degree, the amplitude of all the objective functions were gentle, while the labial inclination of implant and amplitude of all the objective functions were increased when the angle of abutment increased to 25 degree. CONCLUSIONS: A positive correlation is found between the value of stress of the bone around the implant, and the displacement of implant and the labial inclination of the implant and the angle of abutment. It is necessary to decrease the labial inclination of the implant and the angle of abutment, especially strictly control the labial inclination of the implant. Taking the stress and displacement into consideration, both of two angles ranging from 0 degree to 20 degree are the best optimal choice for the anterior implants. When both of two angles increase to much greater than 20 degree, the value of stress increase remarkably, which will decrease the chance of successful implant. PMID- 25938144 TI - [Biomechanical analysis on healing process of sagittal fracture of the mandibular condyle after rigid fixation]. AB - PURPOSE: To analyze the biomechanical healing process on rigid fixation of sagittal fracture of the mandibular condyle (SFMC), and to provide guidelines for surgical treatment. METHODS: Three-dimensional finite element model (3D-FEAM) of mandible and condyle was established. The right condyle was simulated as SFMC with 0.1 mm space across the condyle length ways. The 3D-FEAM of rigid fixation was established. The biomechanical factors such as stress distribution of condylar surface, displacement around fracture, stress on the plate and stress shielding were calculated during 0, 4, 8 and 12-week after rigid fixation. RESULTS: The maximum equivalent stress of normal condyle was located at the area of middle 1/3 of condylar neck. The maximum equivalent stress at 0-week after fixation was 23 times than that on normal condyle. They were located at the condylar stump and the plate near inferior punctual areas of fracture line. There were little stress on the other areas. The maximum equivalent stress at 4, 8 and 12-week was approximately 6 times than that on normal condyle. They were located at the areas same as the area at 0-week. There were little stress on the other areas at the condyle. The maximum total displacement and maximum total corner were increased 0.57-0.75 mm and 0.01-0.09 degrees respectively during healing process. The maximum equivalent stress at 0-week on the condylar trump was 5-6 times compared with that at 4, 8, and 12-week. The maximum equivalent stress, maximum total displacement and maximum total corner on the fractured fragment were not changed significantly during healing process. The maximum equivalent stress at 0-week on the plate was 7-9 times compared with that at 4, 8, 12-week. CONCLUSIONS: The stress of the condyle and stress shielding of the plate may be the reasons of absorbing and rebuilding on the condyle in healing process of SFMC. The biomechanical parameters increase obviously at 4-week after fixation. Elastic intermaxillary traction is necessary to decrease total displacement and total corner of the condyle, and liquid diet is necessary to decrease equivalent stress within 4 weeks. Rehabilitation training should be used to recover TMJ functions after 4 weeks because the condyle and mandible have the ability to carry out normal functions. PMID- 25938145 TI - [The finite element analysis of stress distribution in different size of MO cavities restored with composite resin inlays]. AB - PURPOSE: To explore the effect of different depth and width of meiso-occlusal (Class II) cavity type on the tooth tissue resistance stress after restoration with composite resin inlays. METHODS: The 3-D finite element model of mandibular first molar with meiso-occlusal (Class II) cavity restored with composite resin inlay was established by using CBCT scanning and reverse engineering software Mimics, Geomagic Studio, and finite element analysis software ANSYS. Comparative analysis of restoration with different depth and width meiso-occlusal (Class II) cavity under the same load of perpendicular and 45 degrees deviation was explored, and finally the main stress and Von-mises stress changed as well as stress distribution were analyzed. RESULTS: The main stress was located in the gingival wall opposite to the inlay, while the major stress concentration area of the tooth was distributed near the canal at the bottom of the cavity. With the increase of the depth and width, the main stress and Von-mises stress distribution areas of tooth were getting larger. The Von-mises stress of tooth was influenced by the width variation of the cavity, while that depth change of cavity was affected by Von Mises stress of the inlay. CONCLUSIONS: With the increase of the depth and width of the cavity as well as lateral loading force, the peak stress of tooth with inlays increased and the distribution of stress concentration is modified after meiso-occlusal (Class II) cavity being inlayed with composite resin. PMID- 25938146 TI - [Preliminary study of bonding strength between diatomite-based dental ceramic and veneering porcelains]. AB - PURPOSE: In order to choose the best veneering porcelain for diatomite-based dental ceramic substrate, the bonding strength between diatomite-based dental ceramics and veneering porcelains was measured, and the microstructure and elements distribution of interface were analyzed. METHODS: The coefficient of thermal expansion (CTE) of diatomite-based dental ceramics was detected by dilatometry. Three veneering porcelain materials were selected with the best CTE matching including alumina veneering porcelain (group A), titanium porcelain veneering porcelain (group B), and E-max veneering porcelain (group C). Shear bonding strength was detected. SEM and EDS were used to observe the interface microstructure and element distribution. Statistical analysis was performed using SPSS 17.0 software package. RESULTS: The CTE of diatomite-based dental ceramics at 25-500 degrees centigrade was 8.85*10-6K-1. The diatomite-based substrate ceramics combined best with group C. Shear bonding strength between group A and C and group B and C both showed significant differences(P<0.05). SEM and EDS showed that the interface of group C sintered tightly and elements permeated on both sides of the interface. CONCLUSIONS: The diatomite-based substrate ceramics combines better with E-max porcelain veneer. PMID- 25938147 TI - [Effects of morphology of the microgroove titanium surface on expression of vinculin in human gingival fibroblasts]. AB - PURPOSE: To investigate the effects of morphology of the microgroove surface on the expression of vinculin in human gingival fibroblasts, with the hope of providing basis for size selection of microgroove for transmucosal part of dental implants. METHODS: Microgroove titanium surfaces were fabricated by photolithography with parallel grooves: 15 MUm, 30 MUm or 60 MUm in width and 5 MUm or 10 MUm in depth. The groups that used different microgroove surfaces were denoted as T15/5, T15/10, T30/5, T30/10, T60/5, and T60/10. Smooth titanium surfaces (T0) were used as controls. Surface topography was detected. HGFs were cultured on the microgroove surfaces. Morphology of vinculin was analyzed using CLSM. Expression level of vinculin was compared among different groups by real time PCR and Western blotting. SPSS17.0 software package was used for statistical analysis. RESTULTS: Immunofluorescence staining revealed increase of green vinculin fluorescent spots as the increase of microgroove width, while T60 group had the highest mRNA and protein expression and T15 group had the lowest. Microgroove depth had no effect on the expression of vinculin under the same width. CONCLUSIONS: Morphology of microgroove surface has effect on the expression of vinculin, and the morphology of microgroove surface in T60 group is the best size for the transmucosal part in terms of expression of vinculin protein expression. PMID- 25938148 TI - [Study on antimicrobial effect of the mixture of Chinese medicine-chitosan to Candida albicans and the possibility as denture adhesive]. AB - PURPOSE: To observe the antimicrobial effect and the tensile bond strength of water-soluble chitosan after adding different Chinese medicines to Candida albicans. METHODS: The extract of 6 kinds of Chinese medicine by decoction in different concentrations were mixed with chitosan, and the most effective mixture inhibiting Candida albicans and the minimal inhibitory concentration (MIC) were explored; Then the tensile bond strength of the mixture was tested and compared with Protefix denture adhesive. The data was analyzed with SPSS17.0 software package. RESULTS: The antibacterial effect of polyphylla-chitosan mixture was the best among the 6 kinds of Chinese medicine- chitosan mixture, and its MIC was 1.563 mg/mL. The tensile bond strength of polyphylla-chitosan mixture at 0 h and 12 h when immersed in artificial saliva were significantly larger than Protefix denture adhesive. The average value and the maximum value was significantly greater than the Protefix denture adhesive (P<0.05). CONCLUSIONS: Polyphylla chitosan mixture has good antibacterial effect on Candida albicans and large tensile bond strength. PMID- 25938149 TI - [Expression of CXC chemokine ligand 16 and chemokine receptor 6 in periodontal tissues of patients with moderately severe periodontitis]. AB - PURPOSE: To investigate the expression and localization of CXCLl6 and its receptor CXCR6 in gingival tissues of patients with chronic periodontitis and analyze the roles in the occurrence and development of periodontitis. METHODS: Gingival tissues with moderately severe periodontitis were collected from 39 patients treated in People's Hospital of Liaoning Province. Forty persons with healthy gingiva were used as control. The age of the enrolled subjects ranged from 35 to 74 years old. Immunohistochemical technique was applied to detect the expression and localization of CXCLl6 and CXCR6 protein gingival tissues of all subjects. The data was analyzed with SPSS 15.0 software package. RESULTS: Compared with normal group, the expression of CXCLl6 and CXCR6 were significantly up-regulated in patients with periodontitis (P<0.05). There was a positive relationship between the protein expression of CXCLl6 and CXCR6 in gingival tissues of patients with periodontitis (r=0.580, P<0.05). CONCLUSIONS: CXCLl6 and CXCR6 may be involved in the development of chronic periodontitis. The expression of CXCLl6 and CXCR6 may work coordinately to promote the development of chronic periodontitis. PMID- 25938150 TI - [The labial and palatal bone thickness in 67 young adults with normal occlusion at the maxillary anterior teeth measured by cone-beam computed tomography]. AB - PURPOSE: To investigate the labial and palatal bone thickness of the maxillary anterior teeth in normal young adults on different reference lines, in order to provide references for clinical treatment. METHODS: Sixty-seven eligible Han nationality young volunteers were scanned by cone-beam computed tomography (CBCT). The labial and palatal bone thickness and the labial bone morphology of the anterior teeth were measured after reconstruction. Paired-sample t test, independent- sample t test, one-way ANOVA and Chi-square test were performed using SPSS17.0 software package. RESULTS: (1)The mean labial bone thicknesses at L1 of canines and L5 of all anterior teeth were more than 1.00 mm, while the thickness of the other labial measurement sites were less than 1.00 mm. The mean palatal bone thickness was more than 1.00 mm. (2) The labial bone was thinner than the palatal bone (P<0.001). (3)The labial bone was the thinnest at L3 and L4 of the anterior teeth (P<0.001). The thickness of palatal bone gradually increased from the L1 to L5(P<0.001). (4)The frequency of the labial bone thinner than 1.00 mm was less than 50% at L2 of canines and L5 of all anterior teeth; The frequency of the labial bone deficiency at L3 and L4 of lateral incisors and L4 of canines was more than 50% in males. (5)The mean buccal bony curvature of canines was larger than that of incisors in males. The distance between root apex and the deepest point of buccal bony curvature was the largest in maxillary central incisors zone in males, while there was no significant difference in females. CONCLUSIONS: The alveolar bone thickness of the maxillary anterior teeth in normal young adults are quite thin or even deficient, and there is diversity of the thickness and morphology between labial and palatal bone. PMID- 25938151 TI - [Analysis of the possible causes of endodontic treatment failure by inspection during apical microsurgery treatment]. AB - PURPOSE: To analyze the possible causes of previous endodontic treatment failure by microscopic inspection during apical microsurgery. METHODS: Two hundred and eighty-nine teeth of previous endodontic treatment failure were collected from patients in Shanghai Xuhui District Dental Center, between January 2006 and January 2014. All surgical procedures were performed by using an operating microscope, and 238 roots were included in the study. The surface of the apical root to be resected or the resected root surface after methylene blue staining was examined during the surgical procedure and inspected with 26 magnification to determine the state of the previous endodontic treatment by using an operating microscope. Fisher's exact test was used to analyze the data with SPSS 19.0 software package. RESULTS: Among the 238 roots with periapical surgery, analysis of the reasons for previous endodontic treatment failure included leaky canal (29.41%), missing canal (15.55%), underfilling (15.55%), anatomical complexity (7.98%), overfilling (4.20%), apical fenestration (4.20%), iatrogenic problem (3.36%), apical calculus (2.52%), apical cracks (1.68%) and unknown reasons (15.55%). The frequency of possible failure causes and tooth position were closely correlated (P<0.001). CONCLUSIONS: Apical microsurgery can better inspect possible causes of previous endodontic treatment failure, in order to improve the success rate of endodontic treatment. PMID- 25938152 TI - [The relationship between labial-lingual inclination and the thickness of the alveolar bone in the mandibular central incisors assessed with cone-beam computed tomography]. AB - PURPOSE: To investigate the alveolar bone thickness of mandibular central incisors with different labial-lingual inclinations by cone-beam computed tomography (CBCT). METHODS: CBCT and lateral cephalometric images of 60 patients were chosen. The data was respectively classified into 3 groups by L1-MP: lingual inclination group (L1-MP<85.6 degrees ); normal group (L1-MP 85.6 degrees -99.6 degrees ), and labial inclination group(L1-MP>99.6 degrees ). Three-dimensional reconstruction was made for CBCT, and the sagittal images of the largest alveolar bone area along the tooth axis were chosen. The central incisor roots were divided into 4 sections from cementoenamel junction to root apex, then the labial and lingual alveolar bone thickness were measured and added up to get total alveolar bone thickness, and the occurrence of fenestration and dehiscence were recorded. The data was analyzed with SPSS 17.0 software package. RESULTS: The alveolar bone thickness on lingual side and the total bone thickness were significantly different between every 2 sections of all the measured zone. The average values of bone thickness on labial side were thinner than that on lingual side in sections of middle 1/2, root apex 1/4 and root apex. The total bone and lingual bone were thinner in lingual inclination group than in labial inclination group at root apex, root apex 1/4 and middle 1/2. Labial and lingual inclination group were more likely to develop dehiscence (P<0.05). CONCLUSIONS: Lingual and total alveolar bone of central incisors become increasingly thinner from root apex area to cementoenamel junction. The total bone and lingual bone are thinner in lingual inclination group than in labial inclination group. Labial or lingual inclined incisors have higher incidence of dehiscence. PMID- 25938153 TI - [Use of fiber-reinforced chemical curing resin to close the inter-proximate space of the posterior teeth]. AB - PURPOSE: To investigate the clinical efficacy of using fiber-reinforced chemical curing resin to close the inter-proximate space of the posterior teeth and block the food impaction. METHODS: One hundred and sixty-two patients with food impaction of posterior teeth were selected in this study. The total number of the food impaction was 170. They were divided into narrow-gap group and wide-gap group according to the damage of the inter-proximate space. Jingjin enamel adhesive reinforced polyethylene fiber ribbon was used in both group to close the inter-proximate space. The patients were reviewed at 6-month and 1-year. After the second follow-up examination, 161 restorations of 154 patients were included in this study. The differences between the 2 groups were analyzed by Chi-square test with SPSS 13.0 software package. RESULTS: Statistical differences were found in the retention rate of the restorations at 6-month between the 2 groups (P<0.05). The retention rate in the narrow-gap group was significantly lower than that in the wide-gap group. However, there was no significant difference between the 2 groups at 1-year. There was no significant difference in integrality between the 2 groups at 6-month and 1-year. CONCLUSIONS: The use of fiber-rein forced chemical curing resin to close the inter-proximate space of the posterior teeth and block the food impaction is more suitable for patients with clinical crown elongation, gingival recession, alveolar bone loss and the tissue damages in the inter-proximate space, which will cause food impaction. PMID- 25938154 TI - [Analysis of the outcomes of squamous cell carcinoma of maxillary sinus with 3 different comprehensive treatments]. AB - PURPOSE: To study the medium or long-term survival rates of different methods used in the treatment of advanced squamous cell carcinoma of the maxillary sinus (SCMS). METHODS: Patients were treated by one of the following methods: 231 patients were treated with induction chemotherapy, followed by radical resection and radiotherapy (CSR); 128 patients were treated with preoperative irradiation (RS), and 87 patients underwent adjuvant radiotherapy (RSR). A total of 446 cases of SCMS from June 1985 to December 2008 were managed with unscheduled application of the above 3 kinds of treatment options. The dose of 231 patients with CSR and 128 patients with RS was 60-70 Gy/30-35 times/5-7 week and 40-50 gy/20-25 times/4 5 week, respectively. Dose in RSR accounted for half of that in CSR. The number of cases undergoing total resection of maxilla, subtotal resection of maxilla and extended excision of maxilla were 299, 111 and 36, respectively (13 cases had orbital exenteration). The number of patients with therapeutic radical neck dissection, functional neck dissection and supraomohyoid neck dissection were 49, 73 and 56, respectively. The data was analyzed with SPSS16.0 software package. RESULTS: Five-year survival rate in 446 cases was 45.96% (205/446), and 220 patients died of tumors, among which 84.09% (185/220) of death were due to local recurrences. The 5-year survival rate of CSR, RS, and RSR were 45.88% (106/23), 46.09% (59/128) and 45.97% (40/87), respectively; Totally 83.33% of CSR, 85.71% of RS and 83.72% of RSR died of local recurrences. There was no significant difference in the survival rates among CSR, RS and RSR. CONCLUSIONS: Unscheduled comprehensive treatment have a higher 5-year survival rate in this advanced SCMS. Elective neck irradiation and neck dissection are necessary for medium or advanced squamous cell carcinoma of maxillary sinus. PMID- 25938155 TI - [Comparison of two different flap designs in removal of impacted wisdom tooth]. AB - PURPOSE: The purpose of this study was to compare the effect of two different flap designs on surgical removal of impacted mandibular third molars. METHODS: Four hundred patients who required removal of impacted mandibular third molars were included in the study. They were divided into group A and group B randomly. Patients in group A received distal incision flap and group B underwent angular incision flap. The effect of flap design on surgical time, incidence of dry socket, pain, swelling and trismus was evaluated postoperatively. Data analysis was carried out with SPSS 13.0 software package. RESULTS: The surgical time was longer in group A than in group B 3 days postoperatively. Facial swelling and trismus were less in group A than in group B 3 days postoperatively. There was no significant difference in two groups 7 days postoperatively. CONCLUSIONS: The distal incision flap design can release facial swelling and trismus in surgical removal of impacted mandibular third molars. PMID- 25938156 TI - [Expression of Ki-67 and P53 protein in oral squamous cell carcinoma and its clinical significance]. AB - PURPOSE: To investigate the clinical and pathological features and its relationship with the expression of Ki-67 and p53 protein in oral squamous cell carcinoma. METHODS: Immunohistochemical SP staining method was used to quantify the protein expression levels of Ki-67 and p53 protein in 10 cases of normal oral mucosa, 16 cases of oral leukoplakia (OLK) tissue, and 48 cases of oral squamous cell carcinoma. The relationship of the expression of Ki-67 and p53 protein to clinical and pathological data was analyzed, and SPSS17.0 software package was used for statistical analysis. RESULTS: The positive expression rate of Ki-67 protein in normal oral mucosa, oral leukoplakia and oral squamous cell carcinoma was 30%, 56.3% and 79.2%, respectively; The positive expression rate of p53 was 0%, 43.8%, and 70.8%, respectively; Ki-67 and p53 expression had significant difference among normal oral mucosa, oral leukoplakia and oral squamous cell carcinoma (P<0.05); The expression of Ki-67 protein was significantly elevated with tumor stage, differentiation and cervical lymph node metastasis (P<0.05); The expression of p53 protein was significantly related to the degree of tumor differentiation (P<0.05); The expression of Ki-67 and p53 was positively correlated in oral squamous cell carcinoma (P<0.05). CONCLUSIONS: The high expression of Ki-67 and p53 protein in oral squamous cell carcinoma tissues may play an important role in the development of oral squamous cell carcinoma. PMID- 25938157 TI - [Soft tissue linear evaluation of fixed Twin-block appliance treatment and tooth extraction in skeletal Class II malocclusion]. AB - PURPOSE: This cephalometric study was designed to evaluate the soft tissue profile effects of Twin-block combined with straight wire appliances to treat growing adolescents with skeletal Class II malocclusion and mandibular retrognathia. METHODS: The samples comprised 31 growing individuals with skeletal Class II and mandibular retrognathia. They were divided into 2 groups. The study group (18 patients) was treated with fixed Twin-block combined with fixed appliance, while the control group (13 patients) was only treated with fixed appliance after tooth extraction. Pretreatment and posttreatment lateral cephalograms were taken before and after Twin-block treatment and after all the fixed appliance treatment. Linear cephalometric measurements of soft tissue were analyzed statistically. Intragroup and intergroup changes of the 2 groups were evaluated using SPSS 15.0 software package. RESULTS: Significant changes of G' Pg', Li-1, Si-B and Ls-E line between before and after treatment were found in the study group, while Li-1, Ls-E line and Li-E line changed significantly in control group. The change of Li-E line was different between the 2 groups. CONCLUSIONS: Twin-block combined with fixed appliance treatment is better than extraction with fixed appliance treatment in promoting lower facial profile in cases of skeletal Class II malocclusion and mandibular retrognathia with growth potentials. PMID- 25938158 TI - [Preventive effect of dexmedetomidine on postoperative delirium in elderly patients with oral cancer]. AB - PURPOSE: To observe and analyze the preventive effect of dexmedetomidine on postoperative delirium in elderly patients with oral cancer. METHODS: One hundred and fifty-six elderly patients with oral cancer who received radical surgery under general anesthesia were studied. They were randomly divided into 2 groups: experimental group (n=78) and control group (n=78). All patients stayed in PACU for 2 hours after surgery, and then were transferred to SICU when they had waken up. Subsequently, patients in experimental group were assigned to take intravenous dexmedetomidine at a dose of 0.2 MUg/kg.h for 12 hours while patients in control group were assigned to take intravenous normal saline for 12 hours. All patients were given compound analgesia consisted of tramadol and tropisetron in the same dose. During the first three postoperative days, patients were evaluated with the Confusion Assessment Method for the Intensive Care Unit (CAM ICU), Visual Analogue Scale and Richmond Agitation Sedation Scale twice a day(8:00 am and 8:00 pm). Statistical analysis was performed using SPSS16.0 software package. RESULTS: There was no significant difference on postoperative VAS, the incidence of postoperative bradycardia and hypotension between 2 groups. In addition, no postoperative respiratory depression was found in 2 groups. Richmond Agitation Sedation Scale on the first and second day after surgery in the experimental group was better than in the control group. The incidence of postoperative delirium, nausea and vomiting in the experimental group was lower than in the control group. CONCLUSIONS: Intravenous dexmedetomidine at a dose of 0.2 MUg/kg.h for 12 hours after operation in elderly patients with oral cancer can ameliorate postoperative sedation status, reduce the incidence of postoperative delirium, and will not cause postoperative bradycardia, hypotension and other complications. PMID- 25938159 TI - [Correlation analysis between psychosomatic symptoms of adult and cooperation behaviors]. AB - PURPOSE: To investigate whether the psychosomatic symptoms of patients are related to the degree of cooperation. METHODS: Ninety-one malocclusion adults (31 males, 60 females, aged from 20 to 45 years) were selected and determined with Symptom Checklist-90 (SCL-90) to evaluate their psychosomatic symptoms. The inspected and filed noncooperation behaviors were examined and recorded 6 months after orthodontic treatment started. The data was analyzed by one-sample t test, independent-sample t test and Spearman rank correlation coefficient with SPSS 20.0 software package. RESULTS: Adult malocclusion patients scored significantly higher than the nation norm on the factors of interpersonal sensitivity, anxiety, schizophrenia and compulsion (P<0.05). The score of noncooperation behaviors showed a scale of 0 to 19, with an average of 7.2 +/- 1.4 points. There was positive correlation between psychological problems and noncooperation behaviors of adult patients (r=0.35). CONCLUSIONS: The study confirms that the psychosomatic symptoms of adult malocclusion patients are associated with the degree of cooperation. Having known well about the psychology of adult malocclusion patient before orthodontic treatment is initiated, and orthodontists can relieve psychological disorders in patients to improve their cooperating quality. PMID- 25938160 TI - [Evaluation of labial surface root filling combined with porcelain dental restoration]. AB - PURPOSE: To analyze the effect of porcelain dental restoration combined with labial surface root filling for the anterior teeth. METHODS: One hundred cases with anterior teeth protrusion treated in our department from January 2010 to January 2014 underwent porcelain dental restoration combined with labial surface root filling. The measurements in cephalometric X-ray films before and after treatment were compared, and porcelain dental appearance and function were evaluated. The data was statistically analyzed with SPSS18.0 software package. RESULTS: After treatment, U1-SN, U1-X, U1-Y were significantly lower than before treatment (P<0.01). U1-L1 was significantly higher after treatment (P<0.01). The incidence of gingivitis after treatment decreased significantly (X(2)=16.2749,P=0.0000<0.01). The excellent rate of outline of porcelain teeth after treatment, correction of protruding anterior teeth, fitting with adjacent teeth and alleviation of deep overbite and deep cover was 96.00%, 95.00%, 98.00% and 91.00%, respectively. CONCLUSIONS: Porcelain dental restoration after root canal treatment can effectively improve anterior teeth protrusion and increase the aesthetic appearance, which is worthy of clinical application. PMID- 25938161 TI - [Application of miniscrew for extraction of mesially impacted wisdom tooth adjacent to the inferior alveolar nerve canal]. AB - PURPOSE: To study the value of miniscrew for extraction of mesially impacted wisdom tooth adjacent to the inferior alveolar nerve canal. METHODS: Fourteen mesially impacted wisdom teeth were proven to be adjacent to the inferior alveolar nerve canal by means of cone-beam CT scan. The treatment began with the miniscrew traction of the wisdom teeth. After 2-5 months, they were moved away from the canal and then extracted. RESULTS: After extraction, all 14 cases did not show any obvious side effect. CONCLUSIONS: Application of miniscrew traction is a valuable method for minimally invasive extraction of mesially impacted wisdom tooth that is adjacent to the inferior alveolar nerve canal. PMID- 25938162 TI - [Analysis and reflections of dental qualification examination for oversea dentists in Beijing]. AB - PURPOSE: To improve the management of qualification examination for oversea dentists in Beijing based on analysis of examinations during 2000-2013. METHODS: The information of examinees for qualification examination of oversea dentists during 2000-2013 were collected and analyzed in Beijing. RESULTS: Among 142 examinees from 21 countries, China Hong Kong and Taiwan region, the pass rate was 48.2% for general dentists and 66.7% for dental specialists. The pass rate was highest among examinees whose native language was English or Chinese. CONCLUSIONS: For oversea dentists who participate in the qualification examination in Beijing, besides the knowledge and skills, much more attention should be paid to prepare the examination and improve the Chinese or English language ability. PMID- 25938163 TI - Triflic acid catalyzed formal [3 + 2] cycloaddition of donor-acceptor oxiranes and nitriles: a facile access to 3-oxazolines. AB - A TfOH-catalyzed chemoselective [3 + 2] cycloaddition of donor-acceptor oxiranes and nitriles is described. This reaction provides an efficient and practical method for the preparation of useful 3-oxazolines in good to excellent yields (up to 99%). PMID- 25938164 TI - Structural Insight into an Alzheimer's Brain-Derived Spherical Assembly of Amyloid beta by Solid-State NMR. AB - Accumulating evidence suggests that various neurodegenerative diseases, including Alzheimer's disease (AD), are linked to cytotoxic diffusible aggregates of amyloid proteins, which are metastable intermediate species in protein misfolding. This study presents the first site-specific structural study on an intermediate called amylospheroid (ASPD), an AD-derived neurotoxin composed of oligomeric amyloid-beta (Abeta). Electron microscopy and immunological analyses using ASPD-specific "conformational" antibodies established synthetic ASPD for the 42-residue Abeta(1-42) as an excellent structural/morphological analogue of native ASPD extracted from AD patients, the level of which correlates with the severity of AD. (13)C solid-state NMR analyses of approximately 20 residues and interstrand distances demonstrated that the synthetic ASPD is made of a homogeneous single conformer containing parallel beta-sheets. These results provide profound insight into the native ASPD, indicating that Abeta is likely to self-assemble into the toxic intermediate with beta-sheet structures in AD brains. This approach can be applied to various intermediates relevant to amyloid diseases. PMID- 25938165 TI - Upregulation of glycans containing 3' fucose in a subset of pancreatic cancers uncovered using fusion-tagged lectins. AB - The fucose post-translational modification is frequently increased in pancreatic cancer, thus forming the basis for promising biomarkers, but a subset of pancreatic cancer patients does not elevate the known fucose-containing biomarkers. We hypothesized that such patients elevate glycan motifs with fucose in linkages and contexts different from the known fucose-containing biomarkers. We used a database of glycan array data to identify the lectins CCL2 to detect glycan motifs with fucose in a 3' linkage; CGL2 for motifs with fucose in a 2' linkage; and RSL for fucose in all linkages. We used several practical methods to test the lectins and determine the optimal mode of detection, and we then tested whether the lectins detected glycans in pancreatic cancer patients who did not elevate the sialyl-Lewis A glycan, which is upregulated in ~75% of pancreatic adenocarcinomas. Patients who did not upregulate sialyl-Lewis A, which contains fucose in a 4' linkage, tended to upregulate fucose in a 3' linkage, as detected by CCL2, but they did not upregulate total fucose or fucose in a 2' linkage. CCL2 binding was high in cancerous epithelia from pancreatic tumors, including areas negative for sialyl-Lewis A and a related motif containing 3' fucose, sialyl Lewis X. Thus, glycans containing 3' fucose may complement sialyl-Lewis A to contribute to improved detection of pancreatic cancer. Furthermore, the use of panels of recombinant lectins may uncover details about glycosylation that could be important for characterizing and detecting cancer. PMID- 25938167 TI - Distinct longitudinal patterns of absenteeism and their antecedents in full-time Australian employees. AB - This paper investigated distinct longitudinal trajectories of absenteeism over time, and underlying demographic, work, and health antecedents. Data from the Household, Income, and Labor Dynamics in Australia Survey were used; this is a panel study of a representative sample of Australian households. This paper focused on 2,481 full-time employees across a 5-year period. Information on annual sick leave and relevant sociodemographic, work, and health-related factors was collected through interviews and self-completed surveys. Growth mixture modeling indicated 4 distinct longitudinal patterns of absenteeism over time. The moderate absenteeism trajectory (34.8%) of the sample had 4-5 days of sick leave per year and was used as the reference group. The low absenteeism trajectory (33.5%) had 1-2 days of absenteeism per year, while the no absenteeism trajectory (23.6%) had very low rates of absenteeism (<1 day per year). Finally, a smaller trajectory accounting for 8.1% of the sample had high levels of absenteeism (>11 days per year). Compared with the moderate absenteeism trajectory, the high absenteeism trajectory was characterized by poor health; the no absenteeism and low absenteeism trajectories had better health but may also reflect processes relating to presenteeism. These results provide important insights into the nature of absenteeism in Australian employees, and suggest that different patterns of absenteeism over time could reflect a range of demographic, work, and health related factors. PMID- 25938166 TI - Asymmetric synthesis and in vitro and in vivo activity of tetrahydroquinolines featuring a diverse set of polar substitutions at the 6 position as mixed efficacy MU opioid receptor/delta opioid receptor ligands. AB - We previously reported a small series of mixed-efficacy MU opioid receptor (MOR) agonist/delta opioid receptor (DOR) antagonist peptidomimetics featuring a tetrahydroquinoline scaffold and showed the promise of this series as effective analgesics after intraperitoneal administration in mice. We report here an expanded structure-activity relationship study of the pendant region of these compounds and focus in particular on the incorporation of heteroatoms into this side chain. These analogues provide new insight into the binding requirements for this scaffold at MOR, DOR, and the kappa opioid receptor (KOR), and several of them (10j, 10k, 10m, and 10n) significantly improve upon the overall MOR agonist/DOR antagonist profile of our previous compounds. In vivo data for 10j, 10k, 10m, and 10n are also reported and show the antinociceptive potency and duration of action of compounds 10j and 10m to be comparable to those of morphine. PMID- 25938168 TI - Do the aryl hydrocarbon receptor interacting protein variants (Q228K and Q307R) play a role in patients with familial and sporadic hormone-secreting pituitary adenomas? AB - AIM: The aim of this study was to examine mutations in the aryl hydrocarbon receptor-interacting protein (AIP) gene by sequence analysis of exons 1-6 using leukocyte genomic DNA obtained from a cohort of familial isolated pituitary adenoma (FIPA) and apparent sporadic functional pituitary adenoma Turkish patients. METHODS: Fourteen FIPA and 90 sporadic pituitary adenoma (somatotrophinoma, prolactinoma, and corticotrophinoma) patients, 1 sporadic gigantism case, and 70 healthy controls were included in the study. RESULTS: We did not detect AIP mutations in patients with FIPAs or sporadic pituitary adenomas, including the gigantism case. Only two exonic homozygous missense single-nucleotide polymorphisms (rs641081 [Q228K] and rs4930195 [Q307R]) were identified in the AIP locus. Minor allele frequencies of the Q307R and Q228K variants were significantly higher in FIPA patients compared to controls. In addition, the minor allele frequency of the Q228K variant was significantly increased in patients with sporadic somatotrophinomas compared to controls, whereas the minor allele frequency of the Q307R variant was significantly increased in corticotrophinoma patients compared to controls. Conversely, the minor allele frequencies of Q228R and Q307R variants were similar between patients with prolactinomas and controls. No AIP gene mutation or variant was observed in the sporadic gigantism patient. These results suggest that Q228K and Q307R variants in the AIP gene might be involved in the genetic susceptibility to familial and sporadic pituitary adenomas (somatotrophinoma and corticotrophinoma) in the Turkish population. PMID- 25938169 TI - Regioselective decarboxylative cross-coupling of carboxy isoquinoline N-oxides. AB - A straightforward method for direct decarboxylative arylation of 1- and 3-carboxy isoquinaldic acid N-oxides with aryl iodides is reported. The reaction proceeded selectively at the carboxy function site to exclusively give the corresponding C 1 or C-3 arylated product. This methodology tolerates various aryl iodides substituted by electronically different groups. Combined with subsequent Reissert Henze chlorination and SNAr amination, the decarboxylative arylation provides an efficient access to 1,3-functionalized isoquinoline-based antitumor agent. PMID- 25938170 TI - Plasmomechanical Resonators Based on Dimer Nanoantennas. AB - Nanomechanical resonators are highly suitable as sensors of minute forces, displacements, or masses. We realize a single plasmonic dimer antenna of subwavelength size, integrated with silicon nitride nanobeams. The sensitive dependence of the antenna response on the beam displacement creates a plasmomechanical system of deeply subwavelength size in all dimensions. We use it to demonstrate transduction of thermal vibrations to scattered light fields and discuss the noise properties and achievable coupling strengths in these systems. PMID- 25938171 TI - Evaluating the Effects of Aromatics Content in Gasoline on Gaseous and Particulate Matter Emissions from SI-PFI and SIDI Vehicles. AB - We assessed the emissions response of a fleet of seven light-duty gasoline vehicles for gasoline fuel aromatic content while operating over the LA92 driving cycle. The test fleet consisted of model year 2012 vehicles equipped with spark ignition (SI) and either port fuel injection (PFI) or direct injection (DI) technology. Three gasoline fuels were blended to meet a range of total aromatics targets (15%, 25%, and 35% by volume) while holding other fuel properties relatively constant within specified ranges, and a fourth fuel was formulated to meet a 35% by volume total aromatics target but with a higher octane number. Our results showed statistically significant increases in carbon monoxide, nonmethane hydrocarbon, particulate matter (PM) mass, particle number, and black carbon emissions with increasing aromatics content for all seven vehicles tested. Only one vehicle showed a statistically significant increase in total hydrocarbon emissions. The monoaromatic hydrocarbon species that were evaluated showed increases with increasing aromatic content in the fuel. Changes in fuel composition had no statistically significant effect on the emissions of nitrogen oxides (NOx), formaldehyde, or acetaldehyde. A good correlation was also found between the PM index and PM mass and number emissions for all vehicle/fuel combinations with the total aromatics group being a significant contributor to the total PM index followed by naphthalenes and indenes. PMID- 25938172 TI - Nanocomposite Hydrogels: 3D Polymer-Nanoparticle Synergies for On-Demand Drug Delivery. AB - Considerable progress in the synthesis and technology of hydrogels makes these materials attractive structures for designing controlled-release drug delivery systems. In particular, this review highlights the latest advances in nanocomposite hydrogels as drug delivery vehicles. The inclusion/incorporation of nanoparticles in three-dimensional polymeric structures is an innovative means for obtaining multicomponent systems with diverse functionality within a hybrid hydrogel network. Nanoparticle-hydrogel combinations add synergistic benefits to the new 3D structures. Nanogels as carriers for cancer therapy and injectable gels with improved self-healing properties have also been described as new nanocomposite systems. PMID- 25938174 TI - Rapid maxillary expansion: Do banded teeth develop more external root resorption than non-banded anchorage teeth? AB - OBJECTIVE: To compare external root resorption (ERR) when bands and wires are used as orthodontic anchorage during rapid maxillary expansion (RME). MATERIALS AND METHODS: Histologic analysis was performed on 108 sites from 18 maxillary first premolars and on 36 sites from six mandibular first premolars in nine subjects (mean age = 15.2 +/- 1.4 years) 3 months after RME. Maxillary teeth were pooled into two groups (n = 54 each) according to the type of orthodontic anchorage (band group [BG] vs wire group [WG]). Anchorage type was randomly chosen in a split-mouth design. Mandibular first premolars, which were not subjected to orthodontic forces, were used as the control group (CG). RESULTS: All premolars in the BG and WG showed ERR at the level of the cementum and dentin. Repair with cementum cells was observed in all resorption areas, but complete repair was rarely found. No statistically significant difference was found between the BG and WG with regard to the ERR. No association was found between the root height position (middle or cervical third) and the incidence of ERR. Buccal root surfaces showed a higher amount of ERR compared with the palatal and interproximal surfaces. ERR was not found in any teeth in the CG. CONCLUSION: All maxillary first premolars subjected to RME showed ERR and partial cementum repair. Banded teeth did not develop more ERR than nonbanded anchorage teeth. PMID- 25938175 TI - Interaction of novel fluorescent nanoscale ionic silicate platelets with biomaterials for biosensors. AB - The nano silicate platelets (NSPs) of 100 * 100 * 1 nm(3) in dimension were previously derived from the exfoliation of naturally occurring sodium montmorillonite clay, and their affinity to the surface of bacteria was revealed. The unique characteristics of ionic charges (=Si-O-Na(+)) and the presence of siloxanol functionalities (=Si-OH) allowed the organic modification of NSP to form NSP-tethering poly(hydroxyethyl methacrylate) (PHEMA) pendants through a sol gel and living polymerization. By attaching nathphalimide-type fluorescence onto NSP-PHEMA, a new class of fluorescent organic-inorganic hybrid (NSP-PHEMA-HA), was prepared and its photoluminescence (PL) and bacterial trapping properties were characterized. The investigation of PL emission revealed that the fluorescent NSP hybrids could be used to detect bacteria and possess the potential for the biosensor applications. PMID- 25938176 TI - Maple Bark Biochar Affects Rhizoctonia solani Metabolism and Increases Damping Off Severity. AB - Many studies have investigated the effect of biochar on plant yield, nutrient uptake, and soil microbial populations; however, little work has been done on its effect on soilborne plant diseases. To determine the effect of maple bark biochar on Rhizoctonia damping-off, 11 plant species were grown in a soilless potting substrate amended with different concentrations of biochar and inoculated or not with Rhizoctonia solani anastomosis group 4. Additionally, the effect of biochar amendment on R. solani growth and metabolism in vitro was evaluated. Increasing concentrations of maple bark biochar increased Rhizoctonia damping-off of all 11 plant species. Using multivariate analyses, we observed positive correlations between biochar amendments, disease severity and incidence, abundance of culturable bacterial communities, and physicochemical parameters. Additionally, biochar amendment significantly increased R. solani growth and hyphal extension in vitro, and altered its primary metabolism, notably the mannitol and tricarboxylic acid cycles and the glycolysis pathway. One or several organic compounds present in the biochar, as identified by gas chromatography-mass spectrometry analysis, may be metabolized by R. solani. Taken together, these results indicate that future studies on biochar should focus on the effect of its use as an amendment on soilborne plant pathogens before applying it to soils. PMID- 25938177 TI - Development of a DNA Macroarray for the Detection and Identification of Fungal Pathogens Causing Decline of Young Grapevines. AB - Young vine decline (YVD) is a complex disease caused by at least 51 different fungi and responsible for important economic losses to the grapevine industry worldwide. YVD fungi are known to occur in planting material. Hence, detection prior to planting is critical to assure longevity of newly established vineyards. A DNA macroarray based on reverse dot-blot hybridization containing 102 oligonucleotides complementary to portions of the beta-tubulin region was developed for detection of YVD fungi. Specificity of the array was first evaluated against 138 pure fungal cultures representing 72 different taxa from nine genera, including 37 YVD species. In total, 61 species, including 34 YVD pathogens, were detected and identified by the array. The detection limit of the array was below 0.1 pg of genomic DNA. The array was validated against artificially inoculated canes and soil and commercial planting material, with the latter showing a high incidence of YVD fungi in nursery plants otherwise not detected by traditional plating and culturing. This DNA array proved to be a rapid and specific tool to simultaneously detect and identify most YVD fungi in a single test, which has the potential to be used in commercial diagnostics or by the grapevine nursery industry to determine the health status of the planting material. PMID- 25938179 TI - Social identity and socially shared retrieval-induced forgetting: The effects of group membership. AB - In a conversation, speakers and listeners will often influence each other's memories, and in doing so, promote the formation of a shared, or collective, memory. One means by which a mnemonic consensus emerges is through socially shared retrieval-induced forgetting (SSRIF). When listeners attend to the speakers' selective retrieval of previously encountered events, they forget unmentioned but related information more than they forget unrelated, unmentioned previously studied information. As a consequence, both speaker and listeners come to remember-and forget-the event in a similar way. SSRIF appears to be dependent on listeners concurrently retrieving the information with the speaker. We asked here whether such concurrent retrieval is a function of group membership, thereby underscoring the connection between a basic mnemonic mechanism-retrieval-induced forgetting-and a social function of communicative interaction-building a shared representation. In Experiment 1, Princeton students listening to a speaker selectively recall previously studied material showed SSRIF when the speaker was identified as a fellow Princeton student, but not when he or she was identified as a Yale student. In Experiment 2, activating a common student identity before the listening task triggered concurrent retrieval in Princeton students when listening to both Princeton and Yale speakers. Thus, similar patterns of selective forgetting are more likely to occur between speakers and listeners if they belong to the same social group. Basic mnemonic mechanisms seem to be adapted to promote the emergence of shared mnemonic representations that preserve group membership and group identity. PMID- 25938178 TI - The dynamics of categorization: Unraveling rapid categorization. AB - We explore a puzzle of visual object categorization: Under normal viewing conditions, you spot something as a dog fastest, but at a glance, you spot it faster as an animal. During speeded category verification, a classic basic-level advantage is commonly observed (Rosch, Mervis, Gray, Johnson, & Boyes-Braem, 1976), with categorization as a dog faster than as an animal (superordinate) or Golden Retriever (subordinate). A different story emerges during ultra-rapid categorization with limited exposure duration (<30 ms), with superordinate categorization faster than basic or subordinate categorization (Thorpe, Fize, & Marlot, 1996). These two widely cited findings paint contrary theoretical pictures about the time course of categorization, yet no previous study has investigated them together. We systematically examined two experimental factors that could explain the qualitative difference in categorization across the two paradigms: exposure duration and category trial context. Mapping out the time course of object categorization by manipulating exposure duration and the timing of a post-stimulus mask revealed that brief exposure durations favor superordinate-level categorization, but with more time a basic-level advantage emerges. However, these advantages were modulated by category trial context. With randomized target categories, the superordinate advantage was eliminated; and with only four repetitions of superordinate categorization within an otherwise randomized context, the basic-level advantage was eliminated. Contrary to theoretical accounts that dictate a fixed priority for certain levels of abstraction in visual processing and access to semantic knowledge, the dynamics of object categorization are flexible, depending jointly on the level of abstraction, time for perceptual encoding, and category context. PMID- 25938180 TI - Distant but relative: Similarities and differences in gender role beliefs among African American and Vietnamese American women. AB - OBJECTIVES: Research attempting to identify similarities or disentangle differences in ethnic minority gender role beliefs has been largely absent in the literature, and a gap remains for qualitative examinations of such phenomena. The purpose of this study is to fill this gap in the literature by providing a qualitative examination of the differences and similarities of gender role beliefs among African American and Vietnamese American women. METHODS: Thematic analyses were conducted with data gathered from 8 focus groups with 44 African American women (mean age = 44 years) and 4 focus Groups 47 Vietnamese American women (mean age = 42 years). Women were diverse in generational, religious, and educational backgrounds. RESULTS: Two similar primary themes emerged: (a) women's roles as chief caretakers and (b) women's responsibility to fulfill multiple roles. There were also similar experiences of a need to convey strength and be self-sacrificial. Two distinct differences that emerged from the focus groups were beliefs about interpersonal interactions and perceptions of societal expectations. CONCLUSIONS: This study demonstrates that the conceptualization of gender role beliefs, although at times similar, diverges among culturally different groups. To account for these and other culturally nuanced differences, measures of gender role beliefs should be culturally tailored and culturally specific. However, researchers have largely excluded ethnic minority women in the development of the most widely used measures of gender role beliefs in the U.S. The inclusion of diverse women in research will help prevent pitfalls of conflating and ignoring intragroup differences among different groups of marginalized women. PMID- 25938181 TI - Enhancement and Mitigation Mechanisms of Protein Fouling of Ultrafiltration Membranes under Different Ionic Strengths. AB - To determine further the enhancement and mitigation mechanisms of protein fouling, filtration experiments were carried out with polyvinylidene fluoride (PVDF) ultrafiltration (UF) membranes and bovine serum albumin (BSA) over a range of ionic strengths. The interaction forces, the adsorption behavior of BSA on the membrane surface, and the structure of the BSA adsorbed layers at corresponding ionic strengths were investigated. Results indicate that when the ionic strength increased from 0 to 1 mM, there was a decrease in the PVDF-BSA and BSA-BSA electrostatic repulsion forces, resulting in a higher deposition rate of BSA onto the membrane surface, and the formation of a denser BSA layer; consequently, membrane fouling was enhanced. However, at ionic strengths of 10 and 100 mM, membrane fouling and the BSA removal rate decreased significantly. This was mainly due to the increased hydration repulsion forces, which caused a decrease in the PVDF-BSA and BSA-BSA interaction forces accompanied by a decreased hydrodynamic radius and increased diffusion coefficient of BSA. Consequently, BSA passed more easily through the membrane and into permeate. There was less accumulation of BSA on the membrane surface. A more nonrigid and open structure BSA layer was formed on the membrane surface. PMID- 25938182 TI - Label-free nanopore proximity bioassay for platelet-derived growth factor detection. AB - Rapid and sensitive detection of biomarkers with ultralow concentrations remains a great challenge in disease diagnostics. Herein, we present a label-free alpha hemolysin (alpha-HL) nanopore proximity bioassay for protein biomarker detection by a binding-induced DNA strand displacement strategy. In this bioassay, an individual target protein, platelet-derived growth factor B-chain (PDGF-BB), was selectively recognized by two oligonucleotide affinity ligands in which an output DNA was released and translocated through alpha-HL nanopore with a spikelike short current block. The frequency of the current block events had a linear relationship with the concentration of PDGF-BB with a wide linear dynamic range of 5 orders of magnitude and a detection limit at 500 fM. The selectivity and anti-interference capability of this bioassay show great potential for biomarker detection in bioanalytical chemistry. PMID- 25938183 TI - Breathing new perspectives into chronic obstructive pulmonary disease. PMID- 25938184 TI - Safety of metformin in patients with chronic obstructive pulmonary disease and type 2 diabetes mellitus. AB - Type 2 diabetes mellitus (T2DM) is commonly associated with chronic obstructive pulmonary disease (COPD). Metformin is a valuable treatment for T2DM, and may offer additional benefits in COPD. However, due to its rare association with lactic acidosis, its safety in COPD is uncertain. We retrospectively identified patients with T2DM who had been admitted to hospital for COPD exacerbations. We compared those who were taking metformin with those who were not, with respect to their lactate concentration (primary endpoint) and survival (secondary endpoint). The study cohort (n = 130) had a mean (+/-standard deviation) age of 73.0 +/- 9.8 years and 47 (36%) were female. Arterial blood gases were recorded in 120 cases: 88 (73%) were hypoxemic, 45 (38%) were in respiratory failure and 33 (28%) had respiratory acidosis. The 51 patients (39%) in the metformin group had a median (interquartile range) lactate concentration of 1.45 mmol/L (1.10-2.05) versus 1.10 mmol/L (0.80-1.50) in the non-metformin group (p = 0.012). Median survival was 5.2 years (95% CI 4.5-5.8) versus 1.9 years (1.1-2.6), respectively (hazard ratio 0.57; 95% CI 0.35-0.94). This remained significant in a multivariate model adjusted for measurable confounders. In conclusion, among patients with COPD at high risk for lactate accumulation, metformin therapy was associated with a minor elevation of lactate concentration of doubtful clinical significance. Metformin was associated with a survival benefit, but this must be interpreted cautiously due to possible effects from unmeasured confounders. Viewed collectively, the results suggest that COPD should not present a barrier to the investigational or clinical use of metformin. PMID- 25938185 TI - Ultrasound based assessment of coronary artery flow and coronary flow reserve using the pressure overload model in mice. AB - Transthoracic Doppler echocardiography (TTDE) is a clinically useful, noninvasive tool for studying coronary artery flow velocity and coronary flow reserve (CFR) in humans. Reduced CFR is accompanied by marked intramyocardial and pericoronary fibrosis and is used as an indication of the severity of dysfunction. This study explores, step-by-step, the real-time changes measured in the coronary flow velocity, CFR and systolic to diastolic peak velocity (S/D) ratio in the setting of an aortic banding model in mice. By using a Doppler transthoracic imaging technique that yields reproducible and reliable data, the method assesses changes in flow in the septal coronary artery (SCA), for a period of over two weeks in mice, that previously either underwent aortic banding or thoracotomy. During imaging, hyperemia in all mice was induced by isoflurane, an anesthetic that increased coronary flow velocity when compared with resting flow. All images were acquired by a single imager. Two ratios, (1) CFR, the ratio between hyperemic and baseline flow velocities, and (2) systolic (S) to diastolic (D) flow were determined, using a proprietary software and by two independent observers. Importantly, the observed changes in coronary flow preceded LV dysfunction as evidenced by normal LV mass and fractional shortening (FS). The method was benchmarked against the current gold standard of coronary assessment, histopathology. The latter technique showed clear pathologic changes in the coronary artery in the form of peri-coronary fibrosis that correlated to the flow changes as assessed by echocardiography. The study underscores the value of using a non-invasive technique to monitor coronary circulation in mouse hearts. The method minimizes redundant use of research animals and demonstrates that advanced ultrasound-based indices, such as CFR and S/D ratios, can serve as viable diagnostic tools in a variety of investigational protocols including drug studies and the study of genetically modified strains. PMID- 25938186 TI - Weighing patients within cognitive-behavioural therapy for eating disorders: How, when and why. AB - While weight, beliefs about weight and weight changes are key issues in the pathology and treatment of eating disorders, there is substantial variation in whether and how psychological therapists weigh their patients. This review considers the reasons for that variability, highlighting the differences that exist in clinical protocols between therapies, as well as levels of reluctance on the part of some therapists and patients. It is noted that there have been substantial changes over time in the recommendations made within therapies, including cognitive-behavioural therapy (CBT). The review then makes the case for all CBT therapists needing to weigh their patients in session and for the patient to be aware of their weight, in order to give the best chance of cognitive, emotional and behavioural progress. Specific guidance is given as to how to weigh, stressing the importance of preparation of the patient and presentation, timing and execution of the task. Consideration is given to reasons that clinicians commonly report for not weighing patients routinely, and counter arguments and solutions are presented. Finally, there is consideration of procedures to follow with some special groups of patients. PMID- 25938187 TI - Mindfulness and acceptance-based group therapy and traditional cognitive behavioral group therapy for social anxiety disorder: Mechanisms of change. AB - The present study investigated mechanisms of change for two group treatments for social anxiety disorder (SAD): cognitive behavioral group therapy (CBGT) and mindfulness and acceptance-based group therapy (MAGT). Participants were treatment completers (n = 37 for MAGT, n = 32 for CBGT) from a randomized clinical trial. Cognitive reappraisal was the hypothesized mechanism of change for CBGT. Mindfulness and acceptance were hypothesized mechanisms of change for MAGT. Latent difference score (LDS) analysis results demonstrate that cognitive reappraisal coupling (in which cognitive reappraisal is negatively associated with the subsequent rate of change in social anxiety) had a greater impact on social anxiety for CBGT than MAGT. The LDS bidirectional mindfulness model (mindfulness predicts subsequent change in social anxiety; social anxiety predicts subsequent change in mindfulness) was supported for both treatments. Results for acceptance were less clear. Cognitive reappraisal may be a more important mechanism of change for CBGT than MAGT, whereas mindfulness may be an important mechanism of change for both treatments. PMID- 25938188 TI - The modified hole board--measuring behavior, cognition and social interaction in mice and rats. AB - This protocol describes the modified hole board (mHB), which combines features from a traditional hole board and open field and is designed to measure multiple dimensions of unconditioned behavior in small laboratory mammals (e.g., mice, rats, tree shrews and small primates). This paradigm is a valuable alternative for the use of a behavioral test battery, since a broad behavioral spectrum of an animal's behavioral profile can be investigated in one single test. The apparatus consists of a box, representing the 'protected' area, separated from a group compartment. A board, on which small cylinders are staggered in three lines, is placed in the center of the box, representing the 'unprotected' area of the set up. The cognitive abilities of the animals can be measured by baiting some cylinders on the board and measuring the working and reference memory. Other unconditioned behavior, such as activity-related-, anxiety-related- and social behavior, can be observed using this paradigm. Behavioral flexibility and the ability to habituate to a novel environment can additionally be observed by subjecting the animals to multiple trials in the mHB, revealing insight into the animals' adaptive capacities. Due to testing order effects in a behavioral test battery, naive animals should be used for each individual experiment. By testing multiple behavioral dimensions in a single paradigm and thereby circumventing this issue, the number of experimental animals used is reduced. Furthermore, by avoiding social isolation during testing and without the need to food deprive the animals, the mHB represents a behavioral test system, inducing if any, very low amount of stress. PMID- 25938189 TI - Longitudinal analysis of latent classes of psychopathology and patterns of class migration in survivors of severe injury. AB - OBJECTIVE: Little research to date has explored the typologies of psychopathology following trauma, beyond development of particular diagnoses such as posttraumatic stress disorder (PTSD). The objective of this study was to determine the longitudinal patterns of these typologies, especially the movement of persons across clusters of psychopathology. METHOD: In this 6-year longitudinal study, 1,167 hospitalized severe injury patients who were recruited between April 2004-February 2006 were analyzed, with repeated measures at baseline, 3 months, 12 months, and 72 months after injury. All patients met the DSM-IV criterion A1 for PTSD. Structured clinical interviews were used to assess psychiatric disorders at each follow-up point. Latent class analysis and latent transition analysis were applied to assess clusters of individuals determined by psychopathology. The Mini International Neuropsychiatric Interview (MINI) and Clinician-Administered PTSD Scale (CAPS) were employed to complete diagnoses. RESULTS: Four latent classes were identified at each time point: (1) Alcohol/Depression class (3 months, 2.1%; 12 months, 1.3%; and 72 months, 1.1%), (2) Alcohol class (3 months, 3.3%; 12 months, 3.7%; and 72 months, 5.4%), (3) PTSD/Depression class (3 months, 10.3%; 12 months, 11.5%; and 72 months, 6.4%), and (4) No Disorder class (3 months, 84.2%; 12 months, 83.5%; and 72 months, 87.1%). Latent transition analyses conducted across the 2 transition points (12 months and 72 months) found consistently high levels of stability in the No Disorder class (90.9%, 93.0%, respectively) but lower and reducing levels of consistency in the PTSD/Depression class (81.3%, 46.6%), the Alcohol/Depression class (59.7%, 21.5%), and the Alcohol class (61.0%, 36.5%), demonstrating high levels of between-class migration. CONCLUSIONS: Despite the array of psychiatric disorders that may develop following severe injury, a 4-class model best described the data with excellent classification certainty. The high levels of migration across classes indicate a complex pattern of psychopathology expression over time. The findings have considerable implications for tailoring multifocused interventions to class type, as well as flexible stepped care models, and for the potential development and delivery of transdiagnostic interventions targeting underlying mechanisms. PMID- 25938190 TI - Gene delivery to rat and human Schwann cells and nerve segments: a comparison of AAV 1-9 and lentiviral vectors. AB - Schwann cells (SCs) in an injured peripheral nerve form pathways for regenerating axons. Although these cells initially support regeneration, SCs lose their pro regenerative properties following a prolonged period of denervation. Gene transfer to SC can enhance their therapeutic potential. In this article, we compared adeno-associated viral (AAV) vectors based on serotypes 1-9 for their capability to transduce cultured primary rat and human SCs and nerve segments. AAV1 is the best serotype to transduce rat SCs, whereas AAV2 and AAV6 performed equally well in human SCs. Transduction of monolayers of cultured rat and human SCs did not accurately predict the transduction efficiency in nerve segments. Rat nerve segments could be genetically modified equally well by a set of four AAV vectors (AAV1, AAV5, AAV7, AAV9), whereas AAV2 was superior in human nerve segments. The current experiments were undertaken as a first step towards future clinical implementation of ex vivo AAV-based gene therapy in surgical nerve repair. The transduction of rat and human SCs and nerve segments by entirely different AAV serotypes, as documented here, highlights one of the challenges of translating gene therapy from experimental animals to human patients. PMID- 25938191 TI - Single-step cloning-screening method: a new tool for developing and studying high titer viral vector producer cells. AB - This article describes a novel method merging the cloning of viral vector producer cells with vector titer screening, allowing for screening 200-500 clones in 2 weeks. It makes use of a GFP separated into two fragments, S10 and S11 (Split GFP), fluorescing only upon transcomplementation. Producer cells carrying a S11 viral transgene are cloned in 96-well plates and co-cultured with target cells stably expressing S10. During the period of clone expansion, S11 viruses infect S10 target cells reconstituting the GFP signal. Transcomplemented fluorescence data provide direct estimation of the clone's productivity and can be analyzed in terms of density distribution, offering valuable information on the average productivity of the cell population and allowing the identification of high-producing clones. The method was validated by establishing a retrovirus producer from a nude cell line, in <3 months, inserting three vector constructs without clone selection or screening in between. Clones producing up to 10(8) infectious particles per ml were obtained, delivering optimal ratios of infectious-to-total particles (1 to 5). The method was additionally used to evaluate the production performance of HEK 293 and HEK 293T cell lines demonstrating that the latter sustains increased titers. Finally, it was used to study genetic manipulation of glutathione metabolism in retrovirus production showing that changing cell metabolism steers higher vector expression with titer increases of more than one order of magnitude.This method is a valuable tool not only for cell line development but also for genetic manipulation of viral vector and/or producer cells contributing to advancing the field of viral gene therapy. PMID- 25938192 TI - Safety and antitumor effect of oncolytic and helper-dependent adenoviruses expressing interleukin-12 variants in a hamster pancreatic cancer model. AB - Gene transfer of potent immunostimulatory cytokines such as interleukin-12 (IL 12) is a potential treatment for advanced cancer. Different vectors and IL-12 modifications have been developed to avoid side effects associated with high serum levels of the cytokine, while preserving its antitumor properties. Here we have evaluated two alternative strategies using the Syrian hamster as a model for pancreatic cancer metastatic to the liver. Local administration of an oncolytic adenovirus (OAV) expressing a single-chain version of IL-12 caused transient, very intense elevations of IL-12 in serum, resulting in severe toxicity at sub therapeutic doses. Anchoring IL-12 to the membrane of infected cells by fusion with the transmembrane domain of CD4 reduced systemic exposure to IL-12 and increased the tolerance to the OAV. However, only a modest increase in the therapeutic range was achieved because antitumor potency was also reduced. In contrast, systemic administration of a helper-dependent adenoviral vector (HDAd) equipped with a Mifepristone-inducible expression system allowed sustained and controlled IL-12 production from the liver. This treatment was well tolerated and inhibited the progression of hepatic metastases. We conclude that HDAds are safer than OAVs for the delivery of IL-12, and are promising vectors for immunogene therapy approaches against pancreatic cancer. PMID- 25938195 TI - Care and Outcomes of Patients With In-Hospital Stroke. AB - IMPORTANCE: A sizeable minority of strokes occur in hospitalized patients. However, little is known about the presentation, care, and outcomes of stroke in this subgroup of patients. OBJECTIVE: To examine stroke care delivery and outcomes for patients with in-hospital vs community-onset stroke. DESIGN, SETTING, AND PARTICIPANTS: Prospective cohort study of all patients older than 18 years with acute stroke seen in the emergency department or admitted to the hospital at participating centers (all regional stroke centers in Ontario, Canada) between July 1, 2003, and March 31, 2012, including those with stroke onset during hospitalization for another cause. MAIN OUTCOMES AND MEASURES: We compared processes of stroke care delivery, including time to neuroimaging and rates of thrombolysis, as well as outcomes, including death and disability, in those with in-hospital vs community-onset stroke. We used multiple logistic regression models to adjust for age, sex, comorbid conditions, and stroke type and severity. RESULTS: The study sample included 973 patients with in-hospital stroke and 28 837 with community-onset stroke. Patients with in-hospital stroke compared with those with community-onset stroke had significantly longer waiting times from symptom recognition to neuroimaging (median, 4.5 vs 1.2 hours; P < .001; for <2 hours, 32% vs 63%; adjusted odds ratio [AOR] = 0.21; 95% CI, 0.18 0.24), lower use of thrombolysis (12% vs 19% of those with ischemic stroke; AOR = 0.54; 95% CI, 0.43-0.67; P < .001), and longer time from stroke recognition to administration of thrombolysis (median, 2.0 vs 1.2 hours; P < .001). After adjustment for age, stroke severity, and other factors, mortality rates at 30 days and 1 year after stroke were similar in those with in-hospital stroke and community-onset stroke; however, those with in-hospital stroke had a longer median length of stay following stroke onset (17 vs 8 days; P < .001), were more likely to be dead or disabled at discharge (77% vs 65% with modified Rankin Scale score of 3-6; AOR = 1.64; 95% CI, 1.38-1.96; P < .001), and were less likely to be discharged home from the hospital (35% vs 44%; AOR = 0.76; 95% CI, 0.64-0.90; P < .001). CONCLUSIONS AND RELEVANCE: Compared with those with community-onset stroke, patients with in-hospital stroke had delays in investigations and treatment, suggesting a need for a standardized approach to the recognition and management of in-hospital stroke, with the aim of ensuring access to rapid acute stroke care. PMID- 25938193 TI - Local delivery of the Neuregulin1 receptor ecto-domain (ecto-ErbB4) has a positive effect on regenerated nerve fiber maturation. AB - The Neuregulin/ErbB system plays an important role in the peripheral nervous system, under both normal and pathological conditions. We previously demonstrated that expression of soluble ecto-ErbB4, the released extracellular fragment of the ErbB4 receptor, stimulated glial cell migration in vitro. In this study we examined the possibility of manipulating this system in vivo in order to improve injured peripheral nerve regeneration. Transected rat median nerves of adult female Wistar rats were repaired with a 10-mm-long graft made by muscle-in-vein combined nerve guide previously transduced with either the adeno-associated viral (AAV) vector AAV2-LacZ or AAV2-ecto-ErbB4. Autologous nerve grafts were used as control. Both stereological and functional analyses were performed to assess nerve regeneration. Data show that delivery of soluble ecto-ErbB4 by gene transfer in the muscle-in-vein combined nerve guide has a positive effect on fiber maturation, suggesting that it could represent a potential tool for improving peripheral nerve regeneration. PMID- 25938194 TI - Broadly Conserved Fungal Effector BEC1019 Suppresses Host Cell Death and Enhances Pathogen Virulence in Powdery Mildew of Barley (Hordeum vulgare L.). AB - The interaction of barley, Hordeum vulgare L., with the powdery mildew fungus Blumeria graminis f. sp. hordei is a well-developed model to investigate resistance and susceptibility to obligate biotrophic pathogens. The 130-Mb Blumeria genome encodes approximately 540 predicted effectors that are hypothesized to suppress or induce host processes to promote colonization. Blumeria effector candidate (BEC)1019, a single-copy gene encoding a putative, secreted metalloprotease, is expressed in haustorial feeding structures, and host induced gene silencing of BEC1019 restricts haustorial development in compatible interactions. Here, we show that Barley stripe mosaic virus-induced gene silencing of BEC1019 significantly reduces fungal colonization of barley epidermal cells, demonstrating that BEC1019 plays a central role in virulence. In addition, delivery of BEC1019 to the host cytoplasm via Xanthomonas type III secretion suppresses cultivar nonspecific hypersensitive reaction (HR) induced by Xanthomonas oryzae pv. oryzicola, as well as cultivar-specific HR induced by AvrPphB from Pseudomonas syringae pv. phaseolicola. BEC1019 homologs are present in 96 of 241 sequenced fungal genomes, including plant pathogens, human pathogens, and free-living nonpathogens. Comparative analysis revealed variation at several amino acid positions that correlate with fungal lifestyle and several highly conserved, noncorrelated motifs. Site-directed mutagenesis of one of these, ETVIC, compromises the HR-suppressing activity of BEC1019. We postulate that BEC1019 represents an ancient, broadly important fungal protein family, members of which have evolved to function as effectors in plant and animal hosts. PMID- 25938196 TI - Approach to thyroid cytology: rationale for standardisation. PMID- 25938197 TI - A resonant pressure microsensor capable of self-temperature compensation. AB - Resonant pressure microsensors are widely used in the fields of aerospace exploration and atmospheric pressure monitoring due to their advantages of quasi digital output and long-term stability, which, however, requires the use of additional temperature sensors for temperature compensation. This paper presents a resonant pressure microsensor capable of self-temperature compensation without the need for additional temperature sensors. Two doubly-clamped "H" type resonant beams were arranged on the pressure diaphragm, which functions as a differential output in response to pressure changes. Based on calibration of a group of intrinsic resonant frequencies at different pressure and temperature values, the functions with inputs of two resonant frequencies and outputs of temperature and pressure under measurement were obtained and thus the disturbance of temperature variations on resonant frequency shifts was properly addressed. Before compensation, the maximal errors of the measured pressure values were over 1.5% while after compensation, the errors were less than 0.01% of the full pressure scale (temperature range of -40 degrees C to 70 degrees C and pressure range of 50 kPa to 110 kPa). PMID- 25938198 TI - Sensitive, fast, and specific immunoassays for methyltestosterone detection. AB - An indirect competitive enzyme-linked immunosorbent assay (icELISA) and an immunochromatographic strip assay using a highly specific monoclonal antibody, were developed to detect methyltestosterone (MT) residues in animal feed. The optimized icELISA had a half-inhibition concentration value of 0.26 ng/mL and a limit of detection value of 0.045 ng/mL. There was no cross-reactivity with eight analogues, revealing high specificity for MT. Based on icELISA results, the recovery rate of MT in animal feed was 82.4%-100.6%. The results were in accordance with those obtained by gas chromatography-mass spectrometry. The developed immunochromatographic strip assay, as the first report for MT detection, had a visual cut-off value of 1 ng/mL in PBS, 2.5 ng/g in fish feed, and 2.5 ng/g in pig feed. Therefore, these immunoassays are useful and fast tools for MT residue detection in animal feed. PMID- 25938199 TI - A New Indoor Positioning System Architecture Using GPS Signals. AB - The pseudolite system is a good alternative for indoor positioning systems due to its large coverage area and accurate positioning solution. However, for common Global Positioning System (GPS) receivers, the pseudolite system requires some modifications of the user terminals. To solve the problem, this paper proposes a new pseudolite-based indoor positioning system architecture. The main idea is to receive real-world GPS signals, repeat each satellite signal and transmit those using indoor transmitting antennas. The transmitted GPS-like signal can be processed (signal acquisition and tracking, navigation data decoding) by the general receiver and thus no hardware-level modification on the receiver is required. In addition, all Tx can be synchronized with each other since one single clock is used in Rx/Tx. The proposed system is simulated using a software GPS receiver. The simulation results show the indoor positioning system is able to provide high accurate horizontal positioning in both static and dynamic situations. PMID- 25938200 TI - Silver Nanoparticle-Enhanced Resonance Raman Sensor of Chromium(III) in Seawater Samples. AB - Tris(hydroxymethyl)aminomethane ethylenediaminetetraacetic acid (Tris-EDTA), upon binding Cr(III) in aqueous solutions at pH 8.0 on silver nanoparticles (AgNPs), was found to provide a sensitive and selective Raman marker band at ~563 cm-1, which can be ascribed to the metal-N band. UV-Vis absorption spectra also supported the aggregation and structural change of EDTA upon binding Cr(III). Only for Cr(III) concentrations above 500 nM, the band at ~563 cm-1 become strongly intensified in the surface-enhanced Raman scattering spectra. This band, due to the metal-EDTA complex, was not observed in the case of 50 mM of K+, Cd2+, Mg2+, Ca2+, Mn2+, Co2+, Na+, Cu2+, NH4+, Hg2+, Ni2+, Fe3+, Pb2+, Fe2+, and Zn2+ ions. Seawater samples containing K, Mg, Ca, and Na ion concentrations higher than 8 mM also showed the characteristic Raman band at ~563 cm-1 above 500 nM, validating our method. Our approach may be useful in detecting real water samples by means of AgNPs and Raman spectroscopy. PMID- 25938201 TI - Unsupervised classification of surface defects in wire rod production obtained by eddy current sensors. AB - An unsupervised approach to classify surface defects in wire rod manufacturing is developed in this paper. The defects are extracted from an eddy current signal and classified using a clustering technique that uses the dynamic time warping distance as the dissimilarity measure. The new approach has been successfully tested using industrial data. It is shown that it outperforms other classification alternatives, such as the modified Fourier descriptors. PMID- 25938202 TI - Joint infrared target recognition and segmentation using a shape manifold-aware level set. AB - We propose new techniques for joint recognition, segmentation and pose estimation of infrared (IR) targets. The problem is formulated in a probabilistic level set framework where a shape constrained generative model is used to provide a multi class and multi-view shape prior and where the shape model involves a couplet of view and identity manifolds (CVIM). A level set energy function is then iteratively optimized under the shape constraints provided by the CVIM. Since both the view and identity variables are expressed explicitly in the objective function, this approach naturally accomplishes recognition, segmentation and pose estimation as joint products of the optimization process. For realistic target chips, we solve the resulting multi-modal optimization problem by adopting a particle swarm optimization (PSO) algorithm and then improve the computational efficiency by implementing a gradient-boosted PSO (GB-PSO). Evaluation was performed using the Military Sensing Information Analysis Center (SENSIAC) ATR database, and experimental results show that both of the PSO algorithms reduce the cost of shape matching during CVIM-based shape inference. Particularly, GB PSO outperforms other recent ATR algorithms, which require intensive shape matching, either explicitly (with pre-segmentation) or implicitly (without pre segmentation). PMID- 25938203 TI - Reduction of Central Venous Catheter Use in Medical Inpatients Through Regular Physician Audits Using an Online Tool. PMID- 25938204 TI - Cyber victimization by peers: Prospective associations with adolescent social anxiety and depressive symptoms. AB - Peer victimization that occurs via electronic media, also termed cybervictimization, is a growing area of concern for adolescents. The current study evaluated the short-term prospective relationship between cybervictimization and adolescents' symptoms of social anxiety and depression over a six-week period. Participants were 839 high-school aged adolescents (14-18 years; 58% female; 73% Hispanic White), who completed measures of traditional peer victimization, cybervictimization, depression, and social anxiety at two time points. Findings supported the distinctiveness of cybervictimization as a unique form of peer victimization. Furthermore, only cybervictimization was associated with increased levels of depressive symptoms over time, and only relational victimization was associated with increased social anxiety over time, after controlling for the comorbidity of social anxiety and depression among youth. Cybervictimization appears to be a unique form of victimization that contributes to adolescents' depressive symptoms and may be important to target in clinical and preventive interventions for adolescent depression. PMID- 25938205 TI - Multidistance diffuse correlation spectroscopy for simultaneous estimation of blood flow index and optical properties. AB - Traditionally, diffuse correlation spectroscopy (DCS) measures microvascular blood flow by fitting a physical model to the measurement of the intensity autocorrelation function from a single source-detector pair. This analysis relies on the accurate knowledge of the optical properties, absorption, and reduced scattering coefficients of the medium. Therefore, DCS is often deployed together with diffuse optical spectroscopy. We present an algorithm that employs multidistance DCS (MD-DCS) for simultaneous measurement of bloodflow index, as well as an estimate of the optical properties of the tissue. The algorithm has been validated through noise-free and noise-added simulated data and phantom measurements. A longitudinal in vivo measurement ofa mouse tumor is also shown. MD-DCS is introduced as a stand-alone system for small source-detector separations (<2 cm) for noninvasive measurement of microvascular blood flow. PMID- 25938206 TI - Differentiation of MCF-7 tumor cells from leukocytes and fibroblast cells using epithelial cell adhesion molecule targeted multicore surface-enhanced Raman spectroscopy labels. AB - Identification of tumor and normal cells is a promising application of Raman spectroscopy. The throughput of Raman-assisted cell sorting is limited by low sensitivity. Surface-enhanced Raman spectroscopy (SERS) is a well-recognized candidate to increase the intensity of Raman signals of cells. First, different strategies are summarized to detect tumor cells using targeted SERS probes. Then, a protocol is described to prepare multicore-SERS-labels (MSLs) by aggregating gold nanoparticles, coating with a reporter molecule and a thin silver shell to further boost enhancement, encapsulating with a stable silica layer, and functionalizing by epithelial cell adhesion molecule (EpCAM) antibodies. Raman, dark field and fluorescence microscopy proved the specific and nonspecific binding of functionalized and nonfunctionalized MSLs to MCF-7 tumor cells, leukocytes from blood, and nontransformed human foreskin fibroblasts. Raman imaging and dark field microscopy indicated no uptake of MSLs, yet binding to the cellular membrane. Viability tests were performed with living tumor cells to demonstrate the low toxicity of MSL-EpCAM. The SERS signatures were detected from cells with exposure times down to 25 ms at 785-nm laser excitation. The prospects of these MSLs in multiplex assays, for enumeration and sorting of circulating tumor cells in microfluidic chips, are discussed. PMID- 25938207 TI - Optical detection of middle ear infection using spectroscopic techniques: phantom experiments. AB - A noninvasive optical technique, which is based on a combination of reflectance spectroscopy and gas in scattering media absorption spectroscopy, is demonstrated. It has the potential to improve diagnostics of middle ear infections. An ear phantom prepared with a tissue cavity, which was covered with scattering material, was used for spectroscopic measurements. Diffuse reflectance spectra of the phantom eardrum were measured with a reflectance probe. The presence of oxygen and water vapor as well as gas exchange in the phantom cavity were studied with a specially designed fiber-optic probe for backscattering detection geometry. The results suggest that this method can be developed for improved clinical detection of middle ear infection. PMID- 25938208 TI - Sources of variability in the quantification of tissue optical properties by multidiameter single-fiber reflectance and fluorescence spectroscopy. AB - Recently, a multidiameter single-fiber reflectance and fluorescence spectroscopy device has been developed that enabled us to extract the autofluorescence of tissue that is corrected for the optical properties. Such a system has been incorporated in the population-based Rotterdam Study to investigate the autofluorescence of the skin. Since the device will be used by different operators over many years, it is essential that the results are comparable between users. It is, however, unclear how different methods of handling the probe might influence the outcome. Variability of blood oxygen saturation, blood volume fraction and vessel diameter, average gamma, reduced scattering coefficient at 800 nm, and integrated intrinsic fluorescence measured in three volunteers were assessed within and between eight untrained users. A variability of less than one standard deviation from the group mean was defined as an acceptable limit. Three mature volunteers were also included to assess the intrauser variability of mature skin. The variation in the measured parameters suggests that variation is dominated by tissue heterogeneity. Most users measured within one standard deviation of the group mean. Notably, corrected intrinsic fluorescence showed low intra- and interuser variability. These results strongly suggest that variability is mostly caused by tissue heterogeneity and is not user induced. PMID- 25938209 TI - Testing sensory and multisensory function in children with autism spectrum disorder. AB - In addition to impairments in social communication and the presence of restricted interests and repetitive behaviors, deficits in sensory processing are now recognized as a core symptom in autism spectrum disorder (ASD). Our ability to perceive and interact with the external world is rooted in sensory processing. For example, listening to a conversation entails processing the auditory cues coming from the speaker (speech content, prosody, syntax) as well as the associated visual information (facial expressions, gestures). Collectively, the "integration" of these multisensory (i.e., combined audiovisual) pieces of information results in better comprehension. Such multisensory integration has been shown to be strongly dependent upon the temporal relationship of the paired stimuli. Thus, stimuli that occur in close temporal proximity are highly likely to result in behavioral and perceptual benefits--gains believed to be reflective of the perceptual system's judgment of the likelihood that these two stimuli came from the same source. Changes in this temporal integration are expected to strongly alter perceptual processes, and are likely to diminish the ability to accurately perceive and interact with our world. Here, a battery of tasks designed to characterize various aspects of sensory and multisensory temporal processing in children with ASD is described. In addition to its utility in autism, this battery has great potential for characterizing changes in sensory function in other clinical populations, as well as being used to examine changes in these processes across the lifespan. PMID- 25938210 TI - Dual-Energy Multidetector-Row Computed Tomography of the Hepatic Arterial System: Optimization of Energy and Material-Specific Reconstruction Techniques. AB - PURPOSE: To investigate the optimal dual-energy reconstruction technique for the visualization of the hepatic arterial system during dual-energy multidetector computed tomographic (MDCT) angiography of the liver. MATERIALS AND METHODS: Twenty-nine nonconsecutive patients underwent dual-energy MDCT angiography of the liver. Synthesized monochromatic (40, 50, 60, and 80 keV) and iodine density data sets were reconstructed. Aortic attenuation, noise, and contrast-to-noise ratio (CNR) were measured. In addition, volume-rendered images were generated and qualitatively assessed by 2 independent readers, blinded to technique. The impact of body size on the readers' scores was also assessed. RESULTS: Aortic attenuation, noise, and CNR increased progressively with decreasing keV and were significantly higher between 40 and 60 keV (P < 0.001). There was a significant improvement of readers' visualization of arterial anatomy at lower monochromatic energies (P < 0.001). Iodine density images yielded significantly higher CNR compared with all monochromatic data sets (P < 0.001). However, iodine density images were scored nondiagnostic by the 2 readers. CONCLUSIONS: Synthesized monochromatic images between 40 and 60 keV maximize the magnitude of arterial enhancement and improve visualization of hepatic arterial anatomy at dual-energy MDCT angiography of the liver. Larger body sizes may counteract the benefits of using lower monochromatic energies. PMID- 25938211 TI - Low-Dose Computed Tomography With Adaptive Statistical Iterative Reconstruction and Low Tube Voltage in Craniocervical Computed Tomographic Angiography: Impact of Body Mass Index. AB - OBJECTIVES: To assess radiation dose and image quality using Adaptive Statistical Iterative Reconstruction (ASIR) in craniocervical computed tomographic angiography and to further evaluate the impact of body mass index (BMI) on image quality. METHODS: A total of 178 consecutive patients (112 men, 66 women; age range, 25-79 years) were enrolled in this prospective study and randomly divided into 2 groups: group A (conventional group): 120 kV, filtered back-projection reconstruction, and group B (low-dose group): 100 kV, 40% ASIR reconstruction. Radiation dose and image quality between groups A and B were compared. Correlation coefficients were calculated between quantitative image quality measurement and BMI, and between radiation dose and BMI using Pearson correlation. Two experienced radiologists independently evaluated the image quality with 4-point scores, and interrater reliability was calculated using kappa analysis. RESULTS: The volume CT dose index, dose-length product, and effective dose of group B were lower than those of group A (each P < 0.01), with decreases of 23.99%, 25.15% and 25.47% respectively. Positive correlations existed between radiation dose and BMI for both groups A and B (each P < 0.01). Group B had lower image noise, higher attenuation, higher signal-to-noise ratio (SNR) and contrast-to-noise ratio (CNR), and higher subjective score than did group A (each P < 0.01). Computed tomographic values had negative correlations with BMI for the head, neck, and shoulders in both groups A and B (each P < 0.01). Image noise, SNR, and CNR had no correlations with BMI for the head and neck in both groups (each P > 0.01). On the contrary, image noise had a positive correlation, and SNR and CNR had a negative correlations with BMI for the shoulders in group A (each P < 0.01), but in contrast, no such correlations were found in group B (each P > 0.01). CONCLUSIONS: In craniocervical CTA, ASIR can improve the image quality and reduce radiation dose in patients. Furthermore, ASIR reduced the variances of image quality of different body sizes in the shoulders. PMID- 25938212 TI - Multiparametric Prostate Magnetic Resonance Imaging at 3 T: Failure of Magnetic Resonance Spectroscopy to Provide Added Value. AB - PURPOSE: To assess the effect of proton magnetic resonance spectroscopy imaging (MRSI) on the accuracy of multiparametric magnetic resonance imaging (mpMRI) at 3 T for prostate cancer detection. MATERIALS AND METHODS: Thirty-four patients with prostate cancer were included in this retrospective study. All patients underwent preoperative mpMRI on a 3-T scanner before radical prostatectomy. Magnetic resonance imaging evaluation was based on the prostate imaging-reporting and data system classification system. The accuracy of mpMRI with and without MRSI was determined using receiver operating characteristic analysis, with histology as the reference standard. RESULTS: Multiparametric MRI including MRSI had a sensitivity of 57.0% and a specificity of 89.2% for sextant-based cancer detection. Multiparametric MRI without MRSI had a sensitivity of 58.1% and a specificity of 87.4%. There was no significant difference regarding the accuracy of mpMRI with and without MRSI (P = 0.48). CONCLUSION: The addition of MRSI does not improve the accuracy of 3 T mpMRI for sextant localization of prostate cancer. PMID- 25938213 TI - Effect of Reducing Field of View on Multidetector Quantitative Computed Tomography Parameters of Airway Wall Thickness in Asthma. AB - OBJECTIVE: We reduced the computed tomography (CT)-reconstructed field of view (FOV), increasing pixel density across airway structures and reducing partial volume effects, to determine whether this would improve accuracy of airway wall thickness quantification. METHODS: We performed CT imaging on a lung phantom and 29 participants. Images were reconstructed at 30-, 15-, and 10-cm FOV using a medium-smooth kernel. Cross-sectional airway dimensions were compared at each FOV with repeated-measures analysis of variance. RESULTS: Phantom measurements were more accurate when FOV decreased from 30 to 15 cm (P < 0.05). Decreasing FOV further to 10 cm did not significantly improve accuracy. Human airway measurements similarly decreased by decreasing FOV (P < 0.001). Percent changes in all measurements when reducing FOV from 30 to 15 cm were less than 3%. CONCLUSIONS: Airway measurements at 30-cm FOV are near the limits of CT resolution using a medium-smooth kernel. Reducing reconstructed FOV would minimally increase sensitivity to detect differences in airway dimensions. PMID- 25938214 TI - Automatic exposure control systems designed to maintain constant image noise: effects on computed tomography dose and noise relative to clinically accepted technique charts. AB - OBJECTIVE: To compare computed tomography dose and noise arising from use of an automatic exposure control (AEC) system designed to maintain constant image noise as patient size varies with clinically accepted technique charts and AEC systems designed to vary image noise. MATERIALS AND METHODS: A model was developed to describe tube current modulation as a function of patient thickness. Relative dose and noise values were calculated as patient width varied for AEC settings designed to yield constant or variable noise levels and were compared to empirically derived values used by our clinical practice. Phantom experiments were performed in which tube current was measured as a function of thickness using a constant-noise-based AEC system and the results were compared with clinical technique charts. RESULTS: For 12-, 20-, 28-, 44-, and 50-cm patient widths, the requirement of constant noise across patient size yielded relative doses of 5%, 14%, 38%, 260%, and 549% and relative noises of 435%, 267%, 163%, 61%, and 42%, respectively, as compared with our clinically used technique chart settings at each respective width. Experimental measurements showed that a constant noise-based AEC system yielded 175% relative noise for a 30-cm phantom and 206% relative dose for a 40-cm phantom compared with our clinical technique chart. CONCLUSIONS: Automatic exposure control systems that prescribe constant noise as patient size varies can yield excessive noise in small patients and excessive dose in obese patients compared with clinically accepted technique charts. Use of noise-level technique charts and tube current limits can mitigate these effects. PMID- 25938215 TI - Procedure-oriented torsional anatomy of the proximal arm for spasticity injection. AB - This is the first in a series of papers related to the new concept of "torsional" anatomy. The objective of this article is to provide musculoskeletal ultrasound (MSKUS) anatomy of the upper arm in the position of hemispastic flexion as a reference relevant to needle procedures. METHODS: The MSKUS images were obtained in a healthy human subject. A pair of MSKUS images was recorded for each level: the first in anatomic neutral and second in hemispastic position. RESULTS: At the proximal 1/3 level of the upper arm, the pectoralis major rotated out of view. At the middle of the upper arm, the biceps rotated medially, and the brachialis rotated from far lateral to the middle of the screen. At the distal 1/3 level of the upper arm, the radial nerve rotated more anteriorly. At the distal 1/6 level of the upper arm, the biceps shifted and was replaced by the brachialis and brachioradialis. The radial nerve also rotated more anteriorly and superficially. DISCUSSION: With torsion, it is possible that intended muscle targets, such as the pectoralis, are missed, and unintended targets, such as the radial nerve, are accidentally injected in the upper arm. CONCLUSIONS: It is hoped that this series of images will increase the accuracy and safety of needle placement for spasticity and nerve block injections in the proximal upper arm. PMID- 25938216 TI - Morphological Characteristics of Round Window Niche in Congenital Aural Atresia and Stenosis Patients. AB - OBJECTIVE: The aim of this study was to measure the round window niche (RWN) among congenital aural atresia (CAA), congenital aural stenosis (CAS) and control groups and to analyze whether differences exist between them. METHODS: Computed tomography images of 10 normal subjects (20 ears), 27 CAS patients (30 ears) and 25 CAA patients (30 ears) were analyzed. We measured RWN on the basis of 3 dimensional reconstruction. RESULTS: The anterior wall length and the depth of RWN were smaller in control group than those in the CAS group; furthermore, the anterior wall length and the depth of RWN in CAS group were smaller than those in CAA group (P < 0.05). The posterior wall length of RWN was found smaller in the control group than that in both hCAS and CAA groups (P < 0.05). The superior and inferior wall lengths of RWN were found smaller in control group than those in the CAA group (P < 0.05). There were no statistically significant differences in the sizes of the round window membrane and niche opening or the angle between the plane of the RWN opening and the round window membrane plane among all groups. CONCLUSIONS: The RWN walls lengths and its depth tended to be longer with the aggravation of the aural malformations. Our calculation results may provide some information for a better design and a safer implantation of the floating mass transducer in the area of RWN. PMID- 25938218 TI - First trimester erythropoietin (EPO) serum concentration as a potential marker for abnormal placentation disorders. Reference values for erythropoietin (EPO) concentration at 11-13+6 weeks of gestation. AB - OBJECTIVES: To investigate the possible effect of abnormal placentation disorders such as preeclampsia (PE), pregnancy induced hypertension (PIH) and intrauterine growth restriction (IUGR) on erythropoietin (EPO) serum concentration in women in the first trimester of pregnancy. MATERIAL AND METHODS: A prospective study was performed in a group of pregnant women between 11 and 13+6 weeks' gestation. Serum concentration of EPO, beta HCG, PAPP-A and PlGF was measured. Mean arterial pressure (MAP) and uterine artery pulsatility index was calculated. RESULTS: A group of 198 analyzed patients was divided into three groups depending on pregnancy outcome: abnormal placentation group (n=30), macrosomia (n=13) and control group (n=155). EPO concentrations between the three groups of patients revealed that they differ significantly (F=15.172, P<0.001). EPO concentration is significantly higher in abnormal placentation patients compared to the control group (P<0.001) and macrosomia group (P=0.004). The most significant increase in EPO concentration was detected within patients with PIH. Also the uterine artery pulsatility index was positively correlated with EPO concentration (P<0.01). CONCLUSIONS: First-trimester maternal EPO concentration might be considered as a possible marker of abnormal placentation disorders and should be given more attention in future prospective studies. PMID- 25938219 TI - A special issue on gestational diabetes. PMID- 25938220 TI - The molecular medicine of acid ceramidase. AB - Acid ceramidase (N-acylsphingosine deacylase, EC 3.5.1.23; AC) is the lipid hydrolase responsible for the degradation of ceramide into sphingosine and free fatty acids within lysosomes. The enzymatic activity was first identified over four decades ago and is deficient in two rare inherited disorders, Farber lipogranulomatosis (Farber disease) and spinal muscular atrophy with myoclonic epilepsy (SMA-PME). Importantly, AC not only hydrolyzes ceramide into sphingosine within acidic compartments, but also can synthesize ceramide from sphingosine at neutral pH, suggesting that the enzyme may have diverse functions depending on its subcellular location and the local pH. Within cells, AC exists in a complex with other lipid hydrolases and requires a polypeptide cofactor (saposin D) for full hydrolytic activity. Recent studies also have shown that AC is overexpressed in several human cancers, and that inhibition of this enzyme may be a useful cancer drug target. Aberrant AC activity has also been described in several other common diseases. The cDNA and gene (ASAH1) encoding AC have been isolated, several mouse models of AC deficiency have been constructed, and the recombinant enzyme is currently being manufactured for the treatment of Farber disease and SMA-PME. Current information concerning the biology of this enzyme and its role in human disease is reviewed within. PMID- 25938221 TI - Modeling gene-covariate interactions in sparse regression with group structure for genome-wide association studies. AB - In genome-wide association studies (GWAS), it is of interest to identify genetic variants associated with phenotypes. For a given phenotype, the associated genetic variants are usually a sparse subset of all possible variants. Traditional Lasso-type estimation methods can therefore be used to detect important genes. But the relationship between genotypes at one variant and a phenotype may be influenced by other variables, such as sex and life style. Hence it is important to be able to incorporate gene-covariate interactions into the sparse regression model. In addition, because there is biological knowledge on the manner in which genes work together in structured groups, it is desirable to incorporate this information as well. In this paper, we present a novel sparse regression methodology for gene-covariate models in association studies that not only allows such interactions but also considers biological group structure. Simulation results show that our method substantially outperforms another method, in which interaction is considered, but group structure is ignored. Application to data on total plasma immunoglobulin E (IgE) concentrations in the Framingham Heart Study (FHS), using sex and smoking status as covariates, yields several potentially interesting gene-covariate interactions. PMID- 25938217 TI - Clinical chorioamnionitis at term II: the intra-amniotic inflammatory response. AB - OBJECTIVE: Recent studies indicate that clinical chorioamnionitis is a heterogeneous condition and only approximately one-half of the patients have bacteria in the amniotic cavity, which is often associated with intra-amniotic inflammation. The objective of this study is to characterize the nature of the inflammatory response within the amniotic cavity in patients with clinical chorioamnionitis at term according to the presence or absence of 1) bacteria in the amniotic cavity and 2) intra-amniotic inflammation. MATERIALS AND METHODS: A retrospective cross-sectional case-control study was conducted to examine cytokine and chemokine concentrations in the amniotic fluid (AF). Cases consisted of women with clinical chorioamnionitis at term (n=45). Controls were women with uncomplicated pregnancies at term who did not have intra-amniotic inflammation and were in labor (n=24). Women with clinical chorioamnionitis were classified according to the results of AF cultures, broad-range polymerase chain reaction coupled with electrospray ionization mass spectrometry, and AF concentration of interleukin-6 (IL-6) into those: 1) without intra-amniotic inflammation, 2) with microbial-associated intra-amniotic inflammation, and 3) with intra-amniotic inflammation without detectable bacteria. The AF concentrations of 29 cytokines/chemokines were determined using sensitive and specific V-PLEX immunoassays. RESULTS: 1) The AF concentrations of pro- and anti-inflammatory cytokines/chemokines such as interferon gamma (IFN-gamma), tumor necrosis factor alpha (TNF-alpha), interleukin-4 (IL-4), macrophage inflammatory protein-1 beta (MIP-1beta), and interleukin-8 (IL-8) (except Eotaxin-3) were significantly higher in women with clinical chorioamnionitis at term than in controls (term labor without intra-amniotic inflammation); 2) patients with microbial-associated intra-amniotic inflammation, and those with intra-amniotic inflammation without detectable bacteria, had a dramatic differential expression of cytokines and chemokines in AF compared to patients with spontaneous labor without intra amniotic inflammation. However, no difference could be detected in the pattern of the intra-amniotic inflammatory response between patients with intra-amniotic inflammation with and without detectable bacteria; and 3) in patients with clinical chorioamnionitis at term but without intra-amniotic inflammation, the behavior of cytokines and chemokines in the AF was similar to those in spontaneous labor at term. CONCLUSIONS: Patients with clinical chorioamnionitis who had microbial-associated intra-amniotic inflammation or intra-amniotic inflammation without detectable bacteria had a dramatic upregulation of the intra amniotic inflammatory response assessed by amniotic fluid concentrations of cytokines. A subset of patients with term clinical chorioamnionitis does not have intra-amniotic infection/inflammation, as demonstrated by elevated AF concentrations of inflammation-related proteins, when compared to women in term labor with uncomplicated pregnancies, suggesting over-diagnosis. These observations constitute the first characterization of the cytokine/chemokine network in the amniotic cavity of patients with clinical chorioamnionitis at term. PMID- 25938222 TI - In vitro assessment of CYP1A2 and 2C9 inhibition potential of Withania somnifera and Centella asiatica in human liver microsomes. AB - BACKGROUND: Several herbal drugs and allopathic medicines when co-administered can lead to severe herb-drug interactions. Hence, this study was undertaken in order to assess the in vitro inhibition potential of Withania somnifera and Centella asiatica with cytochrome P450 (CYP) 1A2 and 2C9 enzyme using human liver microsomes. METHODS: Inhibitory potential of crude extracts of both the medicinal plants along with their principal phytoconstituents were investigated using selective probe substrate technique. IC50, Ki values and mode of inhibition were determined. RESULTS: The results of the study revealed that W. somnifera showed no significant interaction with both the isoforms of CYP. However, ethanolic extract of C. asiatica significantly inhibited both CYP1A2 (IC50 value - 42.23+/ 3.65 MUg/mL/Ki value - 14.93+/-4.59 MUg/mL) and 2C9 enzyme (IC50 value - 48.41+/ 4.64 MUg/mL/Ki value - 23.89+/-3.14 MUg/mL) in a competitive manner. The flavonoids, quercetin and kaempferol showed potent (IC50 values less than 10 MUM) inhibition of CYP1A2 activity with no significant inhibition of CYP2C9 enzyme. CONCLUSIONS: Thus, these findings of the study might be helpful for safe and effective use of C. asiatica in clinical practice. However, its in vivo interaction study in humans is still warranted. PMID- 25938223 TI - A Proteoliposome-Based Efflux Assay to Determine Single-molecule Properties of Cl Channels and Transporters. AB - The last 15 years have been characterized by an explosion in the ability to overexpress and purify membrane proteins from prokaryotic organisms as well as from eukaryotes. This increase has been largely driven by the successful push to obtain structural information on membrane proteins. However, the ability to functionally interrogate these proteins has not advanced at the same rate and is often limited to qualitative assays of limited quantitative value, thereby limiting the mechanistic insights that they can provide. An assay to quantitatively investigate the transport activity of reconstituted Cl(-) channels or transporters is described. The assay is based on the measure of the efflux rate of Cl(-) from proteoliposomes following the addition of the K(+) ionophore valinomycin to shunt the membrane potential. An ion sensitive electrode is used to follow the time-course of ion efflux from proteoliposomes reconstituted with the desired protein. The method is highly suited for mechanistic studies, as it allows for the quantitative determination of key properties of the reconstituted protein, such as its unitary transport rate, the fraction of active protein and the molecular mass of the functional unit. The assay can also be utilized to determine the effect of small molecule compounds that directly inhibit/activate the reconstituted protein, as well as to test the modulatory effects of the membrane composition or lipid-modifying reagents. Where possible, direct comparison between results obtained using this method were found to be in good agreement with those obtained using electrophysiological approaches. The technique is illustrated using CLC-ec1, a CLC-type H(+)/Cl(-) exchanger, as a model system. The efflux assay can be utilized to study any Cl(-) conducting channel/transporter and, with minimal changes, can be adapted to study any ion transporting protein. PMID- 25938225 TI - Fabrication of Two-Component, Brush-on-Brush Topographical Microstructures by Combination of Atom-Transfer Radical Polymerization with Polymer End Functionalization and Photopatterning. AB - Poly(oligoethylene glycol methyl ether methacrylate) (POEGMEMA) brushes, grown from silicon oxide surfaces by surface-initiated atom transfer radical polymerization (SI-ATRP), were end-capped by reaction with sodium azide leading to effective termination of polymerization. Reduction of the terminal azide to an amine, followed by derivatization with the reagent of choice, enabled end functionalization of the polymers. Reaction with bromoisobutryl bromide yielded a terminal bromine atom that could be used as an initiator for ATRP with a second, contrasting monomer (methacrylic acid). Attachment of a nitrophenyl protecting group to the amine facilitated photopatterning: when the sample was exposed to UV light through a mask, the amine was deprotected in exposed regions, enabling selective bromination and the growth of a patterned brush by ATRP. Using this approach, micropatterned pH-responsive poly(methacrylic acid) (PMAA) brushes were grown on a protein resistant planar poly(oligoethylene glycol methyl ether methacrylate) (POEGMEMA) brush. Atomic force microscopy analysis by tapping mode and PeakForce quantitative nanomechanical mapping (QNM) mode allowed topographical verification of the spatially specific secondary brush growth and its stimulus responsiveness. Chemical confirmation of selective polymer growth was achieved by secondary ion mass spectrometry (SIMS). PMID- 25938224 TI - Investigating the function of deep cortical and subcortical structures using stereotactic electroencephalography: lessons from the anterior cingulate cortex. AB - Stereotactic Electroencephalography (SEEG) is a technique used to localize seizure foci in patients with medically intractable epilepsy. This procedure involves the chronic placement of multiple depth electrodes into regions of the brain typically inaccessible via subdural grid electrode placement. SEEG thus provides a unique opportunity to investigate brain function. In this paper we demonstrate how SEEG can be used to investigate the role of the dorsal anterior cingulate cortex (dACC) in cognitive control. We include a description of the SEEG procedure, demonstrating the surgical placement of the electrodes. We describe the components and process required to record local field potential (LFP) data from consenting subjects while they are engaged in a behavioral task. In the example provided, subjects play a cognitive interference task, and we demonstrate how signals are recorded and analyzed from electrodes in the dorsal anterior cingulate cortex, an area intimately involved in decision-making. We conclude with further suggestions of ways in which this method can be used for investigating human cognitive processes. PMID- 25938226 TI - Aquareovirus NS80 Initiates Efficient Viral Replication by Retaining Core Proteins within Replication-Associated Viral Inclusion Bodies. AB - Viral inclusion bodies (VIBs) are specific intracellular compartments for reoviruses replication and assembly. Aquareovirus nonstructural protein NS80 has been identified to be the major constituent for forming globular VIBs in our previous study. In this study, we investigated the role of NS80 in viral structural proteins expression and viral replication. Immunofluorescence assays showed that NS80 could retain five core proteins or inner-capsid proteins (VP1 VP4 and VP6), but not outer-capsid proteins (VP5 and VP7), within VIBs in co transfected or infected cells. Further co-immunoprecipitation analysis confirmed that NS80 could interact with each core protein respectively. In addition, we found that newly synthesized viral RNAs co-localized with VIBs. Furthermore, time course analysis of viral structural proteins expression showed that the expression of NS80 was detected first, followed by the detection of inner shell protein VP3, and then of other inner-capsid proteins, suggesting that VIBs were essential for the formation of viral core frame or progeny virion. Moreover, knockdown of NS80 by shRNA not only inhibited the expression of aquareovirus structural proteins, but also inhibited viral infection. These results indicated that NS80-based VIBs were formed at earlier stage of infection, and NS80 was able to coordinate the expression of viral structural proteins and viral replication. PMID- 25938227 TI - Risk of Active Tuberculosis in HIV-Infected Patients in Taiwan with Free Access to HIV Care and a Positive T-Spot.TB Test. AB - BACKGROUND: Interferon-gamma release assays (IGRAs) have been used to identify individuals at risk for developing active tuberculosis (TB). However, data regarding the risk of TB development in HIV-infected patients testing positive for IGRAs remain sparse in the era of combination antiretroviral therapy. METHODS: Between 2011 and 2013, 608 HIV-infected patients without active TB undergoing T-Spot.TB testing were enrolled in this prospective observational study at a university hospital designated for HIV care in Taiwan with a declining TB incidence from 72 per 100,000 population in 2005 to 53 per 100,000 population in 2012. All of the subjects were followed until September 30, 2014. The national TB registry was accessed to identify any TB cases among those lost to follow-up. RESULTS: T-Spot.TB tested negative in 534 patients (87.8%), positive in 64 patients (10.5%), and indeterminate in 10 patients (1.6%). In multivariate analysis, positive T-Spot.TB was significantly associated with older age (adjusted odds ratio [AOR], 1.172 per 10-year increase; 95% confidence interval [CI], 1.022-1.344, P=0.023), past history of TB (AOR, 13.412; 95% CI, 6.106 29.460, P<0.001), and higher CD4 counts at enrollment (AOR, per 50-cell/MUl increase, 1.062; 95% CI, 1.017-1.109, P=0.007). Of the 64 patients testing positive for T-Spot.TB, none received isoniazid preventive therapy and all but 5 received combination antiretroviral therapy at the end of follow-up with the latest CD4 count and plasma HIV RNA load being 592.8 cells/MUL and 1.85 log10 copies/mL, respectively. One patient (1.6%) developed active TB after 167 person years of follow-up (PYFU), resulting in an incidence rate of 0.599 per 100 PFYU. None of the 534 patients testing negative for T-Spot.TB developed TB after 1380 PYFU, nor did the 24 patients with old TB and positive T-Spot.TB tests develop TB after 62.33 PYFU. CONCLUSIONS: The risk of developing active TB in HIV-infected patients with positive T-Spot.TB receiving combination antiretroviral therapy is low in Taiwan where the national TB program has led to a sustained decrease in TB incidence. PMID- 25938228 TI - A Synthetic Lethal Screen Identifies a Role for Lin-44/Wnt in C. elegans Embryogenesis. AB - BACKGROUND: The C. elegans proteins PTP-3/LAR-RPTP and SDN-1/Syndecan are conserved cell adhesion molecules. Loss-of-function (LOF) mutations in either ptp 3 or sdn-1 result in low penetrance embryonic developmental defects. Work from other systems has shown that syndecans can function as ligands for LAR receptors in vivo. We used double mutant analysis to test whether ptp-3 and sdn-1 function in a linear genetic pathway during C. elegans embryogenesis. RESULTS: We found animals with LOF in both sdn-1 and ptp-3 exhibited a highly penetrant synthetic lethality (SynLet), with only a small percentage of animals surviving to adulthood. Analysis of the survivors demonstrated that these animals had a synergistic increase in the penetrance of embryonic developmental defects. Together, these data strongly suggested PTP-3 and SDN-1 function in parallel during embryogenesis. We subsequently used RNAi to knockdown ~3,600 genes predicted to encode secreted and/or transmembrane molecules to identify genes that interacted with ptp-3 or sdn-1. We found that the Wnt ligand, lin-44, was SynLet with sdn-1, but not ptp-3. We used 4-dimensional time-lapse analysis to characterize the interaction between lin-44 and sdn-1. We found evidence that loss of lin-44 caused defects in the polarization and migration of endodermal precursors during gastrulation, a previously undescribed role for lin-44 that is strongly enhanced by the loss of sdn-1. CONCLUSIONS: PTP-3 and SDN-1 function in compensatory pathways during C. elegans embryonic and larval development, as simultaneous loss of both genes has dire consequences for organismal survival. The Wnt ligand lin-44 contributes to the early stages of gastrulation in parallel to sdn-1, but in a genetic pathway with ptp-3. Overall, the SynLet phenotype provides a robust platform to identify ptp-3 and sdn-1 interacting genes, as well as other genes that function in development, yet might be missed in traditional forward genetic screens. PMID- 25938229 TI - The Reduction of Peripheral Blood CD4+ T Cell Indicates Persistent Organ Failure in Acute Pancreatitis. AB - OBJECTIVE: Few data are available on the potential role of inflammatory mediators and T lymphocytes in persistent organ failure (POF) in acute pancreatitis (AP). We conducted a retrospective study to characterize their role in the progression of POF in AP. METHODS: A total of 69 AP patients presented within 24 hours from symptom onset developing organ failure (OF) on admission were included in our study. There were 39 patients suffering from POF and 30 from transient OF (TOF). On the 1st, 3rd and 7th days after admission, blood samples were collected for biochemical concentration monitoring including serum IL-1beta, IL-6, TNF-alpha and high-sensitivity C-reactive protein (hs-CRP). The proportions of peripheral CD4(+) and CD8(+) T lymphocytes were assessed based on flow cytometry simultaneously. RESULTS: Patients with POF showed a significantly higher value of IL-1beta and hs-CRP on day 7 compared with the group of TOF (P < 0.05). Proportions of CD4(+) T cells on days 1, 3, 7 and CD4(+)/ CD8(+) ratio on day 1 were statistically lower in the group of POF patients (P < 0.05). A CD4(+) T cell proportion of 30.34% on day 1 predicted POF with an area under the curve (AUC) of 0.798, a sensitivity with 61.54% and specificity with 90.00%, respectively. CONCLUSIONS: The reduction of peripheral blood CD4(+) T lymphocytes is associated with POF in AP, and may act as a potential predictor. PMID- 25938230 TI - Free Levels of Selected Organic Solutes and Cardiovascular Morbidity and Mortality in Hemodialysis Patients: Results from the Retained Organic Solutes and Clinical Outcomes (ROSCO) Investigators. AB - BACKGROUND AND OBJECTIVES: Numerous substances accumulate in the body in uremia but those contributing to cardiovascular morbidity and mortality in dialysis patients are still undefined. We examined the association of baseline free levels of four organic solutes that are secreted in the native kidney - p-cresol sulfate, indoxyl sulfate, hippurate and phenylacetylglutamine - with outcomes in hemodialysis patients. DESIGN, SETTING, PARTICIPANTS AND MEASUREMENTS: We measured these solutes in stored specimens from 394 participants of a US national prospective cohort study of incident dialysis patients. We examined the relation of each solute and a combined solute index to cardiovascular mortality and morbidity (first cardiovascular event) using Cox proportional hazards regression adjusted for demographics, comorbidities, clinical factors and laboratory tests including Kt/VUREA. RESULTS: Mean age of the patients was 57 years, 65% were white and 55% were male. In fully adjusted models, a higher p-cresol sulfate level was associated with a greater risk (HR per SD increase; 95% CI) of cardiovascular mortality (1.62; 1.17-2.25; p=0.004) and first cardiovascular event (1.60; 1.23-2.08; p<0.001). A higher phenylacetylglutamine level was associated with a greater risk of first cardiovascular event (1.37; 1.18-1.58; p<0.001). Patients in the highest quintile of the combined solute index had a 96% greater risk of cardiovascular mortality (1.96; 1.05-3.68; p=0.04) and 62% greater risk of first cardiovascular event (1.62; 1.12-2.35; p=0.01) compared with patients in the lowest quintile. Results were robust in sensitivity analyses. CONCLUSIONS: Free levels of uremic solutes that are secreted by the native kidney are associated with a higher risk of cardiovascular morbidity and mortality in incident hemodialysis patients. PMID- 25938231 TI - Manipulation of the rice L-galactose pathway: evaluation of the effects of transgene overexpression on ascorbate accumulation and abiotic stress tolerance. AB - Ascorbic acid (AsA) is the most abundant water-soluble antioxidant in plants, and it plays a crucial role in plant growth, development and abiotic stress tolerance. In the present study, six key Arabidopsis or rapeseed genes involved in AsA biosynthesis were constitutively overexpressed in an elite Japonica rice cultivar. These genes encoded the GDP-mannose pyrophosphorylase (GMP), GDP mannose-3',5'-epimerase (GME), GDP-L-galactose phosphorylase (GGP), L-galactose-1 phosphate phosphatase (GPP), L-galactose dehydrogenase (GDH), and L-galactono-1,4 lactone dehydrogenase (GalLDH). The effects of transgene expression on rice leaf AsA accumulation were carefully evaluated. In homozygous transgenic seedlings, AtGGP transgenic lines had the highest AsA contents (2.55-fold greater than the empty vector transgenic control), followed by the AtGME and AtGDH transgenic lines. Moreover, with the exception of the AtGPP lines, the increased AsA content also provoked an increase in the redox state (AsA/DHA ratio). To evaluate salt tolerance, AtGGP and AtGME transgenic seedlings were exposed to salt stress for one week. The relative plant height, root length and fresh weight growth rates were significantly higher for the transgenic lines compared with the control plants. Altogether, our results suggest that GGP may be a key rate-limiting step in rice AsA biosynthesis, and the plants with elevated AsA contents demonstrated enhanced tolerance for salt stress. PMID- 25938232 TI - Cruzipain Activates Latent TGF-beta from Host Cells during T. cruzi Invasion. AB - Several studies indicate that the activity of cruzipain, the main lysosomal cysteine peptidase of Trypanosoma cruzi, contributes to parasite infectivity. In addition, the parasitic invasion process of mammalian host cells is described to be dependent on the activation of the host TGF-beta signaling pathway by T. cruzi. Here, we tested the hypothesis that cruzipain could be an important activator of latent TGF-beta and thereby trigger TGF-beta-mediated events crucial for the development of Chagas disease. We found that live epimastigotes of T. cruzi, parasite lysates and purified cruzipain were able to activate latent TGF beta in vitro. This activation could be inhibited by the cysteine peptidase inhibitor Z-Phe-Ala-FMK. Moreover, transfected parasites overexpressing chagasin, a potent endogenous cruzipain inhibitor, prevented latent TGF-beta activation. We also observed that T. cruzi invasion, as well as parasite intracellular growth, were inhibited by the administration of Z-Phe-Ala-FMK or anti-TGF-beta neutralizing antibody to Vero cell cultures. We further demonstrated that addition of purified cruzipain enhanced the invasive activity of trypomastigotes and that this effect could be completely inhibited by addition of a neutralizing anti-TGF-beta antibody. Taken together, these results demonstrate that the activities of cruzipain and TGF-beta in the process of cell invasion are functionally linked. Our data suggest that cruzipain inhibition is an interesting chemotherapeutic approach for Chagas disease not only because of its trypanocidal activity, but also due to the inhibitory effect on TGF-beta activation. PMID- 25938233 TI - A Pilot Study to Evaluate Haemostatic Function, following Shock Wave Lithotripsy (SWL) for the Treatment of Solitary Kidney Stones. AB - PURPOSE: The number of patients undergoing shock wave lithotripsy (SWL) in the UK for solitary unilateral kidney stones is increasing annually. The development of postoperative complications such as haematuria and sepsis following SWL is likely to increase. Comparing a range of biological markers with the aim of monitoring or predicting postoperative complications following SWL has not been extensively researched. The main purpose of this pilot-study was to test the hypothesis that SWL results in changes to haemostatic function. Subsequently, this pilot-study would form a sound basis to undertake future investigations involving larger cohorts. METHODS: Twelve patients undergoing SWL for solitary unilateral kidney stones were recruited. From patients (8 male and 4 females) aged between 31-72 years (median-43 years), venous blood samples were collected pre-operatively (baseline), at 30, 120 and 240 minutes postoperatively. Specific haemostatic biomarkers [platelet counts, prothrombin time (PT), activated partial thromboplastin time (aPTT), fibrinogen, D-dimer, von Willebrand Factor (vWF), sE selectin and plasma viscosity (PV)] were measured. RESULTS: Platelet counts and fibrinogen concentration were significantly decreased following SWL (p = 0.027 and p = 0.014 respectively), while D-dimer and vWF levels significantly increased following SWL (p = 0.019 and p = 0.001 respectively). PT, APTT, sE-selectin and PV parameters were not significantly changed following SWL (p>0.05). CONCLUSIONS: Changes to specific biomarkers such as plasma fibrinogen and vWF suggest that these represent a more clinically relevant assessment of the extent of haemostatic involvement following SWL. Analysis of such markers, in the future, may potentially provide valuable data on "normal" response after lithotripsy, and could be expanded to identify or predict those patients at risk of coagulopathy following SWL. The validation and reliability will be assessed through the assessment of larger cohorts. PMID- 25938234 TI - Pentacyclic Triterpenoids Inhibit IKKbeta Mediated Activation of NF-kappaB Pathway: In Silico and In Vitro Evidences. AB - Pentacyclic Triterpenoids (PTs) and their analogues as well as derivatives are emerging as important drug leads for various diseases. They act through a variety of mechanisms and a majority of them inhibit the nuclear factor kappa-beta (NF kappaB) signaling pathway. In this study, we examined the effects of the naturally occurring PTs on IkappaB kinase-beta (IKKbeta), which has great scientific relevance in the NF-kappaB signaling pathway. On virtual screening, 109 PTs were screened through the PASS (prediction of activity spectra of substances) software for prediction of NF-kappaB inhibitory activity followed by docking on the NEMO/IKKbeta association complex (PDB: 3BRV) and testing for compliance with the softened Lipinski's Rule of Five using Schrodinger (LLC, New York, USA). Out of the projected 45 druggable PTs, Corosolic Acid (CA), Asiatic Acid (AA) and Ursolic Acid (UA) were assayed for IKKbeta kinase activity in the cell free medium. The UA exhibited a potent IKKbeta inhibitory effect on the hotspot kinase assay with IC50 of 69 MUM. Whereas, CA at 50 MUM concentration markedly reduced the NF-kappaB luciferase activity and phospho-IKKbeta protein expressions. The PTs tested, attenuated the expression of the NF-kappaB cascade proteins in the LPS-stimulated RAW 264.7 cells, prevented the phosphorylation of the IKKalpha/beta and blocked the activation of the Interferon-gamma (IFN-gamma). The results suggest that the IKKbeta inhibition is the major mechanism of the PTs induced NF-kappaB inhibition. PASS predictions along with in-silico docking against the NEMO/IKKbeta can be successfully applied in the selection of the prospective NF-kappaB inhibitory downregulators of IKKbeta phosphorylation. PMID- 25938235 TI - Forced fusion in multisensory heading estimation. AB - It has been shown that the Central Nervous System (CNS) integrates visual and inertial information in heading estimation for congruent multisensory stimuli and stimuli with small discrepancies. Multisensory information should, however, only be integrated when the cues are redundant. Here, we investigated how the CNS constructs an estimate of heading for combinations of visual and inertial heading stimuli with a wide range of discrepancies. Participants were presented with 2s visual-only and inertial-only motion stimuli, and combinations thereof. Discrepancies between visual and inertial heading ranging between 0-90 degrees were introduced for the combined stimuli. In the unisensory conditions, it was found that visual heading was generally biased towards the fore-aft axis, while inertial heading was biased away from the fore-aft axis. For multisensory stimuli, it was found that five out of nine participants integrated visual and inertial heading information regardless of the size of the discrepancy; for one participant, the data were best described by a model that explicitly performs causal inference. For the remaining three participants the evidence could not readily distinguish between these models. The finding that multisensory information is integrated is in line with earlier findings, but the finding that even large discrepancies are generally disregarded is surprising. Possibly, people are insensitive to discrepancies in visual-inertial heading angle because such discrepancies are only encountered in artificial environments, making a neural mechanism to account for them otiose. An alternative explanation is that detection of a discrepancy may depend on stimulus duration, where sensitivity to detect discrepancies differs between people. PMID- 25938236 TI - Prevalence of Thymine--Adenine Dinucleotide Repeat, IL28B and IFNL4 in Thai Population and Correlation with Spontaneous Clearance and Treatment Outcome of Hepatitis C Infection. AB - BACKGROUND: The interleukin-28B (IL28B) gene polymorphism is a strong baseline predictor of sustained virological response (SVR) in hepatitis C virus (HCV) treatment. The length of thymine--adenine dinucleotide repeats, or (TA)n, in the regulatory region of IL28B can affect interferon transcription. In order to determine predictive values in HCV infection, we explored the correlation among factors including (TA)n genotypes, clinical features, interferon-lambda-3 (IFNL3) and interferon-lambda-4 (IFNL4) polymorphisms, and HCV treatment outcome. METHODS: Sera from 492 patients with chronic HCV infection, 101 individuals with spontaneous HCV clearance and 123 healthy blood donors (control group) were analyzed. Genotyping of the (TA)n was performed by direct sequencing. The rs12979860 (IFNL3) was identified using nested PCR and sequencing, while ss469415590 (IFNL4) was identified by real-time PCR. RESULTS: The distribution of (TA)n was similar between individuals with spontaneous HCV clearance and chronic HCV infection, but differed significantly from healthy controls. Individuals with both (TA)n alleles >= 12 had significantly higher SVR rate compared to individuals with at least one (TA)n <12 allele. This strong correlation was seen for patients infected with HCV-1, HCV-3, and HCV-6. The (TA)n genotypes were not associated with HCV viral load, ALT levels and liver stiffness, but were correlated with platelet counts (p<0.001). In contrast, rs12979860 (CC) and ss469415590 (TT/TT) genotypes were associated with higher SVR rated only in patients with HCV-1. CONCLUSIONS: The (TA)n genotypes were not associated with spontaneous clearance of HCV infection but associated with treatment response in patients infected with HCV-1, HCV-3 and HCV-6. In contrast, IFNL3 and IFNL4 polymorphisms were predictive of treatment outcome only for patients infected with HCV-1. PMID- 25938237 TI - HYS-32-Induced Microtubule Catastrophes in Rat Astrocytes Involves the PI3K GSK3beta Signaling Pathway. AB - HYS-32 is a novel derivative of combretastatin-A4 (CA-4) previously shown to induce microtubule coiling in rat primary astrocytes. In this study, we further investigated the signaling mechanism and EB1, a microtubule-associated end binding protein, involved in HYS-32-induced microtubule catastrophes. Confocal microscopy with double immunofluorescence staining revealed that EB1 accumulates at the growing microtubule plus ends, where they exhibit a bright comet-like staining pattern in control astrocytes. HYS-32 induced microtubule catastrophes in both a dose- and time-dependent manner and dramatically increased the distances between microtubule tips and the cell border. Treatment of HYS-32 (5 MUM) eliminated EB1 localization at the microtubule plus ends and resulted in an extensive redistribution of EB1 to the microtubule lattice without affecting the beta-tubulin or EB1 protein expression. Time-lapse experiments with immunoprecipitation further displayed that the association between EB-1 and beta tubulin was significantly decreased following a short-term treatment (2 h), but gradually increased in a prolonged treatment (6-24 h) with HYS-32. Further, HYS 32 treatment induced GSK3beta phosphorylation at Y216 and S9, where the ratio of GSK3beta-pY216 to GSK3beta-pS9 was first elevated followed by a decrease over time. Co-treatment of astrocytes with HYS-32 and GSK3beta inhibitor SB415286 attenuated the HYS-32-induced microtubule catastrophes and partially prevented EB1 dissociation from the plus end of microtubules. Furthermore, co-treatment with PI3K inhibitor LY294002 inhibited HYS-32-induced GSK3beta-pS9 and partially restored EB1 distribution from the microtubule lattice to plus ends. Together these findings suggest that HYS-32 induces microtubule catastrophes by preventing EB1 from targeting to microtubule plus ends through the GSK3beta signaling pathway. PMID- 25938238 TI - Clinicopathologic Characteristics of Oestrogen Receptor-Positive/Progesterone Receptor-Negative/Her2-Negative Breast Cancer According to a Novel Definition of Negative Progesterone Receptor Status: A Large Population-Based Study from China. AB - PURPOSE: A lack of progesterone receptor (PgR) expression in oestrogen receptor positive (ER+) tumours is associated with worse survival. PgR status is usually defined as positive or negative using 1% positive nuclei as a cut-off point. In this study, we aimed to assess the clinicopathologic characteristics of ER+/PgR /HER2- tumours by comparing them with ER+/PgR+/HER2- tumours using a PgR cut-off point of 20% as a divisive criterion. METHODS: We analysed 1,522 patients with primary breast cancer who had undergone surgery at the Cancer Center of Fudan University between 2012 and 2014. Age, grade, tumour size, lymph node status and lymphovascular invasion were assessed. Multinomial logistic regression, linear regression and chi-square test models were applied to assess associations between ER, PR and clinical features. RESULTS: ER+/PgR-/HER2- tumours showed poorer clinicopathologic characteristics relative to ER+/PgR+/HER2- tumours using a PgR threshold of 20% instead of 1%. The clinicopathologic characteristics did not differ between tumours with purely negative PgR expression and tumours with a PgR percentage ranging from 1% to 19%. The prognostic significance of PR expression appeared more pronounced in patients under a high Ki-67 status than those under a low Ki-67 status. CONCLUSIONS: Based on these findings, we propose the use of a novel threshold of 20% to define PgR status. Nevertheless, the impact of this new criterion on patient management and clinical treatment requires additional study. PMID- 25938239 TI - Proposal of a Nutritional Quality Index (NQI) to Evaluate the Nutritional Supplementation of Sportspeople. AB - BACKGROUND: Numerous supplements are used by sportspeople. They are not always appropriate for the individual or the sports activity and may do more harm than good. Vitamin and mineral supplements are unnecessary if the energy intake is sufficient to maintain body weight and derives from a diet with an adequate variety of foods. The study objectives were to evaluate the main nutrients used as supplements in sports and to propose a nutritional quality index (NQI) that enables sportspeople to optimize their use of supplements and detect and remedy possible nutritional deficits. MATERIAL AND METHODS: A nutritional study was performed in 485 sportspeople recruited from Centros Andaluces de Medicina del Deporte, (CAMD). All completed socio-demographic, food frequency, and lifestyle questionnaires. The nutritional quality of their diet and need for supplementation were evaluated by scoring their dietary intake with and without supplementation, yielding two NQI scores (scales of 0-21 points) for each participant. RESULTS: A superior mean NQI score was obtained when the supplements taken by participants were not included (16. 28 (SD of 3.52)) than when they were included (15.47 (SD: 3.08)), attributable to an excessive intake of some nutrients through supplementation. CONCLUSIONS: These results indicate that sportspeople with a varied and balanced diet do not need supplements, which appear to offer no performance benefits and may pose a health risk. PMID- 25938240 TI - Two methods for engaging with the community in setting priorities for child health research: who engages? AB - OBJECTIVE: The aims of this study were to assess participatory methods for obtaining community views on child health research. BACKGROUND: Community participation in research is recognised as an important part of the research process; however, there has been inconsistency in its implementation and application in Australia. The Western Australian Telethon Kids Institute Participation Program employs a range of methods for fostering active involvement of community members in its research. These include public discussion forums, called Community Conversations. While participation levels are good, the attendees represent only a sub-section of the Western Australian population. Therefore, we conducted a telephone survey of randomly selected households to evaluate its effectiveness in eliciting views from a broader cross-section of the community about our research agenda and community participation in research, and whether the participants would be representative of the general population. We also conducted two Conversations, comparing the survey as a recruitment tool and normal methods using the Participation Program. RESULTS: While the telephone survey was a good method for eliciting community views about research, there were marked differences in the profile of study participants compared to the general population (e.g. 78% vs 50% females). With a 26% response rate, the telephone survey was also more expensive than a Community Conversation. The cold calling approach proved an unsuccessful recruitment method, with only two out of a possible 816 telephone respondents attending a Conversation. CONCLUSION: While the results showed that both of the methods produced useful input for our research program, we could not conclude that either method gained input that was representative of the entire community. The Conversations were relatively low cost and provided more in-depth information about one subject, whereas the telephone survey provided information across a greater range of subjects, and allowed more quantitative analysis. PMID- 25938241 TI - Internet-delivered cognitive-behavioral therapy for social anxiety disorder in Romania: a randomized controlled trial. AB - BACKGROUND AND AIMS: Internet-based cognitive-behavioral therapy (iCBT) for social anxiety disorder has been found effective, as attested by independently conducted randomized controlled trials in four languages. The study aim is to test the efficacy of an iCBT program in a culture where it was not tested before (i.e. Romania). METHODS: Participants (n = 76) were recruited, screened and randomized to either a nine-week guided iCBT or a wait-list control group in April and May 2012. Self-report measures were collected before (April 2012) and after the intervention (July 2012), as well as six months later (January 2013). Although social anxiety was assessed with multiple measures, the Liebowitz Social Anxiety Scale - Self Report version (LSAS-SR) and Social Phobia Inventory (SPIN) were used as the primary outcome measures. RESULTS: A significant difference with a large between-group effect size in favor of iCBT was found (Cohen's d = 1.19 for LSAS-SR and d = 1.27 for SPIN). Recovery rates show that 36.8% (n = 14) in the treatment group score below the SPIN clinical cut-off compared to only 2.6% (n = 1) in the wait-list control group. Post-intervention clinical interviews also revealed that 34.2% (n = 13) of the treatment group was completely recovered (full remission) while additionally 36.8% (n = 14) retained some social anxiety symptoms (partial remission). However, an important study limitation is that post intervention interviewers were not blinded to the study conditions. The program also effectively reduced depression and dysfunctional thinking (between-group Cohen's d = 0.84 for depression and d = 0.63 for dysfunctional thinking). Moreover, the iCBT intervention appears to have a long-term impact for participants' functioning, as the treatment gains were maintained six months later. CONCLUSIONS: Internet-delivered interventions display a high potential to quickly and widely disseminate effective evidence-based programs around the world. This study provides support for guided iCBT as a promising treatment approach in Romania. TRIAL REGISTRATION: ClinicalTrials.gov NCT01557894. PMID- 25938242 TI - ADP-ribosyltransferases and poly ADP-ribosylation. AB - Protein ADP-ribosylation is an important posttranslational modification that plays versatile roles in multiple biological processes. ADP-ribosylation is catalyzed by a group of enzymes known as ADP-ribosyltransferases (ARTs). Using nicotinamide adenine dinucleotide (NAD(+)) as the donor, ARTs covalently link single or multiple ADP-ribose moieties from NAD(+) to the substrates, forming mono ADP-ribosylation or poly ADP-ribosylation (PARylation). Novel functions of ARTs and ADPribosylation have been revealed over the past few years. Here we summarize the current knowledge on ARTs and PARylation. PMID- 25938243 TI - The effects of constraints and mastery on mental and physical health: Conceptual and methodological considerations. AB - Perceived control and health are closely interrelated in adulthood and old age. However, less is known regarding the differential implications of 2 facets of perceived control, constraints and mastery, for mental and physical health. Furthermore, a limitation of previous research testing the pathways linking perceived control to mental and physical health is that mediation was tested with cross-sectional designs and not in a longitudinal mediation design that accounts for temporal ordering and prior confounds. Using data from the Health and Retirement Study (HRS; n = 7,612, M age = 68, SD = 10.66; 59% women) we examined the effect of constraints and mastery on 4-year changes in mental and physical health and whether physical activity mediated such effects in a longitudinal mediation design. Using confirmatory factor analysis, we modeled the 2-factor structure of perceived control that consisted of constraints and mastery. In our longitudinal mediation model, where we accounted for possible confounders (e.g., age, gender, education, neuroticism, conscientiousness, memory, and health conditions), constraints showed a stronger total effect on mental and physical health, than mastery, such that more constraints were associated with 4-year declines in mental and physical health. Physical activity did not mediate the effect of constraints and mastery on mental and physical health (indirect effect). To demonstrate the importance of a longitudinal mediation model that accounts for confounders, we also estimated the mediated effect using 2 models commonly used in the literature: cross-sectional mediation model and longitudinal mediation model without accounting for confounders. These mediation models indicated a spurious indirect effect that cannot be causally interpreted. Our results showcase that constraints and mastery have differential implications for mental and physical health, as well as how a longitudinal mediation design can illustrate (or not) pathways in developmental processes. Our discussion focuses on the conceptual and methodological implications of a 2 facet model of perceived control and the strengths of longitudinal mediation designs for testing conceptual models of human development. PMID- 25938244 TI - Genetic and environmental architecture of changes in episodic memory from middle to late middle age. AB - Episodic memory is a complex construct at both the phenotypic and genetic level. Ample evidence supports age-related cognitive stability and change being accounted for by general and domain-specific factors. We hypothesized that general and specific factors would underlie change even within this single cognitive domain. We examined 6 measures from 3 episodic memory tests in a narrow age cohort at middle and late middle age. The factor structure was invariant across occasions. At both timepoints 2 of 3 test-specific factors (story recall, design recall) had significant genetic influences independent of the general memory factor. Phenotypic stability was moderate to high, and primarily accounted for by genetic influences, except for 1 test-specific factor (list learning). Mean change over time was nonsignificant for 1 test-level factor; 1 declined; 1 improved. The results highlight the phenotypic and genetic complexity of memory and memory change, and shed light on an understudied period of life. PMID- 25938245 TI - Computerized spatial navigation training during 14 days of bed rest in healthy older adult men: Effect on gait performance. AB - Prolonged physical inactivity or bed rest (BR) due to illness or other factors can result in significant declines in physical health and even cognitive functions. Based on random selection, 7 healthy older adult men received computerized spatial navigation training, while 8 served as active controls during 14-day BR. Greater post-BR declines were seen in normal and complex (dual task) walking for the control as compared to intervention group, suggesting that computerized spatial navigation training can successfully moderate detrimental BR effects. Findings underline the generalization of cognitive-based intervention to the motor domain and potentially support their use to supplement BR interventions (e.g., exercise and nutrition). PMID- 25938246 TI - Validating older adults' reports of less mind-wandering: An examination of eye movements and dispositional influences. AB - The Control Failures * Concerns theory perspective proposes that mind-wandering occurs, in part, because of failures to inhibit distracting thoughts from entering consciousness (McVay & Kane, 2012). Despite older adults (OAs) exhibiting poorer inhibition, they report less mind-wandering than do young adults (YAs). Proposed explanations include (a) that OAs' thought reports are less valid due to an unawareness of, or reluctance to report, task-unrelated thoughts (TUTs) and (b) that dispositional factors protect OAs from mind wandering. The primary goal of the current study was to test the validity of thought reports via eye-tracking. A secondary goal was to examine whether OAs' greater mindfulness (Splevins, Smith, & Simpson, 2009) or more positive mood (Carstensen, Isaacowitz, & Charles, 1999) protects them from TUTs. We found that eye movement patterns predicted OAs' TUT reports and YAs' task-related interference (TRI, or thoughts about one's performance) reports. Additionally, poor comprehension was associated with more TUTs in both age groups and more TRI in YAs. These results support the validity of OAs' thought reports. Concerning the second aim of the study, OAs' greater tendency to observe their surroundings (a facet of mindfulness) was related to increased TRI, and OAs' more positive mood and greater motivation partially mediated age differences in TUTs. OAs' reduced TUT reports appear to be genuine and potentially related to dispositional factors. PMID- 25938247 TI - A dyadic approach to health, cognition, and quality of life in aging adults. AB - Married couples evidence interdependence in their psychological and physical wellbeing across the life span. This is particularly true in aging populations that experience declines in physical health and cognitive ability. This study investigated the effects of partners' physical health and cognition on quality of life (QoL) in a series of bivariate latent curve growth models. The sample included aging married couples (N = 8,187) who participated in the Survey of Health, Ageing, and Retirement in Europe (SHARE) study and provided data across 6 years. Results indicated that husbands' and wives' baseline levels and rates of change in QoL covaried significantly over time. In addition, husbands' and wives' physical health and cognition predicted their partners' baseline level of QoL above and beyond their own health and cognition, and these effects were of equivalent size for both men and women. The findings suggest that as couples age, husbands' and wives' QoL, cognition, and health are predictive of their partners' QoL. PMID- 25938248 TI - Situation model updating in young and older adults: Global versus incremental mechanisms. AB - Readers construct mental models of situations described by text. Activity in narrative text is dynamic, so readers must frequently update their situation models when dimensions of the situation change. Updating can be incremental, such that a change leads to updating just the dimension that changed, or global, such that the entire model is updated. Here, we asked whether older and young adults make differential use of incremental and global updating. Participants read narratives containing changes in characters and spatial location and responded to recognition probes throughout the texts. Responses were slower when probes followed a change, suggesting that situation models were updated at changes. When either dimension changed, responses to probes for both dimensions were slowed; this provides evidence for global updating. Moreover, older adults showed stronger evidence of global updating than did young adults. One possibility is that older adults perform more global updating to offset reduced ability to manipulate information in working memory. PMID- 25938249 TI - Daily stressors and emotional reactivity in individuals with mild cognitive impairment and cognitively healthy controls. AB - Daily experiences of stress are common and have been associated with worse affect among older adults. People with mild cognitive impairment (PWMCI) have measurable memory deficits in between normal cognition and dementia and have been identified as having greater psychological distress than cognitively healthy older adults (CHOAs). Little is known about whether daily stressors contribute to distress among PWMCI. We hypothesized that compared with CHOAs, PWMCI would have higher daily negative affect and lower daily positive affect, report greater numbers and severity of daily stressors, and experience greater emotional reactivity to daily stressors. Fifteen clinically diagnosed PWMCI and 25 CHOAs completed daily reports of stressors, stressor severity, and positive and negative affect over an 8-day period. PWMCI reported higher daily negative affect, lower daily positive affect, and higher numbers and greater severity of memory stressors but did not differ from CHOAs in numbers or severity of general stressors. Cognitive status was a moderator of the daily stress-affect relationship. Days with greater numbers and severity of general daily stressors were associated with higher negative affect only for PWMCI. The numbers and severity of memory stressors were not associated with negative affect. In addition, more severe general daily stressors and memory stressors were associated with lower positive affect for all participants. Results suggest that PWMCI are less resilient in the face of daily stress than are CHOAs in terms of negative affect, perhaps because of declines in reserve capacity. The study presents a promising approach to understanding stress and coping in predementia states of cognition. PMID- 25938250 TI - The interactive effect of negative reversal learning and age on depression: Possible cognitive mechanisms underlying the elevated depressive symptoms in older adults. AB - The present study aimed to test possible cognitive mechanisms that may underlie the elevated depressive symptoms in older adults. One hundred forty-one individuals (ages 32-85) with no evidence of general cognitive impairments were tested on a novel reversal paradigm and underwent clinical interviews to assess levels of depressive and anxiety symptoms. The authors found that oldest-older adults have a selective impairment in reversal learning from negative to positive. This impairment interacted with age to predict levels of depressive symptoms. The results suggest possible cognitive mechanisms that link between impaired ability to reverse negative outcomes and elevated depressive symptoms in older age. PMID- 25938251 TI - Cognitive processes in the Breakfast Task: Planning and monitoring. AB - The Breakfast Task (Craik & Bialystok, 2006) is a computerized task that simulates the planning and monitoring requirements involved in cooking breakfast, an everyday activity important for functional independence. In Experiment 1, 28 adults performed the Breakfast Task, and outcome measures were examined with principal component analysis to elucidate the structure of cognitive processes underlying performance. Analyses revealed a 2-component structure which putatively captured global planning and local monitoring abilities. In Experiment 2, the structure of Breakfast Task performance was cross-validated on a new sample of 59 healthy older adults who also performed tests assessing working memory, processing speed, inhibition, reasoning and prospective memory. Factor analyses showed that the global planning component from the Breakfast Task was significantly correlated with individual differences in executive functions but the local monitoring component was independent of such functions. The Breakfast Task provides a fast, enjoyable, and lifelike assessment of complex everyday planning and monitoring, and their underlying processes such as working memory and executive functions. PMID- 25938252 TI - Contingent capture effects in temporal order judgments. AB - The contingent attentional capture hypothesis proposes that visual stimuli that do not possess characteristics relevant for the current task will not capture attention, irrespective of their bottom-up saliency. Typically, contingent capture is tested in a spatial cuing paradigm, comparing manual reaction times (RTs) across different conditions. However, attention may act through several mechanisms and RTs may not be ideal to disentangle those different components. In 3 experiments, we examined whether color singleton cues provoke cuing effects in temporal order judgments (TOJs) and whether they would be contingent on attentional control sets. Experiment 1 showed that color singleton cues indeed produce cuing effects in TOJs, even in a cluttered and dynamic target display containing multiple heterogeneous distractors. In Experiment 2, consistent with contingent capture, we observed reliable cuing effects only when the singleton cue matched participants' current attentional control set. Experiment 3 suggests that a sensory interaction account of the differences found in Experiment 2 is unlikely. Our results help to discern the attentional components that may play a role in contingent capture. Further, we discuss a number of other effects (e.g., reversed cuing effects) that are found in RTs, but so far have not been reported in TOJs. Those differences suggest that RTs are influenced by a multitude of mechanisms; however, not all of these mechanisms may affect TOJs. We conclude by highlighting how the study of attentional capture in TOJs provides valuable insights for the attention literature, but also for studies concerned with the perceived timing between stimuli. PMID- 25938253 TI - Faster than the speed of rejection: Object identification processes during visual search for multiple targets. AB - When engaged in a visual search for two targets, participants are slower and less accurate in their responses, relative to their performance when searching for singular targets. Previous work on this "dual-target cost" has primarily focused on the breakdown of attentional guidance when looking for two items. Here, we investigated how object identification processes are affected by dual-target search. Our goal was to chart the speed at which distractors could be rejected, to assess whether dual-target search impairs object identification. To do so, we examined the capacity coefficient, which measures the speed at which decisions can be made, and provides a baseline of parallel performance against which to compare. We found that participants could search at or above this baseline, suggesting that dual-target search does not impair object identification abilities. We also found substantial differences in performance when participants were asked to search for simple versus complex images. Somewhat paradoxically, participants were able to reject complex images more rapidly than simple images. We suggest that this reflects the greater number of features that can be used to identify complex images, a finding that has important consequences for understanding object identification in visual search more generally. PMID- 25938255 TI - PIA: An Intuitive Protein Inference Engine with a Web-Based User Interface. AB - Protein inference connects the peptide spectrum matches (PSMs) obtained from database search engines back to proteins, which are typically at the heart of most proteomics studies. Different search engines yield different PSMs and thus different protein lists. Analysis of results from one or multiple search engines is often hampered by different data exchange formats and lack of convenient and intuitive user interfaces. We present PIA, a flexible software suite for combining PSMs from different search engine runs and turning these into consistent results. PIA can be integrated into proteomics data analysis workflows in several ways. A user-friendly graphical user interface can be run either locally or (e.g., for larger core facilities) from a central server. For automated data processing, stand-alone tools are available. PIA implements several established protein inference algorithms and can combine results from different search engines seamlessly. On several benchmark data sets, we show that PIA can identify a larger number of proteins at the same protein FDR when compared to that using inference based on a single search engine. PIA supports the majority of established search engines and data in the mzIdentML standard format. It is implemented in Java and freely available at https://github.com/mpc bioinformatics/pia. PMID- 25938256 TI - Trp-Trp Cross-Linking: A Structure-Reactivity Relationship in the Formation and Design of Hyperstable Peptide beta-Hairpin and alpha-Helix Scaffolds. AB - Using model peptide beta-hairpin scaffolds, the facile formation of a remarkably stable covalently cross-linked modification is reported in the tryptophan side chain, which confers hyperstability to the scaffold and displays a unique structure-reactivity relationship. This strategy is also validated to obtain a thermostable alpha-helix. Such imposition of conformational constraints can have versatile applications in peptide-based drug discovery, and this strategy may improve peptide bioavailability. PMID- 25938254 TI - Utilizing murine inducible telomerase alleles in the studies of tissue degeneration/regeneration and cancer. AB - Telomere dysfunction-induced loss of genome integrity and its associated DNA damage signaling and checkpoint responses are well-established drivers that cause tissue degeneration during ageing. Cancer, with incidence rates greatly increasing with age, is characterized by short telomere lengths and high telomerase activity. To study the roles of telomere dysfunction and telomerase reactivation in ageing and cancer, the protocol shows how to generate two murine inducible telomerase knock-in alleles 4-Hydroxytamoxifen (4-OHT)-inducible TERT Estrogen Receptor (mTERT-ER) and Lox-Stopper-LoxTERT (LSL-mTERT). The protocol describes the procedures to induce telomere dysfunction and reactivate telomerase activity in mTERT-ER and LSL-mTERT mice in vivo. The representative data show that reactivation of telomerase activity can ameliorate the tissue degenerative phenotypes induced by telomere dysfunction. In order to determine the impact of telomerase reactivation on tumorigenesis, we generated prostate tumor model G4 PB Cre4 Pten(L/L) p53(L/L) LSL-mTERT(L/L) and thymic T-cell lymphoma model G4 Atm(-/ ) mTERT(ER/ER). The representative data show that telomerase reactivation in the backdrop of genomic instability induced by telomere dysfunction can greatly enhance tumorigenesis. The protocol also describes the procedures used to isolate neural stem cells (NSCs) from mTERT-ER and LSL-mTERT mice and reactivate telomerase activity in NSCs in vitro. The representative data show that reactivation of telomerase can enhance the self-renewal capability and neurogenesis in vitro. Finally, the protocol describes the procedures for performing telomere FISH (Fluorescence In Situ Hybridization) on both mouse FFPE (Formalin Fixed and Paraffin Embedded) brain tissues and metaphase chromosomes of cultured cells. PMID- 25938257 TI - Revisit of Pressure-Induced Phase Transition in PbSe: Crystal Structure, and Thermoelastic and Electrical Properties. AB - Lead selenide, PbSe, an important lead chalcogenide semiconductor, has been investigated using in-situ high-pressure/high-temperature synchrotron X-ray diffraction and electrical resistivity measurements. For the first time, high quality X-ray diffraction data were collected for the intermediate orthorhombic PbSe. Combined with ab initio calculations, we find a Cmcm, InI-type symmetry for the intermediate phase, which is structurally more favorable than the anti-GeS type Pnma. At room temperature, the onset of the cubic-orthorhombic transition was observed at ~3.5 GPa with a ~3.4% volume reduction. At an elevated temperature of 1000 K, the reversed orthorhombic-to-cubic transition was observed at 6.12 GPa, indicating a positive Clapeyron slope for the phase boundary. Interestingly, phase-transition induced elastic softening in PbSe was also observed, which can be mainly attributed to the loosely bonded trigonal prisms along the b-axis in the Cmcm structure. In a comparison with the cubic phase, orthorhombic PbSe exhibits a large negative pressure dependence of electrical resistivity. In addition, thermoelastic properties of orthorhombic PbSe have been derived from isothermal compression data, such as the temperature derivative of bulk modulus and thermally induced pressure. PMID- 25938258 TI - Life cycle assessment of cellulose nanofibrils production by mechanical treatment and two different pretreatment processes. AB - Nanocellulose is a bionanomaterial with many promising applications, but high energy use in production has been described as a potential obstacle for future use. In fact, life cycle assessment studies have indicated high life cycle energy use for nanocellulose. In this study, we assess the cradle-to-gate environmental impacts of three production routes for a particular type of nanocellulose called cellulose nanofibrils (CNF) made from wood pulp. The three production routes are (1) the enzymatic production route, which includes an enzymatic pretreatment, (2) the carboxymethylation route, which includes a carboxymethylation pretreatment, and (3) one route without pretreatment, here called the no pretreatment route. The results show that CNF produced via the carboxymethylation route clearly has the highest environmental impacts due to large use of solvents made from crude oil. The enzymatic and no pretreatment routes both have lower environmental impacts, of similar magnitude. A sensitivity analysis showed that the no pretreatment route was sensitive to the electricity mix, and the carboxymethylation route to solvent recovery. When comparing the results to those of other carbon nanomaterials, it was shown that in particular CNF produced via the enzymatic and no pretreatment routes had comparatively low environmental impacts. PMID- 25938259 TI - Quantitatively analyzing metathesis catalyst activity and structural features in silica-supported tungsten imido-alkylidene complexes. AB - A broad series of fully characterized, well-defined silica-supported W metathesis catalysts with the general formula [(=SiO)W(?NAr)(?CHCMe2R)(X)] (Ar = 2,6 iPr2C6H3 (AriPr), 2,6-Cl2C6H3 (ArCl), 2-CF3C6H4 (ArCF3), and C6F5 (ArF5); X = OC(CF3)3 (OtBuF9), OCMe(CF3)2 (OtBuF6), OtBu, OSi(OtBu)3, 2,5-dimethylpyrrolyl (Me2Pyr) and R = Me or Ph) was prepared by grafting bis-X substituted complexes [W(NAr)(?CHCMe2R)(X)2] on silica partially dehydroxylated at 700 degrees C (SiO2 (700)), and their activity was evaluated with the goal to obtain detailed structure-activity relationships. Quantitative influence of the ligand set on the activity (turnover frequency, TOF) in self-metathesis of cis-4-nonene was investigated using multivariate linear regression analysis tools. The TOF of these catalysts (activity) can be well predicted from simple steric and electronic parameters of the parent protonated ligands; it is described by the mutual contribution of the NBO charge of the nitrogen or the IR intensity of the symmetric N-H stretch of the ArNH2, corresponding to the imido ligand, together with the Sterimol B5 and pKa of HX, representing the X ligand. This quantitative and predictive structure-activity relationship analysis of well-defined heterogeneous catalysts shows that high activity is associated with the combination of X and NAr ligands of opposite electronic character and paves the way toward rational development of metathesis catalysts. PMID- 25938260 TI - Dynamics of Na(+)(Benzene) + Benzene Association and Ensuing Na(+)(Benzene)2* Dissociation. AB - Chemical dynamics simulations were used to study Bz + Na(+)(Bz) -> Na(+)(Bz)2* association and the ensuing dissociation of the Na(+)(Bz)2* cluster (Bz = benzene). An interesting and unexpected reaction found from the simulations is direct displacement, for which the colliding Bz molecule displaces the Bz molecule attached to Na(+), forming Na(+)(Bz). The rate constant for Bz + Na(+)(Bz) association was calculated at 750 and 1000 K, and found to decrease with increase in temperature. By contrast, the direct displacement rate constant increases with temperature. The cross section and rate constant for direct displacement are approximately an order of magnitude lower than those for association. The Na(+)(Bz)2* cluster, formed by association, dissociates with a biexponential probability, with the rate constant for the short-time component approximately an order of magnitude larger than that for the longer time component. The latter rate constant agrees with that of Rice-Ramsperger-Kassel Marcus (RRKM) theory, consistent with rapid intramolecular vibrational energy redistribution (IVR) and intrinsic RRKM dynamics for the Na(+)(Bz)2* cluster. A coupled phase space model was used to analyze the biexponential dissociation probability. PMID- 25938261 TI - Structural Basis for Different Substrate Profiles of Two Closely Related Class D beta-Lactamases and Their Inhibition by Halogens. AB - OXA-163 and OXA-48 are closely related class D beta-lactamases that exhibit different substrate profiles. OXA-163 hydrolyzes oxyimino-cephalosporins, particularly ceftazidime, while OXA-48 prefers carbapenem substrates. OXA-163 differs from OXA-48 by one substitution (S212D) in the active-site beta5 strand and a four-amino acid deletion (214-RIEP-217) in the loop connecting the beta5 and beta6 strands. Although the structure of OXA-48 has been determined, the structure of OXA-163 is unknown. To further understand the basis for their different substrate specificities, we performed enzyme kinetic analysis, inhibition assays, X-ray crystallography, and molecular modeling. The results confirm the carbapenemase nature of OXA-48 and the ability of OXA-163 to hydrolyze the oxyimino-cephalosporin ceftazidime. The crystal structure of OXA 163 determined at 1.72 A resolution reveals an expanded active site compared to that of OXA-48, which allows the bulky substrate ceftazidime to be accommodated. The structural differences with OXA-48, which cannot hydrolyze ceftazidime, provide a rationale for the change in substrate specificity between the enzymes. OXA-163 also crystallized under another condition that included iodide. The crystal structure determined at 2.87 A resolution revealed iodide in the active site accompanied by several significant conformational changes, including a distortion of the beta5 strand, decarboxylation of Lys73, and distortion of the substrate-binding site. Further studies showed that both OXA-163 and OXA-48 are inhibited in the presence of iodide. In addition, OXA-10, which is not a member of the OXA-48-like family, is also inhibited by iodide. These findings provide a molecular basis for the hydrolysis of ceftazidime by OXA-163 and, more broadly, show how minor sequence changes can profoundly alter the active-site configuration and thereby affect the substrate profile of an enzyme. PMID- 25938262 TI - Tailoring Dielectric and Actuated Properties of Elastomer Composites by Bioinspired Poly(dopamine) Encapsulated Graphene Oxide. AB - In this study, we obtained dielectric elastomer composites with controllable dielectric and actuated properties by using a biomimetic method. We used dopamine (DA) to simultaneously coat the graphene oxide (GO) and partially reduce GO by self-polymerization of DA on GO. The poly(dopamine) (PDA) coated GO (GO-PDA) was assembled around rubber latex particles by hydrogen bonding interaction between carboxyl groups of carboxylated nitrile rubber (XNBR) and imino groups or phenolic hydroxyl groups of GO-PDA during latex compounding, forming a segregated GO-PDA network at a low percolation threshold. The results showed that the introduction of PDA on GO prevented the restack of GO in the matrix. The dielectric and actuated properties of the composites depend on the thickness of PDA shell. The dielectric loss and the elastic modulus decrease, and the breakdown strength increases with increasing the thickness of PDA shell. The maximum actuated strain increases from 1.7% for GO/XNBR composite to 4.4% for GO PDA/XNBR composites with the PDA thickness of about 5.4 nm. The actuated strain at a low electric field (2 kV/mm) obviously increases from 0.2% for pure XNBR to 2.3% for GO-PDA/XNBR composite with the PDA thickness of 1.1 nm, much higher than that of other DEs reported in previous studies. Thus, we successfully obtained dielectric composites with low dielectric loss and improved breakdown strength and actuated strain at a low electric field, facilitating the wide application of dielectric elastomers. PMID- 25938263 TI - Plasmon Enhanced Internal Photoemission in Antenna-Spacer-Mirror Based Au/TiO2 Nanostructures. AB - Emission of photoexcited hot electrons from plasmonic metal nanostructures to semiconductors is key to a number of proposed nanophotonics technologies for solar harvesting, water splitting, photocatalysis, and a variety of optical sensing and photodetector applications. Favorable materials and catalytic properties make systems based on gold and TiO2 particularly interesting, but the internal photoemission efficiency for visible light is low because of the wide bandgap of the semiconductor. We investigated the incident photon-to-electron conversion efficiency of thin TiO2 films decorated with Au nanodisk antennas in an electrochemical circuit and found that incorporation of a Au mirror beneath the semiconductor amplified the photoresponse for light with wavelength lambda = 500-950 nm by a factor 2-10 compared to identical structures lacking the mirror component. Classical electrodynamics simulations showed that the enhancement effect is caused by a favorable interplay between localized surface plasmon excitations and cavity modes that together amplify the light absorption in the Au/TiO2 interface. The experimentally determined internal quantum efficiency for hot electron transfer decreases monotonically with wavelength, similar to the probability for interband excitations with energy higher than the Schottky barrier obtained from a density functional theory band structure simulation of a thin Au/TiO2 slab. PMID- 25938264 TI - Phosphine-Catalyzed Diastereoselective Synthesis of beta-Lactones from Disubstituted Ketenes and alpha-Chiral Oxyaldehydes. AB - In this article we describe a catalytic procedure for the diastereoselective synthesis of beta-lactones bearing two stereogenic centers, from disubstituted ketenes and alpha-chiral oxyaldehydes. Tri-n-butylphosphine was found to be the optimal catalyst in terms of effecting both good yield and diastereoselectivity (dr from 3:1 to 32:1 for 8 examples) in beta-lactone formation. The major isomer of the beta-lactone products was determined to be the anti-diastereomer, and its formation was rationalized by a polar Felkin-Anh model. Involvement of phosphonium enolate intermediates in the reaction mechanism was indicated through reaction monitoring by (31)P NMR spectroscopy. The utility of the methodology is demonstrated by a short synthesis of a (+)-peloruside A synthon. PMID- 25938265 TI - A protocol for lentiviral transduction and downstream analysis of intestinal organoids. AB - Intestinal crypt-villus structures termed organoids, can be kept in sustained culture three dimensionally when supplemented with the appropriate growth factors. Since organoids are highly similar to the original tissue in terms of homeostatic stem cell differentiation, cell polarity and presence of all terminally differentiated cell types known to the adult intestinal epithelium, they serve as an essential resource in experimental research on the epithelium. The possibility to express transgenes or interfering RNA using lentiviral or retroviral vectors in organoids has increased opportunities for functional analysis of the intestinal epithelium and intestinal stem cells, surpassing traditional mouse transgenics in speed and cost. In the current video protocol we show how to utilize transduction of small intestinal organoids with lentiviral vectors illustrated by use of doxycylin inducible transgenes, or IPTG inducible short hairpin RNA for overexpression or gene knockdown. Furthermore, considering organoid culture yields minute cell counts that may even be reduced by experimental treatment, we explain how to process organoids for downstream analysis aimed at quantitative RT-PCR, RNA-microarray and immunohistochemistry. Techniques that enable transgene expression and gene knock down in intestinal organoids contribute to the research potential that these intestinal epithelial structures hold, establishing organoid culture as a new standard in cell culture. PMID- 25938266 TI - Methyl 3-((6-methoxy-1,4-dihydroindeno[1,2-c]pyrazol-3-yl)amino)benzoate (GN39482) as a tubulin polymerization inhibitor identified by MorphoBase and ChemProteoBase profiling methods. AB - A series of indenopyrazoles was synthesized from the corresponding indanones and phenyl isothiocyanates in two steps. Among the compounds synthesized, methyl 3 ((6-methoxy-1,4-dihydroindeno[1,2-c]pyrazol-3-yl)amino)benzoate 6m (GN39482) was found to possess a promising antiproliferative activity toward human cancer cells without affecting any antimicrobial and antimalarial activities at 100 nM. Both a methoxy group at R(1) position and a methoxycarbonyl group at R(2) position of the anilinoquinazoline framework are essential for the high cell growth inhibition. Both MorphoBase and ChemProteoBase profiling analyses suggested that compound 6m was classified as a tubulin inhibitor. Indeed, compound 6m inhibited the acetylated tubulin accumulation and the microtubule formation and induced G2/M cell cycle arrest in HeLa cells, revealing that a promising antiproliferative activity of compound 6m toward human cancer cells is probably caused by the tubulin polymerization inhibition. PMID- 25938267 TI - Effect of ashing temperature on accurate determination of plutonium in soil samples. AB - An acidic leaching method using HNO3 is widely employed to release the global fallout Pu from soil samples for further chemical separations in radioecology and toxicology studies and in many applications using Pu as a useful tracer. In the method's sample ash treatment step to decompose organic matter in soil, various ashing temperatures (400-900 degrees C) are used; however, the effect of ashing temperature on the accurate Pu analysis has not been well investigated. In this study, two standard reference soils (IAEA-soil-6 and IAEA-375) were used to determine the ashing temperature effect (from 375 to 600 degrees C) on the HNO3 leaching method. The Pu analytical results of both standard reference materials showed that lower (239+240)Pu activity was observed when the ashing temperature exceeded 450 degrees C, and the (239+240)Pu activity continued to decrease as the ashing temperature was raised. Approximately 40% of the Pu content could not be leached out by concentrated HNO3 after ashing for 4 h at 600 degrees C. The Pu loss was attributed to the formation of refractory materials, which are insoluble in HNO3 solution. This hypothesis was confirmed by the XRD analysis of soil samples, which revealed that plagioclase-like silicate materials were formed after high-temperature ashing. To ensure Pu release efficiency in HNO3 leaching, we recommend 450 degrees C as the ideal ashing temperature. This recommendation is also useful for analysis of other important artificial radionuclides (e.g., (137)Cs, (90)Sr, (241)Am) for which an ashing process is needed to decompose the organic content in soil samples. PMID- 25938268 TI - Electroconvulsive therapy in 197 patients with a severe, drug-resistant bipolar mixed state: treatment outcome and predictors of response. AB - OBJECTIVE: We prospectively evaluated the short-term outcome and the predictors of response to electroconvulsive therapy (ECT) in a large sample of patients with a bipolar mixed state. METHOD: From January 2006 to May 2011, we performed an analysis using data obtained from 197 of 203 consecutive patients with a bipolar mixed state, according to DSM-IV-TR diagnostic criteria, who were treated with ECT at the Department of Psychiatry of the University of Pisa. All patients were evaluated prior to and after the ECT course using the Hamilton Depression Rating Scale-17 (HDRS-17), Young Mania Rating Scale (YMRS), Brief Psychiatric Rating Scale (BPRS), and Clinical Global Impressions (CGI) scale. The CGI subscale "global improvement" and final HDRS-17 and YMRS total scores were used to identify nonresponder, responder, and remitter groups. RESULTS: At the end of the ECT course, 55 patients (27.9%) were considered nonresponders, 82 responders (41.6%), and 60 remitters (30.5%). As expected, at the end of the ECT trial, the CGI-Severity scale (CGI-S; P < .0001), HDRS-17 (P < .0001), and BPRS (P < .0001) scores were significantly lower in remitters than in responders and nonresponders. Using backward stepwise logistic regression, the length of current episode, lifetime comorbidity of obsessive-compulsive disorder, and baseline YMRS total mean score were statistically significant predictors of nonresponse versus remission (P < .0001). CONCLUSIONS: Less than 30% of the patients included in the study were nonresponders to ECT. Long-lasting mixed episode with excitatory symptoms and lifetime comorbidity of obsessive-compulsive disorder significantly predicted a lack of complete remission. PMID- 25938269 TI - Malnutrition and Adverse Effects in Cardiac Surgery. PMID- 25938270 TI - One-Year Clinical Outcome after Left Ventricular Assist Device Malfunction. AB - BACKGROUND: Left ventricular assist device (LVAD) implants bear the risk of driveline/device infections and technical failures. METHODS: We assessed clinical outcome in LVAD patients with device-related complications. Group 1 (n = 12) received device exchange (DEx) as destination therapy (DT), group 2 (n = 15) received DEx as a bridge to transplant (BTT), group 3 (n = 34) was allocated to receive high-urgency (HU) heart transplantation (HTx), and group 4 (n = 27) had device-related complications that could only be solved by HTx. Primary endpoint was 1-year overall survival. RESULTS: Age and Simplified Acute Physiology Score II differed significantly between groups and were highest in group 1, lowest in group 3. One-year survival in groups 1 to 4 was 66.7, 60.0, 82.4, and 70.4% (p = 0.30). Covariate-adjusted odds ratio of 1-year survival (reference: group 1) was for group 2 = 1.52 (95% confidence interval [CI]: 0.42-5.57), for group 3 = 1.13 (95% CI: 0.28-4.56), and for group 4 = 1.89 (95% CI: 0.51-7.04; p for trend 0.70). Clinical complications (need of mechanical ventilator support, extracorporeal circulatory membrane oxygenation (ECMO) implants, kidney/liver dialysis) were comparable between groups. CONCLUSION: Data indicate similar 1 year clinical outcomes in LVAD patients with device-related complications receiving DEx or HTx. PMID- 25938271 TI - Sphingomyelinase D/ceramide 1-phosphate in cell survival and inflammation. AB - Sphingolipids are major constituents of biological membranes of eukaryotic cells. Many studies have shown that sphingomyelin (SM) is a major phospholipid in cell bilayers and is mainly localized to the plasma membrane of cells, where it serves both as a building block for cell architecture and as a precursor of bioactive sphingolipids. In particular, upregulation of (C-type) sphingomyelinases will produce ceramide, which regulates many physiological functions including apoptosis, senescence, or cell differentiation. Interestingly, the venom of some arthropodes including spiders of the genus Loxosceles, or the toxins of some bacteria such as Corynebacterium tuberculosis, or Vibrio damsela possess high levels of D-type sphingomyelinase (SMase D). This enzyme catalyzes the hydrolysis of SM to yield ceramide 1-phosphate (C1P), which promotes cell growth and survival and is a potent pro-inflammatory agent in different cell types. In particular, C1P stimulates cytosolic phospholipase A2 leading to arachidonic acid release and the subsequent formation of eicosanoids, actions that are all associated to the promotion of inflammation. In addition, C1P potently stimulates macrophage migration, which has also been associated to inflammatory responses. Interestingly, this action required the interaction of C1P with a specific plasma membrane receptor, whereas accumulation of intracellular C1P failed to stimulate chemotaxis. The C1P receptor is coupled to Gi proteins and activates of the PI3K/Akt and MEK/ERK1-2 pathways upon ligation with C1P. The proposed review will address novel aspects on the control of inflammatory responses by C1P and will highlight the molecular mechanisms whereby C1P exerts these actions. PMID- 25938273 TI - An Assay for Measuring the Effects of Ethanol on the Locomotion Speed of Caenorhabditis elegans. AB - Alcohol use disorders are a significant public health concern, for which there are few effective treatment strategies. One difficulty that has delayed the development of more effective treatments is the relative lack of understanding of the molecular underpinnings of the effects of ethanol on behavior. The nematode, Caenorhabditis elegans (C. elegans), provides a useful model in which to generate and test hypotheses about the molecular effects of ethanol. Here, we describe an assay that has been developed and used to examine the roles of particular genes and environmental factors in behavioral responses to ethanol, in which locomotion is the behavioral output. Ethanol dose-dependently causes an acute depression of crawling on an agar surface. The effects are dynamic; animals exposed to a high concentration demonstrate an initial strong depression of crawling, referred to here as initial sensitivity, and then partially recover locomotion speed despite the continued presence of the drug. This ethanol-induced behavioral plasticity is referred to here as the development of acute functional tolerance. This assay has been used to demonstrate that these two phenotypes are distinct and genetically separable. The straightforward locomotion assay described here is suitable for examining the effects of both genetic and environmental manipulations on these acute behavioral responses to ethanol in C. elegans. PMID- 25938272 TI - Do the A subunits contribute to the differences in the toxicity of Shiga toxin 1 and Shiga toxin 2? AB - Shiga toxin producing Escherichia coli O157:H7 (STEC) is one of the leading causes of food-poisoning around the world. Some STEC strains produce Shiga toxin 1 (Stx1) and/or Shiga toxin 2 (Stx2) or variants of either toxin, which are critical for the development of hemorrhagic colitis (HC) or hemolytic uremic syndrome (HUS). Currently, there are no therapeutic treatments for HC or HUS. E. coli O157:H7 strains carrying Stx2 are more virulent and are more frequently associated with HUS, which is the most common cause of renal failure in children in the US. The basis for the increased potency of Stx2 is not fully understood. Shiga toxins belong to the AB5 family of protein toxins with an A subunit, which depurinates a universally conserved adenine residue in the alpha-sarcin/ricin loop (SRL) of the 28S rRNA and five copies of the B subunit responsible for binding to cellular receptors. Recent studies showed differences in the structure, receptor binding, dependence on ribosomal proteins and pathogenicity of Stx1 and Stx2 and supported a role for the B subunit in differential toxicity. However, the current data do not rule out a potential role for the A1 subunits in the differential toxicity of Stx1 and Stx2. This review highlights the recent progress in understanding the differences in the A1 subunits of Stx1 and Stx2 and their role in defining toxicity. PMID- 25938274 TI - Genome-enabled analysis of plant-pathogen migration. AB - Trade in plant and plant products has profoundly affected the global distribution and diversity of plant pathogens. Identification of migration pathways can be used to monitor or manage pathogen movement for proactive disease management or quarantine measures. Genomics-based genetic marker discovery is allowing unprecedented collection of population genetic data for plant pathogens. These data can be used for detailed analysis of the ancestry of population samples and therefore for analysis of migration. Reconstruction of migration histories has confirmed previous hypotheses based on observational data and led to unexpected new findings on the origins of pathogens and source populations for past and recent migration. The choice of software for analysis depends on the type of migration being studied and the reproductive mode of the pathogen. Biased sampling and complex population structures are potential challenges to accurate inference of migration pathways. PMID- 25938275 TI - Playing on a pathogen's weakness: using evolution to guide sustainable plant disease control strategies. AB - Wild plants and their associated pathogens are involved in ongoing interactions over millennia that have been modified by coevolutionary processes to limit the spatial extent and temporal duration of disease epidemics. These interactions are disrupted by modern agricultural practices and social activities, such as intensified monoculture using superior varieties and international trading of agricultural commodities. These activities, when supplemented with high resource inputs and the broad application of agrochemicals, create conditions uniquely conducive to widespread plant disease epidemics and rapid pathogen evolution. To be effective and durable, sustainable disease management requires a significant shift in emphasis to overtly include ecoevolutionary principles in the design of adaptive management programs aimed at minimizing the evolutionary potential of plant pathogens by reducing their genetic variation, stabilizing their evolutionary dynamics, and preventing dissemination of pathogen variants carrying new infectivity or resistance to agrochemicals. PMID- 25938276 TI - Dissecting the molecular network of virus-plant interactions: the complex roles of host factors. AB - A successful infection by a plant virus results from the complex molecular interplay between the host plant and the invading virus. Thus, dissecting the molecular network of virus-host interactions advances the understanding of the viral infection process and may assist in the development of novel antiviral strategies. In the past decade, molecular identification and functional characterization of host factors in the virus life cycle, particularly single stranded, positive-sense RNA viruses, have been a research focus in plant virology. As a result, a number of host factors have been identified. These host factors are implicated in all the major steps of the infection process. Some host factors are diverted for the viral genome translation, some are recruited to improvise the viral replicase complexes for genome multiplication, and others are components of transport complexes for cell-to-cell spread via plasmodesmata and systemic movement through the phloem. This review summarizes current knowledge about host factors and discusses future research directions. PMID- 25938277 TI - Molecular mechanisms of nematode-nematophagous microbe interactions: basis for biological control of plant-parasitic nematodes. AB - Plant-parasitic nematodes cause significant damage to a broad range of vegetables and agricultural crops throughout the world. As the natural enemies of nematodes, nematophagous microorganisms offer a promising approach to control the nematode pests. Some of these microorganisms produce traps to capture and kill the worms from the outside. Others act as internal parasites to produce toxins and virulence factors to kill the nematodes from within. Understanding the molecular basis of microbe-nematode interactions provides crucial insights for developing effective biological control agents against plant-parasitic nematodes. Here, we review recent advances in our understanding of the interactions between nematodes and nematophagous microorganisms, with a focus on the molecular mechanisms by which nematophagous microorganisms infect nematodes and on the nematode defense against pathogenic attacks. We conclude by discussing several key areas for future research and development, including potential approaches to apply our recent understandings to develop effective biocontrol strategies. PMID- 25938278 TI - Hemochromatosis gene mutations may affect the survival of patients with myelodysplastic syndrome. AB - Objectives The recent availability of potent oral iron chelators is renewing an interest in the assessment of the possible impact of HFE genetics in myelodysplastic syndrome (MDS). Methods Thirty-six newly diagnosed patients with MDS were studied for parameters of iron metabolism in addition to C282Y and H63D mutations of the HFE gene. Results Mutations were present in 11 out of 36 patients (31%), which was not different from our general population and were equally distributed among MDS subtypes. Mutated patients had higher ferritin levels (P = 0.039) and lower TIBC (P = 0.018). Ferritin was found to be higher for the untransfused mutated patients (P = 0.017), but not for transfusion dependent patients in whom ferritin levels correlated significantly with the number of blood units received (P = 0.04). There was no difference in the number of blood units received between the mutated and wild type patients. A new observation made was that the mutated patients had a lower overall survival in addition to a poorer leukemia free survival (P = 0.004 and P = 0.003, respectively). Discussion The HFE gene mutations are not more frequent in MDS patients. Iron overload in mutated patients was higher but there was no correlation found using supportive therapy for anemia. The effect of mutations on survival could be mediated by changes in iron metabolism. Conclusion The HFE genotype may predict MDS prognosis and there is a need for further studies. It remains a challenging question if HFE mutated MDS patients should be considered for potent iron chelation therapy. PMID- 25938279 TI - Upper respiratory symptoms worsen over time and relate to clinical phenotype in chronic obstructive pulmonary disease. AB - RATIONALE: How nasal symptoms in patients with chronic obstructive pulmonary disease (COPD) change over time and resolve during naturally occurring exacerbations has not been described previously. OBJECTIVES: To evaluate the evolution and impact of upper airway symptoms in a well-defined COPD cohort when stable and at exacerbation. METHODS: Patients in the London COPD cohort were asked about the presence of nasal symptoms (nasal discharge, sneezing, postnasal drip, blocked nose, and anosmia) over an 8-year period (2005-2013) every 3 months at routine clinic visits while in a stable state and daily during exacerbations with the use of diary cards. Data were prospectively collected, and, in a subgroup of patients, COPD Assessment Test scores and human rhinovirus identification by polymerase chain reaction were available. Patients were also defined as having infrequent or frequent exacerbations (<2 or >=2 exacerbations/yr, respectively). MEASUREMENTS AND MAIN RESULTS: At an aggregate of 4,368 visits, 209 patients with COPD were asked about their nasal symptoms. At 2,033 visits when the patients were stable, the odds ratio (OR) for nasal discharge increased by 1.32% per year (95% confidence interval [CI], 1.19-1.45; P < 0.001); the OR for sneezing increased by 1.16% (95% CI, 1.05-1.29; P = 0.005); the OR for postnasal drip increased by 1.18% (95% CI, 1.03-1.36; P = 0.016); and the OR for anosmia increased by 1.19% (95% CI, 1.03-1.37; P = 0.015). At visits when the patients were having exacerbations, nasal discharge was present for 7 days and blocked nose, sneezing, and postnasal drip increased for just 3 days. Anosmia did not change. Nasal discharge was more likely in patients with frequent exacerbations (OR, 1.96; 95% CI, 1.17-3.28; P = 0.011), and COPD Assessment Test scores were higher by 1.06 units (95% CI, 0.32-1.80; P = 0.005) when patients were stable and higher by 1.30 units (95% CI, 0.05-2.57; P = 0.042) during exacerbations. CONCLUSIONS: Upper airway symptoms increase over time in patients with COPD and are related to the frequent exacerbation phenotype. These longitudinal changes may be due to increasing airway inflammation or to progression of COPD. PMID- 25938280 TI - Pulmonary clearance kinetics and extrapulmonary translocation of seven titanium dioxide nano- and submicron materials following intratracheal administration in rats. AB - We evaluated and compared the pulmonary clearance kinetics and extrapulmonary translocations of seven titanium dioxide (TiO2) nano- and submicron particles with different characteristics, including size, shape and surface coating. Varying doses of TiO2 nano- and submicron particles dispersed in 0.2% disodium phosphate solution were intratracheally administered to male F344 rats. The rats were euthanized under anesthesia for 3, 28 and 91 days after administration. Ti levels in pulmonary and various extrapulmonary organs were determined using inductively coupled plasma-sector field mass spectrometry (ICP-SFMS). The lungs, including bronchoalveolar lavage fluid (BALF), contained 55-89% of the administered TiO2 dose at 3 days after administration. The pulmonary clearance rate constants, estimated using a one-compartment model, were higher after administration of 0.375-2.0 mg/kg body weight (bw) (0.016-0.020/day) than after administration of 3.0-6.0 mg/kg bw (0.0073-0.013/day) for six uncoated TiO2. In contrast, the clearance rate constant was 0.011, 0.0046 and 0.00018/day following administration of 0.67, 2.0 and 6.0 mg/kg bw TiO2 nanoparticle with Al(OH)3 coating, respectively. Translocation of TiO2 from the lungs to the thoracic lymph nodes increased in a time- and dose-dependent manner. Furthermore, the translocation of TiO2 from the lungs to the thoracic lymph nodes after 91 days was higher when Al(OH)3 coated TiO2 was administered (0.93-6.4%), as compared to uncoated TiO2 (0.016-1.8%). Slight liver translocation was observed (<0.11%), although there was no clear trend related to dose or elapsed time. No significant translocation was observed in other organs including the kidney, spleen and brain. PMID- 25938283 TI - COPD: Journal of Chronic Obstructive Pulmonary Disease. Preface. PMID- 25938282 TI - A genome-wide nanotoxicology screen of Saccharomyces cerevisiae mutants reveals the basis for cadmium sulphide quantum dot tolerance and sensitivity. AB - The use of cadmium sulphide quantum dots (CdS QDs) is increasing, particularly in the electronics industry. Their size (1-10 nm in diameter) is, however, such that they can be taken up by living cells. Here, a bakers' yeast (Saccharomyces cerevisiae) deletion mutant collection has been exploited to provide a high throughput means of revealing the genetic basis for tolerance/susceptibility to CdS QD exposure. The deletion of 112 genes, some associated with the abiotic stress response, some with various metabolic processes, some with mitochondrial organization, some with transport and some with DNA repair, reduced the level of tolerance to CdS QDs. A gene ontology analysis highlighted the role of oxidative stress in determining the cellular response. The transformation of sensitive mutants with centromeric plasmids harbouring DNA from a wild type strain restored the wild type growth phenotype when the complemented genes encoded either HSC82, DSK2 or ALD3. The use of these simple eukaryote knock-out mutants for functional toxicogenomic analysis will inform studies focusing on higher organisms. PMID- 25938284 TI - The impact of smoke exposure on the clinical phenotype of alpha-1 antitrypsin deficiency in Ireland: exploiting a national registry to understand a rare disease. AB - Individuals with Alpha-1 antitrypsin deficiency (AATD) have mutations in the SERPINA1 gene causing genetic susceptibility to early onset lung and liver disease that may result in premature death. Environmental interactions have a significant impact in determining the disease phenotype and outcome in AATD. The aim of this study was to assess the impact of smoke exposure on the clinical phenotype of AATD in Ireland. Clinical demographics and available thoracic computerised tomography (CT) imaging were detected from 139 PiZZ individuals identified from the Irish National AATD Registry. Clinical information was collected by questionnaire. Data was analysed to assess AATD disease severity and evaluate predictors of clinical phenotype. Questionnaires were collected from 107/139 (77%) and thoracic CT evaluation was available in 72/107 (67.2%). 74% of respondents had severe Chronic Obstructive Pulmonary Disease (COPD) (GOLD stage C or D). Cigarette smoking was the greatest predictor of impairment in FEV1 and DLCO (%predicted) and the extent of emphysema correlated most significantly with DLCO. Interestingly the rate of FEV1 decline was similar in ex-smokers when compared to never-smokers. Passive smoke exposure in childhood resulted in a greater total pack-year smoking history. Radiological evidence of bronchiectasis was a common finding and associated with increasing age. The Irish National AATD Registry facilitates clinical and basic science research of this condition in Ireland. This study illustrates the detrimental effect of smoke exposure on the clinical phenotype of AATD in Ireland and the benefit of immediate smoking cessation at any stage of lung disease. PMID- 25938281 TI - Short-term exposure to engineered nanomaterials affects cellular epigenome. AB - Extensive incorporation of engineered nanomaterials (ENMs) into industrial and biomedical applications increases the risks of exposure to these potentially hazardous materials. While the geno- and cytotoxic effects of ENMs have been investigated, the potential of ENMs to target the cellular epigenome remains largely unknown. Our goal was to determine whether industry relevant ENMs can affect the epigenome at low cytotoxic doses. A panel of cells relevant to inhalation exposures such as human and murine macrophages (THP-1 and RAW264.7, respectively) and human small airway epithelial cells (SAEC) were exposed to printer-emitted engineered nanoparticles (PEPs), mild steel welding fumes (MS WF), copper oxide (CuO) and titanium dioxide nanoparticles. Toxicological effects, including cytotoxicity, oxidative stress and inflammatory responses were assessed, taking into consideration in vitro dosimetry. The effects of ENMs on cellular epigenome were determined by addressing the global and transposable elements (TEs)-associated DNA methylation and expression of DNA methylation machinery and TEs. The percentage of ENMs-induced cytotoxicity for all cell lines was in the range of 0-15%. Oxidative stress was evident in SAEC after exposure to PEPs and in THP-1 when exposed to CuO. In addition, exposure to ENMs resulted in modest alterations in DNA methylation of two most abundant TEs in mammalian genomes, LINE-1 and Alu/SINE, their transcriptional reactivation, and decreased expression of DNA methylation machinery in a cell-, dose- and ENM-dependent manner. These results indicate that exposure to ENMs at environmentally relevant concentrations, aside from the geno- and cytotoxic effects, can also affect the epigenome of target cells. PMID- 25938285 TI - Activity of the alpha-1 antitrypsin deficiency registry in Belgium. AB - A Belgian alpha-1-antitrypsin (AAT) deficiency registry has been established in 2003. Currently 55 patients are included. At the same time, a working group has been set up for publishing national guidelines. In 2014, several Belgian patients founded Alpha-1 Global. We hope that the integrated activities of all the stakeholders involved in AAT deficiency will permit a high quality care for all patients suffering from this disabling disease. PMID- 25938287 TI - The national alpha-1 antitrypsin deficiency registry in Poland. AB - The alpha-1 antitrypsin deficiency (AATD) targeted screening program, together with the National Registry, were established in Poland in 2010 soon after the AATD diagnostics became available. Between 2010 and 2014 a total of 2525 samples were collected from respiratory patients countrywide; 55 patients with severe AAT deficiency or rare mutations were identified and registered, including 36 PiZZ subjects (65%). The majority of AATD patients were diagnosed with COPD (40%) or emphysema (7%), but also with bronchial asthma (16%) and bronchiectasis (13%). Therefore, the registry has proved instrumental in setting-up the AATD-dedicated network of respiratory medical centres in Poland. Since augmentation therapy is not reimbursed in our country, the smoking cessation guidance, optimal pharmacotherapy of respiratory symptoms as well the early detection, and effective treatment of exacerbations is absolutely essential. PMID- 25938286 TI - Alpha-1 antitrypsin deficiency in Canada: regional disparities in diagnosis and management. AB - BACKGROUND: Since 1999, as part of the Alpha1 International Registry (AIR), the Canadian Alpha-1 Antitrypsin Deficiency (AATD) Registry has maintained demographic and medical information volunteered by AATD individuals. METHODS: We undertook a retrospective chart review to describe the characteristics of registry participants. Inclusion criteria were ZZ phenotype or other severe deficiency and written consent. We reviewed baseline medical records and annual follow-ups, conducted by mail. RESULTS: The number of registrants ranged from 8.7 per million in British Columbia and Ontario to 1.3 per million in Quebec. Similarly, the rate of augmentation therapy use ranged from 7.7 per million in British Columbia to 0.1 per million in Quebec. 290 patients (146 males), most PiZZ, were enrolled by 2013. Patients with lung disease reported symptoms onset at (mean +/- SD) 40 +/- 11 years but were diagnosed as AATD at 47 +/- 10 years. Typical patients were ex-smokers with respiratory symptoms, severely reduced FEV1, an accelerated rate of FEV1 decline, and minimal bronchodilator response. A subgroup diagnosed by liver disease or familial screening was younger and had better preserved lung function but a similar rate of FEV1 decline. There were 63 deaths, of which 29 were lung-related and 6 were liver-related. Average age at death was 60.5 +/- 11.2 years. DISCUSSION: Most patients experience a diagnostic delay of seven years after symptom onset, a period during which lung health may deteriorate further. There is marked regional variation in the rate of diagnosis and specific therapy usage for AAT in Canada. PMID- 25938288 TI - Spanish Registry of Patients With Alpha-1 Antitrypsin Deficiency; Comparison of the Characteristics of PISZ and PIZZ Individuals. AB - Alpha-1 antitrypsin deficiency (AATD) is associated with an increased risk of pulmonary emphysema and liver disease. The growing interest in this deficiency in Spain led to the development of the Spanish Registry of Patients with Alpha-1 Antitrypsin Deficiency (REDAAT) in 1993. At present, the REDAAT is a network of more than 350 health care professionals and the database includes a total of 511 individuals. The adult population included consists of 469 individuals (91.8% of the total) and their phenotype distribution is: 348 Pi*ZZ (74.2%), 100 Pi*SZ (21.3%) and 21 carriers of rare variants (4.5%). The most frequent diagnosis is lung disease (74.6%). Patients with chronic obstructive pulmonary disease (COPD) registered in the REDAAT constitute approximately 15% of the expected cases of AATD-related COPD in Spain. Pi*ZZ showed more severe impairment in lung function and younger age at baseline compared with Pi*SZ. The mean decline in FEV1 in the Pi*ZZ subgroup was -23 ml/year (SD:142.8), being -18 ml/year (SD:108.8) in Pi*SZ. Forty-five percent of the Pi*ZZ individuals received augmentation therapy. A total of 61 deaths was recorded. The characteristics of the REDAAT population demonstrate some differential trends compared to other series: distribution of phenotypes, inclusion of children and patients treated with replacement therapy. Patients with the Pi*SZ phenotype were older and had milder lung function impairment. The most important challenge of this registry is to collect good quality long-term data that will allow better understanding of the natural history of the disease in real life. PMID- 25938289 TI - Conductivity in Exhaled Breath Condensate from Subjects with Emphysema and Type ZZ alpha-1-Antitrypsin Deficiency. AB - The assessment of biomarkers in biological samples from the lung has long been employed. Upon cooling water vapor present in exhaled breath, variable amounts of droplets of condensate (EBC) containing volatile and non-volatile compounds may be easily and non-invasively obtained from patients of any age.Objective of the present study was to compare the level of EBC conductivity determined for cohorts of individuals with different inflammatory lung disorders with that of healthy never-smoking individuals.The conductivity in EBC of PiZZ-Alpha-1-antitrypsin deficiency patients with a diagnosis of emphysema (PiZZ-AATD) was 3 fold lower than in spouse controls (54.5 +/- 11.6 vs 165.3 +/- 10.7 MUS/cm). Non-PiZZ emphysema patients had conductivity in EBC of 59.6 +/- 5.8 MUS/cm and patients with sarcoidosis without airflow obstruction had EBC conductivity of 178,8 +/- 6,2 MUS/cm, ?not significantly different (p = 0.5) from healthy controls. Conductivity in serial EBC samples from patients with PiZZ-AATD emphysema and healthy controls was stable in 6 different samples collected over a period of 14 months. We conclude that conductivity values in EBC can be used as a correction factor for dilution of non-volatile components in EBC. PMID- 25938290 TI - The Clinical Profile of Subjects Included in the Swedish National Register on Individuals with Severe Alpha 1-Antitrypsin deficiency. AB - The Swedish national register of severe alpha1-antitrypsin (AAT) deficiency was established in 1991. The main aims are to prospectively study the natural history of severe AAT deficiency, and to improve the knowledge of AAT deficiency. The inclusion criteria in the register are age >= 18 years, and the PiZ phenotype diagnosed by isoelectric focusing. The register is kept updated by means of repeated questionnaires providing data to allow analysis of the mode of identification, lung and liver function, smoking-habits, respiratory symptoms and diagnoses as reported by physicians. Until February 2014, a total of 1553 PiZZ individuals had been included in the register. The 1102 subjects still alive constituted about 20% of the adult PiZZ individuals in Sweden. Forty-three percent of the subjects had been identified during investigation of respiratory symptoms, 7% by an investigation of liver disease, 26% in an investigation of other pathological conditions, and 24% in a population or family screening. Forty five percent of the subjects had never smoked, 47% were ex-smokers, and 8% current smokers. Twenty-eight percent of the never-smokers, 72% of the ex smokers, and 61% of the current smokers fulfilled the criteria for COPD with a FEV1/FVC ratio of <0.70. Among the 451 deceased, the most common cause of death was respiratory diseases (55%), followed by liver diseases (13%). We conclude that the detection rate of severe AAT deficiency is relatively high in Sweden. Large numbers of subjects are identified for other reasons than respiratory symptoms, and the majority of these have never smoked. PMID- 25938291 TI - The United States Alpha-1 Foundation Research Registry: Genesis, Impact and Future. AB - The Alpha-1 Foundation Research Registry has a long history of facilitating research studies in the United States. The current contact registry is used to invite participants to research studies. However, the next generation of individuals diagnosed with alpha-1 antitrypsin deficiency may look quite different from historical cohorts. This paper uses data from the Alpha Coded Testing (ACT) study, a home genetic testing program in which deficient individuals are invited to participate in the Registry, to demonstrate the impact that selection bias can introduce into registry data. Environmental tobacco smoke (ETS) exposure is rapidly declining in the United States. We queried whether consecutive non-smokers with or without childhood ETS in ACT (N = 801) had been diagnosed with COPD more often if deficiency genes were defined in subsequent testing. The prevalence of COPD was not different between cohorts with or without ETS exposure between normal (PiMM and PiMS), moderately deficient (PiMZ, PiMNull, and PiSS), and severely deficient (PiSZ, PiZZ, PiSNull, and PiZNull) genotypes. Surprisingly, age adjusted COPD Severity Scores in this cohort were higher for individuals with normal genotypes compared to moderately (P<0.001) and severely (P = 0.04) deficient genotypes. Ascertainment bias of testing within families (which yields the highest incidence of deficiency genotypes) also finds many family members without symptoms, even over the age of 40. We conclude that the future utility of registries will depend on accurate determination of testing mechanics. Larger database initiatives using the COPD Patient Powered Research Network are described. PMID- 25938292 TI - Health-related quality of life in patients with alpha-1 antitrypsin deficiency: the French experience. AB - The French registry of patients with alpha-1 antitrypsin deficiency (AATD) associated emphysema was launched in 2006. Here, we aimed to report on the baseline characteristics of these patients, their health-related quality of life (HRQoL) and factors associated with HRQoL. Another goal was to survey the practices of French physicians regarding augmentation therapy. We included 273 patients with AATD, emphysema, obstructive-pattern [forced expiratory volume in 1 sec/forced volume capacity (FEV1/FVC) < 0.7], FEV1 <= 80% predicted. Mean (SD) age was 51.8 (11.1) years, 240 (87.9%) of patients were smokers or ex-smokers, mean (SD) FEV1 was 40.5% (15.7) predicted. Mean (SD) SGRQ score was 49.0 (20.0) and was higher for females than males (52.7 [20.7] vs 46.8 [18.2]; p = 0.01). Dyspnea showed the strongest association with SGRQ score (r = 0.65; p < 0.0001), followed by chronic bronchitis (r = 0.33; p < 0.0001) and wheezing (r = 0.32; p < 0.0001). Number of exacerbations in the year before inclusion was also significantly associated with SGRQ score (r = 0.36; p < 0.0001). The SGRQ score was associated with the 6-min walking distance (r = -0.53, p < 0.0001), FEV1 (% predicted, r = -0.53, p < 0.0001) and DLCO (% predicted, r = -0.52, p < 0.0001). It was also associated with the GOLD 2006 (r = 0.53; p < 0.0001) and GOLD 2011 (r = 0.63; p< 0.0001) classifications and with the BODE index (r = 0.37; p < 0.0001). Age, history of tobacco smoking or current smoking did not show any association with SGRQ total scores. On multivariate analysis, a model including age, chronic bronchitis, dyspnea (MRC scale), diffusing lung capacity and 6-min walking distance explained 57% of the variation in the score. The French registry provides important insights into the clinical characteristics of French patients with AATD-related emphysema. PMID- 25938293 TI - Italian registry of patients with alpha-1 antitrypsin deficiency: general data and quality of life evaluation. AB - Alpha1-antitrypsin Deficiency (AATD) is a rare hereditary disorder with an estimated prevalence of about 1/5000 individuals in Italy. Deficient patients are at a higher risk of developing lung emphysema and chronic liver disease. The low estimated prevalence of AATD prompted the establishment of a registry with the aim of learning more about the natural history and the quality of care of these patients. The Italian registry for AATD was established in 1996. In this study, genetic and clinical findings of Italian AATD patients are presented. Moreover, we also evaluated the changes in health-related quality of life (HRQoL) in patients with COPD and AAT deficiency over a three-year period, in relation to augmentation therapy. In a period spanning 18 years (1996-2014) a total of 422 adult subjects with severe AATD were enrolled, namely 258 PI*ZZ, 74 PI*SZ, 4 PI*SS and 86 patients with at least one rare deficient allele. The 21.3% frequency for AATD patients with at least one deficient rare variant is the highest so far recorded in national registries of AATD. The registry data allow a detailed characterization of the natural course of the disease and the level of patient care, as well as confirm the usefulness of early AATD detection. PMID- 25938295 TI - Antitrypsin Deficiency Assessment and Programme for Treatment (ADAPT): The United Kingdom Registry. AB - The study of rare diseases is compromised by its rarity. The establishment of national and international registries can overcome many of the problems and be used for many monogenetic conditions with relatively consistent outcomes and thus lead to a consistency of clinical management by centres of excellence. However, in Alpha-1 antitrypsin deficiency (AATD), the outcome is highly variable in terms of the organ(s) most affected and the diversity of disease penetration and progression. This creates the added difficulty of understanding the disease sufficiently to monitor and advise the patients to the standard required and importantly design and deliver clinical trials that address the many facets of the disease. The development of research registries and centres of excellence provides the necessary expertise and data to further the understanding and management of diseases like AATD though with significant cost implications. The ADAPT programme was established in 1996 with extensive core funding to enable patients to be seen from all regions of the United Kingdom as an addition to the National Health Service without appointment time constraints and with the purpose of collecting extensive state of the art demographics. The model has proven to be highly productive providing new insights especially into the lung disease, generating and delivering on clinical trials and importantly establishing active patient groups and participation. PMID- 25938294 TI - Sex differences in alpha-1-antitrypsin deficiency lung disease-analysis from the German registry. AB - Alpha-1-antitrypsin deficiency (AATD) is a rare condition with clinical manifestations of the lung and the liver. There is evidence that the gender affects the clinical presentation of non-AATD chronic obstructive lung disease (COPD). The aim of this study was to analyze gender-dependent disease pattern in AATD-based COPD. Data from 1066 individuals from the German AATD registry were analyzed by descriptive and analytical statistics. The AAT genotypes comprised 820 individuals with PiZZ (male 56%, female 45%), 109 with PI SZ (male 55%; female 45%), and others (n = 137). A subgroup of 422 patients with available post bronchodilator FEV1% predicted was analyzed in detail after stratification in spirometric GOLD stages I-IV. The age of the registered individuals is 52.2 +/- 13.4 years (male: 51.91 +/- 13.86 years; female: 52.76 +/- 13.39 years). Female patients with GOLD I-IV showed lower numbers of pack-years and lower BMI. The time between the first symptom and the establishment of the correct diagnosis was significantly longer in female (14.47 +/- 16.46 years) as compared to male individuals (12.39 +/- - 14.38 years, p = 0.04). In conclusion, the data of the registry allow to characterize the natural course of the disease and highlight differences in the clinical presentation of patients with AATD-dependent COPD. PMID- 25938296 TI - Does Robotic Telerounding Enhance Nurse-Physician Collaboration Satisfaction About Care Decisions? AB - BACKGROUND: Delivering healthcare using remote robotic telepresence is an evolving practice in medical and surgical intensive critical care units and will likely have varied implications for work practices and working relationships in intensive care units. Our study assessed the nurse-physician collaboration satisfaction about care decisions from surgical intensive critical care nurses during remote robotic telepresence night rounds in comparison with conventional telephone night rounds. MATERIALS AND METHODS: This study used a randomized trial to test whether robotic telerounding enhances the nurse-physician collaboration satisfaction about care decisions. A physician randomly used either the conventional telephone or the RP-7 robot (InTouch((r)) Health, Santa Barbara, CA) to perform nighttime rounding in a surgical intensive care unit. The Collaboration and Satisfaction About Care Decisions (CSACD) survey instrument was used to measure the nurse-physician collaboration. The CSACD scores were compared using the signed-rank test with a significant p value of <=0.05. RESULTS: From December 1, 2011 to December 13, 2012, 20 off-shift nurses submitted 106 surveys during telephone rounds and 108 surveys during robot rounds. The median score of surveys during robot rounds was slightly but not significantly higher than telephone rounds (51.3 versus 50.5; p=0.3). However, the CSACD score was significantly increased from baseline with robot rounds (51.3 versus 43.0; p=0.01), in comparison with telephone rounds (50.5 versus 43.0; p=0.09). The mediators, including age, working experience, and robot acceptance, were not significantly (p>0.1) correlated with the CSACD score difference (robot versus telephone). CONCLUSIONS: Robot rounding in the intensive care unit was comparable but not superior to the telephone in regard to the nurse-physician collaboration and satisfaction about care decision. The working experience and technology acceptance of intensive care nurses did not contribute to the preference of night shift rounding method from the aspect of collaboration with the physician about care decision-making. PMID- 25938297 TI - Diffusion imaging in the rat cervical spinal cord. AB - Magnetic resonance imaging (MRI) is the state of the art approach for assessing the status of the spinal cord noninvasively, and can be used as a diagnostic and prognostic tool in cases of disease or injury. Diffusion weighted imaging (DWI), is sensitive to the thermal motion of water molecules and allows for inferences of tissue microstructure. This report describes a protocol to acquire and analyze DWI of the rat cervical spinal cord on a small-bore animal system. It demonstrates an imaging setup for the live anesthetized animal and recommends a DWI acquisition protocol for high-quality imaging, which includes stabilization of the cord and control of respiratory motion. Measurements with diffusion weighting along different directions and magnitudes (b-values) are used. Finally, several mathematical models of the resulting signal are used to derive maps of the diffusion processes within the spinal cord tissue that provide insight into the normal cord and can be used to monitor injury or disease processes noninvasively. PMID- 25938298 TI - Crystal Structure of Fad35R from Mycobacterium tuberculosis H37Rv in the Apo State. AB - Fad35R from Mycobacterium tuberculosis binds to the promoter site of Fad35 operon and its DNA binding activities are reduced in the presence of tetracycline and palmitoyl-CoA. We resolved the crystal structure of Fad35R using single wavelength anomalous diffraction method (SAD). Fad35R comprises canonical DNA binding domain (DBD) and ligand binding domain (LBD), but displays several distinct structural features. Two recognition helices of two monomers in the homodimer are separated by ~ 48 A and two core triangle-shaped ligand binding cavities are well exposed to solvent. Structural comparison with DesT and QacR structures suggests that ligand binding-induced movement of alpha7, which adopts a straight conformation in the Fad35R, may be crucial to switch the conformational states between repressive and derepressive forms. Two DBDs are packed asymmetrically, creating an alternative dimer interface which coincides with the possible tetramer interface that connects the two canonical dimers. Quaternary state of alternative dimer mimics a closed-state structure in which two recognition helices are distanced at ~ 35 A and ligand binding pockets are inaccessible. Results of biophysical studies indicate that Fad35R has the propensity to oligomerize in solution in the presence of tetracycline. We present the first structure of a FadR homologue from mycobacterium and the structure reveals DNA and ligand binding features of Fad35R and also provides a view on alternative quaternary states that mimic open and closed forms of the regulator. PMID- 25938299 TI - Functional human liver preservation and recovery by means of subnormothermic machine perfusion. AB - There is currently a severe shortage of liver grafts available for transplantation. Novel organ preservation techniques are needed to expand the pool of donor livers. Machine perfusion of donor liver grafts is an alternative to traditional cold storage of livers and holds much promise as a modality to expand the donor organ pool. We have recently described the potential benefit of subnormothermic machine perfusion of human livers. Machine perfused livers showed improving function and restoration of tissue ATP levels. Additionally, machine perfusion of liver grafts at subnormothermic temperatures allows for objective assessment of the functionality and suitability of a liver for transplantation. In these ways a great many livers that were previously discarded due to their suboptimal quality can be rescued via the restorative effects of machine perfusion and utilized for transplantation. Here we describe this technique of subnormothermic machine perfusion in detail. Human liver grafts allocated for research are perfused via the hepatic artery and portal vein with an acellular oxygenated perfusate at 21 degrees C. PMID- 25938301 TI - Formation of nanotunnels inside a resist film in laser interference lithography. AB - A few kinds of 2-diazo-1-naphthoquinone-4-sulfonates of poly(4-hydroxylstyrene) were prepared to form one-component i-line photoresists. In the laser interference lithography experiments of some of the photoresists, nanotunnels were observed to be aligned in the interior of the resist film. The shape and size of the nanotunnels remain virtually unchanged even under an increased exposure dose, indicating that the exposure energy is confined within the tunnel space. The formation of the nanotunnels results from the effect of standing waves and the permeation of developer from the surface deep into the resist films. PMID- 25938300 TI - What does a professionalism assessment scale measure? PMID- 25938302 TI - The Patient Protection and Affordable Care Act and Chronic Neurological Illnesses: Benefits and Challenges. PMID- 25938307 TI - Selection of elderly patients for colorectal cancer screening. PMID- 25938303 TI - Safety and Procedural Success of Left Atrial Appendage Exclusion With the Lariat Device: A Systematic Review of Published Reports and Analytic Review of the FDA MAUDE Database. AB - IMPORTANCE: The Lariat device has received US Food and Drug Administration (FDA) 510(k) clearance for soft-tissue approximation and is being widely used off-label for left atrial appendage (LAA) exclusion. A comprehensive analysis of safety and effectiveness has not been reported. OBJECTIVES: To perform a systematic review of published literature to assess safety and procedural success, defined as successful closure of the LAA during the index procedure, of the Lariat device. We performed a formal analytic review of the FDA MAUDE (Manufacturer and User Facility Device Experience) database to compile adverse event reports from real world practice with the Lariat. DATA SOURCES: For the systematic review, PubMed, EMBASE, CINAHL, and the Cochrane Library were searched from January 2007 through August 2014 to identify all studies reporting use of the Lariat device in 3 or more patients. The FDA MAUDE database was queried for adverse events reports related to Lariat use. DATA EXTRACTIONS AND SYNTHESIS: Data were abstracted in duplicate by 2 physician reviewers. Events from published literature were pooled using a generic inverse variance weighting with a random effects model. Cumulative and individual adverse events were also reported using the FDA MAUDE data set. MAIN OUTCOMES AND MEASURES: Procedural adverse events and procedural success. RESULTS: In the systematic review, 5 reports of Lariat device use in 309 participants were identified. Specific complications weighted for inverse of variance of individual studies were urgent need for cardiac surgery (2.3%; 7 of 309 procedures) and death (0.3%; 1 of 309 procedures). Procedural success was 90.3% (279 of 309 procedures). In the FDA MAUDE database, there were 35 unique reports of adverse events with use of the Lariat device. Among these, we identified 5 adverse event reports that noted pericardial effusion and death and an additional 23 reported urgent cardiac surgery without mention of death. CONCLUSIONS AND RELEVANCE: This review of published reports and case reports identified risks of adverse events with off-label use of the Lariat device for LAA exclusion. Formal, controlled investigations into the safety and efficacy of the device for this indication are warranted. PMID- 25938308 TI - Selection of elderly patients for colorectal cancer screening. PMID- 25938309 TI - Insertion site for central venous catheters. PMID- 25938310 TI - Insertion site for central venous catheters. PMID- 25938311 TI - Further insight into the cardiovascular risk calculator: time to rethink the strategy? PMID- 25938312 TI - Should the term coagulopathy in cirrhosis be abandoned? PMID- 25938313 TI - Sufficiency of Information in 510(k) Summaries. PMID- 25938314 TI - Overuse of antibiotics in primary health care: a practitioner- or patient-induced problem? PMID- 25938315 TI - Educating residents why less is more with telemetry. PMID- 25938316 TI - Sufficiency of Information in 510(k) Summaries-Reply. PMID- 25938317 TI - Educating residents why less is more with telemetry-reply. PMID- 25938318 TI - Risks and benefits of resumption of anticoagulation following traumatic brain injury remain complex and uncertain. PMID- 25938319 TI - Risks and benefits of resumption of anticoagulation following traumatic brain injury remain complex and uncertain-reply. PMID- 25938320 TI - Lactulose vs Polyethylene Glycol for Treatment of Hepatic Encephalopathy. PMID- 25938321 TI - Lactulose vs Polyethylene Glycol for Treatment of Hepatic Encephalopathy. PMID- 25938323 TI - Errors in intervention cost per smoker. PMID- 25938324 TI - Error in text. PMID- 25938322 TI - Lactulose vs Polyethylene Glycol for Treatment of Hepatic Encephalopathy-Reply. PMID- 25938325 TI - Incorrect author name. PMID- 25938326 TI - Erroneous and veridical recall are not two sides of the same coin: Evidence from semantic distraction in free recall. AB - Two experiments examined the extent to which erroneous recall blocks veridical recall using, as a vehicle for study, the disruptive impact of distractors that are semantically similar to a list of words presented for free recall. Instructing participants to avoid erroneous recall of to-be-ignored spoken distractors attenuated their recall but this did not influence the disruptive effect of those distractors on veridical recall (Experiment 1). Using an externalized output-editing procedure-whereby participants recalled all items that came to mind and identified those that were erroneous-the usual between sequences semantic similarity effect on erroneous and veridical recall was replicated but the relationship between the rate of erroneous and veridical recall was weak (Experiment 2). The results suggest that forgetting is not due to veridical recall being blocked by similar events. PMID- 25938328 TI - Correction to Hardman and Cowan (2014). PMID- 25938327 TI - Studying on borrowed time: How does testing impair new learning? AB - Retrieving studied materials often enhances subsequent learning of new materials (Pastotter & Bauml, 2014). However, retrieval has also been shown to impair new learning (Finn & Roediger, 2013). In this article, we attempted to determine when retrieval enhances and when it impairs new learning. We argue that testing impairs new learning when one intermixes testing with new learning, which biases participants to relearn the tested information at the expense of the new information. We refer to this as the borrowed time hypothesis. Consistent with this idea, we reduced or eliminated test-impaired new learning by discouraging time borrowing. Moreover, testing enhanced new learning only when the test trials and new learning trials were presented in separate blocks. These results suggest that test-impaired new learning and test-enhanced new learning are based on different underlying mechanisms and that they are not simply the flipped side of the same coin. PMID- 25938329 TI - New method for the rapid extraction of natural products: efficient isolation of shikimic acid from star anise. AB - A new, practical, rapid, and high-yielding process for the pressurized hot water extraction (PHWE) of multigram quantities of shikimic acid from star anise (Illicium verum) using an unmodified household espresso machine has been developed. This operationally simple and inexpensive method enables the efficient and straightforward isolation of shikimic acid and the facile preparation of a range of its synthetic derivatives. PMID- 25938330 TI - Correction to Coutinho et al. (2014). PMID- 25938332 TI - Response to Comment on "Comparison of Water Use for Hydraulic Fracturing for Unconventional Oil and Gas versus Conventional Oil". PMID- 25938331 TI - Visualization of high speed liquid jet impaction on a moving surface. AB - Two apparatuses for examining liquid jet impingement on a high-speed moving surface are described: an air cannon device (for examining surface speeds between 0 and 25 m/sec) and a spinning disk device (for examining surface speeds between 15 and 100 m/sec). The air cannon linear traverse is a pneumatic energy-powered system that is designed to accelerate a metal rail surface mounted on top of a wooden projectile. A pressurized cylinder fitted with a solenoid valve rapidly releases pressurized air into the barrel, forcing the projectile down the cannon barrel. The projectile travels beneath a spray nozzle, which impinges a liquid jet onto its metal upper surface, and the projectile then hits a stopping mechanism. A camera records the jet impingement, and a pressure transducer records the spray nozzle backpressure. The spinning disk set-up consists of a steel disk that reaches speeds of 500 to 3,000 rpm via a variable frequency drive (VFD) motor. A spray system similar to that of the air cannon generates a liquid jet that impinges onto the spinning disc, and cameras placed at several optical access points record the jet impingement. Video recordings of jet impingement processes are recorded and examined to determine whether the outcome of impingement is splash, splatter, or deposition. The apparatuses are the first that involve the high speed impingement of low-Reynolds-number liquid jets on high speed moving surfaces. In addition to its rail industry applications, the described technique may be used for technical and industrial purposes such as steelmaking and may be relevant to high-speed 3D printing. PMID- 25938333 TI - Delirium Associated With Griseofulvin and Disulfiram Coadministration. PMID- 25938334 TI - Validation of the Multidimensional Acculturative Stress Inventory on adolescents of Mexican origin. AB - The Multidimensional Acculturative Stress Inventory (MASI), a 36-item measure that assesses acculturative stress among people of Mexican origin living in the United States, was tested on 331 adolescent (14-20 years of age) high school students (204 female, 127 male) of Mexican origin. Exploratory factor analyses yielded 4 factors: bicultural practices conflict (9 items), Spanish competency pressures (8 items), English competency pressures (8 items), and bicultural self consciousness (2 items). These factors accounted for 59.5% of the variance and correlated in the expected directions with criterion measures of acculturation and the Psychological General Well-Being Schedule. Bicultural practices conflict and bicultural self-consciousness emerged as the first and fourth factors for adolescents, which differed from the last 2 factors observed in a previous study of adults by Rodriguez, Myers, Mira, Flores, and Garcia-Hernandez (2002)- pressure to acculturate and pressure against acculturation. Comparisons of the MASI factor structures between adolescents and adults also revealed that English competency pressures and Spanish competency pressures played a prominent role for both adolescents in this study and adults in the study by Rodriguez et al. (2002). The congruence and difference in factor structure of the MASI between adolescents and adults indicates that both groups experience acculturative stress because of English- and Spanish-language competency pressures, but adolescents differentially experience difficulties in negotiating between American and Latino practices and identities. The results highlight the importance of assessing acculturative stress from both Latino and American culture and recognizing the varying levels of these sources of acculturative stress by generation. PMID- 25938335 TI - The ASQ and R-PDQ telephone-administered validation within the OTIS antidepressant in pregnancy study. AB - This study aimed to assess the telephone administration of the 12-month Ages and Stages Questionnaire (ASQ) and the 9- to 24-month Revised Prescreening Denver Questionnaire (R-PDQ) using the Antidepressants in Pregnancy Study cohort from the Organization of Teratology Information Specialists. The ASQ includes five domains (communication, gross motor, fine motor, problem-solving, and personal social). The R-PDQ tests four areas of development (gross motor, fine motor, personal-social, and language). Both instruments were self and telephone administered to mothers at 12 months postpartum. Concordance between the telephone and self-administration was assessed with intraclass correlation coefficients (ICCs) with 95% CIs. For the ASQ, concordance between test scores was substantial for the communication scale (ICC = 0.76, 95% CI [0.63, 0.85]), almost perfect for the gross motor scale (ICC = 0.83, 95% CI [0.73, 0.89]), and moderate for the fine motor, problem-solving, and personal-social scales (ICC = 0.43, 95% CI [0.19, 0.61]; ICC = 0.42, 95% CI [0.19, 0.61]; and ICC = 0.50, 95% CI [0.29, 0.67], respectively). Regarding the R-PDQ, concordance between test scores was as follows: gross motor (ICC = 0.90, 95% CI [0.83, 0.94]), language (ICC = 0.57, 95% CI [0.36, 0.73]), and personal-social scales (ICC = 0.26, 95% CI [0.00, 0.49]). For the fine motor scale, the correlation between both modes was 100%. The 12-month ASQ telephone administration could be an alternative for children developmental screening. Except the personal-social scale, the 9- to 24 month R-PDQ could be telephone-administered for prescreening development. PMID- 25938336 TI - The impact of definition and question order on the prevalence of bullying victimization using student self-reports. AB - Accurate measurement is essential to determining the prevalence of bullying and evaluating the effectiveness of intervention efforts. The most common measurement approach is through anonymous self-report surveys, but previous studies have suggested that students do not adhere to standard definitions of bullying and may be influenced by the order of questions about types of victimization. In the current study, we have presented findings from 2 randomized experiments designed to determine (a) the impact of using or not using a definition of bullying and (b) asking about general versus specific types of bullying victimization and how the order of these questions affects victimization-prevalence rates. The study was conducted using a sample of 17,301 students attending 119 high schools. Findings indicate that the use of a definition had no impact on prevalence rates, but asking specific bullying-victimization questions (e.g., "I have been verbally bullied at school") prior to general bullying-victimization questions (e.g., "I have been bullied at school"), resulted in a 29-76% increase in victimization prevalence rates. Results suggest that surveys that ask general-to-specific bullying-victimization questions, such as those found in national and international surveys, may be underreporting bullying victimization. PMID- 25938338 TI - Adding delayed recall to the ADAS-cog improves measurement precision in mild Alzheimer's disease: Implications for predicting instrumental activities of daily living. AB - As research increasingly focuses on preclinical stages of Alzheimer's disease (AD), instruments must be retooled to identify early cognitive markers of AD. A supplemental delayed recall subtest for the Alzheimer's Disease Assessment Scale cognitive (ADAS-cog; Mohs, Rosen, & Davis, 1983; Rosen, Mohs, & Davis, 1984) is commonly implemented, but it is not known precisely where along the spectrum of cognitive dysfunction this subtest yields incremental information beyond what is gained from the standard ADAS-cog, or whether it can improve prediction of functional outcomes. An item response theory approach can analyze this in a psychometrically rigorous way. Seven hundred eighty-eight patients with AD or amnestic complaints or impairment completed a battery including the ADAS-cog and 2 activities of daily living measures. The delayed recall subtest slightly improved the ADAS-cog's measurement precision in the mild range of cognitive dysfunction and increased prediction of instrumental activities of daily living for individuals with subjective memory impairment. PMID- 25938337 TI - Differential item functioning in the Cambridge Mental Disorders in the Elderly (CAMDEX) Depression Scale across middle age and late life. AB - A long-standing and critical problem in the study of aging and depression is the comparability of measurement across age groups. While psychological measures of depression typically show increased incidence of symptoms with increasing age, rates of depression diagnosis do not show the same age trend. This analysis presents tests of differential item functioning on the depression section of the CAMDEX interview schedule, using factor analysis-derived affective and somatic subscales (McGue & Christensen, 1997). Results for the affective subscale show significant differences in item functioning in the majority of the affective items as a function of age (items "Happy Life," "Lonely," "Nervous" "Worthless," and "Future": chi6(2) = [30.193, 255.971] across items, all p < .0001). Analyses for the somatic subscale show differential item functioning is limited to a single item relating to coping (chi6(2) = 180.754, p < .0001). These results indicate that differences in depression symptoms across age groups are not entirely consistent with a unidimensional depression trait, and that the measurement structure of depression varies over the life span. PMID- 25938340 TI - Cationic tungsten-oxo-alkylidene-N-heterocyclic carbene complexes: highly active olefin metathesis catalysts. AB - The synthesis, structure, and olefin metathesis activity of the first neutral and cationic W-oxo-alkylidene-N-heterocyclic carbene (NHC) catalysts are reported. Neutral W-oxo-alkylidene-NHC catalysts can be prepared in up to 90% isolated yield. Depending on the ligands used, they possess either an octahedral (Oh) or trigonal bipyramidal ligand sphere. They can be activated with excess AlCl3 to form cationic olefin metathesis-active W-complexes; however, these readily convert into neutral chloro-complexes. Well-defined, stable cationic species can be prepared by stoichiometric substitution of one chloro ligand in the parent, neutral W-oxo-alkylidene-NHC complexes with Ag(MeCN)2B(Ar(F))4 or NaB(Ar(F))4; B(Ar(F))4 = B(3,5-(CF3)2-C6H3)4. They are highly active olefin metathesis catalysts, allowing for turnover numbers up to 10,000 in various olefin metathesis reactions including alkenes bearing nitrile, sec-amine, and thioether groups. PMID- 25938339 TI - Psychometric evaluation of responses to the NEO-PI-3 in a multi-ethnic sample of adults in India. AB - Cross-cultural studies have demonstrated the utility of the NEO scales in organizing research on personality development (McCrae, 2004). The NEO PI-3 is the latest updated version that has modified item content more suitable to younger populations and to adults with lower literacy levels. The present study examined the utility of the English version of the NEO PI-3 in a multiethnic sample of adults from India (N = 188) by examining mean level data, Cronbach's alpha, retest reliabilities, and construct validity with particular attention given to previous findings that used the NEO Personality Inventory-Revised (NEO PI-R) in an Indian sample. Principal components analyses employing orthogonal procrustean rotations demonstrated convergence with U.S. norms and prior Indian data. The current Cronbach's alpha and retest reliability values were slightly better than data using the NEO-PI-R in 2 Indian samples (Lodhi, Deo, & Belhekar, 2002; Singh, 2009). Scores correlated significantly, and in appropriate ways, with several psychosocial measures. These findings underscore the potential utility of the NEO PI-3 in research among those for whom English is a second language. PMID- 25938341 TI - Complexity of the folding transition of the B domain of protein A revealed by the high-speed tracking of single-molecule fluorescence time series. AB - The equilibrium unfolding transition of the B domain of protein A (BdpA) was investigated by using single-molecule fluorescence spectroscopy based on line confocal detection of fast-flowing samples. The method achieved the time resolution of 120 MUs and the observation time of a few milliseconds in the single-molecule time-series measurements of fluorescence resonance energy transfer (FRET). Two samples of BdpA doubly labeled with donor and acceptor fluorophores, the first possessing fluorophores at residues 22 and 55 (sample 1) and the second at residues 5 and 55 (sample 2), were prepared. The equilibrium unfolding transition induced by guanidium chloride (GdmCl) was monitored by bulk measurements and demonstrated that the both samples obey the apparent two-state unfolding. In the absence of GdmCl, the single-molecule FRET measurements for the both samples showed a single peak assignable to the native state (N). The FRET efficiency for N shifts to lower values as the increase of GdmCl concentration, suggesting the swelling of the native state structure. At the higher concentration of GdmCl, the both samples convert to the unfolded state (U). Near the unfolding midpoint for sample 1, the kinetic exchange between N and U causes the averaging of the two states and the higher values of the relative fluctuation. The time series for different molecules in U showed slightly different FRET efficiencies, suggesting the apparent heterogeneity. Thus, the high-speed tracking of fluorescence signals from single molecules revealed a complexity and heterogeneity hidden in the apparent two-state behavior of protein folding. PMID- 25938343 TI - Co-oximetry interference. PMID- 25938342 TI - Protein Tyrosine Kinase 6 Regulates UVB-Induced Signaling and Tumorigenesis in Mouse Skin. AB - Protein tyrosine kinase 6 (PTK6, also called BRK) is an intracellular tyrosine kinase expressed in the epithelial linings of the gastrointestinal tract and the skin, where it is expressed in nondividing differentiated cells. We found that PTK6 expression increases in the epidermis following UVB treatment. To evaluate the roles of PTK6 in the skin following UVB-induced damage, we exposed back skin of Ptk6 +/+ and Ptk6 -/- SENCAR mice to incremental doses of UVB for 30 weeks. Wild-type mice were more sensitive to UVB and exhibited increased inflammation and greater activation of signal transducer and activator of transcription-3 (STAT3) than Ptk6-/- mice. Disruption of Ptk6 did not have an impact on proliferation, although PTK6 was expressed and activated in basal epithelial cells in wild-type mice following UVB treatment. However, wild-type mice exhibited shortened tumor latency and increased tumor load compared with Ptk6-/- mice, and STAT3 activation was increased in these tumors. PTK6 activation was detected in UVB-induced tumors, and this correlated with increased activating phosphorylation of focal adhesion kinase (FAK) and breast cancer anti-estrogen resistance 1 (BCAR1). Activation of PTK6 was also detected in human squamous cell carcinomas of the skin. Although PTK6 has roles in normal differentiation, it also contributes to UVB-induced injury and tumorigenesis in vivo. PMID- 25938344 TI - Correlation between MET protein expression and MET gene copy number in a Caucasian cohort of non-small cell lung cancers according to the new IASLC/ATS/ERS classification. AB - MET pathway is a promising target in non-small cell lung cancers (NSCLC) requiring companion tests. The aim of this study was to compare MET expression/gene copy number in a Caucasian population of NSCLC patients.We analysed 201 NSCLC, with 141 adenocarcinomas classified according to 2011 IASLC recommendations, for MET expression by immunohistochemistry (IHC) and gene copy number (GCN) by silver in situ hybridisation (SISH) on tissue microarrays. Mutations in EGFR, KRAS, BRAF, HER2, PIK3CA genes and ALK rearrangements were determined.MET overexpression was observed in 44% and a high MET GCN (>=5 copies) in 14%. MET CGN was correlated with MET expression, regardless of IHC scores (p < 0.001) but only 31% of MET overexpressed cases were SISH positive. MET overexpression/GCN number was more frequent in ADC than the other types (p < 0.001), the highest in high grade (74%/34%) and sarcomatoid ADC (86%/43%). Mutations of current genes or ALK rearrangements were identified in overexpressed or amplified MET cases. MET overexpression was an independent prognostic factor for overall survival in non-smoker NSCLC in univariate (p = 0.01) and multivariate (p = 0.01) analyses.MET overexpression is more frequent than MET high GCN, particularly in high grade ADC, regardless of EGFR, KRAS, BRAF, HER2, PIK3CA and ALK status in NSCLC. PMID- 25938345 TI - Metachronous classical Hodgkin's lymphoma and ALK-positive anaplastic large cell lymphoma. PMID- 25938346 TI - BRAF mutation detection in hairy cell leukaemia from archival haematolymphoid specimens. AB - Hairy cell leukaemia (HCL) is a rare, indolent chronic B-cell leukaemia accounting for approximately 2% of all adult leukaemias. The recent association of the BRAF p.Val600Glu (V600E) mutation in HCL makes it a valuable molecular diagnostic marker. We compared the ability of Sanger sequencing, fluorescent single-strand conformational polymorphism (F-SSCP) and high resolution melting (HRM) analysis to detect BRAF mutations in 20 cases of HCL consisting of four archival Romanowsky stained air-dried peripheral blood and bone marrow aspirate smears, 12 mercury fixed decalcified bone marrow trephine biopsies, three formalin fixed, paraffin embedded (FFPE) splenectomy samples and one fresh peripheral blood sample. DNA was amplified and BRAF mutation status determined by the three methods above. V600E mutation was identified in 94%, 89% and 72% of HCL cases by F-SSCP, HRM and Sanger sequencing, respectively. In one case, in addition to the p.Val600Glu mutation, a p.Lys601Thr (K601T) mutation was identified. DNA from archival slide scrapings, mercury-fixed and FFPE tissue can be used to identify BRAF mutations with high sensitivity, especially using HRM/F SSCP. The V600E mutation can be used as a supplementary molecular marker to aid in the diagnosis of HCL and the presence of the mutation may provide a target for therapy. PMID- 25938347 TI - Prototheca wickerhamii olecranon bursitis successfully treated with adjunctive systemic itraconazole. PMID- 25938348 TI - The effect of dabigatran on haemostasis tests: a comprehensive assessment using in vitro and ex vivo samples. AB - The new direct oral anticoagulants (DOACS) dabigatran, rivaroxaban, apixaban and edoxaban provide alternatives to warfarin for treatment and prevention of atrial fibrillation and venous thromboembolic disease in various settings. These have been developed as not requiring laboratory monitoring; however, under certain clinical situations, including recent haemorrhage/thrombosis, emergency surgical procedures, testing may be indicated.The aim of this study was to assess findings of haemostasis laboratory tests for one of the DOACs, dabigatran (Pradaxa), tested across a wide range of laboratory assays.Laboratories (n = 72) enrolled in the Royal College of Pathologists of Australasia Quality Assurance Programs (RCPAQAP) Haematology program were sent set(s) of seven dabigatran spiked plasma samples covering the concentration 0-800 ng/mL. Also, 30 ex vivo patient samples under therapy with dabigatran were assessed.Prothrombin time and activated partial thromboplastin time assays showed some sensitivity to dabigatran; however, a normal result could not inform on drug exclusion. The thrombin time (TT) was very sensitive to dabigatran, and a normal TT could generally be used for drug exclusion. More specialised assays such as the Hemoclot, a direct thrombin inhibition assay, and in-house dilute TT methods, showed good reproducibility and concordance with expected drug levels assessed by mass spectrometry and were effective to quantify drug levels. Dabigatran also affected factor assays, lupus anticoagulant and factor inhibitor measurement, leading to potential misinterpretation of test results. Ex vivo sample testing provided similar and extended information.Dabigatran affects many haemostasis tests. Some can be used to predict the presence, absence or quantity of dabigatran in patient plasma. For others, interference may lead to false conclusions regarding patients' haemostatic status. PMID- 25938349 TI - Epidemiology of invasive group A Streptococcus infections in Sydney, Australia. AB - There is concern of global resurgence of invasive group A Streptococcus (iGAS) infections. We compared the clinical and molecular epidemiology of patients admitted with iGAS over two time periods, 2008 and 2010, in Western Sydney, Australia. The annual incidence was 19 cases per 100,000 admissions in 2008, compared to 33 per 100,000 in 2010. An increasing proportion of patients died (0% versus 13%), had an APACHE II score >=30 (0% versus 19%), and had no known risk factors (12% versus 25%). A potential skin source was identified as a trigger in fewer cases in 2010 (36% versus 11%). In total, there were 27 different emm types and 11 different emm clusters. There were some new emm types/clusters in 2010 that were not present in 2008. However, the study was not adequately powered to detect statistically significant differences in the distribution of emm types (p = 0.06) and emm clusters (p = 0.16) between the two years. There were also no clear associations between emm types/clusters and severity and clinical manifestations of iGAS infections. Although the proposed 30-valent M protein vaccine encompasses only 47% of our isolates, it will likely provide coverage for at least 71% of iGAS infections due to cross-opsonisation. PMID- 25938350 TI - Langerhans cell histiocytosis: a comprehensive review. AB - Langerhans cell histiocytosis (LCH) is currently regarded as a myeloid neoplasm, with remarkably broad clinical spectrum, ranging from isolated skin or bone lesions to a disseminated disease that can involve nearly any organ. LCH is generally regarded as a sporadic disease that occurs predominantly in the paediatric population. The diagnosis of LCH is confirmed by immunohistochemistry (IHC) by demonstrating the presence of dendritic cell markers such as S100 protein, in addition to CD1a and langerin. Contrary to previous beliefs, recent literature reveals that the pathogenesis of LCH might involve a clonal process implicating BRAF c.1799T>A (p.Val600Glu) and other mutations [(600DLAT) B-RAF and (T599A) B-RAF, somatic MAP2K1 mutations].Through this review article, we have summarised the latest understanding of the biological and salient histological characteristics of LCH and its potential morphological mimics. PMID- 25938351 TI - Validation of mitosis counting by automated phosphohistone H3 (PHH3) digital image analysis in a breast carcinoma tissue microarray. AB - Mitosis counting in H&E stained sections is the most informative constituent of the Nottingham histological grade in breast carcinoma prognosis. Phosphohistone H3 (PHH3) immunohistochemistry (IHC) is a highly specific marker of mitoses, with practical application in identifying mitoses in poorly fixed or distorted tissue and is of prognostic significance in breast carcinoma. Our aim was to assess methods of PHH3 IHC mitosis counting in a tissue microarray (TMA) of 2 mm cores from 36 resected breast carcinomas. Mitoses in H&E and PHH3 stained slides were manually scored by pathologist consensus and expressed as counts/2 mm. PHH3 stained cores were also evaluated by automated digital image analysis (DIA). Results were compared using Spearman correlation. A strong and significant correlation was observed between manual PHH3 and manual H&E mitotic counts (correlation = 0.81; p < 0.0001) and between automated PHH3 DIA and manual H&E mitotic counts (correlation = 0.79; p < 0.0001). More mitoses were identified with PHH3 IHC than with H&E. Manual and DIA PHH3 counts were strongly and significantly correlated (correlation = 0.83; p < 0.0001) and of similar absolute values. PHH3 DIA is a valid alternative to manual counting with potential application in breast cancer reporting and prognostication. PMID- 25938352 TI - Malignant inflammatory myofibroblastic tumour of the uterus. PMID- 25938353 TI - Monoclonal precursor T-cell infiltrate in recurrent thymoma: a case report. PMID- 25938354 TI - A rare case of primary retroperitoneal mucinous neoplasm in a male patient. PMID- 25938355 TI - Is vitamin D testing at a tertiary referral hospital consistent with guideline recommendations? AB - To determine if 25 hydroxyvitamin D (25OHD) testing at our tertiary referral hospital is consistent with guideline recommendations concerning the clinical indications for testing, the timing of repeat testing and utilisation of the test result, we conducted a retrospective audit of electronic laboratory and patient case records. We included adult inpatients and outpatients who had serum 25OHD measured during a randomly selected one-week audit period and who had patient case records available for detailed review. The audit sample comprised 184 serum 25OHD measurements (134 initial and 50 repeat tests). There were 81 (60%) initial and 15 (30%) repeat tests [96 (52%) overall] that were consistent with guideline recommendations concerning clinical indication, timing of repeat testing and utilisation of result. Almost half the 25 hydroxyvitamin D tests audited were potentially unnecessary and/or not utilised clinically. Improved adherence to guideline recommendations for 25 hydroxyvitamin D testing, utilisation of test results and enforcement of new indications for testing due to be introduced by Medicare Australia could result in significant cost savings without adversely affecting patient outcomes. PMID- 25938356 TI - Retrospective reassessment of gestational diabetes mellitus diagnosis by using the new classification. PMID- 25938358 TI - Misdiagnosed MYH9 related inherited macrothrombocytopenia with an inadvertent splenectomy. PMID- 25938357 TI - Increased apolipoprotein A5 expression in human and rat non-alcoholic fatty livers. AB - Apolipoprotein A5 (apoA5) is a potent regulator of triglyceride (TG) metabolism and therefore may contribute to the pathogenesis of non-alcoholic fatty liver disease (NAFLD), a disease characterised by excessive TG-rich lipid droplets in hepatocytes. To test this hypothesis, we examined the mRNA expression of apoA5 in paediatric NAFLD livers in comparison to healthy controls. According to microarray and quantitative real-time PCR, human NAFLD livers exhibited elevated apoA5 expression compared to healthy controls. The apoA5 expression levels were positively correlated with hepatic TG storage and a marker for lipid droplets (perilipin), but were not correlated with plasma TG levels. These observations were confirmed with a NAFLD rat model. Interestingly, apoA5 expression was not altered in cultured fat-laden HepG2 cells, demonstrating that fat storage does not induce apoA5 in NAFLD livers. Therefore, the correlation between apoA5 and intracellular fat storage is likely explained by the potent effect of apoA5 in promoting intracellular fat storage. Our NAFLD patients and rats had elevated insulin resistance, which may have a role in elevating apoA5 expression in NAFLD livers. Our data support the hypothesis that apoA5 promotes hepatic TG storage and therefore contributes to the pathogenesis of NAFLD, and may represent a potential target for therapeutic intervention. PMID- 25938359 TI - Loss of expression of BAP1 predicts longer survival in mesothelioma. AB - BRCA1-associated protein 1 (BAP1) is a tumour suppressor gene frequently inactivated in mesothelioma, rarely also in association with germline mutation. BAP1 mutations have been associated with improved prognosis and distinct clinicopathological features. We sought to determine the clinicopathological significance of BAP1 immunohistochemistry (IHC) in mesothelioma.We performed IHC on a tissue microarray (TMA) cohort comprising all available thoracic mesotheliomas encountered during the period 1991-2014 at our institution (n = 229). All cases were independently reviewed to confirm the diagnosis and subclassify as epithelioid, sarcomatoid or biphasic. The median age at diagnosis was 72 years; 188 (82.1%) were male; 120 (52.4%) were epithelioid (median survival 13.0 months), 67 (29.3%) sarcomatoid (median survival 5.6 months) and 42 (18.3%) biphasic (median survival 10.6 months). Negative staining for BAP1 (defined as completely absent nuclear staining in the presence of positive internal controls in non-neoplastic cells) occurred in 106 (46.3%) mesotheliomas. There was complete interobserver concordance for BAP1 IHC status. BAP1 loss was strongly associated with younger age at onset (p < 0.01) and epithelioid differentiation (p < 0.01). BAP1 loss predicted an improved median survival of 16.11 months (95% CI 12.16-20.06) versus 6.34 months (95% CI 5.34-7.34), p < 0.01. In a multivariate model including age, gender and histological type, BAP1 loss, younger age and epithelioid differentiation remained protective (all p < 0.01).If our results are confirmed by others, BAP1 IHC may have a role to predict prolonged survival or triage formal genetic testing for germline BAP1 mutation in patients presenting with mesothelioma. PMID- 25938360 TI - Antimicrobial susceptibility reporting and treatment selection for AmpC-producing Enterobacteriaceae: what do microbiologists and infectious disease practitioners actually practice? PMID- 25938362 TI - Tophaceous gout in the pelvis. PMID- 25938361 TI - High reproducibility of histological diagnosis of human papillomavirus-related intraepithelial lesions of the anal canal. AB - In a natural history study of anal human papillomavirus (HPV) infection and HPV related lesions, we examined the reproducibility of histological high-grade squamous intraepithelial lesion (HSIL). Three expert anogenital pathologists share the reporting of histological specimens from the Study of the Prevention of Anal Cancer (SPANC), utilising Lower Anogenital Squamous Terminology (LAST) criteria. In total, 194 previously reported biopsies were randomly chosen within diagnostic strata [50 HSIL-anal intraepithelial neoplasia (AIN) 3; 45 HSIL-AIN 2; 49 'flat' low-grade squamous intraepithelial lesion (LSIL); 50 'exophytic' LSIL; and 50 negative for squamous intraepithelial lesion] and reviewed by each of these three pathologists. Consensus was defined as agreement between at least two review diagnoses, using a binary classification of HSIL and non-HSIL, or if consensus was not obtained in this way, it was achieved through a multiheader microscope session by the three pathologists. We found very high agreement between original and consensus diagnoses (Kappa = 0.886) and between each pathologist's review and consensus (Kappas = 0.926, 0.917 and 0.905). Intra observer agreement for the three pathologists was 0.705, 1.000 and 0.854. This high level of diagnostic reproducibility indicates that the findings of SPANC should be robust and provide reliable information about HPV-related anal canal disease. PMID- 25938363 TI - Colonisation with Pneumocystis jirovecii in Australian infants. PMID- 25938364 TI - Evaluation of p16INK4a immunostaining for the detection of high-grade changes in cervical cytology. AB - Since its introduction in Australia in 2007, the human papillomavirus (HPV) vaccine has led to a markedly lower prevalence of vaccine targeted HPV genotype infections as well as HPV disease including genital warts and histologically confirmed high-grade (HG) cervical abnormalities. To increase the ability to identify abnormal cells in lower prevalence, adjunct markers can be incorporated to improve the sensitivity and specificity of cytology test. One such marker is p16(p16), which is detectable in cells expressing the E7 oncogene encoded by high risk HPVs (HR-HPV). In this study, the sensitivity and specificity of p16 immunostaining in detection of underlying HG lesions was evaluated in a cohort of 454 women undergoing surgical treatment for biopsy proven cervical dysplasia. Overall, p16 positive cells were detected in 321 (71%) of cytology preparations evaluated. Comparison of p16 staining on cytological preparations to histology diagnosis available on 212 patients, showed 26 (54%), 41 (78%) and 80 (90%) of cytology preparations to be p16 positive in women with CIN1, CIN2 and CIN3, respectively (p < 0.005). HPV16 and 18 were the most prevalent genotypes in HG lesions and were highly correlated with p16 staining. p16 staining provides an additional marker which can assist in better detecting underlying HG lesion in cytology smears with low disease prevalence. PMID- 25938365 TI - Acute myeloid leukaemia and myelodysplastic syndromes with 50% or greater erythroblasts: a diagnostic conundrum. AB - Acute myeloid leukaemia (AML) and myelodysplastic syndromes (MDS) with >=50% erythroblasts comprise up to 5% of all cases of AML and 15% of MDS. The classification of these entities is currently fraught with difficulty and requires integration of clinical, morphological and cytogenetic features. The current World Health Organization classification of haematopoietic tumours recognises the entities of pure erythroid leukaemia and acute erythroid leukaemia (erythroid/myeloid), however, some cases of AML with erythroid predominance may also fulfil criteria for AML with myelodysplasia-related changes or therapy related myeloid neoplasms. Among these entities, pure erythroid leukaemia remains poorly characterised due to its rarity. In addition, there is significant clinicopathological overlap between acute erythroid leukaemia and cases of MDS with >=50% erythroblasts. In this review, we discuss current areas of controversy regarding these disorders and present our approach to their diagnosis and classification. PMID- 25938366 TI - Re: Nationwide prevalence of lymph node metastases in Gleason score 3 + 3 = 6 prostate cancer. PMID- 25938367 TI - Re: Nationwide prevalence of lymph node metastases in Gleason score 3 + 3 = 6 prostate cancer: authors' reply. PMID- 25938368 TI - Spatial and temporal patterns of stranded intertidal marine debris: is there a picture of global change? AB - Floating and stranded marine debris is widespread. Increasing sea levels and altered rainfall, solar radiation, wind speed, waves, and oceanic currents associated with climatic change are likely to transfer more debris from coastal cities into marine and coastal habitats. Marine debris causes economic and ecological impacts, but understanding the scope of these requires quantitative information on spatial patterns and trends in the amounts and types of debris at a global scale. There are very few large-scale programs to measure debris, but many peer-reviewed and published scientific studies of marine debris describe local patterns. Unfortunately, methods of defining debris, sampling, and interpreting patterns in space or time vary considerably among studies, yet if data could be synthesized across studies, a global picture of the problem may be avaliable. We analyzed 104 published scientific papers on marine debris in order to determine how to evaluate this. Although many studies were well designed to answer specific questions, definitions of what constitutes marine debris, the methods used to measure, and the scale of the scope of the studies means that no general picture can emerge from this wealth of data. These problems are detailed to guide future studies and guidelines provided to enable the collection of more comparable data to better manage this growing problem. PMID- 25938369 TI - Homocysteine is biosynthesized from aspartate semialdehyde and hydrogen sulfide in methanogenic archaea. AB - The biosynthetic route for homocysteine, intermediate in methionine biosynthesis, is unknown in some methanogenic archaea because homologues of the canonical required genes cannot be identified. Here we demonstrate that Methanocaldococcus jannaschii can biosynthesize homocysteine from aspartate semialdehyde and hydrogen sulfide. Additionally, we confirm the genes involved in this new pathway in Methanosarcina acetivorans. A possible series of reactions in which a thioaldehyde is formed and then reduced to a thiol are proposed. This represents a novel route for the biosynthesis of homocysteine and exemplifies unique aspects of sulfur chemistry occurring in prebiotic environments and in early life forms. PMID- 25938370 TI - Rapid, optimized interactomic screening. AB - We must reliably map the interactomes of cellular macromolecular complexes in order to fully explore and understand biological systems. However, there are no methods to accurately predict how to capture a given macromolecular complex with its physiological binding partners. Here, we present a screening method that comprehensively explores the parameters affecting the stability of interactions in affinity-captured complexes, enabling the discovery of physiological binding partners in unparalleled detail. We have implemented this screen on several macromolecular complexes from a variety of organisms, revealing novel profiles for even well-studied proteins. Our approach is robust, economical and automatable, providing inroads to the rigorous, systematic dissection of cellular interactomes. PMID- 25938371 TI - CONSERTING: integrating copy-number analysis with structural-variation detection. AB - We developed Copy Number Segmentation by Regression Tree in Next Generation Sequencing (CONSERTING), an algorithm for detecting somatic copy-number alteration (CNA) using whole-genome sequencing (WGS) data. CONSERTING performs iterative analysis of segmentation on the basis of changes in read depth and the detection of localized structural variations, with high accuracy and sensitivity. Analysis of 43 cancer genomes from both pediatric and adult patients revealed novel oncogenic CNAs, complex rearrangements and subclonal CNAs missed by alternative approaches. PMID- 25938372 TI - MS-DIAL: data-independent MS/MS deconvolution for comprehensive metabolome analysis. AB - Data-independent acquisition (DIA) in liquid chromatography (LC) coupled to tandem mass spectrometry (MS/MS) provides comprehensive untargeted acquisition of molecular data. We provide an open-source software pipeline, which we call MS DIAL, for DIA-based identification and quantification of small molecules by mass spectral deconvolution. For a reversed-phase LC-MS/MS analysis of nine algal strains, MS-DIAL using an enriched LipidBlast library identified 1,023 lipid compounds, highlighting the chemotaxonomic relationships between the algal strains. PMID- 25938374 TI - Micro- and nanoparticles by electrospray: advances and applications in foods. AB - Micro- and nanotechnology are tools being used strongly in the area of food technology. The electrospray technique is booming because of its importance in developing micro- and nanoparticles containing an active ingredient as bioactive compounds, enhancing molecules of flavors, odors, and packaging coatings, and developing polymers that are obtained from food (proteins, carbohydrates), as chitosan, alginate, gelatin, agar, starch, or gluten. The electrospray technique compared to conventional techniques such as nanoprecipitation, emulsion diffusion, double-emulsification, and layer by layer provides greater advantages to develop micro- and nanoparticles because it is simple, low cost, uses a low amount of solvents, and products are obtained in one step. This technique could also be applied in the agrifood sector for the preparation of controlled and/or prolonged release systems of fertilizer or agrochemicals, for which more research must be conducted. PMID- 25938373 TI - MIMP: predicting the impact of mutations on kinase-substrate phosphorylation. AB - Protein phosphorylation is important in cellular pathways and altered in disease. We developed MIMP (http://mimp.baderlab.org/), a machine learning method to predict the impact of missense single-nucleotide variants (SNVs) on kinase substrate interactions. MIMP analyzes kinase sequence specificities and predicts whether SNVs disrupt existing phosphorylation sites or create new sites. This helps discover mutations that modify protein function by altering kinase networks and provides insight into disease biology and therapy development. PMID- 25938375 TI - A Cross-Section Study of the Ontogeny of Gender Roles in Women with DSD. AB - A review of gender role (GR) differentiation from early childhood through adulthood was conducted on males and females in general, as well as on females affected by congenital adrenal hyperplasia (CAH) due to 21-hydroxylase deficiency or complete androgen insensitivity syndrome (CAIS). Additionally, retrospective and current, self-rated GR assessments were evaluated from women with CAH (n = 9) or CAIS (n = 12), and unaffected women and men ranging in age from 16 to 59 years. Overall, GR differentiation occurs in early childhood and persists through adulthood. With advanced age, this differentiation may evolve into androgyny or even become undifferentiated for the general population. While more studies of GR exist for girls and women with CAH compared to those affected by CAIS, some developmental patterns can be observed from the limited data that exist. First, girls and women with CAIS report a female GR that persists through adulthood. Second, girls and women with CAH are more likely to report less feminine/ more masculine play in childhood followed by interests in male-typical leisure activities and career choices in adulthood. However, our data indicate that women with CAH report more feminine/ less masculine patterns of GR with age. Self reported GR for women with CAH was indistinguishable from that of women with CAIS at the time of study participation in adulthood. With the availability of effective medications for treating hormone deficiencies associated with CAH, affected women are expected to live a full lifespan. Thus, our understanding of psychosexual development into older age is warranted. PMID- 25938376 TI - Prevalence and Factors Associated With Low Aerobic Performance Levels in Adolescents: A Systematic Review. AB - Low aerobic performance levels have been considered one of the risk factors for premature mortality, regardless of presence of other health problems. The critical analysis of studies on the prevalence of low aerobic performance and associated factors may contribute to the epidemiological knowledge and analysis / discussion of socio-cultural aspects that influence low aerobic performance. The aim of this systematic review was to identify studies on the prevalence of low aerobic performance levels and possible associations between low aerobic performance and demographic/ biological factors, lifestyle and excess body fat in adolescents (11-19 years). The search was conducted in PubMed and SciELO databases using descriptors "aerobic capacity" or "aerobic fitness", "cardiorespiratory capacity" or "cardiorespiratory fitness", "aerobic power" or "aerobic endurance" or "cardiorespiratory endurance" and "adolescents". After the search and exclusion criteria, 33 articles were selected. Factors that were associated with low aerobic performance levels were female gender, low income, low consumption of dairy products and/or bread/cereals, increased consumption of sweetened beverages, insufficient physical activity level, excessive screen time and excess body fat. The heterogeneity of factors related to low aerobic performance levels demonstrates the complexity of this topic and the need for further studies to obtain definitive conclusions. PMID- 25938377 TI - Prevalence of Obesity in Children and Adolescents in Brazil: A Meta-analysis of Cross-sectional Studies. AB - BACKGROUND: Obesity in children/adolescents is a major public health problem worldwide. In Brazil there is great variability in published data on the prevalence of obesity among children/adolescents. AIMS: To show a systematic review with meta-analysis of cross-sectional studies, conducted in Brazil between 2008 and 2014. METHODS: A systematic review and meta-analysis was conducted the outcome of which was obesity (Body Mass Index >= 95th percentile for sex/age). A graphical presentation was done separately (Forest plot) for the results. Global and dichotomous outcomes were presented by employing, respectively the gross rates of prevalence and prevalence ratio (PR) and its confidence intervals at 95% (95% CI). The degree of heterogeneity was calculated employing the Q Cochran, while the I2 test was used to describe the variation between studies. RESULTS: Twenty-one studies with a sample of 18,463 children/adolescents were included; the overall prevalence of obesity was 14.1%. Among boys it was 16.1% and in girls it was 14.95%. There was no difference in obesity prevalence between sexes (PR 1.06; 95%CI: 0.81 to 1.40; p>0.05). CONCLUSIONS: The prevalence of obesity among children and adolescents in Brazil is high and urgently needs measures to prevent consequences associated with the disease, as well as measures to reduce the impact, in the short term, the overweight and childhood obesity. PMID- 25938378 TI - Psoriasis in Children: A Review. AB - Psoriasis is a chronic, immune-mediated, inflammatory systemic disease which targets primarily the skin. It presents a genetic basis, affecting 1 to 3% of the white population. Nevertheless, the existence of two psoriasis incidence peaks has been suggested (one in adolescence before 20 years of age and another in adulthood) onset may occur at any age, including childhood and adolescence, in which its prevalence ranges between 0.7% and 1.2%. As for adult psoriasis, pediatric psoriasis has recently been associated with obesity, metabolic syndrome, increased waist circumference percentiles, and metabolic laboratory abnormalities, warranting early monitoring and lifestyle modifications. In addition, due to psoriasis chronic nature and frequently occurring relapses, psoriatic patients tend to have an impaired quality of life, often requiring long term treatment. Therefore, education of both pediatric patients and their parents is essential to successful and safe disease management. However, systemic treatment of children is challenging as the absence of standardized guidelines and the fact that evidence-based data form randomized controlled trials are very limited. This review shows an overview of the current understanding of the pathogenesis, comorbidities, differential diagnosis, treatment and prevention of pediatric psoriasis, also presenting with an emphasis on the necessity of an integrated treatment approach involving different specialists such as dermatologist, pediatricians, rheumatologists, etc. PMID- 25938379 TI - Recent Concise Viewpoints of Chronic Active Epstein-Barr Virus Infection. AB - Chronic active Epstein-Barr virus infection (CAEBV) is characterized mainly by prolonged or intermittent fever, lymphadenopathy and hepatosplenomegaly without definite underlying diseases at the diagnosis. Patients with CAEBV also may have various life-threatening conditions including hematological, neurological, pulmonary, cardiac, digestive tract, ocular and/or dermal disorders. Additionally, during the course of illness, they often develop hematological malignancies such as T cell, NK cell or B cell lymphoproliferative disorder (LPD) and/or lymphoma. No causative pathogenetic mechanisms have been sufficiently clarified, and additionally no promising efficacious treatment was demonstrated except for the hematopoietic stem cell transplantation (HSCT) in cases who develop T cell or NK cell LPD or lymphoma. This minireview outlines the recent development for the comprehensive viewpoints of CAEBV mainly regarding to virological, immunological, pathological and therapeutical progresses. PMID- 25938380 TI - A 2015 Update on The Natural History and Diagnosis of Nicotine Addiction. AB - This review will describe the biological and behavioral aspects of nicotine addiction as it develops during adolescence and advances over a lifetime. Symptoms of physical nicotine dependence typically appear when adolescents are smoking only a few cigarettes each month. Physical dependence develops through a set sequence of symptoms that correlate with changes in brain structure in addiction circuits. Smokers often describe their symptoms of physical dependence as "wanting," then "craving," and eventually "needing" to smoke. These symptoms appear whenever the smoker goes too long without smoking. The intensity of abstinence-induced craving correlates with spontaneous activation of addiction related networks in the brain as illustrated in the graphical abstract of this article. Initially, smoking a single cigarette can keep withdrawal symptoms at bay for weeks, but as tolerance develops, cigarettes must be smoked at progressively shorter intervals to suppress withdrawal symptoms. The physiologic need to repeatedly self-administer nicotine at shorter intervals explains a full spectrum of addictive symptoms and behaviors. PMID- 25938381 TI - Air Ambient-Operated pNIPAM-Based Flexible Actuators Stimulated by Human Body Temperature and Sunlight. AB - Harnessing a natural power source such as the human body temperature or sunlight should realize ultimate low-power devices. In particular, macroscale and flexible actuators that do not require an artificial power source have tremendous potential. Here we propose and demonstrate electrically powerless polymer-based actuators operated at ambient conditions using a packaging technique in which the stimulating power source is produced by heat from the human body or sunlight. The actuating angle, force, and reliability are discussed as functions of temperature and exposure to sunlight. Furthermore, a wearable device platform and a smart curtain actuated by the temperature of human skin and sunlight, respectively, are demonstrated as the first proof-of-concepts. These nature-powered actuators should realize a new class of ultimate low-power devices. PMID- 25938382 TI - Structural Diversity of Arthropod Biophotonic Nanostructures Spans Amphiphilic Phase-Space. AB - Many organisms, especially arthropods, produce vivid interference colors using diverse mesoscopic (100-350 nm) integumentary biophotonic nanostructures that are increasingly being investigated for technological applications. Despite a century of interest, precise structural knowledge of many biophotonic nanostructures and the mechanisms controlling their development remain tentative, when such knowledge can open novel biomimetic routes to facilely self-assemble tunable, multifunctional materials. Here, we use synchrotron small-angle X-ray scattering and electron microscopy to characterize the photonic nanostructure of 140 integumentary scales and setae from ~127 species of terrestrial arthropods in 85 genera from 5 orders. We report a rich nanostructural diversity, including triply periodic bicontinuous networks, close-packed spheres, inverse columnar, perforated lamellar, and disordered spongelike morphologies, commonly observed as stable phases of amphiphilic surfactants, block copolymer, and lyotropic lipid water systems. Diverse arthropod lineages appear to have independently evolved to utilize the self-assembly of infolding lipid-bilayer membranes to develop biophotonic nanostructures that span the phase-space of amphiphilic morphologies, but at optical length scales. PMID- 25938383 TI - Regiospecific Benzoylation of Electron-Deficient N-Heterocycles with Methylbenzenes via a Minisci-Type Reaction. AB - A regioselective cross-dehydrogenative coupling between electron-deficient N heterocycles (isoquinoline, quinolines, and quinoxalines) and methylbenzenes leading to regiospecific C-aroylation has been accomplished using AlCl3 as the catalyst in the presence of oxidant TBHP. This protocol is a practical alternative to the classical Minisci reaction. PMID- 25938384 TI - [Antiangiogenic therapy of malignant pheochromocytoma and paraganglioma with the view to the recent scientific developments]. AB - Pheochromocytoma is a very rare tumor that stems from chromaffin cells and usually develops in the adrenal glands. Its equivalent, which exists outside of the adrenal glands, is paraganglioma. Approximately 10-26% of pheochromocytoma is malignant, what poses a significant therapeutical problem, as its presence, together with an abundant production of catecholamines, may lead to a number of perilous complications, such as spinal cord oppression or the damage of organs, what is responsible for producing catecholamines. Due to the risk that the tumor is, it is essential to event new and effective ways of treatment. In case of malignant tumors stemming from chromaffin cells, much is expected from antiangiogenic medicine. Its functioning consists of stopping of the process of neovascularization, which is indispensable for the development of the tumor. Sunitinib - a tyrosine kinase inhibitor - is perhaps the most promising antiangiogenic medicine, whose effectiveness is currently being evaluated in 2nd phase clinical trials. Attempts are also being made to conduct treatment with the use of other medicine of similar functioning, such as: thalidomide, imatinib or evrolimus. PMID- 25938385 TI - [Etiology and own experience in the primary monosymptomatic nocturnal enuresis in children]. AB - Primary monosymptomatic nocturnal enuresis (PMNE) is the most frequent (85%) type of enuresis in children. It remains a diagnostic and therapeutic challenge to establish its etiology and implement a proper treatment. AIM: The aim of the study was to establish the causes of PMNE in children on the basis of own investigations and assess factors having influence over PMNE etiology, which would enable the choice of effective therapy. MATERIALS AND METHODS: The study concerned 85 children with PMNE aged from 5 to 15 years. The patients were under the care of Nephrology Outpatient Clinic at Institute of Mather and Child in years 2009-2014. The detailed medical history, physical examination as well as laboratory investigations of blood and urine, and radiological investigations of the urinary tract, were carried out. Statistical analysis was performed using R software. RESULTS: In all patients, we have successfully detected the etiology of children of PMNE. The basic, equally frequent (62.3%), PMNE etiopathogenetic factors turned to be: too small bladder capacity resulting from the detrusor hyperactivity, and night polyuria mainly caused by vasopressin deficiency or abnormal eating and hygienic habits, occurring separately or in conjunction with each other. Too small bladder capacity occurred mainly (37.6%, group C) as the only etiological factor of PMNE, and in 24.7% (group A) in a conjunction with nocturnal polyuria due to decreased excretion of vasopressin. Night polyuria was caused by the deficiency of vasopressin in most cases (37.6%) and occurred mainly (24.7%, group D) in a conjunction with small bladder capacity, and rarely alone (12.9%, group B). In 24.7% (group A) it appeared due to eating and hygienic abnormal habits. We have proved statistically significant differences in mean voiding frequency and volume (p<0.0001) between groups A-B and C-D. Mean morning urine specific gravity (p<0.0001) also differed significantly between group C and B (p<0.0001) as well as C and D (p=0.0004). CONCLUSIONS: PMNE in all patients was attributed to specific causes outside the circle of psychological disorders what reduced patient stigmatization. PMNE etiology is very complex and diverse. It still remains a challenge and requires and individual diagnostic and therapeutic approach. Voiding frequency above 8 daily with voiding volumes usually below 100 ml suggest etiology connected with small bladder capacity, while morning urine specific gravities below 1.021 g/ml can be connected with vasopressin deficiency or excessive fluid intake before the bedtime. The developed diagnostic approach along with borderline values are hints that can aid physicians in establishing PMNE causes. PMID- 25938386 TI - [The effects of endothelin 1 and an inhibitor of phosphorylation of IkappaB on the content of free sulfhydryl groups (-SH) and protein in rat kidney]. AB - Endothelin (ET)-1 is a potent vasoconstrictor. ET-1 an increase in the synthesis of transcription factor NF-kappaB, which is responsible for the production of reactive oxygen species (ROS), and cytokines. AIM: The aim of the study was to determine whether blocking NF-kappaB pathway affects the content of free -SH groups and total protein in rat kidney homogenates. MATERIALS AND METHODS: Experiments were carried out on four groups of male rats of Wistar-Kyoto strain. Group I - control was administered into the femoral vein solution of 0.9 % NaCl; in group II and III - was given endothelin-1 at doses of 1.5 and 12.5 MUg/kg b.w., group IV - was given BAY 11-7082 (inhibitor of phosporylation of IkappaBalpha) at a dose of 10 mg/kg b.w. 30 min prior to administration of ET-1 at a dose of 12.5 MUg/kg b.w. RESULTS: Administration of ET-1 at doses of 1.5 and 12.5 MUg/kg b.w. resulted in a statistically significant reduction of free -SH groups and protein in kidney homogenates compared to the control group. In contrast, administration of an inhibitor of nuclear factor NF-kappaB (BAY 11-7082 (10 mg/kg b.w.) during the oxidative stress induced by ET-1 (12.5 MUg/kg b.w.) significantly increased the concentration of free -SH groups (p <0.001) and protein (p <0.01) in the kidney. CONCLUSIONS: ET-1 caused dose-dependent significant reduction of concentration free -SH groups and total protein. A inhibitor of phosphorylation of IkappaBalpha (BAY 11-7082) given during the oxidative stress induced by ET-1 (12.5 MUg/kg b.w.) significantly increased the concentration of free -SH groups and protein in the kidney tissue. PMID- 25938387 TI - [The prevalence of sarcopenic obesity in postmenopausal women in depending on the used methodology - preliminary study]. AB - Postmenopausal period brings changes in body composition. Among the major alterations the tendency to decrease in fat free mass (FFM) and increase in the amount of fat mass (FM) are observed. Simultaneously loss of muscle mass and decline in muscle strength with the advancing age are observed. Coexistence of sarcopenia and obesity creates a new category of obesity - sarcopenic obesity (SO), which may cause numerous negative consequences. Therefore, clinicians attention should be drawn to this issue. Unfortunately clear criteria to its identification are lacking. AIM: The aim of the present investigation was to determine the prevalence of sarcopenic obesity in postmenopausal women in depending on different definition. MATERIALS AND METHODS: Thirty two postmenopausal women (Group 1) and thirty one young, healthy women (Group 2) participated in the study. Within Group 1 SO was identified, while Group 2 was used for defining to cut-off points. All participants underwent body composition analysis by bioelectrical impedance. Additionally height, body weight and hand grip strength were measured. Sarcopenic obesity was defined by the combination of obesity and sarcopenia. RESULTS: Using different criteria for SO identification diversified study results in the prevalence of SO were observed (21.87 to 84.37%). The highest percentage of SO persons was observed while using the Skeletal Mass Index (SMI) derived cut off score, with fat mass (FM%), the most inclusive. In contrast, the lowest number of sarcopenic obese cases were observed when FFMI based on own group cut-off point was used and in the case of using MMI derived cut-off point defined for French population. CONCLUSIONS: Prevalence of sarcopenic obesity varied, depending on the used criteria. Due to discrepancies between the criteria of sarcopenic obesity identification, standardization of definition and muscle mass predictive equations are required. Development of reference values for Polish population should be undertaken. PMID- 25938388 TI - [Impact on the development of parental awareness of excess weight in children]. AB - A lot of publications emphasize the special role of parents' eating habits and their lifestyle on the prevalence of excess body weight in children. AIM: The aim of this study was to answer the question whether parents of children who are overweight and obese are aware of this problem and what factors affect their perception of the excess body weight degree in their offspring. MATERIALS AND METHODS: The study included 137 children aged 6,5- 13,5 years. 23 respondents were overweight and 76 obese. Compared group consisted of 113 children. All patients underwent physical examination with anthropometric measurements. Parents were asked to complete a questionnaire, where they evaluated the degree of excess body weight of their child. We also asked about both parents' weight and body height, their education and chronic diseases occurring in the family. RESULTS: In the group of obese children 56.2% of the respondents came from families where one parent had excess body weight while 32.9% of them from families where this problem affected both parents. In 51.3% of patients with a body mass index (BMI) above 95 centil, parents wrongly assessed the degree of excess body weight of their child, in overweight group this proportion accounted for 8.7%. There was a statistically significant (p = 0.007) correlation between the degree of children's excess body weight and the ability of parents to estimate that. Parents' education had no influence on the incidence of excess body weight in children and their ability to determine its extent. In the group of obese and overweight children only 4% of parents recognized obesity as a chronic disease. CONCLUSIONS: Parents of children who are overweight and obese have lower awareness about their child's weight in comparison to parents of children with normal weight. There is a statistical correlation between parents' perception of excess body weight and the development of obesity in children. PMID- 25938389 TI - [Use of rituximab in the induction of remission of severe, resistant and recurrent form of polyangiitis associated with c-ANCA antibodies - case report]. AB - Indications for rituximab (RTX) have recently widened. We present a case of 25 years old patient with anti-neutrophil cytoplasmic antibody (ANCA)-associated vasculitis of high disease activity. The patient in severe condition, massive changes of nasal sinuses, with destruction of the orbit bones, with inflammatory infiltrations of the optical nerves and end stage renal disease was admitted to Nephrology Clinic to begin renal replacement therapy (RRT). Chest HRCT reveled changes of "frosted glass", enlarged mediastinal lymphatic nodes and fluid in pleural cavities. C-ANCA antibodies was 23 IU/ml (norm: <2IU/ml). Due to the lack of therapeutic possibilities (exceeded cumulative dose of cyclophosfamide, recurrence of the disease during treatment with mycophenolate mofetil) rituximab was introduced. After proving high expression of CD 20 antigen on the surface of B lymphocytes, two doses of rituximab were administrated (1,0g every two weeks). 8 weeks after the second dose remission of lungs disorders was observed, c- ANCA level decreased to 3,7IU/ml and the granulomatous mass around the optical nerve was stable. 12 months later another supporting dose of rituximab was administrated. Now, 18 months after relapse of the disease patient is in good condition waiting for kidney transplantation. Rituximab is save, well tolerated and effective. Particularly high efficiency of RTX have been observed against lung disorders. No significant remission of granuloma infiltration in the orbits has been noted. Better evaluation of efficiency and safety of rituximab needs further evaluation. PMID- 25938390 TI - [Retroperitoneal perforation of duodenum - surgical approach]. AB - Retroperitoneal perforation of the duodenum, caused by abdominal trauma, endoscopic examination or diverticulitis, is a serious clinical problem, because of it's lack of specific symptoms. Surgical treatment is often performed in sepsis. That is why the knowledge of adequate techniques is crucial for surgeons. We would like to present our model of surgical approach, based on several trauma center's cases. Among the methods and techniques presented we emphasize the duodenal by-pass with bile duct drainage. Post-op cases of gastrojejunal anastomosis' bleeding prompt to implement a selective vagotomy, which however requires further studies. PMID- 25938391 TI - [Fibrates in the light of large clinical trials]. AB - Peroxisome proliferator-activated receptor (PPAR)alpha activators (fibrates) are one of the major group of hypolipidemic agents, that have been presented to have clinical benefits in prevention and treatment of cardiovascular disorders. Apart from their well-known hypolipidemic properties, fibrates produce other so-called pleiotropic effects, including anti-inflammatory and anti-oxidant action, as well as reduction in procoagulant activity and improvement in endothelial function. These observations are in line with some of the results from large randomised clinical trials, which indicated the benefits from therapy with fibrates other than we could expect from their hypolipidemic properties. Nevertheless, the analysis of these studies supports the argument that patients with mixed dyslipidemia and carbohydrate metabolism disturbances are the group, which benefits the most from fibrate therapy. In this article, particular attention is devoted to the results of the large clinical trials. We try to explain the differences between the results of various studies. PMID- 25938392 TI - [Dietary prevention and treatment of diverticular disease of the colon]. AB - Diverticular disease is more often categorized as a civilization disease that affects both women and men, especially at an old age. The pathophysiology remains complex and arises from the interaction between dietary fiber intake, bowel motility and mucosal changes in the colon. Obesity, smoking, low physical activity, low-fiber diet (poor in vegetables, fruit, whole grain products, seeds and nuts) are among factors that increase the risk for developing diverticular disease. Additionally, the colonic outpouchings may be influenced by involutional changes of the gastrointestinal tract. Therefore, the fiber rich diet (25-40 g/day) plays an important role in prevention, as well as nonpharmacological treatment of uncomplicated diverticular disease. The successful goal of the therapy can be achieved by well-balanced diet or fiber supplements intake. Research indicate the effectiveness of probiotics in dietary management during the remission process. Moreover, drinking of appropriate water amount and excluding from the diet products decreasing colonic transit time - should be also applied. PMID- 25938393 TI - [Current concepts in surgical treatment of chronic ankle joint instability]. AB - Ankle sprain is one of the most common musculoskeletal injuries. Initial treatment of choice in acute injury is conservative and is obtained by immobilization. The goal of such treatment is to heal ruptured capsular ligamentous complex. However, despite the conservative treatment some patients develop chronic ankle instability as a result of injury. In those cases, surgical anatomical and non-anatomical ligamentous reconstruction is advised. Aim of the study was evaluation of the results obtained with various surgical techniques in view of published data. According to most authors, in patients who experienced chronic ankle instability, surgical technique of anatomical repair is preferred. In cases when anatomical repair might not be undertaken due to technical capabilities, anatomical reconstruction using autoor allografts is advised. PMID- 25938394 TI - [General principles of effective communication between physician and patient with selected mental disorders]. AB - Faced with the growing frequency of mental disorders occurrence and considering the necessity of improving the patient care, it is particularly important that physicians of different specialties knew the general principles of effective communication with patients who are mentally ill. Equally important is to spread the knowledge of the symptomatology of various mental illnesses. Studies published by the Institute of Psychiatry and Neurology involving persons between 18 and 64 years old, show that 8 millions Poles suffers or suffered from mental disorders. This represents almost 25% of Polish society. The above data confirm, that basic knowledge of criteria for diagnosing mental disorders and their treatment by primary care physicians, determines the success of the entire health care system. It must be taken into consideration that frequently patients seeing general practitioner (GP) are suffering from more than one mental illness or it is accompanied by somatic disease. Adequate communication determines effective treatment. Simple yet exact message, ability to adapt it to patient and problems reported by him, is a valuable means in daily medical practice. It reduces the risk of iatrogenic disorder, encourages the efficiency of the entire therapeutic process. Good cooperation with the patient is also determined by patience, empathy, understanding, and competence. The aim of this study is to present the principles of effective communication between doctor and patient suffering from selected mental disorders. The article defines the concept of communication. It shows symptomatology of primary psychiatric disorders. Moreover, the most common difficulties in relationship between the doctor and the patient had been pointed. PMID- 25938396 TI - Personalized Medicine: Is it a concept only for the super-rich? PMID- 25938395 TI - Induction of Murine Intestinal Inflammation by Adoptive Transfer of Effector CD4+ CD45RB high T Cells into Immunodeficient Mice. AB - There are many different animal models available for studying the pathogenesis of human inflammatory bowel diseases (IBD), each with its own advantages and disadvantages. We describe here an experimental colitis model that is initiated by adoptive transfer of syngeneic splenic CD4(+)CD45RB(high) T cells into T and B cell deficient recipient mice. The CD4(+)CD45RB(high) T cell population that largely consists of naive effector cells is capable of inducing chronic intestinal inflammation, closely resembling key aspects of human IBD. This method can be manipulated to study aspects of disease onset and progression. Additionally it can be used to study the function of innate, adaptive, and regulatory immune cell populations, and the role of environmental exposures, i.e., the microbiota, in intestinal inflammation. In this article we illustrate the methodology for inducing colitis with a step-by-step protocol. This includes a video demonstration of key technical aspects required to successfully develop this murine model of experimental colitis for research purposes. PMID- 25938397 TI - Materia medica & diagnostic dilemmas in Downton Abbey. PMID- 25938398 TI - Cluster of Vaccine-related Invasive Pneumococcal Disease in Previously Vaccinated Healthy Children in Rhode Island. PMID- 25938399 TI - Actual and perceived HBV status among Asian Pacific Islander Americans in Rhode Island: a cross-sectional study. AB - Chronic hepatitis B (HBV) in the Asian and Pacific Islander (API) American population is an under-recognized health issue in the United States. Among foreign-born API, the prevalence of HBV is approximately 10%. The prevalence in the general population is below 0.5%; among non-Hispanic whites it is below 0.2%. We examined beliefs held by the API populations in Rhode Island (RI) about personal HBV status and compared them with their actual HBV status. Of 59 total study participants, only 19 (32%) participants correctly knew their HBV status. Six (10%) participants were carriers of HBV; 18 (31%) lacked immunity to the virus. This pilot study suggests the RI API population is not knowledgeable about their own HBV status and are inadequately screened, vaccinated against, and treated for HBV. Increased statewide screening and education efforts, tailored to address this population, are needed to identify and inform those in need of medical attention or vaccination. PMID- 25938400 TI - Expectation, the placebo effect and the response to treatment. AB - What we believe we will experience from a treatment--our expectation--has a substantial impact on what we actually experience. Expectation has been established as a key process behind the placebo effect. Studies in both laboratory and clinical settings consistently show that when people ingest a pharmacologically inert substance (placebo) but believe that it is an active substance, they experience both the subjective sensations and physiologic effects expected from that active substance. Expectation has an important place in the response to "real" treatment as well. This paper provides an overview of the data which point to the role of expectation in both the placebo effect and the response to treatment. These data suggest that clinicians might enhance the benefit of all treatments by promoting patients' positive expectations. PMID- 25938401 TI - How expectation works: psychologic and physiologic pathways. AB - Although expectation has been the most widely studied of the mechanisms that drive the placebo effect, we still don't know how it works. We don't know how the thought that one will respond to a substance in a certain way is converted to symptom relief, intoxication, or airway resistance; the pathway between expectation of a response and the response itself remains uncharted. Nonetheless, in the last decade, brain-imaging studies have begun to uncover this pathway. This paper reviews both long-standing psychologic concepts about the underpinnings of expectation and some of the contemporary brain imaging research, which shows that when expectation alleviates depression, produces pain relief or improves parkinsonian symptoms, these effects come with relevant changes in brain activity and chemistry. These findings oblige us to reevaluate some of the traditional common sense notions of how expectation brings about its effects and how placebos work. PMID- 25938402 TI - Divergent elbow dislocation and risk of compartment syndrome. AB - BACKGROUND: Divergent pediatric elbow dislocations are very rare injuries. CASE: An eight-year-old boy presented to the emergency department with elbow pain after a fall. On examination his elbow was swollen; skin and neurovascular function were intact. Radiographs demonstrated a divergent elbow dislocation. After successful closed reduction under sedation, the arm was casted; gentle motion was initiated at three weeks. At four months, the patient had full strength, no symptoms, and nearly full range of motion. INTERPRETATION: The literature on the treatment of this injury is limited because of its rarity. We present a case of successful nonoperative management. The return of this patient for compressive symptoms should serve as a reminder that these injuries may be at high risk for compartment syndrome, possibly due to the high level of soft tissue disruption. PMID- 25938403 TI - 'Angina' of the papillary muscle: an overlooked but reversible etiology of mitral regurgitation. PMID- 25938404 TI - Chest pain in a 60-year-old man. PMID- 25938405 TI - Socio-demographic Variation of Adult Seatbelt Non-use in Rhode Island--Different Data Sources. PMID- 25938406 TI - Metabolic Heat Stress Adaption in Transition Cows: Differences in Macronutrient Oxidation between Late-Gestating and Early-Lactating German Holstein Dairy Cows. AB - High ambient temperatures have severe adverse effects on biological functions of high-yielding dairy cows. The metabolic adaption to heat stress was examined in 14 German Holsteins transition cows assigned to two groups, one heat-stressed (HS) and one pair-fed (PF) at the level of HS. After 6 days of thermoneutrality and ad libitum feeding (P1), cows were challenged for 6 days (P2) by heat stress (temperature humidity index (THI) = 76) or thermoneutral pair-feeding in climatic chambers 3 weeks ante partum and again 3 weeks post-partum. On the sixth day of each period P1 or P2, oxidative metabolism was analyzed for 24 hours in open circuit respiration chambers. Water and feed intake, vital parameters and milk yield were recorded. Daily blood samples were analyzed for glucose, beta hydroxybutyric acid, non-esterified fatty acids, urea, creatinine, methyl histidine, adrenaline and noradrenaline. In general, heat stress caused marked effects on water homeorhesis with impairments of renal function and a strong adrenergic response accompanied with a prevalence of carbohydrate oxidation over fat catabolism. Heat-stressed cows extensively degraded tissue protein as reflected by the increase of plasma urea, creatinine and methyl histidine concentrations. However, the acute metabolic heat stress response in dry cows differed from early-lactating cows as the prepartal adipose tissue was not refractory to lipolytic, adrenergic stimuli, and the rate of amino acid oxidation was lower than in the postpartal stage. Together with the lower endogenous metabolic heat load, metabolic adaption in dry cows is indicative for a higher heat tolerance and the prioritization of the nutritional requirements of the fast growing near-term fetus. These findings indicate that the development of future nutritional strategies for attenuating impairments of health and performance due to ambient heat requires the consideration of the physiological stage of dairy cows. PMID- 25938407 TI - XRCC1 Polymorphisms and Urinary 8-Hydroxydeoxyguanine Levels Are Associated with Urothelial Carcinoma. AB - The aim of this study was to examine the associations between the combined effects of urinary 8-Hydroxydeoxyguanine (8-OHdG) level and polymorphisms of XRCC1 Arg194Trp and XRCC1 Arg399Gln on the risk of urothelial carcinoma (UC). We conducted a hospital-based case-control study that included 168 cases of UC and 336 age- and gender-matched healthy controls. We used polymerase chain reaction and restriction fragment length polymorphism analyses to examine the genotypes of XRCC1 Arg194Trp and XRCC1 Arg399Gln. We used a competitive in vitro enzyme-linked immunosorbent assay to determine urinary 8-OHdG levels. The XRCC1 399 Gln/Gln genotype and the XRCC1 194 Arg/Arg genotype were positively correlated to UC (OR [95%CI] = 2.27 [1.20-4.27] and 1.59 [1.06-2.36], respectively). Urinary 8-OHdG levels were associated with UC in a dose-dependent manner. Participants with the XRCC1 (Arg399Gln) Gln/Gln genotype or the G-C/A-C haplotype of XRCC1 and a high urinary 8-OHdG level had a significantly higher risk of UC than those with the Arg/Arg + Arg/Gln genotype or the G-T haplotype and a low urinary 8-OHdG level. This is the first study to investigate the combined effect of urinary 8-OHdG level and XRCC1 polymorphisms on UC risk. The findings are especially meaningful for participants with XRCC1 399Gln or XRCC1 Arg194 genotypes and a high urinary 8 OHdG level, since these variables are associated with an increased risk of UC. PMID- 25938408 TI - Anterior cruciate ligament reconstruction in a rabbit model using silk-collagen scaffold and comparison with autograft. AB - The objective of the present study was to perform an in vivo assessment of a novel silk-collagen scaffold for anterior cruciate ligament (ACL) reconstruction. First, a silk-collagen scaffold was fabricated by combining sericin-extracted knitted silk fibroin mesh and type I collagen to mimic the components of the ligament. Scaffolds were electron-beam sterilized and rolled up to replace the ACL in 20 rabbits in the scaffold group, and autologous semitendinosus tendons were used to reconstruct the ACL in the autograft control group. At 4 and 16 weeks after surgery, grafts were retrieved and analyzed for neoligament regeneration and tendon-bone healing. To evaluate neoligament regeneration, H&E and immunohistochemical staining was performed, and to assess tendon-bone healing, micro-CT, biomechanical test, H&E and Russell-Movat pentachrome staining were performed. Cell infiltration increased over time in the scaffold group, and abundant fibroblast-like cells were found in the core of the scaffold graft at 16 weeks postoperatively. Tenascin-C was strongly positive in newly regenerated tissue at 4 and 16 weeks postoperatively in the scaffold group, similar to observations in the autograft group. Compared with the autograft group, tendon bone healing was better in the scaffold group with trabecular bone growth into the scaffold. The results indicate that the silk-collagen scaffold has considerable potential for clinical application. PMID- 25938409 TI - An individual-based model of zebrafish population dynamics accounting for energy dynamics. AB - Developing population dynamics models for zebrafish is crucial in order to extrapolate from toxicity data measured at the organism level to biological levels relevant to support and enhance ecological risk assessment. To achieve this, a dynamic energy budget for individual zebrafish (DEB model) was coupled to an individual based model of zebrafish population dynamics (IBM model). Next, we fitted the DEB model to new experimental data on zebrafish growth and reproduction thus improving existing models. We further analysed the DEB-model and DEB-IBM using a sensitivity analysis. Finally, the predictions of the DEB-IBM were compared to existing observations on natural zebrafish populations and the predicted population dynamics are realistic. While our zebrafish DEB-IBM model can still be improved by acquiring new experimental data on the most uncertain processes (e.g. survival or feeding), it can already serve to predict the impact of compounds at the population level. PMID- 25938410 TI - Corporate social responsibility: a real options approach to the challenge of financial sustainability. AB - BACKGROUND: In contemporary complex societies, social values like ethics, corporate social responsibility, and being respectful with the environment, among others, are becoming social requirements. Corporations are expected to fulfill them and, according to empirical evidence, an overwhelming majority aspires to good social valuation. At the same time, the maximization of market share value in the long run continues to be the central corporate goal. Making environmental and social expenses compatible with value creation is a central challenge for corporations since it implies the financial sustainability of Corporate Social Responsibility (CSR). METHODS AND RESULTS: The value creation capacity of CSR projects, mainly through innovation, is widely acknowledged in economic literature and corporate practice. This fact arouses the need of having a quantitative framework capable of summarizing the value creation capacity of the variables involved in CSR projects. With this aim we build up a sensitivity analysis of real option ratios that studies and quantifies the value creation capacity of CSR projects connected with innovation. Ratio analysis has the advantage of being scale independent. Hence, it furnishes a homogeneous framework to express the interaction of value creation variables and, thus, supports strategic thinking quantitatively. Often, CSR expenses can be regarded as preliminary projects that create the opportunity to undertake a full future project. For them, we obtain the minimum expectations scenario that makes financially sustainable a preliminary project that can be interpreted as a call option. We propose a classification of CSR projects from the decision analysis perspective following a two-fold approach: Their relationship with value creation and their links with existing corporate activities. This classification of CSR projects aims at contributing to choose the best capital budgeting method to study the financial sustainability of the project and identifying those CSR projects that fulfill the required features to be studied from the real options perspective. PMID- 25938411 TI - Slit-surface electrospinning: a novel process developed for high-throughput fabrication of core-sheath fibers. AB - In this work, we report on the development of slit-surface electrospinning--a process that co-localizes two solutions along a slit surface to spontaneously emit multiple core-sheath cone-jets at rates of up to 1 L/h. To the best of our knowledge, this is the first time that production of electrospun core-sheath fibers has been scaled to this magnitude. Fibers produced in this study were defect-free (i.e. non-beaded) and core-sheath geometry was visually confirmed under scanning electron microscopy. The versatility of our system was demonstrated by fabrication of (1) fibers encapsulating a drug, (2) bicomponent fibers, (3) hollow fibers, and (4) fibers from a polymer that is not normally electrospinnable. Additionally, we demonstrate control of the process by modulating parameters such as flow rate, solution viscosity, and fixture design. The technological achievements demonstrated in this work significantly advance core-sheath electrospinning towards commercial and manufacturing viability. PMID- 25938412 TI - Excitation-contraction coupling in zebrafish ventricular myocardium is regulated by trans-sarcolemmal Ca2+ influx and sarcoplasmic reticulum Ca2+ release. AB - Zebrafish (Danio rerio) have become a popular model in cardiovascular research mainly due to identification of a large number of mutants with structural defects. In recent years, cardiomyopathies and other diseases influencing contractility of the heart have been studied in zebrafish mutants. However, little is known about the regulation of contractility of the zebrafish heart on a tissue level. The aim of the present study was to elucidate the role of trans sarcolemmal Ca(2+)-flux and sarcoplasmic reticulum Ca(2+)-release in zebrafish myocardium. Using isometric force measurements of fresh heart slices, we characterised the effects of changes of the extracellular Ca(2+)-concentration, trans-sarcolemmal Ca(2+)-flux via L-type Ca(2+)-channels and Na(+)-Ca(2+) exchanger, and Ca(2+)-release from the sarcoplasmic reticulum as well as beating frequency and beta-adrenergic stimulation on contractility of adult zebrafish myocardium. We found an overall negative force-frequency relationship (FFR). Inhibition of L-type Ca(2+)-channels by verapamil (1 MUM) decreased force of contraction to 22 +/- 7% compared to baseline (n=4, p<0.05). Ni(2+) was the only substance to prolong relaxation (5 mM, time after peak to 50% relaxation: 73 +/- 3 ms vs. 101 +/- 8 ms, n=5, p<0.05). Surprisingly though, inhibition of the sarcoplasmic Ca(2+)-release decreased force development to 54 +/- 3% in ventricular (n=13, p<0.05) and to 52 +/- 8% in atrial myocardium (n=5, p<0.05) suggesting a substantial role of SR Ca(2+)-release in force generation. In line with this finding, we observed significant post pause potentiation after pauses of 5 s (169 +/- 7% force compared to baseline, n=8, p<0.05) and 10 s (198 +/- 9% force compared to baseline, n=5, p<0.05) and mildly positive lusitropy after beta adrenergic stimulation. In conclusion, force development in adult zebrafish ventricular myocardium requires not only trans-sarcolemmal Ca2+-flux, but also intact sarcoplasmic reticulum Ca(2+)-cycling. In contrast to mammals, FFR is strongly negative in the zebrafish heart. These aspects need to be considered when using zebrafish to model human diseases of myocardial contractility. PMID- 25938413 TI - A novel approach to identifying physical markers of cryo-damage in bull spermatozoa. AB - Cryopreservation is an efficient way to store spermatozoa and plays a critical role in the livestock industry as well as in clinical practice. During cryopreservation, cryo-stress causes substantial damage to spermatozoa. In present study, the effects of cryo-stress at various cryopreservation steps, such as dilution / cooling, adding cryoprtectant, and freezing were studied in spermatozoa collected from 9 individual bull testes. The motility (%), motion kinematics, capacitation status, mitochondrial activity, and viability of bovine spermatozoa at each step of the cryopreservation process were assessed using computer-assisted sperm analysis, Hoechst 33258/chlortetracycline fluorescence, rhodamine 123 staining, and hypo-osmotic swelling test, respectively. The results demonstrate that the cryopreservation steps reduced motility (%), rapid speed (%), and mitochondrial activity, whereas medium/slow speed (%), and the acrosome reaction were increased (P < 0.05). Differences (Delta) of the acrosome reaction were higher in dilution/cooling step (P < 0.05), whereas differences (Delta) of motility, rapid speed, and non-progressive motility were higher in cryoprotectant and freezing as compared to dilution/cooling (P < 0.05). On the other hand, differences (Delta) of mitochondrial activity, viability, and progressive motility were higher in freezing step (P < 0.05) while the difference (Delta) of the acrosome reaction was higher in dilution/cooling (P < 0.05). Based on these results, we propose that freezing / thawing steps are the most critical in cryopreservation and may provide a logical ground of understanding on the cryo damage. Moreover, these sperm parameters might be used as physical markers of sperm cryo-damage. PMID- 25938414 TI - Development of a comprehensive hospital-based elder abuse intervention: an initial systematic scoping review. AB - INTRODUCTION: Elder abuse, a universal human rights problem, is associated with many negative consequences. In most jurisdictions, however, there are no comprehensive hospital-based interventions for elder abuse that address the totality of needs of abused older adults: psychological, physical, legal, and social. As the first step towards the development of such an intervention, we undertook a systematic scoping review. OBJECTIVES: Our primary objective was to systematically extract and synthesize actionable and applicable recommendations for components of a multidisciplinary intersectoral hospital-based elder abuse intervention. A secondary objective was to summarize the characteristics of the responses reviewed, including methods of development and validation. METHODS: The grey and scholarly literatures were systematically searched, with two independent reviewers conducting the title, abstract and full text screening. Documents were considered eligible for inclusion if they: 1) addressed a response (e.g., an intervention) to elder abuse, 2) contained recommendations for responding to abused older adults with potential relevance to a multidisciplinary and intersectoral hospital-based elder abuse intervention; and 3) were available in English. ANALYSIS: The extracted recommendations for care were collated, coded, categorized into themes, and further reviewed for relevancy to a comprehensive hospital-based response. Characteristics of the responses were summarized using descriptive statistics. RESULTS: 649 recommendations were extracted from 68 distinct elder abuse responses, 149 of which were deemed relevant and were categorized into 5 themes: Initial contact; Capacity and consent; Interview with older adult, caregiver, collateral contacts, and/or suspected abuser; ASSESSMENT: physical/forensic, mental, psychosocial, and environmental/functional; and care plan. Only 6 responses had been evaluated, suggesting a significant gap between development and implementation of recommendations. DISCUSSION: To address the lack of evidence to support the recommendations extracted in this review, in a future study, a group of experts will formally evaluate each recommendation for its inclusion in a comprehensive hospital-based response. PMID- 25938415 TI - Confounding factors to predict the awakening effect-site concentration of propofol in target-controlled infusion based on propofol and fentanyl anesthesia. AB - We conducted a large retrospective study to investigate the confounding factors that predict Ce ROC under propofol-based TIVA with TCI. We recorded sex, age, height, weight, Ce LOC, Ce ROC, total propofol and fentanyl consumption dose, and anesthetic time. Simple linear regression models were used to identify potential predictors of Ce ROC, and multiple linear regression models were used to identify the confounding predictors of Ce ROC. We found that Ce ROC correlated with age, sex, Ce LOC, and both total fentanyl and propofol consumption dose. The prediction formula was: Ce ROC = 0.87 - 0.06 * age + 0.18 * Ce LOC + 0.04 (if fentanyl consumption > 150 MUg; if not, ignore this value) + 0.07 * (1 or 2, according to the total propofol consumption dose, 1 for a propofol amount 1000 2000 mg and 2 for a propofol amount > 2000 mg). We simplified the formula further as Ce ROC = 0.87 - 0.06 * age + 0.18 * Ce LOC. In conclusion, Ce ROC can be predicted under TCI with propofol- and fentanyl-based TIVA. The confounding factors that predicted propofol Ce ROC are age, sex, Ce LOC, and total consumption dose of propofol and fentanyl. PMID- 25938416 TI - Bacterial pathogens and community composition in advanced sewage treatment systems revealed by metagenomics analysis based on high-throughput sequencing. AB - This study used 454 pyrosequencing, Illumina high-throughput sequencing and metagenomic analysis to investigate bacterial pathogens and their potential virulence in a sewage treatment plant (STP) applying both conventional and advanced treatment processes. Pyrosequencing and Illumina sequencing consistently demonstrated that Arcobacter genus occupied over 43.42% of total abundance of potential pathogens in the STP. At species level, potential pathogens Arcobacter butzleri, Aeromonas hydrophila and Klebsiella pneumonia dominated in raw sewage, which was also confirmed by quantitative real time PCR. Illumina sequencing also revealed prevalence of various types of pathogenicity islands and virulence proteins in the STP. Most of the potential pathogens and virulence factors were eliminated in the STP, and the removal efficiency mainly depended on oxidation ditch. Compared with sand filtration, magnetic resin seemed to have higher removals in most of the potential pathogens and virulence factors. However, presence of the residual A. butzleri in the final effluent still deserves more concerns. The findings indicate that sewage acts as an important source of environmental pathogens, but STPs can effectively control their spread in the environment. Joint use of the high-throughput sequencing technologies is considered a reliable method for deep and comprehensive overview of environmental bacterial virulence. PMID- 25938417 TI - Tree Species Composition and Harvest Intensity Affect Herbivore Density and Leaf Damage on Beech, Fagus sylvatica, in Different Landscape Contexts. AB - Most forests are exposed to anthropogenic management activities that affect tree species composition and natural ecosystem processes. Changes in ecosystem processes such as herbivory depend on management intensity, and on regional environmental conditions and species pools. Whereas influences of specific forest management measures have already been addressed for different herbivore taxa on a local scale, studies considering effects of different aspects of forest management across different regions are rare. We assessed the influence of tree species composition and intensity of harvesting activities on arthropod herbivores and herbivore-related damage to beech trees, Fagus sylvatica, in 48 forest plots in three regions of Germany. We found that herbivore abundance and damage to beech trees differed between regions and that - despite the regional differences - density of tree-associated arthropod taxa and herbivore damage were consistently affected by tree species composition and harvest intensity. Specifically, overall herbivore damage to beech trees increased with increasing dominance of beech trees - suggesting the action of associational resistance processes - and decreased with harvest intensity. The density of leaf chewers and mines was positively related to leaf damage, and several arthropod groups responded to beech dominance and harvest intensity. The distribution of damage patterns was consistent with a vertical shift of herbivores to higher crown layers during the season and with higher beech dominance. By linking quantitative data on arthropod herbivore abundance and herbivory with tree species composition and harvesting activity in a wide variety of beech forests, our study helps to better understand the influence of forest management on interactions between a naturally dominant deciduous forest tree and arthropod herbivores. PMID- 25938418 TI - Physical exercise enhances cognitive flexibility as well as astrocytic and synaptic markers in the medial prefrontal cortex. AB - Physical exercise enhances a wide range of cognitive functions in humans. Running induced cognitive enhancement has also been demonstrated in rodents but with a strong emphasis on tasks that require the hippocampus. Additionally, studies designed to identify mechanisms that underlie cognitive enhancement with physical exercise have focused on running-induced changes in neurons with little attention paid to such changes in astrocytes. To further our understanding of how the brain changes with physical exercise, we investigated whether running alters performance on cognitive tasks that require the prefrontal cortex and whether any such changes are associated with astrocytic, as well as neuronal, plasticity. We found that running enhances performance on cognitive tasks known to rely on the prefrontal cortex. By contrast, we found no such improvement on a cognitive task known to rely on the perirhinal cortex. Moreover, we found that running enhances synaptic, dendritic and astrocytic measures in several brain regions involved in cognition but that changes in the latter measures were more specific to brain regions associated with cognitive improvements. These findings suggest that physical exercise induces widespread plasticity in both neuronal and nonneuronal elements and that both types of changes may be involved in running-induced cognitive enhancement. PMID- 25938419 TI - Correction: A novel minimally-invasive method to sample human endothelial cells for molecular profiling. PMID- 25938420 TI - Bariatric Surgery Induces Disruption in Inflammatory Signaling Pathways Mediated by Immune Cells in Adipose Tissue: A RNA-Seq Study. AB - BACKGROUND: Bariatric surgery is associated to improvements in obesity-associated comorbidities thought to be mediated by a decrease of adipose inflammation. However, the molecular mechanisms behind these beneficial effects are poorly understood. METHODOLOGY/PRINCIPAL FINDINGS: We analyzed RNA-seq expression profiles in adipose tissue from 22 obese women before and 3 months after surgery. Of 15,972 detected genes, 1214 were differentially expressed after surgery at a 5% false discovery rate. Upregulated genes were mostly involved in the basal cellular machinery. Downregulated genes were enriched in metabolic functions of adipose tissue. At baseline, 26 modules of coexpressed genes were identified. The four most stable modules reflected the innate and adaptive immune responses of adipose tissue. A first module reflecting a non-specific signature of innate immune cells, mainly macrophages, was highly conserved after surgery with the exception of DUSP2 and CD300C. A second module reflected the adaptive immune response elicited by T lymphocytes; after surgery, a disconnection was observed between genes involved in T-cell signaling and mediators of the signal transduction such as CXCR1, CXCR2, GPR97, CCR7 and IL7R. A third module reflected neutrophil-mediated inflammation; after surgery, several genes were dissociated from the module, including S100A8, S100A12, CD300E, VNN2, TUBB1 and FAM65B. We also identified a dense network of 19 genes involved in the interferon-signaling pathway which was strongly preserved after surgery, with the exception of DDX60, an antiviral factor involved in RIG-I-mediated interferon signaling. A similar loss of connection was observed in lean mice compared to their obese counterparts. CONCLUSIONS/SIGNIFICANCE: These results suggest that improvements of the inflammatory state following surgery might be explained by a disruption of immuno-inflammatory cascades involving a few crucial molecules which could serve as potential therapeutic targets. PMID- 25938421 TI - Small-conductance Ca2+-activated potassium type 2 channels regulate the formation of contextual fear memory. AB - Small-conductance, Ca2+ activated K+ channels (SK channels) are expressed at high levels in brain regions responsible for learning and memory. In the current study we characterized the contribution of SK2 channels to synaptic plasticity and to different phases of hippocampal memory formation. Selective SK2 antisense treatment facilitated basal synaptic transmission and theta-burst induced LTP in hippocampal brain slices. Using the selective SK2 antagonist Lei-Dab7 or SK2 antisense probes, we found that hippocampal SK2 channels are critical during two different time windows: 1) blockade of SK2 channels before the training impaired fear memory, whereas, 2) blockade of SK2 channels immediately after the training enhanced contextual fear memory. We provided the evidence that the post-training cleavage of the SK2 channels was responsible for the observed bidirectional effect of SK2 channel blockade on memory consolidation. Thus, Lei-Dab7-injection before training impaired the C-terminal cleavage of SK2 channels, while Lei-Dab7 given immediately after training facilitated the C-terminal cleavage. Application of the synthetic peptide comprising a leucine-zipper domain of the C-terminal fragment to Jurkat cells impaired SK2 channel-mediated currents, indicating that the endogenously cleaved fragment might exert its effects on memory formation by blocking SK2 channel-mediated currents. Our present findings suggest that SK2 channel proteins contribute to synaptic plasticity and memory not only as ion channels but also by additionally generating a SK2 C-terminal fragment, involved in both processes. The modulation of fear memory by down-regulating SK2 C terminal cleavage might have applicability in the treatment of anxiety disorders in which fear conditioning is enhanced. PMID- 25938422 TI - The Relative Concentrations of Nutrients and Toxins Dictate Feeding by a Vertebrate Browser, the Greater Glider Petauroides volans. AB - Although ecologists believe that vertebrate herbivores must select a diet that allows them to meet their nutritional requirements, while avoiding intoxication by plant secondary metabolites, this is remarkably difficult to show. A long series of field and laboratory experiments means that we have a good understanding of the factors that affect feeding by leaf-eating marsupials. This knowledge and the natural intraspecific variation in Eucalyptus chemistry allowed us to test the hypothesis that the feeding decisions of greater gliders (Petauroides volans) depend on the concentrations of available nitrogen (incorporating total nitrogen, dry matter digestibility and tannins) and of formylated phloroglucinol compounds (FPCs), potent antifeedants unique to Eucalyptus. We offered captive greater gliders foliage from two species of Eucalyptus, E. viminalis and E. melliodora, which vary naturally in their concentrations of available nitrogen and FPCs. We then measured the amount of foliage eaten by each glider and compared this with our laboratory analyses of foliar total nitrogen, available nitrogen and FPCs for each tree offered. The concentration of FPCs was the main factor that determined how much gliders ate of E. viminalis and E. melliodora, but in gliders fed E. viminalis the concentration of available nitrogen was also a significant influence. In other words, greater gliders ate E. viminalis leaves with a particular combination of FPCs and available nitrogen that maximised the nutritional gain but minimised their ingestion of toxins. In contrast, the concentration of total nitrogen was not correlated with feeding. This study is among the first to empirically show that browsing herbivores select a diet that balances the potential gain (available nutrients) and the potential costs (plant secondary chemicals) of eating leaves. The major implication of the study is that it is essential to identify the limiting nutrients and relevant toxins in a system in order to understand feeding behaviour. PMID- 25938423 TI - Preparation and Biodistribution of Technetium-99m-Labeled Bis- Misonidazole (MISO) as an Imaging Agent for Tumour Hypoxia. AB - Diagnosis of tumour hypoxia is an important aspect in determining the course of tumour therapy. In this study, we developed a novel imaging agent, (99m)Tc ethylenedicysteine-bis-misonidazole ((99m)Tc-EC-MISO), for diagnosing tumour hypoxia. We used 2-nitroimidazole as a reactant to synthesize the amino derivative of misonidazole (MISO) in the first step and then conjugated the di amino derivative of MISO to the chelating agent ethylenedicysteine (EC) for labelling (99m)Tc in the second step. (99m)Tc-pertechnetate ((99m)TcO4-) was reduced by tin chloride (SnCl2) for radiolabeling. The radiochemical purity was up to 94%. Tissue biodistribution and SPECT/CT imaging studies were conducted on subcutaneous gliomal tumour-bearing mice. The tumour-to-muscle ratio in the (99m)Tc-EC-MISO group increased with time, up to 4.6 at 4 h after injection. SPECT/CT imaging confirmed that the tumours could be visualized clearly with (99m)Tc-EC-MISO at 2 h. By introducing a second 2-nitroimidazole redox centre, an apparent hypoxic accumulation of this novel (99m)Tc-labeled imaging agent in the tumour was observed. PMID- 25938424 TI - Exploring the synthesis and anticancer potential of L-tyrosine-platinum(II) hybrid molecules. AB - The search for new specific chemotherapeutic drugs designed to minimize the toxic side effects resulting from chemotherapy is still a subject of intense research. The objective of the current study was to design a non-steroidal-platinum(II) derivative that would target the estrogen receptor alpha (ERalpha) without triggering estrogenic cell proliferation. For this purpose, the amino acid L tyrosine was modified and attached to a cisplatin analog. Hence, the L-tyrosine portion of the molecule could possibly act as a transporter to target the ERalpha protein and, by doing so concentrate the cytotoxic moiety to hormone-dependent breast cancer cells. Herein, we describe three different alternative methodologies that were used to make these new anticancer molecules. The L tyrosine-Pt(II) hybrid 5b was made in four steps with 36% overall yield by the first method, in six steps with 11% overall yield by the second method and, in four steps with 23% overall yield by the third method. Preliminary biological activity on breast cancer cell lines indicated that the final hybrids (5a and 5b) were unfortunately inactive but their platinum(II) precursors (14a and 14b) showed activity similar to that of cisplatin. PMID- 25938425 TI - Design, Synthesis and Biological Evaluation of Palladium (II) Complexes with 1 (substituted benzyl) azetidine-3,3-dicarboxylates as Leaving Group. AB - A series of palladium complexes with 2,2'-bipyridine and 1-(substituted benzyl) azetidine- 3, 3-dicarboxylates as ligands were synthesized and characterized by IR, (1)H-NMR, ESI-MS spectra and elemental analysis. The in vitro cytotoxicity assays were carried out against A549, HCT-116, HepG-2 and SGC7901 cancer cell lines. The result showed that most of the complexes possessed moderate antiproliferative activity against HCT-116, HepG-2 and SGC7901 cell lines. Complex 12 (with 2,2'-bipyridine and 1-(3-methoxylbenzyl)azetidine-3,3 dicarboxylate as ligand) was the most potent antitumor agent among all thirteen complexes, which showed comparable or better cytotoxicity against all four tested cancer cell lines than carboplatin. The interaction between complex 12 and pET22b plasmid DNA was investigated by agarose gel electrophoresis, and the result of the study showed that complex 12 had no obvious interaction with the plasmid DNA. PMID- 25938426 TI - Synthesis and Antibacterial Activity of Novel Quaternary Ammonium Pyridoxine Derivatives. AB - A series of 26 quaternary ammonium pyridoxine derivatives were synthesized and their cytotoxicity and antibacterial activities against clinically relevant bacterial strains were tested in vitro. The antibacterial activity of mono ammonium salts increased with the rise of the lipophilicity and compound 3,3,5 trimethyl-8,8-dioctyl-1,7,8,9-tetrahydro-[1,3]dioxino[5,4-d]pyrrolo[3,4-b]pyridin 8-ium chloride (2d) reaches a maximum among them. Bis-ammonium salt of pyridoxine 4 with two dimethyloctylamine groups also demonstrated high antibacterial activity despite lower lipophilicity. The results of MTT assay indicated that HEK 293 cells were more sensitive than HSF to quaternary ammonium pyridoxine derivatives. Compounds 2d and 4 did not induce the damage of the DNA and might be of interest in the development of new antimicrobials. PMID- 25938427 TI - Targeting tumor vasculature with aptamer-functionalized doxorubicin-polylactide nanoconjugates for enhanced cancer therapy. AB - An A10 aptamer (Apt)-functionalized, sub-100 nm doxorubicin-polylactide (Doxo PLA) nanoconjugate (NC) with controlled release profile was developed as an intravenous therapeutic strategy to effectively target and cytoreduce canine hemangiosarcoma (cHSA), a naturally occurring solid tumor malignancy composed solely of tumor-associated endothelium. cHSA consists of a pure population of malignant endothelial cells expressing prostate-specific membrane antigen (PSMA) and is an ideal comparative tumor model system for evaluating the specificity and feasibility of tumor-associated endothelial cell targeting by A10 Apt functionalized NC (A10 NC). In vitro, A10 NCs were selectively internalized across a panel of PSMA-expressing cancer cell lines, and when incorporating Doxo, A10 Doxo-PLA NCs exerted greater cytotoxic effects compared to nonfunctionalized Doxo-PLA NCs and free Doxo. Importantly, intravenously delivered A10 NCs selectively targeted PSMA-expressing tumor-associated endothelial cells at a cellular level in tumor-bearing mice and dramatically increased the uptake of NCs by endothelial cells within the local tumor microenvironment. By virtue of controlled drug release kinetics and selective tumor-associated endothelial cell targeting, A10 Doxo-PLA NCs possess a desirable safety profile in vivo, being well-tolerated following high-dose intravenous infusion in mice, as supported by the absence of any histologic organ toxicity. In cHSA-implanted mice, two consecutive intravenous infusions of A10 Doxo-PLA NCs exerted rapid and substantial cytoreductive activities within a period of 7 days, resulting in greater than 70% reduction in macroscopic tumor-associated endothelial cell burden as a consequence of enhanced cell death and necrosis. PMID- 25938428 TI - Is antibiotic prophylaxis beneficial in acute pancreatitis?--First update. AB - This Living FRISBEE (Living FRIendly Summary of the Body of Evidence using Epistemonikos) is an update of the summary published in August 2014, based on two systematic reviews appeared in January and February 2015. There is controversy about the effects of prophylactic antibiotics in acute pancreatitis. Searching in Epistemonikos database, which is maintained by screening 30 databases, we identified 18 systematic reviews including 19 randomised studies overall. We combined the evidence using meta-analysis and generated a summary of findings following the GRADE approach. We concluded that prophylactic antibiotics may reduce mortality and length of hospitalization in patients with acute pancreatitis, but the certainty of the evidence is low. The probability that future evidence change what we know is high. PMID- 25938429 TI - Estimating the Basic Reproductive Number (R0) for African Swine Fever Virus (ASFV) Transmission between Pig Herds in Uganda. AB - African swine fever (ASF) is a highly contagious, lethal and economically devastating haemorrhagic disease of domestic pigs. Insights into the dynamics and scale of virus transmission can be obtained from estimates of the basic reproduction number (R0). We estimate R0 for ASF virus in small holder, free range pig production system in Gulu, Uganda. The estimation was based on data collected from outbreaks that affected 43 villages (out of the 289 villages with an overall pig population of 26,570) between April 2010 and November 2011. A total of 211 outbreaks met the criteria for inclusion in the study. Three methods were used, specifically; (i) GIS- based identification of the nearest infectious neighbour based on the Euclidean distance between outbreaks, (ii) epidemic doubling time, and (iii) a compartmental susceptible-infectious (SI) model. For implementation of the SI model, three approaches were used namely; curve fitting (CF), a linear regression model (LRM) and the SI/N proportion. The R0 estimates from the nearest infectious neighbour and epidemic doubling time methods were 3.24 and 1.63 respectively. Estimates from the SI-based method were 1.58 for the CF approach, 1.90 for the LRM, and 1.77 for the SI/N proportion. Since all these values were above one, they predict the observed persistence of the virus in the population. We hypothesize that the observed variation in the estimates is a consequence of the data used. Higher resolution and temporally better defined data would likely reduce this variation. This is the first estimate of R0 for ASFV in a free range smallholder pig keeping system in sub-Saharan Africa and highlights the requirement for more efficient application of available disease control measures. PMID- 25938430 TI - Representation of Sound Objects within Early-Stage Auditory Areas: A Repetition Effect Study Using 7T fMRI. AB - Environmental sounds are highly complex stimuli whose recognition depends on the interaction of top-down and bottom-up processes in the brain. Their semantic representations were shown to yield repetition suppression effects, i. e. a decrease in activity during exposure to a sound that is perceived as belonging to the same source as a preceding sound. Making use of the high spatial resolution of 7T fMRI we have investigated the representations of sound objects within early stage auditory areas on the supratemporal plane. The primary auditory cortex was identified by means of tonotopic mapping and the non-primary areas by comparison with previous histological studies. Repeated presentations of different exemplars of the same sound source, as compared to the presentation of different sound sources, yielded significant repetition suppression effects within a subset of early-stage areas. This effect was found within the right hemisphere in primary areas A1 and R as well as two non-primary areas on the antero-medial part of the planum temporale, and within the left hemisphere in A1 and a non-primary area on the medial part of Heschl's gyrus. Thus, several, but not all early-stage auditory areas encode the meaning of environmental sounds. PMID- 25938431 TI - Violacein Treatment Modulates Acute and Chronic Inflammation through the Suppression of Cytokine Production and Induction of Regulatory T Cells. AB - Inflammation is a necessary process to control infection. However, exacerbated inflammation, acute or chronic, promotes deleterious effects in the organism. Violacein (viola), a quorum sensing metabolite from the Gram-negative bacterium Chromobacterium violaceum, has been shown to protect mice from malaria and to have beneficial effects on tumors. However, it is not known whether this drug possesses anti-inflammatory activity. In this study, we investigated whether viola administration is able to reduce acute and chronic autoimmune inflammation. For that purpose, C57BL/6 mice were intraperitoneally injected with 1 MUg of LPS and were treated with viola (3.5mg/kg) via i.p. at the same time-point. Three hours later, the levels of inflammatory cytokines in the sera and phenotypical characterization of leukocytes were determined. Mice treated with viola presented a significant reduction in the production of inflammatory cytokines compared with untreated mice. Interestingly, although viola is a compound derived from bacteria, it did not induce inflammation upon administration to naive mice. To test whether viola would protect mice from an autoimmune inflammation, Experimental Autoimmune Encephalomyelitis (EAE)-inflicted mice were given viola i.p. at disease onset, at the 10th day from immunization. Viola-treated mice developed mild EAE disease in contrast with placebo-treated mice. The frequencies of dendritic cells and macrophages were unaltered in EAE mice treated with viola. However, the sole administration of viola augmented the levels of splenic regulatory T cells (CD4+Foxp3+). We also found that adoptive transfer of viola elicited regulatory T cells significantly reduced EAE. Our study shows, for the first time, that violacein is able to modulate acute and chronic inflammation. Amelioration relied in suppression of cytokine production (in acute inflammation) and stimulation of regulatory T cells (in chronic inflammation). New studies must be conducted in order to assess the possible use of viola in therapeutic approaches in human autoimmune diseases. PMID- 25938432 TI - Tn-seq explorer: a tool for analysis of high-throughput sequencing data of transposon mutant libraries. AB - Tn-seq is a high throughput technique for analysis of transposon mutant libraries. Tn-seq Explorer was developed as a convenient and easy-to-use package of tools for exploration of the Tn-seq data. In a typical application, the user will have obtained a collection of sequence reads adjacent to transposon insertions in a reference genome. The reads are first aligned to the reference genome using one of the tools available for this task. Tn-seq Explorer reads the alignment and the gene annotation, and provides the user with a set of tools to investigate the data and identify possibly essential or advantageous genes as those that contain significantly low counts of transposon insertions. Emphasis is placed on providing flexibility in selecting parameters and methodology most appropriate for each particular dataset. Tn-seq Explorer is written in Java as a menu-driven, stand-alone application. It was tested on Windows, Mac OS, and Linux operating systems. The source code is distributed under the terms of GNU General Public License. The program and the source code are available for download at http://www.cmbl.uga.edu/downloads/programs/Tn_seq_Explorer/ and https://github.com/sina-cb/Tn-seqExplorer. PMID- 25938433 TI - A study of molecular signals deregulating mismatch repair genes in prostate cancer compared to benign prostatic hyperplasia. AB - Prostate cancer is one of the leading causes of mortality among aging males. There is an unmet requirement of clinically useful biomarkers for early detection of prostate cancer to reduce the liabilities of overtreatment and accompanying morbidity. The present population-based study investigates the factors disrupting expression of multiple functionally related genes of DNA mismatch repair pathway in prostate cancer patients to identify molecular attributes distinguishing adenocarcinoma from benign hyperplasia of prostate. Gene expression was compared between tissue samples from prostate cancer and benign prostatic hyperplasia using real-time-PCR, western blot and immunohistochemistry. Assessment of genotypes of seven single-nucleotide-polymorphisms of three MMR genes was conducted using PCR-coupled RFLP and sequencing. Promoter methylation was interrogated by methylation-specific-PCR and bisulfite-sequencing. Interaction between microRNAs and MMR genes was verified by 3'UTR-based dual luciferase assays. Concurrent reduction of three MMR genes namely hMLH1, hMSH6 and hMSH2 (34 85%, P<0.05) was observed in prostate cancer tissues. hMSH6 polymorphism rs1800932(Pro92Pro) conferred a borderline protection in cancer patients (OR = 0.33, 95% CI = 0.15-0.75). Relative transcript level of hMLH1 was inversely related (r = -0.59, P<0.05) with methylation quotient of its promoter which showed a significantly higher methylation density (P = 0.008, Z = -2.649) in cancer patients. hsa-miR-155, hsa-miR-141 and hsa-miR-21 gene expressions were significantly elevated (66-85%, P<0.05) in tumor specimens and negatively correlated (r = -0.602 to -0.527, P<0.05) with that of MMR genes. hsa-miR-155 & hsa-miR-141 and hsa-miR-155 & hsa-miR-21 were demonstrated to bind to their putative seed sequences in hMLH1 and hMSH6 3'UTRs respectively. Relatively higher expression of DNA methyl-transferases (DNMT1 and DNMT3b) and HIF-1alpha genes (34 50%, P<0.05) were also detected in tumor tissues. This study provides statistical evidence that MMR deficiency is correlated with hypermethylation of hMLH1 promoter and upregulation of hsa-miR-155, hsa-miR-141 and hsa-miR-21 in prostate cancer. This comparative study reflects that microRNA expression level, particularly hsa-miR-155, exhibits predictive signature of prostate adenocarcinoma. PMID- 25938434 TI - Whole Genomic Analysis of Human G12P[6] and G12P[8] Rotavirus Strains that Have Emerged in Myanmar. AB - G12 rotaviruses are emerging rotavirus strains causing severe diarrhea in infants and young children worldwide. However, the whole genomes of only a few G12 strains have been fully sequenced and analyzed. In this study, we sequenced and characterized the complete genomes of six G12 strains (RVA/Human tc/MMR/A14/2011/G12P[8], RVA/Human-tc/MMR/A23/2011/G12P[6], RVA/Human tc/MMR/A25/2011/G12P[8], RVA/Human-tc/MMR/P02/2011/G12P[8], RVA/Human tc/MMR/P39/2011/G12P[8], and RVA/Human-tc/MMR/P43/2011/G12P[8]) detected in six stool samples from children with acute gastroenteritis in Myanmar. On whole genomic analysis, all six Myanmarese G12 strains were found to have a Wa-like genetic backbone: G12-P[8]-I1-R1-C1-M1-A1-N1-T1-E1-H1 for strains A14, A25, P02, P39, and P43, and G12-P[6]-I1-R1-C1-M1-A1-N1-T1-E1-H1 for strain A23. Phylogenetic analysis showed that most genes of the six strains examined in this study were genetically related to globally circulating human G1, G3, G9, and G12 strains. Of note is that the NSP4 gene of strain A23 exhibited the closest relationship with the cognate genes of human-like bovine strains as well as human strains, suggesting the occurrence of reassortment between human and bovine strains. Furthermore, strains A14, A25, P02, P39, and P43 were very closely related to one another in all the 11 gene segments, indicating derivation of the five strains from a common origin. On the other hand, strain A23 consistently formed distinct clusters as to all the 11 gene segments, indicating a distinct origin of strain A23 from that of strains A14, A25, P02, P39, and P43. To our knowledge, this is the first report on whole genome-based characterization of G12 strains that have emerged in Myanmar. Our observations will provide important insights into the evolutionary dynamics of spreading G12 rotaviruses in Asia. PMID- 25938435 TI - RNA-Seq Based De Novo Transcriptome Assembly and Gene Discovery of Cistanche deserticola Fleshy Stem. AB - BACKGROUNDS: Cistanche deserticola is a completely non-photosynthetic parasitic plant with great medicinal value and mainly distributed in desert of Northwest China. Its dried fleshy stem is a crucial tonic in traditional Chinese medicine with roles of mainly improving male sexual function and strengthening immunity, but few mechanistic studies have been conducted partly due to the lack of genomic and transcriptomic resources. RESULTS: In this study, we performed deep transcriptome sequencing in fleshy stem of C. deserticola, and about 80 million reads were generated using Illumina pair-end sequencing on HiSeq2000 platform. Using trinity assembler, we obtained 95,787 transcript sequences with transcript lengths ranging from 200 bp to 15,698 bp, having an average length of 950 bases and the N50 length of 1,519 bases. 63,957 transcripts were identified actively expressed with FPKM >= 0.5, in which 30,098 transcripts were annotated with gene descriptions or gene ontology terms by sequence similarity analyses against several public databases (Uniprot, NR and Nt at NCBI, and KEGG). Furthermore, we identified key enzyme genes involved in biosynthesis of lignin and phenylethanoid glycosides (PhGs) which are known to be the primary active ingredients. Four phenylalanine ammonia-lyase (PAL) genes, the first key enzyme in lignin and PhG biosynthesis, were identified based on sequences comparison and phylogenetic analysis. Two biosynthesis pathways of PhGs were also proposed for the first time. CONCLUSIONS: In all, we completed a global analysis of the C. deserticola fleshy stem transcriptome using RNA-seq technology. A collection of enzyme genes related to biosynthesis of lignin and phenylethanoid glysides were identified from the assembled and annotated transcripts, and the gene family of PAL was also predicted. The sequence data from this study will provide a valuable resource for conducting future phenylethanoid glysides biosynthesis researches and functional genomic studies in this important medicinal plant. PMID- 25938436 TI - Bacterial Diversity Associated with Cinachyra cavernosa and Haliclona pigmentifera, Cohabiting Sponges in the Coral Reef Ecosystem of Gulf of Mannar, Southeast Coast of India. AB - Sponges are abundant, diverse and functionally important organisms of coral reef ecosystems. Sponge-associated microorganisms have been receiving greater attention because of their significant contribution to sponge biomass, biogeochemical cycles and biotechnological potentials. However, our understanding of the sponge microbiome is limited to a few species of sponges from restricted geographical locations. Here, we report for the first time the bacterial diversity of two cohabiting sponges, viz. Cinachyra cavernosa and Haliclona pigmentifera, as well as that in the ambient water from the coral reef ecosystems of the Gulf of Mannar, located along the southeast coast of India. Two hundred and fifty two clones in the 16S rRNA gene library of these sponges were grouped into eight distinct phyla, of which four belonged to the core group that are associated only with sponges. Phylogenetic analysis of the core bacteria showed close affinity to other sponge-associated bacteria from different geographical locations. gamma-Proteobacteria, Chloroflexi, Planctomycetes and Deferribacter were the core groups in C. cavernosa while beta and delta-Proteobacteria performed this role in H. pigmentifera. We observed greater OTU diversity for C. cavernosa (H| 2.07) compared to H. pigmentifera (H| 1.97). UniFrac analysis confirmed the difference in bacterial diversity of the two sponge species and also between the sponges and the reef water (p<0.001). The results of our study restate the existence of a host driven force in shaping the sponge microbiome. PMID- 25938437 TI - Diverse Kir expression contributes to distinct bimodal distribution of resting potentials and vasotone responses of arterioles. AB - The resting membrane potential (RP) of vascular smooth muscle cells (VSMCs) is a major determinant of cytosolic calcium concentration and vascular tone. The heterogeneity of RPs and its underlying mechanism among different vascular beds remain poorly understood. We compared the RPs and vasomotion properties between the guinea pig spiral modiolar artery (SMA), brain arterioles (BA) and mesenteric arteries (MA). We found: 1) RPs showed a robust bimodal distribution peaked at 76 and -40 mV evenly in the SMA, unevenly at -77 and -51 mV in the BA and ~-71 and -52 mV in the MA. Ba(2+) 0.1 mM eliminated their high RP peaks ~-75 mV. 2) Cells with low RP (~-45 mV) hyperpolarized in response to 10 mM extracellular K(+), while cells with a high RP depolarized, and cells with intermediate RP (~ 58 mV) displayed an initial hyperpolarization followed by prolonged depolarization. Moderate high K(+) typically induced dilation, constriction and a dilation followed by constriction in the SMA, MA and BA, respectively. 3) Boltzmann-fit analysis of the Ba(2+)-sensitive inward rectifier K(+) (Kir) whole cell current showed that the maximum Kir conductance density significantly differed among the vessels, and the half-activation voltage was significantly more negative in the MA. 4) Corresponding to the whole-cell data, computational modeling simulated the three RP distribution patterns and the dynamics of RP changes obtained experimentally, including the regenerative swift shifts between the two RP levels after reaching a threshold. 5) Molecular works revealed strong Kir2.1 and Kir2.2 transcripts and Kir2.1 immunolabeling in all 3 vessels, while Kir2.3 and Kir2.4 transcript levels varied. We conclude that a dense expression of functional Kir2.X channels underlies the more negative RPs in endothelial cells and a subset of VSMC in these arterioles, and the heterogeneous Kir function is primarily responsible for the distinct bimodal RPs among these arterioles. The fast Kir-based regenerative shifts between two RP states could form a critical mechanism for conduction/spread of vasomotion along the arteriole axis. PMID- 25938438 TI - Association between CEBPE Variant and Childhood Acute Leukemia Risk: Evidence from a Meta-Analysis of 22 Studies. AB - The CCAAT/enhancer binding proteins (CEBPs) have been involved in the etiology of acute leukemia (AL) and investigated in numerous genetic association studies, however, the results were inconclusive. The current meta-analysis was conducted to clarify the effect of CEBPE rs2239633 variant on childhood AL risk. Electronic literature search was performed on August 15, 2014, from databases of Medline, PubMed, Embase, and Web of Science. A total of 22 case-control studies were eligible for the pooled analysis. The results demonstrated that rs2239633 A allele was significantly associated with a decreased risk of childhood AL (A vs G: OR=0.87, 95%CI = 0.80, 0.94, p<0.001), especially in B-cell ALL subgroup (A vs G: OR = 0.79, 95%CI = 0.74, 0.83, p<0.001), but not among T-cell ALL or AML subgroups. In the stratified analysis by ethnicity, the association was observed in Europeans (A vs G: OR = 0.80, 95%CI = 0.76, 0.84, p<0.001) but not in Asian and mixed populations. Moreover, the results of sensitivity and cumulative meta analysis indicated the robustness of our results. Also, Begg's and Egger's tests did not indicate any evidence of obvious asymmetry. In summary, our study provided evidence that CEBPE rs2239633 variant is associated with decreased risk of childhood B-cell ALL in Europeans. PMID- 25938439 TI - Novel Clinical Evidence of an Association between Homocysteine and Insulin Resistance in Patients with Hypothyroidism or Subclinical Hypothyroidism. AB - OBJECTIVE: Hypothyroidism (HO) can induce significant metabolic dysfunction and increase cardiovascular disease risk. In the present study, we investigated the relationship between homocysteine (Hcy) and insulin resistance (IR) in patients with HO or subclinical hypothyroidism (SHO). METHODS: A total of 270 subjects were enrolled. All subjects were divided into the following three groups: HO, SHO and control. Plasma levels of Hcy were measured, and each patient's homeostatic index of insulin resistance (HOMA-IR) was calculated. Statistical analyses were carried out to evaluate the correlations among groups and to determine the predictors of IR in patients with HO or SHO. RESULTS: The HOMA-IR value was significantly higher in the HO group than in the SHO and control groups. Plasma levels of Hcy were markedly increased in the HO group compared with those of the SHO group and controls. In addition, plasma levels of Hcy were positively correlated with the HOMA-IR values in both the HO and SHO groups. Multiple linear regression models showed that plasma levels of Hcy and free thyroxine (FT4) were the only predictors of HOMA-IR in patients with HO or SHO. CONCLUSIONS: Plasma levels of Hcy and HOMA-IR were increased in patients with HO or SHO. Our results suggest that HO and SHO may increase the risk for atherogenesis and cardiovascular disease by increased IR. The increased IR induced by hyperhomocysteinemia in patients with HO or SHO may partially explain this adverse effect. PMID- 25938440 TI - Use of an autologous liver round ligament flap zeros postoperative bile leak after curative resection of hilar cholangiocarcinoma. AB - BACKGROUND: Postoperative bile leak is a major surgical morbidity after curative resection with hepaticojejunostomy for hilar cholangiocarcinoma, especially in Bismuth-Corlette types III and IV. This retrospective study assessed the effectiveness and safety of an autologous hepatic round ligament flap (AHRLF) for reducing bile leak after hilar hepaticojejunostomy. METHODS: Nine type III and IV hilar cholangiocarcinoma patients were consecutively hospitalized for elective perihilar partial hepatectomy with hilar hepaticojejunostomy using an AHRLF between October 2009 and September 2013. The AHRLF was harvested to reinforce the perihilar hepaticojejunostomy. Main outcome measures included operative time, blood loss, postoperative recovery times, morbidity, bile leak, R0 resection rate, and overall survival. RESULTS: All patients underwent uneventful R0 resection with hilar hepaticojejunostomy. No patient experienced postoperative bile leak. CONCLUSIONS: The AHRLF was associated with lack of bile leak after curative perihilar hepatectomy with hepaticojejunostomy for hilar cholangiocarcinoma, without compromising oncologic safety, and is recommended in selected patients. PMID- 25938441 TI - Oxidant trade-offs in immunity: an experimental test in a lizard. AB - Immune system functioning and maintenance entails costs which may limit investment into other processes such as reproduction. Yet, the proximate mechanisms and 'currencies' mediating the costs of immune responses remain elusive. In vertebrates, up-regulation of the innate immune system is associated with rapid phagocytic production of pro-oxidant molecules (so-called 'oxidative burst' responses). Oxidative burst responses are intended to eliminate pathogens but may also constitute an immunopathological risk as they may induce oxidative damage to self cells. To minimize the risk of infection and, at the same time, damage to self, oxidative burst activity must be carefully balanced. The current levels of pro- and antioxidants (i.e. the individual oxidative state) is likely to be a critical factor affecting this balance, but this has not yet been evaluated. Here, we perform an experiment on wild-caught painted dragon lizards (Ctenophorus pictus) to examine how the strength of immune-stimulated oxidative burst responses of phagocytes in whole blood relates to individual oxidative status under control conditions and during an in vivo immune challenge with Escherichia coli lipopolysaccharide (LPS). Under control conditions, oxidative burst responses were not predicted by the oxidative status of the lizards. LPS injected individuals showed a strong increase in pro-oxidant levels and a strong decrease in antioxidant levels compared to control individuals demonstrating a shift in the pro-/antioxidant balance. Oxidative burst responses in LPS-injected lizards were positively related to post-challenge extracellular pro-oxidants (reflecting the level of cell activation) and negatively related to pre-challenge levels of mitochondrial superoxide (suggesting an immunoregulatory effect of this pro-oxidant). LPS-challenged males had higher oxidative burst responses than females, and in females oxidative burst responses seemed to depend more strongly on antioxidant status than in males. Our results confirm the idea that oxidative state may constrain the activity of the innate immune system. These constraints may have important consequences for the way selection acts on pro-oxidant generating processes. PMID- 25938444 TI - Correction: SIRT1 Is a Regulator in High Glucose-Induced Inflammatory Response in RAW264.7 Cells. PMID- 25938442 TI - Predicting stroop effect from spontaneous neuronal activity: a study of regional homogeneity. AB - The Stroop effect is one of the most robust and well-studied phenomena in cognitive psychology and cognitive neuroscience. However, little is known about the relationship between intrinsic brain activity and the individual differences of this effect. In the present study, we explored this issue by examining whether resting-state functional magnetic resonance imaging (rs-fMRI) signals could predict individual differences in the Stroop effect of healthy individuals. A partial correlation analysis was calculated to examine the relationship between regional homogeneity (ReHo) and Stroop effect size, while controlling for age, sex, and framewise displacement (FD). The results showed positive correlations in the left inferior frontal gyrus (LIFG), the left insula, the ventral anterior cingulate cortex (vACC), and the medial frontal gyrus (MFG), and negative correlation in the left precentral gyrus (LPG). These results indicate the possible influences of the LIFG, the left insula, and the LPG on the efficiency of cognitive control, and demonstrate that the key nodes of default mode network (DMN) may be important in goal-directed behavior and/or mental effort during cognitive control tasks. PMID- 25938443 TI - The ATP Receptors P2X7 and P2X4 Modulate High Glucose and Palmitate-Induced Inflammatory Responses in Endothelial Cells. AB - Endothelial cells lining the blood vessels are principal players in vascular inflammatory responses. Dysregulation of endothelial cell function caused by hyperglycemia, dyslipidemia, and hyperinsulinemia often result in impaired vasoregulation, oxidative stress, inflammation, and altered barrier function. Various stressors including high glucose stimulate the release of nucleotides thus initiating signaling via purinergic receptors. However, purinergic modulation of inflammatory responses in endothelial cells caused by high glucose and palmitate remains unclear. In the present study, we investigated whether the effect of high glucose and palmitate is mediated by P2X7 and P2X4 and if they play a role in endothelial cell dysfunction. Transcript and protein levels of inflammatory genes as well as reactive oxygen species production, endothelial leukocyte adhesion, and cell permeability were investigated in human umbilical vein endothelial cells exposed to high glucose and palmitate. We report high glucose and palmitate to increase levels of extracellular ATP, expression of P2X7 and P2X4, and inflammatory markers. Both P2X7 and P2X4 antagonists inhibited high glucose and palmitate-induced interleukin-6 levels with the former having a significant effect on interleukin-8 and cyclooxygenase-2. The effect of the antagonists was confirmed with siRNA knockdown of the receptors. In addition, P2X7 mediated both high glucose and palmitate-induced increase in reactive oxygen species levels and decrease in endothelial nitric oxide synthase. Blocking P2X7 inhibited high glucose and palmitate-induced expression of intercellular adhesion molecule-1 and vascular cell adhesion molecule-1 as well as leukocyte-endothelial cell adhesion. Interestingly, high glucose and palmitate enhanced endothelial cell permeability that was dependent on both P2X7 and P2X4. Furthermore, antagonizing the P2X7 inhibited high glucose and palmitate-mediated activation of p38-mitogen activated protein kinase. These findings support a novel role for P2X7 and P2X4 coupled to induction of inflammatory molecules in modulating high glucose and palmitate-induced endothelial cell activation and dysfunction. PMID- 25938445 TI - Effects of three different types of antifreeze proteins on mouse ovarian tissue cryopreservation and transplantation. AB - BACKGROUND: Ovarian tissue (OT) cryopreservation is effective in preserving fertility in cancer patients who have concerns about fertility loss due to cancer treatment. However, the damage incurred at different steps during the cryopreservation procedure may cause follicular depletion; hence, preventing chilling injury would help maintain ovarian function. OBJECTIVE: This study was designed to investigate the beneficial effects of different antifreeze proteins (AFPs) on mouse ovarian tissue cryopreservation and transplantation. METHODOLOGY: Ovaries were obtained from 5-week-old B6D2F1 mice, and each ovary was cryopreserved using two-step vitrification and four-step warming procedures. In Experiment I, ovaries were randomly allocated into fresh, vitrification control, and nine experimental groups according to the AFP type (FfIBP, LeIBP, type III) and concentration (0.1, 1, 10 mg/mL) used. After vitrification and warming, 5,790 ovarian follicles were evaluated using histology and TUNEL assays, and immunofluorescence for tauH2AX and Rad51 was used to detect DNA double-strand breaks (DSBs) and repair (DDR), respectively. In Experiment II, 20 mice were randomly divided into two groups: one where the vitrification and warming media were supplemented with 10 mg/mL LeIBP, and the other where media alone were used (control). Ovaries were then autotransplanted under both kidney capsules 7 days after vitrification together with the addition of 10 mg/mL LeIBP in the vitrification-warming media. After transplantation, the ovarian follicles, the percentage of apoptotic follicles, the extent of the CD31-positive area, and the serum FSH levels of the transplanted groups were compared. PRINCIPAL FINDINGS: In Experiment I, the percentage of total grade 1 follicles was significantly higher in the 10 mg/mL LeIBP group than in the vitrification control, while all AFP treated groups had significantly improved grade 1 primordial follicle numbers compared with those of the vitrification control. The number of apoptotic (TUNEL positive) follicles was significantly decreased in the groups treated with 1 and 10 mg/mL LeIBP. The proportion of tauH2AX-positive follicles was significantly reduced in all AFP-treated groups, while the proportion of Rad51-positive follicles was significantly decreased in only the FfIBP- and LeIBP-treated groups. In Experiment II, after autotransplantation of OT vitrified with 10 mg/mL of LeIBP, the percentage of total grade 1 and primordial grade 1 follicles, and the extent of the CD31-positive area, were increased significantly. Moreover, the levels of serum FSH and the percentage of TUNEL-positive follicles were significantly lower in the LeIBP-treated than in the control group. CONCLUSION: A supplementation with high concentrations of AFPs had protective effects on follicle preservation during OT vitrification-warming procedures. The group treated with LeIBP was protected most effectively. The beneficial effects of LeIBP were also observed after autotransplantation of vitrified-warmed OT. Further studies are necessary to determine the exact mechanism of these protective effects. PMID- 25938446 TI - Bias in Observational Studies of the Association between Menopausal Hormone Therapy and Breast Cancer. AB - BACKGROUND: During the period 1985-2000 the breast cancer incidence rates increased 50% in the age group invited to mammography screening in Norway and Sweden. Simultaneously, use of hormone replacement treatment therapy (HT) increased 5 times. Several influential observational studies showed that HT was associated with 50% to 100% increased risk of breast cancer and most for those using combined (estrogen plus progestin) hormone replacement therapy (CHT). In contrast, the randomized WHI trial reported that CHT increased the risk by 10% for those not having previously used hormones and 24% when including previous users in the analyses. In another randomized trial, estrogen use only was not associated with any increased risk at all. After the WHI trial was published in 2003, use of HT dropped 70% within 5 years in Norway and Sweden while breast cancer rates were essentially unchanged. After 2008, HT use has dropped further and breast cancer incidence rates have started increasing again. The study objective is to calculate and to explain potential bias in the observational study design. METHODS AND FINDINGS: Here we use data from the randomized WHI trial and analyze these data as done in the observational studies to calculate the magnitude of the potential biases in the observational study design. Time varying effect of hormones and categorization of the follow-up time may increase the hazard ratio for long-term users from 1.10 to 1.48. Selective retrospective reporting of hormone use may further increase the hazard ratio to 1.68. CONCLUSIONS: We suggest that the mechanism causing higher hazard ratio of breast cancer (compared to the observational studies) is the time-varying effect of CHT on the breast cancer risk and selective retrospective reporting of hormone use. Other risk factors for the increase in breast cancer risk in the age group 50-69 years should be considered, for example, overdiagnosis. PMID- 25938447 TI - Bibliometric trend and patent analysis in nano-alloys research for period 2000 2013. AB - This paper presents an overview of current situation in nano-alloys investigations based on bibliometric and patent analysis. Bibliometric analysis data, for period from 2000 to September 2013, were obtained using Scopus database as selected index database, whereas analyzed parameters were: number of scientific papers per years, authors, countries, affiliations, subject areas and document types. Analysis of nano-alloys patents was done with specific database, using the International Patent Classification and Patent Scope for the period from 2003 to 2013 year. Information found in this database was the number of patents, patent classification by country, patent applicators, main inventors and pub date. PMID- 25938448 TI - HIGHER MODIFIED BECK DEPRESSION INVENTORY SCORES ARE ASSOCIATED WITH BODY, EATING, AND EXERCISE COMPARISONS BUT DECREASED EXERCISE AMOUNTS. AB - Previous research has indicated that exercise can lead to decreased depression symptoms. The relationship of depression with right frontal lobe activity and self-image (body, eating, and exercise) were investigated as reasons why depressive symptoms might lead to decreased exercise. 120 college students (79 women) completed design fluency tasks followed by a set of questionnaires on depression and exercise. High (M = 23.03, SD = 5.92) and low quartiles (M = 3.11, SD = 1.59) were created using the Modified Beck Depression Inventory (mBDI) for primary analyses. The group with higher mBDI scores produced fewer unique designs (suggesting lower right frontal activity) and was more likely to make comparisons based on body shape, eating, and exercise. The group with higher mBDI scores reported significantly less strenuous and moderate exercise. These findings indicate that the relationship between exercise and depression could work in both directions. While exercise can be used as a potential treatment to decrease depression, increased depressive symptoms could be a hindrance to exercise. PMID- 25938449 TI - THE LIMITED EFFECT OF COINCIDENT ORIENTATION ON THE CHOICE OF INTRINSIC AXIS (.). AB - The allocentric system computes and represents general object-to-object spatial relationships to provide a spatial frame of reference other than the egocentric system. The intrinsic frame-of-reference system theory, which suggests people learn the locations of objects based upon an intrinsic axis, is important in research about the allocentric system. The purpose of the current study was to determine whether the effect of coincident orientation on the choice of intrinsic axis was limited. Two groups of participants (24 men, 24 women; M age = 24 yr., SD = 2) encoded different spatial layouts in which the objects shared the coincident orientation of 315 degrees and 225 degrees separately at learning perspective (0 degrees ). The response pattern of partial-scene-recognition task following learning reflected different strategies for choosing the intrinsic axis under different conditions. Under the 315 degrees object-orientation condition, the objects' coincident orientation was as important as the symmetric axis in the choice of the intrinsic axis. However, participants were more likely to choose the symmetric axis as the intrinsic axis under the 225 degrees object orientation condition. The results suggest the effect of coincident orientation on the choice of intrinsic axis is limited. PMID- 25938450 TI - PHYSIOLOGICAL RESPONSES AND ENERGETICS OF COMPETITIVE GROUP EXERCISE IN FEMALE AEROBIC GYMNASTS WITH DIFFERENT LEVELs OF PERFORMANCE. AB - This study investigated the aerobic fitness and physiologic and energetic responses during competitive exercise in aerobic gymnasts. The gymnasts performed a graded treadmill test and competitive group exercises. Energetic response was calculated from oxygen uptake and blood lactate changes. Peak oxygen uptake was similar in International (M = 45.4 ml . kg(-1) . min.(-1), SD = 3.9) and National (M = 44.7 ml . kg(-1) . min.(-1), SD = 3.6) level groups. During their competitive routines, total energy and the fractions of aerobic, anaerobic alactic, and anaerobic lactic energy were 1,847.7 (SD = 293.9) and 1,747.3 (SD = 196.7) J . kg(-1), 53.5% (SD = 3.1) and 60.3% (SD = 6.1), 25.4% (SD = 5.9) and 21.4% (SD = 5.2), and 21.1% (SD = 5.8) and 18.3% (SD = 4.5) in international and national level athletes, respectively (p > .05). The contribution of anaerobic energy was higher in the international level group (p = .03). It is concluded that the aerobic fitness and absolute energetic and physiological responses of athletes during competitive activities were not different between the aerobic gymnasts groups with different levels of performance, but a higher relative contribution of anaerobic energy was observed in the group with a higher performance level. PMID- 25938451 TI - A social gradient in fatal opioids and cocaine related overdoses? AB - BACKGROUND: To determine the existence of a social gradient in fatal overdose cases related to non-prescribed opioids and cocaine use, recorded in Luxembourg between 1994 and 2011. METHODS: Overdose cases were individually matched with four controls in a nested case-control study design, according to sex, year of birth, drug administration route and duration of drug use. The study sample, composed of 272 cases and 1,056 controls, was stratified according to a Social Inequality Accumulation Score (SIAS), based on educational attainment, employment, income, financial situation of subjects and the professional status of their father or legal guardian. Least squares linear regression analysis on overdose mortality rates and ridit scores were applied to determine the Relative Index of Inequality (RII) of the study sample. RESULTS: A negative linear relationship between the overdose mortality rate and the relative socioeconomic position was observed. We found a difference in mortality of 29.22 overdose deaths per 100 drug users in the lowest socioeconomic group compared to the most advantaged group. In terms of the Relative Inequality Index, the overdose mortality rate of opioid and cocaine users with lowest socioeconomic profiles was 9.88 times as high as that of their peers from the highest socioeconomic group (95% CI 6.49-13.26). CONCLUSIONS: Our findings suggest the existence of a marked social gradient in opioids and cocaine related overdose fatalities. Harm reduction services should integrate socially supportive offers, not only because of their general aim of social (re)integration but crucially in order to meet their most important objective, that is to reduce drug-related mortality. PMID- 25938452 TI - Kinetic Estimation of GFR Improves Prediction of Dialysis and Recovery after Kidney Transplantation. AB - BACKGROUND: The early prediction of delayed graft function (DGF) would facilitate patient management after kidney transplantation. METHODS: In a single-centre retrospective analysis, we investigated kinetic estimated GFR under non-steady state conditions, KeGFR, in prediction of DGF. KeGFR(sCr) was calculated at 4h, 8h and 12h in 56 recipients of deceased donor kidneys from initial serum creatinine (sCr) concentrations, estimated creatinine production rate, volume of distribution, and the difference between consecutive sCr values. The utility of KeGFR(sCr) for DGF prediction was compared with, sCr, plasma cystatin C (pCysC), and KeGFR(pCysC) similarly derived from pCysC concentrations. RESULTS: At 4h, the KeGFR(sCr) area under the receiver operator characteristic curve (AUC) for DGF prediction was 0.69 (95% CI: 0.56-0.83), while sCr was not useful (AUC 0.56, (CI: 0.41-0.72). Integrated discrimination improvement analysis showed that the KeGFR(sCr) improved a validated clinical prediction model at 4h, 8h, and 12h, increasing the AUC from 0.68 (0.52-0.83) to 0.88 (0.78-0.99) at 12h (p = 0.01). KeGFR(pCysC) also improved DGF prediction. In contrast, sCr provided no improvement at any time point. CONCLUSIONS: Calculation of KeGFR from sCr facilitates early prediction of DGF within 4 hours of renal transplantation. PMID- 25938453 TI - Developmental predictors of inattention-hyperactivity from pregnancy to early childhood. AB - OBJECTIVE: The objective of the study was to characterize the developmental sequence of pre- and postnatal risk factors for inattention-hyperactivity symptoms in preschoolers. MATERIALS AND METHODS: Longitudinal data came from a French population based birth cohort study (EDEN; N = 1311 mother-child pairs followed from the pregnancy onwards). Inattention-hyperactivity symptoms were assessed with the Strengths and Difficulties Questionnaire when participating children were 3 years of age. Potential risk factors were classified in four domains (fetal exposures and child somatic characteristics, child temperament, child neurodevelopmental status, psychosocial environment) and four periods (before pregnancy, prenatal/birth, infancy, toddlerhood). Their role as potential moderator or mediator was tested with path analysis to determine the developmental sequence. RESULTS: A low family socioeconomic status before pregnancy was the main environmental risk factor for inattention-hyperactivity symptoms at 3 years, and its effect occurred via two pathways. The first was a risk pathway, where lower SES was associated with higher maternal depression and anxiety during pregnancy; then to higher maternal and child distress and dysregulation in infancy; and in turn to higher levels of inattention hyperactivity at 3 years. The second was a protective pathway, where higher SES was associated with longer duration of breastfeeding during infancy; then to better child neurodevelopmental status in toddlerhood; and in turn to lower levels of inattention-hyperactivity at 3 years. DISCUSSION: This study identified psychosocial factors at several developmental periods that represent potential targets for preventing the emergence of inattention-hyperactivity symptoms in early childhood. PMID- 25938454 TI - Use of recommended search strategies in systematic reviews and the impact of librarian involvement: a cross-sectional survey of recent authors. AB - BACKGROUND: Previous research looking at published systematic reviews has shown that their search strategies are often suboptimal and that librarian involvement, though recommended, is low. Confidence in the results, however, is limited due to poor reporting of search strategies the published articles. OBJECTIVES: To more accurately measure the use of recommended search methods in systematic reviews, the levels of librarian involvement, and whether librarian involvement predicts the use of recommended methods. METHODS: A survey was sent to all authors of English-language systematic reviews indexed in the Database of Abstracts of Reviews of Effects (DARE) from January 2012 through January 2014. The survey asked about their use of search methods recommended by the Institute of Medicine, Cochrane Collaboration, and the Agency for Healthcare Research and Quality and if and how a librarian was involved in the systematic review. Rates of use of recommended methods and librarian involvement were summarized. The impact of librarian involvement on use of recommended methods was examined using a multivariate logistic regression. RESULTS: 1560 authors completed the survey. Use of recommended search methods ranged widely from 98% for use of keywords to 9% for registration in PROSPERO and were generally higher than in previous studies. 51% of studies involved a librarian, but only 64% acknowledge their assistance. Librarian involvement was significantly associated with the use of 65% of recommended search methods after controlling for other potential predictors. Odds ratios ranged from 1.36 (95% CI 1.06 to 1.75) for including multiple languages to 3.07 (95% CI 2.06 to 4.58) for using controlled vocabulary. CONCLUSIONS: Use of recommended search strategies is higher than previously reported, but many methods are still under-utilized. Librarian involvement predicts the use of most methods, but their involvement is under-reported within the published article. PMID- 25938455 TI - The understanding and interpretation of innovative technology-enabled multidimensional physical activity feedback in patients at risk of future chronic disease. AB - BACKGROUND: Innovative physical activity monitoring technology can be used to depict rich visual feedback that encompasses the various aspects of physical activity known to be important for health. However, it is unknown whether patients who are at risk of chronic disease would understand such sophisticated personalised feedback or whether they would find it useful and motivating. The purpose of the present study was to determine whether technology-enabled multidimensional physical activity graphics and visualisations are comprehensible and usable for patients at risk of chronic disease. METHOD: We developed several iterations of graphics depicting minute-by-minute activity patterns and integrated physical activity health targets. Subsequently, patients at moderate/high risk of chronic disease (n=29) and healthcare practitioners (n=15) from South West England underwent full 7-days activity monitoring followed by individual semi-structured interviews in which they were asked to comment on their own personalised visual feedback Framework analysis was used to gauge their interpretation and of personalised feedback, graphics and visualisations. RESULTS: We identified two main components focussing on (a) the interpretation of feedback designs and data and (b) the impact of personalised visual physical activity feedback on facilitation of health behaviour change. Participants demonstrated a clear ability to understand the sophisticated personal information plus an enhanced physical activity knowledge. They reported that receiving multidimensional feedback was motivating and could be usefully applied to facilitate their efforts in becoming more physically active. CONCLUSION: Multidimensional physical activity feedback can be made comprehensible, informative and motivational by using appropriate graphics and visualisations. There is an opportunity to exploit the full potential created by technological innovation and provide sophisticated personalised physical activity feedback as an adjunct to support behaviour change. PMID- 25938456 TI - Additional Evidence That the Polymerase Subunits Contribute to the Viral Replication and the Virulence of H5N1 Avian Influenza Virus Isolates in Mice. AB - Genetically similar H5N1 viruses circulating in the avian reservoir exhibit different levels of pathogenicity in mice. In this study, we characterized two highly pathogenic H5N1 avian isolates--A/Hunan/316/2005 (HN05), which is highly pathogenic in mice, and A/Hubei/489/2004 (HB04), which is nonpathogenic. In mammalian cells, HN05 replicates more efficiently than HB04, although both viruses have similar growth kinetics in avian cells. We used reverse genetics to generate recombinant H5N1 strains containing genes from HN05 and HB04 and examined their virulence. HN05 genes encoding the polymerase complex determine pathogenicity and viral replication ability both in vitro and in vivo. The PB2 subunit plays an important role in enhancing viral replication, and the PB1 and PA subunits contribute mainly to pathogenicity in mice. These results can be used to elucidate host-range expansion and the molecular basis of the high virulence of H5N1 viruses in mammalian species. PMID- 25938457 TI - Cell chemotaxis on paper for diagnostics. AB - Microfluidic chemotaxis platforms have historically been utilized to probe phenomena such as neutrophil migration and are beginning to be developed for diagnostic applications; however, current microfluidic chemotaxis systems require specialized engineering equipment such as syringe pumps and long time frames (hours) to develop a chemokine gradient, and cell chemotaxis typically requires multiple additional hours. The paperfluidic device described in this work is a low-cost, sharp (2 mm wide), quasi-stable (at least 20 min) and rapidly generated (<1 s) chemokine gradient system capable of examining cell migration response over short time frames (20 min) that can be easily assembled. A proof-of-concept experiment on human pan-T cells showed significant (p ? 0.01) directed migration to the chemokine gradient over the control condition. This new technique for cell migration studies provides a foundational step in designing microfluidic chemotactic platforms for point-of-care diagnostics. PMID- 25938458 TI - Assessing the Long-Term Impact of Treating Hepatitis C Virus (HCV)-Infected People Who Inject Drugs in the UK and the Relationship between Treatment Uptake and Efficacy on Future Infections. AB - OBJECTIVE: The prevalence of the hepatitis C virus (HCV) remains high amongst people who inject drugs (PWID) and accounts for the majority of newly acquired infections. This study aims to quantify the value of treatment amongst PWID with more efficacious treatments and at increased uptake rates, with respect to the avoidance of future infections and subsequent long-term complications of HCV. METHODS: A dynamic HCV transmission and disease progression model was developed, incorporating acute and chronic infection and their long-term complications (decompensated cirrhosis, cancer, liver transplant and mortality), with the potential for HCV transmission to other PWID prior to successful treatment. The model was populated with prevalence and therapy data from a UK setting. Scenarios of current standard of care (SoC) treatment efficacy and uptake were compared to anticipated sustained virologic response (SVR) rates of 90-100% and increased uptake over varied horizons. RESULTS: SoC led to modest reductions in prevalence; >5% after 200 years. New treatments achieving 90% SVR could reduce prevalence below 5% within 60 years at current uptake rates or within 5 years if all patients are treated. Amongst 4,240 PWID, chronic HCV infections avoided as a result of increasing treatment uptake over the period 2015-2027 ranged from 20 580 and 34-912 with SoC and 90% SVR rates respectively. The reduction in downstream HCV infections due to increasing treatment uptake resulted in an approximate discounted gain of 300 life-years (from avoiding reduced life expectancy from HCV infection) and a gain of 1,700 QALYs (from avoiding the disutility of HCV infection and related complications), with a projected L5.4 million cost saving. CONCLUSION: While improved SVR profiles led to reductions in modelled prevalence, increased treatment uptake was the key driver of future infections avoided. Increased treatment among PWID with new more efficacious therapies could significantly change the future dynamics, cost and health burden of HCV-related disease. PMID- 25938459 TI - Amorfrutins Are Natural PPARgamma Agonists with Potent Anti-inflammatory Properties. AB - Amorfrutins are isoprenoid-substituted benzoic acid derivatives, which were found in Amorpha fruticosa L. (bastard indigo) and in Glycyrrhiza foetida Desf. (licorice). Recently, amorfrutins were shown to be selective activators of the nuclear receptor PPARgamma. Here, we investigated the effects and PPARgamma-based mechanisms of reducing inflammation in colon cells by treatment with amorfrutins. In TNF-alpha-stimulated colon cells amorfrutin A (1) reduced significantly the expression and secretion of several inflammation mediators, in part due to interaction with PPARgamma. These results support the hypothesis that amorfrutins may have the potential to treat inflammation disorders such as chronic inflammatory bowel diseases. PMID- 25938460 TI - CD36/SR-B2-TLR2 Dependent Pathways Enhance Porphyromonas gingivalis Mediated Atherosclerosis in the Ldlr KO Mouse Model. AB - There is strong epidemiological association between periodontal disease and cardiovascular disease but underlying mechanisms remain ill-defined. Because the human periodontal disease pathogen, Porphyromonas gingivalis (Pg), interacts with innate immune receptors Toll-like Receptor (TLR) 2 and CD36/scavenger receptor-B2 (SR-B2), we studied how CD36/SR-B2 and TLR pathways promote Pg-mediated atherosclerosis. Western diet fed low density lipoprotein receptor knockout (Ldlr degrees ) mice infected orally with Pg had a significant increase in lesion burden compared with uninfected controls.This increase was entirely CD36/SR-B2 dependent, as there was no significant change in lesion burden between infected and uninfected Cd36o/Ldlro mice [corrected]. Western diet feeding promoted enhanced CD36/SR-B2-dependent IL1beta generation and foam cell formation as a result of Pg lipopolysaccharide (PgLPS) exposure. CD36/SR-B2 and TLR2 were necessary for inflammasome activation and optimal IL1beta generation, but also resulted in LPS induced lethality (pyroptosis). Modified forms of LDL inhibited Pg-mediated IL1beta generation in a CD36/SR-B2-dependent manner and prevented pyroptosis, but promoted foam cell formation. Our data show that Pg infection in the oral cavity can lead to significant TLR2-CD36/SR-B2 dependent IL1beta release. In the vessel wall, macrophages encountering systemic release of IL1beta, PgLPS and modified LDL have increased lipid uptake, foam cell formation, and release of IL1beta, but because pyroptosis is inhibited, this enables macrophage survival and promotes increased plaque development. These studies may explain increased lesion burden as a result of periodontal disease, and suggest strategies for development of therapeutics. PMID- 25938461 TI - MicroRNA-135b Regulates Leucine Zipper Tumor Suppressor 1 in Cutaneous Squamous Cell Carcinoma. AB - Cutaneous squamous cell carcinoma (cSCC) is the second most common skin malignancy and it presents a therapeutic challenge in organ transplant recipient patients. Despite the need, there are only a few targeted drug treatment options. Recent studies have revealed a pivotal role played by microRNAs (miRNAs) in multiple cancers, but only a few studies tested their function in cSCC. Here, we analyzed differential expression of 88 cancer related miRNAs in 43 study participants with cSCC; 32 immunocompetent, 11 OTR patients, and 15 non-lesional skin samples by microarray analysis. Of the examined miRNAs, miR-135b was the most upregulated (13.3-fold, 21.5-fold; p=0.0001) in both patient groups. Similarly, the miR-135b expression was also upregulated in three cSCC cell lines when evaluated by quantitative real-time PCR. In functional studies, inhibition of miR-135b by specific anti-miR oligonucleotides resulted in upregulation of its target gene LZTS1 mRNA and protein levels and led to decreased cell motility and invasion of both primary and metastatic cSCC cell lines. In contrast, miR-135b overexpression by synthetic miR-135b mimic induced further down-regulation of LZTS1 mRNA in vitro and increased cancer cell motility and invasiveness. Immunohistochemical evaluation of 67 cSCC tumor tissues demonstrated that miR 135b expression inversely correlated with LZTS1 staining intensity and the tumor grade. These results indicate that miR-135b functions as an oncogene in cSCC and provide new understanding into its pathological role in cSCC progression and invasiveness. PMID- 25938462 TI - Dopamine Promotes Motor Cortex Plasticity and Motor Skill Learning via PLC Activation. AB - Dopaminergic neurons in the ventral tegmental area, the major midbrain nucleus projecting to the motor cortex, play a key role in motor skill learning and motor cortex synaptic plasticity. Dopamine D1 and D2 receptor antagonists exert parallel effects in the motor system: they impair motor skill learning and reduce long-term potentiation. Traditionally, D1 and D2 receptor modulate adenylyl cyclase activity and cyclic adenosine monophosphate accumulation in opposite directions via different G-proteins and bidirectionally modulate protein kinase A (PKA), leading to distinct physiological and behavioral effects. Here we show that D1 and D2 receptor activity influences motor skill acquisition and long term synaptic potentiation via phospholipase C (PLC) activation in rat primary motor cortex. Learning a new forelimb reaching task is severely impaired in the presence of PLC, but not PKA-inhibitor. Similarly, long term potentiation in motor cortex, a mechanism involved in motor skill learning, is reduced when PLC is inhibited but remains unaffected by the PKA inhibitor. Skill learning deficits and reduced synaptic plasticity caused by dopamine antagonists are prevented by co-administration of a PLC agonist. These results provide evidence for a role of intracellular PLC signaling in motor skill learning and associated cortical synaptic plasticity, challenging the traditional view of bidirectional modulation of PKA by D1 and D2 receptors. These findings reveal a novel and important action of dopamine in motor cortex that might be a future target for selective therapeutic interventions to support learning and recovery of movement resulting from injury and disease. PMID- 25938463 TI - Oldest pathology in a tetrapod bone illuminates the origin of terrestrial vertebrates. AB - The origin of terrestrial tetrapods was a key event in vertebrate evolution, yet how and when it occurred remains obscure, due to scarce fossil evidence. Here, we show that the study of palaeopathologies, such as broken and healed bones, can help elucidate poorly understood behavioural transitions such as this. Using high resolution finite element analysis, we demonstrate that the oldest known broken tetrapod bone, a radius of the primitive stem tetrapod Ossinodus pueri from the mid-Visean (333 million years ago) of Australia, fractured under a high-force, impact-type loading scenario. The nature of the fracture suggests that it most plausibly occurred during a fall on land. Augmenting this are new osteological observations, including a preferred directionality to the trabecular architecture of cancellous bone. Together, these results suggest that Ossinodus, one of the first large (>2m length) tetrapods, spent a significant proportion of its life on land. Our findings have important implications for understanding the temporal, biogeographical and physiological contexts under which terrestriality in vertebrates evolved. They push the date for the origin of terrestrial tetrapods further back into the Carboniferous by at least two million years. Moreover, they raise the possibility that terrestriality in vertebrates first evolved in large tetrapods in Gondwana rather than in small European forms, warranting a re evaluation of this important evolutionary event. PMID- 25938464 TI - Quantitative detection of pharmaceuticals using a combination of paper microfluidics and wavelength modulated Raman spectroscopy. AB - Raman spectroscopy has proven to be an indispensable technique for the identification of various types of analytes due to the fingerprint vibration spectrum obtained. Paper microfluidics has also emerged as a low cost, easy to fabricate and portable approach for point of care testing. However, due to inherent background fluorescence, combining Raman spectroscopy with paper microfluidics is to date an unmet challenge in the absence of using surface enhanced mechanisms. We describe the first use of wavelength modulated Raman spectroscopy (WMRS) for analysis on a paper microfluidics platform. This study demonstrates the ability to suppress the background fluorescence of the paper using WMRS and the subsequent implementation of this technique for pharmaceutical analysis. The results of this study demonstrate that it is possible to discriminate between both paracetamol and ibuprofen, whilst, also being able to detect the presence of each analyte quantitatively at nanomolar concentrations. PMID- 25938465 TI - Correction: Individualized Homeopathic Treatment and Fluoxetine for Moderate to Severe Depression in Peri- and Postmenopausal Women (HOMDEP-MENOP Study): A Randomized, Double-Dummy, Double-Blind, Placebo-Controlled Trial. PMID- 25938466 TI - Dynamics of influenza seasonality at sub-regional levels in India and implications for vaccination timing. AB - BACKGROUND: Influenza surveillance is an important tool to identify emerging/reemerging strains, and defining seasonality. We describe the distinct patterns of circulating strains of the virus in different areas in India from 2009 to 2013. METHODS: Patients in ten cities presenting with influenza like illness in out-patient departments of dispensaries/hospitals and hospitalized patients with severe acute respiratory infections were enrolled. Nasopharangeal swabs were tested for influenza viruses by real-time RT-PCR, and subtyping; antigenic and genetic analysis were carried out using standard assays. RESULTS: Of the 44,127 ILI/SARI cases, 6,193 (14.0%) were positive for influenza virus. Peaks of influenza were observed during July-September coinciding with monsoon in cities Delhi and Lucknow (north), Pune (west), Allaphuza (southwest), Nagpur (central), Kolkata (east) and Dibrugarh (northeast), whereas Chennai and Vellore (southeast) revealed peaks in October-November, coinciding with the monsoon months in these cities. In Srinagar (Northern most city at 34 degrees N latitude) influenza circulation peaked in January-March in winter months. The patterns of circulating strains varied over the years: whereas A/H1N1pdm09 and type B co circulated in 2009 and 2010, H3N2 was the predominant circulating strain in 2011, followed by circulation of A/H1N1pdm09 and influenza B in 2012 and return of A/H3N2 in 2013. Antigenic analysis revealed that most circulating viruses were close to vaccine selected viral strains. CONCLUSIONS: Our data shows that India, though physically located in northern hemisphere, has distinct seasonality that might be related to latitude and environmental factors. While cities with temperate seasonality will benefit from vaccination in September-October, cities with peaks in the monsoon season in July-September will benefit from vaccination in April-May. Continued surveillance is critical to understand regional differences in influenza seasonality at regional and sub-regional level, especially in countries with large latitude span. PMID- 25938467 TI - Pesticide Side Effects in an Agricultural Soil Ecosystem as Measured by amoA Expression Quantification and Bacterial Diversity Changes. AB - BACKGROUND AND METHODS: Assessing the effects of pesticide hazards on microbiological processes in the soil is currently based on analyses that provide limited insight into the ongoing processes. This study proposes a more comprehensive approach. The side effects of pesticides may appear as changes in the expression of specific microbial genes or as changes in diversity. To assess the impact of pesticides on gene expression, we focused on the amoA gene, which is involved in ammonia oxidation. We prepared soil microcosms and exposed them to dazomet, mancozeb or no pesticide. We hypothesized that the amount of amoA transcript decreases upon pesticide application, and to test this hypothesis, we used reverse-transcription qPCR. We also hypothesized that bacterial diversity is affected by pesticides. This hypothesis was investigated via 454 sequencing and diversity analysis of the 16S ribosomal RNA and RNA genes, representing the active and total soil bacterial communities, respectively. RESULTS AND CONCLUSION: Treatment with dazomet reduced both the bacterial and archaeal amoA transcript numbers by more than two log units and produced long-term effects for more than 28 days. Mancozeb also inhibited the numbers of amoA transcripts, but only transiently. The bacterial and archaeal amoA transcripts were both sensitive bioindicators of pesticide side effects. Additionally, the numbers of bacterial amoA transcripts correlated with nitrate production in N-amended microcosms. Dazomet reduced the total bacterial numbers by one log unit, but the population size was restored after twelve days. The diversity of the active soil bacteria also seemed to be re-established after twelve days. However, the total bacterial diversity as reflected in the 16S ribosomal RNA gene sequences was largely dominated by Firmicutes and Proteobacteria at day twelve, likely reflecting a halt in the growth of early opportunists and the re-establishment of a more diverse population. We observed no effects of mancozeb on diversity. PMID- 25938468 TI - MicroRNA Expression Profiling in Clear Cell Renal Cell Carcinoma: Identification and Functional Validation of Key miRNAs. AB - OBJECTIVE: This study aims to profile dysregulated microRNA (miRNA) expression in clear cell renal cell carcinoma (ccRCC) and to identify key regulatory miRNAs in ccRCC. METHODS AND RESULTS: miRNA expression profiles in nine pairs of ccRCC tumor samples at three different stages and the adjacent, non-tumorous tissues were investigated using miRNA arrays. Eleven miRNAs were identified to be commonly dysregulated, including three up-regulated (miR-487a, miR-491-3p and miR 452) and eight down-regulated (miR-125b, miR-142-3p, miR-199a-5p, miR-22, miR-299 3p, miR-29a, miR-429, and miR-532-5p) in tumor tissues as compared with adjacent normal tissues. The 11 miRNAs and their predicted target genes were analyzed by Gene Ontology and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment analysis, and three key miRNAs (miR-199a-5p, miR-22 and miR-429) were identified by microRNA-gene network analysis. Dysregulation of the three key miRNAs were further validated in another cohort of 15 ccRCC samples, and the human kidney carcinoma cell line 786-O, as compared with five normal kidney samples. Further investigation showed that over-expression of miR-199a-5p significantly inhibited the invasion ability of 786-O cells. Luciferase reporter assays indicated that miR-199a-5p regulated expression of TGFBR1 and JunB by directly interacting with their 3' untranslated regions. Transfection of miR-199a 5p successfully suppressed expression of TGFBR1 and JunB in the human embryonic kidney 293T cells, further confirming the direct regulation of miR-199a-5p on these two genes. CONCLUSIONS: This study identified 11 commonly dysregulated miRNAs in ccRCC, three of which (miR-199a-5p, miR-22 and miR-429) may represent key miRNAs involved in the pathogenesis of ccRCC. Further studies suggested that miR-199a-5p plays an important role in inhibition of cell invasion of ccRCC cells by suppressing expression of TGFBR1 and JunB. PMID- 25938470 TI - Subclinical Hypothyroidism During Pregnancy-Should You Expect This When You Are Expecting?: A Teachable Moment. PMID- 25938469 TI - Liraglutide improves pancreatic Beta cell mass and function in alloxan-induced diabetic mice. AB - Glucagon-like peptide-1 (GLP-1) receptor agonists potentiate glucose-induced insulin secretion. In addition, they have been reported to increase pancreatic beta cell mass in diabetic rodents. However, the precise mode of action of GLP-1 receptor agonists still needs to be elucidated. Here we clarify the effects of the human GLP-1 analog liraglutide on beta cell fate and function by using an inducible Cre/loxP-based pancreatic beta cell tracing system and alloxan-induced diabetic mice. Liraglutide was subcutaneously administered once daily for 30 days. The changes in beta cell mass were examined as well as glucose tolerance and insulin secretion. We found that chronic liraglutide treatment improved glucose tolerance and insulin response to oral glucose load. Thirty-day treatment with liraglutide resulted in a 2-fold higher mass of pancreatic beta cells than that in vehicle group. Liraglutide increased proliferation rate of pancreatic beta cells and prevented beta cells from apoptotic cells death. However, the relative abundance of YFP-labeled beta cells to total beta cells was no different before and after liraglutide treatment, suggesting no or little contribution of neogenesis to the increase in beta cell mass. Liraglutide reduced oxidative stress in pancreatic islet cells of alloxan-induced diabetic mice. Furthermore, the beneficial effects of liraglutide in these mice were maintained two weeks after drug withdrawal. In conclusion, chronic liraglutide treatment improves hyperglycemia by ameliorating beta cell mass and function in alloxan-induced diabetic mice. PMID- 25938471 TI - Immune checkpoint inhibition: therapeutic implications in epithelial ovarian cancer. AB - Ovarian cancer accounts for more deaths than any other gynecologic malignancy. According to the Ovarian Cancer National Alliance, overall mortality rates due to ovarian cancer have not significantly improved in 40 years, a statistic that highlights the need for innovative treatment strategies. Immune checkpoint inhibitors are part of an emerging immunotherapeutic model that seeks to "inhibit the inhibitors" of adequate cancer immunosurveillance. Immune checkpoints encompass a variety of inhibitory pathways that downregulate an immune response, which allows them to assume an important physiologic role in maintaining homeostasis. While cancer cells are adept at utilizing these pathways to their advantage, basic scientists, translational researchers, and clinical trialists are making great strides in this area of investigation. This review article will focus on the development of anti-CTLA-4 and anti-PD1 monoclonal antibodies, their current role in the treatment of advanced stage EOC, and recently published patents that incorporate the use of immune checkpoint inhibition in the treatment of cancer. PMID- 25938472 TI - Preclinical Study of Novel Gene Silencer Pyrrole-Imidazole Polyamide Targeting Human TGF-beta1 Promoter for Hypertrophic Scars in a Common Marmoset Primate Model. AB - We report a preclinical study of a pyrrole-imidazole (PI) polyamide that targets the human transforming growth factor (hTGF)-beta1 gene as a novel transcriptional gene silencer in a common marmoset primate model. We designed and then synthesized PI polyamides to target the hTGF-beta1 promoter. We examined effects of seven PI polyamides (GB1101-1107) on the expression of hTGF-beta1 mRNA stimulated with phorbol 12-myristate 13-acetate (PMA) in human vascular smooth muscle cells. GB1101, GB1105 and GB1106 significantly inhibited hTGF-beta1 mRNA expression. We examined GB1101 as a PI polyamide to hTGF-beta1 for hypertrophic scars in marmosets in vivo. Injection of GB1101 completely inhibited hypertrophic scar formation at 35 days post-incision and inhibited cellular infiltration, TGF beta1 and vimentin staining, and epidermal thickness. Mismatch polyamide did not affect hypertrophic scarring or histological changes. Epidermis was significantly thinner with GB1101 than with water and mismatch PI polyamides. We developed the PI polyamides for practical ointment medicines for the treatment of hypertrophic scars. FITC-labeled GB1101 with solbase most efficiently distributed in the nuclei of epidermal keratinocytes, completely suppressed hypertropic scarring at 42 days after incision, and considerably inhibited epidermal thickness and vimentin-positive fibroblasts. PI polyamides targeting hTGF-beta1 promoter with solbase ointment will be practical medicines for treating hypertrophic scars after surgical operations and skin burns. PMID- 25938473 TI - Development of high performance liquid chromatography methods with charged aerosol detection for the determination of lincomycin, spectinomycin and its impurities in pharmaceutical products. AB - Novel and simple liquid chromatography methods with charged aerosol detection (LC CAD) for simultaneous quantitation of lincomycin and spectinomycin and its related substances have been developed and tested. This type of analysis is complicated due to the different chromatographic behavior of these two agents and the lack of chromophores in spectinomycin complex. CAD seems to be a promising alternative to overcome these difficulties. It shows a consistent inter-analyte response, independent of chemical structure of an analyte. It also enables the direct quantification of related substances for which no reference standards were available, with good accuracy and precision. Chromatographic separations were achieved using a C18 Hypersil((r)) Gold column, with mobile phases consisting of water, acetonitrile and trifluoroacetic acid. All impurities were identified using time-of-flight mass spectrometry with electrospray ionization. The developed methods have been successfully used in the routine quality control analysis of pharmaceutical preparations. PMID- 25938474 TI - Real-world outcomes of paliperidone palmitate compared to daily oral antipsychotic therapy in schizophrenia: a randomized, open-label, review board blinded 15-month study. AB - OBJECTIVE: The Paliperidone Palmitate Research in Demonstrating Effectiveness (PRIDE) study compared the effects of once-monthly paliperidone palmitate with daily oral antipsychotics on treatment failure in adults with schizophrenia. METHOD: The PRIDE study is a 15-month, randomized, multicenter study (May 5, 2010, to December 9, 2013) of adult subjects with a DSM-IV diagnosis of schizophrenia and a history of incarceration. Subjects were randomly assigned to once-monthly paliperidone palmitate injections or daily oral antipsychotics (randomly assigned from 7 acceptable, prespecified oral antipsychotics) for 15 months. The primary end point was time to first treatment failure, defined as arrest/incarceration; psychiatric hospitalization; suicide; treatment discontinuation or supplementation due to inadequate efficacy, safety, or tolerability; or increased psychiatric services to prevent hospitalization. Time to first treatment failure was determined by a blinded event-monitoring board and analyzed with the Kaplan-Meier method. RESULTS: In this study, 450 patients were randomly assigned, and 444 were included in the intent-to-treat population. Paliperidone palmitate was associated with significant delay in time to first treatment failure versus oral antipsychotics (hazard ratio, 1.43; 95% CI, 1.09 1.88; log rank P = .011). Observed treatment failure rates over 15 months were 39.8% and 53.7%, respectively. Arrest/incarceration and psychiatric hospitalization were the most common reasons for treatment failure in the paliperidone palmitate and oral antipsychotic groups (21.2% vs 29.4% and 8.0% vs 11.9%, respectively). The 5 most common treatment-emergent adverse events for the paliperidone palmitate treatment group were injection site pain (18.6% of subjects), insomnia (16.8%), weight increased (11.9%), akathisia (11.1%), and anxiety (10.6%). CONCLUSIONS: In a trial designed to reflect real-world management of schizophrenia, once-monthly paliperidone palmitate demonstrated superiority compared to oral antipsychotics in delaying time to treatment failure. TRIAL REGISTRATION: Clinicaltrials.gov Identifier: NCT01157351. PMID- 25938475 TI - Imidacloprid sorption kinetics, equilibria, and degradation in sandy soils of Florida. AB - Imidacloprid (IMD) is a neonicotinoid insecticide soil-drenched on sandy soils of southwest Florida for the control of Diaphorina citri Kuwayama or Asian citrus psyllid (ACP). The ACP vectors causal pathogens of a devastating citrus disease called citrus greening. Understanding the behavior of IMD in these soils and plants is critical to its performance against target pests. Samples from Immokalee fine sand (IFS) were used for sorption kinetics and equilibria experiments. IMD kinetics data were described by the one-site mass transfer (OSMT) model and reached equilibrium between 6 and 12 h. Batch equilibrium and degradation studies revealed that IMD was weakly sorbed (K(OC) = 163-230) and persistent, with a half-life of 1.0-2.6 years. Consequently, IMD has the potential to leach below the citrus root zone after the soil-drench applications. PMID- 25938476 TI - Comparative Evaluation of Sloppy Molecular Beacon and Dual-Labeled Probe Melting Temperature Assays to Identify Mutations in Mycobacterium tuberculosis Resulting in Rifampin, Fluoroquinolone and Aminoglycoside Resistance. AB - Several molecular assays to detect resistance to Rifampin, the Fluoroquinolones, and Aminoglycosides in Mycobacterium tuberculosis (M. tuberculosis) have been recently described. A systematic approach for comparing these assays in the laboratory is needed in order to determine the relative advantage of each assay and to decide which ones should be advanced to evaluation. We performed an analytic comparison of a Sloppy Molecular Beacon (SMB) melting temperature (Tm) assay and a Dual labeled probe (DLP) Tm assay. Both assays targeted the M. tuberculosis rpoB, gyrA, rrs genes and the eis promoter region. The sensitivity and specificity to detect mutations, analytic limit of detection (LOD) and the detection of heteroresistance were tested using a panel of 56 clinical DNA samples from drug resistant M. tuberculosis strains. Both SMB and DLP assays detected 29/29 (100%) samples with rpoB RRDR mutations and 3/3 (100%) samples with eis promoter mutations correctly. The SMB assay detected all 17/17 gyrA mutants and 22/22 rrs mutants, while the DLP assay detected 16/17 (94%) gyrA mutants and 12/22 (55%) rrs mutants. Both assays showed comparable LODs for detecting rpoB and eis mutations; however, the SMB assay LODs were at least two logs better for detecting wild type and mutants in gyrA and rrs targets. The SMB assay was also moderately better at detecting heteroresistance. In summary, both assays appeared to be promising methods to detect drug resistance associated mutations in M. tuberculosis; however, the relative advantage of each assay varied under each test condition. PMID- 25938478 TI - Weight loss and impact on quality of life in Parkinson's disease. AB - INTRODUCTION: Weight loss is common in Parkinson's Disease (PD) and sometimes may precede the diagnosis. Weight loss is associated with multiple factors but its impact on health-related quality of life (HRQL) in PD remains unknown. We sought to investigate the factors associated with weight change and to quantify its effect on HRQL. METHODS: The National Parkinson Foundation Quality Improvement Initiative (NPF-QII) data was used to analyze PD patients longitudinally between two visits, separated by 12 +/- 6 months. Multiple linear regression analyses were used to assess the associations between baseline covariates and body weight change per month, and to evaluate whether, and to what degree, Parkinson's Disease Questionnaire (PDQ-39) scores were affected. RESULTS: A higher Hoehn & Yahr stage, higher number of comorbidities, older age, lower MOCA estimate, and higher rate of levodopa usage were observed in patients who lost weight. Multivariate regression analysis indicated that age and levodopa usage were significantly associated with weight loss. Furthermore, monthly body weight loss was significantly associated with HRQL decline in PD patients. Loss of 1 lb (0.45 kg) per month was associated with a decline in QOL: an increase of 0.5% in PDQ-39 Summary Index score (p=0.004), and 1.1% and 1.5% increases in the mobility and ADL dimensions, respectively. CONCLUSION: Weight loss in PD is common and seems to correlate with worsened HRQL. Awareness of factors associated with weight loss and its relation to HRQL may help practitioners improve patient management and expectations. PMID- 25938477 TI - Chronic Trichuris muris Infection in C57BL/6 Mice Causes Significant Changes in Host Microbiota and Metabolome: Effects Reversed by Pathogen Clearance. AB - Trichuris species are a globally important and prevalent group of intestinal helminth parasites, in which Trichuris muris (mouse whipworm) is an ideal model for this disease. This paper describes the first ever highly controlled and comprehensive investigation into the effects of T. muris infection on the faecal microbiota of mice and the effects on the microbiota following successful clearance of the infection. Communities were profiled using DGGE, 454 pyrosequencing, and metabolomics. Changes in microbial composition occurred between 14 and 28 days post infection, resulting in significant changes in alpha and beta- diversity. This impact was dominated by a reduction in the diversity and abundance of Bacteroidetes, specifically Prevotella and Parabacteroides. Metabolomic analysis of stool samples of infected mice at day 41 showed significant differences to uninfected controls with a significant increase in the levels of a number of essential amino acids and a reduction in breakdown of dietary plant derived carbohydrates. The significant reduction in weight gain by infected mice probably reflects these metabolic changes and the incomplete digestion of dietary polysaccharides. Following clearance of infection the intestinal microbiota underwent additional changes gradually transitioning by day 91 towards a microbiota of an uninfected animal. These data indicate that the changes in microbiota as a consequence of infection were transitory requiring the presence of the pathogen for maintenance. Interestingly this was not observed for all of the key immune cell populations associated with chronic T. muris infection. This reflects the highly regulated chronic response and potential lasting immunological consequences of dysbiosis in the microbiota. Thus infection of T. muris causes a significant and substantial impact on intestinal microbiota and digestive function of mice with affects in long term immune regulation. PMID- 25938479 TI - Interventions for lowering plasma homocysteine levels in kidney transplant recipients. AB - BACKGROUND: Elevated homocysteine levels have been shown to be an independent risk factor for cardiovascular disease. However studies of homocysteine lowering in general and end-stage kidney disease (ESKD) populations have not demonstrated a reduction in cardiovascular event rates. Kidney transplant recipients have high homocysteine levels, high cardiovascular event rates and, unlike the ESKD population, may achieve normalisation of homocysteine levels with homocysteine lowering therapies. Thus may benefit from homocysteine lowering therapy. OBJECTIVES: To evaluate the effects of established homocysteine lowering therapy on cardiovascular mortality in patients with functioning kidney transplants. SEARCH METHODS: We searched the Cochrane Renal Group's Specialised Register to 16 March 2015 through contact with the Trials' Search Co-ordinator using search terms relevant to this review. SELECTION CRITERIA: Randomised controlled trials of any therapy that has been shown to significantly lower homocysteine levels conducted in people with functioning kidney transplants. Studies were to be included if they compared homocysteine lowering therapy with placebo or usual care, or compare higher versus lower doses of homocysteine lowering therapy. DATA COLLECTION AND ANALYSIS: Two authors independently assessed study quality and extracted data. Results were to be expressed as the risk ratio (RR) for dichotomous outcomes or mean difference (MD) for continuous outcomes with 95% confidence intervals (CI). Data was to be pooled using the random effects model. MAIN RESULTS: The literature search yielded 359 reports of which only one study was identified that met our inclusion criteria and reported relevant clinical endpoints. This study randomised 4110 adult participants with a functioning kidney transplant and elevated homocysteine levels to folic acid plus high dose B multivitamins or low dose multivitamins who were followed for a mean 4.0 years. Despite effectively lowering homocysteine levels) in homocysteine levels at follow-up (MD -4.40 MUmol/L, 95% CI -5.98 to -2.82) there was no evidence the intervention impacted on any of the outcomes reported including cardiovascular mortality (RR 0.91, 95% CI 0.69 to 1.20), all-cause mortality (RR 1.04, 95% CI 0.88 to 1.22), myocardial infarction (RR 1.02, 95% CI 0.77 to 1.35), stroke (RR 1.08, 95% CI 0.69 to 1.71), commencement of renal replacement therapy (RR 1.12, 95% CI 0.91 to 1.37) or all reported adverse events (RR 1.02, 95% CI 0.87 to 1.20). There was no evidence the intervention impacted on the primary endpoint of the study, a cardiovascular event composite (RR 0.99, 95% CI 0.85 to 1.15). The study was of high quality. AUTHORS' CONCLUSIONS: There is no current evidence to support the use of homocysteine lowering therapy for cardiovascular disease prevention in kidney transplant recipients. PMID- 25938480 TI - Evaluation of four commonly used DNA barcoding Loci for chinese medicinal plants of the family schisandraceae. AB - Many species of Schisandraceae are used in traditional Chinese medicine and are faced with contamination and substitution risks due to inaccurate identification. Here, we investigated the discriminatory power of four commonly used DNA barcoding loci (ITS, trnH-psbA, matK, and rbcL) and corresponding multi-locus combinations for 135 individuals from 33 species of Schisandraceae, using distance-, tree-, similarity-, and character-based methods, at both the family level and the genus level. Our results showed that the two spacer regions (ITS and trnH-psbA) possess higher species-resolving power than the two coding regions (matK and rbcL). The degree of species resolution increased with most of the multi-locus combinations. Furthermore, our results implied that the best DNA barcode for the species discrimination at the family level might not always be the most suitable one at the genus level. Here we propose the combination of ITS+trnH-psbA+matK+rbcL as the most ideal DNA barcode for discriminating the medicinal plants of Schisandra and Kadsura, and the combination of ITS+trnH-psbA as the most suitable barcode for Illicium species. In addition, the closely related species Schisandra rubriflora Rehder & E. H. Wilson and Schisandra grandiflora Hook.f. & Thomson, were paraphyletic with each other on phylogenetic trees, suggesting that they should not be distinct species. Furthermore, the samples of these two species from the southern Hengduan Mountains region formed a distinct cluster that was separated from the samples of other regions, implying the presence of cryptic diversity. The feasibility of DNA barcodes for identification of geographical authenticity was also verified here. The database and paradigm that we provide in this study could be used as reference for the authentication of traditional Chinese medicinal plants utilizing DNA barcoding. PMID- 25938481 TI - Remembering the Benefits of Vaccination. PMID- 25938482 TI - Cyclization of the urokinase receptor-derived ser-arg-ser-arg-tyr Peptide generates a potent inhibitor of trans-endothelial migration of monocytes. AB - The receptor for the urokinase-type plasminogen activator (uPAR) is a widely recognized master regulator of cell migration and uPAR88-92 is the minimal sequence required to induce cell motility. We and others have previously documented that the uPAR88-92 sequence, even in the form of synthetic linear peptide (SRSRY), interacts with the formyl peptide receptor type 1 (FPR1), henceforth inducing cell migration of several cell lines, including monocytes. FPR1 is mainly expressed by mammalian phagocytic leukocytes and plays a crucial role in chemotaxis. In this study, we present evidence that the cyclization of the SRSRY sequence generates a new potent and stable inhibitor of monocyte trafficking. In rat basophilic leukaemia RBL-2H3/ETFR cells expressing high levels of constitutively activated FPR1, the cyclic SRSRY peptide ([SRSRY]) blocks FPR1 mediated cell migration by interfering with both internalization and ligand-uptake of FPR1. Similarly to RBL-2H3/ETFR cells, [SRSRY] competes with fMLF for binding to FPR1 and prevents agonist-induced FPR1 internalization in human monocyte THP-1 cells. Unlike scramble [RSSYR], [SRSRY] inhibits fMLF directed migration of monocytes in a dose-dependent manner, with IC50 value of 0.01 nM. PMA-differentiated THP-1 cell exposure to fMLF gradient causes a marked cytoskeletal re-organization with the formation of F-actin rich pseudopodia that are prevented by the addition of [SRSRY]. Furthermore, [SRSRY] prevents migration of human primary monocytes and trans-endothelial migration of monocytes. Our findings indicate that [SRSRY] is a new FPR1 inhibitor which may suggest the development of new drugs for treating pathological conditions sustained by increased motility of monocytes, such as chronic inflammatory diseases. PMID- 25938483 TI - Brucella melitensis Biovar 1 and Brucella abortus S19 Vaccine Strain Infections in Milkers Working at Cattle Farms in the Khartoum Area, Sudan. AB - BACKGROUND: Human brucellosis is a preventable zoonoses that may become persistent, causing, if left untreated, severe localized disease. Occupational exposure to infected animals or animal products and consumption of fresh contaminated dairy are main risk factors. METHODS: One hundred farmworkers employed at two cattle farms one in Khartoum North and one in Omdurman were screened for the presence of specific antibodies and seropositive workers were invited to donate a blood sample for blood culture. Molecular typing was used to characterize Brucella isolates. RESULTS: Ten percent of farmworkers tested seropositive and while Brucella melitensis biovar 1 was isolated from the blood of three individuals, an isolate identical to the B. abortus S19 vaccine strain was isolated from a fourth person. All four bacteremic individuals were employed as milkers and did not have obvious disease. CONCLUSIONS: The isolation of the highly infectious pathogen B. melitensis from seropositive workers is consistent with the notion that the pathogen may persist in the blood without causing overt disease. While vaccination with strain S19 is essential for the control of bovine brucellosis the vaccine strain may be transmitted to the human population and protective measures remain important to prevent exposure also in view of the presence of B. melitensis. To create awareness for this potentially severe disease more information on the prevalence of the pathogen in different risk groups and in livestock in the Sudan is needed. PMID- 25938484 TI - Morphological Observations and Fatty Acid Composition of Indoor-Cultivated Cordyceps sinensis at a High-Altitude Laboratory on Sejila Mountain, Tibet. AB - Cordyceps sinensis, a caterpillar entomopathogenic fungus-host larva complex, is a rare medicinal herb found in the Qinghai-Tibetan Plateau and its surrounding high-altitude areas. The alternation of generations in the life cycle, whatever the fungus or its host insect, requires special growth conditions. However, it is difficult to simulate the growth conditions of C. sinensis, which hinders its artificial cultivation. In this work, the life cycle from the host larva to C. sinensis was observed in an indoor-cultivation laboratory at 4,200 m a.s.l. on Sejila Mountain, Tibet. Comparative examinations between indoor-cultivated and wild C. sinensis demonstrated that the indoor-cultivated C. sinensis preferred to germinate multiple long, slim stromata at diverse positions on dead larvae, including but not limited to their heads. Their fatty acid composition shows a significant difference in the levels of polyunsaturated fatty acids (PUFAs). In indoor-cultivated C. sinensis, PUFAs constituted 24.59% and 49.43%, respectively, of neutral and polar lipids; meanwhile, in wild C. sinensis, PUFAs represented 34.34% and 61.25% of neutral and polar lipids, respectively. These observations and fatty acid data suggest that environmental factors, particularly temperature, soil pressure and light intensity, strongly affect the growth of C. sinensis. Our new findings may provide important information for improving techniques for the large-scale artificial cultivation of C. sinensis. PMID- 25938485 TI - Investigate the binding of catechins to trypsin using docking and molecular dynamics simulation. AB - To explore the inhibitory mechanism of catechins for digestive enzymes, we investigated the binding mode of catechins to a typical digestive enzyme-trypsin and analyzed the structure-activity relationship of catechins, using an integration of molecular docking, molecular dynamics simulation and binding free energy calculation. We found that catechins with different structures bound to a conservative pocket S1 of trypsin, which is comprised of residues 189-195, 214 220 and 225-228. In the trypsin-catechin complexes, Asp189 by forming strong hydrogen bonding, and Gln192, Trp215 and Gly216 through hydrophobic interactions, all significantly contribute to the binding of catechins. The number and the position of hydroxyl and aromatic groups, the structure of stereoisomers, and the orientation of catechins in the binding pocket S1 of trypsin all affect the binding affinity. The binding affinity is in the order of Epigallocatechin gallate (EGCG) > Epicatechin gallate (ECG) > Epicatechin (EC) > Epigallocatechin (EGC), and 2R-3R EGCG shows the strongest binding affinity out of other stereoisomers. Meanwhile, the synergic conformational changes of residues and catechins were also analyzed. These findings will be helpful in understanding the knowledge of interactions between catechins and trypsin and referable for the design of novel polyphenol based functional food and nutriceutical formulas. PMID- 25938486 TI - The Effect on mortality of fluconazole or echinocandins treatment in candidemia in internal medicine wards [corrected]. AB - The incidence of candidemia has increased over the past two decades, with an increased number of cases in Internal Medicine and a prevalence ranging from 24% to 57%. This single-center retrospective study was performed to evaluate the epidemiology and the risk factors associated with mortality of candidemia in patients admitted to Internal Medicine wards (IMWs) of the City of Health and Sciences, Molinette Hospital, Turin, from January 2004 to December 2012. For each patient, demographic, clinical and microbiological data were collected. A case of candidemia was defined as a patient with at least one blood culture positive for Candida spp. Amongst 670 episodes of candidemia, 274 (41%) episodes occurred in IMWs. The mortality was 39% and was associated at multivariate analysis with sepsis, cirrhosis and neurologic diseases, whilst removal of central venous catheter <=48h was significantly associated with survival. In the 77 patients treated with early antifungal therapy the mortality was 29% and was not significantly different with caspofungin or fluconazole, whilst in patients with definitive therapy the mortality was significantly lower with echinocandins compared to fluconazole (11.7% Vs. 39%; p=0.0289), a finding confirmed by multivariate analysis. The mortality was significantly associated with sepsis, cirrhosis and neurologic diseases, whilst CVC removal <=48h was associated with survival. In patients with early therapy, fluconazole or caspofungin were equally effective. However, echinocandins were significantly more effective as definitive treatment, a finding not explained by differences in treatment delays. Further studies are needed to understand the full potential of these different therapeutic strategies in IMWs. PMID- 25938487 TI - Molecular Cloning and Characterisation of Farnesyl Pyrophosphate Synthase from Tripterygium wilfordii. AB - Farnesylpyrophosphate synthase (FPS) catalyzes the biosynthesis of farnesyl pyrophosphate (FPP), which is an important precursor of sesquiterpenoids such as artemisinin and wilfordine. In the present study, we report the molecular cloning and characterization of two full-length cDNAs encoding FPSs from Tripterygium wilfordii (TwFPSs). TwFPSs maintained their capability to synthesise FPP in vitro when purified as recombinant proteins from E. coli. Consistent with the endogenous role of FPS in FPP biosynthesis, TwFPSs were highly expressed in T. wilfordii roots, and were up-regulated upon methyl jasmonate (MeJA) treatment. The global gene expression profiles suggested that the TwFPSs might play an important regulatory role interpenoid biosynthesis in T. wilfordii, laying the groundwork for the future study of the synthetic biology of natural terpene products. PMID- 25938488 TI - Automated Gel Size Selection to Improve the Quality of Next-generation Sequencing Libraries Prepared from Environmental Water Samples. AB - Next-generation sequencing of environmental samples can be challenging because of the variable DNA quantity and quality in these samples. High quality DNA libraries are needed for optimal results from next-generation sequencing. Environmental samples such as water may have low quality and quantities of DNA as well as contaminants that co-precipitate with DNA. The mechanical and enzymatic processes involved in extraction and library preparation may further damage the DNA. Gel size selection enables purification and recovery of DNA fragments of a defined size for sequencing applications. Nevertheless, this task is one of the most time-consuming steps in the DNA library preparation workflow. The protocol described here enables complete automation of agarose gel loading, electrophoretic analysis, and recovery of targeted DNA fragments. In this study, we describe a high-throughput approach to prepare high quality DNA libraries from freshwater samples that can be applied also to other environmental samples. We used an indirect approach to concentrate bacterial cells from environmental freshwater samples; DNA was extracted using a commercially available DNA extraction kit, and DNA libraries were prepared using a commercial transposon based protocol. DNA fragments of 500 to 800 bp were gel size selected using Ranger Technology, an automated electrophoresis workstation. Sequencing of the size-selected DNA libraries demonstrated significant improvements to read length and quality of the sequencing reads. PMID- 25938489 TI - Does Reproductive Investment Decrease Telomere Length in Menidia menidia? AB - Given finite resources, intense investment in one life history trait is expected to reduce investment in others. Although telomere length appears to be strongly tied to age in many taxa, telomere maintenance requires energy. We therefore hypothesize that telomere maintenance may trade off against other life history characters. We used natural variation in laboratory populations of Atlantic silversides (Menidia menidia) to study the relationship between growth, fecundity, life expectancy, and relative telomere length. In keeping with several other studies on fishes, we found no clear dependence of telomere length on age. However, we did find that more fecund fish tended to have both reduced life expectancy and shorter telomeres. This result is consistent with the hypothesis that there is a trade-off between telomere maintenance and reproductive output. PMID- 25938490 TI - Correction: Functional Study of miR-27a in Human Hepatic Stellate Cells by Proteomic Analysis: Comprehensive View and a Role in Myogenic Tans Differentiation. PMID- 25938492 TI - The Impact of Flap Creation Methods for Sub-Bowman's Keratomileusis (SBK) on the Central Thickness of Bowman's Layer. AB - PURPOSE: To determine the impact of flap creation methods for sub-Bowman's keratomileusis (SBK) on central Bowman's layer thickness. METHODS: SBK flaps were made by Moria microkeratome for 20 subjects and by femtosecond (FEMTO) laser for 21 subjects. Corneal sublayer thicknesses were measured by ultra-high resolution optical coherence tomography before SBK and at 1 day, 1 week, 2 weeks, and 1 month afterwards. Each subject was imaged twice on each visit. Thicknesses of central epithelium, Bowman's layer, flap, and total cornea were calculated using a custom-made automated image processing algorithm. The repeatability of sublayer thickness measurements was tested by the intraclass correlation coefficient (ICC) and by the coefficient of repeatability (CoR) at 1 week post-SBK. RESULTS: ICCs of the Moria and FEMTO groups were >= 0.959 and >= 0.961 respectively for all sublayer measurements. The segmentation CoRs were less than 6.78% and 5.63% respectively. For both groups, microdistortions were present in the epithelium and Bowman's layer after SKB. The flap thickness of the Moria group was 9.8 MUm (95% confidence interval: 4.8 - 14.8 MUm) thinner than the FEMTO group one day after SBK (independent samples t-test, P < 0.05). Bowman's layer became thicker by 1.6 +/- 1.1 MUm and 1.7 +/- 1.6 MUm one day post-SBK for the Moria and FEMTO groups (repeated ANOVA, P < 0.05) and then remained stable. Corneal and sublayer thickness were similar between the two groups. CONCLUSIONS: Central Bowman's layer thickness increased 1 day post-SBK. Flap creation by Moria microkeratome and femtosecond laser did not have significantly different impacts on Bowman's layer thickness following SBK. TRIAL REGISTRATION: Chinese Clinical Trial Registry (ChiCTR) NO: ChiCTR-OCH-14004525. PMID- 25938491 TI - Novel Pactamycin Analogs Induce p53 Dependent Cell-Cycle Arrest at S-Phase in Human Head and Neck Squamous Cell Carcinoma (HNSCC) Cells. AB - Pactamycin, although putatively touted as a potent antitumor agent, has never been used as an anticancer drug due to its high cytotoxicity. In this study, we characterized the effects of two novel biosynthetically engineered analogs of pactamycin, de-6MSA-7-demethyl-7-deoxypactamycin (TM-025) and 7-demethyl-7 deoxypactamycin (TM-026), in head and neck squamous cell carcinoma (HNSCC) cell lines SCC25 and SCC104. Both TM-025 and TM-026 exert growth inhibitory effects on HNSCC cells by inhibiting cell proliferation. Interestingly, unlike their parent compound pactamycin, the analogs do not inhibit synthesis of nascent protein in a cell-based assay. Furthermore, they do not induce apoptosis or autophagy in a dose- or a time-dependent manner, but induce mild senescence in the tested cell lines. Cell cycle analysis demonstrated that both analogs significantly induce cell cycle arrest of the HNSCC cells at S-phase resulting in reduced accumulation of G2/M-phase cells. The pactamycin analogs induce expression of cell cycle regulatory proteins including master regulator p53, its downstream target p21Cip1/WAF1, p27kip21, p19, cyclin E, total and phospho Cdc2 (Tyr15) and Cdc25C. Besides, the analogs mildly reduce cyclin D1 expression without affecting expression of cyclin B, Cdk2 and Cdk4. Specific inhibition of p53 by pifithrin alpha reduces the percentage of cells accumulated in S-phase, suggesting contribution of p53 to S-phase increase. Altogether, our results demonstrate that Pactamycin analogs TM-025 and TM-026 induce senescence and inhibit proliferation of HNSCC cells via accumulation in S-phase through possible contribution of p53. The two PCT analogs can be widely used as research tools for cell cycle inhibition studies in proliferating cancer cells with specific mechanisms of action. PMID- 25938493 TI - Haematology and Plasma Biochemistry of Wild Black Flying-Foxes, (Pteropus alecto) in Queensland, Australia. AB - This paper establishes reference ranges for hematologic and plasma biochemistry values in wild Black flying-foxes (Pteropus alecto) captured in South East Queensland, Australia. Values were found to be consistent with those of other Pteropus species. Four hundred and forty-seven animals were sampled over 12 months and significant differences were found between age, sex, reproductive and body condition cohorts in the sample population. Mean values for each cohort fell within the determined normal adult reference range, with the exception of elevated levels of alkaline phosphatase in juvenile animals. Hematologic and biochemistry parameters of injured animals showed little or no deviation from the normal reference values for minor injuries, while two animals with more severe injury or abscessation showed leucocytosis, anaemia, thrombocytosis, hyperglobulinemia and hypoalbuminemia. PMID- 25938494 TI - The Development and Validation of the Osteoporosis Prevention and Awareness Tool (OPAAT) in Malaysia. AB - OBJECTIVES: To develop and validate Osteoporosis Prevention and Awareness Tool (OPAAT) in Malaysia. METHODS: The OPAAT was modified from the Malaysian Osteoporosis Knowledge Tool and developed from an exploratory study on patients. Face and content validity was established by an expert panel. The OPAAT consists of 30 items, categorized into three domains. A higher score indicates higher knowledge level. English speaking non-osteoporotic postmenopausal women >= 50 years of age and pharmacists were included in the study. RESULTS: A total of 203 patients and 31 pharmacists were recruited. Factor analysis extracted three domains. Flesch reading ease was 59.2. The mean +/- SD accuracy rate was 0.60 +/- 0.22 (range: 0.26-0.94). The Cronbach's alpha for each domain ranged from 0.286 0.748. All items were highly correlated (Spearman's rho: 0.761-0.990, p < 0.05), with no significant change in the overall test-retest scores, indicating that OPAAT has achieved stable reliability. Pharmacists had higher knowledge score than patients (80.9 +/- 8.7 vs 63.6 +/- 17.4, p < 0.001), indicating that the OPAAT was able to discriminate between the knowledge levels of pharmacists and patients. CONCLUSION: The OPAAT was found to be a valid and reliable instrument for assessing patient's knowledge about osteoporosis and its prevention in Malaysia. The OPAAT can be used to identify individuals in need of osteoporosis educational intervention. PMID- 25938496 TI - Correction: an investigation of the endocrine-disruptive effects of bisphenol a in human and rat fetal testes. PMID- 25938495 TI - Functional Validation of Rare Human Genetic Variants Involved in Homologous Recombination Using Saccharomyces cerevisiae. AB - Systems for the repair of DNA double-strand breaks (DSBs) are necessary to maintain genome integrity and normal functionality of cells in all organisms. Homologous recombination (HR) plays an important role in repairing accidental and programmed DSBs in mitotic and meiotic cells, respectively. Failure to repair these DSBs causes genome instability and can induce tumorigenesis. Rad51 and Rad52 are two key proteins in homologous pairing and strand exchange during DSB induced HR; both are highly conserved in eukaryotes. In this study, we analyzed pathogenic single nucleotide polymorphisms (SNPs) in human RAD51 and RAD52 using the Polymorphism Phenotyping (PolyPhen) and Sorting Intolerant from Tolerant (SIFT) algorithms and observed the effect of mutations in highly conserved domains of RAD51 and RAD52 on DNA damage repair in a Saccharomyces cerevisiae based system. We identified a number of rad51 and rad52 alleles that exhibited severe DNA repair defects. The functionally inactive SNPs were located near ATPase active site of Rad51 and the DNA binding domain of Rad52. The rad51-F317I, rad52-R52W, and rad52-G107C mutations conferred hypersensitivity to methyl methane sulfonate (MMS)-induced DNA damage and were defective in HR-mediated DSB repair. Our study provides a new approach for detecting functional and loss-of function genetic polymorphisms and for identifying causal variants in human DNA repair genes that contribute to the initiation or progression of cancer. PMID- 25938497 TI - A case of May-Thurner syndrome with inconsistent radiological and surgical findings. AB - May-Thurner syndrome is the result of compression of the left common iliac vein between the right common iliac artery and the overlying vertebrae. In this case report, we describe an 11-year-old boy presenting with swelling of the left lower extremity. An iliac MR venography showed compression of the left proximal iliac vein between the vertebra and the left iliac artery. In surgery, it was seen that the left common iliac vein was connected to the postero-inferior part of the inferior vena cava, and it was compressed between the right common iliac artery and the columna vertebralis, which was inconsistent with the radiological findings. An interposition of the great saphenous vein graft between the left common iliac vein and the inferior vena cava was made, with a successful outcome. Our case is interesting in that it showed inconsistent findings between the radiological images and surgery. PMID- 25938498 TI - Endocarditis tricuspid sub-aigue of post abortion: report of a case. AB - Tricuspid infective endocarditis is rare and represents five to 10% of all cases of infective endocarditis. It occurs predominantly in intravenous drug users, and patients with central venous catheters or intracardiac probes. We report on the case of subacute tricuspid infective endocarditis in a girl of 17 years. She had no particular cardiovascular history. She was admitted for a persistent fever with cachexy, cough and thoracic pains, and right heart failure that appeared one month after a clandestine abortion. Transthoracic echocardiography found several vegetations on the tricuspid valve with massive tricuspid regurgitation. The chest X-ray showed bilateral excavated lung abscesses and condensation areas. Blood culture was not done and broad-spectrum antibiotic therapy was given. She was apyretic after 10 days. However, the massive tricuspid regurgitation with right heart failure persisted. She was discharged from hospital after 40 days of treatment. Although rare, infective endocarditis is one of the more serious complications of gynaecological procedures, particularly clandestine abortion. Therefore any young girl with persistent fever must be suspected of clandestine abortion. PMID- 25938499 TI - A Novel Method for Rearing Zebrafish by Using Freshwater Rotifers (Brachionus calyciflorus). AB - The zebrafish (Danio rerio) has become a powerful model organism for studying developmental processes and genetic diseases. However, there remain several problems in previous rearing methods. In this study, we demonstrate a novel method for rearing zebrafish larvae by using a new first food, freshwater rotifers (Brachionus calyciflorus). Feeding experiments indicated that freshwater rotifers are suitable as the first food for newly hatched larval fish. In addition, we revisited and improved a feeding schedule from 5 to 40 days postfertilization. Our feeding method using freshwater rotifers accelerated larval growth. At 49 dpf, one pair out of 10 pairs successfully produced six fertilized eggs. At 56, 63, and 71 dpf, 6 out of the 10 pairs constantly produced normal embryos. Our method will improve the husbandry of the zebrafish. PMID- 25938500 TI - CD38 is expressed on inflammatory cells of the intestine and promotes intestinal inflammation. AB - The enzyme CD38 is expressed on a variety of hematopoietic and non-hematopoietic cells and is involved in diverse processes such as generation of calcium mobilizing metabolites, cell activation, and chemotaxis. Here, we show that under homeostatic conditions CD38 is highly expressed on immune cells of the colon mucosa of C57BL/6 mice. Myeloid cells recruited to this tissue upon inflammation also express enhanced levels of CD38. To determine the role of CD38 in intestinal inflammation, we applied the dextran sulfate sodium (DSS) colitis model. Whereas wild-type mice developed severe colitis, CD38-/- mice had only mild disease following DSS-treatment. Histologic examination of the colon mucosa revealed pronounced inflammatory damage with dense infiltrates containing numerous granulocytes and macrophages in wild-type animals, while these findings were significantly attenuated in CD38-/- mice. Despite attenuated histological findings, the mRNA expression of inflammatory cytokines and chemokines was only marginally lower in the colons of CD38-/- mice as compared to wild-type mice. In conclusion, our results identify a function for CD38 in the control of inflammatory processes in the colon. PMID- 25938501 TI - Integrating Community-Based Interventions to Reverse the Convergent TB/HIV Epidemics in Rural South Africa. AB - The WHO recommends integrating interventions to address the devastating TB/HIV co epidemics in South Africa, yet integration has been poorly implemented and TB/HIV control efforts need strengthening. Identifying infected individuals is particularly difficult in rural settings. We used mathematical modeling to predict the impact of community-based, integrated TB/HIV case finding and additional control strategies on South Africa's TB/HIV epidemics. We developed a model incorporating TB and HIV transmission to evaluate the effectiveness of integrating TB and HIV interventions in rural South Africa over 10 years. We modeled the impact of a novel screening program that integrates case finding for TB and HIV in the community, comparing it to status quo and recommended TB/HIV control strategies, including GeneXpert, MDR-TB treatment decentralization, improved first-line TB treatment cure rate, isoniazid preventive therapy, and expanded ART. Combining recommended interventions averted 27% of expected TB cases (95% CI 18-40%) 18% HIV (95% CI 13-24%), 60% MDR-TB (95% CI 34-83%), 69% XDR-TB (95% CI 34-90%), and 16% TB/HIV deaths (95% CI 12-29). Supplementing these interventions with annual community-based TB/HIV case finding averted a further 17% of TB cases (44% total; 95% CI 31-56%), 5% HIV (23% total; 95% CI 17-29%), 8% MDR-TB (68% total; 95% CI 40-88%), 4% XDR-TB (73% total; 95% CI 38-91%), and 8% TB/HIV deaths (24% total; 95% CI 16-39%). In addition to increasing screening frequency, we found that improving TB symptom questionnaire sensitivity, second line TB treatment delays, default before initiating TB treatment or ART, and second-line TB drug efficacy were significantly associated with even greater reductions in TB and HIV cases. TB/HIV epidemics in South Africa were most effectively curtailed by simultaneously implementing interventions that integrated community-based TB/HIV control strategies and targeted drug-resistant TB. Strengthening existing TB and HIV treatment programs is needed to further reduce disease incidence. PMID- 25938502 TI - Distribution characteristics of normal pure-tone thresholds. AB - OBJECTIVE: This study examined the statistical properties of normal air conduction thresholds obtained with automated and manual audiometry to test the hypothesis that thresholds are normally distributed and to examine the distributions for evidence of bias in manual testing. DESIGN: Four databases were mined for normal thresholds. One contained audiograms obtained with an automated method. The other three were obtained with manual audiometry. Frequency distributions were examined for four test frequencies (250, 500, 1000, and 2000 Hz). STUDY SAMPLE: The analysis is based on 317 569 threshold determinations of 80 547 subjects from four clinical databases. RESULTS: Frequency distributions of thresholds obtained with automated audiometry are normal in form. Corrected for age, the mean thresholds are within 1.5 dB of reference equivalent threshold sound pressure levels. Frequency distributions of thresholds obtained by manual audiometry are shifted toward higher thresholds. Two of the three datasets obtained by manual audiometry are positively skewed. CONCLUSIONS: The positive shift and skew of the manual audiometry data may result from tester bias. The striking scarcity of thresholds below 0 dB HL suggests that audiologists place less importance on identifying low thresholds than they do for higher-level thresholds. We refer to this as the Good enough bias and suggest that it may be responsible for differences in distributions of thresholds obtained by automated and manual audiometry. PMID- 25938503 TI - Feasibility of a bilateral 4000-6000 Hz notch as a phenotype for genetic association analysis. AB - OBJECTIVE: Noise-induced hearing loss (NIHL) is a worldwide health problem and a growing concern among young people. Although some people appear to be more susceptible to NIHL, genetic association studies lack a specific phenotype. We tested the feasibility of a bilateral 4000-6000 Hz audiometric notch as a phenotype for identifying genetic contributions to hearing loss in young adults. DESIGN: A case-control-control study was conducted to examine selected SNPs in 52 genes previously associated with hearing loss and/or expressed in the cochlea. A notch was defined as a minimum of a 15-dB drop at 4000-6000 Hz from the previous best threshold with a 5-dB 'recovery' at 8000 Hz. STUDY SAMPLE: Participants were 252 individuals of European descent taken from a population of 640 young adults who are students of classical music. Participants were grouped as No-notch (NN), Unilateral Notch (UN), or Bilateral Notch (BN). RESULTS: The strongest evidence of a genetic association with the 4000-6000 Hz notch was a nonsynonymous SNP variant in the ESRR- gene (rs61742642:C> T, P386S). Carriers of the minor allele accounted for 26% of all bilateral losses. CONCLUSION: This study indicates that the 4000-6000 Hz bilateral notch is a feasible phenotype for identifying genetic susceptibility to hearing loss. PMID- 25938504 TI - Supporting living well with hearing loss: A Delphi review of self-management support. AB - OBJECTIVES: To assess consensus amongst stakeholders in adult auditory rehabilitation on what processes might support self-management. DESIGN: A three round Delphi review was conducted online. Participants responded to five questions relating to living well with a hearing loss and the clinical processes that might support living well. Responses were analysed using thematic analysis. In further rounds, statements arising from the analysis were scored using a nine point Likert scale, independently and then in the light of the collated panel responses. Statements reaching pre-defined criteria for consensus were identified. STUDY SAMPLE: A panel of 26 stakeholders in adult auditory rehabilitation were consulted, including people with hearing loss and researchers and professionals who design and implement process change. RESULTS: There was consensus on clinical skills and behaviours that might help individuals live well, including processes that inform and involve the individual with the hearing loss (e.g. providing information about hearing and collaborative goal setting, respectively). The panel identified potential emotional, cognitive, and behavioural markers for living well with a hearing loss. CONCLUSIONS: The results of this review provide a rationale for the development and evaluation of interventions that include collaborative clinical behaviours as part of self management support. PMID- 25938505 TI - Value of Computerized 3D Shape Analysis in Differentiating Encapsulated from Invasive Thymomas. AB - OBJECTIVES: To retrospectively investigate the added value of quantitative 3D shape analysis in differentiating encapsulated from invasive thymomas. MATERIALS AND METHODS: From February 2002 to October 2013, 53 patients (25 men and 28 women; mean age, 53.94 +/- 13.13 years) with 53 pathologically-confirmed thymomas underwent preoperative chest CT scans (slice thicknesses <= 2.5 mm). Twenty-three tumors were encapsulated thymomas and 30 were invasive thymomas. Their clinical and CT characteristics were evaluated. In addition, each thymoma was manually segmented from surrounding structures, and their 3D shape features were assessed using an in-house developed software program. To evaluate the added value of 3D shape features in differentiating encapsulated from invasive thymomas, logistic regression analysis and receiver-operating characteristics curve (ROC) analysis were performed. RESULTS: Significant differences were observed between encapsulated and invasive thymomas, in terms of cystic changes (p=0.004), sphericity (p=0.016), and discrete compactness (p=0.001). Subsequent binary logistic regression analysis revealed that absence of cystic change (adjusted odds ratio (OR) = 6.636; p=0.015) and higher discrete compactness (OR = 77.775; p=0.012) were significant differentiators of encapsulated from invasive thymomas. ROC analyses revealed that the addition of 3D shape analysis to clinical and CT features (AUC, 0.955; 95% CI, 0.935-0.975) provided significantly higher performance in differentiating encapsulated from invasive thymomas than clinical and CT features (AUC, 0.666; 95% CI, 0.626-0.707) (p<0.001). CONCLUSION: Addition of 3D shape analysis, particularly discrete compactness, can improve differentiation of encapsulated thymomas from invasive thymomas. PMID- 25938506 TI - Spatial patterns of movement of dung beetle species in a tropical forest suggest a new trap spacing for dung beetle biodiversity studies. AB - A primary goal of community ecologists is to understand the processes underlying the spatiotemporal patterns of species distribution. Understanding the dispersal process is of great interest in ecology because it is related to several mechanisms driving community structure. We investigated the mobility of dung beetles using mark-release-recapture technique, and tested the usefulness of the current recommendation for interaction distance between baited pitfall traps in the Brazilian Atlantic Forest. We found differences in mean movement rate between Scarabaeinae species, and between species with different sets of ecological traits. Large-diurnal-tunneler species showed greater mobility than did both large-nocturnal tunneler and roller species. Our results suggest that, based on the analyses of the whole community or the species with the highest number of recaptured individuals, the minimum distance of 50 m between pairs of baited pitfall traps proposed roughly 10 years ago is inadequate. Dung beetle species with different sets of ecological traits may differ in their dispersal ability, so we suggest a new minimum distance of 100 m between pairs of traps to minimize interference between baited pitfall traps for sampling copronecrophagous Scarabaeinae dung beetles. PMID- 25938507 TI - Split-care patients and their caregivers: how collaborative is collaborative care? AB - This study assessed the experiences of patients receiving split-care treatment, focusing on communication between the two treating professionals and its impact on patient satisfaction. Studies have documented that for more than 20% of patients, no communication occurs between providers, and the present study provides further data. Split-care patients completed a 23-item questionnaire on SurveyMonkey via Mechanical Turk, a crowd-sourcing Website, assessing patients' split-care experiences, including whether their providers had communicated and the impact of communication on patients' satisfaction with treatment. Of respondents who knew if their providers communicated, 30% reported that no communication occurred. Similarly, 30% and 36% of respondents were never asked by their psychotherapist or psychopharmacologist, respectively, for permission to speak to the other professional. Non-communication yielded significantly lower patient satisfaction with treatment. This study replicates the high frequency of non-communication between providers of split care and has great implications for the impact of communication on treatment compliance and outcome. PMID- 25938508 TI - Antennal Transcriptome Analysis of Odorant Reception Genes in the Red Turpentine Beetle (RTB), Dendroctonus valens. AB - BACKGROUND: The red turpentine beetle (RTB), Dendroctonus valens LeConte (Coleoptera: Curculionidae, Scolytinae), is a destructive invasive pest of conifers which has become the second most important forest pest nationwide in China. Dendroctonus valens is known to use host odors and aggregation pheromones, as well as non-host volatiles, in host location and mass-attack modulation, and thus antennal olfaction is of the utmost importance for the beetles' survival and fitness. However, information on the genes underlying olfaction has been lacking in D. valens. Here, we report the antennal transcriptome of D. valens from next generation sequencing, with the goal of identifying the olfaction gene repertoire that is involved in D. valens odor-processing. RESULTS: We obtained 51 million reads that were assembled into 61,889 genes, including 39,831 contigs and 22,058 unigenes. In total, we identified 68 novel putative odorant reception genes, including 21 transcripts encoding for putative odorant binding proteins (OBP), six chemosensory proteins (CSP), four sensory neuron membrane proteins (SNMP), 22 odorant receptors (OR), four gustatory receptors (GR), three ionotropic receptors (IR), and eight ionotropic glutamate receptors. We also identified 155 odorant/xenobiotic degradation enzymes from the antennal transcriptome, putatively identified to be involved in olfaction processes including cytochrome P450s, glutathione-S-transferases, and aldehyde dehydrogenase. Predicted protein sequences were compared with counterparts in Tribolium castaneum, Megacyllene caryae, Ips typographus, Dendroctonus ponderosae, and Agrilus planipennis. CONCLUSION: The antennal transcriptome described here represents the first study of the repertoire of odor processing genes in D. valens. The genes reported here provide a significant addition to the pool of identified olfactory genes in Coleoptera, which might represent novel targets for insect management. The results from our study also will assist with evolutionary analyses of coleopteran olfaction. PMID- 25938509 TI - Primary care patients' perspectives of barriers and enablers of primary prevention and health promotion-a meta-ethnographic synthesis. AB - BACKGROUND: Primary care (PC) patients have difficulties in committing to and incorporating primary prevention and health promotion (PP&HP) activities into their long-term care. We aimed to re-interpret, for the first time, qualitative findings regarding factors affecting PC patients' acceptance of PP&HP activities. METHODS AND FINDINGS: A meta-ethnographic synthesis was generated following electronic and manual searches that retrieved 29 articles. Papers were reviewed and translated to produce a re-interpretation of the extracted concepts. The factors affecting PC patients' receptiveness to PP&HP activities were framed in a four-level ecological model (intrapersonal, interpersonal, institutional and environment and society). Intrapersonal factors (patients' beliefs/attitudes, knowledge, skills, self-concept, motivation and resources) were the most numerous, with almost 25 different factors. Public health education to modify erroneous beliefs and values regarding PP&HP could encourage a transition to healthier lifestyles. Health care professionals' abilities to communicate and involve patients in the decision-making process can act as facilitators. Biopsychosocial training (with emphasis on communication skills) for health professionals must start with undergraduates. Increased consultation time, the use of reminders, follow-up visits and tools for communicating risk and motivating patients could be applied at the intrapersonal level. Collaborative care involving other health professionals (nutritionists or psychotherapists) and family and community stakeholders (teachers or gym trainers) was important in developing healthier habits. Patients also cited barriers related to the built environment and socioeconomic difficulties that highlighted the need for policies promoting social justice and equity. Encouraging PP&HP using social marketing strategies and regulating media to control its impact on health were also cited. Only the perspectives of PC patients in the context of chronic conditions were considered thus limiting extrapolation to other contexts. CONCLUSIONS: Several factors affect PP&HP. This must be taken into account when designing PP&HP activities if they are to be successfully implemented and maintained in routine practice. PMID- 25938510 TI - A High Throughput Protein Microarray Approach to Classify HIV Monoclonal Antibodies and Variant Antigens. AB - In recent years, high throughput discovery of human recombinant monoclonal antibodies (mAbs) has been applied to greatly advance our understanding of the specificity, and functional activity of antibodies against HIV. Thousands of antibodies have been generated and screened in functional neutralization assays, and antibodies associated with cross-strain neutralization and passive protection in primates, have been identified. To facilitate this type of discovery, a high throughput-screening tool is needed to accurately classify mAbs, and their antigen targets. In this study, we analyzed and evaluated a prototype microarray chip comprised of the HIV-1 recombinant proteins gp140, gp120, gp41, and several membrane proximal external region peptides. The protein microarray analysis of 11 HIV-1 envelope-specific mAbs revealed diverse binding affinities and specificities across clades. Half maximal effective concentrations, generated by our chip analysis, correlated significantly (P<0.0001) with concentrations from ELISA binding measurements. Polyclonal immune responses in plasma samples from HIV-1 infected subjects exhibited different binding patterns, and reactivity against printed proteins. Examining the totality of the specificity of the humoral response in this way reveals the exquisite diversity, and specificity of the humoral response to HIV. PMID- 25938511 TI - Ancient DNA reveals that the genetic structure of the northern Han Chinese was shaped prior to 3,000 years ago. AB - The Han Chinese are the largest ethnic group in the world, and their origins, development, and expansion are complex. Many genetic studies have shown that Han Chinese can be divided into two distinct groups: northern Han Chinese and southern Han Chinese. The genetic history of the southern Han Chinese has been well studied. However, the genetic history of the northern Han Chinese is still obscure. In order to gain insight into the genetic history of the northern Han Chinese, 89 human remains were sampled from the Hengbei site which is located in the Central Plain and dates back to a key transitional period during the rise of the Han Chinese (approximately 3,000 years ago). We used 64 authentic mtDNA data obtained in this study, 27 Y chromosome SNP data profiles from previously studied Hengbei samples, and genetic datasets of the current Chinese populations and two ancient northern Chinese populations to analyze the relationship between the ancient people of Hengbei and present-day northern Han Chinese. We used a wide range of population genetic analyses, including principal component analyses, shared mtDNA haplotype analyses, and geographic mapping of maternal genetic distances. The results show that the ancient people of Hengbei bore a strong genetic resemblance to present-day northern Han Chinese and were genetically distinct from other present-day Chinese populations and two ancient populations. These findings suggest that the genetic structure of northern Han Chinese was already shaped 3,000 years ago in the Central Plain area. PMID- 25938512 TI - Mixed Mating System Are Regulated by Fecundity in Shorea curtisii (Dipterocarpaceae) as Revealed by Comparison under Different Pollen Limited Conditions. AB - The maintenance of mixed mating was studied in Shorea curtisii, a dominant and widely distributed dipterocarp species in Southeast Asia. Paternity and hierarchical Bayesian analyses were used to estimate the parameters of pollen dispersal kernel, male fecundity and self-pollen affinity. We hypothesized that partial self incompatibility and/or inbreeding depression reduce the number of selfed seeds if the mother trees receive sufficient pollen, whereas reproductive assurance increases the numbers of selfed seeds under low amounts of pollen. Comparison of estimated parameters of self-pollen affinity between high density undisturbed and low density selectively logged forests indicated that self-pollen was selectively excluded from mating in the former, probably due to partial self incompatibility or inbreeding depression until seed maturation. By estimating the self-pollen affinity of each mother tree in both forests, mother trees with higher amount of self-pollen indicated significance of self-pollen affinity with negative estimated value. The exclusion of self-fertilization and/or inbreeding depression during seed maturation occurred in the mother trees with large female fecundity, whereas reproductive assurance increased self-fertilization in the mother trees with lower female fecundity. PMID- 25938513 TI - High milk consumption does not affect prostate tumor progression in two mouse models of benign and neoplastic lesions. AB - Epidemiological studies that have investigated whether dairy (mainly milk) diets are associated with prostate cancer risk have led to controversial conclusions. In addition, no existing study clearly evaluated the effects of dairy/milk diets on prostate tumor progression, which is clinically highly relevant in view of the millions of men presenting with prostate pathologies worldwide, including benign prostate hyperplasia (BPH) or high-grade prostatic intraepithelial neoplasia (HGPIN). We report here a unique interventional animal study to address this issue. We used two mouse models of fully penetrant genetically-induced prostate tumorigenesis that were investigated at the stages of benign hyperplasia (probasin-Prl mice, Pb-Prl) or pre-cancerous PIN lesions (KIMAP mice). Mice were fed high milk diets (skim or whole) for 15 to 27 weeks of time depending on the kinetics of prostate tumor development in each model. Prostate tumor progression was assessed by tissue histopathology examination, epithelial proliferation, stromal inflammation and fibrosis, tumor invasiveness potency and expression of various tumor markers relevant for each model (c-Fes, Gprc6a, activated Stat5 and p63). Our results show that high milk consumption (either skim or whole) did not promote progression of existing prostate tumors when assessed at early stages of tumorigenesis (hyperplasia and neoplasia). For some parameters, and depending on milk type, milk regimen could even exhibit slight protective effects towards prostate tumor progression by decreasing the expression of tumor-related markers like Ki-67 and Gprc6a. In conclusion, our study suggests that regular milk consumption should not be considered detrimental for patients presenting with early-stage prostate tumors. PMID- 25938514 TI - In Vitro and In Vivo Evaluations of PLGA Microspheres Containing Nalmefene. AB - Poor patient compliance, untoward reactions and unstable blood drug levels after the bolus administration are impeding the pharmacotherapy for insobriety. A long acting preparation may address these limitations. The aim of this paper was to further investigate the in vitro characteristics and in vivo performances of nalmefene microspheres. Nalmefene was blended with poly (lactide-co-glycolide) (PLGA) to prepare the target microspheres by an O/O emulsification solvent evaporation method. The prepared microspheres exhibited a controlled release profile of nalmefene in vitro over 4 weeks, which was well fitted with a first order model. In vitro degradation study showed that the drug release in vitro was dominated by both drug diffusion and polymer degradation mechanisms. Pharmacokinetics study indicated that the prepared microspheres could provide a relatively constant of nalmefene plasma concentration for at least one month in rats. The in vivo pharmacokinetics profile was well correlated with the in vitro drug release. Pharmacodynamics studies revealed that the drug loaded microspheres could produce a long-acting antagonism efficacy on rats. These results demonstrated the promising application of injectable PLGA microspheres containing nalmefene for the long-term treatment of alcohol dependence. PMID- 25938515 TI - Delay discounting of food by rhesus monkeys: Cocaine and food choice in isomorphic and allomorphic situations. AB - Research on delay discounting has focused largely on nondrug reinforcers in an isomorphic context in which choice is between alternatives that involve the same type of reinforcer. Less often, delay discounting has been studied with drug reinforcers in a more ecologically valid allomorphic context where choice is between alternatives involving different types of reinforcers. The present experiment is the first to examine discounting of drug and nondrug reinforcers in both isomorphic and allomorphic situations using a theoretical model (i.e., the hyperbolic discounting function) that allows for comparisons of discounting rates between reinforcer types and amounts. The goal of the current experiment was to examine discounting of a delayed, nondrug reinforcer (food) by male rhesus monkeys when the immediate alternative was either food (isomorphic situation) or cocaine (allomorphic situation). In addition, we sought to determine whether there was a magnitude effect with delayed food in the allomorphic situation. Choice of immediate food and immediate cocaine increased with amount and dose, respectively. Choice functions for immediate food and cocaine generally shifted leftward as delay increased. Compared to isomorphic situations in which food was the immediate alternative, delayed food was discounted more steeply in allomorphic situations where cocaine was the immediate alternative. Notably, discounting was not affected by the magnitude of the delayed reinforcer. These data indicate that how steeply a delayed nondrug reinforcer is discounted may depend more on the qualitative characteristics of the immediate reinforcer and less on the magnitude of the delayed one. PMID- 25938516 TI - Effects of the Selective Stretch-Activated Channel Blocker GsMtx4 on Stretch Induced Changes in Refractoriness in Isolated Rat Hearts and on Ventricular Premature Beats and Arrhythmias after Coronary Occlusion in Swine. AB - Mechanical factors may contribute to ischemic ventricular arrhythmias. GsMtx4 peptide, a selective stretch-activated channel blocker, inhibits stretch-induced atrial arrhythmias. We aimed to assess whether GsMtx4 protects against ventricular ectopy and arrhythmias following coronary occlusion in swine. First, the effects of 170-nM GsMtx4 on the changes in the effective refractory period (ERP) induced by left ventricular (LV) dilatation were assessed in 8 isolated rat hearts. Then, 44 anesthetized, open-chest pigs subjected to 50-min left anterior descending artery occlusion and 2-h reperfusion were blindly allocated to GsMtx4 (57 MUg/kg iv. bolus and 3.8 MUg/kg/min infusion, calculated to attain the above concentration in plasma) or saline, starting 5-min before occlusion and continuing until after reflow. In rat hearts, LV distension induced progressive reductions in ERP (35+/-2, 32+/-2, and 29+/-2 ms at 0, 20, and 40 mmHg of LV end diastolic pressure, respectively, P<0.001) that were prevented by GsMTx4 (33+/-2, 33+/-2, and 32+/-2 ms, respectively, P=0.002 for the interaction with LV end diastolic pressure). Pigs receiving GsMtx4 had similar number of ventricular premature beats during the ischemic period as control pigs (110+/-28 vs. 103+/ 21, respectively, P=0.842). There were not significant differences among treated and untreated animals in the incidence of ventricular fibrillation (13.6 vs. 22.7%, respectively, P=0.696) or tachycardia (36.4 vs. 50.0%, P=0.361) or in the number of ventricular tachycardia episodes during the occlusion period (1.8+/-0.7 vs. 5.5+/-2.6, P=0.323). Thus, GsMtx4 administered under these conditions does not suppress ventricular ectopy following coronary occlusion in swine. Whether it might protect against malignant arrhythmias should be tested in studies powered for these outcomes. PMID- 25938517 TI - miR-141 and miR-200a, Revelation of New Possible Players in Modulation of Th17/Treg Differentiation and Pathogenesis of Multiple Sclerosis. AB - BACKGROUND: One of the main issues in pathogenesis of MS is Th17/Treg imbalance. There are growing interests in nominating miRNAs involved in Th17 cell differentiation, suggesting them as new therapeutic agents that may reduce progression of different autoimmune diseases specially MS. OBJECTIVES: We assessed transcript levels of miR-141 and miR-200a in MS patients, during relapsing and remitting phases. We also investigated possible role of miR-141, miR-200a in inducing differentiation to Th17 cells. MATERIALS AND METHODS: Forty RR-MS patient samples including relapsing (n=20) and remitting (n=20) phases were chosen. Expression level of miR-141 and miR-200a were measured by RT-q PCR and compared to healthy control group (n=10). In-silico analyses on miR-141 and miR 200a targetome showed involvement of both miRNAs in T helper cell differentiation pathways including TGF-beta, mTOR and JAK/STAT. RESULTS: We observed that percentage of RORgammat+ CD4+ T cells increase in relapsing phase while FOXP3+ CD4+ increase in remitting phase of MS patients. Furthermore, both miR-141 and miR-200a show up-regulation in relapsing phase of MS patients compared to remitting and control groups. Interestingly, expression level of target genes of miR-141 and miR-200a, which were assessed through in-silico methods, show down regulation in relapsing phase of MS patients. CONCLUSIONS: According to our results, miR-141 and miR-200a may be key miRNAs in progression of symptoms of MS through inducing differentiation of Th17 cells and inhibiting differentiation to Treg cells. Our data suggest that these miRNAs may probably inhibit negative regulators of Th17 cell differentiation, thus promoting its differentiation. PMID- 25938518 TI - Insulator-to-Proton-Conductor Transition in a Dense Metal-Organic Framework. AB - Metal-organic frameworks (MOFs) are prone to exhibit phase transitions under stimuli such as changes in pressure, temperature, or gas sorption because of their flexible and responsive structures. Here we report that a dense MOF, ((CH3)2NH2)2[Li2Zr(C2O4)4], exhibits an abrupt increase in proton conductivity from <10(-9) to 3.9 * 10(-5) S/cm at 17 degrees C (activation energy, 0.64 eV) upon exposure to humidity. The conductivities were determined using single crystals, and the structures were analyzed by X-ray diffraction and X-ray pair distribution function analysis. The initial anhydrous structure transforms to another dense structure via topotactic hydration (H2O/Zr = 0.5), wherein one fourth of the Li ions are irreversibly rearranged and coordinated by water molecules. This structure further transforms into a third crystalline structure by water uptake (H2O/Zr = 4.0). The abrupt increase in conductivity is reversible and is associated with the latter reversible structure transformation. The H2O molecules coordinated to Li ions, which are formed in the first step of the transformation, are considered to be the proton source, and the absorbed water molecules, which are formed in the second step, are considered to be proton carriers. PMID- 25938519 TI - Differentiation of a Human Neural Stem Cell Line on Three Dimensional Cultures, Analysis of MicroRNA and Putative Target Genes. AB - Neural stem cells (NSCs) are capable of self-renewal and differentiation into neurons, astrocytes and oligodendrocytes under specific local microenvironments. In here, we present a set of methods used for three dimensional (3D) differentiation and miRNA analysis of a clonal human neural stem cell (hNSC) line, currently in clinical trials for stroke disability (NCT01151124 and NCT02117635, Clinicaltrials.gov). HNSCs were derived from an ethical approved first trimester human fetal cortex and conditionally immortalized using retroviral integration of a single copy of the c-mycER(TAM)construct. We describe how to measure axon process outgrowth of hNSCs differentiated on 3D scaffolds and how to quantify associated changes in miRNA expression using PCR array. Furthermore we exemplify computational analysis with the aim of selecting miRNA putative targets. SOX5 and NR4A3 were identified as suitable miRNA putative target of selected significantly down-regulated miRNAs in differentiated hNSC. MiRNA target validation was performed on SOX5 and NR4A3 3'UTRs by dual reporter plasmid transfection and dual luciferase assay. PMID- 25938520 TI - Comment on "Comparison of Water Use for Hydraulic Fracturing for Unconventional Oil and Gas versus Conventional Oil". PMID- 25938521 TI - Organically Modified Saponites: SAXS Study of Swelling and Application in Caffeine Removal. AB - This study aimed to assess the capacity of saponite modified with n hexadecyltrimethylammonium bromide (CTAB) and/or 3-aminopropyltriethoxysilane (APTS) to adsorb and remove caffeine from aqueous solutions. Powder X-ray diffraction (PXRD) revealed increased basal spacing in the modified saponites. Small-angle X-ray scattering (SAXS) confirmed the PXRD results; it also showed how the different clay layers were stacked and provided information on the swelling of natural saponite and of the saponites functionalized with CTAB and/or APTS. Thermal analyses, infrared spectroscopy, scanning electron microscopy, element chemical analysis, and textural analyses confirmed functionalization of the natural saponite. The maximum adsorption capacity at equilibrium was 80.54 mg/g, indicating that the saponite modified with 3-aminopropyltriethoxysilane constitutes an efficient and suitable caffeine adsorbent. PMID- 25938523 TI - Imaging technology and somatic dysfunction theory. PMID- 25938522 TI - False Discovery Rates in PET and CT Studies with Texture Features: A Systematic Review. AB - PURPOSE: A number of recent publications have proposed that a family of image derived indices, called texture features, can predict clinical outcome in patients with cancer. However, the investigation of multiple indices on a single data set can lead to significant inflation of type-I errors. We report a systematic review of the type-I error inflation in such studies and review the evidence regarding associations between patient outcome and texture features derived from positron emission tomography (PET) or computed tomography (CT) images. METHODS: For study identification PubMed and Scopus were searched (1/2000 9/2013) using combinations of the keywords texture, prognostic, predictive and cancer. Studies were divided into three categories according to the sources of the type-I error inflation and the use or not of an independent validation dataset. For each study, the true type-I error probability and the adjusted level of significance were estimated using the optimum cut-off approach correction, and the Benjamini-Hochberg method. To demonstrate explicitly the variable selection bias in these studies, we re-analyzed data from one of the published studies, but using 100 random variables substituted for the original image-derived indices. The significance of the random variables as potential predictors of outcome was examined using the analysis methods used in the identified studies. RESULTS: Fifteen studies were identified. After applying appropriate statistical corrections, an average type-I error probability of 76% (range: 34-99%) was estimated with the majority of published results not reaching statistical significance. Only 3/15 studies used a validation dataset. For the 100 random variables examined, 10% proved to be significant predictors of survival when subjected to ROC and multiple hypothesis testing analysis. CONCLUSIONS: We found insufficient evidence to support a relationship between PET or CT texture features and patient survival. Further fit for purpose validation of these image derived biomarkers should be supported by appropriate biological and statistical evidence before their association with patient outcome is investigated in prospective studies. PMID- 25938524 TI - Variations in the diagnosis and treatment of somatic dysfunction between 4 osteopathic residency programs. AB - CONTEXT: The American Osteopathic Association requires the integration of osteo pathic principles and practice in all specialty residency training programs that it accredits, but the 4 residencies with the most integration of osteopathic manipulative medicine (OMM) have differences in training and emphasis on OMM as a primary treatment modality. OBJECTIVE: To study differences in OMM use for spinal pain between the neuro-musculoskeletal medicine/OMM (NMM/OMM), the family practice/osteopath-ic manipulative treatment (FP/OMT), the integrated FP/OMT and NMM/OMM (FP/NMM), and the internal medicine and NMM/OMM (IM/NMM) specialty residency training programs. METHODS: Medical records were reviewed for patient encounters from September 2011 through October 2013 at NMM/OMM, FP/OMT, FP/NMM, and IM/NMM residencies in a family medicine and OMM specialty clinic. Records were screened for a diagnosis of cervicalgia, thoracalgia, lumbago, or backache. The identifed encounters were compared to determine between-specialty differences in the number of chief complaints, non-somatic dysfunction assessments, body regions with diagnosed somatic dysfunction, body regions managed with OMT, and number and type of OMT techniques used. RESULTS: Eighteen residents had 2925 patient encounters that included 1 or more spinal pain diagnoses. Overall, 2767 patients (95%) received OMT. The probability (95% CI) of residents using OMT was 0.99 (0.98-0.99) for the NMM/OMM residents, 0.66 (0.55-0.77) for the FP/OMT residents, 0.94 (0.88-0.97) for the FP/NMM residents, and 0.997 (0.98-1.0) for the IM/NMM residents. The FP/OMT residents were less likely to manage spinal pain using OMT (P<.001) and documented fewer somatic dysfunction assessments and fewer musculoskeletal assessments (P<.001), but they documented significantly more non somatic dysfunction assessments (P<.001). When using OMT, the FP/OMT residents diagnosed somatic dysfunction in fewer mean (95% CI) body regions (2.9 [2.4-3.5]) than the NMM/OMM (5.5 [4.9-6.2]), the FP/NMM (5.5 [4.8-6.3]), or the IM/NMM (4.6 [3.4-6.0]) residents (P<.001). The FP/OMT residents also managed fewer mean (95% CI) body regions with OMT (3.5 [3.0-4.1]) than the NMM/OMM (5.7 [5.2-6.3]), the FP/NMM (5.6 [5.0-6.3]), or the IM/NMM (4.7 [3.7-6.0]) residents (P<.001). CONCLUSION: Although the FP/OMT residents used OMT less frequently than the other residents during spinal pain encounters, they provided care for a larger number and a wider variety of non-somatic dysfunction assessments. PMID- 25938525 TI - Lymphatic pump treatment as an adjunct to antibiotics for pneumonia in a rat model. AB - BACKGROUND: Lymphatic pump treatment (LPT) is a technique used by osteopathic physicians as an adjunct to antibiotics for patients with respiratory tract infections, and previous studies have demonstrated that LPT reduces bacterial load in the lungs of rats with pneumonia. Currently, it is unknown whether LPT affects drug effcacy. OBJECTIVE: To determine whether the combination of antibiotics and LPT would reduce bacterial load in the lungs of rats with acute pneumonia. METHODS: Rats were infected intranasally with 5*107 colony-forming units (CFU) of Streptococcus pneumoniae. At 24, 48, and 72 hours after infection, the rats received no therapy (control), 4 minutes of sham therapy, or 4 minutes of LPT, followed by subcutaneous injection of 40 mg/kg of levofoxacin or sterile phosphate-buffered saline. At 48, 72, and 96 hours after infection, the spleens and lungs were collected, and S pneumoniae CFU were enumerated. Blood was analyzed for a complete blood cell count and leukocyte differential count. RESULTS: At 48 and 72 hours after infection, no statistically significant differences in pulmonary CFU were found between control, sham therapy, or LPT when phosphate-buffered saline was administered; however, the reduction in CFU was statistically significant in all rats given levofoxacin. The combination of sham therapy and levofoxacin decreased bacterial load at 72 and 96 hours after infection, and LPT and levofoxacin significantly reduced CFU compared with sham therapy and levofoxacin at both time points (P<.05). Colony-forming units were not detected in the spleens at any time. No statistically significant differences in hematologic findings between any treatment groups were found at any time point measured. CONCLUSION: The results suggest that 3 applications of LPT induces an additional protective mechanism when combined with levofoxacin and support its use as an adjunctive therapy for the management of pneumonia; however, the mechanism responsible for this protection is unclear. PMID- 25938526 TI - Canadian DOs: International Expansion of Osteopathic Medical Education North of the Border. AB - CONTEXT: The growth of osteopathic medicine in the United States has led to a vibrant expansion of the profession internationally. Canadian students represent the majority of international applicants and matriculants to US colleges of osteopathic medicine (COMs); however, to our knowledge, no studies have explored this population. OBJECTIVE: To gain a better understanding of Canadian students attending US colleges of osteopathic medicine by examining their residency training preference, visa preference, intent to practice in the United States or Canada, receptiveness to incorporating osteopathic manipulative medicine into practice, specialty preference, estimated debt incurred, and effect of debt on specialty choice. METHODS: A 10-question electronic survey was sent to Canadian osteopathic medical students in the 17 COMs and branch campuses that accept international applicants. The initial survey pool consisted of frst-, second-, third-, and fourth-year medical students (classes of 2014-2017) compiled from a database managed by the Canadian Osteopathic Medical Student Association. RESULTS: Of the 102 students contacted, 66 (65%) completed the survey. Respondents had a strong desire to practice in Canada (44 [67%]) but were considering an Accreditation Council on Graduate Medical Education (ACGME) or dually accredited residency program in the United States (46 [70%] and 15 [23%], respectively) that would sponsor an H1B visa. Respondents were receptive to incorporating osteopathic manipulative medicine into practice (44 [67%]). Most respondents chose non-primary care specialties (40 [61%]) and incurred a debt of more than $200,000 (44 of 65 [68%]); however, debt had a limited infuence on respondents' choice of specialty (chi23=1.911; P=.591). CONCLUSION: Most respondents planned to complete ACGME training, to return to Canada to practice medicine, and to practice in a non-primary care specialty. As a growing population that will play a large role in the expansion and reception of the profession internationally, Canadian osteopathic medical students and US-trained Canadian DOs merit further examination. PMID- 25938527 TI - Research dissemination: guiding the novice researcher on the publication path. AB - Dissemination is an important part of translational research. When the results of high-quality studies reach a wide audience of peers, they provide an evidence base that can guide practice and improve patient care and safety. From proposal to publication, the authors provide the novice researcher with advice on ethics, tips on selecting a journal, a summary of manuscript requirements, and a brief outline of the submission process and outcomes. By demystifying these processes and outlining some of the basic requirements, the authors hope to encourage novice researchers to engage in quality research and prepare them for disseminating their results. PMID- 25938528 TI - Pulmonary lymphangitic carcinomatosis from metastatic gastric adenocarcinoma: case report. AB - Pulmonary lymphangitic carcinomatosis (PLC) is the diffuse infltration of lymphatic systems by adenocarcinomas. Because of its vague clinical symptoms and absence of malignant features, confrmatory diagnosis requires transbronchial or open-lung biopsy. Tumor spread is postulated to occur by means of retrograde lymphatic permeation with tumor growth along the lymphatic channels and involvement of vascular endothelial growth factor-C in a signaling pathway. The authors describe the case of a 45-year-old woman whose presentation with cough and dyspnea led to diagnosis of pulmonary lymphangitic carcinomatosis with superimposed pulmonary hypertension, tumor thrombotic microangiopathy, and ultimately metastatic signet ring cell gastric adenocarcinoma. Because of the patient's poor prognosis, she was given palliative care and died 29 days after admission. This case emphasizes the importance of the osteopathic principle of treating the whole patient and evaluating all organ systems. Physicians should be aware of PLC from gastric adenocarcinoma and consider it in patients with pulmonary symptoms who are unresponsive to antibiotics. PMID- 25938529 TI - Spontaneous Pneumomediastinum in a Pediatric Patient After a 1600-m Run: Case Report and Literature Review. AB - Pneumomediastinum occurs as a result of traumatic or iatrogenic causes or in patients with preexisting lung conditions such as interstitial lung disease, asthma, and chronic obstructive pulmonary disease. Spontaneous pneumomedi-astinum (SPM), however, is rarely seen in clinical practice. The authors report the case of a 14-year-old boy who presented to the emergency department with chest discomfort and shortness of breath after a 1600-m run as part of a physical education class. The patient was found to have SPM, was admitted to the pediatric service for monitoring and pain control, and made a full recovery within 24 hours. This case is notable because SPM occurred in the absence of identifable organic causes and as the result of sustained noncontact physical activity. A review of the literature provides background information and highlights pathophysiologic processes of SPM and suggested treatment. Physicians should consider pneu-momediastinum in young patients or runners presenting with chest pain even in the absence of any known inciting event. PMID- 25938533 TI - Saddle pulmonary embolus. PMID- 25938534 TI - Long-term effects of retinal gene therapy in childhood blindness. PMID- 25938535 TI - A 3-Year Longitudinal Study of Risk for Bipolar Spectrum Psychopathology. AB - Current clinical and epidemiological research provides support for a continuum of bipolar psychopathology: a bipolar spectrum that ranges from subthreshold characteristics to clinical disorders. The present research examined risk for bipolar spectrum psychopathology at a 3-year follow-up assessment in a nonclinically ascertained sample of 112 young adults identified by the Hypomanic Personality Scale (HPS). Participants completed diagnostic interviews assessing bipolar psychopathology, borderline personality traits, substance use disorders, impulsivity, and psychosocial functioning. At the original assessment, 18 of the 112 participants met criteria for a bipolar spectrum disorder. At the follow-up, an additional 13 had developed bipolar spectrum disorders. A total of 58% of participants scoring in the upper quartile of the HPS qualified for bipolar spectrum disorders at the follow-up, including 27% with DSM-IV-TR disorders. The HPS predicted new cases and total number of cases of bipolar spectrum disorders, as well as total number of DSM-IV-TR bipolar disorders. The HPS also predicted hyperthymic temperament or history of hypomania, grandiose traits, impulsivity, substance use disorders, psychosocial impairment, and borderline traits. The majority of these effects were significant after removing participants with DSM IV-TR bipolar disorders from the analyses, suggesting that the results were not driven by a subset of participants with clinical disorders. Overall, these results offer further support for the bipolar spectrum construct and the predictive validity of the HPS as a measure of bipolar spectrum psychopathology. PMID- 25938536 TI - Do sleep disturbances and psychotic-like experiences in adolescence share genetic and environmental influences? AB - Sleep disturbances regularly co-occur with clinical psychotic disorders and dimensions of psychotic-like experiences (PLEs). One possible explanation for this, which has yet to be tested, is that similar genetic or environmental influences underlie sleep disturbances and vulnerability to PLEs. We conducted a twin study to test this possibility in relation to sleep disturbances and six specific PLEs in adolescence in the general population. Approximately 5,000 16 year-old twin pairs completed the Pittsburgh Sleep Quality Index and Insomnia Severity Index. PLEs were assessed using the Specific PLEs Questionnaire, comprising five self-report subscales (Paranoia, Hallucinations, Cognitive Disorganization, Grandiosity, and Anhedonia) and one parent-report subscale (Negative Symptoms). The associations between these measures were tested using structural equation twin model fitting. Paranoia, Hallucinations, and Cognitive Disorganization displayed moderate and significant correlations with both sleep measures (0.32-.42), while Negative Symptoms, Anhedonia, and Grandiosity showed lower correlations (0.01-0.17). Genetic and environmental influences significantly overlapped across PLEs (Paranoia, Hallucinations, Cognitive Disorganization) and both types of sleep disturbance (mean genetic and nonshared environmental correlations = 0.54 and 0.24, respectively). These estimates reduced, yet remained significant, after controlling for negative affect. The association between PLEs with sleep disturbances in adolescence is partly due to genetic and environmental influences that are common to them both. These findings indicate that the known neurobiology of sleep disturbance may provide clues regarding the causes of PLEs in adolescence. PMID- 25938537 TI - Translational activation of oskar mRNA: reevaluation of the role and importance of a 5' regulatory element [corrected]. AB - Local translation of oskar (osk) mRNA at the posterior pole of the Drosophila oocyte is essential for axial patterning of the embryo, and is achieved by a program of translational repression, mRNA localization, and translational activation. Multiple forms of repression are used to prevent Oskar protein from accumulating at sites other than the oocyte posterior. Activation is mediated by several types of cis-acting elements, which presumably control different forms of activation. We characterize a 5' element, positioned in the coding region for the Long Osk isoform and in the extended 5' UTR for translation of the Short Osk isoform. This element was previously thought to be essential for osk mRNA translation, with a role in posterior-specific release from repression. From our work, which includes assays which separate the effects of mutations on RNA regulatory elements and protein coding capacity, we find that the element is not essential, and conclude that there is no evidence supporting a role for the element only at the posterior of the oocyte. The 5' element has a redundant role, and is only required when Long Osk is not translated from the same mRNA. Mutations in the element do disrupt the anchoring function of Long Osk protein through their effects on the amino acid sequence, a confounding influence on interpretation of previous experiments. PMID- 25938538 TI - Hepatoma-derived growth factor/nucleolin axis as a novel oncogenic pathway in liver carcinogenesis. AB - Hepatoma-derived growth factor (HDGF) overexpression is involved in liver fibrosis and carcinogenesis. However, the receptor(s) and signaling for HDGF remain unclear. By using affinity chromatography and proteomic techniques, nucleolin (NCL) was identified and validated as a HDGF-interacting membrane protein in hepatoma cells. Exogenous HDGF elicited the membrane NCL accumulation within 0.5 hour by protein stabilization and transcriptional NCL upregulation within 24 hours. Blockade of surface NCL by antibodies neutralization potently suppressed HDGF uptake and HDGF-stimulated phosphatidylinositol 3-kinase (PI3K)/Akt signaling in hepatoma cells. By using rescectd hepatocellular carcinoma (HCC) tissues, immunohistochemical analysis revealed NCL overexpression was correlated with tumour grades, vascular invasion, serum alpha-fetoprotein levels and the poor survival in HCC patients. Multivariate analysis showed NCL was an independent prognostic factor for survival outcome of HCC patients after surgery. To delineate the role of NCL in liver carcinogenesis, ectopic NCL overexpression promoted the oncogenic behaviours and induced PI3K/Akt activation in hepatoma cells. Conversely, NCL knockdown by RNA interference attenuated the oncogenic behaviours and PI3K/Akt signaling, which could be partially rescued by exogenous HDGF supply. In summary, this study provides the first evidence that surface NCL transmits the oncogenic signaling of HDGF and facilitates a novel diagnostic and therapeutic target for HCC. PMID- 25938539 TI - PARP inhibitor ABT-888 affects response of MDA-MB-231 cells to doxorubicin treatment, targeting Snail expression. AB - To overcome cancer cells resistance to pharmacological therapy, the development of new therapeutic approaches becomes urgent. For this purpose, the use of poly(ADP-ribose) polymerase (PARP) inhibitors in combination with other cytotoxic agents could represent an efficacious strategy. Poly(ADP-ribosyl)ation (PARylation) is a post-translational modification that plays a well characterized role in the cellular decisions of life and death. Recent findings indicate that PARP-1 may control the expression of Snail, the master gene of epithelial mesenchymal transition (EMT). Snail is highly represented in different resistant tumors, functioning as a factor regulating anti-apoptotic programmes. MDA-MB-231 is a Snail-expressing metastatic breast cancer cell line, which exhibits chemoresistance properties when treated with damaging agents. In this study, we show that the PARP inhibitor ABT-888 was capable to modulate the MDA-MB-231 cell response to doxorubicin, leading to an increase in the rate of apoptosis. Our further results indicate that PARP-1 controlled Snail expression at transcriptional level in cells exposed to doxorubicin. Given the increasing interest in the employment of PARP inhibitors as chemotherapeutic adjuvants, our in vitro results suggest that one of the mechanisms through which PARP inhibition can chemosensitize cancer cells in vivo, is targeting Snail expression thus promoting apoptosis. PMID- 25938540 TI - Overexpression of Id1 in transgenic mice promotes mammary basal stem cell activity and breast tumorigenesis. AB - Inhibitor of differentiation/DNA binding (Id)1 is a crucial regulator of mammary development and breast cancer progression. However, its effect on stemness and tumorigenesis in mammary epithelial cells remains undefined. Herein, we demonstrate that Id1 induces mammary tumorigenesis by increasing normal and malignant mammary stem cell (MaSC) activities in transgenic mice. MaSC-enriched basal cell expansion and increased self-renewal and in vivo regenerative capacity of MaSCs are observed in the mammary glands of MMTV-Id1 transgenic mice. Furthermore, MMTV-Id1 mice develop ductal hyperplasia and mammary tumors with highly expressed basal markers. Id1 also increases breast cancer stem cell (CSC) population and activity in human breast cancer lines. Moreover, the effects of Id1 on normal and malignant stem cell activities are mediated by the Wnt/c-Myc pathway. Collectively, these findings provide in vivo genetic evidence of Id1 functions as an oncogene in breast cancer and indicate that Id1 regulates mammary basal stem cells by activating the Wnt/c-Myc pathway, thereby contributing to breast tumor development. PMID- 25938541 TI - HGFL supports mammary tumorigenesis by enhancing tumor cell intrinsic survival and influencing macrophage and T-cell responses. AB - The Ron receptor is overexpressed in human breast cancers and is associated with heightened metastasis and poor survival. Ron overexpression in the mammary epithelium of mice is sufficient to induce aggressive mammary tumors with a high degree of metastasis. Despite the well-documented role of Ron in breast cancer, few studies have examined the necessity of the endogenous Ron ligand, hepatocyte growth factor-like protein (HGFL) in mammary tumorigenesis. Herein, mammary tumor growth and metastasis were examined in mice overexpressing Ron in the mammary epithelium with or without HGFL. HGFL ablation decreased oncogenic Ron activation and delayed mammary tumor initiation. HGFL was important for tumor cell proliferation and survival. HGFL loss resulted in increased numbers of macrophages and T-cells within the tumor. T-cell proliferation and cytotoxicity dramatically increased in HGFL deficient mice. Biochemical analysis of HGFL proficient tumors showed increased local HGFL production, with HGFL loss decreasing beta-catenin expression and NF-kappaB activation. Re-expression of HGFL in HGFL deficient tumor cells stimulated cell migration and invasion with coordinate activation of NF-kappaB and reduced apoptosis. Together, these results demonstrate critical in vivo functions for HGFL in promoting breast tumorigenesis and suggest that targeting HGFL may inhibit tumor growth and reactivate anti tumor immune responses. PMID- 25938544 TI - Lactate promotes PGE2 synthesis and gluconeogenesis in monocytes to benefit the growth of inflammation-associated colorectal tumor. AB - Reprogramming energy metabolism, such as enhanced glycolysis, is an Achilles' heel in cancer treatment. Most studies have been performed on isolated cancer cells. Here, we studied the energy-transfer mechanism in inflammatory tumor microenvironment. We found that human THP-1 monocytes took up lactate secreted from tumor cells through monocarboxylate transporter 1. In THP-1 monocytes, the oxidation product of lactate, pyruvate competed with the substrate of proline hydroxylase and inhibited its activity, resulting in the stabilization of HIF 1alpha under normoxia. Mechanistically, activated hypoxia-inducible factor 1 alpha in THP-1 monocytes promoted the transcriptions of prostaglandin endoperoxide synthase 2 and phosphoenolpyruvate carboxykinase, which were the key enzyme of prostaglandin E2 synthesis and gluconeogenesis, respectively, and promote the growth of human colon cancer HCT116 cells. Interestingly, lactate could not accelerate the growth of colon cancer directly in vivo. Instead, the human monocytic cells affected by lactate would play critical roles to 'feed' the colon cancer cells. Thus, recycling of lactate for glucose regeneration was reported in cancer metabolism. The anabolic metabolism of monocytes in inflammatory tumor microenvironment may be a critical event during tumor development, allowing accelerated tumor growth. PMID- 25938547 TI - Protonolysis and amide exchange reactions of a three-coordinate cobalt amide complex supported by an N-heterocyclic carbene ligand. AB - A three-coordinate cobalt species, IPrCoCl{N(SiMe3)2} [1; IPr = 1,3-bis(2,6 diisopropylphenyl)imidazolin-2-ylidene], was synthesized by the reaction of {IPrCoCl2}2 with NaN(SiMe3)2. Compound 1 is a useful starting material for low coordinate (IPr)Co species. 1 reacts with 2,6-di-tert-butyl-4-methylphenol (BHT H) via aminolysis of the Co-N bond to generate a three-coordinate phenoxide complex, IPrCoCl(O-2,6-(t)Bu2-4-MeC6H2) (2). The reaction of 1 with 2,6 diisopropylaniline (NH2DIPP) generates IPrCoCl(NHDIPP) (4), which undergoes disproportionation to form a mixture of 4, {IPrCoCl2}2, and IPrCo(NHDIPP)2 (3). The same product mixture is formed by the reaction of 1 with Li[NH(DIPP)], which unexpectedly proceeds by amide exchange. Compound 3 was synthesized independently by the reaction of {IPrCoCl2}2 with 4 equiv of Li[NH(DIPP)]. The reaction of 1 with the bulkier lithium 2,6-dimesitylanilide (LiNHDMP) also proceeds by amide exchange to generate IPrCoCl(NHDMP) (5), which is stable toward disproportionation. Compounds 1 and 2 exhibit trigonal-planar geometries at cobalt in the solid state. The solid-state structure of 3 also contains a trigonal-planar cobalt center and exhibits close Co---H contacts involving the methine hydrogen atoms of the NH(DIPP) groups in the axial positions. The solid state structure of 5 features an interaction between cobalt and a flanking aryl group of the anilide ligand, resulting in pyramidalization of the cobalt center. PMID- 25938546 TI - Platelet response during the second cycle of decitabine treatment predicts response and survival for myelodysplastic syndrome patients. AB - Despite the efficacy of decitabine to myelodysplastic syndrome (MDS), there is a wide range of responses, and no definite predictive marker has been identified. This study aimed to describe the efficacy of decitabine and to identify potential predictors of response and survival in patients with MDS. We retrospectively analyzed clinical data of MDS patients at Samsung Medical Center between August 2008 and August 2011. The response assessment was conducted using the International Working Group (IWG) response criteria for MDS. We analyzed 101 MDS patients (total 613 cycles) who received decitabine for a median of four cycles. The overall response was 52.5% (n = 53/101). The median time to any response was two cycles with the median overall survival of 16.7 months. Patients who showed hematologic improvement had significantly longer survival than those who did not (9.8 vs. 22.9 months, p = 0.004). The difference in OS was evident in the Intermediate-2/High risk group (p = 0.002) but not in the Intermediate-1 risk group (p = 0.145). Multivariate analysis confirmed that platelet response (no platelet transfusions for at least 3 days) during the second cycle of treatment was an independent predictor for response, OS and Leukemia free survival. Based on the results of this study, for patients with hematological improvement, recovery of platelet count by the second cycle of therapy can be used as an early predictive marker of improved survival and an increased response rate. PMID- 25938542 TI - CDC20 maintains tumor initiating cells. AB - Glioblastoma is the most prevalent and lethal primary intrinsic brain tumor. Glioblastoma displays hierarchical arrangement with a population of self-renewing and tumorigenic glioma tumor initiating cells (TICs), or cancer stem cells. While non-neoplastic neural stem cells are generally quiescent, glioblastoma TICs are often proliferative with mitotic control offering a potential point of fragility. Here, we interrogate the role of cell-division cycle protein 20 (CDC20), an essential activator of anaphase-promoting complex (APC) E3 ubiquitination ligase, in the maintenance of TICs. By chromatin analysis and immunoblotting, CDC20 was preferentially expressed in TICs relative to matched non-TICs. Targeting CDC20 expression by RNA interference attenuated TIC proliferation, self-renewal and in vivo tumor growth. CDC20 disruption mediated its effects through induction of apoptosis and inhibition of cell cycle progression. CDC20 maintains TICs through degradation of p21CIP1/WAF1, a critical negative regulator of TICs. Inhibiting CDC20 stabilized p21CIP1/WAF1, resulting in repression of several genes critical to tumor growth and survival, including CDC25C, c-Myc and Survivin. Transcriptional control of CDC20 is mediated by FOXM1, a central transcription factor in TICs. These results suggest CDC20 is a critical regulator of TIC proliferation and survival, linking two key TIC nodes-FOXM1 and p21CIP1/WAF1 elucidating a potential point for therapeutic intervention. PMID- 25938545 TI - ING5 inhibits cancer aggressiveness via preventing EMT and is a potential prognostic biomarker for lung cancer. AB - The proteins of the Inhibitor of Growth (ING) candidate tumor suppressor family are involved in multiple cellular functions such as cell cycle regulation, apoptosis, and chromatin remodeling. ING5 is the new member of the family whose actual role in tumor suppression is not known. Here we show that ING5 overexpression in lung cancer A549 cells inhibited cell proliferation and invasiveness, while ING5 knockdown in lung cancer H1299 cells promoted cell aggressiveness. ING5 overexpression also abrogated tumor growth and invasive abilities of lung cancer cells in mouse xenograft models. Further study showed that ING5 overexpression inhibited EMT indicated by increase of E-cadherin and decrease of N-cadherin, Snail and slug at mRNA and protein levels, which was accompanied with morphological changes. cDNA microarray and subsequent qRT-PCR validation revealed that ING5 significantly downregulated expression of EMT (epithelial to mesenchymal transition)-inducing genes including CEACAM6, BMP2 and CDH11. Clinical study by tissue microarray showed that nuclear ING5 negatively correlated with clinical stages and lymph node metastasis of lung cancer. Furthermore, high level of nuclear ING5 was associated with a better prognosis. Taken together, these findings uncover an important role for ING5 as a potent tumor suppressor in lung cancer growth and metastasis. PMID- 25938543 TI - By reducing hexokinase 2, resveratrol induces apoptosis in HCC cells addicted to aerobic glycolysis and inhibits tumor growth in mice. AB - Cancer cells exhibit an altered metabolic phenotype known as the aerobic glycolysis. The expression of HK2 changes the metabolic phenotype of cells to support cancerous growth. In the present study, we investigated the inhibitory effect of resveratrol on HK2 expression and hepatocellular carcinoma (HCC) cell glycolysis. Aerobic glycolysis was observed in four HCC cell lines compared to the normal hepatic cells. Resveratrol sensitized aerobic glycolytic HCC cells to apoptosis, and this effect was attenuated by glycolytic inhibitors. The induction of mitochondrial apoptosis was associated with the decrease of HK2 expression by resveratrol in HCC cells. In addition, resveratrol enhanced sorafenib induced cell growth inhibition in aerobic glycolytic HCC cells. Combination treatment with both reagents inhibited the growth and promoted apoptosis of HCC-bearing mice. The reduction of HK2 by resveratrol provides a new dimension to clinical HCC therapies aimed at preventing disease progression. PMID- 25938548 TI - Childhood hospitalisation with infection and cardiovascular disease in early-mid adulthood: a longitudinal population-based study. AB - BACKGROUND: Pathogen-specific and overall infection burden may contribute to atherosclerosis and cardiovascular disease (CVD), but the effect of infection severity and timing is unknown. We investigated whether childhood infection related hospitalisation (IRH, a marker of severity) was associated with subsequent adult CVD hospitalisation. METHODS: Using longitudinal population based statutorily-collected administrative health data from Western Australia (1970-2009), we identified adults hospitalised with CVD (ischaemic heart disease, ischaemic stroke, and peripheral vascular disease) and matched them (10:1) to population controls. We used Cox regression to assess relationships between number and type of childhood IRH and adulthood CVD hospitalisation, adjusting for sex, age, Indigenous status, socioeconomic status, and birth weight. RESULTS: 631 subjects with CVD-related hospitalisation in adulthood (>= 18 years) were matched with 6310 controls. One or more childhood (< 18 years) IRH was predictive of adult CVD-related hospitalisation (adjusted hazard ratio, 1.3; 95% CI 1.1-1.6; P < 0.001). The association showed a dose-response; >= 3 childhood IRH was associated with a 2.2 times increased risk of CVD-related hospitalisation in adulthood (adjusted hazard ratio, 2.2; 95% CI 1.7-2.9; P < 0.001). The association was observed across all clinical diagnostic groups of infection (upper respiratory tract infection, lower respiratory tract infection, infectious gastroenteritis, urinary tract infection, skin and soft tissue infection, and other viral infection), and individually with CVD diagnostic categories (ischaemic heart disease, ischaemic stroke and peripheral vascular disease). CONCLUSIONS: Severe childhood infection is associated with CVD hospitalisations in adulthood in a dose-dependent manner, independent of population-level risk factors. PMID- 25938549 TI - Harlequin testicle and other uncommon pathologies masquerading at routine scrotal ultrasound. AB - Many scrotal conditions manifest similarly as pain, swelling, a palpable abnormality, or a combination of these symptoms. Most common scrotal pathologies have characteristic accompanying sonographic findings. Less common pathologies can have similar clinical presentations, and imaging with scrotal ultrasound is required to aid in proper diagnosis. This article focuses on several of these less commonly encountered scrotal pathologies--including testicular segmental infarction, scrotal filariasis, scrotal mesothelioma, seminiferous tubule fibrosis, and scrotal leiomyosarcoma--and compares and contrasts them to more routine diagnoses. Familiarity with both typical and atypical scrotal conditions is necessary to make accurate diagnoses at ultrasound to guide appropriate treatment and avoid unnecessary surgery.